sentence text	spreadsheet text	event interval start	event interval end	trigger	rule	polarity	pred_polarity	controller sp	controller reach raw	controller reach	controlled sp	controlled reach raw	controlled reach	controller start	controller end	controlled start	controlled end
ABCA1 mediates cellular free cholesterol ( FC ) and phospholipid ( PL ) efflux to apolipoprotein A-I ( apoA-I ) , resulting in the formation of nascent HDL that undergo subsequent maturation to become plasma HDL 2 .	ABCA1 mediates cellular free cholesterol (FC) and phospholipid (PL) efflux to apolipoprotein A-I (apoA-I), resulting in the formation of nascent HDL that undergo subsequent maturation to become plasma HDL 2.	0	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	0	1	15	17
ABC1 is expressed on the plasma membrane and the Golgi complex , mediates apo-AI associated export of cholesterol and phospholipids from the cell , and is regulated by cholesterol flux .	ABC1 is expressed on the plasma membrane and the Golgi complex, mediates apo-AI associated export of cholesterol and phospholipids from the cell, and is regulated by cholesterol flux.	0	26	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABC1	ABC1 is expressed	abc1	apo-AI	apo-AI	apo-ai	0	1	13	14
When LXRs are stimulated by natural or synthetic ligands , or when cells are loaded with cholesterol , transcriptional expressions of ABCA1 , and ABCG1 are induced and lead to an increase in cholesterol release to ApoA-I , ApoE , or HDL .	When LXRs are stimulated by natural or synthetic ligands, or when cells are loaded with cholesterol, transcriptional expressions of ABCA1, and ABCG1 are induced and lead to an increase in cholesterol release to ApoA-I, ApoE, or HDL.	19	41	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	ABCA1	expressions of ABCA1	abca1	ApoA-I	ApoA-I	apoa-i	21	22	36	37
These gene knockdown studies support the central role of cellular PIP2 in ABCA1 mediated apoA1 binding and cholesterol efflux .	These gene knockdown studies support the central role of cellular PIP2 in ABCA1 mediated apoA1 binding and cholesterol efflux.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA1	apoA1	apoA1	12	13	14	15
Peroxisome proliferator activated receptor alpha ( PPARalpha ) can increase expression of liver X receptor alpha ( LXRalpha ) in macrophages and thereby promote the expression of ABCA1 , which , in turn , mediates cholesterol efflux to apoA1 .	Peroxisome proliferator activated receptor alpha (PPARalpha) can increase expression of liver X receptor alpha (LXRalpha) in macrophages and thereby promote the expression of ABCA1, which, in turn, mediates cholesterol efflux to apoA1.	0	39	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	Peroxisome proliferator activated receptor alpha (PPARalpha) can increase expression of liver X receptor alpha (LXRalpha) in macrophages and thereby promote the expression of ABCA1	abca1	apoA1	apoA1	apoa1	27	28	38	39
However , the precise molecular mechanisms by which ABCA1 mediates cholesterol efflux to apoA-I remains elusive , which presents a major barrier for the development of pharmacological interventions .	However, the precise molecular mechanisms by which ABCA1 mediates cholesterol efflux to apoA-I remains elusive, which presents a major barrier for the development of pharmacological interventions.	8	14	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	8	9	13	14
Expression of exogenous ABCA1 restores apoA1 dependent cholesterol efflux in Sertoli TM4 cells .	Expression of exogenous ABCA1 restores apoA1 dependent cholesterol efflux in Sertoli TM4 cells.	0	6	restores	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ABCA1	Expression of exogenous ABCA1	abca1	apoA1	apoA1	apoa1	3	4	5	6
These results suggest the following new scenario of nascent HDL formation : ABCA1 , which colocalizes with apoA-I in acidic intracellular compartments , including the Golgi and endosome , increases acidity at the membrane surface on the luminal side by PS translocase activity and causes apoA-I to form nascent HDL .	These results suggest the following new scenario of nascent HDL formation : ABCA1, which colocalizes with apoA-I in acidic intracellular compartments, including the Golgi and endosome, increases acidity at the membrane surface on the luminal side by PS translocase activity and causes apoA-I to form nascent HDL.	12	46	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	12	13	45	46
ABCA1 mediates ApoA-I and ApoA-I Mimetic Peptide Mobilization of Extracellular Cholesterol Microdomains Deposited by Macrophages .	ABCA1 mediates ApoA-I and ApoA-I Mimetic Peptide Mobilization of Extracellular Cholesterol Microdomains Deposited by Macrophages.	0	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	ApoA-I	ApoA-I	ApoA-I	0	1	2	3
Overexpression of STARD3 increased ABCA1 protein levels , and cholesterol efflux in human THP-1 macrophages and increased lipidation of exogenous apoA-I in McRH-7777 hepatoma cells .	Overexpression of STARD3 increased ABCA1 protein levels, and cholesterol efflux in human THP-1 macrophages and increased lipidation of exogenous apoA-I in McRH-7777 hepatoma cells.	0	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	Overexpression of STARD3 increased ABCA1 protein levels	abca1	apoA-I	apoA-I	apoa-i	4	5	20	21
Overexpression of ABCA1 dramatically increased binding of both PLTP and apoA-I to common sites on the cell surface .	Overexpression of ABCA1 dramatically increased binding of both PLTP and apoA-I to common sites on the cell surface.	0	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	Overexpression of ABCA1	abca1	apoA-I	apoA-I	apoa-i	2	3	10	11
In addition , the knockdown of ABCA1 by RNA interference eliminated the inhibition effect of ApoA-I on TGF-beta1-induced EndMT .	In addition, the knockdown of ABCA1 by RNA interference eliminated the inhibition effect of ApoA-I on TGF-beta1-induced EndMT.	4	16	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	ApoA-I	ApoA-I	ApoA-I	6	7	15	16
Experimental studies show that inactivation of Abca1 increases plasma removal and renal degradation of lipid-free ApoA-I .	Experimental studies show that inactivation of Abca1 increases plasma removal and renal degradation of lipid-free ApoA-I.	4	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abca1	Abca1	Abca1	ApoA-I	ApoA-I	ApoA-I	6	7	15	16
ABCA1-GFP expression in wild type fibroblasts also reduced late endosome associated NPC1 , induced a marked uptake of fluorescent apoA-I into ABCA1-GFP-containing endosomes ( that shuttled between late endosomes and the cell surface ) , and enhanced apoA-I-mediated cholesterol efflux .	ABCA1-GFP expression in wild type fibroblasts also reduced late endosome associated NPC1, induced a marked uptake of fluorescent apoA-I into ABCA1-GFP-containing endosomes (that shuttled between late endosomes and the cell surface), and enhanced apoA-I-mediated cholesterol efflux.	0	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1-GFP	ABCA1-GFP expression	abca1-gfp	apoA-I	apoA-I	apoa-i	0	1	19	20
XREF_BIBR , XREF_BIBR The efflux of cholesterol and phospholipids onto apoA-I mediated by ABCA1 converts apoA-I into nascent HDL , which can then act as an efficient acceptor for ABCG1 mediated cholesterol efflux .	XREF_BIBR, XREF_BIBR The efflux of cholesterol and phospholipids onto apoA-I mediated by ABCA1 converts apoA-I into nascent HDL, which can then act as an efficient acceptor for ABCG1 mediated cholesterol efflux.	8	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	13	14	10	11
Silencing STAT3 or ABCA1 in macrophages decreased the ability of apoA-I to inhibit cytokine production .	Silencing STAT3 or ABCA1 in macrophages decreased the ability of apoA-I to inhibit cytokine production.	1	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	3	4	10	11
Therefore , ABCA1 deficiency leads to intracellular accumulation of CE , precludes the conversion of the lipid-poor Apo A-I particles into pre-beta HDL , and promotes a rapid catabolism of the poorly lipidated Apo A-I , mostly by the kidney .	Therefore, ABCA1 deficiency leads to intracellular accumulation of CE, precludes the conversion of the lipid-poor Apo A-I particles into pre-beta HDL, and promotes a rapid catabolism of the poorly lipidated Apo A-I, mostly by the kidney.	2	35	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	Apo A-I	Apo A-I	Apo A-I	2	3	33	35
During this process , the ATP-binding-membrane-cassette transporter A1 ( ABCA1 ) mediates the efflux of excess cholesterol and phospholipids from peripheral cells , such as macrophages , to lipid-poor apoA-I , forming nascent HDL particles .	During this process, the ATP-binding-membrane-cassette transporter A1 (ABCA1) mediates the efflux of excess cholesterol and phospholipids from peripheral cells, such as macrophages, to lipid-poor apoA-I, forming nascent HDL particles.	7	30	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	9	10	29	30
It has been reported that ABCA1 , which is a member of the A subfamily and mediates the efflux of cholesterol and phosphatidylcholine to lipid-free apoA-I or apoE [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , reduced Abeta secretion from cells [ XREF_BIBR , XREF_BIBR ] .	It has been reported that ABCA1, which is a member of the A subfamily and mediates the efflux of cholesterol and phosphatidylcholine to lipid-free apoA-I or apoE [XREF_BIBR, XREF_BIBR, XREF_BIBR], reduced Abeta secretion from cells [XREF_BIBR, XREF_BIBR].	5	36	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	5	6	25	26
These apoA-I mimetic peptides increased cellular cholesterol efflux by both ABCA1 and ABCG1 pathways XREF_BIBR .	These apoA-I mimetic peptides increased cellular cholesterol efflux by both ABCA1 and ABCG1 pathways XREF_BIBR.	0	14	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	10	11	1	2
In contrast , the interventions studied here increase the rate of cholesterol loading onto lipid-poor ApoA-I mediated by ABCA1 .	In contrast, the interventions studied here increase the rate of cholesterol loading onto lipid-poor ApoA-I mediated by ABCA1.	12	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	ApoA-I	ApoA-I	ApoA-I	18	19	15	16
The molecular mechanism by which ABCA1 mediates cellular binding of apolipoprotein A-I ( apoA1 ) and nascent HDL assembly is not well understood .	The molecular mechanism by which ABCA1 mediates cellular binding of apolipoprotein A-I (apoA1) and nascent HDL assembly is not well understood.	5	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	5	6	10	12
The experiment that included an additional washing step to remove cyclodextrin revealed that conditioned medium with PL/apoAI particles made by ABCA1 could not stimulate passive FC efflux , suggesting that ABCA1 directly mediates both PL and FC efflux to apoAI .	The experiment that included an additional washing step to remove cyclodextrin revealed that conditioned medium with PL/apoAI particles made by ABCA1 could not stimulate passive FC efflux, suggesting that ABCA1 directly mediates both PL and FC efflux to apoAI.	30	40	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoAI	apoAI	apoAI	30	31	39	40
Probucol , an ABCA1 inactivator , inhibited these reactions , as well as the reversible binding of apoA-I to HepG2 .	Probucol, an ABCA1 inactivator, inhibited these reactions, as well as the reversible binding of apoA-I to HepG2.	3	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	3	4	17	18
Here , we demonstrate that ABCA1 also directly mediates the production of apoA-I free microparticles .	Here, we demonstrate that ABCA1 also directly mediates the production of apoA-I free microparticles.	5	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	5	6	12	13
Lack of ABCA1 in humans and mice causes abnormal lipidation and increased catabolism of HDL , resulting in very low plasma apoA-I , apoA-II , and HDL .	Lack of ABCA1 in humans and mice causes abnormal lipidation and increased catabolism of HDL, resulting in very low plasma apoA-I, apoA-II, and HDL.	0	26	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	2	3	21	22
ABCA1 and ABCG1 promote the efflux of cholesterol to respectively APO-AI and HDL .	ABCA1 and ABCG1 promote the efflux of cholesterol to respectively APO-AI and HDL.	0	12	promote	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	APO-AI	APO-AI	APO-AI	0	1	10	11
ABCA1 mediates the cellular efflux of phospholipids and cholesterol to lipid-free apoA-1 , contributing to the generation of pre-beta-HDL and discoidal HDL particles , the first steps of HDL metabolism .	ABCA1 mediates the cellular efflux of phospholipids and cholesterol to lipid-free apoA-1, contributing to the generation of pre-beta-HDL and discoidal HDL particles, the first steps of HDL metabolism.	0	12	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-1	apoA-1	apoA-1	0	1	11	12
Because paraoxon ' s ability to attenuate macrophage cholesterol efflux was dependent on the type of cholesterol acceptor used , we speculated that paraoxon might reduce the expression of the cholesterol transporter ABCA1 that mediates cholesterol efflux to ApoA1 because efflux to this acceptor was the most reduced following paraoxon treatment of THP-1 foam cells .	Because paraoxon 's ability to attenuate macrophage cholesterol efflux was dependent on the type of cholesterol acceptor used, we speculated that paraoxon might reduce the expression of the cholesterol transporter ABCA1 that mediates cholesterol efflux to ApoA1 because efflux to this acceptor was the most reduced following paraoxon treatment of THP-1 foam cells.	23	39	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	paraoxon might reduce the expression of the cholesterol transporter ABCA1	abca1	ApoA1	ApoA1	apoa1	32	33	38	39
Even when ABCA1 surface expression is taken into account ( XREF_FIG ) , our data indicates that Cav1 expression , but not ABCA1 expression , increases apoA-I surface binding sites in MEFs : Cav1 -/- MEFs treated with the LXR agonist had similar ABCA1 expression in the plasma membrane than untreated WT MEFs , yet their apoA-I binding capacity is vastly different .	Even when ABCA1 surface expression is taken into account (XREF_FIG), our data indicates that Cav1 expression, but not ABCA1 expression, increases apoA-I surface binding sites in MEFs : Cav1 -/- MEFs treated with the LXR agonist had similar ABCA1 expression in the plasma membrane than untreated WT MEFs, yet their apoA-I binding capacity is vastly different.	22	29	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1 expression	abca1	apoA-I	apoA-I	apoa-i	22	23	26	27
Recent advances in our understanding of ABCA1 have demonstrated that ABCA1 also mediates unfolding the N terminus of apoAI on the cell surface , followed by lipidation of apoAI and release of nascent HDL .	Recent advances in our understanding of ABCA1 have demonstrated that ABCA1 also mediates unfolding the N terminus of apoAI on the cell surface, followed by lipidation of apoAI and release of nascent HDL.	10	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoAI	apoAI	apoAI	10	11	18	19
fmHDL prepared with [ 3 H ] apo A-I was used to determine whether ABCA1 mediated efflux to fmHDL ( apo A-I ) was due to apo A-I dissociation from fmHDL , followed by ABCA1 dependent lipidation of the lipid-poor apolipoprotein .	fmHDL prepared with [3 H] apo A-I was used to determine whether ABCA1 mediated efflux to fmHDL (apo A-I) was due to apo A-I dissociation from fmHDL, followed by ABCA1 dependent lipidation of the lipid-poor apolipoprotein.	14	19	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	fmHDL	fmHDL	fmHDL	14	15	18	19
It is well known that ABCA1 and ABCG1 mediate cholesterol efflux to apoA1 and HDL , respectively .	It is well known that ABCA1 and ABCG1 mediate cholesterol efflux to apoA1 and HDL, respectively.	5	14	mediate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA1	apoA1	apoA1	5	6	12	13
The ABCA1 protein mediates the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I ( ApoAI ) , the major apolipoprotein component of HDL .	The ABCA1 protein mediates the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I (ApoAI), the major apolipoprotein component of HDL.	1	16	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	1	2	14	16
Small , dense HDL subfractions are the most efficient mediators of cholesterol efflux , and ABCA1 mediates cholesterol efflux to small dense HDL and to lipid-free apolipoprotein A-I .	Small, dense HDL subfractions are the most efficient mediators of cholesterol efflux, and ABCA1 mediates cholesterol efflux to small dense HDL and to lipid-free apolipoprotein A-I.	15	28	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	15	16	26	28
In conclusion , our findings showed that the substrate for ABCA1 mediated CEC ( i.e. ApoA-I and prebeta1-HDL ) was significantly suppressed in NAFLD patients indicating that ApoA-I and prebeta1-HDL could be the cause of the impairment observed in HDL CECs .	In conclusion, our findings showed that the substrate for ABCA1 mediated CEC (i.e. ApoA-I and prebeta1-HDL) was significantly suppressed in NAFLD patients indicating that ApoA-I and prebeta1-HDL could be the cause of the impairment observed in HDL CECs.	8	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	ApoA-I	ApoA-I	ApoA-I	10	11	15	16
The efflux of cholesterol and phospholipids to apoA-I mediated by ABCA1 converts apoA-I into nascent high density lipoprotein , which can then act as an efficient acceptor for ABCG1 mediated cholesterol efflux , followed by formation of mature HDL particles [ XREF_BIBR - XREF_BIBR ] .	The efflux of cholesterol and phospholipids to apoA-I mediated by ABCA1 converts apoA-I into nascent high density lipoprotein, which can then act as an efficient acceptor for ABCG1 mediated cholesterol efflux, followed by formation of mature HDL particles [XREF_BIBR - XREF_BIBR].	1	11	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	10	11	7	8
ABCA-1 primarily mediates the cholesterol efflux to lipid-poor apoA-I as studies in macrophages from ABCA1-knockout or -overexpressing mice have indicated .	ABCA-1 primarily mediates the cholesterol efflux to lipid-poor apoA-I as studies in macrophages from ABCA1-knockout or -overexpressing mice have indicated.	0	9	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA-1	ABCA-1	ABCA-1	apoA-I	apoA-I	apoA-I	0	1	8	9
It is well established that the activity of ABCA1 in the plasma membrane enhances binding of apoA-I to the cell surface , but there has been controversy about the role of this binding in the acquisition of membrane PL by apoA-I .	It is well established that the activity of ABCA1 in the plasma membrane enhances binding of apoA-I to the cell surface, but there has been controversy about the role of this binding in the acquisition of membrane PL by apoA-I.	6	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	8	9	16	17
The presence of active ABCA1 in the plasma membrane promotes binding of apoA-I to the cell surface .	The presence of active ABCA1 in the plasma membrane promotes binding of apoA-I to the cell surface.	1	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	4	5	12	13
ABCA1 promotes cholesterol efflux to lipid-poor apoA-I , the major HDL protein , while ABCG1 induces cholesterol efflux to intact HDL particles XREF_BIBR .	ABCA1 promotes cholesterol efflux to lipid-poor apoA-I, the major HDL protein, while ABCG1 induces cholesterol efflux to intact HDL particles XREF_BIBR.	0	11	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	0	1	6	7
ABCA1 mediates the transport of cellular cholesterol and phospholipids to APOA-1 to generate nascent HDL particles [ XREF_BIBR ] .	ABCA1 mediates the transport of cellular cholesterol and phospholipids to APOA-1 to generate nascent HDL particles [XREF_BIBR].	0	11	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	APOA-1	APOA-1	APOA-1	0	1	10	11
As with ABCA1 mediated apo A-I lipidation , FC increases the size and number of rHDL species formed by the association of apos A-I and A-II with DMPC .	As with ABCA1 mediated apo A-I lipidation, FC increases the size and number of rHDL species formed by the association of apos A-I and A-II with DMPC.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apo A-I	apo A-I	apo A-I	2	3	4	6
Current data suggest that in endothelial cells ABCA1 and ABCG1 mediate the activation of intracellular signaling pathways primarily through the efflux of cholesterol and oxysterols to apoA-I and HDL .	Current data suggest that in endothelial cells ABCA1 and ABCG1 mediate the activation of intracellular signaling pathways primarily through the efflux of cholesterol and oxysterols to apoA-I and HDL.	7	28	mediate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	7	8	26	27
Interestingly , IL-6 markedly induced ABCA1 expression and enhanced ABCA1 mediated cholesterol efflux from human macrophages to apoAI .	Interestingly, IL-6 markedly induced ABCA1 expression and enhanced ABCA1 mediated cholesterol efflux from human macrophages to apoAI.	2	18	enhanced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	IL-6 markedly induced ABCA1 expression	abca1	apoAI	apoAI	apoai	5	6	17	18
ABC1 expression markedly increased cellular cholesterol and phospholipid efflux to apoA-I but had only minor effects on lipid efflux to HDL .	ABC1 expression markedly increased cellular cholesterol and phospholipid efflux to apoA-I but had only minor effects on lipid efflux to HDL.	0	11	increased	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABC1	ABC1 expression	abc1	apoA-I	apoA-I	apoa-i	0	1	10	11
Importantly , this led to a defect in ABCA1 mediated efflux to APOAI .	Importantly, this led to a defect in ABCA1 mediated efflux to APOAI.	8	13	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	APOAI	APOAI	APOAI	8	9	12	13
To further demonstrate the central role of PIP2 in ABCA1 mediated apoA1 binding and cholesterol efflux , we performed siRNA knockdown of PIP5K , the enzyme that converts PI5P to PIP2 .	To further demonstrate the central role of PIP2 in ABCA1 mediated apoA1 binding and cholesterol efflux, we performed siRNA knockdown of PIP5K, the enzyme that converts PI5P to PIP2.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA1	apoA1	apoA1	9	10	11	12
ABCA1 promotes cholesterol efflux to lipid-poor APOA1 , which is the building block of HDL , whereas ABCG1 promotes efflux to mature HDL particles .	ABCA1 promotes cholesterol efflux to lipid-poor APOA1, which is the building block of HDL, whereas ABCG1 promotes efflux to mature HDL particles.	0	12	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	APOA1	APOA1	APOA1	0	1	6	7
These results suggest that pitavastatin efficiently increases apoA-I in the culture medium of HepG2 cells by promoting apoA-I production through inhibition of HMG-CoA reductase and suppression of Rho activity and by protecting apoA-I from catabolism through ABCA1 induction and lipidation of apoA-I .	These results suggest that pitavastatin efficiently increases apoA-I in the culture medium of HepG2 cells by promoting apoA-I production through inhibition of HMG-CoA reductase and suppression of Rho activity and by protecting apoA-I from catabolism through ABCA1 induction and lipidation of apoA-I.	36	42	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	36	37	41	42
The up-regulation of ABCA1 increases cholesterol efflux and consequently the lipidation of brain apoE and apoA-I , thus decreasing their catabolism .	The up-regulation of ABCA1 increases cholesterol efflux and consequently the lipidation of brain apoE and apoA-I, thus decreasing their catabolism.	1	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	3	4	15	16
ABCA1 deficiency can lead to impaired cholesterol efflux to HDL or apolipoprotein A-I ( APOA1 ) , decreased apoE secretion , and increased secretion of inflammatory cytokines and chemokines [ XREF_BIBR ] .	ABCA1 deficiency can lead to impaired cholesterol efflux to HDL or apolipoprotein A-I (APOA1), decreased apoE secretion, and increased secretion of inflammatory cytokines and chemokines [XREF_BIBR].	0	13	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	0	1	11	13
The ABCA1 protein mediates the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I .	The ABCA1 protein mediates the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I.	1	16	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	1	2	14	16
Whereas ABCA1 promotes cholesterol efflux to lipid-poor apoA-1 , ABCG1 induces cholesterol efflux to HDL particles .	Whereas ABCA1 promotes cholesterol efflux to lipid-poor apoA-1, ABCG1 induces cholesterol efflux to HDL particles.	1	8	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-1	apoA-1	apoA-1	1	2	7	8
10 As with ABCA1 mediated apo A-I lipidation , 3 FC increases the size and number of rHDL species formed from apo A-I and DMPC .	10 As with ABCA1 mediated apo A-I lipidation, 3 FC increases the size and number of rHDL species formed from apo A-I and DMPC.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apo A-I	apo A-I	apo A-I	3	4	5	7
The efflux of cellular phospholipid and free cholesterol to apolipoprotein A-I promoted by ABCA1 is essential for HDL biogenesis .	The efflux of cellular phospholipid and free cholesterol to apolipoprotein A-I promoted by ABCA1 is essential for HDL biogenesis.	9	14	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	13	14	9	11
Whereas ABCA1 mediates a unidirectional transport , mostly to apoA-I , HDL mediated efflux is a bidirectional , diffusional process that involves multiple transporters and represents a complex pathway for which the contribution of autophagy remains to be studied in greater detail .	Whereas ABCA1 mediates a unidirectional transport, mostly to apoA-I, HDL mediated efflux is a bidirectional, diffusional process that involves multiple transporters and represents a complex pathway for which the contribution of autophagy remains to be studied in greater detail.	1	10	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	1	2	9	10
EL is also upregulated during inflammation and works in conjunction with SAA to reduce nascent HDL formation by impeding ABCA1 mediated lipidation of apoA-I [ XREF_BIBR ] .	EL is also upregulated during inflammation and works in conjunction with SAA to reduce nascent HDL formation by impeding ABCA1 mediated lipidation of apoA-I [XREF_BIBR].	19	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	19	20	23	24
One is that apoA-I forms complexes with phospholipid and cholesterol at the cell surface in a process promoted by ABCA1 activity .	One is that apoA-I forms complexes with phospholipid and cholesterol at the cell surface in a process promoted by ABCA1 activity.	3	20	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	19	20	3	4
Silencing ABCA-1 abrogated the effect of apoA-I , but not HDL , while silencing ABCG-1 or SRB-1 abrogated the effect of HDL but not apoA-I .	Silencing ABCA-1 abrogated the effect of apoA-I, but not HDL, while silencing ABCG-1 or SRB-1 abrogated the effect of HDL but not apoA-I.	0	7	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA-1	ABCA-1	ABCA-1	apoA-I	apoA-I	apoA-I	1	2	6	7
Thus , cell surface PIP2 is required for ABCA1 mediated apoA1 binding and cholesterol efflux .	Thus, cell surface PIP2 is required for ABCA1 mediated apoA1 binding and cholesterol efflux.	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA1	apoA1	apoA1	8	9	10	11
ABCA1 , the mutant molecule in Tangier Disease , mediates efflux of cellular cholesterol to apoA-I and is induced by liver X receptor ( LXR )/retinoid X receptor ( RXR ) transcription factors .	ABCA1, the mutant molecule in Tangier Disease, mediates efflux of cellular cholesterol to apoA-I and is induced by liver X receptor (LXR)/retinoid X receptor (RXR) transcription factors.	0	18	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	0	1	15	16
Several models of ABCA1 mediated cholesterol efflux have been proposed , including a two-step model in which ABCA1 first mediates PC efflux to apo-A1 , and this apo-A1 PC complex accepts cholesterol in an ABCA1 independent manner [ XREF_BIBR ] .	Several models of ABCA1 mediated cholesterol efflux have been proposed, including a two-step model in which ABCA1 first mediates PC efflux to apo-A1, and this apo-A1 PC complex accepts cholesterol in an ABCA1 independent manner [XREF_BIBR].	17	24	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apo-A1	apo-A1	apo-A1	17	18	23	24
ABCA1 and ABCG1 have important functions in the RCT pathway : ( 1 ) In the liver , ABCA1 mediates the initial lipidation of apoA1 to form nascent HDL particles and ( 2 ) In peripheral tissues , particularly macrophages in atherosclerotic lesions , ABCA1 mediates the efflux of cellular cholesterol to this nascent HDL , while ABCG1 contributes to the further lipidation of HDL .	ABCA1 and ABCG1 have important functions in the RCT pathway : (1) In the liver, ABCA1 mediates the initial lipidation of apoA1 to form nascent HDL particles and (2) In peripheral tissues, particularly macrophages in atherosclerotic lesions, ABCA1 mediates the efflux of cellular cholesterol to this nascent HDL, while ABCG1 contributes to the further lipidation of HDL.	18	25	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA1	apoA1	apoA1	18	19	24	25
However , all ABCA1 isoforms led to apoAI unfolding at the cell surface , which was higher for the isoforms that increased apoAI binding .	However, all ABCA1 isoforms led to apoAI unfolding at the cell surface, which was higher for the isoforms that increased apoAI binding.	3	8	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoAI	apoAI	apoAI	3	4	7	8
Next , ABCA1 mediates the partial unfolding of the N-terminus of apoAI .	Next, ABCA1 mediates the partial unfolding of the N-terminus of apoAI.	2	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoAI	apoAI	apoAI	2	3	11	12
In a recent study , we identified a new step in the HDL biogenesis , the ABCA1 mediated unfolding the N-terminal domain of apoAI on the cell surface 42 .	In a recent study, we identified a new step in the HDL biogenesis, the ABCA1 mediated unfolding the N-terminal domain of apoAI on the cell surface 42.	15	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoAI	apoAI	apoAI	16	17	23	24
Blocking ABCA1 with an anti-ABCA1 antibody abolished the effect of apoA-I .	Blocking ABCA1 with an anti-ABCA1 antibody abolished the effect of apoA-I.	0	11	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	1	2	10	11
ABCA1 promotes the efflux of phospholipids and cholesterol to lipid-poor apo-AI via a process that involves the direct binding of apo-AI to the ABCA1 transporter , whereas ABCG1 and SR-BI are key mediators of macrophage cholesterol efflux to mature HDL [ XREF_BIBR ] .	ABCA1 promotes the efflux of phospholipids and cholesterol to lipid-poor apo-AI via a process that involves the direct binding of apo-AI to the ABCA1 transporter, whereas ABCG1 and SR-BI are key mediators of macrophage cholesterol efflux to mature HDL [XREF_BIBR].	0	13	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apo-AI	apo-AI	apo-AI	0	1	10	11
In the small intestine , however , apoM and apoAI were upregulated by 30-60 % and ABCA1 by 250-430 % .	In the small intestine, however, apoM and apoAI were upregulated by 30-60% and ABCA1 by 250-430%.	7	17	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoAI	apoAI	apoAI	16	17	9	10
Rifampicin , 27-HOC , and a potent LXRalpha agonist , T0901317 , induced ABCA1 and ABCG1 protein expression and stimulated cholesterol efflux from intestine cells to apolipoprotein A-I and HDL .	Rifampicin, 27-HOC, and a potent LXRalpha agonist, T0901317, induced ABCA1 and ABCG1 protein expression and stimulated cholesterol efflux from intestine cells to apolipoprotein A-I and HDL.	0	28	stimulated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	Rifampicin, 27-HOC, and a potent LXRalpha agonist, T0901317, induced ABCA1 and ABCG1 protein expression	abca1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein a-i	13	14	26	28
Data from this report demonstrated that knockdown of ABCA1 diminished apoAI mediated transcellular cholesterol transport in MAECs , while knockdown of ABCG1 or SR-B1 , or inhibition of SR-B1 attenuated HDL mediated transendothelial cholesterol transport .	Data from this report demonstrated that knockdown of ABCA1 diminished apoAI mediated transcellular cholesterol transport in MAECs, while knockdown of ABCG1 or SR-B1, or inhibition of SR-B1 attenuated HDL mediated transendothelial cholesterol transport.	6	14	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoAI	apoAI	apoAI	8	9	10	11
ABCA1 plays a key role in reverse cholesterol transport and stimulates cholesterol and phospholipid efflux to apo A-I , which is one of the first stages in reverse cholesterol transport XREF_BIBR .	ABCA1 plays a key role in reverse cholesterol transport and stimulates cholesterol and phospholipid efflux to apo A-I, which is one of the first stages in reverse cholesterol transport XREF_BIBR.	0	18	stimulates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apo A-I	apo A-I	apo A-I	0	1	16	18
ABCA1 is thought to initiate the cholesterol loading of lipid-poor ApoA-I , leading to subsequent maturation of HDL particles .	ABCA1 is thought to initiate the cholesterol loading of lipid-poor ApoA-I, leading to subsequent maturation of HDL particles.	0	11	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	ApoA-I	ApoA-I	ApoA-I	0	1	10	11
As described above , ABCA1 promotes cellular cholesterol efflux to apoA-1 and is also primarily responsible for initiating HDL formation in the liver .	As described above, ABCA1 promotes cellular cholesterol efflux to apoA-1 and is also primarily responsible for initiating HDL formation in the liver.	4	15	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-1	apoA-1	apoA-1	4	5	10	11
It is proposed that the initial binding of apoA-I to ABCA1 , which couples to a G protein , leads to activation of adenylyl cyclase , cAMP production , and subsequent PKA mediated ABCA1 phosphorylation , allowing lipidation of apoA-I through ABCA1 [ XREF_BIBR ] .	It is proposed that the initial binding of apoA-I to ABCA1, which couples to a G protein, leads to activation of adenylyl cyclase, cAMP production, and subsequent PKA mediated ABCA1 phosphorylation, allowing lipidation of apoA-I through ABCA1 [XREF_BIBR].	6	40	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	binding of apoA-I to ABCA1, which couples to a G protein, leads to activation of adenylyl cyclase, cAMP production, and subsequent PKA mediated ABCA1 phosphorylation	abca1	apoA-I	apoA-I	apoa-i	33	34	39	40
Recent studies using targeted approach to delete Abca1 only in liver showed that expression of ABCA1 in this organ causes profound hypo-alphalipoproteinemia and kidney hypercatabolism of apoA-I , and modulates the susceptibility to atherosclerosis .	Recent studies using targeted approach to delete Abca1 only in liver showed that expression of ABCA1 in this organ causes profound hypo-alphalipoproteinemia and kidney hypercatabolism of apoA-I, and modulates the susceptibility to atherosclerosis.	13	27	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	expression of ABCA1	abca1	apoA-I	apoA-I	apoa-i	15	16	26	27
The dynamics of ABCA1 mediated apoA-I lipidation were investigated in intact human fibroblasts induced with 22 ( R )-hydroxycholesterol and 9-cis-retinoic acid ( stimulated cells ) .	The dynamics of ABCA1 mediated apoA-I lipidation were investigated in intact human fibroblasts induced with 22 (R)-hydroxycholesterol and 9-cis-retinoic acid (stimulated cells).	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	3	4	5	6
Oxysterols ( ligand for LXR ) and 9-cis-retinoic acid ( ligand for RXR ) induce ABCA1 expression in cultured neurons and glial cells and increase the ef-flux of apoA-I- and apoE specific cholesterol from the cells .	Oxysterols (ligand for LXR) and 9-cis-retinoic acid (ligand for RXR) induce ABCA1 expression in cultured neurons and glial cells and increase the ef-flux of apoA-I- and apoE specific cholesterol from the cells.	7	32	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	9-cis-retinoic acid (ligand for RXR) induce ABCA1 expression	abca1	apoA-I-	apoA-I-	apoa-i-	15	16	28	29
ABCA1 promotes cellular cholesterol efflux to lipid-free apoA-I , generating nascent HDL particles .	ABCA1 promotes cellular cholesterol efflux to lipid-free apoA-I, generating nascent HDL particles.	0	8	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	0	1	7	8
ABCA1 mediates N-terminal unfolding of apoAI on the cell surface .	ABCA1 mediates N-terminal unfolding of apoAI on the cell surface.	0	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoAI	apoAI	apoAI	0	1	5	6
Cholesterol transport requires cholesterol transporters ATP binding cassette ( ABC ) family members ABCA1 and ABCG1 ; ABCA1 mediates cholesterol efflux to the lipid-poor cholesterol acceptor apoA-I , yielding a nascent HDL , while ABCG1 mediates cholesterol efflux to mature HDL XREF_BIBR - XREF_BIBR .	Cholesterol transport requires cholesterol transporters ATP binding cassette (ABC) family members ABCA1 and ABCG1; ABCA1 mediates cholesterol efflux to the lipid-poor cholesterol acceptor apoA-I, yielding a nascent HDL, while ABCG1 mediates cholesterol efflux to mature HDL XREF_BIBR - XREF_BIBR.	17	27	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	17	18	26	27
ABCA1 mediates efflux of cholesterol and phospholipids to lipid-free or lipid-poor apoA-1 , which leads to formation of nascent HDL ( XREF_FIG ) .	ABCA1 mediates efflux of cholesterol and phospholipids to lipid-free or lipid-poor apoA-1, which leads to formation of nascent HDL (XREF_FIG).	0	14	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-1	apoA-1	apoA-1	0	1	11	12
In THP1 macrophages , macrophage PPARgamma activation has been shown to promote ABCA1 mediated apoA-I specific efflux , as well as ABCG-1 mediated efflux to HDL3 as a cholesterol acceptor .	In THP1 macrophages, macrophage PPARgamma activation has been shown to promote ABCA1 mediated apoA-I specific efflux, as well as ABCG-1 mediated efflux to HDL3 as a cholesterol acceptor.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	12	13	14	15
It is generally accepted that ABCA1 promotes the efflux from cells , including macrophages , to lipid-poor APOA1 containing particles , which are HDL precursors present in plasma .	It is generally accepted that ABCA1 promotes the efflux from cells, including macrophages, to lipid-poor APOA1 containing particles, which are HDL precursors present in plasma.	5	18	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	APOA1	APOA1	APOA1	5	6	17	18
In addition to discoidal HDL , ABCA1 mediated efflux generates lipid-poor apoA-I with one molecule of apolipoprotein [ XREF_BIBR , XREF_BIBR ] .	In addition to discoidal HDL, ABCA1 mediated efflux generates lipid-poor apoA-I with one molecule of apolipoprotein [XREF_BIBR, XREF_BIBR].	6	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	6	7	11	12
Consistent with localization of ABCA1 at the basolateral ( vascular ) cell surface , expression of ABCA1-GFP stimulated apoA-I mediated efflux of WIF-B cell cholesterol into the culture medium .	Consistent with localization of ABCA1 at the basolateral (vascular) cell surface, expression of ABCA1-GFP stimulated apoA-I mediated efflux of WIF-B cell cholesterol into the culture medium.	14	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ABCA1-GFP	expression of ABCA1-GFP	abca1-gfp	apoA-I	apoA-I	apoa-i	16	17	18	19
Hence , the low capacity of ABCA1 mediated apoA-I binding site may explain why a 2-fold increase in ABCA1 surface expression did not significantly increase total apoA-I binding .	Hence, the low capacity of ABCA1 mediated apoA-I binding site may explain why a 2-fold increase in ABCA1 surface expression did not significantly increase total apoA-I binding.	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	6	7	8	9
Activators of peroxisome proliferator activated receptor gamma ( PPARgamma ) , as well as PPARalpha , increase expression of liver X receptor alpha ( LXRalpha ) in macrophages and promote the expression of ABCA1 , which , in turn , mediates cholesterol efflux to apoA1 .	Activators of peroxisome proliferator activated receptor gamma (PPARgamma), as well as PPARalpha, increase expression of liver X receptor alpha (LXRalpha) in macrophages and promote the expression of ABCA1, which, in turn, mediates cholesterol efflux to apoA1.	31	45	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	expression of ABCA1	abca1	apoA1	apoA1	apoa1	33	34	44	45
Lipid solubilization is central to ABCA1 mediated efflux of cellular lipids to apoA-I .	Lipid solubilization is central to ABCA1 mediated efflux of cellular lipids to apoA-I.	3	13	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	5	6	12	13
Therefore , the fact that BFA did not affect the rate of apoA-I recycling suggests that ABCA1 does not mediate apoA-I uptake .	Therefore, the fact that BFA did not affect the rate of apoA-I recycling suggests that ABCA1 does not mediate apoA-I uptake.	16	21	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	16	17	20	21
We present a model in which ABCA1 remodels the plasma membrane and , independently , promotes the cellular binding of apoAI .	We present a model in which ABCA1 remodels the plasma membrane and, independently, promotes the cellular binding of apoAI.	6	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoAI	apoAI	apoAI	6	7	20	21
Cell culture studies have shown that apart from lipidating apoA-I directly , ABCA1 can also mediate cholesterol delivery indirectly to apoA-I in the plasma membrane .	Cell culture studies have shown that apart from lipidating apoA-I directly, ABCA1 can also mediate cholesterol delivery indirectly to apoA-I in the plasma membrane.	12	24	mediate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	12	13	20	21
Furthermore , the hepatic overexpression of ABCA1 , by infusion of adenovirus expressing ABCA1 into mice , induces apoAI dependent cholesterol efflux from primary hepatocytes and also increases plasma HDL and apoAI levels XREF_BIBR , XREF_BIBR .	Furthermore, the hepatic overexpression of ABCA1, by infusion of adenovirus expressing ABCA1 into mice, induces apoAI dependent cholesterol efflux from primary hepatocytes and also increases plasma HDL and apoAI levels XREF_BIBR, XREF_BIBR.	4	33	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	overexpression of ABCA1	abca1	apoAI	apoAI	apoai	6	7	31	32
The function of ABCA1 is to mediate apolipoprotein A-I ( apoA-I )-dependent cholesterol efflux , which has been identified as an important target in the treatment of atherosclerosis [ XREF_BIBR , XREF_BIBR ] .	The function of ABCA1 is to mediate apolipoprotein A-I (apoA-I)-dependent cholesterol efflux, which has been identified as an important target in the treatment of atherosclerosis [XREF_BIBR, XREF_BIBR].	1	9	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	3	4	7	9
ABCA1 mediates cholesterol efflux to lipid-poor apoA-I , which then forms a nascent HDL , and ABCG1 is involved in cholesterol efflux to HDL .	ABCA1 mediates cholesterol efflux to lipid-poor apoA-I, which then forms a nascent HDL, and ABCG1 is involved in cholesterol efflux to HDL.	0	10	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	0	1	6	7
Because ABCA1 mediates lipidation of apoA-I and formation of nascent HDL [ XREF_BIBR ] , apoA-I of Tangier ' s disease patients is poorly lipidated and is rapidly catabolized .	Because ABCA1 mediates lipidation of apoA-I and formation of nascent HDL [XREF_BIBR], apoA-I of Tangier 's disease patients is poorly lipidated and is rapidly catabolized.	1	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	1	2	5	6
Although the mechanism of interaction between ABCA1 and apoA-I has not been completely resolved , ABCA1 overexpression has been shown to enhance the cellular binding and uptake of apoA-I .	Although the mechanism of interaction between ABCA1 and apoA-I has not been completely resolved, ABCA1 overexpression has been shown to enhance the cellular binding and uptake of apoA-I.	15	29	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1 overexpression	abca1	apoA-I	apoA-I	apoa-i	15	16	28	29
XREF_BIBR A study by Johnston and Waxman XREF_BIBR demonstrated that PPARalpha could increase the expression of LXRalpha in macrophages and thereby promote the expression of ABCA1 , which subsequently mediates cholesterol efflux to apoA1 .	XREF_BIBR A study by Johnston and Waxman XREF_BIBR demonstrated that PPARalpha could increase the expression of LXRalpha in macrophages and thereby promote the expression of ABCA1, which subsequently mediates cholesterol efflux to apoA1.	23	34	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	expression of ABCA1	abca1	apoA1	apoA1	apoa1	25	26	33	34
Depletion of Rab8 in foam cell inhibits cholesterol efflux to apoA-I in part by the reduction of ABCA1 level at the PM [ XREF_BIBR ] .	Depletion of Rab8 in foam cell inhibits cholesterol efflux to apoA-I in part by the reduction of ABCA1 level at the PM [XREF_BIBR].	6	19	inhibits	Negative_activation_syntax_3_verb	Positive_activation	Positive_activation	ABCA1	ABCA1 level	abca1	apoA-I	apoA-I	apoa-i	17	18	10	11
We previously showed that ABCG1 mediates the efflux of choline phospholipids ( mainly SM ) to HDL , whereas ABCA1 mediates the efflux of choline phospholipids ( mainly PC ) to lipid-free apoA-I in HEK293 cells XREF_BIBR .	We previously showed that ABCG1 mediates the efflux of choline phospholipids (mainly SM) to HDL, whereas ABCA1 mediates the efflux of choline phospholipids (mainly PC) to lipid-free apoA-I in HEK293 cells XREF_BIBR.	19	36	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	19	20	32	33
Additionally , treatment of symptomatic AD mice with GW3965 , an LXR agonist that stimulates ABCA1 expression , increases apoA-I more dramatically in the CNS compared to the periphery .	Additionally, treatment of symptomatic AD mice with GW3965, an LXR agonist that stimulates ABCA1 expression, increases apoA-I more dramatically in the CNS compared to the periphery.	11	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	LXR agonist that stimulates ABCA1 expression	abca1	apoA-I	apoA-I	apoa-i	15	16	19	20
Supporting this concept are experimental studies showing that inactivation of Abca1 increases plasma removal and renal degradation of lipid-free ApoA-I .	Supporting this concept are experimental studies showing that inactivation of Abca1 increases plasma removal and renal degradation of lipid-free ApoA-I.	8	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abca1	Abca1	Abca1	ApoA-I	ApoA-I	ApoA-I	10	11	19	20
This has been recently confirmed suggesting that in mouse macrophages ABCA1 mediated apoA-I , but not HDL uptake is required for cholesterol efflux XREF_BIBR .	This has been recently confirmed suggesting that in mouse macrophages ABCA1 mediated apoA-I, but not HDL uptake is required for cholesterol efflux XREF_BIBR.	10	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	10	11	12	13
Changes in transcription of ABCA-1 are thought to enhance the reverse TC transport and increase the apoA-I specific regurgitation of cholesterol while Changes in transcription of LPL are thought to enhance lipolysis of VLDL triglycerides resulting in reducing plasma TG levels and apoB proteasome degradation .	Changes in transcription of ABCA-1 are thought to enhance the reverse TC transport and increase the apoA-I specific regurgitation of cholesterol while Changes in transcription of LPL are thought to enhance lipolysis of VLDL triglycerides resulting in reducing plasma TG levels and apoB proteasome degradation.	2	17	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA-1	transcription of ABCA-1	abca-1	apoA-I	apoA-I	apoa-i	4	5	16	17
Large-scale ABCA1 mediated lipid efflux and gel filtration analysis of fmHDL .	Large-scale ABCA1 mediated lipid efflux and gel filtration analysis of fmHDL.	0	11	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	fmHDL	fmHDL	fmHDL	1	2	10	11
In summary , the present study has shown that LRP1 participates in apoAI mediated efflux of cholesterol and phospholipids by controlling ABCA1 expression at the transcriptional level .	In summary, the present study has shown that LRP1 participates in apoAI mediated efflux of cholesterol and phospholipids by controlling ABCA1 expression at the transcriptional level.	12	23	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ABCA1	ABCA1 expression	abca1	apoAI	apoAI	apoai	21	22	12	13
In conclusion , ABCA1 , but not SR-BI , modulates the transcytosis of apoA-I through endothelial cells .	In conclusion, ABCA1, but not SR-BI, modulates the transcytosis of apoA-I through endothelial cells.	3	14	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	3	4	13	14
Under these conditions , there were very low levels of ABCA1- or ABCG1 mediated efflux to either apoA-I or HDL .	Under these conditions, there were very low levels of ABCA1- or ABCG1 mediated efflux to either apoA-I or HDL.	8	19	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1-	levels of ABCA1-	abca1-	apoA-I	apoA-I	apoa-i	10	11	17	18
There are several models proposed for the interaction of apoA-I with ABCA1 as well as the lipidation of apoA-I mediated by ABCA1 .	There are several models proposed for the interaction of apoA-I with ABCA1 as well as the lipidation of apoA-I mediated by ABCA1.	16	22	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	21	22	18	19
In both cell types , PPARgamma ligands ( 15d-PGJ2 , troglitazone and pioglitazone ) reduced ABCA1 expression and ABCA1 mediated cholesterol efflux to apoAI , with most by troglitazone .	In both cell types, PPARgamma ligands (15d-PGJ2, troglitazone and pioglitazone) reduced ABCA1 expression and ABCA1 mediated cholesterol efflux to apoAI, with most by troglitazone.	15	24	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1 expression	abca1	apoAI	apoAI	apoai	15	16	23	24
ABCA1 , an ATP binding cassette ( ABC ) subfamily A exporter , mediates the cellular efflux of phospholipids and cholesterol to the extracellular acceptor apolipoprotein A-I ( apoA-I ) for generation of nascent high-density lipoprotein ( HDL ) .	ABCA1, an ATP binding cassette (ABC) subfamily A exporter, mediates the cellular efflux of phospholipids and cholesterol to the extracellular acceptor apolipoprotein A-I (apoA-I) for generation of nascent high-density lipoprotein (HDL).	0	27	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	0	1	25	27
We found that PPARgamma agonist treatment led to no significant change in total cholesterol efflux to 2.5 % human serum , but promoted ABCA1 mediated apolipoprotein A-I specific efflux , and ABCG-1 mediated efflux to HDL3 ( unpublished ) , consistent with previously published literature [ XREF_BIBR , XREF_BIBR ] .	We found that PPARgamma agonist treatment led to no significant change in total cholesterol efflux to 2.5% human serum, but promoted ABCA1 mediated apolipoprotein A-I specific efflux, and ABCG-1 mediated efflux to HDL3 (unpublished), consistent with previously published literature [XREF_BIBR, XREF_BIBR].	22	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	23	24	25	27
For fmHDL exposed to ABCA1 expressing cells , the A 523 peak overlapped with an enlarged [ 14 H ] cholesterol peak and a prominent [ 3 H ] choline-phospholipid peak , indicating that ABCA1 supported cholesterol and phospholipid efflux to fmHDL ( apo A-I ) .	For fmHDL exposed to ABCA1 expressing cells, the A 523 peak overlapped with an enlarged [14 H] cholesterol peak and a prominent [3 H] choline-phospholipid peak, indicating that ABCA1 supported cholesterol and phospholipid efflux to fmHDL (apo A-I).	34	44	supported	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	fmHDL	fmHDL	fmHDL	34	35	41	42
In aortic endothelial cells , ABCA1 and the ectopic beta-ATPase mediate cell-surface internalization and transport of lipid-free apoA-I .	In aortic endothelial cells, ABCA1 and the ectopic beta-ATPase mediate cell-surface internalization and transport of lipid-free apoA-I.	5	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	5	6	17	18
ABCA1 mediates cholesterol transport from glia to ApoE and ApoA-I and is critical for efficient secretion and lipidation of brain ApoE .	ABCA1 mediates cholesterol transport from glia to ApoE and ApoA-I and is critical for efficient secretion and lipidation of brain ApoE.	0	12	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	ApoA-I	ApoA-I	ApoA-I	0	1	9	10
Probucol , an inhibitor of ABCA1 , and BLT-1 were used to ascertain the extent to which the ABCA1 and SR-BI pathways , respectively , contributed to macrophage cholesterol efflux to fmHDL ( apo A-I ) .	Probucol, an inhibitor of ABCA1, and BLT-1 were used to ascertain the extent to which the ABCA1 and SR-BI pathways, respectively, contributed to macrophage cholesterol efflux to fmHDL (apo A-I).	18	34	contributed	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	fmHDL	fmHDL	fmHDL	18	19	31	32
We show here that c-Abl increases the cellular p73 abundance through a mode of posttranslational regulation .	We show here that c-Abl increases the cellular p73 abundance through a mode of posttranslational regulation.	4	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	4	5	8	9
Nevertheless , treatment with Doxorubicin and Cisplatin enhances binding of Pin1 to p73 via Ser412 , Thr442 , and Thr482 target sites , which is partly due to activation of p73 by c-Abl and p38 kinase .	Nevertheless, treatment with Doxorubicin and Cisplatin enhances binding of Pin1 to p73 via Ser412, Thr442, and Thr482 target sites, which is partly due to activation of p73 by c-Abl and p38 kinase.	28	35	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	32	33	30	31
Thus , to efficiently trigger apoptosis , Rb must be inactivated ; this can be achieved by viral oncoproteins , by mutations in Rb , by phosphorylation of cell-cycle proteins ( for example , once phosphorylated in S and G2 phase , c-Abl is released and can activate p73 ) or by proteolysis by caspases .	Thus, to efficiently trigger apoptosis, Rb must be inactivated; this can be achieved by viral oncoproteins, by mutations in Rb, by phosphorylation of cell-cycle proteins (for example, once phosphorylated in S and G2 phase, c-Abl is released and can activate p73) or by proteolysis by caspases.	42	49	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	42	43	48	49
The non receptor tyrosine kinase c-Abl is activated in response to DNA damage and induces p73 dependent apoptosis .	The non receptor tyrosine kinase c-Abl is activated in response to DNA damage and induces p73 dependent apoptosis.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	5	6	15	16
Furthermore , we found that activation of p38 is sufficient to enhance the stability of p73 , and that the transcriptional activation of p73 by c-Abl requires the activity of p38 .	Furthermore, we found that activation of p38 is sufficient to enhance the stability of p73, and that the transcriptional activation of p73 by c-Abl requires the activity of p38.	21	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	25	26	23	24
Our results show that c-Abl stimulates p73 mediated transactivation and apoptosis .	Our results show that c-Abl stimulates p73 mediated transactivation and apoptosis.	4	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	4	5	6	7
Taken together , these data suggest that Akt activation upon DNA damage may counteract p73 activation induced by JNK and c-Abl via inhibition of Yap nuclear translocation .	Taken together, these data suggest that Akt activation upon DNA damage may counteract p73 activation induced by JNK and c-Abl via inhibition of Yap nuclear translocation.	14	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	20	21	14	15
51 Activation of p73 by c-Abl in response to DNA damage is dependent on the presence of an intact mismatch repair system and involves the Mut L homolog-1 ( MLH1 ) .	51 Activation of p73 by c-Abl in response to DNA damage is dependent on the presence of an intact mismatch repair system and involves the Mut L homolog-1 (MLH1).	1	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	5	6	3	4
Radiation induces ATM dependent c-Abl phosphorylation which then activates p73 .	Radiation induces ATM dependent c-Abl phosphorylation which then activates p73.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl phosphorylation	c-abl	p73	p73	p73	4	5	9	10
Furthermore , c-Abl knockdown reduced the accumulation of p73 protein at 4hpi , but not at 24hpi .	Furthermore, c-Abl knockdown reduced the accumulation of p73 protein at 4hpi, but not at 24hpi.	2	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	2	3	8	9
In fact , Pin1 is required for the c-Abl induced p73 activation and accumulation upon cytotoxic stress and p300 mediated p73 acetylation is strongly impaired in Pin1 deficient cells , since Pin1 mediated isomerization regulates p300-p73 binding .	In fact, Pin1 is required for the c-Abl induced p73 activation and accumulation upon cytotoxic stress and p300 mediated p73 acetylation is strongly impaired in Pin1 deficient cells, since Pin1 mediated isomerization regulates p300-p73 binding.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	8	9	10	11
Thus , activation of p73 by c-Abl may play an important role in cancer therapy , especially in cancer cells that lose p53 function , but express p73 .	Thus, activation of p73 by c-Abl may play an important role in cancer therapy, especially in cancer cells that lose p53 function, but express p73.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	6	7	4	5
Mig6 and Abl but Not Src and Abl Triggers p73 Dependent Cell Death .	Mig6 and Abl but Not Src and Abl Triggers p73 Dependent Cell Death.	0	12	Triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	p73	p73	p73	2	3	9	10
Nuclear localization of c-Abl causes activation of p73 by phosphorylation at Y99 , thus inducing cell apoptosis [ XREF_BIBR ] .	Nuclear localization of c-Abl causes activation of p73 by phosphorylation at Y99, thus inducing cell apoptosis [XREF_BIBR].	1	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	3	4	7	8
ABL1 dependent up-regulation of TAp73 upon treatment with CDDP .	ABL1 dependent up-regulation of TAp73 upon treatment with CDDP.	0	5	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ABL1	ABL1	ABL1	TAp73	TAp73	TAp73	0	1	4	5
Knockdown of p73 , c-Abl , JNK or Yap using siRNAs shows that p73 plays a critical role in combination treatment enhanced apoptosis and the expression of pro apoptotic and anti-apoptotic mediators , and that c-Abl , JNK and Yap are upstream mediators of p73 in combination treatment responses .	Knockdown of p73, c-Abl, JNK or Yap using siRNAs shows that p73 plays a critical role in combination treatment enhanced apoptosis and the expression of pro apoptotic and anti-apoptotic mediators, and that c-Abl, JNK and Yap are upstream mediators of p73 in combination treatment responses.	35	48	are upstream mediators	Positive_activation_copula_1	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	35	36	44	45
As presented in XREF_FIG , knockdown of ABL1 prevented up-regulation of TAp73 .	As presented in XREF_FIG, knockdown of ABL1 prevented up-regulation of TAp73.	5	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ABL1	ABL1	ABL1	TAp73	TAp73	TAp73	7	8	11	12
Taken together , our data suggest a serotype- and cell type specific mechanism , by which EV71 induces Abl kinase activity , which in turn triggers Cdk5 signalling for neuronal apoptosis .	Taken together, our data suggest a serotype- and cell type specific mechanism, by which EV71 induces Abl kinase activity, which in turn triggers Cdk5 signalling for neuronal apoptosis.	18	27	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	Cdk5	Cdk5	Cdk5	18	19	26	27
For instance tau phosphorylation is modulated via activity of the tyrosine kinase Abl modulating Cdk5 activation in a transgenic mouse model of AD .	For instance tau phosphorylation is modulated via activity of the tyrosine kinase Abl modulating Cdk5 activation in a transgenic mouse model of AD.	7	15	modulating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	Cdk5	Cdk5	Cdk5	12	13	14	15
In addition , c-Abl modulates Cdk5 activity via phosphorylation of tyrosine 15 in cooperation with cleavage of p35 to p25 .	In addition, c-Abl modulates Cdk5 activity via phosphorylation of tyrosine 15 in cooperation with cleavage of p35 to p25.	3	6	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	Cdk5	Cdk5	Cdk5	3	4	5	6
The S6K-Ser 411 phosphorylation level is associated with Abl mediated Cdk5 and p35 activity ( Kumar etal .	The S6K-Ser 411 phosphorylation level is associated with Abl mediated Cdk5 and p35 activity (Kumar etal.	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Abl	Abl	Abl	Cdk5	Cdk5	Cdk5	8	9	10	11
When we analyzed MCF10A cells , we found that the basal activity of CDK5 was very low , as determined by the low expression of its p35 activator and low phosphorylation of tyrosine 15 in CDK5 , a finding that was correlated with low expression of c-Abl , which stimulates the CDK5 kinase activity by phosphorylating CDK5 tyrosine 15 .	When we analyzed MCF10A cells, we found that the basal activity of CDK5 was very low, as determined by the low expression of its p35 activator and low phosphorylation of tyrosine 15 in CDK5, a finding that was correlated with low expression of c-Abl, which stimulates the CDK5 kinase activity by phosphorylating CDK5 tyrosine 15.	44	59	stimulates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	c-Abl	expression of c-Abl	c-abl	CDK5	phosphorylating CDK5 tyrosine 15	cdk5	46	47	56	57
A variety of reporters can be used to quantify activity in this pathway ; Abl mediated Cdk5 and p35 activity , detected from the S6K-pSer 411 immunoreactivity ( Hou etal .	A variety of reporters can be used to quantify activity in this pathway; Abl mediated Cdk5 and p35 activity, detected from the S6K-pSer 411 immunoreactivity (Hou etal.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Abl	Abl	Abl	Cdk5	Cdk5	Cdk5	14	15	16	17
For example , when cells are exposed to IR , ATM phosphorylates Abl at S465 and activates Abl kinase activity .	For example, when cells are exposed to IR, ATM phosphorylates Abl at S465 and activates Abl kinase activity.	10	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	ATM phosphorylates Abl at S465	abl	Abl	Abl	abl	12	13	17	18
The initial and an essential event is the interaction between the Crk SH3 ( N ) domain and three of the four PR motifs of Abl , inducing transactivation of c-Abl to phosphorylate CrkII at Y221 in the spacer region [ XREF_BIBR , XREF_BIBR ] .	The initial and an essential event is the interaction between the Crk SH3 (N) domain and three of the four PR motifs of Abl, inducing transactivation of c-Abl to phosphorylate CrkII at Y221 in the spacer region [XREF_BIBR, XREF_BIBR].	23	31	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	c-Abl	c-Abl	c-Abl	25	26	30	31
These data are extremely significant , as they indicate that PDGFR-beta phosphorylates Abl kinases on tyrosine residues known to activate Abelson activity , which was demonstrated using both in vitro and in vivo ( in cells ) methods : c-Abl ( Y245 , Y412 ; SH2-SH-1-KR ; in cells ) and Arg ( Y271 ; SH2-SH3 ; in vitro ) .	These data are extremely significant, as they indicate that PDGFR-beta phosphorylates Abl kinases on tyrosine residues known to activate Abelson activity, which was demonstrated using both in vitro and in vivo (in cells) methods : c-Abl (Y245, Y412; SH2-SH-1-KR; in cells) and Arg (Y271; SH2-SH3; in vitro).	10	51	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	PDGFR-beta phosphorylates Abl kinases on tyrosine residues	abl	c-Abl	c-Abl	c-abl	12	13	39	40
Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1 dependent manner , putting forward the role of miR-203 as a TSG whose re-expression might have therapeutic benefits in specific hematopoietic malignancies .	Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1 dependent manner, putting forward the role of miR-203 as a TSG whose re-expression might have therapeutic benefits in specific hematopoietic malignancies.	0	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABL1	Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels	abl1	ABL1	ABL1	abl1	4	5	17	18
Overexpression of wild-type Abl1 , but not kinase defective Abl1 , can rescue the mutant phenotypes of Abl1 knockout mice , suggesting that ABL1 kinase activity is essential for normal development 17 .	Overexpression of wild-type Abl1, but not kinase defective Abl1, can rescue the mutant phenotypes of Abl1 knockout mice, suggesting that ABL1 kinase activity is essential for normal development 17.	0	19	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl1	Overexpression of wild-type Abl1	abl1	Abl1	Abl1	abl1	3	4	17	18
Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1 dependent manner .	Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1 dependent manner.	0	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABL1	Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels	abl1	ABL1	ABL1	abl1	4	5	17	18
Furthermore , we show that activated Abl allows the ligand activated EGFR to escape Cbl dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR.Cbl complex without affecting Cbl protein stability .	Furthermore, we show that activated Abl allows the ligand activated EGFR to escape Cbl dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR.Cbl complex without affecting Cbl protein stability.	5	12	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	EGFR	EGFR	EGFR	6	7	11	12
In addition , we showed that Abl kinases are activated downstream of EGFR , Her-2 , and IGF-1R in some breast cancer cells [ XREF_BIBR ] .	In addition, we showed that Abl kinases are activated downstream of EGFR, Her-2, and IGF-1R in some breast cancer cells [XREF_BIBR].	6	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	EGFR	EGFR	EGFR	6	7	12	13
Activated Abl allows EGFR to escape Cbl dependent downregulation by preventing the recruitment of Cbl to the plasma membrane [ XREF_BIBR ] .	Activated Abl allows EGFR to escape Cbl dependent downregulation by preventing the recruitment of Cbl to the plasma membrane [XREF_BIBR].	0	5	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	EGFR	EGFR	EGFR	1	2	3	4
These results suggest that ZnMt3 in cultured astrocytes may be a normal component of c-Abl activation in EGF receptor signaling .	These results suggest that ZnMt3 in cultured astrocytes may be a normal component of c-Abl activation in EGF receptor signaling.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	EGF receptor	EGF receptor	EGF receptor	14	15	17	19
Although c-Abl has been shown to modulate EGFR endocytosis , and EGFR surface expression positively correlates with ADCC , EGFR surface expression was unchanged by ABL1 knockdown or imatinib exposure .	Although c-Abl has been shown to modulate EGFR endocytosis, and EGFR surface expression positively correlates with ADCC, EGFR surface expression was unchanged by ABL1 knockdown or imatinib exposure.	1	8	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	EGFR	EGFR	EGFR	1	2	7	8
Inhibition of Src and Abl kinases with the dual specificity drug saracatinib suppressed EGFR activation and ECM degradation in HNSCC , suggesting that Src is responsible for mediating the pro invasive signals resultant from imatinib mediated Abl family kinase inactivation .	Inhibition of Src and Abl kinases with the dual specificity drug saracatinib suppressed EGFR activation and ECM degradation in HNSCC, suggesting that Src is responsible for mediating the pro invasive signals resultant from imatinib mediated Abl family kinase inactivation.	2	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	EGFR	EGFR	EGFR	4	5	13	14
Binding of full-length Crk or the isolated SH2 domains of GAP or Abl resulted in a significant protection of phosphorylated EGFR against dephosphorylation by cellular phosphatase activity , but did not appear to stimulate the intrinsic tyrosine kinase activity of the EGFR .	Binding of full-length Crk or the isolated SH2 domains of GAP or Abl resulted in a significant protection of phosphorylated EGFR against dephosphorylation by cellular phosphatase activity, but did not appear to stimulate the intrinsic tyrosine kinase activity of the EGFR.	8	42	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	EGFR	EGFR	EGFR	12	13	41	42
To determine whether activation of c-Abl in newborn rat cardiomyocytes could enhance CAT activity and phosporylation , cells were incubated for 1 hour with 5-( 1,3-diaryl-1H-pyra-zol-4-yl ) hydantoin ( DPH , 200 mumol/L ) , a small molecule c-Abl activator , prior to hypoxia treatment .	To determine whether activation of c-Abl in newborn rat cardiomyocytes could enhance CAT activity and phosporylation, cells were incubated for 1 hour with 5-(1,3-diaryl-1H-pyra-zol-4-yl) hydantoin (DPH, 200 mumol/L), a small molecule c-Abl activator, prior to hypoxia treatment.	3	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	CAT	CAT	CAT	5	6	12	13
These data demonstrate that activation of c-Abl enhances CAT activity and RV function following IR injury in the newborn but not in adult hearts .	These data demonstrate that activation of c-Abl enhances CAT activity and RV function following IR injury in the newborn but not in adult hearts.	4	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	CAT	CAT	CAT	6	7	8	9
Because c-Abl is known to modulate CAT , we examined basal protein levels of c-Abl in newborn and adult rat heart .	Because c-Abl is known to modulate CAT, we examined basal protein levels of c-Abl in newborn and adult rat heart.	1	7	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	CAT	CAT	CAT	1	2	6	7
Recent studies have shown that catalase activity is stimulated by the c-Abl and Arg tyrosine kinases .	Recent studies have shown that catalase activity is stimulated by the c-Abl and Arg tyrosine kinases.	5	15	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	catalase	catalase	catalase	11	12	5	6
We were also interested in determining the role of Src family kinases in AngII mediated PKD activation and aldosterone production , since Toker and colleagues have demonstrated that Src and Abl can activate PKD in HeLa cells .	We were also interested in determining the role of Src family kinases in AngII mediated PKD activation and aldosterone production, since Toker and colleagues have demonstrated that Src and Abl can activate PKD in HeLa cells.	28	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	PKD	PKD	PKD	30	31	33	34
Thus it is conceivable that RIN1 mediated activation of Abl kinases in turn activates PKD and thereby inhibits cell migration .	Thus it is conceivable that RIN1 mediated activation of Abl kinases in turn activates PKD and thereby inhibits cell migration.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	RIN1 mediated activation of Abl	abl	PKD	PKD	pkd	9	10	14	15
To further delineate the functional interaction between c-Abl and MST2 , an in vitro MST2 kinase assay was performed and we observed that c-Abl significantly enhanced the kinase activity of MST2 ( XREF_FIG ) by using the recombinant protein of FOXO3 forkhead domain ( FD ) as the substrate .	To further delineate the functional interaction between c-Abl and MST2, an in vitro MST2 kinase assay was performed and we observed that c-Abl significantly enhanced the kinase activity of MST2 (XREF_FIG) by using the recombinant protein of FOXO3 forkhead domain (FD) as the substrate.	23	32	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	MST2	MST2	MST2	23	24	30	31
AIB1 and SRC-3-dependent transcription and phenotypic changes , such as cell growth and focus formation , can be reversed by an Abl kinase inhibitor , imatinib .	AIB1 and SRC-3-dependent transcription and phenotypic changes, such as cell growth and focus formation, can be reversed by an Abl kinase inhibitor, imatinib.	0	23	reversed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	AIB1	AIB1	AIB1	21	22	0	1
Interestingly , high levels of Y-1357 phospho-AIB1 are found in HER2 and Neu induced mammary tumors [ XREF_BIBR ] and in human tumors ( unpublished data ) suggesting that Abl kinase activation of AIB1 may play a functional role in mammary tumorigenesis .	Interestingly, high levels of Y-1357 phospho-AIB1 are found in HER2 and Neu induced mammary tumors [XREF_BIBR] and in human tumors (unpublished data) suggesting that Abl kinase activation of AIB1 may play a functional role in mammary tumorigenesis.	29	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Abl	Abl	Abl	AIB1	AIB1	AIB1	29	30	33	34
Two Abl kinase inhibitors , AT9283 and PHA739358 , as well as siRNAs targeting Abl , significantly inhibited the activation of SRC-3 by MCB-613 ( XREF_FIG ) , confirming that oxidative stress induced by MCB-613 contributes to SRC activation via the Abl kinase signaling pathway .	Two Abl kinase inhibitors, AT9283 and PHA739358, as well as siRNAs targeting Abl, significantly inhibited the activation of SRC-3 by MCB-613 (XREF_FIG), confirming that oxidative stress induced by MCB-613 contributes to SRC activation via the Abl kinase signaling pathway.	1	22	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	SRC-3	SRC-3	SRC-3	1	2	21	22
Based on these findings , c-Abl may enhance caspase-9 autoprocessing when responding to DNA damage stresses , although the general mechanism of Tyr153 phosphorylation regarding the regulation of caspase-9 stays clarified [ XREF_BIBR ] .	Based on these findings, c-Abl may enhance caspase-9 autoprocessing when responding to DNA damage stresses, although the general mechanism of Tyr153 phosphorylation regarding the regulation of caspase-9 stays clarified [XREF_BIBR].	5	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	caspase-9	caspase-9	caspase-9	5	6	8	9
Moreover , inhibition of c-Abl with STI571 blocked DNA damage induced autoprocessing of caspase-9 to the p35 subunit and activation of caspase-3 .	Moreover, inhibition of c-Abl with STI571 blocked DNA damage induced autoprocessing of caspase-9 to the p35 subunit and activation of caspase-3.	2	14	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	caspase-9	caspase-9	caspase-9	4	5	13	14
The so called BRCA1-A complex comprises RAP80 , Abraxas and CCDC98 , the deubiquitinase BRCC36 , BRCC45 and MERIT40 , which are thought to target BRCA1 to IR induced foci through the interaction of RAP80 with polyubiquitin chains such as is thought to occur at histone gamma-H2AX [ XREF_BIBR , XREF_BIBR ] ( see XREF_FIG ) .	The so called BRCA1-A complex comprises RAP80, Abraxas and CCDC98, the deubiquitinase BRCC36, BRCC45 and MERIT40, which are thought to target BRCA1 to IR induced foci through the interaction of RAP80 with polyubiquitin chains such as is thought to occur at histone gamma-H2AX [XREF_BIBR, XREF_BIBR] (see XREF_FIG).	6	26	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCDC98	CCDC98	CCDC98	BRCA1	BRCA1	BRCA1	10	11	25	26
Moreover , CCDC98 controls both DNA damage induced formation of BRCA1 foci and BRCA1 dependent G2/M checkpoint activation .	Moreover, CCDC98 controls both DNA damage induced formation of BRCA1 foci and BRCA1 dependent G2/M checkpoint activation.	2	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCDC98	CCDC98	CCDC98	BRCA1	BRCA1	BRCA1	2	3	10	11
ABI-1 promoted engulfment and migration independently of the known engulfment pathways downstream of or in parallel to ABL-1 .	ABI-1 promoted engulfment and migration independently of the known engulfment pathways downstream of or in parallel to ABL-1.	0	18	promoted	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABI-1	ABI-1	ABI-1	ABL-1	ABL-1	ABL-1	0	1	17	18
GST-Crk transactivated Abl kinase , whereas GST-Abi1 failed to activate Abl kinase under these conditions ( lane 2 versus lane 4 ) .	GST-Crk transactivated Abl kinase, whereas GST-Abi1 failed to activate Abl kinase under these conditions (lane 2 versus lane 4).	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GST-Abi1	GST-Abi1	GST-Abi1	Abl	Abl	Abl	6	7	10	11
The c-Abl inactive analogs induced cytotoxicity and ER stress , at similar or greater potencies and magnitudes as imatinib .	The c-Abl inactive analogs induced cytotoxicity and ER stress, at similar or greater potencies and magnitudes as imatinib.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	ER	ER	ER	1	2	7	8
In these experiments , four protein substrates were identified ( FLJ22795 , SH3YL1 , CRKL , ABI1 ) that were uniquely phosphorylated on arrays treated with the Abl protein kinase .	In these experiments, four protein substrates were identified (FLJ22795, SH3YL1, CRKL, ABI1) that were uniquely phosphorylated on arrays treated with the Abl protein kinase.	10	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Abl	Abl	Abl	ABI1	ABI1	ABI1	27	28	16	17
We also analyzed the reciprocal effects of Abi1 and Crk on Abl signaling in Abi1 (-/-) MEFs reconstituted with Abi1 to rule out the possibility that other Abi1 isoforms may compensate for Abi1-Iso2 in the HS683 tumor cells .	We also analyzed the reciprocal effects of Abi1 and Crk on Abl signaling in Abi1 (-/-) MEFs reconstituted with Abi1 to rule out the possibility that other Abi1 isoforms may compensate for Abi1-Iso2 in the HS683 tumor cells.	11	16	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Abl	Abl	Abl	Abi1	Abi1	Abi1	11	12	14	15
Drosophila Trio ( equally related to KALRN and TRIO ) plays an essential role in Abl mediated axonal outgrowth 26 , leading to the prediction that Abl and/or Abl2 and Arg play similar roles in vertebrates .	Drosophila Trio (equally related to KALRN and TRIO) plays an essential role in Abl mediated axonal outgrowth 26, leading to the prediction that Abl and/or Abl2 and Arg play similar roles in vertebrates.	13	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	Abl2	Abl2	Abl2	15	16	28	29
Src mediated activation of the Abl family kinase Arg also leads to the phosphorylation of cortactin , resulting in the recruitment of Nck1 to the invadopodia .	Src mediated activation of the Abl family kinase Arg also leads to the phosphorylation of cortactin, resulting in the recruitment of Nck1 to the invadopodia.	0	23	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Src mediated activation of the Abl	abl	Nck1	Nck1	nck1	5	6	22	23
These findings suggest a novel signaling pathway by which c-Abl mediates WRN nuclear localization and catalytic activities in response to DNA damage .	These findings suggest a novel signaling pathway by which c-Abl mediates WRN nuclear localization and catalytic activities in response to DNA damage.	9	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	WRN	WRN	WRN	9	10	11	12
Abl1 mediated Tyr 261 phosphorylation of Abl2 increases protein stability of Abl2 [ XREF_BIBR ] , while phosphorylation of Tyr 147 in the SH3-SH2 connector region of BCR-ABL protein by Src family kinases ( Hck , Lyn , and Fyn ) modulate BCR-ABL protein conformation and transforming activity [ XREF_BIBR ] .	Abl1 mediated Tyr 261 phosphorylation of Abl2 increases protein stability of Abl2 [XREF_BIBR], while phosphorylation of Tyr 147 in the SH3-SH2 connector region of BCR-ABL protein by Src family kinases (Hck, Lyn, and Fyn) modulate BCR-ABL protein conformation and transforming activity [XREF_BIBR].	0	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl2	Abl1 mediated Tyr 261 phosphorylation of Abl2	abl2	Abl2	Abl2	abl2	6	7	11	12
To further prove the importance of Abl kinase activation in RIN1 controlled filopodial motility , we introduced RIN1 mutants defective in Abl kinase activation ( RIN1 QM ) or modulation of Abl kinase activity ( RIN1 S292A ) into Rin1 - / - neurons .	To further prove the importance of Abl kinase activation in RIN1 controlled filopodial motility, we introduced RIN1 mutants defective in Abl kinase activation (RIN1 QM) or modulation of Abl kinase activity (RIN1 S292A) into Rin1 - / - neurons.	6	43	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Abl	Abl	Abl	RIN1	RIN1	RIN1	6	7	10	11
ACE inhibition impairs angiotensin II production , resulting in a number of positive cardiovascular benefits .	ACE inhibition impairs angiotensin II production, resulting in a number of positive cardiovascular benefits.	0	5	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	3	5
In smooth muscle cells and mesangial cells , the angiotensin II synthesized by ACE increases mRNA expression and the activity of PAI-1 , which promotes antifibrinolysis and the accumulation of extracellular matrix .	In smooth muscle cells and mesangial cells, the angiotensin II synthesized by ACE increases mRNA expression and the activity of PAI-1, which promotes antifibrinolysis and the accumulation of extracellular matrix.	8	14	synthesized	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	13	14	9	11
38 Ang II is the main effector molecule of the RAS and is produced from angiotensinogen by the action of renin and ACE .	38 Ang II is the main effector molecule of the RAS and is produced from angiotensinogen by the action of renin and ACE.	1	23	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	22	23	1	3
On the other hand , ACE inhibition reduces Ang II production , thus reducing its effect on both AT 1 Rs and AT 2 Rs .	On the other hand, ACE inhibition reduces Ang II production, thus reducing its effect on both AT 1 Rs and AT 2 Rs.	5	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	5	6	8	10
However , the role of ACE independent production of Ang II by the chymase enzyme in burn injuries remains unclear .	However, the role of ACE independent production of Ang II by the chymase enzyme in burn injuries remains unclear.	5	11	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	5	6	9	11
ACE is a dipeptidyl carboxypeptidase I ( EC.3.4.15.1 ) that activates angiotensin I through cleavage of the carboxyterminal dipeptide into the potent vasoconstrictor angiotensin II ( ang II ) , inactivating the vasodilator peptide bradykinin .	ACE is a dipeptidyl carboxypeptidase I (EC.3.4.15.1) that activates angiotensin I through cleavage of the carboxyterminal dipeptide into the potent vasoconstrictor angiotensin II (ang II), inactivating the vasodilator peptide bradykinin.	3	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	dipeptidyl carboxypeptidase I	dipeptidyl carboxypeptidase I	dipeptidyl carboxypeptidase I	angiotensin I	angiotensin I	angiotensin I	3	6	11	13
Moreover , ACE contributes only a small portion to the total Ang I conversion , as shown in biochemical studies in ventricular and coronary homogenates or functionally as Ang I contractions in isolated rings of coronary arteries .	Moreover, ACE contributes only a small portion to the total Ang I conversion, as shown in biochemical studies in ventricular and coronary homogenates or functionally as Ang I contractions in isolated rings of coronary arteries.	2	13	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	2	3	11	13
Angiotensin converting enzyme ( ACE ) increases blood pressure by converting the inactive angiotensin I ( decapeptide ) to the active angiotensin II ( octapeptide ) , which is a potent vasoconstrictor hormone and aldosterone stimulating peptide that controls fluid-electrolyte balance and blood pressure .	Angiotensin converting enzyme (ACE) increases blood pressure by converting the inactive angiotensin I (decapeptide) to the active angiotensin II (octapeptide), which is a potent vasoconstrictor hormone and aldosterone stimulating peptide that controls fluid-electrolyte balance and blood pressure.	2	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	4	5	13	15
Since the blood vessels of the scar drain to the remaining LV myocardium , the high ACE activity present in the fibrous scar may increase the angiotensin II concentration and decrease bradykinin in the cardiac tissues surrounding the infarcted area .	Since the blood vessels of the scar drain to the remaining LV myocardium, the high ACE activity present in the fibrous scar may increase the angiotensin II concentration and decrease bradykinin in the cardiac tissues surrounding the infarcted area.	16	28	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	16	17	26	28
It is characterized by the release of renin and the eventual conversion into angiotensin II catalyzed by ACE .	It is characterized by the release of renin and the eventual conversion into angiotensin II catalyzed by ACE.	2	18	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	17	18	13	15
Furthermore , the Ace gene was up-regulated , representing increase of angiotensin II , an inducer of these transcription factors and fetal genes in cardiac hypertrophy .	Furthermore, the Ace gene was up-regulated, representing increase of angiotensin II, an inducer of these transcription factors and fetal genes in cardiac hypertrophy.	3	13	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ace	Ace	Ace	angiotensin II	angiotensin II	angiotensin II	3	4	11	13
At the acute stage of renal ischemia and reperfusion induced AKI , ACE inhibition substantially contributed to the amelioration of acute injury by improving renal function , inhibiting systemic and intrarenal angiotensin-II , attenuating intrarenal inflammation and preserving renal tissue structure .	At the acute stage of renal ischemia and reperfusion induced AKI, ACE inhibition substantially contributed to the amelioration of acute injury by improving renal function, inhibiting systemic and intrarenal angiotensin-II, attenuating intrarenal inflammation and preserving renal tissue structure.	12	32	contributed	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin-II	angiotensin-II	angiotensin-II	12	13	31	32
Angiotensin II is locally produced in the ischaemic heart by both serine protease ( s ) and chymostatin inhibitable protease ( s ) , but not by angiotensin converting enzyme .	Angiotensin II is locally produced in the ischaemic heart by both serine protease (s) and chymostatin inhibitable protease (s), but not by angiotensin converting enzyme.	0	30	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Angiotensin II	Angiotensin II	Angiotensin II	27	30	0	2
In the current study , elevated ACE activity in hypertensive heart may enhance the conversion of angiotensin I ( Ang I ) into bioactive angiotensin II ( Ang II ) which clearly mirrors the part of Ang II in myocardial fibrosis .	In the current study, elevated ACE activity in hypertensive heart may enhance the conversion of angiotensin I (Ang I) into bioactive angiotensin II (Ang II) which clearly mirrors the part of Ang II in myocardial fibrosis.	6	19	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	6	7	16	18
ACE inhibition increased renal and plasma ANG I levels 2.8- and 12-fold , respectively , and decreased renal and plasma ANG II levels 75-78 % .	ACE inhibition increased renal and plasma ANG I levels 2.8- and 12-fold, respectively, and decreased renal and plasma ANG II levels 75-78%.	0	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	0	1	20	22
XREF_BIBR Therefore , it is likely that ACE susceptibility in KS is a result of increased genetic expression due to polymorphisms of the ACE gene , which in turn would lead to increased angiotensin II formation .	XREF_BIBR Therefore, it is likely that ACE susceptibility in KS is a result of increased genetic expression due to polymorphisms of the ACE gene, which in turn would lead to increased angiotensin II formation.	23	35	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	23	24	33	35
ACE inhibition prevents the conversion of angiotensin I to angiotensin II by ACE thus attenuating the sodium retention , vasoconstriction , SNS activation , and remodelling induced by RAS activation .	ACE inhibition prevents the conversion of angiotensin I to angiotensin II by ACE thus attenuating the sodium retention, vasoconstriction, SNS activation, and remodelling induced by RAS activation.	0	8	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	0	1	6	8
This finding suggested that ACE mediated AngII and AT1R signaling system may not be involved in acute renal failure induced by CDDP ( Daemen et al ., 1999 ) .	This finding suggested that ACE mediated AngII and AT1R signaling system may not be involved in acute renal failure induced by CDDP (Daemen et al., 1999).	4	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	4	5	6	7
ACE catalyzes the conversion of angiotensin-I to angiotensin-II which causes the muscles surrounding blood vessels to contract , thereby restricting the blood flow and increasing blood pressure .	ACE catalyzes the conversion of angiotensin-I to angiotensin-II which causes the muscles surrounding blood vessels to contract, thereby restricting the blood flow and increasing blood pressure.	0	9	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin-II	angiotensin-II	angiotensin-II	0	1	7	8
This can be a mechanism to suppress circulating ACE mediated conversion of angiotensin I , which can lead to systemic ( nonspecific ) effects ( XREF_FIG ) .	This can be a mechanism to suppress circulating ACE mediated conversion of angiotensin I, which can lead to systemic (nonspecific) effects (XREF_FIG).	8	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	8	9	12	14
ACE , an enzyme located in the endothelial cell membrane , activates angiotensin I and angiotensin II , and deactivates bradykinin .	ACE, an enzyme located in the endothelial cell membrane, activates angiotensin I and angiotensin II, and deactivates bradykinin.	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	15	17
ACE ( angiotensin-1 converting enzyme ) increases angiotensin-II , which elevates blood pressure .	ACE (angiotensin-1 converting enzyme) increases angiotensin-II, which elevates blood pressure.	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin-II	angiotensin-II	angiotensin-II	0	1	7	8
11 These adverse effects are mainly mediated by an increased ACE dependent , localized production of angiotensin II ( AngII ) .	11 These adverse effects are mainly mediated by an increased ACE dependent, localized production of angiotensin II (AngII).	6	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	10	11	16	18
Angiotensin II ( ANGII ) is produced by proteolytic cleavage of its precursor angiotensin I by angiotensin converting enzyme ( ACE ) .	Angiotensin II (ANGII) is produced by proteolytic cleavage of its precursor angiotensin I by angiotensin converting enzyme (ACE).	0	19	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Angiotensin II	Angiotensin II	Angiotensin II	16	19	0	2
Angiotensin 2 production by ACE and stimulation of the angiotensin 1 ( AT1 ) receptor subtype reduces nitric oxide bioavailability , promotes inflammation and fibrosis .	Angiotensin 2 production by ACE and stimulation of the angiotensin 1 (AT1) receptor subtype reduces nitric oxide bioavailability, promotes inflammation and fibrosis.	0	12	production	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Angiotensin 2	Angiotensin 2	Angiotensin 2	4	5	0	2
ACE is present at the apical membrane of distal nephron cells allowing paracrine generation of Ang II from Ang I [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	ACE is present at the apical membrane of distal nephron cells allowing paracrine generation of Ang II from Ang I [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	17	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	0	1	15	17
Angiotensin converting enzyme ( ACE ) inhibitors reduce the production of angiotensin II , whereas angiotensin receptor blocker ( ARB ) drugs inhibit the binding of angiotensin II to the angiotensin II type 1 receptor .	Angiotensin converting enzyme (ACE) inhibitors reduce the production of angiotensin II, whereas angiotensin receptor blocker (ARB) drugs inhibit the binding of angiotensin II to the angiotensin II type 1 receptor.	4	13	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	11	13
Inhibition of ACE enzymatic activity by selective ACE inhibitors blocks the generation of Ang II and thereby acts as a suitable approach for the treatment of high blood pressure .	Inhibition of ACE enzymatic activity by selective ACE inhibitors blocks the generation of Ang II and thereby acts as a suitable approach for the treatment of high blood pressure.	2	15	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	2	3	13	15
On the other hand , the angiotensin converting enzyme ( ACE ) -- producer of Ang II -- deactivates bradykinin production ; bradykinin is a peptide that may induce tissue protection during ischemia by promoting the release of prostaglandins which , in turn , improve blood flow and oxygen delivery to the heart [ XREF_BIBR ] .	On the other hand, the angiotensin converting enzyme (ACE) -- producer of Ang II -- deactivates bradykinin production; bradykinin is a peptide that may induce tissue protection during ischemia by promoting the release of prostaglandins which, in turn, improve blood flow and oxygen delivery to the heart [XREF_BIBR].	5	18	producer	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Ang II	Ang II	Ang II	6	9	15	17
Angiotensin converting enzyme ( ACE ) inhibitors block the neurohormonal conversion of angiotensin I to angiotensin II , a potent vasoconstrictor .	Angiotensin converting enzyme (ACE) inhibitors block the neurohormonal conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.	4	14	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	4	5	12	14
The enzyme renin cleaves AGT forming angiotensin I , and ACE or kinase II as dipeptidyl carboxypeptidase encoded by the ACE gene produces the active hormone angiotensin II that promotes vasoconstriction .	The enzyme renin cleaves AGT forming angiotensin I, and ACE or kinase II as dipeptidyl carboxypeptidase encoded by the ACE gene produces the active hormone angiotensin II that promotes vasoconstriction.	10	28	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	10	11	26	28
Theoretically , the ACE and ACE2 balance would also mediate the relative concentrations of Ang II and Ang 1-7 in the brain .	Theoretically, the ACE and ACE2 balance would also mediate the relative concentrations of Ang II and Ang 1-7 in the brain.	3	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	3	4	14	16
While ACE synthesizes Ang II from Ang I , however , ACE2 serves the opposite function , degrading Ang II to Ang-( 1-7 ) .	While ACE synthesizes Ang II from Ang I, however, ACE2 serves the opposite function, degrading Ang II to Ang-(1-7).	1	8	synthesizes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	1	2	6	8
Ang II is produced by ACE through hydrolysis of its precursor Ang I. Ang II is the major vasoactive peptide in the RAS , acting as a potent vasoconstrictor through its receptor AT1R ( XREF_FIG ) .	Ang II is produced by ACE through hydrolysis of its precursor Ang I. Ang II is the major vasoactive peptide in the RAS, acting as a potent vasoconstrictor through its receptor AT1R (XREF_FIG).	0	6	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	5	6	0	2
In control kidneys , afferent arteriole vasoconstriction produced by ANG I was significantly attenuated by ACE inhibition , but not by serine protease inhibition .	In control kidneys, afferent arteriole vasoconstriction produced by ANG I was significantly attenuated by ACE inhibition, but not by serine protease inhibition.	7	16	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG I	ANG I	ANG I	15	16	9	11
The renin-angiotensin system plays a major role in the control of blood pressure due to the production of angiotensin II by ACE .	The renin-angiotensin system plays a major role in the control of blood pressure due to the production of angiotensin II by ACE.	3	22	production	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	21	22	18	20
Angiotensin converting enzyme ( ACE ) catalyzes the conversion of angiotensin to angiotensin II , a potent vasoconstrictor , and inactivation of bradykinin , a potent vasodilator .	Angiotensin converting enzyme (ACE) catalyzes the conversion of angiotensin to angiotensin II, a potent vasoconstrictor, and inactivation of bradykinin, a potent vasodilator.	0	20	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Angiotensin converting enzyme	Angiotensin converting enzyme	Angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	0	3	12	14
This is the first study to demonstrate that 20-HETE , a key constrictor eicosanoid in the microcirculation , induces ACE and AT1R expression and increases Angiotensin II levels , suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of RAS that is likely initiated at the level of ACE induction .	This is the first study to demonstrate that 20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and AT1R expression and increases Angiotensin II levels, suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of RAS that is likely initiated at the level of ACE induction.	8	29	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and AT1R expression	ace	Angiotensin II	Angiotensin II	angiotensin ii	19	20	25	27
ACE inhibition prevents formation of angiotensin II , one of the most potent vasoconstrictors .	ACE inhibition prevents formation of angiotensin II, one of the most potent vasoconstrictors.	0	13	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	5	7
Further studies were performed to evaluate whether ACE mediates Ang II synthesis during hypoxia .	Further studies were performed to evaluate whether ACE mediates Ang II synthesis during hypoxia.	7	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	7	8	9	11
However , serum ACE activity also increased suggesting that the potential beneficial effects of higher ACE2 may be offset by ACE acting to increase Ang II and metabolize Ang-( 1-7 ) .	However, serum ACE activity also increased suggesting that the potential beneficial effects of higher ACE2 may be offset by ACE acting to increase Ang II and metabolize Ang-(1-7).	18	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	20	21	24	26
Angiotensin II produced separately by ACE and chymase , participates independently in the development of vascular derangements .	Angiotensin II produced separately by ACE and chymase, participates independently in the development of vascular derangements.	0	7	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Angiotensin II	Angiotensin II	Angiotensin II	5	6	0	2
Additionally , Ang-II synthesis by cardiac fibroblasts , extracellular as well as intracellular , is catalyzed by ACE .	Additionally, Ang-II synthesis by cardiac fibroblasts, extracellular as well as intracellular, is catalyzed by ACE.	2	18	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang-II	Ang-II	Ang-II	17	18	2	3
Therefore , in SSc , not only endothelial dysfunction , but also vascular damage , linked to ACE I/D polymorphism , may significantly contribute to accelerated macrovascular disease , as the ACE D allele , by regulating both the production of angiotensin II and the degradation of bradykinin , contributes to mechanisms involved in the induction and maintenance of vessel wall modification .	Therefore, in SSc, not only endothelial dysfunction, but also vascular damage, linked to ACE I/D polymorphism, may significantly contribute to accelerated macrovascular disease, as the ACE D allele, by regulating both the production of angiotensin II and the degradation of bradykinin, contributes to mechanisms involved in the induction and maintenance of vessel wall modification.	31	50	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	31	32	41	43
23 Angiotensin-II is produced by the action of ACE on angiotensin-I .	23 Angiotensin-II is produced by the action of ACE on angiotensin-I.	0	9	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Angiotensin-II	Angiotensin-II	Angiotensin-II	8	9	1	2
Higher ACE levels , related to the ACE D allele , may promote the production of angiotensin II and the degradation of bradykinin .	Higher ACE levels, related to the ACE D allele, may promote the production of angiotensin II and the degradation of bradykinin.	1	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE levels	ace	angiotensin II	angiotensin II	angiotensin ii	1	2	16	18
An inhibitor of kininase II ( D-3-mercapto-2-methylpropranoyl-L-proline ( S , S ] ( captopril ) reduced the contractile effects of angiotensin I in the three preparations and potentiated the stimulatory or inhibitory effects of bradykinin : captopril did not have effect on the affinities of B2 receptor antagonists and did not modify the effects of angiotensin II.	An inhibitor of kininase II (D-3-mercapto-2-methylpropranoyl-L-proline (S, S] (captopril) reduced the contractile effects of angiotensin I in the three preparations and potentiated the stimulatory or inhibitory effects of bradykinin : captopril did not have effect on the affinities of B2 receptor antagonists and did not modify the effects of angiotensin II.	1	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	kininase II	kininase II	kininase II	angiotensin I	angiotensin I	angiotensin I	3	5	20	22
ACE inhibition can not completely inhibit the production of angiotensin II but ARBs can fully inhibit the effect of angiotensin I on AT 1 and this causes the accumulation of angiotensin II that via AT 2 receptor causes dilation of blood vessels and decreased cell proliferation .	ACE inhibition can not completely inhibit the production of angiotensin II but ARBs can fully inhibit the effect of angiotensin I on AT 1 and this causes the accumulation of angiotensin II that via AT 2 receptor causes dilation of blood vessels and decreased cell proliferation.	0	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	9	11
Arterial stiffness is inversely related to bioavailability of NO ; XREF_BIBR thus , ACE may contribute to arterial stiffness by increasing angiotensin II and degrading bradykinin .	Arterial stiffness is inversely related to bioavailability of NO; XREF_BIBR thus, ACE may contribute to arterial stiffness by increasing angiotensin II and degrading bradykinin.	13	25	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	13	14	21	23
Variants in the ACE gene that increase angiotensin II plasma concentrations can elevate risk of AF , while selective cardiac overexpression of ACEs causes atrial dilation , fibrosis , and increased susceptibility of AF .	Variants in the ACE gene that increase angiotensin II plasma concentrations can elevate risk of AF, while selective cardiac overexpression of ACEs causes atrial dilation, fibrosis, and increased susceptibility of AF.	3	10	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	3	4	7	9
Although acute ACE inhibition decreases plasma Ang II , chronic treatment results in an escape phenomenon in which Ang II levels return to pretreatment levels .	Although acute ACE inhibition decreases plasma Ang II, chronic treatment results in an escape phenomenon in which Ang II levels return to pretreatment levels.	2	8	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	2	3	6	8
The high levels of ACE stimulating angiotensin II conversion [ XREF_BIBR ] can also induce the production of angiotensin II induced transforming growth factor-beta ( TGF-beta ) .	The high levels of ACE stimulating angiotensin II conversion [XREF_BIBR] can also induce the production of angiotensin II induced transforming growth factor-beta (TGF-beta).	4	10	stimulating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	6	8
The vascular effects of angiotensin converting enzyme inhibitors are mediated by the inhibition of the dual action of angiotensin converting enzyme ( ACE ) : production of angiotensin II and degradation of bradykinin .	The vascular effects of angiotensin converting enzyme inhibitors are mediated by the inhibition of the dual action of angiotensin converting enzyme (ACE) : production of angiotensin II and degradation of bradykinin.	16	29	production	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	18	21	27	29
These data show that ANG I effects are mainly mediated by ACE in AA and muscular EA but not in thin EA .	These data show that ANG I effects are mainly mediated by ACE in AA and muscular EA but not in thin EA.	4	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG I	ANG I	ANG I	11	12	4	6
Blockade of ACE activity prevents the formation of the vasoconstrictor and mitogen Ang II and the degradation of the vasodilators bradykinin and Ang-( 1-7 ) , leading to a reduction in blood pressure as well as the myriad of beneficial effects attributed to ACE inhibition .	Blockade of ACE activity prevents the formation of the vasoconstrictor and mitogen Ang II and the degradation of the vasodilators bradykinin and Ang-(1-7), leading to a reduction in blood pressure as well as the myriad of beneficial effects attributed to ACE inhibition.	2	16	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	2	3	12	14
Endothelial angiotensin converting enzyme ( ACE ) proteolyzes Ang I and produces circulating angiotensin II ( Ang II ) .	Endothelial angiotensin converting enzyme (ACE) proteolyzes Ang I and produces circulating angiotensin II (Ang II).	0	17	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	1	4	13	15
Inhibiting ACE prevents the conversion of angiotensin I to angiotensin II , a potent vasoconstrictor .	Inhibiting ACE prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.	0	8	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	1	2	6	8
To define the role of ACE mediated AngII production in experimental atherosclerosis , we initially determined effects of inhibition of this enzyme on lesion formation during infusion of AngI , the direct AngII precursor .	To define the role of ACE mediated AngII production in experimental atherosclerosis, we initially determined effects of inhibition of this enzyme on lesion formation during infusion of AngI, the direct AngII precursor.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	5	6	7	8
17 Therefore , we determined whether ACE inhibition also reduced atherosclerosis in AngII infused mice .	17 Therefore, we determined whether ACE inhibition also reduced atherosclerosis in AngII infused mice.	6	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	6	7	12	13
14 Inhibition of ACE will thus decrease both the formation of angiotensin II and the degradation of bradykinin ( XREF_FIG ) .	14 Inhibition of ACE will thus decrease both the formation of angiotensin II and the degradation of bradykinin (XREF_FIG).	1	13	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	3	4	11	13
Thus , decreased lung ACE activity could possibly contribute to keeping plasma Ang II levels in the normal range .	Thus, decreased lung ACE activity could possibly contribute to keeping plasma Ang II levels in the normal range.	4	14	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	4	5	12	14
This study investigates whether angiotensin converting enzyme ( ACE ) inhibitors can block high glucose induced increase of angiotensin II ( Ang II ) levels in cultured rat mesangial cells .	This study investigates whether angiotensin converting enzyme (ACE) inhibitors can block high glucose induced increase of angiotensin II (Ang II) levels in cultured rat mesangial cells.	4	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	4	7	18	20
Angiotensin II produced by ACE is a vasoconstrictor agent , known by promoting smooth muscle cells proliferation and determining structural cardiac changes that could lead to myocardial necrosis and congestive heart failure [ XREF_BIBR ] .	Angiotensin II produced by ACE is a vasoconstrictor agent, known by promoting smooth muscle cells proliferation and determining structural cardiac changes that could lead to myocardial necrosis and congestive heart failure [XREF_BIBR].	0	8	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Angiotensin II	Angiotensin II	Angiotensin II	4	5	0	2
In fact , ACE promotes the conversion of angiotensin I into the potent vasoconstrictor angiotensin II as well as inactivating the bradykinin a vasodilator [ XREF_BIBR ] .	In fact, ACE promotes the conversion of angiotensin I into the potent vasoconstrictor angiotensin II as well as inactivating the bradykinin a vasodilator [XREF_BIBR].	3	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	3	4	8	10
In contrast , in vivo experiments in mice demonstrated that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors prevents the conversion of Ang I to Ang II , while BK protection requires the inhibition of the two ACE active sites .	In contrast, in vivo experiments in mice demonstrated that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors prevents the conversion of Ang I to Ang II, while BK protection requires the inhibition of the two ACE active sites.	12	31	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	21	22	29	31
Angiotensin converting enzyme ( ACE ) upregulation in the stroma cells of arthritis rheumatoid joints may produce a higher tissue concentration of angiotensin II ( angII ) , which is a vasoconstrictor and mitogen factor that causes local hypoxia and synovial proliferation .	Angiotensin converting enzyme (ACE) upregulation in the stroma cells of arthritis rheumatoid joints may produce a higher tissue concentration of angiotensin II (angII), which is a vasoconstrictor and mitogen factor that causes local hypoxia and synovial proliferation.	4	25	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	22	24
Angiotensin converting enzyme ( ACE ) activated nearly 100 % of ANG I to ANG II in a single pass through the PDA , whereas PCM conversion was estimated to be less than 10 % .	Angiotensin converting enzyme (ACE) activated nearly 100% of ANG I to ANG II in a single pass through the PDA, whereas PCM conversion was estimated to be less than 10%.	2	19	activated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	4	5	14	16
ANG II , produced by ACE , is the main effector molecule in the RAS .	ANG II, produced by ACE, is the main effector molecule in the RAS.	0	11	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	5	6	0	2
These authors concluded that Ang II produced by ACE does not necessarily promote ventricular enlargement or dysfunction , but can cause abnormal cardiac electrical activity .	These authors concluded that Ang II produced by ACE does not necessarily promote ventricular enlargement or dysfunction, but can cause abnormal cardiac electrical activity.	4	9	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	8	9	4	6
ACE mediated Ang II formation from Ang I by normal PMs was higher ( 15 +/- 3 % ) when compared to Ang-( 1-12 ) ( 2 +/- 1 % ) .	ACE mediated Ang II formation from Ang I by normal PMs was higher (15 +/- 3%) when compared to Ang-(1-12) (2 +/- 1%).	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	0	1	2	4
ACE activates angiotensin I and inactivates bradykinin , resulting in decreased tissue perfusion , vascular smooth muscle cell growth XREF_BIBR , and stimulation of plasminogen-activator inhibitor type I XREF_BIBR .	ACE activates angiotensin I and inactivates bradykinin, resulting in decreased tissue perfusion, vascular smooth muscle cell growth XREF_BIBR, and stimulation of plasminogen-activator inhibitor type I XREF_BIBR.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	0	1	2	4
It should be noted that inhibition of angiotensin II production by ACE may be valuable in hypertension and inflammation .	It should be noted that inhibition of angiotensin II production by ACE may be valuable in hypertension and inflammation.	7	12	production	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	11	12	7	9
Angiotensin converting enzyme ( ACE ) , produced primarily in the epithelial cells of the lung , catalyzes the conversion of Ang I to Ang II and attenuation of the enzyme actions by selective inhibitors , such as enalopril , captopril , perindopril , is among the therapeutic modalities commonly used to treat patients with high blood pressure .	Angiotensin converting enzyme (ACE), produced primarily in the epithelial cells of the lung, catalyzes the conversion of Ang I to Ang II and attenuation of the enzyme actions by selective inhibitors, such as enalopril, captopril, perindopril, is among the therapeutic modalities commonly used to treat patients with high blood pressure.	0	26	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Angiotensin converting enzyme	Angiotensin converting enzyme	Angiotensin converting enzyme	Ang II	Ang II	Ang II	0	3	24	26
In addition , glomerulonephritis produced significant effects on plasma angiotensin II concentrations , whereby ACE inhibition no longer lowered plasma angiotensin II levels and in fact produced an increase .	In addition, glomerulonephritis produced significant effects on plasma angiotensin II concentrations, whereby ACE inhibition no longer lowered plasma angiotensin II levels and in fact produced an increase.	14	25	lowered	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	14	15	20	22
It has been demonstrated previously that intrarenal ANG II is augmented by an angiotensin converting enzyme ( ACE ) dependent mechanism in the non ischemic kidney , but the role of ACE independent production of ANG II in the kidney by the enzyme chymase is unknown .	It has been demonstrated previously that intrarenal ANG II is augmented by an angiotensin converting enzyme (ACE) dependent mechanism in the non ischemic kidney, but the role of ACE independent production of ANG II in the kidney by the enzyme chymase is unknown.	6	16	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	ANG II	ANG II	ANG II	13	16	7	9
ACE catalyzes Ang I into Ang II [ XREF_BIBR ] .	ACE catalyzes Ang I into Ang II [XREF_BIBR].	0	4	catalyzes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	0	1	2	4
ACE induces the catalytic conversion of angiotensin I to angiotensin II which represents a crucial step in the regulation of the RAA axis in turn involved in the regulation of blood pressure and serum electrolytes .	ACE induces the catalytic conversion of angiotensin I to angiotensin II which represents a crucial step in the regulation of the RAA axis in turn involved in the regulation of blood pressure and serum electrolytes.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	0	1	6	8
ACE cleaves angiotensin I to produce angiotensin II , a powerful vasoconstrictor that has been identified as a major factor in renal and hypertension .	ACE cleaves angiotensin I to produce angiotensin II, a powerful vasoconstrictor that has been identified as a major factor in renal and hypertension.	0	11	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	6	8
Since ACE catalyzes the conversion of angiotensin I to angiotensin II , and angiotensin II may trigger the inflammatory effect and oxidative stress , the connection between a sympathetic activation and oxidative stress may exist in our experimental groups .	Since ACE catalyzes the conversion of angiotensin I to angiotensin II, and angiotensin II may trigger the inflammatory effect and oxidative stress, the connection between a sympathetic activation and oxidative stress may exist in our experimental groups.	1	11	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	1	2	9	11
Nevertheless , there is evidence to support the concept that in the early phases of organ tissue damage , the RAS is activated , but the ACE pathway producing angiotensin II is not always employed .	Nevertheless, there is evidence to support the concept that in the early phases of organ tissue damage, the RAS is activated, but the ACE pathway producing angiotensin II is not always employed.	26	31	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	26	27	29	31
Angiotensin II is synthesized and modified by proteolysis of angiotensinogen ( AGT ) by angiotensin converting enzyme ( ACE ) .	Angiotensin II is synthesized and modified by proteolysis of angiotensinogen (AGT) by angiotensin converting enzyme (ACE).	0	17	synthesized	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Angiotensin II	Angiotensin II	Angiotensin II	14	17	0	2
As such , both ACE and chymase contribute to produce angiotensin II in the aortic valve .	As such, both ACE and chymase contribute to produce angiotensin II in the aortic valve.	3	15	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	10	12
All together this data suggest the possible involvement of ACE and chymase dependent production of Ang II during I/R induced cardiac injury while the lack of an additive effect of captopril and chymostatin to PPC mediated protection may however suggest the existence of a common downstream effector pathway .	All together this data suggest the possible involvement of ACE and chymase dependent production of Ang II during I/R induced cardiac injury while the lack of an additive effect of captopril and chymostatin to PPC mediated protection may however suggest the existence of a common downstream effector pathway.	9	17	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	9	10	15	17
It is thus possible that developmentally regulated patterns of AT1 receptor expression might offer some level of protection against the potentially detrimental effects of ACE mediated angiotensin II synthesis .	It is thus possible that developmentally regulated patterns of AT1 receptor expression might offer some level of protection against the potentially detrimental effects of ACE mediated angiotensin II synthesis.	22	28	mediated	Positive_early_activation	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	24	25	26	28
Angiotensin converting enzyme ( ACE ) inhibitors produce a profound and consistent inhibition of angiotensin II production , but they exert only a mild and transient antialdosterone effect .	Angiotensin converting enzyme (ACE) inhibitors produce a profound and consistent inhibition of angiotensin II production, but they exert only a mild and transient antialdosterone effect.	4	16	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	14	16
The involvement of ACE dependent and chymase mediated intracellular production of Ang II were tested by infusion of captopril or chymostatin at reperfusion , respectively .	The involvement of ACE dependent and chymase mediated intracellular production of Ang II were tested by infusion of captopril or chymostatin at reperfusion, respectively.	3	13	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	3	4	11	13
These results are consistent with the hypothesis that fetal vascular ACE might contribute angiotensin II to the fetus , whilst syncytial ACE2 might hypothetically have a role in converting angiotensin II to angiotensin 1-7 in maternal blood .	These results are consistent with the hypothesis that fetal vascular ACE might contribute angiotensin II to the fetus, whilst syncytial ACE2 might hypothetically have a role in converting angiotensin II to angiotensin 1-7 in maternal blood.	8	17	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	10	11	13	15
The interpretation of the hormonal changes in the present case may be as follows : ( i ) production of Angiotensin I , the substrate of ACE , is markedly increased to overcome the defective ACE activity , ( ii ) the missense ( p.R259H ) mutant ACE has minimal residual function or other proteolytic enzyme systems are activated due to defective ACE function and ( iii ) a small portion of markedly increased Angiotensin I is converted to Angiotensin II by minimally functioning mutant ACE or via other proteolytic enzyme systems ( XREF_FIG ) .	The interpretation of the hormonal changes in the present case may be as follows : (i) production of Angiotensin I, the substrate of ACE, is markedly increased to overcome the defective ACE activity, (ii) the missense (p.R259H) mutant ACE has minimal residual function or other proteolytic enzyme systems are activated due to defective ACE function and (iii) a small portion of markedly increased Angiotensin I is converted to Angiotensin II by minimally functioning mutant ACE or via other proteolytic enzyme systems (XREF_FIG).	24	76	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Angiotensin I	Angiotensin I	Angiotensin I	26	27	74	76
Thus , under basal circumstances , tissue ACE and , to a lesser degree , the circulating form of ACE combine to produce the final concentration of angiotensin II and other ACE substrates .	Thus, under basal circumstances, tissue ACE and, to a lesser degree, the circulating form of ACE combine to produce the final concentration of angiotensin II and other ACE substrates.	17	32	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	19	20	27	29
Ang II is produced predominantly by the effect of angiotensin converting enzyme ( ACE ) on angiotensin I ( Ang I ) .	Ang II is produced predominantly by the effect of angiotensin converting enzyme (ACE) on angiotensin I (Ang I).	0	12	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Ang II	Ang II	Ang II	9	12	0	2
It prevents the conversion of angiotensin I into angiotensin II mediated by ACE and the inactivation of kinins , resulting in decreased levels of vasoconstrictor peptide angiotensin II and the accumulation of kinins [ XREF_BIBR ] .	It prevents the conversion of angiotensin I into angiotensin II mediated by ACE and the inactivation of kinins, resulting in decreased levels of vasoconstrictor peptide angiotensin II and the accumulation of kinins [XREF_BIBR].	1	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	12	13	8	10
While a robust clinical and experimental literature established the importance of the ACE mediated Ang II production in the regulation of blood pressure and cardiorenal function , the role of this enzyme as a primary loci for Ang II formation from Ang I remains an open question as conversion of Ang I to Ang II in tissues can proceed despite complete ACE inhibition and the effectiveness of these drugs in the prevention of cardiac arrhythmias , and the progression of cardiac dysfunction is not completely certain .	While a robust clinical and experimental literature established the importance of the ACE mediated Ang II production in the regulation of blood pressure and cardiorenal function, the role of this enzyme as a primary loci for Ang II formation from Ang I remains an open question as conversion of Ang I to Ang II in tissues can proceed despite complete ACE inhibition and the effectiveness of these drugs in the prevention of cardiac arrhythmias, and the progression of cardiac dysfunction is not completely certain.	9	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	12	13	14	16
Our results reinforce the hypothesis that chymase is a major serine protease implicated in the ACE independent production of Ang II in human arteries .	Our results reinforce the hypothesis that chymase is a major serine protease implicated in the ACE independent production of Ang II in human arteries.	15	21	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	15	16	19	21
It should be noted , however , that acute ACE inhibition reduces the ANG-II concentration , but prolonged ACEIs treatment leads to ACE up-regulation and increases the ANG-II and ANG-I ratio .	It should be noted, however, that acute ACE inhibition reduces the ANG-II concentration, but prolonged ACEIs treatment leads to ACE up-regulation and increases the ANG-II and ANG-I ratio.	9	14	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG-II	ANG-II	ANG-II	9	10	13	14
Angiotensin-converting-enzyme ( ACE ) inhibitors not only decrease the production of angiotensin II but also decrease the degradation of bradykinin .	Angiotensin-converting-enzyme (ACE) inhibitors not only decrease the production of angiotensin II but also decrease the degradation of bradykinin.	0	13	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiotensin-converting-enzyme	Angiotensin-converting-enzyme	Angiotensin-converting-enzyme	angiotensin II	angiotensin II	angiotensin II	0	1	11	13
ACE promotes the formation of angiotensin II from angiotensin I and inactivates the vasodilator bradykinin ; the net result is vasopressin activity [ XREF_BIBR , XREF_BIBR ] .	ACE promotes the formation of angiotensin II from angiotensin I and inactivates the vasodilator bradykinin; the net result is vasopressin activity [XREF_BIBR, XREF_BIBR].	0	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	5	7
The primary function of ACE in the RAAS is to produce the potent vasoconstrictor angiotensin II from its inactive precursor angiotensin I , thereby increasing blood pressure .	The primary function of ACE in the RAAS is to produce the potent vasoconstrictor angiotensin II from its inactive precursor angiotensin I, thereby increasing blood pressure.	2	16	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	14	16
ACE catalyses the conversion of angiotensin I to angiotensin II , which causes vasoconstriction .	ACE catalyses the conversion of angiotensin I to angiotensin II, which causes vasoconstriction.	0	12	catalyses	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	8	10
For instance , in the heart , Ang II is synthesized locally by cardiac ACE following uptake of renin and angiotensinogen from the circulation .	For instance, in the heart, Ang II is synthesized locally by cardiac ACE following uptake of renin and angiotensinogen from the circulation.	7	16	synthesized	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	14	15	7	9
Angiotensin converting enzyme ( ACE ) inhibitors inhibit both the formation of angiotensin II and the catabolism of bradykinin ( BK ) .	Angiotensin converting enzyme (ACE) inhibitors inhibit both the formation of angiotensin II and the catabolism of bradykinin (BK).	0	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiotensin converting enzyme	Angiotensin converting enzyme	Angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	0	3	12	14
15 Specifically , our group found that local Ang II synthesis by renal ACE is indispensable for the development of experimental hypertension : in mice lacking renal ACE , neither Ang II infusion nor nitric oxide depletion can induce hypertensive disease .	15 Specifically, our group found that local Ang II synthesis by renal ACE is indispensable for the development of experimental hypertension : in mice lacking renal ACE, neither Ang II infusion nor nitric oxide depletion can induce hypertensive disease.	8	14	synthesis	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	13	14	8	10
The inhibition of ACE thus prevents the secretion of angiotensin II , allowing the treatment of hypertension as well as congestive heart failure .	The inhibition of ACE thus prevents the secretion of angiotensin II, allowing the treatment of hypertension as well as congestive heart failure.	1	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	3	4	9	11
Inhibitors of angiotensin converting enzyme block the conversion of angiotensin I to angiotensin II , the active hormone of the renin-angiotensin system .	Inhibitors of angiotensin converting enzyme block the conversion of angiotensin I to angiotensin II, the active hormone of the renin-angiotensin system.	0	11	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin I	angiotensin I	angiotensin I	2	5	9	11
Angiotensin converting enzyme ( ACE ) inhibition by captopril ( 10 micromol/l ) abolished the effect of Ang I and des-Asp-Ang I but had no influence on the effect of the other metabolites .	Angiotensin converting enzyme (ACE) inhibition by captopril (10 micromol/l) abolished the effect of Ang I and des-Asp-Ang I but had no influence on the effect of the other metabolites.	4	19	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	4	5	17	19
In the RAS , ACE produces angiotensin II with vasoconstrictive activity , while in the KKS , ACE inactivates bradykinin with the ability to induce vascular relaxation [ XREF_BIBR XREF_BIBR XREF_BIBR ] .	In the RAS, ACE produces angiotensin II with vasoconstrictive activity, while in the KKS, ACE inactivates bradykinin with the ability to induce vascular relaxation [XREF_BIBR XREF_BIBR XREF_BIBR].	4	10	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	6	8
Angiotensin converting enzyme ( ACE ) inhibition with captopril abolished Ang II release while Ang I levels increased more than 10-fold .	Angiotensin converting enzyme (ACE) inhibition with captopril abolished Ang II release while Ang I levels increased more than 10-fold.	4	12	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	4	5	10	12
In cardiac tissue , however , ACE inhibition has been suggested to inhibit only a fraction of angiotensin II formed , indicating that other enzymatic pathways can be of importance .	In cardiac tissue, however, ACE inhibition has been suggested to inhibit only a fraction of angiotensin II formed, indicating that other enzymatic pathways can be of importance.	6	19	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	6	7	17	19
In response to Ang II infusion , renal ACE deficient mice did not develop hypertension and failed to increase renal Ang II or reduce urinary sodium excretion as seen in wild-type mice [ XREF_BIBR ] .	In response to Ang II infusion, renal ACE deficient mice did not develop hypertension and failed to increase renal Ang II or reduce urinary sodium excretion as seen in wild-type mice [XREF_BIBR].	8	22	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	8	9	20	22
Based on previous studies XREF_BIBR XREF_BIBR and our results , we confirmed that activation of the AT1R and p38 MAPK pathway altered the RAS by up-regulation of the ACE and ACE2 ratio , which increased ACE , Ang II , and AT1R , but decreased ACE2 , Ang ( 1-7 ) and Mas .	Based on previous studies XREF_BIBR XREF_BIBR and our results, we confirmed that activation of the AT1R and p38 MAPK pathway altered the RAS by up-regulation of the ACE and ACE2 ratio, which increased ACE, Ang II, and AT1R, but decreased ACE2, Ang (1-7) and Mas.	28	39	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	28	29	37	39
Breakthrough has been shown in patients on ARBs , 6 indicating that ATII derived from non ACE catalysis of angiotensin 1 ( AT1 ) to ATII is unlikely to play a role in breakthrough .	Breakthrough has been shown in patients on ARBs, 6 indicating that ATII derived from non ACE catalysis of angiotensin 1 (AT1) to ATII is unlikely to play a role in breakthrough.	16	22	catalysis	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin 1	angiotensin 1	angiotensin 1	16	17	19	21
The ACE D allele was correlated with an increase in serum or cardiac ACE , thus increasing the conversion of angiotensin I to the peptide precursor angiotensin II which induces aldosterone production [ XREF_BIBR - XREF_BIBR ] .	The ACE D allele was correlated with an increase in serum or cardiac ACE, thus increasing the conversion of angiotensin I to the peptide precursor angiotensin II which induces aldosterone production [XREF_BIBR - XREF_BIBR].	1	22	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	1	2	20	22
For example , ACE inhibition will prevent stimulation of smooth muscle cell angiotensin II receptors , thereby blocking both contractile and proliferative actions .	For example, ACE inhibition will prevent stimulation of smooth muscle cell angiotensin II receptors, thereby blocking both contractile and proliferative actions.	3	17	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	3	4	12	14
However , insulin added to EC induces a marked activation of ACE and the activated ACE promotes the conversion of Ang I to Ang II and cell growth under conditions of high insulin concentration .	However, insulin added to EC induces a marked activation of ACE and the activated ACE promotes the conversion of Ang I to Ang II and cell growth under conditions of high insulin concentration.	9	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	11	12	20	22
Similarly , both heart ACE- and IF ACE mediated Ang II formation appear to be inhibited by the endogenous inhibitor Ang-( 1-9 ) formed by heart CPA like activity .	Similarly, both heart ACE- and IF ACE mediated Ang II formation appear to be inhibited by the endogenous inhibitor Ang-(1-9) formed by heart CPA like activity.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	7	8	9	11
Oppositely , the in vivo studies in mice revealed that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors reduced the conversion of angiotensin I to angiotensin II ; however , bradykinin protection involves the inhibition of the dual ACE active sites ( Georgiadis et al ., 2003 ) .	Oppositely, the in vivo studies in mice revealed that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors reduced the conversion of angiotensin I to angiotensin II; however, bradykinin protection involves the inhibition of the dual ACE active sites (Georgiadis et al., 2003).	12	31	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	21	22	29	31
Angiotensin converting enzyme ( ACE ) inhibitors block the conversion of angiotensin I to a potent vasoconstrictor , angiotensin II , and can be used to treat renin dependent hypertension .	Angiotensin converting enzyme (ACE) inhibitors block the conversion of angiotensin I to a potent vasoconstrictor, angiotensin II, and can be used to treat renin dependent hypertension.	4	13	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	4	5	11	13
Ang I is cleaved in the lungs and the vascular endothelium by ACE to produce the octapeptide angiotensin II ( Ang II ) .	Ang I is cleaved in the lungs and the vascular endothelium by ACE to produce the octapeptide angiotensin II (Ang II).	3	19	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	12	13	17	19
Ang II is also produced by non ACE enzymes , such as serine protease chymase , which have been found in the heart , vasculature , and other tissues [ XREF_BIBR , XREF_BIBR ] .	Ang II is also produced by non ACE enzymes, such as serine protease chymase, which have been found in the heart, vasculature, and other tissues [XREF_BIBR, XREF_BIBR].	0	8	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	7	8	0	2
Notably , milk proteins also possess bioactive peptides that have ACE-inhibitory properties [ XREF_BIBR ] , and the ACE product angiotensin II enhances adipocyte lipid storage , promotes inflammation via activation of the NFkappaB pathway , and stimulates ROS mediated insulin resistance [ XREF_BIBR ] .	Notably, milk proteins also possess bioactive peptides that have ACE-inhibitory properties [XREF_BIBR], and the ACE product angiotensin II enhances adipocyte lipid storage, promotes inflammation via activation of the NFkappaB pathway, and stimulates ROS mediated insulin resistance [XREF_BIBR].	17	37	product	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	18	19	20	22
Simply put , renin and ACE produce angiotensin II , which affects the brain ( increased thirst ) , the gut ( increased salt absorption ) , the adrenals ( aldosterone production ) , the kidneys ( salt and water retention ) , the heart ( increased cardiac output ) , and vascular smooth muscle ( vasoconstriction ) .	Simply put, renin and ACE produce angiotensin II, which affects the brain (increased thirst), the gut (increased salt absorption), the adrenals (aldosterone production), the kidneys (salt and water retention), the heart (increased cardiac output), and vascular smooth muscle (vasoconstriction).	3	11	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	5	6	7	9
ACE inhibition prevents the formation of angiotensin II , which has been shown to be a potent stimulus of superoxide producing enzymes in atherosclerosis .	ACE inhibition prevents the formation of angiotensin II, which has been shown to be a potent stimulus of superoxide producing enzymes in atherosclerosis.	0	17	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	6	8
Ovariectomy leads to reduced NO bioavailability which accounts for the impaired endothelium dependent relaxations during estrogen deficiency through a cluster of inter connected cellular events in the vascular wall : ( i ) increased expression of ACE , ( ii ) augmented production of angiotensin II leading to over-expression of AT 1 R , ( iii ) greater production of ROS due to increased expression and activity of NAD ( P ) H oxidase , and ( iv ) the increased content of nitrotyrosine , a footprint for increased formation of peroxynitrite from NO and O 2 -.	Ovariectomy leads to reduced NO bioavailability which accounts for the impaired endothelium dependent relaxations during estrogen deficiency through a cluster of inter connected cellular events in the vascular wall : (i) increased expression of ACE, (ii) augmented production of angiotensin II leading to over-expression of AT 1 R, (iii) greater production of ROS due to increased expression and activity of NAD (P) H oxidase, and (iv) the increased content of nitrotyrosine, a footprint for increased formation of peroxynitrite from NO and O 2 -.	34	95	production	Positive_regulation_syntax_7_noun	Positive_activation	Positive_regulation	ACE	expression of ACE	ace	angiotensin II	angiotensin II leading to over-expression of AT 1 R, (iii) greater production of ROS due to increased expression and activity of NAD (P) H oxidase	angiotensin ii	36	37	44	46
It is known that in renin-angiotensin aldosterone system , angiotensin II produced by ACE stimulates aldosterone synthase to secrete aldosterone that regulates water and salt retention XREF_BIBR ; on the other hand , in kallikren-kinin system , ACE proteolyses bradykinin deterring NO production , the net result of this cascade being increased vascular resistance and high BP XREF_BIBR , XREF_BIBR .	It is known that in renin-angiotensin aldosterone system, angiotensin II produced by ACE stimulates aldosterone synthase to secrete aldosterone that regulates water and salt retention XREF_BIBR; on the other hand, in kallikren-kinin system, ACE proteolyses bradykinin deterring NO production, the net result of this cascade being increased vascular resistance and high BP XREF_BIBR, XREF_BIBR.	9	14	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	13	14	9	11
Angiotensin converting enzyme ( ACE )-inhibitory peptide blocks the conversion of angiotensin I to angiotensin II.	Angiotensin converting enzyme (ACE)-inhibitory peptide blocks the conversion of angiotensin I to angiotensin II.	2	13	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	4	5	11	13
ACE can catalyse the conversion of angiotensin I to angiotensin II , and angiotensin II is a potent vasoconstrictor that increases peripheral vascular resistance and consequently elevates arterial pressure [ XREF_BIBR , XREF_BIBR ] .	ACE can catalyse the conversion of angiotensin I to angiotensin II, and angiotensin II is a potent vasoconstrictor that increases peripheral vascular resistance and consequently elevates arterial pressure [XREF_BIBR, XREF_BIBR].	0	11	catalyse	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	9	11
Angiotensin converting enzyme ( ACE ) inhibitors inhibit the synthesis of angiotensin II and subsequently vasodilation of the renal efferent vessels with a subsequent fall in GFR .	Angiotensin converting enzyme (ACE) inhibitors inhibit the synthesis of angiotensin II and subsequently vasodilation of the renal efferent vessels with a subsequent fall in GFR.	4	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	11	13
In addition , Ace was modestly increased only on day 14 , suggesting a possible local increase in angiotensin II production in the healing colonic tissue .	In addition, Ace was modestly increased only on day 14, suggesting a possible local increase in angiotensin II production in the healing colonic tissue.	3	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ace	Ace	Ace	angiotensin II	angiotensin II	angiotensin II	3	4	18	20
The functional linking between both systems is based on the non specificity of the angiotensin converting enzyme ( ACE ) that on the one hand produces angiotensin II and on the other hand degrades kinins such as bradykinin or substance P to inactive metabolites [ XREF_BIBR ] , [ XREF_BIBR ] .	The functional linking between both systems is based on the non specificity of the angiotensin converting enzyme (ACE) that on the one hand produces angiotensin II and on the other hand degrades kinins such as bradykinin or substance P to inactive metabolites [XREF_BIBR], [XREF_BIBR].	16	32	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	18	19	26	28
This review discusses to what degree these findings can be considered as unequivocal evidence for ACE mediated Ang II formation in the kidney as an independent determinant of hypertension .	This review discusses to what degree these findings can be considered as unequivocal evidence for ACE mediated Ang II formation in the kidney as an independent determinant of hypertension.	13	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	15	16	17	19
Endothelial cells are a major source of angiotensin converting enzyme ( ACE ) , which produces angiotensin II and degrades bradykinin , in normal arteries .	Endothelial cells are a major source of angiotensin converting enzyme (ACE), which produces angiotensin II and degrades bradykinin, in normal arteries.	9	18	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	11	12	16	18
The overexpression of ACE and AT1 in dystrophic muscle would likely result in the increased production of Ang II , which may act on these cells in an autocrine manner via AT1 .	The overexpression of ACE and AT1 in dystrophic muscle would likely result in the increased production of Ang II, which may act on these cells in an autocrine manner via AT1.	1	19	production	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	ACE	overexpression of ACE	ace	Ang II	Ang II	ang ii	3	4	17	19
Taken together , it is tempting to speculate that ACE inhibition , which decreases angiotensin II and increases bradykinin , exacerbates collagen loss and thus fails to prevent LV dilatation in a pure volume overload .	Taken together, it is tempting to speculate that ACE inhibition, which decreases angiotensin II and increases bradykinin, exacerbates collagen loss and thus fails to prevent LV dilatation in a pure volume overload.	9	16	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	9	10	14	16
The presence of [ 3H ] captopril binding is consistent with an ACE mediated production of angiotensin II in some brain regions .	The presence of [3H] captopril binding is consistent with an ACE mediated production of angiotensin II in some brain regions.	9	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	12	13	16	18
Angiotensin II , which is produced by angiotensin converting enzyme ( ACE ) , causes hypertension by constricting resistance vessels .	Angiotensin II, which is produced by angiotensin converting enzyme (ACE), causes hypertension by constricting resistance vessels.	0	14	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Angiotensin II	Angiotensin II	Angiotensin II	7	10	0	2
Thus HIF-1alpha inhibited ACE2 expression , and the accumulated ANG II catalyzed by ACE is a key mediator in the downregulation of ACE2 by HIF-1alpha .	Thus HIF-1alpha inhibited ACE2 expression, and the accumulated ANG II catalyzed by ACE is a key mediator in the downregulation of ACE2 by HIF-1alpha.	7	17	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	13	14	9	11
ACE inhibition reduces circulating angiotensin II and thus limits the downstream activation of MAPK signalling pathways , possibly preventing the alteration of the vascular phenotype to preserve normal vascular function .	ACE inhibition reduces circulating angiotensin II and thus limits the downstream activation of MAPK signalling pathways, possibly preventing the alteration of the vascular phenotype to preserve normal vascular function.	0	6	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	4	6
Conversely , inhibition of angiotensin II production by ACE may be beneficial in management of hypertension and inflammation .	Conversely, inhibition of angiotensin II production by ACE may be beneficial in management of hypertension and inflammation.	4	9	production	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	8	9	4	6
Angiotensin converting enzyme ( encoded by the gene DCP1 , also known as ACE ) catalyses the conversion of angiotensin I to the physiologically active peptide angiotensin II , which controls fluid-electrolyte balance and systemic blood pressure .	Angiotensin converting enzyme (encoded by the gene DCP1, also known as ACE) catalyses the conversion of angiotensin I to the physiologically active peptide angiotensin II, which controls fluid-electrolyte balance and systemic blood pressure.	0	28	catalyses	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Angiotensin converting enzyme	Angiotensin converting enzyme	Angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	0	3	26	28
Ang II , produced locally by endothelial ACE , is one of the key substances that affects endothelial function ( or dysfunction ) .	Ang II, produced locally by endothelial ACE, is one of the key substances that affects endothelial function (or dysfunction).	0	8	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	7	8	0	2
Our current study focused on the influence of ACE inhibition , which primarily lowers angiotensin II generation , and consequently aldosterone secretion .	Our current study focused on the influence of ACE inhibition, which primarily lowers angiotensin II generation, and consequently aldosterone secretion.	8	16	lowers	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	8	9	14	16
Campbell et al XREF_BIBR showed that ACE knockout mice display 95 % to 97 % reductions in intrarenal Ang II content and that acute ACE inhibition reduces kidney Ang II content by > 90 % in wild-type controls .	Campbell et al XREF_BIBR showed that ACE knockout mice display 95% to 97% reductions in intrarenal Ang II content and that acute ACE inhibition reduces kidney Ang II content by> 90% in wild-type controls.	24	30	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	24	25	28	30
Even maximally recommended doses of ACE inhibitors do not completely prevent ACE mediated formation of angiotensin II in chronic heart failure , and those patients with increased aldosterone levels during ACE inhibition have impaired exercise capacity .	Even maximally recommended doses of ACE inhibitors do not completely prevent ACE mediated formation of angiotensin II in chronic heart failure, and those patients with increased aldosterone levels during ACE inhibition have impaired exercise capacity.	10	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	11	12	15	17
Angiotensin-I-converting enzyme ( ACE ) catalyzes the conversion of angiotensin I to angiotensin II , a potent vasoconstrictor .	Angiotensin-I-converting enzyme (ACE) catalyzes the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.	0	17	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Angiotensin-I-converting enzyme	Angiotensin-I-converting enzyme	Angiotensin-I-converting enzyme	angiotensin II	angiotensin II	angiotensin II	0	2	12	14
XREF_FIG also demonstrates that in the heart and vasculature , Ang II is produced by both mast cell chymase and through conventional renin-angiotensin pathway conversion of Ang I to Ang II by angiotensin- converting enzyme ( ACE ) XREF_BIBR .	XREF_FIG also demonstrates that in the heart and vasculature, Ang II is produced by both mast cell chymase and through conventional renin-angiotensin pathway conversion of Ang I to Ang II by angiotensin- converting enzyme (ACE) XREF_BIBR.	10	35	produced	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	angiotensin- converting enzyme	angiotensin- converting enzyme	angiotensin- converting enzyme	Ang II	Ang II	Ang II	32	35	10	12
XREF_BIBR - XREF_BIBR Thus , we surmise that , in WT mice , angiotensin II produced by renal tubular ACE opposes the compensatory natriuretic response to a sodium load .	XREF_BIBR - XREF_BIBR Thus, we surmise that, in WT mice, angiotensin II produced by renal tubular ACE opposes the compensatory natriuretic response to a sodium load.	13	20	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	19	20	13	15
These data suggest that ANG II increases ACE and attenuates ACE2 expression in neurons via the ANG II type 1 receptor , p38 MAPK , and ERK1/2 signaling pathways .	These data suggest that ANG II increases ACE and attenuates ACE2 expression in neurons via the ANG II type 1 receptor, p38 MAPK, and ERK1/2 signaling pathways.	2	8	increases	Positive_activation_token_1_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	7	8	4	6
The ACE type 2 ( ACE2 ) increases angiotensin 1-7 production and counterbalances ACE effects .	The ACE type 2 (ACE2) increases angiotensin 1-7 production and counterbalances ACE effects.	1	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin 1-7	angiotensin 1-7	angiotensin 1-7	1	2	8	10
Moreover , the increased expression of ACE in the carotid body could enhance the kinetics of enzymatic convertion of Ang I to Ang II in the carotid body .	Moreover, the increased expression of ACE in the carotid body could enhance the kinetics of enzymatic convertion of Ang I to Ang II in the carotid body.	4	21	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	expression of ACE	ace	Ang I	Ang I	ang i	6	7	19	21
Furthermore , the inhibition of ACE does not prevent the formation of angiotensin II through alternative pathways , and thus the inhibition of RAS is often incomplete , especially under pathologic conditions stimulating RAS .	Furthermore, the inhibition of ACE does not prevent the formation of angiotensin II through alternative pathways, and thus the inhibition of RAS is often incomplete, especially under pathologic conditions stimulating RAS.	3	14	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	5	6	12	14
Our results suggest the presence of other pathways for AngII production not mediated by ACE , or growth factors other than AngII in pressure-overload cardiac hypertrophy .	Our results suggest the presence of other pathways for AngII production not mediated by ACE, or growth factors other than AngII in pressure-overload cardiac hypertrophy.	9	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	14	15	9	10
Circulating ( pro ) renin , angiotensinogen , ANG I and ANG II enter the interstitium via diffusion , and interstitial ANG II generation is mediated , at least in part , by basolaterally located endothelial ACE .	Circulating (pro) renin, angiotensinogen, ANG I and ANG II enter the interstitium via diffusion, and interstitial ANG II generation is mediated, at least in part, by basolaterally located endothelial ACE.	21	37	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	36	37	21	23
Inhibitors of the ACE block the formation of Ang II but also cause a respective increase in the concentrations of Ang I that can subsequently be converted to Ang II by other pathways , such as the chymase system .	Inhibitors of the ACE block the formation of Ang II but also cause a respective increase in the concentrations of Ang I that can subsequently be converted to Ang II by other pathways, such as the chymase system.	0	10	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	3	4	8	10
Conversely , ACE , which activates AGT in the renin-angiotensin pathway , can inactivate bradykinin .	Conversely, ACE, which activates AGT in the renin-angiotensin pathway, can inactivate bradykinin.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AGT	AGT	AGT	2	3	6	7
Renin cleaves angiotensinogen to angiotensin I , which is further catalyzed to angiotensin II by ACE .	Renin cleaves angiotensinogen to angiotensin I, which is further catalyzed to angiotensin II by ACE.	0	16	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensinogen	angiotensinogen	angiotensinogen	15	16	2	3
Angiotensin II ( AngII ) , a major bioactive product of RAS , is produced through two-step cleavage of angiotensinogen by renin and angiotensin converting enzyme ( ACE ) .	Angiotensin II (AngII), a major bioactive product of RAS, is produced through two-step cleavage of angiotensinogen by renin and angiotensin converting enzyme (ACE).	0	26	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Angiotensin II	Angiotensin II	Angiotensin II	23	26	0	2
These findings show for the first time that activation of the RAS results from as little as 1 hour of UUO and that up-regulation of renin mRNA and ACE activity lead to increase Ang II production which down-regulates AT1-R mRNA as early as 6 hours post-UUO .	These findings show for the first time that activation of the RAS results from as little as 1 hour of UUO and that up-regulation of renin mRNA and ACE activity lead to increase Ang II production which down-regulates AT1-R mRNA as early as 6 hours post-UUO.	28	35	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	28	29	33	35
AngII is generated from angiotensin converting enzyme ( ACE ) cleaving angiotensin I , which is produced by renin induced cleavage of angiotensinogen .	AngII is generated from angiotensin converting enzyme (ACE) cleaving angiotensin I, which is produced by renin induced cleavage of angiotensinogen.	6	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensinogen	angiotensinogen	angiotensinogen	8	9	22	23
Also , drugs that stimulate the production of angiotensin II , such as diuretics , calcium channel blockers ( CCBs ) and angiotensin receptor blockers ( ARBs ) , provide additional stroke reduction than drugs that suppress angiotensin II production such as beta-blockers and angiotensin converting enzyme ( ACE ) inhibitors .	Also, drugs that stimulate the production of angiotensin II, such as diuretics, calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs), provide additional stroke reduction than drugs that suppress angiotensin II production such as beta-blockers and angiotensin converting enzyme (ACE) inhibitors.	37	49	production	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	48	49	37	39
In the renin angiotensin aldoterone system , the action of the angiotensin converting enzyme produces angiotensin II from angiotensin I.	In the renin angiotensin aldoterone system, the action of the angiotensin converting enzyme produces angiotensin II from angiotensin I.	8	19	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	11	14	15	17
We hypothesize that granuloma macrophages regulate inflammation by release of angiotensin converting enzyme , which produces angiotensin II , and that angiotensin II in turn modulates monocyte and macrophage activity .	We hypothesize that granuloma macrophages regulate inflammation by release of angiotensin converting enzyme, which produces angiotensin II, and that angiotensin II in turn modulates monocyte and macrophage activity.	8	18	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	10	13	16	18
Angiotensin II ( Ang II ) is a main effector molecule of the RAS and is produced from the substrate angiotensinogen ( AGT ) through sequential enzymatic cleavage by renin and the angiotensin converting enzyme ( ACE ) .	Angiotensin II (Ang II) is a main effector molecule of the RAS and is produced from the substrate angiotensinogen (AGT) through sequential enzymatic cleavage by renin and the angiotensin converting enzyme (ACE).	0	35	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Angiotensin II	Angiotensin II	Angiotensin II	32	35	0	2
ACE catalyzes the conversion of angiotensin I to vasoconstrictor angiotensin II , and also inactivates the antihypertensive vasodilator bradykinin .	ACE catalyzes the conversion of angiotensin I to vasoconstrictor angiotensin II, and also inactivates the antihypertensive vasodilator bradykinin.	0	14	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	9	11
Increased ACE and ACE2 ratios may induce Ang II overactivation and accelerate cardiac remodeling in patients with moderate to severe heart failure .	Increased ACE and ACE2 ratios may induce Ang II overactivation and accelerate cardiac remodeling in patients with moderate to severe heart failure.	0	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	1	2	7	9
Angiotensin-I is catalyzed into octapeptides by angiotensin converting enzyme ( ACE-dipeptidyl carboxypeptidase ) , produced in the lungs and lymphocytes , to form angiotensin II , which is an active peptide .	Angiotensin-I is catalyzed into octapeptides by angiotensin converting enzyme (ACE-dipeptidyl carboxypeptidase), produced in the lungs and lymphocytes, to form angiotensin II, which is an active peptide.	0	9	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Angiotensin-I	Angiotensin-I	Angiotensin-I	6	9	0	1
In summary , these results demonstrate that endogenous ACE mediated Ang II formation plays a significant role in the increases of blood pressure , plasma Ang II , and intrarenal Ang II during Ang II induced hypertension , because pharmacological inhibition of this enzyme with lisinopril significantly ameliorates such changes in Ang II infused mice .	In summary, these results demonstrate that endogenous ACE mediated Ang II formation plays a significant role in the increases of blood pressure, plasma Ang II, and intrarenal Ang II during Ang II induced hypertension, because pharmacological inhibition of this enzyme with lisinopril significantly ameliorates such changes in Ang II infused mice.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	8	9	10	12
ACE inhibition does not block the production of Ang-II completely , which can be present in the bloodstream as a result of the activation of alternative enzymes , such as cathepsin G , CAGE , and chymase , which in normal situations play a minor role in the conversion of Ang-I .	ACE inhibition does not block the production of Ang-II completely, which can be present in the bloodstream as a result of the activation of alternative enzymes, such as cathepsin G, CAGE, and chymase, which in normal situations play a minor role in the conversion of Ang-I.	0	9	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang-II	Ang-II	Ang-II	0	1	8	9
In another study , when endogenous AngII production was reduced by ACE inhibition , AngII infused mice became normotensive [ XREF_BIBR , XREF_BIBR ] .	In another study, when endogenous AngII production was reduced by ACE inhibition, AngII infused mice became normotensive [XREF_BIBR, XREF_BIBR].	6	12	reduced	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	11	12	6	7
In a classical RAS , angiotensin ( Ang ) II produced from Ang I by an angiotensin converting enzyme ( ACE ) is a strong bioactive substance and its activation contributes to the development of the hypertension [ XREF_BIBR ] .	In a classical RAS, angiotensin (Ang) II produced from Ang I by an angiotensin converting enzyme (ACE) is a strong bioactive substance and its activation contributes to the development of the hypertension [XREF_BIBR].	5	21	produced	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	20	21	12	14
Therefore , simultaneous inhibition of renin and ACE activities would prevent the formation of both angiotensin-I and angiotensin-II , which produces a more efficient regulation of RAS when compared to the use of individual enzyme inhibitors alone XREF_BIBR .	Therefore, simultaneous inhibition of renin and ACE activities would prevent the formation of both angiotensin-I and angiotensin-II, which produces a more efficient regulation of RAS when compared to the use of individual enzyme inhibitors alone XREF_BIBR.	5	17	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin-I	angiotensin-I	angiotensin-I	7	8	15	16
Angiotensin II , a circulating protein that regulates vascular smooth muscle tone , is synthesized by ACE and exerts its effects via two receptor types , ATI and II.	Angiotensin II, a circulating protein that regulates vascular smooth muscle tone, is synthesized by ACE and exerts its effects via two receptor types, ATI and II.	0	18	synthesized	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Angiotensin II	Angiotensin II	Angiotensin II	16	17	0	2
The difference may be due to that ACEI can inhibit AngII synthesis catalyzed by ACE in cardiac fibroblasts , but can not inhibit AngII synthesis catalyzed by chymase in cardiac myocytes [ XREF_BIBR , XREF_BIBR ] .	The difference may be due to that ACEI can inhibit AngII synthesis catalyzed by ACE in cardiac fibroblasts, but can not inhibit AngII synthesis catalyzed by chymase in cardiac myocytes [XREF_BIBR, XREF_BIBR].	10	17	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	14	15	10	11
To determine whether inhibition of angiotensin converting enzyme ( ACE ) can prevent angiotensin II production in the coronary circulation induced by percutaneous transluminal coronary angioplasty ( PTCA ) in patients with myocardial ischaemia .	To determine whether inhibition of angiotensin converting enzyme (ACE) can prevent angiotensin II production in the coronary circulation induced by percutaneous transluminal coronary angioplasty (PTCA) in patients with myocardial ischaemia.	3	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	5	8	13	15
Captopril had higher efficacy than that is for 4-fold diluted endogenous human serum inhibitor ( 50-100 kDa fraction ) on recombinant ACE catalyzing angiotensin I to angiotensin II conversion measured by HPLC , while no inhibitory effect was detected in the case of serum proteins below 50 kDa ( < 50 kDa , XREF_FIG ) .	Captopril had higher efficacy than that is for 4-fold diluted endogenous human serum inhibitor (50-100 kDa fraction) on recombinant ACE catalyzing angiotensin I to angiotensin II conversion measured by HPLC, while no inhibitory effect was detected in the case of serum proteins below 50 kDa (< 50 kDa, XREF_FIG).	13	25	catalyzing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	21	22	23	25
Thus , the perception of RAS as a simple cascade leading to the formation of angiotensin II ( Ang II ) by ACE and exerting its action by AT 1 and AT 2 receptors XREF_BIBR has been replaced by concept of complex regulatory network with several cross signalling mechanisms .	Thus, the perception of RAS as a simple cascade leading to the formation of angiotensin II (Ang II) by ACE and exerting its action by AT 1 and AT 2 receptors XREF_BIBR has been replaced by concept of complex regulatory network with several cross signalling mechanisms.	10	23	leading	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	22	23	15	17
An other implication of the high degree of inhibition of serum ACE by HSA is that ACE mediated angiotensin I to angiotensin II conversion can be a rate limiting step in the renin-angiotensin-aldosterone system ( RAAS ) .	An other implication of the high degree of inhibition of serum ACE by HSA is that ACE mediated angiotensin I to angiotensin II conversion can be a rate limiting step in the renin-angiotensin-aldosterone system (RAAS).	16	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	16	17	18	20
These results demonstrate that ACE , rather than chymase , contributes to atherosclerosis through enzymatic converting activity to generate AngII from the cleavage of AngI .	These results demonstrate that ACE, rather than chymase, contributes to atherosclerosis through enzymatic converting activity to generate AngII from the cleavage of AngI.	4	20	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	4	5	19	20
Angiotensin converting enzyme ( ACE ) inhibitors block the conversion of angiotensin I to the active peptide angiotensin II and increase the availability of bradykinin .	Angiotensin converting enzyme (ACE) inhibitors block the conversion of angiotensin I to the active peptide angiotensin II and increase the availability of bradykinin.	4	20	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	4	5	11	13
ACE mediates AngI induced atherosclerosis , and ACE expression in leukocytes modestly contributes to atherosclerotic development in hypercholesterolemic mice .	ACE mediates AngI induced atherosclerosis, and ACE expression in leukocytes modestly contributes to atherosclerotic development in hypercholesterolemic mice.	0	3	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AngI	AngI	AngI	0	1	2	3
Angiotensin II is produced by ACE when rennin , an enzyme , acts on angiotensinogen to produce angiotensin I.	Angiotensin II is produced by ACE when rennin, an enzyme, acts on angiotensinogen to produce angiotensin I.	0	6	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Angiotensin II	Angiotensin II	Angiotensin II	5	6	0	2
Angiotensin converting enzyme ( ACE ) inhibitors as well as angiotensin II receptor antagonists are able to prevent the vasoconstrictive effect of angiotensin II on the efferent renal vessels , which is believed to play an important role in renovascular hypertension .	Angiotensin converting enzyme (ACE) inhibitors as well as angiotensin II receptor antagonists are able to prevent the vasoconstrictive effect of angiotensin II on the efferent renal vessels, which is believed to play an important role in renovascular hypertension.	4	24	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	22	24
In general , VEGF stimulates endothelial cell proliferation and migration , processes which contribute to tumor angiogenesis , while ACE accelerates the de novo production of angiotensin II , which forms a positive feedback loop .	In general, VEGF stimulates endothelial cell proliferation and migration, processes which contribute to tumor angiogenesis, while ACE accelerates the de novo production of angiotensin II, which forms a positive feedback loop.	19	28	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	19	20	26	28
We conclude that angiotensin I and bradykinin-( 1-7 ) are present in the cardiac extravascular compartment of mice lacking vascular ACE , and extravascular ACE produces angiotensin II and metabolizes bradykinin-( 1-7 ) in this compartment .	We conclude that angiotensin I and bradykinin-(1-7) are present in the cardiac extravascular compartment of mice lacking vascular ACE, and extravascular ACE produces angiotensin II and metabolizes bradykinin-(1-7) in this compartment.	10	35	produces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	24	25	26	28
Since ACE produces angiotensin II in the heart , ACE inhibitors ( ACEIs ) may prevent coronary vasoconstriction and increase coronary blood flow .	Since ACE produces angiotensin II in the heart, ACE inhibitors (ACEIs) may prevent coronary vasoconstriction and increase coronary blood flow.	1	7	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	1	2	3	5
This finding contrasts with previous studies reporting increased PRA during Ang II blockade by ACE inhibition or ARB therapy in male and female rats .	This finding contrasts with previous studies reporting increased PRA during Ang II blockade by ACE inhibition or ARB therapy in male and female rats.	7	15	increased	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	14	15	10	12
XREF_BIBR The complementary mechanisms of action of these 2 drug classes also create a strong rationale for combination therapy in high-risk patients because Ang II can be produced by non ACE pathways that are unaffected by ACE inhibitors , and furthermore , ACE inhibitor treatment results in upregulation of the AT 1 receptor .	XREF_BIBR The complementary mechanisms of action of these 2 drug classes also create a strong rationale for combination therapy in high-risk patients because Ang II can be produced by non ACE pathways that are unaffected by ACE inhibitors, and furthermore, ACE inhibitor treatment results in upregulation of the AT 1 receptor.	23	31	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	30	31	23	25
Fosinopril sodium , as an ACE inhibitor , downregulated ACE expression and eventually reduced the tissue AngII concentration but had no effect on ACE2 .	Fosinopril sodium, as an ACE inhibitor, downregulated ACE expression and eventually reduced the tissue AngII concentration but had no effect on ACE2.	0	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	Fosinopril sodium, as an ACE inhibitor, downregulated ACE expression	ace	AngII	AngII	angii	9	10	16	17
An increase in the ACE activity may increase the local production of angiotensin II in the carotid body and thus its agonist action at the AT1 receptor .	An increase in the ACE activity may increase the local production of angiotensin II in the carotid body and thus its agonist action at the AT1 receptor.	4	14	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	12	14
Moreover , ACE inhibition via captopril alone was unable to reduce the generation of Ang II from Ang I in all the groups , perhaps due to the presence of other proteases such as neprilysin ( NEP ) , Cathepsin G , carboxyl peptidases ( CPP ) , rat elastase-2 and other chymases , which are also capable of converting Ang I to Ang II [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Moreover, ACE inhibition via captopril alone was unable to reduce the generation of Ang II from Ang I in all the groups, perhaps due to the presence of other proteases such as neprilysin (NEP), Cathepsin G, carboxyl peptidases (CPP), rat elastase-2 and other chymases, which are also capable of converting Ang I to Ang II [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	19	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	2	3	17	19
Furthermore , the mechanisms for intrarenal Ang II generation differ , and chymase activity is enhanced in clipped kidneys , whereas ACE mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys .	Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.	21	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	21	22	23	25
XREF_BIBR XREF_BIBR - XREF_BIBR The formation of ANG II from angiotensin I is catalysed by ACE .	XREF_BIBR XREF_BIBR - XREF_BIBR The formation of ANG II from angiotensin I is catalysed by ACE.	5	16	catalysed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	15	16	10	12
The Ang II present in the bovine pericardial fluid is partially produced by the action of the ACE existing in that fluid , pericardial parietal mesothelial cells being a source of that ACE .	The Ang II present in the bovine pericardial fluid is partially produced by the action of the ACE existing in that fluid, pericardial parietal mesothelial cells being a source of that ACE.	1	18	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	17	18	1	3
Cardiac chymase mediated Ang II formation from Ang-( 1-12 ) was found to be 10-15-times higher than ACE mediated Ang II formation from Ang I , corroborating our recently reported findings in the male SHR heart .	Cardiac chymase mediated Ang II formation from Ang-(1-12) was found to be 10-15-times higher than ACE mediated Ang II formation from Ang I, corroborating our recently reported findings in the male SHR heart.	15	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	17	18	19	21
XREF_BIBR Since Ang II can be produced by non ACE pathways unaffected by ACE inhibitors and furthermore , ACE inhibitor treatment results in upregulation of the AT 1 -receptor , combination therapy may be necessary to achieve a more complete blockade of the RAS than with ACE inhibitors alone .	XREF_BIBR Since Ang II can be produced by non ACE pathways unaffected by ACE inhibitors and furthermore, ACE inhibitor treatment results in upregulation of the AT 1 -receptor, combination therapy may be necessary to achieve a more complete blockade of the RAS than with ACE inhibitors alone.	2	10	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	9	10	2	4
ACE catalyzes the conversion of angiotensin I to angiotensin II ( Ang ) , and Ang II stimulates release of PAI-1 , the major inhibitor of tissue-type plasminogen activator ( t-PA ) and urokinase in the vasculature .	ACE catalyzes the conversion of angiotensin I to angiotensin II (Ang), and Ang II stimulates release of PAI-1, the major inhibitor of tissue-type plasminogen activator (t-PA) and urokinase in the vasculature.	0	11	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	8	10
This study demonstrates for the first time a very high capacity for conversion of Ang I to Ang II mediated by both ACE and chymase in the ISF space of the dog heart in vivo .	This study demonstrates for the first time a very high capacity for conversion of Ang I to Ang II mediated by both ACE and chymase in the ISF space of the dog heart in vivo.	17	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	22	23	17	19
We found that intracerebroventricular injection of Ang I , the substrate of ACE , induced Ang II like physiological actions , including an increase of fetal BP and plasma AVP concentrations , as well as c-fos expression in the putative cardiovascular nuclei such as the paraventricular nuclei .	We found that intracerebroventricular injection of Ang I, the substrate of ACE, induced Ang II like physiological actions, including an increase of fetal BP and plasma AVP concentrations, as well as c-fos expression in the putative cardiovascular nuclei such as the paraventricular nuclei.	10	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	12	13	15	17
Captopril , an inhibitor of ACE , suppressed the Ang I induced responses significantly [ E25 ] .	Captopril, an inhibitor of ACE, suppressed the Ang I induced responses significantly [E25].	3	11	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	5	6	9	11
Angiotensin II is produced by angiotensin converting enzyme ( ACE ) from angiotensin I.	Angiotensin II is produced by angiotensin converting enzyme (ACE) from angiotensin I.	0	8	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Angiotensin II	Angiotensin II	Angiotensin II	5	8	0	2
XREF_BIBR The active octapeptide angiotensin II , produced from angiotensin I by the angiotensin converting enzyme ( ACE ) , stimulates the production of aldosterone by inducing the rate limiting steroidogenic acute regulatory protein ( StAR ) .	XREF_BIBR The active octapeptide angiotensin II, produced from angiotensin I by the angiotensin converting enzyme (ACE), stimulates the production of aldosterone by inducing the rate limiting steroidogenic acute regulatory protein (StAR).	0	16	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	13	16	4	6
Therefore , inhibition of ACE activity can decrease Ang II production and finally decrease blood pressure .	Therefore, inhibition of ACE activity can decrease Ang II production and finally decrease blood pressure.	4	10	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	4	5	8	10
XREF_BIBR ACE catalyzes the conversion of angiotensin I to angiotensin II , and ACE inhibitors block this step in the RAS .	XREF_BIBR ACE catalyzes the conversion of angiotensin I to angiotensin II, and ACE inhibitors block this step in the RAS.	0	11	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	1	2	9	11
ACE , a luminal transmembrane endothelial glycoprotein , produces Ang II , a vasoconstricting , pro oxidant , pro thrombotic and pro inflammatory peptide [ XREF_BIBR , XREF_BIBR ] .	ACE, a luminal transmembrane endothelial glycoprotein, produces Ang II, a vasoconstricting, pro oxidant, pro thrombotic and pro inflammatory peptide [XREF_BIBR, XREF_BIBR].	0	11	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	0	1	9	11
ACE inhibition , in turn , lowers the synthesis of angiotensin II , which result in attenuation of vasoconstriction and blood pressure .	ACE inhibition, in turn, lowers the synthesis of angiotensin II, which result in attenuation of vasoconstriction and blood pressure.	0	14	lowers	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	10	12
Local ACE inhibition in these ischemic hearts antagonized ANG I but not ANG II effects and enhanced BK effects .	Local ACE inhibition in these ischemic hearts antagonized ANG I but not ANG II effects and enhanced BK effects.	1	14	antagonized	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	1	2	12	14
The conversion of AngI by ACE produces AngII , a BP boosting protein that promotes the vasoconstriction of small arteries and indirectly increases BP .	The conversion of AngI by ACE produces AngII, a BP boosting protein that promotes the vasoconstriction of small arteries and indirectly increases BP.	3	10	produces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	5	6	7	8
The function of ACE is to activate angiotensin II , a vasoconstrictor , as well as inactivating bradykinin , a vasodilator , resulting in increased BP .	The function of ACE is to activate angiotensin II, a vasoconstrictor, as well as inactivating bradykinin, a vasodilator, resulting in increased BP.	1	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	3	4	7	9
Inhibition of angiotensin converting enzyme ( ACE ) attenuates the formation of angiotensin II and enhances the vasodepressor effect of endogenous kinins .	Inhibition of angiotensin converting enzyme (ACE) attenuates the formation of angiotensin II and enhances the vasodepressor effect of endogenous kinins.	0	14	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	2	5	12	14
Normal renal development and renal function in these mouse models indicate that angiotensin II production by ACE from renal origin is thus not necessary to ensure proper organogenesis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Normal renal development and renal function in these mouse models indicate that angiotensin II production by ACE from renal origin is thus not necessary to ensure proper organogenesis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	12	19	production	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	16	17	12	14
Additionally , Ang II synthesis by cardiac fibroblasts , extracellular as well as intracellular , is catalyzed by ACE .	Additionally, Ang II synthesis by cardiac fibroblasts, extracellular as well as intracellular, is catalyzed by ACE.	2	19	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	18	19	2	4
Thus , ACEi ameliorates the increases in blood pressure and intrarenal Ang II content caused by Ang II infusions , indicating that endogenous ACE mediated Ang II formation plays a significant role in the increases of blood pressure and intrarenal Ang II during Ang II induced hypertension .	Thus, ACEi ameliorates the increases in blood pressure and intrarenal Ang II content caused by Ang II infusions, indicating that endogenous ACE mediated Ang II formation plays a significant role in the increases of blood pressure and intrarenal Ang II during Ang II induced hypertension.	22	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	23	24	25	27
By restoring the bradykinin and angiotensin II balance , ACE inhibition reduces the rate of endothelial apoptosis and experimental results suggest that ACE inhibition can also improve the production and mobilization of endothelial progenitor cells from bone marrow .	By restoring the bradykinin and angiotensin II balance, ACE inhibition reduces the rate of endothelial apoptosis and experimental results suggest that ACE inhibition can also improve the production and mobilization of endothelial progenitor cells from bone marrow.	5	12	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	9	10	5	7
Attenuation of Ang II Signaling by ACE Inhibition In Vivo Reduces eNOS Glutathionylation and Improves Endothelium Dependent Vasorelaxation .	Attenuation of Ang II Signaling by ACE Inhibition In Vivo Reduces eNOS Glutathionylation and Improves Endothelium Dependent Vasorelaxation.	2	7	Signaling	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	6	7	2	4
These results suggest that hypertension associated oxidative stress and its consequences may be decreased by either ACE inhibition or AT1 receptor antagonist , emphasizing the role of angiotensin II in hypertensive renal damage .	These results suggest that hypertension associated oxidative stress and its consequences may be decreased by either ACE inhibition or AT1 receptor antagonist, emphasizing the role of angiotensin II in hypertensive renal damage.	13	29	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	16	17	27	29
Interestingly , some data suggests that angiotensin converting enzyme ( ACE ) polymorphisms that increase angiotensin II levels may affect the risk of developing ARDS and mortality .	Interestingly, some data suggests that angiotensin converting enzyme (ACE) polymorphisms that increase angiotensin II levels may affect the risk of developing ARDS and mortality.	10	17	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	10	11	15	17
ACE activates angiotensin-I into a potent vasoconstrictor called angiotensin-II .	ACE activates angiotensin-I into a potent vasoconstrictor called angiotensin-II.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin-I	angiotensin-I	angiotensin-I	0	1	2	3
Background- Angiotensin II , produced by angiotensin-converting-enzyme ( ACE ) , enhances oxidative stress and atherogenesis .	Background- Angiotensin II, produced by angiotensin-converting-enzyme (ACE), enhances oxidative stress and atherogenesis.	0	11	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin-converting-enzyme	angiotensin-converting-enzyme	angiotensin-converting-enzyme	Angiotensin II	Angiotensin II	Angiotensin II	6	7	1	3
Thus , the aortic PDGF beta-receptor , activated by ACE mediated Ang II , seems to be responsible for vascular remodeling in hypertensive rats .	Thus, the aortic PDGF beta-receptor, activated by ACE mediated Ang II, seems to be responsible for vascular remodeling in hypertensive rats.	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	9	10	11	13
Inhibitors of ACE can reduce the impact of Ang II and potentiate the kinins , thus contributing to restore the cardiovascular homeostasis .	Inhibitors of ACE can reduce the impact of Ang II and potentiate the kinins, thus contributing to restore the cardiovascular homeostasis.	0	10	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	2	3	8	10
Regarding protection by the ACE inhibitor , it may be argued that ACE mediated ANG II synthesis in the circulation or by cardiac fibroblasts had a role in cardiac dysfunction .	Regarding protection by the ACE inhibitor, it may be argued that ACE mediated ANG II synthesis in the circulation or by cardiac fibroblasts had a role in cardiac dysfunction.	12	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	12	13	14	16
ANG II , produced by ACE , is necessary for fibrosis in pulmonary and vascular smooth muscle cells .	ANG II, produced by ACE, is necessary for fibrosis in pulmonary and vascular smooth muscle cells.	0	8	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	5	6	0	2
Acute angiotensin converting enzyme inhibition reduced angiotensin I induced vasoconstriction by 78 % in the hearts of normotensive rats and by 82 % in the hypertensive rats ( p < 0.05 ) , whereas in vivo angiotensin converting enzyme inhibition potentiated angiotensin I induced vasoconstriction in the hearts of normotensive and hipertensive rats ( p < 0.05 ) .	Acute angiotensin converting enzyme inhibition reduced angiotensin I induced vasoconstriction by 78% in the hearts of normotensive rats and by 82% in the hypertensive rats (p < 0.05), whereas in vivo angiotensin converting enzyme inhibition potentiated angiotensin I induced vasoconstriction in the hearts of normotensive and hipertensive rats (p < 0.05).	0	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin I	angiotensin I	angiotensin I	1	4	6	8
Angiotensin converting enzyme ( ACE ) , a key component of the RAAS , is essential for production of Angiotensin II ( AngII ) , a hormone with receptors throughout the HPA axis known to help regulate stress response in animals [ XREF_BIBR ] .	Angiotensin converting enzyme (ACE), a key component of the RAAS, is essential for production of Angiotensin II (AngII), a hormone with receptors throughout the HPA axis known to help regulate stress response in animals [XREF_BIBR].	0	23	is essential for production	Positive_activation_copula_1	Positive_activation	Positive_activation	Angiotensin converting enzyme	Angiotensin converting enzyme	Angiotensin converting enzyme	AngII	AngII	AngII	0	3	22	23
The key effector peptide in RAS is angiotensin II ( Ang-II ) , which is produced by cleavage of angiotensin I by the angiotensin converting enzyme ( ACE ) , and exerts its effects through the AT1 receptor .	The key effector peptide in RAS is angiotensin II (Ang-II), which is produced by cleavage of angiotensin I by the angiotensin converting enzyme (ACE), and exerts its effects through the AT1 receptor.	3	31	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	23	26	7	9
ACE promotes the production of angiotensin II ( Ang II ) from angiotensin I ( Ang I ) , which has a direct vasoconstrictor effect on the vessels that increase blood pressure .	ACE promotes the production of angiotensin II (Ang II) from angiotensin I (Ang I), which has a direct vasoconstrictor effect on the vessels that increase blood pressure.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	5	7
ACE inhibition with captopril reduced the staining of Ang II in Muller cells of the diabetic retinas ( XREF_FIG ) .	ACE inhibition with captopril reduced the staining of Ang II in Muller cells of the diabetic retinas (XREF_FIG).	0	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	0	1	8	10
A state of ACE2 deficiency and ACE excess would potentiate Ang II accumulation by further shifting the balance away from Ang II degradation and in favor of Ang II formation ( XREF_FIG ) .	A state of ACE2 deficiency and ACE excess would potentiate Ang II accumulation by further shifting the balance away from Ang II degradation and in favor of Ang II formation (XREF_FIG).	6	12	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	6	7	10	12
We hypothesized that the local renin-angiotensin system is activated under conditions of continuous flow , and our results suggest that Ang II is synthesized not by systemic ACE in serum or local ACE in pulmonary tissue , but by other ACE independent pathways , such as the chymase pathway .	We hypothesized that the local renin-angiotensin system is activated under conditions of continuous flow, and our results suggest that Ang II is synthesized not by systemic ACE in serum or local ACE in pulmonary tissue, but by other ACE independent pathways, such as the chymase pathway.	20	32	synthesized	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	27	28	20	22
In patients with low plasma ACE and high AII concentrations , non ACE mediated production of AII may be operative .	In patients with low plasma ACE and high AII concentrations, non ACE mediated production of AII may be operative.	11	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AII	AII	AII	12	13	16	17
These results indicate that the changes accompanying the alteration to the synthetic phenotype in homogeneous cultures of VSMCs increase expression of proteases such as cathepsin D and ACE , which then produce Ang II , and that these changes increase expression of growth factors that then induce growth of VSMCs .	These results indicate that the changes accompanying the alteration to the synthetic phenotype in homogeneous cultures of VSMCs increase expression of proteases such as cathepsin D and ACE, which then produce Ang II, and that these changes increase expression of growth factors that then induce growth of VSMCs.	21	34	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	27	28	32	34
ACE catalyzes the conversion of angiotensin I to angiotensin II , and the metabolism of other peptides such as bradykinin XREF_BIBR .	ACE catalyzes the conversion of angiotensin I to angiotensin II, and the metabolism of other peptides such as bradykinin XREF_BIBR.	0	13	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	8	10
Thus , inhibiting ACE decreases the production of angiotensin II and therefore decreases blood pressure raising effects .	Thus, inhibiting ACE decreases the production of angiotensin II and therefore decreases blood pressure raising effects.	2	12	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	3	4	8	10
While renin and angiotensin converting enzyme ( ACE ) work coordinately to produce angiotensin II , these enzymes are very different .	While renin and angiotensin converting enzyme (ACE) work coordinately to produce angiotensin II, these enzymes are very different.	5	15	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	7	8	13	15
ACE can increase blood pressure by converting the inactive decapeptide angiotensin-I to the potent vasoconstrictor angiotensin-II ( an octapeptide ) .	ACE can increase blood pressure by converting the inactive decapeptide angiotensin-I to the potent vasoconstrictor angiotensin-II (an octapeptide).	0	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin-I	angiotensin-I	angiotensin-I	0	1	10	11
In the endothelium , ACE catalyzes the conversion of angiotensin I to angiotensin II where the latter is a potent vasoconstrictor .	In the endothelium, ACE catalyzes the conversion of angiotensin I to angiotensin II where the latter is a potent vasoconstrictor.	4	20	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	12	14
The ACE catalyzes the conversion of angiotensin-I to angiotensin-II which causes the muscles surrounding blood vessels to contract , thereby restricting the blood flow and increasing blood pressure .	The ACE catalyzes the conversion of angiotensin-I to angiotensin-II which causes the muscles surrounding blood vessels to contract, thereby restricting the blood flow and increasing blood pressure.	0	10	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin-II	angiotensin-II	angiotensin-II	1	2	8	9
ACE and ACE2 produce angiotensin II ( Ang II ) , a vasopressor that induces cardiovascular remodeling , and Ang 1-7 , a vasodilator with an antiremodeling effect .	ACE and ACE2 produce angiotensin II (Ang II), a vasopressor that induces cardiovascular remodeling, and Ang 1-7, a vasodilator with an antiremodeling effect.	0	19	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	4	6
Furthermore , chymase is the predominate enzyme for ACE independent production of Ang II in vascular tissues of humans , monkeys , dogs , and hamsters [ XREF_BIBR , XREF_BIBR ] .	Furthermore, chymase is the predominate enzyme for ACE independent production of Ang II in vascular tissues of humans, monkeys, dogs, and hamsters [XREF_BIBR, XREF_BIBR].	8	14	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	8	9	12	14
Importantly , it has been demonstrated that chymase is responsible for approximately 70 % to 80 % of Ang II generated in human heart tissue and it is also a major serine protease response for ACE independent production of Ang II in human arteries .	Importantly, it has been demonstrated that chymase is responsible for approximately 70% to 80% of Ang II generated in human heart tissue and it is also a major serine protease response for ACE independent production of Ang II in human arteries.	35	41	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	35	36	39	41
It was found that angiotensin converting enzyme ( ACE ) mRNA and protein expression were increased markedly , ACE activity and angiotensin II content were also elevated significantly in rat heart 1 h after acute pressure overload , and the increases were kept at high level .	It was found that angiotensin converting enzyme (ACE) mRNA and protein expression were increased markedly, ACE activity and angiotensin II content were also elevated significantly in rat heart 1 h after acute pressure overload, and the increases were kept at high level.	6	23	increased	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	8	9	21	23
In addition , captopril ( an ACE inhibitory drug ) was not more effective than HSA in the same assay ( even applied at high concentrations ) , suggesting that either captopril is not a complete antagonist at vascular ACE or alternatively , angiotensin I responses were not exclusively mediated by ACE in this location .	In addition, captopril (an ACE inhibitory drug) was not more effective than HSA in the same assay (even applied at high concentrations), suggesting that either captopril is not a complete antagonist at vascular ACE or alternatively, angiotensin I responses were not exclusively mediated by ACE in this location.	43	54	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	51	52	43	45
Similar effect was reported in the same study with AngI and was attenuated moexiprilat ( an ACE inhibitor ) , suggesting the production of AngII by ACE in bone cells from AngI 4 .	Similar effect was reported in the same study with AngI and was attenuated moexiprilat (an ACE inhibitor), suggesting the production of AngII by ACE in bone cells from AngI 4.	20	29	production	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	26	27	24	25
42 Blocking ACE induced angiotensin II effects may attenuate the rapid decline of lung function .	42 Blocking ACE induced angiotensin II effects may attenuate the rapid decline of lung function.	1	8	induced	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	2	3	4	6
Moreover , HRS treatment suppressed ACE expression and locally reduced angiotensin II generation in left ventricles of SHR .	Moreover, HRS treatment suppressed ACE expression and locally reduced angiotensin II generation in left ventricles of SHR.	2	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	HRS treatment suppressed ACE expression	ace	angiotensin II	angiotensin II	angiotensin ii	5	6	10	12
Moreover , we recently showed that cultured mouse podocytes predominantly metabolize ANG-I to ANG-1-7 and ANG-2-10 via conversion mediated by neprilysin ( NEP ) and aminopeptidase-A ( APA ) respectively , with less detectable ACE mediated ANG-II formation XREF_BIBR .	Moreover, we recently showed that cultured mouse podocytes predominantly metabolize ANG-I to ANG-1-7 and ANG-2-10 via conversion mediated by neprilysin (NEP) and aminopeptidase-A (APA) respectively, with less detectable ACE mediated ANG-II formation XREF_BIBR.	4	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG-II	ANG-II	ANG-II	34	35	36	37
Once Ang I has plateaued , further inhibition of ACE decreases Ang II and therefore BP .	Once Ang I has plateaued, further inhibition of ACE decreases Ang II and therefore BP.	7	13	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	9	10	11	13
Both ACE and chymase contribute to the generation of functionally active angiotensin II in HCAs .	Both ACE and chymase contribute to the generation of functionally active angiotensin II in HCAs.	0	13	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	1	2	11	13
In another study , when endogenous AngII production was reduced by ACE inhibition , AngII infused mice became normotensive XREF_BIBR , XREF_BIBR .	In another study, when endogenous AngII production was reduced by ACE inhibition, AngII infused mice became normotensive XREF_BIBR, XREF_BIBR.	6	12	reduced	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	11	12	6	7
These results indicate that local Ang II production by ACE and chymase is involved in the hyperplasia seen in injured intima , and the difference in the inhibitory action of candesartan and enalapril reflects the extent of contribution of each enzyme .	These results indicate that local Ang II production by ACE and chymase is involved in the hyperplasia seen in injured intima, and the difference in the inhibitory action of candesartan and enalapril reflects the extent of contribution of each enzyme.	5	11	production	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	9	10	5	7
ACE catalyzes the conversion of inactive Angiotensin-I ( Ang-I ) to Angiotensin-II ( Ang-II ) .	ACE catalyzes the conversion of inactive Angiotensin-I (Ang-I) to Angiotensin-II (Ang-II).	0	13	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Angiotensin-II	Angiotensin-II	Angiotensin-II	0	1	11	12
An important action of chymase is the angiotensin converting enzyme ( ACE )-independent synthesis of angiotensin II , which occurs immediately after its release into the interstitial tissues after vascular injury .	An important action of chymase is the angiotensin converting enzyme (ACE)-independent synthesis of angiotensin II, which occurs immediately after its release into the interstitial tissues after vascular injury.	11	17	synthesis	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	11	12	15	17
Thus the conversion of Ang I to Ang II induced by ACE could be more important in the initiation and progression of healthy tissue to gingivitis and/or gingivitis to periodontitis rather than the maintenance of chronic periodontitis .	Thus the conversion of Ang I to Ang II induced by ACE could be more important in the initiation and progression of healthy tissue to gingivitis and/or gingivitis to periodontitis rather than the maintenance of chronic periodontitis.	7	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	11	12	7	9
The ACE degrades bradykinin in the KKS and synthesizes Angiotensin II from Angiotensin I in the RAAS [ XREF_BIBR ] .	The ACE degrades bradykinin in the KKS and synthesizes Angiotensin II from Angiotensin I in the RAAS [XREF_BIBR].	0	13	synthesizes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Angiotensin II	Angiotensin II	Angiotensin II	1	2	9	11
XREF_BIBR XREF_BIBR XREF_BIBR - XREF_BIBR Mean plasma ACE levels in individuals with the DD genotype are higher than those in individuals with the II genotype , and individuals with the ID genotype have intermediate mean plasma ACE levels 31 ; therefore , we could conclude that higher ACE DD genotype might contribute to ACE activity XREF_BIBR , XREF_BIBR and therefore increased the production of angiotensin II , and that the higher ACE DD genotype might increase the risk of HA maladaptation .	XREF_BIBR XREF_BIBR XREF_BIBR - XREF_BIBR Mean plasma ACE levels in individuals with the DD genotype are higher than those in individuals with the II genotype, and individuals with the ID genotype have intermediate mean plasma ACE levels 31; therefore, we could conclude that higher ACE DD genotype might contribute to ACE activity XREF_BIBR, XREF_BIBR and therefore increased the production of angiotensin II, and that the higher ACE DD genotype might increase the risk of HA maladaptation.	46	66	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	47	48	64	66
Inhibition of angiotensin converting enzyme activity by SQ 14 225 ( captopril ) abolished the production of angiotensin III ( ANG III ) and the pressor response to infused ANG I 1/2 .	Inhibition of angiotensin converting enzyme activity by SQ 14 225 (captopril) abolished the production of angiotensin III (ANG III) and the pressor response to infused ANG I 1/2.	0	26	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin III	angiotensin III	angiotensin III	2	5	17	19
Inhibitors of the ACE reduce the production of Ang II and have been proven to be effective blood pressure lowering agents .	Inhibitors of the ACE reduce the production of Ang II and have been proven to be effective blood pressure lowering agents.	0	10	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	3	4	8	10
Local production of Ang II by ACE and chymase is stimulated by stress and ischemic insult [ XREF_BIBR ] and has been implicated in post ischemic cardiac remodeling [ XREF_BIBR ] .	Local production of Ang II by ACE and chymase is stimulated by stress and ischemic insult [XREF_BIBR] and has been implicated in post ischemic cardiac remodeling [XREF_BIBR].	1	8	production	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	6	7	3	5
Studies using animal models further suggested that the inflammation and apoptosis in VILI is , at least in part , due to ACE mediated angiotensin II production ; and that the inhibition of ACE by captopril ( an ACE inhibitor used for the treatment of hypertension and some types of congestive heart failure ) may attenuate VILI through the reduction of inflammatory cytokines , inhibition of apoptosis as well as decrease of PAI-1 , the elevated expression of which was found to be associated with poor clinical outcomes in both pediatric and adult ALI .	Studies using animal models further suggested that the inflammation and apoptosis in VILI is, at least in part, due to ACE mediated angiotensin II production; and that the inhibition of ACE by captopril (an ACE inhibitor used for the treatment of hypertension and some types of congestive heart failure) may attenuate VILI through the reduction of inflammatory cytokines, inhibition of apoptosis as well as decrease of PAI-1, the elevated expression of which was found to be associated with poor clinical outcomes in both pediatric and adult ALI.	20	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	22	23	24	26
ACE can drive formation of vasoconstrictor ANG II but preferentially degrades vasodilator bradykinin .	ACE can drive formation of vasoconstrictor ANG II but preferentially degrades vasodilator bradykinin.	0	10	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	0	1	6	8
For example , ACE inhibition prevents stimulation of smooth muscle cell angiotensin II receptors , thereby blocking both contractile and proliferative actions .	For example, ACE inhibition prevents stimulation of smooth muscle cell angiotensin II receptors, thereby blocking both contractile and proliferative actions.	3	16	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	3	4	11	13
We asked if the local upregulation of ACE resulted in upregulation of Ang II in the mutant aorta .	We asked if the local upregulation of ACE resulted in upregulation of Ang II in the mutant aorta.	5	14	resulted in upregulation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	7	8	12	14
Moreover , as ACE inhibition may reduce Ang-II generation and inhibit conversion of Ang-( 1-7 ) into inactive Ang-( 1-5 ) XREF_BIBR , combining exogenous Ang-( 1-7 ) with ACE inhibitors might provide more cardioprotection than single therapy .	Moreover, as ACE inhibition may reduce Ang-II generation and inhibit conversion of Ang-(1-7) into inactive Ang-(1-5) XREF_BIBR, combining exogenous Ang-(1-7) with ACE inhibitors might provide more cardioprotection than single therapy.	3	8	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang-II	Ang-II	Ang-II	3	4	7	8
These results suggest an important role for the production of angiotensin II by ACE in the progression of atherosclerosis in human coronary arteries .	These results suggest an important role for the production of angiotensin II by ACE in the progression of atherosclerosis in human coronary arteries.	2	16	production	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	13	14	10	12
Presumably , release of angiotensinogen , renin and ACE into the extracellular space in colonic mucosa would increase Ang II to stimulate malignant colonocytes and stromal cells .	Presumably, release of angiotensinogen, renin and ACE into the extracellular space in colonic mucosa would increase Ang II to stimulate malignant colonocytes and stromal cells.	2	20	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	8	9	18	20
They demonstrated that Ang I and BK-( 1-7 ) were present in the extravascular compartment of the heart of mice lacking vascular ACE , where extravascular ACE expression produced Ang II and metabolised BK-( 1-7 ) .	They demonstrated that Ang I and BK-(1-7) were present in the extravascular compartment of the heart of mice lacking vascular ACE, where extravascular ACE expression produced Ang II and metabolised BK-(1-7).	26	31	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE expression	ace	Ang II	Ang II	ang ii	26	27	29	31
Lisinopril inhibits ACE activity , thereby reducing plasma angiotensin II and aldosterone and increasing plasma renin activity .	Lisinopril inhibits ACE activity, thereby reducing plasma angiotensin II and aldosterone and increasing plasma renin activity.	2	10	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	2	3	8	10
This study revealed that inhibition of ACE activity by ACE inhibitors could not prevent increases in angiotensin II production in the coronary circulation induced by PTCA .	This study revealed that inhibition of ACE activity by ACE inhibitors could not prevent increases in angiotensin II production in the coronary circulation induced by PTCA.	6	18	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	6	7	16	18
The classical circulating RAS includes angiotensinogen ( the precursor of angiotensin ) , the enzymes renin and angiotensin converting enzyme ( ACE ) , which produces the bioactive angiotensin II , and its receptors , AT-1 and AT-2 .	The classical circulating RAS includes angiotensinogen (the precursor of angiotensin), the enzymes renin and angiotensin converting enzyme (ACE), which produces the bioactive angiotensin II, and its receptors, AT-1 and AT-2.	17	37	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	17	20	28	30
In this regard , angiotensin II , which is produced from angiotensin I by ACE , is known to promote atherosclerosis in hyperlipidemic mice without changing blood pressure .	In this regard, angiotensin II, which is produced from angiotensin I by ACE, is known to promote atherosclerosis in hyperlipidemic mice without changing blood pressure.	4	19	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	14	15	4	6
These finding suggest that LPS decreases endothelial ACE activity in septic patients ; in turn , this decrease in ACE activity may decrease angiotensin II production and bradykinin catabolism and thus play a role in the pathogenesis of septic shock .	These finding suggest that LPS decreases endothelial ACE activity in septic patients; in turn, this decrease in ACE activity may decrease angiotensin II production and bradykinin catabolism and thus play a role in the pathogenesis of septic shock.	19	25	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	19	20	23	25
ACE , a key zinc metallopeptidase , catalyses the conversion of angiotensin I to angiotensin II , which is the main active product of the RAS XREF_BIBR .	ACE, a key zinc metallopeptidase, catalyses the conversion of angiotensin I to angiotensin II, which is the main active product of the RAS XREF_BIBR.	0	22	catalyses	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	0	1	14	16
Furthermore , captopril , an inhibitor of ACE , significantly suppressed central Ang I increased fetal swallowing and plasma OT .	Furthermore, captopril, an inhibitor of ACE, significantly suppressed central Ang I increased fetal swallowing and plasma OT.	5	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	7	8	12	14
This ACE independent production of Ang II appears to be caused by serine proteases , one of which presumably is chymase .	This ACE independent production of Ang II appears to be caused by serine proteases, one of which presumably is chymase.	1	7	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	1	2	5	7
28 ACE and AngII play a key role in the development of cardiovascular diseases and can be modulated by some components of ACE gene abnormalities and disorders .	28 ACE and AngII play a key role in the development of cardiovascular diseases and can be modulated by some components of ACE gene abnormalities and disorders.	1	24	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	22	23	3	4
XREF_BIBR - XREF_BIBR For example , the knowledge that the angiotensin II peptide -- a ligand for the angiotensin receptor and a potent vasoconstrictor that causes hypertension -- is produced by angiotensin converting enzyme ( ACE ) led to the development of ACE inhibitors as anti-hypertensive drugs .	XREF_BIBR - XREF_BIBR For example, the knowledge that the angiotensin II peptide -- a ligand for the angiotensin receptor and a potent vasoconstrictor that causes hypertension -- is produced by angiotensin converting enzyme (ACE) led to the development of ACE inhibitors as anti-hypertensive drugs.	10	34	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	31	34	10	12
ACE promotes conversion of inactive angiotensin I into the active vasoconstrictor compound angiotensin II via renin-angiotensin and the kinin-kallikrein systems .	ACE promotes conversion of inactive angiotensin I into the active vasoconstrictor compound angiotensin II via renin-angiotensin and the kinin-kallikrein systems.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	0	1	5	7
However , increased ACE and ACE2 ratios may induce angiotensin II over-activation and accelerate cardiac remodeling in patients with moderate to severe heart failure .	However, increased ACE and ACE2 ratios may induce angiotensin II over-activation and accelerate cardiac remodeling in patients with moderate to severe heart failure.	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	3	4	9	11
Because ACE polymorphism modulates local production of angiotensin II , a powerful coronary vasoconstrictor , it may influence left ventricular mass in general as well as in coexisting disease states such as hypertension and cardiomyopathy .	Because ACE polymorphism modulates local production of angiotensin II, a powerful coronary vasoconstrictor, it may influence left ventricular mass in general as well as in coexisting disease states such as hypertension and cardiomyopathy.	1	13	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	1	2	7	9
XREF_BIBR Angiotensin converting enzyme catalyzes the conversion of Angiotensin I to Angiotensin II , but also degrades bradykinin , when the same enzyme is known as kininase II or dipeptidylcaboxypeptidase I. Inhibition of kininase II prevents degradation of bradykinin and other kinins , predisposing to development of angioedema .	XREF_BIBR Angiotensin converting enzyme catalyzes the conversion of Angiotensin I to Angiotensin II, but also degrades bradykinin, when the same enzyme is known as kininase II or dipeptidylcaboxypeptidase I. Inhibition of kininase II prevents degradation of bradykinin and other kinins, predisposing to development of angioedema.	0	16	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Angiotensin converting enzyme	Angiotensin converting enzyme	Angiotensin converting enzyme	Angiotensin II	Angiotensin II	Angiotensin II	1	4	11	13
This second mechanism is probably quite important since only 60 % of angiotensin II is synthesized by ACE dependent pathways in the human renal cortex and neither acute nor chronic ACE inhibition completely eliminates angiotensin II from the plasma .	This second mechanism is probably quite important since only 60% of angiotensin II is synthesized by ACE dependent pathways in the human renal cortex and neither acute nor chronic ACE inhibition completely eliminates angiotensin II from the plasma.	30	38	eliminates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	30	31	34	36
Renal ACE mRNA levels increased in Ang I infused rats compared with those in vehicle infused rats ( 1.9 +/- 0.4 vs. 1.0 +/- 0.1 fold , respectively , P < 0.05 ) .	Renal ACE mRNA levels increased in Ang I infused rats compared with those in vehicle infused rats (1.9 +/- 0.4 vs. 1.0 +/- 0.1 fold, respectively, P < 0.05).	1	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE mRNA levels	ace	Ang I	Ang I	ang i	1	2	6	8
Ang II , AT ( 1 ) receptor , and ACE are expressed at strategic sites of human atherosclerotic coronary arteries , suggesting that Ang II is produced primarily by ACE within coronary plaques .	Ang II, AT (1) receptor, and ACE are expressed at strategic sites of human atherosclerotic coronary arteries, suggesting that Ang II is produced primarily by ACE within coronary plaques.	24	31	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	30	31	24	26
PA12 may act as a circulating substrate for cardiac chymase mediated AngII production , in contrast to ACE mediated AngII production from AngI .	PA12 may act as a circulating substrate for cardiac chymase mediated AngII production, in contrast to ACE mediated AngII production from AngI.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	17	18	19	20
Equivalence of ACEI can be established by their effect of inhibiting ACE , which in turn leads to reduced ang II and to elevation of PRA via the known negative feedback mechanism .	Equivalence of ACEI can be established by their effect of inhibiting ACE, which in turn leads to reduced ang II and to elevation of PRA via the known negative feedback mechanism.	8	23	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	ang II	ang II	ang II	11	12	19	21
The augmented AGT production and secretion increase AGT delivered to the distal nephron segments which can interact with renin and ACE produced by principal cells of CNT and CD cells to form more Ang II and stimulate distal transport activity .	The augmented AGT production and secretion increase AGT delivered to the distal nephron segments which can interact with renin and ACE produced by principal cells of CNT and CD cells to form more Ang II and stimulate distal transport activity.	16	35	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	20	21	33	35
Elevated vascular angiotensin converting enzyme activity appears to increase local production of angiotensin II , which results in vasoconstriction by acting directly and indirectly through adrenergic nerves on vascular smooth muscle .	Elevated vascular angiotensin converting enzyme activity appears to increase local production of angiotensin II, which results in vasoconstriction by acting directly and indirectly through adrenergic nerves on vascular smooth muscle.	0	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	2	5	12	14
Systemic inhibition of angiotensin converting enzyme with enalapril ( 25 mg/kg , per os for 14 days ) produces a large decrease in ANG II receptors localized exclusively in the subfornical organ ( SFO ) of the SHR , and no alterations in ANG II receptors in the normotensive WKY rats .	Systemic inhibition of angiotensin converting enzyme with enalapril (25 mg/kg, per os for 14 days) produces a large decrease in ANG II receptors localized exclusively in the subfornical organ (SFO) of the SHR, and no alterations in ANG II receptors in the normotensive WKY rats.	1	45	produces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	ANG II	ANG II	ANG II	3	6	43	45
ACE inhibition prevents the conversion of angiotensin I to angiotensin II , a potent vasoconstrictor .	ACE inhibition prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.	0	8	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	0	1	6	8
Angiotensin converting enzyme 2 ( ACE2 ) is a homologue of the angiotensin converting enzyme ( ACE ) that catalyzes Ang II into Ang-( 1-7 ) .	Angiotensin converting enzyme 2 (ACE2) is a homologue of the angiotensin converting enzyme (ACE) that catalyzes Ang II into Ang-(1-7).	14	22	catalyzes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	16	17	20	22
MEKi resulted in immediate activation of STAT3 , while STAT3i resulted in TACE induced , AREG dependent activation of EGFR and ERK .	MEKi resulted in immediate activation of STAT3, while STAT3i resulted in TACE induced, AREG dependent activation of EGFR and ERK.	12	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	12	13	19	20
We first explored in A549 cells in vitro the effect of PS on the level of EGFR phosphorylation and the expression of ADAM10 and ADAM17 , known to induce EGFR activation through ligand cleavage , ( XREF_FIG ) .	We first explored in A549 cells in vitro the effect of PS on the level of EGFR phosphorylation and the expression of ADAM10 and ADAM17, known to induce EGFR activation through ligand cleavage, (XREF_FIG).	20	30	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	expression of ADAM10 and ADAM17	adam17	EGFR	EGFR	egfr	24	25	29	30
In differentiated primary bronchial epithelial cells ( HBEC-ALI ) , inhibitors of EGFR and of ADAM17 completely abolished ADAM17 substrate shedding as well as EGFR dependent CXCL8 mRNA induction [ XREF_BIBR ] , illustrating the strong interrelationship between the key elements of the EGFR and ADAM17 axis ( XREF_FIG ) .	In differentiated primary bronchial epithelial cells (HBEC-ALI), inhibitors of EGFR and of ADAM17 completely abolished ADAM17 substrate shedding as well as EGFR dependent CXCL8 mRNA induction [XREF_BIBR], illustrating the strong interrelationship between the key elements of the EGFR and ADAM17 axis (XREF_FIG).	10	30	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	15	16	24	25
3.4 Loss of ADAM17 Greatly Inhibits EGFR Activation and Mucus Production in Colonic Epithelia .	3.4 Loss of ADAM17 Greatly Inhibits EGFR Activation and Mucus Production in Colonic Epithelia.	1	7	Inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ADAM17	Loss of ADAM17	adam17	EGFR	EGFR	egfr	3	4	6	7
Put together , the studies by Wiesen and Sternlicht support a model where Areg is shed from epithelial cells by ADAM17 , which activates EGFR on stromal cells .	Put together, the studies by Wiesen and Sternlicht support a model where Areg is shed from epithelial cells by ADAM17, which activates EGFR on stromal cells.	15	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	20	21	24	25
Further , in IB3 cells , TAPI-1 and TACE siRNA knockdown suppressed exaggerated EGFR-P and IL-8 production markedly , whereas in C38 cells , the effects of TACE inhibition on these responses were minimal , indicating that TACE dependent EGFR activation contributed to the exuberant IL-8 response in IB3 cells .	Further, in IB3 cells, TAPI-1 and TACE siRNA knockdown suppressed exaggerated EGFR-P and IL-8 production markedly, whereas in C38 cells, the effects of TACE inhibition on these responses were minimal, indicating that TACE dependent EGFR activation contributed to the exuberant IL-8 response in IB3 cells.	8	15	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR-P	EGFR-P	EGFR-P	8	9	13	14
Moreover , we observed that treatment of neurons with Ang-II resulted in up-regulation of ADAM17 , consistent with previous reports showing that EGF receptor transactivation is mediated by Ang-II stimulation of ADAM17 .	Moreover, we observed that treatment of neurons with Ang-II resulted in up-regulation of ADAM17, consistent with previous reports showing that EGF receptor transactivation is mediated by Ang-II stimulation of ADAM17.	22	32	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGF receptor	EGF receptor	EGF receptor	31	32	22	24
EGFR transactivation required ligand binding to EGF receptors and was mediated by ADAM17 .	EGFR transactivation required ligand binding to EGF receptors and was mediated by ADAM17.	0	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	12	13	0	1
ADAM17 was also shown to activate EGFR via TGFA cleavage in cancers [ XREF_BIBR ] .	ADAM17 was also shown to activate EGFR via TGFA cleavage in cancers [XREF_BIBR].	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	0	1	6	7
Previous investigation has demonstrated that ADAM17 activates a variety of epidermal growth factor receptor ( EGFR ) ligands by shearing , thereby promoting tumour cell proliferation , invasion and metastasis .	Previous investigation has demonstrated that ADAM17 activates a variety of epidermal growth factor receptor (EGFR) ligands by shearing, thereby promoting tumour cell proliferation, invasion and metastasis.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	5	6	10	14
Possibly , the need for prompt ADAM17 mediated EGFR activation is central in tissues of high turnover , such as the intestinal epithelium .	Possibly, the need for prompt ADAM17 mediated EGFR activation is central in tissues of high turnover, such as the intestinal epithelium.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	6	7	8	9
In particular , ADAM17 released amphiregulin promotes proliferation and motility of head and neck squamous cell carcinoma , and amphiregulin and/or HB-EGF activated by ADAM17 stimulated EGFR and consequent activation of MAPK/ERK1/2 and prosurvival AKT signaling in squamous cell carcinoma or lung cancer .	In particular, ADAM17 released amphiregulin promotes proliferation and motility of head and neck squamous cell carcinoma, and amphiregulin and/or HB-EGF activated by ADAM17 stimulated EGFR and consequent activation of MAPK/ERK1/2 and prosurvival AKT signaling in squamous cell carcinoma or lung cancer.	22	29	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	24	25	26	27
Importantly , ADAM17 mediated EGFR activation is essential for gut regeneration , and Adam17 and Egfr deficient mice are more susceptible to colitis induced by oral administration of the sulfated polysaccharide dextran sodium sulfate ( DSS ) [ XREF_BIBR - XREF_BIBR ] .	Importantly, ADAM17 mediated EGFR activation is essential for gut regeneration, and Adam17 and Egfr deficient mice are more susceptible to colitis induced by oral administration of the sulfated polysaccharide dextran sodium sulfate (DSS) [XREF_BIBR - XREF_BIBR].	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	2	3	4	5
In NCI-H292 cells , TAPI-1 , a metalloprotease inhibitor with relative selectivity for TACE , and TACE siRNA knockdown prevented EGFR activation and IL-8 production induced by CFTR-172 completely .	In NCI-H292 cells, TAPI-1, a metalloprotease inhibitor with relative selectivity for TACE, and TACE siRNA knockdown prevented EGFR activation and IL-8 production induced by CFTR-172 completely.	16	21	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	16	17	20	21
In vascular smooth muscle cells , a metalloproteinase ADAM17 mediates epidermal growth factor receptor ( EGFR ) transactivation , which may be responsible for cardiovascular remodeling but not hypertension induced by AngII .	In vascular smooth muscle cells, a metalloproteinase ADAM17 mediates epidermal growth factor receptor (EGFR) transactivation, which may be responsible for cardiovascular remodeling but not hypertension induced by AngII.	6	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	8	9	10	14
Given that ADAM17 enhances cell invasion and the degree of malignancy by activating EGFR in a variety of tumor cells , we propose that ADAM17 may have the same role as an oncogene in glioma , however , the underlying mechanism remains to be investigated .	Given that ADAM17 enhances cell invasion and the degree of malignancy by activating EGFR in a variety of tumor cells, we propose that ADAM17 may have the same role as an oncogene in glioma, however, the underlying mechanism remains to be investigated.	2	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	2	3	13	14
The suppression of AngII induced EGFR activation and vascular hypertrophy in ADAM17 deficient mice is in line with our past in vitro observations that genetic ADAM17 inhibition or silencing prevents EGFR transactivation and subsequent hypertrophic responses in cultured VSMCs XREF_BIBR , XREF_BIBR .	The suppression of AngII induced EGFR activation and vascular hypertrophy in ADAM17 deficient mice is in line with our past in vitro observations that genetic ADAM17 inhibition or silencing prevents EGFR transactivation and subsequent hypertrophic responses in cultured VSMCs XREF_BIBR, XREF_BIBR.	25	31	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	25	26	30	31
Through the secretion of epidermal growth factor receptor ( EGFR ) ligands , ADAM17 can activate the EGFR and is involved in various downstream signalling pathways .	Through the secretion of epidermal growth factor receptor (EGFR) ligands, ADAM17 can activate the EGFR and is involved in various downstream signalling pathways.	13	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	13	14	17	18
ADAM17 has been shown to shed ligands of EGFR , such as amphiregulin and TNFalpha , and subsequently activate EGFR , thereby improving the proliferation and migration of lung cancer cells .	ADAM17 has been shown to shed ligands of EGFR, such as amphiregulin and TNFalpha, and subsequently activate EGFR, thereby improving the proliferation and migration of lung cancer cells.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	0	1	19	20
Thus proper mammary morphogenesis requires the ADAM17 mediated release of AREG from ductal epithelial cells , the subsequent activation of EGFR on stromal cells , and EGFR dependent stromal responses that in return elicit a new set of epithelial responses , all culminating in the formation of a fully functional ductal tree .	Thus proper mammary morphogenesis requires the ADAM17 mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree.	5	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	6	7	20	21
The metalloprotease , ADAM17 activates EGFR by releasing pro EGFR ligands .	The metalloprotease, ADAM17 activates EGFR by releasing pro EGFR ligands.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	3	4	5	6
We hypothesized that the failure of intestinal epithelial cells to proliferate was caused by the fact that ADAM17 ex/ex mice could not cleave and thereby systemically activate ligands of the EGF-R .	We hypothesized that the failure of intestinal epithelial cells to proliferate was caused by the fact that ADAM17 ex/ex mice could not cleave and thereby systemically activate ligands of the EGF-R.	17	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGF-R	EGF-R	EGF-R	17	18	30	31
Thus , ADAM17 induces shedding of the EGF receptor ligand amphiregulin that can induce expression of MMP2 .	Thus, ADAM17 induces shedding of the EGF receptor ligand amphiregulin that can induce expression of MMP2.	2	17	induces	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ADAM17	ADAM17	adam17	EGF receptor	EGF receptor ligand amphiregulin that can induce expression of MMP2	egf receptor	2	3	7	9
These studies demonstrate that lung epithelial cells secrete AMCase via an EGFR dependent pathway that is activated by ADAM17 and mediates its effects via Ras .	These studies demonstrate that lung epithelial cells secrete AMCase via an EGFR dependent pathway that is activated by ADAM17 and mediates its effects via Ras.	11	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	18	19	11	12
A growing number of studies reported that ADAM17 induces EGFR transactivation in different types of cells such as vascular smooth muscle cell [ XREF_BIBR ] , cardiac cell [ XREF_BIBR ] , hepatic stellate cell [ XREF_BIBR ] , and endothelial cell [ XREF_BIBR ] , and the same effect was also observed in our results as well .	A growing number of studies reported that ADAM17 induces EGFR transactivation in different types of cells such as vascular smooth muscle cell [XREF_BIBR], cardiac cell [XREF_BIBR], hepatic stellate cell [XREF_BIBR], and endothelial cell [XREF_BIBR], and the same effect was also observed in our results as well.	7	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	7	8	9	10
However , blockade of TACE inhibits not only TNF-alpha secretion but also EGFR signaling .	However, blockade of TACE inhibits not only TNF-alpha secretion but also EGFR signaling.	2	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	4	5	12	13
Direct activation of TACE mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor dependent cell proliferation .	Direct activation of TACE mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor dependent cell proliferation.	1	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGF receptor	EGF receptor	EGF receptor	3	4	12	14
ADAM17 mediates EGFR transactivation induced by CXCL12 in colon cancer cells .	ADAM17 mediates EGFR transactivation induced by CXCL12 in colon cancer cells.	0	3	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	0	1	2	3
We therefore assume that the increased Erk MAPK activity , observed in many carcinomas , increases the TACE mediated release of TGF-alpha ligands and , consequently , the EGFR activation .	We therefore assume that the increased Erk MAPK activity, observed in many carcinomas, increases the TACE mediated release of TGF-alpha ligands and, consequently, the EGFR activation.	16	29	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	17	18	28	29
For instance , ADAM17 enhances migration and invasion of breast cancer and glioblastoma stem cells by promoting EGFR signaling through shedding of several EGFR ligands [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] and PI3K and AKT activation , for example , shown for TGF-alpha shedding in triple negative breast cancer cell invasion [ XREF_BIBR ] and EGFR activation in hypoxia induced glioma cell invasion [ XREF_BIBR ] .	For instance, ADAM17 enhances migration and invasion of breast cancer and glioblastoma stem cells by promoting EGFR signaling through shedding of several EGFR ligands [XREF_BIBR, XREF_BIBR, XREF_BIBR] and PI3K and AKT activation, for example, shown for TGF-alpha shedding in triple negative breast cancer cell invasion [XREF_BIBR] and EGFR activation in hypoxia induced glioma cell invasion [XREF_BIBR].	3	18	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	3	4	17	18
Thus , inhibition of ADAM-17 might therefore be expected to decrease EGFR homodimeric signalling , as well as signalling from the EGFR-HER2 and EGFR-HER3 complexes .	Thus, inhibition of ADAM-17 might therefore be expected to decrease EGFR homodimeric signalling, as well as signalling from the EGFR-HER2 and EGFR-HER3 complexes.	2	13	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM-17	ADAM-17	ADAM-17	EGFR	EGFR	EGFR	4	5	11	12
The phenotype is ascribed to result from disturbance of cell differentiation and tissue development , which may be caused by failure of ADAM17 to activate EGFR .	The phenotype is ascribed to result from disturbance of cell differentiation and tissue development, which may be caused by failure of ADAM17 to activate EGFR.	20	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	22	23	25	26
The present study aimed to investigate whether ADAM17 induced EGFR transactivation is involved in microglial cell survival following spinal cord injury ( SCI ) .	The present study aimed to investigate whether ADAM17 induced EGFR transactivation is involved in microglial cell survival following spinal cord injury (SCI).	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	7	8	9	10
Indeed , consistent with their observations , we found that ADAM17 activation of EGFR was required for robust KRAS activity in acinar cells .	Indeed, consistent with their observations, we found that ADAM17 activation of EGFR was required for robust KRAS activity in acinar cells.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	10	11	13	14
As shown in XREF_FIG , in contrast to WT mice , milk duct development was reduced in ADAM17 ex/ex mice at 12 wk ( XREF_FIG , right ) , indicating that AR induced milk duct formation required ADAM17 mediated cleavage of this EGF-R ligand .	As shown in XREF_FIG, in contrast to WT mice, milk duct development was reduced in ADAM17 ex/ex mice at 12 wk (XREF_FIG, right), indicating that AR induced milk duct formation required ADAM17 mediated cleavage of this EGF-R ligand.	36	43	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGF-R	EGF-R	EGF-R	37	38	42	43
In the AOM model , colonocyte ADAM17 deletion reduced EGFR signals and colonic tumor development ( p < 0.05 ) .	In the AOM model, colonocyte ADAM17 deletion reduced EGFR signals and colonic tumor development (p < 0.05).	6	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	6	7	9	10
Infection of wt ADAM-17 , but not the catalytically-inactive E406A mutant ADAM-17 restored EGFR activation ( XREF_FIG ) and reduced apoptosis induced by H. pylori ( XREF_FIG ) , indicating a requirement for ADAM-17 in the H. pylori induced EGFR activation dependent cell survival phenotype .	Infection of wt ADAM-17, but not the catalytically-inactive E406A mutant ADAM-17 restored EGFR activation (XREF_FIG) and reduced apoptosis induced by H. pylori (XREF_FIG), indicating a requirement for ADAM-17 in the H. pylori induced EGFR activation dependent cell survival phenotype.	0	14	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM-17	ADAM-17	ADAM-17	EGFR	EGFR	EGFR	3	4	13	14
In addition , estrogen is a potent inducer of amphiregulin , and G-protein-coupled receptors can stimulate ADAM17 mediated EGFR transactivation in culture .	In addition, estrogen is a potent inducer of amphiregulin, and G-protein-coupled receptors can stimulate ADAM17 mediated EGFR transactivation in culture.	16	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	16	17	18	19
Src kinase acts upstream of the ADAM17 mediated EGFR transactivation and mediates collagen IV synthesis .	Src kinase acts upstream of the ADAM17 mediated EGFR transactivation and mediates collagen IV synthesis.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	6	7	8	9
In this regard , as in the case of INCB3619 studies , deletion of colonocyte ADAM17 did not significantly reduce pEGFR in colonic tumors , but did decrease pErbB2 , pERK , and Hes1 , suggesting contributions from other ADAM17 sensitive pathways such as Notch1 .	In this regard, as in the case of INCB3619 studies, deletion of colonocyte ADAM17 did not significantly reduce pEGFR in colonic tumors, but did decrease pErbB2, pERK, and Hes1, suggesting contributions from other ADAM17 sensitive pathways such as Notch1.	12	23	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	pEGFR	pEGFR	pEGFR	15	16	20	21
Because PKC induced association of cellular-Sarcoma ( c-Src ) and TACE and ADAM17 is required for TACE and ADAM17 enzyme activation in some cancer cells , we hypothesized that PKC and c-Src impact TACE and ADAM17 mediated activation of EGFR signaling pathway in porcine granulosa and cumulus cells .	Because PKC induced association of cellular-Sarcoma (c-Src) and TACE and ADAM17 is required for TACE and ADAM17 enzyme activation in some cancer cells, we hypothesized that PKC and c-Src impact TACE and ADAM17 mediated activation of EGFR signaling pathway in porcine granulosa and cumulus cells.	35	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	35	36	39	40
The signal seems to include a feed forward mechanism involving vascular ADAM17 induction , which enhances EGFR ligand production and subsequent EGFR activation and vascular remodeling .	The signal seems to include a feed forward mechanism involving vascular ADAM17 induction, which enhances EGFR ligand production and subsequent EGFR activation and vascular remodeling.	11	22	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	11	12	21	22
Additionally , elevated EGFR signalling caused by excess ADAM17 activity is associated with cancer progression XREF_BIBR .	Additionally, elevated EGFR signalling caused by excess ADAM17 activity is associated with cancer progression XREF_BIBR.	3	9	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	8	9	3	4
Activation of TACE by p38 MAPK in breast carcinoma cells leads to a release of TGF-alpha ligands , resulting in increased EGF receptor activation and proliferation .	Activation of TACE by p38 MAPK in breast carcinoma cells leads to a release of TGF-alpha ligands, resulting in increased EGF receptor activation and proliferation.	0	23	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGF receptor	EGF receptor	EGF receptor	2	3	21	23
ADAM17 activates many ERBB ligands which keeps ERBB pathways activated [ XREF_BIBR ] .	ADAM17 activates many ERBB ligands which keeps ERBB pathways activated [XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	ERBB	ERBB	ERBB	0	1	3	4
The adverse effects of renal TACE driven TGFalpha activation of the EGFR could also compromise graft survival .	The adverse effects of renal TACE driven TGFalpha activation of the EGFR could also compromise graft survival.	2	12	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	5	6	11	12
In the present study , we demonstrate for the first time that phosphorylation of TACE at serine/threonine residues by tobacco smoke induces amphiregulin release and EGFR activation .	In the present study, we demonstrate for the first time that phosphorylation of TACE at serine/threonine residues by tobacco smoke induces amphiregulin release and EGFR activation.	12	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	phosphorylation of TACE	tace	EGFR	EGFR	egfr	14	15	25	26
Kornfeld et al reported that ADAM17 could activate EGFR by releasing amphiregulin , thereby enhancing the proliferation and invasion of head and neck squamous carcinoma cells .	Kornfeld et al reported that ADAM17 could activate EGFR by releasing amphiregulin, thereby enhancing the proliferation and invasion of head and neck squamous carcinoma cells.	5	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	5	6	8	9
ADAM17 stimulates EGFR and AKT , suggesting transfected hADAM17 had a functionally appropriate effect .	ADAM17 stimulates EGFR and AKT, suggesting transfected hADAM17 had a functionally appropriate effect.	0	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	0	1	2	3
We evaluated the role of TNF converting enzyme ( TACE ) , a metalloprotease disintegrin that proteolytically processes plasma membrane anchored EGFR ligand precursors into their mature active forms , in wound induced EGFR activation and epithelial restitution .	We evaluated the role of TNF converting enzyme (TACE), a metalloprotease disintegrin that proteolytically processes plasma membrane anchored EGFR ligand precursors into their mature active forms, in wound induced EGFR activation and epithelial restitution.	7	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	9	10	33	34
The up-regulation of EGFR by ADAM17 stems from the critical ability of this metalloprotease to cleave multiple EGFR ligands , such as EGF itself , TGFalpha ; epiregulin ; heparin binding EGF like growth factor ( HB-EGF ) , and neuregulins beta1 and beta2 .	The up-regulation of EGFR by ADAM17 stems from the critical ability of this metalloprotease to cleave multiple EGFR ligands, such as EGF itself, TGFalpha; epiregulin; heparin binding EGF like growth factor (HB-EGF), and neuregulins beta1 and beta2.	1	6	up-regulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	5	6	3	4
Next , using the TgNotch3 R169C model , we provided pharmacological evidence that , in the setting of CADASIL , attenuated ADAM17 and HB-EGF-dependent activation of ErbB1 and ErbB4 underlies deficits in evoked CBF responses and cerebral arterial tone .	Next, using the TgNotch3 R169C model, we provided pharmacological evidence that, in the setting of CADASIL, attenuated ADAM17 and HB-EGF-dependent activation of ErbB1 and ErbB4 underlies deficits in evoked CBF responses and cerebral arterial tone.	21	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	ErbB1	ErbB1	ErbB1	21	22	26	27
Kornfeld et al reported that ADAM17 can activate the EGFR through the release of regulatory proteins in two ways to thereby enhance the proliferation and invasion of head and neck squamous cell carcinoma .	Kornfeld et al reported that ADAM17 can activate the EGFR through the release of regulatory proteins in two ways to thereby enhance the proliferation and invasion of head and neck squamous cell carcinoma.	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	5	6	9	10
By up-regulating the ligands of EGFR , ADAM17 can promote glioma cells malignant phenotype by increased proliferation , invasion , and angiogenesis .	By up-regulating the ligands of EGFR, ADAM17 can promote glioma cells malignant phenotype by increased proliferation, invasion, and angiogenesis.	3	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	7	8	5	6
TACE mediated EGFR transactivation promotes EMT mediated cancer progression in breast epithelial cells .	TACE mediated EGFR transactivation promotes EMT mediated cancer progression in breast epithelial cells.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	0	1	2	3
An important upstream regulator of EGFR phosphorylation is ADAM17 , which activates EGFR through a ligand cleavage mechanism [ XREF_BIBR ] .	An important upstream regulator of EGFR phosphorylation is ADAM17, which activates EGFR through a ligand cleavage mechanism [XREF_BIBR].	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	8	9	12	13
In conclusion , our data show that the effect of PACS-2 on ADAM17 mediated EGFR activation has negligible impact on DSS induced colitis and the Apc Min model of cancer .	In conclusion, our data show that the effect of PACS-2 on ADAM17 mediated EGFR activation has negligible impact on DSS induced colitis and the Apc Min model of cancer.	10	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	12	13	14	15
Whether PACS-1 exerts similar regulatory effects on ADAM17 mediated EGFR activation as PACS-2 is a present unknown .	Whether PACS-1 exerts similar regulatory effects on ADAM17 mediated EGFR activation as PACS-2 is a present unknown.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	7	8	9	10
Injury induced ADAM17 pathway upregulation causes sustained EGFR activation in WT mice , while this effect of injury is impaired in ADAM17ex/ex mice .	Injury induced ADAM17 pathway upregulation causes sustained EGFR activation in WT mice, while this effect of injury is impaired in ADAM17ex/ex mice.	2	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	2	3	7	8
The data thus far are consistent with a model in which TGFalpha expression is upregulated in basal like and triple negative breast cancers , and is liberated by TACE or a TACE like protease to activate the EGFR pathway leading to increased migration , proliferation and invasion .	The data thus far are consistent with a model in which TGFalpha expression is upregulated in basal like and triple negative breast cancers, and is liberated by TACE or a TACE like protease to activate the EGFR pathway leading to increased migration, proliferation and invasion.	26	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	28	29	37	38
ADAM17 induced EGFR transactivation is considered a major contributor in Ang-II-induced vascular remodeling .	ADAM17 induced EGFR transactivation is considered a major contributor in Ang-II-induced vascular remodeling.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	0	1	2	3
ADAM17 dependent shedding of EGFR ligands such as AREG results in activation of EGFR through an autocrine feedback loop , which modulates basal EGFR activity ( DeWitt etal .	ADAM17 dependent shedding of EGFR ligands such as AREG results in activation of EGFR through an autocrine feedback loop, which modulates basal EGFR activity (DeWitt etal.	0	14	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	0	1	13	14
We conclude that activation of both P2Y6 receptors and ADAM17 mediates the low-dose gamma-radiation-induced activation of EGFR , as evaluated in terms of focus formation , in A549 cells .	We conclude that activation of both P2Y6 receptors and ADAM17 mediates the low-dose gamma-radiation-induced activation of EGFR, as evaluated in terms of focus formation, in A549 cells.	3	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	9	10	16	17
However , other reports show that ADAM17 lacking its cytoplasmic domain can still trigger stimulus evoked shedding and EGFR transactivation , a finding seemingly at odds with any role for phosphorylation in ADAM17 activation .	However, other reports show that ADAM17 lacking its cytoplasmic domain can still trigger stimulus evoked shedding and EGFR transactivation, a finding seemingly at odds with any role for phosphorylation in ADAM17 activation.	6	19	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	6	7	18	19
TACE activates the EGFR through GEF-H1 .	TACE activates the EGFR through GEF-H1.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	0	1	3	4
High expression of ADAM-17 may further increase release of epidermal growth factor receptor ( EGFR ) ligands including EGF , androgen receptor ( AR ) , heparin binding ( HB )-EGF , transforming growth factor ( TGF-alpha ) and epiregulin ( EPR ) , that result in the over-activation of EGFR which , in turn , plays a significant role in cleaving the S2 site in the Notch signal pathway .	High expression of ADAM-17 may further increase release of epidermal growth factor receptor (EGFR) ligands including EGF, androgen receptor (AR), heparin binding (HB)-EGF, transforming growth factor (TGF-alpha) and epiregulin (EPR), that result in the over-activation of EGFR which, in turn, plays a significant role in cleaving the S2 site in the Notch signal pathway.	1	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM-17	expression of ADAM-17	adam-17	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	3	4	9	13
Therefore , it is likely that ADAM17 mediates EGFR transactivation in response to arterial injury through multiple EGFR ligands rather than through one single ligand .	Therefore, it is likely that ADAM17 mediates EGFR transactivation in response to arterial injury through multiple EGFR ligands rather than through one single ligand.	6	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	6	7	8	9
ADAM17 promotes EGFR and AKT signaling activity .	ADAM17 promotes EGFR and AKT signaling activity.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	0	1	2	3
Activation of ADAM-17 ( also known as TACE ) by gastric releasing peptide ( GRP ) is a potent activating stimulus to increase amphiregulin levels and activate EGFR in SCCHN [ XREF_BIBR ] .	Activation of ADAM-17 (also known as TACE) by gastric releasing peptide (GRP) is a potent activating stimulus to increase amphiregulin levels and activate EGFR in SCCHN [XREF_BIBR].	0	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM-17	ADAM-17	ADAM-17	EGFR	EGFR	EGFR	2	3	27	28
These results indicated that ADAM17 promoted microglial cell survival predominantly by activating the EGFR signalling pathway .	These results indicated that ADAM17 promoted microglial cell survival predominantly by activating the EGFR signalling pathway.	4	15	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	4	5	13	14
In human tongue epithelial carcinoma cells ( SCC-9 ) squamous carcinoma cell line ADAM17 mediates also amphiregulin shedding and EGFR transactivation by LPA [ XREF_BIBR ] and in human urinary bludder epithelial cells ( TccSup ) ADAM15 mediates LPA induced shedding of TGF-beta [ XREF_BIBR ] .	In human tongue epithelial carcinoma cells (SCC-9) squamous carcinoma cell line ADAM17 mediates also amphiregulin shedding and EGFR transactivation by LPA [XREF_BIBR] and in human urinary bludder epithelial cells (TccSup) ADAM15 mediates LPA induced shedding of TGF-beta [XREF_BIBR].	12	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	13	14	19	20
Consistent with a recent report XREF_BIBR , our results demonstrate the critical importance of Src in ADAM17 activation by either ATP or EGF , the latter finding indicating that EGFR dependent activation of ADAM17 may serve to augment or prolong EGFR activation in a feed-forward mechanism .	Consistent with a recent report XREF_BIBR, our results demonstrate the critical importance of Src in ADAM17 activation by either ATP or EGF, the latter finding indicating that EGFR dependent activation of ADAM17 may serve to augment or prolong EGFR activation in a feed-forward mechanism.	31	41	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	33	34	40	41
The TNF-alpha-elicited EGFR , ERK , and RhoA stimulation were mediated by the TNF-alpha convertase enzyme ( TACE ) that can release EGFR ligands .	The TNF-alpha-elicited EGFR, ERK, and RhoA stimulation were mediated by the TNF-alpha convertase enzyme (TACE) that can release EGFR ligands.	0	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha convertase	TNF-alpha convertase	TNF-alpha convertase	EGFR	EGFR	EGFR	13	15	2	3
Also , EGFR activity and ADAM17 expression are enhanced in the neointima after angioplasty , and dominant negative ADAM17 gene-transfer prevents the EGFR activation and neointimal hyperplasia 8 .	Also, EGFR activity and ADAM17 expression are enhanced in the neointima after angioplasty, and dominant negative ADAM17 gene-transfer prevents the EGFR activation and neointimal hyperplasia 8.	18	23	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	18	19	22	23
We have shown that ADAM17 mediated EGFR transactivation via heparin binding EGF like growth factor ( HB-EGF ) shedding is required for extracellular signal regulated kinase ( ERK ) activation but not for intracellular Ca 2+ elevation or Rho kinase activation XREF_BIBR - XREF_BIBR .	We have shown that ADAM17 mediated EGFR transactivation via heparin binding EGF like growth factor (HB-EGF) shedding is required for extracellular signal regulated kinase (ERK) activation but not for intracellular Ca 2+ elevation or Rho kinase activation XREF_BIBR - XREF_BIBR.	4	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	4	5	6	7
These data indicate that HB-EGF released from HSC3 cells by TACE stimulates EGFR in an autocrine manner , which in turn activates invasion activity via MMP-9 upregulation .	These data indicate that HB-EGF released from HSC3 cells by TACE stimulates EGFR in an autocrine manner, which in turn activates invasion activity via MMP-9 upregulation.	5	13	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	10	11	12	13
The present study indicated that the EGFR signalling pathway was activated by ADAM17 .	The present study indicated that the EGFR signalling pathway was activated by ADAM17.	6	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	12	13	6	7
Knockdown of ADAM17 blocks UVA induced EGFR activation and cell cycle progression , which demonstrates that ADAM17 mediates the EGFR and cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation [ XREF_BIBR ] .	Knockdown of ADAM17 blocks UVA induced EGFR activation and cell cycle progression, which demonstrates that ADAM17 mediates the EGFR and cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation [XREF_BIBR].	16	27	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	16	17	19	20
ADAM17 induces activation of the EGFR through ligand cleavage .	ADAM17 induces activation of the EGFR through ligand cleavage.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	0	1	5	6
This finding would indicate that under basal conditions , AT2 receptor activation by angiotensin II contributed to the baroreflex regulation of RSNA and HR .	This finding would indicate that under basal conditions, AT2 receptor activation by angiotensin II contributed to the baroreflex regulation of RSNA and HR.	9	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	13	15	9	10
In contrast , Plzf is found to activate GATA4 transcription by binding to angiotensin II activated AT2 receptor [ XREF_BIBR , XREF_BIBR ] .	In contrast, Plzf is found to activate GATA4 transcription by binding to angiotensin II activated AT2 receptor [XREF_BIBR, XREF_BIBR].	11	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	13	15	16	17
Finally , AngII alone or together with IGF-1 , but not IGF-1 alone , increased the attachment of AT2 mRNA to polysomal fractions .	Finally, AngII alone or together with IGF-1, but not IGF-1 alone, increased the attachment of AT2 mRNA to polysomal fractions.	2	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AngII	AngII	AngII	AT2	AT2	AT2	2	3	18	19
Ang II mediated as well as selective AT2 receptor stimulation mediated apoptosis was associated with the activation of caspase-3 , a central downstream effector of the caspase cascade executing the cell death program .	Ang II mediated as well as selective AT2 receptor stimulation mediated apoptosis was associated with the activation of caspase-3, a central downstream effector of the caspase cascade executing the cell death program.	0	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	0	2	7	8
AngII signals through two types of angiotensin receptors , AT1 and AT2 5 .	AngII signals through two types of angiotensin receptors, AT1 and AT2 5.	0	12	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AngII	AngII	AngII	AT2	AT2	AT2	0	1	11	12
ANG II activation of AT1 and AT2 receptors also results in a cascade of events that include the phosphorylation and activation of various kinases including Akt , p38 MAPK , AMPK , cAMP dependent protein kinase ( PKA ) , MAPK kinase , and other MAPKs , all of which lead to increased phosphorylation of NOS and increased NOS catalytic activity .	ANG II activation of AT1 and AT2 receptors also results in a cascade of events that include the phosphorylation and activation of various kinases including Akt, p38 MAPK, AMPK, cAMP dependent protein kinase (PKA), MAPK kinase, and other MAPKs, all of which lead to increased phosphorylation of NOS and increased NOS catalytic activity.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ANG II	ANG II	ANG II	AT2	AT2	AT2	0	2	6	7
Renin-angiotensin system signaling is subsequently mediated by angiotensin II type 1 and 2 receptors ( AGTR1 and AGTR2 ) , which are locally expressed in all important sites of emerging angio-hematopoiesis including the YS , liver , kidney , embryonic aorta , and retinal and choroid regions .	Renin-angiotensin system signaling is subsequently mediated by angiotensin II type 1 and 2 receptors (AGTR1 and AGTR2), which are locally expressed in all important sites of emerging angio-hematopoiesis including the YS, liver, kidney, embryonic aorta, and retinal and choroid regions.	5	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AGTR2	AGTR2	AGTR2	7	9	17	18
These pleiotropic effects might be related to angiotensin II mediated activation of the AT2 receptor .	These pleiotropic effects might be related to angiotensin II mediated activation of the AT2 receptor.	7	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	7	9	13	14
These results indicate that Ang II can up-regulate the AT1 and AT2 receptors in cardiomyocytes but that ghrelin inhibits the up-regulation of AT1 receptor but does not affect AT2 receptor expression .	These results indicate that Ang II can up-regulate the AT1 and AT2 receptors in cardiomyocytes but that ghrelin inhibits the up-regulation of AT1 receptor but does not affect AT2 receptor expression.	4	12	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	4	6	11	12
This increase in circulating angiotensin II might theoretically lead to an excessive stimulation of the AT2 receptor subtype , but since the function of this receptor is not known it is impossible to evaluate the implications of this reactive rise .	This increase in circulating angiotensin II might theoretically lead to an excessive stimulation of the AT2 receptor subtype, but since the function of this receptor is not known it is impossible to evaluate the implications of this reactive rise.	3	17	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	4	6	15	16
Indeed , angiotensin II may promote enterocyte apoptosis through binding to AT2 , which is expressed in the duodenum and jejunum [ XREF_BIBR , XREF_BIBR ] .	Indeed, angiotensin II may promote enterocyte apoptosis through binding to AT2, which is expressed in the duodenum and jejunum [XREF_BIBR, XREF_BIBR].	2	16	promote	Positive_regulation_syntax_7_verb	Positive_activation	Positive_regulation	angiotensin II	angiotensin II	angiotensin ii	AT2	AT2, which is expressed	at2	2	4	11	12
Therefore , we can not exclude the possibility that AT2 receptors in the PVN are activated by AngII that is released from presynaptic axon terminals and possibly independent of astrocytes .	Therefore, we can not exclude the possibility that AT2 receptors in the PVN are activated by AngII that is released from presynaptic axon terminals and possibly independent of astrocytes.	9	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AngII	AngII	AngII	AT2	AT2	AT2	17	18	9	10
In addition , Ang-II induced hypertrophy associated markers and pre-treatment with the AT1 antagonist , but not AT2 anatagonist , markedly attenuated ACM hypertrophy ( XREF_SUPPLEMENTARY ) .	In addition, Ang-II induced hypertrophy associated markers and pre-treatment with the AT1 antagonist, but not AT2 anatagonist, markedly attenuated ACM hypertrophy (XREF_SUPPLEMENTARY).	3	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-II	Ang-II	Ang-II	AT2	AT2	AT2	3	4	17	18
While the AT2 receptor is naturally stimulated by the Ang II , the inherent Mas receptor agonist is Ang ( 1-7 ) which is formed by cleavage of Ang II by ACE2 [ XREF_BIBR ] .	While the AT2 receptor is naturally stimulated by the Ang II, the inherent Mas receptor agonist is Ang (1-7) which is formed by cleavage of Ang II by ACE2 [XREF_BIBR].	2	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	9	11	2	3
In addition , aliskiren attenuates valsartan induced increases in angiotensin II levels , thus preventing AT2 receptor mediated cardioprotection by valsartan .	In addition, aliskiren attenuates valsartan induced increases in angiotensin II levels, thus preventing AT2 receptor mediated cardioprotection by valsartan.	3	16	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	angiotensin II	aliskiren attenuates valsartan induced increases in angiotensin II levels	angiotensin ii	AT2	AT2	at2	9	11	15	16
AT2 receptor activation by endogenous AngII slightly decreased L ( p ) over that of the control ( p = 0.02 ) .	AT2 receptor activation by endogenous AngII slightly decreased L (p) over that of the control (p = 0.02).	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AngII	AngII	AngII	AT2	AT2	AT2	5	6	0	1
Ang II also activates AT2 receptors , which frequently generate responses that oppose the consequences of AT1-receptor stimulation .	Ang II also activates AT2 receptors, which frequently generate responses that oppose the consequences of AT1-receptor stimulation.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	0	2	4	5
Therefore , it seems that , when AT1 receptors are inactivated , AngII activates AT2 receptors in MNCs , eliciting overactivity of NOS , increased NO production , and inhibition of VP and OT secretion .	Therefore, it seems that, when AT1 receptors are inactivated, AngII activates AT2 receptors in MNCs, eliciting overactivity of NOS, increased NO production, and inhibition of VP and OT secretion.	12	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AngII	AngII	AngII	AT2	AT2	AT2	12	13	14	15
The hypothesis that endogenous angiotensin II ( Ang II ) chronically supports baroreflex control of lumbar sympathetic nerve activity ( LSNA ) and heart rate ( HR ) via AT1 but not AT2 receptors was tested in conscious , normotensive rats .	The hypothesis that endogenous angiotensin II (Ang II) chronically supports baroreflex control of lumbar sympathetic nerve activity (LSNA) and heart rate (HR) via AT1 but not AT2 receptors was tested in conscious, normotensive rats.	3	33	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	4	6	32	33
In cultured VSMCs from wild-type mice , Ang II increased NF-kappaB activity that was partially inhibited by AT1 ( losartan ) and AT2 ( PD123319 ) antagonists .	In cultured VSMCs from wild-type mice, Ang II increased NF-kappaB activity that was partially inhibited by AT1 (losartan) and AT2 (PD123319) antagonists.	7	26	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	7	9	22	23
Ang II activates both AT1 and AT2 receptors .	Ang II activates both AT1 and AT2 receptors.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	0	2	6	7
Hence , the feedback induced increase in plasma levels of angiotensin II levels may , per se , activate vascular AT2 receptors that are available and generate bradykinin .	Hence, the feedback induced increase in plasma levels of angiotensin II levels may, per se, activate vascular AT2 receptors that are available and generate bradykinin.	10	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II levels	angiotensin ii	AT2	AT2	at2	10	12	20	21
As a result , increased Ang II targets AT2 receptors .	As a result, increased Ang II targets AT2 receptors.	5	9	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	5	7	8	9
Ang II mediates its complex physiological effects by binding to two subtypes of receptors , AGTR1 and Angiotensin II receptor type II ( AGTR2 ) , that belong to a superfamily of G-protein-coupled receptors ( GPCRs ) .	Ang II mediates its complex physiological effects by binding to two subtypes of receptors, AGTR1 and Angiotensin II receptor type II (AGTR2), that belong to a superfamily of G-protein-coupled receptors (GPCRs).	0	27	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AGTR2	AGTR2	AGTR2	0	2	23	24
Lastly , to further elucidate the mechanism by which ghrelin inhibits Ang II action , the expression of the AT1 and AT2 receptors was evaluated ; the results showed that Ang II up-regulates the AT1 and AT2 receptors in cardiomyocytes , whereas ghrelin inhibits AT1 receptor up-regulation but does not affect AT2 receptor expression .	Lastly, to further elucidate the mechanism by which ghrelin inhibits Ang II action, the expression of the AT1 and AT2 receptors was evaluated; the results showed that Ang II up-regulates the AT1 and AT2 receptors in cardiomyocytes, whereas ghrelin inhibits AT1 receptor up-regulation but does not affect AT2 receptor expression.	30	37	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	30	32	36	37
These results imply that in the heart Ang II activates AT 2 to transmit a hypertrophic signal .	These results imply that in the heart Ang II activates AT 2 to transmit a hypertrophic signal.	7	12	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT 2	AT 2	AT 2	7	9	10	12
In cultured human and rat DRG neurons , AT2 activation by ANGII enhanced the capsaicin induced , TRPV1 mediated calcium influx and associated increase in cAMP , and this was prevented by the AT2 antagonist EM401A 7 .	In cultured human and rat DRG neurons, AT2 activation by ANGII enhanced the capsaicin induced, TRPV1 mediated calcium influx and associated increase in cAMP, and this was prevented by the AT2 antagonist EM401A 7.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ANGII	ANGII	ANGII	AT2	AT2	AT2	11	12	8	9
Ang II mediates its function primarily through angiotensin II receptor types 1 ( AT1 ) and 2 ( AT2 ) .	Ang II mediates its function primarily through angiotensin II receptor types 1 (AT1) and 2 (AT2).	0	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	0	2	18	19
The increase in Ang II after ARB treatment allows stimulation of the AT2 receptor .	The increase in Ang II after ARB treatment allows stimulation of the AT2 receptor.	3	13	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	3	5	12	13
Ang II infusion resulted in an up-regulation of AT2 in tubular cells and de novo AT2 expression in glomeruli and vessels , associated with the presence of inflammatory cells .	Ang II infusion resulted in an up-regulation of AT2 in tubular cells and de novo AT2 expression in glomeruli and vessels, associated with the presence of inflammatory cells.	0	9	up-regulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	0	2	8	9
The addition of 1 microM ANGII did not further enhanced the AT2 mediated growth inhibition in HEK 293 cells that stably expressed Myc-AT2 receptor variant ( XREF_FIG ) .	The addition of 1 microM ANGII did not further enhanced the AT2 mediated growth inhibition in HEK 293 cells that stably expressed Myc-AT2 receptor variant (XREF_FIG).	1	26	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGII	ANGII	ANGII	AT2	AT2	AT2	5	6	11	12
Although angiotensin II can also induce vasorelaxation by stimulating AT2 receptors and upregulating eNOS and inducible NO synthase ( iNOS ) expression , vasoconstriction is predominant in most circumstances as it reduces eNOS derived NO by promoting eNOS uncoupling through monocyte dependent S glutathionylation 143 .	Although angiotensin II can also induce vasorelaxation by stimulating AT2 receptors and upregulating eNOS and inducible NO synthase (iNOS) expression, vasoconstriction is predominant in most circumstances as it reduces eNOS derived NO by promoting eNOS uncoupling through monocyte dependent S glutathionylation 143.	1	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	1	3	9	10
Second , Ang II elicited an AT2 receptor mediated increase in I ( K ) followed by an AT1 receptor mediated decrease in I ( K ) .	Second, Ang II elicited an AT2 receptor mediated increase in I (K) followed by an AT1 receptor mediated decrease in I (K).	2	9	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	2	4	6	7
However , these effects are counterbalanced by Ang II mediated AT2 signaling .	However, these effects are counterbalanced by Ang II mediated AT2 signaling.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	7	9	10	11
Upon AT2 receptor activation by AngII , ATIP1 and SHP-1 remain associated but detach from the AT2 receptor and translocate from the cell membrane to the nucleus .	Upon AT2 receptor activation by AngII, ATIP1 and SHP-1 remain associated but detach from the AT2 receptor and translocate from the cell membrane to the nucleus.	1	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AngII	AngII	AngII	AT2	AT2	AT2	5	6	1	2
Angiotensin II elicits pial artery dilation by activating angiotensin AT1 and angiotensin AT2 receptors .	Angiotensin II elicits pial artery dilation by activating angiotensin AT1 and angiotensin AT2 receptors.	0	13	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiotensin II	Angiotensin II	Angiotensin II	AT2	AT2	AT2	0	2	12	13
46 In addition to the vasodilator or hypotensive effect , the proangiogenic effect of losartan may also be mediated by the following mechanism : ARB blocks AT1 receptors , whereas unbound angiotensin II stimulates AT2 receptors , which in turn increase angiogenic factors , such as vascular endothelial growth factor receptors , Tie-2 expression and the angiopoietin-1 and angiopoietin-2 ratio .	46 In addition to the vasodilator or hypotensive effect, the proangiogenic effect of losartan may also be mediated by the following mechanism : ARB blocks AT1 receptors, whereas unbound angiotensin II stimulates AT2 receptors, which in turn increase angiogenic factors, such as vascular endothelial growth factor receptors, Tie-2 expression and the angiopoietin-1 and angiopoietin-2 ratio.	30	35	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	31	33	34	35
AngII activates the angiotensin 1 ( AT1 ) receptor resulting in vasoconstriction , while AngIII activates the angiotensin 2 ( AT2 ) receptor that promotes vasodilation and protects against hypertension .	AngII activates the angiotensin 1 (AT1) receptor resulting in vasoconstriction, while AngIII activates the angiotensin 2 (AT2) receptor that promotes vasodilation and protects against hypertension.	14	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AngIII	AngIII	AngIII	AT2	AT2	AT2	14	15	20	21
These results suggest that in conscious , normotensive LS rats , endogenous Ang II supports LSNA and HR over a wide MAP range via AT1 but not AT2 receptors .	These results suggest that in conscious, normotensive LS rats, endogenous Ang II supports LSNA and HR over a wide MAP range via AT1 but not AT2 receptors.	12	28	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	12	14	27	28
A-II activation of AT 2 is associated with increased free fatty acids ( FFAs ) , resulting in increased FFA flux to the liver and hence increased triglycerides .	A-II activation of AT 2 is associated with increased free fatty acids (FFAs), resulting in increased FFA flux to the liver and hence increased triglycerides.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	A-II	A-II	A-II	AT 2	AT 2	AT 2	0	1	3	5
In conclusion , Ang II induces venoconstriction by activating AT1 and AT2 receptors .	In conclusion, Ang II induces venoconstriction by activating AT1 and AT2 receptors.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	3	5	11	12
In comparison , stimulation of AT2 by Ang II was not accompanied by mobilization of intracellular calcium .	In comparison, stimulation of AT2 by Ang II was not accompanied by mobilization of intracellular calcium.	3	9	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	7	9	5	6
Both a circulating and multiple tissue localized systems have been identified , and are generally portrayed as a series of reactions that occur sequentially with a single outcome : angiotensinogen is cleaved by renin to form angiotensin I , which in turn is processed by angiotensin converting enzyme ( ACE ) to angiotensin II , which then activates either the AT1 or the AT2 plasma membrane receptor .	Both a circulating and multiple tissue localized systems have been identified, and are generally portrayed as a series of reactions that occur sequentially with a single outcome : angiotensinogen is cleaved by renin to form angiotensin I, which in turn is processed by angiotensin converting enzyme (ACE) to angiotensin II, which then activates either the AT1 or the AT2 plasma membrane receptor.	46	66	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	52	54	63	64
Here we review current data on these controversies , including new data that support the notion that angiotensin II activation of the cardiac AT2 receptor subtype inhibits the effects of angiotensin II on the immediate growth response in the adult heart .	Here we review current data on these controversies, including new data that support the notion that angiotensin II activation of the cardiac AT2 receptor subtype inhibits the effects of angiotensin II on the immediate growth response in the adult heart.	17	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	17	19	23	24
In addition to stimulating AT1 receptors , Ang II also stimulates AT2 receptors .	In addition to stimulating AT1 receptors, Ang II also stimulates AT2 receptors.	7	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	7	9	11	12
Our results show that angiotensin II activates AT1 and AT2 , which have mutually counteracting haemodynamic effects , and that AT2 regulates central nervous system functions , including behaviour .	Our results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	4	6	9	10
In light of these findings we conclude that , when the integrity of adrenal tissue is preserved , ANG-II stimulates aldosterone secretion by activating both AT1 and AT2 receptors , the major role being played by AT1 receptors located on ZG cells .	In light of these findings we conclude that, when the integrity of adrenal tissue is preserved, ANG-II stimulates aldosterone secretion by activating both AT1 and AT2 receptors, the major role being played by AT1 receptors located on ZG cells.	18	28	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANG-II	ANG-II	ANG-II	AT2	AT2	AT2	18	19	27	28
In the gastrointestinal tract , physiological quantities of ANG II stimulate the AT2 receptor releasing NO and cGMP leading to increased sodium and water absorption .	In the gastrointestinal tract, physiological quantities of ANG II stimulate the AT2 receptor releasing NO and cGMP leading to increased sodium and water absorption.	6	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANG II	quantities of ANG II	ang ii	AT2	AT2	at2	8	10	12	13
As described above , AngII stimulation of AT2 receptors is commonly considered to exert opposite effects to AngII stimulation of AT1 receptors .	As described above, AngII stimulation of AT2 receptors is commonly considered to exert opposite effects to AngII stimulation of AT1 receptors.	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AngII	AngII	AngII	AT2	AT2	AT2	4	5	7	8
Ang II induced contraction was still greater in the AT2 receptor null mice when calibrated by the maximum tension induced by 90 mM KCl .	Ang II induced contraction was still greater in the AT2 receptor null mice when calibrated by the maximum tension induced by 90 mM KCl.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	0	2	9	10
With the AT1 receptor blocked , angiotensin II is available to activate the angiotensin type 2 ( AT2 ) receptor , which mediates several potentially beneficial effects in the cardiovascular system , including vasodilation , antiproliferation , and apoptosis .	With the AT1 receptor blocked, angiotensin II is available to activate the angiotensin type 2 (AT2) receptor, which mediates several potentially beneficial effects in the cardiovascular system, including vasodilation, antiproliferation, and apoptosis.	6	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	6	8	17	18
In addition , it is now apparent that the therapeutic reduction in BP with AT1 receptor blockade ( eg , losartan , valsartan , candesartan ) is mediated by ANG II stimulation of the AT2 receptor , leading to increased levels of BK , NO , and cGMP .	In addition, it is now apparent that the therapeutic reduction in BP with AT1 receptor blockade (eg, losartan, valsartan, candesartan) is mediated by ANG II stimulation of the AT2 receptor, leading to increased levels of BK, NO, and cGMP.	29	35	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ANG II	ANG II	ANG II	AT2	AT2	AT2	29	31	34	35
In addition to the AT1 receptor , angiotensin II also activates the AT2 receptor , which could exert neuroprotection [ XREF_BIBR ] .	In addition to the AT1 receptor, angiotensin II also activates the AT2 receptor, which could exert neuroprotection [XREF_BIBR].	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	7	9	12	13
AngII also stimulates AT2 receptors that are frequently considered to antagonize the effects of AT1 receptor stimulation .	AngII also stimulates AT2 receptors that are frequently considered to antagonize the effects of AT1 receptor stimulation.	0	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AngII	AngII	AngII	AT2	AT2	AT2	0	1	3	4
For example , ARB therapies , by blocking the negative feedback control of renin secretion , also increase Ang II levels that stimulate the AT2 receptor , leading to cardioprotection .	For example, ARB therapies, by blocking the negative feedback control of renin secretion, also increase Ang II levels that stimulate the AT2 receptor, leading to cardioprotection.	3	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	ARB therapies, by blocking the negative feedback control of renin secretion, also increase Ang II levels	ang ii	AT2	AT2	at2	18	20	24	25
These results suggested that curcumin has dual effects on Ang II modulated AT1 and AT2 receptors .	These results suggested that curcumin has dual effects on Ang II modulated AT1 and AT2 receptors.	9	15	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	9	11	14	15
To investigate whether angiotensin II type 2 ( AT2 ) receptor ( AT2-r ) promoter activity and expression are modulated by angiotensin II ( Ang II ) , and whether the AT1 receptor ( AT1-r ) is involved in this effect .	To investigate whether angiotensin II type 2 (AT2) receptor (AT2-r) promoter activity and expression are modulated by angiotensin II (Ang II), and whether the AT1 receptor (AT1-r) is involved in this effect.	8	25	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	21	23	8	9
During treatment with AT1-ant , increased angiotensin II could activate AT2 receptors , with an antitrophic effect .	During treatment with AT1-ant, increased angiotensin II could activate AT2 receptors, with an antitrophic effect.	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT2	AT2	AT2	6	8	10	11
Unlike AT1 receptors , the functional consequences of AngII stimulation of AT2 receptors have generated an inconsistent literature in which effects are generally modest .	Unlike AT1 receptors, the functional consequences of AngII stimulation of AT2 receptors have generated an inconsistent literature in which effects are generally modest.	8	12	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AngII	AngII	AngII	AT2	AT2	AT2	8	9	11	12
Basolateral stimulation of AGTR1 by ANGII activates anion secretion in cultured principal cells , and we now show that the epididymis can respond to luminal ANGII .	Basolateral stimulation of AGTR1 by ANGII activates anion secretion in cultured principal cells, and we now show that the epididymis can respond to luminal ANGII.	1	6	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ANGII	ANGII	ANGII	AGTR1	AGTR1	AGTR1	5	6	3	4
As expected , AngII treatment resulted in the down-regulation of ACE2 , slight decrease in Mas expression and up-regulation of AGTR1 , indicating the suppression of Ang ( 1-7 ) expression and the activation of AngII- AGTR1 pathway .	As expected, AngII treatment resulted in the down-regulation of ACE2, slight decrease in Mas expression and up-regulation of AGTR1, indicating the suppression of Ang (1-7) expression and the activation of AngII- AGTR1 pathway.	3	21	up-regulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	AngII	AngII	AngII	AGTR1	AGTR1	AGTR1	3	4	20	21
In conclusion , our results show that AngII infusion increases blood pressure and ROS production in AT1aR containing PVN neurons of males , but not females .	In conclusion, our results show that AngII infusion increases blood pressure and ROS production in AT1aR containing PVN neurons of males, but not females.	7	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AngII	AngII	AngII	AT1aR	AT1aR	AT1aR	7	8	16	17
In order to examine this question , we conducted AFM based measurements of single cell contractility in response to AT1aR activation triggered by the full agonist Ang II ( 1nM ) or the beta-arrestin biased agonist SII ( 10 microM ) ( XREF_FIG ) .	In order to examine this question, we conducted AFM based measurements of single cell contractility in response to AT1aR activation triggered by the full agonist Ang II (1nM) or the beta-arrestin biased agonist SII (10 microM) (XREF_FIG).	19	28	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT1aR	AT1aR	AT1aR	26	28	19	20
Moreover , Ang II activates AGTR1 , which couples to the heterotrimeric G proteins G q/11 ( to stimulate phospholipase C mediated calcium mobilization ) , G i/o , G 12/13 and G s , as well as the other monomeric G proteins .	Moreover, Ang II activates AGTR1, which couples to the heterotrimeric G proteins G q/11 (to stimulate phospholipase C mediated calcium mobilization), G i/o, G 12/13 and G s, as well as the other monomeric G proteins.	2	42	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AGTR1	AGTR1	AGTR1	2	4	5	6
The Ang II enhanced responses were significantly blunted in AT1aR -/- mice .	The Ang II enhanced responses were significantly blunted in AT1aR -/- mice.	1	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	AT1aR	AT1aR	AT1aR	1	3	9	10
Adult male wild-type ( Agtr1a +/+ ) , heterozygous ( Agtr1a +/-) , and Agtr1a-/- were treated with vehicle , ANG II ( 40 ng/min ip via osmotic minipump ) , or ANG II plus the AT ( 1 ) antagonist losartan ( 10 mg.kg (-1) .	Adult male wild-type (Agtr1a +/+), heterozygous (Agtr1a +/-), and Agtr1a-/- were treated with vehicle, ANG II (40 ng/min ip via osmotic minipump), or ANG II plus the AT (1) antagonist losartan (10 mg.kg (-1).	2	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ANG II	ANG II	ANG II	Agtr1a	Agtr1a	Agtr1a	20	22	10	11
The data suggest that the sexual dimorphism in AngII induced hypertension is associated with sex differences in ROS production in AT1aR containing PVN cells , but not with post-synaptic NMDA receptor trafficking .	The data suggest that the sexual dimorphism in AngII induced hypertension is associated with sex differences in ROS production in AT1aR containing PVN cells, but not with post-synaptic NMDA receptor trafficking.	6	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AngII	AngII	AngII	AT1aR	AT1aR	AT1aR	8	9	20	21
In AT1aR deficient mice treated with angiotensin II , systolic pressure was not increased , and renal function was not affected .	In AT1aR deficient mice treated with angiotensin II, systolic pressure was not increased, and renal function was not affected.	1	8	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT1aR	AT1aR	AT1aR	6	8	1	2
Both beta-arrestin 1 and beta-arrestin 2 showed similar roles in agonist stimulated receptor desensitization , while the beta-arrestin 2 may have more profound effects on angiotensin II stimulated internalization of the AGTR1 85 .	Both beta-arrestin 1 and beta-arrestin 2 showed similar roles in agonist stimulated receptor desensitization, while the beta-arrestin 2 may have more profound effects on angiotensin II stimulated internalization of the AGTR1 85.	23	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AGTR1	AGTR1	AGTR1	25	27	31	32
In contrast , beta-arrestin-mediated signaling following angiotensin II ( Ang II ) stimulation of AT1aR or isoproterenol stimulation of beta2AR has a slower and more prolonged pattern of ERK activation [ XREF_BIBR , XREF_BIBR ] .	In contrast, beta-arrestin-mediated signaling following angiotensin II (Ang II) stimulation of AT1aR or isoproterenol stimulation of beta2AR has a slower and more prolonged pattern of ERK activation [XREF_BIBR, XREF_BIBR].	6	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	AT1aR	AT1aR	AT1aR	6	8	14	15
Anti-PIP 2 antibodies initially increased TRPC6 activity induced by Ang II , which is likely to be caused by removal of an inhibitory action of endogenous PIP 2 .	Anti-PIP 2 antibodies initially increased TRPC6 activity induced by Ang II, which is likely to be caused by removal of an inhibitory action of endogenous PIP 2.	5	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	9	11	5	6
Ang II induces membrane ruffling and the loss of stress fibers , similar to the depletion of synaptopodin or of TRPC6 ( 71 ; see section below ) .	Ang II induces membrane ruffling and the loss of stress fibers, similar to the depletion of synaptopodin or of TRPC6 (71; see section below).	0	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	0	2	20	21
Angiotensin II activates TRPC6 channels in freshly isolated mouse glomeruli and in transfected CHO cells .	Angiotensin II activates TRPC6 channels in freshly isolated mouse glomeruli and in transfected CHO cells.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiotensin II	Angiotensin II	Angiotensin II	TRPC6	TRPC6	TRPC6	0	2	3	4
Paxillin staining was also significantly reduced in TRPC6 depleted cells treated with Ang II , indicating a reduction in focal adhesions ( AT1R : 30 +/- 4 versus 10 +/- 1 ; wild type : 35 +/- 5 versus 5 +/- 2 ) ( XREF_FIG , and XREF_SUPPLEMENTARY ) .	Paxillin staining was also significantly reduced in TRPC6 depleted cells treated with Ang II, indicating a reduction in focal adhesions (AT1R : 30 +/- 4 versus 10 +/- 1; wild type : 35 +/- 5 versus 5 +/- 2) (XREF_FIG, and XREF_SUPPLEMENTARY).	5	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	12	14	7	8
With high intracellular Ca ( 2+ ) buffering conditions ( 10 mm BAPTA ) , 10 nm Ang II induced TRPC6 channel activity was increased by about five-fold compared to channel activity with low Ca ( 2+ ) buffering .	With high intracellular Ca (2+) buffering conditions (10 mm BAPTA), 10 nm Ang II induced TRPC6 channel activity was increased by about five-fold compared to channel activity with low Ca (2+) buffering.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	17	19	20	21
We have shown previously that Ang II activates native TRPC6 channels in mouse podocytes 31 and type 1 diabetic STZ-SS rats 21 .	We have shown previously that Ang II activates native TRPC6 channels in mouse podocytes 31 and type 1 diabetic STZ-SS rats 21.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	5	7	9	10
19 AngII induces podocyte dysmotility via the protein kinase G mediated downregulation of transient receptor potential canonical 6 ( TRPC6 ) activity .	19 AngII induces podocyte dysmotility via the protein kinase G mediated downregulation of transient receptor potential canonical 6 (TRPC6) activity.	0	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AngII	AngII	AngII	TRPC6	TRPC6	TRPC6	1	2	19	20
As shown on XREF_FIG and summarized in XREF_FIG , Ang II significantly increased TRPC6 P o in CHO cells , similar to native TRPC like channels of the podocytes in the freshly isolated mouse glomeruli .	As shown on XREF_FIG and summarized in XREF_FIG, Ang II significantly increased TRPC6 P o in CHO cells, similar to native TRPC like channels of the podocytes in the freshly isolated mouse glomeruli.	9	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	9	11	13	14
Ang II , a ligand to Gq coupled receptor activates TRPC6 channel in podocytes 33 .	Ang II, a ligand to Gq coupled receptor activates TRPC6 channel in podocytes 33.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	0	2	10	11
For example , application of 1 nM ANG II activates TRPC6 channels via a mechanism that is directly associated with diacylglycerol , and independent of PKC .	For example, application of 1 nM ANG II activates TRPC6 channels via a mechanism that is directly associated with diacylglycerol, and independent of PKC.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANG II	ANG II	ANG II	TRPC6	TRPC6	TRPC6	7	9	10	11
Angiotensin II ( Ang II ) levels are found to be elevated in diabetes ; furthermore , it was reported that Ang II causes activation of TRPC6 in podocytes .	Angiotensin II (Ang II) levels are found to be elevated in diabetes; furthermore, it was reported that Ang II causes activation of TRPC6 in podocytes.	21	28	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	21	23	26	27
XREF_BIBR , XREF_BIBR Furthermore , angiotensin II ( AngII ) activates specific TRPC6 mediated intracellular pathways in the podocyte .	XREF_BIBR, XREF_BIBR Furthermore, angiotensin II (AngII) activates specific TRPC6 mediated intracellular pathways in the podocyte.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AngII	AngII	AngII	TRPC6	TRPC6	TRPC6	8	9	12	13
XREF_BIBR , XREF_BIBR Recent studies demonstrated that Ang II enhances albuminuria by activating TRPC6 channels .	XREF_BIBR, XREF_BIBR Recent studies demonstrated that Ang II enhances albuminuria by activating TRPC6 channels.	7	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	7	9	13	14
Therefore we investigated the role of endogenous PIP 2 on TRPC6 activity by studying the effect of anti-PIP 2 antibodies on TRPC6 activity induced by Ang II and OAG in inside-out patches .	Therefore we investigated the role of endogenous PIP 2 on TRPC6 activity by studying the effect of anti-PIP 2 antibodies on TRPC6 activity induced by Ang II and OAG in inside-out patches.	21	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	25	27	21	22
The ion channel TRPC6 is activated in podocytes directly by Ang II and interestingly , similar to patients with TRPC6 mutations , a podocyte specific transgenic rat model for the human Ang II type 1 receptor ( AT1R ) develops progressive proteinuria culminating in FSGS [ XREF_BIBR - XREF_BIBR ] .	The ion channel TRPC6 is activated in podocytes directly by Ang II and interestingly, similar to patients with TRPC6 mutations, a podocyte specific transgenic rat model for the human Ang II type 1 receptor (AT1R) develops progressive proteinuria culminating in FSGS [XREF_BIBR - XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	10	12	3	4
An increase in Ca 2+ influx elicited by angiotensin II induced TRPC6 channel activation in podocytes has also been reported in diabetic nephropathy XREF_BIBR .	An increase in Ca 2+ influx elicited by angiotensin II induced TRPC6 channel activation in podocytes has also been reported in diabetic nephropathy XREF_BIBR.	6	13	induced	Positive_early_activation	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	TRPC6	TRPC6	TRPC6	8	10	11	12
Importantly , pretreating podocytes with the ROS quencher manganese ( III ) tetrakis ( 4-benzoic acid ) porphyrin chloride ( MnTBAP ) eliminated AII activation of TRPC6 .	Importantly, pretreating podocytes with the ROS quencher manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) eliminated AII activation of TRPC6.	23	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AII	AII	AII	TRPC6	TRPC6	TRPC6	23	24	26	27
However , there are still a lot of mysteries of podocyte BK channels in suspense , ( 1 ) inactivation mechanism underlying the positive-feedback regulation of BK on Ca 2+ signal in podocytes , ( 2 ) regulation of BK channel on the cytoskeleton of podocytes , ( 3 ) the reason why angiotensin II activated TRPC6 , but inhibited the BK .	However, there are still a lot of mysteries of podocyte BK channels in suspense, (1) inactivation mechanism underlying the positive-feedback regulation of BK on Ca 2+ signal in podocytes, (2) regulation of BK channel on the cytoskeleton of podocytes, (3) the reason why angiotensin II activated TRPC6, but inhibited the BK.	53	57	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	TRPC6	TRPC6	TRPC6	53	55	56	57
These data suggest that PIP 2 inhibits TRPC6 activity stimulated by Ang II and OAG but also that PIP 2 acts as a precursor for endogenous DAG production by Ang II.	These data suggest that PIP 2 inhibits TRPC6 activity stimulated by Ang II and OAG but also that PIP 2 acts as a precursor for endogenous DAG production by Ang II.	7	13	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	11	13	7	8
16 Besides , it was highlighted that the deleterious effects of Ang II on podocytes and its pathogenic role in glomerular diseases coincides with enhanced TRPC6 expression 17 and that Ang II activation of TRPC6 channels in rat podocytes requires generation of reactive oxygen species .	16 Besides, it was highlighted that the deleterious effects of Ang II on podocytes and its pathogenic role in glomerular diseases coincides with enhanced TRPC6 expression 17 and that Ang II activation of TRPC6 channels in rat podocytes requires generation of reactive oxygen species.	30	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	30	32	34	35
Moreover , in zero external Ca ( 2+ ) ( 0 [ Ca ( 2+ ) ] ( o ) ) 100 nm Ang II induced TRPC6 channel activity in outside-out patches .	Moreover, in zero external Ca (2+) (0 [Ca (2+)] (o)) 100 nm Ang II induced TRPC6 channel activity in outside-out patches.	23	28	induced	Positive_early_activation	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	23	25	26	27
PLCepsilon-/- podocytes however , were undistinguishable from WT podocytes in their angiotensin II induced formation of actin stress fibers and their GTPgammaS induced TRPC6 activation , pointing to a redundant role of PLCepsilon mediated TRPC6 activation at least in podocytes .	PLCepsilon-/- podocytes however, were undistinguishable from WT podocytes in their angiotensin II induced formation of actin stress fibers and their GTPgammaS induced TRPC6 activation, pointing to a redundant role of PLCepsilon mediated TRPC6 activation at least in podocytes.	8	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	TRPC6	TRPC6	TRPC6	11	13	23	24
We demonstrate here that Ang II up-regulates TRPC6 activity in intact podocytes of freshly isolated glomeruli and that this channel ' s activation further results in extensive Ca 2+ flux in podocytes .	We demonstrate here that Ang II up-regulates TRPC6 activity in intact podocytes of freshly isolated glomeruli and that this channel 's activation further results in extensive Ca 2+ flux in podocytes.	4	8	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	4	6	7	8
Angiotensin II has been proposed to activate TRPC6 in rabbit mesenteric arteries , while endothelin-1 activates TRPC3 and TRPC7 .	Angiotensin II has been proposed to activate TRPC6 in rabbit mesenteric arteries, while endothelin-1 activates TRPC3 and TRPC7.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiotensin II	Angiotensin II	Angiotensin II	TRPC6	TRPC6	TRPC6	0	2	7	8
Our previous studies XREF_BIBR on the wild type and TRPC6 knockout mice revealed that Ang II activated TRPC6 calcium channels in the podocytes .	Our previous studies XREF_BIBR on the wild type and TRPC6 knockout mice revealed that Ang II activated TRPC6 calcium channels in the podocytes.	14	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	14	16	17	18
Moreover , in podocytes PLCbeta isoforms are essential for angiotensin II mediated activation of TRPC6 and PLCgamma1 seems to be important for translocation of TRPC6 to the plasma membrane .	Moreover, in podocytes PLCbeta isoforms are essential for angiotensin II mediated activation of TRPC6 and PLCgamma1 seems to be important for translocation of TRPC6 to the plasma membrane.	7	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	angiotensin II	angiotensin II	angiotensin II	TRPC6	TRPC6	TRPC6	9	11	14	15
Our results show that , in PCa , loss of PTEN enhances the levels of ADAM17 thereby promoting the activation of NOTCH signalling .	Our results show that, in PCa, loss of PTEN enhances the levels of ADAM17 thereby promoting the activation of NOTCH signalling.	10	22	promoting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ADAM17	PTEN enhances the levels of ADAM17	adam17	NOTCH	NOTCH	notch	15	16	21	22
By contrast , the related ADAM , TACE , is sufficient to induce ligand independent Notch activation when expressed at levels approaching those seen in developing brain tissue .	By contrast, the related ADAM, TACE, is sufficient to induce ligand independent Notch activation when expressed at levels approaching those seen in developing brain tissue.	5	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch	Notch	Notch	7	8	15	16
It would therefore be interesting to test if increased c-Myc following ADAM17-overexpression was due to activation of Notch by ADAM17 .	It would therefore be interesting to test if increased c-Myc following ADAM17-overexpression was due to activation of Notch by ADAM17.	13	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	19	20	17	18
Specifically , we find that active PKD1 induced the expression of Adam10 , Adam17 and MMP-7 , all metalloproteinases that activate Notch directly by S2 cleavage and were previously linked to PDAC .	Specifically, we find that active PKD1 induced the expression of Adam10, Adam17 and MMP-7, all metalloproteinases that activate Notch directly by S2 cleavage and were previously linked to PDAC.	6	22	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Adam17	PKD1 induced the expression of Adam10, Adam17	adam17	Notch	Notch	notch	13	14	21	22
Although TACE cleaves and induces Notch signaling activity , TACE also mediates TNF-alpha shedding .	Although TACE cleaves and induces Notch signaling activity, TACE also mediates TNF-alpha shedding.	1	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch	Notch	Notch	1	2	5	6
It is possible that INCB3619 inhibited aberrant Notch signaling by blocking ADAM10 , whereas colonocyte ADAM17 deletion inhibited release of Notch ligands such as Jagged1 or Jagged2 .	It is possible that INCB3619 inhibited aberrant Notch signaling by blocking ADAM10, whereas colonocyte ADAM17 deletion inhibited release of Notch ligands such as Jagged1 or Jagged2.	15	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	15	16	20	21
Collectively , our results suggest that inhibition of ADAM17 suppresses the Notch signaling pathway , resulting in decreased MMP-2 , MMP-9 and VEGF , leading to inhibition of invasion or migration by CD133 expressing liver CSCs after irradiation .	Collectively, our results suggest that inhibition of ADAM17 suppresses the Notch signaling pathway, resulting in decreased MMP-2, MMP-9 and VEGF, leading to inhibition of invasion or migration by CD133 expressing liver CSCs after irradiation.	6	13	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	8	9	11	12
Taken together , our results suggest that the Notch pathway is inhibited by suppression of ADAM17 during metastasis of CD133 expressing liver CSCs after radiotherapy .	Taken together, our results suggest that the Notch pathway is inhibited by suppression of ADAM17 during metastasis of CD133 expressing liver CSCs after radiotherapy.	8	16	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	15	16	8	9
These results strongly support our hypothesis involving Syndecan-3 in regulating TACE mediated cleavage of Notch at the S2 site .	These results strongly support our hypothesis involving Syndecan-3 in regulating TACE mediated cleavage of Notch at the S2 site.	10	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch	Notch	Notch	10	11	14	15
ADAM family proteins TACE ( ADAM 17 ) and Kuzbanian ( ADAM 10 ) mediate regulation of Notch extracellular domain shedding .	ADAM family proteins TACE (ADAM 17) and Kuzbanian (ADAM 10) mediate regulation of Notch extracellular domain shedding.	0	19	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM 17	ADAM 17	ADAM 17	Notch	Notch	Notch	5	7	17	18
Inhibition of ADAM-17 down-regulates the Notch pathway ( Guo etal .	Inhibition of ADAM-17 down-regulates the Notch pathway (Guo etal.	0	6	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM-17	ADAM-17	ADAM-17	Notch	Notch	Notch	2	3	5	6
Because ADAM-17 is involved in Notch activation , this finding suggests that ADAM-17 activation of Notch correlates with RCC progression .	Because ADAM-17 is involved in Notch activation, this finding suggests that ADAM-17 activation of Notch correlates with RCC progression.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ADAM-17	ADAM-17	ADAM-17	Notch	Notch	Notch	12	13	15	16
Hong reported [ XREF_BIBR ] that proteolysis and initiation of Notch receptor signaling induced by ADAM17 are effectively reduced by RECK , which further inhibits the expression of the stemness marker gene CD133 and represses stem cell like characteristics in GC cells .	Hong reported [XREF_BIBR] that proteolysis and initiation of Notch receptor signaling induced by ADAM17 are effectively reduced by RECK, which further inhibits the expression of the stemness marker gene CD133 and represses stem cell like characteristics in GC cells.	10	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	15	16	10	11
Upon cell-stress , e.g ., ionizing radiation or cytotoxic chemotherapeutic agents , Notch will be activated and cleaved by metalloproteases domain-17 ( ADAM-17 ) , leading to the release of the Notch intracellular domain ( NICD ) XREF_BIBR - XREF_BIBR .	Upon cell-stress, e.g., ionizing radiation or cytotoxic chemotherapeutic agents, Notch will be activated and cleaved by metalloproteases domain-17 (ADAM-17), leading to the release of the Notch intracellular domain (NICD) XREF_BIBR - XREF_BIBR.	12	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM-17	ADAM-17	ADAM-17	Notch	Notch	Notch	22	23	12	13
A corollary of these observations is that single inhibition of ADAM10 or ADAM17 would fail to abrogate NOTCH signaling in leukemic lymphoblasts .	A corollary of these observations is that single inhibition of ADAM10 or ADAM17 would fail to abrogate NOTCH signaling in leukemic lymphoblasts.	8	18	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	NOTCH	NOTCH	NOTCH	12	13	17	18
Analysis of proteases involved in activation of Notch signalling has highlighted an increased S2 processing of Notch receptors mediated by the ADAM17 metalloprotease .	Analysis of proteases involved in activation of Notch signalling has highlighted an increased S2 processing of Notch receptors mediated by the ADAM17 metalloprotease.	16	22	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	21	22	16	17
Murthy et al ., demonstrated that the ADAM17 mediated Notch activation in keratinocytes occurred in a ligand independent manner .	Murthy et al., demonstrated that the ADAM17 mediated Notch activation in keratinocytes occurred in a ligand independent manner.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	7	8	9	10
Notch signaling is activated by binding of DSL ligands to the Notch receptor , which induces proteolytic cleavage of Notch by ADAM and TACE metalloproteases and subsequent cleavage by gamma-secretase to generate the Notch intracellular signaling fragment NICD XREF_BIBR , XREF_BIBR .	Notch signaling is activated by binding of DSL ligands to the Notch receptor, which induces proteolytic cleavage of Notch by ADAM and TACE metalloproteases and subsequent cleavage by gamma-secretase to generate the Notch intracellular signaling fragment NICD XREF_BIBR, XREF_BIBR.	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch	Notch	Notch	23	24	0	1
An indirect mechanism by which fibulin-3 can activate Notch in GBM involves increased activity of the metalloproteases ADAM10 and ADAM17 18 , which cleave and activates Notch receptors 26 .	An indirect mechanism by which fibulin-3 can activate Notch in GBM involves increased activity of the metalloproteases ADAM10 and ADAM17 18, which cleave and activates Notch receptors 26.	11	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	19	20	26	27
The Notch signaling pathway is inhibited by suppression of ADAM17 in CD133 expressing liver CSCs .	The Notch signaling pathway is inhibited by suppression of ADAM17 in CD133 expressing liver CSCs.	1	11	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	9	10	1	2
Increased ADAM17 in ADAM10 B-/- B cells could lead to aberrant Notch signaling and increased fibrosis within the lymph node ( XREF_FIG ) .	Increased ADAM17 in ADAM10 B-/- B cells could lead to aberrant Notch signaling and increased fibrosis within the lymph node (XREF_FIG).	0	14	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	1	2	11	12
In contrast , TACE , which is elevated in expression in developing Drosophila nervous system , can efficiently activate Notch in a ligand independent manner .	In contrast, TACE, which is elevated in expression in developing Drosophila nervous system, can efficiently activate Notch in a ligand independent manner.	3	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch	Notch	Notch	3	4	19	20
Therefore , Notch signaling in the radial glial cells of the alar plate can be activated by ADAM17 shedding , resulting in the maintenance of the radial glial cells in the ventricular zone ( XREF_FIG ) .	Therefore, Notch signaling in the radial glial cells of the alar plate can be activated by ADAM17 shedding, resulting in the maintenance of the radial glial cells in the ventricular zone (XREF_FIG).	2	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	17	18	2	3
ADAM17 also activates Notch in adult epidermis .	ADAM17 also activates Notch in adult epidermis.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	0	1	3	4
In C. elegans , two genes encode ADAM metalloproteases that mediate Notch signaling : ADAM10 and sup -17 and ADAM17 and adm -4 .	In C. elegans, two genes encode ADAM metalloproteases that mediate Notch signaling : ADAM10 and sup -17 and ADAM17 and adm -4.	6	21	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch	Notch	Notch	19	20	11	12
Kuz and TACE can activate Notch independent of ligand .	Kuz and TACE can activate Notch independent of ligand.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch	Notch	Notch	2	3	5	6
We observe a 17-fold activation of Notch in C6 TACE ( i ) cells relative to control C6 cells , again indicating a constitutive activation of Notch by TACE ( XREF_FIG ) .	We observe a 17-fold activation of Notch in C6 TACE (i) cells relative to control C6 cells, again indicating a constitutive activation of Notch by TACE (XREF_FIG).	21	30	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch	Notch	Notch	28	29	26	27
Inhibition of ADAM-17 more effectively down-regulates the Notch pathway than that of gamma-secretase in renal carcinoma .	Inhibition of ADAM-17 more effectively down-regulates the Notch pathway than that of gamma-secretase in renal carcinoma.	0	8	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM-17	ADAM-17	ADAM-17	Notch	Notch	Notch	2	3	7	8
TACE can activate Notch in ligand independent manner .	TACE can activate Notch in ligand independent manner.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch	Notch	Notch	0	1	3	4
These authors argue that the TACE processing product of Notch ( similar to the DeltaE construct we use ) remains associated with the apical membrane in Nicastrin or PS mutant cells , and in WT cells only a small amount of this molecule can be found in endocytic vesicles .	These authors argue that the TACE processing product of Notch (similar to the DeltaE construct we use) remains associated with the apical membrane in Nicastrin or PS mutant cells, and in WT cells only a small amount of this molecule can be found in endocytic vesicles.	5	10	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch	Notch	Notch	5	6	9	10
Adiponectin activates AdipoR1 and AdipoR2 , which alter AMPK and PPAR , respectively , and promote glucose and lipid metabolism , which leads to their anti-diabetic properties being exerted [ XREF_BIBR ] .	Adiponectin activates AdipoR1 and AdipoR2, which alter AMPK and PPAR, respectively, and promote glucose and lipid metabolism, which leads to their anti-diabetic properties being exerted [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Adiponectin	Adiponectin	Adiponectin	AdipoR2	AdipoR2	AdipoR2	0	1	4	5
Adiponectin activates two different receptors , AdipoR1 and AdipoR2 ; these receptors are expressed by most cells including normal mammary epithelial cells and breast cancer cells .	Adiponectin activates two different receptors, AdipoR1 and AdipoR2; these receptors are expressed by most cells including normal mammary epithelial cells and breast cancer cells.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Adiponectin	Adiponectin	Adiponectin	AdipoR2	AdipoR2	AdipoR2	0	1	8	9
Adiponectin function is mediated through its receptors : AdipoR1 and AdipoR2 .	Adiponectin function is mediated through its receptors : AdipoR1 and AdipoR2.	0	11	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Adiponectin	Adiponectin	Adiponectin	AdipoR2	AdipoR2	AdipoR2	0	1	10	11
In addition , an inverse correlation between circulating adiponectin and skeletal muscle ceramide content was demonstrated in healthy men.101 Ceramide signalling in HFrEF further mainly depends upon adiponectin activation of both AdipoR1 and AdipoR2 .	In addition, an inverse correlation between circulating adiponectin and skeletal muscle ceramide content was demonstrated in healthy men.101 Ceramide signalling in HFrEF further mainly depends upon adiponectin activation of both AdipoR1 and AdipoR2.	27	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	27	28	33	34
Adiponectin receptors 1 ( AdipoR1 ) and 2 ( AdipoR2 ) in the liver are stimulated by full-length adiponectin and they activate the phosphorylation of AMPK and PPAR-alpha , respectively [ XREF_BIBR ] .	Adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2) in the liver are stimulated by full-length adiponectin and they activate the phosphorylation of AMPK and PPAR-alpha, respectively [XREF_BIBR].	1	19	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	18	19	9	10
These findings are consistent with literatures that adiponectin activates its receptors , adipoR1 and adipoR2 , then increases the activity of AMPK to exert its function , XREF_BIBR , XREF_BIBR which leads to detailed studies on the crystal structures and small-molecule agonist of adipoR1 and adipoR2 .	These findings are consistent with literatures that adiponectin activates its receptors, adipoR1 and adipoR2, then increases the activity of AMPK to exert its function, XREF_BIBR, XREF_BIBR which leads to detailed studies on the crystal structures and small-molecule agonist of adipoR1 and adipoR2.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	adipoR2	adipoR2	adipoR2	7	8	14	15
XREF_BIBR identified an orally synthetic small-molecule adiponectin receptor agonist , named AdipRon , that binds to and activates the adiponectin receptor1 ( AdipoR1 ) and AdipoR2 receptors that mediate adiponectin ' s antidiabetic action .	XREF_BIBR identified an orally synthetic small-molecule adiponectin receptor agonist, named AdipRon, that binds to and activates the adiponectin receptor1 (AdipoR1) and AdipoR2 receptors that mediate adiponectin 's antidiabetic action.	6	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	6	7	25	26
Adiponectin has been proposed to mediate its effects via at least two transmembrane receptors , adiponectin receptor 1 ( AdipoR1 ) and adiponectin receptor 2 ( AdipoR2 ) [ XREF_BIBR ] .	Adiponectin has been proposed to mediate its effects via at least two transmembrane receptors, adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2) [XREF_BIBR].	0	27	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Adiponectin	Adiponectin	Adiponectin	AdipoR2	AdipoR2	AdipoR2	0	1	26	27
Activation of AdipoR1 and/or AdipoR2 by adiponectin stimulates the activation of peroxisome-proliferator-activated receptor-alpha ( PPARalpha ) , AMP activated protein kinase ( AMPK ) , and p38 mitogen activated protein kinase .	Activation of AdipoR1 and/or AdipoR2 by adiponectin stimulates the activation of peroxisome-proliferator-activated receptor-alpha (PPARalpha), AMP activated protein kinase (AMPK), and p38 mitogen activated protein kinase.	0	7	Activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	6	7	4	5
RER was 0.964 +/- 0.022 and 0.876 +/- 0.019 in AdipoR2 null mice treated with vehicle or adiponectin , respectively ( XREF_FIG ) .	RER was 0.964 +/- 0.022 and 0.876 +/- 0.019 in AdipoR2 null mice treated with vehicle or adiponectin, respectively (XREF_FIG).	10	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	17	18	10	11
Adiponectin action is meditated by the adiponectin receptors AdipoR1 , which activates AMPK , and AdipoR2 , which activates the PPARalpha signaling pathway .	Adiponectin action is meditated by the adiponectin receptors AdipoR1, which activates AMPK, and AdipoR2, which activates the PPARalpha signaling pathway.	6	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	6	7	15	16
Adiponectin activates two main seven transmembrane receptors , adiponectin receptor 1 ( adipoR1 ) and adiponectin receptor 2 ( adipoR2 ) 10 .	Adiponectin activates two main seven transmembrane receptors, adiponectin receptor 1 (adipoR1) and adiponectin receptor 2 (adipoR2) 10.	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Adiponectin	Adiponectin	Adiponectin	adipoR2	adipoR2	adipoR2	0	1	19	20
While gAdN preferentially binds to adipoR1 , HMW adiponectin preferentially stimulates adipoR2 10 .	While gAdN preferentially binds to adipoR1, HMW adiponectin preferentially stimulates adipoR2 10.	7	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	adipoR2	adipoR2	adipoR2	8	9	11	12
The metabolic effects of adiponectin are mediated by adiponectin receptors 1 ( ADIPOR1 ) and 2 ( ADIPOR2 ) .	The metabolic effects of adiponectin are mediated by adiponectin receptors 1 (ADIPOR1) and 2 (ADIPOR2).	2	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	ADIPOR2	ADIPOR2	ADIPOR2	4	5	17	18
Adiponectin activates 2 seven-transmembrane receptors , adiponectin receptor 1 ( adipoR1 ) and adiponectin receptor 2 ( adipoR2 ) , and stimulation of either receptor leads to regulation of metabolic effects through activation of metabolic effects through a number of pathways including AMPK and MAPK .	Adiponectin activates 2 seven-transmembrane receptors, adiponectin receptor 1 (adipoR1) and adiponectin receptor 2 (adipoR2), and stimulation of either receptor leads to regulation of metabolic effects through activation of metabolic effects through a number of pathways including AMPK and MAPK.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Adiponectin	Adiponectin	Adiponectin	adipoR2	adipoR2	adipoR2	0	1	17	18
Adiponectin activates the AdipoR1 and AdipoR2 isoforms , but in liver the isoform receptor AdipoR2 is mainly used by adiponectin 25 .	Adiponectin activates the AdipoR1 and AdipoR2 isoforms, but in liver the isoform receptor AdipoR2 is mainly used by adiponectin 25.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Adiponectin	Adiponectin	Adiponectin	AdipoR2	AdipoR2	AdipoR2	0	1	5	6
In general , AdipoR1 and AdipoR2 are activated by different types of adiponectin .	In general, AdipoR1 and AdipoR2 are activated by different types of adiponectin.	3	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	12	13	5	6
In that study , AdipoR1and AdipoR2 transfected cells showed greater cholesterol efflux when treated with Adiponectin .	In that study, AdipoR1and AdipoR2 transfected cells showed greater cholesterol efflux when treated with Adiponectin.	4	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Adiponectin	Adiponectin	Adiponectin	AdipoR2	AdipoR2	AdipoR2	15	16	5	6
Adiponectin mediates its insulin sensitizing effects via its receptors ADIPOR1 and ADIPOR2 , the expression of which are downregulated in obesity.48 Using PBMC as a surrogate for adipose tissue ,34 the AINS increased ADIPOR1 and ADIPOR2 mRNA expression relative to placebo treatment .	Adiponectin mediates its insulin sensitizing effects via its receptors ADIPOR1 and ADIPOR2, the expression of which are downregulated in obesity.48 Using PBMC as a surrogate for adipose tissue,34 the AINS increased ADIPOR1 and ADIPOR2 mRNA expression relative to placebo treatment.	0	15	mediates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Adiponectin	Adiponectin	adiponectin	ADIPOR2	ADIPOR2, the expression	adipor2	0	1	11	12
The functions of adiponectin are mediated via three different receptors , that is , AdipoR1 , AdipoR2 , and T-cadherin , which are abundant in skeletal muscle .	The functions of adiponectin are mediated via three different receptors, that is, AdipoR1, AdipoR2, and T-cadherin, which are abundant in skeletal muscle.	1	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	3	4	16	17
By contrast , adiponectin alone and FSH alone increased Adipor1 and Adipor2 in COCs whereas adiponectin and FSH together failed to increase mRNA encoding these receptors ( XREF_FIG ) .	By contrast, adiponectin alone and FSH alone increased Adipor1 and Adipor2 in COCs whereas adiponectin and FSH together failed to increase mRNA encoding these receptors (XREF_FIG).	3	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	Adipor2	Adipor2	Adipor2	3	4	11	12
Adiponectin elicits pleiotropic actions via ubiquitously expressed AdipoR1 , and AdipoR2 , which is more restricted to the liver 49 .	Adiponectin elicits pleiotropic actions via ubiquitously expressed AdipoR1, and AdipoR2, which is more restricted to the liver 49.	0	15	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Adiponectin	Adiponectin	Adiponectin	AdipoR2	AdipoR2	AdipoR2	0	1	10	11
Free fatty acid ( FFA ) might be produced from lipid hydrolysis by the adiponectin stimulated AdipoR2 , and PPARalpha activation by the produced FFA would increase the expression of the target genes , such as UCP2 .	Free fatty acid (FFA) might be produced from lipid hydrolysis by the adiponectin stimulated AdipoR2, and PPARalpha activation by the produced FFA would increase the expression of the target genes, such as UCP2.	8	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	14	15	16	17
These effects are assumed to be mediated by the recently discovered adiponectin receptors AdipoR1 and AdipoR2 .	These effects are assumed to be mediated by the recently discovered adiponectin receptors AdipoR1 and AdipoR2.	6	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	11	12	15	16
However , it can not be excluded the adiponectin induced S1P formation is also the result of AdipoR1 and AdipoR2 mediated activation of other ceramidases .	However, it can not be excluded the adiponectin induced S1P formation is also the result of AdipoR1 and AdipoR2 mediated activation of other ceramidases.	7	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	8	9	19	20
XREF_BIBR - XREF_BIBR Globular adiponectin seems to mainly activate AdipoR1 , whereas AdipoR2 engages mainly with full-length adiponectin .	XREF_BIBR - XREF_BIBR Globular adiponectin seems to mainly activate AdipoR1, whereas AdipoR2 engages mainly with full-length adiponectin.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR1	AdipoR1	AdipoR1	4	5	9	10
Indeed , adiponectin enhances the coimmunoprecipitation of AdipoR1 , APPL1 , ERalpha , IGF-IR , and c-Src in MCF-7 cells .	Indeed, adiponectin enhances the coimmunoprecipitation of AdipoR1, APPL1, ERalpha, IGF-IR, and c-Src in MCF-7 cells.	2	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR1	AdipoR1	AdipoR1	2	3	7	8
Moreover , adiponectin promotes AdipoR1 dependent ceramidase activity to regulate ceramide levels XREF_BIBR .	Moreover, adiponectin promotes AdipoR1 dependent ceramidase activity to regulate ceramide levels XREF_BIBR.	2	5	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR1	AdipoR1	AdipoR1	2	3	4	5
The uptake of DHA is mediated by adiponectin receptor 1 ( AdipoR1 ) , a heptahelical transmembrane protein with a topology that is inverse to that of the G-proteins .	The uptake of DHA is mediated by adiponectin receptor 1 (AdipoR1), a heptahelical transmembrane protein with a topology that is inverse to that of the G-proteins.	5	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR1	AdipoR1	AdipoR1	7	8	11	12
No significant differences were observed in the RER at any time during the 24 hrs recording when comparing AdipoR1 mice treated with vehicle or adiponectin .	No significant differences were observed in the RER at any time during the 24 hrs recording when comparing AdipoR1 mice treated with vehicle or adiponectin.	18	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR1	AdipoR1	AdipoR1	24	25	18	19
Duan et al [ XREF_BIBR ] reported that chikusetsu saponin increased adiponectin level and enhanced neuronal AdipoR1 as well as downstream molecules of adiponectin including AMPK , and glycogen synthase kinase 3 beta ( GSK-3beta ) expression , in a concentration dependent manner in diabetic mice .	Duan et al [XREF_BIBR] reported that chikusetsu saponin increased adiponectin level and enhanced neuronal AdipoR1 as well as downstream molecules of adiponectin including AMPK, and glycogen synthase kinase 3 beta (GSK-3beta) expression, in a concentration dependent manner in diabetic mice.	8	30	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	chikusetsu saponin increased adiponectin level	adiponectin	AdipoR1	AdipoR1	adipor1	11	12	16	17
The biological effects of adiponectin are known to be mediated through the two adiponectin receptor subtypes AdipoR1 and R2 [ XREF_BIBR ] , which subsequently activate AMP kinase , PPARalpha ligand , and mitogen activated protein kinase ( MAPK ) , and regulate fatty-acid oxidation and glucose uptake [ XREF_BIBR ] .	The biological effects of adiponectin are known to be mediated through the two adiponectin receptor subtypes AdipoR1 and R2 [XREF_BIBR], which subsequently activate AMP kinase, PPARalpha ligand, and mitogen activated protein kinase (MAPK), and regulate fatty-acid oxidation and glucose uptake [XREF_BIBR].	2	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR1	AdipoR1	AdipoR1	4	5	16	17
AdipoR1 protein expression and localization in islets from AdipoR1 mice as well as in an AdipoR1 transfected mouse insulinoma cell line were confirmed , as was the activation of both AMPK and Akt in AdipoR1 mice by adiponectin .	AdipoR1 protein expression and localization in islets from AdipoR1 mice as well as in an AdipoR1 transfected mouse insulinoma cell line were confirmed, as was the activation of both AMPK and Akt in AdipoR1 mice by adiponectin.	27	38	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR1	AdipoR1	AdipoR1	37	38	34	35
Adiponectin activates AMPK downstream of its receptors ( AdipoR1 and 2 ) in a variety of tissues to conserve energy by inhibiting anabolic processes .	Adiponectin activates AMPK downstream of its receptors (AdipoR1 and 2) in a variety of tissues to conserve energy by inhibiting anabolic processes.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Adiponectin	Adiponectin	Adiponectin	AdipoR1	AdipoR1	AdipoR1	0	1	8	9
Upon binding to collagen III , GPR56 activates RhoA via coupling to Galpha 12/13 XREF_BIBR .	Upon binding to collagen III, GPR56 activates RhoA via coupling to Galpha 12/13 XREF_BIBR.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR56	GPR56	GPR56	RhoA	RhoA	RhoA	6	7	8	9
As for intracellular signaling , GPR56 couples to the Galpha ( 12/13 ) family of G proteins and activates RhoA pathway upon ligand binding .	As for intracellular signaling, GPR56 couples to the Galpha (12/13) family of G proteins and activates RhoA pathway upon ligand binding.	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR56	GPR56	GPR56	RhoA	RhoA	RhoA	5	6	19	20
The binding of collagen III and GPR56 inhibits neural migration through coupling to Galpha 12/13 and activates RhoA pathway .	The binding of collagen III and GPR56 inhibits neural migration through coupling to Galpha 12/13 and activates RhoA pathway.	1	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR56	GPR56	GPR56	RhoA	RhoA	RhoA	6	7	17	18
Both GPR56 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] and CD97 [ XREF_BIBR ] have been shown to activate the Rho pathway via coupling to Galpha 12/13 , and CIRL-1 and latrophilin-1 has been demonstrated to couple to both Galpha q and Galpha o [ XREF_BIBR , XREF_BIBR ] .	Both GPR56 [XREF_BIBR, XREF_BIBR, XREF_BIBR] and CD97 [XREF_BIBR] have been shown to activate the Rho pathway via coupling to Galpha 12/13, and CIRL-1 and latrophilin-1 has been demonstrated to couple to both Galpha q and Galpha o [XREF_BIBR, XREF_BIBR].	1	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR56	GPR56	GPR56	Rho	Rho	Rho	1	2	20	21
It has been recently demonstrated that truncating GPR56 through removing GPR56 N up to the GPS domain enhances GPR56 mediated RhoA activation [ XREF_BIBR ] .	It has been recently demonstrated that truncating GPR56 through removing GPR56 N up to the GPS domain enhances GPR56 mediated RhoA activation [XREF_BIBR].	17	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	GPR56	GPR56	GPR56	RhoA	RhoA	RhoA	18	19	20	21
Furthermore , knockdown of GPR56 via Gpr56 shRNA or the absence of GPR56 altogether attenuated RhoA activation upon the addition of collagen III , suggesting that collagen III activates RhoA through GPR56 .	Furthermore, knockdown of GPR56 via Gpr56 shRNA or the absence of GPR56 altogether attenuated RhoA activation upon the addition of collagen III, suggesting that collagen III activates RhoA through GPR56.	2	16	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR56	GPR56	GPR56	RhoA	RhoA	RhoA	4	5	15	16
Mechanism for Adhesion G Protein Coupled Receptor GPR56 Mediated RhoA Activation Induced By Collagen III Stimulation .	Mechanism for Adhesion G Protein Coupled Receptor GPR56 Mediated RhoA Activation Induced By Collagen III Stimulation.	0	10	Mediated	Positive_early_activation	Positive_activation	Positive_activation	GPR56	GPR56	GPR56	RhoA	RhoA	RhoA	7	8	9	10
Overexpression of GPR56 C alone enhanced RhoA activation , suggesting that the binding of GPR56 N to GPR56 C probably inhibits GPR56 downstream signaling XREF_BIBR .	Overexpression of GPR56 C alone enhanced RhoA activation, suggesting that the binding of GPR56 N to GPR56 C probably inhibits GPR56 downstream signaling XREF_BIBR.	0	7	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR56	Overexpression of GPR56	gpr56	RhoA	RhoA	rhoa	2	3	6	7
Upon binding to collagen III , GPR56 activates RhoA via coupling to Galpha 12/13 .	Upon binding to collagen III, GPR56 activates RhoA via coupling to Galpha 12/13.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR56	GPR56	GPR56	RhoA	RhoA	RhoA	6	7	8	9
This prediction is consistent with a recent report on the regulation of the aGPCR CD97 by shear stress as well as our recent finding that the GPR56 ligand , collagen III , activates RhoA by removing GPR56-NTF from the cell surface .	This prediction is consistent with a recent report on the regulation of the aGPCR CD97 by shear stress as well as our recent finding that the GPR56 ligand, collagen III, activates RhoA by removing GPR56-NTF from the cell surface.	26	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR56	GPR56	GPR56	RhoA	RhoA	RhoA	26	27	33	34
Previous in vitro studies show that Gpr56 couples to Galpha 12/13 and activates RhoA to control migration of mammalian neural precursor cells XREF_BIBR - XREF_BIBR .	Previous in vitro studies show that Gpr56 couples to Galpha 12/13 and activates RhoA to control migration of mammalian neural precursor cells XREF_BIBR - XREF_BIBR.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gpr56	Gpr56	Gpr56	RhoA	RhoA	RhoA	6	7	13	14
The precise steps responsible for activating Notch1 in the venous beds of mutant mice require further study , but we note that Dll4 itself can exert long-distant effects following its release into exosomes and that ADAM 17 ( up-regulated more than 2-fold in Snail1 KO ECs ) can activate Notch1 signaling in a ligand independent fashion XREF_BIBR , XREF_BIBR .	The precise steps responsible for activating Notch1 in the venous beds of mutant mice require further study, but we note that Dll4 itself can exert long-distant effects following its release into exosomes and that ADAM 17 (up-regulated more than 2-fold in Snail1 KO ECs) can activate Notch1 signaling in a ligand independent fashion XREF_BIBR, XREF_BIBR.	35	50	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM 17	ADAM 17	ADAM 17	Notch1	Notch1	Notch1	35	37	49	50
This study identifies that iRhom2 regulates hair shaft and IRS differentiation by specifically modulating Notch1 and Wnt signaling pathway which maybe mediated by TACE .	This study identifies that iRhom2 regulates hair shaft and IRS differentiation by specifically modulating Notch1 and Wnt signaling pathway which maybe mediated by TACE.	14	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch1	Notch1	Notch1	23	24	14	15
Initially , two independent groups concluded that ADAM17 ( TNF-alpha converting enzyme , TACE ) initiates signaling by performing S2 cleavage of the Notch1 receptor .	Initially, two independent groups concluded that ADAM17 (TNF-alpha converting enzyme, TACE) initiates signaling by performing S2 cleavage of the Notch1 receptor.	7	24	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch1	Notch1	Notch1	7	8	23	24
Endothelial specific knockdown of Adam17 reduced collateral formation , consistent with its roles in endothelial cell migration and embryonic vascular stabilization , but not in activation of ligand bound Notch1 .	Endothelial specific knockdown of Adam17 reduced collateral formation, consistent with its roles in endothelial cell migration and embryonic vascular stabilization, but not in activation of ligand bound Notch1.	2	30	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Adam17	Adam17	Adam17	Notch1	Notch1	Notch1	4	5	29	30
Initially , two independent groups using in vitro models concluded that ADAM17 ( TNF converting enzyme ) initiates Notch1 signaling by cleaving Notch1 in monocytic precursors and MEFs .	Initially, two independent groups using in vitro models concluded that ADAM17 (TNF converting enzyme) initiates Notch1 signaling by cleaving Notch1 in monocytic precursors and MEFs.	11	19	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch1	Notch1	Notch1	11	12	18	19
After activation , Notch can be cleaved to its intracellular domain ( NICD ) by ADAM10 , TACE and gamma-secretase , allowing the NICD to become capable of target gene activation [ XREF_BIBR ] .	After activation, Notch can be cleaved to its intracellular domain (NICD) by ADAM10, TACE and gamma-secretase, allowing the NICD to become capable of target gene activation [XREF_BIBR].	6	25	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	NICD	NICD	NICD	17	18	23	24
In this study , we discovered that iRhom2 regulate murine hair follicle differentiation by specifically modulating Notch1 and Wnt signaling pathway which maybe mediated by TACE .	In this study, we discovered that iRhom2 regulate murine hair follicle differentiation by specifically modulating Notch1 and Wnt signaling pathway which maybe mediated by TACE.	16	26	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch1	Notch1	Notch1	25	26	16	17
The absence of ADAM17 mediated Delta like cleavage fits our model that ADAM17 activates Notch1 , possibly by releasing Jagged-1 and -2 , and promotes the CSC phenotype in CRC cells .	The absence of ADAM17 mediated Delta like cleavage fits our model that ADAM17 activates Notch1, possibly by releasing Jagged-1 and -2, and promotes the CSC phenotype in CRC cells.	12	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ADAM17	ADAM17	ADAM17	Notch1	Notch1	Notch1	12	13	14	15
DeltaE TM is very analogous to the natural TACE processing product of Notch1 that is generated after ligand binding .	DeltaE TM is very analogous to the natural TACE processing product of Notch1 that is generated after ligand binding.	8	13	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch1	Notch1	Notch1	8	9	12	13
Similarly , expression of exogenous Adam10 or Adam17 in mouse embryonic fibroblasts ( MEFs ) derived from Adam10 and Adam17 knockout animals , effectively increased activation of NOTCH1 signaling upon expression of activated forms of NOTCH1 in these cells ( XREF_FIG ) .	Similarly, expression of exogenous Adam10 or Adam17 in mouse embryonic fibroblasts (MEFs) derived from Adam10 and Adam17 knockout animals, effectively increased activation of NOTCH1 signaling upon expression of activated forms of NOTCH1 in these cells (XREF_FIG).	2	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Adam17	expression of exogenous Adam10 or Adam17	adam17	NOTCH1	NOTCH1	notch1	7	8	27	28
Furthermore , we found that TACE dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR .	Furthermore, we found that TACE dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch1	Notch1	Notch1	5	6	9	10
This study suggests that iRhom2 regulates hair shaft and IRS differentiation by specifically modulating Notch1 and Wnt signaling pathway which maybe mediated by TACE .	This study suggests that iRhom2 regulates hair shaft and IRS differentiation by specifically modulating Notch1 and Wnt signaling pathway which maybe mediated by TACE.	14	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	Notch1	Notch1	Notch1	23	24	14	15
MET induced cells expressed less a basic helix-loop-helix transcription factor ( TWIST ) in western blot analysis , and we confirm that BMP receptor ( Alk2 ) siRNA transduction could restore TWIST protein expression via blocking of Smad 1 , 5 and 8 signaling .	MET induced cells expressed less a basic helix-loop-helix transcription factor (TWIST) in western blot analysis, and we confirm that BMP receptor (Alk2) siRNA transduction could restore TWIST protein expression via blocking of Smad 1, 5 and 8 signaling.	23	39	restore	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	Alk2	Alk2	Alk2	Smad 1	Smad 1	Smad 1	25	26	37	39
For example , ALK5 activates Smad2 and Smad3 ( canonical TGFbeta and Smad dependent signaling pathway ) whereas ALK2 , ALK3 , and ALK6 activate Smad1 , Smad5 , and Smad8 ( BMP signaling pathway ) [ XREF_BIBR - XREF_BIBR ] .	For example, ALK5 activates Smad2 and Smad3 (canonical TGFbeta and Smad dependent signaling pathway) whereas ALK2, ALK3, and ALK6 activate Smad1, Smad5, and Smad8 (BMP signaling pathway) [XREF_BIBR - XREF_BIBR].	18	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK2	ALK2	ALK2	Smad1	Smad1	Smad1	18	19	25	26
In contrast , ALK1 and ALK2 primarily activate Smad1 and Smad5 , and are usually associated with BMP signaling .	In contrast, ALK1 and ALK2 primarily activate Smad1 and Smad5, and are usually associated with BMP signaling.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK2	ALK2	ALK2	Smad1	Smad1	Smad1	5	6	8	9
ALK5 activates Smad2 and 3 via the canonical TGFbeta signaling pathway whereas ALK2 , 3 and 6 can activate Smad1 , 5 and 8 , which are transducers of the BMP signaling pathway .	ALK5 activates Smad2 and 3 via the canonical TGFbeta signaling pathway whereas ALK2, 3 and 6 can activate Smad1, 5 and 8, which are transducers of the BMP signaling pathway.	12	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK2	ALK2	ALK2	Smad1	Smad1	Smad1	12	13	19	20
ALK5 activates Smad2 and 3 while ALK2 or ALK3 activates Smad1 , 5 , and 8 .	ALK5 activates Smad2 and 3 while ALK2 or ALK3 activates Smad1, 5, and 8.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK2	ALK2	ALK2	Smad1	Smad1	Smad1	6	7	10	11
Thus , ALK1 and ALK2 induce Smad1 dependent pathways and ALK2 functions to mediate BMP7 but not activin signaling .	Thus, ALK1 and ALK2 induce Smad1 dependent pathways and ALK2 functions to mediate BMP7 but not activin signaling.	2	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK2	ALK2	ALK2	Smad1	Smad1	Smad1	4	5	6	7
Smad2 and Smad3 are activated through carboxy-terminal phosphorylation by the TGF-beta and activin receptors TbRI and ActRIB , whereas Smad1 , Smad5 and Smad8 are activated by ALK-1 , ALK-2 , BMP-RIA and ALK -3 and BMP-RIB and ALK -6 in response to BMP1-4 or other ligands .	Smad2 and Smad3 are activated through carboxy-terminal phosphorylation by the TGF-beta and activin receptors TbRI and ActRIB, whereas Smad1, Smad5 and Smad8 are activated by ALK-1, ALK-2, BMP-RIA and ALK -3 and BMP-RIB and ALK -6 in response to BMP1-4 or other ligands.	19	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ALK-2	ALK-2	ALK-2	Smad1	Smad1	Smad1	29	30	19	20
PACAP can activate three different subtypes of receptors which are widely distributed in the CNS : the PACAP specific PAC1 receptor and two PACAP and VIP-indifferent VPAC1 and VPAC2 receptors .	PACAP can activate three different subtypes of receptors which are widely distributed in the CNS : the PACAP specific PAC1 receptor and two PACAP and VIP-indifferent VPAC1 and VPAC2 receptors.	0	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PACAP	PACAP	PACAP	VPAC1	VPAC1	VPAC1	0	1	26	27
XREF_BIBR But wild PACAP can activate the receptors VPAC1 and VPAC2 , and VPAC1 mediated hepatic glucose increase counteracts the increased insulin secretion by VPAC2 activation .	XREF_BIBR But wild PACAP can activate the receptors VPAC1 and VPAC2, and VPAC1 mediated hepatic glucose increase counteracts the increased insulin secretion by VPAC2 activation.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PACAP	PACAP	PACAP	VPAC1	VPAC1	VPAC1	3	4	8	9
Interestingly , MMA dilation to 1,000-fold higher concentrations of PACAP38 ( i.e ., 3 nM ) were not abolished but were reduced by approximately 50 % ( XREF_FIG ) , consistent with higher concentrations of PACAP38 causing activation of PAC1 receptors as well as VPAC1 and/or VPAC2 receptors .	Interestingly, MMA dilation to 1,000-fold higher concentrations of PACAP38 (i.e., 3 nM) were not abolished but were reduced by approximately 50% (XREF_FIG), consistent with higher concentrations of PACAP38 causing activation of PAC1 receptors as well as VPAC1 and/or VPAC2 receptors.	35	47	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PACAP38	PACAP38	PACAP38	VPAC1	VPAC1	VPAC1	35	36	44	45
PACAP and VIP activated distinct PAC1 and VPAC1 receptors , respectively .	PACAP and VIP activated distinct PAC1 and VPAC1 receptors, respectively.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PACAP	PACAP	PACAP	VPAC1	VPAC1	VPAC1	0	1	7	8
Consistent with the hypotensive effect mediated by VPAC2 receptors , at least a study has demonstrated that PACAP , synthesized in the adrenal medulla , is able to activate VPAC1 and VPAC2 receptors in the zona glomerulosa of the adrenal gland , ultimately promoting the systemic release of aldosterone , an endogenous hypotensive hormone [ XREF_BIBR ] .	Consistent with the hypotensive effect mediated by VPAC2 receptors, at least a study has demonstrated that PACAP, synthesized in the adrenal medulla, is able to activate VPAC1 and VPAC2 receptors in the zona glomerulosa of the adrenal gland, ultimately promoting the systemic release of aldosterone, an endogenous hypotensive hormone [XREF_BIBR].	17	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PACAP	PACAP	PACAP	VPAC1	VPAC1	VPAC1	17	18	29	30
The PAC1 receptor is more selective for PACAP while the VPAC1 and VPAC2 receptors can be potently activated by VIP or PACAP [ XREF_BIBR ] .	The PAC1 receptor is more selective for PACAP while the VPAC1 and VPAC2 receptors can be potently activated by VIP or PACAP [XREF_BIBR].	10	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PACAP	PACAP	PACAP	VPAC1	VPAC1	VPAC1	21	22	10	11
Its 3 G protein coupled receptors ( GPCRs ) can be activated by both forms : PAC 1 is specific for PACAP , whereas VPAC 1 and VPAC 2 are activated by both VIP and PACAP .	Its 3 G protein coupled receptors (GPCRs) can be activated by both forms : PAC 1 is specific for PACAP, whereas VPAC 1 and VPAC 2 are activated by both VIP and PACAP.	24	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PACAP	PACAP	PACAP	VPAC 1	VPAC 1	VPAC 1	35	36	24	26
The purpose of this study was to determine whether all D-vasoactive intestinal peptide ( VIP ) , an inactive optical isomer of L-VIP , modulates the vasorelaxant effects of human L-VIP and pituitary adenylate cyclase activating peptide ( PACAP ) 1-38 , two ubiquitous and pleiotropic neuropeptides that activate VPAC1 and VPAC2 , two VIP subtype receptors , in the intact peripheral microcirculation .	The purpose of this study was to determine whether all D-vasoactive intestinal peptide (VIP), an inactive optical isomer of L-VIP, modulates the vasorelaxant effects of human L-VIP and pituitary adenylate cyclase activating peptide (PACAP) 1-38, two ubiquitous and pleiotropic neuropeptides that activate VPAC1 and VPAC2, two VIP subtype receptors, in the intact peripheral microcirculation.	36	62	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PACAP	PACAP	PACAP	VPAC1	VPAC1	VPAC1	38	39	49	50
Interestingly , AKT1 activation has been reported to cause genomic instability via nuclear localization of BRCA1 [ XREF_BIBR ] , and PI3KCA ( upstream of AKT1 ) mutation could affect DDR pathway by Brca1 protein localization .	Interestingly, AKT1 activation has been reported to cause genomic instability via nuclear localization of BRCA1 [XREF_BIBR], and PI3KCA (upstream of AKT1) mutation could affect DDR pathway by Brca1 protein localization.	2	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	BRCA1	BRCA1	BRCA1	2	3	15	16
Akt1 promotes chromosomal instability in Brca1 deficient cells .	Akt1 promotes chromosomal instability in Brca1 deficient cells.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	Brca1	Brca1	Brca1	0	1	5	6
Depletion of Akt1 increases HR in Brca1 deficient cells .	Depletion of Akt1 increases HR in Brca1 deficient cells.	0	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt1	Akt1	Akt1	Brca1	Brca1	Brca1	2	3	6	7
In particular , overexpression of AKT1 induces the sequestration of BRCA1 and RAD51 in the cytoplasm , leading to the inhibition of HR .	In particular, overexpression of AKT1 induces the sequestration of BRCA1 and RAD51 in the cytoplasm, leading to the inhibition of HR.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT1	overexpression of AKT1	akt1	BRCA1	BRCA1	brca1	5	6	10	11
Akt-1 activation was shown to induce cytoplasmic retention of BRCA1 protein in breast cancer cells .	Akt-1 activation was shown to induce cytoplasmic retention of BRCA1 protein in breast cancer cells.	0	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt-1	Akt-1	Akt-1	BRCA1	BRCA1	BRCA1	0	1	9	10
More directly related to the questions discussed here , the overexpression of AKT1 has been shown to promote the sequestration of BRCA1 and RAD51 to the cytoplasm [ XREF_BIBR , XREF_BIBR ] .	More directly related to the questions discussed here, the overexpression of AKT1 has been shown to promote the sequestration of BRCA1 and RAD51 to the cytoplasm [XREF_BIBR, XREF_BIBR].	10	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT1	overexpression of AKT1	akt1	BRCA1	BRCA1	brca1	12	13	21	22
In contrast , myr-AKT1 , which did not induce BRCA1 chromatin dissociation , failed to induce formation of gammaH2AX and 53BP1 foci or increase the levels of chromatin associated gammaH2AX and 53BP1 ( XREF_FIG ) .	In contrast, myr-AKT1, which did not induce BRCA1 chromatin dissociation, failed to induce formation of gammaH2AX and 53BP1 foci or increase the levels of chromatin associated gammaH2AX and 53BP1 (XREF_FIG).	3	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	myr-AKT1	myr-AKT1	myr-AKT1	BRCA1	BRCA1	BRCA1	3	4	9	10
In wild-type sporadic breast cancer lines , AKT1 has been shown to promote cytoplasmic retention of BRCA1 and Rad51 .	In wild-type sporadic breast cancer lines, AKT1 has been shown to promote cytoplasmic retention of BRCA1 and Rad51.	7	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	BRCA1	BRCA1	BRCA1	7	8	16	17
For example , the activation of AKT1 by a growth factor ( heregulin beta1 ) or by hormones ( IGF-1 and estrogen ) ( in other words , physiological activation mechanisms ) promotes the nuclear localization of BRCA1 [ XREF_BIBR , XREF_BIBR ] .	For example, the activation of AKT1 by a growth factor (heregulin beta1) or by hormones (IGF-1 and estrogen) (in other words, physiological activation mechanisms) promotes the nuclear localization of BRCA1 [XREF_BIBR, XREF_BIBR].	4	41	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	BRCA1	BRCA1	BRCA1	6	7	37	38
Thus , we conclude that depletion of Akt1 increases HR in Brca1 deficient cells .	Thus, we conclude that depletion of Akt1 increases HR in Brca1 deficient cells.	5	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt1	Akt1	Akt1	Brca1	Brca1	Brca1	7	8	11	12
One possibility is that ALK2 preferentially activates Smad5 .	One possibility is that ALK2 preferentially activates Smad5.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK2	ALK2	ALK2	Smad5	Smad5	Smad5	4	5	7	8
The precise mechanism underlying the activation of Smad5 by ALK2 in the present experiments remains unclear .	The precise mechanism underlying the activation of Smad5 by ALK2 in the present experiments remains unclear.	3	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ALK2	ALK2	ALK2	Smad5	Smad5	Smad5	9	10	7	8
ALK5 and ALK4 typically activate Smad2 and Smad3 .	ALK5 and ALK4 typically activate Smad2 and Smad3.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK4	ALK4	ALK4	Smad2	Smad2	Smad2	2	3	5	6
In addition , we show that enforced expression of AIF can induce neuronal cell death in a Bax- and caspase independent manner .	In addition, we show that enforced expression of AIF can induce neuronal cell death in a Bax- and caspase independent manner.	7	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AIF	expression of AIF	aif	Bax-	Bax-	bax-	9	10	17	18
There was no difference in cell growth in HCT-116 WT cells subjected to transient apoptosis inducing factor ( AIF ) inhibition ; however , HCT-116 Bax (-/-) cells treated with AIF siRNA followed by ionizing radiation had a significant survival advantage compared with control treated cells , implicating AIF in the radiosensitivity of Bax (-/-) cells .	There was no difference in cell growth in HCT-116 WT cells subjected to transient apoptosis inducing factor (AIF) inhibition; however, HCT-116 Bax (-/-) cells treated with AIF siRNA followed by ionizing radiation had a significant survival advantage compared with control treated cells, implicating AIF in the radiosensitivity of Bax (-/-) cells.	24	36	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	AIF	AIF	AIF	Bax	Bax	Bax	30	31	25	26
These results indicated that RES-BSANP-elicited cell death may not occur via a classical Cyto c mitochondria cytosol translocation mechanism but rather , a caspase independent mechanism of cell death via the nucleus directed shuttling of AIF and Cyto c. Activation of Bax and its mitochondrial translocation are the key regulatory events during induction of mitochondrial membrane depolarization .	These results indicated that RES-BSANP-elicited cell death may not occur via a classical Cyto c mitochondria cytosol translocation mechanism but rather, a caspase independent mechanism of cell death via the nucleus directed shuttling of AIF and Cyto c. Activation of Bax and its mitochondrial translocation are the key regulatory events during induction of mitochondrial membrane depolarization.	35	42	Activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AIF	AIF	AIF	Bax	Bax	Bax	35	36	41	42
The possibility of whether the Akt1 isoform activates IKKalpha to create inflammatory feedback to insulin resistance mediated by Akt2 is plausible , but unknown .	The possibility of whether the Akt1 isoform activates IKKalpha to create inflammatory feedback to insulin resistance mediated by Akt2 is plausible, but unknown.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	IKKalpha	IKKalpha	IKKalpha	5	6	8	9
In this three-step signalling cascade , phosphatidylinositol-3 kinase ( PI3K ) phosphorylates protein kinase B ( AKT ) , which then activates I-kappaB kinase ( IKK ) , followed by phosphorylation and degradation of the NF-kappaB inhibitor I-kappaB .	In this three-step signalling cascade, phosphatidylinositol-3 kinase (PI3K) phosphorylates protein kinase B (AKT), which then activates I-kappaB kinase (IKK), followed by phosphorylation and degradation of the NF-kappaB inhibitor I-kappaB.	11	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein kinase B	phosphorylates protein kinase B	protein kinase b	I-kappaB kinase	I-kappaB kinase	i-kappab kinase	12	15	22	24
The highly expressed PTOP and TRF1 groups were observed having increased telomerase activity .	The highly expressed PTOP and TRF1 groups were observed having increased telomerase activity.	0	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTOP	PTOP	PTOP	telomerase	telomerase	telomerase	3	4	11	12
On the other hand , ACD is a core protein in the shelterin complex and mediates the access of telomerase to the telomere .	On the other hand, ACD is a core protein in the shelterin complex and mediates the access of telomerase to the telomere.	5	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACD	ACD	ACD	telomerase	telomerase	telomerase	5	6	19	20
The activated Akt1 then increased the activity of CDK2 and accelerated the cell cycle progression of 3T3-L1 cells .	The activated Akt1 then increased the activity of CDK2 and accelerated the cell cycle progression of 3T3-L1 cells.	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	CDK2	CDK2	CDK2	2	3	8	9
We also confirmed the GPR56 mediated transcriptional activity by silencing GPR56 expression through shRNA mediated RNA interference .	We also confirmed the GPR56 mediated transcriptional activity by silencing GPR56 expression through shRNA mediated RNA interference.	2	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	GPR56	GPR56 expression	gpr56	GPR56	GPR56	gpr56	10	11	4	5
Akt1 was shown to phosphorylate Ser1177 and activate eNOS in ECs , and to increase NO synthesis and cGMP elevation during platelet activation and thus promoting platelet secretion and aggregation .	Akt1 was shown to phosphorylate Ser1177 and activate eNOS in ECs, and to increase NO synthesis and cGMP elevation during platelet activation and thus promoting platelet secretion and aggregation.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	eNOS	eNOS	eNOS	0	1	8	9
Interestingly , AKT1 also promotes activation of eNOS through phosphorylation [ XREF_BIBR ] .	Interestingly, AKT1 also promotes activation of eNOS through phosphorylation [XREF_BIBR].	2	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	eNOS	eNOS	eNOS	2	3	7	8
Both shear stress and insulin increase endothelial NO production via activation of PI-3-kinase and protein kinase B ( PKB and Akt ) , which activate eNOS by Ser1179 phosphorylation [ XREF_BIBR ] .	Both shear stress and insulin increase endothelial NO production via activation of PI-3-kinase and protein kinase B (PKB and Akt), which activate eNOS by Ser1179 phosphorylation [XREF_BIBR].	12	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	eNOS	eNOS	eNOS	14	17	25	26
Although the AKT1 mediated activation of eNOS by FSS has been reported to be independent of changes in intracellular calcium , it is more likely that the phosphorylation of S1177 renders the enzyme more responsive to much lower levels of calcium .	Although the AKT1 mediated activation of eNOS by FSS has been reported to be independent of changes in intracellular calcium, it is more likely that the phosphorylation of S1177 renders the enzyme more responsive to much lower levels of calcium.	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	eNOS	eNOS	eNOS	2	3	6	7
21 In addition , this occurs though activation of phosphatidylinositol 3-kinase , which stimulates protein kinase B ( Akt ) activity , thus activating NOS3 .	21 In addition, this occurs though activation of phosphatidylinositol 3-kinase, which stimulates protein kinase B (Akt) activity, thus activating NOS3.	14	25	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	NOS3	NOS3	NOS3	14	17	24	25
For example , Akt1 stimulates eNOS in endothelial cells but not in VSMCs .	For example, Akt1 stimulates eNOS in endothelial cells but not in VSMCs.	3	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	eNOS	eNOS	eNOS	3	4	5	6
Akt1 activates NOS3 by direct phosphorylation .	Akt1 activates NOS3 by direct phosphorylation.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	NOS3	NOS3	NOS3	0	1	2	3
The activation of phosphatidylinositol 3-kinase ( PI3-K ) further activates protein kinase B ( PKB and Akt ) , which subsequently enhances eNOS activation and vascular NO generation .	The activation of phosphatidylinositol 3-kinase (PI3-K) further activates protein kinase B (PKB and Akt), which subsequently enhances eNOS activation and vascular NO generation.	10	23	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	eNOS	eNOS	eNOS	10	13	22	23
Following activation , AKT-1 activates Rac-1 and eNOS , which may act in concert to induce actin dependent outward spreading of endothelial cells that increases endothelial barrier function in response to S1P .	Following activation, AKT-1 activates Rac-1 and eNOS, which may act in concert to induce actin dependent outward spreading of endothelial cells that increases endothelial barrier function in response to S1P.	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT-1	AKT-1	AKT-1	eNOS	eNOS	eNOS	3	4	7	8
Previous study has indicated that eNOS can be activated by the serine/threonine protein kinase Akt ( protein kinase B ) on serine 1177 , leading to the production of NO [ XREF_BIBR ] , which plays an important role in protecting brain tissue by augmenting rCBF after cerebral ischemia [ XREF_BIBR ] .	Previous study has indicated that eNOS can be activated by the serine/threonine protein kinase Akt (protein kinase B) on serine 1177, leading to the production of NO [XREF_BIBR], which plays an important role in protecting brain tissue by augmenting rCBF after cerebral ischemia [XREF_BIBR].	5	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	eNOS	eNOS	eNOS	16	19	5	6
Previously , it was reported that Akt-1 , but not Akt-2 , is important for basal and vascular endothelial growth factor stimulated eNOS activity/NO release .	Previously, it was reported that Akt-1, but not Akt-2, is important for basal and vascular endothelial growth factor stimulated eNOS activity/NO release.	6	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt-1	Akt-1	Akt-1	eNOS	eNOS	eNOS	6	7	22	23
Since Akt1 can activate eNOS by direct phosphorylation at Ser1177 , total and p-eNOS Ser1177 protein content were determined .	Since Akt1 can activate eNOS by direct phosphorylation at Ser1177, total and p-eNOS Ser1177 protein content were determined.	1	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	eNOS	eNOS	eNOS	1	2	4	5
The RUNX3 mediated inhibition of Akt1 caused beta-catenin protein degradation and then cyclin D1 downregulation .	The RUNX3 mediated inhibition of Akt1 caused beta-catenin protein degradation and then cyclin D1 downregulation.	3	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	beta-catenin	beta-catenin	beta-catenin	5	6	7	8
As shown in XREF_FIG , expression of low levels of Akt1 increased beta-catenin transactivation , whereas further increased Akt1 expression repressed beta-catenin transactivation , analogous to that observed with IFNgamma ( XREF_FIG ) .	As shown in XREF_FIG, expression of low levels of Akt1 increased beta-catenin transactivation, whereas further increased Akt1 expression repressed beta-catenin transactivation, analogous to that observed with IFNgamma (XREF_FIG).	8	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	levels of Akt1	akt1	beta-catenin	beta-catenin	beta-catenin	10	11	12	13
Indeed , upon PDGFR activation in VSMCs , the Akt1 kinase can potentially activate beta-catenin both through its direct phosphorylation at Ser522 [ XREF_BIBR , XREF_BIBR ] and by inhibiting its attenuator GSK3beta [ XREF_BIBR , XREF_BIBR ] .	Indeed, upon PDGFR activation in VSMCs, the Akt1 kinase can potentially activate beta-catenin both through its direct phosphorylation at Ser522 [XREF_BIBR, XREF_BIBR] and by inhibiting its attenuator GSK3beta [XREF_BIBR, XREF_BIBR].	9	15	potentially activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	beta-catenin	beta-catenin	beta-catenin	9	10	14	15
Notably , overexpressing miR-542-3p decreased AKT1 phosphorylation and directly and indirectly repressed nuclear translocation and transactivation activity of beta-catenin to exert its anti-invasive effect .	Notably, overexpressing miR-542-3p decreased AKT1 phosphorylation and directly and indirectly repressed nuclear translocation and transactivation activity of beta-catenin to exert its anti-invasive effect.	3	19	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT1	miR-542-3p decreased AKT1 phosphorylation	akt1	beta-catenin	beta-catenin	beta-catenin	5	6	18	19
In addition we also show that the HoxA5 mediated increase in stability of adherens junctions requires Akt1 activity and introduction of constitutively active myr-Akt in EOMA cells also increased retention of beta-catenin in adherens junctions .	In addition we also show that the HoxA5 mediated increase in stability of adherens junctions requires Akt1 activity and introduction of constitutively active myr-Akt in EOMA cells also increased retention of beta-catenin in adherens junctions.	16	32	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	beta-catenin	beta-catenin	beta-catenin	16	17	31	32
Akt1 activates beta-catenin signaling induced by poly ( I : C ) .	Akt1 activates beta-catenin signaling induced by poly (I : C).	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	beta-catenin	beta-catenin	beta-catenin	0	1	2	3
We provide evidence for a selective involvement of the mTOR target Akt2 in tumoral growth .	We provide evidence for a selective involvement of the mTOR target Akt2 in tumoral growth.	6	14	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Akt2	Akt2	Akt2	mTOR	mTOR	mTOR	11	12	9	10
Unexpectedly , AKT1 , AKT2 , and AKT3 knockdown by shRNAs , whether singly or in combination , enhanced mTOR activation ( XREF_SUPPLEMENTARY ) , and although the mechanism is unclear , these data provide an additional rationale for dual targeting of AKT and mTOR in mesothelioma .	Unexpectedly, AKT1, AKT2, and AKT3 knockdown by shRNAs, whether singly or in combination, enhanced mTOR activation (XREF_SUPPLEMENTARY), and although the mechanism is unclear, these data provide an additional rationale for dual targeting of AKT and mTOR in mesothelioma.	2	20	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT2	AKT2	AKT2	mTOR	mTOR	mTOR	4	5	19	20
Akt2 knockout alleviated cardiac phenotypes and augmented mTOR inhibition induced by caloric restriction [ XREF_BIBR ] .	Akt2 knockout alleviated cardiac phenotypes and augmented mTOR inhibition induced by caloric restriction [XREF_BIBR].	0	8	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt2	Akt2	Akt2	mTOR	mTOR	mTOR	0	1	7	8
Lastly , ablation of Akt2 does not increase mTOR activation as tumor burden increases .	Lastly, ablation of Akt2 does not increase mTOR activation as tumor burden increases.	2	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt2	Akt2	Akt2	mTOR	mTOR	mTOR	4	5	8	9
Akt2 , which plays a centralized role in the PI-3K pathway stimulates mTOR activity , which then stimulates p70S6K activityresulting in subsequent protein synthesis ( XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY Figs ) .	Akt2, which plays a centralized role in the PI-3K pathway stimulates mTOR activity, which then stimulates p70S6K activityresulting in subsequent protein synthesis (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY Figs).	0	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt2	Akt2	Akt2	mTOR	mTOR	mTOR	0	1	12	13
This is consistent with previous observations that Akt2 and Akt3 activate mTOR .	This is consistent with previous observations that Akt2 and Akt3 activate mTOR.	7	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt2	Akt2	Akt2	mTOR	mTOR	mTOR	7	8	11	12
In this circuit , IRF6 positively induced AKT1 that upregulated MDM2 , which in turn repressed TP53 in HNSCC .	In this circuit, IRF6 positively induced AKT1 that upregulated MDM2, which in turn repressed TP53 in HNSCC.	6	15	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	MDM2	MDM2	MDM2	7	8	10	11
We validated that Akt1 overexpression upregulated Mdm2 protein followed by downregulation of the p53 dependent p21 protein expression .	We validated that Akt1 overexpression upregulated Mdm2 protein followed by downregulation of the p53 dependent p21 protein expression.	3	7	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1 overexpression	akt1	Mdm2	Mdm2	mdm2	3	4	6	7
Activation of Akt1 can induce MDM2 mediated degradation of p53 and may thereby suppress p53 dependent effects on tumor formation .	Activation of Akt1 can induce MDM2 mediated degradation of p53 and may thereby suppress p53 dependent effects on tumor formation.	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	MDM2	MDM2	MDM2	2	3	5	6
Transient transfection studies revealed that constitutively active Akt1 up-regulated ERalpha at the post-transcriptional level .	Transient transfection studies revealed that constitutively active Akt1 up-regulated ERalpha at the post-transcriptional level.	6	10	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	ERalpha	ERalpha	ERalpha	7	8	9	10
However , AKT2 induced ERalpha activity was not inhibited by tamoxifen but was completely abolished by ICI 164,384 , implicating that AKT2 activated ERalpha contributes to tamoxifen resistance .	However, AKT2 induced ERalpha activity was not inhibited by tamoxifen but was completely abolished by ICI 164,384, implicating that AKT2 activated ERalpha contributes to tamoxifen resistance.	21	24	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AKT2	AKT2	AKT2	ERalpha	ERalpha	ERalpha	21	22	23	24
Our results indicate that in ER positive breast cancer cells , Akt2 modulates ER transcriptional activity at multiple levels , including ( i ) the regulation of ER expression and its nuclear retention and ( ii ) the activation of one of its downstream targets , the Forkhead transcription factor FoxO3a .	Our results indicate that in ER positive breast cancer cells, Akt2 modulates ER transcriptional activity at multiple levels, including (i) the regulation of ER expression and its nuclear retention and (ii) the activation of one of its downstream targets, the Forkhead transcription factor FoxO3a.	11	15	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt2	Akt2	Akt2	ER	ER	ER	11	12	13	14
The ability of interleukin-3 dependent cells to stimulate plasma membrane localization of GLUT1 and glucose import requires phosphatidylinositol 3-kinase ( PI3K ) [ XREF_BIBR , XREF_BIBR ] , but expression of myr-Akt1 can induce GLUT1 plasma membrane localization and HKI activity in the absence of interleukin-3 [ XREF_BIBR ] .	The ability of interleukin-3 dependent cells to stimulate plasma membrane localization of GLUT1 and glucose import requires phosphatidylinositol 3-kinase (PI3K) [XREF_BIBR, XREF_BIBR], but expression of myr-Akt1 can induce GLUT1 plasma membrane localization and HKI activity in the absence of interleukin-3 [XREF_BIBR].	29	40	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	myr-Akt1	expression of myr-Akt1	myr-akt1	HKI	HKI	hki	31	32	39	40
It was previously demonstrated that , in endothelial cells , hyperglycemia induced protein kinase C and mitogen activated protein kinase , as well as protein kinase B activation , may enhance the activity of p300 [ XREF_BIBR ] .	It was previously demonstrated that, in endothelial cells, hyperglycemia induced protein kinase C and mitogen activated protein kinase, as well as protein kinase B activation, may enhance the activity of p300 [XREF_BIBR].	24	36	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	p300	p300	p300	24	27	34	35
Given that IGF activated Akt1 modulates p300 to associate with MyoD , it is intriguing to hypothesize how other parallel regulatory schemas of this signaling pathway alter fundamental changes in TF binding and chromatin states that drive muscle regeneration after severe trauma .	Given that IGF activated Akt1 modulates p300 to associate with MyoD, it is intriguing to hypothesize how other parallel regulatory schemas of this signaling pathway alter fundamental changes in TF binding and chromatin states that drive muscle regeneration after severe trauma.	4	7	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	p300	p300	p300	4	5	6	7
One could speculate that TERT is activated by Akt1 in the mitochondria and Telomerase activity in conjunction with RMRP is involved in the control of gene expression , possibly also of genes encoding respiratory chain complexes .	One could speculate that TERT is activated by Akt1 in the mitochondria and Telomerase activity in conjunction with RMRP is involved in the control of gene expression, possibly also of genes encoding respiratory chain complexes.	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt1	Akt1	Akt1	TERT	TERT	TERT	8	9	4	5
Conversely , AKT1 has been shown to phosphorylate and negatively regulate GSK3 beta and positively regulate WNK1 .	Conversely, AKT1 has been shown to phosphorylate and negatively regulate GSK3 beta and positively regulate WNK1.	2	17	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	WNK1	WNK1	WNK1	2	3	16	17
In XREF_FIG C , AKT1 activation of WNK1 is conserved as from the four stimuli ( EGF , TGFA , EPGC , INS ) activating WNK1 in human and rat , only EGF signaling is not similar in rat and human cells .	In XREF_FIG C, AKT1 activation of WNK1 is conserved as from the four stimuli (EGF, TGFA, EPGC, INS) activating WNK1 in human and rat, only EGF signaling is not similar in rat and human cells.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	WNK1	WNK1	WNK1	4	5	7	8
As AKT2 may activate beta-catenin by inhibition of GSK-3beta XREF_BIBR and Wnt and beta-catenin signal pathway is very important in cancer cell progression , including CRC XREF_BIBR , we next to detect whether miR-194 inhibits CRC cell invasion via blocking Wnt and beta-catenin pathway .	As AKT2 may activate beta-catenin by inhibition of GSK-3beta XREF_BIBR and Wnt and beta-catenin signal pathway is very important in cancer cell progression, including CRC XREF_BIBR, we next to detect whether miR-194 inhibits CRC cell invasion via blocking Wnt and beta-catenin pathway.	1	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT2	AKT2	AKT2	beta-catenin	beta-catenin	beta-catenin	1	2	4	5
It was reported that Akt2 specifically activated ezrin at T567 phosphorylation site [ XREF_BIBR ] .	It was reported that Akt2 specifically activated ezrin at T567 phosphorylation site [XREF_BIBR].	4	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt2	Akt2	Akt2	ezrin	ezrin	ezrin	4	5	7	8
Phosphorylation of protein kinase B ( Akt ) via several intermediate steps by PI3K ultimately leads to translocation of glucose transporter 4 ( GLUT4 ) to the cardiomyocyte cell surface and facilitates glucose uptake .	Phosphorylation of protein kinase B (Akt) via several intermediate steps by PI3K ultimately leads to translocation of glucose transporter 4 (GLUT4) to the cardiomyocyte cell surface and facilitates glucose uptake.	0	29	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein kinase B	Phosphorylation of protein kinase B	protein kinase b	GLUT4	GLUT4	glut4	2	5	23	24
Specifically , iAs III and MAs III inhibited insulin dependent phosphorylation of protein kinase B ( PKB and Akt ) , thus preventing translocation of GLUT4 ( insulin sensitive glucose transporter ) from the perinuclear compartment of adipocytes to the plasma membrane .	Specifically, iAs III and MAs III inhibited insulin dependent phosphorylation of protein kinase B (PKB and Akt), thus preventing translocation of GLUT4 (insulin sensitive glucose transporter) from the perinuclear compartment of adipocytes to the plasma membrane.	2	27	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	protein kinase B	iAs III and MAs III inhibited insulin dependent phosphorylation of protein kinase B	protein kinase b	GLUT4	GLUT4	glut4	12	15	25	26
Blocking AKT1 reversed the increase of E-cadherin and decrease of Vimentin evoked by nuclear OPN , whereas AKT2 blockage failed to achieve this effect ( XREF_FIG ) .	Blocking AKT1 reversed the increase of E-cadherin and decrease of Vimentin evoked by nuclear OPN, whereas AKT2 blockage failed to achieve this effect (XREF_FIG).	0	11	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	Vimentin	Vimentin	Vimentin	1	2	10	11
In an apparently reciprocal relationship , AKT isoforms regulate intermediate filament expression in epithelial cancer cell lines , as overexpression of AKT1 increases K8/K18 levels and AKT2 upregulates K18 and vimentin .	In an apparently reciprocal relationship, AKT isoforms regulate intermediate filament expression in epithelial cancer cell lines, as overexpression of AKT1 increases K8/K18 levels and AKT2 upregulates K18 and vimentin.	19	31	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT1	overexpression of AKT1	akt1	vimentin	vimentin	vimentin	21	22	30	31
PIKfyve is stimulated by protein kinase B , a close relative of SGK3 , phosphorylating serine and threonine residues within a similar core consensus sequence ( RXRXX [ S/T ] ) XREF_BIBR .	PIKfyve is stimulated by protein kinase B, a close relative of SGK3, phosphorylating serine and threonine residues within a similar core consensus sequence (RXRXX [S/T]) XREF_BIBR.	0	7	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	PIKfyve	PIKfyve	PIKfyve	4	7	0	1
The ubiquitously expressed protein kinase B ( PKB and Akt ) activates the phosphatidylinositol-3-phosphate-5-kinase PIKfyve , which in turn regulates a variety of carriers and channels .	The ubiquitously expressed protein kinase B (PKB and Akt) activates the phosphatidylinositol-3-phosphate-5-kinase PIKfyve, which in turn regulates a variety of carriers and channels.	3	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	PIKfyve	PIKfyve	PIKfyve	3	6	14	15
One of them is AKT1 , which enhances SRPK2 kinase activity toward SRSF2 and ACIN1 .	One of them is AKT1, which enhances SRPK2 kinase activity toward SRSF2 and ACIN1.	2	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	SRPK2	SRPK2	SRPK2	4	5	8	9
Silencing AKT2 using siRNA increased Gli1 transcriptional activity and conversely , overexpression of constitutively active AKT2 ( myr-AKT2 ) decreased Gli1 transcriptional activity .	Silencing AKT2 using siRNA increased Gli1 transcriptional activity and conversely, overexpression of constitutively active AKT2 (myr-AKT2) decreased Gli1 transcriptional activity.	11	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT2	overexpression of constitutively active AKT2	akt2	Gli1	Gli1	gli1	15	16	20	21
MDM4 , P53 regulator is also stimulated by AKT1 .	MDM4, P53 regulator is also stimulated by AKT1.	0	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT1	AKT1	AKT1	MDM4	MDM4	MDM4	8	9	0	1
The protective effects of MO are dependent on Akt dependent activation of eNOS signaling .	The protective effects of MO are dependent on Akt dependent activation of eNOS signaling.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	8	9	12	13
In vitro , vandetanib decreased Akt phosphorylation and NO production , yet increased eNOS membrane content .	In vitro, vandetanib decreased Akt phosphorylation and NO production, yet increased eNOS membrane content.	3	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	vandetanib decreased Akt phosphorylation	akt	eNOS	eNOS	enos	5	6	13	14
TRPV1 activation increased the phosphorylation of Akt , CaMKII , and eNOS in the aortas of wild-type mice but failed to activate eNOS in TRPV1 deficient aortas .	TRPV1 activation increased the phosphorylation of Akt, CaMKII, and eNOS in the aortas of wild-type mice but failed to activate eNOS in TRPV1 deficient aortas.	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	TRPV1 activation increased the phosphorylation of Akt	akt	eNOS	eNOS	enos	6	7	22	23
Of note , the AKT kinase can also signal directly to activate eNOS , contributing to high NO levels .	Of note, the AKT kinase can also signal directly to activate eNOS, contributing to high NO levels.	4	13	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	4	5	12	13
In addition , Akt enhances glucose uptake [ XREF_BIBR ] and Akt dependent activation of eNOS ( endothelial Nitric Oxide Synthase ) [ XREF_BIBR ] triggering changes in mitochondrial respiration , which may also play a role in regulating cell survival in the setting of metabolic stress .	In addition, Akt enhances glucose uptake [XREF_BIBR] and Akt dependent activation of eNOS (endothelial Nitric Oxide Synthase) [XREF_BIBR] triggering changes in mitochondrial respiration, which may also play a role in regulating cell survival in the setting of metabolic stress.	11	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	11	12	15	16
Studies of VEGF and shear-stress-mediated phosphorylation of eNOS indicated that the serine/threonine protein kinase Akt and PKB mediates the activation of eNOS , leading to increase NO production [ XREF_BIBR ] .	Studies of VEGF and shear-stress-mediated phosphorylation of eNOS indicated that the serine/threonine protein kinase Akt and PKB mediates the activation of eNOS, leading to increase NO production [XREF_BIBR].	14	22	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKB	PKB	PKB	eNOS	eNOS	eNOS	16	17	21	22
Our observation of the co-expression of eNOS , p-ERK , and p-Akt raises the possibility that eNOS upregulation during reoxygenation may be partly mediated by the activation of the Akt and ERK pathways .	Our observation of the co-expression of eNOS, p-ERK, and p-Akt raises the possibility that eNOS upregulation during reoxygenation may be partly mediated by the activation of the Akt and ERK pathways.	16	32	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	29	30	16	17
Stimulation of the phosphatidylinositol-3-OH kinase and Akt pathway improves serine phosphorylation and induces eNOS activation and NO release .	Stimulation of the phosphatidylinositol-3-OH kinase and Akt pathway improves serine phosphorylation and induces eNOS activation and NO release.	6	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	6	7	13	14
Akt in turn phosphorylates and thereby activates eNOS , resulting in increased NO production .	Akt in turn phosphorylates and thereby activates eNOS, resulting in increased NO production.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	0	1	7	8
We then studied the role of the PI3K-Akt pathway in flow induced eNOS activation .	We then studied the role of the PI3K-Akt pathway in flow induced eNOS activation.	7	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	eNOS	eNOS	eNOS	7	8	12	13
Taken together with XREF_FIG , these results are in agreement with the PI3K and Akt pathway being fundamentally involved in low-dose nitroglycerin induced eNOS dependent nitric oxide production by endothelial cells .	Taken together with XREF_FIG, these results are in agreement with the PI3K and Akt pathway being fundamentally involved in low-dose nitroglycerin induced eNOS dependent nitric oxide production by endothelial cells.	12	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	14	15	23	24
A role for a membrane caveolae localized ERalpha46 in rapid NO release via PI3K and Akt activated eNOS has been reported in endothelial cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	A role for a membrane caveolae localized ERalpha46 in rapid NO release via PI3K and Akt activated eNOS has been reported in endothelial cells [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	11	20	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	15	16	17	18
9 Akt protein kinase is known to activate eNOS via direct phosphorylation of serine 1177 .	9 Akt protein kinase is known to activate eNOS via direct phosphorylation of serine 1177.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	1	2	8	9
It was reported that Akt can activate eNOS , which can cause the production of NO [ XREF_BIBR ] .	It was reported that Akt can activate eNOS, which can cause the production of NO [XREF_BIBR].	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	4	5	7	8
Ginseng extract administration stimulated nongenomic Akt mediated eNOS activation , enhanced NO production , improved vessel wall thickening , and alleviated hypertension in SHRs , confirming the physiological relevance of previous in vitro studies with ginsenosides .	Ginseng extract administration stimulated nongenomic Akt mediated eNOS activation, enhanced NO production, improved vessel wall thickening, and alleviated hypertension in SHRs, confirming the physiological relevance of previous in vitro studies with ginsenosides.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	5	6	7	8
The activation of eNOS by AKT contributes to the important physiological effects of AKT on apoptosis , cell attachment and cell proliferation [ XREF_BIBR - XREF_BIBR ] .	The activation of eNOS by AKT contributes to the important physiological effects of AKT on apoptosis, cell attachment and cell proliferation [XREF_BIBR - XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	5	6	3	4
Thymosin beta4 stimulates Akt and eNOS phosphorylation and upregulates eNOS signaling in preconditioned EPCs ; thymosin beta4 can also increase the survival ratio of transplanted EPCs via NO mediated vascular tissue relaxation and augmented blood flow .	Thymosin beta4 stimulates Akt and eNOS phosphorylation and upregulates eNOS signaling in preconditioned EPCs; thymosin beta4 can also increase the survival ratio of transplanted EPCs via NO mediated vascular tissue relaxation and augmented blood flow.	0	10	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Thymosin beta4 stimulates Akt and eNOS phosphorylation	akt	eNOS	eNOS	enos	3	4	9	10
Although the molecular targets of prostanoids have not been elucidated fully [ XREF_BIBR ] , the protective effect of the statin atorvastatin ( ATV ) in reducing myocardial infarct size ( when administered before ischemia or upon reperfusion ) appears to involve both the up-regulation and PI3K and Akt dependent activation of eNOS [ XREF_BIBR ] , the NF-kappaB-dependent induction of iNOS and COX-2 , and finally COX-2 S nitrosylation and activation [ XREF_BIBR , XREF_BIBR ] .	Although the molecular targets of prostanoids have not been elucidated fully [XREF_BIBR], the protective effect of the statin atorvastatin (ATV) in reducing myocardial infarct size (when administered before ischemia or upon reperfusion) appears to involve both the up-regulation and PI3K and Akt dependent activation of eNOS [XREF_BIBR], the NF-kappaB-dependent induction of iNOS and COX-2, and finally COX-2 S nitrosylation and activation [XREF_BIBR, XREF_BIBR].	48	54	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	48	49	52	53
ANGPT1 also induces the PI3K and AKT mediated activation of eNOS and NO release in endothelial cells [ XREF_BIBR , XREF_BIBR ] .	ANGPT1 also induces the PI3K and AKT mediated activation of eNOS and NO release in endothelial cells [XREF_BIBR, XREF_BIBR].	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	6	7	10	11
PI3K activation and subsequent Akt pathway engagement results in eNOS activation by phosphorylation at Ser1177 , and leads to NO generation necessary for effective cell migration [ XREF_BIBR ] .	PI3K activation and subsequent Akt pathway engagement results in eNOS activation by phosphorylation at Ser1177, and leads to NO generation necessary for effective cell migration [XREF_BIBR].	4	11	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	4	5	9	10
Activation of Akt is known to modulate eNOS activity through phosphorylation of eNOS at Ser 1177 XREF_BIBR , XREF_BIBR .	Activation of Akt is known to modulate eNOS activity through phosphorylation of eNOS at Ser 1177 XREF_BIBR, XREF_BIBR.	0	8	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	7	8
Src activation induced the phosphorylation of caveolin-1 , Akt and eNOS , and promoted dissociation of eNOS from caveolin-1 .	Src activation induced the phosphorylation of caveolin-1, Akt and eNOS, and promoted dissociation of eNOS from caveolin-1.	0	17	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Src activation induced the phosphorylation of caveolin-1, Akt	akt	eNOS	eNOS	enos	8	9	16	17
By inducing eNOS activity , activation of the PI3K and Akt pathway can enhance the cell survival [ XREF_BIBR , XREF_BIBR ] .	By inducing eNOS activity, activation of the PI3K and Akt pathway can enhance the cell survival [XREF_BIBR, XREF_BIBR].	2	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	10	11	2	3
Akt is well known to mediate activation of eNOS XREF_BIBR .	Akt is well known to mediate activation of eNOS XREF_BIBR.	0	9	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	0	1	8	9
In addition , AKT activates eNOS , which contributes to tumor maintenance [ XREF_BIBR , XREF_BIBR ] .	In addition, AKT activates eNOS, which contributes to tumor maintenance [XREF_BIBR, XREF_BIBR].	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	3	4	5	6
34 Our data suggest for the first time that impaired endothelial function results from sFLT1 blockade of autocrine VEGF-A action and the subsequent reduction in AKT mediated eNOS Ser 1177 phosphorylation .	34 Our data suggest for the first time that impaired endothelial function results from sFLT1 blockade of autocrine VEGF-A action and the subsequent reduction in AKT mediated eNOS Ser 1177 phosphorylation.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	25	26	27	28
Given the critical role of PI3K-Akt signaling in eNOS activation , the observed down-regulation of Akt can further diminish endothelial NO production in a hyperphosphatemic state .	Given the critical role of PI3K-Akt signaling in eNOS activation, the observed down-regulation of Akt can further diminish endothelial NO production in a hyperphosphatemic state.	5	9	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	eNOS	eNOS	eNOS	5	6	8	9
eNOS is activated by the phosphorylation of serine ( Ser1177 ) of the protein kinase Akt and PKB and is also known to regulate glomerular hemodynamics by generation of nitric oxide ( NO ) [ XREF_BIBR , XREF_BIBR ] .	eNOS is activated by the phosphorylation of serine (Ser1177) of the protein kinase Akt and PKB and is also known to regulate glomerular hemodynamics by generation of nitric oxide (NO) [XREF_BIBR, XREF_BIBR].	0	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKB	phosphorylation of serine (Ser1177) of the protein kinase Akt and PKB	pkb	eNOS	eNOS	enos	17	18	0	1
eNOS activity was induced by the increase of Akt phosphorylation [ XREF_BIBR ] .	eNOS activity was induced by the increase of Akt phosphorylation [XREF_BIBR].	0	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	eNOS	eNOS	enos	8	9	0	1
The MDBK cell culture system was used as a model to examine whether the function of AKT and PKB may be associated with the ability of GH to modulate the activation state of the NO generating enzyme eNOS .	The MDBK cell culture system was used as a model to examine whether the function of AKT and PKB may be associated with the ability of GH to modulate the activation state of the NO generating enzyme eNOS.	14	38	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	16	17	37	38
In DHA treated HCAEC , acute activation of Akt by VEGF enhanced the activity of eNOS and caused nearly a 3.0 fold increase in NOx production .	In DHA treated HCAEC, acute activation of Akt by VEGF enhanced the activity of eNOS and caused nearly a 3.0 fold increase in NOx production.	6	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	8	9	15	16
This study indicates that addition of low-amplitude pulses to circulation through pG ( z ) produces endothelial dependent vasodilatation due to increased NO in rats , which is mediated via activation of eNOS , in part , by the Akt and PI3K pathway .	This study indicates that addition of low-amplitude pulses to circulation through pG (z) produces endothelial dependent vasodilatation due to increased NO in rats, which is mediated via activation of eNOS, in part, by the Akt and PI3K pathway.	30	42	activation	Positive_activation_syntax_6_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	39	40	32	33
Moreover , magnolol mediated up-regulation of NO/cyclic GMP and PKG pathway and Akt phosphorylation leading to increase of eNOS activity were markedly abolished by blocking PPAR-beta and gamma activity .	Moreover, magnolol mediated up-regulation of NO/cyclic GMP and PKG pathway and Akt phosphorylation leading to increase of eNOS activity were markedly abolished by blocking PPAR-beta and gamma activity.	12	19	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	eNOS	eNOS	enos	12	13	18	19
Activation of the protein kinase Akt and PKB mediates VEGF dependent endothelial cell survival and eNOS activation .	Activation of the protein kinase Akt and PKB mediates VEGF dependent endothelial cell survival and eNOS activation.	0	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKB	PKB	PKB	eNOS	eNOS	eNOS	7	8	15	16
In addition to nNOS , eNOS upregulated by the PI3K and Akt pathway also takes part in neuroprotection in RIC [ XREF_BIBR ] .	In addition to nNOS, eNOS upregulated by the PI3K and Akt pathway also takes part in neuroprotection in RIC [XREF_BIBR].	5	14	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	11	12	5	6
The later finding suggests that Akt mediated cNOS activation plays an essential role in the mechanism of ghrelin action on the LPS induced impairment in mucin synthesis .	The later finding suggests that Akt mediated cNOS activation plays an essential role in the mechanism of ghrelin action on the LPS induced impairment in mucin synthesis.	5	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	cNOS	cNOS	cNOS	5	6	7	8
Moreover , the AKT pathway activates eNOS through direct phosphorylation of AKT at Ser473 in response to laminar flow XREF_BIBR , XREF_BIBR , XREF_BIBR .	Moreover, the AKT pathway activates eNOS through direct phosphorylation of AKT at Ser473 in response to laminar flow XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	3	4	6	7
Phosphorylation of the serine threonine kinase Akt , which activates eNOS , was substantially reduced in sinusoidal endothelial cells from injured livers .	Phosphorylation of the serine threonine kinase Akt, which activates eNOS, was substantially reduced in sinusoidal endothelial cells from injured livers.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Phosphorylation of the serine threonine kinase Akt	akt	eNOS	eNOS	enos	6	7	10	11
The evaluation of vessels stimulated with insulin from each group could provide more convincing evidence that alteration of PI3K and Akt mediated eNOS signaling pathways contributes to insulin response .	The evaluation of vessels stimulated with insulin from each group could provide more convincing evidence that alteration of PI3K and Akt mediated eNOS signaling pathways contributes to insulin response.	16	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	20	21	22	23
Simvastatin modulates central BP control in the NTS of SHRs by increasing Ras mediated activation of the PI3K-Akt and ERK1/2-RSK signalling pathways , which then up-regulates eNOS activation .	Simvastatin modulates central BP control in the NTS of SHRs by increasing Ras mediated activation of the PI3K-Akt and ERK1/2-RSK signalling pathways, which then up-regulates eNOS activation.	0	27	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-Akt	Simvastatin modulates central BP control in the NTS of SHRs by increasing Ras mediated activation of the PI3K-Akt	pi3k-akt	eNOS	eNOS	enos	17	18	26	27
It is well known that Akt activates eNOS and enhances NO production 32 and that release of NO from vascular endothelial cells is essential for promoting angiogenesis and collateral vessel remodeling in response to ischemia 28 .	It is well known that Akt activates eNOS and enhances NO production 32 and that release of NO from vascular endothelial cells is essential for promoting angiogenesis and collateral vessel remodeling in response to ischemia 28.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	5	6	7	8
The activation and phosphorylation of ERK1/2 and Akt proteins modulate the activation of eNOS in various tissues .	The activation and phosphorylation of ERK1/2 and Akt proteins modulate the activation of eNOS in various tissues.	3	16	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	phosphorylation of ERK1/2 and Akt	akt	eNOS	eNOS	enos	7	8	13	14
We then investigated whether the PI3K and Akt signalling pathway mediates GPR30 dependent eNOS activation in HUVECs under H/R conditions .	We then investigated whether the PI3K and Akt signalling pathway mediates GPR30 dependent eNOS activation in HUVECs under H/R conditions.	7	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	7	8	13	14
It should be noted that stretch induced eNOS activation and NO production by the PKA and Akt pathways were not absolutely separate .	It should be noted that stretch induced eNOS activation and NO production by the PKA and Akt pathways were not absolutely separate.	7	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	16	17	7	8
Akt dependent phosphorylation leads to the posttranslational activation of the eNOS via phosphorylation of the amino acid Ser1177 , which has been described as an important anti-apoptotic signaling pathway in endothelial cells .	Akt dependent phosphorylation leads to the posttranslational activation of the eNOS via phosphorylation of the amino acid Ser1177, which has been described as an important anti-apoptotic signaling pathway in endothelial cells.	0	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt dependent phosphorylation	akt	eNOS	eNOS	enos	0	1	10	11
XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR These activated Ser kinases decrease insulin receptor-1 ( IRS-1 ) tyrosine ( p ) and engagement with phosphoinositol 3-kinase ( PI3-K ) , with a resultant decrease in protein kinase B ( Akt ) mediated ( p )/activation of eNOS .	XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR These activated Ser kinases decrease insulin receptor-1 (IRS-1) tyrosine (p) and engagement with phosphoinositol 3-kinase (PI3-K), with a resultant decrease in protein kinase B (Akt) mediated (p)/activation of eNOS.	6	47	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	39	40	46	47
Further , Akt activates eNOS in ECs by phosphorylation of eNOS at serine 1177 , resulting in increased activity of the enzyme and enhanced NO .	Further, Akt activates eNOS in ECs by phosphorylation of eNOS at serine 1177, resulting in increased activity of the enzyme and enhanced NO.	2	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	4	5
Given that eNOS is activated by the PI3K-Akt pathway [ XREF_BIBR ] , it is most likely that NO generated by the PI3K-Akt-dependent eNOS activation pathway positively regulates the Ca v 1.2 LTCC activity .	Given that eNOS is activated by the PI3K-Akt pathway [XREF_BIBR], it is most likely that NO generated by the PI3K-Akt-dependent eNOS activation pathway positively regulates the Ca v 1.2 LTCC activity.	2	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	eNOS	eNOS	eNOS	7	8	2	3
Using chemical inhibitors and gene specific RNA knockdown , we further studied the role of PKA- and PI3K and Akt mediated eNOS activation and NO production in stretch induced WBP exocytosis and leukocyte adhesion in endothelial cells .	Using chemical inhibitors and gene specific RNA knockdown, we further studied the role of PKA- and PI3K and Akt mediated eNOS activation and NO production in stretch induced WBP exocytosis and leukocyte adhesion in endothelial cells.	13	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	19	20	21	22
94 RhoA and ROCK inhibition or treatment with statins stabilizes eNOS mRNA as well as AKT mediated activation of eNOS .	94 RhoA and ROCK inhibition or treatment with statins stabilizes eNOS mRNA as well as AKT mediated activation of eNOS.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	15	16	19	20
Conversely , previous studies have determined that phosphorylation of Akt may activate eNOS , which is the downstream target of RISK pathways , and may induce p-eNOS function as a cardiovascular protective molecule .	Conversely, previous studies have determined that phosphorylation of Akt may activate eNOS, which is the downstream target of RISK pathways, and may induce p-eNOS function as a cardiovascular protective molecule.	7	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	phosphorylation of Akt	akt	eNOS	eNOS	enos	9	10	12	13
Akt phosphorylation at serine 1177 activates eNOS that leads to NO production in endothelial cells .	Akt phosphorylation at serine 1177 activates eNOS that leads to NO production in endothelial cells.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation at serine 1177	akt	eNOS	eNOS	enos	0	1	6	7
Moreover , platelets express the endothelial isoform of nitric oxide synthase ( eNOS ) , which is activated by the increase in cytoplasmic free calcium as well as the PI3K and Akt activation associated with platelet aggregation ; hence , the NO produced within stimulated platelets acts as a feedback brake on aggregation .	Moreover, platelets express the endothelial isoform of nitric oxide synthase (eNOS), which is activated by the increase in cytoplasmic free calcium as well as the PI3K and Akt activation associated with platelet aggregation; hence, the NO produced within stimulated platelets acts as a feedback brake on aggregation.	10	32	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	31	32	12	13
One of these is eNOS , which is activated through phosphorylation at serine 1177 by Akt .	One of these is eNOS, which is activated through phosphorylation at serine 1177 by Akt.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	15	16	4	5
Interestingly , exercise training improves vasodilation in response to ACh and insulin by the same pathway of PI3K and Akt mediated eNOS signaling cascades .	Interestingly, exercise training improves vasodilation in response to ACh and insulin by the same pathway of PI3K and Akt mediated eNOS signaling cascades.	15	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	19	20	21	22
eNOS is an Akt target and the activation of eNOS by Akt is one of the most important physiological effects of Akt on cell attachment in endothelial cells 27 .	eNOS is an Akt target and the activation of eNOS by Akt is one of the most important physiological effects of Akt on cell attachment in endothelial cells 27.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	11	12	9	10
Therefore , it may be concluded that DAQ B1 induced activation of Akt may activate eNOS and consequently reduce oxidative stress to improve vascular endothelial dysfunction .	Therefore, it may be concluded that DAQ B1 induced activation of Akt may activate eNOS and consequently reduce oxidative stress to improve vascular endothelial dysfunction.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	B1 induced activation of Akt	akt	eNOS	eNOS	enos	12	13	15	16
In this study , we provided the evidence that ( i ) ciglitazone protected in vitro cultured RMVECs by reducing cell apoptosis and ageing ; ( ii ) ciglitazone promotes nitric oxide synthesis through activating Akt and upregulating eNOS expression ; ( iii ) ciglitazone improves angiogenesis through Akt dependent VEGF signalling and ( iv ) PPARgamma dependent AMPK phosphorylation induced by ciglitazone downregulates the ox-LDL receptor , LOX-1 , and enhances Akt and eNOS activities , thereby further enhanced nitric oxide synthesis .	In this study, we provided the evidence that (i) ciglitazone protected in vitro cultured RMVECs by reducing cell apoptosis and ageing; (ii) ciglitazone promotes nitric oxide synthesis through activating Akt and upregulating eNOS expression; (iii) ciglitazone improves angiogenesis through Akt dependent VEGF signalling and (iv) PPARgamma dependent AMPK phosphorylation induced by ciglitazone downregulates the ox-LDL receptor, LOX-1, and enhances Akt and eNOS activities, thereby further enhanced nitric oxide synthesis.	45	75	enhances	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	48	49	74	75
These results strongly suggest that the anti-ischemia reperfusion injury effect of RSE might result from , or at least involves , PI3K and Akt activated eNOS activation in the early phase of ischemia ( 15min after ischemia ) .	These results strongly suggest that the anti-ischemia reperfusion injury effect of RSE might result from, or at least involves, PI3K and Akt activated eNOS activation in the early phase of ischemia (15min after ischemia).	21	26	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	23	24	25	26
HSP90 and active Akt together increased eNOS activity synergistically , which was reversed by GA ..	HSP90 and active Akt together increased eNOS activity synergistically, which was reversed by GA..	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	3	4	6	7
Thus , the antagonism of Akt phosphorylation caused by CRP underlies the actions of the pentraxin on the capacity of insulin to activate eNOS .	Thus, the antagonism of Akt phosphorylation caused by CRP underlies the actions of the pentraxin on the capacity of insulin to activate eNOS.	5	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	eNOS	eNOS	enos	5	6	23	24
It remained to be reasonably established if treatment of tBHQ via Akt increase eNOS derived NO production in AngII induced endothelial dysfunction .	It remained to be reasonably established if treatment of tBHQ via Akt increase eNOS derived NO production in AngII induced endothelial dysfunction.	9	14	increase	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	11	12	13	14
The formation of a complex between HSPC and endothelial NO synthase ( eNOS ) is a prerequisite for subsequent Akt mediated eNOS activation resulting in NO generation .	The formation of a complex between HSPC and endothelial NO synthase (eNOS) is a prerequisite for subsequent Akt mediated eNOS activation resulting in NO generation.	16	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	19	20	21	22
Akt kinase activates eNOS by directly phosphorylating the enzyme at Ser1179 ( in bovine eNOS , eNOS-Ser1177 in humans , and eNOS-Ser1176 in mice ) .	Akt kinase activates eNOS by directly phosphorylating the enzyme at Ser1179 (in bovine eNOS, eNOS-Ser1177 in humans, and eNOS-Ser1176 in mice).	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	0	1	3	4
Akt mediated eNOS upregulation in neurons and vascular endothelial cells is required for LPS induced tolerance against HI in the neonatal rat brain .	Akt mediated eNOS upregulation in neurons and vascular endothelial cells is required for LPS induced tolerance against HI in the neonatal rat brain.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	0	1	2	3
Our previous study had indicated that exercise training protects MI induced injury of peripheral mesenteric arteries via a PI3K and Akt mediated eNOS dependent pathway .	Our previous study had indicated that exercise training protects MI induced injury of peripheral mesenteric arteries via a PI3K and Akt mediated eNOS dependent pathway.	15	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	20	21	22	23
It has been demonstrated that e-NOS activation induced by insulin is mediated by the PI3K-Akt pathway resulting in e-NOS phosphorylation in Ser 1177 independently of Ca 2+ -CaM pathway XREF_BIBR .	It has been demonstrated that e-NOS activation induced by insulin is mediated by the PI3K-Akt pathway resulting in e-NOS phosphorylation in Ser 1177 independently of Ca 2+ -CaM pathway XREF_BIBR.	5	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	e-NOS	e-NOS	e-NOS	14	15	5	6
Akt activates eNOS , which leads to NO production XREF_BIBR .	Akt activates eNOS, which leads to NO production XREF_BIBR.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	0	1	2	3
Full understanding of the role of NO in IH , however , should include monitoring not only of the expression of Akt activated eNOS , but also of transcriptionally activated iNOS , which has been shown to play a key role in IH induced delayed cardioprotection [ XREF_BIBR , XREF_BIBR ] .	Full understanding of the role of NO in IH, however, should include monitoring not only of the expression of Akt activated eNOS, but also of transcriptionally activated iNOS, which has been shown to play a key role in IH induced delayed cardioprotection [XREF_BIBR, XREF_BIBR].	19	26	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Akt	expression of Akt	akt	eNOS	eNOS	enos	21	22	23	24
XREF_BIBR demonstrated that ROS from EGCG induce endothelium dependent NO mediated relaxation of coronary artery rings through Akt dependent activation of eNOS , but the real contribution of ROS to the long-term in vitro effects of polyphenols XREF_BIBR is still under debate .	XREF_BIBR demonstrated that ROS from EGCG induce endothelium dependent NO mediated relaxation of coronary artery rings through Akt dependent activation of eNOS, but the real contribution of ROS to the long-term in vitro effects of polyphenols XREF_BIBR is still under debate.	17	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	17	18	21	22
It is well recognized that PI3K and Akt is the upstream signaling of eNOS .	It is well recognized that PI3K and Akt is the upstream signaling of eNOS.	5	14	is the upstream signaling	Positive_activation_copula_1	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	7	8	13	14
Here we demonstrate that the serine/threonine protein kinase Akt and PKB mediates the activation of eNOS , leading to increased NO production .	Here we demonstrate that the serine/threonine protein kinase Akt and PKB mediates the activation of eNOS, leading to increased NO production.	4	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	8	9	15	16
Taken together , our results showed that IPC increased Akt phosphorylation , which in turn activated eNOS and NO generation to alleviate the I/R injury of ischemic kidneys .	Taken together, our results showed that IPC increased Akt phosphorylation, which in turn activated eNOS and NO generation to alleviate the I/R injury of ischemic kidneys.	7	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	IPC increased Akt phosphorylation	akt	eNOS	eNOS	enos	9	10	16	17
It was manifested in this study that exercise training increased the phosphorylation of Akt and eNOS , and activation of Akt stimulated eNOS and then increased NO production .	It was manifested in this study that exercise training increased the phosphorylation of Akt and eNOS, and activation of Akt stimulated eNOS and then increased NO production.	18	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	20	21	22	23
Specifically , this is secondary to the PI3K and Akt signaling pathway that activates eNOS and , in turn , accelerates Ca ++ cycling .	Specifically, this is secondary to the PI3K and Akt signaling pathway that activates eNOS and, in turn, accelerates Ca ++ cycling.	9	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	9	10	14	15
Since both AKT and ERK1/2 are part of the TLR4 pathway and are able to activate eNOS , the phosphorylation status upon exposure towards LPS +/- UDCA-LPE was analyzed ( XREF_FIG ) .	Since both AKT and ERK1/2 are part of the TLR4 pathway and are able to activate eNOS, the phosphorylation status upon exposure towards LPS +/- UDCA-LPE was analyzed (XREF_FIG).	1	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	2	3	16	17
Akt activates eNOS by phosphorylation at Ser 1177 , resulting in NO production Our findings are consistent with earlier studies showing that SDF-1-induced chemotaxis of T lymphocytes involves G i protein coupled PI3K activation and Akt phosphorylation .	Akt activates eNOS by phosphorylation at Ser 1177, resulting in NO production Our findings are consistent with earlier studies showing that SDF-1-induced chemotaxis of T lymphocytes involves G i protein coupled PI3K activation and Akt phosphorylation.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	0	1	2	3
It is well established that AKT may activate eNOS by phosphorylation at Ser 1177 residue [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It is well established that AKT may activate eNOS by phosphorylation at Ser 1177 residue [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	5	6	8	9
XREF_BIBR Akt mediated stimulation of NOS3 induces protein kinase G dependent degranulation of platelets .	XREF_BIBR Akt mediated stimulation of NOS3 induces protein kinase G dependent degranulation of platelets.	0	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	NOS3	NOS3	NOS3	1	2	5	6
The binding of insulin to its receptors at the level of peripheral endothelial cells [ XREF_BIBR ] activates the phosphorylation of the insulin-receptor substrate which initiates a phosphorylation of a series of down-stream substrates , among them the PI3K and Akt pathway [ XREF_BIBR , XREF_BIBR ] , that finally activate eNOS [ XREF_BIBR , XREF_BIBR ] .	The binding of insulin to its receptors at the level of peripheral endothelial cells [XREF_BIBR] activates the phosphorylation of the insulin-receptor substrate which initiates a phosphorylation of a series of down-stream substrates, among them the PI3K and Akt pathway [XREF_BIBR, XREF_BIBR], that finally activate eNOS [XREF_BIBR, XREF_BIBR].	38	55	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	40	41	51	52
WSS induces Akt phosphorylation at Ser473 , which then mediates eNOS activation and subsequent NO production .	WSS induces Akt phosphorylation at Ser473, which then mediates eNOS activation and subsequent NO production.	0	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	WSS induces Akt phosphorylation at Ser473	akt	eNOS	eNOS	enos	2	3	10	11
XREF_BIBR demonstrated that eNOS activation is mediated by the phosphorylation of AKT in cultured endothelial cells , thus demonstrating a link between eNOS and AKT activation .	XREF_BIBR demonstrated that eNOS activation is mediated by the phosphorylation of AKT in cultured endothelial cells, thus demonstrating a link between eNOS and AKT activation.	3	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	phosphorylation of AKT	akt	eNOS	eNOS	enos	11	12	3	4
Testosterone induced phosphorylation of the Ser/Thr kinase Akt and eNOS leads to NO synthase 3 ( NOS3 ) activation and production of nitric oxide ( NO ) XREF_BIBR .	Testosterone induced phosphorylation of the Ser/Thr kinase Akt and eNOS leads to NO synthase 3 (NOS3) activation and production of nitric oxide (NO) XREF_BIBR.	0	18	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Akt	Testosterone induced phosphorylation of the Ser/Thr kinase Akt	akt	NOS3	NOS3	nos3	7	8	16	17
Studies have shown that cardioprotection is associated with NO production following Akt mediated eNOS activation [ XREF_BIBR , XREF_BIBR ] .	Studies have shown that cardioprotection is associated with NO production following Akt mediated eNOS activation [XREF_BIBR, XREF_BIBR].	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	11	12	13	14
These results show that dysfunctional PI3K and Akt mediated eNOS signaling plays an important role in post-MI-associated IR .	These results show that dysfunctional PI3K and Akt mediated eNOS signaling plays an important role in post-MI-associated IR.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	7	8	9	10
Further experiments in transfected COS cells expressing either wild-type or S1177A mutant eNOS led us to identify the serine 1177 as the critical residue for the hsp90 dependent Akt mediated activation of eNOS .	Further experiments in transfected COS cells expressing either wild-type or S1177A mutant eNOS led us to identify the serine 1177 as the critical residue for the hsp90 dependent Akt mediated activation of eNOS.	28	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	28	29	32	33
In endothelial cells , the PI3K-Akt pathway is robustly activated by VEGF , and Akt activates eNOS [ XREF_BIBR ] .	In endothelial cells, the PI3K-Akt pathway is robustly activated by VEGF, and Akt activates eNOS [XREF_BIBR].	14	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	14	15	16	17
Also , Akt , eNOS , and HO-1 exhibit an elaborate integration : Akt activates eNOS by calcium independent phosphorylation XREF_BIBR , and NO activates PI-3K , an important Akt regulator , and under some conditions , Akt itself XREF_BIBR .	Also, Akt, eNOS, and HO-1 exhibit an elaborate integration : Akt activates eNOS by calcium independent phosphorylation XREF_BIBR, and NO activates PI-3K, an important Akt regulator, and under some conditions, Akt itself XREF_BIBR.	13	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	13	14	15	16
eNOS is activated by the serine/threonine protein kinase Akt and PKB and is up-regulated by VEGF .	eNOS is activated by the serine/threonine protein kinase Akt and PKB and is up-regulated by VEGF.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKB	PKB	PKB	eNOS	eNOS	eNOS	10	11	0	1
In particular , since eNOS is activated in response to phosphorylation by AKT and impaired AKT activity is involved in endothelial dysfunction , AKT overexpression should result in the correction of impaired phenotype .	In particular, since eNOS is activated in response to phosphorylation by AKT and impaired AKT activity is involved in endothelial dysfunction, AKT overexpression should result in the correction of impaired phenotype.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	12	13	4	5
It is thus apparent that Akt directly activates eNOS in endothelial cells .	It is thus apparent that Akt directly activates eNOS in endothelial cells.	5	11	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	5	6	8	9
In conclusion , the present study has revealed that nicorandil attenuates MCT induced vascular endothelial damage and apoptosis and PAH through the production of eNOS and anti-apoptotic factors , which is mediated by the PI3K and Akt and ERK1/2 signaling pathways .	In conclusion, the present study has revealed that nicorandil attenuates MCT induced vascular endothelial damage and apoptosis and PAH through the production of eNOS and anti-apoptotic factors, which is mediated by the PI3K and Akt and ERK1/2 signaling pathways.	24	37	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	36	37	24	25
CR is evident to trigger NO production upon Akt mediated eNOS activation in mice .	CR is evident to trigger NO production upon Akt mediated eNOS activation in mice.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	8	9	10	11
For example , eNOS can be activated by Akt phosphorylation at Ser 1177 and Ser 614 , and protein kinase A ( PKA ) can also phosphorylate eNOS at both Ser 1177 and Ser 633 .	For example, eNOS can be activated by Akt phosphorylation at Ser 1177 and Ser 614, and protein kinase A (PKA) can also phosphorylate eNOS at both Ser 1177 and Ser 633.	3	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation at Ser 1177	akt	eNOS	eNOS	enos	8	9	3	4
reported that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle , that the Akt and eNOS pathway might be particularly susceptible to the adverse effects of conditions such as obesity and insulin resistance and that insulin stimulated Akt activated eNOS to a degree that was proportional to the amount of eNOS protein available .	reported that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle, that the Akt and eNOS pathway might be particularly susceptible to the adverse effects of conditions such as obesity and insulin resistance and that insulin stimulated Akt activated eNOS to a degree that was proportional to the amount of eNOS protein available.	47	62	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	47	48	49	50
This results in the activation of the proliferation and survival pathways involving Akt activation , which then stimulates eNOS and NO production in HUAECs .	This results in the activation of the proliferation and survival pathways involving Akt activation, which then stimulates eNOS and NO production in HUAECs.	12	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	12	13	18	19
HUVECs exposure to Probenecid restored Akt insulin induced phosphorylation levels in presence of UA and the increased Akt phosphorylation resulted , in turn , in an enhanced eNOS activation .	HUVECs exposure to Probenecid restored Akt insulin induced phosphorylation levels in presence of UA and the increased Akt phosphorylation resulted, in turn, in an enhanced eNOS activation.	17	29	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	eNOS	eNOS	enos	17	18	27	28
Inhibition of Akt activation with Akt knockout mice reduced effects of hyperoxia on large tidal volume induced eNOS activation .	Inhibition of Akt activation with Akt knockout mice reduced effects of hyperoxia on large tidal volume induced eNOS activation.	2	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	17	18
Furthermore , Akt mediated eNOS upregulation in neurons and vascular endothelial cells have been implicated in LPS induced preconditioning [ XREF_BIBR ] .	Furthermore, Akt mediated eNOS upregulation in neurons and vascular endothelial cells have been implicated in LPS induced preconditioning [XREF_BIBR].	2	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	4	5
In addition , Akt directly mediates eNOS activation , leading to increased NO production in EC .	In addition, Akt directly mediates eNOS activation, leading to increased NO production in EC.	3	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	3	4	6	7
This is exemplified in penile erection , which involves vasodilation of the corpora cavernosae with erection being initiated by calcium-calmodulin activation of nNOS followed by Akt stimulation of eNOS .	This is exemplified in penile erection, which involves vasodilation of the corpora cavernosae with erection being initiated by calcium-calmodulin activation of nNOS followed by Akt stimulation of eNOS.	25	29	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	25	26	28	29
Taken together , these data identify the p38 MAPK as an upstream component of Akt mediated eNOS activation .	Taken together, these data identify the p38 MAPK as an upstream component of Akt mediated eNOS activation.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	14	15	16	17
Moreover , eNOS , an important mediator in angiogenesis , is activated through direct phosphorylation by AMPK and Akt .	Moreover, eNOS, an important mediator in angiogenesis, is activated through direct phosphorylation by AMPK and Akt.	2	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	18	19	2	3
Phosphorylation of nNOS at threonine 1296 inhibits NO production , and activation of PKB activity by cAMP induces eNOS activation .	Phosphorylation of nNOS at threonine 1296 inhibits NO production, and activation of PKB activity by cAMP induces eNOS activation.	13	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKB	PKB	PKB	eNOS	eNOS	eNOS	13	14	18	19
Our study provides an alternative explanation , namely , that DDAH1 acts to increase NO production not only by removing endogenous NOS inhibitors , but also by causing Akt phosphorylation which in turn increases eNOS activity by increasing p-eNOS Ser1177 .	Our study provides an alternative explanation, namely, that DDAH1 acts to increase NO production not only by removing endogenous NOS inhibitors, but also by causing Akt phosphorylation which in turn increases eNOS activity by increasing p-eNOS Ser1177.	28	35	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	eNOS	eNOS	enos	28	29	34	35
Together , these data suggest that ghrelin countering effect on the LPS induced proapoptotic events occurs with the involvement of Src and Akt kinase mediated cNOS activation through phosphorylation , that appears to be dependent upon the extent of cNOS protein S nitrosylation .	Together, these data suggest that ghrelin countering effect on the LPS induced proapoptotic events occurs with the involvement of Src and Akt kinase mediated cNOS activation through phosphorylation, that appears to be dependent upon the extent of cNOS protein S nitrosylation.	20	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	cNOS	cNOS	cNOS	22	23	25	26
Protein kinase Akt directly activates eNOS and promotes production of NO in ECs 14 .	Protein kinase Akt directly activates eNOS and promotes production of NO in ECs 14.	0	7	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	5	6
In conclusion , the A2B AR activation driven angiogenesis via cAMP-PKA-CREB mediated VEGF production and PI3K and AKT dependent upregulation of eNOS in HMEC-1 .	In conclusion, the A2B AR activation driven angiogenesis via cAMP-PKA-CREB mediated VEGF production and PI3K and AKT dependent upregulation of eNOS in HMEC-1.	17	22	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	17	18	21	22
In conclusion , EGCg causes endothelium dependent NO mediated relaxations of coronary artery rings through the Akt dependent activation of eNOS in endothelial cells .	In conclusion, EGCg causes endothelium dependent NO mediated relaxations of coronary artery rings through the Akt dependent activation of eNOS in endothelial cells.	16	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	16	17	20	21
Several signal transduction pathways -PI3K and Akt , ERK , mitogen activated protein kinase ( MAPK ) , and eNOS -- have been proposed as the mechanism underlying the protective effect of the apelinergic system .	Several signal transduction pathways -PI3K and Akt, ERK, mitogen activated protein kinase (MAPK), and eNOS -- have been proposed as the mechanism underlying the protective effect of the apelinergic system.	4	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	6	7	19	20
Western blot analysis showed that the extent of phosphorylation of Akt , an active form of Akt , was increased by cerivastatin while it was reduced by LY294002 , suggesting an involvement of PI3 kinase and Akt dependent activation of endothelial NOS .	Western blot analysis showed that the extent of phosphorylation of Akt, an active form of Akt, was increased by cerivastatin while it was reduced by LY294002, suggesting an involvement of PI3 kinase and Akt dependent activation of endothelial NOS.	36	42	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	endothelial NOS	endothelial NOS	endothelial NOS	36	37	40	42
Recently , it has been suggested that Ang II inhibits Akt induced eNOS activation and NO release in ECs and that Ang II infusion decreases NO production in aorta by causing eNOS uncoupling .	Recently, it has been suggested that Ang II inhibits Akt induced eNOS activation and NO release in ECs and that Ang II infusion decreases NO production in aorta by causing eNOS uncoupling.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	10	11	12	13
We investigated if NO production happens downstream of VEGF signaling , and saw significantly higher levels of NO in VEGF188 cells , when compared to WT and VEGF164 concomitant with increased P-Akt levels , known to promote eNOS activity .	We investigated if NO production happens downstream of VEGF signaling, and saw significantly higher levels of NO in VEGF188 cells, when compared to WT and VEGF164 concomitant with increased P-Akt levels, known to promote eNOS activity.	31	38	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P-Akt	P-Akt levels	p-akt	eNOS	eNOS	enos	31	32	37	38
HDL associated lysophospholipids were shown to be responsible for the vasodilatory effect of HDL via a lysophospholipid receptor ( sphingosine-1-phosphate receptor ) , causing Akt mediated activation of eNOS .	HDL associated lysophospholipids were shown to be responsible for the vasodilatory effect of HDL via a lysophospholipid receptor (sphingosine-1-phosphate receptor), causing Akt mediated activation of eNOS.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	24	25	28	29
AKT being actived by PIP3 , promotes the generation of cNOS and NO [ XREF_BIBR ] .	AKT being actived by PIP3, promotes the generation of cNOS and NO [XREF_BIBR].	0	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	cNOS	cNOS	cNOS	0	1	10	11
LY294002 completely inhibited the GA activated phosphorylation of Akt , while only partially inhibiting eNOS .	LY294002 completely inhibited the GA activated phosphorylation of Akt, while only partially inhibiting eNOS.	0	15	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	LY294002 completely inhibited the GA activated phosphorylation of Akt	akt	eNOS	eNOS	enos	8	9	14	15
P-Akt , which is activated by VEGF , could activate eNOS and increases the ratio of p-eNOS to total eNOS .	P-Akt, which is activated by VEGF, could activate eNOS and increases the ratio of p-eNOS to total eNOS.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P-Akt	P-Akt	P-Akt	eNOS	eNOS	eNOS	0	1	10	11
The pioneer work by Fulton et al reported that Akt activates eNOS by phosphorylating Ser 1179 in transfected COS cells XREF_BIBR .	The pioneer work by Fulton et al reported that Akt activates eNOS by phosphorylating Ser 1179 in transfected COS cells XREF_BIBR.	9	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	9	10	11	12
eNOS is reportedly regulated by various proteins in different subcellular locations ; for example , Ca 2+ / calmodulin mediated activation of eNOS is mainly effective at the PM , whereas AKT driven activation of eNOS is most pronounced in the Golgi .	eNOS is reportedly regulated by various proteins in different subcellular locations; for example, Ca 2+ / calmodulin mediated activation of eNOS is mainly effective at the PM, whereas AKT driven activation of eNOS is most pronounced in the Golgi.	31	36	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	31	32	35	36
[ XREF_BIBR XREF_BIBR ] On the other hand , activation of eNOS by Akt generates NO and activates mitochondrial KATP channels in a cGMP dependent manner , leading to acute cardioprotection .	[XREF_BIBR XREF_BIBR] On the other hand, activation of eNOS by Akt generates NO and activates mitochondrial KATP channels in a cGMP dependent manner, leading to acute cardioprotection.	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	13	14	11	12
Taken together with the L-NAME data , this suggests that part of the vasorelaxation seen to AEA in human arteries is through cannabinoid receptor signalling to MAPKs and Akt activating eNOS .	Taken together with the L-NAME data, this suggests that part of the vasorelaxation seen to AEA in human arteries is through cannabinoid receptor signalling to MAPKs and Akt activating eNOS.	24	31	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	28	29	30	31
Consistent with these results , siRNA mediated knockdown of Akt abolished tBHQ enhanced NO production and eNOS activity , while control siRNA had no effects ( XREF_FIG ) .	Consistent with these results, siRNA mediated knockdown of Akt abolished tBHQ enhanced NO production and eNOS activity, while control siRNA had no effects (XREF_FIG).	7	17	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	9	10	16	17
Activation of G i / Akt induced eNOS dependent vasorelaxation via agonism of S1P 3 in isolated rat aortae or S1P 1 in bovine lung EC XREF_BIBR , XREF_BIBR .	Activation of G i / Akt induced eNOS dependent vasorelaxation via agonism of S1P 3 in isolated rat aortae or S1P 1 in bovine lung EC XREF_BIBR, XREF_BIBR.	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	5	6	7	8
In turn , Akt activates the eNOS by phosphorylation of serine residue 1177 [ XREF_BIBR , XREF_BIBR ] .	In turn, Akt activates the eNOS by phosphorylation of serine residue 1177 [XREF_BIBR, XREF_BIBR].	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	3	4	6	7
Furthermore , inhibition of PKA preferentially attenuated eNOS activation in the early phase , while inhibition of the PI3K and Akt pathway reduced eNOS activation in the late phase , suggesting that the PKA and PI3K and Akt pathways play distinct roles in a time dependent manner .	Furthermore, inhibition of PKA preferentially attenuated eNOS activation in the early phase, while inhibition of the PI3K and Akt pathway reduced eNOS activation in the late phase, suggesting that the PKA and PI3K and Akt pathways play distinct roles in a time dependent manner.	18	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	20	21	23	24
In both BAEC and HMEC , eNOS phosphorylation was temporally paralleled by Akt activation , indicating the involvement of the PI3K and Akt pathway in GTN induced eNOS activation .	In both BAEC and HMEC, eNOS phosphorylation was temporally paralleled by Akt activation, indicating the involvement of the PI3K and Akt pathway in GTN induced eNOS activation.	20	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	22	23	27	28
Akt phosphorylation induces eNOS activation , which is directly responsible for the NO production in endothelium .	Akt phosphorylation induces eNOS activation, which is directly responsible for the NO production in endothelium.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	eNOS	eNOS	enos	0	1	3	4
Ginseng extract administration was previously shown to enhance NO production , improve vessel wall thickening , alleviate hypertension , and stimulate nongenomic Akt mediated eNOS activation in spontaneously hypertensive rats XREF_BIBR .	Ginseng extract administration was previously shown to enhance NO production, improve vessel wall thickening, alleviate hypertension, and stimulate nongenomic Akt mediated eNOS activation in spontaneously hypertensive rats XREF_BIBR.	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	22	23	24	25
However , O-GlcNAc-modified Akt is not able to activate eNOS , thereby leading to decreased nitric oxide production .	However, O-GlcNAc-modified Akt is not able to activate eNOS, thereby leading to decreased nitric oxide production.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	3	4	9	10
Akt phosphorylation activated eNOS ( at Ser ( 1177 ) ) , and Akt also regulated the ability of Src to phosphorylate GIT1 as well as GIT1-eNOS association .	Akt phosphorylation activated eNOS (at Ser (1177)), and Akt also regulated the ability of Src to phosphorylate GIT1 as well as GIT1-eNOS association.	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	eNOS	eNOS	enos	0	1	3	4
Further study indicated that the activation of eNOS was not mediated through estrogen receptors or tyrosine kinase inhibition , but via a phosphatidylinositol 3-kinase ( PI3K )/Akt-dependent signaling pathway , as the eNOS activity and related NO release were largely abolished by pharmacological inhibitors of PI3K or Akt .	Further study indicated that the activation of eNOS was not mediated through estrogen receptors or tyrosine kinase inhibition, but via a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent signaling pathway, as the eNOS activity and related NO release were largely abolished by pharmacological inhibitors of PI3K or Akt.	32	48	abolished	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	47	48	32	33
These results demonstrate that HSP90 and Akt synergistically activate eNOS and suggest that this synergy contributes to Ca2 +-independent eNOS activation in response to insulin .	These results demonstrate that HSP90 and Akt synergistically activate eNOS and suggest that this synergy contributes to Ca2 +-independent eNOS activation in response to insulin.	4	10	synergistically activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	6	7	9	10
We hypothesized that Akt activation , which upregulates eNOS in neurons and endothelial cells , is required for LPS preconditioning induced tolerance against HI in the neonatal brain .	We hypothesized that Akt activation, which upregulates eNOS in neurons and endothelial cells, is required for LPS preconditioning induced tolerance against HI in the neonatal brain.	3	9	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	3	4	8	9
NOS3 can also be activated directly by Akt phosphorylation without intracellular increases in Ca 2+ [ XREF_BIBR , XREF_BIBR ] .	NOS3 can also be activated directly by Akt phosphorylation without intracellular increases in Ca 2+ [XREF_BIBR, XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	NOS3	NOS3	nos3	7	8	0	1
Akt dependent phosphorylation leads to the posttranslational activation of eNOS via phosphorylation of the amino acid Ser1177 , which has been described as an important anti-apoptotic signaling pathway in endothelial cells .	Akt dependent phosphorylation leads to the posttranslational activation of eNOS via phosphorylation of the amino acid Ser1177, which has been described as an important anti-apoptotic signaling pathway in endothelial cells.	0	11	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt dependent phosphorylation	akt	eNOS	eNOS	enos	0	1	9	10
eNOS can be activated independently of Ca 2+ upon phosphorylation by Akt kinase in response to stimuli such as shear stress , estrogens and insulin [ XREF_BIBR ] .	eNOS can be activated independently of Ca 2+ upon phosphorylation by Akt kinase in response to stimuli such as shear stress, estrogens and insulin [XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	11	12	0	1
Since Akt dependent activation of eNOS stimulates angiogenesis and is also responsible for tumor maintenance , the considerable decreased expression of eNOS in IP6 treated PC-3 tumor xenografts provides additional support that inhibition of PI3K/Akt/eNOS signaling is a significant mechanism by which IP6 mediates its antiproliferative and antiangiogenic response in vivo .	Since Akt dependent activation of eNOS stimulates angiogenesis and is also responsible for tumor maintenance, the considerable decreased expression of eNOS in IP6 treated PC-3 tumor xenografts provides additional support that inhibition of PI3K/Akt/eNOS signaling is a significant mechanism by which IP6 mediates its antiproliferative and antiangiogenic response in vivo.	1	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	1	2	5	6
The interaction of Hsp90 and eNOS creates a complex with Akt , which allows eNOS and Akt to both function on the same domain of Hsp90 .	The interaction of Hsp90 and eNOS creates a complex with Akt, which allows eNOS and Akt to both function on the same domain of Hsp90.	6	16	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	10	11	14	15
Both the large tidal volume ventilation of Akt mutant mice and the pharmacological inhibition of Akt with LY294002 attenuated neutrophil sequestration , MIP-2 protein production , and Akt and eNOS activation .	Both the large tidal volume ventilation of Akt mutant mice and the pharmacological inhibition of Akt with LY294002 attenuated neutrophil sequestration, MIP-2 protein production, and Akt and eNOS activation.	13	30	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	15	16	29	30
Akt activates eNOS by phosphorylation and SIRT1 does the same by deacetylation XREF_BIBR , XREF_BIBR , thereby functionally linking SIRT1 with Akt for maintaining the endothelial cellular function and agiogenesis 86 .	Akt activates eNOS by phosphorylation and SIRT1 does the same by deacetylation XREF_BIBR, XREF_BIBR, thereby functionally linking SIRT1 with Akt for maintaining the endothelial cellular function and agiogenesis 86.	0	7	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	0	1	2	3
Even expression of constitutively active Akt failed to stimulate eNOS activity in UAEC and did not overcome the inhibitory effect of wortmannin , either alone or in the presence of ATP [ XREF_BIBR ] .	Even expression of constitutively active Akt failed to stimulate eNOS activity in UAEC and did not overcome the inhibitory effect of wortmannin, either alone or in the presence of ATP [XREF_BIBR].	1	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	expression of constitutively active Akt	akt	eNOS	eNOS	enos	5	6	9	10
XREF_BIBR In particular , the IRS-1 and Akt pathway activates eNOS by phosphorylation at the Serine 1177 residue which promotes NO production .	XREF_BIBR In particular, the IRS-1 and Akt pathway activates eNOS by phosphorylation at the Serine 1177 residue which promotes NO production.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	7	8	10	11
PI3K and AKT is known to mediate VEGF activation of eNOS .	PI3K and AKT is known to mediate VEGF activation of eNOS.	0	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	2	3	10	11
This study explored the role of PI3K and AKT signaling during genistein promoted eNOS activation .	This study explored the role of PI3K and AKT signaling during genistein promoted eNOS activation.	6	14	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	8	9	13	14
In addition , Akt phosphorylation activates eNOS XREF_BIBR which releases NO that , in turn , stimulates vascular remodelling and angiogenesis .	In addition, Akt phosphorylation activates eNOS XREF_BIBR which releases NO that, in turn, stimulates vascular remodelling and angiogenesis.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	eNOS	eNOS	enos	3	4	6	7
204 In endothelial cells , the activation of AKT by statins results in stimulation of eNOS activity , leading to increased NO synthesis and neoangiogenesis while the increased production of endothelial NO in the central nervous system points to a role for statins in regulating sympathetic and vagal outflow , and inhibiting central angiotensin-II mechanisms .	204 In endothelial cells, the activation of AKT by statins results in stimulation of eNOS activity, leading to increased NO synthesis and neoangiogenesis while the increased production of endothelial NO in the central nervous system points to a role for statins in regulating sympathetic and vagal outflow, and inhibiting central angiotensin-II mechanisms.	6	16	results in stimulation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	8	9	15	16
eNOS is activated and phosphorylated by the PI3K-Akt pathway [ XREF_BIBR , XREF_BIBR ] .	eNOS is activated and phosphorylated by the PI3K-Akt pathway [XREF_BIBR, XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	eNOS	eNOS	eNOS	7	8	0	1
It activates Akt XREF_BIBR , XREF_BIBR , XREF_BIBR , which promotes eNOS activation XREF_BIBR , increasing the production of nitric oxide ( NO * ) and leading to mitochondrial biogenesis XREF_BIBR - XREF_BIBR through the expression of the peroxisome proliferator activated receptor-gamma coactivator 1alpha ( PGC-1alpha ) , a master regulator of mitochondrial mass .	It activates Akt XREF_BIBR, XREF_BIBR, XREF_BIBR, which promotes eNOS activation XREF_BIBR, increasing the production of nitric oxide (NO *) and leading to mitochondrial biogenesis XREF_BIBR - XREF_BIBR through the expression of the peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha), a master regulator of mitochondrial mass.	2	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	11	12
Insulin stimulates Akt phosphorylation and thereby activates eNOS [ XREF_BIBR , XREF_BIBR ] .	Insulin stimulates Akt phosphorylation and thereby activates eNOS [XREF_BIBR, XREF_BIBR].	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Insulin stimulates Akt phosphorylation	akt	eNOS	eNOS	enos	2	3	7	8
In another study it was demonstrated that endothelial nitric oxide synthase ( eNOS ) is a modulator of angiogenesis , and that Akt activates eNOS via a phosphorylation pathway [ XREF_BIBR ] .	In another study it was demonstrated that endothelial nitric oxide synthase (eNOS) is a modulator of angiogenesis, and that Akt activates eNOS via a phosphorylation pathway [XREF_BIBR].	22	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	22	23	24	25
Therefore , it may be concluded that DAQ B1 induced activation of Akt may activate eNOS and consequently reduce oxidative stress to improve hypertension associated vascular endothelial dysfunction .	Therefore, it may be concluded that DAQ B1 induced activation of Akt may activate eNOS and consequently reduce oxidative stress to improve hypertension associated vascular endothelial dysfunction.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	B1 induced activation of Akt	akt	eNOS	eNOS	enos	12	13	15	16
These effects of GJ were attenuated not only by calcium chelators including EGTA and BAPTA-AM , but also by LY294002 , a PI3K and Akt inhibitor , indicating calcium- and PI3K and Akt dependent activation of eNOS by GJ .	These effects of GJ were attenuated not only by calcium chelators including EGTA and BAPTA-AM, but also by LY294002, a PI3K and Akt inhibitor, indicating calcium- and PI3K and Akt dependent activation of eNOS by GJ.	32	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	32	33	36	37
More recently folic acid induced PI3K and Akt mediated activation of eNOS via phosphorylation at Ser1179 has been suggested .	More recently folic acid induced PI3K and Akt mediated activation of eNOS via phosphorylation at Ser1179 has been suggested.	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	7	8	11	12
Because eNOS is activated by Akt dependent phosphorylation to produce nitric oxide ( NO ) , we determined the subcellular distribution of eNOS phosphorylated on serine 1179 using a variety of methodologies .	Because eNOS is activated by Akt dependent phosphorylation to produce nitric oxide (NO), we determined the subcellular distribution of eNOS phosphorylated on serine 1179 using a variety of methodologies.	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt dependent phosphorylation	akt	eNOS	eNOS	enos	5	6	1	2
HSP90 , a highly conserved stress protein , is essential for Akt mediated activation of eNOS and prevention of proteosomal degradation of PI 3 K ( XREF_FIG ) [ XREF_BIBR ] .	HSP90, a highly conserved stress protein, is essential for Akt mediated activation of eNOS and prevention of proteosomal degradation of PI 3 K (XREF_FIG) [XREF_BIBR].	11	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	11	12	15	16
Given that phosphorylation of Ser1177 by Akt is critical for activation of eNOS , we investigated the effects of irisin in this regard .	Given that phosphorylation of Ser1177 by Akt is critical for activation of eNOS, we investigated the effects of irisin in this regard.	2	13	is critical for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	Akt	phosphorylation of Ser1177 by Akt	akt	eNOS	eNOS	enos	6	7	12	13
41 Furthermore , HSP90 and active AKT together increased eNOS activity by ~ 9 fold , which was abolished by disrupting HSP90-eNOS binding using Geldanamycin .	41 Furthermore, HSP90 and active AKT together increased eNOS activity by ~ 9 fold, which was abolished by disrupting HSP90-eNOS binding using Geldanamycin.	3	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	6	7	9	10
While the activation of eNOS by Akt and PKB dependent phosphorylation , leading to NO release , and the inhibition of enzyme activity by bradykinin ( BK )-mediated phosphorylation of eNOS in endothelial cells are established , the phosphorylation of eNOS in odontoblasts is unknown .	While the activation of eNOS by Akt and PKB dependent phosphorylation, leading to NO release, and the inhibition of enzyme activity by bradykinin (BK)-mediated phosphorylation of eNOS in endothelial cells are established, the phosphorylation of eNOS in odontoblasts is unknown.	2	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Akt	Akt and PKB dependent phosphorylation	akt	eNOS	eNOS	enos	6	7	4	5
Next , Akt causes eNOS to be phosphorylated and NO production to increase [ XREF_BIBR ] .	Next, Akt causes eNOS to be phosphorylated and NO production to increase [XREF_BIBR].	2	5	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	4	5
At higher concentrations of quercetin ( 30-100muM ) , eNOS activity was decreased in bovine aortic endothelial cells by decreasing Ser617 phosphorylation , and also ser473 Akt phosphorylation 126 .	At higher concentrations of quercetin (30-100muM), eNOS activity was decreased in bovine aortic endothelial cells by decreasing Ser617 phosphorylation, and also ser473 Akt phosphorylation 126.	9	27	decreased	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Ser617 phosphorylation, and also ser473 Akt	akt	eNOS	eNOS	enos	26	27	9	10
Such evidence indicated that Akt phosphorylation could activate eNOS , which lead to NO releasing , and resulted in ROS reducing .	Such evidence indicated that Akt phosphorylation could activate eNOS, which lead to NO releasing, and resulted in ROS reducing.	4	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	eNOS	eNOS	enos	4	5	8	9
Once phosphorylated , Akt activates eNOS , leading to increased NO production .	Once phosphorylated, Akt activates eNOS, leading to increased NO production.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	3	4	5	6
Stimulation of Akt enhances the activity of eNOS by phosphorylating serine at 1177 XREF_BIBR , XREF_BIBR .	Stimulation of Akt enhances the activity of eNOS by phosphorylating serine at 1177 XREF_BIBR, XREF_BIBR.	0	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	7	8
AKT and ERK1/2 have been shown to induce eNOS leading to an increase of NO production [ XREF_BIBR , XREF_BIBR ] .	AKT and ERK1/2 have been shown to induce eNOS leading to an increase of NO production [XREF_BIBR, XREF_BIBR].	0	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	0	1	8	9
Phosphorylation of eNOS at Ser 615 by PKA and Akt increases eNOS activity and appears to be important for regulating interactions between eNOS and other proteins , and for phosphorylation of eNOS at other sites .	Phosphorylation of eNOS at Ser 615 by PKA and Akt increases eNOS activity and appears to be important for regulating interactions between eNOS and other proteins, and for phosphorylation of eNOS at other sites.	9	12	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	9	10	11	12
The cis-Golgi eNOS is fully activated by Akt dependent phosphorylation .	The cis-Golgi eNOS is fully activated by Akt dependent phosphorylation.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt dependent phosphorylation	akt	eNOS	eNOS	enos	7	8	2	3
Our results indicate that EGCG induced endothelium dependent vasodilation is primarily based on rapid activation of eNOS by a phosphatidylinositol 3-kinase-, PKA-, and Akt dependent increase in eNOS activity , independently of an altered eNOS protein content .	Our results indicate that EGCG induced endothelium dependent vasodilation is primarily based on rapid activation of eNOS by a phosphatidylinositol 3-kinase-, PKA-, and Akt dependent increase in eNOS activity, independently of an altered eNOS protein content.	23	28	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	23	24	27	28
In the present study , we test the hypothesis that LA improves endothelial function through PI 3 -kinase and Akt mediated eNOS activation .	In the present study, we test the hypothesis that LA improves endothelial function through PI 3 -kinase and Akt mediated eNOS activation.	19	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	19	20	21	22
HSP70 improves functional recovery and reduces infarct size after ischemia through the protection of mitochondrial function , while HSP90 exerts pro angiogenic effects through Akt and eNOS XREF_BIBR increasing eNOS activity and nitric oxide release XREF_BIBR , by a calmodulin dependent mechanism XREF_BIBR .	HSP70 improves functional recovery and reduces infarct size after ischemia through the protection of mitochondrial function, while HSP90 exerts pro angiogenic effects through Akt and eNOS XREF_BIBR increasing eNOS activity and nitric oxide release XREF_BIBR, by a calmodulin dependent mechanism XREF_BIBR.	24	30	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	24	25	29	30
XREF_BIBR showed that a high-fat , high-sugar diet resulted in decreased Akt protein expression in aorta and heart tissue ; they suggested that eNOS activation by Akt and therefore endothelial function may be impaired by HFS .	XREF_BIBR showed that a high-fat, high-sugar diet resulted in decreased Akt protein expression in aorta and heart tissue; they suggested that eNOS activation by Akt and therefore endothelial function may be impaired by HFS.	23	30	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	26	27	23	24
Phosphorylation of PI3K-Akt activates multiple downstream substrates : glycogen synthase kinase-3 , apoptotic proteins ( BAD , BAX , p53 and caspases ) , eNOS and PKC .	Phosphorylation of PI3K-Akt activates multiple downstream substrates : glycogen synthase kinase-3, apoptotic proteins (BAD, BAX, p53 and caspases), eNOS and PKC.	0	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-Akt	Phosphorylation of PI3K-Akt	pi3k-akt	eNOS	eNOS	enos	2	3	24	25
Inhibition of Akt activation and/or 14-3-3 function strongly reduces beta-catenin signaling and decreases cell proliferation .	Inhibition of Akt activation and/or 14-3-3 function strongly reduces beta-catenin signaling and decreases cell proliferation.	2	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	9	10
Here , we provide evidence that cell-autonomous N-cadherin co-ordinates both Wnt dependent and AKT mediated beta-catenin activation .	Here, we provide evidence that cell-autonomous N-cadherin co-ordinates both Wnt dependent and AKT mediated beta-catenin activation.	10	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	13	14	15	16
Together , these observations suggest that N-cadherin engagement leads to phosphorylation of Akt and subsequent Akt mediated phosphoryation and activation of beta-catenin .	Together, these observations suggest that N-cadherin engagement leads to phosphorylation of Akt and subsequent Akt mediated phosphoryation and activation of beta-catenin.	8	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	15	16	21	22
Since both beta-catenin signalling and nephron patterning was modulated via the PI3K pathway , we tested whether AKT positively regulates beta-catenin signalling via phosphorylation of beta-catenin at Ser552 , as demonstrated elsewhere .	Since both beta-catenin signalling and nephron patterning was modulated via the PI3K pathway, we tested whether AKT positively regulates beta-catenin signalling via phosphorylation of beta-catenin at Ser552, as demonstrated elsewhere.	17	21	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	17	18	20	21
In fact , beta-catenin tyrosine ( Y ) phosphorylation by active receptor tyrosine kinases affects Wnt signaling XREF_BIBR , and enhanced AKT mediated beta-catenin activation has already been reported in BE associated carcinogenesis XREF_BIBR .	In fact, beta-catenin tyrosine (Y) phosphorylation by active receptor tyrosine kinases affects Wnt signaling XREF_BIBR, and enhanced AKT mediated beta-catenin activation has already been reported in BE associated carcinogenesis XREF_BIBR.	21	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	21	22	23	24
XREF_BIBR Based on the present in vivo data , one might speculate that it is the AF-1 in ERalpha that interacts with the IGF-I receptor and that this interaction lowers the threshold levels of IGF-I necessary to stimulate IGF-I receptor activation , resulting in initiation of phosphatidylinositol 3-kinase/protein kinase B ( AKT )-dependent activation of beta-catenin and altered lymphoid enhancing factor/T cell factor transcription , which in turn results in increased cortical bone formation .	XREF_BIBR Based on the present in vivo data, one might speculate that it is the AF-1 in ERalpha that interacts with the IGF-I receptor and that this interaction lowers the threshold levels of IGF-I necessary to stimulate IGF-I receptor activation, resulting in initiation of phosphatidylinositol 3-kinase/protein kinase B (AKT)-dependent activation of beta-catenin and altered lymphoid enhancing factor/T cell factor transcription, which in turn results in increased cortical bone formation.	51	58	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	51	52	55	56
We suggest that the Akt mediated activation of beta-catenin leads to inhibition of trophoblast apoptosis following increased expression of iNOS .	We suggest that the Akt mediated activation of beta-catenin leads to inhibition of trophoblast apoptosis following increased expression of iNOS.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	4	5	8	9
In conclusion , we show that FGF pathway induced proliferation of embryonic hepatoblasts and Mat1a -/- liver cancer stem cells is in part dependent on AKT mediated beta-catenin activation and subsequent CBP and beta-catenin driven transcription .	In conclusion, we show that FGF pathway induced proliferation of embryonic hepatoblasts and Mat1a -/- liver cancer stem cells is in part dependent on AKT mediated beta-catenin activation and subsequent CBP and beta-catenin driven transcription.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	25	26	27	28
It was demonstrated that the decreased bone formation was caused by reduced levels of activated beta-catenin , precipitated by a loss of phosphorylated GSK3beta , and phosphorylated AKT and PKB , targeting beta-catenin for degradation .	It was demonstrated that the decreased bone formation was caused by reduced levels of activated beta-catenin, precipitated by a loss of phosphorylated GSK3beta, and phosphorylated AKT and PKB, targeting beta-catenin for degradation.	26	33	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKB	phosphorylated AKT and PKB	pkb	beta-catenin	beta-catenin	beta-catenin	29	30	32	33
Akt phosphorylation promotes nuclear beta-catenin accumulation XREF_BIBR and we have previously shown in macrophages that LAB binds to the p85 subunit of PI3K , likely via Grb2 XREF_BIBR suggesting that this may be a possible mechanism for LAB mediated regulation of beta-catenin translocation .	Akt phosphorylation promotes nuclear beta-catenin accumulation XREF_BIBR and we have previously shown in macrophages that LAB binds to the p85 subunit of PI3K, likely via Grb2 XREF_BIBR suggesting that this may be a possible mechanism for LAB mediated regulation of beta-catenin translocation.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	beta-catenin	beta-catenin	beta-catenin	0	1	4	5
Second , our data also demonstrated that Akt activated beta-catenin by directly phosphorylating GSK-3beta at Ser 9 to inhibit GSK-3beta-driven beta-catenin degradation .	Second, our data also demonstrated that Akt activated beta-catenin by directly phosphorylating GSK-3beta at Ser 9 to inhibit GSK-3beta-driven beta-catenin degradation.	7	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
We plan to further investigate if beta-catenin activation by PI3K and Akt occurs through AKT mediated phosphorylation of GSK-3beta or through direct phosphorylation of beta-catenin by AKT .	We plan to further investigate if beta-catenin activation by PI3K and Akt occurs through AKT mediated phosphorylation of GSK-3beta or through direct phosphorylation of beta-catenin by AKT.	6	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	11	12	6	7
Finally , expression of a dominant negative ( kinase-dead ) Akt also reduced both baseline beta-catenin signaling in high-density primary cortical precursor cultures as well as Wnt stimulated beta-catenin signaling ( XREF_FIG ) .	Finally, expression of a dominant negative (kinase-dead) Akt also reduced both baseline beta-catenin signaling in high-density primary cortical precursor cultures as well as Wnt stimulated beta-catenin signaling (XREF_FIG).	2	29	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	expression of a dominant negative (kinase-dead) Akt	akt	beta-catenin	beta-catenin	beta-catenin	10	11	28	29
Therefore PI3K-AKT , inducing stabilization of the two KSRP target transcripts beta-catenin and PP2ACA , could enhance the cellular levels of beta-catenin protein operating a combinatorial positive control .	Therefore PI3K-AKT, inducing stabilization of the two KSRP target transcripts beta-catenin and PP2ACA, could enhance the cellular levels of beta-catenin protein operating a combinatorial positive control.	1	22	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	beta-catenin	beta-catenin	beta-catenin	1	2	21	22
Moreover , Akt can also activate beta-catenin indirectly through inactivation of GSK-3beta through its direct phosphorylation at Ser 9 .	Moreover, Akt can also activate beta-catenin indirectly through inactivation of GSK-3beta through its direct phosphorylation at Ser 9.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
Activation of the Akt pathway increased transcription activity of beta-catenin and protein synthesis by activation of S6 .	Activation of the Akt pathway increased transcription activity of beta-catenin and protein synthesis by activation of S6.	3	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	3	4	9	10
By conducting a proteomic analysis of the beta and catenin complex , we show that 14-3-3zeta exists in the beta and catenin complex and facilitates activation of beta-catenin by Akt , which , intriguingly , appears to be predominantly in ISCs .	By conducting a proteomic analysis of the beta and catenin complex, we show that 14-3-3zeta exists in the beta and catenin complex and facilitates activation of beta-catenin by Akt, which, intriguingly, appears to be predominantly in ISCs.	16	38	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	29	30	27	28
He et al demonstrated that AKT dependent activation of beta-catenin promotes self-renewal of intestinal stem and progenitor cells XREF_BIBR .	He et al demonstrated that AKT dependent activation of beta-catenin promotes self-renewal of intestinal stem and progenitor cells XREF_BIBR.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
The postnatal cardiomyocyte differentiation and proliferation depends on the redox activation of phosphatidyl inositol 3-kinase , Akt pathway that in turn modulates the beta catenin signaling , whereby regulating the proper cardiac specification , progenitor expansion , and myocardial growth [ XREF_BIBR ] .	The postnatal cardiomyocyte differentiation and proliferation depends on the redox activation of phosphatidyl inositol 3-kinase, Akt pathway that in turn modulates the beta catenin signaling, whereby regulating the proper cardiac specification, progenitor expansion, and myocardial growth [XREF_BIBR].	16	25	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta catenin	beta catenin	beta catenin	16	17	23	25
According to a previous study XREF_BIBR , the phosphorylation of AKT could activate the WNT and beta-catenin pathway through phosphorylating and inhibiting GSK3beta .	According to a previous study XREF_BIBR, the phosphorylation of AKT could activate the WNT and beta-catenin pathway through phosphorylating and inhibiting GSK3beta.	8	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	phosphorylation of AKT	akt	beta-catenin	beta-catenin	beta-catenin	10	11	16	17
We hypothesized that Akt activates beta-catenin and promotes downstream transcriptional activity .	We hypothesized that Akt activates beta-catenin and promotes downstream transcriptional activity.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	3	4	5	6
Inhibition of the PI3K and Akt pathway suppressed the Wnt and beta-catenin pathway by activation of glycogen synthase kinase-3beta ( GSK-3beta ) and degradation of beta-catenin .	Inhibition of the PI3K and Akt pathway suppressed the Wnt and beta-catenin pathway by activation of glycogen synthase kinase-3beta (GSK-3beta) and degradation of beta-catenin.	3	12	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	5	6	11	12
Besides , a previous study also validated that Akt signaling can directly stimulate the activity of beta-catenin .	Besides, a previous study also validated that Akt signaling can directly stimulate the activity of beta-catenin.	8	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	8	9	16	17
Inactivation of Akt using inhibitors LY294002 and MK2206 could elevate the SCD1 inhibition mediated downregulation of p-GSK3beta and beta-catenin in T98G-R and U87-R cell lines .	Inactivation of Akt using inhibitors LY294002 and MK2206 could elevate the SCD1 inhibition mediated downregulation of p-GSK3beta and beta-catenin in T98G-R and U87-R cell lines.	0	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	18	19
We observed that activating Akt by EGF promoted SCD1 mediated upregulation of p-GSK3beta and beta-catenin in T98G and U87 cell lines .	We observed that activating Akt by EGF promoted SCD1 mediated upregulation of p-GSK3beta and beta-catenin in T98G and U87 cell lines.	3	15	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	4	5	14	15
In conclusion , we demonstrate that FGF signaling , partly through AKT mediated beta-catenin activation , regulates the expansion of the A6 + ive HPCs and A6 + ive HNF4alpha + ive hepatocytes .	In conclusion, we demonstrate that FGF signaling, partly through AKT mediated beta-catenin activation, regulates the expansion of the A6 + ive HPCs and A6 + ive HNF4alpha + ive hepatocytes.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	11	12	13	14
For example , PI3K and Akt has also been found to mediate beta-catenin through activation of IkappaB kinase .	For example, PI3K and Akt has also been found to mediate beta-catenin through activation of IkappaB kinase.	3	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	5	6	12	13
Notably , knockdown of PTEN activated Akt mediated beta-catenin and inhibited Foxo1 , which implies a specific role for Akt/beta-catenin/Foxo1 signaling in the regulation of IR triggered inflammation in the liver .	Notably, knockdown of PTEN activated Akt mediated beta-catenin and inhibited Foxo1, which implies a specific role for Akt/beta-catenin/Foxo1 signaling in the regulation of IR triggered inflammation in the liver.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
The PI3K and Akt pathway is reported to be activated by multiple types of mechanical stress [ XREF_BIBR , XREF_BIBR ] , which can inhibit GSK-3beta and activate beta-catenin [ XREF_BIBR ] .	The PI3K and Akt pathway is reported to be activated by multiple types of mechanical stress [XREF_BIBR, XREF_BIBR], which can inhibit GSK-3beta and activate beta-catenin [XREF_BIBR].	1	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	3	4	28	29
In addition TRbeta1 is essential for the T3 upregulation of the Akt targets beta-catenin , p70S6K , and for the phosphorylation of Bad and mTOR .	In addition TRbeta1 is essential for the T3 upregulation of the Akt targets beta-catenin, p70S6K, and for the phosphorylation of Bad and mTOR.	8	15	targets	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	11	12	13	14
Because inhibition of either EGFR or Akt signaling reduced the transcriptional activity of beta-catenin , we next determined whether the same treatments could also prevent the increase in cell proliferation following Dsc2 knockdown .	Because inhibition of either EGFR or Akt signaling reduced the transcriptional activity of beta-catenin, we next determined whether the same treatments could also prevent the increase in cell proliferation following Dsc2 knockdown.	6	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	6	7	13	14
To investigate whether PI3K and PTEN mediated Akt signaling activates beta-catenin to regulate innate immunity networks in vitro , we next used PI3K inhibitor ( LY 294002 ) in LPS stimulated BMM cultures .	To investigate whether PI3K and PTEN mediated Akt signaling activates beta-catenin to regulate innate immunity networks in vitro, we next used PI3K inhibitor (LY 294002) in LPS stimulated BMM cultures.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	PTEN mediated Akt	akt	beta-catenin	beta-catenin	beta-catenin	7	8	10	11
XREF_BIBR AKT inhibits glycogen synthase kinase 3 ( GSK3 )-beta by phosphorylating it at SER 9 position and thereby promotes beta-catenin towards division phase .	XREF_BIBR AKT inhibits glycogen synthase kinase 3 (GSK3)-beta by phosphorylating it at SER 9 position and thereby promotes beta-catenin towards division phase.	0	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	1	2	20	21
It is possible that the result of these two inhibitory interactions is that activation of PKB by integrin signaling functions to positively activate beta-catenin signaling .	It is possible that the result of these two inhibitory interactions is that activation of PKB by integrin signaling functions to positively activate beta-catenin signaling.	13	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKB	PKB	PKB	beta-catenin	beta-catenin	beta-catenin	15	16	23	24
Relevant here is the finding that PGE 2 treatment leads to Akt activation ; activated Akt subsequently stimulates beta-catenin signaling in several ways .	Relevant here is the finding that PGE 2 treatment leads to Akt activation; activated Akt subsequently stimulates beta-catenin signaling in several ways.	14	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	15	16	18	19
In vitro analyses using FGF10 treated HepG2 cells demonstrated AKT mediated beta-CATENIN activation but not enhanced cell migration .	In vitro analyses using FGF10 treated HepG2 cells demonstrated AKT mediated beta-CATENIN activation but not enhanced cell migration.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-CATENIN	beta-CATENIN	beta-CATENIN	9	10	11	12
XREF_BIBR Furthermore , Akt inhibits glycogen synthase kinase-3 ( GSK3 ) , thus Akt directly prevents beta-catenin degradation .	XREF_BIBR Furthermore, Akt inhibits glycogen synthase kinase-3 (GSK3), thus Akt directly prevents beta-catenin degradation.	12	17	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	13	14	16	17
PI3K and AKT mediated beta-catenin activation protects cells from senescence and increases cell proliferation , EMT and cell invasion .	PI3K and AKT mediated beta-catenin activation protects cells from senescence and increases cell proliferation, EMT and cell invasion.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
We investigated whether phosphoinositide 3- kinase ( PI3K ) is required for Akt mediated activation of beta-catenin during intestinal inflammation .	We investigated whether phosphoinositide 3- kinase (PI3K) is required for Akt mediated activation of beta-catenin during intestinal inflammation.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	12	13	16	17
Additionally , enhanced activation of AKT does not increase nuclear beta-catenin [ XREF_BIBR ] .	Additionally, enhanced activation of AKT does not increase nuclear beta-catenin [XREF_BIBR].	3	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
Our lab demonstrated that mechanically activated Akt increased beta-catenin activity , finally resulting in inhibition of MSC adipogenesis .	Our lab demonstrated that mechanically activated Akt increased beta-catenin activity, finally resulting in inhibition of MSC adipogenesis.	5	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
This result shows that phosphorylation at Ser552 is essential for AKT induced beta-catenin stabilization .	This result shows that phosphorylation at Ser552 is essential for AKT induced beta-catenin stabilization.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	10	11	12	13
Inactivation of AKT signalling attenuated DVL1 mediated inhibition of GSK-3beta and accumulation of beta-catenin , in both A2780 and A2780 and Taxol cells .	Inactivation of AKT signalling attenuated DVL1 mediated inhibition of GSK-3beta and accumulation of beta-catenin, in both A2780 and A2780 and Taxol cells.	2	14	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	2	3	13	14
N-cadherin adhesion can lead to phosphatidylinositol 3-kinase ( PI3K )-mediated activation of AKT [ XREF_BIBR ] , and activated AKT signaling can stimulate beta-catenin signaling .	N-cadherin adhesion can lead to phosphatidylinositol 3-kinase (PI3K)-mediated activation of AKT [XREF_BIBR], and activated AKT signaling can stimulate beta-catenin signaling.	19	24	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	19	20	23	24
Interestingly , the PI3K-AKT pathway has been shown to directly activate beta-catenin signaling during lung development as well as in the adult airway epithelium after injury ( see below ) .	Interestingly, the PI3K-AKT pathway has been shown to directly activate beta-catenin signaling during lung development as well as in the adult airway epithelium after injury (see below).	3	12	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
Furthermore , blockage of AKT by MK-2206 attenuated TIP30 decrease induced activation of beta-catenin and upregulation of Vimentin .	Furthermore, blockage of AKT by MK-2206 attenuated TIP30 decrease induced activation of beta-catenin and upregulation of Vimentin.	2	15	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	4	5	13	14
25 Phosphorylation of AKT can also promote beta-catenin transcriptional activity via glycogen synthase kinase 3 ( GSKbeta ) inactivation and subsequent translocation of beta-catenin to the nucleus , where the wnt target genes Wisp1 and Cox2 are then transcribed .	25 Phosphorylation of AKT can also promote beta-catenin transcriptional activity via glycogen synthase kinase 3 (GSKbeta) inactivation and subsequent translocation of beta-catenin to the nucleus, where the wnt target genes Wisp1 and Cox2 are then transcribed.	1	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	Phosphorylation of AKT	akt	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
The results suggest that the host defense against C. rodentium requires epithelial PI3K activation to induce Akt mediated beta-catenin signaling and the clearance of C. rodentium independent of adaptive immune responses .	The results suggest that the host defense against C. rodentium requires epithelial PI3K activation to induce Akt mediated beta-catenin signaling and the clearance of C. rodentium independent of adaptive immune responses.	15	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	16	17	18	19
In fact , although AKT signaling leads to inhibition of GSK-3 via serine phosphorylation , AKT signaling does not cause stabilization and accumulation of beta-catenin [ XREF_BIBR , XREF_BIBR ] .	In fact, although AKT signaling leads to inhibition of GSK-3 via serine phosphorylation, AKT signaling does not cause stabilization and accumulation of beta-catenin [XREF_BIBR, XREF_BIBR].	15	28	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	15	16	24	25
This evidence suggests that the PI3K and Akt signaling pathway cooperates to increase beta-catenin activity in Phop c Salmonella infections .	This evidence suggests that the PI3K and Akt signaling pathway cooperates to increase beta-catenin activity in Phop c Salmonella infections.	7	14	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	13	14
Moreover , Akt mediated beta-catenin activation provides a negative feedback to the nuclear Foxo1 .	Moreover, Akt mediated beta-catenin activation provides a negative feedback to the nuclear Foxo1.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
Thereby , disruption of BMP signaling by mutations silencing receptor function inactivates PTEN which , in turn , activates AKT mediating an accumulation of beta-catenin [ XREF_BIBR ] .	Thereby, disruption of BMP signaling by mutations silencing receptor function inactivates PTEN which, in turn, activates AKT mediating an accumulation of beta-catenin [XREF_BIBR].	19	26	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	19	20	24	25
Conclusion : FGF signaling regulates the proliferation and survival of embryonic and transformed progenitor cells in part through AKT mediated activation of beta-catenin and downstream interaction with the transcriptional co-activator CBP .	Conclusion : FGF signaling regulates the proliferation and survival of embryonic and transformed progenitor cells in part through AKT mediated activation of beta-catenin and downstream interaction with the transcriptional co-activator CBP.	16	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	18	19	22	23
Enhanced AKT mediated beta-Catenin activation is seen in BE associated carcinogenesis .	Enhanced AKT mediated beta-Catenin activation is seen in BE associated carcinogenesis.	1	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-Catenin	beta-Catenin	beta-Catenin	1	2	3	4
In addition , AKT dependent phosphorylation and inhibition of GSK3beta activity enhances beta-catenin protein stability through decreased phosphorylation of beta-catenin at Ser33/34/Thr41 residues [ XREF_BIBR , XREF_BIBR ] .	In addition, AKT dependent phosphorylation and inhibition of GSK3beta activity enhances beta-catenin protein stability through decreased phosphorylation of beta-catenin at Ser33/34/Thr41 residues [XREF_BIBR, XREF_BIBR].	3	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT dependent phosphorylation	akt	beta-catenin	beta-catenin	beta-catenin	3	4	12	13
In a recent study from our laboratory , we show that PGE 2 increases osteocyte gap junction function by transcriptional regulation of Cx43 through GSK-3 and beta-catenin pathway mediated by independent activation of PI3K and AKT and cAMP-PKA pathways [ XREF_BIBR - XREF_BIBR ] .	In a recent study from our laboratory, we show that PGE 2 increases osteocyte gap junction function by transcriptional regulation of Cx43 through GSK-3 and beta-catenin pathway mediated by independent activation of PI3K and AKT and cAMP-PKA pathways [XREF_BIBR - XREF_BIBR].	24	36	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	35	36	26	27
Taken together , these results suggest that Akt enhances beta-catenin signaling in Dsc2 deficient cells by promoting the nuclear localization of active beta-catenin without inducing accumulation of the total protein level of beta-catenin .	Taken together, these results suggest that Akt enhances beta-catenin signaling in Dsc2 deficient cells by promoting the nuclear localization of active beta-catenin without inducing accumulation of the total protein level of beta-catenin.	7	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
Akt and ILK can trigger the activation of nuclear transcription factor beta-catenin and activator protein ( AP ) -1 by GSK-3beta , which makes them enter the nucleus , activate nuclear transcription processes , causes the reduction of epithelial cell adhesion , increases the synthesis of matrix metalloproteinase ( MMP ) -9 and alpha-SMA and finally affects the induction and progression of the EMT process .	Akt and ILK can trigger the activation of nuclear transcription factor beta-catenin and activator protein (AP) -1 by GSK-3beta, which makes them enter the nucleus, activate nuclear transcription processes, causes the reduction of epithelial cell adhesion, increases the synthesis of matrix metalloproteinase (MMP) -9 and alpha-SMA and finally affects the induction and progression of the EMT process.	0	14	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	0	1	11	12
21 Since , in IECs , Akt dependent activation of beta-catenin signaling contributes to the regulation of IEC proliferation , XREF_BIBR , XREF_BIBR we investigated whether the binding of post-migrated PMNs to apically expressed ICAM-1 could trigger epithelial activation of Akt and beta-catenin signaling .	21 Since, in IECs, Akt dependent activation of beta-catenin signaling contributes to the regulation of IEC proliferation, XREF_BIBR, XREF_BIBR we investigated whether the binding of post-migrated PMNs to apically expressed ICAM-1 could trigger epithelial activation of Akt and beta-catenin signaling.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	6	7	10	11
Hence , the activation of Akt is considered to induce beta-catenin stabilization in cytoplasm .	Hence, the activation of Akt is considered to induce beta-catenin stabilization in cytoplasm.	3	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
beta-catenin is upregulated by the AKT and GSK3beta pathway , which thereby triggers the cell cycle by enhancing cyclin D1 expression XREF_BIBR .	beta-catenin is upregulated by the AKT and GSK3beta pathway, which thereby triggers the cell cycle by enhancing cyclin D1 expression XREF_BIBR.	0	8	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	5	6	0	1
PI3K induced and Akt mediated beta-catenin signaling are required for progenitor cell activation during the progression from CUC to CAC ; these factors might be used as biomarkers of dysplastic transformation in the colon .	PI3K induced and Akt mediated beta-catenin signaling are required for progenitor cell activation during the progression from CUC to CAC; these factors might be used as biomarkers of dysplastic transformation in the colon.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	3	4	5	6
Interestingly , the PI3K and Akt pathway also increases the stability of beta-catenin in prostate cancer [ XREF_BIBR ] .	Interestingly, the PI3K and Akt pathway also increases the stability of beta-catenin in prostate cancer [XREF_BIBR].	3	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	5	6	12	13
To better understand the role of targeting the MNK-eIF4E axis by CGP57380 in the suppression of beta-catenin nuclear translocation , we noted the main findings of two previous studies showing that eIF4E phosphorylation leads to AKT activation , which in turn promotes beta-catenin signaling XREF_BIBR , and that AKT mediated phosphorylation of beta-catenin at serine 552 ( S552 ) is a necessary step in beta-catenin nuclear translocation and activation XREF_BIBR .	To better understand the role of targeting the MNK-eIF4E axis by CGP57380 in the suppression of beta-catenin nuclear translocation, we noted the main findings of two previous studies showing that eIF4E phosphorylation leads to AKT activation, which in turn promotes beta-catenin signaling XREF_BIBR, and that AKT mediated phosphorylation of beta-catenin at serine 552 (S552) is a necessary step in beta-catenin nuclear translocation and activation XREF_BIBR.	35	44	promotes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	35	36	42	43
XREF_BIBR - XREF_BIBR Other factors and potential mechanism involved chronic subclinical inflammation , abnormal carbohydrate and lipid metabolism , abnormalities in sex hormone metabolism , and excessive activation of Akt and mammalian target of rapamycin and Wnt and Beta-catenin pathways .	XREF_BIBR - XREF_BIBR Other factors and potential mechanism involved chronic subclinical inflammation, abnormal carbohydrate and lipid metabolism, abnormalities in sex hormone metabolism, and excessive activation of Akt and mammalian target of rapamycin and Wnt and Beta-catenin pathways.	29	39	target	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	Beta-catenin	Beta-catenin	Beta-catenin	29	30	38	39
In this study , we observed increased AKT mediated beta-catenin activation and cell proliferation in the periportal region with two weeks of in vivo Fgf10 over-expression concurrent with DDC treatment .	In this study, we observed increased AKT mediated beta-catenin activation and cell proliferation in the periportal region with two weeks of in vivo Fgf10 over-expression concurrent with DDC treatment.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
PI3K-AKT Activation Prolongs beta-Catenin mRNA Half-Life by Targeting KSRP .	PI3K-AKT Activation Prolongs beta-Catenin mRNA Half-Life by Targeting KSRP.	0	5	Prolongs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	beta-Catenin	beta-Catenin	beta-Catenin	0	1	3	4
Taken together , these data suggest that AKT mediated beta-catenin activation is sufficient but not necessary to expand this cell population .	Taken together, these data suggest that AKT mediated beta-catenin activation is sufficient but not necessary to expand this cell population.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
PI3k and Akt signal transduction pathway can inhibit GSK3beta and then promote beta-catenin to activate cyclin D1 promoter via the TCF site .	PI3k and Akt signal transduction pathway can inhibit GSK3beta and then promote beta-catenin to activate cyclin D1 promoter via the TCF site.	2	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	12	13
Next , we determined whether constitutively active Akt ( Myr.Akt ) could abrogate the effects of beta-catenin silencing on cell migration and invasion .	Next, we determined whether constitutively active Akt (Myr.Akt) could abrogate the effects of beta-catenin silencing on cell migration and invasion.	6	17	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	16	17
PTEN mediated Akt activates beta-catenin and negatively regulates Foxo1 signaling in vitro .	PTEN mediated Akt activates beta-catenin and negatively regulates Foxo1 signaling in vitro.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	PTEN mediated Akt	akt	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
XREF_BIBR , XREF_BIBR These results suggest that Akt and Gsk3beta axis mediated beta-catenin activation in islets may regulate beta-cell growth and function in c-Kit Wv/+ mice .	XREF_BIBR, XREF_BIBR These results suggest that Akt and Gsk3beta axis mediated beta-catenin activation in islets may regulate beta-cell growth and function in c-Kit Wv/+ mice.	7	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	12	13
Thus , by these two mechanisms , Akt activation promotes the activation and accumulation of nuclear beta-catenin XREF_BIBR .	Thus, by these two mechanisms, Akt activation promotes the activation and accumulation of nuclear beta-catenin XREF_BIBR.	7	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	16	17
Thus , AKT can activate beta-catenin and TCF transcriptional activity both by indirect stabilization of beta-catenin through inhibition of GSK3beta and by direct phoshorylation of beta-catenin which promotes beta-catenin nuclear accumulation .	Thus, AKT can activate beta-catenin and TCF transcriptional activity both by indirect stabilization of beta-catenin through inhibition of GSK3beta and by direct phoshorylation of beta-catenin which promotes beta-catenin nuclear accumulation.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	2	3	5	6
In addition , L. donovani triggers AKT activation of the anti-apoptotic beta-catenin , inhibiting the pro apoptotic transcriptional regulator FOXO-1 .	In addition, L. donovani triggers AKT activation of the anti-apoptotic beta-catenin, inhibiting the pro apoptotic transcriptional regulator FOXO-1.	6	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	6	7	11	12
Given that beta-catenin activation regulates the expansion of the A6 + ive cell population with DDC injury and that FGF promotes AKT dependent beta-catenin activation of embryonic and tumor initiating HPC in vitro , we sought to determine if FGF signaling induces AKT mediated beta-catenin activation in DDC liver injury .	Given that beta-catenin activation regulates the expansion of the A6 + ive cell population with DDC injury and that FGF promotes AKT dependent beta-catenin activation of embryonic and tumor initiating HPC in vitro, we sought to determine if FGF signaling induces AKT mediated beta-catenin activation in DDC liver injury.	41	45	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	42	43	44	45
T 3 promotes the PI3K and Akt signaling and PI3K and Akt induced beta-catenin activation .	T 3 promotes the PI3K and Akt signaling and PI3K and Akt induced beta-catenin activation.	4	14	induced	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	6	7	13	14
beta-catenin activation by the PI3K and AKT pathway has also been reported in HepG2 and HeLa cells .	beta-catenin activation by the PI3K and AKT pathway has also been reported in HepG2 and HeLa cells.	0	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	6	7	0	1
T 3 -mediated Wnt-4 expression , beta-catenin activation , cell proliferation , and terminal differentiation of growth plate chondrocytes are partially prevented by the IGF1R inhibitor picropodophyllin as well as by the PI3K and Akt signaling inhibitors LY294002 and Akti1/2 .	T 3 -mediated Wnt-4 expression, beta-catenin activation, cell proliferation, and terminal differentiation of growth plate chondrocytes are partially prevented by the IGF1R inhibitor picropodophyllin as well as by the PI3K and Akt signaling inhibitors LY294002 and Akti1/2.	6	36	prevented	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	34	35	6	7
Conversely , PI3K and Akt signaling , which is activated by receptor tyrosine kinases ( RTKs ) , may positively regulate beta-catenin transcriptional activity independent of Wnt-Fzd interaction [ XREF_BIBR ] .	Conversely, PI3K and Akt signaling, which is activated by receptor tyrosine kinases (RTKs), may positively regulate beta-catenin transcriptional activity independent of Wnt-Fzd interaction [XREF_BIBR].	2	23	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	4	5	21	22
Thus , we conclude that while a large percentage of PROM1 pos cells co-express FGFR , only a small fraction of PROM1 pos cells are proliferating via FGF induced AKT mediated beta-catenin pathway activation .	Thus, we conclude that while a large percentage of PROM1 pos cells co-express FGFR, only a small fraction of PROM1 pos cells are proliferating via FGF induced AKT mediated beta-catenin pathway activation.	29	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	29	30	31	32
Biochemical analyses showed that peptide induced alpha5beta1 integrin priming transiently increased PI3K and Akt phosphorylation and promoted Wnt and beta-catenin transcriptional activity independently of RRET .	Biochemical analyses showed that peptide induced alpha5beta1 integrin priming transiently increased PI3K and Akt phosphorylation and promoted Wnt and beta-catenin transcriptional activity independently of RRET.	7	21	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	integrin priming transiently increased PI3K and Akt phosphorylation	akt	beta-catenin	beta-catenin	beta-catenin	13	14	19	20
35 AKT can activate beta-catenin by inhibiting GSK3beta .	35 AKT can activate beta-catenin by inhibiting GSK3beta.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	1	2	4	5
Additionally , increased levels of nuclear beta-catenin phosphorylated at Serine 552 in cultured primary hepatoblasts , Mat1a -/- cells , and also in ex vivo embryonic liver explants indicate AKT dependent activation of beta-catenin downstream of FGFR activation ; conversely , the addition of AKT inhibitor Ly294002 completely abrogated beta-catenin activation .	Additionally, increased levels of nuclear beta-catenin phosphorylated at Serine 552 in cultured primary hepatoblasts, Mat1a -/- cells, and also in ex vivo embryonic liver explants indicate AKT dependent activation of beta-catenin downstream of FGFR activation; conversely, the addition of AKT inhibitor Ly294002 completely abrogated beta-catenin activation.	29	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	29	30	33	34
Akt mediates PPP2CA silencing induced activation of beta-catenin and NF-kappaB .	Akt mediates PPP2CA silencing induced activation of beta-catenin and NF-kappaB.	0	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	0	1	7	8
IFNgamma mediated Akt activation promotes 14.3.3 zeta and pbeta-cat552 association and beta-catenin redistribution .	IFNgamma mediated Akt activation promotes 14.3.3 zeta and pbeta-cat552 association and beta-catenin redistribution.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	IFNgamma mediated Akt	akt	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
The previous data all demonstrate that AKT inhibition blocks strain related beta-catenin activity .	The previous data all demonstrate that AKT inhibition blocks strain related beta-catenin activity.	6	12	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	6	7	11	12
Their phosphorylation increased beta , catenin , and TCF complex through inactivation of GSK3beta , indicating that phosphorylation of ERK1/2 and/or Akt induces activation of beta-catenin signaling pathway .	Their phosphorylation increased beta, catenin, and TCF complex through inactivation of GSK3beta, indicating that phosphorylation of ERK1/2 and/or Akt induces activation of beta-catenin signaling pathway.	17	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	phosphorylation of ERK1/2 and/or Akt	akt	beta-catenin	beta-catenin	beta-catenin	21	22	25	26
PI3K and Akt mediated activation of beta-catenin , a positive regulator of epithelial-mesenchymal transition and fibrosis , was observed in the lungs of insulin treated mice and lung cells .	PI3K and Akt mediated activation of beta-catenin, a positive regulator of epithelial-mesenchymal transition and fibrosis, was observed in the lungs of insulin treated mice and lung cells.	0	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
Previous work has demonstrated that Akt can directly activate beta-catenin ; the reduced activation of Akt observed after resveratrol treatment can therefore be at least partially responsible for the detected diminished activation of beta-catenin [ XREF_BIBR ] .	Previous work has demonstrated that Akt can directly activate beta-catenin; the reduced activation of Akt observed after resveratrol treatment can therefore be at least partially responsible for the detected diminished activation of beta-catenin [XREF_BIBR].	5	10	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
Similarly , pharmacological inhibitors of AKT and beta-catenin not only attenuated the induction of total and active beta-catenin forms , but also prevented the increase in the number of colonies after cadmium exposure .	Similarly, pharmacological inhibitors of AKT and beta-catenin not only attenuated the induction of total and active beta-catenin forms, but also prevented the increase in the number of colonies after cadmium exposure.	3	18	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	5	6	17	18
XREF_BIBR These results were consistent with the notion that PI3K and Akt activation cooperated with Wnt to activate beta-catenin signaling in ISC and progenitor cells .	XREF_BIBR These results were consistent with the notion that PI3K and Akt activation cooperated with Wnt to activate beta-catenin signaling in ISC and progenitor cells.	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	11	12	18	19
Total lung beta-catenin was unchanged in any low PIP isolated lung group , but Akt inhibition during high PIP ventilation significantly decreased total beta-catenin by 86 % .	Total lung beta-catenin was unchanged in any low PIP isolated lung group, but Akt inhibition during high PIP ventilation significantly decreased total beta-catenin by 86%.	14	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	14	15	23	24
In many types of human cancer , Akt mediated beta-catenin nuclear accumulation and increased transcriptional activity that promotes tumor development .	In many types of human cancer, Akt mediated beta-catenin nuclear accumulation and increased transcriptional activity that promotes tumor development.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
However , FAK Y397 phosphorylation ( indicating FAK activation ) , GSK3alpha and beta phosphorylation ( indicating GSK3 inactivation ) and Akt S473 phosphorylation ( indicating Akt activity ) increased with stiffness , suggesting integrin dependent signaling activates beta-catenin ( XREF_FIG , XREF_SUPPLEMENTARY , XREF_FIG ) .	However, FAK Y397 phosphorylation (indicating FAK activation), GSK3alpha and beta phosphorylation (indicating GSK3 inactivation) and Akt S473 phosphorylation (indicating Akt activity) increased with stiffness, suggesting integrin dependent signaling activates beta-catenin (XREF_FIG, XREF_SUPPLEMENTARY, XREF_FIG).	3	44	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Y397 phosphorylation (indicating FAK activation), GSK3alpha and beta phosphorylation (indicating GSK3 inactivation) and Akt	akt	beta-catenin	beta-catenin	beta-catenin	21	22	38	39
Akt activation provides a powerful antiapoptotic signal and also mediates the inactivation of GSK3beta , stabilization of beta-catenin , and subsequent stimulation of beta-catenin-dependent transcription [ XREF_BIBR ] .	Akt activation provides a powerful antiapoptotic signal and also mediates the inactivation of GSK3beta, stabilization of beta-catenin, and subsequent stimulation of beta-catenin-dependent transcription [XREF_BIBR].	0	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	0	1	17	18
In this study , we show that FGF signaling promotes the initial expansion of a DDC induced periportal A6 + ive HNF4alpha -ive cell and A6 + ive HNF4alpha + ive hepatocyte populations in association with AKT mediated activation of beta-catenin .	In this study, we show that FGF signaling promotes the initial expansion of a DDC induced periportal A6 + ive HNF4alpha -ive cell and A6 + ive HNF4alpha + ive hepatocyte populations in association with AKT mediated activation of beta-catenin.	36	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	36	37	40	41
Results showed that T cell activation induced Akt mediated activation of beta-catenin as levels of P-beta-catenin 552 in nuclear fractions rose .	Results showed that T cell activation induced Akt mediated activation of beta-catenin as levels of P-beta-catenin 552 in nuclear fractions rose.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	11	12
We have recently described that phosphatidylinositol 3-kinase/AKT ( PI3K-AKT ) activation induces stabilization and accumulation of the labile beta-catenin mRNA through an impairment of KSRP function .	We have recently described that phosphatidylinositol 3-kinase/AKT (PI3K-AKT) activation induces stabilization and accumulation of the labile beta-catenin mRNA through an impairment of KSRP function.	6	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	beta-catenin	beta-catenin	beta-catenin	8	9	18	19
XREF_BIBR , XREF_BIBR Since , PI3K and AKT signaling is known to activate beta-catenin transcriptional activity , it is seemly possible that PAK1 cooperates with PI3K and AKT signaling to sustain Wnt and beta-catenin activity .	XREF_BIBR, XREF_BIBR Since, PI3K and AKT signaling is known to activate beta-catenin transcriptional activity, it is seemly possible that PAK1 cooperates with PI3K and AKT signaling to sustain Wnt and beta-catenin activity.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	7	8	13	14
It has been recently shown that nuclear AKT inhibits , whereas membrane tethered AKT stimulates beta-catenin transcriptional activity [ XREF_BIBR ] , underscoring a complex nature of the crosstalk between the canonical Wnt and AKT signaling pathways .	It has been recently shown that nuclear AKT inhibits, whereas membrane tethered AKT stimulates beta-catenin transcriptional activity [XREF_BIBR], underscoring a complex nature of the crosstalk between the canonical Wnt and AKT signaling pathways.	12	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	13	14	15	16
P-beta-catenin 552 staining of CID , sporadic dysplasia , and cancer suggest increased PI3K and Akt mediated beta-catenin signaling may be a biomarker of neoplastic transformation in the colon .	P-beta-catenin 552 staining of CID, sporadic dysplasia, and cancer suggest increased PI3K and Akt mediated beta-catenin signaling may be a biomarker of neoplastic transformation in the colon.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	15	16	17	18
Furthermore , in Wnt overexpressing PC12 cells , dominant negative Akt decreased free beta-catenin and derepressed nerve growth factor induced differentiation .	Furthermore, in Wnt overexpressing PC12 cells, dominant negative Akt decreased free beta-catenin and derepressed nerve growth factor induced differentiation.	8	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	10	11	13	14
Activated Dvl inhibits the beta-catenin destruction complex - through recruitment of Axin at the plasma membrane and induction of the Akt mediated inactivation of GSK-3beta via Ser9 phosphorylation - and causes beta-catenin stabilization and cytosolic accumulation .	Activated Dvl inhibits the beta-catenin destruction complex - through recruitment of Axin at the plasma membrane and induction of the Akt mediated inactivation of GSK-3beta via Ser9 phosphorylation - and causes beta-catenin stabilization and cytosolic accumulation.	15	32	causes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	20	21	31	32
A previous study found that Akt mediated increases in nuclear beta-catenin signalling results in increased glycolysis and mitochondrial dysfunction in oesophageal squamous cell carcinoma .	A previous study found that Akt mediated increases in nuclear beta-catenin signalling results in increased glycolysis and mitochondrial dysfunction in oesophageal squamous cell carcinoma.	5	11	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
Of note , while numerous reports have demonstrated a clear role for Akt activation in the regulation of beta-catenin-dependent transcription , PI3K and Akt does not enhance the transcriptional activity of beta-catenin in all cell types , suggesting that Akt and beta-catenin signaling may occur in a tissue- and/or context dependent manner .	Of note, while numerous reports have demonstrated a clear role for Akt activation in the regulation of beta-catenin-dependent transcription, PI3K and Akt does not enhance the transcriptional activity of beta-catenin in all cell types, suggesting that Akt and beta-catenin signaling may occur in a tissue- and/or context dependent manner.	21	32	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	23	24	31	32
However , our results indicate that PI3K-AKT consistently induces beta-catenin mRNA stabilization and protein accumulation in both cell lines .	However, our results indicate that PI3K-AKT consistently induces beta-catenin mRNA stabilization and protein accumulation in both cell lines.	6	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	beta-catenin	beta-catenin	beta-catenin	6	7	9	10
Phosphorylation of serine 552 of beta-Catenin has been shown to be mediated by Akt , which targets beta-Catenin for nuclear import and triggers a subsequent increase in the transcription of the TCF/LEF target genes [ XREF_BIBR ] .	Phosphorylation of serine 552 of beta-Catenin has been shown to be mediated by Akt, which targets beta-Catenin for nuclear import and triggers a subsequent increase in the transcription of the TCF/LEF target genes [XREF_BIBR].	0	22	mediated	Positive_regulation_syntax_2_verb	Positive_activation	Positive_regulation	Akt	Akt	akt	beta-Catenin	Phosphorylation of serine 552 of beta-Catenin	beta-catenin	13	14	5	6
Phosphorylated-beta-catenin ( 552 ) , which is driven by Akt activation , has been identified as a potential intestinal stem cell marker [ XREF_BIBR ] .	Phosphorylated-beta-catenin (552), which is driven by Akt activation, has been identified as a potential intestinal stem cell marker [XREF_BIBR].	0	14	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Phosphorylated-beta-catenin	Phosphorylated-beta-catenin	Phosphorylated-beta-catenin	9	10	0	1
Similarly , pharmacological inhibitors of AKT and beta-catenin not only attenuated the induction of total and active beta-catenin , but also prevented an increase in the number of colonies after Cr ( VI ) exposure ( XREF_FIG ) .	Similarly, pharmacological inhibitors of AKT and beta-catenin not only attenuated the induction of total and active beta-catenin, but also prevented an increase in the number of colonies after Cr (VI) exposure (XREF_FIG).	3	18	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	5	6	17	18
During intestinal inflammation , the activation of PI3K and AKT pathway also collaborates with WNT and Frizzled pathway to further enhance beta-catenin activation in the intestinal stem cells that may be critical for the CAC progression .	During intestinal inflammation, the activation of PI3K and AKT pathway also collaborates with WNT and Frizzled pathway to further enhance beta-catenin activation in the intestinal stem cells that may be critical for the CAC progression.	7	22	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	9	10	21	22
AKT mediated beta-catenin signaling activation is required for progenitor cell activation during the progression from chronic ulcerative colitis to colitis associated cancer [ XREF_BIBR ] .	AKT mediated beta-catenin signaling activation is required for progenitor cell activation during the progression from chronic ulcerative colitis to colitis associated cancer [XREF_BIBR].	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	0	1	2	3
In summary , we show that coordinate activation of Ras and beta-catenin drives AKT dependent tumor cell proliferation , migration , and colony formation , as well as tumor growth and lung metastases .	In summary, we show that coordinate activation of Ras and beta-catenin drives AKT dependent tumor cell proliferation, migration, and colony formation, as well as tumor growth and lung metastases.	7	14	drives	Positive_activation_token_1_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	13	14	11	12
PI3K and Akt increases the stability of nuclear beta-catenin by phosphorylation and inactivation of the downstream substrate , GSK3beta , in prostate cancer cells , and PTEN deletion can augment PI3K and AKT action and increase cellular beta-catenin [ XREF_BIBR ] .	PI3K and Akt increases the stability of nuclear beta-catenin by phosphorylation and inactivation of the downstream substrate, GSK3beta, in prostate cancer cells, and PTEN deletion can augment PI3K and AKT action and increase cellular beta-catenin [XREF_BIBR].	0	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
This stimulates a cascade of events , including activation of insulin like growth factor I receptor ( IGF-IR ) , phosphatidylinositol 3-kinase-mediated phosphorylation of AKT , inhibition of GSK-3beta , increased activation of beta-catenin , and associated lymphoid enhancing factor/T cell factor mediated transcription .	This stimulates a cascade of events, including activation of insulin like growth factor I receptor (IGF-IR), phosphatidylinositol 3-kinase-mediated phosphorylation of AKT, inhibition of GSK-3beta, increased activation of beta-catenin, and associated lymphoid enhancing factor/T cell factor mediated transcription.	20	34	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	phosphatidylinositol 3-kinase-mediated phosphorylation of AKT	akt	beta-catenin	beta-catenin	beta-catenin	24	25	33	34
In contrast to this simple hypothesis , experimental evidence argues that the PI3K and AKT pathway does not activate WNT and beta-catenin .	In contrast to this simple hypothesis, experimental evidence argues that the PI3K and AKT pathway does not activate WNT and beta-catenin.	12	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	14	15	21	22
The consequence of this interaction is activation of phosphatidylinositol 3-kinase ( PI3K ) signaling through Akt , which subsequently activates NF-kappaB and beta-catenin .	The consequence of this interaction is activation of phosphatidylinositol 3-kinase (PI3K) signaling through Akt, which subsequently activates NF-kappaB and beta-catenin.	13	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	15	16	22	23
Therefore , the exact mechanism by which PI3K and Akt upregulates beta-catenin remains to be elucidated .	Therefore, the exact mechanism by which PI3K and Akt upregulates beta-catenin remains to be elucidated.	7	12	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	9	10	11	12
PI3K-Akt signaling cooperates with Wnt to increase beta-catenin signaling during inflammation .	PI3K-Akt signaling cooperates with Wnt to increase beta-catenin signaling during inflammation.	0	8	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	beta-catenin	beta-catenin	beta-catenin	0	1	7	8
Furthermore , treatment of SK-CO15 cells with EGF enhances beta-catenin signaling , an effect that is diminished by treatment with EGFR , PI3K , and Akt inhibitors or by targeted depletion of Akt using siRNA ( XREF_FIG ) .	Furthermore, treatment of SK-CO15 cells with EGF enhances beta-catenin signaling, an effect that is diminished by treatment with EGFR, PI3K, and Akt inhibitors or by targeted depletion of Akt using siRNA (XREF_FIG).	9	34	diminished	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	32	33	9	10
We confirmed that the beta-catenin pathway is indeed activated in PC9M2 cells by determination of enhanced phosphorylation of Akt and GSK3alpha , cytoplasmic localization of beta-catenin and activation of Axin2 gene transcription .	We confirmed that the beta-catenin pathway is indeed activated in PC9M2 cells by determination of enhanced phosphorylation of Akt and GSK3alpha, cytoplasmic localization of beta-catenin and activation of Axin2 gene transcription.	4	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	phosphorylation of Akt	akt	beta-catenin	beta-catenin	beta-catenin	18	19	4	5
This conclusion was contrary to prior work suggesting that this effect may be mediated through COX2 activity ; it was found that PI3K and Akt inhibition potently inhibited Wnt and beta-catenin activity in endothelial cells and prevented formation of capillary endothelial tubes in vitro [ XREF_BIBR ] .	This conclusion was contrary to prior work suggesting that this effect may be mediated through COX2 activity; it was found that PI3K and Akt inhibition potently inhibited Wnt and beta-catenin activity in endothelial cells and prevented formation of capillary endothelial tubes in vitro [XREF_BIBR].	22	31	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	24	25	30	31
Our observations suggest that cell-autonomous N-cadherin functions in both Wnt mediated and AKT mediated beta-catenin transcriptional activation .	Our observations suggest that cell-autonomous N-cadherin functions in both Wnt mediated and AKT mediated beta-catenin transcriptional activation.	12	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	12	13	14	15
Akt also enhances beta-catenin by phosphorylating and thereby inactivating glycogen synthase kinase-3 ( GSK3 ) ; this prevents inactivation of beta-catenin by unphosphorylated GSK3 , since Ser21 unphosphorylated GSK-3alpha and Ser9 unphosphorylated GSK-3beta phosphorylate beta-catenin at its Ser33/Ser37/Thr41 residues , leading to its degradation .	Akt also enhances beta-catenin by phosphorylating and thereby inactivating glycogen synthase kinase-3 (GSK3); this prevents inactivation of beta-catenin by unphosphorylated GSK3, since Ser21 unphosphorylated GSK-3alpha and Ser9 unphosphorylated GSK-3beta phosphorylate beta-catenin at its Ser33/Ser37/Thr41 residues, leading to its degradation.	0	4	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	0	1	3	4
Collectively , these results demonstrate that zymosan-TLR-2 mediate Akt dependent activation of beta-catenin and Erk imparts anti-inflammatory phenotype on DCs .	Collectively, these results demonstrate that zymosan-TLR-2 mediate Akt dependent activation of beta-catenin and Erk imparts anti-inflammatory phenotype on DCs.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	8	9	12	13
To test if concomitant dysregulation of the WNT and CTNNB1 and PI3K and AKT pathways could synergize to cause testicular cancer , Pten ( tm1Hwu and tm1Hwu ) ; Ctnnb1 ( tm1Mmt/+ ) ; Amhr2 ( tm3 ( cre ) Bhr/+ ) mice that express a dominant , stable CTNNB1 mutant and lack the expression of phosphatase and tensin homolog ( PTEN ) in their Sertoli cells were generated .	To test if concomitant dysregulation of the WNT and CTNNB1 and PI3K and AKT pathways could synergize to cause testicular cancer, Pten (tm1Hwu and tm1Hwu); Ctnnb1 (tm1Mmt/+); Amhr2 (tm3 (cre) Bhr/+) mice that express a dominant, stable CTNNB1 mutant and lack the expression of phosphatase and tensin homolog (PTEN) in their Sertoli cells were generated.	13	31	synergize	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	Ctnnb1	Ctnnb1	Ctnnb1	13	14	29	30
Furthermore , our findings suggest that N-cadherin mediated activation of AKT signaling functions in cortical precursors in vivo to promote beta-catenin signaling , and inhibition of AKT leads to reduced beta-catenin signaling and premature exit from the VZ , neuronal differentiation , and increased apoptosis .	Furthermore, our findings suggest that N-cadherin mediated activation of AKT signaling functions in cortical precursors in vivo to promote beta-catenin signaling, and inhibition of AKT leads to reduced beta-catenin signaling and premature exit from the VZ, neuronal differentiation, and increased apoptosis.	6	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	N-cadherin mediated activation of AKT	akt	beta-catenin	beta-catenin	beta-catenin	10	11	20	21
beta-catenin can also be activated by AKT signaling pathway , which is predominantly active in gastric cancer 43 .	beta-catenin can also be activated by AKT signaling pathway, which is predominantly active in gastric cancer 43.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	6	7	0	1
Notably , regulation of beta-catenin by the cadherin family of cell adhesion molecules has received significant attention in the field of tumor biology and , more recently , the PI3K and Akt signaling axis has been shown to promote beta-catenin signaling and cell proliferation in mouse models of intestinal carcinogenesis and inflammation .	Notably, regulation of beta-catenin by the cadherin family of cell adhesion molecules has received significant attention in the field of tumor biology and, more recently, the PI3K and Akt signaling axis has been shown to promote beta-catenin signaling and cell proliferation in mouse models of intestinal carcinogenesis and inflammation.	31	40	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	31	32	39	40
PI3K and Akt pathway is involved in Wnt3a induced proliferation and beta-catenin nuclear accumulation in NIH3T3 cells XREF_BIBR .	PI3K and Akt pathway is involved in Wnt3a induced proliferation and beta-catenin nuclear accumulation in NIH3T3 cells XREF_BIBR.	0	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
Data indicate that Akt signaling cooperates with Wnt to activate beta-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 ( P-beta-catenin 552 ) .	Data indicate that Akt signaling cooperates with Wnt to activate beta-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-beta-catenin 552).	3	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	3	4	10	11
To understand the TNF induced signal changes in epithelial HF stem cells , we performed iTRAQ analysis ; the result shows TNF induces AKT phosphorylation ( p-AKT ) in epidermal stem cells ( Epi-SCs ) and Lgr5 + cells , and AKT signals positively regulate beta-catenin signalling .	To understand the TNF induced signal changes in epithelial HF stem cells, we performed iTRAQ analysis; the result shows TNF induces AKT phosphorylation (p-AKT) in epidermal stem cells (Epi-SCs) and Lgr5 + cells, and AKT signals positively regulate beta-catenin signalling.	41	46	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	41	42	45	46
Introduction of RONdelta170 into HCT116 cells blocked MSP induced Erkl/2 and AKT phosphorylation , reduced cytoplasmic beta-catenin accumulation , restored glycogen synthase kinase-beta activity , and attenuated various tumorigenic activities .	Introduction of RONdelta170 into HCT116 cells blocked MSP induced Erkl/2 and AKT phosphorylation, reduced cytoplasmic beta-catenin accumulation, restored glycogen synthase kinase-beta activity, and attenuated various tumorigenic activities.	2	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	RONdelta170 into HCT116 cells blocked MSP induced Erkl/2 and AKT phosphorylation	akt	beta-catenin	beta-catenin	beta-catenin	11	12	16	17
As discussed above , Akt can potentially regulate the beta-catenin pathway through two different , but non mutually exclusive mechanisms .	As discussed above, Akt can potentially regulate the beta-catenin pathway through two different, but non mutually exclusive mechanisms.	4	10	potentially regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	4	5	9	10
Together , these studies support a model in which mechanically induced GSK3beta inactivation and activation of Akt promotes mobilization of beta-catenin from a membrane sequestered pool that accumulates in the cytoplasm and subsequently translocates to the nucleus where it regulates the expression of mechanically responsive genes .	Together, these studies support a model in which mechanically induced GSK3beta inactivation and activation of Akt promotes mobilization of beta-catenin from a membrane sequestered pool that accumulates in the cytoplasm and subsequently translocates to the nucleus where it regulates the expression of mechanically responsive genes.	12	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	16	17	20	21
18 Wnt and beta-catenin signaling is stimulated by the Akt pathway XREF_BIBR , XREF_BIBR via inhibition of GSK3beta activity and suppressed by PTEN .	18 Wnt and beta-catenin signaling is stimulated by the Akt pathway XREF_BIBR, XREF_BIBR via inhibition of GSK3beta activity and suppressed by PTEN.	3	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	9	10	3	4
The PI3K and AKT pathway positively regulates the Wnt and beta-catenin signaling pathway by the increase of intracellular beta-catenin levels from AKT phosphorylation which then induces the movement of beta-catenin into the nucleus to bind with TCF/LEF .	The PI3K and AKT pathway positively regulates the Wnt and beta-catenin signaling pathway by the increase of intracellular beta-catenin levels from AKT phosphorylation which then induces the movement of beta-catenin into the nucleus to bind with TCF/LEF.	1	12	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	3	4	10	11
Specifically , as indicated in the schematic , recent studies show that the production of VEGF in tumor cells is connected to survivin expression via PI3K and Akt dependent activation of beta-catenin and Tcf-Lef-mediated VEGF transcription [ XREF_BIBR ] , as is described below .	Specifically, as indicated in the schematic, recent studies show that the production of VEGF in tumor cells is connected to survivin expression via PI3K and Akt dependent activation of beta-catenin and Tcf-Lef-mediated VEGF transcription [XREF_BIBR], as is described below.	25	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	27	28	31	32
In the non canonical pathway , Akt activates beta-catenin , which is implicated in CSC self-renewal , proliferation and development 24 .	In the non canonical pathway, Akt activates beta-catenin, which is implicated in CSC self-renewal, proliferation and development 24.	6	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
In contrast to HuR , KSRP was reported to de-stabilize beta-catenin mRNA and provide a platform on which both Wnt stimulation and the PI3K and AKT pathway could trigger beta-catenin accumulation by counteracting the activity of KSRP .	In contrast to HuR, KSRP was reported to de-stabilize beta-catenin mRNA and provide a platform on which both Wnt stimulation and the PI3K and AKT pathway could trigger beta-catenin accumulation by counteracting the activity of KSRP.	23	30	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	25	26	29	30
The mechanism of this cooperation of two signaling pathways appears to be complex and multifactorial , including the Notch mediated EGFR activation , 21 IGF-1R activation , XREF_BIBR , XREF_BIBR and PTEN downregulation , XREF_BIBR , XREF_BIBR and the Akt mediated nuclear factor kappaB activation , hypoxia inducible factor-1alpha stabilization , 25 and beta-catenin activation , 27 as well as the association of Notch1 with PI3K .	The mechanism of this cooperation of two signaling pathways appears to be complex and multifactorial, including the Notch mediated EGFR activation, 21 IGF-1R activation, XREF_BIBR, XREF_BIBR and PTEN downregulation, XREF_BIBR, XREF_BIBR and the Akt mediated nuclear factor kappaB activation, hypoxia inducible factor-1alpha stabilization, 25 and beta-catenin activation, 27 as well as the association of Notch1 with PI3K.	12	54	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	39	40	53	54
The possible mechanism might be the activation of beta-catenin by PI3k and AKT pathway as reported in HepG2 cells XREF_BIBR and alveolar macrophages XREF_BIBR .	The possible mechanism might be the activation of beta-catenin by PI3k and AKT pathway as reported in HepG2 cells XREF_BIBR and alveolar macrophages XREF_BIBR.	6	13	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	12	13	8	9
Dectin-1 phosphorylates AKT and may thus induce beta-catenin , a transcription factor required by gut tolerogenic DCs .	Dectin-1 phosphorylates AKT and may thus induce beta-catenin, a transcription factor required by gut tolerogenic DCs.	0	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	Dectin-1 phosphorylates AKT	akt	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
The PI3Kinase and Akt pathway is known to be interconnected with the Wnt pathway through the phosphorylation of its effecting factor Akt , which can stimulate beta-catenin .	The PI3Kinase and Akt pathway is known to be interconnected with the Wnt pathway through the phosphorylation of its effecting factor Akt, which can stimulate beta-catenin.	16	27	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	phosphorylation of its effecting factor Akt	akt	beta-catenin	beta-catenin	beta-catenin	21	22	26	27
Overall , these data support a critical function for PI3K and AKT signaling , but not MAPK signaling , in beta-catenin stabilization in thyroid tumor cells .	Overall, these data support a critical function for PI3K and AKT signaling, but not MAPK signaling, in beta-catenin stabilization in thyroid tumor cells.	9	21	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	11	12	20	21
Therefore , Akt activation can promote the transcriptional activity of beta-catenin through repression of the GSK3-beta-mediated proteosomal degradation .	Therefore, Akt activation can promote the transcriptional activity of beta-catenin through repression of the GSK3-beta-mediated proteosomal degradation.	2	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	10	11
Wnt5a activated beta-catenin independent signaling including calmodulin dependent protein kinase II ( CaMKII ) , JNK , p38 , ERK1/2 , p65 and Akt .	Wnt5a activated beta-catenin independent signaling including calmodulin dependent protein kinase II (CaMKII), JNK, p38, ERK1/2, p65 and Akt.	2	24	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	23	24	2	3
To confirm that Akt mediates the activation of beta-catenin signaling in Dsc2 deficient cells , we performed knockdown experiments using specific siRNAs against Dsc2 , Akt , or both proteins and examined the effects on beta-catenin-dependent transcription ( Supplemental Figure 3 ) .	To confirm that Akt mediates the activation of beta-catenin signaling in Dsc2 deficient cells, we performed knockdown experiments using specific siRNAs against Dsc2, Akt, or both proteins and examined the effects on beta-catenin-dependent transcription (Supplemental Figure 3).	2	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
According to these data , it seems that beta-catenin activation by alpha5beta1 integrin and AKT pathway does not trigger cell survival and resistance to therapy in our experimental conditions .	According to these data, it seems that beta-catenin activation by alpha5beta1 integrin and AKT pathway does not trigger cell survival and resistance to therapy in our experimental conditions.	8	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	14	15	8	9
Collectively , the Ang1 and Tie2 signal potentiates basal Notch signal controlling vascular quiescence by up-regulating Dll4 through AKT mediated activation of beta-catenin .	Collectively, the Ang1 and Tie2 signal potentiates basal Notch signal controlling vascular quiescence by up-regulating Dll4 through AKT mediated activation of beta-catenin.	15	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	18	19	22	23
Actually , one of the key actions of IL-1beta is to activate Akt signaling ; based on the canonical Wnt pathway , inactivation of the serine/threonine kinase GSK3 by Akt increases beta-catenin accumulation and expression of Tcf/Lef target genes .	Actually, one of the key actions of IL-1beta is to activate Akt signaling; based on the canonical Wnt pathway, inactivation of the serine/threonine kinase GSK3 by Akt increases beta-catenin accumulation and expression of Tcf/Lef target genes.	27	32	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	29	30	31	32
Upregulation of the PI3K-AKT pathway decreases degradation of beta-catenin via inhibition of GSK3beta ( as a part of beta-catenin degradation complex ) .	Upregulation of the PI3K-AKT pathway decreases degradation of beta-catenin via inhibition of GSK3beta (as a part of beta-catenin degradation complex).	3	10	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
To confirm whether Akt functions downstream of N-cadherin to mediate beta-catenin signaling , we co-expressed myristoylated ( active ) Akt along with shRNA to N-cadherin and measured beta-catenin signaling by TOP-flash reporters .	To confirm whether Akt functions downstream of N-cadherin to mediate beta-catenin signaling, we co-expressed myristoylated (active) Akt along with shRNA to N-cadherin and measured beta-catenin signaling by TOP-flash reporters.	3	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	3	4	10	11
During acute DDC treatment , FGF signaling promotes the expansion of A6 expressing liver cells partly via AKT dependent activation of beta-CATENIN expansion of A6 + ive periportal cells and possibly by reprogramming of centrolobular hepatocytes .	During acute DDC treatment, FGF signaling promotes the expansion of A6 expressing liver cells partly via AKT dependent activation of beta-CATENIN expansion of A6 + ive periportal cells and possibly by reprogramming of centrolobular hepatocytes.	17	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-CATENIN	beta-CATENIN	beta-CATENIN	17	18	21	22
PI3K induced and Akt mediated beta-catenin signaling are required for progenitor cell activation .	PI3K induced and Akt mediated beta-catenin signaling are required for progenitor cell activation.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	3	4	5	6
The authors also showed that Ang1 dependent potentiation of Dll4 and Notch signalling required Akt mediated activation of beta-catenin , which formed a complex with NICD XREF_BIBR , providing in vitro evidence for an integrated network of endothelial pathways promoting vascular maturation and stability .	The authors also showed that Ang1 dependent potentiation of Dll4 and Notch signalling required Akt mediated activation of beta-catenin, which formed a complex with NICD XREF_BIBR, providing in vitro evidence for an integrated network of endothelial pathways promoting vascular maturation and stability.	14	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	14	15	18	19
In ISCs the mechanism by which AKT activates beta-catenin signaling is via direct phosphorylation of beta-catenin at residue Serine 552 , which primes beta-catenin for 14-3-3zeta binding and stabilization [ XREF_BIBR ] .	In ISCs the mechanism by which AKT activates beta-catenin signaling is via direct phosphorylation of beta-catenin at residue Serine 552, which primes beta-catenin for 14-3-3zeta binding and stabilization [XREF_BIBR].	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
Seven percent of RRV induced PROM1 pos cells co-stained positively for pSer552-beta-CATENIN , the AKT mediated activated form of beta-catenin ( XREF_SUPPLEMENTARY ) .	Seven percent of RRV induced PROM1 pos cells co-stained positively for pSer552-beta-CATENIN, the AKT mediated activated form of beta-catenin (XREF_SUPPLEMENTARY).	13	21	mediated activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	14	15	19	20
We also showed that beta-catenin and Snail are dramatically upregulated in Ishikawa-Luc-Rank cells and that AKT signaling inhibitor induces beta-catenin and Snail suppression at protein and mRNA levels .	We also showed that beta-catenin and Snail are dramatically upregulated in Ishikawa-Luc-Rank cells and that AKT signaling inhibitor induces beta-catenin and Snail suppression at protein and mRNA levels.	15	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	15	16	19	20
Moreover , we show that canonical Wnt and Akt and GSK -3 signaling pathways do not activate beta-catenin in CR cells : LGK-974 , a potent inhibitor of Wnt secretion , does not inhibit beta-catenin activation , and Akt signaling ( which inactivates GSK-3 ) is dramatically reduced in CR HECs , PrECs and HMECs .	Moreover, we show that canonical Wnt and Akt and GSK -3 signaling pathways do not activate beta-catenin in CR cells : LGK-974, a potent inhibitor of Wnt secretion, does not inhibit beta-catenin activation, and Akt signaling (which inactivates GSK-3) is dramatically reduced in CR HECs, PrECs and HMECs.	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	8	9	17	18
These results indicate that inhibition of PTEN by phosphorylation could activate PI3K and Akt signaling and subsequent GSK3beta inhibition , which in the end activate Wnt and beta-catenin signaling and promote the growth of colon tumor cells .	These results indicate that inhibition of PTEN by phosphorylation could activate PI3K and Akt signaling and subsequent GSK3beta inhibition, which in the end activate Wnt and beta-catenin signaling and promote the growth of colon tumor cells.	11	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	13	14	27	28
However , down-regulation of Akt and DSH proteins by Phyllanthus could cause activation of GSK3beta and degradation of beta-catenin and c-myc .	However, down-regulation of Akt and DSH proteins by Phyllanthus could cause activation of GSK3beta and degradation of beta-catenin and c-myc.	4	20	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	4	5	18	19
We evaluate the effect of RFA in restoring AKT mediated beta-Catenin signaling in regenerative epithelium .	We evaluate the effect of RFA in restoring AKT mediated beta-Catenin signaling in regenerative epithelium.	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-Catenin	beta-Catenin	beta-Catenin	8	9	10	11
The previous evidence indicated that beta-catenin accumulation induced by Akt phosphorylation could trigger Wnt and beta-catenin signaling by binding T cell factor and lymphoid enhancer factor transcription factors .	The previous evidence indicated that beta-catenin accumulation induced by Akt phosphorylation could trigger Wnt and beta-catenin signaling by binding T cell factor and lymphoid enhancer factor transcription factors.	5	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	beta-catenin	beta-catenin	beta-catenin	9	10	5	6
XREF_BIBR Thus , we wanted to determine if our results from IL-10 -/- colitis recapitulate molecular events that occur in human disease and investigate whether Akt mediated beta-catenin activation also increases in UCD and cancer .	XREF_BIBR Thus, we wanted to determine if our results from IL-10 -/- colitis recapitulate molecular events that occur in human disease and investigate whether Akt mediated beta-catenin activation also increases in UCD and cancer.	25	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	25	26	27	28
In contrast to this , experimental evidence argues against this simplified scenario , as Akt activation failed to promote Wnt and beta-catenin signaling when insulin and constitutively active Akt were administrated [ XREF_BIBR ] .	In contrast to this, experimental evidence argues against this simplified scenario, as Akt activation failed to promote Wnt and beta-catenin signaling when insulin and constitutively active Akt were administrated [XREF_BIBR].	14	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	14	15	21	22
Reduced activation of AKT , in turn , increases the levels of glycogen synthase kinase-3beta ( GSK-3beta ) and the degradation of beta-catenin .	Reduced activation of AKT, in turn, increases the levels of glycogen synthase kinase-3beta (GSK-3beta) and the degradation of beta-catenin.	1	23	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	3	4	22	23
74 Ectopic expression of activated Akt did not appear to activate beta-catenin signaling in the cells examined as measured by changes in the levels of accumulation of cytosolic beta-catenin activation of LEF1 dependent transcription .	74 Ectopic expression of activated Akt did not appear to activate beta-catenin signaling in the cells examined as measured by changes in the levels of accumulation of cytosolic beta-catenin activation of LEF1 dependent transcription.	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	expression of activated Akt	akt	beta-catenin	beta-catenin	beta-catenin	5	6	11	12
AKT dependent activation of beta-catenin is also observed in the proliferating cells at later stages ( E18.5 ) of embryonic liver development ( XREF_SUPPLEMENTARY ) .	AKT dependent activation of beta-catenin is also observed in the proliferating cells at later stages (E18.5) of embryonic liver development (XREF_SUPPLEMENTARY).	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	0	1	4	5
Constitutive activation of AKT by PI3K signaling , by PTEN and PI3K mutations , leads to the phosphorylation of GSK3beta targeting it for degradation , and thus allowing free beta-catenin to translocate to the nucleus 52 .	Constitutive activation of AKT by PI3K signaling, by PTEN and PI3K mutations, leads to the phosphorylation of GSK3beta targeting it for degradation, and thus allowing free beta-catenin to translocate to the nucleus 52.	1	31	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	3	4	29	30
It is well known that PI3K and Akt signaling induces nuclear beta-catenin accumulation through the inhibition of GSK3beta XREF_BIBR , XREF_BIBR .	It is well known that PI3K and Akt signaling induces nuclear beta-catenin accumulation through the inhibition of GSK3beta XREF_BIBR, XREF_BIBR.	5	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	11	12
Previous studies have shown that beta-catenin is directly regulated by the Akt pathway [ XREF_BIBR ] and act as a mediator of resveratrol in the induction of chondrogenic differentiation of mesenchymal stem cells [ XREF_BIBR ] .	Previous studies have shown that beta-catenin is directly regulated by the Akt pathway [XREF_BIBR] and act as a mediator of resveratrol in the induction of chondrogenic differentiation of mesenchymal stem cells [XREF_BIBR].	5	17	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	11	12	5	6
Furthermore , the active CXCL5-CXCR2 axis enhanced the phosphorylation of Akt at Ser 473 residue and that of glycogen synthase kinase-3 ( GSK-3beta ) at Ser 9 residue , and accelerated the nuclear accumulation of beta-catenin in PTC cells .	Furthermore, the active CXCL5-CXCR2 axis enhanced the phosphorylation of Akt at Ser 473 residue and that of glycogen synthase kinase-3 (GSK-3beta) at Ser 9 residue, and accelerated the nuclear accumulation of beta-catenin in PTC cells.	4	36	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	CXCL5-CXCR2 axis enhanced the phosphorylation of Akt at Ser 473	akt	beta-catenin	beta-catenin	beta-catenin	10	11	35	36
Reactive oxygen species mediate Cr ( VI )-induced carcinogenesis through PI3K and AKT dependent activation of GSK-3 beta and beta-catenin signaling .	Reactive oxygen species mediate Cr (VI)-induced carcinogenesis through PI3K and AKT dependent activation of GSK-3 beta and beta-catenin signaling.	10	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	12	13	19	20
Models of mutated BMPR1A and deficient phosphatase and tensin homolog ( PTEN ) signaling indicate that Akt activation enhances beta-catenin signaling .	Models of mutated BMPR1A and deficient phosphatase and tensin homolog (PTEN) signaling indicate that Akt activation enhances beta-catenin signaling.	16	20	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	16	17	19	20
XREF_BIBR , XREF_BIBR Prior reports suggest that Akt positively regulates beta-catenin signaling , most likely acting at the level of the beta-catenin destruction complex although its precise mechanism of action remains largely debatable .	XREF_BIBR, XREF_BIBR Prior reports suggest that Akt positively regulates beta-catenin signaling, most likely acting at the level of the beta-catenin destruction complex although its precise mechanism of action remains largely debatable.	7	11	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	10	11
Thus , PI3K and Akt mediated beta-catenin activation participates in the generation of CID in mice .	Thus, PI3K and Akt mediated beta-catenin activation participates in the generation of CID in mice.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	4	5	6	7
Mechanistic studies reveal the involvement of Akt mediated activation of beta-catenin and NF-kappaB in PPP2CA loss induced EMT and potentiation of PCa cell migration and invasion .	Mechanistic studies reveal the involvement of Akt mediated activation of beta-catenin and NF-kappaB in PPP2CA loss induced EMT and potentiation of PCa cell migration and invasion.	6	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	6	7	10	11
We further demonstrated that DDX3 upregulated KRAS transcription and enhanced oncogenic KRAS mediated tumor invasion following beta-catenin and TCF activation by MEK and ERK and PI3K and AKT signaling XREF_BIBR .	We further demonstrated that DDX3 upregulated KRAS transcription and enhanced oncogenic KRAS mediated tumor invasion following beta-catenin and TCF activation by MEK and ERK and PI3K and AKT signaling XREF_BIBR.	16	29	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	27	28	16	17
Despite this lack of information , it is recognized that activation of the PI3K and Akt and Wnt and beta-catenin pathways may cooperate to enhance beta-catenin activity in C. rodentium infection mice models ( XREF_FIG ) .	Despite this lack of information, it is recognized that activation of the PI3K and Akt and Wnt and beta-catenin pathways may cooperate to enhance beta-catenin activity in C. rodentium infection mice models (XREF_FIG).	10	26	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	15	16	25	26
Activation of PI3K and AKT leads to the phosphorylation and inactivation of GSK3beta , permitting beta-catenin to accumulate in the cytosol and the nucleus .	Activation of PI3K and AKT leads to the phosphorylation and inactivation of GSK3beta, permitting beta-catenin to accumulate in the cytosol and the nucleus.	0	16	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	4	5	15	16
The PI3K and AKT signaling pathway can also activate the WNT and CTNNB1 pathway through inactivation of GSK3beta [ XREF_BIBR ] .	The PI3K and AKT signaling pathway can also activate the WNT and CTNNB1 pathway through inactivation of GSK3beta [XREF_BIBR].	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	CTNNB1	CTNNB1	CTNNB1	3	4	12	13
We found that overexpression of Rak reduced Akt phosphorylation ( XREF_FIG , top right panel ) and repressed beta-catenin nuclear localization and activity as indicated by reporter constructs that contained three repeats of wild-type ( TOP ) or mutant ( FOP ) Tcf4 ( T cell factor )-binding sites ( XREF_FIG , bottom ) .	We found that overexpression of Rak reduced Akt phosphorylation (XREF_FIG, top right panel) and repressed beta-catenin nuclear localization and activity as indicated by reporter constructs that contained three repeats of wild-type (TOP) or mutant (FOP) Tcf4 (T cell factor)-binding sites (XREF_FIG, bottom).	3	42	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	overexpression of Rak reduced Akt phosphorylation	akt	beta-catenin	beta-catenin	beta-catenin	7	8	18	19
Herein , we investigate the role of FGF signaling and AKT mediated beta-catenin activation in acute DDC liver injury .	Herein, we investigate the role of FGF signaling and AKT mediated beta-catenin activation in acute DDC liver injury.	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	10	11	12	13
Supporting evidence comes from a study of BMP1a deficient mice in which the inactivation of either PTEN or BMP signaling activates Akt , which in-turn coordinates with the Wnt signal to fully activate beta-catenin in intestinal stem cells ( ISC ) [ XREF_BIBR ] .	Supporting evidence comes from a study of BMP1a deficient mice in which the inactivation of either PTEN or BMP signaling activates Akt, which in-turn coordinates with the Wnt signal to fully activate beta-catenin in intestinal stem cells (ISC) [XREF_BIBR].	20	37	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	21	22	33	34
Prior data from our group demonstrated that Akt cooperates with Wnt to activate beta-catenin [ XREF_BIBR ] .	Prior data from our group demonstrated that Akt cooperates with Wnt to activate beta-catenin [XREF_BIBR].	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	13	14
Mechanistically , we find important roles of Akt driven beta-catenin and NF-kappaB activation in PPP2CA downregulation induced epithelial-to-mesenchymal transition ( EMT ) and invasiveness of PCa cells .	Mechanistically, we find important roles of Akt driven beta-catenin and NF-kappaB activation in PPP2CA downregulation induced epithelial-to-mesenchymal transition (EMT) and invasiveness of PCa cells.	5	12	driven	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
Given that Akt and HBxAg also activate beta-catenin , experiments were designed to determine whether URG7 blocked apoptosis via activation of beta-catenin .	Given that Akt and HBxAg also activate beta-catenin, experiments were designed to determine whether URG7 blocked apoptosis via activation of beta-catenin.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
Instead , N-cadherin function was linked to AKT activity , with AKT stimulating beta-catenin activity through direct phosphorylation and perhaps also indirectly through GSK3 inhibition ( XREF_FIG ) .	Instead, N-cadherin function was linked to AKT activity, with AKT stimulating beta-catenin activity through direct phosphorylation and perhaps also indirectly through GSK3 inhibition (XREF_FIG).	11	14	stimulating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	11	12	13	14
This was unexpected given that AKT has been reported to promote the activity of the E3 ubiquitin ligase MDM2 , the important negative regulator of p53 .	This was unexpected given that AKT has been reported to promote the activity of the E3 ubiquitin ligase MDM2, the important negative regulator of p53.	5	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	5	6	18	19
In particular , whereas AKT promotes MDM2 stabilization under normal conditions , the kinase may , directly or indirectly , facilitate MDM2 degradation following DNA damage .	In particular, whereas AKT promotes MDM2 stabilization under normal conditions, the kinase may, directly or indirectly, facilitate MDM2 degradation following DNA damage.	4	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	4	5	6	7
It would be interesting to learn whether or not the Akt mediated phosphorylation of MDM2 and the Akt mediated stabilization of CSN6 cooperate with each other toward the Akt mediated MDM2 activation .	It would be interesting to learn whether or not the Akt mediated phosphorylation of MDM2 and the Akt mediated stabilization of CSN6 cooperate with each other toward the Akt mediated MDM2 activation.	25	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	28	29	30	31
Activated PI3K phosphorylates AKT , which in turn activates IKKA , MTOR ( FRAP1 ) and MDM2 and inhibits FKHR , CASP9 , BAD , p27 and p21 genes [ XREF_BIBR - XREF_BIBR ] .	Activated PI3K phosphorylates AKT, which in turn activates IKKA, MTOR (FRAP1) and MDM2 and inhibits FKHR, CASP9, BAD, p27 and p21 genes [XREF_BIBR - XREF_BIBR].	1	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	PI3K phosphorylates AKT	akt	MDM2	MDM2	mdm2	3	4	16	17
They also inhibit p21 indirectly by increasing murine double minute 2 ( MDM2 ) , a negative regulator of p21 [ XREF_BIBR ] , which is also promoted by PI3K and Akt signaling in GC [ XREF_BIBR ] .	They also inhibit p21 indirectly by increasing murine double minute 2 (MDM2), a negative regulator of p21 [XREF_BIBR], which is also promoted by PI3K and Akt signaling in GC [XREF_BIBR].	6	32	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	31	32	12	13
The migration of phospho-Ser166-MDM2 was altered , suggesting that AKT may promote alternative post-translational modifications of MDM2 .	The migration of phospho-Ser166-MDM2 was altered, suggesting that AKT may promote alternative post-translational modifications of MDM2.	9	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	9	10	16	17
Taken together , these results indicate that AKT induces DNA damage independent p53 stabilisation via ARF- and PML independent nucleolar sequestration of MDM2 .	Taken together, these results indicate that AKT induces DNA damage independent p53 stabilisation via ARF- and PML independent nucleolar sequestration of MDM2.	7	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	7	8	22	23
HIF2alpha suppresses p53 via Akt mediated activation of Hdm2 .	HIF2alpha suppresses p53 via Akt mediated activation of Hdm2.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Hdm2	Hdm2	Hdm2	4	5	8	9
Akt has been shown to phosphorylate Mdm2 on S166 and S186 and allow Mdm2 to move from the cytoplasm to nuclear compartment [ XREF_BIBR ] .	Akt has been shown to phosphorylate Mdm2 on S166 and S186 and allow Mdm2 to move from the cytoplasm to nuclear compartment [XREF_BIBR].	0	15	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt has been shown to phosphorylate Mdm2 on S166 and S186	akt	Mdm2	Mdm2	mdm2	0	1	13	14
After phosphorylation by AKT , MDM2 is activated and localised in the nucleus to induce p53 degradation and cell survival .	After phosphorylation by AKT, MDM2 is activated and localised in the nucleus to induce p53 degradation and cell survival.	1	9	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	3	4	5	6
The PI3K downstream target Akt was shown to activate Mdm2 XREF_BIBR and , thus , activation of PI3K by helium may facilitate an interaction between phospho-Mdm2 and p53 that leads to the metabolism of the apoptotic protein XREF_BIBR and prevents its detrimental association with GSK-3beta .	The PI3K downstream target Akt was shown to activate Mdm2 XREF_BIBR and, thus, activation of PI3K by helium may facilitate an interaction between phospho-Mdm2 and p53 that leads to the metabolism of the apoptotic protein XREF_BIBR and prevents its detrimental association with GSK-3beta.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	4	5	9	10
These results are intriguing given that previous reports demonstrate that AKT promotes the activity of the E3 ubiquitin ligase MDM2 , the important negative regulator of p53 .	These results are intriguing given that previous reports demonstrate that AKT promotes the activity of the E3 ubiquitin ligase MDM2, the important negative regulator of p53.	10	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	10	11	19	20
Therefore , CXCR2 could mediate Akt induced Mdm2 , resulting in inhibition of p53 dependent p21 upregulation in p53WT ovarian cancer , followed by increased cell proliferation and finally high mortality rate .	Therefore, CXCR2 could mediate Akt induced Mdm2, resulting in inhibition of p53 dependent p21 upregulation in p53WT ovarian cancer, followed by increased cell proliferation and finally high mortality rate.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	5	6	7	8
Dominant negative Akt inhibits nuclear entry of Mdm2 , thus increasing the cellular level of p53 and transcriptional activity [ XREF_BIBR ] .	Dominant negative Akt inhibits nuclear entry of Mdm2, thus increasing the cellular level of p53 and transcriptional activity [XREF_BIBR].	0	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	2	3	7	8
It has been shown that AKT can lead to activation of Mdm2 , resulting in inactivation of p53 and inhibition of p53 dependent apoptosis [ XREF_BIBR ] .	It has been shown that AKT can lead to activation of Mdm2, resulting in inactivation of p53 and inhibition of p53 dependent apoptosis [XREF_BIBR].	5	12	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	Mdm2	Mdm2	Mdm2	5	6	11	12
Our main finding is that CXCR2 negatively regulates p21 via Akt mediated Mdm2 in p53 dependent and independent manner in ovarian cancer cell proliferation .	Our main finding is that CXCR2 negatively regulates p21 via Akt mediated Mdm2 in p53 dependent and independent manner in ovarian cancer cell proliferation.	8	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	10	11	12	13
AKT directly activates murine double minute 2 ( MDM2 ) , a negative regulator of p53 .	AKT directly activates murine double minute 2 (MDM2), a negative regulator of p53.	0	9	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	0	1	8	9
Phosphorylation of MDM2 on Ser 166 and Ser 186 by Akt stimulates translocation of MDM2 to the nucleus , where it binds to p53 and targets p53 degradation by the proteosome .	Phosphorylation of MDM2 on Ser 166 and Ser 186 by Akt stimulates translocation of MDM2 to the nucleus, where it binds to p53 and targets p53 degradation by the proteosome.	0	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Phosphorylation of MDM2 on Ser 166 and Ser 186 by Akt	akt	MDM2	MDM2	mdm2	10	11	14	15
Akt in turn activates MDM2 by phosphorylation at Ser 166 and -186 , resulting in diminished cellular levels and transcriptional activity of p53 .	Akt in turn activates MDM2 by phosphorylation at Ser 166 and -186, resulting in diminished cellular levels and transcriptional activity of p53.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	0	1	4	5
Therefore , the opposite directionality Akt triggered Mdm2 and PHF20 translocations and antagonistic functions of Mmd2 and PHF20 synergistically contribute to p53 regulation .	Therefore, the opposite directionality Akt triggered Mdm2 and PHF20 translocations and antagonistic functions of Mmd2 and PHF20 synergistically contribute to p53 regulation.	2	10	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	5	6	7	8
c-Met regulates the activity of Akt protein , and activated Akt modulates mdm2 protein , a p53 negative regulator [ XREF_BIBR ] .	c-Met regulates the activity of Akt protein, and activated Akt modulates mdm2 protein, a p53 negative regulator [XREF_BIBR].	9	13	modulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	mdm2	mdm2	mdm2	10	11	12	13
Activation of Akt promotes the entry of MDM2 into the nucleus and its interaction with the tumor suppressor protein p53 .	Activation of Akt promotes the entry of MDM2 into the nucleus and its interaction with the tumor suppressor protein p53.	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	2	3	7	8
Notch activation has been shown to increase cell survival through the activation of the PI3K-Akt pathway , which leads to increased murine double minute 2 ( MDM2 ) activity and consequent p53 degradation [ XREF_BIBR , XREF_BIBR ] .	Notch activation has been shown to increase cell survival through the activation of the PI3K-Akt pathway, which leads to increased murine double minute 2 (MDM2) activity and consequent p53 degradation [XREF_BIBR, XREF_BIBR].	14	28	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	MDM2	MDM2	MDM2	14	15	26	27
They propose that activated Akt promotes stabilization of Mdm2 , thereby inactivating p53 .	They propose that activated Akt promotes stabilization of Mdm2, thereby inactivating p53.	3	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	4	5	8	9
Activation of Akt signalling pathway promotes nuclear entry of Mdm2 .	Activation of Akt signalling pathway promotes nuclear entry of Mdm2.	2	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	2	3	9	10
In this pathway , beta-arrestin-1 , which is activated via beta ( 2 ) ARs , facilitates the AKT mediated activation of Mdm2 and functions as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase , Mdm2 .	In this pathway, beta-arrestin-1, which is activated via beta (2) ARs, facilitates the AKT mediated activation of Mdm2 and functions as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, Mdm2.	17	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	Mdm2	Mdm2	Mdm2	18	19	22	23
p53 negatively regulates the IGF-1/PI3k/Akt pathway by increasing the transcription of target genes such as IGF-BP3 or PTEN , and is also conversely regulated by Akt , which activates the MDM2 , a trigger for p53 degradation .	p53 negatively regulates the IGF-1/PI3k/Akt pathway by increasing the transcription of target genes such as IGF-BP3 or PTEN, and is also conversely regulated by Akt, which activates the MDM2, a trigger for p53 degradation.	23	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	25	26	30	31
Therefore , AKT mediated activation of MDM2 , a negative regulator of p53 , can have a significant impact on UV stress responses by preventing p53 mediated cell cycle arrest and apoptosis induction ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	Therefore, AKT mediated activation of MDM2, a negative regulator of p53, can have a significant impact on UV stress responses by preventing p53 mediated cell cycle arrest and apoptosis induction (XREF_FIG) [XREF_BIBR, XREF_BIBR].	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	2	3	6	7
It was suggested PTEN can stabilize p53 by blocking AKT mediated activation of MDM2 .	It was suggested PTEN can stabilize p53 by blocking AKT mediated activation of MDM2.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	9	10	13	14
The activation of AKT has been shown to phosphorylate MDM2 , and increase the nuclear localization of MDM2 .	The activation of AKT has been shown to phosphorylate MDM2, and increase the nuclear localization of MDM2.	1	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	3	4	17	18
The activated EGFR leads to phosphorylation of Akt , which directly upregulates Mdm2 .	The activated EGFR leads to phosphorylation of Akt, which directly upregulates Mdm2.	2	13	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	EGFR leads to phosphorylation of Akt	akt	Mdm2	Mdm2	mdm2	7	8	12	13
PI3K-AKT activates MDM2 , promoting its translation to the nucleus with the subsequent ubiquitination and degradation of p53 , leading to inhibition of apoptosis .	PI3K-AKT activates MDM2, promoting its translation to the nucleus with the subsequent ubiquitination and degradation of p53, leading to inhibition of apoptosis.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	MDM2	MDM2	MDM2	0	1	2	3
CXCR2 reduced romidepsin induced p21 upregulation by activating Akt induced Mdm2 .	CXCR2 reduced romidepsin induced p21 upregulation by activating Akt induced Mdm2.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	8	9	10	11
We can also assume that AKT promotes MDM2 nuclear localisation , but that its activity is controlled by the AKT mediated NPM-ARF nucleoplasmic pool once there .	We can also assume that AKT promotes MDM2 nuclear localisation, but that its activity is controlled by the AKT mediated NPM-ARF nucleoplasmic pool once there.	4	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	5	6	7	8
Inactivation of p53 by SPARC resulted from AKT dependent activation of MDM2 and we demonstrated that p53 is activated upon knockdown of SPARC in melanoma cells XREF_BIBR .	Inactivation of p53 by SPARC resulted from AKT dependent activation of MDM2 and we demonstrated that p53 is activated upon knockdown of SPARC in melanoma cells XREF_BIBR.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	7	8	11	12
Pharmacological and genetic approaches determined that potentiated NMDARs activated the kinase Akt , which then activated the E3 ubiquitin ligase Mdm2 .	Pharmacological and genetic approaches determined that potentiated NMDARs activated the kinase Akt, which then activated the E3 ubiquitin ligase Mdm2.	8	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	11	12	20	21
In addition , beta2-adrenergic receptor activation can also lead to activation of the phosphoinositide-3-kinase and Akt pathway , which increases MDM2 activation resulting in loss of p53 function .	In addition, beta2-adrenergic receptor activation can also lead to activation of the phosphoinositide-3-kinase and Akt pathway, which increases MDM2 activation resulting in loss of p53 function.	13	21	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	15	16	20	21
These results indicate that Akt activated MDM2 is critical in suppressing p53 dependent apoptosis in vivo .	These results indicate that Akt activated MDM2 is critical in suppressing p53 dependent apoptosis in vivo.	4	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	4	5	6	7
The serine/threonine kinase Akt promotes cellular survival by blocking apoptosis , which it achieves by binding and regulating many downstream effectors ; e.g ., NF-kappaB , Bcl-2 family proteins , and MDM2 [ XREF_BIBR ] .	The serine/threonine kinase Akt promotes cellular survival by blocking apoptosis, which it achieves by binding and regulating many downstream effectors; e.g., NF-kappaB, Bcl-2 family proteins, and MDM2 [XREF_BIBR].	0	33	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	3	4	31	32
XREF_BIBR Conversely , PI3k activates Akt , which in turn activates Mdm2 to inhibit p53 .	XREF_BIBR Conversely, PI3k activates Akt, which in turn activates Mdm2 to inhibit p53.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	5	6	11	12
This finding is in keeping with studies showing that AKT physically associates with MDM2 and phosphorylates MDM2 at Ser166 and Ser186 , leading to nuclear translocation and degradation of the tumour-suppressor p53 , and that activation of MDM2 by AKT in mammary epithelium delays mammary involution and accelerates mammary tumorigenesis .	This finding is in keeping with studies showing that AKT physically associates with MDM2 and phosphorylates MDM2 at Ser166 and Ser186, leading to nuclear translocation and degradation of the tumour-suppressor p53, and that activation of MDM2 by AKT in mammary epithelium delays mammary involution and accelerates mammary tumorigenesis.	7	47	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	39	40	37	38
Activation of MDM2 by Akt in Mammary Epithelium Delays Mammary Involution and Accelerates Mammary Tumorigenesis .	Activation of MDM2 by Akt in Mammary Epithelium Delays Mammary Involution and Accelerates Mammary Tumorigenesis.	0	12	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	4	5	2	3
Promoter , knockdown and overexpression studies have revealed that Akt induced Mdm2 plays a critical role in CXCR2 mediated proliferation of ovarian cancer by inhibiting p53 function to induce p21 .	Promoter, knockdown and overexpression studies have revealed that Akt induced Mdm2 plays a critical role in CXCR2 mediated proliferation of ovarian cancer by inhibiting p53 function to induce p21.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	9	10	11	12
While we have previously determined that the immediate downregulation of p53 upon Chlamydia infection is a result of proteasomal degradation of the protein mediated by the PI3K-Akt dependent activation of HDM2 , our recent work shows that the miR-30c dependent suppression of p53 translation occurs close to 20 hours post infection and appears to be a stable means to ensure low levels of p53 .	While we have previously determined that the immediate downregulation of p53 upon Chlamydia infection is a result of proteasomal degradation of the protein mediated by the PI3K-Akt dependent activation of HDM2, our recent work shows that the miR-30c dependent suppression of p53 translation occurs close to 20 hours post infection and appears to be a stable means to ensure low levels of p53.	26	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	HDM2	HDM2	HDM2	26	27	30	31
AKT , an important downstream effector of FGFR , promotes cell survival by activating the p53 repressor MDM2 and blocking the pro apoptotic proteins BAD and BIM [ XREF_BIBR ] .	AKT, an important downstream effector of FGFR, promotes cell survival by activating the p53 repressor MDM2 and blocking the pro apoptotic proteins BAD and BIM [XREF_BIBR].	0	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	0	1	17	18
We have confirmed that CXCR2 mediates Akt induced Mdm2 in p53-null cells as observed in p53WT cells .	We have confirmed that CXCR2 mediates Akt induced Mdm2 in p53-null cells as observed in p53WT cells.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	6	7	8	9
It was reported that Akt could induce an MDM2 dependent downregulation of p53 , and suppression of Akt sensitized chemoresistant cells to cisplatin in a p53 dependent manner .	It was reported that Akt could induce an MDM2 dependent downregulation of p53, and suppression of Akt sensitized chemoresistant cells to cisplatin in a p53 dependent manner.	4	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	4	5	8	9
Conclusively , CXCR2 is a negative regulator of p21 via the Akt induced Mdm2 in p53 dependent and independent manner in ovarian cancer .	Conclusively, CXCR2 is a negative regulator of p21 via the Akt induced Mdm2 in p53 dependent and independent manner in ovarian cancer.	8	19	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	11	12	13	14
Whether Akt mediated MDM2 and P53 and GSK3beta-Fyn-Nrf2 pathways were also involved in LDR induced cardiac protection is still unclear .	Whether Akt mediated MDM2 and P53 and GSK3beta-Fyn-Nrf2 pathways were also involved in LDR induced cardiac protection is still unclear.	1	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	1	2	3	4
Besides , MDM2 and p53 can be regulated at transcriptional levels mutually , and modulated by the AKT pathway at posttranscriptional level [ XREF_BIBR , XREF_BIBR ] .	Besides, MDM2 and p53 can be regulated at transcriptional levels mutually, and modulated by the AKT pathway at posttranscriptional level [XREF_BIBR, XREF_BIBR].	2	18	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	17	18	2	3
Post-transcriptionally , Akt can activate HDM2 through phosphorylation of Ser 166 and Ser 186 .	Post-transcriptionally, Akt can activate HDM2 through phosphorylation of Ser 166 and Ser 186.	2	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	HDM2	HDM2	HDM2	2	3	5	6
CXCR2 enhances the Akt induced Mdm2 which inhibits HDACi induced p21 in a p53 independent manner , leading to faster cancer progression and higher mortality rate .	CXCR2 enhances the Akt induced Mdm2 which inhibits HDACi induced p21 in a p53 independent manner, leading to faster cancer progression and higher mortality rate.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	3	4	5	6
The Akt activation induces Mdm2 , a key negative regulator of p53 [ XREF_BIBR ] .	The Akt activation induces Mdm2, a key negative regulator of p53 [XREF_BIBR].	1	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	1	2	4	5
Thus , although it is clear that AKT positively regulates MDM2 , the precise molecular mechanisms seem to be cell type- and context dependent .	Thus, although it is clear that AKT positively regulates MDM2, the precise molecular mechanisms seem to be cell type- and context dependent.	7	11	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	7	8	10	11
Furthermore PI3K and Akt , via the mTOR kinase , promote the translation and nuclear import of Mdm2 , which inhibits TP53 activity both in vitro and in vivo [ XREF_BIBR ] .	Furthermore PI3K and Akt, via the mTOR kinase, promote the translation and nuclear import of Mdm2, which inhibits TP53 activity both in vitro and in vivo [XREF_BIBR].	1	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	3	4	17	18
Akt and mTOR can regulate suppression of p53 , and Akt can activate mdm2 and promote p53 degradation .	Akt and mTOR can regulate suppression of p53, and Akt can activate mdm2 and promote p53 degradation.	10	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	mdm2	mdm2	mdm2	10	11	13	14
AKT activates Mdm2 [ XREF_BIBR ] , and inhibits p21 [ XREF_BIBR ] .	AKT activates Mdm2 [XREF_BIBR], and inhibits p21 [XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	Mdm2	Mdm2	Mdm2	0	1	2	3
AKT also functioned to activate and enhance MDM2 activity [ XREF_BIBR , XREF_BIBR ] .	AKT also functioned to activate and enhance MDM2 activity [XREF_BIBR, XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	0	1	7	8
CXCR2 is a negative regulator of p21 in p53 dependent and independent manner via Akt mediated Mdm2 in ovarian cancer .	CXCR2 is a negative regulator of p21 in p53 dependent and independent manner via Akt mediated Mdm2 in ovarian cancer.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	14	15	16	17
This study further demonstrated that the inhibitory effect was mediated through the proteasomal degradation of nuclear factor of activated T cells ( NFAT ) , via Akt mediated activation of the mdm2 ( mouse double minute 2 ) ubiquitin ligase .	This study further demonstrated that the inhibitory effect was mediated through the proteasomal degradation of nuclear factor of activated T cells (NFAT), via Akt mediated activation of the mdm2 (mouse double minute 2) ubiquitin ligase.	26	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	mdm2	mdm2	mdm2	26	27	31	32
The results were consistent with previous study which indicated that AKT mediated MDM2 Ser 166 and Ser 168 phosphorylations are critical for the translocation of MDM2 to nucleus .	The results were consistent with previous study which indicated that AKT mediated MDM2 Ser 166 and Ser 168 phosphorylations are critical for the translocation of MDM2 to nucleus.	10	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	10	11	12	13
The serine/threonine kinase AKT promotes cellular survival by blocking apoptosis , which it achieves by binding and regulating many downstream effectors ; e.g ., NF-kappaB , Bcl-2 family proteins , and MDM2 .	The serine/threonine kinase AKT promotes cellular survival by blocking apoptosis, which it achieves by binding and regulating many downstream effectors; e.g., NF-kappaB, Bcl-2 family proteins, and MDM2.	0	32	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	3	4	31	32
As the level of p53 was not significantly altered by ABL , this suggested that the mechanism in which ABL arrested cell proliferation was independent of Akt mediated MDM2 activation but was possibly mediated by altering G1 to S phase transition .	As the level of p53 was not significantly altered by ABL, this suggested that the mechanism in which ABL arrested cell proliferation was independent of Akt mediated MDM2 activation but was possibly mediated by altering G1 to S phase transition.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	26	27	28	29
TP53 is degraded by MDM2 , a ubiquitin ligase for TP53 , and the MDM2 function is augmented by the kinase activity of Akt .	TP53 is degraded by MDM2, a ubiquitin ligase for TP53, and the MDM2 function is augmented by the kinase activity of Akt.	14	24	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	23	24	14	15
To study the role of Akt activated MDM2 in mammary development and tumorigenesis , we generated transgenic mice expressing MDM2 or Akt phosphorylated form of MDM2 ( MDM2DD ) in the mammary epithelium .	To study the role of Akt activated MDM2 in mammary development and tumorigenesis, we generated transgenic mice expressing MDM2 or Akt phosphorylated form of MDM2 (MDM2DD) in the mammary epithelium.	3	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	5	6	7	8
And It has been demonstrated that phosphorylation of Akt increased the translocation of MDM2 from the cytoplasm to the nucleus [ XREF_BIBR ] .	And It has been demonstrated that phosphorylation of Akt increased the translocation of MDM2 from the cytoplasm to the nucleus [XREF_BIBR].	6	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	phosphorylation of Akt	akt	MDM2	MDM2	mdm2	8	9	13	14
Importantly , inhibition of the PI3K and Akt pathway blocks the activation of Mdm2 by RSV and preserves the p53 response .	Importantly, inhibition of the PI3K and Akt pathway blocks the activation of Mdm2 by RSV and preserves the p53 response.	5	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	7	8	13	14
Impairment of Akt activation by VCO also deactivated Mdm2 that effected overexpression of p53 which in turn upregulated p21 expression .	Impairment of Akt activation by VCO also deactivated Mdm2 that effected overexpression of p53 which in turn upregulated p21 expression.	2	10	deactivated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	2	3	8	9
12 Based on a previous study , beta-arr1 facilitated Akt mediated activation of MDM2 ( human murine double minute 2 , the E3 ligase for p53 ) and also promoted MDM2 binding to , and degradation of , p53 by acting as a molecular scaffold .	12 Based on a previous study, beta-arr1 facilitated Akt mediated activation of MDM2 (human murine double minute 2, the E3 ligase for p53) and also promoted MDM2 binding to, and degradation of, p53 by acting as a molecular scaffold.	9	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	9	10	13	14
Interestingly , romidepsin induced p21 involves Akt induced Mdm2 in a p53 independent manner by downregulating Akt and Mdm2 protein levels .	Interestingly, romidepsin induced p21 involves Akt induced Mdm2 in a p53 independent manner by downregulating Akt and Mdm2 protein levels.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	6	7	8	9
Akt activation , in turn , potentially activated MDM2 , leading to enhanced p53 ubiquitination and potential blockage of GSK3beta .	Akt activation, in turn, potentially activated MDM2, leading to enhanced p53 ubiquitination and potential blockage of GSK3beta.	0	9	potentially activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	0	1	8	9
To directly study the role of Akt activated MDM2 in mammary development and tumorigenesis , we generated transgenic mice expressing the Akt phosphorylated form of MDM2 ( MDM2DDS166D and S186D ) in the mammary epithelium .	To directly study the role of Akt activated MDM2 in mammary development and tumorigenesis, we generated transgenic mice expressing the Akt phosphorylated form of MDM2 (MDM2DDS166D and S186D) in the mammary epithelium.	4	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	6	7	8	9
Taken together , our data show that RasGRP3 exerts its oncogenic effect in PTC through Akt mediated MDM2 activation .	Taken together, our data show that RasGRP3 exerts its oncogenic effect in PTC through Akt mediated MDM2 activation.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	15	16	17	18
One possible mechanism for this surprising phenotype was that Akt activated the E3 ubiquitin ligase HDM2 , causing ubiquitination and degradation of NFAT , an invasion promoting factor .	One possible mechanism for this surprising phenotype was that Akt activated the E3 ubiquitin ligase HDM2, causing ubiquitination and degradation of NFAT, an invasion promoting factor.	9	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	HDM2	HDM2	HDM2	9	10	15	16
Earlier study showed that Akt activated MDM2 has an increased ability to degrade p53 , we then examined whether the defective apoptosis in mammary glands from MMTV and MDM2DD mice was dependent on the change of p53 expression .	Earlier study showed that Akt activated MDM2 has an increased ability to degrade p53, we then examined whether the defective apoptosis in mammary glands from MMTV and MDM2DD mice was dependent on the change of p53 expression.	4	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	4	5	6	7
Studies in xenograft tumor models in mice revealed that niosome formulation of Akt siRNA and TQ combination enhanced the apoptosis and MDM2 inhibition in therapy resistant cancer [ XREF_BIBR ] .	Studies in xenograft tumor models in mice revealed that niosome formulation of Akt siRNA and TQ combination enhanced the apoptosis and MDM2 inhibition in therapy resistant cancer [XREF_BIBR].	12	22	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	12	13	21	22
One interesting potential molecular link between b2AR activation and aging has emerged from a recent study , which shows that stimulation of beta2ARs in response to chronic stress leads through PKA and beta-arrestin to accelerated DNA damage and destabilization of p53 through Akt mediated Mdm2 activation .	One interesting potential molecular link between b2AR activation and aging has emerged from a recent study, which shows that stimulation of beta2ARs in response to chronic stress leads through PKA and beta-arrestin to accelerated DNA damage and destabilization of p53 through Akt mediated Mdm2 activation.	40	45	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	42	43	44	45
Then , beta-arrestin 1 facilitated AKT mediated activation of MDM2 and also promoted MDM2 protein binding to , and degradation of p53 protein , by acting as a molecular scaffold .	Then, beta-arrestin 1 facilitated AKT mediated activation of MDM2 and also promoted MDM2 protein binding to, and degradation of p53 protein, by acting as a molecular scaffold.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	5	6	9	10
It has been reported that the activated PI3K and Akt pathway activates MDM2 to terminate the p53 response , leading to tumor growth and survival [ XREF_BIBR ] .	It has been reported that the activated PI3K and Akt pathway activates MDM2 to terminate the p53 response, leading to tumor growth and survival [XREF_BIBR].	9	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	9	10	12	13
In mice and in human cell lines , beta-arrestin-1 ( ARRB1 ) , activated via beta 2 -adrenoreceptors , facilitates AKT mediated activation of MDM2 and also promotes MDM2 binding to , and degradation of , p53 , by acting as a molecular scaffold .	In mice and in human cell lines, beta-arrestin-1 (ARRB1), activated via beta 2 -adrenoreceptors, facilitates AKT mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold.	19	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	20	21	24	25
Furthermore , CXCR2 inhibits HDACi induced p21 in p53-null ovarian cancer cells via Akt mediated Mdm2 in a p53 independent manner .	Furthermore, CXCR2 inhibits HDACi induced p21 in p53-null ovarian cancer cells via Akt mediated Mdm2 in a p53 independent manner.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	13	14	15	16
However , re-expression of ARF appears to be dominant over AKT mediated control of MDM2 activity ( XREF_SUPPLEMENTARY ) .	However, re-expression of ARF appears to be dominant over AKT mediated control of MDM2 activity (XREF_SUPPLEMENTARY).	8	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	10	11	14	15
Additionally , in this study , we confirmed that LDR prevented diabetic cardiomyopathy at the late-stage of diabetes and this was because of suppression of diabetes induced apoptosis and oxidative stress via the Akt mediated MDM2 and P53 pathways and the Nrf2 and keap1 pathway respectively .	Additionally, in this study, we confirmed that LDR prevented diabetic cardiomyopathy at the late-stage of diabetes and this was because of suppression of diabetes induced apoptosis and oxidative stress via the Akt mediated MDM2 and P53 pathways and the Nrf2 and keap1 pathway respectively.	30	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	33	34	35	36
HDACi like romidepsin is well known to induce p21 in p53-null ovarian cancer cells [ XREF_BIBR , XREF_BIBR ] , which can suppress the Akt induced Mdm2 followed by slower cell proliferation and lower mortality rate .	HDACi like romidepsin is well known to induce p21 in p53-null ovarian cancer cells [XREF_BIBR, XREF_BIBR], which can suppress the Akt induced Mdm2 followed by slower cell proliferation and lower mortality rate.	23	27	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	24	25	26	27
Further more , Akt promotes E3 ubiquitin ligase HDM2 mediated degradation of NFATc2 to block breast cancer mobility and invasion [ XREF_BIBR ] .	Further more, Akt promotes E3 ubiquitin ligase HDM2 mediated degradation of NFATc2 to block breast cancer mobility and invasion [XREF_BIBR].	3	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	HDM2	HDM2	HDM2	3	4	8	9
These studies have established that phosphorylation by Akt activates MDM2 , thereby maintaining p53 levels low .	These studies have established that phosphorylation by Akt activates MDM2, thereby maintaining p53 levels low.	5	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	7	8	9	10
It is also unlikely that AKT signaling pathway promotes the p53 transactivation , since AKT is shown to enhance MDM2 mediated degradation of p53 .	It is also unlikely that AKT signaling pathway promotes the p53 transactivation, since AKT is shown to enhance MDM2 mediated degradation of p53.	14	20	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	14	15	19	20
30 Therefore , it is reasonable to assume that decreased AKT activation in PRKD2 silenced cells could inactivate Mdm2 and thereby stabilize p53 .	30 Therefore, it is reasonable to assume that decreased AKT activation in PRKD2 silenced cells could inactivate Mdm2 and thereby stabilize p53.	10	19	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	Mdm2	Mdm2	Mdm2	10	11	18	19
We observed that RPS19 depletion induces a significant increase in MDM2 whereas AKT overexpression causes a recovery of MDM2 to control level .	We observed that RPS19 depletion induces a significant increase in MDM2 whereas AKT overexpression causes a recovery of MDM2 to control level.	12	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT overexpression	akt	MDM2	MDM2	mdm2	12	13	18	19
Activation of Mdm2 by Akt phosphorylation blocks p53 and protects from apoptosis in other systems [ XREF_BIBR ] .	Activation of Mdm2 by Akt phosphorylation blocks p53 and protects from apoptosis in other systems [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	4	5	2	3
Akt promotes nuclear location of HDM2 , which is crucial for HDM2 to inhibit transcriptional activity of p53 and target p53 for degradation .	Akt promotes nuclear location of HDM2, which is crucial for HDM2 to inhibit transcriptional activity of p53 and target p53 for degradation.	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	HDM2	HDM2	HDM2	0	1	5	6
Activation of AKT induced stabilization of the MDMX and MDM2 heterocomplex , thus promoting p53 accumulation in the cytoplasm .	Activation of AKT induced stabilization of the MDMX and MDM2 heterocomplex, thus promoting p53 accumulation in the cytoplasm.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	2	3	9	10
Our findings offer in vivo evidence that activation of MDM2 by Akt contributes to mammary development and tumorigenesis .	Our findings offer in vivo evidence that activation of MDM2 by Akt contributes to mammary development and tumorigenesis.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	11	12	9	10
XREF_BIBR , XREF_BIBR Previous studies have shown that MDM2 is stimulated by Akt phosphorylation , providing a potential link between p53 and PI 3-kinase signaling .	XREF_BIBR, XREF_BIBR Previous studies have shown that MDM2 is stimulated by Akt phosphorylation, providing a potential link between p53 and PI 3-kinase signaling.	8	14	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	MDM2	MDM2	mdm2	12	13	8	9
Conversely , arrestin-2 , but not arrestin-3 , recruited to active b2AR has been reported to facilitate Akt mediated activation of Mdm2 promoting Mdm2 dependent degradation of p53 .	Conversely, arrestin-2, but not arrestin-3, recruited to active b2AR has been reported to facilitate Akt mediated activation of Mdm2 promoting Mdm2 dependent degradation of p53.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	17	18	21	22
We found that 14-3-3zeta can destabilize p53 protein partially through PI3K-Akt activation of Mdm2 and by downregualtion of 14-3-3sigma .	We found that 14-3-3zeta can destabilize p53 protein partially through PI3K-Akt activation of Mdm2 and by downregualtion of 14-3-3sigma.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	Mdm2	Mdm2	Mdm2	10	11	13	14
The serine/threonine specific protein kinase Akt promotes cellular survival by blocking apoptosis , which it achieves by binding and regulating many downstream effectors ; e.g ., NF-kappaB , Bcl-2 family proteins , and MDM2 [ XREF_BIBR , XREF_BIBR ] .	The serine/threonine specific protein kinase Akt promotes cellular survival by blocking apoptosis, which it achieves by binding and regulating many downstream effectors; e.g., NF-kappaB, Bcl-2 family proteins, and MDM2 [XREF_BIBR, XREF_BIBR].	0	35	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	5	6	33	34
Additionally , since Akt also activates MDM2 and inhibits p53 , combination strategies with Akt inhibitors may have additive benefits in OS .	Additionally, since Akt also activates MDM2 and inhibits p53, combination strategies with Akt inhibitors may have additive benefits in OS.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	3	4	6	7
Taking our current findings together with these observations , it seems likely that PI3K-Akt signalling , stimulated by fibronectin , might enhance the ability of MDM2 to reduce the inhibitory effect of p53 in microglia , which in turn leads to the up-regulation of P2X 4 R gene expression .	Taking our current findings together with these observations, it seems likely that PI3K-Akt signalling, stimulated by fibronectin, might enhance the ability of MDM2 to reduce the inhibitory effect of p53 in microglia, which in turn leads to the up-regulation of P2X 4 R gene expression.	13	26	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	MDM2	MDM2	MDM2	13	14	25	26
In addition to the previously reported links involving AKT mediated activation of MDM2 and the p53 mediated induction of the phosphatase and tensin homolog ( PTEN ) [ XREF_BIBR , XREF_BIBR ] , we propose that p53 , through an indirect mechanism involving the p21/Rb/E2F pathway , represses the expression of SREBP1c and its downstream target SCD .	In addition to the previously reported links involving AKT mediated activation of MDM2 and the p53 mediated induction of the phosphatase and tensin homolog (PTEN) [XREF_BIBR, XREF_BIBR], we propose that p53, through an indirect mechanism involving the p21/Rb/E2F pathway, represses the expression of SREBP1c and its downstream target SCD.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	8	9	12	13
Furthermore , AKT activates MDM2 that regulates p53 stability ; therefore , reduced AKT function will preclude MDM2 negative regulation of p53 , leading to p53 activation under low-nutrient conditions .	Furthermore, AKT activates MDM2 that regulates p53 stability; therefore, reduced AKT function will preclude MDM2 negative regulation of p53, leading to p53 activation under low-nutrient conditions.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	2	3	4	5
Because we found that MDM2 activation by the PI3K and AKT cascade is an ARRB1 dependent event , we examined the binding between beta-arrestins and p53 , a known MDM2 substrate .	Because we found that MDM2 activation by the PI3K and AKT cascade is an ARRB1 dependent event, we examined the binding between beta-arrestins and p53, a known MDM2 substrate.	4	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	10	11	4	5
Previous studies showed that HER-2 mediated AKT activation to induce translocation of MDM2 from the cytoplasm to the nucleus .	Previous studies showed that HER-2 mediated AKT activation to induce translocation of MDM2 from the cytoplasm to the nucleus.	4	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	HER-2 mediated AKT	akt	MDM2	MDM2	mdm2	6	7	12	13
31 IRS1 can associate with ErbB3 in ERalpha positive breast cancer cells , where TAM resistance induced by IRS1 overexpression and activation may be due to AKT mediated ERalpha activation .	31 IRS1 can associate with ErbB3 in ERalpha positive breast cancer cells, where TAM resistance induced by IRS1 overexpression and activation may be due to AKT mediated ERalpha activation.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	ERalpha	ERalpha	ERalpha	26	27	28	29
Infection of MCF-7 cells with an adenovirus encoding myristoylated , constitutively active Akt induced ER reporter activity in the absence of estradiol and resulted in tamoxifen resistance of these cells in culture .	Infection of MCF-7 cells with an adenovirus encoding myristoylated, constitutively active Akt induced ER reporter activity in the absence of estradiol and resulted in tamoxifen resistance of these cells in culture.	11	23	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	12	13	14	15
Importantly , TAS-117 enhances cytotoxicity induced by proteasome inhibitors ( bortezomib and carfilzomib ) by inhibition of proteasome inhibitor induced Akt activation and induction of fatal ER stress , associated with increased CHOP expression .	Importantly, TAS-117 enhances cytotoxicity induced by proteasome inhibitors (bortezomib and carfilzomib) by inhibition of proteasome inhibitor induced Akt activation and induction of fatal ER stress, associated with increased CHOP expression.	17	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	Akt	proteasome inhibitor induced Akt	akt	ER	ER	er	20	21	26	27
PI3K and AKT and MAPK and ERK pathway activation is mediated via CHOP and induces ER stress XREF_BIBR .	PI3K and AKT and MAPK and ERK pathway activation is mediated via CHOP and induces ER stress XREF_BIBR.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ER	ER	ER	2	3	15	16
In XREF_FIG , the count of transfected cells showing ERalpha nuclear fluorescence indicates that overexpression of either Deltap85alpha or dominant negative AKT induces nuclear retention of ERalpha in 60-min estradiol treated MCF-7 cells .	In XREF_FIG, the count of transfected cells showing ERalpha nuclear fluorescence indicates that overexpression of either Deltap85alpha or dominant negative AKT induces nuclear retention of ERalpha in 60-min estradiol treated MCF-7 cells.	14	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	overexpression of either Deltap85alpha or dominant negative AKT	akt	ERalpha	ERalpha	eralpha	21	22	26	27
Since both the Akt and MAPK pathways can activate ERalpha via phosphorylation [ XREF_BIBR - XREF_BIBR ] , we examined ERalpha phosphorylation at S167 .	Since both the Akt and MAPK pathways can activate ERalpha via phosphorylation [XREF_BIBR - XREF_BIBR], we examined ERalpha phosphorylation at S167.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	3	4	9	10
Recent studies indicate that PI3K and Akt and MEK and ERK signalling pathways are important intracellular mediators in ER induced phase II enzymes in intestinal epithelial Caco-2 cells [ XREF_BIBR ] .	Recent studies indicate that PI3K and Akt and MEK and ERK signalling pathways are important intracellular mediators in ER induced phase II enzymes in intestinal epithelial Caco-2 cells [XREF_BIBR].	4	19	are important intracellular mediators	Positive_activation_copula_1	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	6	7	18	19
Prolactin activation of MAPK and ERK and PI3K and Akt also activates ERalpha in the absence of an ERalpha ligand .	Prolactin activation of MAPK and ERK and PI3K and Akt also activates ERalpha in the absence of an ERalpha ligand.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	9	10	12	13
Interestingly , Akt inhibition with BEZ235 partially blocks ER stress and its associated EMT in lung adenocarcinoma cells induced by EerI , as revealed by western blot analysis .	Interestingly, Akt inhibition with BEZ235 partially blocks ER stress and its associated EMT in lung adenocarcinoma cells induced by EerI, as revealed by western blot analysis.	2	9	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	2	3	8	9
This genomic ERalpha activity can also be induced via ligand independent phosphorylation of the receptor ' s AF-1 domain by Akt and ERK1/2 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	This genomic ERalpha activity can also be induced via ligand independent phosphorylation of the receptor 's AF-1 domain by Akt and ERK1/2 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	22	induced	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	Akt	phosphorylation of the receptor 's AF-1 domain by Akt	akt	ERalpha	ERalpha	eralpha	20	21	2	3
In the results of this study , we observed that Akt deactivation by LY294002 ( PI3K inhibitor ) and PI3K siRNA blocked E 2 -, BSA-E 2 - and/or ERalpha mediated cardioprotective properties during LPS stimulation .	In the results of this study, we observed that Akt deactivation by LY294002 (PI3K inhibitor) and PI3K siRNA blocked E 2 -, BSA-E 2 - and/or ERalpha mediated cardioprotective properties during LPS stimulation.	10	30	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	10	11	29	30
We previously showed that the suppression of PKC by GO6976 ( a potential PKC alpha and beta inhibitor ) triggers apoptosis through Akt mediated ER stress .	We previously showed that the suppression of PKC by GO6976 (a potential PKC alpha and beta inhibitor) triggers apoptosis through Akt mediated ER stress.	22	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	22	23	24	25
Our gene reporter assays revealed that ERalpha , not ERbeta , was targeted by AKT , resulting in transcriptional potentiation of the full-length Bcl-2 promoter , ultimately leading to increased Bcl-2 protein levels .	Our gene reporter assays revealed that ERalpha, not ERbeta, was targeted by AKT, resulting in transcriptional potentiation of the full-length Bcl-2 promoter, ultimately leading to increased Bcl-2 protein levels.	6	15	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ERalpha	ERalpha	ERalpha	14	15	6	7
For instance , both AKT and ERK can activate ER by phosphorylation in breast cancer .	For instance, both AKT and ERK can activate ER by phosphorylation in breast cancer.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ER	ER	ER	4	5	9	10
This induction coincides temporally with ER stress induced Akt activity and is attenuated by Akt inhibition .	This induction coincides temporally with ER stress induced Akt activity and is attenuated by Akt inhibition.	5	15	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	14	15	5	6
This mutation and subsequent Akt activation resulted in the activation of ERalpha dependent pathways that play an important role in the tumorigenesis of endometrial cancer [ XREF_BIBR ] .	This mutation and subsequent Akt activation resulted in the activation of ERalpha dependent pathways that play an important role in the tumorigenesis of endometrial cancer [XREF_BIBR].	4	12	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	4	5	11	12
Serines S104 S106 , S118 , and S167 appear to play a role in the activation of ER-alpha by Akt .	Serines S104 S106, S118, and S167 appear to play a role in the activation of ER-alpha by Akt.	10	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	ER-alpha	ER-alpha	ER-alpha	19	20	17	18
E2 increased the phosphorylation of Akt and eNOS that was not reversed by ICI 182,780 , supporting an ER independent mechanism .	E2 increased the phosphorylation of Akt and eNOS that was not reversed by ICI 182,780, supporting an ER independent mechanism.	0	20	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	E2 increased the phosphorylation of Akt	akt	ER	ER	er	5	6	18	19
It was reported that the MAPK and PI3K and AKT pathways could activate the estrogen receptor ( ER ) XREF_BIBR , XREF_BIBR .	It was reported that the MAPK and PI3K and AKT pathways could activate the estrogen receptor (ER) XREF_BIBR, XREF_BIBR.	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	estrogen receptor	estrogen receptor	estrogen receptor	9	10	14	16
Previous studies in cell lines from breast , lung and prostate cancer have shown that the PI3K and Akt pathway can be differentially regulated to modulate cellular ER stress .	Previous studies in cell lines from breast, lung and prostate cancer have shown that the PI3K and Akt pathway can be differentially regulated to modulate cellular ER stress.	16	28	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	18	19	27	28
The findings of the present study revealed that anti-microRNA-148a protected cells against ovariectomy induced osteoporosis through ERalpha by PI3K and AKT signaling .	The findings of the present study revealed that anti-microRNA-148a protected cells against ovariectomy induced osteoporosis through ERalpha by PI3K and AKT signaling.	13	21	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ERalpha	ERalpha	ERalpha	20	21	16	17
Given the observations that activation of AKT and mTOR signalling and induction of ER stress were critical for TSA mediated cell death , a fine tuning investigation was required for addressing the association between these pathways and ER stress gene expression .	Given the observations that activation of AKT and mTOR signalling and induction of ER stress were critical for TSA mediated cell death, a fine tuning investigation was required for addressing the association between these pathways and ER stress gene expression.	6	14	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	ER	ER	ER	6	7	13	14
These results suggest that OSCC cells expressed functional ERalpha , whose activity can be enhanced by FAK and AKT signaling , and this was critical for promoting cell growth .	These results suggest that OSCC cells expressed functional ERalpha, whose activity can be enhanced by FAK and AKT signaling, and this was critical for promoting cell growth.	6	19	enhanced	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ERalpha	ERalpha	ERalpha	18	19	8	9
Third , constitutively active PI3K or Akt induced ER activity but reduced PR levels and activity .	Third, constitutively active PI3K or Akt induced ER activity but reduced PR levels and activity.	0	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	6	7	8	9
Additionally , we found that two critical kinases , Akt and extracellular signal regulated kinase ( ERK ) , mediated the activation of ERalpha and VSMC proliferation .	Additionally, we found that two critical kinases, Akt and extracellular signal regulated kinase (ERK), mediated the activation of ERalpha and VSMC proliferation.	9	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	9	10	23	24
DTDO ( 20 muM ) reduced activating Akt phosphorylation , upregulated markers of ER stress , and increased PARP cleavage .	DTDO (20 muM) reduced activating Akt phosphorylation, upregulated markers of ER stress, and increased PARP cleavage.	7	14	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	ER	ER	er	7	8	13	14
In the same way , it has also been reported that the Akt overexpression in breast cancer cells expressing estrogen receptor alpha ( ERalpha ) led to the activation of ERalpha in the absence of estrogen and the induction of ERalpha target genes pS2 , Bcl-2 , and MIC-1 .	In the same way, it has also been reported that the Akt overexpression in breast cancer cells expressing estrogen receptor alpha (ERalpha) led to the activation of ERalpha in the absence of estrogen and the induction of ERalpha target genes pS2, Bcl-2, and MIC-1.	12	31	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt overexpression	akt	ERalpha	ERalpha	eralpha	12	13	30	31
In these cases , peptide growth factor activation of the PI3K-AKT signaling cascades potentiated ERalpha transcriptional activity .	In these cases, peptide growth factor activation of the PI3K-AKT signaling cascades potentiated ERalpha transcriptional activity.	10	16	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	ERalpha	ERalpha	ERalpha	10	11	14	15
Furthermore , in the study of Park et al , the stabilization and up-regulation of ERalpha by Akt was accompanied by a simultaneous reduction in its transcriptional activity [ XREF_BIBR ] .	Furthermore, in the study of Park et al, the stabilization and up-regulation of ERalpha by Akt was accompanied by a simultaneous reduction in its transcriptional activity [XREF_BIBR].	11	18	up-regulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	17	18	15	16
We found that the Panx3 ER Ca 2+ channel was activated through Akt signaling ( XREF_FIG ) , distinct from IP3 mediated activation of ubiquitous IP3R ER Ca 2+ channels .	We found that the Panx3 ER Ca 2+ channel was activated through Akt signaling (XREF_FIG), distinct from IP3 mediated activation of ubiquitous IP3R ER Ca 2+ channels.	12	29	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	12	13	26	27
Furthermore , AKT is thought to mediate ER stress induced apoptotic pathways as well as ER stress related anabolic resistance .	Furthermore, AKT is thought to mediate ER stress induced apoptotic pathways as well as ER stress related anabolic resistance.	2	8	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ER	ER	ER	2	3	7	8
Previously it has been reported that up-regulated expression of AKT and PI3k which in turn activates hormonal receptor ER-alpha , resulting in increased expression of IGF-1R and EGFR .	Previously it has been reported that up-regulated expression of AKT and PI3k which in turn activates hormonal receptor ER-alpha, resulting in increased expression of IGF-1R and EGFR.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	expression of AKT	akt	ER-alpha	ER-alpha	er-alpha	9	10	18	19
Overactivation of PI3K and Akt pathway by myristoylated Akt1 in estrogen- or MPA dependent tumor cells induced ER and PR activation and ligand independent tumor growth affecting endocrine therapy sensitivity [ XREF_BIBR ] .	Overactivation of PI3K and Akt pathway by myristoylated Akt1 in estrogen- or MPA dependent tumor cells induced ER and PR activation and ligand independent tumor growth affecting endocrine therapy sensitivity [XREF_BIBR].	2	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	4	5	17	18
Preclinical studies have shown that Akt can activate the ER pathway independent of estrogen availability and that the combination of mTOR inhibitors with endocrine therapy can overcome this resistance XREF_BIBR , XREF_BIBR .	Preclinical studies have shown that Akt can activate the ER pathway independent of estrogen availability and that the combination of mTOR inhibitors with endocrine therapy can overcome this resistance XREF_BIBR, XREF_BIBR.	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	5	6	9	10
Western blot analysis demonstrated that in cells depleted of ESR1 and treated with PCI-24781 , Akt protein , activity , and signaling are down regulated , while pro apoptotic Bim and Bax are up regulated and PARP cleavage is significantly increased .	Western blot analysis demonstrated that in cells depleted of ESR1 and treated with PCI-24781, Akt protein, activity, and signaling are down regulated, while pro apoptotic Bim and Bax are up regulated and PARP cleavage is significantly increased.	7	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Akt	Akt	Akt	ESR1	ESR1	ESR1	15	16	9	10
However , independently of which mechanism takes place , it was recently shown that reduction or absence of KLF6 abrogates the negative control of breast cancer cell proliferation triggered by Estrogen Receptor alpha through the signaling pathway mediated by c-Src and Akt activation XREF_BIBR .	However, independently of which mechanism takes place, it was recently shown that reduction or absence of KLF6 abrogates the negative control of breast cancer cell proliferation triggered by Estrogen Receptor alpha through the signaling pathway mediated by c-Src and Akt activation XREF_BIBR.	30	43	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Estrogen Receptor	Estrogen Receptor	Estrogen Receptor	41	42	30	32
Phosphorylation site mapping has demonstrated that serine 118 ( S118 ) in AF-1 is phosphorylated by Erk1/2 MAPK , resulting in stimulation of ERalpha activity , whilst phosphorylation of serine 167 ( S167 ) in AF-1 by AKT and p90RSK also stimulates ERalpha activity .	Phosphorylation site mapping has demonstrated that serine 118 (S118) in AF-1 is phosphorylated by Erk1/2 MAPK, resulting in stimulation of ERalpha activity, whilst phosphorylation of serine 167 (S167) in AF-1 by AKT and p90RSK also stimulates ERalpha activity.	27	43	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	phosphorylation of serine 167 (S167) in AF-1 by AKT	akt	ERalpha	ERalpha	eralpha	37	38	42	43
The autophosphorylation of AKT and ERK can , in turn , activate downstream mediator ER-alpha , resulting in up-regulation of IGF-1R and EGFR expressions .	The autophosphorylation of AKT and ERK can, in turn, activate downstream mediator ER-alpha, resulting in up-regulation of IGF-1R and EGFR expressions.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	autophosphorylation of AKT	akt	ER-alpha	ER-alpha	er-alpha	3	4	14	15
Effect of Akt activation and SB216763 on LPS induced ER stress in vitro .	Effect of Akt activation and SB216763 on LPS induced ER stress in vitro.	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	2	3	9	10
XREF_BIBR In another study in cultured Pompe patient fibroblasts , the inactivation of Akt can lead to autophagy , in a ER stress independent manner , via the suppression of mTOR signaling .	XREF_BIBR In another study in cultured Pompe patient fibroblasts, the inactivation of Akt can lead to autophagy, in a ER stress independent manner, via the suppression of mTOR signaling.	11	22	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	13	14	21	22
Here we show that phosphatidylinositol ( PI ) 3-kinase and AKT activate ERalpha in the absence of estrogen .	Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ERalpha in the absence of estrogen.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ERalpha	ERalpha	ERalpha	10	11	12	13
Akt can directly activate the estrogen receptor by phosphorylation in the absence of estrogen , thus promoting estrogen independent growth and resistance to hormone therapy .	Akt can directly activate the estrogen receptor by phosphorylation in the absence of estrogen, thus promoting estrogen independent growth and resistance to hormone therapy.	0	7	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	estrogen receptor	estrogen receptor	estrogen receptor	0	1	5	7
We found that NOS2 expression was associated with Akt activation in both ER positive and ER negative tumors XREF_BIBR .	We found that NOS2 expression was associated with Akt activation in both ER positive and ER negative tumors XREF_BIBR.	8	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	8	9	12	13
These findings further demonstrate the importance of defective Akt signaling , a critical component of intact insulin receptor signaling , in ER stress induced macrophage apoptosis and raise caution about the use of p38 inhibitors , currently under development as anti-inflammatory agents in a number of diseases including type 2 diabetes , XREF_BIBR in insulin-resistance subjects .	These findings further demonstrate the importance of defective Akt signaling, a critical component of intact insulin receptor signaling, in ER stress induced macrophage apoptosis and raise caution about the use of p38 inhibitors, currently under development as anti-inflammatory agents in a number of diseases including type 2 diabetes, XREF_BIBR in insulin-resistance subjects.	8	22	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	8	9	21	22
Moreover , estrogen-metabolism mediated oxidative stress can also augment the nongenomic ER actions like activation of downstream signaling kinases such as mitogen activated protein kinase ( MAPK ) and AKT , which orchestrate cell proliferation and survival XREF_BIBR , XREF_BIBR .	Moreover, estrogen-metabolism mediated oxidative stress can also augment the nongenomic ER actions like activation of downstream signaling kinases such as mitogen activated protein kinase (MAPK) and AKT, which orchestrate cell proliferation and survival XREF_BIBR, XREF_BIBR.	8	32	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ER	ER	ER	29	30	11	12
Akt induces translation via the mTORC1 pathway and could increase the protein load of the ER .	Akt induces translation via the mTORC1 pathway and could increase the protein load of the ER.	0	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	0	1	15	16
Further complications in this area arise from two recent reports that PI3K and Akt can activate the ER in the absence of oestrogen [ XREF_BIBR , XREF_BIBR ] .	Further complications in this area arise from two recent reports that PI3K and Akt can activate the ER in the absence of oestrogen [XREF_BIBR, XREF_BIBR].	11	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	13	14	17	18
In osteoblasts , Panx3 also forms channels in the ER that are activated by PI3K-Akt signaling .	In osteoblasts, Panx3 also forms channels in the ER that are activated by PI3K-Akt signaling.	6	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	ER	ER	ER	14	15	9	10
Studies using mutants of ER-alpha demonstrated that Akt increased estrogen receptor activity through the amino-terminal activation function-1 ( AF-1 ) .	Studies using mutants of ER-alpha demonstrated that Akt increased estrogen receptor activity through the amino-terminal activation function-1 (AF-1).	7	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	estrogen receptor	estrogen receptor	estrogen receptor	7	8	9	11
In addition , metformin treatment attenuated the albumin induced phosphorylation of AKT and the downstream targets of mTOR , and prevented albumin mediated inductions of EMT marker ( alpha-SMA ) , pro apoptotic ER stress marker CHOP , and apoptotic caspases -12 and -3 in renal cells .	In addition, metformin treatment attenuated the albumin induced phosphorylation of AKT and the downstream targets of mTOR, and prevented albumin mediated inductions of EMT marker (alpha-SMA), pro apoptotic ER stress marker CHOP, and apoptotic caspases -12 and -3 in renal cells.	3	36	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	metformin treatment attenuated the albumin induced phosphorylation of AKT	akt	ER	ER	er	11	12	33	34
In contrast , ER-beta causes reduction in Akt signalling in ERalpha positive breast cancer cells , thus affecting cell proliferation and survival along with increasing the sensitivity of cells for tamoxifen ( ER antagonist ) treatment [ XREF_BIBR ] .	In contrast, ER-beta causes reduction in Akt signalling in ERalpha positive breast cancer cells, thus affecting cell proliferation and survival along with increasing the sensitivity of cells for tamoxifen (ER antagonist) treatment [XREF_BIBR].	7	17	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	7	8	10	11
Furthermore , the Akt and mTOR pathway promotes ATP demanding processes , such as protein synthesis [ XREF_BIBR ] , in the ER .	Furthermore, the Akt and mTOR pathway promotes ATP demanding processes, such as protein synthesis [XREF_BIBR], in the ER.	3	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	3	4	22	23
An additional link between PI3K/Akt/mTOR and ER signaling pathways hinged on the fact that Akt can activate ERalpha pathway in the absence of estrogen , and the combination of endocrine therapy with mTOR inhibitors was able to overcome endocrine therapy resistance .	An additional link between PI3K/Akt/mTOR and ER signaling pathways hinged on the fact that Akt can activate ERalpha pathway in the absence of estrogen, and the combination of endocrine therapy with mTOR inhibitors was able to overcome endocrine therapy resistance.	14	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	14	15	17	18
Aberrant Akt activation has been shown to cause ER stress and activates the UPR that then switches on the apoptotic machinery .	Aberrant Akt activation has been shown to cause ER stress and activates the UPR that then switches on the apoptotic machinery.	1	9	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	1	2	8	9
In this study , we show that inactivated Akt induces ER stress independent autophagy via mTOR suppression in patient fibroblasts .	In this study, we show that inactivated Akt induces ER stress independent autophagy via mTOR suppression in patient fibroblasts.	7	11	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	8	9	10	11
Until now , we did not have a proof to explain why CPT increases p-AKT in non breast cancer cells , but we thought that deactivation of AKT is related to inhibit ERalpha in breast cancer cells .	Until now, we did not have a proof to explain why CPT increases p-AKT in non breast cancer cells, but we thought that deactivation of AKT is related to inhibit ERalpha in breast cancer cells.	25	33	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ERalpha	ERalpha	ERalpha	27	28	32	33
Elevated MAPK or Akt activity could stimulate ERalpha activity by increasing phosphorylation of serine residues in ERalpha AF-1 domain , including the well characterized MAPK sensitive ERalpha serine118 ( S118 ) site .	Elevated MAPK or Akt activity could stimulate ERalpha activity by increasing phosphorylation of serine residues in ERalpha AF-1 domain, including the well characterized MAPK sensitive ERalpha serine118 (S118) site.	3	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	3	4	7	8
Inhibition of PI3K and AKT signaling strongly impaired FGF7 triggered ER degradation .	Inhibition of PI3K and AKT signaling strongly impaired FGF7 triggered ER degradation.	4	11	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	ER	ER	ER	4	5	10	11
Effects of Akt activation on LPS induced ER stress response .	Effects of Akt activation on LPS induced ER stress response.	2	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	2	3	7	8
This mutation and subsequent Akt activation resulted in the activation of ERalpha dependent pathways which play an important role in endometrial cancer tumorigenesis .	This mutation and subsequent Akt activation resulted in the activation of ERalpha dependent pathways which play an important role in endometrial cancer tumorigenesis.	4	12	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	4	5	11	12
Akt or Src kinase inhibitors block ER stress and EMT in lung adenocarcinoma cells .	Akt or Src kinase inhibitors block ER stress and EMT in lung adenocarcinoma cells.	0	7	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	0	1	6	7
Rapid activation of AKT , which repressed the activity of EZH2 and levels of H3K27me3 in chromatin , distinguished GEN from BPA , despite the fact that both xenoestrogens were able to induce genomic ER signaling and transactivate the expression of estrogen responsive genes in the developing uterus .	Rapid activation of AKT, which repressed the activity of EZH2 and levels of H3K27me3 in chromatin, distinguished GEN from BPA, despite the fact that both xenoestrogens were able to induce genomic ER signaling and transactivate the expression of estrogen responsive genes in the developing uterus.	1	35	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ER	ER	ER	3	4	34	35
Consistent with this scenario , a previous study showed that Akt overexpression can increase the intensity of ERalpha staining , the number of ERalpha positive cells and the frequency of ER+ tumors in DMBA treated mice , although it did not show whether these tumors were PR positive .	Consistent with this scenario, a previous study showed that Akt overexpression can increase the intensity of ERalpha staining, the number of ERalpha positive cells and the frequency of ER+ tumors in DMBA treated mice, although it did not show whether these tumors were PR positive.	10	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt overexpression	akt	ERalpha	ERalpha	eralpha	10	11	17	18
Obesity associated circulating factors enhance Akt mediated activation of ERalpha and nongenomic ERalpha activity .	Obesity associated circulating factors enhance Akt mediated activation of ERalpha and nongenomic ERalpha activity.	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	ERalpha	ERalpha	ERalpha	5	6	9	10
In vitro studies have demonstrated that phosphatidylinositol 3-kinase ( PI3K ) and AKT activate ER in the absence of estrogen .	In vitro studies have demonstrated that phosphatidylinositol 3-kinase (PI3K) and AKT activate ER in the absence of estrogen.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ER	ER	ER	12	13	14	15
Inhibitors of EGFR , ERBB2 , MAPK and AKT pathways could be used to block ER extranuclear signaling in ERalpha positive tumors that exhibit deregulation of these pathways XREF_BIBR , XREF_BIBR .	Inhibitors of EGFR, ERBB2, MAPK and AKT pathways could be used to block ER extranuclear signaling in ERalpha positive tumors that exhibit deregulation of these pathways XREF_BIBR, XREF_BIBR.	2	17	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ER	ER	ER	8	9	15	16
In in vitro studies , it was shown that PI3K and AKT can activate ER in the absence of estrogen , and constitutively active AKT causes tamoxifen resistance .	In in vitro studies, it was shown that PI3K and AKT can activate ER in the absence of estrogen, and constitutively active AKT causes tamoxifen resistance.	9	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ER	ER	ER	11	12	14	15
Moreover , both MAPK and AKT can directly enhance the classic genomic transcriptional activity of ER in the absence of oestrogens further contributing to endocrine resistance .	Moreover, both MAPK and AKT can directly enhance the classic genomic transcriptional activity of ER in the absence of oestrogens further contributing to endocrine resistance.	3	16	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	ER	ER	ER	5	6	15	16
On the other hand , Akt ( PKB ) has been shown to stimulate glucose uptake by influencing glucose transporter 4 ( GLUT4 ) [ XREF_BIBR ] .	On the other hand, Akt (PKB) has been shown to stimulate glucose uptake by influencing glucose transporter 4 (GLUT4) [XREF_BIBR].	5	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	GLUT4	GLUT4	GLUT4	5	6	22	23
A parallel use of AKT inhibitor with P2X7 agonist treated cells or with conditioned medium markedly decreased Glut4 protein and localization suggesting P2X7r and AKT phosphorylation mediated GLUT4 translocation and induction were downstream of leptin ( XREF_FIG ) .	A parallel use of AKT inhibitor with P2X7 agonist treated cells or with conditioned medium markedly decreased Glut4 protein and localization suggesting P2X7r and AKT phosphorylation mediated GLUT4 translocation and induction were downstream of leptin (XREF_FIG).	22	28	mediated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AKT	AKT phosphorylation	akt	GLUT4	GLUT4	glut4	24	25	27	28
AKT promotes GLUT4 membrane localization by inhibitory phosphorylation of AKT Substrate of 160kDa ( AS160 ) .	AKT promotes GLUT4 membrane localization by inhibitory phosphorylation of AKT Substrate of 160kDa (AS160).	0	4	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	GLUT4	GLUT4	GLUT4	0	1	2	3
In myocytes , phosphorylation of Akt ( pAkt ) triggers translocation of the glucose transporter GLUT4 to the sarcolemma , which enables glucose to enter the myocytes [ XREF_BIBR ] .	In myocytes, phosphorylation of Akt (pAkt) triggers translocation of the glucose transporter GLUT4 to the sarcolemma, which enables glucose to enter the myocytes [XREF_BIBR].	3	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	phosphorylation of Akt	akt	GLUT4	GLUT4	glut4	5	6	15	16
Furthermore , expression of constitutively active Akt induces GLUT4 to redistribute to the plasma membrane even when microtubules are disrupted XREF_BIBR .	Furthermore, expression of constitutively active Akt induces GLUT4 to redistribute to the plasma membrane even when microtubules are disrupted XREF_BIBR.	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	expression of constitutively active Akt	akt	GLUT4	GLUT4	glut4	6	7	8	9
The GLUT4 translocation is also increased in these cells following co-incubation with P2X7r agonist and is mediated by AKT phosphorylation .	The GLUT4 translocation is also increased in these cells following co-incubation with P2X7r agonist and is mediated by AKT phosphorylation.	1	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT phosphorylation	akt	GLUT4	GLUT4	glut4	18	19	1	2
Moreover , GIPR expression is enhanced during the differentiation process of adipocytes , similar to that described in 3T3-L1 cells , and activation of GIPR up-regulates the expression of aP2 , a fat cell marker , and enhances adipocyte glucose uptake through PKB activation and subsequent membrane translocation of GLUT4 .	Moreover, GIPR expression is enhanced during the differentiation process of adipocytes, similar to that described in 3T3-L1 cells, and activation of GIPR up-regulates the expression of aP2, a fat cell marker, and enhances adipocyte glucose uptake through PKB activation and subsequent membrane translocation of GLUT4.	42	50	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PKB	PKB	PKB	GLUT4	GLUT4	GLUT4	42	43	49	50
Akt activates glucose transporter 4 ( GLUT4 ) , which moves to the cell surface to transport glucose into the cell .	Akt activates glucose transporter 4 (GLUT4), which moves to the cell surface to transport glucose into the cell.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	GLUT4	GLUT4	GLUT4	0	1	6	7
Over-expression of p62 increases phosphorylation of Akt at S473 and T308 , which is a downstream target of IRS-1 , and promotes the translocation of GLUT4 to the cell membrane for glucose uptake 106 .	Over-expression of p62 increases phosphorylation of Akt at S473 and T308, which is a downstream target of IRS-1, and promotes the translocation of GLUT4 to the cell membrane for glucose uptake 106.	0	26	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Over-expression of p62 increases phosphorylation of Akt at S473 and T308	akt	GLUT4	GLUT4	glut4	6	7	25	26
Akt is located at the heart of this cascade , and activation of Akt by phosphorylation leads to the translocation of glucose transporter 4 ( GLUT4 ) to the plasma membrane to initiate glucose uptake .	Akt is located at the heart of this cascade, and activation of Akt by phosphorylation leads to the translocation of glucose transporter 4 (GLUT4) to the plasma membrane to initiate glucose uptake.	11	32	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	GLUT4	GLUT4	GLUT4	13	14	25	26
The up-regulated phosphorylation of AKT increased GLUT4 transmembrane to transport glucose , accelerating glycometabolism [ XREF_BIBR ] .	The up-regulated phosphorylation of AKT increased GLUT4 transmembrane to transport glucose, accelerating glycometabolism [XREF_BIBR].	2	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	phosphorylation of AKT	akt	GLUT4	GLUT4	glut4	4	5	6	7
In addition , alpha-PGG induces phosphorylation of the IR and Akt , activates PI 3-kinase , and stimulates membrane translocation of GLUT 4 .	In addition, alpha-PGG induces phosphorylation of the IR and Akt, activates PI 3-kinase, and stimulates membrane translocation of GLUT 4.	3	23	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	alpha-PGG induces phosphorylation of the IR and Akt	akt	GLUT 4	GLUT 4	glut 4	10	11	21	23
Akt ( PKB ) stimulates glucose uptake by modulating glucose transporter 4 ( GLUT4 ) [ XREF_BIBR ] .	Akt (PKB) stimulates glucose uptake by modulating glucose transporter 4 (GLUT4) [XREF_BIBR].	0	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKB	PKB	PKB	GLUT4	GLUT4	GLUT4	2	3	13	14
Surprisingly , insulin induced subcellular redistribution of GLUT4 was preserved in MK-2206 treated Akt1 W80A and Akt2 W80A adipocytes , indicating that both Akt kinases mediate insulin signalling to GLUT4 .	Surprisingly, insulin induced subcellular redistribution of GLUT4 was preserved in MK-2206 treated Akt1 W80A and Akt2 W80A adipocytes, indicating that both Akt kinases mediate insulin signalling to GLUT4.	23	30	mediate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	GLUT4	GLUT4	GLUT4	23	24	29	30
Active AKT phosphorylates and inhibits TSC2 ( activating protein synthesis through Rheb and mTOR ) , inactivates GSK3beta , FOXO1 , BAD , and BIM ( to stimulate cell cycle progression and block apoptosis ) , and promotes GLUT4 trafficking to the plasma membrane , enhancing glucose metabolism .	Active AKT phosphorylates and inhibits TSC2 (activating protein synthesis through Rheb and mTOR), inactivates GSK3beta, FOXO1, BAD, and BIM (to stimulate cell cycle progression and block apoptosis), and promotes GLUT4 trafficking to the plasma membrane, enhancing glucose metabolism.	0	39	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	GLUT4	GLUT4	GLUT4	1	2	38	39
Indeed , estrogen has been shown to increase phosphorylation of insulin receptor substrate and Akt [ XREF_BIBR ] and activate GLUT-4 and glucose uptake into muscle [ XREF_BIBR ] in other model systems .	Indeed, estrogen has been shown to increase phosphorylation of insulin receptor substrate and Akt [XREF_BIBR] and activate GLUT-4 and glucose uptake into muscle [XREF_BIBR] in other model systems.	2	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	estrogen has been shown to increase phosphorylation of insulin receptor substrate and Akt	akt	GLUT-4	GLUT-4	glut-4	14	15	20	21
The activation of Akt and PKB stimulates GLUT4 , which results in enhanced glucose uptake .	The activation of Akt and PKB stimulates GLUT4, which results in enhanced glucose uptake.	1	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKB	PKB	PKB	GLUT4	GLUT4	GLUT4	5	6	7	8
In summary , in C2C12 muscle cells cultured in normal high-glucose DMEM , transfection and overexpression of CAV3 increased the phosphorylation of Akt , AMPK and p70s6K , increased the plasma membrane localization of GLUT4 protein , and increased glucose uptake , cell growth and proliferation .	In summary, in C2C12 muscle cells cultured in normal high-glucose DMEM, transfection and overexpression of CAV3 increased the phosphorylation of Akt, AMPK and p70s6K, increased the plasma membrane localization of GLUT4 protein, and increased glucose uptake, cell growth and proliferation.	17	35	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	CAV3 increased the phosphorylation of Akt	akt	GLUT4	GLUT4	glut4	22	23	34	35
Transgenic activation of Akt and insulin stimulation of myrAkt1 transgenic cardiomyocytes increased sarcolemmal insertion of myc-GLUT4 to levels equivalent to that observed in insulin stimulated wild-type controls .	Transgenic activation of Akt and insulin stimulation of myrAkt1 transgenic cardiomyocytes increased sarcolemmal insertion of myc-GLUT4 to levels equivalent to that observed in insulin stimulated wild-type controls.	3	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	myc-GLUT4	myc-GLUT4	myc-GLUT4	3	4	15	16
In the first , PKB stimulates GLUT-4 exocytosis either ( 17 ) directly or ( 18 ) via activation of atypical protein kinases C : PKC-zeta and -gamma ( designated as aPKC in XREF_FIG ) .	In the first, PKB stimulates GLUT-4 exocytosis either (17) directly or (18) via activation of atypical protein kinases C : PKC-zeta and -gamma (designated as aPKC in XREF_FIG).	4	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKB	PKB	PKB	GLUT-4	GLUT-4	GLUT-4	4	5	6	7
We hypothesized that activated IRS or a lack of activated IR deters activation of Akt , which then causes GLUT4 in the cell membrane to be exposed .	We hypothesized that activated IRS or a lack of activated IR deters activation of Akt, which then causes GLUT4 in the cell membrane to be exposed.	12	26	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	GLUT4	GLUT4	GLUT4	14	15	19	20
XREF_BIBR XREF_BIBR Interestingly , AKT is able to stimulate the metabolism of glucose through activation of AS160 , the substrate of AKT , and promotes transposition of GLUT4 and absorption of glucose into muscle cells .	XREF_BIBR XREF_BIBR Interestingly, AKT is able to stimulate the metabolism of glucose through activation of AS160, the substrate of AKT, and promotes transposition of GLUT4 and absorption of glucose into muscle cells.	4	29	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	GLUT4	GLUT4	GLUT4	4	5	27	28
In adipocytes , mTORC2 phosphorylates Akt Serine473 , leading to increased phosphorylation of and inhibition of AS160 , and thereby stimulates the GLUT4 exocytosis .	In adipocytes, mTORC2 phosphorylates Akt Serine473, leading to increased phosphorylation of and inhibition of AS160, and thereby stimulates the GLUT4 exocytosis.	3	23	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	mTORC2 phosphorylates Akt	akt	GLUT4	GLUT4	glut4	5	6	22	23
The loss of function T309A mutation and the gain of function S474D mutation provide additional evidence that insulin activation of Akt is necessary and sufficient to induce Glut4 redistribution to the plasma membrane of adipocytes .	The loss of function T309A mutation and the gain of function S474D mutation provide additional evidence that insulin activation of Akt is necessary and sufficient to induce Glut4 redistribution to the plasma membrane of adipocytes.	18	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Glut4	Glut4	Glut4	20	21	27	28
Overexpression of constitutively active AKT directly promotes glucose transport and translocation of GLUT1 and GLUT4 to the plasma membrane .	Overexpression of constitutively active AKT directly promotes glucose transport and translocation of GLUT1 and GLUT4 to the plasma membrane.	0	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	Overexpression of constitutively active AKT	akt	GLUT4	GLUT4	glut4	4	5	14	15
The insulin dependent Akt phosphorylation has been shown to mediate the translocation of GLUT4 to the plasma membrane , thereby leading to the enhancement of glucose uptake and its oxidation by the I/R stressed heart .	The insulin dependent Akt phosphorylation has been shown to mediate the translocation of GLUT4 to the plasma membrane, thereby leading to the enhancement of glucose uptake and its oxidation by the I/R stressed heart.	3	14	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	GLUT4	GLUT4	glut4	3	4	13	14
Phosphorylation of Akt at Ser473 by mTORC2 17 promotes anti-apoptotic and cell survival pathways 18 and stimulates translocation of GLUT4 and transport of glucose 19 .	Phosphorylation of Akt at Ser473 by mTORC2 17 promotes anti-apoptotic and cell survival pathways 18 and stimulates translocation of GLUT4 and transport of glucose 19.	0	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Phosphorylation of Akt at Ser473	akt	GLUT4	GLUT4	glut4	2	3	19	20
The mode of action of Astragalus polysaccharides includes Akt activation and upregulation of Glut4 and inhibition of inflammation via the PTP1B and NFkappaB pathway [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The mode of action of Astragalus polysaccharides includes Akt activation and upregulation of Glut4 and inhibition of inflammation via the PTP1B and NFkappaB pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	Glut4	Glut4	Glut4	8	9	13	14
It is established that constitutively active Akt induces GLUT4 translocation independent of insulin stimulation .	It is established that constitutively active Akt induces GLUT4 translocation independent of insulin stimulation.	5	9	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	GLUT4	GLUT4	GLUT4	6	7	8	9
XREF_BIBR The Akt substrate of 160 kDa ( AS160 ) , also known as TBC1D4 , is an established candidate in Akt and PKB induced GLUT-4 translocation in skeletal muscle .	XREF_BIBR The Akt substrate of 160 kDa (AS160), also known as TBC1D4, is an established candidate in Akt and PKB induced GLUT-4 translocation in skeletal muscle.	19	26	induced	Positive_early_activation	Positive_activation	Positive_activation	PKB	PKB	PKB	GLUT-4	GLUT-4	GLUT-4	23	24	25	26
The survival of TCM involves phosphorylation of STAT5a and FOXO3a , the latter involving Akt activation of IKKalpha and beta and modification of FOXO3a .	The survival of TCM involves phosphorylation of STAT5a and FOXO3a, the latter involving Akt activation of IKKalpha and beta and modification of FOXO3a.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	14	15	17	18
Data from our studies indicate that PI3K and Akt drive IKKalpha onto the mTORC2 complex , promoting a feedforward process to maintain mTORC2 activity .	Data from our studies indicate that PI3K and Akt drive IKKalpha onto the mTORC2 complex, promoting a feedforward process to maintain mTORC2 activity.	6	21	drive	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	8	9	10	11
More specifically , in lung cancer , CCL5 contributes to the activation of the alphavbeta3 integrin and to cell migration through PI3K and Akt , which in turn activates IKKalpha and beta and NF-kappaB [ XREF_BIBR ] .	More specifically, in lung cancer, CCL5 contributes to the activation of the alphavbeta3 integrin and to cell migration through PI3K and Akt, which in turn activates IKKalpha and beta and NF-kappaB [XREF_BIBR].	8	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	23	24	29	30
It was shown that PI3K and Akt activates NF-kappaB activity in an IKKalpha dependent manner .	It was shown that PI3K and Akt activates NF-kappaB activity in an IKKalpha dependent manner.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	6	7	12	13
More specifically , CCL5 contributes to the activation of the alphavbeta3 integrin and to cell migration through PI3K and Akt , which in turn activates IKKalpha and beta and NF-kappaB [ XREF_BIBR ] .	More specifically, CCL5 contributes to the activation of the alphavbeta3 integrin and to cell migration through PI3K and Akt, which in turn activates IKKalpha and beta and NF-kappaB [XREF_BIBR].	4	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	19	20	25	26
Reports suggest that PI3K and Akt and NIK primarily activate IKKalpha , whereas MEKK1 and atypical protein kinase C activate IKKbeta [ XREF_BIBR - XREF_BIBR ] .	Reports suggest that PI3K and Akt and NIK primarily activate IKKalpha, whereas MEKK1 and atypical protein kinase C activate IKKbeta [XREF_BIBR - XREF_BIBR].	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	5	6	10	11
Taken together , our results suggest that TGF-beta1 acts through PI3K and Akt , which in turn activates IKKalpha and beta and NF-kappaB , resulting in the activations of beta1 integrins and contributing the migration of human lung cancer cells .	Taken together, our results suggest that TGF-beta1 acts through PI3K and Akt, which in turn activates IKKalpha and beta and NF-kappaB, resulting in the activations of beta1 integrins and contributing the migration of human lung cancer cells.	8	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	12	13	18	19
In addition , IKKalpha ubiquitination enhanced by HBx and Akt also contributed to the IKKalpha accumulation in the nucleus , indicating the involvement of ubiquitination in Akt increased IKKalpha nuclear transport in response to HBx .	In addition, IKKalpha ubiquitination enhanced by HBx and Akt also contributed to the IKKalpha accumulation in the nucleus, indicating the involvement of ubiquitination in Akt increased IKKalpha nuclear transport in response to HBx.	24	30	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	26	27	28	29
AKT binds to and increases the activity of IKKalpha , which is required for NF-kappaB activation XREF_BIBR .	AKT binds to and increases the activity of IKKalpha, which is required for NF-kappaB activation XREF_BIBR.	0	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	IKKalpha	IKKalpha	IKKalpha	0	1	8	9
Activated AKT induces IKKalpha , another major downstream kinase in the TNFalpha signalling pathway [ XREF_BIBR ] .	Activated AKT induces IKKalpha, another major downstream kinase in the TNFalpha signalling pathway [XREF_BIBR].	0	8	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	IKKalpha	IKKalpha	IKKalpha	1	2	3	4
Taken together , these results suggest that the osteoblast derived TGF-beta1 acts through Akt and ERK , which in turn activates IKKalpha and beta and NF-kappaB , resulting in the activations of beta1 and beta3 integrins and contributing the migration of breast cancer cell .	Taken together, these results suggest that the osteoblast derived TGF-beta1 acts through Akt and ERK, which in turn activates IKKalpha and beta and NF-kappaB, resulting in the activations of beta1 and beta3 integrins and contributing the migration of breast cancer cell.	11	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	13	14	21	22
It has been reported that CCL5 could acts through PI3K and Akt , which in turn activates IKKalpha and beta and NF-kappaB , and contributing to the migration of human lung cancer cells [ XREF_BIBR ] , and NF-kappaB activation could promote the expression of MMP9 [ XREF_BIBR ] .	It has been reported that CCL5 could acts through PI3K and Akt, which in turn activates IKKalpha and beta and NF-kappaB, and contributing to the migration of human lung cancer cells [XREF_BIBR], and NF-kappaB activation could promote the expression of MMP9 [XREF_BIBR].	7	21	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	11	12	17	18
It has been reported that CCL5 acts through PI3K and Akt , which in turn activates IKKalpha and beta and NF-kappaB , resulting in the activation of alphavbeta3 integrin and contributing to the migration of human lung cancer cells 32 .	It has been reported that CCL5 acts through PI3K and Akt, which in turn activates IKKalpha and beta and NF-kappaB, resulting in the activation of alphavbeta3 integrin and contributing to the migration of human lung cancer cells 32.	6	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	10	11	16	17
Akt , which was previously reported to activate IKKalpha , did not participate in the PDK1 dependent IKKbeta or NF-kappaB activation .	Akt, which was previously reported to activate IKKalpha, did not participate in the PDK1 dependent IKKbeta or NF-kappaB activation.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	0	1	8	9
Akt activates IKKalpha by phosphorylation of Threonine 23 , which then phosphorylates IkappaBalpha , leading to IkappaBalpha degradation and NF-kappaB activation .	Akt activates IKKalpha by phosphorylation of Threonine 23, which then phosphorylates IkappaBalpha, leading to IkappaBalpha degradation and NF-kappaB activation.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	0	1	2	3
These results indicate that AKT may directly activate IKKalpha and IKKbeta to phosphorylate IkappaBalpha , and we confirmed by Western blot that HGF treatment of RPTEC phosphorylates IKKalpha and beta , in an AKT dependent manner , since this phosphorylation was blocked by pre-incubation with LY-294002 ( XREF_SUPPLEMENTARY ) .	These results indicate that AKT may directly activate IKKalpha and IKKbeta to phosphorylate IkappaBalpha, and we confirmed by Western blot that HGF treatment of RPTEC phosphorylates IKKalpha and beta, in an AKT dependent manner, since this phosphorylation was blocked by pre-incubation with LY-294002 (XREF_SUPPLEMENTARY).	4	10	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	IKKalpha	IKKalpha	IKKalpha	4	5	8	9
IKKalpha ubiquitination , which is enhanced by HBx and Akt , contributes to IKKalpha accumulation in the nucleus , thereby indicating the involvement of ubiquitination in the Akt increased IKKalpha nuclear transport in response to HBx XREF_BIBR .	IKKalpha ubiquitination, which is enhanced by HBx and Akt, contributes to IKKalpha accumulation in the nucleus, thereby indicating the involvement of ubiquitination in the Akt increased IKKalpha nuclear transport in response to HBx XREF_BIBR.	24	31	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	27	28	29	30
Akt also activates IkappaB kinase-alpha ( IKK-alpha ) , causing the degradation of IkappaB , which in turn activates NF-kappaB XREF_BIBR , and can also increase the transactivation potential of the RelA and p65 subunit of NF-kappaB XREF_BIBR .	Akt also activates IkappaB kinase-alpha (IKK-alpha), causing the degradation of IkappaB, which in turn activates NF-kappaB XREF_BIBR, and can also increase the transactivation potential of the RelA and p65 subunit of NF-kappaB XREF_BIBR.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IkappaB kinase-alpha	IkappaB kinase-alpha	IkappaB kinase-alpha	0	1	3	5
It was further demonstrated that YC-1 may activate the sGC/cGMP/PKG pathway to induce Ras and PI3K and Akt activation , which in turn initiates IKKalpha and beta and NF-kappaB activation XREF_BIBR .	It was further demonstrated that YC-1 may activate the sGC/cGMP/PKG pathway to induce Ras and PI3K and Akt activation, which in turn initiates IKKalpha and beta and NF-kappaB activation XREF_BIBR.	17	30	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	17	18	24	25
Li and Stark [ XREF_BIBR ] have suggested that Akt activation of IKKalpha could be upstream of the phosphorylation of p65 by IKK .	Li and Stark [XREF_BIBR] have suggested that Akt activation of IKKalpha could be upstream of the phosphorylation of p65 by IKK.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	9	10	12	13
This study shows that Akt binds to and increases the activity of IKKalpha and thereby increases p52 production in cells .	This study shows that Akt binds to and increases the activity of IKKalpha and thereby increases p52 production in cells.	4	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	4	5	12	13
Taken together , these results suggest that the BMP-2 acts through PI3K and Akt , which in turn activates IKKalpha and beta and NF-kappaB , resulting in the activations of beta1 integrin and contributing the migration of human chondrosarcoma cells .	Taken together, these results suggest that the BMP-2 acts through PI3K and Akt, which in turn activates IKKalpha and beta and NF-kappaB, resulting in the activations of beta1 integrin and contributing the migration of human chondrosarcoma cells.	9	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	13	14	19	20
Activated Akt stimulates IKKalpha activity by phosphorylating it at Thr23 .	Activated Akt stimulates IKKalpha activity by phosphorylating it at Thr23.	0	4	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	IKKalpha	IKKalpha	IKKalpha	1	2	3	4
These results provide the first evidence that TGFbeta intercepts Akt kinase activity in the nucleus to block inactivation of GSK3beta , leading to attenuation of PDGF induced CDK2 activity and DNA synthesis .	These results provide the first evidence that TGFbeta intercepts Akt kinase activity in the nucleus to block inactivation of GSK3beta, leading to attenuation of PDGF induced CDK2 activity and DNA synthesis.	9	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	CDK2	CDK2	CDK2	9	10	27	28
Maddika et al indicated that inhibitors of PI3-kinase or Akt not only inhibited CDK2 activation but also protected cells from Apoptin induced cell death , and Akt mediated activation of CDK2 was caused by direct phosphorylation as well as by the phosphorylation induced degradation of its inhibitor p27 ( Kip1 ) [ XREF_BIBR ] .	Maddika et al indicated that inhibitors of PI3-kinase or Akt not only inhibited CDK2 activation but also protected cells from Apoptin induced cell death, and Akt mediated activation of CDK2 was caused by direct phosphorylation as well as by the phosphorylation induced degradation of its inhibitor p27 (Kip1) [XREF_BIBR].	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	CDK2	CDK2	CDK2	26	27	30	31
It is interesting to note that AKT and ERK were shown to up-regulate CK1 and CDK2 activity , respectively , and DYRK1A was reported to prolong ERK activity by forming and stabilizing the RAS/B-RAF/MEK1complex .	It is interesting to note that AKT and ERK were shown to up-regulate CK1 and CDK2 activity, respectively, and DYRK1A was reported to prolong ERK activity by forming and stabilizing the RAS/B-RAF/MEK1complex.	6	16	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	CDK2	CDK2	CDK2	6	7	15	16
Akt activated CDK2 by direct phosphorylation as well as by the phosphorylation induced degradation of the inhibitor p27 ( Kip1 ) .	Akt activated CDK2 by direct phosphorylation as well as by the phosphorylation induced degradation of the inhibitor p27 (Kip1).	0	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	CDK2	CDK2	CDK2	0	1	2	3
Nonetheless , the marked hyperplasia in response to doxycycline induction of AKT that occurs despite high levels of p27 indicate that AKT may be blocking the CDK2 inhibitory function of p27 by novel mechanisms that remain to be identified .	Nonetheless, the marked hyperplasia in response to doxycycline induction of AKT that occurs despite high levels of p27 indicate that AKT may be blocking the CDK2 inhibitory function of p27 by novel mechanisms that remain to be identified.	21	28	blocking	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	CDK2	CDK2	CDK2	21	22	26	27
Apoptin phosphorylation has been proposed to be regulated by Akt activated CDK-2 and PKC kinase XREF_BIBR , XREF_BIBR , XREF_BIBR .	Apoptin phosphorylation has been proposed to be regulated by Akt activated CDK-2 and PKC kinase XREF_BIBR, XREF_BIBR, XREF_BIBR.	7	15	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	CDK-2	CDK-2	CDK-2	9	10	11	12
Akt and protein kinase B ( PKB ) XREF_BIBR , XREF_BIBR , serum and glucocorticoid induced kinase 1 ( SGK1 ) XREF_BIBR , cyclin dependent kinase 2 ( CDK2 ) XREF_BIBR and IkB kinase ( IKK ) XREF_BIBR phosphorylate Foxo proteins , resulting in their nuclear exclusion while c-Jun-N-terminal kinase ( JNK ) XREF_BIBR and mammalian sterile 20 like kinase 1 ( MST1 ) XREF_BIBR phosphorylate Foxo proteins , causing their nuclear retention .	Akt and protein kinase B (PKB) XREF_BIBR, XREF_BIBR, serum and glucocorticoid induced kinase 1 (SGK1) XREF_BIBR, cyclin dependent kinase 2 (CDK2) XREF_BIBR and IkB kinase (IKK) XREF_BIBR phosphorylate Foxo proteins, resulting in their nuclear exclusion while c-Jun-N-terminal kinase (JNK) XREF_BIBR and mammalian sterile 20 like kinase 1 (MST1) XREF_BIBR phosphorylate Foxo proteins, causing their nuclear retention.	0	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	CDK2	CDK2	CDK2	0	1	28	29
AKT and ERK were shown to up-regulate CK1 [ XREF_BIBR ] and CDK2 [ XREF_BIBR ] activity .	AKT and ERK were shown to up-regulate CK1 [XREF_BIBR] and CDK2 [XREF_BIBR] activity.	0	13	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	CDK2	CDK2	CDK2	0	1	12	13
PD-1 inhibits Skp2 by inhibiting PIK3 and Akt and Ras/MEK/ERK signaling leading to increase of p27kip1 and inhibition of Cdk2 .	PD-1 inhibits Skp2 by inhibiting PIK3 and Akt and Ras/MEK/ERK signaling leading to increase of p27kip1 and inhibition of Cdk2.	7	20	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Cdk2	Cdk2	Cdk2	7	8	19	20
As a whole , these data suggest that inhibition of either mTORC1/2 or Akt reduced the biochemical ( XREF_FIG ) and functional ( XREF_FIG ) activity of CDK2 , thus giving support to the predictions from the network model ( XREF_FIG ) .	As a whole, these data suggest that inhibition of either mTORC1/2 or Akt reduced the biochemical (XREF_FIG) and functional (XREF_FIG) activity of CDK2, thus giving support to the predictions from the network model (XREF_FIG).	8	28	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	CDK2	CDK2	CDK2	13	14	27	28
Inhibition of Akt inactivates Cdk2 and Cyclin A associated kinase activity .	Inhibition of Akt inactivates Cdk2 and Cyclin A associated kinase activity.	0	10	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Cdk2	Cdk2	Cdk2	2	3	4	5
The fact suggested that inhibitors of PI3-kinase or Akt inhibited CDK2 activation hence to protect cells from Apoptin-induce cell death [ XREF_BIBR , XREF_BIBR ] .	The fact suggested that inhibitors of PI3-kinase or Akt inhibited CDK2 activation hence to protect cells from Apoptin-induce cell death [XREF_BIBR, XREF_BIBR].	4	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	CDK2	CDK2	CDK2	8	9	10	11
Akt activation stimulated Cdk2 and Cyclin A associated kinase activation and then promoted the movement of cells into the S phase , and prolonged and unscheduled activation of Akt and Cdk2 and Cyclin-A might create a cellular disharmony which eventually led to apoptosis ( XREF_FIG ) .	Akt activation stimulated Cdk2 and Cyclin A associated kinase activation and then promoted the movement of cells into the S phase, and prolonged and unscheduled activation of Akt and Cdk2 and Cyclin-A might create a cellular disharmony which eventually led to apoptosis (XREF_FIG).	0	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Cdk2	Cdk2	Cdk2	0	1	3	4
The mechanism by which Akt or NF-kappaB inhibition diminish cyclinA or p-CDK2 in our study is unclear , but Chiron et al reported that PI3K inhibitors induced cell cycle arrest by downregulating CDK4/6 [ XREF_BIBR ] , and NF-kappaB was reported to be associated with cell cycle regulation [ XREF_BIBR ] .	The mechanism by which Akt or NF-kappaB inhibition diminish cyclinA or p-CDK2 in our study is unclear, but Chiron et al reported that PI3K inhibitors induced cell cycle arrest by downregulating CDK4/6 [XREF_BIBR], and NF-kappaB was reported to be associated with cell cycle regulation [XREF_BIBR].	4	12	diminish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	p-CDK2	p-CDK2	p-CDK2	4	5	11	12
It has been reported that p300 stability is modulated by Akt activation , and the phosphorylation at S1834 is required for this p300 stabilization .	It has been reported that p300 stability is modulated by Akt activation, and the phosphorylation at S1834 is required for this p300 stabilization.	5	11	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	p300	p300	p300	10	11	5	6
Our study provides a new insight into the molecular mechanism by which Akt promotes the transcriptional potential of p300 .	Our study provides a new insight into the molecular mechanism by which Akt promotes the transcriptional potential of p300.	12	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	p300	p300	p300	12	13	18	19
In response to upstream signaling events , AKT stimulates p300 and CBP HAT activity following AKT mediated phosphorylation of p300 and CBP at S1834 and T1871 , respectively [ XREF_BIBR ] .	In response to upstream signaling events, AKT stimulates p300 and CBP HAT activity following AKT mediated phosphorylation of p300 and CBP at S1834 and T1871, respectively [XREF_BIBR].	7	24	stimulates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	AKT	AKT	akt	p300	AKT mediated phosphorylation of p300 and CBP at S1834	p300	7	8	19	20
We have previously found that Akt positively regulates p300 function in proliferating cells XREF_BIBR .	We have previously found that Akt positively regulates p300 function in proliferating cells XREF_BIBR.	5	9	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	p300	p300	p300	5	6	8	9
It will therefore be interesting to determine whether PI3K-AKT signalling could activate gene enhancer elements by inhibiting EZH2 and activating p300 to switch H3K27 from a tri methylated state to an acetylated state ( XREF_FIG ) .	It will therefore be interesting to determine whether PI3K-AKT signalling could activate gene enhancer elements by inhibiting EZH2 and activating p300 to switch H3K27 from a tri methylated state to an acetylated state (XREF_FIG).	8	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	p300	p300	p300	8	9	20	21
Because TGF-beta induces PAI-1 expression through association of Smad3 with CBP as well as Akt activated p300 in rat MCs , TGF-beta signaling may generally involve these histone modifying proteins ( p300 and CBP ) that are activated by Akt to enhance chromatin remodeling and target gene expression .	Because TGF-beta induces PAI-1 expression through association of Smad3 with CBP as well as Akt activated p300 in rat MCs, TGF-beta signaling may generally involve these histone modifying proteins (p300 and CBP) that are activated by Akt to enhance chromatin remodeling and target gene expression.	2	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	p300	p300	p300	14	15	16	17
In MCs , miR-192 is induced initially through Smad3 signaling and then through a long lasting epigenetic mechanism involving Ets1 and histone H3 acetylation by Akt activated p300 , and this is consistent with findings in the glomeruli from db/db mice [ XREF_BIBR ] .	In MCs, miR-192 is induced initially through Smad3 signaling and then through a long lasting epigenetic mechanism involving Ets1 and histone H3 acetylation by Akt activated p300, and this is consistent with findings in the glomeruli from db/db mice [XREF_BIBR].	18	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	p300	p300	p300	25	26	27	28
Thus , inhibition of AKT might attenuate CBP and p300 activity , resulting in reduction of transactivation of ETS1 and ETS2 target genes .	Thus, inhibition of AKT might attenuate CBP and p300 activity, resulting in reduction of transactivation of ETS1 and ETS2 target genes.	2	10	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	p300	p300	p300	4	5	9	10
Upon EGF stimulation , AKT phosphorylated and activated the kinase PIKfyve , which promotes vesicle trafficking to lysosomes .	Upon EGF stimulation, AKT phosphorylated and activated the kinase PIKfyve, which promotes vesicle trafficking to lysosomes.	4	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT phosphorylated	akt	PIKfyve	PIKfyve	pikfyve	4	5	10	11
Incubation of AKT with PIKfyve in vitro increases PIKfyve activity towards PI3P to generate PI ( 3,5 ) P 2 , suggesting AKT activates PIKfyve .	Incubation of AKT with PIKfyve in vitro increases PIKfyve activity towards PI3P to generate PI (3,5) P 2, suggesting AKT activates PIKfyve.	0	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	PIKfyve	PIKfyve	PIKfyve	2	3	24	25
To determine if AKT directly regulates PIKfyve , we tested the effect of AKT inhibition or mutation of the AKT phosphorylation sites on the in vitro kinase activity of PIKfyve by immuno precipitating the PIKfyve , ArPIKfyve , and SAC3 complex from cells stimulated with or without EGF and pre-treated with DMSO or AKTVIII .	To determine if AKT directly regulates PIKfyve, we tested the effect of AKT inhibition or mutation of the AKT phosphorylation sites on the in vitro kinase activity of PIKfyve by immuno precipitating the PIKfyve, ArPIKfyve, and SAC3 complex from cells stimulated with or without EGF and pre-treated with DMSO or AKTVIII.	3	7	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	PIKfyve	PIKfyve	PIKfyve	3	4	6	7
Taken together with the observations that AKT regulates PIKfyve phosphorylation and PIKfyve activity in cells these data suggest AKT directly activates the phosphoinositide kinase activity of PIKfyve .	Taken together with the observations that AKT regulates PIKfyve phosphorylation and PIKfyve activity in cells these data suggest AKT directly activates the phosphoinositide kinase activity of PIKfyve.	18	27	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	PIKfyve	PIKfyve	PIKfyve	18	19	26	27
Therefore , it is possible that Akt could directly regulate PDE3B in an insulin independent manner .	Therefore, it is possible that Akt could directly regulate PDE3B in an insulin independent manner.	6	11	directly regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	PDE3B	PDE3B	PDE3B	6	7	10	11
It is well known that activation of PDE3B by PKB or PKA can modulate insulin signaling in adipocytes [ XREF_BIBR ] .	It is well known that activation of PDE3B by PKB or PKA can modulate insulin signaling in adipocytes [XREF_BIBR].	5	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PKB	PKB	PKB	PDE3B	PDE3B	PDE3B	9	10	7	8
While our data supports a model whereby mTORC2 activity controls Akt mediated activation of PDE3B by insulin , this remains to be established .	While our data supports a model whereby mTORC2 activity controls Akt mediated activation of PDE3B by insulin, this remains to be established.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	PDE3B	PDE3B	PDE3B	10	11	14	15
PDE3B and possibly PDE3A can also be activated by PI3K and PKB signaling triggered by insulin , insulin growth factor ( IGF-1 ) , and leptin .	PDE3B and possibly PDE3A can also be activated by PI3K and PKB signaling triggered by insulin, insulin growth factor (IGF-1), and leptin.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKB	PKB	PKB	PDE3B	PDE3B	PDE3B	11	12	0	1
PDE3B itself is activated by Akt phosphorylation downstream of insulin signaling [ XREF_BIBR ] .	PDE3B itself is activated by Akt phosphorylation downstream of insulin signaling [XREF_BIBR].	0	7	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	PDE3B	PDE3B	pde3b	5	6	0	1
XREF_BIBR - XREF_BIBR Once activated , AKT can target downstream modulators of apoptosis such as GSK3beta , IRS-1 ( insulin receptor substrate-1 ) , PDE-3B ( phosphodiesterase-3B ) , BAD , caspase-9 , Forkhead proteins , NF-kappaB , mTOR , nitric oxide synthase ( NOS ) , Raf protein kinase , and BRCA1 .	XREF_BIBR - XREF_BIBR Once activated, AKT can target downstream modulators of apoptosis such as GSK3beta, IRS-1 (insulin receptor substrate-1), PDE-3B (phosphodiesterase-3B), BAD, caspase-9, Forkhead proteins, NF-kappaB, mTOR, nitric oxide synthase (NOS), Raf protein kinase, and BRCA1.	6	26	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	PDE-3B	PDE-3B	PDE-3B	6	7	24	25
ARK5 enhanced the invasive and metastatic potential of MDA-MB-231 cells under regulation by Akt .	ARK5 enhanced the invasive and metastatic potential of MDA-MB-231 cells under regulation by Akt.	0	14	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ARK5	ARK5	ARK5	13	14	0	1
It is possible that Akt activated ARK5 is involved in the negative regulatory feedback loop for the ASK1-MEK-MAPK signal transduction pathway .	It is possible that Akt activated ARK5 is involved in the negative regulatory feedback loop for the ASK1-MEK-MAPK signal transduction pathway.	4	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	ARK5	ARK5	ARK5	4	5	6	7
Akt dependent phosphorylation at Ser 600 can induce ARK5 activation .	Akt dependent phosphorylation at Ser 600 can induce ARK5 activation.	0	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt dependent phosphorylation at Ser 600	akt	ARK5	ARK5	ark5	0	1	8	9
In addition , NUAK1 enhanced the invasive and metastatic potential of breast cancer cells under regulation by Akt .	In addition, NUAK1 enhanced the invasive and metastatic potential of breast cancer cells under regulation by Akt.	3	18	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	NUAK1	NUAK1	NUAK1	17	18	3	4
Since NUAK1 activation by AKT is involved in driving cell cycle progression caused by loss of PTEN , loss of NUAK1 function would directly reduce cell cycle progression .	Since NUAK1 activation by AKT is involved in driving cell cycle progression caused by loss of PTEN, loss of NUAK1 function would directly reduce cell cycle progression.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	NUAK1	NUAK1	NUAK1	4	5	1	2
Estrogen activated the AKT pathway in BRCA1 deficient tumor cells independent of ER , and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression .	Estrogen activated the AKT pathway in BRCA1 deficient tumor cells independent of ER, and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression.	18	29	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	BRCA1	BRCA1	BRCA1	18	19	26	27
In this study , we show that tamoxifen resistant breast cancer cells are resistant to DNA damaging chemotherapy because of upregulated BARD1 and BRCA1 , which is caused by activated PI3K and AKT pathway .	In this study, we show that tamoxifen resistant breast cancer cells are resistant to DNA damaging chemotherapy because of upregulated BARD1 and BRCA1, which is caused by activated PI3K and AKT pathway.	20	33	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	BRCA1	BRCA1	BRCA1	32	33	23	24
AKT activation also appears to support nuclear localization of BRCA1 , and co-expression of activated AKT with intact BRCA1 decreases radiation sensitivity , suggesting this interaction has functional consequences for BRCA1 function in DNA repair .	AKT activation also appears to support nuclear localization of BRCA1, and co-expression of activated AKT with intact BRCA1 decreases radiation sensitivity, suggesting this interaction has functional consequences for BRCA1 function in DNA repair.	0	10	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	BRCA1	BRCA1	BRCA1	0	1	9	10
These findings suggest that BRCA1 regulates Akt signaling and the PI3K and Akt pathway modulates the ability of BRCA1 to repress ER-alpha , in part through serine phosphorylation events in the activation function-1 domain of ER-alpha .	These findings suggest that BRCA1 regulates Akt signaling and the PI3K and Akt pathway modulates the ability of BRCA1 to repress ER-alpha, in part through serine phosphorylation events in the activation function-1 domain of ER-alpha.	6	19	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	BRCA1	BRCA1	BRCA1	6	7	18	19
First , western blot analysis suggests higher levels of AKT activation in both BRCA1 and BRCA2 mutant cell lines at baseline prior to any drug treatment .	First, western blot analysis suggests higher levels of AKT activation in both BRCA1 and BRCA2 mutant cell lines at baseline prior to any drug treatment.	9	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	BRCA1	BRCA1	BRCA1	9	10	13	14
Both AKT and BRCA1 regulate the cell-cycle and genomic stability through the CHK1 pathway , and BRCA1 regulates estrogen receptor-alpha ( ER ) activity in a PI3K and AKT dependent manner , strongly supporting the notion that the AKT pathway contributes to BRCA1 mediated tumorigenesis .	Both AKT and BRCA1 regulate the cell-cycle and genomic stability through the CHK1 pathway, and BRCA1 regulates estrogen receptor-alpha (ER) activity in a PI3K and AKT dependent manner, strongly supporting the notion that the AKT pathway contributes to BRCA1 mediated tumorigenesis.	38	43	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	BRCA1	BRCA1	BRCA1	38	39	42	43
AKT activation also appears to support nuclear localization of BRCA1 , and co-expression of activated AKT with BRCA1 decreases radiation sensitivity , suggesting this interaction has functional consequences for BRCA1 ' s role in DNA repair .	AKT activation also appears to support nuclear localization of BRCA1, and co-expression of activated AKT with BRCA1 decreases radiation sensitivity, suggesting this interaction has functional consequences for BRCA1 's role in DNA repair.	0	10	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	BRCA1	BRCA1	BRCA1	0	1	9	10
Studies have reported that DNMT1 gene expression was controlled via transcription factor Fli-1 in erythroleukemia cells XREF_BIBR , that DNMT1 expression was increased through the JAK-STAT pathway in malignant T lymphocytes XREF_BIBR , and that AKT activity inhibited DNMT1 degradation in multiple cell lines XREF_BIBR .	Studies have reported that DNMT1 gene expression was controlled via transcription factor Fli-1 in erythroleukemia cells XREF_BIBR, that DNMT1 expression was increased through the JAK-STAT pathway in malignant T lymphocytes XREF_BIBR, and that AKT activity inhibited DNMT1 degradation in multiple cell lines XREF_BIBR.	35	39	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	DNMT1	DNMT1	DNMT1	35	36	38	39
Therefore , drugs targeting DNMT protein inactivation and depletion , such as MDM2 , AKT and CDKs inhibitors may prove to be a good therapeutic strategy for cancer treatment .	Therefore, drugs targeting DNMT protein inactivation and depletion, such as MDM2, AKT and CDKs inhibitors may prove to be a good therapeutic strategy for cancer treatment.	4	17	inactivation	Negative_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	AKT	AKT	AKT	DNMT	DNMT	DNMT	14	15	4	5
Sun and associates have reported that Akt enhances DNMT1 protein stability by inhibition of its ubiquitin-proteasome mediated degradation [ XREF_BIBR ] .	Sun and associates have reported that Akt enhances DNMT1 protein stability by inhibition of its ubiquitin-proteasome mediated degradation [XREF_BIBR].	6	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	DNMT1	DNMT1	DNMT1	6	7	8	9
At the post-transcriptional level RTKs could act by controlling AKT phosphorylation , which is found to enhance DNMT1 protein stabilization .	At the post-transcriptional level RTKs could act by controlling AKT phosphorylation, which is found to enhance DNMT1 protein stabilization.	9	19	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT phosphorylation	akt	DNMT1	DNMT1	dnmt1	9	10	17	18
As methylation at Lys142 promotes DNMT1 degradation by the proteasome , AKT phosphorylation increases the stability of DNMT1 56 .	As methylation at Lys142 promotes DNMT1 degradation by the proteasome, AKT phosphorylation increases the stability of DNMT1 56.	11	18	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT phosphorylation	akt	DNMT1	DNMT1	dnmt1	11	12	17	18
In addition , activation of Akt may indirectly prolong the half-life of DNMT1 [ XREF_BIBR , XREF_BIBR ] .	In addition, activation of Akt may indirectly prolong the half-life of DNMT1 [XREF_BIBR, XREF_BIBR].	3	16	prolong	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	DNMT1	DNMT1	DNMT1	5	6	12	13
Constitutively active Akt ( CA-Akt ) rescues mahanine mediated DNMT1 and DNMT3B degradation in BPH1 cells .	Constitutively active Akt (CA-Akt) rescues mahanine mediated DNMT1 and DNMT3B degradation in BPH1 cells.	1	12	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	DNMT1	DNMT1	DNMT1	2	3	9	10
These data confirm that DNMT stability is mediated by Akt activity and a disruption of Akt activation decreases DNMT levels in prostate cancer cells .	These data confirm that DNMT stability is mediated by Akt activity and a disruption of Akt activation decreases DNMT levels in prostate cancer cells.	4	10	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	DNMT	DNMT	DNMT	9	10	4	5
However , inhibition of AKT by specific inhibitors ( AKTi ) reduced but did not eliminate the characteristic phospho-bands of BMI1 in ovarian cancer cells , CP20 and OV90 .	However, inhibition of AKT by specific inhibitors (AKTi) reduced but did not eliminate the characteristic phospho-bands of BMI1 in ovarian cancer cells, CP20 and OV90.	2	21	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	BMI1	BMI1	BMI1	4	5	20	21
While overexpression of PTEN alone did not affect AKT activation in DU145 cells , which is consistent with other publications [ XREF_BIBR , XREF_BIBR ] , ectopic PTEN reversed the increase in AKT activation observed in DU145 cells overexpressing BMI1 ( Fig XREF_FIG ) .	While overexpression of PTEN alone did not affect AKT activation in DU145 cells, which is consistent with other publications [XREF_BIBR, XREF_BIBR], ectopic PTEN reversed the increase in AKT activation observed in DU145 cells overexpressing BMI1 (Fig XREF_FIG).	32	42	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	BMI1	BMI1	BMI1	32	33	39	40
Indeed , we have recently demonstrated that lower ( more tolerated ) doses of AKT targeted therapy could target and radiosensitize glioblastoma TICs overexpressing BMI-1 .	Indeed, we have recently demonstrated that lower (more tolerated) doses of AKT targeted therapy could target and radiosensitize glioblastoma TICs overexpressing BMI-1.	12	25	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	BMI-1	BMI-1	BMI-1	14	15	24	25
We have previously reported that p16 and AKT are potential cancer-relevant targets of BMI1 and Mel-18 in human fibroblasts and breast cancer cells respectively .	We have previously reported that p16 and AKT are potential cancer-relevant targets of BMI1 and Mel-18 in human fibroblasts and breast cancer cells respectively.	5	15	are potential cancer-relevant targets	Positive_activation_copula_1	Positive_activation	Positive_activation	AKT	AKT	AKT	BMI1	BMI1	BMI1	7	8	13	14
Our data also demonstrate a potentially novel mechanism to understand UCP2 ' s tumor promoting role , which is through the AKT dependent activation of PFKFB2 and thereby , the metabolic shift to glycolysis ( the Warburg effect ) .	Our data also demonstrate a potentially novel mechanism to understand UCP2 's tumor promoting role, which is through the AKT dependent activation of PFKFB2 and thereby, the metabolic shift to glycolysis (the Warburg effect).	21	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	PFKFB2	PFKFB2	PFKFB2	21	22	25	26
AKT activation upregulates the GATA-1 and FOXO3 transcriptional pathways with resulting inhibition of apoptosis , modulation of cell cycle and enhanced maturation of erythroid cells .	AKT activation upregulates the GATA-1 and FOXO3 transcriptional pathways with resulting inhibition of apoptosis, modulation of cell cycle and enhanced maturation of erythroid cells.	0	8	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	GATA-1	GATA-1	GATA-1	0	1	4	5
GATA1 , which is a key regulator of erythroid development essential for the survival of erythroid precursors and their terminal differentiation , is targeted by PI3K and AKT for phosphorylation and activation .	GATA1, which is a key regulator of erythroid development essential for the survival of erythroid precursors and their terminal differentiation, is targeted by PI3K and AKT for phosphorylation and activation.	0	28	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	GATA1	GATA1	GATA1	27	28	0	1
AKT signaling promotes the attachment of HK1 and HK2 to the mitochondrial outer membrane via the voltage dependent anion channel ( VDAC ) [ XREF_BIBR ] .	AKT signaling promotes the attachment of HK1 and HK2 to the mitochondrial outer membrane via the voltage dependent anion channel (VDAC) [XREF_BIBR].	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	HK1	HK1	HK1	0	1	6	7
We further explored the mechanism of AKT mediated HK1 regulation and found lower HK1 ubiquitination levels in LINC00470 transfected cells treated with MG132 , and a restoration experiment was performed by knocking down AKT .	We further explored the mechanism of AKT mediated HK1 regulation and found lower HK1 ubiquitination levels in LINC00470 transfected cells treated with MG132, and a restoration experiment was performed by knocking down AKT.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	HK1	HK1	HK1	6	7	8	9
In addition to its roles in stimulating glucose transport , Akt can also promote hexokinase1 and phosphofructokinase activity ; these are two important enzymes in the production of glycolytic intermediates [ XREF_BIBR - XREF_BIBR ] .	In addition to its roles in stimulating glucose transport, Akt can also promote hexokinase1 and phosphofructokinase activity; these are two important enzymes in the production of glycolytic intermediates [XREF_BIBR - XREF_BIBR].	10	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	hexokinase1	hexokinase1	hexokinase1	10	11	14	15
By using the panel of Akt knockdown oligonucleotides and the control , our results suggested that inhibition of Akt suppressed in vitro cell proliferation in both PTPRG-down-regulated HONE1 and HK1 cells .	By using the panel of Akt knockdown oligonucleotides and the control, our results suggested that inhibition of Akt suppressed in vitro cell proliferation in both PTPRG-down-regulated HONE1 and HK1 cells.	16	30	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	HK1	HK1	HK1	18	19	29	30
Hence , this study has further strengthened the significance of the MDM2-p53 pathway on tumorigenesis through a novel link of Akt mediated CSN6 activation .	Hence, this study has further strengthened the significance of the MDM2-p53 pathway on tumorigenesis through a novel link of Akt mediated CSN6 activation.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	CSN6	CSN6	CSN6	20	21	22	23
We previously showed that S60 of CSN6 has an Akt phosphorylation site [ XREF_BIBR ] and that Akt increases the steady-state expression of CSN6 [ XREF_BIBR ] , which in turn will be translating into E6AP stabilization .	We previously showed that S60 of CSN6 has an Akt phosphorylation site [XREF_BIBR] and that Akt increases the steady-state expression of CSN6 [XREF_BIBR], which in turn will be translating into E6AP stabilization.	17	25	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	CSN6	CSN6	CSN6	17	18	23	24
Our mechanistic studies showed that EGF and Akt mediated CSN6 S60 phosphorylation and subse quent stabilization of E6AP thereby causing p53 downregulation and promoting cell proliferation , cell transformation as well as tumorigenesis .	Our mechanistic studies showed that EGF and Akt mediated CSN6 S60 phosphorylation and subse quent stabilization of E6AP thereby causing p53 downregulation and promoting cell proliferation, cell transformation as well as tumorigenesis.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	CSN6	CSN6	CSN6	7	8	9	10
For instance , Akt can positively regulate CSN6 by phosphorylation .	For instance, Akt can positively regulate CSN6 by phosphorylation.	3	8	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	CSN6	CSN6	CSN6	3	4	7	8
PFKFB3 could be upregulated by rasfonin and downregulated by Akt inhibition , whereas PFKFB3 deprivation attenuated rasfonin induced autophagic fluxes .	PFKFB3 could be upregulated by rasfonin and downregulated by Akt inhibition, whereas PFKFB3 deprivation attenuated rasfonin induced autophagic fluxes.	0	10	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	PFKFB3	PFKFB3	PFKFB3	9	10	0	1
PFKFB3 is activated by Akt [ XREF_BIBR ] , and more recently was shown to be a key regulator of angiogenesis [ XREF_BIBR , XREF_BIBR ] .	PFKFB3 is activated by Akt [XREF_BIBR], and more recently was shown to be a key regulator of angiogenesis [XREF_BIBR, XREF_BIBR].	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	PFKFB3	PFKFB3	PFKFB3	4	5	0	1
PI3K-Akt pathway inhibitors , Akti-1/2 and LY294002 , reduced PFKFB3 gene induction by PHA , as well as Fru-2 ,6-P 2 and lactate production .	PI3K-Akt pathway inhibitors, Akti-1/2 and LY294002, reduced PFKFB3 gene induction by PHA, as well as Fru-2,6-P 2 and lactate production.	0	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	PFKFB3	PFKFB3	PFKFB3	0	1	9	10
In the refed state , hepatic Clk2 is induced by insulin and Akt signaling , where Clk2 then phosphorylates the SR domain on PGC-1alpha .	In the refed state, hepatic Clk2 is induced by insulin and Akt signaling, where Clk2 then phosphorylates the SR domain on PGC-1alpha.	5	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Clk2	Clk2	Clk2	12	13	6	7
Moreover , as Clk2 is induced by insulin and Akt in the refed state suggests that Clk2 may be an important component of the physiologic refed response by suppressing gluconeogenesis .	Moreover, as Clk2 is induced by insulin and Akt in the refed state suggests that Clk2 may be an important component of the physiologic refed response by suppressing gluconeogenesis.	3	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Clk2	Clk2	Clk2	9	10	3	4
In addition , we provide evidences that Akt kinase activity is important for Akt to enhance the protein stability and transcriptional activity of Dlx5 .	In addition, we provide evidences that Akt kinase activity is important for Akt to enhance the protein stability and transcriptional activity of Dlx5.	7	24	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Dlx5	Dlx5	Dlx5	7	8	23	24
Akt activation increases protein stability , osteogenic activity , and transcriptional activity of Osx and Dlx5 XREF_BIBR , revealing that Osx regulates bone formation through different signaling pathways , including a novel mechanism involving Akt during osteoblast differentiation .	Akt activation increases protein stability, osteogenic activity, and transcriptional activity of Osx and Dlx5 XREF_BIBR, revealing that Osx regulates bone formation through different signaling pathways, including a novel mechanism involving Akt during osteoblast differentiation.	0	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Dlx5	Dlx5	Dlx5	0	1	15	16
Blockade of the Akt and phosphoinositide 3-kinase ( PI3-kinase ) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce alpha-SMA , ezrin , paxillin , and moesin and to promote matrix contraction .	Blockade of the Akt and phosphoinositide 3-kinase (PI3-kinase) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce alpha-SMA, ezrin, paxillin, and moesin and to promote matrix contraction.	0	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ezrin	ezrin	ezrin	3	4	24	25
Taken together , Akt activated Ezrin Tyr353 and NF-kappaB in EGF treated TSCC cells .	Taken together, Akt activated Ezrin Tyr353 and NF-kappaB in EGF treated TSCC cells.	3	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Ezrin	Ezrin	Ezrin	3	4	5	6
Epithelial-mesenchymal transition induced by EGF is mainly due to Akt mediated activation of Ezrin Tyr353 and NF-kappaB .	Epithelial-mesenchymal transition induced by EGF is mainly due to Akt mediated activation of Ezrin Tyr353 and NF-kappaB.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	Ezrin	Ezrin	Ezrin	9	10	13	14
Thus , whereas VEGF does not stimulate eNOS phosphorylation in the absence of Akt1 via residual Akt2 in mouse lung endothelial cells , we clearly show that insulin mediated activation of Akt2 is sufficient to activate eNOS in the vasculature .	Thus, whereas VEGF does not stimulate eNOS phosphorylation in the absence of Akt1 via residual Akt2 in mouse lung endothelial cells, we clearly show that insulin mediated activation of Akt2 is sufficient to activate eNOS in the vasculature.	27	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt2	insulin mediated activation of Akt2	akt2	eNOS	eNOS	enos	31	32	36	37
In conclusion , global null deletion of Ceacam1 caused an increase in blood pressure with increased RAS activation together with upregulation of PRR via PI3K-Akt activation of CREB-1 , ATF1 , ATF2 and NF-kappaB p65 transcription factors .	In conclusion, global null deletion of Ceacam1 caused an increase in blood pressure with increased RAS activation together with upregulation of PRR via PI3K-Akt activation of CREB-1, ATF1, ATF2 and NF-kappaB p65 transcription factors.	24	36	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	CREB-1	CREB-1	CREB-1	24	25	27	28
We further established that PI3K and Akt induced CREB-1 activation lead to enhanced MMP-9 expression which was likely involved in reduced FN accumulation by enhancing degradation of FN .	We further established that PI3K and Akt induced CREB-1 activation lead to enhanced MMP-9 expression which was likely involved in reduced FN accumulation by enhancing degradation of FN.	4	10	induced	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	CREB-1	CREB-1	CREB-1	6	7	8	9
Thus , PI ( 3,4,5 ) P3 and B23 complex and nuclear Akt effectors might coordinately mediate PIKE and nuclear PI3K signaling in promoting cell survival by NGF .	Thus, PI (3,4,5) P3 and B23 complex and nuclear Akt effectors might coordinately mediate PIKE and nuclear PI3K signaling in promoting cell survival by NGF.	12	21	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	PIKE	PIKE	PIKE	12	13	17	18
It is known that GGAP2 can modulate Akt activity but it is possible that Akt can also modulate the activity of GGAP2 .	It is known that GGAP2 can modulate Akt activity but it is possible that Akt can also modulate the activity of GGAP2.	14	22	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	GGAP2	GGAP2	GGAP2	14	15	21	22
To determine if Akt can modulate the GTPase activity of GGAP2 , we carried out immunoprecipitation with lysates from 293T cells overexpressing Flag tagged vector , wild-type and S629A GGAP2 incubated with GTP conjugated agarose beads followed by Western blot using anti-Flag antibody .	To determine if Akt can modulate the GTPase activity of GGAP2, we carried out immunoprecipitation with lysates from 293T cells overexpressing Flag tagged vector, wild-type and S629A GGAP2 incubated with GTP conjugated agarose beads followed by Western blot using anti-Flag antibody.	3	11	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	GGAP2	GGAP2	GGAP2	3	4	10	11
Recent findings confirmed that AKT can promote stabilization of MDM4 via a post-transcriptional mechanism [ XREF_BIBR ] .	Recent findings confirmed that AKT can promote stabilization of MDM4 via a post-transcriptional mechanism [XREF_BIBR].	4	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM4	MDM4	MDM4	4	5	9	10
Further , Akt stimulates Osx dependent activation of the Oc , Alp and Bsp promoters in transfection assays , indicating that phophorylation by Akt increases protein stability and Osx activity during osteoblast differentiation [ XREF_BIBR ] .	Further, Akt stimulates Osx dependent activation of the Oc, Alp and Bsp promoters in transfection assays, indicating that phophorylation by Akt increases protein stability and Osx activity during osteoblast differentiation [XREF_BIBR].	2	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Osx	Osx	Osx	2	3	4	5
Akt3 Promotes P-body Localization of Ago2 .	Akt3 Promotes P-body Localization of Ago2.	0	6	Promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt3	Akt3	Akt3	Ago2	Ago2	Ago2	0	1	5	6
Through the literatures we found that PDK1 may activate AKT2 phosphorylation XREF_BIBR and the anti-apoptotic protein XIAP can be activated by AKT2 XREF_BIBR .	Through the literatures we found that PDK1 may activate AKT2 phosphorylation XREF_BIBR and the anti-apoptotic protein XIAP can be activated by AKT2 XREF_BIBR.	13	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT2	AKT2	AKT2	XIAP	XIAP	XIAP	21	22	16	17
Our data suggest that AKT phosphorylation causes a fraction of ALY and REF to bind more tightly in complexes at speckled domains .	Our data suggest that AKT phosphorylation causes a fraction of ALY and REF to bind more tightly in complexes at speckled domains.	4	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT phosphorylation	akt	ALY	ALY	aly	4	5	10	11
MK2206 , a selective inhibitor of Akt , abolished the neuroprotective effects of MB , inhibited the phosphorylation of Akt and prevented the nuclear localization of MEF2D .	MK2206, a selective inhibitor of Akt, abolished the neuroprotective effects of MB, inhibited the phosphorylation of Akt and prevented the nuclear localization of MEF2D.	4	27	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt, abolished the neuroprotective effects of MB, inhibited the phosphorylation of Akt	akt	MEF2D	MEF2D	mef2d	6	7	26	27
Specifically , AKT inhibition or genetic interference with PDK-1-mediated AKT activation prevents the downregulation of FOXO target genes encoding proteins important for naive CD8 T cell trafficking : L-selectin ( CD62L ) , KLF2 , CC motif chemokine receptor 7 ( CCR7 ) , and sphingosine-1 phosphate receptor 1 ( S1P1 ) .	Specifically, AKT inhibition or genetic interference with PDK-1-mediated AKT activation prevents the downregulation of FOXO target genes encoding proteins important for naive CD8 T cell trafficking : L-selectin (CD62L), KLF2, CC motif chemokine receptor 7 (CCR7), and sphingosine-1 phosphate receptor 1 (S1P1).	2	51	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	S1P1	S1P1	S1P1	2	3	50	51
PKC and Akt can modulate the anti-apoptotic function of PEA-15 through phosphorylation [ XREF_BIBR ] .	PKC and Akt can modulate the anti-apoptotic function of PEA-15 through phosphorylation [XREF_BIBR].	0	10	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	PEA-15	PEA-15	PEA-15	2	3	9	10
The Drosophila melanogaster caspase-9 homolog Dronc is activated by Dark , D. melanogaster Apaf-1 homolog XREF_BIBR , XREF_BIBR , which forms the fly apoptosome in the presence of dATP 25 .	The Drosophila melanogaster caspase-9 homolog Dronc is activated by Dark, D. melanogaster Apaf-1 homolog XREF_BIBR, XREF_BIBR, which forms the fly apoptosome in the presence of dATP 25.	3	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	13	14	3	4
Released Cyt c in cytosol initiates the assembly of apoptosome by binding with Apaf 1 , which in turn activates caspase 9 .	Released Cyt c in cytosol initiates the assembly of apoptosome by binding with Apaf 1, which in turn activates caspase 9.	11	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf 1	Apaf 1	Apaf 1	caspase 9	caspase 9	caspase 9	13	15	20	22
Caspase-9 , a mitochondria mediated initiation caspase , is directly activated by Apaf-1 and cytochrome c and triggers activation of execution caspases 3 , 6 , and 7 , leading to DNA fragmentation and cell death .	Caspase-9, a mitochondria mediated initiation caspase, is directly activated by Apaf-1 and cytochrome c and triggers activation of execution caspases 3, 6, and 7, leading to DNA fragmentation and cell death.	0	17	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	Caspase-9	Caspase-9	Caspase-9	12	13	0	1
Ultimately it may result in the release of apoptotic proteins such as cyto-c , Apaf-1 which trigger caspase-9 activation .	Ultimately it may result in the release of apoptotic proteins such as cyto-c, Apaf-1 which trigger caspase-9 activation.	12	18	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	14	15	17	18
For example , cytochrome c transfers electrons between complex III and IV in the mitochondrial respiratory chain , but when released from mitochondria , cytochrome c activates the mammalian Apaf-1 apoptosome , an oligomeric structure that activates caspase-9 to kill cells [ XREF_BIBR , XREF_BIBR ] .	For example, cytochrome c transfers electrons between complex III and IV in the mitochondrial respiratory chain, but when released from mitochondria, cytochrome c activates the mammalian Apaf-1 apoptosome, an oligomeric structure that activates caspase-9 to kill cells [XREF_BIBR, XREF_BIBR].	29	38	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	29	30	37	38
As explained in the context of XREF_FIG , bistability requires that XIAP binds to and inhibits Apaf1 activated Casp9 upon weak stimulation , so that low Casp3 activity can be maintained .	As explained in the context of XREF_FIG, bistability requires that XIAP binds to and inhibits Apaf1 activated Casp9 upon weak stimulation, so that low Casp3 activity can be maintained.	15	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Apaf1	Apaf1	Apaf1	Casp9	Casp9	Casp9	16	17	18	19
During stress induced apoptosis , the initiator caspase-9 is activated by the Apaf-1 apoptosome and must remain bound to retain significant catalytic activity .	During stress induced apoptosis, the initiator caspase-9 is activated by the Apaf-1 apoptosome and must remain bound to retain significant catalytic activity.	5	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	12	13	7	8
Cytochrome c complexed with Apaf-1 activates caspase 9 , which leads to the activation of downstream caspases [ XREF_BIBR ] .	Cytochrome c complexed with Apaf-1 activates caspase 9, which leads to the activation of downstream caspases [XREF_BIBR].	2	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase 9	caspase 9	caspase 9	4	5	6	8
The results that knockdown of Apaf-1 completely abolished activation of caspase-9 and other caspases , as well as the cleavage of PARP , clearly indicate that PSAP induced caspase-9 activation is mediated by the Apaf-1-cytochrome c complex .	The results that knockdown of Apaf-1 completely abolished activation of caspase-9 and other caspases, as well as the cleavage of PARP, clearly indicate that PSAP induced caspase-9 activation is mediated by the Apaf-1-cytochrome c complex.	3	13	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	5	6	10	11
Once cytochrome c is released into the cytosol , initiator caspase-9 is activated by apoptotic protease activating factor-1 , or APAF .	Once cytochrome c is released into the cytosol, initiator caspase-9 is activated by apoptotic protease activating factor-1, or APAF.	9	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apoptotic protease activating factor-1	apoptotic protease activating factor-1	apoptotic protease activating factor-1	caspase-9	caspase-9	caspase-9	14	18	10	11
Initial caspase-9 was cleaved at 16 hours after PEA treatment , suggesting that caspase-9 may be activated by the increase of Apaf-1 and E2F-1 .	Initial caspase-9 was cleaved at 16 hours after PEA treatment, suggesting that caspase-9 may be activated by the increase of Apaf-1 and E2F-1.	13	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	21	22	13	14
Cytoplasmic cytochrome C ( Cyc ) and apoptotic protease activating factor 1 ( Apaf-1 ) form a heptameric apoptotic complex that binds to , cleaves , and thereby activates the caspase-9 zymogen .	Cytoplasmic cytochrome C (Cyc) and apoptotic protease activating factor 1 (Apaf-1) form a heptameric apoptotic complex that binds to, cleaves, and thereby activates the caspase-9 zymogen.	8	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	13	14	30	31
In contrast , the WT caspase-9 was activated by Apaf-1 in a concentration dependent manner ( XREF_FIG A , lanes 1-4 ) .	In contrast, the WT caspase-9 was activated by Apaf-1 in a concentration dependent manner (XREF_FIG A, lanes 1-4).	3	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	9	10	5	6
Overexpression of Apaf-1 in melanoma , leukemia , and cervical cancer cells resulted in activation of caspase-9 indicating that apoptosome function was restored .	Overexpression of Apaf-1 in melanoma, leukemia, and cervical cancer cells resulted in activation of caspase-9 indicating that apoptosome function was restored.	0	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Apaf-1	Overexpression of Apaf-1	apaf-1	caspase-9	caspase-9	caspase-9	2	3	16	17
Bcl-xL also interacts with apoptotic protease activating factor 1 ( Apaf-1 ) in the cytosol and inhibits the Apaf-1 dependent activation of caspase-9 [ XREF_BIBR ] .	Bcl-xL also interacts with apoptotic protease activating factor 1 (Apaf-1) in the cytosol and inhibits the Apaf-1 dependent activation of caspase-9 [XREF_BIBR].	18	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	18	19	22	23
Vpr induced release of cytochrome c into the cytosol facilitates aggregation of the apoptosome , consisting of cytochrome c , procaspase-9 , and Apaf-1 and subsequent sequential activation of caspase-9 and caspase-3 , eventually leading to apoptosis .	Vpr induced release of cytochrome c into the cytosol facilitates aggregation of the apoptosome, consisting of cytochrome c, procaspase-9, and Apaf-1 and subsequent sequential activation of caspase-9 and caspase-3, eventually leading to apoptosis.	23	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	23	24	29	30
These experiments demonstrate that Bcl-XL associates with caspase-9 and Apaf-1 , and show that Bcl-XL inhibits the maturation of caspase-9 mediated by Apaf-1 , a process that is evolutionarily conserved from nematodes to humans .	These experiments demonstrate that Bcl-XL associates with caspase-9 and Apaf-1, and show that Bcl-XL inhibits the maturation of caspase-9 mediated by Apaf-1, a process that is evolutionarily conserved from nematodes to humans.	17	25	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	22	23	19	20
Expression of Apaf-1 enhanced the killing activity of caspase-9 that required the CED-4-like domain of Apaf-1 .	Expression of Apaf-1 enhanced the killing activity of caspase-9 that required the CED-4-like domain of Apaf-1.	0	9	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Expression of Apaf-1	apaf-1	caspase-9	caspase-9	caspase-9	2	3	8	9
Caspase 9 is a critical component of the mitochondrial or intrinsic apoptotic pathway and is activated by Apaf-1 following release of cytochrome c from mitochondria in response to a variety of stimuli .	Caspase 9 is a critical component of the mitochondrial or intrinsic apoptotic pathway and is activated by Apaf-1 following release of cytochrome c from mitochondria in response to a variety of stimuli.	0	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1 following release of cytochrome c from mitochondria	apaf-1	Caspase 9	Caspase 9	caspase 9	17	18	0	2
Necroptosis was originally discovered in Apaf-1-mutant mice , in which the key adaptor protein Apaf-1 that mediates caspase-9 activation is blocked XREF_BIBR XREF_BIBR XREF_BIBR .	Necroptosis was originally discovered in Apaf-1-mutant mice, in which the key adaptor protein Apaf-1 that mediates caspase-9 activation is blocked XREF_BIBR XREF_BIBR XREF_BIBR.	10	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	14	15	17	18
Cell death occurs due to the presence of cytochrome c in the cell cytoplasm , which together with Apaf1 activates caspase 9 .	Cell death occurs due to the presence of cytochrome c in the cell cytoplasm, which together with Apaf1 activates caspase 9.	16	22	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Apaf1	Apaf1	Apaf1	caspase 9	caspase 9	caspase 9	18	19	20	22
The most important process involved in the mitochondrial apoptosis pathway is the release of the membrane interspace protein cyt-C ; following its release cyt-C forms an apoptotic body with apoptotic protease activating factor 1 , thus activating caspase 9 , caspase 3 and caspase 7 to initiate apoptosis .	The most important process involved in the mitochondrial apoptosis pathway is the release of the membrane interspace protein cyt-C; following its release cyt-C forms an apoptotic body with apoptotic protease activating factor 1, thus activating caspase 9, caspase 3 and caspase 7 to initiate apoptosis.	29	43	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoptotic protease activating factor 1	apoptotic protease activating factor 1	apoptotic protease activating factor 1	caspase 9	caspase 9	caspase 9	29	34	37	39
Caspase 9 is activated by the Apaf1 ( apoptotic protease activating factor 1 ) apoptosome in the cytoplasm , whose formation is triggered by MOMP ( mitochondrial outer membrane permeabilization ) and the release of cytochrome c from mitochondria to cytosol [ XREF_BIBR , XREF_BIBR ] .	Caspase 9 is activated by the Apaf1 (apoptotic protease activating factor 1) apoptosome in the cytoplasm, whose formation is triggered by MOMP (mitochondrial outer membrane permeabilization) and the release of cytochrome c from mitochondria to cytosol [XREF_BIBR, XREF_BIBR].	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf1	Apaf1	Apaf1	Caspase 9	Caspase 9	Caspase 9	6	7	0	2
Cells undergoing apoptosis release cytochrome c from the mitochondrial intermembranous space into the cytosol , which is necessary for Apaf-1 activation of caspase 9 and caspase 3 .	Cells undergoing apoptosis release cytochrome c from the mitochondrial intermembranous space into the cytosol, which is necessary for Apaf-1 activation of caspase 9 and caspase 3.	19	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase 9	caspase 9	caspase 9	19	20	22	24
This results in the release of cytochrome c which intereacts with apoptotic protease activating factor 1 ( APAF1 ) , which activates caspase-9 .	This results in the release of cytochrome c which intereacts with apoptotic protease activating factor 1 (APAF1), which activates caspase-9.	14	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF1	APAF1	APAF1	caspase-9	caspase-9	caspase-9	17	18	22	23
The latter interacts with the adapter Apaf-1 which enables the initiator caspase-9 to be activated .	The latter interacts with the adapter Apaf-1 which enables the initiator caspase-9 to be activated.	2	14	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	6	7	11	12
Both the released cytochrome c and upregulated Apaf-1 induced the activation of caspase-9 leading to the activation of caspase-3 and PARP .	Both the released cytochrome c and upregulated Apaf-1 induced the activation of caspase-9 leading to the activation of caspase-3 and PARP.	7	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	7	8	12	13
Importantly , Diva interacted with Apaf-1 , an adapter molecule that activates caspase-9 , a central death protease of the apoptotic pathway .	Importantly, Diva interacted with Apaf-1, an adapter molecule that activates caspase-9, a central death protease of the apoptotic pathway.	3	17	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	5	6	12	13
Apoptotic signaling during oxygen deprivation occurs through the release of cytochrome c and apaf-1 mediated caspase-9 activation .	Apoptotic signaling during oxygen deprivation occurs through the release of cytochrome c and apaf-1 mediated caspase-9 activation.	13	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	apaf-1	apaf-1	apaf-1	caspase-9	caspase-9	caspase-9	13	14	15	16
The liberated cytochrome c interacts with APAF1 then triggers caspase 9 .	The liberated cytochrome c interacts with APAF1 then triggers caspase 9.	6	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF1	APAF1	APAF1	caspase 9	caspase 9	caspase 9	6	7	9	11
The Apaf-1 apoptosome induces formation of caspase-9 homo- and heterodimers with distinct activities .	The Apaf-1 apoptosome induces formation of caspase-9 homo- and heterodimers with distinct activities.	1	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	1	2	6	7
The released cyt c binds to apoptosis protease activating factor 1 ( Apaf-1 ) to form cyt c and Apaf-1 complex , which then activate caspase-9 XREF_BIBR , followed by activation of downstream death effectors such as caspase-3 , caspase-6 , and caspase-7 XREF_BIBR .	The released cyt c binds to apoptosis protease activating factor 1 (Apaf-1) to form cyt c and Apaf-1 complex, which then activate caspase-9 XREF_BIBR, followed by activation of downstream death effectors such as caspase-3, caspase-6, and caspase-7 XREF_BIBR.	19	26	activate	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	19	20	25	26
Direct recruitment and activation of caspase-9 by Apaf-1 through the homophilic CARD and CARD ( Caspase Recruitment Domain ) interaction is critical for the activation of caspases downstream of mitochondrial damage in apoptosis .	Direct recruitment and activation of caspase-9 by Apaf-1 through the homophilic CARD and CARD (Caspase Recruitment Domain) interaction is critical for the activation of caspases downstream of mitochondrial damage in apoptosis.	1	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	7	8	5	6
Released cytochrome c into the cytosol binds to apoptotic protease activating factor 1 , which then activates caspase-9 by cleaving procaspase-9 .	Released cytochrome c into the cytosol binds to apoptotic protease activating factor 1, which then activates caspase-9 by cleaving procaspase-9.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoptotic protease activating factor 1	apoptotic protease activating factor 1	apoptotic protease activating factor 1	caspase-9	caspase-9	caspase-9	8	13	17	18
The release of mitochondrial apoptogenic proteins , such as cytochrome c , into the cytoplasm leads to Apaf-1 dependent activation of caspase-9 , which is a key event in this pathway .	The release of mitochondrial apoptogenic proteins, such as cytochrome c, into the cytoplasm leads to Apaf-1 dependent activation of caspase-9, which is a key event in this pathway.	17	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	17	18	21	22
Here we show that Apaf-1 can dimerize via the CED-4 homologous and linker domains of the molecule providing a means by which Apaf-1 can promote the clustering of caspase-9 and facilitate its activation .	Here we show that Apaf-1 can dimerize via the CED-4 homologous and linker domains of the molecule providing a means by which Apaf-1 can promote the clustering of caspase-9 and facilitate its activation.	22	30	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	22	23	28	29
The western blotting findings of the present study indicated that SCB treatment promoted the expression of Apaf-1 and then activated caspase-9 and -3 .	The western blotting findings of the present study indicated that SCB treatment promoted the expression of Apaf-1 and then activated caspase-9 and -3.	10	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	SCB treatment promoted the expression of Apaf-1	apaf-1	caspase-9	caspase-9	caspase-9	16	17	20	21
Once cytochrome c is in the cytosol , cytochrome c together with Apaf-1 activates caspase-9 , and the latter then activates caspase-3 .	Once cytochrome c is in the cytosol, cytochrome c together with Apaf-1 activates caspase-9, and the latter then activates caspase-3.	10	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	12	13	14	15
To extend these findings , we used cells in which mitochondrial dependent caspase activity was inhibited by APAF-1 knockdown XREF_BIBR or by CRISPR and Cas -9 deletion of caspase-9 ( XREF_SUPPLEMENTARY ) .	To extend these findings, we used cells in which mitochondrial dependent caspase activity was inhibited by APAF-1 knockdown XREF_BIBR or by CRISPR and Cas -9 deletion of caspase-9 (XREF_SUPPLEMENTARY).	15	30	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF-1	APAF-1	APAF-1	caspase-9	caspase-9	caspase-9	17	18	28	29
XREF_BIBR created a 13-ODE model that described activation of caspase-9 by Apaf-1 , consequent activation of caspase-3 , and inhibition of caspases by XIAP .	XREF_BIBR created a 13-ODE model that described activation of caspase-9 by Apaf-1, consequent activation of caspase-3, and inhibition of caspases by XIAP.	6	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	11	12	9	10
Alternatively , cytochrome C released from damaged mitochondria is detected by APAF-1 , which activates Caspase-9 .	Alternatively, cytochrome C released from damaged mitochondria is detected by APAF-1, which activates Caspase-9.	9	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF-1	APAF-1	APAF-1	Caspase-9	Caspase-9	Caspase-9	11	12	15	16
The Apaf-1 complex initially results in activation of caspase-9 followed by the activation of other caspases .	The Apaf-1 complex initially results in activation of caspase-9 followed by the activation of other caspases.	1	9	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	1	2	8	9
Caspase-9 is activated by the Apaf-1 apoptosome in the cytoplasm whose formation is triggered by the release of mitochondrial cytochrome c from mitochondria to cytosol .	Caspase-9 is activated by the Apaf-1 apoptosome in the cytoplasm whose formation is triggered by the release of mitochondrial cytochrome c from mitochondria to cytosol.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	Caspase-9	Caspase-9	Caspase-9	5	6	0	1
When binding to cytochrome c in the presence of dATP , purified full-length Apaf-1 forms the apoptosome and activates caspase-9 ( XREF_FIG , lane 5 ) .	When binding to cytochrome c in the presence of dATP, purified full-length Apaf-1 forms the apoptosome and activates caspase-9 (XREF_FIG, lane 5).	12	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	13	14	19	20
Activation of p53 leads to stimulation and release of cytochrome c in the mitochondria thereby activating Apaf1 , which in turn stimulates caspase 9 eventually leading to cell death [ XREF_BIBR ] .	Activation of p53 leads to stimulation and release of cytochrome c in the mitochondria thereby activating Apaf1, which in turn stimulates caspase 9 eventually leading to cell death [XREF_BIBR].	15	25	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf1	Apaf1	Apaf1	caspase 9	caspase 9	caspase 9	16	17	22	24
The early activation of intrinsic caspase-9 is associated with the release of cytochrome c from damaged mitochondria which subsequently interacts with apoptosis protease activating factor , Apaf-1 , causing self-cleavage and activation of caspase-9 .	The early activation of intrinsic caspase-9 is associated with the release of cytochrome c from damaged mitochondria which subsequently interacts with apoptosis protease activating factor, Apaf-1, causing self-cleavage and activation of caspase-9.	24	34	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	26	27	33	34
In the cytoplasm , cytochrome C forms a complex with procaspase 9 , ATP and APAF-1 ( apoptosome ) to promote the activation of caspase 9 .	In the cytoplasm, cytochrome C forms a complex with procaspase 9, ATP and APAF-1 (apoptosome) to promote the activation of caspase 9.	13	26	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF-1	APAF-1	APAF-1	caspase 9	caspase 9	caspase 9	15	16	24	26
The oligomerization of Apaf-1 promotes the allosteric activation of caspase 9 by forming the Apaf-1 apoptosome .	The oligomerization of Apaf-1 promotes the allosteric activation of caspase 9 by forming the Apaf-1 apoptosome.	1	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase 9	caspase 9	caspase 9	3	4	9	11
However , inhbition of APAF-1 methylation by 5-aza deoxycytidine , restores the Apoptosome formation and the activation of Casp 9 .	However, inhbition of APAF-1 methylation by 5-aza deoxycytidine, restores the Apoptosome formation and the activation of Casp 9.	4	20	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF-1	APAF-1 methylation	apaf-1	Casp 9	Casp 9	casp 9	4	5	18	20
This protein inhibits the IAP , which are characterized by the blockage of caspase activity , while interacting with apoptotic protease activating factor 1 ( Apaf-1 ) enabling the catalytic activity of caspase-9 , the central protease mediator of the intrinsic pathway .	This protein inhibits the IAP, which are characterized by the blockage of caspase activity, while interacting with apoptotic protease activating factor 1 (Apaf-1) enabling the catalytic activity of caspase-9, the central protease mediator of the intrinsic pathway.	22	37	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	25	26	32	33
Cytochrome c in complex with Apaf -1 activates caspase-9 and other downstream caspases XREF_BIBR .	Cytochrome c in complex with Apaf -1 activates caspase-9 and other downstream caspases XREF_BIBR.	3	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Apaf -1	Apaf -1	Apaf -1	caspase-9	caspase-9	caspase-9	5	7	8	9
Overexpression of Apaf1 protein using Ad-rApaf1 adenovirus caused increased activation of caspase-9 in DOX treated NRCM ( XREF_FIG ) .	Overexpression of Apaf1 protein using Ad-rApaf1 adenovirus caused increased activation of caspase-9 in DOX treated NRCM (XREF_FIG).	0	12	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf1	Overexpression of Apaf1	apaf1	caspase-9	caspase-9	caspase-9	2	3	11	12
Then , cytochrome c together with Apaf-1 activate caspase-9 , leading to the apoptotic caspase cascade .	Then, cytochrome c together with Apaf-1 activate caspase-9, leading to the apoptotic caspase cascade.	4	9	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	6	7	8	9
In addition , the unprocessed and cleaved forms of caspase-9 co-immunoprecipitated with Livin in vivo , and recombinant Livin could inhibit the activation of caspase-9 induced by Apaf-1 , cytochrome c , and dATP .	In addition, the unprocessed and cleaved forms of caspase-9 co-immunoprecipitated with Livin in vivo, and recombinant Livin could inhibit the activation of caspase-9 induced by Apaf-1, cytochrome c, and dATP.	22	33	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	27	28	24	25
In the apoptosis pathway in mammals , cytochrome c and dATP are critical cofactors in the activation of caspase 9 by Apaf-1 .	In the apoptosis pathway in mammals, cytochrome c and dATP are critical cofactors in the activation of caspase 9 by Apaf-1.	13	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase 9	caspase 9	caspase 9	21	22	18	20
In the cytosol , cytochrome c combines with the CED-4 homologue , Apaf-1 , thereby triggering Apaf-1-mediated activation of caspase-9 [ XREF_BIBR ] .	In the cytosol, cytochrome c combines with the CED-4 homologue, Apaf-1, thereby triggering Apaf-1-mediated activation of caspase-9 [XREF_BIBR].	10	21	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	12	13	19	20
Overexpression of Apaf1 protein using Ad-rApaf1 adenovirus in DOX treated ARCM did not increase the activity of caspase-9 ( XREF_FIG ) .	Overexpression of Apaf1 protein using Ad-rApaf1 adenovirus in DOX treated ARCM did not increase the activity of caspase-9 (XREF_FIG).	0	19	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf1	Overexpression of Apaf1	apaf1	caspase-9	caspase-9	caspase-9	2	3	17	18
This difference raises the question of how caspase-9 is activated by the Apaf-1 apoptosome .	This difference raises the question of how caspase-9 is activated by the Apaf-1 apoptosome.	7	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	12	13	7	8
XREF_BIBR , XREF_BIBR Cytochrome c combines with the apoptotic factor Apaf-1 , which activates the proapoptotic caspase-9 and initiates the caspase cascade reaction .	XREF_BIBR, XREF_BIBR Cytochrome c combines with the apoptotic factor Apaf-1, which activates the proapoptotic caspase-9 and initiates the caspase cascade reaction.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	10	11	16	17
Apaf-1 increases the catalytic activity of caspase-9 by allosteric regulation .	Apaf-1 increases the catalytic activity of caspase-9 by allosteric regulation.	0	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	0	1	6	7
Thus , overexpression of Apaf1 upregulated the activation of caspase-9 in NRCM but not in ARCM .	Thus, overexpression of Apaf1 upregulated the activation of caspase-9 in NRCM but not in ARCM.	2	10	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf1	overexpression of Apaf1	apaf1	caspase-9	caspase-9	caspase-9	4	5	9	10
In the presence of dATP , Apaf-1 and cytochrome c can activate caspase 9 and then caspase 3 .	In the presence of dATP, Apaf-1 and cytochrome c can activate caspase 9 and then caspase 3.	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase 9	caspase 9	caspase 9	6	7	12	14
Apaf-1 activates caspase-9 by cleaving it at Asp315 .	Apaf-1 activates caspase-9 by cleaving it at Asp315.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	0	1	2	3
These signals lead to the release of cytochrome c from the intermembrane space of the mitochondria to the cytosol , where it interacts with the apoptosome , a large complex containing procaspase-9 , APAF-1 , and dATP , activating caspase-9 .	These signals lead to the release of cytochrome c from the intermembrane space of the mitochondria to the cytosol, where it interacts with the apoptosome, a large complex containing procaspase-9, APAF-1, and dATP, activating caspase-9.	30	40	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF-1	APAF-1	APAF-1	caspase-9	caspase-9	caspase-9	33	34	39	40
The released cytochrome c in turn activates cytosolic apoptotic protease activating factor1 ( APAF1 ) , which then activates the downstream caspase-9 and caspase-3-dependent cascade [ XREF_BIBR ] .	The released cytochrome c in turn activates cytosolic apoptotic protease activating factor1 (APAF1), which then activates the downstream caspase-9 and caspase-3-dependent cascade [XREF_BIBR].	11	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF1	APAF1	APAF1	caspase-9	caspase-9	caspase-9	13	14	21	22
The molecular mechanism by which caspase-9 is activated by the Apaf-1 apoptosome remains largely unknown .	The molecular mechanism by which caspase-9 is activated by the Apaf-1 apoptosome remains largely unknown.	5	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	10	11	5	6
Furthermore , melatonin induced Apaf-1 expression , triggered cytochrome C release , and stimulated caspase-3 and caspase-9 activities and cleavage , leading to an activation of the Apaf-1-dependent apoptotic pathway .	Furthermore, melatonin induced Apaf-1 expression, triggered cytochrome C release, and stimulated caspase-3 and caspase-9 activities and cleavage, leading to an activation of the Apaf-1-dependent apoptotic pathway.	2	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	melatonin induced Apaf-1 expression	apaf-1	caspase-9	caspase-9	caspase-9	4	5	16	17
One such positive regulator is mammalian apoptotic protease activating factor-1 ( Apaf1 ) , which activates the caspase-9 zymogen through formation of an oligomeric apoptosome upon the release of cytochrome c from mitochondria XREF_BIBR - XREF_BIBR .	One such positive regulator is mammalian apoptotic protease activating factor-1 (Apaf1), which activates the caspase-9 zymogen through formation of an oligomeric apoptosome upon the release of cytochrome c from mitochondria XREF_BIBR - XREF_BIBR.	6	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoptotic protease activating factor-1	apoptotic protease activating factor-1	apoptotic protease activating factor-1	caspase-9	caspase-9	caspase-9	6	10	17	18
Oligomerization of APAF-1 promotes the allosteric activation of caspase-9 .	Oligomerization of APAF-1 promotes the allosteric activation of caspase-9.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF-1	APAF-1	APAF-1	caspase-9	caspase-9	caspase-9	2	3	8	9
Furthermore , Apaf-1 promoted the processing and activation of caspase-9 in vivo .	Furthermore, Apaf-1 promoted the processing and activation of caspase-9 in vivo.	2	11	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	2	3	9	10
This results in a net efflux of cytochrome-c from the mitochondria to the cytosol and the initiation of the well studied Apaf-1 mediated caspase-9 activation pathway .	This results in a net efflux of cytochrome-c from the mitochondria to the cytosol and the initiation of the well studied Apaf-1 mediated caspase-9 activation pathway.	16	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	21	22	23	24
In a similar fashion , caspase-9 is activated by the Apaf-1 apoptosome formed upon cytochrome c release from the mitochondria .	In a similar fashion, caspase-9 is activated by the Apaf-1 apoptosome formed upon cytochrome c release from the mitochondria.	5	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	10	11	5	6
Up-regulated Apaf-1 subsequently induced the cleavage of caspase-9 ( 37 kDa ) , which in turn induced sequential cleavage of caspase-3 ( 17 and 19 kDa ) and PARP ( 89 kDa ) .	Up-regulated Apaf-1 subsequently induced the cleavage of caspase-9 (37 kDa), which in turn induced sequential cleavage of caspase-3 (17 and 19 kDa) and PARP (89 kDa).	0	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	1	2	7	8
The molecular phenotypes of Apaf-1 variants were determined by in vitro reconstruction of the apoptosome complex in which Apaf-1 activates caspase 9 and thus initiates a cascade of proteolytic events leading to apoptotic destruction of the cell .	The molecular phenotypes of Apaf-1 variants were determined by in vitro reconstruction of the apoptosome complex in which Apaf-1 activates caspase 9 and thus initiates a cascade of proteolytic events leading to apoptotic destruction of the cell.	18	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase 9	caspase 9	caspase 9	18	19	20	22
Caspase-9 , the initial caspase in the mitochondrial apoptotic cascade also appears to be regulated in this manner since formation of an intermolecular disulfide with apoptotic protease activating factor 1 ( Apaf-1 ) stimulates auto-cleavage of caspase-9 and initiation of the apoptotic cascade .	Caspase-9, the initial caspase in the mitochondrial apoptotic cascade also appears to be regulated in this manner since formation of an intermolecular disulfide with apoptotic protease activating factor 1 (Apaf-1) stimulates auto-cleavage of caspase-9 and initiation of the apoptotic cascade.	28	38	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	31	32	36	37
XREF_BIBR , XREF_BIBR Previous studies have shown that caspase-9 is activated in response to cytochrome c due to clustering of caspase-9 by Apaf-1 and that this results in activation of caspase-3 , XREF_BIBR , XREF_BIBR which is the main initiator of caspases .	XREF_BIBR, XREF_BIBR Previous studies have shown that caspase-9 is activated in response to cytochrome c due to clustering of caspase-9 by Apaf-1 and that this results in activation of caspase-3, XREF_BIBR, XREF_BIBR which is the main initiator of caspases.	8	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	22	23	8	9
In the cytosol , cytochrom c , APAF-1 , ATP and the initiator procaspase-9 are forming the apoptosome multiprotein complex and activate the initiator caspase-9 .	In the cytosol, cytochrom c, APAF-1, ATP and the initiator procaspase-9 are forming the apoptosome multiprotein complex and activate the initiator caspase-9.	5	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF-1	APAF-1	APAF-1	caspase-9	caspase-9	caspase-9	7	8	24	25
Apaf-1 DeltaWD40 activates caspase-9 in a constitutive manner in the absence of Cc .	Apaf-1 DeltaWD40 activates caspase-9 in a constitutive manner in the absence of Cc.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	0	1	3	4
In the cytoplasm , cytochrome c , Apaf-1 , and ATP form the apoptosome and activate caspase-9 , thereby initiating the postmitochondrial mediated caspase cascade by activating effector caspases 3 and 7 .	In the cytoplasm, cytochrome c, Apaf-1, and ATP form the apoptosome and activate caspase-9, thereby initiating the postmitochondrial mediated caspase cascade by activating effector caspases 3 and 7.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	7	8	16	17
Once released into the cytosol , cytochrome c binds to its adaptor molecule , Apaf-1 , which oligomerizes and then activates pro-caspase-9 .	Once released into the cytosol, cytochrome c binds to its adaptor molecule, Apaf-1, which oligomerizes and then activates pro-caspase-9.	12	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	pro-caspase-9	pro-caspase-9	pro-caspase-9	14	15	21	22
Since Apaf-1 could activate caspase-9 and thus initiate intrinsic apoptotic pathway , these findings for the first time implied that aberrant increase of apoptosis may play an important causative role in , rather than a symptom of , major depressive disorder in a subgroup of patients carrying specific alleles of APAF-1 .	Since Apaf-1 could activate caspase-9 and thus initiate intrinsic apoptotic pathway, these findings for the first time implied that aberrant increase of apoptosis may play an important causative role in, rather than a symptom of, major depressive disorder in a subgroup of patients carrying specific alleles of APAF-1.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	1	2	4	5
Intrinsic apoptosis critically relies on mitochondrial outer membrane permeabilization ( MOMP ) , a process that results in the holocytochrome c ( CYTC )-, deoxy-ATP- and apoptotic peptidase activating factor 1 ( APAF1 )-dependent activation of caspase-9 ( CASP9 ) and CASP3 .	Intrinsic apoptosis critically relies on mitochondrial outer membrane permeabilization (MOMP), a process that results in the holocytochrome c (CYTC)-, deoxy-ATP- and apoptotic peptidase activating factor 1 (APAF1)-dependent activation of caspase-9 (CASP9) and CASP3.	32	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	APAF1	APAF1	APAF1	caspase-9	caspase-9	caspase-9	32	33	36	37
We wished to determine whether inhibiting events downstream of the mitochondria , such as activation of caspase-9 by Apaf-1 , would also promote long-term clonogenic survival .	We wished to determine whether inhibiting events downstream of the mitochondria, such as activation of caspase-9 by Apaf-1, would also promote long-term clonogenic survival.	14	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	18	19	16	17
Cytochrome c integrated with Apaf-1 and pro-caspase-9 , which activated caspase-9 and subsequently caspase-3 .	Cytochrome c integrated with Apaf-1 and pro-caspase-9, which activated caspase-9 and subsequently caspase-3.	2	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	4	5	10	11
However , the engineered dimeric caspase-9 exhibits a catalytic activity that is only a small fraction of that of the WT caspase-9 activated by Apaf-1 .	However, the engineered dimeric caspase-9 exhibits a catalytic activity that is only a small fraction of that of the WT caspase-9 activated by Apaf-1.	17	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	24	25	21	22
However , release of cytochrome c does not guarantee the formation of the apoptosome with apaf-1 and subsequent activation of caspase 9 .	However, release of cytochrome c does not guarantee the formation of the apoptosome with apaf-1 and subsequent activation of caspase 9.	15	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	apaf-1	apaf-1	apaf-1	caspase 9	caspase 9	caspase 9	15	16	20	22
Whereas Bcl-xL interacts with Apaf1 to prevent apoptosis by inhibiting Apaf1 dependent activation of caspase 9 XREF_BIBR .	Whereas Bcl-xL interacts with Apaf1 to prevent apoptosis by inhibiting Apaf1 dependent activation of caspase 9 XREF_BIBR.	10	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Apaf1	Apaf1	Apaf1	caspase 9	caspase 9	caspase 9	10	11	14	16
Apaf-1 and cytochrome c release leads to the activation of caspase 9 , the subsequent activation of downstream effector caspases and the execution of glucocorticoid induced apoptosis ( XREF_FIG ) .	Apaf-1 and cytochrome c release leads to the activation of caspase 9, the subsequent activation of downstream effector caspases and the execution of glucocorticoid induced apoptosis (XREF_FIG).	0	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase 9	caspase 9	caspase 9	0	1	10	12
One consequence , dependent on Bax or Bak , is the release of cytochrome c from mitochondria , which serves as a cofactor for activation of caspase-9 by Apaf-1 , thereby unleashing a proteolytic cascade .	One consequence, dependent on Bax or Bak, is the release of cytochrome c from mitochondria, which serves as a cofactor for activation of caspase-9 by Apaf-1, thereby unleashing a proteolytic cascade.	19	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	28	29	26	27
Cyto c induces the oligomerization of apoptotic protease activating factor 1 ( Apaf-1 ) , which subsequently activates caspase-9 .	Cyto c induces the oligomerization of apoptotic protease activating factor 1 (Apaf-1), which subsequently activates caspase-9.	9	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	12	13	18	19
Because Apaf-1 requires cytochrome c to activate caspase-9 , and Bcl-2 prevents mitochondrial cytochrome c release , Bcl-2 is widely believed to inhibit apoptosis by safeguarding mitochondrial membrane integrity .	Because Apaf-1 requires cytochrome c to activate caspase-9, and Bcl-2 prevents mitochondrial cytochrome c release, Bcl-2 is widely believed to inhibit apoptosis by safeguarding mitochondrial membrane integrity.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	1	2	7	8
Cytochrome c and Apaf-1 form the apoptosome and activate caspase-9 as shown in XREF_FIG .	Cytochrome c and Apaf-1 form the apoptosome and activate caspase-9 as shown in XREF_FIG.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	3	4	9	10
Livin also inhibits the activation of caspase-9 induced by cytochrome c , Apaf-1 and dATP [ XREF_BIBR ] .	Livin also inhibits the activation of caspase-9 induced by cytochrome c, Apaf-1 and dATP [XREF_BIBR].	4	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	12	13	6	7
Such multimeric protein complexes are commonly known as apoptosome and death inducing signaling complexes ; caspase-9 is activated by the Apaf-1 apoptosome and caspase-8 is activated by the adapter FADD .	Such multimeric protein complexes are commonly known as apoptosome and death inducing signaling complexes; caspase-9 is activated by the Apaf-1 apoptosome and caspase-8 is activated by the adapter FADD.	15	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	20	21	15	16
Since the delivery of cytochrome c into the cytosol can also trigger the apoptosome by binding to Apaf-1 , which will activate caspase-9 [ XREF_BIBR ] , we assessed whether the cytochrome c transduction protocol delivered sufficient cytochrome c to trigger casapase-9 cleavage .	Since the delivery of cytochrome c into the cytosol can also trigger the apoptosome by binding to Apaf-1, which will activate caspase-9 [XREF_BIBR], we assessed whether the cytochrome c transduction protocol delivered sufficient cytochrome c to trigger casapase-9 cleavage.	15	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	17	18	22	23
Specifically , overexpression of CRABP-II , in the absence of RA , up-regulated the expression of Apaf1 and triggered caspase 7 and caspase 9 cleavage .	Specifically, overexpression of CRABP-II, in the absence of RA, up-regulated the expression of Apaf1 and triggered caspase 7 and caspase 9 cleavage.	2	24	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf1	overexpression of CRABP-II, in the absence of RA, up-regulated the expression of Apaf1	apaf1	caspase 9	caspase 9	caspase 9	16	17	22	24
Mammalian Apaf-1 associates with the apoptosome activating caspase-9 , and more importantly , the sole Apaf-1 CARD can increase caspase-9 activity by forming a large hetero-oligomer of Apaf-1 , CARD , and caspase-9 complex 42 .	Mammalian Apaf-1 associates with the apoptosome activating caspase-9, and more importantly, the sole Apaf-1 CARD can increase caspase-9 activity by forming a large hetero-oligomer of Apaf-1, CARD, and caspase-9 complex 42.	1	20	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	1	2	19	20
A critical component of the intrinsic apoptotic pathway is caspase-9 , which is activated by Apaf-1 in the apoptosome , a large complex assembled in response to release of cytochrome c from mitochondria .	A critical component of the intrinsic apoptotic pathway is caspase-9, which is activated by Apaf-1 in the apoptosome, a large complex assembled in response to release of cytochrome c from mitochondria.	2	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	15	16	9	10
Next , we examined whether the dimeric caspase-9 can be activated by Apaf-1 the same way as the WT caspase-9 .	Next, we examined whether the dimeric caspase-9 can be activated by Apaf-1 the same way as the WT caspase-9.	5	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	12	13	7	8
Furthermore , deletion of apoptotic protease activating factor-1 ( APAF-1 ) , a cytosolic molecule which mediates caspase 9 activation after binding to mitochondrial cytochrome c , rendered cells resistant to aspirin induced apoptosis .	Furthermore, deletion of apoptotic protease activating factor-1 (APAF-1), a cytosolic molecule which mediates caspase 9 activation after binding to mitochondrial cytochrome c, rendered cells resistant to aspirin induced apoptosis.	7	19	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	APAF-1	APAF-1	APAF-1	caspase 9	caspase 9	caspase 9	9	10	17	19
In the apoptosome , cytochrome c and Apaf-1 activate caspase-9 which subsequently leads to the activation of caspase-3 .	In the apoptosome, cytochrome c and Apaf-1 activate caspase-9 which subsequently leads to the activation of caspase-3.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	7	8	9	10
These results suggest that the dimerization of caspase-9 may be qualitatively different from the way in which Apaf-1 activates caspase-9 .	These results suggest that the dimerization of caspase-9 may be qualitatively different from the way in which Apaf-1 activates caspase-9.	17	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	17	18	19	20
Only when both dATP and cytochrome c were added into S-100 cytosolic extract , Apaf-1 monomer in S-100 extract formed an apoptosome in vitro thereby producing the cleaved form of caspase-9 and caspase-3 .	Only when both dATP and cytochrome c were added into S-100 cytosolic extract, Apaf-1 monomer in S-100 extract formed an apoptosome in vitro thereby producing the cleaved form of caspase-9 and caspase-3.	14	32	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	14	15	30	31
Caspase-9 , a key caspase in the mitochondrial cell death pathway [ XREF_BIBR , XREF_BIBR ] is then activated by the oligomeric Apaf-1 .	Caspase-9, a key caspase in the mitochondrial cell death pathway [XREF_BIBR, XREF_BIBR] is then activated by the oligomeric Apaf-1.	0	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	Caspase-9	Caspase-9	Caspase-9	22	23	0	1
Cytochrome c interacts with apoptotic protease activating factor 1 ( APAF1 ) , which activates caspase-9 .	Cytochrome c interacts with apoptotic protease activating factor 1 (APAF1), which activates caspase-9.	7	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF1	APAF1	APAF1	caspase-9	caspase-9	caspase-9	10	11	15	16
Thus , TSA not only increased Apaf-1 expression but also triggered functional activation of caspase-9 in ovarian cancer cells .	Thus, TSA not only increased Apaf-1 expression but also triggered functional activation of caspase-9 in ovarian cancer cells.	2	15	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	TSA not only increased Apaf-1 expression	apaf-1	caspase-9	caspase-9	caspase-9	6	7	14	15
Formation of the apoptosome APAF-1 complex from Cyt c and pro-caspase-9 activates caspase-9 .	Formation of the apoptosome APAF-1 complex from Cyt c and pro-caspase-9 activates caspase-9.	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF-1	APAF-1	APAF-1	caspase-9	caspase-9	caspase-9	4	5	12	13
Upon binding to cytochrome c , apoptotic protease activating factor ( Apaf-1 ) initiated formation of the apoptosome and the activation of caspase-9 , which subsequently activates other caspases and induces apoptosis .	Upon binding to cytochrome c, apoptotic protease activating factor (Apaf-1) initiated formation of the apoptosome and the activation of caspase-9, which subsequently activates other caspases and induces apoptosis.	9	23	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	11	12	22	23
However , the oligomeric Apaf-1 apoptosome even more effectively enhances caspase-9 activity for its downstream target , caspase-3 .	However, the oligomeric Apaf-1 apoptosome even more effectively enhances caspase-9 activity for its downstream target, caspase-3.	4	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	4	5	10	11
The oligomerization of Apaf-1 activates caspase 9 , which , in turn , induces the proteolytic cleavage of other substrates involved in cell death [ XREF_BIBR - XREF_BIBR ] .	The oligomerization of Apaf-1 activates caspase 9, which, in turn, induces the proteolytic cleavage of other substrates involved in cell death [XREF_BIBR - XREF_BIBR].	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase 9	caspase 9	caspase 9	3	4	5	7
Recent studies have shown that caspase-9 is activated in response to cytochrome c due to clustering of caspase-9 by Apaf-1 and that this results in activation of Caspases-3 .	Recent studies have shown that caspase-9 is activated in response to cytochrome c due to clustering of caspase-9 by Apaf-1 and that this results in activation of Caspases-3.	5	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	19	20	5	6
Assuming that the Apaf-1 apoptosome is similar in structure to the CED-4 apoptosome , an Apaf-1 hutch theoretically could drive dimerization and activation of caspase-9 .	Assuming that the Apaf-1 apoptosome is similar in structure to the CED-4 apoptosome, an Apaf-1 hutch theoretically could drive dimerization and activation of caspase-9.	15	25	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	15	16	24	25
Apaf-1 catalyzes the conversion of Procaspase-9 to active Caspase-9 , triggering the caspase cascade , leading eventually to Caspase-3 activation and apoptosis .	Apaf-1 catalyzes the conversion of Procaspase-9 to active Caspase-9, triggering the caspase cascade, leading eventually to Caspase-3 activation and apoptosis.	0	9	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	Caspase-9	Caspase-9	Caspase-9	0	1	8	9
That is , caspase-9 was activated without support for multiplication and activation by Apaf-1 , and the activated caspase-9 may be physically disconnected from the caspase cascade .	That is, caspase-9 was activated without support for multiplication and activation by Apaf-1, and the activated caspase-9 may be physically disconnected from the caspase cascade.	3	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	13	14	3	4
One possibility is that another caspase such as caspase-2 takes over when caspase-9 is absent or ca not be activated by Apaf-1 .	One possibility is that another caspase such as caspase-2 takes over when caspase-9 is absent or ca n't be activated by Apaf-1.	12	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	21	22	12	13
Apaf-1 induces the formation of apoptosomes and activates caspase-9 .	Apaf-1 induces the formation of apoptosomes and activates caspase-9.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	0	1	8	9
The oligomerization of Apaf-1 activates Caspase 9 , which , in turn , induces the proteolytic cleavage of other substrates involved in cell death ( XREF_FIG ) [ XREF_BIBR ] .	The oligomerization of Apaf-1 activates Caspase 9, which, in turn, induces the proteolytic cleavage of other substrates involved in cell death (XREF_FIG) [XREF_BIBR].	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	Caspase 9	Caspase 9	Caspase 9	3	4	5	7
Despite the differences in reported free caspase-9 activity , a consistent observation is that DeltaCARD caspase-9 does not exhibit significant enhancement in activity in the presence of the Apaf-1 and cytochrome c. Addition of the isolated Apaf-1 CARD further enhances caspase-9 activity by five-fold , in vitro .	Despite the differences in reported free caspase-9 activity, a consistent observation is that DeltaCARD caspase-9 does not exhibit significant enhancement in activity in the presence of the Apaf-1 and cytochrome c. Addition of the isolated Apaf-1 CARD further enhances caspase-9 activity by five-fold, in vitro.	36	41	enhances	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	36	37	40	41
Based on the mechanism of caspase-9 activation induced by Apaf-1 , it is postulated that NLRs drive caspase-1 activation through their oligomerization and induced proximity of caspase-1 molecules XREF_BIBR , XREF_BIBR .	Based on the mechanism of caspase-9 activation induced by Apaf-1, it is postulated that NLRs drive caspase-1 activation through their oligomerization and induced proximity of caspase-1 molecules XREF_BIBR, XREF_BIBR.	5	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	9	10	5	6
The catalytic activity of caspase-9 is significantly enhanced in this complex , demonstrating that Apaf-1 CARD allosterically up-regulates caspase-9 activity .	The catalytic activity of caspase-9 is significantly enhanced in this complex, demonstrating that Apaf-1 CARD allosterically up-regulates caspase-9 activity.	14	19	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	14	15	18	19
These results show that activation of caspase 9 by Apaf-1 and subsequent activation of caspase 3 can be recapitulated in S. cerevisiae .	These results show that activation of caspase 9 by Apaf-1 and subsequent activation of caspase 3 can be recapitulated in S. cerevisiae.	4	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase 9	caspase 9	caspase 9	9	10	6	8
Once released , cytochrome c together with Apaf-1 activates caspase-9 , and the latter then activates caspase-3 XREF_BIBR .	Once released, cytochrome c together with Apaf-1 activates caspase-9, and the latter then activates caspase-3 XREF_BIBR.	5	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	7	8	9	10
Cytochrome-c , released in the presence of ( d ) ATP , binds to and activates the adaptor protein Apaf-1 , which in turn recruits caspase-9 , leading to the formation of apoptosome , the activation of caspase-9 and subsequent activation of executioner caspases -3 and -7 [ XREF_BIBR ] .	Cytochrome-c, released in the presence of (d) ATP, binds to and activates the adaptor protein Apaf-1, which in turn recruits caspase-9, leading to the formation of apoptosome, the activation of caspase-9 and subsequent activation of executioner caspases -3 and -7 [XREF_BIBR].	16	38	leading to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	19	20	37	38
Apaf-1 , a protein that stimulates caspase-9 and activates apoptosis , also can act as a target of miR-155 , and up-regulation of miR-155 inhibits the sensitivity of NSCLC cells to CDDP by modulating the DNA damage response ( DDR ) and apoptosis .	Apaf-1, a protein that stimulates caspase-9 and activates apoptosis, also can act as a target of miR-155, and up-regulation of miR-155 inhibits the sensitivity of NSCLC cells to CDDP by modulating the DNA damage response (DDR) and apoptosis.	0	13	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	0	1	6	7
As a result cytochrome C and APAF-1 ( apoptotic protease activating factor 1 ) are released from the inter-membrane space and activate caspase 9 through cleavage .	As a result cytochrome C and APAF-1 (apoptotic protease activating factor 1) are released from the inter-membrane space and activate caspase 9 through cleavage.	4	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APAF-1	APAF-1	APAF-1	caspase 9	caspase 9	caspase 9	6	7	22	24
Here we tested the ability of apo cytochrome c to inhibit caspase-9 activation induced by recombinant Apaf-1 .	Here we tested the ability of apo cytochrome c to inhibit caspase-9 activation induced by recombinant Apaf-1.	11	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	16	17	11	12
ANGPT1 , secreted from pericytes , activates TEK and TIE2 receptor to maintain endothelial quiescence or stabilization , whereas ANGPT2 , secreted from endothelial cells themselves by VEGF or hypoxia signaling , inhibits TEK to promote endothelial activation or sprouting .	ANGPT1, secreted from pericytes, activates TEK and TIE2 receptor to maintain endothelial quiescence or stabilization, whereas ANGPT2, secreted from endothelial cells themselves by VEGF or hypoxia signaling, inhibits TEK to promote endothelial activation or sprouting.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGPT1	ANGPT1	ANGPT1	TIE2	TIE2	TIE2	0	1	9	10
In an intact endothelial monolayer , angiopoietin-1 promotes the interaction of Tie2 with the vascular endothelial protein tyrosine phosphatase VE-PTP .	In an intact endothelial monolayer, angiopoietin-1 promotes the interaction of Tie2 with the vascular endothelial protein tyrosine phosphatase VE-PTP.	6	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	Tie2	Tie2	Tie2	6	7	11	12
The mechanism by which Angpt-2 influences vascular leakage and inflammation is likely through downstream inhibition of Tie-2 signaling as Tie-2 stimulation by Angpt-1 or unrelated peptides mitigates both phenomena .	The mechanism by which Angpt-2 influences vascular leakage and inflammation is likely through downstream inhibition of Tie-2 signaling as Tie-2 stimulation by Angpt-1 or unrelated peptides mitigates both phenomena.	19	25	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Angpt-1	Angpt-1	Angpt-1	Tie-2	Tie-2	Tie-2	22	23	19	20
In contrast to natural circulating sTie2 , a ligand trap consisting of a dimeric Tie2 ectodomain fusion protein was far more effective at blocking Angpt1 induced cellular Tie2 activation .	In contrast to natural circulating sTie2, a ligand trap consisting of a dimeric Tie2 ectodomain fusion protein was far more effective at blocking Angpt1 induced cellular Tie2 activation.	24	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie2	Tie2	Tie2	24	25	27	28
Work with cultured endothelial cells has shown that Tie2 can be activated ( phosphorylated ) by the related cytokine Angiopoietin 1 ( Ang1 ) [ XREF_BIBR , XREF_BIBR ] .	Work with cultured endothelial cells has shown that Tie2 can be activated (phosphorylated) by the related cytokine Angiopoietin 1 (Ang1) [XREF_BIBR, XREF_BIBR].	8	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Angiopoietin 1	Angiopoietin 1	Angiopoietin 1	Tie2	Tie2	Tie2	19	21	8	9
Given the absence of redundant systems to bypass the function of Tie2 , it was speculated that exogenous repletion of Angpt1 rescues Tie2 signalling and thus effectively abolishes microvascular leakage in ischemia-reperfusion injury ( IRI ) .	Given the absence of redundant systems to bypass the function of Tie2, it was speculated that exogenous repletion of Angpt1 rescues Tie2 signalling and thus effectively abolishes microvascular leakage in ischemia-reperfusion injury (IRI).	18	23	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie2	Tie2	Tie2	20	21	22	23
In fibroblasts , activation of the PDGF receptor induces EphrinB1 phosphorylation , as does activation of Tie2 by angiopoietin-1 in endothelial cells .	In fibroblasts, activation of the PDGF receptor induces EphrinB1 phosphorylation, as does activation of Tie2 by angiopoietin-1 in endothelial cells.	13	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	Tie2	Tie2	Tie2	18	19	16	17
In contrast , binding of angiopoietin-1 ( Ang-1 ) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes .	In contrast, binding of angiopoietin-1 (Ang-1) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	Tie2	Tie2	Tie2	5	6	10	11
ANGPT1 expressed by pericytes binds to and activates the TIE2 receptor on endothelial cells , thereby promoting pericyte attachment to capillaries .	ANGPT1 expressed by pericytes binds to and activates the TIE2 receptor on endothelial cells, thereby promoting pericyte attachment to capillaries.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGPT1	ANGPT1 expressed	angpt1	TIE2	TIE2	tie2	0	1	9	10
Tie2 receptor is activated by angiopoietin-1 ( Agpt-1 ) that is derived by periendothelial cells .	Tie2 receptor is activated by angiopoietin-1 (Agpt-1) that is derived by periendothelial cells.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	Tie2	Tie2	Tie2	5	6	0	1
Thus , we speculate that stable or increased levels of ANGPT2 with context induced agonist activity could serve as a potential negative feedback mechanism to compensate for decreased endothelial TIE2 signalling caused by the reduction in ANGPT1 and TIE2 levels .	Thus, we speculate that stable or increased levels of ANGPT2 with context induced agonist activity could serve as a potential negative feedback mechanism to compensate for decreased endothelial TIE2 signalling caused by the reduction in ANGPT1 and TIE2 levels.	29	40	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANGPT1	ANGPT1 and TIE2 levels	angpt1	TIE2	TIE2	tie2	36	37	29	30
Angiopoietin-1 activates Tie-2 , leading to receptor autophosphorylation upon binding , and it simulates endothelial cell migration in vitro and contributes to blood vessel stabilization by recruitment of pericytes [ XREF_BIBR ] .	Angiopoietin-1 activates Tie-2, leading to receptor autophosphorylation upon binding, and it simulates endothelial cell migration in vitro and contributes to blood vessel stabilization by recruitment of pericytes [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie-2	Tie-2	Tie-2	0	1	2	3
Tie2 activation by Angiopoietin-1 reduces , while Tie2-blockade by Angiopoietin-2 increases inflammation and permeability during sepsis .	Tie2 activation by Angiopoietin-1 reduces, while Tie2-blockade by Angiopoietin-2 increases inflammation and permeability during sepsis.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie2	Tie2	Tie2	3	4	0	1
Tie-2 activated by Angpt-1 stimulates Rap1 GTPase , which reduces radial stress fibres via Rac1 and nonmuscle myosin II , independent of VE-cadherin .	Tie-2 activated by Angpt-1 stimulates Rap1 GTPase, which reduces radial stress fibres via Rac1 and nonmuscle myosin II, independent of VE-cadherin.	0	4	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Angpt-1	Angpt-1	Angpt-1	Tie-2	Tie-2	Tie-2	3	4	0	1
While Angiopoietin-1 obligately activates its Tie2 receptor , Angiopoietin-2 can activate Tie2 on some cells , while it blocks Tie2 activation on others .	While Angiopoietin-1 obligately activates its Tie2 receptor, Angiopoietin-2 can activate Tie2 on some cells, while it blocks Tie2 activation on others.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie2	Tie2	Tie2	1	2	5	6
The tight control of Angiopoietin-1 ( Angpt1 ) and Angiopoietin- 2 ( Angpt2 ) levels is critical in minimizing microvascular derangements that are the direct result of negative interference of Angpt2 with Angpt1 mediated Tie-2 signaling .	The tight control of Angiopoietin-1 (Angpt1) and Angiopoietin- 2 (Angpt2) levels is critical in minimizing microvascular derangements that are the direct result of negative interference of Angpt2 with Angpt1 mediated Tie-2 signaling.	4	35	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie-2	Tie-2	Tie-2	6	7	34	35
Angiopoietins are a family of ligands that bind to the EC membrane receptor tyrosine kinase TIE2 ( also known as TEK ) , Angpt-1 and Angpt-2 can activate TIE2 at different affinities .	Angiopoietins are a family of ligands that bind to the EC membrane receptor tyrosine kinase TIE2 (also known as TEK), Angpt-1 and Angpt-2 can activate TIE2 at different affinities.	23	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angpt-1	Angpt-1	Angpt-1	TIE2	TIE2	TIE2	23	24	28	29
They also release Angiopoietin1 that activates Tie2 on human mast cells .	They also release Angiopoietin1 that activates Tie2 on human mast cells.	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin1	Angiopoietin1	Angiopoietin1	Tie2	Tie2	Tie2	3	4	6	7
Angiopoietin1 activates Tie2 to promote blood vessel maturation and stabilisation , whereas angiopoietin2 is thought to function largely as a Tie2 antagonist to promote tumour angiogenesis .	Angiopoietin1 activates Tie2 to promote blood vessel maturation and stabilisation, whereas angiopoietin2 is thought to function largely as a Tie2 antagonist to promote tumour angiogenesis.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin1	Angiopoietin1	Angiopoietin1	Tie2	Tie2	Tie2	0	1	2	3
Pericytes produce angiopoietin-1 , which activates Tie2 signaling to promote endothelial cell maturation [ XREF_BIBR , XREF_BIBR ] .	Pericytes produce angiopoietin-1, which activates Tie2 signaling to promote endothelial cell maturation [XREF_BIBR, XREF_BIBR].	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	Tie2	Tie2	Tie2	2	3	6	7
Activation of the Tie-2 signaling by Angpt1 stabilizes EC junctions and enhances vascular integrity [ XREF_BIBR ] .	Activation of the Tie-2 signaling by Angpt1 stabilizes EC junctions and enhances vascular integrity [XREF_BIBR].	3	7	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie-2	Tie-2	Tie-2	6	7	3	4
It has been reported that Angpt2 and Tie-1 downregulate Angpt1 induced Tie-2 signaling , and Angpt actions in kidney development are further modified by VEGFA and integrins XREF_BIBR .	It has been reported that Angpt2 and Tie-1 downregulate Angpt1 induced Tie-2 signaling, and Angpt actions in kidney development are further modified by VEGFA and integrins XREF_BIBR.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie-2	Tie-2	Tie-2	9	10	11	12
A Designed Angiopoietin-1 Variant , Dimeric CMP-Ang1 Activates Tie2 and Stimulates Angiogenesis and Vascular Stabilization in N-glycan Dependent Manner .	A Designed Angiopoietin-1 Variant, Dimeric CMP-Ang1 Activates Tie2 and Stimulates Angiogenesis and Vascular Stabilization in N-glycan Dependent Manner.	0	10	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie2	Tie2	Tie2	2	3	8	9
Furthermore , all endothelial cells were shown to express angiopoietin receptor ( Tie-2 ) that may be activated by both angiopoietin-1 ( Ang-1 ) and angiopoietin-2 ( Ang-2 ) .	Furthermore, all endothelial cells were shown to express angiopoietin receptor (Tie-2) that may be activated by both angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2).	10	27	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	Tie-2	Tie-2	Tie-2	20	21	12	13
Similarly , the domain on the carboxyl side of the kinase domain can be autoinhibitory as has been demonstrated for EGFR and the receptor TIE2 , an RTK that is activated by angiopoietin-1 .	Similarly, the domain on the carboxyl side of the kinase domain can be autoinhibitory as has been demonstrated for EGFR and the receptor TIE2, an RTK that is activated by angiopoietin-1.	18	33	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	TIE2	TIE2	TIE2	32	33	24	25
ANGPT1 and angiopoietin receptor ( TIE-2 ) promote cell survival and induce anti-inflammatory signals in contrast to ANGPT2 and TIE-2 , which have a pro inflammatory effect with VEGF acting as a co-factor .	ANGPT1 and angiopoietin receptor (TIE-2) promote cell survival and induce anti-inflammatory signals in contrast to ANGPT2 and TIE-2, which have a pro inflammatory effect with VEGF acting as a co-factor.	0	22	induce	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ANGPT1	ANGPT1	ANGPT1	TIE-2	TIE-2	TIE-2	0	1	19	20
Our results show that Angpt1 activation of cellular Tie2 is poorly responsive to sTie2 .	Our results show that Angpt1 activation of cellular Tie2 is poorly responsive to sTie2.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie2	Tie2	Tie2	4	5	8	9
Angiopoietin-1 ( Angpt-1 ) stimulates Tie-2 , a receptor tyrosine kinase whose expression is largely limited to the endothelium .	Angiopoietin-1 (Angpt-1) stimulates Tie-2, a receptor tyrosine kinase whose expression is largely limited to the endothelium.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie-2	Tie-2	Tie-2	0	1	5	6
Angpt-1 activates Tie2 to promote EC survival and quiescence and thus contributes to neovessel stabilitization and maturation during embryonic development , as well as the maintenance of postnatal vascular homeostasis XREF_BIBR .	Angpt-1 activates Tie2 to promote EC survival and quiescence and thus contributes to neovessel stabilitization and maturation during embryonic development, as well as the maintenance of postnatal vascular homeostasis XREF_BIBR.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angpt-1	Angpt-1	Angpt-1	Tie2	Tie2	Tie2	0	1	2	3
Activation of Tie2 by Angpt-1 leads to Akt mediated Foxo1 phosphorylation at both Ser 256 and Thr 24 and a consequent reduction in Angpt-2 .	Activation of Tie2 by Angpt-1 leads to Akt mediated Foxo1 phosphorylation at both Ser 256 and Thr 24 and a consequent reduction in Angpt-2.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Angpt-1	Angpt-1	Angpt-1	Tie2	Tie2	Tie2	4	5	2	3
Indeed , angiopoietin 1 ( Ang1 ) activates TEK receptor , which triggers the activation of Rous sarcoma virus ( Ras ) homologous A ( RhoA ) , which , in turn , inhibits Src proteins [ XREF_BIBR ] .	Indeed, angiopoietin 1 (Ang1) activates TEK receptor, which triggers the activation of Rous sarcoma virus (Ras) homologous A (RhoA), which, in turn, inhibits Src proteins [XREF_BIBR].	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiopoietin 1	angiopoietin 1	angiopoietin 1	TEK	TEK	TEK	2	4	8	9
However , dimeric sTie2 is able to inhibit Angpt1 activation of endothelial Tie2 at much lower concentrations .	However, dimeric sTie2 is able to inhibit Angpt1 activation of endothelial Tie2 at much lower concentrations.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie2	Tie2	Tie2	8	9	12	13
Angiopoietin 1 induces Tie2 signaling as a receptor activator and maintains blood vessel formation , whereas angiopoietin 2 destabilizes vessels by blocking Tie2 signaling as an antagonist of angiopoietin 1 and acts with vascular endothelial growth factor to initiate angiogenesis .	Angiopoietin 1 induces Tie2 signaling as a receptor activator and maintains blood vessel formation, whereas angiopoietin 2 destabilizes vessels by blocking Tie2 signaling as an antagonist of angiopoietin 1 and acts with vascular endothelial growth factor to initiate angiogenesis.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin 1	Angiopoietin 1	Angiopoietin 1	Tie2	Tie2	Tie2	0	2	3	4
TEK function is modulated by its ligand ANGPT1 , which is also involved in Schlemm ' s canal development .	TEK function is modulated by its ligand ANGPT1, which is also involved in Schlemm 's canal development.	0	12	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANGPT1	ANGPT1	ANGPT1	TEK	TEK	TEK	7	8	0	1
Addition of 0.18 nM Angpt1 to cells resulted in activation of Tie2 .	Addition of 0.18 nM Angpt1 to cells resulted in activation of Tie2.	0	12	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie2	Tie2	Tie2	4	5	11	12
It should be noted that glomerular component mesangial cells produced Angpt1 , which was thought to induce Tie-2 and Angpt2 in neighboring endothelial cells .	It should be noted that glomerular component mesangial cells produced Angpt1, which was thought to induce Tie-2 and Angpt2 in neighboring endothelial cells.	9	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie-2	Tie-2	Tie-2	10	11	17	18
Angiopoietin-1 activates the Tie-2 signalling while angiopoietin-2 inhibits this activation .	Angiopoietin-1 activates the Tie-2 signalling while angiopoietin-2 inhibits this activation.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie-2	Tie-2	Tie-2	0	1	3	4
Tie2 stimulation by Angpt1 potentiates survival and maintenance signals from surrounding cells and ECM which maintain endothelial cells in a quiescent state .	Tie2 stimulation by Angpt1 potentiates survival and maintenance signals from surrounding cells and ECM which maintain endothelial cells in a quiescent state.	0	4	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie2	Tie2	Tie2	3	4	0	1
In blood endothelial cells ( BECs ) , ANGPT2 is described as an antagonist of ANGPT1 mediated TIE2 activation , while the situation is reversed in lymphatic endothelial cells ( LECs ) , where ANGPT2 serves as the primary TIE2 agonist .	In blood endothelial cells (BECs), ANGPT2 is described as an antagonist of ANGPT1 mediated TIE2 activation, while the situation is reversed in lymphatic endothelial cells (LECs), where ANGPT2 serves as the primary TIE2 agonist.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	ANGPT1	ANGPT1	ANGPT1	TIE2	TIE2	TIE2	15	16	17	18
Angiopoietin-1 is the principal activator of Tie2 ; additionally , it stimulates the migration of endothelial cells in vitro and promotes satellite cell self-renewal [ XREF_BIBR ] .	Angiopoietin-1 is the principal activator of Tie2; additionally, it stimulates the migration of endothelial cells in vitro and promotes satellite cell self-renewal [XREF_BIBR].	0	7	is the principal activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie2	Tie2	Tie2	0	1	6	7
It was demonstrated , both in vitro and in vivo , that such cells promote the return to quiescence of muscle progenitors by angiopoietin-1 release , through Angiopoietin-1 and Tie-2 signalling system .	It was demonstrated, both in vitro and in vivo, that such cells promote the return to quiescence of muscle progenitors by angiopoietin-1 release, through Angiopoietin-1 and Tie-2 signalling system.	14	31	promote	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	Tie-2	Tie-2	Tie-2	23	24	29	30
Since the original report by Witzenbichler and colleagues [ XREF_BIBR ] in 2005 , several studies have confirmed that activation of the non redundant and endothelial specific Tie2 receptor pathway by adenoviral overexpression of its agonist ligand Angpt1 ( AdAngpt1 ) is sufficient to prevent endotoxemia induced vascular leakage [ XREF_BIBR ] and subsequent AKI [ XREF_BIBR ] and ALI [ XREF_BIBR ] in rodents .	Since the original report by Witzenbichler and colleagues [XREF_BIBR] in 2005, several studies have confirmed that activation of the non redundant and endothelial specific Tie2 receptor pathway by adenoviral overexpression of its agonist ligand Angpt1 (AdAngpt1) is sufficient to prevent endotoxemia induced vascular leakage [XREF_BIBR] and subsequent AKI [XREF_BIBR] and ALI [XREF_BIBR] in rodents.	19	38	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	Angpt1	overexpression of its agonist ligand Angpt1	angpt1	Tie2	Tie2	tie2	37	38	27	28
Angpt1 induced Tek activation results in endothelial cell survival and quiescence .	Angpt1 induced Tek activation results in endothelial cell survival and quiescence.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tek	Tek	Tek	0	1	2	3
Angiopoietin-1 appears to activate Tie2 , evidenced by increased tyrosine phosphorylation of Tie2 , whereas angiopoietin-2 seems to have both agonistic and antagonistic properties depending on the local environment of the Tie2 receptor [ XREF_BIBR ] .	Angiopoietin-1 appears to activate Tie2, evidenced by increased tyrosine phosphorylation of Tie2, whereas angiopoietin-2 seems to have both agonistic and antagonistic properties depending on the local environment of the Tie2 receptor [XREF_BIBR].	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie2	Tie2	Tie2	0	1	4	5
Angiopoietin-1 ( Ang1 ) binds to and activates Tie2 receptor tyrosine kinase .	Angiopoietin-1 (Ang1) binds to and activates Tie2 receptor tyrosine kinase.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie2	Tie2	Tie2	0	1	8	9
It heterodimerizes with TIE2 and modulates TIE2 signaling induced by ANGPT1 and ANGPT2 [ XREF_BIBR ] .	It heterodimerizes with TIE2 and modulates TIE2 signaling induced by ANGPT1 and ANGPT2 [XREF_BIBR].	6	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANGPT1	ANGPT1	ANGPT1	TIE2	TIE2	TIE2	10	11	6	7
In conclusion , this study shows that normal and pathological levels of sTie2 have little effect on Angpt1 induced Tie2 clustering and activation in endothelial cells .	In conclusion, this study shows that normal and pathological levels of sTie2 have little effect on Angpt1 induced Tie2 clustering and activation in endothelial cells.	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie2	Tie2	Tie2	17	18	19	20
Angiopoietin-1 ( Ang1 ) activation of Tie2 receptors on endothelial cells ( ECs ) reduces adhesion by tumor cells ( TCs ) and limits junctional permeability to TC diapedesis .	Angiopoietin-1 (Ang1) activation of Tie2 receptors on endothelial cells (ECs) reduces adhesion by tumor cells (TCs) and limits junctional permeability to TC diapedesis.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie2	Tie2	Tie2	0	1	6	7
Activation of Tie1 ectodomain cleavage increases cartilage oligomeric protein angiopoietin 1 activation of Tie2 .	Activation of Tie1 ectodomain cleavage increases cartilage oligomeric protein angiopoietin 1 activation of Tie2.	5	14	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	angiopoietin 1	angiopoietin 1	angiopoietin 1	Tie2	Tie2	Tie2	9	11	13	14
These observations suggest that a model developed to explain effects of Tie2 and the angiopoietins in the ovary also applies to their actions in the eye [ XREF_BIBR ] : stimulation of Tie2 by Angpt1 acts to stabilize retinal or choroidal vessels and reduces their ability to sprout new vessels in the presence of VEGF , whereas Angpt2 promotes dephosphorylation of Tie2 , destabilizing vessels and enabling VEGF to stimulate sprouting of NV .	These observations suggest that a model developed to explain effects of Tie2 and the angiopoietins in the ovary also applies to their actions in the eye [XREF_BIBR] : stimulation of Tie2 by Angpt1 acts to stabilize retinal or choroidal vessels and reduces their ability to sprout new vessels in the presence of VEGF, whereas Angpt2 promotes dephosphorylation of Tie2, destabilizing vessels and enabling VEGF to stimulate sprouting of NV.	30	35	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie2	Tie2	Tie2	34	35	32	33
Like VEGF , angiopoietin-1 is an endothelial cell specific growth factor , in which induces EC to recruit pericytes and smooth muscle cells to become incorporated in the vessel wall by producing PDGF and other factors when Tie-2 is activated by angiopoietin-1 XREF_BIBR .	Like VEGF, angiopoietin-1 is an endothelial cell specific growth factor, in which induces EC to recruit pericytes and smooth muscle cells to become incorporated in the vessel wall by producing PDGF and other factors when Tie-2 is activated by angiopoietin-1 XREF_BIBR.	37	42	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	Tie-2	Tie-2	Tie-2	41	42	37	38
Angpt 1 is known to activate the Tie2 receptor ; therefore , it was clear that Tie2 activation was attenuated by the Angpt 1 antagonist .	Angpt 1 is known to activate the Tie2 receptor; therefore, it was clear that Tie2 activation was attenuated by the Angpt 1 antagonist.	16	24	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Angpt 1	Angpt 1	Angpt 1	Tie2	Tie2	Tie2	22	24	16	17
Angiopoietin-Tie receptor signalling occurs in the reverse direction , as the secretion of angiopoietin-1 by mural cells activates the Tie2 receptor on ECs , promoting pericyte adhesion and tightening of endothelial cell junctions 3 .	Angiopoietin-Tie receptor signalling occurs in the reverse direction, as the secretion of angiopoietin-1 by mural cells activates the Tie2 receptor on ECs, promoting pericyte adhesion and tightening of endothelial cell junctions 3.	11	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	Tie2	Tie2	Tie2	13	14	19	20
For example , Angiopoietin-1 , which is normally secreted by pericytes and activates its endothelial receptor Tie2 , has been shown to restore the vascular defects caused by pericyte ablation in the retina , stabilizing vessels and preventing edema and hemorrhage despite the persistent absence of mural cells XREF_BIBR .	For example, Angiopoietin-1, which is normally secreted by pericytes and activates its endothelial receptor Tie2, has been shown to restore the vascular defects caused by pericyte ablation in the retina, stabilizing vessels and preventing edema and hemorrhage despite the persistent absence of mural cells XREF_BIBR.	3	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin-1	Angiopoietin-1	Angiopoietin-1	Tie2	Tie2	Tie2	3	4	16	17
Our simulations show that sTie2 remains relatively ineffective at modulating Angpt1 activation of cellular Tie2 tetramerization even when cellular Tie2 levels are varied over a 100-fold range .	Our simulations show that sTie2 remains relatively ineffective at modulating Angpt1 activation of cellular Tie2 tetramerization even when cellular Tie2 levels are varied over a 100-fold range.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Angpt1	Angpt1	Angpt1	Tie2	Tie2	Tie2	10	11	14	15
Furthermore , activation of TIE-2 by angiopoietin-1 ( ANG-1 ) results in phosphorylation of TRBP , a DICER co-factor , which facilitates miRNA processing .	Furthermore, activation of TIE-2 by angiopoietin-1 (ANG-1) results in phosphorylation of TRBP, a DICER co-factor, which facilitates miRNA processing.	2	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	angiopoietin-1	angiopoietin-1	angiopoietin-1	TIE-2	TIE-2	TIE-2	6	7	4	5
The presence of an adequate amount of apoC-II increased the maximal activity of LpL ( Vmax ( triolein ) ) from 0.48 +/- 0.21 to 6.81 +/- 0.45 and from 0.32 +/- 0.04 to 7.13 +/- 0.64 mmol/h/mg with a slight decrease in the apparent Michaelis constant ( Km ( triolein ) ) for small ( from 90 to 54 microM triolein ) and large ( from 1.00 to 0.65 mM triolein ) particles , respectively .	The presence of an adequate amount of apoC-II increased the maximal activity of LpL (Vmax (triolein)) from 0.48 +/- 0.21 to 6.81 +/- 0.45 and from 0.32 +/- 0.04 to 7.13 +/- 0.64 mmol/h/mg with a slight decrease in the apparent Michaelis constant (Km (triolein)) for small (from 90 to 54 microM triolein) and large (from 1.00 to 0.65 mM triolein) particles, respectively.	5	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC-II	amount of apoC-II	apoc-ii	LpL	LpL	lpl	7	8	13	14
On the endothelial cells , LPL is activated by apoC-II and inhibited by apoC-III and ANGPTL4 .	On the endothelial cells, LPL is activated by apoC-II and inhibited by apoC-III and ANGPTL4.	5	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	LPL	LPL	LPL	9	10	5	6
The overall structure and the internal dynamics , combined with previous mutation data , give important clues toward a possible mechanism for the activation of LPL by apoCII .	The overall structure and the internal dynamics, combined with previous mutation data, give important clues toward a possible mechanism for the activation of LPL by apoCII.	14	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	apoCII	apoCII	apoCII	LPL	LPL	LPL	27	28	25	26
The presence of apolipoprotein C-II , the apolipoprotein activator of lipoprotein lipase , partly reverses the inhibition of lipoprotein lipase by benzene boronic acid .	The presence of apolipoprotein C-II, the apolipoprotein activator of lipoprotein lipase, partly reverses the inhibition of lipoprotein lipase by benzene boronic acid.	3	20	reverses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	apolipoprotein C-II	apolipoprotein C-II	apolipoprotein C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	5	18	20
This leads to subsequent elevation of serum apolipoprotein C2 ( APOC2 ) , which enhances lipoprotein lipase activity and allows for increased uptake of TAGs into peripheral tissues like the heart , skeletal muscle , and adipose tissue ( XREF_FIG ) .	This leads to subsequent elevation of serum apolipoprotein C2 (APOC2), which enhances lipoprotein lipase activity and allows for increased uptake of TAGs into peripheral tissues like the heart, skeletal muscle, and adipose tissue (XREF_FIG).	8	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APOC2	APOC2	APOC2	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	10	11	15	17
This observation is surprising when considering the respective functions of apoC-II and apoC-III , which are to activate and inhibit lipoprotein lipase activity , respectively XREF_BIBR .	This observation is surprising when considering the respective functions of apoC-II and apoC-III, which are to activate and inhibit lipoprotein lipase activity, respectively XREF_BIBR.	8	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	10	11	20	22
As mature chylomicrons circulate , the newly acquired ApoC2 on the particle surface activates LPL , which is bound to epithelial surfaces of capillaries in adipose and muscle tissue where it is differentially expressed according to fed and fasting conditions XREF_BIBR .	As mature chylomicrons circulate, the newly acquired ApoC2 on the particle surface activates LPL, which is bound to epithelial surfaces of capillaries in adipose and muscle tissue where it is differentially expressed according to fed and fasting conditions XREF_BIBR.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoC2	ApoC2	ApoC2	LPL	LPL	LPL	8	9	14	15
APOA4 influences chylomicron synthesis , modulates the activation of LPL by apolipoprotein C-II , and activates lecithin-cholesterol acyltransferase [ XREF_BIBR , XREF_BIBR ] .	APOA4 influences chylomicron synthesis, modulates the activation of LPL by apolipoprotein C-II, and activates lecithin-cholesterol acyltransferase [XREF_BIBR, XREF_BIBR].	7	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	apolipoprotein C-II	apolipoprotein C-II	apolipoprotein C-II	LPL	LPL	LPL	11	13	9	10
ApoC2 , an upregulated gene in regression , activates lipoprotein lipase XREF_BIBR .	ApoC2, an upregulated gene in regression, activates lipoprotein lipase XREF_BIBR.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoC2	ApoC2	ApoC2	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	9	11
Apo C-III effectively inhibited , in a dose dependent manner , the activation of lipoprotein lipase induced by apo C-II .	Apo C-III effectively inhibited, in a dose dependent manner, the activation of lipoprotein lipase induced by apo C-II.	14	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apo C-II	apo C-II	apo C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	18	20	14	16
ApoB48 is required for chylomicron formation , ApoE mediates the interaction of CRs and VLDLs with their receptors , and ApoC-II is an activator of lipoprotein lipase .	ApoB48 is required for chylomicron formation, ApoE mediates the interaction of CRs and VLDLs with their receptors, and ApoC-II is an activator of lipoprotein lipase.	20	27	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ApoC-II	ApoC-II	ApoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	20	21	25	27
ApoA-I and apoC-I activate lecithin and cholesterol acyltransferase ; apoC-II is an activator of lipoprotein lipase .	ApoA-I and apoC-I activate lecithin and cholesterol acyltransferase; apoC-II is an activator of lipoprotein lipase.	9	16	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	9	10	14	16
As ApoC-II is an activator of lipoprotein lipase , which is expressed in the capillary endothelial cells in tissues active in triglyceride metabolism , preferential accumulation of PMB-CNTs in the capillary endothelial cells of adipose tissue may be at least partly attributed to the ApoC and PMB-CNT interactivity .	As ApoC-II is an activator of lipoprotein lipase, which is expressed in the capillary endothelial cells in tissues active in triglyceride metabolism, preferential accumulation of PMB-CNTs in the capillary endothelial cells of adipose tissue may be at least partly attributed to the ApoC and PMB-CNT interactivity.	1	12	is an activator	Positive_regulation_copula_1	Positive_activation	Positive_regulation	ApoC-II	ApoC-II	apoc-ii	lipoprotein lipase	lipoprotein lipase, which is expressed	lipoprotein lipase	1	2	6	8
LPL is activated by apo C-II and inhibited by apo C-III , which can also inhibit HL activity [ XREF_BIBR ] .	LPL is activated by apo C-II and inhibited by apo C-III, which can also inhibit HL activity [XREF_BIBR].	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apo C-II	apo C-II	apo C-II	LPL	LPL	LPL	4	6	0	1
Apolipoprotein C-III is a potent inhibitor , whereas the apolipoprotein C-II is an activator of lipoprotein lipase , and for the normal functioning lipoprotein lipase requires the presence of apoC-II , as a cofactor [ XREF_BIBR ] .	Apolipoprotein C-III is a potent inhibitor, whereas the apolipoprotein C-II is an activator of lipoprotein lipase, and for the normal functioning lipoprotein lipase requires the presence of apoC-II, as a cofactor [XREF_BIBR].	9	17	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	apolipoprotein C-II	apolipoprotein C-II	apolipoprotein C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	9	11	15	17
Apo C-II is an activator of lipoprotein lipase ( LPL ) and a regulator of plasma triglyceride levels .	Apo C-II is an activator of lipoprotein lipase (LPL) and a regulator of plasma triglyceride levels.	0	8	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Apo C-II	Apo C-II	Apo C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	2	6	8
It is also required for efficient activation of lipoprotein lipase by ApoC-II , which is a potent activator of LCAT .	It is also required for efficient activation of lipoprotein lipase by ApoC-II, which is a potent activator of LCAT.	3	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ApoC-II	ApoC-II	ApoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	11	12	8	10
Consistently , recent reports showed that infusion of recombinant apoC2 in mice results in decrease of TG levels , and an apoC2 mimetic peptide activates LPL and decreases triglyceride levels in mice .	Consistently, recent reports showed that infusion of recombinant apoC2 in mice results in decrease of TG levels, and an apoC2 mimetic peptide activates LPL and decreases triglyceride levels in mice.	21	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC2	apoC2	apoC2	LPL	LPL	LPL	21	22	25	26
LpL activity was enhanced greater than 10-fold by apoC-II ; 1 M NaCl inhibited enzyme activity .	LpL activity was enhanced greater than 10-fold by apoC-II; 1 M NaCl inhibited enzyme activity.	0	9	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	LpL	LpL	LpL	8	9	0	1
ApoC-II is an obligate activator of LPL , and its absence can lead to FCS XREF_BIBR .	ApoC-II is an obligate activator of LPL, and its absence can lead to FCS XREF_BIBR.	0	7	is an obligate activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ApoC-II	ApoC-II	ApoC-II	LPL	LPL	LPL	0	1	6	7
A high ratio of apoCII and apoCIII promotes LPL activity , whereas a low apoCII and apoCIII ratio inhibits LPL function .	A high ratio of apoCII and apoCIII promotes LPL activity, whereas a low apoCII and apoCIII ratio inhibits LPL function.	2	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoCII	apoCII	apoCII	LPL	LPL	LPL	4	5	8	9
In the capillaries of muscles and adipose tissues , lipoprotein lipase ( LPL ) , activated by apoC-II , converts TG to fatty acids and glycerol .	In the capillaries of muscles and adipose tissues, lipoprotein lipase (LPL), activated by apoC-II, converts TG to fatty acids and glycerol.	9	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	17	18	9	11
These results support that apoC2 , when regulated within physiological range , positively regulates LPL activities and plasma TG uptake in mice .	These results support that apoC2, when regulated within physiological range, positively regulates LPL activities and plasma TG uptake in mice.	4	15	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	apoC2	apoC2	apoC2	LPL	LPL	LPL	4	5	14	15
ApoC-II enhances the catalytic activity of LPL , which hydrolyzes triglycerides in VLDL .	ApoC-II enhances the catalytic activity of LPL, which hydrolyzes triglycerides in VLDL.	0	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoC-II	ApoC-II	ApoC-II	LPL	LPL	LPL	0	1	6	7
Apo C-II is known to activate the lipoprotein lipase and , thus , plays a key role in lipid metabolism .	Apo C-II is known to activate the lipoprotein lipase and, thus, plays a key role in lipid metabolism.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apo C-II	Apo C-II	Apo C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	2	7	9
Kinetic analysis of activation of lipoprotein lipase by apo C-2 indicates that the lipase co-protein increase the rate of lipolysis by adsorption to enzyme at the lipid interface , with formation of a 1:1 molar complex , whose dissociation constant in the presence of triglyceride substrate is about 3 X 10 (-13) moles cm-3 .	Kinetic analysis of activation of lipoprotein lipase by apo C-2 indicates that the lipase co-protein increase the rate of lipolysis by adsorption to enzyme at the lipid interface, with formation of a 1:1 molar complex, whose dissociation constant in the presence of triglyceride substrate is about 3 X 10 (-13) moles cm-3.	3	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	apo C-2	apo C-2	apo C-2	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	8	10	5	7
ApoC-III has been shown in vitro to inhibit lipolysis by several mechanisms , including displacing lipoproteins from the negatively charged cell surface [ XREF_BIBR ] , inducing conformational changes in apoE and inhibiting the activation of LPL by displacing the LPL activator apoC-II from the lipoprotein surface [ XREF_BIBR ] .	ApoC-III has been shown in vitro to inhibit lipolysis by several mechanisms, including displacing lipoproteins from the negatively charged cell surface [XREF_BIBR], inducing conformational changes in apoE and inhibiting the activation of LPL by displacing the LPL activator apoC-II from the lipoprotein surface [XREF_BIBR].	38	43	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	LPL	LPL	LPL	42	43	40	41
APOC3 is an important inhibitor of the lipolysis of triglyceride rich lipoproteins via countering APOC2 activation of lipoprotein lipase [ XREF_BIBR ] .	APOC3 is an important inhibitor of the lipolysis of triglyceride rich lipoproteins via countering APOC2 activation of lipoprotein lipase [XREF_BIBR].	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	APOC2	APOC2	APOC2	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	14	15	17	19
35 In uremia patients , hypertriglyceridemia can also result from a relative increase in plasma ApoC3 ( an inhibitor of lipoprotein lipase ) and a relative decrease in plasma ApoC2 ( an activator of lipoprotein lipase ) .	35 In uremia patients, hypertriglyceridemia can also result from a relative increase in plasma ApoC3 (an inhibitor of lipoprotein lipase) and a relative decrease in plasma ApoC2 (an activator of lipoprotein lipase).	26	36	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	ApoC2	ApoC2	ApoC2	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	29	30	34	36
Dr Young : How apo-CII activates LPL is not clear .	Dr Young : How apo-CII activates LPL is not clear.	4	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	apo-CII	apo-CII	apo-CII	LPL	LPL	LPL	4	5	6	7
Minimal amounts of apoC-II are required to activate lipoprotein lipase beyond which there is no apparent increase in activity .	Minimal amounts of apoC-II are required to activate lipoprotein lipase beyond which there is no apparent increase in activity.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC-II	amounts of apoC-II	apoc-ii	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	8	10
Two apolipoproteins known to regulate VLDL lipolysis by lipoprotein lipase are apoC-II and apoC-III , which activate and inhibit lipoprotein lipase , respectively .	Two apolipoproteins known to regulate VLDL lipolysis by lipoprotein lipase are apoC-II and apoC-III, which activate and inhibit lipoprotein lipase, respectively.	1	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	11	12	19	21
Remnants prepared using this method acquire apoC-II , which activates hepatic lipoprotein lipase , and apoE , for clearance by the liver , from HDL present in the post-heparin plasma .	Remnants prepared using this method acquire apoC-II, which activates hepatic lipoprotein lipase, and apoE, for clearance by the liver, from HDL present in the post-heparin plasma.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	7	11	13
Acquisition of ApoC-II on CM surface enables the activation of lipoprotein lipase ( LPL ) .	Acquisition of ApoC-II on CM surface enables the activation of lipoprotein lipase (LPL).	0	12	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoC-II	ApoC-II	ApoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	10	12
However , in the jejunum , the level of Apoc3 mRNA expression ( inhibitor of LPL ) was significantly decreased in inulin treated groups ( main effect p-value treatment < 0.05 ) whereas the level of Apoc2 ( activator of LPL ) was increased in WD groups ( main effect p-value diet < 0.05 ) .	However, in the jejunum, the level of Apoc3 mRNA expression (inhibitor of LPL) was significantly decreased in inulin treated groups (main effect p-value treatment < 0.05) whereas the level of Apoc2 (activator of LPL) was increased in WD groups (main effect p-value diet < 0.05).	34	41	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Apoc2	level of Apoc2	apoc2	LPL	LPL	lpl	36	37	40	41
ApoC-II is an activator of LPL which hydrolyzes the core TGs , thereby , releasing FFAs and lowering TG levels .	ApoC-II is an activator of LPL which hydrolyzes the core TGs, thereby, releasing FFAs and lowering TG levels.	0	6	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ApoC-II	ApoC-II	ApoC-II	LPL	LPL	LPL	0	1	5	6
Apo A-IV has a role in radicals catabolism , activation of lipoprotein lipase by apoC-II and activation of LCAT .	Apo A-IV has a role in radicals catabolism, activation of lipoprotein lipase by apoC-II and activation of LCAT.	9	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	14	15	11	13
The transfer process involves anchoring to endothelial surfaces by glycosylphosphatidylinositol anchored HDL binding protein 1 and activation of LPL by apoCII , resulting in the hydrolysis of VLDL TG , the release of free fatty acids , and the formation of VLDL remnant particles .	The transfer process involves anchoring to endothelial surfaces by glycosylphosphatidylinositol anchored HDL binding protein 1 and activation of LPL by apoCII, resulting in the hydrolysis of VLDL TG, the release of free fatty acids, and the formation of VLDL remnant particles.	10	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	apoCII	apoCII	apoCII	LPL	LPL	LPL	20	21	18	19
During this process , the C apolipoproteins including apo C-II , which activates lipoprotein lipase , and apo C-III , which inhibits this enzyme , as well as apo A-I and apo A-IV are transferred to high-density lipoproteins ( HDLs ) .	During this process, the C apolipoproteins including apo C-II, which activates lipoprotein lipase, and apo C-III, which inhibits this enzyme, as well as apo A-I and apo A-IV are transferred to high-density lipoproteins (HDLs).	8	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apo C-II	apo C-II	apo C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	8	10	13	15
A quantitative relationship between fatty acyl chain length and the extent of maximal activation of LpL by apoC-II was observed : the logarithm of the activation factor is a linear function of the number of carbon atoms of a single fatty acyl chain of the substrates .	A quantitative relationship between fatty acyl chain length and the extent of maximal activation of LpL by apoC-II was observed : the logarithm of the activation factor is a linear function of the number of carbon atoms of a single fatty acyl chain of the substrates.	13	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	LpL	LpL	LpL	17	18	15	16
Increasing ApoCII or decreasing ApoCIII stimulates LPL to hydrolyze triglycerides carried by VLDL , thus accelerates serum VLDL clearance upon FXR activation .	Increasing ApoCII or decreasing ApoCIII stimulates LPL to hydrolyze triglycerides carried by VLDL, thus accelerates serum VLDL clearance upon FXR activation.	0	15	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ApoCII	ApoCII	ApoCII	LPL	LPL	LPL	1	2	6	7
ApoC-II is a protein activator of lipoprotein lipase which is an enzyme that hydrolyses triacylglycerol during the metabolism of chylomicrons and very low-density lipoproteins 24 .	ApoC-II is a protein activator of lipoprotein lipase which is an enzyme that hydrolyses triacylglycerol during the metabolism of chylomicrons and very low-density lipoproteins 24.	0	8	is a protein activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ApoC-II	ApoC-II	ApoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	6	8
We conclude that while guinea pig apoC-II is fully competent to stimulate lipoprotein lipase , the sum of several different factors explains the low ability of guinea pig plasma to accomplish stimulation .	We conclude that while guinea pig apoC-II is fully competent to stimulate lipoprotein lipase, the sum of several different factors explains the low ability of guinea pig plasma to accomplish stimulation.	4	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	7	12	14
Apolipoprotein C-II ( apoC-II ) , which is known to activate lipoprotein lipase ( LPL ) , was identified by ordered differential display ( ODD )-polymerase chain reaction ( PCR ) as a cDNA fragment exhibiting a distinct increase in expression during 12-O-tetradecanoylphorbol 13-acetate ( TPA )-induced differentiation of promonocytic U937 cells into monocytes and macrophages .	Apolipoprotein C-II (apoC-II), which is known to activate lipoprotein lipase (LPL), was identified by ordered differential display (ODD)-polymerase chain reaction (PCR) as a cDNA fragment exhibiting a distinct increase in expression during 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced differentiation of promonocytic U937 cells into monocytes and macrophages.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apolipoprotein C-II	Apolipoprotein C-II	Apolipoprotein C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	2	11	13
Once in the bloodstream , lipoprotein lipase ( LPL ) , an enzyme that is activated by apo C-II on the surface of chylomicrons , causes the chylomicrons to release fatty acids from triglycerides .	Once in the bloodstream, lipoprotein lipase (LPL), an enzyme that is activated by apo C-II on the surface of chylomicrons, causes the chylomicrons to release fatty acids from triglycerides.	5	19	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	apo C-II	apo C-II	apo C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	17	19	5	7
Apoa5 and Apoc2 activate Lpl , whose activity is further augmented by Apoa4 , to facilitate the delivery of hydrolyzed fatty acids to peripheral cells and hence to lower plasma TG levels XREF_BIBR , XREF_BIBR .	Apoa5 and Apoc2 activate Lpl, whose activity is further augmented by Apoa4, to facilitate the delivery of hydrolyzed fatty acids to peripheral cells and hence to lower plasma TG levels XREF_BIBR, XREF_BIBR.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apoc2	Apoc2	Apoc2	Lpl	Lpl	Lpl	2	3	4	5
Depletion of lncLSTR increases apoC2 expression , initiating LPL activation and enhances serum triglycerides clearance .	Depletion of lncLSTR increases apoC2 expression, initiating LPL activation and enhances serum triglycerides clearance.	4	9	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC2	apoC2 expression	apoc2	LPL	LPL	lpl	4	5	8	9
Of all of the peptides comprising fraction V , only apo C-II activated a purified preparation of rat adipose tissue lipoprotein lipase .	Of all of the peptides comprising fraction V, only apo C-II activated a purified preparation of rat adipose tissue lipoprotein lipase.	10	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apo C-II	apo C-II	apo C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	10	12	20	22
These results suggest that apolipoprotein C-II enhances the activity of LpL by increasing the affinity of the active site of LpL for triacylglycerol .	These results suggest that apolipoprotein C-II enhances the activity of LpL by increasing the affinity of the active site of LpL for triacylglycerol.	4	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apolipoprotein C-II	apolipoprotein C-II	apolipoprotein C-II	LpL	LpL	LpL	4	6	10	11
Addition of normal plasma to the assay as source for apoC-II enhanced LPL activity only to a limited extent .	Addition of normal plasma to the assay as source for apoC-II enhanced LPL activity only to a limited extent.	8	13	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	LPL	LPL	LPL	10	11	12	13
ApoC-II is a co-activator of lipoprotein lipase ( LPL ) and is known to be induced by FXR XREF_BIBR .	ApoC-II is a co-activator of lipoprotein lipase (LPL) and is known to be induced by FXR XREF_BIBR.	0	15	is a co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ApoC-II	ApoC-II	ApoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	5	7
Apolipoprotein C-II , a protein found associated with all major classes of plasma lipoproteins , is a potent activator of the enzyme lipoprotein lipase .	Apolipoprotein C-II, a protein found associated with all major classes of plasma lipoproteins, is a potent activator of the enzyme lipoprotein lipase.	0	24	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Apolipoprotein C-II	Apolipoprotein C-II	Apolipoprotein C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	2	22	24
For example , ApoC-II , a component of VLDL and chylomicrons , activates LPL , whereas ApoC-III inhibits LPL 33 .	For example, ApoC-II, a component of VLDL and chylomicrons, activates LPL, whereas ApoC-III inhibits LPL 33.	3	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ApoC-II	ApoC-II	ApoC-II	LPL	LPL	LPL	3	4	18	19
We suggest that while the binding of apoC-II to the lipid surface promotes the formation of a high and affinity complex of apoC-II and LpL , activation occurs via direct helix-helix interactions between apoC-II39-62 and the loop covering the active site of LpL .	We suggest that while the binding of apoC-II to the lipid surface promotes the formation of a high and affinity complex of apoC-II and LpL, activation occurs via direct helix-helix interactions between apoC-II39-62 and the loop covering the active site of LpL.	5	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	LpL	LpL	LpL	7	8	24	25
Apo-C-II is the major activator of lipoprotein lipase , an enzyme which plays a key role in lipoprotein catabolism .	Apo-C-II is the major activator of lipoprotein lipase, an enzyme which plays a key role in lipoprotein catabolism.	0	8	is the major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Apo-C-II	Apo-C-II	Apo-C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	6	8
Furthermore , analysis of apolipoprotein profiles from the blood of Ces1g deficient mice showed protein composition changes , including increased apoE and apoCIII ( an endogenous inhibitor of lipoprotein lipase ( LpL ) ) and decreased apoCII levels ( an endogenous activator of LpL ) , which can cause blunted blood apoB containing lipoprotein clearance and contribute to the observed hyperlipidemia .	Furthermore, analysis of apolipoprotein profiles from the blood of Ces1g deficient mice showed protein composition changes, including increased apoE and apoCIII (an endogenous inhibitor of lipoprotein lipase (LpL)) and decreased apoCII levels (an endogenous activator of LpL), which can cause blunted blood apoB containing lipoprotein clearance and contribute to the observed hyperlipidemia.	4	44	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	apoCII	apolipoprotein profiles from the blood of Ces1g deficient mice showed protein composition changes, including increased apoE and apoCIII (an endogenous inhibitor of lipoprotein lipase (LpL)) and decreased apoCII levels	apocii	LpL	LpL	lpl	36	37	43	44
Interestingly , it was shown that LVP treatment with ApoC-II activated LPL leads to a shift of particles to higher-densities and to a lower amount of virion associated ApoE , crucially reducing HCV infectivity [ XREF_BIBR , XREF_BIBR ] .	Interestingly, it was shown that LVP treatment with ApoC-II activated LPL leads to a shift of particles to higher-densities and to a lower amount of virion associated ApoE, crucially reducing HCV infectivity [XREF_BIBR, XREF_BIBR].	7	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoC-II	ApoC-II	ApoC-II	LPL	LPL	LPL	9	10	11	12
Apo-CII is an activator of LPL , whereas apo-CIII inhibits the activity of the enzyme [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Apo-CII is an activator of LPL, whereas apo-CIII inhibits the activity of the enzyme [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	6	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Apo-CII	Apo-CII	Apo-CII	LPL	LPL	LPL	0	1	5	6
To elucidate the mechanism by which apolipoprotein C-II ( apoC-II ) enhances the activity of lipoprotein lipase ( LpL ) , discoidal phospholipid complexes were prepared with apoC-III and di [ ( 14 ) C ] palmitoyl phosphatidylcholine ( DPPC ) and containing various amounts of apoC-II .	To elucidate the mechanism by which apolipoprotein C-II (apoC-II) enhances the activity of lipoprotein lipase (LpL), discoidal phospholipid complexes were prepared with apoC-III and di [(14) C] palmitoyl phosphatidylcholine (DPPC) and containing various amounts of apoC-II.	3	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apolipoprotein C-II	apolipoprotein C-II	apolipoprotein C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	8	15	17
These studies suggest that the maximal activation of LPL by apoC-II requires a minimal sequence contained within residues 55 -- 78 .	These studies suggest that the maximal activation of LPL by apoC-II requires a minimal sequence contained within residues 55 -- 78.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	LPL	LPL	LPL	10	11	8	9
FCS may be due to pathogenic variants in lipoprotein lipase ( LPL ) , as well as in other proteins , such as apolipoprotein C-II and apolipoprotein A-V ( activators of LPL ) , GPIHBP1 ( the molecular platform required for LPL activity on endothelial surface ) and LMF1 ( a factor required for intracellular formation of active LPL ) .	FCS may be due to pathogenic variants in lipoprotein lipase (LPL), as well as in other proteins, such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface) and LMF1 (a factor required for intracellular formation of active LPL).	23	32	activators	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	apolipoprotein C-II	apolipoprotein C-II	apolipoprotein C-II	LPL	LPL	LPL	23	25	31	32
In contrast , more is known about the portions of the apo-CII molecule that are required to activate LPL .	In contrast, more is known about the portions of the apo-CII molecule that are required to activate LPL.	11	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apo-CII	apo-CII	apo-CII	LPL	LPL	LPL	11	12	18	19
ApoCII , at the physiological plasma level , is a specific activator of lipoprotein lipase and plays a central role in regulating the lipoprotein derived triglyceride hydrolysis .	ApoCII, at the physiological plasma level, is a specific activator of lipoprotein lipase and plays a central role in regulating the lipoprotein derived triglyceride hydrolysis.	0	16	is a specific activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ApoCII	ApoCII	ApoCII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	13	15
Lipoprotein lipase ( LpL ) activity is enhanced by apolipoprotein C-II ( apoC-II ) , a 79 amino acid residue peptide .	Lipoprotein lipase (LpL) activity is enhanced by apolipoprotein C-II (apoC-II), a 79 amino acid residue peptide.	0	11	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apolipoprotein C-II	apolipoprotein C-II	apolipoprotein C-II	Lipoprotein lipase	Lipoprotein lipase	Lipoprotein lipase	9	11	0	2
ApoC-II , on the other hand , is a major activator of lipoprotein lipase , which is required for an efficient processing of triglyceride rich lipoproteins in the circulation .	ApoC-II, on the other hand, is a major activator of lipoprotein lipase, which is required for an efficient processing of triglyceride rich lipoproteins in the circulation.	0	14	is a major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ApoC-II	ApoC-II	ApoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	12	14
At intermediate concentrations ( approximately 4 mg/dL ) and in normolipidemic subjects , apoC-II activates LPL .	At intermediate concentrations (approximately 4 mg/dL) and in normolipidemic subjects, apoC-II activates LPL.	13	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	LPL	LPL	LPL	13	14	15	16
Hydrolysis of a short-chain fatty acid ester indicated that R75S does not directly affect activation of LPL by apoC-II .	Hydrolysis of a short-chain fatty acid ester indicated that R75S does not directly affect activation of LPL by apoC-II.	13	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	LPL	LPL	LPL	18	19	16	17
However , analogous to circulating lipoproteins where overexpression of many apolipoproteins including apoC-II that activates lipoprotein lipase ( LpL ) results in hypertriglyceridemia , 58 excess protein coating of the lipid droplet by amphipathic proteins prevents lipolysis by non physiologic processes .	However, analogous to circulating lipoproteins where overexpression of many apolipoproteins including apoC-II that activates lipoprotein lipase (LpL) results in hypertriglyceridemia, 58 excess protein coating of the lipid droplet by amphipathic proteins prevents lipolysis by non physiologic processes.	7	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	12	13	15	17
Serum amyloid A proteins are a family of apolipoproteins associated with high-density lipoprotein in plasma ; apolipoprotein C-II is responsible for activation of lipoprotein lipase .	Serum amyloid A proteins are a family of apolipoproteins associated with high-density lipoprotein in plasma; apolipoprotein C-II is responsible for activation of lipoprotein lipase.	16	25	is responsible for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	apolipoprotein C-II	apolipoprotein C-II	apolipoprotein C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	16	18	23	25
Apolipoprotein C-II ( APOC2 ) is an obligatory activator of lipoprotein lipase .	Apolipoprotein C-II (APOC2) is an obligatory activator of lipoprotein lipase.	0	12	is an obligatory activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Apolipoprotein C-II	Apolipoprotein C-II	Apolipoprotein C-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	2	10	12
Apolipoprotein CII ( apoCII ) activates lipoprotein lipase ( LPL ) .	Apolipoprotein CII (apoCII) activates lipoprotein lipase (LPL).	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoCII	apoCII	apoCII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	6	8
However , there is also conflicting evidence that Ang-2 may cause Tie2 activation in stressed endothelial cells XREF_BIBR .	However, there is also conflicting evidence that Ang-2 may cause Tie2 activation in stressed endothelial cells XREF_BIBR.	8	12	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	8	9	11	12
It is plausible that ANGPT2 antagonizes ANGPT1 in quiescent ECs to inhibit TIE2 activation while it synergizes ANGPT1 in TIE2 phosphorylation to promote angiogenesis .	It is plausible that ANGPT2 antagonizes ANGPT1 in quiescent ECs to inhibit TIE2 activation while it synergizes ANGPT1 in TIE2 phosphorylation to promote angiogenesis.	4	13	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	4	5	12	13
This loop in the antagonist Ang2 permits Tie1 and Tie2 heterodimerization , whereas the equivalent loop in the agonist Ang1 disrupts the electrostatic interaction , promoting Tie2 clustering and activation of downstream signaling cascades .	This loop in the antagonist Ang2 permits Tie1 and Tie2 heterodimerization, whereas the equivalent loop in the agonist Ang1 disrupts the electrostatic interaction, promoting Tie2 clustering and activation of downstream signaling cascades.	1	27	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	5	6	26	27
Independently , another report indicates that interactions between Tie-1 and Tie-2 play an important role in the activation of Tie-2 by ANG-2 .	Independently, another report indicates that interactions between Tie-1 and Tie-2 play an important role in the activation of Tie-2 by ANG-2.	11	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ANG-2	ANG-2	ANG-2	Tie-2	Tie-2	Tie-2	21	22	19	20
In addition , we show that Ang-2 , like Ang-1 , activates Tie2 and Akt signaling in vivo , thereby inhibiting the expression of FOXO1 target genes .	In addition, we show that Ang-2, like Ang-1, activates Tie2 and Akt signaling in vivo, thereby inhibiting the expression of FOXO1 target genes.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	6	7	12	13
To determine if ANGPT2 enhances TIE2 signaling above the effect of VEPTP inhibition alone , we tested the downstream signaling activity in response to either ANGPT2 or VEPTP inhibition alone or in combination in primary and transformed endothelial cell-lines .	To determine if ANGPT2 enhances TIE2 signaling above the effect of VEPTP inhibition alone, we tested the downstream signaling activity in response to either ANGPT2 or VEPTP inhibition alone or in combination in primary and transformed endothelial cell-lines.	3	6	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	3	4	5	6
XREF_BIBR The ability of the aptamer to selectively block ANGPT2 mediated TIE2 activation , but not ANGPT1 mediated TIE2 activation , was first confirmed in vitro using a TIE2 receptor phosphorylation assay ( XREF_FIG ) .	XREF_BIBR The ability of the aptamer to selectively block ANGPT2 mediated TIE2 activation, but not ANGPT1 mediated TIE2 activation, was first confirmed in vitro using a TIE2 receptor phosphorylation assay (XREF_FIG).	8	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	9	10	11	12
Ang-2 does not result in activation of the receptor Tie2 .	Ang-2 does not result in activation of the receptor Tie2.	0	10	result in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	0	1	9	10
Such a cell dependent Tie2 activation by Ang2 was explained by comparing EPCs and HUVECs , where most Tie2 receptors in EPCs were found to be present unbound to Tie1 , whereas those in HUVECs existed as heterocomplexes with Tie1 .	Such a cell dependent Tie2 activation by Ang2 was explained by comparing EPCs and HUVECs, where most Tie2 receptors in EPCs were found to be present unbound to Tie1, whereas those in HUVECs existed as heterocomplexes with Tie1.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	7	8	4	5
Paradoxically , VEGF induced shedding of Tie2 by AKT signaling has been recently described in endothelial cells , and AKT induced Ang2 promotes the endocytosis of Tie2 XREF_BIBR , XREF_BIBR , XREF_BIBR .	Paradoxically, VEGF induced shedding of Tie2 by AKT signaling has been recently described in endothelial cells, and AKT induced Ang2 promotes the endocytosis of Tie2 XREF_BIBR, XREF_BIBR, XREF_BIBR.	19	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	AKT induced Ang2	ang2	Tie2	Tie2	tie2	21	22	26	27
Alternatively , when Tie1 and Tie2 expressing U2OS or EA.hy 926 cells are treated with similar concentrations of Ang-2 , no changes in the Tie1-Tie2 association and/or Tie2 localization are observed ( Compare XREF_FIG and right bottom panels in XREF_FIG ) .	Alternatively, when Tie1 and Tie2 expressing U2OS or EA.hy 926 cells are treated with similar concentrations of Ang-2, no changes in the Tie1-Tie2 association and/or Tie2 localization are observed (Compare XREF_FIG and right bottom panels in XREF_FIG).	3	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	18	19	5	6
Oppositely , Ang-2 increased pTie-2 in the absence of Ang-1 in MS-1 cells ( XREF_SUPPLEMENTARY ) .	Oppositely, Ang-2 increased pTie-2 in the absence of Ang-1 in MS-1 cells (XREF_SUPPLEMENTARY).	2	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	pTie-2	pTie-2	pTie-2	2	3	4	5
Angiopoietin-2 , produced by activated EC , upregulates its receptor Tie2 on macrophages and maintains these M2 like cells in the neighborhood of blood vessels , at least for a while .	Angiopoietin-2, produced by activated EC, upregulates its receptor Tie2 on macrophages and maintains these M2 like cells in the neighborhood of blood vessels, at least for a while.	0	14	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angiopoietin-2	Angiopoietin-2	Angiopoietin-2	Tie2	Tie2	Tie2	0	1	10	11
For instance , Ang2 activates Tie2 in cultured endothelial cells , inducing chemotaxis and tube formation .	For instance, Ang2 activates Tie2 in cultured endothelial cells, inducing chemotaxis and tube formation.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	3	4	5	6
To investigate the effect of tumor cells on Ang2 induced Tie2 signaling , we cultured Tie2-GFP expressing blood vascular endothelial cells on Transwell filters in the presence or absence of the LNM35 lung carcinoma cells in the lower compartment .	To investigate the effect of tumor cells on Ang2 induced Tie2 signaling, we cultured Tie2-GFP expressing blood vascular endothelial cells on Transwell filters in the presence or absence of the LNM35 lung carcinoma cells in the lower compartment.	1	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	8	9	10	11
In mice carrying orthotopic mammary tumors , ANG2 blockade inhibited tumor angiogenesis , growth , and metastasis , and impaired the activity of proangiogenic TIE2 + macrophages .	In mice carrying orthotopic mammary tumors, ANG2 blockade inhibited tumor angiogenesis, growth, and metastasis, and impaired the activity of proangiogenic TIE2 + macrophages.	7	26	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ANG2	ANG2	ANG2	TIE2	TIE2	TIE2	7	8	24	25
To further explore the role of the Tie-2 pathway in this system , ES cells were treated with either Ang-1 or Ang-2 .	To further explore the role of the Tie-2 pathway in this system, ES cells were treated with either Ang-1 or Ang-2.	7	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	21	22	7	8
Ang1 and Ang2 were shown to stimulate Tie2 independent cell adhesion of ECs and fibroblasts to Ang1- or Ang2 coated surfaces through alpha 5 beta 1 and alpha v beta 5 integrin mediated activation of ERK and focal adhesion kinase ( FAK ) signaling [ XREF_BIBR ] .	Ang1 and Ang2 were shown to stimulate Tie2 independent cell adhesion of ECs and fibroblasts to Ang1- or Ang2 coated surfaces through alpha 5 beta 1 and alpha v beta 5 integrin mediated activation of ERK and focal adhesion kinase (FAK) signaling [XREF_BIBR].	0	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	2	3	7	8
However , high concentrations of Ang2 or prolonged exposure of endothelial cells to Ang2 have been shown to activate Tie2 signaling , although the mechanisms of this paradoxical agonist activity of Ang2 are not well understood [ XREF_BIBR ] .	However, high concentrations of Ang2 or prolonged exposure of endothelial cells to Ang2 have been shown to activate Tie2 signaling, although the mechanisms of this paradoxical agonist activity of Ang2 are not well understood [XREF_BIBR].	5	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	5	6	19	20
Accordingly , it has been described that HBV and HCV could enhance Ang2 promoter expression through mitogen activated protein kinase ( MAPK ) pathways XREF_BIBR and other authors have reported that pericytes express a functionally active Tie2 receptor which may be significantly upregulated by both Ang1 and Ang2 , concluding that the Angiopoietin and Tie2 axis influences the activation state and recruitment of pericytes during angiogenesis XREF_BIBR .	Accordingly, it has been described that HBV and HCV could enhance Ang2 promoter expression through mitogen activated protein kinase (MAPK) pathways XREF_BIBR and other authors have reported that pericytes express a functionally active Tie2 receptor which may be significantly upregulated by both Ang1 and Ang2, concluding that the Angiopoietin and Tie2 axis influences the activation state and recruitment of pericytes during angiogenesis XREF_BIBR.	36	48	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	47	48	36	37
Exogenous Ang2 activates Tie2 and the promigratory , prosurvival PI3K and Akt pathway in ECs but with less potency and lower affinity than exogenous Ang1 .	Exogenous Ang2 activates Tie2 and the promigratory, prosurvival PI3K and Akt pathway in ECs but with less potency and lower affinity than exogenous Ang1.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	1	2	3	4
The context dependent activation of Tie2 by Ang2 likely occurs when Tie1 is not present in high concentrations within the cell , highlighting the complexity of Tie receptor regulation .	The context dependent activation of Tie2 by Ang2 likely occurs when Tie1 is not present in high concentrations within the cell, highlighting the complexity of Tie receptor regulation.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	7	8	5	6
In contrast , Ang2 was first identified as an endogenous antagonist to Tie2 but is now recognized to have context dependent agonistic properties , and has been reported to activate the Tie2 receptor at high concentration or during prolonged incubation .	In contrast, Ang2 was first identified as an endogenous antagonist to Tie2 but is now recognized to have context dependent agonistic properties, and has been reported to activate the Tie2 receptor at high concentration or during prolonged incubation.	3	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	3	4	31	32
In the absence of Ang-1 , or when Ang-2 is present in high concentrations , Ang-2 can stimulate Tie2 signaling XREF_BIBR .	In the absence of Ang-1, or when Ang-2 is present in high concentrations, Ang-2 can stimulate Tie2 signaling XREF_BIBR.	15	20	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	15	16	18	19
Recent studies found that Ang2 can directly stimulate Tie2 and that both Ang1 and Ang2 can be pro inflammatory .	Recent studies found that Ang2 can directly stimulate Tie2 and that both Ang1 and Ang2 can be pro inflammatory.	4	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	4	5	8	9
In cell culture , Ang2 promotes cell migration and invasion in Tie2 deficient breast cancer cells through the alpha ( 5 ) beta ( 1 ) integrin and integrin linked kinase ( ILK )/Akt , GSK-3beta/Snail/E-cadherin signaling pathway .	In cell culture, Ang2 promotes cell migration and invasion in Tie2 deficient breast cancer cells through the alpha (5) beta (1) integrin and integrin linked kinase (ILK)/Akt, GSK-3beta/Snail/E-cadherin signaling pathway.	4	30	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	4	5	11	12
Such a cell dependent differential reactivity of Ang2 was for the first time found to be modulated by physical association between Tie1 and Tie2 , which inhibited Ang2 mediated Tie2 activation .	Such a cell dependent differential reactivity of Ang2 was for the first time found to be modulated by physical association between Tie1 and Tie2, which inhibited Ang2 mediated Tie2 activation.	26	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	27	28	29	30
Therefore , during ischemia the increased Ang2 may block Tie2 mediated inhibition of NF-kappaB , resulting in increased ICAM-1 and VCAM-1 expression and the subsequent monocyte adhesion .	Therefore, during ischemia the increased Ang2 may block Tie2 mediated inhibition of NF-kappaB, resulting in increased ICAM-1 and VCAM-1 expression and the subsequent monocyte adhesion.	4	11	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	6	7	9	10
In another study , an ANGPT2 antibody that stimulated TIE2 activation was used to stabilize the vasculature in mouse sepsis models whereas conventional ANGPT2-TIE2 neutralizing antibodies were less effective .	In another study, an ANGPT2 antibody that stimulated TIE2 activation was used to stabilize the vasculature in mouse sepsis models whereas conventional ANGPT2-TIE2 neutralizing antibodies were less effective.	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	5	6	9	10
144 It was also noted by the authors of this study that ANG-2 in fibroblasts could activate TIE2 receptors when VEGF is absent , and this ANG-2 stimulation may lead to vessel regression .	144 It was also noted by the authors of this study that ANG-2 in fibroblasts could activate TIE2 receptors when VEGF is absent, and this ANG-2 stimulation may lead to vessel regression.	12	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANG-2	ANG-2	ANG-2	TIE2	TIE2	TIE2	12	13	17	18
Taken together , loss and gain of function studies in mice suggest that Ang2 might function as an antagonist of Ang1 to modulate Tie2 receptor activity .	Taken together, loss and gain of function studies in mice suggest that Ang2 might function as an antagonist of Ang1 to modulate Tie2 receptor activity.	13	25	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	13	14	23	24
Ang-1 or Ang-2 activates the transmembrane endothelial tyrosine kinase Tie2 , which mediates the quiescent , healthy state of blood vessels [ XREF_BIBR ] .	Ang-1 or Ang-2 activates the transmembrane endothelial tyrosine kinase Tie2, which mediates the quiescent, healthy state of blood vessels [XREF_BIBR].	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	2	3	9	10
The secretion of ANGPT2 by tumour cells has been proposed to induce chemotaxis of TIE2 + monocytes XREF_BIBR , XREF_BIBR , XREF_BIBR .	The secretion of ANGPT2 by tumour cells has been proposed to induce chemotaxis of TIE2 + monocytes XREF_BIBR, XREF_BIBR, XREF_BIBR.	1	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	3	4	14	15
One explanation is that Angpt 2 may also activate Tie2 receptor during the development of glomerular hypertrophy following uninephrectomy .	One explanation is that Angpt 2 may also activate Tie2 receptor during the development of glomerular hypertrophy following uninephrectomy.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angpt 2	Angpt 2	Angpt 2	Tie2	Tie2	Tie2	4	6	9	10
Interestingly , overexpression of another ligand of Tie-2 , Ang-2 , causes a phenotype similar to Tie-2-deficient mice , XREF_BIBR - XREF_BIBR suggesting that Ang-2 might function as an antagonist of Ang-1 to modulate the activity of Tie-2 .	Interestingly, overexpression of another ligand of Tie-2, Ang-2, causes a phenotype similar to Tie-2-deficient mice, XREF_BIBR - XREF_BIBR suggesting that Ang-2 might function as an antagonist of Ang-1 to modulate the activity of Tie-2.	24	38	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	24	25	37	38
Ang2 , but not Ang1 , induces the concomitant and transient expression of Tie2 and VE-PTP mRNA .	Ang2, but not Ang1, induces the concomitant and transient expression of Tie2 and VE-PTP mRNA.	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	0	1	13	14
Our results demonstrate that the activation of Tie-2 by Ang2 stimulation was as effective as by Ang1 stimulation in bmLECs .	Our results demonstrate that the activation of Tie-2 by Ang2 stimulation was as effective as by Ang1 stimulation in bmLECs.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie-2	Tie-2	Tie-2	9	10	7	8
On the contrary , Angiopoietin-2 , is unable to dissociate the inhibitory Tie2 and Tie1 complexes upon binding Tie2 and , therefore , does not induce Tie2 clustering and signaling , yet behaves as a competitive antagonist by blocking further binding of Ang-1 .	On the contrary, Angiopoietin-2, is unable to dissociate the inhibitory Tie2 and Tie1 complexes upon binding Tie2 and, therefore, does not induce Tie2 clustering and signaling, yet behaves as a competitive antagonist by blocking further binding of Ang-1.	4	32	induce	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Angiopoietin-2	Angiopoietin-2	Angiopoietin-2	Tie2	Tie2	Tie2	4	5	26	27
Both in vitro and in vivo experiments showed that Ang2 promoted angiogenicity of human cord blood derived EPCs , where Ang2 directly activated Tie2 and its related downstream signaling molecules .	Both in vitro and in vivo experiments showed that Ang2 promoted angiogenicity of human cord blood derived EPCs, where Ang2 directly activated Tie2 and its related downstream signaling molecules.	20	29	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	20	21	23	24
Both Ang1 and Ang2 activate the EC membrane receptor tyrosine kinase TIE2 .	Both Ang1 and Ang2 activate the EC membrane receptor tyrosine kinase TIE2.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	TIE2	TIE2	TIE2	3	4	11	12
Ang-2 , an Ang secreted mainly from ECs , activates Tie-2 , which is much weaker than Ang-1 and acts as an antagonist of Ang-1 to detach pericytes from ECs .	Ang-2, an Ang secreted mainly from ECs, activates Tie-2, which is much weaker than Ang-1 and acts as an antagonist of Ang-1 to detach pericytes from ECs.	0	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	0	1	10	11
XREF_BIBR ; XREF_BIBR ; XREF_BIBR Ang2 carries out its effects through binding to Tie2 , a tyrosine kinase receptor specific to BECs , and through unknown mechanisms , Ang2 can either activate or repress Tie2 signaling .	XREF_BIBR; XREF_BIBR; XREF_BIBR Ang2 carries out its effects through binding to Tie2, a tyrosine kinase receptor specific to BECs, and through unknown mechanisms, Ang2 can either activate or repress Tie2 signaling.	28	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	28	29	34	35
Firstly , both Ang1 and Ang2 activated Tie-2 and downstream ERK1/2 in bmLEC .	Firstly, both Ang1 and Ang2 activated Tie-2 and downstream ERK1/2 in bmLEC.	3	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie-2	Tie-2	Tie-2	5	6	7	8
Although Ang2 at high concentration weakly activated Tie2 and p70 S6K , it failed to activate Ras and MAPK , or to induce cell proliferation .	Although Ang2 at high concentration weakly activated Tie2 and p70 S6K, it failed to activate Ras and MAPK, or to induce cell proliferation.	1	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	1	2	7	8
Conversely , PECAM1 acts as a brake on the positive signaling induced by Ang-2 on Tie-2 , thus reducing the rate and degree of vascular sprouting .	Conversely, PECAM1 acts as a brake on the positive signaling induced by Ang-2 on Tie-2, thus reducing the rate and degree of vascular sprouting.	11	16	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	13	14	15	16
In addition , Ang2 blocking targeted the Tie2 positive pro angiogenic macrophage ( TEM ) population in the lung metastasis .	In addition, Ang2 blocking targeted the Tie2 positive pro angiogenic macrophage (TEM) population in the lung metastasis.	3	11	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	3	4	7	8
A number of in vitro studies have shown that ANGPT2 can activate the TIE2 receptor under various circumstances including in non ECs lacking inhibitory coreceptors , XREF_BIBR over extended periods of time XREF_BIBR or at very high concentrations .	A number of in vitro studies have shown that ANGPT2 can activate the TIE2 receptor under various circumstances including in non ECs lacking inhibitory coreceptors, XREF_BIBR over extended periods of time XREF_BIBR or at very high concentrations.	9	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	9	10	13	14
Golvatinib inhibited the Tie2 upregulation induced by hypoxia and Ang2 .	Golvatinib inhibited the Tie2 upregulation induced by hypoxia and Ang2.	3	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	9	10	3	4
Recently , extracellular cleavage of TIE1 has been shown to play a role in ANGPT2 mediated TIE2 antagonism in BECs during inflammation .	Recently, extracellular cleavage of TIE1 has been shown to play a role in ANGPT2 mediated TIE2 antagonism in BECs during inflammation.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	14	15	16	17
Although both Ang-1 and Ang-2 mediate Tie-2 clustering at cell-cell contacts , their differential signalling may explain their opposing effects on vascular stability .	Although both Ang-1 and Ang-2 mediate Tie-2 clustering at cell-cell contacts, their differential signalling may explain their opposing effects on vascular stability.	2	7	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	4	5	6	7
Ang-2 activates TIE-2 on some cells but blocks it on others while Ang-1 consistently activates TIE-2 .	Ang-2 activates TIE-2 on some cells but blocks it on others while Ang-1 consistently activates TIE-2.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	TIE-2	TIE-2	TIE-2	0	1	2	3
Under different conditions , ANG-2 can either enhance Tie-2 signaling to promote vessel remodeling , or it can suppress phosphorylation of Tie-2 and its downstream targets to cause vessel instability and regression .	Under different conditions, ANG-2 can either enhance Tie-2 signaling to promote vessel remodeling, or it can suppress phosphorylation of Tie-2 and its downstream targets to cause vessel instability and regression.	4	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANG-2	ANG-2	ANG-2	Tie-2	Tie-2	Tie-2	4	5	8	9
Tie2 Dependent Neovascularization of the Ischemic Hindlimb Is Mediated by Angiopoietin-2 .	Tie2 Dependent Neovascularization of the Ischemic Hindlimb Is Mediated by Angiopoietin-2.	0	11	Mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Angiopoietin-2	Angiopoietin-2	Angiopoietin-2	Tie2	Tie2	Tie2	10	11	0	1
Collectively , these results support a mechanism in which the aptamer selectively blocks ANGPT2 mediated TIE2 activation and does not interfere with the interaction between ANGPT1 and TIE2 .	Collectively, these results support a mechanism in which the aptamer selectively blocks ANGPT2 mediated TIE2 activation and does not interfere with the interaction between ANGPT1 and TIE2.	12	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	13	14	15	16
ANGPT2 also stimulates TIE2 + macrophages to upregulate interleukin 10 ( IL10 ) , which likely suppresses cytotoxic T cells in PV tumor areas .	ANGPT2 also stimulates TIE2 + macrophages to upregulate interleukin 10 (IL10), which likely suppresses cytotoxic T cells in PV tumor areas.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	0	1	3	4
In the first case , Tie2 inhibition could be mediated by inhibition of either Ang1 or Ang2 separately or both together , while in the second case , multi-kinase small molecule inhibitors show low target specificity .	In the first case, Tie2 inhibition could be mediated by inhibition of either Ang1 or Ang2 separately or both together, while in the second case, multi-kinase small molecule inhibitors show low target specificity.	5	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	16	17	5	6
Increased levels of Ang-2 in diabetic animals and in vitreous fluid of patients with proliferative diabetic retinopathy support the role of the Ang-2 and Tie-2 system in the pathogenesis of diabetic retinopathy , but the underlying mechanisms remain to be investigated .	Increased levels of Ang-2 in diabetic animals and in vitreous fluid of patients with proliferative diabetic retinopathy support the role of the Ang-2 and Tie-2 system in the pathogenesis of diabetic retinopathy, but the underlying mechanisms remain to be investigated.	1	25	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	levels of Ang-2	ang-2	Tie-2	Tie-2	tie-2	3	4	24	25
ANG-1 and ANG-2 can activate TIE-2 to enhance survival , growth and migration of LECs under various physiological and pathological circumstances [ XREF_BIBR ] .	ANG-1 and ANG-2 can activate TIE-2 to enhance survival, growth and migration of LECs under various physiological and pathological circumstances [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANG-2	ANG-2	ANG-2	TIE-2	TIE-2	TIE-2	2	3	5	6
With reduced VEGF availability , an increase in Ang-2 level following Cd exposure blocks Tie-2 signaling , which is essential for vascular growth [ XREF_BIBR ] .	With reduced VEGF availability, an increase in Ang-2 level following Cd exposure blocks Tie-2 signaling, which is essential for vascular growth [XREF_BIBR].	8	15	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2 level	ang-2	Tie-2	Tie-2	tie-2	8	9	14	15
In this case Tie1 cleavage would increase both Ang1 mediated Tie2 activation and Ang2 mediated Tie2 activation .	In this case Tie1 cleavage would increase both Ang1 mediated Tie2 activation and Ang2 mediated Tie2 activation.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	13	14	15	16
While previous knockout mouse studies have demonstrated a role for ANGPT2 in lymphatic development , to our knowledge this report of a requirement for TIE2 signaling in lymphatic development , demonstrating ANGPT2 activation of TIE2 occurs in LECs in vivo , is unique .	While previous knockout mouse studies have demonstrated a role for ANGPT2 in lymphatic development, to our knowledge this report of a requirement for TIE2 signaling in lymphatic development, demonstrating ANGPT2 activation of TIE2 occurs in LECs in vivo, is unique.	31	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	31	32	34	35
Autocrine Ang2 signalling in Tie2 silenced endothelial cells and in the Ang2 transgenic mice , which show reduced Tie2 localization in the endothelial cell-cell junctions , promotes changes in the cytoskeleton , matrix adhesion and cell junctions that lead to reduced cell-cell adhesion .	Autocrine Ang2 signalling in Tie2 silenced endothelial cells and in the Ang2 transgenic mice, which show reduced Tie2 localization in the endothelial cell-cell junctions, promotes changes in the cytoskeleton, matrix adhesion and cell junctions that lead to reduced cell-cell adhesion.	1	5	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	1	2	4	5
In certain contexts or at high levels , Ang2 has also been shown to activate Tie2 .	In certain contexts or at high levels, Ang2 has also been shown to activate Tie2.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	8	9	15	16
Generally ANG2 is a weaker agonist for the TIE2 receptor , and in the presence of ANG1 it actually inhibits its actions ; but if ANG1 is absent ANG2 activates the TIE2 receptor and downstream signalling of PI3K and AKT ( XREF_FIG ) .	Generally ANG2 is a weaker agonist for the TIE2 receptor, and in the presence of ANG1 it actually inhibits its actions; but if ANG1 is absent ANG2 activates the TIE2 receptor and downstream signalling of PI3K and AKT (XREF_FIG).	28	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANG2	ANG2	ANG2	TIE2	TIE2	TIE2	28	29	31	32
The impact of Tie1 on Ang2 activation of Tie2 was further examined by suppression of Tie1 expression using siRNA .	The impact of Tie1 on Ang2 activation of Tie2 was further examined by suppression of Tie1 expression using siRNA.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	5	6	8	9
Here , we observed that Ang2 further enhanced the gelatinolytic properties of TEMs but not Tie2 - monocytes .	Here, we observed that Ang2 further enhanced the gelatinolytic properties of TEMs but not Tie2 - monocytes.	5	17	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	5	6	15	16
Furthermore , both Ang-1 and Ang-2 were reported to induce HUVEC tube formation via Tie-2 receptor , suggesting that both Ang-1 and Ang-2 activate Tie-2 signaling in the absence of pericytes or smooth muscle cells [ XREF_BIBR ] .	Furthermore, both Ang-1 and Ang-2 were reported to induce HUVEC tube formation via Tie-2 receptor, suggesting that both Ang-1 and Ang-2 activate Tie-2 signaling in the absence of pericytes or smooth muscle cells [XREF_BIBR].	20	25	activate	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	22	23	24	25
However , Ang1 and Ang2 were found to bind differently and Tie1 does not affect Ang2 binding or total number of Tie2 receptors ( partially ) activated by Ang2 .	However, Ang1 and Ang2 were found to bind differently and Tie1 does not affect Ang2 binding or total number of Tie2 receptors (partially) activated by Ang2.	21	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	28	29	21	22
Association of cell surface Tie1 with Tie2 inhibited Ang-2 mediated Tie2 activation .	Association of cell surface Tie1 with Tie2 inhibited Ang-2 mediated Tie2 activation.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	8	9	10	11
Together , these data indicate that ANG2 activation of Tie2 supports stable enlargement of normal nonleaky vessels , but reduction of Tie1 in inflammation leads to ANG2 antagonism of Tie2 and initiates a positive feedback loop wherein FOXO1 driven ANG2 expression promotes vascular remodeling and leakage .	Together, these data indicate that ANG2 activation of Tie2 supports stable enlargement of normal nonleaky vessels, but reduction of Tie1 in inflammation leads to ANG2 antagonism of Tie2 and initiates a positive feedback loop wherein FOXO1 driven ANG2 expression promotes vascular remodeling and leakage.	26	30	antagonism	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ANG2	ANG2	ANG2	Tie2	Tie2	Tie2	26	27	29	30
In contrast exogenously administered Angpt2 has been demonstrated to activate Tie2 and limit angiogenesis both in vivo and in vitro XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	In contrast exogenously administered Angpt2 has been demonstrated to activate Tie2 and limit angiogenesis both in vivo and in vitro XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angpt2	Angpt2	Angpt2	Tie2	Tie2	Tie2	4	5	10	11
Contrary to Ang-1 and Tie2 signaling Ang-2 autocrine signaling via the Tie2 receptor results in loss of cell-cell contacts and vascular destabilization ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	Contrary to Ang-1 and Tie2 signaling Ang-2 autocrine signaling via the Tie2 receptor results in loss of cell-cell contacts and vascular destabilization (XREF_FIG) [XREF_BIBR, XREF_BIBR].	0	13	signaling	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	6	7	4	5
One possibility is that enhanced inflammation in LPS injured ANGPT2 OVR mice could be due to the chemoattractant properties of ANGPT2 , which has previously been shown to recruit TIE2 positive monocytes and macrophages and neutrophils , XREF_BIBR while decreased vascular leak could be mediated separately through the ANGPT2 dependent activation of endothelial TIE2 .	One possibility is that enhanced inflammation in LPS injured ANGPT2 OVR mice could be due to the chemoattractant properties of ANGPT2, which has previously been shown to recruit TIE2 positive monocytes and macrophages and neutrophils, XREF_BIBR while decreased vascular leak could be mediated separately through the ANGPT2 dependent activation of endothelial TIE2.	48	54	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	48	49	53	54
In stressed endothelial cells , especially in cancer , Ang2 can activate Tie2 signaling and contribute to vessel stabilization .	In stressed endothelial cells, especially in cancer, Ang2 can activate Tie2 signaling and contribute to vessel stabilization.	9	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	9	10	12	13
Recently , it has been reported that Ang-2 may be a predictive marker in antiangiogenic therapy.49 , 50 Angiopoietin-2 is one of the ligands for the receptor tyrosine kinase Tie2 , which is expressed on endothelial cells.49 , 50 Angiopoietin-1 is an agonistic ligand for Tie2 and phosphorylates it ; however , Ang-2 does not activate Tie2 at any reasonable dose and therefore acts as an antagonist for Ang-1 .	Recently, it has been reported that Ang-2 may be a predictive marker in antiangiogenic therapy.49, 50 Angiopoietin-2 is one of the ligands for the receptor tyrosine kinase Tie2, which is expressed on endothelial cells.49, 50 Angiopoietin-1 is an agonistic ligand for Tie2 and phosphorylates it; however, Ang-2 does not activate Tie2 at any reasonable dose and therefore acts as an antagonist for Ang-1.	52	63	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	52	53	56	57
Ang-2 may also act as a Tie-2 agonist , being involved in postnatal vascular remodeling events [ XREF_BIBR ] , because Ang-2 can activate Tie-2 and stimulate both endothelial cell migration and endothelial cell capillary like tube formation in vitro [ XREF_BIBR , XREF_BIBR ] .	Ang-2 may also act as a Tie-2 agonist, being involved in postnatal vascular remodeling events [XREF_BIBR], because Ang-2 can activate Tie-2 and stimulate both endothelial cell migration and endothelial cell capillary like tube formation in vitro [XREF_BIBR, XREF_BIBR].	21	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	21	22	24	25
The high-density lipoprotein apolipoprotein A-I ( ApoA-I ) stimulates the enzyme lecithin-cholesterol acyltransferase ( LCAT ) in the reverse cholesterol transport pathway .	The high-density lipoprotein apolipoprotein A-I (ApoA-I) stimulates the enzyme lecithin-cholesterol acyltransferase (LCAT) in the reverse cholesterol transport pathway.	4	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase	6	7	11	13
However , 22-mer peptides derived from the apoA-I consensus sequence that efficiently activated LCAT and associated with lipids did not significantly inhibit atherosclerosis in C57Bl/6J mice on a high-fat diet , indicating that these two features are not sufficient for in vivo antiatherosclerotic efficacy .	However, 22-mer peptides derived from the apoA-I consensus sequence that efficiently activated LCAT and associated with lipids did not significantly inhibit atherosclerosis in C57Bl/6J mice on a high-fat diet, indicating that these two features are not sufficient for in vivo antiatherosclerotic efficacy.	7	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	7	8	13	14
Nascent HDL form preferred substrates for lecithin : cholesterol acyltransferase ( LCAT ) that is activated by apoA-I and , to a lesser extent , by other exchangeable ( water-soluble ) apolipoproteins .	Nascent HDL form preferred substrates for lecithin : cholesterol acyltransferase (LCAT) that is activated by apoA-I and, to a lesser extent, by other exchangeable (water-soluble) apolipoproteins.	9	23	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	17	18	11	12
Therefore , this region is most likely involved in the activation of LCAT by apoA-I .	Therefore, this region is most likely involved in the activation of LCAT by apoA-I.	7	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	14	15	12	13
Human apoA-I self-associates more and activates human lecithin-cholesterol acyltransferase better than mouse apoA-I .	Human apoA-I self-associates more and activates human lecithin-cholesterol acyltransferase better than mouse apoA-I.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase	1	2	7	9
Four isoforms of human apolipoprotein A-I ( apo A-I ) : the normal allele product and the corresponding Lys 107 deletion mutant , and apo A-I with sulfoxidized Met 112 and Met 148 residues and the corresponding reduced form , were investigated in their lipid binding properties , structures , and abilities to activate lecithin-cholesterol acyltransferase .	Four isoforms of human apolipoprotein A-I (apo A-I) : the normal allele product and the corresponding Lys 107 deletion mutant, and apo A-I with sulfoxidized Met 112 and Met 148 residues and the corresponding reduced form, were investigated in their lipid binding properties, structures, and abilities to activate lecithin-cholesterol acyltransferase.	4	56	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase	4	6	54	56
Therefore , in this study we have investigated how conformational changes in several exposed regions of Apo-AI might cause LCAT activation and for this purpose , designed a strategy to investigate three Apo AI derived peptides .	Therefore, in this study we have investigated how conformational changes in several exposed regions of Apo-AI might cause LCAT activation and for this purpose, designed a strategy to investigate three Apo AI derived peptides.	14	20	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apo-AI	Apo-AI	Apo-AI	LCAT	LCAT	LCAT	16	17	19	20
These results also provide the foundation for the next generation of studies investigating how LCAT is activated by HDL particles and , in particular , by ApoA-I .	These results also provide the foundation for the next generation of studies investigating how LCAT is activated by HDL particles and, in particular, by ApoA-I.	14	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	LCAT	LCAT	LCAT	26	27	14	15
ApoA-I is the major activator of LCAT in plasma so PC and FC molecules in HDL particles are the preferred substrates .	ApoA-I is the major activator of LCAT in plasma so PC and FC molecules in HDL particles are the preferred substrates.	0	8	is the major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	LCAT	LCAT	LCAT	0	1	6	7
Conformational features of the calculated structures for LAP-20 are discussed relative to models for apolipoprotein A-I activation of LCAT .	Conformational features of the calculated structures for LAP-20 are discussed relative to models for apolipoprotein A-I activation of LCAT.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	LCAT	LCAT	LCAT	14	16	18	19
On the other hand , addition of apo A-II ( 0.1-3.0 nmol and assay ) or addition of lecithin-cholesterol liposome containing apo A-II ( 0.1-3.0 nmol and assay ) to lecithin-cholesterol liposome containing apo A-I ( 0.8 nmol and assay ) did not significantly alter apo A-I activation of LCAT activity .	On the other hand, addition of apo A-II (0.1-3.0 nmol and assay) or addition of lecithin-cholesterol liposome containing apo A-II (0.1-3.0 nmol and assay) to lecithin-cholesterol liposome containing apo A-I (0.8 nmol and assay) did not significantly alter apo A-I activation of LCAT activity.	45	50	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	apo A-I	apo A-I	apo A-I	LCAT	LCAT	LCAT	45	47	49	50
Meanwhile , amino acids 135-170 of apoA-I increase the binding of LCAT to lipoproteins .	Meanwhile, amino acids 135-170 of apoA-I increase the binding of LCAT to lipoproteins.	3	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	6	7	11	12
XREF_BIBR The results demonstrated that apoA-I M was unable to activate mouse LCAT to the same extent as WT apoA-I ( XREF_FIG ) .	XREF_BIBR The results demonstrated that apoA-I M was unable to activate mouse LCAT to the same extent as WT apoA-I (XREF_FIG).	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	5	6	12	13
This observation leads to the speculation that , as part of the mechanism of apoA-I activation of LCAT , interaction of the central helix 5 presentation tunnel with LCAT might drive the formation of a full helix 5 hinged domain , exposing the ester bonds of the underlying phospholipid acyl chains to the phospholipase A2 like active site of the enzyme .	This observation leads to the speculation that, as part of the mechanism of apoA-I activation of LCAT, interaction of the central helix 5 presentation tunnel with LCAT might drive the formation of a full helix 5 hinged domain, exposing the ester bonds of the underlying phospholipid acyl chains to the phospholipase A2 like active site of the enzyme.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	14	15	17	18
As shown in XREF_SUPPLEMENTARY , both apo A-I and CS-6253 increased LCAT activity , similar to nHDL-apo A-I ( FER = 7.74 +/-0.35 %/h ; vs nHDL CS-6253 FER = 7.41 +/-0.25 %/h ) .	As shown in XREF_SUPPLEMENTARY, both apo A-I and CS-6253 increased LCAT activity, similar to nHDL-apo A-I (FER = 7.74 +/-0.35%/h; vs nHDL CS-6253 FER = 7.41 +/-0.25%/h).	6	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apo A-I	apo A-I	apo A-I	LCAT	LCAT	LCAT	6	8	11	12
In these WT mice , HDL was enriched in phosphatidylcholine ( PC ) ( XREF_FIG ) , which is the substrate for the LCAT activity XREF_BIBR , indicating that squalene is favoring the secretion of an HDL enriched in LCAT and with an appropriate endowment of PC to facilitate its action and thereby reverse cholesterol transport and without changes in the LCAT activators APOA1 or APOA4 XREF_BIBR .	In these WT mice, HDL was enriched in phosphatidylcholine (PC) (XREF_FIG), which is the substrate for the LCAT activity XREF_BIBR, indicating that squalene is favoring the secretion of an HDL enriched in LCAT and with an appropriate endowment of PC to facilitate its action and thereby reverse cholesterol transport and without changes in the LCAT activators APOA1 or APOA4 XREF_BIBR.	9	66	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	APOA1	APOA1	APOA1	LCAT	LCAT	LCAT	63	64	61	62
The evidence from this study suggests that the role of apoA-I and other apolipoproteins in activating LCAT is to adjust the conformation of LCAT with respect to the lipid surface , increase the binding of LCAT , and drive the lid to the open state .	The evidence from this study suggests that the role of apoA-I and other apolipoproteins in activating LCAT is to adjust the conformation of LCAT with respect to the lipid surface, increase the binding of LCAT, and drive the lid to the open state.	10	36	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	10	11	35	36
These findings agree with previous experimental reports showing that apoA-I increases the binding of LCAT to lipids compared with apolipoprotein-free small unilamellar vesicles .	These findings agree with previous experimental reports showing that apoA-I increases the binding of LCAT to lipids compared with apolipoprotein-free small unilamellar vesicles.	9	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	9	10	14	15
An apoA-I mimetic peptide increases LCAT activity in mice through increasing HDL concentration .	An apoA-I mimetic peptide increases LCAT activity in mice through increasing HDL concentration.	1	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	1	2	5	6
From these data we conclude that several areas of apoA-I spanning the middle region of the apolipoprotein act in concert to stimulate LCAT activity , possibly by cooperative interaction with the enzyme .	From these data we conclude that several areas of apoA-I spanning the middle region of the apolipoprotein act in concert to stimulate LCAT activity, possibly by cooperative interaction with the enzyme.	7	23	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	9	10	22	23
The results demonstrated that both hybrid apoA-I variants were unable to activate LCAT to the same extent as the WT proteins ( XREF_FIG ) .	The results demonstrated that both hybrid apoA-I variants were unable to activate LCAT to the same extent as the WT proteins (XREF_FIG).	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	6	7	12	13
Apolipoprotein A-I [ ApoA-I ] activates the enzyme Lecithin-Cholesterol Acyl-Transferase to esterify cell cholesterol for transport to liver .	Apolipoprotein A-I [ApoA-I] activates the enzyme Lecithin-Cholesterol Acyl-Transferase to esterify cell cholesterol for transport to liver.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apolipoprotein A-I	Apolipoprotein A-I	Apolipoprotein A-I	Lecithin-Cholesterol Acyl-Transferase	Lecithin-Cholesterol Acyl-Transferase	Lecithin-Cholesterol Acyl-Transferase	0	2	8	10
LCAT is activated by apoA-I to form cholesteryl ester .	LCAT is activated by apoA-I to form cholesteryl ester.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	4	5	0	1
With the activation of LCAT by apoA-I , FC is converted to CE , resulting in the formation of spheroidal HDL like particles .	With the activation of LCAT by apoA-I, FC is converted to CE, resulting in the formation of spheroidal HDL like particles.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	6	7	4	5
It is known that HDL-C oxidation modifies apolipoprotein A-I structure , which alters the ability of the HDL-C lipoproteins to activate lecithin-cholesterol acyltransferase , therefore inhibiting the esterification and removal of extrahepatic cholesterol .	It is known that HDL-C oxidation modifies apolipoprotein A-I structure, which alters the ability of the HDL-C lipoproteins to activate lecithin-cholesterol acyltransferase, therefore inhibiting the esterification and removal of extrahepatic cholesterol.	7	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase	7	9	21	23
This potential difference in conformational flexibility at the geometric center of each molecule may explain the remarkable difference in monomer and dimer dynamics between apoA-IV ( slow ) and apoA-I ( fast ) as well as why apoA-I is the superior activator of LCAT .	This potential difference in conformational flexibility at the geometric center of each molecule may explain the remarkable difference in monomer and dimer dynamics between apoA-IV (slow) and apoA-I (fast) as well as why apoA-I is the superior activator of LCAT.	37	44	is the superior activator	Positive_activation_copula_1	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	37	38	43	44
All purified lecithin-cholesterol acyltransferase species were activated by human apolipoprotein A-I and were similarly inhibited by p-hydroxymercuribenzoate and phenylmethylsulfonyl fluoride .	All purified lecithin-cholesterol acyltransferase species were activated by human apolipoprotein A-I and were similarly inhibited by p-hydroxymercuribenzoate and phenylmethylsulfonyl fluoride.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase	9	11	2	4
Apo A-I activates LCAT , and the LCAT reaction largely occurs on very-small HDL ( HDL-VS ) and small HDL ( HDL-S ) particles , transforming these particles into the larger spherical alpha migrating forms of HDL ( HDL-M , HDL-L and HDL-VL ) ( XREF_FIG ) .	Apo A-I activates LCAT, and the LCAT reaction largely occurs on very-small HDL (HDL-VS) and small HDL (HDL-S) particles, transforming these particles into the larger spherical alpha migrating forms of HDL (HDL-M, HDL-L and HDL-VL) (XREF_FIG).	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apo A-I	Apo A-I	Apo A-I	LCAT	LCAT	LCAT	0	2	3	4
XREF_FIG A and XREF_FIG B , human HDL associated LCAT had a basal LCAT activity converting 4.6 % to cholesteryl ester ; proteoliposome containing ApoA-I increased LCAT activity by 5.9 fold while peptidosome containing D-4F showed no LCAT activation in the assay .	XREF_FIG A and XREF_FIG B, human HDL associated LCAT had a basal LCAT activity converting 4.6% to cholesteryl ester; proteoliposome containing ApoA-I increased LCAT activity by 5.9 fold while peptidosome containing D-4F showed no LCAT activation in the assay.	23	27	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	LCAT	LCAT	LCAT	24	25	26	27
ApoA-I mimetics retain functional properties of apoA-I , such as the ability to form complexes with lipids , promote cell cholesterol efflux , and activate LCAT .	ApoA-I mimetics retain functional properties of apoA-I, such as the ability to form complexes with lipids, promote cell cholesterol efflux, and activate LCAT.	0	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	LCAT	LCAT	LCAT	0	1	25	26
The exact mechanism by which apoA-I activates LCAT is not known [ XREF_BIBR - XREF_BIBR ] , but one proposal is that it stabilizes an active conformation of LCAT , similar to the way colipase activates pancreatic lipase [ XREF_BIBR , XREF_BIBR ] .	The exact mechanism by which apoA-I activates LCAT is not known [XREF_BIBR - XREF_BIBR], but one proposal is that it stabilizes an active conformation of LCAT, similar to the way colipase activates pancreatic lipase [XREF_BIBR, XREF_BIBR].	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	5	6	7	8
XREF_BIBR Plasma LCAT binds to and is activated by apoAI .	XREF_BIBR Plasma LCAT binds to and is activated by apoAI.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apoAI	apoAI	apoAI	LCAT	LCAT	LCAT	9	10	2	3
In addition , apoA-I not only is activator of LCAT but also is a critical ligand of the HDL receptor scavenger receptor BI ( SR-BI ) and the interaction of apoA-I and SR-BI may facilitate hepatic selective uptake of HDL-C in the RCT pathway .	In addition, apoA-I not only is activator of LCAT but also is a critical ligand of the HDL receptor scavenger receptor BI (SR-BI) and the interaction of apoA-I and SR-BI may facilitate hepatic selective uptake of HDL-C in the RCT pathway.	3	10	is activator	Positive_activation_copula_1	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	3	4	9	10
LCAT is activated through an unknown mechanism by apolipoprotein A-I ( ApoA-I ) and other mimetic peptides that form a belt around HDL .	LCAT is activated through an unknown mechanism by apolipoprotein A-I (ApoA-I) and other mimetic peptides that form a belt around HDL.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	LCAT	LCAT	LCAT	8	10	0	1
Physiologically , the efficiency of reverse cholesterol transport depends on the activity of lecithin : cholesterol acyltransferase ( LCAT ) , and apoA-I activates LCAT to facilitate reverse cholesterol transport and HDL maturation .	Physiologically, the efficiency of reverse cholesterol transport depends on the activity of lecithin : cholesterol acyltransferase (LCAT), and apoA-I activates LCAT to facilitate reverse cholesterol transport and HDL maturation.	22	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	22	23	24	25
ApoAI is known to activate LCAT and the similar apoAI concentrations observed could account for the lack of difference in the activity of LCAT .	ApoAI is known to activate LCAT and the similar apoAI concentrations observed could account for the lack of difference in the activity of LCAT.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoAI	ApoAI	ApoAI	LCAT	LCAT	LCAT	0	1	5	6
ApoA1 and A2 on HDL stimulate the enzyme LCAT , which then esterifies the cell surface cholesterol molecules to form cholesteryl ester , which migrate to the core of the HDL particle to form mature migrating HDL [ XREF_BIBR ] .	ApoA1 and A2 on HDL stimulate the enzyme LCAT, which then esterifies the cell surface cholesterol molecules to form cholesteryl ester, which migrate to the core of the HDL particle to form mature migrating HDL [XREF_BIBR].	0	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoA1	ApoA1	ApoA1	LCAT	LCAT	LCAT	0	1	8	9
This becomes especially important , if the gene under study has pleiotropic effects , i.e. affects multiple phenotypic traits , as is the case for APOA1 : mutations in APOA1 have been associated with an inability to activate LCAT and with hereditary amyloidosis XREF_BIBR - XREF_BIBR .	This becomes especially important, if the gene under study has pleiotropic effects, i.e. affects multiple phenotypic traits, as is the case for APOA1 : mutations in APOA1 have been associated with an inability to activate LCAT and with hereditary amyloidosis XREF_BIBR - XREF_BIBR.	27	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APOA1	APOA1	APOA1	LCAT	LCAT	LCAT	29	30	38	39
The results suggest that Hpt inhibits the reverse transport of cholesterol by preventing ApoA1 stimulation of the LCAT activity .	The results suggest that Hpt inhibits the reverse transport of cholesterol by preventing ApoA1 stimulation of the LCAT activity.	13	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ApoA1	ApoA1	ApoA1	LCAT	LCAT	LCAT	13	14	17	18
ApoA-I activates LCAT that converts lipoprotein cholesterol to cholesteryl ester ( CE ) .	ApoA-I activates LCAT that converts lipoprotein cholesterol to cholesteryl ester (CE).	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	LCAT	LCAT	LCAT	0	1	2	3
Incubation of antibody AI-11 with high density lipoprotein or rA-I HDL inhibited apoA-I activation of LCAT .	Incubation of antibody AI-11 with high density lipoprotein or rA-I HDL inhibited apoA-I activation of LCAT.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	12	13	15	16
Because apoA-I is an activator of lecithin-cholesterol acyltransferase ( LCAT ) , which is expressed in the brain [ XREF_BIBR ] , apoA-I must participate in intercellular cholesterol transport in the CNS as in the case of peripheral cholesterol transport .	Because apoA-I is an activator of lecithin-cholesterol acyltransferase (LCAT), which is expressed in the brain [XREF_BIBR], apoA-I must participate in intercellular cholesterol transport in the CNS as in the case of peripheral cholesterol transport.	1	15	is an activator	Positive_regulation_copula_1	Positive_activation	Positive_regulation	apoA-I	apoA-I	apoa-i	lecithin-cholesterol acyltransferase	lecithin-cholesterol acyltransferase (LCAT), which is expressed	lecithin-cholesterol acyltransferase	1	2	6	8
ApoA-I can activate the LCAT , and LCAT may catalyze unesterified cholesterol to CE and promote the conversion of prebeta 1 -HDL and HDL 3 to HDL 2 , hence , the increased of TG levels along with the reduction of apoA-I levels resulting in the increase contents of small sized HDL particles and decrease contents of large sized HDL particles .	ApoA-I can activate the LCAT, and LCAT may catalyze unesterified cholesterol to CE and promote the conversion of prebeta 1 -HDL and HDL 3 to HDL 2, hence, the increased of TG levels along with the reduction of apoA-I levels resulting in the increase contents of small sized HDL particles and decrease contents of large sized HDL particles.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	LCAT	LCAT	LCAT	0	1	4	5
XREF_BIBR , XREF_BIBR , XREF_BIBR LCAT is activated by ApoA-I , 171 a major protein component of HDL , and transfers acyl chains from phosphatidylcholines ( PCs , or lecithins ) to cholesterol to form cholesteryl esters on the surface of HDL particles .	XREF_BIBR, XREF_BIBR, XREF_BIBR LCAT is activated by ApoA-I, 171 a major protein component of HDL, and transfers acyl chains from phosphatidylcholines (PCs, or lecithins) to cholesterol to form cholesteryl esters on the surface of HDL particles.	0	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	LCAT	LCAT	LCAT	9	10	5	6
ApoAI activates LCAT to a greater extent than apoE .	ApoAI activates LCAT to a greater extent than apoE.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoAI	ApoAI	ApoAI	LCAT	LCAT	LCAT	0	1	2	3
We propose that the central helix 4-helix 5-helix 6 domain in apoA-I is the unique structural element that provides full specificity to apoA-I activation of LCAT through substantially more LCAT binding and substrate binding and presentation to LCAT thorough the presentation tunnel .	We propose that the central helix 4-helix 5-helix 6 domain in apoA-I is the unique structural element that provides full specificity to apoA-I activation of LCAT through substantially more LCAT binding and substrate binding and presentation to LCAT thorough the presentation tunnel.	22	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	22	23	25	26
ApoA1 is an important activator of LCAT , and modified ApoA1 may compromise RCT and cause atherosclerosis [ XREF_BIBR ] .	ApoA1 is an important activator of LCAT, and modified ApoA1 may compromise RCT and cause atherosclerosis [XREF_BIBR].	0	7	is an important activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ApoA1	ApoA1	ApoA1	LCAT	LCAT	LCAT	0	1	6	7
ApoA-I deficiency can also lead to low HDL and secondarily to low LCAT , but again % CE is relatively normal .	ApoA-I deficiency can also lead to low HDL and secondarily to low LCAT, but again% CE is relatively normal.	0	13	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	LCAT	LCAT	LCAT	0	1	12	13
Meanwhile , apoA-I is not only activator of LCAT but also is a critical ligand of the HDL receptor SR-BI and the interaction of apoA-I and SR-BI may facilitate hepatic selective uptake of HDL-C in the RCT pathway hence play a vital role in the maturation process of HDL subclasses [ XREF_BIBR , XREF_BIBR ] .	Meanwhile, apoA-I is not only activator of LCAT but also is a critical ligand of the HDL receptor SR-BI and the interaction of apoA-I and SR-BI may facilitate hepatic selective uptake of HDL-C in the RCT pathway hence play a vital role in the maturation process of HDL subclasses [XREF_BIBR, XREF_BIBR].	2	9	is not only activator	Positive_activation_copula_1	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	2	3	8	9
An early apoA-I mimetic peptide ( ETC-642 ) promotes LCAT activation and has entered clinical development [ XREF_BIBR ] .	An early apoA-I mimetic peptide (ETC-642) promotes LCAT activation and has entered clinical development [XREF_BIBR].	2	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	2	3	9	10
Previously , we reported that a synthetic peptide , P2a , binds to and displaces Hpt from ApoA-I restoring the LCAT cholesterol esterification activity in the presence of Hpt .	Previously, we reported that a synthetic peptide, P2a, binds to and displaces Hpt from ApoA-I restoring the LCAT cholesterol esterification activity in the presence of Hpt.	14	23	restoring	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	LCAT	LCAT	LCAT	17	18	20	21
Notably , the concentration of total apoA-I protein in human plasma is in the range of 35-55 muM ( 1-1.5 mg/ml ) , however the EC 50 of LCAT activation by free apoA-I is only 72.8 nM ( 2 mug/ml ) which is similar to the EC 50 values of free or discoidal apoA-I in stimulating ABCA1 dependent cholesterol efflux ( 101 or 103 nM , Fig .	Notably, the concentration of total apoA-I protein in human plasma is in the range of 35-55 muM (1-1.5 mg/ml), however the EC 50 of LCAT activation by free apoA-I is only 72.8 nM (2 mug/ml) which is similar to the EC 50 values of free or discoidal apoA-I in stimulating ABCA1 dependent cholesterol efflux (101 or 103 nM, Fig.	28	33	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	32	33	28	29
To test this hypothesis , a monoclonal antibody AI-11 that inhibits apoA-I activation of LCAT was used to measure apoA-I in interstitial fluid and plasma .	To test this hypothesis, a monoclonal antibody AI-11 that inhibits apoA-I activation of LCAT was used to measure apoA-I in interstitial fluid and plasma.	11	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	11	12	14	15
Tentatives of gene therapy in mice induced by adenovirus mediated transfer of human apo A-I and LCAT genes also increased circulating apo A-I and LCAT .	Tentatives of gene therapy in mice induced by adenovirus mediated transfer of human apo A-I and LCAT genes also increased circulating apo A-I and LCAT.	13	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apo A-I	apo A-I	apo A-I	LCAT	LCAT	LCAT	13	15	24	25
APOA-I is an activator of LCAT , whereas APOA-II neither activates nor inhibits LCAT activity [ XREF_BIBR ] .	APOA-I is an activator of LCAT, whereas APOA-II neither activates nor inhibits LCAT activity [XREF_BIBR].	0	6	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	APOA-I	APOA-I	APOA-I	LCAT	LCAT	LCAT	0	1	5	6
The maturation of HDL results from the conversion of free cholesterol to CE by the enzyme lecithin : cholesterol acyltransferase ( LCAT ) , which is activated by apoA-I .	The maturation of HDL results from the conversion of free cholesterol to CE by the enzyme lecithin : cholesterol acyltransferase (LCAT), which is activated by apoA-I.	19	29	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	28	29	21	22
Lecithin cholesterol acyltransferase ( LCAT ) , which is activated by apoA-I , converts free cholesterol to cholesteryl esters ( CE ) in HDL .	Lecithin cholesterol acyltransferase (LCAT), which is activated by apoA-I, converts free cholesterol to cholesteryl esters (CE) in HDL.	2	12	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	11	12	4	5
Although ALK ( + ) ALCL cells produce endogenous IL-22 , the addition of recombinant IL-22 to ALK ( + ) ALCL cell lines significantly increased STAT3 activation , cell proliferation , and colony formation in soft agar .	Although ALK (+) ALCL cells produce endogenous IL-22, the addition of recombinant IL-22 to ALK (+) ALCL cell lines significantly increased STAT3 activation, cell proliferation, and colony formation in soft agar.	15	34	increased	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	17	18	26	27
ALK is able to directly activate STAT3 pathway that indeed plays a pivotal role for the survival and proliferation of ALK driven tumors [ XREF_BIBR ] .	ALK is able to directly activate STAT3 pathway that indeed plays a pivotal role for the survival and proliferation of ALK driven tumors [XREF_BIBR].	0	7	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	0	1	6	7
The high frequency of Mcl-1 , Bcl-2 , and Bcl-X ( L ) positive ALCL cases in the ALK- group compared with the ALK+ group indicates that ALK induced STAT3 activation is not the main regulatory pathway in ALCL .	The high frequency of Mcl-1, Bcl-2, and Bcl-X (L) positive ALCL cases in the ALK- group compared with the ALK+ group indicates that ALK induced STAT3 activation is not the main regulatory pathway in ALCL.	27	30	induced	Positive_early_activation	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	27	28	29	30
In SU-DHL-1cells , NPM and ALK induces the expression of ICOS , a T-cell growth promoting costimulatory receptor that amplifies the signal generated by the antigen specific TCR , and NPM and ALK mediated activation of STAT3 suppresses the expression of the ICOS inhibitor miR-219 [ XREF_BIBR ] .	In SU-DHL-1cells, NPM and ALK induces the expression of ICOS, a T-cell growth promoting costimulatory receptor that amplifies the signal generated by the antigen specific TCR, and NPM and ALK mediated activation of STAT3 suppresses the expression of the ICOS inhibitor miR-219 [XREF_BIBR].	30	37	mediated	Positive_early_activation	Positive_activation	Negative_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	32	33	36	37
Wild-type ALK has been previously shown to activate ERK and STAT3 signaling in response to agonist antibody treatment with similar kinetics to what we observed upon ethanol treatment .	Wild-type ALK has been previously shown to activate ERK and STAT3 signaling in response to agonist antibody treatment with similar kinetics to what we observed upon ethanol treatment.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	1	2	10	11
Activation of STAT3 by ALK results in increased transcription of genes that prevent apoptosis and promote cell cycle progression .	Activation of STAT3 by ALK results in increased transcription of genes that prevent apoptosis and promote cell cycle progression.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	4	5	2	3
ALK also activates the MAPK and ERK , PI3K and AKT and signal transducer and activator of transcription 3 ( STAT3 ) signaling pathways .	ALK also activates the MAPK and ERK, PI3K and AKT and signal transducer and activator of transcription 3 (STAT3) signaling pathways.	0	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	0	1	20	21
Although the precise molecular mechanisms underlying ALK activation of STAT3 are unknown , it is clear from these studies that loss of STAT3 activity , either by RNA interference mediated knockdown of STAT3 or by addition of STAT3 inhibitors XREF_BIBR , XREF_BIBR , reduces the growth and viability of four neuroblastoma lines .	Although the precise molecular mechanisms underlying ALK activation of STAT3 are unknown, it is clear from these studies that loss of STAT3 activity, either by RNA interference mediated knockdown of STAT3 or by addition of STAT3 inhibitors XREF_BIBR, XREF_BIBR, reduces the growth and viability of four neuroblastoma lines.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	6	7	9	10
ALK dependent neurite outgrowth in PC12 and SK-N-SH neuroblastoma cells requires ERK signaling and activation of STAT3 by ALK appears to be important for increasing MYCN expression and neuroblastoma proliferation .	ALK dependent neurite outgrowth in PC12 and SK-N-SH neuroblastoma cells requires ERK signaling and activation of STAT3 by ALK appears to be important for increasing MYCN expression and neuroblastoma proliferation.	10	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	18	19	16	17
ALK activates STAT3 in PC12 cells .	ALK activates STAT3 in PC12 cells.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	0	1	2	3
In light of the activation of STAT3 by ALK , we also investigated the interaction of ALK with STAT3 .	In light of the activation of STAT3 by ALK, we also investigated the interaction of ALK with STAT3.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	8	9	6	7
To confirm whether AKT , MAPK and STAT3 activation was mediated by ALK and IGF-1R , EWS cells were exposed to either ST/V or V/ST treatments in the presence of the dual ALK and IGF-1R inhibitor , AZD3463 .	To confirm whether AKT, MAPK and STAT3 activation was mediated by ALK and IGF-1R, EWS cells were exposed to either ST/V or V/ST treatments in the presence of the dual ALK and IGF-1R inhibitor, AZD3463.	7	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	12	13	7	8
ALK induced STAT3 activation plays a variety of roles in cancer cells , including regulation of availability of hypoxia inducible factors under hypoxic conditions [ XREF_BIBR ] .	ALK induced STAT3 activation plays a variety of roles in cancer cells, including regulation of availability of hypoxia inducible factors under hypoxic conditions [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	0	1	2	3
Lack of TIMP-1 expression in the tumour cells of ALK positive ALCLs argues against a direct role for ALK induced activation of STAT3 in the regulation of TIMP-1 expression in ALCL .	Lack of TIMP-1 expression in the tumour cells of ALK positive ALCLs argues against a direct role for ALK induced activation of STAT3 in the regulation of TIMP-1 expression in ALCL.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	18	19	22	23
Given that antibody mediated blockade of CD274 in conjunction with T cell depletion therapy leads to complete tumor regression , targeting NPM and ALK mediated STAT3 activity may offer therapeutic advantages for the treatment of T cell lymphoma .	Given that antibody mediated blockade of CD274 in conjunction with T cell depletion therapy leads to complete tumor regression, targeting NPM and ALK mediated STAT3 activity may offer therapeutic advantages for the treatment of T cell lymphoma.	21	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	23	24	25	26
These data indicate that NPM and ALK activates STAT3 and that PP2A and lack of protein inhibitor of activated STAT3 may be important in maintaining STAT3 in the activated state in the ALK+ TCL cells .	These data indicate that NPM and ALK activates STAT3 and that PP2A and lack of protein inhibitor of activated STAT3 may be important in maintaining STAT3 in the activated state in the ALK+ TCL cells.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	6	7	8	9
Here we report that NPM and ALK induces continuous activation of STAT3 .	Here we report that NPM and ALK induces continuous activation of STAT3.	4	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	6	7	11	12
STAT3 is activated by ALK , either directly or through JAK XREF_BIBR .	STAT3 is activated by ALK, either directly or through JAK XREF_BIBR.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	4	5	0	1
The ALK chimeras activate STAT3 , whose deregulated program is required for the maintenance of the neoplastic phenotype in ALK + ALCL .	The ALK chimeras activate STAT3, whose deregulated program is required for the maintenance of the neoplastic phenotype in ALK + ALCL.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	1	2	4	5
XREF_BIBR Further , in ALK positive anaplastic large-cell lymphoma cells that overexpress STAT3 , inhibition of ALK leads to downregulation of total and active STAT3 .	XREF_BIBR Further, in ALK positive anaplastic large-cell lymphoma cells that overexpress STAT3, inhibition of ALK leads to downregulation of total and active STAT3.	4	13	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	4	5	12	13
As SOCS3 is induced by activated signal transducer and activator of transcription 3 ( STAT3 ) , and ALK activates STAT3 , we hypothesized that SOCS3 may play a role in ALK+ ALCL pathogenesis via the Janus kinase 3 ( JAK3 )-STAT3 pathway .	As SOCS3 is induced by activated signal transducer and activator of transcription 3 (STAT3), and ALK activates STAT3, we hypothesized that SOCS3 may play a role in ALK+ ALCL pathogenesis via the Janus kinase 3 (JAK3)-STAT3 pathway.	18	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	18	19	20	21
This discovery may point to a ligand independent role for ligand independent oncogenesis constitutive activation of STAT3 by ALK and possibly MET .	This discovery may point to a ligand independent role for ligand independent oncogenesis constitutive activation of STAT3 by ALK and possibly MET.	3	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	18	19	16	17
Persistent Stat3 activation by NPM and ALK facilitates induction of Treg like phenotypes in ALCLs by promoting secretion of IL-10 and TGF-beta as well as expression of Foxp3 .	Persistent Stat3 activation by NPM and ALK facilitates induction of Treg like phenotypes in ALCLs by promoting secretion of IL-10 and TGF-beta as well as expression of Foxp3.	1	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ALK	ALK	ALK	Stat3	Stat3	Stat3	6	7	1	2
In vitro , ALK ATI constitutively activates MAPK , AKT , and STAT3 signaling and is inhibited by small molecule ALK inhibitors .	In vitro, ALK ATI constitutively activates MAPK, AKT, and STAT3 signaling and is inhibited by small molecule ALK inhibitors.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	3	4	12	13
We show here that activated ALK robustly activates STAT3 on Tyr705 in a number of independent neuroblastoma cell lines .	We show here that activated ALK robustly activates STAT3 on Tyr705 in a number of independent neuroblastoma cell lines.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	5	6	8	9
The results show that in advanced-stage pediatric ALCL , although most tumors express ALK and a majority show activated STAT3 , cytoplasmic localization of survivin and TIMP1 is not frequent , nor is expression of CD56 .	The results show that in advanced-stage pediatric ALCL, although most tumors express ALK and a majority show activated STAT3, cytoplasmic localization of survivin and TIMP1 is not frequent, nor is expression of CD56.	13	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	13	14	19	20
We also provide evidence that the apoA-I induced apoE secretion from macrophages and the enhancement of PLTP activity by apoA-I are unrelated phenomena .	We also provide evidence that the apoA-I induced apoE secretion from macrophages and the enhancement of PLTP activity by apoA-I are unrelated phenomena.	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	6	7	8	9
Our investigation clearly shows that apoA-I effectively increases the release of cholesterol , as well as largely increasing the secretion of apoE by mature adipocytes .	Our investigation clearly shows that apoA-I effectively increases the release of cholesterol, as well as largely increasing the secretion of apoE by mature adipocytes.	5	22	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	5	6	21	22
Addition of apoA-I and HDL increased apoE recycling to 45 +/- 3 % and 46 +/- 3 % , respectively , similar to the amount of apoE recycled after pulsing the cells with ( 125 ) I.apoE.HDL .	Addition of apoA-I and HDL increased apoE recycling to 45 +/- 3% and 46 +/- 3%, respectively, similar to the amount of apoE recycled after pulsing the cells with (125) I.apoE.HDL.	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	2	3	6	7
ApoA-I increases apoE secretion with minimal effect upon apoE gene expression .	ApoA-I increases apoE secretion with minimal effect upon apoE gene expression.	0	3	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	apoE	apoE	apoE	0	1	2	3
In addition to increasing cholesterol efflux , apoA-I is known to activate apoE secretion , at least in macrophages .	In addition to increasing cholesterol efflux, apoA-I is known to activate apoE secretion, at least in macrophages.	7	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	7	8	12	13
Aortic valve area ( AVA ) increased in both ApoE (-/-) and Wrn mice treated with the ApoA-I mimetic compared with placebo .	Aortic valve area (AVA) increased in both ApoE (-/-) and Wrn mice treated with the ApoA-I mimetic compared with placebo.	6	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	ApoE	ApoE	ApoE	17	18	9	10
We conclude that apoA-I concurrently stimulates apoE secretion and cholesterol efflux from foam cell macrophages and that lipoprotein derived apoA-I may enhance local secretion and accumulation of apoE in atherosclerotic lesions .	We conclude that apoA-I concurrently stimulates apoE secretion and cholesterol efflux from foam cell macrophages and that lipoprotein derived apoA-I may enhance local secretion and accumulation of apoE in atherosclerotic lesions.	3	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	3	4	6	7
Brefeldin A inhibits basal apoE secretion but not apoA-I induced apoE secretion .	Brefeldin A inhibits basal apoE secretion but not apoA-I induced apoE secretion.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	8	9	10	11
Moreover , a range of 11- and 22-mer alpha-helical peptides representing amphipathic alpha-helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal alpha-helix ( domains 220-241 ) stimulates cholesterol efflux .	Moreover, a range of 11- and 22-mer alpha-helical peptides representing amphipathic alpha-helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal alpha-helix (domains 220-241) stimulates cholesterol efflux.	13	18	stimulate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	15	16	17	18
Unlike previous results with hepatocytes and macrophages , neither apoA-I nor upregulation of ABCA1 stimulated apoE recycling .	Unlike previous results with hepatocytes and macrophages, neither apoA-I nor upregulation of ABCA1 stimulated apoE recycling.	8	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	9	10	15	16
Whereas BFA effectively decreases the basal secretion of apoE , the results obtained clearly reveal that BFA does not affect apoA-I induced secretion of apoE .	Whereas BFA effectively decreases the basal secretion of apoE, the results obtained clearly reveal that BFA does not affect apoA-I induced secretion of apoE.	19	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	20	21	24	25
There were significantly increased TG , ApoAIII , ApoE , TC / HDL-C , ApoCIII non B , ApoCIII : B and decreased HDL-C , ApoAI , HDL-C and ApoAI , ApoAI and ApoCIII , ApoB and ApoCIII ratios comparing HD patients to the control group .	There were significantly increased TG, ApoAIII, ApoE, TC / HDL-C, ApoCIII non B, ApoCIII : B and decreased HDL-C, ApoAI, HDL-C and ApoAI, ApoAI and ApoCIII, ApoB and ApoCIII ratios comparing HD patients to the control group.	3	38	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoAI	ApoAI	ApoAI	ApoE	ApoE	ApoE	25	26	8	9
We show here that apoA-I strongly stimulates apoE secretion , suggesting that in pathological conditions , such as obesity , the combination of low HDL-c levels ( carrying apoA-I ) and oxidative stress contributes to a major reduction in adipocyte apoE secretion .	We show here that apoA-I strongly stimulates apoE secretion, suggesting that in pathological conditions, such as obesity, the combination of low HDL-c levels (carrying apoA-I) and oxidative stress contributes to a major reduction in adipocyte apoE secretion.	4	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	4	5	7	8
In order to clarify how apoA-I increased the adipocyte secretion of apoE , we chose to use the Golgi secretion inhibitor , BFA .	In order to clarify how apoA-I increased the adipocyte secretion of apoE, we chose to use the Golgi secretion inhibitor, BFA.	5	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	5	6	11	12
ApoA-I also stimulates secretion of apolipoprotein E ( apoE ) from macrophage foam cells , although the mechanism of this process is not understood .	ApoA-I also stimulates secretion of apolipoprotein E (apoE) from macrophage foam cells, although the mechanism of this process is not understood.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoA-I	ApoA-I	ApoA-I	apolipoprotein E	apolipoprotein E	apolipoprotein E	0	1	5	7
Numerous studies have shown that apoA-I is able to activate cholesterol efflux as well as the secretion of apoE [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Numerous studies have shown that apoA-I is able to activate cholesterol efflux as well as the secretion of apoE [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	5	6	18	19
Our results confirm existing data which show that apoA-I strongly stimulates apoE secretion from macrophages , an effect that is likely to contribute to the antiatherogenic potential of HDL .	Our results confirm existing data which show that apoA-I strongly stimulates apoE secretion from macrophages, an effect that is likely to contribute to the antiatherogenic potential of HDL.	8	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	8	9	11	12
The addition of apoA-I to the cell media increased apoE secretion from the cells , in a concentration dependent fashion , without affecting cellular apoE levels .	The addition of apoA-I to the cell media increased apoE secretion from the cells, in a concentration dependent fashion, without affecting cellular apoE levels.	1	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	3	4	9	10
We conclude that 1 ) HDL apoE recycles in a quantitatively comparable fashion to VLDL apoE ; 2 ) apoE recycling can be modulated by extracellular apoA-I but is not affected by endogenous apoE ; and 3 ) recycling occurs in macrophages as well as in hepatocytes , suggesting that the process is not cell specific .	We conclude that 1) HDL apoE recycles in a quantitatively comparable fashion to VLDL apoE; 2) apoE recycling can be modulated by extracellular apoA-I but is not affected by endogenous apoE; and 3) recycling occurs in macrophages as well as in hepatocytes, suggesting that the process is not cell specific.	19	27	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	26	27	19	20
If the over-expression of human apoA-I caused displacement of apoE from the HDL , the levels of hepatic apoE mRNA should remain the same in WT and the apoAI-Tg mice .	If the over-expression of human apoA-I caused displacement of apoE from the HDL, the levels of hepatic apoE mRNA should remain the same in WT and the apoAI-Tg mice.	2	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	over-expression of human apoA-I	apoa-i	apoE	apoE	apoe	5	6	9	10
Moreover , DHC markedly decreased plasma levels of LDL-C , VLDL-C , TG and inflammatory cytokines , including IL-1beta , IL-6 , TNF-alpha and CRP , and increased plasma levels of HDL-C and apoA1 , and thus significantly suppressed atherosclerotic plaque formation in apoE -/- mice fed a high-fat and high-cholesterol diet .	Moreover, DHC markedly decreased plasma levels of LDL-C, VLDL-C, TG and inflammatory cytokines, including IL-1beta, IL-6, TNF-alpha and CRP, and increased plasma levels of HDL-C and apoA1, and thus significantly suppressed atherosclerotic plaque formation in apoE -/- mice fed a high-fat and high-cholesterol diet.	2	44	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA1	DHC markedly decreased plasma levels of LDL-C, VLDL-C, TG and inflammatory cytokines, including IL-1beta, IL-6, TNF-alpha and CRP, and increased plasma levels of HDL-C and apoA1	apoa1	apoE	apoE	apoe	33	34	43	44
Moreover , PLTP deletion from macrophages reduces apoE secretion [ XREF_BIBR ] suggesting that PLTP could play a role in the apoA-I induced apoE secretion .	Moreover, PLTP deletion from macrophages reduces apoE secretion [XREF_BIBR] suggesting that PLTP could play a role in the apoA-I induced apoE secretion.	16	24	induced	Positive_early_activation	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	21	22	23	24
Because transgenic mice overexpressing human apoA-I from the liver ( h-apoA-I TgN ) are protected from the atherogenesis induced by apoE deficiency , we hypothesized that the presence of apoA-I in the vessel wall could reduce the negative effect of apoE deficiency on lesion growth .	Because transgenic mice overexpressing human apoA-I from the liver (h-apoA-I TgN) are protected from the atherogenesis induced by apoE deficiency, we hypothesized that the presence of apoA-I in the vessel wall could reduce the negative effect of apoE deficiency on lesion growth.	27	41	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	29	30	40	41
It has been shown that apolipoprotein A-I ( ApoA-I ) stimulates the secretion of apolipoprotein E ( ApoE ) from human macrophages .	It has been shown that apolipoprotein A-I (ApoA-I) stimulates the secretion of apolipoprotein E (ApoE) from human macrophages.	5	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein E	apolipoprotein E	apolipoprotein E	5	7	14	16
Interestingly , the enhancement of apoE secretion induced by apoA-I is concentration dependent , but even at levels as high as 80 mug/ml a saturation of the system could not be demonstrated .	Interestingly, the enhancement of apoE secretion induced by apoA-I is concentration dependent, but even at levels as high as 80 mug/ml a saturation of the system could not be demonstrated.	5	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	9	10	5	6
We also showed that : ( i ) siRNA mediated CETP gene silencing diminished apoE secretion from both non loaded and lipid loaded macrophages ; ( ii ) addition of apoA-I partially restored apoE secretion from lipid loaded macrophages with the silenced CETP gene .	We also showed that : (i) siRNA mediated CETP gene silencing diminished apoE secretion from both non loaded and lipid loaded macrophages; (ii) addition of apoA-I partially restored apoE secretion from lipid loaded macrophages with the silenced CETP gene.	28	34	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	30	31	33	34
In the current study , 4F also attenuated endotoxin induced changes in HDL composition , thus potentially negating secondary effects of altered apolipoproteins ( reduced apoA-I and apoA-IV ; increased apoE ) on cytokine release .	In the current study, 4F also attenuated endotoxin induced changes in HDL composition, thus potentially negating secondary effects of altered apolipoproteins (reduced apoA-I and apoA-IV; increased apoE) on cytokine release.	24	31	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	25	26	30	31
We demonstrate that apoA-I induces a strong increase in cholesterol release and apoE secretion from adipocytes , whereas it has no transcriptional effect on ABCA1 or apoE genes .	We demonstrate that apoA-I induces a strong increase in cholesterol release and apoE secretion from adipocytes, whereas it has no transcriptional effect on ABCA1 or apoE genes.	3	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	3	4	12	13
In addition , apoA-I also stimulates the secretion of apolipoprotein E ( apoE ) ; this action is probably partially dependent on ABCA1 [ XREF_BIBR ] .	In addition, apoA-I also stimulates the secretion of apolipoprotein E (apoE); this action is probably partially dependent on ABCA1 [XREF_BIBR].	3	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apolipoprotein E	apolipoprotein E	apolipoprotein E	3	4	9	11
Finally , because apoA-I enhances both PLTP activity and apoE secretion from MFC we questioned whether apoA-I mediate its effect on apoE secretion by enhancing the PLTP activity .	Finally, because apoA-I enhances both PLTP activity and apoE secretion from MFC we questioned whether apoA-I mediate its effect on apoE secretion by enhancing the PLTP activity.	3	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	3	4	9	10
HDL increased the flotation of apoAI to 12-fold and very low density lipoprotein ( VLDL ) increased the flotation of apoCIII and apoE to 6.5- and 5.5-fold , respectively .	HDL increased the flotation of apoAI to 12-fold and very low density lipoprotein (VLDL) increased the flotation of apoCIII and apoE to 6.5- and 5.5-fold, respectively.	3	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoAI	apoAI	apoAI	apoE	apoE	apoE	5	6	22	23
The inter-relationship between apoA-I and apoE has been previously shown in the periphery , namely that apoA-I can induce the secretion of apoE , possibly through modulation of the apoE recycling process [ XREF_BIBR - XREF_BIBR ] .	The inter-relationship between apoA-I and apoE has been previously shown in the periphery, namely that apoA-I can induce the secretion of apoE, possibly through modulation of the apoE recycling process [XREF_BIBR - XREF_BIBR].	16	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	16	17	22	23
We hypothesized that interaction between apoA-I and apoE contributed to the antiatherogenic properties of apoA-I , and therefore investigated whether apoA-I stimulated secretion of apoE by foam cell macrophages .	We hypothesized that interaction between apoA-I and apoE contributed to the antiatherogenic properties of apoA-I, and therefore investigated whether apoA-I stimulated secretion of apoE by foam cell macrophages.	20	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	20	21	24	25
We conclude that apoA-I stimulates secretion of apoE independently of cholesterol efflux , and that this represents a novel , ABCA-1-independent , positive feedback pathway for stimulation of potentially anti-atherogenic apoE secretion by alpha-helix-containing molecules including apoA-I and apoE .	We conclude that apoA-I stimulates secretion of apoE independently of cholesterol efflux, and that this represents a novel, ABCA-1-independent, positive feedback pathway for stimulation of potentially anti-atherogenic apoE secretion by alpha-helix-containing molecules including apoA-I and apoE.	3	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	3	4	7	8
Finally , apoA-I stimulates apoE secretion normally from macrophages of two unrelated subjects with genetically confirmed Tangier Disease ( mutations C733R and c.5220-5222delTCT ; and mutations A1046D and c.4629-4630insA ) , despite severely inhibited cholesterol efflux .	Finally, apoA-I stimulates apoE secretion normally from macrophages of two unrelated subjects with genetically confirmed Tangier Disease (mutations C733R and c.5220-5222delTCT; and mutations A1046D and c.4629-4630insA), despite severely inhibited cholesterol efflux.	2	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	2	3	4	5
On the other hand , apoA-I stimulates secretion of apoE independently of cholesterol efflux in a human macrophage cell line ; this effect reflects a novel , ABCA1 independent , positive feedback pathway for stimulation of apoE secretion .	On the other hand, apoA-I stimulates secretion of apoE independently of cholesterol efflux in a human macrophage cell line; this effect reflects a novel, ABCA1 independent, positive feedback pathway for stimulation of apoE secretion.	5	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	5	6	9	10
Also , transcriptional activation of hTERT in human T cell leukemia -- lymphoma virus-1 infected cells was mediated by PI3K and PI3K and AKT dependent activation of hTERT was reported to be accomplished by ectopic expression of EGFR in oral squamous epithelial cells .	Also, transcriptional activation of hTERT in human T cell leukemia -- lymphoma virus-1 infected cells was mediated by PI3K and PI3K and AKT dependent activation of hTERT was reported to be accomplished by ectopic expression of EGFR in oral squamous epithelial cells.	23	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AKT	AKT	AKT	hTERT	hTERT	hTERT	23	24	27	28
The kinase Akt increases telomerase activity by phosphorilation hTERT in the melanoma cell line XREF_BIBR .	The kinase Akt increases telomerase activity by phosphorilation hTERT in the melanoma cell line XREF_BIBR.	0	5	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	2	3	4	5
Recombinant Akt dose-dependently increased telomerase activity , and telomerase was inhibited at the transcriptional and post-translational levels by LY294002 , suggesting that PI-3K and Akt is one of the key signaling proteins involved in telomerase regulation .	Recombinant Akt dose-dependently increased telomerase activity, and telomerase was inhibited at the transcriptional and post-translational levels by LY294002, suggesting that PI-3K and Akt is one of the key signaling proteins involved in telomerase regulation.	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	1	2	4	5
Here we found that 7721 hepatoma cells held a higher redox homeostasis threshold than L02 normal liver cells which caused 7721 cells to have a higher demand for ROS ; MnSOD over-expression in 7721 decreased endogenous reactive oxygen species ( ROS ) and inhibited telomerase activity ; Akt phosphorylation inhibitor and NAC both inhibited 7721 telomerase activity .	Here we found that 7721 hepatoma cells held a higher redox homeostasis threshold than L02 normal liver cells which caused 7721 cells to have a higher demand for ROS; MnSOD over-expression in 7721 decreased endogenous reactive oxygen species (ROS) and inhibited telomerase activity; Akt phosphorylation inhibitor and NAC both inhibited 7721 telomerase activity.	47	56	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	telomerase	telomerase	telomerase	47	48	55	56
We also observed that PTX-2 treatment attenuated the phosphorylation of Akt , thereby reducing the phosphorylation and nuclear translocation of hTERT .	We also observed that PTX-2 treatment attenuated the phosphorylation of Akt, thereby reducing the phosphorylation and nuclear translocation of hTERT.	4	21	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	PTX-2 treatment attenuated the phosphorylation of Akt	akt	hTERT	hTERT	htert	10	11	20	21
However , whereas Ly-294002 significantly decreased telomerase activity in unirradiated glioma cells , it failed to prevent the radiation induced increase in telomerase activity in irradiated cells , ruling out a role of the PI3K and AKT pathway in the radiation induced upregulation of telomerase activity in our model .	However, whereas Ly-294002 significantly decreased telomerase activity in unirradiated glioma cells, it failed to prevent the radiation induced increase in telomerase activity in irradiated cells, ruling out a role of the PI3K and AKT pathway in the radiation induced upregulation of telomerase activity in our model.	36	45	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	telomerase	telomerase	telomerase	36	37	44	45
Inhibition of ERK , Src , or Akt suppressed telomerase activity in HSC-1 cells , but to a lesser extent than did treatment with AG 1478 .	Inhibition of ERK, Src, or Akt suppressed telomerase activity in HSC-1 cells, but to a lesser extent than did treatment with AG 1478.	0	10	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	7	8	9	10
The Akt pathway has been shown to activate telomerase either by phosphorylation of the hTERT subunit XREF_BIBR or by both post-translational and transcriptional mechanisms XREF_BIBR , XREF_BIBR .	The Akt pathway has been shown to activate telomerase either by phosphorylation of the hTERT subunit XREF_BIBR or by both post-translational and transcriptional mechanisms XREF_BIBR, XREF_BIBR.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	1	2	8	9
Our results showing that telomerase upregulation was not abolished by the PI3K and AKT pathway inhibition , suggests that personalized combined therapies associating PI3K and telomerase inhibitors or telomere G-quadruplex ligands should be considered to improve the radiosensitization in telomerase expressing high-grade gliomas .	Our results showing that telomerase upregulation was not abolished by the PI3K and AKT pathway inhibition, suggests that personalized combined therapies associating PI3K and telomerase inhibitors or telomere G-quadruplex ligands should be considered to improve the radiosensitization in telomerase expressing high-grade gliomas.	4	15	abolished	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	telomerase	telomerase	telomerase	13	14	4	5
TERT plays an extensive role in the maintenance of functional telomeres , and TERT can be activated by AKT and HSP90 and inhibited by c-Abl .	TERT plays an extensive role in the maintenance of functional telomeres, and TERT can be activated by AKT and HSP90 and inhibited by c-Abl.	13	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	TERT	TERT	TERT	18	19	13	14
Furthermore , AKT is frequently dysregulated in cancer cells and activates several MYC and MAD1 target genes such as human telomerase reverse transcriptase ( hTERT ) and ornithine decarboxylase ( ODC ) [ XREF_BIBR - XREF_BIBR ] .	Furthermore, AKT is frequently dysregulated in cancer cells and activates several MYC and MAD1 target genes such as human telomerase reverse transcriptase (hTERT) and ornithine decarboxylase (ODC) [XREF_BIBR - XREF_BIBR].	2	23	dysregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	telomerase reverse transcriptase	telomerase reverse transcriptase	telomerase reverse transcriptase	2	3	20	23
AKT may modulate telomerase activity through a number of mechanisms , and Perifosine impacts pathways other than AKT , such as the p38 pathway [ XREF_BIBR ] , which may help explain some of the varying telomere biological responses to the drug .	AKT may modulate telomerase activity through a number of mechanisms, and Perifosine impacts pathways other than AKT, such as the p38 pathway [XREF_BIBR], which may help explain some of the varying telomere biological responses to the drug.	0	15	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	telomerase	telomerase	telomerase	0	1	3	4
AKT has a phosphorylation consensus target sequence within mouse telomerase , and increasing amounts of nuclear AKT increase telomerase activity .	AKT has a phosphorylation consensus target sequence within mouse telomerase, and increasing amounts of nuclear AKT increase telomerase activity.	16	19	increase	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	telomerase	telomerase	telomerase	16	17	18	19
Thus , these observations suggest that Akt kinase enhances human telomerase activity through phosphorylation of hTERT subunit as one of its substrate proteins .	Thus, these observations suggest that Akt kinase enhances human telomerase activity through phosphorylation of hTERT subunit as one of its substrate proteins.	6	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	6	7	10	11
Interestingly , a combined inhibition of VEGF and the PI3K and AKT pathway or HIF-1alpha abrogates hTERT upregulation by bevacizumab ( XREF_FIG ) .	Interestingly, a combined inhibition of VEGF and the PI3K and AKT pathway or HIF-1alpha abrogates hTERT upregulation by bevacizumab (XREF_FIG).	9	17	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	hTERT	hTERT	hTERT	11	12	16	17
The further results also confirmed that celecoxib , an inhibitor of Akt phosphorylation , could significantly repressed telomerase activity alone and enhance the repression of telomerase activity combined with GA ..	The further results also confirmed that celecoxib, an inhibitor of Akt phosphorylation, could significantly repressed telomerase activity alone and enhance the repression of telomerase activity combined with GA..	11	18	repressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	telomerase	telomerase	telomerase	11	12	17	18
Moreover , AKT activation enhances telomerase activity , inhibits apoptosis blocking the release of cytochrome c from the mitochondria and inactivating pro apoptotic factors such as Bad and pro caspase 9 , and regulates modulators of angiogenesis through the activation of nitric oxide synthase [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Moreover, AKT activation enhances telomerase activity, inhibits apoptosis blocking the release of cytochrome c from the mitochondria and inactivating pro apoptotic factors such as Bad and pro caspase 9, and regulates modulators of angiogenesis through the activation of nitric oxide synthase [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	6	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	telomerase	telomerase	telomerase	2	3	5	6
In any event , the inhibition of Akt phosphorylation and NF-kappaB by CDDO-Me would impair nuclear accumulation of hTERT since phosphorylated hTERT must associate with Akt and NF-kappaB for nuclear translocation [ XREF_BIBR , XREF_BIBR ] .	In any event, the inhibition of Akt phosphorylation and NF-kappaB by CDDO-Me would impair nuclear accumulation of hTERT since phosphorylated hTERT must associate with Akt and NF-kappaB for nuclear translocation [XREF_BIBR, XREF_BIBR].	7	19	impair	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	hTERT	hTERT	htert	7	8	18	19
Furthermore , the inhibition of Akt and NF-kappaB by CDDO-Me could also impair nuclear accumulation of hTERT since hTERT associates with both Akt and NF-kappaB for nuclear translocation [ XREF_BIBR ] .	Furthermore, the inhibition of Akt and NF-kappaB by CDDO-Me could also impair nuclear accumulation of hTERT since hTERT associates with both Akt and NF-kappaB for nuclear translocation [XREF_BIBR].	3	17	impair	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	hTERT	hTERT	hTERT	5	6	16	17
Inhibition of PI3K or AKT signaling pathways reduced telomerase activity in HTLV-I cells .	Inhibition of PI3K or AKT signaling pathways reduced telomerase activity in HTLV-I cells.	2	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	telomerase	telomerase	telomerase	4	5	8	9
Protein kinase Akt also activates telomerase by phosphorylating hTERT in melanoma and epithelial cells ( Kang et al , 1999 ; Breitschopf et al , 2001 ) .	Protein kinase Akt also activates telomerase by phosphorylating hTERT in melanoma and epithelial cells (Kang et al, 1999; Breitschopf et al, 2001).	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	2	3	5	6
Receptor mediated activation of Akt triggers antiapoptotic mechanisms , induces NF-kappaB transcription , increases tumor invasion and neoangiogenesis , and enhances telomerase activity .	Receptor mediated activation of Akt triggers antiapoptotic mechanisms, induces NF-kappaB transcription, increases tumor invasion and neoangiogenesis, and enhances telomerase activity.	0	22	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Receptor mediated activation of Akt triggers antiapoptotic mechanisms, induces NF-kappaB transcription	akt	telomerase	telomerase	telomerase	4	5	21	22
Although the mechanism by which the PI3K and AKT pathway upregulates hTERT is unclear , it has been suggested that it could be mediated by direct phosphorylation of serine residues in hTERT by p-AKT [ XREF_BIBR ] .	Although the mechanism by which the PI3K and AKT pathway upregulates hTERT is unclear, it has been suggested that it could be mediated by direct phosphorylation of serine residues in hTERT by p-AKT [XREF_BIBR].	6	12	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	hTERT	hTERT	hTERT	8	9	11	12
Akt has also been shown to stimulate telomerase activity and replication [ XREF_BIBR ] .	Akt has also been shown to stimulate telomerase activity and replication [XREF_BIBR].	0	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	0	1	7	8
Indeed , activated Akt enhances human telomerase activity through phosphorylation of the hTERT subunit ( Kang et al , 1999 ) , inhibits the proapoptotic factor Bad ( Nicholson and Anderson , 2002 ) and , in T lymphocytes , has a key role in G 1 -S phase progression through the regulation of pRB ( retinoblastoma protein ) phosphorylation ( Brennan et al , 1997 ) .	Indeed, activated Akt enhances human telomerase activity through phosphorylation of the hTERT subunit (Kang et al, 1999), inhibits the proapoptotic factor Bad (Nicholson and Anderson, 2002) and, in T lymphocytes, has a key role in G 1 -S phase progression through the regulation of pRB (retinoblastoma protein) phosphorylation (Brennan et al, 1997).	2	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	3	4	6	7
This suggests that phosphorylation of Akt ( Ser473 ) alone is not sufficient and might require other players such as ERK in order to restore telomerase activity .	This suggests that phosphorylation of Akt (Ser473) alone is not sufficient and might require other players such as ERK in order to restore telomerase activity.	3	26	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	phosphorylation of Akt (Ser473	akt	telomerase	telomerase	telomerase	5	6	25	26
Third , Akt has been shown to enhance human telomerase activity through phosphorylation of hTERT subunit .	Third, Akt has been shown to enhance human telomerase activity through phosphorylation of hTERT subunit.	0	10	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	2	3	9	10
The Akt kinase ( known also as protein kinase B ) shows a specificity to serine/threonine residues and enhances human telomerase activity through TERT phosphorylation .	The Akt kinase (known also as protein kinase B) shows a specificity to serine/threonine residues and enhances human telomerase activity through TERT phosphorylation.	1	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	1	2	20	21
Either Akt phosphorylation inhibitor , LY294002 , or NAC could inhibit 7721 telomerase activity ( XREF_FIG B ) .	Either Akt phosphorylation inhibitor, LY294002, or NAC could inhibit 7721 telomerase activity (XREF_FIG B).	1	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation	akt	telomerase	telomerase	telomerase	1	2	12	13
In contrast , no association was observed between VLDL APOA-V concentration and any of the VLDL kinetic parameters , despite the evidence from in-vitro and animal studies that APOA-V enhances LPL activity and enhances the uptake of TRLs by the liver .	In contrast, no association was observed between VLDL APOA-V concentration and any of the VLDL kinetic parameters, despite the evidence from in-vitro and animal studies that APOA-V enhances LPL activity and enhances the uptake of TRLs by the liver.	28	33	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APOA-V	APOA-V	APOA-V	LPL	LPL	LPL	28	29	30	31
Using [ 3H ]-triolein-labeled VLDL like particles , the researchers found that purified apoA5 protein could stimulate LPL activity in a dose dependent manner ; injection of [ 3H ]-triolein-labeled VLDL like particles into APOA5 transgenic mice could significantly accelerate the rate of TRLs clearance of VLDL compared with that in control group , suggesting that apoA5 could increase the effect of LPL in reducing plasma TG level [ XREF_BIBR ] .	Using [3H]-triolein-labeled VLDL like particles, the researchers found that purified apoA5 protein could stimulate LPL activity in a dose dependent manner; injection of [3H]-triolein-labeled VLDL like particles into APOA5 transgenic mice could significantly accelerate the rate of TRLs clearance of VLDL compared with that in control group, suggesting that apoA5 could increase the effect of LPL in reducing plasma TG level [XREF_BIBR].	13	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA5	apoA5	apoA5	LPL	LPL	LPL	13	14	17	18
Other players in this process are apoA5 , which can stimulate LpL , and the angiopoietin like proteins ( angptl3 and angptl4 ) , which can interfere with LpL activity .	Other players in this process are apoA5, which can stimulate LpL, and the angiopoietin like proteins (angptl3 and angptl4), which can interfere with LpL activity.	1	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA5	apoA5	apoA5	LpL	LpL	LpL	6	7	11	12
Since APOA5 stimulates the activity of lipoprotein lipase , we tested whether changes in adipose tissue lipase activity contributed to the selective changes in size of fat pad as seen for male A5tg mice .	Since APOA5 stimulates the activity of lipoprotein lipase, we tested whether changes in adipose tissue lipase activity contributed to the selective changes in size of fat pad as seen for male A5tg mice.	1	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APOA5	APOA5	APOA5	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	1	2	6	8
Overexpression of APOA5 has been shown to increase LPL activity in an animal model .	Overexpression of APOA5 has been shown to increase LPL activity in an animal model.	0	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APOA5	Overexpression of APOA5	apoa5	LPL	LPL	lpl	2	3	8	9
Here , we studied the role of LPL and two potent modifiers , the LPL inhibitor apoC-III and the LPL activator apoA-V , in APOE2-knockin ( APOE2 ) mice .	Here, we studied the role of LPL and two potent modifiers, the LPL inhibitor apoC-III and the LPL activator apoA-V, in APOE2-knockin (APOE2) mice.	5	22	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	apoA-V	apoA-V	apoA-V	LPL	LPL	LPL	21	22	19	20
It may act proatherogenic by promoting intimal SMC migration and by regulating apolipoprotein A-V dependent activation of lipoprotein lipase to modulate systemic triglyceride levels .	It may act proatherogenic by promoting intimal SMC migration and by regulating apolipoprotein A-V dependent activation of lipoprotein lipase to modulate systemic triglyceride levels.	12	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	apolipoprotein A-V	apolipoprotein A-V	apolipoprotein A-V	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	12	14	17	19
Although the underlying mechanism for the TG lowering effect of apoA5 has not been well defined , several lines of evidence indicate that apoA5 stimulates lipoprotein lipase ( LPL ) activity [ XREF_BIBR - XREF_BIBR ] .	Although the underlying mechanism for the TG lowering effect of apoA5 has not been well defined, several lines of evidence indicate that apoA5 stimulates lipoprotein lipase (LPL) activity [XREF_BIBR - XREF_BIBR].	23	27	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA5	apoA5	apoA5	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	23	24	25	27
By activating proteoglycans bound lipoprotein lipase ( LPL ) , apoA-V can accelerate TG hydrolysis from VLDL and chylomicrons independent from other apoproteins .	By activating proteoglycans bound lipoprotein lipase (LPL), apoA-V can accelerate TG hydrolysis from VLDL and chylomicrons independent from other apoproteins.	4	13	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-V	apoA-V	apoA-V	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	10	11	4	6
Insofar as apoA-V does not directly activate LPL [ XREF_BIBR , XREF_BIBR ] , its effects on plasma triacylglycerol are manifest indirectly , via interaction with GPIHBP1 .	Insofar as apoA-V does not directly activate LPL [XREF_BIBR, XREF_BIBR], its effects on plasma triacylglycerol are manifest indirectly, via interaction with GPIHBP1.	2	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-V	apoA-V	apoA-V	LPL	LPL	LPL	2	3	7	8
The APOA5 gene codes for a 366-amino acid protein , apoA-V , which enhances lipoprotein lipase ( LPL ) activity .	The APOA5 gene codes for a 366-amino acid protein, apoA-V, which enhances lipoprotein lipase (LPL) activity.	3	16	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-V	apoA-V	apoA-V	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	10	11	14	16
The mechanism by which ApoA5 reduces plasma TG concentrations is not completely understood , although it has been established that ApoA5 activates LPL activity , thus accelerating hydrolysis of TG rich lipoproteins .	The mechanism by which ApoA5 reduces plasma TG concentrations is not completely understood, although it has been established that ApoA5 activates LPL activity, thus accelerating hydrolysis of TG rich lipoproteins.	20	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoA5	ApoA5	ApoA5	LPL	LPL	LPL	20	21	22	23
Some data have suggested that apo-AV increases LPL activity .	Some data have suggested that apo-AV increases LPL activity.	5	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apo-AV	apo-AV	apo-AV	LPL	LPL	LPL	5	6	7	8
This pathway is mediated by increased expression of LPL and the LPL activator apolipoprotein A-V and reduced expression of the LPL inhibitor apolipoprotein C-III [ XREF_BIBR , XREF_BIBR ] .	This pathway is mediated by increased expression of LPL and the LPL activator apolipoprotein A-V and reduced expression of the LPL inhibitor apolipoprotein C-III [XREF_BIBR, XREF_BIBR].	11	15	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	apolipoprotein A-V	apolipoprotein A-V	apolipoprotein A-V	LPL	LPL	LPL	13	15	11	12
LPL activity is increased by apolipoprotein A-V ( APOA5 ) , but reduced by apolipoprotein C-III ( APOC3 ) and angiopoietin like 4 ( ANGPTL4 ) , all of which have been associated with CAD in a genome-widesignificant fashion .	LPL activity is increased by apolipoprotein A-V (APOA5), but reduced by apolipoprotein C-III (APOC3) and angiopoietin like 4 (ANGPTL4), all of which have been associated with CAD in a genome-widesignificant fashion.	0	7	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apolipoprotein A-V	apolipoprotein A-V	apolipoprotein A-V	LPL	LPL	LPL	5	7	0	1
It may act as proatherogenic factor by promoting intimal SMC migration and by regulating apoA-V dependent activation of LPL thus modulating triglyceride plasma levels .	It may act as proatherogenic factor by promoting intimal SMC migration and by regulating apoA-V dependent activation of LPL thus modulating triglyceride plasma levels.	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	apoA-V	apoA-V	apoA-V	LPL	LPL	LPL	14	15	18	19
The primary known function of apoA-V is to act as cofactor and stimulate LPL and plasma clearance of TRLs LMF1 has been shown to be essential for the maturation of both LPL and hepatic lipase ( HL ) to their full functional forms .	The primary known function of apoA-V is to act as cofactor and stimulate LPL and plasma clearance of TRLs LMF1 has been shown to be essential for the maturation of both LPL and hepatic lipase (HL) to their full functional forms.	3	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-V	apoA-V	apoA-V	LPL	LPL	LPL	5	6	13	14
Many studies have demonstrated that APOA5 enhances the activity of the lipoprotein lipase ( LPL ) , which leads to diminution of TG levels in VLDL particles .	Many studies have demonstrated that APOA5 enhances the activity of the lipoprotein lipase (LPL), which leads to diminution of TG levels in VLDL particles.	5	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APOA5	APOA5	APOA5	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	5	6	11	13
The plasma of this patient was found to activate LPL in vitro less efficiently than control plasma , thus suggesting that apoA-V might be an activator of LPL .	The plasma of this patient was found to activate LPL in vitro less efficiently than control plasma, thus suggesting that apoA-V might be an activator of LPL.	21	28	be an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	apoA-V	apoA-V	apoA-V	LPL	LPL	LPL	21	22	27	28
Accordingly , the knock-down of ALK expression in cell model systems led to a marked decrease of cell proliferation clearly indicating ALK as a critical player in NB development XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR .	Accordingly, the knock-down of ALK expression in cell model systems led to a marked decrease of cell proliferation clearly indicating ALK as a critical player in NB development XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR.	5	25	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK expression	alk	ALK	ALK	alk	5	6	21	22
Consistently , ceritinib with MS209 or verapamil effectively suppressed ALK phosphorylation ( XREF_FIG B ) and inhibited phospho-ALK reactivation when the cells were treated with 1muM of ceritinib ( XREF_FIG C ) .	Consistently, ceritinib with MS209 or verapamil effectively suppressed ALK phosphorylation (XREF_FIG B) and inhibited phospho-ALK reactivation when the cells were treated with 1muM of ceritinib (XREF_FIG C).	2	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ALK	ceritinib with MS209 or verapamil effectively suppressed ALK phosphorylation	alk	phospho-ALK	phospho-ALK	phospho-alk	9	10	17	18
In contrast to earlier studies in which an excellent correlation was observed between ALK translocations and ALK expression , in colorectal carcinoma , increased ALK gene copy number does not translate to increased ALK protein expression , thereby resulting in poor correlation between ALK FISH and ALK IHC .	In contrast to earlier studies in which an excellent correlation was observed between ALK translocations and ALK expression, in colorectal carcinoma, increased ALK gene copy number does not translate to increased ALK protein expression, thereby resulting in poor correlation between ALK FISH and ALK IHC.	16	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK expression	alk	ALK	ALK	alk	16	17	24	25
In sum , increased ALK expression drives resistance associated with preserved STAT3 activation but leads to increased ALK signaling when drug is withdrawn .	In sum, increased ALK expression drives resistance associated with preserved STAT3 activation but leads to increased ALK signaling when drug is withdrawn.	4	18	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	ALK	ALK expression	alk	ALK	ALK	alk	4	5	17	18
Together , these findings argue that PTN up-regulates ALK expression , but menin represses ALK expression indirectly through inhibiting PTN expression , downregulating two crucial components of the PTN pathway , PTN and the downstream receptor ALK .	Together, these findings argue that PTN up-regulates ALK expression, but menin represses ALK expression indirectly through inhibiting PTN expression, downregulating two crucial components of the PTN pathway, PTN and the downstream receptor ALK.	12	37	downregulating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ALK	menin represses ALK expression	alk	ALK	ALK	alk	14	15	36	37
To control for possible founder effects in our transgenic lines , and to examine whether overexpression of wild-type ALK ( ALKWT ) as well as mutationally activated ALK could collaborate with MYCN in neuroblastoma pathogenesis , we overexpressed either activated human ALK or human ALKWT in MYCN fish .	To control for possible founder effects in our transgenic lines, and to examine whether overexpression of wild-type ALK (ALKWT) as well as mutationally activated ALK could collaborate with MYCN in neuroblastoma pathogenesis, we overexpressed either activated human ALK or human ALKWT in MYCN fish.	15	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	overexpression of wild-type ALK	alk	ALK	ALK	alk	18	19	27	28
When present in cis with an ALK translocation , this mutation ( also detected in neuroblastomas ) causes an increase in ALK phosphorylation , cell growth and downstream signaling .	When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth and downstream signaling.	17	23	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	ALK phosphorylation	alk	ALK	ALK	alk	21	22	21	22
17-DMAG inhibited protein levels of ALK , EGFR , and MET , even in the presence of ligand activation , and suppressed of AKT and ERK1/2 phosphorylation , thereby inducing apoptosis of ALK rearranged NSCLC cells , irrespective of the presence of HGF or EGFR ligands .	17-DMAG inhibited protein levels of ALK, EGFR, and MET, even in the presence of ligand activation, and suppressed of AKT and ERK1/2 phosphorylation, thereby inducing apoptosis of ALK rearranged NSCLC cells, irrespective of the presence of HGF or EGFR ligands.	0	33	inducing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ALK	17-DMAG inhibited protein levels of ALK	alk	ALK	ALK	alk	5	6	32	33
Here we show that mouse Alk expression increases in striatal neurons upon downregulation of Lmo4 by RNA interference ( RNAi ) , implicating Alk as a negatively regulated target of LMO4 .	Here we show that mouse Alk expression increases in striatal neurons upon downregulation of Lmo4 by RNA interference (RNAi), implicating Alk as a negatively regulated target of LMO4.	5	24	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Alk	Alk expression	alk	Alk	Alk	alk	5	6	23	24
In contrast to the patients with ALK positive neuroblastoma , the 19 year old patient with alveolar RMS and high expression of full-length ALK clearly produced ALK antibodies .	In contrast to the patients with ALK positive neuroblastoma, the 19 year old patient with alveolar RMS and high expression of full-length ALK clearly produced ALK antibodies.	20	27	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK	expression of full-length ALK	alk	ALK	ALK	alk	23	24	26	27
However , Tie 2 , which is constitutively activated by basal angiopoietin 1 expression [ XREF_BIBR ] , was not expressed .	However, Tie 2, which is constitutively activated by basal angiopoietin 1 expression [XREF_BIBR], was not expressed.	2	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	angiopoietin 1	angiopoietin 1 expression	angiopoietin 1	Tie	Tie	tie	11	13	2	3
Tie1 can be activated by an Angiopoietin 1 ( Ang1 ) chimeric protein ( COMP-Ang1 ) as well as by native Ang1 and Ang4 , but not by Ang2 or Ang3 .	Tie1 can be activated by an Angiopoietin 1 (Ang1) chimeric protein (COMP-Ang1) as well as by native Ang1 and Ang4, but not by Ang2 or Ang3.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Angiopoietin 1	Angiopoietin 1	Angiopoietin 1	Tie1	Tie1	Tie1	6	8	0	1
The interaction of apoA-I and its mimetic peptides with ABCA1 expressing cells rapidly activates JAK2 , and this enhances the direct interaction of apoA-I with ABCA1 required for lipid removal from the cells .	The interaction of apoA-I and its mimetic peptides with ABCA1 expressing cells rapidly activates JAK2, and this enhances the direct interaction of apoA-I with ABCA1 required for lipid removal from the cells.	1	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	JAK2	JAK2	JAK2	3	4	14	15
Significantly , the JAK2 and STAT3 pathway can also be activated by synthetic apoA-I mimetic peptides , and one of the peptides , peptide 5A , which has been shown to decrease atherosclerosis with very little side effects compared to other peptides [ XREF_BIBR , XREF_BIBR ] , is more specific than other peptides in activating the JAK2 and STAT3 pathway ( Tang , unpublished data ) , raising the possibility of finding peptides or small molecules for ligand and receptor interactions to regulate both the lipid transport and anti-inflammatory activity of ABCA1 .	Significantly, the JAK2 and STAT3 pathway can also be activated by synthetic apoA-I mimetic peptides, and one of the peptides, peptide 5A, which has been shown to decrease atherosclerosis with very little side effects compared to other peptides [XREF_BIBR, XREF_BIBR], is more specific than other peptides in activating the JAK2 and STAT3 pathway (Tang, unpublished data), raising the possibility of finding peptides or small molecules for ligand and receptor interactions to regulate both the lipid transport and anti-inflammatory activity of ABCA1.	3	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	JAK2	JAK2	JAK2	13	14	3	4
We have previously shown that the interaction of apoA-I with ABCA1 activates signaling molecule Janus kinase 2 ( JAK2 ) , which optimizes the cholesterol efflux activity of ABCA1 .	We have previously shown that the interaction of apoA-I with ABCA1 activates signaling molecule Janus kinase 2 (JAK2), which optimizes the cholesterol efflux activity of ABCA1.	6	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	JAK2	JAK2	JAK2	8	9	18	19
Thus , the interaction of apoA-I with ABCA1 expressing macrophages activates a JAK2 and STAT3 pathway that has anti-inflammatory activity .	Thus, the interaction of apoA-I with ABCA1 expressing macrophages activates a JAK2 and STAT3 pathway that has anti-inflammatory activity.	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoA-I	apoA-I	apoA-I	JAK2	JAK2	JAK2	5	6	12	13
For instance , PARKIN is further reported to interact with Activating molecule in BECN1 regulated autophagy protein 1 ( AMBRA1 ) that activates BECLIN1 complex , endorsing the AP formation nearby .	For instance, PARKIN is further reported to interact with Activating molecule in BECN1 regulated autophagy protein 1 (AMBRA1) that activates BECLIN1 complex, endorsing the AP formation nearby.	16	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AMBRA1	AMBRA1	AMBRA1	BECLIN1	BECLIN1	BECLIN1	19	20	23	24
Ambra1 deletion severely inhibits the Beclin1 mediated induction of autophagy .	Ambra1 deletion severely inhibits the Beclin1 mediated induction of autophagy.	0	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Ambra1	Ambra1	Ambra1	Beclin1	Beclin1	Beclin1	0	1	5	6
Another layer of complexity in higher eukaryotic organisms , beyond the diversity of signaling inputs to Beclin 1 , has emerged from the identification of mammalian specific autophagy proteins such as AMBRA1 ( autophagy and Beclin -1 regulator 1 ) that activate the Beclin 1 containing PI3KC3-C1 complex and the recent identification of a mammalian specific Beclin 1 homolog , Beclin 2 [ XREF_BIBR ] .	Another layer of complexity in higher eukaryotic organisms, beyond the diversity of signaling inputs to Beclin 1, has emerged from the identification of mammalian specific autophagy proteins such as AMBRA1 (autophagy and Beclin -1 regulator 1) that activate the Beclin 1 containing PI3KC3-C1 complex and the recent identification of a mammalian specific Beclin 1 homolog, Beclin 2 [XREF_BIBR].	28	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AMBRA1	AMBRA1	AMBRA1	Beclin 1	Beclin 1	Beclin 1	31	32	43	45
AMBRA-1 enhances the activity of BECLIN-1 , and thus mediates autophagosome nucleation .	AMBRA-1 enhances the activity of BECLIN-1, and thus mediates autophagosome nucleation.	0	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AMBRA-1	AMBRA-1	AMBRA-1	BECLIN-1	BECLIN-1	BECLIN-1	0	1	5	6
XREF_BIBR BCL2 can also regulate BECN1 induced autophagy by sequestering AMBRA1 ( the activator of BECN1 ) at the mitochondria .	XREF_BIBR BCL2 can also regulate BECN1 induced autophagy by sequestering AMBRA1 (the activator of BECN1) at the mitochondria.	9	16	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	AMBRA1	AMBRA1	AMBRA1	BECN1	BECN1	BECN1	10	11	15	16
We noted that previous studies had suggested that AKT may activate WNK1 XREF_BIBR , and since both chemokine receptors and the TCR are known to activate AKT via phosphoinositide-3-kinase ( PI3-kinase ) , we tested the potential involvement of these kinases in the activation of WNK1 .	We noted that previous studies had suggested that AKT may activate WNK1 XREF_BIBR, and since both chemokine receptors and the TCR are known to activate AKT via phosphoinositide-3-kinase (PI3-kinase), we tested the potential involvement of these kinases in the activation of WNK1.	8	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	WNK1	WNK1	WNK1	8	9	11	12
Akt and PKB1 activation of WNK1 in the kidney is also seen in db/db mice suggesting it has a role in the hypertension seen in the metabolic syndrome [ XREF_BIBR ] .	Akt and PKB1 activation of WNK1 in the kidney is also seen in db/db mice suggesting it has a role in the hypertension seen in the metabolic syndrome [XREF_BIBR].	0	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	WNK1	WNK1	WNK1	0	1	5	6
Our previous study found that activation of Akt triggers WNK1 mediated lung cancer progression [ XREF_BIBR ] .	Our previous study found that activation of Akt triggers WNK1 mediated lung cancer progression [XREF_BIBR].	5	10	triggers	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	WNK1	WNK1	WNK1	7	8	9	10
49 As the majority of schizophrenia patients in our study were treated with second generation antipsychotic drugs ( XREF_SUPPLEMENTARY ) and because of the suggested activation of WNK1 by Akt signaling pathways ( XREF_FIG ) , it appears that the significant difference in WNK1 levels reported in the CA1 of schizophrenia patients compared with controls might be influenced by psychotropic treatment .	49 As the majority of schizophrenia patients in our study were treated with second generation antipsychotic drugs (XREF_SUPPLEMENTARY) and because of the suggested activation of WNK1 by Akt signaling pathways (XREF_FIG), it appears that the significant difference in WNK1 levels reported in the CA1 of schizophrenia patients compared with controls might be influenced by psychotropic treatment.	25	31	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	WNK1	WNK1	WNK1	29	30	27	28
AKT has been reported to phosphorylate WNK1 on Thr60 XREF_BIBR , XREF_BIBR , however this phosphorylation does not lead to activation of WNK1 kinase activity , so it remains unclear how AKT activates WNK1 .	AKT has been reported to phosphorylate WNK1 on Thr60 XREF_BIBR, XREF_BIBR, however this phosphorylation does not lead to activation of WNK1 kinase activity, so it remains unclear how AKT activates WNK1.	31	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	WNK1	WNK1	WNK1	31	32	33	34
With no lysine 1 ( WNK1 ) , which may be activated by Akt , is important in cell proliferation and invasion , contributing to carcinogenesis and cancer progression [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	With no lysine 1 (WNK1), which may be activated by Akt, is important in cell proliferation and invasion, contributing to carcinogenesis and cancer progression [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	WNK1	WNK1	WNK1	13	14	5	6
Perilipin 2 staining clearly demarcated large lipid droplets in the control and Ldlr gRNA groups , while livers from mice treated with Ldlr+ Apob gRNAs showed numerous small lipid droplets per cell with intense staining .	Perilipin 2 staining clearly demarcated large lipid droplets in the control and Ldlr gRNA groups, while livers from mice treated with Ldlr+ Apob gRNAs showed numerous small lipid droplets per cell with intense staining.	12	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Apob	Apob	Apob	Ldlr	Ldlr	Ldlr	23	24	12	13
It is well known that chylomicrons and products of their enzymatic degradation ( LDL and VLDL ) are transported inside hepatocytes using the LDL receptor mediated by ApoB , an intrinsic component of low-density lipoprotein particles [ XREF_BIBR ] .	It is well known that chylomicrons and products of their enzymatic degradation (LDL and VLDL) are transported inside hepatocytes using the LDL receptor mediated by ApoB, an intrinsic component of low-density lipoprotein particles [XREF_BIBR].	23	31	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ApoB	ApoB	ApoB	LDL receptor	LDL receptor	LDL receptor	27	28	23	25
In this context , PCSK9 mediated degradation of hepatic LDLR can cause hypertriglyceridemia by liberating apoB from LDLR induced intracellular catabolism as well as reducing uptake of nascent apoB containing lipoproteins ( eg , VLDL ) .	In this context, PCSK9 mediated degradation of hepatic LDLR can cause hypertriglyceridemia by liberating apoB from LDLR induced intracellular catabolism as well as reducing uptake of nascent apoB containing lipoproteins (eg, VLDL).	11	18	cause	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	apoB	apoB	apoB	LDLR	LDLR	LDLR	15	16	17	18
We have shown first , that apoB mediates the binding of small VLDL Sf 20-60 and IDL , as well as LDL , to the LDL receptor .	We have shown first, that apoB mediates the binding of small VLDL Sf 20-60 and IDL, as well as LDL, to the LDL receptor.	6	27	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	apoB	apoB	apoB	LDL receptor	LDL receptor	LDL receptor	6	7	25	27
This is in contrast to the report by Crooke et al that Ldlr -/- mice treated with an apoB antisense oligonucleotides had a reduction of apoB mRNA by 74 % but still had 48 % levels of LDL-cholesterol compared to the pretreatment levels .	This is in contrast to the report by Crooke et al that Ldlr -/- mice treated with an apoB antisense oligonucleotides had a reduction of apoB mRNA by 74% but still had 48% levels of LDL-cholesterol compared to the pretreatment levels.	12	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	apoB	apoB	apoB	Ldlr	Ldlr	Ldlr	18	19	12	13
Rare mutations in apolipoprotein B ( apoB ) can cause defective binding of low-density lipoproteins ( LDLs ) to the LDL receptor , leading to elevated plasma cholesterol levels and premature atherosclerosis .	Rare mutations in apolipoprotein B (apoB) can cause defective binding of low-density lipoproteins (LDLs) to the LDL receptor, leading to elevated plasma cholesterol levels and premature atherosclerosis.	1	22	cause	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	apoB	apoB	apoB	LDL receptor	LDL receptor	LDL receptor	6	7	20	22
Based on the Akt and mTOR driven regulation of YB-1 we hypothesized that fisetin will inhibit Akt mediated YB-1 Ser 102 phosphorylation .	Based on the Akt and mTOR driven regulation of YB-1 we hypothesized that fisetin will inhibit Akt mediated YB-1 Ser 102 phosphorylation.	15	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	YB-1	YB-1	YB-1	16	17	18	19
Previous studies have shown that YB-1 activated by Akt and the activation of MAPK and ERK appeared YB-1 of normally localizing in the cytoplasm translocated into nucleus , leading to activation of the MDR1 expression XREF_BIBR .	Previous studies have shown that YB-1 activated by Akt and the activation of MAPK and ERK appeared YB-1 of normally localizing in the cytoplasm translocated into nucleus, leading to activation of the MDR1 expression XREF_BIBR.	5	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	YB-1	YB-1	YB-1	8	9	5	6
We show that the PI3K and AKT and p53 signalling , growth factors and chemotherapeutic agents increase YB-1 promoter activity .	We show that the PI3K and AKT and p53 signalling, growth factors and chemotherapeutic agents increase YB-1 promoter activity.	6	19	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	YB-1	YB-1	YB-1	6	7	17	18
Previous reports have shown that ENZ induces activation of AKT [ XREF_BIBR ] ; in turn , activated AKT leads to phospho activation of the transcription and translation factor YB-1 [ XREF_BIBR ] .	Previous reports have shown that ENZ induces activation of AKT [XREF_BIBR]; in turn, activated AKT leads to phospho activation of the transcription and translation factor YB-1 [XREF_BIBR].	17	30	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	YB-1	YB-1	YB-1	18	19	29	30
Androgen deprivation can activate AKT by decreasing expression of the FKBP5 gene , which is a chaperone for the AKT phosphatase PHLPP1 , and a recent study found that AKT could stimulate the YB1 transcription factor and thereby enhance ERBB2 gene transcription .	Androgen deprivation can activate AKT by decreasing expression of the FKBP5 gene, which is a chaperone for the AKT phosphatase PHLPP1, and a recent study found that AKT could stimulate the YB1 transcription factor and thereby enhance ERBB2 gene transcription.	29	35	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	YB1	YB1	YB1	29	30	33	34
Moreover , AKT upregulates Tbx3 as another pluripotency gene and causes acetylaton of STAT3 at lysine 686 ( K686 ) , which induces more stable homodimer formation of STAT3 , probably followed by the activation of Klf4 and Oct3/4 .	Moreover, AKT upregulates Tbx3 as another pluripotency gene and causes acetylaton of STAT3 at lysine 686 (K686), which induces more stable homodimer formation of STAT3, probably followed by the activation of Klf4 and Oct3/4.	2	10	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	Tbx3	Tbx3	Tbx3	2	3	4	5
E-cadherin is a known TBX3 target [ XREF_BIBR ] and its expression has been shown to be inhibited by the AKT pathway in melanoma cells [ XREF_BIBR ] suggesting that AKT induced phosphorylation of TBX3 may be required to inhibit E-cadherin levels in these cells .	E-cadherin is a known TBX3 target [XREF_BIBR] and its expression has been shown to be inhibited by the AKT pathway in melanoma cells [XREF_BIBR] suggesting that AKT induced phosphorylation of TBX3 may be required to inhibit E-cadherin levels in these cells.	30	42	induced	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	AKT	AKT	akt	TBX3	phosphorylation of TBX3 may be required to inhibit E-cadherin levels	tbx3	30	31	34	35
Briefly , the PI3K-AKT signalling pathway stimulates Tbx3 resulting in upregulated key pluripotency factor expression levels ( Oct3/4 , Nanog , and Sox2 ) .	Briefly, the PI3K-AKT signalling pathway stimulates Tbx3 resulting in upregulated key pluripotency factor expression levels (Oct3/4, Nanog, and Sox2).	3	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	Tbx3	Tbx3	Tbx3	3	4	7	8
For instance , Nanog expression is promoted by LIF through two parallel pathways : the JAK and STAT3 pathway , which activates Klf4 , and the PI3K and AKT pathway , which activates Tbx3 .	For instance, Nanog expression is promoted by LIF through two parallel pathways : the JAK and STAT3 pathway, which activates Klf4, and the PI3K and AKT pathway, which activates Tbx3.	26	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	Tbx3	Tbx3	Tbx3	28	29	33	34
To investigate the possibility that AKT phosphorylation enhances the ability of TBX3 to promote migration we next compared the impact of WT TBX3 and the TBX3 S720A and TBX3 S720E mutants on the migratory ability of the WM1650 RGP melanoma cells using an in vitro cell motility assay .	To investigate the possibility that AKT phosphorylation enhances the ability of TBX3 to promote migration we next compared the impact of WT TBX3 and the TBX3 S720A and TBX3 S720E mutants on the migratory ability of the WM1650 RGP melanoma cells using an in vitro cell motility assay.	5	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT phosphorylation	akt	TBX3	TBX3	tbx3	5	6	11	12
Akt mediated vimentin phosphorylation of Ser 39 has been reported to enhance the ability of the intermediate filament protein to induce motility and invasion [ XREF_BIBR ] .	Akt mediated vimentin phosphorylation of Ser 39 has been reported to enhance the ability of the intermediate filament protein to induce motility and invasion [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Akt	Akt	Akt	vimentin	vimentin	vimentin	0	1	2	3
Finally , cell line models with low Akt pathway activation and low levels of Vimentin gave rise to more reliable xenograft models .	Finally, cell line models with low Akt pathway activation and low levels of Vimentin gave rise to more reliable xenograft models.	7	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	Vimentin	Vimentin	Vimentin	7	8	14	15
AKT inhibition is known to induce the activation of caspases ; our results elucidate the mechanism by demonstrating that AKT blockade induces caspase dependent Vim proteolysis in vitro and in vivo .	AKT inhibition is known to induce the activation of caspases; our results elucidate the mechanism by demonstrating that AKT blockade induces caspase dependent Vim proteolysis in vitro and in vivo.	19	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	Vim	Vim	Vim	19	20	24	25
In contrast to STS cells , no constitutive AKT induced Vim phoshorylation was observed in normal mesenchymal cells ( XREF_SUPPLEMENTARY ) .	In contrast to STS cells, no constitutive AKT induced Vim phoshorylation was observed in normal mesenchymal cells (XREF_SUPPLEMENTARY).	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	Vim	Vim	Vim	8	9	10	11
The serine/threonine kinase Akt is an important mediator of cell survival and cell proliferation XREF_BIBR , XREF_BIBR and VCP has been shown to be a target of Akt signaling in neuronal cells and breast cancer cells XREF_BIBR , XREF_BIBR , XREF_BIBR .	The serine/threonine kinase Akt is an important mediator of cell survival and cell proliferation XREF_BIBR, XREF_BIBR and VCP has been shown to be a target of Akt signaling in neuronal cells and breast cancer cells XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	19	is an important mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	Akt	Akt	Akt	VCP	VCP	VCP	3	4	18	19
Additionally , bFGF promoted EMT by altering the interaction between GSK-3beta and Twist1 , resulting in the enhanced stability of Twist1 mediated by the AKT and GSK-3beta signalling pathway .	Additionally, bFGF promoted EMT by altering the interaction between GSK-3beta and Twist1, resulting in the enhanced stability of Twist1 mediated by the AKT and GSK-3beta signalling pathway.	18	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	Twist1	Twist1	Twist1	24	25	20	21
We found that Akt was activated in Hela and MCF7 cells expressing Twist .	We found that Akt was activated in Hela and MCF7 cells expressing Twist.	3	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	Twist	Twist	Twist	3	4	12	13
The activation of PI3K-Akt signaling also activates Twist1 XREF_BIBR , XREF_BIBR .	The activation of PI3K-Akt signaling also activates Twist1 XREF_BIBR, XREF_BIBR.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	Twist1	Twist1	Twist1	3	4	7	8
Furthermore , WTX controls cell-cell adhesion through interactions with APC at the plasma membrane and modulates the activity of the WT1 ( Wilms tumor 1 ) transcription factor in the nucleus .	Furthermore, WTX controls cell-cell adhesion through interactions with APC at the plasma membrane and modulates the activity of the WT1 (Wilms tumor 1) transcription factor in the nucleus.	2	27	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WTX	WTX	WTX	WT1	WT1	WT1	2	3	20	21
Thus , although WTX enhancement of WT1 function has been reported 86 , existing mutation data do not consistently support a model whereby WTX and WT1 mutations are functionally redundant .	Thus, although WTX enhancement of WT1 function has been reported 86, existing mutation data do not consistently support a model whereby WTX and WT1 mutations are functionally redundant.	3	7	enhancement	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	WTX	WTX	WTX	WT1	WT1	WT1	3	4	6	7
For example , human angiopoietin-4 ( ANGPT4 ) , an important angiogenesis growth factor , has been shown to activate TEK ( tyrosine protein kinase receptor ) , while the mouse sequence-ortholog ( Angpt4 ) has been shown to inhibit TEK XREF_BIBR .	For example, human angiopoietin-4 (ANGPT4), an important angiogenesis growth factor, has been shown to activate TEK (tyrosine protein kinase receptor), while the mouse sequence-ortholog (Angpt4) has been shown to inhibit TEK XREF_BIBR.	4	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGPT4	ANGPT4	ANGPT4	TEK	TEK	TEK	6	7	20	21
Ttc3 targets Akt , and Akt is downregulated in alcohol exposed embryos .	Ttc3 targets Akt, and Akt is downregulated in alcohol exposed embryos.	0	5	targets	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	Ttc3	Ttc3	Ttc3	2	3	0	1
In addition , PGE 2 has been shown to induce the expression of amphiregulin [ XREF_BIBR ] , a ligand for EGFR and activates EGFR signaling .	In addition, PGE 2 has been shown to induce the expression of amphiregulin [XREF_BIBR], a ligand for EGFR and activates EGFR signaling.	3	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	PGE 2 has been shown to induce the expression of amphiregulin	amphiregulin	EGFR	EGFR	egfr	13	14	24	25
ADAM17-/- mice still express AREG that normally activates EGFR during mammary gland development , but , in these mice , it is not cleaved from its membrane tethered form and can not activate EGFR [ XREF_BIBR ] .	ADAM17-/- mice still express AREG that normally activates EGFR during mammary gland development, but, in these mice, it is not cleaved from its membrane tethered form and can not activate EGFR [XREF_BIBR].	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	4	5	8	9
AREG causes sustained EGFR activation in proximal tubule cells in a cleavage dependent manner .	AREG causes sustained EGFR activation in proximal tubule cells in a cleavage dependent manner.	0	4	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	0	1	3	4
Our model actually showed that AREG could activate EGFR as efficiently as equimolar EGF when the amount of cell surface EGFR increased ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Our model actually showed that AREG could activate EGFR as efficiently as equimolar EGF when the amount of cell surface EGFR increased (XREF_FIG and XREF_SUPPLEMENTARY).	5	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	5	6	8	9
On the other hand , the substantial impact of AREG overexpression on tumor growth compared with that of TGF-alpha raises the possibility that the ligands may influence tumor growth in a manner independent of autrocrine EGFR driven signaling .	On the other hand, the substantial impact of AREG overexpression on tumor growth compared with that of TGF-alpha raises the possibility that the ligands may influence tumor growth in a manner independent of autrocrine EGFR driven signaling.	9	36	raises	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG overexpression	areg	EGFR	EGFR	egfr	9	10	35	36
Our recent study shows that AREG treatment induces EGFR down-regulation in human granulosa cells XREF_BIBR .	Our recent study shows that AREG treatment induces EGFR down-regulation in human granulosa cells XREF_BIBR.	5	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	5	6	8	9
This result suggests that the changes in the stability and trafficking of EGFR activated by AREG have important downstream effects .	This result suggests that the changes in the stability and trafficking of EGFR activated by AREG have important downstream effects.	8	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	15	16	12	13
More recently we have shown that AREG activation of EGFR results in an increase in the steady state levels of EGFR and accumulation of EGFR at the cell surface .	More recently we have shown that AREG activation of EGFR results in an increase in the steady state levels of EGFR and accumulation of EGFR at the cell surface.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	6	7	9	10
By contrast to EGF , AREG did not induce individual components of this signature , suggesting that AREG activated EGFR might escape this negative feedback mechanism .	By contrast to EGF, AREG did not induce individual components of this signature, suggesting that AREG activated EGFR might escape this negative feedback mechanism.	17	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	17	18	19	20
Similarly , TAZ , a paralog of YAP also induces AREG production and activation of EGFR signaling .	Similarly, TAZ, a paralog of YAP also induces AREG production and activation of EGFR signaling.	10	16	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	10	11	15	16
EGF strongly induced EGFR phosphorylation ( at Tyr1073 ) early after stimulation ( from 15 minutes to 1 hour ) , whereas AREG activated EGFR at this phosphorylation site only at the later time-points ( from day 7 to day 14 ) , when the effect of EGF on EGFR activation was no longer significant ( XREF_FIG ; XREF_SUPPLEMENTARY for quantification data ) .	EGF strongly induced EGFR phosphorylation (at Tyr1073) early after stimulation (from 15 minutes to 1 hour), whereas AREG activated EGFR at this phosphorylation site only at the later time-points (from day 7 to day 14), when the effect of EGF on EGFR activation was no longer significant (XREF_FIG; XREF_SUPPLEMENTARY for quantification data).	22	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	22	23	24	25
Amphiregulin then promotes EGFR activation within the stromal compartment of the gland driving the correct branching of this organ XREF_BIBR , XREF_BIBR .	Amphiregulin then promotes EGFR activation within the stromal compartment of the gland driving the correct branching of this organ XREF_BIBR, XREF_BIBR.	0	4	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Amphiregulin	Amphiregulin	Amphiregulin	EGFR	EGFR	EGFR	0	1	3	4
Previous studies using the iFGFR model have shown that Areg expression can be induced by FGFR1 and leads to activation of EGFR signaling to promote mammary tumorigenesis [ XREF_BIBR ] .	Previous studies using the iFGFR model have shown that Areg expression can be induced by FGFR1 and leads to activation of EGFR signaling to promote mammary tumorigenesis [XREF_BIBR].	9	22	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Areg	Areg expression	areg	EGFR	EGFR	egfr	9	10	21	22
In the present work , we found that AREG stimulated EGFR affects cell signaling and gene expression in a manner distinct from that of EGF stimulated EGFR in the same cell line .	In the present work, we found that AREG stimulated EGFR affects cell signaling and gene expression in a manner distinct from that of EGF stimulated EGFR in the same cell line.	8	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	8	9	10	11
While EGFR signaling mechanisms have been reviewed comprehensively elsewhere , how AREG may mediate differential effects of EGFR signaling to promote tissue homeostasis is a key area of investigation .	While EGFR signaling mechanisms have been reviewed comprehensively elsewhere, how AREG may mediate differential effects of EGFR signaling to promote tissue homeostasis is a key area of investigation.	11	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	11	12	17	18
Further , AREG induced EGFR accumulation on the plasma membrane compensates for the weak association between AREG and EGFR .	Further, AREG induced EGFR accumulation on the plasma membrane compensates for the weak association between AREG and EGFR.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	2	3	4	5
The unique activation of EGFR by AREG is hypothesized to aid in tissue repair through differentiation and proliferation of tissue resident cells , such as epithelial cells , which express EGFR [ XREF_BIBR ] .	The unique activation of EGFR by AREG is hypothesized to aid in tissue repair through differentiation and proliferation of tissue resident cells, such as epithelial cells, which express EGFR [XREF_BIBR].	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	6	7	4	5
A critical factor induced by estrogen receptor alpha ( Esr1 ) in the mammary epithelium is the Egf family member amphiregulin ( Areg ) , which activates stromal Egfr signaling XREF_BIBR - XREF_BIBR .	A critical factor induced by estrogen receptor alpha (Esr1) in the mammary epithelium is the Egf family member amphiregulin (Areg), which activates stromal Egfr signaling XREF_BIBR - XREF_BIBR.	20	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Areg	Areg	Areg	Egfr	Egfr	Egfr	22	23	28	29
Interestingly , tumours with high expression levels of amphiregulin ( AREG ) and epiregulin ( EREG ) , two ligands that can activate EGFR and have shown clinical relevance for the treatment of CRC patients , XREF_BIBR clustered in the groups of patients with wildtype like signatures ( XREF_FIG ) showing an inverse correlation with the scores of the three KRAS , BRAF and PIK3CA oncogenic signatures ( AREG : Pearson correlations -0.39 , -0.42 and -0.47 ; EREG : -0.51 , -0.53 and -0.58 , respectively ) .	Interestingly, tumours with high expression levels of amphiregulin (AREG) and epiregulin (EREG), two ligands that can activate EGFR and have shown clinical relevance for the treatment of CRC patients, XREF_BIBR clustered in the groups of patients with wildtype like signatures (XREF_FIG) showing an inverse correlation with the scores of the three KRAS, BRAF and PIK3CA oncogenic signatures (AREG : Pearson correlations -0.39, -0.42 and -0.47; EREG : -0.51, -0.53 and -0.58, respectively).	6	24	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	amphiregulin	levels of amphiregulin	amphiregulin	EGFR	EGFR	egfr	8	9	23	24
In this loop , AREG stimulation of EGFR results in AREG transcription and secretion allowing for AREG to signal EGFR continuously .	In this loop, AREG stimulation of EGFR results in AREG transcription and secretion allowing for AREG to signal EGFR continuously.	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	4	5	7	8
Further work is required to understand the mechanistic basis for EGFR stability and cell surface localization of AREG activated EGFR .	Further work is required to understand the mechanistic basis for EGFR stability and cell surface localization of AREG activated EGFR.	15	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	17	18	19	20
AREG stimulated EGFR has a long half-life compared to EGF stimulated EGFR , and is either stabilized or recycled to the cell surface , resulting in overexpression of EGFR at the protein level ( Willmarth etal ., 2008 ) .	AREG stimulated EGFR has a long half-life compared to EGF stimulated EGFR, and is either stabilized or recycled to the cell surface, resulting in overexpression of EGFR at the protein level (Willmarth etal., 2008).	0	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	0	1	11	12
AREG and EGF Differently Activate EGFR in Airway BC .	AREG and EGF Differently Activate EGFR in Airway BC.	0	8	Activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	0	1	5	6
For example , gefitinib and cetuximab are predicted to be more effective when EGFR activation is driven by amphiregulin ( AR ) than by epidermal growth factor ( EGF ) due to differences in affinity and time scales for receptor occupancy .	For example, gefitinib and cetuximab are predicted to be more effective when EGFR activation is driven by amphiregulin (AR) than by epidermal growth factor (EGF) due to differences in affinity and time scales for receptor occupancy.	13	20	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	18	19	13	14
The ability of neutralising antibodies to AREG but not to TGF-alpha or HB-EGF to reduce PTHrP transcripts in both lines demonstrated that AREG was the primary activator of EGFR in cell lines .	The ability of neutralising antibodies to AREG but not to TGF-alpha or HB-EGF to reduce PTHrP transcripts in both lines demonstrated that AREG was the primary activator of EGFR in cell lines.	22	31	was the primary activator	Positive_activation_copula_1	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	22	23	28	29
Studies by Werb and coworkers revealed a potential mechanism by which epithelial derived AREG activates EGFR on neighboring stromal cells [ XREF_BIBR ] .	Studies by Werb and coworkers revealed a potential mechanism by which epithelial derived AREG activates EGFR on neighboring stromal cells [XREF_BIBR].	12	21	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	13	14	15	16
This suggested there might possibly be some sort of antagonism of EGFR signaling caused by AREG overexpression .	This suggested there might possibly be some sort of antagonism of EGFR signaling caused by AREG overexpression.	11	17	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AREG	AREG overexpression	areg	EGFR	EGFR	egfr	15	16	11	12
In particular , AREG induced EGFR accumulation on the cell surface followed by the secretion of high-affinity ligands , such as EGF or TGFalpha , could lead to the hyperactivation of EGFR-ERK signaling .	In particular, AREG induced EGFR accumulation on the cell surface followed by the secretion of high-affinity ligands, such as EGF or TGFalpha, could lead to the hyperactivation of EGFR-ERK signaling.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	3	4	5	6
In 32D/EGFR myeloid and MCF10A breast cells , soluble amphiregulin ( AR ) , transforming growth factor alpha ( TGFalpha ) , neuregulin 2 beta , and epigen stimulate greater EGFR coupling to cell proliferation and DNA synthesis than do EGF , betacellulin , heparin binding EGF like growth factor , and epiregulin .	In 32D/EGFR myeloid and MCF10A breast cells, soluble amphiregulin (AR), transforming growth factor alpha (TGFalpha), neuregulin 2 beta, and epigen stimulate greater EGFR coupling to cell proliferation and DNA synthesis than do EGF, betacellulin, heparin binding EGF like growth factor, and epiregulin.	8	31	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	9	10	30	31
To identify signaling changes that were specifically associated with AREG mediated EGFR signaling versus EGF mediated signaling , we looked for similarities in the expression or activation of proteins in MCF-10A+ AREG and SUM-149 cells compared to MCF-10A+ EGF cells .	To identify signaling changes that were specifically associated with AREG mediated EGFR signaling versus EGF mediated signaling, we looked for similarities in the expression or activation of proteins in MCF-10A+ AREG and SUM-149 cells compared to MCF-10A+ EGF cells.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	9	10	11	12
We next examined if exogenous AREG , TGF-alpha , HBEGF , or the prototype ligand EGF causes EGFR turnover in MDA-231 cells .	We next examined if exogenous AREG, TGF-alpha, HBEGF, or the prototype ligand EGF causes EGFR turnover in MDA-231 cells.	4	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	5	6	17	18
These results indicate that EGFR activation , caused predominantly by AREG , induced crizotinib resistance in # 2 cells .	These results indicate that EGFR activation, caused predominantly by AREG, induced crizotinib resistance in # 2 cells.	4	11	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	10	11	4	5
Besides the direct effects that autocrine or paracrine , a recent study has identified exosome mediated AREG signaling in human breast and colorectal cancer cells , which activates EGFR resulting cell invasion [ XREF_BIBR ] .	Besides the direct effects that autocrine or paracrine, a recent study has identified exosome mediated AREG signaling in human breast and colorectal cancer cells, which activates EGFR resulting cell invasion [XREF_BIBR].	16	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	16	17	28	29
Amphiregulin has been shown to stimulate EGFR activation and tumor cell growth in colon cancer cell lines [ XREF_BIBR ] .	Amphiregulin has been shown to stimulate EGFR activation and tumor cell growth in colon cancer cell lines [XREF_BIBR].	0	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Amphiregulin	Amphiregulin	Amphiregulin	EGFR	EGFR	EGFR	0	1	6	7
In the present studies , we demonstrate that AREG activated EGFR , in the context of PTEN loss , results in the activation of an oncogenic signaling network that drives many aspects of the malignant potential of the cells and may also influence intrinsic drug resistance .	In the present studies, we demonstrate that AREG activated EGFR, in the context of PTEN loss, results in the activation of an oncogenic signaling network that drives many aspects of the malignant potential of the cells and may also influence intrinsic drug resistance.	8	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	8	9	10	11
In lung and esophageal adenocarcinoma cell lines , AGR2 induces the expression of the epidermal growth factor receptor ( EGFR ) ligand amphiregulin ( AREG ) via the Hippo signaling pathway co-activator YAP1 and subsequently stimulates EGFR signaling and proliferation [ XREF_BIBR ] .	In lung and esophageal adenocarcinoma cell lines, AGR2 induces the expression of the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) via the Hippo signaling pathway co-activator YAP1 and subsequently stimulates EGFR signaling and proliferation [XREF_BIBR].	8	37	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	AGR2 induces the expression of the epidermal growth factor receptor (EGFR) ligand amphiregulin	amphiregulin	EGFR	EGFR	egfr	22	23	36	37
We examined ligand mediated activation of EGFR and determined the effect of amphiregulin mediated autocrine activation of EGFR on the development of cell cycle arrest in vitro and stable disease in patients with NSCLC treated with gefitinib or erlotinib .	We examined ligand mediated activation of EGFR and determined the effect of amphiregulin mediated autocrine activation of EGFR on the development of cell cycle arrest in vitro and stable disease in patients with NSCLC treated with gefitinib or erlotinib.	10	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	12	13	17	18
Here , we show that CML exosomes , carrying AREG , are able to activate EGFR signalling in stromal cells leading to increased IL8 expression and secretion 12 .	Here, we show that CML exosomes, carrying AREG, are able to activate EGFR signalling in stromal cells leading to increased IL8 expression and secretion 12.	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	9	10	15	16
Here , we investigated whether the FGFR1 induced increase in AREG and EREG expression might coordinately increase EGFR signaling to promote mammary tumorigenesis .	Here, we investigated whether the FGFR1 induced increase in AREG and EREG expression might coordinately increase EGFR signaling to promote mammary tumorigenesis.	10	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG and EREG expression	areg	EGFR	EGFR	egfr	10	11	17	18
Hence , the induction of EGFR signaling by AREG or EGF in HH- or SAG stimulated Daoy cells allows stable production of GLI1 protein despite a downregulation of GLI1 transcript levels .	Hence, the induction of EGFR signaling by AREG or EGF in HH- or SAG stimulated Daoy cells allows stable production of GLI1 protein despite a downregulation of GLI1 transcript levels.	5	14	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	8	9	5	6
We report here that AREG mediated EGFR activation by itself is sufficient to induce up-regulation of FN1 at the message and protein level .	We report here that AREG mediated EGFR activation by itself is sufficient to induce up-regulation of FN1 at the message and protein level.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	4	5	6	7
In the current study , we evaluated EGFR ligands amphiregulin , EGF , and TGF-alpha , in EGFR wild-type NSCLC and HNSCC and their relationship with the efficacy of the EGFR directed antibody cetuximab and the EGFR TKI gefitinib .	In the current study, we evaluated EGFR ligands amphiregulin, EGF, and TGF-alpha, in EGFR wild-type NSCLC and HNSCC and their relationship with the efficacy of the EGFR directed antibody cetuximab and the EGFR TKI gefitinib.	9	38	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	9	10	36	37
Substantial evidence implicates the involvement of AREG induced constitutive activation of the EGFR pathway in human tylosis .	Substantial evidence implicates the involvement of AREG induced constitutive activation of the EGFR pathway in human tylosis.	4	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	6	7	12	13
In ERalpha negative cells , secreted amphiregulin activates EGFR signaling to promote cell proliferation .	In ERalpha negative cells, secreted amphiregulin activates EGFR signaling to promote cell proliferation.	5	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	6	7	8	9
3.3 Influence of AREG mediated EGFR activation on gene expression in MCF-10A and SUM-149 cells .	3.3 Influence of AREG mediated EGFR activation on gene expression in MCF-10A and SUM-149 cells.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	3	4	5	6
HBEGF is not shed from the plasma membrane and does not participate in autocrine receptor signaling in MDA-231 cells , while shed TGF-alpha and AREG activate the EGFR and stimulate the production of cytokines that attract and differentiate monocytes .	HBEGF is not shed from the plasma membrane and does not participate in autocrine receptor signaling in MDA-231 cells, while shed TGF-alpha and AREG activate the EGFR and stimulate the production of cytokines that attract and differentiate monocytes.	22	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	24	25	27	28
These data , together with our in vitro data , suggest that amphiregulin , which can activate the EGFR --> GM-CSF axis , is another potential target for therapeutic development .	These data, together with our in vitro data, suggest that amphiregulin, which can activate the EGFR --> GM-CSF axis, is another potential target for therapeutic development.	12	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	12	13	18	19
These results suggested that AREG mediated EGFR accumulation on the plasma membrane compensated for the weak association between AREG and EGFR , thereby contributing to the efficient signal transduction and stimulation of cell growth ( XREF_FIG ) .	These results suggested that AREG mediated EGFR accumulation on the plasma membrane compensated for the weak association between AREG and EGFR, thereby contributing to the efficient signal transduction and stimulation of cell growth (XREF_FIG).	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	4	5	6	7
However , by contrast to the classical EGFR feedback elements that usually terminate EGFR signaling , AREG activates EGFR in a unique manner , distinct from EGF , which does not lead to EGFR down-modulation .	However, by contrast to the classical EGFR feedback elements that usually terminate EGFR signaling, AREG activates EGFR in a unique manner, distinct from EGF, which does not lead to EGFR down-modulation.	16	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	16	17	18	19
The CRTC1-MAML2 oncoprotein may upregulate the epidermal growth factor receptor ( EGFR ) ligand , amphiregulin ( AREG ) , which activates the EGFR signaling pathway in an autocrine manner , ultimately stimulating MEC cell growth and survival [ XREF_BIBR ] .	The CRTC1-MAML2 oncoprotein may upregulate the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG), which activates the EGFR signaling pathway in an autocrine manner, ultimately stimulating MEC cell growth and survival [XREF_BIBR].	15	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	17	18	23	24
Of note , AREG mediated EGFR activation resulted in dramatically elevated levels of FN1 .	Of note, AREG mediated EGFR activation resulted in dramatically elevated levels of FN1.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	3	4	5	6
The CRTC1-MAML2 oncoprotein induced the upregulation of the epidermal growth factor receptor ( EGFR ) ligand Amphiregulin ( AREG ) by co-activating the transcription factor CREB , and AREG subsequently activated EGFR signaling in an autocrine manner that promoted MEC cell growth and survival .	The CRTC1-MAML2 oncoprotein induced the upregulation of the epidermal growth factor receptor (EGFR) ligand Amphiregulin (AREG) by co-activating the transcription factor CREB, and AREG subsequently activated EGFR signaling in an autocrine manner that promoted MEC cell growth and survival.	28	32	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	28	29	31	32
Consistent with this concept , our data show that the pattern of AREG induced EGFR activation in airway BC is distinct from that evoked by EGF .	Consistent with this concept, our data show that the pattern of AREG induced EGFR activation in airway BC is distinct from that evoked by EGF.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	12	13	14	15
Our studies in EGFR wild-type NSCLC and HNSCC suggest that in a subset of these cell lines EGFR is activated by an autocrine production of amphiregulin , which promotes cell growth .	Our studies in EGFR wild-type NSCLC and HNSCC suggest that in a subset of these cell lines EGFR is activated by an autocrine production of amphiregulin, which promotes cell growth.	17	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	25	26	17	18
In different studies , EGFR activation by epiregulin and/or amphiregulin completely or partially recapitulates the LH induced cGMP decrease .	In different studies, EGFR activation by epiregulin and/or amphiregulin completely or partially recapitulates the LH induced cGMP decrease.	4	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	9	10	4	5
Amphiregulin does not target EGFR for lysosomal degradation but causes fast as well as slow EGFR recycling .	Amphiregulin does not target EGFR for lysosomal degradation but causes fast as well as slow EGFR recycling.	0	9	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Amphiregulin	Amphiregulin	Amphiregulin	EGFR	EGFR	EGFR	0	1	4	5
Amphiregulin triggered epidermal growth factor receptor activation confers in vivo crizotinib-resistance of EML4-ALK lung cancer and circumvention by epidermal growth factor receptor inhibitors .	Amphiregulin triggered epidermal growth factor receptor activation confers in vivo crizotinib-resistance of EML4-ALK lung cancer and circumvention by epidermal growth factor receptor inhibitors.	0	6	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Amphiregulin	Amphiregulin	Amphiregulin	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	2	6
In the present study , we investigated the mechanisms by which amphiregulin activation of the epidermal growth factor receptor ( EGFR ) regulates these altered phenotypes .	In the present study, we investigated the mechanisms by which amphiregulin activation of the epidermal growth factor receptor (EGFR) regulates these altered phenotypes.	11	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	11	12	15	19
Increasing evidence has shown that AREG activated the EGFR which is an important mechanism in the development of hepatocarcinoma .	Increasing evidence has shown that AREG activated the EGFR which is an important mechanism in the development of hepatocarcinoma.	5	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	5	6	8	9
In conclusion , autocrine AREG stimulation of the EGFR may serve as the intrinsic factor that drives high levels of PTHrP gene expression in the RWGT2 line , whereas this pathway appears to play a secondary role in the extrinsic activation of the gene in HARA tumours by host factors .	In conclusion, autocrine AREG stimulation of the EGFR may serve as the intrinsic factor that drives high levels of PTHrP gene expression in the RWGT2 line, whereas this pathway appears to play a secondary role in the extrinsic activation of the gene in HARA tumours by host factors.	4	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	4	5	8	9
Together , AREG activates EGFR in the human airway epithelium in a unique , distinct from EGF manner , which is associated with stabilization of EGFR expression on the BC surface .	Together, AREG activates EGFR in the human airway epithelium in a unique, distinct from EGF manner, which is associated with stabilization of EGFR expression on the BC surface.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	2	3	4	5
This effect is mediated by EGFR , as increasing concentrations of AREG overcome partial antagonism of EGFR signaling by a fixed concentration of EGF ; the rightward shift of the AREG dose response curve in the presence of a fixed concentration of EGF indicates that EGF competitively antagonizes AREG stimulation of EGFR signaling , thereby reducing the potency ( but not efficacy ) of AREG ( as in XREF_FIG ) .	This effect is mediated by EGFR, as increasing concentrations of AREG overcome partial antagonism of EGFR signaling by a fixed concentration of EGF; the rightward shift of the AREG dose response curve in the presence of a fixed concentration of EGF indicates that EGF competitively antagonizes AREG stimulation of EGFR signaling, thereby reducing the potency (but not efficacy) of AREG (as in XREF_FIG).	48	52	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	48	49	51	52
In addition , we demonstrated previously that AREG mediated EGFR signaling influences the Wnt pathway by transcriptionally down-regulating the expression of DKK1 and SFRP1 , two negative regulators of Wnt activity ( Baillo etal ., 2011 ) .	In addition, we demonstrated previously that AREG mediated EGFR signaling influences the Wnt pathway by transcriptionally down-regulating the expression of DKK1 and SFRP1, two negative regulators of Wnt activity (Baillo etal., 2011).	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	7	8	9	10
In addition , we identified that amphiregulin ( AREG ) , a down-stream target of YAP which activated EGF receptors ( EGFR ) , mediated an LPA stimulated and EGFR dependent long-term ( 16 hr ) cell migration .	In addition, we identified that amphiregulin (AREG), a down-stream target of YAP which activated EGF receptors (EGFR), mediated an LPA stimulated and EGFR dependent long-term (16 hr) cell migration.	6	34	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	8	9	29	30
However , because the mature AREG protein is truncated at the C-terminus and lacks a conserved leucine residue essential for high affinity binding to EGFR , AREG is known to activate EGFR less strongly than does EGF [ XREF_BIBR ] .	However, because the mature AREG protein is truncated at the C-terminus and lacks a conserved leucine residue essential for high affinity binding to EGFR, AREG is known to activate EGFR less strongly than does EGF [XREF_BIBR].	26	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	26	27	31	32
As MCF-10A cells secrete AREG ( amphiregulin ) , another EGFR ligand [ XREF_BIBR ] , we reasoned SerpinB5 phosphorylation in starved cells could be a consequence of autocrine activation of EGFR by AREG .	As MCF-10A cells secrete AREG (amphiregulin), another EGFR ligand [XREF_BIBR], we reasoned SerpinB5 phosphorylation in starved cells could be a consequence of autocrine activation of EGFR by AREG.	26	34	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	33	34	31	32
The EGFR is activated by a family of growth factors namely EGF , Amphiregulin , TGFalpha and neuregulin XREF_BIBR .	The EGFR is activated by a family of growth factors namely EGF, Amphiregulin, TGFalpha and neuregulin XREF_BIBR.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Amphiregulin	Amphiregulin	Amphiregulin	EGFR	EGFR	EGFR	13	14	1	2
In turn , AREG induces a unique EGFR activation pattern in BC , distinct from that evoked by EGF , leading to BC- and mucous hyperplasia , altered ciliated cell differentiation , and impaired barrier integrity .	In turn, AREG induces a unique EGFR activation pattern in BC, distinct from that evoked by EGF, leading to BC- and mucous hyperplasia, altered ciliated cell differentiation, and impaired barrier integrity.	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	3	4	7	8
Furthermore , though both AREG and TGFalpha are known to promote EGFR recycling rather than degradation , these ligands in MEGM medium showed opposing effects on K5 + K19 - hMEC differentiation , AREG favoring luminal lineage and TGFalpha myoepithelial lineage .	Furthermore, though both AREG and TGFalpha are known to promote EGFR recycling rather than degradation, these ligands in MEGM medium showed opposing effects on K5 + K19 - hMEC differentiation, AREG favoring luminal lineage and TGFalpha myoepithelial lineage.	3	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	4	5	11	12
We reported previously that in SUM-149 cells , autocrine signaling loops induced by AREG mediated EGFR activation result in expression of IL-1alpha and activation of NF-kappaB ( Streicher etal ., 2007 ) .	We reported previously that in SUM-149 cells, autocrine signaling loops induced by AREG mediated EGFR activation result in expression of IL-1alpha and activation of NF-kappaB (Streicher etal., 2007).	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	13	14	15	16
These observations provide evidence that AREG mediated activation of endogenous EGFR is required for full transformation downstream of YAP .	These observations provide evidence that AREG mediated activation of endogenous EGFR is required for full transformation downstream of YAP.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	5	6	10	11
Exposure of CRC and PDAC cells to DCA resulted in co-localization of Src and TACE to the cell membrane , resulting in AREG dependent activation of EGFR , MAPK and STAT3 signaling .	Exposure of CRC and PDAC cells to DCA resulted in co-localization of Src and TACE to the cell membrane, resulting in AREG dependent activation of EGFR, MAPK and STAT3 signaling.	22	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	22	23	26	27
Firstly , our sequencing results demonstrated that TNFalpha treatment increased genes that regulate EGFR activation such as HB-EGF or AREG [ XREF_BIBR - XREF_BIBR ] .	Firstly, our sequencing results demonstrated that TNFalpha treatment increased genes that regulate EGFR activation such as HB-EGF or AREG [XREF_BIBR - XREF_BIBR].	13	20	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	19	20	13	14
An aryl hydrocarbon receptor antagonist abrogates the elevated expression of epiregulin and amphiregulin and diminishes the invasive phenotype of rheumatoid arthritis FLSs [ XREF_BIBR ] , suggesting that epiregulin and/or amphiregulin stimulation of EGFR signaling contributes to the pathogenesis of rheumatoid arthritis .	An aryl hydrocarbon receptor antagonist abrogates the elevated expression of epiregulin and amphiregulin and diminishes the invasive phenotype of rheumatoid arthritis FLSs [XREF_BIBR], suggesting that epiregulin and/or amphiregulin stimulation of EGFR signaling contributes to the pathogenesis of rheumatoid arthritis.	30	34	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	30	31	33	34
Of note , EGFR activation by AREG in some cell types has been reported to involve an autocrine loop culminating in EGFR dependent AREG induction XREF_BIBR .	Of note, EGFR activation by AREG in some cell types has been reported to involve an autocrine loop culminating in EGFR dependent AREG induction XREF_BIBR.	3	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	6	7	3	4
Thus , AREG functions in regulating the invasive phenotype , and we propose that this regulation may be through altered signaling that occurs when AREG activates plasma membrane localized EGFR .	Thus, AREG functions in regulating the invasive phenotype, and we propose that this regulation may be through altered signaling that occurs when AREG activates plasma membrane localized EGFR.	24	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	24	25	29	30
As expected , AREG and TGF-alpha did not induce rapid EGFR turnover ; moreover , HBEGF , which induces rapid EGFR turnover in other cell types , failed to do so in MDA-231 cells ( XREF_FIG ) .	As expected, AREG and TGF-alpha did not induce rapid EGFR turnover; moreover, HBEGF, which induces rapid EGFR turnover in other cell types, failed to do so in MDA-231 cells (XREF_FIG).	3	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	3	4	10	11
Second , AREG induces a unique activation of EGFR in BC , distinct from that evoked by EGF , and promotes EGF independent lesions , for example , BC- and mucous hyperplasia , and , similar to EGF , suppresses ciliated cell differentiation and TJ barrier integrity .	Second, AREG induces a unique activation of EGFR in BC, distinct from that evoked by EGF, and promotes EGF independent lesions, for example, BC- and mucous hyperplasia, and, similar to EGF, suppresses ciliated cell differentiation and TJ barrier integrity.	2	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	2	3	8	9
Taken together our data indicated that exosomal AREG induces the activation of EGFR pathway that increases , in pre-osteoclasts treated with NSCLC-exosomes , the expression of RANKL at mRNA and protein levels .	Taken together our data indicated that exosomal AREG induces the activation of EGFR pathway that increases, in pre-osteoclasts treated with NSCLC-exosomes, the expression of RANKL at mRNA and protein levels.	6	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	7	8	12	13
Because AREG activates EGFR via an autocrine loop in SUM-149 cells , we used AREG knock-down versions of SUM-149 cells to examine the responsiveness of these cells to AREG ( XREF_FIG A ) .	Because AREG activates EGFR via an autocrine loop in SUM-149 cells, we used AREG knock-down versions of SUM-149 cells to examine the responsiveness of these cells to AREG (XREF_FIG A).	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	1	2	3	4
For example , amphiregulin producing epithelial cells elicit paracrine activation of EGFR in stromal cells to dictate mammary ductal morphogenesis , and TGF-beta mediates inhibition of mammary ductal and alveolar growth via epithelial-stromal interaction .	For example, amphiregulin producing epithelial cells elicit paracrine activation of EGFR in stromal cells to dictate mammary ductal morphogenesis, and TGF-beta mediates inhibition of mammary ductal and alveolar growth via epithelial-stromal interaction.	3	14	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	3	4	11	12
In addition to our findings , several studies have demonstrated that AREG activates EGFR signaling to synthesize , secrete , and activate proteins involved in invasion and metastasis such as urokinase-type plasminogen activator ( uPA ) , matrix metalloproteinase 9 ( MMP-9 ) , and extracellular matrix metalloproteinase inducer ( EMMPRIN ) [ XREF_BIBR - XREF_BIBR ] .	In addition to our findings, several studies have demonstrated that AREG activates EGFR signaling to synthesize, secrete, and activate proteins involved in invasion and metastasis such as urokinase-type plasminogen activator (uPA), matrix metalloproteinase 9 (MMP-9), and extracellular matrix metalloproteinase inducer (EMMPRIN) [XREF_BIBR - XREF_BIBR].	11	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	11	12	13	14
showed that AREG promotes the recycling of EGFR to the plasma membrane .	showed that AREG promotes the recycling of EGFR to the plasma membrane.	2	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	2	3	7	8
A possible mechanism of resistance to exemestane is that amphiregulin activates the EGFR pathway and leads to the activation of the MAPK pathway that drives cell proliferation [ XREF_BIBR ] .	A possible mechanism of resistance to exemestane is that amphiregulin activates the EGFR pathway and leads to the activation of the MAPK pathway that drives cell proliferation [XREF_BIBR].	9	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	9	10	12	13
However , EGF , but not AREG , further decreased the total EGFR amount ( XREF_FIG , lower panel ) , consistent with the known ability of EGF to cause rapid EGFR down-modulation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] and suggesting that AREG activated EGFR might escape this negative regulation .	However, EGF, but not AREG, further decreased the total EGFR amount (XREF_FIG, lower panel), consistent with the known ability of EGF to cause rapid EGFR down-modulation [XREF_BIBR, XREF_BIBR, XREF_BIBR] and suggesting that AREG activated EGFR might escape this negative regulation.	43	47	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	43	44	45	46
Further , substantial evidence implicates the involvement of AREG induced constitutive activation of the EGFR pathway in tylosis .	Further, substantial evidence implicates the involvement of AREG induced constitutive activation of the EGFR pathway in tylosis.	6	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	8	9	14	15
We demonstrated that LAMA84- exosomes carrying AREG activate EGFR on stromal cells , thus inducing the downstream signalling and in particular the expression of SNAIL .	We demonstrated that LAMA84- exosomes carrying AREG activate EGFR on stromal cells, thus inducing the downstream signalling and in particular the expression of SNAIL.	5	9	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	6	7	8	9
Src dependent Y845 phosphorylation also contributes to ERK and MAPK activation and proliferation of normal keratinocytes , which involves amphiregulin mediated autocrine signaling of EGFR [ XREF_BIBR ] .	Src dependent Y845 phosphorylation also contributes to ERK and MAPK activation and proliferation of normal keratinocytes, which involves amphiregulin mediated autocrine signaling of EGFR [XREF_BIBR].	18	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	19	20	24	25
EGFR is activated by several ligands : EGF , TGF-alpha , epiregulin , and amphiregulin .	EGFR is activated by several ligands : EGF, TGF-alpha, epiregulin, and amphiregulin.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	14	15	0	1
Consistent with this hypothesis , expression of EGF in cells irreversibly blocks AREG stimulation of EGFR coupling to cell proliferation .	Consistent with this hypothesis, expression of EGF in cells irreversibly blocks AREG stimulation of EGFR coupling to cell proliferation.	12	16	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	12	13	15	16
Introducing further complexity , analyses of ligand-receptor interactions have suggested that recombinant AREG does not induce efficient dimerization of EGFR [ XREF_BIBR ] .	Introducing further complexity, analyses of ligand-receptor interactions have suggested that recombinant AREG does not induce efficient dimerization of EGFR [XREF_BIBR].	11	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	12	13	19	20
AREG induced EGFR activation at later time-points was further confirmed by IF analysis of the epithelium derived after 14 days of ALI culture from AREG treated BC using the antibodies against EGFR phosphorylated at Tyr1068 ( XREF_SUPPLEMENTARY ) , an EGFR phosphorylation site that has been implicated in AREG signaling in the airway epithelium [ XREF_BIBR ] .	AREG induced EGFR activation at later time-points was further confirmed by IF analysis of the epithelium derived after 14 days of ALI culture from AREG treated BC using the antibodies against EGFR phosphorylated at Tyr1068 (XREF_SUPPLEMENTARY), an EGFR phosphorylation site that has been implicated in AREG signaling in the airway epithelium [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	0	1	2	3
Indeed , earlier biochemical studies using epithelial cell lines have demonstrated that , compared to EGF , AREG induced signaling does not target EGFR for degradation but , instead , promotes EGFR recycling to the plasma membrane [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Indeed, earlier biochemical studies using epithelial cell lines have demonstrated that, compared to EGF, AREG induced signaling does not target EGFR for degradation but, instead, promotes EGFR recycling to the plasma membrane [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	17	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	17	18	23	24
We have shown that AREG found in LAMA84- exosomes activates EGFR signalling in human stromal cells through a paracrine mechanism and that gefitinib , a specific inhibitor of EGFR activation , or neutralizing antibody anti-AREG may revert the effects mediated by LAMA84- exosomes .	We have shown that AREG found in LAMA84- exosomes activates EGFR signalling in human stromal cells through a paracrine mechanism and that gefitinib, a specific inhibitor of EGFR activation, or neutralizing antibody anti-AREG may revert the effects mediated by LAMA84- exosomes.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	4	5	10	11
Increased expression of DUSP6 , which blocks the EGFR pathway at MAPK , is associated with decreased likelihood of disease control , while increased expression of AREG and EREG , which stimulate the EGFR pathway , are associated with increased likelihood of disease control .	Increased expression of DUSP6, which blocks the EGFR pathway at MAPK, is associated with decreased likelihood of disease control, while increased expression of AREG and EREG, which stimulate the EGFR pathway, are associated with increased likelihood of disease control.	24	34	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	expression of AREG	areg	EGFR	EGFR	egfr	26	27	33	34
Upon shedding from epithelial cells , IL6R and AREG activate the shared interleukin receptor gp130 and EGFR , respectively , on epithelial cells ( autocrine ) , as well as on underlying myofibroblasts and myeloid cells ( paracrine ) ( Burgel and Nadel 2008 ; Nechemia-Arbely etal .	Upon shedding from epithelial cells, IL6R and AREG activate the shared interleukin receptor gp130 and EGFR, respectively, on epithelial cells (autocrine), as well as on underlying myofibroblasts and myeloid cells (paracrine) (Burgel and Nadel 2008; Nechemia-Arbely etal.	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	8	9	16	17
EGFR can be activated , apart from EGF , also by other functionally related ligands , such as TGF-alpha , heparin binding EGF ( HB-EGF ) , amphiregulin ( Areg ) , and epiregulin .	EGFR can be activated, apart from EGF, also by other functionally related ligands, such as TGF-alpha, heparin binding EGF (HB-EGF), amphiregulin (Areg), and epiregulin.	0	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	27	28	0	1
Overall , these data indicate that TCDD induced EGFR down-regulation in NHEKs is caused by AREG , TGF-alpha , and EREG , while TGF-alpha enhances receptor recycling to maintain a pool of EGFR at the cell surface .	Overall, these data indicate that TCDD induced EGFR down-regulation in NHEKs is caused by AREG, TGF-alpha, and EREG, while TGF-alpha enhances receptor recycling to maintain a pool of EGFR at the cell surface.	8	20	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	15	16	8	9
Earlier studies have identified distinct EGFR trafficking patterns induced by EGF and AREG in various epithelial cell lines : whereas EGF targets EGFR for lysosomal degradation , AREG causes EGFR recycling , potentially relevant to different biological functions exerted by these growth factors [ XREF_BIBR , XREF_BIBR ] .	Earlier studies have identified distinct EGFR trafficking patterns induced by EGF and AREG in various epithelial cell lines : whereas EGF targets EGFR for lysosomal degradation, AREG causes EGFR recycling, potentially relevant to different biological functions exerted by these growth factors [XREF_BIBR, XREF_BIBR].	25	30	causes	Positive_activation_token_1_verb	Positive_activation	Negative_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	27	28	29	30
EGF , TGFalpha , and amphiregulin are expressed in NSCLCs , and activate EGFR and its downstream signaling pathways by autocrine loops [ XREF_BIBR ] .	EGF, TGFalpha, and amphiregulin are expressed in NSCLCs, and activate EGFR and its downstream signaling pathways by autocrine loops [XREF_BIBR].	0	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin are expressed	amphiregulin	EGFR	EGFR	egfr	5	6	13	14
Three ligands , AREG , HB-EGF and TGFA , activated EGFR even in the presence of cetuximab in both cell lines , but the effects of EGF on EGFR in the presence of cetuximab were minimal .	Three ligands, AREG, HB-EGF and TGFA, activated EGFR even in the presence of cetuximab in both cell lines, but the effects of EGF on EGFR in the presence of cetuximab were minimal.	1	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	3	4	10	11
Furthermore , EGFR , activated by amphiregulin but not epidermal growth factor , results in the prompt activation of the transcription factor nuclear factor-kappaB ( NF-kappaB ) , which is required for transcriptional activation of IL-1 .	Furthermore, EGFR, activated by amphiregulin but not epidermal growth factor, results in the prompt activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which is required for transcriptional activation of IL-1.	2	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	6	7	2	3
Suppression of AREG by ectopic miR-34a expression prevented tumor invasion , and inhibited EGFR , which might be the potential molecular targets for future HNSCC therapy .	Suppression of AREG by ectopic miR-34a expression prevented tumor invasion, and inhibited EGFR, which might be the potential molecular targets for future HNSCC therapy.	0	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	2	3	13	14
Thus amphiregulin , which is expressed as a transmembrane precursor , must be proteolytically shed from the epithelial cell surface to activate EGFR on nearby stromal cells .	Thus amphiregulin, which is expressed as a transmembrane precursor, must be proteolytically shed from the epithelial cell surface to activate EGFR on nearby stromal cells.	1	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin, which is expressed	amphiregulin	EGFR	EGFR	egfr	1	2	22	23
Thus , the observed phosphorylation of PRB is consistent with Areg production and activation of EGFR signaling in the epithelium and correlates with proliferation of cells expressing PRB .	Thus, the observed phosphorylation of PRB is consistent with Areg production and activation of EGFR signaling in the epithelium and correlates with proliferation of cells expressing PRB.	10	16	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Areg	Areg	Areg	EGFR	EGFR	EGFR	10	11	15	16
These data suggest that LAMA84- exosomes trigger an AREG mediated activation of EGFR in HS5 stromal cells .	These data suggest that LAMA84- exosomes trigger an AREG mediated activation of EGFR in HS5 stromal cells.	8	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	8	9	12	13
This data is consistent with our recent study demonstrating that CRTC1-MAML2 fusion induced expression of an EGFR ligand AREG , which acted in an autocrine fashion and bound to functional EGFR on human MEC cells to initiate EGFR signaling and activate MAPK signaling .	This data is consistent with our recent study demonstrating that CRTC1-MAML2 fusion induced expression of an EGFR ligand AREG, which acted in an autocrine fashion and bound to functional EGFR on human MEC cells to initiate EGFR signaling and activate MAPK signaling.	10	38	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	CRTC1-MAML2 fusion induced expression of an EGFR ligand AREG	areg	EGFR	EGFR	egfr	18	19	37	38
AREG up-regulates SPRY2 by activating EGFR in human ovarian cancer cells .	AREG up-regulates SPRY2 by activating EGFR in human ovarian cancer cells.	0	6	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	0	1	5	6
For example , a saturating concentration of the EGFR ligand amphiregulin ( AREG ) stimulates greater EGFR coupling to cell proliferation , motility , and metastatic activities than does a saturating concentration of EGF , another EGFR ligand .	For example, a saturating concentration of the EGFR ligand amphiregulin (AREG) stimulates greater EGFR coupling to cell proliferation, motility, and metastatic activities than does a saturating concentration of EGF, another EGFR ligand.	10	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	12	13	16	17
EGFR signaling by AREG and EREG is enhanced in pancreatic carcinomas and contributes to the aggressive nature of the disease XREF_BIBR , XREF_BIBR .	EGFR signaling by AREG and EREG is enhanced in pancreatic carcinomas and contributes to the aggressive nature of the disease XREF_BIBR, XREF_BIBR.	0	5	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	3	4	0	1
Epidermal growth factor receptor pathway ligands EREG and amphiregulin ( AREG ) may stimulate EGFR through an autocrine loop with positive feedback , and elevated EREG may indicate tumour dependence on the EGFR pathway .	Epidermal growth factor receptor pathway ligands EREG and amphiregulin (AREG) may stimulate EGFR through an autocrine loop with positive feedback, and elevated EREG may indicate tumour dependence on the EGFR pathway.	5	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	10	11	14	15
These findings suggest that AREG would likely drive autocrine EGFR signaling in the two hypercalcemia inducing SCC lines and the high levels of this ligand may contribute to greater PTHrP levels in the RWGT2 line .	These findings suggest that AREG would likely drive autocrine EGFR signaling in the two hypercalcemia inducing SCC lines and the high levels of this ligand may contribute to greater PTHrP levels in the RWGT2 line.	4	10	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	4	5	9	10
Although EGF , HB-EGF , TGF-alpha , AREG , EREG and betacellulin all can induce an uptake of EGFR from the plasma membrane , a very high concentration of some of them is required .	Although EGF, HB-EGF, TGF-alpha, AREG, EREG and betacellulin all can induce an uptake of EGFR from the plasma membrane, a very high concentration of some of them is required.	1	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	7	8	18	19
Based on the observation that AREG activated EGFR can be maintained on the BC surface and that chronic stimulation of BC with AREG results in hyperplastic remodeling phenotypes not directly induced by EGF , we hypothesized that , similar to its known autocrine effects in various epithelial cell lines [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , AREG can establish a self amplifying loop in airway BC that operates in EGF independent manner .	Based on the observation that AREG activated EGFR can be maintained on the BC surface and that chronic stimulation of BC with AREG results in hyperplastic remodeling phenotypes not directly induced by EGF, we hypothesized that, similar to its known autocrine effects in various epithelial cell lines [XREF_BIBR, XREF_BIBR, XREF_BIBR], AREG can establish a self amplifying loop in airway BC that operates in EGF independent manner.	5	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	5	6	7	8
According to the results described so far , our data indicated that elevated levels of AREG in NSCLC-exosomes induce EGFR pathway activation thus promoting osteoclast differentiation .	According to the results described so far, our data indicated that elevated levels of AREG in NSCLC-exosomes induce EGFR pathway activation thus promoting osteoclast differentiation.	13	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	levels of AREG	areg	EGFR	EGFR	egfr	15	16	19	20
Various stimuli ( bacterial products , viruses , cigarette smoke , and inflammatory cell products ) and various ligands ( EGF , TGF-alpha , amphiregulin ) can trigger EGFR signaling in airway epithelial cells .	Various stimuli (bacterial products, viruses, cigarette smoke, and inflammatory cell products) and various ligands (EGF, TGF-alpha, amphiregulin) can trigger EGFR signaling in airway epithelial cells.	18	29	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	24	25	28	29
Following the LH surge , AREG and EREG were released from the membrane by actions of ADAM10 or ADAM17 [ XREF_BIBR , XREF_BIBR ] and activated the EGFR in order to propagate signals throughout the follicles prior to ovulation [ XREF_BIBR ] .	Following the LH surge, AREG and EREG were released from the membrane by actions of ADAM10 or ADAM17 [XREF_BIBR, XREF_BIBR] and activated the EGFR in order to propagate signals throughout the follicles prior to ovulation [XREF_BIBR].	5	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	5	6	27	28
AREG then activates the EGFR pathway and leads to the activation of the MAPK pathway that drives cell proliferation .	AREG then activates the EGFR pathway and leads to the activation of the MAPK pathway that drives cell proliferation.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	0	1	4	5
We also demonstrated that AREG can increase EGFR stability and promote EGFR localization to the plasma membrane .	We also demonstrated that AREG can increase EGFR stability and promote EGFR localization to the plasma membrane.	4	10	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	4	5	7	8
Expression profiling demonstrated that AREG activated EGFR regulates gene expression differently than EGF activated EGFR , and functional analysis via genome-scale shRNA screening identified a set of genes , including PLK1 and BIRC5 , that are essential for survival of SUM-149 cells , but are uncoupled from EGFR signaling .	Expression profiling demonstrated that AREG activated EGFR regulates gene expression differently than EGF activated EGFR, and functional analysis via genome-scale shRNA screening identified a set of genes, including PLK1 and BIRC5, that are essential for survival of SUM-149 cells, but are uncoupled from EGFR signaling.	4	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	4	5	6	7
Taken together , it appears that autocrine stimulation of EGFR signaling by amphiregulin is coupled to PTHrP gene expression via EGFR Tyr992 and MAPK , and that this pathway may contribute to PTHrP expression by breast tumor cells .	Taken together, it appears that autocrine stimulation of EGFR signaling by amphiregulin is coupled to PTHrP gene expression via EGFR Tyr992 and MAPK, and that this pathway may contribute to PTHrP expression by breast tumor cells.	9	13	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	12	13	9	10
The primary mechanism for eliciting this function being the shedding of trans-membrane precursors heparin binding epidermal growth factor ( HB-EGF ) and amphiregulin that activate the EGFR receptor , ultimately promoting invasion [ XREF_BIBR ] .	The primary mechanism for eliciting this function being the shedding of trans-membrane precursors heparin binding epidermal growth factor (HB-EGF) and amphiregulin that activate the EGFR receptor, ultimately promoting invasion [XREF_BIBR].	4	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	22	23	26	27
Activation of EGFR by amphiregulin was necessary for induction of ERK activation and the mitogenic effects of CCL20 .	Activation of EGFR by amphiregulin was necessary for induction of ERK activation and the mitogenic effects of CCL20.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	4	5	2	3
18 EGFR is activated by several autocrine ligands including transforming growth factor alpha ( TGFalpha ) and amphiregulin , in addition to EGF .	18 EGFR is activated by several autocrine ligands including transforming growth factor alpha (TGFalpha) and amphiregulin, in addition to EGF.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	17	18	1	2
It is plausible that the newly produced AREG initiates the delayed component of biphasic EGFR activation and contributes to prolonged YB-1 activation induced by LPA .	It is plausible that the newly produced AREG initiates the delayed component of biphasic EGFR activation and contributes to prolonged YB-1 activation induced by LPA.	4	17	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	7	8	14	15
In addition , our group elucidated a mechanism of exemestane-resistance that relies on the hormone like property of this AI to activate the estrogen responsive gene AREG , which drives EGFR dependent signaling and subsequent cell growth .	In addition, our group elucidated a mechanism of exemestane-resistance that relies on the hormone like property of this AI to activate the estrogen responsive gene AREG, which drives EGFR dependent signaling and subsequent cell growth.	21	32	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	26	27	30	31
ADAM17 participates in protein ectodomain shedding of epidermal growth factor ( EGF ) receptor ligands such as heparin binding EGF ( HB-EGF ) , transforming growth factor ( TGF ) alpha , and amphiregulin which , in turn , activate the EGF receptor ( EGFR ) and initiate downstream signaling events leading to cell proliferation , migration , or apoptosis .	ADAM17 participates in protein ectodomain shedding of epidermal growth factor (EGF) receptor ligands such as heparin binding EGF (HB-EGF), transforming growth factor (TGF) alpha, and amphiregulin which, in turn, activate the EGF receptor (EGFR) and initiate downstream signaling events leading to cell proliferation, migration, or apoptosis.	14	47	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGF receptor	EGF receptor	EGF receptor	33	34	41	43
In turn , AREG induced a unique EGFR activation pattern in human airway BC , distinct from that evoked by EGF , leading to BC- and mucous hyperplasia , altered ciliated cell differentiation and impaired barrier integrity .	In turn, AREG induced a unique EGFR activation pattern in human airway BC, distinct from that evoked by EGF, leading to BC- and mucous hyperplasia, altered ciliated cell differentiation and impaired barrier integrity.	3	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	3	4	7	8
EGFR activation by AREG induces multiple downstream signaling pathways including MAPK .	EGFR activation by AREG induces multiple downstream signaling pathways including MAPK.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	3	4	0	1
Epidermal growth factor receptor is typically activated by EGF , TGF-alpha and amphiregulin ligands that are abnormally produced by cancer cells and tumour associated stromal cells .	Epidermal growth factor receptor is typically activated by EGF, TGF-alpha and amphiregulin ligands that are abnormally produced by cancer cells and tumour associated stromal cells.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	Epidermal growth factor receptor	Epidermal growth factor receptor	Epidermal growth factor receptor	12	13	0	4
Taken together , these data suggest that AREG and EREG mediate tumorigenic phenotypes by activating EGFR signaling , and that the oncogenic potential of FGFR1 requires EGFR activation to promote mammary tumorigenesis .	Taken together, these data suggest that AREG and EREG mediate tumorigenic phenotypes by activating EGFR signaling, and that the oncogenic potential of FGFR1 requires EGFR activation to promote mammary tumorigenesis.	7	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	7	8	15	16
In order to analyze if exosomal AREG induced EGFR pathway activation causing osteoclast differentiation , Raw 264.7 cells were first treated with recombinant AREG ( Rec-AREG ) .	In order to analyze if exosomal AREG induced EGFR pathway activation causing osteoclast differentiation, Raw 264.7 cells were first treated with recombinant AREG (Rec-AREG).	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	6	7	8	9
Taken together , we provide evidence that AREG stimulation of EGFR results in high levels of PTHrP gene expression , contributing to cancer associated bone pathology .	Taken together, we provide evidence that AREG stimulation of EGFR results in high levels of PTHrP gene expression, contributing to cancer associated bone pathology.	7	11	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	7	8	10	11
These inhibitors also inhibit heterodimerization and signalling through IGFR and EGFR driven by amphiregulin in mucinous lung adenocarcinoma .	These inhibitors also inhibit heterodimerization and signalling through IGFR and EGFR driven by amphiregulin in mucinous lung adenocarcinoma.	3	17	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	13	14	10	11
Here , we show that pre-maturation in vitro with cAMP modulators enhanced COC gap junctional communication and EGFR signaling stimulated by FSH or AREG in developing COCs from small antral follicles .	Here, we show that pre-maturation in vitro with cAMP modulators enhanced COC gap junctional communication and EGFR signaling stimulated by FSH or AREG in developing COCs from small antral follicles.	17	24	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	23	24	17	18
Amphiregulin Mediates Estrogen , Progesterone , and EGFR Signaling in the Normal Rat Mammary Gland and in Hormone Dependent Rat Mammary Cancers .	Amphiregulin Mediates Estrogen, Progesterone, and EGFR Signaling in the Normal Rat Mammary Gland and in Hormone Dependent Rat Mammary Cancers.	0	8	Mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Amphiregulin	Amphiregulin	Amphiregulin	EGFR	EGFR	EGFR	0	1	7	8
Thus , amphiregulin overexpression stimulates the activation of EGF receptor in ADPKD cystic cells .	Thus, amphiregulin overexpression stimulates the activation of EGF receptor in ADPKD cystic cells.	2	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin overexpression	amphiregulin	EGF receptor	EGF receptor	egf receptor	2	3	8	10
Essential Role of c-Cbl in Amphiregulin induced Recycling and Signaling of Endogenous Epidermal Growth Factor Receptor ( EGFR ) .	Essential Role of c-Cbl in Amphiregulin induced Recycling and Signaling of Endogenous Epidermal Growth Factor Receptor (EGFR).	3	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Amphiregulin	Amphiregulin	Amphiregulin	Epidermal Growth Factor Receptor	Epidermal Growth Factor Receptor	Epidermal Growth Factor Receptor	5	6	12	16
In summary , our results with AREG- knock-down versions of SUM-149 cells not only point to roles of the autocrine ligand in maintaining proliferation of the cells in an autocrine manner , but provide further support for the hypothesis that AREG activated EGFR is a major driver of invasion in breast cancer cells .	In summary, our results with AREG- knock-down versions of SUM-149 cells not only point to roles of the autocrine ligand in maintaining proliferation of the cells in an autocrine manner, but provide further support for the hypothesis that AREG activated EGFR is a major driver of invasion in breast cancer cells.	40	43	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	40	41	42	43
MMP1 and ADAMTS1 proteolytically cleave the membrane bound epidermal growth factor ( EGF ) family ligands , including heparinbinding epidermal growth factor like growth factor ( HB-EGF ) and amphiregulin , which activate epidermal growth factor receptor ( EGFR ) signaling in osteoblasts , leading to reduced expression of osteoprotegerin , the decoy receptor and antagonist of RANKL .	MMP1 and ADAMTS1 proteolytically cleave the membrane bound epidermal growth factor (EGF) family ligands, including heparinbinding epidermal growth factor like growth factor (HB-EGF) and amphiregulin, which activate epidermal growth factor receptor (EGFR) signaling in osteoblasts, leading to reduced expression of osteoprotegerin, the decoy receptor and antagonist of RANKL.	7	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	29	30	33	37
In lung adenocarcinoma cells from Kras and Tp53-mutant animals and human lung cancer cell lines , ZEB1 activated PI3K by derepressing miR-200 targets , including amphiregulin ( AREG ) , betacellulin ( BTC ) , and the transcription factor GATA6 , which stimulated an EGFR and ERBB2 autocrine loop .	In lung adenocarcinoma cells from Kras and Tp53-mutant animals and human lung cancer cell lines, ZEB1 activated PI3K by derepressing miR-200 targets, including amphiregulin (AREG), betacellulin (BTC), and the transcription factor GATA6, which stimulated an EGFR and ERBB2 autocrine loop.	25	48	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	27	28	44	45
Since all known biological effects of AREG are mediated by binding to EGFR , our results suggest the invasive effect of AREG exosomes is due , at least in part , to exosomal AREG activation of recipient cell EGFR .	Since all known biological effects of AREG are mediated by binding to EGFR, our results suggest the invasive effect of AREG exosomes is due, at least in part, to exosomal AREG activation of recipient cell EGFR.	33	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	33	34	38	39
Moreover , the trend of DCA stimulated AREG shedding activity was consistent with the finding of DCA stimulated EGFR signalling activation .	Moreover, the trend of DCA stimulated AREG shedding activity was consistent with the finding of DCA stimulated EGFR signalling activation.	7	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	7	8	18	19
Thus , AREG stimulates EGFR signaling of greater duration than does EGF .	Thus, AREG stimulates EGFR signaling of greater duration than does EGF.	2	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	2	3	4	5
Exogenous AREG stimulation of the HTB-182 and EGFR cell line increased P1and P3 derived PTHrP transcripts 6-fold ; however , exogenous EGF was less effective in increasing P1 and P3 transcripts than in the RWGT2 or HARA lines ( XREF_FIG ) .	Exogenous AREG stimulation of the HTB-182 and EGFR cell line increased P1and P3 derived PTHrP transcripts 6-fold; however, exogenous EGF was less effective in increasing P1 and P3 transcripts than in the RWGT2 or HARA lines (XREF_FIG).	1	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	1	2	7	8
Cleavage of pro AREG and pro EREG by the MMPs results in protein release and autocrine signaling to activate EGFR 13 .	Cleavage of pro AREG and pro EREG by the MMPs results in protein release and autocrine signaling to activate EGFR 13.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	3	4	19	20
Insufficient dephosphorylation of the androgen receptor leads to continuous activation of the androgen receptor and enhances the androgen receptor mediated signalling pathways .	Insufficient dephosphorylation of the androgen receptor leads to continuous activation of the androgen receptor and enhances the androgen receptor mediated signalling pathways.	1	14	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	androgen receptor	dephosphorylation of the androgen receptor	androgen receptor	androgen receptor	androgen receptor	androgen receptor	4	6	12	14
The mechanisms of this reactivation are numerous and include molecular events such as AR amplification , AR mutations , overexpression of AR cofactors , increased intratumoral androgen synthesis , ligand independent AR activation by cytokines or growth factors , and constitutively active AR variants [ XREF_BIBR - XREF_BIBR ] .	The mechanisms of this reactivation are numerous and include molecular events such as AR amplification, AR mutations, overexpression of AR cofactors, increased intratumoral androgen synthesis, ligand independent AR activation by cytokines or growth factors, and constitutively active AR variants [XREF_BIBR - XREF_BIBR].	19	32	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	overexpression of AR	ar	AR	AR	ar	21	22	31	32
Many investigators have demonstrated that AR acetylation enhances AR activity and PCa cell survival XREF_BIBR , XREF_BIBR .	Many investigators have demonstrated that AR acetylation enhances AR activity and PCa cell survival XREF_BIBR, XREF_BIBR.	5	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR acetylation	ar	AR	AR	ar	5	6	8	9
The ligand activated human androgen receptor ( AR ) is known to control the growth of the prostate gland .	The ligand activated human androgen receptor (AR) is known to control the growth of the prostate gland.	1	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	7	8	4	6
Although CHP-1 shows poor androgen receptor ( AR ) signalling upon dihydrotestosterone stimulation , forced expression of AR enabled evaluation of AR signalling .	Although CHP-1 shows poor androgen receptor (AR) signalling upon dihydrotestosterone stimulation, forced expression of AR enabled evaluation of AR signalling.	15	22	enabled	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	expression of AR	ar	AR	AR	ar	17	18	21	22
Inhibition of AR expression by siRNA obviously blocked the promoting or suppressing effect of R1881 or AR antagonists , respectively on sphere formation of both cell lines .	Inhibition of AR expression by siRNA obviously blocked the promoting or suppressing effect of R1881 or AR antagonists, respectively on sphere formation of both cell lines.	2	17	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	2	3	16	17
XREF_BIBR D2 was capable of blocking hormone driven AR transactivation in LNCaP and LAPC4 cells , as well as transcription of AR regulated genes in C4-2 and CWR22Rv1 cells , and reduced receptor dependent xenograft tumor growth .	XREF_BIBR D2 was capable of blocking hormone driven AR transactivation in LNCaP and LAPC4 cells, as well as transcription of AR regulated genes in C4-2 and CWR22Rv1 cells, and reduced receptor dependent xenograft tumor growth.	7	22	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	transcription of AR	ar	AR	AR	ar	21	22	8	9
In addition , up to 30 % of patients experience a drop in prostate specific antigen ( PSA ) after discontinuing antiandrogens ( Small et al , 2004 ) , explained in part by the development of AR gene mutations , or gene amplification and increased AR expression that may cause AR antagonists to behave as agonists ( Chen et al , 2004 ) .	In addition, up to 30% of patients experience a drop in prostate specific antigen (PSA) after discontinuing antiandrogens (Small et al, 2004), explained in part by the development of AR gene mutations, or gene amplification and increased AR expression that may cause AR antagonists to behave as agonists (Chen et al, 2004).	46	52	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	46	47	51	52
Androgen Receptor ( AR ) gene is associated with Prostate cancer ( PCa ) and hence targeting androgen-and AR signaling axis remains the most promising primary therapeutic option to treat the disease .	Androgen Receptor (AR) gene is associated with Prostate cancer (PCa) and hence targeting androgen-and AR signaling axis remains the most promising primary therapeutic option to treat the disease.	0	20	targeting	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Androgen Receptor	Androgen Receptor	Androgen Receptor	AR	AR	AR	0	2	18	19
In vitro studies demonstrate that Akt and protein kinase B phosphorylates AR at serine residues ( Ser 210 and Ser 790 ) resulting in modulation of AR transcriptional activity ( Lin et al , 2001 , 2003 ) and suggesting that AR phosphorylation might promote development of HRPC .	In vitro studies demonstrate that Akt and protein kinase B phosphorylates AR at serine residues (Ser 210 and Ser 790) resulting in modulation of AR transcriptional activity (Lin et al, 2001, 2003) and suggesting that AR phosphorylation might promote development of HRPC.	5	28	resulting in modulation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	AR	Akt and protein kinase B phosphorylates AR at serine residues (Ser 210	ar	AR	AR	ar	11	12	26	27
The androgen independence of the adult prostate epithelial stem cells is supported by the tissue recombination studies of Gerry Cunha , which documented that epithelial morphogenesis occurs even when AR protein is not expressed by prostate epithelial cells as long as there is expression and signaling of AR in the supporting stromal cells XREF_BIBR .	The androgen independence of the adult prostate epithelial stem cells is supported by the tissue recombination studies of Gerry Cunha, which documented that epithelial morphogenesis occurs even when AR protein is not expressed by prostate epithelial cells as long as there is expression and signaling of AR in the supporting stromal cells XREF_BIBR.	42	53	is expression and signaling	Positive_activation_copula_1	Positive_activation	Positive_activation	AR	expression and signaling of AR	ar	AR	AR	ar	47	48	47	48
The authors concluded that ADT enhances AR transcription , which leads to increased AR pre-mRNA that is processed through splicing to generate mRNAs encoding AR-V7 as well as full-length AR .	The authors concluded that ADT enhances AR transcription, which leads to increased AR pre-mRNA that is processed through splicing to generate mRNAs encoding AR-V7 as well as full-length AR.	4	30	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	AR	ADT enhances AR transcription	ar	AR	AR	ar	6	7	29	30
This is supported by our observations that the association between Etk and AR is increased after castration and Etk induces tyrosine phosphorylation of AR , leading an increase in AR stability and transcriptional activity under androgen depleted conditions .	This is supported by our observations that the association between Etk and AR is increased after castration and Etk induces tyrosine phosphorylation of AR, leading an increase in AR stability and transcriptional activity under androgen depleted conditions.	18	30	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Etk induces tyrosine phosphorylation of AR	ar	AR	AR	ar	23	24	29	30
Many underlying mechanisms have been proposed : increased AR expression through AR gene amplification , increased AR sensitivity through enhanced AR stability and nuclear localization , broadened AR ligand specificity through mutations in its ligand binding domain , and increased AR activity through post-translational modifications XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Many underlying mechanisms have been proposed : increased AR expression through AR gene amplification, increased AR sensitivity through enhanced AR stability and nuclear localization, broadened AR ligand specificity through mutations in its ligand binding domain, and increased AR activity through post-translational modifications XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	8	41	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	8	9	40	41
These findings indicate that Ser 81 phosphorylation by CDK9 stabilizes AR chromatin binding for transcription and suggest that CDK1 mediated Ser 81 phosphorylation during mitosis provides a pool of Ser 81 phosphorylation AR that can be readily recruited to chromatin for gene reactivation and may enhance AR activity in PCa .	These findings indicate that Ser 81 phosphorylation by CDK9 stabilizes AR chromatin binding for transcription and suggest that CDK1 mediated Ser 81 phosphorylation during mitosis provides a pool of Ser 81 phosphorylation AR that can be readily recruited to chromatin for gene reactivation and may enhance AR activity in PCa.	18	47	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	CDK1 mediated Ser 81 phosphorylation during mitosis provides a pool of Ser 81 phosphorylation AR	ar	AR	AR	ar	32	33	46	47
GATA-1 also regulates the androgen receptor corepressor 19 kDa ( ARR19 ) , which co-translocates into the nucleus with AR and suppresses AR activity through the recruitment of HDAC4 XREF_BIBR , XREF_BIBR .	GATA-1 also regulates the androgen receptor corepressor 19 kDa (ARR19), which co-translocates into the nucleus with AR and suppresses AR activity through the recruitment of HDAC4 XREF_BIBR, XREF_BIBR.	4	23	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	4	6	22	23
Androgen induces androgen receptor ( AR ) nuclear import , which allows AR to act as a transcriptional factor and ultimately leads to biological activity .	Androgen induces androgen receptor (AR) nuclear import, which allows AR to act as a transcriptional factor and ultimately leads to biological activity.	2	14	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	2	4	12	13
The conformational change in the AR also allows AR nuclear localization , increased AR phosphorylation in the nuclear compartment , AR homodimer formation , and its interaction with DNA .	The conformational change in the AR also allows AR nuclear localization, increased AR phosphorylation in the nuclear compartment, AR homodimer formation, and its interaction with DNA.	8	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR phosphorylation	ar	AR	AR	ar	13	14	8	9
Taken together , these results show that increased AR levels are unable to explain the profound cistrome change observed in LHSAR cells and prostate tumors and support the hypothesis that expression of HOXB13 and FOXA1 in immortalized LHSAR cells reprogrammed the AR cistrome to resemble the pattern observed in prostate tumors .	Taken together, these results show that increased AR levels are unable to explain the profound cistrome change observed in LHSAR cells and prostate tumors and support the hypothesis that expression of HOXB13 and FOXA1 in immortalized LHSAR cells reprogrammed the AR cistrome to resemble the pattern observed in prostate tumors.	8	42	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR levels	ar	AR	AR	ar	8	9	41	42
ErbB signaling decreases endogenous AR protein expression and represses AR transcriptional activity in LNCaP cells .	ErbB signaling decreases endogenous AR protein expression and represses AR transcriptional activity in LNCaP cells.	0	11	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	ErbB signaling decreases endogenous AR protein expression	ar	AR	AR	ar	4	5	9	10
The most common mechanism driving CRPC development appears to be reactivated AR signaling mediated by high levels of AR and its variants in PCa .	The most common mechanism driving CRPC development appears to be reactivated AR signaling mediated by high levels of AR and its variants in PCa.	11	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AR	levels of AR	ar	AR	AR	ar	18	19	11	12
Similarly , we found AR overexpression could also lead to AR recruitment to the gained ARBS , supporting that they are authentic AR targets ( XREF_SUPPLEMENTARY ) .	Similarly, we found AR overexpression could also lead to AR recruitment to the gained ARBS, supporting that they are authentic AR targets (XREF_SUPPLEMENTARY).	4	25	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR overexpression	ar	AR	AR	ar	4	5	22	23
Taken together , Ach not only enhances AR expression but activates AR in HCC cells .	Taken together, Ach not only enhances AR expression but activates AR in HCC cells.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Ach not only enhances AR expression	ar	AR	AR	ar	7	8	11	12
In adult female rats not treated with DENA , removal of the ovary increased liver androgen receptor levels but testosterone did not further enhance the androgen receptor status of ovariectomized rats .	In adult female rats not treated with DENA, removal of the ovary increased liver androgen receptor levels but testosterone did not further enhance the androgen receptor status of ovariectomized rats.	15	27	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor levels	androgen receptor	androgen receptor	androgen receptor	androgen receptor	15	17	25	27
For example , the luminal AR subtype can be treated with androgen receptor antagonists [ XREF_BIBR ] .	For example, the luminal AR subtype can be treated with androgen receptor antagonists [XREF_BIBR].	5	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	11	13	5	6
A previous report indicated that AR nuclear translocation was induced by phosphorylation of AR at Tyr 534 site by Src tyrosine kinase [ XREF_BIBR ] .	A previous report indicated that AR nuclear translocation was induced by phosphorylation of AR at Tyr 534 site by Src tyrosine kinase [XREF_BIBR].	5	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AR	phosphorylation of AR at Tyr 534	ar	AR	AR	ar	13	14	5	6
Overexpression of AR , frequently due to genomic amplification of the AR gene , enhances transcriptional activation of AR to low levels of androgen in the castrate host [ XREF_BIBR ] .	Overexpression of AR, frequently due to genomic amplification of the AR gene, enhances transcriptional activation of AR to low levels of androgen in the castrate host [XREF_BIBR].	0	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Overexpression of AR	ar	AR	AR	ar	2	3	18	19
From the above results , CNPY2 increased AR protein levels and promoted AR transactivation of the AR target genes , which might promote cell growth of prostate cancer .	From the above results, CNPY2 increased AR protein levels and promoted AR transactivation of the AR target genes, which might promote cell growth of prostate cancer.	5	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	CNPY2 increased AR protein levels	ar	AR	AR	ar	7	8	12	13
Various molecular mechanisms ( e.g ., androgen receptor gene amplification , overexpression , or mutations , enhanced AR signal transduction ) have been reported in castration resistant prostate cancers [ XREF_BIBR ] .	Various molecular mechanisms (e.g., androgen receptor gene amplification, overexpression, or mutations, enhanced AR signal transduction) have been reported in castration resistant prostate cancers [XREF_BIBR].	2	19	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	6	8	17	18
In LNCaP cells , the reporter activity driven by PSA enhancer can be induced by DHT treatment through endogenous AR and the overexpression of wildtype AR modestly increased this endogenous AR activity .	In LNCaP cells, the reporter activity driven by PSA enhancer can be induced by DHT treatment through endogenous AR and the overexpression of wildtype AR modestly increased this endogenous AR activity.	22	31	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	overexpression of wildtype AR	ar	AR	AR	ar	25	26	30	31
This association may be the result of changes in androgen metabolism that occur with obesity and are mediated by the androgen receptor ( AR ) .	This association may be the result of changes in androgen metabolism that occur with obesity and are mediated by the androgen receptor (AR).	10	24	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	20	22	23	24
In castrate resistant PCa , traditional therapies that only target androgen receptor ( AR ) have become obsolete due to reprograming in AR activity to make the cells independent of androgen .	In castrate resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen.	6	14	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	13	14	10	12
The effects of androgen receptor ( AR )-mediated prostate cancer growth are dependent upon the translocation of cytosolic ligand activated AR into the nucleus with subsequent binding to transcriptional DNA elements .	The effects of androgen receptor (AR)-mediated prostate cancer growth are dependent upon the translocation of cytosolic ligand activated AR into the nucleus with subsequent binding to transcriptional DNA elements.	3	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	3	5	20	21
Whereas HDAC inhibitor treatment can lower androgen receptor protein levels in prostate cancer cells , we show that independent of AR protein levels , HDAC inhibitors block AR activity through inhibiting the assembly of coactivator and RNA polymerase II complex after AR binds to the enhancers of target genes .	Whereas HDAC inhibitor treatment can lower androgen receptor protein levels in prostate cancer cells, we show that independent of AR protein levels, HDAC inhibitors block AR activity through inhibiting the assembly of coactivator and RNA polymerase II complex after AR binds to the enhancers of target genes.	20	28	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR protein levels	ar	AR	AR	ar	20	21	27	28
CRPC may also be related to amplification of AR signaling caused by overexpression of AR itself , or AR coactivators , such as the steroid receptor coactivators ( SRCs ) [ XREF_BIBR - XREF_BIBR ] .	CRPC may also be related to amplification of AR signaling caused by overexpression of AR itself, or AR coactivators, such as the steroid receptor coactivators (SRCs) [XREF_BIBR - XREF_BIBR].	8	33	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AR	overexpression of AR	ar	AR	AR	ar	14	15	8	9
Over-expression of AR co-activators may enhance AR response to low levels of androgen or allow AR response to non androgen ligands [ XREF_BIBR ] .	Over-expression of AR co-activators may enhance AR response to low levels of androgen or allow AR response to non androgen ligands [XREF_BIBR].	0	16	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Over-expression of AR	ar	AR	AR	ar	2	3	15	16
Therefore , a partial antagonist , or selective androgen receptor modulator ( SARM ) such as the steroidal AR antagonist CR1447 might offer an advantage over the non steroidal AR antagonists .	Therefore, a partial antagonist, or selective androgen receptor modulator (SARM) such as the steroidal AR antagonist CR1447 might offer an advantage over the non steroidal AR antagonists.	8	20	modulator	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	18	19	8	10
Enzalutamide is a second generation androgen receptor ( AR ) inhibitor that binds to and blocks the AR with higher affinity than previously available AR inhibitors .	Enzalutamide is a second generation androgen receptor (AR) inhibitor that binds to and blocks the AR with higher affinity than previously available AR inhibitors.	5	18	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	androgen receptor	androgen receptor (AR) inhibitor that binds	androgen receptor	AR	AR	ar	5	7	17	18
Among these , the androgen receptor splice variants ( AR-Vs ) , particularly variant 7 ( AR-V7 ) , have been implicated in resistance to enzalutamide and abiraterone in preclinical studies , and they can not be targeted by currently available AR directed drugs .	Among these, the androgen receptor splice variants (AR-Vs), particularly variant 7 (AR-V7), have been implicated in resistance to enzalutamide and abiraterone in preclinical studies, and they can not be targeted by currently available AR directed drugs.	4	42	targeted	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	41	42	4	6
AR phosphorylation at Ser 650 is increased in the cytoplasm of ER negative breast cancer cells and ductal carcinoma , while the nuclear AR phosphorylation at Ser 650 is decreased , supporting the idea that phosphorylation at Ser 650 may be important in nuclear export of AR in more aggressive breast cancers .	AR phosphorylation at Ser 650 is increased in the cytoplasm of ER negative breast cancer cells and ductal carcinoma, while the nuclear AR phosphorylation at Ser 650 is decreased, supporting the idea that phosphorylation at Ser 650 may be important in nuclear export of AR in more aggressive breast cancers.	0	47	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR phosphorylation at Ser 650	ar	AR	AR	ar	0	1	46	47
Resveratrol alone increased AR protein expression in the DLP , supporting the concept of the AR functioning as a tumor suppressor prior to the development of prostate cancer by inhibiting uncontrolled proliferation in normal prostate epithelium .	Resveratrol alone increased AR protein expression in the DLP, supporting the concept of the AR functioning as a tumor suppressor prior to the development of prostate cancer by inhibiting uncontrolled proliferation in normal prostate epithelium.	0	16	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Resveratrol alone increased AR protein expression	ar	AR	AR	ar	3	4	15	16
This result is further supported by the observation that knocking-down endogenous RNF6 in CWR-R1 and C4-2B cells under the serum free conditions diminished the expression level of a well established AR target gene product PSA , concurrent with the reduction of AR ubiquitination ( XREF_FIG ) .	This result is further supported by the observation that knocking-down endogenous RNF6 in CWR-R1 and C4-2B cells under the serum free conditions diminished the expression level of a well established AR target gene product PSA, concurrent with the reduction of AR ubiquitination (XREF_FIG).	22	43	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR ubiquitination	ar	AR	AR	ar	41	42	30	31
We report for the first time that in addition to STAT3 , Fer is required for IL-6 mediated AR activation by phosphorylating AR tyrosine 223 and binding via its SH2 domain .	We report for the first time that in addition to STAT3, Fer is required for IL-6 mediated AR activation by phosphorylating AR tyrosine 223 and binding via its SH2 domain.	17	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	phosphorylating AR tyrosine 223	ar	AR	AR	ar	22	23	18	19
In prostate cancer cell lines , androgen receptor ( AR ) coactivators modulate the transcriptional activity of AR .	In prostate cancer cell lines, androgen receptor (AR) coactivators modulate the transcriptional activity of AR.	6	18	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	6	8	17	18
HOXB13 , a homeobox domain containing gene , is strongly expressed in the prostate from embryonic stages to adulthood and has been shown to directly interact with the androgen receptor ( AR ) , functioning to activate or repress distinct AR target genes XREF_BIBR - XREF_BIBR .	HOXB13, a homeobox domain containing gene, is strongly expressed in the prostate from embryonic stages to adulthood and has been shown to directly interact with the androgen receptor (AR), functioning to activate or repress distinct AR target genes XREF_BIBR - XREF_BIBR.	28	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	28	30	40	41
Particularly , AR was transcriptionally activated by Src mediated phosphorylation of AR at Y534 in the absence of androgen [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Particularly, AR was transcriptionally activated by Src mediated phosphorylation of AR at Y534 in the absence of androgen [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	14	mediated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	AR	AR	ar	AR	phosphorylation of AR at Y534	ar	2	3	11	12
However , RNF6 was found to mediate an atypical ubiquitination of the androgen receptor ( AR ) and promotes the transcriptional activity and specificity of AR in prostate cancer [ XREF_BIBR ] .	However, RNF6 was found to mediate an atypical ubiquitination of the androgen receptor (AR) and promotes the transcriptional activity and specificity of AR in prostate cancer [XREF_BIBR].	2	26	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	RNF6 was found to mediate an atypical ubiquitination of the androgen receptor	androgen receptor	AR	AR	ar	12	14	25	26
Loss of AR phosphorylation significantly reduced the rate of AR clearance , suggesting that phosphorylation of AR at the Akt consensus sites is important for AR degradation .	Loss of AR phosphorylation significantly reduced the rate of AR clearance, suggesting that phosphorylation of AR at the Akt consensus sites is important for AR degradation.	2	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR phosphorylation	ar	AR	AR	ar	2	3	9	10
AR overexpression enhances AR mediated repression of DNA replication genes .	AR overexpression enhances AR mediated repression of DNA replication genes.	0	4	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR overexpression	ar	AR	AR	ar	0	1	3	4
Our data showed that after treatment with testosterone , either alone or in combination with 17beta-oestradiol , there was overexpression of the androgen receptor in alveolar or ductal epithelial cells .	Our data showed that after treatment with testosterone, either alone or in combination with 17beta-oestradiol, there was overexpression of the androgen receptor in alveolar or ductal epithelial cells.	18	24	was overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	androgen receptor	overexpression of the androgen receptor	androgen receptor	androgen receptor	androgen receptor	androgen receptor	22	24	22	24
A significant decrease in AR protein level was detected , confirming that PROTAC-5 targets and degrades AR .	A significant decrease in AR protein level was detected, confirming that PROTAC-5 targets and degrades AR.	4	17	degrades	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR protein level	ar	AR	AR	ar	4	5	16	17
In parallel to G protein signaling , activated beta 2 AR can be phosphorylated and binds to beta-arrestin , initiating desensitization , endocytosis of beta 2 AR and beta-arrestin-dependent signaling .	In parallel to G protein signaling, activated beta 2 AR can be phosphorylated and binds to beta-arrestin, initiating desensitization, endocytosis of beta 2 AR and beta-arrestin-dependent signaling.	9	27	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR can be phosphorylated and binds to beta-arrestin	ar	AR	AR	ar	10	11	26	27
AZD3514 exerted inhibitory effects on AR expression and ligand driven nuclear accumulation of AR [ XREF_BIBR ] .	AZD3514 exerted inhibitory effects on AR expression and ligand driven nuclear accumulation of AR [XREF_BIBR].	5	15	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	5	6	13	14
Knockdown of PABPC1 decreased nuclear AR protein levels and inhibited androgen activation of the AR target PSA in LNCaP and C4-2 cells .	Knockdown of PABPC1 decreased nuclear AR protein levels and inhibited androgen activation of the AR target PSA in LNCaP and C4-2 cells.	2	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	PABPC1 decreased nuclear AR protein levels	ar	AR	AR	ar	5	6	14	15
Increased AR expression may enhance any weak residual AR activity that remains after castration , and can enhance growth of a PCa cell line in castrated mice [ XREF_BIBR ] .	Increased AR expression may enhance any weak residual AR activity that remains after castration, and can enhance growth of a PCa cell line in castrated mice [XREF_BIBR].	1	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	1	2	8	9
A particularly important and clinically relevant biomarker in prostate cancer is the androgen-receptor splice variant 7 ( AR-V7 ) , which encodes an androgen receptor ( AR ) protein isoform that constitutively activates the AR pathway in the absence of androgens .	A particularly important and clinically relevant biomarker in prostate cancer is the androgen-receptor splice variant 7 (AR-V7), which encodes an androgen receptor (AR) protein isoform that constitutively activates the AR pathway in the absence of androgens.	23	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	23	25	34	35
The results further showed that treatment of T , either alone or in combination with E2 , there was overexpression of the androgen receptor ( AR ) in alveolar or ductal epithelial cells but not in stromal cells .	The results further showed that treatment of T, either alone or in combination with E2, there was overexpression of the androgen receptor (AR) in alveolar or ductal epithelial cells but not in stromal cells.	18	24	was overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	androgen receptor	overexpression of the androgen receptor	androgen receptor	androgen receptor	androgen receptor	androgen receptor	22	24	22	24
AR gene overexpression causing AR hypersensitivity to declining concentrations of androgen and cross stimulation of AR signaling by other growth factors and how AR transmigration into nucleus to modulate transcriptional network are some of the prominent features that need a detailed investigation with reference to methyl jasmonates and algae derived components .	AR gene overexpression causing AR hypersensitivity to declining concentrations of androgen and cross stimulation of AR signaling by other growth factors and how AR transmigration into nucleus to modulate transcriptional network are some of the prominent features that need a detailed investigation with reference to methyl jasmonates and algae derived components.	0	5	causing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AR	AR gene overexpression	ar	AR	AR	ar	0	1	4	5
Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR positive , but not AR negative , prostate cancer cells .	Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR positive, but not AR negative, prostate cancer cells.	6	23	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	PRMT5 by a specific inhibitor reduces the expression of AR	ar	AR	AR	ar	15	16	22	23
Overexpression of the AR 1/2/3/CE3 variant ( also referred to as AR-V7 or AR3 ) , the AR v567es variant , or a truncated AR variant of mouse origin ( mAR-V4 ) in LNCaP cells can induce androgen independent expression of AR target genes and growth under castrate conditions in vitro and in vivo .	Overexpression of the AR 1/2/3/CE3 variant (also referred to as AR-V7 or AR3), the AR v567es variant, or a truncated AR variant of mouse origin (mAR-V4) in LNCaP cells can induce androgen independent expression of AR target genes and growth under castrate conditions in vitro and in vivo.	0	43	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Overexpression of the AR	ar	AR	AR	ar	3	4	41	42
Further , depletion of URI increases the expression of the AR target gene NKX-3.1 , decreases the recruitment of Art-27 , and increases AR occupancy at the NKX-3.1 promoter .	Further, depletion of URI increases the expression of the AR target gene NKX-3.1, decreases the recruitment of Art-27, and increases AR occupancy at the NKX-3.1 promoter.	4	24	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	URI increases the expression of the AR	ar	AR	AR	ar	10	11	23	24
Therefore , metformin induced AMPK activation mainly suppressed AR protein level and consequently inhibited AR functions .	Therefore, metformin induced AMPK activation mainly suppressed AR protein level and consequently inhibited AR functions.	2	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	metformin induced AMPK activation mainly suppressed AR protein level	ar	AR	AR	ar	8	9	14	15
Although androgen deprivation therapy ( ADT ) is initially effective for the treatment of progressive prostate cancer , it inevitably fails due to the onset of diverse resistance mechanisms that restore androgen receptor ( AR ) signaling .	Although androgen deprivation therapy (ADT) is initially effective for the treatment of progressive prostate cancer, it inevitably fails due to the onset of diverse resistance mechanisms that restore androgen receptor (AR) signaling.	28	35	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	34	35	31	33
Specifically , Tip60 can acetylate the AR , a key transcription factor in CaP , to promote increased AR transcriptional activity XREF_BIBR and Tip60 expression has also been shown to correlate with disease progression XREF_BIBR .	Specifically, Tip60 can acetylate the AR, a key transcription factor in CaP, to promote increased AR transcriptional activity XREF_BIBR and Tip60 expression has also been shown to correlate with disease progression XREF_BIBR.	2	28	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Tip60 can acetylate the AR	ar	AR	AR	ar	6	7	18	19
For example , Heparin binding EGF ( HB-EGF ) , an ErbB1/4 ligand , decreases AR protein expression through activation of mTOR and decreased AR mRNA translation [ XREF_BIBR - XREF_BIBR ] .	For example, Heparin binding EGF (HB-EGF), an ErbB1/4 ligand, decreases AR protein expression through activation of mTOR and decreased AR mRNA translation [XREF_BIBR - XREF_BIBR].	5	26	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	EGF (HB-EGF), an ErbB1/4 ligand, decreases AR protein expression	ar	AR	AR	ar	15	16	24	25
Shikonin suppresses AR expression at the transcriptional level and subsequently inhibits the transcriptional activity of AR , resulting in inhibition of cell proliferation in androgen positive prostate cancer cells .	Shikonin suppresses AR expression at the transcriptional level and subsequently inhibits the transcriptional activity of AR, resulting in inhibition of cell proliferation in androgen positive prostate cancer cells.	0	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	Shikonin suppresses AR expression	ar	AR	AR	ar	2	3	15	16
They further showed that hPIRH2 interacts with AR lead to enhance AR target gene expression and also targets AR co-repressor HDAC1 and represses gene silencing .	They further showed that hPIRH2 interacts with AR lead to enhance AR target gene expression and also targets AR co-repressor HDAC1 and represses gene silencing.	7	17	lead	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	AR	AR	ar	AR	AR target gene expression	ar	7	8	11	12
Again , ciglitazone and rosiglitazone decreased DHT- induced AR transcriptional activation in the LNCaP cells , but did not decrease AR activation stimulated by DHT in the C4-2 cells .	Again, ciglitazone and rosiglitazone decreased DHT- induced AR transcriptional activation in the LNCaP cells, but did not decrease AR activation stimulated by DHT in the C4-2 cells.	2	21	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	ciglitazone and rosiglitazone decreased DHT- induced AR	ar	AR	AR	ar	8	9	20	21
An increase in AR protein expression is postulated to enable low circulating levels of androgens that are present following orchidectomy or treatment with LHRH agonists , to activate the AR even in the presence of antiandrogens ( Koivisto et al , 1997 ) .	An increase in AR protein expression is postulated to enable low circulating levels of androgens that are present following orchidectomy or treatment with LHRH agonists, to activate the AR even in the presence of antiandrogens (Koivisto et al, 1997).	3	30	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR protein expression	ar	AR	AR	ar	3	4	29	30
In cells with AGAP2 knockdown , however , plasma membrane beta 2 AR levels remained decreased at 30 min of recovery , supporting a critical role for AGAP2 in beta 2 AR recycling .	In cells with AGAP2 knockdown, however, plasma membrane beta 2 AR levels remained decreased at 30 min of recovery, supporting a critical role for AGAP2 in beta 2 AR recycling.	12	32	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR levels	ar	AR	AR	ar	12	13	31	32
For example , RNA knockdown of AR expression in the human prostate cancer cell line LNCaP impedes ligand independent AR activation and delays the progression of tumours subcutaneously induced in mice 47 .	For example, RNA knockdown of AR expression in the human prostate cancer cell line LNCaP impedes ligand independent AR activation and delays the progression of tumours subcutaneously induced in mice 47.	6	20	impedes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	6	7	19	20
Androgen receptor ( AR ) coactivators modulate the transcriptional activity of AR and may activate AR associated genes upon androgen deprivation .	Androgen receptor (AR) coactivators modulate the transcriptional activity of AR and may activate AR associated genes upon androgen deprivation.	0	12	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Androgen receptor	Androgen receptor	Androgen receptor	AR	AR	AR	0	2	11	12
Through direct physical interaction with the AR , Src is able to phosphorylate the AR and thereby induce ligand independent AR activation ( one of the key mechanisms of castration resistant PC ) .	Through direct physical interaction with the AR, Src is able to phosphorylate the AR and thereby induce ligand independent AR activation (one of the key mechanisms of castration resistant PC).	8	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Src is able to phosphorylate the AR	ar	AR	AR	ar	14	15	20	21
On the other hand , PPP1 overexpression increased AR expression and markedly enhanced AR transcriptional activity in prostate cancer cells XREF_BIBR .	On the other hand, PPP1 overexpression increased AR expression and markedly enhanced AR transcriptional activity in prostate cancer cells XREF_BIBR.	5	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	PPP1 overexpression increased AR expression	ar	AR	AR	ar	8	9	13	14
The ligand activated human androgen receptor ( AR ) supports the growth of the prostate gland .	The ligand activated human androgen receptor (AR) supports the growth of the prostate gland.	1	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	7	8	4	6
The presence of the alpha ( 2C ) AR within the heterodimer resulted in a marked reduction in the level of GRK2 mediated alpha ( 2A ) AR phosphorylation , which was accompanied by a qualitative attenuation of beta-arrestin recruitment .	The presence of the alpha (2C) AR within the heterodimer resulted in a marked reduction in the level of GRK2 mediated alpha (2A) AR phosphorylation, which was accompanied by a qualitative attenuation of beta-arrestin recruitment.	22	29	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR phosphorylation	ar	AR	AR	ar	27	28	27	28
Our finding that ARD1 mediated AR acetylation at K618 activates AR and induces ligand dependent AR-HSP90 dissociation offers a mechanism by which AR activation can be interrupted independent of HSP90 inactivation .	Our finding that ARD1 mediated AR acetylation at K618 activates AR and induces ligand dependent AR-HSP90 dissociation offers a mechanism by which AR activation can be interrupted independent of HSP90 inactivation.	3	11	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AR	ARD1 mediated AR acetylation at K618	ar	AR	AR	ar	5	6	10	11
One hypothesis suggested is that CDK5 phosphorylation of AR S81 causes AR nuclear localization and stabilization .	One hypothesis suggested is that CDK5 phosphorylation of AR S81 causes AR nuclear localization and stabilization.	5	12	causes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AR	CDK5 phosphorylation of AR S81	ar	AR	AR	ar	8	9	11	12
Together , our results indicate that propofol suppresses nuclear androgen receptor protein levels , and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells .	Together, our results indicate that propofol suppresses nuclear androgen receptor protein levels, and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells.	6	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	androgen receptor	propofol suppresses nuclear androgen receptor protein levels	androgen receptor	androgen receptor	androgen receptor	androgen receptor	9	11	16	18
The androgen receptor is activated by androgen to mediate most of the AR biological effects .	The androgen receptor is activated by androgen to mediate most of the AR biological effects.	1	14	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	1	3	12	13
Interestingly , another study suggests that the levels of AR potentiate the recruitment of AR and the components of the transcription machinery to chromatin in order to enhance the acetylation on H3K9 and on H3K14 in CRPC cells even in an androgen deprivation environment [ XREF_BIBR ] .	Interestingly, another study suggests that the levels of AR potentiate the recruitment of AR and the components of the transcription machinery to chromatin in order to enhance the acetylation on H3K9 and on H3K14 in CRPC cells even in an androgen deprivation environment [XREF_BIBR].	7	15	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	levels of AR	ar	AR	AR	ar	9	10	14	15
RNF6 induces AR ubiquitination and promotes AR transcriptional activity .	RNF6 induces AR ubiquitination and promotes AR transcriptional activity.	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	RNF6 induces AR ubiquitination	ar	AR	AR	ar	2	3	6	7
XREF_BIBR - XREF_BIBR Akt mediated AR phosphorylation has been shown to increase the interaction of AR with the transcriptional factor p300 and CBP , inhibiting AR ubiquitination and degradation .	XREF_BIBR - XREF_BIBR Akt mediated AR phosphorylation has been shown to increase the interaction of AR with the transcriptional factor p300 and CBP, inhibiting AR ubiquitination and degradation.	3	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Akt mediated AR phosphorylation	ar	AR	AR	ar	5	6	15	16
Second , promiscuous activation of AR by overexpression of AR coactivators and down regulation of its corepressors XREF_BIBR .	Second, promiscuous activation of AR by overexpression of AR coactivators and down regulation of its corepressors XREF_BIBR.	3	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	AR	overexpression of AR	ar	AR	AR	ar	9	10	5	6
Aside from the implication that a polyQ expansion is not necessary for pathology , this observation is puzzling because polyQ AR is associated with loss of AR function , whereas overexpression of WT AR would be expected to increase AR signaling .	Aside from the implication that a polyQ expansion is not necessary for pathology, this observation is puzzling because polyQ AR is associated with loss of AR function, whereas overexpression of WT AR would be expected to increase AR signaling.	30	40	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	overexpression of WT AR	ar	AR	AR	ar	33	34	39	40
The AKT mediated phosphorylation and activation of the androgen receptor ( AR ) induces its nuclear localization and transcriptional regulation of AR target genes .	The AKT mediated phosphorylation and activation of the androgen receptor (AR) induces its nuclear localization and transcriptional regulation of AR target genes.	1	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	AKT mediated phosphorylation and activation of the androgen receptor	androgen receptor	AR	AR	ar	8	10	21	22
As ubiquitination of AR causes a change in AR activity or stability and impacts both survival and growth of prostate cancer cells , deubiquitination of these sites has an equally important role .	As ubiquitination of AR causes a change in AR activity or stability and impacts both survival and growth of prostate cancer cells, deubiquitination of these sites has an equally important role.	1	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	ubiquitination of AR	ar	AR	AR	ar	3	4	8	9
To determine if elevated nuclear AR expression leads to increased AR transcriptional activity , the expression of AR target genes was quantitated by qRT-PCR .	To determine if elevated nuclear AR expression leads to increased AR transcriptional activity, the expression of AR target genes was quantitated by qRT-PCR.	5	12	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	5	6	10	11
Taken together , these results suggest that selenium disrupts AR signaling at multiple stages , including AR mRNA expression , mRNA stability , protein degradation , nuclear translocation , and recruitment of coregulators .	Taken together, these results suggest that selenium disrupts AR signaling at multiple stages, including AR mRNA expression, mRNA stability, protein degradation, nuclear translocation, and recruitment of coregulators.	9	19	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	AR	AR mRNA expression	ar	AR	AR	ar	16	17	9	10
Because these H3K4me1 positive , H3K4me3 negative regions exhibit striking cell type specificity XREF_BIBR , XREF_BIBR , we used this signature to characterize potential enhancers in prostatic LNCaP cells in which one of key regulatory transcriptional programs is mediated by the androgen receptor ( AR ) .	Because these H3K4me1 positive, H3K4me3 negative regions exhibit striking cell type specificity XREF_BIBR, XREF_BIBR, we used this signature to characterize potential enhancers in prostatic LNCaP cells in which one of key regulatory transcriptional programs is mediated by the androgen receptor (AR).	28	45	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	41	43	44	45
Thus , one could argue that these findings could be supported by more direct genetic manipulations ( e.g ., AR overexpression and knockdown ) , but increasing AR expression may not necessarily enhance AR activity ( as seen in 364 cells ) , transient transfections would influence viability ( similarly to manipulating AR activity in XREF_FIG ) , and stable transfections would involve long-term culture and thus experience the same caveats .	Thus, one could argue that these findings could be supported by more direct genetic manipulations (e.g., AR overexpression and knockdown), but increasing AR expression may not necessarily enhance AR activity (as seen in 364 cells), transient transfections would influence viability (similarly to manipulating AR activity in XREF_FIG), and stable transfections would involve long-term culture and thus experience the same caveats.	27	34	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	27	28	33	34
This paper discusses the structure of androgen receptor , current antiandrogen therapies , the emerging therapies that target the AR , epigenetic modulation of AR , and therapies targeting epigenetic modulation .	This paper discusses the structure of androgen receptor, current antiandrogen therapies, the emerging therapies that target the AR, epigenetic modulation of AR, and therapies targeting epigenetic modulation.	6	20	target	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	6	8	19	20
Furthermore , AR activation can be enhanced by AR acetylation induced by IL-4 in prostate cancer cells .	Furthermore, AR activation can be enhanced by AR acetylation induced by IL-4 in prostate cancer cells.	2	10	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AR	AR acetylation	ar	AR	AR	ar	8	9	2	3
Since a CRPC phenotype is associated with expression of the AR variant AR-V7 , which activates AR signaling in the absence of ligand XREF_BIBR XREF_BIBR XREF_BIBR , we examined the impact of VT-464 on AR-V7-mediated reporter activity in PC3 cells .	Since a CRPC phenotype is associated with expression of the AR variant AR-V7, which activates AR signaling in the absence of ligand XREF_BIBR XREF_BIBR XREF_BIBR, we examined the impact of VT-464 on AR-V7-mediated reporter activity in PC3 cells.	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	expression of the AR	ar	AR	AR	ar	10	11	16	17
HBC abrogated AR interaction with CaM , suppressed phosphorylation of AR Serine81 , and blocked the binding of AR to androgen response elements .	HBC abrogated AR interaction with CaM, suppressed phosphorylation of AR Serine81, and blocked the binding of AR to androgen response elements.	0	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	HBC abrogated AR interaction with CaM, suppressed phosphorylation of AR	ar	AR	AR	ar	10	11	18	19
We suggest that DNA dependent protein kinase phosphorylation of the androgen receptor , or an interacting component , helps target the androgen receptor for export from the nucleus .	We suggest that DNA dependent protein kinase phosphorylation of the androgen receptor, or an interacting component, helps target the androgen receptor for export from the nucleus.	3	23	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	DNA dependent protein kinase phosphorylation of the androgen receptor	androgen receptor	androgen receptor	androgen receptor	androgen receptor	10	12	21	23
RNF6 induced ubiquitination of AR promotes recruitment of AR co-activators .	RNF6 induced ubiquitination of AR promotes recruitment of AR co-activators.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	RNF6 induced ubiquitination of AR	ar	AR	AR	ar	4	5	8	9
Incubation of minced rat ventral prostate with 3 '-deoxyadenosine ( 3 '-dA ) prior to labeling with the androgen , tritiated 7 alpha , 17 alpha-dimethyl-19-nortestosterone , reduced the level of androgen receptor bound to chromatin and increased the level of cytosolic androgen receptor and the fraction of cytosolic androgen receptor that did not bind to DNA .	Incubation of minced rat ventral prostate with 3 '-deoxyadenosine (3 '-dA) prior to labeling with the androgen, tritiated 7 alpha, 17 alpha-dimethyl-19-nortestosterone, reduced the level of androgen receptor bound to chromatin and increased the level of cytosolic androgen receptor and the fraction of cytosolic androgen receptor that did not bind to DNA.	29	44	increased	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	androgen receptor	level of androgen receptor	androgen receptor	androgen receptor	level of cytosolic androgen receptor	androgen receptor	31	33	42	44
Other groups have shown that the binding of heparin to EGF decreases AR protein expression through activation of mammalian target of rapamycin and decreased translation AR mRNA [ XREF_BIBR , XREF_BIBR ] .	Other groups have shown that the binding of heparin to EGF decreases AR protein expression through activation of mammalian target of rapamycin and decreased translation AR mRNA [XREF_BIBR, XREF_BIBR].	6	26	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	binding of heparin to EGF decreases AR protein expression	ar	AR	AR	ar	12	13	25	26
This contrasts with the effect of R1881 at the KLK3 gene enhancer- increased enrichment of AR and histone acetylation ( XREF_FIG ) .	This contrasts with the effect of R1881 at the KLK3 gene enhancer- increased enrichment of AR and histone acetylation (XREF_FIG).	12	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR and histone acetylation	ar	AR	AR	ar	15	16	15	16
Conversely , the glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta mediated phosphorylation of the androgen receptor , thereby enabling androgen receptor driven transcription to occur .	Conversely, the glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta mediated phosphorylation of the androgen receptor, thereby enabling androgen receptor driven transcription to occur.	3	27	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta mediated phosphorylation of the androgen receptor	androgen receptor	androgen receptor	androgen receptor	androgen receptor	20	22	25	27
Expression of AR inhibited cell population growth of AR negative DTE cells at the G1 to S phase of the cell cycle .	Expression of AR inhibited cell population growth of AR negative DTE cells at the G1 to S phase of the cell cycle.	0	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Expression of AR	ar	AR	AR	ar	2	3	8	9
Transgenic overexpression of human AR in the Gendothelium of diabetic mice accelerates atherosclerosis formation and inhibition of endothelial AR reduces intracellular ROS , EC migration and proliferation .	Transgenic overexpression of human AR in the Gendothelium of diabetic mice accelerates atherosclerosis formation and inhibition of endothelial AR reduces intracellular ROS, EC migration and proliferation.	1	19	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	overexpression of human AR	ar	AR	AR	ar	4	5	18	19
YK11 is a selective androgen receptor modulator ( SARM ) , which activates AR without the N/C interaction .	YK11 is a selective androgen receptor modulator (SARM), which activates AR without the N/C interaction.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	4	6	13	14
Taken together , the results of these studies showed that CXCL12 mediated AR nuclear translocation in the absence of androgen and augmented AR accumulation in the presence of androgen .	Taken together, the results of these studies showed that CXCL12 mediated AR nuclear translocation in the absence of androgen and augmented AR accumulation in the presence of androgen.	10	23	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	CXCL12 mediated AR	ar	AR	AR	ar	12	13	22	23
Androgen receptor ( AR ) mRNA in the endometrium increased by treatment with E. Cotreatment of gilts with E and DHT did not alter the E induced AR mRNA increase .	Androgen receptor (AR) mRNA in the endometrium increased by treatment with E. Cotreatment of gilts with E and DHT did not alter the E induced AR mRNA increase.	0	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Androgen receptor	Androgen receptor	Androgen receptor	AR	AR	AR	0	2	27	28
Interestingly the interaction of AR with Src has been shown to lead to AR activation by phosphorylation of AR [ XREF_BIBR ] .	Interestingly the interaction of AR with Src has been shown to lead to AR activation by phosphorylation of AR [XREF_BIBR].	11	20	lead	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	AR	phosphorylation of AR	ar	AR	AR	ar	18	19	13	14
For this reason we constructed AR expression vectors in order to examine the hypotheses that AR expression above a threshold level would be required in order to activate the classical AR target genes in either the epithelial or the mesenchymal context .	For this reason we constructed AR expression vectors in order to examine the hypotheses that AR expression above a threshold level would be required in order to activate the classical AR target genes in either the epithelial or the mesenchymal context.	15	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	15	16	30	31
In this study , we found that overexpression of GDIalpha inhibits AR expression and downregulates AR activity .	In this study, we found that overexpression of GDIalpha inhibits AR expression and downregulates AR activity.	7	16	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	overexpression of GDIalpha inhibits AR expression	ar	AR	AR	ar	11	12	15	16
Some reports in prostate cancer have identified miRs in androgen receptor ( AR ) signaling , such as miR-21 , owing to AR binding on the defined promoter , was directly up-regulated by AR [ XREF_BIBR ] .	Some reports in prostate cancer have identified miRs in androgen receptor (AR) signaling, such as miR-21, owing to AR binding on the defined promoter, was directly up-regulated by AR [XREF_BIBR].	9	35	up-regulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	33	34	9	11
Consequently , HOXB13 suppresses the growth of AR expressing PCa cells , which can be counteracted by the addition of hormone activated AR .	Consequently, HOXB13 suppresses the growth of AR expressing PCa cells, which can be counteracted by the addition of hormone activated AR.	5	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expressing	ar	AR	AR	ar	7	8	22	23
Multiple mechanisms underlying continued activation of AR in CRPC tumors include AR gene amplification , increased AR expression , AR point mutations , expression of AR splice variants , and intratumoral production of androgen [ XREF_BIBR ] .	Multiple mechanisms underlying continued activation of AR in CRPC tumors include AR gene amplification, increased AR expression, AR point mutations, expression of AR splice variants, and intratumoral production of androgen [XREF_BIBR].	11	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	16	17	11	12
Expression of AR v567es variant increases the stability of full-length AR protein without increasing mRNA levels in LNCaP cells .	Expression of AR v567es variant increases the stability of full-length AR protein without increasing mRNA levels in LNCaP cells.	0	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Expression of AR	ar	AR	AR	ar	2	3	10	11
We observed that AR level increased gradually from 4 to 20 h after release from isoleucine blockade , suggesting the importance of AR in G 1 / S transition .	We observed that AR level increased gradually from 4 to 20 h after release from isoleucine blockade, suggesting the importance of AR in G 1 / S transition.	3	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR level	ar	AR	AR	ar	3	4	22	23
In addition to these genetic aberrations , elevated AR activity can be caused by anomalous androgen production , signal transduction cross-talk , altered AR co-factor expression or activity , or alternative AR splicing [ XREF_BIBR - XREF_BIBR ] .	In addition to these genetic aberrations, elevated AR activity can be caused by anomalous androgen production, signal transduction cross-talk, altered AR co-factor expression or activity, or alternative AR splicing [XREF_BIBR - XREF_BIBR].	8	26	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AR	AR co-factor expression	ar	AR	AR	ar	23	24	8	9
In contrast , co-expression of W183Abeta 1 AR with WTbeta 1 AR did not lead to the retention of WTbeta 1 AR ( XREF_FIG ) , consistent with the decreased propensity of W183Abeta 1 AR to associate with the WTbeta 1 AR ( XREF_FIG ; 4.7-fold increase in BRET 50 when compare with WTbeta 1 AR self-assembly ) .	In contrast, co-expression of W183Abeta 1 AR with WTbeta 1 AR did not lead to the retention of WTbeta 1 AR (XREF_FIG), consistent with the decreased propensity of W183Abeta 1 AR to associate with the WTbeta 1 AR (XREF_FIG; 4.7-fold increase in BRET 50 when compare with WTbeta 1 AR self-assembly).	3	34	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	AR	co-expression of W183Abeta 1 AR	ar	AR	AR	ar	7	8	21	22
Increased AR expression resulting from high copy numbers of the AR gene leads to constitutive activation of AR in the castrate environment and resistance to first generation antiandrogens such as bicalutamide [ XREF_BIBR ] .	Increased AR expression resulting from high copy numbers of the AR gene leads to constitutive activation of AR in the castrate environment and resistance to first generation antiandrogens such as bicalutamide [XREF_BIBR].	1	18	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	1	2	17	18
Since , PP1C plays an important role in nuclear retention of AR by dephosphorylating AR , it is likely that decreased LMTK2 protein and/or activity would result in an increase in AR activity and sensitivity to androgens , events precisely observed in CRPC .	Since, PP1C plays an important role in nuclear retention of AR by dephosphorylating AR, it is likely that decreased LMTK2 protein and/or activity would result in an increase in AR activity and sensitivity to androgens, events precisely observed in CRPC.	3	15	retention	Positive_activation_token_2_noun	Positive_activation	Positive_activation	AR	dephosphorylating AR	ar	AR	AR	ar	14	15	11	12
The RNF6 induced non canonical polyubiquitination of AR can promote the binding of AR co-activators such as ARA54 that have ubiquitin binding domains ( XREF_FIG ) .	The RNF6 induced non canonical polyubiquitination of AR can promote the binding of AR co-activators such as ARA54 that have ubiquitin binding domains (XREF_FIG).	5	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	polyubiquitination of AR	ar	AR	AR	ar	7	8	13	14
The androgen independence of the adult prostate epithelial stem cells is documented by the fact that epithelial morphogenesis occurs even when androgen receptor is not expressed by prostate epithelial cells as long as there is expression and signaling of AR in the supporting stromal cells [ XREF_BIBR ] .	The androgen independence of the adult prostate epithelial stem cells is documented by the fact that epithelial morphogenesis occurs even when androgen receptor is not expressed by prostate epithelial cells as long as there is expression and signaling of AR in the supporting stromal cells [XREF_BIBR].	34	44	is expression and signaling	Positive_activation_copula_1	Positive_activation	Positive_activation	AR	expression and signaling of AR	ar	AR	AR	ar	39	40	39	40
Testosterone passes through the cell membrane and into the cytoplasm where it , or its more physiologically effective metabolite 5alpha-dihydrotestosterone ( DHT ) , binds to and activates the androgen receptor ( AR ) .	Testosterone passes through the cell membrane and into the cytoplasm where it, or its more physiologically effective metabolite 5alpha-dihydrotestosterone (DHT), binds to and activates the androgen receptor (AR).	9	33	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	32	33	29	31
In assays performed using this cell line transfected with the cDNA for the androgen receptor , flutamide is a pure antagonist , and 2-hydroxyflutamide , while a more potent androgen receptor ( AR ) antagonist , activates the AR at higher concentrations .	In assays performed using this cell line transfected with the cDNA for the androgen receptor, flutamide is a pure antagonist, and 2-hydroxyflutamide, while a more potent androgen receptor (AR) antagonist, activates the AR at higher concentrations.	29	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	29	31	38	39
Several studies in human PCa cells have found that AKT can phosphorylate AR at a site in its N-terminal domain ( Ser213 ) and thereby decrease AR transcriptional activity or enhance its ubiquitylation and degradation by MDM2 , while other studies show that AKT mediated phosphorylation of AR can increase AR protein and activity .	Several studies in human PCa cells have found that AKT can phosphorylate AR at a site in its N-terminal domain (Ser213) and thereby decrease AR transcriptional activity or enhance its ubiquitylation and degradation by MDM2, while other studies show that AKT mediated phosphorylation of AR can increase AR protein and activity.	43	51	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AKT mediated phosphorylation of AR	ar	AR	AR	ar	47	48	50	51
Finally , MDV3100 reduces translocation of the AR from the cytoplasm into the nucleus , blocking binding of the AR to androgen response elements of DNA , with resultant tumoricidal activity as opposed to the cytostatic activity that first generation anti-androgens exhibit in these model systems 8 ( XREF_FIG ) .	Finally, MDV3100 reduces translocation of the AR from the cytoplasm into the nucleus, blocking binding of the AR to androgen response elements of DNA, with resultant tumoricidal activity as opposed to the cytostatic activity that first generation anti-androgens exhibit in these model systems 8 (XREF_FIG).	2	30	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	MDV3100 reduces translocation of the AR from the cytoplasm	ar	AR	AR	ar	7	8	19	20
The developmental profile of AR expression in the mouse cortex and hippocampus not only implicates AR in the organization and function of neural circuits for higher cognitive function , such as learning and memory , but also supports AR as a direct target through which different levels of circulating androgens can differentially regulate cortical and hippocampal development and function between the sexes .	The developmental profile of AR expression in the mouse cortex and hippocampus not only implicates AR in the organization and function of neural circuits for higher cognitive function, such as learning and memory, but also supports AR as a direct target through which different levels of circulating androgens can differentially regulate cortical and hippocampal development and function between the sexes.	4	39	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	4	5	38	39
A polyclonal antibody , PA1 , raised in a rabbit against fusion proteins containing fragments of the human prostatic androgen receptor ( AR ) was used to map the distribution of AR like immunoreactivity in the brains of adult male and female cynomolgus monkeys .	A polyclonal antibody, PA1, raised in a rabbit against fusion proteins containing fragments of the human prostatic androgen receptor (AR) was used to map the distribution of AR like immunoreactivity in the brains of adult male and female cynomolgus monkeys.	2	23	raised	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	22	23	19	21
These findings also conclude that exogenous AR expression was able to induce a classical androgen dependent AR transcriptome in , such as KLK3 , KLK2 FKBP5 , in epithelial type cells but not in mesenchymal type cells .	These findings also conclude that exogenous AR expression was able to induce a classical androgen dependent AR transcriptome in, such as KLK3, KLK2 FKBP5, in epithelial type cells but not in mesenchymal type cells.	6	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	6	7	16	17
Serine 81 phosphorylation of AR is strongly associated with PCa growth and proliferation and induces AR transcriptional activity [ XREF_BIBR , XREF_BIBR ] .	Serine 81 phosphorylation of AR is strongly associated with PCa growth and proliferation and induces AR transcriptional activity [XREF_BIBR, XREF_BIBR].	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Serine 81 phosphorylation of AR	ar	AR	AR	ar	4	5	15	16
Thus , overexpression of decoy AR 1-558 allows the AR to be in the nucleus yet still prevents the interaction of endogenous AR with AREs to reduce transcription of genes regulated by AR .	Thus, overexpression of decoy AR 1-558 allows the AR to be in the nucleus yet still prevents the interaction of endogenous AR with AREs to reduce transcription of genes regulated by AR.	2	23	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	overexpression of decoy AR	ar	AR	AR	ar	5	6	22	23
Because we also observed ~ 3-fold elevation of AR expression in FOXA1 RNAi treated cells ( XREF_SUPPLEMENTARY ) , we tested the possibility that increased AR expression might trigger these effects , finding that AR overexpression alone was insufficient to induce AR reprogramming ( XREF_SUPPLEMENTARY ) .	Because we also observed ~ 3-fold elevation of AR expression in FOXA1 RNAi treated cells (XREF_SUPPLEMENTARY), we tested the possibility that increased AR expression might trigger these effects, finding that AR overexpression alone was insufficient to induce AR reprogramming (XREF_SUPPLEMENTARY).	34	42	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR overexpression	ar	AR	AR	ar	34	35	41	42
Co-expression of FGFR1 and AR causes AR variants .	Co-expression of FGFR1 and AR causes AR variants.	0	7	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Co-expression of FGFR1 and AR	ar	AR	AR	ar	4	5	6	7
Allergic rhinitis ( AR ) has been previously associated with chronic rhinosinusitis ( CRS ) by virtue of similar inflammatory profiles and increased prevalence of AR in patients with CRS XREF_BIBR , XREF_BIBR .	Allergic rhinitis (AR) has been previously associated with chronic rhinosinusitis (CRS) by virtue of similar inflammatory profiles and increased prevalence of AR in patients with CRS XREF_BIBR, XREF_BIBR.	0	26	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Allergic rhinitis	Allergic rhinitis	Allergic rhinitis	AR	AR	AR	0	2	25	26
Interestingly , overexpression of AR DeltaLBD increased level of the endogenous full length AR , which was also observed in AR DeltaLBD transfected LNCaP AD cells ( XREF_SUPPLEMENTARY ) indicating that overexpression of AR DeltaLBD somehow increased the stability of the full length AR .	Interestingly, overexpression of AR DeltaLBD increased level of the endogenous full length AR, which was also observed in AR DeltaLBD transfected LNCaP AD cells (XREF_SUPPLEMENTARY) indicating that overexpression of AR DeltaLBD somehow increased the stability of the full length AR.	2	18	increased	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	AR	overexpression of AR	ar	AR	level of the endogenous full length AR	ar	4	5	13	14
At pubertal onset , intra-testicular testosterone concentration significantly increases which induces expression of AR , subsequently causing an AR signaling cascade resulting in decreased AMH concentration and prostate gland growth and differentiation .	At pubertal onset, intra-testicular testosterone concentration significantly increases which induces expression of AR, subsequently causing an AR signaling cascade resulting in decreased AMH concentration and prostate gland growth and differentiation.	5	20	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	testosterone concentration significantly increases which induces expression of AR	ar	AR	AR	ar	13	14	18	19
Persistent androgen receptor ( AR ) transcriptional activity underlies resistance to AR targeted therapy and progression to lethal castration resistant prostate cancer ( CRPC ) .	Persistent androgen receptor (AR) transcriptional activity underlies resistance to AR targeted therapy and progression to lethal castration resistant prostate cancer (CRPC).	1	12	underlies	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	1	3	11	12
Hormone or androgen deprivation therapy ( ADT ) , which acts to suppress the androgen receptor ( AR ) signaling by androgen depletion or AR antagonists , is still the principal treatment option for locally advanced and metastatic prostate cancers .	Hormone or androgen deprivation therapy (ADT), which acts to suppress the androgen receptor (AR) signaling by androgen depletion or AR antagonists, is still the principal treatment option for locally advanced and metastatic prostate cancers.	14	25	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	24	25	14	16
Overexpression of the AR increased both percentage of SA-beta-Gal-positive cells and cell size and DHT enhanced the AR effects ( XREF_FIG ) .	Overexpression of the AR increased both percentage of SA-beta-Gal-positive cells and cell size and DHT enhanced the AR effects (XREF_FIG).	0	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Overexpression of the AR	ar	AR	AR	ar	3	4	17	18
Activin A promotes migration of prostate cancer cells to osteoblasts , elevates the AR gene transcription through Smads through binding to AR promoter , and induces nuclear translocation of AR to interact with Smad3 .	Activin A promotes migration of prostate cancer cells to osteoblasts, elevates the AR gene transcription through Smads through binding to AR promoter, and induces nuclear translocation of AR to interact with Smad3.	0	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Activin A promotes migration of prostate cancer cells to osteoblasts, elevates the AR gene transcription	ar	AR	AR	ar	13	14	29	30
Interestingly , AR/p52 -02 also reduced cytoplasmic levels of pAR ser81 in C4-2 cells , but not in LNCaP , under the -R condition Inhibitor AR/p52 -02 induces ubiquitination of the AR , thereby reducing AR stability .	Interestingly, AR/p52 -02 also reduced cytoplasmic levels of pAR ser81 in C4-2 cells, but not in LNCaP, under the -R condition Inhibitor AR/p52 -02 induces ubiquitination of the AR, thereby reducing AR stability.	22	36	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	-R condition Inhibitor AR/p52 -02 induces ubiquitination of the AR	ar	AR	AR	ar	31	32	35	36
It was later discovered that the increased clusterin levels are most likely due to castration induced apoptosis of the prostatic epithelium rather than direct action of the androgen receptor ( AR ) .	It was later discovered that the increased clusterin levels are most likely due to castration induced apoptosis of the prostatic epithelium rather than direct action of the androgen receptor (AR).	15	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	30	31	27	29
The mode of action of these new compounds is either inhibition of androgen synthesis at the CYP17A1 enzyme covering also adrenal and intracrine androgen sources , or a full androgen receptor ( AR ) blockade antagonizes the AR function by directly binding this transcription factor with high affinity .	The mode of action of these new compounds is either inhibition of androgen synthesis at the CYP17A1 enzyme covering also adrenal and intracrine androgen sources, or a full androgen receptor (AR) blockade antagonizes the AR function by directly binding this transcription factor with high affinity.	29	38	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	29	31	37	38
PP1 inhibition enhanced proteasome mediated AR degradation , while PP1alpha overexpression increased AR expression and markedly enhanced AR transcriptional activity .	PP1 inhibition enhanced proteasome mediated AR degradation, while PP1alpha overexpression increased AR expression and markedly enhanced AR transcriptional activity.	0	19	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	PP1 inhibition enhanced proteasome mediated AR degradation, while PP1alpha overexpression increased AR expression	ar	AR	AR	ar	12	13	17	18
Recent evidence suggests that CRPC is caused by augmented androgen and androgen receptor ( AR ) signaling involving AR hypersensitivity , promiscuous activation of the AR , de novo production of androgens and activation of the AR by cytokines and growth factors ; these findings have led to the development of novel agents targeting AR signaling .	Recent evidence suggests that CRPC is caused by augmented androgen and androgen receptor (AR) signaling involving AR hypersensitivity, promiscuous activation of the AR, de novo production of androgens and activation of the AR by cytokines and growth factors; these findings have led to the development of novel agents targeting AR signaling.	6	19	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	11	13	18	19
CRPC which is resistant to castration is thought to result from increased activation of the androgen and androgen receptor ( AR ) signaling pathway , which may be augmented by AR coactivators .	CRPC which is resistant to castration is thought to result from increased activation of the androgen and androgen receptor (AR) signaling pathway, which may be augmented by AR coactivators.	15	31	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	30	31	17	19
Depletion of BMI1 decreases AR protein levels and inhibits AR signaling pathway in prostate cancer cells .	Depletion of BMI1 decreases AR protein levels and inhibits AR signaling pathway in prostate cancer cells.	2	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	BMI1 decreases AR protein levels	ar	AR	AR	ar	4	5	9	10
XREF_BIBR The potent activity of cEt modified oligonucleotides in skeletal muscle has also been demonstrated for an androgen receptor ( AR ) targeting ASO in AR transgenic mice .	XREF_BIBR The potent activity of cEt modified oligonucleotides in skeletal muscle has also been demonstrated for an androgen receptor (AR) targeting ASO in AR transgenic mice.	17	27	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	17	19	25	26
These include AR gene amplification , increased AR expression , AR point mutations frequently occurring in the ligand binding domain that broaden ligand specificity , overexpression of AR coactivators , and intratumoral production of androgen .	These include AR gene amplification, increased AR expression, AR point mutations frequently occurring in the ligand binding domain that broaden ligand specificity, overexpression of AR coactivators, and intratumoral production of androgen.	2	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	7	8	2	3
Interestingly , Ack1 or Src knockdown or dasatinib did not inhibit EGF induced AR Tyr 267 phosphorylation or EGF stimulated AR activity , suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr 267 .	Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF induced AR Tyr 267 phosphorylation or EGF stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr 267.	2	21	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	AR	Ack1 or Src knockdown or dasatinib did not inhibit EGF induced AR	ar	AR	AR	ar	13	14	20	21
Interestingly , overexpression of the beta 2 AR increases phosphorylation and channel activity of K v 7.1 independent of agonist stimulation of the beta 2 AR .	Interestingly, overexpression of the beta 2 AR increases phosphorylation and channel activity of K v 7.1 independent of agonist stimulation of the beta 2 AR.	2	26	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	overexpression of the beta 2 AR	ar	AR	AR	ar	7	8	25	26
Ectopic expression of AR reverses MSA suppression of both AR trans-activation and cell growth , suggesting that AR signaling is a key mediator of MSA effect .	Ectopic expression of AR reverses MSA suppression of both AR trans-activation and cell growth, suggesting that AR signaling is a key mediator of MSA effect.	1	10	reverses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	expression of AR	ar	AR	AR	ar	3	4	9	10
To further assess whether AR mRNA was autologously regulated , neonatal male rats were treated with the androgen receptor antagonist , flutamide .	To further assess whether AR mRNA was autologously regulated, neonatal male rats were treated with the androgen receptor antagonist, flutamide.	4	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	17	19	4	5
Indeed , CDK1 phosphorylates AR and thereby enhances AR activity during progression of castration resistant PCa [ XREF_BIBR ] .	Indeed, CDK1 phosphorylates AR and thereby enhances AR activity during progression of castration resistant PCa [XREF_BIBR].	2	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	CDK1 phosphorylates AR	ar	AR	AR	ar	4	5	8	9
Our findings suggest that the levels of AR potentiate the recruitment of the AR , as well as components of the basic transcription machinery , to chromatin and affect the acetylation of histones in the presence of low levels of androgens .	Our findings suggest that the levels of AR potentiate the recruitment of the AR, as well as components of the basic transcription machinery, to chromatin and affect the acetylation of histones in the presence of low levels of androgens.	5	14	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	levels of AR	ar	AR	AR	ar	7	8	13	14
AR Ser515 and Ser578 phosphorylation promote AR transcriptional activity , since PSA-luciferase activity was inhibited in CWR-R1 cells cultured in low-androgen conditions when either or both serine residues were mutated to alanine , an amino acid that can not be phosphorylated [ XREF_BIBR ] .	AR Ser515 and Ser578 phosphorylation promote AR transcriptional activity, since PSA-luciferase activity was inhibited in CWR-R1 cells cultured in low-androgen conditions when either or both serine residues were mutated to alanine, an amino acid that can not be phosphorylated [XREF_BIBR].	0	8	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR Ser515 and Ser578 phosphorylation	ar	AR	AR	ar	0	1	6	7
The AR dependent reporter activity in PC3 cells , which does not express AR was stimulated by transient overexpression of wild-type AR and two mutant full length AR with respect to the vector plasmid control .	The AR dependent reporter activity in PC3 cells, which does not express AR was stimulated by transient overexpression of wild-type AR and two mutant full length AR with respect to the vector plasmid control.	1	27	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AR	overexpression of wild-type AR	ar	AR	AR	ar	21	22	1	2
RNF6 dependent AR ubiquitination is enhanced by androgen treatment , promotes AR transcriptional activity , and selectively drives androgen dependent expression of a subset of AR target genes .	RNF6 dependent AR ubiquitination is enhanced by androgen treatment, promotes AR transcriptional activity, and selectively drives androgen dependent expression of a subset of AR target genes.	2	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR ubiquitination	ar	AR	AR	ar	2	3	11	12
Further development , specificity studies , and mechanistic characterization are still needed , but the compounds identified in this study inhibit LARG mediated RhoA nucleotide exchange with micromolar potency in vitro .	Further development, specificity studies, and mechanistic characterization are still needed, but the compounds identified in this study inhibit LARG mediated RhoA nucleotide exchange with micromolar potency in vitro.	21	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	21	22	23	24
LARG silence inhibited RhoA and ROCK pathway and CRC cell invasion .	LARG silence inhibited RhoA and ROCK pathway and CRC cell invasion.	0	6	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	0	1	3	4
PDZ-RhoGEF and LARG recruited by Class B plexins activate RhoA , mediating an important branch of the signaling pathway .	PDZ-RhoGEF and LARG recruited by Class B plexins activate RhoA, mediating an important branch of the signaling pathway.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	2	3	9	10
By interaction with FAK , LARG activates RGMa and thereby increases RhoA activation ( XREF_FIG ) .	By interaction with FAK, LARG activates RGMa and thereby increases RhoA activation (XREF_FIG).	5	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	5	6	11	12
Double knockdown of LARG and GEF-H1 totally abrogated RhoA activation .	Double knockdown of LARG and GEF-H1 totally abrogated RhoA activation.	1	9	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	3	4	8	9
LARG may activate RhoA in the limited region of the cell , such as the growing tip of the neurites .	LARG may activate RhoA in the limited region of the cell, such as the growing tip of the neurites.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	0	1	3	4
Y16 binds to the junction site of the DH-PH domains of LARG with a ~ 80 nM K ( d ) and suppresses LARG catalyzed RhoA activation dose dependently .	Y16 binds to the junction site of the DH-PH domains of LARG with a ~ 80 nM K (d) and suppresses LARG catalyzed RhoA activation dose dependently.	22	27	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	23	24	25	26
This suggests a potential pharmacophore for inhibiting LARG stimulated RhoA nucleotide exchange which may be explained by the long shallow pocket of the LARG and RhoA interaction site XREF_BIBR .	This suggests a potential pharmacophore for inhibiting LARG stimulated RhoA nucleotide exchange which may be explained by the long shallow pocket of the LARG and RhoA interaction site XREF_BIBR.	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	7	8	9	10
First , we showed that LARG could promote RhoA activation in platelets , a phenomenon not observed in the Williams et.al paper .	First, we showed that LARG could promote RhoA activation in platelets, a phenomenon not observed in the Williams et.al paper.	5	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	5	6	8	9
Our data from mice lacking Galpha 12 / Galpha 13 or LARG specifically in SMCs suggest that Galpha 12 / Galpha 13 promotes VSMC differentiation through LARG mediated activation of RhoA .	Our data from mice lacking Galpha 12 / Galpha 13 or LARG specifically in SMCs suggest that Galpha 12 / Galpha 13 promotes VSMC differentiation through LARG mediated activation of RhoA.	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	26	27	30	31
While LARG activates Rho to inhibit outgrowth , LMO4 most likely does so by regulating gene expression .	While LARG activates Rho to inhibit outgrowth, LMO4 most likely does so by regulating gene expression.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	Rho	Rho	Rho	1	2	3	4
Compound Selectivity for LARG stimulated RhoA nucleotide binding .	Compound Selectivity for LARG stimulated RhoA nucleotide binding.	1	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	3	4	5	6
This is in line with LARG mediated activation of RhoA reported for other repulsive cues such as S1P , semaphorin4D , and repulsive guidance molecule RGMa .	This is in line with LARG mediated activation of RhoA reported for other repulsive cues such as S1P, semaphorin4D, and repulsive guidance molecule RGMa.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	5	6	9	10
The data in this report suggest that LARG plays a critical role in plexin-B1 signaling to stimulate Rho activation and cytoskeletal reorganization .	The data in this report suggest that LARG plays a critical role in plexin-B1 signaling to stimulate Rho activation and cytoskeletal reorganization.	7	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	Rho	Rho	Rho	7	8	17	18
Since then , LARG- mediated Rho activation has been shown to be important in prostate cancer ( PC-3 ) and breast cancer ( MDA-MB-435 ) cell morphology , motility , and invasion upon extracellular stimulation by the GPCR ligands bombesin , thrombin , and lysophosphatidic acid XREF_BIBR , XREF_BIBR , XREF_BIBR .	Since then, LARG- mediated Rho activation has been shown to be important in prostate cancer (PC-3) and breast cancer (MDA-MB-435) cell morphology, motility, and invasion upon extracellular stimulation by the GPCR ligands bombesin, thrombin, and lysophosphatidic acid XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG-	LARG-	LARG-	Rho	Rho	Rho	3	4	5	6
To assess the role of LARG in human platelets , aggregation assays were performed with freshly isolated human platelets in the presence of Y16 , a LARG inhibitor developed by Dr. Yi Zheng ' s group ( Cincinnati Children ' s Hospital ) , which inhibits LARG mediated Rho activation in a dose dependent manner .	To assess the role of LARG in human platelets, aggregation assays were performed with freshly isolated human platelets in the presence of Y16, a LARG inhibitor developed by Dr. Yi Zheng 's group (Cincinnati Children 's Hospital), which inhibits LARG mediated Rho activation in a dose dependent manner.	45	49	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	Rho	Rho	Rho	46	47	48	49
Nevertheless , this and the activation of RhoA by LARG do not preclude an effect of loss of CD98hc on p190 RhoGAP as well .	Nevertheless, this and the activation of RhoA by LARG do not preclude an effect of loss of CD98hc on p190 RhoGAP as well.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	9	10	7	8
Activation of RhoA by LARG and PDZ-RhoGEF is enhanced when they are tyrosine phosphorylated by FAK .	Activation of RhoA by LARG and PDZ-RhoGEF is enhanced when they are tyrosine phosphorylated by FAK.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	4	5	2	3
Thus , Sm specific LARG deficient mice phenocopy Sm-12/13-KO mice , indicating that the G 12 / G 13 -dependent differentiation of VSMCs in vivo involves LARG dependent activation of RhoA .	Thus, Sm specific LARG deficient mice phenocopy Sm-12/13-KO mice, indicating that the G 12 / G 13 -dependent differentiation of VSMCs in vivo involves LARG dependent activation of RhoA.	26	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	26	27	30	31
Active Galpha 13 has been shown to directly interact and activate p115RhoGEF [ XREF_BIBR ] , while another member of p115RhoGEF , LARG , interacts with Galpha q and Galpha 12/13 to activate RhoA [ XREF_BIBR ] .	Active Galpha 13 has been shown to directly interact and activate p115RhoGEF [XREF_BIBR], while another member of p115RhoGEF, LARG, interacts with Galpha q and Galpha 12/13 to activate RhoA [XREF_BIBR].	20	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	22	23	33	34
However , it is as yet unclear whether the RhoA activation by LARG is required for abscission .	However, it is as yet unclear whether the RhoA activation by LARG is required for abscission.	9	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	12	13	9	10
We attempted to obtain more insight into the mechanism of LARG mediated RhoA activation .	We attempted to obtain more insight into the mechanism of LARG mediated RhoA activation.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	10	11	12	13
Notably , Sema4D is known to activate the MAPK pathway , which is dependent on the C-terminus of plexin-B1 and LARG mediated activation of RhoA [ XREF_BIBR ] .	Notably, Sema4D is known to activate the MAPK pathway, which is dependent on the C-terminus of plexin-B1 and LARG mediated activation of RhoA [XREF_BIBR].	18	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	20	21	24	25
Several downstream molecular components are involved in the DC-SIGN mediated internalization of viral particles ; stimulation of DC-SIGN by HIV-1 gp120 activates the Rho guanine nucleotide-exchange factor , LARG , which in turn activates Rho-GTPases and recruits scaffold molecules such as Leukocyte specific protein 1 ( LSP1 ) , KSR1 , CNKs and Rho to form a signalosome complex XREF_BIBR .	Several downstream molecular components are involved in the DC-SIGN mediated internalization of viral particles; stimulation of DC-SIGN by HIV-1 gp120 activates the Rho guanine nucleotide-exchange factor, LARG, which in turn activates Rho-GTPases and recruits scaffold molecules such as Leukocyte specific protein 1 (LSP1), KSR1, CNKs and Rho to form a signalosome complex XREF_BIBR.	21	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	Rho	Rho	Rho	28	29	23	24
One possible explanation is that LARG contributes to the neurite retraction by activating any of the Rho family GTPases other than RhoA ( such as RhoB or RhoC ) or other cytoskeletal regulators that promote neurite retraction .	One possible explanation is that LARG contributes to the neurite retraction by activating any of the Rho family GTPases other than RhoA (such as RhoB or RhoC) or other cytoskeletal regulators that promote neurite retraction.	5	18	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	Rho	Rho	Rho	5	6	16	17
G04 was able to inhibit the nucleotide exchange of RhoA catalyzed by LARG dose-dependently ( XREF_FIG ) but was inactive in affecting Cdc42 and Rac1 exchange catalyzed by their selective GEFs , intersectin and TrioN , respectively ( data not shown ) .	G04 was able to inhibit the nucleotide exchange of RhoA catalyzed by LARG dose-dependently (XREF_FIG) but was inactive in affecting Cdc42 and Rac1 exchange catalyzed by their selective GEFs, intersectin and TrioN, respectively (data not shown).	7	13	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	12	13	9	10
PDZ-RhoGEF and LARG are specific activators of RhoA , but do not activate other members of the RhoGTPase family .	PDZ-RhoGEF and LARG are specific activators of RhoA, but do not activate other members of the RhoGTPase family.	0	8	are specific activators	Positive_activation_copula_1	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	2	3	7	8
It has been proposed that Dia1 , LARG , and RhoA constitute a positive feedback loop to potentiate the RhoA signaling pathway .	It has been proposed that Dia1, LARG, and RhoA constitute a positive feedback loop to potentiate the RhoA signaling pathway.	5	21	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	7	8	19	20
This suggests the possibility that LARG contributes to neurite retraction by locally activating RhoA through this positive feedback mechanism .	This suggests the possibility that LARG contributes to neurite retraction by locally activating RhoA through this positive feedback mechanism.	5	14	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	5	6	13	14
LARG then binds and activates RhoA GTPase in response to EGF or FBS stimulation in a RSK2 dependent manner .	LARG then binds and activates RhoA GTPase in response to EGF or FBS stimulation in a RSK2 dependent manner.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	0	1	5	6
RSK2 Phosphorylates LARG and Induces LARG Dependent RhoA Activation .	RSK2 Phosphorylates LARG and Induces LARG Dependent RhoA Activation.	0	8	Induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	RSK2 Phosphorylates LARG	larg	RhoA	RhoA	rhoa	2	3	7	8
The role of Lbc family specific structure features for LARG mediated RhoA activation in cells .	The role of Lbc family specific structure features for LARG mediated RhoA activation in cells.	1	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	9	10	11	12
G 12 / G 13 promotes VSMC differentiation through LARG mediated activation of RhoA .	G 12 / G 13 promotes VSMC differentiation through LARG mediated activation of RhoA.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	9	10	13	14
We found that LARG could complex with RhoA , but not Rac or Cdc42 , in vitro , and that expression of LARG caused an increase in the levels of the activated GTP bound form of RhoA , but not Rac1 or Cdc42 , in vivo .	We found that LARG could complex with RhoA, but not Rac or Cdc42, in vitro, and that expression of LARG caused an increase in the levels of the activated GTP bound form of RhoA, but not Rac1 or Cdc42, in vivo.	20	37	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	expression of LARG	larg	RhoA	RhoA	rhoa	22	23	36	37
We show that in response to these signals RSK2 directly binds the RhoGEF LARG and phosphorylates it , thereby promoting LARG activation of RhoA GTPases .	We show that in response to these signals RSK2 directly binds the RhoGEF LARG and phosphorylates it, thereby promoting LARG activation of RhoA GTPases.	20	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	20	21	23	24
These data point out an important role for ICAM-1 , Ect2 and LARG signalling in controlling RhoA mediated endothelial pore confinement and EC barrier protection during neutrophil diapedesis .	These data point out an important role for ICAM-1, Ect2 and LARG signalling in controlling RhoA mediated endothelial pore confinement and EC barrier protection during neutrophil diapedesis.	8	17	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	12	13	16	17
These data demonstrate that LARG is the first functional Dbl protein mutated in cancer and indicate LARG mediated activation of RhoA may play a role in the development of human leukemias .	These data demonstrate that LARG is the first functional Dbl protein mutated in cancer and indicate LARG mediated activation of RhoA may play a role in the development of human leukemias.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	16	17	20	21
Clearly , additional studies will be necessary to identify the spatial and temporal patterns of RhoA activation that are necessary for cell migration and to determine whether LARG ( and other RhoGEFs ) activate RhoA within specific cellular compartments .	Clearly, additional studies will be necessary to identify the spatial and temporal patterns of RhoA activation that are necessary for cell migration and to determine whether LARG (and other RhoGEFs) activate RhoA within specific cellular compartments.	27	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	27	28	34	35
Force directly applied to integrins triggers Rho activation through the activation of two guanine nucleotide exchange factors ( GEFs ) , LARG and GEF-H1 [ XREF_BIBR ] .	Force directly applied to integrins triggers Rho activation through the activation of two guanine nucleotide exchange factors (GEFs), LARG and GEF-H1 [XREF_BIBR].	5	25	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	Rho	Rho	Rho	21	22	6	7
Rather , Galpha 12/13 activates RhoGEFs , e.g ., p115RhoGEF or LARG , which activate Rho , and then Rho directly binds to and activates PLC-epsilon .	Rather, Galpha 12/13 activates RhoGEFs, e.g., p115RhoGEF or LARG, which activate Rho, and then Rho directly binds to and activates PLC-epsilon.	4	16	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	Rho	Rho	Rho	11	12	15	16
Thus , the mechanism of RGMa induced activation of RhoA by LARG can not be explained by alteration of association of Unc5B with LARG in the ligand dependent manner .	Thus, the mechanism of RGMa induced activation of RhoA by LARG can not be explained by alteration of association of Unc5B with LARG in the ligand dependent manner.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	11	12	9	10
LARG , which is a RhoGEF , is recruited to this receptor complex and induces RhoA activation .	LARG, which is a RhoGEF, is recruited to this receptor complex and induces RhoA activation.	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	0	1	15	16
It therefore provides us a starting point toward a more potent inhibitor to RhoA activation catalyzed by LARG .	It therefore provides us a starting point toward a more potent inhibitor to RhoA activation catalyzed by LARG.	13	18	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	17	18	13	14
The role of S1P 2 in SM differentiation was also recently confirmed since its activation was required for the expression of SM specific alpha-actin after arterial injury XREF_BIBR and LARG mediated RhoA activation leading to SM differentiation XREF_BIBR .	The role of S1P 2 in SM differentiation was also recently confirmed since its activation was required for the expression of SM specific alpha-actin after arterial injury XREF_BIBR and LARG mediated RhoA activation leading to SM differentiation XREF_BIBR.	27	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	29	30	31	32
We then sought to investigate whether CYLD mediated deubiquitination of LARG could promote RhoA activity by enhancing the GEF activity of LARG .	We then sought to investigate whether CYLD mediated deubiquitination of LARG could promote RhoA activity by enhancing the GEF activity of LARG.	6	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	CYLD mediated deubiquitination of LARG	larg	RhoA	RhoA	rhoa	10	11	13	14
We have previously demonstrated that the LARG protein activates RhoA , a member of the Rho family of small GTPases , by catalyzing the exchange of GTP for GDP .	We have previously demonstrated that the LARG protein activates RhoA, a member of the Rho family of small GTPases, by catalyzing the exchange of GTP for GDP.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	6	7	9	10
In this study , we provide the first evidence that LARG mediated activation of RhoA is modulated by cylindromatosis ( CYLD ) , a deubiquitinase involved in the regulation of nuclear factor kappaB ( NF-kappaB ) and several other signaling pathways XREF_BIBR - XREF_BIBR .	In this study, we provide the first evidence that LARG mediated activation of RhoA is modulated by cylindromatosis (CYLD), a deubiquitinase involved in the regulation of nuclear factor kappaB (NF-kappaB) and several other signaling pathways XREF_BIBR - XREF_BIBR.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	10	11	14	15
PDZ-RhoGEF and LARG activate Rho , which then activates Rho kinase ( ROCK ) causing actin depolymerization and growth cone collapse [ XREF_BIBR ] ( XREF_FIG ) .	PDZ-RhoGEF and LARG activate Rho, which then activates Rho kinase (ROCK) causing actin depolymerization and growth cone collapse [XREF_BIBR] (XREF_FIG).	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	Rho	Rho	Rho	2	3	4	5
RSK2 mediated phosphorylation of LARG and subsequent activation of RhoA GTPase promote cellular migration and invasion .	RSK2 mediated phosphorylation of LARG and subsequent activation of RhoA GTPase promote cellular migration and invasion.	0	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LARG	RSK2 mediated phosphorylation of LARG	larg	RhoA	RhoA	rhoa	4	5	9	10
XREF_BIBR Consistently , our study proved that LARG silence reduced RhoA and ROCK activation , SRF activation and CRC cell invasion induced by FMNL2 .	XREF_BIBR Consistently, our study proved that LARG silence reduced RhoA and ROCK activation, SRF activation and CRC cell invasion induced by FMNL2.	7	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	7	8	10	11
Both PDZ-RhoGEF and LARG , a GEF containing a PH domain , can be phosphorylated by FAK in response to thrombin , thereby enhancing the activation of Rho [ XREF_BIBR ] .	Both PDZ-RhoGEF and LARG, a GEF containing a PH domain, can be phosphorylated by FAK in response to thrombin, thereby enhancing the activation of Rho [XREF_BIBR].	1	29	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG, a GEF containing a PH domain, can be phosphorylated	larg	Rho	Rho	rho	3	4	27	28
The LARG ( leukemia associated Rho GEF ) protein mediates activation of RhoA and signals for bleb associated cancer evasion [ XREF_BIBR ] .	The LARG (leukemia associated Rho GEF) protein mediates activation of RhoA and signals for bleb associated cancer evasion [XREF_BIBR].	0	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	1	2	12	13
Activated G alpha q , as well as G alpha 12 and G alpha 13 , cooperated with LARG and caused synergistic activation of RhoA , suggesting that all three G alpha subunits stimulate LARG mediated activation of RhoA .	Activated G alpha q, as well as G alpha 12 and G alpha 13, cooperated with LARG and caused synergistic activation of RhoA, suggesting that all three G alpha subunits stimulate LARG mediated activation of RhoA.	34	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	34	35	38	39
p115RhoGEF activates RhoA and the catalytic activity of p115RhoGEF is required for its regulation of epithelial plasticity .	p115RhoGEF activates RhoA and the catalytic activity of p115RhoGEF is required for its regulation of epithelial plasticity.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	0	1	2	3
Our data show that PKC-alpha but not PKC-beta mediates p115RhoGEF phosphorylation , which in turn triggers RhoA activation , and then promotes F-actin rearrangement and barrier permeability in BMECs in response to TNF-alpha .	Our data show that PKC-alpha but not PKC-beta mediates p115RhoGEF phosphorylation, which in turn triggers RhoA activation, and then promotes F-actin rearrangement and barrier permeability in BMECs in response to TNF-alpha.	4	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	PKC-alpha but not PKC-beta mediates p115RhoGEF phosphorylation	p115rhogef	RhoA	RhoA	rhoa	9	10	16	17
This switch region of Galpha 13 interacts with p115RhoGEF activating Rho and then Rho associated protein kinase ( ROCK ) [ XREF_BIBR , XREF_BIBR ] .	This switch region of Galpha 13 interacts with p115RhoGEF activating Rho and then Rho associated protein kinase (ROCK) [XREF_BIBR, XREF_BIBR].	6	13	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	Rho	Rho	Rho	8	9	10	11
3 It has been shown only recently that AngII exerts its AT1R dependent contractile effect in the vascular smooth muscle cells through phosphorylation of JAK2 and the nucleotide exchange factor for RhoA , Arhgef1 , which then activates the RhoA cascade toward Rho-kinase , finally resulting in contraction of these cells .	3 It has been shown only recently that AngII exerts its AT1R dependent contractile effect in the vascular smooth muscle cells through phosphorylation of JAK2 and the nucleotide exchange factor for RhoA, Arhgef1, which then activates the RhoA cascade toward Rho-kinase, finally resulting in contraction of these cells.	31	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Arhgef1	Arhgef1	Arhgef1	RhoA	RhoA	RhoA	33	34	39	40
This increase in p115RhoGEF expression is not sufficient to restore RhoA activity downstream of ICAM-1 , however it may well be that p115RhoGEF activity compensates for other signaling pathways in the LARG KD cells .	This increase in p115RhoGEF expression is not sufficient to restore RhoA activity downstream of ICAM-1, however it may well be that p115RhoGEF activity compensates for other signaling pathways in the LARG KD cells.	3	11	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF expression	p115rhogef	RhoA	RhoA	rhoa	3	4	10	11
Our results show that overexpression of p115RhoGEF leads to activation of RhoA , and since the effects of overexpression on junctional E-cadherin and protrusions are blocked upon inactivation of the GEF catalytic activity of p115RhoGEF , these results suggest that the overexpression phenotype of p115RhoGEF is dependent upon its GEF catalytic activity .	Our results show that overexpression of p115RhoGEF leads to activation of RhoA, and since the effects of overexpression on junctional E-cadherin and protrusions are blocked upon inactivation of the GEF catalytic activity of p115RhoGEF, these results suggest that the overexpression phenotype of p115RhoGEF is dependent upon its GEF catalytic activity.	4	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	p115RhoGEF	overexpression of p115RhoGEF	p115rhogef	RhoA	RhoA	rhoa	6	7	11	12
Binding of hyaluronan to CD44v3 promotes p115RhoGEF mediated activation of RhoA [ XREF_BIBR ] .	Binding of hyaluronan to CD44v3 promotes p115RhoGEF mediated activation of RhoA [XREF_BIBR].	6	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	6	7	10	11
In addition , PKCalpha mediated phosphorylation of p115RhoGEF induced by thrombin was shown to stimulate RhoA activation in HUVECs .	In addition, PKCalpha mediated phosphorylation of p115RhoGEF induced by thrombin was shown to stimulate RhoA activation in HUVECs.	3	16	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	PKCalpha mediated phosphorylation of p115RhoGEF	p115rhogef	RhoA	RhoA	rhoa	7	8	15	16
Arhgef1 strongly activates RhoA activity while concomitantly inhibits Rac1 and Cdc42 activities .	Arhgef1 strongly activates RhoA activity while concomitantly inhibits Rac1 and Cdc42 activities.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Arhgef1	Arhgef1	Arhgef1	RhoA	RhoA	RhoA	0	1	3	4
It has been reported that p115RhoGEF , tyrosine phosphorylated in response to angiotensin II , activates RhoA in vascular smooth muscle .	It has been reported that p115RhoGEF, tyrosine phosphorylated in response to angiotensin II, activates RhoA in vascular smooth muscle.	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	5	6	16	17
It has been believed that this role of Galpha 13 is mediated via the Galpha 13 -dependent activation of RhoGEFs , including p115RhoGEF ( ARHGEF1 ) , which subsequently activates the small GTPase RhoA .	It has been believed that this role of Galpha 13 is mediated via the Galpha 13 -dependent activation of RhoGEFs, including p115RhoGEF (ARHGEF1), which subsequently activates the small GTPase RhoA.	11	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	22	23	33	34
The authors attributed the phenotype to increased activation of RhoA mediated by p115RhoGEF .	The authors attributed the phenotype to increased activation of RhoA mediated by p115RhoGEF.	7	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	12	13	9	10
For example , both p115RhoGEF and LARG GEF are regulated by G12/13 and can activate RhoA .	For example, both p115RhoGEF and LARG GEF are regulated by G12/13 and can activate RhoA.	3	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	4	5	15	16
While some RhoGEFs are capable of activating multiple small GTPases , the catalytic activity of p115RhoGEF has been thoroughly studied biochemically and has been shown to selectively activate Rho ( RhoA , B , or C ) , but not Rac , Cdc42 , or TC10 XREF_BIBR , XREF_BIBR .	While some RhoGEFs are capable of activating multiple small GTPases, the catalytic activity of p115RhoGEF has been thoroughly studied biochemically and has been shown to selectively activate Rho (RhoA, B, or C), but not Rac, Cdc42, or TC10 XREF_BIBR, XREF_BIBR.	13	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	15	16	30	31
Expression of the dominant negative p115RhoGEF was able to inhibit activation of both RhoA and JNK1 in response to either retinoic acid or the expression of a constitutively activated mutant of G alpha ( 13 ) .	Expression of the dominant negative p115RhoGEF was able to inhibit activation of both RhoA and JNK1 in response to either retinoic acid or the expression of a constitutively activated mutant of G alpha (13).	0	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p115RhoGEF	Expression of the dominant negative p115RhoGEF	p115rhogef	RhoA	RhoA	rhoa	5	6	13	14
Experiments using FRET based RhoA activity biosensor showed that p115RhoGEF overexpression activated RhoA in both MCF7 and MDA-MB-231 , and the effects of p115RhoGEF were dependent on its GEF catalytic activity as expression of the catalytically inactive mutant p115RhoGEF ( p115RhoGEF DH mutant ) in MCF7 and MDA-MB-231 cells had no effect on epithelial plasticity , i.e. no change in adherens junctions or protrusions ( XREF_FIG ) .	Experiments using FRET based RhoA activity biosensor showed that p115RhoGEF overexpression activated RhoA in both MCF7 and MDA-MB-231, and the effects of p115RhoGEF were dependent on its GEF catalytic activity as expression of the catalytically inactive mutant p115RhoGEF (p115RhoGEF DH mutant) in MCF7 and MDA-MB-231 cells had no effect on epithelial plasticity, i.e. no change in adherens junctions or protrusions (XREF_FIG).	9	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF overexpression	p115rhogef	RhoA	RhoA	rhoa	9	10	12	13
Expression of luciferase was used as an indirect readout of p115RhoGEF mediated Rho activity in cell lysates .	Expression of luciferase was used as an indirect readout of p115RhoGEF mediated Rho activity in cell lysates.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	Rho	Rho	Rho	10	11	12	13
Expression of the constitutively active mutant form of p115RhoGEF ( guanine nucleotide exchange factor ) was found to activate RhoA and JNK1 activities .	Expression of the constitutively active mutant form of p115RhoGEF (guanine nucleotide exchange factor) was found to activate RhoA and JNK1 activities.	6	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	8	9	19	20
p115RhoGEF , a specific guanine nucleotide exchange factors ( GEFs ) activates RhoA , triggering RhoA dependent cytoskeletal remodeling .	p115RhoGEF, a specific guanine nucleotide exchange factors (GEFs) activates RhoA, triggering RhoA dependent cytoskeletal remodeling.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	0	1	12	13
Both Galpha12 and Galpha13 bind the RH domain of RhoGEFs [ XREF_BIBR ] , but a role in driving their catalytic activity is better supported for Galpha13 : stimulation of purified p115RhoGEF by Galpha13 but not Galpha12 was observed in a reconstituted system measuring RhoA activation , and cell based studies of p115RhoGEF mediated Rho signaling also showed selectivity for Galpha13 [ XREF_BIBR XREF_BIBR ] .	Both Galpha12 and Galpha13 bind the RH domain of RhoGEFs [XREF_BIBR], but a role in driving their catalytic activity is better supported for Galpha13 : stimulation of purified p115RhoGEF by Galpha13 but not Galpha12 was observed in a reconstituted system measuring RhoA activation, and cell based studies of p115RhoGEF mediated Rho signaling also showed selectivity for Galpha13 [XREF_BIBR XREF_BIBR].	50	55	mediated	Positive_early_activation	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	Rho	Rho	Rho	52	53	54	55
Furthermore , we showed that Arhgef1 silencing inhibited the activity of RhoA , and pharmacological blockade of RhoA activity promoted neurite outgrowth in NPC derived neurons .	Furthermore, we showed that Arhgef1 silencing inhibited the activity of RhoA, and pharmacological blockade of RhoA activity promoted neurite outgrowth in NPC derived neurons.	5	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Arhgef1	Arhgef1	Arhgef1	RhoA	RhoA	RhoA	5	6	11	12
3.1 PM association of p115-RhoGEF induces Rho dependent neurite retraction in PC12 cells .	3.1 PM association of p115-RhoGEF induces Rho dependent neurite retraction in PC12 cells.	2	7	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p115-RhoGEF	p115-RhoGEF	p115-RhoGEF	Rho	Rho	Rho	4	5	6	7
G-kinase activation inhibited SRF dependent transcription induced by upstream RhoA activators including Galpha ( 13 ) and p115RhoGEF , with Galpha ( 13 )-induced Rho.GTP loading inhibited by G-kinase .	G-kinase activation inhibited SRF dependent transcription induced by upstream RhoA activators including Galpha (13) and p115RhoGEF, with Galpha (13)-induced Rho.GTP loading inhibited by G-kinase.	9	18	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	17	18	9	10
The binding of HA to MDA-MB-231 cells stimulates p115RhoGEF mediated RhoA signaling and Rho kinase ( ROK ) activity , which , in turn , increases serine/threonine phosphorylation of the adaptor protein , Gab-1 ( Grb2 associated binder-1 ) .	The binding of HA to MDA-MB-231 cells stimulates p115RhoGEF mediated RhoA signaling and Rho kinase (ROK) activity, which, in turn, increases serine/threonine phosphorylation of the adaptor protein, Gab-1 (Grb2 associated binder-1).	7	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	8	9	10	11
Whereas G 12/13 activation promotes p115 Rho GEF mediated RhoA induced Rho kinase activation , which phosphorylates and inhibits MLC phosphatase and thereby protects MLC from dephosphorylation and increases endothelial cell contraction .	Whereas G 12/13 activation promotes p115 Rho GEF mediated RhoA induced Rho kinase activation, which phosphorylates and inhibits MLC phosphatase and thereby protects MLC from dephosphorylation and increases endothelial cell contraction.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	p115 Rho GEF	p115 Rho GEF	p115 Rho GEF	RhoA	RhoA	RhoA	5	8	9	10
In addition , P115RhoGEF , the regulator of G protein signaling domain , transmits cell migration and adhesion signals from GPCR , and leads to the activation of Rho [ XREF_BIBR - XREF_BIBR ] .	In addition, P115RhoGEF, the regulator of G protein signaling domain, transmits cell migration and adhesion signals from GPCR, and leads to the activation of Rho [XREF_BIBR - XREF_BIBR].	3	30	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	P115RhoGEF	P115RhoGEF	P115RhoGEF	Rho	Rho	Rho	3	4	28	29
Taken together , our results show that PKC-alpha phosphorylation of p115RhoGEF mediates TNF-alpha signaling to RhoA , and that this plays a critical role in signaling F-actin rearrangement and barrier dysfunction in BMECs .	Taken together, our results show that PKC-alpha phosphorylation of p115RhoGEF mediates TNF-alpha signaling to RhoA, and that this plays a critical role in signaling F-actin rearrangement and barrier dysfunction in BMECs.	7	16	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	p115RhoGEF	PKC-alpha phosphorylation of p115RhoGEF	p115rhogef	RhoA	RhoA	rhoa	10	11	15	16
Previous work indicated that HA ( mixed sizes ) promotes the interaction between CD44 and several Rho specific guanine nucleotide exchange factors [ e.g ., p115RhoGEF and LARG ] , thereby up-regulating RhoA ( a member of the Rho subclass of the Ras superfamily ) , leading to altered cytoskeleton mediated cell functions .	Previous work indicated that HA (mixed sizes) promotes the interaction between CD44 and several Rho specific guanine nucleotide exchange factors [e.g., p115RhoGEF and LARG], thereby up-regulating RhoA (a member of the Rho subclass of the Ras superfamily), leading to altered cytoskeleton mediated cell functions.	4	35	up-regulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	HA (mixed sizes) promotes the interaction between CD44 and several Rho specific guanine nucleotide exchange factors [e.g., p115RhoGEF and LARG	p115rhogef	RhoA	RhoA	rhoa	25	26	32	33
p115RhoGEF has been shown to specifically activate Rho proteins , and not Rac or Cdc42 XREF_BIBR , XREF_BIBR .	p115RhoGEF has been shown to specifically activate Rho proteins, and not Rac or Cdc42 XREF_BIBR, XREF_BIBR.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	Rho	Rho	Rho	0	1	7	8
p115RhoGEF activates RhoA and requires members of the DRF family to regulate epithelial plasticity .	p115RhoGEF activates RhoA and requires members of the DRF family to regulate epithelial plasticity.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	0	1	2	3
The FAK and p66 Shc complex specifically bound and activated the Rho guanyl exchange factors p115-RhoGEF and GEF-H1 , leading to tension induced RhoA activation .	The FAK and p66 Shc complex specifically bound and activated the Rho guanyl exchange factors p115-RhoGEF and GEF-H1, leading to tension induced RhoA activation.	14	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115-RhoGEF	p115-RhoGEF	p115-RhoGEF	RhoA	RhoA	RhoA	15	16	23	24
Following stimulation of platelets with thrombin or the thromboxane mimetic U46619 , RhoA is activated by ARHGEF1 ( p115RhoGEF ) [ XREF_BIBR ] .	Following stimulation of platelets with thrombin or the thromboxane mimetic U46619, RhoA is activated by ARHGEF1 (p115RhoGEF) [XREF_BIBR].	12	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ARHGEF1	ARHGEF1	ARHGEF1	RhoA	RhoA	RhoA	16	17	12	13
We hypothesized that suppression of p115RhoGEF may inhibit activation of RhoA and prevent LPS induced brain microvascular endothelial cell hyperpermeability .	We hypothesized that suppression of p115RhoGEF may inhibit activation of RhoA and prevent LPS induced brain microvascular endothelial cell hyperpermeability.	3	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	5	6	10	11
Overexpression of p115RhoGEF has been previously shown to stimulate RhoA dependent transcription from the SRE [ XREF_BIBR ] .	Overexpression of p115RhoGEF has been previously shown to stimulate RhoA dependent transcription from the SRE [XREF_BIBR].	0	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	Overexpression of p115RhoGEF	p115rhogef	RhoA	RhoA	rhoa	2	3	9	10
Rho is downstream of and directly activated by p115-RhoGEF , and it is therefore surprising and unexpected that inhibition of Rho would affect PM recruitment of p115-RhoGEF .	Rho is downstream of and directly activated by p115-RhoGEF, and it is therefore surprising and unexpected that inhibition of Rho would affect PM recruitment of p115-RhoGEF.	0	9	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p115-RhoGEF	p115-RhoGEF	p115-RhoGEF	Rho	Rho	Rho	8	9	0	1
XREF_BIBR In agreement with these results , when MII contractility is inhibited , betaPix accumulates in assembling nascent adhesions and promotes Rac1 activation .	XREF_BIBR In agreement with these results, when MII contractility is inhibited, betaPix accumulates in assembling nascent adhesions and promotes Rac1 activation.	13	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	betaPix	betaPix	betaPix	Rac1	Rac1	Rac1	13	14	21	22
XREF_BIBR In addition to its GEF function , beta-Pix serves to target Rac1 to these membrane ruffles .	XREF_BIBR In addition to its GEF function, beta-Pix serves to target Rac1 to these membrane ruffles.	8	13	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	8	9	12	13
To understand how optoPlexin may regulate Cdc42 and Rac1 , we focused on a ubiquitously expressed RhoGEF beta-Pix , which activates Cdc42 and Rac1 and mediates cross-talk between RhoA and Cdc42 and Rac1 .	To understand how optoPlexin may regulate Cdc42 and Rac1, we focused on a ubiquitously expressed RhoGEF beta-Pix, which activates Cdc42 and Rac1 and mediates cross-talk between RhoA and Cdc42 and Rac1.	11	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	17	18	23	24
We previously identified a series of regulatory proteins that associate with Rac1 through its hypervariable C-terminal domain , including the Rac1 activator beta-Pix ( also known as Rho guanine-nucleotide-exchange factor 7 ) and the membrane adapter caveolin-1 .	We previously identified a series of regulatory proteins that associate with Rac1 through its hypervariable C-terminal domain, including the Rac1 activator beta-Pix (also known as Rho guanine-nucleotide-exchange factor 7) and the membrane adapter caveolin-1.	9	36	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	22	23	20	21
These data provide a model for Rac1 targeting through its activator beta-Pix , which drives integrin mediated localized Rac1 activation in polarized migrating cells .	These data provide a model for Rac1 targeting through its activator beta-Pix, which drives integrin mediated localized Rac1 activation in polarized migrating cells.	7	19	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	11	12	18	19
Thus , binding of both betaPIX and Rich2 may increase the activation state of Rac1 and Cdc42 in the dendritic spine due to the different effects of Shank3 on the activity of these proteins [ XREF_BIBR , XREF_BIBR ] .	Thus, binding of both betaPIX and Rich2 may increase the activation state of Rac1 and Cdc42 in the dendritic spine due to the different effects of Shank3 on the activity of these proteins [XREF_BIBR, XREF_BIBR].	2	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	betaPIX	betaPIX	betaPIX	Rac1	Rac1	Rac1	5	6	14	15
These data suggest that Rac1 can be targeted to the membrane by beta-Pix while in complex with RhoGDI .	These data suggest that Rac1 can be targeted to the membrane by beta-Pix while in complex with RhoGDI.	4	13	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	12	13	4	5
beta-PIX in nascent FAs induces Rac1 activation , negatively regulates FA maturation and promotes cell migration .	beta-PIX in nascent FAs induces Rac1 activation, negatively regulates FA maturation and promotes cell migration.	0	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-PIX	beta-PIX	beta-PIX	Rac1	Rac1	Rac1	0	1	5	6
beta-Pix can target Rac1 to the plasma membrane .	beta-Pix can target Rac1 to the plasma membrane.	0	4	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	0	1	3	4
Based on this study and previous work , we propose that decreased expression of beta-pix in fn40a mutants ( hypomorphic allele ) decreases Rac1 function to activate Mek1/2 , which then increases the level of phosphorylated Erk and Mmp9 transcription and translation , leading to abnormal vascular permeability and disruption of vascular integrity .	Based on this study and previous work, we propose that decreased expression of beta-pix in fn40a mutants (hypomorphic allele) decreases Rac1 function to activate Mek1/2, which then increases the level of phosphorylated Erk and Mmp9 transcription and translation, leading to abnormal vascular permeability and disruption of vascular integrity.	12	24	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-pix	expression of beta-pix	beta-pix	Rac1	Rac1	rac1	14	15	23	24
XREF_BIBR Moreover , FAK can bind to and phosphorylate betaPix , and thereby , enhance betaPix binding to Rac1 and the translocation of Rac1 to adhesions .	XREF_BIBR Moreover, FAK can bind to and phosphorylate betaPix, and thereby, enhance betaPix binding to Rac1 and the translocation of Rac1 to adhesions.	3	24	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	betaPix	FAK can bind to and phosphorylate betaPix	betapix	Rac1	Rac1	rac1	9	10	23	24
However , cytoplasmic pSTAT3 may also directly influence cell migration and process outgrowth , as found in fibroblasts , by binding to Rac1 activator beta-PIX , modulating cytoskeletal re-organization XREF_BIBR .	However, cytoplasmic pSTAT3 may also directly influence cell migration and process outgrowth, as found in fibroblasts, by binding to Rac1 activator beta-PIX, modulating cytoskeletal re-organization XREF_BIBR.	20	25	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	beta-PIX	beta-PIX	beta-PIX	Rac1	Rac1	Rac1	24	25	22	23
Thus , betaPIX , which is known to modulate EGFR function , activates Rac1 , causing EGF dependent oxidant production .	Thus, betaPIX, which is known to modulate EGFR function, activates Rac1, causing EGF dependent oxidant production.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	betaPIX	betaPIX	betaPIX	Rac1	Rac1	Rac1	2	3	13	14
Pak , which is involved in beta-Pix activation of Rac1 , demonstrates increased activity in the context of Ephexin1 mediated axonal outgrowth .	Pak, which is involved in beta-Pix activation of Rac1, demonstrates increased activity in the context of Ephexin1 mediated axonal outgrowth.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	6	7	9	10
Among its various functions , active PAK phosphorylates the focal adhesion protein paxillin on Ser 273 , providing a binding site for the recruitment of the scaffold protein GIT1 ; GIT1 binds both betaPIX , a guanine-nucleotide exchange factor that activates Rac , and PAK , which is activated in turn by Rac .	Among its various functions, active PAK phosphorylates the focal adhesion protein paxillin on Ser 273, providing a binding site for the recruitment of the scaffold protein GIT1; GIT1 binds both betaPIX, a guanine-nucleotide exchange factor that activates Rac, and PAK, which is activated in turn by Rac.	31	44	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	betaPIX	betaPIX	betaPIX	Rac	Rac	Rac	33	34	41	42
Rac be subsequently activated by beta-Pix and also localises to the membrane .	Rac be subsequently activated by beta-Pix and also localises to the membrane.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac	Rac	Rac	5	6	0	1
Activation of Rac1 by beta-PIX promotes lamellipodial protrusion and nascent adhesion turnover , resulting in enhanced cell migration .	Activation of Rac1 by beta-PIX promotes lamellipodial protrusion and nascent adhesion turnover, resulting in enhanced cell migration.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	beta-PIX	beta-PIX	beta-PIX	Rac1	Rac1	Rac1	4	5	2	3
Furthermore , overexpression of betaPIX produced active Rac like changes in cell morphology presumably through increased GEF activity .	Furthermore, overexpression of betaPIX produced active Rac like changes in cell morphology presumably through increased GEF activity.	2	8	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	betaPIX	overexpression of betaPIX	betapix	Rac	Rac	rac	4	5	7	8
Myosin II activity also regulates the molecular composition of adhesions , as it promotes the recruitment of mechanosensitive proteins such as zyxin and vinculin , and negatively regulates Rac activators such as beta-Pix which leads to small , dynamic adhesions .	Myosin II activity also regulates the molecular composition of adhesions, as it promotes the recruitment of mechanosensitive proteins such as zyxin and vinculin, and negatively regulates Rac activators such as beta-Pix which leads to small, dynamic adhesions.	28	34	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac	Rac	Rac	32	33	28	29
Indeed , the cells with reduced beta-Pix expression also showed reduced Rac1 activity after adhesion ( XREF_FIG ) , confirming that beta-Pix mediates adhesion induced Rac1 activation .	Indeed, the cells with reduced beta-Pix expression also showed reduced Rac1 activity after adhesion (XREF_FIG), confirming that beta-Pix mediates adhesion induced Rac1 activation.	21	26	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	21	22	25	26
In this context it is remarkable that overactivation of Rac1 caused by overexpression of beta-PIX , or constitutively active Rac1 results in formation of aberrant dendritic protrusions and reduction of normal spines and synapses , the phenotype characteristic of KCC2 deficient neurons .	In this context it is remarkable that overactivation of Rac1 caused by overexpression of beta-PIX, or constitutively active Rac1 results in formation of aberrant dendritic protrusions and reduction of normal spines and synapses, the phenotype characteristic of KCC2 deficient neurons.	7	15	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-PIX	overexpression of beta-PIX	beta-pix	Rac1	Rac1	rac1	14	15	9	10
Synaptic activity activates various Rac modulators , such as Tiam1 , Kalirin-7 , and betaPIX , and enhances the formation of dendritic spines through the activation of the Rac signaling pathway .	Synaptic activity activates various Rac modulators, such as Tiam1, Kalirin-7, and betaPIX, and enhances the formation of dendritic spines through the activation of the Rac signaling pathway.	4	15	modulators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	betaPIX	betaPIX	betaPIX	Rac	Rac	Rac	14	15	4	5
We show that beta-PIX is required for Rac1 activity and lamellipodial protrusion induced by myosinII inhibition , suggesting that beta-PIX may enhance Rac1 activity locally in myosinII-free cell regions such as lamellipodia .	We show that beta-PIX is required for Rac1 activity and lamellipodial protrusion induced by myosinII inhibition, suggesting that beta-PIX may enhance Rac1 activity locally in myosinII-free cell regions such as lamellipodia.	19	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-PIX	beta-PIX	beta-PIX	Rac1	Rac1	Rac1	19	20	22	23
beta-PIX activates Rac1 GTPase by catalyzing the exchange of GDP to GTP .	beta-PIX activates Rac1 GTPase by catalyzing the exchange of GDP to GTP.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-PIX	beta-PIX	beta-PIX	Rac1	Rac1	Rac1	0	1	2	3
These data suggest that the differential localization of beta-Pix in polarized cells drives localized activation of Rac1 .	These data suggest that the differential localization of beta-Pix in polarized cells drives localized activation of Rac1.	6	17	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	8	9	16	17
Finally , Rac1 activation by beta-Pix was abrogated when their interaction was blocked by the Rac1 COOH-terminal peptide or when the beta-Pix W43K mutant was used .	Finally, Rac1 activation by beta-Pix was abrogated when their interaction was blocked by the Rac1 COOH-terminal peptide or when the beta-Pix W43K mutant was used.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	5	6	2	3
Rac1 is activated downstream of the NMDA receptor by the Rac1 specific GEF TIAM1 , and by the Cdc42- and Rac1 specific GEFs kalirin-7 and betaPIX .	Rac1 is activated downstream of the NMDA receptor by the Rac1 specific GEF TIAM1, and by the Cdc42- and Rac1 specific GEFs kalirin-7 and betaPIX.	0	26	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	betaPIX	betaPIX	betaPIX	Rac1	Rac1	Rac1	25	26	0	1
In this study , we show that the Rho GTPase Rac1 , via a proline stretch in its COOH terminus , binds directly to the SH3 domain of the Cdc42 and Rac activator beta-Pix ( p21 activated kinase [ Pak ]-interacting exchange factor ) .	In this study, we show that the Rho GTPase Rac1, via a proline stretch in its COOH terminus, binds directly to the SH3 domain of the Cdc42 and Rac activator beta-Pix (p21 activated kinase [Pak]-interacting exchange factor).	26	34	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac	Rac	Rac	33	34	31	32
Since IPA-3 reduced PAK2 autophosphorylation at Ser192/197 , PAK should stay associated with beta-Pix and therefore prevent beta-Pix induced Rac activation .	Since IPA-3 reduced PAK2 autophosphorylation at Ser192/197, PAK should stay associated with beta-Pix and therefore prevent beta-Pix induced Rac activation.	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac	Rac	Rac	17	18	19	20
In the periphery , AT1R signaling stimulates the RhoGEFs Arhgef1 19 and p63RhoGEF 22 , which activate RhoA and Rho kinase , and inhibits the RhoGAP p190A 49 which , in turn , inhibits RhoA and Rho kinase .	In the periphery, AT1R signaling stimulates the RhoGEFs Arhgef1 19 and p63RhoGEF 22, which activate RhoA and Rho kinase, and inhibits the RhoGAP p190A 49 which, in turn, inhibits RhoA and Rho kinase.	6	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	12	13	17	18
The remaining component of RhoA mediated Ca 2+ -sensitized force reflected by the subsequent magnitude of the response to GTPgammaS was increased in vessels where p63RhoGEF expression was reduced , consistent with p63RhoGEF mediating ET-1 activation of RhoA .	The remaining component of RhoA mediated Ca 2+ -sensitized force reflected by the subsequent magnitude of the response to GTPgammaS was increased in vessels where p63RhoGEF expression was reduced, consistent with p63RhoGEF mediating ET-1 activation of RhoA.	30	38	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	32	33	37	38
In aortic SM cells p63RhoGEF activation of RhoA occurred within the first 30 seconds .	In aortic SM cells p63RhoGEF activation of RhoA occurred within the first 30 seconds.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	4	5	7	8
We further demonstrate that active G alpha ( q ) or G alpha11 , but not G alpha12 or G alpha13 , strongly enhances p63RhoGEF induced RhoA activation by direct protein protein interaction with p63RhoGEF at its C-terminal half .	We further demonstrate that active G alpha (q) or G alpha11, but not G alpha12 or G alpha13, strongly enhances p63RhoGEF induced RhoA activation by direct protein protein interaction with p63RhoGEF at its C-terminal half.	24	27	induced	Positive_early_activation	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	24	25	26	27
As carbachol activation of muscarinic acetylcholine receptors results only in G q/11 activation , a Galpha q/11 induced p63RhoGEF activation of RhoA seems to be more important in PLCepsilon induced TRPC6 activation in this cell type .	As carbachol activation of muscarinic acetylcholine receptors results only in G q/11 activation, a Galpha q/11 induced p63RhoGEF activation of RhoA seems to be more important in PLCepsilon induced TRPC6 activation in this cell type.	18	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	18	19	21	22
As is discussed below , Bves regulates GEFT activity , which in turn modulates downstream Rho GTPases .	As is discussed below, Bves regulates GEFT activity, which in turn modulates downstream Rho GTPases.	7	16	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GEFT	GEFT	GEFT	Rho	Rho	Rho	7	8	15	16
When expressed in human embryonic kidney cells , both p63RhoGEF and GEFT caused activation of RhoA , but not Rac1 or Cdc42 , and induced serum response factor mediated gene transcription , which was fully blunted by the Rho inactivating C3 transferase .	When expressed in human embryonic kidney cells, both p63RhoGEF and GEFT caused activation of RhoA, but not Rac1 or Cdc42, and induced serum response factor mediated gene transcription, which was fully blunted by the Rho inactivating C3 transferase.	8	24	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	9	10	15	16
Unlike its direct interactions with Cdc42 and Rac1 , which alter the signaling and localization of MLK3 , MLK3 acts on Rho to negatively regulate its activity via interaction with the Rho activator p63RhoGEF .	Unlike its direct interactions with Cdc42 and Rac1, which alter the signaling and localization of MLK3, MLK3 acts on Rho to negatively regulate its activity via interaction with the Rho activator p63RhoGEF.	28	34	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	Rho	Rho	Rho	33	34	31	32
We therefore conclude that p63RhoGEF and GEFT are apparently isoforms derived from the same gene and that GEFT , similar to p63RhoGEF , activates RhoA in several cell types .	We therefore conclude that p63RhoGEF and GEFT are apparently isoforms derived from the same gene and that GEFT, similar to p63RhoGEF, activates RhoA in several cell types.	17	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GEFT	GEFT	GEFT	RhoA	RhoA	RhoA	17	18	24	25
Both p63RhoGEF 580 and p63RhoGEF 619 activate RhoA and Cdc42 .	Both p63RhoGEF 580 and p63RhoGEF 619 activate RhoA and Cdc42.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	1	2	7	8
Over-expression of p63RhoGEF activated RhoA , which was inhibited by co-expression of both , MLK3 WT and KI ( XREF_FIG ) .	Over-expression of p63RhoGEF activated RhoA, which was inhibited by co-expression of both, MLK3 WT and KI (XREF_FIG).	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p63RhoGEF	Over-expression of p63RhoGEF	p63rhogef	RhoA	RhoA	rhoa	2	3	4	5
P63RhoGEF ( encoded by the gene ARHGEF25 ) mediates activation of RhoA by Galphaq in smooth muscle cells XREF_BIBR XREF_BIBR and has been proposed as a key regulator of angiotensin II induced effects on vascular smooth muscle tissue XREF_BIBR XREF_BIBR .	P63RhoGEF (encoded by the gene ARHGEF25) mediates activation of RhoA by Galphaq in smooth muscle cells XREF_BIBR XREF_BIBR and has been proposed as a key regulator of angiotensin II induced effects on vascular smooth muscle tissue XREF_BIBR XREF_BIBR.	0	23	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P63RhoGEF	P63RhoGEF	P63RhoGEF	RhoA	RhoA	RhoA	0	1	11	12
To test for a direct interaction between Arg 341 and Arg 68 of RhoA , we measured the rate of nucleotide exchange catalyzed on RhoA-WT , RhoA-R68A , and RhoA-R68E by the p63RhoGEF DH/PH , DH/PH-R 341A , and DH/PH-R 341E variants .	To test for a direct interaction between Arg 341 and Arg 68 of RhoA, we measured the rate of nucleotide exchange catalyzed on RhoA-WT, RhoA-R68A, and RhoA-R68E by the p63RhoGEF DH/PH, DH/PH-R 341A, and DH/PH-R 341E variants.	22	33	catalyzed	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA-WT	RhoA-WT	RhoA-WT	32	33	24	25
Up to now it has been unclear when and where p63RhoGEF activates RhoA in living cells .	Up to now it has been unclear when and where p63RhoGEF activates RhoA in living cells.	10	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	10	11	12	13
Moreover , we show that p63RhoGEF activation of RhoA in intact cells is dependent on the presence of the PH domain .	Moreover, we show that p63RhoGEF activation of RhoA in intact cells is dependent on the presence of the PH domain.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	5	6	8	9
For example , MLK3 binds to the Rho activator p63RhoGEF , impeding its activation by Galphaq and thus preventing Rho activation .	For example, MLK3 binds to the Rho activator p63RhoGEF, impeding its activation by Galphaq and thus preventing Rho activation.	4	10	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	Rho	Rho	Rho	9	10	7	8
Since this interaction is required for p63RhoGEF activation of Rho elicited by Galphaq , decreased complex formation may be sufficient to account for the MLK3 induced inhibition of Rho activation in HM1 cells stimulated with carbachol , as well as the MLK3 induced inhibition of Rho dependent SRF transcription stimulated by active Galphaq .	Since this interaction is required for p63RhoGEF activation of Rho elicited by Galphaq, decreased complex formation may be sufficient to account for the MLK3 induced inhibition of Rho activation in HM1 cells stimulated with carbachol, as well as the MLK3 induced inhibition of Rho dependent SRF transcription stimulated by active Galphaq.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	Rho	Rho	Rho	6	7	9	10
Altogether , these results suggest that G alphaq/11 coupling to p63RhoGEF mediates RhoA activation by agonists such as AngII , phenylephrine and ET-1 that solely or partially couple through G alphaq/11 and that these signaling pathways in conjunction with PLCbeta induced Ca 2+ release contribute to basal and stimulated increases in blood pressure and vessel remodeling ( XREF_FIG ) .	Altogether, these results suggest that G alphaq/11 coupling to p63RhoGEF mediates RhoA activation by agonists such as AngII, phenylephrine and ET-1 that solely or partially couple through G alphaq/11 and that these signaling pathways in conjunction with PLCbeta induced Ca 2+ release contribute to basal and stimulated increases in blood pressure and vessel remodeling (XREF_FIG).	8	13	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	10	11	12	13
P63RhoGEF 580 and p63RhoGEF 619 can activate RhoA and Cdc42 via stimulation of endogenous Galphaq coupled histamine-1-receptors ( H 1 R ) .	P63RhoGEF 580 and p63RhoGEF 619 can activate RhoA and Cdc42 via stimulation of endogenous Galphaq coupled histamine-1-receptors (H 1 R).	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p63RhoGEF	P63RhoGEF	P63RhoGEF	RhoA	RhoA	RhoA	0	1	7	8
We hypothesized that the specific mediator of Gq/11 dependent RhoA activation p63RhoGEF , which is expressed in cardiac fibroblasts , plays a role in the underlying processes .	We hypothesized that the specific mediator of Gq/11 dependent RhoA activation p63RhoGEF, which is expressed in cardiac fibroblasts, plays a role in the underlying processes.	7	12	activation	Positive_activation_token_1_noun	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	11	12	9	10
Recently , it was reported that p63RhoGEF induced RhoA activation is important for PMT derived inhibition of osteoblastogenesis by transactivation of the MAP kinase cascade .	Recently, it was reported that p63RhoGEF induced RhoA activation is important for PMT derived inhibition of osteoblastogenesis by transactivation of the MAP kinase cascade.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	6	7	8	9
We propose that G ( q )-distinctive sites evolved to drive specificity of G ( q ) interactions to GRK2 but not p63RhoGEF , a G ( q ) specific effector that activates the small GTPase RhoA XREF_BIBR - XREF_BIBR .	We propose that G (q)-distinctive sites evolved to drive specificity of G (q) interactions to GRK2 but not p63RhoGEF, a G (q) specific effector that activates the small GTPase RhoA XREF_BIBR - XREF_BIBR.	11	37	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	22	23	36	37
By employing the FRET sensor we show that a plasma membrane located RhoGEF , p63RhoGEF , can rapidly activate RhoA through endogenous GPCRs and that localized RhoA activity at the cell periphery correlates with actin polymerization .	By employing the FRET sensor we show that a plasma membrane located RhoGEF, p63RhoGEF, can rapidly activate RhoA through endogenous GPCRs and that localized RhoA activity at the cell periphery correlates with actin polymerization.	12	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	14	15	19	20
Using the DORA-RhoA biosensor , we observe very fast activation of RhoA by p63RhoGEF with a t ( 1/2 ) of 21 +/-0.7 s. Interestingly , the GPCR mediated activation of a GTPase at the plasma membrane is substantially faster than the activation of a receptor tyrosine kinase mediated GTPase like HRAS at the plasma membrane , which has a t ( 1/2 ) in the order of minutes XREF_BIBR .	Using the DORA-RhoA biosensor, we observe very fast activation of RhoA by p63RhoGEF with a t (1/2) of 21 +/-0.7 s. Interestingly, the GPCR mediated activation of a GTPase at the plasma membrane is substantially faster than the activation of a receptor tyrosine kinase mediated GTPase like HRAS at the plasma membrane, which has a t (1/2) in the order of minutes XREF_BIBR.	6	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	13	14	11	12
Thus the increased Vps34 activity caused by ATG14 pS29 is unlikely due to the change of ATG14 interactions with above components in the Vps34 complex .	Thus the increased Vps34 activity caused by ATG14 pS29 is unlikely due to the change of ATG14 interactions with above components in the Vps34 complex.	3	8	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATG14	ATG14	ATG14	Vps34	Vps34	Vps34	7	8	3	4
We find that in the canonical autophagy pathway , ULK1 phosphorylates ATG14 , which promotes Vps34 lipid kinase activity .	We find that in the canonical autophagy pathway, ULK1 phosphorylates ATG14, which promotes Vps34 lipid kinase activity.	9	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG14	ULK1 phosphorylates ATG14	atg14	Vps34	Vps34	vps34	11	12	15	16
Overexpression of Atg14L stimulates the kinase activity of hVps34 , and induces autophagy , whereas Atg14L knockdown reduces PtdIns ( 3 ) P production , and inhibits autophagy [ XREF_BIBR , XREF_BIBR ] .	Overexpression of Atg14L stimulates the kinase activity of hVps34, and induces autophagy, whereas Atg14L knockdown reduces PtdIns (3) P production, and inhibits autophagy [XREF_BIBR, XREF_BIBR].	0	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14L	Overexpression of Atg14L	atg14l	hVps34	hVps34	hvps34	2	3	8	9
ULK1 mediated Atg14L phosphorylation activates VPS34 kinase activity , which is required for the nucleation of the phagophore membrane .	ULK1 mediated Atg14L phosphorylation activates VPS34 kinase activity, which is required for the nucleation of the phagophore membrane.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14L	ULK1 mediated Atg14L phosphorylation	atg14l	VPS34	VPS34	vps34	2	3	5	6
In mammals , a core Vps34 complex consisting of Vps34 , Beclin 1 ( a homologue of yeast Vps30 and Atg6 ) , Vps15 and Atg14L is directed to the AP nucleation site along the ER membrane by Atg14L to promote local synthesis of PI3P and initiate AP biogenesis , likely at sites of contact between ER and mitochondria [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In mammals, a core Vps34 complex consisting of Vps34, Beclin 1 (a homologue of yeast Vps30 and Atg6), Vps15 and Atg14L is directed to the AP nucleation site along the ER membrane by Atg14L to promote local synthesis of PI3P and initiate AP biogenesis, likely at sites of contact between ER and mitochondria [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	39	directed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg14L	Atg14L	Atg14L	Vps34	Vps34	Vps34	38	39	5	6
Atg14L was also shown to enhance VPS34 lipid kinase activity , which is critical for autophagosome formation .	Atg14L was also shown to enhance VPS34 lipid kinase activity, which is critical for autophagosome formation.	0	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14L	Atg14L	Atg14L	VPS34	VPS34	VPS34	0	1	6	7
Interestingly , the Atg14L mediated stimulation of Vps34 activity occurred only when co-expressing Beclin 1 .	Interestingly, the Atg14L mediated stimulation of Vps34 activity occurred only when co-expressing Beclin 1.	3	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Atg14L	Atg14L	Atg14L	Vps34	Vps34	Vps34	3	4	7	8
This result suggests that over-expression of Atg14L enhances Vps34 activity in a Beclin 1 dependent manner .	This result suggests that over-expression of Atg14L enhances Vps34 activity in a Beclin 1 dependent manner.	4	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14L	over-expression of Atg14L	atg14l	Vps34	Vps34	vps34	6	7	8	9
It has additionally been shown that ATG14 increases VPS34 catalytic activity in a Beclin 1 dependent manner [ XREF_BIBR ] .	It has additionally been shown that ATG14 increases VPS34 catalytic activity in a Beclin 1 dependent manner [XREF_BIBR].	6	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG14	ATG14	ATG14	VPS34	VPS34	VPS34	6	7	8	9
The ATG14 containing complex stimulates Vps34 activity at the phagophore membranes and is required for autophagy initiation in response to nutrient withdrawal .	The ATG14 containing complex stimulates Vps34 activity at the phagophore membranes and is required for autophagy initiation in response to nutrient withdrawal.	0	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG14	ATG14	ATG14	Vps34	Vps34	Vps34	1	2	5	6
In yeast , Atg14 can direct Vps34 complex to pre-autophagosomal structure ( PAS ) [ XREF_BIBR ] .	In yeast, Atg14 can direct Vps34 complex to pre-autophagosomal structure (PAS) [XREF_BIBR].	3	7	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14	Atg14	Atg14	Vps34	Vps34	Vps34	3	4	6	7
Further analysis of these proteins suggested that Atg14L enhances hVps34 lipid kinase activity and upregulates autophagy , whereas Rubicon reduces hVps34 activity and downregulates autophagy [ XREF_BIBR ] .	Further analysis of these proteins suggested that Atg14L enhances hVps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces hVps34 activity and downregulates autophagy [XREF_BIBR].	7	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14L	Atg14L	Atg14L	hVps34	hVps34	hVps34	7	8	9	10
Finally , our data suggests that the function of beclin 1 in endosome pathways depends on the interaction between beclin 1 and UVRAG , but not Atg14L or RUBICON , all of which are important binding partners of beclin 1 that exist in distinct beclin 1 complexes and modulate VPS34 lipid kinase activity .	Finally, our data suggests that the function of beclin 1 in endosome pathways depends on the interaction between beclin 1 and UVRAG, but not Atg14L or RUBICON, all of which are important binding partners of beclin 1 that exist in distinct beclin 1 complexes and modulate VPS34 lipid kinase activity.	14	52	modulate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Atg14L	Atg14L	Atg14L	VPS34	VPS34	VPS34	26	27	49	50
ATG14 ( yeast Atg14 like ) promotes PIK3C3 kinase activity and enhances autophagy XREF_BIBR , XREF_BIBR .	ATG14 (yeast Atg14 like) promotes PIK3C3 kinase activity and enhances autophagy XREF_BIBR, XREF_BIBR.	0	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG14	ATG14	ATG14	PIK3C3	PIK3C3	PIK3C3	0	1	7	8
Notably , the non autophagy Vps34 complex VIC1 and VIC2 showed quite low lipid kinase activity when normalized with Vps34 protein compared with VIC3 and VIC4 , which is consistent with the reports that Atg14L and UVRAG activate Vps34 activity .	Notably, the non autophagy Vps34 complex VIC1 and VIC2 showed quite low lipid kinase activity when normalized with Vps34 protein compared with VIC3 and VIC4, which is consistent with the reports that Atg14L and UVRAG activate Vps34 activity.	34	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14L	Atg14L	Atg14L	Vps34	Vps34	Vps34	34	35	38	39
As covered in XREF_TABLE , ULK1 phosphorylates VPS34 , BECN1 , and ATG14 , with two of these phosphorylation sites ( BECN1 Ser 15 and ATG14 Ser 29 ) known to promote omegasome formation and VPS34 activity in vitro and in vivo .	As covered in XREF_TABLE, ULK1 phosphorylates VPS34, BECN1, and ATG14, with two of these phosphorylation sites (BECN1 Ser 15 and ATG14 Ser 29) known to promote omegasome formation and VPS34 activity in vitro and in vivo.	5	36	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG14	ULK1 phosphorylates VPS34, BECN1, and ATG14, with two of these phosphorylation sites (BECN1 Ser 15	atg14	VPS34	VPS34	vps34	12	13	35	36
Moreover , overexpressed Atg14L was found to stimulate the kinase activity of Vps34 , whereas Atg14L depleted cells showed reduced PI3P production .	Moreover, overexpressed Atg14L was found to stimulate the kinase activity of Vps34, whereas Atg14L depleted cells showed reduced PI3P production.	2	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14L	Atg14L	Atg14L	Vps34	Vps34	Vps34	3	4	12	13
Atg14 targets the Vps34 kinase complex to the PAS [ XREF_BIBR ] .	Atg14 targets the Vps34 kinase complex to the PAS [XREF_BIBR].	0	5	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14	Atg14	Atg14	Vps34	Vps34	Vps34	0	1	3	4
Fifth , we investigated whether Atg14L modulates Vps34 kinase activity using a novel kinase assay which included Vps15 and p150 XREF_BIBR .	Fifth, we investigated whether Atg14L modulates Vps34 kinase activity using a novel kinase assay which included Vps15 and p150 XREF_BIBR.	5	9	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14L	Atg14L	Atg14L	Vps34	Vps34	Vps34	5	6	7	8
XREF_BIBR , XREF_BIBR Specifically , in a mutually exclusive manner , ATG14L induces Vps34 kinase activity and autophagy independent of UVRAG , whereas Rubicon inhibits autophagy through mediating impaired maturation of the autophagosome .	XREF_BIBR, XREF_BIBR Specifically, in a mutually exclusive manner, ATG14L induces Vps34 kinase activity and autophagy independent of UVRAG, whereas Rubicon inhibits autophagy through mediating impaired maturation of the autophagosome.	11	15	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATG14L	ATG14L	ATG14L	Vps34	Vps34	Vps34	11	12	13	14
Characterization of these novel proteins reveals that Atg14L enhances Vps34 lipid kinase activity and up-regulates autophagy , whereas Rubicon reduces Vps34 activity and down-regulates autophagy .	Characterization of these novel proteins reveals that Atg14L enhances Vps34 lipid kinase activity and up-regulates autophagy, whereas Rubicon reduces Vps34 activity and down-regulates autophagy.	7	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg14L	Atg14L	Atg14L	Vps34	Vps34	Vps34	7	8	9	10
In the Atg12 conjugation system , Atg12 is activated by Atg7 and Atg10 and conjugated to Atg5 , which promotes the formation of the autophagy precursor .	In the Atg12 conjugation system, Atg12 is activated by Atg7 and Atg10 and conjugated to Atg5, which promotes the formation of the autophagy precursor.	6	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg10	Atg10	Atg10	Atg12	Atg12	Atg12	12	13	6	7
In the Atg12 conjugation system , Atg12 is activated by Atg7 and Atg10 , and conjugated to Atg5 ; which promotes the formation of the autophagy precursor [ XREF_BIBR , XREF_BIBR ] .	In the Atg12 conjugation system, Atg12 is activated by Atg7 and Atg10, and conjugated to Atg5; which promotes the formation of the autophagy precursor [XREF_BIBR, XREF_BIBR].	6	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg10	Atg10	Atg10	Atg12	Atg12	Atg12	12	13	6	7
Activated ATG8 or ATG12 is then transferred to the E2 like conjugation enzymes , ATG3 and ATG10 .	Activated ATG8 or ATG12 is then transferred to the E2 like conjugation enzymes, ATG3 and ATG10.	0	17	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG10	ATG10	ATG10	ATG12	ATG12	ATG12	16	17	3	4
Following initiation , elongation of the phagophore involves the activation of two autophagy related ( Atg ) protein dependent ubiquitin like conjugation systems , Atg5 conjugation to Atg12 mediated by Atg7 and Atg10 , and the conjugation of microtubule associated protein light chain 3 ( LC3 ) to phosphatidylethanolamine via Atg3 and Atg10 .	Following initiation, elongation of the phagophore involves the activation of two autophagy related (Atg) protein dependent ubiquitin like conjugation systems, Atg5 conjugation to Atg12 mediated by Atg7 and Atg10, and the conjugation of microtubule associated protein light chain 3 (LC3) to phosphatidylethanolamine via Atg3 and Atg10.	25	33	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg10	Atg10	Atg10	Atg12	Atg12	Atg12	32	33	27	28
The first involves Atg7 activating Atg12 followed by Atg10 mediating the conjugation of Atg12 and Atg5 .	The first involves Atg7 activating Atg12 followed by Atg10 mediating the conjugation of Atg12 and Atg5.	6	15	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg10	Atg10	Atg10	Atg12	Atg12	Atg12	8	9	13	14
Atg7 , an E1 like enzyme , and atg10 , an E2 like enzyme , promote covalent association of Atg12 and Atg5 along with Atg16 to form a heterotrimeric complex that mediates growth of the autophagosome .	Atg7, an E1 like enzyme, and atg10, an E2 like enzyme, promote covalent association of Atg12 and Atg5 along with Atg16 to form a heterotrimeric complex that mediates growth of the autophagosome.	0	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	atg10	atg10	atg10	Atg12	Atg12	Atg12	8	9	19	20
In the first , Atg7 and Atg10 mediate the conjugation of Atg12 to Atg5 , 19 which subsequently interact with Atg16 .	In the first, Atg7 and Atg10 mediate the conjugation of Atg12 to Atg5, 19 which subsequently interact with Atg16.	4	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg10	Atg10	Atg10	Atg12	Atg12	Atg12	6	7	11	12
Fourth , does ATG7 also participate in ATG3 mediated transfer of ATG8 to its target , the lipid phosphatidylethanolamine , or ATG10 mediated transfer of ATG12 to its protein target , ATG5 ?	Fourth, does ATG7 also participate in ATG3 mediated transfer of ATG8 to its target, the lipid phosphatidylethanolamine, or ATG10 mediated transfer of ATG12 to its protein target, ATG5?	21	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG10	ATG10	ATG10	ATG12	ATG12	ATG12	21	22	25	26
ArfGAP1 is directly phosphorylated by LRRK2 and enhances LRRK2 kinase activity .	ArfGAP1 is directly phosphorylated by LRRK2 and enhances LRRK2 kinase activity.	0	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArfGAP1	ArfGAP1 is directly phosphorylated	arfgap1	LRRK2	LRRK2	lrrk2	0	1	8	9
Delta64-ArfGAP1 , a dominant negative ArfGAP1 , and shRNA knockdown of ArfGAP1 reduce LRRK2 toxicity .	Delta64-ArfGAP1, a dominant negative ArfGAP1, and shRNA knockdown of ArfGAP1 reduce LRRK2 toxicity.	0	14	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ArfGAP1	ArfGAP1	ArfGAP1	LRRK2	LRRK2	LRRK2	5	6	13	14
Unexpectedly , we observe that ArfGAP1 enhances the kinase activity of LRRK2 .	Unexpectedly, we observe that ArfGAP1 enhances the kinase activity of LRRK2.	5	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArfGAP1	ArfGAP1	ArfGAP1	LRRK2	LRRK2	LRRK2	5	6	11	12
ArfGAP1 enhances the GTPase activity of LRRK2 .	ArfGAP1 enhances the GTPase activity of LRRK2.	0	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArfGAP1	ArfGAP1	ArfGAP1	LRRK2	LRRK2	LRRK2	0	1	6	7
XREF_BIBR Subsequent studies in mammalian cells and neurons demonstrated that ArfGAP1 and LRRK2 co-localize and interact and that ArfGAP1 promotes the GTPase activity of LRRK2 indicating that it may serve as a GAP like protein .	XREF_BIBR Subsequent studies in mammalian cells and neurons demonstrated that ArfGAP1 and LRRK2 co-localize and interact and that ArfGAP1 promotes the GTPase activity of LRRK2 indicating that it may serve as a GAP like protein.	18	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArfGAP1	ArfGAP1	ArfGAP1	LRRK2	LRRK2	LRRK2	18	19	24	25
Unexpectedly , ArfGAP1 enhances the kinase activity of LRRK2 suggesting a potential requirement of GTP hydrolysis for kinase activation .	Unexpectedly, ArfGAP1 enhances the kinase activity of LRRK2 suggesting a potential requirement of GTP hydrolysis for kinase activation.	2	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArfGAP1	ArfGAP1	ArfGAP1	LRRK2	LRRK2	LRRK2	2	3	8	9
LRRK2 ( leucine rich repeat kinase 2 ) activity , whose mutations are the most common cause for Parkinson ' s Disease , inhibits ArfGAP1 GAP activity and ArfGAP1 is able to stimulate LRRK2 activity XREF_BIBR XREF_BIBR .	LRRK2 (leucine rich repeat kinase 2) activity, whose mutations are the most common cause for Parkinson 's Disease, inhibits ArfGAP1 GAP activity and ArfGAP1 is able to stimulate LRRK2 activity XREF_BIBR XREF_BIBR.	26	36	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArfGAP1	ArfGAP1	ArfGAP1	LRRK2	LRRK2	LRRK2	28	29	33	34
Unexpectedly , ArfGAP1 promotes the kinase activity of LRRK2 suggesting a potential role for GTP hydrolysis in kinase activation .	Unexpectedly, ArfGAP1 promotes the kinase activity of LRRK2 suggesting a potential role for GTP hydrolysis in kinase activation.	2	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArfGAP1	ArfGAP1	ArfGAP1	LRRK2	LRRK2	LRRK2	2	3	8	9
XREF_BIBR , XREF_BIBR Intriguingly , ArfGAP1 also enhances the kinase activity of LRRK2 supporting the idea that GTP hydrolysis can drive kinase activation .	XREF_BIBR, XREF_BIBR Intriguingly, ArfGAP1 also enhances the kinase activity of LRRK2 supporting the idea that GTP hydrolysis can drive kinase activation.	5	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArfGAP1	ArfGAP1	ArfGAP1	LRRK2	LRRK2	LRRK2	5	6	12	13
In the present study , we translate these observations to mammalian cells and demonstrate that ArfGAP1 , the mammalian ortholog of yeast GCS1 , can functionally modulate LRRK2 activity and toxicity .	In the present study, we translate these observations to mammalian cells and demonstrate that ArfGAP1, the mammalian ortholog of yeast GCS1, can functionally modulate LRRK2 activity and toxicity.	15	28	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArfGAP1	ArfGAP1	ArfGAP1	LRRK2	LRRK2	LRRK2	15	16	27	28
ERK1/2 are activated by MEK1 and MEK2 , which themselves are activated by Raf-1 , A-Raf or B-Raf XREF_BIBR XREF_BIBR .	ERK1/2 are activated by MEK1 and MEK2, which themselves are activated by Raf-1, A-Raf or B-Raf XREF_BIBR XREF_BIBR.	2	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	A-Raf	A-Raf	A-Raf	MEK1	MEK1	MEK1	15	16	4	5
While A-Raf can activate only MEK1 , B-Raf and C-Raf can activate both MEK1 and MEK2 ; however B-Raf is by far the strongest MEK activator .	While A-Raf can activate only MEK1, B-Raf and C-Raf can activate both MEK1 and MEK2; however B-Raf is by far the strongest MEK activator.	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	A-Raf	A-Raf	A-Raf	MEK1	MEK1	MEK1	1	2	5	6
Indeed , in Hela cells , A-Raf selectively activated MEK-1 in response to EGF , whereas Raf-1 activated both MEK-1 and MEK-2 ( Wu et al , 1996 ) .	Indeed, in Hela cells, A-Raf selectively activated MEK-1 in response to EGF, whereas Raf-1 activated both MEK-1 and MEK-2 (Wu et al, 1996).	6	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	A-Raf	A-Raf	A-Raf	MEK-1	MEK-1	MEK-1	6	7	9	10
In HeLa cells , RAF-1 has been reported to activate both MEK1 and MEK2 isoforms , whereas A-RAF is thought to selectively activate MEK1 in response to EGF .	In HeLa cells, RAF-1 has been reported to activate both MEK1 and MEK2 isoforms, whereas A-RAF is thought to selectively activate MEK1 in response to EGF.	17	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	A-RAF	A-RAF	A-RAF	MEK1	MEK1	MEK1	17	18	23	24
Actually , A-Raf triggers a MEK-1 dependent ERK1 & 2 activation upon EGF-treatment XREF_BIBR with a known ERK1 & 2 nuclear translocation .	Actually, A-Raf triggers a MEK-1 dependent ERK1 & 2 activation upon EGF-treatment XREF_BIBR with a known ERK1 & 2 nuclear translocation.	2	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	A-Raf	A-Raf	A-Raf	MEK-1	MEK-1	MEK-1	2	3	5	6
A recently identified GEF , GEFT , strongly activates Rac1 , cdc42 , and to a lesser degree , RhoA .	A recently identified GEF, GEFT, strongly activates Rac1, cdc42, and to a lesser degree, RhoA.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GEFT	GEFT	GEFT	Rac1	Rac1	Rac1	5	6	9	10
Although GEFT may activate both Rac1 and Cdc42 , its effect on neurite growth is possibly via Rac1 and PAK pathway [ XREF_BIBR ] .	Although GEFT may activate both Rac1 and Cdc42, its effect on neurite growth is possibly via Rac1 and PAK pathway [XREF_BIBR].	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GEFT	GEFT	GEFT	Rac1	Rac1	Rac1	1	2	5	6
Catalytic guanine exchange factor ( GEF ) domains of either p63RhoGEF ( an activator of RhoA/B/C ) or TIAM ( an activator of Rac1 ) were fused to an FKBP12 domain and tagged with a fluorescent protein to examine their localization .	Catalytic guanine exchange factor (GEF) domains of either p63RhoGEF (an activator of RhoA/B/C) or TIAM (an activator of Rac1) were fused to an FKBP12 domain and tagged with a fluorescent protein to examine their localization.	7	24	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	Rac1	Rac1	Rac1	10	11	23	24
Thus , it has been established that Bves and GEFT interact to modulate downstream effector proteins , Rac1 and Cdc42 .	Thus, it has been established that Bves and GEFT interact to modulate downstream effector proteins, Rac1 and Cdc42.	7	18	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GEFT	GEFT	GEFT	Rac1	Rac1	Rac1	9	10	17	18
However , recombinant mouse IL13 receptor alpha2 ( IL-13Ralpha2 ) , which was previously shown to abrogate cytokine effects both under in vitro and in vivo conditions [ XREF_BIBR , XREF_BIBR ] , failed to influence apoE stimulated IL-1RA and G-CSF production in VLDL-R- or apoER2 expressing cells , which argues against the notion that apoE drives the M2 polarization via the IL-13-mediated paracrine loop .	However, recombinant mouse IL13 receptor alpha2 (IL-13Ralpha2), which was previously shown to abrogate cytokine effects both under in vitro and in vivo conditions [XREF_BIBR, XREF_BIBR], failed to influence apoE stimulated IL-1RA and G-CSF production in VLDL-R- or apoER2 expressing cells, which argues against the notion that apoE drives the M2 polarization via the IL-13-mediated paracrine loop.	35	47	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoE	apoE	apoE	VLDL-R-	VLDL-R-	VLDL-R-	36	37	43	44
In addition , apoCs can displace larger proteins such as apoE from VLDL , and thereby inhibit apoE mediated VLDL receptor binding .	In addition, apoCs can displace larger proteins such as apoE from VLDL, and thereby inhibit apoE mediated VLDL receptor binding.	17	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	apoE	apoE	apoE	VLDL receptor	VLDL receptor	VLDL receptor	17	18	19	21
Accordingly , apoE induced tyrosine kinase dependent activation of p38 MAP kinase in VLDL-R- or apoER2 expressing macrophages .	Accordingly, apoE induced tyrosine kinase dependent activation of p38 MAP kinase in VLDL-R- or apoER2 expressing macrophages.	2	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoE	apoE	apoE	VLDL-R-	VLDL-R-	VLDL-R-	2	3	13	14
From these studies , we conclude that apoC1 specifically inhibits the apoE mediated binding of triacylglycerol rich lipoprotein particles to the VLDLR , whereas apoC1 enriched lipoproteins can still bind to the LDLR .	From these studies, we conclude that apoC1 specifically inhibits the apoE mediated binding of triacylglycerol rich lipoprotein particles to the VLDLR, whereas apoC1 enriched lipoproteins can still bind to the LDLR.	10	22	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	apoE	apoE	apoE	VLDLR	VLDLR	VLDLR	11	12	21	22
However , binding and internalization were markedly enhanced when fasted human VLDL was preincubated with either recombinant human apoE ( 3/3 ) or lipoprotein lipase ( LPL ) in CHO cells overexpressing the rabbit or human VLDL receptor .	However, binding and internalization were markedly enhanced when fasted human VLDL was preincubated with either recombinant human apoE (3/3) or lipoprotein lipase (LPL) in CHO cells overexpressing the rabbit or human VLDL receptor.	15	38	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoE	apoE	apoE	VLDL receptor	VLDL receptor	VLDL receptor	18	19	36	38
ApoE and/or apoB100 , the major apolipoprotein constituent of LDL , contribute to the interaction of lipoproteins with five different cellular receptors : 1 ) the low density lipoprotein ( LDL ) receptor ; 2 ) the LDL receptor related protein ( LRP ) ; 3 ) the macrophage receptor for hypertriglyceridemic VLDL ; 4 ) the scavenger receptor ; 5 ) the VLDL receptor .	ApoE and/or apoB100, the major apolipoprotein constituent of LDL, contribute to the interaction of lipoproteins with five different cellular receptors : 1) the low density lipoprotein (LDL) receptor; 2) the LDL receptor related protein (LRP); 3) the macrophage receptor for hypertriglyceridemic VLDL; 4) the scavenger receptor; 5) the VLDL receptor.	0	65	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ApoE	ApoE	ApoE	VLDL receptor	VLDL receptor	VLDL receptor	0	1	63	65
These data suggest that the lack of HIF-1beta in the mouse liver may cause a compensatory activation of HIF-1alpha and HIF-2alpha .	These data suggest that the lack of HIF-1beta in the mouse liver may cause a compensatory activation of HIF-1alpha and HIF-2alpha.	5	20	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIF-1beta	HIF-1beta	HIF-1beta	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	18	19
Another survival benefit is that in certain tumors ( including HCC tumors ) , HIF-1beta and ARNT expression is upregulated by HIF-1alpha , resulting in augmented HIF-1alpha signaling and better survival [ XREF_BIBR ] .	Another survival benefit is that in certain tumors (including HCC tumors), HIF-1beta and ARNT expression is upregulated by HIF-1alpha, resulting in augmented HIF-1alpha signaling and better survival [XREF_BIBR].	14	27	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARNT	ARNT expression	arnt	HIF-1alpha	HIF-1alpha	hif-1alpha	16	17	26	27
ARNT induced HIF-1alpha accumulation in ARNT overexpressing cells ( XREF_FIG ) might be the cause for the observed prolonged HRE reporter activity after re-oxygenation ( XREF_FIG ) .	ARNT induced HIF-1alpha accumulation in ARNT overexpressing cells (XREF_FIG) might be the cause for the observed prolonged HRE reporter activity after re-oxygenation (XREF_FIG).	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	ARNT	ARNT	ARNT	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	2	3
Suppression of this luciferase activity is likely due to a summation of two effects : ( 1 ) Ainp1 reduces the nuclear ARNT levels by sequestering ARNT in the cytoplasm and ( 2 ) Ainp1 inhibits the HIF-1alpha : : ARNT heterodimer formation in the nucleus .	Suppression of this luciferase activity is likely due to a summation of two effects : (1) Ainp1 reduces the nuclear ARNT levels by sequestering ARNT in the cytoplasm and (2) Ainp1 inhibits the HIF-1alpha : : ARNT heterodimer formation in the nucleus.	26	38	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ARNT	ARNT	ARNT	HIF-1alpha	HIF-1alpha	HIF-1alpha	26	27	37	38
Thus , in Hela cells , MEK and ERK1 & 2 signalling upon a mitogenic stimulation is mainly mediated by A-Raf .	Thus, in Hela cells, MEK and ERK1 & 2 signalling upon a mitogenic stimulation is mainly mediated by A-Raf.	6	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	A-Raf	A-Raf	A-Raf	MEK	MEK	MEK	20	21	6	7
The RAF family serine/threonine protein kinases ( RAF-1 , B-RAF , A-RAF ) activates MEK1/2 by phosphorylation .	The RAF family serine/threonine protein kinases (RAF-1, B-RAF, A-RAF) activates MEK1/2 by phosphorylation.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	A-RAF	A-RAF	A-RAF	MEK1/2	MEK1/2	MEK1/2	11	12	14	15
For example , the RAF kinase family consists of three members : ARAF , BRAF and CRAF each of which can activate MEK and ERK signaling XREF_BIBR .	For example, the RAF kinase family consists of three members : ARAF, BRAF and CRAF each of which can activate MEK and ERK signaling XREF_BIBR.	10	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARAF	ARAF	ARAF	MEK	MEK	MEK	12	13	22	23
GTP loaded RAS activates the RAF kinases ( ARAF , BRAF , CRAF ) , which in turn activate the MEK kinases ( MEK1 and MEK2 ) , leading to activation of extracellular-signal-regulated kinase 1 ( ERK1 ) and ERK2 [ XREF_BIBR ] .	GTP loaded RAS activates the RAF kinases (ARAF, BRAF, CRAF), which in turn activate the MEK kinases (MEK1 and MEK2), leading to activation of extracellular-signal-regulated kinase 1 (ERK1) and ERK2 [XREF_BIBR].	8	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARAF	ARAF	ARAF	MEK	MEK	MEK	8	9	20	21
The apparent B-Raf-MEK and Erk uncoupling could reflect heterogeneous hepatocyte populations in the liver where activation of the MEK and Erk axis could be mediated by alternative upstream MEK activators such as C-Raf , A-Raf , or PAK .	The apparent B-Raf-MEK and Erk uncoupling could reflect heterogeneous hepatocyte populations in the liver where activation of the MEK and Erk axis could be mediated by alternative upstream MEK activators such as C-Raf, A-Raf, or PAK.	28	35	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	A-Raf	A-Raf	A-Raf	MEK	MEK	MEK	34	35	28	29
There are three RAF proteins in mammals , A-RAF , B-RAF , and C-RAF , which can all activate MEK , but clearly perform distinct functions in vivo as shown by the phenotypic differences between A-RAF , B-RAF , and C-RAF knock-out mice .	There are three RAF proteins in mammals, A-RAF, B-RAF, and C-RAF, which can all activate MEK, but clearly perform distinct functions in vivo as shown by the phenotypic differences between A-RAF, B-RAF, and C-RAF knock-out mice.	8	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	A-RAF	A-RAF	A-RAF	MEK	MEK	MEK	8	9	19	20
This mechanism provides a credible link between oxidative stress and ER stress by underscoring the reputation of ATF6alpha in the protection of the DA neurons from MPTP induced neurotoxicity that occurs via OS induced activation of ATF6alpha and p38MAPK- mediated enrichment of ATF6alpha transcriptional activity .	This mechanism provides a credible link between oxidative stress and ER stress by underscoring the reputation of ATF6alpha in the protection of the DA neurons from MPTP induced neurotoxicity that occurs via OS induced activation of ATF6alpha and p38MAPK- mediated enrichment of ATF6alpha transcriptional activity.	32	44	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATF6alpha	OS induced activation of ATF6alpha	atf6alpha	ATF6alpha	ATF6alpha	atf6alpha	36	37	42	43
In PHN , excess C16 :0 increased expression of ATF4 and ATF6 ( XREF_FIG ) , consistent with results in mHypoE44 cells XREF_BIBR , and increased expressions of gene targets ATF3 ( target of ATF4 ) and BiP ( target of ATF6 ) ( XREF_FIG ) .	In PHN, excess C16 :0 increased expression of ATF4 and ATF6 (XREF_FIG), consistent with results in mHypoE44 cells XREF_BIBR, and increased expressions of gene targets ATF3 (target of ATF4) and BiP (target of ATF6) (XREF_FIG).	4	42	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	ATF6	C16 :0 increased expression of ATF4 and ATF6	atf6	ATF6	ATF6	atf6	11	12	41	42
Overexpression of ATF6-CA partially restored the cellular proliferation ability of ATF6 -/- hMSCs .	Overexpression of ATF6-CA partially restored the cellular proliferation ability of ATF6 -/- hMSCs.	0	12	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATF6-CA	Overexpression of ATF6-CA	atf6-ca	ATF6	ATF6	atf6	2	3	10	11
Recent studies also demonstrated that eIF-2alpha phosphorylation upregulates ATF6 expression and enhances ATF6 activity and therefore increases the expression of its target genes [ XREF_BIBR ] .	Recent studies also demonstrated that eIF-2alpha phosphorylation upregulates ATF6 expression and enhances ATF6 activity and therefore increases the expression of its target genes [XREF_BIBR].	5	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATF6	eIF-2alpha phosphorylation upregulates ATF6 expression	atf6	ATF6	ATF6	atf6	8	9	12	13
Cleavage of the substrate releases soluble ATF6 from the membrane , which then translocates to the nucleus and activates an ATF6 luciferase reporter construct .	Cleavage of the substrate releases soluble ATF6 from the membrane, which then translocates to the nucleus and activates an ATF6 luciferase reporter construct.	4	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATF6	releases soluble ATF6 from the membrane	atf6	ATF6	ATF6	atf6	6	7	20	21
High levels of APP in neurons , or the APP mutant version associated with AD , promoted the recruitment of APP-BP1 to lipid rafts and activated its death inducing activity .	High levels of APP in neurons, or the APP mutant version associated with AD, promoted the recruitment of APP-BP1 to lipid rafts and activated its death inducing activity.	1	21	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APP	levels of APP	app	APP-BP1	APP-BP1	app-bp1	3	4	20	21
If overexpression of APP activates the AppBp1 pathway as the available data suggest , the lack of APP in neurons near the plaques in late stage AD may result in a functional deficit of AppBp1 .	If overexpression of APP activates the AppBp1 pathway as the available data suggest, the lack of APP in neurons near the plaques in late stage AD may result in a functional deficit of AppBp1.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APP	overexpression of APP	app	AppBp1	AppBp1	appbp1	3	4	6	7
How does APP activate AppBp1 ?	How does APP activate AppBp1?	2	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APP	APP	APP	AppBp1	AppBp1	AppBp1	2	3	4	5
Here we discuss how APP may activate the AppBp1 pathway , which downregulates cell cycle markers and protects genome integrity .	Here we discuss how APP may activate the AppBp1 pathway, which downregulates cell cycle markers and protects genome integrity.	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APP	APP	APP	AppBp1	AppBp1	AppBp1	4	5	8	9
Our observation that overexpression of WT APP and APP ( V642I ) in neurons causes an increase in APP-BP1 protein in the Triton X-100-insoluble fraction suggests that APP-BP1 protein might also be increased in AD brain in the same fraction .	Our observation that overexpression of WT APP and APP (V642I) in neurons causes an increase in APP-BP1 protein in the Triton X-100-insoluble fraction suggests that APP-BP1 protein might also be increased in AD brain in the same fraction.	3	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APP	overexpression of WT APP and APP	app	APP-BP1	APP-BP1	app-bp1	8	9	18	19
Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein ( APP ) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis .	Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis.	18	26	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APP	APP	APP	AppBp1	AppBp1	AppBp1	20	21	25	26
Interestingly , A-Raf does not activate MEK2 , although c-Raf can activate both MEK1 and MEK2 .	Interestingly, A-Raf does not activate MEK2, although c-Raf can activate both MEK1 and MEK2.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	A-Raf	A-Raf	A-Raf	MEK2	MEK2	MEK2	2	3	6	7
However , previously , it has been reported that TGF-alpha and amphiregulin can alternatively activate erbB2 and erbB4 and erbB3 / erbB4 heterodimers , respectively , in other cell types without EGFR expression [ XREF_BIBR , XREF_BIBR ] .	However, previously, it has been reported that TGF-alpha and amphiregulin can alternatively activate erbB2 and erbB4 and erbB3 / erbB4 heterodimers, respectively, in other cell types without EGFR expression [XREF_BIBR, XREF_BIBR].	9	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	amphiregulin	amphiregulin	amphiregulin	erbB2	erbB2	erbB2	11	12	15	16
Upon binding to EGFR , AREG can also induce the activation of ErbB2 , ErbB and ErbB4 [ XREF_BIBR ] .	Upon binding to EGFR, AREG can also induce the activation of ErbB2, ErbB and ErbB4 [XREF_BIBR].	5	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	ErbB2	ErbB2	ErbB2	5	6	12	13
Although there was no increase in GFRalpha3 at this longer time point , it is quite possible that the enhanced levels of artemin present in the skin over this period of time could potentially enhance GFRalpha3 mediated signaling in this population of fibers .	Although there was no increase in GFRalpha3 at this longer time point, it is quite possible that the enhanced levels of artemin present in the skin over this period of time could potentially enhance GFRalpha3 mediated signaling in this population of fibers.	20	37	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	artemin	levels of artemin	artemin	GFRalpha3	GFRalpha3	gfralpha3	22	23	35	36
This observation raises the possibility that changes in nAChR gene expression are directly regulated by Artn activation of GFRalpha3 signaling pathways .	This observation raises the possibility that changes in nAChR gene expression are directly regulated by Artn activation of GFRalpha3 signaling pathways.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Artn	Artn	Artn	GFRalpha3	GFRalpha3	GFRalpha3	15	16	18	19
41 Artemin , which activates Ret and GFRalpha3 , is increased in human atopic skin and artemin treated mice displayed increased sprouting of peripheral nerve fibers and itch like behaviors .	41 Artemin, which activates Ret and GFRalpha3, is increased in human atopic skin and artemin treated mice displayed increased sprouting of peripheral nerve fibers and itch like behaviors.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Artemin	Artemin	Artemin	GFRalpha3	GFRalpha3	GFRalpha3	1	2	7	8
Previous studies of DRG neurons of WT and ART-OE mice have shown that artemin overexpression in skin leads to hypertrophy of GFRalpha3 positive afferents and a 20.5 % increase in total neuron number .	Previous studies of DRG neurons of WT and ART-OE mice have shown that artemin overexpression in skin leads to hypertrophy of GFRalpha3 positive afferents and a 20.5% increase in total neuron number.	13	23	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	artemin	artemin overexpression	artemin	GFRalpha3	GFRalpha3	gfralpha3	13	14	21	22
Recombinant RGS2 and ArhGEF7 increase the GTPase activity of immunopurified full-length LRRK2 in a dose dependent manner in vitro .	Recombinant RGS2 and ArhGEF7 increase the GTPase activity of immunopurified full-length LRRK2 in a dose dependent manner in vitro.	1	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArhGEF7	ArhGEF7	ArhGEF7	LRRK2	LRRK2	LRRK2	3	4	11	12
XREF_BIBR , XREF_BIBR ARHGEF7 was reported to be a putative GEF for LRRK2 since the two proteins were found to interact and ARHGEF7 can enhance the GTPase activity of LRRK2 in vitro .	XREF_BIBR, XREF_BIBR ARHGEF7 was reported to be a putative GEF for LRRK2 since the two proteins were found to interact and ARHGEF7 can enhance the GTPase activity of LRRK2 in vitro.	22	30	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARHGEF7	ARHGEF7	ARHGEF7	LRRK2	LRRK2	LRRK2	22	23	29	30
ArhGEF7 also increases LRRK2 GTPase activity but induces LRRK2 to increase neuronal arborization , length and growth cone formation .	ArhGEF7 also increases LRRK2 GTPase activity but induces LRRK2 to increase neuronal arborization, length and growth cone formation.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ArhGEF7	ArhGEF7	ArhGEF7	LRRK2	LRRK2	LRRK2	0	1	8	9
ATG3 promotes vesicle aggregation and enhances LC3 and GABARAP lipidation .	ATG3 promotes vesicle aggregation and enhances LC3 and GABARAP lipidation.	0	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG3	ATG3	ATG3	GABARAP	GABARAP	GABARAP	0	1	8	9
GABARAP and GATE-16 become processed by Aut2 and Apg4 homologues to expose a C-terminal glycine and are catalyzed by Apg7 ( an E1 like enzyme ) and Aut1 and Apg3 ( an E2 like enzyme ) .	GABARAP and GATE-16 become processed by Aut2 and Apg4 homologues to expose a C-terminal glycine and are catalyzed by Apg7 (an E1 like enzyme) and Aut1 and Apg3 (an E2 like enzyme).	0	30	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Apg3	Apg3	Apg3	GABARAP	GABARAP	GABARAP	29	30	0	1
ASH2L was shown to potentiate the transcriptional activity of GATA3 .	ASH2L was shown to potentiate the transcriptional activity of GATA3.	0	10	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASH2L	ASH2L	ASH2L	GATA3	GATA3	GATA3	0	1	9	10
Finally , we demonstrate that Atg101 stabilizes the expression of Atg13 in the cell , suggesting that Atg101 contributes to Atg13 function by protecting Atg13 from proteasomal degradation .	Finally, we demonstrate that Atg101 stabilizes the expression of Atg13 in the cell, suggesting that Atg101 contributes to Atg13 function by protecting Atg13 from proteasomal degradation.	17	25	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg101	Atg101	Atg101	Atg13	Atg13	Atg13	17	18	24	25
APPL1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances LKB1 cytosolic localization by anchoring this kinase in the cytosol .	APPL1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances LKB1 cytosolic localization by anchoring this kinase in the cytosol.	0	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APPL1	APPL1	APPL1	LKB1	LKB1	LKB1	0	1	12	13
These results suggest that delta-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin and catenin complex .	These results suggest that delta-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin and catenin complex.	4	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARVCF	ARVCF	ARVCF	Erbin	Erbin	Erbin	6	7	14	15
Melanocytes genetically null for ASIP mediators attractin or mahogunin ( Atrn mg-3J and mg-3J or Mgrn1 md-nc and md-nc ) also responded to both ASIP and ASIP-YY in cAMP level , while only ASIP altered their proliferation and ( in part ) shape .	Melanocytes genetically null for ASIP mediators attractin or mahogunin (Atrn mg-3J and mg-3J or Mgrn1 md-nc and md-nc) also responded to both ASIP and ASIP-YY in cAMP level, while only ASIP altered their proliferation and (in part) shape.	2	8	mediators	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ASIP	ASIP	ASIP	attractin	attractin	attractin	4	5	6	7
However , it is unclear the exact mechanism ( s ) of Abeta induced GSK3alpha and GSK3beta increased activities in AD .	However, it is unclear the exact mechanism (s) of Abeta induced GSK3alpha and GSK3beta increased activities in AD.	7	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Abeta	Abeta	Abeta	GSK3alpha	GSK3alpha	GSK3alpha	12	13	14	15
The ATM target CHK2 seems to have an opposite role , which agrees with previous findings showing that CHK2 and ATM have overlapping as well as divergent functions 57 .	The ATM target CHK2 seems to have an opposite role, which agrees with previous findings showing that CHK2 and ATM have overlapping as well as divergent functions 57.	0	6	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	1	2	3	4
Checkpoint signaling is initiated by genotoxic insult by the proximal kinases ATR and ATM , which subsequently activate CHK1 and CHK2 , respectively .	Checkpoint signaling is initiated by genotoxic insult by the proximal kinases ATR and ATM, which subsequently activate CHK1 and CHK2, respectively.	3	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	13	14	20	21
Thirdly , TRF2 has been shown to interact with the ATM target CHK2 at a position close to its Thr68 phosphorylation site , preventing activation of CHK2 .	Thirdly, TRF2 has been shown to interact with the ATM target CHK2 at a position close to its Thr68 phosphorylation site, preventing activation of CHK2.	7	16	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	10	11	12	13
ATM induced Chk2 is a key checkpoint in CPT induced G 2 / M phase arrest through ROS formation .	ATM induced Chk2 is a key checkpoint in CPT induced G 2 / M phase arrest through ROS formation.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	2	3
Chk2 is also activated by ATM in response to single- or double-strand DNA breaks and , consequently , targets Cdc25C phosphatase by stabilizing p53 , which upregulates the activation of cyclin dependent kinase 2 ( Cdk2 ) and cyclin B1 to facilitate G 2 / M phase cell cycle arrest [ XREF_BIBR , XREF_BIBR ] .	Chk2 is also activated by ATM in response to single- or double-strand DNA breaks and, consequently, targets Cdc25C phosphatase by stabilizing p53, which upregulates the activation of cyclin dependent kinase 2 (Cdk2) and cyclin B1 to facilitate G 2 / M phase cell cycle arrest [XREF_BIBR, XREF_BIBR].	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	5	6	0	1
Chk2 activity was reduced by silencing of ATM but not by silencing of ATR , indicating that the activation of ATM in response to DNA damage is responsible for the increase in Chk2 activity in Mus81 -/- cells .	Chk2 activity was reduced by silencing of ATM but not by silencing of ATR, indicating that the activation of ATM in response to DNA damage is responsible for the increase in Chk2 activity in Mus81 -/- cells.	0	8	reduced	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	7	8	0	1
ATM and ATR then activate the checkpoint kinases Chk1 and Chk2 which block cell cycle progression at multiple steps in G1 , S and G2 phases to allow time for repair of the DNA damage prior to entry into mitosis [ XREF_BIBR ] .	ATM and ATR then activate the checkpoint kinases Chk1 and Chk2 which block cell cycle progression at multiple steps in G1, S and G2 phases to allow time for repair of the DNA damage prior to entry into mitosis [XREF_BIBR].	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	10	11
Classically , ATM has been thought to activate Chk2 , and ATR primarily Chk1 .	Classically, ATM has been thought to activate Chk2, and ATR primarily Chk1.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	2	3	8	9
ATM and ATR directly activate a number of signal transducers including the serine/threonine checkpoint kinases 1 and 2 ( CHK1 and CHK2 ) .	ATM and ATR directly activate a number of signal transducers including the serine/threonine checkpoint kinases 1 and 2 (CHK1 and CHK2).	0	22	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	0	1	21	22
While ATM mainly led to the activation of pChk2 and ATR was primarily responsible for the activation of pChk1 , knockdown of all three major phosphatidylinositol 3-kinase-like kinases ( ATM , ATR , and DNA-PKcs ) did not abolish the activation of gammaH2AX during BKPyV infection .	While ATM mainly led to the activation of pChk2 and ATR was primarily responsible for the activation of pChk1, knockdown of all three major phosphatidylinositol 3-kinase-like kinases (ATM, ATR, and DNA-PKcs) did not abolish the activation of gammaH2AX during BKPyV infection.	1	9	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	pChk2	pChk2	pChk2	1	2	8	9
Analysis of the downstream targets showed that FA stimulated ATM preferentially targeted CHK2 versus KAP1 , which was the opposite for the DSB inducers CPT and bleomycin .	Analysis of the downstream targets showed that FA stimulated ATM preferentially targeted CHK2 versus KAP1, which was the opposite for the DSB inducers CPT and bleomycin.	9	14	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	9	10	12	13
Chk1 is activated by ATR in cells treated with ultraviolet radiation [ XREF_BIBR ] , whereas Chk2 is activated by ATM in cells exposed to ionizing radiation [ XREF_BIBR ] .	Chk1 is activated by ATR in cells treated with ultraviolet radiation [XREF_BIBR], whereas Chk2 is activated by ATM in cells exposed to ionizing radiation [XREF_BIBR].	16	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	20	21	16	17
ATM can activate both p53 , a pro apoptotic factor , and CHK2 , which delays cell cycle progression .	ATM can activate both p53, a pro apoptotic factor, and CHK2, which delays cell cycle progression.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	0	1	12	13
This amplification of the locally generated DSB signal later assist in the globalization of the DSB response through massive ATM mediated Chk2 activation ( reviewed in ) .	This amplification of the locally generated DSB signal later assist in the globalization of the DSB response through massive ATM mediated Chk2 activation (reviewed in).	9	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	19	20	21	22
ATM activated CHEK2 regulates P53 , which induces cell-cycle arrest , senescence or apoptosis in response to DNA damage .	ATM activated CHEK2 regulates P53, which induces cell-cycle arrest, senescence or apoptosis in response to DNA damage.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHEK2	CHEK2	CHEK2	0	1	2	3
Of cyclins and Cdks initiating entrance into M phase , BS-IV reduced expression of cyclin B1 and also increased the activation of Chk2 , which are activated by ATM and ATR in response to DNA damage .	Of cyclins and Cdks initiating entrance into M phase, BS-IV reduced expression of cyclin B1 and also increased the activation of Chk2, which are activated by ATM and ATR in response to DNA damage.	20	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	28	29	22	23
Key transducers are the phosphatidyl-inositol-3 kinase like kinases , ATM and ATR , which target the Chk1 and Chk2 effector kinases leading to arrest in specific phases of the cell cycle and DNA repair .	Key transducers are the phosphatidyl-inositol-3 kinase like kinases, ATM and ATR, which target the Chk1 and Chk2 effector kinases leading to arrest in specific phases of the cell cycle and DNA repair.	7	20	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	9	10	18	19
We also found that loss of Nbs1 , which is a member of the MRN DNA damage sensing complex and is required for activation of Chk2 by ATM in response to low levels of DNA damage , caused a significant delay in the increase in PML NB number in response to VP16 ( XREF_FIG and XREF_FIG ) .	We also found that loss of Nbs1, which is a member of the MRN DNA damage sensing complex and is required for activation of Chk2 by ATM in response to low levels of DNA damage, caused a significant delay in the increase in PML NB number in response to VP16 (XREF_FIG and XREF_FIG).	21	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	27	28	25	26
CHK1 is activated by ATR in response to stressors such as replication stress , chemotherapeutic agents , and SSBs ; whereas CHK2 is activated by ATM in response to ionizing radiation , chemotherapeutics , or DSBs [ XREF_BIBR ] .	CHK1 is activated by ATR in response to stressors such as replication stress, chemotherapeutic agents, and SSBs; whereas CHK2 is activated by ATM in response to ionizing radiation, chemotherapeutics, or DSBs [XREF_BIBR].	21	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	25	26	21	22
CHK2 is activated by ATM in a cell cycle independent manner .	CHK2 is activated by ATM in a cell cycle independent manner.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	4	5	0	1
Furthermore , inhibition of ATM by ATM inhibitor abolished 2-ME-activated Chk2 and enhanced radio-cytotoxic effects .	Furthermore, inhibition of ATM by ATM inhibitor abolished 2-ME-activated Chk2 and enhanced radio-cytotoxic effects.	2	11	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	4	5	10	11
Here , we report that the inhibition of SIRT1 by DBC1 in the DNA damage response ( DDR ) also depends on Chk2 , the transducer kinase that is activated by ATM upon DNA lesions and contributes to the spreading of DNA damage signal .	Here, we report that the inhibition of SIRT1 by DBC1 in the DNA damage response (DDR) also depends on Chk2, the transducer kinase that is activated by ATM upon DNA lesions and contributes to the spreading of DNA damage signal.	20	32	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	31	32	22	23
At this point , Chk2 , which is activated by ATM , phosphorylates and suppresses the phosphatase Cdc25-A , thereby preventing activation of cyclin E/cdk2 and thus halting the cell cycle .	At this point, Chk2, which is activated by ATM, phosphorylates and suppresses the phosphatase Cdc25-A, thereby preventing activation of cyclin E/cdk2 and thus halting the cell cycle.	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	10	11	4	5
In contrast , the ATM target CHK2 ( cell cycle checkpoint kinase 2 ) does signal to the cell cycle machinery .	In contrast, the ATM target CHK2 (cell cycle checkpoint kinase 2) does signal to the cell cycle machinery.	3	15	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	4	5	6	7
Results from human fibroblasts proficient or deficient in ATM function ( GM00637 and GM05849 ) indicated that CHK2 activation by irofulven is mediated by the upstream ATM kinase .	Results from human fibroblasts proficient or deficient in ATM function (GM00637 and GM05849) indicated that CHK2 activation by irofulven is mediated by the upstream ATM kinase.	17	27	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	26	27	17	18
Like p53 , CHK2 is also activated through phosphorylation by DNA-PK and ATM and ATR following DNA damage [ XREF_BIBR ] .	Like p53, CHK2 is also activated through phosphorylation by DNA-PK and ATM and ATR following DNA damage [XREF_BIBR].	3	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	12	13	3	4
In response to DNA damage , ATM and ATR-kinases activate Chk2 ( an evolutionarily conserved and well described kinase ) by phosphorylating Thr68 .	In response to DNA damage, ATM and ATR-kinases activate Chk2 (an evolutionarily conserved and well described kinase) by phosphorylating Thr68.	6	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	6	7	10	11
ATM activates Chk2 and ATR activates Chk1 through phosphorylation .	ATM activates Chk2 and ATR activates Chk1 through phosphorylation.	0	5	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	2	3
XREF_BIBR ATM activation of Chk2 kinase further amplifies the signal and expands the number of target proteins .	XREF_BIBR ATM activation of Chk2 kinase further amplifies the signal and expands the number of target proteins.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	1	2	4	5
For example , there are both positive and negative paths from ATM to CHEK2 : the positive path is a direct activation of CHEK2 by ATM , while the negative path is an indirect inhibition , as ATM activates p53 , p53 inhibits MYC , MYC activates E2F1 ( E2F transcription factor 1 ) , and E2F1 activates CHEK2 .	For example, there are both positive and negative paths from ATM to CHEK2 : the positive path is a direct activation of CHEK2 by ATM, while the negative path is an indirect inhibition, as ATM activates p53, p53 inhibits MYC, MYC activates E2F1 (E2F transcription factor 1), and E2F1 activates CHEK2.	21	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	CHEK2	CHEK2	CHEK2	25	26	23	24
CHEK2 is activated by ATM dependent phosphorylation in response to double strand DNA breaks [ XREF_BIBR , XREF_BIBR ] .	CHEK2 is activated by ATM dependent phosphorylation in response to double strand DNA breaks [XREF_BIBR, XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM dependent phosphorylation	atm	CHEK2	CHEK2	chek2	4	5	0	1
Two non redundant checkpoint pathways have been identified and characterized in mammalian cells : the ATR-ATRIP-Chk1 pathway , which is induced by stalled replication forks and activated by gapped duplex DNA ; and the ATM mediated Chk2 pathway , which is induced by DNA double strand breaks ( DSBs ) .	Two non redundant checkpoint pathways have been identified and characterized in mammalian cells : the ATR-ATRIP-Chk1 pathway, which is induced by stalled replication forks and activated by gapped duplex DNA; and the ATM mediated Chk2 pathway, which is induced by DNA double strand breaks (DSBs).	33	37	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	34	35	36	37
ATM driven Chk2 activity is necessary for activation of caspase-7 , whose activity is required for cleavage of the E1 helicase and productive replication .	ATM driven Chk2 activity is necessary for activation of caspase-7, whose activity is required for cleavage of the E1 helicase and productive replication.	0	5	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	2	3
The ATM dependent activation of CHK2 by IR was defective in NBS cells but was restored by ectopic expression of wild-type NBS1 .	The ATM dependent activation of CHK2 by IR was defective in NBS cells but was restored by ectopic expression of wild-type NBS1.	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	1	2	5	6
The transducer proteins include the kinases ATM and ATM- and Rad3 related ( ATR ) ; ATM and ATR phosphorylates and thereby activates the checkpoint kinases Chk1 and Chk2 , which control HuR cytoplasmic abundance and RNA binding , respectively .	The transducer proteins include the kinases ATM and ATM- and Rad3 related (ATR); ATM and ATR phosphorylates and thereby activates the checkpoint kinases Chk1 and Chk2, which control HuR cytoplasmic abundance and RNA binding, respectively.	16	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	16	17	28	29
ATM ( Ataxia Telangiectasia Mutated protein ) is the key activator of p53 and Chk2 in response to genotoxic stress .	ATM (Ataxia Telangiectasia Mutated protein) is the key activator of p53 and Chk2 in response to genotoxic stress.	0	15	is the key activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	14	15
Similarly , ATM can also activate CHK2 ( encoded by CHEK2 ) , which in turn participates in the activation of p53 70 .	Similarly, ATM can also activate CHK2 (encoded by CHEK2), which in turn participates in the activation of p53 70.	2	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	2	3	6	7
Chk1 and Chk2 are activated , via phosphorylation , respectively by ataxia telangiectasia and Rad3 related ( ATR ) and by ataxia telangiectasia mutated protein ( ATM ) [ XREF_BIBR - XREF_BIBR ] .	Chk1 and Chk2 are activated, via phosphorylation, respectively by ataxia telangiectasia and Rad3 related (ATR) and by ataxia telangiectasia mutated protein (ATM) [XREF_BIBR - XREF_BIBR].	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	Chk2	Chk2	Chk2	21	24	2	3
Chk2 is activated primarily by ATM or DNA-PK ( also ATR and hMPs1 ) via phosphorylation of Thr68 in the SQ/TQ cluster domain , which initiates homodimerization of Chk2 monomers followed by trans-activating autophosphorylation of residues Thr383 and Thr387 and then cis phosphorylation of Ser516 .	Chk2 is activated primarily by ATM or DNA-PK (also ATR and hMPs1) via phosphorylation of Thr68 in the SQ/TQ cluster domain, which initiates homodimerization of Chk2 monomers followed by trans-activating autophosphorylation of residues Thr383 and Thr387 and then cis phosphorylation of Ser516.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	5	6	0	1
Ataxia telangiectasia mutated ( ATM ) can activate Chk2 and through this kinase mediate cell cycle arrest .	Ataxia telangiectasia mutated (ATM) can activate Chk2 and through this kinase mediate cell cycle arrest.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	4	5	8	9
XREF_BIBR Phosphorylated Chk2 is the activated state of Chk2 , an effector kinase in the DNA damage network that is activated by ATM ( ataxia telangiectasia mutated ) when DNA double-strand damage occurs .	XREF_BIBR Phosphorylated Chk2 is the activated state of Chk2, an effector kinase in the DNA damage network that is activated by ATM (ataxia telangiectasia mutated) when DNA double-strand damage occurs.	6	32	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	22	23	8	9
Chk2 is also activated by ATR and ATM kinases and shares some common substrates with Chk1 .	Chk2 is also activated by ATR and ATM kinases and shares some common substrates with Chk1.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	7	8	0	1
Although the levels of p53 Ser15 phosphorylation were similar in both types of cells , phosphorylation of ATM , and especially activation of CHK1 and CHK2 , was distinctly higher in undifferentiated EC cells than in differentiated EC cells .	Although the levels of p53 Ser15 phosphorylation were similar in both types of cells, phosphorylation of ATM, and especially activation of CHK1 and CHK2, was distinctly higher in undifferentiated EC cells than in differentiated EC cells.	15	26	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	ATM	phosphorylation of ATM	atm	CHK2	CHK2	chk2	17	18	25	26
In response to double-strand DNA breaks , CHEK2 is activated by ataxia telangiectasia mutated ( ATM ) and is involved in cell cycle control , DNA repair and apoptosis .	In response to double-strand DNA breaks, CHEK2 is activated by ataxia telangiectasia mutated (ATM) and is involved in cell cycle control, DNA repair and apoptosis.	7	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	CHEK2	CHEK2	CHEK2	11	14	7	8
Importantly , these findings were corroborated by the findings that low ATM expression signaled a poor prognosis among patients harboring TP53 and CHK2 wild-type tumors , contrasting an improved prognosis in tumors harboring TP53 and CHEK2 mutations .	Importantly, these findings were corroborated by the findings that low ATM expression signaled a poor prognosis among patients harboring TP53 and CHK2 wild-type tumors, contrasting an improved prognosis in tumors harboring TP53 and CHEK2 mutations.	11	24	signaled	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM expression	atm	CHK2	CHK2	chk2	11	12	22	23
Upon generation of DNA DSBs , ATM phosphorylates and thereby activates the checkpoint kinase Chk2 [ XREF_BIBR ] .	Upon generation of DNA DSBs, ATM phosphorylates and thereby activates the checkpoint kinase Chk2 [XREF_BIBR].	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	6	7	14	15
DNA damage triggers ATM and ATR protein kinases which activate Chk1 and Chk2 .	DNA damage triggers ATM and ATR protein kinases which activate Chk1 and Chk2.	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	3	4	12	13
Following DNA damage , ATM and ATR are activated and stimulate Chk1 and Chk2 .	Following DNA damage, ATM and ATR are activated and stimulate Chk1 and Chk2.	4	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	4	5	13	14
ATM signaling normally activates CHK2 kinase and downstream targets SMC1 and p53 .	ATM signaling normally activates CHK2 kinase and downstream targets SMC1 and p53.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	0	1	4	5
Upon ionizing radiation , CHK2 is activated by ATM kinase and regulates the S-phase and G1-S checkpoints , apoptosis , and DNA repair by phosphorylating downstream target proteins such as p53 and Brca1 .	Upon ionizing radiation, CHK2 is activated by ATM kinase and regulates the S-phase and G1-S checkpoints, apoptosis, and DNA repair by phosphorylating downstream target proteins such as p53 and Brca1.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	8	9	4	5
As mentioned above , in response to DNA lesions , ATM and/or ATR activate CHK1 and CHK2 , which in turn activate E2F1 [ XREF_BIBR ] .	As mentioned above, in response to DNA lesions, ATM and/or ATR activate CHK1 and CHK2, which in turn activate E2F1 [XREF_BIBR].	10	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	10	11	16	17
Figure XREF_FIG demonstrates that the ATM pathway is activated in response to 2cPE , as proved by the phosphorylation of the ATM substrates KAP1 , Smc1 , Chk2 and p53 .	Figure XREF_FIG demonstrates that the ATM pathway is activated in response to 2cPE, as proved by the phosphorylation of the ATM substrates KAP1, Smc1, Chk2 and p53.	5	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	5	6	27	28
In response to cellular stress , p53 is rapidly stabilized and activated by posttranslational modification at serines 15 and 20 mediated through ATM and CHK2 , respectively , and CHK2 is itself activated by ATM .	In response to cellular stress, p53 is rapidly stabilized and activated by posttranslational modification at serines 15 and 20 mediated through ATM and CHK2, respectively, and CHK2 is itself activated by ATM.	29	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	34	35	29	30
ATR and ATM bind to the chromosomes at the site of DNA damage and trigger the activation of two other kinases , Chk1 and Chk2 .	ATR and ATM bind to the chromosomes at the site of DNA damage and trigger the activation of two other kinases, Chk1 and Chk2.	0	25	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	2	3	24	25
Since the ataxia telangiectasia mutated ( ATM ) gene is required for IR induced activation of Chk2 , it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation .	Since the ataxia telangiectasia mutated (ATM) gene is required for IR induced activation of Chk2, it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation.	2	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	Chk2	Chk2	Chk2	2	5	16	17
Chk2 is activated through phosphorylation of Thr68 by ATM in response to DNA DSBs .	Chk2 is activated through phosphorylation of Thr68 by ATM in response to DNA DSBs.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	8	9	0	1
After the appearance of a DSB , ATM activates Chk2 and triggers the nucleolytic processing of the DSB into extended regions of single stranded DNA .	After the appearance of a DSB, ATM activates Chk2 and triggers the nucleolytic processing of the DSB into extended regions of single stranded DNA.	7	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	7	8	9	10
In the case of HPV , expression of viral proteins from the HPV episome leads to ATM kinase activation , which , in turn , activates Chk2 .	In the case of HPV, expression of viral proteins from the HPV episome leads to ATM kinase activation, which, in turn, activates Chk2.	16	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	16	17	26	27
When ATM activates Chk2 , this kinase phosphorylates cdc25A , which is primed for ubiquination and subsequent degradation [ XREF_BIBR ] .	When ATM activates Chk2, this kinase phosphorylates cdc25A, which is primed for ubiquination and subsequent degradation [XREF_BIBR].	1	4	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	1	2	3	4
It has been reported that IR treatment could upregulate ATM expression and consequentially lead to phosphorylation of checkpoint kinase 2 ( CHK2 ) , H2AX and 53BP1 XREF_BIBR - XREF_BIBR , XREF_BIBR , which promoted us to further examine the effect of miR-18a on the ATM downstream target proteins .	It has been reported that IR treatment could upregulate ATM expression and consequentially lead to phosphorylation of checkpoint kinase 2 (CHK2), H2AX and 53BP1 XREF_BIBR - XREF_BIBR, XREF_BIBR, which promoted us to further examine the effect of miR-18a on the ATM downstream target proteins.	5	29	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	IR treatment could upregulate ATM expression	atm	CHK2	CHK2	chk2	9	10	21	22
Likewise , inhibition of ATM with KU55933 prevented CHK2 activation caused by UV exposure but did not abrogate SOX9 depletion .	Likewise, inhibition of ATM with KU55933 prevented CHK2 activation caused by UV exposure but did n't abrogate SOX9 depletion.	2	9	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	4	5	8	9
Upon DNA damage , activated ATM and ATR trigger the activation of their downstream targets CHK1 and CHK2 which , in turn , phosphorylate and activate WEE1 kinase .	Upon DNA damage, activated ATM and ATR trigger the activation of their downstream targets CHK1 and CHK2 which, in turn, phosphorylate and activate WEE1 kinase.	5	18	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	5	6	17	18
On the other hand , we noted a decrease in steady-state levels of the ATR and ATM kinases , and of the adaptor protein 53BP1 which is critical for ATM mediated Chk2 activation in response to DSBs ( XREF_FIG B and C , compare lanes 1 and 2 with 3 and 4 ) .	On the other hand, we noted a decrease in steady-state levels of the ATR and ATM kinases, and of the adaptor protein 53BP1 which is critical for ATM mediated Chk2 activation in response to DSBs (XREF_FIG B and C, compare lanes 1 and 2 with 3 and 4).	29	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	29	30	31	32
The signal transduction cascade is further amplified by transducer checkpoint kinases , CHK1 and CHK2 , which are activated upon phosphorylation by ATM and ATR .	The signal transduction cascade is further amplified by transducer checkpoint kinases, CHK1 and CHK2, which are activated upon phosphorylation by ATM and ATR.	10	24	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	22	23	14	15
Although the MRN complex is not functional in cells coinfected with AAV2 and Ad , ATM and DNA-PK , two main kinases in DDR [ XREF_BIBR ] mediate downstream signaling to SMC1 , Chk1 , Chk2 , H2AX , XRCC4 , and RPA [ XREF_BIBR , XREF_BIBR ] .	Although the MRN complex is not functional in cells coinfected with AAV2 and Ad, ATM and DNA-PK, two main kinases in DDR [XREF_BIBR] mediate downstream signaling to SMC1, Chk1, Chk2, H2AX, XRCC4, and RPA [XREF_BIBR, XREF_BIBR].	15	36	mediate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	15	16	35	36
Chk2 is activated primarily by ATM in response to DSBs .	Chk2 is activated primarily by ATM in response to DSBs.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	5	6	0	1
Some studies reported that when DNA was damaged , Chk2 is activated by ATM and ATR through the phosphorylation of residue Thr68 .	Some studies reported that when DNA was damaged, Chk2 is activated by ATM and ATR through the phosphorylation of residue Thr68.	9	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	13	14	9	10
In mice , CHK2 is activated by ATM in female germ cells during early meiosis and regulates cell cycle progression and spindle assembly during oocyte maturation and early embryo development .	In mice, CHK2 is activated by ATM in female germ cells during early meiosis and regulates cell cycle progression and spindle assembly during oocyte maturation and early embryo development.	3	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	7	8	3	4
In response to DNA damage , DNA-PK and ATM activate Chk2 that is central to the induction of cell cycle arrest and apoptosis .	In response to DNA damage, DNA-PK and ATM activate Chk2 that is central to the induction of cell cycle arrest and apoptosis.	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	8	9	10	11
Previous studies showed that Chk2 was necessary for proper mitosis progression and was primarily activated by ATM in response to DNA double strand breaks .	Previous studies showed that Chk2 was necessary for proper mitosis progression and was primarily activated by ATM in response to DNA double strand breaks.	4	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	16	17	4	5
Locally active ATM and ATR further phosphorylate and activate checkpoint kinases 1 and 2 ( Chk1 and Chk2 ) that rapidly spread the signal to downstream target proteins , such as p53 and Cdc25 phosphatases .	Locally active ATM and ATR further phosphorylate and activate checkpoint kinases 1 and 2 (Chk1 and Chk2) that rapidly spread the signal to downstream target proteins, such as p53 and Cdc25 phosphatases.	1	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	2	3	17	18
Similarly , when severe DNA damage such as DSBs is induced by ionizing radiation ( IR ) , DSB signals mostly activate the sensor kinase ATM , which in turn activates the effector Chk2 kinase leading to cell cycle G2 arrest [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Similarly, when severe DNA damage such as DSBs is induced by ionizing radiation (IR), DSB signals mostly activate the sensor kinase ATM, which in turn activates the effector Chk2 kinase leading to cell cycle G2 arrest [XREF_BIBR, XREF_BIBR - XREF_BIBR].	21	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	25	26	33	34
ATR mainly activates Chek1 in response to ultraviolet damage , whereas ATM activates p53 and Chek2 in response to ionizing radiation damage .	ATR mainly activates Chek1 in response to ultraviolet damage, whereas ATM activates p53 and Chek2 in response to ionizing radiation damage.	11	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chek2	Chek2	Chek2	11	12	15	16
In normal cells , ATM activates both Chk2 and p53 which reside primarily within the nucleus .	In normal cells, ATM activates both Chk2 and p53 which reside primarily within the nucleus.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	4	5	7	8
PP5 deficient MEFs displayed a defect in the G2/M checkpoint after IR , a decrease in Atm activity , and less phosphorylation of the Atm targets Chk2 and Nbs1 after DNA damage [ XREF_BIBR ] .	PP5 deficient MEFs displayed a defect in the G2/M checkpoint after IR, a decrease in Atm activity, and less phosphorylation of the Atm targets Chk2 and Nbs1 after DNA damage [XREF_BIBR].	21	28	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atm	phosphorylation of the Atm	atm	Chk2	Chk2	chk2	24	25	26	27
ATM promotes the activation of BRCA1 , CHK2 , and p53 leading to the induction of response genes such as CDKN1A ( p21 ) , GADD45A and RRM2B that promote cell cycle arrest and DNA repair .	ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A and RRM2B that promote cell cycle arrest and DNA repair.	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	0	1	7	8
The serine threonine checkpoint kinases Chk1 and Chk2 are activated by the ATR and ATM kinases in response to DNA breaks and form the key link between the sensing kinases ATR and ATM and the cell cycle machinery [ XREF_BIBR ] .	The serine threonine checkpoint kinases Chk1 and Chk2 are activated by the ATR and ATM kinases in response to DNA breaks and form the key link between the sensing kinases ATR and ATM and the cell cycle machinery [XREF_BIBR].	4	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	14	15	7	8
It is well known that in response to DNA damage involving DSBs Chk2 is activated by ATM .	It is well known that in response to DNA damage involving DSBs Chk2 is activated by ATM.	12	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	16	17	12	13
In S. cerevisiae , Mec1 activates both Rad53 and Chk1 , while in mammalian cells ATM primarily activates Chk2 ( Rad53 in budding yeast ) and ATR activates Chk1 .	In S. cerevisiae, Mec1 activates both Rad53 and Chk1, while in mammalian cells ATM primarily activates Chk2 (Rad53 in budding yeast) and ATR activates Chk1.	15	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Rad53	Rad53	Rad53	15	16	20	21
Persistent presence of DNA breaks typically triggers G1/S checkpoint activation mediated by the ATM and CHEK2 pathway and delays DNA replication in the S phase .	Persistent presence of DNA breaks typically triggers G1/S checkpoint activation mediated by the ATM and CHEK2 pathway and delays DNA replication in the S phase.	10	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHEK2	CHEK2	CHEK2	13	14	15	16
CHK2 is activated primarily in response to DSB through the phosphorylation of T68 by ATM [ XREF_BIBR - XREF_BIBR ] and subsequent oligomerization and autophosphorylation at T383 and T387 [ XREF_BIBR , XREF_BIBR ] .	CHK2 is activated primarily in response to DSB through the phosphorylation of T68 by ATM [XREF_BIBR - XREF_BIBR] and subsequent oligomerization and autophosphorylation at T383 and T387 [XREF_BIBR, XREF_BIBR].	0	16	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	ATM	phosphorylation of T68 by ATM	atm	CHK2	CHK2	chk2	14	15	0	1
Chk2 is activated via phosphorylation at threonine 68 by ATM in response to DNA damage and transmits the signal from the DNA damage response pathway to the apoptotic pathway XREF_BIBR XREF_BIBR XREF_BIBR .	Chk2 is activated via phosphorylation at threonine 68 by ATM in response to DNA damage and transmits the signal from the DNA damage response pathway to the apoptotic pathway XREF_BIBR XREF_BIBR XREF_BIBR.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	9	10	0	1
These studies suggest that RAS activation may lead to a strong hyperproliferative phase followed by a senescence response possibly due to activation of the DNA damage response following hyper-replication of DNA , mediated by ataxia telangiectasia mutated ( ATM ) , CHK kinase I ( CHK1 ) , and CHK kinase II ( CHK2 ) signaling pathways .	These studies suggest that RAS activation may lead to a strong hyperproliferative phase followed by a senescence response possibly due to activation of the DNA damage response following hyper-replication of DNA, mediated by ataxia telangiectasia mutated (ATM), CHK kinase I (CHK1), and CHK kinase II (CHK2) signaling pathways.	32	54	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	CHK2	CHK2	CHK2	34	37	53	54
Taken together , these results demonstrate that DNA-PKcs , but not the ATM kinase , activates Chk2 during mitosis .	Taken together, these results demonstrate that DNA-PKcs, but not the ATM kinase, activates Chk2 during mitosis.	12	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	12	13	16	17
Chk1 and Chk2 are proteins that are activated following DNA damage ; Chk1 is activated by ATR ( ataxia-telangiectasia and Rad3 related ) primarily in response to the detection of single strand breaks bulky lesions , while Chk2 is activated by ATM ( ataxia-telangiectasia mutated ) following the detection of double strand breaks in DNA [ XREF_BIBR ] .	Chk1 and Chk2 are proteins that are activated following DNA damage; Chk1 is activated by ATR (ataxia-telangiectasia and Rad3 related) primarily in response to the detection of single strand breaks bulky lesions, while Chk2 is activated by ATM (ataxia-telangiectasia mutated) following the detection of double strand breaks in DNA [XREF_BIBR].	37	42	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	41	42	37	38
Several of these pathways involve the ATM mediated activation of Chk2 in mammals ( PRD-4 in Neurospora ) , which primarily serves to arrest cellular division .	Several of these pathways involve the ATM mediated activation of Chk2 in mammals (PRD-4 in Neurospora), which primarily serves to arrest cellular division.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	6	7	10	11
Additionally , ATM activates the checkpoint kinases 2 ( CHK2 ) , that causes inactivation of the cell division cycle 25 ( CDC25 ) phosphatase .	Additionally, ATM activates the checkpoint kinases 2 (CHK2), that causes inactivation of the cell division cycle 25 (CDC25) phosphatase.	2	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	2	3	9	10
Following the induction of DNA double strand breaks in S-phase , ATM activates CHK2 by phosphorylation on threonine 68 ( T68 ) .	Following the induction of DNA double strand breaks in S-phase, ATM activates CHK2 by phosphorylation on threonine 68 (T68).	11	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	11	12	13	14
Chk1 is thought to be activated through phosphorylation of its Ser345 residue by ATR , and Chk2 is activated through phosphorylation of Thr68 by ATM .	Chk1 is thought to be activated through phosphorylation of its Ser345 residue by ATR, and Chk2 is activated through phosphorylation of Thr68 by ATM.	16	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	24	25	16	17
In response to DSB and DNA damage , ATM recognizes it and activates Chk2 that , subsequently , by phosphorylation activates p53 [ XREF_BIBR ] .	In response to DSB and DNA damage, ATM recognizes it and activates Chk2 that, subsequently, by phosphorylation activates p53 [XREF_BIBR].	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	8	9	13	14
Upon induction of irreparable DSBs , the ATM mediated increase of HIC1 SUMOylation is independent of its effector kinase Chk2 .	Upon induction of irreparable DSBs, the ATM mediated increase of HIC1 SUMOylation is independent of its effector kinase Chk2.	6	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	7	8	19	20
In response to double-strand DNA breaks , CHEK2 is activated by ataxia telangiectasia mutated ( ATM ) and involved in cell cycle control , DNA repair and apoptosis .	In response to double-strand DNA breaks, CHEK2 is activated by ataxia telangiectasia mutated (ATM) and involved in cell cycle control, DNA repair and apoptosis.	7	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	CHEK2	CHEK2	CHEK2	11	14	7	8
XREF_FIG , Olaparib induced ATM phosphorylation and activated its downstream effector Chk2 , and subsequently up-regulated Rad51 .	XREF_FIG, Olaparib induced ATM phosphorylation and activated its downstream effector Chk2, and subsequently up-regulated Rad51.	2	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	Olaparib induced ATM phosphorylation	atm	Chk2	Chk2	chk2	4	5	11	12
In line with this , short interfering RNA ( siRNA )-mediated depletion of ATM markedly reduced the detection of IR induced hnRNP K phosphorylation ( XREF_FIG , top panel ; see lower panels for demonstrations of ATM depletion and effects on IR induced , ATM mediated CHK2 Thr 68 phosphorylation ) .	In line with this, short interfering RNA (siRNA)-mediated depletion of ATM markedly reduced the detection of IR induced hnRNP K phosphorylation (XREF_FIG, top panel; see lower panels for demonstrations of ATM depletion and effects on IR induced, ATM mediated CHK2 Thr 68 phosphorylation).	44	47	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	44	45	46	47
In Rad1 depleted cells , Atr dependent Chk1 activation was impaired whereas Atm mediated Chk2 activation was unaffected , suggesting that the sliding clamp is required primarily in Atr dependent signal activation .	In Rad1 depleted cells, Atr dependent Chk1 activation was impaired whereas Atm mediated Chk2 activation was unaffected, suggesting that the sliding clamp is required primarily in Atr dependent signal activation.	12	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Atm	Atm	Atm	Chk2	Chk2	Chk2	12	13	14	15
In the example in Figure XREF_FIG , we see the genes ATM , CHK1 , CHK2 and MDM2 with the relationships : ATM activating CHK1 , CHK2 and MDM2 inhibiting p53 .	In the example in Figure XREF_FIG, we see the genes ATM, CHK1, CHK2 and MDM2 with the relationships : ATM activating CHK1, CHK2 and MDM2 inhibiting p53.	22	27	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	22	23	26	27
SDS-PAGE mobility of the ATM target Chk2 was reduced in response to 10 Gy ionizing radiation , indicative of the Chk2 phosphorylation .	SDS-PAGE mobility of the ATM target Chk2 was reduced in response to 10 Gy ionizing radiation, indicative of the Chk2 phosphorylation.	1	7	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	4	5	6	7
ATM triggers the activation of p53 , Chk2 and indirectly a cytoplasmic form of Mdm2 - a natural inhibitor of p53 .	ATM triggers the activation of p53, Chk2 and indirectly a cytoplasmic form of Mdm2 - a natural inhibitor of p53.	0	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	7	8
The combination treatment induced an S-phase checkpoint response through activation of Chk2 and Chk1 by the ataxia telangiectasia mutated and ataxia telangiectasia mutated and Rad3 related kinases , leading to phosphorylation and decreased Cdc25A levels .	The combination treatment induced an S-phase checkpoint response through activation of Chk2 and Chk1 by the ataxia telangiectasia mutated and ataxia telangiectasia mutated and Rad3 related kinases, leading to phosphorylation and decreased Cdc25A levels.	3	19	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	Chk2	Chk2	Chk2	16	19	11	12
Minimally , Chk2 is activated by phosphorylation of ATM in response to double strand breaks while Chk1 is activated by ATR in response to single stranded DNA [ XREF_BIBR ] .	Minimally, Chk2 is activated by phosphorylation of ATM in response to double strand breaks while Chk1 is activated by ATR in response to single stranded DNA [XREF_BIBR].	2	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	phosphorylation of ATM	atm	Chk2	Chk2	chk2	8	9	2	3
ATM and ATR are central to the entire DNA damage response and directly regulate at least two effector kinases : Chk1 and Chk2 .	ATM and ATR are central to the entire DNA damage response and directly regulate at least two effector kinases : Chk1 and Chk2.	0	23	directly regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	22	23
It is not known how ATM phosphorylation activates hCds1 function and whether the phosphorylation is linked to the FHA .	It is not known how ATM phosphorylation activates hCds1 function and whether the phosphorylation is linked to the FHA.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM phosphorylation	atm	hCds1	hCds1	hcds1	5	6	8	9
Concurrently , ATM activates CHK2 leading to the stabilization and accumulation of p53 , a pivotal mediator of either pause and repair , or permanent growth arrest and cell death .	Concurrently, ATM activates CHK2 leading to the stabilization and accumulation of p53, a pivotal mediator of either pause and repair, or permanent growth arrest and cell death.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	2	3	4	5
XREF_BIBR The CHK1 and CHK2 kinases , the main effectors of the DNA damage response pathway , are activated after genotoxic insults by the ataxia telangiectasia mutated ( ATM ) and ATM-Rad3-related ( ATR ) kinases .	XREF_BIBR The CHK1 and CHK2 kinases, the main effectors of the DNA damage response pathway, are activated after genotoxic insults by the ataxia telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) kinases.	2	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	CHK2	CHK2	CHK2	24	27	4	5
Checkpoint kinase 2 ( CHK2 , CDS1 , RAD53 ) is activated by ataxia telangiectasia mutated ( ATM ) in response to gamma irradiation .	Checkpoint kinase 2 (CHK2, CDS1, RAD53) is activated by ataxia telangiectasia mutated (ATM) in response to gamma irradiation.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	Checkpoint kinase 2	Checkpoint kinase 2	Checkpoint kinase 2	13	16	0	3
XREF_BIBR At the DSBs , ATM activates Chk2 by phosphorylation on T68 and other sites .	XREF_BIBR At the DSBs, ATM activates Chk2 by phosphorylation on T68 and other sites.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	5	6	7	8
However , analysis of the downstream ATM target Chk2 revealed that Chk2 phosphorylation in response to DNA damage was significantly impaired in nesprin-2-depleted , but not lamin A/C depleted , VSMCs , although lamin A/C depleted lysates displayed a modest , nonsignificant reduction in Chk2 phosphorylation ( XREF_FIG ) .	However, analysis of the downstream ATM target Chk2 revealed that Chk2 phosphorylation in response to DNA damage was significantly impaired in nesprin-2-depleted, but not lamin A/C depleted, VSMCs, although lamin A/C depleted lysates displayed a modest, nonsignificant reduction in Chk2 phosphorylation (XREF_FIG).	2	9	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	6	7	8	9
In mammalian cells , ATM kinase activates the downstream kinases CHK1 and CHK2 , which correspond to Cds1 and Chk1 , respectively , in fission yeast XREF_BIBR .	In mammalian cells, ATM kinase activates the downstream kinases CHK1 and CHK2, which correspond to Cds1 and Chk1, respectively, in fission yeast XREF_BIBR.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	4	5	12	13
Giardia also lacks the Chk1 and Chk2 checkpoint kinases that are activated by ATM and ATR , and the downstream TLK kinases [ XREF_BIBR ] .	Giardia also lacks the Chk1 and Chk2 checkpoint kinases that are activated by ATM and ATR, and the downstream TLK kinases [XREF_BIBR].	6	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	13	14	6	7
XREF_BIBR It may be concluded , therefore , that in the cells treated with TPT or MXT Chk2 was activated by ATM .	XREF_BIBR It may be concluded, therefore, that in the cells treated with TPT or MXT Chk2 was activated by ATM.	17	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	21	22	17	18
After DNA damage is detected , the ATM and ATR kinases also activate their downstream effectors CHK1 and CHK2 , beginning a broad range of signaling , from inactivation of CDC25 leading to G2 arrest to TP53 mediated apoptosis .	After DNA damage is detected, the ATM and ATR kinases also activate their downstream effectors CHK1 and CHK2, beginning a broad range of signaling, from inactivation of CDC25 leading to G2 arrest to TP53 mediated apoptosis.	7	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	7	8	18	19
ATM and ATR activate checkpoint kinases Chk2 and Chk1 , respectively .	ATM and ATR activate checkpoint kinases Chk2 and Chk1, respectively.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	6	7
ATM and ATR activate the CHK1 and CHK2 proteins , which in turn bring about cessation of growth and cellular apoptosis through a cascade involving the p53 and RB1 proteins [ XREF_BIBR ] .	ATM and ATR activate the CHK1 and CHK2 proteins, which in turn bring about cessation of growth and cellular apoptosis through a cascade involving the p53 and RB1 proteins [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	0	1	7	8
These two relationships are illustrated in Figure XREF_FIG where we see ATM activating CHK1 , CHK2 and MDM2 inhibiting p53 .	These two relationships are illustrated in Figure XREF_FIG where we see ATM activating CHK1, CHK2 and MDM2 inhibiting p53.	11	16	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	11	12	15	16
ATM dependent activation of Chk2 leads to activation of cell-cycle checkpoint arrest at G1/S and G2/M [ XREF_BIBR , XREF_BIBR ] .	ATM dependent activation of Chk2 leads to activation of cell-cycle checkpoint arrest at G1/S and G2/M [XREF_BIBR, XREF_BIBR].	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	4	5
ATM dependent activation of Chk2 is the major PIKK-Chk pathway activated by IR .	ATM dependent activation of Chk2 is the major PIKK-Chk pathway activated by IR.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	4	5
ATR is structurally related to the ATM protein kinase , which plays a primary role in the response to DSBs , and directly activates the CHK2 protein kinase .	ATR is structurally related to the ATM protein kinase, which plays a primary role in the response to DSBs, and directly activates the CHK2 protein kinase.	6	27	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	6	7	25	26
ATM can activate the checkpoint kinase Chk2 , resulting in phosphorylation of Cdc25C , and ultimately in the accumulation of inactive Cdc2 .	ATM can activate the checkpoint kinase Chk2, resulting in phosphorylation of Cdc25C, and ultimately in the accumulation of inactive Cdc2.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	6	7
ATM initiated CHK2 activation , reached a maximum at 15 min post-IR , and then dropped to negligible levels at 3 h post-IR in MEF cells , which is consistent with the cell cycle trend of G2/M arrest being released after 8 h post-IR in MEF cells .	ATM initiated CHK2 activation, reached a maximum at 15 min post-IR, and then dropped to negligible levels at 3 h post-IR in MEF cells, which is consistent with the cell cycle trend of G2/M arrest being released after 8 h post-IR in MEF cells.	0	15	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	0	1	2	3
These results establish that in human T cells , CHK2 is targeted by ATM , and that the overall defect of this pathway can be attributed to ATM insufficiency owing to chronic HCV infection .	These results establish that in human T cells, CHK2 is targeted by ATM, and that the overall defect of this pathway can be attributed to ATM insufficiency owing to chronic HCV infection.	9	14	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	13	14	9	10
The ataxia telangiectasia mutated ( ATM ) and the ataxia telangiectasia related ( ATR ) kinases are activated in response to double-strand breaks and , in turn , activate the checkpoint kinases Chk1 and Chk2 .	The ataxia telangiectasia mutated (ATM) and the ataxia telangiectasia related (ATR) kinases are activated in response to double-strand breaks and, in turn, activate the checkpoint kinases Chk1 and Chk2.	2	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	5	6	34	35
This activated form of ATM then activates downstream Chk2 kinase by phosphorylation of its Thr68 .	This activated form of ATM then activates downstream Chk2 kinase by phosphorylation of its Thr68.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	4	5	8	9
DNA double-strand breaks activate the intracellular ATM kinase , and ATM can activate the nuclear CHEK2 through a series of phosphorylation reactions .	DNA double-strand breaks activate the intracellular ATM kinase, and ATM can activate the nuclear CHEK2 through a series of phosphorylation reactions.	10	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHEK2	CHEK2	CHEK2	10	11	15	16
Phosphorylation of ATR and ATM activates the checkpoint kinases CHK1 and CHK2 , respectively .	Phosphorylation of ATR and ATM activates the checkpoint kinases CHK1 and CHK2, respectively.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	Phosphorylation of ATR and ATM	atm	CHK2	CHK2	chk2	4	5	11	12
Following DNA damage , ATM preferentially activates CHEK2 .	Following DNA damage, ATM preferentially activates CHEK2.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHEK2	CHEK2	CHEK2	4	5	7	8
Mammalian Chk2 is activated by the ATM kinase in response to double strand DNA breaks and other types of DNA damage XREF_BIBR .	Mammalian Chk2 is activated by the ATM kinase in response to double strand DNA breaks and other types of DNA damage XREF_BIBR.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	6	7	1	2
Nucleolin depleted 48BR and MRC5SV cells exhibited reduced ATM auto-phosphorylation and reduced phosphorylation of its substrates SMC1 , NBS1 , p53 , Chk2 , RPA34 , DNA-PKcs and gamma-H2AX , but depletion of nucleolin did not influence the expression of their proteins ( XREF_FIG and S4AB ) .	Nucleolin depleted 48BR and MRC5SV cells exhibited reduced ATM auto-phosphorylation and reduced phosphorylation of its substrates SMC1, NBS1, p53, Chk2, RPA34, DNA-PKcs and gamma-H2AX, but depletion of nucleolin did not influence the expression of their proteins (XREF_FIG and S4AB).	0	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	Nucleolin depleted 48BR and MRC5SV cells exhibited reduced ATM auto-phosphorylation	atm	Chk2	Chk2	chk2	8	9	22	23
Subsequent phosphorylation of p53 by ATM and ATM induced CHK2 results in p53 stabilization , ultimately intensifying transcription of p53 responsive genes involved in DNA repair , cell-cycle checkpoint control and apoptosis .	Subsequent phosphorylation of p53 by ATM and ATM induced CHK2 results in p53 stabilization, ultimately intensifying transcription of p53 responsive genes involved in DNA repair, cell-cycle checkpoint control and apoptosis.	3	10	induced	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	7	8	9	10
On the other hand , TIM is responsible for the activation of CHK2 by ATM in response to doxorubicin induced DNA double strand breaks [ XREF_BIBR ] .	On the other hand, TIM is responsible for the activation of CHK2 by ATM in response to doxorubicin induced DNA double strand breaks [XREF_BIBR].	10	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	14	15	12	13
Among the most important , ATM and ATR respectively target the two serine threonine protein kinases : checkpoint kinase 2 ( CHK2 ) and CHK1 , that function as key signal transducers of the DDR .	Among the most important, ATM and ATR respectively target the two serine threonine protein kinases : checkpoint kinase 2 (CHK2) and CHK1, that function as key signal transducers of the DDR.	5	22	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	5	6	21	22
As is discussed above , ATM and ATR can activate Chk2 and Chk1 to modulate cell cycle arrest .	As is discussed above, ATM and ATR can activate Chk2 and Chk1 to modulate cell cycle arrest.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	5	6	10	11
Chk2 may be activated by other ATM related kinases , such as ATR or DNA-PKcs that have been demonstrated to target Chk2 in vitro .	Chk2 may be activated by other ATM related kinases, such as ATR or DNA-PKcs that have been demonstrated to target Chk2 in vitro.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	6	7	0	1
ATR and ATM phosphorylate and activate the effector kinases Chk1 and Chk2 , respectively .	ATR and ATM phosphorylate and activate the effector kinases Chk1 and Chk2, respectively.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	2	3	11	12
[ XREF_BIBR ] For example , ATM mediated Chk2 activation results in inhibition of the Cdc25 family members and activation of the G2/M checkpoint .	[XREF_BIBR] For example, ATM mediated Chk2 activation results in inhibition of the Cdc25 family members and activation of the G2/M checkpoint.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	6	7	8	9
Increased ATM phosphorylation triggered by PPP2R2A attenuation dramatically upregulated the activity of the downstream effector kinase CHK2 , resulting in G ( 1 ) to S-phase cell-cycle arrest and downregulation of BRCA1 and RAD51 .	Increased ATM phosphorylation triggered by PPP2R2A attenuation dramatically upregulated the activity of the downstream effector kinase CHK2, resulting in G (1) to S-phase cell-cycle arrest and downregulation of BRCA1 and RAD51.	1	17	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM phosphorylation	atm	CHK2	CHK2	chk2	1	2	16	17
In response to DNA damage , the ataxia-telangiectasia mutated ( ATM ) is activated through autophosphorylation of the Ser1981 residue and activates the distal transducer kinase checkpoint kinase 2 ( Chk2 ) , resulting in G2/M checkpoint initiation [ XREF_BIBR ] .	In response to DNA damage, the ataxia-telangiectasia mutated (ATM) is activated through autophosphorylation of the Ser1981 residue and activates the distal transducer kinase checkpoint kinase 2 (Chk2), resulting in G2/M checkpoint initiation [XREF_BIBR].	7	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	10	11	30	31
R16 induces G ( 2 ) arrest via an ATM activated Chk2 executed pathway , accompanied by reducing Chk1 .	R16 induces G (2) arrest via an ATM activated Chk2 executed pathway, accompanied by reducing Chk1.	6	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	9	10	11	12
While Ser403 is directly phosphorylated by ATM , the other two sites are phosphorylated by Chk1 and Chk2 , two crucial kinases that are activated by ATM and ATR and in turn initiate cell cycle checkpoints [ XREF_BIBR - XREF_BIBR ] .	While Ser403 is directly phosphorylated by ATM, the other two sites are phosphorylated by Chk1 and Chk2, two crucial kinases that are activated by ATM and ATR and in turn initiate cell cycle checkpoints [XREF_BIBR - XREF_BIBR].	13	28	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	26	27	17	18
On one hand , the response to DSBs such as those generated by ionizing radiation ( IR ) is triggered through ATM , and the signal is further amplified by ATM dependent activation of the downstream kinase Chk2 .	On one hand, the response to DSBs such as those generated by ionizing radiation (IR) is triggered through ATM, and the signal is further amplified by ATM dependent activation of the downstream kinase Chk2.	30	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	30	31	37	38
Generally , ATM activates Chk2 by phosphorylation it on Thr 68 XREF_BIBR , XREF_BIBR , while ATR activates Chk1 XREF_BIBR .	Generally, ATM activates Chk2 by phosphorylation it on Thr 68 XREF_BIBR, XREF_BIBR, while ATR activates Chk1 XREF_BIBR.	2	7	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	2	3	4	5
In addition , ATR and ATM activate the checkpoint kinases Chk1 and Chk2 , respectively , which modify p53 as well .	In addition, ATR and ATM activate the checkpoint kinases Chk1 and Chk2, respectively, which modify p53 as well.	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	5	6	12	13
Similarly , two IR induced autophosphorylation sites of a downstream ATM target Chk2 , Ser 260 and Ser 379 [ XREF_BIBR , XREF_BIBR ] , were also not significantly changed .	Similarly, two IR induced autophosphorylation sites of a downstream ATM target Chk2, Ser 260 and Ser 379 [XREF_BIBR, XREF_BIBR], were also not significantly changed.	6	17	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	10	11	12	13
XREF_BIBR , XREF_BIBR ATM activates the transcription factors , p53 and E2F1 , and the downstream effecter kinases , Chk2 and Chk1 , located at the nexus of the DNA repair and cell cycle progression pathways .	XREF_BIBR, XREF_BIBR ATM activates the transcription factors, p53 and E2F1, and the downstream effecter kinases, Chk2 and Chk1, located at the nexus of the DNA repair and cell cycle progression pathways.	2	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	3	4	19	20
Since ATM kinases are known to activate Chk1 and Chk2 , we next to examine whether the expression of p-Chk1 and p-Chk2 in response to Jaridonin is ATM dependent using caffeine , a known inhibitor of ATM kinases .	Since ATM kinases are known to activate Chk1 and Chk2, we next to examine whether the expression of p-Chk1 and p-Chk2 in response to Jaridonin is ATM dependent using caffeine, a known inhibitor of ATM kinases.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	1	2	9	10
In budding yeast , Mec1 activates both Rad53 and Chk1 XREF_BIBR , while in human cells Chk2 is activated by ATM and Chk1 by ATR XREF_BIBR .	In budding yeast, Mec1 activates both Rad53 and Chk1 XREF_BIBR, while in human cells Chk2 is activated by ATM and Chk1 by ATR XREF_BIBR.	16	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	20	21	16	17
For example , DNA damage is sensed by the ATM and ATR kinases , which in turn activate CHK2 and CHK1 , respectively .	For example, DNA damage is sensed by the ATM and ATR kinases, which in turn activate CHK2 and CHK1, respectively.	9	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	9	10	18	19
In addition to them cooperating with the related kinase DNA-PK to phosphorylate various proteins at DNA-damage sites , such as histone H2AX ( to yield a phosphorylated species termed gammaH2AX ) , ATM and ATR phosphorylate and activate the downstream effector checkpoint kinases Chk2 and Chk1 , respectively .	In addition to them cooperating with the related kinase DNA-PK to phosphorylate various proteins at DNA-damage sites, such as histone H2AX (to yield a phosphorylated species termed gammaH2AX), ATM and ATR phosphorylate and activate the downstream effector checkpoint kinases Chk2 and Chk1, respectively.	32	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	32	33	43	44
55 CHEK1 is activated by ATR while CHEK2 is activated by ATM , although some crosstalk between these pathways occurs .	55 CHEK1 is activated by ATR while CHEK2 is activated by ATM, although some crosstalk between these pathways occurs.	7	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHEK2	CHEK2	CHEK2	11	12	7	8
Therefore , the activation of Chk2 by ATM is counteracted by the ATM dependent deactivation of Chk2 by Wip1 .	Therefore, the activation of Chk2 by ATM is counteracted by the ATM dependent deactivation of Chk2 by Wip1.	12	17	deactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	12	13	16	17
By enhancing the activity of ATM on Chk2 ( labels U2 , U11 ) , E2F1 forms a positive feedback loop , where ATM activates Chk2 and Chk2 further increases the activity of E2F1 by phosphorylation .	By enhancing the activity of ATM on Chk2 (labels U2, U11), E2F1 forms a positive feedback loop, where ATM activates Chk2 and Chk2 further increases the activity of E2F1 by phosphorylation.	23	29	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	23	24	25	26
Generally , ATM activates Chk2 , while ATR primarily activates Chk1 , although considerable cross-talk between ATM and ATR occurs .	Generally, ATM activates Chk2, while ATR primarily activates Chk1, although considerable cross-talk between ATM and ATR occurs.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	2	3	4	5
As shown in XREF_FIG , both the phosphorylated and total levels of ATM , the ATM target Chk2 , and the ATR target Chk1 were increased in HFK-31 cells compared to uninfected HFKs , indicating activation of ATM and ATR signaling pathways , as published previously .	As shown in XREF_FIG, both the phosphorylated and total levels of ATM, the ATM target Chk2, and the ATR target Chk1 were increased in HFK-31 cells compared to uninfected HFKs, indicating activation of ATM and ATR signaling pathways, as published previously.	10	18	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	15	16	17	18
Chk1 and Chk2 are often activated by ATM and ATR , resulting in a cascade of activation of further downstream signals .	Chk1 and Chk2 are often activated by ATM and ATR, resulting in a cascade of activation of further downstream signals.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	7	8	2	3
These results are consistent with the fact that Chk1 and Chk2 are predominantly activated by ATR and ATM respectively and further support the data presented in XREF_FIG .	These results are consistent with the fact that Chk1 and Chk2 are predominantly activated by ATR and ATM respectively and further support the data presented in XREF_FIG.	8	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	17	18	10	11
XREF_BIBR - XREF_BIBR In response to induction of DSBs ATM activates Chk2 via phosphorylation of Thr68 of this kinase which leads to Chk2 dimerization and acquirement of the catalytic activity .	XREF_BIBR - XREF_BIBR In response to induction of DSBs ATM activates Chk2 via phosphorylation of Thr68 of this kinase which leads to Chk2 dimerization and acquirement of the catalytic activity.	6	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	9	10	11	12
Recently , Zhu found that the chemicals amonafide and R16 can induce DNA DSBs , which trigger the ATM activated Chk2 executed pathway and ultimately lead to G 2 phase arrest , in HCT116 cells XREF_BIBR .	Recently, Zhu found that the chemicals amonafide and R16 can induce DNA DSBs, which trigger the ATM activated Chk2 executed pathway and ultimately lead to G 2 phase arrest, in HCT116 cells XREF_BIBR.	16	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	18	19	20	21
ATR activation results in the activation of Chk1 through phosphorylation at Ser317 and Ser345 XREF_BIBR , XREF_BIBR , while ATM activation induces Chk2 activity through phosphorylation at Thr68 XREF_BIBR , XREF_BIBR .	ATR activation results in the activation of Chk1 through phosphorylation at Ser317 and Ser345 XREF_BIBR, XREF_BIBR, while ATM activation induces Chk2 activity through phosphorylation at Thr68 XREF_BIBR, XREF_BIBR.	19	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	19	20	22	23
Inactivation of the ATM-Chk2 pathway involves the Cdk1 and Plk1 dependent inactivation of the adaptor protein 53BP1 ( that facilitates sustained Chk2 activation by ATM as well as direct inactivation of Chk2 itself in both mammalian cells and yeast [ XREF_BIBR , XREF_BIBR ] .	Inactivation of the ATM-Chk2 pathway involves the Cdk1 and Plk1 dependent inactivation of the adaptor protein 53BP1 (that facilitates sustained Chk2 activation by ATM as well as direct inactivation of Chk2 itself in both mammalian cells and yeast [XREF_BIBR, XREF_BIBR].	21	25	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	24	25	21	22
Although generally , ATM activates Chk2 and Chk1 is activated by ATR , there is crosstalk between these pathways [ XREF_BIBR ] .	Although generally, ATM activates Chk2 and Chk1 is activated by ATR, there is crosstalk between these pathways [XREF_BIBR].	3	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	3	4	5	6
In G2/M checkpoint , ATM activates Chk2 through phosphorylation at Thr68 [ XREF_BIBR , XREF_BIBR ] .	In G2/M checkpoint, ATM activates Chk2 through phosphorylation at Thr68 [XREF_BIBR, XREF_BIBR].	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	4	5	6	7
The ATM and ATR signaling cascades are important pathways of the DNA damage response , and these signals lead to ATR mediated Chk1 activation and ATM mediated Chk2 activation , followed by the regulation of cell cycle progression and apoptosis [ XREF_BIBR ] .	The ATM and ATR signaling cascades are important pathways of the DNA damage response, and these signals lead to ATR mediated Chk1 activation and ATM mediated Chk2 activation, followed by the regulation of cell cycle progression and apoptosis [XREF_BIBR].	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	25	26	27	28
Given the partial phenotypic rescue of Fancm C4/C4 PGCs by Atm haploinsufficiency and p53 nullizygosity , we hypothesized that the ATM target CHK2 served as the intermediate transducer kinase .	Given the partial phenotypic rescue of Fancm C4/C4 PGCs by Atm haploinsufficiency and p53 nullizygosity, we hypothesized that the ATM target CHK2 served as the intermediate transducer kinase.	19	23	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	20	21	22	23
As shown previously , Chk-2 is activated by the ataxia telangiectasia mutated ( ATM )-mediated responses to DNA damage .	As shown previously, Chk-2 is activated by the ataxia telangiectasia mutated (ATM)-mediated responses to DNA damage.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	Chk-2	Chk-2	Chk-2	9	12	4	5
In the early DDR , ATM activates CHK2 , which , by sequestrating dual-specificity phosphatase Cdc25C in the cytoplasm to inhibit the activation of CDK1 , prevents the activation of cyclin B1 and CDK1 complex , a key mitotic regulator .	In the early DDR, ATM activates CHK2, which, by sequestrating dual-specificity phosphatase Cdc25C in the cytoplasm to inhibit the activation of CDK1, prevents the activation of cyclin B1 and CDK1 complex, a key mitotic regulator.	5	35	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ATM	ATM	atm	CHK2	CHK2, which, by sequestrating dual-specificity phosphatase Cdc25C in the cytoplasm to inhibit the activation of CDK1, prevents the activation of cyclin B1 and CDK1 complex	chk2	5	6	7	8
In summary , our present study demonstrates that ST induces DNA damage and subsequently triggers the ATM activated Chk2- and p53 executed pathways , which contribute to the ST induced G 2 phase arrest in GES-1 cells .	In summary, our present study demonstrates that ST induces DNA damage and subsequently triggers the ATM activated Chk2- and p53 executed pathways, which contribute to the ST induced G 2 phase arrest in GES-1 cells.	15	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2-	Chk2-	Chk2-	16	17	18	19
Following DNA damage , the upstream sensor kinases Rad3 ( ATR ) and Tel1 ( ATM ) phosphorylate histone H2A on a C-terminal serine to generate gammaH2A and activate the downstream DNA damage checkpoint kinases Chk1 and the replication checkpoint kinase Cds1 .	Following DNA damage, the upstream sensor kinases Rad3 (ATR) and Tel1 (ATM) phosphorylate histone H2A on a C-terminal serine to generate gammaH2A and activate the downstream DNA damage checkpoint kinases Chk1 and the replication checkpoint kinase Cds1.	13	42	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Cds1	Cds1	Cds1	15	16	41	42
Because Chk2 is activated as a result of ethanol metabolism , we were interested in determining if the upstream kinase ATM , which is able to activate Chk2 , was affected by ethanol metabolism .	Because Chk2 is activated as a result of ethanol metabolism, we were interested in determining if the upstream kinase ATM, which is able to activate Chk2, was affected by ethanol metabolism.	17	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	20	21	27	28
For this , etoposide treated U2OS-CCAR2 +/+ and CCAR2-/- cells were harvested 6h later and analysed for the phosphorylation of the ATM targets Chk2 and KAP1 .	For this, etoposide treated U2OS-CCAR2 +/+ and CCAR2-/- cells were harvested 6h later and analysed for the phosphorylation of the ATM targets Chk2 and KAP1.	18	25	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	phosphorylation of the ATM	atm	Chk2	Chk2	chk2	21	22	23	24
At the DNA-damage , ATM activates Chk2 by phosphorylation [ XREF_BIBR ] , and then the Chk2 influences the stabilization of p53 [ XREF_BIBR ] .	At the DNA-damage, ATM activates Chk2 by phosphorylation [XREF_BIBR], and then the Chk2 influences the stabilization of p53 [XREF_BIBR].	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	4	5	6	7
CHK2 , activated by ATM , responds primarily to DSBs .	CHK2, activated by ATM, responds primarily to DSBs.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	4	5	0	1
Both ATM and ATR kinases have been reported to activate Chk2 .	Both ATM and ATR kinases have been reported to activate Chk2.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	1	2	10	11
Chk2 is a stable protein being expressed throughout the cell cycle and largely inactive in the absence of DNA damage , but is activated mainly by ATM in response to double-strand DNA breaks ( DSBs ) .	Chk2 is a stable protein being expressed throughout the cell cycle and largely inactive in the absence of DNA damage, but is activated mainly by ATM in response to double-strand DNA breaks (DSBs).	0	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	26	27	0	1
These results are consistent with ATM dependent activation of CHK2 leading to a G2/M arrest and viral genome amplification .	These results are consistent with ATM dependent activation of CHK2 leading to a G2/M arrest and viral genome amplification.	5	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	5	6	9	10
In response to DNA damage , ATM and ATR activate Chk1 and Chk2 kinases which result in Cdc25 phosphatase inhibition and cell cycle arrest ( XREF_FIG ) .	In response to DNA damage, ATM and ATR activate Chk1 and Chk2 kinases which result in Cdc25 phosphatase inhibition and cell cycle arrest (XREF_FIG).	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	6	7	12	13
ATM and ATR targets the protein kinases CHK1 and CHK2 , which together with ATM and ATR suppress cyclin dependent kinase ( CDK ) activity and activate CKIs such as p21 WAF1 and CIP1 in a p53 dependent manner XREF_BIBR , XREF_BIBR .	ATM and ATR targets the protein kinases CHK1 and CHK2, which together with ATM and ATR suppress cyclin dependent kinase (CDK) activity and activate CKIs such as p21 WAF1 and CIP1 in a p53 dependent manner XREF_BIBR, XREF_BIBR.	0	17	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	0	1	9	10
The sensor recruits ATM , which further activates its targets CHK1 and CHK2 .	The sensor recruits ATM, which further activates its targets CHK1 and CHK2.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	3	4	12	13
For example , ATM and ATR activate the checkpoint kinases Chk1 and Chk2 , which phosphorylate and inactivate Cdc25 , an activator of cyclin dependent kinases ( Cdks ) , and thereby prevent Cdk activation and cell cycle progression [ XREF_BIBR ] .	For example, ATM and ATR activate the checkpoint kinases Chk1 and Chk2, which phosphorylate and inactivate Cdc25, an activator of cyclin dependent kinases (Cdks), and thereby prevent Cdk activation and cell cycle progression [XREF_BIBR].	3	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	3	4	12	13
The ATM kinase then activates a series of downstream effectors that can be grouped into three pathways : p53 and p21 , CHK2 and CDC25 and NBS1 and SMC1 [ XREF_BIBR ] [ XREF_BIBR ] [ XREF_BIBR ] .	The ATM kinase then activates a series of downstream effectors that can be grouped into three pathways : p53 and p21, CHK2 and CDC25 and NBS1 and SMC1 [XREF_BIBR] [XREF_BIBR] [XREF_BIBR].	1	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	1	2	22	23
Recognition of DNA lesions by sensor proteins activates ATR or ATM which subsequently activate checkpoint effector kinases checkpoint kinase 1 ( CHK1 ) and checkpoint kinase 2 ( CHK2 ) .	Recognition of DNA lesions by sensor proteins activates ATR or ATM which subsequently activate checkpoint effector kinases checkpoint kinase 1 (CHK1) and checkpoint kinase 2 (CHK2).	7	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	checkpoint kinase 2	checkpoint kinase 2	checkpoint kinase 2	10	11	24	27
Complementarily , whereas Chk2 activation by ATM has a reported role in the G1/S checkpoint [ XREF_BIBR , XREF_BIBR ] , no clear defect in the S and G2/M checkpoints were detected in Chk2 deficient mouse cells [ XREF_BIBR ] .	Complementarily, whereas Chk2 activation by ATM has a reported role in the G1/S checkpoint [XREF_BIBR, XREF_BIBR], no clear defect in the S and G2/M checkpoints were detected in Chk2 deficient mouse cells [XREF_BIBR].	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	6	7	3	4
Here we show that the ATM dependent activation of Chk2 by gamma- radiation requires Nbs1 , the gene product involved in the Nijmegen breakage syndrome ( NBS ) , a disorder that shares with AT a variety of phenotypic defects including chromosome fragility , radiosensitivity , and radioresistant DNA synthesis .	Here we show that the ATM dependent activation of Chk2 by gamma- radiation requires Nbs1, the gene product involved in the Nijmegen breakage syndrome (NBS), a disorder that shares with AT a variety of phenotypic defects including chromosome fragility, radiosensitivity, and radioresistant DNA synthesis.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	5	6	9	10
The interaction between baicalein and MutSalpha dissociates MutSalpha from CHK2 , resulting in the activation of CHK2 by ATM .	The interaction between baicalein and MutSalpha dissociates MutSalpha from CHK2, resulting in the activation of CHK2 by ATM.	11	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	18	19	16	17
Upon their recruitment to DNA damage sites , ATM and ATR activate the Checkpoint Kinase 2 ( Chk2 ) and Checkpoint kinase 1 ( Chk1 ) , respectively , even though an extensive communication exists between the two signaling avenues .	Upon their recruitment to DNA damage sites, ATM and ATR activate the Checkpoint Kinase 2 (Chk2) and Checkpoint kinase 1 (Chk1), respectively, even though an extensive communication exists between the two signaling avenues.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Checkpoint Kinase 2	Checkpoint Kinase 2	Checkpoint Kinase 2	8	9	13	16
The phosphatase activity of Cdc25C is inactivated by Chk1 and Chk2 , which are activated by ATM and ATR in response to DNA damage .	The phosphatase activity of Cdc25C is inactivated by Chk1 and Chk2, which are activated by ATM and ATR in response to DNA damage.	6	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	16	17	10	11
While ATM and ATR were initially reported to activate Chk2 and Chk1 respectively , this concept was challenged by studies that show crosstalks between these kinases XREF_BIBR .	While ATM and ATR were initially reported to activate Chk2 and Chk1 respectively, this concept was challenged by studies that show crosstalks between these kinases XREF_BIBR.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	1	2	9	10
In response to DNA damage , ATM primarily activates Chk2 ( when there are DNA double-strand breaks ) , whereas ATR mainly activates Chk1 .	In response to DNA damage, ATM primarily activates Chk2 (when there are DNA double-strand breaks), whereas ATR mainly activates Chk1.	6	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	6	7	9	10
Checkpoint kinase 2 ( Chk2 ) plays a key role in response of the cell cycle progression machinery to DNA damage Activation of Chk2 mediated by ATM involves its phosphorylation on Thr68 which leads to Chk2 dimerization .	Checkpoint kinase 2 (Chk2) plays a key role in response of the cell cycle progression machinery to DNA damage Activation of Chk2 mediated by ATM involves its phosphorylation on Thr68 which leads to Chk2 dimerization.	21	27	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	26	27	23	24
ATM effectors involved in DNA damage induced cell-cycle arrest and induction of programmed cell death include the checkpoint kinase Chk2 and the multi-functional transcription factor p53 .	ATM effectors involved in DNA damage induced cell-cycle arrest and induction of programmed cell death include the checkpoint kinase Chk2 and the multi-functional transcription factor p53.	0	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	19	20
The activation of ATM and ATR upon DNA damage leads to the phosphorylation and activation of downstream effector kinases Chk2 and Chk1 , which then regulate a myriad of cellular processes including cell cycle progression XREF_BIBR .	The activation of ATM and ATR upon DNA damage leads to the phosphorylation and activation of downstream effector kinases Chk2 and Chk1, which then regulate a myriad of cellular processes including cell cycle progression XREF_BIBR.	1	25	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	3	4	19	20
Cdt1 proteolysis requires ubiquitination by the Cul4A-DDB1 ubiquitin ligase and takes place independently of the classic DDR pathway mediated by ATM and ATR and CHK1 and CHK2 kinases XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Cdt1 proteolysis requires ubiquitination by the Cul4A-DDB1 ubiquitin ligase and takes place independently of the classic DDR pathway mediated by ATM and ATR and CHK1 and CHK2 kinases XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	18	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	20	21	26	27
With the help of mediators ( including 53BP1 , MDC1 , BRCA1 , MCPH1 and PTIP in ATM signaling , and TopBP1 and Claspin in ATR signaling ) , ATM and ATR activate the effector kinase CHK2 and CHK1 , respectively , which then spread the signal throughout the nucleus XREF_BIBR - XREF_BIBR .	With the help of mediators (including 53BP1, MDC1, BRCA1, MCPH1 and PTIP in ATM signaling, and TopBP1 and Claspin in ATR signaling), ATM and ATR activate the effector kinase CHK2 and CHK1, respectively, which then spread the signal throughout the nucleus XREF_BIBR - XREF_BIBR.	29	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	29	30	36	37
ATM and ATR activate CHEK2 , CHEK1 , p38MAPK , Wee1 and p53 .	ATM and ATR activate CHEK2, CHEK1, p38MAPK, Wee1 and p53.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHEK2	CHEK2	CHEK2	0	1	4	5
Although CHK1 activation is primarily dependent on ataxia telangiectasia mutated ( ATM ) and Rad3 related kinase ( ATR ) activated by stalled replication forks and single-strand DNA breaks , CHK2 is mainly activated by ATM induced by DNA double-strand breaks ( DSBs ) [ XREF_BIBR ] .	Although CHK1 activation is primarily dependent on ataxia telangiectasia mutated (ATM) and Rad3 related kinase (ATR) activated by stalled replication forks and single-strand DNA breaks, CHK2 is mainly activated by ATM induced by DNA double-strand breaks (DSBs) [XREF_BIBR].	30	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	35	36	30	31
ATM mediated activation of Chk2 occurs by phosphorylation at Thr68 , resulting in stabilization of p53 , activation of BRCA-1 for DNA homologous recombination repair , and degradation and sequestration of CDC25A and CDC25C phosphatases to induce cell cycle arrest [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	ATM mediated activation of Chk2 occurs by phosphorylation at Thr68, resulting in stabilization of p53, activation of BRCA-1 for DNA homologous recombination repair, and degradation and sequestration of CDC25A and CDC25C phosphatases to induce cell cycle arrest [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	4	5
During genotoxic stress these enzymes phosphorylate hundreds of substrates either alone , or through the intermediacy of the downstream effector kinases checkpoint kinase 1 ( CHEK1 ) and checkpoint kinase 2 ( CHEK2 ) activated primarily by ATR and ATM , respectively .	During genotoxic stress these enzymes phosphorylate hundreds of substrates either alone, or through the intermediacy of the downstream effector kinases checkpoint kinase 1 (CHEK1) and checkpoint kinase 2 (CHEK2) activated primarily by ATR and ATM, respectively.	28	40	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	checkpoint kinase 2	checkpoint kinase 2	checkpoint kinase 2	39	40	28	31
The key regulators in response to DNA damage are ATM and ATR kinases , which activated Chk1 and Chk2 [ XREF_BIBR ] .	The key regulators in response to DNA damage are ATM and ATR kinases, which activated Chk1 and Chk2 [XREF_BIBR].	9	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	9	10	18	19
Subsequently , ATM activates Chk2 via phosphorylation .	Subsequently, ATM activates Chk2 via phosphorylation.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	2	3	4	5
It was attractive to suppose that , in our experimental conditions , Chk2 permanently activated by ATM also is able to mediate a long-term p21 induction during senescence .	It was attractive to suppose that, in our experimental conditions, Chk2 permanently activated by ATM also is able to mediate a long-term p21 induction during senescence.	12	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	16	17	12	13
Once activated , ATR and ATM selectively phosphorylate and activate two downstream checkpoint effector kinases , Chk1 and Chk2 .	Once activated, ATR and ATM selectively phosphorylate and activate two downstream checkpoint effector kinases, Chk1 and Chk2.	3	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	5	6	18	19
Silencing of ATR or ATM and inhibition of ATM activity by KU-55933 blocked Chk1 activation and RRM2 up-regulation .	Silencing of ATR or ATM and inhibition of ATM activity by KU-55933 blocked Chk1 activation and RRM2 up-regulation.	0	14	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	4	5	13	14
The other component depiciting gene gene relationships refer to relationships ( eg MDM2 inhibits P53 , ATM activates CHK1 ) in the pathway diagram .	The other component depiciting gene gene relationships refer to relationships (eg MDM2 inhibits P53, ATM activates CHK1) in the pathway diagram.	16	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK1	CHK1	CHK1	16	17	18	19
Although Chk1 is primarily activated by ATR in response to various kinds of lesions and Chk2 by ATM in response to DSBs , there is substantial cross-talk between the two pathways making it difficult to unambiguously assign Chk1 and Chk2 to a single checkpoint pathway [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Although Chk1 is primarily activated by ATR in response to various kinds of lesions and Chk2 by ATM in response to DSBs, there is substantial cross-talk between the two pathways making it difficult to unambiguously assign Chk1 and Chk2 to a single checkpoint pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	17	18	1	2
As an additional mechanism to minimize the risk of mutagenesis , UVB irradiated cells also activate a checkpoint signaling cascade mediated by the ATM and Rad3 related ( ATR ) and checkpoint kinase 1 ( CHK1 ) kinases to transiently suppress DNA synthesis and cell cycle progression .	As an additional mechanism to minimize the risk of mutagenesis, UVB irradiated cells also activate a checkpoint signaling cascade mediated by the ATM and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases to transiently suppress DNA synthesis and cell cycle progression.	20	34	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	checkpoint kinase 1	checkpoint kinase 1	checkpoint kinase 1	23	24	31	34
As CHK1 is normally activated by the ATM and ATR kinases , these findings suggest that p33 ING1b might be a downstream target of ATM and ATR-CHK 1 signaling following UV damage .	As CHK1 is normally activated by the ATM and ATR kinases, these findings suggest that p33 ING1b might be a downstream target of ATM and ATR-CHK 1 signaling following UV damage.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK1	CHK1	CHK1	7	8	1	2
These results indicated that ROS mediated the DNA damage induced by SC-III3 , and ROS activated S phase checkpoint through ATM activated Chk1 and Chk2-Cdc 25A and p53-p21 pathway .	These results indicated that ROS mediated the DNA damage induced by SC-III3, and ROS activated S phase checkpoint through ATM activated Chk1 and Chk2-Cdc 25A and p53-p21 pathway.	18	25	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	20	21	22	23
After UV and IR induced DNA damage or replication arrest , ATR and ATM phosphorylation activates CHK1 [ XREF_BIBR ] .	After UV and IR induced DNA damage or replication arrest, ATR and ATM phosphorylation activates CHK1 [XREF_BIBR].	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM phosphorylation	atm	CHK1	CHK1	chk1	13	14	16	17
We hypothesized that Pim-3 overexpression induces the activation of ATM , which subsequently activates Chk1 , leading to augmentation of DNA repair through cell cycle arrest and the DNA repair pathways .	We hypothesized that Pim-3 overexpression induces the activation of ATM, which subsequently activates Chk1, leading to augmentation of DNA repair through cell cycle arrest and the DNA repair pathways.	7	15	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	9	10	14	15
In addition , the damage dependent Chk1 pathway was activated by ATM but not by ATR .	In addition, the damage dependent Chk1 pathway was activated by ATM but not by ATR.	6	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	11	12	6	7
Usually , activation of Chk1 by ATM is responsible for G2/M cell cycle arrest by phosphorylation of Cdc52C at Ser 216 .	Usually, activation of Chk1 by ATM is responsible for G2/M cell cycle arrest by phosphorylation of Cdc52C at Ser 216.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	6	7	4	5
Chk1 is activated by ATM and ATR kinase following single strand DNA damage and results in a G2 arrest of the cell cycle [ XREF_BIBR ] .	Chk1 is activated by ATM and ATR kinase following single strand DNA damage and results in a G2 arrest of the cell cycle [XREF_BIBR].	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	4	5	0	1
In response to DSBs , CHK1 can be activated indirectly by ATM via DSB resection and subsequent ATR recruitment .	In response to DSBs, CHK1 can be activated indirectly by ATM via DSB resection and subsequent ATR recruitment.	5	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK1	CHK1	CHK1	11	12	5	6
Chk1 can be activated either by ATR in the presence of single stranded DNA damage [ XREF_BIBR - XREF_BIBR ] or by ATM in response to double stranded DNA damage [ XREF_BIBR ] .	Chk1 can be activated either by ATR in the presence of single stranded DNA damage [XREF_BIBR - XREF_BIBR] or by ATM in response to double stranded DNA damage [XREF_BIBR].	0	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	22	23	0	1
A Tel1-to-Chk1 checkpoint pathway acting at unresected DSBs provides a mechanism for coupling Chk1 activation to the initial detection of DSBs and suggests that ATM may activate Chk1 by both direct and indirect mechanisms in mammalian cells .	A Tel1-to-Chk1 checkpoint pathway acting at unresected DSBs provides a mechanism for coupling Chk1 activation to the initial detection of DSBs and suggests that ATM may activate Chk1 by both direct and indirect mechanisms in mammalian cells.	24	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	24	25	27	28
Upon IR , lineage negative ( Lin - ) Per2 -/- cells exhibited a diminished ATM kinase response that led to reduced p-CHK1 , p-CHK2 and p-p53 relative to wild type cells .	Upon IR, lineage negative (Lin -) Per2 -/- cells exhibited a diminished ATM kinase response that led to reduced p-CHK1, p-CHK2 and p-p53 relative to wild type cells.	15	26	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	p-CHK1	p-CHK1	p-CHK1	15	16	22	23
Overall , the data presented in the study challenge the model in which Chk1 only functions downstream from ATR and indicate that ATM does signal to Chk1 .	Overall, the data presented in the study challenge the model in which Chk1 only functions downstream from ATR and indicate that ATM does signal to Chk1.	22	27	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	22	23	26	27
Phosphorylation of ATM and ATR has been shown to activate Chk1 and G2 checkpoint upon DNA damage XREF_BIBR .	Phosphorylation of ATM and ATR has been shown to activate Chk1 and G2 checkpoint upon DNA damage XREF_BIBR.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	Phosphorylation of ATM	atm	Chk1	Chk1	chk1	2	3	10	11
ATM activates Chk1 , marked by its phosphorylation at S317 and S345 , which mediates cell cycle arrest .	ATM activates Chk1, marked by its phosphorylation at S317 and S345, which mediates cell cycle arrest.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	0	1	2	3
KU-55933 also decreased early IR and CDDP-IR induced pChk1 , which is consistent with ATM dependent activation of Chk1 early after IR treatment ( XREF_FIG ) .	KU-55933 also decreased early IR and CDDP-IR induced pChk1, which is consistent with ATM dependent activation of Chk1 early after IR treatment (XREF_FIG).	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	14	15	18	19
It is also possible that in the absence of CHK2 , ATM activates CHK1 to stimulate repair responses 65 .	It is also possible that in the absence of CHK2, ATM activates CHK1 to stimulate repair responses 65.	11	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK1	CHK1	CHK1	11	12	13	14
However , Chk1 could be activated by both ATR and ATM on Ser 345 XREF_BIBR .	However, Chk1 could be activated by both ATR and ATM on Ser 345 XREF_BIBR.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	10	11	2	3
Depending on the type of DNA damage , ATR or ATM protein kinases phosphorylate and activate checkpoint kinase 1 ( CHK1 , encoded by the CHEK1 gene ) 69 .	Depending on the type of DNA damage, ATR or ATM protein kinases phosphorylate and activate checkpoint kinase 1 (CHK1, encoded by the CHEK1 gene) 69.	10	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK1	CHK1	CHK1	10	11	20	21
Activation of the G2 checkpoint in response to DNA damage prevents entry of cells into mitosis and is initiated by ATM mediated activation of CHK1 and CHK2 .	Activation of the G2 checkpoint in response to DNA damage prevents entry of cells into mitosis and is initiated by ATM mediated activation of CHK1 and CHK2.	18	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK1	CHK1	CHK1	20	21	24	25
ATM ( ataxia-telangiectasia mutated ) is necessary for activation of Chk1 by ATR ( ATM and Rad3 related ) in response to double stranded DNA breaks ( DSBs ) but not to DNA replication stress .	ATM (ataxia-telangiectasia mutated) is necessary for activation of Chk1 by ATR (ATM and Rad3 related) in response to double stranded DNA breaks (DSBs) but not to DNA replication stress.	0	11	is necessary for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	0	1	10	11
Moreover , it was shown that both ATR and ATM were able to target the SQ rich C terminus of Chk1 on serine 317 and 345 leading to its activation XREF_BIBR , XREF_BIBR - XREF_BIBR .	Moreover, it was shown that both ATR and ATM were able to target the SQ rich C terminus of Chk1 on serine 317 and 345 leading to its activation XREF_BIBR, XREF_BIBR - XREF_BIBR.	7	21	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	9	10	20	21
Once gemcitabine induces DNA damage , the cell cycle checkpoint Chk1 is activated by ATM and ATR and its active phosphorylated forms initiate a downstream cascade of events leading to cell cycle arrest and DNA damage repair .	Once gemcitabine induces DNA damage, the cell cycle checkpoint Chk1 is activated by ATM and ATR and its active phosphorylated forms initiate a downstream cascade of events leading to cell cycle arrest and DNA damage repair.	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	14	15	10	11
CPT causes replication fork regression 20 and collapse 21 , leading to activation of the checkpoint kinase Chk1 by the ATM related ( ATR ) checkpoint kinase ortholog Rad3 22 .	CPT causes replication fork regression 20 and collapse 21, leading to activation of the checkpoint kinase Chk1 by the ATM related (ATR) checkpoint kinase ortholog Rad3 22.	10	21	leading	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	20	21	17	18
It has been previously established that ATM and ATR are required to activate a p53- and Chk1 dependent G2 arrest upon DNA damage .	It has been previously established that ATM and ATR are required to activate a p53- and Chk1 dependent G2 arrest upon DNA damage.	6	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	6	7	16	17
Therefore , ATM mediated Chk1 and Chk2 act at the cell cycle checkpoints by generating ROS to determine whether the damaged cells are repaired , or whether they undergo G 2 / M phase arrest or apoptosis .	Therefore, ATM mediated Chk1 and Chk2 act at the cell cycle checkpoints by generating ROS to determine whether the damaged cells are repaired, or whether they undergo G 2 / M phase arrest or apoptosis.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	2	3	4	5
Silencing ATM and Chk1 with respective SiRNA blocked the activation of ATM and Chk1 and protected the cells from curcumin mediated G2/M cell cycle arrest and apoptosis in pancreatic cancer cells .	Silencing ATM and Chk1 with respective SiRNA blocked the activation of ATM and Chk1 and protected the cells from curcumin mediated G2/M cell cycle arrest and apoptosis in pancreatic cancer cells.	1	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	1	2	13	14
Phosphorylation of ATM can activate Chk1 by phosphorylation on S345 XREF_BIBR .	Phosphorylation of ATM can activate Chk1 by phosphorylation on S345 XREF_BIBR.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	Phosphorylation of ATM	atm	Chk1	Chk1	chk1	2	3	5	6
Upon DNA damage , ATM activates the checkpoint kinase Chk2 and ATR activates Chk1 in a Claspin dependent process ( XREF_FIG ) .	Upon DNA damage, ATM activates the checkpoint kinase Chk2 and ATR activates Chk1 in a Claspin dependent process (XREF_FIG).	4	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	4	5	13	14
Chk1 activation by ATM was reported in cells exposed to ionizing radiation treatment XREF_BIBR , XREF_BIBR and ATM and ATR were required for Chk2 activation in response to replication stress XREF_BIBR .	Chk1 activation by ATM was reported in cells exposed to ionizing radiation treatment XREF_BIBR, XREF_BIBR and ATM and ATR were required for Chk2 activation in response to replication stress XREF_BIBR.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk1	Chk1	Chk1	3	4	0	1
Inhibition of ATM and ATR , but not of Chk1 , markedly reduced the fraction of pChk1 normally degraded in lysosomes ( XREF_FIG ) .	Inhibition of ATM and ATR, but not of Chk1, markedly reduced the fraction of pChk1 normally degraded in lysosomes (XREF_FIG).	0	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	pChk1	pChk1	pChk1	2	3	16	17
Instead , Atg7 mediates the conjugation of Atg5 and Atg12 to form a complex with Atg16 ; a required step in autophagosome formation .	Instead, Atg7 mediates the conjugation of Atg5 and Atg12 to form a complex with Atg16; a required step in autophagosome formation.	2	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	2	3	9	10
In the ATG12 conjugation system , ATG12 is activated by ATG7 , an E1 like enzyme , transferred to ATG10 , an E2 like enzyme , and conjugated to ATG5 to form an ATG12-ATG5 conjugate .	In the ATG12 conjugation system, ATG12 is activated by ATG7, an E1 like enzyme, transferred to ATG10, an E2 like enzyme, and conjugated to ATG5 to form an ATG12-ATG5 conjugate.	6	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	10	11	6	7
XREF_BIBR Atg7 , an E1 like enzyme , activates Atg12 , which is facilitating oligomerization of various autophagy gene products .	XREF_BIBR Atg7, an E1 like enzyme, activates Atg12, which is facilitating oligomerization of various autophagy gene products.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	1	2	9	10
Both Atg12 and Atg5 are activated by Atg7 , which is homologous to the ubiquitin activating enzyme E1 ( Uba1 ) gene encoding an E1 like enzyme that is critical for these conjugation systems [ XREF_BIBR ] and required for the induction of both selective and nonselective autophagy [ XREF_BIBR , XREF_BIBR ] .	Both Atg12 and Atg5 are activated by Atg7, which is homologous to the ubiquitin activating enzyme E1 (Uba1) gene encoding an E1 like enzyme that is critical for these conjugation systems [XREF_BIBR] and required for the induction of both selective and nonselective autophagy [XREF_BIBR, XREF_BIBR].	0	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	7	8	1	2
The E1 ubiquitin activating enzyme like , Atg7 , activates Atg12 that is transferred to Atg10 .	The E1 ubiquitin activating enzyme like, Atg7, activates Atg12 that is transferred to Atg10.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	7	8	10	11
Conditional knock-out mice have been generated for the E1 like enzyme Atg7 , which activates Atg12 , and for the Atg12 acceptor Atg5 .	Conditional knock-out mice have been generated for the E1 like enzyme Atg7, which activates Atg12, and for the Atg12 acceptor Atg5.	8	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	11	12	15	16
Atg7 activates Atg12 in an ATP dependent manner ( it functions as an ubiquitin activating enzyme , E1 ) , leading to the formation of a thioester bond between the C-terminal glycine in Atg12 and a cysteine residue in Atg7 .	Atg7 activates Atg12 in an ATP dependent manner (it functions as an ubiquitin activating enzyme, E1), leading to the formation of a thioester bond between the C-terminal glycine in Atg12 and a cysteine residue in Atg7.	0	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	0	1	2	3
Atg12 is first activated by Atg7 which acts like an E1 ubiquitin activating enzyme in an ATP dependent manner .	Atg12 is first activated by Atg7 which acts like an E1 ubiquitin activating enzyme in an ATP dependent manner.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	5	6	0	1
Atg12 is activated by Atg7 ( E1 activating enzyme ) , transferred to Atg10 ( E2 conjugating enzyme ) and attached to an internal lysine of the substrate protein Atg5 .	Atg12 is activated by Atg7 (E1 activating enzyme), transferred to Atg10 (E2 conjugating enzyme) and attached to an internal lysine of the substrate protein Atg5.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	4	5	0	1
In the canonical pathway of autophagy , ATG7 mediates the conjugation of ATG5 to ATG12 and participates in the elongation of vesicular membranes during autophagosome biogenesis .	In the canonical pathway of autophagy, ATG7 mediates the conjugation of ATG5 to ATG12 and participates in the elongation of vesicular membranes during autophagosome biogenesis.	7	16	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	7	8	14	15
During autophagosome formation , Atg12 is activated by the ubiquitin-E1-like molecule Atg7 .	During autophagosome formation, Atg12 is activated by the ubiquitin-E1-like molecule Atg7.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	11	12	4	5
Atg12 is activated by Atg7 , an E1 like enzyme , which then transfers Atg12 to Atg10 , an E2 like enzyme , which then conjugates Atg12 to Lys 130 of Atg5 .	Atg12 is activated by Atg7, an E1 like enzyme, which then transfers Atg12 to Atg10, an E2 like enzyme, which then conjugates Atg12 to Lys 130 of Atg5.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	4	5	0	1
Atg12 is activated by Atg7 and is involved in the elongation of isolation membranes .	Atg12 is activated by Atg7 and is involved in the elongation of isolation membranes.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	4	5	0	1
Atg12 is activated by Atg7 ( E1 activating enzyme ) , transferred to Atg10 ( E2 conjugating enzyme ) and attached to an internal lysine of the substrate protein Atg5 covalently .	Atg12 is activated by Atg7 (E1 activating enzyme), transferred to Atg10 (E2 conjugating enzyme) and attached to an internal lysine of the substrate protein Atg5 covalently.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	4	5	0	1
Atg12 is first activated by Atg7 and then attached to Atg5 and Atg16 with the help of Atg10 .	Atg12 is first activated by Atg7 and then attached to Atg5 and Atg16 with the help of Atg10.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	5	6	0	1
In the Atg5-Atg12 conjugation system ( first of the two ULS ) , Atg12 is activated by Atg7 ( an E1 like enzyme ) and is then transferred to Atg10 ( an E2 like enzyme ) that is on the target protein Atg5 .	In the Atg5-Atg12 conjugation system (first of the two ULS), Atg12 is activated by Atg7 (an E1 like enzyme) and is then transferred to Atg10 (an E2 like enzyme) that is on the target protein Atg5.	13	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	17	18	13	14
In addition , during autophagosome formation , Atg12 is activated by the enzyme Atg7 ( E1 like ubiquitin ligase ) and then transferred to Atg10 ( E2 like ubiquitin ligase ) to be conjugated to Atg5 ( E3 like ubiquitin ligase ) , forming an autophagosomal precursor .	In addition, during autophagosome formation, Atg12 is activated by the enzyme Atg7 (E1 like ubiquitin ligase) and then transferred to Atg10 (E2 like ubiquitin ligase) to be conjugated to Atg5 (E3 like ubiquitin ligase), forming an autophagosomal precursor.	7	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	13	14	7	8
ATG12 is activated by ATG7 ( E1 ) , transferred to ATG10 ( E2 ) , followed by covalent linkage to an internal lysine on Atg5 .	ATG12 is activated by ATG7 (E1), transferred to ATG10 (E2), followed by covalent linkage to an internal lysine on Atg5.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	4	5	0	1
Second , how does ATG7 mediate specific ATG8 charging of its dedicated E2 enzyme ( ATG3 ) , and ATG12 charging of its dedicated E2 enzyme ( ATG10 ) ?	Second, how does ATG7 mediate specific ATG8 charging of its dedicated E2 enzyme (ATG3), and ATG12 charging of its dedicated E2 enzyme (ATG10)?	4	20	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	4	5	19	20
Expansion and closure of autophagic vesicles involve transient attachment of the ubiquitin like conjugation complex Atg12 and Atg5 at the phagophore , following Atg12 activation by Atg7 ( E1 activating enzyme ) and its transfer to Atg10 ( E2 conjugatingenzyme ) ( XREF_FIG ) .	Expansion and closure of autophagic vesicles involve transient attachment of the ubiquitin like conjugation complex Atg12 and Atg5 at the phagophore, following Atg12 activation by Atg7 (E1 activating enzyme) and its transfer to Atg10 (E2 conjugatingenzyme) (XREF_FIG).	23	27	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	26	27	23	24
However , different studies have revealed that the autophagy related protein 8 ( ATG8 ) and ATG12 are activated by the same E1 enzyme ATG7 3 , and Ub and HLA-F adjacent transcript 10 ( FAT10 ) are activated by Uba1 and Ube1 and Uba6 XREF_BIBR - XREF_BIBR .	However, different studies have revealed that the autophagy related protein 8 (ATG8) and ATG12 are activated by the same E1 enzyme ATG7 3, and Ub and HLA-F adjacent transcript 10 (FAT10) are activated by Uba1 and Ube1 and Uba6 XREF_BIBR - XREF_BIBR.	13	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	24	25	16	17
Core functions of autophagy are mediated by ubiquitin like protein ( UBL ) cascades , in which a homodimeric E1 enzyme , Atg7 , directs the UBLs Atg8 and Atg12 to their respective E2 enzymes , Atg3 and Atg10 .	Core functions of autophagy are mediated by ubiquitin like protein (UBL) cascades, in which a homodimeric E1 enzyme, Atg7, directs the UBLs Atg8 and Atg12 to their respective E2 enzymes, Atg3 and Atg10.	20	30	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	22	23	29	30
Atg12 is activated by Atg7 , which is an E1 like enzyme 45 , and is then transferred to the E2 like enzyme Atg10 47 .	Atg12 is activated by Atg7, which is an E1 like enzyme 45, and is then transferred to the E2 like enzyme Atg10 47.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	4	5	0	1
Atg7 , an E1 like enzyme that activates Atg12 , and Atg10 , an E2 like enzyme , promote the conjugation of Atg12 to Atg5 at the phagophore [ XREF_BIBR , XREF_BIBR ] .	Atg7, an E1 like enzyme that activates Atg12, and Atg10, an E2 like enzyme, promote the conjugation of Atg12 to Atg5 at the phagophore [XREF_BIBR, XREF_BIBR].	0	18	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	0	1	8	9
proteins assembling at the phagopore include ATG7 , which activates ATG12 , enabling it to be transferred to ATG10 , a carrier protein that potentiates covalent linkage of ATG12 to ATG5 .	proteins assembling at the phagopore include ATG7, which activates ATG12, enabling it to be transferred to ATG10, a carrier protein that potentiates covalent linkage of ATG12 to ATG5.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	6	7	10	11
In Atg12-Atg5-Atg16 , Atg12 is initially triggered by the Atg7 in an ATP dependent way .	In Atg12-Atg5-Atg16, Atg12 is initially triggered by the Atg7 in an ATP dependent way.	3	14	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	9	10	3	4
In the ATG5-ATG12 pathway , ATG7 ( E1 like enzyme ) activates ATG12 that is transferred to ATG10 ( E2 like enzyme ) to finally conjugate with ATG5 .	In the ATG5-ATG12 pathway, ATG7 (E1 like enzyme) activates ATG12 that is transferred to ATG10 (E2 like enzyme) to finally conjugate with ATG5.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	5	6	12	13
ATG7 , a key autophagy protein , contributes to form autophagic vascuoles and activates ATG12 .	ATG7, a key autophagy protein, contributes to form autophagic vascuoles and activates ATG12.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	0	1	14	15
In the first , ATG12 is activated by ATG7 , an E1 like ubiquitin activating enzyme , transferred to ATG10 , an E2 like ubiquitin conjugating enzyme which covalently conjugates it to ATG12 .	In the first, ATG12 is activated by ATG7, an E1 like ubiquitin activating enzyme, transferred to ATG10, an E2 like ubiquitin conjugating enzyme which covalently conjugates it to ATG12.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	8	9	4	5
In parallel , Atg12 is activated by Atg7 as well , and then the E2 like Atg10 catalyzes the formation of an Atg5-Atg12 conjugate [ XREF_BIBR ] .	In parallel, Atg12 is activated by Atg7 as well, and then the E2 like Atg10 catalyzes the formation of an Atg5-Atg12 conjugate [XREF_BIBR].	3	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	7	8	3	4
Atg12 and Atg8 activation by the E1 Atg7 .	Atg12 and Atg8 activation by the E1 Atg7.	0	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	7	8	0	1
In yeast and mammals , ATG7 activates ATG12 via C-terminal adenylation , and a conserved cysteine residue is subsequently covalently linked via a thioester bond to the C-terminal glycine residue [ XREF_BIBR ] .	In yeast and mammals, ATG7 activates ATG12 via C-terminal adenylation, and a conserved cysteine residue is subsequently covalently linked via a thioester bond to the C-terminal glycine residue [XREF_BIBR].	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	5	6	7	8
Atg12 , the ubiquitin like Atg protein , is activated by Atg7 , an E1 like enzyme , and Atg10 then conjugated to Atg5 and promotes the formation of the autophagosome precursor .	Atg12, the ubiquitin like Atg protein, is activated by Atg7, an E1 like enzyme, and Atg10 then conjugated to Atg5 and promotes the formation of the autophagosome precursor.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	11	12	0	1
First , ATG7 acts as an E1 ubiquitin activating enzyme and ATG10 as an E2 ubiquitin conjugating enzyme , enabling ATG12 conjugation to ATG5 .	First, ATG7 acts as an E1 ubiquitin activating enzyme and ATG10 as an E2 ubiquitin conjugating enzyme, enabling ATG12 conjugation to ATG5.	2	21	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	2	3	20	21
In one , Atg12 is activated by Atg7 ( E1 activating enzyme ) and attached to an internal lysine of the substrate protein Atg5 covalently .	In one, Atg12 is activated by Atg7 (E1 activating enzyme) and attached to an internal lysine of the substrate protein Atg5 covalently.	3	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	7	8	3	4
In the first system , ATG12 is activated by ATG7 , transferred to ATG10 and ultimately attached to ATG5 .	In the first system, ATG12 is activated by ATG7, transferred to ATG10 and ultimately attached to ATG5.	5	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	9	10	5	6
Atg12 is activated by Atg7 ( an E1 ubiquitin activating enzyme homologue ) , and conjugated through the action of Atg10 ( an E2 ubiquitin conjugating enzyme analogue ) to an internal lysine of Atg5 [ XREF_BIBR ] .	Atg12 is activated by Atg7 (an E1 ubiquitin activating enzyme homologue), and conjugated through the action of Atg10 (an E2 ubiquitin conjugating enzyme analogue) to an internal lysine of Atg5 [XREF_BIBR].	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	4	5	0	1
In the Atg12 system , Atg12 is activated by Atg7 37 , 38 and transferred to Atg10 39 .	In the Atg12 system, Atg12 is activated by Atg7 37, 38 and transferred to Atg10 39.	5	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	9	10	5	6
The Atg7 or E1 like ( activation enzyme ) together with Atg10 or E2 conjugation like enzyme activates the union of Atg5 and Atg12 ( Atg5-Atg12 ) , which is the E3 like or ligation enzyme .	The Atg7 or E1 like (activation enzyme) together with Atg10 or E2 conjugation like enzyme activates the union of Atg5 and Atg12 (Atg5-Atg12), which is the E3 like or ligation enzyme.	0	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	1	2	23	24
Atg7 also activates Atg12 , another ubiquitin like protein , which then becomes covalently bound to Atg5 .	Atg7 also activates Atg12, another ubiquitin like protein, which then becomes covalently bound to Atg5.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	0	1	3	4
Like Atg8 , Atg12 is activated by Atg7 , although Atg12 has its own E2 ( Atg10 ) and target ( Atg5 ) .	Like Atg8, Atg12 is activated by Atg7, although Atg12 has its own E2 (Atg10) and target (Atg5).	3	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	7	8	3	4
In this process , ATG12 , activated first by ATG7 , is transferred to ATG10 , and finally covalently attached to ATG5 .	In this process, ATG12, activated first by ATG7, is transferred to ATG10, and finally covalently attached to ATG5.	4	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	9	10	4	5
Atg7 activates Atg12 and is then transferred to Atg10 and attached covalently to Atg5 .	Atg7 activates Atg12 and is then transferred to Atg10 and attached covalently to Atg5.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	0	1	2	3
In the latter system , Atg12 is activated by Atg7 and then transferred to an E2 like enzyme Atg10 , via which conjugated to Atg5 .	In the latter system, Atg12 is activated by Atg7 and then transferred to an E2 like enzyme Atg10, via which conjugated to Atg5.	5	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	9	10	5	6
Additionally , ATG-7 together with ATG-10 supports the formation of ATG-5 , ATG-12 , and ATG-16L1 complex , enabling the elongation of the autophagosome membrane .	Additionally, ATG-7 together with ATG-10 supports the formation of ATG-5, ATG-12, and ATG-16L1 complex, enabling the elongation of the autophagosome membrane.	2	16	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG-7	ATG-7	ATG-7	ATG-12	ATG-12	ATG-12	2	3	12	13
In this process Atg12 is activated by the E1 activating enzyme Atg7 and transferred to the E2 like protein Atg10 .	In this process Atg12 is activated by the E1 activating enzyme Atg7 and transferred to the E2 like protein Atg10.	3	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	11	12	3	4
Using Arabidopsis thaliana mutants affecting the ATG5 target or the ATG7 E1 required to initiate ligation of both ATG8 and ATG12 , we previously showed that the ATG8/12 conjugation pathways together are important when plants encounter nutrient stress and during senescence .	Using Arabidopsis thaliana mutants affecting the ATG5 target or the ATG7 E1 required to initiate ligation of both ATG8 and ATG12, we previously showed that the ATG8/12 conjugation pathways together are important when plants encounter nutrient stress and during senescence.	10	21	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATG7	ATG7	ATG7	ATG12	ATG12	ATG12	10	11	20	21
For example , Atg12 is activated by Atg7 , a E1 like molecule , and transferred to Atg10 , an E2 like enzyme , and conjugated to Atg5 through an isopeptide bond .	For example, Atg12 is activated by Atg7, a E1 like molecule, and transferred to Atg10, an E2 like enzyme, and conjugated to Atg5 through an isopeptide bond.	3	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	7	8	3	4
In the first system , Atg7 ( E1 like protein ) activates Atg12 , binds with Atg10 ( E2 like protein ) and conjugates with Atg5 [ XREF_BIBR ] .	In the first system, Atg7 (E1 like protein) activates Atg12, binds with Atg10 (E2 like protein) and conjugates with Atg5 [XREF_BIBR].	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	5	6	12	13
In the first of these systems , Atg7 acting like an E1 ubiquitin activating enzyme activates Atg12 in an ATP dependent manner by binding to its carboxyterminal glycine residue .	In the first of these systems, Atg7 acting like an E1 ubiquitin activating enzyme activates Atg12 in an ATP dependent manner by binding to its carboxyterminal glycine residue.	7	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	7	8	16	17
Atg12 and Atg8 and LC3 are both activated by Atg7 .	Atg12 and Atg8 and LC3 are both activated by Atg7.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	9	10	0	1
Once Atg7 activates Atg12 , then Atg5 is conjugated to Atg12 .	Once Atg7 activates Atg12, then Atg5 is conjugated to Atg12.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg7	Atg7	Atg7	Atg12	Atg12	Atg12	1	2	3	4
Also , we will find that autophosphorylation of ATM induces bifurcation of the phosphorylated ATM ( ATM * ) .	Also, we will find that autophosphorylation of ATM induces bifurcation of the phosphorylated ATM (ATM *).	6	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	autophosphorylation of ATM	atm	ATM	ATM	atm	8	9	14	15
DNA damage by genotoxic stress can activate a pathway initiated by ATM ( ataxia telangiectasia mutated ) and ATR ( ATM- and RAD3 related ) , which has been shown to play a critical role in NKG2D ligand induction .	DNA damage by genotoxic stress can activate a pathway initiated by ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3 related), which has been shown to play a critical role in NKG2D ligand induction.	9	16	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	11	12	13	16
The damage induced autophosphorylation of ATM on S1981 has been demonstrated to promote the retention of ATM to DSBs in a manner that is dependent on the Mre11 complex and the mediator protein , MDC1 .	The damage induced autophosphorylation of ATM on S1981 has been demonstrated to promote the retention of ATM to DSBs in a manner that is dependent on the Mre11 complex and the mediator protein, MDC1.	3	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	autophosphorylation of ATM on S1981	atm	ATM	ATM	atm	5	6	16	17
This activates TIP60 histone acetyltransferase ( HAT ) activity to acetylate ATM and histone H4 lysine residues to direct an ATM dependent DDR to the vicinity of DSBs within heterochromatin .	This activates TIP60 histone acetyltransferase (HAT) activity to acetylate ATM and histone H4 lysine residues to direct an ATM dependent DDR to the vicinity of DSBs within heterochromatin.	10	21	direct	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ATM	acetylate ATM and histone H4 lysine residues	atm	ATM	ATM	atm	11	12	20	21
Impairment of ATM acetylation will then block structural changes in ATM that would lead to its monomerization and activation , inhibiting this way release of the ATM kinase domain otherwise hindered inside of its dimer structure XREF_BIBR .	Impairment of ATM acetylation will then block structural changes in ATM that would lead to its monomerization and activation, inhibiting this way release of the ATM kinase domain otherwise hindered inside of its dimer structure XREF_BIBR.	2	11	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM acetylation	atm	ATM	ATM	atm	2	3	10	11
XREF_BIBR Canonical ATM activation initiates after DSB detection by the MRE11-RAD50-NBS1 ( MRN ) complex , end requires MRN mediated ATM anchoring to DNA-ends , XREF_BIBR TIP60 and KAT5 mediated acetylation , XREF_BIBR ATM autophosphorylation , and monomerization XREF_BIBR of the previously inactive ATM dimer .	XREF_BIBR Canonical ATM activation initiates after DSB detection by the MRE11-RAD50-NBS1 (MRN) complex, end requires MRN mediated ATM anchoring to DNA-ends, XREF_BIBR TIP60 and KAT5 mediated acetylation, XREF_BIBR ATM autophosphorylation, and monomerization XREF_BIBR of the previously inactive ATM dimer.	18	34	mediated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ATM	MRN mediated ATM	atm	ATM	acetylation, XREF_BIBR ATM	atm	20	21	33	34
It has been demonstrated that Atm gene expression is upregulated in response to a mitogenic stimulus , resulting in an increase in ATM protein levels [ XREF_BIBR ] .	It has been demonstrated that Atm gene expression is upregulated in response to a mitogenic stimulus, resulting in an increase in ATM protein levels [XREF_BIBR].	5	25	upregulated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Atm	Atm gene expression	atm	ATM	ATM protein levels	atm	5	6	22	23
These results were consistent with previous reports of IR induced cell cycle stage-specificity of ATM activation and p53 at Ser 15 phosphorylation .	These results were consistent with previous reports of IR induced cell cycle stage-specificity of ATM activation and p53 at Ser 15 phosphorylation.	9	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM activation and p53 at Ser 15 phosphorylation	atm	ATM	ATM	atm	14	15	14	15
Upon DNA damage , ATM autophosphorylates on residue Ser1981 , stimulating the dissociation of ATM dimmers and is therefore followed by the release of active ATM monomers [ XREF_BIBR ] .	Upon DNA damage, ATM autophosphorylates on residue Ser1981, stimulating the dissociation of ATM dimmers and is therefore followed by the release of active ATM monomers [XREF_BIBR].	4	19	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM autophosphorylates on residue Ser1981	atm	ATM	ATM	atm	4	5	14	15
Furthermore , we demonstrate that mutant ATNX3 potently activates the DNA damage response ATM signaling pathway in SCA3 , while increased phosphorylation of ATM , H2AX , Chk2 and p53 , and the formation of 53BP1 and gammaH2AX foci in the ATXN3-Q84-expressing cells , SCA3 patients ' brains and SCA3 transgenic mouse brains suggest that mutant ATXN3 induces genomic DNA damage and chronically activates the ATM pathway in SCA3 .	Furthermore, we demonstrate that mutant ATNX3 potently activates the DNA damage response ATM signaling pathway in SCA3, while increased phosphorylation of ATM, H2AX, Chk2 and p53, and the formation of 53BP1 and gammaH2AX foci in the ATXN3-Q84-expressing cells, SCA3 patients ' brains and SCA3 transgenic mouse brains suggest that mutant ATXN3 induces genomic DNA damage and chronically activates the ATM pathway in SCA3.	21	66	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	phosphorylation of ATM	atm	ATM	ATM	atm	23	24	65	66
For example , if ATM autophosphorylation were to enhance ATM activity 2.5-fold and the nonphosphorylatable ATM were expressed 2.5-fold higher than normal , mice expressing the Tg might be normal in terms of ATM function .	For example, if ATM autophosphorylation were to enhance ATM activity 2.5-fold and the nonphosphorylatable ATM were expressed 2.5-fold higher than normal, mice expressing the Tg might be normal in terms of ATM function.	4	10	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM autophosphorylation	atm	ATM	ATM	atm	4	5	9	10
Phosphorylation of ATM activates ATM dependent signaling that is critical for phosphorylation of H2AX , p53 and checkpoint kinases , which are all involved in DNA repair , cell cycle arrest and chromatin remodeling [ XREF_BIBR ] .	Phosphorylation of ATM activates ATM dependent signaling that is critical for phosphorylation of H2AX, p53 and checkpoint kinases, which are all involved in DNA repair, cell cycle arrest and chromatin remodeling [XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	Phosphorylation of ATM	atm	ATM	ATM	atm	2	3	4	5
Expression of human ATM protein containing S1981A mutation fails to restore all ATM function in A-T cells .	Expression of human ATM protein containing S1981A mutation fails to restore all ATM function in A-T cells.	0	13	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	Expression of human ATM	atm	ATM	ATM	atm	3	4	12	13
TMZ resistance in GBM is associated with DNA damage induced activation of the serine/threonine ataxia telangiectasia mutated kinase ( ATM ) .	TMZ resistance in GBM is associated with DNA damage induced activation of the serine/threonine ataxia telangiectasia mutated kinase (ATM).	9	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	19	20	14	17
The activation of Cdk5 by DNA damage directly phosphorylates ATM at serine 794 , which is required for ATM autophosphorylation at serine 1981 to activate ATM kinase activity XREF_BIBR .	The activation of Cdk5 by DNA damage directly phosphorylates ATM at serine 794, which is required for ATM autophosphorylation at serine 1981 to activate ATM kinase activity XREF_BIBR.	8	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	phosphorylates ATM at serine 794	atm	ATM	ATM	atm	9	10	25	26
In turn , ATM autophosphorylation is sufficient to fully activate ATM .	In turn, ATM autophosphorylation is sufficient to fully activate ATM.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM autophosphorylation	atm	ATM	ATM	atm	3	4	10	11
It was shown that demethylation of ATM promoter increased the levels of ATM protein and decreased the radiosensitivety of U87MG cells XREF_BIBR .	It was shown that demethylation of ATM promoter increased the levels of ATM protein and decreased the radiosensitivety of U87MG cells XREF_BIBR.	4	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	demethylation of ATM	atm	ATM	ATM	atm	6	7	12	13
A-T variant is characterized by a milder clinical phenotype and is caused by missense or leaky splice site mutations that produce residual ataxia telangiectasia mutated ( ATM ) kinase activity .	A-T variant is characterized by a milder clinical phenotype and is caused by missense or leaky splice site mutations that produce residual ataxia telangiectasia mutated (ATM) kinase activity.	18	27	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	26	27	22	25
DNA damage pathway that is initiated by ataxia telangiectasia mutated ( ATM ) or ataxia telegiectasia Rad3 related ( ATR ) kinases has been implicated in the expression of murine NKG2D ligands .	DNA damage pathway that is initiated by ataxia telangiectasia mutated (ATM) or ataxia telegiectasia Rad3 related (ATR) kinases has been implicated in the expression of murine NKG2D ligands.	2	12	initiated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ATM	ATM	ATM	7	10	11	12
These sites in SMN are putative substrates for protein kinase C ( PKC ) , casein kinase I/II ( CKI/II ) , cell division cycle 2 ( cdc2 ) , mitogen activated protein kinase p38 ( p38 MAPK ) , epidermal growth factor receptor ( EGFR ) , insulin receptor ( INSR ) , and ataxia telangiectasia mutated ( ATM ) ( XREF_TABLE ) .	These sites in SMN are putative substrates for protein kinase C (PKC), casein kinase I/II (CKI/II), cell division cycle 2 (cdc2), mitogen activated protein kinase p38 (p38 MAPK), epidermal growth factor receptor (EGFR), insulin receptor (INSR), and ataxia telangiectasia mutated (ATM) (XREF_TABLE).	10	60	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	59	60	55	58
XREF_FIG are consistent with hypoxia induced activation of ATM contributing to the H2AX Ser 139 phosphorylation in the spheroid center .	XREF_FIG are consistent with hypoxia induced activation of ATM contributing to the H2AX Ser 139 phosphorylation in the spheroid center.	5	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM contributing to the H2AX Ser 139 phosphorylation	atm	ATM	ATM	atm	8	9	8	9
ATM autophosphorylation initiates the conversion of the inactive ATM dimer to an active monomeric ATM [ XREF_BIBR ] .	ATM autophosphorylation initiates the conversion of the inactive ATM dimer to an active monomeric ATM [XREF_BIBR].	0	9	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM autophosphorylation	atm	ATM	ATM	atm	0	1	8	9
Upon double strand DNA break induction by agents such as bleomycin , cells recruit the Mre11-Rad50-Nbs1 ( MRN ) complex to damaged sites together with ATM , which in turn triggers autophosphorylation of ATM at Ser 1981 and activates ATM protein kinase activity leading to phosphorylation of downstream signaling proteins such as checkpoint kinase 2 ( Chk2 ) at Thr 68 and p53 at Ser 15 ( XREF_FIG ) .	Upon double strand DNA break induction by agents such as bleomycin, cells recruit the Mre11-Rad50-Nbs1 (MRN) complex to damaged sites together with ATM, which in turn triggers autophosphorylation of ATM at Ser 1981 and activates ATM protein kinase activity leading to phosphorylation of downstream signaling proteins such as checkpoint kinase 2 (Chk2) at Thr 68 and p53 at Ser 15 (XREF_FIG).	22	38	triggers	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ATM	ATM	atm	ATM	autophosphorylation of ATM at Ser 1981	atm	25	26	33	34
One targeted the ataxia telangiectasia mutated ( ATM ) gene , whose loss is known to accelerate tumorigenesis in Emu-Myc transgenic mice .	One targeted the ataxia telangiectasia mutated (ATM) gene, whose loss is known to accelerate tumorigenesis in Emu-Myc transgenic mice.	0	8	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	7	8	3	6
This autophosphorylation of ATM was proposed to initiate conversion of inactive ATM dimers to active ATM monomers XREF_BIBR , and this was supported by the observation by several groups that mutation of ATM autophosphorylation sites blocks ATM activation XREF_BIBR , XREF_BIBR and dimer-monomer transition XREF_BIBR .	This autophosphorylation of ATM was proposed to initiate conversion of inactive ATM dimers to active ATM monomers XREF_BIBR, and this was supported by the observation by several groups that mutation of ATM autophosphorylation sites blocks ATM activation XREF_BIBR, XREF_BIBR and dimer-monomer transition XREF_BIBR.	1	12	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	autophosphorylation of ATM	atm	ATM	ATM	atm	3	4	11	12
Strikingly , although all downstream DDR events are attenuated due to NOTCH1 mediated ATM inactivation ( including ATM mediated phosphorylations like : p53 , CHK2 , SMC1 ) , phosphorylation of the ATM main substrate , histone H2AX ( Ser139H2AX , from now on referred as gammaH2AX ) is not affected XREF_BIBR , XREF_BIBR .	Strikingly, although all downstream DDR events are attenuated due to NOTCH1 mediated ATM inactivation (including ATM mediated phosphorylations like : p53, CHK2, SMC1), phosphorylation of the ATM main substrate, histone H2AX (Ser139H2AX, from now on referred as gammaH2AX) is not affected XREF_BIBR, XREF_BIBR.	12	34	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	phosphorylation of the ATM	atm	ATM	ATM	atm	32	33	13	14
Related to the second possibility , it is noted that over-expression of ATM ( both wild-type and S1981A ) in human cells leads to the production of active ATM monomers in the absence of DNA damage and BAC over-expression in the murine system may be a contributing factor to some of these discrepancies .	Related to the second possibility, it is noted that over-expression of ATM (both wild-type and S1981A) in human cells leads to the production of active ATM monomers in the absence of DNA damage and BAC over-expression in the murine system may be a contributing factor to some of these discrepancies.	10	29	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	ATM	over-expression of ATM	atm	ATM	ATM	atm	12	13	28	29
As shown in XREF_FIG , phosphorylation level of ATM ( Ser 1981 ) and ATR ( Ser 426 ) was upregulated after R1881 treatment , demonstrating the activation of both ATM and ATR by androgen treatment .	As shown in XREF_FIG, phosphorylation level of ATM (Ser 1981) and ATR (Ser 426) was upregulated after R1881 treatment, demonstrating the activation of both ATM and ATR by androgen treatment.	6	32	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	level of ATM	atm	ATM	ATM	atm	8	9	30	31
Because H3K9me3 is associated with gene repression , we hypothesized that this chromatin mark may be contributing to hypoxia induced ATM activation through repression of a factor that normally inhibits ATM phosphorylation , such as an ATM specific phosphatase .	Because H3K9me3 is associated with gene repression, we hypothesized that this chromatin mark may be contributing to hypoxia induced ATM activation through repression of a factor that normally inhibits ATM phosphorylation, such as an ATM specific phosphatase.	19	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM phosphorylation	atm	ATM	ATM	atm	30	31	20	21
In response to ionizing radiation , DSBs are detected by the Mre11 , Rad50 , and Nbs1 complex ( MRN complex ) and Ku70/Ku80 complexes which rapidly activate ataxia telangiectasia mutated ( ATM ) and DNA-PK respectively XREF_BIBR .	In response to ionizing radiation, DSBs are detected by the Mre11, Rad50, and Nbs1 complex (MRN complex) and Ku70/Ku80 complexes which rapidly activate ataxia telangiectasia mutated (ATM) and DNA-PK respectively XREF_BIBR.	24	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	32	33	28	31
Ataxia Telangiectasia Mutated ( ATM ) kinase , a central regulator of the DNA damage response regulates the activity of several E3-ubiquitin ligases and the ubiquitination-proteasome system is a consistent target of ATM .	Ataxia Telangiectasia Mutated (ATM) kinase, a central regulator of the DNA damage response regulates the activity of several E3-ubiquitin ligases and the ubiquitination-proteasome system is a consistent target of ATM.	0	33	is a consistent target	Positive_activation_copula_1	Positive_activation	Positive_activation	Ataxia Telangiectasia Mutated	Ataxia Telangiectasia Mutated	Ataxia Telangiectasia Mutated	ATM	ATM	ATM	0	3	32	33
The autophosphorylation of ATM increases the active ATM proteins , which again increases the active ATM proteins .	The autophosphorylation of ATM increases the active ATM proteins, which again increases the active ATM proteins.	1	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	autophosphorylation of ATM	atm	ATM	ATM	atm	3	4	7	8
For example , the RUVBL1/2 complex containing the TIP60 HAT complex acetylates the FAT-C domain of ATM , thereby activating ATM in response to DNA damage .	For example, the RUVBL1/2 complex containing the TIP60 HAT complex acetylates the FAT-C domain of ATM, thereby activating ATM in response to DNA damage.	4	22	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	RUVBL1/2 complex containing the TIP60 HAT complex acetylates the FAT-C domain of ATM	atm	ATM	ATM	atm	16	17	20	21
Furthermore , acetylation of ATM Lys 3016 by Tip60 activates ATM activity in response to DNA damage [ XREF_BIBR ] .	Furthermore, acetylation of ATM Lys 3016 by Tip60 activates ATM activity in response to DNA damage [XREF_BIBR].	2	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	acetylation of ATM Lys 3016	atm	ATM	ATM	atm	4	5	10	11
While ATM is normally considered protective , it has been shown that in response to damage by camptothecin , ATM in post-mitotic neurons is phosphorylated by Cdk5 at Ser794 , promoting further ATM activity that triggers cell death , possibly as a result of re-entry of the neurons into the cell cycle .	While ATM is normally considered protective, it has been shown that in response to damage by camptothecin, ATM in post-mitotic neurons is phosphorylated by Cdk5 at Ser794, promoting further ATM activity that triggers cell death, possibly as a result of re-entry of the neurons into the cell cycle.	17	33	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	camptothecin, ATM in post-mitotic neurons is phosphorylated by Cdk5 at Ser794	atm	ATM	ATM	atm	19	20	32	33
Damage is detected by the MRE11/RAD50/NBS1 ( MRN complex ) , which signals through the phosphotidylinositol 3-kinase ( PI3 ) family members ataxia telangiectasia mutated ( ATM ) , Rad-3-related ( ATR ) and DNA dependent protein kinase ( DNA-pk ) by phosphorylation of H2A histone family member X ( H2AX ) .	Damage is detected by the MRE11/RAD50/NBS1 (MRN complex), which signals through the phosphotidylinositol 3-kinase (PI3) family members ataxia telangiectasia mutated (ATM), Rad-3-related (ATR) and DNA dependent protein kinase (DNA-pk) by phosphorylation of H2A histone family member X (H2AX).	5	27	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	26	27	22	25
As predicted , whilst DPR positive cells did not display any ATM phosphorylation under normal conditions , chloroquine treatment led to pan-nuclear ATM phosphorylation ( XREF_SUPPLEMENTARY , p = 0.004 ) , indicating that DPR expressing cells are indeed responsive to chloroquine and , consequently , are able to activate ATM .	As predicted, whilst DPR positive cells did not display any ATM phosphorylation under normal conditions, chloroquine treatment led to pan-nuclear ATM phosphorylation (XREF_SUPPLEMENTARY, p = 0.004), indicating that DPR expressing cells are indeed responsive to chloroquine and, consequently, are able to activate ATM.	17	51	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	chloroquine treatment led to pan-nuclear ATM phosphorylation	atm	ATM	ATM	atm	22	23	50	51
This is initiated by the MRN ( MRE11-RAD50-NBS1 ) complex which senses double strand breaks and activates the serine/threonine protein kinases ataxia telangiectasia mutated ( ATM ) and ataxia telangiectasia and Rad3 related ( ATR ) .	This is initiated by the MRN (MRE11-RAD50-NBS1) complex which senses double strand breaks and activates the serine/threonine protein kinases ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR).	9	26	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	25	26	21	24
Mouse and human NKG2D ligands are up-regulated in nontumor cell lines by genotoxic stress and stalled DNA replication , conditions known to activate a major DNA damage checkpoint pathway initiated by ataxia telangiectasia mutated ( ATM ) or ATM- and Rad3 related ( ATR ) protein kinases .	Mouse and human NKG2D ligands are up-regulated in nontumor cell lines by genotoxic stress and stalled DNA replication, conditions known to activate a major DNA damage checkpoint pathway initiated by ataxia telangiectasia mutated (ATM) or ATM- and Rad3 related (ATR) protein kinases.	22	46	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ATM-	ATM-	ATM-	31	34	38	39
Silencing ATM expression significantly abrogated the activation of ATM at Ser 1981 , Chk1 at Ser 345 and Cdc25C at Ser 216 in curcumin treated cells and substantially prevented the cells from undergoing G2/M arrest and apoptosis .	Silencing ATM expression significantly abrogated the activation of ATM at Ser 1981, Chk1 at Ser 345 and Cdc25C at Ser 216 in curcumin treated cells and substantially prevented the cells from undergoing G2/M arrest and apoptosis.	1	18	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM expression	atm	ATM	ATM	atm	1	2	8	9
Increasing amounts of ATM kinase but not of its catalytically inactive mutant , significantly augmented ITCH autoubiquitination ( XREF_FIG ) .	Increasing amounts of ATM kinase but not of its catalytically inactive mutant, significantly augmented ITCH autoubiquitination (XREF_FIG).	0	17	Increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM kinase but not of its catalytically inactive mutant, significantly augmented ITCH autoubiquitination	atm	ATM	ATM	atm	3	4	3	4
This is in agreement with our previous data showing a reduction in hydroxyurea induced ATM activation in ATMIN-null cells 25 , and supports the hypothesis that ATMIN promotes ATM signalling in response to replication stress .	This is in agreement with our previous data showing a reduction in hydroxyurea induced ATM activation in ATMIN-null cells 25, and supports the hypothesis that ATMIN promotes ATM signalling in response to replication stress.	12	29	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	hydroxyurea induced ATM	atm	ATM	ATM	atm	14	15	28	29
Very interestingly , pexophagy defects observed in ATM deficient cells are rescued by reconstitution of ATM expression , confirming the direct role of ATM in this response .	Very interestingly, pexophagy defects observed in ATM deficient cells are rescued by reconstitution of ATM expression, confirming the direct role of ATM in this response.	11	24	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM expression	atm	ATM	ATM	atm	15	16	23	24
Conversely , the absence of ATR would promote replication fork collapse and activation of ATM [ XREF_BIBR ] .	Conversely, the absence of ATR would promote replication fork collapse and activation of ATM [XREF_BIBR].	3	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	5	6	14	15
Aphidicolin treatment caused a moderate activation of ATM and Chk2 phosphorylation ( XREF_FIG , lane 2 , and XREF_FIG ) , but this was abolished by knockdown of ATR ( XREF_FIG , lane 5 , and XREF_FIG ) , indicating that it results from the direct activation of ATM by ATR that is known to occur upon replication fork stalling , rather than from DSB formation .	Aphidicolin treatment caused a moderate activation of ATM and Chk2 phosphorylation (XREF_FIG, lane 2, and XREF_FIG), but this was abolished by knockdown of ATR (XREF_FIG, lane 5, and XREF_FIG), indicating that it results from the direct activation of ATM by ATR that is known to occur upon replication fork stalling, rather than from DSB formation.	42	55	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	50	51	48	49
In this system , double stranded DNA oligonucleotides induce the phosphorylation of Chk1 at activating sites targeted by ATR [ ATM ( ataxia telangiectasia mutated ) - and Rad3 related ] and ATM kinases .	In this system, double stranded DNA oligonucleotides induce the phosphorylation of Chk1 at activating sites targeted by ATR [ATM (ataxia telangiectasia mutated) - and Rad3 related] and ATM kinases.	14	23	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	18	19	20	21
Moreover , we demonstrate that ATR can partially reverse the effect of ATM inhibition on HR in the presynapsis stage , but not after its completion .	Moreover, we demonstrate that ATR can partially reverse the effect of ATM inhibition on HR in the presynapsis stage, but not after its completion.	5	13	reverse	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	5	6	12	13
Conversely , ATR contributes to the activation of ATM in response to DNA replication stress by converting inactive ATM dimers into active monomers through direct phosphorylation of ATM XREF_BIBR .	Conversely, ATR contributes to the activation of ATM in response to DNA replication stress by converting inactive ATM dimers into active monomers through direct phosphorylation of ATM XREF_BIBR.	2	19	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	2	3	18	19
Thus , our results suggest that DSB formation , resulting from collapsed replication forks , rather than the stalled replication forks or ATR dependent phosphorylations activates ATM and DNA-PKcs .	Thus, our results suggest that DSB formation, resulting from collapsed replication forks, rather than the stalled replication forks or ATR dependent phosphorylations activates ATM and DNA-PKcs.	22	28	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR dependent phosphorylations	atr	ATM	ATM	atm	22	23	26	27
These results indicate that the phosphorylation of HSP90-Ser164 by Cdc7-Dbf4 is required for the maintenance of ATM and ATR mediated S-phase checkpoint activation , HR DNA repair , and the stability of ATM and ATR signaling component proteins under replication stress .	These results indicate that the phosphorylation of HSP90-Ser164 by Cdc7-Dbf4 is required for the maintenance of ATM and ATR mediated S-phase checkpoint activation, HR DNA repair, and the stability of ATM and ATR signaling component proteins under replication stress.	18	37	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	18	19	32	33
This is consistent with the significant reduction in DSP4 dependent phosphorylation of p53 ser15 by ATM inhibition and increased levels by ATR inhibition .	This is consistent with the significant reduction in DSP4 dependent phosphorylation of p53 ser15 by ATM inhibition and increased levels by ATR inhibition.	15	22	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	21	22	15	16
Chk1 and Chk2 play a central role in transducing genotoxic stress and DNA damage signals from ATR and ATM in which Chk1 seems to be activated by ATR in response to UV induced damage , whereas Chk2 primarily functions through ATM in response to ionizing radiation .	Chk1 and Chk2 play a central role in transducing genotoxic stress and DNA damage signals from ATR and ATM in which Chk1 seems to be activated by ATR in response to UV induced damage, whereas Chk2 primarily functions through ATM in response to ionizing radiation.	18	32	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	27	28	18	19
ATM activation can be induced by ATR .	ATM activation can be induced by ATR.	0	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	6	7	0	1
Microcephalin 1 ( BRIT1 ) expression is an early DNA repair mediator that regulates the recruitment of DNA repair proteins including BRCA1 and BRCA2 , initiates the signaling pathways of ATM serine/threonine kinase or ATR serine/threonine kinase ( ATM and ATR ) after DNA damage .	Microcephalin 1 (BRIT1) expression is an early DNA repair mediator that regulates the recruitment of DNA repair proteins including BRCA1 and BRCA2, initiates the signaling pathways of ATM serine/threonine kinase or ATR serine/threonine kinase (ATM and ATR) after DNA damage.	25	36	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	34	35	30	31
The ATR DNA related pathway is activated in response to single-strand DNA breaks but can augment ATM activity and is mediated through the CHK1 kinase .	The ATR DNA related pathway is activated in response to single-strand DNA breaks but can augment ATM activity and is mediated through the CHK1 kinase.	1	17	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	1	2	16	17
Our results showed that gemcitabine in combination with CHK1 inhibitor resulted in dramatic increase of DNA damage as evidenced by the prolongation of tail moment in the comet assay , ATR mediated gammaH2AX induction , and the activation of the ATR and CHK1 and ATM and CHK2 pathways .	Our results showed that gemcitabine in combination with CHK1 inhibitor resulted in dramatic increase of DNA damage as evidenced by the prolongation of tail moment in the comet assay, ATR mediated gammaH2AX induction, and the activation of the ATR and CHK1 and ATM and CHK2 pathways.	30	47	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	30	31	44	45
Similar to IR , sCLU induction was observed only in ATM +/- cells after UV treatment ( XREF_FIG ) , probably due to ATR dependent activation of ATM after UV exposure .	Similar to IR, sCLU induction was observed only in ATM +/- cells after UV treatment (XREF_FIG), probably due to ATR dependent activation of ATM after UV exposure.	23	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	23	24	27	28
In contrast to DSB induced ATM activation , the C-terminal ATM interaction domain of Nbs1 is not required for ATR dependent activation of ATM in response to DNA replication stress ; however , the Nbs1 N-terminus is essential for ATR dependent activation of ATM XREF_BIBR .	In contrast to DSB induced ATM activation, the C-terminal ATM interaction domain of Nbs1 is not required for ATR dependent activation of ATM in response to DNA replication stress; however, the Nbs1 N-terminus is essential for ATR dependent activation of ATM XREF_BIBR.	39	44	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	39	40	43	44
Signaling downstream of oncogenic stress involves activation of the single stranded DNA dependent ATR pathway and the double stranded break induced ATM pathway .	Signaling downstream of oncogenic stress involves activation of the single stranded DNA dependent ATR pathway and the double stranded break induced ATM pathway.	13	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	13	14	21	22
Immunofluorescence microscopy was next employed to evaluate phosphorylation of H2AX ( gamma-H2AX ) , well characterized as a very early event mediated by ATR and ATM following exposure to UV and IR , respectively .	Immunofluorescence microscopy was next employed to evaluate phosphorylation of H2AX (gamma-H2AX), well characterized as a very early event mediated by ATR and ATM following exposure to UV and IR, respectively.	15	27	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	23	24	25	26
However , several studies have also determined that ATM can be activated by ATR and vice versa [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	However, several studies have also determined that ATM can be activated by ATR and vice versa [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	13	14	8	9
ATM , primarily activated by DNA double-strand breaks , and ATR , activated by single stranded DNA , are master regulators of the cellular response to DNA damage .	ATM, primarily activated by DNA double-strand breaks, and ATR, activated by single stranded DNA, are master regulators of the cellular response to DNA damage.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	10	11	0	1
Moreover , both the radiosensitivity and G2/M checkpoint defect of ATM deficient human cells can be rescued by ectopic expression of yeast Chk1 , demonstrating that a hyperactive ATR pathway is sufficient to stimulate checkpoint signaling and radioresistance in an ATM independent manner .	Moreover, both the radiosensitivity and G2/M checkpoint defect of ATM deficient human cells can be rescued by ectopic expression of yeast Chk1, demonstrating that a hyperactive ATR pathway is sufficient to stimulate checkpoint signaling and radioresistance in an ATM independent manner.	28	42	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	28	29	40	41
The DNA damage response ( DDR ) can be initiated by both the yeast ATR homolog Mec1 , which is activated by pathologic ssDNA generation , and the yeast ATM homolog Tel1 , which associates with damage recruited MRX .	The DNA damage response (DDR) can be initiated by both the yeast ATR homolog Mec1, which is activated by pathologic ssDNA generation, and the yeast ATM homolog Tel1, which associates with damage recruited MRX.	9	31	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	14	15	29	30
Although ATM plays a primary role in the DNA damage response to double stranded DNA breaks , ATR also contributes to the process by activating some of the common ATM and ATR targets .	Although ATM plays a primary role in the DNA damage response to double stranded DNA breaks, ATR also contributes to the process by activating some of the common ATM and ATR targets.	17	32	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	17	18	29	30
XREF_BIBR This process is guided by different DNA structures : ATM and DNA-PK are activated by double stranded breaks ( DBS ) and ATR is activated by Replication Protein A ( RPA ) coated single stranded DNA ( ssDNA ) .	XREF_BIBR This process is guided by different DNA structures : ATM and DNA-PK are activated by double stranded breaks (DBS) and ATR is activated by Replication Protein A (RPA) coated single stranded DNA (ssDNA).	10	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATM	ATM	ATM	23	24	10	11
ATM initiates signaling from DSBs by phosphorylating numerous downstream targets , including the histone variant H2AX to form gamma-H2AX XREF_BIBR , XREF_BIBR .	ATM initiates signaling from DSBs by phosphorylating numerous downstream targets, including the histone variant H2AX to form gamma-H2AX XREF_BIBR, XREF_BIBR.	0	17	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	0	1	15	16
In G1 phase cells , ATM promotes CJ formation independent of H2AX and MDC1 .	In G1 phase cells, ATM promotes CJ formation independent of H2AX and MDC1.	5	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	5	6	11	12
After being activated by complex formation , DNA-PKcs phosphorylates itself and other proteins such as histone H2AX and 53BP1 , which are also targeted by ATM , another PI3 family kinase that responds to DSB formation .	After being activated by complex formation, DNA-PKcs phosphorylates itself and other proteins such as histone H2AX and 53BP1, which are also targeted by ATM, another PI3 family kinase that responds to DSB formation.	15	30	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	histone H2AX	histone H2AX	histone H2AX	25	26	15	17
Therefore , histone H2AX is activated by ATM after DNA damage [ XREF_BIBR ] .	Therefore, histone H2AX is activated by ATM after DNA damage [XREF_BIBR].	2	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	histone H2AX	histone H2AX	histone H2AX	7	8	2	4
XREF_BIBR - XREF_BIBR However , DNA damage also activates PARP1 independent forms of cell death through ATM and ATR , which in turn activate H2AX and p53 stress sensors .	XREF_BIBR - XREF_BIBR However, DNA damage also activates PARP1 independent forms of cell death through ATM and ATR, which in turn activate H2AX and p53 stress sensors.	8	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	16	17	24	25
H2AX is immediately activated by ATM in response to DNA damage and its phosphorylated form , gammaH2AX , flanks the DSB through several megabases .	H2AX is immediately activated by ATM in response to DNA damage and its phosphorylated form, gammaH2AX, flanks the DSB through several megabases.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	5	6	0	1
To determine whether the ATM target H2AX is involved in meiotic telomere dynamics , we investigated telomere and centromere behavior by FISH in wild-type and H2AX deficient testes preparations from 4-wk-old mice ( XREF_FIG A ) .	To determine whether the ATM target H2AX is involved in meiotic telomere dynamics, we investigated telomere and centromere behavior by FISH in wild-type and H2AX deficient testes preparations from 4-wk-old mice (XREF_FIG A).	3	8	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	4	5	6	7
Thus , we conclude that ATM mediated H2AX dependent chromatin changes along RAG cleaved antigen receptor loci prevent unrepaired coding ends from transitioning into chromosome breaks during continued cell cycle progression .	Thus, we conclude that ATM mediated H2AX dependent chromatin changes along RAG cleaved antigen receptor loci prevent unrepaired coding ends from transitioning into chromosome breaks during continued cell cycle progression.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	5	6	7	8
ATM activates H2AX at the DSB site converting it into the phosphorylated form , gammaH2AX , which then anchors DNA damage response proteins to the sites of damage .	ATM activates H2AX at the DSB site converting it into the phosphorylated form, gammaH2AX, which then anchors DNA damage response proteins to the sites of damage.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	0	1	2	3
In conclusion , we demonstrate for the first time a new cell death pathway triggered by mda-7 and IL-24 through ATM mediated activation of H2AX and AIF resulting in caspase independent apoptosis ( XREF_FIG ) that appears unique to neuroblastoma cells , since this effect was not evident in human breast carcinoma or melanoma cells ( XREF_SUPPLEMENTARY ) .	In conclusion, we demonstrate for the first time a new cell death pathway triggered by mda-7 and IL-24 through ATM mediated activation of H2AX and AIF resulting in caspase independent apoptosis (XREF_FIG) that appears unique to neuroblastoma cells, since this effect was not evident in human breast carcinoma or melanoma cells (XREF_SUPPLEMENTARY).	14	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	20	21	24	25
Previous studies suggested that in response to DSB , H2AX near the DSB is targeted by ATM and DNA-PKcs and that H2AX further away from the DSB is phosphorylated either by ATM in a MDC1 independent manner or by ATR after DSB resection .	Previous studies suggested that in response to DSB, H2AX near the DSB is targeted by ATM and DNA-PKcs and that H2AX further away from the DSB is phosphorylated either by ATM in a MDC1 independent manner or by ATR after DSB resection.	9	18	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	16	17	9	10
This is consistent with the data suggesting that ATM is the major kinase that induces H2AX foci and that DNA-PK can phosphorylate H2AX only in the absence of ATM but not in the presence of chemically inhibited ATM XREF_BIBR .	This is consistent with the data suggesting that ATM is the major kinase that induces H2AX foci and that DNA-PK can phosphorylate H2AX only in the absence of ATM but not in the presence of chemically inhibited ATM XREF_BIBR.	14	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	phosphorylate H2AX only in the absence of ATM	atm	H2AX	H2AX	h2ax	28	29	15	16
When DNA breaks occur in normal cells , the ataxia telangiectasia mutated ( ATM ) protein can activate DNA repair and direct histone H2AX to DSBs , leading to rapid histone H2AX phosphorylation to form gammaH2AX .	When DNA breaks occur in normal cells, the ataxia telangiectasia mutated (ATM) protein can activate DNA repair and direct histone H2AX to DSBs, leading to rapid histone H2AX phosphorylation to form gammaH2AX.	9	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	histone H2AX	histone H2AX	histone H2AX	9	12	22	24
ATM is recruited to DNA damage sites via MRN complex ( mre11-rad50-nbs1 ) and then activates H2AX ( a member of H2A histone family ) .	ATM is recruited to DNA damage sites via MRN complex (mre11-rad50-nbs1) and then activates H2AX (a member of H2A histone family).	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	0	1	16	17
As expected , ATM inhibition ( ATMi ) reduced gammaH2AX accumulation ( XREF_SUPPLEMENTARY ) .	As expected, ATM inhibition (ATMi) reduced gammaH2AX accumulation (XREF_SUPPLEMENTARY).	3	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	gammaH2AX	gammaH2AX	gammaH2AX	3	4	9	10
We also immunostained cells for gamma-H2AX , a phosphorylated form of H2AX produced by ATR , ATM , and DNA-PK .	We also immunostained cells for gamma-H2AX, a phosphorylated form of H2AX produced by ATR, ATM, and DNA-PK.	9	17	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	16	17	11	12
By contrast , cells respond differently to DSBs directly caused by gamma-rays [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , which are efficiently repaired through transient up-regulation of H2AX mediated by ATM and SIRT6 [ XREF_BIBR ] .	By contrast, cells respond differently to DSBs directly caused by gamma-rays [XREF_BIBR, XREF_BIBR, XREF_BIBR], which are efficiently repaired through transient up-regulation of H2AX mediated by ATM and SIRT6 [XREF_BIBR].	26	33	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	31	32	28	29
Until recently , it was believed that H2AX activation is mostly mediated by ATM , but recent studies suggest that ATR is responsible for the majority of both early and late ( after 24-h ) responses to ROS even in non S-phase cells .	Until recently, it was believed that H2AX activation is mostly mediated by ATM, but recent studies suggest that ATR is responsible for the majority of both early and late (after 24-h) responses to ROS even in non S-phase cells.	7	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	13	14	7	8
After DNA damage , histone H2AX is activated by ATM , which contributes to the repair of sperm-DNA damage after fertilization and regulates the cell cycle during embryo development .	After DNA damage, histone H2AX is activated by ATM, which contributes to the repair of sperm-DNA damage after fertilization and regulates the cell cycle during embryo development.	4	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	histone H2AX	histone H2AX	histone H2AX	9	10	4	6
CSR DSBs generate a DSB response ( DSBR ) in which ATM activates histone H2AX and 53BP1 in chromatin flanking DSBs , thereby contributing to end joining XREF_BIBR - XREF_BIBR .	CSR DSBs generate a DSB response (DSBR) in which ATM activates histone H2AX and 53BP1 in chromatin flanking DSBs, thereby contributing to end joining XREF_BIBR - XREF_BIBR.	11	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	histone H2AX	histone H2AX	histone H2AX	11	12	13	15
In fact , when H2AX wt MEFs were treated with the dual specificity ATM and DNA-PKcs inhibitor wortmannin , the decrease in nucleosome stability caused by bleomycin was inhibited .	In fact, when H2AX wt MEFs were treated with the dual specificity ATM and DNA-PKcs inhibitor wortmannin, the decrease in nucleosome stability caused by bleomycin was inhibited.	4	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	13	14	4	5
Ataxia telangiectasia mutated ( ATM ) is then recruited to the sites of the breaks where ATM is phosphorylated and activates H2AX , generating phosphorylated H2AX ( gamma H2AX ) .	Ataxia telangiectasia mutated (ATM) is then recruited to the sites of the breaks where ATM is phosphorylated and activates H2AX, generating phosphorylated H2AX (gamma H2AX).	16	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM is phosphorylated	atm	H2AX	H2AX	h2ax	16	17	21	22
Cdk5-ATM signal regulates phosphorylation and function of ATM targets p53 and H2AX .	Cdk5-ATM signal regulates phosphorylation and function of ATM targets p53 and H2AX.	3	12	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	phosphorylation and function of ATM	atm	H2AX	H2AX	h2ax	7	8	11	12
While the physiological relevance of being rescued from such serial transplantation can be debated , it should be noted that activation of the DNA damage response including the ATM target H2AX clearly increases in old versus young stem cells [ XREF_BIBR ] .	While the physiological relevance of being rescued from such serial transplantation can be debated, it should be noted that activation of the DNA damage response including the ATM target H2AX clearly increases in old versus young stem cells [XREF_BIBR].	25	31	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	28	29	30	31
Therefore , histone H2AX is activated by ATM after DNA damage .	Therefore, histone H2AX is activated by ATM after DNA damage.	2	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	histone H2AX	histone H2AX	histone H2AX	7	8	2	4
However , we observed intact mitotic ATM activation in NBS1 deficient cells ( XREF_SUPPLEMENTARY ) .	However, we observed intact mitotic ATM activation in NBS1 deficient cells (XREF_SUPPLEMENTARY).	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	NBS1	NBS1	NBS1	6	7	9	10
Alanine substitution of the eight putative phosphorylation sites yields functional MRN complexes : 1 ) Mre11-SA assembles into MRN complexes ( XREF_FIG ) ; 2 ) MRN-SA complexes bind to chromatin and DNA ( XREF_FIG ) ; 3 ) recombinant MRN-SA supports DNA tethering in MRN depleted extracts ( XREF_FIG ) ; and 4 ) MRN-SA supports ATM activation in MRN depleted extracts ( XREF_FIG ) .	Alanine substitution of the eight putative phosphorylation sites yields functional MRN complexes : 1) Mre11-SA assembles into MRN complexes (XREF_FIG); 2) MRN-SA complexes bind to chromatin and DNA (XREF_FIG); 3) recombinant MRN-SA supports DNA tethering in MRN depleted extracts (XREF_FIG); and 4) MRN-SA supports ATM activation in MRN depleted extracts (XREF_FIG).	57	61	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	57	58	60	61
Activation of ATM in turn phosphorylates NBS1 at S343 and enhances the MRN complex nuclease activity to generate single stranded DNA ( ssDNA ) .	Activation of ATM in turn phosphorylates NBS1 at S343 and enhances the MRN complex nuclease activity to generate single stranded DNA (ssDNA).	0	15	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	2	3	12	13
Both the increased DNA damage in proliferating cells and the apoptotic cell death started earlier in Nbn and Atm deficient , indicating that Atm may promote DSBs repair in Nbn deficient lens progenitor cells and that additional deletion of Atm may lead to broader effects on both dividing and differentiating cells in Nbn deficient lens .	Both the increased DNA damage in proliferating cells and the apoptotic cell death started earlier in Nbn and Atm deficient, indicating that Atm may promote DSBs repair in Nbn deficient lens progenitor cells and that additional deletion of Atm may lead to broader effects on both dividing and differentiating cells in Nbn deficient lens.	23	33	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atm	Atm	Atm	Nbn	Nbn	Nbn	23	24	29	30
Although the first mode ( Mdc1 independent ) is compatible with the proposed role of MRN as a DSB sensor , the second one ( Mdc1 dependent ) likely serves other purposes such as preventing dispersal of the ATM activated MRN to the undamaged nuclear compartments .	Although the first mode (Mdc1 independent) is compatible with the proposed role of MRN as a DSB sensor, the second one (Mdc1 dependent) likely serves other purposes such as preventing dispersal of the ATM activated MRN to the undamaged nuclear compartments.	35	41	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	38	39	40	41
In addition , oxidation of ATM activates the kinase independently of the MRN complex .	In addition, oxidation of ATM activates the kinase independently of the MRN complex.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	5	6	12	13
In contrast to cells coinfected with AAV2 and Ad , but in line with the observed inhibitory effect of the MRN complex on rAAV2 vector transduction , cells deficient in the MRN target ATM , exhibit increased rAAV2 transduction efficiency [ XREF_BIBR ] .	In contrast to cells coinfected with AAV2 and Ad, but in line with the observed inhibitory effect of the MRN complex on rAAV2 vector transduction, cells deficient in the MRN target ATM, exhibit increased rAAV2 transduction efficiency [XREF_BIBR].	27	34	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	33	34	31	32
We next analyzed the phosphorylation status and localization patterns of the ATM target NBS1 using phospho specific antibodies .	We next analyzed the phosphorylation status and localization patterns of the ATM target NBS1 using phospho specific antibodies.	5	14	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	NBS1	NBS1	NBS1	11	12	13	14
The depletion and inhibition of ATM ( or the depletion of the ATM activator NBS1 ) blocked the p38 MAPK and p53S46P pathway that leads to apoptosis in HIV-1 WT or HIV-1 IN D64V -induced syncytia ( XREF_FIG ) .	The depletion and inhibition of ATM (or the depletion of the ATM activator NBS1) blocked the p38 MAPK and p53S46P pathway that leads to apoptosis in HIV-1 WT or HIV-1 IN D64V -induced syncytia (XREF_FIG).	9	15	activator	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	NBS1	NBS1	NBS1	12	13	14	15
Atm deficiency promotes premature growth defect and death of Nbn Nes-Cre mice .	Atm deficiency promotes premature growth defect and death of Nbn Nes-Cre mice.	0	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atm	Atm	Atm	Nbn	Nbn	Nbn	0	1	9	10
ATM is thought to activate an exonuclease activity of the MRN ( Mre11-Rad50-Nbs1 ) complex involved in the strand resection step of recombination [ XREF_BIBR ] .	ATM is thought to activate an exonuclease activity of the MRN (Mre11-Rad50-Nbs1) complex involved in the strand resection step of recombination [XREF_BIBR].	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	0	1	10	11
In summary , we propose a novel model that the stemness factor Sall4 is a key transducer of DNA DSB damage induced chromatin remodeling to MRN dependent ATM signaling in ESCs ( XREF_FIG ) .	In summary, we propose a novel model that the stemness factor Sall4 is a key transducer of DNA DSB damage induced chromatin remodeling to MRN dependent ATM signaling in ESCs (XREF_FIG).	21	28	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	27	28	25	26
In quiescent neurons , ATM promotes transcription dependent removal of Top1cc potentially by facilitating Topo1 degradation independent of its kinase activity or MRN .	In quiescent neurons, ATM promotes transcription dependent removal of Top1cc potentially by facilitating Topo1 degradation independent of its kinase activity or MRN.	4	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	4	5	22	23
For example , suppression of 53BP1 was found to decrease ATM activation in NBS but not WT cell lines .	For example, suppression of 53BP1 was found to decrease ATM activation in NBS but not WT cell lines.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	NBS	NBS	NBS	10	11	13	14
In human cells , ATM and ATR kinases directly target homologous recombination factors Nbs1 and Rad52 and mismatch repair factor Msh2 [ XREF_BIBR ] .	In human cells, ATM and ATR kinases directly target homologous recombination factors Nbs1 and Rad52 and mismatch repair factor Msh2 [XREF_BIBR].	4	22	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Nbs1	Nbs1	Nbs1	4	5	13	14
Furthermore , normal fibroblasts that were exposed to damaged cells , either directly through co-culture or indirectly through conditioned media , demonstrated many other typical DDR markers in DDF , including 53BP1 , phospho-ATM , and the focal presence of the ATM activating MRN complex .	Furthermore, normal fibroblasts that were exposed to damaged cells, either directly through co-culture or indirectly through conditioned media, demonstrated many other typical DDR markers in DDF, including 53BP1, phospho-ATM, and the focal presence of the ATM activating MRN complex.	38	44	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	41	42	43	44
Another branch of S-phase checkpoint control involves ATM targeting of NBS1 , a member of the MRN double strand break repair complex XREF_BIBR ; BRCA1 , the breast cancer susceptibility protein XREF_BIBR ; and SMC1 , a cohesin binding protein XREF_BIBR , XREF_BIBR .	Another branch of S-phase checkpoint control involves ATM targeting of NBS1, a member of the MRN double strand break repair complex XREF_BIBR; BRCA1, the breast cancer susceptibility protein XREF_BIBR; and SMC1, a cohesin binding protein XREF_BIBR, XREF_BIBR.	7	11	targeting	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	NBS1	NBS1	NBS1	7	8	10	11
Although we can not exclude that other phosphorylation sites in Nbs1 contribute to the intra-S phase checkpoint , we speculate that the major phenotypic overlap between AT and NBS patients is caused by a role of Nbs1 upstream rather than downstream of ATM .	Although we can not exclude that other phosphorylation sites in Nbs1 contribute to the intra-S phase checkpoint, we speculate that the major phenotypic overlap between AT and NBS patients is caused by a role of Nbs1 upstream rather than downstream of ATM.	28	43	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	NBS	NBS	NBS	42	43	28	29
SiRNA mediated depletion of ATM and downstream ATM phosphorylation targets NBS1 and BID had little or no significant effect on the level of apoptotic cells in response to the replication inhibitors in the tumour cell lines tested .	SiRNA mediated depletion of ATM and downstream ATM phosphorylation targets NBS1 and BID had little or no significant effect on the level of apoptotic cells in response to the replication inhibitors in the tumour cell lines tested.	2	11	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM and downstream ATM phosphorylation	atm	NBS1	NBS1	nbs1	4	5	10	11
Using a novel fluorescence resonance energy transfer based technique , we demonstrate that ATM and ATR induce Mre11 , Rad50 , and Nbs1 complex redistribution to restarting forks .	Using a novel fluorescence resonance energy transfer based technique, we demonstrate that ATM and ATR induce Mre11, Rad50, and Nbs1 complex redistribution to restarting forks.	13	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Nbs1	Nbs1	Nbs1	13	14	22	23
ATM activation in response to Rag DSBs in MRN deficient abl pre-B cells .	ATM activation in response to Rag DSBs in MRN deficient abl pre-B cells.	0	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	0	1	8	9
One of the first lines of evidence for the interaction between polyomaviruses and the host DDR came from the observation that SV40 large T antigen reduced protein levels of the ATM activating MRN complex [ XREF_BIBR ] and decreased MRN foci formation in response to gamma irradiation [ XREF_BIBR ] .	One of the first lines of evidence for the interaction between polyomaviruses and the host DDR came from the observation that SV40 large T antigen reduced protein levels of the ATM activating MRN complex [XREF_BIBR] and decreased MRN foci formation in response to gamma irradiation [XREF_BIBR].	30	33	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRN	MRN	MRN	30	31	32	33
Based on the contributions of BMI1 to DSB repair as discussed above , it is surprising that BMI1 reduces ATM activation in response to etoposide induced DSBs via binding to NBS1 in a manner in which BMI1 associated E3 ubiquitin ligase activity is not required [ XREF_BIBR ] .	Based on the contributions of BMI1 to DSB repair as discussed above, it is surprising that BMI1 reduces ATM activation in response to etoposide induced DSBs via binding to NBS1 in a manner in which BMI1 associated E3 ubiquitin ligase activity is not required [XREF_BIBR].	19	31	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	NBS1	NBS1	NBS1	19	20	30	31
Surprisingly , we find Pol I inhibition is not itself the direct result of DNA damage but is mediated by ATM kinase activity and the repair factor proteins NBS1 ( also known as NLRP2 ) and MDC1 .	Surprisingly, we find Pol I inhibition is not itself the direct result of DNA damage but is mediated by ATM kinase activity and the repair factor proteins NBS1 (also known as NLRP2) and MDC1.	18	36	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	NBS1	NBS1	NBS1	20	21	28	29
Previous studies have established that the ataxia telangiectasia mutated ( ATM ) activates nuclear Abl via phosphorylation at serine 465 ( S465 ) in the kinase domain in response to ionizing radiation ( IR ) .	Previous studies have established that the ataxia telangiectasia mutated (ATM) activates nuclear Abl via phosphorylation at serine 465 (S465) in the kinase domain in response to ionizing radiation (IR).	6	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	Abl	Abl	Abl	6	9	14	15
Our findings show that nuclear and cytoplasmic Abl kinase is activated early on ( within 5 min ) in response to IR by both ATM and DNAPK , and that while one or the other of these kinases is required , either one is sufficient to activate Abl .	Our findings show that nuclear and cytoplasmic Abl kinase is activated early on (within 5 min) in response to IR by both ATM and DNAPK, and that while one or the other of these kinases is required, either one is sufficient to activate Abl.	7	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Abl	Abl	Abl	24	25	7	8
The requirement of S465 phosphorylation for K921 Abl acetylation further revealed that ATM activated Abl is a substrate for DNA damage responsive acetyl-transferase/s .	The requirement of S465 phosphorylation for K921 Abl acetylation further revealed that ATM activated Abl is a substrate for DNA damage responsive acetyl-transferase/s.	12	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Abl	Abl	Abl	12	13	14	15
c-Abl , activated by ATM kinase , amplifies the DNA damage response in HR pathway .	c-Abl, activated by ATM kinase, amplifies the DNA damage response in HR pathway.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	c-Abl	c-Abl	c-Abl	4	5	0	1
To test the hypothesis that DNAPK participates in early Abl activation after IR , we used the ATM and DNAPK kinase inhibitors ( KU55933 and NU7026 , respectively ) in the Abl-WT-EGFP and Abl-S465A-EGFP cell lines to dissect the potential contributions of each kinase to IR induced Abl activation .	To test the hypothesis that DNAPK participates in early Abl activation after IR, we used the ATM and DNAPK kinase inhibitors (KU55933 and NU7026, respectively) in the Abl-WT-EGFP and Abl-S465A-EGFP cell lines to dissect the potential contributions of each kinase to IR induced Abl activation.	16	48	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Abl	Abl	Abl	17	18	47	48
By confocal imaging , we found that ATM inhibition with KU-55933 also inhibited TAp63 alpha and c-Abl activation in the nuclei of doxo treated oocytes ( XREF_SUPPLEMENTARY ) .	By confocal imaging, we found that ATM inhibition with KU-55933 also inhibited TAp63 alpha and c-Abl activation in the nuclei of doxo treated oocytes (XREF_SUPPLEMENTARY).	7	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	c-Abl	c-Abl	c-Abl	7	8	16	17
These findings suggest that Atm mediated c-Abl activation in cell response to double stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events .	These findings suggest that Atm mediated c-Abl activation in cell response to double stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events.	4	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Atm	Atm	Atm	c-Abl	c-Abl	c-Abl	4	5	6	7
Another was that ATM was able to activate endogenous Abl in the S465 mutant cells to promote phosphorylation of the biosensor peptide .	Another was that ATM was able to activate endogenous Abl in the S465 mutant cells to promote phosphorylation of the biosensor peptide.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Abl	Abl	Abl	3	4	9	10
Atm also activates c-Abl , a non receptor tyrosine kinase , to promote apoptosis .	Atm also activates c-Abl, a non receptor tyrosine kinase, to promote apoptosis.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atm	Atm	Atm	c-Abl	c-Abl	c-Abl	0	1	3	4
ATM might be involved in the phosphorylation of RAD51 via c-Abl , which has been shown to be associated with and activated by ATM .	ATM might be involved in the phosphorylation of RAD51 via c-Abl, which has been shown to be associated with and activated by ATM.	8	24	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	c-Abl	c-Abl	c-Abl	23	24	10	11
In a study by Baskaran et al [ XREF_BIBR ] , ATM was required to activate c-Abl and was due to phosphorylation at serine 465 .	In a study by Baskaran et al [XREF_BIBR], ATM was required to activate c-Abl and was due to phosphorylation at serine 465.	11	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	c-Abl	c-Abl	c-Abl	11	12	16	17
The inhibition of c-Abl by RB is consistent with RB ' s ability to block apoptosis ; while the activation of c-Abl by ATM is consistent with ATM ' s ability to activate cell death .	The inhibition of c-Abl by RB is consistent with RB 's ability to block apoptosis; while the activation of c-Abl by ATM is consistent with ATM 's ability to activate cell death.	19	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	c-Abl	c-Abl	c-Abl	23	24	21	22
[ XREF_BIBR ] These results are consistent with and complementary to previous data indicating that , even though ATM typically activates Abl through the phosphorylation of S465 in response to IR , [ XREF_BIBR ] there also is a functional and likely direct interaction between DNAPK and Abl that occurs in response to DNA damage .	[XREF_BIBR] These results are consistent with and complementary to previous data indicating that, even though ATM typically activates Abl through the phosphorylation of S465 in response to IR, [XREF_BIBR] there also is a functional and likely direct interaction between DNAPK and Abl that occurs in response to DNA damage.	18	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Abl	Abl	Abl	18	19	21	22
XREF_BIBR have reported that Atm mediated c-Abl activation in response to DSBs further activates both Atm and Atr and their downstream effects , enhancing DNA repair .	XREF_BIBR have reported that Atm mediated c-Abl activation in response to DSBs further activates both Atm and Atr and their downstream effects, enhancing DNA repair.	4	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Atm	Atm	Atm	c-Abl	c-Abl	c-Abl	4	5	6	7
Indeed , the serine protein kinase ATM ( Ataxia Telangiectasia Mutated ) activates c-Abl [ XREF_BIBR , XREF_BIBR ] and is required for p73 phosphorylation upon ionizing radiation [ XREF_BIBR ] .	Indeed, the serine protein kinase ATM (Ataxia Telangiectasia Mutated) activates c-Abl [XREF_BIBR, XREF_BIBR] and is required for p73 phosphorylation upon ionizing radiation [XREF_BIBR].	8	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ataxia Telangiectasia Mutated	Ataxia Telangiectasia Mutated	Ataxia Telangiectasia Mutated	c-Abl	c-Abl	c-Abl	8	11	13	14
Activation of c-Abl by ATM via DNA damage is associated with apoptosis induction , inhibiting Paxillin Tyr118 XREF_BIBR , XREF_BIBR , and interacts with RB inhibiting cell death 40 .	Activation of c-Abl by ATM via DNA damage is associated with apoptosis induction, inhibiting Paxillin Tyr118 XREF_BIBR, XREF_BIBR, and interacts with RB inhibiting cell death 40.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	c-Abl	c-Abl	c-Abl	4	5	2	3
In fact , inhibition of both ATM and DNAPK activities abolished Abl activation in our assay , suggesting that one or the other is required , but that either kinase alone is sufficient to activate Abl during the early stages of the DDR .	In fact, inhibition of both ATM and DNAPK activities abolished Abl activation in our assay, suggesting that one or the other is required, but that either kinase alone is sufficient to activate Abl during the early stages of the DDR.	3	12	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Abl	Abl	Abl	6	7	11	12
Induction of ATM for DNA-damage monitoring also activates p53 and BRCA1 , leading to fewer tumors , self-renewal of hematopoietic stem cells , thymocyte survival , but less apoptosis of autoreactive immune cells .	Induction of ATM for DNA-damage monitoring also activates p53 and BRCA1, leading to fewer tumors, self-renewal of hematopoietic stem cells, thymocyte survival, but less apoptosis of autoreactive immune cells.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	BRCA1	BRCA1	BRCA1	2	3	10	11
BRCA1 activated by ATM ( ataxia telangiectasia ) facilitates BRCA2 and RAD51 binding of the overhang followed by the attraction of RAD52 and RAD54 with the help of BLM and WRN proteins .	BRCA1 activated by ATM (ataxia telangiectasia) facilitates BRCA2 and RAD51 binding of the overhang followed by the attraction of RAD52 and RAD54 with the help of BLM and WRN proteins.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	BRCA1	BRCA1	BRCA1	3	4	0	1
Despite these considerations , we found that inhibition of ATR , ATM , or DNA-PK does not block or enhance BRCA1 downregulation , supporting the notion that PIKK mediated BRCA1 phosphorylation , and degradation of the protein , represent distinct signaling processes acting to control BRCA1 function .	Despite these considerations, we found that inhibition of ATR, ATM, or DNA-PK does not block or enhance BRCA1 downregulation, supporting the notion that PIKK mediated BRCA1 phosphorylation, and degradation of the protein, represent distinct signaling processes acting to control BRCA1 function.	7	21	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	BRCA1	BRCA1	BRCA1	11	12	20	21
ATM promotes HR by recruiting BRCA1 to DSBs but can also antagonize BRCA1 and promote NHEJ by recruiting p53 binding protein 1 ( 53BP1 ) , and these antagonistic functions are cell cycle regulated .	ATM promotes HR by recruiting BRCA1 to DSBs but can also antagonize BRCA1 and promote NHEJ by recruiting p53 binding protein 1 (53BP1), and these antagonistic functions are cell cycle regulated.	0	13	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	BRCA1	BRCA1	BRCA1	0	1	12	13
HRR requires large single stranded 3 ' overhangs to initiate repair using the complementary sequence on the sister chromatid XREF_BIBR , which involves activation of BRCA1 by ATM for removal of 53BP1 in late S phase and G2 XREF_BIBR - XREF_BIBR .	HRR requires large single stranded 3 ' overhangs to initiate repair using the complementary sequence on the sister chromatid XREF_BIBR, which involves activation of BRCA1 by ATM for removal of 53BP1 in late S phase and G2 XREF_BIBR - XREF_BIBR.	22	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	BRCA1	BRCA1	BRCA1	27	28	25	26
BRCA1 is activated by ATM after DNA damage and plays a crucial role in DNA repair .	BRCA1 is activated by ATM after DNA damage and plays a crucial role in DNA repair.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	BRCA1	BRCA1	BRCA1	4	5	0	1
BRCA1 becomes phosphorylated and , in turn , activated by ATM and ATR and is involved in transcriptional activation of some DNA repair genes ( see later in the text ) .	BRCA1 becomes phosphorylated and, in turn, activated by ATM and ATR and is involved in transcriptional activation of some DNA repair genes (see later in the text).	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	BRCA1	BRCA1	BRCA1	10	11	0	1
BRCA1 is activated by ATM or CHEK2 kinase phosphorylation and works as a signal processor for DNA damage response .	BRCA1 is activated by ATM or CHEK2 kinase phosphorylation and works as a signal processor for DNA damage response.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM or CHEK2 kinase phosphorylation	atm	BRCA1	BRCA1	brca1	4	5	0	1
The ATM target MDC1 promotes telomere fusions in TRF2 -/- mouse cells by recruiting 53BP1 to deprotected telomeres .	The ATM target MDC1 promotes telomere fusions in TRF2 -/- mouse cells by recruiting 53BP1 to deprotected telomeres.	1	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	1	2	14	15
We next assessed the requirement of NBS in ATM mediated 53BP1 recruitment to sites of replication stress induced damage .	We next assessed the requirement of NBS in ATM mediated 53BP1 recruitment to sites of replication stress induced damage.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	8	9	10	11
The increased mobility is dependent upon ATM activation and expression of 53BP1 , a key factor in DNA double-strand break ( DSB ) repair by non homologous end joining ( NHEJ ) [ XREF_BIBR ] .	The increased mobility is dependent upon ATM activation and expression of 53BP1, a key factor in DNA double-strand break (DSB) repair by non homologous end joining (NHEJ) [XREF_BIBR].	6	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	6	7	11	12
Second , phosphorylation of some ATM targets in 53BP1 deficient mice and human cells is impaired .	Second, phosphorylation of some ATM targets in 53BP1 deficient mice and human cells is impaired.	2	10	targets	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	phosphorylation of some ATM	atm	53BP1	53BP1	53bp1	5	6	8	9
The molecular mechanism by which ATM is activated upon replicative stress to localize the 53BP1 protection complex is unknown .	The molecular mechanism by which ATM is activated upon replicative stress to localize the 53BP1 protection complex is unknown.	5	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	5	6	14	15
ATM signaling is required for the c-NHEJ of telomeres , in part because the ATM target 53BP1 prevents resection at deprotected telomeres and increases their mobility .	ATM signaling is required for the c-NHEJ of telomeres, in part because the ATM target 53BP1 prevents resection at deprotected telomeres and increases their mobility.	13	23	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	14	15	16	17
In contrast , ATM inhibition reduced the number of 53BP1 foci in CDDP exposed OHC nuclei ( Fig XREF_FIG A and B ) .	In contrast, ATM inhibition reduced the number of 53BP1 foci in CDDP exposed OHC nuclei (Fig XREF_FIG A and B).	3	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	3	4	9	10
Of note , the 53BP1 repair protein , targeted by ATM , has been involved in both promoting telomere fusion and efficient V ( D ) J recombination .	Of note, the 53BP1 repair protein, targeted by ATM, has been involved in both promoting telomere fusion and efficient V (D) J recombination.	4	11	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	10	11	4	5
With regard to ATM , although this DNA damage induced kinase has been reported to directly target AMPKalpha phosphorylation to increase mitochondrial biogenesis in etoposide treated HeLa cells [ XREF_BIBR ] , it has also been reported that ROS induced ATM activation led to LKB1 dependent AMPK activation and subsequent mTORC1 inhibition [ XREF_BIBR ] .	With regard to ATM, although this DNA damage induced kinase has been reported to directly target AMPKalpha phosphorylation to increase mitochondrial biogenesis in etoposide treated HeLa cells [XREF_BIBR], it has also been reported that ROS induced ATM activation led to LKB1 dependent AMPK activation and subsequent mTORC1 inhibition [XREF_BIBR].	38	45	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ATM	ROS induced ATM	atm	LKB1	LKB1	lkb1	40	41	44	45
LKB1 or AMPK can be activated by ATM , a critical early DNA damage response protein XREF_BIBR .	LKB1 or AMPK can be activated by ATM, a critical early DNA damage response protein XREF_BIBR.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	LKB1	LKB1	LKB1	7	8	0	1
However , in contrast to that study , we found that in MCF7 cells at 1 h after treatment , LKB1 is exclusively cytoplasmic , and that LKB1 activation by ATM results in AMPK activation , which was not examined in this earlier report .	However, in contrast to that study, we found that in MCF7 cells at 1 h after treatment, LKB1 is exclusively cytoplasmic, and that LKB1 activation by ATM results in AMPK activation, which was not examined in this earlier report.	27	31	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	LKB1	LKB1	LKB1	30	31	27	28
One clue to address this question has recently been presented [ XREF_BIBR ] in which cytoplasmic ATM autophosphorylated at Ser 1981 in response to oxidative stress activates a liver kinase B1 ( LKB1 )-AMP activated protein kinase ( AMPK ) cascade ( XREF_FIG ) .	One clue to address this question has recently been presented [XREF_BIBR] in which cytoplasmic ATM autophosphorylated at Ser 1981 in response to oxidative stress activates a liver kinase B1 (LKB1)-AMP activated protein kinase (AMPK) cascade (XREF_FIG).	15	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	liver kinase B1	liver kinase B1	liver kinase B1	16	17	28	31
For example , in response to DNA damage , ATM phosphorylates and activates LKB1 , activating AMPK .	For example, in response to DNA damage, ATM phosphorylates and activates LKB1, activating AMPK.	9	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	LKB1	LKB1	LKB1	9	10	13	14
Our research into mechanisms of TSC2 regulation helped uncover a pathway upstream of TSC2 that is regulated by cytoplasmic ATM in response to ROS initiated by ATM activation of LKB1 and AMPK .	Our research into mechanisms of TSC2 regulation helped uncover a pathway upstream of TSC2 that is regulated by cytoplasmic ATM in response to ROS initiated by ATM activation of LKB1 and AMPK.	26	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	LKB1	LKB1	LKB1	26	27	29	30
Thus , ATM and/or Nbs1 could support the end tethering functions of either the Mre11 complex and/or c-NHEJ factors themselves , and thereby limit incorrect end utilization during EJ .	Thus, ATM and/or Nbs1 could support the end tethering functions of either the Mre11 complex and/or c-NHEJ factors themselves, and thereby limit incorrect end utilization during EJ.	2	15	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Mre11	Mre11	Mre11	2	3	14	15
These results provide strong evidence that ATM mediated feedback control of DSBs involves an MRE11 complex dependent ATM activation pathway similar to the response to ionizing radiation .	These results provide strong evidence that ATM mediated feedback control of DSBs involves an MRE11 complex dependent ATM activation pathway similar to the response to ionizing radiation.	6	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRE11	MRE11	MRE11	6	7	14	15
By mediating the phospho ATM driven assembly of BRCA , MRE11 and Rad50 on double strand breaks , nibrin carries a central role in the cellular response to DNA damage [ XREF_BIBR ] .	By mediating the phospho ATM driven assembly of BRCA, MRE11 and Rad50 on double strand breaks, nibrin carries a central role in the cellular response to DNA damage [XREF_BIBR].	1	11	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRE11	MRE11	MRE11	4	5	10	11
ATM kinase activity and mobilization may be required for MRE11 complex conformational changes and ATM kinase inhibition may disrupt MRE11 activity .	ATM kinase activity and mobilization may be required for MRE11 complex conformational changes and ATM kinase inhibition may disrupt MRE11 activity.	14	20	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRE11	MRE11	MRE11	14	15	19	20
ATM in turn stimulates nuclease activity of Mre11 in response to DSBs and Mre11 in cooperation with CtIP carries out early limited resection at the sites of DSBs .	ATM in turn stimulates nuclease activity of Mre11 in response to DSBs and Mre11 in cooperation with CtIP carries out early limited resection at the sites of DSBs.	0	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Mre11	Mre11	Mre11	0	1	7	8
Nevertheless , this mechanism could possibly be responsible for ATM activation in HCT116 cells where low expression levels of the ATM activating MRN-complex protein MRE11 have been described [ XREF_BIBR , XREF_BIBR ] .	Nevertheless, this mechanism could possibly be responsible for ATM activation in HCT116 cells where low expression levels of the ATM activating MRN-complex protein MRE11 have been described [XREF_BIBR, XREF_BIBR].	17	25	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	levels of the ATM	atm	MRE11	MRE11	mre11	20	21	24	25
There are data that indicate that ATM and the ATM activating MRE11 , RAD50 NBS1 ( MRN ) complex does have important activities at replication forks .	There are data that indicate that ATM and the ATM activating MRE11, RAD50 NBS1 (MRN) complex does have important activities at replication forks.	6	20	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MRE11	MRE11	MRE11	9	10	11	12
Several candidate kinases acting downstream of ATM could potentially account for Cip29 phosphorylation , including , for example , cyclin dependent kinase 5 , Polo like kinase1 or the mitogen activated protein kinase family member , c-Jun kinase , although the rapidity of the Cip29 phosphorylation response , which precedes even that of the known ATM target Mre11 , may point towards direct targeting by ATM [ XREF_BIBR ] .	Several candidate kinases acting downstream of ATM could potentially account for Cip29 phosphorylation, including, for example, cyclin dependent kinase 5, Polo like kinase1 or the mitogen activated protein kinase family member, c-Jun kinase, although the rapidity of the Cip29 phosphorylation response, which precedes even that of the known ATM target Mre11, may point towards direct targeting by ATM [XREF_BIBR].	51	58	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Mre11	Mre11	Mre11	55	56	57	58
We further confirmed whether Cdc7-Dbf4 regulates ATR and ATM signaling via direct stabilizing ATR and ATM activating auxiliary proteins , HCLK2 , HSP90 , and Mre11 .	We further confirmed whether Cdc7-Dbf4 regulates ATR and ATM signaling via direct stabilizing ATR and ATM activating auxiliary proteins, HCLK2, HSP90, and Mre11.	9	26	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Mre11	Mre11	Mre11	15	16	25	26
Recent work indicates that SV40 large T antigen can serve as both a substrate for the ATM kinase as well as its direct upstream activator through binding the Nbs1 component of the ATM activating Mre11 , Rad50 , and Nbs1 complex .	Recent work indicates that SV40 large T antigen can serve as both a substrate for the ATM kinase as well as its direct upstream activator through binding the Nbs1 component of the ATM activating Mre11, Rad50, and Nbs1 complex.	29	40	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Mre11	Mre11	Mre11	32	33	34	35
Although ATM can stimulate the activity of Artemis , ATM dependent Artemis activity is required for the resolution of only ~ 10 % of DSBs that are repaired several hours after IR .	Although ATM can stimulate the activity of Artemis, ATM dependent Artemis activity is required for the resolution of only ~ 10% of DSBs that are repaired several hours after IR.	1	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Artemis	Artemis	Artemis	1	2	7	8
Two proteins that stand out that differ between yeast and mammalian cells are DNA-PK , a protein kinase that is activated by the presence of DSBs , and Artemis , a nuclease whose activity is modulated by DNA-PK and ATM .	Two proteins that stand out that differ between yeast and mammalian cells are DNA-PK, a protein kinase that is activated by the presence of DSBs, and Artemis, a nuclease whose activity is modulated by DNA-PK and ATM.	13	40	modulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Artemis	Artemis	Artemis	39	40	28	29
The ATM dependent phosphorylation increases the Artemis exonuclease activity and thus may help processing of DNA ends during the DSB repair [ XREF_BIBR ] .	The ATM dependent phosphorylation increases the Artemis exonuclease activity and thus may help processing of DNA ends during the DSB repair [XREF_BIBR].	1	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM dependent phosphorylation	atm	Artemis	Artemis	artemis	1	2	6	7
In analogy to our previous study , we confirmed that ATM and Artemis operate in the same repair pathway by analyzing the repair defect in Artemis cells treated with the specific ATM small molecule inhibitor KU55933 .	In analogy to our previous study, we confirmed that ATM and Artemis operate in the same repair pathway by analyzing the repair defect in Artemis cells treated with the specific ATM small molecule inhibitor KU55933.	25	35	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ATM	ATM	ATM	Artemis	Artemis	Artemis	31	32	25	26
Moreover , inhibition of Atm signaling in Artemis -/- abl pre-B cells led to the diminished localization of these cells in the bone marrow ( XREF_SUPPLEMENTARY ) .	Moreover, inhibition of Atm signaling in Artemis -/- abl pre-B cells led to the diminished localization of these cells in the bone marrow (XREF_SUPPLEMENTARY).	4	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Atm	Atm	Atm	Artemis	Artemis	Artemis	4	5	7	8
The authors demonstrated that USP7 degradation is initiated by the PPM1G protein phosphatase , which is activated by ATM dependent phosphorylation in response to DNA damage .	The authors demonstrated that USP7 degradation is initiated by the PPM1G protein phosphatase, which is activated by ATM dependent phosphorylation in response to DNA damage.	10	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM dependent phosphorylation	atm	PPM1G	PPM1G	ppm1g	18	19	10	11
In response to DNA damage , the protein phosphatase PPM1G is activated by ATM that results in dephosphorylation , and therefore destabilization , of USP7S .	In response to DNA damage, the protein phosphatase PPM1G is activated by ATM that results in dephosphorylation, and therefore destabilization, of USP7S.	6	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	PPM1G	PPM1G	PPM1G	13	14	9	10
Our data demonstrate that ATM phosphorylation regulates PPM1G activity and that ATM knockdown abolishes DNA damage dependent dephosphorylation of USP7S by PPM1G , supporting our model where PPM1G is activated by direct ATM phosphorylation .	Our data demonstrate that ATM phosphorylation regulates PPM1G activity and that ATM knockdown abolishes DNA damage dependent dephosphorylation of USP7S by PPM1G, supporting our model where PPM1G is activated by direct ATM phosphorylation.	11	22	abolishes	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ATM	ATM	atm	PPM1G	dephosphorylation of USP7S by PPM1G	ppm1g	11	12	21	22
The ATM and ATR dependent phosphorylation of H2AX is causes the accumulation of MDC1 , which is the key regulator for the micro-environment at the vicinity of the damaged DNA .	The ATM and ATR dependent phosphorylation of H2AX is causes the accumulation of MDC1, which is the key regulator for the micro-environment at the vicinity of the damaged DNA.	0	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MDC1	MDC1	MDC1	1	2	13	14
In response of DSB damage , MDC1 was activated by ataxia telangiectasia mutated ( ATM ) protein kinase and recruit DNA damage repair ( DDR ) factors to DSB sites [ XREF_BIBR ] .	In response of DSB damage, MDC1 was activated by ataxia telangiectasia mutated (ATM) protein kinase and recruit DNA damage repair (DDR) factors to DSB sites [XREF_BIBR].	6	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	MDC1	MDC1	MDC1	10	13	6	7
The gamma-H2AX mark acts as a platform for hierarchical recruitment and retention of key DDR factors , including the mediator protein MDC1 , promoting amplification of the DDR by further ATM activation and consequent gamma-H2AX spreading .	The gamma-H2AX mark acts as a platform for hierarchical recruitment and retention of key DDR factors, including the mediator protein MDC1, promoting amplification of the DDR by further ATM activation and consequent gamma-H2AX spreading.	17	31	promoting	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	MDC1	MDC1	MDC1	30	31	21	22
Since ATM activation and recruitment of early signaling factors MDC1 and RNF8 are not affected by inactivation of RNF20 , the authors proposed that RNF20/40 act downstream of signaling , but before initiation of repair .	Since ATM activation and recruitment of early signaling factors MDC1 and RNF8 are not affected by inactivation of RNF20, the authors proposed that RNF20/40 act downstream of signaling, but before initiation of repair.	1	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	MDC1	MDC1	MDC1	1	2	9	10
To investigate the mechanisms that led to the observed reduced survival rate , increased percentage of cells in the G 2 / M phase , and increased apoptosis rate , following X-rays and carbon ion irradiation with or without NU7026-treatment in A459 cells , the expression levels of DNA-PKcs were examined in A549 cells treated with the ATM and ATR-inhibitor CGK733 and ionizing radiation .	To investigate the mechanisms that led to the observed reduced survival rate, increased percentage of cells in the G 2 / M phase, and increased apoptosis rate, following X-rays and carbon ion irradiation with or without NU7026-treatment in A459 cells, the expression levels of DNA-PKcs were examined in A549 cells treated with the ATM and ATR-inhibitor CGK733 and ionizing radiation.	46	63	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ATM	ATM	ATM	DNA-PKcs	DNA-PKcs	DNA-PKcs	57	58	48	49
Moreover , depression of c-Myc largely attenuated the ionizing radiation induced phosphorylation of the ataxia telangiectasia mutated ( ATM ) and decreased the in vitro kinase activity of DNA-PKcs .	Moreover, depression of c-Myc largely attenuated the ionizing radiation induced phosphorylation of the ataxia telangiectasia mutated (ATM) and decreased the in vitro kinase activity of DNA-PKcs.	4	29	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ataxia telangiectasia mutated	c-Myc largely attenuated the ionizing radiation induced phosphorylation of the ataxia telangiectasia mutated	ataxia telangiectasia mutated	DNA-PKcs	DNA-PKcs	dna-pkcs	14	17	28	29
The ability of ATM to compensate for DNA-PKcs kinase activity depends on the integrity of three threonines in DNA-PKcs that are phosphorylation targets of ATM , suggesting that ATM can modulate DNA-PKcs activity through direct phosphorylation of DNA-PKcs .	The ability of ATM to compensate for DNA-PKcs kinase activity depends on the integrity of three threonines in DNA-PKcs that are phosphorylation targets of ATM, suggesting that ATM can modulate DNA-PKcs activity through direct phosphorylation of DNA-PKcs.	28	32	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	DNA-PKcs	DNA-PKcs	DNA-PKcs	28	29	31	32
Since the phenotypes we observed in cells expressing S314A Bub1 recapitulate the defects in Bub1 knock-down cells , we conclude that ATM mediated Bub1 serine 314 phosphorylation is critical for the function of Bub1 in the DNA damage response .	Since the phenotypes we observed in cells expressing S314A Bub1 recapitulate the defects in Bub1 knock-down cells, we conclude that ATM mediated Bub1 serine 314 phosphorylation is critical for the function of Bub1 in the DNA damage response.	21	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Bub1	Bub1	Bub1	21	22	23	24
We observed that the Serine314 to Alanine mutation had a dominant negative effect against endogenous Bub1 , and the Serine 314 to Glutamic Acid substitution increased H2A Thr121 phosphorylation , indicating that ATM mediated Bub1 serine 314 phosphorylation regulates Bub1 activity .	We observed that the Serine314 to Alanine mutation had a dominant negative effect against endogenous Bub1, and the Serine 314 to Glutamic Acid substitution increased H2A Thr121 phosphorylation, indicating that ATM mediated Bub1 serine 314 phosphorylation regulates Bub1 activity.	32	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Bub1	Bub1	Bub1	32	33	34	35
We show that Bub1 mediated Histone H2A threonine 121 phosphorylation is induced by IR and this requires ATM mediated Bub1 serine 314 phosphorylation .	We show that Bub1 mediated Histone H2A threonine 121 phosphorylation is induced by IR and this requires ATM mediated Bub1 serine 314 phosphorylation.	16	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Bub1	Bub1	Bub1	17	18	19	20
Further , we demonstrate that ATM mediated Bub1 serine 314 phosphorylation is required for IR induced Bub1 activation and for efficient DNA repair .	Further, we demonstrate that ATM mediated Bub1 serine 314 phosphorylation is required for IR induced Bub1 activation and for efficient DNA repair.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Bub1	Bub1	Bub1	5	6	7	8
3.5 ATM mediated Bub1 serine 314 phosphorylation is required for Bub1 activation and optimal DNA damage responses .	3.5 ATM mediated Bub1 serine 314 phosphorylation is required for Bub1 activation and optimal DNA damage responses.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Bub1	Bub1	Bub1	1	2	3	4
Finally , we showed that ATM mediated Bub1 serine 314 phosphorylation was required for IR induced Bub1 activation and for the optimal DDR .	Finally, we showed that ATM mediated Bub1 serine 314 phosphorylation was required for IR induced Bub1 activation and for the optimal DDR.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	Bub1	Bub1	Bub1	5	6	7	8
Upon gammaIR , a source of replication independent DSBs , ATM activates FANCD2 by phosphorylation [ XREF_BIBR ] .	Upon gammaIR, a source of replication independent DSBs, ATM activates FANCD2 by phosphorylation [XREF_BIBR].	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	FANCD2	FANCD2	FANCD2	10	11	12	13
In AT cells ( which express nonfunctional ATM ) , TonEBP and OREBP transcriptional and transactivating activity are further increased by expression of wild-type ATM but not of S1981A ATM .	In AT cells (which express nonfunctional ATM), TonEBP and OREBP transcriptional and transactivating activity are further increased by expression of wild-type ATM but not of S1981A ATM.	10	25	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	expression of wild-type ATM	atm	TonEBP	TonEBP	tonebp	24	25	10	11
However , in HEK293 cells transfected with HRE-luciferase reporter , the pharmacological inhibition of ATM and PI3K with 1 uM of Wortmannin did not prevent the protein induction of NFAT5 by hypoxia ( XREF_FIG ) .	However, in HEK293 cells transfected with HRE-luciferase reporter, the pharmacological inhibition of ATM and PI3K with 1 uM of Wortmannin did not prevent the protein induction of NFAT5 by hypoxia (XREF_FIG).	12	30	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	NFAT5	NFAT5	NFAT5	14	15	29	30
Further , ATM XREF_BIBR , PARP1 XREF_BIBR , and MDC1 ( present studies ) all contribute to regulation of high NaCl induced activation of TonEBP and OREBP .	Further, ATM XREF_BIBR, PARP1 XREF_BIBR, and MDC1 (present studies) all contribute to regulation of high NaCl induced activation of TonEBP and OREBP.	2	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	TonEBP	TonEBP	TonEBP	2	3	24	25
However , little is known about ATM mediated TRF1 phosphorylation site ( s ) in vivo .	However, little is known about ATM mediated TRF1 phosphorylation site (s) in vivo.	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATM	ATM	ATM	TRF1	TRF1	TRF1	6	7	8	9
On the other hand , we found that treatment of cells with KU55933 , a specific inhibitor of ATM , completely abrogated the ability of ( pT371 ) TRF1 to form IR induced foci ( XREF_FIG A and B ) .	On the other hand, we found that treatment of cells with KU55933, a specific inhibitor of ATM, completely abrogated the ability of (pT371) TRF1 to form IR induced foci (XREF_FIG A and B).	16	29	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	TRF1	TRF1	TRF1	18	19	28	29
We have shown that S367 phosphorylation by ATM targets TRF1 to proteasome dependent nuclear foci , which is associated with its increased susceptibility to protein degradation .	We have shown that S367 phosphorylation by ATM targets TRF1 to proteasome dependent nuclear foci, which is associated with its increased susceptibility to protein degradation.	5	10	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	TRF1	TRF1	TRF1	7	8	9	10
TRF1 dissociation from the telomere may be caused by its phosphorylation by ATM , which causes proteasomal TRF1 degradation [ XREF_BIBR ] .	TRF1 dissociation from the telomere may be caused by its phosphorylation by ATM, which causes proteasomal TRF1 degradation [XREF_BIBR].	7	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	TRF1	TRF1	TRF1	12	13	17	18
Because the HPV 8 E6 mediated reduction of ATR is dependent on the ability of HPV 8 E6 to bind and promote the degradation of p300 [ XREF_BIBR ] , we hypothesized that the reduction of ATM protein levels would be similarly dependent on the ability of HPV 8 E6 to promote p300 degradation .	Because the HPV 8 E6 mediated reduction of ATR is dependent on the ability of HPV 8 E6 to bind and promote the degradation of p300 [XREF_BIBR], we hypothesized that the reduction of ATM protein levels would be similarly dependent on the ability of HPV 8 E6 to promote p300 degradation.	36	53	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM protein levels	atm	p300	p300	p300	36	37	52	53
ATM increases p300 activity , suggesting that p300 activity also oscillates after DNA damage .	ATM increases p300 activity, suggesting that p300 activity also oscillates after DNA damage.	0	3	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	p300	p300	p300	0	1	2	3
Thus , ATM inhibition prevents the accumulation of RAD52 , p300 and CBP , and SIRT2 and SIRT3 at DSB sites , thereby causing the intra-cellular diffusion of these proteins , even after IR treatment .	Thus, ATM inhibition prevents the accumulation of RAD52, p300 and CBP, and SIRT2 and SIRT3 at DSB sites, thereby causing the intra-cellular diffusion of these proteins, even after IR treatment.	2	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	p300	p300	p300	2	3	10	11
The activation of KSRP by ATM phosphorylation appears to be site specific , as phosphorylation on Ser670 and Ser274 imposes more profound effects on the KSRP activity than Ser132 phosphorylation .	The activation of KSRP by ATM phosphorylation appears to be site specific, as phosphorylation on Ser670 and Ser274 imposes more profound effects on the KSRP activity than Ser132 phosphorylation.	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATM	ATM phosphorylation	atm	KSRP	KSRP	ksrp	5	6	3	4
It is widely accepted that ATM deficiency is associated with sensitivity to oxidative stress and we propose that under these conditions cells lacking functional ATM would not be able to enhance the required amount of PNKP protein .	It is widely accepted that ATM deficiency is associated with sensitivity to oxidative stress and we propose that under these conditions cells lacking functional ATM would not be able to enhance the required amount of PNKP protein.	24	36	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	PNKP	PNKP	PNKP	24	25	35	36
Indeed , we were able to show that an siRNA knockdown of ATM , which significantly reduces the level of PNKP phosphorylation , prevented the increased stability of PNKP in response to oxidative DNA damage ( XREF_FIG C and D ) .	Indeed, we were able to show that an siRNA knockdown of ATM, which significantly reduces the level of PNKP phosphorylation, prevented the increased stability of PNKP in response to oxidative DNA damage (XREF_FIG C and D).	10	22	reduces	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ATM	ATM	atm	PNKP	PNKP phosphorylation	pnkp	12	13	20	21
It has also been demonstrated that ATF2 is activated by ATM through phosphorylation in the DNA damage response .	It has also been demonstrated that ATF2 is activated by ATM through phosphorylation in the DNA damage response.	6	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	ATF2	ATF2	ATF2	10	11	6	7
It is already known that RASSF1A can be modulated by ATM levels and associates with the nucleotide excision repair enzyme , XPA .	It is already known that RASSF1A can be modulated by ATM levels and associates with the nucleotide excision repair enzyme, XPA.	5	12	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM levels	atm	RASSF1A	RASSF1A	rassf1a	10	11	5	6
In addition , EXO1 , which is involved in the processive stage of DSB resection together with BLM following the initial resection carried out by CtIP , is also stimulated by ATM phosphorylation ( XREF_FIG ) .	In addition, EXO1, which is involved in the processive stage of DSB resection together with BLM following the initial resection carried out by CtIP, is also stimulated by ATM phosphorylation (XREF_FIG).	3	33	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM phosphorylation	atm	EXO1	EXO1	exo1	31	32	3	4
What stands out in the present study is ATM mediated control of Exonuclease 1 activity limiting the extent of resection .	What stands out in the present study is ATM mediated control of Exonuclease 1 activity limiting the extent of resection.	1	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Exonuclease 1	Exonuclease 1	Exonuclease 1	8	9	12	14
In this context , ATM promotes HIF1a stabilization by direct phosphorylation on Ser696 , culminating on mTORC1 inhibition .	In this context, ATM promotes HIF1a stabilization by direct phosphorylation on Ser696, culminating on mTORC1 inhibition.	4	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	HIF1a	HIF1a	HIF1a	4	5	6	7
To cite some examples , ATM activation in response to DNA damage has been shown to be reduced in Hif-1alpha knock-out murine fibroblasts , while loss of ATM prevented the stabilization and activity of HIF-1alpha under hypoxic conditions .	To cite some examples, ATM activation in response to DNA damage has been shown to be reduced in Hif-1alpha knock-out murine fibroblasts, while loss of ATM prevented the stabilization and activity of HIF-1alpha under hypoxic conditions.	25	35	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	loss of ATM	atm	HIF-1alpha	HIF-1alpha	hif-1alpha	27	28	34	35
Because the RPA32 N-terminus is targeted by the PIKKs ATM , ATR and DNA-PK in response to damage , we examined the importance of each of these kinases for RPA phosphorylation and ubiquitylation using specific inhibitors .	Because the RPA32 N-terminus is targeted by the PIKKs ATM, ATR and DNA-PK in response to damage, we examined the importance of each of these kinases for RPA phosphorylation and ubiquitylation using specific inhibitors.	2	13	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	RPA32	RPA32	RPA32	9	10	2	3
However , ATM dependent targeting of BLM in a formaldehyde specific cellular response does not exclude a possible role for ATR kinase .	However, ATM dependent targeting of BLM in a formaldehyde specific cellular response does not exclude a possible role for ATR kinase.	2	9	targeting	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	BLM	BLM	BLM	2	3	6	7
Our previous studies have shown that Smad1 is upregulated and activated by Atm in DNA damage response , which can further bind to p53 and promote p53 stabilization .	Our previous studies have shown that Smad1 is upregulated and activated by Atm in DNA damage response, which can further bind to p53 and promote p53 stabilization.	6	13	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Atm	Atm	Atm	Smad1	Smad1	Smad1	12	13	6	7
In response to IR or other genotoxic stress , Fbxo31 is targeted by the checkpoint kinase ATM for phosphorylation , which results in the accumulation of Fbxo31 .	In response to IR or other genotoxic stress, Fbxo31 is targeted by the checkpoint kinase ATM for phosphorylation, which results in the accumulation of Fbxo31.	9	17	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Fbxo31	Fbxo31	Fbxo31	16	17	9	10
Following the initial hypothesis that TDP1 was a target for DDR kinases [ XREF_BIBR ] , ATM and DNA-PK were both found to activate TDP1 by phosphorylation at serine 81 ( S81 , XREF_FIG ) [ XREF_BIBR ] .	Following the initial hypothesis that TDP1 was a target for DDR kinases [XREF_BIBR], ATM and DNA-PK were both found to activate TDP1 by phosphorylation at serine 81 (S81, XREF_FIG) [XREF_BIBR].	16	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	TDP1	TDP1	TDP1	16	17	24	25
RRM2B is induced upon activation of the DNA damage pathway transcriptionally by p53 XREF_BIBR XREF_BIBR XREF_BIBR and post-translationally by ATM XREF_BIBR .	RRM2B is induced upon activation of the DNA damage pathway transcriptionally by p53 XREF_BIBR XREF_BIBR XREF_BIBR and post-translationally by ATM XREF_BIBR.	0	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	RRM2B	RRM2B	RRM2B	19	20	0	1
While it was initially thought that ATR responds to DSBs independently of ATM , recent studies have found that ATR acts downstream of ATM and MRN to activate Chk1 in response to DSBs during S and G 2 phases of the cell cycle ( XREF_FIG ) .	While it was initially thought that ATR responds to DSBs independently of ATM, recent studies have found that ATR acts downstream of ATM and MRN to activate Chk1 in response to DSBs during S and G 2 phases of the cell cycle (XREF_FIG).	19	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	19	20	28	29
In human cells , following DNA damage or drug induced fork stalling , Cdc7 kinase remains active and phosphorylates Claspin , a mediator protein for ATR dependent activation of Chk1 .	In human cells, following DNA damage or drug induced fork stalling, Cdc7 kinase remains active and phosphorylates Claspin, a mediator protein for ATR dependent activation of Chk1.	25	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	25	26	29	30
Previous studies showed that MK-8776 and other Chk1 inhibitors block Chk1 autophosphorylation on Ser 296 and that VE-821 abrogates ATR mediated Chk1 Ser 345 phosphorylation , suggesting that these phosphorylation events may provide an effective way to assess disruption of this signaling pathway in clinical trials .	Previous studies showed that MK-8776 and other Chk1 inhibitors block Chk1 autophosphorylation on Ser 296 and that VE-821 abrogates ATR mediated Chk1 Ser 345 phosphorylation, suggesting that these phosphorylation events may provide an effective way to assess disruption of this signaling pathway in clinical trials.	18	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	19	20	21	22
This indicates that HELQ is involved in ATR mediated CHK1 activation but not in ATR mediated FANCD2 monoubiquitination .	This indicates that HELQ is involved in ATR mediated CHK1 activation but not in ATR mediated FANCD2 monoubiquitination.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	7	8	9	10
Mec1 and ATR activates effector kinases Chk1 and Rad53 , the yeast ortholog of human Chk2 .	Mec1 and ATR activates effector kinases Chk1 and Rad53, the yeast ortholog of human Chk2.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	2	3	6	7
Additionally , ATM and ATR activated Chk1 and Chk2 kinases phosphorylate the p53 transactivation domain on serine 20 , thereby stimulating p53 activity .	Additionally, ATM and ATR activated Chk1 and Chk2 kinases phosphorylate the p53 transactivation domain on serine 20, thereby stimulating p53 activity.	2	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	4	5	6	7
ATR then activates CHK1 through phosphorylation of Ser345 and Ser317 to coordinate cellular responses to replication stress .	ATR then activates CHK1 through phosphorylation of Ser345 and Ser317 to coordinate cellular responses to replication stress.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	0	1	3	4
SCF betaTrCP also regulates checkpoint recovery : the ubiquitin dependent degradation of CLASPIN ( a DNA binding protein required for the ATR mediated activation of Chk1 in response to DNA replication stress ) in G2 allows efficient termination of DNA replication checkpoint which is necessary for progression of the cell into mitosis [ XREF_BIBR - XREF_BIBR ] .	SCF betaTrCP also regulates checkpoint recovery : the ubiquitin dependent degradation of CLASPIN (a DNA binding protein required for the ATR mediated activation of Chk1 in response to DNA replication stress) in G2 allows efficient termination of DNA replication checkpoint which is necessary for progression of the cell into mitosis [XREF_BIBR - XREF_BIBR].	21	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	21	22	25	26
In addition to Claspin , a second replication fork associated complex , Tim and Tipin , may also mediate activation of CHK1 by ATR XREF_BIBR , XREF_BIBR .	In addition to Claspin, a second replication fork associated complex, Tim and Tipin, may also mediate activation of CHK1 by ATR XREF_BIBR, XREF_BIBR.	19	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	23	24	21	22
We further propose that during the DNA damage response , the association of hMYH with hTopBP1 is necessary for the cell cycle arrest caused by ATR mediated activation of Chk1 .	We further propose that during the DNA damage response, the association of hMYH with hTopBP1 is necessary for the cell cycle arrest caused by ATR mediated activation of Chk1.	25	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	25	26	29	30
These results , therefore , suggest that ATR regulation of HR contributes to cell survival more than ATR mediated activation of Chk1 in cells treated with agents that induce lesions repaired by HR .	These results, therefore, suggest that ATR regulation of HR contributes to cell survival more than ATR mediated activation of Chk1 in cells treated with agents that induce lesions repaired by HR.	17	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	17	18	21	22
While the two pathways are interdependent , ATR generally signals replication dependent damage through CHK1 ( checkpoint kinase 1 ) whereas ATM signals in response to DSBs via CHK2 ( checkpoint kinase 2 ) [ XREF_BIBR , XREF_BIBR ] .	While the two pathways are interdependent, ATR generally signals replication dependent damage through CHK1 (checkpoint kinase 1) whereas ATM signals in response to DSBs via CHK2 (checkpoint kinase 2) [XREF_BIBR, XREF_BIBR].	7	19	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	checkpoint kinase 1	checkpoint kinase 1	checkpoint kinase 1	7	8	16	19
Interestingly , we found that E7 maintains high levels of DNA repair factors required for productive replication through increased protein stability , rather than exclusively through increased gene expression , with exceptions limited to the ATR target Chk1 , and the homologous recombination repair factors BRCA1 and Rad51 .	Interestingly, we found that E7 maintains high levels of DNA repair factors required for productive replication through increased protein stability, rather than exclusively through increased gene expression, with exceptions limited to the ATR target Chk1, and the homologous recombination repair factors BRCA1 and Rad51.	32	38	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	35	36	37	38
In turn , ATR activates the cell cycle kinase Chk1 by phosphorylation ( at serine 345 ) , leading to a suppression of origin firing and DNA elongation , and cell cycle arrest in S/G , which promote repair and prevent premature mitosis , thereby maintaining genomic stability .	In turn, ATR activates the cell cycle kinase Chk1 by phosphorylation (at serine 345), leading to a suppression of origin firing and DNA elongation, and cell cycle arrest in S/G, which promote repair and prevent premature mitosis, thereby maintaining genomic stability.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	3	4	9	10
It may be required for ATM or ATR activation of Chk1 and Chk2 .	It may be required for ATM or ATR activation of Chk1 and Chk2.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	7	8	10	11
[ XREF_BIBR - XREF_BIBR ] Particularly , Mcl-1 is linked to regulating cell-cycle progression and is partially mediated through PCNA , interactions with CDK1 , and ATR dependent activation of Chk1 following DNA damage .	[XREF_BIBR - XREF_BIBR] Particularly, Mcl-1 is linked to regulating cell-cycle progression and is partially mediated through PCNA, interactions with CDK1, and ATR dependent activation of Chk1 following DNA damage.	26	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	26	27	30	31
Since DSB dependent PD-L1 expression requires Chk1 activity , which is activated by ATR on single stranded DNA ( ssDNA )-replication protein A ( RPA ) , we hypothesised that the greater PD-L1 upregulation after IR in Ku80 depleted cells may be due to Chk1 overactivation following an increase in DNA end resection .	Since DSB dependent PD-L1 expression requires Chk1 activity, which is activated by ATR on single stranded DNA (ssDNA)-replication protein A (RPA), we hypothesised that the greater PD-L1 upregulation after IR in Ku80 depleted cells may be due to Chk1 overactivation following an increase in DNA end resection.	6	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	13	14	6	7
In response to UV radiation CHK1 activation by ATR has been shown to activate LATS2 [ XREF_BIBR ] .	In response to UV radiation CHK1 activation by ATR has been shown to activate LATS2 [XREF_BIBR].	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	8	9	5	6
Once recruited , ATR phosphorylates and thereby activates the serine threonine kinase Chk1 ( Checkpoint kinase 1 ) , which in turn blocks cell cycle progression .	Once recruited, ATR phosphorylates and thereby activates the serine threonine kinase Chk1 (Checkpoint kinase 1), which in turn blocks cell cycle progression.	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Checkpoint kinase 1	Checkpoint kinase 1	Checkpoint kinase 1	3	4	14	17
This block in replication is detected by ATR , which primarily activates Chk1 .	This block in replication is detected by ATR, which primarily activates Chk1.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	7	8	12	13
ATR activates Chk1 , which transduces downstream signals to control gene expression in response to DNA damage .	ATR activates Chk1, which transduces downstream signals to control gene expression in response to DNA damage.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	0	1	2	3
Our results is consistent with a recent report showing that H 2 O 2 can lead to ATR dependent activation of Chk1 in Xenopus egg extracts [ XREF_BIBR ] .	Our results is consistent with a recent report showing that H 2 O 2 can lead to ATR dependent activation of Chk1 in Xenopus egg extracts [XREF_BIBR].	17	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	17	18	21	22
However , at the low concentrations of caffeine used in our experiments , ATR mediated Chk1 activation was unaffected and there was substantial poleta phosphorylation .	However, at the low concentrations of caffeine used in our experiments, ATR mediated Chk1 activation was unaffected and there was substantial poleta phosphorylation.	13	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	13	14	15	16
ATR phosphorylates and activates the Chk1 kinase in response to genotoxic stress [ XREF_BIBR ] .	ATR phosphorylates and activates the Chk1 kinase in response to genotoxic stress [XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	0	1	5	6
Chk1 kinase is activated upon its phosphorylation by ATR on Ser 317 and Ser 345 [ XREF_BIBR ] .	Chk1 kinase is activated upon its phosphorylation by ATR on Ser 317 and Ser 345 [XREF_BIBR].	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	8	9	0	1
This step is necessary for the ATR dependent activation of Chk1 during checkpoint responses .	This step is necessary for the ATR dependent activation of Chk1 during checkpoint responses.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	6	7	10	11
During replicative stress , Claspin mediates the phosphorylation and consequent activation of Chk1 by ATR .	During replicative stress, Claspin mediates the phosphorylation and consequent activation of Chk1 by ATR.	5	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	14	15	12	13
ATR is activated by multiple DNA damage events and replication stress , subsequently activating its substrate CHK1 .	ATR is activated by multiple DNA damage events and replication stress, subsequently activating its substrate CHK1.	0	17	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	0	1	16	17
Furthermore , RPA bound to ssDNA is required for the recruitment of ATR to sites of DNA damage and for ATR mediated CHK1 activation for checkpoint signaling .	Furthermore, RPA bound to ssDNA is required for the recruitment of ATR to sites of DNA damage and for ATR mediated CHK1 activation for checkpoint signaling.	20	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	20	21	22	23
To test the first possibility , we monitored the phosphorylation state of the ATR target Chk1 .	To test the first possibility, we monitored the phosphorylation state of the ATR target Chk1.	10	16	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	13	14	15	16
By performing structure-function studies on the MRN complex in egg extracts , we have observed that the nuclease activity of Mre11 is necessary for ATR regulated activation of Chk1 .	By performing structure-function studies on the MRN complex in egg extracts, we have observed that the nuclease activity of Mre11 is necessary for ATR regulated activation of Chk1.	24	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	24	25	28	29
These genes include CHEK1 , which participates in the G2/M checkpoint and is activated by ATR in response to unresolved DNA damage , and BRCA1 , which is in a surveillance complex that activates double-strand break repair .	These genes include CHEK1, which participates in the G2/M checkpoint and is activated by ATR in response to unresolved DNA damage, and BRCA1, which is in a surveillance complex that activates double-strand break repair.	2	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHEK1	CHEK1	CHEK1	15	16	3	4
Chk1 is classically activated by ATR and is critical for DNA repair through regulation of Cdc proteins ( XREF_FIG ) [ XREF_BIBR ] .	Chk1 is classically activated by ATR and is critical for DNA repair through regulation of Cdc proteins (XREF_FIG) [XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	5	6	0	1
Since ATR and Chk1 , which is activated by ATR dependent phosphorylation , are required for homologous recombination ( HR ) [ XREF_BIBR , XREF_BIBR ] , these checkpoint kinases may also have an important role in regulating proteins involved at this late step of ICL repair .	Since ATR and Chk1, which is activated by ATR dependent phosphorylation, are required for homologous recombination (HR) [XREF_BIBR, XREF_BIBR], these checkpoint kinases may also have an important role in regulating proteins involved at this late step of ICL repair.	1	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR dependent phosphorylation	atr	Chk1	Chk1	chk1	9	10	3	4
In addition , CK1gamma1 is related to DNA damage signaling by catalyzing the phosphorylation of claspin , an adaptor protein critically involved in ATR mediated activation of Chk1 .	In addition, CK1gamma1 is related to DNA damage signaling by catalyzing the phosphorylation of claspin, an adaptor protein critically involved in ATR mediated activation of Chk1.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	23	24	27	28
It was previously reported that transactivation of PUMA was restored during ATR mediated activation of Chk1 [ XREF_BIBR ] .	It was previously reported that transactivation of PUMA was restored during ATR mediated activation of Chk1 [XREF_BIBR].	11	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	11	12	15	16
Since Chk1 is activated by ATR in response to DNA damage , we examined the effect of Chk1 inhibition on centrosome aberrations by treatment with the Chk1 inhibitor UCN-01 at the concentration of 100 nM in the mutant cells .	Since Chk1 is activated by ATR in response to DNA damage, we examined the effect of Chk1 inhibition on centrosome aberrations by treatment with the Chk1 inhibitor UCN-01 at the concentration of 100 nM in the mutant cells.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	5	6	1	2
In response to a slowed or stalled replication fork , the activation of Chk1 by ATR pauses cell cycle progression to allow resolution of delayed replication fork time [ XREF_BIBR ] .	In response to a slowed or stalled replication fork, the activation of Chk1 by ATR pauses cell cycle progression to allow resolution of delayed replication fork time [XREF_BIBR].	11	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	15	16	13	14
CHEK1 encodes checkpoint kinase 1 ( CHK1 ) , which is activated by the kinase ATR when DNA replication is impaired by DNA damage .	CHEK1 encodes checkpoint kinase 1 (CHK1), which is activated by the kinase ATR when DNA replication is impaired by DNA damage.	1	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	15	16	6	7
ATR , in turn , activates Chk1 by phosphorylation at Ser317 and Ser345 [ XREF_BIBR ] .	ATR, in turn, activates Chk1 by phosphorylation at Ser317 and Ser345 [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	0	1	6	7
The ATR mediated activation of Chk1 is dependent upon TopBP1 and Claspin .	The ATR mediated activation of Chk1 is dependent upon TopBP1 and Claspin.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	1	2	5	6
In response to DNA damage , CHK1 is activated by ATR dependent phosphorylation at Ser317 and Ser345 , which is required for CHK1 autophosphorylation at Ser296 .	In response to DNA damage, CHK1 is activated by ATR dependent phosphorylation at Ser317 and Ser345, which is required for CHK1 autophosphorylation at Ser296.	6	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR dependent phosphorylation at Ser317	atr	CHK1	CHK1	chk1	10	11	6	7
Claspin is essential for the ATR dependent activation of Chk1 in Xenopus egg extracts containing incompletely replicated DNA .	Claspin is essential for the ATR dependent activation of Chk1 in Xenopus egg extracts containing incompletely replicated DNA.	5	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	5	6	9	10
Activation of the ATM and ATR targets Chk1 and p53 is associated with the PMN induced G2/M arrest .	Activation of the ATM and ATR targets Chk1 and p53 is associated with the PMN induced G2/M arrest.	0	11	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	5	6	7	8
While Chk2 is downstream of the ATM signaling cascade , Chk1 is mainly activated through phosphorylation by ATR .	While Chk2 is downstream of the ATM signaling cascade, Chk1 is mainly activated through phosphorylation by ATR.	10	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	17	18	10	11
ATR activates cell cycle checkpoints Chk1 and Chk2 in response to DNA damage and is structurally similar to ATM and other PIK members [ XREF_BIBR ] .	ATR activates cell cycle checkpoints Chk1 and Chk2 in response to DNA damage and is structurally similar to ATM and other PIK members [XREF_BIBR].	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	0	1	5	6
As shown in XREF_FIG , CHK1 Ser 317 phosphorylation was markedly increased after UV and completely abolished by ATR inhibition , confirming that ATR was inhibited by AZ20 .	As shown in XREF_FIG, CHK1 Ser 317 phosphorylation was markedly increased after UV and completely abolished by ATR inhibition, confirming that ATR was inhibited by AZ20.	5	19	abolished	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	18	19	5	6
The ATR complex assembles at stalled replication fork and activates checkpoint kinase 1 ( CHK1 ) .	The ATR complex assembles at stalled replication fork and activates checkpoint kinase 1 (CHK1).	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	checkpoint kinase 1	checkpoint kinase 1	checkpoint kinase 1	1	2	10	13
In marked contrast to ATR T1989A , neither ATR S428A nor ATR S435/436/437 A failed to activate Chk1 ( XREF_FIG and XREF_SUPPLEMENTARY ) , showing that among the phosphorylation sites of ATR that we identified , T1989 is the only one critical for ATR activation .	In marked contrast to ATR T1989A, neither ATR S428A nor ATR S435/436/437A failed to activate Chk1 (XREF_FIG and XREF_SUPPLEMENTARY), showing that among the phosphorylation sites of ATR that we identified, T1989 is the only one critical for ATR activation.	8	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	8	9	17	18
Since ATR activates Chk1 , we also treated extracts with the Chk1 inhibitor ( SB-218078 ) , which did not affect DSB dependent phosphorylation of T818 .	Since ATR activates Chk1, we also treated extracts with the Chk1 inhibitor (SB-218078), which did not affect DSB dependent phosphorylation of T818.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	1	2	3	4
The proteins ataxia telangiectasia mutated ( ATM ) and ataxia-telangiectasia and Rad3 related ( ATR ) activate downstream checkpoint kinase 2 ( chk2 ) and checkpoint kinase 1 ( chk1 ) , respectively , that undertake the repair of DNA double-strand breaks .	The proteins ataxia telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3 related (ATR) activate downstream checkpoint kinase 2 (chk2) and checkpoint kinase 1 (chk1), respectively, that undertake the repair of DNA double-strand breaks.	3	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	checkpoint kinase 1	checkpoint kinase 1	checkpoint kinase 1	14	15	25	28
Although an expanding family of proteins appears to be necessary for Chk1 activation , much work implicates ssDNA generated by the inhibition of DNA replication as being critical for the ATR mediated activation of Chk1 .	Although an expanding family of proteins appears to be necessary for Chk1 activation, much work implicates ssDNA generated by the inhibition of DNA replication as being critical for the ATR mediated activation of Chk1.	30	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	30	31	34	35
These observations indicate that ATM is activated by DNA damage in late G2 cells ; however , irradiation induced mitotic delay in DT40 cells has been shown to be dependent on ATR mediated activation of Chk1 .	These observations indicate that ATM is activated by DNA damage in late G2 cells; however, irradiation induced mitotic delay in DT40 cells has been shown to be dependent on ATR mediated activation of Chk1.	31	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	31	32	35	36
Finally , CHK1 activity is controlled primarily by ATR kinase , which activates CHK1 by phosphorylation upon sensing replication stress or DNA damage [ XREF_BIBR , XREF_BIBR ] .	Finally, CHK1 activity is controlled primarily by ATR kinase, which activates CHK1 by phosphorylation upon sensing replication stress or DNA damage [XREF_BIBR, XREF_BIBR].	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	8	9	13	14
To study the mechanism involved in this process , we used tumors obtained from Apc min/+ mice and human colon cancer cells and showed that a deficit in Ino80 induced replication stress , leading to the ATR mediated activation of Chk1 and increased apoptosis .	To study the mechanism involved in this process, we used tumors obtained from Apc min/+ mice and human colon cancer cells and showed that a deficit in Ino80 induced replication stress, leading to the ATR mediated activation of Chk1 and increased apoptosis.	36	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	36	37	40	41
We further reveal that the ATR targets CHK1 and ATM 10 ensure cell survival .	We further reveal that the ATR targets CHK1 and ATM 10 ensure cell survival.	4	11	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	5	6	7	8
The observed S phase accumulation could be due to replication fork arrest that is subsequently recognized by ATR , which then activates Phospho-Chk1 ( XREF_FIG ) .	The observed S phase accumulation could be due to replication fork arrest that is subsequently recognized by ATR, which then activates Phospho-Chk1 (XREF_FIG).	15	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Phospho-Chk1	Phospho-Chk1	Phospho-Chk1	17	18	22	23
Similarly , a phospho-degron signal on CLASPIN ( a protein required for ATR mediated CHEK1 activation following stalled replication forks and DNA end resection during HR ) triggers its ubiquitylation by SCF betaTRCP and subsequent degradation , enabling checkpoint recovery [ XREF_BIBR , XREF_BIBR ] .	Similarly, a phospho-degron signal on CLASPIN (a protein required for ATR mediated CHEK1 activation following stalled replication forks and DNA end resection during HR) triggers its ubiquitylation by SCF betaTRCP and subsequent degradation, enabling checkpoint recovery [XREF_BIBR, XREF_BIBR].	12	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	CHEK1	CHEK1	CHEK1	12	13	14	15
Specifically , inhibition of ATR with either VE821 or AZ20 prevented UV induced CHK1 activation , but did not prevent SOX9 depletion .	Specifically, inhibition of ATR with either VE821 or AZ20 prevented UV induced CHK1 activation, but did not prevent SOX9 depletion.	2	14	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	4	5	13	14
Activation of Chk1 by ATR dependent phosphorylation is central to the normal DNA damage response to prevent excessive formation of DSBs during replication arrest 33 and the RPA coated single stranded DNA is the predominant signal for activation of the ATR-Chk1 signal transduction pathway 34 .	Activation of Chk1 by ATR dependent phosphorylation is central to the normal DNA damage response to prevent excessive formation of DSBs during replication arrest 33 and the RPA coated single stranded DNA is the predominant signal for activation of the ATR-Chk1 signal transduction pathway 34.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR dependent phosphorylation	atr	Chk1	Chk1	chk1	4	5	2	3
Collectively , these data suggested that Chk1 autophosphorylation in vitro can mimic ATR activation of Chk1 , and more importantly , revealed that Chk1-L84G serves as an active as version of Chk1 .	Collectively, these data suggested that Chk1 autophosphorylation in vitro can mimic ATR activation of Chk1, and more importantly, revealed that Chk1-L84G serves as an active as version of Chk1.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	12	13	15	16
Indeed , coexpression of ATR KD , T1989D and ATR T1989A in cells lacking endogenous ATR partially rescued UV induced Chk1 activation ( XREF_FIG ) .	Indeed, coexpression of ATR KD, T1989D and ATR T1989A in cells lacking endogenous ATR partially rescued UV induced Chk1 activation (XREF_FIG).	2	21	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	coexpression of ATR	atr	Chk1	Chk1	chk1	4	5	20	21
Claspin is necessary for the ATR dependent activation of Chk1 in Xenopus egg extracts containing incompletely replicated DNA .	Claspin is necessary for the ATR dependent activation of Chk1 in Xenopus egg extracts containing incompletely replicated DNA.	5	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	5	6	9	10
ATR and ATRIP then promotes the activation of CHK1 , the checkpoint kinase that shields arrested forks from collapse and concomitant inactivation .	ATR and ATRIP then promotes the activation of CHK1, the checkpoint kinase that shields arrested forks from collapse and concomitant inactivation.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	0	1	8	9
ATR also activates CHK1 and CHK2 .	ATR also activates CHK1 and CHK2.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	0	1	3	4
Although Chk1 activation is predominantly mediated by ATR , and Chk2 activation predominantly by ATM , considerable crossover is also apparent between these pathways [ XREF_BIBR - XREF_BIBR ] .	Although Chk1 activation is predominantly mediated by ATR, and Chk2 activation predominantly by ATM, considerable crossover is also apparent between these pathways [XREF_BIBR - XREF_BIBR].	1	8	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	7	8	1	2
Since CHK1 activation by ATR requires only minimal resection , these results suggest that RNF168 regulates 53BP1 chromatin binding to antagonize long-range DSB end resection in BRCA1 deficient cells .	Since CHK1 activation by ATR requires only minimal resection, these results suggest that RNF168 regulates 53BP1 chromatin binding to antagonize long-range DSB end resection in BRCA1 deficient cells.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	4	5	1	2
These ssDNA regions are coated by RPA and this RPA coated structure recruits and activates the ATR kinase , which in turn activates the Chk1 kinase [ XREF_BIBR ] .	These ssDNA regions are coated by RPA and this RPA coated structure recruits and activates the ATR kinase, which in turn activates the Chk1 kinase [XREF_BIBR].	16	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	16	17	24	25
Similarly , ATR is activated by RPA and ATRIP loading onto SS DNA , ultimately activating Chk1 .	Similarly, ATR is activated by RPA and ATRIP loading onto SS DNA, ultimately activating Chk1.	2	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	2	3	16	17
We did not detect any changes in ATR S428 phosphorylation or on another ATR target Chk1 S345 , arguing against an effect on the activation of ATR directly ( XREF_FIG ) .	We did not detect any changes in ATR S428 phosphorylation or on another ATR target Chk1 S345, arguing against an effect on the activation of ATR directly (XREF_FIG).	13	16	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	13	14	15	16
Together , these data suggest a role for RHINO in ATR mediated Chk1 activation driven by TopBP1 and 9-1-1 .	Together, these data suggest a role for RHINO in ATR mediated Chk1 activation driven by TopBP1 and 9-1-1.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	10	11	12	13
ATR and ATRIP activation requires Rad17/9-1-1 complex loading , which is also essential for ATR mediated Chk1 activation .	ATR and ATRIP activation requires Rad17/9-1-1 complex loading, which is also essential for ATR mediated Chk1 activation.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	14	15	16	17
hTopBP1 and hMYH were involved in ATR mediated Chk1 activation , moreover , both of them were associated with ATR and hRad9 which known as checkpoint involved proteins .	hTopBP1 and hMYH were involved in ATR mediated Chk1 activation, moreover, both of them were associated with ATR and hRad9 which known as checkpoint involved proteins.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	6	7	8	9
Chk1 is activated by ATR in response to stalled replication forks in S-phase , and causes S-phase arrest and delay by inhibiting DNA replication origin firing XREF_BIBR .	Chk1 is activated by ATR in response to stalled replication forks in S-phase, and causes S-phase arrest and delay by inhibiting DNA replication origin firing XREF_BIBR.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	4	5	0	1
Along these lines , our results can also help to explain the increased sensitivity of p53 deficient tumours to UCN-01 , a chemical inhibitor of the ATR target Chk1 XREF_BIBR .	Along these lines, our results can also help to explain the increased sensitivity of p53 deficient tumours to UCN-01, a chemical inhibitor of the ATR target Chk1 XREF_BIBR.	26	29	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	26	27	28	29
LT also bound the Claspin mediator protein , which normally facilitates the ATR activation of chk1 and monitors cellular replication origins .	LT also bound the Claspin mediator protein, which normally facilitates the ATR activation of chk1 and monitors cellular replication origins.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	chk1	chk1	chk1	12	13	15	16
Since the checkpoint kinases CHK1 and CHK2 are activated by ATR and ATM and their downstream activity is modulated by BRCA1 and BRCA2 , we examined the effect of the K375M and S338D mutation on CHK1 and CHK2 activity .	Since the checkpoint kinases CHK1 and CHK2 are activated by ATR and ATM and their downstream activity is modulated by BRCA1 and BRCA2, we examined the effect of the K375M and S338D mutation on CHK1 and CHK2 activity.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	10	11	4	5
Exposure to the ribonucleotide reductase inhibitor hydroxyurea ( HU ) stimulated the phosphorylation of the ATR targets CHK1 and replication protein A ( RPA ) , ruling out a deficiency in activation and signaling through the DNA replication stress pathway in these cells ( XREF_FIG ) .	Exposure to the ribonucleotide reductase inhibitor hydroxyurea (HU) stimulated the phosphorylation of the ATR targets CHK1 and replication protein A (RPA), ruling out a deficiency in activation and signaling through the DNA replication stress pathway in these cells (XREF_FIG).	12	21	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	phosphorylation of the ATR	atr	CHK1	CHK1	chk1	15	16	17	18
The checkpoint mediator protein Claspin is essential for the ATR dependent activation of Chk1 in Xenopus egg extracts containing aphidicolin induced DNA replication blocks .	The checkpoint mediator protein Claspin is essential for the ATR dependent activation of Chk1 in Xenopus egg extracts containing aphidicolin induced DNA replication blocks.	9	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	9	10	13	14
ATR activated Chk1 induces a transient cell cycle delay and arrest , which is followed by degradation of cell division cycle 25A ( Cdc25A ) and inhibition of cyclin dependent kinase ( Cdk ) [ XREF_BIBR , XREF_BIBR ] .	ATR activated Chk1 induces a transient cell cycle delay and arrest, which is followed by degradation of cell division cycle 25A (Cdc25A) and inhibition of cyclin dependent kinase (Cdk) [XREF_BIBR, XREF_BIBR].	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	0	1	2	3
Claspin is essential for the ATR dependent activation of Chk1 in Xenopus egg extracts containing incompletely replicated or UV damaged DNA .	Claspin is essential for the ATR dependent activation of Chk1 in Xenopus egg extracts containing incompletely replicated or UV damaged DNA.	5	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	5	6	9	10
Chk1 is primarily activated through phosphorylation on amino-acid residues Ser317 and Ser345 by ATR in response to DNA SSBs 25 and is predominantly responsible for initiating cell cycle arrest , allowing time for DNA repair and cell survival .	Chk1 is primarily activated through phosphorylation on amino-acid residues Ser317 and Ser345 by ATR in response to DNA SSBs 25 and is predominantly responsible for initiating cell cycle arrest, allowing time for DNA repair and cell survival.	0	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	13	14	0	1
Although the present study demonstrated that Chk1 is not activated by ATR , it is very likely that ATR was activated in Mus81 -/- cells .	Although the present study demonstrated that Chk1 is not activated by ATR, it is very likely that ATR was activated in Mus81 -/- cells.	6	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	11	12	6	7
CHK1 activation through phosphorylation at Ser345 and Ser317 is induced by ATR , after phosphorylation at Ser286 and Ser301 by CDKs for an efficient response to DNA damage [ XREF_BIBR ] .	CHK1 activation through phosphorylation at Ser345 and Ser317 is induced by ATR, after phosphorylation at Ser286 and Ser301 by CDKs for an efficient response to DNA damage [XREF_BIBR].	0	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	11	12	0	1
The delay is induced by ATM and ATR activation of the CHK2 and CHK1 kinases , respectively .	The delay is induced by ATM and ATR activation of the CHK2 and CHK1 kinases, respectively.	7	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	7	8	13	14
ATR inhibition by VE-821 blocks downstream Chk1 activation and enhances DNA damage mediated by cisplatin or gemcitabine .	ATR inhibition by VE-821 blocks downstream Chk1 activation and enhances DNA damage mediated by cisplatin or gemcitabine.	0	7	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	0	1	6	7
Moreover , RPA is a key regulator in the ATR dependent activation of Chk1 .	Moreover, RPA is a key regulator in the ATR dependent activation of Chk1.	9	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	9	10	13	14
One of its substrates is the downstream kinase CHK1 which is activated by ATR phosphorylation and needed to prevent fork collapse and regulate origin firing .	One of its substrates is the downstream kinase CHK1 which is activated by ATR phosphorylation and needed to prevent fork collapse and regulate origin firing.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR phosphorylation	atr	CHK1	CHK1	chk1	13	14	8	9
TIPIN , and its partner protein TIMELESS , associate with RPA2 to stabilize stalled forks and promote the accumulation of CHK1 and its regulatory protein CLASPIN to RPA-ssDNA regions where CHK1 can be activated by ATR ( XREF_FIG ) .	TIPIN, and its partner protein TIMELESS, associate with RPA2 to stabilize stalled forks and promote the accumulation of CHK1 and its regulatory protein CLASPIN to RPA-ssDNA regions where CHK1 can be activated by ATR (XREF_FIG).	30	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	35	36	30	31
After DNA damage or replication stress Claspin is phosphorylated by CHK1 , an event that is required for a Claspin-CHK1 interaction and subsequent full activation of CHK1 by ATR , in another example of the network nature of the DDR [ XREF_BIBR - XREF_BIBR ] .	After DNA damage or replication stress Claspin is phosphorylated by CHK1, an event that is required for a Claspin-CHK1 interaction and subsequent full activation of CHK1 by ATR, in another example of the network nature of the DDR [XREF_BIBR - XREF_BIBR].	16	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	28	29	26	27
Claspin mediates the activation of CHK1 by ATR in response to replication stress and its degradation plays a critical role in DNA damage checkpoint recovery .	Claspin mediates the activation of CHK1 by ATR in response to replication stress and its degradation plays a critical role in DNA damage checkpoint recovery.	1	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	7	8	5	6
In Xenopus , the activation of Chk1 by ATR following replicative stress is dependent upon Claspin , a so called mediator protein that , in a phosphoryated state , binds to Chk1 .	In Xenopus, the activation of Chk1 by ATR following replicative stress is dependent upon Claspin, a so called mediator protein that, in a phosphoryated state, binds to Chk1.	4	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	8	9	6	7
These results strongly suggest that HR actively promotes bypass or resolution of DNA gap intermediates created by MutSalpha and MutLalpha recognition of O 6 -meG : T. DNA damage checkpoint responses dependent on MutSalpha and MutLalpha recognition of O 6 -meG : T include ATR dependent activation of CHK1 [ XREF_BIBR - XREF_BIBR ] .	These results strongly suggest that HR actively promotes bypass or resolution of DNA gap intermediates created by MutSalpha and MutLalpha recognition of O 6 -meG : T. DNA damage checkpoint responses dependent on MutSalpha and MutLalpha recognition of O 6 -meG : T include ATR dependent activation of CHK1 [XREF_BIBR - XREF_BIBR].	44	50	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	44	45	48	49
Following DNA damage , multiprotein complexes recruit the transducers ataxia telangiectasia mutated ( ATM ) and ataxia telangiectasia and Rad3 related protein ( ATR ) which activate Chk2 and Chk1 , respectively , despite an existing extensive crosstalk between the ATR-Chk1 and ATM-Chk2 pathways .	Following DNA damage, multiprotein complexes recruit the transducers ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related protein (ATR) which activate Chk2 and Chk1, respectively, despite an existing extensive crosstalk between the ATR-Chk1 and ATM-Chk2 pathways.	17	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	23	24	29	30
Under periods of replicative stress , the ATRIP and ATR module binds to single- stranded DNA and together with Rad17 and the 9-1-1 complex activates Chk1 in a Claspin dependent manner .	Under periods of replicative stress, the ATRIP and ATR module binds to single- stranded DNA and together with Rad17 and the 9-1-1 complex activates Chk1 in a Claspin dependent manner.	7	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	9	10	25	26
Furthermore , KAP1 Ser473 phosphorylation was reduced by caffeine and KU55933 , in line with Chk1 being targeted by ATR in response to etoposide treatment in a manner that is promoted by ATM [ XREF_BIBR ] .	Furthermore, KAP1 Ser473 phosphorylation was reduced by caffeine and KU55933, in line with Chk1 being targeted by ATR in response to etoposide treatment in a manner that is promoted by ATM [XREF_BIBR].	13	21	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	19	20	15	16
Double stranded DNA breaks ( DSBs ) are sensed by the kinases ATM ( ataxia-telangiectasia mutated ) and ATR ( ATM and Rad3 related ) , which activate the effector kinases Checkpoint kinase 1 ( Chk1 ) and Chk2 .	Double stranded DNA breaks (DSBs) are sensed by the kinases ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3 related), which activate the effector kinases Checkpoint kinase 1 (Chk1) and Chk2.	8	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Checkpoint kinase 1	Checkpoint kinase 1	Checkpoint kinase 1	18	19	31	34
To identify candidate downstream signaling pathways of the DNA damage sensing platform in hepatocytes , livers of doxorubicin treated wild-type mice were analyzed for activation of ATM and ATR targets CHK1 and CHK2 ( XREF_FIG A , XREF_SUPPLEMENTARY A , and S8B and data not shown ) .	To identify candidate downstream signaling pathways of the DNA damage sensing platform in hepatocytes, livers of doxorubicin treated wild-type mice were analyzed for activation of ATM and ATR targets CHK1 and CHK2 (XREF_FIG A, XREF_SUPPLEMENTARY A, and S8B and data not shown).	24	35	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	28	29	30	31
The coordinated interaction of specific ATR and ATM substrates with BRCT- and FHA-domain containing molecules leads to the formation of multi protein complexes within nuclear foci in DNA damaged cells , amplifying the DNA damage signal , and leading to activation of the downstream effector kinases Chk1 , Chk2 , and MK2 .	The coordinated interaction of specific ATR and ATM substrates with BRCT- and FHA-domain containing molecules leads to the formation of multi protein complexes within nuclear foci in DNA damaged cells, amplifying the DNA damage signal, and leading to activation of the downstream effector kinases Chk1, Chk2, and MK2.	2	51	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	5	6	46	47
Cdc25A is also targeted for IR dependent degradation by Chk1 XREF_BIBR , which is activated after phosphorylation by ATR on residues S317 and S345 XREF_BIBR , XREF_BIBR .	Cdc25A is also targeted for IR dependent degradation by Chk1 XREF_BIBR, which is activated after phosphorylation by ATR on residues S317 and S345 XREF_BIBR, XREF_BIBR.	9	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	18	19	9	10
Others propose that activation of CHK1 by ATR dependent phosphorylation leads to rapid release of CHK1 from the nucleus to the cytoplasm .	Others propose that activation of CHK1 by ATR dependent phosphorylation leads to rapid release of CHK1 from the nucleus to the cytoplasm.	3	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR dependent phosphorylation	atr	CHK1	CHK1	chk1	7	8	5	6
The N-terminal BRCT domains of TopBP1 are known to be involved in several protein protein interactions ; they interact with the phosphorylated RAD9 tail in the 9-1-1 complex and are required for ATR mediated CHK1 activation in mammalian cells and Xenopus egg extracts .	The N-terminal BRCT domains of TopBP1 are known to be involved in several protein protein interactions; they interact with the phosphorylated RAD9 tail in the 9-1-1 complex and are required for ATR mediated CHK1 activation in mammalian cells and Xenopus egg extracts.	32	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	32	33	34	35
In this context , ATR : ATRIP complexes have been found to activate a CHK1 dependent checkpoint mechanism during S-phase in response to stalled replication forks .	In this context, ATR : ATRIP complexes have been found to activate a CHK1 dependent checkpoint mechanism during S-phase in response to stalled replication forks.	4	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	4	5	14	15
The Timeless and Tipin complex and Claspin are mediators of the ATR dependent activation of Chk1 in the intra-S checkpoint response to stalled DNA replication forks .	The Timeless and Tipin complex and Claspin are mediators of the ATR dependent activation of Chk1 in the intra-S checkpoint response to stalled DNA replication forks.	11	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	11	12	15	16
Claspin mediates the ATR dependent activation of Chk1 , leading to Cdc25A degradation and Cdk1 inhibition .	Claspin mediates the ATR dependent activation of Chk1, leading to Cdc25A degradation and Cdk1 inhibition.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	3	4	7	8
It regulates directly or indirectly the activity of autoregulatory components of the mammalian circadian core , including Clock , Per , and Cry proteins , associates with S phase replication checkpoint proteins Claspin and Tipin , and is required for the phosphorylation and activation of Chk1 by ATR and ATM dependent Chk2 mediated signaling of DNA double strand breaks [ XREF_BIBR , XREF_BIBR ] .	It regulates directly or indirectly the activity of autoregulatory components of the mammalian circadian core, including Clock, Per, and Cry proteins, associates with S phase replication checkpoint proteins Claspin and Tipin, and is required for the phosphorylation and activation of Chk1 by ATR and ATM dependent Chk2 mediated signaling of DNA double strand breaks [XREF_BIBR, XREF_BIBR].	38	51	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	47	48	45	46
For example , a reduction in ATR activity is lethal in the context of oncogene induced replication stress XREF_BIBR - XREF_BIBR or p53 loss XREF_BIBR , XREF_BIBR , and a heightened response to replication stress , as through gene amplification of the ATR target Chk1 , permits cancer cells to tolerate higher levels of such stress 101 .	For example, a reduction in ATR activity is lethal in the context of oncogene induced replication stress XREF_BIBR - XREF_BIBR or p53 loss XREF_BIBR, XREF_BIBR, and a heightened response to replication stress, as through gene amplification of the ATR target Chk1, permits cancer cells to tolerate higher levels of such stress 101.	39	45	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	42	43	44	45
Subsequent investigations have defined a molecular model in which Claspin acts as an adaptor or scaffold protein to facilitate activation of Chk1 by ATR within a multi protein complex that forms on single stranded DNA at stalled replication forks and sites of DNA damage .	Subsequent investigations have defined a molecular model in which Claspin acts as an adaptor or scaffold protein to facilitate activation of Chk1 by ATR within a multi protein complex that forms on single stranded DNA at stalled replication forks and sites of DNA damage.	18	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	23	24	21	22
CHK1 is activated by the ATR kinase in response to DNA damage that stalls replication fork progression .	CHK1 is activated by the ATR kinase in response to DNA damage that stalls replication fork progression.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	5	6	0	1
It has been shown that the N terminal three BRCTs ( BRCT0/1/2 ) of TopBP1 can interact with the phosphorylated Rad9 tail of the Rad9-Hus1-Rad1 ( 9-1-1 ) complex to assist ATR mediated activation of CHK1 in mammalian cells .	It has been shown that the N terminal three BRCTs (BRCT0/1/2) of TopBP1 can interact with the phosphorylated Rad9 tail of the Rad9-Hus1-Rad1 (9-1-1) complex to assist ATR mediated activation of CHK1 in mammalian cells.	31	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	31	32	35	36
For instance , in human cells CDC7 phosphorylation of the mediator protein CLASPIN is important for full activation of CHK1 by ATR and for maintaining cell viability in the presence of drugs that affect replication fork progression .	For instance, in human cells CDC7 phosphorylation of the mediator protein CLASPIN is important for full activation of CHK1 by ATR and for maintaining cell viability in the presence of drugs that affect replication fork progression.	14	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	21	22	19	20
All four novel ATR pathway inhibitors suppressed HU induced pChk1 at concentrations below 30 muM in the immunofluorescence imaging assays , while caffeine required 3,000 muM for the same degree of pChk1 inhibition ( XREF_FIG ) .	All four novel ATR pathway inhibitors suppressed HU induced pChk1 at concentrations below 30 muM in the immunofluorescence imaging assays, while caffeine required 3,000 muM for the same degree of pChk1 inhibition (XREF_FIG).	3	10	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	pChk1	pChk1	pChk1	3	4	9	10
The loss of Ccq1 results in progressive telomere shortening and persistent ATR dependent activation of Chk1 .	The loss of Ccq1 results in progressive telomere shortening and persistent ATR dependent activation of Chk1.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	11	12	15	16
We did not observe major cell cycle fluctuations in the level of Claspin , an adaptor protein required for ATR mediated Chk1 activation , in our elutriation experiments ( data not shown ) .	We did not observe major cell cycle fluctuations in the level of Claspin, an adaptor protein required for ATR mediated Chk1 activation, in our elutriation experiments (data not shown).	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	19	20	21	22
To distinguish these possibilities , we analyzed the phosphorylation of Chk1 and Chk2 in cells treated with ATR siRNA .	To distinguish these possibilities, we analyzed the phosphorylation of Chk1 and Chk2 in cells treated with ATR siRNA.	8	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	17	18	10	11
DNA lesions are recognized by a network of sensor and mediator factors that result in the rapid recruitment of proteins involved in DNA damage repair such as ataxia telangiectasia mutated ( ATM ) and ATM-Rad3 related ( ATR ) , which then activate the checkpoint proteins Chk1 and Chk2 with subsequent arrest of the cell cycle [ XREF_BIBR ] .	DNA lesions are recognized by a network of sensor and mediator factors that result in the rapid recruitment of proteins involved in DNA damage repair such as ataxia telangiectasia mutated (ATM) and ATM-Rad3 related (ATR), which then activate the checkpoint proteins Chk1 and Chk2 with subsequent arrest of the cell cycle [XREF_BIBR].	34	48	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	37	38	46	47
Treatment of primary human keratinocytes with caffeine inhibited UVB induced increase in ATR mediated formation of p-Chk1 ( Ser 345 ) , and apoptosis was increased .	Treatment of primary human keratinocytes with caffeine inhibited UVB induced increase in ATR mediated formation of p-Chk1 (Ser 345), and apoptosis was increased.	10	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	p-Chk1	p-Chk1	p-Chk1	12	13	16	17
In order for cells to enter mitosis following DNA damage checkpoint responses , claspin must be degraded , thereby relieving further ATR mediated CHK1 associated cell cycle arrest .	In order for cells to enter mitosis following DNA damage checkpoint responses, claspin must be degraded, thereby relieving further ATR mediated CHK1 associated cell cycle arrest.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	21	22	23	24
After ATR activated CHK1 , this will then phosphorylate CDC25 .	After ATR activated CHK1, this will then phosphorylate CDC25.	1	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	1	2	3	4
Alternatively , if Tim-Tipin suppresses the formation of ssDNA , creating a reliance on ATR-Chk1 for fork stability , reduction of Tim-Tipin in combination with complete elimination of ATR mediated Chk1 activation should synergistically increase genomic instability .	Alternatively, if Tim-Tipin suppresses the formation of ssDNA, creating a reliance on ATR-Chk1 for fork stability, reduction of Tim-Tipin in combination with complete elimination of ATR mediated Chk1 activation should synergistically increase genomic instability.	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	28	29	30	31
Interestingly , these pockets were not required for 9-1-1 chromatin localization or ATR mediated CHK1 activation but were necessary for interactions between HUS1 and its binding partner MYH , suggesting that they serve as interaction domains for the recruitment and coordination of downstream effectors at damage sites .	Interestingly, these pockets were not required for 9-1-1 chromatin localization or ATR mediated CHK1 activation but were necessary for interactions between HUS1 and its binding partner MYH, suggesting that they serve as interaction domains for the recruitment and coordination of downstream effectors at damage sites.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	12	13	14	15
ATM phosphorylates and activates checkpoint kinase 2 ( CHEK2 ; also known as CHK2 ) , a known regulator of the G1/S checkpoint ; while ATR targets the related checkpoint kinase 1 ( CHEK1 ; also known as CHK1 ) , a known regulator the intra-S and G2/M checkpoints [ XREF_BIBR ] .	ATM phosphorylates and activates checkpoint kinase 2 (CHEK2; also known as CHK2), a known regulator of the G1/S checkpoint; while ATR targets the related checkpoint kinase 1 (CHEK1; also known as CHK1), a known regulator the intra-S and G2/M checkpoints [XREF_BIBR].	25	38	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHEK1	CHEK1	CHEK1	25	26	33	34
Claspin is a critical mediator protein in the DNA replication checkpoint , responsible for ATR dependent activation of the effector kinase Chk1 .	Claspin is a critical mediator protein in the DNA replication checkpoint, responsible for ATR dependent activation of the effector kinase Chk1.	14	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	14	15	21	22
Claspin was found as a critical mediator in the intra-S-phase cell cycle checkpoint , which is responsible for ATR dependent activation of Chk1 .	Claspin was found as a critical mediator in the intra-S-phase cell cycle checkpoint, which is responsible for ATR dependent activation of Chk1.	18	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	18	19	22	23
CLASPIN is a critical mediator in the DNA replication checkpoint , responsible for ATR dependent activation of CHK1 .	CLASPIN is a critical mediator in the DNA replication checkpoint, responsible for ATR dependent activation of CHK1.	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	13	14	17	18
This activates ATR , which then activates CHK1 via phosphorylation on Ser 317 and Ser 345 .	This activates ATR, which then activates CHK1 via phosphorylation on Ser 317 and Ser 345.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	2	3	7	8
MCF7 control cells ( MCF7-shEV ) showed an efficient accumulation of activated ATR target CHK1 ( p-CHK1S296 ) and phosphorylated H2AX ( gamma-H2AX ) following UVC treatment .	MCF7 control cells (MCF7-shEV) showed an efficient accumulation of activated ATR target CHK1 (p-CHK1S296) and phosphorylated H2AX (gamma-H2AX) following UVC treatment.	9	16	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	12	13	14	15
Based on our finding that hMYH interacts with 9-1-1 and hTopBP1 , we identified hMYH as the likely factor involved in ATR mediated activation of Chk1 .	Based on our finding that hMYH interacts with 9-1-1 and hTopBP1, we identified hMYH as the likely factor involved in ATR mediated activation of Chk1.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	21	22	25	26
To further clarify this , we used UCN-01 , a specific inhibitor of the ATR target checkpoint kinase 1 .	To further clarify this, we used UCN-01, a specific inhibitor of the ATR target checkpoint kinase 1.	14	19	target	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	checkpoint kinase 1	checkpoint kinase 1	checkpoint kinase 1	14	15	16	19
After amplification of the DDR signals , ATM and ATR activate CHK1 and CHK2 kinases , which phosphorylate and activate CDC25 and p53 , leading to transient growth arrest allowing cells to repair the DNA damage .	After amplification of the DDR signals, ATM and ATR activate CHK1 and CHK2 kinases, which phosphorylate and activate CDC25 and p53, leading to transient growth arrest allowing cells to repair the DNA damage.	7	14	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	9	10	11	12
ATR mediated Chk1 signaling is also critical for regulating DNA replication .	ATR mediated Chk1 signaling is also critical for regulating DNA replication.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	0	1	2	3
The presence of p53 was associated with reduced phospho-Chk1 ( Ser317 ) induction in tumors or in UVB exposed epidermis , suggesting that p53 may down-regulate ATR activation of Chk1 .	The presence of p53 was associated with reduced phospho-Chk1 (Ser317) induction in tumors or in UVB exposed epidermis, suggesting that p53 may down-regulate ATR activation of Chk1.	26	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	26	27	29	30
For instance , AKT1 destabilizes p53 via the phosphorylation of Mdm2 [ XREF_BIBR ] ; AKT1 controls the basal expression of XRCC1 [ XREF_BIBR ] ; the activation of AKT1 leads to the sequestration of CHK1 to the cytoplasm [ XREF_BIBR - XREF_BIBR ] , and AKT1 phosphorylates and prevents the activation of CHK1 by ATR and ATM [ XREF_BIBR ] ; finally , AKT1 reduces the abundance of gamma-gH2AX foci [ XREF_BIBR , XREF_BIBR ] in asynchronous cells , and inhibits the activation of CHK1 and the repair of DSBs at the end of G2 [ XREF_BIBR ] .	For instance, AKT1 destabilizes p53 via the phosphorylation of Mdm2 [XREF_BIBR]; AKT1 controls the basal expression of XRCC1 [XREF_BIBR]; the activation of AKT1 leads to the sequestration of CHK1 to the cytoplasm [XREF_BIBR - XREF_BIBR], and AKT1 phosphorylates and prevents the activation of CHK1 by ATR and ATM [XREF_BIBR]; finally, AKT1 reduces the abundance of gamma-gH2AX foci [XREF_BIBR, XREF_BIBR] in asynchronous cells, and inhibits the activation of CHK1 and the repair of DSBs at the end of G2 [XREF_BIBR].	51	97	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	55	56	53	54
Indeed , one of the key resemblances of the Vpr effect to the HU/UV effect is the ATR mediated Chk1 activation through Chk1-Ser 345 phosphorylation .	Indeed, one of the key resemblances of the Vpr effect to the HU/UV effect is the ATR mediated Chk1 activation through Chk1-Ser 345 phosphorylation.	0	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	17	18	19	20
Here , we show that replication protein A ( RPA ) , a protein complex that associates with single stranded DNA ( ssDNA ) , is required for the recruitment of ATR to sites of DNA damage and for ATR mediated Chk1 activation in human cells .	Here, we show that replication protein A (RPA), a protein complex that associates with single stranded DNA (ssDNA), is required for the recruitment of ATR to sites of DNA damage and for ATR mediated Chk1 activation in human cells.	26	42	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	39	40	41	42
On the other hand , depletion of MTA1 compromises the ATR mediated Chk1 activation following UV treatment , accompanied by a marked down-regulation of Chk1 and its interacting partner Claspin , an adaptor protein that is required for the phosphorylation and activation of Chk1 by ATR .	On the other hand, depletion of MTA1 compromises the ATR mediated Chk1 activation following UV treatment, accompanied by a marked down-regulation of Chk1 and its interacting partner Claspin, an adaptor protein that is required for the phosphorylation and activation of Chk1 by ATR.	8	13	mediated	Positive_early_activation	Positive_activation	Negative_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	10	11	12	13
Rad3 , the Schizosaccharomyces pombe ortholog of human ATR and Saccharomyces cerevisiae Mec1 , activates the checkpoint kinase Chk1 in response to DNA double-strand breaks ( DSBs ) .	Rad3, the Schizosaccharomyces pombe ortholog of human ATR and Saccharomyces cerevisiae Mec1, activates the checkpoint kinase Chk1 in response to DNA double-strand breaks (DSBs).	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	8	9	18	19
Chk1 is activated via phosphorylaton by ATR after genotoxic stress .	Chk1 is activated via phosphorylaton by ATR after genotoxic stress.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	6	7	0	1
In this process , ATR was reported to activate the checkpoint kinases Chk1 and Chk2 .	In this process, ATR was reported to activate the checkpoint kinases Chk1 and Chk2.	4	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	4	5	12	13
Activation of Chk1 by ATR in response to DNA damage or replication stress results in inhibition of Cdc25 phosphatases , cyclin-Cdk inhibition , and cell cycle arrest ( for review see ) .	Activation of Chk1 by ATR in response to DNA damage or replication stress results in inhibition of Cdc25 phosphatases, cyclin-Cdk inhibition, and cell cycle arrest (for review see).	0	12	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	4	5	2	3
During the S and G2 phase , CHK1 is activated by ATR following ATM and MRN mediated resection of the DSB [ XREF_BIBR ] ( See XREF_FIG ) .	During the S and G2 phase, CHK1 is activated by ATR following ATM and MRN mediated resection of the DSB [XREF_BIBR] (See XREF_FIG).	7	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	11	12	7	8
The requirement of Rad9 for ATR mediated Chk1 activation has been well established [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , as has the transient negative regulation of TLK1 by Chk1 [ XREF_BIBR , XREF_BIBR ] .	The requirement of Rad9 for ATR mediated Chk1 activation has been well established [XREF_BIBR, XREF_BIBR, XREF_BIBR], as has the transient negative regulation of TLK1 by Chk1 [XREF_BIBR, XREF_BIBR].	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	5	6	7	8
Rad9 is part of the 9-1-1 protein complex that is loaded to sites of damaged DNA , and it activates the Rad3 ATR checkpoint kinase , which in turn activates the downstream kinase Chk1 that can block cell cycle progression .	Rad9 is part of the 9-1-1 protein complex that is loaded to sites of damaged DNA, and it activates the Rad3 ATR checkpoint kinase, which in turn activates the downstream kinase Chk1 that can block cell cycle progression.	22	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	22	23	33	34
In addition , Claspin as an adaptor protein is required for the phosphorylation and activation of Chk1 by ATR [ XREF_BIBR ] .	In addition, Claspin as an adaptor protein is required for the phosphorylation and activation of Chk1 by ATR [XREF_BIBR].	12	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	18	19	16	17
Claspin is an essential mediator in the DNA replication checkpoint , responsible for ATR dependent activation of Chk1 [ XREF_BIBR ] .	Claspin is an essential mediator in the DNA replication checkpoint, responsible for ATR dependent activation of Chk1 [XREF_BIBR].	13	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	13	14	17	18
Surprisingly , the ubiquitination of PCNA is independent of ATR , but regulated by Claspin , a replication protein that mediates the activation of Chk1 by ATR .	Surprisingly, the ubiquitination of PCNA is independent of ATR, but regulated by Claspin, a replication protein that mediates the activation of Chk1 by ATR.	20	27	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	26	27	24	25
Instead , ATR activates Chk1 locally at centromeres to promote Aurora B activation , ensuring accurate chromosome segregation in mitosis .	Instead, ATR activates Chk1 locally at centromeres to promote Aurora B activation, ensuring accurate chromosome segregation in mitosis.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	2	3	4	5
ATR , with Claspin and the Rad9 , Rad1 , and Hus1 complex , activates Chk1 after DNA damage .	ATR, with Claspin and the Rad9, Rad1, and Hus1 complex, activates Chk1 after DNA damage.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	0	1	15	16
CHK1 kinase is activated by ATR through the phosphorylation on serine 317 ( ser317 ) and on serine 345 ( ser345 ) .	CHK1 kinase is activated by ATR through the phosphorylation on serine 317 (ser317) and on serine 345 (ser345).	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	5	6	0	1
CHK1 is activated by the ATR kinase in response to DNA damages that stall replication fork progression [ XREF_BIBR ] .	CHK1 is activated by the ATR kinase in response to DNA damages that stall replication fork progression [XREF_BIBR].	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	5	6	0	1
A recent study showed that H 2 O 2 can lead to ATR dependent activation of Chk1 in Xenopus egg extracts [ XREF_BIBR ] .	A recent study showed that H 2 O 2 can lead to ATR dependent activation of Chk1 in Xenopus egg extracts [XREF_BIBR].	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	12	13	16	17
ATR activation of CHK1 .	ATR activation of CHK1.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	0	1	3	4
ATR dependent activation of Chk1 is mediated by Claspin .	ATR dependent activation of Chk1 is mediated by Claspin.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	0	1	4	5
ATR dependent activation of the kinase Chk1 is the initial step in signal transduction in the DNA replication checkpoint , which allows a cell to enter mitosis only after the completion of DNA replication .	ATR dependent activation of the kinase Chk1 is the initial step in signal transduction in the DNA replication checkpoint, which allows a cell to enter mitosis only after the completion of DNA replication.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	0	1	6	7
DSBs are detected by ATM ( ataxia telangiectasia mutated ) and ATR ( ataxia telangiectasia and Rad3 related ) proteins , which signal downstream to CHK1 , CHK2 ( checkpoint kinases ) and p53 .	DSBs are detected by ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related) proteins, which signal downstream to CHK1, CHK2 (checkpoint kinases) and p53.	2	26	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	11	12	25	26
Claspin associates with the replication fork and is one of the major checkpoint mediators for Chk1 activation by ATR in response to replication stress .	Claspin associates with the replication fork and is one of the major checkpoint mediators for Chk1 activation by ATR in response to replication stress.	15	20	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	18	19	15	16
Recently , the N-terminal BRCT domains of TopBP1 are shown to interact with phosphorylated Rad9 tail in the 9-1-1 complex and be required for ATR mediated Chk1 activation in mammalian cell lines and Xenopus egg extracts .	Recently, the N-terminal BRCT domains of TopBP1 are shown to interact with phosphorylated Rad9 tail in the 9-1-1 complex and be required for ATR mediated Chk1 activation in mammalian cell lines and Xenopus egg extracts.	22	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	24	25	26	27
Therefore the role of the MRN complex in the ATR dependent activation of Chk1 appears to be largely unrelated to its role in the activation of ATM .	Therefore the role of the MRN complex in the ATR dependent activation of Chk1 appears to be largely unrelated to its role in the activation of ATM.	9	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	9	10	13	14
The best characterized mechanisms are the checkpoint responses mediated by ATR activation of CHK1 .	The best characterized mechanisms are the checkpoint responses mediated by ATR activation of CHK1.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	10	11	13	14
Because Crb2/53BP1 is not required for Chk1 activation in metazoans , it is unclear what role , if any , TopBP1 and Mus101 plays in promoting activation of Chk1 by ATR .	Because Crb2/53BP1 is not required for Chk1 activation in metazoans, it is unclear what role, if any, TopBP1 and Mus101 plays in promoting activation of Chk1 by ATR.	25	31	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	30	31	28	29
Consistent with the fact that ATR activates Chk1 in the nucleus , the phosphorylation of S280 is stimulated after UV irradiation and required for efficient UV induced Chk1 activation ( XREF_FIG ) .	Consistent with the fact that ATR activates Chk1 in the nucleus, the phosphorylation of S280 is stimulated after UV irradiation and required for efficient UV induced Chk1 activation (XREF_FIG).	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	5	6	7	8
21 Although ATM responds to IR induced double-strand breaks and activates chk2 , ATR responds to DNA damaging agents such as UV light and activates chk1 .	21 Although ATM responds to IR induced double-strand breaks and activates chk2, ATR responds to DNA damaging agents such as UV light and activates chk1.	13	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	chk1	chk1	chk1	13	14	25	26
Both MUTYH and the 9-1-1 complex participate in an ATR mediated Chk1 activation cell signal cascade [ XREF_BIBR ] [ XREF_BIBR ] .	Both MUTYH and the 9-1-1 complex participate in an ATR mediated Chk1 activation cell signal cascade [XREF_BIBR] [XREF_BIBR].	6	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	9	10	11	12
Likewise , ATR activates Chk1 , leading to the degradation of Cdc25A in response to UV [ XREF_BIBR , XREF_BIBR ] .	Likewise, ATR activates Chk1, leading to the degradation of Cdc25A in response to UV [XREF_BIBR, XREF_BIBR].	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	2	3	4	5
As mentioned above , ATR activation of CHK1 , a major effector typically associated with S-phase and G2-phase cell cycle arrest in response to diverse DNA damage stimuli , is inhibited during MVM infection [ XREF_BIBR ] .	As mentioned above, ATR activation of CHK1, a major effector typically associated with S-phase and G2-phase cell cycle arrest in response to diverse DNA damage stimuli, is inhibited during MVM infection [XREF_BIBR].	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	4	5	7	8
However , depletion of MTA1 compromises the ATR mediated Chk1 activation following UV treatment .	However, depletion of MTA1 compromises the ATR mediated Chk1 activation following UV treatment.	5	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	7	8	9	10
It is well accepted that the ATR dependent activation of Chk1 in response to incompletely replicated and damaged DNA leads to inhibition of origin firing at chromosomal regions that are not already engaged in replication .	It is well accepted that the ATR dependent activation of Chk1 in response to incompletely replicated and damaged DNA leads to inhibition of origin firing at chromosomal regions that are not already engaged in replication.	6	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	6	7	10	11
ATR dependent phosphorylation activates Chk1 at residue Ser345 [ XREF_BIBR ] , and ATM phosphorylates Chk2 at residue Thr68 [ XREF_BIBR ] .	ATR dependent phosphorylation activates Chk1 at residue Ser345 [XREF_BIBR], and ATM phosphorylates Chk2 at residue Thr68 [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR dependent phosphorylation	atr	Chk1	Chk1	chk1	0	1	4	5
Collectively , our results indicated that upon Chel A treatment , ATR activated Chk2 , and in turn mediated p53 phsphorylation and stabilization , subsequently resulting cancer cell apoptosis and inhibition of anchorage independent growth of cancer cells .	Collectively, our results indicated that upon Chel A treatment, ATR activated Chk2, and in turn mediated p53 phsphorylation and stabilization, subsequently resulting cancer cell apoptosis and inhibition of anchorage independent growth of cancer cells.	11	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk2	Chk2	Chk2	11	12	13	14
While cisplatin treatment induced Chk2 phosphorylation , this was abrogated by AZD6738 in H23 cells but not H460 cells , indicating ATR dependent activation of Chk2 in the absence of active ATM ( XREF_SUPPLEMENTARY ) .	While cisplatin treatment induced Chk2 phosphorylation, this was abrogated by AZD6738 in H23 cells but not H460 cells, indicating ATR dependent activation of Chk2 in the absence of active ATM (XREF_SUPPLEMENTARY).	21	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk2	Chk2	Chk2	21	22	25	26
These checkpoints are controlled by ATM ( ataxia telangiectasia mutated ) and ATR ( ataxia telangiectasia and Rad3 related protein ) kinases which activate downstream effector kinases Chk1 ( checkpoint kinase 1 ) and Chk2 , respectively .	These checkpoints are controlled by ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related protein) kinases which activate downstream effector kinases Chk1 (checkpoint kinase 1) and Chk2, respectively.	3	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk2	Chk2	Chk2	12	13	34	35
In higher eukaryotes , ATR activation primarily leads to Chk1 kinase activation during the S-phase checkpoint , rather than Rad53 homolog Chk2 [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In higher eukaryotes, ATR activation primarily leads to Chk1 kinase activation during the S-phase checkpoint, rather than Rad53 homolog Chk2 [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	29	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk2	Chk2	Chk2	4	5	21	22
XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR Since Chk2 itself is not wortmannin sensitive , we predicted ATR as an additional kinase crucial for MDMX phosphorylation mediated degradation , whereby Chk2 is activated by ATR ( equation 60 ) .	XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR Since Chk2 itself is not wortmannin sensitive, we predicted ATR as an additional kinase crucial for MDMX phosphorylation mediated degradation, whereby Chk2 is activated by ATR (equation 60).	30	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk2	Chk2	Chk2	34	35	30	31
In some circumstances , CHK2 can also be activated by ATR XREF_BIBR , XREF_BIBR .	In some circumstances, CHK2 can also be activated by ATR XREF_BIBR, XREF_BIBR.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CHK2	CHK2	CHK2	10	11	4	5
Rad53 , activated by Mec1 ( a yeast homologue of ATR ) , protects forks from collapsing and arrests the cell cycle .	Rad53, activated by Mec1 (a yeast homologue of ATR), protects forks from collapsing and arrests the cell cycle.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Rad53	Rad53	Rad53	10	11	0	1
In terms of time course , it was noticeable that Chk1 was activated prior to Chk2 , consistent with a rapid replication stress and single strand break signalling which is mediated by ATR .	In terms of time course, it was noticeable that Chk1 was activated prior to Chk2, consistent with a rapid replication stress and single strand break signalling which is mediated by ATR.	12	33	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	Chk2	Chk2	Chk2	32	33	15	16
Aurora kinase A is involved in centrosome and spindle assembly and activates Plk1 at the G2/M transition [ XREF_BIBR ] .	Aurora kinase A is involved in centrosome and spindle assembly and activates Plk1 at the G2/M transition [XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Aurora kinase A	Aurora kinase A	Aurora kinase A	Plk1	Plk1	Plk1	0	3	12	13
Two recent independent studies have demonstrated that Plk-1 activation by Aurora-A , mediated by its interaction with a G2-M expressed protein Bora , are essential for mitotic entry and recovery from checkpoint arrest .	Two recent independent studies have demonstrated that Plk-1 activation by Aurora-A, mediated by its interaction with a G2-M expressed protein Bora, are essential for mitotic entry and recovery from checkpoint arrest.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Aurora-A	Aurora-A	Aurora-A	Plk-1	Plk-1	Plk-1	10	11	7	8
PLK1 could be activated by the concerted function of AURKA and the cofactor Bora [ XREF_BIBR ] .	PLK1 could be activated by the concerted function of AURKA and the cofactor Bora [XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AURKA	AURKA	AURKA	PLK1	PLK1	PLK1	9	10	0	1
It has been established that the phosphorylation induced activation of Plk1 by Aur-A functionally depends on the presence of Bora , XREF_BIBR , XREF_BIBR , XREF_BIBR probably involving the Bora N-terminus .	It has been established that the phosphorylation induced activation of Plk1 by Aur-A functionally depends on the presence of Bora, XREF_BIBR, XREF_BIBR, XREF_BIBR probably involving the Bora N-terminus.	7	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Aur-A	Aur-A	Aur-A	Plk1	Plk1	Plk1	12	13	10	11
A study of AURKA and regulation of the cell cycle in cancer through multiple signal pathways found that AURKA diminished pRb , p53 , P21waf1 and cip1 , and p27cip and kip but increased Plk1 , CDC25 , CDK1 , and cyclin B1 to promote cell cycle progression [ XREF_BIBR ] .	A study of AURKA and regulation of the cell cycle in cancer through multiple signal pathways found that AURKA diminished pRb, p53, P21waf1 and cip1, and p27cip and kip but increased Plk1, CDC25, CDK1, and cyclin B1 to promote cell cycle progression [XREF_BIBR].	18	42	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AURKA	AURKA	AURKA	Plk1	Plk1	Plk1	18	19	34	35
XREF_BIBR , XREF_BIBR Plk1 is part of the serine/threonine kinases related to the cell cycle regulation and is activated by AURKA .	XREF_BIBR, XREF_BIBR Plk1 is part of the serine/threonine kinases related to the cell cycle regulation and is activated by AURKA.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AURKA	AURKA	AURKA	Plk1	Plk1	Plk1	20	21	3	4
AURKA activated Plk1 creates its own PBD docking site on Cep192 by phosphorylating Cep192 Thr 44 ; a subsequent AURKA independent PBD docking site centered on Cep192 Ser 995 has been reported , although the separation of the functional roles of Thr 44 and Ser 995 needs further investigation .	AURKA activated Plk1 creates its own PBD docking site on Cep192 by phosphorylating Cep192 Thr 44; a subsequent AURKA independent PBD docking site centered on Cep192 Ser 995 has been reported, although the separation of the functional roles of Thr 44 and Ser 995 needs further investigation.	0	16	activated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	AURKA	AURKA	aurka	Plk1	Plk1 creates its own PBD docking site on Cep192 by phosphorylating Cep192 Thr 44	plk1	0	1	2	3
Aurora kinase A activates PLK1 , which regulates spindle formation as DNA damage arrested cells move into mitosis .	Aurora kinase A activates PLK1, which regulates spindle formation as DNA damage arrested cells move into mitosis.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Aurora kinase A	Aurora kinase A	Aurora kinase A	PLK1	PLK1	PLK1	0	3	4	5
Additionally , the AURKA target PLK1 , previously identified as a synthetic lethal interaction with KRAS XREF_BIBR , was also diminished upon FOSL1 inhibition in a genotype specific manner ( XREF_FIG ) .	Additionally, the AURKA target PLK1, previously identified as a synthetic lethal interaction with KRAS XREF_BIBR, was also diminished upon FOSL1 inhibition in a genotype specific manner (XREF_FIG).	2	20	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	AURKA	AURKA	AURKA	PLK1	PLK1	PLK1	3	4	5	6
Phosphorylation of Bora at Ser 252 ( human ) by cdk1 creates a PBD docking site and promotes Bora and Plk1 interaction ; consistently , phosphorylation of Bora by cdk1 enhances its ability to stimulate AURKA mediated Plk1 activation .	Phosphorylation of Bora at Ser 252 (human) by cdk1 creates a PBD docking site and promotes Bora and Plk1 interaction; consistently, phosphorylation of Bora by cdk1 enhances its ability to stimulate AURKA mediated Plk1 activation.	34	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	AURKA	AURKA	AURKA	Plk1	Plk1	Plk1	35	36	37	38
It is possible that the residual 50 % active AURKA is sufficient to activate Plk1 .	It is possible that the residual 50% active AURKA is sufficient to activate Plk1.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AURKA	AURKA	AURKA	Plk1	Plk1	Plk1	9	10	14	15
Given both AURKA and AURKB can activate PLK1 , it is not unexpected that small-molecule inhibitors PLK1 and AURKA or AURKB can cooperate in suppressing PLK1 functions .	Given both AURKA and AURKB can activate PLK1, it is not unexpected that small-molecule inhibitors PLK1 and AURKA or AURKB can cooperate in suppressing PLK1 functions.	0	12	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	AURKA	AURKA	AURKA	PLK1	PLK1	PLK1	2	3	7	8
It is noteworthy that an active BLM seems to be unnecessary to the activation of BRCA1 , either after gamma-rays or HU , even though BRCA1 and BLM helicase are activated by ATR in response to stalled replication , and despite the fact that they colocalize after replication arrest .	It is noteworthy that an active BLM seems to be unnecessary to the activation of BRCA1, either after gamma-rays or HU, even though BRCA1 and BLM helicase are activated by ATR in response to stalled replication, and despite the fact that they colocalize after replication arrest.	25	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	BRCA1	BRCA1	BRCA1	32	33	25	26
BRCA1 and BRCA2 are integral to the early stages of DNA damage recognition and repair ; BRCA1 is activated by ATR and is involved in cell cycle arrest and replication fork stalling ( with CHEK2 ) , and breakage site stabilization ( with BRIP1 and BARD1 ) through directly binding the damaged DNA .	BRCA1 and BRCA2 are integral to the early stages of DNA damage recognition and repair; BRCA1 is activated by ATR and is involved in cell cycle arrest and replication fork stalling (with CHEK2), and breakage site stabilization (with BRIP1 and BARD1) through directly binding the damaged DNA.	16	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	BRCA1	BRCA1	BRCA1	20	21	16	17
Previous studies indicated that ATR could activate BRCA1 via CHK2 when it interacts with ATRIP [ XREF_BIBR , XREF_BIBR ] , and promote G2/M phase transition via PLK1 [ XREF_BIBR , XREF_BIBR ] , and BRCA1 also could ?	Previous studies indicated that ATR could activate BRCA1 via CHK2 when it interacts with ATRIP [XREF_BIBR, XREF_BIBR], and promote G2/M phase transition via PLK1 [XREF_BIBR, XREF_BIBR], and BRCA1 also could?	4	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	BRCA1	BRCA1	BRCA1	4	5	7	8
Later , this same group further elaborated on the role of BRCA1 in infection by showing Vpr induced ATR dependent activation of BRCA1 at serine substrate S1423 as a response to genotoxic stress , suggesting a model for Vpr induced apoptosis via transcriptional regulation of the BRCA1 target gene , GADD45alpha [ XREF_BIBR ] .	Later, this same group further elaborated on the role of BRCA1 in infection by showing Vpr induced ATR dependent activation of BRCA1 at serine substrate S1423 as a response to genotoxic stress, suggesting a model for Vpr induced apoptosis via transcriptional regulation of the BRCA1 target gene, GADD45alpha [XREF_BIBR].	16	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	Vpr induced ATR	atr	BRCA1	BRCA1	brca1	18	19	22	23
Early studies showed that ATR phosphorylated and activated the key HRR regulatory protein BRCA1 [ XREF_BIBR ] .	Early studies showed that ATR phosphorylated and activated the key HRR regulatory protein BRCA1 [XREF_BIBR].	4	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR phosphorylated	atr	BRCA1	BRCA1	brca1	4	5	13	14
To test if IHO1 has a role similar to HORMAD1 , we examined recruitment of ATR and the ATR activator BRCA1 as well as ATR activity ( gammaH2AX accumulation ) on unsynapsed chromatin .	To test if IHO1 has a role similar to HORMAD1, we examined recruitment of ATR and the ATR activator BRCA1 as well as ATR activity (gammaH2AX accumulation) on unsynapsed chromatin.	13	21	activator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	BRCA1	BRCA1	BRCA1	18	19	20	21
Since phosphorylation of ATR at S435 promotes NER by recruiting XPA to photolesions , we reasoned that AKAP12 is necessary for efficient transport of XPA to UV damage .	Since phosphorylation of ATR at S435 promotes NER by recruiting XPA to photolesions, we reasoned that AKAP12 is necessary for efficient transport of XPA to UV damage.	1	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	phosphorylation of ATR at S435	atr	XPA	XPA	xpa	3	4	10	11
XPA Mediated Regulation of Global Nucleotide Excision Repair by ATR Is p53 Dependent and Occurs Primarily in S-Phase .	XPA Mediated Regulation of Global Nucleotide Excision Repair by ATR Is p53 Dependent and Occurs Primarily in S-Phase.	0	10	Mediated Regulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	XPA	XPA	XPA	9	10	0	1
We also examined whether any of the major downstream checkpoint substrates of ATR such as p53 , Chk1 or MK2 , is involved in the regulation of the UV induced XPA nuclear import .	We also examined whether any of the major downstream checkpoint substrates of ATR such as p53, Chk1 or MK2, is involved in the regulation of the UV induced XPA nuclear import.	10	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	XPA	XPA	XPA	12	13	30	31
We also identified p53 as the ATR regulated downstream protein required for the UV induced XPA nuclear import and the removal of UV-DNA damage .	We also identified p53 as the ATR regulated downstream protein required for the UV induced XPA nuclear import and the removal of UV-DNA damage.	5	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	XPA	XPA	XPA	6	7	15	16
As XPA is indispensable for NER 42 and since phosphorylation of ATR at S435 enhances NER by recruiting XPA to UV induced DNA damage 19 , we wished to determine how cAMP and physiologic MC1R ligands impacted ATR-pS435-XPA recruitment to cisplatin damaged DNA .	As XPA is indispensable for NER 42 and since phosphorylation of ATR at S435 enhances NER by recruiting XPA to UV induced DNA damage 19, we wished to determine how cAMP and physiologic MC1R ligands impacted ATR-pS435-XPA recruitment to cisplatin damaged DNA.	9	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	phosphorylation of ATR at S435	atr	XPA	XPA	xpa	11	12	18	19
ATR actively targeted XPA for regulation of its nuclear import in response to DNA damage [ XREF_BIBR ] , and p53 also mediates XPA nuclear localization [ XREF_BIBR ] .	ATR actively targeted XPA for regulation of its nuclear import in response to DNA damage [XREF_BIBR], and p53 also mediates XPA nuclear localization [XREF_BIBR].	0	4	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	XPA	XPA	XPA	0	1	3	4
ATR promotes the association of XPA with RASSF1A [ XREF_BIBR ] .	ATR promotes the association of XPA with RASSF1A [XREF_BIBR].	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	XPA	XPA	XPA	0	1	5	6
Disruption of the AKAP12-ATR axis abolishes ATR phosphorylation at Serine 435 , reduces recruitment of XPA to photoproducts , blunts NER and elevates UV induced mutagenesis .	Disruption of the AKAP12-ATR axis abolishes ATR phosphorylation at Serine 435, reduces recruitment of XPA to photoproducts, blunts NER and elevates UV induced mutagenesis.	3	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	AKAP12-ATR axis abolishes ATR phosphorylation at Serine 435	atr	XPA	XPA	xpa	6	7	15	16
By contrast , siRNA knockdown of ATR in the A549 cells did significantly reduce the UV induced nuclear import of XPA ( XREF_FIG ) , confirming the involvement of ATR and p53 checkpoint pathway in the regulation of XPA nuclear import .	By contrast, siRNA knockdown of ATR in the A549 cells did significantly reduce the UV induced nuclear import of XPA (XREF_FIG), confirming the involvement of ATR and p53 checkpoint pathway in the regulation of XPA nuclear import.	4	22	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	XPA	XPA	XPA	6	7	20	21
ATR also activates the FANCI and FANCD2 dimer through phosphorylation .	ATR also activates the FANCI and FANCD2 dimer through phosphorylation.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	FANCD2	FANCD2	FANCD2	0	1	6	7
ATR also targets the Fanconi-anemia protein FANCD2 to regulate inter-strand crosslink repair .	ATR also targets the Fanconi-anemia protein FANCD2 to regulate inter-strand crosslink repair.	0	8	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	FANCD2	FANCD2	FANCD2	0	1	6	7
Surprisingly , inhibition of ATR through the use of caffeine or siRNA both failed to decrease the level of polyamide induced FANCD2-Ub .	Surprisingly, inhibition of ATR through the use of caffeine or siRNA both failed to decrease the level of polyamide induced FANCD2-Ub.	2	22	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	FANCD2-Ub	FANCD2-Ub	FANCD2-Ub	4	5	21	22
ATR specific inhibitor ( VE-821 ) [ XREF_BIBR ] , but not ATM inhibitor , impaired the formation of both FA core complex and FANCD2 foci ( XREF_FIG and XREF_SUPPLEMENTARY , XREF_SUPPLEMENTARY ) , indicating that ATR kinase activity is required for FA core complex foci formation .	ATR specific inhibitor (VE-821) [XREF_BIBR], but not ATM inhibitor, impaired the formation of both FA core complex and FANCD2 foci (XREF_FIG and XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY), indicating that ATR kinase activity is required for FA core complex foci formation.	0	25	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	FANCD2	FANCD2	FANCD2	0	1	24	25
ATR also mediates the transient association of FANCD2 ( FANConi Anemia Complementation Group D2 ) to the MCM helicase complex at stalled replication forks , although it is not known whether this is related or not to the MCM2 phosphorylation event described above [ XREF_BIBR ] .	ATR also mediates the transient association of FANCD2 (FANConi Anemia Complementation Group D2) to the MCM helicase complex at stalled replication forks, although it is not known whether this is related or not to the MCM2 phosphorylation event described above [XREF_BIBR].	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	FANCD2	FANCD2	FANCD2	0	1	7	8
ATR targets the Fanconi-anaemia proteins , FANCD2 and FANCI to regulate inter-strand crosslink repair [ XREF_BIBR ] : ATR phosphorylation of FANCD2 promotes its localisation to DNA damage foci through monoubiquitination [ XREF_BIBR ] .	ATR targets the Fanconi-anaemia proteins, FANCD2 and FANCI to regulate inter-strand crosslink repair [XREF_BIBR] : ATR phosphorylation of FANCD2 promotes its localisation to DNA damage foci through monoubiquitination [XREF_BIBR].	0	10	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	FANCD2	FANCD2	FANCD2	0	1	6	7
Importantly , ATR depletion , but not ATM , abolished RPA1 depletion induced FANCD2-Ub , suggesting that ATR activation mediated FANCD2-Ub .	Importantly, ATR depletion, but not ATM, abolished RPA1 depletion induced FANCD2-Ub, suggesting that ATR activation mediated FANCD2-Ub.	2	14	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	FANCD2-Ub	FANCD2-Ub	FANCD2-Ub	2	3	13	14
We treated extracts with caffeine , an inhibitor of ATM and ATR kinase activity and found that inhibition of ATR enzymatic activity did not reduce the chromatin binding of FANCD2 or FA core complex proteins ( XREF_FIG ) , indicating that ATR plays a structural but not enzymatic role in the chromatin recruitment of FANCD2 .	We treated extracts with caffeine, an inhibitor of ATM and ATR kinase activity and found that inhibition of ATR enzymatic activity did not reduce the chromatin binding of FANCD2 or FA core complex proteins (XREF_FIG), indicating that ATR plays a structural but not enzymatic role in the chromatin recruitment of FANCD2.	19	34	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	FANCD2	FANCD2	FANCD2	19	20	29	30
For example , ATR promotes the association of the Fanconi Anemia ( FA ) protein FANCD2 with the MCM replicative helicase , and this interaction slows DNA synthesis and prevents formation of long ssDNA stretches under conditions of reduced nucleotide pools 17 .	For example, ATR promotes the association of the Fanconi Anemia (FA) protein FANCD2 with the MCM replicative helicase, and this interaction slows DNA synthesis and prevents formation of long ssDNA stretches under conditions of reduced nucleotide pools 17.	3	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	FANCD2	FANCD2	FANCD2	3	4	15	16
A water load test may be informative , and measurement of co-peptin levels may be considered , in substitution for direct measurement of AVP , to aid diagnosis and guide diagnostic sequencing of AVPR2 .	A water load test may be informative, and measurement of co-peptin levels may be considered, in substitution for direct measurement of AVP, to aid diagnosis and guide diagnostic sequencing of AVPR2.	11	34	aid	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	co-peptin	co-peptin levels	co-peptin	AVPR2	AVPR2	avpr2	11	12	33	34
Overexpression of the AURKA interacting TPX2 peptide has been shown to cause mislocalisation of AURKA from spindle microtubules in Xenopus XREF_BIBR XREF_BIBR and human cells XREF_BIBR XREF_BIBR .	Overexpression of the AURKA interacting TPX2 peptide has been shown to cause mislocalisation of AURKA from spindle microtubules in Xenopus XREF_BIBR XREF_BIBR and human cells XREF_BIBR XREF_BIBR.	0	15	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AURKA	Overexpression of the AURKA	aurka	AURKA	AURKA	aurka	3	4	14	15
There is an overexpression of both AURKA and TPX2 in many different cancer forms , including ovarian cancer XREF_BIBR , XREF_BIBR , and it has been proposed that TPX2 and AURKA is a functional unit with oncogenic properties XREF_BIBR .	There is an overexpression of both AURKA and TPX2 in many different cancer forms, including ovarian cancer XREF_BIBR, XREF_BIBR, and it has been proposed that TPX2 and AURKA is a functional unit with oncogenic properties XREF_BIBR.	1	8	is an overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	AURKA	overexpression of both AURKA	aurka	AURKA	AURKA	aurka	6	7	6	7
Taken together , these results confirm that , in lung cells , AURKA and AURKB are KRAS targets , and strongly suggest that KRAS signaling upregulates AURKA and AURKB transcription or promotes AURKA and AURKB mRNA stability .	Taken together, these results confirm that, in lung cells, AURKA and AURKB are KRAS targets, and strongly suggest that KRAS signaling upregulates AURKA and AURKB transcription or promotes AURKA and AURKB mRNA stability.	23	36	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AURKA	KRAS signaling upregulates AURKA and AURKB transcription	aurka	AURKA	AURKA	aurka	26	27	32	33
Molecular studies demonstrated that loss of TFF1 correlates with increased levels of TNF activated NF-kappaB and overexpression of Aurora Kinase A ( AURKA ) .	Molecular studies demonstrated that loss of TFF1 correlates with increased levels of TNF activated NF-kappaB and overexpression of Aurora Kinase A (AURKA).	13	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AURKA	AURKA	AURKA	Aurora Kinase A	Aurora Kinase A	Aurora Kinase A	22	23	18	21
However , our results suggest changes in AurA expression in cancer may promote quantitative changes in AurA activity more than qualitative phosphorylation of novel substrates .	However, our results suggest changes in AurA expression in cancer may promote quantitative changes in AurA activity more than qualitative phosphorylation of novel substrates.	7	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AurA	AurA expression	aura	AurA	AurA	aura	7	8	16	17
We show that MMSET mediated methylation of AURKA induces interaction with p53 as well as enhanced kinase activity of AURKA , which results in the proteasomal degradation of p53 .	We show that MMSET mediated methylation of AURKA induces interaction with p53 as well as enhanced kinase activity of AURKA, which results in the proteasomal degradation of p53.	3	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AURKA	MMSET mediated methylation of AURKA	aurka	AURKA	AURKA	aurka	7	8	19	20
Mutations of NBS1 and ATR cause human genomic instability syndrome NBS and ATR-Seckel , respectively , both of which feature neurodevelopmental defects .	Mutations of NBS1 and ATR cause human genomic instability syndrome NBS and ATR-Seckel, respectively, both of which feature neurodevelopmental defects.	0	12	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	NBS	NBS	NBS	4	5	10	11
This conclusion was furthermore supported by the results of in vivo experiments ; the expression of the N-terminal region of NBS1 fused to PCNA induces ATR activation in Rad17 knockout cells , and the expression of the ATR activation domain of TOPBP1 fused to PCNA induces ATR activation in Nbs1 knockout cells .	This conclusion was furthermore supported by the results of in vivo experiments; the expression of the N-terminal region of NBS1 fused to PCNA induces ATR activation in Rad17 knockout cells, and the expression of the ATR activation domain of TOPBP1 fused to PCNA induces ATR activation in Nbs1 knockout cells.	46	51	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATR	ATR	ATR	Nbs1	Nbs1	Nbs1	46	47	49	50
In parallel , Mec1 and ATR kinase is recruited to and activated on RPA coated single stranded DNAs in a Ddc2 and ATRIP dependent manner XREF_BIBR .	In parallel, Mec1 and ATR kinase is recruited to and activated on RPA coated single stranded DNAs in a Ddc2 and ATRIP dependent manner XREF_BIBR.	3	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATRIP	ATRIP	ATRIP	5	6	22	23
The conformational flexibility of ATR allows ATRIP to properly lock the N-termini of the two ATR monomers to favor ATR and ATRIP complex formation and functional diversity .	The conformational flexibility of ATR allows ATRIP to properly lock the N-termini of the two ATR monomers to favor ATR and ATRIP complex formation and functional diversity.	2	9	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	ATRIP	ATRIP	ATRIP	4	5	6	7
To gain more insight into the interplay between ATR and the FA pathway , we wished to test whether the activation of the FA pathway is affected by the absence of the canonical ATR activators RAD17 or TOPBP1 .	To gain more insight into the interplay between ATR and the FA pathway, we wished to test whether the activation of the FA pathway is affected by the absence of the canonical ATR activators RAD17 or TOPBP1.	29	37	activators	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	RAD17	RAD17	RAD17	33	34	35	36
Furthermore , others have reported that the normal phosphorylation of Aurkb by the mitotic kinase , Bub1 , is dramatically increased in Bub1 transgenic mice , causing hyperphosphorylation and increased Aurkb activity XREF_BIBR .	Furthermore, others have reported that the normal phosphorylation of Aurkb by the mitotic kinase, Bub1, is dramatically increased in Bub1 transgenic mice, causing hyperphosphorylation and increased Aurkb activity XREF_BIBR.	8	32	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Aurkb	phosphorylation of Aurkb	aurkb	Aurkb	Aurkb	aurkb	10	11	30	31
Accordingly , we found that transcription and translation of AURKB were upregulated promoting increases AURKB signaling .	Accordingly, we found that transcription and translation of AURKB were upregulated promoting increases AURKB signaling.	5	15	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AURKB	transcription and translation of AURKB	aurkb	AURKB	AURKB	aurkb	9	10	14	15
52 ATM activation was observes by H17 but not by K17 , suggesting that pathways downstream of AURKA or AURKB may activate ATM ( XREF_FIG ) .	52 ATM activation was observes by H17 but not by K17, suggesting that pathways downstream of AURKA or AURKB may activate ATM (XREF_FIG).	14	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AURKB	AURKB	AURKB	ATM	ATM	ATM	19	20	22	23
The data suggested that AURKA acts to inhibit the inhibitory activity of BRCA1 .	The data suggested that AURKA acts to inhibit the inhibitory activity of BRCA1.	4	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AURKA	AURKA	AURKA	BRCA1	BRCA1	BRCA1	4	5	12	13
However , key components of the depicted molecular wiring diagram are probably missing , such as a phosphatase that regulates AURKA mediated modification of BRCA1 and RHAMM .	However, key components of the depicted molecular wiring diagram are probably missing, such as a phosphatase that regulates AURKA mediated modification of BRCA1 and RHAMM.	19	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AURKA	AURKA	AURKA	BRCA1	BRCA1	BRCA1	20	21	24	25
We show that CtIP is phosphorylated at T818 ( T859 in humans ) by ATR , and that ATR phosphorylation at T818 and other sites promotes stable association of CtIP to damaged chromosomes , allowing CtIP dependent resection .	We show that CtIP is phosphorylated at T818 (T859 in humans) by ATR, and that ATR phosphorylation at T818 and other sites promotes stable association of CtIP to damaged chromosomes, allowing CtIP dependent resection.	18	30	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR phosphorylation	atr	CtIP	CtIP	ctip	18	19	29	30
Interestingly , the checkpoint kinase ATR , when activated , modulates the relative activity of EXO1 and CtIP : ATR mediated phosphorylation of EXO1 renders it vulnerable to proteolysis , whereas ATR mediated phosphorylation of CtIP is required for its chromatin binding and resection activity .	Interestingly, the checkpoint kinase ATR, when activated, modulates the relative activity of EXO1 and CtIP : ATR mediated phosphorylation of EXO1 renders it vulnerable to proteolysis, whereas ATR mediated phosphorylation of CtIP is required for its chromatin binding and resection activity.	2	18	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	CtIP	CtIP	CtIP	5	6	17	18
The phosphorylation of Axin-1 by GSK3beta accelerates the association of Axin-1 with beta-catenin .	The phosphorylation of Axin-1 by GSK3beta accelerates the association of Axin-1 with beta-catenin.	1	11	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Axin-1	phosphorylation of Axin-1	axin-1	Axin-1	Axin-1	axin-1	3	4	10	11
MLL fusion proteins have been demonstrated to function as dominant negative mutants that abrogate ATR mediated stabilization of MLL and compromise the S-phase checkpoint .	MLL fusion proteins have been demonstrated to function as dominant negative mutants that abrogate ATR mediated stabilization of MLL and compromise the S-phase checkpoint.	14	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	MLL	MLL	MLL	14	15	18	19
Thus , our results show that BDNF specifically up-regulates its full-length TrkB receptor in cortical neurons of the penumbra area and prevents their death in an in vivo model of focal ischemia .	Thus, our results show that BDNF specifically up-regulates its full-length TrkB receptor in cortical neurons of the penumbra area and prevents their death in an in vivo model of focal ischemia.	6	21	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	11	12
Four fractions were found to significantly decrease BDNF induced TrkB activity ( XREF_FIG ) , including Fragment # ( 05 ) , corresponding to region III .	Four fractions were found to significantly decrease BDNF induced TrkB activity (XREF_FIG), including Fragment # (05), corresponding to region III.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	9	10
Our previous studies indicated that BDNF activation of the TrkB signal transduction pathway blocked the cytotoxic effects of chemotherapeutic drugs via the phosphatidylinositol 3-kinase pathway .	Our previous studies indicated that BDNF activation of the TrkB signal transduction pathway blocked the cytotoxic effects of chemotherapeutic drugs via the phosphatidylinositol 3-kinase pathway.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	9	10
Importantly , BDNF mediated TrkB activation promotes neuronal synaptic activity via the activation of the CREB transcription factor , which drives expression and activation of intracellular signaling pathways through the action of AMPA and NDMA receptors XREF_BIBR , XREF_BIBR .	Importantly, BDNF mediated TrkB activation promotes neuronal synaptic activity via the activation of the CREB transcription factor, which drives expression and activation of intracellular signaling pathways through the action of AMPA and NDMA receptors XREF_BIBR, XREF_BIBR.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	4	5
Therefore , as other studies suggest , also the use of transgenic animals indicate that BDNF mediated TrkB activation is required for the antidepressant behavioural response of antidepressants in behavioural paradigms .	Therefore, as other studies suggest, also the use of transgenic animals indicate that BDNF mediated TrkB activation is required for the antidepressant behavioural response of antidepressants in behavioural paradigms.	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	17	18
XREF_BIBR Extracellular BDNF stimulates TrkB receptors on the hilar segments of mossy fibers to induce axonal branching , which may create hyperexcitable dentate circuits .	XREF_BIBR Extracellular BDNF stimulates TrkB receptors on the hilar segments of mossy fibers to induce axonal branching, which may create hyperexcitable dentate circuits.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	4	5
The results from previous studies indicated that the increased BDNF release had activated TrkB during inflammatory pain XREF_BIBR .	The results from previous studies indicated that the increased BDNF release had activated TrkB during inflammatory pain XREF_BIBR.	9	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	13	14
BDNF induced TrkB activation confers antiapoptotic , tumorigenic , invasive , and metastatic capacities upon cancer cells [ XREF_BIBR - XREF_BIBR ] .	BDNF induced TrkB activation confers antiapoptotic, tumorigenic, invasive, and metastatic capacities upon cancer cells [XREF_BIBR - XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Because retrolinkin recruits WAVE1 to endocytic sites of BDNF activated TrkB , endocytosis of the ligand-receptor signal complex might be facilitated by WAVE1 promoted actin polymerization .	Because retrolinkin recruits WAVE1 to endocytic sites of BDNF activated TrkB, endocytosis of the ligand-receptor signal complex might be facilitated by WAVE1 promoted actin polymerization.	6	11	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
Additionally , independent of PKA , Gs coupled CRF 1 receptor signaling in limbic neurons can activate Epac ( exchange protein directly activated by cyclic AMP ) which , in turn , potentiates BDNF stimulated TrkB signaling by trafficking TrkB receptors to neuronal membranes .	Additionally, independent of PKA, Gs coupled CRF 1 receptor signaling in limbic neurons can activate Epac (exchange protein directly activated by cyclic AMP) which, in turn, potentiates BDNF stimulated TrkB signaling by trafficking TrkB receptors to neuronal membranes.	32	36	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	33	34	35	36
Using this assay , we found that BDNF induced significantly more TrkB internalization in active neurons ( stimulated with TBS ) than in inactive neurons ( XREF_FIG B ; TBS + CNQX and MK801 or Kyn ) .	Using this assay, we found that BDNF induced significantly more TrkB internalization in active neurons (stimulated with TBS) than in inactive neurons (XREF_FIG B; TBS + CNQX and MK801 or Kyn).	7	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	11	12
Since cue dependent fear conditioning is known to require , and be exquisitely sensitive to , BDNF activation of TrkB , these data are consistent with deoxygedunin acting on the TrkB system in vivo to enhance cue dependent fear learning .	Since cue dependent fear conditioning is known to require, and be exquisitely sensitive to, BDNF activation of TrkB, these data are consistent with deoxygedunin acting on the TrkB system in vivo to enhance cue dependent fear learning.	16	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	19	20
Although data from aforementioned knockdown experiments showed that WAVE1 is required for endocytosis of BDNF activated TrkB , coIP assay using antibodies against WAVE1 or Trk receptors did not detect interaction between WAVE1 and Trk ( XREF_FIG ) .	Although data from aforementioned knockdown experiments showed that WAVE1 is required for endocytosis of BDNF activated TrkB, coIP assay using antibodies against WAVE1 or Trk receptors did not detect interaction between WAVE1 and Trk (XREF_FIG).	12	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	16	17
In cultured rat hippocampal neurons , acute and gradual increases in BDNF elicited transient and sustained activation of TrkB receptor and its downstream signaling , respectively , leading to differential expression of Homer1 and Arc .	In cultured rat hippocampal neurons, acute and gradual increases in BDNF elicited transient and sustained activation of TrkB receptor and its downstream signaling, respectively, leading to differential expression of Homer1 and Arc.	9	19	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	18	19
While BDNF is known to induce endocytosis of TrkB in a clathrin dependent manner to an early endocytic compartment , the mechanisms of NT4 mediated TrkB trafficking is not known .	While BDNF is known to induce endocytosis of TrkB in a clathrin dependent manner to an early endocytic compartment, the mechanisms of NT4 mediated TrkB trafficking is not known.	1	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	8	9
Another change with regard to BDNF effects may involve TrkB receptors , which are activated by BDNF and neuroprotective .	Another change with regard to BDNF effects may involve TrkB receptors, which are activated by BDNF and neuroprotective.	9	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	9	10
To explain increased TrkB synaptic signaling in the Ts65Dn cortex , we envisioned several possibilities : increased expression of TrkB , increased expression or protein levels of BDNF , increased access of BDNF to TrkB , decreased retrograde trafficking of TrkB positive endosomes , or decreased downregulation of activated TrkB .	To explain increased TrkB synaptic signaling in the Ts65Dn cortex, we envisioned several possibilities : increased expression of TrkB, increased expression or protein levels of BDNF, increased access of BDNF to TrkB, decreased retrograde trafficking of TrkB positive endosomes, or decreased downregulation of activated TrkB.	22	50	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	expression or protein levels of BDNF	bdnf	TrkB	TrkB	trkb	27	28	49	50
Accumulation of TrkB in both EEA1 and Rab7 positive endosomes could arise from two potential problems : 1 ) constitutively endocytosed TrKB activated by endogenous BDNF is not sorted from early to late endosomes and as a consequence TrkB accumulates within early EEA1- positive endosomes .	Accumulation of TrkB in both EEA1 and Rab7 positive endosomes could arise from two potential problems : 1) constitutively endocytosed TrKB activated by endogenous BDNF is not sorted from early to late endosomes and as a consequence TrkB accumulates within early EEA1- positive endosomes.	21	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrKB	TrKB	TrKB	25	26	21	22
Even though primary neurospheres derived from the DG of adult TrkB knockout mice and treated with BDNF displayed reduction in both number and size relative to those derived from the control mice , 46 the effect of BDNF on neurogenesis in vivo was not measured in the TrkB knockout mice .	Even though primary neurospheres derived from the DG of adult TrkB knockout mice and treated with BDNF displayed reduction in both number and size relative to those derived from the control mice, 46 the effect of BDNF on neurogenesis in vivo was not measured in the TrkB knockout mice.	10	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	10	11
TrkB is activated by three neurotrophic factors -- BDNF , neurotrophin-3 , and neurotrophin-4 -- to influence multiple processes including neuronal differentiation and survival , long-term potentiation , learning , and memory .	TrkB is activated by three neurotrophic factors -- BDNF, neurotrophin-3, and neurotrophin-4 -- to influence multiple processes including neuronal differentiation and survival, long-term potentiation, learning, and memory.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	0	1
In LAR-/- neurons , BDNF induced activation of TrkB , Shc , AKT , ERK , and CREB was significantly decreased ; while in LAR transfected neurons , BDNF induced CREB activation was augmented .	In LAR-/- neurons, BDNF induced activation of TrkB, Shc, AKT, ERK, and CREB was significantly decreased; while in LAR transfected neurons, BDNF induced CREB activation was augmented.	4	20	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	8	9
Activation of trkB by BDNF triggers intracellular signaling cascades that effectively modulate voltage gated , ligand gated and second-messenger gated ion channels [ XREF_BIBR , XREF_BIBR ] .	Activation of trkB by BDNF triggers intracellular signaling cascades that effectively modulate voltage gated, ligand gated and second-messenger gated ion channels [XREF_BIBR, XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	4	5	2	3
In the future it will be interesting to determine whether Vav GEFs regulate TrkB receptor endocytosis , and whether internalization of the BDNF activated TrkB receptor is important for TBS-LTP and dendritic spine plasticity .	In the future it will be interesting to determine whether Vav GEFs regulate TrkB receptor endocytosis, and whether internalization of the BDNF activated TrkB receptor is important for TBS-LTP and dendritic spine plasticity.	19	25	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	22	23	24	25
The activation of TrkB by BDNF initiates a downstream signal that is crucial for plasticity and memory development [ XREF_BIBR - XREF_BIBR ] .	The activation of TrkB by BDNF initiates a downstream signal that is crucial for plasticity and memory development [XREF_BIBR - XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	3	4
Even though BDNF and GDNF both activate tyrosine kinases , i.e ., trkB and c-ret , only BDNF appears to sustain Ca v 2.2 clustering and F-actin assembly in growth cones .	Even though BDNF and GDNF both activate tyrosine kinases, i.e., trkB and c-ret, only BDNF appears to sustain Ca v 2.2 clustering and F-actin assembly in growth cones.	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	2	3	12	13
We have previously found that activation of TrkB by BDNF is required for fear memory formation and , separately , that GABA A receptor subunits are dynamically regulated during fear memory consolidation .	We have previously found that activation of TrkB by BDNF is required for fear memory formation and, separately, that GABA A receptor subunits are dynamically regulated during fear memory consolidation.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	7	8
The molecular mechanism of how TrkB activation by BDNF and NT4 leads to diverse outcomes is unknown .	The molecular mechanism of how TrkB activation by BDNF and NT4 leads to diverse outcomes is unknown.	5	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	5	6
BDNF mediated activation of TrkB results in the recruitment of Cdk5 to the activated receptors , leading to phosphorylation of Cdk5 by TrkB at Tyr15 [ XREF_BIBR ] , which has been demonstrated to enhance Cdk5 activity [ XREF_BIBR ] .	BDNF mediated activation of TrkB results in the recruitment of Cdk5 to the activated receptors, leading to phosphorylation of Cdk5 by TrkB at Tyr15 [XREF_BIBR], which has been demonstrated to enhance Cdk5 activity [XREF_BIBR].	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
In BDNF induced TrkB endocytic trafficking and signaling , retrolinkin mediates not only endocytosis of the signal complex but also postendocytic trafficking of the signaling endosomes carrying activated TrkB via its interaction with endophilin A1 .	In BDNF induced TrkB endocytic trafficking and signaling, retrolinkin mediates not only endocytosis of the signal complex but also postendocytic trafficking of the signaling endosomes carrying activated TrkB via its interaction with endophilin A1.	0	10	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	3	4
The normalization of the phosphorylated TrkB with total TrkB showed a strong and significant activation of TrkB by BDNF ( ANOVA , p < 0.001 ) as expected , and a relatively weak activation of the receptor by B-5 and B-3 ( ANOVA , p = 0.035 and p = 0.0237 respectively ) .	The normalization of the phosphorylated TrkB with total TrkB showed a strong and significant activation of TrkB by BDNF (ANOVA, p < 0.001) as expected, and a relatively weak activation of the receptor by B-5 and B-3 (ANOVA, p = 0.035 and p = 0.0237 respectively).	9	48	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	16	17
Acute BDNF induced activation of TrkB receptors significantly increased tyrosine phosphorylation of Kv1.3 in the OB , as shown using a combined immunoprecipitation and Western blot analysis .	Acute BDNF induced activation of TrkB receptors significantly increased tyrosine phosphorylation of Kv1.3 in the OB, as shown using a combined immunoprecipitation and Western blot analysis.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	5	6
Specifically , we demonstrate the necessity of proteins associated with trafficking of ciliary cargo ( BBS4 ) or with ciliogenesis ( KIF3A ) in activation of TrkB by BDNF .	Specifically, we demonstrate the necessity of proteins associated with trafficking of ciliary cargo (BBS4) or with ciliogenesis (KIF3A) in activation of TrkB by BDNF.	8	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	28	29	26	27
BDNF then activates the TrkB signaling pathway , causing phosphorylation and activation of downstream effector proteins ERK1/2 and Akt through the MEK and PI3K signaling pathways , respectively .	BDNF then activates the TrkB signaling pathway, causing phosphorylation and activation of downstream effector proteins ERK1/2 and Akt through the MEK and PI3K signaling pathways, respectively.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
Studies with neuroblastoma cell lines have shown that BDNF stimulation induces TrkB mediated induction of chemotaxis and invasion .	Studies with neuroblastoma cell lines have shown that BDNF stimulation induces TrkB mediated induction of chemotaxis and invasion.	8	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	11	12
Because both retrolinkin and endophilin A1 are required for dendrite development as well as ERK signaling , and retrolinkin but not endophilin A1 is required for BDNF induced TrkB endocytosis , we reasoned that endophilin A1 functions downstream of retrolinkin in BDNF-TrkB endocytic trafficking .	Because both retrolinkin and endophilin A1 are required for dendrite development as well as ERK signaling, and retrolinkin but not endophilin A1 is required for BDNF induced TrkB endocytosis, we reasoned that endophilin A1 functions downstream of retrolinkin in BDNF-TrkB endocytic trafficking.	26	29	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	26	27	28	29
TrkB is commonly activated by BDNF ( avians lack the alternative ligand NT-4 ) , although NT-3 can activate TrkB less potently .	TrkB is commonly activated by BDNF (avians lack the alternative ligand NT-4), although NT-3 can activate TrkB less potently.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	0	1
This study reveals the following : ( 1 ) expression of trkB , BDNF , and NT-4 are not modulated by an excess of serotonin during barrel formation , ( 2 ) TrkB signaling limits branching of TCAs in inappropriate supragranular cortical layers , and ( 3 ) serotonin and TrkB signaling act together to cluster thalamocortical axons in layer IV .	This study reveals the following : (1) expression of trkB, BDNF, and NT-4 are not modulated by an excess of serotonin during barrel formation, (2) TrkB signaling limits branching of TCAs in inappropriate supragranular cortical layers, and (3) serotonin and TrkB signaling act together to cluster thalamocortical axons in layer IV.	9	34	modulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	expression of trkB, BDNF	bdnf	TrkB	TrkB	trkb	13	14	32	33
Second , and consistent with this , we find AP-2 to be largely dispensable for BDNF induced TrkB endocytosis in cultured neurons ( see XREF_SUPPLEMENTARY ) .	Second, and consistent with this, we find AP-2 to be largely dispensable for BDNF induced TrkB endocytosis in cultured neurons (see XREF_SUPPLEMENTARY).	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	17	18
TrkB stimulation by BDNF activates PI3-K and MAPK and the effects of TrkB activation on fear memory consolidation may be mediated through these signaling cascades .	TrkB stimulation by BDNF activates PI3-K and MAPK and the effects of TrkB activation on fear memory consolidation may be mediated through these signaling cascades.	0	4	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	0	1
In this study , apoptotic cells were observed increasing after K252a treatment , which was considered that TrkB activated by BDNF was participated in the survival of HepG2 and HCCLM3 cells .	In this study, apoptotic cells were observed increasing after K252a treatment, which was considered that TrkB activated by BDNF was participated in the survival of HepG2 and HCCLM3 cells.	17	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	17	18
Taken together , these results indicate that the observed outgrowth of wild type TrkB transfected Baf3 cells over mock- and mutant TrkB transfected cells in the presence of BDNF may be attributed to BDNF stimulated TrkB signaling .	Taken together, these results indicate that the observed outgrowth of wild type TrkB transfected Baf3 cells over mock- and mutant TrkB transfected cells in the presence of BDNF may be attributed to BDNF stimulated TrkB signaling.	31	36	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	33	34	35	36
Additionally , BDNF may promote TrkB signaling to maintain acetylcholine receptor clustering at the neuromuscular junction .	Additionally, BDNF may promote TrkB signaling to maintain acetylcholine receptor clustering at the neuromuscular junction.	2	6	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	5	6
BDNF mediated activation of TrkB receptors has been shown to be important in memory , mood , behavior and the rescue of neurons threatened by injury or disease .	BDNF mediated activation of TrkB receptors has been shown to be important in memory, mood, behavior and the rescue of neurons threatened by injury or disease.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
Another recent strategy is the development of BDNF mimetics specifically enhancing TrkB signaling , which have showed promising results in rodent neurodegenerative models XREF_BIBR .	Another recent strategy is the development of BDNF mimetics specifically enhancing TrkB signaling, which have showed promising results in rodent neurodegenerative models XREF_BIBR.	7	12	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	11	12
BDNF mediated TrkB activation is well known for neuronal survival via various signaling pathways under different conditions .	BDNF mediated TrkB activation is well known for neuronal survival via various signaling pathways under different conditions.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
BDNF mediated activation of TrkB can also compromise GABA mediated inhibition [ XREF_BIBR ] .	BDNF mediated activation of TrkB can also compromise GABA mediated inhibition [XREF_BIBR].	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
This is also supported by a recent report that , under inflammatory conditions , enhanced production of BDNF in DRG neurons might activate presynaptic trkB receptors via an autocrine and paracrine signal to synergistically act with cytokines such as TNFalpha , and upregulate synaptic excitability in pain transmission [ XREF_BIBR ] .	This is also supported by a recent report that, under inflammatory conditions, enhanced production of BDNF in DRG neurons might activate presynaptic trkB receptors via an autocrine and paracrine signal to synergistically act with cytokines such as TNFalpha, and upregulate synaptic excitability in pain transmission [XREF_BIBR].	15	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	17	18	24	25
Therefore , one can hypothesize that BDNF stimulated TrkB signaling could potentially coordinate the delivery of key molecules at post-synaptic lipid rafts to promote synaptic plasticity .	Therefore, one can hypothesize that BDNF stimulated TrkB signaling could potentially coordinate the delivery of key molecules at post-synaptic lipid rafts to promote synaptic plasticity.	6	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
BDNF mediated activation of TrkB receptors likely involves signaling through CREB and ATF-1 , since BDNF increased CREB immunoreactivity in phrenic motoneurons following SH , compared to aCSF .	BDNF mediated activation of TrkB receptors likely involves signaling through CREB/ATF-1, since BDNF increased CREB immunoreactivity in phrenic motoneurons following SH, compared to aCSF.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
Unlike LM22A-4 , the full agonist BDNF ( 250ng/ml ) activated TrkB receptors in slices from both WT and Mecp2 KO mice ( n = 4 ; P < 0.01 ) .	Unlike LM22A-4, the full agonist BDNF (250ng/ml) activated TrkB receptors in slices from both WT and Mecp2 KO mice (n = 4; P < 0.01).	3	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	11	12
Application of BDNF to cultured hippocampal neurons induced a significant TrkB internalization over the spontaneous or ligand independent internalization of TrkB ( XREF_FIG B , right , lanes 1 and 2 ; and XREF_FIG A , lanes 3 and 4 ) .	Application of BDNF to cultured hippocampal neurons induced a significant TrkB internalization over the spontaneous or ligand independent internalization of TrkB (XREF_FIG B, right, lanes 1 and 2; and XREF_FIG A, lanes 3 and 4).	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	10	11
Low doses of BDNF rapidly induce a TrkB dependent potentiation at developing NMJs in culture .	Low doses of BDNF rapidly induce a TrkB dependent potentiation at developing NMJs in culture.	1	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	7	8
This complements our previous findings and shows that stable membrane deposits of BDNF could potentiate TrkB receptor activation cell autonomously and drive glutamatergic synapse number by confining activity to its own neurites .	This complements our previous findings and shows that stable membrane deposits of BDNF could potentiate TrkB receptor activation cell autonomously and drive glutamatergic synapse number by confining activity to its own neurites.	10	18	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	15	16
Interestingly , BDNF also induced an endothelium and TrkB dependent relaxation .	Interestingly, BDNF also induced an endothelium and TrkB dependent relaxation.	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	8	9
The TrkB receptor is activated by Bdnf and controls three different major pathways , the P13 kinase cascade , the PLC-gamma1 cascade and the ERK1/2 MAPK cascade XREF_BIBR , the last one of which was predominantly affected by both 5-Htt +/- and PS .	The TrkB receptor is activated by Bdnf and controls three different major pathways, the P13 kinase cascade, the PLC-gamma1 cascade and the ERK1/2 MAPK cascade XREF_BIBR, the last one of which was predominantly affected by both 5-Htt +/- and PS.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bdnf	Bdnf	Bdnf	TrkB	TrkB	TrkB	6	7	1	2
Our lab has previously found that BDNF activation of TrkB is required for fear memory formation and that GABA A receptor subunits and the GABA A clustering protein gephyrin are dynamically regulated during fear memory consolidation .	Our lab has previously found that BDNF activation of TrkB is required for fear memory formation and that GABA A receptor subunits and the GABA A clustering protein gephyrin are dynamically regulated during fear memory consolidation.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	9	10
Activation of TrkB by BDNF or other agonists can protect neurons from Abeta toxicity [ XREF_BIBR - XREF_BIBR ] , while blockade of TrkB attenuates the neuroprotective effects of NE against Abeta toxicity in culture [ XREF_BIBR ] .	Activation of TrkB by BDNF or other agonists can protect neurons from Abeta toxicity [XREF_BIBR - XREF_BIBR], while blockade of TrkB attenuates the neuroprotective effects of NE against Abeta toxicity in culture [XREF_BIBR].	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
While the monovalent Fab fragment did not display TrkB agonism , it did , however , show antagonism for BDNF mediated TrkB activation at low micromolar concentrations ( XREF_FIG ) , suggesting that bivalency was required for agonism ( as reflected by the F ( ab ' ) 2 fragment ) and that the binding site for the antibody overlaped , at least in part , with that of BDNF ( as reflected by the Fab fragment ) .	While the monovalent Fab fragment did not display TrkB agonism, it did, however, show antagonism for BDNF mediated TrkB activation at low micromolar concentrations (XREF_FIG), suggesting that bivalency was required for agonism (as reflected by the F (ab ') 2 fragment) and that the binding site for the antibody overlaped, at least in part, with that of BDNF (as reflected by the Fab fragment).	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	19	20	21	22
First , BDNF triggered TrkB endocytosis requires retrolinkin activity , and there is a high degree of colocalization between retrolinkin and pTrk and APPL1 on vesicular structures upon BDNF stimulation .	First, BDNF triggered TrkB endocytosis requires retrolinkin activity, and there is a high degree of colocalization between retrolinkin and pTrk and APPL1 on vesicular structures upon BDNF stimulation.	2	5	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	4	5
Although both BDNF and NT4 activate the same receptors , TrkB and p75 , they play different regulatory roles in taste development .	Although both BDNF and NT4 activate the same receptors, TrkB and p75, they play different regulatory roles in taste development.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	10	11
TrkB receptor activation by BDNF sets in motion three major signaling transduction pathways : the mitogen activated protein kinase ( MAPK ) pathway , the phosphatidyl-inositol 3-kinase ( PI3K ) pathway , and the phospholipase C ( PLC ) pathway .	TrkB receptor activation by BDNF sets in motion three major signaling transduction pathways : the mitogen activated protein kinase (MAPK) pathway, the phosphatidyl-inositol 3-kinase (PI3K) pathway, and the phospholipase C (PLC) pathway.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	0	1
In contrast , mossy fibers express TrkB receptor that is activated by synaptic BDNF .	In contrast, mossy fibers express TrkB receptor that is activated by synaptic BDNF.	6	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	13	14	6	7
Having found that retrolinkin interacts with the CYFIP1/2 subunit of the WAVE1 complex and that WAVE1 is required for endocytosis and signaling of BDNF activated TrkB , we reasoned that retrolinkin might function by recruiting the WAVE1 complex to endocytic sites of activated TrkB to promote actin polymerization .	Having found that retrolinkin interacts with the CYFIP1/2 subunit of the WAVE1 complex and that WAVE1 is required for endocytosis and signaling of BDNF activated TrkB, we reasoned that retrolinkin might function by recruiting the WAVE1 complex to endocytic sites of activated TrkB to promote actin polymerization.	19	26	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	23	24	25	26
Our previous study indicated that BDNF activation of TrkB induced an increase in secretion of VEGF in neuronal cell lines that was dependent on induction of HIF-1alpha and HIF-1alpha dependent transcription from the VEGF promoter ( Nakmura et al , 2005 ) .	Our previous study indicated that BDNF activation of TrkB induced an increase in secretion of VEGF in neuronal cell lines that was dependent on induction of HIF-1alpha and HIF-1alpha dependent transcription from the VEGF promoter (Nakmura et al, 2005).	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	8	9
A recent study has demonstrated that structural synaptic plasticity is mediated by activity dependent release of BDNF and subsequent autocrine stimulation of TrkB signaling .	A recent study has demonstrated that structural synaptic plasticity is mediated by activity dependent release of BDNF and subsequent autocrine stimulation of TrkB signaling.	16	23	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	22	23
Another challenge is to regulate the amounts of trophic factor , as high concentrations of BDNF can cause the down-regulation of TrkB receptors , as has been reported in motor neuron clinical trials [ XREF_BIBR ] .	Another challenge is to regulate the amounts of trophic factor, as high concentrations of BDNF can cause the down-regulation of TrkB receptors, as has been reported in motor neuron clinical trials [XREF_BIBR].	13	22	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	21	22
Various intercellular signaling molecules can trigger lasting changes in the ability of synapses to express plasticity and BDNF mediated activation of the TrkB pathway has been implicated in this process .	Various intercellular signaling molecules can trigger lasting changes in the ability of synapses to express plasticity and BDNF mediated activation of the TrkB pathway has been implicated in this process.	17	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	17	18	22	23
Therefore , elevated levels of BDNF protein in SNc might very well induce an internalization process and a later proteolysis of the trkB receptor .	Therefore, elevated levels of BDNF protein in SNc might very well induce an internalization process and a later proteolysis of the trkB receptor.	5	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	5	6	22	23
TrkB activation by BDNF is essential for appetite regulation and energy homeostasis [ XREF_BIBR ] .	TrkB activation by BDNF is essential for appetite regulation and energy homeostasis [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	0	1
Given the fact that local BDNF activation of TrkB receptors potentiates VTA dopamine cell excitability in cocaine withdrawal and midbrain infusions of BDNF enhance forebrain dopamine release , further experimentation , perhaps employing gain of TrkB function approaches , is needed before the role of TrkB in the VTA in cocaine reward can be ruled out .	Given the fact that local BDNF activation of TrkB receptors potentiates VTA dopamine cell excitability in cocaine withdrawal and midbrain infusions of BDNF enhance forebrain dopamine release, further experimentation, perhaps employing gain of TrkB function approaches, is needed before the role of TrkB in the VTA in cocaine reward can be ruled out.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	8	9
TrkB located at the pre- and post-synaptic membranes is activated by BDNF , leading to increased PI3K and mTOR signaling and enhanced local translation of mRNAs such as Ca ++ modulated proteins .	TrkB located at the pre- and post-synaptic membranes is activated by BDNF, leading to increased PI3K and mTOR signaling and enhanced local translation of mRNAs such as Ca ++ modulated proteins.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	0	1
Motor neuron progenitors in the ventral neural tube from the chick embryo express TrkB and when ventral neural tube explants are treated with BDNF , there is an increase in the number of motor neurons produced and BrdU incorporation [ XREF_BIBR ] .	Motor neuron progenitors in the ventral neural tube from the chick embryo express TrkB and when ventral neural tube explants are treated with BDNF, there is an increase in the number of motor neurons produced and BrdU incorporation [XREF_BIBR].	12	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	23	24	13	14
Recently , our lab also identified BDNF tetrapeptides ( peptide B1-B5 ) which can modulate TrkB signaling and exert neurotrophic effect in mouse hippocampal primary neuronal cultures [ XREF_BIBR ] .	Recently, our lab also identified BDNF tetrapeptides (peptide B1-B5) which can modulate TrkB signaling and exert neurotrophic effect in mouse hippocampal primary neuronal cultures [XREF_BIBR].	6	16	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	15	16
Furthermore , we detected that SPRED2 is phosphorylated after BDNF stimulated TrkB activation .	Furthermore, we detected that SPRED2 is phosphorylated after BDNF stimulated TrkB activation.	9	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	11	12
In humans , we found that a 5-day 5Hz-rTMS protocol similarly increased BDNF induced TrkB activation in lymphocytes .	In humans, we found that a 5-day 5Hz-rTMS protocol similarly increased BDNF induced TrkB activation in lymphocytes.	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	14	15
Furthermore , exogenous BDNF is known to activate TrkB in these neurons .	Furthermore, exogenous BDNF is known to activate TrkB in these neurons.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	8	9
BDNF activation of TrkB also stimulates mobilization of neurotransmitter containing synaptic vesicles via TrkB binding to an actin/Myo6/GIPC1 motor complex .	BDNF activation of TrkB also stimulates mobilization of neurotransmitter containing synaptic vesicles via TrkB binding to an actin/Myo6/GIPC1 motor complex.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
The results highlight the importance of BDNF induced TrkB receptor signaling in rescuing HD mediated apoptotic features in striatal cells .	The results highlight the importance of BDNF induced TrkB receptor signaling in rescuing HD mediated apoptotic features in striatal cells.	4	10	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
As expected , expression of Flag-TrkB and A-F 592A enabled survival of sympathetic neurons treated with BDNF acting exclusively on distal axons ( XREF_FIG ) .	As expected, expression of Flag-TrkB and A-F 592A enabled survival of sympathetic neurons treated with BDNF acting exclusively on distal axons (XREF_FIG).	5	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	Flag-TrkB	Flag-TrkB	Flag-TrkB	16	17	5	6
Activation of TrkB by BDNF has been repeatedly shown to be associated with , and required for , the acquisition of classical conditioned fear in rodent models XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Activation of TrkB by BDNF has been repeatedly shown to be associated with, and required for, the acquisition of classical conditioned fear in rodent models XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
To assess whether BDNF triggered TrkB activation is required for CTA memory formation , K252a , a potent inhibitor of Trk receptors , or the same volume of vehicle was bilaterally infused into specific brain regions 30 min before saccharin administration ( XREF_FIG ) .	To assess whether BDNF triggered TrkB activation is required for CTA memory formation, K252a, a potent inhibitor of Trk receptors, or the same volume of vehicle was bilaterally infused into specific brain regions 30 min before saccharin administration (XREF_FIG).	3	6	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	5	6
For example , BDNF induced TrkB receptor signaling was shown to be crucial in rescuing caspase-3-mediated cell death , specifically in Huntington mutant striatal cells [ XREF_BIBR ] .	For example, BDNF induced TrkB receptor signaling was shown to be crucial in rescuing caspase-3-mediated cell death, specifically in Huntington mutant striatal cells [XREF_BIBR].	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	5	6
The activation of nicotinic receptors has effects upon the BDNF-TrkB pathway , inducing cell proliferation by promoting the release of BDNF , which in turn activates TrkB receptors .	The activation of nicotinic receptors has effects upon the BDNF-TrkB pathway, inducing cell proliferation by promoting the release of BDNF, which in turn activates TrkB receptors.	18	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	26	27
Although the mechanism by which the D5R phosphorylates Akt at Ser473 remains unknown , it has been shown that BDNF can induce Akt phosphorylation at Ser473 in cortical neuronal culture , suggesting that increased Akt signalling may be secondary to BDNF induced activation of TrkB .	Although the mechanism by which the D5R phosphorylates Akt at Ser473 remains unknown, it has been shown that BDNF can induce Akt phosphorylation at Ser473 in cortical neuronal culture, suggesting that increased Akt signalling may be secondary to BDNF induced activation of TrkB.	38	45	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	40	41	44	45
Finally , neuronal activity promotes BDNF induced TrkB endocytosis , a signaling event important for many long-term BDNF functions .	Finally, neuronal activity promotes BDNF induced TrkB endocytosis, a signaling event important for many long-term BDNF functions.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	7	8
Previous studies have shown that the activation of TrkB by BDNF could mediate the anoikis suppression and metastasis by activating PI3K and AKT pathway [ XREF_BIBR ] .	Previous studies have shown that the activation of TrkB by BDNF could mediate the anoikis suppression and metastasis by activating PI3K and AKT pathway [XREF_BIBR].	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	8	9
In support of this , BDNF activation of TrkB has been found to induce vascular endothelial growth factor ( VEGF ) expression via hypoxia inducible factor-1-alpha ( HIF-1-alpha ) in neuroblastoma cells [ XREF_BIBR ] .	In support of this, BDNF activation of TrkB has been found to induce vascular endothelial growth factor (VEGF) expression via hypoxia inducible factor-1-alpha (HIF-1-alpha) in neuroblastoma cells [XREF_BIBR].	5	22	activation	Positive_regulation_syntax_3_noun	Positive_activation	Positive_regulation	BDNF	BDNF	bdnf	TrkB	TrkB has been found to induce vascular endothelial growth factor (VEGF) expression	trkb	5	6	8	9
The decreased N-methyl-D-aspartate receptor ( NMDAR ) levels and sustained activation of TrkB by BDNF could serve as protective mechanisms for Muller cell survival .	The decreased N-methyl-D-aspartate receptor (NMDAR) levels and sustained activation of TrkB by BDNF could serve as protective mechanisms for Muller cell survival.	7	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	12	13
Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation .	Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation.	1	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	12	13
These results suggest that BDNF released from postsynaptic cells activates presynaptic TrkB , leading to LTP .	These results suggest that BDNF released from postsynaptic cells activates presynaptic TrkB, leading to LTP.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	11	12
BDNF activation triggers changes in TrkB mediated intracellular signaling and transcription factor activity .	BDNF activation triggers changes in TrkB mediated intracellular signaling and transcription factor activity.	0	6	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	5	6
Whereas proBDNF preferentially acts at the NGF receptor , p75NTR , mature BDNF tends to selectively activate TrkB .	Whereas proBDNF preferentially acts at the NGF receptor, p75NTR, mature BDNF tends to selectively activate TrkB.	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	17	18
To determine if the TrkB dependent collapse of Cl - gradient and inhibitory signaling induced by SL is mediated by BDNF , we examined the effects of DBB stimulation on MNCs in hypothalamic explants from SL rats having normal and reduced expression of BDNF within the supraoptic nucleus .	To determine if the TrkB dependent collapse of Cl - gradient and inhibitory signaling induced by SL is mediated by BDNF, we examined the effects of DBB stimulation on MNCs in hypothalamic explants from SL rats having normal and reduced expression of BDNF within the supraoptic nucleus.	4	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	4	5
In our studies , we found a significant elevation in pTrkB 10 min after BDNF injection into either the core or shell , indicating that infused BDNF triggered TrkB activation .	In our studies, we found a significant elevation in pTrkB 10 min after BDNF injection into either the core or shell, indicating that infused BDNF triggered TrkB activation.	25	29	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	26	27	28	29
The lithium neuroprotection requires BDNF induction and activation of its receptor TrkB , and is associated with upregulation of Bcl-2 , downregulation of the pro apoptotic proteins p53 and Bax , and inhibition of caspase-3 .	The lithium neuroprotection requires BDNF induction and activation of its receptor TrkB, and is associated with upregulation of Bcl-2, downregulation of the pro apoptotic proteins p53 and Bax, and inhibition of caspase-3.	4	12	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	11	12
Activation of TrkB by BDNF affects several intracellular cascades that influence neuronal repair and survival , and so modulation of the receptor is of interest from a therapeutic standpoint .	Activation of TrkB by BDNF affects several intracellular cascades that influence neuronal repair and survival, and so modulation of the receptor is of interest from a therapeutic standpoint.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
This indicates that the contribution of BDNF mediated TrkB activation is a necessary event in EE mediated neuroprotection against chronic HH .	This indicates that the contribution of BDNF mediated TrkB activation is a necessary event in EE mediated neuroprotection against chronic HH.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
To determine how SH2B1beta promotes BDNF induced neurite outgrowth , PC12-GFP+ TrkB and PC12-SH2B1beta+ TrkB cell lines were treated with 50 ng/ml BDNF for 5 , 10 , 30 and 60 min .	To determine how SH2B1beta promotes BDNF induced neurite outgrowth, PC12-GFP+ TrkB and PC12-SH2B1beta+ TrkB cell lines were treated with 50 ng/ml BDNF for 5, 10, 30 and 60 min.	10	31	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	22	23	11	12
Additionally , TrkB receptors activated by 7,8-DHF are not degraded , but instead are recycled to the cell surface after internalization , as opposed to BDNF activated TrkB receptors , which are tagged for ubiquitination and degraded after internalization ( Liu et al ., 2014 ) .	Additionally, TrkB receptors activated by 7,8-DHF are not degraded, but instead are recycled to the cell surface after internalization, as opposed to BDNF activated TrkB receptors, which are tagged for ubiquitination and degraded after internalization (Liu et al., 2014).	25	28	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	25	26	27	28
Immunoblotting with a p-TrkB antibody showed that both unmodified BDNF and biotin-BDNF were able to induce TrkB activation ( XREF_FIG ) .	Immunoblotting with a p-TrkB antibody showed that both unmodified BDNF and biotin-BDNF were able to induce TrkB activation (XREF_FIG).	7	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	16	17
To determine whether increased BDNF levels could lead to TrkB activation , we evaluated the p-TrkB levels using immunoprecipitation with the TrkB antibody and immunoblotting with the phosphotyrosine antibody ( XREF_FIG ) .	To determine whether increased BDNF levels could lead to TrkB activation, we evaluated the p-TrkB levels using immunoprecipitation with the TrkB antibody and immunoblotting with the phosphotyrosine antibody (XREF_FIG).	4	10	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF levels	bdnf	TrkB	TrkB	trkb	4	5	9	10
31 Stimulation of TrkB by BDNF enhanced invasion and migration of HNSCC cells .	31 Stimulation of TrkB by BDNF enhanced invasion and migration of HNSCC cells.	1	6	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	3	4
BDNF can activate the high-affinity receptor TrkB as well as the low-affinity pan-NT receptor p75NTR , both which have been previously shown to be expressed by human ASM cells [ XREF_BIBR ] .	BDNF can activate the high-affinity receptor TrkB as well as the low-affinity pan-NT receptor p75NTR, both which have been previously shown to be expressed by human ASM cells [XREF_BIBR].	0	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	6	7
Several observations from our study support the hypothesis that this form of LTP is mediated by BDNF activated TrkB signaling .	Several observations from our study support the hypothesis that this form of LTP is mediated by BDNF activated TrkB signaling.	14	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	18	19
Here we report that caffeine , at concentrations representing moderate to high levels of consumption in humans , induces an NMDA receptor independent form of LTP ( CAF LTP ) in the CA1 region of the hippocampus by promoting calcium dependent secretion of BDNF , which subsequently activates TrkB mediated signaling required for the expression of CAF LTP .	Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor independent form of LTP (CAF LTP) in the CA1 region of the hippocampus by promoting calcium dependent secretion of BDNF, which subsequently activates TrkB mediated signaling required for the expression of CAF LTP.	41	50	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	43	44	48	49
This mutation has little or no effect on BDNF mediated TrkB signaling .	This mutation has little or no effect on BDNF mediated TrkB signaling.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
BDNF activates its high-affinity receptor TrkB and promotes neuronal survival ; restoring BDNF signaling is thus of particular therapeutic interest .	BDNF activates its high-affinity receptor TrkB and promotes neuronal survival; restoring BDNF signaling is thus of particular therapeutic interest.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	5	6
To determine the importance of BBS4 in BDNF dependent ciliary localization of TRKB , we examined shBBS4 transfected cells treated with BDNF for 24 hours and immunostained for TRKB as well as ciliary markers .	To determine the importance of BBS4 in BDNF dependent ciliary localization of TRKB, we examined shBBS4 transfected cells treated with BDNF for 24 hours and immunostained for TRKB as well as ciliary markers.	10	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	21	22	12	13
It is usually assumed that in the adult brain that BDNF is released by axon terminals and activates TrkB in the post-synaptic cell .	It is usually assumed that in the adult brain that BDNF is released by axon terminals and activates TrkB in the post-synaptic cell.	10	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	18	19
The TrkB activation by BDNF was shown to enhance the proliferation and survival of transitional cell carcinoma cell lines , whereas a TrkB antagonist suppressed their migration and invasion .	The TrkB activation by BDNF was shown to enhance the proliferation and survival of transitional cell carcinoma cell lines, whereas a TrkB antagonist suppressed their migration and invasion.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	1	2
The location of the trkB receptors that are activated by endogenously released BDNF in the present study is most likely on dendrites of postsynaptic pyramidal neurons in layer 2/3 .	The location of the trkB receptors that are activated by endogenously released BDNF in the present study is most likely on dendrites of postsynaptic pyramidal neurons in layer 2/3.	4	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	12	13	4	5
Importantly , BDNF yielded higher phospho-TrkB levels in WT compared to R6/2 cultures , indicating that BDNF induced activation of TrkB is blunted in R6/2 cultures .	Importantly, BDNF yielded higher phospho-TrkB levels in WT compared to R6/2 cultures, indicating that BDNF induced activation of TrkB is blunted in R6/2 cultures.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	20	21
BDNF stimulation increased the association of TrkB with NMDAR in both groups .	BDNF stimulation increased the association of TrkB with NMDAR in both groups.	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	6	7
In order to ascertain whether BDNF activation of TrkB was linked with exercise induced neuroprotection , rats were given K252a , a known inhibitor of TrkB receptors [ XREF_BIBR ] .	In order to ascertain whether BDNF activation of TrkB was linked with exercise induced neuroprotection, rats were given K252a, a known inhibitor of TrkB receptors [XREF_BIBR].	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	8	9
We found that TrkB and TrkC , the receptors for brain derived neurotrophic factor ( BDNF ) and neurotrophin-3 ( NT-3 ) , are activated by epidermal growth factor receptor ( EGFR ) signaling rather than by BDNF or NT-3 in embryonic mouse cortical precursor cells .	We found that TrkB and TrkC, the receptors for brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are activated by epidermal growth factor receptor (EGFR) signaling rather than by BDNF or NT-3 in embryonic mouse cortical precursor cells.	3	39	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	37	38	3	4
One mechanism by which CORT or stressor exposure during adolescence may impact PFC dependent behaviors later in life is by reducing BDNF dependent stimulation of trkB .	One mechanism by which CORT or stressor exposure during adolescence may impact PFC dependent behaviors later in life is by reducing BDNF dependent stimulation of trkB.	21	26	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	21	22	25	26
BDNF activates TRKB on the cell surface , which leads to the initiation of intracellular signaling cascades and different biological responses in neurons .	BDNF activates TRKB on the cell surface, which leads to the initiation of intracellular signaling cascades and different biological responses in neurons.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	0	1	2	3
Release of BDNF could stimulate TrkB receptors and PI3K-Akt and ERK signaling , which is required for ketamine activation of mTOR .	Release of BDNF could stimulate TrkB receptors and PI3K-Akt and ERK signaling, which is required for ketamine activation of mTOR.	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	5	6
21 After BDNF mediated activation of TrkB , signals are mediated by different intracellular cascades , of which the Ras and ERK-MAPK pathway is one of the most prominent .	21 After BDNF mediated activation of TrkB, signals are mediated by different intracellular cascades, of which the Ras and ERK-MAPK pathway is one of the most prominent.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	6	7
An alternative explanation is that E2 releases BDNF which then stimulates TrkB receptors through conventional ligand binding .	An alternative explanation is that E2 releases BDNF which then stimulates TrkB receptors through conventional ligand binding.	5	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	11	12
There is evidence to suggest that primary cilia in epithelial cells are enriched for lipid rafts XREF_BIBR , supporting our observation that the presence of BDNF triggers localization of TRKB to the cilium .	There is evidence to suggest that primary cilia in epithelial cells are enriched for lipid rafts XREF_BIBR, supporting our observation that the presence of BDNF triggers localization of TRKB to the cilium.	23	30	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	25	26	29	30
BDNF activation of TrkB , as well as the trafficking of this receptor , is cAMP dependent [ XREF_BIBR ] .	BDNF activation of TrkB, as well as the trafficking of this receptor, is cAMP dependent [XREF_BIBR].	0	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
Note that although an increase in TrkB endocytosis was observed in endophilin A1 depleted cells , this effect is statistically insignificant , indicating that only retrolinkin is required for BDNF triggered TrkB internalization .	Note that although an increase in TrkB endocytosis was observed in endophilin A1 depleted cells, this effect is statistically insignificant, indicating that only retrolinkin is required for BDNF triggered TrkB internalization.	27	32	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	29	30	31	32
BDNF activation of the TrkB receptor leads to induction of Egr3 synthesis via a PKC and MAPK dependent pathway .	BDNF activation of the TrkB receptor leads to induction of Egr3 synthesis via a PKC and MAPK dependent pathway.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
Specifically , TrkB activation by BDNF promotes cell growth and induces drug resistant neuroblastoma phenotypes XREF_BIBR - XREF_BIBR .	Specifically, TrkB activation by BDNF promotes cell growth and induces drug resistant neuroblastoma phenotypes XREF_BIBR - XREF_BIBR.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	2	3
As dopamine afferents to the striatum also express BDNF , which activates TRKB receptors , a possible interaction between DA and BDNF and TRKB signalling exists .	As dopamine afferents to the striatum also express BDNF, which activates TRKB receptors, a possible interaction between DA and BDNF and TRKB signalling exists.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	8	9	12	13
We used a cell surface biotinylation assay ( EZ-Link LC-Biotin , Thermo ) to measure whether BDNF induced TrkB internalization was at all affected by IL-1beta over the relevant timecourse of IL-1beta treatment .	We used a cell surface biotinylation assay (EZ-Link LC-Biotin, Thermo) to measure whether BDNF induced TrkB internalization was at all affected by IL-1beta over the relevant timecourse of IL-1beta treatment.	16	19	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	18	19
More recently , the high affinity TrkB receptor activation , induced by its specific ligand BDNF , has been demonstrated to induce an EMT like transformation in epithelial cells through a Twist-Snail signaling axis , which is dependent on the MAPK pathway [ XREF_BIBR ] .	More recently, the high affinity TrkB receptor activation, induced by its specific ligand BDNF, has been demonstrated to induce an EMT like transformation in epithelial cells through a Twist-Snail signaling axis, which is dependent on the MAPK pathway [XREF_BIBR].	6	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	6	7
Thus , these findings suggest that BDNF released from small-diameter TRG neurons upregulates trkB through an paracrine and autocrine mechanism , increasing spontaneous activity and triggering the release of chemical neuromodulators ( CGRP , SP and ATP ) which act on the neighboring neurons or satellite glial cells via a similar mechanism [ XREF_BIBR - XREF_BIBR , XREF_BIBR ] .	Thus, these findings suggest that BDNF released from small-diameter TRG neurons upregulates trkB through an paracrine and autocrine mechanism, increasing spontaneous activity and triggering the release of chemical neuromodulators (CGRP, SP and ATP) which act on the neighboring neurons or satellite glial cells via a similar mechanism [XREF_BIBR - XREF_BIBR, XREF_BIBR].	6	14	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	6	7	13	14
Previously , we found BDNF activation of TrkB through PI3K and Akt protects NB from etoposide and cisplatin induced cell death .	Previously, we found BDNF activation of TrkB through PI3K and Akt protects NB from etoposide and cisplatin induced cell death.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	7	8
BDNF addition increased the CI of both TrkB and TrkB and p75 cells in serum-free medium , as detected by RT-CES .	BDNF addition increased the CI of both TrkB and TrkB and p75 cells in serum-free medium, as detected by RT-CES.	0	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	7	8
These data raised the hypothesis that BDNF may act as an autocrine factor on endothelial cells or in a paracrine manner to induce activation of TrkB on neighboring pericytes , to stabilize nascent blood vessels .	These data raised the hypothesis that BDNF may act as an autocrine factor on endothelial cells or in a paracrine manner to induce activation of TrkB on neighboring pericytes, to stabilize nascent blood vessels.	6	31	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	25	26
Next , to verify that retrolinkin recruits WAVE1 through CYFIP1/2 to promote actin polymerization at BDNF-TrkB endocytic sites , we overexpressed the retrolinkin C-terminus as dominant negative mutant to disrupt the interaction between full-length retrolinkin and CYFIP1/2 in neurons and monitored accumulation of F-actin around BDNF activated TrkB and pTrk .	Next, to verify that retrolinkin recruits WAVE1 through CYFIP1/2 to promote actin polymerization at BDNF-TrkB endocytic sites, we overexpressed the retrolinkin C-terminus as dominant negative mutant to disrupt the interaction between full-length retrolinkin and CYFIP1/2 in neurons and monitored accumulation of F-actin around BDNF activated TrkB and pTrk.	43	49	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	45	46	47	48
The neurotrophin brain derived neurotrophic factor ( BDNF ) supports neuronal survival during development and promotes connectivity and plasticity in the adult brain by activating its tyrosine kinase receptor TrkB .	The neurotrophin brain derived neurotrophic factor (BDNF) supports neuronal survival during development and promotes connectivity and plasticity in the adult brain by activating its tyrosine kinase receptor TrkB.	2	30	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	29	30
Furthermore , BDNF induced activation of TrkB signaling in vivo promotes prostacyclin biosynthesis by cerebral arteries XREF_BIBR .	Furthermore, BDNF induced activation of TrkB signaling in vivo promotes prostacyclin biosynthesis by cerebral arteries XREF_BIBR.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	6	7
BDNF triggers TrkB receptor dependent different intracellular signaling pathways and exhibits beneficial effect for the treatment of depression in experimental studies [ XREF_BIBR ] .	BDNF triggers TrkB receptor dependent different intracellular signaling pathways and exhibits beneficial effect for the treatment of depression in experimental studies [XREF_BIBR].	0	10	triggers	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Selective inhibition of BDNF activation of TrkB restored reversal learning this model of developmental drug exposure .	Selective inhibition of BDNF activation of TrkB restored reversal learning this model of developmental drug exposure.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	6	7
The subsequent increase in NF-kappaB transcriptional activity mediates up-regulation of TrkB , which itself is activated by its ligand BDNF signal through pAkt to enhance NF-kappaB activation , establishing an autocrine signaling loop .	The subsequent increase in NF-kappaB transcriptional activity mediates up-regulation of TrkB, which itself is activated by its ligand BDNF signal through pAkt to enhance NF-kappaB activation, establishing an autocrine signaling loop.	8	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	19	20	10	11
Depletion of Numb either by shRNA or conditional knockout impairs BDNF induced TrkB endocytosis and polarized localization of TrkB to leading processes of migrating GCPs .	Depletion of Numb either by shRNA or conditional knockout impairs BDNF induced TrkB endocytosis and polarized localization of TrkB to leading processes of migrating GCPs.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	12	13
More recent studies confirm that BDNF mediates these effects during development by activating its receptor tyrosine kinase TrkB XREF_BIBR .	More recent studies confirm that BDNF mediates these effects during development by activating its receptor tyrosine kinase TrkB XREF_BIBR.	5	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	17	18
In this region , we find that BDNF activates pre-synaptic trkB receptors to enhance spontaneous release probability , while simultaneously triggering the postsynaptic release of eCBs that act to decrease release via presynaptic CB1 receptors .	In this region, we find that BDNF activates pre-synaptic trkB receptors to enhance spontaneous release probability, while simultaneously triggering the postsynaptic release of eCBs that act to decrease release via presynaptic CB1 receptors.	7	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	7	8	10	11
The PHn-CC-EX region of Tiam1 blocks the ability of Tiam1 to bind to membranes , an essential step in its activation of Rac1 , blunts its GEF activity in COS-7 cells transfected with TrkB and treated with BDNF and interferes with BDNF stimulated morphogenesis in neurons .	The PHn-CC-EX region of Tiam1 blocks the ability of Tiam1 to bind to membranes, an essential step in its activation of Rac1, blunts its GEF activity in COS-7 cells transfected with TrkB and treated with BDNF and interferes with BDNF stimulated morphogenesis in neurons.	31	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	37	38	33	34
To determine if BDNF protects PC12 cells in the absence of TrkB receptors , PC12 cells were treated with BDNF for 24h and cell viability was evaluated by measuring released LDH ( described in Methods ) .	To determine if BDNF protects PC12 cells in the absence of TrkB receptors, PC12 cells were treated with BDNF for 24h and cell viability was evaluated by measuring released LDH (described in Methods).	11	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	19	20	11	12
The data clearly show that BDNF stimulation caused a significant increase in synaptic PFN1 and PFN2a ( XREF_FIG ) and that , in contrast to the NMDA receptor activity , both isoforms respond to BDNF induced TrkB receptor activity in the same manner .	The data clearly show that BDNF stimulation caused a significant increase in synaptic PFN1 and PFN2a (XREF_FIG) and that, in contrast to the NMDA receptor activity, both isoforms respond to BDNF induced TrkB receptor activity in the same manner.	32	38	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	34	35	36	37
Regulated expression and secretion of BDNF , which activates TrkB receptor signaling , is known to play a critical role in cognition .	Regulated expression and secretion of BDNF, which activates TrkB receptor signaling, is known to play a critical role in cognition.	1	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	expression and secretion of BDNF	bdnf	TrkB	TrkB	trkb	5	6	9	10
TrkB receptors are activated by BDNF induced formation of receptor dimers , whereupon the dimerized receptors rapidly phosphorylate each other and activate downstream signaling pathways [ XREF_BIBR - XREF_BIBR ] .	TrkB receptors are activated by BDNF induced formation of receptor dimers, whereupon the dimerized receptors rapidly phosphorylate each other and activate downstream signaling pathways [XREF_BIBR - XREF_BIBR].	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	0	1
TrkB activation by BDNF renders neuroblastoma cells resistant to chemotherapy of a whole host of mechanisms via activation of the PI3K pathway .	TrkB activation by BDNF renders neuroblastoma cells resistant to chemotherapy of a whole host of mechanisms via activation of the PI3K pathway.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	0	1
Withdrawal of BDNF from the medium after stimulation for 3 h allowed the delayed induction , which was caused at the transcriptional level and dependent upon the initial contact between exogenously added BDNF and TrkB , the effect of which was time- and dose dependent .	Withdrawal of BDNF from the medium after stimulation for 3 h allowed the delayed induction, which was caused at the transcriptional level and dependent upon the initial contact between exogenously added BDNF and TrkB, the effect of which was time- and dose dependent.	0	43	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	34	35
These findings support the conclusion that BDNF but not vesicular zinc activates TrkB in hippocampal mossy fiber axons under physiological conditions .	These findings support the conclusion that BDNF but not vesicular zinc activates TrkB in hippocampal mossy fiber axons under physiological conditions.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	12	13
In a central nervous system trauma model , using adult rat retinal ganglion cells ( RGC ) , it was observed that in vivo injection of BDNF enhanced neuronal survival by activating the TrkB , MAPK and PI3K-PKB pathways and inhibited caspase-3-induced apoptosis .	In a central nervous system trauma model, using adult rat retinal ganglion cells (RGC), it was observed that in vivo injection of BDNF enhanced neuronal survival by activating the TrkB, MAPK and PI3K-PKB pathways and inhibited caspase-3-induced apoptosis.	24	38	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	26	27	33	34
Activation of TrkB by BDNF results in the phosphorylation of several tyrosine residues and stimulation of important signaling pathways such as MAPK , PI3K and phospholipase C-gamma [ XREF_BIBR ] .	Activation of TrkB by BDNF results in the phosphorylation of several tyrosine residues and stimulation of important signaling pathways such as MAPK, PI3K and phospholipase C-gamma [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
These results suggest that MDC could effectively block BDNF induced TrkB endocytosis in hippocampal neurons .	These results suggest that MDC could effectively block BDNF induced TrkB endocytosis in hippocampal neurons.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
In their active cleaved form , each neurotrophin selectively activates one of three types of Trk receptors ( XREF_FIG ) , NGF activates TrkA , NT-3 activates TrkC , while both BDNF and NT-4 activate TrkB receptors .	In their active cleaved form, each neurotrophin selectively activates one of three types of Trk receptors (XREF_FIG), NGF activates TrkA, NT-3 activates TrkC, while both BDNF and NT-4 activate TrkB receptors.	30	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	31	32	35	36
Recent studies have further demonstrated that BDNF can be released from dendritic spines during the induction of LTP to activate TrkB receptors in the same spine to regulate sLTP .	Recent studies have further demonstrated that BDNF can be released from dendritic spines during the induction of LTP to activate TrkB receptors in the same spine to regulate sLTP.	6	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	20	21
IBS-D FSN mediated visceral hypersensitivity mice over-expressed colonic BDNF , GFAP , TrkB and SP , which were inhibited by BDNF knockdown in BDNF +/- mice .	IBS-D FSN mediated visceral hypersensitivity mice over-expressed colonic BDNF, GFAP, TrkB and SP, which were inhibited by BDNF knockdown in BDNF +/- mice.	8	21	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	12	13
In particular , microglial BDNF in the spinal cord is well established in neuronal disinhibition in neuropathic pain in the following signaling cascade : the BDNF activation of neuronal TrkB receptor , downregulation of the K + -Cl - cotransporter KCC2 , disruption of Cl - homeostasis , and hence the reduced strength of GABA A - and glycine receptor mediated inhibition .	In particular, microglial BDNF in the spinal cord is well established in neuronal disinhibition in neuropathic pain in the following signaling cascade : the BDNF activation of neuronal TrkB receptor, downregulation of the K + -Cl - cotransporter KCC2, disruption of Cl - homeostasis, and hence the reduced strength of GABA A - and glycine receptor mediated inhibition.	25	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	25	26	29	30
Electrophysiological studies reveal that one biological consequence of BDNF mediated TrkB activation locally within mossy fiber boutons may be a form of LTP of the mossy fiber-CA3 synapse that is presynaptic in both its induction and expression .	Electrophysiological studies reveal that one biological consequence of BDNF mediated TrkB activation locally within mossy fiber boutons may be a form of LTP of the mossy fiber-CA3 synapse that is presynaptic in both its induction and expression.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
These results suggest that BDNF mediated TrkB activation contributes to the EMT progression and the poor prognosis in SACC .	These results suggest that BDNF mediated TrkB activation contributes to the EMT progression and the poor prognosis in SACC.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	6	7
On the contrary , mature BDNF ( mBDNF ) selectively activates TrkB , a member of the tyrosine kinase receptors family , to promote survival and differentiation , increasing the branching of axons and dendrites and stabilizing synaptic contacts [ XREF_BIBR ] .	On the contrary, mature BDNF (mBDNF) selectively activates TrkB, a member of the tyrosine kinase receptors family, to promote survival and differentiation, increasing the branching of axons and dendrites and stabilizing synaptic contacts [XREF_BIBR].	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	11	12
Overall , BDNF signaling and activation of the TrkB receptor are thought to be required for the behavioral effects of antidepressant drugs in rodents .	Overall, BDNF signaling and activation of the TrkB receptor are thought to be required for the behavioral effects of antidepressant drugs in rodents.	2	9	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	8	9
However , given that TrkB receptor can be activated by both BDNF and NT-3 , the next logical step was to explore , in the same paradigm , specific BDNF or NT-3 deficient mice without any pharmacological treatment .	However, given that TrkB receptor can be activated by both BDNF and NT-3, the next logical step was to explore, in the same paradigm, specific BDNF or NT-3 deficient mice without any pharmacological treatment.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	4	5
Only the full-length isoform contains a tyrosine kinase domain , which mediates the downstream signaling transduction of TrkB activated by BDNF or NT4 .	Only the full-length isoform contains a tyrosine kinase domain, which mediates the downstream signaling transduction of TrkB activated by BDNF or NT4.	15	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	17	18
This stimulation induced spine loss appears to be specific to EphB receptors , since BDNF stimulation of TrkB receptors caused no detectable change in spine density in Bcr-GD-expressing neurons ( XREF_SUPPLEMENTARY ) .	This stimulation induced spine loss appears to be specific to EphB receptors, since BDNF stimulation of TrkB receptors caused no detectable change in spine density in Bcr-GD-expressing neurons (XREF_SUPPLEMENTARY).	14	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	17	18
Neuronal excitation mediated via BDNF activation of TrkB and/or signaling by metabotropic glutamate receptors , results in the dissociation of the FMRP and CYFIP1 complex from eIF4E , permitting translation .	Neuronal excitation mediated via BDNF activation of TrkB and/or signaling by metabotropic glutamate receptors, results in the dissociation of the FMRP and CYFIP1 complex from eIF4E, permitting translation.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	7	8
The phosphorylation of ERK through beta-arrestin 2 mediates the src activation , which then potentiates BDNF stimulated TrkB signaling possibly by trafficking TrkB receptors to neuronal membranes [ XREF_BIBR , XREF_BIBR ] .	The phosphorylation of ERK through beta-arrestin 2 mediates the src activation, which then potentiates BDNF stimulated TrkB signaling possibly by trafficking TrkB receptors to neuronal membranes [XREF_BIBR, XREF_BIBR].	14	18	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	17	18
Interestingly , studies that have been performed in controlled in vitro systems that involve isolated precursor cells that were derived from the dentate gyrus ( AHPCs ) have shown that BDNF induces the activation of the TrkB receptor and , consequentially , might activate signaling pathways that favor survival and neuronal differentiation .	Interestingly, studies that have been performed in controlled in vitro systems that involve isolated precursor cells that were derived from the dentate gyrus (AHPCs) have shown that BDNF induces the activation of the TrkB receptor and, consequentially, might activate signaling pathways that favor survival and neuronal differentiation.	30	43	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	30	31	36	37
Simultaneous activation of p75 NTR by proNGF , and TrkB signaling by BDNF elicited apoptosis despite TrkB phosphorylation .	Simultaneous activation of p75 NTR by proNGF, and TrkB signaling by BDNF elicited apoptosis despite TrkB phosphorylation.	9	13	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	9	10
NGF activates the TrkA receptor ; BDNF and NT-4/5 activate the TrkB receptor ; and NT-3 activates the TrkC receptor .	NGF activates the TrkA receptor; BDNF and NT-4/5 activate the TrkB receptor; and NT-3 activates the TrkC receptor.	6	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	11	12
This study showed that BDNF application to cultured hippocampal neurons in the absence of KCl stimulation was sufficient to increase dendritic levels of both BDNF and TrkB mRNAs in the presence of the transcription inhibitor , actinomycin .	This study showed that BDNF application to cultured hippocampal neurons in the absence of KCl stimulation was sufficient to increase dendritic levels of both BDNF and TrkB mRNAs in the presence of the transcription inhibitor, actinomycin.	4	27	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	26	27
Previously , we found that GSB-106 , the mimetic of BDNF , activates TrkB and its ER K and the AKT signaling pathways [ XREF_BIBR ] involved in neuronal survival and this fact could presumably underly its antidepressant effect .	Previously, we found that GSB-106, the mimetic of BDNF, activates TrkB and its ER K and the AKT signaling pathways [XREF_BIBR] involved in neuronal survival and this fact could presumably underly its antidepressant effect.	8	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	13	14
Further , BDNF activation of presynaptic TrkB within the NAc can directly stimulate dopamine neurotransmission , supporting an underlying diminution of dopamine signaling in these mice .	Further, BDNF activation of presynaptic TrkB within the NAc can directly stimulate dopamine neurotransmission, supporting an underlying diminution of dopamine signaling in these mice.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	6	7
Following TrkB activation stimulated by BDNF , the mitogen activated protein kinase and extracellular signal regulated protein kinase ( MAPK and ERK ) , phospholipase Cgamma ( PLCgamma ) , and phosphatidylinositol 3-kinase ( PI3K ) pathways are primarily triggered [ XREF_BIBR ] .	Following TrkB activation stimulated by BDNF, the mitogen activated protein kinase and extracellular signal regulated protein kinase (MAPK and ERK), phospholipase Cgamma (PLCgamma), and phosphatidylinositol 3-kinase (PI3K) pathways are primarily triggered [XREF_BIBR].	1	6	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	1	2
The activation of TrkB by BDNF leads to an enhanced PI3K and Akt signaling [ XREF_BIBR ] .	The activation of TrkB by BDNF leads to an enhanced PI3K and Akt signaling [XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	3	4
When BDNF activates TrkB signaling in dendrites , it promotes the interaction of Rab11 endosomes with Myosin Vb .	When BDNF activates TrkB signaling in dendrites, it promotes the interaction of Rab11 endosomes with Myosin Vb.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	3	4
TrkA and TrkB are differentially regulated in neuroblastoma tumor cells and , consistent with the differences in functional effects , the transcriptome regulated by NGF activation of TrkA is markedly different from the transcriptome regulated by BDNF activation of TrkB .	TrkA and TrkB are differentially regulated in neuroblastoma tumor cells and, consistent with the differences in functional effects, the transcriptome regulated by NGF activation of TrkA is markedly different from the transcriptome regulated by BDNF activation of TrkB.	36	40	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	36	37	39	40
Brain derived neurotrophic factor ( BDNF ) activation of TrkB receptors is also responsible for activation of the PI3K and Akt pathway and inhibition of GSK3beta via Ser9 phosphorylation [ XREF_BIBR - XREF_BIBR ] .	Brain derived neurotrophic factor (BDNF) activation of TrkB receptors is also responsible for activation of the PI3K and Akt pathway and inhibition of GSK3beta via Ser9 phosphorylation [XREF_BIBR - XREF_BIBR].	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	9	10
These results suggest that BDNF might be activating the TrkB receptor in immature neurons during pattern separation and that expression of BDNF might be the necessary stimulus for memory consolidation of similar representations to occur within the DG .	These results suggest that BDNF might be activating the TrkB receptor in immature neurons during pattern separation and that expression of BDNF might be the necessary stimulus for memory consolidation of similar representations to occur within the DG.	4	10	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	9	10
NGF binds TrkA receptors , NT-4 and BDNF preferentially activate TrkB receptors , and NT-3 interacts with TrkC receptors .	NGF binds TrkA receptors, NT-4 and BDNF preferentially activate TrkB receptors, and NT-3 interacts with TrkC receptors.	5	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	10	11
These conclusions are based upon the following critical findings : ( 1 ) human derived cancer associated fibroblasts potentiate in vitro invasion and in vivo metastasis in models of squamous cell cancer ( 2 ) phenotypic behavioral changes induced by CAFs are coordinated by BDNF mediated TrkB signaling axis cascade that incites a pro invasive expression profile ( 3 ) regional metastasis in mouse models of SCC is regulated in part by BDNF-TrkB signaling in the tumor microenvironment via CAFs ( 4 ) stromal specific BDNF expression predicts outcomes for patients with SCC .	These conclusions are based upon the following critical findings : (1) human derived cancer associated fibroblasts potentiate in vitro invasion and in vivo metastasis in models of squamous cell cancer (2) phenotypic behavioral changes induced by CAFs are coordinated by BDNF mediated TrkB signaling axis cascade that incites a pro invasive expression profile (3) regional metastasis in mouse models of SCC is regulated in part by BDNF-TrkB signaling in the tumor microenvironment via CAFs (4) stromal specific BDNF expression predicts outcomes for patients with SCC.	42	49	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	44	45	46	47
An Akt activity assay detected an increased Akt activity indicated by phosphorylated GSK-3alpha and beta ( Ser21/9 ) in TrkB expressing cells treated with BDNF ( XREF_FIG ) .	An Akt activity assay detected an increased Akt activity indicated by phosphorylated GSK-3alpha and beta (Ser21/9) in TrkB expressing cells treated with BDNF (XREF_FIG).	19	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	24	25	19	20
BDNF stimulation of TrkB receptors results in the activation of intracellular signaling pathways of Akt and the MAPKs extracellular signal regulated kinases 1 and 2 ( ERK 1/2 ) , thus promoting cell survival .	BDNF stimulation of TrkB receptors results in the activation of intracellular signaling pathways of Akt and the MAPKs extracellular signal regulated kinases 1 and 2 (ERK 1/2), thus promoting cell survival.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
We also find that BDNF promotes the proliferation of TrkB positive sympathoblasts in cell culture .	We also find that BDNF promotes the proliferation of TrkB positive sympathoblasts in cell culture.	4	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	9	10
These data indicate that activation of nicotinic receptors has effects upon the BDNF-TrkB pathway , inducing cell proliferation by promoting the release of BDNF , which in turn activates TrkB receptors .	These data indicate that activation of nicotinic receptors has effects upon the BDNF-TrkB pathway, inducing cell proliferation by promoting the release of BDNF, which in turn activates TrkB receptors.	21	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	23	24	29	30
Activation of TrkB by BDNF Promotes Carcinogenesis in EC .	Activation of TrkB by BDNF Promotes Carcinogenesis in EC.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
Although TrkB and TrkC could be stimulated by BDNF and NT-3 , the activation of these receptors was not affected in knockout mice lacking BDNF 14 and/or NT-3 .	Although TrkB and TrkC could be stimulated by BDNF and NT-3, the activation of these receptors was not affected in knockout mice lacking BDNF 14 and/or NT-3.	1	10	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	1	2
PC12-GFP+ TrkB and PC12-R555E+ TrkB cells were treated with 50 ng/ml BDNF for 5 , 10 , 30 and 60 min .	PC12-GFP+ TrkB and PC12-R555E+ TrkB cells were treated with 50 ng/ml BDNF for 5, 10, 30 and 60 min.	0	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	1	2
BDNF and NT4/5 activation of TrkB lead to the activation of CREB in pathological conditions XREF_BIBR .	BDNF and NT4/5 activation of TrkB lead to the activation of CREB in pathological conditions XREF_BIBR.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	5	6
The results indicate that the neuroprotective function of BDNF against hypoxia induced neurotoxicity requires the participation of TrkB and is transduced via the Ras-MAPK signaling pathway .	The results indicate that the neuroprotective function of BDNF against hypoxia induced neurotoxicity requires the participation of TrkB and is transduced via the Ras-MAPK signaling pathway.	6	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	17	18
In the presence of an axon growth inhibitory environment , agents that either activate TrkB or inhibit the binding of BDNF to p75 NTR can be used as better therapeutic candidates in CNS axon regeneration since the BDNF and p75 NTR complex potentially compromises the ability of BDNF to activate TrkB to enhance growth of axotomized CNS axons [ XREF_BIBR ] .	In the presence of an axon growth inhibitory environment, agents that either activate TrkB or inhibit the binding of BDNF to p75 NTR can be used as better therapeutic candidates in CNS axon regeneration since the BDNF and p75 NTR complex potentially compromises the ability of BDNF to activate TrkB to enhance growth of axotomized CNS axons [XREF_BIBR].	36	51	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	37	38	50	51
In the present study , we demonstrate that the majority of BDNF activated TrkB endocytosis in the somatodendritic region of hippocampal neurons is clathrin independent .	In the present study, we demonstrate that the majority of BDNF activated TrkB endocytosis in the somatodendritic region of hippocampal neurons is clathrin independent.	9	14	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	13	14
Estradiol also enhances retrograde transport of BDNF , which could directly increase TrkB activation in axons .	Estradiol also enhances retrograde transport of BDNF, which could directly increase TrkB activation in axons.	4	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	12	13
The greater BDNF induced TrkB activation in the lymphocytes of the rTMS group compared to the sham group was also reflected by the significantly higher levels of BDNF induced pY-TrkB , Shc and PLC-gamma1 recruited ( XREF_FIG ) , as well as of phosphorylated ERK ( pY-ERK ) and Akt ( pS473-akt ) ( XREF_FIG ) .	The greater BDNF induced TrkB activation in the lymphocytes of the rTMS group compared to the sham group was also reflected by the significantly higher levels of BDNF induced pY-TrkB, Shc and PLC-gamma1 recruited (XREF_FIG), as well as of phosphorylated ERK (pY-ERK) and Akt (pS473-akt) (XREF_FIG).	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	4	5
The main finding in this report is that when BDNF activates TrkB on axons or dendrites , the complex undergoes endocytosis and stimulates the de novo synthesis of proteins that are important for mutant SOD toxicity of motor neurons .	The main finding in this report is that when BDNF activates TrkB on axons or dendrites, the complex undergoes endocytosis and stimulates the de novo synthesis of proteins that are important for mutant SOD toxicity of motor neurons.	9	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	11	12
Activation of TrkB by BDNF induces chemotaxis and invasion in HNSCC .	Activation of TrkB by BDNF induces chemotaxis and invasion in HNSCC.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
In addition , upon neuropathic pain , the dorsal horn microglia produces BDNF , which stimulates the neuronal TrkB receptor and induces a shift in the chloride gradient in nociceptive neurons .	In addition, upon neuropathic pain, the dorsal horn microglia produces BDNF, which stimulates the neuronal TrkB receptor and induces a shift in the chloride gradient in nociceptive neurons.	11	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	18	19
Low doses of BDNF up-regulate trkB receptors while high doses down-regulate trkB receptors [ XREF_BIBR ] .	Low doses of BDNF up-regulate trkB receptors while high doses down-regulate trkB receptors [XREF_BIBR].	1	6	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	3	4	5	6
The activation of TrkB by BDNF triggers various signaling cascades including the Ras and mitogen activated protein ( MAP ) kinase ( Ras and MAPK ) pathway , the phosphatidylinositol 3-kinase ( PI3-Kinase )/Akt pathway and the phospholipase C gamma ( PLCgamma ) pathway .	The activation of TrkB by BDNF triggers various signaling cascades including the Ras and mitogen activated protein (MAP) kinase (Ras and MAPK) pathway, the phosphatidylinositol 3-kinase (PI3-Kinase)/Akt pathway and the phospholipase C gamma (PLCgamma) pathway.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	3	4
BDNF activates TrkB ( tropomysin related kinase B ) , which stimulates several signaling cascades , including the MAPK ( mitogen activated protein kinase ) and PI3K ( phosphatidylinositol 3-kinase )-Akt pathways .	BDNF activates TrkB (tropomysin related kinase B), which stimulates several signaling cascades, including the MAPK (mitogen activated protein kinase) and PI3K (phosphatidylinositol 3-kinase)-Akt pathways.	0	11	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
However , the anorexigenic TrkB stimulus , which is mediated by BDNF in the VMH , is under dietary control and was shown to be suppressed following fasting in mice XREF_BIBR .	However, the anorexigenic TrkB stimulus, which is mediated by BDNF in the VMH, is under dietary control and was shown to be suppressed following fasting in mice XREF_BIBR.	4	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	4	5
Activation of TrkB by BDNF invokes the mitogen activated protein ( MAP ) kinase pathway .	Activation of TrkB by BDNF invokes the mitogen activated protein (MAP) kinase pathway.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
According to such a paracrine action , BDNF secreted by cerebral capillaries into the cerebral interstitial fluid might be recognized by and activate neuronal TrkB receptors thereby increasing synapses strength and cognitive abilities .	According to such a paracrine action, BDNF secreted by cerebral capillaries into the cerebral interstitial fluid might be recognized by and activate neuronal TrkB receptors thereby increasing synapses strength and cognitive abilities.	7	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	24	25
Expression of G37R mutant superoxide dismutase ( SOD ) in motor neurons will lead to death and this depends on BDNF activation of TrkB on axons and/or dendrites .	Expression of G37R mutant superoxide dismutase (SOD) in motor neurons will lead to death and this depends on BDNF activation of TrkB on axons and/or dendrites.	20	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	23	24
Importantly , our findings suggest that BDNF activation of TrkB receptors located specifically on NAc neurons is more important for maintaining sensitivity to cocaine reward than actions at TrkB receptors located on VTA neurons .	Importantly, our findings suggest that BDNF activation of TrkB receptors located specifically on NAc neurons is more important for maintaining sensitivity to cocaine reward than actions at TrkB receptors located on VTA neurons.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	9	10
We previously demonstrated that disruption of TrkB activation using lentiviral expression of a dominant negative form of TrkB into the basolateral amygdala blocked the acquisition of fear and the consolidation of extinction , which suggests that BDNF dependent activation of TrkB in the amygdala regulates the learning of fear and extinction memories .	We previously demonstrated that disruption of TrkB activation using lentiviral expression of a dominant negative form of TrkB into the basolateral amygdala blocked the acquisition of fear and the consolidation of extinction, which suggests that BDNF dependent activation of TrkB in the amygdala regulates the learning of fear and extinction memories.	36	43	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	36	37	40	41
In the presence of epidermal growth factor ( EGF ) and basic fibroblast growth factor ( bFGF ) , DG NPCs formed neurospheres , which expressed TrkB receptor that could be activated by exogenous BDNF ( XREF_FIG ) .	In the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), DG NPCs formed neurospheres, which expressed TrkB receptor that could be activated by exogenous BDNF (XREF_FIG).	26	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	34	35	26	27
Furthermore , activation of TrkB signalling by BDNF in hypoxia enhances mechanical airway contractility to ACh through a mechanism that requires NO .	Furthermore, activation of TrkB signalling by BDNF in hypoxia enhances mechanical airway contractility to ACh through a mechanism that requires NO.	4	9	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	4	5
Similarly , in cerebellar granule neurons , the expression of p75 NTR facilitates AKT activation in response to the activation of TrkB by BDNF [ XREF_BIBR ] .	Similarly, in cerebellar granule neurons, the expression of p75 NTR facilitates AKT activation in response to the activation of TrkB by BDNF [XREF_BIBR].	19	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	23	24	21	22
Second , blood BDNF may activate the TrkB receptors of adrenal medulla during acute stress .	Second, blood BDNF may activate the TrkB receptors of adrenal medulla during acute stress.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	7	8
These results suggest that aging inhibits BDNF mediated TrkB signaling and that TMS reverses this effect .	These results suggest that aging inhibits BDNF mediated TrkB signaling and that TMS reverses this effect.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
Our results demonstrate that in cerebral arteries , BDNF induced activation of TrkB receptor signaling in vivo promotes PGI 2 biosynthesis .	Our results demonstrate that in cerebral arteries, BDNF induced activation of TrkB receptor signaling in vivo promotes PGI 2 biosynthesis.	8	14	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	12	13
These results show that injected BDNF activates TrkB related signaling cascades in the NAc core .	These results show that injected BDNF activates TrkB related signaling cascades in the NAc core.	4	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	7	8
It is possible that the differing effects that TrkB inhibition has on neurons overexpressing BDNF mRNAs could be a result of TrkB downregulation caused by overexpression of specific BDNF mRNAs , specifically mRNA with one of the 3 ' UTRs .	It is possible that the differing effects that TrkB inhibition has on neurons overexpressing BDNF mRNAs could be a result of TrkB downregulation caused by overexpression of specific BDNF mRNAs, specifically mRNA with one of the 3 ' UTRs.	21	29	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	overexpression of specific BDNF	bdnf	TrkB	TrkB	trkb	28	29	21	22
Acute administration of BDNF in the hippocampus potentiates the uptake of 5-HT by activating TrkB .	Acute administration of BDNF in the hippocampus potentiates the uptake of 5-HT by activating TrkB.	1	15	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	14	15
Similar to hTERT-RPE1 cells , however , suppression of BBS4 expression in these cells significantly reduced phosphorylation of the receptor , reducing activation to a level less than that in cells cultured in BDNF deficient media ( XREF_FIG ) , providing further support for a role for BBS4 in activation of TRKB by BDNF .	Similar to hTERT-RPE1 cells, however, suppression of BBS4 expression in these cells significantly reduced phosphorylation of the receptor, reducing activation to a level less than that in cells cultured in BDNF deficient media (XREF_FIG), providing further support for a role for BBS4 in activation of TRKB by BDNF.	40	54	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	53	54	51	52
It is therefore conceivable that the presynaptic secretion of BDNF into synaptic cleft after stimulation could activate the TrkB tag within the vicinity of the stimulated synapses .	It is therefore conceivable that the presynaptic secretion of BDNF into synaptic cleft after stimulation could activate the TrkB tag within the vicinity of the stimulated synapses.	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	18	19
Both BDNF and TrkB show high expression in the cortex , and BDNF mediated activation of TrkB is associated with dendritic growth , axonal outgrowth and synaptic plasticity .	Both BDNF and TrkB show high expression in the cortex, and BDNF mediated activation of TrkB is associated with dendritic growth, axonal outgrowth and synaptic plasticity.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	16	17
NGF specifically recognizes trkA , whereas BDNF and NT4 specifically activate trkB receptors .	NGF specifically recognizes trkA, whereas BDNF and NT4 specifically activate trkB receptors.	6	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	6	7	11	12
Our study demonstrated that CC1-EGFP inhibited TrkB anterograde axonal transport , caused less TrkB distribution in the pre-synapse and disrupted BDNF induced pre-synaptic vesicle release and TrkB retrograde signaling transmission .	Our study demonstrated that CC1-EGFP inhibited TrkB anterograde axonal transport, caused less TrkB distribution in the pre-synapse and disrupted BDNF induced pre-synaptic vesicle release and TrkB retrograde signaling transmission.	20	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	26	27
We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody , and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons .	We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	5	6
Together , these data suggest that BDNF synthesized in either VTA or NAc neurons is important for maintaining sensitivity to cocaine reward but only BDNF activation of TrkB receptors in the NAc mediates this effect .	Together, these data suggest that BDNF synthesized in either VTA or NAc neurons is important for maintaining sensitivity to cocaine reward but only BDNF activation of TrkB receptors in the NAc mediates this effect.	24	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	24	25	27	28
The BDNF induced increase in TrkB associated NMDARs and PSD-95 in hippocampus was , however , not affected by the 5-day rTMS treatment ( p = 0.17 ; XREF_TABLE ) .	The BDNF induced increase in TrkB associated NMDARs and PSD-95 in hippocampus was, however, not affected by the 5-day rTMS treatment (p = 0.17; XREF_TABLE).	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	5	6
TrkB activation by BDNF has been shown to promote the progression of several cancers , however , the existence and functional roles of both BDNF and TrkB in TCC have not been elucidated .	TrkB activation by BDNF has been shown to promote the progression of several cancers, however, the existence and functional roles of both BDNF and TrkB in TCC have not been elucidated.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	0	1
To obtain additional insights on the mechanisms underlying the role of Slitrk5 in BDNF mediated TrkB signaling , we conducted a series of biochemical and fluorescence based immunocytochemical assays .	To obtain additional insights on the mechanisms underlying the role of Slitrk5 in BDNF mediated TrkB signaling, we conducted a series of biochemical and fluorescence based immunocytochemical assays.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	13	14	15	16
Consistent with our results with TrkA in PC12 cells , TrkB is recruited into lipid rafts in cortical neurons treated with BDNF XREF_BIBR .	Consistent with our results with TrkA in PC12 cells, TrkB is recruited into lipid rafts in cortical neurons treated with BDNF XREF_BIBR.	8	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	21	22	10	11
Despite this increasing awareness of the many important roles played by BDNF activation of TrkB , a fuller understanding of this system and the use of potential TrkB acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB receptors in vivo .	Despite this increasing awareness of the many important roles played by BDNF activation of TrkB, a fuller understanding of this system and the use of potential TrkB acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB receptors in vivo.	11	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	14	15
However , BDNF activation of phospho-TrkB and phospho-Erk1/2 is attenuated , and is associated with reduced BDNF mediated survival and phenotypic maintenance of R6/2 cultures .	However, BDNF activation of phospho-TrkB and phospho-Erk1/2 is attenuated, and is associated with reduced BDNF mediated survival and phenotypic maintenance of R6/2 cultures.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	phospho-TrkB	phospho-TrkB	phospho-TrkB	2	3	5	6
BDNF , but not NT4 , targets TrkB receptor efficiently to the degradative pathway .	BDNF, but not NT4, targets TrkB receptor efficiently to the degradative pathway.	0	8	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	7	8
XREF_FIG schematically represents the involvement of calpain in mTOR signaling pathway after TrkB receptor stimulation by BDNF .	XREF_FIG schematically represents the involvement of calpain in mTOR signaling pathway after TrkB receptor stimulation by BDNF.	12	17	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	12	13
Phosphorylation of TRKB in BBS4 deficient cells treated with BDNF , however , was reduced by 53 % to a level that was statistically indistinguishable from control cells cultured in BDNF deficient media ( XREF_FIG ) .	Phosphorylation of TRKB in BBS4 deficient cells treated with BDNF, however, was reduced by 53% to a level that was statistically indistinguishable from control cells cultured in BDNF deficient media (XREF_FIG).	0	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	9	10	2	3
The Th1 cytokine IL-2 stimulated production of trkB mRNA but not of trkC , whereas the Th2 cytokine IL-4 enhanced NT-3 but not BDNF mRNA expression .	The Th1 cytokine IL-2 stimulated production of trkB mRNA but not of trkC, whereas the Th2 cytokine IL-4 enhanced NT-3 but not BDNF mRNA expression.	3	26	production	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	BDNF	BDNF mRNA expression	bdnf	trkB	trkB	trkb	23	24	7	8
In another example , BDNF mediated TrkB signaling is critical for the formation of Meissner corpuscles , but is dispensable or plays a minor role for the development of other RA mechanoreceptors .	In another example, BDNF mediated TrkB signaling is critical for the formation of Meissner corpuscles, but is dispensable or plays a minor role for the development of other RA mechanoreceptors.	4	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	6	7
To this end , PC12-GFP+ TrkB and PC12-SH2B1beta+ TrkB cells were treated with 50 ng/ml BDNF for the 5 , 10 , 30 and 60 min .	To this end, PC12-GFP+ TrkB and PC12-SH2B1beta+ TrkB cells were treated with 50 ng/ml BDNF for the 5, 10, 30 and 60 min.	4	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	5	6
Furthermore , inhibition of BDNF action with scavenger TrkB-IgG , decreased levels of BDNF and TrkB mRNAs in the dendritic compartment after KCl stimulation .	Furthermore, inhibition of BDNF action with scavenger TrkB-IgG, decreased levels of BDNF and TrkB mRNAs in the dendritic compartment after KCl stimulation.	4	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	15	16
Since NTs can be released by mast cells as well as bone marrow stromal cells , our data , together with our recent report demonstrating SM induction by BDNF mediated activation of TRKB [ XREF_BIBR ] , suggest an important role of autocrine and/or paracrine activation of TRKs in the pathogenesis of mastocytosis .	Since NTs can be released by mast cells as well as bone marrow stromal cells, our data, together with our recent report demonstrating SM induction by BDNF mediated activation of TRKB [XREF_BIBR], suggest an important role of autocrine and/or paracrine activation of TRKs in the pathogenesis of mastocytosis.	28	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	28	29	32	33
We further implemented in vivo and in vitro studies and demonstrated that BDNF mediated colon-to-bladder sensory cross activation involved the TrkB - PLCgamma-calcium and calmodulin dependent protein kinase II ( CaMKII ) cascade .	We further implemented in vivo and in vitro studies and demonstrated that BDNF mediated colon-to-bladder sensory cross activation involved the TrkB - PLCgamma-calcium and calmodulin-dependent protein kinase II (CaMKII) cascade.	12	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	20	21
Following the reports that brain derived neurotrophic factor ( BDNF ) and its tyrosine kinase receptor TrkB are often detected in NB tumors derived from patients with an unfavorable prognosis 5 , we identified that BDNF activation of TrkB attenuated the sensitivity of NB cells to chemotherapy 6 .	Following the reports that brain derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB are often detected in NB tumors derived from patients with an unfavorable prognosis 5, we identified that BDNF activation of TrkB attenuated the sensitivity of NB cells to chemotherapy 6.	35	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	35	36	38	39
This is in contrast to previously published reports about BDNF mediated activation of TrkB .	This is in contrast to previously published reports about BDNF mediated activation of TrkB.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	13	14
If our results indicating that BDNF promotes proliferation of TrkB positive sympathoblasts in the chicken embryo can be extrapolated to the subset of TrkB positive sympathoblasts in murine ganglia , then these TrkB positive cells may be neurons destined to innervate the erector pilli .	If our results indicating that BDNF promotes proliferation of TrkB positive sympathoblasts in the chicken embryo can be extrapolated to the subset of TrkB positive sympathoblasts in murine ganglia, then these TrkB positive cells may be neurons destined to innervate the erector pilli.	5	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	9	10
Neuroprotective Effects of Reactive Oxygen Species Mediated by BDNF Independent Activation of TrkB .	Neuroprotective Effects of Reactive Oxygen Species Mediated by BDNF Independent Activation of TrkB.	8	13	Activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	12	13
After activation of tyrosine kinase B ( TrkB ) receptors by BDNF , proteins such as Arc , Homer2 , LIMK1 are released .	After activation of tyrosine kinase B (TrkB) receptors by BDNF, proteins such as Arc, Homer2, LIMK1 are released.	1	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	7	8
Biochemically , the degree of channel phosphorylation by BDNF induced TrkB activation is no longer directly related to the degree of functional current suppression when adaptors are added to the mix .	Biochemically, the degree of channel phosphorylation by BDNF induced TrkB activation is no longer directly related to the degree of functional current suppression when adaptors are added to the mix.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
Moreover , inhibition of aPKC kinase activity by chelerythrine significantly prevents BDNF induced Numb ( XREF_FIG ) and TrkB polarization ( XREF_FIG ) .	Moreover, inhibition of aPKC kinase activity by chelerythrine significantly prevents BDNF induced Numb (XREF_FIG) and TrkB polarization (XREF_FIG).	11	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	18	19
Therefore , we asked whether Numb interaction with TrkB plays a role in BDNF induced TrkB endocytosis , polarization and GCP migration .	Therefore, we asked whether Numb interaction with TrkB plays a role in BDNF induced TrkB endocytosis, polarization and GCP migration.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	13	14	15	16
These BDNF induced TrkB signaling changes are caused by altered TrkB conformation and increased BDNF binding affinity resulting from dramatically reduced proBDNF and BDNF release at pre- and post-synaptic sites .	These BDNF induced TrkB signaling changes are caused by altered TrkB conformation and increased BDNF binding affinity resulting from dramatically reduced proBDNF and BDNF release at pre- and post-synaptic sites.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	3	4
Thus , while BDNF activation of TrkB receptors may facilitate dopamine release in the NAc , the relative contribution of postsynaptic TrkB receptors on medium spiny NAc neurons in addictive behavior is poorly understood .	Thus, while BDNF activation of TrkB receptors may facilitate dopamine release in the NAc, the relative contribution of postsynaptic TrkB receptors on medium spiny NAc neurons in addictive behavior is poorly understood.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	6	7
Estrogen and BDNF activate similar signal transduction pathways through estrogen receptors and trkB , respectively , and conjointly influence neural growth , survival , and plasticity in hippocampus and PFC .	Estrogen and BDNF activate similar signal transduction pathways through estrogen receptors and trkB, respectively, and conjointly influence neural growth, survival, and plasticity in hippocampus and PFC.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	2	3	12	13
By contrast , SFK activity is not essential for BDNF mediated activation of TrkB , yet SFK activity is increased as a consequence of TrkB activation by BDNF .	By contrast, SFK activity is not essential for BDNF mediated activation of TrkB, yet SFK activity is increased as a consequence of TrkB activation by BDNF.	9	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	13	14
TrkB activation by BDNF follows the general scheme for receptor tyrosine kinases and initiates three major cascades of signalling pathways : phospholipase Cgamma ( PLCgamma ) , phosphatidylinositol 3-kinase ( PI3K ) , and the well characterized cascade governed by extracellular signal regulated kinases ( ERK ) , member of the mitogen activated protein kinase ( MAPK ) family .	TrkB activation by BDNF follows the general scheme for receptor tyrosine kinases and initiates three major cascades of signalling pathways : phospholipase Cgamma (PLCgamma), phosphatidylinositol 3-kinase (PI3K), and the well characterized cascade governed by extracellular signal regulated kinases (ERK), member of the mitogen activated protein kinase (MAPK) family.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	0	1
Of note is the fact that neither ligand affected survival of EV or TrkB expressing adherent cells ( XREF_SUPPLEMENTARY ) , indicating that activation of TrkB by BDNF or NTF3 affects anoikis specifically .	Of note is the fact that neither ligand affected survival of EV or TrkB expressing adherent cells (XREF_SUPPLEMENTARY), indicating that activation of TrkB by BDNF or NTF3 affects anoikis specifically.	23	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	27	28	25	26
Our results reveal a BDNF induced TrkB translocation into the lipid rafts , and such translocation is important for BDNF induced synaptic modulation in CNS neurons .	Our results reveal a BDNF induced TrkB translocation into the lipid rafts, and such translocation is important for BDNF induced synaptic modulation in CNS neurons.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	6	7
Cortical neurons populations are known to express both TrkB and LINGO-1 and BDNF induced TrkB activity up-regulates LINGO-1 mRNA in hippocampal neurons .	Cortical neurons populations are known to express both TrkB and LINGO-1 and BDNF induced TrkB activity up-regulates LINGO-1 mRNA in hippocampal neurons.	8	15	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	14	15
BDNF activation of TrkB contributes by approximately 40 % to the increase in pERK in dorsal horn neurons following peripherally applied noxious stimuli or bath application of capsaicin in spinal slices ex vivo .	BDNF activation of TrkB contributes by approximately 40% to the increase in pERK in dorsal horn neurons following peripherally applied noxious stimuli or bath application of capsaicin in spinal slices ex vivo.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
More generally , BDNF activation of TrkB has been proposed to play a role in blocking the default pro apoptotic pathway that is theoretically present in all neurons .	More generally, BDNF activation of TrkB has been proposed to play a role in blocking the default pro apoptotic pathway that is theoretically present in all neurons.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	6	7
To understand how activation of the BDNF and TrkB pathway affected the biology of NB tumors , we and other investigators determined that BDNF activation of TrkB did not significantly alter NB cell growth , but enhanced cell survival under stress conditions such as serum starvation XREF_BIBR , XREF_BIBR .	To understand how activation of the BDNF and TrkB pathway affected the biology of NB tumors, we and other investigators determined that BDNF activation of TrkB did n't significantly alter NB cell growth, but enhanced cell survival under stress conditions such as serum starvation XREF_BIBR, XREF_BIBR.	23	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	23	24	26	27
To dissect biological actions and the signaling pathways downstream of TrkB in pericytes and SMCs , human umbilical SMCs were treated with BDNF .	To dissect biological actions and the signaling pathways downstream of TrkB in pericytes and SMCs, human umbilical SMCs were treated with BDNF.	7	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	22	23	10	11
Neurons overexpressing wild-type FGFR1 also displayed more filopodia than control neurons , in accord with our previous findings , and , notably , this elevation in filopodial density was suppressed when neurons were chronically treated from the beginning of the culture period with BDNF , the NT that specifically activates TrkB .	Neurons overexpressing wild-type FGFR1 also displayed more filopodia than control neurons, in accord with our previous findings, and, notably, this elevation in filopodial density was suppressed when neurons were chronically treated from the beginning of the culture period with BDNF, the NT that specifically activates TrkB.	34	51	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	43	44	50	51
BDNF activates TrkB , which can stimulate the mitogen activated protein kinase ( MAPK ) and phosphatidylinositol 3-kinase ( PI3K )-Akt signaling pathways .	BDNF activates TrkB, which can stimulate the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathways.	0	6	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Implantation of BDNF transfected fibroblasts into the somatosensory cortex after stroke results in upregulation of TrkB receptors in cortical neurons of the penumbra and increased neuron survival in the cortex [ XREF_BIBR ] .	Implantation of BDNF transfected fibroblasts into the somatosensory cortex after stroke results in upregulation of TrkB receptors in cortical neurons of the penumbra and increased neuron survival in the cortex [XREF_BIBR].	0	16	results in upregulation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	15	16
The neurotrophin BDNF activates the tyrosine kinase receptor TrkB and has been shown to potentiate CNTF induced oligodendrocyte survival in vitro .	The neurotrophin BDNF activates the tyrosine kinase receptor TrkB and has been shown to potentiate CNTF induced oligodendrocyte survival in vitro.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	8	9
Sympathetic neurons express TrkA and TrkC , which are not activated by BDNF , and express p75 , but not the BDNF specific TrkB .	Sympathetic neurons express TrkA and TrkC, which are not activated by BDNF, and express p75, but not the BDNF specific TrkB.	2	24	activated	Positive_regulation_syntax_2_verb	Positive_activation	Positive_regulation	BDNF	BDNF	bdnf	TrkB	express p75, but not the BDNF specific TrkB	trkb	12	13	23	24
Experiments with MeCP2 -deficient mice have shown an improvement of symptoms by the administration of a small molecule agonist to the neurotrophin receptor TrkB that is activated by BDNF .	Experiments with MeCP2 -deficient mice have shown an improvement of symptoms by the administration of a small molecule agonist to the neurotrophin receptor TrkB that is activated by BDNF.	6	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	28	29	23	24
BDNF Increased Induction of eNOS Derived NO and Enhanced Trk-B in Septic Shock Rats .	BDNF Increased Induction of eNOS Derived NO and Enhanced Trk-B in Septic Shock Rats.	0	13	Enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	Trk-B	Trk-B	Trk-B	0	1	9	10
BDNF activates TrkB receptors and induces protein synthesis dependent LTP in vitro and in vivo .	BDNF activates TrkB receptors and induces protein synthesis dependent LTP in vitro and in vivo.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
NGF activates TrkA , BDNF and NT4/5 activate TrkB , and NT3 activates TrkC .	NGF activates TrkA, BDNF and NT4/5 activate TrkB, and NT3 activates TrkC.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	8	9
We found that k252a also inhibited BDNF induced TrkB internalization in the absence of TBS ( XREF_FIG C ) , suggesting that the tyrosine kinase activity is involved in TrkB endocytosis in nonstimulated hippocampal neurons .	We found that k252a also inhibited BDNF induced TrkB internalization in the absence of TBS (XREF_FIG C), suggesting that the tyrosine kinase activity is involved in TrkB endocytosis in nonstimulated hippocampal neurons.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
Thus , it is possible that blood BDNF , in a similar manner to blood NGF , activates TrkB of adrenal medulla during acute stress .	Thus, it is possible that blood BDNF, in a similar manner to blood NGF, activates TrkB of adrenal medulla during acute stress.	6	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	18	19
However , the possible paracrine role of TrkB activation by BDNF in the brain microenvironment in metastatic Her2+ breast cancer needs to be further elucidated .	However, the possible paracrine role of TrkB activation by BDNF in the brain microenvironment in metastatic Her2+ breast cancer needs to be further elucidated.	7	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	7	8
Thus , it can be hypothesized that BDNF mediated TrkB activation may lead to a rapid modulation of ion channels in the interneuron membrane .	Thus, it can be hypothesized that BDNF mediated TrkB activation may lead to a rapid modulation of ion channels in the interneuron membrane.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	9	10
TrkB , a potent anoikis suppressor , is overexpressed in several kinds of malignancies , and BDNF mediated activation of TrkB ( ligand binding to the receptor ) contributes to anoikis resistance of cancer cells , including HCC [ XREF_BIBR ] .	TrkB, a potent anoikis suppressor, is overexpressed in several kinds of malignancies, and BDNF mediated activation of TrkB (ligand binding to the receptor) contributes to anoikis resistance of cancer cells, including HCC [XREF_BIBR].	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	20	21
It has been demonstrated that ROS act in a neuroprotective manner by BDNF independent activation of TrkB and that the neurotoxic consequences of ROS are paralleled by neuroprotective consequences [ XREF_BIBR ] .	It has been demonstrated that ROS act in a neuroprotective manner by BDNF independent activation of TrkB and that the neurotoxic consequences of ROS are paralleled by neuroprotective consequences [XREF_BIBR].	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	16	17
BDNF can also bind to p75 neurotrophin receptor ( p75 NTR ) modulating TrkB signaling .	BDNF can also bind to p75 neurotrophin receptor (p75 NTR) modulating TrkB signaling.	0	14	modulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	13	14
It is not completely clear how BDNF leads to increased TrkB activation in DRG neurons of diabetic rats .	It is not completely clear how BDNF leads to increased TrkB activation in DRG neurons of diabetic rats.	6	11	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	10	11
Each neurotrophin preferentially binds to a specific Trk : NGF activates TrkA , BDNF and NT-4/5 activate TrkB while NT-3 binds preferentially to TrkC [ XREF_BIBR ] .	Each neurotrophin preferentially binds to a specific Trk : NGF activates TrkA, BDNF and NT-4/5 activate TrkB while NT-3 binds preferentially to TrkC [XREF_BIBR].	11	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	13	14	17	18
Activation of TrkB by BDNF in G12 cells was inhibited by CEP-751 in a dose dependent fashion .	Activation of TrkB by BDNF in G12 cells was inhibited by CEP-751 in a dose dependent fashion.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
TrkB signaling mediated by BDNF but not NT-4 also suppresses these sympathetic terminations .	TrkB signaling mediated by BDNF but not NT-4 also suppresses these sympathetic terminations.	0	7	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	0	1
While trkB kinase is activated by BDNF , NT-3 , and NT-4 , but the other subtypes trkA and trkC are activated by NGF and NT-3 , respectively .	While trkB kinase is activated by BDNF, NT-3, and NT-4, but the other subtypes trkA and trkC are activated by NGF and NT-3, respectively.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	6	7	1	2
BDNF induced TrkB signaling modulates synaptic transmission by enhancing presynaptic glutamate release and increasing the open probability of postsynaptic NMDA receptor ion channel [ XREF_BIBR ] .	BDNF induced TrkB signaling modulates synaptic transmission by enhancing presynaptic glutamate release and increasing the open probability of postsynaptic NMDA receptor ion channel [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
In rat cerebellar granule neurons , BDNF induced activation of TrkB receptors resulted in a Ca 2+ dependant growth-cone turning .	In rat cerebellar granule neurons, BDNF induced activation of TrkB receptors resulted in a Ca 2+ dependant growth-cone turning.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	10	11
The fact that BDNF peptides are able to activate weakly the TrkB receptor suggests that they could act as partial agonists .	The fact that BDNF peptides are able to activate weakly the TrkB receptor suggests that they could act as partial agonists.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	11	12
These results showed that BDNF promoted the invasion of TrkB positive A549 cells probably via Pyk2 phosphorylation in Tyr402 , and the activations of both Pyk2 and ERK were participated in BDNF induced invasion of A549 cells .	These results showed that BDNF promoted the invasion of TrkB positive A549 cells probably via Pyk2 phosphorylation in Tyr402, and the activations of both Pyk2 and ERK were participated in BDNF induced invasion of A549 cells.	4	12	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	9	10
Thus , excessive activation of L-type Ca2+ channels causes granule cells to express BDNF , and extracellularly released BDNF stimulates TrkB receptors present on the hilar segment of the MFs to induce axonal branching , which may establish hyperexcitable dentate circuits .	Thus, excessive activation of L-type Ca2+ channels causes granule cells to express BDNF, and extracellularly released BDNF stimulates TrkB receptors present on the hilar segment of the MFs to induce axonal branching, which may establish hyperexcitable dentate circuits.	17	21	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	20	21
Central to the activation of pLTF is hypoxia induced release of serotonin from brainstem raphe neurons , which binds 5-HT 2 receptors of phrenic motor neurons to trigger protein synthesis of BDNF and subsequent activation of TrkB signaling that involves the downstream effectors extracellular signal regulated protein kinase ( ERK ) and Akt [ XREF_BIBR - XREF_BIBR ] .	Central to the activation of pLTF is hypoxia induced release of serotonin from brainstem raphe neurons, which binds 5-HT 2 receptors of phrenic motor neurons to trigger protein synthesis of BDNF and subsequent activation of TrkB signaling that involves the downstream effectors extracellular signal regulated protein kinase (ERK) and Akt [XREF_BIBR - XREF_BIBR].	31	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	31	32	36	37
Alternatively , it is possible that chronic overexpression of BDNF produced TrkB receptor desensitization , whereas acute injection failed to do so .	Alternatively, it is possible that chronic overexpression of BDNF produced TrkB receptor desensitization, whereas acute injection failed to do so.	7	13	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	overexpression of BDNF	bdnf	TrkB	TrkB	trkb	9	10	11	12
This phenomenon suggests that up-regulation of BDNF in DRG may , in addition to its post-synaptic effect in spinal dorsal horn , act as an autocrine and/or paracrine signal to activate the pre-synaptic trkB receptor and regulate synaptic excitability in pain transmission , thereby contributing to the development of hyperalgesia .	This phenomenon suggests that up-regulation of BDNF in DRG may, in addition to its post-synaptic effect in spinal dorsal horn, act as an autocrine and/or paracrine signal to activate the pre-synaptic trkB receptor and regulate synaptic excitability in pain transmission, thereby contributing to the development of hyperalgesia.	4	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	6	7	33	34
Furthermore , enhanced level of BDNF did not cause alteration of total TrkB or phosphorylated TrkB expression 16-20 h after the last self administration of the drug .	Furthermore, enhanced level of BDNF did not cause alteration of total TrkB or phosphorylated TrkB expression 16-20 h after the last self administration of the drug.	3	13	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	level of BDNF	bdnf	TrkB	TrkB	trkb	5	6	12	13
Studies have shown that KCC2 function is in part influenced by Brain Derived Neurotrophic Factor ( BDNF ) activation of tyrosine kinase B ( TrkB ) receptors .	Studies have shown that KCC2 function is in part influenced by Brain Derived Neurotrophic Factor (BDNF) activation of tyrosine kinase B (TrkB) receptors.	11	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Brain Derived Neurotrophic Factor	Brain Derived Neurotrophic Factor	Brain Derived Neurotrophic Factor	TrkB	TrkB	TrkB	11	15	24	25
TrkB activated by exogenous BDNF confers resistance to anoikis XREF_BIBR - XREF_BIBR , XREF_BIBR , and induces EMT through transcriptional activation of several EMT inducing transcription factors XREF_BIBR , XREF_BIBR , XREF_BIBR .	TrkB activated by exogenous BDNF confers resistance to anoikis XREF_BIBR - XREF_BIBR, XREF_BIBR, and induces EMT through transcriptional activation of several EMT inducing transcription factors XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	0	1
How does BDNF induced TrkB receptor activation enhance phrenic burst amplitude ?	How does BDNF induced TrkB receptor activation enhance phrenic burst amplitude?	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	4	5
Binding of BDNF activates TrkB , leading to activation of downstream signaling proteins , such as protein kinase B ( also known as Akt ) , which are involved in the formation of dendritic spines .	Binding of BDNF activates TrkB, leading to activation of downstream signaling proteins, such as protein kinase B (also known as Akt), which are involved in the formation of dendritic spines.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	4	5
BDNF Activation of TrkB Promotes Numb Polarization .	BDNF Activation of TrkB Promotes Numb Polarization.	0	4	Activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
In summary , our data demonstrate the ability of a BDNF loop domain mimetic to enhance TrkB activation and restore wildtype respiratory frequency in Mecp2 Het mice .	In summary, our data demonstrate the ability of a BDNF loop domain mimetic to enhance TrkB activation and restore wildtype respiratory frequency in Mecp2 Het mice.	10	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	16	17
BDNF activation of TrkB promotes the association of TrkB with Src family kinases ( SFK ) , leading to SFK activation and tyrosine phosphorylation of GluN2A and GluN2B .	BDNF activation of TrkB promotes the association of TrkB with Src family kinases (SFK), leading to SFK activation and tyrosine phosphorylation of GluN2A and GluN2B.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	8	9
The increased BDNF induced TrkB activation in the prenatal cocaine exposed brains may therefore represent a neuroprotective adaptation in response to dampened NMDAR activity [ XREF_BIBR ] .	The increased BDNF induced TrkB activation in the prenatal cocaine exposed brains may therefore represent a neuroprotective adaptation in response to dampened NMDAR activity [XREF_BIBR].	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	4	5
In humans , rTMS decreases the resting motor threshold ( RMT ) and increases BDNF induced TrkB activation in lymphocytes .	In humans, rTMS decreases the resting motor threshold (RMT) and increases BDNF induced TrkB activation in lymphocytes.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	16	17
Thus , continuous BDNF activation of TrkB is required for persistent activation of the ERK1/2 pathway and induction of NPY production .	Thus, continuous BDNF activation of TrkB is required for persistent activation of the ERK1/2 pathway and induction of NPY production.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	6	7
Thus , Erk1/2 MAPK phosphorylation could depend on the activation of TrkB induced by BDNF dependent dimerization .	Thus, Erk1/2 MAPK phosphorylation could depend on the activation of TrkB induced by BDNF dependent dimerization.	9	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	11	12
XREF_BIBR BDNF mediated TrkB signaling is important in conferring epileptogenesis in adult rats ; XREF_BIBR however the roles of TrkA and TrkC are less well understood .	XREF_BIBR BDNF mediated TrkB signaling is important in conferring epileptogenesis in adult rats; XREF_BIBR however the roles of TrkA and TrkC are less well understood.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	3	4
We then confirmed that BDNF acts on TrkB positive cells : BDNF increases the number of TrkB expressing cells that incorporate BrdU 2.6 - 4-fold over control and it also increases the overall number of TrkB positive cells 2 - 2.5-fold over control .	We then confirmed that BDNF acts on TrkB positive cells : BDNF increases the number of TrkB expressing cells that incorporate BrdU 2.6 - 4-fold over control and it also increases the overall number of TrkB positive cells 2 - 2.5-fold over control.	11	18	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	16	17
BDNF stimulated TrkB signaling activates ERK ( pT 202 / pY 204 -ERK ) and Akt ( pS 473 -Akt ) through the binding of adaptor proteins such as Shc and N-Shc to phosphotyrosine residues on activated TrkB [ XREF_BIBR ] .	BDNF stimulated TrkB signaling activates ERK (pT 202 / pY 204 -ERK) and Akt (pS 473 -Akt) through the binding of adaptor proteins such as Shc and N-Shc to phosphotyrosine residues on activated TrkB [XREF_BIBR].	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
The application of mBDNF was sufficient to rescue L-LTP when protein synthesis was inhibited ; suggesting that BDNF activated TrkB signalling is the key mechanism for L-LTP induction .	The application of mBDNF was sufficient to rescue L-LTP when protein synthesis was inhibited; suggesting that BDNF activated TrkB signalling is the key mechanism for L-LTP induction.	17	20	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	17	18	19	20
We next asked whether the loss of KIF3A would alter TRKB activation by assessing the protein levels of both TRKB and pTRKB in whole cell lysates of shKIF3A treated cells treated with BDNF .	We next asked whether the loss of KIF3A would alter TRKB activation by assessing the protein levels of both TRKB and pTRKB in whole cell lysates of shKIF3A treated cells treated with BDNF.	16	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	pTRKB	pTRKB	pTRKB	32	33	21	22
In contrast very few colonies are formed by WT TrkB cells in the absence of BDNF ( XREF_FIG ) but many are formed when WT TrkB NCM-1 cells are stimulated by BDNF ( XREF_FIG ) .	In contrast very few colonies are formed by WT TrkB cells in the absence of BDNF (XREF_FIG) but many are formed when WT TrkB NCM-1 cells are stimulated by BDNF (XREF_FIG).	25	33	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	31	32	25	26
In agreement with our previous observations , BDNF and NT4 elicit similar levels of TrkB endocytosis ( XREF_FIG ) .	In agreement with our previous observations, BDNF and NT4 elicit similar levels of TrkB endocytosis (XREF_FIG).	7	15	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	14	15
In primary cultures BDNF promotes co-precipitation of Numb and TrkB ( XREF_FIG ) .	In primary cultures BDNF promotes co-precipitation of Numb and TrkB (XREF_FIG).	3	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	9	10
Activation of trkB by BDNF ( brain derived neurotrophic factor ) accelerated Kir3 deactivation following termination of mu opioid receptor signaling .	Activation of trkB by BDNF (brain derived neurotrophic factor) accelerated Kir3 deactivation following termination of mu opioid receptor signaling.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	4	5	2	3
TrkB activation by BDNF triggers the downstream signalling including phosphorylation of ERK , Akt and PLCgamma-1 [ XREF_BIBR ] .	TrkB activation by BDNF triggers the downstream signalling including phosphorylation of ERK, Akt and PLCgamma-1 [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	0	1
They function sequentially in an early endocytic trafficking pathway for BDNF activated TrkB , which provides spatiotemporal control of downstream ERK signaling from endosomes .	They function sequentially in an early endocytic trafficking pathway for BDNF activated TrkB, which provides spatiotemporal control of downstream ERK signaling from endosomes.	8	15	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	12	13
In addition , BDNF treatment increased glomerular nephrin , TrkB , p-cofilin , F-actin , and p-Limk1 , as demonstrated by immunofluorescence and western blot ( XREF_SUPPLEMENTARY ) .	In addition, BDNF treatment increased glomerular nephrin, TrkB, p-cofilin, F-actin, and p-Limk1, as demonstrated by immunofluorescence and western blot (XREF_SUPPLEMENTARY).	3	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	9	10
Our results showed that BDNF activation of TrkB increased the TB3 cell migration and invasion in vitro , and metastasis was significantly increased in TrkB expressing TB3 tumors compared to that in non-TrkB-expressing TB3 tumors in vivo .	Our results showed that BDNF activation of TrkB increased the TB3 cell migration and invasion in vitro, and metastasis was significantly increased in TrkB expressing TB3 tumors compared to that in non-TrkB-expressing TB3 tumors in vivo.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	7	8
Similar results were obtained using the same approach to evaluate TrkB activation by exogenous BDNF in DIV7 cortical cultures prepared from WT and KalSR KO mice ( data not shown ) .	Similar results were obtained using the same approach to evaluate TrkB activation by exogenous BDNF in DIV7 cortical cultures prepared from WT and KalSR KO mice (data not shown).	10	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	10	11
Extracellular BDNF then acts in an autocrine fashion to activate TrkB signaling , including Rac1 , as well as mTORC1 signaling as reported in our recent study ( XREF_SUPPLEMENTARY ) .	Extracellular BDNF then acts in an autocrine fashion to activate TrkB signaling, including Rac1, as well as mTORC1 signaling as reported in our recent study (XREF_SUPPLEMENTARY).	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	10	11
TrkA expressing NB cells treated with NGF ( which activates MAPK ) increase the number and length of extended neurites and decrease cell proliferation resulting in a more mature neuronal appearing cell , while TrkB expressing NB cells treated with ligand ( BDNF ) increase cell proliferation without morphologic differentiation .	TrkA expressing NB cells treated with NGF (which activates MAPK) increase the number and length of extended neurites and decrease cell proliferation resulting in a more mature neuronal appearing cell, while TrkB expressing NB cells treated with ligand (BDNF) increase cell proliferation without morphologic differentiation.	34	43	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	42	43	34	35
Further , phospholipase C was a critical signaling intermediate between BDNF activation of TrkB and the initiation of NFAT dependent transcription .	Further, phospholipase C was a critical signaling intermediate between BDNF activation of TrkB and the initiation of NFAT dependent transcription.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	13	14
BDNF activation of TrkB in turn activates several intracellular cascades , including the Ras-Raf-ERK ( extracellular-signal regulated kinase ) , phosphatidylinositol-3-kinase ( PI3K )-AKT , and PLCgamma ( phospholipase Cgamma ) pathways .	BDNF activation of TrkB in turn activates several intracellular cascades, including the Ras-Raf-ERK (extracellular-signal regulated kinase), phosphatidylinositol-3-kinase (PI3K)-AKT, and PLCgamma (phospholipase Cgamma) pathways.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
The results demonstrate that BDNF induced TrkB activation and calcium entry via TRPC are both required for BDNF transcription effects .	The results demonstrate that BDNF induced TrkB activation and calcium entry via TRPC are both required for BDNF transcription effects.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	6	7
Background and aims The molecular mechanisms underlying neuropathic pain are incompletely understood , but recent data suggest that down-regulation of the chloride extruding co-transporter KCC2 in spinal cord sensory neurons is critical : Following peripheral nerve injury , activated microglia in the spinal cord release BDNF , which stimulates neuronal TrkB receptors and ultimately results in the reduction of KCC2 levels .	Background and aims The molecular mechanisms underlying neuropathic pain are incompletely understood, but recent data suggest that down-regulation of the chloride extruding co-transporter KCC2 in spinal cord sensory neurons is critical : Following peripheral nerve injury, activated microglia in the spinal cord release BDNF, which stimulates neuronal TrkB receptors and ultimately results in the reduction of KCC2 levels.	39	51	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	45	46	50	51
Quantification of these results confirmed that there was no significant difference in TrkB endocytosis between WT and Slitrk5 -/- striatal neurons after BDNF treatment ( XREF_SUPPLEMENTARY ) , in agreement with our observation of similar levels of BDNF induced TrkB activation at this time point .	Quantification of these results confirmed that there was no significant difference in TrkB endocytosis between WT and Slitrk5 -/- striatal neurons after BDNF treatment (XREF_SUPPLEMENTARY), in agreement with our observation of similar levels of BDNF induced TrkB activation at this time point.	35	40	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	37	38	39	40
BDNF induced TrkB activation was detected in lymphocytes from both sham- and rTMS treated rats , as indicated by the increased pY-TrkB levels .	BDNF induced TrkB activation was detected in lymphocytes from both sham- and rTMS treated rats, as indicated by the increased pY-TrkB levels.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Clearly , these findings support that 7,8-DHF and BDNF activate TrkB with different mechanisms .	Clearly, these findings support that 7,8-DHF and BDNF activate TrkB with different mechanisms.	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
Taken together , these results show that Myo5a mediates BDNF dependent TrkB-FL recycling and contributes to BDNF induced TrkB spine translocation and prolonged downstream signaling .	Taken together, these results show that Myo5a mediates BDNF dependent TrkB-FL recycling and contributes to BDNF induced TrkB spine translocation and prolonged downstream signaling.	14	20	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	18	19
Assessment of striatal glutamate dynamics using electrochemical recordings indicated that local application of BDNF directly induces glutamate release by activating presynaptic trkB receptors on glutamatergic terminals , and this effect followed a bell shaped dose response pattern similar to strategy shifting performance .	Assessment of striatal glutamate dynamics using electrochemical recordings indicated that local application of BDNF directly induces glutamate release by activating presynaptic trkB receptors on glutamatergic terminals, and this effect followed a bell shaped dose response pattern similar to strategy shifting performance.	11	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	13	14	21	22
Memory consolidation also requires BDNF activation of TrkB receptors in the amygdala and hippocampus .	Memory consolidation also requires BDNF activation of TrkB receptors in the amygdala and hippocampus.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	7	8
Studies using heterozygous BDNF null mice and mice overexpressing truncated TrkB ( TrkB .	Studies using heterozygous BDNF null mice and mice overexpressing truncated TrkB (TrkB.	3	12	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	10	11
These results suggest that activation of TrkB by BDNF in HuSMCs activates the Rho and ROCK pathway to induce morphological changes associated with migration in this cell population .	These results suggest that activation of TrkB by BDNF in HuSMCs activates the Rho and ROCK pathway to induce morphological changes associated with migration in this cell population.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	6	7
Since acute AD treatment increases phosphorylation of CREB , a critical upstream regulator of BDNF synthesis in a TrkB dependent manner XREF_BIBR , it is tempting to speculate that this ligand independent TrkB activation is contributing the AD induced BDNF synthesis in brain XREF_BIBR which further leads to BDNF dependent TrkB phosphorylation after prolonged AD administration .	Since acute AD treatment increases phosphorylation of CREB, a critical upstream regulator of BDNF synthesis in a TrkB dependent manner XREF_BIBR, it is tempting to speculate that this ligand independent TrkB activation is contributing the AD induced BDNF synthesis in brain XREF_BIBR which further leads to BDNF dependent TrkB phosphorylation after prolonged AD administration.	14	21	synthesis	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	18	19
Taken together , our data indicate that serotonin acts on 5-HT1 ( A ) autoreceptors , causing up-regulation of BDNF , which activates trkB to promote serotonergic phenotype specific markers .	Taken together, our data indicate that serotonin acts on 5-HT1 (A) autoreceptors, causing up-regulation of BDNF, which activates trkB to promote serotonergic phenotype specific markers.	17	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	19	20	23	24
In vitro experiments in cultured rat hippocampal neurons have shown that exposure to BDNF activates TrkB leading to downstream signaling cascades and the promotion of neurite elongation , and enlargement of the head of dendritic spines [ XREF_BIBR ] .	In vitro experiments in cultured rat hippocampal neurons have shown that exposure to BDNF activates TrkB leading to downstream signaling cascades and the promotion of neurite elongation, and enlargement of the head of dendritic spines [XREF_BIBR].	11	29	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	13	14	15	16
TrkB was not only activated by BDNF , but also could be transactivated by EGF receptor ( EGFR ) signaling , as recently shown in early neurons that form the cortical layers of the brain XREF_BIBR .	TrkB was not only activated by BDNF, but also could be transactivated by EGF receptor (EGFR) signaling, as recently shown in early neurons that form the cortical layers of the brain XREF_BIBR.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	0	1
BDNF activation of TrkB plays an important role not only in the development of CNS , but also at mature synapses and during learning and memory .	BDNF activation of TrkB plays an important role not only in the development of CNS, but also at mature synapses and during learning and memory.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
We also observed a significant decrease in the activation of TRKB in cells treated with BDNF ( XREF_FIG ) .	We also observed a significant decrease in the activation of TRKB in cells treated with BDNF (XREF_FIG).	8	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	15	16	10	11
Transgenic overexpression of BDNF enhances limbic epileptogenesis , as does direct infusion of BDNF into hippocampus of adult rodents , suggesting that excess activation of TrkB by BDNF is sufficient to promote limbic epilepsy .	Transgenic overexpression of BDNF enhances limbic epileptogenesis, as does direct infusion of BDNF into hippocampus of adult rodents, suggesting that excess activation of TrkB by BDNF is sufficient to promote limbic epilepsy.	23	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	27	28	25	26
BDNF initiates TrkB receptor dependent different intracellular signaling pathway and exhibits beneficial effect for the treatment of depression in experimental studies [ XREF_BIBR ] .	BDNF initiates TrkB receptor dependent different intracellular signaling pathway and exhibits beneficial effect for the treatment of depression in experimental studies [XREF_BIBR].	0	10	initiates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
In one condition of the AHA-SILAC media , BDNF also was included to activate the TrkB pathway .	In one condition of the AHA-SILAC media, BDNF also was included to activate the TrkB pathway.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	15	16
It is noteworthy that while increased basal activation of TrkBfull was evident in the NAc of juvenile rats compared to their adult counterparts in response to elevated BDNF levels , no effect of SKF 83959 on BDNF induced TrkB activation was observed .	It is noteworthy that while increased basal activation of TrkBfull was evident in the NAc of juvenile rats compared to their adult counterparts in response to elevated BDNF levels, no effect of SKF 83959 on BDNF induced TrkB activation was observed.	31	39	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	36	37	38	39
In rat cerebellar granule neurons , BDNF induced activation of TrkB receptors resulted in a Ca 2+ -dependent growth-cone turning .	In rat cerebellar granule neurons, BDNF induced activation of TrkB receptors resulted in a Ca 2+ -dependent growth-cone turning.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	10	11
Recent evidence has indicated that BDNF induced TrkB signaling could be a method of preventing cisplatin induced cytotoxicity in neuroblastomas and an upregulation in both BDNF and the TrKB receptor has been associated with cisplatin resistance in carcinoma cells .	Recent evidence has indicated that BDNF induced TrkB signaling could be a method of preventing cisplatin induced cytotoxicity in neuroblastomas and an upregulation in both BDNF and the TrKB receptor has been associated with cisplatin resistance in carcinoma cells.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	7	8
To test whether the activation of TrkB by BDNF can reverse the impaired STDP in the IL-mPFC of BDNF Met and Met mice , we pre-treated BDNF Met and Met brain slices with BDNF ( 25ng/ml for I-1.5 hr ) .	To test whether the activation of TrkB by BDNF can reverse the impaired STDP in the IL-mPFC of BDNF Met and Met mice, we pre-treated BDNF Met and Met brain slices with BDNF (25ng/ml for I-1.5 hr).	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	6	7
Given the clear difference in disease severity seen in the trkB heterozygotes with the less potent and immunization conditions ( XREF_FIG , XREF_TABLE ) , we asked whether there are consistent changes in neurotrophic and gliotrophic factors in EAE , including BDNF that activates trkB .	Given the clear difference in disease severity seen in the trkB heterozygotes with the less potent and immunization conditions (XREF_FIG, XREF_TABLE), we asked whether there are consistent changes in neurotrophic and gliotrophic factors in EAE, including BDNF that activates trkB.	36	45	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	41	42	44	45
Together , we propose that CTZ induced initial increase of neuronal activity may trigger BDNF release , which activates TrkB receptors and further increases neuronal activity .	Together, we propose that CTZ induced initial increase of neuronal activity may trigger BDNF release, which activates TrkB receptors and further increases neuronal activity.	14	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	19	20
After 60min of BDNF stimulation , BDNF mediated TrkB activation provoked phosphorylation of SPRED2 ( XREF_FIG ) .	After 60min of BDNF stimulation, BDNF mediated TrkB activation provoked phosphorylation of SPRED2 (XREF_FIG).	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
Importantly , the increased pTrkB-706 could indicate a BDNF mediated enhanced TrkB activation , which is linked to hyperglutamatergic activity in the hippocampus .	Importantly, the increased pTrkB-706 could indicate a BDNF mediated enhanced TrkB activation, which is linked to hyperglutamatergic activity in the hippocampus.	7	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	11	12
To demonstrate that BDNF and 7,8-dihydroxyflavone modulate dopamine release by activating the TrkB receptor , both genotypes were pretreated with K252a .	To demonstrate that BDNF and 7,8-dihydroxyflavone modulate dopamine release by activating the TrkB receptor, both genotypes were pretreated with K252a.	3	13	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	12	13
Estradiol enhances BDNF expression and release , which could increase TrkB activation in proportion to BDNF availability .	Estradiol enhances BDNF expression and release, which could increase TrkB activation in proportion to BDNF availability.	0	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	Estradiol enhances BDNF expression	bdnf	TrkB	TrkB	trkb	2	3	10	11
Brain derived neurotrophic factor mediated TrkB activation can promote neuronal synaptic activity through activation of the transcription factor cyclic adenosine monophosphate ( cAMP ) response element binding ( CREB ) , a critical signal for the formation of long-term learning and memory XREF_BIBR .	Brain derived neurotrophic factor mediated TrkB activation can promote neuronal synaptic activity through activation of the transcription factor cyclic adenosine monophosphate (cAMP) response element binding (CREB), a critical signal for the formation of long-term learning and memory XREF_BIBR.	0	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	Brain derived neurotrophic factor	Brain derived neurotrophic factor	Brain derived neurotrophic factor	TrkB	TrkB	TrkB	0	4	5	6
In the presence of Dynasore ( 80muM ) , an inhibitor of dynamin [ XREF_BIBR ] , BDNF induced TrkB internalization was suppressed , supporting the view that IL-1beta does not affect BDNF induced internalization of TrkB .	In the presence of Dynasore (80muM), an inhibitor of dynamin [XREF_BIBR], BDNF induced TrkB internalization was suppressed, supporting the view that IL-1beta does not affect BDNF induced internalization of TrkB.	14	20	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	17	18	19	20
Moreover , activation of TrkB by BDNF produces structural changes in the hippocampal dentate granule cells [ XREF_BIBR ] similar to those identified in the epileptic brain [ XREF_BIBR ] .	Moreover, activation of TrkB by BDNF produces structural changes in the hippocampal dentate granule cells [XREF_BIBR] similar to those identified in the epileptic brain [XREF_BIBR].	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	4	5
Although activation of TrkB signaling by small molecule BDNF mimetics reversed motor deficits caused by rat TBI , it did not attenuate brain tissue damage and the precise mechanisms of the protective effect were not investigated XREF_BIBR .	Although activation of TrkB signaling by small molecule BDNF mimetics reversed motor deficits caused by rat TBI, it did not attenuate brain tissue damage and the precise mechanisms of the protective effect were not investigated XREF_BIBR.	3	9	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	3	4
We have previously found that activation of TrkB by BDNF was required for fear memory formation and , separately , that GABA A R subunits and gephyrin were dynamically regulated during fear memory consolidation .	We have previously found that activation of TrkB by BDNF was required for fear memory formation and, separately, that GABA A R subunits and gephyrin were dynamically regulated during fear memory consolidation.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	7	8
Together these results indicate that Arp2/3 is required for endocytosis of BDNF activated TrkB and works downstream of the WAVE1 complex .	Together these results indicate that Arp2/3 is required for endocytosis of BDNF activated TrkB and works downstream of the WAVE1 complex.	9	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	13	14
The BDNF gradient stimulates endocytosis of TrkB and associated signaling molecules , causing asymmetric accumulation of signaling endosomes at the subcellular location where BDNF concentration is maximal .	The BDNF gradient stimulates endocytosis of TrkB and associated signaling molecules, causing asymmetric accumulation of signaling endosomes at the subcellular location where BDNF concentration is maximal.	1	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	6	7
NGF activates TrkA in sensory and sympathetic neurons XREF_BIBR , and BDNF and NT-4/5 activate TrkB in motor neurons XREF_BIBR , XREF_BIBR .	NGF activates TrkA in sensory and sympathetic neurons XREF_BIBR, and BDNF and NT-4/5 activate TrkB in motor neurons XREF_BIBR, XREF_BIBR.	11	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	15	16
The imbalance between TrkB and p75 NTR levels in a HD cellular model did not affect BDNF mediated TrkB activation of prosurvival pathways but induced activation of apoptotic cascades as demonstrated by increased JNK phosphorylation .	The imbalance between TrkB and p75 NTR levels in a HD cellular model did not affect BDNF mediated TrkB activation of prosurvival pathways but induced activation of apoptotic cascades as demonstrated by increased JNK phosphorylation.	15	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	18	19
Mechanistically , exogenous BDNF activates presynaptic TrkB receptors and enhances depolarization induced glutamate release from cortical synaptosomes via ERK dependent phosphorylation of synapsin and enhances depolarization evoked , glutamate exocytosis by activation of PLC , which induces the release of intracellular Ca ++ stores in cultured cortical neurons .	Mechanistically, exogenous BDNF activates presynaptic TrkB receptors and enhances depolarization induced glutamate release from cortical synaptosomes via ERK dependent phosphorylation of synapsin and enhances depolarization evoked, glutamate exocytosis by activation of PLC, which induces the release of intracellular Ca ++ stores in cultured cortical neurons.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	6	7
Taken together these results suggest that a BDNF induced p75 ( NTR )-mediated ACh release potentiating mechanism and a BDNF induced trkB mediated release inhibitory mechanism may contribute to developmental synapse disconnection .	Taken together these results suggest that a BDNF induced p75 (NTR)-mediated ACh release potentiating mechanism and a BDNF induced trkB mediated release inhibitory mechanism may contribute to developmental synapse disconnection.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	19	20	21	22
XREF_BIBR , XREF_BIBR We also observed that intracisternal injections of AdBDNF resulted in increased cerebral arterial expression of BDNF and subsequent activation of TrkB receptors .	XREF_BIBR, XREF_BIBR We also observed that intracisternal injections of AdBDNF resulted in increased cerebral arterial expression of BDNF and subsequent activation of TrkB receptors.	18	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	23	24
Our studies with BDNF activation of TrkB indicate that mGluR5 ( pS1126 )-Pin1 signaling couples to NMDA receptors in both D1 and D2 expressing medium spiny neurons since all cells respond to BDNF .	Our studies with BDNF activation of TrkB indicate that mGluR5 (pS1126)-Pin1 signaling couples to NMDA receptors in both D1 and D2 expressing medium spiny neurons since all cells respond to BDNF.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	6	7
These data suggest that Kv1.3 is not only modulated by direct phosphorylation in the presence of BDNF activated TrkB kinase , but also may be fine tuned via regulation of surface expression while in the proximity of neurotrophic factor receptors .	These data suggest that Kv1.3 is not only modulated by direct phosphorylation in the presence of BDNF activated TrkB kinase, but also may be fine tuned via regulation of surface expression while in the proximity of neurotrophic factor receptors.	14	25	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	18	19
BDNF activated TrkB , but caused rapid down-regulation of activated receptors and maintained only minimal survival .	BDNF activated TrkB, but caused rapid down-regulation of activated receptors and maintained only minimal survival.	0	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Insulin Growth factor-1 ( IGF-1 ) is a growth factor that , by binding to the IGF-1 receptor , activates similar intracellular signaling cascades to those triggered by BDNF activation of TrkB receptors .	Insulin Growth factor-1 (IGF-1) is a growth factor that, by binding to the IGF-1 receptor, activates similar intracellular signaling cascades to those triggered by BDNF activation of TrkB receptors.	28	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	28	29	31	32
We have reported that BDNF activation of TrkB induces an increase in VEGF production in neuronal cell lines and the increased production of VEGF is dependent on the concomitant induction of HIF-1alpha .	We have reported that BDNF activation of TrkB induces an increase in VEGF production in neuronal cell lines and the increased production of VEGF is dependent on the concomitant induction of HIF-1alpha.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	7	8
At 60min stimulation , both BDNF and 7,8-DHF substantially increase TrkB endocytosis and its early endosomal residency but 7,8-DHF seems more robust than BDNF .	At 60min stimulation, both BDNF and 7,8-DHF substantially increase TrkB endocytosis and its early endosomal residency but 7,8-DHF seems more robust than BDNF.	4	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	10	11
Together , these findings suggest that BDNF mediated TrkB activation exerts differential impact in regulating emotional response under basal and stress conditions .	Together, these findings suggest that BDNF mediated TrkB activation exerts differential impact in regulating emotional response under basal and stress conditions.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
BDNF Activated TrkB Depolarizes E GABA during SL .	BDNF Activated TrkB Depolarizes E GABA during SL.	0	5	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Transactivation of nascent TrkB in hippocampal neurons resulting from exposure to the neuropeptide PACAP caused Golgi fragmentation , whereas BDNF dependent activation of TrkB did not .	Transactivation of nascent TrkB in hippocampal neurons resulting from exposure to the neuropeptide PACAP caused Golgi fragmentation, whereas BDNF dependent activation of TrkB did not.	19	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	19	20	23	24
Consequently , BDNF stimulates TrkB receptors and leads to fast activation of the mammalian target of rapamycin ( mTOR ) signaling pathway , resulting in the augmentation of the synaptogenesis in the prefrontal cortex ( PFC ) .	Consequently, BDNF stimulates TrkB receptors and leads to fast activation of the mammalian target of rapamycin (mTOR) signaling pathway, resulting in the augmentation of the synaptogenesis in the prefrontal cortex (PFC).	2	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	4	5
Although most studies have been focused on the generation of BDNF mimetic molecules , which can activate all TrkB receptors , the present results suggest that any such effort should consider possible effects on the function of the cardiovascular system .	Although most studies have been focused on the generation of BDNF mimetic molecules, which can activate all TrkB receptors, the present results suggest that any such effort should consider possible effects on the function of the cardiovascular system.	10	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	18	19
In order to design new neuroprotective therapies based on BDNF delivery , it is important to define whether BDNF mediated TrkB signaling is affected in HD .	In order to design new neuroprotective therapies based on BDNF delivery, it is important to define whether BDNF mediated TrkB signaling is affected in HD.	18	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	20	21
BDNF activation of TrkB can be very fast , and phosphatases can shut off TrkB function in the range of minutes .	BDNF activation of TrkB can be very fast, and phosphatases can shut off TrkB function in the range of minutes.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
Also , BDNF independent activation of TrkB FL receptors has been previously demonstrated [ XREF_BIBR ] and we hypothesize that both BDNF independent and dependent activation coexist in our experimental system .	Also, BDNF independent activation of TrkB FL receptors has been previously demonstrated [XREF_BIBR] and we hypothesize that both BDNF independent and dependent activation coexist in our experimental system.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	6	7
Herein , we have genetically dissected pathways activated downstream of the TrkB receptor that are required for specific aspects of the taste system regulated by the two neurotrophins NT-4 and BDNF .	Herein, we have genetically dissected pathways activated downstream of the TrkB receptor that are required for specific aspects of the taste system regulated by the two neurotrophins NT-4 and BDNF.	7	31	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	30	31	11	12
A growing body of evidence suggests that BDNF mediated TrkB signaling is both sufficient and necessary for antidepressant like behaviors in rodents .	A growing body of evidence suggests that BDNF mediated TrkB signaling is both sufficient and necessary for antidepressant like behaviors in rodents.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	9	10
This signal has been shown to promote the granule cell survival through BDNF mediated TrkB activation , leading to Purkinje cell differentiation by increasing the granule-Purkinje cell interaction .	This signal has been shown to promote the granule cell survival through BDNF mediated TrkB activation, leading to Purkinje cell differentiation by increasing the granule-Purkinje cell interaction.	6	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	14	15
For example , BDNF mediated TrkB signaling plays a major role in the formation of peripheral Meissner corpuscles , whereas Ret signaling is shown here more critical in controlling central projections by these mechanoreceptors .	For example, BDNF mediated TrkB signaling plays a major role in the formation of peripheral Meissner corpuscles, whereas Ret signaling is shown here more critical in controlling central projections by these mechanoreceptors.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	5	6
Mature BDNF activates TrkB receptors , and activated MAPK and ERK , thereby positively impacting brain function [ XREF_BIBR ] .	Mature BDNF activates TrkB receptors, and activated MAPK and ERK, thereby positively impacting brain function [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	3	4
Studies from our laboratory indicate that a BDNF gradient stimulates the localization of TrkB containing signaling endosomes in or adjacent to the leading process of migrating GCPs .	Studies from our laboratory indicate that a BDNF gradient stimulates the localization of TrkB containing signaling endosomes in or adjacent to the leading process of migrating GCPs.	7	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	13	14
BDNF and NGF activate the TrkA and TrkB receptors , respectively and the TrkB receptors have high degree of sequence similarity between them [ XREF_BIBR ] .	BDNF and NGF activate the TrkA and TrkB receptors, respectively and the TrkB receptors have high degree of sequence similarity between them [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	7	8
Increases in GABARalpha4 subunit are transcriptionally regulated by BDNF activation of the TrkB receptor , leading to upregulation of the early growth response factor ( Egr3 ) pathway .	Increases in GABARalpha4 subunit are transcriptionally regulated by BDNF activation of the TrkB receptor, leading to upregulation of the early growth response factor (Egr3) pathway.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	12	13
BDNF , NT-3 and NT-4 can activate TRKB , while TRKA can be activated only by NGF and NT-3 .	BDNF, NT-3 and NT-4 can activate TRKB, while TRKA can be activated only by NGF and NT-3.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	0	1	7	8
BDNF mediated TrkB signaling is both sufficient and necessary for antidepressant like behaviors XREF_BIBR , XREF_BIBR .	BDNF mediated TrkB signaling is both sufficient and necessary for antidepressant like behaviors XREF_BIBR, XREF_BIBR.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
These results indicate that Akt is a key signaling component by which BDNF activation of the TrkB signal transduction pathway protects neuroblastoma cells from chemotherapy induced cell death .	These results indicate that Akt is a key signaling component by which BDNF activation of the TrkB signal transduction pathway protects neuroblastoma cells from chemotherapy induced cell death.	12	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	16	17
BDNF mediated activation of TrkB receptors induces an activation of the phosphatidylinositol 3-kinase ( PI3K ) , which , by changing the inner plasma membrane composition of inositol phospholipids , causes a translocation of Akt ( protein kinase B ) to the plasma membrane 171 .	BDNF mediated activation of TrkB receptors induces an activation of the phosphatidylinositol 3-kinase (PI3K), which, by changing the inner plasma membrane composition of inositol phospholipids, causes a translocation of Akt (protein kinase B) to the plasma membrane 171.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
LM22A-4 , on the other hand , does not bind p75 and , in addition , does not fully compete for BDNF activation of TrkB .	LM22A-4, on the other hand, does not bind p75 and, in addition, does not fully compete for BDNF activation of TrkB.	21	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	21	22	24	25
Meanwhile , mature BDNF preferentially stimulates the trkB receptor .	Meanwhile, mature BDNF preferentially stimulates the trkB receptor.	2	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	3	4	7	8
We applied QD-BDNF probes to study the internalization of BDNF activated TrkB receptors at the level of single BDNF-TrkB complexes .	We applied QD-BDNF probes to study the internalization of BDNF activated TrkB receptors at the level of single BDNF-TrkB complexes.	9	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	11	12
Likewise , activation of TrkB by Brain Derived Neurotrophic Factor ( BDNF ) leads to serine 727 ( S727 ) phosphorylation of STAT3 in hippocampal and cortical neurons .	Likewise, activation of TrkB by Brain Derived Neurotrophic Factor (BDNF) leads to serine 727 (S727) phosphorylation of STAT3 in hippocampal and cortical neurons.	2	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Brain Derived Neurotrophic Factor	Brain Derived Neurotrophic Factor	Brain Derived Neurotrophic Factor	TrkB	TrkB	TrkB	6	10	4	5
Together these data suggest that WAVE1 mediated actin dependent endocytosis of BDNF activated TrkB in the somatodendritic region of hippocampal neurons is clathrin independent .	Together these data suggest that WAVE1 mediated actin dependent endocytosis of BDNF activated TrkB in the somatodendritic region of hippocampal neurons is clathrin independent.	9	22	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	13	14
BDNF activation of TrkB receptors on SPNs is necessary to maintain normal dendritic and synaptic function [ XREF_BIBR - XREF_BIBR ] .	BDNF activation of TrkB receptors on SPNs is necessary to maintain normal dendritic and synaptic function [XREF_BIBR - XREF_BIBR].	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
We demonstrated that BDNF induced TrkB dimerization led to LIMK1 dimerization and transphosphorylation independent of TrkB kinase activity , which could further enhance the activation and stabilization of LIMK1 .	We demonstrated that BDNF induced TrkB dimerization led to LIMK1 dimerization and transphosphorylation independent of TrkB kinase activity, which could further enhance the activation and stabilization of LIMK1.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	5	6
Additionally , BDNF dependent activation of the TrkB receptor has been demonstrated to promote the physical interaction between TrkB and GGTase-I , and consequently , to increase GGTase-I prenylation activity XREF_BIBR .	Additionally, BDNF dependent activation of the TrkB receptor has been demonstrated to promote the physical interaction between TrkB and GGTase-I, and consequently, to increase GGTase-I prenylation activity XREF_BIBR.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	7	8
BDNF can also activate TrkB receptors located on presynaptic glutamatergic and GABAergic terminals .	BDNF can also activate TrkB receptors located on presynaptic glutamatergic and GABAergic terminals.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
Here , we provide evidence that NT-3 and BDNF- synthesizing cells and those producing TrkB and TrkC receptors respond to the stimulation differently in individual components of the H-reflex circuitry , as reflected by their differentiated mRNA expression .	Here, we provide evidence that NT-3 and BDNF- synthesizing cells and those producing TrkB and TrkC receptors respond to the stimulation differently in individual components of the H-reflex circuitry, as reflected by their differentiated mRNA expression.	6	18	synthesizing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF-	BDNF-	BDNF-	TrkB	TrkB	TrkB	8	9	14	15
Confocal microscopy analysis indicated that , compared with control cells , there was a significant decrease in colocalization between pTrk and phalloidin puncta in WAVE1 depleted neurons ( XREF_FIG ) , indicating that WAVE1 activity is required for actin polymerization during endocytosis of BDNF activated TrkB endocytosis .	Confocal microscopy analysis indicated that, compared with control cells, there was a significant decrease in colocalization between pTrk and phalloidin puncta in WAVE1 depleted neurons (XREF_FIG), indicating that WAVE1 activity is required for actin polymerization during endocytosis of BDNF activated TrkB endocytosis.	41	46	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	43	44	45	46
Notably , we have previously shown that BDNF activation of the TrkB receptor is required within the amygdala for consolidation of fear memories XREF_BIBR .	Notably, we have previously shown that BDNF activation of the TrkB receptor is required within the amygdala for consolidation of fear memories XREF_BIBR.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	11	12
Although all members of Slitrk family expressed in the postsynaptic compartment induce presynaptic differentiation by trans-synaptic interaction with Protein Tyrosine Phosphatases ( PRPs ) located in the presynaptic side , Slitrk5 has emerged as a TrkB receptor component that facilitates BDNF induced TrkB signaling required to dendrite morphogenesis of striatal GABAergic neurons .	Although all members of Slitrk family expressed in the postsynaptic compartment induce presynaptic differentiation by trans-synaptic interaction with Protein Tyrosine Phosphatases (PRPs) located in the presynaptic side, Slitrk5 has emerged as a TrkB receptor component that facilitates BDNF induced TrkB signaling required to dendrite morphogenesis of striatal GABAergic neurons.	40	43	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	40	41	42	43
Since the acute interference with BDNF signaling did not completely block MF-LTP , our results provide evidence that an additional mechanism besides BDNF induced TrkB signaling contributes to this type of LTP .	Since the acute interference with BDNF signaling did not completely block MF-LTP, our results provide evidence that an additional mechanism besides BDNF induced TrkB signaling contributes to this type of LTP.	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	22	23	24	25
The effect of CEP-751 on TrkB activation by BDNF was examined in G12 cells in culture by immunoprecipitation with antipan Trk antiserum , followed by Western blot analysis using antiphosphotyrosine antibodies .	The effect of CEP-751 on TrkB activation by BDNF was examined in G12 cells in culture by immunoprecipitation with antipan Trk antiserum, followed by Western blot analysis using antiphosphotyrosine antibodies.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	5	6
This mini review examines the roles of TrkB receptor activation by BDNF particularly in relation to activity dependent synaptic plasticity on Purkinje cells and recent studies on the acute modulation of GABAergic synapses by BDNF .	This mini review examines the roles of TrkB receptor activation by BDNF particularly in relation to activity dependent synaptic plasticity on Purkinje cells and recent studies on the acute modulation of GABAergic synapses by BDNF.	7	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	7	8
BDNF induced activation of TrkB is essential to synaptic plasticity and contributes to the pathogenesis of schizophrenia .	BDNF induced activation of TrkB is essential to synaptic plasticity and contributes to the pathogenesis of schizophrenia.	0	11	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
A study shows that the additional BDNF release by activated microglia increases BDNF and TrKB signaling , inducing additional microglial activation .	A study shows that the additional BDNF release by activated microglia increases BDNF and TrKB signaling, inducing additional microglial activation.	6	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrKB	TrKB	TrKB	6	7	14	15
An alternative possibility is that NMDA receptor signaling can positively modulate the BDNF signaling cascade , which could then act in an autocrine manner to activate TrkB receptors on abGCs and impact dendritic complexity .	An alternative possibility is that NMDA receptor signaling can positively modulate the BDNF signaling cascade, which could then act in an autocrine manner to activate TrkB receptors on abGCs and impact dendritic complexity.	12	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	26	27
However , BDNF also activates TrkB and plays a crucial role in OL proliferation , differentiation , and myelination XREF_BIBR XREF_BIBR .	However, BDNF also activates TrkB and plays a crucial role in OL proliferation, differentiation, and myelination XREF_BIBR XREF_BIBR.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	5	6
Binding of BDNF not only activates TrkB , it also triggers internalization of the ligand and receptor complex , which is then transported in the form of signaling endosomes to mediate downstream signaling events .	Binding of BDNF not only activates TrkB, it also triggers internalization of the ligand and receptor complex, which is then transported in the form of signaling endosomes to mediate downstream signaling events.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	6	7
While the lack of effect of methamphetamine on total TrkB is consistent with previous studies using amphetamine treatments , a possible explanation for no effect on pTrkB-706 could be that BDNF mediated TrkB activation occurs in a time dependent manner following BDNF release .	While the lack of effect of methamphetamine on total TrkB is consistent with previous studies using amphetamine treatments, a possible explanation for no effect on pTrkB-706 could be that BDNF mediated TrkB activation occurs in a time dependent manner following BDNF release.	30	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	30	31	32	33
High-frequency stimulation of neurons converts BDNF induced TrkB signaling from a transient to a sustained mode .	High-frequency stimulation of neurons converts BDNF induced TrkB signaling from a transient to a sustained mode.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	7	8
We found that , in rats , rTMS augments BDNF induced TrkB activation in both PFCX and lymphocytes , and these changes are significantly correlated .	We found that, in rats, rTMS augments BDNF induced TrkB activation in both PFCX and lymphocytes, and these changes are significantly correlated.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	11	12
Upon loss of BBS4 expression , TRKB activation by BDNF was significantly reduced .	Upon loss of BBS4 expression, TRKB activation by BDNF was significantly reduced.	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	9	10	6	7
Activation of TrkB by BDNF triggers two major intracellular cascades [ XREF_BIBR - XREF_BIBR ] , namely , the Shc and the PLCgamma pathways .	Activation of TrkB by BDNF triggers two major intracellular cascades [XREF_BIBR - XREF_BIBR], namely, the Shc and the PLCgamma pathways.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
Then the extracellular BDNF would further stimulate its membrane receptor -- TrkB and regulate gene expression and neuroplasticity through subsequent signaling .	Then the extracellular BDNF would further stimulate its membrane receptor -- TrkB and regulate gene expression and neuroplasticity through subsequent signaling.	1	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	11	12
Our previous studies have shown that BDNF activation of TrkB induces resistance to chemotherapy via activation of phosphoinositide-3-kinase ( PI3K )/Akt pathway .	Our previous studies have shown that BDNF activation of TrkB induces resistance to chemotherapy via activation of phosphoinositide-3-kinase (PI3K)/Akt pathway.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	9	10
A marked increase of phosphorylated Erk 1/2 is observed when WT TrkB HEK293 cells are treated with BDNF and DeltaIgTrkB HEK293 cells ( XREF_FIG ) albeit at significantly lower levels when compared to the BDNF stimulated WT TrkB ( XREF_FIG ) .	A marked increase of phosphorylated Erk 1/2 is observed when WT TrkB HEK293 cells are treated with BDNF and DeltaIgTrkB HEK293 cells (XREF_FIG) albeit at significantly lower levels when compared to the BDNF stimulated WT TrkB (XREF_FIG).	31	39	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	34	35	37	38
Brain derived neurotrophic factor ( BDNF ) activates its receptor TrkB , which in turn phosphorylates and activates Fyn kinase specifically bound to an SH3 binding motif in L I-II of Na V 1.2 channels .	Brain derived neurotrophic factor (BDNF) activates its receptor TrkB, which in turn phosphorylates and activates Fyn kinase specifically bound to an SH3 binding motif in L I-II of Na V 1.2 channels.	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	10	11
Studies in neuroblastoma cell lines have shown that BDNF stimulation induces TrkB mediated cell invasion XREF_BIBR .	Studies in neuroblastoma cell lines have shown that BDNF stimulation induces TrkB mediated cell invasion XREF_BIBR.	8	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	11	12
Next , we investigated whether Slitrk5 affects BDNF mediated TrkB signaling .	Next, we investigated whether Slitrk5 affects BDNF mediated TrkB signaling.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	9	10
Thus , although it is unlikely that BDNF induced TrkB translocation into lipid rafts is mediated by p75 NTR through its interaction with TrkB , our experiments could not rule out the possibility that a protein X is an intermediate for BDNF induced TrkB translocation into rafts .	Thus, although it is unlikely that BDNF induced TrkB translocation into lipid rafts is mediated by p75 NTR through its interaction with TrkB, our experiments could not rule out the possibility that a protein X is an intermediate for BDNF induced TrkB translocation into rafts.	39	44	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	41	42	43	44
BDNF activates TrkB signaling and its downstream effectors , including extracellular signal regulated kinase ( ERK ) .	BDNF activates TrkB signaling and its downstream effectors, including extracellular signal regulated kinase (ERK).	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
BDNF induced TrkB accumulation at lipid rafts was prevented by blocking the internalization of TrkB .	BDNF induced TrkB accumulation at lipid rafts was prevented by blocking the internalization of TrkB.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
These studies suggest that Slitrk5 optimally interacts with a TrkB receptor complex that is activated by BDNF .	These studies suggest that Slitrk5 optimally interacts with a TrkB receptor complex that is activated by BDNF.	9	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	9	10
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR To our opinion , it is unlikely that BDNF activates TrkB and induces Na V 1.9 activity and subsequent N-type channel gating in motoneurons .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR To our opinion, it is unlikely that BDNF activates TrkB and induces Na V 1.9 activity and subsequent N-type channel gating in motoneurons.	15	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	17	18
XREF_BIBR BDNF mediates effects of exercise on synaptic plasticity and neurogenesis by activating TrkB .	XREF_BIBR BDNF mediates effects of exercise on synaptic plasticity and neurogenesis by activating TrkB.	0	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	13	14
Western blotting analysis detected no change in the kinetics of TrkB phosphorylation in neurons depleted of retrolinkin or endophilin A1 ( XREF_FIG ) , indicating that neither protein is involved in BDNF triggered TrkB activation .	Western blotting analysis detected no change in the kinetics of TrkB phosphorylation in neurons depleted of retrolinkin or endophilin A1 (XREF_FIG), indicating that neither protein is involved in BDNF triggered TrkB activation.	29	34	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	31	32	33	34
The increased BDNF induced TrkB activation following rTMS in PFCX could have resulted from altered BDNF binding affinity , since no discernible changes in TrkB level were found .	The increased BDNF induced TrkB activation following rTMS in PFCX could have resulted from altered BDNF binding affinity, since no discernible changes in TrkB level were found.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	4	5
The BDNF mediated TrkB activation known to provide neuroprotection through alteration of various pathways but mainly two pathways shows utmost contribution ( ERK and PI3K pathway ) .	The BDNF mediated TrkB activation known to provide neuroprotection through alteration of various pathways but mainly two pathways shows utmost contribution (ERK and PI3K pathway).	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	3	4
Together , these data suggest that BDNF activation of TrkB receptors mediates the sequestration of membrane alpha1 subunits via differential phosphorylation pathways in hippocampal and amygdala neurons .	Together, these data suggest that BDNF activation of TrkB receptors mediates the sequestration of membrane alpha1 subunits via differential phosphorylation pathways in hippocampal and amygdala neurons.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	9	10
Here , we show that high-frequency neuronal activity converts BDNF induced TrkB ( also known as NTRK2 ) signaling from a transient to a sustained mode .	Here, we show that high-frequency neuronal activity converts BDNF induced TrkB (also known as NTRK2) signaling from a transient to a sustained mode.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	11	12
Another promising compound is the BDNF mimetic LM22A-4 , which selectively activates TrkB but not other Trk family members .	Another promising compound is the BDNF mimetic LM22A-4, which selectively activates TrkB but not other Trk family members.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	12	13
One possibility for this difference might be due to the time point analyzed , at which BDNF induces significantly higher degradation ( 73 % degradation of TrkB ) than NT4 ( 32 % degradation of TrkB ) .	One possibility for this difference might be due to the time point analyzed, at which BDNF induces significantly higher degradation (73% degradation of TrkB) than NT4 (32% degradation of TrkB).	16	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	26	27
Thus BDNF activation of TrkB amplifies neurotransmitter release , thereby stimulating and re-enforcing synaptic communication .	Thus BDNF activation of TrkB amplifies neurotransmitter release, thereby stimulating and re-enforcing synaptic communication.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	4	5
Our previous studies indicated that BDNF activation of TrkB induces chemo-resistance through activation of phosphoinositide-3-kinase ( PI3K )/Akt pathway .	Our previous studies indicated that BDNF activation of TrkB induces chemo-resistance through activation of phosphoinositide-3-kinase (PI3K)/Akt pathway.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	8	9
Of note , TRKB and TRKC are also expressed by neoplastic mast cells [ XREF_BIBR ] , and mast cells express mRNA for all NTs and release at least active NGF , NT-3 ( can activate all TRKs ) , and NT-4 ( both BDNF and NT-4 can activate TRKB ) [ XREF_BIBR ] .	Of note, TRKB and TRKC are also expressed by neoplastic mast cells [XREF_BIBR], and mast cells express mRNA for all NTs and release at least active NGF, NT-3 (can activate all TRKs), and NT-4 (both BDNF and NT-4 can activate TRKB) [XREF_BIBR].	43	50	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	44	45	49	50
XREF_BIBR , XREF_BIBR Epac dependent CRF 1 receptor signaling via the ERK-MAPK pathway has been found to potentiate BDNF stimulated TrkB signaling ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR Epac dependent CRF 1 receptor signaling via the ERK-MAPK pathway has been found to potentiate BDNF stimulated TrkB signaling (XREF_FIG).	17	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	20	21
NGF specifically activates TrkA , BDNF and NT-4/5 activates TrkB , and NT-3 is specific to TrkC [ XREF_BIBR ] .	NGF specifically activates TrkA, BDNF and NT-4/5 activates TrkB, and NT-3 is specific to TrkC [XREF_BIBR].	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	9	10
BDNF mediated TrkB activation has been found to exert contrasting effects on seizures , depending on the epilepsy model , the time of administration in the natural history of the experimental disease , and the TrkB activation or inhibition strategy .	BDNF mediated TrkB activation has been found to exert contrasting effects on seizures, depending on the epilepsy model, the time of administration in the natural history of the experimental disease, and the TrkB activation or inhibition strategy.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Spontaneous internalization of TrkB was also detected in cells not treated with BDNF , although the levels were lower ( XREF_FIG A , -BDNF ) .	Spontaneous internalization of TrkB was also detected in cells not treated with BDNF, although the levels were lower (XREF_FIG A, -BDNF).	1	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	3	4
VGLUT Upregulation Depends on TrkB Receptor Activation Specifically Induced by BDNF .	VGLUT Upregulation Depends on TrkB Receptor Activation Specifically Induced by BDNF.	4	11	Induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	4	5
Some of the effect of activity on dendritic trafficking of BDNF and TrkB mRNAs appears to result from activity induced BDNF release , because pulse application of BDNF to cultured neurons increased accumulation of BDNF and TrkB mRNAs in dendrites via a phosphatidylinositol-3 kinase ( PI3K ) dependent pathway .	Some of the effect of activity on dendritic trafficking of BDNF and TrkB mRNAs appears to result from activity induced BDNF release, because pulse application of BDNF to cultured neurons increased accumulation of BDNF and TrkB mRNAs in dendrites via a phosphatidylinositol-3 kinase (PI3K) dependent pathway.	25	37	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	27	28	36	37
TrkB overexpressing SH-SY5Y G7 cells were treated with 5.5 nM BDNF , 1.9 x E10/ml aTrkB NPs , 1.9 x E9/ml aTrkB NPs and 1.9 x E10/mL BSA linked NPs .	TrkB overexpressing SH-SY5Y G7 cells were treated with 5.5 nM BDNF, 1.9 x E10/ml aTrkB NPs, 1.9 x E9/ml aTrkB NPs and 1.9 x E10/mL BSA linked NPs.	0	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	0	1
Second , previous reports [ XREF_BIBR , XREF_BIBR ] show that EGFR is overexpressed and abnormally activated in lung cancers , and that exogenous BDNF increases TrkB activation and affects cancer cell signaling [ XREF_BIBR ] .	Second, previous reports [XREF_BIBR, XREF_BIBR] show that EGFR is overexpressed and abnormally activated in lung cancers, and that exogenous BDNF increases TrkB activation and affects cancer cell signaling [XREF_BIBR].	23	29	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	24	25	26	27
However , overexpression of BDNF has been shown to cause downregulation of TrkB receptors .	However, overexpression of BDNF has been shown to cause downregulation of TrkB receptors.	2	13	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	overexpression of BDNF	bdnf	TrkB	TrkB	trkb	4	5	12	13
BDNF activates TrkB , leading to stimulation of PI3K and formation of PIP3 ( XREF_FIG ) .	BDNF activates TrkB, leading to stimulation of PI3K and formation of PIP3 (XREF_FIG).	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
These data suggest that , at least in rodents , activation of TrkB receptors induced by BDNF is essential for the antidepressant effect .	These data suggest that, at least in rodents, activation of TrkB receptors induced by BDNF is essential for the antidepressant effect.	12	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	12	13
These events ultimately result in a protracted , if not permanent , upregulation of synaptic excitability , as BDNF induced TrkB activation enhances glutamatergic neurotransmission , rapid NMDAR subunit phosphorylation and LTP .	These events ultimately result in a protracted, if not permanent, upregulation of synaptic excitability, as BDNF induced TrkB activation enhances glutamatergic neurotransmission, rapid NMDAR subunit phosphorylation and LTP.	18	21	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	20	21
Hence , stimulation induced BDNF activation of TrkB receptors appears to be critically dependent on synaptically released zinc , concurrent activation of D1- and TrkB receptors would then act synergistically to markedly facilitate the induction of LTP in the BLA .	Hence, stimulation induced BDNF activation of TrkB receptors appears to be critically dependent on synaptically released zinc, concurrent activation of D1- and TrkB receptors would then act synergistically to markedly facilitate the induction of LTP in the BLA.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	7	8
Combined these results strongly suggest that elevation of BDNF levels increases extracellular concentrations of the neurotrophin and thereby tonically promotes TrkB activation .	Combined these results strongly suggest that elevation of BDNF levels increases extracellular concentrations of the neurotrophin and thereby tonically promotes TrkB activation.	8	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF levels	bdnf	TrkB	TrkB	trkb	8	9	20	21
Using BDNF-GFP , we show that BDNF mediated TrkB retrograde trafficking is impaired in Tg2576 axons .	Using BDNF-GFP, we show that BDNF mediated TrkB retrograde trafficking is impaired in Tg2576 axons.	6	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
The result shows that while NT-3 activates both receptors in our system , BDNF specifically activates TrkB , without affecting TrkC .	The result shows that while NT-3 activates both receptors in our system, BDNF specifically activates TrkB, without affecting TrkC.	13	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	13	14	16	17
In a recent study , Kumamaru et al observed neurotrophin receptor expression on the cell membranes of NSCs and identified the activation of TrkB by BDNF , a process that supports neuron survival and promotes differentiation of developing neurons .	In a recent study, Kumamaru et al observed neurotrophin receptor expression on the cell membranes of NSCs and identified the activation of TrkB by BDNF, a process that supports neuron survival and promotes differentiation of developing neurons.	19	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	25	26	23	24
By promoting Ret phosphorylation in a GDNF independent manner , the BDNF stimulated TrkB , causes the induction of the neurite outgrowth and expression of differentiation specific molecular markers .	By promoting Ret phosphorylation in a GDNF independent manner, the BDNF stimulated TrkB, causes the induction of the neurite outgrowth and expression of differentiation specific molecular markers.	10	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	13	14
Similar increases in ex vivo BDNF induced TrkB activation and signaling were observed in postmortem Alzheimer ' s disease brains in which NMDAR function is severely compromised [ XREF_BIBR , XREF_BIBR ] .	Similar increases in ex vivo BDNF induced TrkB activation and signaling were observed in postmortem Alzheimer 's disease brains in which NMDAR function is severely compromised [XREF_BIBR, XREF_BIBR].	1	8	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	7	8
These results suggest that GC induced increase in hippocampal TrkB activation by BDNF could mediate the enhancement of contextual fear memory induced by GC .	These results suggest that GC induced increase in hippocampal TrkB activation by BDNF could mediate the enhancement of contextual fear memory induced by GC.	9	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	9	10
In further studies , BDNF stimulation of TrkB has been shown to be capable of rescuing inactivation or loss of the polysialated head ( PSA ) of PSA-NCAM , a molecule critical for cell adhesion during the migratory process .	In further studies, BDNF stimulation of TrkB has been shown to be capable of rescuing inactivation or loss of the polysialated head (PSA) of PSA-NCAM, a molecule critical for cell adhesion during the migratory process.	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	7	8
Mature BDNF activates TrkB receptor to promote survival , growth and differentiation of select neuronal types .	Mature BDNF activates TrkB receptor to promote survival, growth and differentiation of select neuronal types.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	3	4
Similar to its intracellular effects on neurons , BDNF induced TrkB activation leads to MAPK p42/44 and AKT phosphor ylation , resulting in cyclic AMP response element binding protein activation .	Similar to its intracellular effects on neurons, BDNF induced TrkB activation leads to MAPK p42/44 and AKT phosphor ylation, resulting in cyclic AMP response element binding protein activation.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
It was previously observed that IL-1beta interferes with BDNF induced TrkB mediated signal transduction and protection of cortical neurons from apoptosis evoked by deprivation from trophic support [ Tong L ., Balazs R ., Soiampornkul R ., Thangnipon W ., Cotman C.W ., 2007 .	It was previously observed that IL-1beta interferes with BDNF induced TrkB mediated signal transduction and protection of cortical neurons from apoptosis evoked by deprivation from trophic support [Tong L., Balazs R., Soiampornkul R., Thangnipon W., Cotman C.W., 2007.	8	15	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
These findings provide evidence that the secretion of BDNF from proprioceptive sensory terminals activates TrkB receptors on GABApre neurons to promote the synaptic accumulation of GAD65 .	These findings provide evidence that the secretion of BDNF from proprioceptive sensory terminals activates TrkB receptors on GABApre neurons to promote the synaptic accumulation of GAD65.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	14	15
Previous studies have shown that BDNF activation of its cognate receptor TrkB mediates GCP migration .	Previous studies have shown that BDNF activation of its cognate receptor TrkB mediates GCP migration.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	11	12
In the absence of BDNF , only very low level of basic autophosphorylation of the fusion receptors was observed , and BDNF treatment could enhance the phospholylation of the fused TrkB receptor molecules .	In the absence of BDNF, only very low level of basic autophosphorylation of the fusion receptors was observed, and BDNF treatment could enhance the phospholylation of the fused TrkB receptor molecules.	21	32	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	21	22	30	31
Since BDNF activation of TrkB receptors functions to transiently dissociate the beta-catenin from the cadherin , while glutamatergic activation of NMDA receptors functions to increase the association , it is possible that the two systems may interact to produce the transient destabilization and re-stabilization of synapses .	Since BDNF activation of TrkB receptors functions to transiently dissociate the beta-catenin from the cadherin, while glutamatergic activation of NMDA receptors functions to increase the association, it is possible that the two systems may interact to produce the transient destabilization and re-stabilization of synapses.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	4	5
We have genetically dissected pathways activated downstream of the TrkB receptor that are required for specific aspects of the taste system controlled by the two neurotrophins NT-4 and BDNF .	We have genetically dissected pathways activated downstream of the TrkB receptor that are required for specific aspects of the taste system controlled by the two neurotrophins NT-4 and BDNF.	5	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	28	29	9	10
We further identified that ( 1 ) LINGO-1 was co-expressed with BDNF receptor , TrkB in the RGCs , and ( 2 ) BDNF combined with LINGO-1-Fc activated more TrkB in the injured retina compared to BDNF alone .	We further identified that (1) LINGO-1 was co-expressed with BDNF receptor, TrkB in the RGCs, and (2) BDNF combined with LINGO-1-Fc activated more TrkB in the injured retina compared to BDNF alone.	23	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	23	24	29	30
To examine the effects of SH2B1beta ( R555E ) on BDNF induced neurite outgrowth , PC12-GFP+ TrkB , PC12-SH2B1beta+ TrkB and PC12-R555E+ TrkB cell lines were treated with 100 ng/ml BDNF for 1 or 3 days .	To examine the effects of SH2B1beta (R555E) on BDNF induced neurite outgrowth, PC12-GFP+ TrkB, PC12-SH2B1beta+ TrkB and PC12-R555E+ TrkB cell lines were treated with 100 ng/ml BDNF for 1 or 3 days.	13	35	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	30	31	16	17
Mechanistically , the activation of TrkB by BDNF has shown to activate various intracellular signaling pathways including Akt , Src , or MAPK resulting in cell proliferation , and apoptosis resistance in models of human cancer XREF_BIBR , XREF_BIBR .	Mechanistically, the activation of TrkB by BDNF has shown to activate various intracellular signaling pathways including Akt, Src, or MAPK resulting in cell proliferation, and apoptosis resistance in models of human cancer XREF_BIBR, XREF_BIBR.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	5	6
13 Trk receptors include subtypes TrkA , TrkB , and TrkC , which are activated by nerve growth factor , BDNF , and neurotrophin-3 , respectively .	13 Trk receptors include subtypes TrkA, TrkB, and TrkC, which are activated by nerve growth factor, BDNF, and neurotrophin-3, respectively.	3	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	7	8
BDNF can stimulate TrkB receptor signaling pathways on both postsynaptic and presynaptic terminals via autocrine and paracrine pathways .	BDNF can stimulate TrkB receptor signaling pathways on both postsynaptic and presynaptic terminals via autocrine and paracrine pathways.	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
Dark rearing is known to down-regulate BDNF induced activation of TrkB receptors [ XREF_BIBR ] , despite increased BDNF protein expression [ XREF_BIBR ] .	Dark rearing is known to down-regulate BDNF induced activation of TrkB receptors [XREF_BIBR], despite increased BDNF protein expression [XREF_BIBR].	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	10	11
For example , NGF is the specific ligand of TrkA , while BDNF activates TrkB .	For example, NGF is the specific ligand of TrkA, while BDNF activates TrkB.	12	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	14	15
BDNF stimulates tumor cell disaggregation and increases the ability of TrkB expressing neuroblastoma tumor cells to degrade and invade through extracellular matrix proteins .	BDNF stimulates tumor cell disaggregation and increases the ability of TrkB expressing neuroblastoma tumor cells to degrade and invade through extracellular matrix proteins.	0	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	10	11
Although endophilin A1 is not required for BDNF triggered TrkB endocytosis , depletion of endophilin A1 impaired the acute activation of ERK1/2 .	Although endophilin A1 is not required for BDNF triggered TrkB endocytosis, depletion of endophilin A1 impaired the acute activation of ERK1/2.	7	10	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	9	10
In this case , activity dependent increases in both BDNF mRNA and protein level would result in more BDNF release , which subsequently would activate downstream TrkB signaling .	In this case, activity dependent increases in both BDNF mRNA and protein level would result in more BDNF release, which subsequently would activate downstream TrkB signaling.	18	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	26	27
It was found that BDNF activation of TrkB induced chemo-resistance in NB , and that was mainly mediated by PI3K and Akt signaling pathway .	It was found that BDNF activation of TrkB induced chemo-resistance in NB, and that was mainly mediated by PI3K and Akt signaling pathway.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	7	8
29 Available evidence suggests that overexpression of BDNF can cause tachyphylaxis of the biological response through the downregulation of TrkB and its subsequent degradation , 30 as well as replacement of functional TrkB receptors by truncated TrkB receptors lacking kinase activity .	29 Available evidence suggests that overexpression of BDNF can cause tachyphylaxis of the biological response through the downregulation of TrkB and its subsequent degradation, 30 as well as replacement of functional TrkB receptors by truncated TrkB receptors lacking kinase activity.	5	33	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	overexpression of BDNF	bdnf	TrkB	TrkB	trkb	7	8	32	33
K252a , a protein kinase inhibitor , reduced the NT-4- and BDNF induced response of the NIH3T3 and trkB cells .	K252a, a protein kinase inhibitor, reduced the NT-4- and BDNF induced response of the NIH3T3 and trkB cells.	9	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	11	12	18	19
TrkB receptor activation by BDNF results in its dimerization and in the autophosphorylation of specific tyrosine residues in its cytoplasmic kinase domain .	TrkB receptor activation by BDNF results in its dimerization and in the autophosphorylation of specific tyrosine residues in its cytoplasmic kinase domain.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	0	1
The BM derived BDNF activation of TrkB via activation of the PI-3kinase and Akt pathway desensitizes myeloma tumor cells to the drugs clinically used to treat multiple myeloma .	The BM derived BDNF activation of TrkB via activation of the PI-3kinase and Akt pathway desensitizes myeloma tumor cells to the drugs clinically used to treat multiple myeloma.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	6	7
Once released , BDNF activation of TrkB receptors can result in significant downregulation of potassium-chloride co-transporter KCC2 in dorsal horn neurons , especially those in lamina I.	Once released, BDNF activation of TrkB receptors can result in significant downregulation of potassium-chloride co-transporter KCC2 in dorsal horn neurons, especially those in lamina I.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	6	7
BDNF activates the tyrosine kinase receptor TrkB that mediates down-stream signaling cascades involved in growth and survival including phosphotidylinositol-3 kinase / Akt pathways , the c-AMP response element ( CREB ) and the Ras and Mitogen activated protein kinase pathways .	BDNF activates the tyrosine kinase receptor TrkB that mediates down-stream signaling cascades involved in growth and survival including phosphotidylinositol-3 kinase / Akt pathways, the c-AMP response element (CREB) and the Ras and Mitogen activated protein kinase pathways.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	6	7
We have shown previously that BDNF mediated TrkB activation can regulate the expression of KCC2 differentially in adult and in early postnatal neurons [ XREF_BIBR - XREF_BIBR ] .	We have shown previously that BDNF mediated TrkB activation can regulate the expression of KCC2 differentially in adult and in early postnatal neurons [XREF_BIBR - XREF_BIBR].	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	7	8
45 Alternatively , or additionally , the resultant depolarization from AMPA receptor activity can activate voltage-dependant calcium channels , allowing calcium influx and exocytosis of BDNF , which can then activate TrkB receptors , in turn setting off an intracellular signaling cascade that includes phosphorylation and thus activation of Akt ( also known as protein kinase B ) and extracellular signal regulated protein kinase ( ERK ) .	45 Alternatively, or additionally, the resultant depolarization from AMPA receptor activity can activate voltage-dependant calcium channels, allowing calcium influx and exocytosis of BDNF, which can then activate TrkB receptors, in turn setting off an intracellular signaling cascade that includes phosphorylation and thus activation of Akt (also known as protein kinase B) and extracellular signal regulated protein kinase (ERK).	21	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	25	26	31	32
Here we show that chronic high salt intake impairs baroreceptor inhibition of rat VP neurons through a brain derived neurotrophic factor ( BDNF )-dependent activation of TrkB receptors and downregulation of KCC2 expression , which prevents inhibitory GABAergic signaling .	Here we show that chronic high salt intake impairs baroreceptor inhibition of rat VP neurons through a brain derived neurotrophic factor (BDNF)-dependent activation of TrkB receptors and downregulation of KCC2 expression, which prevents inhibitory GABAergic signaling.	22	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	22	23	26	27
These results indicate that the activation of TrkB by BDNF induces the activation of PI3-K via IRS-1 and -2 rather than by a direct interaction of TrkB with PI3-K in cultured cortical neurons .	These results indicate that the activation of TrkB by BDNF induces the activation of PI3-K via IRS-1 and -2 rather than by a direct interaction of TrkB with PI3-K in cultured cortical neurons.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	7	8
Extracellular BDNF stimulates TrkB receptors on the hilar segment of the mossy fiber to induce axonal branching , which may create hyperexcitable dentate circuits [ XREF_BIBR ] .	Extracellular BDNF stimulates TrkB receptors on the hilar segment of the mossy fiber to induce axonal branching, which may create hyperexcitable dentate circuits [XREF_BIBR].	0	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	3	4
These findings support the following conclusions : ( 1 ) BDNF but not vesicular zinc promotes the activation of TrkB in the adult mouse brain under physiological conditions ; and ( 2 ) Elimination of vesicular zinc evokes a homeostatic response evident by enhanced expression of BDNF which in turn promotes activation of TrkB .	These findings support the following conclusions : (1) BDNF but not vesicular zinc promotes the activation of TrkB in the adult mouse brain under physiological conditions; and (2) Elimination of vesicular zinc evokes a homeostatic response evident by enhanced expression of BDNF which in turn promotes activation of TrkB.	44	54	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	expression of BDNF	bdnf	TrkB	TrkB	trkb	46	47	53	54
In contrast , in the mature hippocampus , TrkB activation by BDNF during seizure downregulates KCC2 .	In contrast, in the mature hippocampus, TrkB activation by BDNF during seizure downregulates KCC2.	8	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	8	9
We hypothesized that this BDNF up-regulation and subsequent activation of its receptor TrkB might play a critical role in mediating the neuroprotective effects of lithium .	We hypothesized that this BDNF up-regulation and subsequent activation of its receptor TrkB might play a critical role in mediating the neuroprotective effects of lithium.	4	13	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	12	13
Moreover , the newly synthesized BDNF in the IC activates TrkB receptors .	Moreover, the newly synthesized BDNF in the IC activates TrkB receptors.	2	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	10	11
PC12-GFP+ TrkB and PC12-SH2B1beta+ TrkB cells were stimulated by 50 ng/ml BDNF for the indicated time in the presence or absence of selective pharmacological inhibitors of the MAPK or PI3K-AKT pathways and the neurite outgrowth was analyzed .	PC12-GFP+ TrkB and PC12-SH2B1beta+ TrkB cells were stimulated by 50 ng/ml BDNF for the indicated time in the presence or absence of selective pharmacological inhibitors of the MAPK or PI3K-AKT pathways and the neurite outgrowth was analyzed.	0	15	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	1	2
Then , we determined whether in human subjects , 5-day 5Hz rTMS induced changes in both electrophysiological markers of LTP like phenomena and BDNF induced Trk-B activation in lymphocytes .	Then, we determined whether in human subjects, 5-day 5Hz rTMS induced changes in both electrophysiological markers of LTP like phenomena and BDNF induced Trk-B activation in lymphocytes.	23	26	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	Trk-B	Trk-B	Trk-B	23	24	25	26
According to previously published reports and our data , TrkB is overexpressed and abnormally activated in lung cancer , and exogenous BDNF increases TrkB activation and affects its downstream function .	According to previously published reports and our data, TrkB is overexpressed and abnormally activated in lung cancer, and exogenous BDNF increases TrkB activation and affects its downstream function.	20	26	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	21	22	23	24
There are 3 receptors : TrkA receptors activated by NGF and NT-3 , TrkB receptors activated by BDNF and NT-4 , as well as NT-3 , but with less affinity , and TrkC receptors activated by NT-3 ( for review , see refs 34 ) .	There are 3 receptors : TrkA receptors activated by NGF and NT-3, TrkB receptors activated by BDNF and NT-4, as well as NT-3, but with less affinity, and TrkC receptors activated by NT-3 (for review, see refs 34).	13	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	17	18	13	14
In addition , BDNF mediated activation of TrkB is important for activity dependent regulation of GABAergic synapse development .	In addition, BDNF mediated activation of TrkB is important for activity dependent regulation of GABAergic synapse development.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	7	8
Genetic deletion of numb and numbl impairs BDNF induced aPKC activation in GCPs , suggesting BDNF stimulation of TrkB recruits Numb , which in turn acts as an adaptor to recruit and activate aPKC via the PTB region .	Genetic deletion of numb and numbl impairs BDNF induced aPKC activation in GCPs, suggesting BDNF stimulation of TrkB recruits Numb, which in turn acts as an adaptor to recruit and activate aPKC via the PTB region.	15	19	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	18	19
We have demonstrated that FTY720-P enhances the production of BDNF , which activates TrkB and ERK1/2 signaling .	We have demonstrated that FTY720-P enhances the production of BDNF, which activates TrkB and ERK1/2 signaling.	7	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	13	14
Together , these studies demonstrate that Numb is required for BDNF induced TrkB endocytosis in GCPs .	Together, these studies demonstrate that Numb is required for BDNF induced TrkB endocytosis in GCPs.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	12	13
In this mechanism , BDNF mediated TrkB activation at the distal axon was shown to induce a retrograde Erk1/2 signal , which in turn activates immediate early gene transcription in the nucleus .	In this mechanism, BDNF mediated TrkB activation at the distal axon was shown to induce a retrograde Erk1/2 signal, which in turn activates immediate early gene transcription in the nucleus.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	6	7
However , the signaling mechanisms that link BDNF activated TrkB to F-actin remodeling enzymes and dendritic spine morphological plasticity remain poorly understood .	However, the signaling mechanisms that link BDNF activated TrkB to F-actin remodeling enzymes and dendritic spine morphological plasticity remain poorly understood.	7	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	9	10
95 Collectively , the data suggest that BDNF dependent activation of TrkB signaling is required for the development of the central sensitization process that underlies the development of persistent heat and mechanical hypersensitivity in the setting of tissue inflammation or injury .	95 Collectively, the data suggest that BDNF dependent activation of TrkB signaling is required for the development of the central sensitization process that underlies the development of persistent heat and mechanical hypersensitivity in the setting of tissue inflammation or injury.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	11	12
Brain derived neurotrophic factor mediated TrkB activation has been shown to promote neuronal synaptic activity through activation of the transcription factor , CREB , which drives the expression and activation of intracellular signaling pathways through the action of two types of glutamate gated ion channels ; AMPA and NMDA receptors XREF_BIBR , XREF_BIBR .	Brain derived neurotrophic factor mediated TrkB activation has been shown to promote neuronal synaptic activity through activation of the transcription factor, CREB, which drives the expression and activation of intracellular signaling pathways through the action of two types of glutamate gated ion channels; AMPA and NMDA receptors XREF_BIBR, XREF_BIBR.	0	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Brain derived neurotrophic factor	Brain derived neurotrophic factor	Brain derived neurotrophic factor	TrkB	TrkB	TrkB	0	4	5	6
In the present study , we observed an age dependent switch from a TrkB receptor readily activated by BDNF but not by ADs during early postnatal stage to a receptor activated by ADs but less sensitive to direct ex vivo BDNF stimulation in late postnatal stage and adulthood .	In the present study, we observed an age dependent switch from a TrkB receptor readily activated by BDNF but not by ADs during early postnatal stage to a receptor activated by ADs but less sensitive to direct ex vivo BDNF stimulation in late postnatal stage and adulthood.	13	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	13	14
Accumulation of WAVE1 at the endocytic sites of BDNF activated TrkB requires retrolinkin .	Accumulation of WAVE1 at the endocytic sites of BDNF activated TrkB requires retrolinkin.	6	11	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
Interestingly , BDNF activation of TrkB receptors regulates positively GR activity on its target gene expression by phosphorylating two key serine residues on the receptor [ XREF_BIBR ] .	Interestingly, BDNF activation of TrkB receptors regulates positively GR activity on its target gene expression by phosphorylating two key serine residues on the receptor [XREF_BIBR].	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	5	6
BDNF stimulation of the exogenously expressed TrkB receptors amplified the APP metabolism effects and cotransfection of the TrkB truncated isoforms with TrkB FL altered the effects on APP metabolism .	BDNF stimulation of the exogenously expressed TrkB receptors amplified the APP metabolism effects and cotransfection of the TrkB truncated isoforms with TrkB FL altered the effects on APP metabolism.	0	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	6	7
BDNF mimetics have been shown to activate TrkB signalling and prevent neuronal degeneration in rodents [ XREF_BIBR ] .	BDNF mimetics have been shown to activate TrkB signalling and prevent neuronal degeneration in rodents [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	7	8
NGF specifically activates TrkA ; NT-3 activates TrkC ; and BDNF and NT-4/5 activate TrkB .	NGF specifically activates TrkA; NT-3 activates TrkC; and BDNF and NT-4/5 activate TrkB.	10	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	14	15
Retrolinkin recruits the WAVE1 protein complex to facilitate BDNF induced TrkB endocytosis and dendrite outgrowth .	Retrolinkin recruits the WAVE1 protein complex to facilitate BDNF induced TrkB endocytosis and dendrite outgrowth.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
SY5Y and TrkB cells were treated with BDNF and subsequently the surface proteins were biotinylated , immunoprecipitated and immunoblotted with anti-Y5R antibody .	SY5Y and TrkB cells were treated with BDNF and subsequently the surface proteins were biotinylated, immunoprecipitated and immunoblotted with anti-Y5R antibody.	0	8	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	2	3
BDNF mediated activation of TrkB enhanced invasiveness and migration in vitro , which could be impaired by transient transfection using Gal-1-specific siRNA or a neutralizing antibody directed against Gal-1 .	BDNF mediated activation of TrkB enhanced invasiveness and migration in vitro, which could be impaired by transient transfection using Gal-1-specific siRNA or a neutralizing antibody directed against Gal-1.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
The GFP-TrkB fusion protein was inactive in the absence of BDNF , and could be activated by BDNF added to the culture media , as shown by Western blotting using antibody against phosphorylated TrkB .	The GFP-TrkB fusion protein was inactive in the absence of BDNF, and could be activated by BDNF added to the culture media, as shown by Western blotting using antibody against phosphorylated TrkB.	1	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	GFP-TrkB	GFP-TrkB	GFP-TrkB	17	18	1	2
Stimulation of tyrosine kinase B ( TrkB ) receptors by BDNF leads to the activation of proteins such as Arc , Homer2 , LIMK1 that are known to promote actin polymerization and consequently the enlargement of dendritic spine heads .	Stimulation of tyrosine kinase B (TrkB) receptors by BDNF leads to the activation of proteins such as Arc, Homer2, LIMK1 that are known to promote actin polymerization and consequently the enlargement of dendritic spine heads.	0	11	Stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	6	7
Pretreatment with 10 muM MDC for 15 min reversed BDNF induced TrkB internalization ( XREF_FIG B ) .	Pretreatment with 10 muM MDC for 15 min reversed BDNF induced TrkB internalization (XREF_FIG B).	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	11	12
Thus , BDNF activation of trkB could inhibit Kir3 by facilitating channel deactivation .	Thus, BDNF activation of trkB could inhibit Kir3 by facilitating channel deactivation.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	2	3	5	6
First , not all BDNF expressing cells may undergo gene recombination , thus some BDNF protein could still remain to support TrkB positive nerve fibers .	First, not all BDNF expressing cells may undergo gene recombination, thus some BDNF protein could still remain to support TrkB positive nerve fibers.	14	24	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	21	22
Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 ( TrkB ) receptors .	Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 (TrkB) receptors.	1	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF levels	bdnf	TrkB	TrkB	trkb	1	2	19	20
A similar role for hnRNP K in the release of transcripts used for local translation may be hypothesized in the BDNF induced dendritic synthesis of BDNF and TrkB receptors , and in the translation of the hnRNP K mRNAs at the synapse .	A similar role for hnRNP K in the release of transcripts used for local translation may be hypothesized in the BDNF induced dendritic synthesis of BDNF and TrkB receptors, and in the translation of the hnRNP K mRNAs at the synapse.	17	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	27	28
BDNF has been shown to protect cells from chemotherapy , and it is known that the phosphorylation of Akt is central to BDNF activation of TrkB signaling [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	BDNF has been shown to protect cells from chemotherapy, and it is known that the phosphorylation of Akt is central to BDNF activation of TrkB signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR].	22	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	22	23	25	26
In mice , this increase is dependent on signaling through the TrkB receptor , which is activated by brain derived neurotrophic factor ( BDNF ) , which itself is known to induce maturation of PV+ interneurons .	In mice, this increase is dependent on signaling through the TrkB receptor, which is activated by brain derived neurotrophic factor (BDNF), which itself is known to induce maturation of PV+ interneurons.	11	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	brain derived neurotrophic factor	brain derived neurotrophic factor	brain derived neurotrophic factor	TrkB	TrkB	TrkB	18	22	11	12
XREF_BIBR BDNF induces dimerisation of TRKB with kinase activation and autophosphorylation of tyrosine residues , with subsequent activation of several adaptor proteins , which , in turn leads to phosphorylation of phosphoinositide 3-kinase , mitogen activated protein kinase and extracellular signal regulated kinase , phospholipase Cgamma1 and cyclic adenosine monophosphate ( cAMP )-responsive element binding protein , all downstream pathways regulating neurite outgrowth , cell survival , cellular differentiation and synaptic plasticity .	XREF_BIBR BDNF induces dimerisation of TRKB with kinase activation and autophosphorylation of tyrosine residues, with subsequent activation of several adaptor proteins, which, in turn leads to phosphorylation of phosphoinositide 3-kinase, mitogen activated protein kinase and extracellular signal regulated kinase, phospholipase Cgamma1 and cyclic adenosine monophosphate (cAMP)-responsive element binding protein, all downstream pathways regulating neurite outgrowth, cell survival, cellular differentiation and synaptic plasticity.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	1	2	5	6
Whether and how the NPFs are recruited to endocytic sites of BDNF activated TrkB to promote actin polymerization remains unknown .	Whether and how the NPFs are recruited to endocytic sites of BDNF activated TrkB to promote actin polymerization remains unknown.	9	18	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	13	14
Furthermore , we examined whether the candidate compounds can inhibit the phospho activation of TrkB , which was mediated by BDNF .	Furthermore, we examined whether the candidate compounds can inhibit the phospho activation of TrkB, which was mediated by BDNF.	12	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	14	15
The importance of the BDNF and TrkB signaling pathway in regulating CNS function has led to many studies exploring the therapeutic potential of BDNF and TrkB for various neurological diseases , including TBI .	The importance of the BDNF and TrkB signaling pathway in regulating CNS function has led to many studies exploring the therapeutic potential of BDNF and TrkB for various neurological diseases, including TBI.	1	26	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	25	26
Electron and super-resolution microscopy analyses revealed that the fast moving sub-diffraction-limited CTB carriers contained the TrkB neurotrophin receptor , transiently activated by synaptic activity in a BDNF independent manner .	Electron and super-resolution microscopy analyses revealed that the fast moving sub-diffraction-limited CTB carriers contained the TrkB neurotrophin receptor, transiently activated by synaptic activity in a BDNF independent manner.	15	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	26	27	15	16
As BDNF stimulates TrkB internalization and polarization of TrkB containing signaling endosomes in migrating GCPs ( XREF_FIG ) , Numb is appropriately positioned to work with alpha-adaptin to mediate TrkB endocytosis in migrating GCPs .	As BDNF stimulates TrkB internalization and polarization of TrkB containing signaling endosomes in migrating GCPs (XREF_FIG), Numb is appropriately positioned to work with alpha-adaptin to mediate TrkB endocytosis in migrating GCPs.	1	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	3	4
However , this aptamer not only acts as a simple partial agonist that is not functionally different from an endogenous ligand , Brain Derived Neurotrophic Factor ( BDNF ) , but also partially inhibits BDNF mediated TrkB activation .	However, this aptamer not only acts as a simple partial agonist that is not functionally different from an endogenous ligand, Brain Derived Neurotrophic Factor (BDNF), but also partially inhibits BDNF mediated TrkB activation.	33	37	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	34	35	36	37
Moreover , activation of TrkA or TrkB by their specific ligands in vitro confirmed up-regulation of Gal-1 only upon BDNF mediated TrkB stimulation [ XREF_BIBR ] .	Moreover, activation of TrkA or TrkB by their specific ligands in vitro confirmed up-regulation of Gal-1 only upon BDNF mediated TrkB stimulation [XREF_BIBR].	16	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	19	20	21	22
3.4 TrkB activation by exogenous BDNF in vitro is altered in the absence of Kalrn .	3.4 TrkB activation by exogenous BDNF in vitro is altered in the absence of Kalrn.	1	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	1	2
In slices obtained from sham treated animals , In sham treated animals , BDNF significantly increased tyrosine phosphorylated full-length TrkB ( pY-145-KDa TrkB ) and truncated TrkB ( pY-95-KDa TrkB ) .	In slices obtained from sham treated animals, In sham treated animals, BDNF significantly increased tyrosine phosphorylated full-length TrkB (pY-145-KDa TrkB) and truncated TrkB (pY-95-KDa TrkB).	13	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	13	14	19	20
However , these findings are in contrast to Suzuki and colleague ' s observations , in which BDNF induced TrkB receptor activation in lipid rafts stimulated the ERK and MAPK pathway .	However, these findings are in contrast to Suzuki and colleague 's observations, in which BDNF induced TrkB receptor activation in lipid rafts stimulated the ERK and MAPK pathway.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	17	18	19	20
For instance , BDNF triggers the TrkB receptor tyrosine kinases .	For instance, BDNF triggers the TrkB receptor tyrosine kinases.	3	9	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	6	7
This notion is supported by a number of observations : ( a ) inhibition of the Trk kinase activity by K252a or AG879 significantly inhibited BDNF induced translocation of TrkB-FL ; ( b ) NT-4 , which activates the TrkB RTK , also induced TrkB-FL translocation ; ( c ) 1-min exposure of BDNF , which activates TrkB , was sufficient to partition TrkB-FL into rafts .	This notion is supported by a number of observations : (a) inhibition of the Trk kinase activity by K252a or AG879 significantly inhibited BDNF induced translocation of TrkB-FL; (b) NT-4, which activates the TrkB RTK, also induced TrkB-FL translocation; (c) 1-min exposure of BDNF, which activates TrkB, was sufficient to partition TrkB-FL into rafts.	51	58	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	53	54	57	58
The low molecular weight TrkB ligand , ANA-12 , selectively binds to the TrkB receptor thereby blocking BDNF induced TrkB activation and inhibiting intracellular signaling cascades downstream of TrkB .	The low molecular weight TrkB ligand, ANA-12, selectively binds to the TrkB receptor thereby blocking BDNF induced TrkB activation and inhibiting intracellular signaling cascades downstream of TrkB.	16	20	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	17	18	19	20
In summary , we propose a model wherein the neurotrophin receptor TrkB in growth plate chondrocytes is activated by BDNF to halt proliferation and promote differentiation via the activation of the MAPK p38 .	In summary, we propose a model wherein the neurotrophin receptor TrkB in growth plate chondrocytes is activated by BDNF to halt proliferation and promote differentiation via the activation of the MAPK p38.	8	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	19	20	11	12
It is well known that the rodent gustatory system develops under tight control of two neurotrophins , brain derived neurotrophic factor ( BDNF ) and neurotrophin-4 ( NT-4 ) , preferentially activating their high affinity receptor TrkB [ XREF_BIBR , XREF_BIBR ] .	It is well known that the rodent gustatory system develops under tight control of two neurotrophins, brain derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4), preferentially activating their high affinity receptor TrkB [XREF_BIBR, XREF_BIBR].	15	38	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	brain derived neurotrophic factor	brain derived neurotrophic factor	brain derived neurotrophic factor	TrkB	TrkB	TrkB	17	21	36	37
Increasing BDNF levels after treatment with exogenous recombinant human BDNF ( rhBDNF ) at 100 ng/ml significantly promoted the activation of TrKB and the progression of EMT in SACC cells .	Increasing BDNF levels after treatment with exogenous recombinant human BDNF (rhBDNF) at 100 ng/ml significantly promoted the activation of TrKB and the progression of EMT in SACC cells.	1	22	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF levels	bdnf	TrKB	TrKB	trkb	1	2	21	22
Preclinical reports have described that AD transgenic mouse models show decreased cortical BDNF expression and BDNF mediated TrkB retrograde trafficking impairment in neuronal culture submitted to beta-amyloid peptides ( Peng et al ., 2009 ; Poon et al ., 2011 ) .	Preclinical reports have described that AD transgenic mouse models show decreased cortical BDNF expression and BDNF mediated TrkB retrograde trafficking impairment in neuronal culture submitted to beta-amyloid peptides (Peng et al., 2009; Poon et al., 2011).	9	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	17	18
Increases in GABARalpha4 subunits are transcriptionally regulated by BDNF activation of the TrkB receptor , its downstream signaling cascades ( protein kinase C ( PKC ) and mitogen activated protein kinase ( MAPK ) ) , as well as upregulation of its target ( early growth response factor 3 ( Egr3 ) ) 16 .	Increases in GABARalpha4 subunits are transcriptionally regulated by BDNF activation of the TrkB receptor, its downstream signaling cascades (protein kinase C (PKC) and mitogen activated protein kinase (MAPK)), as well as upregulation of its target (early growth response factor 3 (Egr3)) 16.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	12	13
This report summarizes patterns of mRNA expression for the brain derived neurotrophic factor ( BDNF ) together with its high-affinity neurotrophin receptor trkB within the hen ovary during follicle development , describes hormonal mechanisms for the regulation of trkB gene expression and provides preliminary evidence for a novel function for BDNF mediated TrkB signaling within the granulosa layer .	This report summarizes patterns of mRNA expression for the brain derived neurotrophic factor (BDNF) together with its high-affinity neurotrophin receptor trkB within the hen ovary during follicle development, describes hormonal mechanisms for the regulation of trkB gene expression and provides preliminary evidence for a novel function for BDNF mediated TrkB signaling within the granulosa layer.	48	53	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	50	51	52	53
However , BDNF , 20 ng/ml still induced a significant activation of TrkB ( ANOVA , p = 0.032 ) .	However, BDNF, 20 ng/ml still induced a significant activation of TrkB (ANOVA, p = 0.032).	2	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	12	13
BDNF treatment of the adult cortical PSD resulted in a 5-fold increase in trkB autophosphorylation , supporting the contention that the PSD contains functional trkB .	BDNF treatment of the adult cortical PSD resulted in a 5-fold increase in trkB autophosphorylation, supporting the contention that the PSD contains functional trkB.	0	25	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	0	1	24	25
TrkB is activated by BDNF , and its downstream signaling pathways play an important role in suppressing epileptogenesis in the hippocampus .	TrkB is activated by BDNF, and its downstream signaling pathways play an important role in suppressing epileptogenesis in the hippocampus.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	0	1
Downregulation of KCC2 transporter is a consequence of the increased BDNF mediated TrKB activation , which suppresses the normal Cl dependent fast inhibition in GABAergic neurons [ XREF_BIBR ] .	Downregulation of KCC2 transporter is a consequence of the increased BDNF mediated TrKB activation, which suppresses the normal Cl dependent fast inhibition in GABAergic neurons [XREF_BIBR].	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrKB	TrKB	TrKB	10	11	12	13
The oligomers also induce a deficit in BDNF mediated TrkB retrograde trafficking [ XREF_BIBR ] by disrupting ubiquitin [ XREF_BIBR ] and calcium homeostasis [ XREF_BIBR ] .	The oligomers also induce a deficit in BDNF mediated TrkB retrograde trafficking [XREF_BIBR] by disrupting ubiquitin [XREF_BIBR] and calcium homeostasis [XREF_BIBR].	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	9	10
These findings show that abolishing BDNF function as well as BDNF induced TrkB activation affected synapse formation in Mecp2 Null/y autaptic neurons , postulating the mechanistic role of BDNF in regulating synaptic function in RTT like excitatory neurons .	These findings show that abolishing BDNF function as well as BDNF induced TrkB activation affected synapse formation in Mecp2 Null/y autaptic neurons, postulating the mechanistic role of BDNF in regulating synaptic function in RTT like excitatory neurons.	4	13	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	12	13
These findings together support the notion that trkB activation by BDNF expressed in the brain is essential for appetite regulation and energy homeostasis .	These findings together support the notion that trkB activation by BDNF expressed in the brain is essential for appetite regulation and energy homeostasis.	7	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF expressed	bdnf	trkB	trkB	trkb	10	11	7	8
Together , these findings suggest TrkB activation by BDNF mediates the internalization of GABA A Ralpha1 subunits .	Together, these findings suggest TrkB activation by BDNF mediates the internalization of GABA A Ralpha1 subunits.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	5	6
Additionally , in vitro experiments on R6/2 striatal cultures show that BDNF activation of phospho-TrkB and the Erk1/2 pathway is impaired in association with a reduction in BDNF mediated neurotrophic effects on MSNs .	Additionally, in vitro experiments on R6/2 striatal cultures show that BDNF activation of phospho-TrkB and the Erk1/2 pathway is impaired in association with a reduction in BDNF mediated neurotrophic effects on MSNs.	11	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	phospho-TrkB	phospho-TrkB	phospho-TrkB	11	12	14	15
Retrolinkin , not endophilin A1 , is required for BDNF triggered TrkB endocytosis in CNS neurons .	Retrolinkin, not endophilin A1, is required for BDNF triggered TrkB endocytosis in CNS neurons.	9	12	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	11	12
We observed reduction in total TrkB levels in neurons treated with BDNF neutralizing antibody as compared to control IgG treated neurons .	We observed reduction in total TrkB levels in neurons treated with BDNF neutralizing antibody as compared to control IgG treated neurons.	5	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	5	6
BDNF released by cortical neurons activates TrkB receptors at striatal dendrites to promote striatum survival .	BDNF released by cortical neurons activates TrkB receptors at striatal dendrites to promote striatum survival.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	6	7
TrkB receptors have been activated by BDNF released by human mesenchymal stem cells ( hMSC ) implanted intranigrally to regulate neurotrophin expression [ XREF_BIBR ] with a potential application in Parkinson ' s disease therapy .	TrkB receptors have been activated by BDNF released by human mesenchymal stem cells (hMSC) implanted intranigrally to regulate neurotrophin expression [XREF_BIBR] with a potential application in Parkinson 's disease therapy.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	0	1
Additionally , in tumor cells , Brain Derived Neurotrophic factor ( BDNF )-mediated activation of TrkB was shown to be dependent on hsp90 .	Additionally, in tumor cells, Brain Derived Neurotrophic factor (BDNF)-mediated activation of TrkB was shown to be dependent on hsp90.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	15	16
The high amounts of TrkB in EEA1 and Rab7 positive endosomes in EndophilinA TKO neurons - even in conditions without stimulation by exogenous BDNF - suggests that TrkB receptors previously activated by endogenous BDNF accumulate in early and late endosomes in EndophilinA TKO neurons .	The high amounts of TrkB in EEA1 and Rab7 positive endosomes in EndophilinA TKO neurons - even in conditions without stimulation by exogenous BDNF - suggests that TrkB receptors previously activated by endogenous BDNF accumulate in early and late endosomes in EndophilinA TKO neurons.	27	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	33	34	27	28
As in the animal study , BDNF induced TrkB activation was detected in lymphocytes from both sham and rTMS sessions , as indicated by the 5-10 fold increase in pY-TrkB 145- and 95-KDa levels .	As in the animal study, BDNF induced TrkB activation was detected in lymphocytes from both sham and rTMS sessions, as indicated by the 5-10 fold increase in pY-TrkB 145- and 95-KDa levels.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
Activation of TrkB by BDNF is known to promote neuronal survival by engaging the PI 3 kinase-Akt signaling pathway , the extracellular signal regulated kinases ( ERKs ) , and the transcription factor CREB in neurons .	Activation of TrkB by BDNF is known to promote neuronal survival by engaging the PI 3 kinase-Akt signaling pathway, the extracellular signal regulated kinases (ERKs), and the transcription factor CREB in neurons.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
In stable cell lines over-expressing dog TrkB , we observed that both BDNF and TAM-163 increased pTrkB , pPLCgamma1 and pERK1/2 in a dose dependent manner ( XREF_SUPPLEMENTARY ) , confirming the cross-reactivity of TAM-163 with this species .	In stable cell lines over-expressing dog TrkB, we observed that both BDNF and TAM-163 increased pTrkB, pPLCgamma1 and pERK1/2 in a dose dependent manner (XREF_SUPPLEMENTARY), confirming the cross-reactivity of TAM-163 with this species.	11	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	pTrkB	pTrkB	pTrkB	12	13	16	17
During this period , etoposide treatment was associated with the dephosphorylation and activation of GSK-3beta in the mitochondria that was blocked by BDNF activation of TrkB .	During this period, etoposide treatment was associated with the dephosphorylation and activation of GSK-3beta in the mitochondria that was blocked by BDNF activation of TrkB.	22	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	22	23	25	26
BDNF Stimulates the Interactions of HAP1 and TrkB and HAP1 and p75 NTR .	BDNF Stimulates the Interactions of HAP1 and TrkB and HAP1 and p75 NTR.	0	8	Stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	7	8
In hippocampal neurons , BDNF activation of the TrkB receptor regulates CREB dependent gene expression largely by activating the ERK dependent kinase signaling cascade , resulting in direct phosphorylation of CREB Ser133 by Msk1/2 XREF_BIBR - XREF_BIBR .	In hippocampal neurons, BDNF activation of the TrkB receptor regulates CREB dependent gene expression largely by activating the ERK dependent kinase signaling cascade, resulting in direct phosphorylation of CREB Ser133 by Msk1/2 XREF_BIBR - XREF_BIBR.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	8	9
To determine whether rTMS also affected BDNF-TrkB signaling and their interaction with the NMDARs in peripheral tissues , we measured BDNF induced TrkB activation in isolated lymphocytes .	To determine whether rTMS also affected BDNF-TrkB signaling and their interaction with the NMDARs in peripheral tissues, we measured BDNF induced TrkB activation in isolated lymphocytes.	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	22	23
As an alternative approach to determine whether Arp2/3 plays a role in BDNF induced TrkB internalization , an inhibitor of Arp2/3 activity , CK-666 , was applied to hippocampal neurons .	As an alternative approach to determine whether Arp2/3 plays a role in BDNF induced TrkB internalization, an inhibitor of Arp2/3 activity, CK-666, was applied to hippocampal neurons.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	14	15
BDNF activation of TrkB is key for the enhancement of activity stimulated excitation of neurons that is needed for memory development and maintenance .	BDNF activation of TrkB is key for the enhancement of activity stimulated excitation of neurons that is needed for memory development and maintenance.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
While these observations suggest that activation of TrkB by BDNF and subsequent engagement of downstream signaling protein will most likely recruit neuronal mechanisms , they do not rule out the involvement of glia cells .	While these observations suggest that activation of TrkB by BDNF and subsequent engagement of downstream signaling protein will most likely recruit neuronal mechanisms, they do not rule out the involvement of glia cells.	5	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	7	8
Here we demonstrate that BDNF dependent activation of TrkB stimulates atypical PKC , and this process requires Numb .	Here we demonstrate that BDNF dependent activation of TrkB stimulates atypical PKC, and this process requires Numb.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	8	9
Indeed , both BDNF and NT4 exposure produced greater proliferation of TrkB and p75 cells than observed in cells expressing TrkB alone ( XREF_FIG ) .	Indeed, both BDNF and NT4 exposure produced greater proliferation of TrkB and p75 cells than observed in cells expressing TrkB alone (XREF_FIG).	3	14	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	11	12
Therefore , the BDNF that was released at the onset of the REM sleep episode activates TrkB autoreceptors and increases BDNF synthesis , but the continuous release of BDNF is diminished .	Therefore, the BDNF that was released at the onset of the REM sleep episode activates TrkB autoreceptors and increases BDNF synthesis, but the continuous release of BDNF is diminished.	2	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	16	17
Similarly , respiratory frequency in mutant mice was recovered by a small analog of BDNF that can be administered systemically and activate the TrkB receptor ( Schmid et al ., 2012 ) .	Similarly, respiratory frequency in mutant mice was recovered by a small analog of BDNF that can be administered systemically and activate the TrkB receptor (Schmid et al., 2012).	12	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	23	24
We also show that this is probably linked to an alteration of downstream TrkB signaling kinases caused by a downregulation of the axonal transport of BDNF .	We also show that this is probably linked to an alteration of downstream TrkB signaling kinases caused by a downregulation of the axonal transport of BDNF.	13	26	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	25	26	13	14
Moreover , BDNF stimulates association of TrkB with Numb ( XREF_FIG ) and promotes TrkB polarization .	Moreover, BDNF stimulates association of TrkB with Numb (XREF_FIG) and promotes TrkB polarization.	2	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	6	7
Given that retrolinkin interacts with the CYFIP1/2 subunits of the WAVE regulatory complex and that the colocalization between WAVE1 and BDNF activated TrkB during endocytosis requires retrolinkin , we reasoned that retrolinkin recruits WAVE1 through its interaction with CYFIP1/2 to the plasma membrane to facilitate BDNF-TrkB endocytosis and signaling .	Given that retrolinkin interacts with the CYFIP1/2 subunits of the WAVE regulatory complex and that the colocalization between WAVE1 and BDNF activated TrkB during endocytosis requires retrolinkin, we reasoned that retrolinkin recruits WAVE1 through its interaction with CYFIP1/2 to the plasma membrane to facilitate BDNF-TrkB endocytosis and signaling.	16	25	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	22	23
Surprisingly , epileptogenesis induced TrkB activation was found in animals with a conditional lack of BDNF , so the question was whether a non BDNF ligand might be able to activate TrkB .	Surprisingly, epileptogenesis induced TrkB activation was found in animals with a conditional lack of BDNF, so the question was whether a non BDNF ligand might be able to activate TrkB.	24	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	24	25	31	32
Cyclotraxin-B was found to inhibit BDNF induced TrkB activity through a non competitive mechanism with a high potency ( IC 50 = 0.30 +/-0.07 nM ; XREF_FIG ) .	Cyclotraxin-B was found to inhibit BDNF induced TrkB activity through a non competitive mechanism with a high potency (IC 50 = 0.30 +/-0.07 nM; XREF_FIG).	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	7	8
Taken together , these results are consistent with our findings that NT-3 and NGF do not promote proliferation of St. 29/30 ( E6.5 ) sympathoblasts , and support the assertion that BDNF promotes proliferation of TrkB positive sympathoblasts in culture .	Taken together, these results are consistent with our findings that NT-3 and NGF do not promote proliferation of St. 29/30 (E6.5) sympathoblasts, and support the assertion that BDNF promotes proliferation of TrkB positive sympathoblasts in culture.	31	37	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	31	32	35	36
The present study was undertaken to evaluate the ability of a small molecule , non peptide BDNF loop 2 domain mimetic , LM22A-4 , which functions as a direct and specific partial agonist of TrkB , but not p75 , to increase TrkB activation and improve breathing in a mouse model of RTT .	The present study was undertaken to evaluate the ability of a small molecule, non peptide BDNF loop 2 domain mimetic, LM22A-4, which functions as a direct and specific partial agonist of TrkB, but not p75, to increase TrkB activation and improve breathing in a mouse model of RTT.	16	43	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	42	43
Mechanisms identified for KCC2 down-regulation include calpain dependent cleavage XREF_BIBR , phosphorylation of KCC2 at tyrosine 903/1087 XREF_BIBR as well as dephosphorylation at serine 940 XREF_BIBR and BDNF induced TrkB activation XREF_BIBR .	Mechanisms identified for KCC2 down-regulation include calpain dependent cleavage XREF_BIBR, phosphorylation of KCC2 at tyrosine 903/1087 XREF_BIBR as well as dephosphorylation at serine 940 XREF_BIBR and BDNF induced TrkB activation XREF_BIBR.	25	31	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	27	28	29	30
TrkB and TrkB and p75 cells were treated with a range of BDNF concentrations , and whole cell lysates were collected for immunoblotting .	TrkB and TrkB and p75 cells were treated with a range of BDNF concentrations, and whole cell lysates were collected for immunoblotting.	0	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	0	1
The positive control BDNF ( 100 ng/ml ) strongly activated TrkB , as TrkB was robustly phosphorylated .	The positive control BDNF (100 ng/ml) strongly activated TrkB, as TrkB was robustly phosphorylated.	3	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	10	11
Brain derived neurotrophic factor ( BDNF ) activates its receptor TrkB , and promotes neuronal survival , differentiation , and synaptic functions .	Brain derived neurotrophic factor (BDNF) activates its receptor TrkB, and promotes neuronal survival, differentiation, and synaptic functions.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	10	11
This result again suggests that spontaneous synaptic activity in nonstimulated cultures may also influence BDNF induced TrkB endocytosis .	This result again suggests that spontaneous synaptic activity in nonstimulated cultures may also influence BDNF induced TrkB endocytosis.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	16	17
For this experiment , B27 growth supplement was withdrawn from healthy cultures of cortical neurons , which results in cell death that can be rescued by BDNF , thereby demonstrating a TrkB dependent mechanism in neuronal cell survival .	For this experiment, B27 growth supplement was withdrawn from healthy cultures of cortical neurons, which results in cell death that can be rescued by BDNF, thereby demonstrating a TrkB dependent mechanism in neuronal cell survival.	24	33	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	26	27	31	32
To examine the effects of SH2B1beta on BDNF induced neurite outgrowth , PC12-GFP+ TrkB and PC12-SH2B1beta+ TrkB cell lines were mock treated or treated with 100 ng/ml BDNF for 1 or 3 days .	To examine the effects of SH2B1beta on BDNF induced neurite outgrowth, PC12-GFP+ TrkB and PC12-SH2B1beta+ TrkB cell lines were mock treated or treated with 100 ng/ml BDNF for 1 or 3 days.	10	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	27	28	13	14
In further studies , BDNF stimulation of TrkB was shown to be capable of rescuing the inactivation or loss of the polysialated head ( PSA ) of PSA-NCAM , a molecule critical for cell adhesion during the migratory process .	In further studies, BDNF stimulation of TrkB was shown to be capable of rescuing the inactivation or loss of the polysialated head (PSA) of PSA-NCAM, a molecule critical for cell adhesion during the migratory process.	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	7	8
Given that neural activity promotes BDNF mediated TrkB activation and TrkB signaling is required for activity dependent differentiation of hippocampal NSPCs , BDNF is likely to be a critical factor to promote NSPC derived newborn neuron survival and integration into neural circuitry .	Given that neural activity promotes BDNF mediated TrkB activation and TrkB signaling is required for activity dependent differentiation of hippocampal NSPCs, BDNF is likely to be a critical factor to promote NSPC derived newborn neuron survival and integration into neural circuitry.	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	7	8
To test this possibility , we examined BDNF triggered TrkB internalization in hippocampal neurons using a surface biotinylation assay .	To test this possibility, we examined BDNF triggered TrkB internalization in hippocampal neurons using a surface biotinylation assay.	7	10	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	9	10
The results of current study also revealed that activation of TrkB by BDNF was enhanced in the CR cell lines , and led to robust induction of the Akt , MAPK , and Src signaling pathways that exceeded the effects in the parental lines .	The results of current study also revealed that activation of TrkB by BDNF was enhanced in the CR cell lines, and led to robust induction of the Akt, MAPK, and Src signaling pathways that exceeded the effects in the parental lines.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	10	11
Plasma BDNF might activate TrkB receptors in the adrenal medulla during acute stress .	Plasma BDNF might activate TrkB receptors in the adrenal medulla during acute stress.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	4	5
We hypothesized that the neurotrophin brain derived neurotrophic factor ( BDNF ) activates its receptor , TrkB , in the hippocampus during epileptogenesis and that BDNF mediated activation of TrkB is required for epileptogenesis .	We hypothesized that the neurotrophin brain derived neurotrophic factor (BDNF) activates its receptor, TrkB, in the hippocampus during epileptogenesis and that BDNF mediated activation of TrkB is required for epileptogenesis.	25	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	25	26	29	30
Mature BDNF preferentially activates TrkB , directly promoting survival and axonal growth , whereas proBDNF binds to the p75NTR-sortilin receptor complex to promote apoptosis , or to the p75NTR , NgR , and LINGO complex to inhibit neurite outgrowth .	Mature BDNF preferentially activates TrkB, directly promoting survival and axonal growth, whereas proBDNF binds to the p75NTR-sortilin receptor complex to promote apoptosis, or to the p75NTR, NgR, and LINGO complex to inhibit neurite outgrowth.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	4	5
While there was no discernible difference in TrkB and NMDAR complex level under basal conditions , prenatal cocaine exposure increased BDNF induced TrkB association with NMDARs by 56 % [ t ( 6 ) = 5.3325 , p = 0.00033 ] in the hippocampus and by 49 % [ t ( 7 ) = 5.0283 , p = 0.00015 ] in PFCX above that of the saline treated group ( XREF_FIG ) .	While there was no discernible difference in TrkB and NMDAR complex level under basal conditions, prenatal cocaine exposure increased BDNF induced TrkB association with NMDARs by 56% [t (6) = 5.3325, p = 0.00033] in the hippocampus and by 49% [t (7) = 5.0283, p = 0.00015] in PFCX above that of the saline treated group (XREF_FIG).	19	23	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	20	21	22	23
We herein report that BDNF activation of TrkB receptors rapidly enhances spontaneous quantal transmitter release in CA1 pyramidal neurons of hippocampal slice cultures by Ca 2+ mobilization from intracellular stores , a signal further amplified by Ca 2+ entry through TRPC plasma membrane channels .	We herein report that BDNF activation of TrkB receptors rapidly enhances spontaneous quantal transmitter release in CA1 pyramidal neurons of hippocampal slice cultures by Ca 2+ mobilization from intracellular stores, a signal further amplified by Ca 2+ entry through TRPC plasma membrane channels.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	7	8
In whole , these studies prove a compelling argument for BDNF activated TrkB as a necessary role in epileptogenesis in the kindling model .	In whole, these studies prove a compelling argument for BDNF activated TrkB as a necessary role in epileptogenesis in the kindling model.	8	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	10	11	12	13
Treatment of neurons with BDNF stimulated TrkB activity in neurons expressing full length TrkB , but not in neurons transfected with TrkB increment ICD .	Treatment of neurons with BDNF stimulated TrkB activity in neurons expressing full length TrkB, but not in neurons transfected with TrkB increment ICD.	2	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	6	7
BDNF induced TrkB activation regulates glutamatergic synapse number in a cellautonomous and autocrine manner .	BDNF induced TrkB activation regulates glutamatergic synapse number in a cellautonomous and autocrine manner.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Furthermore , addition of BDNF to cells significantly increased basal body localization of TRKB in both control and shKIF3A treated cells ( XREF_FIG ) .	Furthermore, addition of BDNF to cells significantly increased basal body localization of TRKB in both control and shKIF3A treated cells (XREF_FIG).	2	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	4	5	13	14
Signaling cascades induced by BDNF and its receptor , the receptor tyrosine kinase TrkB , link neuronal growth and differentiation with synaptic plasticity .	Signaling cascades induced by BDNF and its receptor, the receptor tyrosine kinase TrkB, link neuronal growth and differentiation with synaptic plasticity.	2	14	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	13	14
Finally , microtubule binding and microfluidic chamber assays revealed that JIP1 and JIP3 cooperate to relieve kinesin-1 autoinhibition , which depends on the binding of JIP1 to kinesin-1 heavy chain ( KHC ) and light chain ( KLC ) and the binding of JIP3 to KLC and is essential for TrkB anterograde axonal transport and BDNF induced TrkB retrograde signal .	Finally, microtubule binding and microfluidic chamber assays revealed that JIP1 and JIP3 cooperate to relieve kinesin-1 autoinhibition, which depends on the binding of JIP1 to kinesin-1 heavy chain (KHC) and light chain (KLC) and the binding of JIP3 to KLC and is essential for TrkB anterograde axonal transport and BDNF induced TrkB retrograde signal.	55	59	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	55	56	57	58
Secondly , plasma BDNF might activate TrkB receptors of the adrenal medulla during acute stress .	Secondly, plasma BDNF might activate TrkB receptors of the adrenal medulla during acute stress.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	6	7
Activation of TrkB by BDNF enhances synaptic plasticity , and learning and memory , by multiple transcriptional and post-transcriptional mechanisms that involve the PI3-kinase - Akt pathway and extracellular signal regulate kinases ( ERKs 1 and 2 ) .	Activation of TrkB by BDNF enhances synaptic plasticity, and learning and memory, by multiple transcriptional and post-transcriptional mechanisms that involve the PI3-kinase - Akt pathway and extracellular signal regulate kinases (ERKs 1 and 2).	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
Increases in GABARalpha4 subunit are transcriptionally regulated by BDNF activation of the TrkB receptor which leads to upregulation of the early growth response factor ( Egr3 ) pathway via a PKC and MAPK dependent pathway [ XREF_BIBR ] .	Increases in GABARalpha4 subunit are transcriptionally regulated by BDNF activation of the TrkB receptor which leads to upregulation of the early growth response factor (Egr3) pathway via a PKC and MAPK dependent pathway [XREF_BIBR].	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	12	13
BDNF can activate TrkB signaling cascades resulting in MM cells growth , migration , and chemoprotection and appears to have a major contribution to the pathogenesis of MM .	BDNF can activate TrkB signaling cascades resulting in MM cells growth, migration, and chemoprotection and appears to have a major contribution to the pathogenesis of MM.	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	3	4
In specific , they provide additional support or the idea that BDNF dependent AIH induced pLTF requires TrkB activation within phrenic motor neurons per se .	In specific, they provide additional support or the idea that BDNF dependent AIH induced pLTF requires TrkB activation within phrenic motor neurons per se.	11	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	17	18
BDNF induced TrkB activation engages NMDARs [ XREF_BIBR ] to cause rapid NMDAR phosphorylation [ XREF_BIBR ] and enhances glutamatergic neurotransmission [ XREF_BIBR ] leading to LTP [ XREF_BIBR , XREF_BIBR ] .	BDNF induced TrkB activation engages NMDARs [XREF_BIBR] to cause rapid NMDAR phosphorylation [XREF_BIBR] and enhances glutamatergic neurotransmission [XREF_BIBR] leading to LTP [XREF_BIBR, XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
BDNF stimulates axonal growth by activating the TrkB receptor tyrosine kinase , and as this response does not depend on the hydrolysis of DAG , there is no obvious basis for postulating a role for the endocannabinoid signaling in the response .	BDNF stimulates axonal growth by activating the TrkB receptor tyrosine kinase, and as this response does not depend on the hydrolysis of DAG, there is no obvious basis for postulating a role for the endocannabinoid signaling in the response.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	7	8
We propose that BDNF released from diabetic DRG neurons activates neuronal TrkB through an autocrine mechanism .	We propose that BDNF released from diabetic DRG neurons activates neuronal TrkB through an autocrine mechanism.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	11	12
30 CRF 1 receptor Epac signaling then activates the extracellular signal regulated kinase-mitogen-activated protein kinase ( ERK-MAPK ) cascade , which , in turn , potentiates BDNF stimulated TrkB signaling , possibly by trafficking TrkB receptors to neuronal membranes .	30 CRF 1 receptor Epac signaling then activates the extracellular signal regulated kinase-mitogen-activated protein kinase (ERK-MAPK) cascade, which, in turn, potentiates BDNF stimulated TrkB signaling, possibly by trafficking TrkB receptors to neuronal membranes.	25	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	26	27	28	29
A role for BBS4 in TRKB receptor activation by BDNF , therefore , might suggest that the receptor localizes to cilia .	A role for BBS4 in TRKB receptor activation by BDNF, therefore, might suggest that the receptor localizes to cilia.	5	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	9	10	5	6
By using a peptide that competitively inhibits the association between UCH-L1 and TrkB , we show that the blockade of UCH-L1-regulated TrkB deubiquitination leads to increased BDNF induced TrkB internalization and consequently directs the internalized TrkB to the degradation pathway , resulting in increased degradation of surface TrkB and attenuation of TrkB activation and its downstream signaling pathways .	By using a peptide that competitively inhibits the association between UCH-L1 and TrkB, we show that the blockade of UCH-L1-regulated TrkB deubiquitination leads to increased BDNF induced TrkB internalization and consequently directs the internalized TrkB to the degradation pathway, resulting in increased degradation of surface TrkB and attenuation of TrkB activation and its downstream signaling pathways.	23	32	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	26	27	28	29
What is the functional role of BDNF induced TrkB translocation into lipid rafts ?	What is the functional role of BDNF induced TrkB translocation into lipid rafts?	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
Mature BDNF induced TrkB activation would then promote long lasting potentiation of synaptic efficacy in M1 .	Mature BDNF induced TrkB activation would then promote long lasting potentiation of synaptic efficacy in M1.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	3	4
The multifaceted effects of BDNF after SCI may be linked to SCI induced changes in ( i ) expression of TrkB receptor and downstream kinases , ( ii ) GABA transmission due to altered expression of chloride transporters , and ( iii ) the activity of astroglial cells .	The multifaceted effects of BDNF after SCI may be linked to SCI induced changes in (i) expression of TrkB receptor and downstream kinases, (ii) GABA transmission due to altered expression of chloride transporters, and (iii) the activity of astroglial cells.	2	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	20	21
Although BDNF transiently activates TrkB , leading to receptor internalization and ubiquitination and degradation , in contrast , 7,8-DHF-triggered TrkB phosphorylation lasts for hours , and the internalized receptors are not degraded .	Although BDNF transiently activates TrkB, leading to receptor internalization and ubiquitination and degradation, in contrast, 7,8-DHF-triggered TrkB phosphorylation lasts for hours, and the internalized receptors are not degraded.	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	1	2	4	5
BDNF is transported anterogradely and retrogradely and can activate TrkB receptors both pre- and postsynaptically .	BDNF is transported anterogradely and retrogradely and can activate TrkB receptors both pre- and postsynaptically.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	9	10
Research has shown that the activation of TrkB by BDNF increases with exercise and is reduced in models of fatigue .	Research has shown that the activation of TrkB by BDNF increases with exercise and is reduced in models of fatigue.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	7	8
Multiple post-translational modification signals are involved in the activation of TrkB by BDNF .	Multiple post-translational modification signals are involved in the activation of TrkB by BDNF.	5	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	10	11
Therefore , one possible reason that our results did not demonstrate that activity of CEP-701 could be predicted based on expression of TrkB is that exogenous BDNF is needed in in vitro models to activate the TrkB pathway .	Therefore, one possible reason that our results did not demonstrate that activity of CEP-701 could be predicted based on expression of TrkB is that exogenous BDNF is needed in in vitro models to activate the TrkB pathway.	25	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	26	27	36	37
In addition , microenvironmental BDNF mediated activation of TrkB resulted in increased metastatic potential of Her2+ cells and formation of Her2-TrkB heterodimers on breast cancer cells .	In addition, microenvironmental BDNF mediated activation of TrkB resulted in increased metastatic potential of Her2+ cells and formation of Her2-TrkB heterodimers on breast cancer cells.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	8	9
BDNF in turn activates TrkB receptors , which leads to down-regulation of KCC2 .	BDNF in turn activates TrkB receptors, which leads to down-regulation of KCC2.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	4	5
This released BDNF activates TrkB autoreceptors , which in turn increases the synthesis of BDNF .	This released BDNF activates TrkB autoreceptors, which in turn increases the synthesis of BDNF.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	4	5
In addition , BDNF application increases the dendritic localization of beta-actin , BDNF , and TrkB mRNAs .	In addition, BDNF application increases the dendritic localization of beta-actin, BDNF, and TrkB mRNAs.	3	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	15	16
In addition , BDNF induced TrkB activation stimulates the PI3K and AKT signaling pathways , which play a principal role in promoting neuronal survival and synaptic plasticity and antidepressant like actions , suggesting that VGF may feedback regulate the PI3K/AKT/mTOR signaling in hippocampus of mice .	In addition, BDNF induced TrkB activation stimulates the PI3K and AKT signaling pathways, which play a principal role in promoting neuronal survival and synaptic plasticity and antidepressant like actions, suggesting that VGF may feedback regulate the PI3K/AKT/mTOR signaling in hippocampus of mice.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	5	6
Lithium which has long been used for the management of bipolar disorders and mood stabilisation enhances BDNF expression and activates TrkB receptor in the cortical neurons which imparts neuroprotection against glutamate excitotoxicity [ XREF_BIBR ] .	Lithium which has long been used for the management of bipolar disorders and mood stabilisation enhances BDNF expression and activates TrkB receptor in the cortical neurons which imparts neuroprotection against glutamate excitotoxicity [XREF_BIBR].	0	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	Lithium which has long been used for the management of bipolar disorders and mood stabilisation enhances BDNF expression	bdnf	TrkB	TrkB	trkb	16	17	20	21
Moreover , BDNF activation of phospho-TrkB and downstream signal transduction was attenuated in R6/2 striatal cultures .	Moreover, BDNF activation of phospho-TrkB and downstream signal transduction was attenuated in R6/2 striatal cultures.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	phospho-TrkB	phospho-TrkB	phospho-TrkB	2	3	5	6
Retrolinkin recruits WAVE1 to the plasma membrane to activate Arp2/3 dependent actin polymerization , which is required for BDNF induced TrkB endocytosis and signaling during dendrite development .	Retrolinkin recruits WAVE1 to the plasma membrane to activate Arp2/3 dependent actin polymerization, which is required for BDNF induced TrkB endocytosis and signaling during dendrite development.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	20	21
Activation of TrkB by BDNF or 7,8-DHF increased intracellular Ca ( 2+ ) ( [ Ca ( 2+ ) ] i ) , an effect that was significantly larger in CHox cells .	Activation of TrkB by BDNF or 7,8-DHF increased intracellular Ca (2+) ([Ca (2+)] i), an effect that was significantly larger in CHox cells.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	2	3
Previous finding suggests that the responsiveness of TrkB to BDNF is regulated during development ; BDNF readily activates TrkB in early postnatal rat brain microslices , but this effect of BDNF is strongly blunted after the second week postnatally XREF_BIBR .	Previous finding suggests that the responsiveness of TrkB to BDNF is regulated during development; BDNF readily activates TrkB in early postnatal rat brain microslices, but this effect of BDNF is strongly blunted after the second week postnatally XREF_BIBR.	15	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	18	19
The upregulation of BDNF by treadmill training may enhance this process by releasing more BDNF at the growth cones and activating trkB receptors in an autocrine fashion .	The upregulation of BDNF by treadmill training may enhance this process by releasing more BDNF at the growth cones and activating trkB receptors in an autocrine fashion.	1	22	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	3	4	21	22
Together these data indicate that BDNF stimulation of TrkB recruits Numb to the activated receptor , and that Numb functions both as an endocytic adapter and a scaffold protein to recruit and activate aPKC .	Together these data indicate that BDNF stimulation of TrkB recruits Numb to the activated receptor, and that Numb functions both as an endocytic adapter and a scaffold protein to recruit and activate aPKC.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	8	9
Alternative studies show that the immature , proneurotrophin form of BDNF selectively activates p75 neurotrophin receptors ( p75NTR ) , which can increase NF-kappaB transcriptional activity ; while mature BDNF only stimulates TrkB neurotrophin receptors , which are intrinsically neuroprotective .	Alternative studies show that the immature, proneurotrophin form of BDNF selectively activates p75 neurotrophin receptors (p75NTR), which can increase NF-kappaB transcriptional activity; while mature BDNF only stimulates TrkB neurotrophin receptors, which are intrinsically neuroprotective.	28	34	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	29	30	32	33
Yet the steps between BDNF induced TrkB activation and changes in GABA A R function remain unclear .	Yet the steps between BDNF induced TrkB activation and changes in GABA A R function remain unclear.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	6	7
On the other hand , BDNF secreted at active synapses may induce TrkB receptors relocation from extra-synaptic sites to particular membrane microdomains enriched in synaptic zones , which could represent a complementary mechanism to the ones mentioned above .	On the other hand, BDNF secreted at active synapses may induce TrkB receptors relocation from extra-synaptic sites to particular membrane microdomains enriched in synaptic zones, which could represent a complementary mechanism to the ones mentioned above.	5	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	12	13
TrkB is activated equally by BDNF and NT4/5 and to a lesser extent by NT3 [ XREF_BIBR ] .	TrkB is activated equally by BDNF and NT4/5 and to a lesser extent by NT3 [XREF_BIBR].	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	0	1
According to this view , ketamine rapidly increases extracellular glutamate that contributes to depolarization and BDNF release , which in turn stimulates TrkB receptors .	According to this view, ketamine rapidly increases extracellular glutamate that contributes to depolarization and BDNF release, which in turn stimulates TrkB receptors.	13	23	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	15	16	22	23
BDNF can activate presynaptic trkB receptors on the DRG , inducing hypersensitivity in WT mice , whereas in eIF4E S209A mice , nociceptor hyperexcitability is diminished creating a blunted effect early on .	BDNF can activate presynaptic trkB receptors on the DRG, inducing hypersensitivity in WT mice, whereas in eIF4E S209A mice, nociceptor hyperexcitability is diminished creating a blunted effect early on.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	0	1	4	5
Coimmunoprecipitation and coimmunostaining demonstrated LAR interaction with TrkB that is increased by BDNF exposure .	Coimmunoprecipitation and coimmunostaining demonstrated LAR interaction with TrkB that is increased by BDNF exposure.	3	13	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	7	8
BDNF promotes neuronal survival and differentiation and modulates synaptic plasticity by activating the TrkB receptor tyrosine kinase .	BDNF promotes neuronal survival and differentiation and modulates synaptic plasticity by activating the TrkB receptor tyrosine kinase.	0	16	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	13	14
Subsequent evaluations confirmed that activation of TrkB by BDNF in SH-SY5Y-TrkB ( G12 ) cells was inhibited by CEP-751 in a dose dependent fashion [ XREF_BIBR ] .	Subsequent evaluations confirmed that activation of TrkB by BDNF in SH-SY5Y-TrkB (G12) cells was inhibited by CEP-751 in a dose dependent fashion [XREF_BIBR].	4	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	6	7
We obtained data that , similar to its effects on EphB2 receptor , ZVLL has no effects on the constitutive levels of TrkB ( XREF_FIG , lanes marked O ) but reduces both , the BDNF induced TrkB metabolism ( XREF_FIG , lanes marked 3h ) and the BDNF dependent neuroprotection ( XREF_FIG ) .	We obtained data that, similar to its effects on EphB2 receptor, ZVLL has no effects on the constitutive levels of TrkB (XREF_FIG, lanes marked O) but reduces both, the BDNF induced TrkB metabolism (XREF_FIG, lanes marked 3h) and the BDNF dependent neuroprotection (XREF_FIG).	34	38	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	35	36	37	38
By contrast , truncated TrkA and TrkB were robustly activated by NGF or BDNF , respectively ( XREF_FIG ) , suggesting that amitriptyline binding motif is not required for neurotrophins to trigger Trk receptor activation .	By contrast, truncated TrkA and TrkB were robustly activated by NGF or BDNF, respectively (XREF_FIG), suggesting that amitriptyline binding motif is not required for neurotrophins to trigger Trk receptor activation.	3	14	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	13	14	6	7
We propose models depicting the mutual regulation of SFKs and TrkB following activation of TrkB by zinc and BDNF .	We propose models depicting the mutual regulation of SFKs and TrkB following activation of TrkB by zinc and BDNF.	10	19	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	10	11
Since a robust BDNF up-regulation in the cortex of aged APdE9 mice was not associated with increased levels of Bdnf mRNA and enhanced TrkB signaling , it is unlikely that the increased BDNF protein resulted from increased BDNF synthesis .	Since a robust BDNF up-regulation in the cortex of aged APdE9 mice was not associated with increased levels of Bdnf mRNA and enhanced TrkB signaling, it is unlikely that the increased BDNF protein resulted from increased BDNF synthesis.	3	24	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	23	24
The activation of TrkB by BDNF has been suggested to enhance neuroblastoma cell survival and resistance to chemotherapy [ XREF_BIBR ] .	The activation of TrkB by BDNF has been suggested to enhance neuroblastoma cell survival and resistance to chemotherapy [XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	3	4
TrkB expressing neuroblastoma tumor cells treated with BDNF are less sensitive to cytotoxic drugs , survive under conditions of limiting growth factors , and display enhanced invasiveness and increased VEGF production .	TrkB expressing neuroblastoma tumor cells treated with BDNF are less sensitive to cytotoxic drugs, survive under conditions of limiting growth factors, and display enhanced invasiveness and increased VEGF production.	0	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	0	1
Importantly , these observations are potentially consistent with previous reports of intracellular regulation of BDNF dependent activation of TrkB .	Importantly, these observations are potentially consistent with previous reports of intracellular regulation of BDNF dependent activation of TrkB.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	18	19
TRKB , encoded by NTRK2 , is activated by BDNF and has been shown to promote neural cell plasticity and survival [ XREF_BIBR ] .	TRKB, encoded by NTRK2, is activated by BDNF and has been shown to promote neural cell plasticity and survival [XREF_BIBR].	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	9	10	0	1
In addition , intracortical BDNF infusions induced a sustained local activation of the TrkB receptor .	In addition, intracortical BDNF infusions induced a sustained local activation of the TrkB receptor.	4	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	13	14
The following steps occur once the cancer cells have invaded BM : first , BDNF derived from bone metastatic gastric cancer can stimulate TrkB on OBs [ XREF_BIBR , XREF_BIBR ] to directly promote RANKL production [ XREF_BIBR , XREF_BIBR ] .	The following steps occur once the cancer cells have invaded BM : first, BDNF derived from bone metastatic gastric cancer can stimulate TrkB on OBs [XREF_BIBR, XREF_BIBR] to directly promote RANKL production [XREF_BIBR, XREF_BIBR].	14	24	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	23	24
BDNF activated TrkB traffics through APPL1 positive endosomes .	BDNF activated TrkB traffics through APPL1 positive endosomes.	0	3	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Titration assay showed that BDNF elicited TrkB activation at a concentration of 1-30 nmol/l and the signals escalated as the doses increased ( XREF_SUPPLEMENTARY ) .	Titration assay showed that BDNF elicited TrkB activation at a concentration of 1-30 nmol/l and the signals escalated as the doses increased (XREF_SUPPLEMENTARY).	4	7	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	6	7
Moreover , a study reported that actin depolymerization rather than polymerization is essential for internalization of NGF activated TrkA in distal axons of sympathetic neurons , in contrast to our findings that WAVE1 promoted actin polymerization is required for endocytosis of BDNF activated TrkB in dendrites of CNS neurons .	Moreover, a study reported that actin depolymerization rather than polymerization is essential for internalization of NGF activated TrkA in distal axons of sympathetic neurons, in contrast to our findings that WAVE1 promoted actin polymerization is required for endocytosis of BDNF activated TrkB in dendrites of CNS neurons.	39	44	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	41	42	43	44
Increased BDNF expression is likely to enhance the activation of TrkB downstream pathways , possibly involving a cascade of events that include MAPK , phosphatidylinositol and/or PLC-gamma pathways .	Increased BDNF expression is likely to enhance the activation of TrkB downstream pathways, possibly involving a cascade of events that include MAPK, phosphatidylinositol and/or PLC-gamma pathways.	1	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF expression	bdnf	TrkB	TrkB	trkb	1	2	10	11
To determine if BDNF or NTF3 activate TrkB signaling in a breast cancer model , we stably transfected empty vector ( EV ) or TrkB into MCF7 and T47D cells ( XREF_FIG ) .	To determine if BDNF or NTF3 activate TrkB signaling in a breast cancer model, we stably transfected empty vector (EV) or TrkB into MCF7 and T47D cells (XREF_FIG).	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	7	8
The cleaved ( mature ) BDNF can activate TrkB receptors and promote cell survival and synaptic plasticity .	The cleaved (mature) BDNF can activate TrkB receptors and promote cell survival and synaptic plasticity.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	8	9
BDNF was demonstrated to activate TrkB receptors , which in turn activated PLCgamma .	BDNF was demonstrated to activate TrkB receptors, which in turn activated PLCgamma.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	5	6
It is possible that the continuous administration of BDNF produces a down-regulation of its high-affinity TrkB receptor , leading to a decrease of neuronal responsiveness to BDNF .	It is possible that the continuous administration of BDNF produces a down-regulation of its high-affinity TrkB receptor, leading to a decrease of neuronal responsiveness to BDNF.	6	16	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	15	16
Overall , the results of this study suggest that dopamine D1 receptor signaling can contribute to increase BDNF protein synthesis , which could potentially initiate BDNF and TrkB activity .	Overall, the results of this study suggest that dopamine D1 receptor signaling can contribute to increase BDNF protein synthesis, which could potentially initiate BDNF and TrkB activity.	17	28	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	17	18	27	28
Neurotrophins exert their influence on neurons mainly through Trk receptor tyrosine kinases : NGF activates TrkA ; BDNF and NT4/5 activate TrkB ; and NT3 activates TrkC .	Neurotrophins exert their influence on neurons mainly through Trk receptor tyrosine kinases : NGF activates TrkA; BDNF and NT4/5 activate TrkB; and NT3 activates TrkC.	17	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	17	18	21	22
BDNF mediated TrkB signaling is required to protect striatal neurons against NMDA induced excitotoxicity , 23 which is well known to contributes to the striatal cell loss in HD .	BDNF mediated TrkB signaling is required to protect striatal neurons against NMDA induced excitotoxicity, 23 which is well known to contributes to the striatal cell loss in HD.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Similarly , longer survival effects and activation of the ERK signaling pathway are found in axotomized RGCs that are transfected with the TrkB gene and treated with exogenous BDNF in the rat retina .	Similarly, longer survival effects and activation of the ERK signaling pathway are found in axotomized RGCs that are transfected with the TrkB gene and treated with exogenous BDNF in the rat retina.	22	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	28	29	22	23
The retinal neuroepithelium has been shown to be a site where BDNF induced activation of the TrkB pathway occurs , which promotes the differentiation and survival of the retinal pigment epithelium ( Liu et al ., 1997 ) .	The retinal neuroepithelium has been shown to be a site where BDNF induced activation of the TrkB pathway occurs, which promotes the differentiation and survival of the retinal pigment epithelium (Liu et al., 1997).	11	17	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	16	17
To our knowledge , so far no studies have specifically addressed BDNF induced activation of TrkB receptors in the context of their partitioning at post-synaptic rafts , although a plethora of studies attributes a role of post-synaptic BDNF-TrkB signaling in synapse formation and plasticity .	To our knowledge, so far no studies have specifically addressed BDNF induced activation of TrkB receptors in the context of their partitioning at post-synaptic rafts, although a plethora of studies attributes a role of post-synaptic BDNF-TrkB signaling in synapse formation and plasticity.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	15	16
These data suggest that a stress induced activation of TrkB by BDNF in the anterior BNST is an important mechanism contributing to social withdrawal in female California mice .	These data suggest that a stress induced activation of TrkB by BDNF in the anterior BNST is an important mechanism contributing to social withdrawal in female California mice.	7	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	9	10
BDNF induced TrkB activation stimulates pro survival mediated by PI3K-AKT and MEK-Erk pathways .	BDNF induced TrkB activation stimulates pro survival mediated by PI3K-AKT and MEK-Erk pathways.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Therefore , as found with isolated mitochondria , neither CsA nor BKA were able to inhibit Bax induced release of cytochrome C in intact cells .	Therefore, as found with isolated mitochondria, neither CsA nor BKA were able to inhibit Bax induced release of cytochrome C in intact cells.	15	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	16	17	20	22
Effectors BAK and BAX oligomerize and form pores in the outer mitochondrial membrane , allowing cytochrome C ( and other mitochondrial proteins such as Smac/Diablo ) to escape to the cytoplasm .	Effectors BAK and BAX oligomerize and form pores in the outer mitochondrial membrane, allowing cytochrome C (and other mitochondrial proteins such as Smac/Diablo) to escape to the cytoplasm.	3	17	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome C	cytochrome C	cytochrome C	3	4	15	17
Activation of caspase was induced independently from the CD95 and CD95L signaling pathway by release of mitochondrial cytochrome C , apparently triggered by Bax and Bak [ XREF_BIBR ] .	Activation of caspase was induced independently from the CD95 and CD95L signaling pathway by release of mitochondrial cytochrome C, apparently triggered by Bax and Bak [XREF_BIBR].	17	27	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	23	24	17	19
Bax and Bak , called the effector Bcl-2 proteins , function downstream of BOPs and enable release of cytochrome c into the cytosol .	Bax and Bak, called the effector Bcl-2 proteins, function downstream of BOPs and enable release of cytochrome c into the cytosol.	0	20	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	18	20
It has been suggested that a high Bax to Bcl-2 ratio can cause MMP collapse and result in the release of cytochrome c and subsequent apoptosis .	It has been suggested that a high Bax to Bcl-2 ratio can cause MMP collapse and result in the release of cytochrome c and subsequent apoptosis.	5	23	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	21	23
In cells undergoing staurosporine induced apoptosis , levels of the pro apoptotic protein Bax at the mitochondrion are increased , resulting in release of cytochrome c and subsequent activation of caspase 9 and caspase 3 [ XREF_BIBR , XREF_BIBR ] .	In cells undergoing staurosporine induced apoptosis, levels of the pro apoptotic protein Bax at the mitochondrion are increased, resulting in release of cytochrome c and subsequent activation of caspase 9 and caspase 3 [XREF_BIBR, XREF_BIBR].	7	26	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	levels of the pro apoptotic protein Bax	bax	cytochrome c	cytochrome c	cytochrome c	13	14	24	26
On the other hand , in cells injected with Ab # 25 and rBax , the distribution of cytochrome c and F 1 ATPase was almost completely concordant ( XREF_FIG ) , as is the case in healthy cells ( data not shown ) , indicating that Bax induced cytochrome c release was prevented by Ab # 25 .	On the other hand, in cells injected with Ab # 25 and rBax, the distribution of cytochrome c and F 1 ATPase was almost completely concordant (XREF_FIG), as is the case in healthy cells (data not shown), indicating that Bax induced cytochrome c release was prevented by Ab # 25.	47	51	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	47	48	49	51
The activation and oligomerization of Bax results in the formation of a voltage dependent anion channel ( VDAC )-containing pore or the permeabilization of the mitochondrial membranes to initiate cytochrome c release , which activates downstream effector caspases .	The activation and oligomerization of Bax results in the formation of a voltage dependent anion channel (VDAC)-containing pore or the permeabilization of the mitochondrial membranes to initiate cytochrome c release, which activates downstream effector caspases.	1	31	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	29	31
On the other hand , a reducing agent , dithiothreitol ( DTT ) , inhibited BAX insertion and oligomerization augmented by tBID or Ca 2+ and suppressed the BAX mediated release of cytochrome c and Smac/DIABLO but failed to inhibit Ca 2+ -induced swelling .	On the other hand, a reducing agent, dithiothreitol (DTT), inhibited BAX insertion and oligomerization augmented by tBID or Ca 2+ and suppressed the BAX mediated release of cytochrome c and Smac/DIABLO but failed to inhibit Ca 2+ -induced swelling.	27	39	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	28	29	32	34
Of all the Bcl-2 family of pro survival proteins , Bcl-x L has been specifically implicated as a critical link between BAD- and BAX mediated cytochrome C release .	Of all the Bcl-2 family of pro survival proteins, Bcl-x L has been specifically implicated as a critical link between BAD- and BAX mediated cytochrome C release.	19	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome C	cytochrome C	cytochrome C	23	24	25	27
Their overexpression increases the Bax and Bcl -2 ratio allowing the release of cytochrome C from mitochondria to promote apoptosis [ XREF_BIBR ] .	Their overexpression increases the Bax and Bcl -2 ratio allowing the release of cytochrome C from mitochondria to promote apoptosis [XREF_BIBR].	3	15	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	4	5	13	15
Bcl-2 , p-Bad ( phosphate-Bcl-2-associated death promoter ) and Bcl-xL ( B-cell lymphoma-extra large ) prevent cytochrome c release whereas Bad , Bak and Bax enhance cytochrome c release from mitochondria [ XREF_BIBR ] .	Bcl-2, p-Bad (phosphate-Bcl-2-associated death promoter) and Bcl-xL (B-cell lymphoma-extra large) prevent cytochrome c release whereas Bad, Bak and Bax enhance cytochrome c release from mitochondria [XREF_BIBR].	20	28	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	24	25	26	28
On the other hand increasing of Bax and Bcl-2ratio up-regulates caspase-3and releases cytochrome C from mitochondria and finally induces cell apoptosis .	On the other hand increasing of Bax and Bcl-2ratio up-regulates caspase-3and releases cytochrome C from mitochondria and finally induces cell apoptosis.	4	14	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	6	7	12	14
Calpain is also able to cleave pro apoptotic Bcl-2 family proteins including Bid and Bax , which in turn mediates cytochrome c release and initiates the apoptotic execution XREF_BIBR - XREF_BIBR .	Calpain is also able to cleave pro apoptotic Bcl-2 family proteins including Bid and Bax, which in turn mediates cytochrome c release and initiates the apoptotic execution XREF_BIBR - XREF_BIBR.	10	22	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	14	15	20	22
The repurified BAX ( A112C-V177C ) retained 6A7 positivity ( XREF_SUPPLEMENTARY ) , but was unable to induce cytochrome c release ( XREF_SUPPLEMENTARY ) .	The repurified BAX (A112C-V177C) retained 6A7 positivity (XREF_SUPPLEMENTARY), but was unable to induce cytochrome c release (XREF_SUPPLEMENTARY).	0	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	2	3	18	20
By contrast , PKA phosphorylation of Bax promotes its translocation to mitochondria and triggers cytochrome c release and apoptosis [ XREF_BIBR , XREF_BIBR ] .	By contrast, PKA phosphorylation of Bax promotes its translocation to mitochondria and triggers cytochrome c release and apoptosis [XREF_BIBR, XREF_BIBR].	3	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	PKA phosphorylation of Bax	bax	cytochrome c	cytochrome c	cytochrome c	6	7	14	16
Bax and Bak induce cytochrome c release .	Bax and Bak induce cytochrome c release.	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	4	6
Expression of the pro apoptotic protein Bax in yeast Saccharomyces cerevisiae induces a release of cytochrome c accompanied by a decrease of the amount of cytochrome c oxidase .	Expression of the pro apoptotic protein Bax in yeast Saccharomyces cerevisiae induces a release of cytochrome c accompanied by a decrease of the amount of cytochrome c oxidase.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Expression of the pro apoptotic protein Bax	bax	cytochrome c	cytochrome c	cytochrome c	6	7	15	17
For example , Bcl-2 inhibits apoptosis by inhibiting cytochrome c release and caspase activation , while Bax promotes apoptosis by inducing the release of cytochrome c , which then triggers the downstream apoptosis event [ XREF_BIBR ] .	For example, Bcl-2 inhibits apoptosis by inhibiting cytochrome c release and caspase activation, while Bax promotes apoptosis by inducing the release of cytochrome c, which then triggers the downstream apoptosis event [XREF_BIBR].	16	26	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	24	26
This initiates pro apoptosis changes in Bax and Bcl-x ( L ) and Bax translocation to the mitochondria , inducing cytochrome c release .	This initiates pro apoptosis changes in Bax and Bcl-x (L) and Bax translocation to the mitochondria, inducing cytochrome c release.	13	22	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax translocation to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	13	14	20	22
Interestingly , Drp1 was also reported to bind cardiolipin and this interaction was required for BAX induced cytochrome c release in vitro [ XREF_BIBR ] .	Interestingly, Drp1 was also reported to bind cardiolipin and this interaction was required for BAX induced cytochrome c release in vitro [XREF_BIBR].	15	19	induced	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	15	16	17	19
During NGF deprivation , sympathetic neurons activate the MLK-JNK signaling pathway , which leads to the up-regulation of proapoptotic BH3-only Bcl-2 family members , followed by Bax mediated cytochrome c release and caspase activation .	During NGF deprivation, sympathetic neurons activate the MLK-JNK signaling pathway, which leads to the up-regulation of proapoptotic BH3-only Bcl-2 family members, followed by Bax mediated cytochrome c release and caspase activation.	24	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	26	27	28	30
Here , we showed that in isolated mitochondria , Bim induced loss of membrane potential and cytochrome c release like Bax and Bak , with these changes being inhibited by an anti-VDAC antibody .	Here, we showed that in isolated mitochondria, Bim induced loss of membrane potential and cytochrome c release like Bax and Bak, with these changes being inhibited by an anti-VDAC antibody.	14	22	potential	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	20	21	16	18
BAX and BAD are both pro apoptotic members of the Bcl-2 family and mediate the release of cytochrome c from the mitochondria and thus induce the intrinsic apoptotic pathway [ XREF_BIBR ] .	BAX and BAD are both pro apoptotic members of the Bcl-2 family and mediate the release of cytochrome c from the mitochondria and thus induce the intrinsic apoptotic pathway [XREF_BIBR].	0	24	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	0	1	17	19
26 How Bax triggers release of cytochrome c is not well understood , but it likely involves the formation of the mitochondrial permeability transition pore .	26 How Bax triggers release of cytochrome c is not well understood, but it likely involves the formation of the mitochondrial permeability transition pore.	2	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	6	8
The Bcl-2 protein family are important regulators of caspase-9 activation , where the Bcl-2 and Bax ratio in the mitochondria modulate the level of cytochrome c release after apoptotic stimuli ( Adams and Cory , 1998 ; Hengartner , 2000 ) .	The Bcl-2 protein family are important regulators of caspase-9 activation, where the Bcl-2 and Bax ratio in the mitochondria modulate the level of cytochrome c release after apoptotic stimuli (Adams and Cory, 1998; Hengartner, 2000).	13	26	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	24	26
The main finding of our study with isolated brain mitochondria is that recombinant BAX oligo induces massive cytochrome c release by the mechanism associated with the mPT but without involvement of oxidative stress .	The main finding of our study with isolated brain mitochondria is that recombinant BAX oligo induces massive cytochrome c release by the mechanism associated with the mPT but without involvement of oxidative stress.	12	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	13	14	17	19
However , the molecular mechanisms by which Bax triggers cytochrome c release are unknown .	However, the molecular mechanisms by which Bax triggers cytochrome c release are unknown.	7	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	9	11
During mechanistic studies of cell death , B2 upregulated expression of the proapoptotic gene Bax ( 2.8 fold at 48 h pt ) and induced loss of mitochondria membrane potential ( MMP ) but not mitochondrial cytochrome c release .	During mechanistic studies of cell death, B2 upregulated expression of the proapoptotic gene Bax (2.8 fold at 48 h pt) and induced loss of mitochondria membrane potential (MMP) but not mitochondrial cytochrome c release.	7	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	B2 upregulated expression of the proapoptotic gene Bax	bax	cytochrome c	cytochrome c	cytochrome c	14	15	36	38
Therefore , ROS/RS appear to lie both up- and downstream of cytochrome c redistribution in NGF deprived sympathetic neurons and other cells and are a critical component of the mechanism by which Bax causes cytochrome c release .	Therefore, ROS/RS appear to lie both up- and downstream of cytochrome c redistribution in NGF deprived sympathetic neurons and other cells and are a critical component of the mechanism by which Bax causes cytochrome c release.	32	36	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	32	33	34	36
Bax , a proapoptotic member of the Bcl-2 family , interacts with MPT pore to induce permeability transition and cytochrome c release which is a key event in apoptosis [ XREF_BIBR ] .	Bax, a proapoptotic member of the Bcl-2 family, interacts with MPT pore to induce permeability transition and cytochrome c release which is a key event in apoptosis [XREF_BIBR].	0	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	19	21
Mechanistically , the association of HK with mitochondria interferes with cytochrome c release induced by Bax and Bak , as well as the ensuing activation of caspases and apoptosis .	Mechanistically, the association of HK with mitochondria interferes with cytochrome c release induced by Bax and Bak, as well as the ensuing activation of caspases and apoptosis.	10	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	10	12
In isolated mitochondria , recombinant Bax enhanced succinate induced cardiolipin oxidation and cytochrome c release .	In isolated mitochondria, recombinant Bax enhanced succinate induced cardiolipin oxidation and cytochrome c release.	4	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	12	14
35 Moreover , Bax has been reported to induce cytochrome c release that in turn activates caspase 3 .	35 Moreover, Bax has been reported to induce cytochrome c release that in turn activates caspase 3.	3	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	9	11
A decreased Bax to Bcl-2 ratio can inhibit cytochrome c release , and consequently suppresses apoptosis [ XREF_BIBR ] , since the release of cytochrome c from the mitochondria is known to activate apoptosis .	A decreased Bax to Bcl-2 ratio can inhibit cytochrome c release, and consequently suppresses apoptosis [XREF_BIBR], since the release of cytochrome c from the mitochondria is known to activate apoptosis.	2	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	8	10
Cytoplasmic cytochrome C release is promoted by Bax [ XREF_BIBR ] and inhibited by Bcl-2 and Bc-xL [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Cytoplasmic cytochrome C release is promoted by Bax [XREF_BIBR] and inhibited by Bcl-2 and Bc-xL [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	9	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	7	8	1	3
Therefore , the observed cytochrome c release in the presence of xanthurenic acid in isolated mitochondria is not mediated by Bax dimerization .	Therefore, the observed cytochrome c release in the presence of xanthurenic acid in isolated mitochondria is not mediated by Bax dimerization.	4	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	20	21	4	6
BAX mediated the release of mitochondrial cytochrome c , activation of caspase-3 and cell death partially through the lysosome-cathepsin B-tBid pathway .	BAX mediated the release of mitochondrial cytochrome c, activation of caspase-3 and cell death partially through the lysosome-cathepsin B-tBid pathway.	0	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
Bax , Bad , and Bid form channels allowing the release of cytochrome c from the mitochondrial inter-membrane space .	Bax, Bad, and Bid form channels allowing the release of cytochrome c from the mitochondrial inter-membrane space.	0	14	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	12	14
Silencing Bax with a specific small interfering RNA blocked manumycin induced mitochondrial condensation and cytochrome c release , arguing the dependence of manumycin induced apoptosis on Bax .	Silencing Bax with a specific small interfering RNA blocked manumycin induced mitochondrial condensation and cytochrome c release, arguing the dependence of manumycin induced apoptosis on Bax.	0	16	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	14	16
In addition , BAD SAHB A , which has the identical staple position as BIM SAHB A but otherwise contains distinct amino acid sequence , did not bind ( XREF_SUPPLEMENTARY ) or oligomerize ( XREF_FIG ) BAX , or induce BAX mediated cytochrome c release ( XREF_FIG , XREF_SUPPLEMENTARY ) .	In addition, BAD SAHB A, which has the identical staple position as BIM SAHB A but otherwise contains distinct amino acid sequence, did not bind (XREF_SUPPLEMENTARY) or oligomerize (XREF_FIG) BAX, or induce BAX mediated cytochrome c release (XREF_FIG, XREF_SUPPLEMENTARY).	39	44	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	40	41	42	44
As seen with liposomes , Bcl-XL inhibited tBid and Bax mediated cytochrome c release .	As seen with liposomes, Bcl-XL inhibited tBid and Bax mediated cytochrome c release.	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	9	10	11	13
Bax and Bid potentiate cytochrome c release , whereas Bcl-2 and Bcl-X ( L ) antagonize this event .	Bax and Bid potentiate cytochrome c release, whereas Bcl-2 and Bcl-X (L) antagonize this event.	0	6	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	4	6
When expressed in yeast , full-length untagged human Bax remains cytosolic and induces neither cytochrome c release nor cell death .	When expressed in yeast, full-length untagged human Bax remains cytosolic and induces neither cytochrome c release nor cell death.	5	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	14	16
Increased levels of Bax protein have been shown to directly induce release of cytochrome c by forming a pore in the outer membrane of mitochondria [ XREF_BIBR ] .	Increased levels of Bax protein have been shown to directly induce release of cytochrome c by forming a pore in the outer membrane of mitochondria [XREF_BIBR].	3	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	13	15
Meanwhile , esculetin increased the activities of caspase-3 and caspase-9 , promoted bax expression , decreased bcl-2 expression , and triggered collapse of mitochondrial membrane potential , and increased cytochrome c release from mitochondria .	Meanwhile, esculetin increased the activities of caspase-3 and caspase-9, promoted bax expression, decreased bcl-2 expression, and triggered collapse of mitochondrial membrane potential, and increased cytochrome c release from mitochondria.	2	31	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	bax	esculetin increased the activities of caspase-3 and caspase-9, promoted bax expression	bax	cytochrome c	cytochrome c	cytochrome c	12	13	29	31
Most of the available data surrounding the apoptotic pathway suggest that BAK and BAX mediation of cytochrome c release ( irrespective of whether components of the permeability transition pore complex are involved ) mark apoptotic cell death , whereas cytochrome c release exclusively mediated by VDAC and ANT implies non apoptotic , mainly necrotic cell death XREF_BIBR .	Most of the available data surrounding the apoptotic pathway suggest that BAK and BAX mediation of cytochrome c release (irrespective of whether components of the permeability transition pore complex are involved) mark apoptotic cell death, whereas cytochrome c release exclusively mediated by VDAC and ANT implies non apoptotic, mainly necrotic cell death XREF_BIBR.	11	18	mediation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	13	14	16	18
We conclude that JNK dependent regulation of Bax is essential to mediate the apoptotic release of cytochrome c regardless of Bid and Bim activation .	We conclude that JNK dependent regulation of Bax is essential to mediate the apoptotic release of cytochrome c regardless of Bid and Bim activation.	5	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	16	18
The presence of the voltage dependent anion channel was not required either for Bax oligomerization or for Bax induced cytochrome c release .	The presence of the voltage dependent anion channel was not required either for Bax oligomerization or for Bax induced cytochrome c release.	10	21	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	17	18	19	21
In apoptosis , the Bcl-2 family protein Bax ( and Bak ) also inserts into the mitochondrial outer membrane to form a permeation pore that allows the release of cytochrome c from the intermembrane space to the cytoplasm .	In apoptosis, the Bcl-2 family protein Bax (and Bak) also inserts into the mitochondrial outer membrane to form a permeation pore that allows the release of cytochrome c from the intermembrane space to the cytoplasm.	3	31	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	29	31
However , other groups found that cytochrome c release and cell killing mediated by heterologously expressed BAX did not depend on the presence of cardiolipin .	However, other groups found that cytochrome c release and cell killing mediated by heterologously expressed BAX did not depend on the presence of cardiolipin.	6	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	16	17	6	8
As is well known , Bax is a pro apoptotic member of the Bcl-2 protein group and induces mitochondrial disruption and the release of cytochrome-c , thus activating caspase-9 followed by Apaf-1 factor , which then turns on the intrinsic caspase cascade .	As is well known, Bax is a pro apoptotic member of the Bcl-2 protein group and induces mitochondrial disruption and the release of cytochrome-c, thus activating caspase-9 followed by Apaf-1 factor, which then turns on the intrinsic caspase cascade.	5	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome-c	cytochrome-c	cytochrome-c	5	6	24	25
Upon apoptotic stimuli , BAX , which resides on the mitochondrial outer membrane , dysregulated the mitochondrial outer membrane permeability and induced the release of cytochrome c from the mitochondrial intermembrane space to cytosol [ XREF_BIBR ] .	Upon apoptotic stimuli, BAX, which resides on the mitochondrial outer membrane, dysregulated the mitochondrial outer membrane permeability and induced the release of cytochrome c from the mitochondrial intermembrane space to cytosol [XREF_BIBR].	4	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	4	5	25	27
Previous studies showed that Bax and Bcl -2 acted in mitochondria to cause the cytochrome c release into cytoplasm , and then cytochrome c , apoptotic protease activating factor-1 , and procaspase-9 formed a complex leading to caspase-9 activation .	Previous studies showed that Bax and Bcl -2 acted in mitochondria to cause the cytochrome c release into cytoplasm, and then cytochrome c, apoptotic protease activating factor-1, and procaspase-9 formed a complex leading to caspase-9 activation.	4	16	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	14	16
Of note , while the mechanism by which Bax induces cytochrome c release is still a matter of intense debate , our results suggested that , in the context of complex I deficiency , this phenomenon seems to be independent of the mitochondrial permeability transition pore , since Bax induced cytochrome c release in MPP + ( 1-methyl-4-phenylpyridinium ion )-treated brain mitochondria was not responsive to the mitochondrial pore blocker cyclosporin A and mice deficient for cyclophilin D , a critical component of the mitochondrial pore , did not exhibit a reduced susceptibility to MPTP [ XREF_BIBR ] .	Of note, while the mechanism by which Bax induces cytochrome c release is still a matter of intense debate, our results suggested that, in the context of complex I deficiency, this phenomenon seems to be independent of the mitochondrial permeability transition pore, since Bax induced cytochrome c release in MPP + (1-methyl-4-phenylpyridinium ion)-treated brain mitochondria was not responsive to the mitochondrial pore blocker cyclosporin A and mice deficient for cyclophilin D, a critical component of the mitochondrial pore, did not exhibit a reduced susceptibility to MPTP [XREF_BIBR].	48	52	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	48	49	50	52
The presence of Bax and Bcl-2 also caused the release of cytochrome c in the mitochondria , the results of which are concordant with those of Zhang et al .	The presence of Bax and Bcl-2 also caused the release of cytochrome c in the mitochondria, the results of which are concordant with those of Zhang et al.	1	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	11	13
One explanation for this contradictory finding is that upon activation Bax changes its conformation , translocated to the outer mitochondrial membrane , and induced cytochrome C release , so that transcriptional activation is not required to induce or accelerate apoptotic cell death .	One explanation for this contradictory finding is that upon activation Bax changes its conformation, translocated to the outer mitochondrial membrane, and induced cytochrome C release, so that transcriptional activation is not required to induce or accelerate apoptotic cell death.	9	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	10	11	24	26
4-HPR causes elevation of Bax to induce mitochondrial release of cytochrome c for activation of caspase-3 and also to release AIF into the cytosol and its nuclear translocation for apoptosis .	4-HPR causes elevation of Bax to induce mitochondrial release of cytochrome c for activation of caspase-3 and also to release AIF into the cytosol and its nuclear translocation for apoptosis.	2	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	10	12
The increased Bax and Bcl -2 ratio leads to DeltaPsim collapse , cytochrome c release , caspase-3 activation , and eventually apoptosis [ XREF_BIBR ] .	The increased Bax and Bcl -2 ratio leads to DeltaPsim collapse, cytochrome c release, caspase-3 activation, and eventually apoptosis [XREF_BIBR].	0	14	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	12	14
High glucose also causes a 2 fold increase in Bax expression , which induced cytochrome C release which in turn stimulates apoptosis activating factor , caspase 9 and caspase 3 [ XREF_BIBR ] .	High glucose also causes a 2 fold increase in Bax expression, which induced cytochrome C release which in turn stimulates apoptosis activating factor, caspase 9 and caspase 3 [XREF_BIBR].	1	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	glucose also causes a 2 fold increase in Bax expression	bax	cytochrome C	cytochrome C	cytochrome c	9	10	14	16
Oligomeric BAX induces mitochondrial permeability transition and complete cytochrome c release without oxidative stress .	Oligomeric BAX induces mitochondrial permeability transition and complete cytochrome c release without oxidative stress.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	1	2	8	10
Using CRD1 and PGS1 deletion yeast strains it was shown , that mitochondria lacking cardiolipin are able to release cytochrome c when treated with Bax XREF_BIBR and that the expression of Bax in these strains induces killing as it does in wild type strains XREF_BIBR .	Using CRD1 and PGS1 deletion yeast strains it was shown, that mitochondria lacking cardiolipin are able to release cytochrome c when treated with Bax XREF_BIBR and that the expression of Bax in these strains induces killing as it does in wild type strains XREF_BIBR.	19	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	24	25	19	21
The family can be divided into pro apoptotic proteins like BAX , BAK , which potentiate MOMP , cytochrome c release and cell death , and anti-apoptotic proteins like BCL2 , BCLxl , BCLw which inhibit MOMP to allow cell survival [ XREF_BIBR - XREF_BIBR ] .	The family can be divided into pro apoptotic proteins like BAX, BAK, which potentiate MOMP, cytochrome c release and cell death, and anti-apoptotic proteins like BCL2, BCLxl, BCLw which inhibit MOMP to allow cell survival [XREF_BIBR - XREF_BIBR].	4	20	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	10	11	18	20
We found that BAX SAHB , like BIM SAHB , engaged BAX at the N-terminal trigger site and induced sequence specific BAX oligomerization and BAX mediated cytochrome c release 68 .	We found that BAX SAHB, like BIM SAHB, engaged BAX at the N-terminal trigger site and induced sequence specific BAX oligomerization and BAX mediated cytochrome c release 68.	18	28	mediated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	21	22	26	28
Increased Bax and Bcl -2 ratio leads to DeltaPsim collapse , cytochrome c release , caspase-3 activation , and eventually apoptosis [ XREF_BIBR ] .	Increased Bax and Bcl -2 ratio leads to DeltaPsim collapse, cytochrome c release, caspase-3 activation, and eventually apoptosis [XREF_BIBR].	0	13	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	11	13
The proapoptotic proteins Bax and Bak form oligometric channels in the mitochondrial outer membrane , and cause the exit of the cytochrome c into the cytosol .	The proapoptotic proteins Bax and Bak form oligometric channels in the mitochondrial outer membrane, and cause the exit of the cytochrome c into the cytosol.	0	23	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	21	23
Bax Triggers the Release of Cytochrome C from Mitochondria in a Dose- and Time dependent Manner .	Bax Triggers the Release of Cytochrome C from Mitochondria in a Dose- and Time dependent Manner.	0	7	Triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome C	Cytochrome C	Cytochrome C	0	1	5	7
Bcl-2 proteins inhibit cytochrome c release by protecting permeability transition and stabilising the function of the outer mitochondrial membrane , whereas Bax proteins induce the release of cytochrome c XREF_BIBR XREF_BIBR - XREF_BIBR .	Bcl-2 proteins inhibit cytochrome c release by protecting permeability transition and stabilising the function of the outer mitochondrial membrane, whereas Bax proteins induce the release of cytochrome c XREF_BIBR XREF_BIBR - XREF_BIBR.	21	30	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	21	22	27	29
Although the mechanism by which Bax triggers cytochrome c release is not clear , studies in cell-free systems have shown that Bax interacts either with the mitochondrial permeability transition ( PT ) pore components , the voltage dependent anion channel ( Shimizu et al , 1999 ) and the adenine nucleotide translocator ( Marzo et al , 1998 ) , or with cardiolipin of the outer membrane ( Kuwana et al , 2002 ) to form megachannels that allow the passage of cytochrome c.	Although the mechanism by which Bax triggers cytochrome c release is not clear, studies in cell-free systems have shown that Bax interacts either with the mitochondrial permeability transition (PT) pore components, the voltage dependent anion channel (Shimizu et al, 1999) and the adenine nucleotide translocator (Marzo et al, 1998), or with cardiolipin of the outer membrane (Kuwana et al, 2002) to form megachannels that allow the passage of cytochrome c.	5	9	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	7	9
These findings suggest that Bax mediates cytochrome c release and mitochondrial depolarization in lymphocytes , at least in part , via its interaction with mitochondrial Kv1.3 .	These findings suggest that Bax mediates cytochrome c release and mitochondrial depolarization in lymphocytes, at least in part, via its interaction with mitochondrial Kv1.3.	4	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	6	8
In addition , DMOG treatment increased the expression of hexokinase 2 ( Hk2 ) , a primary initiator of glycolysis that binds mitochondria to inhibit Bax induced cytochrome c release and apoptosis XREF_BIBR , in both the proximal and distal parts of the skin flaps relative to those of the untreated group ( XREF_FIG ) .	In addition, DMOG treatment increased the expression of hexokinase 2 (Hk2), a primary initiator of glycolysis that binds mitochondria to inhibit Bax induced cytochrome c release and apoptosis XREF_BIBR, in both the proximal and distal parts of the skin flaps relative to those of the untreated group (XREF_FIG).	24	29	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	25	26	27	29
Furthermore , the decrease of Bax expression impairs the release of cytochrome C from the mitochondrial inner membrane , which in turn compromises the activation of procaspase 9 and procaspase 3 .	Furthermore, the decrease of Bax expression impairs the release of cytochrome C from the mitochondrial inner membrane, which in turn compromises the activation of procaspase 9 and procaspase 3.	5	13	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax expression	bax	cytochrome C	cytochrome C	cytochrome c	5	6	11	13
When active Bim is overexpressed in Bax and Bak double deficient mitochondria , low levels ( about 50nM ) of recombinant Bax are sufficient to cause cytochrome c release .	When active Bim is overexpressed in Bax and Bak double deficient mitochondria, low levels (about 50nM) of recombinant Bax are sufficient to cause cytochrome c release.	14	28	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	levels (about 50nM) of recombinant Bax	bax	cytochrome c	cytochrome c	cytochrome c	21	22	26	28
Rather , the cytochrome C release induced by Bax is facilitated by Mg 2+ and can not be blocked by PTP inhibitors .	Rather, the cytochrome C release induced by Bax is facilitated by Mg 2+ and can not be blocked by PTP inhibitors.	3	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	8	9	3	5
Furthermore , the addition of naltrindole lead to changes in the brain glioma cell membrane potential and regulated Bax translocation to the mitochondrial membrane , consequently promoting the release of cytochrome c into the cytoplasm , followed by the activation of caspase-9 and -3 , which caused cell apoptosis .	Furthermore, the addition of naltrindole lead to changes in the brain glioma cell membrane potential and regulated Bax translocation to the mitochondrial membrane, consequently promoting the release of cytochrome c into the cytoplasm, followed by the activation of caspase-9 and -3, which caused cell apoptosis.	18	32	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax translocation to the mitochondrial membrane	bax	cytochrome c	cytochrome c	cytochrome c	18	19	30	32
The conformationally altered Bax protein oligomerizes on the mitochondrial outer membrane , induces cytochrome c release , and then causes the cells to undergo apoptosis [ XREF_BIBR ] .	The conformationally altered Bax protein oligomerizes on the mitochondrial outer membrane, induces cytochrome c release, and then causes the cells to undergo apoptosis [XREF_BIBR].	3	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	13	15
These results , together with our observation that Bax and Bak but not Bid and Bik induce cytochrome c release in mitochondria isolated from yeast cells ( unpublished observation ) , suggest that Bid and Bik probably targets a distinct molecule on the mitochondrial outer membrane to induce cytochrome c release ( XREF_FIG ) .	These results, together with our observation that Bax and Bak but not Bid and Bik induce cytochrome c release in mitochondria isolated from yeast cells (unpublished observation), suggest that Bid and Bik probably targets a distinct molecule on the mitochondrial outer membrane to induce cytochrome c release (XREF_FIG).	8	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	17	19
In addition , we found that an oxidative stress was not required for a complete cytochrome c release produced by BAX oligo or by antibiotic alamethicin , which eliminated barrier properties of the OMM [ XREF_BIBR ] .	In addition, we found that an oxidative stress was not required for a complete cytochrome c release produced by BAX oligo or by antibiotic alamethicin, which eliminated barrier properties of the OMM [XREF_BIBR].	15	21	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	20	21	15	17
Moreover , Bax is known to trigger cytochrome c release when added directly to isolated mitochondria .	Moreover, Bax is known to trigger cytochrome c release when added directly to isolated mitochondria.	2	9	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	7	9
Mitochondrial dynamics have been extensively studied in the context of classical cell death models involving Bax mediated cytochrome c release .	Mitochondrial dynamics have been extensively studied in the context of classical cell death models involving Bax mediated cytochrome c release.	15	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	17	19
Bax induces the release of cytochrome c and activates the Bax initiated mitochondria pathway and the capsese 3 dependent apoptotic pathway .	Bax induces the release of cytochrome c and activates the Bax initiated mitochondria pathway and the capsese 3 dependent apoptotic pathway.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Once localized to the mitochondrial outer membrane , Bax induces the release of cytochrome c into the cytosol and the ensuing caspase activation and cell death .	Once localized to the mitochondrial outer membrane, Bax induces the release of cytochrome c into the cytosol and the ensuing caspase activation and cell death.	8	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	13	15
Selenite triggers a conformational change in Bax , as detected by the 6A7 antibody , and leads to Bax translocation into the mitochondria , where Bax forms oligomers to mediate cytochrome c release .	Selenite triggers a conformational change in Bax, as detected by the 6A7 antibody, and leads to Bax translocation into the mitochondria, where Bax forms oligomers to mediate cytochrome c release.	25	32	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	25	26	30	32
In the mitochondrial apoptosis pathway , caspase activation is triggered by BAX and BAK dependent permeabilization of the outer mitochondrial membrane ( OMM ) allowing the release of cytochrome c into the cytosol where it stimulates events leading to caspase activation .	In the mitochondrial apoptosis pathway, caspase activation is triggered by BAX and BAK dependent permeabilization of the outer mitochondrial membrane (OMM) allowing the release of cytochrome c into the cytosol where it stimulates events leading to caspase activation.	11	30	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	11	12	28	30
However , oxidative stress could also promote the mPT [ XREF_BIBR ] , which we found to be associated with the cytochrome c release induced by BAX oligo in brain mitochondria .	However, oxidative stress could also promote the mPT [XREF_BIBR], which we found to be associated with the cytochrome c release induced by BAX oligo in brain mitochondria.	21	30	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	26	27	21	23
There is compelling evidence that Bax channel activity stimulates cytochrome c release leading ultimately to cell death , which is a key event in ischemic injuries and neurodegenerative diseases .	There is compelling evidence that Bax channel activity stimulates cytochrome c release leading ultimately to cell death, which is a key event in ischemic injuries and neurodegenerative diseases.	5	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	9	11
Oligomeric Bax and Bak proteins that are inserted into the outer mitochondrial membrane can cause alterations of membrane permeability and the release of cytochrome c , which eventually activates caspase 3 for executing cell apoptosis [ XREF_BIBR ] .	Oligomeric Bax and Bak proteins that are inserted into the outer mitochondrial membrane can cause alterations of membrane permeability and the release of cytochrome c, which eventually activates caspase 3 for executing cell apoptosis [XREF_BIBR].	0	25	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	23	25
It is known that the oligomeric form of the pro apoptotic protein BAX stimulates cytochrome c release .	It is known that the oligomeric form of the pro apoptotic protein BAX stimulates cytochrome c release.	6	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	12	13	14	16
Although the induction of Puma only ( not depicted ) or that of wild-type Bax only ( XREF_FIG ) had no detectable effect on yeast viability , the coexpression of Bax and Puma induced yeast cell death ( XREF_FIG ) and cytochrome c release ( XREF_FIG ) .	Although the induction of Puma only (not depicted) or that of wild-type Bax only (XREF_FIG) had no detectable effect on yeast viability, the coexpression of Bax and Puma induced yeast cell death (XREF_FIG) and cytochrome c release (XREF_FIG).	28	43	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	coexpression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	30	31	41	43
In response to apoptotic stimuli , Bad and Bax translocate to mitochondria to initiate the release of cytochrome c , which is able to trigger the apoptotic signaling cascade by activating the caspase-9 and caspase-3 , resulting in nuclear fragmentation and cell death [ XREF_BIBR ] .	In response to apoptotic stimuli, Bad and Bax translocate to mitochondria to initiate the release of cytochrome c, which is able to trigger the apoptotic signaling cascade by activating the caspase-9 and caspase-3, resulting in nuclear fragmentation and cell death [XREF_BIBR].	6	19	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax translocate to mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	8	9	17	19
These data support the hypothesis that stimulation of Bax mediated cytochrome c release by both agents from the mitochondria and formation of the apoptosome results in the initial activation of caspase-9 .	These data support the hypothesis that stimulation of Bax mediated cytochrome c release by both agents from the mitochondria and formation of the apoptosome results in the initial activation of caspase-9.	6	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	10	12
Thus , irrespective of PT dependence , Bax induced cytochrome c release always requires the VDAC ( XREF_FIG ) .	Thus, irrespective of PT dependence, Bax induced cytochrome c release always requires the VDAC (XREF_FIG).	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	9	11
Previous studies have shown that translocation of Bax from the cytosol to mitochondria induces the release of cytochrome c from mitochondria and thereby leads to activation of caspases .	Previous studies have shown that translocation of Bax from the cytosol to mitochondria induces the release of cytochrome c from mitochondria and thereby leads to activation of caspases.	5	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	translocation of Bax from the cytosol to mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	7	8	17	19
Oligomeric Bax pore inhibitors ( Bci1 and Bci2 ) have been shown to prevent cytochrome c release from ischemic hippocampal cells in gerbils XREF_BIBR .	Oligomeric Bax pore inhibitors (Bci1 and Bci2) have been shown to prevent cytochrome c release from ischemic hippocampal cells in gerbils XREF_BIBR.	1	16	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	14	16
Caspases activated by Bax induced cytochrome c released from mitochondria apparently gain access to the mitochondrial intermembrane space following OMM permeabilization where they cleave the NDUFS1 subunit of the first respiratory complex .	Caspases activated by Bax induced cytochrome c released from mitochondria apparently gain access to the mitochondrial intermembrane space following OMM permeabilization where they cleave the NDUFS1 subunit of the first respiratory complex.	1	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	5	7
Granzyme and perforin- and Fas dependent cell death require the activation of executioner caspase pathways including caspase 3 and 7 or mitochondrial cytochrome c efflux mediated by Bad and Bax .	Granzyme and perforin- and Fas dependent cell death require the activation of executioner caspase pathways including caspase 3 and 7 or mitochondrial cytochrome c efflux mediated by Bad and Bax.	22	30	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	29	30	22	24
z-VAD-fmk did neither prevent Bax expression nor Bax induced intracytosolic release of cytochrome c , but prevented cell death induction ( XREF_FIG A ) , nuclear DNA degradation ( hypodiploidy ) and mitochondrial transmembrane potential ( DeltaPsim ) loss , caspase-9 , and caspase-3 processing , PARP cleavage , and the intracytosolic release of AIF ( XREF_FIG A ) .	z-VAD-fmk did neither prevent Bax expression nor Bax induced intracytosolic release of cytochrome c, but prevented cell death induction (XREF_FIG A), nuclear DNA degradation (hypodiploidy) and mitochondrial transmembrane potential (DeltaPsim) loss, caspase-9, and caspase-3 processing, PARP cleavage, and the intracytosolic release of AIF (XREF_FIG A).	4	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax expression	bax	cytochrome c	cytochrome c	cytochrome c	4	5	12	14
While pro apoptotic Bax promotes the release of cytochrome C into the cytosol from mitochondria , the anti-apoptotic Bcl-2 preserves the integrity of the mitochondria [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	While pro apoptotic Bax promotes the release of cytochrome C into the cytosol from mitochondria, the anti-apoptotic Bcl-2 preserves the integrity of the mitochondria [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	3	4	8	10
During p73 dependent apoptosis , p73 is localized and remains within the nucleus , whereas Bax translocates from the cytosol to the mitochondria to trigger cytochrome c release , indicating an indirect interaction between p73 and Bax .	During p73 dependent apoptosis, p73 is localized and remains within the nucleus, whereas Bax translocates from the cytosol to the mitochondria to trigger cytochrome c release, indicating an indirect interaction between p73 and Bax.	15	27	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax translocates from the cytosol to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	15	16	25	27
To explicitly link the BAX SAHB interaction with functional activation of BAX , we performed BAX oligomerization and BAX mediated cytochrome c release assays .	To explicitly link the BAX SAHB interaction with functional activation of BAX, we performed BAX oligomerization and BAX mediated cytochrome c release assays.	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	18	19	20	22
The ` executioners ' , Bak and Bax , initiate apoptosis by increasing mitochondrial outer membrane permeability and facilitating the release of mitochondrial cytochrome c to the cytosol , which activates downstream signaling .	The ` executioners ', Bak and Bax, initiate apoptosis by increasing mitochondrial outer membrane permeability and facilitating the release of mitochondrial cytochrome c to the cytosol, which activates downstream signaling.	2	25	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	23	25
Using mitochondria isolated from different mutants of the yeast Saccharomyces cerevisiae and recombinant proteins , we have now investigated components of the mitochondrial outer membrane that might be required for tBid and Bax induced cytochrome c release .	Using mitochondria isolated from different mutants of the yeast Saccharomyces cerevisiae and recombinant proteins, we have now investigated components of the mitochondrial outer membrane that might be required for tBid and Bax induced cytochrome c release.	28	36	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	32	33	34	36
Bax induces cytochrome C release by multiple mechanisms in the mitochondria 51 , and modulation of this process is one of the most promising strategies in drug design XREF_BIBR - XREF_BIBR .	Bax induces cytochrome C release by multiple mechanisms in the mitochondria 51, and modulation of this process is one of the most promising strategies in drug design XREF_BIBR - XREF_BIBR.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	0	1	2	4
The Bax channel inhibitors prevented cytochrome c release from mitochondria , inhibited the decrease in the mitochondrial membrane potential , and protected cells against apoptosis .	The Bax channel inhibitors prevented cytochrome c release from mitochondria, inhibited the decrease in the mitochondrial membrane potential, and protected cells against apoptosis.	1	7	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	5	7
While amphiphilic cations , such as dibucaine and propranolol , inhibit Bax mediated cytochrome c release , transient receptor potential channel inhibitors inhibit mitochondrial swelling and cytochrome c release induced by the inner membrane permeability transition .	While amphiphilic cations, such as dibucaine and propranolol, inhibit Bax mediated cytochrome c release, transient receptor potential channel inhibitors inhibit mitochondrial swelling and cytochrome c release induced by the inner membrane permeability transition.	11	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	13	15
Bax can trigger the release of Cytochrome c ( 17kDa ) , SMAC/DIABLO ( 27kDa ) and AIF ( 67kDa ) from purified mitochondria , suggesting that Bax pore size is larger than the size of these proteins .	Bax can trigger the release of Cytochrome c (17kDa), SMAC/DIABLO (27kDa) and AIF (67kDa) from purified mitochondria, suggesting that Bax pore size is larger than the size of these proteins.	0	8	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome c	Cytochrome c	Cytochrome c	0	1	6	8
The imbalance of Bcl-2 and Bax can induce the release of cytochrome c from the mitochondria , which can bind with the Apaf-1 and pro-caspase-9 to form apoptosome .	The imbalance of Bcl-2 and Bax can induce the release of cytochrome c from the mitochondria, which can bind with the Apaf-1 and pro-caspase-9 to form apoptosome.	1	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	11	13
BAX activates the release of Cytochrome C via membrane remodeling and increasing membrane permeability , which subsequently results in the activation of caspases ( XREF_FIG ) .	BAX activates the release of Cytochrome C via membrane remodeling and increasing membrane permeability, which subsequently results in the activation of caspases (XREF_FIG).	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	Cytochrome C	Cytochrome C	Cytochrome C	0	1	5	7
Moreover , Bax triggers the release of cytochrome C from isolated mitochondria after overexpression in many cell types ; however , how Bax triggers the release of cytochrome C is still unknown .	Moreover, Bax triggers the release of cytochrome C from isolated mitochondria after overexpression in many cell types; however, how Bax triggers the release of cytochrome C is still unknown.	22	29	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	22	23	27	29
Induction of Bax by the Tet-On system initiated cytochrome c release from mitochondria , caspase-3 activation , and apoptosis to some extent in DLD-1 cells .	Induction of Bax by the Tet-On system initiated cytochrome c release from mitochondria, caspase-3 activation, and apoptosis to some extent in DLD-1 cells.	0	10	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	8	10
Cyclosporine , an inhibitor of the permeability transition , blocked this Bax mediated cytochrome c release 65 .	Cyclosporine, an inhibitor of the permeability transition, blocked this Bax mediated cytochrome c release 65.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	13	15
Although Bax is found only in higher eukaryotes , it was shown that recombinant mammalian Bax induces the release of cytochrome c upon incubation with isolated yeast mitochondria .	Although Bax is found only in higher eukaryotes, it was shown that recombinant mammalian Bax induces the release of cytochrome c upon incubation with isolated yeast mitochondria.	13	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	20	22
Using isolated mitochondria , we found that recombinant Bax and Bak , proapoptotic members of the Bcl-2 family , induced mitochondrial Deltapsi loss , swelling , and cytochrome c release .	Using isolated mitochondria, we found that recombinant Bax and Bak, proapoptotic members of the Bcl-2 family, induced mitochondrial Deltapsi loss, swelling, and cytochrome c release.	7	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	27	29
As we all know , Bax promotes the release of cytochrome c , and activates caspase-9 and caspase-3 .	As we all know, Bax promotes the release of cytochrome c, and activates caspase-9 and caspase-3.	5	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	10	12
Once they are activated , effector proteins BAX and BAK oligomerize in the mitochondrial outer membrane to promote MOMP and cytochrome c release .	Once they are activated, effector proteins BAX and BAK oligomerize in the mitochondrial outer membrane to promote MOMP and cytochrome c release.	5	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	7	8	20	22
However , it still remains unknown whether BAX oligo causes a release of cytochrome c from brain mitochondria in an mPT dependent or mPT independent manner .	However, it still remains unknown whether BAX oligo causes a release of cytochrome c from brain mitochondria in an mPT dependent or mPT independent manner.	7	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	7	8	13	15
Alternatively , antagonists of MAC potentially could protect transplanted neuronal precursor cells from apoptosis , as well as prevent HIV-1 induced lymphocyte depletion , severe congenital neutropenia , and other pathologies associated with Bax induced cytochrome c release .	Alternatively, antagonists of MAC potentially could protect transplanted neuronal precursor cells from apoptosis, as well as prevent HIV-1 induced lymphocyte depletion, severe congenital neutropenia, and other pathologies associated with Bax induced cytochrome c release.	31	37	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	33	34	35	37
Importantly , the same antibodies inhibited Bax induced cytochrome c release in the absence of Ca 2+ , that was PT inhibitor resistant .	Importantly, the same antibodies inhibited Bax induced cytochrome c release in the absence of Ca 2+, that was PT inhibitor resistant.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
As Bax and Bak oligomers mediate the release of cytochrome c from mitochondria , this could explain , in part , the ability of mtHK to maintain mitochondrial integrity and inhibit apoptosis [ XREF_BIBR , XREF_BIBR ] .	As Bax and Bak oligomers mediate the release of cytochrome c from mitochondria, this could explain, in part, the ability of mtHK to maintain mitochondrial integrity and inhibit apoptosis [XREF_BIBR, XREF_BIBR].	1	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	9	11
In this scenario , complex I blockade increases the soluble pool of cytochrome c in the mitochondrial intermembrane space through oxidative mechanisms , whereas activation of pro cell death protein Bax triggers neuronal death by permeabilizing the outer mitochondrial membrane and releasing cytochrome c into the cytosol .	In this scenario, complex I blockade increases the soluble pool of cytochrome c in the mitochondrial intermembrane space through oxidative mechanisms, whereas activation of pro cell death protein Bax triggers neuronal death by permeabilizing the outer mitochondrial membrane and releasing cytochrome c into the cytosol.	24	44	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	30	31	42	44
Induction of MAC formation by several means , such as staurosporine treatment , IL-3 withdrawal , exogenous expression of Bax and tBid lead to release of cytochrome c in different cell lines .	Induction of MAC formation by several means, such as staurosporine treatment, IL-3 withdrawal, exogenous expression of Bax and tBid lead to release of cytochrome c in different cell lines.	17	28	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	19	20	26	28
Cleaved caspase-8 is involved in initiating the extrinsic pathway , while BAX polymerization mediates mitochondrial cytochrome c release as an early step in the intrinsic pathway .	Cleaved caspase-8 is involved in initiating the extrinsic pathway, while BAX polymerization mediates mitochondrial cytochrome c release as an early step in the intrinsic pathway.	11	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	11	12	15	17
After translocation to the mitochondria , Bax induces the release of cytochrome C , and Akt inhibits apoptosis by altering mitochondrial membrane potentials , thus inhibiting the release of cytochrome C [ XREF_BIBR - XREF_BIBR ] .	After translocation to the mitochondria, Bax induces the release of cytochrome C, and Akt inhibits apoptosis by altering mitochondrial membrane potentials, thus inhibiting the release of cytochrome C [XREF_BIBR - XREF_BIBR].	6	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	6	7	11	13
During apoptosis , translocation of Bax from the cytosol to the mitochondria in the spinal cords of G93A mice XREF_BIBR triggers the release of cytochrome c from the mitochondria XREF_BIBR .	During apoptosis, translocation of Bax from the cytosol to the mitochondria in the spinal cords of G93A mice XREF_BIBR triggers the release of cytochrome c from the mitochondria XREF_BIBR.	3	26	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	translocation of Bax from the cytosol to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	5	6	24	26
As shown in XREF_FIG B ( bottom ) , PT independent cytochrome c release induced by Bax was also inhibited by both Ab # 20 and Ab # 25 , indicating an essential role of the VDAC in Bax induced cytochrome c release regardless of PT dependency .	As shown in XREF_FIG B (bottom), PT independent cytochrome c release induced by Bax was also inhibited by both Ab # 20 and Ab # 25, indicating an essential role of the VDAC in Bax induced cytochrome c release regardless of PT dependency.	36	42	induced	Positive_early_activation	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	38	39	40	42
In addition , ATR-1 can cause Bax activation and release of cytochrome c and Smac/Diablo into cytosol .	In addition, ATR-1 can cause Bax activation and release of cytochrome c and Smac/Diablo into cytosol.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	11	13
Deletion of Bak and Bax prevents release of mitochondrial cytochrome C and blocks the apoptotic response of intrinsic apoptotic inducers STS and etoposide .	Deletion of Bak and Bax prevents release of mitochondrial cytochrome C and blocks the apoptotic response of intrinsic apoptotic inducers STS and etoposide.	0	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	4	5	9	11
Previously , BAK and BAX lacing the C-terminal fragment ( BAXDeltaC ) were shown to induce modest cytochrome c ( Cyt c ) release from rat brain mitochondria when activated by tBID .	Previously, BAK and BAX lacing the C-terminal fragment (BAXDeltaC) were shown to induce modest cytochrome c (Cyt c) release from rat brain mitochondria when activated by tBID.	2	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	4	5	17	19
It has been shown that Bax high levels induces apoptosis by increasing the release of cytochrome c and caspase activation in vivo and in vitro XREF_BIBR .	It has been shown that Bax high levels induces apoptosis by increasing the release of cytochrome c and caspase activation in vivo and in vitro XREF_BIBR.	5	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax high levels	bax	cytochrome c	cytochrome c	cytochrome c	5	6	15	17
Increased oligomerization of Bax within the mitochondrial outer membrane promotes cytochrome c release into the cytosol .	Increased oligomerization of Bax within the mitochondrial outer membrane promotes cytochrome c release into the cytosol.	1	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	10	12
In contrast , the upregulation and redistribution of Bax from the cytosol to the mitochondria could promote the release of cytochrome c XREF_BIBR .	In contrast, the upregulation and redistribution of Bax from the cytosol to the mitochondria could promote the release of cytochrome c XREF_BIBR.	4	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	20	22
The overexpression of Bax protein modulates mitochondrial membrane potential and increases cytochrome c release in cell cytoplasm .	The overexpression of Bax protein modulates mitochondrial membrane potential and increases cytochrome c release in cell cytoplasm.	1	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	overexpression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	3	4	11	13
Here , we report the identification of a soluble form of the pilus protein FimA from the culture supernatants of E. coli K1 , Salmonella , and Shigella that can potently inhibit Bax mediated release of cytochrome c from isolated mitochondria .	Here, we report the identification of a soluble form of the pilus protein FimA from the culture supernatants of E. coli K1, Salmonella, and Shigella that can potently inhibit Bax mediated release of cytochrome c from isolated mitochondria.	31	38	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	32	33	36	38
The imbalance of Bax and Bcl -2 promoted additional release of cytochrome-c , which contributes to the activation of caspase-9 and the subsequent activation of caspase-3 .	The imbalance of Bax and Bcl -2 promoted additional release of cytochrome-c, which contributes to the activation of caspase-9 and the subsequent activation of caspase-3.	1	14	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome-c	cytochrome-c	cytochrome-c	3	4	11	12
Bax can promote the release of cytochrome C into the cytosol from mitochondria .	Bax can promote the release of cytochrome C into the cytosol from mitochondria.	0	8	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	0	1	6	8
BAX and BAK begin to form the oligomers , destroy the mitochondrial outer membrane , and promote cytochrome c release , which activate caspase-9 to cleaved caspase-9 , depending on activated APAF1 .	BAX and BAK begin to form the oligomers, destroy the mitochondrial outer membrane, and promote cytochrome c release, which activate caspase-9 to cleaved caspase-9, depending on activated APAF1.	0	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	0	1	17	19
Bax has been reported to induce cytochrome c release both in Bax expressing cells and in isolated mitochondria incubated with recombinant oligomerized Bax .	Bax has been reported to induce cytochrome c release both in Bax expressing cells and in isolated mitochondria incubated with recombinant oligomerized Bax.	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
In addition , PHA665752 induced apoptosis occurs through activation of Bax mediated release of cytochrome c and activation of caspases .	In addition, PHA665752 induced apoptosis occurs through activation of Bax mediated release of cytochrome c and activation of caspases.	8	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	10	11	14	16
It has been shown that after activated by some BH3 only proteins , Bax can induce the release of cytochrome c from purified mitochondria , and the release of dextrans up to 2,000 kDa from liposomes .	It has been shown that after activated by some BH3 only proteins, Bax can induce the release of cytochrome c from purified mitochondria, and the release of dextrans up to 2,000 kDa from liposomes.	13	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	13	14	19	21
Bax is an apoptosis promoter of Bcl-2 family , under the influence of apoptotic stimuli , such as oxidative stress , Bax could cause the release of cytochrome C and stimulate programmed cell death .	Bax is an apoptosis promoter of Bcl-2 family, under the influence of apoptotic stimuli, such as oxidative stress, Bax could cause the release of cytochrome C and stimulate programmed cell death.	21	30	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	21	22	27	29
It was found that corosolic acid increased the Bax and Bcl -2 ratio by up-regulating Bax expression , disrupted mitochondrial membrane potential and triggered the release of cytochrome c from mitochondria into the cytoplasm .	It was found that corosolic acid increased the Bax and Bcl -2 ratio by up-regulating Bax expression, disrupted mitochondrial membrane potential and triggered the release of cytochrome c from mitochondria into the cytoplasm.	5	29	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	acid increased the Bax and Bcl -2 ratio by up-regulating Bax expression	bax	cytochrome c	cytochrome c	cytochrome c	15	16	27	29
The pro apoptotic protein Bax can translocate to the outer membrane of mitochondria , change mitochondrial membrane permeability , and promote the loss of Deltapsim and cytochrome c release XREF_BIBR , XREF_BIBR .	The pro apoptotic protein Bax can translocate to the outer membrane of mitochondria, change mitochondrial membrane permeability, and promote the loss of Deltapsim and cytochrome c release XREF_BIBR, XREF_BIBR.	0	29	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax can translocate to the outer membrane	bax	cytochrome c	cytochrome c	cytochrome c	4	5	26	28
Increased Bax and Bcl -2 ratio leads to cytochrome C release , caspase-3 activation , and eventually apoptosis [ XREF_BIBR ] .	Increased Bax and Bcl -2 ratio leads to cytochrome C release, caspase-3 activation, and eventually apoptosis [XREF_BIBR].	0	10	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	1	2	8	10
Cytochrome c release and caspase activation are prevented by Bcl-2 , while Bax promotes cytochrome c release and caspase-3 activation [ XREF_BIBR ] .	Cytochrome c release and caspase activation are prevented by Bcl-2, while Bax promotes cytochrome c release and caspase-3 activation [XREF_BIBR].	12	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	12	13	14	16
The release of cytochrome c induced in our experiments either by BAX oligo or by alamethicin was not accompanied by the increased generation of ROS .	The release of cytochrome c induced in our experiments either by BAX oligo or by alamethicin was not accompanied by the increased generation of ROS.	3	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	11	12	3	5
The Bax and Bcl -2 ratio is an important determinant of cytochrome c release from mitochondria in response to apoptotic stimuli ; a high Bax and Bcl -2 ratio promotes cytochrome c release while low ratios inhibit release , and release of cytochrome c in turn activates caspase proteins .	The Bax and Bcl -2 ratio is an important determinant of cytochrome c release from mitochondria in response to apoptotic stimuli; a high Bax and Bcl -2 ratio promotes cytochrome c release while low ratios inhibit release, and release of cytochrome c in turn activates caspase proteins.	22	32	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	24	25	30	32
Moreover , although Bax induced cytochrome c release was not dependent on tBid , the two proteins could function synergistically .	Moreover, although Bax induced cytochrome c release was not dependent on tBid, the two proteins could function synergistically.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	5	7
p53 can be activated upon oxidative stress and initiates apoptosis through binding to mitochondrial Bcl-2 , displacing Bax , which induces apoptosis and cytochrome C release from the mitochondria .	p53 can be activated upon oxidative stress and initiates apoptosis through binding to mitochondrial Bcl-2, displacing Bax, which induces apoptosis and cytochrome C release from the mitochondria.	14	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	17	18	23	25
In addition , BAX SAHB dose-responsively triggered BAX mediated mitochondrial cytochrome c release ( XREF_FIG ) , but had no effect in the absence of added recombinant BAX ( XREF_SUPPLEMENTARY ) .	In addition, BAX SAHB dose-responsively triggered BAX mediated mitochondrial cytochrome c release (XREF_FIG), but had no effect in the absence of added recombinant BAX (XREF_SUPPLEMENTARY).	7	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	7	8	10	12
PrP does not colocalize with Bax in normal or apoptotic primary neurons and can not prevent Bax mediated cytochrome c release in a mitochondrial cell-free system .	PrP does not colocalize with Bax in normal or apoptotic primary neurons and can not prevent Bax mediated cytochrome c release in a mitochondrial cell-free system.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	18	20
It has been shown that the introduction of recombinant Bax protein into isolated mitochondria induced cytochrome c release .	It has been shown that the introduction of recombinant Bax protein into isolated mitochondria induced cytochrome c release.	9	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	9	10	15	17
Bax and Bak induced the release of cytochrome c , whereas anti-apoptotic Bcl-2 family members inhibited the release of cytochrome c.	Bax and Bak induced the release of cytochrome c, whereas anti-apoptotic Bcl-2 family members inhibited the release of cytochrome c.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	7	9
This is relevant because activated Bax causes the release of cytochrome C from mitochondria .	This is relevant because activated Bax causes the release of cytochrome C from mitochondria.	4	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	5	6	10	12
These results demonstrate that immature brain mitochondria and mitochondria from undifferentiated neural cells are particularly sensitive to cytochrome c release mediated by endogenous Bax and a BH3 death domain peptide .	These results demonstrate that immature brain mitochondria and mitochondria from undifferentiated neural cells are particularly sensitive to cytochrome c release mediated by endogenous Bax and a BH3 death domain peptide.	17	29	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	23	24	17	19
Furthermore , Bax overexpressed in Cc-GFP-HeLa treated with FCCP induced cytochrome c-GFP release in a similar number of cells as compared with control cells ( not shown ) .	Furthermore, Bax overexpressed in Cc-GFP-HeLa treated with FCCP induced cytochrome c-GFP release in a similar number of cells as compared with control cells (not shown).	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax overexpressed	bax	cytochrome c-GFP	cytochrome c-GFP	cytochrome c-gfp	2	3	10	12
Bax binds to the mitochondrial membrane and induces cytochrome c release , which subsequently activates caspase-9 and caspase-3 leading to downstream apoptotic responses XREF_BIBR .	Bax binds to the mitochondrial membrane and induces cytochrome c release, which subsequently activates caspase-9 and caspase-3 leading to downstream apoptotic responses XREF_BIBR.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
When apoptosis is triggered , Bak and Bax undergo conformational changes to form homo-oligomers and mediate cytochrome c release .	When apoptosis is triggered, Bak and Bax undergo conformational changes to form homo-oligomers and mediate cytochrome c release.	5	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	16	18
Notably , apoptosis induced by FGFR4 depletion was found to be FLIP-, caspase 8-, caspase 9- and Bax dependent , suggesting that FLIP downregulation following FGFR4 silencing leads to caspase 8 activation , which then cross-talks with the mitochondria to promote Bax mediated release of cytochrome c and activation of caspase 9 followed by activation of the executioner caspases 3 and 7 .	Notably, apoptosis induced by FGFR4 depletion was found to be FLIP-, caspase 8-, caspase 9- and Bax dependent, suggesting that FLIP downregulation following FGFR4 silencing leads to caspase 8 activation, which then cross-talks with the mitochondria to promote Bax mediated release of cytochrome c and activation of caspase 9 followed by activation of the executioner caspases 3 and 7.	40	47	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	41	42	45	47
Bax mediates the permeabilization of the outer mitochondrial membrane and the release of cytochrome c into the cytoplasm , which activates caspase-3 to induce chromosome cleavage and apoptosis .	Bax mediates the permeabilization of the outer mitochondrial membrane and the release of cytochrome c into the cytoplasm, which activates caspase-3 to induce chromosome cleavage and apoptosis.	0	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
Testing roles of Bax and Bak in C12 induced depolarization of Deltaphi mito and release of cytochrome C from mitochondria in MEF .	Testing roles of Bax and Bak in C12 induced depolarization of Deltaphi mito and release of cytochrome C from mitochondria in MEF.	1	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	3	4	16	18
Overexpression of mitochondrially located catalase ( MitoCatalase ) specifically increased basal Bcl-2 and decreased basal Bax expression , suppressed cytokine mediated reduction of Bcl-2 , and thereby prevented the release of cytochrome c , Smac/DIABLO and the activation of caspase-9 and -3 .	Overexpression of mitochondrially located catalase (MitoCatalase) specifically increased basal Bcl-2 and decreased basal Bax expression, suppressed cytokine mediated reduction of Bcl-2, and thereby prevented the release of cytochrome c, Smac/DIABLO and the activation of caspase-9 and -3.	0	33	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Overexpression of mitochondrially located catalase (MitoCatalase) specifically increased basal Bcl-2 and decreased basal Bax expression	bax	cytochrome c	cytochrome c	cytochrome c	15	16	31	33
Bax Induces Mitochondrial Shrinking and Triggers Cytochrome C Efflux from Mitochondria .	Bax Induces Mitochondrial Shrinking and Triggers Cytochrome C Efflux from Mitochondria.	0	8	Triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome C	Cytochrome C	Cytochrome C	0	1	6	8
Bax activates the release of cytochrome c , while DDB2 promotes the degradation of p21 , which leads to activation of E2F1 and induction of Apaf-1 .	Bax activates the release of cytochrome c, while DDB2 promotes the degradation of p21, which leads to activation of E2F1 and induction of Apaf-1.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
For example , Bax has been shown to translocate from the cytosol to the mitochondrial membrane after treatment with an apoptotic stimulus ( Zhang et al , 1998 ) , and cause subsequent cytochrome c release and caspase activation .	For example, Bax has been shown to translocate from the cytosol to the mitochondrial membrane after treatment with an apoptotic stimulus (Zhang et al, 1998), and cause subsequent cytochrome c release and caspase activation.	3	35	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	33	35
The Bcl-2 family has pro and anti-apoptotic roles , BcL-2 itself is a pro survival protein , while Bax is involved in permeabilization of the mitochondrial outer membrane , causing release of cytochrome c and other apoptotic factors into the cytosol XREF_BIBR .	The Bcl-2 family has pro and anti-apoptotic roles, BcL-2 itself is a pro survival protein, while Bax is involved in permeabilization of the mitochondrial outer membrane, causing release of cytochrome c and other apoptotic factors into the cytosol XREF_BIBR.	18	34	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	18	19	32	34
Dimerization of tBid and Bax leads to the opening of mitochondrial transition pore , thereby releasing cytochrome C , which initiates caspase 3 dependent cell death .	Dimerization of tBid and Bax leads to the opening of mitochondrial transition pore, thereby releasing cytochrome C, which initiates caspase 3 dependent cell death.	0	18	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	4	5	16	18
Although how Bax and Bak induce the MOMP remains elusive , it seems to be clear that Bax coalescence through translocation to the OMM and Bak activation promote mitochondrial fragmentation and cytochrome c release .	Although how Bax and Bak induce the MOMP remains elusive, it seems to be clear that Bax coalescence through translocation to the OMM and Bak activation promote mitochondrial fragmentation and cytochrome c release.	17	33	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	17	18	31	33
HK2 has been proposed to inhibit apoptosis by inhibiting Bax mediated cytochrome c release and downstream apoptotic initiation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , although a specific mechanism for this has yet to be delineated .	HK2 has been proposed to inhibit apoptosis by inhibiting Bax mediated cytochrome c release and downstream apoptotic initiation [XREF_BIBR, XREF_BIBR, XREF_BIBR], although a specific mechanism for this has yet to be delineated.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	9	10	11	13
A study in thyroid cancer cells showed that BASP1 overexpression increases the expression of bax , promote cytochrome C release , and activate caspase-3 , which ultimately results in apoptosis 25 .	A study in thyroid cancer cells showed that BASP1 overexpression increases the expression of bax, promote cytochrome C release, and activate caspase-3, which ultimately results in apoptosis 25.	8	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	bax	BASP1 overexpression increases the expression of bax	bax	cytochrome C	cytochrome C	cytochrome c	14	15	17	19
In particular , Bax , a Bcl-2 family member protein , moves from the cytosol to the mitochondria , inducing cytochrome c release .	In particular, Bax, a Bcl-2 family member protein, moves from the cytosol to the mitochondria, inducing cytochrome c release.	3	22	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	20	22
The link may be that Bax is activated to oligomerize and release cytochrome c by membrane hemifusion intermediates that are formed during mitochondrial fission .	The link may be that Bax is activated to oligomerize and release cytochrome c by membrane hemifusion intermediates that are formed during mitochondrial fission.	5	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	12	14
Further , tBid and Bim promote Bax mediated cytochrome c release [ XREF_BIBR ] .	Further, tBid and Bim promote Bax mediated cytochrome c release [XREF_BIBR].	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
Moreover , Bid and Bax induced cytochrome c and AK release from mitochondria incubated in buffer alone ( XREF_FIG ) .	Moreover, Bid and Bax induced cytochrome c and AK release from mitochondria incubated in buffer alone (XREF_FIG).	2	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	6	8
The chemotherapeutic properties of curcumin have been reported as inducing lung cancer cell death through Bax upregulation and Bcl-2 , Bcl-XL downregulation , causing AIF and cytochrome c release [ XREF_BIBR ] .	The chemotherapeutic properties of curcumin have been reported as inducing lung cancer cell death through Bax upregulation and Bcl-2, Bcl-XL downregulation, causing AIF and cytochrome c release [XREF_BIBR].	15	28	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	26	28
Cytochrome c from the mitochondria , mediated by Bax and Bcl2 , has been implicated in ER stress associated apoptosis [ XREF_BIBR ] .	Cytochrome c from the mitochondria, mediated by Bax and Bcl2, has been implicated in ER stress associated apoptosis [XREF_BIBR].	0	10	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome c	Cytochrome c	Cytochrome c	8	9	0	2
During apoptosis , BAX translocates to mitochondria , causing release of cytochrome c into the cytosol [ XREF_BIBR ] .	During apoptosis, BAX translocates to mitochondria, causing release of cytochrome c into the cytosol [XREF_BIBR].	3	13	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX translocates to mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	3	4	11	13
Human , full-length , monomeric BAX promoted complete cytochrome c release at 20 nM .	Human, full-length, monomeric BAX promoted complete cytochrome c release at 20 nM.	2	10	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	5	6	8	10
p73 activates the transcription of Bax and Bcl-2 , causing the release of cytochrome c from the mitochondria .	p73 activates the transcription of Bax and Bcl-2, causing the release of cytochrome c from the mitochondria.	0	15	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	p73 activates the transcription of Bax	bax	cytochrome c	cytochrome c	cytochrome c	5	6	13	15
Although the receptor signaling pathway in apoptosis was not observed by 5-FU , Bax induced cytochrome c and caspase 3 was also observed in a receptor independent pathway by 5-FU and CDDP .	Although the receptor signaling pathway in apoptosis was not observed by 5-FU, Bax induced cytochrome c and caspase 3 was also observed in a receptor independent pathway by 5-FU and CDDP.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	13	14	15	17
When microinjected into cells , these anti-VDAC antibodies , but not control antibodies , also prevented Bax induced cytochrome c release and apoptosis , whereas the antibodies did not prevent Bid induced apoptosis , indicating that the VDAC is essential for Bax induced , but not Bid induced , apoptogenic mitochondrial changes and apoptotic cell death .	When microinjected into cells, these anti-VDAC antibodies, but not control antibodies, also prevented Bax induced cytochrome c release and apoptosis, whereas the antibodies did not prevent Bid induced apoptosis, indicating that the VDAC is essential for Bax induced, but not Bid induced, apoptogenic mitochondrial changes and apoptotic cell death.	16	20	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	18	20
In the extrinsic pathway , the binding of ligands to membrane death-receptors leads to the activation of caspase-8 ; In the intrinsic pathway , Bax induces the release of cytochrome c from the mitochondria , leading to the apoptosome formation and activation of caspase 9 , and subsequent caspase 3 activation .	In the extrinsic pathway, the binding of ligands to membrane death-receptors leads to the activation of caspase-8; In the intrinsic pathway, Bax induces the release of cytochrome c from the mitochondria, leading to the apoptosome formation and activation of caspase 9, and subsequent caspase 3 activation.	24	31	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	24	25	29	31
In our experimental paradigm of axonal degeneration , pharmacological inhibition of mitochondrial fission by Mdivi-1 , which is described to inhibit direct apoptotic signaling through mitochondrial fission and cytochrome c release caused by BAX signalization XREF_BIBR XREF_BIBR , protects axons from the deleterious effects of rotenone .	In our experimental paradigm of axonal degeneration, pharmacological inhibition of mitochondrial fission by Mdivi-1, which is described to inhibit direct apoptotic signaling through mitochondrial fission and cytochrome c release caused by BAX signalization XREF_BIBR XREF_BIBR, protects axons from the deleterious effects of rotenone.	28	36	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	33	34	28	30
BCL-2 acts primarily , if not exclusively , at the level of mitochondria to prevent BAX mediated cytochrome c release , whereas NGF , KCl , or cAMP may abort the apoptotic program at multiple checkpoints .	BCL-2 acts primarily, if not exclusively, at the level of mitochondria to prevent BAX mediated cytochrome c release, whereas NGF, KCl, or cAMP may abort the apoptotic program at multiple checkpoints.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	15	16	17	19
These results indicated that the VDAC is essential for Bax induced cytochrome c release in mammalian cells .	These results indicated that the VDAC is essential for Bax induced cytochrome c release in mammalian cells.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	9	10	11	13
First , BAX oligo produced cytochrome c release , which was suppressed by inhibitors of the mPT .	First, BAX oligo produced cytochrome c release, which was suppressed by inhibitors of the mPT.	2	7	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	2	3	5	7
The activation of the proapoptotic Bcl-2 family member Bax , induces permeabilization of the mitochondrial outer membrane and release of cytochrome c leading to caspase dependent apoptosis [ XREF_BIBR , XREF_BIBR ] .	The activation of the proapoptotic Bcl-2 family member Bax, induces permeabilization of the mitochondrial outer membrane and release of cytochrome c leading to caspase dependent apoptosis [XREF_BIBR, XREF_BIBR].	1	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	20	22
Lysosomal enzymes accidentally released into the cytosol can trigger programmed cell death by directly damaging mitochondrial membranes or indirectly by cleaving BID and initiating apoptosis through BAX mediated cytochrome c release .	Lysosomal enzymes accidentally released into the cytosol can trigger programmed cell death by directly damaging mitochondrial membranes or indirectly by cleaving BID and initiating apoptosis through BAX mediated cytochrome c release.	23	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	26	27	28	30
However , other evidence indicates that Bax mediated cytochrome c release is cyclosporine insensitive and therefore independent of the permeability transition 55 .	However, other evidence indicates that Bax mediated cytochrome c release is cyclosporine insensitive and therefore independent of the permeability transition 55.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
The Tempo and heat combination also caused Bax mediated cytochrome c release , but switched heat induced apoptosis to the particular pyknotic cell death , resulting in the irreparable inhibition of proliferation .	The Tempo and heat combination also caused Bax mediated cytochrome c release, but switched heat induced apoptosis to the particular pyknotic cell death, resulting in the irreparable inhibition of proliferation.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	9	11
At a concentration of 125 nM , Bax caused the release of the intermembranous proteins cytochrome c and adenylate kinase and the release from the matrix of sequestered calcein , effects prevented by the inhibitor of the PTP cyclosporin A ( CSA ) .	At a concentration of 125 nM, Bax caused the release of the intermembranous proteins cytochrome c and adenylate kinase and the release from the matrix of sequestered calcein, effects prevented by the inhibitor of the PTP cyclosporin A (CSA).	7	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	15	17
Cleavage of Beclin-1 inhibits autophagy and the C-terminal fragment translocates to the mitochondria along with proapoptotic protein , Bax promoting the release of cytochrome C to the cytosol inducing apoptosis .	Cleavage of Beclin-1 inhibits autophagy and the C-terminal fragment translocates to the mitochondria along with proapoptotic protein, Bax promoting the release of cytochrome C to the cytosol inducing apoptosis.	16	25	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	18	19	23	25
Traslocation of Bax homodimers to mitochondria leads to release of cytochrome C to the cytosol and its binding to APAF-1 with formation of the apoptosome and recruitment of procaspase-9 .	Traslocation of Bax homodimers to mitochondria leads to release of cytochrome C to the cytosol and its binding to APAF-1 with formation of the apoptosome and recruitment of procaspase-9.	2	12	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	2	3	10	12
When Bax in mitochondria triggers cytochrome c release , the apoptosome complex activates caspase 9 which further stimulates other downstream caspases , such as caspase 3 .	When Bax in mitochondria triggers cytochrome c release, the apoptosome complex activates caspase 9 which further stimulates other downstream caspases, such as caspase 3.	1	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	5	7
Here we show that expression of the proapoptotic protein Bax in T. brucei causes the release of cytochrome c , the depolarization of the mitochondrial membrane potential and mitochondrial fission .	Here we show that expression of the proapoptotic protein Bax in T. brucei causes the release of cytochrome c, the depolarization of the mitochondrial membrane potential and mitochondrial fission.	4	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of the proapoptotic protein Bax	bax	cytochrome c	cytochrome c	cytochrome c	9	10	17	19
Also , the ratio of Bax and Bcl -2 was increased leading to changes in mitochondria membrane potential ( DeltaPsim ) and release of cytochrome c , whereas the baicalein induced apoptosis was partially abrogated by pretreatment with the pan-caspase inhibitor z-VAD-fmk , the accumulation of G2/M cells remained .	Also, the ratio of Bax and Bcl -2 was increased leading to changes in mitochondria membrane potential (DeltaPsim) and release of cytochrome c, whereas the baicalein induced apoptosis was partially abrogated by pretreatment with the pan-caspase inhibitor z-VAD-fmk, the accumulation of G2/M cells remained.	3	26	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	24	26
Bax mediates apoptosis by inducing the release of cytochrome c from mitochondria , which in turn causes activation of caspases [ XREF_BIBR ] .	Bax mediates apoptosis by inducing the release of cytochrome c from mitochondria, which in turn causes activation of caspases [XREF_BIBR].	0	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
Here 3,6-dibromocarbazole piperazine derivatives of 2-propanol are described as the first small and potent modulators of the cytochrome c release triggered by Bid induced Bax activation in a mitochondrial assay .	Here 3,6-dibromocarbazole piperazine derivatives of 2-propanol are described as the first small and potent modulators of the cytochrome c release triggered by Bid induced Bax activation in a mitochondrial assay.	17	25	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bid induced Bax	bax	cytochrome c	cytochrome c	cytochrome c	24	25	17	19
Interestingly , Gao and Dou [ XREF_BIBR ] reported that calpain can cleave Bax , thereby generating a Bax and p18 fragment which mediates cytochrome c release and initiates execution of apoptosis .	Interestingly, Gao and Dou [XREF_BIBR] reported that calpain can cleave Bax, thereby generating a Bax and p18 fragment which mediates cytochrome c release and initiates execution of apoptosis.	18	26	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	18	19	24	26
As recently reported for hepatocytes from BAK-/- mice [ XREF_BIBR ] , BAK deficient Jurkat cells were also resistant to tBid induction of cytochrome c release , suggesting that in these leukemic cells , BAK is involved in mitochondrial cytochrome c release induced by either tBid or Bax .	As recently reported for hepatocytes from BAK-/- mice [XREF_BIBR], BAK deficient Jurkat cells were also resistant to tBid induction of cytochrome c release, suggesting that in these leukemic cells, BAK is involved in mitochondrial cytochrome c release induced by either tBid or Bax.	39	48	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	47	48	39	41
In contrast , just overexpression of the pro apoptotic protein Bax has been shown to trigger cytochrome c efflux from mitochondria .	In contrast, just overexpression of the pro apoptotic protein Bax has been shown to trigger cytochrome c efflux from mitochondria.	4	18	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	overexpression of the pro apoptotic protein Bax	bax	cytochrome c	cytochrome c	cytochrome c	10	11	16	18
Studies have shown Bax , Bad , Bak promote the release of cytochrome c , while bcl-2 and Bcl-X L delays this response and promote cell survival .	Studies have shown Bax, Bad, Bak promote the release of cytochrome c, while bcl-2 and Bcl-X L delays this response and promote cell survival.	3	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	12	14
Cytochrome c release induced by 10.8 mug/ml of BAX oligo occurred in a time dependent manner and was completed within 30 minutes ( XREF_FIG ) .	Cytochrome c release induced by 10.8 mug/ml of BAX oligo occurred in a time dependent manner and was completed within 30 minutes (XREF_FIG).	0	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	Cytochrome c	Cytochrome c	Cytochrome c	8	9	0	2
The insertion of Bax into the mitochondrial membrane induces the release of cytochrome C and the induction of apoptotic cell death .	The insertion of Bax into the mitochondrial membrane induces the release of cytochrome C and the induction of apoptotic cell death.	1	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	3	4	12	14
The increased level of H 2 O 2 induces p53 activation and over expression of Bax protein that modulates mitochondrial membrane potential and trigger cytochrome c release .	The increased level of H 2 O 2 induces p53 activation and over expression of Bax protein that modulates mitochondrial membrane potential and trigger cytochrome c release.	13	26	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	15	16	24	26
25 In addition , cytochrome c release , also triggered by Bax activity , was detected in sensory hair cells treated with aminoglycosides .	25 In addition, cytochrome c release, also triggered by Bax activity, was detected in sensory hair cells treated with aminoglycosides.	4	12	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	4	6
It also induces the activation of the Bax , Puma , and Noxa proteins causing mitochondrial pore formation and release of cytochrome-c .	It also induces the activation of the Bax, Puma, and Noxa proteins causing mitochondrial pore formation and release of cytochrome-c.	4	22	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome-c	cytochrome-c	cytochrome-c	7	8	21	22
Bid induces a conformational change of Bax , and Bax induces the release of cytochrome c from the mitochondria during apoptosis .	Bid induces a conformational change of Bax, and Bax induces the release of cytochrome c from the mitochondria during apoptosis.	9	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	9	10	14	16
The produced protein forms tBid and pBim lead to exhaustion of the Bcl2 buffer and finally to cytochrome c release mediated by active Bax and Bak ( 6E ) .	The produced protein forms tBid and pBim lead to exhaustion of the Bcl2 buffer and finally to cytochrome c release mediated by active Bax and Bak (6E).	17	27	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	23	24	17	19
For instance , LMP can initiate caspase cascades via the intrinsic apoptosis pathway through cleavage of Bid and induction of Bax mediated release of cytochrome c , but cathepsins are able to mediate cell death in a caspase independent manner as well [ XREF_BIBR ] .	For instance, LMP can initiate caspase cascades via the intrinsic apoptosis pathway through cleavage of Bid and induction of Bax mediated release of cytochrome c, but cathepsins are able to mediate cell death in a caspase independent manner as well [XREF_BIBR].	18	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	20	21	24	26
Thus , Bid and Bax , like the factors present in Xenopus egg cytosol , induced cytochrome c release without gross changes in mitochondrial morphology .	Thus, Bid and Bax, like the factors present in Xenopus egg cytosol, induced cytochrome c release without gross changes in mitochondrial morphology.	2	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	16	18
The mechanisms by which Bax triggers cytochrome c release are unknown .	The mechanisms by which Bax triggers cytochrome c release are unknown.	4	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	6	8
Alternatively , the release of cytochrome c induced by BAX oligo from liver mitochondria was hypothesized to occur also in two steps involving loosening of cytochrome c binding to the inner mitochondrial membrane ( IMM ) due to oxidative stress and lipid peroxidation followed by its dissociation from the membrane and escape through the permeabilized OMM [ XREF_BIBR ] .	Alternatively, the release of cytochrome c induced by BAX oligo from liver mitochondria was hypothesized to occur also in two steps involving loosening of cytochrome c binding to the inner mitochondrial membrane (IMM) due to oxidative stress and lipid peroxidation followed by its dissociation from the membrane and escape through the permeabilized OMM [XREF_BIBR].	5	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	9	10	5	7
The increase in Bax mRNA expression levels and contents and the decrease in Bcl-2 mRNA expression levels and contents in our study caused the cytochrome c release and apoptosis initiation in the spleen .	The increase in Bax mRNA expression levels and contents and the decrease in Bcl-2 mRNA expression levels and contents in our study caused the cytochrome c release and apoptosis initiation in the spleen.	3	26	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax mRNA expression levels	bax	cytochrome c	cytochrome c	cytochrome c	3	4	24	26
Addition of recombinant Bid or Bax to reconstituted Xenopus egg extracts ( mitochondria mixed with cytosol ) caused the rapid release of mitochondrial cytochrome c ( XREF_FIG ) and the activation of DEVDases ( not shown ) .	Addition of recombinant Bid or Bax to reconstituted Xenopus egg extracts (mitochondria mixed with cytosol) caused the rapid release of mitochondrial cytochrome c (XREF_FIG) and the activation of DEVDases (not shown).	0	25	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	23	25
Previous studies have reported that the proapoptotic factor Bax enhanced the mitochondrial release of cytochrome c and activated caspase-9 and caspase-3 to execute the apoptotic program ; conversely , the anti-apoptotic protein Bcl-2 inhibited Bax activation and cytochrome c release , and prevented apoptosis .	Previous studies have reported that the proapoptotic factor Bax enhanced the mitochondrial release of cytochrome c and activated caspase-9 and caspase-3 to execute the apoptotic program; conversely, the anti-apoptotic protein Bcl-2 inhibited Bax activation and cytochrome c release, and prevented apoptosis.	5	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	14	16
This redirection requires functional ER signaling and is mediated by a depletion of Bcl-2 and an induction of Bax and Bak , manifesting in cytochrome C release and PARP cleavage .	This redirection requires functional ER signaling and is mediated by a depletion of Bcl-2 and an induction of Bax and Bak, manifesting in cytochrome C release and PARP cleavage.	8	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	18	19	24	26
Bcl-2 and Bax also play very important roles in mitochondrial pathway , the down-regulation of Bcl-2 and the up-regulation of Bax can induce the release of cytochrome-C ( cytosol ) from mitochondria , trigger the activity of caspase-3 and -9 and finally cause cell apoptosis .	Bcl-2 and Bax also play very important roles in mitochondrial pathway, the down-regulation of Bcl-2 and the up-regulation of Bax can induce the release of cytochrome-C (cytosol) from mitochondria, trigger the activity of caspase-3 and -9 and finally cause cell apoptosis.	18	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome-C	cytochrome-C	cytochrome-C	20	21	26	27
Bax , the Bcl-2-associated X protein , promotes apoptosis by releasing cytochrome c and other proapoptotic factors from mitochondria to cytoplasm .	Bax, the Bcl-2-associated X protein, promotes apoptosis by releasing cytochrome c and other proapoptotic factors from mitochondria to cytoplasm.	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	11	13
Upon activation , Bax and Bak mediate the disruption of the mitochondrial membrane potential and the subsequent release of Apaf-1 and cytochrome c into the cytosol .	Upon activation, Bax and Bak mediate the disruption of the mitochondrial membrane potential and the subsequent release of Apaf-1 and cytochrome c into the cytosol.	3	23	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	21	23
XREF_BIBR , XREF_BIBR Downregulation of Bcl-2 and upregulation of Bax can induce the release of cytochrome C from the mitochondria into the cytosol , triggering the activity of caspase-3 and -9 and eventually causing apoptosis .	XREF_BIBR, XREF_BIBR Downregulation of Bcl-2 and upregulation of Bax can induce the release of cytochrome C from the mitochondria into the cytosol, triggering the activity of caspase-3 and -9 and eventually causing apoptosis.	3	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	9	10	15	17
Bax has also been shown to induce mitochondrial cytochrome C release into the cytosol followed by rapid activation of caspases causing cell death [ XREF_BIBR ] .	Bax has also been shown to induce mitochondrial cytochrome C release into the cytosol followed by rapid activation of caspases causing cell death [XREF_BIBR].	0	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	0	1	8	10
We show that in cells transiently transfected with bax , Bax localizes to mitochondria and induces the release of cytochrome c , activation of caspase-3 , membrane blebbing , nuclear fragmentation , and cell death .	We show that in cells transiently transfected with bax, Bax localizes to mitochondria and induces the release of cytochrome c, activation of caspase-3, membrane blebbing, nuclear fragmentation, and cell death.	10	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	10	11	19	21
Bcl-2 family proteins play an important role in controlling the intrinsic pathway , wherein Bcl-2 and Bcl-XL normally suppress apoptosis by inhibiting the release of cytochrome c. Conversely , BAD , BAX , and BAK-1 promote apoptosis by inducing cytochrome c release XREF_BIBR , XREF_BIBR .	Bcl-2 family proteins play an important role in controlling the intrinsic pathway, wherein Bcl-2 and Bcl-XL normally suppress apoptosis by inhibiting the release of cytochrome c. Conversely, BAD, BAX, and BAK-1 promote apoptosis by inducing cytochrome c release XREF_BIBR, XREF_BIBR.	29	42	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	31	32	39	41
BAX can then be activated and directed to the mitochondria by BAD to facilitate cytochrome c release [ XREF_BIBR ] .	BAX can then be activated and directed to the mitochondria by BAD to facilitate cytochrome c release [XREF_BIBR].	0	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	0	1	14	16
Conversely , overexpressing Bax promotes cytochrome c release and activates apoptotic enzymes , leading to cell death [ XREF_BIBR ] .	Conversely, overexpressing Bax promotes cytochrome c release and activates apoptotic enzymes, leading to cell death [XREF_BIBR].	2	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	5	7
Interestingly , Bcl-2 over-expression renders cells resistant to apoptosis when it homodimerizes , whereas , up-regulation of Bax alters Bcl-2 and Bax ratio in cellular microenvironment and cause release of cytochrome c from mitochondria into cytosol [ XREF_BIBR ] .	Interestingly, Bcl-2 over-expression renders cells resistant to apoptosis when it homodimerizes, whereas, up-regulation of Bax alters Bcl-2 and Bax ratio in cellular microenvironment and cause release of cytochrome c from mitochondria into cytosol [XREF_BIBR].	15	32	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	17	18	30	32
Furthermore , Bax can induce transport of cytochrome c in liposomes .	Furthermore, Bax can induce transport of cytochrome c in liposomes.	2	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	7	9
Bax and Bak allow cytochrome c to pass through VDAC out of liposomes , but passage is prevented by Bcl-x ( L ) .	Bax and Bak allow cytochrome c to pass through VDAC out of liposomes, but passage is prevented by Bcl-x (L).	0	6	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	4	6
The BAX protein enhances the release of cytochrome c from mitochondria and thereby promotes apoptosis 38 , while the BCL2L1 protein inhibits the release of cytochrome c from mitochondria , preventing apoptosis 39 .	The BAX protein enhances the release of cytochrome c from mitochondria and thereby promotes apoptosis 38, while the BCL2L1 protein inhibits the release of cytochrome c from mitochondria, preventing apoptosis 39.	1	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	1	2	7	9
These results suggested that an increased ratio of Bax and Bcl -2 can induce cytochrome c release , thereby increasing apoptosis .	These results suggested that an increased ratio of Bax and Bcl -2 can induce cytochrome c release, thereby increasing apoptosis.	6	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	14	16
The protein Bcl-2 prevents the cytochrome c release and therefor inhibits the activation of caspases , oppositely the protein Bax induces the cytochrome c release , caspase-3 activation , membrane blebbing , nuclear fragmentation , and cell death .	The protein Bcl-2 prevents the cytochrome c release and therefor inhibits the activation of caspases, oppositely the protein Bax induces the cytochrome c release, caspase-3 activation, membrane blebbing, nuclear fragmentation, and cell death.	17	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	19	20	22	24
Increased levels of Bax proteins have been reported to directly induce the release of cytochrome c by forming a pore in the outer membrane of the mitochondria .	Increased levels of Bax proteins have been reported to directly induce the release of cytochrome c by forming a pore in the outer membrane of the mitochondria.	3	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	14	16
Our results suggest that the mitochondrial calpain plays an essential role in apoptotic commitment by cleaving Bax and generating the Bax and p18 fragment , which in turn mediates cytochrome c release and initiates the apoptotic execution .	Our results suggest that the mitochondrial calpain plays an essential role in apoptotic commitment by cleaving Bax and generating the Bax and p18 fragment, which in turn mediates cytochrome c release and initiates the apoptotic execution.	20	31	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	20	21	29	31
However , the facts that silencing each of Bak and Bax modestly but significantly prevented the cytotoxicity of the combination treatment compared with single drugs treatment in HCC cells ( XREF_FIG ) indicated that FTS pretreatment potentiated the DHA and ARS triggered Bak and Bax activation and subsequent intrinsic apoptotic pathway , which were further verified by the enhanced effect of FTS on the DHA and ARS induced DeltaPsim loss and cytochrome c release ( XREF_FIG ) .	However, the facts that silencing each of Bak and Bax modestly but significantly prevented the cytotoxicity of the combination treatment compared with single drugs treatment in HCC cells (XREF_FIG) indicated that FTS pretreatment potentiated the DHA and ARS triggered Bak and Bax activation and subsequent intrinsic apoptotic pathway, which were further verified by the enhanced effect of FTS on the DHA and ARS induced DeltaPsim loss and cytochrome c release (XREF_FIG).	42	73	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	44	45	71	73
We reported that Bax lies upstream from all of the increased ROS/RS following withdrawal of NGF from these neurons and presented evidence that these ROS/RS are a critical part of the mechanism by which Bax induces release of cytochrome c from their mitochondria XREF_BIBR , XREF_BIBR , XREF_BIBR .	We reported that Bax lies upstream from all of the increased ROS/RS following withdrawal of NGF from these neurons and presented evidence that these ROS/RS are a critical part of the mechanism by which Bax induces release of cytochrome c from their mitochondria XREF_BIBR, XREF_BIBR, XREF_BIBR.	34	40	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	34	35	38	40
Although other BCL2 proteins ( including Bcl2 , Bcl XL and Bak and Bid ) also mediate apoptosis , Bax is critical in our model , since RNAi mediated Bax knockdown is sufficient to markedly reduce both mitochondrial AIF and cytochrome C leakage ( XREF_FIG ) .	Although other BCL2 proteins (including Bcl2, Bcl XL and Bak and Bid) also mediate apoptosis, Bax is critical in our model, since RNAi mediated Bax knockdown is sufficient to markedly reduce both mitochondrial AIF and cytochrome C leakage (XREF_FIG).	29	42	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	29	30	40	42
In contrast , proapoptotic members , Bax , Bid , and Bad , induce the release of cytochrome C resulting in mitochondrial dysfunction .	In contrast, proapoptotic members, Bax, Bid, and Bad, induce the release of cytochrome C resulting in mitochondrial dysfunction.	4	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	6	7	17	19
The TOM complex is a receptor of the mitochondrial outer membrane required for tBid and Bax induced cytochrome c release XREF_BIBR .	The TOM complex is a receptor of the mitochondrial outer membrane required for tBid and Bax induced cytochrome c release XREF_BIBR.	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	17	19
Moreover , HD downregulated the Bcl-2 expression , upregulated the Bax expression and the Bax and Bcl -2 ratio , promoted the disruption of MMP , induced the release of cytochrome c from mitochondria to cytosol , and increased the activity of caspase-3 in MSCs .	Moreover, HD downregulated the Bcl-2 expression, upregulated the Bax expression and the Bax and Bcl -2 ratio, promoted the disruption of MMP, induced the release of cytochrome c from mitochondria to cytosol, and increased the activity of caspase-3 in MSCs.	2	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	HD downregulated the Bcl-2 expression, upregulated the Bax expression	bax	cytochrome c	cytochrome c	cytochrome c	10	11	30	32
The oligomerization of Bax in the mitochondrial membrane has been shown to induce cytochrome c release , meanwhile pro apoptotic Bcl-2 cleavage product was reported to localize on mitochondrial membrane and caused release of cytochrome c.	The oligomerization of Bax in the mitochondrial membrane has been shown to induce cytochrome c release, meanwhile pro apoptotic Bcl-2 cleavage product was reported to localize on mitochondrial membrane and caused release of cytochrome c.	1	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	13	15
The over expression of Bax might have modulated mitochondria membrane potential and thereby cytochrome c release .	The over expression of Bax might have modulated mitochondria membrane potential and thereby cytochrome c release.	2	15	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	4	5	13	15
Bax induces the release of cytochrome c and the activation of caspase-9 and -3 both in vivo and in vitro .	Bax induces the release of cytochrome c and the activation of caspase-9 and -3 both in vivo and in vitro.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
The authors show that Bax activation underlies cytochrome c release and caspase-9 cleavage and place the BH3-only protein Bad as an upstream regulator .	The authors show that Bax activation underlies cytochrome c release and caspase-9 cleavage and place the BH3-only protein Bad as an upstream regulator.	4	9	underlies	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	7	9
As an ion channel component of the mitochondrial membrane , Bax protein enhanced the cytochrome C passage through the mitochondrial membrane , as well as activated caspase-9 and caspase-3 , thus leading to apoptosis [ XREF_BIBR ] .	As an ion channel component of the mitochondrial membrane, Bax protein enhanced the cytochrome C passage through the mitochondrial membrane, as well as activated caspase-9 and caspase-3, thus leading to apoptosis [XREF_BIBR].	10	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	10	11	14	16
Here , we present new data which further corroborates an important role of this channel in the sequence of events leading to Bax induced cytochrome c release .	Here, we present new data which further corroborates an important role of this channel in the sequence of events leading to Bax induced cytochrome c release.	20	26	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	22	23	24	26
Following translocation to the mitochondrial membrane , Bax initiates cytochrome c release and subsequently activates caspase during apoptosis .	Following translocation to the mitochondrial membrane, Bax initiates cytochrome c release and subsequently activates caspase during apoptosis.	7	14	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	9	11
The Bcl-2 subfamily contains anti-apoptotic proteins such as Bcl-2 and Bcl-X L , which reduce cytochrome c release and loss of mitochondrial transmembrane potential ( Deltapsi m ) , whereas the Bax subfamily contains pro apoptotic proteins such as Bax and Bak , which induce cytochrome c release and loss of Deltapsi m [ XREF_BIBR - XREF_BIBR ] .	The Bcl-2 subfamily contains anti-apoptotic proteins such as Bcl-2 and Bcl-X L, which reduce cytochrome c release and loss of mitochondrial transmembrane potential (Deltapsi m), whereas the Bax subfamily contains pro apoptotic proteins such as Bax and Bak, which induce cytochrome c release and loss of Deltapsi m [XREF_BIBR - XREF_BIBR].	36	47	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	39	40	45	47
Ellipticine increased the expression of Bax , but decreased the level of Bcl-2 , Bcl-XL and X linked inhibitor of apoptosis protein ( XIAP ) , and subsequently triggered the mitochondrial apoptotic pathway ( release of cytochrome c , and activation of caspase-9 and -3 ) .	Ellipticine increased the expression of Bax, but decreased the level of Bcl-2, Bcl-XL and X linked inhibitor of apoptosis protein (XIAP), and subsequently triggered the mitochondrial apoptotic pathway (release of cytochrome c, and activation of caspase-9 and -3).	0	38	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Ellipticine increased the expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	5	6	36	38
None of the Bax proteins caused cytochrome c release merely through physical perturbation of the mitochondrial outer membrane .	None of the Bax proteins caused cytochrome c release merely through physical perturbation of the mitochondrial outer membrane.	3	8	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	6	8
Finally , evidence suggests that Bax is able to induce the efflux of cytochrome c from mitochondria 444547485668 .	Finally, evidence suggests that Bax is able to induce the efflux of cytochrome c from mitochondria 444547485668.	5	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	13	15
These data support a two-phase model of Bax translocation in which Bax targets the mitochondrial intermembrane contact sites and releases cytochrome c in the first phase , and is then packaged into large aggregates on mitochondria in the second .	These data support a two-phase model of Bax translocation in which Bax targets the mitochondrial intermembrane contact sites and releases cytochrome c in the first phase, and is then packaged into large aggregates on mitochondria in the second.	11	30	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	20	22
Developing sympathetic neurons ( postnatal day 5 [ P5 ] ) are acutely dependent on NGF for survival and undergo Bax mediated cytochrome c release and caspase activation when deprived of NGF .	Developing sympathetic neurons (postnatal day 5 [P5]) are acutely dependent on NGF for survival and undergo Bax mediated cytochrome c release and caspase activation when deprived of NGF.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	20	21	22	24
In addition , the anti-apoptotic protein Bcl-2 suppresses apoptosis by preventing the release of cytochrome c whereas the pro apoptotic protein Bcl-2-associated X protein ( Bax ) promotes apoptosis by enhancing cytochrome c release .	In addition, the anti-apoptotic protein Bcl-2 suppresses apoptosis by preventing the release of cytochrome c whereas the pro apoptotic protein Bcl-2-associated X protein (Bax) promotes apoptosis by enhancing cytochrome c release.	23	33	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	25	26	31	33
The constitutive balanced ratio of Bax and Bcl-XL in K562 mitochondria allowed the formation of active Bax and cytochrome c release from mitochondria in the presence of a BH3-only protein , tBid , in a cell-free system .	The constitutive balanced ratio of Bax and Bcl-XL in K562 mitochondria allowed the formation of active Bax and cytochrome c release from mitochondria in the presence of a BH3-only protein, tBid, in a cell-free system.	3	20	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	18	20
These results indicate that mPTP activation is the predominant pathway for Bax induced cytochrome c release from MCF7 mitochondria and for apoptosis induction in the whole cell .	These results indicate that mPTP activation is the predominant pathway for Bax induced cytochrome c release from MCF7 mitochondria and for apoptosis induction in the whole cell.	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	13	15
IAPs are a group of anti-apoptotic proteins , which protect the cell from various triggers of apoptosis like Fas and TNF-alpha ligation , Bax mediated mitochondrial disruption , caspase activation , cytochrome c release , chemotherapeutic agents , radiation and viral infection .	IAPs are a group of anti-apoptotic proteins, which protect the cell from various triggers of apoptosis like Fas and TNF-alpha ligation, Bax mediated mitochondrial disruption, caspase activation, cytochrome c release, chemotherapeutic agents, radiation and viral infection.	23	33	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	23	24	31	33
However , pro apoptotic Bax protein translocates to mitochondria upon exposure to stimuli of apoptosis XREF_BIBR , and induces the release of cytochrome c and activation of caspase in vitro XREF_BIBR .	However, pro apoptotic Bax protein translocates to mitochondria upon exposure to stimuli of apoptosis XREF_BIBR, and induces the release of cytochrome c and activation of caspase in vitro XREF_BIBR.	4	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	22	24
ATP , another inhibitor of the mPT [ XREF_BIBR ] , also attenuated cytochrome c release induced by BAX oligo ( XREF_FIG ) but did not influence BAX oligo insertion ( not shown ) .	ATP, another inhibitor of the mPT [XREF_BIBR], also attenuated cytochrome c release induced by BAX oligo (XREF_FIG) but did not influence BAX oligo insertion (not shown).	13	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	18	19	13	15
UV radiation induced apoptosis requires Bax mediated cytochrome c release [ XREF_BIBR , XREF_BIBR ] .	UV radiation induced apoptosis requires Bax mediated cytochrome c release [XREF_BIBR, XREF_BIBR].	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	7	9
We also found that ursolic acid induced Bax up-regulation and Bcl-2 down-regulation and release of cytochrome C to the cytosol from mitochondria .	We also found that ursolic acid induced Bax up-regulation and Bcl-2 down-regulation and release of cytochrome C to the cytosol from mitochondria.	4	17	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Bax	ursolic acid induced Bax	bax	cytochrome C	cytochrome C	cytochrome c	7	8	15	17
Finally , consistent with the finding that activated PKC-delta triggers the redistribution and activation of Bax , a Bcl-2 family protein that can directly induce cytochrome c release and downstream apoptotic cascade , we observed markedly increased levels of Bax in brain slices exposed to misfolded PrP .	Finally, consistent with the finding that activated PKC-delta triggers the redistribution and activation of Bax, a Bcl-2 family protein that can directly induce cytochrome c release and downstream apoptotic cascade, we observed markedly increased levels of Bax in brain slices exposed to misfolded PrP.	11	27	induce	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	25	27
Because cells of each bax genotype had identical amounts of cytochrome c , these data again suggest that Bax can affect ROS/RS levels independent of Bax induced cytochrome c redistribution .	Because cells of each bax genotype had identical amounts of cytochrome c, these data again suggest that Bax can affect ROS/RS levels independent of Bax induced cytochrome c redistribution.	23	29	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	25	26	27	29
Bax Plays a Key Role in the Bid induced Release of Cytochrome c from Mitochondria .	Bax Plays a Key Role in the Bid induced Release of Cytochrome c from Mitochondria.	0	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome c	Cytochrome c	Cytochrome c	0	1	11	13
Release of cytochrome c from the mitochondria into the cytosol is a key event in mitochondria dependent apoptosis , and Bax has been reported to induce cytochrome c release and subsequent activation of caspase-9 .	Release of cytochrome c from the mitochondria into the cytosol is a key event in mitochondria dependent apoptosis, and Bax has been reported to induce cytochrome c release and subsequent activation of caspase-9.	20	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	20	21	26	28
However , because knockdown of Bak and Bax blocked both Bax activation and significant cytochrome c release but still allowed apoptotic extrusion to occur ; we reasoned that the caspase cascade may be important for cellular extrusion .	However, because knockdown of Bak and Bax blocked both Bax activation and significant cytochrome c release but still allowed apoptotic extrusion to occur; we reasoned that the caspase cascade may be important for cellular extrusion.	3	16	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	14	16
p53 induced downregulation of Bcl-2 and upregulation of Bax promote cytochrome C release from the mitochondria and caspase-3 activation causes cell death XREF_BIBR XREF_BIBR .	p53 induced downregulation of Bcl-2 and upregulation of Bax promote cytochrome C release from the mitochondria and caspase-3 activation causes cell death XREF_BIBR XREF_BIBR.	4	12	promote	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	8	9	10	12
The insertion of Bax into mitochondrial membrane causes the release of cytochrome c and dissipation of mitochondrial membrane potential ( DeltaPsim ) .	The insertion of Bax into mitochondrial membrane causes the release of cytochrome c and dissipation of mitochondrial membrane potential (DeltaPsim).	1	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	11	13
45 Bcl-2 inhibits apoptosis by preventing mitochondrial membrane depolarization 46 whereas Bax promotes apoptosis by inducing mitochondrial membrane depolarization and cytochrome c release .	45 Bcl-2 inhibits apoptosis by preventing mitochondrial membrane depolarization 46 whereas Bax promotes apoptosis by inducing mitochondrial membrane depolarization and cytochrome c release.	11	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	20	22
Perhaps more telling is that in the CypD-null mitochondria , which are more resistant to MPT , Bax and Bid proteins were still able to elicit cytochrome c release to the same extent as normal mitochondria and CypD-null cells were just as sensitive to apoptotic stimuli as wild type cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Perhaps more telling is that in the CypD-null mitochondria, which are more resistant to MPT, Bax and Bid proteins were still able to elicit cytochrome c release to the same extent as normal mitochondria and CypD-null cells were just as sensitive to apoptotic stimuli as wild type cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	17	28	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	17	18	26	28
In isolated mitochondria , we found that 14-3-3 theta inhibited the integration of Bax and Bax induced cytochrome c release .	In isolated mitochondria, we found that 14-3-3 theta inhibited the integration of Bax and Bax induced cytochrome c release.	11	19	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	17	19
The anti-apoptotic members Bcl-2 and Mcl-1 can prevent apoptosis induction by inhibition of mitochondrial cytochrome C release while the pro apoptotic protein Bax can induce apoptosis by stimulating cytochrome C release [ XREF_BIBR - XREF_BIBR ] .	The anti-apoptotic members Bcl-2 and Mcl-1 can prevent apoptosis induction by inhibition of mitochondrial cytochrome C release while the pro apoptotic protein Bax can induce apoptosis by stimulating cytochrome C release [XREF_BIBR - XREF_BIBR].	18	30	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	22	23	28	30
An increase in the Bax and Bcl2 ratio leads to release of cytochrome c followed by stepwise activation of caspases leading to cell death .	An increase in the Bax and Bcl2 ratio leads to release of cytochrome c followed by stepwise activation of caspases leading to cell death.	4	14	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	12	14
Accordingly , the likely scenario is that Bax triggers VDAC opening and cytochrome c release , leading to opening of inner membrane channel ( s ) such as ANTs via a mutual interaction that results in Deltapsi loss and the PT , which might subsequently induce another phase of cytochrome c release .	Accordingly, the likely scenario is that Bax triggers VDAC opening and cytochrome c release, leading to opening of inner membrane channel (s) such as ANTs via a mutual interaction that results in Deltapsi loss and the PT, which might subsequently induce another phase of cytochrome c release.	7	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	12	14
Interference RNA knockdown of Bax blocked OPA1 and cytochrome c release after THG treatment but did not prevent the MPT , showing that Bax was essential for the release of cytochrome c by MPT .	Interference RNA knockdown of Bax blocked OPA1 and cytochrome c release after THG treatment but did not prevent the MPT, showing that Bax was essential for the release of cytochrome c by MPT.	2	10	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	8	10
Study by BETTAIEB XREF_BIBR also suggest that heat stress induced translocation of Bax from cytosol to mitochondria triggers the release of cytochrome c from the mitochondria XREF_BIBR .	Study by BETTAIEB XREF_BIBR also suggest that heat stress induced translocation of Bax from cytosol to mitochondria triggers the release of cytochrome c from the mitochondria XREF_BIBR.	10	23	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	translocation of Bax from cytosol to mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	12	13	21	23
In particular , the protein expression ratio of Bax to Bcl2 ( antiapoptotic protein ) alters the mitochondrial membrane potential and initiates cytochrome c release and the subsequent caspase activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In particular, the protein expression ratio of Bax to Bcl2 (antiapoptotic protein) alters the mitochondrial membrane potential and initiates cytochrome c release and the subsequent caspase activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	24	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	22	24
Recombinant Bax protein alone caused the ROS generation and release of cytochrome c from isolated mitochondria and , again , CoQ ( 10 ) inhibited these Bax induced mitochondrial dysfunctions .	Recombinant Bax protein alone caused the ROS generation and release of cytochrome c from isolated mitochondria and, again, CoQ (10) inhibited these Bax induced mitochondrial dysfunctions.	1	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	11	13
A previous study reported that injection of anti-VDAC1 antibodies into cells prevented Bax induced cytochrome c release and the loss of mitochondrial membrane potential , which consequently resulted in decreased apoptosis XREF_BIBR .	A previous study reported that injection of anti-VDAC1 antibodies into cells prevented Bax induced cytochrome c release and the loss of mitochondrial membrane potential, which consequently resulted in decreased apoptosis XREF_BIBR.	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	12	13	14	16
With the use of these inhibitors , we clearly demonstrated that BAX oligo induces mPT in isolated brain mitochondria and that mPT is involved in cytochrome c release induced by BAX oligo .	With the use of these inhibitors, we clearly demonstrated that BAX oligo induces mPT in isolated brain mitochondria and that mPT is involved in cytochrome c release induced by BAX oligo.	25	31	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	30	31	25	27
Consequently , the relocation of Bax onto mitochondria induces the leakage of cytochrome c into the cytosol and initiates the corresponding apoptosis .	Consequently, the relocation of Bax onto mitochondria induces the leakage of cytochrome c into the cytosol and initiates the corresponding apoptosis.	3	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	12	14
Excessive Bax and Bak ( XREF_TABLE ) , reactive oxygen species ( ROS ) ( XREF_TABLE ) , and increased calcium ions provoked the mitochondrial cytochrome c release from mitochondria to cytosol .	Excessive Bax and Bak (XREF_TABLE), reactive oxygen species (ROS) (XREF_TABLE), and increased calcium ions provoked the mitochondrial cytochrome c release from mitochondria to cytosol.	0	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	25	27
The overexpression of Bax modulated mitochondria membrane potential and increased cytochrome c release .	The overexpression of Bax modulated mitochondria membrane potential and increased cytochrome c release.	1	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	overexpression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	3	4	10	12
XREF_FIG show statistical analyses of cytochrome c release induced by BAX oligo .	XREF_FIG show statistical analyses of cytochrome c release induced by BAX oligo.	5	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	10	11	5	7
The pro apoptotic Bcl-2-family protein Bax has been shown to cause mitochondrial permeabilization and cytochrome c release .	The pro apoptotic Bcl-2-family protein Bax has been shown to cause mitochondrial permeabilization and cytochrome c release.	0	16	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	14	16
Bax oligomers insert into the mitochondrial outer membrane and promote the releasing of cytochrome C , leading to caspase activation and apoptosis .	Bax oligomers insert into the mitochondrial outer membrane and promote the releasing of cytochrome C, leading to caspase activation and apoptosis.	0	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	0	1	13	15
Thus , inhibition of autophagy could induce p53 interaction with Bax leading to increase in cytochrome c release and apoptosis .	Thus, inhibition of autophagy could induce p53 interaction with Bax leading to increase in cytochrome c release and apoptosis.	6	17	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	10	11	15	17
Supporting our results obtained with isolated mitochondria , we found that neither cyclosporin A nor BKA , a long-term inhibitor of the PTP , were able to inhibit Bax induced cytochrome C release after overexpression in COS cells .	Supporting our results obtained with isolated mitochondria, we found that neither cyclosporin A nor BKA, a long-term inhibitor of the PTP, were able to inhibit Bax induced cytochrome C release after overexpression in COS cells.	27	32	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	28	29	30	32
Studies in models of global cerebral ischemia indicate that the inhibition of Bax channels can prevent the decrease in mitochondrial membrane potential and the release of cytochrome c from mitochondria , and protect neurons against apoptosis [ XREF_BIBR ] .	Studies in models of global cerebral ischemia indicate that the inhibition of Bax channels can prevent the decrease in mitochondrial membrane potential and the release of cytochrome c from mitochondria, and protect neurons against apoptosis [XREF_BIBR].	12	28	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	12	13	26	28
In the H2O2 induced H9c2 cardiomyocytes , which mimicked the I/R injury in vivo , VEGF-C pre-treatment decreased the LDH release and MDA content , blocked H2O2 induced apoptosis by inhibiting the pro apoptotic protein Bax expression and its translocation to the mitochondrial membrane , and consequently attenuated H2O2 induced decrease of mitochondrial membrane potential and increase of cytochrome c release from mitochondria .	In the H2O2 induced H9c2 cardiomyocytes, which mimicked the I/R injury in vivo, VEGF-C pre-treatment decreased the LDH release and MDA content, blocked H2O2 induced apoptosis by inhibiting the pro apoptotic protein Bax expression and its translocation to the mitochondrial membrane, and consequently attenuated H2O2 induced decrease of mitochondrial membrane potential and increase of cytochrome c release from mitochondria.	15	60	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	VEGF-C pre-treatment decreased the LDH release and MDA content, blocked H2O2 induced apoptosis by inhibiting the pro apoptotic protein Bax expression	bax	cytochrome c	cytochrome c	cytochrome c	35	36	58	60
Bcl-2 , which gates the mitochondria , is downregulated by Bax allowing cytochrome C to translocate from the mitochondria into the cytoplasmic space .	Bcl-2, which gates the mitochondria, is downregulated by Bax allowing cytochrome C to translocate from the mitochondria into the cytoplasmic space.	8	14	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	10	11	12	14
These results suggest that Bax triggers cytochrome C release independently of at least two major components of the PTP , cyclophilin D ( cyclosporin A target ) , and the ANT ( BKA target ) .	These results suggest that Bax triggers cytochrome C release independently of at least two major components of the PTP, cyclophilin D (cyclosporin A target), and the ANT (BKA target).	4	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	4	5	6	8
18 In type-II cells , resistance to TRAIL induced apoptosis can be mediated by high expression of anti-apoptotic Bcl-2 family members such as Bcl-2 , Bcl-xL and Mcl-1 that antagonize truncated Bid triggered Bax and Bak mediated mitochondrial outer membrane permeabilization and the consequent release of the pro apoptotic factors cytochrome c and Smac/DIABLO .	18 In type-II cells, resistance to TRAIL induced apoptosis can be mediated by high expression of anti-apoptotic Bcl-2 family members such as Bcl-2, Bcl-xL and Mcl-1 that antagonize truncated Bid triggered Bax and Bak mediated mitochondrial outer membrane permeabilization and the consequent release of the pro apoptotic factors cytochrome c and Smac/DIABLO.	33	52	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	33	34	50	52
Bcl-xL has been reported to widely enhance cell survival and inhibit cytochrome C release , while Bax in response to several apoptotic stimuli enhances release of cytochrome C , leading to activation of caspase cascade [ XREF_BIBR ] .	Bcl-xL has been reported to widely enhance cell survival and inhibit cytochrome C release, while Bax in response to several apoptotic stimuli enhances release of cytochrome C, leading to activation of caspase cascade [XREF_BIBR].	16	28	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	16	17	26	28
The first phase involves the Bax induced release of cytochrome c , and the second phase involves packaging of Bax monomers close to mitochondria .	The first phase involves the Bax induced release of cytochrome c, and the second phase involves packaging of Bax monomers close to mitochondria.	4	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	9	11
Besides , Bax and Bak are also able to promote the release of cytochrome c and other pro apoptotic factors from the mitochondria , ultimately leading to activation of caspases by inducing the opening of mitochondrial voltage dependent anion channel ( VDAC ) and/or forming the oligomeric pore MAC .	Besides, Bax and Bak are also able to promote the release of cytochrome c and other pro apoptotic factors from the mitochondria, ultimately leading to activation of caspases by inducing the opening of mitochondrial voltage dependent anion channel (VDAC) and/or forming the oligomeric pore MAC.	2	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	13	15
XREF_BIBR , XREF_BIBR Since Bax insertion into the mitochondria triggers release of cytochrome c and caspase activation XREF_BIBR , we quantified Bax activation by the appearance of immunofluorescent foci following incubation with the conformation specific antibody 6A7 .	XREF_BIBR, XREF_BIBR Since Bax insertion into the mitochondria triggers release of cytochrome c and caspase activation XREF_BIBR, we quantified Bax activation by the appearance of immunofluorescent foci following incubation with the conformation specific antibody 6A7.	4	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	12	14
During the apoptotic process , Bax forms oligomers and transfers from cytoplasm to mitochondrial membrane [ XREF_BIBR ] , then Bax oligomer interacts with pore protein of mitochondrial membrane , results in increased membrane permeability , and induces release of cytochrome c from mitochondria to cytosol , finally actives the caspase [ XREF_BIBR ] , leading to mitochondrial electron transport , DNA fracture and furtherly deterioration , thereby caused apoptosis [ XREF_BIBR ] .	During the apoptotic process, Bax forms oligomers and transfers from cytoplasm to mitochondrial membrane [XREF_BIBR], then Bax oligomer interacts with pore protein of mitochondrial membrane, results in increased membrane permeability, and induces release of cytochrome c from mitochondria to cytosol, finally actives the caspase [XREF_BIBR], leading to mitochondrial electron transport, DNA fracture and furtherly deterioration, thereby caused apoptosis [XREF_BIBR].	20	42	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	20	21	40	42
The pro apoptotic member Bax translocates to the mitochondrion and integrates into the OMM , where Bax promotes the excretion of cytochrome c into the cytosol and the disruption of DeltaPsim , whereas anti-apoptotic protein Bcl-2 prevents this process by preserving mitochondrial integrity .	The pro apoptotic member Bax translocates to the mitochondrion and integrates into the OMM, where Bax promotes the excretion of cytochrome c into the cytosol and the disruption of DeltaPsim, whereas anti-apoptotic protein Bcl-2 prevents this process by preserving mitochondrial integrity.	16	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	21	23
In a cellular model of glutamate induced , NMDA receptor mediated excitotoxicity , primary CGCs pretreated for seven days with lithium ( 0.5 mM to 5.0 mM ) decreased protein levels of the pro apoptotic molecules p53 and Bax , inhibited the mitochondrial release of pro apoptotic protein cytochrome c , and increased protein levels of the pro survival molecule B-cell lymphoma and leukemia -2 ( Bcl-2 ) compared to non pretreated controls XREF_BIBR .	In a cellular model of glutamate induced, NMDA receptor mediated excitotoxicity, primary CGCs pretreated for seven days with lithium (0.5 mM to 5.0 mM) decreased protein levels of the pro apoptotic molecules p53 and Bax, inhibited the mitochondrial release of pro apoptotic protein cytochrome c, and increased protein levels of the pro survival molecule B-cell lymphoma and leukemia -2 (Bcl-2) compared to non pretreated controls XREF_BIBR.	8	50	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	NMDA receptor mediated excitotoxicity, primary CGCs pretreated for seven days with lithium (0.5 mM to 5.0 mM) decreased protein levels of the pro apoptotic molecules p53 and Bax	bax	cytochrome c	cytochrome c	cytochrome c	38	39	48	50
Taken together , these findings demonstrate that inflammatory cytokines induce Bax mediated mitochondrial dysfunction and cytochrome c release .	Taken together, these findings demonstrate that inflammatory cytokines induce Bax mediated mitochondrial dysfunction and cytochrome c release.	10	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	10	11	15	17
Sympathetic neuronal death induced by nerve growth factor ( NGF ) deprivation requires the macromolecular synthesis dependent translocation of BAX from the cytosol to mitochondria and its subsequent integration into the mitochondrial outer membrane , followed by BAX mediated cytochrome c ( cyt c ) release .	Sympathetic neuronal death induced by nerve growth factor (NGF) deprivation requires the macromolecular synthesis dependent translocation of BAX from the cytosol to mitochondria and its subsequent integration into the mitochondrial outer membrane, followed by BAX mediated cytochrome c (cyt c) release.	35	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	37	38	39	41
Bid and Bax , as well as pro apoptotic factors endogenous to the Xenopus system , initiated the release of multiple intermembrane space proteins , namely cytochrome c , adenylate kinase ( AK ) and sulfite oxidase ( SOx ) .	Bid and Bax, as well as pro apoptotic factors endogenous to the Xenopus system, initiated the release of multiple intermembrane space proteins, namely cytochrome c, adenylate kinase (AK) and sulfite oxidase (SOx).	0	28	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	26	28
It has been suggested that a high Bax to Bcl-2 ratio can cause DeltaPsim collapse , release of cytochrome c , and subsequent apoptosis [ XREF_BIBR ] .	It has been suggested that a high Bax to Bcl-2 ratio can cause DeltaPsim collapse, release of cytochrome c, and subsequent apoptosis [XREF_BIBR].	5	20	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	18	20
Based on these observations , we have proposed that Bax and Bak target VDAC to induce cytochrome c release , whereas Bid and Bik induces cytochrome c release by a mechanism not involving the VDAC ( Shimizu and Tsujimoto 2000 ; Tsujimoto and Shimizu 2000b ) .	Based on these observations, we have proposed that Bax and Bak target VDAC to induce cytochrome c release, whereas Bid and Bik induces cytochrome c release by a mechanism not involving the VDAC (Shimizu and Tsujimoto 2000; Tsujimoto and Shimizu 2000b).	9	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	9	10	16	18
As NCS induced apoptosis involves cytochrome c 23 and as pro apoptotic protein BAX promotes the release of cytochrome c from mitochondria , 24 the levels of BAX and cytochrome c in NCS treated cells was determined .	As NCS induced apoptosis involves cytochrome c 23 and as pro apoptotic protein BAX promotes the release of cytochrome c from mitochondria, 24 the levels of BAX and cytochrome c in NCS treated cells was determined.	10	20	promotes	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	13	14	18	20
The proapoptotic protein Bax , through oligomerization with Bak , translocates from the cytoplasm to mitochondria to increase mitochondrial outer membrane permeabilization , triggering cytochrome c release and caspase-3 activity XREF_BIBR .	The proapoptotic protein Bax, through oligomerization with Bak, translocates from the cytoplasm to mitochondria to increase mitochondrial outer membrane permeabilization, triggering cytochrome c release and caspase-3 activity XREF_BIBR.	0	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax, through oligomerization with Bak, translocates from the cytoplasm to mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	3	4	24	26
These observations , coupled with reports showing that Bax causes the release of mitochondrial cytochrome c , implicate Bax as a central mediator of the apoptotic process .	These observations, coupled with reports showing that Bax causes the release of mitochondrial cytochrome c, implicate Bax as a central mediator of the apoptotic process.	8	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	14	16
Furthermore , Bax may promote the release of cytochrome c from the mitochondria to induce apoptosis .	Furthermore, Bax may promote the release of cytochrome c from the mitochondria to induce apoptosis.	2	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	8	10
However , Ca 2+ , in contrast to BAX oligo , did not produce a detectable cytochrome c release ( XREF_FIG ) while BAX oligo caused a massive release of cytochrome c ( XREF_FIG ) .	However, Ca 2+, in contrast to BAX oligo, did not produce a detectable cytochrome c release (XREF_FIG) while BAX oligo caused a massive release of cytochrome c (XREF_FIG).	23	32	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	23	24	30	32
We considered that apoptosis is irreversibly activated when concentration reaches the threshold which corresponds to the minimal amount of oligomerized Bax molecules required to trigger the cytochrome C release into the cytosol .	We considered that apoptosis is irreversibly activated when concentration reaches the threshold which corresponds to the minimal amount of oligomerized Bax molecules required to trigger the cytochrome C release into the cytosol.	20	28	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	20	21	26	28
Unexpectedly , Bcl-2 also fails to prevent Bax induced cytochrome c release , although it co-localizes with Bax to mitochondria .	Unexpectedly, Bcl-2 also fails to prevent Bax induced cytochrome c release, although it co-localizes with Bax to mitochondria.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	9	11
The balance between expression levels of antiapoptotic Bcl-2 and proapoptotic BAX is crucial for cell survival or death , wherein increase of the BAX and Bcl -2 ratio will activate the release of cytochrome c from mitochondria and subsequently activate the intrinsic apoptotic pathway .	The balance between expression levels of antiapoptotic Bcl-2 and proapoptotic BAX is crucial for cell survival or death, wherein increase of the BAX and Bcl -2 ratio will activate the release of cytochrome c from mitochondria and subsequently activate the intrinsic apoptotic pathway.	20	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	23	24	33	35
The intrinsic pathway is regulated by Bax and Bcl-XL and involves Bax induced mitochondrial dysfunction and release of cytochrome c as antecedent events leading to caspase-3 activation .	The intrinsic pathway is regulated by Bax and Bcl-XL and involves Bax induced mitochondrial dysfunction and release of cytochrome c as antecedent events leading to caspase-3 activation.	11	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	18	20
Consequently , it seems likely that the massive release of cytochrome c induced by BAX oligo proceeds by a mechanism involving permeabilization of the OMM accompanied by mPT dependent mitochondrial remodeling without necessity for oxidative stress dependent loosening of cytochrome c attachment to the IMM .	Consequently, it seems likely that the massive release of cytochrome c induced by BAX oligo proceeds by a mechanism involving permeabilization of the OMM accompanied by mPT dependent mitochondrial remodeling without necessity for oxidative stress dependent loosening of cytochrome c attachment to the IMM.	10	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	14	15	10	12
Bax mediated mitochondrial outer membrane permeabilization and regulated cytochrome c release from mitochondria [ XREF_BIBR ] .	Bax mediated mitochondrial outer membrane permeabilization and regulated cytochrome c release from mitochondria [XREF_BIBR].	0	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
Moreover , the balance between expression levels of anti-apoptotic Bcl-2 and pro apoptotic Bax is also critical for cell survival and death XREF_BIBR , where increase of the Bax and Bcl -2 ratio activates the release of cytochrome C from mitochondria and subsequently activates the intrinsic apoptotic pathway XREF_BIBR .	Moreover, the balance between expression levels of anti-apoptotic Bcl-2 and pro apoptotic Bax is also critical for cell survival and death XREF_BIBR, where increase of the Bax and Bcl -2 ratio activates the release of cytochrome C from mitochondria and subsequently activates the intrinsic apoptotic pathway XREF_BIBR.	25	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	28	29	37	39
4-HPR causes elevation of Bax to induce mitochondrial release of cytochrome c for activation of caspase-3 and caspase-7 and also to release AIF into the cytosol and its nuclear translocation for apoptosis [ XREF_BIBR ] .	4-HPR causes elevation of Bax to induce mitochondrial release of cytochrome c for activation of caspase-3 and caspase-7 and also to release AIF into the cytosol and its nuclear translocation for apoptosis [XREF_BIBR].	2	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	10	12
Bax itself has been shown to induce cytochrome c release in isolated mitochondria 44454647 and when overexpressed in whole cells 62 .	Bax itself has been shown to induce cytochrome c release in isolated mitochondria 44454647 and when overexpressed in whole cells 62.	0	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	7	9
Bax induced release of cytochrome c from mitochondria and the subsequent activation of cytosolic caspases are central to this death .	Bax induced release of cytochrome c from mitochondria and the subsequent activation of cytosolic caspases are central to this death.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	4	6
The intrinsic pathway involves functional incapacitation of mitochondria by pro apoptotic Bcl2 family members , including Bax , Bak , and Bik , that cause mitochondria potential loss and release cytochrome c to activate caspase 9 , which in turn activates executor caspases (-3, -7 ) and destroys cellular proteins [ XREF_BIBR ] .	The intrinsic pathway involves functional incapacitation of mitochondria by pro apoptotic Bcl2 family members, including Bax, Bak, and Bik, that cause mitochondria potential loss and release cytochrome c to activate caspase 9, which in turn activates executor caspases (-3, -7) and destroys cellular proteins [XREF_BIBR].	16	32	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	30	32
It has been long reported that Bax can be directly activated by Bim to trigger cytochrome c release and therefore promote the cascade caspase reaction and programmed cell death , which is a major core of the intrinsic apoptosis pathway at the mitochondria .	It has been long reported that Bax can be directly activated by Bim to trigger cytochrome c release and therefore promote the cascade caspase reaction and programmed cell death, which is a major core of the intrinsic apoptosis pathway at the mitochondria.	6	20	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	15	17
19 Furthermore , downstream of BAX and BAK insertion into the mitochondrial outer membrane , oxidization of PUFA rich mitochondrial cardiolipins ( a class of glycerophospholipids synthesized in the mitochondrion ) on the outer leaflet of the mitochondrial inner membrane promotes the release of cytochrome C and other key apoptotic effectors from the mitochondria into the cytosol .	19 Furthermore, downstream of BAX and BAK insertion into the mitochondrial outer membrane, oxidization of PUFA rich mitochondrial cardiolipins (a class of glycerophospholipids synthesized in the mitochondrion) on the outer leaflet of the mitochondrial inner membrane promotes the release of cytochrome C and other key apoptotic effectors from the mitochondria into the cytosol.	5	46	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome C	cytochrome C	cytochrome C	5	6	44	46
Major sequences in the two pathways are as follows : Dephosphorylation of the prosurvival Akt pathway leads to apoptosis : Dephosphorylated Akt causes dephosphorylation ( activation ) of Bad ; dephosphorylated Bad is released from Scaffold 14-3-3 protein ; dephosphorylated Bad initiates Bad-Bcl-x L binding ; Bad-Bcl-x L binding causes dissociation of Bax- Bcl-x L , thereby freeing Bax ; Bax causes Cytochrome C release ; Cytochrome C activates procaspase cleavage ; and Caspase cascades lead to apoptosis .	Major sequences in the two pathways are as follows : Dephosphorylation of the prosurvival Akt pathway leads to apoptosis : Dephosphorylated Akt causes dephosphorylation (activation) of Bad; dephosphorylated Bad is released from Scaffold 14-3-3 protein; dephosphorylated Bad initiates Bad-Bcl-x L binding; Bad-Bcl-x L binding causes dissociation of Bax- Bcl-x L, thereby freeing Bax; Bax causes Cytochrome C release; Cytochrome C activates procaspase cleavage; and Caspase cascades lead to apoptosis.	60	64	causes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome C	Cytochrome C	Cytochrome C	60	61	62	64
Bax and Bak mediated mitochondrial membrane permeabilization results in the release of cytochrome c from the intermembrane space XREF_BIBR .	Bax and Bak mediated mitochondrial membrane permeabilization results in the release of cytochrome c from the intermembrane space XREF_BIBR.	0	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	12	14
Higher concentrations of BAX oligo produced larger cytochrome c release , culminating at 10.8 mug/ml of BAX oligo .	Higher concentrations of BAX oligo produced larger cytochrome c release, culminating at 10.8 mug/ml of BAX oligo.	1	9	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	3	4	7	9
Since we have previously shown that Bax induced cytochrome c release largely depends on mitochondrial respiration under our experimental conditions ( Shimizu and Tsujimoto 2000 ) , and since VDAC is involved in mitochondrial respiration ( for review see Colombini 1989 ) by acting as a gate for respiratory substrates , the possibility was raised that the anti-VDAC antibodies inhibited respiration and thereby blocked the action of Bax on the mitochondria .	Since we have previously shown that Bax induced cytochrome c release largely depends on mitochondrial respiration under our experimental conditions (Shimizu and Tsujimoto 2000), and since VDAC is involved in mitochondrial respiration (for review see Colombini 1989) by acting as a gate for respiratory substrates, the possibility was raised that the anti-VDAC antibodies inhibited respiration and thereby blocked the action of Bax on the mitochondria.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
DIM and butyrate combination treatment induced the expression of pro apoptotic Bax and Bak proteins , triggered Bax dimerization and activation , and caused release of cytochrome c and Smac proteins from mitochondria .	DIM and butyrate combination treatment induced the expression of pro apoptotic Bax and Bak proteins, triggered Bax dimerization and activation, and caused release of cytochrome c and Smac proteins from mitochondria.	0	28	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	DIM and butyrate combination treatment induced the expression of pro apoptotic Bax	bax	cytochrome c	cytochrome c	cytochrome c	11	12	26	28
For example , cytosolic Bax translocation to mitochondria triggers cytosolic Cytochrome c release for inducing apoptosis , whereas Bcl-2 and/or Bcl-xL can block cytosolic Cytochrome c release for depressing apoptosis XREF_BIBR - XREF_BIBR .	For example, cytosolic Bax translocation to mitochondria triggers cytosolic Cytochrome c release for inducing apoptosis, whereas Bcl-2 and/or Bcl-xL can block cytosolic Cytochrome c release for depressing apoptosis XREF_BIBR - XREF_BIBR.	4	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax translocation to mitochondria	bax	Cytochrome c	Cytochrome c	cytochrome c	4	5	10	12
Bax promotes the release of cytochrome c from mitochondria , resulting in the apoptotic caspase cascade .	Bax promotes the release of cytochrome c from mitochondria, resulting in the apoptotic caspase cascade.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
In a further response to apoptotic stimuli , Bax undergoes a conformational change and integrates into the mitochondrial membrane , inducing release of cytochrome c , and activation of caspase-9 and thus caspase-3 [ XREF_BIBR ] .	In a further response to apoptotic stimuli, Bax undergoes a conformational change and integrates into the mitochondrial membrane, inducing release of cytochrome c, and activation of caspase-9 and thus caspase-3 [XREF_BIBR].	8	25	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	23	25
Bcl-2 and Bcl-x L block Bax translocation to the mitochondria , maintain mitochondrial membrane potential , and prevent the release of cytochrome c from the mitochondria [ XREF_BIBR , XREF_BIBR ] .	Bcl-2 and Bcl-x L block Bax translocation to the mitochondria, maintain mitochondrial membrane potential, and prevent the release of cytochrome c from the mitochondria [XREF_BIBR, XREF_BIBR].	5	23	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax translocation to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	5	6	21	23
Increased Bax and Bcl -2 ratio leads to the dysfunction of mitochondria by triggering mitochondrial outer membrane permeabilization and releasing cytochrome c into the plasma , which eventually causes caspase mediated apoptosis [ XREF_BIBR ] .	Increased Bax and Bcl -2 ratio leads to the dysfunction of mitochondria by triggering mitochondrial outer membrane permeabilization and releasing cytochrome c into the plasma, which eventually causes caspase mediated apoptosis [XREF_BIBR].	0	22	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	20	22
The anti-apoptotic protein Bcl-2 inhibits apoptosis by preventing the release of cytochrome c , XREF_BIBR while Bax promotes mitochondrial membrane damage and cytochrome c release , XREF_BIBR leading to the activation of caspase 9 and 3 and cellular apoptosis ( XREF_FIG ) .	The anti-apoptotic protein Bcl-2 inhibits apoptosis by preventing the release of cytochrome c, XREF_BIBR while Bax promotes mitochondrial membrane damage and cytochrome c release, XREF_BIBR leading to the activation of caspase 9 and 3 and cellular apoptosis (XREF_FIG).	16	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	22	24
Up-regulated Bax , a pro apoptotic molecule , induces release of the cytochrome c from mitochondria , which leads to cleavage of caspase-9 .	Up-regulated Bax, a pro apoptotic molecule, induces release of the cytochrome c from mitochondria, which leads to cleavage of caspase-9.	0	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	12	14
Upon HDACI treatment , acetylated Ku70 releases Bax , allowing it to translocate to mitochondria and trigger cytochrome c release , leading to caspase dependent death .	Upon HDACI treatment, acetylated Ku70 releases Bax, allowing it to translocate to mitochondria and trigger cytochrome c release, leading to caspase dependent death.	4	19	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	acetylated Ku70 releases Bax	bax	cytochrome c	cytochrome c	cytochrome c	7	8	17	19
In Apaf1 -/- mice , vice versa , Bax and Bak and other Bcl-2 family members enable cytochrome c release in response to developmental signals from surrounding tissues ; the mitochondria start their depolarization program and autophagy sustains cell survival until metabolites for energy production are totally consumed and secondary cellular destruction takes place .	In Apaf1 -/- mice, vice versa, Bax and Bak and other Bcl-2 family members enable cytochrome c release in response to developmental signals from surrounding tissues; the mitochondria start their depolarization program and autophagy sustains cell survival until metabolites for energy production are totally consumed and secondary cellular destruction takes place.	8	19	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	17	19
This increased Bax leads to the drop of mitochondrial membrane potential , the release of cytochrome c , and the activation of caspase 9 and caspase 3 sequentially , which were observed in this study .	This increased Bax leads to the drop of mitochondrial membrane potential, the release of cytochrome c, and the activation of caspase 9 and caspase 3 sequentially, which were observed in this study.	2	17	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	15	17
Wang et al showed that Bax may increase the release of cytochrome c from mitochondria into cytoplasm and exert a pro apoptotic effect .	Wang et al showed that Bax may increase the release of cytochrome c from mitochondria into cytoplasm and exert a pro apoptotic effect.	5	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	11	13
After an apoptotic stimulus , Bax is translocated into the mitochondria and promotes the release of cytochrome c [ XREF_BIBR ] , possibly by forming a pore [ XREF_BIBR ] or a voltage dependent anion channel in the outer mitochondrial membrane .	After an apoptotic stimulus, Bax is translocated into the mitochondria and promotes the release of cytochrome c [XREF_BIBR], possibly by forming a pore [XREF_BIBR] or a voltage dependent anion channel in the outer mitochondrial membrane.	5	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	16	18
Bax , a pro apoptotic protein , induces the initiation of caspase activated apoptosis pathway and mitochondrial cytochrome c release via changes in mitochondrial membrane permeability .	Bax, a pro apoptotic protein, induces the initiation of caspase activated apoptosis pathway and mitochondrial cytochrome c release via changes in mitochondrial membrane permeability.	0	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	17	19
Finally , cytochrome c release induced by BAX oligo had an inverse correlation with the rate of ROS generation .	Finally, cytochrome c release induced by BAX oligo had an inverse correlation with the rate of ROS generation.	2	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	7	8	2	4
Moreover , we also found that CP-31398 increased Bax expression , altered mitochondrial membrane potential causing the release of cytochrome c , and induced the cleavage of caspases-9 and -3 .	Moreover, we also found that CP-31398 increased Bax expression, altered mitochondrial membrane potential causing the release of cytochrome c, and induced the cleavage of caspases-9 and -3.	6	21	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	CP-31398 increased Bax expression	bax	cytochrome c	cytochrome c	cytochrome c	8	9	19	21
Transient over-expression of Bax results in release of ER Ca 2+ , with a subsequent increase in mitochondrial Ca 2+ and enhanced cytochrome c release .	Transient over-expression of Bax results in release of ER Ca 2+, with a subsequent increase in mitochondrial Ca 2+ and enhanced cytochrome c release.	1	24	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	over-expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	3	4	22	24
It is known that oligomerization of Bax molecules in mitochondria is a major mechanism through which Bax induces cytochrome c ( Cyt c ) release .	It is known that oligomerization of Bax molecules in mitochondria is a major mechanism through which Bax induces cytochrome c (Cyt c) release.	16	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	18	20
BAX localization on the mitochondrial membrane causes the release of cytochrome c release , which in turn activates the caspase cascade resulting apoptotic cell death [ XREF_BIBR ] .	BAX localization on the mitochondrial membrane causes the release of cytochrome c release, which in turn activates the caspase cascade resulting apoptotic cell death [XREF_BIBR].	0	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	0	1	10	12
We further show that Cdk2 activation status does not interfere with a procedure that lies downstream of cytochrome c release induced by Bax protein .	We further show that Cdk2 activation status does not interfere with a procedure that lies downstream of cytochrome c release induced by Bax protein.	17	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	22	23	17	19
Taken together , these data suggest that andrographolide induced changes in Bax and Bcl -2 ratio might trigger the release of cytochrome c from mitochondria and enhance the deposition in cytoplasm which could bind to Apaf-1 and subsequently lead to apoptosis .	Taken together, these data suggest that andrographolide induced changes in Bax and Bcl -2 ratio might trigger the release of cytochrome c from mitochondria and enhance the deposition in cytoplasm which could bind to Apaf-1 and subsequently lead to apoptosis.	11	23	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	21	23
Bcl-2 can inhibit Bax pore formation and Bax mediated cytochrome c release , possibly by the interaction between Bcl-2 pore and Bax pore leading to the formation of non functional complexes in the membrane .	Bcl-2 can inhibit Bax pore formation and Bax mediated cytochrome c release, possibly by the interaction between Bcl-2 pore and Bax pore leading to the formation of non functional complexes in the membrane.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	9	11
We show here that recombinant Bax protein induced cytochrome c release in isolated mitochondria without detectable swelling .	We show here that recombinant Bax protein induced cytochrome c release in isolated mitochondria without detectable swelling.	5	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	8	10
Notably , under condition of apoptosis induced by the NFkappaB inhibitor , Bax appeared to be translocated back to the mitochondria and triggered the release of Cytochrome C in the cytosol for the induction of apoptosis .	Notably, under condition of apoptosis induced by the NFkappaB inhibitor, Bax appeared to be translocated back to the mitochondria and triggered the release of Cytochrome C in the cytosol for the induction of apoptosis.	12	28	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome C	Cytochrome C	Cytochrome C	12	13	26	28
Moreover , FK18 increased Akt phosphorylation under both normoxic and OGD conditions , attenuated mitochondrial translocation of the proapoptotic protein Bad , up-regulated the expression of Bcl-2 and Bax , and inhibited the release of cytochrome c from the mitochondria into the cytoplasm .	Moreover, FK18 increased Akt phosphorylation under both normoxic and OGD conditions, attenuated mitochondrial translocation of the proapoptotic protein Bad, up-regulated the expression of Bcl-2 and Bax, and inhibited the release of cytochrome c from the mitochondria into the cytoplasm.	2	37	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	FK18 increased Akt phosphorylation under both normoxic and OGD conditions, attenuated mitochondrial translocation of the proapoptotic protein Bad, up-regulated the expression of Bcl-2 and Bax	bax	cytochrome c	cytochrome c	cytochrome c	28	29	35	37
Following flavonoid treatments , increase in Bax : Bcl-2 ratio and decrease in DeltaPsi m triggered accumulation of cytosolic cytochrome c for increasing activation and activity of caspase-9 ( XREF_FIG ) .	Following flavonoid treatments, increase in Bax : Bcl-2 ratio and decrease in DeltaPsi m triggered accumulation of cytosolic cytochrome c for increasing activation and activity of caspase-9 (XREF_FIG).	4	21	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	19	21
The findings revealed that the TalphaPcZn-PDT treatment of LoVo cells resulted in the induction of apoptosis , the formation of p38 MAPK and caspase -9 complexes , the activation of p38 MAPK , caspase-9 , caspase-3 and Bid , the downregulation of Bcl-2 , the reduction of mitochondrial membrane potential ( DeltaPsim ) , the upregulation of Bax and the release of apoptosis inducing factor ( AIF ) and cytochrome c ( Cyto c ) .	The findings revealed that the TalphaPcZn-PDT treatment of LoVo cells resulted in the induction of apoptosis, the formation of p38 MAPK and caspase -9 complexes, the activation of p38 MAPK, caspase-9, caspase-3 and Bid, the downregulation of Bcl-2, the reduction of mitochondrial membrane potential (DeltaPsim), the upregulation of Bax and the release of apoptosis inducing factor (AIF) and cytochrome c (Cyto c).	55	71	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	57	58	69	71
Activation of the pro apoptotic Bax and Bak proteins induces mitochondrial outer membrane permeabilization and cytochrome C release from the mitochondria , leading to downstream caspase activation , DNA cleavage , and apoptotic cell death [ XREF_BIBR ] .	Activation of the pro apoptotic Bax and Bak proteins induces mitochondrial outer membrane permeabilization and cytochrome C release from the mitochondria, leading to downstream caspase activation, DNA cleavage, and apoptotic cell death [XREF_BIBR].	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	5	6	15	17
Corresponding to an increasing level of p53 , an inducer of apoptosis , the level of Bax also increases in mitochondria , allowing significant release of mitochondrial cytochrome c into the cytosol , thus initiating the onset of apoptosis .	Corresponding to an increasing level of p53, an inducer of apoptosis, the level of Bax also increases in mitochondria, allowing significant release of mitochondrial cytochrome c into the cytosol, thus initiating the onset of apoptosis.	14	29	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	level of Bax	bax	cytochrome c	cytochrome c	cytochrome c	16	17	27	29
Treatment with Tempo ( 10 mM , 37 degrees C/30 min ) and hyperthermia ( 44 degrees C/30 min ) induced 30 and 70-80 % apoptosis , respectively , through Bax mediated cytochrome c release and DEVDase activation .	Treatment with Tempo (10 mM, 37 degrees C/30 min) and hyperthermia (44 degrees C/30 min) induced 30 and 70-80% apoptosis, respectively, through Bax mediated cytochrome c release and DEVDase activation.	21	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	30	31	32	34
This process is mediated in part by the proteolytic activation of the pro apoptotic molecules , Bid and Bax , resulting in MOMP and cytochrome C release XREF_BIBR .	This process is mediated in part by the proteolytic activation of the pro apoptotic molecules, Bid and Bax, resulting in MOMP and cytochrome C release XREF_BIBR.	3	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	18	19	24	26
Insertion of Bax , but not Bcl-2 and Delta34 , into mitochondria triggered a rapid release of cytochrome c from the mitochondria .	Insertion of Bax, but not Bcl-2 and Delta34, into mitochondria triggered a rapid release of cytochrome c from the mitochondria.	0	19	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	17	19
Overexpression of Bax in sympathetic neurons is sufficient to induce cytochrome c release and apoptosis in the presence of NGF .	Overexpression of Bax in sympathetic neurons is sufficient to induce cytochrome c release and apoptosis in the presence of NGF.	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Overexpression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	2	3	10	12
XREF_BIBR SIRT1 deacetylation of p53 lysine 382 ( mouse K379 ) prevents p53 nuclear translocation , promoting transcription independent apoptosis via BAX mediated cytochrome c release .	XREF_BIBR SIRT1 deacetylation of p53 lysine 382 (mouse K379) prevents p53 nuclear translocation, promoting transcription independent apoptosis via BAX mediated cytochrome c release.	19	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	21	22	23	25
Pro apoptotic Bax and Bak promote the release of cytochrome c or diablo from mitochondria leading to caspase activation .	Pro apoptotic Bax and Bak promote the release of cytochrome c or diablo from mitochondria leading to caspase activation.	0	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	9	11
Bcl-2 family proteins are involved in intrinsic apoptosis pathway ; therefore , the downregulation of Bcl-2 and Bax ratio promotes the release of cytochrome c from the mitochondria to the cytoplasm under oxidative stress and then induces the forming of an apoptosome containing APAF-1 , cytochrome c , and procaspase-9 .	Bcl-2 family proteins are involved in intrinsic apoptosis pathway; therefore, the downregulation of Bcl-2 and Bax ratio promotes the release of cytochrome c from the mitochondria to the cytoplasm under oxidative stress and then induces the forming of an apoptosome containing APAF-1, cytochrome c, and procaspase-9.	15	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	17	18	23	25
Bim , a BH3-only Bcl-2 family member , functions upstream of Bax mediated cytochrome c release from the mitochondria [ XREF_BIBR , XREF_BIBR ] .	Bim, a BH3-only Bcl-2 family member, functions upstream of Bax mediated cytochrome c release from the mitochondria [XREF_BIBR, XREF_BIBR].	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	13	15
Previous studies indicated that overexpression of BAX induces apoptosis with loss of mitochondrial potential , an early release of cytochrome c preceding many apoptosis associated morphological alterations as well as caspase activation and subsequent substrate proteolysis [ XREF_BIBR ] .	Previous studies indicated that overexpression of BAX induces apoptosis with loss of mitochondrial potential, an early release of cytochrome c preceding many apoptosis associated morphological alterations as well as caspase activation and subsequent substrate proteolysis [XREF_BIBR].	4	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	overexpression of BAX	bax	cytochrome c	cytochrome c	cytochrome c	6	7	19	21
In mammals , members of the proapoptotic Bax subfamily of proteins translocate from the cytosol to the mitochondrial membrane and cause a release of cytochrome c during apoptosis .	In mammals, members of the proapoptotic Bax subfamily of proteins translocate from the cytosol to the mitochondrial membrane and cause a release of cytochrome c during apoptosis.	7	26	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	24	26
Immunostaining for cytochrome c showed that addition of the truncated Bax caused clear release of cytochrome c in 83 +/- 2 % of bax +/+ permeabilized neurons but only in 25 +/- 2 % of bax -/- permeabilized cells ( XREF_SUPPLEMENTARY ) .	Immunostaining for cytochrome c showed that addition of the truncated Bax caused clear release of cytochrome c in 83 +/- 2% of bax +/+ permeabilized neurons but only in 25 +/- 2% of bax -/- permeabilized cells (XREF_SUPPLEMENTARY).	6	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	10	11	15	17
Likewise , in mitochondrial release assays that employed BAX and BAK doubly deficient mouse liver mitochondria prepared from Alb-cre pos Bax flox/- Bak -/- mice , BIM SAHB induced dose responsive BAX mediated cytochrome c release ( XREF_FIG ) .	Likewise, in mitochondrial release assays that employed BAX and BAK doubly deficient mouse liver mitochondria prepared from Alb-cre pos Bax flox/- Bak -/- mice, BIM SAHB induced dose responsive BAX mediated cytochrome c release (XREF_FIG).	28	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	31	32	33	35
TOM complex on the outer membrane of mitochondria was the entry gate for the proteins that were imported into the mitochondria 23 and was also found to be necessary for tBid and Bax induced cytochrome C release .	TOM complex on the outer membrane of mitochondria was the entry gate for the proteins that were imported into the mitochondria 23 and was also found to be necessary for tBid and Bax induced cytochrome C release.	30	36	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	32	33	34	36
The pathway regulates the mitochondrial membrane permeability by downregulation of Bcl-2 and upregulation of p53 , Bax , and Bak , triggering the cytochrome c release from mitochondria into cytosol .	The pathway regulates the mitochondrial membrane permeability by downregulation of Bcl-2 and upregulation of p53, Bax, and Bak, triggering the cytochrome c release from mitochondria into cytosol.	8	25	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	23	25
Bax is a pro apoptotic member and has been reported to promote cytochrome c release and induce the activation of the downstream caspase family through the intrinsic death pathway [ XREF_BIBR ] .	Bax is a pro apoptotic member and has been reported to promote cytochrome c release and induce the activation of the downstream caspase family through the intrinsic death pathway [XREF_BIBR].	0	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	12	14
We conclude , first , that the efflux of cytochrome c induced by tBid or Bax is not dependent on PT or swelling and , second , that mitochondrial loss of cytochrome c is not sufficient to induce PT .	We conclude, first, that the efflux of cytochrome c induced by tBid or Bax is not dependent on PT or swelling and, second, that mitochondrial loss of cytochrome c is not sufficient to induce PT.	9	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	9	11
The mitochondrial membrane bound HKII has been shown to promote the high glycolytic tumor phenotype and to inhibit Bax induced cytochrome c mediated apoptosis in HeLa cells XREF_BIBR , XREF_BIBR .	The mitochondrial membrane bound HKII has been shown to promote the high glycolytic tumor phenotype and to inhibit Bax induced cytochrome c mediated apoptosis in HeLa cells XREF_BIBR, XREF_BIBR.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	18	19	20	22
Calpain cleaves many substrates , including cytoskeletal proteins , axonal and myelin proteins , and pro apoptotic Bax causing mitochondrial cytochrome c release and activation of caspase-3 .	Calpain cleaves many substrates, including cytoskeletal proteins, axonal and myelin proteins, and pro apoptotic Bax causing mitochondrial cytochrome c release and activation of caspase-3.	1	22	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	17	18	20	22
Bax can promote the release of cytochrome c from the mitochondria to the cytosol which eventually contributes to the activation of caspase-3 .	Bax can promote the release of cytochrome c from the mitochondria to the cytosol which eventually contributes to the activation of caspase-3.	0	8	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
We found that BAX oligo caused a complete release of cytochrome c in a concentration- and time dependent manner .	We found that BAX oligo caused a complete release of cytochrome c in a concentration- and time dependent manner.	3	12	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	3	4	10	12
In the following experiments , we addressed the question of whether the intensity of oxidative stress , judged as the rate of ROS generation by mitochondria , correlated with the release of cytochrome c induced by BAX oligo or alamethicin .	In the following experiments, we addressed the question of whether the intensity of oxidative stress, judged as the rate of ROS generation by mitochondria, correlated with the release of cytochrome c induced by BAX oligo or alamethicin.	32	39	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	36	37	32	34
Pretreatment of BEAS-2B cells with Vam3 ( 5 mumol/L ) or resveratrol ( 5 mumol/L ) significantly suppressed CSC induced apoptosis , and prevented CSC induced Bax level increase in the mitochondria , mitochondrial membrane potential loss , cytochrome c release and caspase-9 activation .	Pretreatment of BEAS-2B cells with Vam3 (5 mumol/L) or resveratrol (5 mumol/L) significantly suppressed CSC induced apoptosis, and prevented CSC induced Bax level increase in the mitochondria, mitochondrial membrane potential loss, cytochrome c release and caspase-9 activation.	18	40	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Bax	CSC induced apoptosis, and prevented CSC induced Bax	bax	cytochrome c	cytochrome c	cytochrome c	26	27	38	40
In contrast , Ca ( 2+ )-independent cytochrome c release is induced by oligomeric Bax protein and occurs without mitochondrial swelling or the release of matrix proteins , although our data also indicate that Bax enhances permeability transition induced cytochrome c release .	In contrast, Ca (2+)-independent cytochrome c release is induced by oligomeric Bax protein and occurs without mitochondrial swelling or the release of matrix proteins, although our data also indicate that Bax enhances permeability transition induced cytochrome c release.	34	41	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	34	35	39	41
This Bax overexpression induced cytochrome c release , a reduction of cytochrome c oxidase activity and mitochondrial membrane potential ( Delta ( Psi ) m ) .	This Bax overexpression induced cytochrome c release, a reduction of cytochrome c oxidase activity and mitochondrial membrane potential (Delta (Psi) m).	1	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax overexpression	bax	cytochrome c	cytochrome c	cytochrome c	1	2	4	6
Moreover , BAX and BAK overexpression is sufficient to enhance Ca 2+ release into the mitochondria , leading to permeabilization and increased cytochrome c release .	Moreover, BAX and BAK overexpression is sufficient to enhance Ca 2+ release into the mitochondria, leading to permeabilization and increased cytochrome c release.	2	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX and BAK overexpression	bax	cytochrome c	cytochrome c	cytochrome c	2	3	22	24
Anti-VDAC Antibodies Inhibit Bax induced Cytochrome c Release in Cells .	Anti-VDAC Antibodies Inhibit Bax induced Cytochrome c Release in Cells.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome c	Cytochrome c	Cytochrome c	3	4	5	7
An addition of BAX oligo to mitochondria caused cytochrome c release in a concentration- and time dependent fashion .	An addition of BAX oligo to mitochondria caused cytochrome c release in a concentration- and time dependent fashion.	1	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	3	4	8	10
For example , prosurvival members of the Bcl-2 family prevent apoptosis in response to trophic factor withdrawal by inhibiting Bax induced opening of the mitochondrial permeabilization pore , cytochrome c release , and subsequent caspase activation .	For example, prosurvival members of the Bcl-2 family prevent apoptosis in response to trophic factor withdrawal by inhibiting Bax induced opening of the mitochondrial permeabilization pore, cytochrome c release, and subsequent caspase activation.	19	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	19	20	28	30
BAX subsequently translocates to the mitochondrion and induces cytochrome c release and caspase activation .	BAX subsequently translocates to the mitochondrion and induces cytochrome c release and caspase activation.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX subsequently translocates to the mitochondrion	bax	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
In order to evaluate the role of mitochondrial swelling in the OMM permeabilization , we compared mitochondrial swelling and the release of cytochrome c induced by BAX oligo or a bolus of Ca 2+ .	In order to evaluate the role of mitochondrial swelling in the OMM permeabilization, we compared mitochondrial swelling and the release of cytochrome c induced by BAX oligo or a bolus of Ca 2+.	22	30	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	26	27	22	24
The bcl-2-associated X protein ( bax ) promotes release of cytochrome C and consequently exhibits pro apoptotic properties .	The bcl-2-associated X protein (bax) promotes release of cytochrome C and consequently exhibits pro apoptotic properties.	3	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	bax	bax	bax	cytochrome C	cytochrome C	cytochrome C	5	6	10	12
Here , we reconfirm that Bax can trigger the release of cytochrome C after overexpression in different cell types and directly when added to isolated mitochondria .	Here, we reconfirm that Bax can trigger the release of cytochrome C after overexpression in different cell types and directly when added to isolated mitochondria.	5	22	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	5	6	11	13
Bax inhibition and Bcl-2 activation suppress release of cytochrome c from mitochondria that prevents cleavage of caspase-3 .	Bax inhibition and Bcl-2 activation suppress release of cytochrome c from mitochondria that prevents cleavage of caspase-3.	0	10	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
Pro apoptotic Bak and Bax are effector molecules of the Bcl-2 family and induce release of cytochrome c from mitochondria , presumably through their ability to form pores at the mitochondrial outer membrane .	Pro apoptotic Bak and Bax are effector molecules of the Bcl-2 family and induce release of cytochrome c from mitochondria, presumably through their ability to form pores at the mitochondrial outer membrane.	2	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	16	18
It has been confirmed that the formation of Bax channels promotes the release of cytochrome c and enter the cytoplasm , which can make the separation of Bcl-2 and Apaf1 , and then activate caspase to induce apoptosis .	It has been confirmed that the formation of Bax channels promotes the release of cytochrome c and enter the cytoplasm, which can make the separation of Bcl-2 and Apaf1, and then activate caspase to induce apoptosis.	8	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	14	16
ZEA treatment upregulated Bax expression , promoted cytochrome c release into the cytosol , and triggered mitochondria mediated apoptosis .	ZEA treatment upregulated Bax expression, promoted cytochrome c release into the cytosol, and triggered mitochondria mediated apoptosis.	0	9	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	ZEA treatment upregulated Bax expression	bax	cytochrome c	cytochrome c	cytochrome c	3	4	7	9
After IR , elevated expression of activated caspases and Bax and decreased levels of Bcl-2 were observed in starved Eca-109 cells , along with stimulated release of cytochrome c and decreased MOMP .	After IR, elevated expression of activated caspases and Bax and decreased levels of Bcl-2 were observed in starved Eca-109 cells, along with stimulated release of cytochrome c and decreased MOMP.	4	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of activated caspases and Bax	bax	cytochrome c	cytochrome c	cytochrome c	9	10	27	29
Subsequently , Bax inserts and induces cytochrome c release [ XREF_BIBR ] .	Subsequently, Bax inserts and induces cytochrome c release [XREF_BIBR].	2	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	6	8
Furthermore , western blot evaluation revealed elevated levels of the apoptotic drivers Bax and Bim , increased release of cytochrome C in the cytoplasm and PARP cleavage in MCF7 cells treated with the combination compared to untreated and single agent treated cells ( XREF_FIG .	Furthermore, western blot evaluation revealed elevated levels of the apoptotic drivers Bax and Bim, increased release of cytochrome C in the cytoplasm and PARP cleavage in MCF7 cells treated with the combination compared to untreated and single agent treated cells (XREF_FIG.	7	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	levels of the apoptotic drivers Bax	bax	cytochrome C	cytochrome C	cytochrome c	12	13	19	21
In colon cancer cells in response to the short chain fatty acid anion butyrate , the nonsteroidal anti-inflammatory drug sulindac , or the chemotherapeutic drug 5-fluorouracil , NR4A1 induces apoptosis by nuclear cytoplasmic translocation but without direct mitochondrial targeting , although Bax is redistributed to mitochondria and induces cytochrome c release XREF_BIBR .	In colon cancer cells in response to the short chain fatty acid anion butyrate, the nonsteroidal anti-inflammatory drug sulindac, or the chemotherapeutic drug 5-fluorouracil, NR4A1 induces apoptosis by nuclear cytoplasmic translocation but without direct mitochondrial targeting, although Bax is redistributed to mitochondria and induces cytochrome c release XREF_BIBR.	41	51	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	41	42	48	50
We recently reported that Bax peptide H2-H3 promotes cell death by inducing Bax mediated cytochrome c release and by antagonizing Bcl-2 ' s inhibition on Bax .	We recently reported that Bax peptide H2-H3 promotes cell death by inducing Bax mediated cytochrome c release and by antagonizing Bcl-2 's inhibition on Bax.	12	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	12	13	14	16
Furthermore , Bax activator molecules ( cleaved Bid protein and the Bim BH3 peptide ) synergistically induced cytochrome c release when introduced into cells along with derepressor BH3 peptides .	Furthermore, Bax activator molecules (cleaved Bid protein and the Bim BH3 peptide) synergistically induced cytochrome c release when introduced into cells along with derepressor BH3 peptides.	2	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	17	19
Bax promotes the release of cytochrome c in mitochondria and causes apoptosis through the activation of multiple caspases .	Bax promotes the release of cytochrome c in mitochondria and causes apoptosis through the activation of multiple caspases.	0	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Cytochrome c release triggered by Bax from the mitochondrial membrane initiates apoptosis .	Cytochrome c release triggered by Bax from the mitochondrial membrane initiates apoptosis.	0	6	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome c	Cytochrome c	Cytochrome c	5	6	0	2
The oligomeric form of Bax promotes the loss of mitochondrial membrane integrity and causes the release of cytochrome c [ XREF_BIBR ] .	The oligomeric form of Bax promotes the loss of mitochondrial membrane integrity and causes the release of cytochrome c [XREF_BIBR].	2	20	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	17	19
Several ions were tested for their ability to influence Bax induced release of cytochrome C from mitochondria .	Several ions were tested for their ability to influence Bax induced release of cytochrome C from mitochondria.	8	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	9	10	13	15
Our study suggests that cytosolic cathepsin D triggers Bax mediated cytochrome c release by proteolytic activation of Bid .	Our study suggests that cytosolic cathepsin D triggers Bax mediated cytochrome c release by proteolytic activation of Bid.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	10	12
Studies with fibroblasts have shown that JNK activation and the pro apoptotic protein Bax , a Bcl2 family member [ XREF_BIBR ] , are sufficient to cause the caspase independent release of cytochrome c , which leads to apoptosis .	Studies with fibroblasts have shown that JNK activation and the pro apoptotic protein Bax, a Bcl2 family member [XREF_BIBR], are sufficient to cause the caspase independent release of cytochrome c, which leads to apoptosis.	7	34	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	13	14	32	34
Subsequent oligomerization could provide the driving force for Bax mediated cytochrome C release while the lipidic nature of the pores is maintained .	Subsequent oligomerization could provide the driving force for Bax mediated cytochrome C release while the lipidic nature of the pores is maintained.	6	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	8	9	10	12
During many forms of apoptosis , Bax , a pro apoptotic protein of the Bcl-2 family , translocates from the cytosol to the mitochondria and induces cytochrome c release , followed by caspase activation and DNA degradation .	During many forms of apoptosis, Bax, a pro apoptotic protein of the Bcl-2 family, translocates from the cytosol to the mitochondria and induces cytochrome c release, followed by caspase activation and DNA degradation.	6	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax, a pro apoptotic protein of the Bcl-2 family, translocates from the cytosol to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	6	7	26	28
Moreover , at low respiratory chain activity , we demonstrate that , unlike a mitochondrial Ca2+ upload , Bax , a pro apoptotic Bcl-2-family protein , is able to trigger a massive release of cytochrome c from one of these ANT1 structures .	Moreover, at low respiratory chain activity, we demonstrate that, unlike a mitochondrial Ca2+ upload, Bax, a pro apoptotic Bcl-2-family protein, is able to trigger a massive release of cytochrome c from one of these ANT1 structures.	18	36	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	18	19	34	36
YLT322 increased the expression of Bax , decreased the expression of Bcl-2 , and induced the release of cytochrome c which activates the mitochondrial apoptotic pathway .	YLT322 increased the expression of Bax, decreased the expression of Bcl-2, and induced the release of cytochrome c which activates the mitochondrial apoptotic pathway.	0	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	YLT322 increased the expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	5	6	18	20
Bax , a pro apoptotic member of the Bcl-2 family , induces the release of cytochrome c from mitochondria , thereby activating caspase-9 .	Bax, a pro apoptotic member of the Bcl-2 family, induces the release of cytochrome c from mitochondria, thereby activating caspase-9.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	15	17
The intrinsic pathway is dependent on mitochondria and triggers an imbalance between antiapoptotic factors such as Bcl-2 ( diminished ) and apoptotic factors such as Bax ( elevated ) that might induce cytochrome c release and promote the formation of the mitochondrial transitory pore .	The intrinsic pathway is dependent on mitochondria and triggers an imbalance between antiapoptotic factors such as Bcl-2 (diminished) and apoptotic factors such as Bax (elevated) that might induce cytochrome c release and promote the formation of the mitochondrial transitory pore.	22	36	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	25	26	32	34
Studies have shown that an increase of Bcl-2 and a decrease of Bax prevented the release of cytochrome c in mitochondria , and therefore inhibit the cascade of apoptosis .	Studies have shown that an increase of Bcl-2 and a decrease of Bax prevented the release of cytochrome c in mitochondria, and therefore inhibit the cascade of apoptosis.	10	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	12	13	17	19
Upon induction of apoptosis , Bax accumulates on the mitochondrial OM , undergoes conformational changes to expose a helical domain , and triggers the release of cytochrome c and other proapoptotic effectors .	Upon induction of apoptosis, Bax accumulates on the mitochondrial OM, undergoes conformational changes to expose a helical domain, and triggers the release of cytochrome c and other proapoptotic effectors.	5	28	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	26	28
Active Bax oligomers cause the release of cytochrome c from mitochondria and activate caspase-9 by cytosolic cytochrome c.	Active Bax oligomers cause the release of cytochrome c from mitochondria and activate caspase-9 by cytosolic cytochrome c.	1	9	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	7	9
Bax and Bak promote apoptosis by perturbing the permeability of the mitochondrial outer membrane ( referred to as MOMP ) and facilitating the release of cytochrome c , a cofactor for activation of caspase-9 that , in turn , activates the effector caspases-3 , -6 , and -7 [ XREF_BIBR ] .	Bax and Bak promote apoptosis by perturbing the permeability of the mitochondrial outer membrane (referred to as MOMP) and facilitating the release of cytochrome c, a cofactor for activation of caspase-9 that, in turn, activates the effector caspases-3, -6, and -7 [XREF_BIBR].	0	27	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	25	27
In conclusion , we obtained evidence that the VDAC is essential for Bax induced ( but not Bid induced ) apoptotic cytochrome c release and apoptotic death and apoptosis induced by etoposide , paclitaxel , and staurosporine in mammalian cells .	In conclusion, we obtained evidence that the VDAC is essential for Bax induced (but not Bid induced) apoptotic cytochrome c release and apoptotic death and apoptosis induced by etoposide, paclitaxel, and staurosporine in mammalian cells.	12	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	12	13	21	23
Additionally , binding of HK to mitochondria inhibits Bax induced cytochrome c release and apoptosis .	Additionally, binding of HK to mitochondria inhibits Bax induced cytochrome c release and apoptosis.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	10	12
The antiapoptotic protein Bcl-2 is located in the mitochondrial wall and prevents mitochondrial release of cytochrome c , while the proapoptotic protein Bax resides in the cytosol but can be translocated to mitochondria to induce cytochrome c release .	The antiapoptotic protein Bcl-2 is located in the mitochondrial wall and prevents mitochondrial release of cytochrome c, while the proapoptotic protein Bax resides in the cytosol but can be translocated to mitochondria to induce cytochrome c release.	19	37	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax resides in the cytosol but can be translocated to mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	22	23	35	37
In the present study , we showed that beta , beta-dimethylacrylshikonin down-regulated the expression of XIAP , cIAP-2 and Bcl-2 and up-regulated the expression of Bak and Bax , and caused the loss of mitochondrial membrane potential and release of cytochrome c in SGC-7901 cells , consistent with mitochondria dependent apoptosis .	In the present study, we showed that beta,beta-dimethylacrylshikonin down-regulated the expression of XIAP, cIAP-2 and Bcl-2 and up-regulated the expression of Bak and Bax, and caused the loss of mitochondrial membrane potential and release of cytochrome c in SGC-7901 cells, consistent with mitochondria dependent apoptosis.	8	42	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	beta,beta-dimethylacrylshikonin down-regulated the expression of XIAP, cIAP-2 and Bcl-2 and up-regulated the expression of Bak and Bax	bax	cytochrome c	cytochrome c	cytochrome c	27	28	40	42
Bax , a pro apoptotic protein , triggers the release of cytochrome c from mitochondria .	Bax, a pro apoptotic protein, triggers the release of cytochrome c from mitochondria.	0	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	11	13
In addition , we report that ARC co-immunoprecipitated with the pro apoptotic protein Bax , which causes cytochrome c release when activated .	In addition, we report that ARC co-immunoprecipitated with the pro apoptotic protein Bax, which causes cytochrome c release when activated.	7	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	13	14	17	19
As shown ( XREF_FIG ) , TAT-AIP failed to inhibit either tBid and Bax induced cytochrome c release or calpain I induced AIF release in isolated brain mitochondria , suggesting that the inhibitory effect of TAT-AIP on cytochrome c and AIF release after H-I is secondary instead of primary .	As shown (XREF_FIG), TAT-AIP failed to inhibit either tBid and Bax induced cytochrome c release or calpain I induced AIF release in isolated brain mitochondria, suggesting that the inhibitory effect of TAT-AIP on cytochrome c and AIF release after H-I is secondary instead of primary.	11	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	13	14	15	17
However , others have shown that Bax induced cytochrome c efflux can occur independent of any changes in inner membrane permeability and is cyclosporine-insensitive [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	However, others have shown that Bax induced cytochrome c efflux can occur independent of any changes in inner membrane permeability and is cyclosporine-insensitive [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	23	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
In isolated mitochondria , these antibodies prevented Bax induced cytochrome c release and loss of the mitochondrial membrane potential ( Deltapsi ) , but not Bid induced cytochrome c release .	In isolated mitochondria, these antibodies prevented Bax induced cytochrome c release and loss of the mitochondrial membrane potential (Deltapsi), but not Bid induced cytochrome c release.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	9	11
Furthermore , Bax induces cytochrome c release in wild type yeast cells but not VDAC1 deficient yeast cells .	Furthermore, Bax induces cytochrome c release in wild type yeast cells but not VDAC1 deficient yeast cells.	2	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	4	6
Neurotrophin withdrawal pathways converge on the pro apoptotic Bcl-2 family member Bax , which causes cytochrome c release from mitochondria [ XREF_BIBR , XREF_BIBR ] .	Neurotrophin withdrawal pathways converge on the pro apoptotic Bcl-2 family member Bax, which causes cytochrome c release from mitochondria [XREF_BIBR, XREF_BIBR].	3	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	15	17
At the mitochondrial outer membrane activated Bax promotes the release of cytochrome c ( a mitochondrion intermembrane space protein ) into the cytosol .	At the mitochondrial outer membrane activated Bax promotes the release of cytochrome c (a mitochondrion intermembrane space protein) into the cytosol.	6	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	11	13
In addition , PECAM-1 markedly suppressed Bax overexpression induced cytochrome c release , caspase activation , and nuclear fragmentation .	In addition, PECAM-1 markedly suppressed Bax overexpression induced cytochrome c release, caspase activation, and nuclear fragmentation.	6	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax overexpression	bax	cytochrome c	cytochrome c	cytochrome c	6	7	9	11
We now report that Bax is sufficient to trigger the release of cytochrome C from isolated mitochondria .	We now report that Bax is sufficient to trigger the release of cytochrome C from isolated mitochondria.	4	14	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	4	5	12	14
Bax promotes the release of cytochrome c into the cytosol from mitochondria , which in turn activates caspase-3 .	Bax promotes the release of cytochrome c into the cytosol from mitochondria, which in turn activates caspase-3.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Bax promotes the release of cytochrome c XREF_BIBR that is important to the activation of caspase cascade XREF_BIBR while Bcl-2 is anti-apoptotic by regulating the activity of Bax .	Bax promotes the release of cytochrome c XREF_BIBR that is important to the activation of caspase cascade XREF_BIBR while Bcl-2 is anti-apoptotic by regulating the activity of Bax.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
The proapoptosis proteins Bax could promote cytochrome C release through opening of permeability transition pore ( PTP ) ; meanwhile , the prosurvival proteins Bcl-2 and Bcl-XL could prevent the opening of PTP through competition or directly inhibiting PTP opening , by which they have anti-apoptotic effect .	The proapoptosis proteins Bax could promote cytochrome C release through opening of permeability transition pore (PTP); meanwhile, the prosurvival proteins Bcl-2 and Bcl-XL could prevent the opening of PTP through competition or directly inhibiting PTP opening, by which they have anti-apoptotic effect.	0	8	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	3	4	6	8
In the presence of recombinant Bcl-w protein , however , the release of cytochrome c induced by Bax or calcium was largely inhibited .	In the presence of recombinant Bcl-w protein, however, the release of cytochrome c induced by Bax or calcium was largely inhibited.	13	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	17	18	13	15
The data shown in XREF_FIG suggests that some of the ROS/RS increase after NGF withdrawal is caused by caspases activated downstream of Bax induced cytochrome c release .	The data shown in XREF_FIG suggests that some of the ROS/RS increase after NGF withdrawal is caused by caspases activated downstream of Bax induced cytochrome c release.	19	26	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	22	23	24	26
Bax apart from forming hetero-oligomeric channels with VDAC , can also form homo-oligomeric large-conductance ion pores on the outer mitochondrial membrane and promote cytochrome c release XREF_BIBR ( XREF_FIG ) .	Bax apart from forming hetero-oligomeric channels with VDAC, can also form homo-oligomeric large-conductance ion pores on the outer mitochondrial membrane and promote cytochrome c release XREF_BIBR (XREF_FIG).	0	26	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	23	25
While Myc can sensitize cells to apoptosis by a variety of mechanisms [ XREF_BIBR ] , one generally critical step seems to be its ability to trigger a configurational change in Bax needed to allow it to insert into the mitochondria outer membrane , where Bax must go to trigger cytochrome c release , caspase activation , and cell suicide [ XREF_BIBR , XREF_BIBR ] .	While Myc can sensitize cells to apoptosis by a variety of mechanisms [XREF_BIBR], one generally critical step seems to be its ability to trigger a configurational change in Bax needed to allow it to insert into the mitochondria outer membrane, where Bax must go to trigger cytochrome c release, caspase activation, and cell suicide [XREF_BIBR, XREF_BIBR].	45	52	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	45	46	50	52
We conclude that Bax does not induce cytochrome c release by acting on VDAC .	We conclude that Bax does not induce cytochrome c release by acting on VDAC.	3	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	7	9
Furthermore , CFT and CPL increased the expression of Bax and p53 , and caused the translocation of cytochrome c from the mitochondria to the cytoplasm .	Furthermore, CFT and CPL increased the expression of Bax and p53, and caused the translocation of cytochrome c from the mitochondria to the cytoplasm.	2	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	CFT and CPL increased the expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	9	10	18	20
This change in Bax stimulates the release of cytochrome C from mitochondria which activates caspase-3 .	This change in Bax stimulates the release of cytochrome C from mitochondria which activates caspase-3.	1	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	3	4	8	10
In this pathway , a proapoptotic factor Bax protein increases the permeability of the mitochondrial membrane by translocation from the cytoplasm to the membrane and initiates cytochrome c release ; Bcl-2 is an antiapoptotic protein which counteracts Bax , binding to the outer mitochondrial membrane , maintaining membrane integrity , and enhancing cell survival [ XREF_BIBR , XREF_BIBR ] .	In this pathway, a proapoptotic factor Bax protein increases the permeability of the mitochondrial membrane by translocation from the cytoplasm to the membrane and initiates cytochrome c release; Bcl-2 is an antiapoptotic protein which counteracts Bax, binding to the outer mitochondrial membrane, maintaining membrane integrity, and enhancing cell survival [XREF_BIBR, XREF_BIBR].	7	28	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	26	28
Classical pathway of p53 dependent apoptosis exploits BAX mediated release of cytochrome-c and AIF , which are actively involved in caspase activation and protein or DNA degradation XREF_BIBR .	Classical pathway of p53 dependent apoptosis exploits BAX mediated release of cytochrome-c and AIF, which are actively involved in caspase activation and protein or DNA degradation XREF_BIBR.	6	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome-c	cytochrome-c	cytochrome-c	7	8	11	12
Especially interesting in this context is a report that Bax induced mitochondrial fission and Bax initiated cytochrome c release are separable events and that Bcl-2 family proteins can influence mitochondrial fission-fusion dynamics in HD cells independently of apoptosis .	Especially interesting in this context is a report that Bax induced mitochondrial fission and Bax initiated cytochrome c release are separable events and that Bcl-2 family proteins can influence mitochondrial fission-fusion dynamics in HD cells independently of apoptosis.	12	18	initiated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	14	15	16	18
Bax translocates to mitochondria and causes cytochrome c release into the cytosol to promote HeLa cell apoptosis .	Bax translocates to mitochondria and causes cytochrome c release into the cytosol to promote HeLa cell apoptosis.	0	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax translocates to mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
Increased cytosolic Bax translocation to mitochondria triggers cytosolic Cytochrome c release for inducing apoptosis , whereas increased Bcl-2 and/or Bcl-xL inhibits cytosolic Cytochrome c release for depressing apoptosis XREF_BIBR - XREF_BIBR .	Increased cytosolic Bax translocation to mitochondria triggers cytosolic Cytochrome c release for inducing apoptosis, whereas increased Bcl-2 and/or Bcl-xL inhibits cytosolic Cytochrome c release for depressing apoptosis XREF_BIBR - XREF_BIBR.	2	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax translocation to mitochondria	bax	Cytochrome c	Cytochrome c	cytochrome c	2	3	8	10
Bax induces cytochrome c release into the cytosol from damaged mitochondria , which could provoke activation of caspase-9 and subsequent effectors caspase-3 , -6 , and -7 .	Bax induces cytochrome c release into the cytosol from damaged mitochondria, which could provoke activation of caspase-9 and subsequent effectors caspase-3, -6, and -7.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	2	4
VDAC1 plays an essential role in apoptosis in mammalian cells , in particular , the apoptosis signaling initiated by Bax induced cytochrome c release from mitochondria [ XREF_BIBR , XREF_BIBR ] .	VDAC1 plays an essential role in apoptosis in mammalian cells, in particular, the apoptosis signaling initiated by Bax induced cytochrome c release from mitochondria [XREF_BIBR, XREF_BIBR].	17	23	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	19	20	21	23
When cisplatin induces generation of ROS , Bax was activated and transported to the mitochondrial outer membrane and changes its permeability , causing the opening of the mitochondrial permeability transition pores ( MPTPs ) , releasing the cytochrome c into the cytosol , and leading to activation of caspase 9 , as well as downstream caspases and inducing caspase dependent manner .	When cisplatin induces generation of ROS, Bax was activated and transported to the mitochondrial outer membrane and changes its permeability, causing the opening of the mitochondrial permeability transition pores (MPTPs), releasing the cytochrome c into the cytosol, and leading to activation of caspase 9, as well as downstream caspases and inducing caspase dependent manner.	7	39	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	37	39
BAX and BCL-2 activate caspases by promoting the release of cytochrome C from mitochondrion .	BAX and BCL-2 activate caspases by promoting the release of cytochrome C from mitochondrion.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome C	cytochrome C	cytochrome C	0	1	10	12
In response to death stimuli , Bax protein undergoes conformational changes that expose membrane targeting domains , resulting in its translocation to mitochondrial membranes , where Bax inserts and causes release of cytochrome c and other apoptogenic proteins .	In response to death stimuli, Bax protein undergoes conformational changes that expose membrane targeting domains, resulting in its translocation to mitochondrial membranes, where Bax inserts and causes release of cytochrome c and other apoptogenic proteins.	6	34	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	32	34
Additionally , baicalein caused a mitochondrial membrane potential ( MMP ) , the truncation of Bid , and the translocation of pro apoptotic Bax to the mitochondria , thereby inducing the release of cytochrome c into the cytosol .	Additionally, baicalein caused a mitochondrial membrane potential (MMP), the truncation of Bid, and the translocation of pro apoptotic Bax to the mitochondria, thereby inducing the release of cytochrome c into the cytosol.	2	35	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	baicalein caused a mitochondrial membrane potential (MMP), the truncation of Bid, and the translocation of pro apoptotic Bax to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	23	24	33	35
These findings suggest that Bax and Bak initiated remodeling of mitochondrial networks and cytochrome c release are separate events and that the proteins in the Bcl-2 family influence mitochondrial fission-fusion dynamics , independent of apoptosis .	These findings suggest that Bax and Bak initiated remodeling of mitochondrial networks and cytochrome c release are separate events and that the proteins in the Bcl-2 family influence mitochondrial fission-fusion dynamics, independent of apoptosis.	4	15	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	13	15
In addition , oridonin increased the expression of the apoptosis inducer , Bax , promoted the release of cytochrome c without affecting Bcl-2 expression , and activated down-stream caspase-9 in the mitochondrial pathway .	In addition, oridonin increased the expression of the apoptosis inducer, Bax, promoted the release of cytochrome c without affecting Bcl-2 expression, and activated down-stream caspase-9 in the mitochondrial pathway.	10	20	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	12	13	18	20
Calpain plays an essential role in apoptotic commitment by cleaving Bax and generating the Bax and p18 fragment , which in turn mediates cytochrome c release and initiates the apoptotic execution [ XREF_BIBR ] .	Calpain plays an essential role in apoptotic commitment by cleaving Bax and generating the Bax and p18 fragment, which in turn mediates cytochrome c release and initiates the apoptotic execution [XREF_BIBR].	14	25	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	14	15	23	25
An important issue is whether a second tBid action , independent of Bak and Bax , is also required to enhance cytochrome c mobility in the intermembrane spaces .	An important issue is whether a second tBid action, independent of Bak and Bax, is also required to enhance cytochrome c mobility in the intermembrane spaces.	10	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	14	15	21	23
Mitochondria depleted of short lived proteins by cycloheximide ( CHX ) become resistant to Bax mediated cytochrome c release .	Mitochondria depleted of short lived proteins by cycloheximide (CHX) become resistant to Bax mediated cytochrome c release.	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	14	15	16	18
We examined the protein expression of a proapoptotic member , Bax , which triggers cytochrome c release , and an antiapoptotic member , Bcl-2 , which inhibits cytochrome c release [ XREF_BIBR ] .	We examined the protein expression of a proapoptotic member, Bax, which triggers cytochrome c release, and an antiapoptotic member, Bcl-2, which inhibits cytochrome c release [XREF_BIBR].	1	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	10	11	14	16
8 It was proposed that the loss of Bcl-x L might prevent cytochrome c release mediated by endogenous Bax present in the OMM and so unmask a latent cytochrome c permeability pathway .	8 It was proposed that the loss of Bcl-x L might prevent cytochrome c release mediated by endogenous Bax present in the OMM and so unmask a latent cytochrome c permeability pathway.	12	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	18	19	12	14
In the present study , our neutralizing anti-VDAC antibodies inhibited Bax induced cytochrome c release that was largely PT inhibitor sensitive .	In the present study, our neutralizing anti-VDAC antibodies inhibited Bax induced cytochrome c release that was largely PT inhibitor sensitive.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	10	11	12	14
The intrinsic apoptotic pathway is initiated by genotoxic stress dependent activation of the proapoptotic Bcl-2 family member Bax , which translocates to the mitochondria and induces mitochondrial outer membrane permeabilization , cytochrome c release , and Apaf-1-dependent activation of the initiator caspase-9 in the apoptosome .	The intrinsic apoptotic pathway is initiated by genotoxic stress dependent activation of the proapoptotic Bcl-2 family member Bax, which translocates to the mitochondria and induces mitochondrial outer membrane permeabilization, cytochrome c release, and Apaf-1-dependent activation of the initiator caspase-9 in the apoptosome.	10	33	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax, which translocates to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	17	18	31	33
In a second set of experiments , heterologous coexpression of tBid and Bax in wild-type and CL-less yeast strains showed that ( i ) tBid binding and the subsequent alteration of mitochondrial bioenergetics increased Bax induced cytochrome c release and ( ii ) the absence of CL favors Bax effects independently of the presence of t-Bid .	In a second set of experiments, heterologous coexpression of tBid and Bax in wild-type and CL-less yeast strains showed that (i) tBid binding and the subsequent alteration of mitochondrial bioenergetics increased Bax induced cytochrome c release and (ii) the absence of CL favors Bax effects independently of the presence of t-Bid.	34	38	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	34	35	36	38
It was previously shown that a high ratio of BAX to BCL-2 can lead to loss of mitochondrial membrane potential , causing a release of cytochrome c and consequently inducing apoptosis [ XREF_BIBR , XREF_BIBR ] .	It was previously shown that a high ratio of BAX to BCL-2 can lead to loss of mitochondrial membrane potential, causing a release of cytochrome c and consequently inducing apoptosis [XREF_BIBR, XREF_BIBR].	7	27	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	9	10	25	27
The BAX protein promotes apoptosis by enhancing the release of cytochrome c from mitochondria 50 , while the BCL2L1 protein prevents apoptosis by inhibiting the release of cytochrome c from mitochondria 51 .	The BAX protein promotes apoptosis by enhancing the release of cytochrome c from mitochondria 50, while the BCL2L1 protein prevents apoptosis by inhibiting the release of cytochrome c from mitochondria 51.	1	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	1	2	10	12
As Bax translocation to the mitochondria results in the release of cytochrome c in the cytosol , inhibition of Bax expression inhibited the release of cytochrome c into the cytosol .	As Bax translocation to the mitochondria results in the release of cytochrome c in the cytosol, inhibition of Bax expression inhibited the release of cytochrome c into the cytosol.	19	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax expression	bax	cytochrome c	cytochrome c	cytochrome c	19	20	25	27
In addition , other than the thymomas , the TSCCs showed lower mRNA expression of the MTCH2 gene that induces apoptosis by cooperation with tBID to facilitate BAX mediated mitochondrial cytochrome c release .	In addition, other than the thymomas, the TSCCs showed lower mRNA expression of the MTCH2 gene that induces apoptosis by cooperation with tBID to facilitate BAX mediated mitochondrial cytochrome c release.	26	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	27	28	30	32
Bax deficient islets were resistant to ribose- or glucose induced cytochrome c release and DNA fragmentation , whereas islets from Bak deficient mice were normally sensitive ( XREF_FIG ) .	Bax deficient islets were resistant to ribose- or glucose induced cytochrome c release and DNA fragmentation, whereas islets from Bak deficient mice were normally sensitive (XREF_FIG).	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	10	12
Simultaneously , Bax promotes cytochrome C release , activates caspases , and induces apoptosis .	Simultaneously, Bax promotes cytochrome C release, activates caspases, and induces apoptosis.	2	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	2	3	4	6
Bax and Bak interact with the MPT to induce a permeability transition and cytochrome c release in isolated mitochondria [ XREF_BIBR , XREF_BIBR ] .	Bax and Bak interact with the MPT to induce a permeability transition and cytochrome c release in isolated mitochondria [XREF_BIBR, XREF_BIBR].	0	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
Bax overexpression in cells or the addition of purified recombinant Bax directly to isolated mitochondria triggers release of cytochrome c into the cytosol [ XREF_BIBR , XREF_BIBR ] with subsequent activation of procaspases 9 and 3 [ XREF_BIBR ] .	Bax overexpression in cells or the addition of purified recombinant Bax directly to isolated mitochondria triggers release of cytochrome c into the cytosol [XREF_BIBR, XREF_BIBR] with subsequent activation of procaspases 9 and 3 [XREF_BIBR].	0	20	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax overexpression	bax	cytochrome c	cytochrome c	cytochrome c	0	1	18	20
As BH3-only protein signaling overcomes Bcl-2 inhibition , BAX and BAK assemble into oligomers in the mitochondrial membrane , promoting the release of cytochrome C into the cytoplasm .	As BH3-only protein signaling overcomes Bcl-2 inhibition, BAX and BAK assemble into oligomers in the mitochondrial membrane, promoting the release of cytochrome C into the cytoplasm.	8	25	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome C	cytochrome C	cytochrome C	8	9	23	25
Upon induction of apoptosis , the pro apoptotic protein Bax translocates to mitochondrial membranes , where it inserts and mediates the release of cytochrome c from the intermembrane space into the cytosol , thereby triggering the activation of the caspase pathway .	Upon induction of apoptosis, the pro apoptotic protein Bax translocates to mitochondrial membranes, where it inserts and mediates the release of cytochrome c from the intermembrane space into the cytosol, thereby triggering the activation of the caspase pathway.	5	25	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax translocates to mitochondrial membranes	bax	cytochrome c	cytochrome c	cytochrome c	9	10	23	25
It is therefore possible that , in these cells , sufficient Bax resides at the mitochondrial membrane to induce cytochrome c release after a death signal , and further apoptotic insult leads to increasing amounts of Bax translocating to the mitochondria .	It is therefore possible that, in these cells, sufficient Bax resides at the mitochondrial membrane to induce cytochrome c release after a death signal, and further apoptotic insult leads to increasing amounts of Bax translocating to the mitochondria.	10	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	19	21
Bax can cause release of cytochrome c after formation of the hetero-oligomer Bax and Bak , whereas Bcl-2 can engage with activator proteins or Bax and Bak , thereby sequestering these proteins [ XREF_BIBR ] .	Bax can cause release of cytochrome c after formation of the hetero-oligomer Bax and Bak, whereas Bcl-2 can engage with activator proteins or Bax and Bak, thereby sequestering these proteins [XREF_BIBR].	0	7	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Indeed , a combination of CsA and ADP , inhibitors of the mPT [ XREF_BIBR - XREF_BIBR ] , significantly diminished cytochrome c release induced by BAX oligo ( XREF_FIG ) .	Indeed, a combination of CsA and ADP, inhibitors of the mPT [XREF_BIBR - XREF_BIBR], significantly diminished cytochrome c release induced by BAX oligo (XREF_FIG).	21	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	26	27	21	23
The pro apoptotic effector BCL-2 proteins BAK ( BCL-2 antagonist killer 1 ) and BAX ( BCL-2 associated x protein ) homo-oligomerize into proteolipid pores within the OMM and are required to promote mitochondrial outer membrane permeabilization ( MOMP ) and cytochrome c release .	The pro apoptotic effector BCL-2 proteins BAK (BCL-2 antagonist killer 1) and BAX (BCL-2 associated x protein) homo-oligomerize into proteolipid pores within the OMM and are required to promote mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release.	4	43	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	14	15	41	43
These observations suggested that nicastrin , as well as the APP and PS proteins , were also involved in the upregulated Bax mediated neuroblastoma cell death and the release of cytochrome c in the neuroblastoma .	These observations suggested that nicastrin, as well as the APP and PS proteins, were also involved in the upregulated Bax mediated neuroblastoma cell death and the release of cytochrome c in the neuroblastoma.	17	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	21	22	30	32
Only recently it was shown that Bax mediates cytochrome c release by forming rings in the outer mitochondrial membrane XREF_BIBR , XREF_BIBR .	Only recently it was shown that Bax mediates cytochrome c release by forming rings in the outer mitochondrial membrane XREF_BIBR, XREF_BIBR.	6	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
Interestingly , blockage of Bax drastically reduced dissipation of DeltaPsi m , and subsequently almost completely inhibited the release of cytochrome c and Smac in TK VI treated cells .	Interestingly, blockage of Bax drastically reduced dissipation of DeltaPsi m, and subsequently almost completely inhibited the release of cytochrome c and Smac in TK VI treated cells.	2	22	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	20	22
Meanwhile , it had reported that collapse of MPP and mitochondrial Bax accumulations were able to induce the procession of cytochrome C release from mitochondria into cytoplasm XREF_BIBR - XREF_BIBR .	Meanwhile, it had reported that collapse of MPP and mitochondrial Bax accumulations were able to induce the procession of cytochrome C release from mitochondria into cytoplasm XREF_BIBR - XREF_BIBR.	11	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	11	12	20	22
Bax accumulates in the mitochondria of yeast naa20Delta and Naa25 -/- MEF cells , but does not promote cytochrome c release , suggesting that an additional step is required for full activation of Bax .	Bax accumulates in the mitochondria of yeast naa20Delta and Naa25 -/- MEF cells, but does not promote cytochrome c release, suggesting that an additional step is required for full activation of Bax.	0	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	18	20
It was shown that Bak and Bax knockdown in HeLa cells significantly suppressed cholix induced cytochrome c release and caspase-7 activation .	It was shown that Bak and Bax knockdown in HeLa cells significantly suppressed cholix induced cytochrome c release and caspase-7 activation.	4	17	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	15	17
Furthermore , it has been shown that human Bax targets mitochondria and leads to cell death in yeast XREF_BIBR and trypanosomes XREF_BIBR , and expression of myc tagged Bax caused cytoplasmic release of cytochrome c in yeast , similar to the effect observed in mammalian cells XREF_BIBR .	Furthermore, it has been shown that human Bax targets mitochondria and leads to cell death in yeast XREF_BIBR and trypanosomes XREF_BIBR, and expression of myc tagged Bax caused cytoplasmic release of cytochrome c in yeast, similar to the effect observed in mammalian cells XREF_BIBR.	28	35	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	28	29	33	35
The change of the ratio of Bax to Bcl-2 can stimulate the release of cytochrome c , which activates caspase-9 and caspase-3 , and it may govern sensitivity to apoptotic stimuli .	The change of the ratio of Bax to Bcl-2 can stimulate the release of cytochrome c, which activates caspase-9 and caspase-3, and it may govern sensitivity to apoptotic stimuli.	4	16	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	14	16
For instance , heterologous expression of the human proapoptotic protein Bax in yeast causes outer mitochondrial membrane permeabilization , cytochrome C release , and cell death [ XREF_BIBR ] .	For instance, heterologous expression of the human proapoptotic protein Bax in yeast causes outer mitochondrial membrane permeabilization, cytochrome C release, and cell death [XREF_BIBR].	4	21	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of the human proapoptotic protein Bax	bax	cytochrome C	cytochrome C	cytochrome c	10	11	19	21
Neutralization of TNF-alpha activity during the time course of renal obstruction effectively preserved Bcl-2 and Bcl-x L expression , decreased Bax expression to almost sham treatment levels and importantly prevented the mitochondrial release of cytochrome C , which heralds imminent cell death .	Neutralization of TNF-alpha activity during the time course of renal obstruction effectively preserved Bcl-2 and Bcl-x L expression, decreased Bax expression to almost sham treatment levels and importantly prevented the mitochondrial release of cytochrome C, which heralds imminent cell death.	2	36	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	TNF-alpha activity during the time course of renal obstruction effectively preserved Bcl-2 and Bcl-x L expression, decreased Bax expression	bax	cytochrome C	cytochrome C	cytochrome c	20	21	34	36
Thus , our results argue in favor of the essential role of mitochondrial remodeling in cytochrome c release induced by BAX oligo .	Thus, our results argue in favor of the essential role of mitochondrial remodeling in cytochrome c release induced by BAX oligo.	15	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	20	21	15	17
Bax mediates cytochrome c release and apoptosis during neurodevelopment .	Bax mediates cytochrome c release and apoptosis during neurodevelopment.	0	4	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	2	4
In addition , chalcone increased the expression of Bax and Bak , but decreased the levels of Bcl-2 and Bcl-X ( L ) and subsequently triggered mitochondrial apoptotic pathway ( release of cytochrome c and activation of caspase-9 and caspase-3 ) .	In addition, chalcone increased the expression of Bax and Bak, but decreased the levels of Bcl-2 and Bcl-X (L) and subsequently triggered mitochondrial apoptotic pathway (release of cytochrome c and activation of caspase-9 and caspase-3).	3	34	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	chalcone increased the expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	8	9	32	34
From the Western blot analyses , activation of Bid , independent of caspase-8 was seen and Bax induced the release of cytochrome c into the cytosol from mitochondria in a dose dependent manner .	From the Western blot analyses, activation of Bid, independent of caspase-8 was seen and Bax induced the release of cytochrome c into the cytosol from mitochondria in a dose dependent manner.	16	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	21	23
Immunocytochemistry failed to reveal the recruitment of Bax to non irradiated mitochondria , which suggests that Bax does not mediate the release of cytochrome c from mitochondria .	Immunocytochemistry failed to reveal the recruitment of Bax to non irradiated mitochondria, which suggests that Bax does not mediate the release of cytochrome c from mitochondria.	16	25	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	23	25
Both BAX oligo - and alamethicin induced cytochrome c releases were accompanied by inhibition of ROS generation , which was assessed by measuring mitochondrial H 2 O 2 release with an Amplex Red assay .	Both BAX oligo - and alamethicin induced cytochrome c releases were accompanied by inhibition of ROS generation, which was assessed by measuring mitochondrial H 2 O 2 release with an Amplex Red assay.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	1	2	7	9
In a different apoptotic pathway , Calp2 causes fragmentation of Bcl-xL ( Bcl2l1 ) and Bcl2 in addition to cleavage of Bax to increase the Bax and bcl2 ratio , a step that mediates cytochrome C release , activates Casp3 and initiates the apoptotic execution .	In a different apoptotic pathway, Calp2 causes fragmentation of Bcl-xL (Bcl2l1) and Bcl2 in addition to cleavage of Bax to increase the Bax and bcl2 ratio, a step that mediates cytochrome C release, activates Casp3 and initiates the apoptotic execution.	25	36	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	25	26	34	36
The Bax serves as a major regulator to accelerate the permeability of mitochondria and release of cytochrome c , whereas the Bcl-2 resides in the mitochondrial wall and protects the integrity of mitochondria against cell apoptosis .	The Bax serves as a major regulator to accelerate the permeability of mitochondria and release of cytochrome c, whereas the Bcl-2 resides in the mitochondrial wall and protects the integrity of mitochondria against cell apoptosis.	0	18	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	16	18
For instance , in rat liver mitochondria , BAX oligo neither induced the mPT nor preventing the mPT with EGTA attenuated cytochrome c release induced by BAX oligo [ XREF_BIBR ] .	For instance, in rat liver mitochondria, BAX oligo neither induced the mPT nor preventing the mPT with EGTA attenuated cytochrome c release induced by BAX oligo [XREF_BIBR].	21	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	26	27	21	23
The anti-apoptotic Bcl-2 in the outer mitochondrial wall suppresses cytochrome c release , whereas pro apoptotic Bax mediates apoptosis by inducing the release of cytochrome c from the mitochondria .	The anti-apoptotic Bcl-2 in the outer mitochondrial wall suppresses cytochrome c release, whereas pro apoptotic Bax mediates apoptosis by inducing the release of cytochrome c from the mitochondria.	14	26	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	24	26
As a pro apoptotic protein , Bax induces release of cytochrome C and other pro apoptotic factors from the mitochondria , leading to activation of caspases .	As a pro apoptotic protein, Bax induces release of cytochrome C and other pro apoptotic factors from the mitochondria, leading to activation of caspases.	6	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	6	7	10	12
A truncated BID ( tBID ) induces overexpression of Bax that modulates MMP and cytochrome c release .	A truncated BID (tBID) induces overexpression of Bax that modulates MMP and cytochrome c release.	2	16	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	BID (tBID) induces overexpression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	9	10	14	16
Bax is one of the Bcl-2 family members that are involved in cell apoptosis , while Bcl-2 can reduce the release of cytochrome C induced by Bax and control apoptosis .	Bax is one of the Bcl-2 family members that are involved in cell apoptosis, while Bcl-2 can reduce the release of cytochrome C induced by Bax and control apoptosis.	22	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	26	27	22	24
It is well known that the increasing of Bax and Bcl -2 ratio will cause the loss of mitochondrial membrane potential and release of cytochrome c , subsequently activate caspase-9 , thus ultimately activate the common downstream apoptosis effector caspase-3 .	It is well known that the increasing of Bax and Bcl -2 ratio will cause the loss of mitochondrial membrane potential and release of cytochrome c, subsequently activate caspase-9, thus ultimately activate the common downstream apoptosis effector caspase-3.	8	26	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	24	26
BAX mediates the release of cytochrome c and apoptosis .	BAX mediates the release of cytochrome c and apoptosis.	0	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Furthermore , Bax accumulation in MFN2- cells increased outer member injury and promoted apoptosis , the release of cytochrome c and Apoptosis Inducing Factor ( AIF ) , pro apoptotic proteins normally restricted to the inter-mitochondrial membrane space ( XREF_FIG ) .	Furthermore, Bax accumulation in MFN2- cells increased outer member injury and promoted apoptosis, the release of cytochrome c and Apoptosis Inducing Factor (AIF), pro apoptotic proteins normally restricted to the inter-mitochondrial membrane space (XREF_FIG).	2	20	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	18	20
Bax causes apoptosis by associating with mitochondria and triggering cytochrome c release , which activates the caspase cascade .	Bax causes apoptosis by associating with mitochondria and triggering cytochrome c release, which activates the caspase cascade.	0	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	9	11
Exactly how Bid , Bax , and related proteins function to cause cytochrome c release is unclear .	Exactly how Bid, Bax, and related proteins function to cause cytochrome c release is unclear.	2	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	12	14
Previous studies suggest that the proapoptotic BH3-only protein BIM plays an important role in BAX mediated cytochrome c release and induction of apoptosis [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	Previous studies suggest that the proapoptotic BH3-only protein BIM plays an important role in BAX mediated cytochrome c release and induction of apoptosis [XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR].	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	14	15	16	18
Bax induces cytochrome c release to activate caspase-3 , causing vesicle formation , nuclear fragmentation , and cell death .	Bax induces cytochrome c release to activate caspase-3, causing vesicle formation, nuclear fragmentation, and cell death.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	2	4
BAX titrations ranging between 5 - 50 nM should provide results that show BAX alone does not induce cytochrome c release , and synergy with C8-BID promotes complete release .	BAX titrations ranging between 5 - 50 nM should provide results that show BAX alone does not induce cytochrome c release, and synergy with C8-BID promotes complete release.	13	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	13	14	18	20
An increase in the Bax and Bcl2 ratio induces the release of cytochrome c followed by sequential activation of caspases and culminating with cell death [ XREF_BIBR ] .	An increase in the Bax and Bcl2 ratio induces the release of cytochrome c followed by sequential activation of caspases and culminating with cell death [XREF_BIBR].	4	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	4	5	12	14
Homodimerization of Bax increases cytochrome c release resulting in the induction of apoptosis .	Homodimerization of Bax increases cytochrome c release resulting in the induction of apoptosis.	0	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	4	6
When activated , Bax stimulates the release of cytochrome C and other apoptogenic mitochondrial proteins into the cytosol to trigger apoptosis .	When activated, Bax stimulates the release of cytochrome C and other apoptogenic mitochondrial proteins into the cytosol to trigger apoptosis.	3	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	3	4	8	10
In contrast , Bax belongs to the pro survival subfamily and promotes apoptosis by translocating into the mitochondrial membrane and facilitating cytochrome c release [ XREF_BIBR ] .	In contrast, Bax belongs to the pro survival subfamily and promotes apoptosis by translocating into the mitochondrial membrane and facilitating cytochrome c release [XREF_BIBR].	3	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	21	23
The pro apoptotic proteins , Bid and Bax , as well as factors present in Xenopus egg cytosol , each induced cytochrome c release when incubated with isolated mitochondria .	The pro apoptotic proteins, Bid and Bax, as well as factors present in Xenopus egg cytosol, each induced cytochrome c release when incubated with isolated mitochondria.	3	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	21	23
During apoptosis , Bax typically induces loss of the electrochemical gradient ( DeltaPsi ) across the inner mitochondrial membrane and opens the voltage dependent anion channel ( VDAC ) allowing cytochrome c to pass through the channel .	During apoptosis, Bax typically induces loss of the electrochemical gradient (DeltaPsi) across the inner mitochondrial membrane and opens the voltage dependent anion channel (VDAC) allowing cytochrome c to pass through the channel.	3	32	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	30	32
It was previously shown that Prop reduces intracellular calcium levels , Bax mediated cytochrome C release and inhibits protein kinase C ( PKC ) activity in a beta-adrenoreceptor independent manner [ XREF_BIBR - XREF_BIBR ] , and it induces cell cycle arrest and apoptosis via Akt and MAPK pathway in melanoma cells [ XREF_BIBR ] .	It was previously shown that Prop reduces intracellular calcium levels, Bax mediated cytochrome C release and inhibits protein kinase C (PKC) activity in a beta-adrenoreceptor independent manner [XREF_BIBR - XREF_BIBR], and it induces cell cycle arrest and apoptosis via Akt and MAPK pathway in melanoma cells [XREF_BIBR].	11	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	11	12	13	15
In ATP depleted cells , Bax knockdown markedly decreased the release of both AIF ( XREF_FIG , top panel - lane 4 vs. lanes 2 & 3 ) and cytochrome c ( middle panel- lane 4 vs. lanes 2 & 3 ) , confirming that Bax contributes to organelle injury after metabolic stress .	In ATP depleted cells, Bax knockdown markedly decreased the release of both AIF (XREF_FIG, top panel - lane 4 vs. lanes 2 & 3) and cytochrome c (middle panel- lane 4 vs. lanes 2 & 3), confirming that Bax contributes to organelle injury after metabolic stress.	5	31	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	29	31
The addition of Bcl-2 to the extracts blocked both the increase in complex IV accessibility and the release of endogenous cytochrome c. Both Bid and Bax Induce Mitochondrial Cytochrome c Release without Gross Mitochondrial Swelling .	The addition of Bcl-2 to the extracts blocked both the increase in complex IV accessibility and the release of endogenous cytochrome c. Both Bid and Bax Induce Mitochondrial Cytochrome c Release without Gross Mitochondrial Swelling.	23	30	Induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome c	Cytochrome c	Cytochrome c	25	26	28	30
Similarly , heterologous expression of Bax induces cell death and cytochrome c release in yeast [ XREF_BIBR , XREF_BIBR ] .	Similarly, heterologous expression of Bax induces cell death and cytochrome c release in yeast [XREF_BIBR, XREF_BIBR].	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	5	6	10	12
The investigation of potential caspase-6 activating mechanisms revealed that laquinimod reduces the expression of Bax , a pro apoptotic molecule that causes mitochondrial cytochrome c release and caspase activation .	The investigation of potential caspase-6 activating mechanisms revealed that laquinimod reduces the expression of Bax, a pro apoptotic molecule that causes mitochondrial cytochrome c release and caspase activation.	12	25	causes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	14	15	23	25
In support of this hypothesis , addition of Bax directly to isolated mitochondria triggers the release of cytochrome c by a mechanism that may involve pore formation .	In support of this hypothesis, addition of Bax directly to isolated mitochondria triggers the release of cytochrome c by a mechanism that may involve pore formation.	6	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	17	19
Among the multidomain pro apoptotic members , Bax can augment apoptosis by perforating the outer mitochondrial membrane in response to oxidative stimuli increasing membrane permeability and subsequntely triggering cytochrome c release 8 .	Among the multidomain pro apoptotic members, Bax can augment apoptosis by perforating the outer mitochondrial membrane in response to oxidative stimuli increasing membrane permeability and subsequntely triggering cytochrome c release 8.	7	30	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	28	30
Elegant biochemical and computational studies have rigorously probed the classic apoptosis mechanisms with purified components and provide compelling evidence for BCL-x L -inhibited , tBID activated , BAX mediated cytochrome c release .	Elegant biochemical and computational studies have rigorously probed the classic apoptosis mechanisms with purified components and provide compelling evidence for BCL-x L -inhibited, tBID activated, BAX mediated cytochrome c release.	27	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	27	28	29	31
As expected , expression of Bax induced the release of cytochrome c from the mitochondria ( XREF_FIG ) , a response that was inhibited by reduction of Atg5 expression .	As expected, expression of Bax induced the release of cytochrome c from the mitochondria (XREF_FIG), a response that was inhibited by reduction of Atg5 expression.	3	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	5	6	10	12
In line with this notion , in a variety of apoptotic models neither Bak nor Bax alone is sufficient to induce maximal cytochrome c release ( indicative of MOMP ) , which requires both molecules .	In line with this notion, in a variety of apoptotic models neither Bak nor Bax alone is sufficient to induce maximal cytochrome c release (indicative of MOMP), which requires both molecules.	13	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	22	24
These results indicate that NGF blocks TG induced Bax translocation to the mitochondria and in this way prevents cytochrome c release and subsequent caspase activation .	These results indicate that NGF blocks TG induced Bax translocation to the mitochondria and in this way prevents cytochrome c release and subsequent caspase activation.	4	20	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	NGF blocks TG induced Bax translocation to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	8	9	18	20
Bax is activated and translocated onto mitochondria to mediate cytochrome c release and apoptosis .	Bax is activated and translocated onto mitochondria to mediate cytochrome c release and apoptosis.	0	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	9	11
16 Dissociation of HK2 from the mitochondria potentiates Bax induced cytochrome c release and apoptosis .	16 Dissociation of HK2 from the mitochondria potentiates Bax induced cytochrome c release and apoptosis.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	10	12
Indeed , there is evidence for involvement of cyclophilin D dependent mPTP opening in the Bax driven cytochrome c release in the isolated mitochondria [ XREF_BIBR ] .	Indeed, there is evidence for involvement of cyclophilin D dependent mPTP opening in the Bax driven cytochrome c release in the isolated mitochondria [XREF_BIBR].	12	19	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	17	19
Preservation of Mitochondrial Structure and Function after Bid- or Bax Mediated Cytochrome c Release .	Preservation of Mitochondrial Structure and Function after Bid- or Bax Mediated Cytochrome c Release.	3	13	Mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	Cytochrome c	Cytochrome c	Cytochrome c	9	10	11	13
The binding of HKII to mitochondria has been shown to inhibit Bax induced cytochrome c release and thereby impair apoptosis XREF_BIBR .	The binding of HKII to mitochondria has been shown to inhibit Bax induced cytochrome c release and thereby impair apoptosis XREF_BIBR.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	11	12	13	15
In this scenario , complex I blockade increases the soluble pool of cytochrome c in the mitochondrial intermembrane space through oxidative mechanisms , whereas activation of pro cell death protein Bax is actually necessary to trigger neuronal death by permeabilizing the outer mitochondrial membrane and releasing cytochrome c into the cytosol .	In this scenario, complex I blockade increases the soluble pool of cytochrome c in the mitochondrial intermembrane space through oxidative mechanisms, whereas activation of pro cell death protein Bax is actually necessary to trigger neuronal death by permeabilizing the outer mitochondrial membrane and releasing cytochrome c into the cytosol.	24	48	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	30	31	46	48
It is well known that Bax activates caspases by promoting the release of mitochondrial cytochrome c , which forms an apoptosome with a number of other factors including caspases .	It is well known that Bax activates caspases by promoting the release of mitochondrial cytochrome c, which forms an apoptosome with a number of other factors including caspases.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	14	16
In each case , point mutagenesis abolished BIM SAHB induced BAX oligomerization ( XREF_FIG ) and BAX mediated cytochrome c release ( XREF_FIG , XREF_SUPPLEMENTARY ) , indicating that interference with key hydrophobic or charge interactions specifically disrupts BIM SAHB engagement of the novel BAX site .	In each case, point mutagenesis abolished BIM SAHB induced BAX oligomerization (XREF_FIG) and BAX mediated cytochrome c release (XREF_FIG, XREF_SUPPLEMENTARY), indicating that interference with key hydrophobic or charge interactions specifically disrupts BIM SAHB engagement of the novel BAX site.	11	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	16	17	18	20
To determine whether inhibition of Bax induced cytochrome c release by Ab # 20 and Ab # 25 was specific to PT associated cytochrome c release , we examined the effect of these antibodies on Bax induced cytochrome c release in the presence of a Ca 2+ chelator that completely inhibited the PT ( Zoratti and Szabo 1995 ; data not shown ) .	To determine whether inhibition of Bax induced cytochrome c release by Ab # 20 and Ab # 25 was specific to PT associated cytochrome c release, we examined the effect of these antibodies on Bax induced cytochrome c release in the presence of a Ca 2+ chelator that completely inhibited the PT (Zoratti and Szabo 1995; data not shown).	3	9	induced	Positive_early_activation	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	7	9
Addition of the caspase inhibitor z-VAD-fmk was able to prevent nuclear condensation but could not inhibit Bax induced cytochrome C release , confirming that caspases are activated downstream of cytochrome C release .	Addition of the caspase inhibitor z-VAD-fmk was able to prevent nuclear condensation but could not inhibit Bax induced cytochrome C release, confirming that caspases are activated downstream of cytochrome C release.	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	16	17	18	20
GSK-3beta can induce apoptosis by phosphorylating Bax resulting in the entry of Bax into the mitochondria , thereby inducing the release of cytochrome C into the cytoplasm .	GSK-3beta can induce apoptosis by phosphorylating Bax resulting in the entry of Bax into the mitochondria, thereby inducing the release of cytochrome C into the cytoplasm.	0	24	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	GSK-3beta can induce apoptosis by phosphorylating Bax	bax	cytochrome C	cytochrome C	cytochrome c	6	7	22	24
The activation of Bax triggers the release of cytochrome c from the intermembrane space into the cytoplasm , which finally activates caspase enzymes that mediate the entrance in the execution phase of the apoptotic program .	The activation of Bax triggers the release of cytochrome c from the intermembrane space into the cytoplasm, which finally activates caspase enzymes that mediate the entrance in the execution phase of the apoptotic program.	1	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	8	10
In contrast , neither the transmembrane domain nor a functional BH3 domain is required for the Bax mediated release of cytochrome c from mitochondria .	In contrast, neither the transmembrane domain nor a functional BH3 domain is required for the Bax mediated release of cytochrome c from mitochondria.	15	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	16	17	20	22
18 In mitochondria from Bax and Bak double deficient MEFs that had not been manipulated , high levels ( 1000nM ) of recombinant Bax caused release of cytochrome c ( XREF_FIG ) .	18 In mitochondria from Bax and Bak double deficient MEFs that had not been manipulated, high levels (1000nM) of recombinant Bax caused release of cytochrome c (XREF_FIG).	17	29	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	levels (1000nM) of recombinant Bax	bax	cytochrome c	cytochrome c	cytochrome c	23	24	27	29
Nevertheless , we examined the cytochrome c release induced by BAX oligo in the presence of 1 mM EGTA and did not find any difference with experiments where we used 10muM EGTA ( XREF_FIG ) .	Nevertheless, we examined the cytochrome c release induced by BAX oligo in the presence of 1 mM EGTA and did not find any difference with experiments where we used 10muM EGTA (XREF_FIG).	5	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	10	11	5	7
BAX translocates to the mitochondria during apoptosis , causing release of cytochrome c into the cytosol .	BAX translocates to the mitochondria during apoptosis, causing release of cytochrome c into the cytosol.	0	13	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX translocates to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	0	1	11	13
Bax and Drp1 colocalize together at scission sites on mitochondria , enabling cytochrome C release from mitochondria XREF_BIBR , XREF_BIBR .	Bax and Drp1 colocalize together at scission sites on mitochondria, enabling cytochrome C release from mitochondria XREF_BIBR, XREF_BIBR.	0	14	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	0	1	12	14
It is perhaps due to the inhibition of Bcl-2 and Bcl-xL that PM facilitates Bax and Bak mediated mitochondrial permeability transition and cytochrome c release .	It is perhaps due to the inhibition of Bcl-2 and Bcl-xL that PM facilitates Bax and Bak mediated mitochondrial permeability transition and cytochrome c release.	14	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	14	15	22	24
The results presented so far indicate that in isolated brain mitochondria BAX oligo induces cytochrome c release that parallels an induction of the mPT .	The results presented so far indicate that in isolated brain mitochondria BAX oligo induces cytochrome c release that parallels an induction of the mPT.	11	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	11	12	14	16
Oxidized wild-type BAX monomer was readily activated by BIM SAHB in both BAX oligomerization and BAX mediated cytochrome c release assays ( XREF_FIG ) .	Oxidized wild-type BAX monomer was readily activated by BIM SAHB in both BAX oligomerization and BAX mediated cytochrome c release assays (XREF_FIG).	9	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	15	16	17	19
Bax deletion prevented both cytochrome c release and caspase 3 activation , and also provided complete protection against proteasomal inhibition induced death .	Bax deletion prevented both cytochrome c release and caspase 3 activation, and also provided complete protection against proteasomal inhibition induced death.	0	6	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	4	6
Bax deletion prevents apoptotic death of NGF deprived neurons by preventing release of cytochrome c from their mitochondria .	Bax deletion prevents apoptotic death of NGF deprived neurons by preventing release of cytochrome c from their mitochondria.	0	15	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
Among these proteins , overexpression of proapoptotic protein Bax induces the release of cytochrome c from the mitochondria .	Among these proteins, overexpression of proapoptotic protein Bax induces the release of cytochrome c from the mitochondria.	4	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	overexpression of proapoptotic protein Bax	bax	cytochrome c	cytochrome c	cytochrome c	8	9	13	15
An important corollary of this result is that the event known as PT ( for review see Zoratti and Szabo 1995 ) is not required for tBid- or Bax induced cytochrome c release ( see Discussion ) .	An important corollary of this result is that the event known as PT (for review see Zoratti and Szabo 1995) is not required for tBid- or Bax induced cytochrome c release (see Discussion).	24	32	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	28	29	30	32
These results demonstrate that the BACE1 enzyme and APP substrate both accumulate in overlapping areas in close proximity to amyloid plaques , precisely where elevated BACE1 cleavage of APP could lead to locally increased Abeta production and exacerbation of amyloid pathology .	These results demonstrate that the BACE1 enzyme and APP substrate both accumulate in overlapping areas in close proximity to amyloid plaques, precisely where elevated BACE1 cleavage of APP could lead to locally increased Abeta production and exacerbation of amyloid pathology.	25	40	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	25	26	34	35
In addition , BACE1 dependent cleavage of low density lipoprotein receptor related protein ( LRP ) can mediate the endocytosis of APP and ApoE [ XREF_BIBR ] and has been suggested to be involved in the pathology of AD .	In addition, BACE1 dependent cleavage of low density lipoprotein receptor related protein (LRP) can mediate the endocytosis of APP and ApoE [XREF_BIBR] and has been suggested to be involved in the pathology of AD.	3	25	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	21	22
These events promoted the BACE1 mediated APP cleavage in APP transgenic mice .	These events promoted the BACE1 mediated APP cleavage in APP transgenic mice.	3	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	4	5	6	7
LRRTM3 Knock-down by siRNA Decreases BACE1 Processing Products of APP .	LRRTM3 Knock-down by siRNA Decreases BACE1 Processing Products of APP.	5	10	Products	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	9	10
Most importantly , BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Abeta generation .	Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Abeta generation.	3	16	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	13	14
Abeta is produced by cleavage of the amyloid precursor protein ( APP ) by the beta and gamma secretases , BACE , and Presenilin ( PS ) .	Abeta is produced by cleavage of the amyloid precursor protein (APP) by the beta and gamma secretases, BACE, and Presenilin (PS).	0	21	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	20	21	0	1
The effects of RJ on AD rabbits may be explained by its regulatory capabilities of proteins involved in Abeta production , transport , degradation and clearance , such as BACE1 , RAGE , LRP1 and IDE .	The effects of RJ on AD rabbits may be explained by its regulatory capabilities of proteins involved in Abeta production, transport, degradation and clearance, such as BACE1, RAGE, LRP1 and IDE.	18	35	production	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	29	30	18	19
As BACE1 contributes to the production of Abeta by cleaving APP , we also found a marked decrease in Abeta 42 production in the hippocampus of 3xTg mice treated with compound 1 ( XREF_FIG ) , while Nissl staining revealed no reduction in cell numbers in the hippocampus .	As BACE1 contributes to the production of Abeta by cleaving APP, we also found a marked decrease in Abeta 42 production in the hippocampus of 3xTg mice treated with compound 1 (XREF_FIG), while Nissl staining revealed no reduction in cell numbers in the hippocampus.	1	11	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	1	2	10	11
BACE1 knockout mice do not produce Abeta and are free from AD associated pathologies including memory deficits and neuronal loss [ XREF_BIBR , XREF_BIBR ] .	BACE1 knockout mice do not produce Abeta and are free from AD associated pathologies including memory deficits and neuronal loss [XREF_BIBR, XREF_BIBR].	0	7	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	6	7
Bace1 deletion abolishes Abeta deposition and rescues cognitive deficits in APP mutant mice [ XREF_BIBR ] .	Bace1 deletion abolishes Abeta deposition and rescues cognitive deficits in APP mutant mice [XREF_BIBR].	0	4	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bace1	Bace1	Bace1	Abeta	Abeta	Abeta	0	1	3	4
Work from our lab and other groups has demonstrated that TNF-alpha directly stimulates astrocytic BACE1 expression to enhance beta-site processing of APP , and suppresses Abeta degradation in microglia .	Work from our lab and other groups has demonstrated that TNF-alpha directly stimulates astrocytic BACE1 expression to enhance beta-site processing of APP, and suppresses Abeta degradation in microglia.	10	26	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	TNF-alpha directly stimulates astrocytic BACE1 expression	bace1	Abeta	Abeta	abeta	14	15	25	26
For instance , in vitro and in vivo evidence indicate that TNFalpha increases Abeta levels by increasing expression of BACE1 , an enzyme that drives Abeta production .	For instance, in vitro and in vivo evidence indicate that TNFalpha increases Abeta levels by increasing expression of BACE1, an enzyme that drives Abeta production.	17	26	drives	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BACE1	expression of BACE1	bace1	Abeta	Abeta	abeta	19	20	25	26
We then address the pathological and pathogenic aspects of CAA , focusing on recent findings about the role of BACE1 mediated Abeta overproduction .	We then address the pathological and pathogenic aspects of CAA, focusing on recent findings about the role of BACE1 mediated Abeta overproduction.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	19	20	21	22
Early application of HNYCR extract can obviously improve the learning and memory ability of APP transgenic mice that has declined , reduce the expressions of APP , BACE1 , PS-1 , and Abeta in the hippocampal CA1 area , reduce the production of Abeta , and slow down the pathological process of brains in APP transgenic mice .	Early application of HNYCR extract can obviously improve the learning and memory ability of APP transgenic mice that has declined, reduce the expressions of APP, BACE1, PS-1, and Abeta in the hippocampal CA1 area, reduce the production of Abeta, and slow down the pathological process of brains in APP transgenic mice.	3	44	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	HNYCR extract can obviously improve the learning and memory ability of APP transgenic mice that has declined, reduce the expressions of APP, BACE1	bace1	Abeta	Abeta	abeta	27	28	43	44
The preserved elevation of BACE1 allows the continued acceleration of beta-cleavage of APP in BACE1 +/-.5 XFAD mice , which would weaken the abilities of partial BACE1 reduction to suppress Abeta accumulation in brain and improve memory during the advanced phase of disease progression .	The preserved elevation of BACE1 allows the continued acceleration of beta-cleavage of APP in BACE1 +/-.5 XFAD mice, which would weaken the abilities of partial BACE1 reduction to suppress Abeta accumulation in brain and improve memory during the advanced phase of disease progression.	2	17	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	4	5	12	13
Taken collectively , biochemical analyses demonstrated that partial BACE1 reduction due to heterozygous gene deletion significantly suppressed the beta-cleavage of APP in 5XFAD mouse brains , resulting in reduced levels of beta-products such as sAPPbeta , C99 , Abeta40 and Abeta42 by ~ 51 % , ~ 55 % , ~ 66 % and ~ 57 % , respectively ( XREF_FIG ) .	Taken collectively, biochemical analyses demonstrated that partial BACE1 reduction due to heterozygous gene deletion significantly suppressed the beta-cleavage of APP in 5XFAD mouse brains, resulting in reduced levels of beta-products such as sAPPbeta, C99, Abeta40 and Abeta42 by ~ 51%, ~ 55%, ~ 66% and ~ 57%, respectively (XREF_FIG).	8	26	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	8	9	20	21
The RanBP9 protein interacts with the cytoplasmic tails of LRP , APP and BACE1 proteins promoting BACE1 dependent cleavage of APP and Abeta generation both in vitro and in vivo .	The RanBP9 protein interacts with the cytoplasmic tails of LRP, APP and BACE1 proteins promoting BACE1 dependent cleavage of APP and Abeta generation both in vitro and in vivo.	9	23	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	13	14	20	21
These data suggest that BACE1 may mediate Abeta overproduction predominantly in axonal structures from multiple neuronal phenotypes in transgenic models of AD , and that the process appears to begin prior to overt extracellular amyloid deposition and proceeds throughout the course of plaque development .	These data suggest that BACE1 may mediate Abeta overproduction predominantly in axonal structures from multiple neuronal phenotypes in transgenic models of AD, and that the process appears to begin prior to overt extracellular amyloid deposition and proceeds throughout the course of plaque development.	4	8	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	7	8
Lastly , our data suggest that Mani might inhibit Bace1 induced cleavage of App as reported for the transmembrane protein reticulon-3 [ XREF_BIBR ] .	Lastly, our data suggest that Mani might inhibit Bace1 induced cleavage of App as reported for the transmembrane protein reticulon-3 [XREF_BIBR].	8	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bace1	Bace1	Bace1	App	App	App	9	10	13	14
We note that BACE1 overexpression would not be expected to increase Abeta production in CHO cells , since previous studies have established that gamma-secretase , rather than beta-secretase , is the rate limiting step in Abeta production in this cell type [ XREF_BIBR ] .	We note that BACE1 overexpression would not be expected to increase Abeta production in CHO cells, since previous studies have established that gamma-secretase, rather than beta-secretase, is the rate limiting step in Abeta production in this cell type [XREF_BIBR].	3	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 overexpression	bace1	Abeta	Abeta	abeta	3	4	11	12
The presence of the CTF99 proteolytic product provides evidence of BACE1 mediated cleavage activity of APP , while detection of the CTF83 fragment demonstrates alpha-secretase activity is also present in M17 cells .	The presence of the CTF99 proteolytic product provides evidence of BACE1 mediated cleavage activity of APP, while detection of the CTF83 fragment demonstrates alpha-secretase activity is also present in M17 cells.	8	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	10	11	15	16
As BACE1 is increased in aging and implicated in AD , we predict that Rheb depletion elicits BACE1 , which is a contributing factor for memory deficit , through BACE1 mediated Abeta accumulation .	As BACE1 is increased in aging and implicated in AD, we predict that Rheb depletion elicits BACE1, which is a contributing factor for memory deficit, through BACE1 mediated Abeta accumulation.	16	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	29	30	31	32
Only a limited amount of APP cleavage by BACE1 takes place at the plasma membrane ; the primary BACE1 mediated APP processing occurs in endocytic vesicles where the low pH environment favors the enzymatic activity .	Only a limited amount of APP cleavage by BACE1 takes place at the plasma membrane; the primary BACE1 mediated APP processing occurs in endocytic vesicles where the low pH environment favors the enzymatic activity.	16	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	18	19	20	21
Although BACE1 reaches the plasma membrane due to vesicle traffic , it is recycled quickly , and very little BACE1 mediated APP cleavage occurs at the plasma membrane ; instead APP is cleaved by BACE primarily in endocytic vesicles .	Although BACE1 reaches the plasma membrane due to vesicle traffic, it is recycled quickly, and very little BACE1 mediated APP cleavage occurs at the plasma membrane; instead APP is cleaved by BACE primarily in endocytic vesicles.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	19	20	21	22
From these experiments , we concluded that delivery of BACE1 to endosomes by virtue of interactions between the [ DE ] XXXL [ LI ] signal and AP-2 is dispensable for the BACE1 catalyzed APP cleavage .	From these experiments, we concluded that delivery of BACE1 to endosomes by virtue of interactions between the [DE] XXXL [LI] signal and AP-2 is dispensable for the BACE1 catalyzed APP cleavage.	32	35	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	32	33	34	35
BACE1 levels are increased in AD , potentially accelerating Abeta generation , but the mechanisms of BACE1 elevation are not fully understood .	BACE1 levels are increased in AD, potentially accelerating Abeta generation, but the mechanisms of BACE1 elevation are not fully understood.	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 levels	bace1	Abeta	Abeta	abeta	0	1	9	10
BACE1 is indispensable for the generation of Abeta , as germline deletion of the BACE1 gene abolishes the generation of Abeta [ XREF_BIBR - XREF_BIBR ] .	BACE1 is indispensable for the generation of Abeta, as germline deletion of the BACE1 gene abolishes the generation of Abeta [XREF_BIBR - XREF_BIBR].	14	22	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	14	15	20	21
APP is cleaved by alpha-secretase ( ADAM ) or beta-secretase ( BACE-1 ) producing the extracellular soluble fragments sAPPalpha or sAPPbeta , respectively .	APP is cleaved by alpha-secretase (ADAM) or beta-secretase (BACE-1) producing the extracellular soluble fragments sAPPalpha or sAPPbeta, respectively.	4	22	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	sAPPbeta	sAPPbeta	sAPPbeta	11	12	20	21
BACE1 has highest concentrations in neurons , has the correct sequence specificity and acidic pH optimum for enzymatic activity , undertakes beta-secretase processing of APP , and increases Abeta generation .	BACE1 has highest concentrations in neurons, has the correct sequence specificity and acidic pH optimum for enzymatic activity, undertakes beta-secretase processing of APP, and increases Abeta generation.	0	29	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	28	29
Transfection of human APP and BACE1 into neurons derived from wild-type and BACE1 (-/-) mice supports cleavage of APP at the canonical beta-secretase site .	Transfection of human APP and BACE1 into neurons derived from wild-type and BACE1 (-/-) mice supports cleavage of APP at the canonical beta-secretase site.	0	19	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	18	19
Lack of Syt-1 expression in PC12 cells lowers endogenous APP-CTF generation and secreted Abeta 40 and Abeta 42 levels , suggesting that Syt-1 may regulate BACE1 mediated cleavage of APP .	Lack of Syt-1 expression in PC12 cells lowers endogenous APP-CTF generation and secreted Abeta 40 and Abeta 42 levels, suggesting that Syt-1 may regulate BACE1 mediated cleavage of APP.	24	30	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	25	26	29	30
When viewing the results from gamma-secretase perspective , BACE-1 inhibition can prevent the Abeta rise evoked by gamma-secretase inhibition at low concentrations without showing any obvious potentiation at higher concentrations .	When viewing the results from gamma-secretase perspective, BACE-1 inhibition can prevent the Abeta rise evoked by gamma-secretase inhibition at low concentrations without showing any obvious potentiation at higher concentrations.	8	14	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	8	9	13	14
Our previous work demonstrated that Abeta42 could increase BACE1 [ XREF_BIBR ] , which in turn might cause increased Abeta generation , creating a positive feed forward mechanism in Alzheimer ' s disease .	Our previous work demonstrated that Abeta42 could increase BACE1 [XREF_BIBR], which in turn might cause increased Abeta generation, creating a positive feed forward mechanism in Alzheimer 's disease.	8	20	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	8	9	19	20
Overexpression of BACE1 increases amyloidogenic APP processing and suppresses glucose oxidation .	Overexpression of BACE1 increases amyloidogenic APP processing and suppresses glucose oxidation.	0	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	Overexpression of BACE1	bace1	APP	APP	app	2	3	5	6
Therefore , RAGE activation by AGEs or Abeta activate BACE1 transcription and thereby , increases Abeta production .	Therefore, RAGE activation by AGEs or Abeta activate BACE1 transcription and thereby, increases Abeta production.	2	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	RAGE activation by AGEs or Abeta activate BACE1 transcription	bace1	Abeta	Abeta	abeta	9	10	15	16
Furthermore , BACE1 heterozygous knockout mice have no reported abnormal phenotypes so far and heterozygous knockout of BACE1 still can reduce Abeta deposition in AD mice [ XREF_BIBR , XREF_BIBR ] .	Furthermore, BACE1 heterozygous knockout mice have no reported abnormal phenotypes so far and heterozygous knockout of BACE1 still can reduce Abeta deposition in AD mice [XREF_BIBR, XREF_BIBR].	15	22	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	17	18	21	22
We recently confirmed that neuron specific knockin of human ( h ) BACE1 induces Abeta accumulation , promotes brain inflammation and recapitulates Alzheimer ' s disease like phenotypes in mice in the absence of mutant APP expression [ XREF_BIBR ] , suggesting that BACE1 represents a molecular risk factor for sporadic Alzheimer ' s disease .	We recently confirmed that neuron specific knockin of human (h) BACE1 induces Abeta accumulation, promotes brain inflammation and recapitulates Alzheimer 's disease like phenotypes in mice in the absence of mutant APP expression [XREF_BIBR], suggesting that BACE1 represents a molecular risk factor for sporadic Alzheimer 's disease.	8	15	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	12	13	14	15
Exploring the mechanisms of this effect , we obtained data that BRI2 decreases the cellular levels of BACE1 thus reducing the beta-cleavage of APP .	Exploring the mechanisms of this effect, we obtained data that BRI2 decreases the cellular levels of BACE1 thus reducing the beta-cleavage of APP.	11	24	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BRI2 decreases the cellular levels of BACE1	bace1	APP	APP	app	17	18	23	24
As partial suppression of BACE1 attenuates Abeta generation and AD related pathology , it might be an ideal target for AD treatment .	As partial suppression of BACE1 attenuates Abeta generation and AD related pathology, it might be an ideal target for AD treatment.	2	7	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	6	7
There is also evidence that BACE1 is upregulated during aging and AD , thus favoring amyloidogenic APP processing .	There is also evidence that BACE1 is upregulated during aging and AD, thus favoring amyloidogenic APP processing.	5	17	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	16	17
The protective A673T APP mutation in humans and genetic deletion of BACE1 in mice both decrease Abeta generation via reduced beta-secretase processing of APP , providing strong proof of concept that BACE1 inhibition should be efficacious for AD .	The protective A673T APP mutation in humans and genetic deletion of BACE1 in mice both decrease Abeta generation via reduced beta-secretase processing of APP, providing strong proof of concept that BACE1 inhibition should be efficacious for AD.	9	17	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	16	17
Once amyloid plaques form , Abeta causes BACE1 levels to increase further , thus accelerating Abeta generation and plaque growth via a positive-feedback loop .	Once amyloid plaques form, Abeta causes BACE1 levels to increase further, thus accelerating Abeta generation and plaque growth via a positive-feedback loop.	5	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	Abeta causes BACE1 levels	bace1	Abeta	Abeta	abeta	7	8	15	16
The initial cleavage of APP is executed either by alpha- ( ADAM 10 and/or 17 ) [ XREF_BIBR ] or beta-secretase ( BACE-1 ) [ XREF_BIBR ] , producing alpha- or beta-soluble APP ( alpha and betasAPP ) , respectively , and a membrane bound C-terminal fragment ( alpha and betaCTF ) .	The initial cleavage of APP is executed either by alpha- (ADAM 10 and/or 17) [XREF_BIBR] or beta-secretase (BACE-1) [XREF_BIBR], producing alpha- or beta-soluble APP (alpha and betasAPP), respectively, and a membrane bound C-terminal fragment (alpha and betaCTF).	20	36	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	APP	APP	APP	22	23	32	33
Other interactions between APP or Abeta with PrP , and reciprocal modulation of AD or scrapie disease progression in mouse have been described as well ; moreover , cellular PrP was shown to inhibit BACE1 mediated Abeta production .	Other interactions between APP or Abeta with PrP, and reciprocal modulation of AD or scrapie disease progression in mouse have been described as well; moreover, cellular PrP was shown to inhibit BACE1 mediated Abeta production.	33	37	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	34	35	36	37
Inhibition of BACE1 proteolytic activity has been confirmed to decrease Abeta generation and amyloid deposition , and thus specific inhibition of BACE1 by small molecules is a current focus for Alzheimer ' s disease therapy .	Inhibition of BACE1 proteolytic activity has been confirmed to decrease Abeta generation and amyloid deposition, and thus specific inhibition of BACE1 by small molecules is a current focus for Alzheimer 's disease therapy.	2	11	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	10	11
Thus , partial suppression of BACE1 attenuates Abeta generation and AD related pathology , suggesting that partial inhibition of BACE1 could be an ideal target for AD treatment .	Thus, partial suppression of BACE1 attenuates Abeta generation and AD related pathology, suggesting that partial inhibition of BACE1 could be an ideal target for AD treatment.	3	8	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	5	6	7	8
Since BACE1 initiates Abeta generation it represents a valuable target to interfere with Abeta production and treatment of AD .	Since BACE1 initiates Abeta generation it represents a valuable target to interfere with Abeta production and treatment of AD.	1	4	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	1	2	3	4
In addition , up-regulation of BACE1 expression has been shown to increase Abeta production ( Sun et al ., 2006 ) , and regulation of BACE1 activity can affect Abeta generation ( Gravenfors et al ., 2012 ; Obregon et al ., 2012 ; Zhu et al ., 2012 ; Yun et al ., 2013 ) .	In addition, up-regulation of BACE1 expression has been shown to increase Abeta production (Sun et al., 2006), and regulation of BACE1 activity can affect Abeta generation (Gravenfors et al., 2012; Obregon et al., 2012; Zhu et al., 2012; Yun et al., 2013).	5	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 expression	bace1	Abeta	Abeta	abeta	5	6	12	13
A more safe and effective therapeutic strategy for AD would be to specifically block BACE1 induced APP cleavage without interfering with BACE1 activity toward other substrates .	A more safe and effective therapeutic strategy for AD would be to specifically block BACE1 induced APP cleavage without interfering with BACE1 activity toward other substrates.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	14	15	16	17
The Ala673Thr mutation and BACE1 gene knockout reduce Abeta generation , strongly suggesting that BACE1 inhibition should prove effective for Alzheimer ' s disease .	The Ala673Thr mutation and BACE1 gene knockout reduce Abeta generation, strongly suggesting that BACE1 inhibition should prove effective for Alzheimer 's disease.	4	9	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	8	9
BACE1 promotes amyloidogenic processing of APP ; when Hebert et al ..	BACE1 promotes amyloidogenic processing of APP; when Hebert et al..	0	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	5	6
Notably , mOS conditions resulted in increased levels of the BACE1 C-terminal cleavage product of APP , beta-CTF .	Notably, mOS conditions resulted in increased levels of the BACE1 C-terminal cleavage product of APP, beta-CTF.	10	17	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	10	11	15	16
Moreover , blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Abeta production , indicating the requirement of BACE internalization for the enhanced activity .	Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Abeta production, indicating the requirement of BACE internalization for the enhanced activity.	4	22	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	4	5	21	22
Abeta is a 39-43 amino acid ( 4kDa ) peptide produced via sequential proteolysis of amyloid precursor protein ( APP ) by beta-secretase and BACE followed by gamma-secretase ( composed of presenilins [ PS ] 1 and 2 ) , to produce Abeta peptides primarily 40 and 42 amino acids in length .	Abeta is a 39-43 amino acid (4kDa) peptide produced via sequential proteolysis of amyloid precursor protein (APP) by beta-secretase and BACE followed by gamma-secretase (composed of presenilins [PS] 1 and 2), to produce Abeta peptides primarily 40 and 42 amino acids in length.	10	25	produced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	24	25	15	18
In this sense , presynaptic dystrophies are sites of APP accumulation and putative Abeta release ( Sanchez-Varo et al ., 2012 ; Torres et al ., 2012 ) and , as recent studies indicate , the accumulation of BACE1 in presynaptic dystrophies surrounding plaques causes increased cleavage of APP and Abeta generation , which could lead to an exacerbation of amyloid pathology in AD ( Sadleir et al ., 2016 ; Torres et al ., 2012 ) .	In this sense, presynaptic dystrophies are sites of APP accumulation and putative Abeta release (Sanchez-Varo et al., 2012; Torres et al., 2012) and, as recent studies indicate, the accumulation of BACE1 in presynaptic dystrophies surrounding plaques causes increased cleavage of APP and Abeta generation, which could lead to an exacerbation of amyloid pathology in AD (Sadleir et al., 2016; Torres et al., 2012).	36	51	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	38	39	50	51
Recently , it has been reported that a small GTPase ADP ribosylation factor 6 ( ARF6 ) is important for regulating the internalization of BACE1 into early endosomes to promote BACE1 mediated APP cleavage .	Recently, it has been reported that a small GTPase ADP ribosylation factor 6 (ARF6) is important for regulating the internalization of BACE1 into early endosomes to promote BACE1 mediated APP cleavage.	29	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	30	31	32	33
Beta-site amyloid precursor protein ( APP ) cleaving enzyme 1 [ beta-secretase 1 ( BACE1 ) ] , a transmembrane aspartyl protease , initiates the processing of the APP during Abeta generation and therefore is the rate limiting enzyme in the amyloidogenic pathway.16 As APP and BACE1 are highly expressed in neurons , it is reasonable to assume there should be a mechanism that segregates the transport of APP and BACE1 to prevent overproduction of Abeta .	Beta-site amyloid precursor protein (APP) cleaving enzyme 1 [beta-secretase 1 (BACE1)], a transmembrane aspartyl protease, initiates the processing of the APP during Abeta generation and therefore is the rate limiting enzyme in the amyloidogenic pathway.16 As APP and BACE1 are highly expressed in neurons, it is reasonable to assume there should be a mechanism that segregates the transport of APP and BACE1 to prevent overproduction of Abeta.	11	29	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-secretase 1	beta-secretase 1	beta-secretase 1	APP	APP	APP	11	13	28	29
Nevertheless , specifically for AD , our results strongly suggest that energy deprivation and the eIF2alpha phosphorylation pathway play major roles in the BACE1 increase observed in AD , and that this BACE1 elevation promotes Abeta production and amyloidogenesis .	Nevertheless, specifically for AD, our results strongly suggest that energy deprivation and the eIF2alpha phosphorylation pathway play major roles in the BACE1 increase observed in AD, and that this BACE1 elevation promotes Abeta production and amyloidogenesis.	32	36	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	32	33	35	36
This suggests that inhibition of BACE1 could prevent or reduce the accumulation of Abeta in the brain , reducing AD related pathology and possibly functional impairments .	This suggests that inhibition of BACE1 could prevent or reduce the accumulation of Abeta in the brain, reducing AD related pathology and possibly functional impairments.	3	14	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	5	6	13	14
In summary , 50 % BACE1 reduction in 5XFAD mice decreases cerebral Abeta42 , plaque load , and BACE1 cleaved fragments of APP in females but not males .	In summary, 50% BACE1 reduction in 5XFAD mice decreases cerebral Abeta42, plaque load, and BACE1 cleaved fragments of APP in females but not males.	5	23	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	22	23
The thalidomide induced Abeta load reduction was caused by inhibition of BACE1 .	The thalidomide induced Abeta load reduction was caused by inhibition of BACE1.	3	12	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	3	4
beta-Site APP cleaving enzyme 1 ( BACE1 ) cleavage of amyloid precursor protein ( APP ) initiates Abeta production .	beta-Site APP cleaving enzyme 1 (BACE1) cleavage of amyloid precursor protein (APP) initiates Abeta production.	0	18	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Site APP cleaving enzyme 1	beta-Site APP cleaving enzyme 1	beta-Site APP cleaving enzyme 1	Abeta	Abeta	Abeta	0	5	17	18
Second , the blockade of BACE1 not only impairs Abeta production but also theoretically prevents all betaAPP related catabolites , some of which appear very toxic , even in absence of Abeta XREF_BIBR XREF_BIBR XREF_BIBR .	Second, the blockade of BACE1 not only impairs Abeta production but also theoretically prevents all betaAPP related catabolites, some of which appear very toxic, even in absence of Abeta XREF_BIBR XREF_BIBR XREF_BIBR.	3	10	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	5	6	9	10
Angiotensin-II induced hypertension in Tg2576 mice , an AD model in which both circulating and cerebral Abeta is elevated due to a mutation in APP , has resulted in increased microvascular amyloid deposition and enhanced BACE-1 mediated-amyloidogenic APP cleavage 12 .	Angiotensin-II induced hypertension in Tg2576 mice, an AD model in which both circulating and cerebral Abeta is elevated due to a mutation in APP, has resulted in increased microvascular amyloid deposition and enhanced BACE-1 mediated-amyloidogenic APP cleavage 12.	34	38	mediated-amyloidogenic	Positive_early_activation	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	APP	APP	APP	35	36	37	38
Studies demonstrate that IL-18 triggers an elevation in the protein levels of APP , BACE1 , and the N-terminal fragment of presenilin-1 and presenilin enhancer 2 which are components of the gamma and secretase complex , suggesting IL-18 accelerates Abeta genesis .	Studies demonstrate that IL-18 triggers an elevation in the protein levels of APP, BACE1, and the N-terminal fragment of presenilin-1 and presenilin enhancer 2 which are components of the gamma and secretase complex, suggesting IL-18 accelerates Abeta genesis.	3	40	accelerates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BACE1	IL-18 triggers an elevation in the protein levels of APP, BACE1	bace1	Abeta	Abeta	abeta	14	15	39	40
An obvious consequence of an upregulation of BACE1 is increased APP processing .	An obvious consequence of an upregulation of BACE1 is increased APP processing.	5	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	7	8	10	11
The enzyme BACE1 ( beta-site APP cleaving enzyme 1 ) plays a crucial role in the generation of Abeta and has therefore been pursued as a small molecular drug target to modulate Abeta production .	The enzyme BACE1 (beta-site APP cleaving enzyme 1) plays a crucial role in the generation of Abeta and has therefore been pursued as a small molecular drug target to modulate Abeta production.	0	33	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	32	33
The sAPP-beta processing was specific and selective after 2.5 hours at 37degreesC , and was possibly mediated by exogenous BACE1 , because it was blocked by a BACE1 inhibitor and BACE1 enzyme levels were enhanced in AD patients .	The sAPP-beta processing was specific and selective after 2.5 hours at 37degreesC, and was possibly mediated by exogenous BACE1, because it was blocked by a BACE1 inhibitor and BACE1 enzyme levels were enhanced in AD patients.	1	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	sAPP-beta	sAPP-beta	sAPP-beta	19	20	1	2
Not only the fact that BACE1 initiates Abeta production in the amyloid cascade but also recent findings that BACE1 expression and activities are elevated in sporadic AD brains favor the notion that this enzyme represents one of the prime therapeutic targets .	Not only the fact that BACE1 initiates Abeta production in the amyloid cascade but also recent findings that BACE1 expression and activities are elevated in sporadic AD brains favor the notion that this enzyme represents one of the prime therapeutic targets.	5	8	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	5	6	7	8
This inhibitor prevents BACE mediated cleavage of APP and generation of Abeta [ XREF_BIBR ] .	This inhibitor prevents BACE mediated cleavage of APP and generation of Abeta [XREF_BIBR].	2	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	APP	APP	APP	3	4	7	8
We observed that the APP processing mediated by BACE1 was inhibited by Tyro3 overexpression in vitro , and the number of senile plaques resulting from Abeta deposition was increased by Tyro3 gene knockdown in an AD mouse model .	We observed that the APP processing mediated by BACE1 was inhibited by Tyro3 overexpression in vitro, and the number of senile plaques resulting from Abeta deposition was increased by Tyro3 gene knockdown in an AD mouse model.	4	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	8	9	4	5
Increased BACE1 mediated cleavage of APP and BACE1 activity in VPS35 mutant mice .	Increased BACE1 mediated cleavage of APP and BACE1 activity in VPS35 mutant mice.	0	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	1	2	5	6
Overexpression or downregulation of BACE1 induces or inhibits APP processing and Abeta generation both in vitro and in vivo [ XREF_BIBR - XREF_BIBR ] .	Overexpression or downregulation of BACE1 induces or inhibits APP processing and Abeta generation both in vitro and in vivo [XREF_BIBR - XREF_BIBR].	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	Overexpression or downregulation of BACE1	bace1	APP	APP	app	4	5	8	9
The amyloidogenic pathway triggered from two sequential cleavages of APP by BACE1 resulted in the formation of Abeta peptides [ XREF_BIBR ] .	The amyloidogenic pathway triggered from two sequential cleavages of APP by BACE1 resulted in the formation of Abeta peptides [XREF_BIBR].	3	12	triggered	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	11	12	9	10
Together , these findings indicate that TNFR1 indeed regulates the BACE1 mRNA level , and that Abeta reduction in APP23 mice after genetic deletion of TNFR1 is caused by decreased BACE1 levels .	Together, these findings indicate that TNFR1 indeed regulates the BACE1 mRNA level, and that Abeta reduction in APP23 mice after genetic deletion of TNFR1 is caused by decreased BACE1 levels.	16	32	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1 levels	bace1	Abeta	Abeta	abeta	30	31	16	17
Our findings suggest novel therapeutic implications of modulating SNX4 to regulate BACE1 mediated beta processing of APP and subsequent Abeta generation .	Our findings suggest novel therapeutic implications of modulating SNX4 to regulate BACE1 mediated beta processing of APP and subsequent Abeta generation.	10	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	19	20
Because BACE1 initiates Abeta generation , it represents a potential target molecule to interfere with Abeta production in therapeutic strategies for AD .	Because BACE1 initiates Abeta generation, it represents a potential target molecule to interfere with Abeta production in therapeutic strategies for AD.	1	4	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	1	2	3	4
Abeta is produced by sequential cleavage of the amyloid precursor protein ( APP ) , by the beta-secretase beta-site APP cleaving enzyme 1 ( BACE1 ) and gamma-secretase .	Abeta is produced by sequential cleavage of the amyloid precursor protein (APP), by the beta-secretase beta-site APP cleaving enzyme 1 (BACE1) and gamma-secretase.	0	23	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	Abeta	Abeta	Abeta	18	23	0	1
We show that overexpression of BACE induces an increase in APP CTFbeta and total brain Abeta peptides .	We show that overexpression of BACE induces an increase in APP CTFbeta and total brain Abeta peptides.	3	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	overexpression of BACE	bace	APP	APP	app	5	6	10	11
Not surprisingly , BACE1 mediated APP processing results in increased neuritic plaques .	Not surprisingly, BACE1 mediated APP processing results in increased neuritic plaques.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	5	6
Because we demonstrated that partial BACE reduction was sufficient to reduce soluble Abeta , we next sought to investigate if there was a concomitant decrease in wild-type tau pathology .	Because we demonstrated that partial BACE reduction was sufficient to reduce soluble Abeta, we next sought to investigate if there was a concomitant decrease in wild-type tau pathology.	5	13	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	5	6	12	13
As we have previously shown that sequestration of APP and BACE1 within the endolysosomal system may likely cause increased intracellular Abeta generation in CHO NPC1-null cells we further analyzed intracellular and secreted Abeta levels upon PADK-treatment of CHOwt cells .	As we have previously shown that sequestration of APP and BACE1 within the endolysosomal system may likely cause increased intracellular Abeta generation in CHO NPC1-null cells we further analyzed intracellular and secreted Abeta levels upon PADK-treatment of CHOwt cells.	6	21	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	10	11	20	21
Our observations of BACE1 accumulation around plaques led us to the hypothesis that elevated levels of BACE1 , APP [ XREF_BIBR , XREF_BIBR ] , and PS1 [ XREF_BIBR ] found in peri-plaque dystrophic neurites would cause increased BACE1 processing of APP and Abeta production , thus exacerbating AD pathogenesis .	Our observations of BACE1 accumulation around plaques led us to the hypothesis that elevated levels of BACE1, APP [XREF_BIBR, XREF_BIBR], and PS1 [XREF_BIBR] found in peri-plaque dystrophic neurites would cause increased BACE1 processing of APP and Abeta production, thus exacerbating AD pathogenesis.	16	44	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	16	17	43	44
Therefore , these data indicate that BACE1 reduction by 50 % is sufficient to suppress de novo Abeta production in both male and female 5XFAD transgenic mice and consequently lower cerebral Abeta , as measured by soluble oligomeric species as well as by guanidine extracted total amounts of Abeta42 or amyloid plaque load .	Therefore, these data indicate that BACE1 reduction by 50% is sufficient to suppress de novo Abeta production in both male and female 5XFAD transgenic mice and consequently lower cerebral Abeta, as measured by soluble oligomeric species as well as by guanidine extracted total amounts of Abeta42 or amyloid plaque load.	6	32	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	6	7	31	32
Novel heparan based drugs could even prevent Alzheimer ' s in two ways -- they might be designed both to inhibit BACE1 production of Abeta and to interfere with HS promotion of Abeta aggregation .	Novel heparan based drugs could even prevent Alzheimer 's in two ways -- they might be designed both to inhibit BACE1 production of Abeta and to interfere with HS promotion of Abeta aggregation.	21	25	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	21	22	24	25
Loss of BACE1 in transgenic mice models of AD prevents Abeta production and APP induced phenotypes .	Loss of BACE1 in transgenic mice models of AD prevents Abeta production and APP induced phenotypes.	0	15	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	Loss of BACE1	bace1	APP	APP	app	2	3	13	14
In vitro study indicated that overload of cholesterol at plasma membrane in primary cultured neurons leads to an increase of Abeta production through increasing BACE1 mediated APP cleavage .	In vitro study indicated that overload of cholesterol at plasma membrane in primary cultured neurons leads to an increase of Abeta production through increasing BACE1 mediated APP cleavage.	15	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	24	25	26	27
Therefore , overexpression of DSCR1 , a calcineurin inhibitor , might reduce BACE1 expression in neurons and thereby decrease Abeta generation , suggesting a negative role of calcineurin dependent BACE1 on the proteolytic cleavage of APP in Drosophila .	Therefore, overexpression of DSCR1, a calcineurin inhibitor, might reduce BACE1 expression in neurons and thereby decrease Abeta generation, suggesting a negative role of calcineurin dependent BACE1 on the proteolytic cleavage of APP in Drosophila.	2	20	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	overexpression of DSCR1, a calcineurin inhibitor, might reduce BACE1 expression	bace1	Abeta	Abeta	abeta	12	13	19	20
Moreover , the resulting rise in BACE1 level should cause an increase in neuronal Abeta generation as well .	Moreover, the resulting rise in BACE1 level should cause an increase in neuronal Abeta generation as well.	6	15	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 level	bace1	Abeta	Abeta	abeta	6	7	14	15
Abeta is generated by the two-step proteolytic cleavage of amyloid precursor protein ( APP ) , which is catalyzed by the beta-site APP cleaving enzyme-1 ( BACE1 , also designated as beta-secretase ) and gamma-secretase .	Abeta is generated by the two-step proteolytic cleavage of amyloid precursor protein (APP), which is catalyzed by the beta-site APP cleaving enzyme-1 (BACE1, also designated as beta-secretase) and gamma-secretase.	9	25	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-site APP cleaving enzyme-1	beta-site APP cleaving enzyme-1	beta-site APP cleaving enzyme-1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	21	25	9	12
Our findings reveal that SNX4 is an important factor in regulating BACE1 trafficking and dysregulation in SNX4 function may increase Abeta production .	Our findings reveal that SNX4 is an important factor in regulating BACE1 trafficking and dysregulation in SNX4 function may increase Abeta production.	11	21	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	20	21
To determine whether the BACE1 variants would modulate Abeta generation , CHO cells stably expressing both APP and wtBACE1 or the phosphomutants were generated .	To determine whether the BACE1 variants would modulate Abeta generation, CHO cells stably expressing both APP and wtBACE1 or the phosphomutants were generated.	4	9	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	8	9
First , caffeine reduced levels of the precursor protein of Abeta , AbetaPP , and of the enzyme BACE1 that initiates the cleavage of AbetaPP to Abeta .	First, caffeine reduced levels of the precursor protein of Abeta, AbetaPP, and of the enzyme BACE1 that initiates the cleavage of AbetaPP to Abeta.	2	27	initiates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BACE1	caffeine reduced levels of the precursor protein of Abeta, AbetaPP, and of the enzyme BACE1	bace1	Abeta	Abeta	abeta	18	19	26	27
Previous reports indicate that association of BACE1 with lipid rafts promotes Abeta production , supporting the importance of this process in Abeta generation .	Previous reports indicate that association of BACE1 with lipid rafts promotes Abeta production, supporting the importance of this process in Abeta generation.	4	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	6	7	11	12
48 In the AD brain , Abeta triggers upregulation of BACE1 expression which promotes Abeta generation , creating a vicious cycle and resulting in Abeta overproduction .	48 In the AD brain, Abeta triggers upregulation of BACE1 expression which promotes Abeta generation, creating a vicious cycle and resulting in Abeta overproduction.	6	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	Abeta triggers upregulation of BACE1 expression	bace1	Abeta	Abeta	abeta	10	11	14	15
However , it is possible that APP processing by alpha-secretase is increased in parallel with that by BACE1 , which might be part of a protective response in the brain , as sAPPalpha has neuroprotective and neurotrophic activities [ XREF_BIBR , XREF_BIBR ] .	However, it is possible that APP processing by alpha-secretase is increased in parallel with that by BACE1, which might be part of a protective response in the brain, as sAPPalpha has neuroprotective and neurotrophic activities [XREF_BIBR, XREF_BIBR].	6	22	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	17	18	6	7
The specificity of the hAPPsw phenotype implies that a BACE1 cleavage product of APP mediates axon dysfunction of OSNs .	The specificity of the hAPPsw phenotype implies that a BACE1 cleavage product of APP mediates axon dysfunction of OSNs.	9	14	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	9	10	13	14
Since Abeta processing is mainly mediated by BACE1 and gamma-secretase , deletion of the upstream delta-secretase predominantly impairs APP cleavage efficiency by BACE1 .	Since Abeta processing is mainly mediated by BACE1 and gamma-secretase, deletion of the upstream delta-secretase predominantly impairs APP cleavage efficiency by BACE1.	1	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	7	8	1	2
Specifically , an active role for BACE1 mediated Abeta overproduction in vascular endothelial cells has been proposed for angiopathic amyloidosis [ XREF_BIBR - XREF_BIBR ] .	Specifically, an active role for BACE1 mediated Abeta overproduction in vascular endothelial cells has been proposed for angiopathic amyloidosis [XREF_BIBR - XREF_BIBR].	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	6	7	8	9
According to this , higher levels of BACE1 activity may modulate the production of key players of AD and prion pathologies by increasing the production of both Abeta and PrP via AICD signalling XREF_BIBR ; although this model has been recently questioned XREF_BIBR .	According to this, higher levels of BACE1 activity may modulate the production of key players of AD and prion pathologies by increasing the production of both Abeta and PrP via AICD signalling XREF_BIBR; although this model has been recently questioned XREF_BIBR.	7	29	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	7	8	27	28
It was shown that the deletion of BACE-1 in transgenic mice overexpressing APPswe abolishes Abeta generation in the brain [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] and rescues behavioral and electrophysiological deficits [ XREF_BIBR , XREF_BIBR ] .	It was shown that the deletion of BACE-1 in transgenic mice overexpressing APPswe abolishes Abeta generation in the brain [XREF_BIBR, XREF_BIBR - XREF_BIBR] and rescues behavioral and electrophysiological deficits [XREF_BIBR, XREF_BIBR].	5	15	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	7	8	14	15
The more specific BACE1 inhibitor IV completely abolished the detection of BACE1 mediated soluble APP ( sAPPbeta ) secretion while the gamma-secretase inhibitor L-685 ,458 had no effect on either sAPP form .	The more specific BACE1 inhibitor IV completely abolished the detection of BACE1 mediated soluble APP (sAPPbeta) secretion while the gamma-secretase inhibitor L-685,458 had no effect on either sAPP form.	9	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	sAPPbeta	sAPPbeta	sAPPbeta	11	12	16	17
High glucose upregulates BACE1 mediated Abeta production through ROS dependent HIF-1alpha and LXRalpha and ABCA1 regulated lipid raft reorganization in SK-N-MC cells .	High glucose upregulates BACE1 mediated Abeta production through ROS dependent HIF-1alpha and LXRalpha and ABCA1 regulated lipid raft reorganization in SK-N-MC cells.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	3	4	5	6
3.5 APP-CTFs , but not Abeta are reduced by BACE1 dosage reduction in Ts2 mice .	3.5 APP-CTFs, but not Abeta are reduced by BACE1 dosage reduction in Ts2 mice.	1	11	reduced	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	9	10	5	6
Accordingly , neuronal depolarization and vesicle turnover have been shown to increase BACE1 mediated APP cleavage and Abeta production .	Accordingly, neuronal depolarization and vesicle turnover have been shown to increase BACE1 mediated APP cleavage and Abeta production.	11	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	12	13	14	15
sAPPbeta , the primary cleavage product of BACE1 , was determined in H4 human neuroglioma cells overexpressing the wild-type human APP 695 .	sAPPbeta, the primary cleavage product of BACE1, was determined in H4 human neuroglioma cells overexpressing the wild-type human APP 695.	5	21	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	7	8	20	21
These results suggest that BACE1 elevation in the endothelia and perivascular neurites may be involved in angiopathic Abeta deposition , while BACE1 elevation in meningeal cells might contribute Abeta to leptomeningeal amyloidosis .	These results suggest that BACE1 elevation in the endothelia and perivascular neurites may be involved in angiopathic Abeta deposition, while BACE1 elevation in meningeal cells might contribute Abeta to leptomeningeal amyloidosis.	21	29	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	21	22	28	29
The inhibition of BACE-1 can prevent the cleavage of APP to Abeta and the formation of amyloid plaques [ XREF_BIBR ] .	The inhibition of BACE-1 can prevent the cleavage of APP to Abeta and the formation of amyloid plaques [XREF_BIBR].	1	10	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	APP	APP	APP	3	4	9	10
XREF_BIBR , XREF_BIBR In summary , cell stress increases BACE1-AS levels , which in turn stimulates BACE1 expression , which could enhance APP processing and Abeta1-42 production .	XREF_BIBR, XREF_BIBR In summary, cell stress increases BACE1-AS levels, which in turn stimulates BACE1 expression, which could enhance APP processing and Abeta1-42 production.	9	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1-AS levels, which in turn stimulates BACE1 expression	bace1	APP	APP	app	16	17	22	23
Together , our data indicate that metformin treatment can decrease BACE1 protein expression and activity , thereby reducing BACE1 cleavage products and Abeta production .	Together, our data indicate that metformin treatment can decrease BACE1 protein expression and activity, thereby reducing BACE1 cleavage products and Abeta production.	6	23	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	metformin treatment can decrease BACE1 protein expression	bace1	Abeta	Abeta	abeta	10	11	22	23
We found that the deletion of a single copy of BACE1 in the CK-p25 and BACE1 +/- compound mice reduced Abeta to baseline levels , and rescued synapse density , synaptic plasticity , and memory impairments in the CK-p25 mice , but not neuronal loss .	We found that the deletion of a single copy of BACE1 in the CK-p25 and BACE1 +/- compound mice reduced Abeta to baseline levels, and rescued synapse density, synaptic plasticity, and memory impairments in the CK-p25 mice, but not neuronal loss.	8	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	10	11	20	21
These data further indicate that increased Abeta , which produced by BACE1 , causes the significant elevation of mtDNA mutation , and this mtDNA mutation may be responsible for both age related dementia and the associated neuropathological changes observed in AD and DSAD .	These data further indicate that increased Abeta, which produced by BACE1, causes the significant elevation of mtDNA mutation, and this mtDNA mutation may be responsible for both age related dementia and the associated neuropathological changes observed in AD and DSAD.	5	12	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	6	7
The resulting ceramide induced enhanced Abeta biogenesis is caused by a post-translational stabilization of the beta-secretase BACE1 due to elevated acetylation of the protein .	The resulting ceramide induced enhanced Abeta biogenesis is caused by a post-translational stabilization of the beta-secretase BACE1 due to elevated acetylation of the protein.	5	17	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	16	17	5	6
To validate the efficacy of BACE1 inhibition , Abeta42 ( a BACE cleavage product of APP ) was measured in the SK-N-BE ( 2 ) neuroblastoma cell model , and sFlag-V5-hSEZ6 and endogenous sSEZ6L in MIN6 cells .	To validate the efficacy of BACE1 inhibition, Abeta42 (a BACE cleavage product of APP) was measured in the SK-N-BE (2) neuroblastoma cell model, and sFlag-V5-hSEZ6 and endogenous sSEZ6L in MIN6 cells.	11	16	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE	BACE	BACE	APP	APP	APP	11	12	15	16
RNAi suppression of sortilin results in decreased BACE1 mediated cleavage of APP .	RNAi suppression of sortilin results in decreased BACE1 mediated cleavage of APP.	4	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	7	8	11	12
Collectively , these findings suggest a potential pathway of isoflurane neurotoxicity ; that isoflurane induces caspase activation and apoptosis , which increases the levels of BACE and gamma-secretase , promoting APP process and Abeta generation .	Collectively, these findings suggest a potential pathway of isoflurane neurotoxicity; that isoflurane induces caspase activation and apoptosis, which increases the levels of BACE and gamma-secretase, promoting APP process and Abeta generation.	13	34	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	isoflurane induces caspase activation and apoptosis, which increases the levels of BACE	bace	Abeta	Abeta	abeta	25	26	33	34
Reduction of BACE1 activity in deltaE9 mice reduced the deposition of Abeta and restored the increase of spine density during EE , but not the impaired reorganization of neural networks .	Reduction of BACE1 activity in deltaE9 mice reduced the deposition of Abeta and restored the increase of spine density during EE, but not the impaired reorganization of neural networks.	2	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	11	12
We have specifically determined levels of Abeta and beta-site of APP cleaving enzyme ( BACE-1 ) , which initiates Abeta production , caspase 12 and gadd153 as markers of ER stress , mitochondrial membrane potential as a marker of mitochondrial stress , the nuclear factor kappaB ( NFkappaB ) and heme-oxygenase 1 ( HO-1 ) two proteins activated by oxidative stress , ROS generation and glutathione depletion and TNF-alpha as marker of inflammation .	We have specifically determined levels of Abeta and beta-site of APP cleaving enzyme (BACE-1), which initiates Abeta production, caspase 12 and gadd153 as markers of ER stress, mitochondrial membrane potential as a marker of mitochondrial stress, the nuclear factor kappaB (NFkappaB) and heme-oxygenase 1 (HO-1) two proteins activated by oxidative stress, ROS generation and glutathione depletion and TNF-alpha as marker of inflammation.	12	20	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	14	15	19	20
Studies from our laboratory and others applied genetic or immunization based approaches to demonstrate that partial reduction of BACE1 suffices to attenuate Abeta related pathology and rescue synaptic and memory deficits in mouse models of AD XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Studies from our laboratory and others applied genetic or immunization based approaches to demonstrate that partial reduction of BACE1 suffices to attenuate Abeta related pathology and rescue synaptic and memory deficits in mouse models of AD XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	16	24	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	18	19	22	23
Our results suggest that greater than 50 % BACE1 inhibition might be necessary to significantly lower Abeta , given that BACE1 is likely to be in excess over APP in the human brain .	Our results suggest that greater than 50% BACE1 inhibition might be necessary to significantly lower Abeta, given that BACE1 is likely to be in excess over APP in the human brain.	8	18	necessary	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	8	9	16	17
Our data suggest that , by generating AICD , gamma-secretase induces transcription of the BACE1 gene resulting in increased production of BACE1 , increased beta-secretase cleavage of APP and increased production of Abeta .	Our data suggest that, by generating AICD, gamma-secretase induces transcription of the BACE1 gene resulting in increased production of BACE1, increased beta-secretase cleavage of APP and increased production of Abeta.	9	33	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	gamma-secretase induces transcription of the BACE1	bace1	Abeta	Abeta	abeta	14	15	32	33
A major rate limiting step for Abeta generation and deposition in Alzheimer ' s disease brains is BACE1 mediated cleavage ( beta-cleavage ) of the amyloid precursor protein ( APP ) .	A major rate limiting step for Abeta generation and deposition in Alzheimer 's disease brains is BACE1 mediated cleavage (beta-cleavage) of the amyloid precursor protein (APP).	3	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	17	18	25	28
Abeta production is initiated by the processing of APP by the beta-amyloid cleavage enzyme 1 ( BACE1 ) which generated a C-terminal fragment of APP , labelled as C99 .	Abeta production is initiated by the processing of APP by the beta-amyloid cleavage enzyme 1 (BACE1) which generated a C-terminal fragment of APP, labelled as C99.	0	19	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	16	17	0	1
The beta-secretase ( BACE1 ) initiates processing of the amyloid precursor protein ( APP ) into Abeta peptides , which have been implicated as central players in the pathology of Alzheimer disease .	The beta-secretase (BACE1) initiates processing of the amyloid precursor protein (APP) into Abeta peptides, which have been implicated as central players in the pathology of Alzheimer disease.	1	12	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	3	4	9	12
sAPPalpha and sAPPbeta fragments were also elevated with SAM activation , and combined activation of APP and BACE1 significantly increased the sAPPbeta and sAPPalpha ratio ( XREF_SUPPLEMENTARY ) and betaCTF ( XREF_SUPPLEMENTARY ) , consistent with a relative increase of the amyloidogenic pathway ( XREF_FIG ) .	sAPPalpha and sAPPbeta fragments were also elevated with SAM activation, and combined activation of APP and BACE1 significantly increased the sAPPbeta and sAPPalpha ratio (XREF_SUPPLEMENTARY) and betaCTF (XREF_SUPPLEMENTARY), consistent with a relative increase of the amyloidogenic pathway (XREF_FIG).	13	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	sAPPbeta	sAPPbeta	sAPPbeta	17	18	21	22
BACE1 mediated APP cleavage constitutes the rate limiting step in Abeta generation [ XREF_BIBR ] .	BACE1 mediated APP cleavage constitutes the rate limiting step in Abeta generation [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	2	3
As BACE1 initiates Abeta generation , more efforts have been made to develop BACE1 inhibitors for clinical use in AD .	As BACE1 initiates Abeta generation, more efforts have been made to develop BACE1 inhibitors for clinical use in AD.	1	4	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	1	2	3	4
In fact , elevated BACE1 expression has been reported to increase APP beta-cleavage and cause neurodegeneration even though Abeta levels are lowered .	In fact, elevated BACE1 expression has been reported to increase APP beta-cleavage and cause neurodegeneration even though Abeta levels are lowered.	4	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 expression	bace1	APP	APP	app	4	5	11	12
To test whether transport of APP to endosomes is required for BACE1 catalyzed APP cleavage , we generated an APP-F615P and D664A construct with additional mutations in all three tyrosine residues ( Y653 , Y682 , and Y687 ) in the cytosolic tail ( APP-3Y-F615P and D664A ) .	To test whether transport of APP to endosomes is required for BACE1 catalyzed APP cleavage, we generated an APP-F615P and D664A construct with additional mutations in all three tyrosine residues (Y653, Y682, and Y687) in the cytosolic tail (APP-3Y-F615P and D664A).	9	14	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	11	12	13	14
To demonstrate the mechanism through which HFD promotes BACE1 mediated APP cleavage , we set out to identify the proteins that associate with BACE1 in mice fed with HFD .	To demonstrate the mechanism through which HFD promotes BACE1 mediated APP cleavage, we set out to identify the proteins that associate with BACE1 in mice fed with HFD.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	8	9	10	11
Thus , elevated BACE 1 levels could enhance amyloidogenic processing of APP causing increased production of Abeta peptides .	Thus, elevated BACE 1 levels could enhance amyloidogenic processing of APP causing increased production of Abeta peptides.	2	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	APP	APP	APP	3	4	11	12
Se-Met Decreased the Production and Deposition of Abeta by Inhibiting Level of APP and BACE1 Mediated APP Processing .	Se-Met Decreased the Production and Deposition of Abeta by Inhibiting Level of APP and BACE1 Mediated APP Processing.	10	17	Mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	14	15	16	17
Knockout of BACE1 , but not BACE2 , completely blocks the generation of Abeta .	Knockout of BACE1, but not BACE2, completely blocks the generation of Abeta.	0	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	13	14
Furthermore , elevated Snapin expression in hAPP mutant neurons reverses the defects in BACE1 retrograde transport and lysosomal degradation , thus reducing APP amyloidogenic processing ( XREF_FIG , XREF_FIG , XREF_SUPPLEMENTARY ) .	Furthermore, elevated Snapin expression in hAPP mutant neurons reverses the defects in BACE1 retrograde transport and lysosomal degradation, thus reducing APP amyloidogenic processing (XREF_FIG, XREF_FIG, XREF_SUPPLEMENTARY).	13	24	reducing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	13	14	22	23
Given that elevated BACE1 did not increase APP processing in GGA3KO ; 5XFAD mice at 4months of age , we next investigated the effect of GGA3 deletion and consequent BACE1 elevation on the processing of endogenous CHL1 .	Given that elevated BACE1 did not increase APP processing in GGA3KO; 5XFAD mice at 4months of age, we next investigated the effect of GGA3 deletion and consequent BACE1 elevation on the processing of endogenous CHL1.	2	8	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	7	8
BACE-1 processing of APP is essential to initiate Abeta generation , which is then promoted by the gamma-secretase .	BACE-1 processing of APP is essential to initiate Abeta generation, which is then promoted by the gamma-secretase.	0	9	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	0	1	8	9
Abeta is produced by the processing of the amyloid precursor protein ( APP ) by BACE1 ( beta-secretase ) and gamma-secretase .	Abeta is produced by the processing of the amyloid precursor protein (APP) by BACE1 (beta-secretase) and gamma-secretase.	0	20	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	15	16	0	1
Most importantly , BACE1 is the initiating and putatively rate limiting enzyme in Abeta generation and BACE1 inhibition would block the production of Abeta and prevent the development of Abeta associated pathologies .	Most importantly, BACE1 is the initiating and putatively rate limiting enzyme in Abeta generation and BACE1 inhibition would block the production of Abeta and prevent the development of Abeta associated pathologies.	16	24	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	16	17	23	24
BACE1 , a 501 amino acid type 1 TM aspartic protease related to the pepsin family , initiates Abeta generation and the resultant cerebral amyloidosis : deposition of Abeta ( for details , _ FIG ) .	BACE1, a 501 amino acid type 1 TM aspartic protease related to the pepsin family, initiates Abeta generation and the resultant cerebral amyloidosis : deposition of Abeta (for details, _ FIG).	0	19	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	18	19
BACE1 initiates the production of Abeta from amyloid precursor protein ( APP ) , and therefore blocking the activity of this enzyme is considered one of the most promising approaches for treating AD XREF_BIBR XREF_BIBR .	BACE1 initiates the production of Abeta from amyloid precursor protein (APP), and therefore blocking the activity of this enzyme is considered one of the most promising approaches for treating AD XREF_BIBR XREF_BIBR.	0	6	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	5	6
While these effects appear to be mediated through increasing Abeta clearance by upregulation of neprilysin ( NEP ) , an endopeptidase that degrades Abeta , MAGL inhibition reduced Abeta and neurodegeneration in AD animals are likely associated with reducing Abeta formation by suppression of beta-site amyloid precursor protein cleaving enzyme 1 ( BACE1 ) , a key enzyme that synthesizes Abeta .	While these effects appear to be mediated through increasing Abeta clearance by upregulation of neprilysin (NEP), an endopeptidase that degrades Abeta, MAGL inhibition reduced Abeta and neurodegeneration in AD animals are likely associated with reducing Abeta formation by suppression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme that synthesizes Abeta.	36	61	synthesizes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	52	53	60	61
Therefore , increased levels of BACE 1 could lead to enhanced production of Abeta , its aggregation , and consequently the activation of signaling pathways associated with the neurodegenerative process .	Therefore, increased levels of BACE 1 could lead to enhanced production of Abeta, its aggregation, and consequently the activation of signaling pathways associated with the neurodegenerative process.	3	21	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	BACE	levels of BACE	bace	Abeta	Abeta	abeta	5	6	13	14
According to this scheme , BACE1 activation and accompanying increase in Abeta production play a key role in the amplification of cellular dysfunctions .	According to this scheme, BACE1 activation and accompanying increase in Abeta production play a key role in the amplification of cellular dysfunctions.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	5	6	11	12
XREF_BIBR , XREF_BIBR Both anesthetics XREF_BIBR and brain ischemia XREF_BIBR have been shown to induce caspase activation and apoptosis , which then enhance levels and activities of BACE to facilitate APP processing and to increase Abeta generation .	XREF_BIBR, XREF_BIBR Both anesthetics XREF_BIBR and brain ischemia XREF_BIBR have been shown to induce caspase activation and apoptosis, which then enhance levels and activities of BACE to facilitate APP processing and to increase Abeta generation.	23	36	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	levels and activities of BACE	bace	Abeta	Abeta	abeta	27	28	35	36
However , NF-kappaB activates the transcription of BACE1 promoter and enhances Abeta production under pathological context .	However, NF-kappaB activates the transcription of BACE1 promoter and enhances Abeta production under pathological context.	2	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	NF-kappaB activates the transcription of BACE1	bace1	Abeta	Abeta	abeta	7	8	11	12
BACE1 initiates processing of the amyloid precursor protein ( APP ) in the production of amyloid beta ( Abeta ) peptide .	BACE1 initiates processing of the amyloid precursor protein (APP) in the production of amyloid beta (Abeta) peptide.	0	8	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	0	1	5	8
The beta-site APP cleaving enzyme-1 ( BACE1 ) mediates the first cleavage of the beta-amyloid precursor protein ( APP ) to yield the amyloid beta-peptide ( Abeta ) , a key pathogenic agent in Alzheimer ' s disease ( AD ) .	The beta-site APP cleaving enzyme-1 (BACE1) mediates the first cleavage of the beta-amyloid precursor protein (APP) to yield the amyloid beta-peptide (Abeta), a key pathogenic agent in Alzheimer 's disease (AD).	1	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-site APP cleaving enzyme-1	beta-site APP cleaving enzyme-1	beta-site APP cleaving enzyme-1	beta-amyloid precursor protein	beta-amyloid precursor protein	beta-amyloid precursor protein	1	5	14	17
Indeed Western Blots confirmed the production of an Abeta fragment in these flies , though it was slightly larger than the Abeta produced by co-expression of human BACE .	Indeed Western Blots confirmed the production of an Abeta fragment in these flies, though it was slightly larger than the Abeta produced by co-expression of human BACE.	18	28	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE	co-expression of human BACE	bace	Abeta	Abeta	abeta	27	28	21	22
Elevated BACE1 levels in AD mouse models increase Abeta generation and deposition [ XREF_BIBR ] .	Elevated BACE1 levels in AD mouse models increase Abeta generation and deposition [XREF_BIBR].	1	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 levels	bace1	Abeta	Abeta	abeta	1	2	8	9
Putative BACE1 mediated beta-site APP cleavage activity is increased in transgenic brain extracts with age , which appears to correlate with elevated soluble Abeta levels .	Putative BACE1 mediated beta-site APP cleavage activity is increased in transgenic brain extracts with age, which appears to correlate with elevated soluble Abeta levels.	0	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	1	2	4	5
For example , controlled cortical impact leads to an upregulation of APP and BACE1 expression in wild-type rats and accelerates Abeta deposition in transgenic-AD mice .	For example, controlled cortical impact leads to an upregulation of APP and BACE1 expression in wild-type rats and accelerates Abeta deposition in transgenic-AD mice.	5	21	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	impact leads to an upregulation of APP and BACE1 expression	bace1	Abeta	Abeta	abeta	13	14	20	21
beta-secretase 1 ( BACE1 ) initiates the proteolysis of amyloid precursor protein ( APP ) to generate Abeta , aggregation of which has been considered to be the main histopathological feature of Alzheimer ' s Disease .	beta-secretase 1 (BACE1) initiates the proteolysis of amyloid precursor protein (APP) to generate Abeta, aggregation of which has been considered to be the main histopathological feature of Alzheimer 's Disease.	0	12	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	3	4	9	12
Increased BACE1 mediated APP cleavage also leads to increased release of AICD , which down-regulates low density lipoprotein related protein 1 ( LRP-1 ) transcription and decreases the amount of LRP1 receptor which is responsible for exogenous cholesterol capture at the plasma membrane [ XREF_BIBR ] .	Increased BACE1 mediated APP cleavage also leads to increased release of AICD, which down-regulates low density lipoprotein related protein 1 (LRP-1) transcription and decreases the amount of LRP1 receptor which is responsible for exogenous cholesterol capture at the plasma membrane [XREF_BIBR].	0	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	1	2	3	4
During our initial screening , this extract potently inhibited the BACE1 mediated cleavage of amyloid precursor protein ( APP ) at our screening concentration of 50 mug/mL .	During our initial screening, this extract potently inhibited the BACE1 mediated cleavage of amyloid precursor protein (APP) at our screening concentration of 50 mug/mL.	9	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	10	11	14	17
Here we show that BACE1 null mice engineered to overexpress human APP ( BACE1 (-/-) .	Here we show that BACE1 null mice engineered to overexpress human APP (BACE1 (-/-).	4	13	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	4	5	11	12
Transgenic mice expressing Abeta also have increased levels of somatodendritic tau , which can be reduced by inhibiting Abeta production through genetic reduction of BACE , the beta-secretase that initiates Abeta cleavage from APP [ XREF_BIBR ] .	Transgenic mice expressing Abeta also have increased levels of somatodendritic tau, which can be reduced by inhibiting Abeta production through genetic reduction of BACE, the beta-secretase that initiates Abeta cleavage from APP [XREF_BIBR].	22	31	initiates	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	24	25	30	31
Taken together , the data suggest exciting possibility that partial inhibition of BACE1 may effectively reduce Abeta deposition without mechanism based toxicity .	Taken together, the data suggest exciting possibility that partial inhibition of BACE1 may effectively reduce Abeta deposition without mechanism based toxicity.	10	17	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	12	13	16	17
BACE overexpression in neuronal and nonneuronal cells increases Abeta generation , whereas genetic ablation of BACE eliminates Abeta production .	BACE overexpression in neuronal and nonneuronal cells increases Abeta generation, whereas genetic ablation of BACE eliminates Abeta production.	13	18	eliminates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	15	16	17	18
Taken together , these data suggest the exciting possibility that partial inhibition of BACE1 may effectively reduce Abeta deposition without mechanism based toxicity .	Taken together, these data suggest the exciting possibility that partial inhibition of BACE1 may effectively reduce Abeta deposition without mechanism based toxicity.	11	18	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	13	14	17	18
BACE1 , a type I transmembrane aspartic acid protease , initiates amyloidogenic APP processing [ XREF_BIBR ] .	BACE1, a type I transmembrane aspartic acid protease, initiates amyloidogenic APP processing [XREF_BIBR].	0	13	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	12	13
In mouse hippocampal primary neurons , knockdown of BACE-1 almost completely blocks Egr-1-induced amyloidogenic APP processing and Abeta synthesis .	In mouse hippocampal primary neurons, knockdown of BACE-1 almost completely blocks Egr-1-induced amyloidogenic APP processing and Abeta synthesis.	6	18	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	8	9	17	18
An increase of NF-kappaB activity in inflammatory status promotes aspartyl protease beta-site APP cleaving enzyme ( BACE1 ) synthesis , thus enhancing APP cleavage , and Abeta genesis where low adiponectin levels are associated with AD [ XREF_BIBR , XREF_BIBR ] .	An increase of NF-kappaB activity in inflammatory status promotes aspartyl protease beta-site APP cleaving enzyme (BACE1) synthesis, thus enhancing APP cleavage, and Abeta genesis where low adiponectin levels are associated with AD [XREF_BIBR, XREF_BIBR].	14	23	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	16	17	22	23
Based on our findings that sAPP-alpha binds and interferes with BACE1 mediated APP processing , suppression of sAPP-alpha likely results in BACE1 disinhibition .	Based on our findings that sAPP-alpha binds and interferes with BACE1 mediated APP processing, suppression of sAPP-alpha likely results in BACE1 disinhibition.	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	10	11	12	13
BACE1 ( beta-site beta-amyloid precursor protein ( APP )-cleaving enzyme 1 ) mediates the first proteolytic cleavage of APP , leading to amyloid beta-peptide ( Abeta ) production .	BACE1 (beta-site beta-amyloid precursor protein (APP)-cleaving enzyme 1) mediates the first proteolytic cleavage of APP, leading to amyloid beta-peptide (Abeta) production.	0	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	18	19
HEK 293 cells stably expressing human APP695 were transfected with cDNA encoding Flag-BACE1 along with control plasmid or with myc-CHIP , and the levels of BACE1 cleavage product of APP ( CTFbeta 99 ) and other proteins were estimated by Western blotting .	HEK 293 cells stably expressing human APP695 were transfected with cDNA encoding Flag-BACE1 along with control plasmid or with myc-CHIP, and the levels of BACE1 cleavage product of APP (CTFbeta 99) and other proteins were estimated by Western blotting.	25	36	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	25	26	29	30
In addition , BACE1 overexpression increases Abeta formation in APP transgenic mice , whereas BACE1 knockout mice produce little or no Abeta , indicating that BACE1 expression plays a critical role in Abeta biosynthesis .	In addition, BACE1 overexpression increases Abeta formation in APP transgenic mice, whereas BACE1 knockout mice produce little or no Abeta, indicating that BACE1 expression plays a critical role in Abeta biosynthesis.	3	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 overexpression	bace1	APP	APP	app	3	4	9	10
Experimental observation from mouse models of AD indicate that a level of BACE1 inhibition between 50 % and 75 % could be sufficient to reduce the rate of Abeta and prevent amyloid deposition without side effect .	Experimental observation from mouse models of AD indicate that a level of BACE1 inhibition between 50% and 75% could be sufficient to reduce the rate of Abeta and prevent amyloid deposition without side effect.	12	29	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	12	13	28	29
Abeta is produced from APP by sequential cleavage by beta-secretase ( beta-site APP cleaving enzyme 1 ; BACE1 ) and gamma-secretase ( presenilin complex ) , and released into the extracellular spaces [ XREF_BIBR ] .	Abeta is produced from APP by sequential cleavage by beta-secretase (beta-site APP cleaving enzyme 1; BACE1) and gamma-secretase (presenilin complex), and released into the extracellular spaces [XREF_BIBR].	0	27	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	Abeta	Abeta	Abeta	11	16	0	1
While increased localization of BACE1 within the ER reduces generation of Abeta , intracellular trafficking of BACE1 to the more acidic endosomes clearly enhances Abeta production .	While increased localization of BACE1 within the ER reduces generation of Abeta, intracellular trafficking of BACE1 to the more acidic endosomes clearly enhances Abeta production.	14	25	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	16	17	24	25
Both isoflurane XREF_BIBR and brain ischemia XREF_BIBR have been shown to induce caspase activation and apoptosis , which then enhance levels and activities of BACE to facilitate APP processing and to increase Abeta generation .	Both isoflurane XREF_BIBR and brain ischemia XREF_BIBR have been shown to induce caspase activation and apoptosis, which then enhance levels and activities of BACE to facilitate APP processing and to increase Abeta generation.	20	33	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	levels and activities of BACE	bace	Abeta	Abeta	abeta	24	25	32	33
The mutation lies at position two of Abeta ( Abeta-A/T ) and has been shown to reduce BACE-1 mediated Abeta generation by 40 % using synthetic peptides as substrates [ XREF_BIBR ] .	The mutation lies at position two of Abeta (Abeta-A/T) and has been shown to reduce BACE-1 mediated Abeta generation by 40% using synthetic peptides as substrates [XREF_BIBR].	16	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	17	18	19	20
Blocking BACE-1 action , on the other hand , blocks Egr-1-induced amyloidogenic APP processing but does not affect tau phosphorylation .	Blocking BACE-1 action, on the other hand, blocks Egr-1-induced amyloidogenic APP processing but does not affect tau phosphorylation.	1	13	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	APP	APP	APP	1	2	12	13
Inhibition of BACE 1 enzyme at the beginning of APP processing would prevent the formation of insoluble toxic Abeta aggregates that is responsible for neurodegeneration in AD .	Inhibition of BACE 1 enzyme at the beginning of APP processing would prevent the formation of insoluble toxic Abeta aggregates that is responsible for neurodegeneration in AD.	2	19	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	2	3	18	19
The enhanced BACE levels will promote APP processing to increase Abeta generation .	The enhanced BACE levels will promote APP processing to increase Abeta generation.	2	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE levels	bace	APP	APP	app	2	3	6	7
Chemical inhibition of BACE1 has been shown to reduce Abeta in animal studies and in human trials .	Chemical inhibition of BACE1 has been shown to reduce Abeta in animal studies and in human trials.	1	10	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	3	4	9	10
Our data demonstrate that lower BACE transcription is responsible for the minority of APP undergoing the amyloidogenic pathway and relatively lower Abeta production in the normal conditions , and that a slight increase in BACE1 can induce a dramatic elevation in Abeta production , indicating that the increase in BACE1 can potentially increase neuritic plaque formation in the pathological condition .	Our data demonstrate that lower BACE transcription is responsible for the minority of APP undergoing the amyloidogenic pathway and relatively lower Abeta production in the normal conditions, and that a slight increase in BACE1 can induce a dramatic elevation in Abeta production, indicating that the increase in BACE1 can potentially increase neuritic plaque formation in the pathological condition.	32	42	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	34	35	41	42
BACE1 was discovered to initiate the cleavage of amyloid precursor protein ( APP ) at the beta-secretase site .	BACE1 was discovered to initiate the cleavage of amyloid precursor protein (APP) at the beta-secretase site.	0	11	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	0	1	8	11
In vitro and in vivo studies have shown that overexpression of BACE elevates Abeta production [ XREF_BIBR , XREF_BIBR ] .	In vitro and in vivo studies have shown that overexpression of BACE elevates Abeta production [XREF_BIBR, XREF_BIBR].	9	14	elevates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	overexpression of BACE	bace	Abeta	Abeta	abeta	11	12	13	14
Because BACE1 promotes amyloidogenesis by initiating cleavage of amyloid precursor protein ( APP ) to form Abeta , investigators believe that dysregulated translation in AD , via elevated p-eIF2alpha , establishes a feedforward loop that progressively diminishes the overall structure and function of the affected neuronal population .	Because BACE1 promotes amyloidogenesis by initiating cleavage of amyloid precursor protein (APP) to form Abeta, investigators believe that dysregulated translation in AD, via elevated p-eIF2alpha, establishes a feedforward loop that progressively diminishes the overall structure and function of the affected neuronal population.	1	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	1	2	8	11
To determine whether BACE1 catalyzed APP cleavage occurs in the early or late secretory pathway , we used the drug brefeldin A ( BFA ) .	To determine whether BACE1 catalyzed APP cleavage occurs in the early or late secretory pathway, we used the drug brefeldin A (BFA).	3	7	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	5	6
On the basis of these findings , we conclude that BACE1 catalyzed APP cleavage does not require localization of these proteins to endosomes .	On the basis of these findings, we conclude that BACE1 catalyzed APP cleavage does not require localization of these proteins to endosomes.	10	16	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	10	11	12	13
BACE1 initiates processing of the amyloid precursor protein to generate amyloid-beta , a hallmark event of Alzheimer ' s disease ( AD ) .	BACE1 initiates processing of the amyloid precursor protein to generate amyloid-beta, a hallmark event of Alzheimer 's disease (AD).	0	8	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	0	1	5	8
Deletion of BACE1 via homologous recombination in mouse models of AD completely abolishes Abeta generation in the brain .	Deletion of BACE1 via homologous recombination in mouse models of AD completely abolishes Abeta generation in the brain.	0	14	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	13	14
Furthermore , administration of 4-O-methylhonokiol alleviated level of Abeta in the brain implying that reduced expression of BACE1 by the compound might be relevant to attenuated Abeta accumulation in the cortex and hippocampus ( XREF_FIG ) .	Furthermore, administration of 4-O-methylhonokiol alleviated level of Abeta in the brain implying that reduced expression of BACE1 by the compound might be relevant to attenuated Abeta accumulation in the cortex and hippocampus (XREF_FIG).	15	27	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	expression of BACE1	bace1	Abeta	Abeta	abeta	17	18	26	27
An in vitro study has suggested that the optimal pH of BACE1 mediated APP cleavage is pH ~ 5.0 , suggesting that an acidic intracellular compartment ( e.g ., endosome ) may be more favorable for BACE1 activation .	An in vitro study has suggested that the optimal pH of BACE1 mediated APP cleavage is pH ~ 5.0, suggesting that an acidic intracellular compartment (e.g., endosome) may be more favorable for BACE1 activation.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	11	12	13	14
Heparan sulfate proteoglycans ( HSPG ) inhibit BACE1 mediated APP cleavage .	Heparan sulfate proteoglycans (HSPG) inhibit BACE1 mediated APP cleavage.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	7	8	9	10
The results show that CHIP significantly reduced BACE1 cleavage product of APP ( CTFbeta 99 ) as compared to control plasmid in both HEK-APP cells and rat primary cortical neurons .	The results show that CHIP significantly reduced BACE1 cleavage product of APP (CTFbeta 99) as compared to control plasmid in both HEK-APP cells and rat primary cortical neurons.	7	13	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	7	8	11	12
Importantly , BACE cDNA transfection or BACE antisense oligonucleotide treatment of APP overexpressing cells increases or decreases production of Abeta and beta-secretase-cleaved APP fragments , respectively .	Importantly, BACE cDNA transfection or BACE antisense oligonucleotide treatment of APP overexpressing cells increases or decreases production of Abeta and beta-secretase-cleaved APP fragments, respectively.	2	23	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	2	3	19	20
Because beta-secretase and beta-site APP cleaving enzyme 1 ( BACE1 ) knockout mice produce much less Abeta and grow normally , a beta-secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side-effects .	Because beta-secretase and beta-site APP cleaving enzyme 1 (BACE1) knockout mice produce much less Abeta and grow normally, a beta-secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side-effects.	6	17	produce	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	9	10	16	17
First , STAT3 increases BACE expression by binding to its promoter and is also thought to mediate Abeta toxicity .	First, STAT3 increases BACE expression by binding to its promoter and is also thought to mediate Abeta toxicity.	2	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	STAT3 increases BACE expression	bace	Abeta	Abeta	abeta	4	5	17	18
Abeta is produced via sequential cleavage - firstly from its parent protein APP by BACE into a 99 amino acid membrane attached stub named C99 , which is then further cut by the gamma and secretase complex via regulated intramembraneous proteolysis to release Abeta .	Abeta is produced via sequential cleavage - firstly from its parent protein APP by BACE into a 99 amino acid membrane attached stub named C99, which is then further cut by the gamma and secretase complex via regulated intramembraneous proteolysis to release Abeta.	0	15	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	14	15	0	1
If 50 % inhibition of BACE1 is able to decrease Abeta production enough to delay disease onset or slow disease progression , this could represent a therapeutic strategy to avoid side effects of almost total BACE1 inhibition .	If 50% inhibition of BACE1 is able to decrease Abeta production enough to delay disease onset or slow disease progression, this could represent a therapeutic strategy to avoid side effects of almost total BACE1 inhibition.	3	11	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	5	6	10	11
Since BACE1 mRNA levels are unchanged , it has been proposed that Abeta accumulation induces posttranscriptional upregulation of BACE1 in plaque surrounding neurons in 5XFAD mice and the BACE1 elevation further accelerates Abeta generation .	Since BACE1 mRNA levels are unchanged, it has been proposed that Abeta accumulation induces posttranscriptional upregulation of BACE1 in plaque surrounding neurons in 5XFAD mice and the BACE1 elevation further accelerates Abeta generation.	28	33	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	28	29	32	33
Although homozygous BACE1 knock-out mice develop certain phenotypic abnormalities including reduced body size , hyperactive behavior , decreased grip strength and elevated pain sensitivity [ XREF_BIBR - XREF_BIBR ] , probably because the cleavage of other BACE1 substrates such as neuregulin 1 [ XREF_BIBR , XREF_BIBR ] and beta-subunits of voltage gated sodium channels [ XREF_BIBR ] is blocked , BACE1 heterozygous knockout mice do not develop such abnormal phenotypes and heterozygous knockout of BACE1 still can reduce Abeta deposition in AD mice [ XREF_BIBR , XREF_BIBR ] .	Although homozygous BACE1 knock-out mice develop certain phenotypic abnormalities including reduced body size, hyperactive behavior, decreased grip strength and elevated pain sensitivity [XREF_BIBR - XREF_BIBR], probably because the cleavage of other BACE1 substrates such as neuregulin 1 [XREF_BIBR, XREF_BIBR] and beta-subunits of voltage gated sodium channels [XREF_BIBR] is blocked, BACE1 heterozygous knockout mice do not develop such abnormal phenotypes and heterozygous knockout of BACE1 still can reduce Abeta deposition in AD mice [XREF_BIBR, XREF_BIBR].	72	79	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	74	75	78	79
Finally , pulse labeling of spinal cords demonstrated that BACE overexpression increases APP turnover such that APP is not available for axonal transport .	Finally, pulse labeling of spinal cords demonstrated that BACE overexpression increases APP turnover such that APP is not available for axonal transport.	9	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE overexpression	bace	APP	APP	app	9	10	12	13
These results suggest that TACE inhibition does not lead to greater APP processing by BACE .	These results suggest that TACE inhibition does not lead to greater APP processing by BACE.	8	15	lead	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	APP	APP	APP	14	15	11	12
BACE1 triggers Abeta generation and acts as a key regulator of Abeta metabolism .	BACE1 triggers Abeta generation and acts as a key regulator of Abeta metabolism.	0	5	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	2	3
The BACE siRNA inhibited the expression of BACE in the SK-N-SH cell and reduced the production of Abeta .	The BACE siRNA inhibited the expression of BACE in the SK-N-SH cell and reduced the production of Abeta.	1	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE siRNA inhibited the expression of BACE	bace	Abeta	Abeta	abeta	1	2	17	18
BACE1 levels and activity are increased in AD brain and are likely to drive Abeta overproduction , but the cause of BACE1 elevation in AD is unknown .	BACE1 levels and activity are increased in AD brain and are likely to drive Abeta overproduction, but the cause of BACE1 elevation in AD is unknown.	0	15	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 levels	bace1	Abeta	Abeta	abeta	0	1	14	15
BACE1 has been reported to be degraded by the lysosomes and ubiquitin-proteasome pathway , and accelerating BACE1 degradation by ubiquitin carboxyl-terminal hydrolase L1 ( UCHL1 ) reduces 99-amino acid carboxy-terminal fragment ( C99 ) and Abeta production .	BACE1 has been reported to be degraded by the lysosomes and ubiquitin-proteasome pathway, and accelerating BACE1 degradation by ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) reduces 99-amino acid carboxy-terminal fragment (C99) and Abeta production.	16	36	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	16	17	35	36
BACE1 deletion abolishes Abeta production in mice without overt abnormalities and the protein is implicated in AD pathogenesis , making it an important therapeutic target for AD .	BACE1 deletion abolishes Abeta production in mice without overt abnormalities and the protein is implicated in AD pathogenesis, making it an important therapeutic target for AD.	0	4	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	3	4
PM 2.5 has been reported to alter the brain inflammatory milieu and accelerate AD progression , mainly through BACE1 catalyzed APP cleavage [ XREF_BIBR ] .	PM 2.5 has been reported to alter the brain inflammatory milieu and accelerate AD progression, mainly through BACE1 catalyzed APP cleavage [XREF_BIBR].	12	21	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	18	19	20	21
beta-Site APP cleaving enzyme 1 ( BACE1 ) , the transmembrane aspartyl protease which initiates Abeta production , is axonally transported in neurons and accumulates in dystrophic neurites near cerebral amyloid deposits in AD .	beta-Site APP cleaving enzyme 1 (BACE1), the transmembrane aspartyl protease which initiates Abeta production, is axonally transported in neurons and accumulates in dystrophic neurites near cerebral amyloid deposits in AD.	0	16	initiates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	beta-Site APP cleaving enzyme 1	beta-Site APP cleaving enzyme 1	beta-Site APP cleaving enzyme 1	Abeta	Abeta	Abeta	0	5	15	16
Augmented BACE1 activity in turn correlated with the enhanced beta-amyloidogenic processing of APP and ultimately increased Abeta production .	Augmented BACE1 activity in turn correlated with the enhanced beta-amyloidogenic processing of APP and ultimately increased Abeta production.	1	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	1	2	16	17
For instance , we have shown that HIF1alpha binding to the BACE1 promoter induces BACE1 expression and results in increased Abeta production in neuroblastoma cells .	For instance, we have shown that HIF1alpha binding to the BACE1 promoter induces BACE1 expression and results in increased Abeta production in neuroblastoma cells.	7	22	production	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	BACE1	HIF1alpha binding to the BACE1 promoter induces BACE1 expression	bace1	Abeta	Abeta	abeta	14	15	20	21
Indeed , it was shown in APP transgenic mice that even a partial reduction of BACE1 can effectively decrease production of Abeta and synaptic deficits .	Indeed, it was shown in APP transgenic mice that even a partial reduction of BACE1 can effectively decrease production of Abeta and synaptic deficits.	13	24	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	15	16	21	22
Since BACE1 cleavage of APP initiates Abeta generation , we also measured endogenous BACE1 levels in the same primary astrocytes that were stimulated by the pro inflammatory agents above .	Since BACE1 cleavage of APP initiates Abeta generation, we also measured endogenous BACE1 levels in the same primary astrocytes that were stimulated by the pro inflammatory agents above.	1	7	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	1	2	6	7
XREF_BIBR Indeed , there is a PPARgamma response element in the promoter region of the BACE1 gene , and binding of PPARgamma to this response element suppresses BACE1 expression and inhibits Abeta production .	XREF_BIBR Indeed, there is a PPARgamma response element in the promoter region of the BACE1 gene, and binding of PPARgamma to this response element suppresses BACE1 expression and inhibits Abeta production.	21	32	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	PPARgamma to this response element suppresses BACE1 expression	bace1	Abeta	Abeta	abeta	27	28	31	32
The data from ELISA and Western blot ( WB ) tests indicated that SNP at lower concentrations ( 0.01 and 0.1 muM ) inhibits BACE1 expression , thus consequently suppresses APP beta-cleavage and decreases Abeta production .	The data from ELISA and Western blot (WB) tests indicated that SNP at lower concentrations (0.01 and 0.1 muM) inhibits BACE1 expression, thus consequently suppresses APP beta-cleavage and decreases Abeta production.	13	35	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	SNP at lower concentrations (0.01 and 0.1 muM) inhibits BACE1 expression	bace1	Abeta	Abeta	abeta	24	25	34	35
Dysfunction of BACE1 and gamma-secretase inevitably causes aberrant APP processing , production of toxic Abeta species , and amyloidogenesis .	Dysfunction of BACE1 and gamma-secretase inevitably causes aberrant APP processing, production of toxic Abeta species, and amyloidogenesis.	0	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	2	3	8	9
Inhibition of the vacuolar H +-ATPase by bafilomycin A1 produced the most robust increase in APP-BACE1 interaction , likely due to reduced efficiency of BACE1 mediated APP cleavage in endosomes with elevated intraluminal pH XREF_BIBR , XREF_BIBR .	Inhibition of the vacuolar H +-ATPase by bafilomycin A1 produced the most robust increase in APP-BACE1 interaction, likely due to reduced efficiency of BACE1 mediated APP cleavage in endosomes with elevated intraluminal pH XREF_BIBR, XREF_BIBR.	22	27	mediated	Positive_early_activation	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	24	25	26	27
beta-Secretase ( BACE ) initiates the amyloidogenic processing of the amyloid precursor protein leading to the generation of the beta-amyloid , the main component of Alzheimer ' s disease senile plaques .	beta-Secretase (BACE) initiates the amyloidogenic processing of the amyloid precursor protein leading to the generation of the beta-amyloid, the main component of Alzheimer 's disease senile plaques.	0	13	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	2	3	10	13
In addition , ER stress has been shown to increase the expression of BACE1 and thus trigger APP processing in ER ( see above ) .	In addition, ER stress has been shown to increase the expression of BACE1 and thus trigger APP processing in ER (see above).	3	18	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	ER stress has been shown to increase the expression of BACE1	bace1	APP	APP	app	13	14	17	18
We also found that decreased BACE1 protein levels were accompanied by a decrease in BACE1 mediated amyloid precursor protein cleavage and amyloid-beta levels .	We also found that decreased BACE1 protein levels were accompanied by a decrease in BACE1 mediated amyloid precursor protein cleavage and amyloid-beta levels.	12	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	14	15	16	19
The two alternative pathways are located in different subcellular compartments : while non amyloidogenic APP processing , which is the major pathway of APP cleavage in all cells , takes place at the plasma membrane , the amyloidogenic APP processing by beta-secretase cleavage takes place in endosomes having a more acidic pH , which is also the pH optimum of BACE1 mediated APP turn over .	The two alternative pathways are located in different subcellular compartments : while non amyloidogenic APP processing, which is the major pathway of APP cleavage in all cells, takes place at the plasma membrane, the amyloidogenic APP processing by beta-secretase cleavage takes place in endosomes having a more acidic pH, which is also the pH optimum of BACE1 mediated APP turn over.	58	63	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	60	61	62	63
Although it is expected that BACE1 inhibition in our model will gradually decrease the production of Abeta , it is intriguing that amyloid plaques are actually cleared and removed in old BACE1 fl/fl/UbcCreER/5xFAD mice .	Although it is expected that BACE1 inhibition in our model will gradually decrease the production of Abeta, it is intriguing that amyloid plaques are actually cleared and removed in old BACE1 fl/fl/UbcCreER/5xFAD mice.	5	17	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	5	6	16	17
This could potentially lead to an increased signaling , which in turn , would accelerate APP processing through BACE1 [ since BACE1 has been shown to be positively regulated by RAGE ] , and thereby increase Abeta production .	This could potentially lead to an increased signaling, which in turn, would accelerate APP processing through BACE1 [since BACE1 has been shown to be positively regulated by RAGE], and thereby increase Abeta production.	21	37	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	21	22	36	37
Indeed , antibody co-patching or GPI anchoring studies have shown that increased APP and BACE1 targeting to lipid rafts leads to increased Abeta [ XREF_BIBR ; XREF_BIBR ] , suggesting that lipid rafts may be a major site of Abeta production .	Indeed, antibody co-patching or GPI anchoring studies have shown that increased APP and BACE1 targeting to lipid rafts leads to increased Abeta [XREF_BIBR; XREF_BIBR], suggesting that lipid rafts may be a major site of Abeta production.	12	24	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	14	15	22	23
Taken together , our results suggest that these polymethoxyflavones ( PMFs ) might be considered as promising BACE1 inhibitory agents that could lower Abeta production in AD .	Taken together, our results suggest that these polymethoxyflavones (PMFs) might be considered as promising BACE1 inhibitory agents that could lower Abeta production in AD.	17	24	lower	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	17	18	23	24
Our studies have demonstrated that SNX12 may participate in AD pathology by interacting with BACE1 , thereby regulating BACE1 intracellular trafficking and BACE1 mediated beta processing of APP in Abeta production .	Our studies have demonstrated that SNX12 may participate in AD pathology by interacting with BACE1, thereby regulating BACE1 intracellular trafficking and BACE1 mediated beta processing of APP in Abeta production.	18	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	18	19	27	28
A priori , increased BACE activity is expected to increase Abeta pathology .	A priori, increased BACE activity is expected to increase Abeta pathology.	4	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	4	5	10	11
Abeta is produced via endoproteolysis by BACE , which cleaves betaAPP at the extracellular domain , and by the presenilin ( PS ) , gamma , and secretase complex , which cleaves betaAPP in the transmembrane domain ( TM ) .	Abeta is produced via endoproteolysis by BACE, which cleaves betaAPP at the extracellular domain, and by the presenilin (PS), gamma, and secretase complex, which cleaves betaAPP in the transmembrane domain (TM).	0	9	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	6	7	0	1
Here , we demonstrate that genetic deletion of the beta-secretase ( BACE1 ) not only abrogates Abeta generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum , brain regions manifesting the most severe amyloidosis in 5XFAD mice .	Here, we demonstrate that genetic deletion of the beta-secretase (BACE1) not only abrogates Abeta generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice.	9	17	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	16	17
Thus , we propose that in addition to Abeta and sAPPbeta , which are two BACE1 cleavage products of APP , sSEZ6 and sSEZ6L may be suitable as biomarkers to monitor BACE1 activity in vivo in CSF .	Thus, we propose that in addition to Abeta and sAPPbeta, which are two BACE1 cleavage products of APP, sSEZ6 and sSEZ6L may be suitable as biomarkers to monitor BACE1 activity in vivo in CSF.	15	20	products	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	15	16	19	20
Secretion of Abeta is also enhanced by spontaneous neuronal activity through an enhanced APP cleavage by BACE in hippocampal neurons overexpressing APP .	Secretion of Abeta is also enhanced by spontaneous neuronal activity through an enhanced APP cleavage by BACE in hippocampal neurons overexpressing APP.	5	22	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	APP	APP	APP	16	17	21	22
In rat hippocampal primary neurons , overexpression of Egr-1 induces BACE-1 expression , activates BACE-1 , promotes amyloidogenic APP processing , and enhances Abeta synthesis .	In rat hippocampal primary neurons, overexpression of Egr-1 induces BACE-1 expression, activates BACE-1, promotes amyloidogenic APP processing, and enhances Abeta synthesis.	6	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	overexpression of Egr-1 induces BACE-1 expression	bace-1	APP	APP	app	10	11	18	19
Studies from our laboratory and others have demonstrated that BACE1 gene deletion ( BACE1 -/-) blocks Abeta production in brain , prevents pathological changes such as Abeta deposition , glial activation and neuron loss , and improves memory dysfunctions in mouse models of AD .	Studies from our laboratory and others have demonstrated that BACE1 gene deletion (BACE1 -/-) blocks Abeta production in brain, prevents pathological changes such as Abeta deposition, glial activation and neuron loss, and improves memory dysfunctions in mouse models of AD.	9	17	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	9	10	16	17
We also found that arresting protein export from the ER and Golgi complex by treatment with BFA blocked BACE1 catalyzed APP cleavage ( XREF_FIG ) , as previously shown .	We also found that arresting protein export from the ER and Golgi complex by treatment with BFA blocked BACE1 catalyzed APP cleavage (XREF_FIG), as previously shown.	17	21	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	18	19	20	21
Confocal analysis revealed that both EHD1 and EHD3 show substantial overlap with APP beta-CTF and/or Abeta in mossy fiber terminals in APPswe and PS1DeltaE9 transgenic mouse brain [ analyzed at 2 months , before the onset of overt extracellular Abeta deposition ] ( XREF_FIG ) , suggesting that in mouse brain , BACE1 in EHD positive structures likely mediates the processing of APP to beta-CTF , the precursor of Abeta .	Confocal analysis revealed that both EHD1 and EHD3 show substantial overlap with APP beta-CTF and/or Abeta in mossy fiber terminals in APPswe and PS1DeltaE9 transgenic mouse brain [analyzed at 2 months, before the onset of overt extracellular Abeta deposition] (XREF_FIG), suggesting that in mouse brain, BACE1 in EHD positive structures likely mediates the processing of APP to beta-CTF, the precursor of Abeta.	52	63	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	52	53	62	63
Along with gamma-secretase , BACE-1 catalyzes the conversion of AbetaPP to Abeta , resulting in elevated levels of toxic forms of Abeta [ XREF_BIBR ] .	Along with gamma-secretase, BACE-1 catalyzes the conversion of AbetaPP to Abeta, resulting in elevated levels of toxic forms of Abeta [XREF_BIBR].	4	12	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	4	5	11	12
It is widely believed that BACE1 initiates APP processing in endosomes , and in the brain this cleavage is known to occur during axonal transport of APP .	It is widely believed that BACE1 initiates APP processing in endosomes, and in the brain this cleavage is known to occur during axonal transport of APP.	5	8	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	7	8
These compounds might be considered as promising BACE1 inhibitory agents that could lower Abeta production in AD .	These compounds might be considered as promising BACE1 inhibitory agents that could lower Abeta production in AD.	7	14	lower	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	7	8	13	14
Our initial studies revealed increased levels of sortilin in post-mortem brain tissue of AD patients and that overexpression of sortilin leads to increased BACE1 mediated cleavage of APP in cultured cells .	Our initial studies revealed increased levels of sortilin in post-mortem brain tissue of AD patients and that overexpression of sortilin leads to increased BACE1 mediated cleavage of APP in cultured cells.	20	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	23	24	27	28
In the present study , we have shown that high glucose induced BACE1 expression and the reorganization of the lipid raft through cholesterol accumulation stimulate Abeta production ( XREF_FIG ) .	In the present study, we have shown that high glucose induced BACE1 expression and the reorganization of the lipid raft through cholesterol accumulation stimulate Abeta production (XREF_FIG).	10	26	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	glucose induced BACE1 expression	bace1	Abeta	Abeta	abeta	12	13	25	26
XREF_BIBR In the promoter region of human BACE1 , two functional NF-kappaB-binding elements were identified , and disruption of NF-kappaB and p65 decreased the expression of BACE1 gene in RelA ( p65 ) knockout cells and expression of NF-kappaB and p65 upregulated BACE cleavage and Abeta production .	XREF_BIBR In the promoter region of human BACE1, two functional NF-kappaB-binding elements were identified, and disruption of NF-kappaB and p65 decreased the expression of BACE1 gene in RelA (p65) knockout cells and expression of NF-kappaB and p65 upregulated BACE cleavage and Abeta production.	24	46	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	expression of BACE1	bace1	Abeta	Abeta	abeta	26	27	45	46
The present study examines the role of saturated fatty acid , palmitic acid ( PA ) , in causing BACE1 upregulation and consequent amyloidogenic processing of beta-amyloid precursor protein ( APP ) , one of the main characteristic signatures of AD pathology .	The present study examines the role of saturated fatty acid, palmitic acid (PA), in causing BACE1 upregulation and consequent amyloidogenic processing of beta-amyloid precursor protein (APP), one of the main characteristic signatures of AD pathology.	19	29	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	beta-amyloid precursor protein	beta-amyloid precursor protein	beta-amyloid precursor protein	19	20	26	29
BACE1 antisense inhibition reduces production of APPsbeta , C99 , and Abeta in cells ; conversely , APPsalpha and C83 generation is elevated .	BACE1 antisense inhibition reduces production of APPsbeta, C99, and Abeta in cells; conversely, APPsalpha and C83 generation is elevated.	0	13	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	11	12
BACE initiates the production of Abeta , so its inhibition provides a valid target for the AD .	BACE initiates the production of Abeta, so its inhibition provides a valid target for the AD.	0	6	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	0	1	5	6
The fine regulation of the growth factor , brain derived nerve factor by sortilin mediates both neuronal and tumor cell survival , whereas in Alzheimer ' s disease sortilin mediated beta secretase-1 trafficking increases the cleavage of the beta-amyloid precursor protein .	The fine regulation of the growth factor, brain derived nerve factor by sortilin mediates both neuronal and tumor cell survival, whereas in Alzheimer 's disease sortilin mediated beta secretase-1 trafficking increases the cleavage of the beta-amyloid precursor protein.	28	41	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta secretase-1	sortilin mediated beta secretase-1	beta secretase-1	beta-amyloid precursor protein	beta-amyloid precursor protein	beta-amyloid precursor protein	30	32	38	41
Subsequent discoveries showed that genetic deletion of BACE1 completely abolishes Abeta production and deposition in vivo , and that BACE1 activity is significantly increased in AD brain .	Subsequent discoveries showed that genetic deletion of BACE1 completely abolishes Abeta production and deposition in vivo, and that BACE1 activity is significantly increased in AD brain.	5	11	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	7	8	10	11
( 1 ) BACE1 initiates the amyloidogenic processing of APP ; therefore , early or active amyloidogenic loci might exhibit site specific BACE1 and Abeta elevation .	(1) BACE1 initiates the amyloidogenic processing of APP; therefore, early or active amyloidogenic loci might exhibit site specific BACE1 and Abeta elevation.	3	10	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	9	10
In contrast to the previously described negative effect of BACE1 mediated cleavage of APP on synaptic function in vitro , our in vivo work indicates that BACE1 mediated cleavage of APP can facilitate learning , memory , and synaptic plasticity .	In contrast to the previously described negative effect of BACE1 mediated cleavage of APP on synaptic function in vitro, our in vivo work indicates that BACE1 mediated cleavage of APP can facilitate learning, memory, and synaptic plasticity.	7	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	9	10	13	14
As expected , heterozygous deletion of BACE reduces soluble Abeta and Abeta oligomers .	As expected, heterozygous deletion of BACE reduces soluble Abeta and Abeta oligomers.	4	12	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	6	7	9	10
Sp1 is transcription activator of the genes encoding beta-site amyloid precursor protein cleaving enzyme ( BACE ) 1 and amyloid precursor protein ( APP ) , abnormal processing of which causes Abeta accumulation in AD brains .	Sp1 is transcription activator of the genes encoding beta-site amyloid precursor protein cleaving enzyme (BACE) 1 and amyloid precursor protein (APP), abnormal processing of which causes Abeta accumulation in AD brains.	13	32	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	15	16	31	32
Partial BACE deletion reduces soluble Abeta and prevents ArcTau learning and memory impairments .	Partial BACE deletion reduces soluble Abeta and prevents ArcTau learning and memory impairments.	1	6	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	1	2	5	6
They showed that small interfering RNAs targeting LRRTM3 inhibit the secretion of Abeta40 , Abeta42 , and sAPPbeta ( the N-terminal APP fragment produced by beta-secretase 1 cleavage ) , whereas overexpression increases the secretion of Abeta .	They showed that small interfering RNAs targeting LRRTM3 inhibit the secretion of Abeta40, Abeta42, and sAPPbeta (the N-terminal APP fragment produced by beta-secretase 1 cleavage), whereas overexpression increases the secretion of Abeta.	21	27	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-secretase 1	beta-secretase 1	beta-secretase 1	APP	APP	APP	25	27	21	22
Since glycogen synthase kinase 3-beta ( GSK3- beta ) is known to play a crucial role in the pathology of AD by hyperphosphorylation of tau protein XREF_BIBR and by influencing the BACE1 mediated cleavage of APP XREF_BIBR , it is of great importance that the activity of GSK3-beta in SH-SY5Y is not altered during co-cultivation with PBECs as shown in XREF_FIG ( 109 % compared to SH-SY5Y mono-cultures ) .	Since glycogen synthase kinase 3-beta (GSK3- beta) is known to play a crucial role in the pathology of AD by hyperphosphorylation of tau protein XREF_BIBR and by influencing the BACE1 mediated cleavage of APP XREF_BIBR, it is of great importance that the activity of GSK3-beta in SH-SY5Y is not altered during co-cultivation with PBECs as shown in XREF_FIG (109% compared to SH-SY5Y mono-cultures).	30	36	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	31	32	35	36
However , in apoptotic conditions induced by staurosporin exposure , reduced levels of seladin-1 clearly increase BACE1 level through protein stabilization and subsequently enhanced cleavage of APP to amyloid-beta peptide .	However, in apoptotic conditions induced by staurosporin exposure, reduced levels of seladin-1 clearly increase BACE1 level through protein stabilization and subsequently enhanced cleavage of APP to amyloid-beta peptide.	11	27	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	levels of seladin-1 clearly increase BACE1 level	bace1	APP	APP	app	16	17	26	27
Several reports demonstrate that BACE1 directed compounds used as inhibitors for enzyme activity or expression may ameliorate memory impairment and Abeta pathology in mice XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Several reports demonstrate that BACE1 directed compounds used as inhibitors for enzyme activity or expression may ameliorate memory impairment and Abeta pathology in mice XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	4	21	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	20	21
In this study , we investigated whether BACE1 trafficking and BACE1 mediated APP processing and Abeta generation are affected by sorting nexin 12 ( SNX12 ) , a member of the sorting nexin ( SNX ) family that is involved in protein trafficking regulation .	In this study, we investigated whether BACE1 trafficking and BACE1 mediated APP processing and Abeta generation are affected by sorting nexin 12 (SNX12), a member of the sorting nexin (SNX) family that is involved in protein trafficking regulation.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	10	11	12	13
Abeta is a heterogeneous mixture of peptides ranging from 37 to 43 amino acids in length [ XREF_BIBR ] produced via sequential cleavage of the amyloid precursor protein ( APP ) by BACE1 and the presenilin , gamma , and secretase complex [ XREF_BIBR - XREF_BIBR ] .	Abeta is a heterogeneous mixture of peptides ranging from 37 to 43 amino acids in length [XREF_BIBR] produced via sequential cleavage of the amyloid precursor protein (APP) by BACE1 and the presenilin, gamma, and secretase complex [XREF_BIBR - XREF_BIBR].	19	40	produced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	32	33	25	28
Experimental induction of ER stress caused by energy deprivation increases BACE1 expression and elevates Abeta production by a mechanism that involves eIF2alpha phosphorylation XREF_BIBR .	Experimental induction of ER stress caused by energy deprivation increases BACE1 expression and elevates Abeta production by a mechanism that involves eIF2alpha phosphorylation XREF_BIBR.	3	15	elevates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	ER stress caused by energy deprivation increases BACE1 expression	bace1	Abeta	Abeta	abeta	10	11	14	15
First , they suggest that OS , as effect of aging , can increase the expression of both presenilin 1 ( PS1 ) and BACE1 , thereby enhancing Abeta production .	First, they suggest that OS, as effect of aging, can increase the expression of both presenilin 1 (PS1) and BACE1, thereby enhancing Abeta production.	5	29	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	OS, as effect of aging, can increase the expression of both presenilin 1 (PS1) and BACE1	bace1	Abeta	Abeta	abeta	24	25	28	29
Another study also demonstrated that the AP-2 and clathrin mediated BACE1 internalization enhances the cleavage of APP by BACE1 .	Another study also demonstrated that the AP-2 and clathrin-mediated BACE1 internalization enhances the cleavage of APP by BACE1.	8	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	clathrin-mediated BACE1	bace1	APP	APP	app	10	11	16	17
Further study demonstrated that this process could be triggered by N-terminal beta-amyloid precursor protein ( N-APP ) generated by trophic factor deprivation induced cleavage of APP by beta-site APP cleaving enzyme 1 ( BACE1 ) because N-APP acts as a necessary and sufficient ligand for DR6 .	Further study demonstrated that this process could be triggered by N-terminal beta-amyloid precursor protein (N-APP) generated by trophic factor deprivation induced cleavage of APP by beta-site APP cleaving enzyme 1 (BACE1) because N-APP acts as a necessary and sufficient ligand for DR6.	22	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	33	34	25	26
Abeta is primarily produced by serial proteolysis of APP by BACE-1 .	Abeta is primarily produced by serial proteolysis of APP by BACE-1.	0	11	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	10	11	0	1
BACE1 possess a catalytic domain containing a pair of aspartic acid residues at its active site , and Abeta production is blocked by BACE1 inhibition , which reduces Abeta production by depleting C99 , acting as a substrate of gamma-secretase .	BACE1 possess a catalytic domain containing a pair of aspartic acid residues at its active site, and Abeta production is blocked by BACE1 inhibition, which reduces Abeta production by depleting C99, acting as a substrate of gamma-secretase.	18	24	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	23	24	18	19
For instance , we have previously shown that HIF-1alpha binding to the BACE1 promoter induces BACE1 expression and results in increased Abeta production in neuroblastoma cells 63 .	For instance, we have previously shown that HIF-1alpha binding to the BACE1 promoter induces BACE1 expression and results in increased Abeta production in neuroblastoma cells 63.	8	23	production	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	BACE1	HIF-1alpha binding to the BACE1 promoter induces BACE1 expression	bace1	Abeta	Abeta	abeta	15	16	21	22
Not only does BACE1 initiate Abeta formation , but the observation that BACE1 levels are elevated in AD [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] provides a direct and compelling reason to develop therapies directed at BACE1 inhibition thus reducing Abeta and its associated toxicities .	Not only does BACE1 initiate Abeta formation, but the observation that BACE1 levels are elevated in AD [XREF_BIBR, XREF_BIBR - XREF_BIBR] provides a direct and compelling reason to develop therapies directed at BACE1 inhibition thus reducing Abeta and its associated toxicities.	36	44	reducing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	36	37	40	41
Previous studies have shown that BACE1 catalyzed APP cleavage exerted positive effects on cognitive function , and AICD , which is correlated with the promotion of synaptic transmission and memory performance , is a potential mediator during this process [ XREF_BIBR ] .	Previous studies have shown that BACE1 catalyzed APP cleavage exerted positive effects on cognitive function, and AICD, which is correlated with the promotion of synaptic transmission and memory performance, is a potential mediator during this process [XREF_BIBR].	5	9	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	7	8
Promising BACE inhibitors are emerging in phase I clinical trials , raising hope that a good safety profile , good pharmacokinetics , and significant Abeta lowering by BACE1 targeting is achievable , which will hopefully translate into an AD modifying strategy .	Promising BACE inhibitors are emerging in phase I clinical trials, raising hope that a good safety profile, good pharmacokinetics, and significant Abeta lowering by BACE1 targeting is achievable, which will hopefully translate into an AD modifying strategy.	24	28	lowering	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	27	28	24	25
In order to develop this specific modulator against BACE1 mediated APP cleavage , we screened peptides derived from the APPswe or APPwt genes , and found that APPsweBBP is the most effective BACE1 inhibitor using a cell-free assay .	In order to develop this specific modulator against BACE1 mediated APP cleavage, we screened peptides derived from the APPswe or APPwt genes, and found that APPsweBBP is the most effective BACE1 inhibitor using a cell-free assay.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	8	9	10	11
Although we can not rule out that biosynthetic transport of BACE1 involves passage through an endosomal compartment en route to the plasma membrane , the ability of BACE1 constructs to cleave the endosomally excluded APP-3Y-F615P and D664A mutant supports the conclusion that endosomal localization is not required for BACE1 mediated APP cleavage .	Although we can not rule out that biosynthetic transport of BACE1 involves passage through an endosomal compartment en route to the plasma membrane, the ability of BACE1 constructs to cleave the endosomally excluded APP-3Y-F615P and D664A mutant supports the conclusion that endosomal localization is not required for BACE1 mediated APP cleavage.	27	51	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	27	28	50	51
BACE1 initiates cleavage of APP to release a membrane bound , 99 amino acid-long C-terminal fragment ( APP-C99 ) , which is further cleaved by gamma-secretase to excise Abeta 11 .	BACE1 initiates cleavage of APP to release a membrane bound, 99 amino acid-long C-terminal fragment (APP-C99), which is further cleaved by gamma-secretase to excise Abeta 11.	0	5	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	4	5
In the previous reports , it is suggested that high glucose treatment or hyperglycemic condition induces ROS and BACE1 mediated Abeta production , critical to high glucose induced neuronal cell apoptosis XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	In the previous reports, it is suggested that high glucose treatment or hyperglycemic condition induces ROS and BACE1 mediated Abeta production, critical to high glucose induced neuronal cell apoptosis XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	18	19	20	21
Since mOS caused no change in either BACE1 mRNA or protein levels , but increased beta-CTF , we reasoned that an alteration in the subcellular distribution of BACE1 might be promoting APP processing .	Since mOS caused no change in either BACE1 mRNA or protein levels, but increased beta-CTF, we reasoned that an alteration in the subcellular distribution of BACE1 might be promoting APP processing.	25	32	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	27	28	31	32
For example , two enzymes partially responsible for LPA or S1P production , autotaxin or SPHK2 , respectively , have been reported to be upregulated in AD brain samples [ XREF_BIBR , XREF_BIBR ] , while S1P exposure reduces the activity of the beta-site APP cleaving enzyme-1 ( BACE1 ) that causes abnormal amyloid beta ( Abeta ) accumulation , a characteristic feature of AD [ XREF_BIBR , XREF_BIBR ] .	For example, two enzymes partially responsible for LPA or S1P production, autotaxin or SPHK2, respectively, have been reported to be upregulated in AD brain samples [XREF_BIBR, XREF_BIBR], while S1P exposure reduces the activity of the beta-site APP cleaving enzyme-1 (BACE1) that causes abnormal amyloid beta (Abeta) accumulation, a characteristic feature of AD [XREF_BIBR, XREF_BIBR].	46	55	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	amyloid beta	amyloid beta	amyloid beta	48	49	53	55
Previous work from our laboratory and others has shown that partial BACE1 gene suppression ( e.g ., haploinsufficiency and siRNA ) reduces Abeta and C99 levels and mitigates AD like pathologies and memory impairments in transgenic mouse models , while some reports indicate the decreased therapeutic efficacies with progression of disease .	Previous work from our laboratory and others has shown that partial BACE1 gene suppression (e.g., haploinsufficiency and siRNA) reduces Abeta and C99 levels and mitigates AD like pathologies and memory impairments in transgenic mouse models, while some reports indicate the decreased therapeutic efficacies with progression of disease.	11	25	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	22	23
In addition , an in vivo study showed that increased lipid peroxidation leads to up regulation of BACE1 expression , which may lead to increased Abeta ( 1-42 ) production [ XREF_BIBR ] .	In addition, an in vivo study showed that increased lipid peroxidation leads to up regulation of BACE1 expression, which may lead to increased Abeta (1-42) production [XREF_BIBR].	17	26	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BACE1	BACE1 expression	bace1	Abeta	Abeta	abeta	17	18	25	26
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR By crossing BACE1 +/- mice with AD transgenic mouse lines , these studies have demonstrated that partial reduction of BACE1 can diminish brain Abeta concentrations and improve AD like phenotypes including amyloid plaque and tau pathologies , synaptic dysfunction and memory deficits .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR By crossing BACE1 +/- mice with AD transgenic mouse lines, these studies have demonstrated that partial reduction of BACE1 can diminish brain Abeta concentrations and improve AD like phenotypes including amyloid plaque and tau pathologies, synaptic dysfunction and memory deficits.	30	37	diminish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	32	33	36	37
This result was confirmed by Western blot analysis of elav ; APP ; BACE fly heads , which demonstrate decreased Abeta levels in the L-685 ,458 treated flies compared to the DMSO ( vehicle ) raised elav ; APP ; BACE heterozygous flies ( XREF_SUPPLEMENTARY ) .	This result was confirmed by Western blot analysis of elav; APP; BACE fly heads, which demonstrate decreased Abeta levels in the L-685,458 treated flies compared to the DMSO (vehicle) raised elav; APP; BACE heterozygous flies (XREF_SUPPLEMENTARY).	35	42	raised	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	APP	APP	APP	40	41	38	39
Importantly , BACE1 overexpression or BACE1 knockdown increases or decreases production of Abeta and beta-secretase-cleaved APP fragments , respectively [ XREF_BIBR ] .	Importantly, BACE1 overexpression or BACE1 knockdown increases or decreases production of Abeta and beta-secretase-cleaved APP fragments, respectively [XREF_BIBR].	2	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 overexpression	bace1	APP	APP	app	2	3	15	16
We demonstrate that increased Abeta generation may be mediated by the upregulation of APP and BACE1 levels in the brain , and that the exacerbation of tau pathology correlates with the increased formation of p25 and subsequent aberrant activation of cdk5 and p25 .	We demonstrate that increased Abeta generation may be mediated by the upregulation of APP and BACE1 levels in the brain, and that the exacerbation of tau pathology correlates with the increased formation of p25 and subsequent aberrant activation of cdk5 and p25.	4	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1 levels	bace1	Abeta	Abeta	abeta	15	16	4	5
To further confirm this interpretation , we collected lysate and medium from hippocampal neurons exposed to R55 and vehicle and respectively measured beta-CTF and sAPPbeta , the two fragments that are produced by the cleavage of APP by BACE1 .	To further confirm this interpretation, we collected lysate and medium from hippocampal neurons exposed to R55 and vehicle and respectively measured beta-CTF and sAPPbeta, the two fragments that are produced by the cleavage of APP by BACE1.	21	39	produced	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	sAPPbeta	sAPPbeta	sAPPbeta	38	39	24	25
Elevated BACE levels and activity would promote amyloidogenic processing of APP , potentially leading to increased Abeta genesis .	Elevated BACE levels and activity would promote amyloidogenic processing of APP, potentially leading to increased Abeta genesis.	1	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE levels	bace	APP	APP	app	1	2	10	11
In addition , silencing of APP and BACE1 expression significantly decreased the production of Abeta in SK-N-MC cells treated with PA-BSA .	In addition, silencing of APP and BACE1 expression significantly decreased the production of Abeta in SK-N-MC cells treated with PA-BSA.	5	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 expression	bace1	Abeta	Abeta	abeta	7	8	14	15
Their study showed that the silencing of ShcC decreased the levels of APP-C-terminal fragments ( APP-CTFs ) , Abeta , and BACE1 in H4 human neuroglioma cells stably overexpressing full-length APP ( H4-FL-APP cells ) , while silencing of the homolog ShcA had no effect .	Their study showed that the silencing of ShcC decreased the levels of APP-C-terminal fragments (APP-CTFs), Abeta, and BACE1 in H4 human neuroglioma cells stably overexpressing full-length APP (H4-FL-APP cells), while silencing of the homolog ShcA had no effect.	7	33	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	ShcC decreased the levels of APP-C-terminal fragments (APP-CTFs), Abeta, and BACE1	bace1	APP	APP	app	21	22	30	31
They found that the reduced GSK3beta activity is involved in reducing BACE1 mediated cleavage of APP and Abeta production by decreasing BACE1 gene transcription and expression .	They found that the reduced GSK3beta activity is involved in reducing BACE1 mediated cleavage of APP and Abeta production by decreasing BACE1 gene transcription and expression.	11	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	17	18
BACE1 is the predominant endogenous beta-secretase , and produces a 99-aminoacid C-terminal fragment of APP ( CTFbeta ) during the amyloidogenic processing of APP .	BACE1 is the predominant endogenous beta-secretase, and produces a 99-aminoacid C-terminal fragment of APP (CTFbeta) during the amyloidogenic processing of APP.	0	16	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	14	15
In cell cultures overexpressing this mutant , BACE cleavage of the mutant APP was decreased by 50 % , thereby decreasing Abeta production .	In cell cultures overexpressing this mutant, BACE cleavage of the mutant APP was decreased by 50%, thereby decreasing Abeta production.	7	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	7	8	21	22
Reports suggest that the secretase beta-site APP cleaving enzyme-1 ( BACE1 ) , increases APP cleavage as a result of eIF2alpha phosphorylation leading to the production of Abeta in neurons .	Reports suggest that the secretase beta-site APP cleaving enzyme-1 (BACE1), increases APP cleavage as a result of eIF2alpha phosphorylation leading to the production of Abeta in neurons.	5	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-site APP cleaving enzyme-1	beta-site APP cleaving enzyme-1	beta-site APP cleaving enzyme-1	APP	APP	APP	5	9	14	15
Beta-secretase cleavage of APP by BACE1 produces APP C-terminal fragment C99 , which can be cleaved by the gamma and secretase complex to form Abeta and subsequently aggregate to form classic AD plaques .	Beta-secretase cleavage of APP by BACE1 produces APP C-terminal fragment C99, which can be cleaved by the gamma and secretase complex to form Abeta and subsequently aggregate to form classic AD plaques.	3	8	produces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	7	8
26 We reasoned that enhanced basicity could increase cell potency by favoring partitioning to the acidic intracellular compartment where BACE1 mediated APP processing is operative .	26 We reasoned that enhanced basicity could increase cell potency by favoring partitioning to the acidic intracellular compartment where BACE1 mediated APP processing is operative.	19	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	19	20	21	22
NF-kappaB activates the transcription of APP , BACE1 , and gamma-secretase and therefore increases generation of Abeta because NF-kappaB is a transcription factor of these genes [ XREF_BIBR , XREF_BIBR ] .	NF-kappaB activates the transcription of APP, BACE1, and gamma-secretase and therefore increases generation of Abeta because NF-kappaB is a transcription factor of these genes [XREF_BIBR, XREF_BIBR].	0	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	NF-kappaB activates the transcription of APP, BACE1	bace1	Abeta	Abeta	abeta	7	8	16	17
Abeta is produced by sequential cleavage of amyloid precursor protein ( APP ) by beta-site APP cleaving enzyme 1 ( BACE1 ) followed by gamma-secretase .	Abeta is produced by sequential cleavage of amyloid precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) followed by gamma-secretase.	0	19	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	Abeta	Abeta	Abeta	14	19	0	1
We have previously described a novel artificial NFEV beta-secretase ( BACE1 ) cleavage site , which when introduced into the amyloid-beta precursor protein ( APP ) , significantly enhances APP cleavage by BACE1 in in vitro and cellular assays .	We have previously described a novel artificial NFEV beta-secretase (BACE1) cleavage site, which when introduced into the amyloid-beta precursor protein (APP), significantly enhances APP cleavage by BACE1 in in vitro and cellular assays.	8	30	enhances	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	10	11	29	30
BACE1 SUMOylation Induces Cognitive Impairment and Abeta Toxicity .	BACE1 SUMOylation Induces Cognitive Impairment and Abeta Toxicity.	0	7	Induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 SUMOylation	bace1	Abeta	Abeta	abeta	0	1	6	7
AD-PCR-Array data revealed that expression of genes directly involved in Abeta production such as App , Bace1 , Psen1 , Ncstn and Aph1a but not Adam9 were significantly increased in MS9II cells compared to MS cells ( XREF_FIG ; 2D ; 3A , B , E and F ) .	AD-PCR-Array data revealed that expression of genes directly involved in Abeta production such as App, Bace1, Psen1, Ncstn and Aph1a but not Adam9 were significantly increased in MS9II cells compared to MS cells (XREF_FIG; 2D; 3A, B, E and F).	10	17	production	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Bace1	Bace1	Bace1	Abeta	Abeta	Abeta	16	17	10	11
Abeta is produced upon intracellular cleavage of the amyloid precursor protein ( APP ) by the BACE1 beta-secretase and subsequent processing of one of the resulting fragments by gamma-secretase .	Abeta is produced upon intracellular cleavage of the amyloid precursor protein (APP) by the BACE1 beta-secretase and subsequent processing of one of the resulting fragments by gamma-secretase.	0	17	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	16	17	0	1
However , this defensive cellular mechanism might have a negative side-effect , as BACE1 translation is activated in response to eIF2-alpha phosphorylation XREF_BIBR , causing breakdown of APP to Abeta .	However, this defensive cellular mechanism might have a negative side-effect, as BACE1 translation is activated in response to eIF2-alpha phosphorylation XREF_BIBR, causing breakdown of APP to Abeta.	13	28	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	13	14	27	28
When overexpressed , sortilin increases BACE1 mediated APP cleavage , while RNAi mediated knockdown decreases Abeta .	When overexpressed, sortilin increases BACE1 mediated APP cleavage, while RNAi mediated knockdown decreases Abeta.	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	7	8
Treatment of APP overexpressing cells with BACE1 antisense oligonucleotides decreases BACE1 mRNA levels , inhibits beta-secretase activity [ XREF_BIBR , XREF_BIBR ] and reduces production of APPsbeta , C99 , and Abeta in cells ; conversely , APPsalpha and C83 generation is elevated .	Treatment of APP overexpressing cells with BACE1 antisense oligonucleotides decreases BACE1 mRNA levels, inhibits beta-secretase activity [XREF_BIBR, XREF_BIBR] and reduces production of APPsbeta, C99, and Abeta in cells; conversely, APPsalpha and C83 generation is elevated.	2	32	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	APP overexpressing cells with BACE1 antisense oligonucleotides decreases BACE1 mRNA levels	bace1	Abeta	Abeta	abeta	10	11	31	32
Moreover , we show that both Syt-1 and Syt-9 increase Abeta levels likely via BACE1 mediated APP processing and thus may play an important role in Alzheimer ' s disease pathology .	Moreover, we show that both Syt-1 and Syt-9 increase Abeta levels likely via BACE1 mediated APP processing and thus may play an important role in Alzheimer 's disease pathology.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	14	15	16	17
A further study of BACE1 heterozygote mice overexpressing mutant human APP ( PDAPP ; BACE1 +/-) showed a considerable reduction in brain Abeta levels and plaque load as compared with PDAPP ; BACE1 +/+ mice [ XREF_BIBR ] .	A further study of BACE1 heterozygote mice overexpressing mutant human APP (PDAPP; BACE1 +/-) showed a considerable reduction in brain Abeta levels and plaque load as compared with PDAPP; BACE1 +/+ mice [XREF_BIBR].	4	12	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	4	5	10	11
Furthermore , SNX6 reduction led to elevated steady-state BACE1 levels as well as increased retrograde transport of BACE1 in the endocytic pathway , suggesting that SNX6 modulates the retrograde trafficking and basal levels of BACE1 , thereby regulating BACE1 mediated APP processing and Abeta biogenesis .	Furthermore, SNX6 reduction led to elevated steady-state BACE1 levels as well as increased retrograde transport of BACE1 in the endocytic pathway, suggesting that SNX6 modulates the retrograde trafficking and basal levels of BACE1, thereby regulating BACE1 mediated APP processing and Abeta biogenesis.	38	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	38	39	40	41
Abeta is produced by the sequential cleavage of APP by BACE1 and gamma-secretase ; therefore , inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer ' s disease .	Abeta is produced by the sequential cleavage of APP by BACE1 and gamma-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer 's disease.	0	12	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	10	11	0	1
This was surprising , considering the prominent , widespread accumulation of Abeta and increased levels of BACE1 and p35 and p25 .	This was surprising, considering the prominent, widespread accumulation of Abeta and increased levels of BACE1 and p35 and p25.	11	20	increased	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	BACE1	levels of BACE1	bace1	Abeta	Abeta	abeta	16	17	11	12
It is hypothesized that Abeta accumulation induces BACE1 through the phospho-eIF2alpha pathway in plaque surrounding neurons of 5XFAD model mice while the BACE1 elevation further accelerates Abeta generation , thus forming positive feedback pathogenic mechanisms XREF_BIBR , XREF_BIBR .	It is hypothesized that Abeta accumulation induces BACE1 through the phospho-eIF2alpha pathway in plaque surrounding neurons of 5XFAD model mice while the BACE1 elevation further accelerates Abeta generation, thus forming positive feedback pathogenic mechanisms XREF_BIBR, XREF_BIBR.	22	27	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	22	23	26	27
BACE inhibition may be not sufficient to decrease brain Abeta plaques and aggregates .	BACE inhibition may be not sufficient to decrease brain Abeta plaques and aggregates.	0	10	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	0	1	9	10
Moreover , BACE levels are highest in neurons of the CNS , BACE has the correct sequence specificity , and BACE overexpressed in cells cleaves APP and increases Abeta production .	Moreover, BACE levels are highest in neurons of the CNS, BACE has the correct sequence specificity, and BACE overexpressed in cells cleaves APP and increases Abeta production.	20	29	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE overexpressed	bace	Abeta	Abeta	abeta	20	21	28	29
Inhibitors of BACE1 prevent the formation of Abeta and would therefore be potential therapeutic agents for AD .	Inhibitors of BACE1 prevent the formation of Abeta and would therefore be potential therapeutic agents for AD.	0	8	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	7	8
A recent study also reports that pharmacological inhibition of PKR successfully blocks BACE1 upregulation in APP and PS1 transgenic mice ; however , these effects do not necessarily lead to cerebral Abeta reduction or cognitive benefits .	A recent study also reports that pharmacological inhibition of PKR successfully blocks BACE1 upregulation in APP and PS1 transgenic mice; however, these effects do not necessarily lead to cerebral Abeta reduction or cognitive benefits.	12	19	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	12	13	15	16
NF-kappaB physiologically represses BACE1 transcription in vitro [ XREF_BIBR , XREF_BIBR ] , therefore limiting Abeta production .	NF-kappaB physiologically represses BACE1 transcription in vitro [XREF_BIBR, XREF_BIBR], therefore limiting Abeta production.	0	16	limiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	NF-kappaB physiologically represses BACE1 transcription	bace1	Abeta	Abeta	abeta	3	4	15	16
However , Bace1 KO mice do not produce Abeta .	However, Bace1 KO mice do not produce Abeta.	2	9	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bace1	Bace1	Bace1	Abeta	Abeta	Abeta	2	3	8	9
These results indicate that AEP deletion reduces Abeta production by attenuating BACE1 mediated cleavage of APP ( XREF_SUPPLEMENTARY ) .	These results indicate that AEP deletion reduces Abeta production by attenuating BACE1 mediated cleavage of APP (XREF_SUPPLEMENTARY).	11	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	11	12	15	16
Higher BACE1 protein levels were observed in the brain of AD patients , while BACE1 gene knocked-out mice were found not to produce Abeta .	Higher BACE1 protein levels were observed in the brain of AD patients, while BACE1 gene knocked-out mice were found not to produce Abeta.	14	24	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	14	15	23	24
A considerably higher intensity band was found in the case of cells co-transfected with Bace1 ( increased production of mCherry-sAPPbeta ) as compared to those co-transfected with Bace1-siRNA ( mostly mCherry-sAPPalpha ) .	A considerably higher intensity band was found in the case of cells co-transfected with Bace1 (increased production of mCherry-sAPPbeta) as compared to those co-transfected with Bace1-siRNA (mostly mCherry-sAPPalpha).	12	21	production	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Bace1	Bace1	Bace1	mCherry-sAPPbeta	mCherry-sAPPbeta	mCherry-sAPPbeta	14	15	19	20
APP protein is cleaved by BACE1 , producing a secreted and soluble fragment of APP ( sAPPbeta ) and C99 C-terminal fragment ( CTF ) , which is further cleaved by the gamma and secretase complex to release Abeta and the APP intracellular domain ( AICD ) .	APP protein is cleaved by BACE1, producing a secreted and soluble fragment of APP (sAPPbeta) and C99 C-terminal fragment (CTF), which is further cleaved by the gamma and secretase complex to release Abeta and the APP intracellular domain (AICD).	3	23	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	14	15
Knockout of BACE1 prevents Abeta production and improves memory in mouse models of Alzheimer ' s disease .	Knockout of BACE1 prevents Abeta production and improves memory in mouse models of Alzheimer 's disease.	0	5	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	4	5
The central hypothesis driving our translation plan is that biochemical inhibition of BACE-1 activity will rescue critical aspects of FXS pathology by reducing amyloidogenic processing of APP .	The central hypothesis driving our translation plan is that biochemical inhibition of BACE-1 activity will rescue critical aspects of FXS pathology by reducing amyloidogenic processing of APP.	12	27	rescue	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE-1	BACE-1	BACE-1	APP	APP	APP	12	13	26	27
Since BACE1 initiates the generation of Abeta , its activity is expected to be highly correlated with overall Abeta mediated pathological functions .	Since BACE1 initiates the generation of Abeta, its activity is expected to be highly correlated with overall Abeta mediated pathological functions.	1	7	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	1	2	6	7
Since dimerization of APP at its E1-ectodomain results in elevated BACE1 mediated cleavage of APP , we have now investigated whether palmitoylation of APP affects its dimerization and whether this leads to elevated beta-cleavage of the protein .	Since dimerization of APP at its E1-ectodomain results in elevated BACE1 mediated cleavage of APP, we have now investigated whether palmitoylation of APP affects its dimerization and whether this leads to elevated beta-cleavage of the protein.	7	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	10	11	14	15
We thus quantified the soluble extracellular cleavage product of APP by BACE1 , termed sAPPbeta , in the hiN cell cultures .	We thus quantified the soluble extracellular cleavage product of APP by BACE1, termed sAPPbeta, in the hiN cell cultures.	2	13	product	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	11	12	9	10
Although no BACE1 mutation has been identified in AD , BACE1 protein and activity levels are significantly increased in AD brains [ XREF_BIBR ] , and elevated BACE1 levels increase Abeta production in BACE1 transgenic ( TG ) mice [ XREF_BIBR , XREF_BIBR ] .	Although no BACE1 mutation has been identified in AD, BACE1 protein and activity levels are significantly increased in AD brains [XREF_BIBR], and elevated BACE1 levels increase Abeta production in BACE1 transgenic (TG) mice [XREF_BIBR, XREF_BIBR].	27	31	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 levels	bace1	Abeta	Abeta	abeta	27	28	30	31
Abeta peptides are generated from sequential cleavages of the amyloid beta precursor protein ( APP ) , which are mediated by the beta-site APP cleaving enzyme 1 ( BACE1 ) and Presenilin and gamma-secretase [ XREF_BIBR - XREF_BIBR ] .	Abeta peptides are generated from sequential cleavages of the amyloid beta precursor protein (APP), which are mediated by the beta-site APP cleaving enzyme 1 (BACE1) and Presenilin and gamma-secretase [XREF_BIBR - XREF_BIBR].	12	27	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	APP	APP	APP	22	27	14	15
These data suggest a mechanism whereby oxLDL lipids and 27OH-C can drive Abeta production by GSH depletion , ASMase driven membrane remodeling , and BACE1 activation in neuronal cells .	These data suggest a mechanism whereby oxLDL lipids and 27OH-C can drive Abeta production by GSH depletion, ASMase driven membrane remodeling, and BACE1 activation in neuronal cells.	11	25	drive	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	24	25	12	13
Because BACE1 initiates the processing of Abeta , inhibition of BACE1 activity could be an effective measure to prevent Abeta accumulation XREF_BIBR .	Because BACE1 initiates the processing of Abeta, inhibition of BACE1 activity could be an effective measure to prevent Abeta accumulation XREF_BIBR.	1	7	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	1	2	6	7
APP but not BACE1 overexpression in HEK293 cells raises intracellular Abeta .	APP but not BACE1 overexpression in HEK293 cells raises intracellular Abeta.	3	11	raises	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 overexpression	bace1	Abeta	Abeta	abeta	3	4	10	11
Abeta is produced by sequential cleavage of amyloid precursor protein ( APP ) by beta-secretase ( BACE1 : beta-site APP cleaving enzyme 1 ) and gamma-secretase .	Abeta is produced by sequential cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1 : beta-site APP cleaving enzyme 1) and gamma-secretase.	0	19	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	16	17	0	1
To determine whether the decrease in Abeta production is caused by the alleviation of APP processing induced by BACE1 downregulation , which could be instigated by Tyro3 overexpression in 293APPswe cells , we incubated the 293APPswe cells overexpressing GFP or Tryo3-CFP in the medium in the absence or presence of Gas6 at different concentration of 12.5 , 25 , 50 or 100 ng/ml .	To determine whether the decrease in Abeta production is caused by the alleviation of APP processing induced by BACE1 downregulation, which could be instigated by Tyro3 overexpression in 293APPswe cells, we incubated the 293APPswe cells overexpressing GFP or Tryo3-CFP in the medium in the absence or presence of Gas6 at different concentration of 12.5, 25, 50 or 100 ng/ml.	14	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	18	19	14	15
The enhanced localization of BACE1 at synaptic sites is suggested to increase release of Abeta by the synaptic terminals and directly facilitates amyloid deposition in AD patients .	The enhanced localization of BACE1 at synaptic sites is suggested to increase release of Abeta by the synaptic terminals and directly facilitates amyloid deposition in AD patients.	2	15	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	14	15
With the correct sequence specificity and at acidic pH optimum for enzymatic activity , BACE1 undertakes processing of APP , and increases Abeta generation .	With the correct sequence specificity and at acidic pH optimum for enzymatic activity, BACE1 undertakes processing of APP, and increases Abeta generation.	14	23	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	14	15	22	23
Possible mechanisms behind this decrease in Abeta generation include : ( i ) decreased levels or impaired maturation of APP , ( ii ) decreased expression of BACE1 and/or gamma-secretase proteins and/or activities , ( iii ) increased degradation of Abeta .	Possible mechanisms behind this decrease in Abeta generation include : (i) decreased levels or impaired maturation of APP, (ii) decreased expression of BACE1 and/or gamma-secretase proteins and/or activities, (iii) increased degradation of Abeta.	13	30	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	27	28	19	20
APP processing is initiated by the shedding of the large ectodomain by either an alpha-secretase ( non amyloidogenic pathway ) or the beta-secretase BACE1 ( amyloidogenic pathway ) .	APP processing is initiated by the shedding of the large ectodomain by either an alpha-secretase (non amyloidogenic pathway) or the beta-secretase BACE1 (amyloidogenic pathway).	0	26	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	23	24	0	1
beta-secretase 1 in turn increases the conversion of the amyloid precursor protein to Abeta 1-42 XREF_BIBR , XREF_BIBR .	beta-secretase 1 in turn increases the conversion of the amyloid precursor protein to Abeta 1-42 XREF_BIBR, XREF_BIBR.	0	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-secretase 1	beta-secretase 1	beta-secretase 1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	0	2	9	12
Importantly , inhibition of PKCdelta by rottlerin markedly reduces BACE1 expression , Abeta levels , and neuritic plaque formation and rescues cognitive deficits in an APP Swedish mutations K594N/M595L/presenilin -1 with an exon 9 deletion-transgenic AD mouse model .	Importantly, inhibition of PKCdelta by rottlerin markedly reduces BACE1 expression, Abeta levels, and neuritic plaque formation and rescues cognitive deficits in an APP Swedish mutations K594N/M595L/presenilin -1 with an exon 9 deletion-transgenic AD mouse model.	4	28	rescues	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	PKCdelta by rottlerin markedly reduces BACE1 expression	bace1	APP	APP	app	9	10	25	26
The discovery of BACE1 transcytosis in neurons provides important insights towards developing a better understanding of the sorting steps where APP and BACE1 trafficking intersect to initiate the production of pathogenic Abeta species .	The discovery of BACE1 transcytosis in neurons provides important insights towards developing a better understanding of the sorting steps where APP and BACE1 trafficking intersect to initiate the production of pathogenic Abeta species.	20	32	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	22	23	31	32
Since inhibition of BACE1 can reduce the formation of Abeta , it is expected that BACE1 inhibitory drugs will be highly beneficial in both cases .	Since inhibition of BACE1 can reduce the formation of Abeta, it is expected that BACE1 inhibitory drugs will be highly beneficial in both cases.	1	10	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	3	4	9	10
Using this construct allowed us to investigate APP processing prior to the endocytic compartment , hence prior to the BACE-1 mediated Abeta generation .	Using this construct allowed us to investigate APP processing prior to the endocytic compartment, hence prior to the BACE-1 mediated Abeta generation.	16	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	19	20	21	22
However , whether the reduced BACE mRNA expression leads to reduced Abeta production is unknown and requires validation .	However, whether the reduced BACE mRNA expression leads to reduced Abeta production is unknown and requires validation.	5	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	BACE	BACE mRNA expression	bace	Abeta	Abeta	abeta	5	6	11	12
BACE mediated cleavage of amyloid precursor protein ( APP ) at the N terminus of the Abeta sequence is the first step in the generation of Abeta and BACE has been shown to be upregulated in sporadic AD brains [ XREF_BIBR , XREF_BIBR ] .	BACE mediated cleavage of amyloid precursor protein (APP) at the N terminus of the Abeta sequence is the first step in the generation of Abeta and BACE has been shown to be upregulated in sporadic AD brains [XREF_BIBR, XREF_BIBR].	0	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	0	1	26	27
The strongest evidence for BACE1 as the beta-secretase in vivo came from analyses of BACE1 deficient mice ( BACE1 -/-) bred to mice overexpressing APP with the Swedish mutation ( Tg2576 ) to produce a BACE1 -/-; APP bigenic strain [ XREF_BIBR - XREF_BIBR ] .	The strongest evidence for BACE1 as the beta-secretase in vivo came from analyses of BACE1 deficient mice (BACE1 -/-) bred to mice overexpressing APP with the Swedish mutation (Tg2576) to produce a BACE1 -/-; APP bigenic strain [XREF_BIBR - XREF_BIBR].	18	28	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	18	19	24	25
The secreted N-terminal BACE1 cleavage product of APP , sAPPbeta , was also decreased significantly in the si-LRRTM3 ( 6667.7 pg/ml +/-246.7 ) vs. si-control ( 8069.7 pg/ml +/-576.1 ) group ( p = 0.03 ) .	The secreted N-terminal BACE1 cleavage product of APP, sAPPbeta, was also decreased significantly in the si-LRRTM3 (6667.7 pg/ml +/-246.7) vs. si-control (8069.7 pg/ml +/-576.1) group (p = 0.03).	3	9	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	7	8
BACE1 initiates the proteolytic process of APP into Abeta , which accumulates to form amyloid plaques .	BACE1 initiates the proteolytic process of APP into Abeta, which accumulates to form amyloid plaques.	0	7	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	6	7
Thus , pro oxidant conditions increase APP levels and enhance BACE1 mediated APP processing and in doing so might contribute to pathogenesis in AD .	Thus, pro oxidant conditions increase APP levels and enhance BACE1 mediated APP processing and in doing so might contribute to pathogenesis in AD.	9	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	10	11	12	13
A previous study of BACE1 heterozygote mice overexpressing mutant human APP platelet derived growth factor promoter ( PDAPP ; BACE1 +/-) showed a considerable reduction in brain Abeta levels and plaque load without side effect [ XREF_BIBR ] .	A previous study of BACE1 heterozygote mice overexpressing mutant human APP platelet derived growth factor promoter (PDAPP; BACE1 +/-) showed a considerable reduction in brain Abeta levels and plaque load without side effect [XREF_BIBR].	4	11	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	4	5	10	11
We found that Fbx2 significantly attenuated the BACE1 mediated beta-cleavage of APP , as assessed by generation of the C-terminal fragment C99 ( XREF_FIG ) .	We found that Fbx2 significantly attenuated the BACE1 mediated beta-cleavage of APP, as assessed by generation of the C-terminal fragment C99 (XREF_FIG).	6	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	7	8	11	12
In contrast , the aspartyl protease beta-site APP cleaving enzyme 1 ( BACE1 ) initiates the amyloidogenic APP processing pathway generating the membrane spanning CTF C99 ( indicating 99 amino acids ) and releasing sAPPbeta into the extracellular space .	In contrast, the aspartyl protease beta-site APP cleaving enzyme 1 (BACE1) initiates the amyloidogenic APP processing pathway generating the membrane spanning CTF C99 (indicating 99 amino acids) and releasing sAPPbeta into the extracellular space.	6	19	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	APP	APP	APP	6	11	17	18
It is currently unclear whether the BACE1 elevation in AD promotes Abeta generation and disease progression .	It is currently unclear whether the BACE1 elevation in AD promotes Abeta generation and disease progression.	6	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	6	7	11	12
Abeta generation is initiated by proteolysis of amyloid precursor protein ( APP ) by the beta-secretase enzyme BACE1 .	Abeta generation is initiated by proteolysis of amyloid precursor protein (APP) by the beta-secretase enzyme BACE1.	0	18	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	17	18	0	1
Moreover , in a transgenic mice model bearing APP mutation , overexpression of BACE increased the processing of APP and contributed to high levels of Abeta [ XREF_BIBR ] .	Moreover, in a transgenic mice model bearing APP mutation, overexpression of BACE increased the processing of APP and contributed to high levels of Abeta [XREF_BIBR].	11	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	overexpression of BACE	bace	APP	APP	app	13	14	18	19
Third , retromer and retromer associated proteins that regulate the sorting of APP from early and late endosomes , regulate BACE1 mediated cleavage of APP ; other proteins that regulate the sorting of BACE1 from endosomes including Golgi localized , gamma-ear containing , ADP ribosylation factor binding 1 ( GGA1 ) and GGA3 play critical roles in BACE1 cleavage .	Third, retromer and retromer associated proteins that regulate the sorting of APP from early and late endosomes, regulate BACE1 mediated cleavage of APP; other proteins that regulate the sorting of BACE1 from endosomes including Golgi localized, gamma-ear containing, ADP ribosylation factor binding 1 (GGA1) and GGA3 play critical roles in BACE1 cleavage.	20	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	20	21	24	25
Aged BACE1 KO mice engineered to overexpress human APP ( BACE1 KO/APPtg ) did not develop amyloid plaques .	Aged BACE1 KO mice engineered to overexpress human APP (BACE1 KO/APPtg) did not develop amyloid plaques.	1	11	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	1	2	8	9
The mutation is located at p2 of Abeta ( Abeta-A/T ) and has been shown to reduce BACE-1 mediated Abeta generation by 40 % using synthetic peptides as substrates .	The mutation is located at p2 of Abeta (Abeta-A/T) and has been shown to reduce BACE-1 mediated Abeta generation by 40% using synthetic peptides as substrates.	16	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	17	18	19	20
As secreted sAPPbeta levels were significantly reduced in PC12 cells lacking Syt-1 expression , our results suggest that Syt-1 regulates Abeta generation by modulating BACE1 mediated cleavage of APP .	As secreted sAPPbeta levels were significantly reduced in PC12 cells lacking Syt-1 expression, our results suggest that Syt-1 regulates Abeta generation by modulating BACE1 mediated cleavage of APP.	24	29	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	24	25	28	29
In contrast , RNAi suppression of sortilin results in decreased BACE1 mediated cleavage of APP .	In contrast, RNAi suppression of sortilin results in decreased BACE1 mediated cleavage of APP.	7	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	10	11	14	15
Importantly , inhibition of BACE1 could prevent or reduce the accumulation of Abeta in the brain , thereby reducing AD related pathology [ XREF_BIBR - XREF_BIBR ] .	Importantly, inhibition of BACE1 could prevent or reduce the accumulation of Abeta in the brain, thereby reducing AD related pathology [XREF_BIBR - XREF_BIBR].	2	13	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	12	13
The local increase of BACE1 levels at the presynaptic terminals is thought to contribute to cerebral amyloid burden in AD by facilitating overproduction of Abeta .	The local increase of BACE1 levels at the presynaptic terminals is thought to contribute to cerebral amyloid burden in AD by facilitating overproduction of Abeta.	4	25	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 levels	bace1	Abeta	Abeta	abeta	4	5	24	25
Our results demonstrate that BACE1 inhibition not only reduces Abeta generation but also downstream AD pathophysiology .	Our results demonstrate that BACE1 inhibition not only reduces Abeta generation but also downstream AD pathophysiology.	4	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	9	10
Mechanistically , neuronal expression of human BACE1 may promote hypothalamic ER stress via ceramide lipotoxicity , activation of eIF2alpha and an integrated stress response [ XREF_BIBR ] , in addition to driving Abeta production [ XREF_BIBR ] .	Mechanistically, neuronal expression of human BACE1 may promote hypothalamic ER stress via ceramide lipotoxicity, activation of eIF2alpha and an integrated stress response [XREF_BIBR], in addition to driving Abeta production [XREF_BIBR].	3	33	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	expression of human BACE1	bace1	Abeta	Abeta	abeta	6	7	32	33
Overexpression of BACE augments the amyloidogenic processing of APP as demonstrated by decreased levels of full-length APP and increased levels of C99 and C89 in vivo .	Overexpression of BACE augments the amyloidogenic processing of APP as demonstrated by decreased levels of full-length APP and increased levels of C99 and C89 in vivo.	0	9	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	Overexpression of BACE	bace	APP	APP	app	2	3	8	9
The ability to manipulate the endosomal localization of BACE1 by mutations in its cytosolic tail allowed us to investigate the importance of this localization for BACE1 catalyzed APP cleavage .	The ability to manipulate the endosomal localization of BACE1 by mutations in its cytosolic tail allowed us to investigate the importance of this localization for BACE1 catalyzed APP cleavage.	18	28	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	25	26	27	28
BACE1 activity was first determined by Western blot analysis of BACE1 mediated cleavage fragments ( betaCTF or C99 and sAPPbeta ) of APP ( XREF_FIG ) .	BACE1 activity was first determined by Western blot analysis of BACE1 mediated cleavage fragments (betaCTF or C99 and sAPPbeta) of APP (XREF_FIG).	0	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	sAPPbeta	sAPPbeta	sAPPbeta	0	1	19	20
Therefore , we hypothesized that enhanced BACE expression leads to increased APP cleavage early in the secretory pathway , depleting APP before its transport to the presynaptic terminal .	Therefore, we hypothesized that enhanced BACE expression leads to increased APP cleavage early in the secretory pathway, depleting APP before its transport to the presynaptic terminal.	6	21	depleting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE expression	bace	APP	APP	app	6	7	20	21
The results shown in XREF_FIG indicated that transport of BACE1 to endosomes is not required for BACE1 catalyzed APP cleavage .	The results shown in XREF_FIG indicated that transport of BACE1 to endosomes is not required for BACE1 catalyzed APP cleavage.	14	19	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	16	17	18	19
To investigate whether increased expression of MAO-B could lead to enhanced Abeta production , we measured secreted Abeta after overexpression of both MAO-B and the immediate gamma-secretase substrate C99 ( the BACE-1 cleavage product of APP ) in HepG2 cells .	To investigate whether increased expression of MAO-B could lead to enhanced Abeta production, we measured secreted Abeta after overexpression of both MAO-B and the immediate gamma-secretase substrate C99 (the BACE-1 cleavage product of APP) in HepG2 cells.	31	36	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	APP	APP	APP	31	32	35	36
AD cybrid data in general are consistent with other data that indicate respiratory chain inhibition or bioenergetic stress shift APP processing away from alpha secretase mediated processing , which should enhance its BACE mediated processing and produce Abeta .	AD cybrid data in general are consistent with other data that indicate respiratory chain inhibition or bioenergetic stress shift APP processing away from alpha secretase mediated processing, which should enhance its BACE mediated processing and produce Abeta.	31	38	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	32	33	37	38
BACE1 initiates the production of Abeta by cleaving the Abeta precursor protein ( APP ) to generate a membrane bound carboxy-terminal fragment ( C99 ) .	BACE1 initiates the production of Abeta by cleaving the Abeta precursor protein (APP) to generate a membrane bound carboxy-terminal fragment (C99).	0	6	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	5	6
Collectively , these data indicate that the BACE1 elevation engendered by GGA3 deletion was sufficient to increase CHL1 but not APP processing in both 5XFAD and non 5XFAD mice , most likely because BACE1 preferentially cleaves CHL1 over APP .	Collectively, these data indicate that the BACE1 elevation engendered by GGA3 deletion was sufficient to increase CHL1 but not APP processing in both 5XFAD and non 5XFAD mice, most likely because BACE1 preferentially cleaves CHL1 over APP.	7	21	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	7	8	20	21
Of note , BACE-1 knockdown in Fmr1 KO mice is expected to reduce Abeta and rescue hyperexcitability and seizures ; however , these phenotypes are exacerbated in BACE-1 KO mice .	Of note, BACE-1 knockdown in Fmr1 KO mice is expected to reduce Abeta and rescue hyperexcitability and seizures; however, these phenotypes are exacerbated in BACE-1 KO mice.	3	16	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	3	4	13	14
For example , it was already described that beta-secretase BACE1 activity increases with age , and as a consequence the levels of Abeta increase [ XREF_BIBR ] .	For example, it was already described that beta-secretase BACE1 activity increases with age, and as a consequence the levels of Abeta increase [XREF_BIBR].	9	25	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	9	10	22	23
BACE1 is mainly responsible for beta-cleavage of APP in vivo , and overexpression of BACE1 increases the production of Abeta in vitro .	BACE1 is mainly responsible for beta-cleavage of APP in vivo, and overexpression of BACE1 increases the production of Abeta in vitro.	12	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	overexpression of BACE1	bace1	Abeta	Abeta	abeta	14	15	19	20
An asparagine endopeptidase is suggested to function as a delta-secretase by cleaving APP at N373 and N585 residues , and this cleavage selectively enhances Abeta levels due to increased BACE1 accessing CTF delta fragments to initiate Abeta generation .	An asparagine endopeptidase is suggested to function as a delta-secretase by cleaving APP at N373 and N585 residues, and this cleavage selectively enhances Abeta levels due to increased BACE1 accessing CTF delta fragments to initiate Abeta generation.	26	37	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	29	30	36	37
The parameters are set according to Table XREF_TABLE , in which the rate of transition of alpha-secretase ( place ALPHA ) mediated APP processing ( aAPP ) is higher than BACE ( BACE ) driven APP digestion ( bAPP ) ( mu = 0.5 , 0.3 respectively ) .	The parameters are set according to Table XREF_TABLE, in which the rate of transition of alpha-secretase (place ALPHA) mediated APP processing (aAPP) is higher than BACE (BACE) driven APP digestion (bAPP) (mu = 0.5, 0.3 respectively).	28	36	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	APP	APP	APP	30	31	35	36
Although the signaling pathway induced by RAGE upon Abeta stimulation differs compared to the study describing the role of AGEs stimulated RAGE in the DM animal model , both reports underline the role of RAGE in promoting the expression of BACE1 , which enhances Abeta production in the brain .	Although the signaling pathway induced by RAGE upon Abeta stimulation differs compared to the study describing the role of AGEs stimulated RAGE in the DM animal model, both reports underline the role of RAGE in promoting the expression of BACE1, which enhances Abeta production in the brain.	38	45	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	expression of BACE1	bace1	Abeta	Abeta	abeta	40	41	44	45
Transgenic human AbetaPP in these rodents is cleaved by intrinsic beta-secretase ( BACE1 ) to produce Abeta .	Transgenic human AbetaPP in these rodents is cleaved by intrinsic beta-secretase (BACE1) to produce Abeta.	10	17	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	12	13	16	17
XREF_BIBR In addition , increasing levels of sortilin in post-mortem brain tissue of AD patients leads to increased BACE1 mediated cleavage of APP in cultured cells .	XREF_BIBR In addition, increasing levels of sortilin in post-mortem brain tissue of AD patients leads to increased BACE1 mediated cleavage of APP in cultured cells.	15	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	18	19	22	23
The vicious cycle of APP proteolytic cleavage giving rise to soluble and amyloidogenic immunostimulators , causing microglial activation , cytokine generation , is closed by the upregulation of BACE1 , ultimately enhancing further APP processing .	The vicious cycle of APP proteolytic cleavage giving rise to soluble and amyloidogenic immunostimulators, causing microglial activation, cytokine generation, is closed by the upregulation of BACE1, ultimately enhancing further APP processing.	26	34	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	28	29	33	34
Consistently , overexpression of calpain in heterologous APP expressing cells up-regulated the level of BACE1 and increased Abeta production .	Consistently, overexpression of calpain in heterologous APP expressing cells up-regulated the level of BACE1 and increased Abeta production.	2	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	overexpression of calpain in heterologous APP expressing cells up-regulated the level of BACE1	bace1	Abeta	Abeta	abeta	14	15	17	18
BACE1 initiates proteolysis of APP at the N terminus of Abeta , forming a large soluble fragment , sAPPbeta , and the remaining membrane bound C terminal fragment ( C-99 ) .	BACE1 initiates proteolysis of APP at the N terminus of Abeta, forming a large soluble fragment, sAPPbeta, and the remaining membrane bound C terminal fragment (C-99).	0	5	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	4	5
A slight increase of BACE1 expression is sufficient to promote C99 and Abeta production under pathological conditions XREF_BIBR .	A slight increase of BACE1 expression is sufficient to promote C99 and Abeta production under pathological conditions XREF_BIBR.	4	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 expression	bace1	Abeta	Abeta	abeta	4	5	12	13
These experiments thus demonstrated that BACE1 catalyzed APP cleavage requires export from the ER .	These experiments thus demonstrated that BACE1 catalyzed APP cleavage requires export from the ER.	5	9	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	7	8
DHEA could play a beneficial role in Alzheimer ' s disease since DHEA has been found to be neuroprotective against amyloid beta protein ( Abeta ) toxicity [ XREF_BIBR ] , to decrease lipid peroxidation in human brain tissue from patients with Alzheimer ' s disease [ XREF_BIBR ] , and to decrease the BACE enzyme that initiates Abeta production [ XREF_BIBR ] .	DHEA could play a beneficial role in Alzheimer 's disease since DHEA has been found to be neuroprotective against amyloid beta protein (Abeta) toxicity [XREF_BIBR], to decrease lipid peroxidation in human brain tissue from patients with Alzheimer 's disease [XREF_BIBR], and to decrease the BACE enzyme that initiates Abeta production [XREF_BIBR].	54	59	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	54	55	58	59
Ethanol exposure of mice for 4weeks increased APP levels and BACE1 expression , promoted Abeta production , increased plaque deposition , and worsened cognitive deficits [ XREF_BIBR ] .	Ethanol exposure of mice for 4weeks increased APP levels and BACE1 expression, promoted Abeta production, increased plaque deposition, and worsened cognitive deficits [XREF_BIBR].	0	15	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	Ethanol exposure of mice for 4weeks increased APP levels and BACE1 expression	bace1	Abeta	Abeta	abeta	10	11	14	15
The levels of secreted APP-beta , a direct BACE1 cleavage product of APP , in Tris-soluble fraction were considerably reduced in the hippocampus and cerebral cortex of APP and RTN3 Tg mice relative to those in APP Tg mice .	The levels of secreted APP-beta, a direct BACE1 cleavage product of APP, in Tris-soluble fraction were considerably reduced in the hippocampus and cerebral cortex of APP and RTN3 Tg mice relative to those in APP Tg mice.	8	13	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	8	9	12	13
Taken together , Abeta induces increases in intracellular calcium that can stimulate BACE1 expression , inducing further Abeta generation [ XREF_BIBR ] .	Taken together, Abeta induces increases in intracellular calcium that can stimulate BACE1 expression, inducing further Abeta generation [XREF_BIBR].	8	18	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	calcium that can stimulate BACE1 expression	bace1	Abeta	Abeta	abeta	12	13	17	18
BACE1 mediated APP processing can occur in endosomes , endoplasmic reticulum and trans-Golgi network or the plasma membrane , but it occurs predominantly in lipid rafts .	BACE1 mediated APP processing can occur in endosomes, endoplasmic reticulum and trans-Golgi network or the plasma membrane, but it occurs predominantly in lipid rafts.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	2	3
Impaired amyloidogenic APP processing in presence of vitamin D and vitamin D analogues is caused by a slight direct effect of these vitamins on beta-secretase activity , and by a decrease in BACE1 gene expression , accompanied by reduced BACE1 protein level .	Impaired amyloidogenic APP processing in presence of vitamin D and vitamin D analogues is caused by a slight direct effect of these vitamins on beta-secretase activity, and by a decrease in BACE1 gene expression, accompanied by reduced BACE1 protein level.	2	35	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1 gene expression	bace1	APP	APP	app	32	33	2	3
Overexpression of wild-type BACE1 , but not non SUMOylated K501R , in wild-type mice and in the APP and PS1 AD mice model highly increases Abeta production .	Overexpression of wild-type BACE1, but not non SUMOylated K501R, in wild-type mice and in the APP and PS1 AD mice model highly increases Abeta production.	0	26	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	Overexpression of wild-type BACE1	bace1	Abeta	Abeta	abeta	3	4	25	26
Our previous studies have shown that isoflurane induced caspase-3 activation can increase the levels of BACE , which will promote APP processing to generate Abeta .	Our previous studies have shown that isoflurane induced caspase-3 activation can increase the levels of BACE, which will promote APP processing to generate Abeta.	6	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	isoflurane induced caspase-3 activation can increase the levels of BACE	bace	APP	APP	app	15	16	20	21
Moderate inhibition of BACE1 activity reduces Abeta production , enhances clearance of myelin debris and improves axonal regeneration after SCI .	Moderate inhibition of BACE1 activity reduces Abeta production, enhances clearance of myelin debris and improves axonal regeneration after SCI.	3	7	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	3	4	6	7
BACE1 -/- mice exhibit endophenotypes typically seen in schizophrenia [ XREF_BIBR , XREF_BIBR ] , leading researchers to test whether partial BACE1 inhibition decreases Abeta load while limiting unwanted side effects .	BACE1 -/- mice exhibit endophenotypes typically seen in schizophrenia [XREF_BIBR, XREF_BIBR], leading researchers to test whether partial BACE1 inhibition decreases Abeta load while limiting unwanted side effects.	21	25	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	21	22	24	25
Considering that 1 ) gamma-secretase inhibitors have possible safety issues which may reduce the doses regarded as safe and 2 ) most gamma-secretase inhibitors appear to cause increases of Abeta levels at low concentrations and 3 ) central efficacy with BACE inhibitors is difficult to achieve , the aim of the present study was to evaluate if BACE-1 inhibition could prevent the Abeta rebound and rise evoked by a gamma-secretase inhibitor and if synergistic efficacy on Abeta secretion could be achieved by combining BACE and gamma-secretase inhibitors .	Considering that 1) gamma-secretase inhibitors have possible safety issues which may reduce the doses regarded as safe and 2) most gamma-secretase inhibitors appear to cause increases of Abeta levels at low concentrations and 3) central efficacy with BACE inhibitors is difficult to achieve, the aim of the present study was to evaluate if BACE-1 inhibition could prevent the Abeta rebound and rise evoked by a gamma-secretase inhibitor and if synergistic efficacy on Abeta secretion could be achieved by combining BACE and gamma-secretase inhibitors.	57	63	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	57	58	62	63
Therefore , BACE inhibition may simultaneously decrease one neurotoxic APP product ( Abeta ) while increasing another ( Aeta-alpha ) .	Therefore, BACE inhibition may simultaneously decrease one neurotoxic APP product (Abeta) while increasing another (Aeta-alpha).	2	10	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	APP	APP	APP	2	3	9	10
The expression of beta-amyloid cleavage enzyme 1 ( BACE-1 ) , one of the key enzymes to produce Abeta , is regulated by several miRNAs including miR-15a and miR-107 XREF_BIBR XREF_BIBR .	The expression of beta-amyloid cleavage enzyme 1 (BACE-1), one of the key enzymes to produce Abeta, is regulated by several miRNAs including miR-15a and miR-107 XREF_BIBR XREF_BIBR.	1	19	produce	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BACE-1	expression of beta-amyloid cleavage enzyme 1 (BACE-1	bace-1	Abeta	Abeta	abeta	8	9	18	19
For example , BACE1-AS prevents the binding of miR-485-5p to BACE1 , augments the expression of BACE1 protein , and promotes Abeta synthesis .	For example, BACE1-AS prevents the binding of miR-485-5p to BACE1, augments the expression of BACE1 protein, and promotes Abeta synthesis.	3	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1-AS prevents the binding of miR-485-5p to BACE1, augments the expression of BACE1	bace1	Abeta	Abeta	abeta	16	17	21	22
Indeed , a recent study that a BACE1 dependent cleavage product of APP is involved in axon pruning in spinal cord neurons and retinotectal projections XREF_BIBR .	Indeed, a recent study that a BACE1 dependent cleavage product of APP is involved in axon pruning in spinal cord neurons and retinotectal projections XREF_BIBR.	7	13	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	7	8	12	13
Thus , although a modest increase in BACE activity , especially in the neocortex , enhanced the deposition of Abeta , larger increases in BACE activity had the unexpected , opposite result .	Thus, although a modest increase in BACE activity, especially in the neocortex, enhanced the deposition of Abeta, larger increases in BACE activity had the unexpected, opposite result.	7	20	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	7	8	19	20
Given Abeta also as one of the oxidative stress sources , oxidative stress production and Abeta generation may set up a vicious cycle , in which oxidative stress contributes to Abeta accumulation ; and Abeta in turn induces oxidative stress , resulting in JNK and c-jun activation and increased level of BACE1 and gamma-secretase , which further enhances Abeta production .	Given Abeta also as one of the oxidative stress sources, oxidative stress production and Abeta generation may set up a vicious cycle, in which oxidative stress contributes to Abeta accumulation; and Abeta in turn induces oxidative stress, resulting in JNK and c-jun activation and increased level of BACE1 and gamma-secretase, which further enhances Abeta production.	34	59	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	Abeta in turn induces oxidative stress, resulting in JNK and c-jun activation and increased level of BACE1	bace1	Abeta	Abeta	abeta	51	52	58	59
Thus , our results demonstrate a spatial segregation of APP cleavage by meprin beta from BACE-1 mediated APP cleavage .	Thus, our results demonstrate a spatial segregation of APP cleavage by meprin beta from BACE-1 mediated APP cleavage.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	APP	APP	APP	15	16	17	18
beta-site APP cleaving enzyme 1 ( BACE1 ) initiates APP cleavage , which has been reported to be an inducer of tau pathology by altering proteasome functions in Alzheimer ' s disease ( AD ) .	beta-site APP cleaving enzyme 1 (BACE1) initiates APP cleavage, which has been reported to be an inducer of tau pathology by altering proteasome functions in Alzheimer 's disease (AD).	0	10	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	beta-site APP cleaving enzyme 1	APP	APP	APP	0	5	9	10
The initiation of Abeta production by BACE1 and the disease associated increase of BACE1 level places BACE1 in the central role of AD pathogenesis [ XREF_BIBR - XREF_BIBR ] .	The initiation of Abeta production by BACE1 and the disease associated increase of BACE1 level places BACE1 in the central role of AD pathogenesis [XREF_BIBR - XREF_BIBR].	3	9	production	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	6	7	3	4
Remarkably , coexpression of BACE1 and APP mutants that are unable to reach endosomes from either the plasma membrane or the TGN does not prevent BACE1 catalyzed APP cleavage , supporting the notion that this cleavage can occur along the late secretory pathway , en route to the plasma membrane .	Remarkably, coexpression of BACE1 and APP mutants that are unable to reach endosomes from either the plasma membrane or the TGN does not prevent BACE1 catalyzed APP cleavage, supporting the notion that this cleavage can occur along the late secretory pathway, en route to the plasma membrane.	24	28	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	25	26	27	28
Sorting nexin 12 interacts with BACE1 and regulates BACE1 mediated APP processing .	Sorting nexin 12 interacts with BACE1 and regulates BACE1 mediated APP processing.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	8	9	10	11
We postulate that Abeta is the BACE1 cleavage product of APP involved in mediating the connectivity phenotype .	We postulate that Abeta is the BACE1 cleavage product of APP involved in mediating the connectivity phenotype.	6	11	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	6	7	10	11
As one possible mechanism for an increase in Abeta , there is evidence from rodent models of ischemia and hypoxia owing to hypoperfusion that a resulting overexpression of p25 and cdk5 increases levels of BACE1 , which in turn increases amyloid precursor protein ( APP ) processing .	As one possible mechanism for an increase in Abeta, there is evidence from rodent models of ischemia and hypoxia owing to hypoperfusion that a resulting overexpression of p25 and cdk5 increases levels of BACE1, which in turn increases amyloid precursor protein (APP) processing.	26	43	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	overexpression of p25 and cdk5 increases levels of BACE1	bace1	amyloid precursor protein	amyloid precursor protein	amyloid precursor protein	34	35	40	43
Therefore , inhibiting BACE-1 has been considered as another attractive approach to prevent Abeta neurotoxicity .	Therefore, inhibiting BACE-1 has been considered as another attractive approach to prevent Abeta neurotoxicity.	2	14	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	3	4	13	14
BACE1 gene deletion in mice abrogates Abeta generation .	BACE1 gene deletion in mice abrogates Abeta generation.	0	7	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	6	7
The interaction of RTN3 with BACE1 is essential for the inhibitory role of RTN3 in the attenuation of BACE1 mediated APP processing .	The interaction of RTN3 with BACE1 is essential for the inhibitory role of RTN3 in the attenuation of BACE1 mediated APP processing.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	18	19	20	21
BACE1 overexpression leads to the production of Abeta in vitro [ XREF_BIBR ] .	BACE1 overexpression leads to the production of Abeta in vitro [XREF_BIBR].	0	11	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1 overexpression	bace1	Abeta	Abeta	abeta	0	1	7	8
The level and activity of BACE1 are shown to increase in AD brain and are proposed to drive Abeta overproduction in AD .	The level and activity of BACE1 are shown to increase in AD brain and are proposed to drive Abeta overproduction in AD.	1	19	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	level and activity of BACE1	bace1	Abeta	Abeta	abeta	5	6	18	19
Indeed , Abeta generation is abolished in BACE1 knockout mice , 41 whereas Abeta formation is increased by the overexpression of BACE1 .	Indeed, Abeta generation is abolished in BACE1 knockout mice, 41 whereas Abeta formation is increased by the overexpression of BACE1.	13	22	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	overexpression of BACE1	bace1	Abeta	Abeta	abeta	21	22	13	14
In this case , there exist progressive pathophysiological changes in axons , including BACE1 mediated Abeta overproduction .	In this case, there exist progressive pathophysiological changes in axons, including BACE1 mediated Abeta overproduction.	10	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	13	14	15	16
As noted , BACE1 levels are significantly elevated in AD brain and might accelerate the production of Abeta .	As noted, BACE1 levels are significantly elevated in AD brain and might accelerate the production of Abeta.	3	18	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 levels	bace1	Abeta	Abeta	abeta	3	4	17	18
As predicted , both BACE1 and gamma-secretase inhibitors dramatically decreased Abeta generation in iPSC derived neural cells derived from all five AD patients , under standard two-dimensional ( 2D ) differentiation conditions .	As predicted, both BACE1 and gamma-secretase inhibitors dramatically decreased Abeta generation in iPSC derived neural cells derived from all five AD patients, under standard two-dimensional (2D) differentiation conditions.	4	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	10	11
These results strongly suggest that eIF2alpha phosphorylation increases BACE1 levels and causes Abeta overproduction , which could be an early , initiating molecular mechanism in sporadic AD [ XREF_BIBR ] .	These results strongly suggest that eIF2alpha phosphorylation increases BACE1 levels and causes Abeta overproduction, which could be an early, initiating molecular mechanism in sporadic AD [XREF_BIBR].	5	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	eIF2alpha phosphorylation increases BACE1 levels	bace1	Abeta	Abeta	abeta	8	9	12	13
Thus , these data strongly support that BACE1 SUMOylation increases its stability and augments Abeta production compared with non SUMOylated mutant , and that BACE1 SUMOylation aggravates Abeta toxicity and escalates cognitive impairment .	Thus, these data strongly support that BACE1 SUMOylation increases its stability and augments Abeta production compared with non SUMOylated mutant, and that BACE1 SUMOylation aggravates Abeta toxicity and escalates cognitive impairment.	7	15	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 SUMOylation	bace1	Abeta	Abeta	abeta	7	8	14	15
Results indicated that apigenin treated mice displayed improvements in memory and learning deficits and a reduction of fibrillar amyloid deposits with lowered insoluble Abeta concentrations , mediated by a decrease in beta-CTF and BACE1 .	Results indicated that apigenin treated mice displayed improvements in memory and learning deficits and a reduction of fibrillar amyloid deposits with lowered insoluble Abeta concentrations, mediated by a decrease in beta-CTF and BACE1.	23	34	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	33	34	23	24
Inhibitors of BACE 1 have not yet been shown to reduce brain Abeta or improve memory deficit in AD patients .	Inhibitors of BACE 1 have not yet been shown to reduce brain Abeta or improve memory deficit in AD patients.	0	13	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	2	3	12	13
Thus , inhibiting BACE1 may block not only Abeta dependent but also Abeta independent pathogenic mechanisms .	Thus, inhibiting BACE1 may block not only Abeta dependent but also Abeta independent pathogenic mechanisms.	2	12	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	3	4	8	9
siRNAs targeting LRRTM3 inhibit the secretion of Abeta40 , Abeta42 , and sAPPbeta , the N-terminal APP fragment produced by BACE1 cleavage , from cultured cells and primary neurons by up to 60 % , whereas overexpression increases Abeta secretion .	siRNAs targeting LRRTM3 inhibit the secretion of Abeta40, Abeta42, and sAPPbeta, the N-terminal APP fragment produced by BACE1 cleavage, from cultured cells and primary neurons by up to 60%, whereas overexpression increases Abeta secretion.	16	21	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	20	21	16	17
BACE1 or APP may conceivably contribute to Abeta in sporadic Alzheimer ' s disease cases .	BACE1 or APP may conceivably contribute to Abeta in sporadic Alzheimer 's disease cases.	0	12	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	7	8
This notion is supported by the findings that deletion or inhibition of BACE1 prevents amyloid pathology and cognitive deficits in APP transgenic mice .	This notion is supported by the findings that deletion or inhibition of BACE1 prevents amyloid pathology and cognitive deficits in APP transgenic mice.	8	22	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	12	13	20	21
Although considerable structural and biochemical data 4 have revealed how the BH3 domain of BH3-only proteins tightly binds to and inhibits the anti-apoptotic BCL-2 proteins , until now very little was understood about how the BH3 domains of BID or BIM induce the permeabilization activity of BAK and BAX .	Although considerable structural and biochemical data 4 have revealed how the BH3 domain of BH3-only proteins tightly binds to and inhibits the anti-apoptotic BCL-2 proteins, until now very little was understood about how the BH3 domains of BID or BIM induce the permeabilization activity of BAK and BAX.	36	49	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	40	41	48	49
Finally , deletion of Bim ( and presumably Hrk ) attenuates BAX dependent cyt c release .	Finally, deletion of Bim (and presumably Hrk) attenuates BAX dependent cyt c release.	2	15	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	BAX	BAX	BAX	4	5	11	12
Indeed , both Bim and PUMA can directly activate Bax which in turn triggers mitochondrial dysfunction and cell death [ XREF_BIBR ] .	Indeed, both Bim and PUMA can directly activate Bax which in turn triggers mitochondrial dysfunction and cell death [XREF_BIBR].	2	13	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	3	4	9	10
We noticed in these experiments that the expression of Bim S caused an early shift of Bax to mitochondria .	We noticed in these experiments that the expression of Bim S caused an early shift of Bax to mitochondria.	7	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	expression of Bim	bim	Bax	Bax	bax	9	10	16	17
Upon certain apoptotic stimuli , Bim can initiate apoptosis by directly activating Bax through interaction with the Bcl-2 and Bax herterodimer complex , which can further induces mitochondrial cell death .	Upon certain apoptotic stimuli, Bim can initiate apoptosis by directly activating Bax through interaction with the Bcl-2 and Bax herterodimer complex, which can further induces mitochondrial cell death.	5	13	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	5	6	12	13
A recent study [ XREF_BIBR ] showed that Bim preferentially activates Bax , while Bid preferentially activates Bak .	A recent study [XREF_BIBR] showed that Bim preferentially activates Bax, while Bid preferentially activates Bak.	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	8	9	11	12
This may indicate that Bim and Puma activate Bak and Bax function indirectly through binding and neutralization of prosurvival Bcl-2 family members .	This may indicate that Bim and Puma activate Bak and Bax function indirectly through binding and neutralization of prosurvival Bcl-2 family members.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	4	5	10	11
Together , these results support the notion that BIM and tBID follow different strategies to trigger BAX driven mitochondrial outer membrane permeabilization with strong potency .	Together, these results support the notion that BIM and tBID follow different strategies to trigger BAX driven mitochondrial outer membrane permeabilization with strong potency.	8	17	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	8	9	16	17
The present , widely accepted model assumes that the interplay of pro- and anti -apoptotic Bcl-2 family members determines the onset of activated T cell death , with the BH3-only protein Bim activating pro apoptotic Bax and Bak .	The present, widely accepted model assumes that the interplay of pro- and anti -apoptotic Bcl-2 family members determines the onset of activated T cell death, with the BH3-only protein Bim activating pro apoptotic Bax and Bak.	18	37	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	31	32	35	36
Bim and other BH3-only proteins are thought to promote apoptosis by binding and inhibiting anti-apoptotic Bcl-2 proteins ( such as Bcl-2 , Bcl-X L and Mcl-1 ) that directly suppress downstream effectors Bax and Bak , which are responsible for disrupting mitochondrial membrane integrity .	Bim and other BH3-only proteins are thought to promote apoptosis by binding and inhibiting anti-apoptotic Bcl-2 proteins (such as Bcl-2, Bcl-X L and Mcl-1) that directly suppress downstream effectors Bax and Bak, which are responsible for disrupting mitochondrial membrane integrity.	0	34	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	32	33
Finally , we found that Bim levels were significantly increased in effector CD8 + T cells lacking Bax and Bak .	Finally, we found that Bim levels were significantly increased in effector CD8 + T cells lacking Bax and Bak.	5	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim levels	bim	Bax	Bax	bax	5	6	17	18
The mechanisms by which these messengers induce cell death remain controversial ; however , Bid , Bim , and Puma are thought to directly activate the executioners Bax and/or Bak , XREF_BIBR - XREF_BIBR whereas the others may antagonize the ability of the antiapoptotic proteins to prevent Bax and Bak activation .	The mechanisms by which these messengers induce cell death remain controversial; however, Bid, Bim, and Puma are thought to directly activate the executioners Bax and/or Bak, XREF_BIBR - XREF_BIBR whereas the others may antagonize the ability of the antiapoptotic proteins to prevent Bax and Bak activation.	14	29	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	16	17	27	28
XREF_BIBR Bax activation is further induced by JNK mediated phosphorylation of Bad and Bim , resulting in inhibition of prosurvival Bcl-xL and Bcl-2 .	XREF_BIBR Bax activation is further induced by JNK mediated phosphorylation of Bad and Bim, resulting in inhibition of prosurvival Bcl-xL and Bcl-2.	1	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bim	JNK mediated phosphorylation of Bad and Bim	bim	Bax	Bax	bax	13	14	1	2
Low nanomolar ( < 10nM ) concentrations of recombinant full-length BID or BIM activate BAX in vitro , whereas micromolar concentrations of BH3 peptides are needed to achieve the same level of BAX activation .	Low nanomolar (< 10nM) concentrations of recombinant full-length BID or BIM activate BAX in vitro, whereas micromolar concentrations of BH3 peptides are needed to achieve the same level of BAX activation.	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	12	13	14	15
To date , several classes of novel direct Bax activators including Bid SAHB A , Bim SAHB , BAM7 , BTC-8 , compound 106 and SMBAs have been identified to effectively induce Bax-mediate apoptosis in vitro and in vivo .	To date, several classes of novel direct Bax activators including Bid SAHB A, Bim SAHB, BAM7, BTC-8, compound 106 and SMBAs have been identified to effectively induce Bax-mediate apoptosis in vitro and in vivo.	8	16	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	15	16	8	9
This finding suggests that R21A interacts directly with and sequesters Bim or that it binds to Bax and prevents Bim mediated activation of Bax .	This finding suggests that R21A interacts directly with and sequesters Bim or that it binds to Bax and prevents Bim mediated activation of Bax.	18	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	19	20	23	24
As a further measure of specificity , we found that R153D mutagenesis of BIM SAHB , which eliminated its BAX activating capacity in the oligomerization and cytochrome c release assays ( XREF_FIG ) , likewise abolished BIM SAHB induced activation of BAX and BAX K21E in a cellular context ( XREF_FIG ) .	As a further measure of specificity, we found that R153D mutagenesis of BIM SAHB, which eliminated its BAX activating capacity in the oligomerization and cytochrome c release assays (XREF_FIG), likewise abolished BIM SAHB induced activation of BAX and BAX K21E in a cellular context (XREF_FIG).	36	44	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	36	37	41	42
Taking advantage of recently published work demonstrating that BIM preferentially promotes BAX mediated MOMP , we next examined the efficiency by which BIM-S affected MOMP in Mfn1 -/- cells treated with mDIVI-1 .	Taking advantage of recently published work demonstrating that BIM preferentially promotes BAX mediated MOMP, we next examined the efficiency by which BIM-S affected MOMP in Mfn1 -/- cells treated with mDIVI-1.	8	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	8	9	11	12
We therefore examined whether Bim S would enhance Bax dependent killing in yeast ( which would have to occur in the absence of anti-apoptotic Bcl-2 proteins ) .	We therefore examined whether Bim S would enhance Bax dependent killing in yeast (which would have to occur in the absence of anti-apoptotic Bcl-2 proteins).	4	10	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	4	5	8	9
In GC resistant primary CLL , Bim was upregulated by dexamethasone , but failed to activate Bax and Bak due to exclusive sequestration to Bcl-2 [ XREF_BIBR ] .	In GC resistant primary CLL, Bim was upregulated by dexamethasone, but failed to activate Bax and Bak due to exclusive sequestration to Bcl-2 [XREF_BIBR].	6	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	6	7	16	17
Following an apoptotic-stress event , BIM translocates to the mitochondria and initiates the mitochondrial cell death pathway by either directly activating BAX like proteins or indirectly binding pro survival BCL-2 family members , thereby releasing the BAX like proteins XREF_BIBR , XREF_BIBR .	Following an apoptotic-stress event, BIM translocates to the mitochondria and initiates the mitochondrial cell death pathway by either directly activating BAX like proteins or indirectly binding pro survival BCL-2 family members, thereby releasing the BAX like proteins XREF_BIBR, XREF_BIBR.	5	23	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM translocates to the mitochondria	bim	BAX	BAX	bax	5	6	21	22
Indeed , BIM SAHB triggered dose dependent oligomerization of BAX ( XREF_FIG ) .	Indeed, BIM SAHB triggered dose dependent oligomerization of BAX (XREF_FIG).	2	11	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	2	3	9	10
Bim expression initiates BAX and BAK mediated mitochondria dependent apoptosis [ XREF_BIBR ] .	Bim expression initiates BAX and BAK mediated mitochondria dependent apoptosis [XREF_BIBR].	0	6	initiates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bim	Bim expression	bim	BAX	BAX	bax	0	1	3	4
Bim presumably activates Bax leading to the accumulation and permeability pore formation of Bax in the mitochondrial outer membrane , causing the decrease of the mitochondrial membrane potential [ XREF_BIBR ] , the release of Cytochrome C and the activation of caspase-9 .	Bim presumably activates Bax leading to the accumulation and permeability pore formation of Bax in the mitochondrial outer membrane, causing the decrease of the mitochondrial membrane potential [XREF_BIBR], the release of Cytochrome C and the activation of caspase-9.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	3	4
Mcl-1-free Bim then initiates Bax and Bak activation and triggers the mitochondrial apoptotic pathway .	Mcl-1-free Bim then initiates Bax and Bak activation and triggers the mitochondrial apoptotic pathway.	0	9	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	1	2	4	5
Also peptides of the BH3 domains of Bid , Bim and Puma were able to drive direct activation of Bax XREF_BIBR .	Also peptides of the BH3 domains of Bid, Bim and Puma were able to drive direct activation of Bax XREF_BIBR.	9	20	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	9	10	19	20
The exposed Bax BH3 domain propagates the activation of other inactive Bax molecules in the same way that Bim activates Bax .	The exposed Bax BH3 domain propagates the activation of other inactive Bax molecules in the same way that Bim activates Bax.	18	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	18	19	20	21
Bim could further promote the release of the proapoptotic protein Bax , which is in turn responsible for mitochondrial dysfunction and caspases activation XREF_BIBR XREF_BIBR .	Bim could further promote the release of the proapoptotic protein Bax, which is in turn responsible for mitochondrial dysfunction and caspases activation XREF_BIBR XREF_BIBR.	0	24	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	10	11
Proplatelet formation could also have been impacted by other members of the intrinsic pathway , such as BIM and BID , which can activate apoptosis independently of BAK and BAX [ XREF_BIBR , XREF_BIBR ] : these could be the focus of future studies .	Proplatelet formation could also have been impacted by other members of the intrinsic pathway, such as BIM and BID, which can activate apoptosis independently of BAK and BAX [XREF_BIBR, XREF_BIBR] : these could be the focus of future studies.	9	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	17	18	29	30
Although both BAX and BAK can be activated by both BIM and BID , the efficiency of the possible interactions of these proteins are not identical .	Although both BAX and BAK can be activated by both BIM and BID, the efficiency of the possible interactions of these proteins are not identical.	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	10	11	2	3
Bim further enhanced Bax dependent killing in yeast .	Bim further enhanced Bax dependent killing in yeast.	0	5	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	3	4
Curcumin upregulates the p53 modulator of apoptosis ( PUMA ) and Noxa , which , in turn , activates the proapoptotic multi-domain Bcl-2 family members Bax , Bim , and Bak and downregulates Bcl-2 and Bcl-xl .	Curcumin upregulates the p53 modulator of apoptosis (PUMA) and Noxa, which, in turn, activates the proapoptotic multi-domain Bcl-2 family members Bax, Bim, and Bak and downregulates Bcl-2 and Bcl-xl.	4	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	27	28	25	26
Although each of these findings on its own may have their limitations , in their sum they strongly suggest that Bax activation and apoptosis by Bim S occurs in the absence of binding to anti-apoptotic Bcl-2 proteins .	Although each of these findings on its own may have their limitations, in their sum they strongly suggest that Bax activation and apoptosis by Bim S occurs in the absence of binding to anti-apoptotic Bcl-2 proteins.	20	26	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	25	26	20	21
Recent studies demonstrate that Mcl-1 may act in survival by sequestering Bim , thereby preventing a Bax dependent apoptotic cascade mediated by free Bim , and consequently preserving mitochondrial membrane potential [ XREF_BIBR , XREF_BIBR ] .	Recent studies demonstrate that Mcl-1 may act in survival by sequestering Bim, thereby preventing a Bax dependent apoptotic cascade mediated by free Bim, and consequently preserving mitochondrial membrane potential [XREF_BIBR, XREF_BIBR].	16	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	23	24	16	17
Thus BID more efficiently activated BAK while BIM more efficiently activated BAX when all components were recombinant .	Thus BID more efficiently activated BAK while BIM more efficiently activated BAX when all components were recombinant.	7	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	7	8	11	12
The free Bim directly activates Bax or inactivates pro survival activity of Bcl-2 .	The free Bim directly activates Bax or inactivates pro survival activity of Bcl-2.	0	7	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	5	6
Furthermore , it was shown recently that the human Bcl-2 family protein BAX is activated by binding of the helical BIM SAHB peptide on the 1-6 face of the protein .	Furthermore, it was shown recently that the human Bcl-2 family protein BAX is activated by binding of the helical BIM SAHB peptide on the 1-6 face of the protein.	9	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	20	21	12	13
The results showed that Bim-EL not Bax was co-immunoprecipitated with Bcl2 , which further confirmed that Bim most likely activates indirectly Bax via binding and engaging anti-apoptotic protein Bcl2 .	The results showed that Bim-EL not Bax was co-immunoprecipitated with Bcl2, which further confirmed that Bim most likely activates indirectly Bax via binding and engaging anti-apoptotic protein Bcl2.	16	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	16	17	21	22
Bim that is not complexed to Bcl-2 would be free to promote apoptosis by activating Bax and/or Bak .	Bim that is not complexed to Bcl-2 would be free to promote apoptosis by activating Bax and/or Bak.	0	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	15	16
BAK and BAX can also be directly activated by the BH3-only proteins , BIM , tBID and PUMA , though only PUMA is upregulated by p53 activation ( see XREF_FIG ) .	BAK and BAX can also be directly activated by the BH3-only proteins, BIM, tBID and PUMA, though only PUMA is upregulated by p53 activation (see XREF_FIG).	0	14	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	13	14	2	3
MAC , whose formation requires Bim induced activation of Bax and a still unidentified protein , is considered as a target for novel cancer therapies but specific MAC activators are not available yet .	MAC, whose formation requires Bim induced activation of Bax and a still unidentified protein, is considered as a target for novel cancer therapies but specific MAC activators are not available yet.	5	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	5	6	9	10
We report that cell death promoting activity of BH3-only protein Bim can be reconstituted in yeast when both Bax and antiapoptotic protein Bcl-X ( L ) are present , suggesting that Bim likely activates Bax indirectly by inhibiting antiapoptotic proteins .	We report that cell death promoting activity of BH3-only protein Bim can be reconstituted in yeast when both Bax and antiapoptotic protein Bcl-X (L) are present, suggesting that Bim likely activates Bax indirectly by inhibiting antiapoptotic proteins.	31	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	31	32	34	35
As an upstream factor of Bax , Bim may promote Bax activation XREF_BIBR - XREF_BIBR and its localization at the outer mitochondrial membrane and form oligomers , which may further mediate mitochondrial apoptotic pathways , such as inducing the release of cytochrome c , a second mitochondria derived activator of caspase and diablo homolog ( Smac/DIABLO ) and apoptosis inducing factor XREF_BIBR - XREF_BIBR .	As an upstream factor of Bax, Bim may promote Bax activation XREF_BIBR - XREF_BIBR and its localization at the outer mitochondrial membrane and form oligomers, which may further mediate mitochondrial apoptotic pathways, such as inducing the release of cytochrome c, a second mitochondria derived activator of caspase and diablo homolog (Smac/DIABLO) and apoptosis inducing factor XREF_BIBR - XREF_BIBR.	7	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	7	8	10	11
Bim ( L ) , a BH3-only member of Bcl-2 family , can directly or indirectly activate the proapoptotic Bax and the subsequent mitochondrial apoptotic pathway .	Bim (L), a BH3-only member of Bcl-2 family, can directly or indirectly activate the proapoptotic Bax and the subsequent mitochondrial apoptotic pathway.	0	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	19	20
XREF_BIBR , XREF_BIBR Although it has been proposed that Bax and Bak activation occurs by default as long as all of the anti-apoptotic Bcl-2 proteins are neutralized by BH3s , 13 liposome studies clearly recapitulate the direct activation model in which tBid or BH3 domain peptides derived from Bid or Bim induce Bax or Bak oligomerization and membrane permeabilization .	XREF_BIBR, XREF_BIBR Although it has been proposed that Bax and Bak activation occurs by default as long as all of the anti-apoptotic Bcl-2 proteins are neutralized by BH3s, 13 liposome studies clearly recapitulate the direct activation model in which tBid or BH3 domain peptides derived from Bid or Bim induce Bax or Bak oligomerization and membrane permeabilization.	46	55	induce	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	50	51	52	53
Bim is a proapoptotic BH3-only Bcl-2 family member.In response to death stimuli , Bim dissociates from the dynein light chain 1 ( DYNLL1 and LC8 ) , where it is inactive , and can then initiate Bax and Bak mediated mitochondria dependent apoptosis .	Bim is a proapoptotic BH3-only Bcl-2 family member.In response to death stimuli, Bim dissociates from the dynein light chain 1 (DYNLL1 and LC8), where it is inactive, and can then initiate Bax and Bak mediated mitochondria dependent apoptosis.	13	37	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	13	14	36	37
Similar to tBID , BIM and PUMA also directly activated BAX to induce its mitochondrial insertion ( XREF_FIG ) .	Similar to tBID, BIM and PUMA also directly activated BAX to induce its mitochondrial insertion (XREF_FIG).	4	12	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	4	5	10	11
An increased level of BIM protein and/or modified BIM protein subsequently results in the activation of BAX and BAK , which , like BIM , are required for negative selection , thereby leading to apoptosome formation and caspase activation .	An increased level of BIM protein and/or modified BIM protein subsequently results in the activation of BAX and BAK, which, like BIM, are required for negative selection, thereby leading to apoptosome formation and caspase activation.	8	18	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	8	9	16	17
In particular , in contrast to a recent report , 25 there was little evidence of Bid preferentially targeting Bak and Bim preferentially targeting Bax , as Bid Bim was approximately fourfold less potent than Bid in activating both Bak and Bax .	In particular, in contrast to a recent report, 25 there was little evidence of Bid preferentially targeting Bak and Bim preferentially targeting Bax, as Bid Bim was approximately fourfold less potent than Bid in activating both Bak and Bax.	19	33	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	21	22	24	25
Here we showed that BID preferentially activates BAK while BIM preferentially activates BAX in both mouse and human cells .	Here we showed that BID preferentially activates BAK while BIM preferentially activates BAX in both mouse and human cells.	9	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	9	10	12	13
Conversely , miR-124 upregulation can inhibit expression of the protein Bim , and reduce translocation of its downstream protein Bax to mitochondria and lysosome , thus suppressing mitochondria apoptotic signaling pathways and normalizing the impaired autophagy process .	Conversely, miR-124 upregulation can inhibit expression of the protein Bim, and reduce translocation of its downstream protein Bax to mitochondria and lysosome, thus suppressing mitochondria apoptotic signaling pathways and normalizing the impaired autophagy process.	2	20	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bim	miR-124 upregulation can inhibit expression of the protein Bim	bim	Bax	Bax	bax	10	11	19	20
The importance of BIM induction in triggering apoptosis was shown in BIM knockdown cells where BAX activation was attenuated by drug combination , consistent with evidence that BIM preferentially activates BAX whereas BID preferentially activates BAK .	The importance of BIM induction in triggering apoptosis was shown in BIM knockdown cells where BAX activation was attenuated by drug combination, consistent with evidence that BIM preferentially activates BAX whereas BID preferentially activates BAK.	27	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	27	28	30	31
In the intrinsic apoptosis pathway , both Bim and Puma can induce Bax or Bak activation and cause cell apoptosis .	In the intrinsic apoptosis pathway, both Bim and Puma can induce Bax or Bak activation and cause cell apoptosis.	6	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	7	8	12	13
In healthy cells , Bax is either located in the cytosol or loosely associated to mitochondria and endoplasmic reticulum , 40 but when the apoptosis is beginning , Bax is directly activated by Bim activation , through which the downstream factors is stimulated to participate in the apoptosis , 41 which could be responsible to the highest apoptosis rate of the Akt1 group , consistent with the study that PI3K dependent Bax and Bak activation promotes the platelets apoptosis .	In healthy cells, Bax is either located in the cytosol or loosely associated to mitochondria and endoplasmic reticulum, 40 but when the apoptosis is beginning, Bax is directly activated by Bim activation, through which the downstream factors is stimulated to participate in the apoptosis, 41 which could be responsible to the highest apoptosis rate of the Akt1 group, consistent with the study that PI3K dependent Bax and Bak activation promotes the platelets apoptosis.	28	34	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	33	34	28	29
Indeed , we previously found that BAX K21E mutagenesis slows ( but does not wholly abrogate ) the kinetics of direct BAX activation by BIM and BAX BH3 helices in vitro , and in Bax -/- Bak -/- mouse embryonic fibroblasts ( MEFs ) reconstituted with BAX K21E and exposed to staurosporine .	Indeed, we previously found that BAX K21E mutagenesis slows (but does not wholly abrogate) the kinetics of direct BAX activation by BIM and BAX BH3 helices in vitro, and in Bax -/- Bak -/- mouse embryonic fibroblasts (MEFs) reconstituted with BAX K21E and exposed to staurosporine.	21	28	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	24	25	21	22
However , our data do not fully exclude either the direct or indirect activation models as previously posited , and indeed , recent studies suggest that these models are not mutually exclusive , in that BIM ( which similar to tBID is proposed to be a ` direct activator ' ) antagonizes antiapoptotic BCL-2 family members and directly activates BAX in vivo .	However, our data do not fully exclude either the direct or indirect activation models as previously posited, and indeed, recent studies suggest that these models are not mutually exclusive, in that BIM (which similar to tBID is proposed to be a ` direct activator ') antagonizes antiapoptotic BCL-2 family members and directly activates BAX in vivo.	34	61	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	35	36	59	60
Therefore , these results suggest that Bim triggers apoptosis by activating Bax in p53 deficient tumors upon actin damage , and that actin inhibitors may be potent chemotherapeutic agents against p53 deficient tumors .	Therefore, these results suggest that Bim triggers apoptosis by activating Bax in p53 deficient tumors upon actin damage, and that actin inhibitors may be potent chemotherapeutic agents against p53 deficient tumors.	6	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	6	7	11	12
BID , BIM , and PUMA Are Essential for Activation of the BAX- and BAK Dependent Cell Death Program .	BID, BIM, and PUMA Are Essential for Activation of the BAX- and BAK Dependent Cell Death Program.	0	13	Are Essential for Activation	Positive_activation_copula_1	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX-	BAX-	BAX-	2	3	12	13
In accordance with these previous studies we also observe that expression of BIM protein and not BAD protein induces BAX and BAK dependent cell death ( data no shown ) .	In accordance with these previous studies we also observe that expression of BIM protein and not BAD protein induces BAX and BAK dependent cell death (data no shown).	10	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	expression of BIM	bim	BAX	BAX	bax	12	13	19	20
Finally , we examined the integration of BAX , BCL-xL , BIM , MCL-1 , and PUMA in the LUV system , which revealed that this unique combination of BCL-2 family proteins did not promote LUV permeabilization unless ABT-737 was added , suggesting that ABT-737 could specifically trigger BIM mediated BAX activation in this setting ( XREF_FIG ) .	Finally, we examined the integration of BAX, BCL-xL, BIM, MCL-1, and PUMA in the LUV system, which revealed that this unique combination of BCL-2 family proteins did not promote LUV permeabilization unless ABT-737 was added, suggesting that ABT-737 could specifically trigger BIM mediated BAX activation in this setting (XREF_FIG).	48	51	mediated	Positive_early_activation	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	48	49	50	51
Among BH3-only molecules , Bid and Bim may directly activate Bax and Bak by a hit-and-run mechanism , whereas other members of this family seem to act by antagonizing the survival activity of antiapoptotic proteins , i.e ., Bcl-2 , Bcl-x L , and Mcl-1 .	Among BH3-only molecules, Bid and Bim may directly activate Bax and Bak by a hit-and-run mechanism, whereas other members of this family seem to act by antagonizing the survival activity of antiapoptotic proteins, i.e., Bcl-2, Bcl-x L, and Mcl-1.	4	12	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	6	7	10	11
Since the BH3-only Bim protein is a potent inducer of mitochondrial apoptosis , Bim knockdown was shown to attenuate caspase-3 , -9 cleavage and Bax and Bak activation by sorafenib plus TRAIL .	Since the BH3-only Bim protein is a potent inducer of mitochondrial apoptosis, Bim knockdown was shown to attenuate caspase-3, -9 cleavage and Bax and Bak activation by sorafenib plus TRAIL.	13	27	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	13	14	24	25
In cells treated with sorafenib and/or TRAIL , however , Bim knockdown attenuated caspase cleavage and reduced Bak and Bax activation , indicating that apoptosis induction by sorafenib plus TRAIL is partially dependent upon Bim .	In cells treated with sorafenib and/or TRAIL, however, Bim knockdown attenuated caspase cleavage and reduced Bak and Bax activation, indicating that apoptosis induction by sorafenib plus TRAIL is partially dependent upon Bim.	10	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	10	11	19	20
We previously demonstrated that a K21E mutation , which reverses the polarity of an electrostatic residue at the BAX trigger site , impairs BIM SAHB induced BAX activation in vitro and in cells .	We previously demonstrated that a K21E mutation, which reverses the polarity of an electrostatic residue at the BAX trigger site, impairs BIM SAHB induced BAX activation in vitro and in cells.	23	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	23	24	26	27
Where c-Myc was absent , Bim , despite its induction by SAHA , failed to activate Bax and was unable to induce apoptosis .	Where c-Myc was absent, Bim, despite its induction by SAHA, failed to activate Bax and was unable to induce apoptosis.	5	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	5	6	16	17
Herein , we show that significant activation preferences exist between these proteins : BID preferentially activates BAK while BIM preferentially activates BAX .	Herein, we show that significant activation preferences exist between these proteins : BID preferentially activates BAK while BIM preferentially activates BAX.	18	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	18	19	21	22
Previous studies indicated that BimL was involved in UV induced apoptosis , but it remains unclear whether Bim activates Bax by directly engaging it or by releasing it from pro survival relatives such as Bcl-xL .	Previous studies indicated that BimL was involved in UV induced apoptosis, but it remains unclear whether Bim activates Bax by directly engaging it or by releasing it from pro survival relatives such as Bcl-xL.	17	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	17	18	19	20
XREF_BIBR , XREF_BIBR The subgroup of BH3-only proteins are separated into the potently proapoptotic members , including Bid , Bim and Puma which can directly activate Bax and Bak to promote mitochondrial release of apoptogenic proteins and the weaker BH3-only proteins that function principally by neutralizing antiapoptotic members ( ' sensitizer and inactivator ' ) .	XREF_BIBR, XREF_BIBR The subgroup of BH3-only proteins are separated into the potently proapoptotic members, including Bid, Bim and Puma which can directly activate Bax and Bak to promote mitochondrial release of apoptogenic proteins and the weaker BH3-only proteins that function principally by neutralizing antiapoptotic members (' sensitizer and inactivator ').	17	28	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	19	20	26	27
The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members , whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly .	The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly.	25	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	25	26	30	31
XREF_BIBR , XREF_BIBR BIM activates Bax to induce mitochondrial dependent apoptosis .	XREF_BIBR, XREF_BIBR BIM activates Bax to induce mitochondrial dependent apoptosis.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	Bax	Bax	Bax	3	4	5	6
In this study we found that the anticancer effect of ABT-737 on human oral cancer cells seems to be mediated through the BH3 domain protein , Bim , which directly activates Bax to trigger apoptosis rather than regulating other Bcl-2 family proteins , such as Bcl-2 and Bcl-xL .	In this study we found that the anticancer effect of ABT-737 on human oral cancer cells seems to be mediated through the BH3 domain protein, Bim, which directly activates Bax to trigger apoptosis rather than regulating other Bcl-2 family proteins, such as Bcl-2 and Bcl-xL.	24	47	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	26	27	31	32
While many studies have demonstrated the ability of Bim to bind to anti-apoptotic proteins , less is known on how Bim activates Bax and Bak .	While many studies have demonstrated the ability of Bim to bind to anti-apoptotic proteins, less is known on how Bim activates Bax and Bak.	20	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	20	21	22	23
Bim also activates Bax , which induces mitochondrial permeabilization and cell death .	Bim also activates Bax, which induces mitochondrial permeabilization and cell death.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	3	4
Concomitantly , the pro apoptotic protein Bim activates Bax and Bak and induces permeabilization of the mitochondrial membrane to release cytochrome c.	Concomitantly, the pro apoptotic protein Bim activates Bax and Bak and induces permeabilization of the mitochondrial membrane to release cytochrome c.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	6	7	8	9
The activated Bim may directly activate pro apoptotic Bax , or indirectly activate Bax by binding anti-apoptotic Bcl-2 family proteins ( e.g ., Bcl-2 and Bcl-X L ) XREF_BIBR , XREF_BIBR .	The activated Bim may directly activate pro apoptotic Bax, or indirectly activate Bax by binding anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2 and Bcl-X L) XREF_BIBR, XREF_BIBR.	0	9	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	8	9
Thus , in four distinct in vitro assays that measure ligand induced BAX activation , BIM SAHB directly and dose-responsively triggered BAX .	Thus, in four distinct in vitro assays that measure ligand induced BAX activation, BIM SAHB directly and dose-responsively triggered BAX.	15	22	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	15	16	21	22
Although Bid and Bim can both activate Bax and Bak , it has been reported that Bim preferentially activates Bax , while Bid preferentially activates Bak [ XREF_BIBR ] .	Although Bid and Bim can both activate Bax and Bak, it has been reported that Bim preferentially activates Bax, while Bid preferentially activates Bak [XREF_BIBR].	16	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	16	17	19	20
Recent data suggests that activators may possess functional differences , with BIM preferentially activating BAX , and BID preferentially activating BAK .	Recent data suggests that activators may possess functional differences, with BIM preferentially activating BAX, and BID preferentially activating BAK.	11	17	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	11	12	14	15
In each of these cells lines , expression of Bim S initiated apoptosis ( XREF_FIG ) , explained by strong binding of Bim S to all prosurvival proteins ( and perhaps direct activation of both Bak and Bax by Bim S ) .	In each of these cells lines, expression of Bim S initiated apoptosis (XREF_FIG), explained by strong binding of Bim S to all prosurvival proteins (and perhaps direct activation of both Bak and Bax by Bim S).	32	40	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	39	40	37	38
However , recent studies have confirmed the direct binding and activation of BAX by BIM and BAK by BID [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	However, recent studies have confirmed the direct binding and activation of BAX by BIM and BAK by BID [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	14	15	12	13
23 Our findings differ from experiments with permeabilized cells ( which may contain prosurvival proteins ) , where Bak was preferentially activated by Bid , while Bax was preferentially activated by Bim .	23 Our findings differ from experiments with permeabilized cells (which may contain prosurvival proteins), where Bak was preferentially activated by Bid, while Bax was preferentially activated by Bim.	26	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	31	32	26	27
Bim expression initiates BAX and BAK mediated mitochondria dependent apoptosis .	Bim expression initiates BAX and BAK mediated mitochondria dependent apoptosis.	0	6	initiates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bim	Bim expression	bim	BAX	BAX	bax	0	1	3	4
How BH3-only family members activate BAX and BAK remains controversial , but BID , BIM , and PUMA are thought to directly activate BAX and BAK , whereas BAD , NOXA , and other BH3-only family members indirectly activate BAX and BAK ( or contribute to their activation ) through neutralization of the antiapoptotic family members XREF_BIBR - XREF_BIBR .	How BH3-only family members activate BAX and BAK remains controversial, but BID, BIM, and PUMA are thought to directly activate BAX and BAK, whereas BAD, NOXA, and other BH3-only family members indirectly activate BAX and BAK (or contribute to their activation) through neutralization of the antiapoptotic family members XREF_BIBR - XREF_BIBR.	12	38	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	14	15	23	24
By contrast , Bax -/- / Bak -/- MEFs treated with the BID and BIM BH3 peptides displayed short , spherical mitochondria ( XREF_FIG middle and bottom panel respectively ) , indicative of mitochondrial fragmentation .	By contrast, Bax -/- / Bak -/- MEFs treated with the BID and BIM BH3 peptides displayed short, spherical mitochondria (XREF_FIG middle and bottom panel respectively), indicative of mitochondrial fragmentation.	1	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BIM	BIM	BIM	Bax	Bax	Bax	14	15	3	4
Importantly , ER stress induced homo-oligomerization of BAX or BAK was blocked by the deficiency of Bim and Puma , supporting that BIM and PUMA are required to activate BAX and BAK upon ER stress ( XREF_FIG ) .	Importantly, ER stress induced homo-oligomerization of BAX or BAK was blocked by the deficiency of Bim and Puma, supporting that BIM and PUMA are required to activate BAX and BAK upon ER stress (XREF_FIG).	22	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	22	23	29	30
In other terms , we can speak of a model in which Bim and PUMA can activate directly Bax when they are no longer antagonized by Bcl-2 , Bcl-xl , and Bcl-w anti-apoptotic proteins , i.e ., when Bad ( or other BH3-only proteins ) engages and represses Bcl-2 , Bcl-xl , and Bcl-w anti-apoptotic proteins .	In other terms, we can speak of a model in which Bim and PUMA can activate directly Bax when they are no longer antagonized by Bcl-2, Bcl-xl, and Bcl-w anti-apoptotic proteins, i.e., when Bad (or other BH3-only proteins) engages and represses Bcl-2, Bcl-xl, and Bcl-w anti-apoptotic proteins.	12	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	12	13	18	19
The pro apoptotic factors Bid and/or Bim are necessary to activate Bax and/or Bak , possibly through neutralizing Bcl-2 and Bcl-X L activity [ XREF_BIBR ] .	The pro apoptotic factors Bid and/or Bim are necessary to activate Bax and/or Bak, possibly through neutralizing Bcl-2 and Bcl-X L activity [XREF_BIBR].	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	6	7	11	12
Genetic deletion of Bid , Bim , and Puma prevents the homo-oligomerization of BAX and BAK and thereby cytochrome c mediated caspase activation in response to diverse death signals .	Genetic deletion of Bid, Bim, and Puma prevents the homo-oligomerization of BAX and BAK and thereby cytochrome c mediated caspase activation in response to diverse death signals.	1	15	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	BAX	BAX	BAX	5	6	13	14
The multi-domain pro apoptotic proteins BAX and BAK are essential for mitochondrial apoptosis and are directly activated by activator BH3-only proteins ( BIM , BID and potentially PUMA ) .	The multi-domain pro apoptotic proteins BAX and BAK are essential for mitochondrial apoptosis and are directly activated by activator BH3-only proteins (BIM, BID and potentially PUMA).	0	27	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	22	23	5	6
Bim , in cooperation with PUMA , induces the activation of the multi-domain executioner proapoptotic protein Bax .	Bim, in cooperation with PUMA, induces the activation of the multi-domain executioner proapoptotic protein Bax.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	16	17
Little is known regarding how BID and BIM trigger the activation of BAK and BAX .	Little is known regarding how BID and BIM trigger the activation of BAK and BAX.	5	15	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	7	8	14	15
BIM SAHB constructs in which the staple was differentially localized along the non interacting surface of the BH3 helix induced BAX activation with similar potency and specificity , whereas a staple placed at the interaction surface disrupted ligand binding and functional activity , as anticipated 58 .	BIM SAHB constructs in which the staple was differentially localized along the non interacting surface of the BH3 helix induced BAX activation with similar potency and specificity, whereas a staple placed at the interaction surface disrupted ligand binding and functional activity, as anticipated 58.	0	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	0	1	20	21
It is possible that Bax can be activated also in the cytosol ( and then translocate to mitochondria ) but we have recently shown that Bax activation by Bim can occur at the outer mitochondrial membrane [ XREF_BIBR ] .	It is possible that Bax can be activated also in the cytosol (and then translocate to mitochondria) but we have recently shown that Bax activation by Bim can occur at the outer mitochondrial membrane [XREF_BIBR].	25	29	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	28	29	25	26
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Upon apoptosis , the ' activator ' BH3s , including truncated Bid ( tBid ) , Bim , and Puma , activate Bax and Bak to mediate cytochrome c efflux , leading to caspase activation .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Upon apoptosis, the ' activator ' BH3s, including truncated Bid (tBid), Bim, and Puma, activate Bax and Bak to mediate cytochrome c efflux, leading to caspase activation.	20	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	25	26	31	32
P53 increases the expression of numerous apoptotic proteins in cells , including BAX activators Bim and DP5 , and the death receptor ligand FasL .	P53 increases the expression of numerous apoptotic proteins in cells, including BAX activators Bim and DP5, and the death receptor ligand FasL.	7	16	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Bim	Bim	Bim	BAX	BAX	BAX	14	15	12	13
In response to cellular stresses , BH3-only proteins Bim and tBid can bind to Bcl2 or Bcl-xL , thereby neutralize their anti-apoptotic effects , and relieve Bax or Bak from Bcl2 bound complexes [ XREF_BIBR ] ; or alternatively Bim and tBid directly activate Bax and Bak [ XREF_BIBR , XREF_BIBR ] , thereby initiating caspase activation and cell death .	In response to cellular stresses, BH3-only proteins Bim and tBid can bind to Bcl2 or Bcl-xL, thereby neutralize their anti-apoptotic effects, and relieve Bax or Bak from Bcl2 bound complexes [XREF_BIBR]; or alternatively Bim and tBid directly activate Bax and Bak [XREF_BIBR, XREF_BIBR], thereby initiating caspase activation and cell death.	39	48	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	39	40	44	45
In contrast to alpha1-alpha2 loop tethered BAX ( L45C-M137C ) but similar to wild-type BAX , BIM SAHB induced dose responsive exposure of the N-terminal 6A7 activation epitope of BAX ( A112C-V177C ) ( XREF_SUPPLEMENTARY ) .	In contrast to alpha1-alpha2 loop tethered BAX (L45C-M137C) but similar to wild-type BAX, BIM SAHB induced dose responsive exposure of the N-terminal 6A7 activation epitope of BAX (A112C-V177C) (XREF_SUPPLEMENTARY).	16	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	16	17	29	30
Hydrogen-deuterium exchange mass spectrometry demonstrated that the N-terminal conformational changes in BAX induced by a triggering BIM BH3 helix were suppressed by the BCL-2 BH4 helix .	Hydrogen-deuterium exchange mass spectrometry demonstrated that the N-terminal conformational changes in BAX induced by a triggering BIM BH3 helix were suppressed by the BCL-2 BH4 helix.	9	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	16	17	11	12
The expression of Bcl-2 family members in these WM cell lines indicate distinct mechanisms leading to a common defect in the intrinsic apoptotic pathway at the point of Bim activation of Bax and Bak .	The expression of Bcl-2 family members in these WM cell lines indicate distinct mechanisms leading to a common defect in the intrinsic apoptotic pathway at the point of Bim activation of Bax and Bak.	28	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	28	29	31	32
It had been suggested that BAX and BAK are activated not by BIM and BID but instead via the inactivation of anti-apoptotic BCL-2 family members [ XREF_BIBR ] .	It had been suggested that BAX and BAK are activated not by BIM and BID but instead via the inactivation of anti-apoptotic BCL-2 family members [XREF_BIBR].	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	12	13	5	6
49 Because Bim is a direct activator of Bax , 50 the activation of BH3-only proteins by AMPK hyperactivation may transmit the atrophic signals to the cell death cascade .	49 Because Bim is a direct activator of Bax, 50 the activation of BH3-only proteins by AMPK hyperactivation may transmit the atrophic signals to the cell death cascade.	2	10	is a direct activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	8	9
Bim may activate bax signaling to mediate ABT-737-induced apoptotic cell death .	Bim may activate bax signaling to mediate ABT-737-induced apoptotic cell death.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	bax	bax	bax	0	1	3	4
p53 , Bid , and Bim stimulate Bax to induce lipid pores in the outer mitochondrial membrane , thereby triggering membrane permeability and the release of cytochrome c , caspases , XREF_BIBR and apoptosis inducing factor .	p53, Bid, and Bim stimulate Bax to induce lipid pores in the outer mitochondrial membrane, thereby triggering membrane permeability and the release of cytochrome c, caspases, XREF_BIBR and apoptosis inducing factor.	0	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	5	6	7	8
Bax , the major core of the intrinsic apoptosis pathway at the mitochondria , is directly mediated by Bim and Akt activation .	Bax, the major core of the intrinsic apoptosis pathway at the mitochondria, is directly mediated by Bim and Akt activation.	0	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	18	19	0	1
In yeast that lacked any Bcl-2 proteins , Bim still enhanced the death action of Bax .	In yeast that lacked any Bcl-2 proteins, Bim still enhanced the death action of Bax.	8	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	8	9	15	16
The intrinsic pathway to apoptosis is regulated by interactions between members of three factions of the Bcl-2 protein family : the BH3-only proteins such as Bim and Bid , which initiate the process , the essential effectors Bax and Bak , and the prosurvival members , which oppose the action of both other factions .	The intrinsic pathway to apoptosis is regulated by interactions between members of three factions of the Bcl-2 protein family : the BH3-only proteins such as Bim and Bid, which initiate the process, the essential effectors Bax and Bak, and the prosurvival members, which oppose the action of both other factions.	22	38	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	25	26	37	38
Specifically , in vitro reconstitutions of BID- and BIM mediated BAX activation revealed that small LUVs , OMVs , and tiny mitochondria ( < 0.5 microns in diameter ) failed to support the stable release and/or insertion of activated BAX monomers ( specially , alpha helix 9 ) into membranes .	Specifically, in vitro reconstitutions of BID- and BIM mediated BAX activation revealed that small LUVs, OMVs, and tiny mitochondria (< 0.5 microns in diameter) failed to support the stable release and/or insertion of activated BAX monomers (specially, alpha helix 9) into membranes.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	8	9	10	11
JNK mediated phosphorylation of Bim within the DLC binding motif prevents this interaction , allowing Bim to bind to Bcl-2 family members and activate Bax and Bak at the mitochondria .	JNK mediated phosphorylation of Bim within the DLC binding motif prevents this interaction, allowing Bim to bind to Bcl-2 family members and activate Bax and Bak at the mitochondria.	0	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	JNK mediated phosphorylation of Bim	bim	Bax	Bax	bax	4	5	24	25
Mechanistically , Bim is thought to activate Bax and Bak by direct binding and/or by binding and inhibiting anti-apoptotic members of the Bcl2 family ( Mcl1 and Bcl-XL ) , which restrain Bak and Bax .	Mechanistically, Bim is thought to activate Bax and Bak by direct binding and/or by binding and inhibiting anti-apoptotic members of the Bcl2 family (Mcl1 and Bcl-XL), which restrain Bak and Bax.	2	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	7	8
Notably , BIM SAHB A increased more membrane association of BAX monomers than BAX dimers ( XREF_SUPPLEMENTARY ) , suggesting that the inability of BAX dimers to permeabilize liposomes is due to impaired translocation of BAX dimers to the membrane .	Notably, BIM SAHB A increased more membrane association of BAX monomers than BAX dimers (XREF_SUPPLEMENTARY), suggesting that the inability of BAX dimers to permeabilize liposomes is due to impaired translocation of BAX dimers to the membrane.	2	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	2	3	10	11
For instance , the BH3 domains of Bid and Bim can activate Bax and Bak in liposomal or mitochondrial settings .	For instance, the BH3 domains of Bid and Bim can activate Bax and Bak in liposomal or mitochondrial settings.	5	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	9	10	12	13
On the contrary , BH3-domain only proteins like Bid , Bim and Puma can activate Bax and Bak to form oligomers in mitochondrial outer membrane resulting in MOMP [ XREF_BIBR , XREF_BIBR ] .	On the contrary, BH3-domain only proteins like Bid, Bim and Puma can activate Bax and Bak to form oligomers in mitochondrial outer membrane resulting in MOMP [XREF_BIBR, XREF_BIBR].	10	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	10	11	15	16
However , Bim has been shown to directly activate Bax , leading to translocation of Bax from cytosol to the mitochondria where it triggers mitochondrial outer membrane permeabilization ( MOMP ) to induce apoptosis .	However, Bim has been shown to directly activate Bax, leading to translocation of Bax from cytosol to the mitochondria where it triggers mitochondrial outer membrane permeabilization (MOMP) to induce apoptosis.	2	10	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	9	10
Some BH3-only proteins ( Bim , Puma , tBid ) very likely activate Bax and Bak directly [ XREF_BIBR , XREF_BIBR ] while the others may act by binding to and inhibiting anti-apoptotic Bcl-2 proteins [ XREF_BIBR , XREF_BIBR ] .	Some BH3-only proteins (Bim, Puma, tBid) very likely activate Bax and Bak directly [XREF_BIBR, XREF_BIBR] while the others may act by binding to and inhibiting anti-apoptotic Bcl-2 proteins [XREF_BIBR, XREF_BIBR].	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	4	5	13	14
Thus , tBID , BIM , and PUMA initiates the activation process of BAX by attacking the alpha1 helix , resulting in the N-terminal exposure of BAX and secondary disengagement of the alpha9 helix that becomes available for mitochondrial targeting .	Thus, tBID, BIM, and PUMA initiates the activation process of BAX by attacking the alpha1 helix, resulting in the N-terminal exposure of BAX and secondary disengagement of the alpha9 helix that becomes available for mitochondrial targeting.	2	14	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	4	5	13	14
Bim is able to directly activate Bax and Bak to cause permeabilization of the outer mitochondrial membrane and induce apoptosis .	Bim is able to directly activate Bax and Bak to cause permeabilization of the outer mitochondrial membrane and induce apoptosis.	0	8	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	6	7
Likewise , BAX activation mediated by BIM ( XREF_FIG , XREF_SUPPLEMENTARY ) and BID ( XREF_FIG , XREF_SUPPLEMENTARY ) also demonstrated a size dependent permeabilization preference .	Likewise, BAX activation mediated by BIM (XREF_FIG, XREF_SUPPLEMENTARY) and BID (XREF_FIG, XREF_SUPPLEMENTARY) also demonstrated a size dependent permeabilization preference.	2	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	6	7	2	3
The authors provide evidence that NuBCP-9 -- converted Bcl-2 does not adopt the membrane permeabilizing function of Bax , and does not mimic the BH3-only proteins Bid or Bim , which can directly activate Bax .	The authors provide evidence that NuBCP-9 -- converted Bcl-2 does not adopt the membrane permeabilizing function of Bax, and does not mimic the BH3-only proteins Bid or Bim, which can directly activate Bax.	22	35	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	28	29	34	35
To exclude the possibility that BID , BIM , and PUMA are required to activate BAX or BAK only in response to genotoxic stress , we investigated potassium-deprivation-induced apoptosis of cultured CGN .	To exclude the possibility that BID, BIM, and PUMA are required to activate BAX or BAK only in response to genotoxic stress, we investigated potassium-deprivation-induced apoptosis of cultured CGN.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	7	8	15	16
To gain insight into the mechanism of BH3-only protein Bim induced apoptosis and its interactions with other Bcl2 family members , we performed reciprocal immunoprecipitation experiments to determine whether Bim directly or indirectly activates Bax .	To gain insight into the mechanism of BH3-only protein Bim induced apoptosis and its interactions with other Bcl2 family members, we performed reciprocal immunoprecipitation experiments to determine whether Bim directly or indirectly activates Bax.	29	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	29	30	34	35
tBID , BIM , and PUMA induce the N-terminal exposure of BAX and remain associated with the N-terminally exposed BAX through the BH1 domain .	tBID, BIM, and PUMA induce the N-terminal exposure of BAX and remain associated with the N-terminally exposed BAX through the BH1 domain.	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	2	3	11	12
It has been reported that Bid preferentially activates Bak while Bim preferentially activates Bax , affecting chemotherapy response [ XREF_BIBR ] .	It has been reported that Bid preferentially activates Bak while Bim preferentially activates Bax, affecting chemotherapy response [XREF_BIBR].	10	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	10	11	13	14
However , Bax -/- / Bak -/- MEFs treated with BID and BIM peptides , did not display diffused GFP within the cell , which is indicative of a lack of cytochrome c release ( XREF_FIG ) .	However, Bax -/- / Bak -/- MEFs treated with BID and BIM peptides, did not display diffused GFP within the cell, which is indicative of a lack of cytochrome c release (XREF_FIG).	2	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BIM	BIM	BIM	Bax	Bax	Bax	12	13	2	3
Different in vitro assays ( oligomerization , 6A7 immunoprecipitation , liposomal and mitochondrial assays ) that measure ligand induced Bax activation indicate that Bim SAHB directly and dose dependently activates Bax .	Different in vitro assays (oligomerization, 6A7 immunoprecipitation, liposomal and mitochondrial assays) that measure ligand induced Bax activation indicate that Bim SAHB directly and dose dependently activates Bax.	23	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	23	24	30	31
XREF_BIBR , XREF_BIBR , XREF_BIBR For example , the NMR structure of a stabilized alpha-helix of the BCL-2 domain ( SAHB ) peptide of the BH3 domain of BIM in complex with full-length BAX has been reported and binding of the BH3 ligand BIM SAHB was shown to trigger BAX activation .	XREF_BIBR, XREF_BIBR, XREF_BIBR For example, the NMR structure of a stabilized alpha-helix of the BCL-2 domain (SAHB) peptide of the BH3 domain of BIM in complex with full-length BAX has been reported and binding of the BH3 ligand BIM SAHB was shown to trigger BAX activation.	43	50	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	43	44	49	50
Our data showing that BIM can more readily activate BAX would thus provide an explanation for the BAX-dependence of c-Myc-induced cell death .	Our data showing that BIM can more readily activate BAX would thus provide an explanation for the BAX-dependence of c-Myc-induced cell death.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	4	5	9	10
JNK can phosphorylate BIM or BID to induce BAX and BAK dependent cell death XREF_BIBR , XREF_BIBR .	JNK can phosphorylate BIM or BID to induce BAX and BAK dependent cell death XREF_BIBR, XREF_BIBR.	0	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	JNK can phosphorylate BIM	bim	BAX	BAX	bax	3	4	8	9
Likewise , since BIM is a direct activator of BAX and BAK , chemotherapies that utilize a BIM dependent mechanism will likely not be successful .	Likewise, since BIM is a direct activator of BAX and BAK, chemotherapies that utilize a BIM dependent mechanism will likely not be successful.	3	11	is a direct activator	Positive_activation_copula_1	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	3	4	9	10
These data indicate that SAHA induces apoptosis through Bim triggered Bax activation and that c-Myc regulates this process by modulating Bcl-2 and Bcl-xL .	These data indicate that SAHA induces apoptosis through Bim triggered Bax activation and that c-Myc regulates this process by modulating Bcl-2 and Bcl-xL.	6	11	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	8	9	10	11
In all cases , it is likely that Bim ( what is here said about Bim probably also applies to Puma ) is activated and then activates Bax and Bak .	In all cases, it is likely that Bim (what is here said about Bim probably also applies to Puma) is activated and then activates Bax and Bak.	8	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	8	9	27	28
In this regard , Bim may act directly on Bax and Bak as shown by the observation that Bim , but not a Puma BH3 peptide , was sufficient to induce oligomerization and activation of Bax and Bak to permeabilize the outer mitochondrial membrane .	In this regard, Bim may act directly on Bax and Bak as shown by the observation that Bim, but not a Puma BH3 peptide, was sufficient to induce oligomerization and activation of Bax and Bak to permeabilize the outer mitochondrial membrane.	18	37	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	18	19	35	36
In summary of the plausible mechanism underlying the synergistic cell death induced by ABT 737 and LY 294002 , reduction in Mcl-1 promotes the release of the apoptotic binding partner Bim from Mcl-1 complexes ; this further increased the effect of increased level of Bim , which through binding BAX ( or BAK ) [ XREF_BIBR ] , activates BAX , and leads to the release of cytochrome C [ XREF_BIBR ] , followed by activation of Apaf-1 and Caspase 9 , and effector caspases thereafter .	In summary of the plausible mechanism underlying the synergistic cell death induced by ABT 737 and LY 294002, reduction in Mcl-1 promotes the release of the apoptotic binding partner Bim from Mcl-1 complexes; this further increased the effect of increased level of Bim, which through binding BAX (or BAK) [XREF_BIBR], activates BAX, and leads to the release of cytochrome C [XREF_BIBR], followed by activation of Apaf-1 and Caspase 9, and effector caspases thereafter.	42	62	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	level of Bim	bim	BAX	BAX	bax	44	45	59	60
In parallel to Annexin V staining , we also monitored the effect of Bim depletion on paclitaxel induced activation of Bax and Bak in these cell lines .	In parallel to Annexin V staining, we also monitored the effect of Bim depletion on paclitaxel induced activation of Bax and Bak in these cell lines.	13	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bim	Bim	Bim	Bax	Bax	Bax	13	14	20	21
However , the molecular mechanism of Bim ( L ) activating Bax activation during TNFalpha induced apoptosis is not fully understood .	However, the molecular mechanism of Bim (L) activating Bax activation during TNFalpha induced apoptosis is not fully understood.	6	12	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	6	7	11	12
We found that nanomolar dosing of BIM proteins sufficed to reverse completely the inhibition of BAX permeabilizing activity exerted by all antiapoptotic proteins tested ( BCL-2 , BCL-X ( L ) , BCL-W , MCL-1 , and A1 ) .	We found that nanomolar dosing of BIM proteins sufficed to reverse completely the inhibition of BAX permeabilizing activity exerted by all antiapoptotic proteins tested (BCL-2, BCL-X (L), BCL-W, MCL-1, and A1).	6	17	reverse	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	6	7	15	16
Presumably Bim , liberated from these two anti-apoptotic proteins , as well as Mcl-1 ( due to down-regulation ) , triggered apoptosis by activating Bax and Bak .	Presumably Bim, liberated from these two anti-apoptotic proteins, as well as Mcl-1 (due to down-regulation), triggered apoptosis by activating Bax and Bak.	1	26	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	1	2	24	25
Is BIM required to cause the direct activation of BAK and BAX or is the inhibitory affect of BIM on numerous anti-apoptotic BCL-2 family members sufficient to promote proper T cell and B cell development and function ?	Is BIM required to cause the direct activation of BAK and BAX or is the inhibitory affect of BIM on numerous anti-apoptotic BCL-2 family members sufficient to promote proper T cell and B cell development and function?	1	12	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	1	2	11	12
Several studies have suggested that Bim proteins can also directly bind and activate Bax and Bak ( reviewed in ) .	Several studies have suggested that Bim proteins can also directly bind and activate Bax and Bak (reviewed in).	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	5	6	13	14
Specifically , we have established that the induction of Puma , but not Bim or Noxa , is necessary and sufficient to induce a conformational change in Bax to its active state , its translocation to the mitochondria and mitochondrial membrane permeabilization .	Specifically, we have established that the induction of Puma, but not Bim or Noxa, is necessary and sufficient to induce a conformational change in Bax to its active state, its translocation to the mitochondria and mitochondrial membrane permeabilization.	7	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	13	14	27	28
Alternatively , Bim can directly activate Bax or Bak through interaction with them ; thus , Bim is an important component for initiating the intrinsic apoptosis pathway .	Alternatively, Bim can directly activate Bax or Bak through interaction with them; thus, Bim is an important component for initiating the intrinsic apoptosis pathway.	2	8	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	6	7
Translocation of activated Bim to mitochondria initiates Bax dependent cytochrome c release and apoptosis [ XREF_BIBR ] .	Translocation of activated Bim to mitochondria initiates Bax dependent cytochrome c release and apoptosis [XREF_BIBR].	0	8	initiates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bim	Translocation of activated Bim to mitochondria	bim	Bax	Bax	bax	3	4	7	8
In yeast , Bim S enhanced the killing activity of Bax in the absence of anti-apoptotic Bcl-2 proteins .	In yeast, Bim S enhanced the killing activity of Bax in the absence of anti-apoptotic Bcl-2 proteins.	3	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	3	4	10	11
The preferences we observed for activation of BAK by BID and activation of BAX by BIM are more quantitative than absolute , particularly in the latter case .	The preferences we observed for activation of BAK by BID and activation of BAX by BIM are more quantitative than absolute, particularly in the latter case.	3	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	15	16	13	14
We find that BIM SAHB engagement directly triggers the functional activation of BAX .	We find that BIM SAHB engagement directly triggers the functional activation of BAX.	3	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	3	4	12	13
Pro apoptotic BH3-domain only proteins such as Bid , Bim and PUMA , induce Bax and Bak activation upon apoptotic induction to promote MMP .	Pro apoptotic BH3-domain only proteins such as Bid, Bim and PUMA, induce Bax and Bak activation upon apoptotic induction to promote MMP.	2	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	9	10	14	15
13 Bim is also known to induce Bax activation directly or indirectly .	13 Bim is also known to induce Bax activation directly or indirectly.	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	1	2	7	8
These results suggested that Bim promotes B cell apoptosis by the inactivation of the prosurvival Bcl-2 family rather than the activation of Bak and Bax , as supported by the functional analysis of Bim in TCR signaling .	These results suggested that Bim promotes B cell apoptosis by the inactivation of the prosurvival Bcl-2 family rather than the activation of Bak and Bax, as supported by the functional analysis of Bim in TCR signaling.	4	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	4	5	24	25
Bim as the direct activator is not only able to interact with and be sequestered by the anti-apoptotic Bcl-2 proteins Mcl-1 and Bcl-xL but also directly bind to and activate the effectors Bax and Bak XREF_BIBR .	Bim as the direct activator is not only able to interact with and be sequestered by the anti-apoptotic Bcl-2 proteins Mcl-1 and Bcl-xL but also directly bind to and activate the effectors Bax and Bak XREF_BIBR.	0	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	32	33
Structural investigations suggest that BAX activation is initiated by BIM ( and by extension , activated BID ) binding to a ' trigger site ' near BAX alpha1 , which leads to amino terminal rearrangements , mobilization of alpha9 , and exposure of the BAX BH3 domain [ XREF_BIBR ] .	Structural investigations suggest that BAX activation is initiated by BIM (and by extension, activated BID) binding to a ' trigger site ' near BAX alpha1, which leads to amino terminal rearrangements, mobilization of alpha9, and exposure of the BAX BH3 domain [XREF_BIBR].	4	10	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	9	10	4	5
Bim eventually activates pro apoptotic Bcl-2 family members ( BAX or BAK ) to induce apoptosis .	Bim eventually activates pro apoptotic Bcl-2 family members (BAX or BAK) to induce apoptosis.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	BAX	BAX	BAX	0	1	9	10
This is particularly true for Bim and Puma , that activate Bax and Bak in their native form , whereas cleavage of Bid is required for it to exert its pro apoptotic activity [ XREF_BIBR ] .	This is particularly true for Bim and Puma, that activate Bax and Bak in their native form, whereas cleavage of Bid is required for it to exert its pro apoptotic activity [XREF_BIBR].	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	5	6	11	12
Likewise , BAX activation mediated by BIM ( XREF_FIG , XREF_SUPPLEMENTARY ) and BID ( XREF_FIG , XREF_SUPPLEMENTARY ) also demonstrated a size dependent permeabilization preference , and the influence of membrane diameter was most dramatic for BIM mediated BAX activation .	Likewise, BAX activation mediated by BIM (XREF_FIG, XREF_SUPPLEMENTARY) and BID (XREF_FIG, XREF_SUPPLEMENTARY) also demonstrated a size dependent permeabilization preference, and the influence of membrane diameter was most dramatic for BIM mediated BAX activation.	37	40	mediated	Positive_early_activation	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	37	38	39	40
These data suggest that BID more efficiently activates BAK while BIM more efficiently activates BAX .	These data suggest that BID more efficiently activates BAK while BIM more efficiently activates BAX.	10	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	10	11	14	15
In relation to mitochondrial function , the prosurvival Bax and Bak form channels in the outer membrane of the mitochondria resulting in release of proapoptogenic signals such as cytochrome c. BH3-only proteins Bad , Bim and Puma promote the formation of Bax and Bak channels .	In relation to mitochondrial function, the prosurvival Bax and Bak form channels in the outer membrane of the mitochondria resulting in release of proapoptogenic signals such as cytochrome c. BH3-only proteins Bad, Bim and Puma promote the formation of Bax and Bak channels.	34	44	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	34	35	41	42
Upon exposure to stress , such as growth factor deprivation , Bim activates proapoptotic Bak and Bax that , in turn , permeabilize the mitochondrial membrane , causing the release of cytochrome C and the consequent activation of caspases to cause programmed cell death .	Upon exposure to stress, such as growth factor deprivation, Bim activates proapoptotic Bak and Bax that, in turn, permeabilize the mitochondrial membrane, causing the release of cytochrome C and the consequent activation of caspases to cause programmed cell death.	11	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	11	12	16	17
Collectively , these data suggest that TRAIL can trigger an apoptotic pathway that involves JNK dependent activation of Bim , which in turn induces Bax mediated permeabilization of lysosomes .	Collectively, these data suggest that TRAIL can trigger an apoptotic pathway that involves JNK dependent activation of Bim, which in turn induces Bax mediated permeabilization of lysosomes.	16	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	18	19	24	25
The critical function of anti-apoptotic Bcl-xL and Mcl-1 in preventing apoptosis has been proposed to sequester BH3-only molecules into stable complexes , thus preventing the activation of Bax and Bak , and also a BH3-only molecule Bim was shown to directly activate Bax and Bak to release cytochrome c XREF_BIBR .	The critical function of anti-apoptotic Bcl-xL and Mcl-1 in preventing apoptosis has been proposed to sequester BH3-only molecules into stable complexes, thus preventing the activation of Bax and Bak, and also a BH3-only molecule Bim was shown to directly activate Bax and Bak to release cytochrome c XREF_BIBR.	33	44	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	36	37	42	43
The mechanism by which BH3-only protein Bim activates Bax remains a matter of active debate .	The mechanism by which BH3-only protein Bim activates Bax remains a matter of active debate.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	6	7	8	9
In contrast to growth in vitro , tumors in vivo are subjected to hypoxia and the induction of BH3-only proteins such as Puma and activation of Bim mediated Bax and Bak dependent apoptosis and tumor repression .	In contrast to growth in vitro, tumors in vivo are subjected to hypoxia and the induction of BH3-only proteins such as Puma and activation of Bim mediated Bax and Bak dependent apoptosis and tumor repression.	24	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	26	27	28	29
BAX activation by BIM or BID requires two independent binding events , leading to the stepwise displacement of alpha-helix 9 , followed by alpha-helices 6-8 .	BAX activation by BIM or BID requires two independent binding events, leading to the stepwise displacement of alpha-helix 9, followed by alpha-helices 6-8.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	3	4	0	1
These findings suggest that hexadecenal induced-JNK activation induces apoptosis through cytochrome c release caused by tBid- and Bim activated Bax .	These findings suggest that hexadecenal induced-JNK activation induces apoptosis through cytochrome c release caused by tBid- and Bim activated Bax.	13	20	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	17	18	19	20
We speculate that JNK mediated Bim phosphorylation potentiates Bax dependent apoptosis .	We speculate that JNK mediated Bim phosphorylation potentiates Bax dependent apoptosis.	3	10	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	JNK mediated Bim phosphorylation	bim	Bax	Bax	bax	5	6	8	9
Therefore the released Bim is not available to activate Bak and Bax and initiate apoptosis .	Therefore the released Bim is not available to activate Bak and Bax and initiate apoptosis.	1	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	3	4	11	12
Glucocorticoid signaling increases the expression of the pro apoptotic Bcl-2 family member Bim , which can activate the pro apoptotic proteins Bax and Bak to disrupt mitochondrial membrane potential , resulting in the release of cytochrome c and other apoptogenic proteins [ XREF_BIBR ] .	Glucocorticoid signaling increases the expression of the pro apoptotic Bcl-2 family member Bim, which can activate the pro apoptotic proteins Bax and Bak to disrupt mitochondrial membrane potential, resulting in the release of cytochrome c and other apoptogenic proteins [XREF_BIBR].	4	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	expression of the pro apoptotic Bcl-2 family member Bim	bim	Bax	Bax	bax	12	13	21	22
Previous studies indicate that BIM , BID , and PUMA function as direct activators of BAX and BAK , whereas the remaining BH3-only family members function as sensitizers , i.e. they can not directly activate BAX and BAK , but they can neutralize the antiapoptotic family members ( BCL-2 , BCL-X L , MCL-1 ) that inhibit direct activators ( XREF_FIG ) XREF_BIBR .	Previous studies indicate that BIM, BID, and PUMA function as direct activators of BAX and BAK, whereas the remaining BH3-only family members function as sensitizers, i.e. they can not directly activate BAX and BAK, but they can neutralize the antiapoptotic family members (BCL-2, BCL-X L, MCL-1) that inhibit direct activators (XREF_FIG) XREF_BIBR.	4	37	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	4	5	35	36
To determine if any of the identified BIFs influenced the function of BAX , we screened the 53 BIFs in a liposomal release assay designed to identify both ( 1 ) direct BAX activators and ( 2 ) sensitizers or inhibitors of direct BAX activation induced by a stapled BIM BH3 helix , BIM SAHB A2 ( aa 145-164 ) 6 .	To determine if any of the identified BIFs influenced the function of BAX, we screened the 53 BIFs in a liposomal release assay designed to identify both (1) direct BAX activators and (2) sensitizers or inhibitors of direct BAX activation induced by a stapled BIM BH3 helix, BIM SAHB A2 (aa 145-164) 6.	43	51	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	49	50	43	44
In summary , our data show that , although cBid , Bim and OICR766A function to activate Bax , they differ in the mechanism by which this happens .	In summary, our data show that, although cBid, Bim and OICR766A function to activate Bax, they differ in the mechanism by which this happens.	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	11	12	17	18
Although it was proposed that activation of BAX and BAK occurred by default as long as all the anti-apoptotic BCL-2 proteins were neutralized by BH3s , the liposome studies clearly recapitulate the direct activation model in which tBID protein or BH3 domain peptides derived from BID or BIM induced BAX oligomerization and membrane permeabilization .	Although it was proposed that activation of BAX and BAK occurred by default as long as all the anti-apoptotic BCL-2 proteins were neutralized by BH3s, the liposome studies clearly recapitulate the direct activation model in which tBID protein or BH3 domain peptides derived from BID or BIM induced BAX oligomerization and membrane permeabilization.	43	50	induced	Positive_early_activation	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	47	48	49	50
Notably , overexpression of BCL-X L provided more protection than DeltaNp63alpha because BIM mediated activation of BAX and BAK occurs in p53 deficient cells .	Notably, overexpression of BCL-X L provided more protection than DeltaNp63alpha because BIM mediated activation of BAX and BAK occurs in p53 deficient cells.	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	12	13	16	17
TGFbeta causes Smad- and the SAPK and p38 dependent transcriptional induction of the pro apoptotic Bcl-2 family members Bmf and Bim , which in turn activate the pro apoptotic factor Bax that induces mitochondrial release of cytochrome c and activation of the apoptosome , leading to caspase dependent apoptosis in hepatocytes and B-lymphocytes [ XREF_BIBR , XREF_BIBR ] .	TGFbeta causes Smad- and the SAPK and p38 dependent transcriptional induction of the pro apoptotic Bcl-2 family members Bmf and Bim, which in turn activate the pro apoptotic factor Bax that induces mitochondrial release of cytochrome c and activation of the apoptosome, leading to caspase dependent apoptosis in hepatocytes and B-lymphocytes [XREF_BIBR, XREF_BIBR].	1	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	20	21	30	31
Furthermore , tBID , BIM , and PUMA , but not BAD or BMF , could directly induce the N-terminal exposure of BAX in vitro ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Furthermore, tBID, BIM, and PUMA, but not BAD or BMF, could directly induce the N-terminal exposure of BAX in vitro (XREF_FIG and XREF_SUPPLEMENTARY).	2	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	4	5	22	23
Bim and Bmf triggered activation of Bak and Bax .	Bim and Bmf triggered activation of Bak and Bax.	0	9	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	8	9
Also , Bim may directly activate Bax and Bak as reported previously .	Also, Bim may directly activate Bax and Bak as reported previously.	2	8	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	6	7
Because BIM and PUMA can directly trigger homo-oligomerization of BAX and BAK , leading to MOM permeabilization and cytochrome c release , they constitute a critical node of the BCL-2 network .	Because BIM and PUMA can directly trigger homo-oligomerization of BAX and BAK, leading to MOM permeabilization and cytochrome c release, they constitute a critical node of the BCL-2 network.	1	11	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	1	2	9	10
The critical function of anti-apoptotic Bcl-xL and Mcl-1 in preventing apoptosis has been proposed to sequester BH3-only molecules into stable complexes , thus preventing the activation of Bax and Bak , and also a BH3-only molecule Bim was shown to directly activate Bax and Bak to release cytochrome c from the mitochondria .	The critical function of anti-apoptotic Bcl-xL and Mcl-1 in preventing apoptosis has been proposed to sequester BH3-only molecules into stable complexes, thus preventing the activation of Bax and Bak, and also a BH3-only molecule Bim was shown to directly activate Bax and Bak to release cytochrome c from the mitochondria.	33	44	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	36	37	42	43
Under apoptosis induction , the disappearance of Mcl-1 allows Bim to exercise its pro apoptotic function and to activate Bax .	Under apoptosis induction, the disappearance of Mcl-1 allows Bim to exercise its pro apoptotic function and to activate Bax.	9	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	9	10	19	20
The pro apoptotic Bcl-2 family member BIM is known to induce BAX activation .	The pro apoptotic Bcl-2 family member BIM is known to induce BAX activation.	5	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	6	7	11	12
Bim is capable of binding to all Bcl-2 proteins with high affinity , activating the pro death Bax and/or Bak .	Bim is capable of binding to all Bcl-2 proteins with high affinity, activating the pro death Bax and/or Bak.	0	19	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	17	18
Hence , many cancer cells are likely ' primed ' to undergo apoptosis upon the administration of BAD and NOXA mimetics that displace BIM and PUMA from BCL-2 and BCL-X L and MCL-1 , respectively , to activate BAX and BAK XREF_BIBR XREF_BIBR XREF_BIBR .	Hence, many cancer cells are likely ' primed ' to undergo apoptosis upon the administration of BAD and NOXA mimetics that displace BIM and PUMA from BCL-2 and BCL-X L and MCL-1, respectively, to activate BAX and BAK XREF_BIBR XREF_BIBR XREF_BIBR.	23	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	23	24	38	39
In our latest BIM SAHB paper , published in the Journal of Clinical Investigation in 2012 , we demonstrated that the original potent and cell-permeable BIM SAHB A ( aa 146-166 ) analog reactivated the death pathway in a series of resistant hematologic cancer cells by broadly engaging anti-apoptotic targets and pro apoptotic BAX , and demonstrated sequence specific in vivo efficacy in suppressing both leukemic growth and Bim -/- autoimmune disease in two mouse models .	In our latest BIM SAHB paper, published in the Journal of Clinical Investigation in 2012, we demonstrated that the original potent and cell-permeable BIM SAHB A (aa 146-166) analog reactivated the death pathway in a series of resistant hematologic cancer cells by broadly engaging anti-apoptotic targets and pro apoptotic BAX, and demonstrated sequence specific in vivo efficacy in suppressing both leukemic growth and Bim -/- autoimmune disease in two mouse models.	25	54	reactivated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	25	26	53	54
Initiation of BAX Activation by BIM SAHB .	Initiation of BAX Activation by BIM SAHB.	0	6	Initiation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	5	6	2	3
Whereas BIM and PUMA directly or indirectly activate Bax ; the pro survival proteins Mcl-1 and Bcl-xL inhibit Bax function at the mitochondria by direct interaction with Bax or indirectly by sequestration of activator BH3-only proteins 60 .	Whereas BIM and PUMA directly or indirectly activate Bax; the pro survival proteins Mcl-1 and Bcl-xL inhibit Bax function at the mitochondria by direct interaction with Bax or indirectly by sequestration of activator BH3-only proteins 60.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	Bax	Bax	Bax	1	2	8	9
Upon cellular stress , Bid and Bim mediate homo-oligomerization of Bax and Bak , which leads to the release of cytochrome c from the mitochondrial intermembrane space .	Upon cellular stress, Bid and Bim mediate homo-oligomerization of Bax and Bak, which leads to the release of cytochrome c from the mitochondrial intermembrane space.	4	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	6	7	10	11
Bim can antagonize all three antiapoptotic proteins and directly activate Bax and Bak .	Bim can antagonize all three antiapoptotic proteins and directly activate Bax and Bak.	0	12	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	10	11
Here we show that the BH3-only Bcl-2 family members , Dp5 and Hrk and Bim , are induced upstream of the Bax checkpoint in neuronal apoptosis in a manner that shows significant dependence on JNK signaling .	Here we show that the BH3-only Bcl-2 family members, Dp5 and Hrk and Bim, are induced upstream of the Bax checkpoint in neuronal apoptosis in a manner that shows significant dependence on JNK signaling.	10	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	14	15	21	22
Bim activates the proapoptotic Bcl-2 protein Bax in the mitochondria to release cytochrome C into the cytosol , which in turn initiates a downstream caspase program leading to apoptosis [ XREF_BIBR , XREF_BIBR ] .	Bim activates the proapoptotic Bcl-2 protein Bax in the mitochondria to release cytochrome C into the cytosol, which in turn initiates a downstream caspase program leading to apoptosis [XREF_BIBR, XREF_BIBR].	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	6	7
The direct activation model states that Bax and Bak can be activated directly by Bim , Bid , and Puma or by other BH3-only proteins through releasing Bim/Bid/Puma from association with antiapoptotic Bcl-2 proteins .	The direct activation model states that Bax and Bak can be activated directly by Bim, Bid, and Puma or by other BH3-only proteins through releasing Bim/Bid/Puma from association with antiapoptotic Bcl-2 proteins.	6	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	14	15	6	7
XREF_BIBR - XREF_BIBR Previous work has demonstrated that a Bim sequence based peptide ( denoted Bim SAHBa ) is able to induce Bax mediated apoptotic responses in nucleated cells .	XREF_BIBR - XREF_BIBR Previous work has demonstrated that a Bim sequence based peptide (denoted Bim SAHBa) is able to induce Bax mediated apoptotic responses in nucleated cells.	9	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	9	10	22	23
Here , we propose a stepwise activation model of BAX and BAK driven by activator BH3s , tBID , BIM , and PUMA ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Here, we propose a stepwise activation model of BAX and BAK driven by activator BH3s, tBID, BIM, and PUMA (XREF_FIG and XREF_SUPPLEMENTARY).	7	20	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	19	20	9	10
XREF_BIBR , XREF_BIBR Bim can activate both Bak and Bax as well as inhibit all pro survival Bcl-2 family members .	XREF_BIBR, XREF_BIBR Bim can activate both Bak and Bax as well as inhibit all pro survival Bcl-2 family members.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	3	4	9	10
JNK also phosphorylates Bim , which leads to its release from the cytoskeleton and induces Bax dependent apoptosis XREF_BIBR XREF_BIBR .	JNK also phosphorylates Bim, which leads to its release from the cytoskeleton and induces Bax dependent apoptosis XREF_BIBR XREF_BIBR.	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	JNK also phosphorylates Bim	bim	Bax	Bax	bax	3	4	15	16
Bax and Bak activation is mediated by Bad , Bik , Bid , and Bim and is due to either the preferential interaction with Bcl-2 and Bcl-X L , or their release from these anti-apoptotic proteins , thus shifting the balance of the different heterodimers toward the formation of the proapoptotic Bax and Bak homodimers .	Bax and Bak activation is mediated by Bad, Bik, Bid, and Bim and is due to either the preferential interaction with Bcl-2 and Bcl-X L, or their release from these anti-apoptotic proteins, thus shifting the balance of the different heterodimers toward the formation of the proapoptotic Bax and Bak homodimers.	0	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	14	15	0	1
Any TNFalpha induced signal that activates Bim ( see below ) would be expected to promote activation of caspase-9 and effector caspases ( either on its own or with tBid ) , because Bim is a potent activator of Bax and Bak ( XREF_SUPPLEMENTARY ;) .	Any TNFalpha induced signal that activates Bim (see below) would be expected to promote activation of caspase-9 and effector caspases (either on its own or with tBid), because Bim is a potent activator of Bax and Bak (XREF_SUPPLEMENTARY;).	33	43	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	33	34	39	40
Direct degradation of Mcl-1 by TRAIL activated caspase-8 or caspase-3 produces Mcl-1-free Bim that mediates a Bax dependent apoptotic cascade .	Direct degradation of Mcl-1 by TRAIL activated caspase-8 or caspase-3 produces Mcl-1-free Bim that mediates a Bax dependent apoptotic cascade.	10	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	12	13	16	17
8 Bim , similar to other BH3-only proteins , contributes to increase the mitochondrial permeability and activation of caspase cascade by directly activating pro apoptotic Bax and Bak 27 or by releasing Bax and Bak from their complexes with pro survival Bcl-2 homologs .	8 Bim, similar to other BH3-only proteins, contributes to increase the mitochondrial permeability and activation of caspase cascade by directly activating pro apoptotic Bax and Bak 27 or by releasing Bax and Bak from their complexes with pro survival Bcl-2 homologs.	0	27	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	1	2	25	26
Upon death stimulation , Bim is released from the microtubules , promoting Bax activation and apoptosis [ XREF_BIBR , XREF_BIBR ] .	Upon death stimulation, Bim is released from the microtubules, promoting Bax activation and apoptosis [XREF_BIBR, XREF_BIBR].	4	13	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	4	5	12	13
BIM can initiate apoptosis by directly activating Bax through interaction with the Bcl-2 and Bax herterodimer complex , which can further induces mitochondrial cell death [ XREF_BIBR , XREF_BIBR ] .	BIM can initiate apoptosis by directly activating Bax through interaction with the Bcl-2 and Bax herterodimer complex, which can further induces mitochondrial cell death [XREF_BIBR, XREF_BIBR].	0	8	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	Bax	Bax	Bax	0	1	7	8
It has been demonstrated that Bim initiates activation of Bax through a direct interaction in vitro [ XREF_BIBR ] .	It has been demonstrated that Bim initiates activation of Bax through a direct interaction in vitro [XREF_BIBR].	5	10	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	5	6	9	10
In this study , we show that although both BID and BIM can activate both BAK and BAX , they exhibit differential activation preferences : BID preferentially activates BAK and BIM preferentially activates BAX .	In this study, we show that although both BID and BIM can activate both BAK and BAX, they exhibit differential activation preferences : BID preferentially activates BAK and BIM preferentially activates BAX.	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	11	12	17	18
Notably , the expression of Bim S ( 1-88 ) or Bim S DeltaDelta together with Bax failed to enhance the Bax effect ( unpublished data ) .	Notably, the expression of Bim S (1-88) or Bim S DeltaDelta together with Bax failed to enhance the Bax effect (unpublished data).	3	22	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	expression of Bim	bim	Bax	Bax	bax	5	6	21	22
Specificity of BIM SAHB Induced BAX Activation .	Specificity of BIM SAHB Induced BAX Activation.	2	6	Induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	2	3	5	6
The BH3 domain containing proteins BIM and PUMA can directly activate the proapoptotic proteins BAX and BAK to permeabilize mitochondria , leading to caspase activation and apoptosis .	The BH3 domain containing proteins BIM and PUMA can directly activate the proapoptotic proteins BAX and BAK to permeabilize mitochondria, leading to caspase activation and apoptosis.	4	18	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	5	6	14	15
This free Bim would then be predicted to initiate apoptotic signaling by either directly and/or indirectly activating Bax and Bak .	This free Bim would then be predicted to initiate apoptotic signaling by either directly and/or indirectly activating Bax and Bak.	0	19	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	17	18
These signals may be BH3 activators such as BIM , or perhaps activated monomeric BAX or BAK .	These signals may be BH3 activators such as BIM, or perhaps activated monomeric BAX or BAK.	5	16	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	8	9	14	15
The activator BH3-only molecules BID , BIM , and PUMA directly activate the apoptotic effectors BAX and BAK , whereas BCL-2 , BCL-X L , and MCL-1 inhibit apoptosis by sequestering BH3s ( XREF_SUPPLEMENTARY ) .	The activator BH3-only molecules BID, BIM, and PUMA directly activate the apoptotic effectors BAX and BAK, whereas BCL-2, BCL-X L, and MCL-1 inhibit apoptosis by sequestering BH3s (XREF_SUPPLEMENTARY).	4	17	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	6	7	15	16
These findings suggest that non phosphorylated , accumulated BIM induces BAX and BAK conformational changes ( activation ) , cytochrome c release , and ultimately apoptosis in this treatment .	These findings suggest that non phosphorylated, accumulated BIM induces BAX and BAK conformational changes (activation), cytochrome c release, and ultimately apoptosis in this treatment.	5	25	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BIM	phosphorylated, accumulated BIM	bim	BAX	BAX	bax	8	9	10	11
The combination of BI-97CI ( Sabutoclax ) with an IL-10 family cytokine , called melanoma differentiation associated gene-7 and interleukin-24 ( mda-7 and Il-24 ) , was marked by autophagy that facilitated NOXA and Bim induced Bax and Bak mediated apoptosis .	The combination of BI-97CI (Sabutoclax) with an IL-10 family cytokine, called melanoma differentiation associated gene-7 and interleukin-24 (mda-7 and Il-24), was marked by autophagy that facilitated NOXA and Bim induced Bax and Bak mediated apoptosis.	32	40	induced	Positive_early_activation	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	34	35	36	37
The effector BAK and BAX can be activated by the BH3-only proteins BIM and BID , also known as activators ( Sarosiek etal ., 2013 ) .	The effector BAK and BAX can be activated by the BH3-only proteins BIM and BID, also known as activators (Sarosiek etal., 2013).	2	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	12	13	4	5
In addition , Bim is able to induce Bax and Bak independent apoptosis in both HCT116 and MEF cells ( XREF_FIG ) .	In addition, Bim is able to induce Bax and Bak independent apoptosis in both HCT116 and MEF cells (XREF_FIG).	3	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	3	4	8	9
The BH3-only proteins Bim and Bid initiate apoptosis signaling through activation of caspase-9 and consequent activation of effector caspases by activating Bax and Bak , either directly and/or indirectly by blocking the pro survival Bcl-2 family members that keep Bax and Bak in check .	The BH3-only proteins Bim and Bid initiate apoptosis signaling through activation of caspase-9 and consequent activation of effector caspases by activating Bax and Bak, either directly and/or indirectly by blocking the pro survival Bcl-2 family members that keep Bax and Bak in check.	0	25	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	3	4	21	22
BIM or BID BH3 peptide induced cell death in Bax -/- / Bak -/- MEFs expressing the dominant negative DRP1 ( XREF_FIG ) .	BIM or BID BH3 peptide induced cell death in Bax -/- / Bak -/- MEFs expressing the dominant negative DRP1 (XREF_FIG).	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	Bax	Bax	Bax	0	1	9	10
In addition , phosphorylation of Bim may reduce its ability to directly interact with the proapoptotic multidomain Bcl-2 family protein Bax , thereby preventing oligomerization of Bax and subsequent cell death .	In addition, phosphorylation of Bim may reduce its ability to directly interact with the proapoptotic multidomain Bcl-2 family protein Bax, thereby preventing oligomerization of Bax and subsequent cell death.	3	30	preventing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	phosphorylation of Bim	bim	Bax	Bax	bax	5	6	26	27
A more recent study comparing BID and BIM proteins and peptides suggests that while BID and BIM can activate BAK and BAX , previously unrecognized differences are observed .	A more recent study comparing BID and BIM proteins and peptides suggests that while BID and BIM can activate BAK and BAX, previously unrecognized differences are observed.	14	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	16	17	21	22
The BID and BIM BH3 domain peptides promote BAK and BAX dependent MOMP and cytochrome c release , whereas the BAD BH3 promotes MOMP by inhibiting BCL-2 , BCL-xL , and BCL-w ( and revealing BID and BIM activity , _ FIG ) , and not by direct BAK and BAX interactions .	The BID and BIM BH3 domain peptides promote BAK and BAX dependent MOMP and cytochrome c release, whereas the BAD BH3 promotes MOMP by inhibiting BCL-2, BCL-xL, and BCL-w (and revealing BID and BIM activity, _ FIG), and not by direct BAK and BAX interactions.	3	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	3	4	10	11
Moreover , our previous studies have demonstrated that BimL , one important isoform of Bim , can promote Bax activation via directly neutralizing Bcl-xL [ XREF_BIBR , XREF_BIBR ] .	Moreover, our previous studies have demonstrated that BimL, one important isoform of Bim, can promote Bax activation via directly neutralizing Bcl-xL [XREF_BIBR, XREF_BIBR].	12	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	14	15	18	19
Recent reports showing that the BH3 domains of Bim and Puma also elicit Bax activation may indicate additional reactions , which do not match the catalytic activation produced by Bid .	Recent reports showing that the BH3 domains of Bim and Puma also elicit Bax activation may indicate additional reactions, which do not match the catalytic activation produced by Bid.	6	14	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	8	9	13	14
Genetic deletion of Bid , Bim , and Puma prevented the homo-oligomerization of BAX and BAK , and thereby cytochrome c mediated activation of caspases in response to diverse death signals in neurons and T lymphocytes , despite the presence of other BH3-only molecules .	Genetic deletion of Bid, Bim, and Puma prevented the homo-oligomerization of BAX and BAK, and thereby cytochrome c mediated activation of caspases in response to diverse death signals in neurons and T lymphocytes, despite the presence of other BH3-only molecules.	1	15	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	BAX	BAX	BAX	5	6	13	14
Bim and Bmf activate proapoptotic Bak and Bax proteins , inducing OMM perforation followed by the release of caspase activating factors into the cytosol and activation of apoptosis XREF_BIBR .	Bim and Bmf activate proapoptotic Bak and Bax proteins, inducing OMM perforation followed by the release of caspase activating factors into the cytosol and activation of apoptosis XREF_BIBR.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	7	8
Bim knockdown successfully attenuated the ABT-737-induced activation of the pro apoptotic molecules Bax and cleaved PARP .	Bim knockdown successfully attenuated the ABT-737-induced activation of the pro apoptotic molecules Bax and cleaved PARP.	0	13	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	12	13
In turn , the fraction of Bax bound to Bcl-2 decreases in response to treatment , thereby indicating that Bim possibly promotes Bax release from the pro survival protein Bcl-2 .	In turn, the fraction of Bax bound to Bcl-2 decreases in response to treatment, thereby indicating that Bim possibly promotes Bax release from the pro survival protein Bcl-2.	19	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	19	20	22	23
Bid and Bim can activate Bax and Bak through direct interaction .	Bid and Bim can activate Bax and Bak through direct interaction.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	5	6
PUMA and and NOXA as well as Bad can inhibit anti-apoptotic members Bcl-2 and Bcl-Xl members where Bid and Bim can activate pro apoptotic members Bax and Bak [ XREF_BIBR - XREF_BIBR ] .	PUMA and and NOXA as well as Bad can inhibit anti-apoptotic members Bcl-2 and Bcl-Xl members where Bid and Bim can activate pro apoptotic members Bax and Bak [XREF_BIBR - XREF_BIBR].	17	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	19	20	25	26
A second model , the ' sensitizer ' model ascribes more complex control to the BH3-only proteins such that Bim and Bid are direct activators of Bax and Bak , inducing permissive conformational changes , whilst BH3-only proteins such as Bad , Bik , Noxa , Hrk and Bmf inhibit the anti-apoptotic proteins thus inducing sensitivity of the Bax and Bak pore forming mechanism to activation by Bim and Bid .	A second model, the ' sensitizer ' model ascribes more complex control to the BH3-only proteins such that Bim and Bid are direct activators of Bax and Bak, inducing permissive conformational changes, whilst BH3-only proteins such as Bad, Bik, Noxa, Hrk and Bmf inhibit the anti-apoptotic proteins thus inducing sensitivity of the Bax and Bak pore forming mechanism to activation by Bim and Bid.	19	28	are direct activators	Positive_activation_copula_1	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	19	20	26	27
This is perhaps not surprising since prevailing models of BAK and BAX activation propose that once BIM and BID activate BAX and BAK , the oligomerization and mitochondrial permeabilization processes can continue independently of the activators , thus freeing BIM and BID to continue activating further BAX and BAK proteins .	This is perhaps not surprising since prevailing models of BAK and BAX activation propose that once BIM and BID activate BAX and BAK, the oligomerization and mitochondrial permeabilization processes can continue independently of the activators, thus freeing BIM and BID to continue activating further BAX and BAK proteins.	16	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	16	17	20	21
Bim directly initiates Bax mediated mitochondrial apoptosis via binding to and stabilizing the alpha-helix of the Bcl-2 domains of Bax .	Bim directly initiates Bax mediated mitochondrial apoptosis via binding to and stabilizing the alpha-helix of the Bcl-2 domains of Bax.	0	6	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	3	4
Furthermore , Bik ectopic expression disrupts Bim and Bcl -2 and Bim and Bcl-xL endogenous complexes triggering Bim release that could induce Bax and Bak activation .	Furthermore, Bik ectopic expression disrupts Bim and Bcl -2 and Bim and Bcl-xL endogenous complexes triggering Bim release that could induce Bax and Bak activation.	17	25	induce	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	17	18	22	23
Other conformational changes not seen in this structure must also occur , as the authors find that an amino-terminal motif in alpha1 ( dubbed 6A7 ) becomes exposed when BAX monomers are activated by BIM SAHB .	Other conformational changes not seen in this structure must also occur, as the authors find that an amino-terminal motif in alpha1 (dubbed 6A7) becomes exposed when BAX monomers are activated by BIM SAHB.	29	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	34	35	29	30
Furthermore , Bim can activate Bax and Bak , thereby initiating the cell apoptosis ( XREF_FIG ) .	Furthermore, Bim can activate Bax and Bak, thereby initiating the cell apoptosis (XREF_FIG).	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	5	6
Although Bim may activate Bak or Bax to regulate the development of B cells and to maintain their homeostasis in the periphery , Bim seems to act preferentially on Bax , but not on Bak , in thymocytes .	Although Bim may activate Bak or Bax to regulate the development of B cells and to maintain their homeostasis in the periphery, Bim seems to act preferentially on Bax, but not on Bak, in thymocytes.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	1	2	6	7
Whether BIM also induces BAX and BAK independent activation of caspase-3 , in the absence of MOMP , remains unclear .	Whether BIM also induces BAX and BAK independent activation of caspase-3, in the absence of MOMP, remains unclear.	1	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	1	2	4	5
In the intrinsic pathway , the BCL-2 family BH3-only molecules , Bid , Bim , and Puma , convey apoptotic signals to trigger homo-oligomerization of multidomain proapoptotic Bax and Bak , which in turn permeabilize mitochondria , leading to the efflux of cytochrome c , the assembly of the apoptosome , and the activation of caspases which mediate apoptosis .	In the intrinsic pathway, the BCL-2 family BH3-only molecules, Bid, Bim, and Puma, convey apoptotic signals to trigger homo-oligomerization of multidomain proapoptotic Bax and Bak, which in turn permeabilize mitochondria, leading to the efflux of cytochrome c, the assembly of the apoptosome, and the activation of caspases which mediate apoptosis.	9	29	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	13	14	27	28
It is important to note that a direct activatioBak and are inhibiten model has also been proposed where BH3-only proteins Bid and Bim directly activate Bax and d by anti-apoptotic Bcl-2 , Bcl-X L , Mcl-1 , Bcl-w , and Bfl/A1 .	It is important to note that a direct activatioBak and are inhibiten model has also been proposed where BH3-only proteins Bid and Bim directly activate Bax and d by anti-apoptotic Bcl-2, Bcl-X L, Mcl-1, Bcl-w, and Bfl/A1.	20	27	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	22	23	25	26
In response to cytotoxic stimuli , that induce cytoskeletal rearrangements , Bim and Bmf may act as stress sensors , released from the cytoskeleton , and induce the activation of Bak and Bax .	In response to cytotoxic stimuli, that induce cytoskeletal rearrangements, Bim and Bmf may act as stress sensors, released from the cytoskeleton, and induce the activation of Bak and Bax.	11	33	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	11	12	32	33
To probe the sequence dependence of BIM SAHB A ( aa 146-166 ) on direct activation of BAX in genetically defined cells , we previously reconstituted Bax -/- Bak -/- MEFs with wild-type BAX and then treated with BIM SAHB A ( aa 146-166 ) in an initial serum-free , detached-cell setting , which enabled us to detect a sequence specific difference in apoptosis induction that linked the cellular activity of BIM SAHB A ( aa 146-166 ) to direct BAX interaction .	To probe the sequence dependence of BIM SAHB A (aa 146-166) on direct activation of BAX in genetically defined cells, we previously reconstituted Bax -/- Bak -/- MEFs with wild-type BAX and then treated with BIM SAHB A (aa 146-166) in an initial serum-free, detached-cell setting, which enabled us to detect a sequence specific difference in apoptosis induction that linked the cellular activity of BIM SAHB A (aa 146-166) to direct BAX interaction.	26	40	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BIM	BIM	BIM	Bax	Bax	Bax	38	39	26	27
Inhibition of Bim by siRNA attenuated conformational changes of Bax , mitochondrial apoptotic events , and activation of caspase-3 , leading to marked inhibition of the synergy between SBHA and TRAIL .	Inhibition of Bim by siRNA attenuated conformational changes of Bax, mitochondrial apoptotic events, and activation of caspase-3, leading to marked inhibition of the synergy between SBHA and TRAIL.	0	16	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	9	10
Bim and Bmf , thus released , can activate Bax and/or Bak to initiate apoptosis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Bim and Bmf, thus released, can activate Bax and/or Bak to initiate apoptosis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	9	10
Interestingly , BIM has been recently shown to activate BAX , 40 while clusterin is a known inhibitor of the pro apoptotic activity of BAX .	Interestingly, BIM has been recently shown to activate BAX, 40 while clusterin is a known inhibitor of the pro apoptotic activity of BAX.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	2	3	9	10
BID preferentially activates BAK while BIM preferentially activates BAX , affecting chemotherapy response .	BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	5	6	8	9
In response to cytotoxic stimuli , that induce cytoskeletal rearrangements , Bim and Bmf may act as stress sensors in thus far that they are released from the cytoskeleton and induce the activation of Bak and Bax XREF_BIBR , XREF_BIBR .	In response to cytotoxic stimuli, that induce cytoskeletal rearrangements, Bim and Bmf may act as stress sensors in thus far that they are released from the cytoskeleton and induce the activation of Bak and Bax XREF_BIBR, XREF_BIBR.	11	37	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	11	12	36	37
BID and BIM can also directly activate BAX and BAK , resulting in pore formation on the MOM [ XREF_BIBR ] .	BID and BIM can also directly activate BAX and BAK, resulting in pore formation on the MOM [XREF_BIBR].	0	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	2	3	7	8
In addition , it was reported that BIM preferentially activates BAX whereas BAK is mostly activated by BID [ XREF_BIBR ] .	In addition, it was reported that BIM preferentially activates BAX whereas BAK is mostly activated by BID [XREF_BIBR].	7	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	7	8	10	11
It should be noted that BIM knockdown and BAX knockdown seemed redundant , consistent with BIM preferentially activating BAX to kill .	It should be noted that BIM knockdown and BAX knockdown seemed redundant, consistent with BIM preferentially activating BAX to kill.	13	19	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	15	16	18	19
In sensitive cells , it is possible that there is not enough Mcl-1 to sequester all of the released Bim , resulting in free Bim , which can then activate Bax and Bak leading to apoptosis .	In sensitive cells, it is possible that there is not enough Mcl-1 to sequester all of the released Bim, resulting in free Bim, which can then activate Bax and Bak leading to apoptosis.	21	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	24	25	30	31
Specifically , BIM can preferentially activate BAX , while BID preferentially activates BAK .	Specifically, BIM can preferentially activate BAX, while BID preferentially activates BAK.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	2	3	6	7
Here we show that both Bim and Bmf are essential to induce Bak and Bax activity for Ngo triggered apoptosis .	Here we show that both Bim and Bmf are essential to induce Bak and Bax activity for Ngo triggered apoptosis.	4	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	5	6	14	15
Mechanistically , G-Rg1 promoted the phosphorylation of Akt and FoxO3a and led to the cytoplasmic translocation of FoxO3a , which in turn suppressed FoxO3a modulated expression of proapoptotic Bim and elevated the ratio of Bcl-2 to Bax .	Mechanistically, G-Rg1 promoted the phosphorylation of Akt and FoxO3a and led to the cytoplasmic translocation of FoxO3a, which in turn suppressed FoxO3a modulated expression of proapoptotic Bim and elevated the ratio of Bcl-2 to Bax.	17	37	elevated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Bim	FoxO3a, which in turn suppressed FoxO3a modulated expression of proapoptotic Bim	bim	Bax	Bax	bax	28	29	36	37
Bim is one of the most powerful BH3-only proteins , able to engage all prosurvival proteins potently and activate Bax directly .	Bim is one of the most powerful BH3-only proteins, able to engage all prosurvival proteins potently and activate Bax directly.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	0	1	19	20
It has been shown that Bax activity can be directly enhanced by Bim , Bid and PUMA .	It has been shown that Bax activity can be directly enhanced by Bim, Bid and PUMA.	5	16	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	12	13	5	6
This suggested that either active Bim was unable to activate Bax , as would be the case in the presence of high levels of Bcl-2 or a similar protein , or that no active Bim was generated in infected cells .	This suggested that either active Bim was unable to activate Bax, as would be the case in the presence of high levels of Bcl-2 or a similar protein, or that no active Bim was generated in infected cells.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	5	6	10	11
Collaborating with the laboratory of Dr. Nico Tjandra , who first solved the solution structure of full-length , inactive BAX , we found that BIM SAHB A ( aa 146-166 ) triggered such rapid oligomerization of BAX that NMR analysis of the interaction was precluded .	Collaborating with the laboratory of Dr. Nico Tjandra, who first solved the solution structure of full-length, inactive BAX, we found that BIM SAHB A (aa 146-166) triggered such rapid oligomerization of BAX that NMR analysis of the interaction was precluded.	24	37	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	24	25	36	37
To examine how BIF-44 and BIM SAHB A2 engagement at distinct sites synergize to trigger BAX activation , we performed HXMS analyses of BAX in the presence of BIF-44 , BIM SAHB A2 , or the combination .	To examine how BIF-44 and BIM SAHB A2 engagement at distinct sites synergize to trigger BAX activation, we performed HXMS analyses of BAX in the presence of BIF-44, BIM SAHB A2, or the combination.	5	16	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	5	6	15	16
By contrast , excess T reg cells are removed by attrition , dependent on the Bim initiated Bak- and Bax dependent intrinsic apoptotic pathway .	By contrast, excess T reg cells are removed by attrition, dependent on the Bim initiated Bak- and Bax dependent intrinsic apoptotic pathway.	14	18	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bak-	Bak-	Bak-	15	16	17	18
BIM Promotes Insertion of the BAK Pore Domain .	BIM Promotes Insertion of the BAK Pore Domain.	0	7	Promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAK	BAK	BAK	0	1	5	6
Bim , but neither Noxa peptide nor obatoclax , stimulated the formation of higher order Bak adducts .	Bim, but neither Noxa peptide nor obatoclax, stimulated the formation of higher order Bak adducts.	0	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bak	Bak	Bak	0	1	15	16
In naive T cells , data suggest that Mcl-1 antagonizes Bak , but under conditions of cytokines withdrawal , the upregulation of Bim may drive Bak independent death of Mcl-1-deficient T cells .	In naive T cells, data suggest that Mcl-1 antagonizes Bak, but under conditions of cytokines withdrawal, the upregulation of Bim may drive Bak independent death of Mcl-1-deficient T cells.	20	27	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bak	Bak	Bak	22	23	25	26
It has been suggested that the BH3-only protein Bim can directly activate Bak , leading to mitochondrial dysfunction and apoptosis [ XREF_BIBR ] .	It has been suggested that the BH3-only protein Bim can directly activate Bak, leading to mitochondrial dysfunction and apoptosis [XREF_BIBR].	5	13	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bak	Bak	Bak	8	9	12	13
Receptor mediated apoptosis activated BID to engage the mitochondrial pathway 29 , but the other apoptotic stimuli tested did not , relying instead on additional direct activator BH3-only proteins such as BIM , which therefore are likely to trigger BAK activation by also engaging the BC groove 3 .	Receptor mediated apoptosis activated BID to engage the mitochondrial pathway 29, but the other apoptotic stimuli tested did not, relying instead on additional direct activator BH3-only proteins such as BIM, which therefore are likely to trigger BAK activation by also engaging the BC groove 3.	28	40	trigger	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAK	BAK	BAK	31	32	39	40
IFNgammaR2 inhibits apoptosis induced by Bim but not Bak .	IFNgammaR2 inhibits apoptosis induced by Bim but not Bak.	1	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bak	Bak	Bak	5	6	8	9
Similar to the response observed with vorinostat treatment , romidepsin induced BCL2L11 in normal and transformed fibroblasts and induced BAK1 in the transformed cells .	Similar to the response observed with vorinostat treatment, romidepsin induced BCL2L11 in normal and transformed fibroblasts and induced BAK1 in the transformed cells.	9	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL2L11	romidepsin induced BCL2L11	bcl2l11	BAK1	BAK1	bak1	11	12	19	20
Because the BakDeltaTM used in this experiment lacks a transmembrane domain , these results not only provide further evidence that Bim and Noxa activate Bak in vitro but also suggest that tethering of Bak to the membrane through its C terminus is potentially dispensable for MOM disruption .	Because the BakDeltaTM used in this experiment lacks a transmembrane domain, these results not only provide further evidence that Bim and Noxa activate Bak in vitro but also suggest that tethering of Bak to the membrane through its C terminus is potentially dispensable for MOM disruption.	20	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bak	Bak	Bak	20	21	24	25
Similar evidence exists for BIM mediated BAK and BAX activation ; and while PUMA was also suggested to promote BAK and BAX activation , this effect may not be direct .	Similar evidence exists for BIM mediated BAK and BAX activation; and while PUMA was also suggested to promote BAK and BAX activation, this effect may not be direct.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	BIM	BIM	BIM	BAK	BAK	BAK	4	5	6	7
In cells in which BIM is silenced , NOXA knockdown decreased cell death since a part of BAK pool is inhibited by MCL-1 and since the BAK free pool is not activated by BIM .	In cells in which BIM is silenced, NOXA knockdown decreased cell death since a part of BAK pool is inhibited by MCL-1 and since the BAK free pool is not activated by BIM.	26	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAK	BAK	BAK	33	34	26	27
Our group recently found that parthenolide increased Bim protein and pycnogenol increased Bak protein by increasing its protein stability , resulting in the induction of apoptosis in human oral cancer supporting that natural products derived compounds can influence Bcl-2 family members to exert their apoptotic activities in oral cancer .	Our group recently found that parthenolide increased Bim protein and pycnogenol increased Bak protein by increasing its protein stability, resulting in the induction of apoptosis in human oral cancer supporting that natural products derived compounds can influence Bcl-2 family members to exert their apoptotic activities in oral cancer.	7	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bak	Bak	Bak	7	8	12	13
NOXA inhibits MCL-1 and BAK is activated by BIM to induce cell death .	NOXA inhibits MCL-1 and BAK is activated by BIM to induce cell death.	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAK	BAK	BAK	8	9	4	5
The Bim.Bak Model and Bim Induced Bak Conformational Changes .	The Bim.Bak Model and Bim Induced Bak Conformational Changes.	2	8	Induced	Positive_early_activation	Positive_activation	Positive_activation	Bim	Bim	Bim	Bak	Bak	Bak	4	5	6	7
Excess Mcl-1 inhibited Bim induced Bak oligomerization , and this inhibition was overcome by Noxa peptide and by obatoclax .	Excess Mcl-1 inhibited Bim induced Bak oligomerization, and this inhibition was overcome by Noxa peptide and by obatoclax.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	Bim	Bim	Bim	Bak	Bak	Bak	3	4	5	6
We have further reported that , unlike the sensitizer Bad , Noxa and Bim bind tightly ( K D values of 20-30nM ) but transiently to the BH3 binding groove of Bak , thereby triggering the formation of a Bak homo-oligomer of ~ 200kDa , MOMP , and killing of intact cells XREF_BIBR .	We have further reported that, unlike the sensitizer Bad, Noxa and Bim bind tightly (K D values of 20-30nM) but transiently to the BH3 binding groove of Bak, thereby triggering the formation of a Bak homo-oligomer of ~ 200kDa, MOMP, and killing of intact cells XREF_BIBR.	9	40	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bak	Bak	Bak	13	14	39	40
In the model to explain these findings , the authors suggested that the pro apoptotic molecules tBID , BIM or BAD could displace VDAC2 from BAK enabling homo-oligomerization of BAK and release of cytochrome c through the mitochondrial outer membrane .	In the model to explain these findings, the authors suggested that the pro apoptotic molecules tBID, BIM or BAD could displace VDAC2 from BAK enabling homo-oligomerization of BAK and release of cytochrome c through the mitochondrial outer membrane.	22	35	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	25	26	33	35
In this regard , BAX- and BAK mediated fission can also release cytochrome c into the cytoplasm leading to caspase activation .	In this regard, BAX- and BAK mediated fission can also release cytochrome c into the cytoplasm leading to caspase activation.	4	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	6	7	12	14
Whereas MCL-1 SAHB D had no effect on the mitochondria in the absence of BID BH3 , addition of MCL-1 SAHB D to BID BH3 exposed mitochondria triggered dose responsive enhancement of BAK mediated cytochrome c release ( XREF_FIG ) .	Whereas MCL-1 SAHB D had no effect on the mitochondria in the absence of BID BH3, addition of MCL-1 SAHB D to BID BH3 exposed mitochondria triggered dose responsive enhancement of BAK mediated cytochrome c release (XREF_FIG).	30	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	32	33	34	36
The substantial difference between Bax and Bak induced and Bid and Bik induced cytochrome c release and apoptosis ( Shimizu and Tsujimoto 2000 ) , however , makes the possibility unlikely that Bid functions only through heterodimerizing with Bcl-2 and Bcl-x L or facilitating Bax and Bak oligomerization , because these two models suggest no difference between Bid induced and Bax and Bak induced cytochrome c release and cell death .	The substantial difference between Bax and Bak induced and Bid and Bik induced cytochrome c release and apoptosis (Shimizu and Tsujimoto 2000), however, makes the possibility unlikely that Bid functions only through heterodimerizing with Bcl-2 and Bcl-x L or facilitating Bax and Bak oligomerization, because these two models suggest no difference between Bid induced and Bax and Bak induced cytochrome c release and cell death.	60	66	induced	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	62	63	64	66
(-)-Gossypol-induced apoptosis was associated with Bak activation and release of cytochrome c from mitochondria , suggesting a mitochondrial mediated apoptotic mechanism .	(-)-Gossypol-induced apoptosis was associated with Bak activation and release of cytochrome c from mitochondria, suggesting a mitochondrial mediated apoptotic mechanism.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	5	6	10	12
With miR-29a/b down regulation , we found an increased expression of targets of miR-29a/b -beta-site amyloid precursor protein cleaving enzyme 1 ( BACE1 ) , p53 upregulated modulator of apoptosis ( PUMA ) and BAK , increased cytochrome c release and apoptosis .	With miR-29a/b down regulation, we found an increased expression of targets of miR-29a/b -beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), p53 upregulated modulator of apoptosis (PUMA) and BAK, increased cytochrome c release and apoptosis.	27	39	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	34	35	37	39
Low levels of Bcl-2 and increased levels of BAK promote the release of cytochrome c from the mitochondria triggering the activation of caspases that regulate the induction and execution of apoptosis 46 .	Low levels of Bcl-2 and increased levels of BAK promote the release of cytochrome c from the mitochondria triggering the activation of caspases that regulate the induction and execution of apoptosis 46.	6	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAK	levels of BAK	bak	cytochrome c	cytochrome c	cytochrome c	8	9	13	15
PP2A B56alpha is involved in BAK mediated cytochrome c release and caspase 3 activation .	PP2A B56alpha is involved in BAK mediated cytochrome c release and caspase 3 activation.	3	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	5	6	7	9
How might this view of Bcl-xL function jibe with the long-held view that Bcl-xL directly suppresses apoptosis by inhibiting Bax and Bak mediated cytochrome c release ?	How might this view of Bcl-xL function jibe with the long-held view that Bcl-xL directly suppresses apoptosis by inhibiting Bax and Bak mediated cytochrome c release?	21	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	21	22	23	25
Bcl-2 homology domain 3 ( BH3 )-only Pro Protein Bim1 is an another pro apoptotic protein and plays an important role in Bax and Bak mediated cytochrome c release and apoptosis [ XREF_BIBR ] .	Bcl-2 homology domain 3 (BH3)-only Pro Protein Bim1 is an another pro apoptotic protein and plays an important role in Bax and Bak mediated cytochrome c release and apoptosis [XREF_BIBR].	20	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	24	25	26	28
Thus , truncated Atg5 may promote apoptosis by acting in a manner reminiscent of some BH3-only proteins that inactivate anti-apoptotic Bcl-2 proteins and permit Bax and Bak mediated cytochrome c release [ XREF_BIBR ] .	Thus, truncated Atg5 may promote apoptosis by acting in a manner reminiscent of some BH3-only proteins that inactivate anti-apoptotic Bcl-2 proteins and permit Bax and Bak mediated cytochrome c release [XREF_BIBR].	23	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	26	27	28	30
Caspase-8 , a key player of this communication platform , can proteolytically activate the BH3 only family member Bid , which induces Bax- and Bak mediated release of cytochrome c and Smac/DIABLO from mitochondria [ XREF_BIBR ] .	Caspase-8, a key player of this communication platform, can proteolytically activate the BH3 only family member Bid, which induces Bax- and Bak mediated release of cytochrome c and Smac/DIABLO from mitochondria [XREF_BIBR].	22	30	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	24	25	28	30
In this section , we will discuss an approach to examine BAK mediated cytochrome c release induced by a direct activator BH3-only protein or a BH3 domain peptide .	In this section, we will discuss an approach to examine BAK mediated cytochrome c release induced by a direct activator BH3-only protein or a BH3 domain peptide.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	11	12	13	15
Moreover , the exposure of RIN-m5F cells to NiCl ( 2 ) induced distinct signals of mitochondria dependent apoptosis , including mitochondrial dysfunction ( the disruption of mitochondrial membrane potential ( MMP ) and increase in mitochondrial cytochrome c release into the cytosol ) , Bak and Bid mRNA up-regulation , and activation of caspase-3 , caspase-7 , and caspase-9 , and poly ( ADP-ribose ) polymerase ( PARP ) degradation .	Moreover, the exposure of RIN-m5F cells to NiCl (2) induced distinct signals of mitochondria dependent apoptosis, including mitochondrial dysfunction (the disruption of mitochondrial membrane potential (MMP) and increase in mitochondrial cytochrome c release into the cytosol), Bak and Bid mRNA up-regulation, and activation of caspase-3, caspase-7, and caspase-9, and poly (ADP-ribose) polymerase (PARP) degradation.	34	49	increase	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	45	46	37	39
Cholix induced cytochrome c release into cytosol was initiated by specific conformational changes of pro apoptotic Bak associated with Bax .	Cholix induced cytochrome c release into cytosol was initiated by specific conformational changes of pro apoptotic Bak associated with Bax.	2	17	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	16	17	2	4
3 The release of Bax and Bak mediated cytochrome c is considered to be a point of no return and a commitment to cell death .	3 The release of Bax and Bak mediated cytochrome c is considered to be a point of no return and a commitment to cell death.	2	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
In type II cells , caspase-8 cleaves Bid to form tBid , which primarily interacts with Bax and Bak at the mitochondrial membrane to promote cytochrome c release .	In type II cells, caspase-8 cleaves Bid to form tBid, which primarily interacts with Bax and Bak at the mitochondrial membrane to promote cytochrome c release.	18	27	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	18	19	25	27
However , nothing is known about the putative tyrosine phosphorylation of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax and Bak mediated cytochrome c release and apoptosis .	However, nothing is known about the putative tyrosine phosphorylation of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax and Bak mediated cytochrome c release and apoptosis.	21	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	26	27	28	30
Dynamin related protein 1 ( Drp1 ) mediates mitochondrial fission and is thought to promote Bax and Bak induced cytochrome c release during apoptosis .	Dynamin related protein 1 (Drp1) mediates mitochondrial fission and is thought to promote Bax and Bak induced cytochrome c release during apoptosis.	14	21	induced	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	17	18	19	21
Pretreatment of cancer cell mitochondria with this BCB prevented cytochrome c release triggered by Bak BH3 , Bim BH3 , t-Bid or ABT-737 treatment ( XREF_FIG ) .	Pretreatment of cancer cell mitochondria with this BCB prevented cytochrome c release triggered by Bak BH3, Bim BH3, t-Bid or ABT-737 treatment (XREF_FIG).	9	15	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	14	15	9	11
Taken together , these mechanistic data demonstrate that MCL-1 SAHB D can directly target native MCL-1 in a complex protein mixture , disrupt the inhibitory MCL-1 and BAK interaction in vitro and in cells , and sensitize BAK mediated mitochondrial cytochrome c release .	Taken together, these mechanistic data demonstrate that MCL-1 SAHB D can directly target native MCL-1 in a complex protein mixture, disrupt the inhibitory MCL-1 and BAK interaction in vitro and in cells, and sensitize BAK mediated mitochondrial cytochrome c release.	36	42	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	37	38	40	42
HK2 is probably associated with an anti-oxidative reaction and inhibition of apoptosis through Bax and Bak mediated cytochrome c release XREF_BIBR .	HK2 is probably associated with an anti-oxidative reaction and inhibition of apoptosis through Bax and Bak mediated cytochrome c release XREF_BIBR.	3	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	15	16	17	19
Bim plays an important role in Bax and Bak mediated cytochrome C release and activation of caspase cascade [ XREF_BIBR ] .	Bim plays an important role in Bax and Bak mediated cytochrome C release and activation of caspase cascade [XREF_BIBR].	4	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome C	cytochrome C	cytochrome C	8	9	10	12
They found that Bcl xL and other members of the apoptosis inhibitory subset of the Bcl-2 family antagonized Bax and Bak induced cytochrome c release , but failed to block mitochondrial fission that is associated with Bax and Bak activation .	They found that Bcl xL and other members of the apoptosis inhibitory subset of the Bcl-2 family antagonized Bax and Bak induced cytochrome c release, but failed to block mitochondrial fission that is associated with Bax and Bak activation.	18	24	induced	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	20	21	22	24
Ginsenoside Rh2 Induces Human Hepatoma Cell Apoptosis via Bax and Bak Triggered Cytochrome C Release and Caspase-9 and Caspase-8 Activation .	Ginsenoside Rh2 Induces Human Hepatoma Cell Apoptosis via Bax and Bak Triggered Cytochrome C Release and Caspase-9 and Caspase-8 Activation.	6	14	Triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	Cytochrome C	Cytochrome C	Cytochrome C	10	11	12	14
These results support the above finding hat CsA prevents BAK induced cytochrome c release whereas CIP has no effect .	These results support the above finding hat CsA prevents BAK induced cytochrome c release whereas CIP has no effect.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	9	10	11	13
Bak causes the release of cytochrome c and activation of the apoptotic caspase cascade .	Bak causes the release of cytochrome c and activation of the apoptotic caspase cascade.	0	7	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Silencing of bak and bax genes or bak gene alone using siRNA significantly suppressed cytochrome c release and caspase-7 activation , but not activation of caspases-3 and -9 .	Silencing of bak and bax genes or bak gene alone using siRNA significantly suppressed cytochrome c release and caspase-7 activation, but not activation of caspases-3 and -9.	2	16	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	bak	bak	bak	cytochrome c	cytochrome c	cytochrome c	2	3	14	16
In response to HI , the Bcl-2 family member Bax is activated and translocates to the mitochondria where it complexes and forms a pore with Bak allowing passage of cytochrome c and apoptosis inducing factor ( AIF ) into the cytosol .	In response to HI, the Bcl-2 family member Bax is activated and translocates to the mitochondria where it complexes and forms a pore with Bak allowing passage of cytochrome c and apoptosis inducing factor (AIF) into the cytosol.	21	31	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	25	26	29	31
Although some authors have argued that cytochrome c release can be mediated by Bak and VDAC forming pores rather than by non specific rupture XREF_BIBR , this is a widely used technique to determine the intactness of the outer mitochondrial membrane XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Although some authors have argued that cytochrome c release can be mediated by Bak and VDAC forming pores rather than by non specific rupture XREF_BIBR, this is a widely used technique to determine the intactness of the outer mitochondrial membrane XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	6	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	13	14	6	8
As direct application of Bak to purified mitochondria induces release of cytochrome c , we examined whether it would synergize with GrB in the setting of mouse S-100 and mitochondria .	As direct application of Bak to purified mitochondria induces release of cytochrome c, we examined whether it would synergize with GrB in the setting of mouse S-100 and mitochondria.	2	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	4	5	11	13
BIM is a member of the BCL-2 pro apoptotic proteins family , which is involved in Bax and Bak mediated cytochrome c release and apoptosis .	BIM is a member of the BCL-2 pro apoptotic proteins family, which is involved in Bax and Bak mediated cytochrome c release and apoptosis.	14	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	18	19	20	22
18 Specifically , emerging evidence indicated that sphingolipid metabolism controls Bax and Bak mediated cytochrome c release and mitochondrial apoptosis .	18 Specifically, emerging evidence indicated that sphingolipid metabolism controls Bax and Bak mediated cytochrome c release and mitochondrial apoptosis.	10	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	12	13	14	16
On the other hand , XREF_BIBR observed that Bcl-x L , as well as other members of the apoptosis-inhibitory subset of the Bcl-2 family , antagonized Bax and/or Bak induced cytochrome c release but failed to block mitochondrial fragmentation associated with Bax and Bak activation .	On the other hand, XREF_BIBR observed that Bcl-x L, as well as other members of the apoptosis-inhibitory subset of the Bcl-2 family, antagonized Bax and/or Bak induced cytochrome c release but failed to block mitochondrial fragmentation associated with Bax and Bak activation.	26	32	induced	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	28	29	30	32
Thus , knockdown of Mcl-1 renders Bax- deficient and Bak expressing DU145 cells susceptible to Nbk induced cytochrome c release and apoptosis .	Thus, knockdown of Mcl-1 renders Bax- deficient and Bak expressing DU145 cells susceptible to Nbk induced cytochrome c release and apoptosis.	9	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak expressing	bak	cytochrome c	cytochrome c	cytochrome c	9	10	17	19
Finally , we showed that mitochondrial p53 disrupted the interaction between the antiapoptotic protein , Bcl-xL , and the proapoptotic protein , Bak , which then caused cytochrome c release and caspase activation .	Finally, we showed that mitochondrial p53 disrupted the interaction between the antiapoptotic protein, Bcl-xL, and the proapoptotic protein, Bak, which then caused cytochrome c release and caspase activation.	20	29	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	22	23	27	29
Cytosolic Bak and BaxCS was now able to mediate complete cytochrome c release by tBid ( XREF_FIG , lane 4 ) .	Cytosolic Bak and BaxCS was now able to mediate complete cytochrome c release by tBid (XREF_FIG, lane 4).	0	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	1	2	10	12
In addition , apigenin increased the Bax , Bad , and Bak levels , but reduced the Bcl-xL , Bcl-2 , and Mcl-1 levels , and subsequently triggered the mitochondrial apoptotic pathway ( release of cytochrome c and activation of caspase-9 , caspase-3 , caspase-7 , and PARP ) .	In addition, apigenin increased the Bax, Bad, and Bak levels, but reduced the Bcl-xL, Bcl-2, and Mcl-1 levels, and subsequently triggered the mitochondrial apoptotic pathway (release of cytochrome c and activation of caspase-9, caspase-3, caspase-7, and PARP).	3	37	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	apigenin increased the Bax, Bad, and Bak levels	bak	cytochrome c	cytochrome c	cytochrome c	11	12	35	37
We next conducted mitochondrial assays to determine if the ability of MCL-1 SAHB D to disrupt the FITC-BAK SAHB A / MCL-1DeltaNDeltaC complex translated into SAHB mediated sensitization of BAK induced cytochrome c release .	We next conducted mitochondrial assays to determine if the ability of MCL-1 SAHB D to disrupt the FITC-BAK SAHB A / MCL-1DeltaNDeltaC complex translated into SAHB mediated sensitization of BAK induced cytochrome c release.	27	33	induced	Positive_early_activation	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	29	30	31	33
Following mitochondrial localization , low dose recombinant Bak restored the mitochondrial release of cytochrome c in response to Bax ; at increased doses it induced cytochrome c release itself .	Following mitochondrial localization, low dose recombinant Bak restored the mitochondrial release of cytochrome c in response to Bax; at increased doses it induced cytochrome c release itself.	6	15	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	7	8	13	15
Studies on other cell types have shows that BAK can induce the release of cytochrome c from mitochondria , independently of mitochondria permeability transition , in combination with BH3 domain-only members of the BL2 family [ XREF_BIBR ] .	Studies on other cell types have shows that BAK can induce the release of cytochrome c from mitochondria, independently of mitochondria permeability transition, in combination with BH3 domain-only members of the BL2 family [XREF_BIBR].	8	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	8	9	14	16
Also , the cytochrome c releasing capability of the Bak deficient mitochondria was restored by insertion of recombinant Bak protein into purified mitochondria .	Also, the cytochrome c releasing capability of the Bak deficient mitochondria was restored by insertion of recombinant Bak protein into purified mitochondria.	3	19	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	18	19	3	5
We have used ABT737 , a BH3 mimetic to trigger Bak mediated cytochrome c release , which results in the activation of caspase-3 and ROCK1 and the subsequent exposure of phosphatidylserine .	We have used ABT737, a BH3 mimetic to trigger Bak mediated cytochrome c release, which results in the activation of caspase-3 and ROCK1 and the subsequent exposure of phosphatidylserine.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	10	11	12	14
The differential , reciprocal degradation of YME1L and OMA1 can also influence other aspects of mitochondrial function regulated by these proteases including mitochondrial protein import , degradation of oxidatively damaged proteins , and BAX and BAK induced cytochrome c release .	The differential, reciprocal degradation of YME1L and OMA1 can also influence other aspects of mitochondrial function regulated by these proteases including mitochondrial protein import, degradation of oxidatively damaged proteins, and BAX and BAK induced cytochrome c release.	33	39	induced	Positive_early_activation	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	35	36	37	39
Caspase-8 , which can proteolytically activate the BH3 only family member Bid , induces Baxand Bak mediated release of cytochrome c and Smac/DIABLO from mitochondria and triggers intrinsic apoptosis .	Caspase-8, which can proteolytically activate the BH3 only family member Bid, induces Baxand Bak mediated release of cytochrome c and Smac/DIABLO from mitochondria and triggers intrinsic apoptosis.	14	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	15	16	19	21
Upon sensing cell stress caused by various insults such as DNA damage , cytokine deprivation , or infection , these BH3-only proteins trigger the insertion of the two pro apoptotic , pore forming proteins BAX and/or BAK , into the OMM , causing the release of the cytochrome c and SMAC .	Upon sensing cell stress caused by various insults such as DNA damage, cytokine deprivation, or infection, these BH3-only proteins trigger the insertion of the two pro apoptotic, pore forming proteins BAX and/or BAK, into the OMM, causing the release of the cytochrome c and SMAC.	31	49	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	36	37	47	49
Proapoptotic Bcl-2 homology 3-only protein Bim plays an important role in Bax and Bak mediated cytochrome c release and apoptosis .	Proapoptotic Bcl-2 homology 3-only protein Bim plays an important role in Bax and Bak mediated cytochrome c release and apoptosis.	9	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	13	14	15	17
We have also shown that Bid and Bik induced cytochrome c release is substantially different from Bax and Bak induced cytochrome c release : ( a ) Bax and Bak induced , but not Bid and Bik induced , cytochrome c release is accompanied by Deltapsi loss ; and ( b ) PT inhibitors and respiratory chain inhibitors block Bax and Bak induced , but not Bid and Bik induced , cytochrome c release ( Shimizu and Tsujimoto 2000 ) .	We have also shown that Bid and Bik induced cytochrome c release is substantially different from Bax and Bak induced cytochrome c release : (a) Bax and Bak induced, but not Bid and Bik induced, cytochrome c release is accompanied by Deltapsi loss; and (b) PT inhibitors and respiratory chain inhibitors block Bax and Bak induced, but not Bid and Bik induced, cytochrome c release (Shimizu and Tsujimoto 2000).	14	22	induced	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	18	19	20	22
(-)-Deprenyl prevents BAK induced cytochrome c release in RLMEC .	(-)-Deprenyl prevents BAK induced cytochrome c release in RLMEC.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	BAK	BAK	BAK	cytochrome c	cytochrome c	cytochrome c	2	3	4	6
A similar observation was made in yeast , where the co-expression of Bax and Bcl-xL induced a greater mitochondrial localization of Bax than when it was expressed alone XREF_BIBR .	A similar observation was made in yeast, where the co-expression of Bax and Bcl-xL induced a greater mitochondrial localization of Bax than when it was expressed alone XREF_BIBR.	10	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	co-expression of Bax	bax	Bax	Bax	bax	12	13	21	22
LPS significantly increased the myocardial Bax expression and slightly decreased Bcl-2 expression ; quercetin pretreatment decreased Bax expression to the control level and significantly lowered Bax and Bcl -2 ratio as compared with the LPS group .	LPS significantly increased the myocardial Bax expression and slightly decreased Bcl-2 expression; quercetin pretreatment decreased Bax expression to the control level and significantly lowered Bax and Bcl -2 ratio as compared with the LPS group.	13	27	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	quercetin pretreatment decreased Bax expression	bax	Bax	Bax	bax	16	17	25	26
As shown in Figure XREF_FIG A , our results indicated that LK-A treatment up-regulated the expression of the pro apoptotic protein Bax and increased the ratio of Bax and Bcl-x L in a dose dependent manner .	As shown in Figure XREF_FIG A, our results indicated that LK-A treatment up-regulated the expression of the pro apoptotic protein Bax and increased the ratio of Bax and Bcl-x L in a dose dependent manner.	11	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	LK-A treatment up-regulated the expression of the pro apoptotic protein Bax	bax	Bax	Bax	bax	21	22	27	28
Spirulina extract ( 1mug/mL ) , considerably inhibited increased ROS and RNS levels , reduction in cytochrome c release , raise in mitochondrial membrane potential , decreased the over expression of proapoptotic protein Bax and suppressed the Bax and Bcl2 ratio with induced apoptosis without affecting cell viability .	Spirulina extract (1mug/mL), considerably inhibited increased ROS and RNS levels, reduction in cytochrome c release, raise in mitochondrial membrane potential, decreased the over expression of proapoptotic protein Bax and suppressed the Bax and Bcl2 ratio with induced apoptosis without affecting cell viability.	16	40	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	cytochrome c release, raise in mitochondrial membrane potential, decreased the over expression of proapoptotic protein Bax	bax	Bax	Bax	bax	33	34	37	38
The increased expression of active caspase 8 , active caspase 3 , and BAX in the experiment may have been activated upon binding of aDR5 scFv with DR5 to induce apoptosis and activate active caspase 8 , active caspase 3 , and BAX .	The increased expression of active caspase 8, active caspase 3, and BAX in the experiment may have been activated upon binding of aDR5 scFv with DR5 to induce apoptosis and activate active caspase 8, active caspase 3, and BAX.	2	43	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	expression of active caspase 8, active caspase 3, and BAX	bax	BAX	BAX	bax	13	14	42	43
Melatonin treatment significantly suppressed Bax protein expression and decreased the Bax and Bcl -2 ratio ( XREF_FIG ) and decreased cytoplasmic cytochrome c levels ( XREF_FIG ) compared with age matched mice without treatment .	Melatonin treatment significantly suppressed Bax protein expression and decreased the Bax and Bcl -2 ratio (XREF_FIG) and decreased cytoplasmic cytochrome c levels (XREF_FIG) compared with age matched mice without treatment.	0	14	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Melatonin treatment significantly suppressed Bax protein expression	bax	Bax	Bax	bax	4	5	10	11
In the upstream , diosgenin increased the expression of Bax , decreased the expression of Bid and Bcl-2 , and augmented the Bax and Bcl -2 ratio .	In the upstream, diosgenin increased the expression of Bax, decreased the expression of Bid and Bcl-2, and augmented the Bax and Bcl -2 ratio.	4	26	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	diosgenin increased the expression of Bax	bax	Bax	Bax	bax	9	10	22	23
After WDR79 was knocked down , the expression of Bcl-2 significantly decreased , whereas Bax protein expression markedly increased , resulting in a low Bcl-2 and Bax ratio in both cell lines tested .	After WDR79 was knocked down, the expression of Bcl-2 significantly decreased, whereas Bax protein expression markedly increased, resulting in a low Bcl-2 and Bax ratio in both cell lines tested.	14	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax protein expression	bax	Bax	Bax	bax	14	15	26	27
It was found that DIM-butyrate combination treatment induces the expression of proapoptotic Bax and Bak proteins triggering Bax dimerization and activation that cause the release of cytochrome c and Smac proteins from mitochondria resulting in initiation of apoptosis [ XREF_BIBR ] .	It was found that DIM-butyrate combination treatment induces the expression of proapoptotic Bax and Bak proteins triggering Bax dimerization and activation that cause the release of cytochrome c and Smac proteins from mitochondria resulting in initiation of apoptosis [XREF_BIBR].	9	18	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of proapoptotic Bax	bax	Bax	Bax	bax	12	13	17	18
The present study revealed that MVA treatment upregulated the expression of Bcl-2 , while downregulating the expression of Bax , which increased the Bcl-2 and Bax ratio and inhibited HMC apoptosis .	The present study revealed that MVA treatment upregulated the expression of Bcl-2, while downregulating the expression of Bax, which increased the Bcl-2 and Bax ratio and inhibited HMC apoptosis.	16	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	Bax	Bax	bax	18	19	25	26
Bax phosphorylation by GSK-3beta stimulated the mitochondrial localization of Bax .	Bax phosphorylation by GSK-3beta stimulated the mitochondrial localization of Bax.	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax phosphorylation	bax	Bax	Bax	bax	0	1	9	10
Our data showed that anthocyanin treatment of DU-145 cells 1 ) down-regulated Bcl-2 protein levels and 2 ) up-regulated Bax levels , which significantly increased the Bax and Bcl -2 ratio , with a concomitant increase in p53 expression .	Our data showed that anthocyanin treatment of DU-145 cells 1) down-regulated Bcl-2 protein levels and 2) up-regulated Bax levels, which significantly increased the Bax and Bcl -2 ratio, with a concomitant increase in p53 expression.	4	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	anthocyanin treatment of DU-145 cells 1) down-regulated Bcl-2 protein levels and 2) up-regulated Bax levels	bax	Bax	Bax	bax	19	20	26	27
In the upstream , MAA increased the expression of Bax , decreased the expression of Bcl-2 , and augmented the Bax and Bcl -2 ratio .	In the upstream, MAA increased the expression of Bax, decreased the expression of Bcl-2, and augmented the Bax and Bcl -2 ratio.	4	24	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	MAA increased the expression of Bax	bax	Bax	Bax	bax	9	10	20	21
Consistent with Bax and Bcl-2 mRNA levels , the expression of Bcl-2 protein decreased as the concentration of AITC increased , whereas Bax protein level increased , indicating a decreasing Bcl-2 and Bax ratio trend as AITC dosage increases ( XREF_TABLE , XREF_FIG ) .	Consistent with Bax and Bcl-2 mRNA levels, the expression of Bcl-2 protein decreased as the concentration of AITC increased, whereas Bax protein level increased, indicating a decreasing Bcl-2 and Bax ratio trend as AITC dosage increases (XREF_TABLE, XREF_FIG).	22	34	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax protein level	bax	Bax	Bax	bax	22	23	32	33
Increased expression of Bax but not Bcl-2 in hypoxic cerebral tissue thus increasing the Bax and Bcl -2 ratio in favor of hypoxia induced apoptosis has been reported .	Increased expression of Bax but not Bcl-2 in hypoxic cerebral tissue thus increasing the Bax and Bcl -2 ratio in favor of hypoxia induced apoptosis has been reported.	1	18	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	Bax	Bax	bax	3	4	14	15
On the other hand , 3 MA by attenuating JNK activity reversed this signaling pathway and decreased the expression of FOXO3a effectors and pro apoptotic marker Bax and , hence , decreased Bax to Bcl-2 ratio .	On the other hand, 3 MA by attenuating JNK activity reversed this signaling pathway and decreased the expression of FOXO3a effectors and pro apoptotic marker Bax and, hence, decreased Bax to Bcl-2 ratio.	6	33	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	MA by attenuating JNK activity reversed this signaling pathway and decreased the expression of FOXO3a effectors and pro apoptotic marker Bax	bax	Bax	Bax	bax	26	27	32	33
Thus , it is possible that , in these cells , the increased expression of Bax induced by GnRH-A is not sufficient to efficiently enhance the Bax and Bcl -2 ratio to trigger apoptosis .	Thus, it is possible that, in these cells, the increased expression of Bax induced by GnRH-A is not sufficient to efficiently enhance the Bax and Bcl -2 ratio to trigger apoptosis.	13	32	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	Bax	Bax	bax	15	16	26	27
In mitochondrion dependent apoptosis , increase of bax and bcl-2 down-expression induce Bax relocation in the outer mitochondrial membrane .	In mitochondrion dependent apoptosis, increase of bax and bcl-2 down-expression induce Bax relocation in the outer mitochondrial membrane.	7	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	bax	bax and bcl-2 down-expression	bax	Bax	Bax	bax	7	8	12	13
The results indicate that at 24 h , MXC increased Bcl-xL and Bax mRNA levels and increased the ratio of Bax and Bcl2 .	The results indicate that at 24 h, MXC increased Bcl-xL and Bax mRNA levels and increased the ratio of Bax and Bcl2.	8	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	MXC increased Bcl-xL and Bax mRNA levels	bax	Bax	Bax	bax	12	13	20	21
RSE significantly suppressed Bax protein expression and decreased Bax and Bcl -2 ratio in intermediate aged hearts compared with the vehicle treatment group .	RSE significantly suppressed Bax protein expression and decreased Bax and Bcl -2 ratio in intermediate aged hearts compared with the vehicle treatment group.	0	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	RSE significantly suppressed Bax protein expression	bax	Bax	Bax	bax	3	4	8	9
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Activator BH3-only proteins contribute to recruitment of BAX to membranes , activating BAX and BAK monomers , which then undergo a substantial conformation change and embed within the bilayer .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Activator BH3-only proteins contribute to recruitment of BAX to membranes, activating BAX and BAK monomers, which then undergo a substantial conformation change and embed within the bilayer.	12	22	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	recruitment of BAX to membranes	bax	BAX	BAX	bax	14	15	19	20
In addition , galanin inhibited Bax expression ( n = 6 , t = 3.24 , p < 0.05 ) , and could inhibit activated Bax as well if normalized to total Bax levels ( right panel of XREF_FIG ) .	In addition, galanin inhibited Bax expression (n = 6, t = 3.24, p < 0.05), and could inhibit activated Bax as well if normalized to total Bax levels (right panel of XREF_FIG).	3	26	inhibit activated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	galanin inhibited Bax expression	bax	Bax	Bax	bax	5	6	25	26
Sham group demonstrated basic expression of both Bcl-2 and Bax and IR induced downregulated Bcl-2 and upregulated Bax .	Sham group demonstrated basic expression of both Bcl-2 and Bax and IR induced downregulated Bcl-2 and upregulated Bax.	4	18	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of both Bcl-2 and Bax	bax	Bax	Bax	bax	9	10	17	18
TGF-beta1 increased Bax transcript level ( evaluated by Bax mRNA and GAPDH mRNA ratio ) and stimulated Bax protein movement from cytosol to organellar membranes , mainly mitochondrial , during 60 min .	TGF-beta1 increased Bax transcript level (evaluated by Bax mRNA and GAPDH mRNA ratio) and stimulated Bax protein movement from cytosol to organellar membranes, mainly mitochondrial, during 60 min.	0	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	TGF-beta1 increased Bax transcript level	bax	Bax	Bax	bax	2	3	17	18
Therefore , the increased Bax levels and the reduced Bcl2 levels caused high Bax and Bcl2 ratios ( greater than 1 ) in a time dependent manner , indicating DN induced apoptosis via regulation of the Bcl-2 family protein mediated mitochondrial pathway .	Therefore, the increased Bax levels and the reduced Bcl2 levels caused high Bax and Bcl2 ratios (greater than 1) in a time dependent manner, indicating DN induced apoptosis via regulation of the Bcl-2 family protein mediated mitochondrial pathway.	4	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax levels	bax	Bax	Bax	bax	4	5	13	14
Our current results revealed that , under chronic cerebral hypoperfusion , baclofen could simultaneously increase the expression of Bcl-2 and Bax ( especially for Bcl-2 ) by promoting the phosphorylation of ERK ( as described below ) XREF_BIBR XREF_BIBR , but up-regulate Bcl-2 and Bax ratio , which might both inhibit autophagy and down-regulate cleaved caspase-3 XREF_BIBR XREF_BIBR XREF_BIBR .	Our current results revealed that, under chronic cerebral hypoperfusion, baclofen could simultaneously increase the expression of Bcl-2 and Bax (especially for Bcl-2) by promoting the phosphorylation of ERK (as described below) XREF_BIBR XREF_BIBR, but up-regulate Bcl-2 and Bax ratio, which might both inhibit autophagy and down-regulate cleaved caspase-3 XREF_BIBR XREF_BIBR XREF_BIBR.	11	45	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	baclofen could simultaneously increase the expression of Bcl-2 and Bax	bax	Bax	Bax	bax	20	21	44	45
In contrast , an abundant amount of Bax causes formation of Bax homodimers that make the cells susceptible to apoptosis [ XREF_BIBR , XREF_BIBR ] .	In contrast, an abundant amount of Bax causes formation of Bax homodimers that make the cells susceptible to apoptosis [XREF_BIBR, XREF_BIBR].	5	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	amount of Bax	bax	Bax	Bax	bax	7	8	11	12
After STIP was silenced , the expression of Bcl-2 was significantly decreased , whereas Bax protein expression was markedly increased , resulting in a high Bax and Bcl -2 ratio in both cell lines .	After STIP was silenced, the expression of Bcl-2 was significantly decreased, whereas Bax protein expression was markedly increased, resulting in a high Bax and Bcl -2 ratio in both cell lines.	14	29	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax protein expression	bax	Bax	Bax	bax	14	15	25	26
c-Myc leads to cell death by upregulating Bax expression causing a lower Bcl2 and Bax ratio under severe hypoxic conditions .	c-Myc leads to cell death by upregulating Bax expression causing a lower Bcl2 and Bax ratio under severe hypoxic conditions.	0	15	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	c-Myc leads to cell death by upregulating Bax expression	bax	Bax	Bax	bax	7	8	14	15
Bax regulates mitochondria associated apoptosis and is a substrate of GSK3beta ; GSK3beta mediated Bax phosphorylation results in Bax activation .	Bax regulates mitochondria associated apoptosis and is a substrate of GSK3beta; GSK3beta mediated Bax phosphorylation results in Bax activation.	12	20	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Bax	GSK3beta mediated Bax phosphorylation	bax	Bax	Bax	bax	14	15	18	19
It is concluded that CZBG combined with Dox can enhance the apoptosis rate in K562 and A02 cells , down-regulate the expression of BCL-2 and up-regulate the expression of BAX , thereby , can reverse the multidrug resistance of K562 and A02 cells by decreasing the ratio of BCL-2 and BAX .	It is concluded that CZBG combined with Dox can enhance the apoptosis rate in K562 and A02 cells, down-regulate the expression of BCL-2 and up-regulate the expression of BAX, thereby, can reverse the multidrug resistance of K562 and A02 cells by decreasing the ratio of BCL-2 and BAX.	27	51	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAX	expression of BAX	bax	BAX	BAX	bax	29	30	50	51
Inhibition of NF-kappaB by JSH-23 or overexpression of AdIkappaBalphaDN restored the decreased expression of Bcl-2 and prevented the HG induced increase in Bax expression , thereby restoring the Bax and Bcl -2 ratio to control levels ( XREF_FIG ) .	Inhibition of NF-kappaB by JSH-23 or overexpression of AdIkappaBalphaDN restored the decreased expression of Bcl-2 and prevented the HG induced increase in Bax expression, thereby restoring the Bax and Bcl -2 ratio to control levels (XREF_FIG).	18	32	restoring	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	HG induced increase in Bax expression	bax	Bax	Bax	bax	22	23	28	29
Inversely , PP2A mediated dephosphorylation of Bax at S184 enhances the proapoptotic function of Bax XREF_BIBR .	Inversely, PP2A mediated dephosphorylation of Bax at S184 enhances the proapoptotic function of Bax XREF_BIBR.	2	15	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	PP2A mediated dephosphorylation of Bax at S184	bax	Bax	Bax	bax	6	7	14	15
The pro apoptotic Bcl-2 member Bax can be regulated by ubiquitination indirectly ; the ubiquitin ligase Trim39 inhibits APC/C Cdh1 mediated ubiquitination and degradation of the Bax activator MOAP-1 , thus enhancing Bax activation and apoptosis XREF_BIBR .	The pro apoptotic Bcl-2 member Bax can be regulated by ubiquitination indirectly; the ubiquitin ligase Trim39 inhibits APC/C Cdh1 mediated ubiquitination and degradation of the Bax activator MOAP-1, thus enhancing Bax activation and apoptosis XREF_BIBR.	14	33	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	ubiquitin ligase Trim39 inhibits APC/C Cdh1 mediated ubiquitination and degradation of the Bax	bax	Bax	Bax	bax	26	27	32	33
Subsequently , mRNA and protein expression levels of Bcl-2 , Bax and caspase-3 were detected in these two cell lines , and it was found that the expression of Bcl-2 significantly decreased , while the expression of Bax and caspase-3 significantly increased compared with the two control groups , resulting in a lower Bcl-2 and Bax ratio at the mRNA ( XREF_FIG ) and protein ( XREF_FIG ) expression level .	Subsequently, mRNA and protein expression levels of Bcl-2, Bax and caspase-3 were detected in these two cell lines, and it was found that the expression of Bcl-2 significantly decreased, while the expression of Bax and caspase-3 significantly increased compared with the two control groups, resulting in a lower Bcl-2 and Bax ratio at the mRNA (XREF_FIG) and protein (XREF_FIG) expression level.	35	56	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	Bax	Bax	bax	37	38	55	56
The active p53 can trigger the transcription of DNA Bax , producing an increased level of Bax protein synthesis [ XREF_BIBR ] .	The active p53 can trigger the transcription of DNA Bax, producing an increased level of Bax protein synthesis [XREF_BIBR].	2	18	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	p53 can trigger the transcription of DNA Bax	bax	Bax	Bax	bax	9	10	16	17
Re-expression of Bax in these cells failed to further enhance p14 ( ARF )-induced apoptosis , suggesting that p14 ( ARF )-induced apoptosis primarily depends on Bak but not Bax in these cells .	Re-expression of Bax in these cells failed to further enhance p14 (ARF)-induced apoptosis, suggesting that p14 (ARF)-induced apoptosis primarily depends on Bak but not Bax in these cells.	0	32	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Re-expression of Bax	bax	Bax	Bax	bax	2	3	29	30
XREF_BIBR More recently , phosphorylation of Bax by GSK3beta has been shown to promote the translocation of Bax to mitochondria and the induction of apoptosis in CGN .	XREF_BIBR More recently, phosphorylation of Bax by GSK3beta has been shown to promote the translocation of Bax to mitochondria and the induction of apoptosis in CGN.	4	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	phosphorylation of Bax	bax	Bax	Bax	bax	6	7	17	18
Bax expression was clearly increased in mcl-1 flox and flox AlbCre mice , suggesting Bax activation being involved in the apoptosis in mcl-1 flox and flox AlbCre mice ( XREF_FIG ) .	Bax expression was clearly increased in mcl-1 flox and flox AlbCre mice, suggesting Bax activation being involved in the apoptosis in mcl-1 flox and flox AlbCre mice (XREF_FIG).	0	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax expression	bax	Bax	Bax	bax	0	1	14	15
The total Bax expression level was increased with FCC treatment in a dose dependent manner , while the total Bcl-2 expression level was decreased , resulting in a higher Bax and Bcl -2 ratio .	The total Bax expression level was increased with FCC treatment in a dose dependent manner, while the total Bcl-2 expression level was decreased, resulting in a higher Bax and Bcl -2 ratio.	2	33	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax expression level	bax	Bax	Bax	bax	2	3	29	30
Conversely , dephosphorylation of Bax at S184 causes a conformational change that promotes the insertion of Bax into mitochondrial membranes and formation of Bax oligomers leading to cytochrome c release and apoptosis .	Conversely, dephosphorylation of Bax at S184 causes a conformational change that promotes the insertion of Bax into mitochondrial membranes and formation of Bax oligomers leading to cytochrome c release and apoptosis.	2	24	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	dephosphorylation of Bax at S184	bax	Bax	Bax	bax	4	5	23	24
XREF_BIBR reported that heat stress induced the mRNA and protein expression of BAX in LLC-PK1 cells , significantly increasing the ratio of Bcl-2 and BAX XREF_BIBR .	XREF_BIBR reported that heat stress induced the mRNA and protein expression of BAX in LLC-PK1 cells, significantly increasing the ratio of Bcl-2 and BAX XREF_BIBR.	3	25	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	heat stress induced the mRNA and protein expression of BAX	bax	BAX	BAX	bax	12	13	24	25
Furthermore , we also analyzed the mRNA expression of caspase-3 in the neuronal tissues of rats and the protein expressions of Bax and Bcl-2 in PC12 cells , our results show that Abeta 25-35 significantly increased the expression of caspase-3 in the brain tissues of the AD rats compared to that of the control rats , while LSS significantly reduced the expressions of caspase-3 mRNA and Bax protein , meantime , increased the protein expression of Bcl-2 and the ratio of Bcl-2 and Bax .	Furthermore, we also analyzed the mRNA expression of caspase-3 in the neuronal tissues of rats and the protein expressions of Bax and Bcl-2 in PC12 cells, our results show that Abeta 25-35 significantly increased the expression of caspase-3 in the brain tissues of the AD rats compared to that of the control rats, while LSS significantly reduced the expressions of caspase-3 mRNA and Bax protein, meantime, increased the protein expression of Bcl-2 and the ratio of Bcl-2 and Bax.	61	84	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expressions of caspase-3 mRNA and Bax	bax	Bax	Bax	bax	66	67	83	84
By contrast , total and mitochondrial associated Bax expression significantly increased in the cells treated with GSK3 siRNA or enzastaurin ( XREF_FIG and XREF_SUPPLEMENTARY ) , resulting in an increase in the mitochondrial associated Bax and HKII ratio .	By contrast, total and mitochondrial associated Bax expression significantly increased in the cells treated with GSK3 siRNA or enzastaurin (XREF_FIG and XREF_SUPPLEMENTARY), resulting in an increase in the mitochondrial associated Bax and HKII ratio.	7	37	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax expression	bax	Bax	Bax	bax	7	8	34	35
Importantly , nicotine induced Bax phosphorylation potently blocks stress induced translocation of Bax from cytosol to mitochondria , impairs Bax insertion into mitochondrial membranes , and reduces the half-life of Bax protein ( i.e. from 9-12 h to < 6 h ) .	Importantly, nicotine induced Bax phosphorylation potently blocks stress induced translocation of Bax from cytosol to mitochondria, impairs Bax insertion into mitochondrial membranes, and reduces the half-life of Bax protein (i.e. from 9-12 h to < 6 h).	4	20	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax phosphorylation	bax	Bax	Bax	bax	4	5	19	20
It has been demonstrated that GSK3beta directly phosphorylates Bax and promotes proapoptotic action of Bax .	It has been demonstrated that GSK3beta directly phosphorylates Bax and promotes proapoptotic action of Bax.	5	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	GSK3beta directly phosphorylates Bax	bax	Bax	Bax	bax	8	9	14	15
Importantly , nicotine induced Bax phosphorylation potently blocks stress induced translocation of Bax from the cytosol to the mitochondria , impairs Bax insertion into mitochondrial membranes , and reduces the half-life of Bax protein [ XREF_BIBR ] .	Importantly, nicotine induced Bax phosphorylation potently blocks stress induced translocation of Bax from the cytosol to the mitochondria, impairs Bax insertion into mitochondrial membranes, and reduces the half-life of Bax protein [XREF_BIBR].	4	22	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax phosphorylation	bax	Bax	Bax	bax	4	5	21	22
The present studies demonstrate that the treatment of cells with a combination of low-dose isoalantolactone and radiation might further reduce the expression of Bcl-2 and increase the expression of Bax , which would lead to an increased Bax and Bcl -2 ratio ; moreover , Cleaved-caspase 3 expression would also increase and result in enhanced radiation induced apoptosis .	The present studies demonstrate that the treatment of cells with a combination of low-dose isoalantolactone and radiation might further reduce the expression of Bcl-2 and increase the expression of Bax, which would lead to an increased Bax and Bcl -2 ratio; moreover, Cleaved-caspase 3 expression would also increase and result in enhanced radiation induced apoptosis.	27	41	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Bax	expression of Bax	bax	Bax	Bax	bax	29	30	37	38
The increased levels of Bax increase the concentrations of Bax and Bax complexes ( proapoptotic complex ) that have been demonstrated to displace the Bcl-2 and Bax complexes ( anti and apoptotic complex ) that compete for the same receptor site on the mitochondrial membrane [ XREF_BIBR ] .	The increased levels of Bax increase the concentrations of Bax and Bax complexes (proapoptotic complex) that have been demonstrated to displace the Bcl-2 and Bax complexes (anti and apoptotic complex) that compete for the same receptor site on the mitochondrial membrane [XREF_BIBR].	2	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	levels of Bax	bax	Bax	Bax	bax	4	5	9	10
H/R treatment dramatically reduced Bcl-2 and Bcl-XL , increased Bax and Bak expression and decreased the ratio of Bcl-2 and Bax .	H/R treatment dramatically reduced Bcl-2 and Bcl-XL, increased Bax and Bak expression and decreased the ratio of Bcl-2 and Bax.	0	21	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	H/R treatment dramatically reduced Bcl-2 and Bcl-XL, increased Bax and Bak expression	bax	Bax	Bax	bax	9	10	20	21
SI/R treatment decreased Bcl-2 ( an anti-apoptotic protein ) expression , and increased Bax ( a pro apoptotic protein ) expression , decreasing the Bcl-2 and Bax ratio ( XREF_FIG ) .	SI/R treatment decreased Bcl-2 (an anti-apoptotic protein) expression, and increased Bax (a pro apoptotic protein) expression, decreasing the Bcl-2 and Bax ratio (XREF_FIG).	0	27	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	SI/R treatment decreased Bcl-2 (an anti-apoptotic protein) expression, and increased Bax (a pro apoptotic protein) expression	bax	Bax	Bax	bax	13	14	26	27
In addition , TGEV infection down-regulated Bcl-2 , up-regulated Bax expression , promoted translocation of Bax to mitochondria , activated mitochondria mediated apoptotic pathway , which in turn caused the release of cytochrome c and the activation of caspase-9 .	In addition, TGEV infection down-regulated Bcl-2, up-regulated Bax expression, promoted translocation of Bax to mitochondria, activated mitochondria mediated apoptotic pathway, which in turn caused the release of cytochrome c and the activation of caspase-9.	6	16	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bcl-2, up-regulated Bax expression	bax	Bax	Bax	bax	9	10	15	16
Only coexpression of BAX and DHHC enzymes 3 , 7 , 11 , 12 or 21 significantly stimulated S palmitoylation of BAX as compared with control , suggesting that these DHHC enzymes are able to palmitoylate BAX .	Only coexpression of BAX and DHHC enzymes 3, 7, 11, 12 or 21 significantly stimulated S palmitoylation of BAX as compared with control, suggesting that these DHHC enzymes are able to palmitoylate BAX.	1	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	coexpression of BAX	bax	BAX	BAX	bax	3	4	21	22
Upregulation of miR-145 expression increased the expression of Bax , thus increasing the Bax and Bcl -2 ratio .	Upregulation of miR-145 expression increased the expression of Bax, thus increasing the Bax and Bcl -2 ratio.	2	17	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	miR-145 expression increased the expression of Bax	bax	Bax	Bax	bax	8	9	13	14
It suggested that BPA can diminish the expression of Bcl-2 , increase the expression of Bax , and thus decrease the ratio of Bcl-2 and Bax .	It suggested that BPA can diminish the expression of Bcl-2, increase the expression of Bax, and thus decrease the ratio of Bcl-2 and Bax.	3	26	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	BPA can diminish the expression of Bcl-2, increase the expression of Bax	bax	Bax	Bax	bax	15	16	25	26
Serum containing Xihuang pill can induce the apoptosis of human breast cancer cells , and the mechanism of estrogen receptor negative breast cancer cell apoptosis may be induced by up-regulating the mRNA expression of TP53 , which can induce the expression of Bax and promote the metastasis of Bax to mitochondria , and ultimately play the role of inducing apoptosis .	Serum containing Xihuang pill can induce the apoptosis of human breast cancer cells, and the mechanism of estrogen receptor negative breast cancer cell apoptosis may be induced by up-regulating the mRNA expression of TP53, which can induce the expression of Bax and promote the metastasis of Bax to mitochondria, and ultimately play the role of inducing apoptosis.	18	49	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	estrogen receptor negative breast cancer cell apoptosis may be induced by up-regulating the mRNA expression of TP53, which can induce the expression of Bax	bax	Bax	Bax	bax	42	43	48	49
As shown in XREF_FIG , in the p53-transcription-dependent pathway , p53 A prompts Bax activation by upregulating the expressions of Bax and PUMA which activates Bax either directly or indirectly ( via binding Bcl-2 and thereby preventing its anti-apoptotic effect on Bax ) .	As shown in XREF_FIG, in the p53-transcription-dependent pathway, p53 A prompts Bax activation by upregulating the expressions of Bax and PUMA which activates Bax either directly or indirectly (via binding Bcl-2 and thereby preventing its anti-apoptotic effect on Bax).	18	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	expressions of Bax	bax	Bax	Bax	bax	20	21	25	26
Ido1 can prevent uterine stromal cells proliferation and enhance the expression of the Bax gene and increase the Bax and Bcl2 ratio under in vitro decidualization .	Ido1 can prevent uterine stromal cells proliferation and enhance the expression of the Bax gene and increase the Bax and Bcl2 ratio under in vitro decidualization.	0	21	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Ido1 can prevent uterine stromal cells proliferation and enhance the expression of the Bax	bax	Bax	Bax	bax	13	14	18	19
SP600125 , a specific inhibitor of JNK MAPK , markedly promoted the expression of Bax and inhibited the Bcl-2 and Bax ratio .	SP600125, a specific inhibitor of JNK MAPK, markedly promoted the expression of Bax and inhibited the Bcl-2 and Bax ratio.	0	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	SP600125, a specific inhibitor of JNK MAPK, markedly promoted the expression of Bax	bax	Bax	Bax	bax	14	15	20	21
Moreover , the upregulated expression of BAX and the downregulated expression of Bcl-2 increased the ratio of BAX to Bcl-2 ( XREF_FIG ) .	Moreover, the upregulated expression of BAX and the downregulated expression of Bcl-2 increased the ratio of BAX to Bcl-2 (XREF_FIG).	4	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	expression of BAX	bax	BAX	BAX	bax	6	7	17	18
When Bax expression is increased , Bax forms homodimers and promotes apoptosis [ XREF_BIBR ] .	When Bax expression is increased, Bax forms homodimers and promotes apoptosis [XREF_BIBR].	1	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax expression	bax	Bax	Bax	bax	1	2	6	7
Overexpression of Bax accelerates apoptotic death and Bax also counters the cell death repressor activity of Bcl-2 .	Overexpression of Bax accelerates apoptotic death and Bax also counters the cell death repressor activity of Bcl-2.	0	8	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Overexpression of Bax	bax	Bax	Bax	bax	2	3	7	8
- on VDAC was not mediated by Bax ( XREF_FIG A ) .	- on VDAC was not mediated by Bax (XREF_FIG A).	1	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	7	8	2	3
The recombinant pro apoptotic proteins Bax and Bak were able to accelerate the opening of VDAC , whereas the anti-apoptotic protein Bcl-xL closes VDAC by binding to it directly [ XREF_BIBR ] .	The recombinant pro apoptotic proteins Bax and Bak were able to accelerate the opening of VDAC, whereas the anti-apoptotic protein Bcl-xL closes VDAC by binding to it directly [XREF_BIBR].	0	16	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	5	6	15	16
Ab # 25 and Ab # 20 , but not NRI , also inhibited the Bax induced enhancement of VDAC activity ( XREF_FIG C ) .	Ab # 25 and Ab # 20, but not NRI, also inhibited the Bax induced enhancement of VDAC activity (XREF_FIG C).	14	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	15	16	19	20
Also , activated tBid and Bax increase the pore size of mitochondrial VDAC for cytochrome c release .	Also, activated tBid and Bax increase the pore size of mitochondrial VDAC for cytochrome c release.	3	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	5	6	12	13
Moreover , Bax mediated VDAC activation and induction of ceramide synthesis were involved in the release of AIF from mitochondria XREF_BIBR .	Moreover, Bax mediated VDAC activation and induction of ceramide synthesis were involved in the release of AIF from mitochondria XREF_BIBR.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	2	3	4	5
In this context , it has been demonstrated that Bax and Bak accelerate the opening of VDAC in reconstituted proteoliposomes , and that VDAC deficient mitochondria do not exhibit Bax and Bak induced Cyt c release and Deltapsi m dissipation occurring in VDAC-proficient control mitochondria [ XREF_BIBR ; S106 ] .	In this context, it has been demonstrated that Bax and Bak accelerate the opening of VDAC in reconstituted proteoliposomes, and that VDAC deficient mitochondria do not exhibit Bax and Bak induced Cyt c release and Deltapsi m dissipation occurring in VDAC-proficient control mitochondria [XREF_BIBR; S106].	9	17	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	9	10	16	17
However , as shown in XREF_FIG D , Ab # 20 and Ab # 25 had no effect on state IV and state III respiration at concentrations sufficient to inhibit cytochrome c release , suggesting that these antibodies inhibited cytochrome c release by directly inhibiting Bax induced enhancement of VDAC activity .	However, as shown in XREF_FIG D, Ab # 20 and Ab # 25 had no effect on state IV and state III respiration at concentrations sufficient to inhibit cytochrome c release, suggesting that these antibodies inhibited cytochrome c release by directly inhibiting Bax induced enhancement of VDAC activity.	45	50	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	45	46	49	50
These data , together with our previous observation that Bax and Bak directly and functionally interact with VDAC , indicated that Bax and Bak targeted the VDAC on the RBC plasma membrane to induce hemolysis , although the possibility was not formally excluded that Bax and Bak acted on RBCs independent of VDAC to trigger hemolysis that was somehow regulated by VDAC .	These data, together with our previous observation that Bax and Bak directly and functionally interact with VDAC, indicated that Bax and Bak targeted the VDAC on the RBC plasma membrane to induce hemolysis, although the possibility was not formally excluded that Bax and Bak acted on RBCs independent of VDAC to trigger hemolysis that was somehow regulated by VDAC.	21	27	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	21	22	26	27
It was found that recombinant Bax induced permeability in liposomes containing VDAC , implying that VDAC can induce membrane permeability in the presence of Bax .	It was found that recombinant Bax induced permeability in liposomes containing VDAC, implying that VDAC can induce membrane permeability in the presence of Bax.	4	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	5	6	11	12
Thus , in the absence of caspases , Bax and Bak may be able to induce the opening of VDAC , which results in the swelling of mitochondrial matrix , rupture of OMM , and death by a caspase independent pathway .	Thus, in the absence of caspases, Bax and Bak may be able to induce the opening of VDAC, which results in the swelling of mitochondrial matrix, rupture of OMM, and death by a caspase independent pathway.	8	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	8	9	19	20
It has also been shown that Bid but not Bax modulates VDAC channel conductance .	It has also been shown that Bid but not Bax modulates VDAC channel conductance.	6	13	modulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	9	10	11	12
Here we create liposomes that carry the mitochondrial porin channel ( also called the voltage dependent anion channel , or VDAC ) to show that the recombinant pro apoptotic proteins Bax and Bak accelerate the opening of VDAC , whereas the anti-apoptotic protein Bcl-x ( L ) closes VDAC by binding to it directly .	Here we create liposomes that carry the mitochondrial porin channel (also called the voltage dependent anion channel, or VDAC) to show that the recombinant pro apoptotic proteins Bax and Bak accelerate the opening of VDAC, whereas the anti-apoptotic protein Bcl-x (L) closes VDAC by binding to it directly.	25	38	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	30	31	37	38
Purified VDAC1 is a substrate for PKA in vitro , and PKA phosphorylation of VDAC inhibits association of VDAC with other proteins , such as Bax and tBid [ XREF_BIBR , XREF_BIBR ] , where tBid but not Bax causes VDAC closure [ XREF_BIBR ] .	Purified VDAC1 is a substrate for PKA in vitro, and PKA phosphorylation of VDAC inhibits association of VDAC with other proteins, such as Bax and tBid [XREF_BIBR, XREF_BIBR], where tBid but not Bax causes VDAC closure [XREF_BIBR].	25	43	causes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	25	26	40	41
Moreover , Bax increases the permeability of VDAC1 function in outer mitochondrial membrane .	Moreover, Bax increases the permeability of VDAC1 function in outer mitochondrial membrane.	2	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC1	VDAC1	VDAC1	2	3	7	8
Since neither Bax association with the mitochondria nor Bax-VDAC interaction was inhibited by Ab # 20 and Ab # 25 ( XREF_FIG and XREF_FIG ) , inhibition of apoptotic mitochondrial changes by these antibodies was not due to simple blocking of Bax association with mitochondria or Bax-VDAC interaction , but was probably due to inhibition of VDAC conformational changes that are normally induced by Bax .	Since neither Bax association with the mitochondria nor Bax-VDAC interaction was inhibited by Ab # 20 and Ab # 25 (XREF_FIG and XREF_FIG), inhibition of apoptotic mitochondrial changes by these antibodies was not due to simple blocking of Bax association with mitochondria or Bax-VDAC interaction, but was probably due to inhibition of VDAC conformational changes that are normally induced by Bax.	56	65	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	VDAC	VDAC	VDAC	64	65	56	57
We have shown that BCL9 enhances beta-catenin mediated transcriptional activity regardless of the mutational status of the Wnt signaling components , increases cell proliferation , migration , invasion and the metastatic potential of tumor cells .	We have shown that BCL9 enhances beta-catenin mediated transcriptional activity regardless of the mutational status of the Wnt signaling components, increases cell proliferation, migration, invasion and the metastatic potential of tumor cells.	4	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	4	5	6	7
BCL9 is a transcriptional co-activator of beta-catenin , and plays critical roles in the pathogenesis of various human cancers , including MM XREF_BIBR , XREF_BIBR - XREF_BIBR .	BCL9 is a transcriptional co-activator of beta-catenin, and plays critical roles in the pathogenesis of various human cancers, including MM XREF_BIBR, XREF_BIBR - XREF_BIBR.	0	9	is a transcriptional co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
Elevated BCL9 could modulate Wnt signaling by enhancing beta-catenin targeted transcription [ XREF_BIBR ] .	Elevated BCL9 could modulate Wnt signaling by enhancing beta-catenin targeted transcription [XREF_BIBR].	0	9	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	1	2	8	9
Fourth , the Wnt pathway is constitutively active in multiple myeloma , owing in part to increased abundance of the B cell lymphoma 9 ( BCL9 ) protein , which activates beta-catenin .	Fourth, the Wnt pathway is constitutively active in multiple myeloma, owing in part to increased abundance of the B cell lymphoma 9 (BCL9) protein, which activates beta-catenin.	25	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	25	26	31	32
Others suggest that TCF/LEF and beta-catenin coactivators such as Pygopus and Bcl9 mediate beta-catenin nuclear import or retention and anchoring .	Others suggest that TCF/LEF and beta-catenin coactivators such as Pygopus and Bcl9 mediate beta-catenin nuclear import or retention and anchoring.	6	15	mediate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bcl9	Bcl9	Bcl9	beta-catenin	beta-catenin	beta-catenin	11	12	13	14
Meanwhile , B cell lymphoma 9 ( BCL9 ) drives Wnt signaling path through direct binding mediated beta-catenin .	Meanwhile, B cell lymphoma 9 (BCL9) drives Wnt signaling path through direct binding mediated beta-catenin.	2	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	7	8	17	18
We next tested whether BCL9 and BCL9-2 mediate Wnt and beta-catenin signaling in myogenic progenitors .	We next tested whether BCL9 and BCL9-2 mediate Wnt and beta-catenin signaling in myogenic progenitors.	4	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	4	5	10	11
BCL9 contributes to transduction of the Wnt signal by promoting transcriptional activity and nuclear retention of beta-catenin [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	BCL9 contributes to transduction of the Wnt signal by promoting transcriptional activity and nuclear retention of beta-catenin [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	22	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	0	1	16	17
Over-expression studies in mammalian cells have shown that BCL9 and Pygopus are sufficient to elevate Wnt and beta-catenin signaling in vitro .	Over-expression studies in mammalian cells have shown that BCL9 and Pygopus are sufficient to elevate Wnt and beta-catenin signaling in vitro.	8	18	elevate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	8	9	17	18
While BCL9 is a co-activator of beta-catenin and it binds to the N-terminus of beta-catenin , there are multiple co-activators and chromatin remodeling proteins that bind to the structurally flexible C-terminal region of beta-catenin .	While BCL9 is a co-activator of beta-catenin and it binds to the N-terminus of beta-catenin, there are multiple co-activators and chromatin remodeling proteins that bind to the structurally flexible C-terminal region of beta-catenin.	1	7	is a co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
Co-expression of BCL9 and pygopus promoted nuclear localization of beta-catenin in SW480 but failed to do so in 293T , HT29 and Hct116 cells [ XREF_BIBR ] , and silencing of APC by RNAi only leads to Tcf activation in a minority of cases ( CF and RI , unpublished data ) .	Co-expression of BCL9 and pygopus promoted nuclear localization of beta-catenin in SW480 but failed to do so in 293T, HT29 and Hct116 cells [XREF_BIBR], and silencing of APC by RNAi only leads to Tcf activation in a minority of cases (CF and RI, unpublished data).	0	10	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	Co-expression of BCL9	bcl9	beta-catenin	beta-catenin	beta-catenin	2	3	9	10
Given that the molecular mechanism by which BCL9 enhances Wnt and beta-catenin signaling is better understood than that of LRRFIP2 , we focused on BCL9 .	Given that the molecular mechanism by which BCL9 enhances Wnt and beta-catenin signaling is better understood than that of LRRFIP2, we focused on BCL9.	7	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	7	8	11	12
BCL9 and FoxM1 mediate beta-catenin nuclear transport , but unlike these proteins , ARF6 localizes to the plasma membrane and endosomes and may not be directly involved in nuclear translocation of beta-catenin .	BCL9 and FoxM1 mediate beta-catenin nuclear transport, but unlike these proteins, ARF6 localizes to the plasma membrane and endosomes and may not be directly involved in nuclear translocation of beta-catenin.	0	6	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	0	1	4	5
We also found that miR-1301 inhibited the migration , invasion , and angiogenesis of HCC cells by targeting BCL9 , which decreased Wnt and beta-catenin signaling .	We also found that miR-1301 inhibited the migration, invasion, and angiogenesis of HCC cells by targeting BCL9, which decreased Wnt and beta-catenin signaling.	5	25	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	18	19	24	25
BCL9 is the co-activator of beta-catenin that has been found to bind to the N-terminal arm-repeats while most of the transcription co-activators interact with the C-terminal domain of beta-catenin .	BCL9 is the co-activator of beta-catenin that has been found to bind to the N-terminal arm-repeats while most of the transcription co-activators interact with the C-terminal domain of beta-catenin.	0	6	is the co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	0	1	5	6
Both BCL9 and BCL9L are known to bind to beta-catenin and trigger the interaction of beta-catenin with the TCF , LEF , and transcriptional complex [ XREF_BIBR ] .	Both BCL9 and BCL9L are known to bind to beta-catenin and trigger the interaction of beta-catenin with the TCF, LEF, and transcriptional complex [XREF_BIBR].	0	16	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	1	2	15	16
Furthermore , BCL9 knockdown in MHCC-LM3 cells resulted in reduced expression beta-catenin targets , CD44 and c-JUN ( XREF_FIG ) .	Furthermore, BCL9 knockdown in MHCC-LM3 cells resulted in reduced expression beta-catenin targets, CD44 and c-JUN (XREF_FIG).	2	13	targets	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
Instead , the mechanism of pathologic Wnt signaling in MM involves post-transcriptional regulation of beta-catenin and increased levels of BCL9 , implicating this beta-catenin co-factor as a bona fide oncogene .	Instead, the mechanism of pathologic Wnt signaling in MM involves post-transcriptional regulation of beta-catenin and increased levels of BCL9, implicating this beta-catenin co-factor as a bona fide oncogene.	14	20	increased	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	BCL9	levels of BCL9	bcl9	beta-catenin	beta-catenin	beta-catenin	19	20	14	15
Specifically , BCL9 promotes transcriptional activity and nuclear retention of beta-catenin .	Specifically, BCL9 promotes transcriptional activity and nuclear retention of beta-catenin.	2	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	2	3	10	11
However , the significant p-value and the shared homology to BRCA1 support BARD1 as a rare OC susceptibility gene .	However, the significant p-value and the shared homology to BRCA1 support BARD1 as a rare OC susceptibility gene.	4	18	support	Positive_activation_token_1_noun	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	12	13	10	11
Biochemical studies revealed that BARD1 potentiates the ubiquitin ligase activity of BRCA1 , which can be reversed through the inhibition of BRCA1-BARD1 association by BRCA1 associated protein 1 ( BAP1 ) 64 .	Biochemical studies revealed that BARD1 potentiates the ubiquitin ligase activity of BRCA1, which can be reversed through the inhibition of BRCA1-BARD1 association by BRCA1 associated protein 1 (BAP1) 64.	4	16	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	4	5	11	12
Recently , BARD1 missense mutations , accompanied by loss of the wild-type allele , have been identified in human breast carcinoma , supporting the notion that BARD1 may participate in BRCA1 mediated tumor suppression .	Recently, BARD1 missense mutations, accompanied by loss of the wild-type allele, have been identified in human breast carcinoma, supporting the notion that BARD1 may participate in BRCA1 mediated tumor suppression.	2	31	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	2	3	30	31
Independently of BRCA1 , BARD1 is an inducer of apoptosis by binding to and stabilizing p53 [ XREF_BIBR - XREF_BIBR ] .	Independently of BRCA1, BARD1 is an inducer of apoptosis by binding to and stabilizing p53 [XREF_BIBR - XREF_BIBR].	0	8	is an inducer	Positive_activation_copula_1	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	4	5	2	3
Inhibition of BARD1 disrupts BRCA1 .	Inhibition of BARD1 disrupts BRCA1.	0	5	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	2	3	4	5
These results suggest that the BARD1 BRCTs might target BRCA1 to DNA damage sites during the early DNA damage response .	These results suggest that the BARD1 BRCTs might target BRCA1 to DNA damage sites during the early DNA damage response.	5	10	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	5	6	9	10
We show that BARD1 promoted nuclear accumulation of BRCA1 , but repressed BRCA1 mediated transactivation by up to 75 % in transfected cells normalized for nuclear BRCA1 levels .	We show that BARD1 promoted nuclear accumulation of BRCA1, but repressed BRCA1 mediated transactivation by up to 75% in transfected cells normalized for nuclear BRCA1 levels.	3	14	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	3	4	12	13
How the BARD1 RING finger enhances the activity of BRCA1 in vitro and stabilizes it in cells is unknown .	How the BARD1 RING finger enhances the activity of BRCA1 in vitro and stabilizes it in cells is unknown.	2	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	2	3	9	10
Alternatively , BARD1 and HP1 and Abraxas and RAP80 may mediate sequential retention of endogenous BRCA1 that can be overcome by overexpressed BRCA1-BRCT fragment .	Alternatively, BARD1 and HP1 and Abraxas and RAP80 may mediate sequential retention of endogenous BRCA1 that can be overcome by overexpressed BRCA1-BRCT fragment.	2	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	2	3	15	16
However , the BARD1 BRCTs mutation did not impair the slow accumulation of BRCA1 to DNA damage sites ( XREF_FIG ) .	However, the BARD1 BRCTs mutation did not impair the slow accumulation of BRCA1 to DNA damage sites (XREF_FIG).	3	14	impair	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	3	4	13	14
Independently of BRCA1 , BARD1 is an inducer of apoptosis by binding to and stabilizing p53 [ XREF_BIBR - XREF_BIBR ] and is upregulated in response to hormones , genotoxic stress , and hypoxia [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Independently of BRCA1, BARD1 is an inducer of apoptosis by binding to and stabilizing p53 [XREF_BIBR - XREF_BIBR] and is upregulated in response to hormones, genotoxic stress, and hypoxia [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	8	is an inducer	Positive_activation_copula_1	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	4	5	2	3
For example , it has been shown that BARD1 and MDMX enhance ubiquitn E3 ligase activity of BRCA1 and MDM2 respectively by stabilizing these proteins XREF_BIBR XREF_BIBR XREF_BIBR .	For example, it has been shown that BARD1 and MDMX enhance ubiquitn E3 ligase activity of BRCA1 and MDM2 respectively by stabilizing these proteins XREF_BIBR XREF_BIBR XREF_BIBR.	8	19	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	8	9	17	18
Similar to ZBRK1 , BRCA1 associated RING domain ( BARD1 ) , another inhibitor of BRCA1 transcriptional activity , represses BRCA1 mediated trans-activation of the GADD45 promoter , even though BARD1 increases the accumulation of BRCA1 in the nucleus [ XREF_BIBR ] .	Similar to ZBRK1, BRCA1 associated RING domain (BARD1), another inhibitor of BRCA1 transcriptional activity, represses BRCA1 mediated trans-activation of the GADD45 promoter, even though BARD1 increases the accumulation of BRCA1 in the nucleus [XREF_BIBR].	30	40	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	30	31	35	36
Enhancement of activity of RING domain hetero-oligomers has also been demonstrated for BRCA1-BARD1 complexes , where the presence of BARD1 in the complex increases the ligase activity of BRCA1 .	Enhancement of activity of RING domain hetero-oligomers has also been demonstrated for BRCA1-BARD1 complexes, where the presence of BARD1 in the complex increases the ligase activity of BRCA1.	17	29	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	19	20	28	29
Taken together , these two observations suggest that BARD1 promotion of the nuclear localization of BRCA1 may prevent BRCA1 degradation by cytosolic 26S proteasomes or other proteases .	Taken together, these two observations suggest that BARD1 promotion of the nuclear localization of BRCA1 may prevent BRCA1 degradation by cytosolic 26S proteasomes or other proteases.	8	19	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	8	9	18	19
We also show that the presence of BARD1 has a secondary effect , as autoubiquitination of BRCA1 and BARD1 heterodimers additionally enhances the affinity of BRCA1 for DNA .	We also show that the presence of BARD1 has a secondary effect, as autoubiquitination of BRCA1 and BARD1 heterodimers additionally enhances the affinity of BRCA1 for DNA.	14	27	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	autoubiquitination of BRCA1 and BARD1	bard1	BRCA1	BRCA1	brca1	18	19	25	26
The mechanism by which BARD1 promotes BRCA1 ligase activity is therefore unclear but may involve stabilizing a conformation of BRCA1 optimal for E2 binding .	The mechanism by which BARD1 promotes BRCA1 ligase activity is therefore unclear but may involve stabilizing a conformation of BRCA1 optimal for E2 binding.	4	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	4	5	6	7
Interestingly , the nuclear export of BRCA1 was directly linked to this proapoptotic activity , which was diminished by mutation of the amino-terminal NES and by BARD1 induced nuclear retention of BRCA1 [ XREF_BIBR ] .	Interestingly, the nuclear export of BRCA1 was directly linked to this proapoptotic activity, which was diminished by mutation of the amino-terminal NES and by BARD1 induced nuclear retention of BRCA1 [XREF_BIBR].	9	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	26	27	31	32
We can speculate that the concomitant expression of BARD1 and BRCA1 in S-phase support the function of BARD1 and BRCA1 heterodimer and FL BARD1 expression in mitosis supports additional BRCA1 independent functions .	We can speculate that the concomitant expression of BARD1 and BRCA1 in S-phase support the function of BARD1 and BRCA1 heterodimer and FL BARD1 expression in mitosis supports additional BRCA1 independent functions.	23	31	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1 expression	bard1	BRCA1	BRCA1	brca1	23	24	29	30
Finally , we were also able to demonstrate Bax activation and loss of mitochondrial Smac in CAF following navitoclax treatment for 48 hrs , thereby , suggesting the mechanisms of navitoclax mediated CAF cytotoxicity in vivo parallels that observed in vitro ( XREF_SUPPLEMENTARY ) .	Finally, we were also able to demonstrate Bax activation and loss of mitochondrial Smac in CAF following navitoclax treatment for 48 hrs, thereby, suggesting the mechanisms of navitoclax mediated CAF cytotoxicity in vivo parallels that observed in vitro (XREF_SUPPLEMENTARY).	8	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Bax	Bax	Bax	Smac	Smac	Smac	8	9	14	15
miR-101 increased Bax expression , decreased Bcl-2 expression , and promoted the release of the Smac protein from the mitochondria into the cytoplasm .	miR-101 increased Bax expression, decreased Bcl-2 expression, and promoted the release of the Smac protein from the mitochondria into the cytoplasm.	0	16	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	miR-101 increased Bax expression	bax	Smac	Smac	smac	2	3	15	16
33 In cells with deficiencies in pore forming Bcl-2 family members , the release of Smac has also been shown to be more readily impaired than cyt-c release , 34 suggesting that scenarios may exist in which limitations in Bax and Bak amounts restrict efficient Smac release .	33 In cells with deficiencies in pore forming Bcl-2 family members, the release of Smac has also been shown to be more readily impaired than cyt-c release, 34 suggesting that scenarios may exist in which limitations in Bax and Bak amounts restrict efficient Smac release.	39	46	restrict	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax and Bak amounts	bax	Smac	Smac	smac	39	40	45	46
ShRNA mediated Smac knockdown and V5 peptide mediated Bax inhibition decreased cytosolic Smac and Cyto c release along with caspase activation and abrogated apoptosis , indicating that Smac and Bax are critical mediators of SapC-DOPS action .	ShRNA mediated Smac knockdown and V5 peptide mediated Bax inhibition decreased cytosolic Smac and Cyto c release along with caspase activation and abrogated apoptosis, indicating that Smac and Bax are critical mediators of SapC-DOPS action.	8	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Smac	Smac	Smac	8	9	12	13
Furthermore , although Smac and cyto c release from the mitochondria occurs in the intrinsic pathway of apoptosis , complete functioning of the extrinsic pathway may require Bax stimulated release of Smac as well .	Furthermore, although Smac and cyto c release from the mitochondria occurs in the intrinsic pathway of apoptosis, complete functioning of the extrinsic pathway may require Bax stimulated release of Smac as well.	26	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Smac	Smac	Smac	27	28	31	32
Consistent with decreased apoptosis , Bax inhibition also attenuated Smac and Cyto c mitochondrial release and reduced caspase-3 activation [ Figure XREF_FIG C , 7D ] .	Consistent with decreased apoptosis, Bax inhibition also attenuated Smac and Cyto c mitochondrial release and reduced caspase-3 activation [Figure XREF_FIG C, 7D].	5	14	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	Smac	Smac	Smac	5	6	9	10
Expression of AXL is upregulated in mesenchymal EMT like cells , suggesting a role of AXL in this phenotypic transition .	Expression of AXL is upregulated in mesenchymal EMT like cells, suggesting a role of AXL in this phenotypic transition.	0	16	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AXL	Expression of AXL	axl	AXL	AXL	axl	2	3	15	16
We demonstrate that the loss of surface Axl abrogates Axl mediated anti-inflammatory activity in vitro and in vivo .	We demonstrate that the loss of surface Axl abrogates Axl mediated anti-inflammatory activity in vitro and in vivo.	4	10	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Axl	loss of surface Axl	axl	Axl	Axl	axl	7	8	9	10
Alternatively , Axl levels were transiently upregulated transfecting Axl cDNA .	Alternatively, Axl levels were transiently upregulated transfecting Axl cDNA.	2	9	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Axl	Axl levels	axl	Axl	Axl	axl	2	3	8	9
Lastly , as novel biomarker based imaging methodologies are optimized and implemented into the clinical arena , real-time monitoring of AXL expression in response to systemic or targeted therapies will markedly enhance our clinical understanding of the role of AXL in lung cancer development and metastasis .	Lastly, as novel biomarker based imaging methodologies are optimized and implemented into the clinical arena, real-time monitoring of AXL expression in response to systemic or targeted therapies will markedly enhance our clinical understanding of the role of AXL in lung cancer development and metastasis.	20	40	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AXL	AXL expression	axl	AXL	AXL	axl	20	21	39	40
The data may be explained by prior studies in which overexpression of AXL and treatment with drugs caused ligand independent autoactivation of AXL [ XREF_BIBR , XREF_BIBR ] .	The data may be explained by prior studies in which overexpression of AXL and treatment with drugs caused ligand independent autoactivation of AXL [XREF_BIBR, XREF_BIBR].	10	24	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AXL	overexpression of AXL	axl	AXL	AXL	axl	12	13	22	23
The loss of Axl from blood monocytes could decrease Axl anti-inflammatory signaling in two ways .	The loss of Axl from blood monocytes could decrease Axl anti-inflammatory signaling in two ways.	1	11	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Axl	loss of Axl	axl	Axl	Axl	axl	3	4	9	10
GM6001 and TAPI-1 , general inhibitors of MMP and ADAM family proteases , restored Axl expression on the DC surface and diminished Axl shedding .	GM6001 and TAPI-1, general inhibitors of MMP and ADAM family proteases, restored Axl expression on the DC surface and diminished Axl shedding.	9	23	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Axl	ADAM family proteases, restored Axl expression	axl	Axl	Axl	axl	14	15	22	23
Expression of mouse Axl using a retroviral vector restored ZIKV infection of human Axl deficient cells ( XREF_FIG ) .	Expression of mouse Axl using a retroviral vector restored ZIKV infection of human Axl deficient cells (XREF_FIG).	0	15	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Axl	Expression of mouse Axl	axl	Axl	Axl	axl	3	4	13	14
For example , IFN alpha2a induces apoptosis in OVCAR3 cells through Bak activation and translocation of AIF from the mitochondria to the nucleus [ XREF_BIBR ] .	For example, IFN alpha2a induces apoptosis in OVCAR3 cells through Bak activation and translocation of AIF from the mitochondria to the nucleus [XREF_BIBR].	11	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Bak	Bak	Bak	AIF	AIF	AIF	11	12	16	17
In conclusion , IFN-alpha2a-induced apoptosis is mediated via the mitochondria associated pathway involving the cleavage of Bid followed by AIF release that involves Bak activation and translocation of AIF from the mitochondria to the nucleus in OVCAR3 cells .	In conclusion, IFN-alpha2a-induced apoptosis is mediated via the mitochondria associated pathway involving the cleavage of Bid followed by AIF release that involves Bak activation and translocation of AIF from the mitochondria to the nucleus in OVCAR3 cells.	23	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Bak	Bak	Bak	AIF	AIF	AIF	23	24	28	29
Therefore , the downregulation of Bcl-xL ( XREF_SUPPLEMENTARY ) and an increase in the amount of Bak ( XREF_FIG ) in HCT 116 cells upon FKC treatment may have caused a disruption in the integrity of the outer mitochondria membrane by increasing its permeability , resulting in the release of cytochrome c , Smac/DIABLO and AIF from the outer membrane of mitochondria into the cytosol ( XREF_FIG ) .	Therefore, the downregulation of Bcl-xL (XREF_SUPPLEMENTARY) and an increase in the amount of Bak (XREF_FIG) in HCT 116 cells upon FKC treatment may have caused a disruption in the integrity of the outer mitochondria membrane by increasing its permeability, resulting in the release of cytochrome c, Smac/DIABLO and AIF from the outer membrane of mitochondria into the cytosol (XREF_FIG).	14	56	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	amount of Bak	bak	AIF	AIF	aif	16	17	55	56
Our study revealed that Bak could induce the release of Cyt c from the mitochondria to the cytosol ; thus , we detected whether Bak induced the release of AIF and endoG during apoptosis .	Our study revealed that Bak could induce the release of Cyt c from the mitochondria to the cytosol; thus, we detected whether Bak induced the release of AIF and endoG during apoptosis.	24	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	AIF	AIF	AIF	24	25	29	30
We found that IFN-alpha2a induced apoptosis is mediated via the mitochondria associated pathway involving the cleavage of Bid followed by AIF release that involves Bak activation and translocation of AIF from the mitochondria to the nucleus in OVCAR3 cells .	We found that IFN-alpha2a induced apoptosis is mediated via the mitochondria associated pathway involving the cleavage of Bid followed by AIF release that involves Bak activation and translocation of AIF from the mitochondria to the nucleus in OVCAR3 cells.	24	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Bak	Bak	Bak	AIF	AIF	AIF	24	25	29	30
In particular , Bax and Bak could promote the release of AIF and EndoG in a caspase independent manner .	In particular, Bax and Bak could promote the release of AIF and EndoG in a caspase independent manner.	3	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	AIF	AIF	AIF	5	6	11	12
Autophagy induced activation of BAX and BAK stimulates the release of AIF into the cytosol with subsequent mitochondrial break-down in autolysosomes .	Autophagy induced activation of BAX and BAK stimulates the release of AIF into the cytosol with subsequent mitochondrial break-down in autolysosomes.	2	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAK	BAK	BAK	AIF	AIF	AIF	6	7	11	12
Indeed , pharmacologic antagonism of Bcl-xL , with ABT-263 , combined with PP242 induced activation of BAD markedly augmented apoptosis of CML-BC cell lines and primary CD34 + progenitors but not those from healthy donors , regardless of drug-resistance induced by bone marrow stromal cell generated signals .	Indeed, pharmacologic antagonism of Bcl-xL, with ABT-263, combined with PP242 induced activation of BAD markedly augmented apoptosis of CML-BC cell lines and primary CD34 + progenitors but not those from healthy donors, regardless of drug-resistance induced by bone marrow stromal cell generated signals.	3	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	BAD	BAD	BAD	5	6	16	17
Tetracaine not only resulted in caspase-3 , caspase-8 and caspase-9 activation and disruption of MTP but also downregulated Bcl-2 and Bcl-xL and upregulated Bad and Bax , along with the upregulation of cytoplasmic cytochrome c ( Cyt .	Tetracaine not only resulted in caspase-3, caspase-8 and caspase-9 activation and disruption of MTP but also downregulated Bcl-2 and Bcl-xL and upregulated Bad and Bax, along with the upregulation of cytoplasmic cytochrome c (Cyt.	17	34	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bad	Bad	Bad	20	21	23	24
In contrast , the amount of Bcl-Xl dramatically increased in mitochondrial fractions of cells treated with pU , pC and pCU , indicating rapid dissociation of BAD from 14-3-3 in cytosolic fractions and association with Bcl-xl in mitochondrial fractions ( XREF_FIG ) Effect of calcineurin inhibitor , FK506 , on pCU induced apoptosis .	In contrast, the amount of Bcl-Xl dramatically increased in mitochondrial fractions of cells treated with pU, pC and pCU, indicating rapid dissociation of BAD from 14-3-3 in cytosolic fractions and association with Bcl-xl in mitochondrial fractions (XREF_FIG) Effect of calcineurin inhibitor, FK506, on pCU induced apoptosis.	4	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bcl-Xl	amount of Bcl-Xl	bcl-xl	BAD	BAD	bad	6	7	26	27
BAD can be activated by Bcl-xL leading to cell apoptosis by suppressing the Bcl-2 family , which acts in the function of Bax .	BAD can be activated by Bcl-xL leading to cell apoptosis by suppressing the Bcl-2 family, which acts in the function of Bax.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	BAD	BAD	BAD	5	6	0	1
Also , in contrast to Apg2 , Bag1 hardly stimulates Hsc70 dissociation from fibrils and fibril solubilization , even at concentrations at which Bag1 and Apg2 NEF activities are comparable .	Also, in contrast to Apg2, Bag1 hardly stimulates Hsc70 dissociation from fibrils and fibril solubilization, even at concentrations at which Bag1 and Apg2 NEF activities are comparable.	7	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bag1	Bag1	Bag1	Hsc70	Hsc70	Hsc70	7	8	10	11
BAG-1 is shown to promote the association of Hsp70 and Hsc70 with proteasome in vitro [ XREF_BIBR ] .	BAG-1 is shown to promote the association of Hsp70 and Hsc70 with proteasome in vitro [XREF_BIBR].	0	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAG-1	BAG-1	BAG-1	Hsc70	Hsc70	Hsc70	0	1	10	11
Bag1 may direct CHIP and Hsc70 regulated protein triage decisions on BCR-ABL immediately after translation to the degradation pathway .	Bag1 may direct CHIP and Hsc70 regulated protein triage decisions on BCR-ABL immediately after translation to the degradation pathway.	0	6	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bag1	Bag1	Bag1	Hsc70	Hsc70	Hsc70	0	1	5	6
We present evidence that the protein BAG-1 is a potential modulator of the molecular chaperones , Hsp70 and Hsc70 .	We present evidence that the protein BAG-1 is a potential modulator of the molecular chaperones, Hsp70 and Hsc70.	4	19	is a potential modulator	Positive_activation_copula_1	Positive_activation	Positive_activation	BAG-1	BAG-1	BAG-1	Hsc70	Hsc70	Hsc70	6	7	18	19
The BAG-1 protein modulates the chaperone activity of Hsc70 and Hsp70 in the mammalian cytosol and nucleus .	The BAG-1 protein modulates the chaperone activity of Hsc70 and Hsp70 in the mammalian cytosol and nucleus.	1	10	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAG-1	BAG-1	BAG-1	Hsc70	Hsc70	Hsc70	1	2	8	9
BAG-1 acts as a cochaperone and stimulates nucleotide exchange of HSC70 and HSP70 ( Hohfeld and Jentsch , 1997 ; Takayama et al , 1997 ; Luders et al , 2000b ; Brehmer et al , 2001 ; Nollen et al , 2001 ) .	BAG-1 acts as a cochaperone and stimulates nucleotide exchange of HSC70 and HSP70 (Hohfeld and Jentsch, 1997; Takayama et al, 1997; Luders et al, 2000b; Brehmer et al, 2001; Nollen et al, 2001).	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAG-1	BAG-1	BAG-1	HSC70	HSC70	HSC70	0	1	10	11
The primarily activation of mitochondria as well as the activation of p53 transcriptional targets such as Puma , Bad and Bax in HCT116 p53 wild type cells further demonstrates the key role of p53 in mediating the compound induced apoptosis .	The primarily activation of mitochondria as well as the activation of p53 transcriptional targets such as Puma, Bad and Bax in HCT116 p53 wild type cells further demonstrates the key role of p53 in mediating the compound induced apoptosis.	11	19	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Bad	Bad	Bad	p53	p53	p53	18	19	11	12
We find that Bad mediated radiosensitization requires p53 but does not influence its transcriptional activity .	We find that Bad mediated radiosensitization requires p53 but does not influence its transcriptional activity.	3	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bad	Bad	Bad	p53	p53	p53	3	4	7	8
BAD is also able to direct p53 to mitochondria and forms there a bad and p53 complex [ XREF_BIBR ] .	BAD is also able to direct p53 to mitochondria and forms there a bad and p53 complex [XREF_BIBR].	0	7	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAD	BAD	BAD	p53	p53	p53	0	1	6	7
Moreover , Bad is able to direct p53 to the mitochondria and forms a p53 and Bad complex at the mitochondria .	Moreover, Bad is able to direct p53 to the mitochondria and forms a p53 and Bad complex at the mitochondria.	2	12	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bad	Bad	Bad	p53	p53	p53	2	3	7	8
To therefore determine whether Bad is causing an increase in p53 transcriptional activity , we tested the induction of the p53 transcriptional targets puma and p21 in irradiated embryos with normal ( endogenous ) or high levels of Bad expression .	To therefore determine whether Bad is causing an increase in p53 transcriptional activity, we tested the induction of the p53 transcriptional targets puma and p21 in irradiated embryos with normal (endogenous) or high levels of Bad expression.	4	12	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bad	Bad	Bad	p53	p53	p53	4	5	10	11
Treatment of bone marrow cells with rhBMP-2 showed a high therapeutic potential observed by the increase in the tumor suppressor protein p53 and pro apoptotic proteins Bad and Bax , and by increased activity of phosphorylated caspase-3 .	Treatment of bone marrow cells with rhBMP-2 showed a high therapeutic potential observed by the increase in the tumor suppressor protein p53 and pro apoptotic proteins Bad and Bax, and by increased activity of phosphorylated caspase-3.	15	28	increase	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	Bad	Bad	Bad	p53	p53	p53	26	27	21	22
To test our model prediction , we measured IL8 , TNFAIP3 and NFKBIA transcript abundance by quantitative PCR in parental HeLa cells treated with siRNA against candidate competitor proteins ( si-p50 , si-p52 and si-BCL3 which respectively target NFKB1 , NFKB2 and BCL3 ) or control siRNA .	To test our model prediction, we measured IL8, TNFAIP3 and NFKBIA transcript abundance by quantitative PCR in parental HeLa cells treated with siRNA against candidate competitor proteins (si-p50, si-p52 and si-BCL3 which respectively target NFKB1, NFKB2 and BCL3) or control siRNA.	21	42	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	si-BCL3	si-BCL3	si-BCL3	NFKB1	NFKB1	NFKB1	34	35	38	39
In contrast to I kappa B alpha ( MAD3 ) , BCL3 does not cause NF-kappa B p50 to be retained in the cytoplasm ; instead , in cotransfection assays , it alters the subnuclear localization of p50 .	In contrast to I kappa B alpha (MAD3), BCL3 does not cause NF-kappa B p50 to be retained in the cytoplasm; instead, in cotransfection assays, it alters the subnuclear localization of p50.	11	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCL3	BCL3	BCL3	p50	p50	p50	11	12	17	18
Bcl-3 can cause derepression of transcription by removing p50 and p52 dimers , which are transcriptionally inactive , from the NF-kappaB sites , thus leading to the binding of an active complex consisting of p65 , Rel-B or c-Rel [ XREF_BIBR ] .	Bcl-3 can cause derepression of transcription by removing p50 and p52 dimers, which are transcriptionally inactive, from the NF-kappaB sites, thus leading to the binding of an active complex consisting of p65, Rel-B or c-Rel [XREF_BIBR].	0	11	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bcl-3	Bcl-3	Bcl-3	p50	p50	p50	0	1	8	9
As single agents , BMX inhibitors may only have a limited effect on apoptosis as dephosphorylation of BAK alone is not sufficient to trigger BAK activation , but in combination with existing cytotoxic agents would be able to significantly sensitise cancer cells to BAK dependent apoptosis .	As single agents, BMX inhibitors may only have a limited effect on apoptosis as dephosphorylation of BAK alone is not sufficient to trigger BAK activation, but in combination with existing cytotoxic agents would be able to significantly sensitise cancer cells to BAK dependent apoptosis.	15	25	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAK	dephosphorylation of BAK	bak	BAK	BAK	bak	17	18	24	25
Consistent with our published data that BIK1 phosphorylates BAK1 , it is likely that phosphorylation of BAK1 by BIK1 potentiates BAK1 ' s activity to phosphorylate PUB12 and PUB13 .	Consistent with our published data that BIK1 phosphorylates BAK1, it is likely that phosphorylation of BAK1 by BIK1 potentiates BAK1 's activity to phosphorylate PUB12 and PUB13.	14	25	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAK1	phosphorylation of BAK1	bak1	BAK1	BAK1	bak1	16	17	20	21
Hsc70 expressed alone had a diffuse cytoplasmic localization , but BAG3 overexpression directed Hsc70 to the juxtamembrane region where CapZ proteins and F-actin are enriched ( XREF_FIG ) .	Hsc70 expressed alone had a diffuse cytoplasmic localization, but BAG3 overexpression directed Hsc70 to the juxtamembrane region where CapZ proteins and F-actin are enriched (XREF_FIG).	10	14	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAG3	BAG3 overexpression	bag3	Hsc70	Hsc70	hsc70	10	11	13	14
BAG3 modulates the substrate of Hsc70 and Hsp70 specifically , and the absence of BAG3 causes the mislocalization and destabilization of the Hsc70 substrate CapZbeta1 , which , with mechanical stress , eventually leads to myofibrillar degeneration , muscle weakness and early death .	BAG3 modulates the substrate of Hsc70 and Hsp70 specifically, and the absence of BAG3 causes the mislocalization and destabilization of the Hsc70 substrate CapZbeta1, which, with mechanical stress, eventually leads to myofibrillar degeneration, muscle weakness and early death.	0	7	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAG3	BAG3	BAG3	Hsc70	Hsc70	Hsc70	0	1	5	6
One of these co-chaperones is BAG3 , which directs the chaperone HSC70 to protein clearance via autophagy and simultaneously provokes a decrease in the proteasomal protein degradation , which indicates a potential cross talk between the two basic degrading systems [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	One of these co-chaperones is BAG3, which directs the chaperone HSC70 to protein clearance via autophagy and simultaneously provokes a decrease in the proteasomal protein degradation, which indicates a potential cross talk between the two basic degrading systems [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	19	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAG3	BAG3	BAG3	HSC70	HSC70	HSC70	5	6	11	12
XREF_BIBR For instance , eIF4E promotes the export of Bcl6 mRNA as well as transcripts encoding other co-factors involved in Bcl6 signaling such as BCOR , NCOR , and SMRT .	XREF_BIBR For instance, eIF4E promotes the export of Bcl6 mRNA as well as transcripts encoding other co-factors involved in Bcl6 signaling such as BCOR, NCOR, and SMRT.	20	29	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	BCOR	BCOR	BCOR	Bcl6	Bcl6	Bcl6	24	25	20	21
BCOR enhances BCL6 mediated transcriptional repression by interacting with histone deacetylases ( HDAC ) [ XREF_BIBR ] .	BCOR enhances BCL6 mediated transcriptional repression by interacting with histone deacetylases (HDAC) [XREF_BIBR].	0	3	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCOR	BCOR	BCOR	BCL6	BCL6	BCL6	0	1	2	3
BCOR ( BCL6 corepressor ; Polycomb group repressive complex-1 variant ) mediates BCL6 function in diffuse large B-cell lymphoma .	BCOR (BCL6 corepressor; Polycomb group repressive complex-1 variant) mediates BCL6 function in diffuse large B-cell lymphoma.	0	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCOR	BCOR	BCOR	BCL6	BCL6	BCL6	0	1	12	13
However , as in the thymus , Bcl3 deficiency substantially enhances SLO phenotypes in Nfkb2 -/- mice : while Nfkb2 -/- and Bcl3 -/- mice have lymph nodes , Nfkb2 -/- Bcl3 -/- mice completely lack these organs [ XREF_BIBR ] .	However, as in the thymus, Bcl3 deficiency substantially enhances SLO phenotypes in Nfkb2 -/- mice : while Nfkb2 -/- and Bcl3 -/- mice have lymph nodes, Nfkb2 -/- Bcl3 -/- mice completely lack these organs [XREF_BIBR].	7	16	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bcl3	Bcl3	Bcl3	Nfkb2	Nfkb2	Nfkb2	7	8	14	15
Stabilized and nuclear localized beta-catenin subsequently upregulates Axin2 expression , upregulated Axin2 shuttles GSK3beta out from the nucleus , and thus nuclear Snail can be stabilized ( Yook etal ., 2006 ) .	Stabilized and nuclear localized beta-catenin subsequently upregulates Axin2 expression, upregulated Axin2 shuttles GSK3beta out from the nucleus, and thus nuclear Snail can be stabilized (Yook etal., 2006).	4	14	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Axin2	beta-catenin subsequently upregulates Axin2 expression	axin2	GSK3beta	GSK3beta	gsk3beta	7	8	13	14
157 Axin2 has additionally been shown to mediate the epithelial-mesenchymal transition ( EMT ) by regulating intra-nuclear activity of GSK-3beta , which is primarily responsible for modulating the stability of a zinc finger transcription factor , Snail1 .	157 Axin2 has additionally been shown to mediate the epithelial-mesenchymal transition (EMT) by regulating intra-nuclear activity of GSK-3beta, which is primarily responsible for modulating the stability of a zinc finger transcription factor, Snail1.	0	24	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Axin2	Axin2	Axin2	GSK-3beta	GSK-3beta	GSK-3beta	1	2	19	20
Similarly , BAG-1 appears to enhance the anti-apoptotic properties of Bcl-2 through direct interaction ( XREF_FIG ) , although BAG-1 shares no sequence homology with Bcl-2 family ' s conserved domains .	Similarly, BAG-1 appears to enhance the anti-apoptotic properties of Bcl-2 through direct interaction (XREF_FIG), although BAG-1 shares no sequence homology with Bcl-2 family 's conserved domains.	2	11	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAG-1	BAG-1	BAG-1	Bcl-2	Bcl-2	Bcl-2	2	3	10	11
Bag1 has been shown to enhance the anti-apoptotic effects of Bcl-2 .	Bag1 has been shown to enhance the anti-apoptotic effects of Bcl-2.	0	11	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bag1	Bag1	Bag1	Bcl-2	Bcl-2	Bcl-2	0	1	10	11
Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination .	Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination.	2	9	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bcl10	Bcl10	Bcl10	NEMO	NEMO	NEMO	4	5	6	7
It has been shown that the adaptor Bcl10 induces NEMO K63 linked ubiquitination 44 .	It has been shown that the adaptor Bcl10 induces NEMO K63 linked ubiquitination 44.	5	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bcl10	Bcl10	Bcl10	NEMO	NEMO	NEMO	7	8	9	10
Ectopic expression of conductin or its up-regulation through small interfering RNA mediated knock-down of APC leads to CIN in chromosomally stable colon cancer cells .	Ectopic expression of conductin or its up-regulation through small interfering RNA mediated knock-down of APC leads to CIN in chromosomally stable colon cancer cells.	1	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	conductin	expression of conductin	conductin	APC	APC	apc	3	4	14	15
Translocation of Bid to the mitochondrial membrane induces oligomerization of Bcl-2 , Bak , and Bax , which promote cytochrome release and finally caspase 9 activation .	Translocation of Bid to the mitochondrial membrane induces oligomerization of Bcl-2, Bak, and Bax, which promote cytochrome release and finally caspase 9 activation.	0	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Translocation of Bid to the mitochondrial membrane	bid	Bax	Bax	bax	2	3	15	16
Caspase-2 , through the cleavage of Bid activates Bax and Bak which form pores in the outer mitochondrial membrane allowing the release of proapoptotic proteins [ XREF_BIBR ] .	Caspase-2, through the cleavage of Bid activates Bax and Bak which form pores in the outer mitochondrial membrane allowing the release of proapoptotic proteins [XREF_BIBR].	4	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	6	7	8	9
Addition of Bcl-x L inhibits Bid SAHB A induced Bax activation .	Addition of Bcl-x L inhibits Bid SAHB A induced Bax activation.	5	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	5	6	9	10
Bid activates bax , another bcl-2 family member and increases mitochondrial permeability , resulting in release of cytochrome c , a key component in apoptosis initiation .	Bid activates bax, another bcl-2 family member and increases mitochondrial permeability, resulting in release of cytochrome c, a key component in apoptosis initiation.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	bax	bax	bax	0	1	2	3
Bid translocates to the mitochondria from the cytosol to induce mitochondrial damage and activate Bax to form Bax multimers [ XREF_BIBR ] .	Bid translocates to the mitochondria from the cytosol to induce mitochondrial damage and activate Bax to form Bax multimers [XREF_BIBR].	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid translocates to the mitochondria from the cytosol	bid	Bax	Bax	bax	0	1	14	15
Thus , our results demonstrate significant differences in the effects of artificially oligomerized BAX oligo and BAX mono activated by t c BID and suggest different mechanisms underlying the OMM permeabilization in these cases .	Thus, our results demonstrate significant differences in the effects of artificially oligomerized BAX oligo and BAX mono activated by t c BID and suggest different mechanisms underlying the OMM permeabilization in these cases.	14	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	22	23	16	17
In the case of BID induced BAX activation , physico-chemical studies have delineated an ordered series of events XREF_BIBR .	In the case of BID induced BAX activation, physico-chemical studies have delineated an ordered series of events XREF_BIBR.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	4	5	6	7
The results obtained in this study revealed that BAX mono activated by t c BID produced alkali resistant BAX insertion and Cyt c release without overt changes in mitochondrial morphology and independently from Deltapsi .	The results obtained in this study revealed that BAX mono activated by t c BID produced alkali resistant BAX insertion and Cyt c release without overt changes in mitochondrial morphology and independently from Deltapsi.	8	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	14	15	8	9
Comparison of this image with the original BioCarta image available at http://www.biocarta.com/pathfiles/h_chemicalPathway.asp readily reveals that our modeling captures most of the important biological details in the original database : the biological process indicated as ' response to radiation ' ( upper right ) promotes BID cleavage which activates BAX ; DNA damage causes activation of ATM-TP53 signaling which is followed by BAX transcription and translocation into the cytoplasm ; activated BAX promotes cytochrome C ( CYCS ) release from mitochondria to cytoplasm by forming a complex with BCL2 and BCL2L1 which in turn inhibits the release of CYCS .	Comparison of this image with the original BioCarta image available at http://www.biocarta.com/pathfiles/h_chemicalPathway.asp readily reveals that our modeling captures most of the important biological details in the original database : the biological process indicated as ' response to radiation ' (upper right) promotes BID cleavage which activates BAX; DNA damage causes activation of ATM-TP53 signaling which is followed by BAX transcription and translocation into the cytoplasm; activated BAX promotes cytochrome C (CYCS) release from mitochondria to cytoplasm by forming a complex with BCL2 and BCL2L1 which in turn inhibits the release of CYCS.	44	49	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	44	45	48	49
Lysosome mediated cell death is associated with degradation of Bax sequestering 14-3-3 proteins , cleavage of the Bax activator Bid , and translocation of Bax to mitochondria , all of which were cathepsin D dependent .	Lysosome mediated cell death is associated with degradation of Bax sequestering 14-3-3 proteins, cleavage of the Bax activator Bid, and translocation of Bax to mitochondria, all of which were cathepsin D dependent.	14	20	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	19	20	17	18
Moreover , addition of Bid directly to isolated mitochondria was sufficient to stimulate the appearance of Bax immunoreactivity towards NH 2 -terminal antibodies .	Moreover, addition of Bid directly to isolated mitochondria was sufficient to stimulate the appearance of Bax immunoreactivity towards NH 2 -terminal antibodies.	2	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	4	5	16	17
Biochemically , Bid can activate Bax or inactivate Bcl-x L , and Bax can inactivate Bcl-x L , all via protein protein interactions .	Biochemically, Bid can activate Bax or inactivate Bcl-x L, and Bax can inactivate Bcl-x L, all via protein protein interactions.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	2	3	5	6
Bid induced exposure of the NH 2 -terminal domain of Bax could reflect either a conformational change in Bax or a displacement of another protein serving to mask critical immunoreactive residues .	Bid induced exposure of the NH 2 -terminal domain of Bax could reflect either a conformational change in Bax or a displacement of another protein serving to mask critical immunoreactive residues.	0	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	0	1	18	19
7 Activated , truncated ( t ) Bid triggers Bax activation to induce mitochondrial membrane permeabilization ( MMP ) accompanied by the release of apoptogenic factors from the mitochondrial inter-membrane space into the cytosol .	7 Activated, truncated (t) Bid triggers Bax activation to induce mitochondrial membrane permeabilization (MMP) accompanied by the release of apoptogenic factors from the mitochondrial inter-membrane space into the cytosol.	7	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	7	8	9	10
Active Bid , also known as truncated Bid ( tBid ) , induces the oligomerization of Bax [ XREF_BIBR ] .	Active Bid, also known as truncated Bid (tBid), induces the oligomerization of Bax [XREF_BIBR].	0	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	1	2	16	17
Antiapoptotic Bcl-2 family members prevent the activation of Bax and Bak either by direct interaction or indirectly by sequestering pro apoptotic BH3-only proteins Bim and Bid that are required to activate Bax and Bak .	Antiapoptotic Bcl-2 family members prevent the activation of Bax and Bak either by direct interaction or indirectly by sequestering pro apoptotic BH3-only proteins Bim and Bid that are required to activate Bax and Bak.	14	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	25	26	31	32
Regardless of the mechanism of OMM permeabilization , our findings strongly suggest the difference between artificially oligomerized BAX oligo and BAX mono activated by t c BID in regard to their ability to induce the mPT and permeabilize the OMM .	Regardless of the mechanism of OMM permeabilization, our findings strongly suggest the difference between artificially oligomerized BAX oligo and BAX mono activated by t c BID in regard to their ability to induce the mPT and permeabilize the OMM.	18	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	26	27	20	21
Consistently , stable knockdown of Bid abrogated I3M induced Bax conformational change and cell death .	Consistently, stable knockdown of Bid abrogated I3M induced Bax conformational change and cell death.	3	11	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	5	6	9	10
In fact , the reversible disassembly and re-assembly of cBid would allow this assistance to occur repeatedly , and would explain why Bid completely activates Bax at stoichiometric ratios much less then 1:1 XREF_BIBR , XREF_BIBR .	In fact, the reversible disassembly and re-assembly of cBid would allow this assistance to occur repeatedly, and would explain why Bid completely activates Bax at stoichiometric ratios much less then 1:1 XREF_BIBR, XREF_BIBR.	22	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	22	23	25	26
Bid is activator of Bax and Bak , which are initiators of apoptosis through stimulating cytochrome c release from mitochondria .	Bid is activator of Bax and Bak, which are initiators of apoptosis through stimulating cytochrome c release from mitochondria.	0	10	is activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	0	1	4	5
Thus , the main finding in our study is that OMM permeabilization induced by artificially oligomerized BAX oligo significantly differs from the permeabilization induced by monomeric BAX mono activated by t c BID .	Thus, the main finding in our study is that OMM permeabilization induced by artificially oligomerized BAX oligo significantly differs from the permeabilization induced by monomeric BAX mono activated by t c BID.	26	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	32	33	26	27
As we mentioned above , the extrinsic pathway of apoptosis may engage the intrinsic one by caspase-8-mediated activation of proteins , such as the activator BH3-only protein Bid , which in turn activates Bax and Bak [ XREF_BIBR ] .	As we mentioned above, the extrinsic pathway of apoptosis may engage the intrinsic one by caspase-8-mediated activation of proteins, such as the activator BH3-only protein Bid, which in turn activates Bax and Bak [XREF_BIBR].	11	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	27	28	33	34
XREF_BIBR , XREF_BIBR In this instance , caspase-8 cleaves and activates the BH3-only protein BID , which in turn activates the proapoptotic BCL-2 family members , BAX or BAK , and induces mitochondrial outer membrane permeabilization ( MOMP ) .	XREF_BIBR, XREF_BIBR In this instance, caspase-8 cleaves and activates the BH3-only protein BID, which in turn activates the proapoptotic BCL-2 family members, BAX or BAK, and induces mitochondrial outer membrane permeabilization (MOMP).	10	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	14	15	26	27
Importantly , knockdown of Bid reduced activation of Bax upon treatment with ABT-737 and TRAIL ( XREF_FIG ) .	Importantly, knockdown of Bid reduced activation of Bax upon treatment with ABT-737 and TRAIL (XREF_FIG).	2	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	4	5	8	9
Interestingly , the intrinsic and extrinsic pathways are connected via Bid , which upon cleavage to t-Bid by caspase-8 translocates to the mitochondria and activates the pro apoptotic proteins Bax and Bak [ XREF_BIBR ] .	Interestingly, the intrinsic and extrinsic pathways are connected via Bid, which upon cleavage to t-Bid by caspase-8 translocates to the mitochondria and activates the pro apoptotic proteins Bax and Bak [XREF_BIBR].	8	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid, which upon cleavage to t-Bid by caspase-8 translocates to the mitochondria	bid	Bax	Bax	bax	10	11	29	30
Following cleavage by caspase-8 , the BH3-only protein , Bid , is known to activate Bax [ XREF_BIBR ] .	Following cleavage by caspase-8, the BH3-only protein, Bid, is known to activate Bax [XREF_BIBR].	7	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	9	10	15	16
In this so called death inducing signalling complex ( DISC ) caspase-8 is activated by proximity mediated dimerization and then either directly cleaves and activates caspase-3 leading to mitochondria independent apoptosis ( so called type I pathway ) or first cleaves Bid whose product tBid then migrates to mitochondria to activate Bax and Bak and MOMP ( type II pathway ) [ XREF_BIBR ] .	In this so called death inducing signalling complex (DISC) caspase-8 is activated by proximity mediated dimerization and then either directly cleaves and activates caspase-3 leading to mitochondria independent apoptosis (so called type I pathway) or first cleaves Bid whose product tBid then migrates to mitochondria to activate Bax and Bak and MOMP (type II pathway) [XREF_BIBR].	40	62	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	41	42	51	52
The series of events leading to BID mediated activation of BAX has been elucidated in vitro .	The series of events leading to BID mediated activation of BAX has been elucidated in vitro.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	6	7	10	11
Importantly , in these complementation studies , addition of Bid was found to potentiate Bax effect .	Importantly, in these complementation studies, addition of Bid was found to potentiate Bax effect.	7	15	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	9	10	14	15
Along with the study of Oh ' s , this study indicated that the overexpression of RBM5 might induce expression of the BH3-only proteins Bim , p-Bad and cleaved Bid , BH3-only proteins further engage directly and activate Bax , this led to changes in the mitochondrial membrane potential , cytochrome c release into the cytosol , and enhanced caspase-9 and caspase-3 activities , thereby inducing apoptosis .	Along with the study of Oh 's, this study indicated that the overexpression of RBM5 might induce expression of the BH3-only proteins Bim, p-Bad and cleaved Bid, BH3-only proteins further engage directly and activate Bax, this led to changes in the mitochondrial membrane potential, cytochrome c release into the cytosol, and enhanced caspase-9 and caspase-3 activities, thereby inducing apoptosis.	29	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	29	30	38	39
Afer activation by death receptors , caspase 8 can cleave BID to form truncated BID ( tBID ) , which localizes to the mitochondria and activates Bax and Bak dependent MOMP leading to apoptosis .	Afer activation by death receptors, caspase 8 can cleave BID to form truncated BID (tBID), which localizes to the mitochondria and activates Bax and Bak dependent MOMP leading to apoptosis.	13	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	Bax	Bax	Bax	14	15	26	27
However , in contrast with non silencing siRNA treated cells , no significant translocation of Bax from cytosol to mitochondria was observed in cells treated with Bid specific siRNA ( middle row ) .	However, in contrast with non silencing siRNA treated cells, no significant translocation of Bax from cytosol to mitochondria was observed in cells treated with Bid specific siRNA (middle row).	13	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Bid	Bid	Bid	Bax	Bax	Bax	26	27	15	16
Bid activates Bax and Bak , which are located on the mitochondrial membrane , to trigger the release of cytochrome c.	Bid activates Bax and Bak, which are located on the mitochondrial membrane, to trigger the release of cytochrome c.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	0	1	2	3
Cleaved BID has the capacity to either block BCL-2 or activate BAK and BAX that induces the release of cytochrome C from mitochondria which ultimately leads to cell death via downstream caspases such as Caspase-9 and -3 .	Cleaved BID has the capacity to either block BCL-2 or activate BAK and BAX that induces the release of cytochrome C from mitochondria which ultimately leads to cell death via downstream caspases such as Caspase-9 and -3.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	1	2	13	14
Even though the involvement of Bax was not considered in this study , it is tempting to speculate that LMP was caused by Bid mediated activation of Bax .	Even though the involvement of Bax was not considered in this study, it is tempting to speculate that LMP was caused by Bid mediated activation of Bax.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	23	24	27	28
Additional models suggest that p53 can physically interact with Bcl-2 and Bcl-x L to release Bid and instigate Bid mediated activation of the multi BH domain proteins Bax and Bak [ XREF_BIBR ] , or can form an activating complex with Bak , thereby disrupting a Bak-inhibitory Bak : Mcl-1 interaction [ XREF_BIBR ] ( XREF_FIG , right panel ) .	Additional models suggest that p53 can physically interact with Bcl-2 and Bcl-x L to release Bid and instigate Bid mediated activation of the multi BH domain proteins Bax and Bak [XREF_BIBR], or can form an activating complex with Bak, thereby disrupting a Bak-inhibitory Bak : Mcl-1 interaction [XREF_BIBR] (XREF_FIG, right panel).	18	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	18	19	27	28
In type II cells , activated caspase-8 at the DISC cleaves the proapoptotic Bcl-2 protein Bid , which then translocates to the mitochondria and activates Bax , leading to mitochondria permeabilization and subsequent activation of caspase-9 .	In type II cells, activated caspase-8 at the DISC cleaves the proapoptotic Bcl-2 protein Bid, which then translocates to the mitochondria and activates Bax, leading to mitochondria permeabilization and subsequent activation of caspase-9.	11	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid, which then translocates to the mitochondria	bid	Bax	Bax	bax	15	16	25	26
Taken together , CD and VOSL treatment can up-regulate the expression of p53 , down-regulate the phosphorylation levels of BID and BAD and increase the ratio of BAX to BCL-2 , to trigger the mitochondrial dependent apoptotic pathway .	Taken together, CD and VOSL treatment can up-regulate the expression of p53, down-regulate the phosphorylation levels of BID and BAD and increase the ratio of BAX to BCL-2, to trigger the mitochondrial dependent apoptotic pathway.	3	28	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	CD and VOSL treatment can up-regulate the expression of p53, down-regulate the phosphorylation levels of BID	bid	BAX	BAX	bax	19	20	27	28
This potentiation may be explained by a change in conformation of Bax induced by Bid .	This potentiation may be explained by a change in conformation of Bax induced by Bid.	9	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	14	15	11	12
Taken together these results suggest that TCTP potentiates Bcl-xL function by increasing its interaction with Bax , and possibly also with Bid , without interfering with Bid mediated activation of Bax .	Taken together these results suggest that TCTP potentiates Bcl-xL function by increasing its interaction with Bax, and possibly also with Bid, without interfering with Bid mediated activation of Bax.	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	26	27	30	31
However , these results do not exclude the possibility that BH3 dependent homodimerization of Bax or interactions with Bax activators such as Bid may either assist or be required for the cell death inducing mechanism of this protein .	However, these results do not exclude the possibility that BH3 dependent homodimerization of Bax or interactions with Bax activators such as Bid may either assist or be required for the cell death inducing mechanism of this protein.	18	23	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	22	23	18	19
Activation of caspase-8 also converts Bid to truncated Bid ( tBid ) , which activates Bax .	Activation of caspase-8 also converts Bid to truncated Bid (tBid), which activates Bax.	7	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	8	9	15	16
Supporting the specificity of the reconstituted system , addition of Bid BH3 peptide carrying a single point mutation ( G/A ) that abolishes Bax binding of Bid in vivo 8 did not support Bax integration into the lipid bilayer ( XREF_FIG ) .	Supporting the specificity of the reconstituted system, addition of Bid BH3 peptide carrying a single point mutation (G/A) that abolishes Bax binding of Bid in vivo 8 did not support Bax integration into the lipid bilayer (XREF_FIG).	10	34	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	10	11	33	34
Truncated Bid ( tBid ) is known to translocate onto mitochondria and activate Bax or Bak mediated mitochondrial outer membrane permeabilization ( MOMP ) .	Truncated Bid (tBid) is known to translocate onto mitochondria and activate Bax or Bak mediated mitochondrial outer membrane permeabilization (MOMP).	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	1	2	13	14
Specifically , p53 releases pro apoptotic BAX and the BH3-only protein Bid from anti-apoptotic BCL-xl , and allows BAX to oligomerize .	Specifically, p53 releases pro apoptotic BAX and the BH3-only protein Bid from anti-apoptotic BCL-xl, and allows BAX to oligomerize.	3	20	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	BAX	BAX	BAX	11	12	18	19
The truncated Bid can in turn inactivate Bcl-2 or activate two multi-domain pro apoptosis Bcl-2 family proteins , Bax and Bak , to trigger mitochondria mediated apoptosis .	The truncated Bid can in turn inactivate Bcl-2 or activate two multi-domain pro apoptosis Bcl-2 family proteins, Bax and Bak, to trigger mitochondria mediated apoptosis.	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	2	3	18	19
It was shown that the member of the extrinsic apoptotic pathway pro-caspase-8 cleaves the BH3 domain-only protein Bid , which in turn , activates Bax , stimulates its integration into mitochondrial membranes and release of cytochrome c [ XREF_BIBR , XREF_BIBR ] .	It was shown that the member of the extrinsic apoptotic pathway pro-caspase-8 cleaves the BH3 domain-only protein Bid, which in turn, activates Bax, stimulates its integration into mitochondrial membranes and release of cytochrome c [XREF_BIBR, XREF_BIBR].	12	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	17	18	24	25
Differences in potency of this order have been reported for Bim- and Bid induced activation of Bax , 33 and we have observed similar differences in Bax binding assays reported here .	Differences in potency of this order have been reported for Bim- and Bid induced activation of Bax, 33 and we have observed similar differences in Bax binding assays reported here.	10	18	induced	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	12	13	16	17
Interestingly , PGE2 and Bid do not activate Bax by the same mechanism , since they do not interact in the same region of Bax , but they can rather cooperate to induce apoptosis .	Interestingly, PGE2 and Bid do not activate Bax by the same mechanism, since they do not interact in the same region of Bax, but they can rather cooperate to induce apoptosis.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	4	5	8	9
In these cells , a caspase-8 generated cleavage product of Bid , named truncated Bid , may contribute to apoptosis by inducing Bax and Bak dependent release of apoptogenic proteins from mitochondria , especially cytochrome c and further SMAC/Diablo and HtrA2 and Omi .	In these cells, a caspase-8 generated cleavage product of Bid, named truncated Bid, may contribute to apoptosis by inducing Bax and Bak dependent release of apoptogenic proteins from mitochondria, especially cytochrome c and further SMAC/Diablo and HtrA2 and Omi.	8	26	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	10	11	22	23
However , in cell-free studies , BH3 peptides from Bim or Bid and the active form of Bid ( truncated Bid [ tBid ] ) can activate Bax or Bak directly and cause MOMP .	However, in cell-free studies, BH3 peptides from Bim or Bid and the active form of Bid (truncated Bid [tBid]) can activate Bax or Bak directly and cause MOMP.	15	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	17	18	27	28
Bid translocates to mitochondria to activate Bax and MMP .	Bid translocates to mitochondria to activate Bax and MMP.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid translocates to mitochondria	bid	Bax	Bax	bax	0	1	6	7
In the extrinsic pathway , activation of caspase-8can either directly activate Casp3 or cleave Bid , a proapoptotic member of the Bcl-2 family of proteins , which then activates Bax 25 .	In the extrinsic pathway, activation of caspase-8can either directly activate Casp3 or cleave Bid, a proapoptotic member of the Bcl-2 family of proteins, which then activates Bax 25.	13	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	14	15	29	30
Death receptors , including TNF-alpha and anti-Fas antibody , induced hepatocytes apoptosis , Bax translocation and conformational change through activation of Bid , which caused Bax to be inserted into the mitochondrial membrane of hepatocytes .	Death receptors, including TNF-alpha and anti-Fas antibody, induced hepatocytes apoptosis, Bax translocation and conformational change through activation of Bid, which caused Bax to be inserted into the mitochondrial membrane of hepatocytes.	19	26	caused	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	21	22	25	26
Upon cleavage by caspase-8 , Bid activates Bax .	Upon cleavage by caspase-8, Bid activates Bax.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	5	6	7	8
Common structural and lipid interacting properties may explain why only Bid , among the BH3-only proteins , is capable to catalytically activate Bax for inducing MOMP .	Common structural and lipid interacting properties may explain why only Bid, among the BH3-only proteins, is capable to catalytically activate Bax for inducing MOMP.	9	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	10	11	22	23
Active BID in turn promotes activation of BAX and BAK leading to mitochondrial dysfunction , pore formation and recruitment of the intrinsic apoptosis pathway , resulting ultimately in GBM cell death .	Active BID in turn promotes activation of BAX and BAK leading to mitochondrial dysfunction, pore formation and recruitment of the intrinsic apoptosis pathway, resulting ultimately in GBM cell death.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	1	2	7	8
Drp1 , which induces mitochondrial fission , has been reported to stimulate Bid induced Bax oligomerization and cytochrome c release by promoting tethering and hemifusion of membranes XREF_BIBR .	Drp1, which induces mitochondrial fission, has been reported to stimulate Bid induced Bax oligomerization and cytochrome c release by promoting tethering and hemifusion of membranes XREF_BIBR.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	12	13	14	15
Upon stimulation , Bid is proteolytically cleaved by caspase-8 and undergoes a posttranslational modification to form truncated Bid ( tBid ) , which then targets the mitochondria and activates Bax and Bak .	Upon stimulation, Bid is proteolytically cleaved by caspase-8 and undergoes a posttranslational modification to form truncated Bid (tBid), which then targets the mitochondria and activates Bax and Bak.	16	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	17	18	29	30
XREF_BIBR , XREF_BIBR , XREF_BIBR Tethering a BID BH3 peptide , or a BID SAHB to the membrane resulted in efficient BAX activation at low nanomolar concentrations albeit with slower membrane permeabilization kinetics compared with full-length tBID .	XREF_BIBR, XREF_BIBR, XREF_BIBR Tethering a BID BH3 peptide, or a BID SAHB to the membrane resulted in efficient BAX activation at low nanomolar concentrations albeit with slower membrane permeabilization kinetics compared with full-length tBID.	13	23	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	13	14	21	22
In addition , the BID and PUMA BH3 can promote remodeling of the BAX structure .	In addition, the BID and PUMA BH3 can promote remodeling of the BAX structure.	4	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	4	5	13	14
The level of tBid generated is therefore below a threshold that is insufficient to trigger Bid mediated Bax or Bak activation .	The level of tBid generated is therefore below a threshold that is insufficient to trigger Bid mediated Bax or Bak activation.	14	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	15	16	17	18
Be cleaved by caspase-8 , activated Bid could lead to the activation of Bax and Bak .	Be cleaved by caspase-8, activated Bid could lead to the activation of Bax and Bak.	5	15	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	6	7	13	14
In cancer cells , Bcl-2 inhibits over-expressed BH3 molecule such as Bid , which can directly activate Bax with a very small rate constant XREF_BIBR , XREF_BIBR , and thus through the Bid-Bcl-2-Bax loop stochastic Bax activation is generated .	In cancer cells, Bcl-2 inhibits over-expressed BH3 molecule such as Bid, which can directly activate Bax with a very small rate constant XREF_BIBR, XREF_BIBR, and thus through the Bid-Bcl-2-Bax loop stochastic Bax activation is generated.	8	18	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	11	12	17	18
It is reported that the overexpression of calpains promotes the cleavage of Bid , which in turn modulates Bax and activates caspase-3 .	It is reported that the overexpression of calpains promotes the cleavage of Bid, which in turn modulates Bax and activates caspase-3.	10	20	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	12	13	18	19
BID then activates and oligomerizes BAX and BAK and the intrinsic apoptotic pathway continues .	BID then activates and oligomerizes BAX and BAK and the intrinsic apoptotic pathway continues.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	0	1	5	6
Bad and Bid trigger the oligomerization of Bak and Bax protein , which permeabilize the outer mitochondrial wall .	Bad and Bid trigger the oligomerization of Bak and Bax protein, which permeabilize the outer mitochondrial wall.	0	10	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	2	3	9	10
Engagement of death receptors such as tumor necrosis factor-R1 and Fas brings about the cleavage of cytosolic Bid to truncated Bid ( tBid ) , which translocates to mitochondria to activate Bax and Bak , resulting in the release of cytochrome c.	Engagement of death receptors such as tumor necrosis factor-R1 and Fas brings about the cleavage of cytosolic Bid to truncated Bid (tBid), which translocates to mitochondria to activate Bax and Bak, resulting in the release of cytochrome c.	19	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid (tBid), which translocates to mitochondria	bid	Bax	Bax	bax	20	21	31	32
Strikingly , nanomolar concentrations of a synthetic BID BH3 peptide that is chemically tethered to the liposomal membrane activated BAX almost as efficiently as tBID itself .	Strikingly, nanomolar concentrations of a synthetic BID BH3 peptide that is chemically tethered to the liposomal membrane activated BAX almost as efficiently as tBID itself.	7	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	7	8	19	20
Cell detachment leads to upregulation and activation of several BH3-only pro apoptotic proteins ( BID , BIM and BDF ) that , in turn , activate BAX and BAK resulting in MOMP and the apoptotic cascade , resulting in cell death [ XREF_BIBR ] .	Cell detachment leads to upregulation and activation of several BH3-only pro apoptotic proteins (BID, BIM and BDF) that, in turn, activate BAX and BAK resulting in MOMP and the apoptotic cascade, resulting in cell death [XREF_BIBR].	12	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	14	15	26	27
XREF_BIBR Bid , in turn , activates Bax and Bak ; both trigger apoptosis .	XREF_BIBR Bid, in turn, activates Bax and Bak; both trigger apoptosis.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	1	2	7	8
Bid Triggers Bax Conformational Change .	Bid Triggers Bax Conformational Change.	0	3	Triggers	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	0	1	2	3
Once activated , CASP2 cleaves the BH3-only protein BID , which then localizes to mitochondria to induce BAX and BAK dependent apoptosis .	Once activated, CASP2 cleaves the BH3-only protein BID, which then localizes to mitochondria to induce BAX and BAK dependent apoptosis.	4	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	8	9	17	18
31 However , both NOXA and the bona fide activator BH3 , BID can activate BAX to permeabilize membranes in vitro , causing NOXA to be classified as an activator BH3-only protein in some reports .	31 However, both NOXA and the bona fide activator BH3, BID can activate BAX to permeabilize membranes in vitro, causing NOXA to be classified as an activator BH3-only protein in some reports.	10	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	12	13	15	16
The Bcl-2 homology domain 3 only ( BH3-only ) protein Bid activates Bax and Bak to mediate the release of cytochrome c into cytosol .	The Bcl-2 homology domain 3 only (BH3-only) protein Bid activates Bax and Bak to mediate the release of cytochrome c into cytosol.	3	14	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	10	11	12	13
The parameters indicate that BID BH3 can activate MOMP in BAX -/- mitochondria significantly faster than BIM BH3 , ( k = 0.115 vs 0.036 % depolarized muM -1 min -1 ) .	The parameters indicate that BID BH3 can activate MOMP in BAX -/- mitochondria significantly faster than BIM BH3, (k = 0.115 vs 0.036% depolarized muM -1 min -1).	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	4	5	10	11
For example , the BID mediated BAX activation is potent for both protein and peptide [ XREF_BIBR ] .	For example, the BID mediated BAX activation is potent for both protein and peptide [XREF_BIBR].	3	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	4	5	6	7
Secondly , when every member of the anti-apoptotic repertoire is associated with a direct activator protein due to pro apoptotic stimulation ( e.g ., every BCL-x L molecule is associated with a molecule of BID ) , a subsequent direct activator molecule can not be inhibited and is readily able to activate effector molecules ( e.g ., BID activates BAX ) leading to MOMP .	Secondly, when every member of the anti-apoptotic repertoire is associated with a direct activator protein due to pro apoptotic stimulation (e.g., every BCL-x L molecule is associated with a molecule of BID), a subsequent direct activator molecule can not be inhibited and is readily able to activate effector molecules (e.g., BID activates BAX) leading to MOMP.	57	60	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	57	58	59	60
Caspase-3 cleaves Bid and the resulting tBid ( M ) further activates Bax .	Caspase-3 cleaves Bid and the resulting tBid (M) further activates Bax.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	2	3	12	13
In vitro , mdivi-1 blocked Bid activated Bax and Bak dependent cytochrome c release .	In vitro, mdivi-1 blocked Bid activated Bax and Bak dependent cytochrome c release.	4	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	5	6	7	8
The indirect mechanism is mediated by the ability of caspase-2 to cleave and activate Bid , which then activates pro apoptotic proteins Bak and Bax to induce mitochondrial permeabilization .	The indirect mechanism is mediated by the ability of caspase-2 to cleave and activate Bid, which then activates pro apoptotic proteins Bak and Bax to induce mitochondrial permeabilization.	11	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	14	15	24	25
Caspase-8 cleaves Bid to a truncated form , tBid , which translocates to the mitochondria , causing activation of Bak and Bax and subsequent activation of the mitochondrial apoptotic pathway .	Caspase-8 cleaves Bid to a truncated form, tBid, which translocates to the mitochondria, causing activation of Bak and Bax and subsequent activation of the mitochondrial apoptotic pathway.	0	29	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	2	3	21	22
Second , neither BID nor BAD contributed to BAX dependent cyt c release and its downstream sequelae in these paradigms .	Second, neither BID nor BAD contributed to BAX dependent cyt c release and its downstream sequelae in these paradigms.	2	16	contributed	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	3	4	8	9
A cleaved form of Bid translocates to the outer mitochondrial membrane and promotes the oligomerization of Bax .	A cleaved form of Bid translocates to the outer mitochondrial membrane and promotes the oligomerization of Bax.	2	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	4	5	16	17
When caspase 8 cleaves Bid , the truncated Bid ( tBid ) is able to activate Bax to form Bax multimers in the mitochondria , thereby leading to the release of cytochrome c independently , with a resultant change in the mitochondrial membrane potential [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	When caspase 8 cleaves Bid, the truncated Bid (tBid) is able to activate Bax to form Bax multimers in the mitochondria, thereby leading to the release of cytochrome c independently, with a resultant change in the mitochondrial membrane potential [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	8	9	16	17
XREF_BIBR - XREF_BIBR By this model , certain BH3-only molecules , namely Bim , Bid and possibly Puma , directly activate Bak and Bax and binding of the anti-apoptotic proteins to these BH3-only activators inhibits apoptotic pathways .	XREF_BIBR - XREF_BIBR By this model, certain BH3-only molecules, namely Bim, Bid and possibly Puma, directly activate Bak and Bax and binding of the anti-apoptotic proteins to these BH3-only activators inhibits apoptotic pathways.	9	24	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	14	15	23	24
The first step for BID induced BAX activation is the association of BID with a membrane , followed by BAX recruitment , insertion , and oligomerization ( XREF_FIG ) .	The first step for BID induced BAX activation is the association of BID with a membrane, followed by BAX recruitment, insertion, and oligomerization (XREF_FIG).	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	4	5	6	7
Bid requires its BH3 domain to indirectly activate Bak and Bax during DNA-damage-induced apoptosis .	Bid requires its BH3 domain to indirectly activate Bak and Bax during DNA-damage-induced apoptosis.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	0	1	10	11
TNFalpha activates caspase 8 to cleave Bid which in turn triggers Bax and Bak to permeabilize mitochondria [ XREF_BIBR , XREF_BIBR ] .	TNFalpha activates caspase 8 to cleave Bid which in turn triggers Bax and Bak to permeabilize mitochondria [XREF_BIBR, XREF_BIBR].	5	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	6	7	11	12
Elegant dynamic fluorescent studies indicate that the activation of BAX by BID is initiated when caspase truncated BID localizes to the mitochondria where it activates a proportion of soluble BAX enabling insertion of BAX into the outer mitochondrial membrane .	Elegant dynamic fluorescent studies indicate that the activation of BAX by BID is initiated when caspase truncated BID localizes to the mitochondria where it activates a proportion of soluble BAX enabling insertion of BAX into the outer mitochondrial membrane.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	11	12	9	10
Apoptosis potentiation by mitogen activated protein kinase ( MAPK ) inhibitors involved both the intrinsic and extrinsic executionary pathways , as demonstrated by Bax activation and cytochrome c release from mitochondria , and by caspase-8 activation and Bid cleavage , respectively ; and the activation of both pathways was prevented by Bcl-2 over-expression .	Apoptosis potentiation by mitogen activated protein kinase (MAPK) inhibitors involved both the intrinsic and extrinsic executionary pathways, as demonstrated by Bax activation and cytochrome c release from mitochondria, and by caspase-8 activation and Bid cleavage, respectively; and the activation of both pathways was prevented by Bcl-2 over-expression.	23	38	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	37	38	23	24
However , it is noteworthy that the concentration of BAX oligo required for complete Cyt c release was 10 times higher [ XREF_BIBR ] than the concentration of t c BID activated BAX mono .	However, it is noteworthy that the concentration of BAX oligo required for complete Cyt c release was 10 times higher [XREF_BIBR] than the concentration of t c BID activated BAX mono.	22	33	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	30	31	32	33
For BAK -/- mitochondria , BID BH3 is only slightly slower than BIM BH3 ( k = 0.021 vs. 0.017 % depolarized muM -1 min -1 ) but significantly less efficient , with an estimated EC50 for the F max of 4.5 muM for BID BH3 and 0.7 muM for BIM BH3 These data confirm a substantial difference in BIM- and BID mediated activation of BAX and BAK .	For BAK -/- mitochondria, BID BH3 is only slightly slower than BIM BH3 (k = 0.021 vs. 0.017% depolarized muM -1 min -1) but significantly less efficient, with an estimated EC50 for the F max of 4.5 muM for BID BH3 and 0.7 muM for BIM BH3 These data confirm a substantial difference in BIM- and BID mediated activation of BAX and BAK.	61	67	mediated	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	61	62	65	66
TNF-R1 activation further induces Bid , which activates Bad and Bax , causing mitochondrial membrane potential to decrease , cytochrome c to be released and caspase 9 to be activated .	TNF-R1 activation further induces Bid, which activates Bad and Bax, causing mitochondrial membrane potential to decrease, cytochrome c to be released and caspase 9 to be activated.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	4	5	10	11
As Bid BH3 peptides and phospholipid bilayer are reported to activate Bax at a membrane interface , 9 the system used in this study represents a minimal system for reconstituting activation and membrane insertion of soluble full-length human Bax monomers .	As Bid BH3 peptides and phospholipid bilayer are reported to activate Bax at a membrane interface, 9 the system used in this study represents a minimal system for reconstituting activation and membrane insertion of soluble full-length human Bax monomers.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	1	2	11	12
Bax mitochondrial membrane insertion triggered by Bid may represent a key step in pathways leading to apoptosis .	Bax mitochondrial membrane insertion triggered by Bid may represent a key step in pathways leading to apoptosis.	0	8	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	6	7	0	1
Yet , the differences in the effects of detergent oligomerized BAX oligo and BAX mono activated by t c BID demonstrated in the present study have to be kept in mind .	Yet, the differences in the effects of detergent oligomerized BAX oligo and BAX mono activated by t c BID demonstrated in the present study have to be kept in mind.	11	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	19	20	13	14
We conclude from these findings that in p53 deficient SV40 transformed MEFs , Bid mediates apoptosis in response to etoposide and IR by virtue of its BH3 domain and does not directly activate Bax and Bak , but most likely relieves them from inhibition by anti-apoptotic Bcl-2 proteins .	We conclude from these findings that in p53 deficient SV40 transformed MEFs, Bid mediates apoptosis in response to etoposide and IR by virtue of its BH3 domain and does not directly activate Bax and Bak, but most likely relieves them from inhibition by anti-apoptotic Bcl-2 proteins.	13	35	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	13	14	33	34
Although a peptide representing the BH3 domain of Bim ( or Bid ) can activate Bax , high concentrations of peptide are required , and recent work shows that tethering Bid peptide to membranes strongly enhances its Bax activating activity .	Although a peptide representing the BH3 domain of Bim (or Bid) can activate Bax, high concentrations of peptide are required, and recent work shows that tethering Bid peptide to membranes strongly enhances its Bax activating activity.	30	39	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	30	31	37	38
Bid activates Bax or Bak at the mitochondrial membrane , thereby causing the release of cytochrome c concomitant with induction of apoptosis [ XREF_BIBR ] .	Bid activates Bax or Bak at the mitochondrial membrane, thereby causing the release of cytochrome c concomitant with induction of apoptosis [XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	0	1	2	3
Activation of Bid then triggers the oligomerization of Bax or Bak , resulting in the release of mitochondrial intermembrane apoptotic proteins such as cytochrome c. Mitochondrial pathway has been shown involved in TRAIL activated apoptosis [ XREF_BIBR ] .	Activation of Bid then triggers the oligomerization of Bax or Bak, resulting in the release of mitochondrial intermembrane apoptotic proteins such as cytochrome c. Mitochondrial pathway has been shown involved in TRAIL activated apoptosis [XREF_BIBR].	0	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	2	3	8	9
Bid was shown to activate Bax independently of the stoichiometric ratio , suggesting that Bid has a catalytic function and that the interaction with Bax is transient .	Bid was shown to activate Bax independently of the stoichiometric ratio, suggesting that Bid has a catalytic function and that the interaction with Bax is transient.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	0	1	5	6
The stapled Bid BH3 peptide was able to activate Bax [ XREF_BIBR ] , was resistant to protease degradation and , by maintaining its alpha-helical form , could penetrate cell membranes and induce apoptosis as was shown in vitro and in vivo with leukemia cells [ XREF_BIBR ] .	The stapled Bid BH3 peptide was able to activate Bax [XREF_BIBR], was resistant to protease degradation and, by maintaining its alpha-helical form, could penetrate cell membranes and induce apoptosis as was shown in vitro and in vivo with leukemia cells [XREF_BIBR].	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	2	3	9	10
Since activated caspase-8 is known to cleave Bid , which in turn targets mitochondrial membrane perturbation and activates the pro apoptotic protein Bax [ XREF_BIBR ] , we also confirmed that the expression of Bax was increased following the treatment of ARPE-19 cells with Stxs .	Since activated caspase-8 is known to cleave Bid, which in turn targets mitochondrial membrane perturbation and activates the pro apoptotic protein Bax [XREF_BIBR], we also confirmed that the expression of Bax was increased following the treatment of ARPE-19 cells with Stxs.	6	24	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	7	8	22	23
-Direct activator pro apoptotic proteins ( Bid , Bim and Puma ) are able to activate Bax and Bak through a hit and run process .	-Direct activator pro apoptotic proteins (Bid, Bim and Puma) are able to activate Bax and Bak through a hit and run process.	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	6	7	16	17
( XREF_FIG ) Perhaps the sole role of CL is to promote BID induced BAX activation and membrane permeabilization ?	(XREF_FIG) Perhaps the sole role of CL is to promote BID induced BAX activation and membrane permeabilization?	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	12	13	14	15
A link with the mitochondrial pathway exists via caspase 8 mediated cleavage of Bid in which the truncated Bid migrates to the mitochondria and activates the pro apoptotic members Bak and Bax .	A link with the mitochondrial pathway exists via caspase 8 mediated cleavage of Bid in which the truncated Bid migrates to the mitochondria and activates the pro apoptotic members Bak and Bax.	16	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	18	19	31	32
Calcium and truncated BID stimulate BAX insertion and oligomerization and BAX mediated outer membrane permeabilization by different mechanisms , in which permeability transition pore induced by calcium and modulation of the SH-redox state play important roles .	Calcium and truncated BID stimulate BAX insertion and oligomerization and BAX mediated outer membrane permeabilization by different mechanisms, in which permeability transition pore induced by calcium and modulation of the SH-redox state play important roles.	3	6	stimulate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	3	4	5	6
The active truncated form of BID ( tBID ) triggers the mitochondrial activation of caspase-9 by inducing the activation of BAK or BAX .	The active truncated form of BID (tBID) triggers the mitochondrial activation of caspase-9 by inducing the activation of BAK or BAX.	3	23	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	5	6	22	23
All BH3-only proteins can antagonise anti-apoptotic Bcl-2 proteins , whereas the BH3-only proteins Bim , Puma and Bid can also directly activate Bax and Bak ( XREF_FIG ) .	All BH3-only proteins can antagonise anti-apoptotic Bcl-2 proteins, whereas the BH3-only proteins Bim, Puma and Bid can also directly activate Bax and Bak (XREF_FIG).	15	26	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	17	18	22	23
In this classic model , cytosolic , full-length Bid is cleaved by caspase-8 , N-terminally myristoylated at the newly exposed amino terminus of glycine 60 and then inserted into mitochondrial membranes to activate Bax and drive apoptosis .	In this classic model, cytosolic, full-length Bid is cleaved by caspase-8, N-terminally myristoylated at the newly exposed amino terminus of glycine 60 and then inserted into mitochondrial membranes to activate Bax and drive apoptosis.	5	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	8	9	33	34
Furthermore , the cafestol treatment induced the cleavage of Bid , caspase-3 , and PARP , and the kahweol treatment up-regulated Bax and down-regulated Bcl-xL [ XREF_BIBR ] .	Furthermore, the cafestol treatment induced the cleavage of Bid, caspase-3, and PARP, and the kahweol treatment up-regulated Bax and down-regulated Bcl-xL [XREF_BIBR].	9	22	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	9	10	21	22
Truncated BID causes Bax to translocate to the mitochondrial membrane causing release of cytochrome c [ XREF_BIBR ] and Second Mitochondria derived Activator of Caspase and DIABLO ( SMAC/DIABLO ) [ XREF_BIBR ] .	Truncated BID causes Bax to translocate to the mitochondrial membrane causing release of cytochrome c [XREF_BIBR] and Second Mitochondria derived Activator of Caspase and DIABLO (SMAC/DIABLO) [XREF_BIBR].	0	4	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	Bax	Bax	Bax	1	2	3	4
Upon the stimulus , the BH3-only protein Bid activates Bax and Bak that results in conformational change and oligomerization , forming an oligomeric pore in the outer mitochondrial membrane called permeability transition pores .	Upon the stimulus, the BH3-only protein Bid activates Bax and Bak that results in conformational change and oligomerization, forming an oligomeric pore in the outer mitochondrial membrane called permeability transition pores.	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	7	8	9	10
Thus , taken together , our results argued strongly in favor of different mechanisms of OMM permeabilization by artificially oligomerized BAX oligo and by monomeric BAX activated by t c BID .	Thus, taken together, our results argued strongly in favor of different mechanisms of OMM permeabilization by artificially oligomerized BAX oligo and by monomeric BAX activated by t c BID.	20	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	30	31	25	26
We also demonstrate that CDIP1 is required for BH3-only protein Bid mediated Bax activation resulting in mitochondrial apoptosis , suggesting that both mitochondrial apoptosis pathways are involved in ER stress induced apoptosis .	We also demonstrate that CDIP1 is required for BH3-only protein Bid mediated Bax activation resulting in mitochondrial apoptosis, suggesting that both mitochondrial apoptosis pathways are involved in ER stress induced apoptosis.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	10	11	12	13
In the direct activation model , Bid activates Bax and/or Bak by a direct physical interaction using its BH3 domain .	In the direct activation model, Bid activates Bax and/or Bak by a direct physical interaction using its BH3 domain.	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	6	7	8	9
Recent results [ XREF_BIBR ] suggest that the BH3 domain-only proteins function to induce apoptosis by two mechanisms : the BID like BH3 domains activate the pro apoptotic BAX and BAK ; and the BAD like BH3 domains bind anti-apoptotic BCL-2 or BCL-X L , thus interfering with their activity .	Recent results [XREF_BIBR] suggest that the BH3 domain-only proteins function to induce apoptosis by two mechanisms : the BID like BH3 domains activate the pro apoptotic BAX and BAK; and the BAD like BH3 domains bind anti-apoptotic BCL-2 or BCL-X L, thus interfering with their activity.	19	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	20	21	28	29
Cytosolic CtD cleaves Bid protein into tBid triggering the insertion of Bax protein into the mitochondrial membrane .	Cytosolic CtD cleaves Bid protein into tBid triggering the insertion of Bax protein into the mitochondrial membrane.	3	12	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	3	4	11	12
Proapoptotic BH3-only proteins such as Bim and Bid activate Bax and Bak to undergo oligomerization that results in channels formation on the outer mitochondrial membrane [ XREF_BIBR - XREF_BIBR ] causing cytochrome c release , which triggers caspase activation .	Proapoptotic BH3-only proteins such as Bim and Bid activate Bax and Bak to undergo oligomerization that results in channels formation on the outer mitochondrial membrane [XREF_BIBR - XREF_BIBR] causing cytochrome c release, which triggers caspase activation.	2	11	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	7	8	9	10
The mechanism by which Bid promotes Bax activation is not understood , and whether Bid is the only protein required for Bax activation is unclear .	The mechanism by which Bid promotes Bax activation is not understood, and whether Bid is the only protein required for Bax activation is unclear.	4	7	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	4	5	6	7
Activation of Bid , Caspase-3 , and PARP , decreased Bcl- xl and increased Bax in cafestol and kahweol treated MSTO-211H cells .	Activation of Bid, Caspase-3, and PARP, decreased Bcl- xl and increased Bax in cafestol and kahweol treated MSTO-211H cells.	2	15	increased	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	2	3	14	15
In caspase-8 mediated apoptosis , caspase-8 cleaves BID to tBID and tBID subsequently promotes the proapoptotic activity of Bax .	In caspase-8 mediated apoptosis, caspase-8 cleaves BID to tBID and tBID subsequently promotes the proapoptotic activity of Bax.	7	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	Bax	Bax	Bax	7	8	18	19
Since thapsigargin is known as ER-stress inducer 25 , we tested ER-stress-induced apoptotic circuit : ER-stress activates JNK , CHOP , and DR-5 expession , then TRAIL activates caspase-8 via DR-5 , and the activated caspase-8 cleaves Bid and enhances JNK , and cleaved Bid activates Bax and Bak to make the pore on MOM XREF_BIBR , XREF_BIBR .	Since thapsigargin is known as ER-stress inducer 25, we tested ER-stress-induced apoptotic circuit : ER-stress activates JNK, CHOP, and DR-5 expession, then TRAIL activates caspase-8 via DR-5, and the activated caspase-8 cleaves Bid and enhances JNK, and cleaved Bid activates Bax and Bak to make the pore on MOM XREF_BIBR, XREF_BIBR.	44	48	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	44	45	46	47
The BH3-only protein BID can induce the formation of Bax dimers and trimers , leading to insertion into isolated mitochondria .	The BH3-only protein BID can induce the formation of Bax dimers and trimers, leading to insertion into isolated mitochondria.	0	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	Bax	Bax	Bax	3	4	9	10
The Bid cleavage product , tBid , induces oligomerization of the pro apoptotic Bcl-2 family members members Bax and Bak and consequent activation of the mitochondrial apoptosis pathway .	The Bid cleavage product, tBid, induces oligomerization of the pro apoptotic Bcl-2 family members members Bax and Bak and consequent activation of the mitochondrial apoptosis pathway.	1	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	1	2	17	18
Caspase-8 cleaves Bid to generate truncated Bid , which activates proapoptotic proteins Bax and Bak to promote apoptosis through the cytochrome c release from the mitochondria and caspase-3 activation .	Caspase-8 cleaves Bid to generate truncated Bid, which activates proapoptotic proteins Bax and Bak to promote apoptosis through the cytochrome c release from the mitochondria and caspase-3 activation.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	6	7	12	13
In ASTC-a-1 cells , full length Bid induced Bax translocation to mitochondria by directly interacting with Bax transiently in response to TNF-alpha treatment before cell shrinkage .	In ASTC-a-1 cells, full length Bid induced Bax translocation to mitochondria by directly interacting with Bax transiently in response to TNF-alpha treatment before cell shrinkage.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	6	7	8	9
There is also strong evidence supporting the hypothesis that Bid is able to directly activate Bax and Bak to trigger the release of caspase activating factors from mitochondria XREF_BIBR - XREF_BIBR .	There is also strong evidence supporting the hypothesis that Bid is able to directly activate Bax and Bak to trigger the release of caspase activating factors from mitochondria XREF_BIBR - XREF_BIBR.	9	17	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	9	10	15	16
Moreover , Bid , which is known to activate Bak and Bax during apoptosis , seems to be dispensable for these processes .	Moreover, Bid, which is known to activate Bak and Bax during apoptosis, seems to be dispensable for these processes.	2	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bax	Bax	Bax	2	3	11	12
BID induces opening of the occluded BC groove of BAK .	BID induces opening of the occluded BC groove of BAK.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	0	1	9	10
Caspase-3 enhances Bid induced Bak activation and the release of AIF and endoG .	Caspase-3 enhances Bid induced Bak activation and the release of AIF and endoG.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	2	3	4	5
Bak oligomerization has been mainly characterized in cells treated with truncated Bid as the apoptotic stimulus .	Bak oligomerization has been mainly characterized in cells treated with truncated Bid as the apoptotic stimulus.	0	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	11	12	0	1
In addition to cell based assays , BAK multimerization has been extensively studies in simpler in vitro models using isolated mitochondria , where addition of the truncated caspase cleaved form of Bid ( tBid ) induces BAK multimerization XREF_BIBR , XREF_BIBR .	In addition to cell based assays, BAK multimerization has been extensively studies in simpler in vitro models using isolated mitochondria, where addition of the truncated caspase cleaved form of Bid (tBid) induces BAK multimerization XREF_BIBR, XREF_BIBR.	29	38	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	BAK	BAK	BAK	31	32	36	37
When the Bak proteins were activated by p7/p15 Bid , approximately 80-90 percent of the cytochrome c molecules were released from the mitochondria except for mutant 111C ( XREF_FIG ) .	When the Bak proteins were activated by p7/p15 Bid, approximately 80-90 percent of the cytochrome c molecules were released from the mitochondria except for mutant 111C (XREF_FIG).	2	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	8	9	2	3
Furthermore , the role of CL likely extends beyond BID and BAX , as a truncated form of BAK directly binds CL resulting in heighted sensitivity to BID induced BAK activation and membrane permeabilization .	Furthermore, the role of CL likely extends beyond BID and BAX, as a truncated form of BAK directly binds CL resulting in heighted sensitivity to BID induced BAK activation and membrane permeabilization.	22	30	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	27	28	29	30
Previous studies have demonstrated that activated Bid can mediate Bak activation and the release of AIF and endoG .	Previous studies have demonstrated that activated Bid can mediate Bak activation and the release of AIF and endoG.	5	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	6	7	9	10
Recombinant Bak can also be directly activated by recombinant tBid , 14 and Bid and BH3-chimaeras can activate recombinant Bak missing its C terminus .	Recombinant Bak can also be directly activated by recombinant tBid, 14 and Bid and BH3-chimaeras can activate recombinant Bak missing its C terminus.	0	14	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	13	14	1	2
These results demonstrated that Bid could upregulate Bak activation ; the release of AIF and endoG ; and subsequently apoptosis .	These results demonstrated that Bid could upregulate Bak activation; the release of AIF and endoG; and subsequently apoptosis.	4	8	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	4	5	7	8
In this study , purified mitochondria devoid of contaminating membrane species ( e.g ., ER ) resisted BID induced BAK and BAX dependent cytochrome c release ; and re-sensitization to BAK and BAX activation was achieved by adding S1P and hexadecenal , respectively .	In this study, purified mitochondria devoid of contaminating membrane species (e.g., ER) resisted BID induced BAK and BAX dependent cytochrome c release; and re-sensitization to BAK and BAX activation was achieved by adding S1P and hexadecenal, respectively.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	17	18	19	20
Finally , excess n/c BID ( 1 muM ) induced full BAK activation and MOMP .	Finally, excess n/c BID (1 muM) induced full BAK activation and MOMP.	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	4	5	11	12
Using biochemical approaches , those authors showed 9 that , during BID induced BAK activation , BAK exposes its BH3 domain , probably revealing a groove corresponding to the hydrophobic BH pocket of the anti-apoptotic proteins at the front of the molecule .	Using biochemical approaches, those authors showed 9 that, during BID induced BAK activation, BAK exposes its BH3 domain, probably revealing a groove corresponding to the hydrophobic BH pocket of the anti-apoptotic proteins at the front of the molecule.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	11	12	13	14
Our observation that BID preferentially activates BAK and that , consequently , BAK deficiency protects cells from apoptosis induced by these agents sheds additional light on mechanisms of resistance to these often used chemotherapies .	Our observation that BID preferentially activates BAK and that, consequently, BAK deficiency protects cells from apoptosis induced by these agents sheds additional light on mechanisms of resistance to these often used chemotherapies.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	3	4	6	7
Although Ile81 of BAK makes direct contact with Ile101 of BID , it appears to be dispensable for BID induced activation of BAK , as it does not contribute significantly to binding or the conformational changes detected by protease sensitivity in CHAPS ( XREF_SUPPLEMENTARY , XREF_FIG ) .	Although Ile81 of BAK makes direct contact with Ile101 of BID, it appears to be dispensable for BID induced activation of BAK, as it does not contribute significantly to binding or the conformational changes detected by protease sensitivity in CHAPS (XREF_SUPPLEMENTARY, XREF_FIG).	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	18	19	22	23
Direct activation of BAK by BID in the absence of membranes induced significant rearrangements in the BH3 , which opened the occluded BC groove by destabilizing contacts between the BH1 and BH3 observed in free BAK 18 .	Direct activation of BAK by BID in the absence of membranes induced significant rearrangements in the BH3, which opened the occluded BC groove by destabilizing contacts between the BH1 and BH3 observed in free BAK 18.	1	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	5	6	3	4
The essence of this technique is to use isolated mitochondria , which contain inactive Bak , and induce cytochrome c ( cyt c ) release through the addition of tBid or Bid ( BH3 peptide ) , which promotes Bak activation .	The essence of this technique is to use isolated mitochondria, which contain inactive Bak, and induce cytochrome c (cyt c) release through the addition of tBid or Bid (BH3 peptide), which promotes Bak activation.	27	40	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	31	32	39	40
The mobility shift was observed only when Bak was activated by p7/p15 Bid ( lanes 7 and 8 , XREF_FIG ) , proving the proximity of the cysteines only in the activated Bak but not in the inactive Bak .	The mobility shift was observed only when Bak was activated by p7/p15 Bid (lanes 7 and 8, XREF_FIG), proving the proximity of the cysteines only in the activated Bak but not in the inactive Bak.	7	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	12	13	7	8
The BID induced BAK activation fully manifested in the presence of membranes , which support the shedding of the N-terminal bundle of BAK ( N terminus to BH3 ) from the C-terminal bundle ( BH3 to C terminus ) , as indicated by the protease sensitivity assay in CHAPS detergent .	The BID induced BAK activation fully manifested in the presence of membranes, which support the shedding of the N-terminal bundle of BAK (N terminus to BH3) from the C-terminal bundle (BH3 to C terminus), as indicated by the protease sensitivity assay in CHAPS detergent.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	1	2	3	4
Although BID BH3 interacts with both BCL-2 and BAK , the results indicate that when BCL-2 is in excess it can sequester the BID BH3 induced activated conformer of BAK , effectively blocking downstream events .	Although BID BH3 interacts with both BCL-2 and BAK, the results indicate that when BCL-2 is in excess it can sequester the BID BH3 induced activated conformer of BAK, effectively blocking downstream events.	23	30	induced activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	23	24	29	30
The BCL-2 homology ( BH ) 3-only protein BID activates BAK to perform this function .	The BCL-2 homology (BH) 3-only protein BID activates BAK to perform this function.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	8	9	10	11
Besides BID and BAX , cardiolipin also seems to bind to a truncated form of BAK leading to an increased sensitivity to BID induced BAK activation and membrane permeabilization [ XREF_BIBR ] .	Besides BID and BAX, cardiolipin also seems to bind to a truncated form of BAK leading to an increased sensitivity to BID induced BAK activation and membrane permeabilization [XREF_BIBR].	16	25	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	22	23	24	25
Interestingly , an equimolar concentration of n/c BID and BCL-xL ( 100 nM ) induced BAK BH4 cleavage by calpain in the absence of MOMP , consistent with MODE 2 inhibition .	Interestingly, an equimolar concentration of n/c BID and BCL-xL (100 nM) induced BAK BH4 cleavage by calpain in the absence of MOMP, consistent with MODE 2 inhibition.	4	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	7	8	15	16
After Bak activation by Bid , epitopes throughout the alpha1 helix are exposed indicating complete dissociation of alpha1 from alpha2 in the core and from alpha6-alpha8 in the latch .	After Bak activation by Bid, epitopes throughout the alpha1 helix are exposed indicating complete dissociation of alpha1 from alpha2 in the core and from alpha6-alpha8 in the latch.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	4	5	1	2
However , t c BID in addition to BAX might also activate BAK , a normal constituent of the OMM [ XREF_BIBR , XREF_BIBR ] .	However, t c BID in addition to BAX might also activate BAK, a normal constituent of the OMM [XREF_BIBR, XREF_BIBR].	2	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	4	5	12	13
Similarly , as shown in XREF_FIG , right panel , suppression of Bid expression repressed the oligomerization of Bak triggered by exposure to cisplatin and the N-HXK II peptide , indicating that Bid cleavage by caspase-2 is necessary for the activation of Bak .	Similarly, as shown in XREF_FIG, right panel, suppression of Bid expression repressed the oligomerization of Bak triggered by exposure to cisplatin and the N-HXK II peptide, indicating that Bid cleavage by caspase-2 is necessary for the activation of Bak.	12	19	repressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid expression	bid	Bak	Bak	bak	12	13	18	19
To determine whether preferential activation of BAK by BID and BAX by BIM were evident in an alternate cell line of epithelial origin , we repeated the MEF experiments with baby mouse kidney ( BMK ) cells having the relevant genotypes .	To determine whether preferential activation of BAK by BID and BAX by BIM were evident in an alternate cell line of epithelial origin, we repeated the MEF experiments with baby mouse kidney (BMK) cells having the relevant genotypes.	4	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	8	9	6	7
BID induced collapse of BAK N-terminal bundle in CHAPS .	BID induced collapse of BAK N-terminal bundle in CHAPS.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	0	1	4	5
Reconstitution experiments using recombinant proteins and permeabilized Bid deficient cells demonstrated that truncated Bid ( tBid ) , but not full-length Bid , potently induced Bak activation and the release of cytochrome c. Further , caspase-8-deficient Jurkat cells efficiently cleaved Bid and were sensitive to drug induced apoptosis .	Reconstitution experiments using recombinant proteins and permeabilized Bid deficient cells demonstrated that truncated Bid (tBid), but not full-length Bid, potently induced Bak activation and the release of cytochrome c. Further, caspase-8-deficient Jurkat cells efficiently cleaved Bid and were sensitive to drug induced apoptosis.	13	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	13	14	25	26
Our combined mutagenesis and truncation analysis suggests that effective activation of BAK by BID requires critical hydrophobic contacts by BID at the four most central hydrophobic residues , I86 , L90 , V93 , and M97 .	Our combined mutagenesis and truncation analysis suggests that effective activation of BAK by BID requires critical hydrophobic contacts by BID at the four most central hydrophobic residues, I86, L90, V93, and M97.	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	13	14	11	12
This suggests that MRSA may induce intestinal epithelial apoptosis by inducing Bid which secondarily induces Bak as its primary downstream mediator .	This suggests that MRSA may induce intestinal epithelial apoptosis by inducing Bid which secondarily induces Bak as its primary downstream mediator.	10	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	11	12	15	16
Bid causes Bak activation and the release of AIF and endoG during apoptosis .	Bid causes Bak activation and the release of AIF and endoG during apoptosis.	0	3	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Bak	Bak	Bak	0	1	2	3
The preferential activation of BAK by BID may therefore be born of the necessity to regulate liver homeostasis via the Fas and FasL system with a high degree of specificity and customization .	The preferential activation of BAK by BID may therefore be born of the necessity to regulate liver homeostasis via the Fas and FasL system with a high degree of specificity and customization.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	6	7	4	5
This study supports and extends others having indicated that different BH3 peptides as well as a BID SAHB can directly activate BAK [ XREF_BIBR - XREF_BIBR ] .	This study supports and extends others having indicated that different BH3 peptides as well as a BID SAHB can directly activate BAK [XREF_BIBR - XREF_BIBR].	16	23	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	16	17	21	22
XREF_BIBR Our experiments identified that a neutral sphingomyelinase activity was responsible to maintain mitochondrial responses to BID induced BAK and BAX activation and apoptosis .	XREF_BIBR Our experiments identified that a neutral sphingomyelinase activity was responsible to maintain mitochondrial responses to BID induced BAK and BAX activation and apoptosis.	12	21	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	BAK	BAK	BAK	16	17	18	19
Cleaved BID translocates to mitochondria and induces cytochrome c release and mitochondrial damage .	Cleaved BID translocates to mitochondria and induces cytochrome c release and mitochondrial damage.	1	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID translocates to mitochondria	bid	cytochrome c	cytochrome c	cytochrome c	1	2	7	9
In this case , signaling requires an additional amplification loop that involves the cleavage of the Bcl-2-family protein Bid by caspase-8 to generate truncated ( t ) Bid and subsequent ( t ) Bid mediated release of cytochrome C from mitochondria .	In this case, signaling requires an additional amplification loop that involves the cleavage of the Bcl-2-family protein Bid by caspase-8 to generate truncated (t) Bid and subsequent (t) Bid mediated release of cytochrome C from mitochondria.	23	39	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome C	cytochrome C	cytochrome C	33	34	37	39
In contrast , it is generally accepted that Bax and cleaved Bid trigger the release of cytochrome c and that activation of caspase-8 leads to cleavage of Bid , thereby inducing mitochondria mediated downstream events .	In contrast, it is generally accepted that Bax and cleaved Bid trigger the release of cytochrome c and that activation of caspase-8 leads to cleavage of Bid, thereby inducing mitochondria mediated downstream events.	11	18	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	11	12	16	18
Using isolated mitochondria , they also showed that MIN inhibited mitochondrial swelling induced by Ca 2+ and Bid ( a pro apoptopic cytoclasmic factor ) , as well as cytochrome c release , indicating that the mitochondria , and perhaps the mPTP ( mitochondrial permeability transition pore ) were direct targets of MIN [ XREF_BIBR ] .	Using isolated mitochondria, they also showed that MIN inhibited mitochondrial swelling induced by Ca 2+ and Bid (a pro apoptopic cytoclasmic factor), as well as cytochrome c release, indicating that the mitochondria, and perhaps the mPTP (mitochondrial permeability transition pore) were direct targets of MIN [XREF_BIBR].	12	31	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	17	18	29	31
As with Bax , we found that Bid induced the release of cytochrome c in a concentration dependent manner .	As with Bax, we found that Bid induced the release of cytochrome c in a concentration dependent manner.	7	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	7	8	12	14
Mitochondria are also involved in extrinsic apoptosis as one of the targets of caspase 8 , activated through death receptor activation is Bid , and truncated Bid ( tBid ) causes mitochondrial outer membrane permeabilization , and subsequent cytochrome C release XREF_BIBR .	Mitochondria are also involved in extrinsic apoptosis as one of the targets of caspase 8, activated through death receptor activation is Bid, and truncated Bid (tBid) causes mitochondrial outer membrane permeabilization, and subsequent cytochrome C release XREF_BIBR.	26	41	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome C	cytochrome C	cytochrome C	26	27	38	40
To evaluate whether the BID BH3 peptide induces cytochrome c release , the BID BH3 peptide was added to isolated mitochondria from wild type and Bax -/- / Bak -/- MEFs .	To evaluate whether the BID BH3 peptide induces cytochrome c release, the BID BH3 peptide was added to isolated mitochondria from wild type and Bax -/- / Bak -/- MEFs.	4	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	4	5	8	10
Furthermore , Bid knockdown ( XREF_FIG ) diminished the level of cytochrome c release in response to SM treatment ( XREF_SUPPLEMENTARY ) .	Furthermore, Bid knockdown (XREF_FIG) diminished the level of cytochrome c release in response to SM treatment (XREF_SUPPLEMENTARY).	2	13	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	2	3	11	13
Treatment with TNF-alpha resulted in activation of caspase 8 and cleavage of BID , which in turn induced cytochrome c release and caspase 9 dependent activation of effector caspases .	Treatment with TNF-alpha resulted in activation of caspase 8 and cleavage of BID, which in turn induced cytochrome c release and caspase 9 dependent activation of effector caspases.	10	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	12	13	18	20
Activated caspase-8 cleaves Bid to truncated Bid ( tBid ) , which sequentially induces mitochondrial cytochrome c release , activation of caspase-9/-3, cleavage of cellular repair proteins and activation of caspase activated DNase , leading to the promotion of apoptosis .	Activated caspase-8 cleaves Bid to truncated Bid (tBid), which sequentially induces mitochondrial cytochrome c release, activation of caspase-9/-3, cleavage of cellular repair proteins and activation of caspase activated DNase, leading to the promotion of apoptosis.	5	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	6	7	15	17
In a cell-free reconstitution system , caspase-8-mediated Bid cleavage and recombinant tBid induced mitochondrial cytochrome c release and ROS generation , which were blocked by Bcl-xL and antioxidant enzymes .	In a cell-free reconstitution system, caspase-8-mediated Bid cleavage and recombinant tBid induced mitochondrial cytochrome c release and ROS generation, which were blocked by Bcl-xL and antioxidant enzymes.	7	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	7	8	14	16
Then , BID activation and release of the tBid fragment [ XREF_BIBR ] , mitochondrial depolarization and cytochrome c release , ROS production and caspase activation are induced , resulting in the complete execution of the intrinsic pathway of apoptosis [ XREF_BIBR , XREF_BIBR ] .	Then, BID activation and release of the tBid fragment [XREF_BIBR], mitochondrial depolarization and cytochrome c release, ROS production and caspase activation are induced, resulting in the complete execution of the intrinsic pathway of apoptosis [XREF_BIBR, XREF_BIBR].	2	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	2	3	17	19
Caspase 8 can also hydrolyze Bid , which causes damage to the mitochondrial outer membrane and triggers cytochrome-C release .	Caspase 8 can also hydrolyze Bid, which causes damage to the mitochondrial outer membrane and triggers cytochrome-C release.	0	18	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Caspase 8 can also hydrolyze Bid	bid	cytochrome-C	cytochrome-C	cytochrome-c	5	6	17	18
Granzyme B Induces Bid Mediated Cytochrome C Release and Mitochondrial Permeability Transition .	Granzyme B Induces Bid Mediated Cytochrome C Release and Mitochondrial Permeability Transition.	2	7	Mediated	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	Cytochrome C	Cytochrome C	Cytochrome C	3	4	5	7
Caspase 8 also can cleave BH3-only protein Bid , a pro apoptotic member of the Bcl-2 family and result in truncated Bid ( tBid ) that promotes cytochrome c release through Bax resulting in the subsequent activation of executioner caspases .	Caspase 8 also can cleave BH3-only protein Bid, a pro apoptotic member of the Bcl-2 family and result in truncated Bid (tBid) that promotes cytochrome c release through Bax resulting in the subsequent activation of executioner caspases.	20	29	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	21	22	27	29
Dephosphorylation of PACS-2 serine 437 may therefore serve as a homeostatic switch that triggers PACS-2 , a mediator of membrane traffic , to become an effector of cell death which translocates full-length Bid to mitochondria or to a lysosome and mitochondria interface where Bid is cleaved to tBid to drive MMP , cytochrome c release and cell death .	Dephosphorylation of PACS-2 serine 437 may therefore serve as a homeostatic switch that triggers PACS-2, a mediator of membrane traffic, to become an effector of cell death which translocates full-length Bid to mitochondria or to a lysosome and mitochondria interface where Bid is cleaved to tBid to drive MMP, cytochrome c release and cell death.	43	54	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	43	44	52	54
The activated form of Bid ( tBid ) causes permeabilization of the mitochondrial membrane , release of cytochrome c , and formation of the apoptosome that activates initiator caspase 9 [ XREF_BIBR ] .	The activated form of Bid (tBid) causes permeabilization of the mitochondrial membrane, release of cytochrome c, and formation of the apoptosome that activates initiator caspase 9 [XREF_BIBR].	2	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	4	5	17	19
Inhibition of caspase 8 by C/EBPbeta prevented TNF induced activation of the mitochondrial death pathway as WT-C and EBPbeta decreased the amount of truncated Bid that translocated to the mitochondria and blocked the cytochrome c release from mitochondria into cytoplasm that occurred in Ad5IkappaB and Ad5LacZ coinfected cells ( XREF_FIG ) .	Inhibition of caspase 8 by C/EBPbeta prevented TNF induced activation of the mitochondrial death pathway as WT-C and EBPbeta decreased the amount of truncated Bid that translocated to the mitochondria and blocked the cytochrome c release from mitochondria into cytoplasm that occurred in Ad5IkappaB and Ad5LacZ coinfected cells (XREF_FIG).	23	35	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bid	Bid that translocated to the mitochondria	bid	cytochrome c	cytochrome c	cytochrome c	24	25	33	35
BID BH3 peptide induced cytochrome c release in the wild type MEFs but not in the Bax -/- / Bak -/- MEFs .	BID BH3 peptide induced cytochrome c release in the wild type MEFs but not in the Bax -/- / Bak -/- MEFs.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	0	1	4	6
The activated Bid ( tBid ) translocates to mitochondria and promotes cytochrome c release and activation of caspase-9 .	The activated Bid (tBid) translocates to mitochondria and promotes cytochrome c release and activation of caspase-9.	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid (tBid) translocates to mitochondria	bid	cytochrome c	cytochrome c	cytochrome c	2	3	11	13
We have previously reported that BID or truncated BID ( tBID ) can induce the release of entrapped trypsin and cytochrome c from large unilamellar vesicles ( LUVs ) .	We have previously reported that BID or truncated BID (tBID) can induce the release of entrapped trypsin and cytochrome c from large unilamellar vesicles (LUVs).	8	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	8	9	20	22
Once cleaved by activated caspase-8 , Bid , a member of the BH3-domain-only subgroup of the BCL-2 family , is activated to release cytochrome C from the mitochondria to induce apoptosis XREF_BIBR .	Once cleaved by activated caspase-8, Bid, a member of the BH3-domain-only subgroup of the BCL-2 family, is activated to release cytochrome C from the mitochondria to induce apoptosis XREF_BIBR.	6	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome C	cytochrome C	cytochrome C	6	7	23	25
Calpain 1 activity also cleaves Bid which induces cytochrome c release and leads to endothelial cell apoptosis .	Calpain 1 activity also cleaves Bid which induces cytochrome c release and leads to endothelial cell apoptosis.	4	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	5	6	8	10
In leukemic cells transfected with an empty vector , anti-Fas Ab treatment activated caspase-8 , decreased the expression of the BH3 domain-only protein Bid , triggered the release of cytochrome c from the mitochondria to the cytosol , and activated caspase-3 .	In leukemic cells transfected with an empty vector, anti-Fas Ab treatment activated caspase-8, decreased the expression of the BH3 domain-only protein Bid, triggered the release of cytochrome c from the mitochondria to the cytosol, and activated caspase-3.	9	31	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	anti-Fas Ab treatment activated caspase-8, decreased the expression of the BH3 domain-only protein Bid	bid	cytochrome c	cytochrome c	cytochrome c	23	24	29	31
The cleaved Bid causes the cytochrome c efflux from mitochondria , then activation of caspase9 and 3 [ XREF_BIBR ] .	The cleaved Bid causes the cytochrome c efflux from mitochondria, then activation of caspase9 and 3 [XREF_BIBR].	0	7	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	2	3	5	7
Translocation of the truncated Bid ( tBid ) to the mitochondria promotes cytochrome c release and activates caspase-9 and downstream caspases .	Translocation of the truncated Bid (tBid) to the mitochondria promotes cytochrome c release and activates caspase-9 and downstream caspases.	0	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Translocation of the truncated Bid (tBid) to the mitochondria	bid	cytochrome c	cytochrome c	cytochrome c	4	5	12	14
The possibility is also unlikely that Bid and Bik forms a channel by itself or destabilizes mitochondrial membrane for cytochrome c release , because , unlike Bax and Bak , Bid is unable to induce cytochrome c release in yeast mitochondria ( our unpublished results ) .	The possibility is also unlikely that Bid and Bik forms a channel by itself or destabilizes mitochondrial membrane for cytochrome c release, because, unlike Bax and Bak, Bid is unable to induce cytochrome c release in yeast mitochondria (our unpublished results).	30	37	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	30	31	35	37
To demonstrate that Bid induced cytochrome c release was mediated by Bax , we tested the ability of Bid to trigger cytochrome c release from mitochondria isolated from the Bax deficient tumor cell line LS180 .	To demonstrate that Bid induced cytochrome c release was mediated by Bax, we tested the ability of Bid to trigger cytochrome c release from mitochondria isolated from the Bax deficient tumor cell line LS180.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	3	4	5	7
BID , a pro apoptotic Bcl-2 family member , promotes cytochrome c release during apoptosis initiated by CD95L or TNF .	BID, a pro apoptotic Bcl-2 family member, promotes cytochrome c release during apoptosis initiated by CD95L or TNF.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	0	1	10	12
Likewise , injection of a Bid BH3 peptide in neurons induced potent release of cytochrome c from the mitochondria that did not result in death ( XREF_SUPPLEMENTARY , XREF_SUPPLEMENTARY ) .	Likewise, injection of a Bid BH3 peptide in neurons induced potent release of cytochrome c from the mitochondria that did not result in death (XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY).	5	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	5	6	14	16
Truncated Bid ( tBid ) induces mitochondrial cytochrome c release .	Truncated Bid (tBid) induces mitochondrial cytochrome c release.	1	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	1	2	7	9
One possibility is that HSP27 may inhibit the intracellular redistribution of Bid , a pro apoptotic member of the Bcl-2 family which , upon moving to mitochondria , induces cytochrome c release by stabilizing F-actin microfilaments [ XREF_BIBR ] .	One possibility is that HSP27 may inhibit the intracellular redistribution of Bid, a pro apoptotic member of the Bcl-2 family which, upon moving to mitochondria, induces cytochrome c release by stabilizing F-actin microfilaments [XREF_BIBR].	9	31	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	11	12	29	31
BID functions by mediating mitochondrial damage induced by caspase-8 and ultimately triggering cytochrome c release [ XREF_BIBR ] .	BID functions by mediating mitochondrial damage induced by caspase-8 and ultimately triggering cytochrome c release [XREF_BIBR].	0	14	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	0	1	12	14
Bid , in turn induces release of cytochrome c from mitochondria and subsequent apoptosis ( XREF_FIG ) .	Bid, in turn induces release of cytochrome c from mitochondria and subsequent apoptosis (XREF_FIG).	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	0	1	7	9
Remarkably , cytochrome c release ( XREF_FIG ) , caspase-9 processing and caspase-3 activation and processing ( XREF_FIG ) as well as apoptosis induction ( XREF_FIG ) were all significantly inhibited by loss of Bid .	Remarkably, cytochrome c release (XREF_FIG), caspase-9 processing and caspase-3 activation and processing (XREF_FIG) as well as apoptosis induction (XREF_FIG) were all significantly inhibited by loss of Bid.	2	35	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Bid	loss of Bid	bid	cytochrome c	cytochrome c	cytochrome c	34	35	2	4
Thus , large-scale mitochondrial morphological alterations are secondary caspase dependent events unnecessary for the efficient release of cytochrome c. Also , in our earlier experiments using isolated mitochondria from Xenopus eggs , we observed no large-scale changes in mitochondrial ultrastructure following treatment with cleaved Bid , which induced complete cytochrome c release .	Thus, large-scale mitochondrial morphological alterations are secondary caspase dependent events unnecessary for the efficient release of cytochrome c. Also, in our earlier experiments using isolated mitochondria from Xenopus eggs, we observed no large-scale changes in mitochondrial ultrastructure following treatment with cleaved Bid, which induced complete cytochrome c release.	43	51	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	44	45	49	51
There is subsequent recruitment of procaspase 8 to the receptor complex where it undergoes self activation followed by caspase 3 activation thru two distinct manners : one pathway involves caspase 8 cleavage of BID thus triggering cytochrome c release .	There is subsequent recruitment of procaspase 8 to the receptor complex where it undergoes self activation followed by caspase 3 activation thru two distinct manners : one pathway involves caspase 8 cleavage of BID thus triggering cytochrome c release.	31	38	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	33	34	36	38
In turn , activated Bid , acting with p53 regulated Bax , leads to cytochrome c released from mitochondria into the cytoplasm .	In turn, activated Bid, acting with p53 regulated Bax, leads to cytochrome c released from mitochondria into the cytoplasm.	3	16	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	4	5	14	16
While the mutant BID peptide did not display release of cytochrome c from the mitochondria , both BID and BIM peptides induced cytochrome c release in the wild type cells as demonstrated by the diffusion pattern of the GFP throughout the cell ( XREF_FIG ) .	While the mutant BID peptide did not display release of cytochrome c from the mitochondria, both BID and BIM peptides induced cytochrome c release in the wild type cells as demonstrated by the diffusion pattern of the GFP throughout the cell (XREF_FIG).	16	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	17	18	22	24
Instead , activated caspase-8 may preferentially cleave the cytosolic protein Bid [ XREF_BIBR ] , causing release of cytochrome c from mitochondria and the formation of the apoptosome to activate caspase-3 ( intrinsic pathway ) .	Instead, activated caspase-8 may preferentially cleave the cytosolic protein Bid [XREF_BIBR], causing release of cytochrome c from mitochondria and the formation of the apoptosome to activate caspase-3 (intrinsic pathway).	6	33	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	10	11	18	20
Caspase-8 is also able to truncate and activate Bcl-2 interacting domain ( BID ) , a pro apoptotic member of Bcl-2 family , subsequently initiating cytochrome C release and apoptosis [ XREF_BIBR ] .	Caspase-8 is also able to truncate and activate Bcl-2 interacting domain (BID), a pro apoptotic member of Bcl-2 family, subsequently initiating cytochrome C release and apoptosis [XREF_BIBR].	10	27	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome C	cytochrome C	cytochrome C	12	13	25	27
Bid like other BH3-only molecules triggers the release of cytochrome c from mitochondria ultimately resulting in activation of caspase-9 [ XREF_BIBR , XREF_BIBR ] .	Bid like other BH3-only molecules triggers the release of cytochrome c from mitochondria ultimately resulting in activation of caspase-9 [XREF_BIBR, XREF_BIBR].	0	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	0	1	9	11
Recombinant wild-type Bid , but not a noncleavable mutant ( D59E ) , restored cytochrome c release .	Recombinant wild-type Bid, but not a noncleavable mutant (D59E), restored cytochrome c release.	0	16	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	2	3	14	16
Bcl-x L and Bcl-2 Inhibit Bid induced Cytochrome c Release .	Bcl-x L and Bcl-2 Inhibit Bid induced Cytochrome c Release.	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	Cytochrome c	Cytochrome c	Cytochrome c	5	6	7	9
Signals originating from death receptors can be linked to mitochondria via Bid , which causes mitochondrial cytochrome c release and caspase-9 activation .	Signals originating from death receptors can be linked to mitochondria via Bid, which causes mitochondrial cytochrome c release and caspase-9 activation.	9	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	11	12	16	18
In the current study , we investigated the mitochondrial localization of Bid and its interactions with mitochondrial phospholipids , focusing on their relationships with Bid induced cytochrome c release .	In the current study, we investigated the mitochondrial localization of Bid and its interactions with mitochondrial phospholipids, focusing on their relationships with Bid induced cytochrome c release.	19	28	induced	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	24	25	26	28
To test whether Bcl-x L and Bcl-2 were able to inhibit Bid induced cytochrome c release , mitochondria were incubated with 100 nM Bid together with 1 muM recombinant Bcl-x L or Bcl-2 .	To test whether Bcl-x L and Bcl-2 were able to inhibit Bid induced cytochrome c release, mitochondria were incubated with 100 nM Bid together with 1 muM recombinant Bcl-x L or Bcl-2.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	11	12	13	15
Bid , a proapoptotic member of the Bcl-2 family , is cleaved by activated caspase-8 , and then truncated Bid ( tBid ) translocates from the cytoplasm to the mitochondria , causing an efflux of cytochrome c from the mitochondria .	Bid, a proapoptotic member of the Bcl-2 family, is cleaved by activated caspase-8, and then truncated Bid (tBid) translocates from the cytoplasm to the mitochondria, causing an efflux of cytochrome c from the mitochondria.	19	37	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid (tBid) translocates from the cytoplasm to the mitochondria	bid	cytochrome c	cytochrome c	cytochrome c	19	20	35	37
13 Indeed , one of the key functions of Bid in activating mitochondria is to trigger the release of mitochondrial Smac/DIABLO , in addition to cytochrome c and other factors .	13 Indeed, one of the key functions of Bid in activating mitochondria is to trigger the release of mitochondrial Smac/DIABLO, in addition to cytochrome c and other factors.	7	27	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	9	10	25	27
Caspase-2-mediated cleavage of Bid has been shown to promote cytochrome c release at the mitochondria during apoptosis .	Caspase-2-mediated cleavage of Bid has been shown to promote cytochrome c release at the mitochondria during apoptosis.	1	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	3	4	9	11
Addition of Bid to mitochondria is sufficient to trigger cytochrome c release .	Addition of Bid to mitochondria is sufficient to trigger cytochrome c release.	0	11	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	2	3	9	11
Studies support that ROS may have a central role in mediating many of these events : JNK activation , mPT induction and Bid mediated cytochrome c release .	Studies support that ROS may have a central role in mediating many of these events : JNK activation, mPT induction and Bid mediated cytochrome c release.	17	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	22	23	24	26
The truncated Bid , however , translocates to the mitochondrial membrane , where it interacts with Bax , enhancing their oligomerization by altering the protein conformation and triggers cytochrome c and Smac release by reducing MMP , activation of caspase-9/3 and cell death [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The truncated Bid, however, translocates to the mitochondrial membrane, where it interacts with Bax, enhancing their oligomerization by altering the protein conformation and triggers cytochrome c and Smac release by reducing MMP, activation of caspase-9/3 and cell death [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	30	triggers	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bid	Bid, however, translocates to the mitochondrial membrane	bid	cytochrome c	cytochrome c	cytochrome c	2	3	28	30
Signal transduction studies revealed that Cd markedly increased the levels of caspase-9 , -8 , -3 , Fas and Bid , decreased mitochondrial membrane potential , enhanced cytochrome c release in the cytosol , disturbed the Bcl-2 family protein balance , cleaved PARP protein and ultimately led to apoptotic cell death .	Signal transduction studies revealed that Cd markedly increased the levels of caspase-9, -8, -3, Fas and Bid, decreased mitochondrial membrane potential, enhanced cytochrome c release in the cytosol, disturbed the Bcl-2 family protein balance, cleaved PARP protein and ultimately led to apoptotic cell death.	5	29	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Cd markedly increased the levels of caspase-9, -8, -3, Fas and Bid	bid	cytochrome c	cytochrome c	cytochrome c	19	20	27	29
It has been reported that cisplatin induces calpain mediated Bid cleavage in association with increased intracellular calcium ion levels and calpain cleaved Bid induces cytochrome c release from mitochondria [ XREF_BIBR ] .	It has been reported that cisplatin induces calpain mediated Bid cleavage in association with increased intracellular calcium ion levels and calpain cleaved Bid induces cytochrome c release from mitochondria [XREF_BIBR].	22	26	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	22	23	24	26
Caspase-8 also cleaves Bid , which induces cytochrome c efflux from the mitochondria and subsequent activation of caspases-9 and -3 , as described above [ XREF_BIBR ] .	Caspase-8 also cleaves Bid, which induces cytochrome c efflux from the mitochondria and subsequent activation of caspases-9 and -3, as described above [XREF_BIBR].	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	3	4	7	9
Moreover , BH3-only proteins Bid and Bim induced full cytochrome c release but only a subtle alteration in cristae junctions , which involved the disassembly of Opa1 complexes [ XREF_BIBR ] .	Moreover, BH3-only proteins Bid and Bim induced full cytochrome c release but only a subtle alteration in cristae junctions, which involved the disassembly of Opa1 complexes [XREF_BIBR].	2	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	4	5	9	11
The cleaved BID now termed truncated Bid ( tBID ) translocates to mitochondria , inducing cytochrome c release , which sequentially activates caspase-9 and -3 .	The cleaved BID now termed truncated Bid (tBID) translocates to mitochondria, inducing cytochrome c release, which sequentially activates caspase-9 and -3.	0	17	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID now termed truncated Bid (tBID) translocates to mitochondria	bid	cytochrome c	cytochrome c	cytochrome c	2	3	15	17
Bid cleaved by activated caspase-8 in the death extrinsic pathway directly triggers the release of cytochrome c from mitochondria .	Bid cleaved by activated caspase-8 in the death extrinsic pathway directly triggers the release of cytochrome c from mitochondria.	0	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	0	1	15	17
Using isolated mitochondria , we showed that Bid and Bik , BH3-only proteins from the Bcl-2 family , induced cytochrome c release but not Deltapsi loss .	Using isolated mitochondria, we showed that Bid and Bik, BH3-only proteins from the Bcl-2 family, induced cytochrome c release but not Deltapsi loss.	7	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	7	8	19	21
When cleaved by activated caspase-8 , the BH3-only proteins Bid can also trigger cytochrome c release by translocation to mitochondria .	When cleaved by activated caspase-8, the BH3-only proteins Bid can also trigger cytochrome c release by translocation to mitochondria.	6	15	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	9	10	13	15
Cyclosporin A can enhance the ability of Bcl-2 to inhibit truncated Bid induced cytochrome c release by mitochondria .	Cyclosporin A can enhance the ability of Bcl-2 to inhibit truncated Bid induced cytochrome c release by mitochondria.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	11	12	13	15
Another link could be Bid , a proapoptotic Bcl-2 family member that , following an activating cleavage event , translocates to mitochondria and mediates cytochrome c release and activation of caspase 9 .	Another link could be Bid, a proapoptotic Bcl-2 family member that, following an activating cleavage event, translocates to mitochondria and mediates cytochrome c release and activation of caspase 9.	1	26	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	4	5	24	26
Bim and Bid activate the mitochondrial amplification loop and induce cytochrome c release , a hallmark of type II apoptosis .	Bim and Bid activate the mitochondrial amplification loop and induce cytochrome c release, a hallmark of type II apoptosis.	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	2	3	10	12
When the extrinsic pathway is activated , Caspase-8 cleavage of BID can trigger cytochrome C release and subsequent events in the intrinsic apoptotic pathway .	When the extrinsic pathway is activated, Caspase-8 cleavage of BID can trigger cytochrome C release and subsequent events in the intrinsic apoptotic pathway.	8	15	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome C	cytochrome C	cytochrome C	10	11	13	15
The BH3 profile of BCL-2 and Emu-Myc white blood cells shows high levels of cytochrome c release when treated with BIM , BID , BAD , PUMA , BMF ( XREF_FIG ) .	The BH3 profile of BCL-2 and Emu-Myc white blood cells shows high levels of cytochrome c release when treated with BIM, BID, BAD, PUMA, BMF (XREF_FIG).	14	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	22	23	14	16
Subsequently , caspase 8 cleaves BH3 interacting domain death agonist ( BID ) , yielding truncated BID ( tBID ) that forms a pore in the mitochondrial membrane and allows cytochrome c leakage .	Subsequently, caspase 8 cleaves BH3 interacting domain death agonist (BID), yielding truncated BID (tBID) that forms a pore in the mitochondrial membrane and allows cytochrome c leakage.	15	32	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	16	17	30	32
Caspase-3 activation by hyperosmotic shock induces proteolysis of Bid and mono-ubiquitinated Bid at Asp 52 increasing the release of cytochrome c and caspase-3 activation , and thus creating a second positive feedback loop .	Caspase-3 activation by hyperosmotic shock induces proteolysis of Bid and mono-ubiquitinated Bid at Asp 52 increasing the release of cytochrome c and caspase-3 activation, and thus creating a second positive feedback loop.	8	21	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	8	9	19	21
The pro death Bcl-2 family protein , Bid , mediates this pathway by inducing mitochondrial releases of cytochrome c and other apoptotic factors .	The pro death Bcl-2 family protein, Bid, mediates this pathway by inducing mitochondrial releases of cytochrome c and other apoptotic factors.	5	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	7	8	17	19
Unlike Bax and Bak , the cytochrome c release induced by Bid and Bik was Ca ( 2+ )-independent , cyclosporin A-insensitive , and respiration independent .	Unlike Bax and Bak, the cytochrome c release induced by Bid and Bik was Ca (2+)-independent, cyclosporin A-insensitive, and respiration independent.	6	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	11	12	6	8
Bid is able to promote cytochrome C release after truncation , antagonising Bcl-2/x .	Bid is able to promote cytochrome C release after truncation, antagonising Bcl-2/x.	0	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome C	cytochrome C	cytochrome C	0	1	5	7
Because a postulated mechanism by which activation of Bid causes cytochrome c release involves changes in DeltaPsim , its status in cervical cancer cells before and after Mith treatment was investigated .	Because a postulated mechanism by which activation of Bid causes cytochrome c release involves changes in DeltaPsim, its status in cervical cancer cells before and after Mith treatment was investigated.	6	12	causes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	8	9	10	12
In another study from our laboratory , XREF_BIBR investigated cannabidiol induced apoptosis in mouse ( EL-4 ) and human ( Jurkat ) leukemia cells , and demonstrated that CBD induced apoptosis occurred through ( 1 ) ligation of the CB2 receptor , ( 2 ) activation of caspases 8 , 9 and 3 , ( 3 ) cleavage of Bid , ( 4 ) increased cytochrome c in the cytosol , ( 5 ) increased ROS production , and ( 6 ) increased NADPH oxidases Nox4 and p22phox .	In another study from our laboratory, XREF_BIBR investigated cannabidiol induced apoptosis in mouse (EL-4) and human (Jurkat) leukemia cells, and demonstrated that CBD induced apoptosis occurred through (1) ligation of the CB2 receptor, (2) activation of caspases 8, 9 and 3, (3) cleavage of Bid, (4) increased cytochrome c in the cytosol, (5) increased ROS production, and (6) increased NADPH oxidases Nox4 and p22phox.	57	67	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	59	60	65	67
The activation of Bid by caspase-8 in this pathway promotes further cytochrome c release , thereby completing a positive feedback loop of caspase activation .	The activation of Bid by caspase-8 in this pathway promotes further cytochrome c release, thereby completing a positive feedback loop of caspase activation.	1	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	3	4	11	13
Moreover , we observed that cytosolic Bid was cleaved XREF_BIBR , probably by active caspase 8 XREF_BIBR XREF_BIBR XREF_BIBR , and subsequently translocated onto the mitochondrial membrane to promote cytochrome c release into the cytosol to activate pro caspase 9 .	Moreover, we observed that cytosolic Bid was cleaved XREF_BIBR, probably by active caspase 8 XREF_BIBR XREF_BIBR XREF_BIBR, and subsequently translocated onto the mitochondrial membrane to promote cytochrome c release into the cytosol to activate pro caspase 9.	5	31	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	6	7	29	31
Notonly do these data parallel the pro neurogenic activities of the three compounds in living mice ( XREF_FIG ) , but - in the case of the two Serono compounds - parallel the reported activities in test tube reactions measuring protection of mitochondria from Bid mediated cytochrome c release .	Notonly do these data parallel the pro neurogenic activities of the three compounds in living mice (XREF_FIG), but - in the case of the two Serono compounds - parallel the reported activities in test tube reactions measuring protection of mitochondria from Bid mediated cytochrome c release.	39	48	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	44	45	46	48
This may seem paradoxical because cleavage of BID by caspase-2 triggers mitochondria cytochrome c release and activates executioner caspases .	This may seem paradoxical because cleavage of BID by caspase-2 triggers mitochondria cytochrome c release and activates executioner caspases.	5	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	7	8	12	14
While we can not exclude that undetected apoptosis may be present in these mice , our data indicate that the degree of Fas mediated BID cleavage may not be sufficient to trigger cytochrome c release and subsequent cleavage of caspase 3 .	While we can not exclude that undetected apoptosis may be present in these mice, our data indicate that the degree of Fas mediated BID cleavage may not be sufficient to trigger cytochrome c release and subsequent cleavage of caspase 3.	22	34	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	Fas mediated BID	bid	cytochrome c	cytochrome c	cytochrome c	24	25	32	34
However , it should also be noted that even in LS180 mitochondria without exogenous Bax , Bid was nevertheless able to induce release of cytochrome c at higher concentrations , suggesting that there may be other proapoptotic targets for Bid in the mitochondrial membrane .	However, it should also be noted that even in LS180 mitochondria without exogenous Bax, Bid was nevertheless able to induce release of cytochrome c at higher concentrations, suggesting that there may be other proapoptotic targets for Bid in the mitochondrial membrane.	16	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	16	17	24	26
Bid alone elicits little release of cytochrome c in mitochondria from Bax deficient tumor cells , whereas Bax and Bid together significantly increase release .	Bid alone elicits little release of cytochrome c in mitochondria from Bax deficient tumor cells, whereas Bax and Bid together significantly increase release.	0	8	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
Like the binding to the mitochondria , this interaction could not be blocked by the mutation in the BH3 domain or by Bcl-x ( L. ) However , a cardiolipin specific dye , 10-N-nonyl acridine orange , could preferentially suppress Bid binding to the mitochondrial contact site and inhibit Bid induced mitochondrial cristae reorganization and cytochrome c release .	Like the binding to the mitochondria, this interaction could not be blocked by the mutation in the BH3 domain or by Bcl-x (L.) However, a cardiolipin specific dye, 10-N-nonyl acridine orange, could preferentially suppress Bid binding to the mitochondrial contact site and inhibit Bid induced mitochondrial cristae reorganization and cytochrome c release.	49	57	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	49	50	55	57
We found that low concentrations of recombinant Bid triggered a greater release of cytochrome c from mitochondria isolated from paclitaxel treated HeLa cells than from mitochondria isolated from control HeLa cells .	We found that low concentrations of recombinant Bid triggered a greater release of cytochrome c from mitochondria isolated from paclitaxel treated HeLa cells than from mitochondria isolated from control HeLa cells.	4	15	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	7	8	13	15
The cleaved Bid translocates to the mitochondrial outer membrane to induce cytochrome-c release and caspase-9 and caspase-3 activation , resulting in TNF mediated hepatocyte death XREF_BIBR , XREF_BIBR .	The cleaved Bid translocates to the mitochondrial outer membrane to induce cytochrome-c release and caspase-9 and caspase-3 activation, resulting in TNF mediated hepatocyte death XREF_BIBR, XREF_BIBR.	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid translocates to the mitochondrial outer membrane	bid	cytochrome-c	cytochrome-c	cytochrome-c	2	3	11	12
Cytochrome C release is mediated by activated Bid in the intrinsic apoptosis pathway and activation of Bid by death receptor initiated signals requires cleavage by activated caspase 8 .	Cytochrome C release is mediated by activated Bid in the intrinsic apoptosis pathway and activation of Bid by death receptor initiated signals requires cleavage by activated caspase 8.	0	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Cytochrome C	Cytochrome C	Cytochrome C	7	8	0	2
Caspase-8 cleaves Bid , generating tBid , which is then translocated to the mitochondria to promote the release of cytochrome c ( Dirks & Leeuwenburgh , 2005 ) .	Caspase-8 cleaves Bid, generating tBid, which is then translocated to the mitochondria to promote the release of cytochrome c (Dirks & Leeuwenburgh, 2005).	0	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	2	3	19	21
Bcl-2 is able to inhibit apoptosis by blocking the release of cytochrome C , while Bid can induce the release of cytochrome C after truncation XREF_BIBR .	Bcl-2 is able to inhibit apoptosis by blocking the release of cytochrome C, while Bid can induce the release of cytochrome C after truncation XREF_BIBR.	15	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome C	cytochrome C	cytochrome C	15	16	21	23
My work showed that Bid was puncturing mitochondrial membranes and causing cytochrome c , a member of the electron transport chain , to leak out .	My work showed that Bid was puncturing mitochondrial membranes and causing cytochrome c, a member of the electron transport chain, to leak out.	4	13	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	4	5	11	13
For the mitochondria dependent pathway , caspase-8-mediated cleavage of BID leads to oligomerisation of Bax and Bak , resulting in the release of cytochrome c. Cytochrome c activates caspase-9 .	For the mitochondria dependent pathway, caspase-8-mediated cleavage of BID leads to oligomerisation of Bax and Bak, resulting in the release of cytochrome c. Cytochrome c activates caspase-9.	7	27	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	Cytochrome c	Cytochrome c	Cytochrome c	9	10	25	27
In this regard , caspase-8-mediated activation of Bid induces the release of cytochrome c from the mitochondria , which , in turn , triggers the formation of the apoptosome protein complex , resulting in the activation of caspase-9 .	In this regard, caspase-8-mediated activation of Bid induces the release of cytochrome c from the mitochondria, which, in turn, triggers the formation of the apoptosome protein complex, resulting in the activation of caspase-9.	5	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	7	8	12	14
This post-proteolytic N myristoylation serves as an activating switch , enhancing BID induced release of cytochrome c and cell death .	This post-proteolytic N myristoylation serves as an activating switch, enhancing BID induced release of cytochrome c and cell death.	11	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	11	12	15	17
Activation of Bid induces cytochrome c release from mitochondria [ XREF_BIBR ] and activation of caspase-9 and -3 , leading to apoptotic cell death by the intrinsic pathway [ XREF_BIBR ] .	Activation of Bid induces cytochrome c release from mitochondria [XREF_BIBR] and activation of caspase-9 and -3, leading to apoptotic cell death by the intrinsic pathway [XREF_BIBR].	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	2	3	4	6
Notably two of them , UL36 and UL37x1 , inhibit death-receptor-induced cell death either directly by binding of procaspase 8 in the case of UL36 or , in the case of UL37x1 , indirectly by sequestration of the pro apoptotic protein BAX , thereby preventing BID induced cytochrome C release from mitochondria and activation of executioner caspases .	Notably two of them, UL36 and UL37x1, inhibit death-receptor-induced cell death either directly by binding of procaspase 8 in the case of UL36 or, in the case of UL37x1, indirectly by sequestration of the pro apoptotic protein BAX, thereby preventing BID induced cytochrome C release from mitochondria and activation of executioner caspases.	44	49	induced	Positive_early_activation	Positive_activation	Positive_activation	BID	BID	BID	cytochrome C	cytochrome C	cytochrome C	45	46	47	49
Death receptor pathway can be amplified by cleavage of a proapoptotic protein Bid , which translocates to mitochondria and initiates cytochrome c release , thus enhances caspase activation .	Death receptor pathway can be amplified by cleavage of a proapoptotic protein Bid, which translocates to mitochondria and initiates cytochrome c release, thus enhances caspase activation.	7	22	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid, which translocates to mitochondria	bid	cytochrome c	cytochrome c	cytochrome c	12	13	20	22
Once activated in the DISC , caspases-8/10 cleave the proapoptotic molecule Bid , which then translocates to the mitochondrial membrane , leads to release of mitochondrial cytochrome c into the cytosol , activates both caspases-9 and -3 , and finally cause apoptosis [ XREF_BIBR - XREF_BIBR ] .	Once activated in the DISC, caspases-8/10 cleave the proapoptotic molecule Bid, which then translocates to the mitochondrial membrane, leads to release of mitochondrial cytochrome c into the cytosol, activates both caspases-9 and -3, and finally cause apoptosis [XREF_BIBR - XREF_BIBR].	8	40	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid, which then translocates to the mitochondrial membrane	bid	cytochrome c	cytochrome c	cytochrome c	11	12	26	28
Once associated with mitochondria , truncated Bid ( tBid ) causes the potent release of cytochrome c , endonuclease G , and smac .	Once associated with mitochondria, truncated Bid (tBid) causes the potent release of cytochrome c, endonuclease G, and smac.	6	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	6	7	15	17
After additional modification , the C-terminal moiety of Bid is translocated to the mitochondria and induces the release of cytochrome c into the cytoplasm .	After additional modification, the C-terminal moiety of Bid is translocated to the mitochondria and induces the release of cytochrome c into the cytoplasm.	6	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	8	9	19	21
The resulting profile showed high levels of cytochrome c release when treated with BIM , BID , NOXA , PUMA , and BMF peptides ( XREF_FIG ) .	The resulting profile showed high levels of cytochrome c release when treated with BIM, BID, NOXA, PUMA, and BMF peptides (XREF_FIG).	7	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	15	16	7	9
Activated caspase-8 also triggers the intrinsic apoptotic pathway by cleaving BH3 interacting domain death agonist ( Bid ) ; truncated Bid translocates to the mitochondria and induces cytochrome C release from the mitochondria , thereby activating caspase-9 and caspase-3 [ XREF_BIBR - XREF_BIBR ] .	Activated caspase-8 also triggers the intrinsic apoptotic pathway by cleaving BH3 interacting domain death agonist (Bid); truncated Bid translocates to the mitochondria and induces cytochrome C release from the mitochondria, thereby activating caspase-9 and caspase-3 [XREF_BIBR - XREF_BIBR].	19	33	induces	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Bid	Bid translocates to the mitochondria	bid	cytochrome C	cytochrome C release from the mitochondria	cytochrome c	20	21	27	29
One of the genes , DOBI ( Downstream of Bid ) , is required for progression of the apoptotic signal through the intrinsic mitochondrial cell death pathway indicating that it may function to mediate cytochrome c release induced by BID cleavage , the other , named MIRSA ( Mina53- related suppressor of apoptosis ) , is a gene that acts to prevent TRAIL induced death .	One of the genes, DOBI (Downstream of Bid), is required for progression of the apoptotic signal through the intrinsic mitochondrial cell death pathway indicating that it may function to mediate cytochrome c release induced by BID cleavage, the other, named MIRSA (Mina53- related suppressor of apoptosis), is a gene that acts to prevent TRAIL induced death.	34	40	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	39	40	34	36
BID initiates the release of cytochrome c from mitochondria , thereby triggering the formation of the apoptosome complex that finally activates caspase-3 XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	BID initiates the release of cytochrome c from mitochondria, thereby triggering the formation of the apoptosome complex that finally activates caspase-3 XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	7	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Alternatively , a mPT independent mechanism was demonstrated where ROS was required for mitochondrial membrane permeabilization and cytochrome c release induced by Bid [ XREF_BIBR ] .	Alternatively, a mPT independent mechanism was demonstrated where ROS was required for mitochondrial membrane permeabilization and cytochrome c release induced by Bid [XREF_BIBR].	17	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	22	23	17	19
Studies have demonstrated that while cells undergo apoptosis through mitochondrial pathway , activation of the proapoptotic BH3-only protein , Bid , will induce the release of cytochrome-c from mitochondria to form apoptosome with caspase-9 , which could link the interaction between intrinsic and extrinsic caspase pathways .	Studies have demonstrated that while cells undergo apoptosis through mitochondrial pathway, activation of the proapoptotic BH3-only protein, Bid, will induce the release of cytochrome-c from mitochondria to form apoptosome with caspase-9, which could link the interaction between intrinsic and extrinsic caspase pathways.	17	27	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome-c	cytochrome-c	cytochrome-c	19	20	26	27
For example , the BH3-domain only protein BID is cleaved by the activation of pro-caspase-8 through the extrinsic pathway , and translocates to the mitochondrion to promote cytochrome C release .	For example, the BH3-domain only protein BID is cleaved by the activation of pro-caspase-8 through the extrinsic pathway, and translocates to the mitochondrion to promote cytochrome C release.	5	29	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID is cleaved by the activation of pro-caspase-8 through the extrinsic pathway, and translocates to the mitochondrion	bid	cytochrome C	cytochrome C	cytochrome c	7	8	27	29
In addition , active caspase 8 can cleave BH3-only protein Bid , a pro apoptotic member of the Bcl-2 family and result in truncated Bid ( tBid ) that promotes cytochrome c release through Bax resulting in the subsequent activation of executioner caspases .	In addition, active caspase 8 can cleave BH3-only protein Bid, a pro apoptotic member of the Bcl-2 family and result in truncated Bid (tBid) that promotes cytochrome c release through Bax resulting in the subsequent activation of executioner caspases.	23	32	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	24	25	30	32
Bid induced Release of Cytochrome c from Mitochondria from Bax deficient Cells .	Bid induced Release of Cytochrome c from Mitochondria from Bax deficient Cells.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	Cytochrome c	Cytochrome c	Cytochrome c	0	1	4	6
The mechanism by which Bid induces cytochrome c release remains elusive .	The mechanism by which Bid induces cytochrome c release remains elusive.	4	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	4	5	6	8
Bid then translocates to the mitochondria and mediates the release of cytochrome c that leads to apoptotic changes .	Bid then translocates to the mitochondria and mediates the release of cytochrome c that leads to apoptotic changes.	0	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid then translocates to the mitochondria	bid	cytochrome c	cytochrome c	cytochrome c	0	1	11	13
A Bid BH3 peptide was able to cause release of cytochrome c from mitochondria that were isolated in buffers lacking phosphatase inhibitors , in line with previous studies ( XREF_FIG ) , whereas a peptide having mutations in four residues critical for association failed to release cytochrome c from isolated mitochondria ( XREF_SUPPLEMENTARY ) .	A Bid BH3 peptide was able to cause release of cytochrome c from mitochondria that were isolated in buffers lacking phosphatase inhibitors, in line with previous studies (XREF_FIG), whereas a peptide having mutations in four residues critical for association failed to release cytochrome c from isolated mitochondria (XREF_SUPPLEMENTARY).	1	12	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	1	2	10	12
Bid cleaved by caspase-8 translocates to mitochondria and causes cytochrome c release , thus linking the two pathways of apoptosis [ XREF_BIBR ] .	Bid cleaved by caspase-8 translocates to mitochondria and causes cytochrome c release, thus linking the two pathways of apoptosis [XREF_BIBR].	0	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid cleaved by caspase-8 translocates to mitochondria	bid	cytochrome c	cytochrome c	cytochrome c	0	1	9	11
Among the extrinsic pathway , caspase-8 cleaves the Bcl-2 related protein Bid , which in turn induces cytochrome c release from mitochondria and caspase-3 activation , likewise resulting in apoptosis [ XREF_BIBR , XREF_BIBR ] .	Among the extrinsic pathway, caspase-8 cleaves the Bcl-2 related protein Bid, which in turn induces cytochrome c release from mitochondria and caspase-3 activation, likewise resulting in apoptosis [XREF_BIBR, XREF_BIBR].	6	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	11	12	17	19
Truncated BID was shown to translocate into mitochondria and promote the release of cytochrome c from mitochondria to cytoplasm [ XREF_BIBR ] .	Truncated BID was shown to translocate into mitochondria and promote the release of cytochrome c from mitochondria to cytoplasm [XREF_BIBR].	0	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	cytochrome c	cytochrome c	cytochrome c	1	2	13	15
BMP2 activates Smad1 , 5 , and 8 , and the activation is suppressed by the inhibitory Smad , Smad6 .	BMP2 activates Smad1, 5, and 8, and the activation is suppressed by the inhibitory Smad, Smad6.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	0	1	2	3
We show that in BMPRII deficient cells , BMP-2 fails to activate pSmad1 but activates pSmad3 ( XREF_FIG ) .	We show that in BMPRII deficient cells, BMP-2 fails to activate pSmad1 but activates pSmad3 (XREF_FIG).	8	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	pSmad1	pSmad1	pSmad1	8	9	12	13
BMP-2 stimulates bone or tooth mineralization via the canonical BMP pathway [ XREF_BIBR - XREF_BIBR ] ; SMAD 1 , 5 , and presumably 8 , propagate BMP signals and are structurally related to Mad that acts downstream of Dpp , a BMP homolog in Drosophila [ XREF_BIBR ] .	BMP-2 stimulates bone or tooth mineralization via the canonical BMP pathway [XREF_BIBR - XREF_BIBR]; SMAD 1, 5, and presumably 8, propagate BMP signals and are structurally related to Mad that acts downstream of Dpp, a BMP homolog in Drosophila [XREF_BIBR].	0	32	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	SMAD 1	SMAD 1	SMAD 1	0	1	17	19
Senescence was bypassed in Ras activated cells when Bmp2 and Smad1 signal was blocked by Bmp2 knockdown , Smad6 induction , or Noggin induction .	Senescence was bypassed in Ras activated cells when Bmp2 and Smad1 signal was blocked by Bmp2 knockdown, Smad6 induction, or Noggin induction.	8	16	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Bmp2	Bmp2	Bmp2	Smad1	Smad1	Smad1	15	16	10	11
BMP2 activates pro oncogenic pathways ( e.g ., phosphoinositide-3 kinase ( PI3K )/mammalian target of rapamycin ( mTOR ) ; SMAD1 , 5/DNA binding protein inhibitor ( ID )-1) and promotes lung tumor growth in mice .	BMP2 activates pro oncogenic pathways (e.g., phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR); SMAD1, 5/DNA binding protein inhibitor (ID)-1) and promotes lung tumor growth in mice.	0	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP2	BMP2	BMP2	SMAD1	SMAD1	SMAD1	0	1	20	21
In cardiac development , a SMAD1 and NKX2 -5 negative feedback loop induced by BMP2 is required for progenitor specification XREF_BIBR .	In cardiac development, a SMAD1 and NKX2 -5 negative feedback loop induced by BMP2 is required for progenitor specification XREF_BIBR.	4	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	SMAD1	SMAD1	SMAD1	14	15	5	6
SVAK-3 , an LMP-1 mimetic compound , potentiates BMP-2 induced Smad1 driven luciferase reporter activity .	SVAK-3, an LMP-1 mimetic compound, potentiates BMP-2 induced Smad1 driven luciferase reporter activity.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad1	Smad1	Smad1	8	9	10	11
Indeed , transcriptional regulation of these genes by pSMAD1 is necessary for sciatic nerve regeneration 119 , and pSMAD1 activation by bone morphogenetic protein 2 ( BMP2 ) and/or BMP4 is sufficient to promote axon growth in DRG neurons in vitro 117 .	Indeed, transcriptional regulation of these genes by pSMAD1 is necessary for sciatic nerve regeneration 119, and pSMAD1 activation by bone morphogenetic protein 2 (BMP2) and/or BMP4 is sufficient to promote axon growth in DRG neurons in vitro 117.	18	25	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	bone morphogenetic protein 2	bone morphogenetic protein 2	bone morphogenetic protein 2	pSMAD1	pSMAD1	pSMAD1	21	25	18	19
Here , we demonstrate that BMP-2 , -5 , and -7 stimulate receptor activated Smad1 , 5 , and 8 , which in turn causes oligomerization of Smad4 in the nucleus .	Here, we demonstrate that BMP-2, -5, and -7 stimulate receptor activated Smad1, 5, and 8, which in turn causes oligomerization of Smad4 in the nucleus.	5	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad1	Smad1	Smad1	5	6	14	15
Interestingly , SMAD1 ,5,8 activation elicited by BMP6 and BMP7 , but not by BMP2 and BMP4 , was preserved even under the exposure of a high concentration of estradiol .	Interestingly, SMAD1,5,8 activation elicited by BMP6 and BMP7, but not by BMP2 and BMP4, was preserved even under the exposure of a high concentration of estradiol.	2	16	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	SMAD1	SMAD1	SMAD1	14	15	2	3
Flow cytometry analysis after treatment of CD90 +/CD29 +/Sca1+ murine MSC cells also showed that treatment with FTY720 enhanced BMP-2 induced smad-1 activity ( as measured by phospho-smad-1 events ) ( XREF_FIG ) .	Flow cytometry analysis after treatment of CD90 +/CD29 +/Sca1+ murine MSC cells also showed that treatment with FTY720 enhanced BMP-2 induced smad-1 activity (as measured by phospho-smad-1 events) (XREF_FIG).	19	22	induced	Positive_early_activation	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	smad-1	smad-1	smad-1	19	20	21	22
Mechanistically , YAP was activated by BMP2 , and the active and nuclear YAP was crucial for BMP2 induction and stabilization of SMAD1 and astrocytic differentiation .	Mechanistically, YAP was activated by BMP2, and the active and nuclear YAP was crucial for BMP2 induction and stabilization of SMAD1 and astrocytic differentiation.	17	25	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	SMAD1	SMAD1	SMAD1	17	18	22	23
BMP2 and BMP4 activate Smad 1 , 5 and 8 , which in turn form a complex with phosphorylated Smad4 to activate down-stream targets .	BMP2 and BMP4 activate Smad 1, 5 and 8, which in turn form a complex with phosphorylated Smad4 to activate down-stream targets.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad 1	Smad 1	Smad 1	0	1	4	6
Because BMP-2 mediates Smad1 activation in human aortic and umbilical venous ECs , we reasoned that in hPAECs , BMP-2 regulates Dvl activity via Smad1 .	Because BMP-2 mediates Smad1 activation in human aortic and umbilical venous ECs, we reasoned that in hPAECs, BMP-2 regulates Dvl activity via Smad1.	1	4	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad1	Smad1	Smad1	1	2	3	4
To test whether Smad-1 signaling is responsible for BMP-2 regulation of OA expression , osteoblast cultures were transfected with Smad1 siRNA , treated with 50 ng/ml of BMP-2 and analyzed by Western blot .	To test whether Smad-1 signaling is responsible for BMP-2 regulation of OA expression, osteoblast cultures were transfected with Smad1 siRNA, treated with 50 ng/ml of BMP-2 and analyzed by Western blot.	19	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	BMP-2	BMP-2	BMP-2	Smad1	Smad1	Smad1	27	28	19	20
Smad1 , a Smad species that is activated by BMP2 , barely interacted with NIC , but did form a complex with NIC in the simultaneous presence of the coactivators P/CAF and p300 .	Smad1, a Smad species that is activated by BMP2, barely interacted with NIC, but did form a complex with NIC in the simultaneous presence of the coactivators P/CAF and p300.	0	18	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	9	10	0	1
For example , BMP2 promotes the osteogenic program by inducing Smad1 and Smad5 that together with Smad4 can interact with Runx2 to control BMP2 dependent targets [ XREF_BIBR ] .	For example, BMP2 promotes the osteogenic program by inducing Smad1 and Smad5 that together with Smad4 can interact with Runx2 to control BMP2 dependent targets [XREF_BIBR].	3	22	promotes	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	BMP2	BMP2	bmp2	Smad1	Smad1 and Smad5 that together with Smad4 can interact with Runx2	smad1	3	4	10	11
Western blot analysis ( XREF_FIG ) shows that smad-1 phosphorylation in BMSCs increases when treated with FTY720 compared to BMP-2 .	Western blot analysis (XREF_FIG) shows that smad-1 phosphorylation in BMSCs increases when treated with FTY720 compared to BMP-2.	8	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	smad-1	smad-1	smad-1	19	20	8	9
BMP-2 induced strong nuclear accumulation of Smad1 , which was significantly decreased in the presence of dynasore ( XREF_FIG ) .	BMP-2 induced strong nuclear accumulation of Smad1, which was significantly decreased in the presence of dynasore (XREF_FIG).	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad1	Smad1	Smad1	0	1	6	7
Here we found that LIF induces expression of BMP2 via STAT3 activation and leads to the consequent activation of Smad1 to efficiently promote astrogliogenic differentiation of NECs .	Here we found that LIF induces expression of BMP2 via STAT3 activation and leads to the consequent activation of Smad1 to efficiently promote astrogliogenic differentiation of NECs.	4	20	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	BMP2	LIF induces expression of BMP2	bmp2	Smad1	Smad1	smad1	8	9	19	20
It seems unlikely BMP-2 or BMP-4 activates the Smad molecules of TGF-beta signal downstream ( Smad2 and Smad3 ) since BMP-2 or BMP-4 usually activates Smad1 , 5 and 8 .	It seems unlikely BMP-2 or BMP-4 activates the Smad molecules of TGF-beta signal downstream (Smad2 and Smad3) since BMP-2 or BMP-4 usually activates Smad1, 5 and 8.	20	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad1	Smad1	Smad1	20	21	25	26
Both BMP-2 and SB431542 were found to stimulate pSMAD1 and we also observed a non canonical repression of pSMAD2 .	Both BMP-2 and SB431542 were found to stimulate pSMAD1 and we also observed a non canonical repression of pSMAD2.	0	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	pSMAD1	pSMAD1	pSMAD1	1	2	8	9
We evaluated the effects of these mutant receptors on Smad1 nuclear migration by immunofluorescence in 2T3 cells that had been treated with BMP2 for 6 h.	We evaluated the effects of these mutant receptors on Smad1 nuclear migration by immunofluorescence in 2T3 cells that had been treated with BMP2 for 6 h.	9	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	22	23	9	10
When 20 nM Noggin was added to a 10 nM BMP2 treated C2C12 cell culture , the SMAD-1 signal index induced by BMP2 was about 50 % decreased and similarly , was approximately 59 % decreased by treatment of 20 nM BMPR1a-ECD .	When 20 nM Noggin was added to a 10 nM BMP2 treated C2C12 cell culture, the SMAD-1 signal index induced by BMP2 was about 50% decreased and similarly, was approximately 59% decreased by treatment of 20 nM BMPR1a-ECD.	17	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	SMAD-1	SMAD-1	SMAD-1	22	23	17	18
These findings suggest that the ERK1/2 pathway downstream of LIF is involved in sustained phosphorylation and activation of Smad1 by BMP2 and provide a possible mechanism for cooperation between intracellular signals activated by LIF and BMP2 in protection against DOX induced injury of cardiomyocytes .	These findings suggest that the ERK1/2 pathway downstream of LIF is involved in sustained phosphorylation and activation of Smad1 by BMP2 and provide a possible mechanism for cooperation between intracellular signals activated by LIF and BMP2 in protection against DOX induced injury of cardiomyocytes.	11	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	20	21	18	19
None of the experimental groups demonstrated increased expression of osteopontin or Smad1 , and only cells treated with concurrent administration of BMP-2 and BMP-7 increased Smad5 expression .	None of the experimental groups demonstrated increased expression of osteopontin or Smad1, and only cells treated with concurrent administration of BMP-2 and BMP-7 increased Smad5 expression.	7	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad1	Smad1	Smad1	21	22	11	12
These alterations seem to affect the dynamics and amplitude of BMP2 induced Smad1 reactivation .	These alterations seem to affect the dynamics and amplitude of BMP2 induced Smad1 reactivation.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	10	11	12	13
Evaluation of the gene expressions of the SMAD family members 1 , 5 , and 8 revealed that SMAD1 was significantly increased after 24h by 20ng/mL BMP2 .	Evaluation of the gene expressions of the SMAD family members 1, 5, and 8 revealed that SMAD1 was significantly increased after 24h by 20ng/mL BMP2.	18	27	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	SMAD1	SMAD1	SMAD1	26	27	18	19
Transcription factors STAT3 and Smad1 , activated by leukemia inhibitory factor ( LIF ) and bone morphogenetic protein 2 ( BMP2 ) , respectively , form a complex with the coactivator p300 to synergistically induce astrocytes from neuroepithelial cells ( NECs ) ( K. Nakashima , M. Yanagisawa , H. Arakawa , N. Kimura , T. Hisatsune , M. Kawabata , K. Miyazono , and T. Taga , Science 284:479-482, 1999 ) .	Transcription factors STAT3 and Smad1, activated by leukemia inhibitory factor (LIF) and bone morphogenetic protein 2 (BMP2), respectively, form a complex with the coactivator p300 to synergistically induce astrocytes from neuroepithelial cells (NECs) (K. Nakashima, M. Yanagisawa, H. Arakawa, N. Kimura, T. Hisatsune, M. Kawabata, K. Miyazono, and T. Taga, Science 284:479-482, 1999).	1	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	bone morphogenetic protein 2	bone morphogenetic protein 2	bone morphogenetic protein 2	Smad1	Smad1	Smad1	15	19	4	5
BMP2 supplementation increased Smad1 signaling in both species .	BMP2 supplementation increased Smad1 signaling in both species.	0	4	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	0	1	3	4
As shown in XREF_FIG , BMP-2 induced strong nuclear accumulation of Smad1 .	As shown in XREF_FIG, BMP-2 induced strong nuclear accumulation of Smad1.	5	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad1	Smad1	Smad1	5	6	11	12
This suggests that BMP2 induces Smad1 migration from cytoplasm towards nuclei .	This suggests that BMP2 induces Smad1 migration from cytoplasm towards nuclei.	3	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	3	4	5	6
XREF_FIG depicts that BMP2 directly activates Smad1 , which in turn makes a complex with CBP and p300 XREF_BIBR XREF_BIBR .	XREF_FIG depicts that BMP2 directly activates Smad1, which in turn makes a complex with CBP and p300 XREF_BIBR XREF_BIBR.	3	11	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	3	4	6	7
We found that BMP-2 induced Smad1 activation , thereby influencing the localization of VDR in the nucleus in the presence of 1,25 ( OH ) 2D3 and resulting in increased RANKL mRNA expression .	We found that BMP-2 induced Smad1 activation, thereby influencing the localization of VDR in the nucleus in the presence of 1,25 (OH) 2D3 and resulting in increased RANKL mRNA expression.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad1	Smad1	Smad1	3	4	5	6
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Nkx2.5 represses BMP2 activated Smad1 signaling to inhibit differentiation .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Nkx2.5 represses BMP2 activated Smad1 signaling to inhibit differentiation.	8	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	9	10	11	12
In the wells for the empty vector , dnBMPR-II , and dnActR-IIB , the intensity of Smad1 fluorescence was much higher in the nuclei than in the cytoplasm , indicating that stimulation with BMP2 induced Smad1 nuclear translocation in these cells ( XREF_FIG ) .	In the wells for the empty vector, dnBMPR-II, and dnActR-IIB, the intensity of Smad1 fluorescence was much higher in the nuclei than in the cytoplasm, indicating that stimulation with BMP2 induced Smad1 nuclear translocation in these cells (XREF_FIG).	31	37	induced	Positive_early_activation	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	33	34	35	36
To verify that SMAD3 , but not SMAD1 , was involved in miR-140 regulation , the cells were treated with BMP2 ( 10ng/ml ) ; rsmiR-140 activity was not affected by this factor ( data not shown ) .	To verify that SMAD3, but not SMAD1, was involved in miR-140 regulation, the cells were treated with BMP2 (10ng/ml); rsmiR-140 activity was not affected by this factor (data not shown).	3	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	SMAD1	SMAD1	SMAD1	20	21	7	8
Conversely , overexpression of the constitutive-active form of MEK1 increased BMP2 induced phosphoration of Smad1 without additional LIF .	Conversely, overexpression of the constitutive-active form of MEK1 increased BMP2 induced phosphoration of Smad1 without additional LIF.	10	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	10	11	14	15
To determine the compartment of LANA-Smad1 interaction , 293T cells were transfected with LANA and Smad1 , then treated with BMP2 and harvested for cell fraction .	To determine the compartment of LANA-Smad1 interaction, 293T cells were transfected with LANA and Smad1, then treated with BMP2 and harvested for cell fraction.	11	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	20	21	15	16
Noggin or BMPR1a-ECD protein efficiently inhibits the SMAD1 signal triggered by BMP2 ligand in a concentration dependent manner .	Noggin or BMPR1a-ECD protein efficiently inhibits the SMAD1 signal triggered by BMP2 ligand in a concentration dependent manner.	7	12	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	SMAD1	SMAD1	SMAD1	11	12	7	8
BMP-2 primarily promotes osteoblast differentiation and mineralization by binding to its specific receptors BMPRII and BMPRI to activate Smad1/5/8 and Smad4 to further transactivate its downstream target genes .	BMP-2 primarily promotes osteoblast differentiation and mineralization by binding to its specific receptors BMPRII and BMPRI to activate Smad1/5/8 and Smad4 to further transactivate its downstream target genes.	0	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	BMPRII	BMPRII	BMPRII	0	1	13	14
GDF5 and BMP2 stimulate the interaction of BMPR-2 with XIAP thereby reducing the ubiquitination of XIAP , which results in enhanced protein stability .	GDF5 and BMP2 stimulate the interaction of BMPR-2 with XIAP thereby reducing the ubiquitination of XIAP, which results in enhanced protein stability.	0	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	BMPR-2	BMPR-2	BMPR-2	2	3	7	8
Notably , the activation of BMPRII by BMP-2 is required for modulation of Smad activation by NF-kappaB in PC cells .	Notably, the activation of BMPRII by BMP-2 is required for modulation of Smad activation by NF-kappaB in PC cells.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	BMPRII	BMPRII	BMPRII	7	8	5	6
BMP2 mediated BMPR2 signaling requires both canonical and non canonical Wnt pathways .	BMP2 mediated BMPR2 signaling requires both canonical and non canonical Wnt pathways.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	BMPR2	BMPR2	BMPR2	0	1	2	3
Remarkably , BMP-2 treatment , that inhibits neurite outgrowth , concomitantly up-regulates BMPRII .	Remarkably, BMP-2 treatment, that inhibits neurite outgrowth, concomitantly up-regulates BMPRII.	2	13	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	BMPRII	BMPRII	BMPRII	2	3	12	13
BMP-2 promotes motility of BMPRII deficient hPAECs by pSmad3 activation via ActRIIa , a member of the TGF-beta receptor superfamily .	BMP-2 promotes motility of BMPRII deficient hPAECs by pSmad3 activation via ActRIIa, a member of the TGF-beta receptor superfamily.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	BMPRII	BMPRII	BMPRII	0	1	4	5
The data suggest that BMP-2 activation of BMPRII is required for NF-kappaB mediated phosphorylation of Smad-1/5/8 in C4-2B cells .	The data suggest that BMP-2 activation of BMPRII is required for NF-kappaB mediated phosphorylation of Smad-1/5/8 in C4-2B cells.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	BMPRII	BMPRII	BMPRII	4	5	7	8
Upon BMP4 stimulation of BMPR2 , Trb3 dissociates from the terminal domain of the receptor and binds to Smurf1 inducing degradation of Smurf1 via the ubiquitin-proteasome pathway .	Upon BMP4 stimulation of BMPR2, Trb3 dissociates from the terminal domain of the receptor and binds to Smurf1 inducing degradation of Smurf1 via the ubiquitin-proteasome pathway.	1	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BMP4	BMP4	BMP4	BMPR2	BMPR2	BMPR2	1	2	4	5
BMPR-2 is activated by BMP-4 , as well as -2 and -7 .	BMPR-2 is activated by BMP-4, as well as -2 and -7.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BMP-4	BMP-4	BMP-4	BMPR-2	BMPR-2	BMPR-2	4	5	0	1
Meantime , to determine whether short period of BMP4 treatment alone could induce BMPRII protein expression changes , we also detect the protein expression of BMPRII after BMP4 exposure at various time points from 5 min to 30 min .	Meantime, to determine whether short period of BMP4 treatment alone could induce BMPRII protein expression changes, we also detect the protein expression of BMPRII after BMP4 exposure at various time points from 5 min to 30 min.	8	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP4	BMP4	BMP4	BMPRII protein	BMPRII protein	BMPRII protein	8	9	13	15
In addition , bone morphogenetic protein 4 ( BMP4 ) expression in the developing extraembryonic mesoderm outgrowth from the epiblast that occurs between trophectoderm and endoderm stimulates BMPR2 in trophectoderm ( absent in epiblast and hypoblast ) .	In addition, bone morphogenetic protein 4 (BMP4) expression in the developing extraembryonic mesoderm outgrowth from the epiblast that occurs between trophectoderm and endoderm stimulates BMPR2 in trophectoderm (absent in epiblast and hypoblast).	8	29	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP4	BMP4) expression	bmp4	BMPR2	BMPR2	bmpr2	8	9	27	28
These findings show that Acvr2a is not required for BMP4 signaling in Bmpr2 Deltatd/+ or Bmpr2 Deltatd and del PaSMCs .	These findings show that Acvr2a is not required for BMP4 signaling in Bmpr2 Deltatd/+ or Bmpr2 Deltatd and del PaSMCs.	9	13	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BMP4	BMP4	BMP4	Bmpr2	Bmpr2	Bmpr2	9	10	12	13
As expected , BMPR-2 was up-regulated in macrophage foam cells treated with BMP4 .	As expected, BMPR-2 was up-regulated in macrophage foam cells treated with BMP4.	3	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BMP4	BMP4	BMP4	BMPR-2	BMPR-2	BMPR-2	12	13	3	4
The polyubiquitin chains on RIP1 synthesized by cIAP1 and Ubc5c were not restricted to K48 or K63 of ubiquitin , as both K48R and K63R mutants of ubiquitin were capable of supporting RIP1 polyubiquitination ( XREF_FIG ) .	The polyubiquitin chains on RIP1 synthesized by cIAP1 and Ubc5c were not restricted to K48 or K63 of ubiquitin, as both K48R and K63R mutants of ubiquitin were capable of supporting RIP1 polyubiquitination (XREF_FIG).	2	9	synthesized	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cIAP1	cIAP1	cIAP1	RIP1	RIP1	RIP1	7	8	4	5
Although the mechanism remains to be elucidated , UBC5 and cIAP1 also support conjugation of RIP1 with non K63 polyubiquitin chains , which results in IKKbeta activation XREF_BIBR .	Although the mechanism remains to be elucidated, UBC5 and cIAP1 also support conjugation of RIP1 with non K63 polyubiquitin chains, which results in IKKbeta activation XREF_BIBR.	8	16	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cIAP1	cIAP1	cIAP1	RIP1	RIP1	RIP1	10	11	15	16
In particular , cIAP-1 and cIAP-2 have been shown to ubiquitinate and activate RIP1 , promoting cancer cell survival by sustained activation of RIP1 mediated pro survival signaling pathways [ XREF_BIBR ] .	In particular, cIAP-1 and cIAP-2 have been shown to ubiquitinate and activate RIP1, promoting cancer cell survival by sustained activation of RIP1 mediated pro survival signaling pathways [XREF_BIBR].	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cIAP-1	cIAP-1	cIAP-1	RIP1	RIP1	RIP1	3	4	13	14
This is not unexpected because we induced with an intrinsic inducer of apoptosis , staurosporin , as opposed to the extrinsic inducer like TNFalpha which is needed to activate the TNFalpha pathway and promote cIAP1 mediated ubiqutination of RIP1 and TRAF2 .	This is not unexpected because we induced with an intrinsic inducer of apoptosis, staurosporin, as opposed to the extrinsic inducer like TNFalpha which is needed to activate the TNFalpha pathway and promote cIAP1 mediated ubiqutination of RIP1 and TRAF2.	33	40	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cIAP1	cIAP1	cIAP1	RIP1	RIP1	RIP1	34	35	38	39
Moreover , inhibition of Rip1 and Rip3 activation by cIAP1 and cIAP2 limits macrophage necrosis XREF_BIBR .	Moreover, inhibition of Rip1 and Rip3 activation by cIAP1 and cIAP2 limits macrophage necrosis XREF_BIBR.	4	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	cIAP1	cIAP1	cIAP1	Rip1	Rip1	Rip1	9	10	4	5
ALK1 can also be activated by BMP-9 or BMP-10 to signal via Smad1/5/8 .	ALK1 can also be activated by BMP-9 or BMP-10 to signal via Smad1/5/8.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BMP-10	BMP-10	BMP-10	ALK1	ALK1	ALK1	8	9	0	1
For example , Alk1 is preferentially activated by BMP9 and BMP10 in endothelial cells ; GDF5 signals mainly through Bmpr1b and not Bmpr1a ; and BMP2/4 and BMP6/7 signal through distinct receptors to induce mesenchymal stem cell differentiation .	For example, Alk1 is preferentially activated by BMP9 and BMP10 in endothelial cells; GDF5 signals mainly through Bmpr1b and not Bmpr1a; and BMP2/4 and BMP6/7 signal through distinct receptors to induce mesenchymal stem cell differentiation.	3	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BMP10	BMP10	BMP10	Alk1	Alk1	Alk1	10	11	3	4
Biochemical studies showed that BMP9 and BMP10 activate ALK1 , inducing phosphorylation of the intracellular signal transducing proteins SMAD1 , SMAD5 , and SMAD8 .	Biochemical studies showed that BMP9 and BMP10 activate ALK1, inducing phosphorylation of the intracellular signal transducing proteins SMAD1, SMAD5, and SMAD8.	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP10	BMP10	BMP10	ALK1	ALK1	ALK1	6	7	8	9
Notch signaling was also activated by bone morphogenic protein-10 ( BMP10 ) , which is known to activate ALK1 and ENG signaling , but was not activated by other vasoactive factors , such as bone morphogenic protein 4 ( BMP4 ) , transforming growth factor-beta ( TGF-beta ) , and vascular endothelial growth factor ( VEGF ) ( XREF_FIG C ) .	Notch signaling was also activated by bone morphogenic protein-10 (BMP10), which is known to activate ALK1 and ENG signaling, but was not activated by other vasoactive factors, such as bone morphogenic protein 4 (BMP4), transforming growth factor-beta (TGF-beta), and vascular endothelial growth factor (VEGF) (XREF_FIG C).	6	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP10	BMP10	BMP10	ALK1	ALK1	ALK1	10	11	18	19
49 As BMP9 and BMP10 both activate ALK1 , this may represent temporally important roles of the ligands .	49 As BMP9 and BMP10 both activate ALK1, this may represent temporally important roles of the ligands.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP10	BMP10	BMP10	ALK1	ALK1	ALK1	4	5	7	8
Recent studies have shown that SMAD dependent signaling in endothelial cells is stimulated by BMP9 and BMP10 ligands activating the orphan ALK1 receptor [ XREF_BIBR , XREF_BIBR ] .	Recent studies have shown that SMAD dependent signaling in endothelial cells is stimulated by BMP9 and BMP10 ligands activating the orphan ALK1 receptor [XREF_BIBR, XREF_BIBR].	12	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP10	BMP10	BMP10	ALK1	ALK1	ALK1	16	17	21	22
This signaling pathway is similar to that of BMP-2 and BMP-4 whereby after binding to BMPR-II , the type I receptor ALK3 or ALK6 activate the Smad1 pathway .	This signaling pathway is similar to that of BMP-2 and BMP-4 whereby after binding to BMPR-II, the type I receptor ALK3 or ALK6 activate the Smad1 pathway.	17	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK3	ALK3	ALK3	Smad1	Smad1	Smad1	21	22	26	27
Based on our in vitro findings , we propose that expression and secretion of BMP4 by quiescent muscle SP cells ( XREF_FIG ) induces proliferation of BMPR1a + Myf5 high muscle MP cells ( XREF_FIG ) .	Based on our in vitro findings, we propose that expression and secretion of BMP4 by quiescent muscle SP cells (XREF_FIG) induces proliferation of BMPR1a + Myf5 high muscle MP cells (XREF_FIG).	10	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP4	expression and secretion of BMP4	bmp4	BMPR1a	BMPR1a	bmpr1a	14	15	26	27
These results demonstrate that BMP4 induces proliferation of BMPR1a + cells , whereas it has no effect on BMPR1a - cells , suggesting that the proliferation induced by BMP4 is mediated via BMPR1a .	These results demonstrate that BMP4 induces proliferation of BMPR1a + cells, whereas it has no effect on BMPR1a - cells, suggesting that the proliferation induced by BMP4 is mediated via BMPR1a.	4	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP4	BMP4	BMP4	BMPR1a	BMPR1a	BMPR1a	4	5	8	9
BMP4 induces proliferation of BMPR1a + cells in human skeletal muscle .	BMP4 induces proliferation of BMPR1a + cells in human skeletal muscle.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP4	BMP4	BMP4	BMPR1a	BMPR1a	BMPR1a	0	1	4	5
Our data demonstrate that BMP4 specifically stimulates proliferation of BMPR1a + cells , whereas it has no effect on BMPR1a - cells , suggesting that BMP4 induced proliferation is likely mediated by the BMPR1a receptor .	Our data demonstrate that BMP4 specifically stimulates proliferation of BMPR1a + cells, whereas it has no effect on BMPR1a - cells, suggesting that BMP4 induced proliferation is likely mediated by the BMPR1a receptor.	4	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP4	BMP4	BMP4	BMPR1a	BMPR1a	BMPR1a	4	5	9	10
Functional studies demonstrate that BMP4 expressed by muscle SP cells induces proliferation of BMP receptor 1a ( BMPR1a )-positive MP cells , and this effect can be reversed by Gremlin .	Functional studies demonstrate that BMP4 expressed by muscle SP cells induces proliferation of BMP receptor 1a (BMPR1a)-positive MP cells, and this effect can be reversed by Gremlin.	4	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP4	BMP4 expressed	bmp4	BMPR1a	BMPR1a	bmpr1a	4	5	17	18
To confirm the direct link between BMP4 , BMPR1A and the increase of DeltaNp73 expression , KG1A cells were treated with BMP4 in the presence of either an anti-BMPR1A blocking antibody or the chemical BMPR1 inhibitor , LDN-193189 .	To confirm the direct link between BMP4, BMPR1A and the increase of DeltaNp73 expression, KG1A cells were treated with BMP4 in the presence of either an anti-BMPR1A blocking antibody or the chemical BMPR1 inhibitor, LDN-193189.	4	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BMP4	BMP4	BMP4	BMPR1A	BMPR1A	BMPR1A	21	22	8	9
cIAP2 contains an E3 ubiquitin ligase domain and can target RIP1 for K63 linked ubiquitination [ XREF_BIBR ] ( XREF_FIG ) .	cIAP2 contains an E3 ubiquitin ligase domain and can target RIP1 for K63 linked ubiquitination [XREF_BIBR] (XREF_FIG).	0	11	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cIAP2	cIAP2	cIAP2	RIP1	RIP1	RIP1	0	1	10	11
In contrast , induced expression of FADD downregulates the mRNA levels of cIAP2 and reduces the degradation of RIP1 , which indicates that FADD protects RIP1 even in the presence of TNF-alpha with subsequent activation of procaspases 8 ( XREF_FIG and XREF_FIG ) .	In contrast, induced expression of FADD downregulates the mRNA levels of cIAP2 and reduces the degradation of RIP1, which indicates that FADD protects RIP1 even in the presence of TNF-alpha with subsequent activation of procaspases 8 (XREF_FIG and XREF_FIG).	4	21	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	cIAP2	expression of FADD downregulates the mRNA levels of cIAP2	ciap2	RIP1	RIP1	rip1	12	13	18	19
Moreover , the widespread expression of BMP2 in cells of skeletal , neurological , cardiac , as well as other tissues supports the pleiotrophic effects of BMP2 haploinsufficiency .	Moreover, the widespread expression of BMP2 in cells of skeletal, neurological, cardiac, as well as other tissues supports the pleiotrophic effects of BMP2 haploinsufficiency.	4	27	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	expression of BMP2	bmp2	BMP2	BMP2	bmp2	6	7	26	27
Moreover , the widespread expression of BMP2 in cells of skeletal , neurological , cardiac , and other tissues supports the pleiotropic effects of BMP2 haploinsufficiency .	Moreover, the widespread expression of BMP2 in cells of skeletal, neurological, cardiac, and other tissues supports the pleiotropic effects of BMP2 haploinsufficiency.	4	25	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	expression of BMP2	bmp2	BMP2	BMP2	bmp2	6	7	24	25
However , Noggin drastically increased the levels of BMP2 in the supernatant , supporting that Noggin can remove BMP2 from Alk3 ( XREF_FIG ) .	However, Noggin drastically increased the levels of BMP2 in the supernatant, supporting that Noggin can remove BMP2 from Alk3 (XREF_FIG).	2	19	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	Noggin drastically increased the levels of BMP2	bmp2	BMP2	BMP2	bmp2	8	9	18	19
These results showed that myocardial expression of Bmp2 rescues AVC specification of Bmp2 deficient mice but leads to lethality at E15.5 .	These results showed that myocardial expression of Bmp2 rescues AVC specification of Bmp2 deficient mice but leads to lethality at E15.5.	5	14	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bmp2	expression of Bmp2	bmp2	Bmp2	Bmp2	bmp2	7	8	12	13
However , addition of increasing amounts of BMP2 increased pSMAD 1/5/8 levels ( XREF_FIG , compare Ad-T , Ad-T +20- or Ad-T +80 ng/mL BMP2 ) .	However, addition of increasing amounts of BMP2 increased pSMAD 1/5/8 levels (XREF_FIG, compare Ad-T, Ad-T +20- or Ad-T +80 ng/mL BMP2).	5	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	amounts of BMP2	bmp2	BMP2	BMP2	bmp2	7	8	24	25
It has been reported that hypoxia induces BMP-2 expression in osteoblasts and hypoxia and VEGF upregulate BMP-2 production in microvascular endothelial cells .	It has been reported that hypoxia induces BMP-2 expression in osteoblasts and hypoxia and VEGF upregulate BMP-2 production in microvascular endothelial cells.	7	17	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2 expression	bmp-2	BMP-2	BMP-2	bmp-2	7	8	16	17
Thus , we suspect that the blockade of RANKL induced BMP-2 secretion by TRAIL may be causing an accumulation of BMP-2 within the cell .	Thus, we suspect that the blockade of RANKL induced BMP-2 secretion by TRAIL may be causing an accumulation of BMP-2 within the cell.	8	21	causing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP-2	RANKL induced BMP-2	bmp-2	BMP-2	BMP-2	bmp-2	10	11	20	21
Among them , only Smad5 is phosphorylated in vivo and in primary cultures treated with Bmp2 , and overexpression of Smad5 is sufficient to induce granule cell differentiation in the presence of Shh .	Among them, only Smad5 is phosphorylated in vivo and in primary cultures treated with Bmp2, and overexpression of Smad5 is sufficient to induce granule cell differentiation in the presence of Shh.	3	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Bmp2	Bmp2	Bmp2	Smad5	Smad5	Smad5	15	16	4	5
In the initial phase of osteoblastic differentiation ( differentiation of MSCs to osteoblast progenitor cells ) , Runx2 inhibited differentiation of MSCs to types of cells other than osteoblasts , which required coordinated action between Runx2 and BMP2 induced Smad5 [ XREF_BIBR ] .	In the initial phase of osteoblastic differentiation (differentiation of MSCs to osteoblast progenitor cells), Runx2 inhibited differentiation of MSCs to types of cells other than osteoblasts, which required coordinated action between Runx2 and BMP2 induced Smad5 [XREF_BIBR].	33	40	induced	Positive_early_activation	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad5	Smad5	Smad5	37	38	39	40
Nuclear p-SMAD5 level was also highest in tumour tissue from mice treated with recombinant BMP2 and lowest in tumour tissue from mice treated with DM .	Nuclear p-SMAD5 level was also highest in tumour tissue from mice treated with recombinant BMP2 and lowest in tumour tissue from mice treated with DM.	1	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	p-SMAD5	p-SMAD5	p-SMAD5	14	15	1	2
Furthermore , BMP-2 increased significantly Smad5 mRNA in the culture on day 3 , indicating BMP-2 involvement in the regulation of Smad5 mRNA expression .	Furthermore, BMP-2 increased significantly Smad5 mRNA in the culture on day 3, indicating BMP-2 involvement in the regulation of Smad5 mRNA expression.	2	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad5	Smad5	Smad5	2	3	5	6
In the initial phase of osteoblastic differentiation ( differentiation of MSCs to OB progenitor cells ) , Runx2 inhibited differentiation of MSCs to types of cells other than OBs , which required coordinated action between Runx2 and BMP2 induced Smad5 [ XREF_BIBR ] .	In the initial phase of osteoblastic differentiation (differentiation of MSCs to OB progenitor cells), Runx2 inhibited differentiation of MSCs to types of cells other than OBs, which required coordinated action between Runx2 and BMP2 induced Smad5 [XREF_BIBR].	33	40	induced	Positive_early_activation	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Smad5	Smad5	Smad5	37	38	39	40
By interacting with XIAP , survivin enhances XIAP stability .	By interacting with XIAP, survivin enhances XIAP stability.	5	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	survivin	survivin	survivin	XIAP	XIAP	XIAP	5	6	7	8
In addition , it was shown that in response to cell death stimuli , survivin associated with XIAP via the BIR domain to promote the stability of XIAP [ XREF_BIBR ] .	In addition, it was shown that in response to cell death stimuli, survivin associated with XIAP via the BIR domain to promote the stability of XIAP [XREF_BIBR].	12	29	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	survivin	survivin	survivin	XIAP	XIAP	XIAP	14	15	27	28
Therefore , presence of survivin may indirectly allow XIAP to function , ultimately leading to inhibition of apoptosis .	Therefore, presence of survivin may indirectly allow XIAP to function, ultimately leading to inhibition of apoptosis.	2	10	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	survivin	survivin	survivin	XIAP	XIAP	XIAP	4	5	8	9
In addition , survivin promotes by complexing XIAP invasion and migration of malignant cells via NF-kappaB pathways , apparently contributing to metastasis XREF_BIBR .	In addition, survivin promotes by complexing XIAP invasion and migration of malignant cells via NF-kappaB pathways, apparently contributing to metastasis XREF_BIBR.	3	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	survivin	survivin	survivin	XIAP	XIAP	XIAP	3	4	7	8
BMP2 , -4 and -7 specifically activate Alk3 ( BMPR1A ) and Alk6 ( BMPR1B ) type I receptors , while BMP6 and BMP7 ( but not BMP2 or -4 ) bind the ALK2 receptor [ XREF_BIBR , XREF_BIBR ] .	BMP2, -4 and -7 specifically activate Alk3 (BMPR1A) and Alk6 (BMPR1B) type I receptors, while BMP6 and BMP7 (but not BMP2 or -4) bind the ALK2 receptor [XREF_BIBR, XREF_BIBR].	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	Alk3	Alk3	Alk3	0	1	7	8
Thus AVE produced BMP2 could potentially signal to BMPR1A on epiblast derivatives in any of these adjoining cell layers ; ( all cell types in the layers portrayed in XREF_FIG are epiblast derived , except for the VE ) .	Thus AVE produced BMP2 could potentially signal to BMPR1A on epiblast derivatives in any of these adjoining cell layers; (all cell types in the layers portrayed in XREF_FIG are epiblast derived, except for the VE).	3	13	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	BMPR1A	BMPR1A	BMPR1A	3	4	8	9
XREF_BIBR , XREF_BIBR Under these conditions , addition of BMP2 or 4 , or heterologous expression of constitutively activated BMPR1A or B receptors leads to pronounced induction of a chondrogenic responsive reporter gene .	XREF_BIBR, XREF_BIBR Under these conditions, addition of BMP2 or 4, or heterologous expression of constitutively activated BMPR1A or B receptors leads to pronounced induction of a chondrogenic responsive reporter gene.	7	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP2	BMP2	BMP2	BMPR1A	BMPR1A	BMPR1A	9	10	19	20
On the other hand , BMP7 activates only ALK2 and the Smad1/5/8 pathway [ XREF_BIBR ] , suggesting that this may play a role in the inhibitory effects of this isoform on EndMT .	On the other hand, BMP7 activates only ALK2 and the Smad1/5/8 pathway [XREF_BIBR], suggesting that this may play a role in the inhibitory effects of this isoform on EndMT.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP7	BMP7	BMP7	ALK2	ALK2	ALK2	5	6	8	9
Activated ALK2 also induced the Tlx2 promoter in the absence of BMP7 .	Activated ALK2 also induced the Tlx2 promoter in the absence of BMP7.	0	12	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP7	BMP7	BMP7	ALK2	ALK2	ALK2	11	12	1	2
Bone morphogenetic protein-7 activates receptor BMPR2 in monocytes , which results in phosphorylation of R-SMAD1/5/8/and activation of down-stream mediators in the Smad pathway .	Bone morphogenetic protein-7 activates receptor BMPR2 in monocytes, which results in phosphorylation of R-SMAD1/5/8/and activation of down-stream mediators in the Smad pathway.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bone morphogenetic protein-7	Bone morphogenetic protein-7	Bone morphogenetic protein-7	BMPR2	BMPR2	BMPR2	0	3	5	6
It is interesting to note that BMP-7 induces a selective increase of BMP signalling components : BMPR-II , BMPR-Ib , and Smad8 .	It is interesting to note that BMP-7 induces a selective increase of BMP signalling components : BMPR-II, BMPR-Ib, and Smad8.	6	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-7	BMP-7	BMP-7	BMPR-II	BMPR-II	BMPR-II	6	7	16	17
Of note , following treatment with follistatin , an inhibitor of BMP-7 signal transduction , significant upregulation of BMPR2 on monocytes and M2 macrophages was abolished suggesting a direct relation between BMP-7 signaling and upregulation of BMPR2 .	Of note, following treatment with follistatin, an inhibitor of BMP-7 signal transduction, significant upregulation of BMPR2 on monocytes and M2 macrophages was abolished suggesting a direct relation between BMP-7 signaling and upregulation of BMPR2.	11	37	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-7	BMP-7	BMP-7	BMPR2	BMPR2	BMPR2	11	12	36	37
In contrast to TGF-beta1 , BMP-2 causes a strong and persistent activation of Smad1/5/8 , its target gene Id2 , and a weak prolonged activation of Smad2 , which is comparable to the effect obtained after treatment with 0.1 ng/ml TGF-beta1 .	In contrast to TGF-beta1, BMP-2 causes a strong and persistent activation of Smad1/5/8, its target gene Id2, and a weak prolonged activation of Smad2, which is comparable to the effect obtained after treatment with 0.1 ng/ml TGF-beta1.	5	30	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad2	Smad2	Smad2	5	6	26	27
XREF_BIBR , XREF_BIBR Taken together , in osteoblasts , ALK3 activates SOST and DKK1 , while both SOST and DKK1 inhibit canonical Wnt signaling and maintain the activity of Wnt and beta-catenin signaling at a certain level .	XREF_BIBR, XREF_BIBR Taken together, in osteoblasts, ALK3 activates SOST and DKK1, while both SOST and DKK1 inhibit canonical Wnt signaling and maintain the activity of Wnt and beta-catenin signaling at a certain level.	9	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK3	ALK3	ALK3	SOST	SOST	SOST	9	10	11	12
Moreover , expression of a constitutively active Bmpr1a transgene in mice resulted in the upregulation of both Dkk1 and Sost and partially rescued the Bmpr1a cKO bone phenotype .	Moreover, expression of a constitutively active Bmpr1a transgene in mice resulted in the upregulation of both Dkk1 and Sost and partially rescued the Bmpr1a cKO bone phenotype.	2	20	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Bmpr1a	expression of a constitutively active Bmpr1a	bmpr1a	Sost	Sost	sost	7	8	19	20
Huh-7 cells stably expressing shRNA targeting cIAP-1 , but not cIAP-2 , displayed enhanced sensitivity to PA mediated apoptosis .	Huh-7 cells stably expressing shRNA targeting cIAP-1, but not cIAP-2, displayed enhanced sensitivity to PA mediated apoptosis.	3	11	targeting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	cIAP-2	cIAP-2	cIAP-2	cIAP-1	cIAP-1	cIAP-1	10	11	6	7
We first asked whether BMPR1A biased BMP2 expression led to differential gene expression to BMPR1B biased .	We first asked whether BMPR1A biased BMP2 expression led to differential gene expression to BMPR1B biased.	4	15	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BMPR1A	BMPR1A	BMPR1A	BMPR1B	BMPR1B	BMPR1B	4	5	14	15
Next , we tested the ability of wild-type mouse ActRIIA and sh-AIIA-resistant ActRIIA mutant cDNAs to rescue BMP7 stimulated chemotaxis in ActRIIA Delta WEHI cells .	Next, we tested the ability of wild-type mouse ActRIIA and sh-AIIA-resistant ActRIIA mutant cDNAs to rescue BMP7 stimulated chemotaxis in ActRIIA Delta WEHI cells.	16	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP7	BMP7	BMP7	ActRIIA	ActRIIA	ActRIIA	17	18	21	22
In our systemic knockout mice utilizing inducible Cre , the cessation of Bmp7 expression at E12.5 permits the initial expansion of progenitor cells and enables us to observe the precocious differentiation of progenitor cells in the absence of Bmp7 .	In our systemic knockout mice utilizing inducible Cre, the cessation of Bmp7 expression at E12.5 permits the initial expansion of progenitor cells and enables us to observe the precocious differentiation of progenitor cells in the absence of Bmp7.	12	39	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bmp7	Bmp7 expression	bmp7	Bmp7	Bmp7	bmp7	12	13	38	39
However , our results showed that BMP10 signaling in E10.5 SM22alpha-Cre ; R26R ; Bmpr1a flox and flox heart sections was not affected by Bmpr1a deletion .	However, our results showed that BMP10 signaling in E10.5 SM22alpha-Cre; R26R; Bmpr1a flox and flox heart sections was not affected by Bmpr1a deletion.	6	15	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BMP10	BMP10	BMP10	Bmpr1a	Bmpr1a	Bmpr1a	6	7	14	15
Interaction of BVR with PKC-beta II as well as BVR mediated activation of PKC-beta II through phosphorylation is critical for its translocation to the membrane .	Interaction of BVR with PKC-beta II as well as BVR mediated activation of PKC-beta II through phosphorylation is critical for its translocation to the membrane.	9	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	BVR	BVR	BVR	PKC-beta	PKC-beta	PKC-beta	9	10	13	14
In addition to immunomodulatory treatments XREF_BIBR , new strategies are being considered based on the knowledge that the BRAF protein modulates the MEK signaling cascade downstream of EGFR .	In addition to immunomodulatory treatments XREF_BIBR, new strategies are being considered based on the knowledge that the BRAF protein modulates the MEK signaling cascade downstream of EGFR.	18	24	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	18	19	22	23
These resistant mechanisms include activation of alternative signaling pathways such as PI3K and AKT or reactivation of the MAPK pathway through a secondary mutation in NRAS , amplification of BRAF gene , activating mutations in MEK , over expression of MAP3K8 ( COT and Tp12 ) and continuous dimerization of truncated BRAF isoforms .	These resistant mechanisms include activation of alternative signaling pathways such as PI3K and AKT or reactivation of the MAPK pathway through a secondary mutation in NRAS, amplification of BRAF gene, activating mutations in MEK, over expression of MAP3K8 (COT and Tp12) and continuous dimerization of truncated BRAF isoforms.	29	36	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	29	30	35	36
Mutant-v-raf murine sarcoma viral oncogene homolog B1 ( BRAF ) is found in approximately 50 % of melanomas 1 and induces constituent MEK and extracellular signal regulated kinase ( ERK ) signaling in melanoma cells .	Mutant-v-raf murine sarcoma viral oncogene homolog B1 (BRAF) is found in approximately 50% of melanomas 1 and induces constituent MEK and extracellular signal regulated kinase (ERK) signaling in melanoma cells.	2	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	8	9	22	23
MAPK pathway targeting with inhibitors of BRAF ( vemurafenib , dabrafenib ) and/or MEK ( trametinib ) provide a therapeutic option for non resectable melanoma tumors driven by oncogenic BRAF kinase ( BRAF V600E ) .	MAPK pathway targeting with inhibitors of BRAF (vemurafenib, dabrafenib) and/or MEK (trametinib) provide a therapeutic option for non resectable melanoma tumors driven by oncogenic BRAF kinase (BRAF V600E).	1	30	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	29	30	13	14
By dimerizing with wild-type CRAF , kinase-dead forms of BRAF can activate MEK and subsequently ERK .	By dimerizing with wild-type CRAF, kinase-dead forms of BRAF can activate MEK and subsequently ERK.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	9	10	12	13
Trametinib is a highly potent and selective small-molecule inhibitor of the MEK kinase that is downstream of and activated by BRAF in the MAPK pathway .	Trametinib is a highly potent and selective small-molecule inhibitor of the MEK kinase that is downstream of and activated by BRAF in the MAPK pathway.	11	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	20	21	11	12
This may result from mutational activation of components of the downstream signaling pathways , such as PIK3CA or BRAF , that directly activate the PI3K and AKT and MEK and ERK pathways , respectively , or activation of another RTK that sustains downstream signaling despite inhibition of the oncogenic RTK .	This may result from mutational activation of components of the downstream signaling pathways, such as PIK3CA or BRAF, that directly activate the PI3K and AKT and MEK and ERK pathways, respectively, or activation of another RTK that sustains downstream signaling despite inhibition of the oncogenic RTK.	7	31	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	18	19	28	29
KI BRAF paradoxically activates MEK and ERK to levels higher than those in cells with WT BRAF via heterodimerization with CRAF ( Raf-1 ) [ XREF_BIBR - XREF_BIBR ] .	KI BRAF paradoxically activates MEK and ERK to levels higher than those in cells with WT BRAF via heterodimerization with CRAF (Raf-1) [XREF_BIBR - XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	1	2	4	5
Thus , it can activate BRAF , which activates MEK and consecutively ERK is activated .	Thus, it can activate BRAF, which activates MEK and consecutively ERK is activated.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	5	6	9	10
RAS mutations ( most frequently N-RAS ) are found in ATC with a variable frequency ranging from 8-60 % depending on the sample series [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] RAF proteins are direct effectors of RAS , and B-RAF is the strongest activator of MEK and the most commonly mutated of the RAF proteins [ XREF_BIBR ] .	RAS mutations (most frequently N-RAS) are found in ATC with a variable frequency ranging from 8-60% depending on the sample series [XREF_BIBR, XREF_BIBR, XREF_BIBR] RAF proteins are direct effectors of RAS, and B-RAF is the strongest activator of MEK and the most commonly mutated of the RAF proteins [XREF_BIBR].	40	51	is the strongest activator	Positive_activation_copula_1	Positive_activation	Positive_activation	B-RAF	B-RAF	B-RAF	MEK	MEK	MEK	40	41	46	47
For the BRaf-MEK inhibitor combination , the inhibitory activity of BRaf reduces the activation of MEK to complement the inhibitory activity of MEK inhibitor .	For the BRaf-MEK inhibitor combination, the inhibitory activity of BRaf reduces the activation of MEK to complement the inhibitory activity of MEK inhibitor.	8	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BRaf	BRaf	BRaf	MEK	MEK	MEK	10	11	15	16
Although it is clear that BRaf induces senescence in melanocytes by activating MEK and ERK , the downstream effectors of its cytostatic effect remain to be identified [ XREF_BIBR , XREF_BIBR ] .	Although it is clear that BRaf induces senescence in melanocytes by activating MEK and ERK, the downstream effectors of its cytostatic effect remain to be identified [XREF_BIBR, XREF_BIBR].	5	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRaf	BRaf	BRaf	MEK	MEK	MEK	5	6	12	13
In fact , in wild-type cells , BRAF and CRAF form homo- and heterodimers on RAS activation ; vemurafenib binding to one member of the dimer causes an allosteric transactivation of the drug-free protomer and activation of MEK and ERK .	In fact, in wild-type cells, BRAF and CRAF form homo- and heterodimers on RAS activation; vemurafenib binding to one member of the dimer causes an allosteric transactivation of the drug-free protomer and activation of MEK and ERK.	7	39	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	7	8	37	38
Additional studies are needed to delineate the relationships among intracellular Ca 2+ , Akt , B-Raf and cAMP dependent activation of the MEK and ERK pathways in PKD .	Additional studies are needed to delineate the relationships among intracellular Ca 2+, Akt, B-Raf and cAMP dependent activation of the MEK and ERK pathways in PKD.	13	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	B-Raf	B-Raf	B-Raf	MEK	MEK	MEK	15	16	22	23
Whereas BRAF kinase impairing mutations increase MEK activity by activating CRAF .	Whereas BRAF kinase impairing mutations increase MEK activity by activating CRAF.	1	7	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	1	2	6	7
Using a conditional knock-in mouse model , we show that endogenous expression of ( L597V ) Braf leads to approximately twofold elevated Braf kinase activity and weak activation of the Mek and Erk pathway .	Using a conditional knock-in mouse model, we show that endogenous expression of (L597V) Braf leads to approximately twofold elevated Braf kinase activity and weak activation of the Mek and Erk pathway.	11	33	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Braf	expression of (L597V) Braf	braf	Mek	Mek	mek	16	17	30	31
It has been hypothesized that B-RAF might be the main activator of MEK in various cell types .	It has been hypothesized that B-RAF might be the main activator of MEK in various cell types.	5	16	be the main activator	Positive_activation_copula_1	Positive_activation	Positive_activation	B-RAF	B-RAF	B-RAF	MEK	MEK	MEK	5	6	12	13
MEK and ERK activation is normal in Raf-1-deficient cells and embryos , and is probably mediated by B-RAF .	MEK and ERK activation is normal in Raf-1-deficient cells and embryos, and is probably mediated by B-RAF.	0	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	B-RAF	B-RAF	B-RAF	MEK	MEK	MEK	17	18	0	1
BRAF V600E mutation results in continuous activation of B-raf and downstream activation of MEK and ERK resulting in the activation of several transcription factors and accumulation of cell cycle proteins .	BRAF V600E mutation results in continuous activation of B-raf and downstream activation of MEK and ERK resulting in the activation of several transcription factors and accumulation of cell cycle proteins.	8	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	B-raf	B-raf	B-raf	MEK	MEK	MEK	8	9	13	14
These results suggest BRAF can activate MEK dependent autophagy , which is necessary for the protective role of BRAF in DYNC1I1 deficiency caused neuronal atrophy .	These results suggest BRAF can activate MEK dependent autophagy, which is necessary for the protective role of BRAF in DYNC1I1 deficiency caused neuronal atrophy.	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	3	4	6	7
In a majority of human cancers , the PI3K and AKT pathway is frequently activated by the activating mutations of PI3K p110alpha ( PIK3CA ) and the loss or inactivating mutation of PTEN , whereas hyper activation of MEK and ERK signaling driven by mutant RAS and BRAF is also a common oncogenic event in a variety of cancers [ XREF_BIBR , XREF_BIBR ] .	In a majority of human cancers, the PI3K and AKT pathway is frequently activated by the activating mutations of PI3K p110alpha (PIK3CA) and the loss or inactivating mutation of PTEN, whereas hyper activation of MEK and ERK signaling driven by mutant RAS and BRAF is also a common oncogenic event in a variety of cancers [XREF_BIBR, XREF_BIBR].	38	48	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	47	48	38	39
The increased apoptosis , observed in human melanoma cell lines when BRAF expression is downregulated using RNA interference , supports a role for oncogenic BRAF driven MEK and ERK overactivation in maintaining the transformed phenotype of malignant melanoma cells ( Hingorani et al , 2003 ; Karasarides et al , 2004 ) .	The increased apoptosis, observed in human melanoma cell lines when BRAF expression is downregulated using RNA interference, supports a role for oncogenic BRAF driven MEK and ERK overactivation in maintaining the transformed phenotype of malignant melanoma cells (Hingorani et al, 2003; Karasarides et al, 2004).	21	29	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	24	25	26	27
Examples of such events include activating mutations of the gene BRAF , which activate the MEK and ERK pathway ?	Examples of such events include activating mutations of the gene BRAF, which activate the MEK and ERK pathway?	6	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	10	11	15	16
When activated by mutations , BRAF activates MEK and this leads to the activation of the ERK signaling pathway to promote cell growth , proliferation , and survival 12 .	When activated by mutations, BRAF activates MEK and this leads to the activation of the ERK signaling pathway to promote cell growth, proliferation, and survival 12.	5	20	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	5	6	7	8
In a non cancer setting , BRAF activates kinases MEK and ERK , which in turn activate transcriptional machinery to promote differentiation , proliferation , growth and apoptosis [ XREF_BIBR ] .	In a non cancer setting, BRAF activates kinases MEK and ERK, which in turn activate transcriptional machinery to promote differentiation, proliferation, growth and apoptosis [XREF_BIBR].	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	6	7	9	10
In melanocytes , BRAF induces the activation of MEK kinase , which in turn activates ERK , final effector of MAPK cascade .	In melanocytes, BRAF induces the activation of MEK kinase, which in turn activates ERK, final effector of MAPK cascade.	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	3	4	8	9
While the activated mutant forms of BRAF and NRAS both activate MEK and MAPK , the activation of these downstream elements is CRAF dependent in melanomas with NRAS mutations , whereas it is BRAF dependent in BRAF-mutant cells XREF_BIBR .	While the activated mutant forms of BRAF and NRAS both activate MEK and MAPK, the activation of these downstream elements is CRAF dependent in melanomas with NRAS mutations, whereas it is BRAF dependent in BRAF-mutant cells XREF_BIBR.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	6	7	11	12
We confirmed this in ' RAS-less ' cells 3 in which MEK and ERK signalling was rescued by BRAF ( V600E ) , BRAF ( K601E ) or NRAS ( Q61K ) but not by wild-type , G466V/E or D594N/G BRAF ( XREF_FIG ) .	We confirmed this in ' RAS-less ' cells 3 in which MEK and ERK signalling was rescued by BRAF (V600E), BRAF (K601E) or NRAS (Q61K) but not by wild-type, G466V/E or D594N/G BRAF (XREF_FIG).	11	28	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	18	19	11	12
We therefore speculated that the MAP kinase pathway may be kept silent through the action of RKIP , which can interfere with either the activation of C-Raf or with the activation of MEK by B-Raf or C-Raf [ XREF_BIBR , XREF_BIBR ] .	We therefore speculated that the MAP kinase pathway may be kept silent through the action of RKIP, which can interfere with either the activation of C-Raf or with the activation of MEK by B-Raf or C-Raf [XREF_BIBR, XREF_BIBR].	30	38	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	B-Raf	B-Raf	B-Raf	MEK	MEK	MEK	34	35	32	33
In fact , 85-90 % of papillary carcinomas possess RET , NTRK1 , BRAF or RAS mutations that induce MEK and ERK signaling .	In fact, 85-90% of papillary carcinomas possess RET, NTRK1, BRAF or RAS mutations that induce MEK and ERK signaling.	11	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	13	14	19	20
However , a rapid development of tumor resistance was observed after these treatments and was found to be related to the BRAF independent activation of MEK .	However, a rapid development of tumor resistance was observed after these treatments and was found to be related to the BRAF independent activation of MEK.	21	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	21	22	25	26
Ras can activate either c-Raf ( also named Raf-1 ) or b-Raf , both of which can activate MEK ( MAP Kinase or ERK Kinase ) , leading to ERK activation .	Ras can activate either c-Raf (also named Raf-1) or b-Raf, both of which can activate MEK (MAP Kinase or ERK Kinase), leading to ERK activation.	2	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	b-Raf	b-Raf	b-Raf	MEK	MEK	MEK	11	12	18	19
In a phase III clinical trial published in 2015 , a combined regimen of a second generation BRAF inhibitor ( dabrafenib ) and a small molecule inhibitor of the BRAF target MEK ( trametinib ) increased median progression-free lifespan to 11.4 months , compared to 7.3 months for vemurafenib monotherapy [ XREF_BIBR ] .	In a phase III clinical trial published in 2015, a combined regimen of a second generation BRAF inhibitor (dabrafenib) and a small molecule inhibitor of the BRAF target MEK (trametinib) increased median progression-free lifespan to 11.4 months, compared to 7.3 months for vemurafenib monotherapy [XREF_BIBR].	26	33	target	Positive_activation_token_1_verb	Positive_activation	Negative_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	29	30	31	32
BRAF , a serine threonine kinase , lies downstream of RAS in the MAP kinase signaling pathway XREF_FIG ) ( BRAF induces MEK to phosphorylate ERK , which enhances cell growth and proliferation .	BRAF, a serine threonine kinase, lies downstream of RAS in the MAP kinase signaling pathway XREF_FIG) (BRAF induces MEK to phosphorylate ERK, which enhances cell growth and proliferation.	20	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	20	21	22	23
One study investigated the effects of conditional knockout of B-Raf , an upstream kinase that activates MEK , in neural progenitor cells ( NPCs ) of developing mice .	One study investigated the effects of conditional knockout of B-Raf, an upstream kinase that activates MEK, in neural progenitor cells (NPCs) of developing mice.	7	17	activates	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	B-Raf	B-Raf	B-Raf	MEK	MEK	MEK	9	10	16	17
These results show that increasing or decreasing BRAF activity ( and consequently , phosphorylation and activation of MEK ) can lead to a decrease or increase , respectively , in the ability of AZD6244 to inhibit MEK mediated phosphorylation of ERK .	These results show that increasing or decreasing BRAF activity (and consequently, phosphorylation and activation of MEK) can lead to a decrease or increase, respectively, in the ability of AZD6244 to inhibit MEK mediated phosphorylation of ERK.	7	18	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	7	8	17	18
The G596R substitution ( found in one case ) impairs the kinase activity of BRAF , which can not activate MEK directly but is still capable of activating MEK-ERK signalling by forming heterodimers with CRAF ( which is activated in a RAS independent manner ) , and also increases the activation of MEK-ERK signalling [ XREF_BIBR ] .	The G596R substitution (found in one case) impairs the kinase activity of BRAF, which can not activate MEK directly but is still capable of activating MEK-ERK signalling by forming heterodimers with CRAF (which is activated in a RAS independent manner), and also increases the activation of MEK-ERK signalling [XREF_BIBR].	12	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	14	15	20	21
K-Ras activates the pathway primarily via Raf-1 , whereas B-Raf activates Mek and signals independently of Raf-1 .	K-Ras activates the pathway primarily via Raf-1, whereas B-Raf activates Mek and signals independently of Raf-1.	9	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	B-Raf	B-Raf	B-Raf	Mek	Mek	Mek	9	10	11	12
BRAF in turn activates the dual tyrosine and serine/threonine kinase MEK , which is mutated only very rarely in CRC [ XREF_BIBR ] .	BRAF in turn activates the dual tyrosine and serine/threonine kinase MEK, which is mutated only very rarely in CRC [XREF_BIBR].	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	0	1	10	11
Moreover , the decreased number of autophagosomes in the presence of MEK inhibitor trametinib indicates that BRAF increases MEK dependent autophagic influx and activity .	Moreover, the decreased number of autophagosomes in the presence of MEK inhibitor trametinib indicates that BRAF increases MEK dependent autophagic influx and activity.	16	21	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	16	17	18	19
RAF1 ( D486N ) , as well as other kinase impaired RAF1 mutants , showed increased heterodimerization with BRAF , which was necessary and sufficient to promote increased MEK and ERK activation .	RAF1 (D486N), as well as other kinase impaired RAF1 mutants, showed increased heterodimerization with BRAF, which was necessary and sufficient to promote increased MEK and ERK activation.	16	31	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	18	19	28	29
BRAF and RAS lesions are known to increase MEK activity in tumors XREF_BIBR , XREF_BIBR , therefore interventions that inhibit MEK activity will reduce and normalize downstream signaling through the constitutively activated MEK-ERK kinase cascade and thus these links are expected .	BRAF and RAS lesions are known to increase MEK activity in tumors XREF_BIBR, XREF_BIBR, therefore interventions that inhibit MEK activity will reduce and normalize downstream signaling through the constitutively activated MEK-ERK kinase cascade and thus these links are expected.	0	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	0	1	8	9
However , unlike ( V600E ) Braf , Mek and Erk pathway activation was mediated by both Craf and Braf , and ATP-competitive RAF inhibitors induced paradoxical Mek and Erk pathway activation .	However, unlike (V600E) Braf, Mek and Erk pathway activation was mediated by both Craf and Braf, and ATP-competitive RAF inhibitors induced paradoxical Mek and Erk pathway activation.	6	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Braf	Braf	Braf	Mek	Mek	Mek	19	20	8	9
B-RAF is an immediately downstream of RAS and activates MAP2K1 and MEK , which in turn activates MAPK1 and ERK2 .	B-RAF is an immediately downstream of RAS and activates MAP2K1 and MEK, which in turn activates MAPK1 and ERK2.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	B-RAF	B-RAF	B-RAF	MEK	MEK	MEK	0	1	11	12
These results are compatible with the notion that B-Raf is the main activator of MEK in most cell types .	These results are compatible with the notion that B-Raf is the main activator of MEK in most cell types.	8	18	is the main activator	Positive_activation_copula_1	Positive_activation	Positive_activation	B-Raf	B-Raf	B-Raf	MEK	MEK	MEK	8	9	14	15
In addition , B-Raf has a greater affinity for MEK and produces a stronger MEK stimulation than Raf-1 .	In addition, B-Raf has a greater affinity for MEK and produces a stronger MEK stimulation than Raf-1.	3	15	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	B-Raf	B-Raf	B-Raf	MEK	MEK	MEK	3	4	14	15
This observation suggests that in AR cells , increased BRAF abundance causes an excess of activated ( phosphorylated ) MEK , and substantially greater MEK inhibition ( either directly by a MEK inhibitor , or indirectly by reducing the phosphorylation of MEK by a BRAF inhibitor ) is required before leading to a decrease in ERK phosphorylation .	This observation suggests that in AR cells, increased BRAF abundance causes an excess of activated (phosphorylated) MEK, and substantially greater MEK inhibition (either directly by a MEK inhibitor, or indirectly by reducing the phosphorylation of MEK by a BRAF inhibitor) is required before leading to a decrease in ERK phosphorylation.	9	20	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	9	10	19	20
Along the RET or BRAF signaling cascades , the activated RET kinase or BRAF activates MEK1/2 , and then mitogen activated protein kinases ( extracellular signal related kinase 1/2 [ ERK1/2 ] ) is activated .	Along the RET or BRAF signaling cascades, the activated RET kinase or BRAF activates MEK1/2, and then mitogen activated protein kinases (extracellular signal related kinase 1/2 [ERK1/2]) is activated.	11	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK1/2	MEK1/2	MEK1/2	13	14	15	16
Since the V600E mutations in B-RAF are known to activate MEK , we also monitored MEK activation upon B-RAF inhibition by treating B-RAF mutated and wild-type melanoma cell lines with a B-RAF inhibitor .	Since the V600E mutations in B-RAF are known to activate MEK, we also monitored MEK activation upon B-RAF inhibition by treating B-RAF mutated and wild-type melanoma cell lines with a B-RAF inhibitor.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	B-RAF	B-RAF	B-RAF	MEK	MEK	MEK	5	6	10	11
In melanoma cell lines , which have acquired resistance to the RAF inhibitor , elevated CRAF protein levels accounted for the acquisition of resistance to RAF inhibitor , and CRAF , but not BRAF activated the MEK and ERK pathway XREF_BIBR .	In melanoma cell lines, which have acquired resistance to the RAF inhibitor, elevated CRAF protein levels accounted for the acquisition of resistance to RAF inhibitor, and CRAF, but not BRAF activated the MEK and ERK pathway XREF_BIBR.	29	40	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	33	34	36	37
BRAF activating mutations result in constitutively active MEK signaling leading to tumor progression .	BRAF activating mutations result in constitutively active MEK signaling leading to tumor progression.	0	9	signaling	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	0	1	7	8
The MEK and ERK signaling pathway may be activated by BRAF in papillary thyroid cancer .	The MEK and ERK signaling pathway may be activated by BRAF in papillary thyroid cancer.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	10	11	1	2
A-Raf preferentially activates MEK1 , while B-Raf and C-Raf activate both MEK1/2 with equal efficiency .	A-Raf preferentially activates MEK1, while B-Raf and C-Raf activate both MEK1/2 with equal efficiency.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	B-Raf	B-Raf	B-Raf	MEK1/2	MEK1/2	MEK1/2	6	7	11	12
In low-grade ovarian tumours , mutations in the MAP3K BRAF gene constitutively activate the downstream kinase MEK .	In low-grade ovarian tumours, mutations in the MAP3K BRAF gene constitutively activate the downstream kinase MEK.	9	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	9	10	16	17
Both B-RAF and N-Ras mutations lead to enhanced MEK and ERK signaling ; however , the mechanism of MEK and ERK activation differs with these mutations .	Both B-RAF and N-Ras mutations lead to enhanced MEK and ERK signaling; however, the mechanism of MEK and ERK activation differs with these mutations.	1	11	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	B-RAF	B-RAF	B-RAF	MEK	MEK	MEK	1	2	8	9
BRAF and NRAS mutations both activate downstream MEK kinase that serves as the gatekeeper of extracellular signal regulated kinase ( ERK ) activation .	BRAF and NRAS mutations both activate downstream MEK kinase that serves as the gatekeeper of extracellular signal regulated kinase (ERK) activation.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	0	1	7	8
B-Raf activates MAPKK ( MEK ) and MEK phosphorylates MAPK ( ERK ) , all of which are required for maintaining vertebrate cellular activities responsive to growth factors stimulation [ XREF_BIBR , XREF_BIBR ] .	B-Raf activates MAPKK (MEK) and MEK phosphorylates MAPK (ERK), all of which are required for maintaining vertebrate cellular activities responsive to growth factors stimulation [XREF_BIBR, XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	B-Raf	B-Raf	B-Raf	MEK	MEK	MEK	0	1	4	5
Following mutant BRAF V600E overexpression , the phosphorylation of both BRAF / CRAF kinases was significantly increased , which resulted in the downstream activation of MEK but not ERK signalling ( XREF_FIG -upper panel , lanes 3-4 ) .	Following mutant BRAF V600E overexpression, the phosphorylation of both BRAF / CRAF kinases was significantly increased, which resulted in the downstream activation of MEK but not ERK signalling (XREF_FIG -upper panel, lanes 3-4).	7	29	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	phosphorylation of both BRAF	braf	MEK	MEK	mek	10	11	25	26
In addition , association of B-Raf and/or Raf-1 with the scaffold protein KSR1 also modulates activation of MEK [ XREF_BIBR - XREF_BIBR ] .	In addition, association of B-Raf and/or Raf-1 with the scaffold protein KSR1 also modulates activation of MEK [XREF_BIBR - XREF_BIBR].	3	19	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	B-Raf	B-Raf	B-Raf	MEK	MEK	MEK	5	6	17	18
More recently , pan-RAF inhibitors that also target Src family kinases ( SFKs ) have been shown to prevent paradoxical pathway activation in pre-clinical models of BRAF-mutant melanoma , a common resistant mechanism to BRAF and dual specificity mitogen activated protein kinase kinase 1 ( MEK ) inhibitors , thus illustrating how polypharmacology can effectively prevent drug resistance [ XREF_BIBR ] .	More recently, pan-RAF inhibitors that also target Src family kinases (SFKs) have been shown to prevent paradoxical pathway activation in pre-clinical models of BRAF-mutant melanoma, a common resistant mechanism to BRAF and dual specificity mitogen activated protein kinase kinase 1 (MEK) inhibitors, thus illustrating how polypharmacology can effectively prevent drug resistance [XREF_BIBR].	34	50	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	34	35	45	46
Resistance to BRAF inhibitors develops relatively rapidly because of BRAF independent activation of MEK and ERK and other chemotherapeutic approaches will be necessary , both for melanomas lacking mutant BRAF and for melanomas that have developed resistance .	Resistance to BRAF inhibitors develops relatively rapidly because of BRAF independent activation of MEK and ERK and other chemotherapeutic approaches will be necessary, both for melanomas lacking mutant BRAF and for melanomas that have developed resistance.	9	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	9	10	13	14
As BRAF activates MEK and MEK inhibitor monotherapy has incomplete efficacy in patients with BRAF V600E-mutant tumors XREF_BIBR , XREF_BIBR , we tested whether YAP1 silencing enhanced the response to MEK inhibitor in HCC364 cells .	As BRAF activates MEK and MEK inhibitor monotherapy has incomplete efficacy in patients with BRAF V600E-mutant tumors XREF_BIBR, XREF_BIBR, we tested whether YAP1 silencing enhanced the response to MEK inhibitor in HCC364 cells.	1	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	1	2	3	4
This experiment also shows that MEK activation driven by kinase-dead BRAF is inhibited by sorafenib ( XREF_FIG E and 4F ) .	This experiment also shows that MEK activation driven by kinase-dead BRAF is inhibited by sorafenib (XREF_FIG E and 4F).	5	11	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	10	11	5	6
MEK kinases are activated by BRAF .	MEK kinases are activated by BRAF.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	5	6	0	1
In melanoma cells harboring the NRAS mutation , the mutated NRAS protein needs CRAF to activate the MEK and ERK pathway XREF_BIBR , and the BRAF protein is phosphorylated by ERK on S151 near the RAS binding domain , which results in the inhibition of the NRAS and BRAF interaction XREF_BIBR .	In melanoma cells harboring the NRAS mutation, the mutated NRAS protein needs CRAF to activate the MEK and ERK pathway XREF_BIBR, and the BRAF protein is phosphorylated by ERK on S151 near the RAS binding domain, which results in the inhibition of the NRAS and BRAF interaction XREF_BIBR.	15	33	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BRAF	BRAF protein is phosphorylated by ERK on S151	braf	MEK	MEK	mek	25	26	17	18
To our knowledge , interstitial nephritis has not been described in patients on BRAF targeted nor MEK targeted therapy for melanoma , although it has been described in a melanoma patient treated with the immune checkpoint inhibitor , ipilimumab .	To our knowledge, interstitial nephritis has not been described in patients on BRAF targeted nor MEK targeted therapy for melanoma, although it has been described in a melanoma patient treated with the immune checkpoint inhibitor, ipilimumab.	11	17	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	13	14	16	17
Taken together with our results , BASH mediates activation of two independent pathways downstream of the BCR through distinct intramolecular sites ; NH 2 -terminal phospho-tyrosine containing motifs function in Btk mediated PLCgamma2 activation , while the SH2 domain accomplishes HPK1 activation .	Taken together with our results, BASH mediates activation of two independent pathways downstream of the BCR through distinct intramolecular sites; NH 2 -terminal phospho-tyrosine containing motifs function in Btk mediated PLCgamma2 activation, while the SH2 domain accomplishes HPK1 activation.	28	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	Btk	Btk	Btk	PLCgamma2	PLCgamma2	PLCgamma2	30	31	32	33
In contrast , Cbl-b was shown to positively regulate Btk mediated activation of PLC-gamma2 in immature DT40 B cells .	In contrast, Cbl-b was shown to positively regulate Btk mediated activation of PLC-gamma2 in immature DT40 B cells.	9	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Btk	Btk	Btk	PLC-gamma2	PLC-gamma2	PLC-gamma2	9	10	13	14
Syk then phosphorylates and activates Btk and Vav , which activate PLCgamma2 and Rac , respectively .	Syk then phosphorylates and activates Btk and Vav, which activate PLCgamma2 and Rac, respectively.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Syk then phosphorylates and activates Btk	btk	PLCgamma2	PLCgamma2	plcgamma2	5	6	11	12
After phosphorylation by Syk and Btk , PLC-gamma2 is activated and generates the second messenger inositol 1,4,5-trisphosphate which leads to Ca 2+ release from intracellular stores .	After phosphorylation by Syk and Btk, PLC-gamma2 is activated and generates the second messenger inositol 1,4,5-trisphosphate which leads to Ca 2+ release from intracellular stores.	1	11	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	PLC-gamma2	PLC-gamma2	PLC-gamma2	5	6	7	8
Here we tested whether Btk : ER activation was sufficient to activate the PLCgamma2 and calcium pathway .	Here we tested whether Btk : ER activation was sufficient to activate the PLCgamma2 and calcium pathway.	4	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	PLCgamma2	PLCgamma2	PLCgamma2	4	5	13	14
We show that Cbl-b positively regulates BCR induced PLC-gamma2/Ca 2+ signaling , and provide evidence suggesting that Cbl-b functions as a scaffold protein to promote Btk mediated PLC-gamma2 activation .	We show that Cbl-b positively regulates BCR induced PLC-gamma2/Ca 2+ signaling, and provide evidence suggesting that Cbl-b functions as a scaffold protein to promote Btk mediated PLC-gamma2 activation.	25	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	Btk	Btk	Btk	PLC-gamma2	PLC-gamma2	PLC-gamma2	25	26	27	28
Since Bam32 binds the same phospholipid as Btk and associates with PLCgamma2 , it is tempting to speculate that Bam32 could regulate the activation of PLCgamma2 by Btk .	Since Bam32 binds the same phospholipid as Btk and associates with PLCgamma2, it is tempting to speculate that Bam32 could regulate the activation of PLCgamma2 by Btk.	21	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Btk	Btk	Btk	PLCgamma2	PLCgamma2	PLCgamma2	27	28	25	26
So far , however , PLCgamma2 activation by Tec and Btk has only been reported to occur in lymphocytes , mast cells and osteoclasts under non infectious conditions XREF_BIBR , XREF_BIBR , XREF_BIBR .	So far, however, PLCgamma2 activation by Tec and Btk has only been reported to occur in lymphocytes, mast cells and osteoclasts under non infectious conditions XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Btk	Btk	Btk	PLCgamma2	PLCgamma2	PLCgamma2	10	11	5	6
BTK phosphorylation targets phospholipase Cgamma2 ( PLCgamma2 ) , with activation of NFkappaB and mitogen activated protein kinase pathways .	BTK phosphorylation targets phospholipase Cgamma2 (PLCgamma2), with activation of NFkappaB and mitogen activated protein kinase pathways.	0	5	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTK	BTK phosphorylation	btk	phospholipase Cgamma2	phospholipase Cgamma2	phospholipase cgamma2	0	1	3	5
Cbl-b Positively Regulates Btk mediated Activation of Phospholipase C-gamma2 in B Cells .	Cbl-b Positively Regulates Btk mediated Activation of Phospholipase C-gamma2 in B Cells.	2	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Btk	Btk	Btk	Phospholipase C-gamma2	Phospholipase C-gamma2	Phospholipase C-gamma2	3	4	7	9
Together , our data are consistent with the notion that PIP3 and/or a high concentration of Btk target the activated PLCgamma2 to its substrate site for maximal catalytic efficiency .	Together, our data are consistent with the notion that PIP3 and/or a high concentration of Btk target the activated PLCgamma2 to its substrate site for maximal catalytic efficiency.	10	21	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	PLCgamma2	PLCgamma2	PLCgamma2	16	17	20	21
These results show that the TKB domain , the COOH-terminal region , and the RING finger domain of Cbl-b are important for Btk mediated PLC-gamma2 activation .	These results show that the TKB domain, the COOH-terminal region, and the RING finger domain of Cbl-b are important for Btk mediated PLC-gamma2 activation.	22	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Btk	Btk	Btk	PLC-gamma2	PLC-gamma2	PLC-gamma2	22	23	24	25
77 Btk in turn activates phospholipase Cgamma2 ( PLCgamma2 ) and PI3Kgamma .	77 Btk in turn activates phospholipase Cgamma2 (PLCgamma2) and PI3Kgamma.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	phospholipase Cgamma2	phospholipase Cgamma2	phospholipase Cgamma2	1	2	5	7
Within this trimolecular arrangement Btk phosphorylates and thereby activates PLC-gamma2 .	Within this trimolecular arrangement Btk phosphorylates and thereby activates PLC-gamma2.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	PLC-gamma2	PLC-gamma2	PLC-gamma2	4	5	9	10
Replacement of Y617 with a negatively charged glutamic acid ( E ) suppressed Btk mediated phospholipase Cgamma2 activation and calcium response in DT-40 cells , whereas Akt activation was not affected .	Replacement of Y617 with a negatively charged glutamic acid (E) suppressed Btk mediated phospholipase Cgamma2 activation and calcium response in DT-40 cells, whereas Akt activation was not affected.	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Btk	Btk	Btk	phospholipase Cgamma2	phospholipase Cgamma2	phospholipase Cgamma2	13	14	15	17
Subsequent phosphorylation of BTK by the Src-kinases and SYK activates phospholipase C-gamma2 , which leads to nuclear factor kappaB and nuclear factor of activated T cells transcriptional activation [ XREF_BIBR ] .	Subsequent phosphorylation of BTK by the Src-kinases and SYK activates phospholipase C-gamma2, which leads to nuclear factor kappaB and nuclear factor of activated T cells transcriptional activation [XREF_BIBR].	1	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTK	phosphorylation of BTK	btk	phospholipase C-gamma2	phospholipase C-gamma2	phospholipase c-gamma2	3	4	10	12
We speculate that IFN-alpha leads to partial phosphorylation of PLCgamma2 , and as a result less Btk or other upstream kinases are required to completely activate PLCgamma2 .	We speculate that IFN-alpha leads to partial phosphorylation of PLCgamma2, and as a result less Btk or other upstream kinases are required to completely activate PLCgamma2.	15	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	PLCgamma2	PLCgamma2	PLCgamma2	16	17	26	27
The most well described of these is PLCgamma2 , which is activated after phosphorylation by Btk leading to increased Ca ++ flux and activation of NF-kappaB .	The most well described of these is PLCgamma2, which is activated after phosphorylation by Btk leading to increased Ca ++ flux and activation of NF-kappaB.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	PLCgamma2	PLCgamma2	PLCgamma2	15	16	7	8
To further confirm that Cbl-b positively regulates Btk mediated PLC-gamma2 activation , we examined the role of Cbl-b in Btk dependent intracellular Ca 2+ ( [ Ca 2+ ] i ) increase upon BCR stimulation .	To further confirm that Cbl-b positively regulates Btk mediated PLC-gamma2 activation, we examined the role of Cbl-b in Btk dependent intracellular Ca 2+ ([Ca 2+] i) increase upon BCR stimulation.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Btk	Btk	Btk	PLC-gamma2	PLC-gamma2	PLC-gamma2	7	8	9	10
Binding of Btk to the linker protein BLNK and SLP -65 is crucial for phosphorylation and activation of phospholipase Cgamma2 by Btk , implicating Btk as a mediator of BCR induced Ca 2+ mobilization 19 .	Binding of Btk to the linker protein BLNK and SLP -65 is crucial for phosphorylation and activation of phospholipase Cgamma2 by Btk, implicating Btk as a mediator of BCR induced Ca 2+ mobilization 19.	16	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Btk	Btk	Btk	phospholipase Cgamma2	phospholipase Cgamma2	phospholipase Cgamma2	21	22	18	20
Btk : ER induced a sustained calcium signal in parental cells but not in PLCgamma2 deficient cells ( Fig XREF_FIG ) , suggesting that Btk : ER modulates calcium signaling by affecting PLCgamma2 activity .	Btk : ER induced a sustained calcium signal in parental cells but not in PLCgamma2 deficient cells (Fig XREF_FIG), suggesting that Btk : ER modulates calcium signaling by affecting PLCgamma2 activity.	24	33	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	PLCgamma2	PLCgamma2	PLCgamma2	24	25	32	33
Btk activates PLCgamma2 , promoting the generation of DAG and the release of intracellular Ca ++ which combine to activate PKCbeta .	Btk activates PLCgamma2, promoting the generation of DAG and the release of intracellular Ca ++ which combine to activate PKCbeta.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	PLCgamma2	PLCgamma2	PLCgamma2	0	1	2	3
PLCgamma2 is then activated by Btk , and cleaves phosphatidylinositol-bisphosphate ( PIP 2 ) into diacylglycerol and inositol ( 1 , 4 , 5 )-trisphosphate ( IP 3 ) by hydrolysis .	PLCgamma2 is then activated by Btk, and cleaves phosphatidylinositol-bisphosphate (PIP 2) into diacylglycerol and inositol (1, 4, 5)-trisphosphate (IP 3) by hydrolysis.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	PLCgamma2	PLCgamma2	PLCgamma2	5	6	0	1
PLC-gamma2 is activated through its tyrosine phosphorylation by Syk and Btk after BCR stimulation .	PLC-gamma2 is activated through its tyrosine phosphorylation by Syk and Btk after BCR stimulation.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	PLC-gamma2	PLC-gamma2	PLC-gamma2	10	11	0	1
Thus , we include a mechanism by which Plcg2 is activated by Syk rather than by Btk .	Thus, we include a mechanism by which Plcg2 is activated by Syk rather than by Btk.	8	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	Plcg2	Plcg2	Plcg2	16	17	8	9
Although cells deficient for molecules involved in Plcgamma2 activation such as syk , BLNK , Btk , and Plcgamma2 were unable to mediate BCR induced arrest of SDF-1 migration , IP 3 R deficient cells ( generated by deletion of the three IP 3 receptor genes ) retained their ability to migrate in response to SDF-1alpha and arrest upon BCR cross linking .	Although cells deficient for molecules involved in Plcgamma2 activation such as syk, BLNK, Btk, and Plcgamma2 were unable to mediate BCR induced arrest of SDF-1 migration, IP 3 R deficient cells (generated by deletion of the three IP 3 receptor genes) retained their ability to migrate in response to SDF-1alpha and arrest upon BCR cross linking.	7	16	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Btk	Btk	Btk	Plcgamma2	Plcgamma2	Plcgamma2	15	16	7	8
The formation of this complex is critical for activation of PLC-gamma2 by Btk and subsequent generation of the second messengers diacylglycerol and inositol-1 ,4,5-trisphosphate ( IP3 ) by cleavage of the membrane lipid phosphatidylinositol-4 ,5-bisphosphate .	The formation of this complex is critical for activation of PLC-gamma2 by Btk and subsequent generation of the second messengers diacylglycerol and inositol-1,4,5-trisphosphate (IP3) by cleavage of the membrane lipid phosphatidylinositol-4,5-bisphosphate.	8	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Btk	Btk	Btk	PLC-gamma2	PLC-gamma2	PLC-gamma2	12	13	10	11
The JM-A conformation induced when EGFR is activated by betacellulin ( BC ) , represented by cluster 12 , is intermediate between the EGF- and TGF-alpha-activated structures , possessing both a hydrophobic and polar interface .	The JM-A conformation induced when EGFR is activated by betacellulin (BC), represented by cluster 12, is intermediate between the EGF- and TGF-alpha-activated structures, possessing both a hydrophobic and polar interface.	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	betacellulin	betacellulin	betacellulin	EGFR	EGFR	EGFR	9	10	5	6
As expected , exposure of cells to EGF specifically activated ErbB1 , whereas BTC promoted only ErbB1 and ErbB4 activation .	As expected, exposure of cells to EGF specifically activated ErbB1, whereas BTC promoted only ErbB1 and ErbB4 activation.	13	19	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	ErbB1	ErbB1	ErbB1	13	14	16	17
BTC promotes ErbB4 as well as ErbB1 dimers with ErbB2 , but not with ErbB3 .	BTC promotes ErbB4 as well as ErbB1 dimers with ErbB2, but not with ErbB3.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	ErbB1	ErbB1	ErbB1	0	1	6	7
BTC induces a stronger EGFR homodimerization compared to the stronger EGFR-HER2 heterodimerization induced by EGF .	BTC induces a stronger EGFR homodimerization compared to the stronger EGFR-HER2 heterodimerization induced by EGF.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	EGFR	EGFR	EGFR	0	1	4	5
In XREF_FIG , we expanded on this finding and showed that EGF , HB-EGF , AR , and beta-cellulin drive EGFR to the nucleus .	In XREF_FIG, we expanded on this finding and showed that EGF, HB-EGF, AR, and beta-cellulin drive EGFR to the nucleus.	9	21	drive	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-cellulin	beta-cellulin	beta-cellulin	EGFR	EGFR	EGFR	18	19	20	21
Betacellulin is commonly expressed in head and neck cancer cell lines , supporting the EGFR dependent activation of PI3K and MEK and ERK signaling .	Betacellulin is commonly expressed in head and neck cancer cell lines, supporting the EGFR dependent activation of PI3K and MEK and ERK signaling.	0	16	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Betacellulin	Betacellulin is commonly expressed	betacellulin	EGFR	EGFR	egfr	0	1	14	15
Activation of ErbB-1 and ErbB-2 by BTC treatment in beta cells .	Activation of ErbB-1 and ErbB-2 by BTC treatment in beta cells.	0	7	Activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	BTC	BTC	BTC	ErbB-1	ErbB-1	ErbB-1	6	7	2	3
ErbB1 and ErbB4 activation mediated by betacellulin expands neural stem cells and neuroblasts in the postnatal brain .	ErbB1 and ErbB4 activation mediated by betacellulin expands neural stem cells and neuroblasts in the postnatal brain.	0	7	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	betacellulin	betacellulin	betacellulin	ErbB1	ErbB1	ErbB1	6	7	0	1
For the ER- phenotype , MinePath identified a discriminant sub-path that is also triggered from extra-cellular factors , HBEGF ( heparin binding EGF like growth ) or BTC ( betacellulin ) , which in turn activate EGFR ( epidermal growth factor receptor ) .	For the ER- phenotype, MinePath identified a discriminant sub-path that is also triggered from extra-cellular factors, HBEGF (heparin binding EGF like growth) or BTC (betacellulin), which in turn activate EGFR (epidermal growth factor receptor).	27	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	betacellulin	betacellulin	betacellulin	EGFR	EGFR	EGFR	29	30	36	37
For the ER- phenotype , the EGFR ( epidermal growth factor receptor ) is activated by the extra-cellular factors ( direct arrow lines in red ; see the explanatory legend at the top-right of the figure ) BTC for both RNAseq and microarray , HBEGF for only microarray and EREG for only RNAseq in order to enter the intra-cellular regulation by the activation of GRB2 , which in turn activates GAB1 .	For the ER- phenotype, the EGFR (epidermal growth factor receptor) is activated by the extra-cellular factors (direct arrow lines in red; see the explanatory legend at the top-right of the figure) BTC for both RNAseq and microarray, HBEGF for only microarray and EREG for only RNAseq in order to enter the intra-cellular regulation by the activation of GRB2, which in turn activates GAB1.	5	42	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	EGFR	EGFR	EGFR	37	38	6	7
This indicates that the internalization of BTC stimulated EGFR in clathrin knockdown cells leads to sorting to early endosomes .	This indicates that the internalization of BTC stimulated EGFR in clathrin knockdown cells leads to sorting to early endosomes.	4	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	EGFR	EGFR	EGFR	6	7	8	9
BTC induced ovarian cancer cell migration requires EGFR , MEK-ERK and PI3K-Akt signaling .	BTC induced ovarian cancer cell migration requires EGFR, MEK-ERK and PI3K-Akt signaling.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	EGFR	EGFR	EGFR	0	1	7	8
Additionally , heparin binding EGF like growth factor and betacellulin target EGFR for lysosomal degradation , but in contrast epiregulin and amphiregulin lead to receptor recycling , similarly to TGF-alpha [ Roepstorff et al ., 2009 ] .	Additionally, heparin binding EGF like growth factor and betacellulin target EGFR for lysosomal degradation, but in contrast epiregulin and amphiregulin lead to receptor recycling, similarly to TGF-alpha [Roepstorff et al., 2009].	7	21	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	betacellulin	betacellulin	betacellulin	EGFR	EGFR	EGFR	9	10	11	12
However , less is known about EGF-R fates induced by the ligands BTC ( betacellulin ) and AR ( amphiregulin ) .	However, less is known about EGF-R fates induced by the ligands BTC (betacellulin) and AR (amphiregulin).	6	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	EGF-R	EGF-R	EGF-R	12	13	6	7
Betacellulin ( BTC ) can activate all four ERBB tyrosine kinase receptors and is a multifunctional EGF like ligand with diverse roles in beta cell differentiation , bone maturation , formation of functional epithelial linings and vascular permeability in different organs .	Betacellulin (BTC) can activate all four ERBB tyrosine kinase receptors and is a multifunctional EGF like ligand with diverse roles in beta cell differentiation, bone maturation, formation of functional epithelial linings and vascular permeability in different organs.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Betacellulin	Betacellulin	Betacellulin	ERBB	ERBB	ERBB	0	1	8	9
Studies of the related mechanisms showed that BTC activates ErbB tyrosine kinase receptors via the ErbB1 , ErbB2 and ErbB4 subunits of EGFR , and that it evokes more Erk phosphorylation than EGF phosphorylation while also evoking Akt phosphorylation , ultimately resulting in a much stronger stimulation of RPC proliferation compared to EGF .	Studies of the related mechanisms showed that BTC activates ErbB tyrosine kinase receptors via the ErbB1, ErbB2 and ErbB4 subunits of EGFR, and that it evokes more Erk phosphorylation than EGF phosphorylation while also evoking Akt phosphorylation, ultimately resulting in a much stronger stimulation of RPC proliferation compared to EGF.	7	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	EGFR	EGFR	EGFR	7	8	22	23
Our study showed that overexpression of BTC results in an EGFR dependent upregulation of cortical bone mass in the appendicular skeleton of mice , uncovering a potential novel anabolic pathway for cortical bone .	Our study showed that overexpression of BTC results in an EGFR dependent upregulation of cortical bone mass in the appendicular skeleton of mice, uncovering a potential novel anabolic pathway for cortical bone.	4	13	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	BTC	overexpression of BTC	btc	EGFR	EGFR	egfr	6	7	10	11
To investigate if HB-EGF and BTC could induce EGFR internalization via macropinocytosis in HeLa cells , we used the macropinocytosis inhibitor amiloride XREF_BIBR .	To investigate if HB-EGF and BTC could induce EGFR internalization via macropinocytosis in HeLa cells, we used the macropinocytosis inhibitor amiloride XREF_BIBR.	3	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	EGFR	EGFR	EGFR	5	6	8	9
Indeed , recent reports suggest that Plk1 is actually activated by Aurora A and its cofactor Bora before it activates CDK1 and promotes mitotic entry [ XREF_BIBR , XREF_BIBR ] .	Indeed, recent reports suggest that Plk1 is actually activated by Aurora A and its cofactor Bora before it activates CDK1 and promotes mitotic entry [XREF_BIBR, XREF_BIBR].	6	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	16	17	6	7
Some of these advances will be reviewed here , including : how cyclin controls passage through Start and maintains coherence of G1/S regulon expression in yeast ; how Plk1 activation is driven by Bora and Aurora A , and its expression is stimulated by FoxM1 in mammalian cells ; and how some of the various dynamic behaviors of spindle assembly and anaphase onset can be produced .	Some of these advances will be reviewed here, including : how cyclin controls passage through Start and maintains coherence of G1/S regulon expression in yeast; how Plk1 activation is driven by Bora and Aurora A, and its expression is stimulated by FoxM1 in mammalian cells; and how some of the various dynamic behaviors of spindle assembly and anaphase onset can be produced.	28	36	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	33	34	28	29
However , direct fusion of Bora and Aurora A can prevent Plk1 inhibition by DNA damaging agents , indicating that the DDR targets the interaction between Aurora A and Bora to establish inhibition of Plk1 .	However, direct fusion of Bora and Aurora A can prevent Plk1 inhibition by DNA damaging agents, indicating that the DDR targets the interaction between Aurora A and Bora to establish inhibition of Plk1.	5	12	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	5	6	11	12
Knowledge of the precise mechanism by which Bora ( and its phosphorylation by Cyclin A-Cdk1 ) helps activate Plk1 ( Polo ) is still lacking and will likely require structural biology approaches .	Knowledge of the precise mechanism by which Bora (and its phosphorylation by Cyclin A-Cdk1) helps activate Plk1 (Polo) is still lacking and will likely require structural biology approaches.	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	7	8	18	19
For instance , Aurora-A and Bora cooperatively activate PLK1 by phosphorylating threonine 210 ( T210 ) in its activation loop ( T-loop ) .	For instance, Aurora-A and Bora cooperatively activate PLK1 by phosphorylating threonine 210 (T210) in its activation loop (T-loop).	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	PLK1	PLK1	PLK1	5	6	8	9
PLK1 is activated through the phosphorylation of its threonine 210 residue ( T 210 ) by Aurora-A in a Bora dependent manner XREF_BIBR XREF_BIBR .	PLK1 is activated through the phosphorylation of its threonine 210 residue (T 210) by Aurora-A in a Bora dependent manner XREF_BIBR XREF_BIBR.	0	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	PLK1	PLK1	PLK1	19	20	0	1
During recovery , PLK1 levels increase , and PLK1 is activated by the action of Bora and Aurora A , which promote PLK1 phosphorylation [ XREF_BIBR , XREF_BIBR ] .	During recovery, PLK1 levels increase, and PLK1 is activated by the action of Bora and Aurora A, which promote PLK1 phosphorylation [XREF_BIBR, XREF_BIBR].	15	24	promote	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Bora	Bora	bora	PLK1	PLK1 phosphorylation	plk1	15	16	22	23
Aurora A and a Plk1 interacting protein , Bora , have been shown to cooperatively activate Plk1 , hence Plk1 and Aurora A are forming a positive feedback loop for mitotic entry .	Aurora A and a Plk1 interacting protein, Bora, have been shown to cooperatively activate Plk1, hence Plk1 and Aurora A are forming a positive feedback loop for mitotic entry.	1	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	8	9	16	17
During G2/M transition , PLK1 is activated by Aurora A kinase and its cofactor Bora 40 .	During G2/M transition, PLK1 is activated by Aurora A kinase and its cofactor Bora 40.	4	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	PLK1	PLK1	PLK1	14	15	4	5
Recent work in Xenopus extracts confirmed this hypothesis and revealed that Cyclin A-Cdk1 phosphorylates Bora to trigger Plk1 activation and mitotic entry [ XREF_BIBR ] .	Recent work in Xenopus extracts confirmed this hypothesis and revealed that Cyclin A-Cdk1 phosphorylates Bora to trigger Plk1 activation and mitotic entry [XREF_BIBR].	11	18	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Cyclin A-Cdk1 phosphorylates Bora	bora	Plk1	Plk1	plk1	14	15	17	18
This degradation does not completely remove all Bora , as we have shown previously , and Bora and Aurora A continue to activate Plk1 also in mitosis .	This degradation does not completely remove all Bora, as we have shown previously, and Bora and Aurora A continue to activate Plk1 also in mitosis.	16	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	16	17	23	24
This not only allows Aurora A to phosphorylate Plk1 at T210 but additionally targets Bora itself as a substrate of Plk1 , since phosphorylation by Plk1 targets Bora for betaTrCP dependent proteasomal degradation .	This not only allows Aurora A to phosphorylate Plk1 at T210 but additionally targets Bora itself as a substrate of Plk1, since phosphorylation by Plk1 targets Bora for betaTrCP dependent proteasomal degradation.	14	28	targets	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	27	28	25	26
Plk1 is activated before mitosis by Aurora-A and its cofactor Bora [ XREF_BIBR ] .	Plk1 is activated before mitosis by Aurora-A and its cofactor Bora [XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	10	11	0	1
Aurora A ( AurA ) is an upstream element in the cascade of kinase activities that control progression from G2 to M phase ( through Bora mediated activation of Plk1 ) and further plays direct roles in the maturation of the centrosome , in microtubule ( MT ) nucleation , and in the activation of other components required to build a bipolar mitotic spindle .	Aurora A (AurA) is an upstream element in the cascade of kinase activities that control progression from G2 to M phase (through Bora mediated activation of Plk1) and further plays direct roles in the maturation of the centrosome, in microtubule (MT) nucleation, and in the activation of other components required to build a bipolar mitotic spindle.	16	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	25	26	29	30
3 The continued association of Plk1 and Bora during the earlier phases of the DDR would allow Plk1 to be available for phosphorylation at T210 , possibly to set it up for rapid re-activation when the damage is rapidly repaired and cells can quickly re-enter the cell cycle .	3 The continued association of Plk1 and Bora during the earlier phases of the DDR would allow Plk1 to be available for phosphorylation at T210, possibly to set it up for rapid re-activation when the damage is rapidly repaired and cells can quickly re-enter the cell cycle.	0	20	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	7	8	17	18
Consistently , we found that overexpression of Bora in MCF-7 cells increased p-Plk1 ( XREF_SUPPLEMENTARY ) and enhanced cell proliferation .	Consistently, we found that overexpression of Bora in MCF-7 cells increased p-Plk1 (XREF_SUPPLEMENTARY) and enhanced cell proliferation.	5	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	overexpression of Bora	bora	p-Plk1	p-Plk1	p-plk1	7	8	12	13
Further , activation of cdk1 leads to the activation of Plk1 by the Aurora-A and Bora kinases XREF_BIBR .	Further, activation of cdk1 leads to the activation of Plk1 by the Aurora-A and Bora kinases XREF_BIBR.	5	17	leads	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	15	16	10	11
Cdk1 phosphorylates SPAT-1 and Bora to trigger PLK-1 activation and drive mitotic entry in C. elegans embryos .	Cdk1 phosphorylates SPAT-1 and Bora to trigger PLK-1 activation and drive mitotic entry in C. elegans embryos.	0	8	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Cdk1 phosphorylates SPAT-1 and Bora	bora	PLK-1	PLK-1	plk-1	4	5	7	8
Here , we report that AIBp also interacts with Plk1 , raising the possibility of functional similarity to Bora , which subsequently promotes Aurora-A-mediated Plk1 activation at Thr210 as well as Aurora-A activation at Thr288 .	Here, we report that AIBp also interacts with Plk1, raising the possibility of functional similarity to Bora, which subsequently promotes Aurora-A-mediated Plk1 activation at Thr210 as well as Aurora-A activation at Thr288.	11	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	18	19	24	25
Cdk1 and cyclin B activity and mitotic entry are further controlled by additional superimposed feedback mechanisms upregulating the mitotic kinases Plk1 and Aurora A , and the Aurora and Plk1 activator Bora , coupling mitotic entry to centrosome maturation , and stimulating expression of proteins of the mitotic entry network , such as cyclin B XREF_BIBR .	Cdk1 and cyclin B activity and mitotic entry are further controlled by additional superimposed feedback mechanisms upregulating the mitotic kinases Plk1 and Aurora A, and the Aurora and Plk1 activator Bora, coupling mitotic entry to centrosome maturation, and stimulating expression of proteins of the mitotic entry network, such as cyclin B XREF_BIBR.	20	32	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	31	32	29	30
PLK1 triggers the beta-TRCP-dependent degradation of Bora in M-phase , while Bora and Aurora A activate PLK1 during checkpoint recovery [ XREF_BIBR ] .	PLK1 triggers the beta-TRCP-dependent degradation of Bora in M-phase, while Bora and Aurora A activate PLK1 during checkpoint recovery [XREF_BIBR].	11	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	PLK1	PLK1	PLK1	11	12	16	17
If DNA damage occurs , but Plk1 has yet to be activated , ATM and ATR prevents Plk1 activation by triggering the degradation of the Plk1 activator Bora through a phosphorylation event [ XREF_BIBR ] .	If DNA damage occurs, but Plk1 has yet to be activated, ATM and ATR prevents Plk1 activation by triggering the degradation of the Plk1 activator Bora through a phosphorylation event [XREF_BIBR].	22	28	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	27	28	25	26
XREF_BIBR Activated cytosolic and membrane bound BRAF then activate MEK1 and MEK2 .	XREF_BIBR Activated cytosolic and membrane bound BRAF then activate MEK1 and MEK2.	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK1	MEK1	MEK1	6	7	9	10
It has been shown that C5aR activation leads to downstream activation of several components of different signaling pathways like PI3K-gamma kinase , phospholipase C beta2 , phospholipase D and Raf-1 and B-Raf mediated activation of MEK-1 .	It has been shown that C5aR activation leads to downstream activation of several components of different signaling pathways like PI3K-gamma kinase, phospholipase C beta2, phospholipase D and Raf-1 and B-Raf mediated activation of MEK-1.	31	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	B-Raf	B-Raf	B-Raf	MEK-1	MEK-1	MEK-1	31	32	35	36
For example , the combination of vemurafenib , which targets BRAF , and cobimetinib , which targets MAP2K1 , was approved by the FDA in 2015 for use in treating BRAF mutated melanoma .	For example, the combination of vemurafenib, which targets BRAF, and cobimetinib, which targets MAP2K1, was approved by the FDA in 2015 for use in treating BRAF mutated melanoma.	9	18	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MAP2K1	MAP2K1	MAP2K1	10	11	17	18
The erbB-4 gene encodes a detected receptor protein that possesses intrinsic tyrosine kinase activity and belongs to the family of the epidermal growth factor receptor ( EGFR ) ; erbB-4 is stimulated by the heregulins and betacellulin , which enables this receptor to form heterodimers with erbB-2 , a prerequisite for erbB-2 activation .	The erbB-4 gene encodes a detected receptor protein that possesses intrinsic tyrosine kinase activity and belongs to the family of the epidermal growth factor receptor (EGFR); erbB-4 is stimulated by the heregulins and betacellulin, which enables this receptor to form heterodimers with erbB-2, a prerequisite for erbB-2 activation.	29	39	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	betacellulin	betacellulin	betacellulin	erbB-4	erbB-4	erbB-4	36	37	29	30
HER3 and HER4 are activated by the four neuregulins ( NRG1-4 ) and , in addition , HER4 is also activated by HB-EGF , betacellulin , and epiregulin ( for more in-depth information , please see ) .	HER3 and HER4 are activated by the four neuregulins (NRG1-4) and, in addition, HER4 is also activated by HB-EGF, betacellulin, and epiregulin (for more in-depth information, please see).	17	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	betacellulin	betacellulin	betacellulin	HER4	HER4	HER4	24	25	17	18
beta-Cellulin , epiregulin ( EREG ) , and heparin binding EGF like growth factor ( HBEGF ) are more promiscuous and activate ERBB4 in addition to ERBB1 .	beta-Cellulin, epiregulin (EREG), and heparin binding EGF like growth factor (HBEGF) are more promiscuous and activate ERBB4 in addition to ERBB1.	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Cellulin	beta-Cellulin	beta-Cellulin	ERBB4	ERBB4	ERBB4	0	1	22	23
The BTC activation of ErbB-4 appears to be independent of ErbB-1 , as shown by pretreatment of cells with an antibody that inhibits binding of EGF agonists to ErbB-1 .	The BTC activation of ErbB-4 appears to be independent of ErbB-1, as shown by pretreatment of cells with an antibody that inhibits binding of EGF agonists to ErbB-1.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BTC	BTC	BTC	ErbB-4	ErbB-4	ErbB-4	1	2	4	5
ErbB4 is activated by members of the neuregulin family , and by some members of the EGF growth factor family ; BTC , EREG , HB-EGF and NRG family .	ErbB4 is activated by members of the neuregulin family, and by some members of the EGF growth factor family; BTC, EREG, HB-EGF and NRG family.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	ErbB4	ErbB4	ErbB4	21	22	0	1
89 However , in contrast to EGF , BTC infusion increased neurogenesis in vivo , an effect attributable to the ability of this EGFR ligand to additionally activate neuroblasts ' HER4 .	89 However, in contrast to EGF, BTC infusion increased neurogenesis in vivo, an effect attributable to the ability of this EGFR ligand to additionally activate neuroblasts ' HER4.	8	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	HER4	HER4	HER4	8	9	30	31
These drug treatment induced processes were found to be mediated by the release of ligands including heregulin and betacellulin that activate HER3 and HER4 via HER2 .	These drug treatment induced processes were found to be mediated by the release of ligands including heregulin and betacellulin that activate HER3 and HER4 via HER2.	14	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	betacellulin	betacellulin	betacellulin	HER4	HER4	HER4	18	19	23	24
The ErbB4 ligands BTC , NRG1beta , NRG2beta , and NRG3 differentially stimulate ErbB4 coupling to survival and proliferation in CEM and ErbB4 cells and differentially stimulate ErbB4 coupling to Shc , p85 , Akt , and Erk1/2 .	The ErbB4 ligands BTC, NRG1beta, NRG2beta, and NRG3 differentially stimulate ErbB4 coupling to survival and proliferation in CEM and ErbB4 cells and differentially stimulate ErbB4 coupling to Shc, p85, Akt, and Erk1/2.	2	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	ErbB4	ErbB4	ErbB4	3	4	13	14
Bub1 promotes the assembly of a subset of these proteins , Mad2 , BubR1 and Bub3 , and Cdc20 , into the SAC effector , the mitotic checkpoint complex ( MCC ) , which targets the anaphase promoting complex and cyclosome ( APC/C ) to inhibit its ability to promote mitotic exit .	Bub1 promotes the assembly of a subset of these proteins, Mad2, BubR1 and Bub3, and Cdc20, into the SAC effector, the mitotic checkpoint complex (MCC), which targets the anaphase promoting complex and cyclosome (APC/C) to inhibit its ability to promote mitotic exit.	0	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	Bub1	Bub1	Bub3	Bub3	Bub3	0	1	15	16
Here , we have considerably extended our understanding of this divergence by showing that the loop motifs in the B3BDs of Bub1 and BubR1 modulate the interaction of Bub3 with MELT P.	Here, we have considerably extended our understanding of this divergence by showing that the loop motifs in the B3BDs of Bub1 and BubR1 modulate the interaction of Bub3 with MELT P.	19	29	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	Bub1	Bub1	Bub3	Bub3	Bub3	21	22	28	29
In this network , Bub3 is activated by Bub1 , Mad1 is activated by an external factor and Bub1 .	In this network, Bub3 is activated by Bub1, Mad1 is activated by an external factor and Bub1.	4	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bub1	Bub1	Bub1	Bub3	Bub3	Bub3	8	9	4	5
The loop regions of Bub1 and BubR1 modulate the interaction of Bub3 with phosphorylated MELT motifs .	The loop regions of Bub1 and BubR1 modulate the interaction of Bub3 with phosphorylated MELT motifs.	2	12	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	Bub1	Bub1	Bub3	Bub3	Bub3	4	5	11	12
In the other branch , Bub1 activates Bub3 who , together with some external factor , activate Mad3 .	In the other branch, Bub1 activates Bub3 who, together with some external factor, activate Mad3.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	Bub1	Bub1	Bub3	Bub3	Bub3	5	6	7	8
The B3BD of Bub1 strongly enhanced binding of Bub3 to phosphorylated MBP-Knl1 MELT1 but not to unphosphorylated MBP-Knl1 MELT1 , while the B3BD of BubR1 had a negligible effect ( XREF_FIG ) .	The B3BD of Bub1 strongly enhanced binding of Bub3 to phosphorylated MBP-Knl1 MELT1 but not to unphosphorylated MBP-Knl1 MELT1, while the B3BD of BubR1 had a negligible effect (XREF_FIG).	1	9	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	Bub1	Bub1	Bub3	Bub3	Bub3	3	4	8	9
Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours , commonly via BRAF amplification and mutations activating NRAS and MEK2 .	Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2.	18	26	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	BRAF	BRAF	MEK2	MEK2	MEK2	18	19	25	26
The various domains of BRCA1 allow it to integrate signals from upstream DNA damage sensing proteins such as ATM and Chk2 , and to recruit phosphoproteins BACH1 , CtIP , PalB2 , as well as heterodimerize with BARD1 to mediate E3 ligase activity .	The various domains of BRCA1 allow it to integrate signals from upstream DNA damage sensing proteins such as ATM and Chk2, and to recruit phosphoproteins BACH1, CtIP, PalB2, as well as heterodimerize with BARD1 to mediate E3 ligase activity.	2	30	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRCA1	BRCA1	BRCA1	CtIP	CtIP	CtIP	4	5	28	29
The significant increase in residual DSBs in cells transfected with antagomirs for miR-1255b , miR-193b * and miR-148b * is ' rescued ' by silencing CtIP ( XREF_FIG ; silencing efficacy shown in XREF_FIG ) , suggesting that increased levels of BRCA1 by miRNA inhibition in G1 promotes CtIP mediated resection .	The significant increase in residual DSBs in cells transfected with antagomirs for miR-1255b, miR-193b * and miR-148b * is ' rescued ' by silencing CtIP (XREF_FIG; silencing efficacy shown in XREF_FIG), suggesting that increased levels of BRCA1 by miRNA inhibition in G1 promotes CtIP mediated resection.	39	50	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRCA1	levels of BRCA1	brca1	CtIP	CtIP	ctip	41	42	48	49
The significantly greater HPRT deletion lengths in BRCA1 depleted cells compared to those of CtIP or MRE11 depleted cells supports the notion that BRCA1 operates downstream of CtIP and MRE11 .	The significantly greater HPRT deletion lengths in BRCA1 depleted cells compared to those of CtIP or MRE11 depleted cells supports the notion that BRCA1 operates downstream of CtIP and MRE11.	5	29	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRCA1	BRCA1	BRCA1	CtIP	CtIP	CtIP	7	8	27	28
BRCA1 not only serves as a scaffold protein that integrates different components of the HR machinery , but also enhances CtIP mediated 5 '-end resection of DSBs .	BRCA1 not only serves as a scaffold protein that integrates different components of the HR machinery, but also enhances CtIP mediated 5 '-end resection of DSBs.	0	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRCA1	BRCA1	BRCA1	CtIP	CtIP	CtIP	0	1	20	21
Once recruited to DSBs , the main regulatory function of BRCA1 is to conscript and activate the end-resection promoting factor CtIP .	Once recruited to DSBs, the main regulatory function of BRCA1 is to conscript and activate the end-resection promoting factor CtIP.	8	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRCA1	BRCA1	BRCA1	CtIP	CtIP	CtIP	10	11	20	21
Both Cdo and Bnip-2 positively regulate myogenic differentiation and promote activation of Cdc42 , suggesting that Cdc42 is itself promyogenic .	Both Cdo and Bnip-2 positively regulate myogenic differentiation and promote activation of Cdc42, suggesting that Cdc42 is itself promyogenic.	1	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bnip-2	Bnip-2	Bnip-2	Cdc42	Cdc42	Cdc42	3	4	12	13
Evidence is presented where BNIP-2 in vivo induces cell dynamics by recruiting Cdc42 via its BCH domain , thus providing a novel mechanism for regulating Cdc42 signaling pathway .	Evidence is presented where BNIP-2 in vivo induces cell dynamics by recruiting Cdc42 via its BCH domain, thus providing a novel mechanism for regulating Cdc42 signaling pathway.	4	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BNIP-2	BNIP-2	BNIP-2	Cdc42	Cdc42	Cdc42	4	5	12	13
Cdo and Bnip-2 promote Cdc42 activity , and Cdc42 promotes myogenesis .	Cdo and Bnip-2 promote Cdc42 activity, and Cdc42 promotes myogenesis.	0	5	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bnip-2	Bnip-2	Bnip-2	Cdc42	Cdc42	Cdc42	2	3	4	5
However , loss- and gain-of-function experiments in myoblasts indicate that Bnip-2 stimulates Cdc42 activity .	However, loss- and gain-of-function experiments in myoblasts indicate that Bnip-2 stimulates Cdc42 activity.	10	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bnip-2	Bnip-2	Bnip-2	Cdc42	Cdc42	Cdc42	10	11	12	13
For example , the BCH domain of human BNIP-2 promotes Cdc42 activation required for cell protrusions XREF_BIBR and muscle cells differentiation XREF_BIBR .	For example, the BCH domain of human BNIP-2 promotes Cdc42 activation required for cell protrusions XREF_BIBR and muscle cells differentiation XREF_BIBR.	5	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BNIP-2	BNIP-2	BNIP-2	Cdc42	Cdc42	Cdc42	8	9	10	11
Unexpectedly , BNIP-2 , either produced as a bacterial recombinant protein or expressed in 293T cells , could stimulate the intrinsic GTPase activity of Cdc42 .	Unexpectedly, BNIP-2, either produced as a bacterial recombinant protein or expressed in 293T cells, could stimulate the intrinsic GTPase activity of Cdc42.	2	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BNIP-2	BNIP-2	BNIP-2	Cdc42	Cdc42	Cdc42	2	3	24	25
Btk targets TFII-I at Y248 , Y357 and Y462 in vitro .	Btk targets TFII-I at Y248, Y357 and Y462 in vitro.	0	8	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	TFII-I	TFII-I	TFII-I	0	1	2	3
Taken together , these data suggest that although the PH domain of Btk is primarily responsible for its physical interaction with TFII-I , an intact kinase domain of Btk is required to enhance transcriptional activity of TFII-I in the nucleus .	Taken together, these data suggest that although the PH domain of Btk is primarily responsible for its physical interaction with TFII-I, an intact kinase domain of Btk is required to enhance transcriptional activity of TFII-I in the nucleus.	26	37	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	TFII-I	TFII-I	TFII-I	28	29	36	37
Lyn transphosphorylates Btk within the activation loop of the kinase domain , allowing subsequent autophosphorylation of the Btk SH3 domain and full Btk activation .	Lyn transphosphorylates Btk within the activation loop of the kinase domain, allowing subsequent autophosphorylation of the Btk SH3 domain and full Btk activation.	0	19	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Lyn transphosphorylates Btk	btk	Btk	Btk	btk	2	3	17	18
Compounds 6 and 7 significantly inhibited the proliferation of Ramos cells which overexpress the BTK enzyme , as well as the autophosphorylation of BTK at Tyr223 and the activation of its downstream signaling molecule PLCgamma2 .	Compounds 6 and 7 significantly inhibited the proliferation of Ramos cells which overexpress the BTK enzyme, as well as the autophosphorylation of BTK at Tyr223 and the activation of its downstream signaling molecule PLCgamma2.	12	28	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTK	autophosphorylation of BTK at Tyr223	btk	BTK	BTK	btk	23	24	14	15
BTK activates ATK signaling in MM cells .	BTK activates ATK signaling in MM cells.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTK	BTK	BTK	ATK	ATK	ATK	0	1	2	3
BTK expression was upregulated at both the protein and mRNA levels in MM1R dex resistant cells , suggesting a possible role of BTK in the mechanism of dex resistance ( Chauhan etal , 2002 ) .	BTK expression was upregulated at both the protein and mRNA levels in MM1R dex resistant cells, suggesting a possible role of BTK in the mechanism of dex resistance (Chauhan etal, 2002).	0	23	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTK	BTK expression	btk	BTK	BTK	btk	0	1	22	23
CGP57380 also suppressed LPS induced TNF-alpha protein synthesis in primary Itk -/- Btk -/- mast cells ( XREF_FIG ) .	CGP57380 also suppressed LPS induced TNF-alpha protein synthesis in primary Itk -/- Btk -/- mast cells (XREF_FIG).	4	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	Itk	Itk	Itk	12	13	10	11
Substitution of the activation segment of Itk with that of Btk activates Itk .	Substitution of the activation segment of Itk with that of Btk activates Itk.	8	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	Itk	Itk	Itk	10	11	12	13
Consistent with this , we observed no change in MAL accumulation in LPS stimulated Itk -/- Btk -/- BMMCs ( XREF_FIG , 1 st panel ) , suggesting that the hyperactive pro inflammatory response in mast cells lacking ITK and BTK is not due to the MAL stabilization .	Consistent with this, we observed no change in MAL accumulation in LPS stimulated Itk -/- Btk -/- BMMCs (XREF_FIG, 1 st panel), suggesting that the hyperactive pro inflammatory response in mast cells lacking ITK and BTK is not due to the MAL stabilization.	13	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	Itk	Itk	Itk	16	17	14	15
Introduction of the activation segment residues of Btk into full-length Itk activates Itk .	Introduction of the activation segment residues of Btk into full-length Itk activates Itk.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	Itk	Itk	Itk	7	8	12	13
In the first branch , Bub1 , together with some external factor , activates ( or recruits ) Mad1 which , in turn , activates ( or recruits ) Mad2 .	In the first branch, Bub1, together with some external factor, activates (or recruits) Mad1 which, in turn, activates (or recruits) Mad2.	5	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	Bub1	Bub1	Mad1	Mad1	Mad1	5	6	18	19
If this is the case , then Bub1 overexpression should be sufficient to increase the recruitment of Mad1 to unattached kinetochores .	If this is the case, then Bub1 overexpression should be sufficient to increase the recruitment of Mad1 to unattached kinetochores.	7	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	Bub1 overexpression	bub1	Mad1	Mad1	mad1	7	8	17	18
Neither Bub1 DeltaCD1 nor Bub1 Delta437-521 efficiently rescued Bub1 dependent Mad1 localization ( XREF_SUPPLEMENTARY ) .	Neither Bub1 DeltaCD1 nor Bub1 Delta437-521 efficiently rescued Bub1 dependent Mad1 localization (XREF_SUPPLEMENTARY).	1	11	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	Bub1	Bub1	Mad1	Mad1	Mad1	1	2	10	11
Since full-length Bora is known to enhance the catalytic activity of Aur-A toward Plk1 , XREF_BIBR , XREF_BIBR , XREF_BIBR we initially examined whether Bora NT shows the same effect during in vitro Plk1 activation .	Since full-length Bora is known to enhance the catalytic activity of Aur-A toward Plk1, XREF_BIBR, XREF_BIBR, XREF_BIBR we initially examined whether Bora NT shows the same effect during in vitro Plk1 activation.	1	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	Aur-A	Aur-A	Aur-A	2	3	11	12
Consistently , Bora does not significantly increase AURKA activity toward substrates other than Plk1 , and the extent of activation of AURKA coimmunoprecipitated with Bora , as assessed by p-Thr-288 , is by far lower than that associated with the fractions immunoprecipitated with TPX2 or Cep192 .	Consistently, Bora does not significantly increase AURKA activity toward substrates other than Plk1, and the extent of activation of AURKA coimmunoprecipitated with Bora, as assessed by p-Thr-288, is by far lower than that associated with the fractions immunoprecipitated with TPX2 or Cep192.	2	8	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bora	Bora	Bora	AURKA	AURKA	AURKA	2	3	7	8
We also show that mutation of the Itk and Btk gatekeeper residues to methionine is sufficient to activate the isolated kinase domains of Tec kinases in the absence of the amino-terminal SH2-kinase linker .	We also show that mutation of the Itk and Btk gatekeeper residues to methionine is sufficient to activate the isolated kinase domains of Tec kinases in the absence of the amino-terminal SH2-kinase linker.	9	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Btk	Btk	Btk	Tec	Tec	Tec	9	10	23	24
Combined analyses of both A431 and Ramos cells treated with probes 3 and 4 identified a total of 29 probe targets ( XREF_FIG and Supplementary Tables 2 and 3 ) , including EGFR and BTK , additional known kinase targets of the tested covalent inhibitors - ERBB2 XREF_BIBR , XREF_BIBR , BLK XREF_BIBR , XREF_BIBR , and TEC 18 - and many other non kinase proteins .	Combined analyses of both A431 and Ramos cells treated with probes 3 and 4 identified a total of 29 probe targets (XREF_FIG and Supplementary Tables 2 and 3), including EGFR and BTK, additional known kinase targets of the tested covalent inhibitors - ERBB2 XREF_BIBR, XREF_BIBR, BLK XREF_BIBR, XREF_BIBR, and TEC 18 - and many other non kinase proteins.	20	58	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	BTK	BTK	BTK	TEC	TEC	TEC	34	35	57	58
BMX knockdown reduced the abundance of pTyr 576/577 FAK in basal and fibronectin ( FN )-stimulated conditions ( XREF_FIG ) , indicating that BMX mediates FAK phosphorylation in response to physiological stimuli .	BMX knockdown reduced the abundance of pTyr 576/577 FAK in basal and fibronectin (FN)-stimulated conditions (XREF_FIG), indicating that BMX mediates FAK phosphorylation in response to physiological stimuli.	0	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BMX	BMX	BMX	FAK	FAK	FAK	0	1	8	9
Together , these findings show that BMX activated FAK by phosphorylating Tyr 577 subsequent to a priming phosphorylation by Src at Tyr 576 .	Together, these findings show that BMX activated FAK by phosphorylating Tyr 577 subsequent to a priming phosphorylation by Src at Tyr 576.	6	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMX	BMX	BMX	FAK	FAK	FAK	6	7	8	9
Because phosphorylation of Thr177 in CaMKI , which is equivalent to Thr239 of DCLK1 , by CaMK kinase enhances CaMKI activity , it has been speculated that DCLK1 kinase activity can be regulated by upstream kinases similar to CaMK kinase 43 .	Because phosphorylation of Thr177 in CaMKI, which is equivalent to Thr239 of DCLK1, by CaMK kinase enhances CaMKI activity, it has been speculated that DCLK1 kinase activity can be regulated by upstream kinases similar to CaMK kinase 43.	1	20	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CaMKI	phosphorylation of Thr177 in CaMKI	camki	CaMKI	CaMKI	camki	5	6	19	20
However , the presence of Ssd increased phospho-Thr 177 -CaMKI content and the phospho-Thr 177 -CaMKI and CaMKI ratio , supporting the notion that both CDDP and Ssd are required to activate CaMKI and that Ssd increases [ Ca 2+ ] c and , in the presence of CDDP which could be essential to these pathways as an adjuvant , induces MMP loss and activation of CaMKI , resulting in Drp1 mediated mitochondrial fragmentation and apoptosis in chemoresistant cells .	However, the presence of Ssd increased phospho-Thr 177 -CaMKI content and the phospho-Thr 177 -CaMKI and CaMKI ratio, supporting the notion that both CDDP and Ssd are required to activate CaMKI and that Ssd increases [Ca 2+] c and, in the presence of CDDP which could be essential to these pathways as an adjuvant, induces MMP loss and activation of CaMKI, resulting in Drp1 mediated mitochondrial fragmentation and apoptosis in chemoresistant cells.	17	67	induces	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	CaMKI	CaMKI	camki	CaMKI	loss and activation of CaMKI	camki	17	18	66	67
Active Aurora B then phosphorylates ATM , which then phosphorylates gamma-H2AX and Bub1 at kinetochores , promoting the accumulation of Mad2 and Cdc20 .	Active Aurora B then phosphorylates ATM, which then phosphorylates gamma-H2AX and Bub1 at kinetochores, promoting the accumulation of Mad2 and Cdc20.	5	22	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	ATM, which then phosphorylates gamma-H2AX and Bub1	bub1	Mad2	Mad2	mad2	12	13	20	21
Ectopic expression of the wild-type Bub1 , but not the Bub1 T609A mutant , in Bub1-RNAi cells restores the kinetochore localization of Plk1 .	Ectopic expression of the wild-type Bub1, but not the Bub1 T609A mutant, in Bub1-RNAi cells restores the kinetochore localization of Plk1.	1	23	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	expression of the wild-type Bub1	bub1	Plk1	Plk1	plk1	5	6	22	23
We find that constitutively active CaM kinase I and IV can activate both ATF1 and CREB .	We find that constitutively active CaM kinase I and IV can activate both ATF1 and CREB.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CaM kinase I	CaM kinase I	CaM kinase I	ATF1	ATF1	ATF1	5	8	13	14
One straightforward explanation for this observation is that Bub1 depletion , but not Bub1 inhibition , caused the displacement of CENP-E from KTs , a motor protein required for efficient chromosome congression .	One straightforward explanation for this observation is that Bub1 depletion, but not Bub1 inhibition, caused the displacement of CENP-E from KTs, a motor protein required for efficient chromosome congression.	8	21	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bub1	Bub1	Bub1	CENP-E	CENP-E	CENP-E	8	9	20	21
During homeostatic conditions , CaMKK2 stimulates OC differentiation by activating phosphorylated form of cyclic adenosine monophosphate ( cAMP ) response element binding protein ( pCREB ) and its transcriptional target , nuclear factor of activated T cells c1 in a CaMKIV dependent manner .	During homeostatic conditions, CaMKK2 stimulates OC differentiation by activating phosphorylated form of cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB) and its transcriptional target, nuclear factor of activated T cells c1 in a CaMKIV dependent manner.	4	42	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CaMKK2	CaMKK2	CaMKK2	CaMKIV	CaMKIV	CaMKIV	4	5	40	41
Additionally , deletion of CaMKK beta , one of the two CaMKK isoforms , reduced CaMK IV activation and CaMK IV deletion in mice worsened stroke outcome .	Additionally, deletion of CaMKK beta, one of the two CaMKK isoforms, reduced CaMK IV activation and CaMK IV deletion in mice worsened stroke outcome.	4	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CaMKK beta	CaMKK beta	CaMKK beta	CaMK IV	CaMK IV	CaMK IV	4	6	19	21
A recent study described a dual regulatory role by which CaMKK2 activation of CaMKIV prevents premature differentiation of mesenchymal stem cells into bone matrix producing osteoblasts , while CaMKK2 activity leads to CREB phosphorylation and subsequent differentiation of osteoclasts .	A recent study described a dual regulatory role by which CaMKK2 activation of CaMKIV prevents premature differentiation of mesenchymal stem cells into bone matrix producing osteoblasts, while CaMKK2 activity leads to CREB phosphorylation and subsequent differentiation of osteoclasts.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CaMKK2	CaMKK2	CaMKK2	CaMKIV	CaMKIV	CaMKIV	10	11	13	14
In neurons , Ca 2+ -induced activation of CREB dependent gene transcription requires concurrent activation of CBP by CaMKIV .	In neurons, Ca 2+ -induced activation of CREB dependent gene transcription requires concurrent activation of CBP by CaMKIV.	12	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CaMKIV	CaMKIV	CaMKIV	CBP	CBP	CBP	18	19	16	17
Re-expression of CaMKIV in Camk4-/- KLS cells results in the rescue of the proliferation defects in vitro as well as in the restoration of CBP and Bcl-2 to wild type levels .	Re-expression of CaMKIV in Camk4-/- KLS cells results in the rescue of the proliferation defects in vitro as well as in the restoration of CBP and Bcl-2 to wild type levels.	0	26	restoration	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	CaMKIV	Re-expression of CaMKIV	camkiv	CBP	CBP	cbp	2	3	24	25
Following an increase in intracellular Ca 2+ , CAMKK2 activates CAMKI , CAMKIV , Akt and AMP activated protein kinase ( AMPK ) in a number of pathways [ XREF_BIBR , XREF_BIBR ] .	Following an increase in intracellular Ca 2+, CAMKK2 activates CAMKI, CAMKIV, Akt and AMP activated protein kinase (AMPK) in a number of pathways [XREF_BIBR, XREF_BIBR].	5	16	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CAMKK2	CAMKK2	CAMKK2	CAMKI	CAMKI	CAMKI	8	9	10	11
CAMKK1 activates CAMK1 and CAMKIV by phosphorylation of their amino acids Thr177 and Thr196 respectively and has been shown to modulate mammalian target of rapamycin complex 1 ( mTORC ) and 5 ' adenosine monophosphate activated protein kinase ( AMPK ) signaling 22 , 23 , 24 .	CAMKK1 activates CAMK1 and CAMKIV by phosphorylation of their amino acids Thr177 and Thr196 respectively and has been shown to modulate mammalian target of rapamycin complex 1 (mTORC) and 5 ' adenosine monophosphate activated protein kinase (AMPK) signaling 22, 23, 24.	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CAMKK1	CAMKK1	CAMKK1	CAMKIV	CAMKIV	CAMKIV	0	1	4	5
CAMK4 is activated by CAMKK1 , and CAMKK1 is activated by CALM ( Soderling ., 1999 ; Fujisawa ., 2001 ; Hook et al ., 2001 ) .	CAMK4 is activated by CAMKK1, and CAMKK1 is activated by CALM (Soderling., 1999; Fujisawa., 2001; Hook et al., 2001).	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CAMKK1	CAMKK1	CAMKK1	CAMK4	CAMK4	CAMK4	4	5	0	1
68 PPP3CA and CAMK4 both activate CREB1 , a transcription factor that is integral to PPARGC1A mediated expression .	68 PPP3CA and CAMK4 both activate CREB1, a transcription factor that is integral to PPARGC1A mediated expression.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CAMK4	CAMK4	CAMK4	CREB1	CREB1	CREB1	3	4	6	7
AMPKalpha2 activation by CaMKKbeta has been known to function in the hypothalamus in controlling food intake .	AMPKalpha2 activation by CaMKKbeta has been known to function in the hypothalamus in controlling food intake.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CaMKKbeta	CaMKKbeta	CaMKKbeta	AMPKalpha2	AMPKalpha2	AMPKalpha2	3	4	0	1
Taken together , these data suggest that AMPKalpha2 is the major catalytic subunit of AMPKalpha which regulates Golgi fragmentation and G2/M transition , and that the CaMKKbeta activates AMPKalpha2 during late G2 phase .	Taken together, these data suggest that AMPKalpha2 is the major catalytic subunit of AMPKalpha which regulates Golgi fragmentation and G2/M transition, and that the CaMKKbeta activates AMPKalpha2 during late G2 phase.	25	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CaMKKbeta	CaMKKbeta	CaMKKbeta	AMPKalpha2	AMPKalpha2	AMPKalpha2	26	27	28	29
The activation of PKB by CaM-kinase kinase alpha was as high as 300-fold after incubation for 30 min under the phosphorylation conditions , and still increased thereafter , suggesting that the maximal activation of PKB on phosphorylation of the Thr ( 308 ) residue is several hundred fold .	The activation of PKB by CaM-kinase kinase alpha was as high as 300-fold after incubation for 30 min under the phosphorylation conditions, and still increased thereafter, suggesting that the maximal activation of PKB on phosphorylation of the Thr (308) residue is several hundred fold.	1	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CaM-kinase kinase alpha	CaM-kinase kinase alpha	CaM-kinase kinase alpha	PKB	PKB	PKB	5	8	3	4
A paradigm changing report by Yano et al indicates that CAMKKalpha causes non canonical Akt activation [ XREF_BIBR ] .	A paradigm changing report by Yano et al indicates that CAMKKalpha causes non canonical Akt activation [XREF_BIBR].	10	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CAMKKalpha	CAMKKalpha	CAMKKalpha	Akt	Akt	Akt	10	11	14	15
However , more recently , it has been suggested that hypoxic stress acts through calcium influx , triggering CaMKKbeta mediated AMPKalpha1 activation ( Gusarova etal .	However, more recently, it has been suggested that hypoxic stress acts through calcium influx, triggering CaMKKbeta mediated AMPKalpha1 activation (Gusarova etal.	17	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	CaMKKbeta	CaMKKbeta	CaMKKbeta	AMPKalpha1	AMPKalpha1	AMPKalpha1	18	19	20	21
Here we found that the T 1 AM mediated increases on Ser 19 and Ser 40 TH were inhibited by blockade of CamKII and PKA by either KN-92 or H-89 , respectively .	Here we found that the T 1 AM mediated increases on Ser 19 and Ser 40 TH were inhibited by blockade of CamKII and PKA by either KN-92 or H-89, respectively.	5	24	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	CamKII	CamKII	CamKII	TH	TH	TH	22	23	16	17
On the other hand , caspase-9 directly activated caspase-3 in the presence of caspase-3 .	On the other hand, caspase-9 directly activated caspase-3 in the presence of caspase-3.	5	9	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	8	9
Furthermore , activated caspase-9 activates downstream caspase-3 and/or -7 , which in turn results in the cleavage or degradation of several key cellular substrates , including PARP , thus leading to apoptosis .	Furthermore, activated caspase-9 activates downstream caspase-3 and/or -7, which in turn results in the cleavage or degradation of several key cellular substrates, including PARP, thus leading to apoptosis.	2	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	6	7
Caspase-9 activates caspase-3 , and results in DNA damage .	Caspase-9 activates caspase-3, and results in DNA damage.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	2	3
Moreover , caspase-9 inhibition impeded caspase-3 activation .	Moreover, caspase-9 inhibition impeded caspase-3 activation.	2	6	impeded	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	5	6
Caspase8 and caspase9 activate caspase3 by proteolytic cleavage and caspase3 then cleaves vital cellular proteins or other caspases XREF_BIBR .	Caspase8 and caspase9 activate caspase3 by proteolytic cleavage and caspase3 then cleaves vital cellular proteins or other caspases XREF_BIBR.	0	11	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase9	caspase9	caspase9	caspase3	caspase3	caspase3	2	3	4	5
Caspase-9 is then activated at the apoptosome and , subsequently , activates pro-caspase-3 .	Caspase-9 is then activated at the apoptosome and, subsequently, activates pro-caspase-3.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	pro-caspase-3	pro-caspase-3	pro-caspase-3	0	1	12	13
Further , investigation of the apoptotic pathway showed increased release of cytochrome c resulting in the activation of caspase-9 , which in turn activated caspase-3 and -6 .	Further, investigation of the apoptotic pathway showed increased release of cytochrome c resulting in the activation of caspase-9, which in turn activated caspase-3 and -6.	16	26	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	18	19	24	25
In addition , activated caspase 9 can cleave and activate downstream effector caspases such as caspase 3 , 6 and 7 .	In addition, activated caspase 9 can cleave and activate downstream effector caspases such as caspase 3, 6 and 7.	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	4	6	15	17
Thus , the activation of caspase-9 should induce the activation of caspase-3 .	Thus, the activation of caspase-9 should induce the activation of caspase-3.	3	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	11	12
This process activates caspase-9 , which in turn cleaves and activates caspase-3 .	This process activates caspase-9, which in turn cleaves and activates caspase-3.	2	12	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	11	12
In addition , palmitate induced activation of mitochondrial transition pores caused depolarization of the mitochondrial inner membrane and cytochrome c release into the cytosol , which stimulates the assembly of the apoptosome leading to activation of caspase-9 , which , in turn , activates caspase-3 , leading to DNA fragmentation and cell death [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, palmitate induced activation of mitochondrial transition pores caused depolarization of the mitochondrial inner membrane and cytochrome c release into the cytosol, which stimulates the assembly of the apoptosome leading to activation of caspase-9, which, in turn, activates caspase-3, leading to DNA fragmentation and cell death [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	34	45	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	36	37	44	45
Once activated , caspase-8 and caspase-10 activate other members of the caspase family , the so called ' executioner caspases ' such as caspase-3 and caspase-7 , either by direct proteolytic processing of their precursors or indirectly , by triggering the release of cytochrome c from the mitochondria : cytochrome c activates caspase-9 , which in turn processes and activates caspase-3 and caspase-7 .	Once activated, caspase-8 and caspase-10 activate other members of the caspase family, the so called ' executioner caspases ' such as caspase-3 and caspase-7, either by direct proteolytic processing of their precursors or indirectly, by triggering the release of cytochrome c from the mitochondria : cytochrome c activates caspase-9, which in turn processes and activates caspase-3 and caspase-7.	51	62	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	52	53	60	61
Cytochrome c triggers the activity of caspase 9 , and activated caspase 9 then stimulates the activity of caspase 3 .	Cytochrome c triggers the activity of caspase 9, and activated caspase 9 then stimulates the activity of caspase 3.	11	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	11	13	18	20
Caspase 9 subsequently induces caspase 3 activation , which triggers the execution of apoptotic cell death .	Caspase 9 subsequently induces caspase 3 activation, which triggers the execution of apoptotic cell death.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	4	6
Furthermore , activated caspase-9 activates downstream caspase-3 which in turn , results in the cleavage or degradation of several key cellular substrates , including PARP , and leads to the subsequent apoptosis .	Furthermore, activated caspase-9 activates downstream caspase-3 which in turn, results in the cleavage or degradation of several key cellular substrates, including PARP, and leads to the subsequent apoptosis.	2	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	6	7
This apoptosome subsequently cleaves the procaspase to its active form of caspase-9 , which in turn activates the effector caspase-3 .	This apoptosome subsequently cleaves the procaspase to its active form of caspase-9, which in turn activates the effector caspase-3.	9	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	11	12	19	20
The activated caspase-9 in turn activates effector caspase-3 , thereby initiating a cascade of proteolytic events .	The activated caspase-9 in turn activates effector caspase-3, thereby initiating a cascade of proteolytic events.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	7	8
On the one hand , caspase-9 enhances Puma activation by cleaving Bcl-2 and Bcl-xL independent of caspase-3 .	On the one hand, caspase-9 enhances Puma activation by cleaving Bcl-2 and Bcl-xL independent of caspase-3.	5	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	16	17
The release of cytochrome c from mitochondria to the cell cytosol stimulates the activation of apoptosis initiator caspase 9 , which then activates effector caspase 3 .	The release of cytochrome c from mitochondria to the cell cytosol stimulates the activation of apoptosis initiator caspase 9, which then activates effector caspase 3.	13	26	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	17	19	24	26
Caspase-3 is activated by the upstream caspase-8 and caspase-9 , since it serves as a convergence point for different signalling pathways .	Caspase-3 is activated by the upstream caspase-8 and caspase-9, since it serves as a convergence point for different signalling pathways.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	8	9	0	1
It has been pointed out that caspase-3 is activated by caspase-9 via activation of BID by caspase-8 , loss of mitochondrial membrane potential ( Deltapsim ) and cytochrome c release in the cytosol .	It has been pointed out that caspase-3 is activated by caspase-9 via activation of BID by caspase-8, loss of mitochondrial membrane potential (Deltapsim) and cytochrome c release in the cytosol.	6	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	10	11	6	7
This complex , called the apoptosome , in presence of dATP , activates Caspase-9 , which in turn activates Caspase-3 leading to the later events involved in cell death [ XREF_BIBR , XREF_BIBR ] .	This complex, called the apoptosome, in presence of dATP, activates Caspase-9, which in turn activates Caspase-3 leading to the later events involved in cell death [XREF_BIBR, XREF_BIBR].	12	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	13	14	19	20
The caspase-9 subsequently activates the downstream executor caspase-3 .	The caspase-9 subsequently activates the downstream executor caspase-3.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	7	8
Caspase-9 is thought to activate caspase-3 , which is known to cleave many nuclear DNA repair enzymes , such as PARP , resulting in nuclear DNA damage and apoptosis [ XREF_BIBR ] .	Caspase-9 is thought to activate caspase-3, which is known to cleave many nuclear DNA repair enzymes, such as PARP, resulting in nuclear DNA damage and apoptosis [XREF_BIBR].	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	5	6
Caspase-3 , which is activated by caspase-9 , contributes to the execution of apoptosis via the activation , hydrolysis and proteolysis of specific substrates such as DNA dependent protein kinases [ XREF_BIBR ] .	Caspase-3, which is activated by caspase-9, contributes to the execution of apoptosis via the activation, hydrolysis and proteolysis of specific substrates such as DNA dependent protein kinases [XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	6	7	0	1
Caspase-3 , the main executioner for apoptosis , can be activated by upstream initiator caspase-9 through intrinsic apoptosis pathway [ XREF_BIBR ] .	Caspase-3, the main executioner for apoptosis, can be activated by upstream initiator caspase-9 through intrinsic apoptosis pathway [XREF_BIBR].	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	14	15	0	1
Brucine induced HepG2 cell apoptosis was caspase dependent , with caspase-3 activated by caspase-9 .	Brucine induced HepG2 cell apoptosis was caspase dependent, with caspase-3 activated by caspase-9.	7	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	13	14	10	11
Cytochrome c release along with procaspase 9 and dATP activates caspase 9 which then activates caspase 3 ; the second pathway involves the direct activation of caspase 3 by caspase 8 [ XREF_BIBR ] .	Cytochrome c release along with procaspase 9 and dATP activates caspase 9 which then activates caspase 3; the second pathway involves the direct activation of caspase 3 by caspase 8 [XREF_BIBR].	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	10	12	15	17
Active caspase-9 then causes activation of caspase-3 , which in turn cleaves many cellular substrates resulting in the biochemical and morphological features characteristic of apoptosis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Active caspase-9 then causes activation of caspase-3, which in turn cleaves many cellular substrates resulting in the biochemical and morphological features characteristic of apoptosis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	6	7
In animal models of ischemic stroke , caspase-9 leads to the activation of caspase-3 , which is considered to be a key mediator of apoptosis .	In animal models of ischemic stroke, caspase-9 leads to the activation of caspase-3, which is considered to be a key mediator of apoptosis.	7	22	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	13	14
Activation of caspase-8 and caspase-9 induced caspase-3 activity , respectively , in apoptosis of extrinsic and intrinsic pathways .	Activation of caspase-8 and caspase-9 induced caspase-3 activity, respectively, in apoptosis of extrinsic and intrinsic pathways.	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	6	7
Both caspase-9 and caspase-8 activate caspase-3 , leading to cellular death 18 .	Both caspase-9 and caspase-8 activate caspase-3, leading to cellular death 18.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	5	6
As we known , mitochondrial pathway ( the mainly apoptosis pathway ) , is characterized by the efflux of cytochrome C from the mitochondria to the cytosol , where the initiator caspase-9 is activated and triggers the activation of caspase-3 XREF_BIBR .	As we known, mitochondrial pathway (the mainly apoptosis pathway), is characterized by the efflux of cytochrome C from the mitochondria to the cytosol, where the initiator caspase-9 is activated and triggers the activation of caspase-3 XREF_BIBR.	29	40	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	31	32	39	40
Caspase-3 has been implicated in macrophage apoptosis and is activated by caspase-9 .	Caspase-3 has been implicated in macrophage apoptosis and is activated by caspase-9.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	11	12	0	1
Caspase-3 is activated by cleavage of caspase-8 and caspase-9 .	Caspase-3 is activated by cleavage of caspase-8 and caspase-9.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	8	9	0	1
In MKN28 cells , panbinostat decreased cFLIP and increased BNIP3L and increased caspase-9 and the combination further decreased cFLIP and enhanced cleavage of caspase-8 and caspase-3 .	In MKN28 cells, panbinostat decreased cFLIP and increased BNIP3L and increased caspase-9 and the combination further decreased cFLIP and enhanced cleavage of caspase-8 and caspase-3.	12	26	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	12	13	25	26
Caspase-9 is an important apoptosis initiator while Caspase-3 is an apoptosis executioner XREF_BIBR , the first initiation of Caspase-9 at lower doses might induce the increase of Caspase-3 , which subsequently would lead to apoptosis .	Caspase-9 is an important apoptosis initiator while Caspase-3 is an apoptosis executioner XREF_BIBR, the first initiation of Caspase-9 at lower doses might induce the increase of Caspase-3, which subsequently would lead to apoptosis.	16	32	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	18	19	27	28
In vitro active caspase-12 is able to directly cleave caspase-9 which subsequentially activates caspase-3 , potentially eliminating the requirements of the mitochondria and the apoptosome to perform ER-stress induced apoptosis [ XREF_BIBR , XREF_BIBR ] .	In vitro active caspase-12 is able to directly cleave caspase-9 which subsequentially activates caspase-3, potentially eliminating the requirements of the mitochondria and the apoptosome to perform ER-stress induced apoptosis [XREF_BIBR, XREF_BIBR].	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	13	14
As a result caspase cascade is started via caspase-9 that in turn stimulates effector caspase-3 [ XREF_BIBR , XREF_BIBR ] .	As a result caspase cascade is started via caspase-9 that in turn stimulates effector caspase-3 [XREF_BIBR, XREF_BIBR].	6	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	14	15
The main mechanism by which manuka appears to exert its anti-proliferative effect on cancer cells is through the activation of the intrinsic apoptotic pathway , involving the induction of the initiator caspase-9 which in turns activates the executioner caspase-3 XREF_BIBR .	The main mechanism by which manuka appears to exert its anti-proliferative effect on cancer cells is through the activation of the intrinsic apoptotic pathway, involving the induction of the initiator caspase-9 which in turns activates the executioner caspase-3 XREF_BIBR.	27	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	31	32	38	39
XREF_BIBR The intrinsic or non death receptor mediated apoptosis is regulated by the B cell lymphoma 2 ( Bcl-2 ) family of proteins and induces mitochondrial dysfunction resulting in activation of caspase 9 , which in turn activates the effector caspase 3 , 6 , and 7 .	XREF_BIBR The intrinsic or non death receptor mediated apoptosis is regulated by the B cell lymphoma 2 (Bcl-2) family of proteins and induces mitochondrial dysfunction resulting in activation of caspase 9, which in turn activates the effector caspase 3, 6, and 7.	29	46	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	31	33	40	42
Caspase-9 facilitates mitochondria related apoptosis after release of cytochrome C. Caspase-8 and caspase-9 activate caspase-3 , which executes apoptosis .	Caspase-9 facilitates mitochondria related apoptosis after release of cytochrome C. Caspase-8 and caspase-9 activate caspase-3, which executes apoptosis.	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	12	13	14	15
Furthermore , the leaked cyt c in association with pro apoptotic factors like Apoptotic Protease Activating Factor-1 ( Apaf-1 ) mediate the activation of caspase-9 ( elicitor caspase ) , which in turn activates caspase-3 ( executioner caspase ) .	Furthermore, the leaked cyt c in association with pro apoptotic factors like Apoptotic Protease Activating Factor-1 (Apaf-1) mediate the activation of caspase-9 (elicitor caspase), which in turn activates caspase-3 (executioner caspase).	22	37	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	24	25	34	35
Mature caspase-9 activates additional caspase-9 molecules as well as caspase-3 , and in turn , the execution of cell apoptosis .	Mature caspase-9 activates additional caspase-9 molecules as well as caspase-3, and in turn, the execution of cell apoptosis.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	9	10
The mitochondrial release of cytochrome c activates pro-caspase-9 , after which activated caspase-9 propagates a caspase cascade to activate other caspases , resulting in the activation of caspase-3 and the induction of apoptosis .	The mitochondrial release of cytochrome c activates pro-caspase-9, after which activated caspase-9 propagates a caspase cascade to activate other caspases, resulting in the activation of caspase-3 and the induction of apoptosis.	7	28	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	pro-caspase-9	pro-caspase-9	pro-caspase-9	caspase-3	caspase-3	caspase-3	7	8	27	28
XREF_BIBR , XREF_BIBR Once activated , the initiator caspase-9 cleaves and thereby activates the executioner caspase-3 and -7 , ultimately leading to apoptosis .	XREF_BIBR, XREF_BIBR Once activated, the initiator caspase-9 cleaves and thereby activates the executioner caspase-3 and -7, ultimately leading to apoptosis.	6	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	15	16
Caspase-9 in turn activates caspase-3 , resulting in apoptosis [ XREF_BIBR ] .	Caspase-9 in turn activates caspase-3, resulting in apoptosis [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	4	5
The activated caspase-9 in turn activates caspase-3 which orchestrates platelet apoptosis .	The activated caspase-9 in turn activates caspase-3 which orchestrates platelet apoptosis.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	6	7
Here we demonstrate in a mouse macrophage cell line ( MH-S cells ) that alpha-quartz silica exposure ( 12.5 mug and cm2 to 50 mug and cm2 ) elicited activation of both caspase 3 and caspase 9 , whereas anatase titanium dioxide ( TiO2 ) , a non fibrogenic particle , did not .	Here we demonstrate in a mouse macrophage cell line (MH-S cells) that alpha-quartz silica exposure (12.5 mug and cm2 to 50 mug and cm2) elicited activation of both caspase 3 and caspase 9, whereas anatase titanium dioxide (TiO2), a non fibrogenic particle, did not.	2	37	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	35	37	32	34
Inhibition of caspase 9 after combination treatment blunted neither JNK1/2/3 activation nor the enhanced expression of BAD and BAX , but did block caspase 3 cleavage , reduced expression of BCL-XL and inhibition of ERK1/2 activity .	Inhibition of caspase 9 after combination treatment blunted neither JNK1/2/3 activation nor the enhanced expression of BAD and BAX, but did block caspase 3 cleavage, reduced expression of BCL-XL and inhibition of ERK1/2 activity.	0	25	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	2	4	23	25
The activation of caspase-9 resulted from the leakage of Cytochrome-c , and then the activated caspase-9 could induce activation of caspase-3 .	The activation of caspase-9 resulted from the leakage of Cytochrome-c, and then the activated caspase-9 could induce activation of caspase-3.	13	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	15	16	20	21
Our results showed that an elevation in level of p53 after combination therapy induced the mitochondrial pathway of apoptosis for activation of caspase-9 , which in turn activated caspase-3 for completion of apoptosis in glioblastoma cells both in culture and xenograft models .	Our results showed that an elevation in level of p53 after combination therapy induced the mitochondrial pathway of apoptosis for activation of caspase-9, which in turn activated caspase-3 for completion of apoptosis in glioblastoma cells both in culture and xenograft models.	20	29	activated	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	22	23	28	29
Reduction of caspase-9 levels , using an shRNA construct , prevented caspase-3 activation and inhibited myoblast fusion .	Reduction of caspase-9 levels, using an shRNA construct, prevented caspase-3 activation and inhibited myoblast fusion.	2	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9 levels	caspase-9	caspase-3	caspase-3	caspase-3	2	3	11	12
[ XREF_BIBR ] Caspase-3 is considered to be the most important of the executioner caspases and is activated by any of the initiator caspases ( caspase-8 , caspase-9 , or caspase-10 ) .	[XREF_BIBR] Caspase-3 is considered to be the most important of the executioner caspases and is activated by any of the initiator caspases (caspase-8, caspase-9, or caspase-10).	1	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	27	28	3	4
Mitochondria mediated apoptosis involves the cleavage of pro caspase 9 into the 36 kDa active caspase 9 , which then cleaves and thereby activates pro caspase 3 .	Mitochondria mediated apoptosis involves the cleavage of pro caspase 9 into the 36 kDa active caspase 9, which then cleaves and thereby activates pro caspase 3.	8	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	15	17	25	27
Diminished Akt signaling promoted the cleavage of caspase 3 , and both caspase 3 cleavage and FasL induction were inhibited by transduction of dominant negative caspase 9 or the caspase 8 inhibitor CrmA .	Diminished Akt signaling promoted the cleavage of caspase 3, and both caspase 3 cleavage and FasL induction were inhibited by transduction of dominant negative caspase 9 or the caspase 8 inhibitor CrmA.	12	27	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	25	27	12	14
Active caspase-9 then activates caspase-3 , which in turn cleaves substrates such as inhibitor of caspase activated DNase ( ICAD ) and PARP , leading to nucelosomal DNA fragmentation and thus apoptosis .	Active caspase-9 then activates caspase-3, which in turn cleaves substrates such as inhibitor of caspase activated DNase (ICAD) and PARP, leading to nucelosomal DNA fragmentation and thus apoptosis.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	4	5
In the mitochondrial pathway , the apoptotic protease activating factor combined with Cytochrome c ( Cyt c ) activates caspase-9 , which in turn , activates downstream caspase-3 .	In the mitochondrial pathway, the apoptotic protease activating factor combined with Cytochrome c (Cyt c) activates caspase-9, which in turn, activates downstream caspase-3.	18	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	19	20	27	28
This cleavage of caspase-9 has been reported to induce cell death by activating the downstream caspase-3 and PARP-1 ( poly ADP-ribose polymerase-1 ) .	This cleavage of caspase-9 has been reported to induce cell death by activating the downstream caspase-3 and PARP-1 (poly ADP-ribose polymerase-1).	1	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	15	16
Activation of caspase-8 and caspase-9 then promote caspase-3 , which in turn hydrolyzes cell specific proteins , and poly ADP ribose polymerase ( PARP ) , thereby inducing apoptosis [ XREF_BIBR , XREF_BIBR ] .	Activation of caspase-8 and caspase-9 then promote caspase-3, which in turn hydrolyzes cell specific proteins, and poly ADP ribose polymerase (PARP), thereby inducing apoptosis [XREF_BIBR, XREF_BIBR].	0	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	7	8
Cytoplasmic cytochrome c complexes with Apaf-1 and activates caspase-9 , which further activates caspase-3 to trigger apoptosis .	Cytoplasmic cytochrome c complexes with Apaf-1 and activates caspase-9, which further activates caspase-3 to trigger apoptosis.	7	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	13	14
Cytochrome c assembles in the cytoplasm with ATP and the scaffold protein apoptosis promoting factor-1 to form the caspase-9 activating apoptosome , which in turn processes and activates caspase-3 .	Cytochrome c assembles in the cytoplasm with ATP and the scaffold protein apoptosis promoting factor-1 to form the caspase-9 activating apoptosome, which in turn processes and activates caspase-3.	18	29	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	18	19	28	29
Apoptosome mediated activation of caspase-9 activates caspase-3 and caspase-7 , which promote cell death .	Apoptosome mediated activation of caspase-9 activates caspase-3 and caspase-7, which promote cell death.	2	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	6	7
We documented that in affected muscle fibres , nuclear chromatin is condensed in lumpy irregular masses and cytochrome c is released into the cytosol to activate , along with Apaf-1 ( apoptotic protease activating factor 1 ) , caspase 9 that , in turn , activates effector caspase 3 , caspase 6 , and caspase 7 , suggesting the execution of the intrinsic apoptotic pathway .	We documented that in affected muscle fibres, nuclear chromatin is condensed in lumpy irregular masses and cytochrome c is released into the cytosol to activate, along with Apaf-1 (apoptotic protease activating factor 1), caspase 9 that, in turn, activates effector caspase 3, caspase 6, and caspase 7, suggesting the execution of the intrinsic apoptotic pathway.	25	54	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	38	40	47	49
Activated Caspase-9 activates Caspase-3 , which then turns on caspase activated DNase and other pro apoptotic factors , leading to DNA fragmentation and cell death XREF_BIBR , XREF_BIBR .	Activated Caspase-9 activates Caspase-3, which then turns on caspase activated DNase and other pro apoptotic factors, leading to DNA fragmentation and cell death XREF_BIBR, XREF_BIBR.	0	7	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	1	2	3	4
Functionally , caspase-3 is an important effector in the apoptotic process , and caspase-9 is an initiator of caspase-3 in the mitochondria dependent pathway [ XREF_BIBR ] .	Functionally, caspase-3 is an important effector in the apoptotic process, and caspase-9 is an initiator of caspase-3 in the mitochondria dependent pathway [XREF_BIBR].	13	23	is an initiator	Positive_activation_copula_1	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	13	14	18	19
Caspase-3 is considered the most important of the executioner caspases and is activated by the initiator caspase-9 .	Caspase-3 is considered the most important of the executioner caspases and is activated by the initiator caspase-9.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	16	17	0	1
Cytosolic cytochrome c participates in the formation of the apoptosome , a multiprotein complex including apoptosis protease activating factor 1 ( Apaf-1 ) and caspase-9 , which activates caspase-3 , an executioner in cell death [ XREF_BIBR ] .	Cytosolic cytochrome c participates in the formation of the apoptosome, a multiprotein complex including apoptosis protease activating factor 1 (Apaf-1) and caspase-9, which activates caspase-3, an executioner in cell death [XREF_BIBR].	17	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	24	25	28	29
These results suggest that cytochrome c and caspase-9 initiate the activation of executor caspase-3 in H2O2 treated PC12 cells , and that Bcl-2 inhibits H2O2 induced release of cytochrome c from mitochondria and then proteolytic processing of procaspase-9 .	These results suggest that cytochrome c and caspase-9 initiate the activation of executor caspase-3 in H2O2 treated PC12 cells, and that Bcl-2 inhibits H2O2 induced release of cytochrome c from mitochondria and then proteolytic processing of procaspase-9.	5	18	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	13	14
The release of cytochrome C from mitochondria to cytoplasm is a trigger of apoptosis pathway , leading to the activation of intrinsic initiator caspase 9 , which in turn activates executioner caspase 3 and caspase 7 [ XREF_BIBR ] .	The release of cytochrome C from mitochondria to cytoplasm is a trigger of apoptosis pathway, leading to the activation of intrinsic initiator caspase 9, which in turn activates executioner caspase 3 and caspase 7 [XREF_BIBR].	19	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	23	25	31	33
The most common effector enzyme caspase-3 is often activated by caspase-9 in response to cytochrome C release from mitochondria and formation of the apoptosome [ XREF_BIBR ] .	The most common effector enzyme caspase-3 is often activated by caspase-9 in response to cytochrome C release from mitochondria and formation of the apoptosome [XREF_BIBR].	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	10	11	5	6
In reference to caspase-3 activity during disuse muscle atrophy , it is possible that caspase-3 is activated by caspase-12 via a calcium release pathway and/or activated by the activation of caspase-9 ( via a mitochondrial pathway ) [ XREF_BIBR , XREF_BIBR ] .	In reference to caspase-3 activity during disuse muscle atrophy, it is possible that caspase-3 is activated by caspase-12 via a calcium release pathway and/or activated by the activation of caspase-9 (via a mitochondrial pathway) [XREF_BIBR, XREF_BIBR].	14	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	30	31	14	15
The caspase-9 cleaves and activates downstream effector caspase-3 .	The caspase-9 cleaves and activates downstream effector caspase-3.	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	7	8
Caspase-3 , a prominent signaling molecule in the apoptosis pathway , is initiated by caspase-9 in the mitochondria dependent pathway .	Caspase-3, a prominent signaling molecule in the apoptosis pathway, is initiated by caspase-9 in the mitochondria dependent pathway.	0	19	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	14	15	0	1
Therefore , it is responsible for activating caspase-9 , which further activates caspase-3 and executes the apoptotic program .	Therefore, it is responsible for activating caspase-9, which further activates caspase-3 and executes the apoptotic program.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	12	13
More detailed studies are needed to define the precise mechanism for hypoxia induced cleavage of procaspase-9 and procaspase-8 ; however , our results clearly demonstrate involvement of both caspase-8 and caspase-9 in hypoxia mediated cleavage of caspase-3 and PARP .	More detailed studies are needed to define the precise mechanism for hypoxia induced cleavage of procaspase-9 and procaspase-8; however, our results clearly demonstrate involvement of both caspase-8 and caspase-9 in hypoxia mediated cleavage of caspase-3 and PARP.	25	38	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	30	31	36	37
The dominant negative caspase-9 blocked UV induced activation of caspase-3 , caspase-9 , and caspase-8 , and also protected cells from the loss of mitochondrial membrane potential .	The dominant negative caspase-9 blocked UV induced activation of caspase-3, caspase-9, and caspase-8, and also protected cells from the loss of mitochondrial membrane potential.	0	18	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	9	10
Caspase-9 then activates down-stream caspases namely caspase-3 and caspase-7 XREF_BIBR , XREF_BIBR leading to the execution of apoptosis ( XREF_FIG ) .	Caspase-9 then activates down-stream caspases namely caspase-3 and caspase-7 XREF_BIBR, XREF_BIBR leading to the execution of apoptosis (XREF_FIG).	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	6	7
Caspase-8 and/or caspase-9 may activate caspase-3 , and their participation in CA1 neuronal damage was evaluated by immunohistochemistry .	Caspase-8 and/or caspase-9 may activate caspase-3, and their participation in CA1 neuronal damage was evaluated by immunohistochemistry.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	5	6
Subsequently , caspase-9 cleaves and thereby activates downstream effector caspases , among them caspase-3 and caspase-7 which then cleave various substrates leading to the characteristic morphological changes associated with apoptosis [ XREF_BIBR ] .	Subsequently, caspase-9 cleaves and thereby activates downstream effector caspases, among them caspase-3 and caspase-7 which then cleave various substrates leading to the characteristic morphological changes associated with apoptosis [XREF_BIBR].	2	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	13	14
Caspase-9 can then go on to activate caspase-3 by truncating the full length inactivated caspase-3 into activated forms , which are responsible for the cell apoptosis .	Caspase-9 can then go on to activate caspase-3 by truncating the full length inactivated caspase-3 into activated forms, which are responsible for the cell apoptosis.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	7	8
Procaspase-9 is cleaved to form caspase-9 , which cleaves downstream caspases and activates caspase-3 .	Procaspase-9 is cleaved to form caspase-9, which cleaves downstream caspases and activates caspase-3.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	13	14
The initiator caspase , caspase-9 cleaves and activates caspase-3 and caspase-7 which are responsible for the execution of apoptosis .	The initiator caspase, caspase-9 cleaves and activates caspase-3 and caspase-7 which are responsible for the execution of apoptosis.	4	13	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	8	9
Several agents have the ability to induce MTP and lead to the formation of the apoptosome and activation of caspase-9 , which in turn activates downstream caspase-3 , which causes caspase-6 activation and then drives the caspase cascade and the cell death mechanism .	Several agents have the ability to induce MTP and lead to the formation of the apoptosome and activation of caspase-9, which in turn activates downstream caspase-3, which causes caspase-6 activation and then drives the caspase cascade and the cell death mechanism.	15	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	19	20	26	27
10 Within the apoptosome , 11 active caspase-9 finally leads to activation of caspase-3 , 12 and subsequent cell death .	10 Within the apoptosome, 11 active caspase-9 finally leads to activation of caspase-3, 12 and subsequent cell death.	5	19	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	13	14
This interaction results in the cleavage of pro-caspase-9 , which in turn activates the effector caspase-3 and/or -7 XREF_BIBR .	This interaction results in the cleavage of pro-caspase-9, which in turn activates the effector caspase-3 and/or -7 XREF_BIBR.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pro-caspase-9	pro-caspase-9	pro-caspase-9	caspase-3	caspase-3	caspase-3	7	8	15	16
Autoactivation of caspase-9 on the apoptosome can then activate caspase-3 to ultimately trigger cell death [ XREF_BIBR ] .	Autoactivation of caspase-9 on the apoptosome can then activate caspase-3 to ultimately trigger cell death [XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	9	10
The cleaved caspase-12 further stimulates the activation of caspase-9 , which in turn activates caspase-3 and lead to apoptosis XREF_BIBR .	The cleaved caspase-12 further stimulates the activation of caspase-9, which in turn activates caspase-3 and lead to apoptosis XREF_BIBR.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	14	15
Active caspase 9 directly cleaves and activates caspase 3 .	Active caspase 9 directly cleaves and activates caspase 3.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	1	3	7	9
Cytochrome c leads caspase-9 activation result in caspase-3 activation .	Cytochrome c leads caspase-9 activation result in caspase-3 activation.	3	9	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	7	8
Caspase-9 activates caspase-3 by proteolytic cleavage and caspase-3 then cleaves vital cellular proteins or other caspases .	Caspase-9 activates caspase-3 by proteolytic cleavage and caspase-3 then cleaves vital cellular proteins or other caspases.	0	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	2	3
Characterization of the apoptotic events in stress induced premature senescence of HDFs showed that in SIPS , caspase-3 was activated not only by the activation of caspase-9 but also by caspase-8 .	Characterization of the apoptotic events in stress induced premature senescence of HDFs showed that in SIPS, caspase-3 was activated not only by the activation of caspase-9 but also by caspase-8.	17	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	26	27	17	18
Cyt c can activate caspase-9 , which in turn activates caspase-3 via the induction of cleavage .	Cyt c can activate caspase-9, which in turn activates caspase-3 via the induction of cleavage.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	10	11
The increased caspase 9 activity would consequently activate more caspase 3 .	The increased caspase 9 activity would consequently activate more caspase 3.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	2	4	9	11
Proapoptotic members of the Bcl-2 family , such as Bax and Bid , undergo conformational change , oligomerization , and translocation to the mitochondria , resulting in cytochrome c release that ultimately induces caspase 9 cleavage and activation ; activated caspase 9 in turn activates caspase 3 .	Proapoptotic members of the Bcl-2 family, such as Bax and Bid, undergo conformational change, oligomerization, and translocation to the mitochondria, resulting in cytochrome c release that ultimately induces caspase 9 cleavage and activation; activated caspase 9 in turn activates caspase 3.	35	47	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	40	42	45	47
Finally , cytochrome c would increase the cleavage caspase-9 protein expression , which triggers caspase-3 activation .	Finally, cytochrome c would increase the cleavage caspase-9 protein expression, which triggers caspase-3 activation.	2	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	cytochrome c would increase the cleavage caspase-9 protein expression	caspase-9	caspase-3	caspase-3	caspase-3	8	9	14	15
Activation of apoptotic signaling pathways results in cytochrome c release from the mitochondria in concert with cleavage and activation of caspase-9 , which in turn also induces caspase-3 activation .	Activation of apoptotic signaling pathways results in cytochrome c release from the mitochondria in concert with cleavage and activation of caspase-9, which in turn also induces caspase-3 activation.	16	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	20	21	27	28
Active caspase-9 cleaves and activates caspase-3 , thereby inducing events that lead to DNA fragmentation and cell death .	Active caspase-9 cleaves and activates caspase-3, thereby inducing events that lead to DNA fragmentation and cell death.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	5	6
On the one hand , activated caspase-9 was initiated followed by caspase-3 activity , and activated caspase-3 cleaved XIAP in a positive feedback loop to strengthen Puma expression .	On the one hand, activated caspase-9 was initiated followed by caspase-3 activity, and activated caspase-3 cleaved XIAP in a positive feedback loop to strengthen Puma expression.	5	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	16	17
The activated caspase-9 in turn promotes the cleavage of caspase-3 as well as its substrate PARP .	The activated caspase-9 in turn promotes the cleavage of caspase-3 as well as its substrate PARP.	0	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	9	10
Caspase 9 is then able to activate other effector caspases such as caspase 7 and caspase 3 triggering further apoptotic processes .	Caspase 9 is then able to activate other effector caspases such as caspase 7 and caspase 3 triggering further apoptotic processes.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	15	17
Subsequently , caspase-9 activation can also lead to caspase-3 and -7 activations .	Subsequently, caspase-9 activation can also lead to caspase-3 and -7 activations.	2	11	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	8	9
Caspase 9 then activates executioner caspase 3 .	Caspase 9 then activates executioner caspase 3.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	5	7
The apoptosome cleaves the procaspase to its active form of caspase-9 , which in turn activates the effector caspase-3 .	The apoptosome cleaves the procaspase to its active form of caspase-9, which in turn activates the effector caspase-3.	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	10	11	18	19
The apoptosome is analogous in function to the DISC , and mediates the activation of caspase-9 , which in turn activates caspase-3 .	The apoptosome is analogous in function to the DISC, and mediates the activation of caspase-9, which in turn activates caspase-3.	13	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	15	16	21	22
Releasing Cyto c can activate caspase-9 , which , in turn , activates executioner caspase-3 via cleavage induction .	Releasing Cyto c can activate caspase-9, which, in turn, activates executioner caspase-3 via cleavage induction.	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	14	15
Once in the cytosol , cytochrome c then promotes caspase-9 activation that further induce caspase-3 activation whereas Smac/DIABLO release the inhibition of XIAP on caspase activation .	Once in the cytosol, cytochrome c then promotes caspase-9 activation that further induce caspase-3 activation whereas Smac/DIABLO release the inhibition of XIAP on caspase activation.	9	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	14	15
In the cytosol , the release of cytochrome c can activate caspase-9 , which in turn cleaves and activates executioner caspase-3 .	In the cytosol, the release of cytochrome c can activate caspase-9, which in turn cleaves and activates executioner caspase-3.	10	21	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	11	12	20	21
On investigating the specific reason for the activation of apoptosis in ER negative MDA-MB-231 cells , we found significant apoptosis induction through the mitochondria mediated intrinsic pathway in which caspase 3 formation was triggered by an elevated level of caspase 9 on ESC8 treatment .	On investigating the specific reason for the activation of apoptosis in ER negative MDA-MB-231 cells, we found significant apoptosis induction through the mitochondria mediated intrinsic pathway in which caspase 3 formation was triggered by an elevated level of caspase 9 on ESC8 treatment.	29	41	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	level of caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	39	41	29	31
The subsequent disruption of DeltaPsi m causes activating caspase-9 , which in turn activates caspase-3 and eventually apoptosis [ XREF_BIBR , XREF_BIBR ] .	The subsequent disruption of DeltaPsi m causes activating caspase-9, which in turn activates caspase-3 and eventually apoptosis [XREF_BIBR, XREF_BIBR].	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	14	15
Caspase 3 is activated by either caspase 8 ( extrinsic pathway ) or caspase 9 ( intrinsic and mitochondrial pathway ) .	Caspase 3 is activated by either caspase 8 (extrinsic pathway) or caspase 9 (intrinsic and mitochondrial pathway).	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	Caspase 3	Caspase 3	Caspase 3	13	15	0	2
It is well known that caspase-9 can activate caspase-3 .	It is well known that caspase-9 can activate caspase-3.	5	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	8	9
The apoptosome leads to activation of caspase-9 , which activates caspase-3 .	The apoptosome leads to activation of caspase-9, which activates caspase-3.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	10	11
Caspase 9 then activates pro caspase 3 , an effector protease of apoptosis , to its active form .	Caspase 9 then activates pro caspase 3, an effector protease of apoptosis, to its active form.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	5	7
p , p '-DDE , beta-BHC and their mixture could induce the apoptosis of Sertoli cells in vitro which was associated with activation of Caspase-3 mediated by cleavage of Caspase-8 and Caspase-9 .	p, p '-DDE, beta-BHC and their mixture could induce the apoptosis of Sertoli cells in vitro which was associated with activation of Caspase-3 mediated by cleavage of Caspase-8 and Caspase-9.	22	32	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	31	32	24	25
The release of Cyt c from the mitochondrion has a crucial role in the apoptotic pathway , as Cyt c may stimulate the formation of apoptotic bodies and subsequently activate caspase-9 which activates caspase-3 .	The release of Cyt c from the mitochondrion has a crucial role in the apoptotic pathway, as Cyt c may stimulate the formation of apoptotic bodies and subsequently activate caspase-9 which activates caspase-3.	29	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	30	31	33	34
The most common and important effector caspase is caspase-3 , which exists as a zymogen and activated by initiator caspases , mainly caspase-8 and caspase-9 .	The most common and important effector caspase is caspase-3, which exists as a zymogen and activated by initiator caspases, mainly caspase-8 and caspase-9.	6	25	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	24	25	8	9
Caspase-9 in turn ultimately leads to the activation of caspase-3 XREF_BIBR .	Caspase-9 in turn ultimately leads to the activation of caspase-3 XREF_BIBR.	0	10	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	9	10
Caspase-9 further activates caspase-3 and caspase-7 , which are responsible for destroying cells XREF_BIBR .	Caspase-9 further activates caspase-3 and caspase-7, which are responsible for destroying cells XREF_BIBR.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	3	4
Released cytochrome c causes formation of the apoptosome and activates initiator caspase 9 , which then activates caspase 3 , leading to the inevitable onset of apoptotic death [ XREF_BIBR ] .	Released cytochrome c causes formation of the apoptosome and activates initiator caspase 9, which then activates caspase 3, leading to the inevitable onset of apoptotic death [XREF_BIBR].	9	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	11	13	17	19
Caspase-9 , which is considered as an initiator of the mitochondria dependent caspase cascade , then activates caspase-3 XREF_BIBR .	Caspase-9, which is considered as an initiator of the mitochondria dependent caspase cascade, then activates caspase-3 XREF_BIBR.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	17	18
It is worth recalling that caspase-3 is a main effector ( executioner ) caspase , responsible for destroying cells and inducing apoptosis ; caspase-9 activates the effector caspase-3 ( and also caspase-6 and -7 ) whereas bax ( bcl-2-associated X protein ) is one of main pro apoptotic bcl-2 family proteins .	It is worth recalling that caspase-3 is a main effector (executioner) caspase, responsible for destroying cells and inducing apoptosis; caspase-9 activates the effector caspase-3 (and also caspase-6 and -7) whereas bax (bcl-2-associated X protein) is one of main pro apoptotic bcl-2 family proteins.	23	43	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	23	24	27	28
The apoptosome leads to the aggregation and activation of caspase-9 , and the activated caspase-9 subsequently cleaves and activates the downstream effector caspases ( caspase-3 , 6 and 7 ) to execute cell death [ XREF_BIBR ] .	The apoptosome leads to the aggregation and activation of caspase-9, and the activated caspase-9 subsequently cleaves and activates the downstream effector caspases (caspase-3, 6 and 7) to execute cell death [XREF_BIBR].	12	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	14	15	24	25
Once activated , caspase-9 activates caspase-3 , which leads to apoptosis [ XREF_BIBR ] .	Once activated, caspase-9 activates caspase-3, which leads to apoptosis [XREF_BIBR].	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	5	6
The release of cytochrome into the cytoplasm allows the formation of an apoptosome complex formed by cytochrome c , Apaf-1 , and caspase 9 which subsequently activates caspase 3 [ XREF_BIBR - XREF_BIBR ] .	The release of cytochrome into the cytoplasm allows the formation of an apoptosome complex formed by cytochrome c, Apaf-1, and caspase 9 which subsequently activates caspase 3 [XREF_BIBR - XREF_BIBR].	9	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	22	24	27	29
The apoptosome cleaves pro-caspase-9 to its active form caspase-9 , which in turn activates the effector caspase-3 XREF_BIBR .	The apoptosome cleaves pro-caspase-9 to its active form caspase-9, which in turn activates the effector caspase-3 XREF_BIBR.	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	16	17
XREF_BIBR Caspase-9 activates caspase-3 and other effector caspases , which proceed to cleave and inactivate the DNA repair enzyme PARP .	XREF_BIBR Caspase-9 activates caspase-3 and other effector caspases, which proceed to cleave and inactivate the DNA repair enzyme PARP.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	1	2	3	4
The cleaved caspase-9 triggered a further activation of caspase-3 , which would execute the cell apoptosis XREF_BIBR .	The cleaved caspase-9 triggered a further activation of caspase-3, which would execute the cell apoptosis XREF_BIBR.	0	12	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	8	9
Once cytochrome c is released from the mitochondria , it forms a complex with apoptosis protease- activating factor-1 ( Apaf-1 ) and activates caspase-9 , which in turn activates caspase-3 .	Once cytochrome c is released from the mitochondria, it forms a complex with apoptosis protease- activating factor-1 (Apaf-1) and activates caspase-9, which in turn activates caspase-3.	22	30	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	23	24	29	30
In this complex , self-cleavage and activation of procaspase-9 generates caspase-9 , which in turn activates caspase-3 in the presence of ATP .	In this complex, self-cleavage and activation of procaspase-9 generates caspase-9, which in turn activates caspase-3 in the presence of ATP.	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	10	11	16	17
TCE induced NHEK apoptosis is mediated intrinsically through the mitochondrial pathway of the decrease of DeltaPsim and the Caspase-9 dependent activation of Caspase-3 .	TCE induced NHEK apoptosis is mediated intrinsically through the mitochondrial pathway of the decrease of DeltaPsim and the Caspase-9 dependent activation of Caspase-3.	18	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	18	19	22	23
Both apoptotic pathways are merged in one point at the end in an apoptotic cell and both caspase 9 and caspase 8 activate caspase 3 at the end ( Kumar , 1997 ; Sternberg et al ., 1999 ; Zheng et al ., 2003 ) .	Both apoptotic pathways are merged in one point at the end in an apoptotic cell and both caspase 9 and caspase 8 activate caspase 3 at the end (Kumar, 1997; Sternberg et al., 1999; Zheng et al., 2003).	16	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	17	19	23	25
Here , our data indicate that beta-lapachone activated caspase-8 , -9 , and -3 , and induced PARP cleavage in a dose dependent manner ( XREF_FIG ) suggesting that activating caspase-8 indicated that the extrinsic pathway may be involved in beta-lapachone-induced apoptosis , as beta-lapachone activated the initiator caspase-9 , which in turn activated the downstream effector caspase-3 leading to PARP cleavage .	Here, our data indicate that beta-lapachone activated caspase-8, -9, and -3, and induced PARP cleavage in a dose dependent manner (XREF_FIG) suggesting that activating caspase-8 indicated that the extrinsic pathway may be involved in beta-lapachone-induced apoptosis, as beta-lapachone activated the initiator caspase-9, which in turn activated the downstream effector caspase-3 leading to PARP cleavage.	45	58	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	48	49	57	58
Caspase 9 then cleaves and activates caspase 3 which , in turn , cleaves numerous protein substrates that execute the cell death process .	Caspase 9 then cleaves and activates caspase 3 which, in turn, cleaves numerous protein substrates that execute the cell death process.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	6	8
The specific inhibitor of caspase-9 Z-LEHD-FMK could block the caspase-3 cleavage induced by 10 mumol/L ginsenoside , but the specific inhibitor of caspase-8 Z-IETD-FMK did not have this effect .	The specific inhibitor of caspase-9 Z-LEHD-FMK could block the caspase-3 cleavage induced by 10 mumol/L ginsenoside, but the specific inhibitor of caspase-8 Z-IETD-FMK did not have this effect.	4	10	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	9	10
14 Cytochrome c release from the mitochondria can activate caspase-9 , which in turn activates executioner caspase-3 via cleavage induction .	14 Cytochrome c release from the mitochondria can activate caspase-9, which in turn activates executioner caspase-3 via cleavage induction.	8	19	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	16	17
Then caspase-3 will be activated by caspase-9 finally resulting in apoptosis .	Then caspase-3 will be activated by caspase-9 finally resulting in apoptosis.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	1	2
As one of the key effectors , caspase-3 is initiated by caspase-9 and involved in the mitochondria mediated pathway .	As one of the key effectors, caspase-3 is initiated by caspase-9 and involved in the mitochondria mediated pathway.	7	13	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	11	12	7	8
Together with Apaf-1 and procaspase-9 , CytC was assembled into the apoptosome to activate caspase-9 , which further activated effector caspase-3 to induce cell death .	Together with Apaf-1 and procaspase-9, CytC was assembled into the apoptosome to activate caspase-9, which further activated effector caspase-3 to induce cell death.	13	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	14	15	20	21
Caspase-9 cleaves and activates caspase-3 .	Caspase-9 cleaves and activates caspase-3.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	4	5
The caspase-8 of the extrinsic pathway and caspase-9 of the intrinsic pathway were activated and gathered together in caspase-3 , and activated caspase-3 caused a series of downstream caspases cascade reactions , then ultimately induced apoptosis through the inhibition of DNA repair , nuclear fragmentation , cell shrinkage , and cell membrane bubble [ XREF_BIBR , XREF_BIBR ] .	The caspase-8 of the extrinsic pathway and caspase-9 of the intrinsic pathway were activated and gathered together in caspase-3, and activated caspase-3 caused a series of downstream caspases cascade reactions, then ultimately induced apoptosis through the inhibition of DNA repair, nuclear fragmentation, cell shrinkage, and cell membrane bubble [XREF_BIBR, XREF_BIBR].	1	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	22	23
In a similar manner , caspase 9 activates caspase 3 , which cleaves numerous targets culminating in the cell ' s destruction .	In a similar manner, caspase 9 activates caspase 3, which cleaves numerous targets culminating in the cell 's destruction.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	5	7	8	10
Cyt-c can cleave and activate caspase-9 , which then activate the downstream caspase-3 .	Cyt-c can cleave and activate caspase-9, which then activate the downstream caspase-3.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	12	13
The release of Cyto C from mitochondria could activate caspase-9 , which in turn activates caspase-3 and caspase-7 to execute cell death [ XREF_BIBR , XREF_BIBR ] .	The release of Cyto C from mitochondria could activate caspase-9, which in turn activates caspase-3 and caspase-7 to execute cell death [XREF_BIBR, XREF_BIBR].	8	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	15	16
The activated caspase 9 then activates caspase 3 and caspase 7 , which in turn activates the early apoptosis process [ XREF_BIBR ] .	The activated caspase 9 then activates caspase 3 and caspase 7, which in turn activates the early apoptosis process [XREF_BIBR].	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	2	4	6	8
In the cytosol , cytochrome c , together with Apaf-1 , activates caspase-9 , which then activates caspase-3 [ XREF_BIBR ] .	In the cytosol, cytochrome c, together with Apaf-1, activates caspase-9, which then activates caspase-3 [XREF_BIBR].	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	12	13	17	18
XREF_BIBR , XREF_BIBR , XREF_BIBR Released cytochrome c triggers the activation of caspase family , such as caspase 9 and its downstream caspase 3 , and shifting the balance of antiapoptotic to proapoptotic status with the involvement of Bcl-2 family proteins contributes to apoptosis .	XREF_BIBR, XREF_BIBR, XREF_BIBR Released cytochrome c triggers the activation of caspase family, such as caspase 9 and its downstream caspase 3, and shifting the balance of antiapoptotic to proapoptotic status with the involvement of Bcl-2 family proteins contributes to apoptosis.	8	24	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	17	19	22	24
The released CYCS interacts and forms a complex with APAF1 in the presence of ATP and activates the key player of the cell death CASP9 , which subsequently activates CASP3 and initiates cell death [ XREF_BIBR ] .	The released CYCS interacts and forms a complex with APAF1 in the presence of ATP and activates the key player of the cell death CASP9, which subsequently activates CASP3 and initiates cell death [XREF_BIBR].	19	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP9	CASP9	CASP9	CASP3	CASP3	CASP3	24	25	29	30
XREF_BIBR - XREF_BIBR Release of these mediators leads to activation of caspase 9 , which in turn activates caspase 3 .	XREF_BIBR - XREF_BIBR Release of these mediators leads to activation of caspase 9, which in turn activates caspase 3.	9	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	11	13	18	20
Caspase-9 then activates caspase-3 by proteolytically processing pro-caspase-3 .	Caspase-9 then activates caspase-3 by proteolytically processing pro-caspase-3.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	3	4
As one of the key effectors , caspase-3 is activated through cleavage by caspase-9 and involved in the mitochondria mediated pathway .	As one of the key effectors, caspase-3 is activated through cleavage by caspase-9 and involved in the mitochondria mediated pathway.	7	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	13	14	7	8
This triggers formation of the canonical ' apoptosome ' via assembly of APAF1 with pro-caspase-9 , cytochrome c , and dATP leading to caspase-9 activation , which in turn activates caspase-3 [ XREF_BIBR , XREF_BIBR ] .	This triggers formation of the canonical ' apoptosome ' via assembly of APAF1 with pro-caspase-9, cytochrome c, and dATP leading to caspase-9 activation, which in turn activates caspase-3 [XREF_BIBR, XREF_BIBR].	23	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	23	24	30	31
This results in the activation of caspase-9 , which then activates caspase-3 , which in turn cleaves various cellular proteins to induce rapid cell death .	This results in the activation of caspase-9, which then activates caspase-3, which in turn cleaves various cellular proteins to induce rapid cell death.	4	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	11	12
Activated caspase-9 activates caspase-3 and caspase-7 , which in turn induces PARP cleavage .	Activated caspase-9 activates caspase-3 and caspase-7, which in turn induces PARP cleavage.	0	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	3	4
Mitochondrial pathway activation results both in the activation of Caspase-3 by Caspase-9 and also relief of Caspase-3 inhibition by the protein DIABLO [ XREF_BIBR ] .	Mitochondrial pathway activation results both in the activation of Caspase-3 by Caspase-9 and also relief of Caspase-3 inhibition by the protein DIABLO [XREF_BIBR].	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	11	12	9	10
Caspase-9 inhibition prevented the activation of both caspase-3 and caspase-8 and also inhibited Bid cleavage , but not cytochrome c release .	Caspase-9 inhibition prevented the activation of both caspase-3 and caspase-8 and also inhibited Bid cleavage, but not cytochrome c release.	0	9	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	7	8
The apoptosome complex can activate initiator caspase-9 , which then activates the downstream effector caspase-3 and induces subsequent cleavage of PARP to execute the apoptotic process XREF_BIBR .	The apoptosome complex can activate initiator caspase-9, which then activates the downstream effector caspase-3 and induces subsequent cleavage of PARP to execute the apoptotic process XREF_BIBR.	4	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	14	15
Studies using antioxidants and specific caspase inhibitors indicated that activation of caspase-8 , but not caspase-9 , mediates ROS dependent caspase-3 activation and suggested that ROS from NADPH oxidase activate caspase-8 .	Studies using antioxidants and specific caspase inhibitors indicated that activation of caspase-8, but not caspase-9, mediates ROS dependent caspase-3 activation and suggested that ROS from NADPH oxidase activate caspase-8.	9	21	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	15	16	20	21
It further activated caspase-9 which subsequently induced caspase-3 and , resulting in PARP cleavage .	It further activated caspase-9 which subsequently induced caspase-3 and, resulting in PARP cleavage.	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	7	8
Caspase 9 then cleaves and activates caspase 3 and 7 , which , in turn , proceed to degrade several cellular substrates , resulting in the morphological changes associated to apoptosis .	Caspase 9 then cleaves and activates caspase 3 and 7, which, in turn, proceed to degrade several cellular substrates, resulting in the morphological changes associated to apoptosis.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	6	8
Induction of apoptosis in cancer cells activates the initiator caspase-9 , which further activates the activator caspase-3 after cleavage .	Induction of apoptosis in cancer cells activates the initiator caspase-9, which further activates the activator caspase-3 after cleavage.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	16	17
First , PDT can activate caspase-8 and caspase-9 , and then the active form of caspase-8 and caspase-9 initiates caspase-3 and caspase-6 activation to subsequently activate the remainder of the caspase cascade , which degrades PARP , and finally leads to apoptosis of tumor cells XREF_BIBR , XREF_BIBR .	First, PDT can activate caspase-8 and caspase-9, and then the active form of caspase-8 and caspase-9 initiates caspase-3 and caspase-6 activation to subsequently activate the remainder of the caspase cascade, which degrades PARP, and finally leads to apoptosis of tumor cells XREF_BIBR, XREF_BIBR.	13	22	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	17	18	19	20
Because caspase-9 activation induces the activation of caspase-3 , the effector caspase , we also assessed CASP3 expression .	Because caspase-9 activation induces the activation of caspase-3, the effector caspase, we also assessed CASP3 expression.	1	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	7	8
On one hand , the released cytochrome c may activate caspase 9 , which activates caspase 3 subsequently .	On one hand, the released cytochrome c may activate caspase 9, which activates caspase 3 subsequently.	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	10	12	15	17
By autoprocessing , pro-caspase-9 is activated and cleaves and activates caspase-3 .	By autoprocessing, pro-caspase-9 is activated and cleaves and activates caspase-3.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pro-caspase-9	pro-caspase-9	pro-caspase-9	caspase-3	caspase-3	caspase-3	3	4	10	11
Both caspase-8 and caspase-9 activate caspase-3 which is responsible for breaking specific cellular proteins during apoptosis XREF_BIBR .	Both caspase-8 and caspase-9 activate caspase-3 which is responsible for breaking specific cellular proteins during apoptosis XREF_BIBR.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	5	6
The activated caspase-9 subsequently activates caspase-3 , which in turn activates the early apoptosis process [ XREF_BIBR ] .	The activated caspase-9 subsequently activates caspase-3, which in turn activates the early apoptosis process [XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	5	6
Caspase-9 levels decreased at involution 12 hours and remained low until involution 48 hours ; caspase-3 is activated by caspase-9 and its cleaved form was detected at involution 48 and 72 hours .	Caspase-9 levels decreased at involution 12 hours and remained low until involution 48 hours; caspase-3 is activated by caspase-9 and its cleaved form was detected at involution 48 and 72 hours.	15	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	19	20	15	16
In the presence of ATP and cytochrome c , apoptotic protease activating factor-1 ( Apaf-1 ) activates caspase-9 , which in turn activates caspase-3 .	In the presence of ATP and cytochrome c, apoptotic protease activating factor-1 (Apaf-1) activates caspase-9, which in turn activates caspase-3.	16	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	17	18	23	24
At 8 h , the pro apoptotic proteins , Bid and Bax , were significantly increased at the gene and protein level which activated caspase cleavage to form cleaved caspase 9 and 8 that activated caspase 3 mediated cell apoptosis .	At 8 h, the pro apoptotic proteins, Bid and Bax, were significantly increased at the gene and protein level which activated caspase cleavage to form cleaved caspase 9 and 8 that activated caspase 3 mediated cell apoptosis.	28	37	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	29	31	35	37
In its turn , caspase-9 activates caspase-3 , thereby triggering the terminal events in the cell-death pathway .	In its turn, caspase-9 activates caspase-3, thereby triggering the terminal events in the cell-death pathway.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	6	7
Caspase-9 is activated within the apoptosome and subsequently mediates the activation of executioner caspase-3 .	Caspase-9 is activated within the apoptosome and subsequently mediates the activation of executioner caspase-3.	0	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	13	14
A caspase 9 selective inhibitor blocked caspase 3 activation but incompletely blocked apoptosis in response to palmitate , suggesting an additional caspase 9 independent pathway .	A caspase 9 selective inhibitor blocked caspase 3 activation but incompletely blocked apoptosis in response to palmitate, suggesting an additional caspase 9 independent pathway.	1	8	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	1	3	6	8
Active caspase-9 in turn activates caspase-3 , which can cleave poly ( ADP-ribose ) polymerase , finally leading to apoptosis.15 , 16 Therefore , it seems likely that mitochondrial CytC release induced by Tan IIA results in caspase-9 and caspase-3 activation , and a classical mitochondria independent pathway participates in Tan IIA induced Eca-109 cell apoptosis ( Fig XREF_FIG ) .	Active caspase-9 in turn activates caspase-3, which can cleave poly (ADP-ribose) polymerase, finally leading to apoptosis.15, 16 Therefore, it seems likely that mitochondrial CytC release induced by Tan IIA results in caspase-9 and caspase-3 activation, and a classical mitochondria independent pathway participates in Tan IIA induced Eca-109 cell apoptosis (Fig XREF_FIG).	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	5	6
Caspase-3 is activated by caspase-9 [ XREF_BIBR - XREF_BIBR ] , and the levels of both cleaved forms increased in NEFA treated cells and decreased following AOE treatment .	Caspase-3 is activated by caspase-9 [XREF_BIBR - XREF_BIBR], and the levels of both cleaved forms increased in NEFA treated cells and decreased following AOE treatment.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	4	5	0	1
This should activate the cysteine protease caspase-9 , which in turn should go on to activate caspase-3 .	This should activate the cysteine protease caspase-9, which in turn should go on to activate caspase-3.	2	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	16	17
Since caspase 3 activity decreased when the cells were cultured with the caspase 9 inhibitor but not with the caspase 8 inhibitor , it is suggested that caspase 3 activity is increased by caspase 9 activation .	Since caspase 3 activity decreased when the cells were cultured with the caspase 9 inhibitor but not with the caspase 8 inhibitor, it is suggested that caspase 3 activity is increased by caspase 9 activation.	27	35	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	33	35	27	29
ER-Ca 2+ , besides activating the calapin-caspase-12 axis also induces mitochondrial dysfunctioning ; the two pathways converge at caspase-9 initiating caspase-3 mediated HKM apoptosis .	ER-Ca 2+, besides activating the calapin-caspase-12 axis also induces mitochondrial dysfunctioning; the two pathways converge at caspase-9 initiating caspase-3 mediated HKM apoptosis.	16	21	initiating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	18	19	20	21
Active caspase-9 then activates caspase-3 , which in turn leads to the degradation of vital cellular proteins and thus apoptosis .	Active caspase-9 then activates caspase-3, which in turn leads to the degradation of vital cellular proteins and thus apoptosis.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	4	5
Once in the cytosol , cytochrome c can activate caspase-9 , which in turn cleaves and activates caspase-3 .	Once in the cytosol, cytochrome c can activate caspase-9, which in turn cleaves and activates caspase-3.	8	18	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	17	18
The net effect is the death of cancer cells through the activation of caspase-3 mediated by caspase-9 , given that induction of apoptosis by ferrite nanoparticles is attributable to their ability to increase the expression of proapoptotic genes , such as caspase-3 , caspase-8 , and caspase-9 genes .	The net effect is the death of cancer cells through the activation of caspase-3 mediated by caspase-9, given that induction of apoptosis by ferrite nanoparticles is attributable to their ability to increase the expression of proapoptotic genes, such as caspase-3, caspase-8, and caspase-9 genes.	11	47	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	16	17	13	14
Subsequently , proteolytic cleavage of caspase-9 activated caspase-3 , which is a main apoptotic executive caspase [ XREF_BIBR ] .	Subsequently, proteolytic cleavage of caspase-9 activated caspase-3, which is a main apoptotic executive caspase [XREF_BIBR].	3	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	7	8
Both caspase-8 and caspase-9 activate caspase-3 , which in turn cleaves several crucial substrates including the DNA repair enzyme poly ( ADP-ribose ) polymerase ( PARP ) [ XREF_BIBR ] .	Both caspase-8 and caspase-9 activate caspase-3, which in turn cleaves several crucial substrates including the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) [XREF_BIBR].	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	5	6
Once in the cytosol , cytochrome c activates caspase-9 , which then further cleaves and activates caspase-3 , causing the induction of apoptosis [ XREF_BIBR ] .	Once in the cytosol, cytochrome c activates caspase-9, which then further cleaves and activates caspase-3, causing the induction of apoptosis [XREF_BIBR].	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	16	17
Apoptosome then activates Caspase-9 and Caspase-9 leads to Caspase-3 activation , ultimately cell death occurs XREF_BIBR .	Apoptosome then activates Caspase-9 and Caspase-9 leads to Caspase-3 activation, ultimately cell death occurs XREF_BIBR.	3	9	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	3	4	8	9
Several studies have demonstrated that mitochondria may play an important role in apoptosis by releasing cytochrome c and activating caspase-9 , which activates caspase-3 that is responsible for DNA-cleavage action .	Several studies have demonstrated that mitochondria may play an important role in apoptosis by releasing cytochrome c and activating caspase-9, which activates caspase-3 that is responsible for DNA-cleavage action.	18	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	19	20	23	24
Both caspase-8 and caspase-9 activate caspase-3 , among other caspases , which in turn cleave several crucial substrates , including the DNA repairing enzyme poly ( ADP-ribose ) polymerase ( PARP ) , into fragments of 89 and 28 kDa .	Both caspase-8 and caspase-9 activate caspase-3, among other caspases, which in turn cleave several crucial substrates, including the DNA repairing enzyme poly (ADP-ribose) polymerase (PARP), into fragments of 89 and 28 kDa.	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	5	6
This leads to activation of caspase 9 , which then activates caspase 3 .	This leads to activation of caspase 9, which then activates caspase 3.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	5	7	11	13
Analysis of the Jurkat T cell induced by tBid gives similar results , though the magnitude of the regression coefficient of k 13 , which describes the activation of Casp3 by Casp9 * , is larger than in the HeLa case , suggesting a stronger role for the intrinsic caspase .	Analysis of the Jurkat T cell induced by tBid gives similar results, though the magnitude of the regression coefficient of k 13, which describes the activation of Casp3 by Casp9 *, is larger than in the HeLa case, suggesting a stronger role for the intrinsic caspase.	27	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Casp9	Casp9	Casp9	Casp3	Casp3	Casp3	31	32	29	30
Bcl-2 is upstream of caspase 9 in apoptosis signaling pathways , but the caspase 9 target caspase 3 acts on Bcl-2 to further lower the threshold for apoptosis , in a positive feedback loop , thus higher Bcl-2 levels could impact on iCasp9 sensitivity .	Bcl-2 is upstream of caspase 9 in apoptosis signaling pathways, but the caspase 9 target caspase 3 acts on Bcl-2 to further lower the threshold for apoptosis, in a positive feedback loop, thus higher Bcl-2 levels could impact on iCasp9 sensitivity.	12	23	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	13	15	16	18
Activated caspase-9 subsequently activates caspase-3 , which will in turn activate procaspase-9 ; this sequence forms positive feedback activation pathway .	Activated caspase-9 subsequently activates caspase-3, which will in turn activate procaspase-9; this sequence forms positive feedback activation pathway.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	4	5
Caspase-9 further activates the effector caspase-3 , which cleaves several hundred cellular proteins , resulting in the characteristic biochemical and morphological features associated with apoptosis , including chromatin condensation , nuclear fragmentation , and externalisation of phosphatidylserine [ XREF_BIBR ] .	Caspase-9 further activates the effector caspase-3, which cleaves several hundred cellular proteins, resulting in the characteristic biochemical and morphological features associated with apoptosis, including chromatin condensation, nuclear fragmentation, and externalisation of phosphatidylserine [XREF_BIBR].	0	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	5	6
Active caspase-9 then activates caspase-3 , which subsequently activates the rest of the caspase cascade and leads to apoptosis .	Active caspase-9 then activates caspase-3, which subsequently activates the rest of the caspase cascade and leads to apoptosis.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	4	5
Moreover , the activated Caspase-9 and Caspase-12 can activate Caspase-3 and Caspase-7 from different pathways .	Moreover, the activated Caspase-9 and Caspase-12 can activate Caspase-3 and Caspase-7 from different pathways.	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	4	5	9	10
Mitochondrial , caspase 8 or caspase 9 activation activates caspase 3 leading to apoptosis [ XREF_BIBR ] .	Mitochondrial, caspase 8 or caspase 9 activation activates caspase 3 leading to apoptosis [XREF_BIBR].	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	5	7	9	11
The release of the pro apoptotic molecule Cyt c from the mitochondrial membrane results in an increased level of Cyt c in the cytoplasm and nucleus , which may activate caspase-9 , which , in turn , triggers the effector caspase-3 [ XREF_BIBR ] .	The release of the pro apoptotic molecule Cyt c from the mitochondrial membrane results in an increased level of Cyt c in the cytoplasm and nucleus, which may activate caspase-9, which, in turn, triggers the effector caspase-3 [XREF_BIBR].	29	42	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	30	31	40	41
Once apoptosis is triggered , whether by extrinsic or intrinsic mechanism , both Caspase 8 and Caspase 9 leads to cleavage and hence activation of the effector Caspase 3 to initiate activation of the caspase cascade [ XREF_BIBR ] .	Once apoptosis is triggered, whether by extrinsic or intrinsic mechanism, both Caspase 8 and Caspase 9 leads to cleavage and hence activation of the effector Caspase 3 to initiate activation of the caspase cascade [XREF_BIBR].	13	30	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	Caspase 3	Caspase 3	Caspase 3	16	18	27	29
Once activated , caspase-8 and caspase-9 activate downstream caspase-3 , triggering cell apoptosis .	Once activated, caspase-8 and caspase-9 activate downstream caspase-3, triggering cell apoptosis.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	8	9
Moreover , PD173074 can activate the intrinsic apoptotic pathway by stimulating Caspase9 , which activated Caspase3 and induced the apoptosis .	Moreover, PD173074 can activate the intrinsic apoptotic pathway by stimulating Caspase9, which activated Caspase3 and induced the apoptosis.	10	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase9	Caspase9	Caspase9	Caspase3	Caspase3	Caspase3	11	12	15	16
Additionally , caspase-8 can cleave Bid ( Bcl-2 homology domain 3 ( BH3 ) interacting domain death agonist ) into truncate Bid ( t-Bid ) , then cause the release of mitochondrial cytochrome c , leading to the activation of caspase-9 , which can then activate caspase-3 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Additionally, caspase-8 can cleave Bid (Bcl-2 homology domain 3 (BH3) interacting domain death agonist) into truncate Bid (t-Bid), then cause the release of mitochondrial cytochrome c, leading to the activation of caspase-9, which can then activate caspase-3 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	38	52	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	40	41	46	47
The apoptosome recruits and activates caspase-9 , which in turn activates caspase-3 and -7 , which then kill the cell by proteolysis .	The apoptosome recruits and activates caspase-9, which in turn activates caspase-3 and -7, which then kill the cell by proteolysis.	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	11	12
The activated caspase-9 activates the downstream caspase-3 , which then activates endonuclease for degrading PARP , finally leading to cell apoptosis [ XREF_BIBR ] .	The activated caspase-9 activates the downstream caspase-3, which then activates endonuclease for degrading PARP, finally leading to cell apoptosis [XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	6	7
In the cytosol , cytochrome c , APAF-1 and caspase-9 form the apoptosome complex and activated caspase-9 triggers the activation of executioner caspase-3 and caspase-7 by cleaving them .	In the cytosol, cytochrome c, APAF-1 and caspase-9 form the apoptosome complex and activated caspase-9 triggers the activation of executioner caspase-3 and caspase-7 by cleaving them.	13	24	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	16	17	22	23
The caspase-9 cleaves and activates downstream effector caspase-3 resulting in programmed cell apoptosis .	The caspase-9 cleaves and activates downstream effector caspase-3 resulting in programmed cell apoptosis.	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	7	8
In the intrinsic cell death pathway , which is mediated by mitochondria , cytochrome c activates caspase-9 , which then activates caspase-3 .	In the intrinsic cell death pathway, which is mediated by mitochondria, cytochrome c activates caspase-9, which then activates caspase-3.	15	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	16	17	21	22
The activated caspase-9 then activates the downstream caspase-3 [ XREF_BIBR - XREF_BIBR ] .	The activated caspase-9 then activates the downstream caspase-3 [XREF_BIBR - XREF_BIBR].	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	7	8
The active caspase-9 initiates the final step in the apoptotic cascade of activating effector caspase-3 .	The active caspase-9 initiates the final step in the apoptotic cascade of activating effector caspase-3.	0	15	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	14	15
The released cytochrome c in the cytosol activates caspase-9 , which consequently induces caspase-3 activation , resulting in the cleavage of several cellular proteins , finally leading to the typical alterations related to cell apoptosis ( e.g ., DNA fragmentation in cell nuclei ) [ XREF_BIBR , XREF_BIBR ] .	The released cytochrome c in the cytosol activates caspase-9, which consequently induces caspase-3 activation, resulting in the cleavage of several cellular proteins, finally leading to the typical alterations related to cell apoptosis (e.g., DNA fragmentation in cell nuclei) [XREF_BIBR, XREF_BIBR].	7	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	13	14
Caspase 3 , an executioner caspase , which is activated by caspase 9 and 8 via the intrinsic and extrinsic pathways respectively , thus brings about the activation of nucleases and finally breaks the DNA in the cell .	Caspase 3, an executioner caspase, which is activated by caspase 9 and 8 via the intrinsic and extrinsic pathways respectively, thus brings about the activation of nucleases and finally breaks the DNA in the cell.	0	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	Caspase 3	Caspase 3	Caspase 3	11	13	0	2
Caspase 3 , the effector caspase in the apoptotic cascade , is activated through cleavage by caspase-9 as a result of increased mitochondrial permeability and release of cytochrome c. PARP is cleaved by activated caspase-3 and cleavage of caspase-3 and PARP are signature events in apoptosis .	Caspase 3, the effector caspase in the apoptotic cascade, is activated through cleavage by caspase-9 as a result of increased mitochondrial permeability and release of cytochrome c. PARP is cleaved by activated caspase-3 and cleavage of caspase-3 and PARP are signature events in apoptosis.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase 3	Caspase 3	Caspase 3	16	17	0	2
In a classical apoptotic cascade , there are two pathways for apoptosis : extrinsic pathway is related with the cleavage of caspase-8 and intrinsic pathway which is mediated by the activation of caspase-9 , both of which activate caspase-3 .	In a classical apoptotic cascade, there are two pathways for apoptosis : extrinsic pathway is related with the cleavage of caspase-8 and intrinsic pathway which is mediated by the activation of caspase-9, both of which activate caspase-3.	30	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	32	33	38	39
Caspase-9 then initiates processing of caspase-3 as well as caspase-7 .	Caspase-9 then initiates processing of caspase-3 as well as caspase-7.	0	6	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	5	6
Caspase-9 , in turn activates caspase-3 , the protease that cleaves the majority of caspase substrates during apoptosis .	Caspase-9, in turn activates caspase-3, the protease that cleaves the majority of caspase substrates during apoptosis.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	5	6
Meanwhile , Caspase-3 can be activated by caspase-8 in death receptor signaling , by caspase-9 in mitochondrial damage , and by caspase-12 in endothelium reticulum ( ER ) stress [ XREF_BIBR ] .	Meanwhile, Caspase-3 can be activated by caspase-8 in death receptor signaling, by caspase-9 in mitochondrial damage, and by caspase-12 in endothelium reticulum (ER) stress [XREF_BIBR].	2	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	14	15	2	3
XREF_BIBR In addition , cytochrome c released from the mitochondria can activate caspase 9 , which then activates caspase 3 and caspase 7 .	XREF_BIBR In addition, cytochrome c released from the mitochondria can activate caspase 9, which then activates caspase 3 and caspase 7.	11	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	12	14	18	20
The released cytochrome c activates caspase-9 , which consequently induces caspase-3 activation , resulting in the cleavage of several cellular proteins , and finally leading to the typical alterations related to cell apoptosis such as DNA fragmentation in cell nuclei .	The released cytochrome c activates caspase-9, which consequently induces caspase-3 activation, resulting in the cleavage of several cellular proteins, and finally leading to the typical alterations related to cell apoptosis such as DNA fragmentation in cell nuclei.	4	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	10	11
The complex apoptosome and Caspase-9 directly activates the catalytic enzyme caspase-3 or caspase-7 and triggers the DNA fragmentation .	The complex apoptosome and Caspase-9 directly activates the catalytic enzyme caspase-3 or caspase-7 and triggers the DNA fragmentation.	2	12	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	4	5	10	11
In type II cells the formation of the DISC complex is reduced and the activation of caspase-3 occurs downstream of the mitochondria : the active form of caspase-8 cleaves Bid , followed by tBid translocation to mitochondria resulting in the release of cytochrome C , apoptosome formation , and the activation of caspase-9 , which then activates caspase-3 triggering the subsequent apoptotic events .	In type II cells the formation of the DISC complex is reduced and the activation of caspase-3 occurs downstream of the mitochondria : the active form of caspase-8 cleaves Bid, followed by tBid translocation to mitochondria resulting in the release of cytochrome C, apoptosome formation, and the activation of caspase-9, which then activates caspase-3 triggering the subsequent apoptotic events.	50	58	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	52	53	57	58
A decreased ratio of Bcl-2 to Bax can induce apoptosis by enhancing mitochondrial apoptotic signaling upstream of caspase-9 , which then activates caspase-3 that results in apoptotic changes [ XREF_BIBR ] .	A decreased ratio of Bcl-2 to Bax can induce apoptosis by enhancing mitochondrial apoptotic signaling upstream of caspase-9, which then activates caspase-3 that results in apoptotic changes [XREF_BIBR].	15	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	17	18	22	23
Caspase-9 , as a protease , can activate the apoptotic effector caspase-3 , eventually causing nuclear apoptosis .	Caspase-9, as a protease, can activate the apoptotic effector caspase-3, eventually causing nuclear apoptosis.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	11	12
Our data has shown translocations of cleaved PKC-delta into mitochondria and nucleus ( XREF_FIG ) which in turn induces caspase-9 mediated caspase-3 cleavage thus forming a feedback loop that further exacerbates the hypertrophic responses XREF_BIBR .	Our data has shown translocations of cleaved PKC-delta into mitochondria and nucleus (XREF_FIG) which in turn induces caspase-9 mediated caspase-3 cleavage thus forming a feedback loop that further exacerbates the hypertrophic responses XREF_BIBR.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	19	20	21	22
Both caspase-9 and -8 will subsequently activate downstream caspase-3 , leading to apoptosis .	Both caspase-9 and -8 will subsequently activate downstream caspase-3, leading to apoptosis.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	8	9
Caspase-3 ( of the terminal common apoptotic pathway ) is also activated by caspase-9 , which is activated by the mitochondria mediated apoptotic pathway .	Caspase-3 (of the terminal common apoptotic pathway) is also activated by caspase-9, which is activated by the mitochondria mediated apoptotic pathway.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	13	14	0	1
Cytosolic cytochrome c activates caspase-9 , which triggers caspase-3 and causes consequent apoptosis .	Cytosolic cytochrome c activates caspase-9, which triggers caspase-3 and causes consequent apoptosis.	3	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	8	9
A decrease of Bcl-2 to Bax ratio is sufficient to promote apoptosis in mammalian cells and induce cell death by directly activating the mitochondrial apoptotic pathway in maturation of caspase-9 , which in turn activates caspase3 [ XREF_BIBR , XREF_BIBR ] .	A decrease of Bcl-2 to Bax ratio is sufficient to promote apoptosis in mammalian cells and induce cell death by directly activating the mitochondrial apoptotic pathway in maturation of caspase-9, which in turn activates caspase3 [XREF_BIBR, XREF_BIBR].	27	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase3	caspase3	caspase3	29	30	35	36
The active Caspase 9 activates executor caspases ( Caspase 3 and 7 ) and this orchestrates apoptosis through the cleavage of key substrates within the cell XREF_BIBR .	The active Caspase 9 activates executor caspases (Caspase 3 and 7) and this orchestrates apoptosis through the cleavage of key substrates within the cell XREF_BIBR.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	Caspase 3	Caspase 3	Caspase 3	2	4	8	10
Caspase 9 in turn cleaves and activates caspase 3 , leading to apoptosis [ XREF_BIBR , XREF_BIBR ] .	Caspase 9 in turn cleaves and activates caspase 3, leading to apoptosis [XREF_BIBR, XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	7	9
Under theses conditions , inhibition of caspase 9 abolished caspase-3 cleavage in cells treated with palmitate for 24 and 48 h.	Under theses conditions, inhibition of caspase 9 abolished caspase-3 cleavage in cells treated with palmitate for 24 and 48 h.	4	10	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase-3	caspase-3	caspase-3	6	8	9	10
The apoptosome , in turn , brings about caspase 9 activation , which consequently promotes the caspase 3 proenzyme to the active protease stage , which then adheres to the group of effector caspase .	The apoptosome, in turn, brings about caspase 9 activation, which consequently promotes the caspase 3 proenzyme to the active protease stage, which then adheres to the group of effector caspase.	8	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	8	10	16	18
Similarly , activated Caspase-9 can activate Caspase-3 , Caspase-7 .	Similarly, activated Caspase-9 can activate Caspase-3, Caspase-7.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	3	4	6	7
It further activated caspase-8 and caspase-9 which subsequently induced caspase-3 and/or caspase-7 activation , resulting in PARP cleavage .	It further activated caspase-8 and caspase-9 which subsequently induced caspase-3 and/or caspase-7 activation, resulting in PARP cleavage.	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	9	10
As extensively discussed in the literature , upon activation , caspase 12 may cleave caspase 9 , which in turn activates the effector caspase 3 [ XREF_BIBR ] .	As extensively discussed in the literature, upon activation, caspase 12 may cleave caspase 9, which in turn activates the effector caspase 3 [XREF_BIBR].	13	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	14	16	23	25
Cytokeratin filaments may thus provide a scaffold whereby active subunits of caspase-9 can activate caspase-3 which , in turn , can activate more caspase-9 so forming an amplification loop to facilitate cleavage of cytokeratin-18 , disruption of the cytoskeleton and the ensuing formation of cytoplasmic inclusions .	Cytokeratin filaments may thus provide a scaffold whereby active subunits of caspase-9 can activate caspase-3 which, in turn, can activate more caspase-9 so forming an amplification loop to facilitate cleavage of cytokeratin-18, disruption of the cytoskeleton and the ensuing formation of cytoplasmic inclusions.	9	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	11	12	14	15
Eventually , the stimulated caspase-9 cleaves and activates the caspase-3 effectors with subsequent apoptosis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Eventually, the stimulated caspase-9 cleaves and activates the caspase-3 effectors with subsequent apoptosis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	9	10
Since caspase-3 may be activated by initiator caspase-9 and -8 , it is significant to show that such caspase activation cascade is induced by 4 microM DAU and TT bisquinones at 6 h in HL-60-S cells .	Since caspase-3 may be activated by initiator caspase-9 and -8, it is significant to show that such caspase activation cascade is induced by 4 microM DAU and TT bisquinones at 6 h in HL-60-S cells.	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	1	2
Casp9 activates the downstream executioner caspase 3 ( casp3 ) which ultimately lead to apoptosis .	Casp9 activates the downstream executioner caspase 3 (casp3) which ultimately lead to apoptosis.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp9	Casp9	Casp9	casp3	casp3	casp3	0	1	8	9
Formation of the apoptosome complex by mitochondria released cytochrome c , Apaf-1 , and dATP and ATP is essential for the activation of initiator caspase-9 , which then activates downstream effector caspase-3 .	Formation of the apoptosome complex by mitochondria released cytochrome c, Apaf-1, and dATP and ATP is essential for the activation of initiator caspase-9, which then activates downstream effector caspase-3.	21	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	24	25	31	32
The OTA induced cytochrome c leads to auto-activation of caspase 9 , which further activates caspase 3 .	The OTA induced cytochrome c leads to auto-activation of caspase 9, which further activates caspase 3.	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	9	11	15	17
In this experiment , caspase-3 , caspase-8 and caspase-9 expression increased in liver tissues in the model group , indicating that the activation of caspase-8 and caspase-9 can activate caspase-3 to initiate a caspase cascade reaction to induce apoptosis of liver cells .	In this experiment, caspase-3, caspase-8 and caspase-9 expression increased in liver tissues in the model group, indicating that the activation of caspase-8 and caspase-9 can activate caspase-3 to initiate a caspase cascade reaction to induce apoptosis of liver cells.	22	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	26	27	29	30
In their model , activated Caspase3 can bind XIAP , and thereby sequesters XIAP away from activated Caspase9 , which in turn activate more Caspase3 .	In their model, activated Caspase3 can bind XIAP, and thereby sequesters XIAP away from activated Caspase9, which in turn activate more Caspase3.	12	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase9	Caspase9	Caspase9	Caspase3	Caspase3	Caspase3	17	18	24	25
Caspase-9 subsequently activates effector caspase-3 , -6 , and -7 , but interestingly , our data did not show statistically significant increases in the three effector proteins [ XREF_BIBR ] .	Caspase-9 subsequently activates effector caspase-3, -6, and -7, but interestingly, our data did not show statistically significant increases in the three effector proteins [XREF_BIBR].	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	4	5
The apoptosome cleaves pro-caspase-9 to its active form of caspase-9 , which in turn activates its effector , caspase-3 , and irreversibly commits cells to death XREF_BIBR .	The apoptosome cleaves pro-caspase-9 to its active form of caspase-9, which in turn activates its effector, caspase-3, and irreversibly commits cells to death XREF_BIBR.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	18	19
Subsequently , the reduction of the MMP activates Caspase-9 , a mitochondrial dependent apoptotic initiator , which in turn activates Caspase-3 , leading to apoptosis .	Subsequently, the reduction of the MMP activates Caspase-9, a mitochondrial dependent apoptotic initiator, which in turn activates Caspase-3, leading to apoptosis.	7	21	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	8	9	20	21
Cytochrome C activates caspase 9 and a series of signaling cascade leads to the activation of caspase 3 and apoptosis in APL cells .	Cytochrome C activates caspase 9 and a series of signaling cascade leads to the activation of caspase 3 and apoptosis in APL cells.	3	18	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	3	5	16	18
During prolong ER stress , caspase-12 migrates from ER to cytosol and cleaves the caspase-9 and further activate caspase-3 .	During prolong ER stress, caspase-12 migrates from ER to cytosol and cleaves the caspase-9 and further activate caspase-3.	13	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	14	15	18	19
Consequently , caspase-9 activates , amongst others , caspase-3 , which , in turn , activates caspases-6 and -7 and is involved in various processes during the demolition phase of apoptosis .	Consequently, caspase-9 activates, amongst others, caspase-3, which, in turn, activates caspases-6 and -7 and is involved in various processes during the demolition phase of apoptosis.	2	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	8	9
Caspase-9 can signal downstream and activate pro-caspase-3 and -7 .	Caspase-9 can signal downstream and activate pro-caspase-3 and -7.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	pro-caspase-3	pro-caspase-3	pro-caspase-3	0	1	6	7
As a result , caspase-9 is activated and induces the activation of caspase-3 .	As a result, caspase-9 is activated and induces the activation of caspase-3.	4	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	12	13
Cytochrome c in the cytosol activates caspase-9 , which activates caspase-3 .	Cytochrome c in the cytosol activates caspase-9, which activates caspase-3.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	10	11
The apoptosome is a multiprotein complex comprising Apaf-1 , cytochrome c , and caspase-9 that functions to activate caspase-3 downstream of mitochondria in response to apoptotic signals .	The apoptosome is a multiprotein complex comprising Apaf-1, cytochrome c, and caspase-9 that functions to activate caspase-3 downstream of mitochondria in response to apoptotic signals.	5	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	13	14	18	19
The release of mature caspase 9 activates additional caspase 9 molecules as well as caspase 3 and 7 .	The release of mature caspase 9 activates additional caspase 9 molecules as well as caspase 3 and 7.	1	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	4	6	14	16
In hypoxic human brain ECs treated with tPA , blockade of caspase-8 , but not MMP-9 , effectively inhibited caspase-3 activation , in contrast , in the absence of tPA , blockade of caspase-9 , but not MMP-8 , effectively inhibited caspase-3 activation .	In hypoxic human brain ECs treated with tPA, blockade of caspase-8, but not MMP-9, effectively inhibited caspase-3 activation, in contrast, in the absence of tPA, blockade of caspase-9, but not MMP-8, effectively inhibited caspase-3 activation.	31	42	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	33	34	41	42
Caspase-9 activates caspase-3 which may cause apoptosis .	Caspase-9 activates caspase-3 which may cause apoptosis.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	2	3
The major caspase involved in this step is caspase-9 , which can cleave itself into the active form within the apoptosome , and then activates the main executor caspase-3 .	The major caspase involved in this step is caspase-9, which can cleave itself into the active form within the apoptosome, and then activates the main executor caspase-3.	2	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	28	29
Caspase 9 activates the effector caspase 3 , which then leads to the cell undergoing apoptosis .	Caspase 9 activates the effector caspase 3, which then leads to the cell undergoing apoptosis.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	5	7
Cytosolic cytochrome c together with apoptosis protease activating factor ( Apaf ) -1 activates caspase-9 , which in turn activates caspase-3 resulting in apoptosis .	Cytosolic cytochrome c together with apoptosis protease activating factor (Apaf) -1 activates caspase-9, which in turn activates caspase-3 resulting in apoptosis.	13	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	14	15	20	21
The differences in caspase 3 activation by upstream caspase 8 and caspase 9 may be due to the unique timing of cell signal transduction in each cell line .	The differences in caspase 3 activation by upstream caspase 8 and caspase 9 may be due to the unique timing of cell signal transduction in each cell line.	3	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	11	13	3	5
Caspase12 can activate caspase9 , which in turn activates caspase3 .	Caspase12 can activate caspase9, which in turn activates caspase3.	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase9	caspase9	caspase9	caspase3	caspase3	caspase3	3	4	9	10
In return , the activated caspase-9 works together with the complex of cyt c , which in turn activates caspase-3 to apoptotic mode of cell death .	In return, the activated caspase-9 works together with the complex of cyt c, which in turn activates caspase-3 to apoptotic mode of cell death.	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	19	20
7 Like caspase-8 , caspase-9 can also activate caspase-3 and initiate cell apoptosis .	7 Like caspase-8, caspase-9 can also activate caspase-3 and initiate cell apoptosis.	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	8	9
Caspase 9 can subsequently activate caspase 3 as well as caspase 1 through the intermediary caspase 8 .	Caspase 9 can subsequently activate caspase 3 as well as caspase 1 through the intermediary caspase 8.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	5	7
Then , caspase 9 triggers the effector caspase-3 and caspase-7 that lead to apoptosis .	Then, caspase 9 triggers the effector caspase-3 and caspase-7 that lead to apoptosis.	2	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase-3	caspase-3	caspase-3	2	4	7	8
Both caspase-8 and caspase-9 could activate caspase-3 , which results in cell death .	Both caspase-8 and caspase-9 could activate caspase-3, which results in cell death.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	6	7
Caspase 8 and caspase 9 activate caspase 3 by proteolytic cleavage , and caspase-3 then cleaves vital cellular proteins or other caspases .	Caspase 8 and caspase 9 activate caspase 3 by proteolytic cleavage, and caspase-3 then cleaves vital cellular proteins or other caspases.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	3	5	6	8
Caspase-3 , an executioner caspase that is activated by caspase-9 , cleaves a broad spectrum of cellular target proteins , including nuclear PARP , which leads to a cell-death cascade .	Caspase-3, an executioner caspase that is activated by caspase-9, cleaves a broad spectrum of cellular target proteins, including nuclear PARP, which leads to a cell-death cascade.	0	11	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	9	10	0	1
Caspase-3 is the most significant member in the apoptotic pathway and can be activated by caspase-8 or caspase-9 [ XREF_BIBR ] .	Caspase-3 is the most significant member in the apoptotic pathway and can be activated by caspase-8 or caspase-9 [XREF_BIBR].	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	17	18	0	1
As reported , caspase-3 , activated by caspase-8 and caspase-9 , cleaves vital cellular proteins , leading to apoptosis via mitochondria dependent pathway [ XREF_BIBR ] .	As reported, caspase-3, activated by caspase-8 and caspase-9, cleaves vital cellular proteins, leading to apoptosis via mitochondria dependent pathway [XREF_BIBR].	3	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	3	4
Intermediate filaments , including vimentin , have been shown to provide a scaffold whereby active subunits of caspase-9 can activate caspase-3 , which , in turn , can activate more caspase-9 resulting in an amplification loop XREF_BIBR , XREF_BIBR .	Intermediate filaments, including vimentin, have been shown to provide a scaffold whereby active subunits of caspase-9 can activate caspase-3, which, in turn, can activate more caspase-9 resulting in an amplification loop XREF_BIBR, XREF_BIBR.	15	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	17	18	20	21
In addition to receptor mediated apoptosis , there is another pathway activated by various forms of cytotoxic stress-inducers like gamma-rays , uv-rays , drugs like Actinomycin-D , removal of cytokines etc that involves altering the mitochondrial permeability transition and subsequent release of cytochrome-c and formation of the Apoptosome , a catalytic multi protein platform that activates Caspase9 , which in turn activates Caspase3 leading to the later events involved in cell death .	In addition to receptor mediated apoptosis, there is another pathway activated by various forms of cytotoxic stress-inducers like gamma-rays, uv-rays, drugs like Actinomycin-D, removal of cytokines etc that involves altering the mitochondrial permeability transition and subsequent release of cytochrome-c and formation of the Apoptosome, a catalytic multi protein platform that activates Caspase9, which in turn activates Caspase3 leading to the later events involved in cell death.	55	67	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase9	Caspase9	Caspase9	Caspase3	Caspase3	Caspase3	56	57	62	63
Both caspase-8 and caspase-9 can activate caspase-3 , a crucial effector caspase conducting the final execution steps of apoptosis program [ XREF_BIBR - XREF_BIBR ] .	Both caspase-8 and caspase-9 can activate caspase-3, a crucial effector caspase conducting the final execution steps of apoptosis program [XREF_BIBR - XREF_BIBR].	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	6	7
Both caspase-8 and caspase-9 activate caspase-3 , which along with other effectors caspases cleave critical cellular proteins , resulting in apoptosis [ XREF_BIBR ] .	Both caspase-8 and caspase-9 activate caspase-3, which along with other effectors caspases cleave critical cellular proteins, resulting in apoptosis [XREF_BIBR].	1	18	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	5	6
Once released , cytochrome c activates caspase 9 , which in turn activates caspase 3 .	Once released, cytochrome c activates caspase 9, which in turn activates caspase 3.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	6	8	13	15
This is supported by our finding that D269H and E195R in combination with nutlin-3 more potently activated caspase 8- and caspase 9 induced caspase 3 cleavage .	This is supported by our finding that D269H and E195R in combination with nutlin-3 more potently activated caspase 8- and caspase 9 induced caspase 3 cleavage.	16	25	induced	Positive_early_activation	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	20	22	23	25
In the cytosol , cytochrome c interacts with Apaf 1 ( apoptotic protease activating factor 1 ) and ATP to form an apoptosome , which recruits and activates the caspase 9 , which in turn activates caspase 3 to mediate cell death .	In the cytosol, cytochrome c interacts with Apaf 1 (apoptotic protease activating factor 1) and ATP to form an apoptosome, which recruits and activates the caspase 9, which in turn activates caspase 3 to mediate cell death.	25	39	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	29	31	36	38
Cytochrome c releasing from mitochondria can activate caspase-9 , which in turn activates executioner caspase-3 via cleavage induction , and PARP , an important substrate of caspase-3 was cleaved .	Cytochrome c releasing from mitochondria can activate caspase-9, which in turn activates executioner caspase-3 via cleavage induction, and PARP, an important substrate of caspase-3 was cleaved.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	14	15
The actived Caspase-9 in turn activates Caspase-3 that subsequently cleaves PARP , which leads to apoptosis XREF_BIBR .	The actived Caspase-9 in turn activates Caspase-3 that subsequently cleaves PARP, which leads to apoptosis XREF_BIBR.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	2	3	6	7
In rPCNs , it was not surprising that activation of caspase-3 was significantly inhibited by the caspase-9 inhibitor Z-LEHD-FMK ( data not shown ) , since caspase-9 is known to activate caspase-3 .	In rPCNs, it was not surprising that activation of caspase-3 was significantly inhibited by the caspase-9 inhibitor Z-LEHD-FMK (data not shown), since caspase-9 is known to activate caspase-3.	26	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	26	27	31	32
The activation of caspase-9 can promote the activation of caspase-3 , and caspase-3 plays a vital role in the apoptotic process [ XREF_BIBR , XREF_BIBR ] .	The activation of caspase-9 can promote the activation of caspase-3, and caspase-3 plays a vital role in the apoptotic process [XREF_BIBR, XREF_BIBR].	1	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	9	10
Here , it is the active form of caspase-8 but not caspase-9 that activates downstream effector caspase-3 , resulting in the cleavage of critical cellular proteins and apoptosis .	Here, it is the active form of caspase-8 but not caspase-9 that activates downstream effector caspase-3, resulting in the cleavage of critical cellular proteins and apoptosis.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	11	12	16	17
The reduced activation of caspase 9 subsequently suppressed downstream caspase 3 , which was activated through the mitochondrial mediated pathway .	The reduced activation of caspase 9 subsequently suppressed downstream caspase 3, which was activated through the mitochondrial mediated pathway.	2	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	4	6	9	11
Heat shock protein-27tg hearts demonstrated significantly less apoptotic cells than those in LC hearts , and there was significantly less activation of caspase 3 and caspase 9 in Hsp-27tg hearts compared with LCs .	Heat shock protein-27tg hearts demonstrated significantly less apoptotic cells than those in LC hearts, and there was significantly less activation of caspase 3 and caspase 9 in Hsp-27tg hearts compared with LCs.	17	29	was significantly less activation	Positive_activation_copula_1	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	25	27	22	24
Caspase 9 in turn activates caspase 3 , an effector proteinase that degrades proteins and causes apoptosis XREF_BIBR XREF_BIBR .	Caspase 9 in turn activates caspase 3, an effector proteinase that degrades proteins and causes apoptosis XREF_BIBR XREF_BIBR.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	5	7
XREF_BIBR Among them , caspase-8 or caspase-9 can activate caspase-3 , which is one of the most important executioner caspases .	XREF_BIBR Among them, caspase-8 or caspase-9 can activate caspase-3, which is one of the most important executioner caspases.	4	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	9	10
Pretreatment with Z-LEHD-FMK , a specific inhibitor of caspase-9 , significantly attenuated APS-1d-induced cell apoptosis , and activation of caspase-3 .	Pretreatment with Z-LEHD-FMK, a specific inhibitor of caspase-9, significantly attenuated APS-1d-induced cell apoptosis, and activation of caspase-3.	6	20	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	19	20
Since mitochondrial release of Smac/Diablo and activation of calpain can cross-talk with caspases for apoptosis , we examined and found activation of caspase-9 ( XREF_FIG ) , which in turn activated the final executioner caspase-3 ( XREF_FIG ) leading to cytoskeletal brakedown and apoptosis .	Since mitochondrial release of Smac/Diablo and activation of calpain can cross-talk with caspases for apoptosis, we examined and found activation of caspase-9 (XREF_FIG), which in turn activated the final executioner caspase-3 (XREF_FIG) leading to cytoskeletal brakedown and apoptosis.	20	38	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	22	23	34	35
This results in cytochrome c release from mitochondria and apoptosome formation with caspase 9 activation , which drastically enhances caspase 3 activation .	This results in cytochrome c release from mitochondria and apoptosome formation with caspase 9 activation, which drastically enhances caspase 3 activation.	12	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	12	14	19	21
Caspase-9 then activates caspase-3 and caspase-7 , which leads to apoptosis .	Caspase-9 then activates caspase-3 and caspase-7, which leads to apoptosis.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	3	4
Caspase-3 , a downstream caspase , is activated by caspase-9 .	Caspase-3, a downstream caspase, is activated by caspase-9.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	9	10	0	1
Interestingly , caspase-2 and -8 were not cleaved or activated during the infection , whilst a selective inhibitor of caspase-9 , Z-LEHD-FMK , blocked the cleavage of caspase-3 and -7 , indicating that only the mitochondria mediated intrinsic apoptotic pathway was activated in EV71 infected astrocytes .	Interestingly, caspase-2 and -8 were not cleaved or activated during the infection, whilst a selective inhibitor of caspase-9, Z-LEHD-FMK, blocked the cleavage of caspase-3 and -7, indicating that only the mitochondria mediated intrinsic apoptotic pathway was activated in EV71 infected astrocytes.	17	29	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	19	20	27	28
Caspase-9 is activated at the apoptosome and , in turn , activates caspase-3 and cleaves PARP XREF_BIBR , XREF_BIBR .	Caspase-9 is activated at the apoptosome and, in turn, activates caspase-3 and cleaves PARP XREF_BIBR, XREF_BIBR.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	12	13
Cytochrome c together with Apaf-1 causes activation of the initiator caspase , caspase-9 , which in turn activates caspase-3 ultimately leading to the degradation of poly ( ADP-ribose ) polymerase ( PARP ) .	Cytochrome c together with Apaf-1 causes activation of the initiator caspase, caspase-9, which in turn activates caspase-3 ultimately leading to the degradation of poly (ADP-ribose) polymerase (PARP).	10	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	12	13	18	19
Cytochrome c in the cytosol activates caspase-8 and caspase-9 , which further activate executioner caspase-3 to induce cell apoptosis .	Cytochrome c in the cytosol activates caspase-8 and caspase-9, which further activate executioner caspase-3 to induce cell apoptosis.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	14	15
This activated caspase-9 in turn activates the executioner caspase-3 , with subsequent execution of the apoptotic process [ XREF_BIBR ] .	This activated caspase-9 in turn activates the executioner caspase-3, with subsequent execution of the apoptotic process [XREF_BIBR].	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	8	9
Caspase-3 , activated by the initiator caspase-9 , is an executive caspase , which receives the apoptosis signal from the mitochondria 31 .	Caspase-3, activated by the initiator caspase-9, is an executive caspase, which receives the apoptosis signal from the mitochondria 31.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	6	7	0	1
This will eventually induce the release of cytochrome c from the mitochondria and the subsequent cleavage of caspase-9 , an initiator caspase that activates the executioner caspase-3 [ XREF_BIBR ] .	This will eventually induce the release of cytochrome c from the mitochondria and the subsequent cleavage of caspase-9, an initiator caspase that activates the executioner caspase-3 [XREF_BIBR].	15	28	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	17	18	26	27
Cytochrome c can combine with Apaf-1 and procaspase-9 , initiates the activation of caspase-9 , which eventually activates downstream effector caspase-3 leading to the activation of the execution phase of apoptosis [ XREF_BIBR , XREF_BIBR ] .	Cytochrome c can combine with Apaf-1 and procaspase-9, initiates the activation of caspase-9, which eventually activates downstream effector caspase-3 leading to the activation of the execution phase of apoptosis [XREF_BIBR, XREF_BIBR].	11	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	13	14	20	21
After release from mitochondria , cytochrome C activates caspase-9 , which in turn activates caspase-3 , resulting in DNA degradation [ XREF_BIBR ] .	After release from mitochondria, cytochrome C activates caspase-9, which in turn activates caspase-3, resulting in DNA degradation [XREF_BIBR].	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	14	15
Moreover , activated caspase-8 and caspase-9 both activated caspase-3 ( 17 and 19 kDa ) and PARP ( 89 kDa ) , and then induced apoptosis ( XREF_FIG ) .	Moreover, activated caspase-8 and caspase-9 both activated caspase-3 (17 and 19 kDa) and PARP (89 kDa), and then induced apoptosis (XREF_FIG).	3	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	8	9
The levels of cleaved caspase-3 , cleaved PARP ( the substrate of caspase-3 ) and caspase-9 ( the modulator of the caspase-3 ) , which had increased following IR injury , were significantly inhibited by NSP in both wild type and tPA -/- mice .	The levels of cleaved caspase-3, cleaved PARP (the substrate of caspase-3) and caspase-9 (the modulator of the caspase-3), which had increased following IR injury, were significantly inhibited by NSP in both wild type and tPA -/- mice.	6	26	modulator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	15	16	21	22
As an initiator in the intrinsic pathway , caspase-9 is cleaved into the active form and goes to activate caspase-3 upon the release of cytochrome c from mitochondria .	As an initiator in the intrinsic pathway, caspase-9 is cleaved into the active form and goes to activate caspase-3 upon the release of cytochrome c from mitochondria.	8	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	19	20
Cytochrome c release from the mitochondria participates with apoptotic protease activating factor-1 in the activation of caspase-9 , which in turn activates caspase-3 .	Cytochrome c release from the mitochondria participates with apoptotic protease activating factor-1 in the activation of caspase-9, which in turn activates caspase-3.	14	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	16	17	22	23
Binding of cytochrome c to Apaf-1 creates an apoptosome complex that activates caspase-9 , which in turn activates caspase-3 .	Binding of cytochrome c to Apaf-1 creates an apoptosome complex that activates caspase-9, which in turn activates caspase-3.	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	12	13	18	19
Caspase-3 is activated by proteolytic cleavage of caspase 9 and is a key apoptotic executive caspase .	Caspase-3 is activated by proteolytic cleavage of caspase 9 and is a key apoptotic executive caspase.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	Caspase-3	Caspase-3	Caspase-3	7	9	0	1
Eventually , caspase-9 cleaves and activates caspase-3 , resulting in the activation of apoptotic cell death .	Eventually, caspase-9 cleaves and activates caspase-3, resulting in the activation of apoptotic cell death.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	6	7
Caspase-8 and caspase-9 can activate caspase-3 via proteolytic cleavage .	Caspase-8 and caspase-9 can activate caspase-3 via proteolytic cleavage.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	5	6
Activated casp8 or casp9 induces Casp-3 , -6 and -7 activity via cleavage of the short prodomain of these latter caspases .	Activated casp8 or casp9 induces Casp-3, -6 and -7 activity via cleavage of the short prodomain of these latter caspases.	0	10	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	casp9	casp9	casp9	Casp-3	Casp-3	Casp-3	3	4	5	6
The activation of caspase-9 causes the cleavage of caspase-3 , a critical executioner of apoptosis .	The activation of caspase-9 causes the cleavage of caspase-3, a critical executioner of apoptosis.	1	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	8	9
Both caspase-9 and caspase-8 can activate apoptotic executor caspase-3 .	Both caspase-9 and caspase-8 can activate apoptotic executor caspase-3.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	8	9
Caspase 3 was activated by caspase 9 , so the pre-caspase 3 reduced .	Caspase 3 was activated by caspase 9, so the pre-caspase 3 reduced.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	Caspase 3	Caspase 3	Caspase 3	5	7	0	2
Because cleaved caspase-9 activates caspase-3 , the latter translocates into nucleus , causing DNA fragmentation and eventually cell death we decided to study whether CoQ10 blocks activation of caspase-3 in cells exposed to UVB .	Because cleaved caspase-9 activates caspase-3, the latter translocates into nucleus, causing DNA fragmentation and eventually cell death we decided to study whether CoQ10 blocks activation of caspase-3 in cells exposed to UVB.	1	5	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	4	5
Cytochrome c release leads to the activation of caspase-9 , which in turn activates caspase-3 and yields the degradation of internal cellular structures and apoptosis execution .	Cytochrome c release leads to the activation of caspase-9, which in turn activates caspase-3 and yields the degradation of internal cellular structures and apoptosis execution.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	14	15
The activated caspase-9 further triggers caspase-3 activation and apoptosis .	The activated caspase-9 further triggers caspase-3 activation and apoptosis.	0	6	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	5	6
Processing of caspase 9 alone was insufficient to cause death of the yeast , which required the further activation of caspase 3 by caspase 9 .	Processing of caspase 9 alone was insufficient to cause death of the yeast, which required the further activation of caspase 3 by caspase 9.	15	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	23	25	20	22
Caspase-3 may be activated by caspase-9 via the mitochondria dependent cytochrome c/caspase -9 intrinsic pathway .	Caspase-3 may be activated by caspase-9 via the mitochondria dependent cytochrome c/caspase -9 intrinsic pathway.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	5	6	0	1
According to our model , activation of caspase-3 by caspase-9 in thymocytes occurs both directly as well as indirectly via a lysosomal amplification loop .	According to our model, activation of caspase-3 by caspase-9 in thymocytes occurs both directly as well as indirectly via a lysosomal amplification loop.	5	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	7	8
Our data thereby showed that this combination therapy induced the mitochondria mediated pathway of apoptosis for activation of caspase-9 , which in turn activated caspase-3 for completion of apoptotic process in GSC and SNB19 cells .	Our data thereby showed that this combination therapy induced the mitochondria mediated pathway of apoptosis for activation of caspase-9, which in turn activated caspase-3 for completion of apoptotic process in GSC and SNB19 cells.	16	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	18	19	24	25
Suppression of caspase 9 processing by p53 depletion also eliminated activating cleavage of its downstream executioner caspase 3 ( XREF_FIG ) , which plays a major role in PARP cleavage and apoptotic death in general .	Suppression of caspase 9 processing by p53 depletion also eliminated activating cleavage of its downstream executioner caspase 3 (XREF_FIG), which plays a major role in PARP cleavage and apoptotic death in general.	2	19	eliminated activating	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	2	4	16	18
In turn , caspase-9 activates caspase-3 , which in turn plays an important role in cell death [ XREF_BIBR , XREF_BIBR ] .	In turn, caspase-9 activates caspase-3, which in turn plays an important role in cell death [XREF_BIBR, XREF_BIBR].	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	5	6
Cytochrome C is released from the intermembrane space of mitochondria into the cytosol and activates the caspase-9 proenzyme , which , in turn , activates caspase-3 , which cleaves PARP to initiate a caspase cascade leading to apoptosis .	Cytochrome C is released from the intermembrane space of mitochondria into the cytosol and activates the caspase-9 proenzyme, which, in turn, activates caspase-3, which cleaves PARP to initiate a caspase cascade leading to apoptosis.	16	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	16	17	25	26
In addition , PKCdelta likely enhances activation of caspase-9 , which further activates the downstream effector caspase-3 , since the PKCdelta specific inhibitor rottlerin attenuates activation of caspase-3 and upstream initiator caspase-9 , at least in our study .	In addition, PKCdelta likely enhances activation of caspase-9, which further activates the downstream effector caspase-3, since the PKCdelta specific inhibitor rottlerin attenuates activation of caspase-3 and upstream initiator caspase-9, at least in our study.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	16	17
Caspase-3 activity in the infected apaf-1-/- MEFs was slightly higher than the background controls , which may be because activated caspase-9 activates caspase-3 when assay samples are prepared in vitro .	Caspase-3 activity in the infected apaf-1-/- MEFs was slightly higher than the background controls, which may be because activated caspase-9 activates caspase-3 when assay samples are prepared in vitro.	19	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	20	21	22	23
Subsequently , the active Caspase-9 can activate Caspase-3 , an effector caspase that cleaves PARP at the onset of apoptosis XREF_BIBR .	Subsequently, the active Caspase-9 can activate Caspase-3, an effector caspase that cleaves PARP at the onset of apoptosis XREF_BIBR.	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	4	5	7	8
Caspases can be activated through multiple ways ; for example , caspase 9 can activate caspase 3 , and caspase 3 in turn activates caspase 9 to form a positive feedback [ XREF_BIBR ] .	Caspases can be activated through multiple ways; for example, caspase 9 can activate caspase 3, and caspase 3 in turn activates caspase 9 to form a positive feedback [XREF_BIBR].	11	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	11	13	15	17
The active caspase-9 proteolytically activates caspase-3 XREF_BIBR .	The active caspase-9 proteolytically activates caspase-3 XREF_BIBR.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	5	6
The apoptosome is a multiprotein complex comprising cytochrome C , Apaf-1 , and caspase-9 that functions to activate caspase-3 , down-stream of the mitochondria apoptosis pathway in response to apoptotic signals .	The apoptosome is a multiprotein complex comprising cytochrome C, Apaf-1, and caspase-9 that functions to activate caspase-3, down-stream of the mitochondria apoptosis pathway in response to apoptotic signals.	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	13	14	18	19
Inhibition of caspase-9 after the addition of the specific caspase-9 inhibitor LEHD-fmk significantly abrogated aeroplysinin-1-induced activation of caspase-2 and caspase-3 ( results not shown ) , indicating the relevant role of caspase-9 as an upstream caspase in the mitochondria mediated apoptosis pathway .	Inhibition of caspase-9 after the addition of the specific caspase-9 inhibitor LEHD-fmk significantly abrogated aeroplysinin-1-induced activation of caspase-2 and caspase-3 (results not shown), indicating the relevant role of caspase-9 as an upstream caspase in the mitochondria mediated apoptosis pathway.	0	20	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	19	20
Active caspase-9 then activates caspase-3 , initiating a cascade of additional caspase activations that culminates in apoptosis .	Active caspase-9 then activates caspase-3, initiating a cascade of additional caspase activations that culminates in apoptosis.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	4	5
In addition , the specific inhibitors of caspase-9 and caspase-3 almost abolished the ANTMHspd induced caspase-9 and caspase-3 activation , respectively .	In addition, the specific inhibitors of caspase-9 and caspase-3 almost abolished the ANTMHspd induced caspase-9 and caspase-3 activation, respectively.	5	18	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	17	18
Caspase-9 cleaves and activates executioner caspase-3 , which triggers the apoptosis .	Caspase-9 cleaves and activates executioner caspase-3, which triggers the apoptosis.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	5	6
After undergoing conformational changes , procaspase-9 was cleaved and activated , and the released caspase-9 activated the downstream caspase-3 ( XREF_FIG ) leading to cell apoptosis .	After undergoing conformational changes, procaspase-9 was cleaved and activated, and the released caspase-9 activated the downstream caspase-3 (XREF_FIG) leading to cell apoptosis.	12	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	14	15	18	19
The apoptosome binds and cleaves pro caspase 9 , releasing activated caspase 9 , which continues to activate caspase 3 and ultimately results in an apoptotic cell .	The apoptosome binds and cleaves pro caspase 9, releasing activated caspase 9, which continues to activate caspase 3 and ultimately results in an apoptotic cell.	2	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	6	8	18	20
Caspase-9 then activates caspase-3 , followed by downstream caspase-2 , -6 , -8 , and -10 activations [ XREF_BIBR ] .	Caspase-9 then activates caspase-3, followed by downstream caspase-2, -6, -8, and -10 activations [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	3	4
Release of cytochrome C can in turn activate caspase-9 which can then activate caspase-3 .	Release of cytochrome C can in turn activate caspase-9 which can then activate caspase-3.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	13	14
In addition , the specific inhibitors of caspase-9 and caspase-3 almost completely abolished the NSC48693 induced cleavage of caspase-9 and caspase-3 , respectively ( XREF_FIG ) .	In addition, the specific inhibitors of caspase-9 and caspase-3 almost completely abolished the NSC48693 induced cleavage of caspase-9 and caspase-3, respectively (XREF_FIG).	5	21	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	20	21
Caspase-9 in turn activates caspase-3 and PARP cleavage , a nuclear protein that detects DNA strand breaks and functions in base excision repair .	Caspase-9 in turn activates caspase-3 and PARP cleavage, a nuclear protein that detects DNA strand breaks and functions in base excision repair.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	4	5
The activated caspase-8 and caspase-9 triggered downstream caspase effectors ( caspase-3 and caspase-7 ) , which further stimulated the proteolytic cleavage of PARP to facilitate cellular disassembly during apoptosis .	The activated caspase-8 and caspase-9 triggered downstream caspase effectors (caspase-3 and caspase-7), which further stimulated the proteolytic cleavage of PARP to facilitate cellular disassembly during apoptosis.	2	12	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	10	11
The pro apoptotic complex , involving Bax , induces pores in the mithocondrial membrane leading to cythocrome C release and caspase-9 activation which activates caspase-3 .	The pro apoptotic complex, involving Bax, induces pores in the mithocondrial membrane leading to cythocrome C release and caspase-9 activation which activates caspase-3.	20	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	20	21	24	25
Caspase-9 cleaves and activates caspase-3 , resulting in widespread proteolysis and cell death .	Caspase-9 cleaves and activates caspase-3, resulting in widespread proteolysis and cell death.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	4	5
Once activated through cleavage , caspase-9 activates the downstream effector caspase-3 that irreversibly causes apoptosis [ XREF_BIBR ] .	Once activated through cleavage, caspase-9 activates the downstream effector caspase-3 that irreversibly causes apoptosis [XREF_BIBR].	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	10	11
The apoptosome then activates caspase-9 , which in turn activates caspase-3 , thereby inducing apoptosis .	The apoptosome then activates caspase-9, which in turn activates caspase-3, thereby inducing apoptosis.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	10	11
Cyt-c is capable of activating caspase-9 by hydrolyzing its proenzyme , and the activated caspase-9 further activates caspase-3 , leading to cell apoptosis .	Cyt-c is capable of activating caspase-9 by hydrolyzing its proenzyme, and the activated caspase-9 further activates caspase-3, leading to cell apoptosis.	12	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	14	15	17	18
The release of cyt c from the mitochondrion plays a crucial role for the execution of the apoptotic pathway because it activates caspase-9 , which subsequently activates caspase-3 .	The release of cyt c from the mitochondrion plays a crucial role for the execution of the apoptotic pathway because it activates caspase-9, which subsequently activates caspase-3.	21	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	22	23	27	28
This structure activates the initiator caspase-9 ( CASP-9 ; EC 3.4.22.62 ) that subsequently activates the executioner caspase-3 ( CASP-3 ; EC 3.4.22.56 ) .	This structure activates the initiator caspase-9 (CASP-9; EC 3.4.22.62) that subsequently activates the executioner caspase-3 (CASP-3; EC 3.4.22.56).	2	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	17	18
Both caspase-8 and caspase-9 activate caspase-3 , which , along with other caspases , cleave critical cellular proteins , resulting in apoptosis .	Both caspase-8 and caspase-9 activate caspase-3, which, along with other caspases, cleave critical cellular proteins, resulting in apoptosis.	1	19	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	5	6
XREF_BIBR Previous research using adoptive Tcells and mesenchymal stromal cells showed that the inducible caspase 9 ( iC9 ) protein , mediated by a small molecule dimerizer , activates caspase 3 , which in turn eliminates damaged or unwanted cells ( XREF_FIG ) .	XREF_BIBR Previous research using adoptive Tcells and mesenchymal stromal cells showed that the inducible caspase 9 (iC9) protein, mediated by a small molecule dimerizer, activates caspase 3, which in turn eliminates damaged or unwanted cells (XREF_FIG).	14	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	14	16	29	31
On the other hand , in intrinsic pathway , caspase-9 ( another initiator caspase ) activates caspase-3 , contributing to apoptotic cell death [ XREF_BIBR , XREF_BIBR ] .	On the other hand, in intrinsic pathway, caspase-9 (another initiator caspase) activates caspase-3, contributing to apoptotic cell death [XREF_BIBR, XREF_BIBR].	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	16	17
The apoptosome recruits , dimerizes , and activates an initiator caspase , caspase-9 , which , in turn , cleaves and activates caspase-3 and -7 XREF_BIBR , XREF_BIBR , XREF_BIBR .	The apoptosome recruits, dimerizes, and activates an initiator caspase, caspase-9, which, in turn, cleaves and activates caspase-3 and -7 XREF_BIBR, XREF_BIBR, XREF_BIBR.	10	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	12	13	22	23
The complex of Apaf-1 , cytochrome c and active caspase-9 , which is referred to as the apoptosome , induces the proteolytically processing and activation of caspase-3 , the protease responsible for the majority of morphological changes associated with apoptosis .	The complex of Apaf-1, cytochrome c and active caspase-9, which is referred to as the apoptosome, induces the proteolytically processing and activation of caspase-3, the protease responsible for the majority of morphological changes associated with apoptosis.	1	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	26	27
Caspase-3 , which is activated by caspase-9 , can cleave proteins involved in damaged DNA recovery or PARP .	Caspase-3, which is activated by caspase-9, can cleave proteins involved in damaged DNA recovery or PARP.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	6	7	0	1
Caspase-9 in turn activates effector caspase-3 , which causes fragmentation of the nucleus , disruption of the cytoskeleton , membrane blebbing , and cellfragmentation [ XREF_BIBR ] .	Caspase-9 in turn activates effector caspase-3, which causes fragmentation of the nucleus, disruption of the cytoskeleton, membrane blebbing, and cellfragmentation [XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	5	6
Caspase-9 could then activate caspase-3 ( XREF_FIG ) for final execution of cells .	Caspase-9 could then activate caspase-3 (XREF_FIG) for final execution of cells.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	4	5
The extrinsic pathway begins after extracellular signaling with death receptors [ XREF_BIBR ] , whereas the intrinsic pathway is initiated by intracellular stimuli that trigger mitochondrial membrane permeabilization , cytochrome C release into the cytosol , and subsequent caspase-9 activation , which activates caspase-3 , the key enzyme for apoptosis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The extrinsic pathway begins after extracellular signaling with death receptors [XREF_BIBR], whereas the intrinsic pathway is initiated by intracellular stimuli that trigger mitochondrial membrane permeabilization, cytochrome C release into the cytosol, and subsequent caspase-9 activation, which activates caspase-3, the key enzyme for apoptosis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	38	47	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	38	39	43	44
The release of cytc from mitochondria into cytoplasm is the key step in apoptosis [ XREF_BIBR ] and cytoplasmic cytc activates caspase-9 , which in turn activates caspase-3 , thereby culminating in apoptosis [ XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	The release of cytc from mitochondria into cytoplasm is the key step in apoptosis [XREF_BIBR] and cytoplasmic cytc activates caspase-9, which in turn activates caspase-3, thereby culminating in apoptosis [XREF_BIBR, XREF_BIBR] (XREF_FIG).	20	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	21	22	27	28
Both caspase 8 and caspase 9 then activate caspase 3 , which is one of the executioner caspases .	Both caspase 8 and caspase 9 then activate caspase 3, which is one of the executioner caspases.	1	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	4	6	8	10
Caspase-3 , the effector caspase in both the Fas- and mitochondrial mediated apoptosis , is activated by the proteolytic cleavage of procaspase-3 by caspase-8 or caspase-9 .	Caspase-3, the effector caspase in both the Fas- and mitochondrial mediated apoptosis, is activated by the proteolytic cleavage of procaspase-3 by caspase-8 or caspase-9.	0	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	25	26	0	1
Taranukhin and colleagues also reported that taurine reduces ischemia induced caspase-8 and caspase-9 expression ( two upstream activators of caspase-3 ) in the paraventricular nucleus ( PVN ) and supraoptic nucleus ( SON ) of the rat ' s hypothalamus [ XREF_BIBR ] .	Taranukhin and colleagues also reported that taurine reduces ischemia induced caspase-8 and caspase-9 expression (two upstream activators of caspase-3) in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the rat 's hypothalamus [XREF_BIBR].	6	20	activators	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	caspase-9	taurine reduces ischemia induced caspase-8 and caspase-9 expression	caspase-9	caspase-3	caspase-3	caspase-3	12	13	19	20
Cocaine significantly increased caspase-3 activity that was blocked by the inhibitors of cytochrome c release ( cyclosporin A ) , caspase-3 ( Ac-DEVD-CHO ) , and caspase-9 ( Z-LEHD-FMK ) , respectively .	Cocaine significantly increased caspase-3 activity that was blocked by the inhibitors of cytochrome c release (cyclosporin A), caspase-3 (Ac-DEVD-CHO), and caspase-9 (Z-LEHD-FMK), respectively.	3	28	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	26	27	3	4
Caspase-9 then activates caspase-3 and other caspases , subsequently inactivating the DNA repair enzyme PARP .	Caspase-9 then activates caspase-3 and other caspases, subsequently inactivating the DNA repair enzyme PARP.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	3	4
We conclude that the hypoxia induced increased activation of caspase-9 , which activates downstream caspase-3 , is mediated by Src kinase .	We conclude that the hypoxia induced increased activation of caspase-9, which activates downstream caspase-3, is mediated by Src kinase.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	14	15
Procaspase-9 was further auto-cleaved to active Caspase-9 , which in turn triggered Caspase-3 via activation of procaspase-3 [ XREF_BIBR XREF_BIBR ] .	Procaspase-9 was further auto-cleaved to active Caspase-9, which in turn triggered Caspase-3 via activation of procaspase-3 [XREF_BIBR XREF_BIBR].	0	14	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	6	7	12	13
Apoptosis is caused by activation of the initiator caspases-8 and caspase-9 , which trigger the effector caspase-3 [ XREF_BIBR ] .	Apoptosis is caused by activation of the initiator caspases-8 and caspase-9, which trigger the effector caspase-3 [XREF_BIBR].	4	18	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	10	11	16	17
Cytochrome c release from mitochondria binds with APAF1 and ATP leading to the activation of the initiator caspase-9 , which in turn activates the effector caspase-3 and 6 .	Cytochrome c release from mitochondria binds with APAF1 and ATP leading to the activation of the initiator caspase-9, which in turn activates the effector caspase-3 and 6.	13	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	17	18	25	26
41 Caspase-3 , which is located at the convergence of intrinsic and extrinsic apoptosis that initiates the ultimate apoptotic executioner mechanisms , is sequentially activated by caspase-9 .	41 Caspase-3, which is located at the convergence of intrinsic and extrinsic apoptosis that initiates the ultimate apoptotic executioner mechanisms, is sequentially activated by caspase-9.	0	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	26	27	1	2
Accordingly , caspase-9 was shown in vitro to activate caspase-3 which in turns activates caspase-6 , responsible for caspase-8 activation XREF_BIBR .	Accordingly, caspase-9 was shown in vitro to activate caspase-3 which in turns activates caspase-6, responsible for caspase-8 activation XREF_BIBR.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	9	10
Cytochrome c then binds to the adaptor protein apoptotic protease activating factor 1 ( APAF-1 ) to form a multi protein complex termed apoptosome , within which the caspase-9 initiates caspase-3 and caspase-7 leading to apoptosis .	Cytochrome c then binds to the adaptor protein apoptotic protease activating factor 1 (APAF-1) to form a multi protein complex termed apoptosome, within which the caspase-9 initiates caspase-3 and caspase-7 leading to apoptosis.	27	33	initiates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	28	29	30	31
Consequently , caspase-9 is activated by proteolytic cleavage and activates pro-caspase-3 and -7 , the executioner caspases [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Consequently, caspase-9 is activated by proteolytic cleavage and activates pro-caspase-3 and -7, the executioner caspases [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	pro-caspase-3	pro-caspase-3	pro-caspase-3	2	3	10	11
Caspase-3 is activated by caspase-8 and caspase-9 , and it participates in apoptosis by cleaving cellular proteins [ XREF_BIBR ] .	Caspase-3 is activated by caspase-8 and caspase-9, and it participates in apoptosis by cleaving cellular proteins [XREF_BIBR].	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	6	7	0	1
As shown in panels 4 and 5 , knockdown of caspase-9 abolished the activation of caspase-3 and caspase-8 ( compare lane 6 with lanes 2 and 4 ) .	As shown in panels 4 and 5, knockdown of caspase-9 abolished the activation of caspase-3 and caspase-8 (compare lane 6 with lanes 2 and 4).	8	19	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	10	11	15	16
Cleaved caspase-9 activates caspase-3 and which then triggers downstream caspase cascades to execute apoptosis .	Cleaved caspase-9 activates caspase-3 and which then triggers downstream caspase cascades to execute apoptosis.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	3	4
The cleavage of caspase-9 enables the proteolytic maturation of caspase-3 and , consequently , the executive phase of cell apoptosis was induced [ XREF_BIBR , XREF_BIBR ] .	The cleavage of caspase-9 enables the proteolytic maturation of caspase-3 and, consequently, the executive phase of cell apoptosis was induced [XREF_BIBR, XREF_BIBR].	1	10	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	9	10
Caspase 9 then activates the rest of the caspase cascade by triggering the caspase 3 leading to apoptosis .	Caspase 9 then activates the rest of the caspase cascade by triggering the caspase 3 leading to apoptosis.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	13	15
The release of cytochrome c from mitochondria results in the formation of apoptosome ( containing also Apaf-1 and caspase-9 ) and activation of caspase-9 [ XREF_BIBR ] , which activates caspase-3 triggering the caspase cascade .	The release of cytochrome c from mitochondria results in the formation of apoptosome (containing also Apaf-1 and caspase-9) and activation of caspase-9 [XREF_BIBR], which activates caspase-3 triggering the caspase cascade.	23	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	23	24	30	31
Caspase-3 activity was effectively restored by addition of recombinant caspase-9 and APAF1 proteins , and to a lesser extent by caspase-9 alone , but not by APAF1 alone .	Caspase-3 activity was effectively restored by addition of recombinant caspase-9 and APAF1 proteins, and to a lesser extent by caspase-9 alone, but not by APAF1 alone.	0	12	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	9	10	0	1
This effector caspase could probably be activated by caspase-9 , but it remains to be explained how caspase-9 is able to activate caspase-3 only in some cells of the primary decidual zone leading to a very moderate regression of the decidual cells .	This effector caspase could probably be activated by caspase-9, but it remains to be explained how caspase-9 is able to activate caspase-3 only in some cells of the primary decidual zone leading to a very moderate regression of the decidual cells.	17	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	17	18	22	23
Cytochrome c release activates caspase-9 , which activates caspase-3 .	Cytochrome c release activates caspase-9, which activates caspase-3.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	8	9
XREF_BIBR Studies have shown that this protein can interact with antiapoptotic Bcl-2 family members , resulting in activation of caspase-9 , XREF_BIBR which subsequently activates caspase-3 , leading to apoptosis .	XREF_BIBR Studies have shown that this protein can interact with antiapoptotic Bcl-2 family members, resulting in activation of caspase-9, XREF_BIBR which subsequently activates caspase-3, leading to apoptosis.	17	26	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	19	20	25	26
The activities of both caspase-8 and caspase-9 were enhanced by BV , promoting caspase-3 activation , leading to DNA fragmentation .	The activities of both caspase-8 and caspase-9 were enhanced by BV, promoting caspase-3 activation, leading to DNA fragmentation.	1	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	13	14
In the end , caspase-9 is activated , promoting the cleavage of caspase-3 and PARP , which contributes to apoptosis and ultimately cell death .	In the end, caspase-9 is activated, promoting the cleavage of caspase-3 and PARP, which contributes to apoptosis and ultimately cell death.	4	17	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	12	13
Caspase-9 activates the key enzyme caspase-3 during cell apoptosis in order to promote follow-up cell apoptosis signals .	Caspase-9 activates the key enzyme caspase-3 during cell apoptosis in order to promote follow-up cell apoptosis signals.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	5	6
The former is initiated through the release of signal factors , including cytochrome c by mitochondria within the cell , along with caspase-9 activation , which , in turn , activates caspase-3 , ultimately resulting in the degradation of activated caspase-3 substrate proteins [ XREF_BIBR , XREF_BIBR ] .	The former is initiated through the release of signal factors, including cytochrome c by mitochondria within the cell, along with caspase-9 activation, which, in turn, activates caspase-3, ultimately resulting in the degradation of activated caspase-3 substrate proteins [XREF_BIBR, XREF_BIBR].	22	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	22	23	31	32
Then , activated caspase-9 activates effector caspase-3 , thereby initiating a proteolytic cascade .	Then, activated caspase-9 activates effector caspase-3, thereby initiating a proteolytic cascade.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	6	7
Caspase-9 activates caspase-3 and -7 by proteolysis .	Caspase-9 activates caspase-3 and -7 by proteolysis.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	2	3
Pro-caspase-3 is downstream of cytochrome c in the apoptotic cascade and is cleaved by active caspase-9 to produce active caspase-3 , which contributes to oligonucleosomal DNA fragmentation , and ultimately leads to apoptosis XREF_BIBR XREF_BIBR .	Pro-caspase-3 is downstream of cytochrome c in the apoptotic cascade and is cleaved by active caspase-9 to produce active caspase-3, which contributes to oligonucleosomal DNA fragmentation, and ultimately leads to apoptosis XREF_BIBR XREF_BIBR.	12	22	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	15	16	19	20
Cytosolic cytochrome c binds to apoptotic protease activating factor 1 ( Apaf-1 ) , in a ternary complex with caspase-9 , leading to caspase-9 activation ; caspase-9 in turn activates caspase-3 XREF_BIBR .	Cytosolic cytochrome c binds to apoptotic protease activating factor 1 (Apaf-1), in a ternary complex with caspase-9, leading to caspase-9 activation; caspase-9 in turn activates caspase-3 XREF_BIBR.	26	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	26	27	30	31
Cytochrome c activates caspase-9 which subsequently activates caspase-3 .	Cytochrome c activates caspase-9 which subsequently activates caspase-3.	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	7	8
Caspase 3 , the effector caspase in the apoptotic cascade , is activated through cleavage by caspase-9 as a result of an increase in mitochondrial permeability and release of cytochrome C. Cleaved caspase 3 was assessed by western blot analysis .	Caspase 3, the effector caspase in the apoptotic cascade, is activated through cleavage by caspase-9 as a result of an increase in mitochondrial permeability and release of cytochrome C. Cleaved caspase 3 was assessed by western blot analysis.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase 3	Caspase 3	Caspase 3	16	17	0	2
Caspase-9 cleaves procaspase-3 and activates caspase-3 .	Caspase-9 cleaves procaspase-3 and activates caspase-3.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	5	6
Caspase-9 can then activate caspase-3 and the other terminal effector molecules .	Caspase-9 can then activate caspase-3 and the other terminal effector molecules.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	4	5
The apoptosome activates caspase-9 , which activates caspase-3 and induces apoptosis [ XREF_BIBR ] .	The apoptosome activates caspase-9, which activates caspase-3 and induces apoptosis [XREF_BIBR].	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	7	8
These observations , together , suggest that caspase 8 and/or caspase 9 mediates activation of caspase 3 like proteases and caspase 2 during the apoptosis induced by peroxynitrite in HL-60 cells .	These observations, together, suggest that caspase 8 and/or caspase 9 mediates activation of caspase 3 like proteases and caspase 2 during the apoptosis induced by peroxynitrite in HL-60 cells.	7	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	10	12	15	17
XREF_BIBR , XREF_BIBR Caspase-9 activates caspase-3 , one of the executioner caspases , as well as caspases-2 , -6 , -8 , and -10 .	XREF_BIBR, XREF_BIBR Caspase-9 activates caspase-3, one of the executioner caspases, as well as caspases-2, -6, -8, and -10.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	3	4	5	6
Caspase-3 , a common downstream apoptosis effector , can be activated by caspase-9 or caspase-8 and cleaved into the active fragment .	Caspase-3, a common downstream apoptosis effector, can be activated by caspase-9 or caspase-8 and cleaved into the active fragment.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	12	13	0	1
Caspase-9 is the upstream caspase in the mitochondria dependent apoptosis pathway and activates Caspase-3 .	Caspase-9 is the upstream caspase in the mitochondria dependent apoptosis pathway and activates Caspase-3.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	0	1	13	14
The intrinsic apoptosis pathway is largely caspase 9 dependent which further activates caspase-3 which has PARP as a substrate , among others .	The intrinsic apoptosis pathway is largely caspase 9 dependent which further activates caspase-3 which has PARP as a substrate, among others.	3	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase-3	caspase-3	caspase-3	6	8	12	13
The complex activates caspase-9 that eventually activates caspase-3 , leading to the degradation and fragmentation of the chromosomal DNA of the apoptotic cell .	The complex activates caspase-9 that eventually activates caspase-3, leading to the degradation and fragmentation of the chromosomal DNA of the apoptotic cell.	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	7	8
Caspase 9 subsequently cleaves procaspase 3 and activates caspase 3 [ XREF_BIBR - XREF_BIBR ] .	Caspase 9 subsequently cleaves procaspase 3 and activates caspase 3 [XREF_BIBR - XREF_BIBR].	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	8	10
Apoptosome activates caspase 9 which then activates the effector caspase 3 resulting in apoptosis .	Apoptosome activates caspase 9 which then activates the effector caspase 3 resulting in apoptosis.	1	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	2	4	9	11
Activation of caspase 9 activates caspase 3 , which initiates apoptosis , and we therefore examined the involvement of caspases in ibrutinib induced apoptosis .	Activation of caspase 9 activates caspase 3, which initiates apoptosis, and we therefore examined the involvement of caspases in ibrutinib induced apoptosis.	0	9	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	2	4	5	7
In the intrinsic mitochondrial apoptotic pathway , p53-target gene products including Bax and Bak are involved in the release of cytochrome c , resulting in activation of caspase-9 , which in turn activates execution-type caspase-3 .	In the intrinsic mitochondrial apoptotic pathway, p53-target gene products including Bax and Bak are involved in the release of cytochrome c, resulting in activation of caspase-9, which in turn activates execution-type caspase-3.	25	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	27	28	34	35
The activated initiator caspases , caspase-8 and caspase-9 , in turn activate the executor caspase-3 and eventually lead to apoptosis .	The activated initiator caspases, caspase-8 and caspase-9, in turn activate the executor caspase-3 and eventually lead to apoptosis.	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	14	15
The two flavonoids activated caspase-8 , which cleaved Bid into tBid ; simultaneously , Bax transferred from cytosol into mitochondria to decrease MMP ; consequentially , cytochrome c released from mitochondria activated caspase-9 , and then caspase-9 activated caspase-3 , which executed the apoptosis .	The two flavonoids activated caspase-8, which cleaved Bid into tBid; simultaneously, Bax transferred from cytosol into mitochondria to decrease MMP; consequentially, cytochrome c released from mitochondria activated caspase-9, and then caspase-9 activated caspase-3, which executed the apoptosis.	36	41	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	36	37	38	39
Pro-caspase-3 is downstream of cytochrome c in the apoptotic cascade and is cleaved by active caspase-9 to produce active caspase-3 .	Pro-caspase-3 is downstream of cytochrome c in the apoptotic cascade and is cleaved by active caspase-9 to produce active caspase-3.	12	20	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	15	16	19	20
Thus , when the level of Bax increases , the mitochondrial membrane becomes permeable to cyt c. Upon its release into cytosol , cyt c , together with Apaf-1 , activates caspase-9 that then activates caspase-3 .	Thus, when the level of Bax increases, the mitochondrial membrane becomes permeable to cyt c. Upon its release into cytosol, cyt c, together with Apaf-1, activates caspase-9 that then activates caspase-3.	30	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	31	32	35	36
Then , caspase-9 is activated , further activating the downstream effector caspase-3 in order to cleave poly ( ADP-ribose ) polymerase-1 ( PARP-1 ) , which is further activated .	Then, caspase-9 is activated, further activating the downstream effector caspase-3 in order to cleave poly (ADP-ribose) polymerase-1 (PARP-1), which is further activated.	2	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	11	12
Caspase-9 may activate caspase-3 , initiating the apoptotic cascade which leads to the cleavage and inactivation of key cellular proteins such as PARP .	Caspase-9 may activate caspase-3, initiating the apoptotic cascade which leads to the cleavage and inactivation of key cellular proteins such as PARP.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	3	4
28 On the other hand , caspase-9 also triggered caspase-3 signaling pathway in the presence of caspase-3 .	28 On the other hand, caspase-9 also triggered caspase-3 signaling pathway in the presence of caspase-3.	6	11	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	9	10
One of the key effector caspases is caspase-3 , which is initiated by caspase-9 , and is involved in the mitochondrial mediated pathway .	One of the key effector caspases is caspase-3, which is initiated by caspase-9, and is involved in the mitochondrial mediated pathway.	5	17	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	13	14	7	8
Caspase-2-mediated changes in mitochondrial permeability can occur without activation of caspase-9 , although these changes in mitochondrial permeability lead to the release of cytochrome c , which activates caspase-9 which then activates caspase-3 XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Caspase-2-mediated changes in mitochondrial permeability can occur without activation of caspase-9, although these changes in mitochondrial permeability lead to the release of cytochrome c, which activates caspase-9 which then activates caspase-3 XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	27	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	28	29	32	33
This type of degeneration like pruning requires classical apoptotic signaling , including the apoptotic factor Bcl2 associated X protein ( Bax ) and also Caspase-9 activation of Caspase-6 and Caspase-3 .	This type of degeneration like pruning requires classical apoptotic signaling, including the apoptotic factor Bcl2 associated X protein (Bax) and also Caspase-9 activation of Caspase-6 and Caspase-3.	24	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	24	25	29	30
XREF_BIBR XREF_BIBR Caspase 7 is supposed to be functionally redundant with caspase 3 , which can be directly activated by caspase 9 to induce the cleave of cellular substrates during apoptosis .	XREF_BIBR XREF_BIBR Caspase 7 is supposed to be functionally redundant with caspase 3, which can be directly activated by caspase 9 to induce the cleave of cellular substrates during apoptosis.	9	23	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	20	22	11	13
In the intrinsic pathway , the BCL-2 family regulate the small molecules such as cytochrome c which leads to the cleavage and activation of caspase 9 , and finally caspase 9 also activate the downstream effector caspase 3 XREF_BIBR .	In the intrinsic pathway, the BCL-2 family regulate the small molecules such as cytochrome c which leads to the cleavage and activation of caspase 9, and finally caspase 9 also activate the downstream effector caspase 3 XREF_BIBR.	29	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	29	31	36	38
Addition of specific inhibitors of caspase-8 ( z-IETD-fmk ) and caspase-9 ( z-LEHD-fmk ) to HUVEC was found to completely inhibit 9t ,12 t-C18 :2-induced activation of caspase-3 , and z-IETD-fmk inhibited the activation of caspase-9 .	Addition of specific inhibitors of caspase-8 (z-IETD-fmk) and caspase-9 (z-LEHD-fmk) to HUVEC was found to completely inhibit 9t,12t-C18 :2-induced activation of caspase-3, and z-IETD-fmk inhibited the activation of caspase-9.	3	28	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	10	11	27	28
Caspase 9 then activates caspase 3 , which cleaves specific key substrates such as PARP leading to apoptotic cell death .	Caspase 9 then activates caspase 3, which cleaves specific key substrates such as PARP leading to apoptotic cell death.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	4	6
It was also found that caspase 9 cleavage can also activate caspase 3 independent of caspase 8 .	It was also found that caspase 9 cleavage can also activate caspase 3 independent of caspase 8.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	5	7	11	13
Similarly , silencing of caspase-8 or caspase-9 in HCT116 inhibited neem induced caspase-3 activation ( XREF_FIG ) .	Similarly, silencing of caspase-8 or caspase-9 in HCT116 inhibited neem induced caspase-3 activation (XREF_FIG).	2	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	12	13
Upon activation , caspase 9 activates caspase 3 , whose action leads to the execution of apoptosis .	Upon activation, caspase 9 activates caspase 3, whose action leads to the execution of apoptosis.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	3	5	6	8
In NASH , cleavage of initiator caspase 9 elicits downstream activation of effector caspase 3 .	In NASH, cleavage of initiator caspase 9 elicits downstream activation of effector caspase 3.	3	15	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	6	8	13	15
This concept also assumes that caspase-9 activates caspase-3 .	This concept also assumes that caspase-9 activates caspase-3.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	7	8
Mitochondrial dysfunction causes the activation of Apaf-1-associated initiator caspases-8 caspase-9 , which , subsequently , activates executioner caspase-3 and induces the cleavage of PARP [ XREF_BIBR ] .	Mitochondrial dysfunction causes the activation of Apaf-1-associated initiator caspases-8 caspase-9, which, subsequently, activates executioner caspase-3 and induces the cleavage of PARP [XREF_BIBR].	4	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	17	18
Once activated , caspase-9 cleaves and activates the effector caspase-3 .	Once activated, caspase-9 cleaves and activates the effector caspase-3.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	9	10
Previous studies in neuroblastoma cells have shown that caspase-12 activates caspase-9 which , in turn , activates caspase-3 , during apoptosis associated with ER stress ( Martinez et al ., 2010 ; Borkham-Kamphorst et al ., 2016 ) .	Previous studies in neuroblastoma cells have shown that caspase-12 activates caspase-9 which, in turn, activates caspase-3, during apoptosis associated with ER stress (Martinez et al., 2010; Borkham-Kamphorst et al., 2016).	9	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	10	11	17	18
The caspase 9 from intrinsic pathway and the caspase 8 from extrinsic pathway directed the cleavage of caspase 3 and finally lead to apoptosis .	The caspase 9 from intrinsic pathway and the caspase 8 from extrinsic pathway directed the cleavage of caspase 3 and finally lead to apoptosis.	0	21	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	1	3	17	19
Caspase-9 sequentially activated the effector caspase-3 , ultimately causing apoptosis in HIV associated dementia [ XREF_BIBR ] .	Caspase-9 sequentially activated the effector caspase-3, ultimately causing apoptosis in HIV associated dementia [XREF_BIBR].	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	5	6
Active caspase-9 , in turn , activates caspase-3 and caspase-7 , eventually leading to apoptosis [ XREF_BIBR ] .	Active caspase-9, in turn, activates caspase-3 and caspase-7, eventually leading to apoptosis [XREF_BIBR].	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	7	8
Caspase-3 is activated through cleavage into two smaller subunits by caspase-8 or caspase-9 when the cells undergo apoptosis and cleaves a number of proteins that are essential for cell survival , such as PARP [ XREF_BIBR ] .	Caspase-3 is activated through cleavage into two smaller subunits by caspase-8 or caspase-9 when the cells undergo apoptosis and cleaves a number of proteins that are essential for cell survival, such as PARP [XREF_BIBR].	0	13	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	12	13	0	1
Caspase-9 activates caspase-3 , which is a terminal effector caspase , catalyzing the final steps in the cell death cascade XREF_BIBR , XREF_BIBR - XREF_BIBR .	Caspase-9 activates caspase-3, which is a terminal effector caspase, catalyzing the final steps in the cell death cascade XREF_BIBR, XREF_BIBR - XREF_BIBR.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	2	3
Cytochrome C , together with apoptosis activating factor 1 ( Apaf-1 ) , activate caspase 9 , which in turn activates the executor caspase 3 [ XREF_BIBR ] .	Cytochrome C, together with apoptosis activating factor 1 (Apaf-1), activate caspase 9, which in turn activates the executor caspase 3 [XREF_BIBR].	13	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	14	16	23	25
These findings suggest that AVO signals activation of caspase-9 initially , which subsequently stimulates caspase-3 enzymatic activity , which then initiates caspase-8 activation to amplify the apoptosis cascade .	These findings suggest that AVO signals activation of caspase-9 initially, which subsequently stimulates caspase-3 enzymatic activity, which then initiates caspase-8 activation to amplify the apoptosis cascade.	6	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	14	15
Caspase-9 activates caspase-3 .	Caspase-9 activates caspase-3.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	2	3
Caspase 9 further activates downstream effector or execution caspases ( caspase 3 and 7 ) .	Caspase 9 further activates downstream effector or execution caspases (caspase 3 and 7).	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	10	12
Activated caspase-9 reactivates caspase-3 , which leads to the disintegration of the nucleus and cytoplasmic substrates .	Activated caspase-9 reactivates caspase-3, which leads to the disintegration of the nucleus and cytoplasmic substrates.	0	6	reactivates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	3	4
Pro-caspase-9 is then activated , and subsequently activates the downstream effector caspase-3 .	Pro-caspase-9 is then activated, and subsequently activates the downstream effector caspase-3.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pro-caspase-9	Pro-caspase-9	Pro-caspase-9	caspase-3	caspase-3	caspase-3	0	1	11	12
Pro-caspase-9 is then autolyticaly cleaved to active caspase-9 , which then activates pro-caspase-3 to active caspase resulting in cleavage of its substrates and apoptosis .	Pro-caspase-9 is then autolyticaly cleaved to active caspase-9, which then activates pro-caspase-3 to active caspase resulting in cleavage of its substrates and apoptosis.	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	pro-caspase-3	pro-caspase-3	pro-caspase-3	7	8	12	13
Activated caspase 9 can proteolytically activate caspase-3 .	Activated caspase 9 can proteolytically activate caspase-3.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase-3	caspase-3	caspase-3	1	3	6	7
Activation of caspase-8 and caspase-9 then promote caspase-3 , which in turn hydrolyzes cell specific proteins , and poly-ADP ribose polymerase ( PARP ) , thereby inducing apoptosis [ XREF_BIBR , XREF_BIBR ] .	Activation of caspase-8 and caspase-9 then promote caspase-3, which in turn hydrolyzes cell specific proteins, and poly-ADP ribose polymerase (PARP), thereby inducing apoptosis [XREF_BIBR, XREF_BIBR].	0	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	7	8
Activation of both pathways was required for mu1 induced apoptosis , as specific inhibition of either caspase-8 or caspase-9 abolished downstream effector caspase-3 activation .	Activation of both pathways was required for mu1 induced apoptosis, as specific inhibition of either caspase-8 or caspase-9 abolished downstream effector caspase-3 activation.	13	23	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	18	19	22	23
In an ATP or dATP dependent manner , procaspase 9 is activated to caspase 9 , which then activates caspase 3 to initiate the final executioner phase of apoptosis .	In an ATP or dATP dependent manner, procaspase 9 is activated to caspase 9, which then activates caspase 3 to initiate the final executioner phase of apoptosis.	11	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	13	15	19	21
Because caspase-9 is a major activator of effector caspase-3 , this action of pAkt may also contribute to neuroprotection .	Because caspase-9 is a major activator of effector caspase-3, this action of pAkt may also contribute to neuroprotection.	1	9	is a major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	8	9
For irreversible activation of caspase-3 , caspase-9 needs to activate caspase-3 constantly , and switch-on states of positive feedbacks needs to be sustained .	For irreversible activation of caspase-3, caspase-9 needs to activate caspase-3 constantly, and switch-on states of positive feedbacks needs to be sustained.	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	10	11
In 6f treated HepG-2 cells , the sub-G ( 0 ) population was remarkably increased ; and in these cells , both caspase-8 and caspase-9 activity was significantly increased , which in turn activated caspase-3 .	In 6f treated HepG-2 cells, the sub-G (0) population was remarkably increased; and in these cells, both caspase-8 and caspase-9 activity was significantly increased, which in turn activated caspase-3.	22	35	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	24	25	34	35
The latter interacts with Apaf-1 to activate caspase-9 , which in turn activates downstream caspase-3 .	The latter interacts with Apaf-1 to activate caspase-9, which in turn activates downstream caspase-3.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	14	15
Either activated caspase-8 in the extrinsic pathway or cytochrome C activated caspase-9 in the intrinsic pathway could activate the final executor caspase-3 to result in apoptosis [ XREF_BIBR ] .	Either activated caspase-8 in the extrinsic pathway or cytochrome C activated caspase-9 in the intrinsic pathway could activate the final executor caspase-3 to result in apoptosis [XREF_BIBR].	11	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	11	12	21	22
Active caspase-9 cleaves and activates caspase-8 and caspase-3 , leading to apoptosis .	Active caspase-9 cleaves and activates caspase-8 and caspase-3, leading to apoptosis.	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	7	8
The exact non apoptosome mechanism by which Casp9 activates the downstream caspases , Casp6 and Casp3 , remains unclear .	The exact non apoptosome mechanism by which Casp9 activates the downstream caspases, Casp6 and Casp3, remains unclear.	7	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp9	Casp9	Casp9	Casp3	Casp3	Casp3	7	8	15	16
In the two pathways , the initiation caspases caspase-9 and caspase-8 are activated first , which further induces the activation of the effector caspase-3 .	In the two pathways, the initiation caspases caspase-9 and caspase-8 are activated first, which further induces the activation of the effector caspase-3.	5	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	23	24
Caspase-9 activates the executioner caspase-3 , which will subsequently cleave several proteins initiating a sequence of catabolic events .	Caspase-9 activates the executioner caspase-3, which will subsequently cleave several proteins initiating a sequence of catabolic events.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	4	5
Mature caspase-9 activates additional caspase-9 molecules as well as caspase-3 in turn for the execution of cell apoptosis .	Mature caspase-9 activates additional caspase-9 molecules as well as caspase-3 in turn for the execution of cell apoptosis.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	9	10
Caspase 9 activation classically leads to executioner caspase 3 activation thus we tested the requirement for , caspase 3 .	Caspase 9 activation classically leads to executioner caspase 3 activation thus we tested the requirement for, caspase 3.	0	12	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	7	9
After cleavage , caspase 9 activates effector caspase 3 .	After cleavage, caspase 9 activates effector caspase 3.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	3	5	7	9
In our study , caspase-3 , PARP ( the substrate of caspase-3 ) and caspase-9 ( the modulator of the caspase-3 ) were all significantly up-regulated after retinal IR injury , which was consistent with previous findings in liver and brain IR injury models [ XREF_BIBR , XREF_BIBR ] .	In our study, caspase-3, PARP (the substrate of caspase-3) and caspase-9 (the modulator of the caspase-3) were all significantly up-regulated after retinal IR injury, which was consistent with previous findings in liver and brain IR injury models [XREF_BIBR, XREF_BIBR].	6	25	modulator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	14	15	20	21
The results revealed a reduction of ( i ) ALR , ( ii ) clusterin and ( iii ) bcl-2 and an increase of ( iv ) caspase-9 , activated caspase-3 , ROS , apoptotic cell number and mitochondrial degeneration .	The results revealed a reduction of (i) ALR, (ii) clusterin and (iii) bcl-2 and an increase of (iv) caspase-9, activated caspase-3, ROS, apoptotic cell number and mitochondrial degeneration.	22	36	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	27	28	30	31
Initiator Caspase-8 and Caspase-9 activate Caspase-3 , cleaving PARP and inducing apoptosis eventually [ XREF_BIBR , XREF_BIBR ] .	Initiator Caspase-8 and Caspase-9 activate Caspase-3, cleaving PARP and inducing apoptosis eventually [XREF_BIBR, XREF_BIBR].	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	3	4	5	6
The activated caspase-9 in turn activates caspase-3 and initiates the proteolytic cascade to trigger apoptosis of OC cells by high concentration of Se [ XREF_BIBR , XREF_BIBR ] .	The activated caspase-9 in turn activates caspase-3 and initiates the proteolytic cascade to trigger apoptosis of OC cells by high concentration of Se [XREF_BIBR, XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	6	7
Furthermore , the pan-caspase inhibitor zVAD-FMK or the tetra-peptide inhibitors of caspase 8 ( zIETD-FMK ) or caspase 9 ( zLEHD-FMK ) did not inhibit caspase 3 cleavage in H 2 O 2 -treated cells .	Furthermore, the pan-caspase inhibitor zVAD-FMK or the tetra-peptide inhibitors of caspase 8 (zIETD-FMK) or caspase 9 (zLEHD-FMK) did not inhibit caspase 3 cleavage in H 2 O 2 -treated cells.	9	27	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	17	19	25	27
The activation of caspase-9 consequently promotes the caspase-3 proenzyme to the active protease stage , which then adheres to the group of effector caspase [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	The activation of caspase-9 consequently promotes the caspase-3 proenzyme to the active protease stage, which then adheres to the group of effector caspase [XREF_BIBR, XREF_BIBR - XREF_BIBR].	1	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	7	8
In addition , caspase-9 inhibition prevented the activation of downstream caspase-3 , whereas the inhibition of caspase-8 did not .	In addition, caspase-9 inhibition prevented the activation of downstream caspase-3, whereas the inhibition of caspase-8 did not.	3	11	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	10	11
The apoptosome cleaves the procaspase-9 to its active form caspase-9 , which subsequently activates the effector caspase-3 .	The apoptosome cleaves the procaspase-9 to its active form caspase-9, which subsequently activates the effector caspase-3.	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	16	17
Caspase 3 is activated by caspase 9 , and PARP is cleaved by activated caspase 3 .	Caspase 3 is activated by caspase 9, and PARP is cleaved by activated caspase 3.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	Caspase 3	Caspase 3	Caspase 3	5	7	0	2
Cleaved Caspase-9 activated Caspase-3 , which correlated with the increased cleaved PARP expression after GGMPN treatments .	Cleaved Caspase-9 activated Caspase-3, which correlated with the increased cleaved PARP expression after GGMPN treatments.	0	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	1	2	3	4
The activation of caspase-3 by caspase-9 is known to depend on the assembly of a multimolecular complex that includes Apaf-1 and caspase-9 .	The activation of caspase-3 by caspase-9 is known to depend on the assembly of a multimolecular complex that includes Apaf-1 and caspase-9.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	3	4
The activated caspase-9 in turn activates effector caspase-3 , thereby initiating a cascade of proteolytic events XREF_BIBR .	The activated caspase-9 in turn activates effector caspase-3, thereby initiating a cascade of proteolytic events XREF_BIBR.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	7	8
While this process does not involve mitochrondria , which also plays an important role in apoptosis , the cleavage of anti-apoptotic Bid to a proapoptotic , truncated tBid by caspase 8 [ XREF_BIBR ] , permits tBid to translocate to mitochrondria and trigger the release of cytochrome c , leading to the activation of caspase 9 , which then activates caspase 3 , and finally apoptosis ( XREF_FIG ) [ XREF_BIBR ] .	While this process does not involve mitochrondria, which also plays an important role in apoptosis, the cleavage of anti-apoptotic Bid to a proapoptotic, truncated tBid by caspase 8 [XREF_BIBR], permits tBid to translocate to mitochrondria and trigger the release of cytochrome c, leading to the activation of caspase 9, which then activates caspase 3, and finally apoptosis (XREF_FIG) [XREF_BIBR].	52	65	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	54	56	60	62
Caspase-3 can be activated by caspase-9 in the mitochondrial pathway [ XREF_BIBR ] .	Caspase-3 can be activated by caspase-9 in the mitochondrial pathway [XREF_BIBR].	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	5	6	0	1
Apaf-1 , which executes programmed cell death in the caspase-9-related pathway , was detected in the cells exhibiting caspase-9 activity , and our results suggest that Apaaf-1 and caspase-9 activates caspase-3 in kidney organogenesis .	Apaf-1, which executes programmed cell death in the caspase-9-related pathway, was detected in the cells exhibiting caspase-9 activity, and our results suggest that Apaaf-1 and caspase-9 activates caspase-3 in kidney organogenesis.	26	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	28	29	30	31
Caspase-3 can be activated through the extrinsic death receptor pathway by Caspase-8 , or through the intrinsic mitochondrial pathway by Caspase-9 .	Caspase-3 can be activated through the extrinsic death receptor pathway by Caspase-8, or through the intrinsic mitochondrial pathway by Caspase-9.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	20	21	0	1
CHOP activation occurs concomitantly with the activation of caspase-12 , and activated caspase-12 in turn produces activation of the caspase cascade , then caspase-12 activates caspase-9 , which in turn activates caspase-3 , leading to cell death XREF_BIBR , XREF_BIBR .	CHOP activation occurs concomitantly with the activation of caspase-12, and activated caspase-12 in turn produces activation of the caspase cascade, then caspase-12 activates caspase-9, which in turn activates caspase-3, leading to cell death XREF_BIBR, XREF_BIBR.	24	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	25	26	31	32
Caspase-9 cleavage mediates the further downstream activation of caspase-3 and -7 .	Caspase-9 cleavage mediates the further downstream activation of caspase-3 and -7.	0	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	8	9
Recently , inhibition of CASP-8 ( a component of extrinsic pathway ) and CASP-9 abrogated caspase 3 ( CASP-3 ) activity has been reported in silibinin treated MCF-7 and T47D cells .	Recently, inhibition of CASP-8 (a component of extrinsic pathway) and CASP-9 abrogated caspase 3 (CASP-3) activity has been reported in silibinin treated MCF-7 and T47D cells.	2	23	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP-9	CASP-9	CASP-9	caspase 3	caspase 3	caspase 3	13	14	15	17
XREF_BIBR Cyt c released from mitochondria can activate caspase-9 , which in turn activates executioner caspase-3 via cleavage induction .	XREF_BIBR Cyt c released from mitochondria can activate caspase-9, which in turn activates executioner caspase-3 via cleavage induction.	7	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	15	16
Caspase-9 is involved in mitochondrial induced apoptosis , and cleaved caspase-9 activates caspase-3 to initiate the caspase cascade , which leads to apoptosis [ XREF_BIBR ] .	Caspase-9 is involved in mitochondrial induced apoptosis, and cleaved caspase-9 activates caspase-3 to initiate the caspase cascade, which leads to apoptosis [XREF_BIBR].	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	10	11	12	13
Activated caspase-9 stimulated caspase-3 , which subsequently triggered the cell apoptosis .	Activated caspase-9 stimulated caspase-3, which subsequently triggered the cell apoptosis.	0	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	3	4
GA also activated caspase-9 , which in turn , is known to activate the downstream effector caspase-3 and lead to PARP cleavage .	GA also activated caspase-9, which in turn, is known to activate the downstream effector caspase-3 and lead to PARP cleavage.	2	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	3	4	16	17
The apoptosome cleaves pro-caspase-9 to its active form of caspase-9 , which in turn activates the effector caspase-3 .	The apoptosome cleaves pro-caspase-9 to its active form of caspase-9, which in turn activates the effector caspase-3.	7	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	9	10	17	18
The released cytochrome-c in turn activates caspase-9 , which subsequently activates caspase-3 9 .	The released cytochrome-c in turn activates caspase-9, which subsequently activates caspase-3 9.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	11	12
When cytochrome c is released from mitochondria into the cytosol , it is responsible for activating caspase-9 , which further activates caspase-3 and executes the apoptotic program [ XREF_BIBR ] .	When cytochrome c is released from mitochondria into the cytosol, it is responsible for activating caspase-9, which further activates caspase-3 and executes the apoptotic program [XREF_BIBR].	13	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	16	17	21	22
The apoptosome activates the initiator caspase-9 which initiates the executioner apoptotic caspase-3 and caspase-7 ( XREF_FIG ) .	The apoptosome activates the initiator caspase-9 which initiates the executioner apoptotic caspase-3 and caspase-7 (XREF_FIG).	2	15	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	11	12
Activation of the initiator caspase-9 leads to the caspase cascade , resulting in effector caspase-3 cleavage and activation followed by proteolysis throughout the cell and eventual death .	Activation of the initiator caspase-9 leads to the caspase cascade, resulting in effector caspase-3 cleavage and activation followed by proteolysis throughout the cell and eventual death.	0	15	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	14	15
Cleaved caspase-9 activated caspase-3 that correlated with the increased expression of cleaved PARP after relevant treatments [ XREF_BIBR , XREF_BIBR ] .	Cleaved caspase-9 activated caspase-3 that correlated with the increased expression of cleaved PARP after relevant treatments [XREF_BIBR, XREF_BIBR].	0	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	1	2	3	4
It was confirmed that TNF-alpha and cytochrome c could activate caspase-8 and caspase-9 , respectively , and both caspase-8 and caspase-9 activated caspase-3 finally [ XREF_BIBR ] .	It was confirmed that TNF-alpha and cytochrome c could activate caspase-8 and caspase-9, respectively, and both caspase-8 and caspase-9 activated caspase-3 finally [XREF_BIBR].	18	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	20	21	22	23
In the intrinsic pathway , Caspase 9 is first activated by mitochondria released cytochrome c and then activates Caspase 3 .	In the intrinsic pathway, Caspase 9 is first activated by mitochondria released cytochrome c and then activates Caspase 3.	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 9	Caspase 9	Caspase 9	Caspase 3	Caspase 3	Caspase 3	5	7	18	20
Due to the formation of mitochondrial apoptosis induced channel ( MAC ) in the outer mitochondrial membrane , cytochrome c is released from mitochondria and binds with apoptotic protease activating factor-1 ( Apaf-1 ) and ATP , which then binds to pro-caspase-9 to create a protein complex apoptosome and cleaves pro caspase and release active form of caspase-9 , which in turn activates the effector caspase-3 [ XREF_BIBR ] .	Due to the formation of mitochondrial apoptosis induced channel (MAC) in the outer mitochondrial membrane, cytochrome c is released from mitochondria and binds with apoptotic protease activating factor-1 (Apaf-1) and ATP, which then binds to pro-caspase-9 to create a protein complex apoptosome and cleaves pro caspase and release active form of caspase-9, which in turn activates the effector caspase-3 [XREF_BIBR].	51	67	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	57	58	65	66
It is proposed that high level SPIONs could induce cell apoptosis via a mitochondria mediated intrinsic pathway by activation of caspase 9 and caspase 3 , an increase of the Bax and Bcl -2 ratio , and down-regulation of HSP70 and HSP90 survivor factors .	It is proposed that high level SPIONs could induce cell apoptosis via a mitochondria mediated intrinsic pathway by activation of caspase 9 and caspase 3, an increase of the Bax and Bcl -2 ratio, and down-regulation of HSP70 and HSP90 survivor factors.	14	25	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	20	22	23	25
Caspase-3 is activated in apoptotic cells by caspase-8 and caspase-9 via extrinsic and intrinsic pathways .	Caspase-3 is activated in apoptotic cells by caspase-8 and caspase-9 via extrinsic and intrinsic pathways.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	9	10	0	1
On the other hand , in the cytosol , cytochrome c triggers activation of initiator caspase 9 could then activate the effector caspase 3 to contribute to activation the mitochondrial apoptosis pathway .	On the other hand, in the cytosol, cytochrome c triggers activation of initiator caspase 9 could then activate the effector caspase 3 to contribute to activation the mitochondrial apoptosis pathway.	12	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	15	17	22	24
The released cytochrome c activates caspase 9 , which consequently induces caspase 3 activation , resulting in the cleavage of several cellular proteins , and finally , leading to the typical alterations related to cell apoptosis such as DNA fragmentation in cell nuclei .	The released cytochrome c activates caspase 9, which consequently induces caspase 3 activation, resulting in the cleavage of several cellular proteins, and finally, leading to the typical alterations related to cell apoptosis such as DNA fragmentation in cell nuclei.	4	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	5	7	11	13
23 The higher anti-apoptotic activity of the acetyl protein could be due to its greater ability to block Bax translocation to mitochondria , release of cytochrome C into the cytoplasm and prevent caspase-8 and caspase-9 mediated activation of caspase-3 .	23 The higher anti-apoptotic activity of the acetyl protein could be due to its greater ability to block Bax translocation to mitochondria, release of cytochrome C into the cytoplasm and prevent caspase-8 and caspase-9 mediated activation of caspase-3.	32	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	34	35	38	39
Our functional analysis confirmed that caspase-3 activation was downregulated in pEGFP-Peripherin cells by inhibitors of calpain , caspase-12 , or caspase-9 .	Our functional analysis confirmed that caspase-3 activation was downregulated in pEGFP-Peripherin cells by inhibitors of calpain, caspase-12, or caspase-9.	5	21	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	20	21	5	6
Our results show that Ang ( 1-7 ) , through Mas , prevents the effects induced by Ang II in the diaphragm muscles and decreases several events associated with apoptosis in the diaphragm ( increased apoptotic nuclei , increased expression of caspase-8 and caspase-9 , increased caspase-3 activity and increased Bax and Bcl -2 ratio ) .	Our results show that Ang (1-7), through Mas, prevents the effects induced by Ang II in the diaphragm muscles and decreases several events associated with apoptosis in the diaphragm (increased apoptotic nuclei, increased expression of caspase-8 and caspase-9, increased caspase-3 activity and increased Bax and Bcl -2 ratio).	39	47	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	expression of caspase-8 and caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	43	44	46	47
The apoptosome activates the initiator caspase , caspase-9 which in turn activates pro-caspase-3 and -7 and promotes apoptosis [ XREF_BIBR ] .	The apoptosome activates the initiator caspase, caspase-9 which in turn activates pro-caspase-3 and -7 and promotes apoptosis [XREF_BIBR].	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	pro-caspase-3	pro-caspase-3	pro-caspase-3	7	8	12	13
Cleavage of caspase-9 by calpain generates truncated caspase-9 that is unable to activate caspase-3 in cell lysates .	Cleavage of caspase-9 by calpain generates truncated caspase-9 that is unable to activate caspase-3 in cell lysates.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	13	14
Caspase 3 can be activated by either the mitochondrial independent caspases 8 and 2 or the mitochondrial dependent caspase 9 ; however , inhibition of caspases 8 ( ZIETD ) or 2 ( ZVDVAD ) were ineffective , whereas inhibition of caspase 9 with ZLEHD fully prevented Arg 72 -p53 mediated neuronal apoptosis ( XREF_FIG ) .	Caspase 3 can be activated by either the mitochondrial independent caspases 8 and 2 or the mitochondrial dependent caspase 9; however, inhibition of caspases 8 (ZIETD) or 2 (ZVDVAD) were ineffective, whereas inhibition of caspase 9 with ZLEHD fully prevented Arg 72 -p53 mediated neuronal apoptosis (XREF_FIG).	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	Caspase 3	Caspase 3	Caspase 3	18	20	0	2
CASP-9 then activates CASP-3 and CASP-7 leading to apoptosis [ XREF_BIBR ] .	CASP-9 then activates CASP-3 and CASP-7 leading to apoptosis [XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP-9	CASP-9	CASP-9	CASP-3	CASP-3	CASP-3	0	1	3	4
Many pro apoptotic signals activate caspase-9 , an initiator protease that activates caspase-3 and downstream caspases to initiate cellular destruction .	Many pro apoptotic signals activate caspase-9, an initiator protease that activates caspase-3 and downstream caspases to initiate cellular destruction.	4	15	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	12	13
Caspase-3 is activated by caspase-9 .	Caspase-3 is activated by caspase-9.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	4	5	0	1
This complex recruits and activates caspase 9 , which in turn activates caspase-3 and -7 to induce cell death [ XREF_BIBR ] .	This complex recruits and activates caspase 9, which in turn activates caspase-3 and -7 to induce cell death [XREF_BIBR].	4	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase-3	caspase-3	caspase-3	5	7	12	13
Conversely , caspase-9 re-expression in caspase-9-deficient Jurkat cells restored caspase-3 activation and apoptosis upon exogenous ceramide treatment .	Conversely, caspase-9 re-expression in caspase-9-deficient Jurkat cells restored caspase-3 activation and apoptosis upon exogenous ceramide treatment.	2	10	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9 re-expression	caspase-9	caspase-3	caspase-3	caspase-3	2	3	9	10
The activated cyto c , Apaf-1 and caspase-9 then form the apoptosome and , ultimately , activate caspase-3 , resulting in nuclear fragmentation .	The activated cyto c, Apaf-1 and caspase-9 then form the apoptosome and, ultimately, activate caspase-3, resulting in nuclear fragmentation.	3	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	17	18
Finally , caspase-8 and caspase-9 would activate caspase-3 to induce apoptosis .	Finally, caspase-8 and caspase-9 would activate caspase-3 to induce apoptosis.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	4	5	7	8
The intrinsic pathway involves the release of apoptotic mediators from mitochondria with the formation of a high molecular weight complex containing cytochrome c , Apaf-1 , and caspase 9 , which activates caspase 3 and the execution phase of apoptosis .	The intrinsic pathway involves the release of apoptotic mediators from mitochondria with the formation of a high molecular weight complex containing cytochrome c, Apaf-1, and caspase 9, which activates caspase 3 and the execution phase of apoptosis.	20	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	27	29	32	34
34 It is well documented that caspase-3 , as a key apoptotic executioner , can be activated by caspase-8 and caspase-9 .	34 It is well documented that caspase-3, as a key apoptotic executioner, can be activated by caspase-8 and caspase-9.	6	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	20	21	6	7
Caspase-8 and caspase-9 probably mediate the activation of caspase-3 under an ischemic condition via extrinsic and intrinsic pathways respectively .	Caspase-8 and caspase-9 probably mediate the activation of caspase-3 under an ischemic condition via extrinsic and intrinsic pathways respectively.	0	9	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	8	9
Caspase-3 , activated by the initiator caspase-9 , is an executive caspase , which receives the apoptosis signal from the mitochondria ; the signal is then transmitted to Poly ( ADP-ribose ) polymerase ( PARP ) , which is associated with the cleavage of genomic DNA [ XREF_BIBR ] .	Caspase-3, activated by the initiator caspase-9, is an executive caspase, which receives the apoptosis signal from the mitochondria; the signal is then transmitted to Poly (ADP-ribose) polymerase (PARP), which is associated with the cleavage of genomic DNA [XREF_BIBR].	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	Caspase-3	Caspase-3	Caspase-3	6	7	0	1
DISC formation results in the activation of caspase-8 , which activates caspase-3 XREF_BIBR .	DISC formation results in the activation of caspase-8, which activates caspase-3 XREF_BIBR.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	11	12
Caspase-8 activates caspase-3 , which in turn degrades fibronectin and focal adhesion kinase and leads to disruption of hepatic architecture and integrity .	Caspase-8 activates caspase-3, which in turn degrades fibronectin and focal adhesion kinase and leads to disruption of hepatic architecture and integrity.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	2	3
Active caspase-8 then directly activates downstream effector caspase-3 resulting in the death of cells classified as type I cells ( XREF_FIG ) [ XREF_BIBR ] .	Active caspase-8 then directly activates downstream effector caspase-3 resulting in the death of cells classified as type I cells (XREF_FIG) [XREF_BIBR].	0	8	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	7	8
The early activation of caspase 8 may directly activate caspase 3 , and subsequent caspase 6 activation may contribute to a strictly caspase dependent cell death pathway by cleaving lamin A , thereby facilitating chromatin condensation .	The early activation of caspase 8 may directly activate caspase 3, and subsequent caspase 6 activation may contribute to a strictly caspase dependent cell death pathway by cleaving lamin A, thereby facilitating chromatin condensation.	2	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	4	6	9	11
Furthermore , LAPC-4 cells treated with BIRM resulted in significant increase in active caspase-8 that in turn activates caspase-3 ( data not shown ) and increased PARP cleavage .	Furthermore, LAPC-4 cells treated with BIRM resulted in significant increase in active caspase-8 that in turn activates caspase-3 (data not shown) and increased PARP cleavage.	7	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	13	14	18	19
Within the DISC , the Fas associated death domain ( FADD ) protein cleaves and thereby activates caspase 8 , which in turn activates caspase 3 , leading to apoptosis ( Stutz et al ., 2012 ) .	Within the DISC, the Fas associated death domain (FADD) protein cleaves and thereby activates caspase 8, which in turn activates caspase 3, leading to apoptosis (Stutz et al., 2012).	16	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	17	19	24	26
Further cleavage of caspase-8 activates caspase-3 and -7 , leading to apoptosis .	Further cleavage of caspase-8 activates caspase-3 and -7, leading to apoptosis.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	5	6
Caspase-8 further cleaves and activates caspase-3 , leading to apoptosis .	Caspase-8 further cleaves and activates caspase-3, leading to apoptosis.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	5	6
Once assembled , this receptor complex activates caspase-8 , a protease that activates caspase-3 by a cleavage dependent mechanism .	Once assembled, this receptor complex activates caspase-8, a protease that activates caspase-3 by a cleavage dependent mechanism.	6	14	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	13	14
Particularly , active form of caspase 8 may trigger the activation of caspase 3 and/or may induce the intrinsic pathway by cleaving the Bcl-2 family member BID 17 .	Particularly, active form of caspase 8 may trigger the activation of caspase 3 and/or may induce the intrinsic pathway by cleaving the Bcl-2 family member BID 17.	3	14	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	5	7	12	14
Alternatively , caspase-8 can indirectly activate caspase-3 by activating the intrinsic apoptosis pathway through the sequential cleavage of Bid , induction of mitochondrial cytochrome c leak , and activation of caspase-9 .	Alternatively, caspase-8 can indirectly activate caspase-3 by activating the intrinsic apoptosis pathway through the sequential cleavage of Bid, induction of mitochondrial cytochrome c leak, and activation of caspase-9.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	6	7
In agreement with enhanced TRAIL death receptor activation upon CD70 binding , caspase-8 activation and processing of the caspase-8 substrates BID and caspase-3 by the various scFv-TRAIL fusion proteins were significantly diminished by blockade of CD70 ( XREF_FIG ) .	In agreement with enhanced TRAIL death receptor activation upon CD70 binding, caspase-8 activation and processing of the caspase-8 substrates BID and caspase-3 by the various scFv-TRAIL fusion proteins were significantly diminished by blockade of CD70 (XREF_FIG).	12	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	12	13	22	23
Caspase-3 is not only activated within the apoptosome but alternatively by caspase-8 and granzyme-B .	Caspase-3 is not only activated within the apoptosome but alternatively by caspase-8 and granzyme-B.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	11	12	0	1
6 The effector caspase-3 is activated by caspase-8 , which cleaves numerous regulatory and structural proteins resulting in cell apoptosis .	6 The effector caspase-3 is activated by caspase-8, which cleaves numerous regulatory and structural proteins resulting in cell apoptosis.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	3	4
These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5 , and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid , which in turn decreases mitochondria membrane potential .	These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential.	28	35	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	30	31	34	35
The ligation of TRAIL leads to the formation of the death inducing signaling complex ( DISC ) and subsequent binding and activation of caspase-8 , which then activates caspase-3 , which in turn leads to cleavage of the death substrates , finally resulting in apoptosis XREF_BIBR .	The ligation of TRAIL leads to the formation of the death inducing signaling complex (DISC) and subsequent binding and activation of caspase-8, which then activates caspase-3, which in turn leads to cleavage of the death substrates, finally resulting in apoptosis XREF_BIBR.	19	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	23	24	28	29
The second ( extrinsic ) pathway involves activation of caspase-8 , which also directly cleaves and activates caspase-3 .	The second (extrinsic) pathway involves activation of caspase-8, which also directly cleaves and activates caspase-3.	7	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	9	10	17	18
This analysis revealed that the activation of caspase-8 and corresponding activation of downstream caspase-3 were enhanced in cells lacking CD74 .	This analysis revealed that the activation of caspase-8 and corresponding activation of downstream caspase-3 were enhanced in cells lacking CD74.	7	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	13	14
The activated caspase 8 could activate caspase 3 either directly or via mitochondrial engagement through cleavage of BID and activation of caspase 9 [ XREF_BIBR - XREF_BIBR ] .	The activated caspase 8 could activate caspase 3 either directly or via mitochondrial engagement through cleavage of BID and activation of caspase 9 [XREF_BIBR - XREF_BIBR].	0	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	2	4	6	8
Furthermore , our study does not determine if caspase-8 directly activates caspase-3 , and thereby indirectly cleaves PARP , nor if the cleavage of caspase-3 is a result of mitochondrial involvement and release of cytochrome C. Nevertheless , we show , by using the pan-caspase inhibitor ( ZVAD-FMK ) , that the cleavage of PARP is caspase dependent , as the pan-caspase inhibitor prevents the Anti-Fas-induced increase in cleaved PARP , and therefore we also demonstrate that the cleavage of PARP is apoptosis dependent .	Furthermore, our study does not determine if caspase-8 directly activates caspase-3, and thereby indirectly cleaves PARP, nor if the cleavage of caspase-3 is a result of mitochondrial involvement and release of cytochrome C. Nevertheless, we show, by using the pan-caspase inhibitor (ZVAD-FMK), that the cleavage of PARP is caspase dependent, as the pan-caspase inhibitor prevents the Anti-Fas-induced increase in cleaved PARP, and therefore we also demonstrate that the cleavage of PARP is apoptosis dependent.	8	16	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	11	12
Caspase 8 mediates cell cycle arrest at the G2-M phase [ XREF_BIBR ] , and activates both cleaved caspase 3 and tBid at the BAX and Bak receptor [ XREF_BIBR , XREF_BIBR ] .	Caspase 8 mediates cell cycle arrest at the G2-M phase [XREF_BIBR], and activates both cleaved caspase 3 and tBid at the BAX and Bak receptor [XREF_BIBR, XREF_BIBR].	0	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	18	20
Activated caspase-8 can not only directly activates downstream caspase-3 , but also cleave Bid to truncated Bid ( tBid ) , which in turn activates the mitochondrial pathway XREF_BIBR .	Activated caspase-8 can not only directly activates downstream caspase-3, but also cleave Bid to truncated Bid (tBid), which in turn activates the mitochondrial pathway XREF_BIBR.	1	9	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	8	9
Caspase-8 cleavage is essential to activate caspase-3 .	Caspase-8 cleavage is essential to activate caspase-3.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	6	7
During death receptor mediated apoptosis , activated caspase-8 can directly activate effector caspase-3 and -7 or cleave Bid to generate a truncated form , tBid .	During death receptor mediated apoptosis, activated caspase-8 can directly activate effector caspase-3 and -7 or cleave Bid to generate a truncated form, tBid.	6	16	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	12	13
Caspase-8 activation can result in direct activation of caspase-3 .	Caspase-8 activation can result in direct activation of caspase-3.	0	9	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	8	9
While with the stretch duration increased to 24 h ( XREF_FIG , black arrows ) , as the combination of the death receptors and its specific ligands reached saturation , the formation of DISC was inefficient and the activation of caspase-3 by caspase-8 occurred mainly in a mitochondrion dependent manner via caspase-9 .	While with the stretch duration increased to 24 h (XREF_FIG, black arrows), as the combination of the death receptors and its specific ligands reached saturation, the formation of DISC was inefficient and the activation of caspase-3 by caspase-8 occurred mainly in a mitochondrion dependent manner via caspase-9.	38	43	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	42	43	40	41
Then , caspase-8 activates caspase-3 directly or triggers mitochondrial signal amplification such as the Bcl-2 family [ XREF_BIBR - XREF_BIBR ] to disrupt transmembrane potential and open the mitochondrial permeability transition pores responsible for releasing apoptogenic factors , such as cytochrome C , into the cytosol [ XREF_BIBR ] .	Then, caspase-8 activates caspase-3 directly or triggers mitochondrial signal amplification such as the Bcl-2 family [XREF_BIBR - XREF_BIBR] to disrupt transmembrane potential and open the mitochondrial permeability transition pores responsible for releasing apoptogenic factors, such as cytochrome C, into the cytosol [XREF_BIBR].	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	4	5
In the DISC complex Fas , via FADD , activates the initiator caspase-8 which in turn activates the effector caspase-3 .	In the DISC complex Fas, via FADD, activates the initiator caspase-8 which in turn activates the effector caspase-3.	9	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	12	13	19	20
Residual caspase-8 in knockdown cells was adequate to activate caspase-3 upon UVB exposure , but the loss of UVB induced caspase-3 activation in the presence of caspase-8 inhibitor shows that caspase-8 is essential .	Residual caspase-8 in knockdown cells was adequate to activate caspase-3 upon UVB exposure, but the loss of UVB induced caspase-3 activation in the presence of caspase-8 inhibitor shows that caspase-8 is essential.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	9	10
In type I cells , the activation of initiator caspase 8 and caspase 10 is sufficient to directly activate effector caspase 3 and caspase 6 , and cause apoptotic cell death .	In type I cells, the activation of initiator caspase 8 and caspase 10 is sufficient to directly activate effector caspase 3 and caspase 6, and cause apoptotic cell death.	6	23	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	9	11	20	22
Since beta-arrestins have been shown to interact with various E3 ligases , and since caspase-8 is a direct activator of caspase-3 , we initially hypothesized that beta-arr1 might be involved in caspase-8 activation .	Since beta-arrestins have been shown to interact with various E3 ligases, and since caspase-8 is a direct activator of caspase-3, we initially hypothesized that beta-arr1 might be involved in caspase-8 activation.	14	21	is a direct activator	Positive_activation_copula_1	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	14	15	20	21
In the IC 25 of BAA , initiator caspase-8 resulted in the activation of caspase-3 .	In the IC 25 of BAA, initiator caspase-8 resulted in the activation of caspase-3.	7	15	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	14	15
Active Caspase-8 proteolytic cleavage and activates Caspase-3 , -6 and -7 ( executioner caspases ) .	Active Caspase-8 proteolytic cleavage and activates Caspase-3, -6 and -7 (executioner caspases).	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Caspase-3	Caspase-3	Caspase-3	1	2	6	7
In type II cells , low-level caspase-8 activation does not result in the direct activation of caspase-3 but cleaves the pro apoptotic BH3-only ( Bcl-2 homology domain 3-only ) protein BID ( BH3 interacting domain death agonist ) .	In type II cells, low-level caspase-8 activation does not result in the direct activation of caspase-3 but cleaves the pro apoptotic BH3-only (Bcl-2 homology domain 3-only) protein BID (BH3 interacting domain death agonist).	6	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	16	17
The activated caspase-8 directly activates caspase-3 which plays a pivotal role in cell apoptosis when being activated .	The activated caspase-8 directly activates caspase-3 which plays a pivotal role in cell apoptosis when being activated.	0	7	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	5	6
Caspase-8 directly activates Caspase-3 , leading to apoptosis .	Caspase-8 directly activates Caspase-3, leading to apoptosis.	0	4	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Caspase-3	Caspase-3	Caspase-3	0	1	3	4
Caspase-8 is a major activator of caspase-3 and amplifies the apoptotic signal by directly activating downstream caspases and cleaving BH3 domain-only members of the Bcl-2 family , such as proapoptotic Bid XREF_BIBR .	Caspase-8 is a major activator of caspase-3 and amplifies the apoptotic signal by directly activating downstream caspases and cleaving BH3 domain-only members of the Bcl-2 family, such as proapoptotic Bid XREF_BIBR.	0	8	is a major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	6	7
Once activated , caspase-8 induces either activation of caspase-3 directly or truncation of Bid to tBid indirectly .	Once activated, caspase-8 induces either activation of caspase-3 directly or truncation of Bid to tBid indirectly.	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	8	9
Caspase-8 activated caspase-3 and T18 in neutrophil cytoplasmic extracts .	Caspase-8 activated caspase-3 and T18 in neutrophil cytoplasmic extracts.	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	2	3
Similarly , caspase-9 inhibitor alone induces partial inhibition of apoptosis , indicating that caspase-8 also directly targets caspase-3 promoting apoptosis independently .	Similarly, caspase-9 inhibitor alone induces partial inhibition of apoptosis, indicating that caspase-8 also directly targets caspase-3 promoting apoptosis independently.	13	18	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	13	14	17	18
TNF-alpha-activated caspase 8 subsequently activates caspase 3 , which in turn activates executioner proteolysis cascade , finally resulting in apoptosis .	TNF-alpha-activated caspase 8 subsequently activates caspase 3, which in turn activates executioner proteolysis cascade, finally resulting in apoptosis.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	1	3	5	7
Inhibition of caspase-8 with Z-IETD-FMK blocked caspase-3 cleavage ( lane 6 ) .	Inhibition of caspase-8 with Z-IETD-FMK blocked caspase-3 cleavage (lane 6).	0	7	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	6	7
Finally , caspase-8 or -9 activate caspase-3 , thus triggering apoptosis .	Finally, caspase-8 or -9 activate caspase-3, thus triggering apoptosis.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	6	7
In early SAP , the stimulation of death receptors such as Fas and tumor necrosis factor receptor 1 ( TNFR1 ) leads to the formation of a death inducing signaling complex and initiator caspase-8 , which initiates downstream caspase-3 .	In early SAP, the stimulation of death receptors such as Fas and tumor necrosis factor receptor 1 (TNFR1) leads to the formation of a death inducing signaling complex and initiator caspase-8, which initiates downstream caspase-3.	28	39	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	33	34	38	39
Infection with double-mutant DeltaM36 and M45mutRHIM virus reveals a signaling pattern in which caspase-8 activates caspase-3 to drive apoptosis with subsequent RIP3 dependent activation of mixed lineage kinase domain like ( MLKL ) leading to necroptosis .	Infection with double-mutant DeltaM36 and M45mutRHIM virus reveals a signaling pattern in which caspase-8 activates caspase-3 to drive apoptosis with subsequent RIP3 dependent activation of mixed lineage kinase domain like (MLKL) leading to necroptosis.	13	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	13	14	15	16
Once activated , the initiator caspase-8 can activate caspase-3 , eventually leading to cell apoptosis .	Once activated, the initiator caspase-8 can activate caspase-3, eventually leading to cell apoptosis.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	8	9
Anti-Fas works through the extrinsic pathway and leads to cell death via caspase-8 dependent activation of caspase-3 .	Anti-Fas works through the extrinsic pathway and leads to cell death via caspase-8 dependent activation of caspase-3.	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	12	13	16	17
In the latter case , Fas associated death domain protein activates caspase-8 , which in turn activates downstream executioners caspase-3 or -7 .	In the latter case, Fas associated death domain protein activates caspase-8, which in turn activates downstream executioners caspase-3 or -7.	10	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	11	12	19	20
Caspase 3 , a key executioner in the apoptotic machinery , cleaves many proteins indispensable for cell survival and is activated through cleavage into two fragments ( 17kDa and 19kDa ) by caspase 8 and/or caspase 9 during apoptosis XREF_BIBR .	Caspase 3, a key executioner in the apoptotic machinery, cleaves many proteins indispensable for cell survival and is activated through cleavage into two fragments (17kDa and 19kDa) by caspase 8 and/or caspase 9 during apoptosis XREF_BIBR.	0	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Caspase 3	Caspase 3	Caspase 3	32	34	0	2
Our data showed that MSP-4-induced apoptosis proteins relied on caspase-8 protein that activated caspase-3 and PARP , which were finally expressed by anti-proliferation and DNA fragmentation in MG63 cells .	Our data showed that MSP-4-induced apoptosis proteins relied on caspase-8 protein that activated caspase-3 and PARP, which were finally expressed by anti-proliferation and DNA fragmentation in MG63 cells.	9	21	activated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3 and PARP, which were finally expressed	caspase-3	9	10	13	14
Selective peptide inhibitors of caspase-9 block processing of caspase-3 and caspase-8 and inhibit apoptosis , whereas a selective inhibitor of caspase-8 blocks neither processing of caspase-3 nor cell death .	Selective peptide inhibitors of caspase-9 block processing of caspase-3 and caspase-8 and inhibit apoptosis, whereas a selective inhibitor of caspase-8 blocks neither processing of caspase-3 nor cell death.	18	26	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	20	21	25	26
Proteolytically activated caspase-8 mediates the activation of terminal effector caspase-3 and causes target cell death .	Proteolytically activated caspase-8 mediates the activation of terminal effector caspase-3 and causes target cell death.	1	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	9	10
Caspase-8 has been shown to activate caspase-3 and other caspase family proteins .	Caspase-8 has been shown to activate caspase-3 and other caspase family proteins.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	6	7
Apoptosis signaling pathways can be categorized into two types : ( i ) type I , mediated by TNFR1 , with activation of caspase-3 by caspase-8 or by tBid , and ( ii ) type II , regulated by anti-apoptotic Bcl-2 proteins , which inhibit the function of pro apoptotic proteins ( such as Bax and Bad ) to block apoptosis mediated by tBid or XIAP protein ( inhibitor of caspase-9 activation - BIRC 4 ) [ XREF_BIBR ] .	Apoptosis signaling pathways can be categorized into two types : (i) type I, mediated by TNFR1, with activation of caspase-3 by caspase-8 or by tBid, and (ii) type II, regulated by anti-apoptotic Bcl-2 proteins, which inhibit the function of pro apoptotic proteins (such as Bax and Bad) to block apoptosis mediated by tBid or XIAP protein (inhibitor of caspase-9 activation - BIRC 4) [XREF_BIBR].	21	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	25	26	23	24
However , the cleaved caspase-8 can activate caspase-3 through two alternative signaling pathways [ XREF_BIBR , XREF_BIBR ] .	However, the cleaved caspase-8 can activate caspase-3 through two alternative signaling pathways [XREF_BIBR, XREF_BIBR].	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	7	8
XREF_BIBR Activated DR5 recruits the adaptor protein FADD , then cleaves procaspase-8 and initiates caspase-8 activation , which activates the downstream effector caspase-3 that leads to apoptosis .	XREF_BIBR Activated DR5 recruits the adaptor protein FADD, then cleaves procaspase-8 and initiates caspase-8 activation, which activates the downstream effector caspase-3 that leads to apoptosis.	14	24	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	14	15	22	23
Therefore , it is generally believed that apoptosis dysregulation may promote the pathogenesis and progression of tumors [ XREF_BIBR , XREF_BIBR ] Caspase-3 , activated directly by caspase-8 , -9 and the apoptosome , is one of the executor caspase that take part in both extrinsic and intrinsic apoptotic pathways .	Therefore, it is generally believed that apoptosis dysregulation may promote the pathogenesis and progression of tumors [XREF_BIBR, XREF_BIBR] Caspase-3, activated directly by caspase-8, -9 and the apoptosome, is one of the executor caspase that take part in both extrinsic and intrinsic apoptotic pathways.	18	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	27	28	22	23
Caspase-8 then activates caspase-3 [ XREF_BIBR , XREF_BIBR ] , which finally executes apoptosis by releasing caspase activated DNAse ( CAD ) from its inhibitor ( ICAD ) with DNA fragmentation as a consequence [ XREF_BIBR ] .	Caspase-8 then activates caspase-3 [XREF_BIBR, XREF_BIBR], which finally executes apoptosis by releasing caspase activated DNAse (CAD) from its inhibitor (ICAD) with DNA fragmentation as a consequence [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	3	4
Caspase-8 activation of caspase-3 is sufficient to initiate death in some but not all cells [ XREF_BIBR ] .	Caspase-8 activation of caspase-3 is sufficient to initiate death in some but not all cells [XREF_BIBR].	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	3	4
Active caspase 8 is released from DISC and initiates the caspase cascade by cleaving caspase 3 .	Active caspase 8 is released from DISC and initiates the caspase cascade by cleaving caspase 3.	0	16	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	1	3	14	16
XREF_BIBR Initiator caspase 8 cleavage and activation can signal directly and induce apoptosis by cleaving effector caspase 3 .	XREF_BIBR Initiator caspase 8 cleavage and activation can signal directly and induce apoptosis by cleaving effector caspase 3.	0	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	2	4	16	18
Caspase-8 induces release of Cyt c and concurrently activates caspase-3 .	Caspase-8 induces release of Cyt c and concurrently activates caspase-3.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	9	10
Caspase-3 is also activated by caspase-8 , which is an initiator caspase activated by plasma membrane death receptors .	Caspase-3 is also activated by caspase-8, which is an initiator caspase activated by plasma membrane death receptors.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	5	6	0	1
The caspase-8 activates caspase-3 that finally disrupts the histoarchitecture of a cell resulting in oocyte apoptosis [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The caspase-8 activates caspase-3 that finally disrupts the histoarchitecture of a cell resulting in oocyte apoptosis [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	3	4
Caspase-8 leads to activation of effector caspase-3 directly ( type I cells ) or via stimulation of cytochrome C release from the mitochondria ( type II cells ) [ XREF_BIBR ] .	Caspase-8 leads to activation of effector caspase-3 directly (type I cells) or via stimulation of cytochrome C release from the mitochondria (type II cells) [XREF_BIBR].	0	9	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	6	7
Upon recruitment , caspase-8 is activated by self-cleavage , and then activates caspase-3 .	Upon recruitment, caspase-8 is activated by self-cleavage, and then activates caspase-3.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	12	13
Taken together these data demonstrate that the initiator caspase-8 can directly activate pro-caspase-3 without the requirement for an accelerator .	Taken together these data demonstrate that the initiator caspase-8 can directly activate pro-caspase-3 without the requirement for an accelerator.	6	13	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	pro-caspase-3	pro-caspase-3	pro-caspase-3	8	9	12	13
It was reported that the efficient and rapid activation of caspase-8 by DISC could directly activate caspase-3 regardless of mitochondria .	It was reported that the efficient and rapid activation of caspase-8 by DISC could directly activate caspase-3 regardless of mitochondria.	8	17	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	10	11	16	17
The activated caspase-8 is released to the cytoplasm to activate downstream caspase-3 and -7 , triggering apoptosis .	The activated caspase-8 is released to the cytoplasm to activate downstream caspase-3 and -7, triggering apoptosis.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8 is released to the cytoplasm	caspase-8	caspase-3	caspase-3	caspase-3	2	3	11	12
These results do not support an alternative pathway in which caspase-8 directly activates caspase-3 .	These results do not support an alternative pathway in which caspase-8 directly activates caspase-3.	10	14	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	10	11	13	14
Activation of caspase-8 activates caspase-3 and induces apoptosis 5 .	Activation of caspase-8 activates caspase-3 and induces apoptosis 5.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	4	5
However , in other cell types ( which are commonly indicated as Type II cells , e.g ., hepatocytes ) , the optimal activation of CASP3 by CASP8 critically relies on MOMP XREF_BIBR .	However, in other cell types (which are commonly indicated as Type II cells, e.g., hepatocytes), the optimal activation of CASP3 by CASP8 critically relies on MOMP XREF_BIBR.	23	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	CASP3	CASP3	CASP3	27	28	25	26
In addition , our study showed that caspase 3 was activated by caspase 8 , not caspase 9 , in Smmc-7721 cells treated with VK ( 2 ) .	In addition, our study showed that caspase 3 was activated by caspase 8, not caspase 9, in Smmc-7721 cells treated with VK (2).	7	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	12	14	7	9
The caspase-8 activated at the DISC further mediates effector caspase-3 activation , followed by execution of apoptotic program .	The caspase-8 activated at the DISC further mediates effector caspase-3 activation, followed by execution of apoptotic program.	0	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	9	10
Caspase-3 activation , which is induced by caspase-8 activation , is a critical pathway in executing cell apoptosis .	Caspase-3 activation, which is induced by caspase-8 activation, is a critical pathway in executing cell apoptosis.	0	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	7	8	0	1
Subsequently , caspase-8 or -9 can activate caspase-3 , which in turn targets and degrades specific and vital cellular proteins , ultimately resulting in nuclear DNA degradation and apoptotic cell death [ XREF_BIBR ] .	Subsequently, caspase-8 or -9 can activate caspase-3, which in turn targets and degrades specific and vital cellular proteins, ultimately resulting in nuclear DNA degradation and apoptotic cell death [XREF_BIBR].	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	7	8
CASP8 becomes active by its homotypic interaction with FADD at the DISC complex , which in turn cleaves and activates the effector caspase 3 ( CASP3 ) .	CASP8 becomes active by its homotypic interaction with FADD at the DISC complex, which in turn cleaves and activates the effector caspase 3 (CASP3).	0	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	caspase 3	caspase 3	caspase 3	0	1	22	24
A number of extracellular signals activate caspase-8 through the Fas receptor pathway and the activation of caspase-8 then promotes caspase-3 activation , which hydrolyzes cell specific proteins , and poly-ADP ribose polymerase , thus inducing apoptosis .	A number of extracellular signals activate caspase-8 through the Fas receptor pathway and the activation of caspase-8 then promotes caspase-3 activation, which hydrolyzes cell specific proteins, and poly-ADP ribose polymerase, thus inducing apoptosis.	14	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	16	17	19	20
Finally , caspase-8 activates caspase-3 in order to trigger the final steps of apoptosis ( XREF_FIG ) .	Finally, caspase-8 activates caspase-3 in order to trigger the final steps of apoptosis (XREF_FIG).	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	4	5
Procaspase 8 triggers the downstream caspase effector and is responsible for the cleavage of caspase 8 , which activates caspase 3 and promotes cellular apoptosis .	Procaspase 8 triggers the downstream caspase effector and is responsible for the cleavage of caspase 8, which activates caspase 3 and promotes cellular apoptosis.	12	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	14	16	19	21
This results in activation of the initiator caspase , caspase 8 , which can activate caspase 3 to bring about the apoptotic phenotype ( XREF_FIG ) .	This results in activation of the initiator caspase, caspase 8, which can activate caspase 3 to bring about the apoptotic phenotype (XREF_FIG).	7	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	9	11	15	17
In type I cells auto-activation of caspase-8 causes direct activation of downstream effector caspase-3 through proteolytic cleavage .	In type I cells auto-activation of caspase-8 causes direct activation of downstream effector caspase-3 through proteolytic cleavage.	4	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	13	14
The predominant apoptotic pathway involves caspase-8 activation of caspase 3 , and is independent of NF-kappaB activation .	The predominant apoptotic pathway involves caspase-8 activation of caspase 3, and is independent of NF-kappaB activation.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase 3	caspase 3	caspase 3	5	6	8	10
CASP8 activation in turn leads to downstream activation of BID and Caspase-3 via proteolytic cleavage and engagement of apoptotic cell death .	CASP8 activation in turn leads to downstream activation of BID and Caspase-3 via proteolytic cleavage and engagement of apoptotic cell death.	0	20	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	Caspase-3	Caspase-3	Caspase-3	0	1	11	12
Pro-caspase-8 is activated in the DISC , which then directly proteolytically cleaves and activates caspase-3 .	Pro-caspase-8 is activated in the DISC, which then directly proteolytically cleaves and activates caspase-3.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pro-caspase-8	Pro-caspase-8	Pro-caspase-8	caspase-3	caspase-3	caspase-3	0	1	14	15
Results of these single-cell measurements suggested that caspase-3 was activated by caspase-8 through two parallel pathways during TNFalpha induced apoptosis in HeLa cells .	Results of these single-cell measurements suggested that caspase-3 was activated by caspase-8 through two parallel pathways during TNFalpha induced apoptosis in HeLa cells.	7	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	11	12	7	8
Caspase-8 then activates caspase-3 .	Caspase-8 then activates caspase-3.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	3	4
Caspase-8 directly activates caspase-3 and cleaves Bid , which then triggers the mitochondrial pathway XREF_BIBR .	Caspase-8 directly activates caspase-3 and cleaves Bid, which then triggers the mitochondrial pathway XREF_BIBR.	0	6	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	3	4
Procaspase-8 undergoes proximity induced activation and cleavage forming caspase-8 which then activates the executioner caspase-3 that causes cell death .	Procaspase-8 undergoes proximity induced activation and cleavage forming caspase-8 which then activates the executioner caspase-3 that causes cell death.	7	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	14	15
In particular , at the end of the three-drug treatment , caspase-8 activation triggered downstream executioner caspase-3 and , to a lesser degree , caspase-7 .	In particular, at the end of the three-drug treatment, caspase-8 activation triggered downstream executioner caspase-3 and, to a lesser degree, caspase-7.	11	24	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	11	12	16	17
DHA treatment for 36 h substantially induced activation of caspase-8 , -9 and -3 ( XREF_FIG ) , and pretreatment with zIETD-fmk or zLEHD-fmk , the inhibitors of caspase-8 or -9 , dramatically prevented the DHA induced caspase-3 activation ( XREF_FIG ) , indicating that caspase-8 and -9 acted as the upstream regulators of casapse-3 activation .	DHA treatment for 36 h substantially induced activation of caspase-8, -9 and -3 (XREF_FIG), and pretreatment with zIETD-fmk or zLEHD-fmk, the inhibitors of caspase-8 or -9, dramatically prevented the DHA induced caspase-3 activation (XREF_FIG), indicating that caspase-8 and -9 acted as the upstream regulators of casapse-3 activation.	26	38	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	28	29	37	38
Inhibition of caspase-8 eliminated the activation of caspase-3 by UVB ( XREF_FIG ) .	Inhibition of caspase-8 eliminated the activation of caspase-3 by UVB (XREF_FIG).	0	8	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	7	8
Furthermore , activation of caspase-8 ( extrinsic pathway ) and -9 ( intrinsic pathway ) stimulates caspase-3 , which in turn induces PARP cleavage XREF_BIBR .	Furthermore, activation of caspase-8 (extrinsic pathway) and -9 (intrinsic pathway) stimulates caspase-3, which in turn induces PARP cleavage XREF_BIBR.	2	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	16	17
Activated caspase 8 can lead to either to downstream activation of caspase 3 ( -1.19 fold , P < 0.05 , XREF_TABLE ) or caspase 7 ( +2.36 fold , P < 0.05 , XREF_TABLE ) .	Activated caspase 8 can lead to either to downstream activation of caspase 3 (-1.19 fold, P < 0.05, XREF_TABLE) or caspase 7 (+2.36 fold, P < 0.05, XREF_TABLE).	1	28	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	1	3	11	13
Subsequently , caspase-8 can activate caspase-3 through two pathways ; either through activation of pro apoptotic Bcl-2 family proteins that cause cytochrome C leakage from the mitochondria , or through caspase-8 directly cleaving caspase-3 into activated and cleaved caspase-3 ( c-caspase-3 ) XREF_BIBR .	Subsequently, caspase-8 can activate caspase-3 through two pathways; either through activation of pro apoptotic Bcl-2 family proteins that cause cytochrome C leakage from the mitochondria, or through caspase-8 directly cleaving caspase-3 into activated and cleaved caspase-3 (c-caspase-3) XREF_BIBR.	2	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	5	6
In death inducing signaling pathway , caspase-8 from the extrinsic pathway directly activates caspase-3 , and facilitates the release of cytochrome-c , which both proteins are imperative part of the intrinsic pathway .	In death inducing signaling pathway, caspase-8 from the extrinsic pathway directly activates caspase-3, and facilitates the release of cytochrome-c, which both proteins are imperative part of the intrinsic pathway.	6	16	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	13	14
Activation of the Caspase-8 also activates the executioner Caspase-3 .	Activation of the Caspase-8 also activates the executioner Caspase-3.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Caspase-3	Caspase-3	Caspase-3	3	4	8	9
Caspase-8 activates its downstream effector caspase-3 , thus functionalising extrinsic pathway .	Caspase-8 activates its downstream effector caspase-3, thus functionalising extrinsic pathway.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	5	6
The activated initiator caspase-8 then activates effector caspase-3 , caspase-6 , and caspase-7 , which triggers the caspase cascade and subsequently results in apoptosis .	The activated initiator caspase-8 then activates effector caspase-3, caspase-6, and caspase-7, which triggers the caspase cascade and subsequently results in apoptosis.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	7	8
It is well established that caspase-8 can directly activate caspase-3 through cleavage and/or indirectly cleave Bid ( 23kd ) into truncated Bid ( tBid ) , which triggers mitochondria dependent activation of the caspase-9 and -3 cascade [ XREF_BIBR ] .	It is well established that caspase-8 can directly activate caspase-3 through cleavage and/or indirectly cleave Bid (23kd) into truncated Bid (tBid), which triggers mitochondria dependent activation of the caspase-9 and -3 cascade [XREF_BIBR].	5	10	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	9	10
The activation of caspase-8 may directly activate caspase-3 , which results in the apoptotic cell death .	The activation of caspase-8 may directly activate caspase-3, which results in the apoptotic cell death.	1	10	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	7	8
Proteolytic Caspase-8 cleaves and activates executioner Caspase-3 , leading to further cell death [ XREF_BIBR ] .	Proteolytic Caspase-8 cleaves and activates executioner Caspase-3, leading to further cell death [XREF_BIBR].	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Caspase-3	Caspase-3	Caspase-3	1	2	6	7
Then , caspase-8 activates caspase-3 , resulting in apoptosis .	Then, caspase-8 activates caspase-3, resulting in apoptosis.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	4	5
XREF_BIBR , XREF_BIBR Indeed , the administration of Z-IETD-FMK appears to prevent apoptosis in human leukemia cells by inhibiting CASP8 mediated activation of CASP3 .	XREF_BIBR, XREF_BIBR Indeed, the administration of Z-IETD-FMK appears to prevent apoptosis in human leukemia cells by inhibiting CASP8 mediated activation of CASP3.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	CASP3	CASP3	CASP3	19	20	23	24
Inhibition of caspase-8 impaired L. interrogans induced caspase-3 and -6 activation , as well as PARP and lamin A/C cleavage and apoptosis , suggesting that apoptosis is initiated via caspase-8 activation .	Inhibition of caspase-8 impaired L. interrogans induced caspase-3 and -6 activation, as well as PARP and lamin A/C cleavage and apoptosis, suggesting that apoptosis is initiated via caspase-8 activation.	2	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	7	8
Transfection with CASP8 siRNA suppressed the expression of caspase-8 protein and the BI 2536 induced cleavage of caspase-3 and -9 .	Transfection with CASP8 siRNA suppressed the expression of caspase-8 protein and the BI 2536 induced cleavage of caspase-3 and -9.	6	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	expression of caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	17	18
Inhibition of Caspase-8 Decreases the Cleavage of Caspase 3 and Decreases the Susceptibility to Apoptosis Induced by rhFasL in RFL-6 Thy-1 ( + ) Cells .	Inhibition of Caspase-8 Decreases the Cleavage of Caspase 3 and Decreases the Susceptibility to Apoptosis Induced by rhFasL in RFL-6 Thy-1 (+) Cells.	0	9	Decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Caspase 3	Caspase 3	Caspase 3	2	3	7	9
The existence of both direct and indirect pathways for the activation of caspase-3 by caspase-8 would explain the differences among cell types in the protective effect of Bcl-2 and Bcl-xL on Fas induced cell death .	The existence of both direct and indirect pathways for the activation of caspase-3 by caspase-8 would explain the differences among cell types in the protective effect of Bcl-2 and Bcl-xL on Fas induced cell death.	10	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	14	15	12	13
In the extrinsic pathway , caspase-8 directly activates downstream effector caspase-3 , caspase-6 , and caspase-7 inducing apoptosis .	In the extrinsic pathway, caspase-8 directly activates downstream effector caspase-3, caspase-6, and caspase-7 inducing apoptosis.	5	15	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	10	11
Steady state A2 is also apoptotic but bypasses mitochondrial components and therefore leads to the direct activation of caspase-3 by caspase-8 .	Steady state A2 is also apoptotic but bypasses mitochondrial components and therefore leads to the direct activation of caspase-3 by caspase-8.	12	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	20	21	18	19
Caspase 3 activation was blocked by a caspase 8 specific inhibitor , placing caspase 8 activation upstream of executioner caspase activation .	Caspase 3 activation was blocked by a caspase 8 specific inhibitor, placing caspase 8 activation upstream of executioner caspase activation.	0	10	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Caspase 3	Caspase 3	Caspase 3	7	9	0	2
Following FAS stimulation , caspase-8 activates caspase-3 , which in turn activates the caspase activated DNAse ( CAD ) by proteolysis of its inhibitor ( ICAD ) .	Following FAS stimulation, caspase-8 activates caspase-3, which in turn activates the caspase activated DNAse (CAD) by proteolysis of its inhibitor (ICAD).	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	6	7
Both 2A pro and 3C pro can induce the death receptor mediated pathway through caspase 8 mediated activation of caspase 3 and cleavage of Bid [ XREF_BIBR ] .	Both 2A pro and 3C pro can induce the death receptor mediated pathway through caspase 8 mediated activation of caspase 3 and cleavage of Bid [XREF_BIBR].	7	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	14	16	19	21
Since caspase-8 was often activated downstream of caspase-3 to comprise a positive feedback loop involving tBid mediated mitochondrial cytochrome c release in chemical agent induced apoptosis of tumor cells [ XREF_BIBR - XREF_BIBR ] , current data could not exclude the possibility that the caspase-8 activation and Bid cleavage observed in HeLa cells overexpressing LAPTM5 were due to the mitochondrial damage mediated activation of caspase-9 and -3 .	Since caspase-8 was often activated downstream of caspase-3 to comprise a positive feedback loop involving tBid mediated mitochondrial cytochrome c release in chemical agent induced apoptosis of tumor cells [XREF_BIBR - XREF_BIBR], current data could not exclude the possibility that the caspase-8 activation and Bid cleavage observed in HeLa cells overexpressing LAPTM5 were due to the mitochondrial damage mediated activation of caspase-9 and -3.	1	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	7	8
Caspase 9 could be activated by caspase 8 which also can activate caspase 3 as well [ XREF_BIBR ] .	Caspase 9 could be activated by caspase 8 which also can activate caspase 3 as well [XREF_BIBR].	4	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	6	8	12	14
[ XREF_BIBR ] Once activated , caspase-8 activates the downstream executioner caspase-3 by proteolytic cleavage of their zymogen forms .	[XREF_BIBR] Once activated, caspase-8 activates the downstream executioner caspase-3 by proteolytic cleavage of their zymogen forms.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	11	12
The initiator caspase-8 can directly activate the effector caspase-3 , which causes cell apoptosis .	The initiator caspase-8 can directly activate the effector caspase-3, which causes cell apoptosis.	0	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	8	9
This compound activates Caspase 8 that induces Caspase 3 production and activates death receptor apoptosis pathway [ XREF_BIBR ] .	This compound activates Caspase 8 that induces Caspase 3 production and activates death receptor apoptosis pathway [XREF_BIBR].	2	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	Caspase 3	Caspase 3	Caspase 3	3	5	7	9
Inhibitors of caspase-8 and caspase-10 reduced caspase-3 activity and subsequent DNA fragmentation induced by sodium butyrate .	Inhibitors of caspase-8 and caspase-10 reduced caspase-3 activity and subsequent DNA fragmentation induced by sodium butyrate.	0	7	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	6	7
These findings point to a type II apoptosis model , in which caspase-8 activation is sufficient to activate caspase-3 and no mitochondrial amplification loop involving Bid and caspase-9 is required , as previously reported .	These findings point to a type II apoptosis model, in which caspase-8 activation is sufficient to activate caspase-3 and no mitochondrial amplification loop involving Bid and caspase-9 is required, as previously reported.	12	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	12	13	18	19
Caspase-8 directly triggers caspase-3 activation or can interact with the intrinsic apoptotic pathway by cleaving Bid ( a pro apoptotic member of the Bcl-2 ( B-cell lymphoma 2 ) family ) to form the truncated Bid ( tBid ) which translocates to the mitochondria and results in the release of cytochrome c.	Caspase-8 directly triggers caspase-3 activation or can interact with the intrinsic apoptotic pathway by cleaving Bid (a pro apoptotic member of the Bcl-2 (B-cell lymphoma 2) family) to form the truncated Bid (tBid) which translocates to the mitochondria and results in the release of cytochrome c.	0	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	3	4
Caspase-8 directly activates the downstream effector , caspase-3 , or cleaves BH3 interacting domain death agonist ( BID ) , a death inducing member of the B cell lymphoma 2 ( Bcl-2 ) family .	Caspase-8 directly activates the downstream effector, caspase-3, or cleaves BH3 interacting domain death agonist (BID), a death inducing member of the B cell lymphoma 2 (Bcl-2) family.	0	8	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	7	8
Activated caspase-8 activates caspase-3 directly .	Activated caspase-8 activates caspase-3 directly.	0	4	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	3	4
In addition , activated caspase-8 induced the cleavage of pro-caspase-3 to activate poly ( ADP ribose ) polymerase ( PARP ) .	In addition, activated caspase-8 induced the cleavage of pro-caspase-3 to activate poly (ADP ribose) polymerase (PARP).	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	pro-caspase-3	pro-caspase-3	pro-caspase-3	4	5	9	10
27 Caspase-8 then activates caspase-3 .	27 Caspase-8 then activates caspase-3.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	1	2	4	5
Caspase 8 and 9 activate Caspase-3 and then Caspase-3 cleaves vital cellular proteins to initialize apoptosis .	Caspase 8 and 9 activate Caspase-3 and then Caspase-3 cleaves vital cellular proteins to initialize apoptosis.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	Caspase-3	Caspase-3	Caspase-3	0	2	5	6
In the death receptor pathway , binding of extracellular death ligands to members of the tumor necrosis factor and nerve growth factor receptor superfamily induces activation of caspase-8 , which in turn activates caspase-3 and 7 , resulting in further caspase activation events and finally cell death .	In the death receptor pathway, binding of extracellular death ligands to members of the tumor necrosis factor and nerve growth factor receptor superfamily induces activation of caspase-8, which in turn activates caspase-3 and 7, resulting in further caspase activation events and finally cell death.	25	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	27	28	33	34
However , in some cell types ( Type II cells ) , such as hepatocytes , the direct activation of caspase-3 by caspase-8 is weak and not sufficient to induce apoptosis .	However, in some cell types (Type II cells), such as hepatocytes, the direct activation of caspase-3 by caspase-8 is weak and not sufficient to induce apoptosis.	18	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	22	23	20	21
Separately , caspase-3 gets activated by the active caspase-8 .	Separately, caspase-3 gets activated by the active caspase-8.	2	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	2	3
Both Casp-8 and 9 then activate Casp-3 , which is responsible for intrinsic apoptotic process [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Both Casp-8 and 9 then activate Casp-3, which is responsible for intrinsic apoptotic process [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp-8	Casp-8	Casp-8	Casp-3	Casp-3	Casp-3	1	2	6	7
The possibility exists that phospho ablated Id2 interacts with the death domain cascade , as caspase 8 has been shown to activate caspase 3 in MDA-MB231 breast cancer cells treated with etoposide XREF_BIBR .	The possibility exists that phospho ablated Id2 interacts with the death domain cascade, as caspase 8 has been shown to activate caspase 3 in MDA-MB231 breast cancer cells treated with etoposide XREF_BIBR.	15	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	15	17	22	24
We conclude that in HL derived B cells , XIAP does not prevent the initial cleavage of caspase-3 induced by caspase-8 or granzyme-B , but rather inhibits the subsequent autocatalytic processing to the mature p17 fragment .	We conclude that in HL derived B cells, XIAP does not prevent the initial cleavage of caspase-3 induced by caspase-8 or granzyme-B, but rather inhibits the subsequent autocatalytic processing to the mature p17 fragment.	15	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	20	21	17	18
However , this does not rule out the possibility that caspase-8 indirectly activates caspase-3 by inducing mitochondrial release of cytochrome c and/or AIF in other cell types .	However, this does not rule out the possibility that caspase-8 indirectly activates caspase-3 by inducing mitochondrial release of cytochrome c and/or AIF in other cell types.	10	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	10	11	13	14
Caspase-8 activates caspase-3 and stimulates the release of cytochrome c by the mitochondria .	Caspase-8 activates caspase-3 and stimulates the release of cytochrome c by the mitochondria.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	2	3
Overexpression of caspase-8 significantly decreased cell number , caused caspase-8 and caspase-3 activation , decreased full-length Bid , caspase-9 , and caspase-7 , and significantly increased DNA fragmentation and M30 positive RPE cells .	Overexpression of caspase-8 significantly decreased cell number, caused caspase-8 and caspase-3 activation, decreased full-length Bid, caspase-9, and caspase-7, and significantly increased DNA fragmentation and M30 positive RPE cells.	0	12	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	Overexpression of caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	11	12
Exposure of the DIV7 and the DIV21 mature cortical neurons ( i.e ., cultured for 7 and 21 Days In Vitro , DIV ) to 300 muM NMDA for 10 min , increased caspase-9 and caspase-3 activities ( XREF_FIG ) , but not caspase-8 activity ( XREF_SUPPLEMENTARY ) .	Exposure of the DIV7 and the DIV21 mature cortical neurons (i.e., cultured for 7 and 21 Days In Vitro, DIV) to 300 muM NMDA for 10 min, increased caspase-9 and caspase-3 activities (XREF_FIG), but not caspase-8 activity (XREF_SUPPLEMENTARY).	32	44	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	43	44	35	36
XREF_FIG , which shows that Rhodiola Crenulata treatment prevents chronic intermittent hypoxia induced cardiac Fas dependent apoptotic pathway ( Fas , FADD , activated caspase 8 , activated caspase 3 ) , prevents chronic intermittent hypoxia induced cardiac mitochondrial dependent apoptotic pathway ( t-Bid , Bad , Bax , activated caspase-9 , and activated caspase-3 as well as decreased anti-apoptotic Bcl-xL , Bcl-2 , p-Bad ) , and enhance chronic intermittent hypoxia induced cardiac VEGF related pro survival pathway ( VEGF , p-PI3k and p-AKT ) .	XREF_FIG, which shows that Rhodiola Crenulata treatment prevents chronic intermittent hypoxia induced cardiac Fas dependent apoptotic pathway (Fas, FADD, activated caspase 8, activated caspase 3), prevents chronic intermittent hypoxia induced cardiac mitochondrial dependent apoptotic pathway (t-Bid, Bad, Bax, activated caspase-9, and activated caspase-3 as well as decreased anti-apoptotic Bcl-xL, Bcl-2, p-Bad), and enhance chronic intermittent hypoxia induced cardiac VEGF related pro survival pathway (VEGF, p-PI3k and p-AKT).	23	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	24	26	28	30
Inflammatory cytokines initiate beta cell apoptosis mainly though the extrinsic pathway and function through several molecules in the death receptor pathway , such as Fas ( CD95 ) , Fas associated death domain ( FADD ) , and the death inducing signaling complex ( DISC ) , leading to the activation and release of caspase 8 , which in turn activate caspase 3 [ XREF_BIBR - XREF_BIBR ] .	Inflammatory cytokines initiate beta cell apoptosis mainly though the extrinsic pathway and function through several molecules in the death receptor pathway, such as Fas (CD95), Fas associated death domain (FADD), and the death inducing signaling complex (DISC), leading to the activation and release of caspase 8, which in turn activate caspase 3 [XREF_BIBR - XREF_BIBR].	50	64	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	54	56	61	63
The ligand-receptor interaction leads to the activation of the effector caspase 8 , which in turn activates the effector caspase 3 directly and/or through mitochondria XREF_BIBR .	The ligand-receptor interaction leads to the activation of the effector caspase 8, which in turn activates the effector caspase 3 directly and/or through mitochondria XREF_BIBR.	6	21	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	10	12	19	21
Caspase-8 cleaves and activates the effector caspase-3 , whose cleaved forms were detectable in all lines tested after treatment with iz-TRAIL .	Caspase-8 cleaves and activates the effector caspase-3, whose cleaved forms were detectable in all lines tested after treatment with iz-TRAIL.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	6	7
Both caspase-8 , and -9 can activate caspase-3 , through proteolytic cleavage .	Both caspase-8, and -9 can activate caspase-3, through proteolytic cleavage.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	7	8
Additionally , it is known that caspase-3 can be activated by caspase-8 through the extrinsic pathway [ XREF_BIBR ] .	Additionally, it is known that caspase-3 can be activated by caspase-8 through the extrinsic pathway [XREF_BIBR].	6	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	11	12	6	7
According to previous studies , caspase-8 activates not only downstream of caspase-3 and caspase-7 [ XREF_BIBR ] , but the Bcl-2 homology Bid , which translocates to mitochondria and blinds to Bax , enable a crosstalk to the mitochondrial apoptotic pathway [ XREF_BIBR ] .	According to previous studies, caspase-8 activates not only downstream of caspase-3 and caspase-7 [XREF_BIBR], but the Bcl-2 homology Bid, which translocates to mitochondria and blinds to Bax, enable a crosstalk to the mitochondrial apoptotic pathway [XREF_BIBR].	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	11	12
During apoptosis , TNFRSF1A binds to tumor necrosis factor ( TNF ) , which then recruits CASP-8 initiating the downstream activation of CASP-3 , the main effector caspase of the apoptotic pathway [ XREF_BIBR , XREF_BIBR ] .	During apoptosis, TNFRSF1A binds to tumor necrosis factor (TNF), which then recruits CASP-8 initiating the downstream activation of CASP-3, the main effector caspase of the apoptotic pathway [XREF_BIBR, XREF_BIBR].	15	23	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP-8	CASP-8	CASP-8	CASP-3	CASP-3	CASP-3	16	17	22	23
CASPASE 8 initiates apoptosis downstream of TNF death receptors by undergoing autocleavage and processing the executioner CASPASE 3 1 .	CASPASE 8 initiates apoptosis downstream of TNF death receptors by undergoing autocleavage and processing the executioner CASPASE 3 1.	0	18	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASPASE 8	CASPASE 8	CASPASE 8	CASPASE 3	CASPASE 3	CASPASE 3	0	2	16	18
Caspase-8 can activate executioner caspase-3 to promote extrinsic cell death through DNA fragmentation and chromatin condensation via CAD , ACINUS , and HELI-CARD or it can cleave BID into tBID , which can activate Bax mediated intrinsic , mitochondrial cell death .	Caspase-8 can activate executioner caspase-3 to promote extrinsic cell death through DNA fragmentation and chromatin condensation via CAD, ACINUS, and HELI-CARD or it can cleave BID into tBID, which can activate Bax mediated intrinsic, mitochondrial cell death.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	4	5
The reason is that cytochrome c is released in both scenarios and its strong impact covers the additional direct caspase-3 activation by caspase-8 .	The reason is that cytochrome c is released in both scenarios and its strong impact covers the additional direct caspase-3 activation by caspase-8.	19	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	22	23	19	20
This complex formation triggers cleavage and activation of caspase-8 or caspase-10 , which in turn activates downstream caspase-3 , -6 , -7 and causes eventual apoptosis XREF_BIBR XREF_BIBR .	This complex formation triggers cleavage and activation of caspase-8 or caspase-10, which in turn activates downstream caspase-3, -6, -7 and causes eventual apoptosis XREF_BIBR XREF_BIBR.	4	23	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	17	18
This is followed by caspase-8 activation , which in turn either directly activates caspase-3 or merges with the mitochondrial pathway via cleavage of the Bcl-2 family member , p22 BID 12 .	This is followed by caspase-8 activation, which in turn either directly activates caspase-3 or merges with the mitochondrial pathway via cleavage of the Bcl-2 family member, p22 BID 12.	4	14	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	13	14
This allows the formation of a death inducing signalling complex by recruiting FAS associated Death Domain and pro-caspase-8 , which leads to the proteolytic activation of caspase-8 , which in turn activates caspase-3 and -7 .	This allows the formation of a death inducing signalling complex by recruiting FAS associated Death Domain and pro-caspase-8, which leads to the proteolytic activation of caspase-8, which in turn activates caspase-3 and -7.	24	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	26	27	32	33
Upon binding to its DR5 receptor , TRAIL induces the activation of caspase-8 that can directly activates caspase-3 via cleavage ( extrinsic pathway ) .	Upon binding to its DR5 receptor, TRAIL induces the activation of caspase-8 that can directly activates caspase-3 via cleavage (extrinsic pathway).	10	22	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	12	13	17	18
While active caspase-8 is classically known to activate caspase-3 in apoptotic cell death , [ XREF_BIBR ] there is evidence for more diverse roles of caspase-8 in inflammatory signaling and caspase-1-mediated cell death by pyroptosis .	While active caspase-8 is classically known to activate caspase-3 in apoptotic cell death, [XREF_BIBR] there is evidence for more diverse roles of caspase-8 in inflammatory signaling and caspase-1-mediated cell death by pyroptosis.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	8	9
The activated caspase-8 promotes the activation of caspase-3 , which in turn induces the characteristics of apoptosis .	The activated caspase-8 promotes the activation of caspase-3, which in turn induces the characteristics of apoptosis.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	7	8
Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8 .	Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8.	9	21	prevented	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	20	21	9	10
The activated caspase-8 and -10 allow the conversion of pro-caspase-3 to its active form which in turn leads to cleavage of the death substrates .	The activated caspase-8 and -10 allow the conversion of pro-caspase-3 to its active form which in turn leads to cleavage of the death substrates.	0	10	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	pro-caspase-3	pro-caspase-3	pro-caspase-3	2	3	9	10
CASP3 is activated directly by caspase-8 , -9 and -10 in the apoptotic cell by extrinsic ( death ligand ) and intrinsic ( mitochondrial ) pathways to initiate apoptosis .	CASP3 is activated directly by caspase-8, -9 and -10 in the apoptotic cell by extrinsic (death ligand) and intrinsic (mitochondrial) pathways to initiate apoptosis.	0	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	CASP3	CASP3	CASP3	5	6	0	1
In these cells , low levels of caspase-8 could probably activate little caspase-3 that XIAP keeps in check preventing the apoptosis cascade , but when XIAP is targeted , the levels of caspase-3 might become enough to trigger apoptosis .	In these cells, low levels of caspase-8 could probably activate little caspase-3 that XIAP keeps in check preventing the apoptosis cascade, but when XIAP is targeted, the levels of caspase-3 might become enough to trigger apoptosis.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	levels of caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	12	13
Once cleaved , the caspase-8 dimer causes the downstream activation of pro-caspase-3 , -6 , and -7 .	Once cleaved, the caspase-8 dimer causes the downstream activation of pro-caspase-3, -6, and -7.	4	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	pro-caspase-3	pro-caspase-3	pro-caspase-3	4	5	11	12
Caspase-8 can then activate caspase-3 and cleave Bid , a specific substrate for caspase-8 , to form truncated Bid ( tBid ) .	Caspase-8 can then activate caspase-3 and cleave Bid, a specific substrate for caspase-8, to form truncated Bid (tBid).	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	4	5
As caspases play a pivotal role in the apoptotic cell death , it has been reported that initiator caspase-8 and -9 activate caspase-3 and -7 directly or indirectly and can be blocked by XIAP .	As caspases play a pivotal role in the apoptotic cell death, it has been reported that initiator caspase-8 and -9 activate caspase-3 and -7 directly or indirectly and can be blocked by XIAP.	17	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	18	19	22	23
In some cell types ( so called type I cells ) caspase-8 directly causes cleavage of effector caspase-3 without the contribution of mitochondria .	In some cell types (so called type I cells) caspase-8 directly causes cleavage of effector caspase-3 without the contribution of mitochondria.	11	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	11	12	17	18
Our results found that DHTS activated caspase-8 ( XREF_FIG ) but did not change pro Bid expression ( XREF_FIG ) , suggesting that caspase-8 activated downstream caspase-3 , thus bypassing the tBid and cytochrome c pathway .	Our results found that DHTS activated caspase-8 (XREF_FIG) but did not change pro Bid expression (XREF_FIG), suggesting that caspase-8 activated downstream caspase-3, thus bypassing the tBid and cytochrome c pathway.	23	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	23	24	26	27
These results are consistent with a model where the full activation of caspase-3 by caspase-8 is dependent on the release of Smac/DIABLO in response to the combined treatment .	These results are consistent with a model where the full activation of caspase-3 by caspase-8 is dependent on the release of Smac/DIABLO in response to the combined treatment.	10	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	14	15	12	13
This activated caspase-8 can activate caspase-3 , an executioner caspase .	This activated caspase-8 can activate caspase-3, an executioner caspase.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	5	6
Activated caspase-8 activates caspase-3 through two pathways .	Activated caspase-8 activates caspase-3 through two pathways.	0	4	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	3	4
The death inducing signaling complex , assembled directly at the death receptors , activates the initiator caspase-8 that in turn activates caspase-3 , -6 , and -7 .	The death inducing signaling complex, assembled directly at the death receptors, activates the initiator caspase-8 that in turn activates caspase-3, -6, and -7.	13	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	16	17	21	22
Indeed , oxLDL can trigger both ( i ) the extrinsic apoptotic pathway mediated by the FLICE inhibitory protein and Fas and Fas ligand [ XREF_BIBR ] that activates caspase-8 , which in turn directly activates caspase-3 and ( ii ) calcium and calpain pathway that activates Bid and the mitochondrial apoptotic pathway , thereby indirectly activating caspase-3 [ XREF_BIBR ] .	Indeed, oxLDL can trigger both (i) the extrinsic apoptotic pathway mediated by the FLICE inhibitory protein and Fas and Fas ligand [XREF_BIBR] that activates caspase-8, which in turn directly activates caspase-3 and (ii) calcium and calpain pathway that activates Bid and the mitochondrial apoptotic pathway, thereby indirectly activating caspase-3 [XREF_BIBR].	28	44	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	29	30	36	37
Another possibility is the involvement of receptor mediated death pathways where the tumor factor necrosis ( TNF ) family of death receptors activate the initiator caspase-8 which can activate caspase-3 without involve the mitochondrial mediated apoptosis .	Another possibility is the involvement of receptor mediated death pathways where the tumor factor necrosis (TNF) family of death receptors activate the initiator caspase-8 which can activate caspase-3 without involve the mitochondrial mediated apoptosis.	22	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	25	26	29	30
The initiator caspase of the extrinsic apoptotic pathway is CASP8 , which upon activation either activates CASP3 directly or indirectly through activation of the mitochondrial apoptotic pathway XREF_BIBR .	The initiator caspase of the extrinsic apoptotic pathway is CASP8, which upon activation either activates CASP3 directly or indirectly through activation of the mitochondrial apoptotic pathway XREF_BIBR.	2	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	CASP3	CASP3	CASP3	9	10	16	17
Both caspase-8 and -9 cause downstream activation of the effector caspase-3 .	Both caspase-8 and -9 cause downstream activation of the effector caspase-3.	0	11	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	10	11
23 Caspase-8 also directly activated caspase-3 and 7 and lead to apoptosis via extrinsic pathway .	23 Caspase-8 also directly activated caspase-3 and 7 and lead to apoptosis via extrinsic pathway.	0	9	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	1	2	5	6
Caspase-8 initiates apoptotic cell death by activating caspase-3 XREF_BIBR , XREF_BIBR .	Caspase-8 initiates apoptotic cell death by activating caspase-3 XREF_BIBR, XREF_BIBR.	0	8	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	7	8
Caspase 3 amplifies caspase 8 initiation signals into a commitment to disassembly , while caspase 8 activates caspase 3 by proteolytic cleavage and cleaves vital cellular proteins .	Caspase 3 amplifies caspase 8 initiation signals into a commitment to disassembly, while caspase 8 activates caspase 3 by proteolytic cleavage and cleaves vital cellular proteins.	14	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	14	16	17	19
However , apoptotic signal transduction involving death receptor signalling resulting in activated initiator caspase-8 , which in turn activates zymogen caspase-3 can not be ruled out .	However, apoptotic signal transduction involving death receptor signalling resulting in activated initiator caspase-8, which in turn activates zymogen caspase-3 can not be ruled out.	9	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	13	14	20	21
Caspase-8 and-10 activate effector caspase-3 , -6 and -7 leading to degradation of intracellular substrates and cell death .	Caspase-8 and-10 activate effector caspase-3, -6 and -7 leading to degradation of intracellular substrates and cell death.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	4	5
Once activated caspase-8 directs apoptotic cell death by activating the downstream executioner caspase-3 .	Once activated caspase-8 directs apoptotic cell death by activating the downstream executioner caspase-3.	1	13	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	12	13
As known , the extrinsic apoptotic pathway is mediated by caspase 8 , which is first activated by the death receptors and , in turn , activates caspase 3 .	As known, the extrinsic apoptotic pathway is mediated by caspase 8, which is first activated by the death receptors and, in turn, activates caspase 3.	8	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	10	12	27	29
In the extrinsic pathway , caspase 3 is activated by caspase 8 which is upstream bound and activated by FADD , which is bound to death receptors such as TNFR , forming the death inducing signaling complex .	In the extrinsic pathway, caspase 3 is activated by caspase 8 which is upstream bound and activated by FADD, which is bound to death receptors such as TNFR, forming the death inducing signaling complex.	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	10	12	5	7
Active caspase-8 might activate caspase-9 and caspase-3 leading to the cleavage of nuclear PARP .	Active caspase-8 might activate caspase-9 and caspase-3 leading to the cleavage of nuclear PARP.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	6	7
TNF-alpha is able to activate caspase-8 , which subsequently activates caspase-3 , thereby initiating the apoptosis cascade .	TNF-alpha is able to activate caspase-8, which subsequently activates caspase-3, thereby initiating the apoptosis cascade.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	10	11
As a crucial caspase , caspase-8 activates caspase-3 , as well as stimulating its hydrolysis and activating polymerase , thereby inducing cell death .	As a crucial caspase, caspase-8 activates caspase-3, as well as stimulating its hydrolysis and activating polymerase, thereby inducing cell death.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	7	8
Additionally , caspase 8 activation results in caspase 3 activation , resulting in apoptosis XREF_BIBR .	Additionally, caspase 8 activation results in caspase 3 activation, resulting in apoptosis XREF_BIBR.	2	10	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	2	4	7	9
When a potent NF-kappaB inhibitor , pyrrolidine dithiocarbamate ( PDTC ) , was added to U937 cell culture in the presence of PMA , apoptosis was triggered by activation of caspase-3 , which was induced by caspase-8 activation .	When a potent NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), was added to U937 cell culture in the presence of PMA, apoptosis was triggered by activation of caspase-3, which was induced by caspase-8 activation.	28	37	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	36	37	30	31
CD95 aggregation was associated with the recruitment of FADD and caspase-8 to the CD95 receptor to form the CD95 death inducing signaling complex ( DISC ) , resulting in caspase-8 activation and cleavage of the effector caspase-3 and PARP .	CD95 aggregation was associated with the recruitment of FADD and caspase-8 to the CD95 receptor to form the CD95 death inducing signaling complex (DISC), resulting in caspase-8 activation and cleavage of the effector caspase-3 and PARP.	29	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	29	30	36	37
Caspase 8 activation results in downstream activation of caspase 9 and caspase 3 .	Caspase 8 activation results in downstream activation of caspase 9 and caspase 3.	0	13	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	11	13
XREF_BIBR , XREF_BIBR , XREF_BIBR In type II cells , which include most cell types , caspase-8 is unable to directly activate caspase-3 .	XREF_BIBR, XREF_BIBR, XREF_BIBR In type II cells, which include most cell types, caspase-8 is unable to directly activate caspase-3.	16	23	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	16	17	22	23
Caspase-8 activation can then result in caspase-3 activation through the mitochondrial independent pathway , and/or through the activation of Bid through the mitochondrial dependent pathway [ XREF_BIBR ] .	Caspase-8 activation can then result in caspase-3 activation through the mitochondrial independent pathway, and/or through the activation of Bid through the mitochondrial dependent pathway [XREF_BIBR].	0	8	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	6	7
Subsequently , this protein complex activates pro-caspase-8 , which proceeds to trigger pro-caspase-3 , the penultimate enzyme for the execution of the apoptotic process .	Subsequently, this protein complex activates pro-caspase-8, which proceeds to trigger pro-caspase-3, the penultimate enzyme for the execution of the apoptotic process.	5	16	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pro-caspase-8	pro-caspase-8	pro-caspase-8	pro-caspase-3	pro-caspase-3	pro-caspase-3	6	7	12	13
In addition , tPA potentiates apoptosis in ischemic endothelium by shifting the apoptotic pathways from caspase-9 to caspase-8 , which directly activates caspase-3 XREF_BIBR ) .	In addition, tPA potentiates apoptosis in ischemic endothelium by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-3 XREF_BIBR).	10	23	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	17	18	22	23
Caspase 8 in turn can activate pro caspase 3 , a feature previously reviewed [ XREF_BIBR - XREF_BIBR ] .	Caspase 8 in turn can activate pro caspase 3, a feature previously reviewed [XREF_BIBR - XREF_BIBR].	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	7	9
FADD in turn can recruit and activate proximal caspase 8 , which subsequently activates effector caspase 3 , either by direct processing via a protease cascade or indirectly via a mitochondrial apoptotic pathway [ XREF_BIBR , XREF_BIBR ] .	FADD in turn can recruit and activate proximal caspase 8, which subsequently activates effector caspase 3, either by direct processing via a protease cascade or indirectly via a mitochondrial apoptotic pathway [XREF_BIBR, XREF_BIBR].	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	8	10	15	17
Subsequently , caspase 8 can either directly cleave and activate caspase 3 and 7 ( type I cells , such as lymphocytes ) similarly to caspase 9 , or can engage the mitochondrial pathway by cleaving the BH3-only protein Bid ( type II cells , such as hepatocytes ) , whose truncated fragment translocates to the mitochondrial outer membrane causing MOMP XREF_BIBR , XREF_BIBR .	Subsequently, caspase 8 can either directly cleave and activate caspase 3 and 7 (type I cells, such as lymphocytes) similarly to caspase 9, or can engage the mitochondrial pathway by cleaving the BH3-only protein Bid (type II cells, such as hepatocytes), whose truncated fragment translocates to the mitochondrial outer membrane causing MOMP XREF_BIBR, XREF_BIBR.	2	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	2	4	10	12
Strikingly , only the DEVD cleaving caspases , caspase-3 and caspase-7 , inactivated DFF45 and ICAD and promoted DNA fragmentation in an in vitro DFF40 and CAD assay , suggesting that granzyme B , caspase-6 , and caspase-8 promote DFF45 and ICAD inactivation and DNA fragmentation indirectly by activating caspase-3 and/or caspase-7 .	Strikingly, only the DEVD cleaving caspases, caspase-3 and caspase-7, inactivated DFF45 and ICAD and promoted DNA fragmentation in an in vitro DFF40 and CAD assay, suggesting that granzyme B, caspase-6, and caspase-8 promote DFF45 and ICAD inactivation and DNA fragmentation indirectly by activating caspase-3 and/or caspase-7.	32	51	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	37	38	49	50
In type I cells , active caspase-8 directly mediates sufficient activation of the effector caspase-3 that triggers execution of apoptosis .	In type I cells, active caspase-8 directly mediates sufficient activation of the effector caspase-3 that triggers execution of apoptosis.	5	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	14	15
High levels of Casp8 directly initiate cleavage of an effector Casp3 , thereby initiating the execution phase of apoptosis [ XREF_BIBR ] .	High levels of Casp8 directly initiate cleavage of an effector Casp3, thereby initiating the execution phase of apoptosis [XREF_BIBR].	1	11	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp8	levels of Casp8	casp8	Casp3	Casp3	casp3	3	4	10	11
Affinity labeling techniques revealed a branched protease cascade in which caspase-8 activates caspase-3 and -7 , and caspase-3 , in turn , activates caspase-6 .	Affinity labeling techniques revealed a branched protease cascade in which caspase-8 activates caspase-3 and -7, and caspase-3, in turn, activates caspase-6.	10	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	10	11	12	13
The death receptors cluster , recruit and activate initiator caspase-8 , which in turn activates executioner caspase-3 and leads to apoptosis .	The death receptors cluster, recruit and activate initiator caspase-8, which in turn activates executioner caspase-3 and leads to apoptosis.	7	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	9	10	16	17
Moreover , the activated caspase-8 activates caspase-3 through two pathways .	Moreover, the activated caspase-8 activates caspase-3 through two pathways.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	6	7
Activation of caspase-8 can both directly activate caspase-3 and affect the Bax function to initiate intrinsic pathway .	Activation of caspase-8 can both directly activate caspase-3 and affect the Bax function to initiate intrinsic pathway.	0	8	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	7	8
Increased level of ROS induced combination of Fas and its receptor FasL leads to the Fas associated protein with death domain ( FADD ) and subsequently leading to the activation of caspase-8 , which in turn activates caspase-3 , leading cell to apoptosis .	Increased level of ROS induced combination of Fas and its receptor FasL leads to the Fas associated protein with death domain (FADD) and subsequently leading to the activation of caspase-8, which in turn activates caspase-3, leading cell to apoptosis.	29	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	31	32	37	38
In general , the activation of caspase-8 leads to the release of caspase-9 to induce the activation of caspase-3 , and ultimately to cause apoptosis .	In general, the activation of caspase-8 leads to the release of caspase-9 to induce the activation of caspase-3, and ultimately to cause apoptosis.	4	19	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	18	19
For example , it has been reported that Fas ligand binding to its death receptor induces apoptosis through the activation of CASP8 , which in turn activates CASP3 and CASP9 .	For example, it has been reported that Fas ligand binding to its death receptor induces apoptosis through the activation of CASP8, which in turn activates CASP3 and CASP9.	19	29	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	CASP3	CASP3	CASP3	21	22	27	28
17AA ( + ) WT1 specific siRNA activated caspase-3 and -9 in the intrinsic apoptosis pathway but not caspase-8 in the extrinsic one .	17AA (+) WT1 specific siRNA activated caspase-3 and -9 in the intrinsic apoptosis pathway but not caspase-8 in the extrinsic one.	0	22	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	18	19	8	9
Caspase-8 works in two sides ; the first one directly activates the downstream effector caspase-3 , the second , caspase-8 induces the truncated Bid ( tBid ) , which in turn results in the release of cytochrome C from the mitochondria into the cytosol .	Caspase-8 works in two sides; the first one directly activates the downstream effector caspase-3, the second, caspase-8 induces the truncated Bid (tBid), which in turn results in the release of cytochrome C from the mitochondria into the cytosol.	0	17	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	14	15
Taken together , these results clearly indicate that MA initially triggers the extrinsic caspase cascade in the Caco-2 cell line via the activation of caspase-8 , which in turn activates caspase-3 without activating Bax or caspase-9 .	Taken together, these results clearly indicate that MA initially triggers the extrinsic caspase cascade in the Caco-2 cell line via the activation of caspase-8, which in turn activates caspase-3 without activating Bax or caspase-9.	22	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	24	25	30	31
In turn , caspase-8 activates caspase-3 , which causes DNA fragmentation and cell death .	In turn, caspase-8 activates caspase-3, which causes DNA fragmentation and cell death.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	5	6
In the case of extrinsic pathway , death-receptor-mediated active caspase-8 directly activates downstream executioner caspase-3 by proteolytic cleavage .	In the case of extrinsic pathway, death-receptor-mediated active caspase-8 directly activates downstream executioner caspase-3 by proteolytic cleavage.	7	15	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	9	10	14	15
Procaspase-8 translocates to the Fas and FADD complex , and it triggers activation of initiator caspase-8 , which in turn directly activates caspase-3 without formation of mitochondria dependent apoptosomes [ XREF_BIBR ] .	Procaspase-8 translocates to the Fas and FADD complex, and it triggers activation of initiator caspase-8, which in turn directly activates caspase-3 without formation of mitochondria dependent apoptosomes [XREF_BIBR].	12	23	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	15	16	22	23
Furthermore , caspase 8 mediates activation of caspase 3 and poly ADP-ribose polymerase ( PARP ) cleavage during TGFbeta1 induced apoptosis in stretching HPTFs .	Furthermore, caspase 8 mediates activation of caspase 3 and poly ADP-ribose polymerase (PARP) cleavage during TGFbeta1 induced apoptosis in stretching HPTFs.	2	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	2	4	7	9
Another manner of caspase 3 activation is by direct activation of caspase 3 by caspase 8 [ XREF_BIBR ] .	Another manner of caspase 3 activation is by direct activation of caspase 3 by caspase 8 [XREF_BIBR].	9	17	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	14	16	11	13
M. tuberculosis RNA strongly activated caspase-8 ( LETD-FMK ) , intermediately activated caspase-3 ( DEVD-FMK ) and had negligible effect on caspase-1 ( YVAD-FMK ) , as determined by flow cytometry ( XREF_FIG ) .	M. tuberculosis RNA strongly activated caspase-8 (LETD-FMK), intermediately activated caspase-3 (DEVD-FMK) and had negligible effect on caspase-1 (YVAD-FMK), as determined by flow cytometry (XREF_FIG).	4	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	12	13
Such co-dependence on both the intrinsic and extrinsic pathways is observed when initial precursor pool of caspase-8 is not sufficient to drive subsequent caspase-3 activation .	Such co-dependence on both the intrinsic and extrinsic pathways is observed when initial precursor pool of caspase-8 is not sufficient to drive subsequent caspase-3 activation.	14	24	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	16	17	23	24
We conclude that NO induces it apoptotic influence by activating caspase-8 in M. fortuitum infected HKM which activated caspase-3 to accomplish the apoptotic cascade .	We conclude that NO induces it apoptotic influence by activating caspase-8 in M. fortuitum infected HKM which activated caspase-3 to accomplish the apoptotic cascade.	9	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	10	11	18	19
One aspect that may be affected by SNX cleavage is apoptosis via death receptors that requires their trafficking in endosomes , where the associated initiator caspase-8 activates the bulk of the executioner caspase-3 .	One aspect that may be affected by SNX cleavage is apoptosis via death receptors that requires their trafficking in endosomes, where the associated initiator caspase-8 activates the bulk of the executioner caspase-3.	22	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	25	26	32	33
Caspase-3 , as an apoptotic effector , is activated by caspase-8 cleavage XREF_BIBR .	Caspase-3, as an apoptotic effector, is activated by caspase-8 cleavage XREF_BIBR.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	10	11	0	1
In one pathway ( the extrinsic ) , caspase-8 activation directly activates effector caspase-3 , which facilitates apoptosis .	In one pathway (the extrinsic), caspase-8 activation directly activates effector caspase-3, which facilitates apoptosis.	8	16	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	13	14
Activated caspase 8 can activate caspase 3 both directly and indirectly by truncation of Bid [ XREF_BIBR ] .	Activated caspase 8 can activate caspase 3 both directly and indirectly by truncation of Bid [XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	1	3	5	7
Then , activated caspase-8 can initiate downstream cleavage of caspase-3 , among other targets , by direct or mitochondrial dependent mechanisms .	Then, activated caspase-8 can initiate downstream cleavage of caspase-3, among other targets, by direct or mitochondrial dependent mechanisms.	2	10	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	9	10
In human cells , activation of TRAIL receptor 1 ( TRAIL-R1 ) and/or TRAIL-R2 stimulates caspase-8 activation , which in turn triggers caspase-3 activation .	In human cells, activation of TRAIL receptor 1 (TRAIL-R1) and/or TRAIL-R2 stimulates caspase-8 activation, which in turn triggers caspase-3 activation.	15	23	triggers	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	15	16	22	23
Ligand binding of TNF-alpha to TNF receptors activates caspase 8 , which in turn triggers caspase 3 , leading to apoptosis .	Ligand binding of TNF-alpha to TNF receptors activates caspase 8, which in turn triggers caspase 3, leading to apoptosis.	7	18	triggers	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	8	10	15	17
Once activated , caspase-8 converts BID into tBID on one hand and activates caspase-3 on the other hand to induce oocyte apoptosis [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Once activated, caspase-8 converts BID into tBID on one hand and activates caspase-3 on the other hand to induce oocyte apoptosis [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	13	14
Inhibition of caspase-8 by Lle-Glu ( OMe )-Thr-Asp ( OMe )-fluoromethyl ketone completely blocked caspase-3 cleavage and apoptosis in UVA treated cells , suggesting that apoptosis was initiated by the Fas pathway .	Inhibition of caspase-8 by Lle-Glu (OMe)-Thr-Asp (OMe)-fluoromethyl ketone completely blocked caspase-3 cleavage and apoptosis in UVA treated cells, suggesting that apoptosis was initiated by the Fas pathway.	0	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	14	15
The caspase-3 activity was also consistent with caspase-8 activity in every condition and had a greater magnitude after AjCTRP9 knockdown , thus suggesting that caspase-8 directly modulates caspase-3 and promotes apoptosis .	The caspase-3 activity was also consistent with caspase-8 activity in every condition and had a greater magnitude after AjCTRP9 knockdown, thus suggesting that caspase-8 directly modulates caspase-3 and promotes apoptosis.	24	29	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	24	25	27	28
In type II pathway , caspase 8 does not directly activate the caspase 3 to execute cell death .	In type II pathway, caspase 8 does not directly activate the caspase 3 to execute cell death.	5	14	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	5	7	12	14
Caspase-8 in turn activates caspase-3 to inducing apoptosis .	Caspase-8 in turn activates caspase-3 to inducing apoptosis.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	4	5
Autoactivation of caspase 8 activates other effector caspases including caspase 3 , 6 and 7 .	Autoactivation of caspase 8 activates other effector caspases including caspase 3, 6 and 7.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	2	4	9	11
Several studies have reported that both caspase-8 and MAPK can either directly activate caspase-3 via Bid or activate the intrinsic apoptotic pathway [ XREF_BIBR , XREF_BIBR ] .	Several studies have reported that both caspase-8 and MAPK can either directly activate caspase-3 via Bid or activate the intrinsic apoptotic pathway [XREF_BIBR, XREF_BIBR].	5	17	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	13	14
Caspase-8 activates caspase-3 , leading to apoptosis .	Caspase-8 activates caspase-3, leading to apoptosis.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	2	3
The activation of caspase-3 by caspase-8 is responsible for the cleavage of cellular substrates [ XREF_BIBR - XREF_BIBR ] .	The activation of caspase-3 by caspase-8 is responsible for the cleavage of cellular substrates [XREF_BIBR - XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	3	4
Involvement of the Fas-FasL pathway does not preclude the participation of GZB , the two mechanisms being convergent , as FasL activates caspase 8 , itself an activator of caspase 3 , which is directly activated by GZB XREF_BIBR .	Involvement of the Fas-FasL pathway does not preclude the participation of GZB, the two mechanisms being convergent, as FasL activates caspase 8, itself an activator of caspase 3, which is directly activated by GZB XREF_BIBR.	21	35	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	22	24	29	31
39 In type-II cells higher ratio of XIAP and caspase -3 resulted in an incomplete activation of caspase-3 by caspase-8 .	39 In type-II cells higher ratio of XIAP and caspase -3 resulted in an incomplete activation of caspase-3 by caspase-8.	11	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	19	20	17	18
Both caspase 8 and 9 activate caspase 3 , which catalyzes the specific cleavage and activation of many key apoptosis related proteins [ XREF_BIBR ] .	Both caspase 8 and 9 activate caspase 3, which catalyzes the specific cleavage and activation of many key apoptosis related proteins [XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	1	3	6	8
However in UHRF1 depleted cells , loss of caspase-8 blocks PARP-1 cleavage ( XREF_FIG , compare lane 2 to lane 4 of panel 3 ) and caspase-3 activation ( XREF_FIG , compare lane 2 to lane 4 of panel 4 ) .	However in UHRF1 depleted cells, loss of caspase-8 blocks PARP-1 cleavage (XREF_FIG, compare lane 2 to lane 4 of panel 3) and caspase-3 activation (XREF_FIG, compare lane 2 to lane 4 of panel 4).	6	27	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-8	loss of caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	26	27
Furthermore , infection with C. trachomatis was able to inhibit CD95 induced apoptosis in Jurkat lymphoid cells , where a mitochondrial contribution is required , but not in SKW6.4 lymphoid cells , where caspase-8 directly activates caspase-3 .	Furthermore, infection with C. trachomatis was able to inhibit CD95 induced apoptosis in Jurkat lymphoid cells, where a mitochondrial contribution is required, but not in SKW6.4 lymphoid cells, where caspase-8 directly activates caspase-3.	33	37	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	33	34	36	37
Among them , caspase-3 , which is activated by caspase-8 or -9 , is one of the most important executioner caspases .	Among them, caspase-3, which is activated by caspase-8 or -9, is one of the most important executioner caspases.	3	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	9	10	3	4
Consequently , the protein complex activates pro-caspase-8 , which proceeds to trigger pro-caspase-3 , the penultimate enzyme for the execution of the apoptotic process [ XREF_BIBR ] .	Consequently, the protein complex activates pro-caspase-8, which proceeds to trigger pro-caspase-3, the penultimate enzyme for the execution of the apoptotic process [XREF_BIBR].	5	16	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pro-caspase-8	pro-caspase-8	pro-caspase-8	pro-caspase-3	pro-caspase-3	pro-caspase-3	6	7	12	13
Activation of caspase-8 and -9 enhances executioner caspase-3 activation and ultimately upregulation of cleaved-PARP .	Activation of caspase-8 and -9 enhances executioner caspase-3 activation and ultimately upregulation of cleaved-PARP.	0	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	7	8
Caspase-3 is an executioner caspase that can be activated by a mitochondrial pathway involving release of cytochrome C [ XREF_BIBR ] ; alternatively , caspase-3 can also be activated by caspase-8 [ XREF_BIBR , XREF_BIBR ] .	Caspase-3 is an executioner caspase that can be activated by a mitochondrial pathway involving release of cytochrome C [XREF_BIBR]; alternatively, caspase-3 can also be activated by caspase-8 [XREF_BIBR, XREF_BIBR].	24	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	30	31	24	25
We further demonstrated that the release of mitochondrial proteins and the activation of calpains occurred upstream of the caspase cascade , in which caspase-9 was activated in response to the release of Cyt c , that caspase-8 activation was caspase and calpain dependent , and that caspase-3 was activated mainly by caspase-8 and -9 .	We further demonstrated that the release of mitochondrial proteins and the activation of calpains occurred upstream of the caspase cascade, in which caspase-9 was activated in response to the release of Cyt c, that caspase-8 activation was caspase and calpain dependent, and that caspase-3 was activated mainly by caspase-8 and -9.	46	53	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	51	52	46	47
In type I cells , large amounts of active caspase-8 formed at the DISC directly induces activation of pro-caspase-3 independently of mitochondria [ XREF_BIBR ] .	In type I cells, large amounts of active caspase-8 formed at the DISC directly induces activation of pro-caspase-3 independently of mitochondria [XREF_BIBR].	6	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	amounts of active caspase-8	caspase-8	pro-caspase-3	pro-caspase-3	pro-caspase-3	9	10	18	19
Active caspase-8 activates caspase-3 , resulting in apoptosis .	Active caspase-8 activates caspase-3, resulting in apoptosis.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	3	4
Finally , we present evidence that the OMM localized active caspase 8 can activate cytosolic caspase 3 and ER localized BAP31 .	Finally, we present evidence that the OMM localized active caspase 8 can activate cytosolic caspase 3 and ER localized BAP31.	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	10	12	15	17
We also observed that DMPS activated the caspase-8-Bid-Bax pathway and that the inhibition of caspase-8 by z-IETD-fmk or small interfering RNA suppressed the cleavage of Bid , cytochrome c release , caspase-3 activation , and apoptotic cell death .	We also observed that DMPS activated the caspase-8-Bid-Bax pathway and that the inhibition of caspase-8 by z-IETD-fmk or small interfering RNA suppressed the cleavage of Bid, cytochrome c release, caspase-3 activation, and apoptotic cell death.	12	32	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	14	15	31	32
Activation of caspase-8 by DISC activates caspase-3 , and consequently induces apoptosis [ XREF_BIBR ] .	Activation of caspase-8 by DISC activates caspase-3, and consequently induces apoptosis [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	6	7
Here , we report that tPA potentiates apoptosis in ischemic human brain endothelium and in mouse cortical neurons treated with N-methyl-D-aspartate ( NMDA ) by shifting the apoptotic pathways from caspase-9 to caspase-8 , which directly activates caspase-3 without amplification through the Bid mediated mitochondrial pathway .	Here, we report that tPA potentiates apoptosis in ischemic human brain endothelium and in mouse cortical neurons treated with N-methyl-D-aspartate (NMDA) by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-3 without amplification through the Bid mediated mitochondrial pathway.	25	38	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	32	33	37	38
Caspase-8 activation causes the cleavage of Caspase-9 and Caspase-3 [ XREF_BIBR , XREF_BIBR ] .	Caspase-8 activation causes the cleavage of Caspase-9 and Caspase-3 [XREF_BIBR, XREF_BIBR].	0	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Caspase-3	Caspase-3	Caspase-3	0	1	8	9
The induction of apoptosis is triggered by the interaction of Fas with its ligand ( FasL ) , a 40-kDa membrane protein allowing recruitment of the adaptor protein Fas associated death domain ( FADD ) and binding of procaspase-8 , resulting in the formation of the death inducing signaling complex ( DISC ) , which finally leads to the activation of effector caspase-3 by active Caspase-8 .	The induction of apoptosis is triggered by the interaction of Fas with its ligand (FasL), a 40-kDa membrane protein allowing recruitment of the adaptor protein Fas associated death domain (FADD) and binding of procaspase-8, resulting in the formation of the death inducing signaling complex (DISC), which finally leads to the activation of effector caspase-3 by active Caspase-8.	56	66	leads	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	65	66	62	63
Caspase 8 activates caspase 3 and can also translocate to the nucleus where it targets nuclear protein of the PARP family , PARP-2 , which , like PARP-1 , is also involved in the maintenance of genomic integrity and cell survival .	Caspase 8 activates caspase 3 and can also translocate to the nucleus where it targets nuclear protein of the PARP family, PARP-2, which, like PARP-1, is also involved in the maintenance of genomic integrity and cell survival.	0	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	3	5
Stimulation of death receptors results in activation of caspase 8 , which in turn activates caspase 3 .	Stimulation of death receptors results in activation of caspase 8, which in turn activates caspase 3.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	8	10	15	17
Caspase-3 cleavage can be activated by caspase-8 whose auto cleavage from pro-caspase-8 occurs following formation of a complex involving the adaptor protein FADD which is normally initiated through binding of Fas or TNF receptors XREF_BIBR .	Caspase-3 cleavage can be activated by caspase-8 whose auto cleavage from pro-caspase-8 occurs following formation of a complex involving the adaptor protein FADD which is normally initiated through binding of Fas or TNF receptors XREF_BIBR.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	6	7	0	1
The death receptors activate caspase 8 , which further activates caspase 3 via Jun-Kinase ( JNK ) to cause apoptosis .	The death receptors activate caspase 8, which further activates caspase 3 via Jun-Kinase (JNK) to cause apoptosis.	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	4	6	10	12
In the extrinsic pathway , caspase-8 activates caspase-3 after it is activated by intracellular and extracellular stimuli [ XREF_BIBR ] .	In the extrinsic pathway, caspase-8 activates caspase-3 after it is activated by intracellular and extracellular stimuli [XREF_BIBR].	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	7	8
In the type I pathway , caspase-8 directly activates the effector caspases ( caspase-3 , -6 and -7 ) resulting in the execution of apoptotic cell death , whereas the type II pathway involves caspase-8-dependent cleavage of Bid .	In the type I pathway, caspase-8 directly activates the effector caspases (caspase-3, -6 and -7) resulting in the execution of apoptotic cell death, whereas the type II pathway involves caspase-8-dependent cleavage of Bid.	6	17	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	13	14
Procaspase-8 is then cleaved to active caspase-8 which in turn activates the effector caspase-3 [ XREF_BIBR ] .	Procaspase-8 is then cleaved to active caspase-8 which in turn activates the effector caspase-3 [XREF_BIBR].	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	13	14
Depending on the cell type , active caspase-8 either directly activates caspase-3 ( type I cells ) or relies on mitochondrial signal amplification ( type II cells ) .	Depending on the cell type, active caspase-8 either directly activates caspase-3 (type I cells) or relies on mitochondrial signal amplification (type II cells).	6	18	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	11	12
Caspase-3 , a key executioner in the apoptotic machinery , cleaves many proteins indispensable for cell survival and is activated through cleavage into two fragments ( 17 kDa and 19 kDa ) by caspase-8 and/or caspase-9 during apoptosis XREF_BIBR , XREF_BIBR .	Caspase-3, a key executioner in the apoptotic machinery, cleaves many proteins indispensable for cell survival and is activated through cleavage into two fragments (17 kDa and 19 kDa) by caspase-8 and/or caspase-9 during apoptosis XREF_BIBR, XREF_BIBR.	0	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	33	34	0	1
The activated caspase-8 protein induced caspase-3 and PARP cleavage , linked to the cell-surface death-receptor apoptotic pathway .	The activated caspase-8 protein induced caspase-3 and PARP cleavage, linked to the cell-surface death-receptor apoptotic pathway.	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	5	6
Caspase-3 is a member of the cysteine aspartic acid protease ( caspase )/IL-1beta-converting enzyme family and is activated directly by caspase-8 , -9 and -10 via extrinsic and intrinsic pathways to initiate apoptosis .	Caspase-3 is a member of the cysteine aspartic acid protease (caspase)/IL-1beta-converting enzyme family and is activated directly by caspase-8, -9 and -10 via extrinsic and intrinsic pathways to initiate apoptosis.	0	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	20	21	0	1
Accordingly , caspases have been broadly classified by their known functions in apoptosis ( caspase-3 , -6 , -7 , -8 , and -9 in mammals ) , and in inflammation ( caspase-1 , -4 , -5 , -12 in humans and caspase-1 , -11 , and -12 in mice ) [ XREF_BIBR ] Caspase-8 stimulates extrinsic apoptosis and active caspase-8 can initiate apoptosis directly by cleaving and thereby activating executioner caspase-3 , caspase-6 and caspase-7 to induce efficient cell death [ XREF_BIBR ] .	Accordingly, caspases have been broadly classified by their known functions in apoptosis (caspase-3, -6, -7, -8, and -9 in mammals), and in inflammation (caspase-1, -4, -5, -12 in humans and caspase-1, -11, and -12 in mice) [XREF_BIBR] Caspase-8 stimulates extrinsic apoptosis and active caspase-8 can initiate apoptosis directly by cleaving and thereby activating executioner caspase-3, caspase-6 and caspase-7 to induce efficient cell death [XREF_BIBR].	57	75	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	60	61	71	72
In response to TRAIL and CHX , C-XIAP-C D148A was slightly less efficient in maintaining Smac inside mitochondria at late times ( XREF_FIG ) , probably because of caspase-8 directly activating caspase-3 and the latter cleaving XIAP between the BIR2 and 3 domains into fragments that can no longer bind efficiently to Smac .	In response to TRAIL and CHX, C-XIAP-C D148A was slightly less efficient in maintaining Smac inside mitochondria at late times (XREF_FIG), probably because of caspase-8 directly activating caspase-3 and the latter cleaving XIAP between the BIR2 and 3 domains into fragments that can no longer bind efficiently to Smac.	14	36	directly activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	28	29	31	32
Caspase-8 and Caspase-10 can accept extracellular death signal and then activate their downstream Caspase-3 and Caspase-7 to induce apoptosis .	Caspase-8 and Caspase-10 can accept extracellular death signal and then activate their downstream Caspase-3 and Caspase-7 to induce apoptosis.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Caspase-3	Caspase-3	Caspase-3	0	1	13	14
TRAIL induced activation of caspase-8 leads to the activation of downstream caspase-9 and caspase-3 .	TRAIL induced activation of caspase-8 leads to the activation of downstream caspase-9 and caspase-3.	0	14	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	TRAIL induced activation of caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	13	14
Caspase-3 can also be activated by caspase-8 after the initiation of the extrinsic apoptotic pathway [ XREF_BIBR , XREF_BIBR ] .	Caspase-3 can also be activated by caspase-8 after the initiation of the extrinsic apoptotic pathway [XREF_BIBR, XREF_BIBR].	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	6	7	0	1
Extrinsic signals to initiate the apoptotic pathways from receptors ( e.g ., Fas ligand ) culminate in the activation of caspase 8 , which activates the effector caspase 3 , while intrinsic signaling requires the participation of the mitochondria in releasing cytochrome c to activate caspase 9 for the downstream activation of caspase 3 .	Extrinsic signals to initiate the apoptotic pathways from receptors (e.g., Fas ligand) culminate in the activation of caspase 8, which activates the effector caspase 3, while intrinsic signaling requires the participation of the mitochondria in releasing cytochrome c to activate caspase 9 for the downstream activation of caspase 3.	18	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	20	22	27	29
Caspase-8 signal transduction eventually activates the caspase-3 to initiate cell death [ XREF_BIBR ] .	Caspase-8 signal transduction eventually activates the caspase-3 to initiate cell death [XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	6	7
Subsequently , caspase-8 cleaves and activates the effector caspase-3 , culminating in the demise of so called type I cells .	Subsequently, caspase-8 cleaves and activates the effector caspase-3, culminating in the demise of so called type I cells.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	8	9
Both factors stimulated caspase-3 activity , which could be inhibited by caspase-8 or caspase-9 inhibitors .	Both factors stimulated caspase-3 activity, which could be inhibited by caspase-8 or caspase-9 inhibitors.	3	14	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	11	12	3	4
described two pathways through which active caspase-8 causes caspase-3 activation .	described two pathways through which active caspase-8 causes caspase-3 activation.	5	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	8	9
The results demonstrated that altholactone was cytotoxic to HeLa ( IC50 = 9.6 mug/mL ) , and apoptotic cell death was manifested by appearance of chromatin condensation and caspase-3 activation , which was inhibited by specific inhibitors of both caspase-8 and -9 .	The results demonstrated that altholactone was cytotoxic to HeLa (IC50 = 9.6 mug/mL), and apoptotic cell death was manifested by appearance of chromatin condensation and caspase-3 activation, which was inhibited by specific inhibitors of both caspase-8 and -9.	28	41	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	39	40	28	29
In NB4 , an inhibitor of caspase 8 blocked not only the activation of caspase 3 but also the loss of deltapsim .	In NB4, an inhibitor of caspase 8 blocked not only the activation of caspase 3 but also the loss of deltapsim.	4	16	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	6	8	14	16
XREF_BIBR Caspase-8 and -9 will then stimulate caspase-3 cleavage .	XREF_BIBR Caspase-8 and -9 will then stimulate caspase-3 cleavage.	0	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	1	2	7	8
Caspase-8 can activate caspase-3 directly or indirectly through cleavage of Bid followed by the activation of caspase-9 .	Caspase-8 can activate caspase-3 directly or indirectly through cleavage of Bid followed by the activation of caspase-9.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	3	4
These receptors mediate the activation of caspase-8 , which , in turn , activate caspase-3 , that cleaves its substrates and induces apoptosis as described above .	These receptors mediate the activation of caspase-8, which, in turn, activate caspase-3, that cleaves its substrates and induces apoptosis as described above.	4	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	14	15
Caspase-8 activates its downstream effector caspase-3 thus functionalizing extrinsic pathway .	Caspase-8 activates its downstream effector caspase-3 thus functionalizing extrinsic pathway.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	5	6
12 Caspase-8 directly activates effector caspase-3 to induce apoptosis through the type I pathway or cleaves the BH3-only protein Bid , generating tBid .	12 Caspase-8 directly activates effector caspase-3 to induce apoptosis through the type I pathway or cleaves the BH3-only protein Bid, generating tBid.	0	15	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	1	2	5	6
Similarly , CASP8 inhibition reduced both CASP3 and CASP6 activation , suggesting that the cross activation of these caspases is common in both the injured cerebrum and retina .	Similarly, CASP8 inhibition reduced both CASP3 and CASP6 activation, suggesting that the cross activation of these caspases is common in both the injured cerebrum and retina.	2	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	CASP3	CASP3	CASP3	2	3	6	7
In hepatocytes expressing IRA , Bid cleavage and cytochrome C release were increased whereas direct activation of caspase-3 by caspase-8 and a more rapid apoptotic process occurred in hepatocytes expressing IRB .	In hepatocytes expressing IRA, Bid cleavage and cytochrome C release were increased whereas direct activation of caspase-3 by caspase-8 and a more rapid apoptotic process occurred in hepatocytes expressing IRB.	15	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	19	20	17	18
Caspase-8 , an initiator caspase , can directly activate caspase-3 bypassing the mitochondrial mediated death pathway [ XREF_BIBR ] .	Caspase-8, an initiator caspase, can directly activate caspase-3 bypassing the mitochondrial mediated death pathway [XREF_BIBR].	0	10	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	9	10
Caspase-8 then activates downstream caspase-3 and induces the classic extrinsic death pathway .	Caspase-8 then activates downstream caspase-3 and induces the classic extrinsic death pathway.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	4	5
It has been shown that the high-dose of hexameric Fas ligand or double Bak and Bax deficiency [ XREF_BIBR ] may lead to circumvention of mitochondrial apoptotic pathways and activation of type I pathway in the hepatocytes , where caspase 8 directly activates caspase 3 and induces apoptosis .	It has been shown that the high-dose of hexameric Fas ligand or double Bak and Bax deficiency [XREF_BIBR] may lead to circumvention of mitochondrial apoptotic pathways and activation of type I pathway in the hepatocytes, where caspase 8 directly activates caspase 3 and induces apoptosis.	39	46	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	39	41	43	45
Caspase-8 can also directly promote the proteolytic activation of caspase-3 .	Caspase-8 can also directly promote the proteolytic activation of caspase-3.	0	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	9	10
Caspase-8 is activated by autoproteolysis and subsequently activates caspase-3 directly or via a lysosomal-mitochondrial amplification loop that involves the release of cytochrome C and APAF-1 , and formation of the apoptosome with caspase-9 [ XREF_BIBR ] .	Caspase-8 is activated by autoproteolysis and subsequently activates caspase-3 directly or via a lysosomal-mitochondrial amplification loop that involves the release of cytochrome C and APAF-1, and formation of the apoptosome with caspase-9 [XREF_BIBR].	0	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	8	9
Caspase 8 activation leads to the activation of caspase 3 and caspase 7 to execute apoptosis .	Caspase 8 activation leads to the activation of caspase 3 and caspase 7 to execute apoptosis.	0	14	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	8	10
Downstream caspase-3 can be directly activated by caspase-8 or via the mitochondrial pathway consisting of the translocation to mitochondria of truncated BID ( t-BID ) [ XREF_BIBR , XREF_BIBR ] .	Downstream caspase-3 can be directly activated by caspase-8 or via the mitochondrial pathway consisting of the translocation to mitochondria of truncated BID (t-BID) [XREF_BIBR, XREF_BIBR].	0	8	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	1	2
Caspase-8 also can indirectly activate caspase-3 through cleavage of Bid to its truncated form ( t-Bid ) [ XREF_BIBR ] .	Caspase-8 also can indirectly activate caspase-3 through cleavage of Bid to its truncated form (t-Bid) [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	5	6
The type I apoptosis pathway is initiated by the activation of death receptors followed by activation of caspase-8 , which subsequently activates caspase-3 , the executor of apoptosis [ XREF_BIBR ] .	The type I apoptosis pathway is initiated by the activation of death receptors followed by activation of caspase-8, which subsequently activates caspase-3, the executor of apoptosis [XREF_BIBR].	15	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	17	18	22	23
Alternatively , caspase 8 can also directly activate caspase 3 forming cleaved caspase 3 27 .	Alternatively, caspase 8 can also directly activate caspase 3 forming cleaved caspase 3 27.	2	10	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	2	4	8	10
Active caspase-8 then activates caspase-3 to execute apoptosis .	Active caspase-8 then activates caspase-3 to execute apoptosis.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	4	5
In type I cells caspase-8 mediated activation of caspase-3 is sufficient to ensure execution of the final steps of apoptosis .	In type I cells caspase-8 mediated activation of caspase-3 is sufficient to ensure execution of the final steps of apoptosis.	0	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	8	9
Caspase-8 , in turn , activates caspase-3 , committing the cell to the final , common pathway of apoptosis .	Caspase-8, in turn, activates caspase-3, committing the cell to the final, common pathway of apoptosis.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	6	7
Caspase-8 activation can then result in caspase-3 activation through the mitochondrial independent pathway , and/or through the activation of Bid , a pro apoptotic BH3-only Bcl-2 family member , which when cleaved induces the mitochondrial release of apoptogenic factors such as Bax and Bak through the mitochondrial dependent pathway XREF_BIBR .	Caspase-8 activation can then result in caspase-3 activation through the mitochondrial independent pathway, and/or through the activation of Bid, a pro apoptotic BH3-only Bcl-2 family member, which when cleaved induces the mitochondrial release of apoptogenic factors such as Bax and Bak through the mitochondrial dependent pathway XREF_BIBR.	0	8	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	6	7
In the extrinsic pathway , binding of ligands to their respective receptors induces oligomerization and activation of caspase-8 , which in turn activates caspase-3 , leading to apoptosis [ XREF_BIBR ] .	In the extrinsic pathway, binding of ligands to their respective receptors induces oligomerization and activation of caspase-8, which in turn activates caspase-3, leading to apoptosis [XREF_BIBR].	13	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	17	18	23	24
Caspase 8 activates Caspase 3 , and caspase 3 can activate Calpain via cleavage of the calpain inhibitor calpastatin [ XREF_BIBR ] .	Caspase 8 activates Caspase 3, and caspase 3 can activate Calpain via cleavage of the calpain inhibitor calpastatin [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	Caspase 3	Caspase 3	0	2	3	5
On the one hand , caspase 8 can cause extrinsic apoptosis by activating caspase 3 which is responsible for PARP cleavage and DNA fracture .	On the one hand, caspase 8 can cause extrinsic apoptosis by activating caspase 3 which is responsible for PARP cleavage and DNA fracture.	5	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	5	7	13	15
In turn , caspase-8 can then activate caspase-3 , although a direct pathway for caspase-8-elicited apoptosis has also been described .	In turn, caspase-8 can then activate caspase-3, although a direct pathway for caspase-8-elicited apoptosis has also been described.	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	7	8
Typically , the death receptor initiated pathway involves activation of initiator caspase-8 , which in turn activates caspase-3 XREF_BIBR .	Typically, the death receptor initiated pathway involves activation of initiator caspase-8, which in turn activates caspase-3 XREF_BIBR.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	11	12	17	18
In contrast , in type II cells very little DISC and small amounts of active caspase-8 sufficient to induce the apoptogenic activity of mitochondria are formed causing a profound activation of both caspase-8 and caspase-3 .	In contrast, in type II cells very little DISC and small amounts of active caspase-8 sufficient to induce the apoptogenic activity of mitochondria are formed causing a profound activation of both caspase-8 and caspase-3.	9	35	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	15	16	34	35
8 During the extrinsic pathway , Caspase-3 is activated by Caspase-8 .	8 During the extrinsic pathway, Caspase-3 is activated by Caspase-8.	6	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Caspase-3	Caspase-3	Caspase-3	10	11	6	7
Active caspase-8 then activates caspase-3 and other caspases by proteolytic processing .	Active caspase-8 then activates caspase-3 and other caspases by proteolytic processing.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	4	5
Active caspase-8 can initiate apoptosis directly by cleaving and thereby activating executioner caspase-3 , caspase-6 and caspase-7 to induce efficient cell death [ XREF_BIBR ] .	Active caspase-8 can initiate apoptosis directly by cleaving and thereby activating executioner caspase-3, caspase-6 and caspase-7 to induce efficient cell death [XREF_BIBR].	0	16	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	12	13
Activated Caspase 8 activates Caspase 3 through two pathways .	Activated Caspase 8 activates Caspase 3 through two pathways.	0	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	Caspase 3	Caspase 3	Caspase 3	1	3	4	6
The predominant apoptotic pathway induced by CML-collagen involved caspase-8 activation of caspase-3 and was independent of NF-kappaB activation .	The predominant apoptotic pathway induced by CML-collagen involved caspase-8 activation of caspase-3 and was independent of NF-kappaB activation.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	11	12
Caspase 8 can directly activate pro caspase 3 , which cleaves target proteins , leading to apoptosis .	Caspase 8 can directly activate pro caspase 3, which cleaves target proteins, leading to apoptosis.	0	10	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	6	8
During apoptotic conditions , caspase-8 can activate caspase-3 directly through an extrinsic pathway .	During apoptotic conditions, caspase-8 can activate caspase-3 directly through an extrinsic pathway.	4	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	7	8
There are two main distinct signalling pathways leading to apoptosis : Extrinsic pathway : initiated by the activation of death receptors , like TNF receptor or Fas receptor , and mediated by caspase-8 , which eventually activates caspase-3 Intrinsic pathway ( a.k.a. mitochondrial pathway ) : initiated by reactive oxidative species ( ROS ) , hypoxia , and so forth ; it requires the disruption of the mitochondrial membrane , which leads to the release of cytochrome c , known to be involved in the activation of caspase-9 , which further activates caspase-3 [ XREF_BIBR ] .	There are two main distinct signalling pathways leading to apoptosis : Extrinsic pathway : initiated by the activation of death receptors, like TNF receptor or Fas receptor, and mediated by caspase-8, which eventually activates caspase-3 Intrinsic pathway (a.k.a. mitochondrial pathway) : initiated by reactive oxidative species (ROS), hypoxia, and so forth; it requires the disruption of the mitochondrial membrane, which leads to the release of cytochrome c, known to be involved in the activation of caspase-9, which further activates caspase-3 [XREF_BIBR].	30	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	32	33	37	38
Active caspase-8 directly activates the effector caspase-3 and stimulates the mitochondrial ( intrinsic ) apoptosis pathway by cleaving the BH3 protein Bid .	Active caspase-8 directly activates the effector caspase-3 and stimulates the mitochondrial (intrinsic) apoptosis pathway by cleaving the BH3 protein Bid.	0	8	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	6	7
Cleaved caspase-8 activated caspase-3 and caspase-9 that correlated with the increased cleaved PARP expression after HTOFN treatments .	Cleaved caspase-8 activated caspase-3 and caspase-9 that correlated with the increased cleaved PARP expression after HTOFN treatments.	0	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	3	4
Direct activation of caspase-3 by caspase-8 seemed insufficient to RA FLS cell death .	Direct activation of caspase-3 by caspase-8 seemed insufficient to RA FLS cell death.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	3	4
Then , activated caspase-8 activates downstream caspase-3 , caspase-6 , and caspase-7 to initiate apoptosis [ XREF_BIBR ] .	Then, activated caspase-8 activates downstream caspase-3, caspase-6, and caspase-7 to initiate apoptosis [XREF_BIBR].	2	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	6	7
Our results show that caspase-8 is processed after T cell stimulation ( as early as 16 h after TCR cross linking ) , and activates caspase-3 , -6 , and -7 , leading to a selective cleavage of their substrates .	Our results show that caspase-8 is processed after T cell stimulation (as early as 16 h after TCR cross linking), and activates caspase-3, -6, and -7, leading to a selective cleavage of their substrates.	4	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	25	26
However , if the magnitude of caspase 8 and 10 activation is not sufficient to directly activate caspase 3 , TRAIL may still induce apoptosis through cleavage of the proapoptotic BH3-only protein Bid to generate truncated Bid ( tBID ) .	However, if the magnitude of caspase 8 and 10 activation is not sufficient to directly activate caspase 3, TRAIL may still induce apoptosis through cleavage of the proapoptotic BH3-only protein Bid to generate truncated Bid (tBID).	4	19	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	6	8	17	19
Caspase-8 , an initiator caspase that activates caspase-3 , was activated by exposure to UV-B at 50-200 mJ/cm ( 2 ) , and this UV activation was significantly reduced by 25-100mM K ( o ) ( + ) .	Caspase-8, an initiator caspase that activates caspase-3, was activated by exposure to UV-B at 50-200 mJ/cm (2), and this UV activation was significantly reduced by 25-100mM K (o) (+).	0	10	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	7	8
Caspase-3 can be alternatively activated through cleavage by caspase-8 , which is activated by death receptors such as Fas ( CD95 ) .	Caspase-3 can be alternatively activated through cleavage by caspase-8, which is activated by death receptors such as Fas (CD95).	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	8	9	0	1
Caspase 3 is activated by caspase 8 and activated caspase 3 can in turn activate other caspases like 6 and 7 , which eventually leads to cell death [ XREF_BIBR ] .	Caspase 3 is activated by caspase 8 and activated caspase 3 can in turn activate other caspases like 6 and 7, which eventually leads to cell death [XREF_BIBR].	0	14	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Caspase 3	Caspase 3	Caspase 3	5	7	0	2
Importantly , knockdown of BID , caspase 8 , DR4 , or FADD decreases BID cleavage , activation of caspase 3 and Annexin-V staining in this cell line ( XREF_FIG ) .	Importantly, knockdown of BID, caspase 8, DR4, or FADD decreases BID cleavage, activation of caspase 3 and Annexin-V staining in this cell line (XREF_FIG).	2	21	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	6	8	19	21
With current data , it can only be suggested that IP 6 induced caspase-3 activation may be mediated by activation of caspase-8 .	With current data, it can only be suggested that IP 6 induced caspase-3 activation may be mediated by activation of caspase-8.	13	22	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	21	22	13	14
Inhibition of caspase-8 drastically reduced the activation of caspase-3 and almost eliminated that of caspase-9 .	Inhibition of caspase-8 drastically reduced the activation of caspase-3 and almost eliminated that of caspase-9.	0	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	8	9
The resulting death inducing signaling complex activates caspase-8 , which subsequently activates caspase-3 .	The resulting death inducing signaling complex activates caspase-8, which subsequently activates caspase-3.	6	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	12	13
A caspase-8 specific inhibitor prevented the Bid cleavage , caspase-3 activation and cell death .	A caspase-8 specific inhibitor prevented the Bid cleavage, caspase-3 activation and cell death.	1	10	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	9	10
The initiator caspase-8 can directly activate pro-caspase-3 without any accelerator [ XREF_BIBR ] .	The initiator caspase-8 can directly activate pro-caspase-3 without any accelerator [XREF_BIBR].	0	7	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	pro-caspase-3	pro-caspase-3	pro-caspase-3	2	3	6	7
According to results of this study , administration of silymarin at all doses induces apoptosis in brain , kidneys and heart involving caspase-8 which then activates caspase-3 .	According to results of this study, administration of silymarin at all doses induces apoptosis in brain, kidneys and heart involving caspase-8 which then activates caspase-3.	14	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	22	23	26	27
Active caspase-8 can trigger direct activation of caspase-3 and cleavage of Bid , followed by mitochondria dependent activation of caspase-9 via cytochrome C release and apoptotic protease activating factor-1 ( Apaf-1 ) activation XREF_BIBR .	Active caspase-8 can trigger direct activation of caspase-3 and cleavage of Bid, followed by mitochondria dependent activation of caspase-9 via cytochrome C release and apoptotic protease activating factor-1 (Apaf-1) activation XREF_BIBR.	0	9	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	7	8
As shown in XREF_FIG , pretreatment of cells with the pan-caspase inhibitor Z-VAD-FMK and caspase-8 inhibitor Z-IETD-FMK significantly blocked caspase-3 cleavage by TPL , but caspase-9 inhibitor Z-LEHD-FMK had no significant effect , suggesting that caspase-3 activation is mainly mediated by caspase-8 .	As shown in XREF_FIG, pretreatment of cells with the pan-caspase inhibitor Z-VAD-FMK and caspase-8 inhibitor Z-IETD-FMK significantly blocked caspase-3 cleavage by TPL, but caspase-9 inhibitor Z-LEHD-FMK had no significant effect, suggesting that caspase-3 activation is mainly mediated by caspase-8.	35	42	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	41	42	35	36
Caspase 8 and 9 represent initiation factors in the extrinsic and intrinsic pathways , respectively , and induce the cleavage of caspase 3 and 7 , the executive factors in the apoptosis pathway .	Caspase 8 and 9 represent initiation factors in the extrinsic and intrinsic pathways, respectively, and induce the cleavage of caspase 3 and 7, the executive factors in the apoptosis pathway.	0	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	21	23
In so called type I cells , active caspase-8 initiates sufficient processing and concomitant activation of the downstream effector caspase-3 that ultimately leads to execution of apoptosis .	In so called type I cells, active caspase-8 initiates sufficient processing and concomitant activation of the downstream effector caspase-3 that ultimately leads to execution of apoptosis.	7	22	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	19	20
Apoptosis are activated through both MAPK pathway ( direct activation of caspase 3 ) or FADD mediated activation of caspase 8 , which in turn leads to the activation of effector caspase , such as caspase 3 [ XREF_BIBR ] .	Apoptosis are activated through both MAPK pathway (direct activation of caspase 3) or FADD mediated activation of caspase 8, which in turn leads to the activation of effector caspase, such as caspase 3 [XREF_BIBR].	9	25	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	caspase 8	FADD mediated activation of caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	19	21	11	13
Suppression of caspase-8 with the specific inhibitor z-IETD-fmk abrogates largely ANDRO/5-FU biological activity by preventing mitochondrial membrane potential disappearance , caspase-3 ,9 activation and subsequent apoptosis .	Suppression of caspase-8 with the specific inhibitor z-IETD-fmk abrogates largely ANDRO/5-FU biological activity by preventing mitochondrial membrane potential disappearance, caspase-3,9 activation and subsequent apoptosis.	0	22	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	20	21
These results suggest that MPT pore and caspase-9 mediate BFA-, TUN-, and H 2 O 2 -induced increases in caspase-3 activation , whereas ROS mediates only H 2 O 2 -induced increases , and caspase-8 mediates BFA- and TUN induced increases in caspase-3 activity .	These results suggest that MPT pore and caspase-9 mediate BFA-, TUN-, and H 2 O 2 -induced increases in caspase-3 activation, whereas ROS mediates only H 2 O 2 -induced increases, and caspase-8 mediates BFA- and TUN induced increases in caspase-3 activity.	34	43	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	34	35	42	43
One is the direct activation of caspase-3 by caspase 8 , and the other is the activation of caspase-9 , also a direct activator of caspase 3 , through the mitochondrial pathway .	One is the direct activation of caspase-3 by caspase 8, and the other is the activation of caspase-9, also a direct activator of caspase 3, through the mitochondrial pathway.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase-3	caspase-3	caspase-3	8	10	6	7
After activation , caspase-8 mediates proteolytic activation of effector caspase-3 and-7 and suffices for efficient apoptotic induction .	After activation, caspase-8 mediates proteolytic activation of effector caspase-3 and-7 and suffices for efficient apoptotic induction.	3	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	9	10
In the extrinsic apoptotic pathway , the activation of Caspase 3 by Caspase 8 cleaves a broad range of apoptosis related protein substrates and induces programmed cell death .	In the extrinsic apoptotic pathway, the activation of Caspase 3 by Caspase 8 cleaves a broad range of apoptosis related protein substrates and induces programmed cell death.	7	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	Caspase 3	Caspase 3	Caspase 3	12	14	9	11
Once activated , caspase-8 activates the downstream executioner caspase-3 by proteolytic cleavage of its zymogen form .	Once activated, caspase-8 activates the downstream executioner caspase-3 by proteolytic cleavage of its zymogen form.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	8	9
23 Although caspase 8 is able to directly activate executioner caspase 3 to initiate apoptosis , this process is greatly amplified through the mitochondrial route ( XREF_FIG ) .	23 Although caspase 8 is able to directly activate executioner caspase 3 to initiate apoptosis, this process is greatly amplified through the mitochondrial route (XREF_FIG).	2	12	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	2	4	10	12
The results suggested that SDT led to activation of caspase 8 , which in turn activated downstream caspase 3 .	The results suggested that SDT led to activation of caspase 8, which in turn activated downstream caspase 3.	7	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	9	11	17	19
Caspase-8 is one of the principal initiator of the extrinsic process and directly activates the effector caspase-3 [ XREF_BIBR ] .	Caspase-8 is one of the principal initiator of the extrinsic process and directly activates the effector caspase-3 [XREF_BIBR].	0	18	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	16	17
The pattern and rate of caspase-8 induced activation of pro-caspase-3 in cytosolic extracts was the same as in a purified system .	The pattern and rate of caspase-8 induced activation of pro-caspase-3 in cytosolic extracts was the same as in a purified system.	1	12	induced	Positive_early_activation	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	pro-caspase-3	pro-caspase-3	pro-caspase-3	5	6	9	10
It is possible that caspase-8 induces caspase-3 and caspase-7 to targed gasdermin-E ( also known as DFNA5 ) to induce pore formation and cell death independent of gasdermin-D [ XREF_BIBR , XREF_BIBR ] .	It is possible that caspase-8 induces caspase-3 and caspase-7 to targed gasdermin-E (also known as DFNA5) to induce pore formation and cell death independent of gasdermin-D [XREF_BIBR, XREF_BIBR].	4	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	6	7
Caspase-8 activates two apoptotic pathways , and the results of the current study confirm that laminarin increases caspase-8 activity and induces LoVo cell apoptosis via the DR pathway ; caspase-8 activates caspase-3 , -6 and -7 , thus inducing apoptosis .	Caspase-8 activates two apoptotic pathways, and the results of the current study confirm that laminarin increases caspase-8 activity and induces LoVo cell apoptosis via the DR pathway; caspase-8 activates caspase-3, -6 and -7, thus inducing apoptosis.	29	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	29	30	31	32
Caspase 8 , an initiator caspase , is activated by the CD95 and TNFR1 pathway and subsequently activates the effector caspase 3 [ XREF_BIBR ] , inducing irreversible apoptosis in the cells .	Caspase 8, an initiator caspase, is activated by the CD95 and TNFR1 pathway and subsequently activates the effector caspase 3 [XREF_BIBR], inducing irreversible apoptosis in the cells.	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	20	22
This was associated with the activation of apoptotic enzyme caspase 3 and mediated by caspase 8 , but not caspase 9 at various concentrations of AZ4 after being cultured for 48 h and 30 h , respectively .	This was associated with the activation of apoptotic enzyme caspase 3 and mediated by caspase 8, but not caspase 9 at various concentrations of AZ4 after being cultured for 48 h and 30 h, respectively.	5	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	14	16	9	11
The activated caspase-8 mediates caspase-3 activation and promotes cell death XREF_BIBR .	The activated caspase-8 mediates caspase-3 activation and promotes cell death XREF_BIBR.	0	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	4	5
Fas-FasL signaling can induce cell apoptosis by activating caspase-8 , which further activates caspase-3 XREF_BIBR .	Fas-FasL signaling can induce cell apoptosis by activating caspase-8, which further activates caspase-3 XREF_BIBR.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	13	14
Caspase-3 plays a central role as the key executioner during many forms of apoptotic cell death , and accordingly caspase 8 activation of caspase-3 is a central feature in the apoptotic signaling pathway stimulated by CD95 [ XREF_BIBR ; XREF_BIBR ] .	Caspase-3 plays a central role as the key executioner during many forms of apoptotic cell death, and accordingly caspase 8 activation of caspase-3 is a central feature in the apoptotic signaling pathway stimulated by CD95 [XREF_BIBR; XREF_BIBR].	19	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase-3	caspase-3	caspase-3	19	21	23	24
Caspase-3 is a downstream executioner of the cascade and can be activated by the activation of caspase-8 , 9 and 12 .	Caspase-3 is a downstream executioner of the cascade and can be activated by the activation of caspase-8, 9 and 12.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	16	17	0	1
In the first pathway , caspase-8 directly activates caspase-3 , -6 and -7 , which induces apoptosis via the DR pathway .	In the first pathway, caspase-8 directly activates caspase-3, -6 and -7, which induces apoptosis via the DR pathway.	5	15	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	8	9
Then , active caspase-8 can either stimulate caspase-3 directly resulting in an immediate apoptosis which is usually regulated by an abundance of inhibitors for apoptosis ; or , it could sometimes require a more complicated but efficient mechanism , which involves the cross-talk between the extrinsic and the intrinsic pathways [ XREF_BIBR - XREF_BIBR ] .	Then, active caspase-8 can either stimulate caspase-3 directly resulting in an immediate apoptosis which is usually regulated by an abundance of inhibitors for apoptosis; or, it could sometimes require a more complicated but efficient mechanism, which involves the cross-talk between the extrinsic and the intrinsic pathways [XREF_BIBR - XREF_BIBR].	2	51	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	7	8
Apoptosis by TNFalpha is mediated by FADD and caspase 8 which in turn activates caspase-3 and/or Bid and the mitochondrial apoptotic pathway XREF_BIBR .	Apoptosis by TNFalpha is mediated by FADD and caspase 8 which in turn activates caspase-3 and/or Bid and the mitochondrial apoptotic pathway XREF_BIBR.	4	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase-3	caspase-3	caspase-3	8	10	14	15
The extrinsic pathway of apoptosis involves a subset of TNF receptors ( TNFR ) including DR3 , Fas , TNF-R1 , TRAIL-R1 , and TRAIL-R2 that function as death receptors and , upon ligand engagement , results in activation of the initiator caspase , caspase 8 , which in turn activates caspase 3 directly or indirectly through BH3 interacting domain death agonist ( Bid ) truncation ( tBid ) , release of cytochrome c , and subsequent activation of caspase 9 through interaction with apoptotic protease activating factor 1 ( APAF1 ) .	The extrinsic pathway of apoptosis involves a subset of TNF receptors (TNFR) including DR3, Fas, TNF-R1, TRAIL-R1, and TRAIL-R2 that function as death receptors and, upon ligand engagement, results in activation of the initiator caspase, caspase 8, which in turn activates caspase 3 directly or indirectly through BH3 interacting domain death agonist (Bid) truncation (tBid), release of cytochrome c, and subsequent activation of caspase 9 through interaction with apoptotic protease activating factor 1 (APAF1).	5	65	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	44	46	51	53
This indicated that Caspase-8 induced by Fas cell surface death receptor or tumor necrosis factor during apoptosis , directly or indirectly activated the downstream effector molecules Caspase-3 , and that the activated Caspase-3 , in turn , cleaved PARP which reactivated the endonuclease , resulting in DNA fragmentation and the promotion of apoptosis of tumor cells .	This indicated that Caspase-8 induced by Fas cell surface death receptor or tumor necrosis factor during apoptosis, directly or indirectly activated the downstream effector molecules Caspase-3, and that the activated Caspase-3, in turn, cleaved PARP which reactivated the endonuclease, resulting in DNA fragmentation and the promotion of apoptosis of tumor cells.	3	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Caspase-3	Caspase-3	Caspase-3	3	4	26	27
The caspase 8/caspase 3 pathway requires functional FADD for activation of caspase 8 activation , which then directly activates effector caspase 3 or the mitochondrial and caspase 9 pathway through cleavage of t-BID .	The caspase 8/caspase 3 pathway requires functional FADD for activation of caspase 8 activation, which then directly activates effector caspase 3 or the mitochondrial and caspase 9 pathway through cleavage of t-BID.	11	22	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	11	13	20	22
Caspase-3 can either be activated directly by caspase-8 ( upon caspase-8 activation through death receptors ) or by a signalling complex referred to as ' apoptosome ' , consisting of cytochrome c , Apaf-1 , caspase-9 ( Li et al , 1997 ) and , at least sometimes , the X linked inhibitor of apoptosis protein ( XIAP ; Bratton et al , 2001 ) .	Caspase-3 can either be activated directly by caspase-8 (upon caspase-8 activation through death receptors) or by a signalling complex referred to as ' apoptosome ', consisting of cytochrome c, Apaf-1, caspase-9 (Li et al, 1997) and, at least sometimes, the X linked inhibitor of apoptosis protein (XIAP; Bratton et al, 2001).	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	7	8	0	1
Proteolytically activated caspase-8 mediates caspase-3 activation and promotes cell death .	Proteolytically activated caspase-8 mediates caspase-3 activation and promotes cell death.	1	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	4	5
Caspase 8 also activates caspase 3 and converges at this point with the intrinsic apoptotic pathway .	Caspase 8 also activates caspase 3 and converges at this point with the intrinsic apoptotic pathway.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	4	6
In type I cells , which are generally lymphoid in origin , caspase-3 is directly activated by caspase-8 , which then cleaves prosurvival substrates ( XREF_FIG ) .	In type I cells, which are generally lymphoid in origin, caspase-3 is directly activated by caspase-8, which then cleaves prosurvival substrates (XREF_FIG).	12	21	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	17	18	12	13
In response to extracellular stimuli , caspase-8 directly activates caspase-3 through the mitochondrial apoptotic pathway .	In response to extracellular stimuli, caspase-8 directly activates caspase-3 through the mitochondrial apoptotic pathway.	6	10	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	9	10
Activation of caspase-8 and/or -10 can trigger subsequent activation of downstream caspase-3 that ultimately leads to cell death via the extrinsic pathway XREF_BIBR .	Activation of caspase-8 and/or -10 can trigger subsequent activation of downstream caspase-3 that ultimately leads to cell death via the extrinsic pathway XREF_BIBR.	0	12	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	11	12
The activation of caspase-8 directly activates caspase-3 or induces mitochondria mediated caspase-3 activation , which results in apoptosis .	The activation of caspase-8 directly activates caspase-3 or induces mitochondria mediated caspase-3 activation, which results in apoptosis.	1	7	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	6	7
Caspase-3 can either be activated directly by caspase-8 ( Type I pathway ) or through activation of the intrinsic pathway depending on mitochondrial dysfunction , and referred to as the Type II death receptor pathway of apoptosis XREF_BIBR .	Caspase-3 can either be activated directly by caspase-8 (Type I pathway) or through activation of the intrinsic pathway depending on mitochondrial dysfunction, and referred to as the Type II death receptor pathway of apoptosis XREF_BIBR.	0	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	7	8	0	1
The subsequent signaling cascade results in caspase-8 activation which also activates caspase-3 .	The subsequent signaling cascade results in caspase-8 activation which also activates caspase-3.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	6	7	11	12
In the wake of activation of caspase-3 by caspase-8 , apoptosis occurred in TRAIL treated tumor cells .	In the wake of activation of caspase-3 by caspase-8, apoptosis occurred in TRAIL treated tumor cells.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	8	9	6	7
The signal in the external mechanism ( receptor dependent pathway ) starts from death receptors , such as Fas or tumor necrosis factor-alpha ( TNF-alpha ) receptors , and is passed to caspase-8 which activates caspase-3 , the caspase that directly triggers apoptosis [ XREF_BIBR ] .	The signal in the external mechanism (receptor dependent pathway) starts from death receptors, such as Fas or tumor necrosis factor-alpha (TNF-alpha) receptors, and is passed to caspase-8 which activates caspase-3, the caspase that directly triggers apoptosis [XREF_BIBR].	30	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	32	33	35	36
We found that MH ( 32degreesC ) and Ac-DEVD-CHO ( 5.96 muMol/L ) had equal effects on blocking the activation of caspase-3 and the OGD induced cleavage of PARP , but neither had any effect on the activation of caspase-8 , which goes on to activate caspase-3 in the apoptotic pathway .	We found that MH (32degreesC) and Ac-DEVD-CHO (5.96 muMol/L) had equal effects on blocking the activation of caspase-3 and the OGD induced cleavage of PARP, but neither had any effect on the activation of caspase-8, which goes on to activate caspase-3 in the apoptotic pathway.	37	47	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	39	40	46	47
This agrees with the fact that initiator caspase-8 was activated first , which subsequently activates the effector caspase-3 .	This agrees with the fact that initiator caspase-8 was activated first, which subsequently activates the effector caspase-3.	6	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	17	18
Caspase-8 and -10 recruited to death receptors autoactivate themselves and activate further effector caspases ( caspase-3 and -7 ) either by direct processing or by engaging the intrinsic death pathway [ XREF_BIBR ] .	Caspase-8 and -10 recruited to death receptors autoactivate themselves and activate further effector caspases (caspase-3 and -7) either by direct processing or by engaging the intrinsic death pathway [XREF_BIBR].	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	15	16
In Type I cells , Fas mediated activation of Casp8 is sufficient to activate the executioner Casp3 ; however , in Type II cells , Fas mediated apoptosis requires Casp8 dependent activation of the BH3-only protein Bid and subsequent engagement of Bax and Bak [ XREF_BIBR ] ( XREF_FIG ) .	In Type I cells, Fas mediated activation of Casp8 is sufficient to activate the executioner Casp3; however, in Type II cells, Fas mediated apoptosis requires Casp8 dependent activation of the BH3-only protein Bid and subsequent engagement of Bax and Bak [XREF_BIBR] (XREF_FIG).	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp8	Fas mediated activation of Casp8	casp8	Casp3	Casp3	casp3	9	10	16	17
Additionally , active caspase-8 can also activate caspase-3 resulting in apoptosis XREF_BIBR .	Additionally, active caspase-8 can also activate caspase-3 resulting in apoptosis XREF_BIBR.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	7	8
At that point , adaptor proteins , such as Fas associated death domain protein ( FADD ) , make caspase-8 and caspase-10 dimerize , which in turn activate the effector caspase-3 and caspase-7 , leading to apoptosis [ XREF_BIBR ] .	At that point, adaptor proteins, such as Fas associated death domain protein (FADD), make caspase-8 and caspase-10 dimerize, which in turn activate the effector caspase-3 and caspase-7, leading to apoptosis [XREF_BIBR].	19	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	19	20	30	31
From activation of these receptors until the final endpoint of apoptosis : caspase-8 is firstly activated , followed by the activation of caspase-3 by caspase-8 .	From activation of these receptors until the final endpoint of apoptosis : caspase-8 is firstly activated, followed by the activation of caspase-3 by caspase-8.	20	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	24	25	22	23
Utilization of a novel ex vivo brain slice culture ( BSC ) model of WNV encephalitis revealed that inhibition of caspase 8 decreases virus induced activation of caspase 3 and tissue injury .	Utilization of a novel ex vivo brain slice culture (BSC) model of WNV encephalitis revealed that inhibition of caspase 8 decreases virus induced activation of caspase 3 and tissue injury.	18	31	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	20	22	27	29
Extrinsic pathway involves interaction of ligands ( Fas and TNF-alpha ) to their transmembrane receptors [ XREF_BIBR ] , thus activating caspase-8 , which further activates caspase-3 directly [ XREF_BIBR ] or by first activating intrinsic pathway followed by activation of caspase-3 [ XREF_BIBR ] .	Extrinsic pathway involves interaction of ligands (Fas and TNF-alpha) to their transmembrane receptors [XREF_BIBR], thus activating caspase-8, which further activates caspase-3 directly [XREF_BIBR] or by first activating intrinsic pathway followed by activation of caspase-3 [XREF_BIBR].	20	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	21	22	26	27
Caspase-8 activation initiates the caspase-3 cascade and also mediates the BAP31 dependent activation of BAX and BAK proteins leading to ER-stress and ecto-CRT expression [ XREF_BIBR ] .	Caspase-8 activation initiates the caspase-3 cascade and also mediates the BAP31 dependent activation of BAX and BAK proteins leading to ER-stress and ecto-CRT expression [XREF_BIBR].	0	5	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	4	5
Stronger caspase-8 activation in PBMO caused more activation of effector caspase-3 and apoptosis ( all p < 0.05 vs. PBMO ) .	Stronger caspase-8 activation in PBMO caused more activation of effector caspase-3 and apoptosis (all p < 0.05 vs. PBMO).	1	16	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	10	11
Active caspase 8 then activates downstream caspases ( Caspase 3 , 5 , and 7 ) , committing the cell to apoptosis [ XREF_BIBR ] .	Active caspase 8 then activates downstream caspases (Caspase 3, 5, and 7), committing the cell to apoptosis [XREF_BIBR].	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Caspase 3	Caspase 3	Caspase 3	1	3	8	10
During apoptosis caspases participate in cascades whereby the upstream ( initiator ) caspases ; caspase-8 , -9 activate the downstream ( executioner ) caspases ; caspase-3 , -7 which cleave a specific group of cellular targets .	During apoptosis caspases participate in cascades whereby the upstream (initiator) caspases; caspase-8, -9 activate the downstream (executioner) caspases; caspase-3, -7 which cleave a specific group of cellular targets.	14	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	14	15	25	26
The active form of caspase-8 not only proteolytically stimulates the executioner caspase-3 , but can also cleave and activate the BH3-only protein , BID ( BH3 interacting-domain death agonist ) , thus causing MOMP and triggering the intrinsic pathway of apoptosis [ XREF_BIBR , XREF_BIBR ] .	The active form of caspase-8 not only proteolytically stimulates the executioner caspase-3, but can also cleave and activate the BH3-only protein, BID (BH3 interacting-domain death agonist), thus causing MOMP and triggering the intrinsic pathway of apoptosis [XREF_BIBR, XREF_BIBR].	2	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	11	12
It is well-known that caspase-3 , a key protease in the apoptotic machinery , is activated by cleavage into two smaller subunits by caspase-8 and/or caspase-9 when the cells undergo apoptosis after synthesis as procaspase-3 XREF_BIBR , XREF_BIBR .	It is well-known that caspase-3, a key protease in the apoptotic machinery, is activated by cleavage into two smaller subunits by caspase-8 and/or caspase-9 when the cells undergo apoptosis after synthesis as procaspase-3 XREF_BIBR, XREF_BIBR.	4	24	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	23	24	4	5
Transmission of the apoptotic signal following Fas ligation may follow either a direct caspase-8 activation of caspase-3 pathway or an indirect pathway with a mitochondrial intermediate step .	Transmission of the apoptotic signal following Fas ligation may follow either a direct caspase-8 activation of caspase-3 pathway or an indirect pathway with a mitochondrial intermediate step.	13	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	13	14	16	17
Both caspase 8 , from the extrinsic pathway , and caspase 9 , from the intrinsic pathway , have been observed to activate the main effector caspase 3 , which in turn activates a caspase cascade to eventually evoke the morphological hallmarks of apoptosis such as DNA fragmentation [ XREF_BIBR , XREF_BIBR ] .	Both caspase 8, from the extrinsic pathway, and caspase 9, from the intrinsic pathway, have been observed to activate the main effector caspase 3, which in turn activates a caspase cascade to eventually evoke the morphological hallmarks of apoptosis such as DNA fragmentation [XREF_BIBR, XREF_BIBR].	0	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	1	3	26	28
Type-I cells , depends mainly on extrinsic apoptotic pathway as activation of DISC in these cells is stable enough to trigger robust activation of caspase-8 , which further activates its downstream effector caspase-3 , resulting in cell death .	Type-I cells, depends mainly on extrinsic apoptotic pathway as activation of DISC in these cells is stable enough to trigger robust activation of caspase-8, which further activates its downstream effector caspase-3, resulting in cell death.	22	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	24	25	32	33
It seems unlikely that caspase-8 activates caspase-3 via other caspases .	It seems unlikely that caspase-8 activates caspase-3 via other caspases.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	6	7
We further evaluated caspase-8 and caspase-3 enzymatic activity when cells were treated with two distinct caspase-8 activators , staurosporine ( STS ) and tumor necrosis factor ( TNF ) .	We further evaluated caspase-8 and caspase-3 enzymatic activity when cells were treated with two distinct caspase-8 activators, staurosporine (STS) and tumor necrosis factor (TNF).	3	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	15	16	5	6
Activation of caspase 3 by caspase 8 can occur by 2 pathways [ XREF_BIBR ] .	Activation of caspase 3 by caspase 8 can occur by 2 pathways [XREF_BIBR].	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	5	7	2	4
3 Activation of caspase-8 and -10 leads to proteolytic stimulation of the downstream effectors caspase-3 , -6 , and -7 , which can cleave intracellular substrates , such as lamin A , poly-( ADP-ribose ) polymerase ( PARP ) , and MEKK1 .	3 Activation of caspase-8 and -10 leads to proteolytic stimulation of the downstream effectors caspase-3, -6, and -7, which can cleave intracellular substrates, such as lamin A, poly-(ADP-ribose) polymerase (PARP), and MEKK1.	1	41	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	14	15
In this way , a more accurate analysis with regards to the apoptotic mechanism can be considered , as one of the main apoptosis pathways used by TNF-alpha antagonists is dependent on caspase 3 , which in turn is strongly influenced by FLIP ( expressed by NF-kappaB ) , the suppressor of caspase 8 ( activator of caspase 3 ) .	In this way, a more accurate analysis with regards to the apoptotic mechanism can be considered, as one of the main apoptosis pathways used by TNF-alpha antagonists is dependent on caspase 3, which in turn is strongly influenced by FLIP (expressed by NF-kappaB), the suppressor of caspase 8 (activator of caspase 3).	50	59	activator	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	52	54	57	59
Depending on the cell type , TNFalpha has been reported to trigger apoptosis through either a mitochondrial dependent pathway or a mitochondrial independent pathway involving direct activation of caspase-3 by caspase-8 .	Depending on the cell type, TNFalpha has been reported to trigger apoptosis through either a mitochondrial dependent pathway or a mitochondrial independent pathway involving direct activation of caspase-3 by caspase-8.	24	31	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	30	31	28	29
Caspase-8 and -9 are both able to activate the effector caspase-3 , -6 and -7 .	Caspase-8 and -9 are both able to activate the effector caspase-3, -6 and -7.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	10	11
Moreover , specific inhibition of caspase-8 by siRNA technology effectively reduced caspase-9 processing , poly ( ADP-ribose ) polymerase ( PARP ) cleavage , caspase-3 activation , and apoptosis in co-treated cells , which indicated that the caspase-8 feedback amplification pathway may have been involved in the apoptosis process .	Moreover, specific inhibition of caspase-8 by siRNA technology effectively reduced caspase-9 processing, poly (ADP-ribose) polymerase (PARP) cleavage, caspase-3 activation, and apoptosis in co-treated cells, which indicated that the caspase-8 feedback amplification pathway may have been involved in the apoptosis process.	3	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	5	6	24	25
After autocatalytic activation of procaspase-8 at the DISC , active initiator caspase-8 can either directly or indirectly ( via the mitochondrial pathway ) activate downstream effector caspases ( caspase-3 , -6 and -7 ) , leading to the cleavage of cellular proteins and subsequent apoptosis [ XREF_BIBR ] .	After autocatalytic activation of procaspase-8 at the DISC, active initiator caspase-8 can either directly or indirectly (via the mitochondrial pathway) activate downstream effector caspases (caspase-3, -6 and -7), leading to the cleavage of cellular proteins and subsequent apoptosis [XREF_BIBR].	9	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	11	12	28	29
Caspase 8 can result in caspase 3 activation .	Caspase 8 can result in caspase 3 activation.	0	8	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	5	7
While assembly of the pro CASP8 activation complex occurs independently of mitochondrial events ( as we have observed it in bax -/- bak1 -/- MEFs ) CASP8 mediated activation of pro CASP3 would allow CASP3 feedback onto the mitochondria leading to further loss of mitochondrial integrity as has been described previously .	While assembly of the pro CASP8 activation complex occurs independently of mitochondrial events (as we have observed it in bax -/- bak1 -/- MEFs) CASP8 mediated activation of pro CASP3 would allow CASP3 feedback onto the mitochondria leading to further loss of mitochondrial integrity as has been described previously.	26	35	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	CASP3	CASP3	CASP3	26	27	34	35
Caspase-3 can be activated directly by caspase-8 through the death receptor pathway or by cleavage of the proapoptotic Bcl-2 family member protein BID .	Caspase-3 can be activated directly by caspase-8 through the death receptor pathway or by cleavage of the proapoptotic Bcl-2 family member protein BID.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	6	7	0	1
These results indicate that in HeLa cervical cancer cells , apoptosis signaling through Fas and CD95 and TRAIL occurs almost exclusively in a Bid dependent manner , with the direct activation of caspase 3 by caspase-8 insufficient to compensate for a loss of Bid expression and to induce cell death .	These results indicate that in HeLa cervical cancer cells, apoptosis signaling through Fas and CD95 and TRAIL occurs almost exclusively in a Bid dependent manner, with the direct activation of caspase 3 by caspase-8 insufficient to compensate for a loss of Bid expression and to induce cell death.	18	36	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase 3	caspase 3	caspase 3	35	36	32	34
Lack of functional Fas receptors and selective pharmacological inhibition of caspase-8 prevents activation of caspase-3 and provides significant neuroprotection .	Lack of functional Fas receptors and selective pharmacological inhibition of caspase-8 prevents activation of caspase-3 and provides significant neuroprotection.	8	15	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	10	11	14	15
DISC formation results in the activation of caspase-8 , which then directly cleaves and activates caspase-3 , -6 , or -7 , the executioner enzymes of apoptosis .	DISC formation results in the activation of caspase-8, which then directly cleaves and activates caspase-3, -6, or -7, the executioner enzymes of apoptosis.	5	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	7	8	15	16
The activated caspase-8 can trigger the activation of caspase-3 and initiate apoptosis .	The activated caspase-8 can trigger the activation of caspase-3 and initiate apoptosis.	0	10	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	8	9
The formation of DISC is followed by the activation of caspase 8 , which sequentially activates caspase 3 to initiate apoptosis [ XREF_BIBR ] .	The formation of DISC is followed by the activation of caspase 8, which sequentially activates caspase 3 to initiate apoptosis [XREF_BIBR].	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	10	12	16	18
Importantly , we found that whereas knockdown of BID , caspase 8 , or FADD impairs activation of caspase 3 following UVC treatment , the effects of DR4 knockdown are negligible .	Importantly, we found that whereas knockdown of BID, caspase 8, or FADD impairs activation of caspase 3 following UVC treatment, the effects of DR4 knockdown are negligible.	6	22	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	10	12	18	20
TRAIL could trigger the extrinsic pathway , and the activation of caspase 8 induces downstream executioner caspase , caspase 3 and caspase 7 and PARP cleavage , and finally leading to apoptosis .	TRAIL could trigger the extrinsic pathway, and the activation of caspase 8 induces downstream executioner caspase, caspase 3 and caspase 7 and PARP cleavage, and finally leading to apoptosis.	9	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	11	13	18	20
In type I cells , the activation of a surface death receptor of tumor necrosis factor receptor superfamily ( TNFRSF ) by its cognate death ligand ( TNFSF ) initiates apoptosis , then a death signal is created and cleaves pro-caspase-8 in active caspase-8 , which activates caspase-3 .	In type I cells, the activation of a surface death receptor of tumor necrosis factor receptor superfamily (TNFRSF) by its cognate death ligand (TNFSF) initiates apoptosis, then a death signal is created and cleaves pro-caspase-8 in active caspase-8, which activates caspase-3.	39	48	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	43	44	47	48
The resulting Fas and FADD complex cleaves pro caspase 8 , which in turn activates caspase 3 .	The resulting Fas and FADD complex cleaves pro caspase 8, which in turn activates caspase 3.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	8	10	15	17
Caspase-8 , which is activated by the induction of tumor necrosis factor-alpha , leads to activation of caspase-3 , which activates apoptotic nucleases .	Caspase-8, which is activated by the induction of tumor necrosis factor-alpha, leads to activation of caspase-3, which activates apoptotic nucleases.	0	20	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	17	18
A signaling amplification loop is activated when caspase-8 levels are insufficient to activate caspase-3 .	A signaling amplification loop is activated when caspase-8 levels are insufficient to activate caspase-3.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8 levels	caspase-8	caspase-3	caspase-3	caspase-3	7	8	13	14
Caspase 3 dependent signaling involved in cardiac differentiation could also be initiated by the activation of the caspase 8 pathway .	Caspase 3 dependent signaling involved in cardiac differentiation could also be initiated by the activation of the caspase 8 pathway.	0	19	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Caspase 3	Caspase 3	Caspase 3	17	19	0	2
Active caspase-8 , in turn , cleaves and activates the effector caspase-3 [ XREF_BIBR ] .	Active caspase-8, in turn, cleaves and activates the effector caspase-3 [XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	1	2	11	12
The nonselective caspase inhibitor ( B-D-FMK ) and the caspase 3 ( Z-DEVD-FMK ) and caspase 8 ( Z-IETD-FMK ) inhibitors reduced ceramide induced cardiomyocyte death and significantly inhibited the activation of caspase 3 .	The nonselective caspase inhibitor (B-D-FMK) and the caspase 3 (Z-DEVD-FMK) and caspase 8 (Z-IETD-FMK) inhibitors reduced ceramide induced cardiomyocyte death and significantly inhibited the activation of caspase 3.	3	34	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	15	17	32	34
When XIAP levels are sufficiently high , cell death may be blocked ; conversely , a low XIAP : caspase-3 ratio promotes cell death , diverting cells from Type II , mitochondrial outer membrane permeabilization ( MOMP )-dependent death , to a Type I pathway in which caspase-3 is directly activated by caspase-8 , leading to cell death even in the absence of MOMP ( see Box 2 ) XREF_BIBR - XREF_BIBR .	When XIAP levels are sufficiently high, cell death may be blocked; conversely, a low XIAP : caspase-3 ratio promotes cell death, diverting cells from Type II, mitochondrial outer membrane permeabilization (MOMP)-dependent death, to a Type I pathway in which caspase-3 is directly activated by caspase-8, leading to cell death even in the absence of MOMP (see Box 2) XREF_BIBR - XREF_BIBR.	47	53	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	52	53	47	48
However , if the magnitude of caspase 8 and 10 activation is not sufficient to directly activate caspase 3 , TRAIL may still induce apoptosis by a pathway involving mitochondrial dysfunction , type II death receptor signaling .	However, if the magnitude of caspase 8 and 10 activation is not sufficient to directly activate caspase 3, TRAIL may still induce apoptosis by a pathway involving mitochondrial dysfunction, type II death receptor signaling.	4	19	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	6	8	17	19
Caspase 8 can then either directly activate caspase-3 or precipitate the intrinsic pathway by releasing cytochrome c from the mitochondrion into the cytosol [ XREF_BIBR ] .	Caspase 8 can then either directly activate caspase-3 or precipitate the intrinsic pathway by releasing cytochrome c from the mitochondrion into the cytosol [XREF_BIBR].	0	9	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase-3	caspase-3	caspase-3	0	2	7	8
Cortisol ( an active GC ) reduced the mRNA expression of caspase 8 ( CASP8 ) and caspase 3 ( CASP3 ) and reduced the enzymatic activity of CASP3 and cell death induced by tumor necrosis factor ( TNF ) and interferon gamma ( IFNG ) in cultured bovine luteal cells .	Cortisol (an active GC) reduced the mRNA expression of caspase 8 (CASP8) and caspase 3 (CASP3) and reduced the enzymatic activity of CASP3 and cell death induced by tumor necrosis factor (TNF) and interferon gamma (IFNG) in cultured bovine luteal cells.	0	31	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase 8	Cortisol (an active GC) reduced the mRNA expression of caspase 8	caspase 8	CASP3	CASP3	casp3	11	13	28	29
In the extracellular pathway , binding of ligands to a death receptor leads to the activation of caspase-8 , which can directly activate caspase-3 .	In the extracellular pathway, binding of ligands to a death receptor leads to the activation of caspase-8, which can directly activate caspase-3.	15	24	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	17	18	23	24
XREF_BIBR , XREF_BIBR High amounts of XIAP prevent indeed the direct activation of CASP3 by CASP8 , a block that can be circumvented by the release of diablo , IAP binding mitochondrial protein ( DIABLO , best known as second mitochondria derived activator of caspases , SMAC ) and other XIAP inhibitors into the cytosol following MOMP .	XREF_BIBR, XREF_BIBR High amounts of XIAP prevent indeed the direct activation of CASP3 by CASP8, a block that can be circumvented by the release of diablo, IAP binding mitochondrial protein (DIABLO, best known as second mitochondria derived activator of caspases, SMAC) and other XIAP inhibitors into the cytosol following MOMP.	11	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	CASP3	CASP3	CASP3	15	16	13	14
Caspase-8 and -9 activation cascades mediated the activation of caspase-3 .	Caspase-8 and -9 activation cascades mediated the activation of caspase-3.	0	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-3	caspase-3	caspase-3	0	1	9	10
Caspase-3 which can be activated by caspase-8 is a key executioner of cell apoptosis and is one of the enzymes known for the activation of different proteins that lead to programmed cell death [ XREF_BIBR ] .	Caspase-3 which can be activated by caspase-8 is a key executioner of cell apoptosis and is one of the enzymes known for the activation of different proteins that lead to programmed cell death [XREF_BIBR].	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-3	Caspase-3	Caspase-3	6	7	0	1
Caspase 8 activation ultimately drives the activation of caspase 3 and/or caspase 7 , either directly , or indirectly by initiating a mitochondrial amplification pathway via the pro apoptotic BCL-2 family member BID 13 .	Caspase 8 activation ultimately drives the activation of caspase 3 and/or caspase 7, either directly, or indirectly by initiating a mitochondrial amplification pathway via the pro apoptotic BCL-2 family member BID 13.	0	11	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 3	caspase 3	caspase 3	0	2	8	10
Inhibitor of caspase-8 significantly inhibited the activation of caspase-2 , caspase-3 and caspase-8 .	Inhibitor of caspase-8 significantly inhibited the activation of caspase-2, caspase-3 and caspase-8.	0	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	10	11
Once activated , caspase-8 causes the cleavage and activation of caspase-3 , caspase-6 , and caspase-7 , resulting in apoptosis .	Once activated, caspase-8 causes the cleavage and activation of caspase-3, caspase-6, and caspase-7, resulting in apoptosis.	3	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	3	4	10	11
Also notable was that BID activation down-stream of autolysosomes appeared to be playing a greater role in cell killing than caspase 8 signaling , suggesting cathepsin and calpain proteases rather than caspase 8 were causing BID cleavage .	Also notable was that BID activation down-stream of autolysosomes appeared to be playing a greater role in cell killing than caspase 8 signaling, suggesting cathepsin and calpain proteases rather than caspase 8 were causing BID cleavage.	12	36	causing	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	BID	BID	BID	31	33	35	36
As activation of caspase-8 can cause cleavage of Bid into tBid , which in turn translocates to the mitochondria to initiate mitochondrial perturbations , 8 we next examined whether Bid may link the extrinsic and intrinsic pathways in this model of apoptosis .	As activation of caspase-8 can cause cleavage of Bid into tBid, which in turn translocates to the mitochondria to initiate mitochondrial perturbations, 8 we next examined whether Bid may link the extrinsic and intrinsic pathways in this model of apoptosis.	1	9	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	3	4	8	9
44 Caspase-8 enhanced BID cleavage which translocates to the mitochondria and activate mitochondrial death pathway .	44 Caspase-8 enhanced BID cleavage which translocates to the mitochondria and activate mitochondrial death pathway.	0	4	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	BID	BID	BID	1	2	3	4
Furthermore , the caspase-8 activity needed to cleave procaspase-3 during TRAIL induced apoptosis is upstream of both the BID- and PUS10 mediated pathways .	Furthermore, the caspase-8 activity needed to cleave procaspase-3 during TRAIL induced apoptosis is upstream of both the BID- and PUS10 mediated pathways.	3	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID-	BID-	BID-	3	4	18	19
Alternatively , death receptor induced apoptosis , including Fas and TRAIL , may lead to the activation of Bid through caspase 8 mediated cleavage of Bid .	Alternatively, death receptor induced apoptosis, including Fas and TRAIL, may lead to the activation of Bid through caspase 8 mediated cleavage of Bid.	13	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	20	22	25	26
Caspase-8 mediates cleavage of Bid to tBid and the translocation of tBid to mitochondria provides a link between extrinsic and intrinsic pathways of apoptosis XREF_BIBR .	Caspase-8 mediates cleavage of Bid to tBid and the translocation of tBid to mitochondria provides a link between extrinsic and intrinsic pathways of apoptosis XREF_BIBR.	0	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	4	5
In addition , caspase-8 mediates the intrinsic pathway via cleavage of the proapoptotic Bid protein , a BH3-only protein , to a truncated Bid ( tBid ) through translocation from the cytosol to the mitochondria , triggering mitochondrial dysfunction , followed by activation of caspase-9 XREF_BIBR .	In addition, caspase-8 mediates the intrinsic pathway via cleavage of the proapoptotic Bid protein, a BH3-only protein, to a truncated Bid (tBid) through translocation from the cytosol to the mitochondria, triggering mitochondrial dysfunction, followed by activation of caspase-9 XREF_BIBR.	3	28	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	3	4	23	24
Caspase 8 ( but not caspase 9 ) antagonism partly but significantly affected receptor mediated Bid activation and cell death ; these processes were not altered by either caspase inhibitor during simple factor withdrawal or glucocorticoid treatment .	Caspase 8 (but not caspase 9) antagonism partly but significantly affected receptor mediated Bid activation and cell death; these processes were not altered by either caspase inhibitor during simple factor withdrawal or glucocorticoid treatment.	0	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	Bid	Bid	Bid	0	2	15	16
These results suggest that release of the lysosomal content in the cytoplasm and the direct or caspase 8 mediated Bid processing may be the main underlying mechanism of PES induced PEL cell death .	These results suggest that release of the lysosomal content in the cytoplasm and the direct or caspase 8 mediated Bid processing may be the main underlying mechanism of PES induced PEL cell death.	4	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	16	18	19	20
We observed a very low level of the p35 cleavage product of Caspase-9 in Compound 1 treated cells consistent with the potential for Caspase-8 activation of BID .	We observed a very low level of the p35 cleavage product of Caspase-9 in Compound 1 treated cells consistent with the potential for Caspase-8 activation of BID.	23	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	BID	BID	BID	23	24	26	27
Pro apoptotic Bid is activated by its proteolytic cleavage by caspase-8 .	Pro apoptotic Bid is activated by its proteolytic cleavage by caspase-8.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	10	11	2	3
In the second one , activated caspase 8 will trigger the cleavage of the bcl ( 2 ) family member Bid , which will act on mitochondria , resulting in cytochrome c release , caspase 9 activation and finally , activation of all executioner caspases .	In the second one, activated caspase 8 will trigger the cleavage of the bcl (2) family member Bid, which will act on mitochondria, resulting in cytochrome c release, caspase 9 activation and finally, activation of all executioner caspases.	5	24	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	6	8	20	21
In type I cells , such as lymphocytes , activation of ' effector caspases ' by FAS induced activation of caspase-8 suffices for cell killing whereas in type II cells , including hepatocytes and pancreatic beta-cells , amplification of the caspase cascade through caspase-8 mediated activation of the pro apoptotic BCL-2 family member BID XREF_BIBR is essential XREF_BIBR - XREF_BIBR .	In type I cells, such as lymphocytes, activation of ' effector caspases ' by FAS induced activation of caspase-8 suffices for cell killing whereas in type II cells, including hepatocytes and pancreatic beta-cells, amplification of the caspase cascade through caspase-8 mediated activation of the pro apoptotic BCL-2 family member BID XREF_BIBR is essential XREF_BIBR - XREF_BIBR.	43	54	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	43	44	53	54
This process is modulated by Bid , which is activated by both caspase-8 and the ROS-Akt signal pathway .	This process is modulated by Bid, which is activated by both caspase-8 and the ROS-Akt signal pathway.	3	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	12	13	5	6
Best known in this regard is the amplification of the Fas ( CD95 ) signal in hepatocytes via caspase 8 mediated cleavage of Bid and activation of the mitochondrial apoptosis pathway .	Best known in this regard is the amplification of the Fas (CD95) signal in hepatocytes via caspase 8 mediated cleavage of Bid and activation of the mitochondrial apoptosis pathway.	16	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	18	20	23	24
These data suggest that hepatocytes and non parenchymal cells in the liver are not obligatory type II cells as previously assumed but that the strength of the death receptor trigger basically determines whether caspase-8 directly activates effector caspases or the BH3-only molecule Bid in the liver .	These data suggest that hepatocytes and non parenchymal cells in the liver are not obligatory type II cells as previously assumed but that the strength of the death receptor trigger basically determines whether caspase-8 directly activates effector caspases or the BH3-only molecule Bid in the liver.	33	45	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	33	34	42	43
Recent studies suggest that vpr causes sustained ERK activation , resulting in caspase 8 mediated cleavage of BID ( BH3 interacting domain death agonist ) to truncated BID , which in turn facilitates Bax mediated mitochondrial injury and apoptosis .	Recent studies suggest that vpr causes sustained ERK activation, resulting in caspase 8 mediated cleavage of BID (BH3 interacting domain death agonist) to truncated BID, which in turn facilitates Bax mediated mitochondrial injury and apoptosis.	10	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	BID	BID	BID	12	14	17	18
Bid , another BH3-only protein , is activated by caspase-8 in response to death receptor signaling and is thought to trigger apoptosis , like Puma , by direct or indirect activation ( via binding and inhibition of pro survival Bcl-2-like proteins ) of Bax and Bak .	Bid, another BH3-only protein, is activated by caspase-8 in response to death receptor signaling and is thought to trigger apoptosis, like Puma, by direct or indirect activation (via binding and inhibition of pro survival Bcl-2-like proteins) of Bax and Bak.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	9	10	0	1
Inhibition of caspase-8 prevented truncation of BID suggesting the involvement of caspase-8 in RBL induced truncation of Bid ( XREF_FIG ) .	Inhibition of caspase-8 prevented truncation of BID suggesting the involvement of caspase-8 in RBL induced truncation of Bid (XREF_FIG).	0	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	2	3	17	18
The present results showed a connection between extrinsic and intrinsic apoptotic pathways because activation of caspase-8 caused proteolytic cleavage of Bid to tBid ( XREF_FIG ) .	The present results showed a connection between extrinsic and intrinsic apoptotic pathways because activation of caspase-8 caused proteolytic cleavage of Bid to tBid (XREF_FIG).	13	21	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	15	16	20	21
However , caspase-8 can also induce apoptosis through the intrinsic mitochondrial pathway by cleaving the cytoplasmic factor Bid , a proapoptotic member of the Bcl-2 family XREF_BIBR .	However, caspase-8 can also induce apoptosis through the intrinsic mitochondrial pathway by cleaving the cytoplasmic factor Bid, a proapoptotic member of the Bcl-2 family XREF_BIBR.	2	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	2	3	17	18
Activation of the mitochondrial pathway may also result from the activation of caspase 8 , hence the extrinsic pathway ; caspase 8 mediates the proteolytic cleavage of Bid to tBid , which inhibits Bcl-2 and permits CytC release .	Activation of the mitochondrial pathway may also result from the activation of caspase 8, hence the extrinsic pathway; caspase 8 mediates the proteolytic cleavage of Bid to tBid, which inhibits Bcl-2 and permits CytC release.	20	28	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	20	22	27	28
The activation of caspase-8 induces pro apoptotic protein Bid which then can regulate the mitochondria by inducing the release of cytochrome-c oxidase into the cytosol .	The activation of caspase-8 induces pro apoptotic protein Bid which then can regulate the mitochondria by inducing the release of cytochrome-c oxidase into the cytosol.	1	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	3	4	8	9
In case of death receptor activation , the propagation of the apoptotic signal is enhanced by caspase-8 mediated activation of Bid [ XREF_BIBR ] .	In case of death receptor activation, the propagation of the apoptotic signal is enhanced by caspase-8 mediated activation of Bid [XREF_BIBR].	16	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	16	17	20	21
Death receptor ( DR ) ligands TNFalpha ( 43 ng/mL ) and TRAIL ( 20 ng/mL ) activate the mitochondrial death pathway via caspase 8 mediated cleavage of Bid XREF_BIBR .	Death receptor (DR) ligands TNFalpha (43 ng/mL) and TRAIL (20 ng/mL) activate the mitochondrial death pathway via caspase 8 mediated cleavage of Bid XREF_BIBR.	21	29	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	23	25	28	29
Key mediators of both pathways are activated irrespective of the fate choice , but apoptotic cells selectively induce the DR4 death receptor pathway , caspase 8 mediated BID cleavage and activation of BAX .	Key mediators of both pathways are activated irrespective of the fate choice, but apoptotic cells selectively induce the DR4 death receptor pathway, caspase 8 mediated BID cleavage and activation of BAX.	22	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	BID	BID	BID	24	26	27	28
Another example of terminal UPR is accumulation of death receptor-5 at the ER , which then engages MOMP through caspase-8 activation and cleavage of the BH3-only protein BID .	Another example of terminal UPR is accumulation of death receptor-5 at the ER, which then engages MOMP through caspase-8 activation and cleavage of the BH3-only protein BID.	19	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	19	20	27	28
Caspase 8 activates Bid to tBid form .	Caspase 8 activates Bid to tBid form.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	Bid	Bid	Bid	0	2	3	4
Here we demonstrate that expression of a caspase-8 non cleavable ( nc ) BID D59A mutant or expression of wild type ( wt ) BID induces apoptosis in Bid -/-, caspase-8 -/-, and wt primary MEFs .	Here we demonstrate that expression of a caspase-8 non cleavable (nc) BID D59A mutant or expression of wild type (wt) BID induces apoptosis in Bid -/-, caspase-8 -/-, and wt primary MEFs.	4	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	expression of a caspase-8	caspase-8	Bid	Bid	bid	7	8	28	29
To further assess the role of JNK activation and caspase-8 mediated Bid cleavage induced by tetrandrine on the mitochondria apoptotic pathway , the MMP was measured .	To further assess the role of JNK activation and caspase-8 mediated Bid cleavage induced by tetrandrine on the mitochondria apoptotic pathway, the MMP was measured.	4	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	9	10	11	12
As shown in our proposed pathway in XREF_FIG , pro apoptotic BID is activated by initiator Caspase-8 cleavage following the activation of the TNFR1 .	As shown in our proposed pathway in XREF_FIG, pro apoptotic BID is activated by initiator Caspase-8 cleavage following the activation of the TNFR1.	10	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	BID	BID	BID	16	17	11	12
29 The cleavage and consequent activation of BID by caspase-8 to generate the activated BID fragment ( tBID ) serves as the conduit through which the apoptotic signal is relayed from the extrinsic to the intrinsic signaling pathway .	29 The cleavage and consequent activation of BID by caspase-8 to generate the activated BID fragment (tBID) serves as the conduit through which the apoptotic signal is relayed from the extrinsic to the intrinsic signaling pathway.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	9	10	7	8
BID , a pro apoptotic member of the BCL-2 family , is activated by caspase 8 , and translocates to OM followed by catalysis of MMP .	BID, a pro apoptotic member of the BCL-2 family, is activated by caspase 8, and translocates to OM followed by catalysis of MMP.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	BID	BID	BID	14	16	0	1
By contrast , loss of the caspase-8 site ( D59 ) did not prevent Bid from overcoming Bcl-2 ' s block of cell death .	By contrast, loss of the caspase-8 site (D59) did not prevent Bid from overcoming Bcl-2 's block of cell death.	6	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	6	7	14	15
The functional redundancy between the intrinsic and extrinsic pathways is clearly illustrated by caspase 8 activation of the BH3-only protein Bid .	The functional redundancy between the intrinsic and extrinsic pathways is clearly illustrated by caspase 8 activation of the BH3-only protein Bid.	13	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	13	15	20	21
These results indicate that activated caspase-8 mediates the cleavage and activation of Bid and the release of AIF and/or EndoG .	These results indicate that activated caspase-8 mediates the cleavage and activation of Bid and the release of AIF and/or EndoG.	4	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	5	6	12	13
The level of Bid protein reduced by TPL was not also decreased by caspase-8 inhibitor Z-IETD-FMK , indicating that Bid cleavage to produce tBid is mediated by active caspase-8 .	The level of Bid protein reduced by TPL was not also decreased by caspase-8 inhibitor Z-IETD-FMK, indicating that Bid cleavage to produce tBid is mediated by active caspase-8.	19	29	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	28	29	19	20
It is known that activated caspase 8 may lead to activation of Bid , a Bcl-2 family protein which in turn destabilizes mitochondrial membrane to initiate caspase 9 mediated intrinsic pathways [ XREF_BIBR ] .	It is known that activated caspase 8 may lead to activation of Bid, a Bcl-2 family protein which in turn destabilizes mitochondrial membrane to initiate caspase 9 mediated intrinsic pathways [XREF_BIBR].	4	13	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	5	7	12	13
Looking more closely at where these caspases intersect in apoptosis signaling pathways , one can see how a transcriptional decrease in caspase-8 can prevent the activation of BID to tBID , ultimately preventing the release of proteins allowing for downstream caspase activation .	Looking more closely at where these caspases intersect in apoptosis signaling pathways, one can see how a transcriptional decrease in caspase-8 can prevent the activation of BID to tBID, ultimately preventing the release of proteins allowing for downstream caspase activation.	19	28	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	21	22	27	28
Further , caspase 8 induced the cleavage of proapototic signaling protein Bid .	Further, caspase 8 induced the cleavage of proapototic signaling protein Bid.	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	2	4	11	12
Caspase-8 activation induced proteolytic cleavage of Bid to tBid , which could translocate from cytosol to mitochondrial membrane to stimulate efficient oligomerization of Bax and thereby activate the mitochondrial pathway of apoptosis .	Caspase-8 activation induced proteolytic cleavage of Bid to tBid, which could translocate from cytosol to mitochondrial membrane to stimulate efficient oligomerization of Bax and thereby activate the mitochondrial pathway of apoptosis.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	6	7
Caspase-8 activation may induce the proteolytic cleavage of Bid to tBid , resulting in tBid translocation from the cytosol to the mitochondrial membrane to stimulate more efficient oligomerization of Bax and thereby activation of the intrinsic apoptotic pathway .	Caspase-8 activation may induce the proteolytic cleavage of Bid to tBid, resulting in tBid translocation from the cytosol to the mitochondrial membrane to stimulate more efficient oligomerization of Bax and thereby activation of the intrinsic apoptotic pathway.	0	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	8	9
The BH3-only BCL-2 family protein BID is activated by caspase-8 cleavage upon engagement of cell surface death receptors .	The BH3-only BCL-2 family protein BID is activated by caspase-8 cleavage upon engagement of cell surface death receptors.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	9	10	5	6
Following death receptor stimulation , BID is activated by caspase-8 cleavage and N myristoylation to target mitochondria , where it activates BAX and BAK or is alternatively sequestered by antiapoptotic BCL2 members , preventing death .	Following death receptor stimulation, BID is activated by caspase-8 cleavage and N myristoylation to target mitochondria, where it activates BAX and BAK or is alternatively sequestered by antiapoptotic BCL2 members, preventing death.	5	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	9	10	5	6
Caspase-8 , combined with its ability to induce apoptosis through the extrinsic pathway , also triggers the intrinsic apoptosis pathway by cleaving the pro apoptotic Bcl-2 family members Bax and Bid to initiate mitochondrial induced apoptosis [ XREF_BIBR - XREF_BIBR ] .	Caspase-8, combined with its ability to induce apoptosis through the extrinsic pathway, also triggers the intrinsic apoptosis pathway by cleaving the pro apoptotic Bcl-2 family members Bax and Bid to initiate mitochondrial induced apoptosis [XREF_BIBR - XREF_BIBR].	0	32	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	30	31
We found that caspase-8 activation by Mtb infection initiated cleavage of BID into tBID , which prompted cleavage and activation of caspase-9 and -3 , leading to apoptosis ( XREF_FIG ) .	We found that caspase-8 activation by Mtb infection initiated cleavage of BID into tBID, which prompted cleavage and activation of caspase-9 and -3, leading to apoptosis (XREF_FIG).	3	12	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	3	4	11	12
As a representative activator protein , we used the caspase-8 cleavage product of Bid ( tBid ) to activate Bax .	As a representative activator protein, we used the caspase-8 cleavage product of Bid (tBid) to activate Bax.	9	18	product	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	9	10	13	14
CO also prevents the activation of Bid by inhibiting the activity of caspase-8 , which activates Bid by cleavage to truncated Bid ( tBid ) [ XREF_BIBR ] .	CO also prevents the activation of Bid by inhibiting the activity of caspase-8, which activates Bid by cleavage to truncated Bid (tBid) [XREF_BIBR].	10	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	12	13	16	17
Bid is activated following cleavage by caspase-8 or other proteases .	Bid is activated following cleavage by caspase-8 or other proteases.	0	9	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	6	7	0	1
XREF_BIBR Bid is activated by caspase 8 , an initiator caspase in the death receptor signaling pathway , and its truncated form t-Bid subsequently becomes incorporated into the mitochondrial cell wall .	XREF_BIBR Bid is activated by caspase 8, an initiator caspase in the death receptor signaling pathway, and its truncated form t-Bid subsequently becomes incorporated into the mitochondrial cell wall.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	5	7	1	2
Knock down of caspase 8 ( activator of Bid ) delayed both Bax-GFP aggregation and Smac and DIABLO-GFP release in CPT treated cells .	Knock down of caspase 8 (activator of Bid) delayed both Bax-GFP aggregation and Smac and DIABLO-GFP release in CPT treated cells.	1	9	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	3	5	8	9
Caspase-8 activation causes proteotytic cleavage of Bid to truncated Bid ( tBid ) , which is then translocated to mitochondria for triggering apoptosis .	Caspase-8 activation causes proteotytic cleavage of Bid to truncated Bid (tBid), which is then translocated to mitochondria for triggering apoptosis.	0	20	causes	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Caspase-8	Caspase-8	caspase-8	Bid	Bid (tBid), which is then translocated to mitochondria	bid	0	1	9	10
36 HY-PDT-induced apoptosis usually operates via two main pathways ( see XREF_FIG ) : the cytoplasmic pathway initiated by CASP8 activation , which subsequently triggers BID and downstream effector caspase activities , XREF_BIBR , XREF_BIBR , XREF_BIBR and the mitochondrial pathway , following light activation of HY , resulting in the loss of mitochondrial membrane integrity , eventually leading to the release of CYT-C from mitochondria into the cytosol .	36 HY-PDT-induced apoptosis usually operates via two main pathways (see XREF_FIG) : the cytoplasmic pathway initiated by CASP8 activation, which subsequently triggers BID and downstream effector caspase activities, XREF_BIBR, XREF_BIBR, XREF_BIBR and the mitochondrial pathway, following light activation of HY, resulting in the loss of mitochondrial membrane integrity, eventually leading to the release of CYT-C from mitochondria into the cytosol.	19	40	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	BID	BID	BID	19	20	25	26
Likewise , mitochondrial signaling can be triggered during activation of the extrinsic cascade , via caspase 8 mediated cleavage of the BH3-only protein Bid .	Likewise, mitochondrial signaling can be triggered during activation of the extrinsic cascade, via caspase 8 mediated cleavage of the BH3-only protein Bid.	8	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	15	17	23	24
A previous study indicated that mitochondrial intrinsic pathway and extrinsic pathway could be linked by Bid , a proapoptotic protein , which could be activated by caspase-8 in the cytoplasm to regulate the mitochondrial membrane potential by forming a complex with Bax .	A previous study indicated that mitochondrial intrinsic pathway and extrinsic pathway could be linked by Bid, a proapoptotic protein, which could be activated by caspase-8 in the cytoplasm to regulate the mitochondrial membrane potential by forming a complex with Bax.	13	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	26	27	15	16
It is also well known that caspase-8 can trigger Bid cleavage into truncated Bid , which subsequently leads to the release of cytochrome c from the mitochondria , thereby triggering the activation of caspase-9 [ XREF_BIBR ] .	It is also well known that caspase-8 can trigger Bid cleavage into truncated Bid, which subsequently leads to the release of cytochrome c from the mitochondria, thereby triggering the activation of caspase-9 [XREF_BIBR].	6	10	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	6	7	9	10
However , GTP induced FAS upregulation through activation of c-jun-N-terminal kinase resulted in FADD phosphorylation , caspase-8 activation and truncation of BID , leading to apoptosis in both LNCaPshV and LNCaPshp53 cells .	However, GTP induced FAS upregulation through activation of c-jun-N-terminal kinase resulted in FADD phosphorylation, caspase-8 activation and truncation of BID, leading to apoptosis in both LNCaPshV and LNCaPshp53 cells.	16	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	16	17	21	22
In some cases , extrinsic signals may lead to low DISC formation , leading to Bid cleavage by activated caspase 8 , changing the MOMP .	In some cases, extrinsic signals may lead to low DISC formation, leading to Bid cleavage by activated caspase 8, changing the MOMP.	13	21	leading	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	19	21	15	16
The release of caspase 8 signals Bid to activate Bax , Bad , and cytochrome C in the cell ' s mitochondria .	The release of caspase 8 signals Bid to activate Bax, Bad, and cytochrome C in the cell 's mitochondria.	1	7	signals	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	3	5	6	7
Furthermore , we demonstrate that granzyme B directly cleaves the proapoptotic molecule Bid , bypassing the need for caspase 8 activation of Bid .	Furthermore, we demonstrate that granzyme B directly cleaves the proapoptotic molecule Bid, bypassing the need for caspase 8 activation of Bid.	18	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	18	20	22	23
In some types of cells , caspase 8 indirectly activates downstream caspases by cleaving the BH3-only protein Bid XREF_BIBR , leading to activation of the Apaf-1 and caspase 9 apoptosome XREF_BIBR .	In some types of cells, caspase 8 indirectly activates downstream caspases by cleaving the BH3-only protein Bid XREF_BIBR, leading to activation of the Apaf-1 and caspase 9 apoptosome XREF_BIBR.	6	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	6	8	17	18
The activated caspase-8 directly activates effecter caspases such as caspase-3 , or cleaves BH3 interacting domain death agonist ( Bid ) to truncated Bid ( tBid ) , leading to intrinsic pathway activation via mitochondrial dysfunction .	The activated caspase-8 directly activates effecter caspases such as caspase-3, or cleaves BH3 interacting domain death agonist (Bid) to truncated Bid (tBid), leading to intrinsic pathway activation via mitochondrial dysfunction.	0	25	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BH3 interacting domain death agonist	BH3 interacting domain death agonist	BH3 interacting domain death agonist	2	3	13	18
BID is activated downstream of death receptors by caspase-8 cleavage and N myristoylation to target mitochondria where it activates BAX , BAK , and the downstream apoptotic pathway .	BID is activated downstream of death receptors by caspase-8 cleavage and N myristoylation to target mitochondria where it activates BAX, BAK, and the downstream apoptotic pathway.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	8	9	0	1
Recombinant human ( rh ) caspase-8 induced the cleavage of the cytochrome c effluxing factor Bid and cytochrome c release from purified mitochondria in the reconstitution system with Bid ( +/+ ) cytosol , but not with Bid (-/-) cytosol .	Recombinant human (rh) caspase-8 induced the cleavage of the cytochrome c effluxing factor Bid and cytochrome c release from purified mitochondria in the reconstitution system with Bid (+/+) cytosol, but not with Bid (-/-) cytosol.	5	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	5	6	15	16
Our data indicate that caspase-8 inhibitor decreased t-Bid and cytochrome c levels suggesting that caspase-8 mediates Bid cleavage in SPARC overexpressed cells ( XREF_SUPPLEMENTARY ) .	Our data indicate that caspase-8 inhibitor decreased t-Bid and cytochrome c levels suggesting that caspase-8 mediates Bid cleavage in SPARC overexpressed cells (XREF_SUPPLEMENTARY).	14	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	14	15	16	17
Upregulated FasL , however , not only triggers the extrinsic death receptor mediated apoptotic signaling pathway , but also initiates the intrinsic mitochondria dependent apoptotic pathway via the cleavage of Bid to tBid by activated caspase-8 .	Upregulated FasL, however, not only triggers the extrinsic death receptor mediated apoptotic signaling pathway, but also initiates the intrinsic mitochondria dependent apoptotic pathway via the cleavage of Bid to tBid by activated caspase-8.	19	36	initiates	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	35	36	30	31
Active caspase-8 which stands at the apex of the extrinsic apoptotic route contributes to procaspase-3 processing and synchronously activates BH3-only protein Bid by cleavage to initiate OMM permeabilization .	Active caspase-8 which stands at the apex of the extrinsic apoptotic route contributes to procaspase-3 processing and synchronously activates BH3-only protein Bid by cleavage to initiate OMM permeabilization.	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	1	2	21	22
In the second pathway , activated caspase 8 triggers cleavage of the Bcl-2 family member Bid , which acts on mitochondria , resulting in cytochrome c release , caspase 9 activation , and , finally , activation of all executioner caspases [ XREF_BIBR ] .	In the second pathway, activated caspase 8 triggers cleavage of the Bcl-2 family member Bid, which acts on mitochondria, resulting in cytochrome c release, caspase 9 activation, and, finally, activation of all executioner caspases [XREF_BIBR].	5	18	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	6	8	15	16
On their part , Bcl-2 homology ( BH ) 3-only proteins , and in particular Bid , can be activated by caspase-8 and lead directly to MOMP activation , thus representing the junction between the intrinsic and the extrinsic apoptotic pathway .	On their part, Bcl-2 homology (BH) 3-only proteins, and in particular Bid, can be activated by caspase-8 and lead directly to MOMP activation, thus representing the junction between the intrinsic and the extrinsic apoptotic pathway.	5	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	21	22	15	16
Subsequently , these data argued in favor of activated caspase-8 promoting Bid upregulation and increasing the Bax and Bcl2 ratio , thus resulting in mitochondrial membrane depolarization , which is in agreement with FasL and Fas signaling .	Subsequently, these data argued in favor of activated caspase-8 promoting Bid upregulation and increasing the Bax and Bcl2 ratio, thus resulting in mitochondrial membrane depolarization, which is in agreement with FasL and Fas signaling.	8	14	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	9	10	11	12
We have previously shown that ionizing radiation induced apoptosis in human lymphoblastoid cells differs according to their p53 status , and that caspase 8 mediated cleavage of BID is involved in the p53 dependent pathway .	We have previously shown that ionizing radiation induced apoptosis in human lymphoblastoid cells differs according to their p53 status, and that caspase 8 mediated cleavage of BID is involved in the p53 dependent pathway.	22	29	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	BID	BID	BID	22	24	27	28
Thus , caspase 8 activation triggers Bid cleavage and truncated Bid translocation to the mitochondria to cause together with the other B-cell lymphoma 2 family members Bax and Bad the mitochondrial outer membrane permeabilization .	Thus, caspase 8 activation triggers Bid cleavage and truncated Bid translocation to the mitochondria to cause together with the other B-cell lymphoma 2 family members Bax and Bad the mitochondrial outer membrane permeabilization.	2	28	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	2	4	6	7
At the same time , mitochondrial dysfunction can also be induced by caspase 8 mediated cleavage of Bid and subsequent Bax and Bak activation , similarly to what was observed after Fas stimulation in type II cells .	At the same time, mitochondrial dysfunction can also be induced by caspase 8 mediated cleavage of Bid and subsequent Bax and Bak activation, similarly to what was observed after Fas stimulation in type II cells.	10	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	12	14	17	18
It is likely that these events involve caspase-8 mediated cleavage of the BH3-only protein Bid to tBid .	It is likely that these events involve caspase-8 mediated cleavage of the BH3-only protein Bid to tBid.	7	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	7	8	14	15
We also examined mitochondrial cytochrome c levels after exposure to the compound , and found a dose dependent reduction in mitochondrial cytochrome c ( XREF_FIG ) , which is in consistent with the activation of Bid by caspase-8 ( XREF_FIG ) .	We also examined mitochondrial cytochrome c levels after exposure to the compound, and found a dose dependent reduction in mitochondrial cytochrome c (XREF_FIG), which is in consistent with the activation of Bid by caspase-8 (XREF_FIG).	14	39	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	37	38	35	36
In addition , caspase 8 can also induce apoptotic cell death through the mitochondrial pathway by cleaving the cytoplasmic factor Bid , a pro apoptotic member of the Bcl-2 protein family .	In addition, caspase 8 can also induce apoptotic cell death through the mitochondrial pathway by cleaving the cytoplasmic factor Bid, a pro apoptotic member of the Bcl-2 protein family.	3	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	3	5	20	21
Hepatocytes and hepatocyte derived cells are known to require the caspase 8 mediated cleavage of the BH3-only protein Bid in order to amplify death receptor signals via the mitochondrial pathway ( type II cells ) .	Hepatocytes and hepatocyte derived cells are known to require the caspase 8 mediated cleavage of the BH3-only protein Bid in order to amplify death receptor signals via the mitochondrial pathway (type II cells).	8	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	10	12	18	19
Caspase-8 either directly activates executioner caspases ( caspase-3/6/7 ) or cleaves Bid into t-Bid , which connects the extrinsic and intrinsic apoptotic pathways [ XREF_BIBR - XREF_BIBR ] .	Caspase-8 either directly activates executioner caspases (caspase-3/6/7) or cleaves Bid into t-Bid, which connects the extrinsic and intrinsic apoptotic pathways [XREF_BIBR - XREF_BIBR].	0	12	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	11	12
In addition , suppression of caspase-8 with the specific inhibitor z-IETD-fmk , as well as the pan-caspase inhibitor z-VAD-fmk , prevented Bid cleavage and subsequent apoptosis .	In addition, suppression of caspase-8 with the specific inhibitor z-IETD-fmk, as well as the pan-caspase inhibitor z-VAD-fmk, prevented Bid cleavage and subsequent apoptosis.	3	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	5	6	21	22
Caspase-8 initiates the mitochondrial pathway by cleaving Bid to tBid , which induces mitochondrial permeabilization that results in the release of cytochrome c.	Caspase-8 initiates the mitochondrial pathway by cleaving Bid to tBid, which induces mitochondrial permeabilization that results in the release of cytochrome c.	0	8	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	7	8
Caspase-8 cleaves caspase-3 to its activated form , causing activation of Bid to truncated Bid ( tBid ) , which amplifies intrinsic apoptosis via activation of Bax .	Caspase-8 cleaves caspase-3 to its activated form, causing activation of Bid to truncated Bid (tBid), which amplifies intrinsic apoptosis via activation of Bax.	0	12	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	11	12
On the other hand , caspase-8 can induce Bid cleavage .	On the other hand, caspase-8 can induce Bid cleavage.	5	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	5	6	8	9
Since caspase 8 is activated during infection , we next check the cleavage of BH3-only protein Bid , a Bcl-2 family pro apoptotic protein targeted by caspase 8 .	Since caspase 8 is activated during infection, we next check the cleavage of BH3-only protein Bid, a Bcl-2 family pro apoptotic protein targeted by caspase 8.	14	28	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	26	28	16	17
Our results clearly show that PTX augments TRAIL mediated activation of caspase-8 and induces cleavage of Bid , although PTX alone can not activate caspase-8 .	Our results clearly show that PTX augments TRAIL mediated activation of caspase-8 and induces cleavage of Bid, although PTX alone can not activate caspase-8.	5	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	PTX augments TRAIL mediated activation of caspase-8	caspase-8	Bid	Bid	bid	11	12	16	17
Bid is processed and thereby activated by caspase-8 in many cell types and systems .	Bid is processed and thereby activated by caspase-8 in many cell types and systems.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	7	8	0	1
Bcl-2 overexpression did not affect caspase-8 activation and cleavage of Bid but blocked the release of cytochrome c and activation of mitochondria localized caspases -2 , -7 , and-9 .	Bcl-2 overexpression did not affect caspase-8 activation and cleavage of Bid but blocked the release of cytochrome c and activation of mitochondria localized caspases -2, -7, and-9.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	5	6	10	11
It is increasingly believed that the cleavage form of Bid ( tBid ) caused by caspase-8 can result in the release of cytochrome c from mitochondria into cytosol , and subsequently activating caspase-9 .	It is increasingly believed that the cleavage form of Bid (tBid) caused by caspase-8 can result in the release of cytochrome c from mitochondria into cytosol, and subsequently activating caspase-9.	7	16	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	15	16	9	10
We also observed that inhibition of caspase-8 by z-IETD-fmk suppressed the caspase-8 and Bid activation , caspase-3-mediated PARP cleavage , and apoptosis .	We also observed that inhibition of caspase-8 by z-IETD-fmk suppressed the caspase-8 and Bid activation, caspase-3-mediated PARP cleavage, and apoptosis.	4	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	6	7	13	14
Activation of caspase-8 through extrinsic signal ( s ) caused Bid activation .	Activation of caspase-8 through extrinsic signal (s) caused Bid activation.	0	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	2	3	10	11
Bid and Bim can be also activated by a direct cleavage by caspase-8 , as well as by the lysosomal protease cathepsin , in response to ceramide , ROS and JNK .	Bid and Bim can be also activated by a direct cleavage by caspase-8, as well as by the lysosomal protease cathepsin, in response to ceramide, ROS and JNK.	0	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	12	13	0	1
Death receptor signalling and mitochondrial pathways are interconnected through the proapoptotic Bcl-2 protein Bid , which is activated by caspase-8 .	Death receptor signalling and mitochondrial pathways are interconnected through the proapoptotic Bcl-2 protein Bid, which is activated by caspase-8.	7	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	19	20	13	14
Caspase-8 inhibition abrogated Bid cleavage and strongly reduced caspase-9 activation , suggesting that the cross-talk mechanism mediated by caspase-8-dependent Bid cleavage can contribute to the activation of the intrinsic apoptotic pathway by CUR+ CA .	Caspase-8 inhibition abrogated Bid cleavage and strongly reduced caspase-9 activation, suggesting that the cross-talk mechanism mediated by caspase-8-dependent Bid cleavage can contribute to the activation of the intrinsic apoptotic pathway by CUR+CA.	0	4	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	3	4
Interestingly , the study found that Bid cleavage following Npe6-PDT was not mediated by caspase-8 ( the normal mechanism of Bid cleavage ) .	Interestingly, the study found that Bid cleavage following Npe6-PDT was not mediated by caspase-8 (the normal mechanism of Bid cleavage).	6	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	14	15	6	7
In this pathway , Bid is activated upon cleavage by caspase-8 .	In this pathway, Bid is activated upon cleavage by caspase-8.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	10	11	4	5
Furthermore , suppression of caspase-8 activity with z-IETD-fmk prevented Bid cleavage and Bax activation during apoptosis .	Furthermore, suppression of caspase-8 activity with z-IETD-fmk prevented Bid cleavage and Bax activation during apoptosis.	4	10	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	4	5	9	10
These results suggested that fucoidan may block the binding of TNF-alpha and its receptor TNFR1 to interfere with the activation of caspase 8 , and then offers protection by inhibiting caspase 8 directly induced extrinsic apoptosis and Bid and Bax mediated intrinsic apoptosis .	These results suggested that fucoidan may block the binding of TNF-alpha and its receptor TNFR1 to interfere with the activation of caspase 8, and then offers protection by inhibiting caspase 8 directly induced extrinsic apoptosis and Bid and Bax mediated intrinsic apoptosis.	29	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	30	32	37	38
In addition , exogenous expression of HIPPI also increases the expression of Caspase1 , Caspase3 , Caspase7 and Caspase8 in cells as well as it induces truncation of Bid and release of AIF from mitochondria [ XREF_BIBR ] .	In addition, exogenous expression of HIPPI also increases the expression of Caspase1, Caspase3, Caspase7 and Caspase8 in cells as well as it induces truncation of Bid and release of AIF from mitochondria [XREF_BIBR].	10	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase8	expression of Caspase1, Caspase3, Caspase7 and Caspase8	caspase8	Bid	Bid	bid	18	19	28	29
Increased cell death did not occur from direct mitochondrial toxicity or a lack of mitophagy , but rather from increased activation of initiator caspase-8 causing Bid cleavage .	Increased cell death did not occur from direct mitochondrial toxicity or a lack of mitophagy, but rather from increased activation of initiator caspase-8 causing Bid cleavage.	20	26	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	23	24	25	26
Here we showed that , besides the specific cleavage and activation of Bid by caspase-8 and caspase-3 , TRAIL induced apoptosis in Jurkat T cells required the specific cleavage of Mcl-1 at Asp 127 and Asp 157 by caspase-3 , while other prototypic antiapoptotic factors such as Bcl-2 or Bcl-X ( L ) seemed not to be affected .	Here we showed that, besides the specific cleavage and activation of Bid by caspase-8 and caspase-3, TRAIL induced apoptosis in Jurkat T cells required the specific cleavage of Mcl-1 at Asp 127 and Asp 157 by caspase-3, while other prototypic antiapoptotic factors such as Bcl-2 or Bcl-X (L) seemed not to be affected.	8	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	14	15	12	13
Caspase-8 further activates Bid , which , in turn , translocates to the mitochondria and activates the intrinsic pathway XREF_BIBR .	Caspase-8 further activates Bid, which, in turn, translocates to the mitochondria and activates the intrinsic pathway XREF_BIBR.	0	15	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Caspase-8	Caspase-8	caspase-8	Bid	Bid, which, in turn, translocates to the mitochondria	bid	0	1	3	4
Furthermore , suppression of caspase-8 activity with Z-IETD-FMK partially inhibited release of cytochrome c and Bid cleavage induced by AMAD , whereas exposure to Z-LETD-FMK , a caspase-9 inhibitor , had no effect .	Furthermore, suppression of caspase-8 activity with Z-IETD-FMK partially inhibited release of cytochrome c and Bid cleavage induced by AMAD, whereas exposure to Z-LETD-FMK, a caspase-9 inhibitor, had no effect.	4	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	4	5	15	16
Simultaneously , caspase-8 can induce Bid cleavage .	Simultaneously, caspase-8 can induce Bid cleavage.	2	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	2	3	5	6
In addition , caspase-8 mediates the intrinsic pathway via cleavage of the pro apoptotic Bid protein , a BH3-only protein , to a truncated Bid ( tBid ) through translocation from the cytosol to the mitochondria , triggering mitochondrial dysfunction , followed by activation of caspase-9 .	In addition, caspase-8 mediates the intrinsic pathway via cleavage of the pro apoptotic Bid protein, a BH3-only protein, to a truncated Bid (tBid) through translocation from the cytosol to the mitochondria, triggering mitochondrial dysfunction, followed by activation of caspase-9.	3	29	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	3	4	24	25
By inhibiting caspase-8 activity , the functional significance of caspase-8 for DR4 and DR5 dependent apoptotic signaling in HCV infected cells was revealed through suppression of HCV induced Bid cleavage and subsequent caspase-9 cleavage ( XREF_FIG ) .	By inhibiting caspase-8 activity, the functional significance of caspase-8 for DR4 and DR5 dependent apoptotic signaling in HCV infected cells was revealed through suppression of HCV induced Bid cleavage and subsequent caspase-9 cleavage (XREF_FIG).	7	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	9	10	28	29
The intrinsic and extrinsic pathways also interact via caspase 8 mediated cleavage of Bid , which leads to mitochondrial outer membrane permeabilization .	The intrinsic and extrinsic pathways also interact via caspase 8 mediated cleavage of Bid, which leads to mitochondrial outer membrane permeabilization.	6	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	8	10	13	14
In Fas induced apoptosis , Bid is activated through cleavage by caspase 8 into a 15.5-kDa C-terminal fragment ( t ( c ) Bid ) and a 6.5 kDa N-terminal fragment ( t ( n ) Bid ) .	In Fas induced apoptosis, Bid is activated through cleavage by caspase 8 into a 15.5-kDa C-terminal fragment (t (c) Bid) and a 6.5 kDa N-terminal fragment (t (n) Bid).	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	11	13	5	6
Caspase-8 mediated cleavage of Bid to tBid and the translocation of tBid to mitochondria provides a link between extrinsic and intrinsic pathways of apoptosis [ XREF_BIBR ] .	Caspase-8 mediated cleavage of Bid to tBid and the translocation of tBid to mitochondria provides a link between extrinsic and intrinsic pathways of apoptosis [XREF_BIBR].	0	5	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	4	5
We hypothesized that JNKs promote Bid accumulation by the phosphorylation at the caspase-8 cleavage site that prevents Bid degradation .	We hypothesized that JNKs promote Bid accumulation by the phosphorylation at the caspase-8 cleavage site that prevents Bid degradation.	12	18	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	12	13	17	18
In some cell types , the apoptotic signaling is further amplified via the mitochondria as a result of the translocation of caspase 8 mediated cleavage of Bid ( BH3 interacting-domain protein ) .	In some cell types, the apoptotic signaling is further amplified via the mitochondria as a result of the translocation of caspase 8 mediated cleavage of Bid (BH3 interacting-domain protein).	19	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	21	23	26	27
IL-21-mediated apoptosis involves caspase-8 and caspase-3 activation and cleavage of their substrates Bid , poly ( ADP-ribose ) polymerase ( PARP ) and of p27Kip-1 [ XREF_BIBR ] .	IL-21-mediated apoptosis involves caspase-8 and caspase-3 activation and cleavage of their substrates Bid, poly (ADP-ribose) polymerase (PARP) and of p27Kip-1 [XREF_BIBR].	3	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	3	4	12	13
In this pathway , Bid is activated upon proteolytic cleavage in its unstructured loop by caspase-8 .	In this pathway, Bid is activated upon proteolytic cleavage in its unstructured loop by caspase-8.	4	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	15	16	4	5
Caspase-8 activation induced the proteolytic cleavage of Bid to tBid , which could translocate from cytosol to mitochondrial membrane to stimulate more efficient oligomerization of Bax and thereby activation of the intrinsic apoptotic pathway .	Caspase-8 activation induced the proteolytic cleavage of Bid to tBid, which could translocate from cytosol to mitochondrial membrane to stimulate more efficient oligomerization of Bax and thereby activation of the intrinsic apoptotic pathway.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	7	8
In hepatocytes , caspase-8-mediated signals are also influenced by a mitochondrial pathway : The cytosolic protein Bid ( BH3 interacting domain death agonist ) is proteolytically activated by caspase-8 and thereby converted into its active form tBID which translocates into the mitochondrial membrane and contributes to increased mitochondrial permeability and subsequent to release cytochrome C from the mitochondria into the cytosol via the membrane proteins Bax and Bac .	In hepatocytes, caspase-8-mediated signals are also influenced by a mitochondrial pathway : The cytosolic protein Bid (BH3 interacting domain death agonist) is proteolytically activated by caspase-8 and thereby converted into its active form tBID which translocates into the mitochondrial membrane and contributes to increased mitochondrial permeability and subsequent to release cytochrome C from the mitochondria into the cytosol via the membrane proteins Bax and Bac.	13	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	28	29	16	17
In addition , activated caspase-8 directly activates effector caspases such as caspase-3 , or cleaves Bid to truncated Bid , both of which lead to intrinsic pathway activation via mitochondrial dysfunction .	In addition, activated caspase-8 directly activates effector caspases such as caspase-3, or cleaves Bid to truncated Bid, both of which lead to intrinsic pathway activation via mitochondrial dysfunction.	3	23	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	4	5	18	19
However , Bax was dispensable for TRAIL induced caspase-8 activation and subsequent cleavage of Bid but crucial for the release of cytochrome c and Smac/Diablo from mitochondria and downstream activation of caspases .	However, Bax was dispensable for TRAIL induced caspase-8 activation and subsequent cleavage of Bid but crucial for the release of cytochrome c and Smac/Diablo from mitochondria and downstream activation of caspases.	6	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	TRAIL induced caspase-8	caspase-8	Bid	Bid	bid	8	9	14	15
Caspase-8 mediated cleavage of BID ( mean PONDR FIT score of 0.374 ) , a BH3-only member of the BCL-2 family , links the extrinsic and intrinsic pathways 96 .	Caspase-8 mediated cleavage of BID (mean PONDR FIT score of 0.374), a BH3-only member of the BCL-2 family, links the extrinsic and intrinsic pathways 96.	0	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	BID	BID	BID	0	1	4	5
We observed that MDGA2 mediated tumour suppressive properties occur through the p53 pathway by downregulation of oncogenic genes ( WT1 , IL6 , SESN2 ) XREF_BIBR and genes associated with neoplastic phenotype ( TP63 , BAI1 ) , XREF_BIBR XREF_BIBR upregulation of tumour suppressors ( EI24 , MSH2 ) , XREF_BIBR XREF_BIBR upregulation of the cell apoptosis regulator BH3 interacting domain death agonist ( BID ) induced by caspase-8 , intrinsic apoptosis initiator caspase-9 and Fas cell surface death receptor XREF_BIBR XREF_BIBR and downregulation of the anti-apoptotic gene BCL2A1 .	We observed that MDGA2 mediated tumour suppressive properties occur through the p53 pathway by downregulation of oncogenic genes (WT1, IL6, SESN2) XREF_BIBR and genes associated with neoplastic phenotype (TP63, BAI1), XREF_BIBR XREF_BIBR upregulation of tumour suppressors (EI24, MSH2), XREF_BIBR XREF_BIBR upregulation of the cell apoptosis regulator BH3 interacting domain death agonist (BID) induced by caspase-8, intrinsic apoptosis initiator caspase-9 and Fas cell surface death receptor XREF_BIBR XREF_BIBR and downregulation of the anti-apoptotic gene BCL2A1.	52	69	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BH3 interacting domain death agonist	BH3 interacting domain death agonist	BH3 interacting domain death agonist	68	69	58	63
XREF_BIBR - XREF_BIBR Active caspase-8 can also initiate ' intrinsic ' or mitochondrial mediated apoptotic pathway by cleaving BID to form truncated BID ( tBID ) .	XREF_BIBR - XREF_BIBR Active caspase-8 can also initiate ' intrinsic ' or mitochondrial mediated apoptotic pathway by cleaving BID to form truncated BID (tBID).	2	20	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	4	5	18	19
Caspase-8 cleavage does not induce per se separation of the two Bid fragments , which remain in a stable complex resembling the full length Bid .	Caspase-8 cleavage does not induce per se separation of the two Bid fragments, which remain in a stable complex resembling the full length Bid.	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	11	12
Caspase-8 either directly activates the downstream cascade of caspases or cleaves Bid into an active truncated form named tBid that connects the extrinsic to the intrinsic apoptotic pathways through mitochondria permeabilization [ XREF_BIBR ] .	Caspase-8 either directly activates the downstream cascade of caspases or cleaves Bid into an active truncated form named tBid that connects the extrinsic to the intrinsic apoptotic pathways through mitochondria permeabilization [XREF_BIBR].	0	12	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	11	12
In type II cells , caspase-8 triggers cleavage of Bid and subsequent release of mitochondrial pro apoptotic factors such as cytochrome c to drive the formation of apoptosome which is consisted with cytochrome c , apoptotic protease activating factor-1 ( Apaf-1 ) , and procaspase-9 [ XREF_BIBR ] .	In type II cells, caspase-8 triggers cleavage of Bid and subsequent release of mitochondrial pro apoptotic factors such as cytochrome c to drive the formation of apoptosome which is consisted with cytochrome c, apoptotic protease activating factor-1 (Apaf-1), and procaspase-9 [XREF_BIBR].	5	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	5	6	9	10
In an alternative pathway , caspase-8 activates crosstalk between the death receptor pathway and the mitochondrial pathway by the cleavage of Bid to Bid , a pro apoptotic member of the Bcl2 family .	In an alternative pathway, caspase-8 activates crosstalk between the death receptor pathway and the mitochondrial pathway by the cleavage of Bid to Bid, a pro apoptotic member of the Bcl2 family.	5	28	activates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	5	6	23	24
In addition , studies have demonstrated that CASP8 could induce the cleavage of Bid ( tBid formation ) , and lead to cytochrome c release with the activation of CASP9 pathway in cell apoptosis .	In addition, studies have demonstrated that CASP8 could induce the cleavage of Bid (tBid formation), and lead to cytochrome c release with the activation of CASP9 pathway in cell apoptosis.	7	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	Bid	Bid	Bid	7	8	13	14
We have previously demonstrated that inhibition of arginase in MDA-MB-468 cells by NOHA induced apoptosis via Caspase-8 mediated BID cleavage , which was blocked by exogenous L-ornithine at the mitochondrial levels [ XREF_BIBR ] .	We have previously demonstrated that inhibition of arginase in MDA-MB-468 cells by NOHA induced apoptosis via Caspase-8 mediated BID cleavage, which was blocked by exogenous L-ornithine at the mitochondrial levels [XREF_BIBR].	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	BID	BID	BID	16	17	18	19
Alternatively , caspase-8 can cleave and thereby activate Bid into tBid , which translocates to mitochondria to initiate the mitochondrial pathway of apoptosis .	Alternatively, caspase-8 can cleave and thereby activate Bid into tBid, which translocates to mitochondria to initiate the mitochondrial pathway of apoptosis.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	2	3	8	9
Generally , Bid is inactive for death induction and is activated on proteolytic cleavage by caspase-8 or other proteases .	Generally, Bid is inactive for death induction and is activated on proteolytic cleavage by caspase-8 or other proteases.	2	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	15	16	2	3
HSP70 also suppresses the caspase-8 mediated cleavage and activation of BID .	HSP70 also suppresses the caspase-8 mediated cleavage and activation of BID.	3	11	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	4	5	10	11
The two pathways are interconnected at multiple levels , but the best characterized link is represented by the BH3-only protein Bid , which can be proteolitically activated by caspase-8 [ XREF_BIBR ] .	The two pathways are interconnected at multiple levels, but the best characterized link is represented by the BH3-only protein Bid, which can be proteolitically activated by caspase-8 [XREF_BIBR].	15	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	28	29	20	21
However suppression of caspase-8 expression did not prevent Bid cleavage in cells treated with cisplatin in the absence or presence of N-HXK II.	However suppression of caspase-8 expression did not prevent Bid cleavage in cells treated with cisplatin in the absence or presence of N-HXK II.	3	9	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8 expression	caspase-8	Bid	Bid	bid	3	4	8	9
Cleavage of the BID protein in the cytoplasm by caspase-8 causes Bid to localise in the cytosol while truncated Bid translocates to the mitochondria and activates the mitochondrial pathway after apoptosis induction through death receptors , and can be used to amplify the apoptotic signal .	Cleavage of the BID protein in the cytoplasm by caspase-8 causes Bid to localise in the cytosol while truncated Bid translocates to the mitochondria and activates the mitochondrial pathway after apoptosis induction through death receptors, and can be used to amplify the apoptotic signal.	7	12	causes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	9	10	11	12
Alternatively , caspase-8 can activate Bid which then promotes leakage of Cytochrome C.	Alternatively, caspase-8 can activate Bid which then promotes leakage of Cytochrome C.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	2	3	5	6
Since caspase-8 functions upstream of caspase-3 , we reasoned that inhibition of caspase-8 in TRAIL treated ML-1 cells would prevent BID cleavage .	Since caspase-8 functions upstream of caspase-3, we reasoned that inhibition of caspase-8 in TRAIL treated ML-1 cells would prevent BID cleavage.	10	21	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	12	13	20	21
Caspase 8 mediated cleavage of the BH3-only protein Bid into a truncated protein ( tBid ) and subsequent translocation of tBid to mitochondria has been implicated in death receptor signaling .	Caspase 8 mediated cleavage of the BH3-only protein Bid into a truncated protein (tBid) and subsequent translocation of tBid to mitochondria has been implicated in death receptor signaling.	0	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	Bid	Bid	Bid	0	2	8	9
Bax deficiency has no effect on TRAIL induced caspase-8 activation and subsequent cleavage of Bid ; however , it results in an incomplete caspase-3 processing because of inhibition by XIAP .	Bax deficiency has no effect on TRAIL induced caspase-8 activation and subsequent cleavage of Bid; however, it results in an incomplete caspase-3 processing because of inhibition by XIAP.	6	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	TRAIL induced caspase-8	caspase-8	Bid	Bid	bid	8	9	14	15
Previous reports have shown that activated caspase 8 cleaves BID and produces a 15-kDa truncated form of BID , named tBID [ XREF_BIBR - XREF_BIBR ] .	Previous reports have shown that activated caspase 8 cleaves BID and produces a 15-kDa truncated form of BID, named tBID [XREF_BIBR - XREF_BIBR].	5	24	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	BID	BID	BID	6	8	17	18
To link mitochondria mediated apoptosis and death-receptor-mediated apoptosis , caspase 8 is activated by the death receptors and cleaves BH3 interacting domain death agonist ( BID ) to generate truncated BID , inducing mitochondria mediated apoptosis [ XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	To link mitochondria mediated apoptosis and death-receptor-mediated apoptosis, caspase 8 is activated by the death receptors and cleaves BH3 interacting domain death agonist (BID) to generate truncated BID, inducing mitochondria mediated apoptosis [XREF_BIBR, XREF_BIBR] (XREF_FIG).	9	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	BH3 interacting domain death agonist	BH3 interacting domain death agonist	BH3 interacting domain death agonist	9	11	19	24
In this scenario , caspase-8 might induce Bid activation and enforce cytochrome c release , thereby amplifying the apoptotic cascade .	In this scenario, caspase-8 might induce Bid activation and enforce cytochrome c release, thereby amplifying the apoptotic cascade.	4	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	4	5	7	8
Caspase-8 allows the dimerization of Bid with Bax or Bcl-2 .	Caspase-8 allows the dimerization of Bid with Bax or Bcl-2.	0	6	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	5	6
These data suggest that FimH acts as a tethered toxin of UPEC that activates caspase dependent urothelial apoptosis via direct induction of the extrinsic pathway and that the intrinsic pathway is activated indirectly as a result of coupling by caspase 8 mediated Bid cleavage .	These data suggest that FimH acts as a tethered toxin of UPEC that activates caspase dependent urothelial apoptosis via direct induction of the extrinsic pathway and that the intrinsic pathway is activated indirectly as a result of coupling by caspase 8 mediated Bid cleavage.	31	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	39	41	42	43
Our data also suggest that LMP occurs earlier than mitochondrial outer membrane permeabilization ; Bid activation initiated by caspase-8 might be reinforced by CtrB in consequence of LMP , which causes a positive feedback loop leading to the accumulation of tBid , and results in lysosome- and mitochondrion dependent apoptosis .	Our data also suggest that LMP occurs earlier than mitochondrial outer membrane permeabilization; Bid activation initiated by caspase-8 might be reinforced by CtrB in consequence of LMP, which causes a positive feedback loop leading to the accumulation of tBid, and results in lysosome- and mitochondrion dependent apoptosis.	14	19	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	18	19	14	15
In contrast , a transient transfection of dominant negative caspase-8 or CrmA or exposure to caspase-8 inhibitor zIETD-fmk inhibited the processing of procaspase-8 and Bid but did not inhibit the cytosolic accumulation of cyt c in either the untreated HL-60 and Apaf-1 cells or the etoposide treated HL-60 and Apaf-1 and HL-60 and neo cells .	In contrast, a transient transfection of dominant negative caspase-8 or CrmA or exposure to caspase-8 inhibitor zIETD-fmk inhibited the processing of procaspase-8 and Bid but did not inhibit the cytosolic accumulation of cyt c in either the untreated HL-60 and Apaf-1 cells or the etoposide treated HL-60 and Apaf-1 and HL-60 and neo cells.	5	25	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	9	10	24	25
BH3 interacting domain death agonist ( Bid ) , a pro apoptotic member of the Bcl-2 family of proteins , is activated through cleavage by caspase-8 .	BH3 interacting domain death agonist (Bid), a pro apoptotic member of the Bcl-2 family of proteins, is activated through cleavage by caspase-8.	0	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BH3 interacting domain death agonist	BH3 interacting domain death agonist	BH3 interacting domain death agonist	25	26	0	5
Activation of Fas induces caspase 8 mediated cleavage of the BH3-only BID protein to the cleaved form cBID , which then translocates to the mitochondria to activate Bax and Bak , resulting in mitochondrial outer membrane permeabilization and cytochrome c release XREF_BIBR , XREF_BIBR .	Activation of Fas induces caspase 8 mediated cleavage of the BH3-only BID protein to the cleaved form cBID, which then translocates to the mitochondria to activate Bax and Bak, resulting in mitochondrial outer membrane permeabilization and cytochrome c release XREF_BIBR, XREF_BIBR.	3	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	BID	BID	BID	4	6	11	12
tBid facilitates the oligomerization of Bax and Bak to form membrane pores that disrupt mitochondrial membranes and release cytochrome c. Thus , caspase 8 mediated cleavage of Bid links extrinsic and intrinsic pathways of apoptosis induction .	tBid facilitates the oligomerization of Bax and Bak to form membrane pores that disrupt mitochondrial membranes and release cytochrome c. Thus, caspase 8 mediated cleavage of Bid links extrinsic and intrinsic pathways of apoptosis induction.	13	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	22	24	27	28
XREF_BIBR Caspase 8 activation triggers the sequential release of lysosomal cathepsin B , XREF_BIBR cleavage of the proapoptotic Bcl-2 family member Bid , XREF_BIBR initiation of the mitochondrial death pathway with release of cytochrome c and activation of downstream effector caspases that induce apoptosis .	XREF_BIBR Caspase 8 activation triggers the sequential release of lysosomal cathepsin B, XREF_BIBR cleavage of the proapoptotic Bcl-2 family member Bid, XREF_BIBR initiation of the mitochondrial death pathway with release of cytochrome c and activation of downstream effector caspases that induce apoptosis.	0	22	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	Bid	Bid	Bid	1	3	21	22
The link between caspase 8 activation and mitochondrial membrane disruption appears to be caspase 8 mediated cleavage of Bid .	The link between caspase 8 activation and mitochondrial membrane disruption appears to be caspase 8 mediated cleavage of Bid.	1	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	13	15	18	19
Bax activation is a hallmark of the intrinsic apoptosis pathway , but may also be activated secondary to extrinsic apoptosis through the caspase-8 dependent activation of Bid [ XREF_BIBR ] .	Bax activation is a hallmark of the intrinsic apoptosis pathway, but may also be activated secondary to extrinsic apoptosis through the caspase-8 dependent activation of Bid [XREF_BIBR].	22	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	22	23	26	27
Hepatic toxicity from GalN and LPS occurs through the classical TNF death cascade of caspase 8 mediated Bid cleavage into tBid which translocates to mitochondria to trigger cytochrome c release , effector caspase cleavage and apoptosis .	Hepatic toxicity from GalN and LPS occurs through the classical TNF death cascade of caspase 8 mediated Bid cleavage into tBid which translocates to mitochondria to trigger cytochrome c release, effector caspase cleavage and apoptosis.	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	14	16	17	18
Caspase-8 Activation and Proteolytic Cleavage of Bid in the Course of EAE .	Caspase-8 Activation and Proteolytic Cleavage of Bid in the Course of EAE.	0	7	Activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	6	7
Caspase-8 is known to activate Bid , and a specific inhibitor of caspase-8 prevented the mitochondrial damage .	Caspase-8 is known to activate Bid, and a specific inhibitor of caspase-8 prevented the mitochondrial damage.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	5	6
Activation may be accomplished by upregulating protein synthesis ( as Smads do for p15 ) , by inhibiting protein degradation ( e.g ., Emi1 inhibits Cdh1 , which promotes the degradation of cyclins A and B ) , by forming multimeric protein complexes ( e.g ., Cdh1 must associate with the anaphase promoting complex to label A- and B-type cyclins for degradation ) , or by post-translational modifications ( e.g ., MEK activates ERK by phosphorylation , and Caspase 8 activates Bid by trimming off a few amino acids ) .	Activation may be accomplished by upregulating protein synthesis (as Smads do for p15), by inhibiting protein degradation (e.g., Emi1 inhibits Cdh1, which promotes the degradation of cyclins A and B), by forming multimeric protein complexes (e.g., Cdh1 must associate with the anaphase promoting complex to label A- and B-type cyclins for degradation), or by post-translational modifications (e.g., MEK activates ERK by phosphorylation, and Caspase 8 activates Bid by trimming off a few amino acids).	78	82	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	Bid	Bid	Bid	78	80	81	82
Analysis of upstream signalling events affected by resveratrol revealed that the activated caspase-8 triggered mitochondrial apoptotic events by inducing Bid cleavage without any alteration in the levels of Bax , Bcl-xL or Bcl2 .	Analysis of upstream signalling events affected by resveratrol revealed that the activated caspase-8 triggered mitochondrial apoptotic events by inducing Bid cleavage without any alteration in the levels of Bax, Bcl-xL or Bcl2.	10	20	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	12	13	19	20
Similarly , mitochondrial signaling may be triggered during activation of the extrinsic cascade , via caspase 8 mediated cleavage of the BH3-only protein Bid .	Similarly, mitochondrial signaling may be triggered during activation of the extrinsic cascade, via caspase 8 mediated cleavage of the BH3-only protein Bid.	8	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	15	17	23	24
Caspase-8 has been implicated in the mechanism of Bid activation after seizures on the basis that caspase-8 pseudosubstrate inhibitors reduced Bid cleavage .	Caspase-8 has been implicated in the mechanism of Bid activation after seizures on the basis that caspase-8 pseudosubstrate inhibitors reduced Bid cleavage.	16	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	16	17	20	21
Bid is a pro apoptotic member of the Bcl-2 family , and many studies have demonstrated that , following apoptotic stimuli , activation of caspase-8 induces cleavage of Bid [ XREF_BIBR , XREF_BIBR ] .	Bid is a pro apoptotic member of the Bcl-2 family, and many studies have demonstrated that, following apoptotic stimuli, activation of caspase-8 induces cleavage of Bid [XREF_BIBR, XREF_BIBR].	22	32	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	24	25	28	29
For example , caspase 8 , the initiator of the extrinsic pathway , mediates the activation of BID , a regulatory , proapoptotic member of the BCL2 family .	For example, caspase 8, the initiator of the extrinsic pathway, mediates the activation of BID, a regulatory, proapoptotic member of the BCL2 family.	3	23	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	BID	BID	BID	3	5	17	18
As a result , the activity of caspase-8 was stimulated causing cleavage of the pro apoptotic protein Bid , which is involved in the permeabilization of the outer mitochondrial membrane and the release of pro apoptotic factors , such as cytochrome c from mitochondria .	As a result, the activity of caspase-8 was stimulated causing cleavage of the pro apoptotic protein Bid, which is involved in the permeabilization of the outer mitochondrial membrane and the release of pro apoptotic factors, such as cytochrome c from mitochondria.	5	21	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	7	8	17	18
Our experiments with gene targeted mice demonstrated that TNFalpha mediated hepatocyte apoptosis requires caspase-8 and involves the pro apoptotic BH3-only proteins Bid , activated by caspase-8 , and Bim , activated by JNK , respectively .	Our experiments with gene targeted mice demonstrated that TNFalpha mediated hepatocyte apoptosis requires caspase-8 and involves the pro apoptotic BH3-only proteins Bid, activated by caspase-8, and Bim, activated by JNK, respectively.	15	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	25	26	21	22
One of the major mechanisms of cross-talk between the intrinsic and extrinsic apoptotic pathways is through Casp-8 mediated cleavage of BID XREF_BIBR , XREF_BIBR , XREF_BIBR .	One of the major mechanisms of cross-talk between the intrinsic and extrinsic apoptotic pathways is through Casp-8 mediated cleavage of BID XREF_BIBR, XREF_BIBR, XREF_BIBR.	4	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp-8	Casp-8	Casp-8	BID	BID	BID	16	17	20	21
Caspase-8 activates the Bcl-2-family protein Bid to engage the intrinsic pathway via Bax .	Caspase-8 activates the Bcl-2-family protein Bid to engage the intrinsic pathway via Bax.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	5	6
On the other hand , in the great majority of cells ( Type II cells ) , the level of death receptor induced activation of caspase-8 is less efficient for direct activation of downstream caspases , but is enough to promote the cleavage of Bid , a member of the Bcl-2 family protein .	On the other hand, in the great majority of cells (Type II cells), the level of death receptor induced activation of caspase-8 is less efficient for direct activation of downstream caspases, but is enough to promote the cleavage of Bid, a member of the Bcl-2 family protein.	20	47	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	death receptor induced activation of caspase-8	caspase-8	Bid	Bid	bid	25	26	44	45
Inhibition of caspase-8 suppressed the expression of Bad and Bid and the subsequent activation of caspase-9 and -3 .	Inhibition of caspase-8 suppressed the expression of Bad and Bid and the subsequent activation of caspase-9 and -3.	0	17	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	2	3	9	10
Caspase mediated activation of proteins is well established in the apoptotic pathway , such as the activation of executioner caspases by initiator caspases or the caspase-8 mediated activation of the pro apoptotic BH3-only protein Bid .	Caspase mediated activation of proteins is well established in the apoptotic pathway, such as the activation of executioner caspases by initiator caspases or the caspase-8 mediated activation of the pro apoptotic BH3-only protein Bid.	25	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	25	26	34	35
In certain cell types , the Fas mediated signal requires amplification of the caspase cascade to cause death , and this is achieved by caspase-8 activation of the pro apoptotic Bid ( BH3 interacting domain death agonist ) , which leads to increase in the mitochondrial membrane permeability and the associated cascade of events .	In certain cell types, the Fas mediated signal requires amplification of the caspase cascade to cause death, and this is achieved by caspase-8 activation of the pro apoptotic Bid (BH3 interacting domain death agonist), which leads to increase in the mitochondrial membrane permeability and the associated cascade of events.	24	42	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	24	25	30	31
The cleavage of Bid activated by caspase-8 might serve as a crosstalk mediator between these two pathways in CRC .	The cleavage of Bid activated by caspase-8 might serve as a crosstalk mediator between these two pathways in CRC.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	6	7	3	4
Caspase-8 mediates the cleavage of full length Bid to generate a truncated form ( tBid ) which translocates to the mitochondria to promote the insertion of Bax into the outer membrane mitochondrial membrane [ XREF_BIBR , XREF_BIBR ] .	Caspase-8 mediates the cleavage of full length Bid to generate a truncated form (tBid) which translocates to the mitochondria to promote the insertion of Bax into the outer membrane mitochondrial membrane [XREF_BIBR, XREF_BIBR].	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	7	8
Although Fas- and TNF receptor induced hepatocyte cell death , a prototypical type II cell , has been suggested to depend on caspase 8 mediated cleavage of the BH3-only protein Bid to tBid and subsequent amplification of the apoptosis signal via the mitochondrial pathway , our own results and those by others demonstrate that Bim is also an essential component of this pathway .	Although Fas- and TNF receptor induced hepatocyte cell death, a prototypical type II cell, has been suggested to depend on caspase 8 mediated cleavage of the BH3-only protein Bid to tBid and subsequent amplification of the apoptosis signal via the mitochondrial pathway, our own results and those by others demonstrate that Bim is also an essential component of this pathway.	20	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	22	24	30	31
Besides , activated caspase-8 can also cause the cleavage of Bid to yield a truncated form , tBid [ XREF_BIBR , XREF_BIBR ] .	Besides, activated caspase-8 can also cause the cleavage of Bid to yield a truncated form, tBid [XREF_BIBR, XREF_BIBR].	2	11	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	3	4	10	11
In addition to directly cleaving and activating caspase-3 , activated caspase-8 can alternatively causes cleavage of Bid , a pro apoptotic Bcl-2 family protein , which translocates to mitochondria , inducing cytochrome c release , sequentially activating caspase-9 and -3 , [ XREF_BIBR ] We therefore attempted to investigate whether TSLP treatment could influence the expression of proteins in mitochondria dependent apoptotic pathway .	In addition to directly cleaving and activating caspase-3, activated caspase-8 can alternatively causes cleavage of Bid, a pro apoptotic Bcl-2 family protein, which translocates to mitochondria, inducing cytochrome c release, sequentially activating caspase-9 and -3, [XREF_BIBR] We therefore attempted to investigate whether TSLP treatment could influence the expression of proteins in mitochondria dependent apoptotic pathway.	9	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	10	11	16	17
This may contribute to the triggering of the extrinsic pathway consisting in caspase 8 activation , which in turn causes BID cleavage and cytochrome c release .	This may contribute to the triggering of the extrinsic pathway consisting in caspase 8 activation, which in turn causes BID cleavage and cytochrome c release.	12	21	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	BID	BID	BID	12	14	20	21
Finally , we show that the extensive caspase 8 cleavage seen during TRAIL-etoposide synergy is a consequence and not a cause of the apoptotic cascade activated downstream of Bid .	Finally, we show that the extensive caspase 8 cleavage seen during TRAIL-etoposide synergy is a consequence and not a cause of the apoptotic cascade activated downstream of Bid.	5	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	7	9	28	29
Activation of caspase-8 induces proteolytic cleavage of Bid to tBid , which is then translocated to mitochondrial membrane for aiding mitochondrial release of pro apoptotic factors into the cytosol .	Activation of caspase-8 induces proteolytic cleavage of Bid to tBid, which is then translocated to mitochondrial membrane for aiding mitochondrial release of pro apoptotic factors into the cytosol.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	2	3	7	8
Active caspase-8 caused the proteolytic cleavage of its substrate 22 kD Bid to generate 15 kD truncated Bid ( tBid ) ( XREF_FIG ) , which could translocate to mitochondria to induce intrinsic apoptotic pathway by releasing cytochrome c from mitochondrial inter membrane space .	Active caspase-8 caused the proteolytic cleavage of its substrate 22 kD Bid to generate 15 kD truncated Bid (tBid) (XREF_FIG), which could translocate to mitochondria to induce intrinsic apoptotic pathway by releasing cytochrome c from mitochondrial inter membrane space.	0	13	caused	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	1	2	11	12
Bid , activated by caspase-8 , induces MMP and mediates the main cross-talk between the extrinsic and intrinsic pathways [ XREF_BIBR , XREF_BIBR ] .	Bid, activated by caspase-8, induces MMP and mediates the main cross-talk between the extrinsic and intrinsic pathways [XREF_BIBR, XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	4	5	0	1
We found melatonin completely blocked caspase-8 activation and proteolytic cleavage of Bid to tBid significantly in VSC4.1 cells treated with H 2 O 2 , LGA , or TNF-alpha ( XREF_FIG ) and post-treatment with luzindole significantly decreased the melatonin action .	We found melatonin completely blocked caspase-8 activation and proteolytic cleavage of Bid to tBid significantly in VSC4.1 cells treated with H 2 O 2, LGA, or TNF-alpha (XREF_FIG) and post-treatment with luzindole significantly decreased the melatonin action.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	5	6	11	12
Alternatively , cathepsin L may activate caspase-8 , which in turns cleaves and activates Bid .	Alternatively, cathepsin L may activate caspase-8, which in turns cleaves and activates Bid.	5	15	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	6	7	14	15
The active caspase-8 also mediates the proteolytic cleavage of Bid into tBid , which is translocated to mitochondria and amplifies the intrinsic apoptosis pathway .	The active caspase-8 also mediates the proteolytic cleavage of Bid into tBid, which is translocated to mitochondria and amplifies the intrinsic apoptosis pathway.	0	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	2	3	9	10
Our findings indicate that during extrinsic apoptosis , caspase-8 can specifically target BID where it is mostly needed , on the surface of mitochondria .	Our findings indicate that during extrinsic apoptosis, caspase-8 can specifically target BID where it is mostly needed, on the surface of mitochondria.	8	17	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	8	9	12	13
Extrinsic apoptotic cascade results in the proteolytic activation of BID by caspase-8 .	Extrinsic apoptotic cascade results in the proteolytic activation of BID by caspase-8.	3	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	11	12	9	10
Inhibition of caspase 8 blocked Bid cleavage and Bax conformational change .	Inhibition of caspase 8 blocked Bid cleavage and Bax conformational change.	0	6	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	2	4	5	6
5 The extrinsic pathway may also be enhanced via the mitochondria , as caspase-8 can process and activate the proapoptotic BH3-only protein Bid leading to truncated Bid ( tBid ) .	5 The extrinsic pathway may also be enhanced via the mitochondria, as caspase-8 can process and activate the proapoptotic BH3-only protein Bid leading to truncated Bid (tBid).	13	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	13	14	22	23
TRAIL promotes caspase-8 activation and can activate executioner caspases through direct cleavage by caspase-8 ( type I ) or via Bid mediated MOMP leading to caspase-9 cleavage ( type II ) .	TRAIL promotes caspase-8 activation and can activate executioner caspases through direct cleavage by caspase-8 (type I) or via Bid mediated MOMP leading to caspase-9 cleavage (type II).	6	21	activate	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	13	14	20	21
Active caspase-8 can activate Bid , which then triggers the mitochondrial pathway to further activate caspase-9 and in turn activates the executioner , caspase-3 , thus committing a cell to apoptosis XREF_BIBR .	Active caspase-8 can activate Bid, which then triggers the mitochondrial pathway to further activate caspase-9 and in turn activates the executioner, caspase-3, thus committing a cell to apoptosis XREF_BIBR.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	1	2	4	5
In this context , it should be noted that activated caspase-8 and -10 can also proteolytically activate pro apoptotic Bcl-2 family member Bid generating tBid XREF_BIBR , XREF_BIBR .	In this context, it should be noted that activated caspase-8 and -10 can also proteolytically activate pro apoptotic Bcl-2 family member Bid generating tBid XREF_BIBR, XREF_BIBR.	9	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	10	11	22	23
Inhibition of caspase-8 activity also reduced hyperglycemia induced Bid activation and caspase-9 cleavage .	Inhibition of caspase-8 activity also reduced hyperglycemia induced Bid activation and caspase-9 cleavage.	2	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	2	3	8	9
For instance , caspase 8 activation , via stimulation of Fas in the plasma membrane , induces rapid activation of Bid and evokes its translocation to mitochondria as tBid .	For instance, caspase 8 activation, via stimulation of Fas in the plasma membrane, induces rapid activation of Bid and evokes its translocation to mitochondria as tBid.	3	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	3	5	20	21
In the intrinsic pathway , caspase-8 promotes the cleavage of Bid and then activates truncated Bid ( tBid ) ultimately leading to mitochondrial mediated apoptosis [ XREF_BIBR ] .	In the intrinsic pathway, caspase-8 promotes the cleavage of Bid and then activates truncated Bid (tBid) ultimately leading to mitochondrial mediated apoptosis [XREF_BIBR].	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	5	6	15	16
As shown in XREF_FIG , suppression of caspase-8 activity with Z-IETD-FMK was found to inhibit cleavage of Bid and PARP induced by dicycloplatin .	As shown in XREF_FIG, suppression of caspase-8 activity with Z-IETD-FMK was found to inhibit cleavage of Bid and PARP induced by dicycloplatin.	7	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	7	8	17	18
In addition , Bid activation was also noted in ApxI treated PAMs , and inhibition of caspase-8 suppressed the activation of Bid and caspase-9 , suggesting that ApxI was able to activate the caspases-8-Bid-caspase-9 pathway .	In addition, Bid activation was also noted in ApxI treated PAMs, and inhibition of caspase-8 suppressed the activation of Bid and caspase-9, suggesting that ApxI was able to activate the caspases-8-Bid-caspase-9 pathway.	14	23	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	16	17	21	22
In addition to activation of the mitochondrial pathway by death stimuli , DRs activate the mitochondrial pathway through caspase 8 mediated cleavage and activation of Bid .	In addition to activation of the mitochondrial pathway by death stimuli, DRs activate the mitochondrial pathway through caspase 8 mediated cleavage and activation of Bid.	13	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	18	20	25	26
Notably , BID is activated upon the activation of the extrinsic pathway and cleavage by caspase-8 to form tBid .	Notably, BID is activated upon the activation of the extrinsic pathway and cleavage by caspase-8 to form tBid.	2	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	BID	BID	BID	15	16	2	3
During death receptor induced apoptosis , Bid is activated through cleavage by caspase-8 or caspase-10 , generating a truncated form , t-Bid , XREF_BIBR , XREF_BIBR .	During death receptor induced apoptosis, Bid is activated through cleavage by caspase-8 or caspase-10, generating a truncated form, t-Bid, XREF_BIBR, XREF_BIBR.	6	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	12	13	6	7
The combination treatment also triggered apoptosis through caspase-8/Bid/Bax activation , and the inhibition of caspase-8 suppressed caspase-8 and Bid activation , caspase-3-mediated PARP cleavage , and concomitant apoptosis .	The combination treatment also triggered apoptosis through caspase-8/Bid/Bax activation, and the inhibition of caspase-8 suppressed caspase-8 and Bid activation, caspase-3-mediated PARP cleavage, and concomitant apoptosis.	12	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	14	15	18	19
Additionally , these results suggest that the caspase 8 mediated cleavage of Bid into tBid , if any , occurred as a down-stream event of mitochondrial damage rather than an initial event that causes mitochondrial damage .	Additionally, these results suggest that the caspase 8 mediated cleavage of Bid into tBid, if any, occurred as a down-stream event of mitochondrial damage rather than an initial event that causes mitochondrial damage.	6	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	7	9	12	13
Caspase-8 can proteolytically activate Bid , which can then facilitate the release of cytochrome c and amplify the apoptotic signal that follows the engagement of death receptors .	Caspase-8 can proteolytically activate Bid, which can then facilitate the release of cytochrome c and amplify the apoptotic signal that follows the engagement of death receptors.	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	Bid	Bid	Bid	0	1	4	5
It is suggested that caspase-8 might activate Bid protein ( BH3 interacting domain ) , which might be a molecular bridge to intrinsic pathway of apoptosis , as it binds to the activated Bax protein on mitochondria surface , and thus contribute to the pore generation in this organelle .	It is suggested that caspase-8 might activate Bid protein (BH3 interacting domain), which might be a molecular bridge to intrinsic pathway of apoptosis, as it binds to the activated Bax protein on mitochondria surface, and thus contribute to the pore generation in this organelle.	4	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	4	5	7	8
We also showed that a blockade of the association of caspase-8 with mitochondria due to cardiolipin deficiency resulted in the inhibition of p43-p10 formation , preventing both Bid cleavage and apoptosis XREF_BIBR .	We also showed that a blockade of the association of caspase-8 with mitochondria due to cardiolipin deficiency resulted in the inhibition of p43-p10 formation, preventing both Bid cleavage and apoptosis XREF_BIBR.	8	28	preventing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	10	11	27	28
Proteolytic Bid cleavage mediated by caspase-8 leads to Bid myristoylation , mitochondrial localization and MOMP induction , an event that suggests a crosstalk event between the two major apoptotic pathways .	Proteolytic Bid cleavage mediated by caspase-8 leads to Bid myristoylation, mitochondrial localization and MOMP induction, an event that suggests a crosstalk event between the two major apoptotic pathways.	1	6	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	5	6	1	2
However the activation of Bid and the induction of MOMP did not appear critical for TNFalpha induced cell death in macrophages since inhibition of caspase 8 suppressed Bid cleavage and the release of cytochrome c but had no effect of cell death .	However the activation of Bid and the induction of MOMP did not appear critical for TNFalpha induced cell death in macrophages since inhibition of caspase 8 suppressed Bid cleavage and the release of cytochrome c but had no effect of cell death.	22	28	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	24	26	27	28
XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR - XREF_BIBR In addition , rhTRAIL can activate the intrinsic pathway of apoptosis independently of p53 through the caspase 8 mediated cleavage of Bid to truncated Bid ( tBid ) facilitating the release of cytochrome c from the mitochondria followed by the activation of caspase 9 and the subsequent activation of the executioner caspases .	XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR - XREF_BIBR In addition, rhTRAIL can activate the intrinsic pathway of apoptosis independently of p53 through the caspase 8 mediated cleavage of Bid to truncated Bid (tBid) facilitating the release of cytochrome c from the mitochondria followed by the activation of caspase 9 and the subsequent activation of the executioner caspases.	11	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	Bid	Bid	Bid	22	24	27	28
Activated caspase-8 can also induce caspase-9 activation through Bid mediated activation of the mitochondria mediated apoptotic pathway .	Activated caspase-8 can also induce caspase-9 activation through Bid mediated activation of the mitochondria mediated apoptotic pathway.	0	6	induce	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	1	2	5	6
These data are consistent with ABT-737 causing increased caspase-9 activation by caspase-8 .	These data are consistent with ABT-737 causing increased caspase-9 activation by caspase-8.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	11	12	8	9
We further observed that heat stress generates ROS , which activates caspase-9 rather than caspase-8 and -4 .	We further observed that heat stress generates ROS, which activates caspase-9 rather than caspase-8 and -4.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	14	15	11	12
To determine if CASP8 activation in casp9 -/- cells exposed to long-term ER stress was a consequence of death receptor activation we employed a blocking antibody strategy .	To determine if CASP8 activation in casp9 -/- cells exposed to long-term ER stress was a consequence of death receptor activation we employed a blocking antibody strategy.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	casp9	casp9	casp9	3	4	6	7
Caspase-9 activation by mitochondrial pathway and caspase-8 activation by extrinsic pathway lead to activation of the executioner caspases , such as caspase-3 or -7 which then directly degrade the proteome and commit cells to death ( XREF_FIG ) .	Caspase-9 activation by mitochondrial pathway and caspase-8 activation by extrinsic pathway lead to activation of the executioner caspases, such as caspase-3 or -7 which then directly degrade the proteome and commit cells to death (XREF_FIG).	0	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-9	Caspase-9	Caspase-9	6	7	0	1
Thus , induction of apoptosis was preceded by the activation of activator caspase-8 , initiating receptor mediated apoptosis , and caspase-9 , initiating mitochondrial apoptosis , as well as the effector caspase-3 .	Thus, induction of apoptosis was preceded by the activation of activator caspase-8, initiating receptor mediated apoptosis, and caspase-9, initiating mitochondrial apoptosis, as well as the effector caspase-3.	9	21	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	12	13	20	21
This suggests that caspase-9 is activated not only by caspase-8 activation but also by other upstream apoptotic signals .	This suggests that caspase-9 is activated not only by caspase-8 activation but also by other upstream apoptotic signals.	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	9	10	3	4
Caspase-9 can be activated by caspase-8 or activated independently by apoptotic protease activating factor 1 on binding of cytochrome c release from the mitochondria .	Caspase-9 can be activated by caspase-8 or activated independently by apoptotic protease activating factor 1 on binding of cytochrome c release from the mitochondria.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-9	Caspase-9	Caspase-9	5	6	0	1
Caspase 8 can also activate caspase 9 via a pro apoptotic Bcl-2 family member , Bid .	Caspase 8 can also activate caspase 9 via a pro apoptotic Bcl-2 family member, Bid.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 8	Caspase 8	Caspase 8	caspase 9	caspase 9	caspase 9	0	2	5	7
It is known that caspase-8 can be activated by stimulation of TLR3 or TLR4 [ XREF_BIBR ] and that caspase-9 can be activated by caspase-8 [ XREF_BIBR , XREF_BIBR ] .	It is known that caspase-8 can be activated by stimulation of TLR3 or TLR4 [XREF_BIBR] and that caspase-9 can be activated by caspase-8 [XREF_BIBR, XREF_BIBR].	19	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	24	25	19	20
Previous studies from our laboratory had indicated that cytochrome c independent processing and activation of caspase-9 by caspase-8 contributed to early amplification of the caspase cascade in tumor necrosis factor ( TNF )-alpha-treated murine cells .	Previous studies from our laboratory had indicated that cytochrome c independent processing and activation of caspase-9 by caspase-8 contributed to early amplification of the caspase cascade in tumor necrosis factor (TNF)-alpha-treated murine cells.	13	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	17	18	15	16
Noscapine treatments significantly ( P < 0.001 ) decreased expression of NF-kB , IkBalpha , P-IkBalpha , BCl 2 and increased expression of cleaved PARP , Bax , activated caspase8 , activated caspase 9 , caspase 3 and cleaved caspase 3 proteins compared to control ( XREF_FIG ) except Noscapine administered at 150 mg/kg/day ( P > 0.05 ) .	Noscapine treatments significantly (P < 0.001) decreased expression of NF-kB, IkBalpha, P-IkBalpha, BCl 2 and increased expression of cleaved PARP, Bax, activated caspase8, activated caspase 9, caspase 3 and cleaved caspase 3 proteins compared to control (XREF_FIG) except Noscapine administered at 150 mg/kg/day (P> 0.05).	26	39	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase8	caspase8	caspase8	caspase 9	caspase 9	caspase 9	29	30	32	34
In contrast , in the activation of apoptosis , another form of cell death , the initiator caspases ' activation platforms , such as death initiation signal complex ( DISC ) and apoptosome , sense pro apoptotic stimuli and activate either death receptor and DISC activated caspase-8 or mitochondrion and cytochrome c/apoptosome activated caspase-9 pathway , respectively XREF_BIBR , XREF_BIBR .	In contrast, in the activation of apoptosis, another form of cell death, the initiator caspases ' activation platforms, such as death initiation signal complex (DISC) and apoptosome, sense pro apoptotic stimuli and activate either death receptor and DISC activated caspase-8 or mitochondrion and cytochrome c/apoptosome activated caspase-9 pathway, respectively XREF_BIBR, XREF_BIBR.	46	54	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	46	47	53	54
Lymphocyte apoptosis is mainly induced by either death receptor dependent activation of caspase-8 or mitochondria dependent activation of caspase-9 .	Lymphocyte apoptosis is mainly induced by either death receptor dependent activation of caspase-8 or mitochondria dependent activation of caspase-9.	12	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	12	13	18	19
Caspase8 triggers a series of molecular events to activate caspase9 which , in turn , activates effector caspases .	Caspase8 triggers a series of molecular events to activate caspase9 which, in turn, activates effector caspases.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase8	Caspase8	Caspase8	caspase9	caspase9	caspase9	0	1	9	10
However , caspase inhibitor assays suggest that CASP9 does not act as an initiator but merely as an effector caspase in an amplification loop and is activated by CASP8 or CASP10 similar to TNF-alpha , which induced apoptosis via activation of CASP9 by CASP8 [ XREF_BIBR , XREF_BIBR ] .	However, caspase inhibitor assays suggest that CASP9 does not act as an initiator but merely as an effector caspase in an amplification loop and is activated by CASP8 or CASP10 similar to TNF-alpha, which induced apoptosis via activation of CASP9 by CASP8 [XREF_BIBR, XREF_BIBR].	39	47	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	CASP9	CASP9	CASP9	43	44	41	42
Also , caspase-8 would activate caspase-9 through the mitochondrial pathway [ XREF_BIBR ] which finally leads to the activation of caspase-3/7 .	Also, caspase-8 would activate caspase-9 through the mitochondrial pathway [XREF_BIBR] which finally leads to the activation of caspase-3/7.	2	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	2	3	5	6
Blocking caspase-8 activity using z-IETD-FMK , a specific inhibitor of caspase-8 , does not completely abrogate caspase-9 activation .	Blocking caspase-8 activity using z-IETD-FMK, a specific inhibitor of caspase-8, does not completely abrogate caspase-9 activation.	1	17	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	1	2	16	17
BID mediates the activation of caspase-9 by caspase-8 through the mitochondrial pathway .	BID mediates the activation of caspase-9 by caspase-8 through the mitochondrial pathway.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	7	8	5	6
To confirm caspase-8 mediated caspase-9 activation , NO induced apoptosis and caspase-9 activation were monitored both in caspase-8 inhibitor pre-treated and NO stimulated cells .	To confirm caspase-8 mediated caspase-9 activation, NO induced apoptosis and caspase-9 activation were monitored both in caspase-8 inhibitor pre-treated and NO stimulated cells.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	2	3	4	5
Moreover , this release is implicated in the cross activation of caspase-9 by caspase-8 , thereby linking the extrinsic and intrinsic apoptotic pathways .	Moreover, this release is implicated in the cross activation of caspase-9 by caspase-8, thereby linking the extrinsic and intrinsic apoptotic pathways.	5	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	13	14	11	12
This result was very surprising , because Jurkat cells are well documented to undergo type II extrinsic apoptosis where caspase-8 is not just required to activate caspase-9 , but caspase-9 is necessary to kill the cell [ XREF_BIBR ] .	This result was very surprising, because Jurkat cells are well documented to undergo type II extrinsic apoptosis where caspase-8 is not just required to activate caspase-9, but caspase-9 is necessary to kill the cell [XREF_BIBR].	19	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	19	20	26	27
We next further investigated whether activation of caspases is necessary for tricetin induced apoptosis of HL-60 cells by an MTS assay using specific inhibitors that respectively inhibit caspase-9 ( Z-LEHD-FMK ) , caspase-8 ( Z-IETD-FMK ) , or a broad-spectrum caspase ( Z-VAD-FMK ) .	We next further investigated whether activation of caspases is necessary for tricetin induced apoptosis of HL-60 cells by an MTS assay using specific inhibitors that respectively inhibit caspase-9 (Z-LEHD-FMK), caspase-8 (Z-IETD-FMK), or a broad-spectrum caspase (Z-VAD-FMK).	21	34	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	32	33	27	28
Furthermore , the inhibition of caspase-8 activity prevented the activation of caspase-9 , suggesting that caspase-9 is activated by cross talk with caspase-8 .	Furthermore, the inhibition of caspase-8 activity prevented the activation of caspase-9, suggesting that caspase-9 is activated by cross talk with caspase-8.	5	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	5	6	11	12
A reasonable candidate for the mediator of caspase-8 activation of caspase-9 is Bid .	A reasonable candidate for the mediator of caspase-8 activation of caspase-9 is Bid.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	7	8	10	11
It is well known that caspase 9 can be activated by caspase 8 or can be activated independently on binding of cytochrome c release from the mitochondria [ XREF_BIBR ] .	It is well known that caspase 9 can be activated by caspase 8 or can be activated independently on binding of cytochrome c release from the mitochondria [XREF_BIBR].	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 9	caspase 9	caspase 9	11	13	5	7
Similarly to the function of caspase 9 in the intrinsic pathway , caspase 8 also leads to effector caspases activation and the degradation phase of apoptosis .	Similarly to the function of caspase 9 in the intrinsic pathway, caspase 8 also leads to effector caspases activation and the degradation phase of apoptosis.	3	17	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 9	caspase 9	caspase 9	12	14	5	7
Inhibition of caspase-8 significantly decreased neuronal cell death , accompanied by reduction of t-Bid , cleaved caspase-9 and cytosol cytochrome c. Smac/DIABLO from mitochondria was not affected .	Inhibition of caspase-8 significantly decreased neuronal cell death, accompanied by reduction of t-Bid, cleaved caspase-9 and cytosol cytochrome c. Smac/DIABLO from mitochondria was not affected.	0	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	2	3	16	17
Of note , knockdown of caspase-8 by stable shRNA transfection prevented caspase-9 , -3 and PARP processing , revealing a role of caspase-8 upstream of the apoptosome ( XREF_FIG ) .	Of note, knockdown of caspase-8 by stable shRNA transfection prevented caspase-9, -3 and PARP processing, revealing a role of caspase-8 upstream of the apoptosome (XREF_FIG).	3	16	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	5	6	11	12
In addition , the level of pro-caspase-9 reduced by TPL was not decreased by caspase-8 inhibitor Z-IETD-FMK , indicating that caspase-9 activation is mediated by active caspase-8 .	In addition, the level of pro-caspase-9 reduced by TPL was not decreased by caspase-8 inhibitor Z-IETD-FMK, indicating that caspase-9 activation is mediated by active caspase-8.	20	27	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	26	27	20	21
Meanwhile , activated caspase-8 , as an upstream signaling molecule in caspase cascades , could induce caspase-9 activation .	Meanwhile, activated caspase-8, as an upstream signaling molecule in caspase cascades, could induce caspase-9 activation.	2	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	3	4	16	17
This is achieved through caspase-8 activation of the mitochondrial , intrinsic pathway and caspase-9 activation .	This is achieved through caspase-8 activation of the mitochondrial, intrinsic pathway and caspase-9 activation.	4	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	4	5	13	14
In addition to direct activation of executor caspases , caspase-8 activation of the initiator caspase-9 also triggers activation of executor caspases .	In addition to direct activation of executor caspases, caspase-8 activation of the initiator caspase-9 also triggers activation of executor caspases.	9	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	9	10	14	15
In addition , we also observed caspase 8 activation , which may activate caspase 9 through BH3 interacting domain death agonist ( Bid ) [ XREF_BIBR ] .	In addition, we also observed caspase 8 activation, which may activate caspase 9 through BH3 interacting domain death agonist (Bid) [XREF_BIBR].	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 9	caspase 9	caspase 9	6	8	13	15
Recent studies of the mitochondrial apoptosis pathway demonstrate that caspase-8 and -10 can also be activated downstream of the mitochondria by caspase-3 , indicating the existence of so called amplification loops where caspase-8 or -10 activate caspase-9 and -3 XREF_BIBR - XREF_BIBR .	Recent studies of the mitochondrial apoptosis pathway demonstrate that caspase-8 and -10 can also be activated downstream of the mitochondria by caspase-3, indicating the existence of so called amplification loops where caspase-8 or -10 activate caspase-9 and -3 XREF_BIBR - XREF_BIBR.	32	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	32	33	36	37
In addition , caspase-3 inhibition prevented caspase-8 activation while caspase-8 inhibition prevented caspase-9 activation .	In addition, caspase-3 inhibition prevented caspase-8 activation while caspase-8 inhibition prevented caspase-9 activation.	9	13	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	9	10	12	13
Local injection of TNF inhibitor down-regulated caspase-8 expression and reduced TUNEL positive cell number , but did not reverse cartilage thickness reduction , caspase-9 up-regulation or cytochrome c release .	Local injection of TNF inhibitor down-regulated caspase-8 expression and reduced TUNEL positive cell number, but did not reverse cartilage thickness reduction, caspase-9 up-regulation or cytochrome c release.	3	24	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-8	TNF inhibitor down-regulated caspase-8 expression	caspase-8	caspase-9	caspase-9	caspase-9	6	7	23	24
Additionally , using both pharamacological as well as genetic approaches we demonstrated that CCL2 mediated neuroprotection involved activation of its cognate receptor CCR2 .	Additionally, using both pharamacological as well as genetic approaches we demonstrated that CCL2 mediated neuroprotection involved activation of its cognate receptor CCR2.	13	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	13	14	22	23
Having determined that this CCL2 induced monocyte migration in vivo was CCR2 mediated , we used this system to characterize the effects of the small molecule CCR2 antagonist MK0812 , a highly potent and selective reagent [ XREF_BIBR , XREF_BIBR ] .	Having determined that this CCL2 induced monocyte migration in vivo was CCR2 mediated, we used this system to characterize the effects of the small molecule CCR2 antagonist MK0812, a highly potent and selective reagent [XREF_BIBR, XREF_BIBR].	3	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	11	12
Here , CCL2 released by inflammatory monocytes may activate pDCs reaching the inflammatory site as well as CCR2 + endothelial cells , promoting pDC adhesion to the endothelium and transendothelial migration .	Here, CCL2 released by inflammatory monocytes may activate pDCs reaching the inflammatory site as well as CCR2 + endothelial cells, promoting pDC adhesion to the endothelium and transendothelial migration.	2	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	2	3	17	18
This minor role of Ccl2 on the RD8 retinal degeneration seems consistent with our previous observation that Ccl2 deficiency does not lead to a significant associated age related retinal degeneration despite an accumulation of subretinal , dysfunctional macrophages XREF_BIBR and may be explained by a minor role of Ccl2 in this process or by a compensatory effect of other chemokine ligands that can bind to and activate CCR2 XREF_BIBR .	This minor role of Ccl2 on the RD8 retinal degeneration seems consistent with our previous observation that Ccl2 deficiency does not lead to a significant associated age related retinal degeneration despite an accumulation of subretinal, dysfunctional macrophages XREF_BIBR and may be explained by a minor role of Ccl2 in this process or by a compensatory effect of other chemokine ligands that can bind to and activate CCR2 XREF_BIBR.	17	68	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ccl2	Ccl2	Ccl2	CCR2	CCR2	CCR2	17	18	67	68
Indeed , CCL2 -/-, CCR2 -/-, and GM-CSF -/- mice as well as mice treated with CCL2 neutralizing antibodies are markedly resistant to EAE .	Indeed, CCL2 -/-, CCR2 -/-, and GM-CSF -/- mice as well as mice treated with CCL2 neutralizing antibodies are markedly resistant to EAE.	2	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	16	17	4	5
MRGPR-X1-induced CCR2 expression is of particular interest , considering that CCL2 induced activation of CCR2 in DRG neurons plays a major role in distinct neuropathic pain syndromes , as demonstrated by significantly diminished neuropathic pain responses found in mice deficient of the CCR2 gene XREF_BIBR and by abolished neuropathy induced hyperalgesia and allodynia after application of CCR2 specific antagonists to wild-type mice XREF_BIBR , XREF_BIBR .	MRGPR-X1-induced CCR2 expression is of particular interest, considering that CCL2 induced activation of CCR2 in DRG neurons plays a major role in distinct neuropathic pain syndromes, as demonstrated by significantly diminished neuropathic pain responses found in mice deficient of the CCR2 gene XREF_BIBR and by abolished neuropathy induced hyperalgesia and allodynia after application of CCR2 specific antagonists to wild-type mice XREF_BIBR, XREF_BIBR.	10	17	induced	Positive_early_activation	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	10	11	14	15
This is in agreement with a previous animal study which showed that a CCL2 antagonizing Spiegelmer reduces the peripheral monocyte count by inhibiting the CCR2 positive monocyte emigration from the bone marrow to the blood [ XREF_BIBR ] .	This is in agreement with a previous animal study which showed that a CCL2 antagonizing Spiegelmer reduces the peripheral monocyte count by inhibiting the CCR2 positive monocyte emigration from the bone marrow to the blood [XREF_BIBR].	12	27	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	13	14	24	25
It was unclear how CCL2 , which is known to have a chemoattractant activity , promotes the migration of CCR2 positive monocytes away from the source of CCL2 gradient in the bone marrow .	It was unclear how CCL2, which is known to have a chemoattractant activity, promotes the migration of CCR2 positive monocytes away from the source of CCL2 gradient in the bone marrow.	4	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	19	20
Monocytes express not only CCR2 but also other chemokine receptors such as CCR5 [ XREF_BIBR ] , and CCR2 can be activated not only by CCL2 but also by CCL7 [ XREF_BIBR ] .	Monocytes express not only CCR2 but also other chemokine receptors such as CCR5 [XREF_BIBR], and CCR2 can be activated not only by CCL2 but also by CCL7 [XREF_BIBR].	18	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	25	26	18	19
Interestingly , upon Lm-OVA secondary infection , XCR1 + DCs promote the induction of the CCR2 ligands CCL2 and CCL7 ( unpublished data ) .	Interestingly, upon Lm-OVA secondary infection, XCR1 + DCs promote the induction of the CCR2 ligands CCL2 and CCL7 (unpublished data).	10	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	17	18	15	16
Moreover , as shown in XREF_FIG ( C ) , the administration of CCR2 inhibitor INCB3344 ( 10nM ) significantly blocked the CCL2 induced up-regulation of Na v 1.8 and CCR2 compared with the sole CCL2 treatment ( P < 0.05 ) .	Moreover, as shown in XREF_FIG (C), the administration of CCR2 inhibitor INCB3344 (10nM) significantly blocked the CCL2 induced up-regulation of Na v 1.8 and CCR2 compared with the sole CCL2 treatment (P < 0.05).	21	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	22	23	30	31
Senescent BECs increase expression of MCP-1 and CCL2 and CX3CL1 which may cause corresponding CCR2 and CX3CR1 expressing cells to infiltrate and inflame in small bile duct lesions in PBC ( XREF_TABLE ) [ XREF_BIBR , XREF_BIBR ] .	Senescent BECs increase expression of MCP-1 and CCL2 and CX3CL1 which may cause corresponding CCR2 and CX3CR1 expressing cells to infiltrate and inflame in small bile duct lesions in PBC (XREF_TABLE) [XREF_BIBR, XREF_BIBR].	3	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	expression of MCP-1 and CCL2	ccl2	CCR2	CCR2	ccr2	7	8	14	15
Our study advances these observations demonstrating that CCL2 controlling steady-state pDC circulation is dependent on microbiota and preferentially drives the trafficking of CCR2 hi pDCs .	Our study advances these observations demonstrating that CCL2 controlling steady-state pDC circulation is dependent on microbiota and preferentially drives the trafficking of CCR2 hi pDCs.	7	23	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	7	8	22	23
These puncta never contained any CXCL12 , indicating that CCR2 positive cells that are in close proximity to CXCL12 expressing cells were activated by endogenous CCL2 that are not labelled in this mouse line ( XREF_FIG ) .	These puncta never contained any CXCL12, indicating that CCR2 positive cells that are in close proximity to CXCL12 expressing cells were activated by endogenous CCL2 that are not labelled in this mouse line (XREF_FIG).	9	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	25	26	9	10
In response to inflammatory cues or tissue injury , CCL2 is up-regulated to recruit CCR2 + monocytes , memory T cells , and DCs .	In response to inflammatory cues or tissue injury, CCL2 is up-regulated to recruit CCR2 + monocytes, memory T cells, and DCs.	9	23	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	9	10	14	15
CCR2 is activated by CCL2 ( also known as monocyte chemotactic protein-1 , MCP-1 ) , CCL7 , CCL8 and CCL12 ( in mice )/CCL13 ( in humans ) , with CCL2 being the most intensely studied ligand [ XREF_BIBR ] .	CCR2 is activated by CCL2 (also known as monocyte chemotactic protein-1, MCP-1), CCL7, CCL8 and CCL12 (in mice)/CCL13 (in humans), with CCL2 being the most intensely studied ligand [XREF_BIBR].	0	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	0	1
XREF_BIBR This implies that CCL2 activates CCR2 , whereas CCL5 stimulates CCR1 and/or CCR5 in distinct subpopulations of microglia .	XREF_BIBR This implies that CCL2 activates CCR2, whereas CCL5 stimulates CCR1 and/or CCR5 in distinct subpopulations of microglia.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	6	7
For example , CCR2 and CD40 on TAMs are activated by CCL2 and CD40L produced in gastric cancer tissues and synergistically promote VEGF production to increase microvessel density [ XREF_BIBR , XREF_BIBR ] .	For example, CCR2 and CD40 on TAMs are activated by CCL2 and CD40L produced in gastric cancer tissues and synergistically promote VEGF production to increase microvessel density [XREF_BIBR, XREF_BIBR].	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	11	12	3	4
We previously showed that Cx3cr1 GFP and GFP MPs overexpress CCL2 , which in turn leads to increased CCR2 + Mos recruitment from the blood .	We previously showed that Cx3cr1 GFP and GFP MPs overexpress CCL2, which in turn leads to increased CCR2 + Mos recruitment from the blood.	9	19	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	10	11	18	19
Groups of wild-type ( WT ) mice , CCR2 deficient mice , lethally irradiated CCR2 deficient and WT mice that were reciprocally bone marrow transplanted ( chimeric CCR2 deficient and WT , respectively ) , chimeric CCR2 deficient mice with an enriched CCR2 ( + ) alveolar macrophage population , and CCR2 deficient mice transfused with CCR2 ( + ) mononuclear cells were treated with intratracheal CCL2 and/or Escherichia coli endotoxin .	Groups of wild-type (WT) mice, CCR2 deficient mice, lethally irradiated CCR2 deficient and WT mice that were reciprocally bone marrow transplanted (chimeric CCR2 deficient and WT, respectively), chimeric CCR2 deficient mice with an enriched CCR2 (+) alveolar macrophage population, and CCR2 deficient mice transfused with CCR2 (+) mononuclear cells were treated with intratracheal CCL2 and/or Escherichia coli endotoxin.	54	70	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	66	67	56	57
Even though monocyte chemoattractant protein-1 ( MCP-1 ) was demonstrated to directly increase extracellular matrix ( ECM ) synthesis , the role of the MCP-1 and CCR2 system in PD related EMT and ECM synthesis in cultured human PMCs ( HPMCs ) and in an animal model of PD has never been elucidated .	Even though monocyte chemoattractant protein-1 (MCP-1) was demonstrated to directly increase extracellular matrix (ECM) synthesis, the role of the MCP-1 and CCR2 system in PD related EMT and ECM synthesis in cultured human PMCs (HPMCs) and in an animal model of PD has never been elucidated.	2	27	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	monocyte chemoattractant protein-1	monocyte chemoattractant protein-1	monocyte chemoattractant protein-1	CCR2	CCR2	CCR2	2	5	26	27
Remarkably , however , neither WT nor CCR2 (-/-) mO were stimulated by CCL2 to migrate across CCR2 (-/-) BMEC .	Remarkably, however, neither WT nor CCR2 (-/-) mO were stimulated by CCL2 to migrate across CCR2 (-/-) BMEC.	7	14	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	13	14	7	8
These results confirm that CCL2 released from the stromal cells act locally and activates CCR2 on nearby cells , which co-express CXCR4 .	These results confirm that CCL2 released from the stromal cells act locally and activates CCR2 on nearby cells, which co-express CXCR4.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	14	15
One of its primary functions is to mobilize monocytes from the bone marrow ( along with CCL2 activating CCR2 ) and promote their migration to the inflamed tissue , but it is also critical for maintaining leukocyte homeostasis in normal conditions [ XREF_BIBR ] .	One of its primary functions is to mobilize monocytes from the bone marrow (along with CCL2 activating CCR2) and promote their migration to the inflamed tissue, but it is also critical for maintaining leukocyte homeostasis in normal conditions [XREF_BIBR].	14	19	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	16	17	18	19
CCL2 mediates its effects by binding to and activating the chemokine receptor CCR2 .	CCL2 mediates its effects by binding to and activating the chemokine receptor CCR2.	0	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	12	13
Activation of CCR2 by CCL2 and N-formyl peptide receptors by fMLP both raise cytoplasmic Ca 2+ by pertussis-toxin-sensitive mechanisms , and Ca 2+ responses and chemotaxis evoked by both are substantially impaired by apyrase .	Activation of CCR2 by CCL2 and N-formyl peptide receptors by fMLP both raise cytoplasmic Ca 2+ by pertussis-toxin-sensitive mechanisms, and Ca 2+ responses and chemotaxis evoked by both are substantially impaired by apyrase.	0	10	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	2	3
Collectively , these findings indicate that CCL2 activates the Hh pathway in a CCR2 dependent manner .	Collectively, these findings indicate that CCL2 activates the Hh pathway in a CCR2 dependent manner.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	6	7	13	14
Mechanistically , IFNAR dependent expression of the chemokine CCL2 mediates the influx of CCR2 + monocytes that differentiate into iM and iDC .	Mechanistically, IFNAR dependent expression of the chemokine CCL2 mediates the influx of CCR2 + monocytes that differentiate into iM and iDC.	4	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	expression of the chemokine CCL2	ccl2	CCR2	CCR2	ccr2	8	9	13	14
In conclusion , blocking CCR5 by maraviroc not only can block CCR5 and CCR2 internalization processes induced by CCL5 and CCL2 , but also inhibit T cell chemotactic activities toward their cognate ligands , respectively .	In conclusion, blocking CCR5 by maraviroc not only can block CCR5 and CCR2 internalization processes induced by CCL5 and CCL2, but also inhibit T cell chemotactic activities toward their cognate ligands, respectively.	11	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	20	21	13	14
CCL2 and CX3CL1 produced by senescent BECs may promote infiltration of corresponding CCR2 and CX3CR1 expressing cells and further aggravate inflammation in bile duct lesion in PBC .	CCL2 and CX3CL1 produced by senescent BECs may promote infiltration of corresponding CCR2 and CX3CR1 expressing cells and further aggravate inflammation in bile duct lesion in PBC.	0	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	12	13
CCL2 ( monocyte chemotactic protein-1 , MCP-1 ) is produced by a variety of cells including macrophages , T cells and epithelial cells , and can activate CCR2 on monocyte and T cells .	CCL2 (monocyte chemotactic protein-1, MCP-1) is produced by a variety of cells including macrophages, T cells and epithelial cells, and can activate CCR2 on monocyte and T cells.	0	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	27	28
CCL2 increased not only CCL22 but also CCR2 and CCR4 .	CCL2 increased not only CCL22 but also CCR2 and CCR4.	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	7	8
We further found that CCL2 induced CC-chemokine receptor 2 ( CCR2 ) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding , association , internalization , and on cholesterol efflux in ECs .	We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CC-chemokine receptor 2	CC-chemokine receptor 2	CC-chemokine receptor 2	4	5	6	9
Emigration of Ly6C hi monocytes from the bone marrow into the circulation is the first step in their recruitment to sites of L. monocytogenes infection and is triggered by CCL2- and CCL7 mediated stimulation of CCR2 chemokine receptors on monocytes .	Emigration of Ly6C hi monocytes from the bone marrow into the circulation is the first step in their recruitment to sites of L. monocytogenes infection and is triggered by CCL2- and CCL7 mediated stimulation of CCR2 chemokine receptors on monocytes.	29	37	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL2-	CCL2-	CCL2-	CCR2	CCR2	CCR2	29	30	35	36
Secretion of C-C chemokine ligand 2 ( CCL2 ) by injured or inflamed tissue cells induces migration of these Ly6C hi CCR2 + monocytes from the bone marrow to the site of infection , where they are involved in the immune defense responses against pathogenic microorganisms XREF_BIBR .	Secretion of C-C chemokine ligand 2 (CCL2) by injured or inflamed tissue cells induces migration of these Ly6C hi CCR2 + monocytes from the bone marrow to the site of infection, where they are involved in the immune defense responses against pathogenic microorganisms XREF_BIBR.	0	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	7	8	21	22
CCL2 , a CC chemokine that stimulates CCR2 , its corresponding receptor expressed on T cells XREF_BIBR , NK cells XREF_BIBR and gammadelta T cells XREF_BIBR , is reported to be expressed by various types of cancer cells including those of glioma XREF_BIBR , melanoma XREF_BIBR , and cancers of the breast XREF_BIBR , prostate XREF_BIBR , colon XREF_BIBR and lung XREF_BIBR .	CCL2, a CC chemokine that stimulates CCR2, its corresponding receptor expressed on T cells XREF_BIBR, NK cells XREF_BIBR and gammadelta T cells XREF_BIBR, is reported to be expressed by various types of cancer cells including those of glioma XREF_BIBR, melanoma XREF_BIBR, and cancers of the breast XREF_BIBR, prostate XREF_BIBR, colon XREF_BIBR and lung XREF_BIBR.	0	31	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	7	8
Finally , the virgin Ccr2 KO/KO mice did not show any change when treated with Ccl2 ( XREF_FIG ) .	Finally, the virgin Ccr2 KO/KO mice did not show any change when treated with Ccl2 (XREF_FIG).	4	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Ccl2	Ccl2	Ccl2	Ccr2	Ccr2	Ccr2	15	16	4	5
We have reported that stimulation by fibronectin increases the release of CCL2 from activated microglia , and CCL2 stimulates the CC chemokine receptor CCR2 of microglia resulting in the stimulation of P2X4R trafficking to the cell surface from lysosomes of microglia XREF_BIBR ) .	We have reported that stimulation by fibronectin increases the release of CCL2 from activated microglia, and CCL2 stimulates the CC chemokine receptor CCR2 of microglia resulting in the stimulation of P2X4R trafficking to the cell surface from lysosomes of microglia XREF_BIBR).	17	25	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	17	18	23	24
The Mm phenolic glycolipid ( PGL-mar ) induces CCL2 expression and mediates CCL2 and CCR2 dependent macrophage recruitment , suggesting that PGL-1 , may play a similar role in Mlep infection .	The Mm phenolic glycolipid (PGL-mar) induces CCL2 expression and mediates CCL2 and CCR2 dependent macrophage recruitment, suggesting that PGL-1, may play a similar role in Mlep infection.	1	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	Mm phenolic glycolipid (PGL-mar) induces CCL2 expression	ccl2	CCR2	CCR2	ccr2	8	9	14	15
Moreover , CCL2 mediated CCR2 , PKCdelta , p38MAPK , and AP-1 pathway promoted the adhesion of monocytes to the OASFs monolayer .	Moreover, CCL2 mediated CCR2, PKCdelta, p38MAPK, and AP-1 pathway promoted the adhesion of monocytes to the OASFs monolayer.	2	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	2	3	4	5
CCL2 activation of CCR2 has been shown to produce various cellular responses via two signal transduction pathways , the PI3K and Akt and ERK 1/2 cascades [ XREF_BIBR - XREF_BIBR ] .	CCL2 activation of CCR2 has been shown to produce various cellular responses via two signal transduction pathways, the PI3K and Akt and ERK 1/2 cascades [XREF_BIBR - XREF_BIBR].	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	3	4
Activation of CCR2 by CCL2 also rapidly modulates DRG neuronal sensitivity and spinal cord synaptic plasticity [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Activation of CCR2 by CCL2 also rapidly modulates DRG neuronal sensitivity and spinal cord synaptic plasticity [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	2	3
In preclinical studies , CCL2 production induced CCR2 + TAMs infiltration [ XREF_BIBR ] .	In preclinical studies, CCL2 production induced CCR2 + TAMs infiltration [XREF_BIBR].	4	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	7	8
These studies showed that CCL2 triggering of endothelial CCR2 increases endothelial and vascular permeability and contributes to efficient leukocyte extravasation .	These studies showed that CCL2 triggering of endothelial CCR2 increases endothelial and vascular permeability and contributes to efficient leukocyte extravasation.	4	9	triggering	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	8	9
CCL2 and CCL4 increased rapidly and significantly by Days 7 and 14 across all groups , suggesting potent CCR2 and CCR5 blockade ( all P < 0.05 vs. Day 1 [ predose ] ) .	CCL2 and CCL4 increased rapidly and significantly by Days 7 and 14 across all groups, suggesting potent CCR2 and CCR5 blockade (all P < 0.05 vs. Day 1 [predose]).	0	26	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	18	19
The CCL2 mediated CCR2 , PKCdelta , p38MAPK , and AP-1 pathway promotes monocytes adhesion to human OASFs .	The CCL2 mediated CCR2, PKCdelta, p38MAPK, and AP-1 pathway promotes monocytes adhesion to human OASFs.	0	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	1	2	3	4
The chemokine C-C motif ligand 2 ( CCL2 ) , also referred to as monocyte chemoattractant protein 1 , is released from injured neurons and activates the C-C chemokine receptor type 2 ( CCR2 ) in macrophages , which induces macrophage activation and proliferation in the dorsal root ganglion ( DRG ) following peripheral nerve injury [ XREF_BIBR , XREF_BIBR ] .	The chemokine C-C motif ligand 2 (CCL2), also referred to as monocyte chemoattractant protein 1, is released from injured neurons and activates the C-C chemokine receptor type 2 (CCR2) in macrophages, which induces macrophage activation and proliferation in the dorsal root ganglion (DRG) following peripheral nerve injury [XREF_BIBR, XREF_BIBR].	0	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	7	8	33	34
To determine whether compound 25 specifically inhibits CXCL12 , the chemotaxis assay was repeated with CCL2 ( also known as monocyte chemoattractant protein-1 , MCP-1 ) , a distinct chemokine that activates the CCR2 receptor ( data not shown ) .	To determine whether compound 25 specifically inhibits CXCL12, the chemotaxis assay was repeated with CCL2 (also known as monocyte chemoattractant protein-1, MCP-1), a distinct chemokine that activates the CCR2 receptor (data not shown).	13	34	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	15	16	33	34
CCL2 increased NMDA induced currents in CCR2 + / vGluT2 + neurons in lamina IIo .	CCL2 increased NMDA induced currents in CCR2 + / vGluT2 + neurons in lamina IIo.	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	6	7
Human osteoclasts are positive for the CCR1 , CCR2 , CCR3 , and CCR4 receptors , while CCR2 and CCR4 are potently induced by RANKL and CCL2 .	Human osteoclasts are positive for the CCR1, CCR2, CCR3, and CCR4 receptors, while CCR2 and CCR4 are potently induced by RANKL and CCL2.	17	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	26	27	17	18
CCL2 activates the CC chemokine receptor 2 ( CCR2 ) that is mainly localized on leucocytes , monocytes or macrophages , and lymphocytes .	CCL2 activates the CC chemokine receptor 2 (CCR2) that is mainly localized on leucocytes, monocytes or macrophages, and lymphocytes.	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	8	9
The recruitment of cells by FXYD5 overexpression was decreased by treating mice with the antibody against CCR2 , and the same effect was observed in mice lacking CCR2 , indicating that FXYD5 induced secretion of CCL2 causes chemotaxis of CCR2 positive monocytes to the alveolar spaces .	The recruitment of cells by FXYD5 overexpression was decreased by treating mice with the antibody against CCR2, and the same effect was observed in mice lacking CCR2, indicating that FXYD5 induced secretion of CCL2 causes chemotaxis of CCR2 positive monocytes to the alveolar spaces.	33	40	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	35	36	39	40
During the inflammatory response , CCL2 is released and activates the CCR2 on neighboring monocytes .	During the inflammatory response, CCL2 is released and activates the CCR2 on neighboring monocytes.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	5	6	11	12
Therefore , CCL2 can activate CCR2 in both neurons and glial cells in the DRG to modulate pain sensitivity .	Therefore, CCL2 can activate CCR2 in both neurons and glial cells in the DRG to modulate pain sensitivity.	2	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	2	3	5	6
However , the EMT process and invasion ability were reversed after transfection with CCR2 siRNA , which indicated that the CCL2 induced HCC invasion and EMT are CCR2 receptor dependent ( XREF_FIG ) .	However, the EMT process and invasion ability were reversed after transfection with CCR2 siRNA, which indicated that the CCL2 induced HCC invasion and EMT are CCR2 receptor dependent (XREF_FIG).	19	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	20	21	27	28
As CCL2 and its receptor CCR2 have been shown to play important roles in the development of Th2 inflammation , we further evaluated the effects of NNY-CCL14 treatment on CCL2 mediated activation of CCR2 .	As CCL2 and its receptor CCR2 have been shown to play important roles in the development of Th2 inflammation, we further evaluated the effects of NNY-CCL14 treatment on CCL2 mediated activation of CCR2.	29	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	29	30	33	34
In contrast , maraviroc did not block CCL5- or CCL2 driven internalization of the structurally related receptors , CCR1 and CCR2 ( XREF_FIG ) .	In contrast, maraviroc did not block CCL5- or CCL2 driven internalization of the structurally related receptors, CCR1 and CCR2 (XREF_FIG).	6	22	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	9	10	20	21
Exogenous spinal administration of CCL2 induces spinal microglial activation and this activation is lost in CCR2 knock-out mice .	Exogenous spinal administration of CCL2 induces spinal microglial activation and this activation is lost in CCR2 knock-out mice.	2	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	15	16
CCL2 mediates the movement of CCR2 + monocytes from blood following hypoxic preconditioning .	CCL2 mediates the movement of CCR2 + monocytes from blood following hypoxic preconditioning.	0	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	5	6
In a genetic mouse model of CRC , inactivation of Ccl2 caused depletion of CCR2 + TAM at the tumor site and reciprocal accumulation of CTL , which prevented tumor progression [ XREF_BIBR ] .	In a genetic mouse model of CRC, inactivation of Ccl2 caused depletion of CCR2 + TAM at the tumor site and reciprocal accumulation of CTL, which prevented tumor progression [XREF_BIBR].	8	15	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ccl2	Ccl2	Ccl2	CCR2	CCR2	CCR2	10	11	14	15
Therefore , we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 ( MCP-1 ) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1 ( +/-) mice .	Therefore, we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 (MCP-1) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1 (+/-) mice.	5	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	monocyte chemotactic protein-1	monocyte chemotactic protein-1	monocyte chemotactic protein-1	CCR2	CCR2	CCR2	12	15	5	6
These observations are distinct from a report where CcL2 induced CCR2 receptor activation was shown to occur mainly in the peripheral nervous system in a demyelination model of neuropathic pain [ XREF_BIBR ] .	These observations are distinct from a report where CcL2 induced CCR2 receptor activation was shown to occur mainly in the peripheral nervous system in a demyelination model of neuropathic pain [XREF_BIBR].	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	CcL2	CcL2	CcL2	CCR2	CCR2	CCR2	8	9	10	11
CCL2 may support prostate cancer survival and motility through binding to its receptor CCR2 .	CCL2 may support prostate cancer survival and motility through binding to its receptor CCR2.	0	14	support	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	13	14
Local upregulation of Ccl2 and Ccr2 gene expression within the lesion supports the concept that the infiltration of peripheral monocytes is CCL2 and CCR2 mediated [ XREF_BIBR ] .	Local upregulation of Ccl2 and Ccr2 gene expression within the lesion supports the concept that the infiltration of peripheral monocytes is CCL2 and CCR2 mediated [XREF_BIBR].	3	26	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ccl2	Ccl2 and Ccr2 gene expression	ccl2	CCR2	CCR2	ccr2	3	4	23	24
We demonstrate that THP-1 cells rapidly secrete ATP during signalling downstream of the CCL2-CCR2 axis and suggest this might act as a mechanism for P2Y 6 receptor co-activation following CCL2 activation of the CCR2 receptor .	We demonstrate that THP-1 cells rapidly secrete ATP during signalling downstream of the CCL2-CCR2 axis and suggest this might act as a mechanism for P2Y 6 receptor co-activation following CCL2 activation of the CCR2 receptor.	29	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	29	30	33	34
Specifically , we prepared both BMEC and mO from wild-type ( WT ) mice and mice deficient in CCR2 ; i.e ., CCR2 (-/-) , and compared the ability of WT and CCR2 (-/-) BMEC to support CCL2 stimulated transendothelial migration of WT and CCR2 (-/-) mO ..	Specifically, we prepared both BMEC and mO from wild-type (WT) mice and mice deficient in CCR2; i.e., CCR2 (-/-), and compared the ability of WT and CCR2 (-/-) BMEC to support CCL2 stimulated transendothelial migration of WT and CCR2 (-/-) mO..	36	47	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	37	38	44	45
In summary , nerve released CCL2 supports prostate cancer migration and PNI though CCR2 mediated signaling .	In summary, nerve released CCL2 supports prostate cancer migration and PNI though CCR2 mediated signaling.	5	14	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	5	6	13	14
There is also evidence that CCL2 can directly bind to and modulate the activity of ion channels independent of CCR2 .	There is also evidence that CCL2 can directly bind to and modulate the activity of ion channels independent of CCR2.	5	20	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	5	6	19	20
Notwithstanding the complexity of these events , the rapid increase in cytosolic free calcium ( Ca 2+ ) concentration upon CCR2 activation by CCL2 is frequently used as a functional assay for measuring the activity of CCR2 antagonists .	Notwithstanding the complexity of these events, the rapid increase in cytosolic free calcium (Ca 2+) concentration upon CCR2 activation by CCL2 is frequently used as a functional assay for measuring the activity of CCR2 antagonists.	20	24	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	23	24	20	21
In the present study , since we found that the activation of CCR2 by CCL2 simultaneously induces tumor cell invasion and Hh pathway activation , we hypothesized that Gli-1 is a critical mediator of the CCL2 induced EMT and cell invasion of HCC cells .	In the present study, since we found that the activation of CCR2 by CCL2 simultaneously induces tumor cell invasion and Hh pathway activation, we hypothesized that Gli-1 is a critical mediator of the CCL2 induced EMT and cell invasion of HCC cells.	10	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	14	15	12	13
By combining patch clamp recording and single-cell PCR in the recorded neurons , our finding showed that CCL2 increased NMDA induced currents exclusively in CCR2 positive excitatory neurons that express vGluT2 but not VIAAT .	By combining patch clamp recording and single-cell PCR in the recorded neurons, our finding showed that CCL2 increased NMDA induced currents exclusively in CCR2 positive excitatory neurons that express vGluT2 but not VIAAT.	17	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	17	18	24	25
The above observations are consistent with a view where CCL2 and CCL11 induce different conformations of CCR2 , which translate to diverse intracellular coupling .	The above observations are consistent with a view where CCL2 and CCL11 induce different conformations of CCR2, which translate to diverse intracellular coupling.	9	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	9	10	16	17
CCL2 -/- HSCs induced decreased migration of WT Tregs compared to that of WT HSCs , and conversely fewer CCR2 -/- Tregs migrated to WT HSCs than did WT Tregs , where migration was more suppressed in CCL2 -/- HSCs ( XREF_FIG ) .	CCL2 -/- HSCs induced decreased migration of WT Tregs compared to that of WT HSCs, and conversely fewer CCR2 -/- Tregs migrated to WT HSCs than did WT Tregs, where migration was more suppressed in CCL2 -/- HSCs (XREF_FIG).	0	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	19	20
Surprisingly we found that CCL2 mediates anti-fibrotic effects independently of CCR2 in human fibroblasts of different origins .	Surprisingly we found that CCL2 mediates anti-fibrotic effects independently of CCR2 in human fibroblasts of different origins.	4	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	10	11
CCL2 mediates the chemotaxis of CCR2 + monocytes and macrophages XREF_BIBR .	CCL2 mediates the chemotaxis of CCR2 + monocytes and macrophages XREF_BIBR.	0	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	5	6
To determine whether CCL2 affected these CCR2 expressing neurons , the neurons were treated with CCL2 ( 0 , 50 , 100 , or 200 ng/mL ) , and a significant change was found in the number of ENK and CCR2 double labeled neurons relative to CCR2 ( F ( 3,15 ) = 139.06 , p < 0.001 ; XREF_FIG ) .	To determine whether CCL2 affected these CCR2 expressing neurons, the neurons were treated with CCL2 (0, 50, 100, or 200 ng/mL), and a significant change was found in the number of ENK and CCR2 double labeled neurons relative to CCR2 (F (3,15) = 139.06, p < 0.001; XREF_FIG).	4	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	15	16	6	7
Recently , we have observed this phenomenon for activation of CCR2 by CCL2 , CCL7 , and CCL8 ( unpublished results ) .	Recently, we have observed this phenomenon for activation of CCR2 by CCL2, CCL7, and CCL8 (unpublished results).	4	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	12	13	10	11
This potentially explains the lack of surface CCR2 on RAW264.7 macrophages in comparison to BMDMs , as the higher autocrine CCL2 production by RAW264.7 macrophages will likely cause greater desensitisation and internalisation of CCR2 .	This potentially explains the lack of surface CCR2 on RAW264.7 macrophages in comparison to BMDMs, as the higher autocrine CCL2 production by RAW264.7 macrophages will likely cause greater desensitisation and internalisation of CCR2.	20	34	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	20	21	33	34
In contrast , transgenic astrocytic CCL2 over-induction increased CCR2 + monocyte infiltration and DA neuronal loss in MPTP mice .	In contrast, transgenic astrocytic CCL2 over-induction increased CCR2 + monocyte infiltration and DA neuronal loss in MPTP mice.	5	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	5	6	8	9
Our findings echo this concept and add a third role in which hyperacute neuronal CCL2 production mediates CCR2 dependent inflammatory monocyte trafficking into the brain , resulting in the creation of an environment that further disrupts neural function and induces pyramidal neuron death [ XREF_BIBR , XREF_BIBR ] .	Our findings echo this concept and add a third role in which hyperacute neuronal CCL2 production mediates CCR2 dependent inflammatory monocyte trafficking into the brain, resulting in the creation of an environment that further disrupts neural function and induces pyramidal neuron death [XREF_BIBR, XREF_BIBR].	14	21	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	14	15	17	18
Chronic inhibition of CCR2 signaling by mutated CCL2 secreted from implanted mesenchymal stem cells resulted in similar improvements .	Chronic inhibition of CCR2 signaling by mutated CCL2 secreted from implanted mesenchymal stem cells resulted in similar improvements.	3	8	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	7	8	3	4
CCL2 promotes CCR2 and CCR5 expressing C17.2 neural progenitor cell migration and their differentiation into neuronal and glial phenotype [ XREF_BIBR , XREF_BIBR ] .	CCL2 promotes CCR2 and CCR5 expressing C17.2 neural progenitor cell migration and their differentiation into neuronal and glial phenotype [XREF_BIBR, XREF_BIBR].	0	6	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	2	3
For example , within the brain , MCP-1 and CCL-2 stimulates its receptor , CCR2 to regulate the communication between neurons , astrocytes and microglia , thereby mediating the recruitment of both resident and peripheral immune cells to sites of injury within the CNS .	For example, within the brain, MCP-1 and CCL-2 stimulates its receptor, CCR2 to regulate the communication between neurons, astrocytes and microglia, thereby mediating the recruitment of both resident and peripheral immune cells to sites of injury within the CNS.	7	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL-2	CCL-2	CCL-2	CCR2	CCR2	CCR2	9	10	14	15
In conclusion , these observations confirm previous findings of increased CCL2 levels in asthma and suggest that ASM derived CCL2 mediated activation of CCR2 promotes FC migration .	In conclusion, these observations confirm previous findings of increased CCL2 levels in asthma and suggest that ASM derived CCL2 mediated activation of CCR2 promotes FC migration.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	19	20	23	24
Recently , we have demonstrated that tumour-cell-derived CCL2 activates CCR2 positive endothelium to increase vascular permeability in vivo .	Recently, we have demonstrated that tumour-cell-derived CCL2 activates CCR2 positive endothelium to increase vascular permeability in vivo.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	7	8	9	10
The results show that CCL2 activates the CCR2 receptor which in turn activates protein kinase Cdelta ( PKCdelta ) , p38MAPK , and AP-1 signaling pathway , leading to the upregulation of VCAM-1 expression .	The results show that CCL2 activates the CCR2 receptor which in turn activates protein kinase Cdelta (PKCdelta), p38MAPK, and AP-1 signaling pathway, leading to the upregulation of VCAM-1 expression.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	7	8
For example , CCL2 released from primary sensory neurons activates CCR2 in microglia , leading to the release of proinflammatory cytokines and growth factors and subsequent central sensitization .	For example, CCL2 released from primary sensory neurons activates CCR2 in microglia, leading to the release of proinflammatory cytokines and growth factors and subsequent central sensitization.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	3	4	10	11
Cancer infiltration into nerves might induce a form of nerve injury that releases CCL2 , which may then induce a nerve repair inflammatory response , induce the migration of CCR2 expressing cancer cells towards these nerves , and ultimately promote PNI .	Cancer infiltration into nerves might induce a form of nerve injury that releases CCL2, which may then induce a nerve repair inflammatory response, induce the migration of CCR2 expressing cancer cells towards these nerves, and ultimately promote PNI.	13	39	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	13	14	29	30
Activation of CCR2 by monocyte chemoattractant protein-1 ( MCP-1 ) , the major CCR2 ligand , is known to mediate chemotaxis and degranulation of monocytes as well as migration of activated effector memory T cells .	Activation of CCR2 by monocyte chemoattractant protein-1 (MCP-1), the major CCR2 ligand, is known to mediate chemotaxis and degranulation of monocytes as well as migration of activated effector memory T cells.	0	14	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	monocyte chemoattractant protein-1	monocyte chemoattractant protein-1	monocyte chemoattractant protein-1	CCR2	CCR2	CCR2	4	7	2	3
In summary , activation of CCR2 by CCL2 results in stimulation of PLC and IP3 R pathway leading to activation of TRPC channels , which in turn , can cause elevation of [ Ca 2+ ] i transients and subsequent activation of ERK / CREB , but not Akt / NF-kappaB pathway ( as summarized in XREF_FIG ) .	In summary, activation of CCR2 by CCL2 results in stimulation of PLC and IP3 R pathway leading to activation of TRPC channels, which in turn, can cause elevation of [Ca 2+] i transients and subsequent activation of ERK / CREB, but not Akt / NF-kappaB pathway (as summarized in XREF_FIG).	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	7	8	5	6
CCL2 may activate both CCR2 and CCR4 receptors , although CCR2 is the predominant functional receptor for CCL2 .	CCL2 may activate both CCR2 and CCR4 receptors, although CCR2 is the predominant functional receptor for CCL2.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	4	5
Ccr2 is activated by the selective ligand Ccl2 , and the nonselective ligands Ccl7 and Ccl12 .	Ccr2 is activated by the selective ligand Ccl2, and the nonselective ligands Ccl7 and Ccl12.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ccl2	Ccl2	Ccl2	Ccr2	Ccr2	Ccr2	7	8	0	1
ACKR4 mediated CCL21 scavenging by lymphatic endothelial cells lining the subcapsular sinus ceiling stabilizes interfollicular CCL21 gradients that direct lymph-borne CCR7 ( + ) APCs into the parenchyma of mouse LN .	ACKR4 mediated CCL21 scavenging by lymphatic endothelial cells lining the subcapsular sinus ceiling stabilizes interfollicular CCL21 gradients that direct lymph-borne CCR7 (+) APCs into the parenchyma of mouse LN.	15	21	direct	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	15	16	20	21
The present study shows that CCR7 activation by CCL21 treatment result in a significant increase in ERK1/2 phosphorylation but not AKT phosphorylation in UBC cells , and CCR7 knockdown by efficacious siRNA transfection significantly decreases ERK1/2 phosphorylation only .	The present study shows that CCR7 activation by CCL21 treatment result in a significant increase in ERK1/2 phosphorylation but not AKT phosphorylation in UBC cells, and CCR7 knockdown by efficacious siRNA transfection significantly decreases ERK1/2 phosphorylation only.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	8	9	5	6
In the absence of CCR7 expression in the host - or CCR7 activation by CCL21 - tumors grow more slowly .	In the absence of CCR7 expression in the host - or CCR7 activation by CCL21 - tumors grow more slowly.	11	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	14	15	11	12
CCL21 stimulation increased the ability of CCR7 positive Tca8113 cells passing through the Matrigel membrane .	CCL21 stimulation increased the ability of CCR7 positive Tca8113 cells passing through the Matrigel membrane.	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	0	1	6	7
CCR7 can be activated by the binding of cytokines CCL19 and CCL21 [ XREF_BIBR ] .	CCR7 can be activated by the binding of cytokines CCL19 and CCL21 [XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	11	12	0	1
XREF_BIBR They produce the CCR7 ligands , CCL19 and CCL21 , required for T-cell attraction and motility and dendritic cell attraction .	XREF_BIBR They produce the CCR7 ligands, CCL19 and CCL21, required for T-cell attraction and motility and dendritic cell attraction.	0	10	produce	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	9	10	4	5
ELC and SLC have similar activities ; both activate the CCR7 receptor , and their genes are located within 100 kb of each other in the human genome .	ELC and SLC have similar activities; both activate the CCR7 receptor, and their genes are located within 100 kb of each other in the human genome.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SLC	SLC	SLC	CCR7	CCR7	CCR7	2	3	10	11
For example , chemokine receptor CXCR4 , which is one of the most studied chemokine receptors , is selectively activated by chemokine CXCL12 , whereas chemokine receptor CCR7 is activated by two chemokines , CCL19 and CCL21 .	For example, chemokine receptor CXCR4, which is one of the most studied chemokine receptors, is selectively activated by chemokine CXCL12, whereas chemokine receptor CCR7 is activated by two chemokines, CCL19 and CCL21.	25	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	36	37	27	28
Increased LEC expression of SLC and CCL21 is found in mesenteric lymph nodes in Crohn ' s disease , but not those in ulcerative colitis [ XREF_BIBR ] , and mediates the immune retention of CCR7 + naive , Th1 T-cells and dendritic cells .	Increased LEC expression of SLC and CCL21 is found in mesenteric lymph nodes in Crohn 's disease, but not those in ulcerative colitis [XREF_BIBR], and mediates the immune retention of CCR7 + naive, Th1 T-cells and dendritic cells.	2	36	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SLC	expression of SLC	slc	CCR7	CCR7	ccr7	4	5	35	36
IPF and UIP fibroblasts showed migration and proliferation in response to CCR7 activation by SLC , but not by ELC , and SLC mediated CCR7 activation seemed to be limited to the extracellular signal regulated kinase ( ERK ) 1/2 and 90-kDa ribosomal S6 kinase ( p90RSK ) pathways , since the p38 mitogen activated protein kinase ( MAPK ) and c-Jun N-terminal kinase ( JNK ) pathways were not activated by SLC XREF_BIBR .	IPF and UIP fibroblasts showed migration and proliferation in response to CCR7 activation by SLC, but not by ELC, and SLC mediated CCR7 activation seemed to be limited to the extracellular signal regulated kinase (ERK) 1/2 and 90-kDa ribosomal S6 kinase (p90RSK) pathways, since the p38 mitogen activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways were not activated by SLC XREF_BIBR.	11	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	SLC	SLC	SLC	CCR7	CCR7	CCR7	14	15	11	12
To reach the draining mediastinal lymph nodes DC are driven by CCR7 , activated by its ligands CCL19 or CCL21 .	To reach the draining mediastinal lymph nodes DC are driven by CCR7, activated by its ligands CCL19 or CCL21.	9	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	19	20	11	12
Secretion of CCL19 and CCL21 by SCCHN cells and by paracrine sources combine to promote activation of CCR7 prosurvival signaling associated with tumor progression and disease relapse .	Secretion of CCL19 and CCL21 by SCCHN cells and by paracrine sources combine to promote activation of CCR7 prosurvival signaling associated with tumor progression and disease relapse.	0	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	4	5	17	18
XREF_BIBR , XREF_BIBR CCL21 expressed in the lymphatic endothelium induces migratory and proliferative responses in CCR7 + fibroblasts .	XREF_BIBR, XREF_BIBR CCL21 expressed in the lymphatic endothelium induces migratory and proliferative responses in CCR7 + fibroblasts.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21 expressed	ccl21	CCR7	CCR7	ccr7	3	4	15	16
In hypersensitivity pulmonitis , increased levels of VEGF-D and VEGF-C have been demonstrated in patients , as well as increased LEC expression of CCL21 that drive CCR7 + immune cell aggregates around lymphatic vessels [ XREF_BIBR ] .	In hypersensitivity pulmonitis, increased levels of VEGF-D and VEGF-C have been demonstrated in patients, as well as increased LEC expression of CCL21 that drive CCR7 + immune cell aggregates around lymphatic vessels [XREF_BIBR].	21	27	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	expression of CCL21	ccl21	CCR7	CCR7	ccr7	23	24	26	27
It has been suggested that CCL21 + lymphatic vessels may contribute to establishment of a memory response by enabling CCR7 + T cells to leave via the tumor lymphatics for re-entry into draining LNs , and our previous observation that CCL21 is significantly upregulated in whole HEV containing Treg depleted tumors supports this .	It has been suggested that CCL21 + lymphatic vessels may contribute to establishment of a memory response by enabling CCR7 + T cells to leave via the tumor lymphatics for re-entry into draining LNs, and our previous observation that CCL21 is significantly upregulated in whole HEV containing Treg depleted tumors supports this.	5	22	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	5	6	19	20
Dendritic cells ( DC ) in other peripheral tissues migrate to lymph nodes in response to chemokines , CCL19 ( ELC ) and CCL21b ( SLC ) , that activate the CCR7 receptor .	Dendritic cells (DC) in other peripheral tissues migrate to lymph nodes in response to chemokines, CCL19 (ELC) and CCL21b (SLC), that activate the CCR7 receptor.	23	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SLC	SLC	SLC	CCR7	CCR7	CCR7	25	26	31	32
However , they significantly differ in their regulation of cytoarchitecture following receptor binding ; indeed , it has been observed that CCL19 , but not CCL21 , induces internalization of CCR7 and desensitizes receptor expressing T cells and mature dendritic cells to a second stimulus of the chemokine .	However, they significantly differ in their regulation of cytoarchitecture following receptor binding; indeed, it has been observed that CCL19, but not CCL21, induces internalization of CCR7 and desensitizes receptor expressing T cells and mature dendritic cells to a second stimulus of the chemokine.	21	31	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	25	26	30	31
However , CCL19 and CCL21 can also direct the metastasis of CCR7 expressing cancers .	However, CCL19 and CCL21 can also direct the metastasis of CCR7 expressing cancers.	2	12	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	4	5	11	12
We reasoned that if T cells relied on SLC triggering of CCR7 , and there was substantial variability in PP-HEV presentation of CCR7 ligand SLC , T cell accumulation should colocalize with SLC expression .	We reasoned that if T cells relied on SLC triggering of CCR7, and there was substantial variability in PP-HEV presentation of CCR7 ligand SLC, T cell accumulation should colocalize with SLC expression.	8	12	triggering	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SLC	SLC	SLC	CCR7	CCR7	CCR7	8	9	11	12
CCR7 is activated by two chemokines : CCL19 and CCL21 .	CCR7 is activated by two chemokines : CCL19 and CCL21.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	9	10	0	1
The entry of blood-borne T and B cells into lymph nodes and Peyer ' s patches occurs preferentially at HEVs through a well defined adhesion cascade that involves ; one , L-selectin and/or alpha4beta7 integrin initiated tethering and rolling ; two , CCL21 dependent activation of CCR7 on adherent lymphocytes ; three , LFA1 mediated firm arrest via binding to its endothelial counter-receptors intercellular adhesion molecule-1 ( ICAM1 ) and ICAM2 ; and four , LFA1-ICAM1-2-directed transendothelial migration .	The entry of blood-borne T and B cells into lymph nodes and Peyer 's patches occurs preferentially at HEVs through a well defined adhesion cascade that involves; one, L-selectin and/or alpha4beta7 integrin initiated tethering and rolling; two, CCL21 dependent activation of CCR7 on adherent lymphocytes; three, LFA1 mediated firm arrest via binding to its endothelial counter-receptors intercellular adhesion molecule-1 (ICAM1) and ICAM2; and four, LFA1-ICAM1-2-directed transendothelial migration.	42	49	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	42	43	46	47
We are aware of the results of other groups who have reported that secretion of CCL21 by HNSCC cells and by other paracrine sources can combine to promote activation of CCR7 prosurvival signaling associated with tumor progression XREF_BIBR , XREF_BIBR .	We are aware of the results of other groups who have reported that secretion of CCL21 by HNSCC cells and by other paracrine sources can combine to promote activation of CCR7 prosurvival signaling associated with tumor progression XREF_BIBR, XREF_BIBR.	13	32	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	15	16	30	31
CCR7 is activated by CCL19 and CCL21 , which are equivalent for G protein signaling but differ in their GRK and beta-arrestin engagement , while all CCR2 ligands have balanced G protein and beta-arrestin signaling but interestingly CCL8 is biased for signaling to beta-arrestin2 vs. beta-arrestin1 .	CCR7 is activated by CCL19 and CCL21, which are equivalent for G protein signaling but differ in their GRK and beta-arrestin engagement, while all CCR2 ligands have balanced G protein and beta-arrestin signaling but interestingly CCL8 is biased for signaling to beta-arrestin2 vs. beta-arrestin1.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	6	7	0	1
To determine whether CCL21 and CCR7 acts through the regulation of VEGFR-3 ligand , LECs were treated with CCL21 in the presence and absence of VEGFR-3 neutralizing antibody ( 1 , 2.5 , 5mug/ml ) .	To determine whether CCL21 and CCR7 acts through the regulation of VEGFR-3 ligand, LECs were treated with CCL21 in the presence and absence of VEGFR-3 neutralizing antibody (1, 2.5, 5mug/ml).	3	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	18	19	5	6
In summary , we present new data supporting a model in which CCL19- and CCL21 mediated CCR7 activation in DCs employ the same signaling pathways , but CCL19 is a temporal signal compared with CCL21 , which is more persistent .	In summary, we present new data supporting a model in which CCL19- and CCL21 mediated CCR7 activation in DCs employ the same signaling pathways, but CCL19 is a temporal signal compared with CCL21, which is more persistent.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	14	15	16	17
Similarly , SLC is selectively expressed on T zone ( but not follicular ) HEVs and is shown to direct the transmigration of CCR7 bearing T cells through induction of firm adhesion and subsequent diapedesis 30313842 .	Similarly, SLC is selectively expressed on T zone (but not follicular) HEVs and is shown to direct the transmigration of CCR7 bearing T cells through induction of firm adhesion and subsequent diapedesis 30313842.	2	26	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SLC	SLC is selectively expressed	slc	CCR7	CCR7	ccr7	2	3	23	24
In fact , CCL19 , but not CCL21 , induced a rapid time- and concentration dependent CCR7 internalization and desensitization , thereby decreasing the ability of CCR7 expressing cells to respond to a second stimulus XREF_BIBR , XREF_BIBR .	In fact, CCL19, but not CCL21, induced a rapid time- and concentration dependent CCR7 internalization and desensitization, thereby decreasing the ability of CCR7 expressing cells to respond to a second stimulus XREF_BIBR, XREF_BIBR.	3	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	7	8	16	17
A central perspective of the present work is that since CCL19 , CCL21 , and tailless-CCL21 seem to activate CCR7 in different ways , it opens up the possibility of designing drugs that interfere with CCR7 signaling in a ligand specific manner .	A central perspective of the present work is that since CCL19, CCL21, and tailless-CCL21 seem to activate CCR7 in different ways, it opens up the possibility of designing drugs that interfere with CCR7 signaling in a ligand specific manner.	10	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	12	13	19	20
Together these findings confirm that addition of the CCR7-ligand CCL21 to Treg expansion media increases Treg activation and expression of CCR7 and CD62L , resulting in an amplified LN homing Treg phenotype ( CCR7 hi CD62L hi CD103 lo ) .	Together these findings confirm that addition of the CCR7-ligand CCL21 to Treg expansion media increases Treg activation and expression of CCR7 and CD62L, resulting in an amplified LN homing Treg phenotype (CCR7 hi CD62L hi CD103 lo).	5	22	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	9	10	20	21
33 We also found sustained chemoattraction of activated T-cells toward CRMs with another chemokine and receptor pair ( CXCL10 binding CXCR3 , data not shown ) , which exhibits receptor desensitization intermediate between CCL19 and CCL21 , suggesting such localized swarming responses are not unique to CCL21 triggering of CCR7 .	33 We also found sustained chemoattraction of activated T-cells toward CRMs with another chemokine and receptor pair (CXCL10 binding CXCR3, data not shown), which exhibits receptor desensitization intermediate between CCL19 and CCL21, suggesting such localized swarming responses are not unique to CCL21 triggering of CCR7.	46	50	triggering	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	46	47	49	50
In a model of rheumatoid arthritis , a CCL21 gradient caused migration of CCR7 + micro-vascular endothelial cells .	In a model of rheumatoid arthritis, a CCL21 gradient caused migration of CCR7 + micro-vascular endothelial cells.	8	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	8	9	13	14
On the other word , CCL21 may activate CCR7 first and then affect T24 cell migration and invasion .	On the other word, CCL21 may activate CCR7 first and then affect T24 cell migration and invasion.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	5	6	8	9
In dendritic cells CCL19 and CCL21 mediated CCR7 G protein dependent signaling leads to activation of MAPK family members ERK1/2 ( MAPK p42/44 ) , p38 , and JNK as well as PI3K .	In dendritic cells CCL19 and CCL21 mediated CCR7 G protein dependent signaling leads to activation of MAPK family members ERK1/2 (MAPK p42/44), p38, and JNK as well as PI3K.	3	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	5	6	7	8
CCR7 signaling is triggered by the chemokines CCL19 and CCL21 , which are constitutively expressed by reticular stromal cells in lymphoid organs .	CCR7 signaling is triggered by the chemokines CCL19 and CCL21, which are constitutively expressed by reticular stromal cells in lymphoid organs.	0	15	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	CCL21, which are constitutively expressed	ccl21	CCR7	CCR7	ccr7	9	10	0	1
Alternatively , Gadkin could modulate CCL21 mediated intracellular CCR7 trafficking and signaling responses , hypotheses which await further testing .	Alternatively, Gadkin could modulate CCL21 mediated intracellular CCR7 trafficking and signaling responses, hypotheses which await further testing.	4	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	5	6	8	9
Indeed , this treatment negatively affected CCL21 induced ERK1/2 activation , but not CCL19 induced activity , supporting an important role of polysialic acid in CCL21 induced CCR7 activation and thus ERK signaling in DCs .	Indeed, this treatment negatively affected CCL21 induced ERK1/2 activation, but not CCL19 induced activity, supporting an important role of polysialic acid in CCL21 induced CCR7 activation and thus ERK signaling in DCs.	23	28	induced	Positive_early_activation	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	25	26	27	28
In this study we investigated the early signaling events of CCR7 initiated by its two endogenous ligands , CCL19 and CCL21 .	In this study we investigated the early signaling events of CCR7 initiated by its two endogenous ligands, CCL19 and CCL21.	8	21	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	20	21	10	11
Chemokines CCL21 and CCL19 recruit and direct the distribution of chemokine receptor CCR7 expressing cells , mostly T cells and DCs , while CXCL13 attracts CXCR5 expressing B cells .	Chemokines CCL21 and CCL19 recruit and direct the distribution of chemokine receptor CCR7 expressing cells, mostly T cells and DCs, while CXCL13 attracts CXCR5 expressing B cells.	0	14	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	1	2	12	13
These results suggest that CCL21 and SCL enhanced the adhesive ability of CCR7 expressing cells , especially in the presence of lymphatic endothelial cells .	These results suggest that CCL21 and SCL enhanced the adhesive ability of CCR7 expressing cells, especially in the presence of lymphatic endothelial cells.	4	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	4	5	12	13
The CCL21 and secondary lymphoid tissue chemokine ( SLC ) produced in lymph nodes causes homing of CCR7 bearing naive T cells and dendritic cells to the lymph nodes .	The CCL21 and secondary lymphoid tissue chemokine (SLC) produced in lymph nodes causes homing of CCR7 bearing naive T cells and dendritic cells to the lymph nodes.	0	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	1	2	17	18
CCR7 mediated leukocyte migration in normal immune responses by two chemokine ligands : CCL19 and CCL21 .	CCR7 mediated leukocyte migration in normal immune responses by two chemokine ligands : CCL19 and CCL21.	0	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	15	16	0	1
We have identified a further mechanism by which chemokines , forming chemokine heteromeric complexes , can activate one type of chemokine receptor : ( i ) CXCL13 enhances CCL19 and CCL21 triggering of CCR7 ; ( ii ) CXCL10 enhances CCL22 triggering of CCR4 ; ( iii ) CCL19 and CCL21 enhance the activity of CCR2 ligands and protect them from degradation ; and ( iv ) CXCL9 enhances migration induced by CXCL12 on CXCR4 + / CXCR3 - malignant B cells .	We have identified a further mechanism by which chemokines, forming chemokine heteromeric complexes, can activate one type of chemokine receptor : (i) CXCL13 enhances CCL19 and CCL21 triggering of CCR7; (ii) CXCL10 enhances CCL22 triggering of CCR4; (iii) CCL19 and CCL21 enhance the activity of CCR2 ligands and protect them from degradation; and (iv) CXCL9 enhances migration induced by CXCL12 on CXCR4 + / CXCR3 - malignant B cells.	28	34	triggering	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	30	31	33	34
Moreover , the inhibitory effect of CCL21 blockade on antigen bearing DC trafficking strongly supports the hypothesis that CCL21 , secreted by lymphatic endothelial cells , promotes CCR7 + cell migration into the afferent lymphatics enroute to draining LN .	Moreover, the inhibitory effect of CCL21 blockade on antigen bearing DC trafficking strongly supports the hypothesis that CCL21, secreted by lymphatic endothelial cells, promotes CCR7 + cell migration into the afferent lymphatics enroute to draining LN.	18	28	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	18	19	27	28
Even the most conservative substitution to Asp ( E193D ) impaired CCR7 activation by CCL21 with no impairment of CCL19 , indicating that the length of the negatively charged side chain matters , and that we manipulated a finely tuned CCL21 interaction domain .	Even the most conservative substitution to Asp (E193D) impaired CCR7 activation by CCL21 with no impairment of CCL19, indicating that the length of the negatively charged side chain matters, and that we manipulated a finely tuned CCL21 interaction domain.	11	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	14	15	11	12
Indeed , up-regulation of CCL21 prior to hapten challenge promotes CCR7 + cells egress from the skin leading to impaired CHS responses .	Indeed, up-regulation of CCL21 prior to hapten challenge promotes CCR7 + cells egress from the skin leading to impaired CHS responses.	2	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	4	5	10	11
beta-arrestin-mediated CCR7 internalization induced by CCL19 and CCL21 was measured in U2OS cells coexpressing untagged receptor DNA , beta-arrestin 2 fused to the beta-gal enzyme acceptor fragment , and endosomes tagged with beta-gal enzyme donor fragment .	beta-arrestin-mediated CCR7 internalization induced by CCL19 and CCL21 was measured in U2OS cells coexpressing untagged receptor DNA, beta-arrestin 2 fused to the beta-gal enzyme acceptor fragment, and endosomes tagged with beta-gal enzyme donor fragment.	1	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	7	8	1	2
The results suggest that CCL21 triggers the activation of CCR7 signaling through CCL21 secreted from cancer cells in an autocrine manner .	The results suggest that CCL21 triggers the activation of CCR7 signaling through CCL21 secreted from cancer cells in an autocrine manner.	4	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	4	5	9	10
Interestingly , podocyte CCL21 was reported to contribute to the podocyte-mesangial cell crosstalk by activating CCR7 receptors in mesangial cells and promoting mesangial cell survival , proliferation , migration and matrix adhesion through activation of glycogen synthase kinase-3 ( GSK-3 ) , protein kinase B ( PKB and Akt ) and integrin linked kinase XREF_BIBR XREF_BIBR XREF_BIBR .	Interestingly, podocyte CCL21 was reported to contribute to the podocyte-mesangial cell crosstalk by activating CCR7 receptors in mesangial cells and promoting mesangial cell survival, proliferation, migration and matrix adhesion through activation of glycogen synthase kinase-3 (GSK-3), protein kinase B (PKB and Akt) and integrin linked kinase XREF_BIBR XREF_BIBR XREF_BIBR.	2	16	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	3	4	15	16
Chemokine ligand21 ( CCL21 ) was used to activate CCR7 and the results revealed that CCR7 upregulation inhibited cell apoptosis and affected apoptosis related protein levels .	Chemokine ligand21 (CCL21) was used to activate CCR7 and the results revealed that CCR7 upregulation inhibited cell apoptosis and affected apoptosis related protein levels.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	3	4	9	10
CCR7 stimulation by CCL19 or CCL21 has recently been shown to result in MAP-kinase phosphorylation and this is likely to be involved in CLL cell survival [ XREF_BIBR ] .	CCR7 stimulation by CCL19 or CCL21 has recently been shown to result in MAP-kinase phosphorylation and this is likely to be involved in CLL cell survival [XREF_BIBR].	0	6	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	5	6	0	1
During EAE , ECs are shown to express CCL2 , CCL19 , and CCL21 , which mediate firm arrest of CCR2 + monocytes and DCs , and CCR7 + CD4 + T cells .	During EAE, ECs are shown to express CCL2, CCL19, and CCL21, which mediate firm arrest of CCR2 + monocytes and DCs, and CCR7 + CD4 + T cells.	7	32	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	13	14	27	28
Significantly , migration of positively selected thymocytes from the cortex to the medulla , a process essential for alphabetaT-cell tolerance induction , requires CCR7 mediated migration promoted by expression of CCL19 and CCL21 by medullary stromal cells XREF_BIBR , with CCR7 also linked to thymic egress of newly selected T-cells XREF_BIBR , at least in the neonatal period .	Significantly, migration of positively selected thymocytes from the cortex to the medulla, a process essential for alphabetaT-cell tolerance induction, requires CCR7 mediated migration promoted by expression of CCL19 and CCL21 by medullary stromal cells XREF_BIBR, with CCR7 also linked to thymic egress of newly selected T-cells XREF_BIBR, at least in the neonatal period.	23	33	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	expression of CCL19 and CCL21	ccl21	CCR7	CCR7	ccr7	32	33	23	24
The functional cooperation between the CXCR4 ligand chemokine CXCL12 and the CCR7 ligand chemokines CCL19 and CCL21 enhances CCR7 dependent T cell motility in vitro as well as cell trafficking into the lymph nodes in vivo .	The functional cooperation between the CXCR4 ligand chemokine CXCL12 and the CCR7 ligand chemokines CCL19 and CCL21 enhances CCR7 dependent T cell motility in vitro as well as cell trafficking into the lymph nodes in vivo.	12	20	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	16	17	18	19
CCR7 dependent migration of APCs , mostly DCs , to initial lymphatics , is primarily directed by a chemotactic gradient of CCL21 and interstitial flow [ XREF_BIBR ] .	CCR7 dependent migration of APCs, mostly DCs, to initial lymphatics, is primarily directed by a chemotactic gradient of CCL21 and interstitial flow [XREF_BIBR].	0	26	directed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	21	22	0	1
CCL21 production by the lymphatic endothelium can also be enhanced by VEGF-C , thereby promoting lymphatic entry of CCR7 + tumor cells .	CCL21 production by the lymphatic endothelium can also be enhanced by VEGF-C, thereby promoting lymphatic entry of CCR7 + tumor cells.	0	21	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	0	1	18	19
Because CCL21 transcripts are also found in a reticular pattern throughout the T zone , it is likely that the podoplanin + stromal cells forming a 3D network are the major local CCL21 source mediating the attraction of CCR7 + T cells and DCs .	Because CCL21 transcripts are also found in a reticular pattern throughout the T zone, it is likely that the podoplanin + stromal cells forming a 3D network are the major local CCL21 source mediating the attraction of CCR7 + T cells and DCs.	32	41	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	32	33	38	39
The concomitant presence of CCL19 and CCL21 and peripheral node addressin ( PNAd positive ) HEVs allows the homing of CCR7 + T cells ( i.e ., naive and central memory ) and mature CCR7 + dendritic cells ( DCs ) from the systemic circulation upon binding to PNAd + HEVs through L-selectin .	The concomitant presence of CCL19 and CCL21 and peripheral node addressin (PNAd positive) HEVs allows the homing of CCR7 + T cells (i.e., naive and central memory) and mature CCR7 + dendritic cells (DCs) from the systemic circulation upon binding to PNAd + HEVs through L-selectin.	2	23	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	6	7	20	21
We demonstrated that activation of CCR7 by CCL21 can induce increased cell viability and mammosphere forming ability of colorectal cells via AKT and GSK-3beta signals .	We demonstrated that activation of CCR7 by CCL21 can induce increased cell viability and mammosphere forming ability of colorectal cells via AKT and GSK-3beta signals.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	7	8	5	6
CK decreased CCL21 levels in lymph nodes and CCR7 expression in DCs and suppressed CCL21 and CCR7 mediated migration of DCs , thus reducing accumulation of DCs in lymph nodes .	CK decreased CCL21 levels in lymph nodes and CCR7 expression in DCs and suppressed CCL21 and CCR7 mediated migration of DCs, thus reducing accumulation of DCs in lymph nodes.	0	18	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL21	CK decreased CCL21 levels	ccl21	CCR7	CCR7	ccr7	2	3	16	17
Importantly , the present study describes a novel strategy of enhancing CCL21 mediated CCR7 signaling in Tregs during ex vivo expansion in order to augment their lymph node homing characteristics ( CCR7 hi CD62L hi CD103 lo ) without losing their suppressive phenotype .	Importantly, the present study describes a novel strategy of enhancing CCL21 mediated CCR7 signaling in Tregs during ex vivo expansion in order to augment their lymph node homing characteristics (CCR7 hi CD62L hi CD103 lo) without losing their suppressive phenotype.	10	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	11	12	13	14
In this regard , podocytes expression of CCL21 activated CCR7 receptors in mesangial cells XREF_BIBR XREF_BIBR XREF_BIBR .	In this regard, podocytes expression of CCL21 activated CCR7 receptors in mesangial cells XREF_BIBR XREF_BIBR XREF_BIBR.	5	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL21	expression of CCL21	ccl21	CCR7	CCR7	ccr7	7	8	9	10
As the cell interacts with the network , bound CCL21 triggers CCR7 to activate beta2 integrins on the DC thereby promoting cell adhesion to the network via ICAM-1-integrin binding , and random migration .	As the cell interacts with the network, bound CCL21 triggers CCR7 to activate beta2 integrins on the DC thereby promoting cell adhesion to the network via ICAM-1-integrin binding, and random migration.	6	12	triggers	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	9	10	11	12
Activated caspase-9 also activates the downstream executioner protein , caspase-3 10 , which plays a critical role during apoptosis 23 .	Activated caspase-9 also activates the downstream executioner protein, caspase-3 10, which plays a critical role during apoptosis 23.	0	13	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	9	10	1	2
Activated caspase 9 in turn activates caspase 3 , which ultimately induces apoptosis via a decrease in the Bcl-2 level .	Activated caspase 9 in turn activates caspase 3, which ultimately induces apoptosis via a decrease in the Bcl-2 level.	0	11	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	6	8	1	3
In addition , FQ16 ( 3 - 7.39 micromol L (-1) ) increased mRNA expression of Bax and protein expression of p53 , Bax , caspase-9 , caspase-3 , separately , and induced cytosolic accumulation of activities caspase-9 and caspase-3 , whereas the mRNA and protein expression of Bcl-2 decreased with no change of caspase-8 .	In addition, FQ16 (3 - 7.39 micromol L (-1)) increased mRNA expression of Bax and protein expression of p53, Bax, caspase-9, caspase-3, separately, and induced cytosolic accumulation of activities caspase-9 and caspase-3, whereas the mRNA and protein expression of Bcl-2 decreased with no change of caspase-8.	3	49	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	FQ16 (3 - 7.39 micromol L (-1)) increased mRNA expression of Bax and protein expression of p53, Bax, caspase-9, caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	27	28	37	38
Caspase-3 , in turn , has been shown to activate caspase-9 through a feedback amplification loop in which caspase-3 cleaves the N-terminal region of caspase-9 and inactivates XIAP itself [ XREF_BIBR ] .	Caspase-3, in turn, has been shown to activate caspase-9 through a feedback amplification loop in which caspase-3 cleaves the N-terminal region of caspase-9 and inactivates XIAP itself [XREF_BIBR].	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	caspase-9	caspase-9	caspase-9	0	1	10	11
Activated caspase-9 , in turn , activates executioner caspases , caspase-3 and caspase -7 leading to apoptosis induction .	Activated caspase-9, in turn, activates executioner caspases, caspase-3 and caspase -7 leading to apoptosis induction.	0	12	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	10	11	1	2
Then , cytochrome c promotes the assembly of the apoptosome that results in caspase-9 activation and subsequent activation of the executioner caspases , including caspase-3 .	Then, cytochrome c promotes the assembly of the apoptosome that results in caspase-9 activation and subsequent activation of the executioner caspases, including caspase-3.	13	25	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	24	25	13	14
XREF_BIBR Caspase 3 further activates Caspase 8 and Caspase 9 and mediates apoptosis .	XREF_BIBR Caspase 3 further activates Caspase 8 and Caspase 9 and mediates apoptosis.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase 3	Caspase 3	Caspase 3	Caspase 9	Caspase 9	Caspase 9	1	3	8	10
Activated caspase 9 could further activate caspase 3 , which then induced cell apoptosis .	Activated caspase 9 could further activate caspase 3, which then induced cell apoptosis.	0	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	6	8	1	3
Activated caspase-9 then activates the key enzyme caspase-3 , which is the most important step for initiating cell apoptosis and elicits the subsequent apoptotic signals .	Activated caspase-9 then activates the key enzyme caspase-3, which is the most important step for initiating cell apoptosis and elicits the subsequent apoptotic signals.	0	20	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	7	8	1	2
Although the absence of caspase-3 in MCF-7 might trigger the caspase-9 activity as suggested by Blanc et .	Although the absence of caspase-3 in MCF-7 might trigger the caspase-9 activity as suggested by Blanc et.	2	11	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	4	5	10	11
Activated caspase-9 then activates downstream caspase-3 , which causes the cleavage or degradation of various key cellular substrates , including PARP , thus resulting in apoptosis .	Activated caspase-9 then activates downstream caspase-3, which causes the cleavage or degradation of various key cellular substrates, including PARP, thus resulting in apoptosis.	0	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	5	6	1	2
Activated caspase-9 can then cleave and activate the downstream effector caspase , caspase-3 , resulting in apoptotic destruction of the cell .	Activated caspase-9 can then cleave and activate the downstream effector caspase, caspase-3, resulting in apoptotic destruction of the cell.	0	14	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	12	13	1	2
Once initiated caspase-9 goes on to activate caspase-3 ( effector caspase ) , which cleaves substrates at aspartate residues and activation of this proteolytic activity appears to be an event in apoptosis XREF_BIBR .	Once initiated caspase-9 goes on to activate caspase-3 (effector caspase), which cleaves substrates at aspartate residues and activation of this proteolytic activity appears to be an event in apoptosis XREF_BIBR.	1	14	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	7	8	2	3
It is well known that caspase-3 is the ultimate executioner caspase of apoptosis and that activated caspase-9 cleaves downstream caspases , including caspase-3 , to initiate the caspase cascade .	It is well known that caspase-3 is the ultimate executioner caspase of apoptosis and that activated caspase-9 cleaves downstream caspases, including caspase-3, to initiate the caspase cascade.	5	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	5	6	16	17
Thus , we describe a pathway where caspase-3 functions to initiate apoptotic damage and caspase-9 and caspase-6 amplify the apoptotic cascade .	Thus, we describe a pathway where caspase-3 functions to initiate apoptotic damage and caspase-9 and caspase-6 amplify the apoptotic cascade.	7	15	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	7	8	14	15
Activated Casp-9 activates the effector Casp-3 leading to degradation of DNA and cellular constituents XREF_BIBR .	Activated Casp-9 activates the effector Casp-3 leading to degradation of DNA and cellular constituents XREF_BIBR.	0	6	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp-3	Casp-3	Casp-3	Casp-9	Casp-9	Casp-9	5	6	1	2
We finally investigated the levels of proliferation related signals ( i.e. p53 , p21 , c-MYC , cyclin D1 ) and apoptosis related proteins ( i.e. p53 , activated caspase-3 , activated caspase-9 , activated PARP ) by western blotting .	We finally investigated the levels of proliferation related signals (i.e. p53, p21, c-MYC, cyclin D1) and apoptosis related proteins (i.e. p53, activated caspase-3, activated caspase-9, activated PARP) by western blotting.	26	34	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	29	30	32	33
Activated caspase 9 in turn stimulates the downstream target caspase 3 , leading to mitochondria mediated apoptosis .	Activated caspase 9 in turn stimulates the downstream target caspase 3, leading to mitochondria mediated apoptosis.	0	11	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	9	11	1	3
Further , deguelin exposure increased caspase-3 activity ( XREF_FIG ) , caused caspase-3 and caspase-9 cleavage ( XREF_FIG ) , while down-regulating Bcl-xl expression ( XREF_FIG ) .	Further, deguelin exposure increased caspase-3 activity (XREF_FIG), caused caspase-3 and caspase-9 cleavage (XREF_FIG), while down-regulating Bcl-xl expression (XREF_FIG).	5	15	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	5	6	14	15
Activated caspase-9 then cleaves caspase-3 resulting in downstream events involved in cell death XREF_BIBR .	Activated caspase-9 then cleaves caspase-3 resulting in downstream events involved in cell death XREF_BIBR.	0	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	4	5	1	2
Both caspase-3 and caspase-7 are target of caspase-9 and are executor caspases of cellular intrinsic apoptotic pathway XREF_BIBR , XREF_BIBR .	Both caspase-3 and caspase-7 are target of caspase-9 and are executor caspases of cellular intrinsic apoptotic pathway XREF_BIBR, XREF_BIBR.	0	8	are target	Positive_activation_copula_1	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	1	2	7	8
We demonstrate that this positive feedback brings about bistability ( i.e ., all-or-none behaviour ) , and that it cooperates with Casp3 mediated feedback cleavage of Casp9 to generate irreversibility in caspase activation .	We demonstrate that this positive feedback brings about bistability (i.e., all-or-none behaviour), and that it cooperates with Casp3 mediated feedback cleavage of Casp9 to generate irreversibility in caspase activation.	21	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp3	Casp3	Casp3	Casp9	Casp9	Casp9	21	22	26	27
Caspase activity is maintained even if the stimulus is removed , as Casp3 , once activated , retains XIAP , and thereby prevents full Casp9 deactivation ( bottom left in XREF_FIG ) .	Caspase activity is maintained even if the stimulus is removed, as Casp3, once activated, retains XIAP, and thereby prevents full Casp9 deactivation (bottom left in XREF_FIG).	12	25	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp3	Casp3	Casp3	Casp9	Casp9	Casp9	12	13	24	25
Activated caspase-9 then stimulated activation of caspase-3 .	Activated caspase-9 then stimulated activation of caspase-3.	0	7	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	6	7	1	2
STP induced HT29 cell apoptosis was associated with caspase-3 activation independent of caspase-8 or caspase-9 activity ; accordingly , inhibitors of the latter caspases were without effect on STP induced apoptosis .	STP induced HT29 cell apoptosis was associated with caspase-3 activation independent of caspase-8 or caspase-9 activity; accordingly, inhibitors of the latter caspases were without effect on STP induced apoptosis.	8	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	8	9	14	15
By Western blotting caspase 3 , caspase 7 , caspase 8 , and caspase 9 protein levels increased in cells at stage 2 compared to cells at stage 1 ( * p < 0.05 ) .	By Western blotting caspase 3, caspase 7, caspase 8, and caspase 9 protein levels increased in cells at stage 2 compared to cells at stage 1 (* p < 0.05).	0	18	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	3	5	13	15
On the other hand , caspase 9 may be activated by caspase 3 later in an autostimulant feedback [ XREF_BIBR ] .	On the other hand, caspase 9 may be activated by caspase 3 later in an autostimulant feedback [XREF_BIBR].	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	11	13	5	7
We demonstrated selective activation of caspases in the thymus during heat shock , i.e. primary activation of initiator caspase 9 ( but not caspase 8 ) and effector caspase 3 ( but not caspase 6 ) .	We demonstrated selective activation of caspases in the thymus during heat shock, i.e. primary activation of initiator caspase 9 (but not caspase 8) and effector caspase 3 (but not caspase 6).	5	30	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	28	30	18	20
Activated caspase-9 in turn activates caspase-3 , which is a major proteolytic enzyme responsible for the ultimate dismantling of cells during apoptotic cell death .	Activated caspase-9 in turn activates caspase-3, which is a major proteolytic enzyme responsible for the ultimate dismantling of cells during apoptotic cell death.	0	12	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	5	6	1	2
The Bax and Bcl-2 proteins were observed to translocate between the mitochondria and the cytoplasm , where they led to a release of cytochrome c. Cytochrome c then activated caspase 9 and caspase 3 , which are important in the apoptosis signaling pathway .	The Bax and Bcl-2 proteins were observed to translocate between the mitochondria and the cytoplasm, where they led to a release of cytochrome c. Cytochrome c then activated caspase 9 and caspase 3, which are important in the apoptosis signaling pathway.	28	34	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	32	34	29	31
As shown in XREF_FIG , upon treatment with JD , the procaspase-9 and procaspase-3 levels decreased , and the cleaved-caspase-9 and cleaved caspase-3 levels increased , indicating the activation of caspase-9 and caspase-3 .	As shown in XREF_FIG, upon treatment with JD, the procaspase-9 and procaspase-3 levels decreased, and the cleaved-caspase-9 and cleaved caspase-3 levels increased, indicating the activation of caspase-9 and caspase-3.	22	32	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3 levels	caspase-3	caspase-9	caspase-9	caspase-9	22	23	30	31
This XIAP redistribution results a positive feedback loop , which , together with Casp3 mediated Casp9 feedback cleavage , suddenly switches the system from low to high Casp3 activity ( transition from point 2 to point 3 in XREF_FIG B ) .	This XIAP redistribution results a positive feedback loop, which, together with Casp3 mediated Casp9 feedback cleavage, suddenly switches the system from low to high Casp3 activity (transition from point 2 to point 3 in XREF_FIG B).	11	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Casp3	Casp3	Casp3	Casp9	Casp9	Casp9	13	14	15	16
In addition , we found that silencing of caspase-3 inhibited caspase-9-induced release of cytochrome c and Smac , as well as the activation of endogenous caspase-9 ( XREF_FIG ) .	In addition, we found that silencing of caspase-3 inhibited caspase-9-induced release of cytochrome c and Smac, as well as the activation of endogenous caspase-9 (XREF_FIG).	6	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	8	9	25	26
Moreover , caspase-3 inhibition markedly reduced the activation of caspase-8 and also almost completely inhibited activation of caspase-9 .	Moreover, caspase-3 inhibition markedly reduced the activation of caspase-8 and also almost completely inhibited activation of caspase-9.	2	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	2	3	17	18
Caspase-3 also activates caspase-9 in an amplifying feedback loop XREF_BIBR .	Caspase-3 also activates caspase-9 in an amplifying feedback loop XREF_BIBR.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	caspase-9	caspase-9	caspase-9	0	1	3	4
We confirmed that silencing of caspase-3 ( XREF_FIG ) inhibited the loss of mitochondrial membrane potential downstream of the dimerization of caspase-9 ( XREF_FIG ) .	We confirmed that silencing of caspase-3 (XREF_FIG) inhibited the loss of mitochondrial membrane potential downstream of the dimerization of caspase-9 (XREF_FIG).	3	23	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	5	6	21	22
Activated caspase 9 then activates caspase 3 , which triggers terminal effector molecules leading to apoptosis ( XREF_FIG ) .	Activated caspase 9 then activates caspase 3, which triggers terminal effector molecules leading to apoptosis (XREF_FIG).	0	9	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	5	7	1	3
Activated caspase 9 activates the terminal effector caspase , caspase 3 , leading rapidly to apoptosis .	Activated caspase 9 activates the terminal effector caspase, caspase 3, leading rapidly to apoptosis.	0	12	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	9	11	1	3
Activated caspase-9 cleaves pro-caspase-3 into its active form , which induces cell apoptosis .	Activated caspase-9 cleaves pro-caspase-3 into its active form, which induces cell apoptosis.	0	10	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pro-caspase-3	pro-caspase-3	pro-caspase-3	caspase-9	caspase-9	caspase-9	3	4	1	2
The caspase 9 is activated by the active caspase 3 .	The caspase 9 is activated by the active caspase 3.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	8	10	1	3
Upstream of caspase-3 , TGF-beta induced mitochondrial depolarization , cytochrome c release , and cleavage of caspase-9 , which suggests that the intrinsic apoptotic pathway mediates TGF-beta-induced apoptosis in RIE-1 and Smad3 cells .	Upstream of caspase-3, TGF-beta induced mitochondrial depolarization, cytochrome c release, and cleavage of caspase-9, which suggests that the intrinsic apoptotic pathway mediates TGF-beta-induced apoptosis in RIE-1 and Smad3 cells.	0	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	2	3	16	17
Subsequent to the up-regulation of dsRNA sensors and their adaptor molecules , there were up-regulation of caspase9 and activated caspase3 in both SK-N-AS and SK-N-FI , but not in other cell lines .	Subsequent to the up-regulation of dsRNA sensors and their adaptor molecules, there were up-regulation of caspase9 and activated caspase3 in both SK-N-AS and SK-N-FI, but not in other cell lines.	13	31	were up-regulation	Positive_activation_copula_1	Positive_activation	Positive_activation	caspase3	caspase3	caspase3	caspase9	caspase9	caspase9	19	20	16	17
Addition of TFF1 ( 10 muM ) almost completely inhibited butyrate induced caspase-3 and -6 activities , and partially reduced caspase-9 activity , but had no effect on caspase-2 .	Addition of TFF1 (10 muM) almost completely inhibited butyrate induced caspase-3 and -6 activities, and partially reduced caspase-9 activity, but had no effect on caspase-2.	2	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-3	TFF1 (10 muM) almost completely inhibited butyrate induced caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	12	13	20	21
Activated caspase-9 can further activate downstream caspase-3 , which in turn leads to tumor cell apoptosis .	Activated caspase-9 can further activate downstream caspase-3, which in turn leads to tumor cell apoptosis.	0	11	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	6	7	1	2
Activated caspase 9 then cleaves pro caspase 3 , initiating a cascade of events , like PARP cleavage , to produce cell death .	Activated caspase 9 then cleaves pro caspase 3, initiating a cascade of events, like PARP cleavage, to produce cell death.	0	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 9	caspase 9	caspase 9	6	8	1	3
The present study established the existence of a protease cascade , in which caspase-3 mediates the activation of caspase-6 triggered by Fas or by caspase-8 in the cytoplasm of Jurkat cells .	The present study established the existence of a protease cascade, in which caspase-3 mediates the activation of caspase-6 triggered by Fas or by caspase-8 in the cytoplasm of Jurkat cells.	13	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	13	14	18	19
We next used the Caspase-3 knockout to determine whether our biochemical data showing that Caspase-3 activates Caspase-6 had an in vivo counterpart .	We next used the Caspase-3 knockout to determine whether our biochemical data showing that Caspase-3 activates Caspase-6 had an in vivo counterpart.	14	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	Caspase-6	Caspase-6	Caspase-6	14	15	16	17
Caspase-3 also activates caspase-6 , an additional effector caspase that contributes to the cleavage of the nuclear envelope .	Caspase-3 also activates caspase-6, an additional effector caspase that contributes to the cleavage of the nuclear envelope.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	caspase-6	caspase-6	caspase-6	0	1	3	4
Overall , our findings strongly suggested that there is a direct two-step protease cascade in Fas stimulated Jurkat cells , in which caspase-8 activated via FADD and MORT1 cleaves pro-caspase-3 , and the activated caspase-3 in turn activates caspase-6 by directly cleaving pro-caspases-6 .	Overall, our findings strongly suggested that there is a direct two-step protease cascade in Fas stimulated Jurkat cells, in which caspase-8 activated via FADD and MORT1 cleaves pro-caspase-3, and the activated caspase-3 in turn activates caspase-6 by directly cleaving pro-caspases-6.	32	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	34	35	38	39
For example , Casp3 was shown to induce processing of Casp6 , which in turn cleaves Casp8 , an activator of Casp3 [ XREF_BIBR ] ( feedback 1 in XREF_FIG A ) .	For example, Casp3 was shown to induce processing of Casp6, which in turn cleaves Casp8, an activator of Casp3 [XREF_BIBR] (feedback 1 in XREF_FIG A).	3	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp3	Casp3	Casp3	Casp6	Casp6	Casp6	3	4	10	11
Knockdown of caspase-3 diminished cleavage of SMSr as well ; however , this effect is likely indirect given that caspase-3 mediates proteolytic activation of caspase-6 [ XREF_BIBR ] and does not recognize SMSr as substrate in vitro ( XREF_FIG B ) .	Knockdown of caspase-3 diminished cleavage of SMSr as well; however, this effect is likely indirect given that caspase-3 mediates proteolytic activation of caspase-6 [XREF_BIBR] and does not recognize SMSr as substrate in vitro (XREF_FIG B).	19	31	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	19	20	24	25
The finding that only Caspase-3 , but not other caspases tested , activates Caspase-6 effectively prompted us to revisit whether Caspase-3 might also contribute to the axon degeneration program .	The finding that only Caspase-3, but not other caspases tested, activates Caspase-6 effectively prompted us to revisit whether Caspase-3 might also contribute to the axon degeneration program.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	Caspase-6	Caspase-6	Caspase-6	4	5	13	14
Caspase 6 is activated by active Caspase 3 and in turn cleaves lamin , resulting in nuclear membrane fragmentation [ XREF_BIBR ] .	Caspase 6 is activated by active Caspase 3 and in turn cleaves lamin, resulting in nuclear membrane fragmentation [XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Caspase 3	Caspase 3	Caspase 3	Caspase 6	Caspase 6	Caspase 6	6	8	0	2
Activation of Caspase-6 by Caspase-3 .	Activation of Caspase-6 by Caspase-3.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	Caspase-6	Caspase-6	Caspase-6	4	5	2	3
10 Caspase-6 is often activated by caspase-3 rather than by initiator caspases 11 and has been shown to undergo self activation both in vitro and in vivo XREF_BIBR , XREF_BIBR .	10 Caspase-6 is often activated by caspase-3 rather than by initiator caspases 11 and has been shown to undergo self activation both in vitro and in vivo XREF_BIBR, XREF_BIBR.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	Caspase-6	Caspase-6	Caspase-6	6	7	1	2
Caspase-3 activates caspase-6 , which in turn plays an essential role in the induction of nuclear shrinkage and nuclear fragmentation .	Caspase-3 activates caspase-6, which in turn plays an essential role in the induction of nuclear shrinkage and nuclear fragmentation.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	caspase-6	caspase-6	caspase-6	0	1	2	3
In our in vitro cultures , we find that genetic deletion of Caspase-3 prevents activation of Caspase-6 and has a stronger protective effect than genetic deletion of Caspase-6 , as expected if Caspase-6 is the more downstream protease .	In our in vitro cultures, we find that genetic deletion of Caspase-3 prevents activation of Caspase-6 and has a stronger protective effect than genetic deletion of Caspase-6, as expected if Caspase-6 is the more downstream protease.	10	17	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	Caspase-6	Caspase-6	Caspase-6	12	13	16	17
CASP3 activates itself as well as CASP6 , 7 and 9 by proteolytic cleavage and amplification of the signal for the execution of apoptosis .	CASP3 activates itself as well as CASP6, 7 and 9 by proteolytic cleavage and amplification of the signal for the execution of apoptosis.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP3	CASP3	CASP3	CASP6	CASP6	CASP6	0	1	6	7
Caspase-6 is activated by caspase-3 and can cleave caspase-8 .	Caspase-6 is activated by caspase-3 and can cleave caspase-8.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	Caspase-6	Caspase-6	Caspase-6	4	5	0	1
It has been reported that caspase-3 is required to activate caspase-6 [ XREF_BIBR ] , and we propose that the presence of cl-C6 at 72 h following hypoxia-ischaemia may be the downstream effect of capase-3 activity which peaks at 24 h following hypoxia-ischaemia [ XREF_BIBR ] .	It has been reported that caspase-3 is required to activate caspase-6 [XREF_BIBR], and we propose that the presence of cl-C6 at 72 h following hypoxia-ischaemia may be the downstream effect of capase-3 activity which peaks at 24 h following hypoxia-ischaemia [XREF_BIBR].	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	5	6	10	11
Caspase-3 is one of the key executioner of apoptosis and induces downstream caspase-6 which in turn target cleavage of important structural proteins such as laminin and keratins [ XREF_BIBR , XREF_BIBR ] .	Caspase-3 is one of the key executioner of apoptosis and induces downstream caspase-6 which in turn target cleavage of important structural proteins such as laminin and keratins [XREF_BIBR, XREF_BIBR].	0	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	caspase-6	caspase-6	caspase-6	0	1	12	13
In addition , caspase-6 could be activated by the addition of either recombinant caspase-3 or caspase-9 to a lysate prepared from untreated embryos .	In addition, caspase-6 could be activated by the addition of either recombinant caspase-3 or caspase-9 to a lysate prepared from untreated embryos.	3	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	13	14	3	4
However , it has been reported that a deficiency in caspase-3 can induce activation of caspase-6 and caspase-7 , and that in caspase-9 can enhance caspase-2 and caspase-6 in knockout mice XREF_BIBR .	However, it has been reported that a deficiency in caspase-3 can induce activation of caspase-6 and caspase-7, and that in caspase-9 can enhance caspase-2 and caspase-6 in knockout mice XREF_BIBR.	8	28	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	10	11	27	28
This process is in part sustained by autocatalytic events , such as the activation of caspase-2 by caspase-3 involved in the feed-forward loop , as well the activation of caspase-6 by caspase-3 that allows an amplification of the final proteolytic events controlling protein degradation and DNA fragmentation .	This process is in part sustained by autocatalytic events, such as the activation of caspase-2 by caspase-3 involved in the feed-forward loop, as well the activation of caspase-6 by caspase-3 that allows an amplification of the final proteolytic events controlling protein degradation and DNA fragmentation.	27	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	31	32	29	30
Selective inhibition of caspase-3 by 100 muM DMQD-CHO blocked the activation of caspase-6 .	Selective inhibition of caspase-3 by 100 muM DMQD-CHO blocked the activation of caspase-6.	1	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	3	4	12	13
Since Casp3 is known to activate Casp6 under certain conditions XREF_BIBR , we also examined the stomachs for the presence of proCasp3 and its active p17 or p20 subunit ( XREF_FIG ) .	Since Casp3 is known to activate Casp6 under certain conditions XREF_BIBR, we also examined the stomachs for the presence of proCasp3 and its active p17 or p20 subunit (XREF_FIG).	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp3	Casp3	Casp3	Casp6	Casp6	Casp6	1	2	6	7
In cells undergoing apoptosis , lamin B was shown to be cleaved by caspase-6 25 , an effector caspase that is activated by caspase-3 in the proteolytic cascade 26 .	In cells undergoing apoptosis, lamin B was shown to be cleaved by caspase-6 25, an effector caspase that is activated by caspase-3 in the proteolytic cascade 26.	11	24	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	23	24	13	14
Furthermore , active caspase 6 is capable of processing and activating procaspase 3 in cellular extracts prepared from non apoptotic CGCs , whereas caspase 3 failed to activate caspase 6 .	Furthermore, active caspase 6 is capable of processing and activating procaspase 3 in cellular extracts prepared from non apoptotic CGCs, whereas caspase 3 failed to activate caspase 6.	23	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 6	caspase 6	caspase 6	23	25	28	30
While studying how Caspase-6 is activated , however , we found , consistent with prior suggestions , that Caspase-3 function is required to activate Caspase-6 , leading us to revisit the role of Caspase-3 in axon degeneration .	While studying how Caspase-6 is activated, however, we found, consistent with prior suggestions, that Caspase-3 function is required to activate Caspase-6, leading us to revisit the role of Caspase-3 in axon degeneration.	18	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	Caspase-6	Caspase-6	Caspase-6	18	19	24	25
This applies not only to the TNFR1 interactors FADD , cFLIP , CASP8 , CYLD , and various IAP family members ( see above ) , but also to proteins that propagate or execute apoptotic signals , such as CASP6 , which is generally activated by CASP8 or CASP3 as one of the final events of apoptosis , and cathepsins , which promote mitochondrial outer membrane permeabilization ( MOMP ) in response to lysosomal damage .	This applies not only to the TNFR1 interactors FADD, cFLIP, CASP8, CYLD, and various IAP family members (see above), but also to proteins that propagate or execute apoptotic signals, such as CASP6, which is generally activated by CASP8 or CASP3 as one of the final events of apoptosis, and cathepsins, which promote mitochondrial outer membrane permeabilization (MOMP) in response to lysosomal damage.	35	49	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CASP3	CASP3	CASP3	CASP6	CASP6	CASP6	48	49	39	40
Following activation of caspase-9 , caspase-3 is cleaved and activated , and caspase-3 directly activates caspase-6 and indirectly activates calpain via calpastatin cleavage [ XREF_BIBR , XREF_BIBR ] .	Following activation of caspase-9, caspase-3 is cleaved and activated, and caspase-3 directly activates caspase-6 and indirectly activates calpain via calpastatin cleavage [XREF_BIBR, XREF_BIBR].	12	18	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	12	13	15	16
In parallel with this result , the activation of caspase-3 in cells exposed to apigenin induced increased cleavage of caspase-6 and -7 .	In parallel with this result, the activation of caspase-3 in cells exposed to apigenin induced increased cleavage of caspase-6 and -7.	7	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	9	10	19	20
A hypothetical cascade pathway has been proposed in which caspase-3 and -7 are activated downstream of caspase-6 .	A hypothetical cascade pathway has been proposed in which caspase-3 and -7 are activated downstream of caspase-6.	9	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-6	caspase-6	caspase-6	9	10	16	17
When the recombinant caspases were added to the extracts from Jurkat cells , caspase 3 produced active caspase 6 like protease , while caspase 6 activated the caspase 3 protease , suggesting that these proteases can activate each other .	When the recombinant caspases were added to the extracts from Jurkat cells, caspase 3 produced active caspase 6 like protease, while caspase 6 activated the caspase 3 protease, suggesting that these proteases can activate each other.	13	20	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 6	caspase 6	caspase 6	13	15	17	19
In the nucleus caspase 3 activates caspase activated DNase ( CAD ) which cleaves nuclear DNA between histones , creating DNA fragments of ~ 160 bp or multiples thereof .	In the nucleus caspase 3 activates caspase activated DNase (CAD) which cleaves nuclear DNA between histones, creating DNA fragments of ~ 160 bp or multiples thereof.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase activated DNase	caspase activated DNase	caspase activated DNase	3	5	6	9
The role of H1 phosphorylation is postulated to modulate DNA recognition and/or DNA cleavage by the caspase 3 mediated activation of caspase activated DNase .	The role of H1 phosphorylation is postulated to modulate DNA recognition and/or DNA cleavage by the caspase 3 mediated activation of caspase activated DNase.	16	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase activated DNase	caspase activated DNase	caspase activated DNase	16	18	21	24
Both internal and external apoptotic pathways meet at the level of caspase-3 , which activates CAD ( caspase activated DNase ) or DFF40 , thereby inducing specific DNA fragmentation and apoptotic cell death [ XREF_BIBR , XREF_BIBR ] .	Both internal and external apoptotic pathways meet at the level of caspase-3, which activates CAD (caspase activated DNase) or DFF40, thereby inducing specific DNA fragmentation and apoptotic cell death [XREF_BIBR, XREF_BIBR].	9	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	level of caspase-3	caspase-3	DFF40	DFF40	dff40	11	12	22	23
DFF40 and CAD is activated by caspase-3 that cuts the nuclease ' s inhibitor DFF45 and ICAD .	DFF40 and CAD is activated by caspase-3 that cuts the nuclease 's inhibitor DFF45 and ICAD.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	DFF40	DFF40	DFF40	6	7	0	1
DFF40 and CAD primary activated through site specific proteolytic cleavage by caspase 3 .	DFF40 and CAD primary activated through site specific proteolytic cleavage by caspase 3.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	DFF40	DFF40	DFF40	11	13	0	1
In apoptotic mammalian cells the fragmentation is catalyzed by DFF40 and CAD DNase primarily activated by caspase 3 through the site specific proteolytic cleavage of DFF45 and ICAD .	In apoptotic mammalian cells the fragmentation is catalyzed by DFF40 and CAD DNase primarily activated by caspase 3 through the site specific proteolytic cleavage of DFF45 and ICAD.	9	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	DFF40	DFF40	DFF40	16	18	9	10
Active caspase-3 activates the caspase activated DNase , leading to oligonucleosomal DNA fragmentation .	Active caspase-3 activates the caspase activated DNase, leading to oligonucleosomal DNA fragmentation.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase activated DNase	caspase activated DNase	caspase activated DNase	1	2	4	7
33 Owing to the ability of c-FLIP to control the apical caspase-8 , which activates the caspase-7 , we investigated whether increased caspase activation has occurred in cells lacking c-FLIP , in turn accounting for RTN4 processing .	33 Owing to the ability of c-FLIP to control the apical caspase-8, which activates the caspase-7, we investigated whether increased caspase activation has occurred in cells lacking c-FLIP, in turn accounting for RTN4 processing.	8	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-7	caspase-7	caspase-7	11	12	16	17
Caspase-8 activates cytoplasmic caspase-7 , which is likely to be the primary caspase responsible for cleavage of CENP-C and INCENP , a key chromosomal passenger protein .	Caspase-8 activates cytoplasmic caspase-7, which is likely to be the primary caspase responsible for cleavage of CENP-C and INCENP, a key chromosomal passenger protein.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-7	caspase-7	caspase-7	0	1	3	4
Caspase-8 can also promote effector caspase-7 activity .	Caspase-8 can also promote effector caspase-7 activity.	0	6	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	caspase-7	caspase-7	caspase-7	0	1	5	6
Activation of caspase 8 can activate caspase 7 , which in turn can cleave PARP [ XREF_BIBR , XREF_BIBR ] .	Activation of caspase 8 can activate caspase 7, which in turn can cleave PARP [XREF_BIBR, XREF_BIBR].	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 7	caspase 7	caspase 7	2	4	6	8
In summary , these data suggest that apoptosis occurring in cells expressing GFP-NDelta360 was initiated through caspase-8 , which further activates caspase-7 , resulting in the cleavage of PARP , and thus apoptosis .	In summary, these data suggest that apoptosis occurring in cells expressing GFP-NDelta360 was initiated through caspase-8, which further activates caspase-7, resulting in the cleavage of PARP, and thus apoptosis.	14	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-7	caspase-7	caspase-7	16	17	21	22
Caspase-7 is activated by an initiator caspase-8 and -9 , or by autocatalysis after specific cleavage at IQAD 198 vS located at the intersubunit linker .	Caspase-7 is activated by an initiator caspase-8 and -9, or by autocatalysis after specific cleavage at IQAD 198 vS located at the intersubunit linker.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	Caspase-7	Caspase-7	Caspase-7	6	7	0	1
Alternatively , caspase-8 activates caspase-7 , and eventually , the cleavage of Bid to tBid in the mitochondria activates caspase-9 via cathepsin D.	Alternatively, caspase-8 activates caspase-7, and eventually, the cleavage of Bid to tBid in the mitochondria activates caspase-9 via cathepsin D.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-7	caspase-7	caspase-7	2	3	4	5
Adressing lysosomal-mitochondrial apoptosis amplification in more detail , we found that within TNF-receptosomes , caspase-8 activates caspase-7 which then activates the lipase acid sphingomyelinase ( A-SMase ) by partial proteolysis in an endo-lysosomal compartment .	Adressing lysosomal-mitochondrial apoptosis amplification in more detail, we found that within TNF-receptosomes, caspase-8 activates caspase-7 which then activates the lipase acid sphingomyelinase (A-SMase) by partial proteolysis in an endo-lysosomal compartment.	14	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-7	caspase-7	caspase-7	14	15	16	17
Untreated cytosol extracts or caspase-8 by itself were unable to induce cytochrome c release .	Untreated cytosol extracts or caspase-8 by itself were unable to induce cytochrome c release.	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	4	5	11	13
Taken together , VDAC1 is required for TRAIL induced caspase-8 processing of BID leading to inhibition of TRAIL induced BAX activation and cytochrome C release , but does not affect the mitochondrial apoptotic response downstream of tBID .	Taken together, VDAC1 is required for TRAIL induced caspase-8 processing of BID leading to inhibition of TRAIL induced BAX activation and cytochrome C release, but does not affect the mitochondrial apoptotic response downstream of tBID.	7	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	TRAIL induced caspase-8	caspase-8	cytochrome C	cytochrome C	cytochrome c	9	10	22	24
If the intrinsic pathway was solely induced by caspase-8 , inhibiting caspase-8 alone should block cytochrome c release and subsequent cell death .	If the intrinsic pathway was solely induced by caspase-8, inhibiting caspase-8 alone should block cytochrome c release and subsequent cell death.	10	17	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	11	12	15	17
Furthermore , caspase 8 also leads to release of pro apoptotic factor cytochrome C [ XREF_BIBR ] .	Furthermore, caspase 8 also leads to release of pro apoptotic factor cytochrome C [XREF_BIBR].	2	15	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	cytochrome C	cytochrome C	cytochrome C	2	4	12	14
BID protein is a mediator of mitochondrial damage induced by caspase-8 ( CASP8 ) that ultimately triggers cytochrome c release 21 .	BID protein is a mediator of mitochondrial damage induced by caspase-8 (CASP8) that ultimately triggers cytochrome c release 21.	8	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	10	11	17	19
In steady state A1 we observed activation of the intrinsic mitochondrial pathway of apoptosis , characterized by a caspase dependent signaling cascade along with caspase-8 mediated tBid cleavage and cytochrome c release .	In steady state A1 we observed activation of the intrinsic mitochondrial pathway of apoptosis, characterized by a caspase dependent signaling cascade along with caspase-8 mediated tBid cleavage and cytochrome c release.	22	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	24	25	29	31
The adaptor proteins increase activation of caspase-8 causing the release of cytochrome c from mitochondria .	The adaptor proteins increase activation of caspase-8 causing the release of cytochrome c from mitochondria.	4	13	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	6	7	11	13
Caspase-8 indirectly mediates the release of cytochrome c from the mitochondria and the activation of caspase-3 , both of which leads to cleavage of cellular components and programmed cell death .	Caspase-8 indirectly mediates the release of cytochrome c from the mitochondria and the activation of caspase-3, both of which leads to cleavage of cellular components and programmed cell death.	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
21 Active caspase-8 then either cleaves the downstream caspase-3 into cleaved caspase-3 or triggers the cytochrome c release , thereby initiating the apoptotic cascades .	21 Active caspase-8 then either cleaves the downstream caspase-3 into cleaved caspase-3 or triggers the cytochrome c release, thereby initiating the apoptotic cascades.	0	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	2	3	15	17
During this cascade , caspase-8 cleaves Bid and induces cytochrome c release and/or directly activates caspase-3 [ XREF_BIBR ] .	During this cascade, caspase-8 cleaves Bid and induces cytochrome c release and/or directly activates caspase-3 [XREF_BIBR].	4	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	4	5	9	11
However , although inhibition of caspase-8 partially prevented mitochondrial cytochrome c release in these cells , MIM depolarisation was caspase-8 independent .	However, although inhibition of caspase-8 partially prevented mitochondrial cytochrome c release in these cells, MIM depolarisation was caspase-8 independent.	3	11	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	5	6	9	11
Mcl-1 also connects the receptor- and mitochondria mediated cell death pathways by antagonizing the caspase-8 cleavage product tBid , which may induce mitochondrial cytochrome C release [ XREF_BIBR , XREF_BIBR ] .	Mcl-1 also connects the receptor- and mitochondria mediated cell death pathways by antagonizing the caspase-8 cleavage product tBid, which may induce mitochondrial cytochrome C release [XREF_BIBR, XREF_BIBR].	14	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome C	cytochrome C	cytochrome C	14	15	23	25
However , these low levels of activated caspase-8 are sufficient to cause MOMP and cytochrome c release and subsequent rapid and strong caspase activation in a further large fraction of cells .	However, these low levels of activated caspase-8 are sufficient to cause MOMP and cytochrome c release and subsequent rapid and strong caspase activation in a further large fraction of cells.	4	16	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	levels of activated caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	7	8	14	16
Therefore , although caspase 8 augments cytochrome c release upon Fas ligation via tBid , it is unlikely to be the case in resting T cells in the absence of death receptor ligands .	Therefore, although caspase 8 augments cytochrome c release upon Fas ligation via tBid, it is unlikely to be the case in resting T cells in the absence of death receptor ligands.	3	8	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	cytochrome c	cytochrome c	cytochrome c	3	5	6	8
However , tBid , which is subsequently generated by FasL induced caspase-8 activation can not be sequestered by Bcl-2 proteins anymore and thus leads to a stronger Bax and Bak activation and the release of cytochrome c into the cytosol .	However, tBid, which is subsequently generated by FasL induced caspase-8 activation can not be sequestered by Bcl-2 proteins anymore and thus leads to a stronger Bax and Bak activation and the release of cytochrome c into the cytosol.	9	37	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	caspase-8	FasL induced caspase-8 activation can not be sequestered by Bcl-2	caspase-8	cytochrome c	cytochrome c	cytochrome c	11	12	35	37
Because caspase 8 initiated caspase cascade is able to trigger the mitochondrial cytochrome c releasing , the cytosol fractions were isolated and then immunoblotted with cytochrome c antibody ( XREF_FIG , right panels ) .	Because caspase 8 initiated caspase cascade is able to trigger the mitochondrial cytochrome c releasing, the cytosol fractions were isolated and then immunoblotted with cytochrome c antibody (XREF_FIG, right panels).	1	14	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	cytochrome c	cytochrome c	cytochrome c	1	3	12	14
Activation of caspase-8 induces the release of cytochrome c from the mitochondria [ XREF_BIBR ] .	Activation of caspase-8 induces the release of cytochrome c from the mitochondria [XREF_BIBR].	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	2	3	7	9
Exogenous l-ornithine did not inhibit NOHA induced caspase-8 activation and cleavage of BH ( 3 ) interacting domain but acted at the mitochondrial level and inhibited the NOHA induced cytochrome c release and apoptosis .	Exogenous l-ornithine did not inhibit NOHA induced caspase-8 activation and cleavage of BH (3) interacting domain but acted at the mitochondrial level and inhibited the NOHA induced cytochrome c release and apoptosis.	1	31	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-8	l-ornithine did not inhibit NOHA induced caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	7	8	29	31
However , inhibition of caspase-8 did not prevent MIM depolarisation ( data not shown ) and only partially prevented cytochrome c release ( XREF_FIG ) .	However, inhibition of caspase-8 did not prevent MIM depolarisation (data not shown) and only partially prevented cytochrome c release (XREF_FIG).	2	21	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	4	5	19	21
Cleavage of caspase-8 and fisetin mediated release of cytochrome c and Smac/Diablo indicated that fisetin induces apoptosis in HCT-116 cells via the activation of both the extrinsic and intrinsic pathways [ XREF_BIBR ] .	Cleavage of caspase-8 and fisetin mediated release of cytochrome c and Smac/Diablo indicated that fisetin induces apoptosis in HCT-116 cells via the activation of both the extrinsic and intrinsic pathways [XREF_BIBR].	0	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	2	3	8	10
As shown in XREF_FIG , exposure of the parental LS-LiM6 cells to TRAIL activates the initiator caspase-8 , which triggers a mitochondria dependent apoptotic amplification loop by activating Bid , inducing the release of cytochrome C ( XREF_FIG ) .	As shown in XREF_FIG, exposure of the parental LS-LiM6 cells to TRAIL activates the initiator caspase-8, which triggers a mitochondria dependent apoptotic amplification loop by activating Bid, inducing the release of cytochrome C (XREF_FIG).	14	36	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome C	cytochrome C	cytochrome C	16	17	34	36
It is known that TRAIL induced caspase-8 activation can lead , via tBid and Bax , to cytochrome c and Smac/DIABLO release from mitochondria .	It is known that TRAIL induced caspase-8 activation can lead, via tBid and Bax, to cytochrome c and Smac/DIABLO release from mitochondria.	4	19	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	caspase-8	TRAIL induced caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	6	7	17	19
Meanwhile , in the extrinsic pathway , pro-caspase-8 activates the mitochondrial cytochrome c release by cleaving Bid [ XREF_BIBR ] , or triggers the downstream caspase effector directly via cleaved caspase-8 .	Meanwhile, in the extrinsic pathway, pro-caspase-8 activates the mitochondrial cytochrome c release by cleaving Bid [XREF_BIBR], or triggers the downstream caspase effector directly via cleaved caspase-8.	7	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pro-caspase-8	pro-caspase-8	pro-caspase-8	cytochrome c	cytochrome c	cytochrome c	7	8	11	13
Caspase-8 promoted cytochrome c release indirectly , by cleaving at least one cytosolic substrate .	Caspase-8 promoted cytochrome c release indirectly, by cleaving at least one cytosolic substrate.	0	4	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	cytochrome c	cytochrome c	cytochrome c	0	1	2	4
In the intrinsic pathway , caspase-8 cleaves BID ( pro apoptotic member of Bcl-2 family ) and causes the release of cytochrome c from the mitochondria .	In the intrinsic pathway, caspase-8 cleaves BID (pro apoptotic member of Bcl-2 family) and causes the release of cytochrome c from the mitochondria.	5	23	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	cytochrome c	cytochrome c	cytochrome c	5	6	21	23
Introduction of C8-BID promoted the rapid release of cytochrome c which was inhibited by co-treatment with BCL-x L ; and the inhibitory activity of BCL-x L was reversed by the addition of PUMA .	Introduction of C8-BID promoted the rapid release of cytochrome c which was inhibited by co-treatment with BCL-x L; and the inhibitory activity of BCL-x L was reversed by the addition of PUMA.	0	10	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	C8-BID	C8-BID	C8-BID	cytochrome c	cytochrome c	cytochrome c	2	3	8	10
Eotaxin , RANTES , and to a lessor extent MCP-3 , but not the other chemokines , activated CC CKR3 as determined by their ability to stimulate a Ca ( 2+ ) - flux .	Eotaxin, RANTES, and to a lessor extent MCP-3, but not the other chemokines, activated CC CKR3 as determined by their ability to stimulate a Ca (2+) - flux.	0	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Eotaxin	Eotaxin	Eotaxin	CKR3	CKR3	CKR3	0	1	19	20
Eotaxin induced CCR3 ( chemokine ( C-C motif ) receptor 3 ) signaling has a critical role in eosinophil chemotactic responses .	Eotaxin induced CCR3 (chemokine (C-C motif) receptor 3) signaling has a critical role in eosinophil chemotactic responses.	0	13	induced	Positive_early_activation	Positive_activation	Positive_activation	Eotaxin	Eotaxin	Eotaxin	CCR3	CCR3	CCR3	0	1	2	3
These data suggest that IL-16-stimulated LTC 4 and IL-4 release may occur through autocrine eotaxin activation of CCR3 receptors [ XREF_BIBR ] .	These data suggest that IL-16-stimulated LTC 4 and IL-4 release may occur through autocrine eotaxin activation of CCR3 receptors [XREF_BIBR].	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	eotaxin	eotaxin	eotaxin	CCR3	CCR3	CCR3	14	15	17	18
Furthermore this study reported that CCR3 , when activated by the ligand CCL11 , increased migration of choroidal endothelial cells , whereas it was inhibited by a CCR3 inhibitor [ XREF_BIBR ] .	Furthermore this study reported that CCR3, when activated by the ligand CCL11, increased migration of choroidal endothelial cells, whereas it was inhibited by a CCR3 inhibitor [XREF_BIBR].	5	14	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	CCL11	CCL11	CCL11	CCR3	CCR3	CCR3	12	13	5	6
CCL11 and CCL26 expressed by skin-resident cells , such as fibroblasts , blood endothelial cells , and keratinocytes , induce infiltration of CCR3 expressing cells such as Th2 cells and eosinophils .	CCL11 and CCL26 expressed by skin-resident cells, such as fibroblasts, blood endothelial cells, and keratinocytes, induce infiltration of CCR3 expressing cells such as Th2 cells and eosinophils.	0	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL11	CCL11 and CCL26 expressed	ccl11	CCR3	CCR3	ccr3	0	1	22	23
The presence of CCR3 in tumor samples correlated with the grade of malignancy indicating that CCL11 could promote progression and dissemination of CCR3 positive RCC .	The presence of CCR3 in tumor samples correlated with the grade of malignancy indicating that CCL11 could promote progression and dissemination of CCR3 positive RCC.	15	24	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL11	CCL11	CCL11	CCR3	CCR3	CCR3	15	16	22	23
The Eotaxin gene family ( Eotaxin1 , Eotaxin2 and Eotaxin3 ) recruits and activates CCR3 bearing cells such as eosinophils , mast cells and Th2 lymphocytes that play a major role in allergic disorders .	The Eotaxin gene family (Eotaxin1, Eotaxin2 and Eotaxin3) recruits and activates CCR3 bearing cells such as eosinophils, mast cells and Th2 lymphocytes that play a major role in allergic disorders.	1	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Eotaxin	Eotaxin	Eotaxin	CCR3	CCR3	CCR3	1	2	14	15
One potential explanation could be the expression of CXCL9 , which blocks eotaxin induced CCR3 mediated eosinophil recruitment XREF_BIBR , XREF_BIBR , in CNV ( XREF_SUPPLEMENTARY ) .	One potential explanation could be the expression of CXCL9, which blocks eotaxin induced CCR3 mediated eosinophil recruitment XREF_BIBR, XREF_BIBR, in CNV (XREF_SUPPLEMENTARY).	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	eotaxin	eotaxin	eotaxin	CCR3	CCR3	CCR3	12	13	14	15
Binding of CCL11 and subsequent activation of CCR3 is thought to occur via a two-step model in which a high affinity interaction between the core residues of the chemokine and the N-terminus of the receptor initially tethers CCL11 to CCR3 .	Binding of CCL11 and subsequent activation of CCR3 is thought to occur via a two-step model in which a high affinity interaction between the core residues of the chemokine and the N-terminus of the receptor initially tethers CCL11 to CCR3.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL11	CCL11	CCL11	CCR3	CCR3	CCR3	2	3	7	8
In vitro AR model demonstrated that the CC-chemokine receptor CCR3 stimulation by eotaxin induced significant increase in the expression of surface 2B4 in eosinophils and Eol-1 cells .	In vitro AR model demonstrated that the CC-chemokine receptor CCR3 stimulation by eotaxin induced significant increase in the expression of surface 2B4 in eosinophils and Eol-1 cells.	9	13	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	eotaxin	eotaxin	eotaxin	CCR3	CCR3	CCR3	12	13	9	10
This would be the case for CCL11 and CCL26 activation of CCR3 , CCL17 and CCL22 activation of CCR4 and CCL5 activation of CCR1 and/or CCR5 , since these ligands displace CCL18 to a greater or lesser extent .	This would be the case for CCL11 and CCL26 activation of CCR3, CCL17 and CCL22 activation of CCR4 and CCL5 activation of CCR1 and/or CCR5, since these ligands displace CCL18 to a greater or lesser extent.	6	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL11	CCL11	CCL11	CCR3	CCR3	CCR3	6	7	11	12
Eotaxin stimulated increases in intracellular calcium and chemotaxis of CCR3 ( + ) T cells .	Eotaxin stimulated increases in intracellular calcium and chemotaxis of CCR3 (+) T cells.	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Eotaxin	Eotaxin	Eotaxin	CCR3	CCR3	CCR3	0	1	9	10
Moreover , they are all able to inhibit CCL11 induced CCR3 + -cell migration and ( cytoplasmic ) [ Ca 2+ i ] changes with no intrinsic activity , and in addition , neither of the CXCR3 agonists induces CCR3 internalization , and thus lack agonistic effects but act as full antagonists .	Moreover, they are all able to inhibit CCL11 induced CCR3 + -cell migration and (cytoplasmic) [Ca 2+ i] changes with no intrinsic activity, and in addition, neither of the CXCR3 agonists induces CCR3 internalization, and thus lack agonistic effects but act as full antagonists.	7	21	induced	Positive_early_activation	Positive_activation	Positive_activation	CCL11	CCL11	CCL11	CCR3	CCR3	CCR3	8	9	10	11
CCR3 is expressed primarily on eosinophils , basophils and Th2 cells and activation of CCR3 by eotaxin regulates the recruitment of these cell types in allergic responses and parasitic infections [ XREF_BIBR - XREF_BIBR ] .	CCR3 is expressed primarily on eosinophils, basophils and Th2 cells and activation of CCR3 by eotaxin regulates the recruitment of these cell types in allergic responses and parasitic infections [XREF_BIBR - XREF_BIBR].	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	eotaxin	eotaxin	eotaxin	CCR3	CCR3	CCR3	16	17	14	15
A role for eotaxin and CCR3 in lipid body biogenesis was also demonstrated to occur in infection driven lipid body formation in eosinophils , but not in macrophages ; a mechanism that was largely dependent on TLR2 dependent macrophage derived eotaxin mediated CCR3 activation [ XREF_BIBR ] .	A role for eotaxin and CCR3 in lipid body biogenesis was also demonstrated to occur in infection driven lipid body formation in eosinophils, but not in macrophages; a mechanism that was largely dependent on TLR2 dependent macrophage derived eotaxin mediated CCR3 activation [XREF_BIBR].	39	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	eotaxin	eotaxin	eotaxin	CCR3	CCR3	CCR3	40	41	42	43
Since wortmannin partially inhibited IL-3- but not eotaxin induced CCR3 down-regulation , receptor down-modulation seems to underlie different signaling events .	Since wortmannin partially inhibited IL-3- but not eotaxin induced CCR3 down-regulation, receptor down-modulation seems to underlie different signaling events.	3	10	induced	Positive_early_activation	Positive_activation	Positive_activation	eotaxin	eotaxin	eotaxin	CCR3	CCR3	CCR3	7	8	9	10
AOP-RANTES , RANTES , eotaxin and eotaxin-2 , but not Met RANTES , induced a downregulation of CCR3 at 37 degrees C. Reexpression of CCR3 on eosinophils was observed within 120 min .	AOP-RANTES, RANTES, eotaxin and eotaxin-2, but not Met RANTES, induced a downregulation of CCR3 at 37 degrees C. Reexpression of CCR3 on eosinophils was observed within 120 min.	0	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	eotaxin	eotaxin	eotaxin	CCR3	CCR3	CCR3	4	5	17	18
The exposure of eosinophils to CCL5 caused a reduction of CCR3 receptor surface expression of 56.1 and 38.03 % , and CCL11 caused CCR3 internalization of 72.7 and 69.8 % after 15 and 60min , respectively .	The exposure of eosinophils to CCL5 caused a reduction of CCR3 receptor surface expression of 56.1 and 38.03%, and CCL11 caused CCR3 internalization of 72.7 and 69.8% after 15 and 60min, respectively.	21	24	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL11	CCL11	CCL11	CCR3	CCR3	CCR3	21	22	23	24
In addition to eosinophil chemoattraction , eotaxin mediated activation of CCR3 triggers the respiratory burst apparatus , induces eosinophil degranulation and upregulates expression of adhesion molecules XREF_BIBR , XREF_BIBR .	In addition to eosinophil chemoattraction, eotaxin mediated activation of CCR3 triggers the respiratory burst apparatus, induces eosinophil degranulation and upregulates expression of adhesion molecules XREF_BIBR, XREF_BIBR.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	eotaxin	eotaxin	eotaxin	CCR3	CCR3	CCR3	6	7	10	11
This differentiation event occurred with equal efficiency in the MLN of CCL25 deficient hosts , demonstrating that CCL25 is not required to induce the CCR9 ( high ) memory phenotype in vivo .	This differentiation event occurred with equal efficiency in the MLN of CCL25 deficient hosts, demonstrating that CCL25 is not required to induce the CCR9 (high) memory phenotype in vivo.	17	29	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	17	18	24	25
In cancer biology , activation of CCR9 by CCL25 promotes cancer cell migration , invasion and expression of matrix metalloproteinases ( MMPs ) , which are key components of cancer invasion and metastasis [ XREF_BIBR ] .	In cancer biology, activation of CCR9 by CCL25 promotes cancer cell migration, invasion and expression of matrix metalloproteinases (MMPs), which are key components of cancer invasion and metastasis [XREF_BIBR].	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	8	9	6	7
Human TECK also induced the in vitro migration of HEK 293/human GPR-9-6 cells .	Human TECK also induced the in vitro migration of HEK 293/human GPR-9-6 cells.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TECK	TECK	TECK	GPR-9-6	GPR-9-6	GPR-9-6	1	2	11	12
We show here that under serum-free conditions and within a concentration range ( 50-200 nM ) , TECK rescued pEGFP-N1 and CCR9 transfected PC12 cells from undergoing apoptosis in serum-free medium ; however , it did not exert a similar effect on the cells in the control .	We show here that under serum-free conditions and within a concentration range (50-200 nM), TECK rescued pEGFP-N1 and CCR9 transfected PC12 cells from undergoing apoptosis in serum-free medium; however, it did not exert a similar effect on the cells in the control.	17	22	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TECK	TECK	TECK	CCR9	CCR9	CCR9	17	18	21	22
XREF_BIBR , XREF_BIBR Under normal circumstances , expression of CCL25 and MAdCAM-1 are absent from the liver , but in PSC both are detectable on hepatic endothelium XREF_BIBR , XREF_BIBR and support the aberrant recruitment of alpha4beta7 + CCR9 + effector lymphocytes from the gut .	XREF_BIBR, XREF_BIBR Under normal circumstances, expression of CCL25 and MAdCAM-1 are absent from the liver, but in PSC both are detectable on hepatic endothelium XREF_BIBR, XREF_BIBR and support the aberrant recruitment of alpha4beta7 + CCR9 + effector lymphocytes from the gut.	7	41	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL25	expression of CCL25	ccl25	CCR9	CCR9	ccr9	9	10	38	39
CCR9 is activated by the chemokine CCL25 , which is specifically expressed in SI .	CCR9 is activated by the chemokine CCL25, which is specifically expressed in SI.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL25	CCL25, which is specifically expressed	ccl25	CCR9	CCR9	ccr9	6	7	0	1
15-18 Activation of CCR9 by CCL25 induces pro migratory responses , including the activation of alpha4beta1 and alpha4beta7 integrins to bind vascular cell adhesion molecule ( VCAM ) -1 and mucosal addressin cell adhesion molecule ( MAdCAM )-1, respectively , on mucosal vessels .	15-18 Activation of CCR9 by CCL25 induces pro migratory responses, including the activation of alpha4beta1 and alpha4beta7 integrins to bind vascular cell adhesion molecule (VCAM) -1 and mucosal addressin cell adhesion molecule (MAdCAM)-1, respectively, on mucosal vessels.	1	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	5	6	3	4
CCL25 , a chemokine expressed by epithelial cells in the small intestine , activates CCR9 for adhesion triggering and chemotaxis .	CCL25, a chemokine expressed by epithelial cells in the small intestine, activates CCR9 for adhesion triggering and chemotaxis.	0	19	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	0	1	14	15
CCR9 + LILs migrated preferentially to CCL25 rather than to CXCL12 or CCL5 and could also be triggered by CCL25 to bind immobilized MAdCAM-1 via alpha4beta7 integrins ( XREF_FIG ) .	CCR9 + LILs migrated preferentially to CCL25 rather than to CXCL12 or CCL5 and could also be triggered by CCL25 to bind immobilized MAdCAM-1 via alpha4beta7 integrins (XREF_FIG).	0	21	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	19	20	0	1
CC chemokine receptor type 9 ( CCR9 ) activation by CCL25 plays a key role in leukocyte recruitment to the gut and represents a therapeutic target in inflammatory bowel disease .	CC chemokine receptor type 9 (CCR9) activation by CCL25 plays a key role in leukocyte recruitment to the gut and represents a therapeutic target in inflammatory bowel disease.	6	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	10	11	6	7
Comparison of our results suggests that CCL25 induction of CCR9 signaling may be more sensitive to inhibition by sema3E than CXCL12 induction of CXCR4 signaling ( data not shown ) .	Comparison of our results suggests that CCL25 induction of CCR9 signaling may be more sensitive to inhibition by sema3E than CXCL12 induction of CXCR4 signaling (data not shown).	6	10	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	6	7	9	10
CCL25 , the ligand of CCR9 , is produced by cortical thymic epithelial cells , thus retaining CCR9 + DP and SP1 thymocytes in the cortex [ XREF_BIBR ] .	CCL25, the ligand of CCR9, is produced by cortical thymic epithelial cells, thus retaining CCR9 + DP and SP1 thymocytes in the cortex [XREF_BIBR].	0	22	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	0	1	17	18
For example , it is possible that selective expression of TECK by epithelial or other cells in the small intestine could direct GPR-9-6 + T lymphocyte migration after the cells have crossed the endothelium and entered the intestinal tissue .	For example, it is possible that selective expression of TECK by epithelial or other cells in the small intestine could direct GPR-9-6 + T lymphocyte migration after the cells have crossed the endothelium and entered the intestinal tissue.	8	26	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TECK	expression of TECK	teck	GPR-9-6	GPR-9-6	gpr-9-6	10	11	22	23
We also report that CCL25 promotes proliferation and CCR9 dependent anti-apoptotic signalling via the PI3K/Akt/GSK/FKHR pathway and independent of FAK .	We also report that CCL25 promotes proliferation and CCR9 dependent anti-apoptotic signalling via the PI3K/Akt/GSK/FKHR pathway and independent of FAK.	4	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	4	5	8	9
12 CCR9 activation by CCL25 plays a key role in leukocyte recruitment to the gut and is a therapeutic target in inflammatory bowel disease .	12 CCR9 activation by CCL25 plays a key role in leukocyte recruitment to the gut and is a therapeutic target in inflammatory bowel disease.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	4	5	1	2
CCL25 , a chemokine expressed in the SI , activates CCR9 for adhesion triggering and chemotaxis .	CCL25, a chemokine expressed in the SI, activates CCR9 for adhesion triggering and chemotaxis.	0	15	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	0	1	10	11
In vitro , CCL25 stimulates CCR9 dependent intracellular signaling , such as intracellular calcium flux and probably recruitment of beta-arrestin proteins , and mediates directed cell migration .	In vitro, CCL25 stimulates CCR9 dependent intracellular signaling, such as intracellular calcium flux and probably recruitment of beta-arrestin proteins, and mediates directed cell migration.	1	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	3	4	5	6
It is possible that expression of TECK by postcapillary venules in the lamina propria or by Peyer ' s patch HEVs may activate GPR-9-6 + T lymphocytes and lead to leukocyte arrest via alpha4beta7-mucosal addressin cell adhesion molecule 1 ( MAdCAM-1 ) interactions , and thus in the selective extravasation of memory intestinal T lymphocytes within the intestine .	It is possible that expression of TECK by postcapillary venules in the lamina propria or by Peyer 's patch HEVs may activate GPR-9-6 + T lymphocytes and lead to leukocyte arrest via alpha4beta7-mucosal addressin cell adhesion molecule 1 (MAdCAM-1) interactions, and thus in the selective extravasation of memory intestinal T lymphocytes within the intestine.	4	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TECK	expression of TECK	teck	GPR-9-6	GPR-9-6	gpr-9-6	6	7	23	24
Researchers have shown that CCR9 that has been activated by its specific ligand CCL25 can interact with many signaling pathways , especially those involved in tumor chemoresistance and metastasis .	Researchers have shown that CCR9 that has been activated by its specific ligand CCL25 can interact with many signaling pathways, especially those involved in tumor chemoresistance and metastasis.	4	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	13	14	4	5
CCL25 can also promote metastasis by recruiting CCR9 + cancer cells into CCL25 expressing tissues , such as the small intestine .	CCL25 can also promote metastasis by recruiting CCR9 + cancer cells into CCL25 expressing tissues, such as the small intestine.	0	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	0	1	7	8
In addition , caspase-3 also activates ROCK-1 , which allows terminal erythroid differentiation in part through phosphorylation of myosin II light chain .	In addition, caspase-3 also activates ROCK-1, which allows terminal erythroid differentiation in part through phosphorylation of myosin II light chain.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK-1	ROCK-1	ROCK-1	3	4	6	7
Ethanol induces a ROCK-I activation that is mediated by RhoA , rather than by caspase-3 cleavage .	Ethanol induces a ROCK-I activation that is mediated by RhoA, rather than by caspase-3 cleavage.	3	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK-I	ROCK-I	ROCK-I	14	15	3	4
Caspase 1 and caspase 3 are transcriptionally upregulated and activated in transgenic HD mice [ XREF_BIBR ] , suggesting that caspase 3 could constitutively activate Rock1 in HD .	Caspase 1 and caspase 3 are transcriptionally upregulated and activated in transgenic HD mice [XREF_BIBR], suggesting that caspase 3 could constitutively activate Rock1 in HD.	20	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	Rock1	Rock1	Rock1	20	22	25	26
ROCK1 ( Rho associated , coiled-coil containing protein kinase 1 ) is activated by caspase-3 consequently increases the level of phosphorylated myosin light chain , resulting in membrane blebbing and initiating apoptosis XREF_BIBR , XREF_BIBR .	ROCK1 (Rho associated, coiled-coil containing protein kinase 1) is activated by caspase-3 consequently increases the level of phosphorylated myosin light chain, resulting in membrane blebbing and initiating apoptosis XREF_BIBR, XREF_BIBR.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK1	ROCK1	ROCK1	14	15	0	1
While ROCK1 is constitutively activated during apoptosis upon its cleavage by caspase-3 and caspase-7 [ XREF_BIBR ] , p53 activates these caspases [ XREF_BIBR ] .	While ROCK1 is constitutively activated during apoptosis upon its cleavage by caspase-3 and caspase-7 [XREF_BIBR], p53 activates these caspases [XREF_BIBR].	1	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK1	ROCK1	ROCK1	11	12	1	2
ROCK-1 is activated by small GTPases ( inducible activation ) or by caspase-3 cleavage ( constitutive activation ) .	ROCK-1 is activated by small GTPases (inducible activation) or by caspase-3 cleavage (constitutive activation).	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK-1	ROCK-1	ROCK-1	12	13	0	1
ROCK1 is activated by RhoA , rather than caspase-3 , in AT-101-treated leukemia cells .	ROCK1 is activated by RhoA, rather than caspase-3, in AT-101-treated leukemia cells.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK1	ROCK1	ROCK1	8	9	0	1
Thus , H 2 O 2 activated caspase-3 through upstream pathways and then activated caspase-3 mediated ROCK1 and MLC activation .	Thus, H 2 O 2 activated caspase-3 through upstream pathways and then activated caspase-3 mediated ROCK1 and MLC activation.	13	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK1	ROCK1	ROCK1	14	15	16	17
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Our results strongly support the hypothesis that ROCK1 is activated by caspase-3 , rather than RhoA , during triptolide mediated apoptosis .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Our results strongly support the hypothesis that ROCK1 is activated by caspase-3, rather than RhoA, during triptolide mediated apoptosis.	14	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK1	ROCK1	ROCK1	18	19	14	15
RhoA , rather than caspase-3 cleavage , mediated the cleavage and activation of ROCK1 that AT-101 induced .	RhoA, rather than caspase-3 cleavage, mediated the cleavage and activation of ROCK1 that AT-101 induced.	4	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK1	ROCK1	ROCK1	4	5	13	14
Furthermore , ROCK1 is cleaved and thereby constitutively activated by caspase-3 at a conserved sequence at its C-terminus that is not found in ROCK2 .	Furthermore, ROCK1 is cleaved and thereby constitutively activated by caspase-3 at a conserved sequence at its C-terminus that is not found in ROCK2.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK1	ROCK1	ROCK1	10	11	2	3
Taken together , these results suggest that RhoA , rather than caspase-3 , activates ROCK1 during AT-101-induced apoptosis .	Taken together, these results suggest that RhoA, rather than caspase-3, activates ROCK1 during AT-101-induced apoptosis.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK1	ROCK1	ROCK1	11	12	14	15
It is known that caspase-3 can activate ROCK1 by removing the inhibitory Cy domain in ROCK1 XREF_BIBR and that HG induces apoptosis and activation of caspase-3 in GEnCs XREF_BIBR .	It is known that caspase-3 can activate ROCK1 by removing the inhibitory Cy domain in ROCK1 XREF_BIBR and that HG induces apoptosis and activation of caspase-3 in GEnCs XREF_BIBR.	4	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ROCK1	ROCK1	ROCK1	4	5	7	8
Together , these data suggest that caspase-3 is the primary inactivator of DFF45 and ICAD and therefore the primary activator of apoptotic DNA fragmentation .	Together, these data suggest that caspase-3 is the primary inactivator of DFF45 and ICAD and therefore the primary activator of apoptotic DNA fragmentation.	6	15	is the primary inactivator	Negative_activation_copula_1	Positive_activation	Negative_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	6	7	14	15
Caspase-3 activity also caused ICAD fragmentation , moderately after monotherapy and mostly after combination therapy , in both cell lines .	Caspase-3 activity also caused ICAD fragmentation, moderately after monotherapy and mostly after combination therapy, in both cell lines.	0	5	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	ICAD	ICAD	ICAD	0	1	4	5
The most prominent increase in the processing of intrinsic pathway effectors caspase-3 and the caspase-3 targets ICAD and Mcl-1 were found in all tested cells lines after treatment with cisplatin in combination with either Mapatumumab or Lexatumumab .	The most prominent increase in the processing of intrinsic pathway effectors caspase-3 and the caspase-3 targets ICAD and Mcl-1 were found in all tested cells lines after treatment with cisplatin in combination with either Mapatumumab or Lexatumumab.	6	20	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	14	15	16	17
To initiate DSBs , caspase-3 results in the activation of caspase activated DNase ( CAD ) by cleaving its inhibitor ICAD .	To initiate DSBs, caspase-3 results in the activation of caspase activated DNase (CAD) by cleaving its inhibitor ICAD.	4	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	4	5	20	21
Caspase-3 mediated cleavage of ICAD releases CAD , allowing it to cleave DNA .	Caspase-3 mediated cleavage of ICAD releases CAD, allowing it to cleave DNA.	0	5	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	ICAD	ICAD	ICAD	0	1	4	5
Also , caspase-3 activity caused ICAD cleavage in both SK-N-BE2 and SH-SY-5Y cells .	Also, caspase-3 activity caused ICAD cleavage in both SK-N-BE2 and SH-SY-5Y cells.	2	6	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	2	3	5	6
Further , activation of caspase-3 led to cleavage of its target proteins PARP-1 and ICAD , which resulted in apoptotic DNA damage .	Further, activation of caspase-3 led to cleavage of its target proteins PARP-1 and ICAD, which resulted in apoptotic DNA damage.	2	17	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	4	5	14	15
Also , caspase-3 activity caused cleavage of ICAD in both SKN-BE2 and SH-SY-5Y cell lines .	Also, caspase-3 activity caused cleavage of ICAD in both SKN-BE2 and SH-SY-5Y cell lines.	2	8	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	2	3	7	8
DEVD cleaving caspase-3 is the primary inactivator of ICAD and therefore the primary activator of apoptotic DNA fragmentation [ XREF_BIBR ] .	DEVD cleaving caspase-3 is the primary inactivator of ICAD and therefore the primary activator of apoptotic DNA fragmentation [XREF_BIBR].	0	9	is the primary inactivator	Negative_activation_copula_1	Positive_activation	Negative_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	2	3	8	9
Also , increased caspase-3 activity mediated ICAD cleavage and PARP fragmention .	Also, increased caspase-3 activity mediated ICAD cleavage and PARP fragmention.	3	7	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	3	4	6	7
Further , caspase-3 activity increased ICAD fragmentation , moderately due to monotherapy and mostly due to combination therapy , in both cell lines .	Further, caspase-3 activity increased ICAD fragmentation, moderately due to monotherapy and mostly due to combination therapy, in both cell lines.	2	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	2	3	5	6
Caspase-3 initiates apoptotic DNA fragmentation by proteolytically inactivating DFF45 ( DNA fragmentation factor-45 )/ICAD ( inhibitor of caspase activated DNase ) , which releases active DFF40 and CAD ( caspase activated DNase ) , the inhibitor ' s associated endonuclease .	Caspase-3 initiates apoptotic DNA fragmentation by proteolytically inactivating DFF45 (DNA fragmentation factor-45)/ICAD (inhibitor of caspase activated DNase), which releases active DFF40 and CAD (caspase activated DNase), the inhibitor 's associated endonuclease.	0	23	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	DFF45	DFF45	DFF45	0	1	8	9
Also , caspase-3 activity caused ICAD cleavage in both SK-N-DZ and SK-N-BE2 cells .	Also, caspase-3 activity caused ICAD cleavage in both SK-N-DZ and SK-N-BE2 cells.	2	6	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	2	3	5	6
For example , caspase-6 is a direct activator of the initiator caspase-8 .	For example, caspase-6 is a direct activator of the initiator caspase-8.	3	12	is a direct activator	Positive_activation_copula_1	Positive_activation	Positive_activation	caspase-6	caspase-6	caspase-6	caspase-8	caspase-8	caspase-8	3	4	11	12
Recently , caspase-6 was reported to mediate caspase-3-induced caspase-8 activation downstream of the mitochondria .	Recently, caspase-6 was reported to mediate caspase-3-induced caspase-8 activation downstream of the mitochondria.	2	9	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-6	caspase-6	caspase-6	caspase-8	caspase-8	caspase-8	2	3	8	9
Inhibition of caspase-6 activity in cells significantly inhibited caspase-8 cleavage and apoptosis , therefore establishing caspase-6 as a major activator of caspase-8 in vivo and confirming that this pathway can have a critical role in promotion of apoptosis .	Inhibition of caspase-6 activity in cells significantly inhibited caspase-8 cleavage and apoptosis, therefore establishing caspase-6 as a major activator of caspase-8 in vivo and confirming that this pathway can have a critical role in promotion of apoptosis.	2	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-6	caspase-6	caspase-6	caspase-8	caspase-8	caspase-8	2	3	8	9
Previous study has reported that caspase-6 is able to activate caspase-8 and involved in mitochondrial response [ XREF_BIBR ] .	Previous study has reported that caspase-6 is able to activate caspase-8 and involved in mitochondrial response [XREF_BIBR].	5	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-6	caspase-6	caspase-6	caspase-8	caspase-8	caspase-8	5	6	10	11
For instance , CASP6 can cleave and activate both CASP2 and CASP8 that are well-known to induce mitochondrial permeabilization 54 , as well as cleave and inactivate the antioxidant protein deglycase DJ-1 , which leads to increase in the production of reactive oxygen species and oxidative stress in neuroblastoma cell lines 55 .	For instance, CASP6 can cleave and activate both CASP2 and CASP8 that are well-known to induce mitochondrial permeabilization 54, as well as cleave and inactivate the antioxidant protein deglycase DJ-1, which leads to increase in the production of reactive oxygen species and oxidative stress in neuroblastoma cell lines 55.	3	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP6	CASP6	CASP6	CASP8	CASP8	CASP8	3	4	11	12
20 In these injury models , CASP6 appears to activate CASP8 in injured RGCs and the inhibitory peptides Z-VEID-FMK and Z-IETD-FMK confer significant neuroprotection , while promoting axon regeneration in the crushed optic nerve .	20 In these injury models, CASP6 appears to activate CASP8 in injured RGCs and the inhibitory peptides Z-VEID-FMK and Z-IETD-FMK confer significant neuroprotection, while promoting axon regeneration in the crushed optic nerve.	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP6	CASP6	CASP6	CASP8	CASP8	CASP8	6	7	10	11
It is also reported that the activation of caspase 6 can trigger caspase 8 .	It is also reported that the activation of caspase 6 can trigger caspase 8.	6	14	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 6	caspase 6	caspase 6	caspase 8	caspase 8	caspase 8	8	10	12	14
Additional interactions such as caspase 6 mediated activation of caspase 8 ( positive feedback ) [ XREF_BIBR ] and/or XIAP degradation of active caspase 3 can further impact the type 1/type 2 choice in a cell type dependent manner .	Additional interactions such as caspase 6 mediated activation of caspase 8 (positive feedback) [XREF_BIBR] and/or XIAP degradation of active caspase 3 can further impact the type 1/type 2 choice in a cell type dependent manner.	1	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase 6	caspase 6	caspase 6	caspase 8	caspase 8	caspase 8	4	6	9	11
Removal of the procaspase-6 prodomain has been reported to be essential for caspase-6 mediated activation of caspase-8 [ XREF_BIBR ] .	Removal of the procaspase-6 prodomain has been reported to be essential for caspase-6 mediated activation of caspase-8 [XREF_BIBR].	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase-6	caspase-6	caspase-6	caspase-8	caspase-8	caspase-8	12	13	16	17
In the related study , we also showed the overexpression of wild-type CASP6 promotes the proteolytic processing of CASP8 in HeLa cells by Fas ligation whereas the overexpression of either a protease deficient mutant , CASP6CS or a constitutively phosphorylated mutant , CASP6SE retards the CASP8 cleavage XREF_BIBR .	In the related study, we also showed the overexpression of wild-type CASP6 promotes the proteolytic processing of CASP8 in HeLa cells by Fas ligation whereas the overexpression of either a protease deficient mutant, CASP6CS or a constitutively phosphorylated mutant, CASP6SE retards the CASP8 cleavage XREF_BIBR.	9	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP6	overexpression of wild-type CASP6	casp6	CASP8	CASP8	casp8	12	13	18	19
Alternatively , active caspase-3 can cleave and activate caspase-6 , which in turn may activate caspase-8 in a positive feedback loop .	Alternatively, active caspase-3 can cleave and activate caspase-6, which in turn may activate caspase-8 in a positive feedback loop.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-6	caspase-6	caspase-6	caspase-8	caspase-8	caspase-8	8	9	15	16
However , a caspase 6 specific inhibitor was shown to reduce caspase 8 and 9 activation , suggesting that in addition to activating the mitochondrial pathway , Stx1 may activate caspase 6 to directly activate caspase 8 ( XREF_FIG ) .	However, a caspase 6 specific inhibitor was shown to reduce caspase 8 and 9 activation, suggesting that in addition to activating the mitochondrial pathway, Stx1 may activate caspase 6 to directly activate caspase 8 (XREF_FIG).	3	15	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 6	caspase 6	caspase 6	caspase 8	caspase 8	caspase 8	3	5	11	13
Fourthly , Caspase 6 , a protease reported to lower the threshold for apoptosis , cleave nuclear lamin , and activate Caspase 8 , was found highly expressed in day 5 replicating blasts ( XREF_FIG ) .	Fourthly, Caspase 6, a protease reported to lower the threshold for apoptosis, cleave nuclear lamin, and activate Caspase 8, was found highly expressed in day 5 replicating blasts (XREF_FIG).	2	25	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Caspase 6	Caspase 6	Caspase 6	Caspase 8	Caspase 8	Caspase 8	2	4	21	23
Casp6 initiates apoptosis in certain cell types by activating Caspase-8 3 , adopts unique conformations relative to other caspases XREF_BIBR , XREF_BIBR , self-activates intramolecularly 6 , does not induce cell death when solely activated in mammalian cell lines XREF_BIBR , XREF_BIBR and has distinct substrate specificity 9 .	Casp6 initiates apoptosis in certain cell types by activating Caspase-8 3, adopts unique conformations relative to other caspases XREF_BIBR, XREF_BIBR, self-activates intramolecularly 6, does not induce cell death when solely activated in mammalian cell lines XREF_BIBR, XREF_BIBR and has distinct substrate specificity 9.	0	10	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Casp6	Casp6	Casp6	Caspase-8	Caspase-8	Caspase-8	0	1	9	10
This finding is supported by a previous report in which efficient activation of caspase-6 by caspase-8 in a cell-free system requires the presence of cytoplasmic extracts .	This finding is supported by a previous report in which efficient activation of caspase-6 by caspase-8 in a cell-free system requires the presence of cytoplasmic extracts.	11	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-6	caspase-6	caspase-6	15	16	13	14
The Th2-cells express the CCR8 receptor [ XREF_BIBR , XREF_BIBR ] , which is activated by CCL1 [ XREF_BIBR ] , and it mediates Th2 cell recruitment to sites of inflammation [ XREF_BIBR , XREF_BIBR ] .	The Th2-cells express the CCR8 receptor [XREF_BIBR, XREF_BIBR], which is activated by CCL1 [XREF_BIBR], and it mediates Th2 cell recruitment to sites of inflammation [XREF_BIBR, XREF_BIBR].	4	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	16	17	4	5
Keratinocyte produced CCL1 targets CCR8 expressing T-lymphocytes and Langerhans cell precursors , and CXCL1 targets the CXCR2 receptor on keratinocytes 34 and neutrophils 35 to promote proliferation and migration .	Keratinocyte produced CCL1 targets CCR8 expressing T-lymphocytes and Langerhans cell precursors, and CXCL1 targets the CXCR2 receptor on keratinocytes 34 and neutrophils 35 to promote proliferation and migration.	1	5	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	2	3	4	5
These data demonstrate that CCL1 mediates its effects on tumor cell migration by activating CCR8 and GPCR signaling in tumor cells .	These data demonstrate that CCL1 mediates its effects on tumor cell migration by activating CCR8 and GPCR signaling in tumor cells.	4	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	4	5	14	15
Tumor cell migration to lymphatic endothelial cells has been shown to be inhibited by suppression of either CCR8 or CCL1 in vitro ; furthermore , recombinant CCL1 promoted the migration of CCR8 + tumor cells .	Tumor cell migration to lymphatic endothelial cells has been shown to be inhibited by suppression of either CCR8 or CCL1 in vitro; furthermore, recombinant CCL1 promoted the migration of CCR8 + tumor cells.	25	34	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	26	27	31	32
CCL1 is produced by SCS LECs and mediated entry of CCR8 + melanoma cells into LNs .	CCL1 is produced by SCS LECs and mediated entry of CCR8 + melanoma cells into LNs.	0	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	0	1	10	11
Because it has not been unequivocally demonstrated that mouse CCL1 activates human CCR8 , we also performed calcium flux studies upon addition of mouse CCL1 to human cells ( HEK-293 , SK-MEL-25 , and MDA-MB-435 ; XREF_FIG ) .	Because it has not been unequivocally demonstrated that mouse CCL1 activates human CCR8, we also performed calcium flux studies upon addition of mouse CCL1 to human cells (HEK-293, SK-MEL-25, and MDA-MB-435; XREF_FIG).	8	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	9	10	12	13
C-terminal processing of CCL1 by CPM enhances CCR8 signaling despite diminished CCR8 binding .	C-terminal processing of CCL1 by CPM enhances CCR8 signaling despite diminished CCR8 binding.	1	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	3	4	7	8
Another chemokine , CCL1 , was shown to promote lymph node entry of melanoma cells expressing the receptor CCR8 , whereas blocking of CCR8 function resulted in decreased lymph node metastasis ( Das etal ., 2013 ) .	Another chemokine, CCL1, was shown to promote lymph node entry of melanoma cells expressing the receptor CCR8, whereas blocking of CCR8 function resulted in decreased lymph node metastasis (Das etal., 2013).	1	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	3	4	18	19
Elevated secretion of CCL1 by tumors , increased presence of CCR8 + myeloid cells in peripheral blood and cancer tissues indicate that CCL1 and CCR8 axis is a component of cancer related inflammation and may contribute to immune evasion .	Elevated secretion of CCL1 by tumors, increased presence of CCR8 + myeloid cells in peripheral blood and cancer tissues indicate that CCL1 and CCR8 axis is a component of cancer related inflammation and may contribute to immune evasion.	1	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	3	4	10	11
In human and mouse tissues , CCL1 secreted by LECs lining subcapsular sinuses was found to mediate the LN entry of CCR8 expressing melanoma cells from afferent lymphatics .	In human and mouse tissues, CCL1 secreted by LECs lining subcapsular sinuses was found to mediate the LN entry of CCR8 expressing melanoma cells from afferent lymphatics.	6	22	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	6	7	21	22
CCL1 also induced a peak migration of CCR8 transfectants at 10 nM but with a more robust response ( XREF_FIG ) .	CCL1 also induced a peak migration of CCR8 transfectants at 10 nM but with a more robust response (XREF_FIG).	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	0	1	7	8
First , the constitutive production of CCL1 by noninflamed skin endothelium is likely to mediate the steady-state extravasation of CCR8 + blood precursors of skin-tropic immune surveillance T cells .	First, the constitutive production of CCL1 by noninflamed skin endothelium is likely to mediate the steady-state extravasation of CCR8 + blood precursors of skin-tropic immune surveillance T cells.	4	22	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL1	CCL1	CCL1	CCR8	CCR8	CCR8	6	7	19	20
This nucleation process provides a mechanism for signal amplification in which a small amount of activated CARMA1 can activate a large number of Bcl10 molecules in the cell ( XREF_FIG ) .	This nucleation process provides a mechanism for signal amplification in which a small amount of activated CARMA1 can activate a large number of Bcl10 molecules in the cell (XREF_FIG).	13	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CARMA1	amount of activated CARMA1	carma1	Bcl10	Bcl10	bcl10	16	17	23	24
Bcl10 CARD forms filaments in a highly cooperative manner , and this process is greatly promoted by oligomerized CARMA1 , supporting the role of CARMA1 as a nucleator .	Bcl10 CARD forms filaments in a highly cooperative manner, and this process is greatly promoted by oligomerized CARMA1, supporting the role of CARMA1 as a nucleator.	0	19	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CARMA1	CARMA1	CARMA1	Bcl10	Bcl10	Bcl10	18	19	0	1
Moreover , CARMA1 induced Bcl10 oligomerization was required for Bcl10 to interact with JNK2-p54 .	Moreover, CARMA1 induced Bcl10 oligomerization was required for Bcl10 to interact with JNK2-p54.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	CARMA1	CARMA1	CARMA1	Bcl10	Bcl10	Bcl10	2	3	4	5
Recent data suggest that CARD11 induces BCL10 to oligomerize into helical filamentous structures , which form a platform for the downstream signaling events of the CBM complex 33 .	Recent data suggest that CARD11 induces BCL10 to oligomerize into helical filamentous structures, which form a platform for the downstream signaling events of the CBM complex 33.	4	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CARD11	CARD11	CARD11	BCL10	BCL10	BCL10	4	5	6	7
Although regulation of this process by the CBM complex is not as well understood as the NF-kappaB pathway , it is thought that TAK1 associates with CARD11 mediated BCL10 oligomers , MKK7 gets recruited , and the selective phosphorylation of JNK2 occurs .	Although regulation of this process by the CBM complex is not as well understood as the NF-kappaB pathway, it is thought that TAK1 associates with CARD11 mediated BCL10 oligomers, MKK7 gets recruited, and the selective phosphorylation of JNK2 occurs.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	CARD11	CARD11	CARD11	BCL10	BCL10	BCL10	26	27	28	29
Agents that target the Bcl10 : CARD11 association , or Bcl10 ubiquitination may emerge as attractive therapeutics for the treatment of DLBCL cases that display dysregulated NF-kappaB activation as a result of oncogenic mutations that disrupt the autoinhibitory action of the CARD11 ID .	Agents that target the Bcl10 : CARD11 association, or Bcl10 ubiquitination may emerge as attractive therapeutics for the treatment of DLBCL cases that display dysregulated NF-kappaB activation as a result of oncogenic mutations that disrupt the autoinhibitory action of the CARD11 ID.	2	12	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CARD11	CARD11 association, or Bcl10 ubiquitination	card11	Bcl10	Bcl10	bcl10	6	7	4	5
In contrast , monomeric CARMA1 ( 8-117 ) did not significantly enhance Bcl10 polymerization .	In contrast, monomeric CARMA1 (8-117) did not significantly enhance Bcl10 polymerization.	3	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CARMA1	CARMA1	CARMA1	Bcl10	Bcl10	Bcl10	4	5	12	13
Indeed , overexpression of CARMA1 enhances PMA- and Bcl10 dependent NF-kappaB activation that is blocked by expression of CARMA1 lacking the Bcl10 interacting domain , demonstrating that CARMA1 acts upstream of Bcl10 .	Indeed, overexpression of CARMA1 enhances PMA- and Bcl10 dependent NF-kappaB activation that is blocked by expression of CARMA1 lacking the Bcl10 interacting domain, demonstrating that CARMA1 acts upstream of Bcl10.	6	19	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	CARMA1	expression of CARMA1	carma1	Bcl10	Bcl10	bcl10	18	19	8	9
Our recent study showed that Bcl10 CARD forms filaments spontaneously in vitro and in cells and this process is greatly enhanced by the presence of CARMA1 [ XREF_BIBR ] .	Our recent study showed that Bcl10 CARD forms filaments spontaneously in vitro and in cells and this process is greatly enhanced by the presence of CARMA1 [XREF_BIBR].	5	27	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CARMA1	CARMA1	CARMA1	Bcl10	Bcl10	Bcl10	25	26	5	6
While this study suggests a role for MST1 in myogenic differentiation , connections between MST1 activation by caspase 3 and the canonical Hippo pathway in muscle remain to be determined .	While this study suggests a role for MST1 in myogenic differentiation, connections between MST1 activation by caspase 3 and the canonical Hippo pathway in muscle remain to be determined.	14	19	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	MST1	MST1	MST1	17	19	14	15
It has been identified that MST1 was activated through cleavage by caspase-3 during in vitro differentiation of the myoblast [ XREF_BIBR ] .	It has been identified that MST1 was activated through cleavage by caspase-3 during in vitro differentiation of the myoblast [XREF_BIBR].	5	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	MST1	MST1	MST1	11	12	5	6
Phosphorylation of BIM results in the initiation of the caspase cascade triggering a positive regulatory loop where active caspase-3 cleaved MST1 initiates other MST1 dependent mechanism of apoptosis [ XREF_BIBR ] .	Phosphorylation of BIM results in the initiation of the caspase cascade triggering a positive regulatory loop where active caspase-3 cleaved MST1 initiates other MST1 dependent mechanism of apoptosis [XREF_BIBR].	17	25	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	MST1	MST1	MST1	18	19	23	24
Regarding YAP regulation , MST1 is activated during myoblast differentiation by caspase3 and active MST1 is needed for proper myoblast differentiation .	Regarding YAP regulation, MST1 is activated during myoblast differentiation by caspase3 and active MST1 is needed for proper myoblast differentiation.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase3	caspase3	caspase3	MST1	MST1	MST1	11	12	4	5
Thus far , two CCK receptors have been molecularly identified to mediate the actions of CCK and gastrin , CCK-A and CCK-B receptors ( CCK-AR and CCK-BR , respectively ) .	Thus far, two CCK receptors have been molecularly identified to mediate the actions of CCK and gastrin, CCK-A and CCK-B receptors (CCK-AR and CCK-BR, respectively).	4	28	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCK	CCK	CCK	CCK-AR	CCK-AR	CCK-AR	4	5	24	25
The most accepted vertebrate scheme is that the nutrients enter duodenum and stimulate CCK secretion , some of the CCK acts in a local paracrine manner to stimulate CCK-1R on the sensory fibers of the vagus nerve .	The most accepted vertebrate scheme is that the nutrients enter duodenum and stimulate CCK secretion, some of the CCK acts in a local paracrine manner to stimulate CCK-1R on the sensory fibers of the vagus nerve.	16	29	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCK	CCK	CCK	CCK-1R	CCK-1R	CCK-1R	19	20	28	29
Moreover , it may also be noted that CCK-1R expression was elevated when macrophages were treated with both CCK concentrations , but only the CCK 10 -6 M + LPS group showed a statistical difference compared to the exclusive LPS treated cells ( 0.91 +/- 0.12 arbitrary units ; F 3,20 = 16.75 ; P < 0.05 ; XREF_FIG ) .	Moreover, it may also be noted that CCK-1R expression was elevated when macrophages were treated with both CCK concentrations, but only the CCK 10 -6 M + LPS group showed a statistical difference compared to the exclusive LPS treated cells (0.91 +/- 0.12 arbitrary units; F 3,20 = 16.75; P < 0.05; XREF_FIG).	8	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CCK	CCK	CCK	CCK-1R	CCK-1R	CCK-1R	18	19	8	9
In addition , CCK-33 maybe activating a different set of CCKAR that is not located in the upper gut , or areas supplied by the celiac artery .	In addition, CCK-33 maybe activating a different set of CCKAR that is not located in the upper gut, or areas supplied by the celiac artery.	3	22	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCK-33	CCK-33	CCK-33	CCKAR	CCKAR	CCKAR	3	4	10	11
Furthermore , these authors observed that CCK stimulates CCK-1R mediated gall bladder contraction .	Furthermore, these authors observed that CCK stimulates CCK-1R mediated gall bladder contraction.	6	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCK	CCK	CCK	CCK-1R	CCK-1R	CCK-1R	6	7	8	9
CCK-1R Is Upregulated by LPS and CCK and Is Responsible for CCK Inhibition in iNOS Expression .	CCK-1R Is Upregulated by LPS and CCK and Is Responsible for CCK Inhibition in iNOS Expression.	0	9	Upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCK	CCK	CCK	CCK-1R	CCK-1R	CCK-1R	6	7	0	1
Since physiological levels of CCK stimulate exocrine pancreatic secretion in humans and rodents , it was assumed that CCK stimulates CCK-A receptor .	Since physiological levels of CCK stimulate exocrine pancreatic secretion in humans and rodents, it was assumed that CCK stimulates CCK-A receptor.	18	22	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCK	CCK	CCK	CCK-A receptor	CCK-A receptor	CCK-A receptor	18	19	20	22
Some other heterodimers such as melanocortin-4 ( hMC4R ) and delta-opioid ( delta-OR ) , MSH ( 7 ) targeting hMC4R and CCK targeting CCK-2R , EMP-ERP heterodimers for c-Met and VEGFR-2 , and peptide heterodimers binding different domains of VEGFR-2 were also briefly mentioned .	Some other heterodimers such as melanocortin-4 (hMC4R) and delta-opioid (delta-OR), MSH (7) targeting hMC4R and CCK targeting CCK-2R, EMP-ERP heterodimers for c-Met and VEGFR-2, and peptide heterodimers binding different domains of VEGFR-2 were also briefly mentioned.	19	35	targeting	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CCK	CCK	CCK	CCK-2R	CCK-2R	CCK-2R	22	23	24	25
In this Letter , we describe the synthesis and evaluation of CCK trimers targeting overexpressed CCK2-R .	In this Letter, we describe the synthesis and evaluation of CCK trimers targeting overexpressed CCK2-R.	11	16	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCK	CCK	CCK	CCK2-R	CCK2-R	CCK2-R	11	12	15	16
Here , we show that a non biased agonist , cholecystokinin ( CCK ) induces conformational states of the CCK2R activating Gq-protein-dependent pathway ( CCK2R ( G ) ) or recruiting beta-arrestin2 ( CCK2R ( beta ) ) that are pharmacologically and structurally distinct .	Here, we show that a non biased agonist, cholecystokinin (CCK) induces conformational states of the CCK2R activating Gq-protein-dependent pathway (CCK2R (G)) or recruiting beta-arrestin2 (CCK2R (beta)) that are pharmacologically and structurally distinct.	8	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCK	CCK	CCK	CCK2R	CCK2R	CCK2R	12	13	19	20
Activation of CCKBR signaling by CCK or gastrin requires interactions of the ligand with both the N-terminus of the receptor ( including the AP target sites , residues 5-21 and 40-57 ) and several additional residues on the extracellular loops and transmembrane pocket of the receptor [ XREF_BIBR ] .	Activation of CCKBR signaling by CCK or gastrin requires interactions of the ligand with both the N-terminus of the receptor (including the AP target sites, residues 5-21 and 40-57) and several additional residues on the extracellular loops and transmembrane pocket of the receptor [XREF_BIBR].	2	7	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCK	CCK	CCK	CCKBR	CCKBR	CCKBR	5	6	2	3
CARD11 mutations may evade this feedback mechanism because CARD11 activates the paracaspase , MALT1 , which cleaves and inactivates A20 .	CARD11 mutations may evade this feedback mechanism because CARD11 activates the paracaspase, MALT1, which cleaves and inactivates A20.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CARD11	CARD11	CARD11	paracaspase	paracaspase	paracaspase	8	9	11	12
These include activating mutations in the BCR associated CD79A/B chains , the MALT1 activator CARMA1 or the TLR adaptor protein MyD88 ( 37 % of cases ) [ XREF_BIBR ] , together with inactivating mutations in A20 , a negative regulator of the NF-kappaB pathway ( 23 % of cases ) [ XREF_BIBR ] .	These include activating mutations in the BCR associated CD79A/B chains, the MALT1 activator CARMA1 or the TLR adaptor protein MyD88 (37% of cases) [XREF_BIBR], together with inactivating mutations in A20, a negative regulator of the NF-kappaB pathway (23% of cases) [XREF_BIBR].	7	15	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	CARMA1	CARMA1	CARMA1	MALT1	MALT1	MALT1	14	15	12	13
Our data support a model that CARM1 promotes the silencing of EZH2 and BAF155 target genes by displacing BAF155 via methylation , which then permits the occupancy of the target gene promoters by EZH2 and their consequent repression by H3K27Me3 .	Our data support a model that CARM1 promotes the silencing of EZH2 and BAF155 target genes by displacing BAF155 via methylation, which then permits the occupancy of the target gene promoters by EZH2 and their consequent repression by H3K27Me3.	6	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CARM1	CARM1	CARM1	BAF155	BAF155	BAF155	6	7	13	14
Subsequently CARM1 was restored in MCF7 CARM1 KO cells expressing either BAF155 WT or BAF155 R1064 , and colony formation assays were performed .	Subsequently CARM1 was restored in MCF7 CARM1 KO cells expressing either BAF155 WT or BAF155 R1064, and colony formation assays were performed.	1	12	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CARM1	CARM1	CARM1	BAF155	BAF155	BAF155	1	2	11	12
The CARM1 KO cell lines enabled identification of CARM1 substrates , notably the SWI/SNF core subunit BAF155 .	The CARM1 KO cell lines enabled identification of CARM1 substrates, notably the SWI/SNF core subunit BAF155.	1	17	enabled	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CARM1	CARM1	CARM1	BAF155	BAF155	BAF155	1	2	16	17
It was originally discovered that Acinus is activated by caspase-3 , which recognizes its consensus DELD target sequence and cleaves it after D1093 ( residue numbering of the Acinus-L isoform is assumed throughout the text ) .	It was originally discovered that Acinus is activated by caspase-3, which recognizes its consensus DELD target sequence and cleaves it after D1093 (residue numbering of the Acinus-L isoform is assumed throughout the text).	5	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	Acinus	Acinus	Acinus	9	10	5	6
Caspase-3 induces processing of Acinus , which leads to chromatin condensation .	Caspase-3 induces processing of Acinus, which leads to chromatin condensation.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	Acinus	Acinus	Acinus	0	1	4	5
Overexpression of Cav-1 in LNCaP cells markedly increased P-LRP6 , P-Akt ( 308 ) , and Glut3 ( 3.1-, 1.5-, and 14-fold , respectively ) and moderately increased active beta-cat and HK2 ( 1.2- and 1.3-fold , respectively ) compared with that of control AdCt .	Overexpression of Cav-1 in LNCaP cells markedly increased P-LRP6, P-Akt (308), and Glut3 (3.1-, 1.5-, and 14-fold, respectively) and moderately increased active beta-cat and HK2 (1.2- and 1.3-fold, respectively) compared with that of control AdCt.	0	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cav-1	Overexpression of Cav-1	cav-1	P-LRP6	P-LRP6	p-lrp6	2	3	8	9
HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization .	HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization.	12	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CAV1	CAV1	CAV1	HMGA1	HMGA1	HMGA1	12	13	15	16
Such inhibition of CCND1 and CCND2 perturbs CDK4 functionality to inactivate the S-phase repressor Rb [ XREF_BIBR ] .	Such inhibition of CCND1 and CCND2 perturbs CDK4 functionality to inactivate the S-phase repressor Rb [XREF_BIBR].	1	8	perturbs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CCND1	CCND1	CCND1	CDK4	CDK4	CDK4	3	4	7	8
Further experiments focused on the role of AZ in the ubiquitin dependent degradation of CCND1 and on inhibition of the activation and reactivation of CDK4 by CCND1 are needed to prove these hypotheses .	Further experiments focused on the role of AZ in the ubiquitin dependent degradation of CCND1 and on inhibition of the activation and reactivation of CDK4 by CCND1 are needed to prove these hypotheses.	22	27	reactivation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCND1	CCND1	CCND1	CDK4	CDK4	CDK4	26	27	24	25
Immortalization of DM1 primary myoblast populations can also be achieved by combined ectopic expression of TERT , mutated CDK4 ( R24C ) and cyclin D1 ( CCND1 ) , which increases the CDK4 kinase activity for efficient Rb hyperphosphorylation .	Immortalization of DM1 primary myoblast populations can also be achieved by combined ectopic expression of TERT, mutated CDK4 (R24C) and cyclin D1 (CCND1), which increases the CDK4 kinase activity for efficient Rb hyperphosphorylation.	24	34	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCND1	CCND1	CCND1	CDK4	CDK4	CDK4	26	27	32	33
CCND1 ( Cyclin D ) drives the G 1 / S phase transition through binding with cyclin dependent kinase 4 ( CDK4 ) and cyclin dependent kinase 6 ( CDK6 ) , which then phosphorylates retinoblastoma ( pRb ) , inducing downstream Cyclin E transcription [ XREF_BIBR ] .	CCND1 (Cyclin D) drives the G 1 / S phase transition through binding with cyclin dependent kinase 4 (CDK4) and cyclin dependent kinase 6 (CDK6), which then phosphorylates retinoblastoma (pRb), inducing downstream Cyclin E transcription [XREF_BIBR].	0	27	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCND1	CCND1	CCND1	CDK4	CDK4	CDK4	0	1	21	22
CCND1 along with associated cyclins activates cyclin dependent kinases ( CDKs ) - CDK4 and CDK6 .	CCND1 along with associated cyclins activates cyclin dependent kinases (CDKs) - CDK4 and CDK6.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCND1	CCND1	CCND1	CDK4	CDK4	CDK4	0	1	13	14
Cyclin D1 ( CCND1 ) is known to activate CDK4 and CDK6 , a key event in mediating G1/S transition [ XREF_BIBR ] .	Cyclin D1 (CCND1) is known to activate CDK4 and CDK6, a key event in mediating G1/S transition [XREF_BIBR].	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCND1	CCND1	CCND1	CDK4	CDK4	CDK4	3	4	9	10
The use of a CCND1 and CDK2 fusion construct allows the role of CCND1 and CDK2 activity to be dissected independently of CCND1 and CDK4 activity .	The use of a CCND1 and CDK2 fusion construct allows the role of CCND1 and CDK2 activity to be dissected independently of CCND1 and CDK4 activity.	1	25	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCND1	CCND1	CCND1	CDK4	CDK4	CDK4	4	5	24	25
Effector memory cells respond to the inflammatory chemokines CCL3 , CCL4 and CCL5 , and upon re-stimulation upregulate CCR5 and become tissue invasive .	Effector memory cells respond to the inflammatory chemokines CCL3, CCL4 and CCL5, and upon re-stimulation upregulate CCR5 and become tissue invasive.	10	20	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	10	11	18	19
We show here that CCR5 activation by MIP-1beta in HeLa-MAGI cells triggered a rapid and substantial PLD activity , as assessed by mass choline production .	We show here that CCR5 activation by MIP-1beta in HeLa-MAGI cells triggered a rapid and substantial PLD activity, as assessed by mass choline production.	4	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MIP-1beta	MIP-1beta	MIP-1beta	CCR5	CCR5	CCR5	7	8	4	5
In this context , it is important to reiterate that the CC chemokine RANTES , MIP-1b and the CXC chemokine SDF-1a , which signal through M-tropic HIV-1 co-receptors CCR5 and CCR3 and T-tropic HIV-1 co-receptor CXCR4 respectively , are activated by G proteins [ XREF_BIBR , XREF_BIBR ] .	In this context, it is important to reiterate that the CC chemokine RANTES, MIP-1b and the CXC chemokine SDF-1a, which signal through M-tropic HIV-1 co-receptors CCR5 and CCR3 and T-tropic HIV-1 co-receptor CXCR4 respectively, are activated by G proteins [XREF_BIBR, XREF_BIBR].	13	39	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIP-1b	MIP-1b	MIP-1b	CCR5	CCR5	CCR5	15	16	28	29
CCL3 , CCL4 and CCL5 , as the main CC chemokines subfamily members , activate immune cells through binding to CC chemokine receptor 5 or CCR5 .	CCL3, CCL4 and CCL5, as the main CC chemokines subfamily members, activate immune cells through binding to CC chemokine receptor 5 or CCR5.	0	26	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	2	3	25	26
Mice lacking CCR5 or treated with a mAb to CCL4 had a reduced proportion and number of neutrophils , DCs , and tissue Mphi in the lungs day 3 postinfection .	Mice lacking CCR5 or treated with a mAb to CCL4 had a reduced proportion and number of neutrophils, DCs, and tissue Mphi in the lungs day 3 postinfection.	1	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	9	10	2	3
We investigated whether activation of CCR5 by MIP-1beta could complement for the ablated Env-CCR5 interaction in R3A-5/6AA infection and therefore enhance bystander pathogenesis .	We investigated whether activation of CCR5 by MIP-1beta could complement for the ablated Env-CCR5 interaction in R3A-5/6AA infection and therefore enhance bystander pathogenesis.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MIP-1beta	MIP-1beta	MIP-1beta	CCR5	CCR5	CCR5	7	8	5	6
We thus investigated whether CCR5 stimulation by CCL4 would elicit PI-PLC beta1 activation .	We thus investigated whether CCR5 stimulation by CCL4 would elicit PI-PLC beta1 activation.	4	8	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	7	8	4	5
Using siRNA gene silencing and pharmacologic inhibition , we show that chemotaxis in response to CCR5 stimulation by MIP-1beta requires activation of Pyk2 , PI3K p85 , and Lyn , as well as MAPK ERK .	Using siRNA gene silencing and pharmacologic inhibition, we show that chemotaxis in response to CCR5 stimulation by MIP-1beta requires activation of Pyk2, PI3K p85, and Lyn, as well as MAPK ERK.	15	19	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MIP-1beta	MIP-1beta	MIP-1beta	CCR5	CCR5	CCR5	18	19	15	16
It was found that BC expression of CCL4 activates CCR5 on bone marrow fibroblasts which results in their expression of connective tissue growth factor and CCN2 .	It was found that BC expression of CCL4 activates CCR5 on bone marrow fibroblasts which results in their expression of connective tissue growth factor and CCN2.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL4	expression of CCL4	ccl4	CCR5	CCR5	ccr5	7	8	9	10
This effect was specific , since rapid clathrin linked endocytosis of transferrin continued in the presence of U83A , and also CCL4 induced CCR5 in the absence of U83A .	This effect was specific, since rapid clathrin linked endocytosis of transferrin continued in the presence of U83A, and also CCL4 induced CCR5 in the absence of U83A.	21	24	induced	Positive_early_activation	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	21	22	23	24
Figure XREF_FIG shows for the first time , that even after washing ( therefore in the absence of continual re-stimulation ) , cell bound U83A durably inhibits CCL4 induction of CCR5 internalisation for up to 2 hours after the initial incubation with U83A .	Figure XREF_FIG shows for the first time, that even after washing (therefore in the absence of continual re-stimulation), cell bound U83A durably inhibits CCL4 induction of CCR5 internalisation for up to 2 hours after the initial incubation with U83A.	27	31	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	27	28	30	31
CCL4 can activate chemokine receptor CCR5 , which is involved in diverse immune responses 11 .	CCL4 can activate chemokine receptor CCR5, which is involved in diverse immune responses 11.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	0	1	5	6
Mice lacking CCR5 or treated with a mAb to CCL4 had more Tregs in the thymus prior to and during infection .	Mice lacking CCR5 or treated with a mAb to CCL4 had more Tregs in the thymus prior to and during infection.	1	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	9	10	2	3
Although the natural ligands RANTES , MIP-1alpha , and MIP-1beta effectively caused disappearance of CCR5 from the cell surface , the downregulation was never > 60 % at a concentration of 100 nM .	Although the natural ligands RANTES, MIP-1alpha, and MIP-1beta effectively caused disappearance of CCR5 from the cell surface, the downregulation was never> 60% at a concentration of 100 nM.	4	15	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIP-1beta	MIP-1beta	MIP-1beta	CCR5	CCR5	CCR5	9	10	14	15
Furthermore , when the chemotaxis receptor CCR5 is activated by MIP1beta ( CCL4 ) a scaffold is made consisting of beta-arrestin 2 , PI3K and some non receptor kinases .	Furthermore, when the chemotaxis receptor CCR5 is activated by MIP1beta (CCL4) a scaffold is made consisting of beta-arrestin 2, PI3K and some non receptor kinases.	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MIP1beta	MIP1beta	MIP1beta	CCR5	CCR5	CCR5	10	11	6	7
The proteasome inhibitors , lactacystin and epoxomicin , attenuated MIP-1beta induced CCR5 down-modulation as detected by fluorescence activated cell sorter analysis and confocal microscopy .	The proteasome inhibitors, lactacystin and epoxomicin, attenuated MIP-1beta induced CCR5 down-modulation as detected by fluorescence activated cell sorter analysis and confocal microscopy.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	MIP-1beta	MIP-1beta	MIP-1beta	CCR5	CCR5	CCR5	9	10	11	12
To determine if signaling through CCR5 directly regulated expression of these molecules , thymocytes were treated with CCL3 , CCL4 , or CCL5 , and KLF2 and S1P 1 transcription was quantified .	To determine if signaling through CCR5 directly regulated expression of these molecules, thymocytes were treated with CCL3, CCL4, or CCL5, and KLF2 and S1P 1 transcription was quantified.	3	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	19	20	5	6
By using an in vitro chemotaxis assay , we found that CCL3 and CCL5 , but not CCL4 , induced a significantly higher migration of CCR5 pos / CD56 bright hepatic NK cells compared to that of CCR5 neg / CD56 dim hepatic NK cells that , as expected , did not respond to CCR5 ligands .	By using an in vitro chemotaxis assay, we found that CCL3 and CCL5, but not CCL4, induced a significantly higher migration of CCR5 pos / CD56 bright hepatic NK cells compared to that of CCR5 neg / CD56 dim hepatic NK cells that, as expected, did not respond to CCR5 ligands.	11	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	17	18	25	26
The results suggest that immunization with SIV grown in human CD4 ( + ) T cells induces CD8-suppressor factor , RANTES , MIP-1alpha and MIP-1beta which may block CCR5 receptors and prevent the virus from binding and fusion to CD4 ( + ) cells .	The results suggest that immunization with SIV grown in human CD4 (+) T cells induces CD8-suppressor factor, RANTES, MIP-1alpha and MIP-1beta which may block CCR5 receptors and prevent the virus from binding and fusion to CD4 (+) cells.	16	29	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MIP-1beta	MIP-1beta	MIP-1beta	CCR5	CCR5	CCR5	24	25	28	29
Chemotaxis upon CCR5 stimulation by CCL4 requires activation of Pyk2 , PI3K p85 , and Lyn , and ERK .	Chemotaxis upon CCR5 stimulation by CCL4 requires activation of Pyk2, PI3K p85, and Lyn, and ERK.	2	6	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	5	6	2	3
Mice lacking CCR5 or treated with an mAb to CCL4 had impaired infiltration of inflammatory cells to the lungs .	Mice lacking CCR5 or treated with an mAb to CCL4 had impaired infiltration of inflammatory cells to the lungs.	1	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	9	10	2	3
CCR5 is expressed by macrophages and lymphocytes , implying that CCL4 directs migration of these CCR5 positive cells toward lymph nodes or other tissues .	CCR5 is expressed by macrophages and lymphocytes, implying that CCL4 directs migration of these CCR5 positive cells toward lymph nodes or other tissues.	10	17	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	10	11	15	16
Syk was also activated upon MIP1beta stimulation of CCR5 L1.2 transfectants or T-cells and associated with RAFTK .	Syk was also activated upon MIP1beta stimulation of CCR5 L1.2 transfectants or T-cells and associated with RAFTK.	5	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MIP1beta	MIP1beta	MIP1beta	CCR5	CCR5	CCR5	5	6	8	9
CCL5 causes CCR1 , CCR3 , and CCR5 internalisation but through different pathways , such that CCR3 is partially degraded and recycled whereas CCR5 is completely recycled in eosinophils [ XREF_BIBR , XREF_BIBR ] .	CCL5 causes CCR1, CCR3, and CCR5 internalisation but through different pathways, such that CCR3 is partially degraded and recycled whereas CCR5 is completely recycled in eosinophils [XREF_BIBR, XREF_BIBR].	0	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	0	1	2	3
Thus , CXCL4 appears to play an auxiliary role in CCL5 mediated CCR1 activation , a function that might be of crucial importance for the in vivo activity of CCL5 .	Thus, CXCL4 appears to play an auxiliary role in CCL5 mediated CCR1 activation, a function that might be of crucial importance for the in vivo activity of CCL5.	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	10	11	12	13
CCL5 promoted in vitro migration of wild type , CCR1- or CCR5 deficient microglia and macrophages that was blocked by the dual CCR1 and CCR5 antagonist , Met CCL5 .	CCL5 promoted in vitro migration of wild type, CCR1- or CCR5 deficient microglia and macrophages that was blocked by the dual CCR1 and CCR5 antagonist, Met CCL5.	0	10	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1-	CCR1-	CCR1-	0	1	9	10
Also , CCL5 promiscuously activates three G-protein-coupled receptors CCR1 , CCR3 and CCR5 which are expressed on a variety of immunologically relevant cell types , thus transmitting extracellular cues to appropriate effector cells as represented in pSTIING ( XREF_FIG and Supplementary Data 3 ) .	Also, CCL5 promiscuously activates three G-protein-coupled receptors CCR1, CCR3 and CCR5 which are expressed on a variety of immunologically relevant cell types, thus transmitting extracellular cues to appropriate effector cells as represented in pSTIING (XREF_FIG and Supplementary Data 3).	2	16	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	CCL5	CCL5	ccl5	CCR1	CCR1, CCR3 and CCR5 which are expressed	ccr1	2	3	8	9
Because CCL5 can activate CCR1 and CCR3 in addition to CCR5 , knockout mice lacking the CCL5 ligand rather than the receptor were used to assess the role of CCL5 on Tat +/- morphine induced inflammation and reactive gliosis .	Because CCL5 can activate CCR1 and CCR3 in addition to CCR5, knockout mice lacking the CCL5 ligand rather than the receptor were used to assess the role of CCL5 on Tat +/- morphine induced inflammation and reactive gliosis.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	1	2	4	5
Whereas CCR1 re-expression after stimulation with CCL3 reached prestimulation levels ( 120 min : 81.3 % relative CCR1 surface expression ) CCL5 induced a prolonged CCR1 internalization ( 120 min : 15.7 % ) .	Whereas CCR1 re-expression after stimulation with CCL3 reached prestimulation levels (120 min : 81.3% relative CCR1 surface expression) CCL5 induced a prolonged CCR1 internalization (120 min : 15.7%).	21	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	21	22	25	26
Indeed , Weber and coworkers demonstrated that WT CCL5 , but not aggregation deficient variants , could induce CCR1 mediated leukocyte arrest , suggesting a role of chemokine oligomers in integrin activation .	Indeed, Weber and coworkers demonstrated that WT CCL5, but not aggregation deficient variants, could induce CCR1 mediated leukocyte arrest, suggesting a role of chemokine oligomers in integrin activation.	7	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	8	9	18	19
Migration of wild type , as well as CCR1-/- and CCR5-/- microglia was stimulated by CCL5 .	Migration of wild type, as well as CCR1-/- and CCR5-/- microglia was stimulated by CCL5.	8	16	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1-/-	CCR1-/-	CCR1-/-	15	16	8	9
Also , whilst chemokine CCL20 exclusively activates chemokine receptor CCR6 , chemokine CCL5 activates receptors CCR1 , CCR3 and CCR5 .	Also, whilst chemokine CCL20 exclusively activates chemokine receptor CCR6, chemokine CCL5 activates receptors CCR1, CCR3 and CCR5.	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	12	13	15	16
U12 , expressed in the late stages of both HHV-6A and HHV-6B infection , is a beta-chemokine receptor homolog related to CCR-1 , -3 and -5 , which can be activated by CCL5 and RANTES , CCL3 and MIP-1alpha , CCL4 and MIP-1beta and CCL2 and MCP-1 , but not by CXCL8 and IL-8 , suggesting a chemokine selectivity distinct from that of other known mammalian chemokine receptors [ XREF_BIBR , XREF_BIBR ] .	U12, expressed in the late stages of both HHV-6A and HHV-6B infection, is a beta-chemokine receptor homolog related to CCR-1, -3 and -5, which can be activated by CCL5 and RANTES, CCL3 and MIP-1alpha, CCL4 and MIP-1beta and CCL2/MCP-1, but not by CXCL8/IL-8, suggesting a chemokine selectivity distinct from that of other known mammalian chemokine receptors [XREF_BIBR, XREF_BIBR].	19	46	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR-1	CCR-1	CCR-1	32	33	21	22
In the same model , activation of CCR1 by CCL5 resulted in the intrahepatic infiltration of NK cells causing hepatocyte damage [ XREF_BIBR ] .	In the same model, activation of CCR1 by CCL5 resulted in the intrahepatic infiltration of NK cells causing hepatocyte damage [XREF_BIBR].	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	9	10	7	8
In addition to CXCR3 , CCL5 also activates the chemokine receptors CCR1 , CCR3 , CCR4 , and CCR5 .	In addition to CXCR3, CCL5 also activates the chemokine receptors CCR1, CCR3, CCR4, and CCR5.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	5	6	11	12
Internalization experiments using eosinophils from CCR1high donors revealed that CCL5 is more effective to induce CCR1 internalization than CCL3 .	Internalization experiments using eosinophils from CCR1high donors revealed that CCL5 is more effective to induce CCR1 internalization than CCL3.	9	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	9	10	15	16
The A549 alveolar type II epithelial like cell culture model was used to demonstrate that alveolar type II cells constitutively express CCR5 which may be upregulated by MIP-1alpha ( CCL3 ) whose expression was induced by the Th1 cytokines IL-1beta and IFN-gamma .	The A549 alveolar type II epithelial like cell culture model was used to demonstrate that alveolar type II cells constitutively express CCR5 which may be upregulated by MIP-1alpha (CCL3) whose expression was induced by the Th1 cytokines IL-1beta and IFN-gamma.	20	34	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MIP-1alpha	MIP-1alpha	MIP-1alpha	CCR5	CCR5	CCR5	27	28	21	22
Stimulation of CCR5 by CCL3 , CCL4 , or CCL5 regulated expression of the transcription factor Kruppel like factor 2 ( KLF2 ) and sphingosine 1-phosphate receptor 1 ( S1P 1 ) in vitro , and expression of both were diminished in thymocytes from CCR5 -/- and CCL4 neutralized mice prior to and during infection .	Stimulation of CCR5 by CCL3, CCL4, or CCL5 regulated expression of the transcription factor Kruppel like factor 2 (KLF2) and sphingosine 1-phosphate receptor 1 (S1P 1) in vitro, and expression of both were diminished in thymocytes from CCR5 -/- and CCL4 neutralized mice prior to and during infection.	0	36	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	4	5	2	3
Recall Farzan and colleagues used CCR5 N-terminal sulfopeptides to rescue CCL3 activation of a CCR5 Delta2-17 receptor .	Recall Farzan and colleagues used CCR5 N-terminal sulfopeptides to rescue CCL3 activation of a CCR5 Delta2-17 receptor.	10	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	10	11	14	15
CCL3 activates CCR1 and CCR5 , both of which were three times higher at D3 in the banded rats .	CCL3 activates CCR1 and CCR5, both of which were three times higher at D3 in the banded rats.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	0	1	4	5
However , both CCL19 and CXCL13 were incapable of potentiating CCL3 induced activation of CCR5 ( XREF_FIG ) .	However, both CCL19 and CXCL13 were incapable of potentiating CCL3 induced activation of CCR5 (XREF_FIG).	10	16	induced	Positive_early_activation	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	10	11	14	15
CCR1 and CCR5 are activated by MIP-1alpha , and CCR3 is activated by eotaxin-1 , leading to eosinophil migration .	CCR1 and CCR5 are activated by MIP-1alpha, and CCR3 is activated by eotaxin-1, leading to eosinophil migration.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MIP-1alpha	MIP-1alpha	MIP-1alpha	CCR5	CCR5	CCR5	6	7	2	3
Identification of a genetic association of variants within the genes involved ( CCR5 and CCL3 / CCL3L1 ) would strongly support the potential use of CCR5 antagonists in the treatment of respiratory conditions 5 .	Identification of a genetic association of variants within the genes involved (CCR5 and CCL3 / CCL3L1) would strongly support the potential use of CCR5 antagonists in the treatment of respiratory conditions 5.	12	26	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	14	15	25	26
Fluorescent organelle labeling and live cell imaging showed CCL3 and CCL5 caused CCR5 to traffic through sorting endosomes , recycling endosomes and the Golgi apparatus .	Fluorescent organelle labeling and live cell imaging showed CCL3 and CCL5 caused CCR5 to traffic through sorting endosomes, recycling endosomes and the Golgi apparatus.	8	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	8	9	12	13
Therefore down-regulation of ccl3 in adults with a history of MA abuse may increase the availability of CCR5 , resulting in more efficient infection by HIV-1 [ XREF_BIBR ] .	Therefore down-regulation of ccl3 in adults with a history of MA abuse may increase the availability of CCR5, resulting in more efficient infection by HIV-1 [XREF_BIBR].	1	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ccl3	ccl3	ccl3	CCR5	CCR5	CCR5	3	4	17	18
In addition , the presence of a relatively high concentration of CCL3 in the upper chamber might prematurely trigger internalization of CCR5 upon ligand binding , thereby decreasing the ability of naive CD4+ T cell to firmly adhere due to lack of integrin activation [ XREF_BIBR ] .	In addition, the presence of a relatively high concentration of CCL3 in the upper chamber might prematurely trigger internalization of CCR5 upon ligand binding, thereby decreasing the ability of naive CD4+ T cell to firmly adhere due to lack of integrin activation [XREF_BIBR].	9	22	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	11	12	21	22
The loss of control of T. cruzi infection in CCR5 deficient mice or in mice treated with neutralization CCL3 antibody are consistent with the studies that recognize that chemokines exert antimicrobial effects against various types of pathogens , including parasites .	The loss of control of T. cruzi infection in CCR5 deficient mice or in mice treated with neutralization CCL3 antibody are consistent with the studies that recognize that chemokines exert antimicrobial effects against various types of pathogens, including parasites.	9	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	18	19	9	10
CCL3 or CCL3 could only activate a CCR5 Delta2-17 induced intracellular calcium flux when the receptor was rescued by the presence of synthetic CCR5 N-terminal peptides containing sulfated tyrosines but not unsulfated counterparts .	CCL3 or CCL3 could only activate a CCR5 Delta2-17 induced intracellular calcium flux when the receptor was rescued by the presence of synthetic CCR5 N-terminal peptides containing sulfated tyrosines but not unsulfated counterparts.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	0	1	7	8
CCL3 is known to activate its cognate receptors CCR5 and CCR1 [ XREF_BIBR ] , and a pharmacological blockade of spinal CCL3 signaling by intrathecal administration of CCR5 antagonists reduces pain hypersensitivity after traumatic nerve injury [ XREF_BIBR , XREF_BIBR ] .	CCL3 is known to activate its cognate receptors CCR5 and CCR1 [XREF_BIBR], and a pharmacological blockade of spinal CCL3 signaling by intrathecal administration of CCR5 antagonists reduces pain hypersensitivity after traumatic nerve injury [XREF_BIBR, XREF_BIBR].	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	0	1	8	9
Mechanistic investigations revealed that CCL5 activates CCR3 , a highly expressed chemokine receptor on CD4+ T cells , and also boosts Gfi1 expression to promote the differentiation of Th2 cells , which enhance the prometastatic activity of tumor associated myeloid cells .	Mechanistic investigations revealed that CCL5 activates CCR3, a highly expressed chemokine receptor on CD4+ T cells, and also boosts Gfi1 expression to promote the differentiation of Th2 cells, which enhance the prometastatic activity of tumor associated myeloid cells.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR3	CCR3	CCR3	4	5	6	7
In addition , CCL5 driven CCR3 activation appears to precede PGD 2 receptor activation within eosinophils , since neutralizing anti-CCL5 or anti-CCR3 antibodies inhibited leptin induced PGD 2 secretion , while it failed to alter PGD 2 -induced LTC 4 synthesis .	In addition, CCL5 driven CCR3 activation appears to precede PGD 2 receptor activation within eosinophils, since neutralizing anti-CCL5 or anti-CCR3 antibodies inhibited leptin induced PGD 2 secretion, while it failed to alter PGD 2 -induced LTC 4 synthesis.	3	9	driven	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR3	CCR3	CCR3	3	4	5	6
XREF_BIBR CCR3 can also be activated by CCL5 and RANTES , CCL7 and MCP3 , CCL and MCP2 , and CCL12 and MCP5 .	XREF_BIBR CCR3 can also be activated by CCL5 and RANTES, CCL7 and MCP3, CCL and MCP2, and CCL12 and MCP5.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR3	CCR3	CCR3	7	8	1	2
Interestingly , CCL5 , the T-cell specific RANTES protein , canonical and predicted interactions lead to activation of its cognate CCR3 receptor .	Interestingly, CCL5, the T-cell specific RANTES protein, canonical and predicted interactions lead to activation of its cognate CCR3 receptor.	2	21	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	CCL5	CCL5	CCL5	CCR3	CCR3	CCR3	2	3	20	21
The failure of HCC-1 to induce chemotaxis would thus have provided intriguing evidence for distinct and agonist specific signal transduction pathways downstream of a chemokine receptor ( i.e ., induction of chemotaxis in response to activation of CCR1 by MIP-1alpha or RANTES , but not by HCC-1 ) .	The failure of HCC-1 to induce chemotaxis would thus have provided intriguing evidence for distinct and agonist specific signal transduction pathways downstream of a chemokine receptor (i.e., induction of chemotaxis in response to activation of CCR1 by MIP-1alpha or RANTES, but not by HCC-1).	35	41	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MIP-1alpha	MIP-1alpha	MIP-1alpha	CCR1	CCR1	CCR1	39	40	37	38
More extensive analysis ( XREF_FIG ) showed that CCL3 induced a potent CCR1 calcium mobilization response in monocytes ( EC 50 of 1.75 nM ) .	More extensive analysis (XREF_FIG) showed that CCL3 induced a potent CCR1 calcium mobilization response in monocytes (EC 50 of 1.75 nM).	8	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR1	CCR1	CCR1	8	9	12	13
Notably , it has been reported that activation of the CCL2-CCR2 axis prompts TAM to secrete another chemokine CCL3 , which in turn activates its receptor CCR1 in TAM and promotes lung metastatic seeding in a breast cancer mouse model [ XREF_BIBR ] .	Notably, it has been reported that activation of the CCL2-CCR2 axis prompts TAM to secrete another chemokine CCL3, which in turn activates its receptor CCR1 in TAM and promotes lung metastatic seeding in a breast cancer mouse model [XREF_BIBR].	15	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR1	CCR1	CCR1	18	19	26	27
Delineation of specific downstream signaling events will be needed to understand the molecular basis for these diverse functional responses mediated by MIP-1alpha activation of CCR1 .	Delineation of specific downstream signaling events will be needed to understand the molecular basis for these diverse functional responses mediated by MIP-1alpha activation of CCR1.	21	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MIP-1alpha	MIP-1alpha	MIP-1alpha	CCR1	CCR1	CCR1	21	22	24	25
Next , secreted CCL3 activates CCR1 on the host and neighbouring cells , which subsequently increases MMP-9 production .	Next, secreted CCL3 activates CCR1 on the host and neighbouring cells, which subsequently increases MMP-9 production.	2	6	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR1	CCR1	CCR1	3	4	5	6
Notably , MIP-1alpha rather than RANTES triggered substantial transmigration of wild-type neutrophils but not Ccr1 -/- neutrophils , indicating that neutrophil transmi gration was mediated by Ccr1 and that MIP-1alpha was more important than RANTES in this process ( XREF_FIG ) .	Notably, MIP-1alpha rather than RANTES triggered substantial transmigration of wild-type neutrophils but not Ccr1 -/- neutrophils, indicating that neutrophil transmi gration was mediated by Ccr1 and that MIP-1alpha was more important than RANTES in this process (XREF_FIG).	2	16	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIP-1alpha	MIP-1alpha	MIP-1alpha	Ccr1	Ccr1	Ccr1	2	3	14	15
Similarly , when human monocytes were examined , both CCL3 and CXCL4 induced significant CCR1 endocytosis at levels similar to those induced in the L1.2 CCR1 cell line .	Similarly, when human monocytes were examined, both CCL3 and CXCL4 induced significant CCR1 endocytosis at levels similar to those induced in the L1.2 CCR1 cell line.	8	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR1	CCR1	CCR1	9	10	14	15
Activation of CCL2-CCR2 signaling promotes CCL3 secretion that activates CCR1 signaling in MAMs .	Activation of CCL2-CCR2 signaling promotes CCL3 secretion that activates CCR1 signaling in MAMs.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL3	CCL3	CCL3	CCR1	CCR1	CCR1	5	6	9	10
In conclusion , our data identify CCR1 as the dominant receptor responsible for MIP-1alpha enhancement of growth factor stimulated MPC proliferation and MIP-1alpha-induced MPC mobilization to peripheral blood , but rule out CCR1 as a dominant receptor for negative regulation of hematopoiesis by MIP-1alpha .	In conclusion, our data identify CCR1 as the dominant receptor responsible for MIP-1alpha enhancement of growth factor stimulated MPC proliferation and MIP-1alpha-induced MPC mobilization to peripheral blood, but rule out CCR1 as a dominant receptor for negative regulation of hematopoiesis by MIP-1alpha.	5	44	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MIP-1alpha	MIP-1alpha	MIP-1alpha	CCR1	CCR1	CCR1	43	44	6	7
MCP-1 triggered directly the rapid biogenesis of distinctive LTB4 synthesizing lipid bodies via CCR2 driven ERK- and PI3K dependent intracellular signaling in in vitro stimulated macrophages .	MCP-1 triggered directly the rapid biogenesis of distinctive LTB4 synthesizing lipid bodies via CCR2 driven ERK- and PI3K dependent intracellular signaling in in vitro stimulated macrophages.	11	17	driven	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CCR2	CCR2	CCR2	ERK-	ERK-	ERK-	13	14	15	16
In particular , we have characterized that elevated GRK2 levels can reduce CCR2 mediated activation of the ERK MAPK route in a manner that is independent of kinase activity and also of G proteins .	In particular, we have characterized that elevated GRK2 levels can reduce CCR2 mediated activation of the ERK MAPK route in a manner that is independent of kinase activity and also of G proteins.	12	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	CCR2	CCR2	CCR2	ERK MAPK	ERK MAPK	ERK MAPK	12	13	17	19
In addition , CCR2 may also initiate intracellular MAPK and Erk activation [ XREF_BIBR ] .	In addition, CCR2 may also initiate intracellular MAPK and Erk activation [XREF_BIBR].	3	11	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR2	CCR2	CCR2	Erk	Erk	Erk	3	4	10	11
CCR2 can rapidly activate MEK and ERK1/2 , and all three receptors can activate ERK1/2 , and MEK via STAT3 .	CCR2 can rapidly activate MEK and ERK1/2, and all three receptors can activate ERK1/2, and MEK via STAT3.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR2	CCR2	CCR2	ERK1/2	ERK1/2	ERK1/2	0	1	6	7
CCR2 signaling results in the activation of PI3K , MAPK , and protein kinase C , and therefore , elicits a broad range of cellular responses .	CCR2 signaling results in the activation of PI3K, MAPK, and protein kinase C, and therefore, elicits a broad range of cellular responses.	0	10	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	CCR2	CCR2	CCR2	MAPK	MAPK	MAPK	0	1	9	10
The MCP-1-elicited lipid body formation was dependent on activation of a CCR2 elicited ERK and P13K signalling [ XREF_BIBR ] .	The MCP-1-elicited lipid body formation was dependent on activation of a CCR2 elicited ERK and P13K signalling [XREF_BIBR].	8	16	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR2	CCR2	CCR2	ERK	ERK	ERK	11	12	13	14
These data indicate that CCR2 ligands , MCP-1 , MCP-2 and MCP-3 , stimulate AKT and ERK activation , ROS production and HSC migration through CCR2 and p47phox .	These data indicate that CCR2 ligands, MCP-1, MCP-2 and MCP-3, stimulate AKT and ERK activation, ROS production and HSC migration through CCR2 and p47phox.	4	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR2	CCR2	CCR2	ERK	ERK	ERK	4	5	16	17
ERK is also activated by CCR2 agonists , e.g ., monocyte chemoattractant protein-1 ( CCL2 ) .	ERK is also activated by CCR2 agonists, e.g., monocyte chemoattractant protein-1 (CCL2).	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCR2	CCR2	CCR2	ERK	ERK	ERK	5	6	0	1
PD-L1 in tumor cells is known to promote immune escape of cancer cells by interacting with programmed cell death protein 1 in tumor infiltrating immune cells .	PD-L1 in tumor cells is known to promote immune escape of cancer cells by interacting with programmed cell death protein 1 in tumor infiltrating immune cells.	0	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PD-L1	PD-L1	PD-L1	programmed cell death protein 1	programmed cell death protein 1	programmed cell death protein 1	0	1	16	21
No difference in p-STAT5 signaling was detected in the Pdcd1 -/- cohorts treated with PDL-1 .	No difference in p-STAT5 signaling was detected in the Pdcd1 -/- cohorts treated with PDL-1.	6	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PDL-1	PDL-1	PDL-1	Pdcd1	Pdcd1	Pdcd1	14	15	9	10
T-lymphocyte and antigen presenting cells ( APCs ) interaction is in fact bi-directional and mediated by PD-L1 and programmed cell death protein 1 ( PD1 ) on APCs and on lymphocytes .	T-lymphocyte and antigen presenting cells (APCs) interaction is in fact bi-directional and mediated by PD-L1 and programmed cell death protein 1 (PD1) on APCs and on lymphocytes.	11	24	mediated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	PD-L1	PD-L1	PD-L1	programmed cell death protein 1	programmed cell death protein 1	programmed cell death protein 1	16	17	18	23
Subsequently , CCL2 was found to also activate CCR4 , a promiscuous chemokine GPCR that is expressed in Th2 lymphocytes .	Subsequently, CCL2 was found to also activate CCR4, a promiscuous chemokine GPCR that is expressed in Th2 lymphocytes.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR4	CCR4	CCR4	2	3	8	9
CCR4 , CX3CR1 , and XCR1 are functionally and structurally present in human ADSC , and are activated by the chemokines CCL2 , CX3CL1 , and XCL1 respectively , which are upregulated in the MPG following CN injury .	CCR4, CX3CR1, and XCR1 are functionally and structurally present in human ADSC, and are activated by the chemokines CCL2, CX3CL1, and XCL1 respectively, which are upregulated in the MPG following CN injury.	0	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR4	CCR4	CCR4	21	22	0	1
Moreover , CCL2 , CCL17 , and CCL22 stimulation induced CCR4 production .	Moreover, CCL2, CCL17, and CCL22 stimulation induced CCR4 production.	2	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR4	CCR4	CCR4	2	3	10	11
CCR4 + is also expressed on Teff ( Th2 and Th17 , among others ) cells , and CCL2 mediates CCR4 + Teff cell infiltration of the GBM microenvironment .	CCR4 + is also expressed on Teff (Th2 and Th17, among others) cells, and CCL2 mediates CCR4 + Teff cell infiltration of the GBM microenvironment.	18	24	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR4	CCR4	CCR4	18	19	20	21
In fact , a dependency on epidermal growth factor receptor ( EGFR ) signaling for chemokine induced ERK1/2 phosphorylation and mitogenesis has been demonstrated for CXCR4 signaling in an ovarian cancer line and by CCR3 signaling in bronchial epithelial cells , as specific inhibitors of EGFR abolish CXCL12 and CXCR4 and CCL11 and CCR3 induced ERK1/2 activation and cell proliferation in these cells , respectively [ XREF_BIBR , XREF_BIBR ] .	In fact, a dependency on epidermal growth factor receptor (EGFR) signaling for chemokine induced ERK1/2 phosphorylation and mitogenesis has been demonstrated for CXCR4 signaling in an ovarian cancer line and by CCR3 signaling in bronchial epithelial cells, as specific inhibitors of EGFR abolish CXCL12 and CXCR4 and CCL11 and CCR3 induced ERK1/2 activation and cell proliferation in these cells, respectively [XREF_BIBR, XREF_BIBR].	47	56	induced	Positive_early_activation	Positive_activation	Positive_activation	CCR3	CCR3	CCR3	ERK1/2	ERK1/2	ERK1/2	53	54	55	56
Based on these findings , we speculated that CCL7 and CCR3 crosstalk could induce ERK and JNK activation sequentially and result in enhanced EMT process .	Based on these findings, we speculated that CCL7 and CCR3 crosstalk could induce ERK and JNK activation sequentially and result in enhanced EMT process.	8	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR3	CCR3	CCR3	ERK	ERK	ERK	10	11	14	15
CCR3 ligands CCL11 and CCL24 caused rapid activation of p42/44 MAPK but not Akt .	CCR3 ligands CCL11 and CCL24 caused rapid activation of p42/44 MAPK but not Akt.	0	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR3	CCR3	CCR3	MAPK	MAPK	MAPK	0	1	10	11
HSCs functionally expressed chemokine receptor-5 ( CCR5 ) , as shown by flow-cytometric analysis and RT-PCR , and the inhibitory effects of a blocking CCR5 antibody on rhRANTES induced ERK activation , proliferation , and migration .	HSCs functionally expressed chemokine receptor-5 (CCR5), as shown by flow-cytometric analysis and RT-PCR, and the inhibitory effects of a blocking CCR5 antibody on rhRANTES induced ERK activation, proliferation, and migration.	24	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR5	CCR5	CCR5	ERK	ERK	ERK	24	25	29	30
This concurs with a previous study where CCR5 was shown to induce antiapoptotic signals via Akt and Erk ( 1/2 ) XREF_BIBR .	This concurs with a previous study where CCR5 was shown to induce antiapoptotic signals via Akt and Erk (1/2) XREF_BIBR.	7	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR5	CCR5	CCR5	Erk	Erk	Erk	7	8	17	18
Triggering of this pathway is mediated by CCR5 coupling to Gialpha proteins and is driven by PC-PLC through mitogen activated protein kinase ( MAPK ) ERK1/2 activation .	Triggering of this pathway is mediated by CCR5 coupling to Gialpha proteins and is driven by PC-PLC through mitogen activated protein kinase (MAPK) ERK1/2 activation.	5	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR5	CCR5	CCR5	ERK1/2	ERK1/2	ERK1/2	7	8	25	26
Earlier we have shown above that the CCR5 downstream signaling activated the kinase Lyn and ERK in infected macrophages ( XREF_FIG ) .	Earlier we have shown above that the CCR5 downstream signaling activated the kinase Lyn and ERK in infected macrophages (XREF_FIG).	7	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR5	CCR5	CCR5	ERK	ERK	ERK	7	8	15	16
Ligation of cell surface CCR5 receptors by CCL3 or CD40 by CD40L activated the ERK1/2 and p38 MAPK signaling pathways that induced A3G mRNA expression and production of the A3G protein .	Ligation of cell surface CCR5 receptors by CCL3 or CD40 by CD40L activated the ERK1/2 and p38 MAPK signaling pathways that induced A3G mRNA expression and production of the A3G protein.	4	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR5	CCR5	CCR5	ERK1/2	ERK1/2	ERK1/2	4	5	14	15
Given that i ) cancer cells harbouring CCNE1 gene amplification depend on CCNE1 expression for their survival , ii ) that one of the main functions of CCNE1 is to activate CDK2 in the transition from G1/S phase [ XREF_BIBR ] , and iii ) that CCNE1 RNAi mediated silencing led to G1 arrest , we posited that cancer cells harbouring CCNE1 gene amplification would be dependent on CDK2 expression and kinase activity for their survival .	Given that i) cancer cells harbouring CCNE1 gene amplification depend on CCNE1 expression for their survival, ii) that one of the main functions of CCNE1 is to activate CDK2 in the transition from G1/S phase [XREF_BIBR], and iii) that CCNE1 RNAi mediated silencing led to G1 arrest, we posited that cancer cells harbouring CCNE1 gene amplification would be dependent on CDK2 expression and kinase activity for their survival.	25	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCNE1	CCNE1	CCNE1	CDK2	CDK2	CDK2	27	28	31	32
In ovary tumors , elevated CCNE1 level is often correlated with higher Cdk2 expression and most of CCNE1 associated tumor promoting effects require the participation of Cdk2 .	In ovary tumors, elevated CCNE1 level is often correlated with higher Cdk2 expression and most of CCNE1 associated tumor promoting effects require the participation of Cdk2.	15	27	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCNE1	CCNE1	CCNE1	Cdk2	Cdk2	Cdk2	17	18	26	27
In addition to its direct function in PI3K activation , CD19 reportedly mediates the processive activation of Lyn creating a positive forward feeding loop [ XREF_BIBR ] and this is predicted to enhance positive signaling by recruiting Btk and VAV [ XREF_BIBR ] .	In addition to its direct function in PI3K activation, CD19 reportedly mediates the processive activation of Lyn creating a positive forward feeding loop [XREF_BIBR] and this is predicted to enhance positive signaling by recruiting Btk and VAV [XREF_BIBR].	10	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD19	CD19	CD19	Lyn	Lyn	Lyn	10	11	17	18
PI3K can also be activated by a process involving direct binding to Lyn , thus the processive CD19 activation of Lyn could further promote PI3K activation [ XREF_BIBR ] .	PI3K can also be activated by a process involving direct binding to Lyn, thus the processive CD19 activation of Lyn could further promote PI3K activation [XREF_BIBR].	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CD19	CD19	CD19	Lyn	Lyn	Lyn	17	18	20	21
CD19 consistently enhanced activation of ERK2 and MEK1 .	CD19 consistently enhanced activation of ERK2 and MEK1.	0	7	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD19	CD19	CD19	ERK2	ERK2	ERK2	0	1	5	6
How can we can reconcile our data with the observed reduction in PIP5K activity in CD19 stimulated Vav1 -/- B cells ?	How can we can reconcile our data with the observed reduction in PIP5K activity in CD19 stimulated Vav1 -/- B cells?	4	18	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CD19	CD19	CD19	Vav1	Vav1	Vav1	15	16	17	18
Additionally CCR1 knocked-out mice had increased ERK1/2 activation .	Additionally CCR1 knocked-out mice had increased ERK1/2 activation.	1	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCR1	CCR1	CCR1	ERK1/2	ERK1/2	ERK1/2	1	2	6	7
We , and others , have demonstrated that the outcome of CD40 receptor activation by its ligand CD40L and CD154 in carcinomas predominantly relies on the way the ligand is presented to the receptor at the cell surface , where membrane bound CD40L ( mCD40L ) but not soluble CD40L ( sCD40L ) induces cell growth arrest and apoptosis .	We, and others, have demonstrated that the outcome of CD40 receptor activation by its ligand CD40L and CD154 in carcinomas predominantly relies on the way the ligand is presented to the receptor at the cell surface, where membrane bound CD40L (mCD40L) but not soluble CD40L (sCD40L) induces cell growth arrest and apoptosis.	11	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	17	18	11	12
These data suggest that T cell activation in situ by M. leprae in tuberculoid leprosy leads to local up-regulation of CD40L , which stimulates CD40 dependent induction of IL-12 in monocytes .	These data suggest that T cell activation in situ by M. leprae in tuberculoid leprosy leads to local up-regulation of CD40L, which stimulates CD40 dependent induction of IL-12 in monocytes.	18	26	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	20	21	24	25
It has long been assumed that IL-12 is initially produced by macrophages in response to various intracellular pathogens and later by DCs , based on the observations that DCs produce IL-12 through ligation of CD40 on DCs by CD40L on activated T cells , or through cross linking of MHC class II molecules by the TCR .	It has long been assumed that IL-12 is initially produced by macrophages in response to various intracellular pathogens and later by DCs, based on the observations that DCs produce IL-12 through ligation of CD40 on DCs by CD40L on activated T cells, or through cross linking of MHC class II molecules by the TCR.	29	42	produce	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	38	39	34	35
T cells provide proliferative and survival cues to SCs and sensitize SCs to PTH through CD40L , a surface molecule of activated T cells that induces CD40 signaling in SCs .	T cells provide proliferative and survival cues to SCs and sensitize SCs to PTH through CD40L, a surface molecule of activated T cells that induces CD40 signaling in SCs.	10	27	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	15	16	26	27
ISF35 is delivered by intratumoral injection , resulting in membrane bound CD40L expression that targets the CD40 receptor on antigen presenting cells at the site of injection .	ISF35 is delivered by intratumoral injection, resulting in membrane bound CD40L expression that targets the CD40 receptor on antigen presenting cells at the site of injection.	11	17	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L expression	cd40l	CD40	CD40	cd40	11	12	16	17
However , since CD40-/- EOCs were significantly more effective than wild-type EOCs , it is quite likely that the CD40 pathway of wild-type EOCs is activated either during the EOC culture process by autocrine CD40L or following transplantation by tissue CD40L .	However, since CD40-/- EOCs were significantly more effective than wild-type EOCs, it is quite likely that the CD40 pathway of wild-type EOCs is activated either during the EOC culture process by autocrine CD40L or following transplantation by tissue CD40L.	19	35	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	34	35	19	20
37 We confirmed that CD40L increased CD86 and CD40 MC by 1.6- and 1.4-fold , respectively ( XREF_FIG ) , and induced CD40 intermediate MC differentiation by 1.7-folds ( XREF_FIG ) .	37 We confirmed that CD40L increased CD86 and CD40 MC by 1.6- and 1.4-fold, respectively (XREF_FIG), and induced CD40 intermediate MC differentiation by 1.7-folds (XREF_FIG).	4	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	4	5	8	9
XREF_BIBR , XREF_BIBR In vitro activation of CD40 by CD40L protects CLL B cells from apoptosis by upregulation of the anti-apoptotic Bcl-2 family proteins Bcl-xL and Mcl-1 , induction of Survivin and activation of the NFkappaB pathway .	XREF_BIBR, XREF_BIBR In vitro activation of CD40 by CD40L protects CLL B cells from apoptosis by upregulation of the anti-apoptotic Bcl-2 family proteins Bcl-xL and Mcl-1, induction of Survivin and activation of the NFkappaB pathway.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	9	10	7	8
MVECs increased the release of soluble BAFF and APRIL after engagement of CD40 on MVECs by CD40L on CLL cells .	MVECs increased the release of soluble BAFF and APRIL after engagement of CD40 on MVECs by CD40L on CLL cells.	1	19	increased	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	16	17	12	13
For instance , CD40 signaling induced by soluble CD40L ( sCD40L ) was potentiated ~ 10-fold upon secondary cross linking of CD40L into higher order multimers [ XREF_BIBR - XREF_BIBR ] .	For instance, CD40 signaling induced by soluble CD40L (sCD40L) was potentiated ~ 10-fold upon secondary cross linking of CD40L into higher order multimers [XREF_BIBR - XREF_BIBR].	3	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	8	9	3	4
They generated LOAd703 which is a designed adenovirus armed with trimerized CD40L and 4-1BBL that activates the CD40 and 4-1BB pathways , respectively .	They generated LOAd703 which is a designed adenovirus armed with trimerized CD40L and 4-1BBL that activates the CD40 and 4-1BB pathways, respectively.	10	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	11	12	17	18
T cells sensitize SCs to PTH through CD40L , a surface molecule of activated T cells that induces CD40 signaling in SCs .	T cells sensitize SCs to PTH through CD40L, a surface molecule of activated T cells that induces CD40 signaling in SCs.	2	19	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	7	8	18	19
CD40L enhances the antigen presentation function of CD40 expressing B cells .	CD40L enhances the antigen presentation function of CD40 expressing B cells.	0	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	0	1	7	8
However , it has been shown that activated dendritic cells can also produce CD40L , which can then act in a paracrine fashion to stimulate CD40 on other dendritic cells , thereby potentially bypassing the defective CD40 expression of T cells in our study .	However, it has been shown that activated dendritic cells can also produce CD40L, which can then act in a paracrine fashion to stimulate CD40 on other dendritic cells, thereby potentially bypassing the defective CD40 expression of T cells in our study.	12	26	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	13	14	25	26
CD40L was upregulated on iNKT cells following alpha-GalCer challenge and induced CD40 signaling in DCs [ XREF_BIBR ] .	CD40L was upregulated on iNKT cells following alpha-GalCer challenge and induced CD40 signaling in DCs [XREF_BIBR].	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	0	1	11	12
The mechanism of this effect is not known but an obvious possibility is that CD40L promotes AD like pathology by activating CD40 .	The mechanism of this effect is not known but an obvious possibility is that CD40L promotes AD like pathology by activating CD40.	14	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	14	15	21	22
Taken together , these findings indicate that in contrast to CP-870 ,893 , CD40 ligand induces CD40 clustering on the cell surface and not receptor internalization .	Taken together, these findings indicate that in contrast to CP-870,893, CD40 ligand induces CD40 clustering on the cell surface and not receptor internalization.	13	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	13	15	16	17
Here we examine the effect of SLAM and SLAM interactions on CD40L induced CD40 signaling pathways in human DCs .	Here we examine the effect of SLAM and SLAM interactions on CD40L induced CD40 signaling pathways in human DCs.	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	11	12	13	14
CD40 on Maturing DCs , Activated by CD40L , Is Critical for Immunogenicity Initiated by alpha-GalCer and NKT Cells .	CD40 on Maturing DCs, Activated by CD40L, Is Critical for Immunogenicity Initiated by alpha-GalCer and NKT Cells.	0	10	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	7	8	0	1
No previous studies have explored the converse phenomenon where CD40L on DC may trigger CD40 on T cells .	No previous studies have explored the converse phenomenon where CD40L on DC may trigger CD40 on T cells.	9	15	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	9	10	14	15
It was also reported that soluble CD40L induced CD40 activation has proangiogenic effects in vitro and in vivo XREF_BIBR , XREF_BIBR , XREF_BIBR .	It was also reported that soluble CD40L induced CD40 activation has proangiogenic effects in vitro and in vivo XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	6	7	8	9
Recently , it has also been demonstrated that increased TNF-alpha production and induction of neuronal injury occur when activated microglia , which exhibit increased CD40 expression , are treated with CD40 ligand 29 .	Recently, it has also been demonstrated that increased TNF-alpha production and induction of neuronal injury occur when activated microglia, which exhibit increased CD40 expression, are treated with CD40 ligand 29.	24	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	30	32	24	25
To study the biological effects of ligation of CD40 mediated by soluble recombinant human CD40 ligand ( srhCD40L ) on the human malignant hematogenous cells and to explore the molecular mechanism thereof .	To study the biological effects of ligation of CD40 mediated by soluble recombinant human CD40 ligand (srhCD40L) on the human malignant hematogenous cells and to explore the molecular mechanism thereof.	6	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	14	16	8	9
These data could suggest that CD40L mediates atherosclerosis development independently of CD40 .	These data could suggest that CD40L mediates atherosclerosis development independently of CD40.	5	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	5	6	11	12
A many-trimer , multimeric form of CD40L is needed to stimulate CD40 .	A many-trimer, multimeric form of CD40L is needed to stimulate CD40.	4	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	6	7	11	12
Ectopic B cell expression of CD40L ( CD154 ) in transgenic mice , which induces increased CD40 signaling [ XREF_BIBR ] , also increases B10 cell numbers .	Ectopic B cell expression of CD40L (CD154) in transgenic mice, which induces increased CD40 signaling [XREF_BIBR], also increases B10 cell numbers.	3	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	expression of CD40L	cd40l	CD40	CD40	cd40	5	6	16	17
CD40L induces intermediate and CD40 intermediate MC differentiation in PBMC .	CD40L induces intermediate and CD40 intermediate MC differentiation in PBMC.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	0	1	4	5
Beside these newly described innate stimuli , the current dogma postulates that 2 signals are necessary to drive T dependent naive B cell proliferation and differentiation into ASC : recognition of an antigen by the B cell specific receptor ( BCR ) and a T cell co-stimulatory signal in which CD40L ( CD154 ) expressed on activated T cells activates CD40 on B cells .	Beside these newly described innate stimuli, the current dogma postulates that 2 signals are necessary to drive T dependent naive B cell proliferation and differentiation into ASC : recognition of an antigen by the B cell specific receptor (BCR) and a T cell co-stimulatory signal in which CD40L (CD154) expressed on activated T cells activates CD40 on B cells.	50	63	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L (CD154) expressed	cd40l	CD40	CD40	cd40	50	51	60	61
Importantly , CHIR-12.12 abrogates CD40L induced growth and survival of CD40 expressing patient multiple myeloma cells in the presence or absence of bone marrow stromal cells ( BMSC ) , without altering constitutive multiple myeloma cell proliferation .	Importantly, CHIR-12.12 abrogates CD40L induced growth and survival of CD40 expressing patient multiple myeloma cells in the presence or absence of bone marrow stromal cells (BMSC), without altering constitutive multiple myeloma cell proliferation.	3	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	4	5	10	11
In an in vitro mixed lymphocyte reaction , CD40L -/- DCs induced less proliferation of CD40 +/+ CD8 + T cells .	In an in vitro mixed lymphocyte reaction, CD40L -/- DCs induced less proliferation of CD40 +/+ CD8 + T cells.	8	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	8	9	15	16
Notably , CD40L on the surface of T cells stimulates CD40 on DCs , increasing their surface expression of costimulatory molecules and secretion of cytokines including IL-12 .	Notably, CD40L on the surface of T cells stimulates CD40 on DCs, increasing their surface expression of costimulatory molecules and secretion of cytokines including IL-12.	2	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	2	3	10	11
Depicted are results obtained from anti-OX40 treated CD40-/- allograft recipients and similar results were generated in WT recipients treated with anti-CD40L and CD40L-/- recipients .	Depicted are results obtained from anti-OX40 treated CD40-/- allograft recipients and similar results were generated in WT recipients treated with anti-CD40L and CD40L-/- recipients.	7	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CD40L-/-	CD40L-/-	CD40L-/-	CD40-/-	CD40-/-	CD40-/-	22	23	7	8
Interestingly , it has been demonstrated that mature adipocytes express CD40 that can be activated , by CD40 ligand or activated CD4+ T cells , to induce secretion of inflammatory cytokines XREF_BIBR .	Interestingly, it has been demonstrated that mature adipocytes express CD40 that can be activated, by CD40 ligand or activated CD4+ T cells, to induce secretion of inflammatory cytokines XREF_BIBR.	9	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	17	19	10	11
This was true when analyzing percentage of phospho-p65-positive cells , but was not as marked when analyzing mean fluorescence intensities , suggesting that TRAILR2 may increase the threshold of CD40L stimulation required to activate CD40 , but may not modify signalling once CD40 has been activated .	This was true when analyzing percentage of phospho-p65-positive cells, but was not as marked when analyzing mean fluorescence intensities, suggesting that TRAILR2 may increase the threshold of CD40L stimulation required to activate CD40, but may not modify signalling once CD40 has been activated.	29	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	29	30	34	35
As a member of the tumor necrosis factor ( TNF ) superfamily the activation of CD40 by CD40-ligand ( CD40L ) plays a crucial role for the development and progression of a variety of inflammatory processes including atherosclerosis .	As a member of the tumor necrosis factor (TNF) superfamily the activation of CD40 by CD40-ligand (CD40L) plays a crucial role for the development and progression of a variety of inflammatory processes including atherosclerosis.	13	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CD40-ligand	CD40-ligand	CD40-ligand	CD40	CD40	CD40	17	18	15	16
In contrast to mice , CD40 signalling triggered by either an agonistic anti-CD40 antibody or soluble CD40L did not induce ICOSL upregulation on human germinal centre B cells within 30 min , 4h or 8h stimulation ( XREF_FIG and XREF_FIG ) across a broad dose-range .	In contrast to mice, CD40 signalling triggered by either an agonistic anti-CD40 antibody or soluble CD40L did not induce ICOSL upregulation on human germinal centre B cells within 30 min, 4h or 8h stimulation (XREF_FIG and XREF_FIG) across a broad dose-range.	5	17	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	16	17	5	6
Genetically modified L cells that express elevated levels of CD154 ( CD40L cells ) were used to stimulate CD40 .	Genetically modified L cells that express elevated levels of CD154 (CD40L cells) were used to stimulate CD40.	11	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	11	12	18	19
Interaction of CD40 and membrane integrated CD40L can initiate bi-directional signaling : CD40L activated CD40 mediated forward signaling and CD40 activated CD40L mediated reverse signaling .	Interaction of CD40 and membrane integrated CD40L can initiate bi-directional signaling : CD40L activated CD40 mediated forward signaling and CD40 activated CD40L mediated reverse signaling.	12	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	12	13	14	15
CD19 also strengthens signals generated by the B-cell antigen receptor ( BCR ) and by CD40 , which is activated by CD40 ligand ( CD40L )-expressing T cells .	CD19 also strengthens signals generated by the B-cell antigen receptor (BCR) and by CD40, which is activated by CD40 ligand (CD40L)-expressing T cells.	4	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	24	25	15	16
In contrast to these effects , CD40 stimulation by either anti-CD40 antibodies or a recombinant soluble CD40 ligand can inhibit the growth of human breast carcinomas and aggressive histology B lymphomas in vitro and in vivo .	In contrast to these effects, CD40 stimulation by either anti-CD40 antibodies or a recombinant soluble CD40 ligand can inhibit the growth of human breast carcinomas and aggressive histology B lymphomas in vitro and in vivo.	6	18	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	16	18	6	7
Modulation of CD40L induced upregulation of CD40 in islet cells .	Modulation of CD40L induced upregulation of CD40 in islet cells.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	2	3	6	7
Studies have indicated that the interaction of the CD40-L + T lymphocytes augments the antigen presenting function of CD40 + professional antigen presenting cells ( APCs ) , which in turn stimulates interacting CD4 + and CD8 + T-cells .	Studies have indicated that the interaction of the CD40-L + T lymphocytes augments the antigen presenting function of CD40 + professional antigen presenting cells (APCs), which in turn stimulates interacting CD4 + and CD8 + T-cells.	5	19	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40-L	CD40-L	CD40-L	CD40	CD40	CD40	8	9	18	19
It results from a mutation of the CD154 gene that encodes for a T-cell membrane protein ( CD40 ligand ) , which is normally able to activate CD40 in B-cells and antigen presenting cells ( APC ) .	It results from a mutation of the CD154 gene that encodes for a T-cell membrane protein (CD40 ligand), which is normally able to activate CD40 in B-cells and antigen presenting cells (APC).	17	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	17	19	27	28
CD40L , like TNF , exists as a trimer [ XREF_BIBR ] , and therefore induces oligomerization of CD40 upon binding .	CD40L, like TNF, exists as a trimer [XREF_BIBR], and therefore induces oligomerization of CD40 upon binding.	0	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	0	1	18	19
High concentrations of CD40L stimulate CD40 , and consequently STAT enzyme system inhibits the expression ofnonstructural proteins ofHCV NS3 and NS5A and E2 core in infected human hepatocytes .	High concentrations of CD40L stimulate CD40, and consequently STAT enzyme system inhibits the expression ofnonstructural proteins ofHCV NS3 and NS5A and E2 core in infected human hepatocytes.	1	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	3	4	5	6
Antioxidant SeMet and specific ERK1/2 inhibitor ( PD98059 ) also effectively blocked CD40L induced CD40 mRNA increase .	Antioxidant SeMet and specific ERK1/2 inhibitor (PD98059) also effectively blocked CD40L induced CD40 mRNA increase.	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	12	13	14	15
As discussed above , it is well established that CD40L on activated CD4 T cells trigger B cell CD40 providing the second signal necessary for T-cell-dependent B lymphocyte activation , subsequent isotype switching , and B cell differentiation and proliferation [ XREF_BIBR - XREF_BIBR ] .	As discussed above, it is well established that CD40L on activated CD4 T cells trigger B cell CD40 providing the second signal necessary for T-cell-dependent B lymphocyte activation, subsequent isotype switching, and B cell differentiation and proliferation [XREF_BIBR - XREF_BIBR].	9	19	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	9	10	18	19
This study is based on the hypothesis that in vivo genetic modification of tumor cells to express CD40L will trigger CD40 on local antigen presenting cells to present tumor antigen to the cellular immune systems , thus eliciting anti-tumor immunity to suppress growth of the tumor .	This study is based on the hypothesis that in vivo genetic modification of tumor cells to express CD40L will trigger CD40 on local antigen presenting cells to present tumor antigen to the cellular immune systems, thus eliciting anti-tumor immunity to suppress growth of the tumor.	17	25	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	17	18	20	21
These data indicate that CD40 stimulation by CD40L promoted adhesion molecule expression .	These data indicate that CD40 stimulation by CD40L promoted adhesion molecule expression.	4	8	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	7	8	4	5
According to this model , CD40L expressing CD4 T cells activate APCs by engaging CD40 ( on APCs ) .	According to this model, CD40L expressing CD4 T cells activate APCs by engaging CD40 (on APCs).	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L expressing	cd40l	CD40	CD40	cd40	5	6	14	15
Lung cancer A549 cells were chosen as target cells and CD40 signals were stimulated by soluble CD40 ligand ( sCD40L ) .	Lung cancer A549 cells were chosen as target cells and CD40 signals were stimulated by soluble CD40 ligand (sCD40L).	10	18	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	16	18	10	11
Stimulation of CD40 by CD40L was reported as the most potent DC stimulus for IL12 production , with IFNgamma as a strong co-stimulatory signal [ XREF_BIBR ] .	Stimulation of CD40 by CD40L was reported as the most potent DC stimulus for IL12 production, with IFNgamma as a strong co-stimulatory signal [XREF_BIBR].	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	4	5	2	3
Crucial events are CD40 ligand ( CD154 ) upregulation on CD4 + helper cells , followed by DC activation through CD40 ligand triggering of CD40 on DC [ XREF_BIBR , XREF_BIBR ] .	Crucial events are CD40 ligand (CD154) upregulation on CD4 + helper cells, followed by DC activation through CD40 ligand triggering of CD40 on DC [XREF_BIBR, XREF_BIBR].	20	25	triggering	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	20	22	24	25
Thus , we suggest that EBV can persist without EBNA3A or EBNA3C expression in vivo , utilizing signals from the microenvironment of secondary lymphoid tissues , including CD40 stimulation by CD40L .	Thus, we suggest that EBV can persist without EBNA3A or EBNA3C expression in vivo, utilizing signals from the microenvironment of secondary lymphoid tissues, including CD40 stimulation by CD40L.	27	31	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	30	31	27	28
Under such stimulation conditions , T cells are activated to express CD40L , which stimulates CD40 dependent production of IL-12 by both monocytes and DCs .	Under such stimulation conditions, T cells are activated to express CD40L, which stimulates CD40 dependent production of IL-12 by both monocytes and DCs.	10	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	11	12	15	16
In addition , OVs have been armed with transgenes encoding membrane bound or soluble CD40 ligand ( CD40L ) , thereby enhancing local CD40 activation within the TME [ XREF_BIBR , XREF_BIBR ] .	In addition, OVs have been armed with transgenes encoding membrane bound or soluble CD40 ligand (CD40L), thereby enhancing local CD40 activation within the TME [XREF_BIBR, XREF_BIBR].	15	24	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	17	18	23	24
For example , T cells express RANKL and CD40L , which activate the cognate receptors RANK and CD40 in osteoclast precursors and osteoblastic cells , respectively .	For example, T cells express RANKL and CD40L, which activate the cognate receptors RANK and CD40 in osteoclast precursors and osteoblastic cells, respectively.	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	8	9	17	18
Osteosarcoma cells and Ewing ' s sarcoma cells expressing CD40 were treated with recombinant soluble CD40 ligand to analyze CD40 function .	Osteosarcoma cells and Ewing 's sarcoma cells expressing CD40 were treated with recombinant soluble CD40 ligand to analyze CD40 function.	8	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	15	17	9	10
Although CD40L mediated CD40 licensing of dendritic cells ( DCs ) by CD4 + T cells is known to be necessary for the generation of a robust CD8 + T cell response , the contribution of CD8 + T cell expressed CD40L on DC licensing is less clear .	Although CD40L mediated CD40 licensing of dendritic cells (DCs) by CD4 + T cells is known to be necessary for the generation of a robust CD8 + T cell response, the contribution of CD8 + T cell expressed CD40L on DC licensing is less clear.	1	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	1	2	3	4
While the role of CD40L induced activation of CD40 + cells in immunity and inflammation is well known , only limited data exist on the reciprocal activation of CD40L + cells .	While the role of CD40L induced activation of CD40 + cells in immunity and inflammation is well known, only limited data exist on the reciprocal activation of CD40L + cells.	2	14	induced	Positive_early_activation	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	4	5	8	9
demonstrated that CD40 inducible responses in EC , mediated by platelet CD40L , are also of functional importance in early tumor growth .	demonstrated that CD40 inducible responses in EC, mediated by platelet CD40L, are also of functional importance in early tumor growth.	2	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	11	12	2	3
In basal culture conditions , CD40 signaling could be induced by the transient establishment of inter-fibroblastic CD40 and CD40 ligand ( CD40L ) functional bridges .	In basal culture conditions, CD40 signaling could be induced by the transient establishment of inter-fibroblastic CD40 and CD40 ligand (CD40L) functional bridges.	5	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	18	20	5	6
In addition to activation by IL-4 or IL-13 , activation of CD40 by CD40 ligand on activated T cells and/or activation of BAFF-R and TACI by BAFF and APRIL are required to induce CSR and IgE production .	In addition to activation by IL-4 or IL-13, activation of CD40 by CD40 ligand on activated T cells and/or activation of BAFF-R and TACI by BAFF and APRIL are required to induce CSR and IgE production.	9	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	13	15	11	12
This demonstrates that a soluble CD40L can stimulate CD40 in a manner indistinguishable from the membrane bound form of the protein .	This demonstrates that a soluble CD40L can stimulate CD40 in a manner indistinguishable from the membrane bound form of the protein.	3	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	5	6	8	9
In vitro experiments confirmed that CD40L expressed by B cells could lead to CD40 activation and internalization on adjacent B cells .	In vitro experiments confirmed that CD40L expressed by B cells could lead to CD40 activation and internalization on adjacent B cells.	5	14	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L expressed	cd40l	CD40	CD40	cd40	5	6	13	14
The reciprocal cross-talk between dendritic cells ( DCs ) and iNKT cells involves the upregulation of CD154 ( CD40L ) that , in turn , triggers CD40 signaling in DCs , inducing their maturation and secretion of IL-12 [ XREF_BIBR ] .	The reciprocal cross-talk between dendritic cells (DCs) and iNKT cells involves the upregulation of CD154 (CD40L) that, in turn, triggers CD40 signaling in DCs, inducing their maturation and secretion of IL-12 [XREF_BIBR].	14	27	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	18	19	26	27
T cells provide proliferative and survival cues to SCs and sensitize SCs to PTH through CD40 Ligand ( CD40L ) , a surface molecule of activated T cells that induces CD40 signaling in SCs .	T cells provide proliferative and survival cues to SCs and sensitize SCs to PTH through CD40 Ligand (CD40L), a surface molecule of activated T cells that induces CD40 signaling in SCs.	16	31	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	18	19	30	31
CD40 signaling is initiated by the engagement of CD40L expressed mainly on activated T helper cells ( Th cells ) , which induces receptor trimerization .	CD40 signaling is initiated by the engagement of CD40L expressed mainly on activated T helper cells (Th cells), which induces receptor trimerization.	0	10	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L expressed	cd40l	CD40	CD40	cd40	8	9	0	1
Soluble CD40 Ligand Stimulates CD40 Dependent Activation of the beta2 Integrin Mac-1 and Protein Kinase C Zeda ( PKCzeta ) in Neutrophils : Implications for Neutrophil-Platelet Interactions and Neutrophil Oxidative Burst .	Soluble CD40 Ligand Stimulates CD40 Dependent Activation of the beta2 Integrin Mac-1 and Protein Kinase C Zeda (PKCzeta) in Neutrophils : Implications for Neutrophil-Platelet Interactions and Neutrophil Oxidative Burst.	1	6	Stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40 Ligand	CD40 Ligand	CD40 Ligand	CD40	CD40	CD40	1	3	4	5
More specifically , CD40 and CD40L signaling is suggested to increase adherence of CD40 positive cells , such as platelets and monocytes , to the vessel wall modulating atherothrombosis 27 .	More specifically, CD40 and CD40L signaling is suggested to increase adherence of CD40 positive cells, such as platelets and monocytes, to the vessel wall modulating atherothrombosis 27.	3	14	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	5	6	13	14
The role of exogenous stimulation of CD40 by CD40 ligand ( CD40L ) in dendritic cell ( DC ) maturation , CC-chemokine production , and CCR5 receptor expression was examined using a soluble trimeric CD40L agonist protein ( CD40LT ) .	The role of exogenous stimulation of CD40 by CD40 ligand (CD40L) in dendritic cell (DC) maturation, CC-chemokine production, and CCR5 receptor expression was examined using a soluble trimeric CD40L agonist protein (CD40LT).	4	10	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	8	10	6	7
CD40L induced CD40 signaling in B-cells is crucial for inducing the expression of BCL6 and Ki67 in GC B-cells , allowing the proliferation of GC B-cells in the dark zone and expression of activation induced deaminase ( AID ) , a transcription factor required for somatic hypermutation ( dark zone ) and Ig class switching ( light zone ) .	CD40L induced CD40 signaling in B-cells is crucial for inducing the expression of BCL6 and Ki67 in GC B-cells, allowing the proliferation of GC B-cells in the dark zone and expression of activation induced deaminase (AID), a transcription factor required for somatic hypermutation (dark zone) and Ig class switching (light zone).	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	0	1	2	3
These findings are in agreement with the data on anti-EpCAM : CD40L and suggest a model where binding of anti-CD20 : CD40L to the cell surface induces CD40 clustering and concomitant crosslinking of CD20 .	These findings are in agreement with the data on anti-EpCAM : CD40L and suggest a model where binding of anti-CD20 : CD40L to the cell surface induces CD40 clustering and concomitant crosslinking of CD20.	21	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	21	22	27	28
The authors demonstrated that CD4 + T cells contributed via CD40L mediated CD40 stimulation to persistence and lymphomagenesis of LMP1 deficient EBV in vivo .	The authors demonstrated that CD4 + T cells contributed via CD40L mediated CD40 stimulation to persistence and lymphomagenesis of LMP1 deficient EBV in vivo.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	10	11	12	13
Some studies have shown that in order to induce strong IL-12 responses in human and mouse DCs , both an innate trigger such as TLR ligation and a second trigger like ligation of CD40 by CD40L on T cells is needed [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Some studies have shown that in order to induce strong IL-12 responses in human and mouse DCs, both an innate trigger such as TLR ligation and a second trigger like ligation of CD40 by CD40L on T cells is needed [XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	38	induce	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	35	36	33	34
RANKL and CD40L expressed on T cells , APC , stromal cells and OB , activate the cognate receptors RANK and CD40 in OCP and OB , respectively .	RANKL and CD40L expressed on T cells, APC, stromal cells and OB, activate the cognate receptors RANK and CD40 in OCP and OB, respectively.	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L expressed	cd40l	CD40	CD40	cd40	2	3	21	22
We recently reported that CD40L mediates atherogenesis independently of CD40 and proposed Mac-1 as an alternate receptor .	We recently reported that CD40L mediates atherogenesis independently of CD40 and proposed Mac-1 as an alternate receptor.	4	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	4	5	9	10
CD40L is predominantly produced as a membrane bound protein that trimerizes upon binding to CD40 but can be cleaved and released as a soluble monomer .	CD40L is predominantly produced as a membrane bound protein that trimerizes upon binding to CD40 but can be cleaved and released as a soluble monomer.	0	18	produced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	0	1	14	15
CD40L activates CD40 thereby stimulating atherogenic immune responses .	CD40L activates CD40 thereby stimulating atherogenic immune responses.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	0	1	2	3
We demonstrated that plasma CD40L levels are positively correlated with plasma HHcy and circulating inflammatory MC in CVD and CKD subjects and that CD40L induces CD40 MC differentiation in PBMC ( XREF_FIG ) .	We demonstrated that plasma CD40L levels are positively correlated with plasma HHcy and circulating inflammatory MC in CVD and CKD subjects and that CD40L induces CD40 MC differentiation in PBMC (XREF_FIG).	23	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	23	24	25	26
CD40 pathway was activated by recombinant mouse CD40L ( mCD40L ) .	CD40 pathway was activated by recombinant mouse CD40L (mCD40L).	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	7	8	0	1
CD40 and CD40L signaling pathway is suggested to increase adherence of CD40 positive cells , such as platelets and monocytes , to the vessel wall 27 .	CD40 and CD40L signaling pathway is suggested to increase adherence of CD40 positive cells, such as platelets and monocytes, to the vessel wall 27.	2	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	2	3	11	12
The B cell surface molecule CD40 may be activated either by its ligand CD40L or by anti-CD40 antibodies .	The B cell surface molecule CD40 may be activated either by its ligand CD40L or by anti-CD40 antibodies.	2	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	13	14	5	6
Previous studies have shown that CD40L expression on mast cells in the TME promotes CD40 signaling on primary WM B cells .	Previous studies have shown that CD40L expression on mast cells in the TME promotes CD40 signaling on primary WM B cells.	5	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L expression	cd40l	CD40	CD40	cd40	5	6	14	15
Recently , we made the surprising finding that CD40L mediates atherogenesis independently of its classic receptor CD40 via a novel interaction with the leukocyte integrin Mac-1 .	Recently, we made the surprising finding that CD40L mediates atherogenesis independently of its classic receptor CD40 via a novel interaction with the leukocyte integrin Mac-1.	8	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	8	9	16	17
Herein we have examined the impact of CD40L mediated CD40 activation on HSV-1 replication in U2OS cells stably expressing the CD40 receptor .	Herein we have examined the impact of CD40L mediated CD40 activation on HSV-1 replication in U2OS cells stably expressing the CD40 receptor.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	7	8	9	10
Other studies have shown that , in order to induce strong IL-12 responses in human and mouse DCs , both an innate trigger such as TLR ligation and a second trigger like ligation of CD40 by CD40L on T cells are needed [ XREF_BIBR , XREF_BIBR ] .	Other studies have shown that, in order to induce strong IL-12 responses in human and mouse DCs, both an innate trigger such as TLR ligation and a second trigger like ligation of CD40 by CD40L on T cells are needed [XREF_BIBR, XREF_BIBR].	9	39	induce	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	36	37	34	35
Another possibility is that DCs expressing CD40L induces CD40 signaling on activated lymphocytes .	Another possibility is that DCs expressing CD40L induces CD40 signaling on activated lymphocytes.	5	9	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	6	7	8	9
The stimulation of CD40 signalling by CD40L and its derivatives can be considered as a useful adjunct in a vaccine strategy against protozoan infections .	The stimulation of CD40 signalling by CD40L and its derivatives can be considered as a useful adjunct in a vaccine strategy against protozoan infections.	3	9	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	6	7	3	4
Human and canine CD40 are 83 % similar , and amino acids predicted to be involved in CD40-CD40L binding are conserved [ XREF_BIBR , XREF_BIBR ] , suggesting an Ad5 vector expressing human CD40L may interact effectively to allow transduction of CD40 expressing canine cells .	Human and canine CD40 are 83% similar, and amino acids predicted to be involved in CD40-CD40L binding are conserved [XREF_BIBR, XREF_BIBR], suggesting an Ad5 vector expressing human CD40L may interact effectively to allow transduction of CD40 expressing canine cells.	32	42	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	33	34	41	42
CD40 stimulated by its antibody or CD40 ligand previously had been demonstrated to induce activation induced cell death in ovarian carcinoma cell lines , colon carcinoma cell lines , breast carcinoma cell lines , and lung carcinoma cell lines and to inhibit their growth in vivo .	CD40 stimulated by its antibody or CD40 ligand previously had been demonstrated to induce activation induced cell death in ovarian carcinoma cell lines, colon carcinoma cell lines, breast carcinoma cell lines, and lung carcinoma cell lines and to inhibit their growth in vivo.	0	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	6	8	0	1
To examine the effect of CD40 ligation on FAF1 expression , CD40 positive carcinomas ( EJ , AGS , Hela cells stably expressing CD40 ) and CD40 negative Hela cells ( XREF_FIG ) were each treated with recombinant soluble CD40L ( 1mug/ml ) for 20min , 2h , 4h and 6h or left untreated as a negative control .	To examine the effect of CD40 ligation on FAF1 expression, CD40 positive carcinomas (EJ, AGS, Hela cells stably expressing CD40) and CD40 negative Hela cells (XREF_FIG) were each treated with recombinant soluble CD40L (1mug/ml) for 20min, 2h, 4h and 6h or left untreated as a negative control.	1	53	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	39	40	26	27
While the expression of CD40 by CD8 + T cells has been shown to be relevant in T cell activation in some contexts , the transient nature of CD40L expression and its requirement for TCR engagement would mean that the direct activation of CD40 by CD40L expressed on another CD8 + T cells either requires the formation of a three-cell cluster of two CD8 + T cells and a DC or the direct recognition of a CD8 + T cell via TCR-cognate peptide MHC engagement by another CD8 + T cell .	While the expression of CD40 by CD8 + T cells has been shown to be relevant in T cell activation in some contexts, the transient nature of CD40L expression and its requirement for TCR engagement would mean that the direct activation of CD40 by CD40L expressed on another CD8 + T cells either requires the formation of a three-cell cluster of two CD8 + T cells and a DC or the direct recognition of a CD8 + T cell via TCR-cognate peptide MHC engagement by another CD8 + T cell.	41	46	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	45	46	43	44
These results indicate that allospecific CD8 + Ts cells generated in vitro suppress CD40L induced upregulation of CD40 in human pancreatic islet cells .	These results indicate that allospecific CD8 + Ts cells generated in vitro suppress CD40L induced upregulation of CD40 in human pancreatic islet cells.	13	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	13	14	17	18
It has been shown that the CD40 ligand and agonistic antibodies can induce endocytosis of CD40 upon binding , [ XREF_BIBR , XREF_BIBR ] which may be responsible for cellular uptake of FGK-LPSiNP in the present case .	It has been shown that the CD40 ligand and agonistic antibodies can induce endocytosis of CD40 upon binding, [XREF_BIBR, XREF_BIBR] which may be responsible for cellular uptake of FGK-LPSiNP in the present case.	6	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	6	8	15	16
The CD40L + CAR T-cells also increased the immunogenicity of CD40 + tumor cells through the upregulation of costimulatory , adhesion , and human leukocyte antigen molecules , as well as the Fas death receptor , and they induced the maturation and secretion of IL-12 by monocyte derived DCs .	The CD40L + CAR T-cells also increased the immunogenicity of CD40 + tumor cells through the upregulation of costimulatory, adhesion, and human leukocyte antigen molecules, as well as the Fas death receptor, and they induced the maturation and secretion of IL-12 by monocyte derived DCs.	0	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	1	2	10	11
CD40 is activated in response to membrane bound or soluble CD40 ligand ( CD40L ) from activated T cells to further stimulate CD40 expressing cells , thus AT inflammation [ XREF_BIBR ] .	CD40 is activated in response to membrane bound or soluble CD40 ligand (CD40L) from activated T cells to further stimulate CD40 expressing cells, thus AT inflammation [XREF_BIBR].	10	24	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	10	12	22	23
To evaluate whether target antigen selective immobilization of scFv : CD40L would augment CD40 signaling , EpCAM - CD40 - HT1080 cells and CD40 transfected HT1080 cells ( HT1080.CD40 ) were co-cultured with EpCAM + / CD40 - DLD-1 .	To evaluate whether target antigen selective immobilization of scFv : CD40L would augment CD40 signaling, EpCAM - CD40 - HT1080 cells and CD40 transfected HT1080 cells (HT1080.CD40) were co-cultured with EpCAM + / CD40 - DLD-1.	10	14	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	10	11	13	14
CD40 stimulation by its soluble recombinant human CD40 ligand directly inhibits human breast cancer cells in vitro and in SCID mice model [ XREF_BIBR ] .	CD40 stimulation by its soluble recombinant human CD40 ligand directly inhibits human breast cancer cells in vitro and in SCID mice model [XREF_BIBR].	0	9	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	7	9	0	1
XREF_BIBR CD40L stimulated CD40 expressing B cells can be expanded from small volumes of blood and have been reported to generate antitumor CD8 + T cells .	XREF_BIBR CD40L stimulated CD40 expressing B cells can be expanded from small volumes of blood and have been reported to generate antitumor CD8 + T cells.	0	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	1	2	3	4
In order to further investigate the possible biological roles of CD40 signaling triggered by CD40L , we subcloned the DNA fragment encoding the extracellular region of human CD40L into the pSK plasmid .	In order to further investigate the possible biological roles of CD40 signaling triggered by CD40L, we subcloned the DNA fragment encoding the extracellular region of human CD40L into the pSK plasmid.	10	15	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	14	15	10	11
Consequently , direct contact of a CD40L bearing cell ( e.g ., an activated CD4+ T cell ) with a CD40 bearing APC allows CD40 clustering and immune activation .	Consequently, direct contact of a CD40L bearing cell (e.g., an activated CD4+ T cell) with a CD40 bearing APC allows CD40 clustering and immune activation.	6	25	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	6	7	24	25
Some of the survival signals that are provided by inflammatory cells to the H/RS cells are the triggering of CD40 signaling by CD40L expressing rosetting T cells , activation of TACI and BCMA through production of their ligand APRIL by neutrophils , and perhaps activation of CD30 through CD30L expressing mast cells and eosinophils .	Some of the survival signals that are provided by inflammatory cells to the H/RS cells are the triggering of CD40 signaling by CD40L expressing rosetting T cells, activation of TACI and BCMA through production of their ligand APRIL by neutrophils, and perhaps activation of CD30 through CD30L expressing mast cells and eosinophils.	19	24	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD40L	CD40L expressing	cd40l	CD40	CD40	cd40	22	23	19	20
T cells that express PTH receptors may be involved in both the anabolic and catabolic actions of PTH through CD40 Ligand , a surface molecule of activated T cells that induces CD40 signaling in stromal cells .	T cells that express PTH receptors may be involved in both the anabolic and catabolic actions of PTH through CD40 Ligand, a surface molecule of activated T cells that induces CD40 signaling in stromal cells.	19	32	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CD40 Ligand	CD40 Ligand	CD40 Ligand	CD40	CD40	CD40	19	21	31	32
CD40 receptor is activated by ligand CD40L ( CD154 ) which is synthesized in inflammation by NK cells , monocytes and lymphocytes B. TRAF proteins are activated in cells by CD40 stimulation and next they stimulate different enzymatic pathways .	CD40 receptor is activated by ligand CD40L (CD154) which is synthesized in inflammation by NK cells, monocytes and lymphocytes B. TRAF proteins are activated in cells by CD40 stimulation and next they stimulate different enzymatic pathways.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	6	7	0	1
CD40 triggering by CD40L is pivotal for B-cell growth , differentiation and isotypic switch ( the process leading to the production of IgG , IgA , IgE or IgD ) as illustrated by the hyper-IgM syndrome in which mutation in the CD40L gene results in a normal or elevated IgM levels but no IgG , IgA , IgE or IgD .	CD40 triggering by CD40L is pivotal for B-cell growth, differentiation and isotypic switch (the process leading to the production of IgG, IgA, IgE or IgD) as illustrated by the hyper-IgM syndrome in which mutation in the CD40L gene results in a normal or elevated IgM levels but no IgG, IgA, IgE or IgD.	0	4	triggering	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	3	4	0	1
CD40L activates CD40 signaling in osteoblastic cells .	CD40L activates CD40 signaling in osteoblastic cells.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	0	1	2	3
In the early 1990s , studies of multiple autoimmune models , including collagen induced arthritis and lupus like disease in NZB and SWR or NZB and NZW F1 mice XREF_BIBR - XREF_BIBR , demonstrated markedly reduced signs of inflammation in mice lacking either CD40 or CD40L , or in wildtype mice treated with CD40L blocking reagents .	In the early 1990s, studies of multiple autoimmune models, including collagen induced arthritis and lupus like disease in NZB and SWR or NZB and NZW F1 mice XREF_BIBR - XREF_BIBR, demonstrated markedly reduced signs of inflammation in mice lacking either CD40 or CD40L, or in wildtype mice treated with CD40L blocking reagents.	41	54	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	53	54	43	44
Thus , we find no evidence that CD40 ligand expressing CD4 T cells are required to activate CD40 on CD8 T cells directly for the full differentiation of the cytotoxic T cell response .	Thus, we find no evidence that CD40 ligand expressing CD4 T cells are required to activate CD40 on CD8 T cells directly for the full differentiation of the cytotoxic T cell response.	7	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40 ligand	CD40 ligand expressing	cd40 ligand	CD40	CD40	cd40	7	9	17	18
In early stages of TD , deletion of CD40L diminished CD40 positive microglia and reduced the neuronal death by 64 % .	In early stages of TD, deletion of CD40L diminished CD40 positive microglia and reduced the neuronal death by 64%.	6	12	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	8	9	10	11
Under physiological conditions , CD40 is activated through engagement by trimeric CD40L .	Under physiological conditions, CD40 is activated through engagement by trimeric CD40L.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	11	12	4	5
T-cells allostimulated in vitro in the presence of ILT3-Fc inhibited CD40L induced upregulation of CD40 in human pancreatic islet cells .	T-cells allostimulated in vitro in the presence of ILT3-Fc inhibited CD40L induced upregulation of CD40 in human pancreatic islet cells.	10	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	10	11	14	15
One study used an adenovirus produced recombinant CD40L fused with IAV NP antigen ( rAD-SNP40L ) to target CD40 during IAV infection ; this treatment successfully enhanced NP specific CTL and antibody responses , reduced lung virus titers , and protected the mice from otherwise lethal IAV infection .	One study used an adenovirus produced recombinant CD40L fused with IAV NP antigen (rAD-SNP40L) to target CD40 during IAV infection; this treatment successfully enhanced NP specific CTL and antibody responses, reduced lung virus titers, and protected the mice from otherwise lethal IAV infection.	5	19	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	7	8	18	19
On exposure to autologous ILS specific T cells , B-CLL SP cells were selectively depleted from the co-culture compared to non SP cells , and their depletion was greater when the cells had been CD40 activated by CD40L ( XREF_FIG ) .	On exposure to autologous ILS specific T cells, B-CLL SP cells were selectively depleted from the co-culture compared to non SP cells, and their depletion was greater when the cells had been CD40 activated by CD40L (XREF_FIG).	28	39	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	37	38	34	35
Since EBV infected B cells can be sustained in vitro in the absence of EBNA3A and EBNA3C by CD40L mediated CD40 engagement , we suggest that the microenvironment of secondary lymphoid tissues , possibly via CD40L on CD4 + T cells , allows for the persistence of EBNA3A and EBNA3C deficient EBV after infection .	Since EBV infected B cells can be sustained in vitro in the absence of EBNA3A and EBNA3C by CD40L mediated CD40 engagement, we suggest that the microenvironment of secondary lymphoid tissues, possibly via CD40L on CD4 + T cells, allows for the persistence of EBNA3A and EBNA3C deficient EBV after infection.	7	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	18	19	20	21
Similarly , heightened CD40 signaling caused by agonistic anti-CD40 or a CD40L transgene in B cells also resulted in skewed short lived plasma cell differentiation of GC B cells accompanied by premature termination of GC reactions , compromised affinity maturation , and diminished generation of long lived plasma cells .	Similarly, heightened CD40 signaling caused by agonistic anti-CD40 or a CD40L transgene in B cells also resulted in skewed short lived plasma cell differentiation of GC B cells accompanied by premature termination of GC reactions, compromised affinity maturation, and diminished generation of long lived plasma cells.	3	12	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	11	12	3	4
G2 to M phase progression is mainly controlled by the Cdc2-cyclin B1 complex , and Cdc25C phosphatase results in activation of Cdc2 by dephosphorylation .	G2 to M phase progression is mainly controlled by the Cdc2-cyclin B1 complex, and Cdc25C phosphatase results in activation of Cdc2 by dephosphorylation.	15	22	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	15	16	21	22
A slight decrease in cyclin B was observed within 6 h of silvestrol exposure and phosphatase Cdc25C protein , which activates Cdc2 , was also decreased .	A slight decrease in cyclin B was observed within 6 h of silvestrol exposure and phosphatase Cdc25C protein, which activates Cdc2, was also decreased.	16	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	16	17	21	22
Normally Cdk1 activates Cdc25C and Cdc25C feeds back to activate Cdk1 , making it difficult to obtain intermediate levels of either Cdc25C phosphorylation or Cdk1 activity .	Normally Cdk1 activates Cdc25C and Cdc25C feeds back to activate Cdk1, making it difficult to obtain intermediate levels of either Cdc25C phosphorylation or Cdk1 activity.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	3	4	10	11
In A549 and CDDP cells , however , Cdc2 activity was supported by the expression of Cdc2 and Cdc25C after the addition of cisplatin , which resulted in G2/M progression .	In A549 and CDDP cells, however, Cdc2 activity was supported by the expression of Cdc2 and Cdc25C after the addition of cisplatin, which resulted in G2/M progression.	8	19	supported	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc25C	expression of Cdc2 and Cdc25C	cdc25c	Cdc2	Cdc2	cdc2	18	19	8	9
Cdc25C activates Cdc2 for entry into mitosis by dephosphorylating Thr and Tyr at the site of inhibitory phosphorylation .	Cdc25C activates Cdc2 for entry into mitosis by dephosphorylating Thr and Tyr at the site of inhibitory phosphorylation.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	0	1	2	3
Human cdc25C protein , a specific tyrosine phosphatase that activates the p34cdc2 protein kinase at mitosis , is itself a phosphoprotein that shows increased phosphorylation during the G2-M transition .	Human cdc25C protein, a specific tyrosine phosphatase that activates the p34cdc2 protein kinase at mitosis, is itself a phosphoprotein that shows increased phosphorylation during the G2-M transition.	1	13	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	cdc25C	cdc25C	cdc25C	p34cdc2	p34cdc2	p34cdc2	1	2	11	12
When cells cycle to the G2/M border , it is primarily the CDC25C phosphatase that removes this inhibitory phosphorylation , thus promoting activation of CDK1 and mitotic entry XREF_BIBR .	When cells cycle to the G2/M border, it is primarily the CDC25C phosphatase that removes this inhibitory phosphorylation, thus promoting activation of CDK1 and mitotic entry XREF_BIBR.	12	28	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25C	CDC25C	CDC25C	CDK1	CDK1	CDK1	12	13	24	25
This isoenzyme is able to activate CDC25c which in turn activates the CDC2 and Cyclin B1 complex leading to the import of Cyclin B1 into the nucleus ( Toyoshima-Morimoto et al , 2002 ) .	This isoenzyme is able to activate CDC25c which in turn activates the CDC2 and Cyclin B1 complex leading to the import of Cyclin B1 into the nucleus (Toyoshima-Morimoto et al, 2002).	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25c	CDC25c	CDC25c	CDC2	CDC2	CDC2	6	7	12	13
At the onset of mitosis , the protein phosphatase Cdc25C activates the Cdc2 and cyclin B1 complex by removing the inhibitory phosphate groups from Thr 14 and Tyr 15 on Cdc2 .	At the onset of mitosis, the protein phosphatase Cdc25C activates the Cdc2 and cyclin B1 complex by removing the inhibitory phosphate groups from Thr 14 and Tyr 15 on Cdc2.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	9	10	12	13
Cdc25C phosphatase in particular mediates cellular entry into mitosis by activating the Cyclin dependent kinase Cdc2 and Cyclin B1 complex XREF_BIBR , XREF_BIBR .	Cdc25C phosphatase in particular mediates cellular entry into mitosis by activating the Cyclin dependent kinase Cdc2 and Cyclin B1 complex XREF_BIBR, XREF_BIBR.	0	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	0	1	15	16
In addition , Cdc25C that activates CyclinB and Cdc2 in G2 XREF_BIBR was decreased .	In addition, Cdc25C that activates CyclinB and Cdc2 in G2 XREF_BIBR was decreased.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	3	4	8	9
In uninfected cells , the cdc25C phosphatase activates cdc2 by removing two inhibitory phosphates .	In uninfected cells, the cdc25C phosphatase activates cdc2 by removing two inhibitory phosphates.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdc25C	cdc25C	cdc25C	cdc2	cdc2	cdc2	5	6	8	9
Cdc25C and Cdc25B activate Cdk1 at the G2/M transition XREF_BIBR , XREF_BIBR .	Cdc25C and Cdc25B activate Cdk1 at the G2/M transition XREF_BIBR, XREF_BIBR.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	0	1	4	5
The second involves ERK1/2 mediated phosphorylation of Cdc25C , the protein phosphatase in Xenopus oocytes that activates the Cdk1 and cyclin B complex through removing the inhibitory phosphorylations on Cdk1 .	The second involves ERK1/2 mediated phosphorylation of Cdc25C, the protein phosphatase in Xenopus oocytes that activates the Cdk1 and cyclin B complex through removing the inhibitory phosphorylations on Cdk1.	3	22	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Cdc25C	ERK1/2 mediated phosphorylation of Cdc25C	cdc25c	Cdk1	Cdk1	cdk1	7	8	18	19
Phosphorylation of Cdc25C on Ser 287 by Chk1 and cAMP dependent protein kinase causes Cdc2 to remain inactive in G 2 -arrested oocytes through binding to 14-3-3 proteins .	Phosphorylation of Cdc25C on Ser 287 by Chk1 and cAMP dependent protein kinase causes Cdc2 to remain inactive in G 2 -arrested oocytes through binding to 14-3-3 proteins.	0	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Phosphorylation of Cdc25C on Ser 287	cdc25c	Cdc2	Cdc2	cdc2	2	3	14	15
At the onset of mitosis , the phosphatase cdc25C can activate cdc2 and cyclin B complex via dephosphorylation of these residues on cdc2 [ XREF_BIBR ] .	At the onset of mitosis, the phosphatase cdc25C can activate cdc2 and cyclin B complex via dephosphorylation of these residues on cdc2 [XREF_BIBR].	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdc25C	cdc25C	cdc25C	cdc2	cdc2	cdc2	8	9	11	12
Entry of eukaryotic cells into M-phase of cell cycle is controlled by cdc2 kinase which is activated by cdc25C and inactivated by Wee1 .	Entry of eukaryotic cells into M-phase of cell cycle is controlled by cdc2 kinase which is activated by cdc25C and inactivated by Wee1.	12	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cdc25C	cdc25C	cdc25C	cdc2	cdc2	cdc2	18	19	12	13
However , Cdc25C is not required for the observed in vitro activation of p34 cdc2 / cyclin B. Cdc25C from mitotic cells activates p34 cdc2 / cyclin B within the extract of cycloheximide treated cells , but Cdc25C of S phase arrested cells does not .	However, Cdc25C is not required for the observed in vitro activation of p34 cdc2 / cyclin B. Cdc25C from mitotic cells activates p34 cdc2 / cyclin B within the extract of cycloheximide treated cells, but Cdc25C of S phase arrested cells does not.	17	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	p34 cdc2	p34 cdc2	p34 cdc2	18	19	23	25
Cdk1 is activated by cdc25c phosphatase activity .	Cdk1 is activated by cdc25c phosphatase activity.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cdc25c	cdc25c	cdc25c	Cdk1	Cdk1	Cdk1	4	5	0	1
Cdc2 kinase is activated by the specific phosphatase Cdc25C [ XREF_BIBR , XREF_BIBR ] .	Cdc2 kinase is activated by the specific phosphatase Cdc25C [XREF_BIBR, XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	8	9	0	1
Among the most important events , it should be noted the activation of phosphatase Cdc25C ( dephosphorylation of ser216 ) , which in turn activates Cdk1 by removing inhibitory phosphate at position 15 tyrosine residues , and a significant increase in Cdk1 cofactor cyclin B1 expression .	Among the most important events, it should be noted the activation of phosphatase Cdc25C (dephosphorylation of ser216), which in turn activates Cdk1 by removing inhibitory phosphate at position 15 tyrosine residues, and a significant increase in Cdk1 cofactor cyclin B1 expression.	11	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	14	15	25	26
The protein phosphatase Cdc25C ( cell division cycle protein 25C , a highly specific phosphoprotein phosphatase ) is a critical activator of Cdk1 ( cyclin dependent kinase 1 ) , which is the master regulator of mitotic entry for eukaryotic cells .	The protein phosphatase Cdc25C (cell division cycle protein 25C, a highly specific phosphoprotein phosphatase) is a critical activator of Cdk1 (cyclin dependent kinase 1), which is the master regulator of mitotic entry for eukaryotic cells.	0	34	is a critical activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	3	4	22	23
Two phosphatases , Cdc25A and Cdc25C , dephosphorylate Tyr 15 and activate Cdk1 XREF_BIBR - XREF_BIBR .	Two phosphatases, Cdc25A and Cdc25C, dephosphorylate Tyr 15 and activate Cdk1 XREF_BIBR - XREF_BIBR.	1	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	5	6	12	13
When cells cycle to the G2/M border , it is primarily the CDC25C phosphatase that removes this inhibitory phosphorylation , thus promoting the activation of CDK1 and mitotic entry [ XREF_BIBR ] .	When cells cycle to the G2/M border, it is primarily the CDC25C phosphatase that removes this inhibitory phosphorylation, thus promoting the activation of CDK1 and mitotic entry [XREF_BIBR].	12	30	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25C	CDC25C	CDC25C	CDK1	CDK1	CDK1	12	13	25	26
In late G2 , Cdc2 is activated by Cdc25C and mitosis progresses .	In late G2, Cdc2 is activated by Cdc25C and mitosis progresses.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	8	9	4	5
Thus although the distribution of endogenous Cdc25C was not significantly affected by Vpr , altered Cdc25C-14-3-3 binding could impair Cdc25C activation of Cdk1 and prevent normal progression through mitosis .	Thus although the distribution of endogenous Cdc25C was not significantly affected by Vpr, altered Cdc25C-14-3-3 binding could impair Cdc25C activation of Cdk1 and prevent normal progression through mitosis.	19	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	19	20	22	23
Based on all of these results , we suggested that Cdc2 action was inhibited by a decrease in Cdc25C and Cdc2 expression and an increase in the association of p21 and Chk2 through p53 dependent pathway .	Based on all of these results, we suggested that Cdc2 action was inhibited by a decrease in Cdc25C and Cdc2 expression and an increase in the association of p21 and Chk2 through p53 dependent pathway.	10	22	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C and Cdc2 expression	cdc25c	Cdc2	Cdc2	cdc2	18	19	10	11
Together these data show that multisite phosphorylation of cdc25C by p34cdc2-cyclin B protein kinase occurs at the G2-M transition and is sufficient to induce the autoamplification of cdc2 and M-phase promoting factor necessary to drive somatic mammalian cells into mitosis .	Together these data show that multisite phosphorylation of cdc25C by p34cdc2-cyclin B protein kinase occurs at the G2-M transition and is sufficient to induce the autoamplification of cdc2 and M-phase promoting factor necessary to drive somatic mammalian cells into mitosis.	6	29	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdc25C	phosphorylation of cdc25C	cdc25c	cdc2	cdc2	cdc2	8	9	27	28
Wee1 could phosphorylate CDK1 at Thr14 and Tyr15 , resulting in inactivation of CDK1 ; while CDC25c could activate CDK1 by de-phosphorylation of Thr14 and Tyr15 and induces formation of the CDK1 and cyclin B1 complex , which in turn leads to M-phase transition of cell cycle XREF_BIBR , XREF_BIBR .	Wee1 could phosphorylate CDK1 at Thr14 and Tyr15, resulting in inactivation of CDK1; while CDC25c could activate CDK1 by de-phosphorylation of Thr14 and Tyr15 and induces formation of the CDK1 and cyclin B1 complex, which in turn leads to M-phase transition of cell cycle XREF_BIBR, XREF_BIBR.	16	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25c	CDC25c	CDC25c	CDK1	CDK1	CDK1	16	17	19	20
The system consists of a positive feedback loop - cyclin B-Cdk1 activates Cdc25C , which in turn activates Cdk1 - and a double negative feedback loop , in which Cdk1 inactivates Wee1A , which in turn inactivates cyclin B-Cdk1 ( XREF_FIG ) .	The system consists of a positive feedback loop - cyclin B-Cdk1 activates Cdc25C, which in turn activates Cdk1 - and a double negative feedback loop, in which Cdk1 inactivates Wee1A, which in turn inactivates cyclin B-Cdk1 (XREF_FIG).	11	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	12	13	18	19
It is possible that CDC25C overexpression , accompanied by increased phosphatase activity , could lead to CDK1 activation , eventually pushing the cell through the checkpoint barrier and acquiring genetic mutations .	It is possible that CDC25C overexpression, accompanied by increased phosphatase activity, could lead to CDK1 activation, eventually pushing the cell through the checkpoint barrier and acquiring genetic mutations.	4	17	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	CDC25C	CDC25C overexpression	cdc25c	CDK1	CDK1	cdk1	4	5	16	17
Cdc25B , but not Cdc25C , immunoprecipitated from the extract directly activated the p34 cdc2 / cyclin B of cycloheximide treated cells as well as that of nontreated cells , although Cdc25C immunoprecipitated from the extract of mitotic cells activated the p34 cdc2 / cyclin B within the extract of cycloheximide treated cells .	Cdc25B, but not Cdc25C, immunoprecipitated from the extract directly activated the p34 cdc2 / cyclin B of cycloheximide treated cells as well as that of nontreated cells, although Cdc25C immunoprecipitated from the extract of mitotic cells activated the p34 cdc2 / cyclin B within the extract of cycloheximide treated cells.	0	15	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	p34 cdc2	p34 cdc2	p34 cdc2	4	5	13	15
Furthermore , in many viruses , such as HIV Vpr and reovirus sigma1s , CDK1 inhibition by suppressing CDC25C and subsequent G 2 / M cell cycle arrest result in increased viral replication [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Furthermore, in many viruses, such as HIV Vpr and reovirus sigma1s, CDK1 inhibition by suppressing CDC25C and subsequent G 2 / M cell cycle arrest result in increased viral replication [XREF_BIBR, XREF_BIBR, XREF_BIBR].	14	21	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Positive_activation	CDC25C	CDC25C	CDC25C	CDK1	CDK1	CDK1	18	19	14	15
49 CDK1 is inactivated by Tyr15 and Thr14 phosphorylation of Wee1 and is activated by Cdc25C through dephosphorylation of Tyr15 and phosphorylation of Thr161 .	49 CDK1 is inactivated by Tyr15 and Thr14 phosphorylation of Wee1 and is activated by Cdc25C through dephosphorylation of Tyr15 and phosphorylation of Thr161.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	CDK1	CDK1	CDK1	15	16	1	2
Chk1 and Chk2 phosphorylate Cdc25C on Ser 216 and consequently induce ubiquitination induced degradation of Cdc25C , which is required to activate the mitotic kinases Cdc2 and cyclin B1 to allow entry into G 2 / M [ XREF_BIBR ] .	Chk1 and Chk2 phosphorylate Cdc25C on Ser 216 and consequently induce ubiquitination induced degradation of Cdc25C, which is required to activate the mitotic kinases Cdc2 and cyclin B1 to allow entry into G 2 / M [XREF_BIBR].	13	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	15	16	25	26
Because Cdc25C activated CDK1 via the dephosphorylation of CDK1 at Thr 14 and Tyr 15 , we concluded that reduced Cdc25C expression might weaken its ability to activate CDK1 .	Because Cdc25C activated CDK1 via the dephosphorylation of CDK1 at Thr-14 and Tyr-15, we concluded that reduced Cdc25C expression might weaken its ability to activate CDK1.	1	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	CDK1	CDK1	CDK1	1	2	3	4
Alternatively , Chk2 induces cell division cycle 25 homolog C ( cdc25C ) phosphorylation and translocation from nuclei to cytosol and , as a result , cdc25C can no longer activate CDK1 for G2/M phase progression and result in cell cycle arrest at G2/M .	Alternatively, Chk2 induces cell division cycle 25 homolog C (cdc25C) phosphorylation and translocation from nuclei to cytosol and, as a result, cdc25C can no longer activate CDK1 for G2/M phase progression and result in cell cycle arrest at G2/M.	9	37	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	cdc25C	cdc25C	cdc25C	CDK1	CDK1	CDK1	11	12	31	32
CDC2 controls cellular entry into mitosis at the G2/M transition , thereby forming complexes with CYCLINS A and B , is activated by CDC25C , and is down-regulated in late M-phase XREF_BIBR .	CDC2 controls cellular entry into mitosis at the G2/M transition, thereby forming complexes with CYCLINS A and B, is activated by CDC25C, and is down-regulated in late M-phase XREF_BIBR.	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC25C	CDC25C	CDC25C	CDC2	CDC2	CDC2	23	24	0	1
Cdc25C activates the cyclin B and Cdk1 complex to induce entry into mitosis by dephosphorylating the inhibitory phosphorylated Thr 14 and Tyr 15 residues in Cdk-1 .	Cdc25C activates the cyclin B and Cdk1 complex to induce entry into mitosis by dephosphorylating the inhibitory phosphorylated Thr 14 and Tyr 15 residues in Cdk-1.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	0	1	6	7
Failure of PP2A to dephosphorylate Cdc25C at mitosis results in prolonged hyperphosphorylation and activation of Cdc25C , causing persistent dephosphorylation and , hence , activation of Cdk1 .	Failure of PP2A to dephosphorylate Cdc25C at mitosis results in prolonged hyperphosphorylation and activation of Cdc25C, causing persistent dephosphorylation and, hence, activation of Cdk1.	4	27	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Cdc25C	dephosphorylate Cdc25C	cdc25c	Cdk1	Cdk1	cdk1	5	6	26	27
The members of this system include Cdc25B and Cdc25C phosphatases , which activate Cdk1 by dephosphorylating Tyr15 and Thr14 XREF_BIBR .	The members of this system include Cdc25B and Cdc25C phosphatases, which activate Cdk1 by dephosphorylating Tyr15 and Thr14 XREF_BIBR.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	8	9	13	14
Cdc25C , a client protein of Hsp90 , activates cdc2 .	Cdc25C, a client protein of Hsp90, activates cdc2.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	cdc2	cdc2	cdc2	0	1	9	10
Mechanistically , SL4 reduces the expression of cyclin A2 and cdc25C and decreases the activity of the cdc2 and cyclin B1 complex .	Mechanistically, SL4 reduces the expression of cyclin A2 and cdc25C and decreases the activity of the cdc2 and cyclin B1 complex.	2	21	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cdc25C	SL4 reduces the expression of cyclin A2 and cdc25C	cdc25c	cdc2	cdc2	cdc2	10	11	17	18
In the nucleus , CDC25C activates the Cyclin B and CDK1 complex to drive the cell through mitosis [ XREF_BIBR ] .	In the nucleus, CDC25C activates the Cyclin B and CDK1 complex to drive the cell through mitosis [XREF_BIBR].	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25C	CDC25C	CDC25C	CDK1	CDK1	CDK1	4	5	10	11
It is well-known that Wee1 inactivates Cdc2 kinase by phosphorylating Tyr 15 , which is removed by Cdc25C phosphatase to activate Cdc2 .	It is well-known that Wee1 inactivates Cdc2 kinase by phosphorylating Tyr 15, which is removed by Cdc25C phosphatase to activate Cdc2.	17	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	17	18	21	22
Thus , phosphatase Cdc25C is unable to activate the nuclear hyper-phosphorylated ( inactive ) CDK1 and cyclin B complex , leading to the delay in the G2/M phase transition of the cell cycle .	Thus, phosphatase Cdc25C is unable to activate the nuclear hyper-phosphorylated (inactive) CDK1 and cyclin B complex, leading to the delay in the G2/M phase transition of the cell cycle.	2	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	CDK1	CDK1	CDK1	3	4	14	15
Cdc2 is activated by the phosphatase Cdc25C .	Cdc2 is activated by the phosphatase Cdc25C.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	6	7	0	1
Plk1 promotes the activation of cyclin B1 and Cdc25C ( an activator of Cdk1 ) and subsequently triggers mitotic entry .	Plk1 promotes the activation of cyclin B1 and Cdc25C (an activator of Cdk1) and subsequently triggers mitotic entry.	3	14	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	8	9	13	14
CDC25B and CDC25C protein activate CDK1 and cyclin B complexes by dephosphorylation , allowing the CDK1 and cyclin B complex to maintain the phosphorylation of FOXM1 ( 33 ) .	CDC25B and CDC25C protein activate CDK1 and cyclin B complexes by dephosphorylation, allowing the CDK1 and cyclin B complex to maintain the phosphorylation of FOXM1 (33).	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25C	CDC25C	CDC25C	CDK1	CDK1	CDK1	2	3	5	6
Cdc25A , Cdc25B and Cdc25C in turn activate Cdk1 , Cdk2 and Cdk4 kinases causing neuronal death .	Cdc25A, Cdc25B and Cdc25C in turn activate Cdk1, Cdk2 and Cdk4 kinases causing neuronal death.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	4	5	8	9
Downstream functions of the PI3K and Akt pathway during G2/M transitions may include inhibition of the Chk1 G2 checkpoint protein or activation of cdc25C , which promotes cdc2 activation and entry into mitosis in primary oocytes from the starfish Asterina pectinifera [ XREF_BIBR ] .	Downstream functions of the PI3K and Akt pathway during G2/M transitions may include inhibition of the Chk1 G2 checkpoint protein or activation of cdc25C, which promotes cdc2 activation and entry into mitosis in primary oocytes from the starfish Asterina pectinifera [XREF_BIBR].	19	28	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdc25C	cdc25C	cdc25C	cdc2	cdc2	cdc2	23	24	27	28
RSK has been shown to phosphorylate and activate filamin , an actin binding protein , which forms a platform for the activation of Cdc2 by Cdc25C .	RSK has been shown to phosphorylate and activate filamin, an actin binding protein, which forms a platform for the activation of Cdc2 by Cdc25C.	16	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	25	26	23	24
In addition , the decreased level of cdc25C by asperolide A treatment may inhibit the action of CDC2 .	In addition, the decreased level of cdc25C by asperolide A treatment may inhibit the action of CDC2.	5	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	cdc25C	level of cdc25C	cdc25c	CDC2	CDC2	cdc2	7	8	17	18
XREF_BIBR Removal of these phosphorylations by the phosphatase Cdc25C activates Cdk1 and cyclin B1 , allowing it to phosphorylate over 300 target substrates , including those involved in chromosome condensation , nuclear envelope breakdown ( NEVB ) , and cytoskeleton reorganization , all of which drives cells into mitosis .	XREF_BIBR Removal of these phosphorylations by the phosphatase Cdc25C activates Cdk1 and cyclin B1, allowing it to phosphorylate over 300 target substrates, including those involved in chromosome condensation, nuclear envelope breakdown (NEVB), and cytoskeleton reorganization, all of which drives cells into mitosis.	4	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	8	9	10	11
Once cells commit to mitotic entry , the Cdc25C phosphatase activates Cdk1 by removing two inhibitory phosphates from Thr14 and Tyr15 [ XREF_BIBR - XREF_BIBR ] .	Once cells commit to mitotic entry, the Cdc25C phosphatase activates Cdk1 by removing two inhibitory phosphates from Thr14 and Tyr15 [XREF_BIBR - XREF_BIBR].	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C	Cdc25C	Cdk1	Cdk1	Cdk1	8	9	11	12
To delineate regulators for this observation , we ran real-time RT-PCR and found that the mRNA levels of CDK1 and CCNB1 , critical determinants of G2/M progression , as well as CDC25c , which could activate CDK1 , reduced significantly compared with control cells .	To delineate regulators for this observation, we ran real-time RT-PCR and found that the mRNA levels of CDK1 and CCNB1, critical determinants of G2/M progression, as well as CDC25c, which could activate CDK1, reduced significantly compared with control cells.	23	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25c	CDC25c	CDC25c	CDK1	CDK1	CDK1	31	32	36	37
The CDC25C phosphatase positively regulates CDK1 activity by removing the inhibitory phosphorylation at Y15 .	The CDC25C phosphatase positively regulates CDK1 activity by removing the inhibitory phosphorylation at Y15.	1	6	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	CDC25C	CDC25C	CDC25C	CDK1	CDK1	CDK1	1	2	5	6
On the other hand , Cdc25C , which is phosphorylated and thereby activated by p34 cdc2 / cyclin B , induces the full activation of p34 cdc2 by forming a positive feedback mutual activation loop .	On the other hand, Cdc25C, which is phosphorylated and thereby activated by p34 cdc2 / cyclin B, induces the full activation of p34 cdc2 by forming a positive feedback mutual activation loop.	5	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25C	Cdc25C, which is phosphorylated	cdc25c	p34 cdc2	p34 cdc2	p34 cdc2	5	6	25	27
Peterson ' s group identified a small molecule inhibitor that they named IPA-3 , by screening for inhibitors that prevented Cdc42 activation of Pak .	Peterson 's group identified a small molecule inhibitor that they named IPA-3, by screening for inhibitors that prevented Cdc42 activation of Pak.	20	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak	Pak	Pak	20	21	23	24
The Rac and Cdc42 activated PAK family of kinases play key roles in promoting integrin based adhesion turnover ( XREF_FIG ) [ XREF_BIBR ] .	The Rac and Cdc42 activated PAK family of kinases play key roles in promoting integrin based adhesion turnover (XREF_FIG) [XREF_BIBR].	1	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	3	4	5	6
B0252.1 is a putative homolog of Cla4 , a Cdc42 activated signal transducing kinase of the PAK ( p21 activated kinase ) family in S. cerevisiae that is functionally important for cell polarity generation .	B0252.1 is a putative homolog of Cla4, a Cdc42 activated signal transducing kinase of the PAK (p21 activated kinase) family in S. cerevisiae that is functionally important for cell polarity generation.	8	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	9	10	16	17
Cdc42 is active in lamellipodial regions and Rac and cdc42 activatied PAK family promotes adhesion turnover based on integrin .	Cdc42 is active in lamellipodial regions and Rac and cdc42 activatied PAK family promotes adhesion turnover based on integrin.	7	12	activatied	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cdc42	cdc42	cdc42	PAK	PAK	PAK	9	10	11	12
Our experiments with small molecule inhibitors have identified integrin signaling pathway components as well as PAK , which is targeted by RAC , RHO and CDC42 , as two of the critical components affected by GFI1B-deficiency in megakaryocytes .	Our experiments with small molecule inhibitors have identified integrin signaling pathway components as well as PAK, which is targeted by RAC, RHO and CDC42, as two of the critical components affected by GFI1B-deficiency in megakaryocytes.	7	26	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK	PAK	PAK	25	26	15	16
We provide evidence that Rac1 and Cdc42 but not Rho activity is downregulated by AZA1 in prostate cancer cells and that combined Rac1 and Cdc42 inhibition suppresses cell proliferation and activation of PAK and AKT and signaling pathways affecting the downstream cell cycle regulator Cyclin D1 and the pro apoptotic protein BAD .	We provide evidence that Rac1 and Cdc42 but not Rho activity is downregulated by AZA1 in prostate cancer cells and that combined Rac1 and Cdc42 inhibition suppresses cell proliferation and activation of PAK and AKT and signaling pathways affecting the downstream cell cycle regulator Cyclin D1 and the pro apoptotic protein BAD.	24	37	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	24	25	32	33
PAK family kinases , conserved from yeasts to humans , are directly activated by Cdc42 or Rac1 through interaction with a conserved N-terminal motif ( corresponding to residues 71 to 137 in alphaPAK ) .	PAK family kinases, conserved from yeasts to humans, are directly activated by Cdc42 or Rac1 through interaction with a conserved N-terminal motif (corresponding to residues 71 to 137 in alphaPAK).	0	16	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	14	15	0	1
Cdc42 can also activate PAK and , thus , may play a role in the NMDA dependent activation of PAK .	Cdc42 can also activate PAK and, thus, may play a role in the NMDA dependent activation of PAK.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	0	1	4	5
This findings fit nicely to previous reports in Schwann cells , showing that merlin phosphorylation and therefore inactivation occurs at paxillin containing membrane domains ( which we showed before to be the small and short living focal complexes in Schwann cells ) through PAK that has been activated by Cdc42 .	This findings fit nicely to previous reports in Schwann cells, showing that merlin phosphorylation and therefore inactivation occurs at paxillin containing membrane domains (which we showed before to be the small and short living focal complexes in Schwann cells) through PAK that has been activated by Cdc42.	21	50	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	49	50	43	44
PAK is activated by RAC1 or CDC42 and is associated with cytoskeleton reorganization .	PAK is activated by RAC1 or CDC42 and is associated with cytoskeleton reorganization.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK	PAK	PAK	6	7	0	1
The Pak ( p21 activated kinase ) family of serine/threonine kinases , which includes Pak1-6 , can be activated by , and serves as an effector for , both Rac and Cdc42 .	The Pak (p21 activated kinase) family of serine/threonine kinases, which includes Pak1-6, can be activated by, and serves as an effector for, both Rac and Cdc42.	0	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak	Pak	Pak	31	32	1	2
In that case the non phosphorylated merlin exerts a suppressor function , inhibiting cdc42 mediated activation of PAK ( Kissil et al ., 2003 ; Hirokawa et al ., 2004 ; Okada et al ., 2005 ) .	In that case the non phosphorylated merlin exerts a suppressor function, inhibiting cdc42 mediated activation of PAK (Kissil et al., 2003; Hirokawa et al., 2004; Okada et al., 2005).	13	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	cdc42	cdc42	cdc42	PAK	PAK	PAK	13	14	17	18
Although Pak is primarily activated by Rac and Cdc42 , there are additional proteins that regulate Pak activity and localization , including three AGC protein kinase family members , Akt-1 , PDK-1 , and cAMP dependent protein kinase .	Although Pak is primarily activated by Rac and Cdc42, there are additional proteins that regulate Pak activity and localization, including three AGC protein kinase family members, Akt-1, PDK-1, and cAMP dependent protein kinase.	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak	Pak	Pak	8	9	1	2
During Drosophila dorsal closure , Cdc42 activates the serine/threonine protein kinase Pak to regulate dynamic actin structure and epithelial plasticity .	During Drosophila dorsal closure, Cdc42 activates the serine/threonine protein kinase Pak to regulate dynamic actin structure and epithelial plasticity.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak	Pak	Pak	5	6	11	12
Inhibition of Cdc42 and Rac1 with clostridial toxin B inhibits PAK activation and lamellae spreading .	Inhibition of Cdc42 and Rac1 with clostridial toxin B inhibits PAK activation and lamellae spreading.	0	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	2	3	10	11
Similarly a Cdc42 specific inhibitor , AZA197 , suppressed colon cancer growth via down-regulation of PAK and ERK activities , and Cyclin D1 expression XREF_BIBR .	Similarly a Cdc42 specific inhibitor, AZA197, suppressed colon cancer growth via down-regulation of PAK and ERK activities, and Cyclin D1 expression XREF_BIBR.	2	18	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	2	3	15	16
By computed homology search , we noticed significant similarities between US3 PK and p21 activated kinase ( PAK ) , which is activated by the Cdc42 or Rac .	By computed homology search, we noticed significant similarities between US3 PK and p21 activated kinase (PAK), which is activated by the Cdc42 or Rac.	15	27	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	25	26	17	18
Additionally , the presence of the second Rac and Cdc42 paralog may activate PAK kinases , in a native or non native way , in the individual mutant strains .	Additionally, the presence of the second Rac and Cdc42 paralog may activate PAK kinases, in a native or non native way, in the individual mutant strains.	9	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	9	10	13	14
Rho family GTPases Rac and Cdc42 have been shown to enhance PAK activity by binding to p21 binding domain of PAK ( PAK-PBD ) .	Rho family GTPases Rac and Cdc42 have been shown to enhance PAK activity by binding to p21 binding domain of PAK (PAK-PBD).	3	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	5	6	11	12
Activation of the first kinase of the cascade , Ste11 , takes place at the plasma membrane through phosphorylation by its upstream activator , the PAK kinase Ste20 , which in turn is activated by the small Rho GTPase Cdc42 .	Activation of the first kinase of the cascade, Ste11, takes place at the plasma membrane through phosphorylation by its upstream activator, the PAK kinase Ste20, which in turn is activated by the small Rho GTPase Cdc42.	25	40	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	39	40	25	26
Scaffold mediated augmentation of Cdc42 GTP production by the GEF may activate PAK activity to hyper-phosphorylate and subsequently inhibit the GEF , serving as a self regulating mechanism .	Scaffold mediated augmentation of Cdc42 GTP production by the GEF may activate PAK activity to hyper-phosphorylate and subsequently inhibit the GEF, serving as a self regulating mechanism.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	4	5	12	13
Regulation of this phosphorylation process can in part be traced back to Rho family GTPases ; for example Rac or Cdc42 mediated activation of PAK kinases leads to phosphorylation and activation of LIM kinase thus increasing cofilin activity [ XREF_BIBR ] .	Regulation of this phosphorylation process can in part be traced back to Rho family GTPases; for example Rac or Cdc42 mediated activation of PAK kinases leads to phosphorylation and activation of LIM kinase thus increasing cofilin activity [XREF_BIBR].	18	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	20	21	24	25
The small GTPases Rac and Cdc42 are potent activators of PAK and are activated in response to integrin ligation .	The small GTPases Rac and Cdc42 are potent activators of PAK and are activated in response to integrin ligation.	3	11	are potent activators	Positive_activation_copula_1	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	5	6	10	11
However , the data are not definitive given that PI3K activates GEFs for the Rac and CDC42 ( cell division control 42 ) GTPases , which can activate S6K and PAK [ XREF_BIBR , XREF_BIBR ] .	However, the data are not definitive given that PI3K activates GEFs for the Rac and CDC42 (cell division control 42) GTPases, which can activate S6K and PAK [XREF_BIBR, XREF_BIBR].	16	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK	PAK	PAK	16	17	30	31
Here we show that Cdc42 mediates the activation of PAK in pT423 by phosphorylation in ALCL cells .	Here we show that Cdc42 mediates the activation of PAK in pT423 by phosphorylation in ALCL cells.	4	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	4	5	9	10
To determine if the defects in insulin stimulated GLUT4 accumulation at the cell surface in the PAK1 KO mice were related to PAK1 signaling , we employed IPA3 , an allosteric inhibitor of PAK kinase activation and signaling activity that is selectively initiated by the small GTPases Rac1 and Cdc42 [ XREF_BIBR , XREF_BIBR ] .	To determine if the defects in insulin stimulated GLUT4 accumulation at the cell surface in the PAK1 KO mice were related to PAK1 signaling, we employed IPA3, an allosteric inhibitor of PAK kinase activation and signaling activity that is selectively initiated by the small GTPases Rac1 and Cdc42 [XREF_BIBR, XREF_BIBR].	33	51	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	49	50	33	34
Pak could be stimulated by cdc42 or Rac3 , which are not reported targets of the Rac inhibitor [ XREF_BIBR ] .	Pak could be stimulated by cdc42 or Rac3, which are not reported targets of the Rac inhibitor [XREF_BIBR].	0	12	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cdc42	cdc42	cdc42	Pak	Pak	Pak	5	6	0	1
PAK binds to and is activated by both Cdc42 and Rac and has been implicated in both Cdc42 and Rac dependent changes in the actin cytoskeleton .	PAK binds to and is activated by both Cdc42 and Rac and has been implicated in both Cdc42 and Rac dependent changes in the actin cytoskeleton.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	8	9	0	1
Specifically , Rac and cdc42 could activate PAK through phosphorylation on Ser518 , which in turn inactivated NF2 to inhibit canonical Hippo signaling [ XREF_BIBR ] .	Specifically, Rac and cdc42 could activate PAK through phosphorylation on Ser518, which in turn inactivated NF2 to inhibit canonical Hippo signaling [XREF_BIBR].	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdc42	cdc42	cdc42	PAK	PAK	PAK	4	5	7	8
Our data also suggest the existence of Rho family GTPases in addition to Cdc42 and Rac1 that can activate Pak on membranes .	Our data also suggest the existence of Rho family GTPases in addition to Cdc42 and Rac1 that can activate Pak on membranes.	3	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak	Pak	Pak	13	14	19	20
Cdc42 also activates the Rac and Rho pathways as well as PAK ( p21 activated kinase ) , and activates downstream effects that lead to changes in gene expression XREF_BIBR .	Cdc42 also activates the Rac and Rho pathways as well as PAK (p21 activated kinase), and activates downstream effects that lead to changes in gene expression XREF_BIBR.	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	0	1	11	12
Feeding directly into this pathway , Rac and Cdc42 activate PAK and consecutively also LIMK .	Feeding directly into this pathway, Rac and Cdc42 activate PAK and consecutively also LIMK.	1	14	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	8	9	10	11
LIMK kinase is activated through phosphorylation by PAK which in turn is activated by Rac and Cdc42 or Rho-kinase for RhoA .	LIMK kinase is activated through phosphorylation by PAK which in turn is activated by Rac and Cdc42 or Rho-kinase for RhoA.	3	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	16	17	7	8
These data suggest that Cdc42 may not directly activate PAK or JNK .	These data suggest that Cdc42 may not directly activate PAK or JNK.	4	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	4	5	9	10
Alternatively , Rac1 and CDC42 target PAK family members , which in turn phosphorylate LIMKs ( LIM domain kinases ) , and ultimately act on the actin severing factor cofilin [ XREF_BIBR - XREF_BIBR ] .	Alternatively, Rac1 and CDC42 target PAK family members, which in turn phosphorylate LIMKs (LIM domain kinases), and ultimately act on the actin severing factor cofilin [XREF_BIBR - XREF_BIBR].	2	23	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK	PAK	PAK	4	5	6	7
Cdc42 activates Pak , which enhances the level of polymerized actin by activation of LIM-kinase leading to phosphorylation of Cofilin , and further impairment of actin depolymerization , thereby potentiating actin reorganization into stress fibers for EC migration XREF_BIBR .	Cdc42 activates Pak, which enhances the level of polymerized actin by activation of LIM-kinase leading to phosphorylation of Cofilin, and further impairment of actin depolymerization, thereby potentiating actin reorganization into stress fibers for EC migration XREF_BIBR.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak	Pak	Pak	0	1	2	3
We have previously identified a family of PP2C phosphatases , POPXs , which can dephosphorylate the CDC42 and RAC activated kinase PAK and downregulate its enzymatic and actin cytoskeletal activity .	We have previously identified a family of PP2C phosphatases, POPXs, which can dephosphorylate the CDC42 and RAC activated kinase PAK and downregulate its enzymatic and actin cytoskeletal activity.	7	22	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CDC42	PP2C phosphatases, POPXs, which can dephosphorylate the CDC42	cdc42	PAK	PAK	pak	16	17	21	22
In an in vitro kinase assay , PAK could be activated by Rac and CDC42 to a similar extent .	In an in vitro kinase assay, PAK could be activated by Rac and CDC42 to a similar extent.	7	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK	PAK	PAK	14	15	7	8
PAK is activated by the small GTPases Rac and Cdc42 , XREF_BIBR and suppressed by PAK inhibitory proteins ( ex .	PAK is activated by the small GTPases Rac and Cdc42, XREF_BIBR and suppressed by PAK inhibitory proteins (ex.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	9	10	0	1
PAK I is activated by Cdc42 ( GTP ) .	PAK I is activated by Cdc42 (GTP).	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	5	6	0	1
PAK2 is a member of the PAK proteins ( a family of serine/threonine kinases ) targeted by small GTP proteins , CDC42 and RAC1 [ XREF_BIBR , XREF_BIBR ] .	PAK2 is a member of the PAK proteins (a family of serine/threonine kinases) targeted by small GTP proteins, CDC42 and RAC1 [XREF_BIBR, XREF_BIBR].	6	22	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK	PAK	PAK	21	22	6	7
Co-expression of active Cdc42 and beta-PIX causes increased activation of the serine threonine kinase PAK , and it is possible that daRhoJ is also activating PAK , causing it to phosphorylate GIT2 .	Co-expression of active Cdc42 and beta-PIX causes increased activation of the serine threonine kinase PAK, and it is possible that daRhoJ is also activating PAK, causing it to phosphorylate GIT2.	0	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Co-expression of active Cdc42	cdc42	PAK	PAK	pak	3	4	14	15
Nef-Pak complexes also contain the GTPases Rac and Cdc42 , which might further activate Pak , as well as GTPase activators such as Vav .	Nef-Pak complexes also contain the GTPases Rac and Cdc42, which might further activate Pak, as well as GTPase activators such as Vav.	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak	Pak	Pak	8	9	14	15
Overexpression of constitutively active forms of Rac1 or Cdc42 alone in cultured cells is sufficient to activate Pak1 .	Overexpression of constitutively active forms of Rac1 or Cdc42 alone in cultured cells is sufficient to activate Pak1.	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	8	9	17	18
To test this , we have studied thrombin effects on Gab1-SHP2 activation and their involvement in Rac1 and Cdc42 mediated PAK1 stimulation in VSMCs .	To test this, we have studied thrombin effects on Gab1-SHP2 activation and their involvement in Rac1 and Cdc42 mediated PAK1 stimulation in VSMCs.	14	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	18	19	20	21
The Cdc42 phenotype can be reverted by expression of a transgene encoding a constitutively active PAK1 , which is directly activated by Cdc42 [ XREF_BIBR ] .	The Cdc42 phenotype can be reverted by expression of a transgene encoding a constitutively active PAK1, which is directly activated by Cdc42 [XREF_BIBR].	11	24	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	22	23	15	16
The small GTPases RHOA , RAC1 , and CDC42 are documented to activate kinases ROCK1 and PAK1 , which are both part of the gastrin regulated Rho GTPase module , and of kinase AKT1 , part of the gastrin regulated AKT1 signaling module .	The small GTPases RHOA, RAC1, and CDC42 are documented to activate kinases ROCK1 and PAK1, which are both part of the gastrin regulated Rho GTPase module, and of kinase AKT1, part of the gastrin regulated AKT1 signaling module.	3	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK1	PAK1	PAK1	8	9	16	17
To separate activation of Pak1 by Cdc42 versus activation by Rac , we devised a genetic screen in yeast that enabled us to create and identify Pak1 mutants that selectively couple to Cdc42 but not Rac1 .	To separate activation of Pak1 by Cdc42 versus activation by Rac, we devised a genetic screen in yeast that enabled us to create and identify Pak1 mutants that selectively couple to Cdc42 but not Rac1.	2	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	6	7	4	5
In multiple cell systems , the Rho GTPase Rac1/2 and Cdc42 bind to and modulate the activation of Pak1 through an N-terminal p21 GTPase-binding-domain ( PBD ) [ XREF_BIBR ] .	In multiple cell systems, the Rho GTPase Rac1/2 and Cdc42 bind to and modulate the activation of Pak1 through an N-terminal p21 GTPase-binding-domain (PBD) [XREF_BIBR].	8	19	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	10	11	18	19
Second , we show that by binding Pak1 , IPA-3 prevents binding of the Pak1 activator Cdc42 , thus providing a mechanistic explanation for how IPA-3 inhibits Pak1 activation .	Second, we show that by binding Pak1, IPA-3 prevents binding of the Pak1 activator Cdc42, thus providing a mechanistic explanation for how IPA-3 inhibits Pak1 activation.	11	17	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	16	17	14	15
Because PAK1 can also be activated by Rac and Cdc42 , we asked whether these GTPases contributed to the CIB1 induced PAK1 activation that was observed in cells adherent to FN .	Because PAK1 can also be activated by Rac and Cdc42, we asked whether these GTPases contributed to the CIB1 induced PAK1 activation that was observed in cells adherent to FN.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	9	10	1	2
Wong and colleagues have proposed a working model in which SLIT-ROBO signaling increases SRGAP2 activity , which in turn , inactivates CDC42 in its GDP bound form and thus would be unable to activate PAK1 .	Wong and colleagues have proposed a working model in which SLIT-ROBO signaling increases SRGAP2 activity, which in turn, inactivates CDC42 in its GDP bound form and thus would be unable to activate PAK1.	21	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK1	PAK1	PAK1	21	22	34	35
Altogether , these results suggest that Rac and Cdc42 may mediate PAK1 dependent signaling in a manner temporally distinct from that of CIB1 and that this temporal and spatial regulation of the interaction of PAK1 with different upstream activators can ultimately affect the coupling of PAK1 to specific downstream signaling components .	Altogether, these results suggest that Rac and Cdc42 may mediate PAK1 dependent signaling in a manner temporally distinct from that of CIB1 and that this temporal and spatial regulation of the interaction of PAK1 with different upstream activators can ultimately affect the coupling of PAK1 to specific downstream signaling components.	6	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	8	9	11	12
Similarly , PAK1/2 phosphorylation was also dose-dependently and significantly reduced up to 72.8 +/-15.8 % ( P < 0.014 ) on AZA197 treatment of HT-29 cells without influencing total PAK protein expression ( Additional file XREF_SUPPLEMENTARY : Figure S4B ) , indicating that Cdc42 inhibition blocks the PAK1 signaling pathway in these colon cancer cells .	Similarly, PAK1/2 phosphorylation was also dose-dependently and significantly reduced up to 72.8 +/-15.8% (P < 0.014) on AZA197 treatment of HT-29 cells without influencing total PAK protein expression (Additional file XREF_SUPPLEMENTARY : Figure S4B), indicating that Cdc42 inhibition blocks the PAK1 signaling pathway in these colon cancer cells.	43	49	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	43	44	47	48
Cdc42 activation and membrane-enrichment of Pak1 are independent signals controlling the timing and spatial extent of aCC dendritogenesis , respectively .	Cdc42 activation and membrane-enrichment of Pak1 are independent signals controlling the timing and spatial extent of aCC dendritogenesis, respectively.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	0	1	5	6
Binding to GTP loaded Cdc42 activates Pak1 , by dissociating the dimer and freeing the kinase domain from the inhibitory switch domain and kinase inhibitory segment .	Binding to GTP loaded Cdc42 activates Pak1, by dissociating the dimer and freeing the kinase domain from the inhibitory switch domain and kinase inhibitory segment.	0	7	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	4	5	6	7
This result suggests that Cdc42 may activate Pak1 kinase activity to maintain apical identity in epithelial cells .	This result suggests that Cdc42 may activate Pak1 kinase activity to maintain apical identity in epithelial cells.	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	4	5	7	8
We review here a novel concept in the regulation of cardiac contractility involving variations in the activity of the multifunctional enzyme , p21 activated kinase 1 ( Pak1 ) , a member of a family of proteins in the small G protein signaling pathway that is activated by Cdc42 and Rac1 .	We review here a novel concept in the regulation of cardiac contractility involving variations in the activity of the multifunctional enzyme, p21 activated kinase 1 (Pak1), a member of a family of proteins in the small G protein signaling pathway that is activated by Cdc42 and Rac1.	24	50	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	48	49	27	28
The allosteric inhibitors identified in the present study suppressed the activity of PAK1 T423E ( XREF_FIG ) and also the Cdc42 dependent ( XREF_FIG ) and sorbitol induced ( XREF_FIG ) activation of Wt-PAK1 .	The allosteric inhibitors identified in the present study suppressed the activity of PAK1 T423E (XREF_FIG) and also the Cdc42 dependent (XREF_FIG) and sorbitol induced (XREF_FIG) activation of Wt-PAK1.	10	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Wt-PAK1	Wt-PAK1	Wt-PAK1	20	21	33	34
Phospho-PAK1 immunostaining confirmed that constitutively active CDC42 is not able to reverse the reduced phospho-PAK1 staining in the membrane of HUVECs with elevated miR302-367 expression , but significantly increased the staining when high KLF2 level was inhibited by siRNA .	Phospho-PAK1 immunostaining confirmed that constitutively active CDC42 is not able to reverse the reduced phospho-PAK1 staining in the membrane of HUVECs with elevated miR302-367 expression, but significantly increased the staining when high KLF2 level was inhibited by siRNA.	5	28	reverse	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	phospho-PAK1	phospho-PAK1	phospho-PAK1	6	7	14	15
PAK1 can be activated by Rac and Cdc42 proteins , yet the morphology of PAK1 -/- macrophages is similar to Wt macrophages and does not resemble that of macrophages lacking Rac1 and Rac2 , which have elongated narrow protrusions .	PAK1 can be activated by Rac and Cdc42 proteins, yet the morphology of PAK1 -/- macrophages is similar to Wt macrophages and does not resemble that of macrophages lacking Rac1 and Rac2, which have elongated narrow protrusions.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	7	8	0	1
Thus Cdc42 and Rac1 activation of Pak1 can be explained by the partial overlap of the latter ' s GDB ( residues 75-118 ) and the dimerization segment and inhibitory switch domain .	Thus Cdc42 and Rac1 activation of Pak1 can be explained by the partial overlap of the latter 's GDB (residues 75-118) and the dimerization segment and inhibitory switch domain.	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	1	2	6	7
Initially , we investigated their ability to suppress the Cdc42 dependent activation of full-length PAK1 .	Initially, we investigated their ability to suppress the Cdc42 dependent activation of full-length PAK1.	9	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	9	10	14	15
Recent studies revealed that the Rho family GTPases Cdc42 and Chp target their downstream effector protein PAK1 for proteasomal degradation .	Recent studies revealed that the Rho family GTPases Cdc42 and Chp target their downstream effector protein PAK1 for proteasomal degradation.	4	19	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	8	9	16	17
XREF_BIBR - XREF_BIBR PAK1 activation by Rac1 and Cdc42 has been well established and biochemically characterized , XREF_BIBR but this simple Rac1 and Cdc42-PAK 1 pathway explains only very partially the spatiotemporal regulation and the multiple cellular roles of PAK1 .	XREF_BIBR - XREF_BIBR PAK1 activation by Rac1 and Cdc42 has been well established and biochemically characterized, XREF_BIBR but this simple Rac1 and Cdc42-PAK 1 pathway explains only very partially the spatiotemporal regulation and the multiple cellular roles of PAK1.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	8	9	3	4
Furthermore , transfection of dominant negative Cdc42 and Rac1 inhibited 12-HETE-induced PAK1 , strongly suggesting that Cdc42 and Rac1 are the upstream activators of 12-HETE-induced PAK1 activation .	Furthermore, transfection of dominant negative Cdc42 and Rac1 inhibited 12-HETE-induced PAK1, strongly suggesting that Cdc42 and Rac1 are the upstream activators of 12-HETE-induced PAK1 activation.	2	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	6	7	11	12
To our surprise , constitutively active CDC42 was not able to fully reverse the reduction of PAK1 activation in miR302-367 highly expressing ECs , which indicating that other signaling molecule besides CDC42 might be involved in the disturbed PAK1/LIM-kinase/Cofilin pathway in ECs with elevated miR302-367 expression .	To our surprise, constitutively active CDC42 was not able to fully reverse the reduction of PAK1 activation in miR302-367 highly expressing ECs, which indicating that other signaling molecule besides CDC42 might be involved in the disturbed PAK1/LIM-kinase/Cofilin pathway in ECs with elevated miR302-367 expression.	5	17	reverse	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK1	PAK1	PAK1	6	7	16	17
E-Syt2 modulates activation of PAK1 by Cdc42 and Rac .	E-Syt2 modulates activation of PAK1 by Cdc42 and Rac.	1	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	6	7	4	5
Dominant negative Ras , Rac , and Cdc42 suppressed PAK1 activation whereas activated Rac1 and Cdc42 were able to stimulate PAK1 even in the absence of any agonists [ XREF_BIBR ] .	Dominant negative Ras, Rac, and Cdc42 suppressed PAK1 activation whereas activated Rac1 and Cdc42 were able to stimulate PAK1 even in the absence of any agonists [XREF_BIBR].	13	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	15	16	20	21
These mediators in turn trigger the activation of PAK1 by Cdc42 and Rac1 [ XREF_BIBR ] .	These mediators in turn trigger the activation of PAK1 by Cdc42 and Rac1 [XREF_BIBR].	6	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	10	11	8	9
Pak-1 is activated by the Rac , Rho , and Cdc42 small GTPases in response to a variety of stimuli including ras and phosphatidylinositol 3 '-kinase/AKT pathway activation .	Pak-1 is activated by the Rac, Rho, and Cdc42 small GTPases in response to a variety of stimuli including ras and phosphatidylinositol 3 '-kinase/AKT pathway activation.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak-1	Pak-1	Pak-1	10	11	0	1
However , with extended adhesion to FN , PAK1 activation in control cells was sensitive to both toxin B and DN Rac and Cdc42 , implicating a role for Rac- and Cdc42 mediated PAK1 activation at these later time points .	However, with extended adhesion to FN, PAK1 activation in control cells was sensitive to both toxin B and DN Rac and Cdc42, implicating a role for Rac- and Cdc42 mediated PAK1 activation at these later time points.	27	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	31	32	33	34
While the classical stress activated signalling pathway activation of p38 MAPK regulates Hsp27 after heat-shock and other stresses , it is more likely that activation of p38 MAPK is downstream of the Cdc-42 and Rac activation of Pak1 with respect to neurite initiation and growth .	While the classical stress activated signalling pathway activation of p38 MAPK regulates Hsp27 after heat-shock and other stresses, it is more likely that activation of p38 MAPK is downstream of the Cdc-42 and Rac activation of Pak1 with respect to neurite initiation and growth.	32	44	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Cdc-42	Cdc-42	Cdc-42	Pak1	Pak1	Pak1	32	33	37	38
We show that Cdc42 can induce an open configuration of Pak1 .	We show that Cdc42 can induce an open configuration of Pak1.	3	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	3	4	10	11
Given that sustained insulin secretion has been correlated with glucose induced filamentous actin ( F-actin ) remodeling , we tested the hypothesis that a Cdc42 activated PAK1 signaling cascade is required to elicit F-actin remodeling to mobilize granules to the cell surface .	Given that sustained insulin secretion has been correlated with glucose induced filamentous actin (F-actin) remodeling, we tested the hypothesis that a Cdc42 activated PAK1 signaling cascade is required to elicit F-actin remodeling to mobilize granules to the cell surface.	23	28	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	24	25	26	27
In addition , the Wnt-1 responsive Cdc42 homolog , an atypical small Rho GTPase regulated by Wnt-1 signaling , also activates PAK1 .	In addition, the Wnt-1 responsive Cdc42 homolog, an atypical small Rho GTPase regulated by Wnt-1 signaling, also activates PAK1.	6	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	6	7	21	22
Interestingly , both Duo and Cdc42 activate PAK1 , leading to cytoskeletal rearrangement through two downstream pathways .	Interestingly, both Duo and Cdc42 activate PAK1, leading to cytoskeletal rearrangement through two downstream pathways.	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	5	6	7	8
The amount of ~ 70-kD band detected by the antiphospho-Pak in lysates from COS cells cotransfected with Pak1 plus wild-type Cdc42 ( XREF_FIG B , lane 1 ) is dramatically less than that detected from cells cotransfected with Pak1 and activated Cdc42 ( XREF_FIG B , lane 2 ) , consistent with the well established fact that Cdc42 must be activated in order to activate Pak1 .	The amount of ~ 70-kD band detected by the antiphospho-Pak in lysates from COS cells cotransfected with Pak1 plus wild-type Cdc42 (XREF_FIG B, lane 1) is dramatically less than that detected from cells cotransfected with Pak1 and activated Cdc42 (XREF_FIG B, lane 2), consistent with the well established fact that Cdc42 must be activated in order to activate Pak1.	57	66	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	57	58	65	66
Because Cdc42 and Duo activate PAK1 directly and indirectly , respectively , we next sought to determine if decreased expression of these proteins is in turn associated with diminished activation of PAK1 .	Because Cdc42 and Duo activate PAK1 directly and indirectly, respectively, we next sought to determine if decreased expression of these proteins is in turn associated with diminished activation of PAK1.	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	1	2	5	6
We review here emerging evidence indicating that p21 activated kinase-1 ( Pak1 ) , a serine/threonine protein kinase directly activated by Cdc42 and Rac1 is an important signaling molecule potentially involved in major cardiac processes regulating excitation and contraction in healthy and disordered hearts .	We review here emerging evidence indicating that p21 activated kinase-1 (Pak1), a serine/threonine protein kinase directly activated by Cdc42 and Rac1 is an important signaling molecule potentially involved in major cardiac processes regulating excitation and contraction in healthy and disordered hearts.	7	23	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	p21 activated kinase-1	p21 activated kinase-1	p21 activated kinase-1	21	22	7	10
Pak1 is activated by Cdc42 and Rac1 , members of the small GTPase family , and , in turn phosphorylates a wide range of targets with diverse functions .	Pak1 is activated by Cdc42 and Rac1, members of the small GTPase family, and, in turn phosphorylates a wide range of targets with diverse functions.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	4	5	0	1
It has recently been demonstrated that the stimulation of p21 activated kinase ( Pak1 ) , which is activated by the small Rho GTPases Rac1 and Cdc42 , is protective during I/R-injury [ XREF_BIBR , XREF_BIBR ] .	It has recently been demonstrated that the stimulation of p21 activated kinase (Pak1), which is activated by the small Rho GTPases Rac1 and Cdc42, is protective during I/R-injury [XREF_BIBR, XREF_BIBR].	11	27	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	26	27	13	14
Further study showed that inhibition of KLF2 upregulation in miR302-367 mutant HUVECs by siRNA abolished the GRB2 blockage , resulting in more GRB2 bringing PAK1 to the cell membrane where active CDC42 led to PAK1 activation , and in turn LIM-kinase Cofilin to prevent F-actin degradation , which might be responsible for the reversal of impaired cell motility with elevated miR302-367 expression in ECs .	Further study showed that inhibition of KLF2 upregulation in miR302-367 mutant HUVECs by siRNA abolished the GRB2 blockage, resulting in more GRB2 bringing PAK1 to the cell membrane where active CDC42 led to PAK1 activation, and in turn LIM-kinase Cofilin to prevent F-actin degradation, which might be responsible for the reversal of impaired cell motility with elevated miR302-367 expression in ECs.	30	43	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK1	PAK1	PAK1	31	32	34	35
Auto-phosphorylation induced by sphingosine-1 occurs at the same sites as those on Pak1 stimulated by Cdc42 and Rac1 .	Auto-phosphorylation induced by sphingosine-1 occurs at the same sites as those on Pak1 stimulated by Cdc42 and Rac1.	10	17	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	15	16	12	13
Interactions of the small GTPases CDC42 and RAC1 with HIV protein Nef activates the p21 activated kinase 1 PAK1 XREF_BIBR , XREF_BIBR , a factor that is critical for efficient viral replication and pathogenesis .	Interactions of the small GTPases CDC42 and RAC1 with HIV protein Nef activates the p21 activated kinase 1 PAK1 XREF_BIBR, XREF_BIBR, a factor that is critical for efficient viral replication and pathogenesis.	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK1	PAK1	PAK1	5	6	18	19
32 P labeled ATP was readily incorporated into BAD when Pak1 was activated by Cdc42 L61 ( XREF_FIG , lanes 1 ) but only a small amount of 32 P-ATP was incorporated into BAD without Cdc42 L61 ( XREF_FIG , lanes 6 ) .	32 P labeled ATP was readily incorporated into BAD when Pak1 was activated by Cdc42 L61 (XREF_FIG, lanes 1) but only a small amount of 32 P-ATP was incorporated into BAD without Cdc42 L61 (XREF_FIG, lanes 6).	10	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	14	15	10	11
Interestingly , activation of PAK1 by co-expression of cdc42 stimulated SRC-3Delta4 localization to the tip of the filopodia in HeLa cells ( the middle image , XREF_SUPPLEMENTARY ) .	Interestingly, activation of PAK1 by co-expression of cdc42 stimulated SRC-3Delta4 localization to the tip of the filopodia in HeLa cells (the middle image, XREF_SUPPLEMENTARY).	2	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	cdc42	co-expression of cdc42	cdc42	PAK1	PAK1	pak1	8	9	4	5
Similarly , PAK1/2 phosphorylation at serine 144/141 was also dose-dependently and significantly reduced up to 52.4 +/-15.1 % ( p < 0.05 ) and 48.1 +/-11.5 % ( p < 0.04 ) , respectively , on AZA1 treatment of EGF stimulated DU 145 and PC-3 cells ( XREF_SUPPLEMENTARY ) , indicating that Rac1 and Cdc42 inhibition blocks the PAK1 signaling pathway in these prostate cancer cells .	Similarly, PAK1/2 phosphorylation at serine 144/141 was also dose-dependently and significantly reduced up to 52.4 +/-15.1% (p < 0.05) and 48.1 +/-11.5% (p < 0.04), respectively, on AZA1 treatment of EGF stimulated DU 145 and PC-3 cells (XREF_SUPPLEMENTARY), indicating that Rac1 and Cdc42 inhibition blocks the PAK1 signaling pathway in these prostate cancer cells.	52	60	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	54	55	58	59
Therefore , the p21 ras related protein CDC42 and Rac1 likely activate a downstream serine/threonine protein kinase in the MAPK and ERK pathway , such as B-RAF or RAF1 , by activating the kinase PAK1 as previously reported in mammalian cells XREF_BIBR , XREF_BIBR .	Therefore, the p21 ras related protein CDC42 and Rac1 likely activate a downstream serine/threonine protein kinase in the MAPK and ERK pathway, such as B-RAF or RAF1, by activating the kinase PAK1 as previously reported in mammalian cells XREF_BIBR, XREF_BIBR.	2	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK1	PAK1	PAK1	7	8	34	35
Under extracellular stimulation , GTPase , Rac1 , and Cdc42 activate Pak1 [ XREF_BIBR ] and these proteins trigger the active rearrangement of the actin cytoskelton and lead to macropinocytosis [ XREF_BIBR ] .	Under extracellular stimulation, GTPase, Rac1, and Cdc42 activate Pak1 [XREF_BIBR] and these proteins trigger the active rearrangement of the actin cytoskelton and lead to macropinocytosis [XREF_BIBR].	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak1	Pak1	Pak1	9	10	11	12
Many studies have demonstrated that Rac1 and Cdc42 target PAK1 in the mediation of cell migration .	Many studies have demonstrated that Rac1 and Cdc42 target PAK1 in the mediation of cell migration.	3	10	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	7	8	9	10
At the end of G2 phase of cell cycle , CDC25B from the nucleus translocates to the cytoplasm , where it activates CDK1 and cyclinB .	At the end of G2 phase of cell cycle, CDC25B from the nucleus translocates to the cytoplasm, where it activates CDK1 and cyclinB.	10	24	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CDC25B	CDC25B from the nucleus translocates to the cytoplasm	cdc25b	CDK1	CDK1	cdk1	10	11	22	23
Cyclin B1-Cdk1 is involved in the early events of mitosis and Cdc25B activates Cdc2 entrying into mitosis [ XREF_BIBR ] .	Cyclin B1-Cdk1 is involved in the early events of mitosis and Cdc25B activates Cdc2 entrying into mitosis [XREF_BIBR].	7	14	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdc25B	Cdc25B	Cdc25B	Cdc2	Cdc2	Cdc2	11	12	13	14
We obtained the same result when we expressed CDC25B , the phosphatase that activates Cdk1 and CycB in mouse oocytes ( XREF_SUPPLEMENTARY ) .	We obtained the same result when we expressed CDC25B, the phosphatase that activates Cdk1 and CycB in mouse oocytes (XREF_SUPPLEMENTARY).	7	19	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	Cdk1	Cdk1	Cdk1	8	9	14	15
Cyclin B1-Cdk1 is involved in the early events of mitosis , and CDC25B activates the cyclin dependent kinase CDC2 for entry into mitosis [ XREF_BIBR ] .	Cyclin B1-Cdk1 is involved in the early events of mitosis, and CDC25B activates the cyclin dependent kinase CDC2 for entry into mitosis [XREF_BIBR].	12	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDC2	CDC2	CDC2	12	13	18	19
CDC25B activates the cyclin dependent kinase cdc2 for entry into mitosis [ XREF_BIBR ] .	CDC25B activates the cyclin dependent kinase cdc2 for entry into mitosis [XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	cdc2	cdc2	cdc2	0	1	6	7
Cdc25B activates the cyclin dependent kinase Cdc2 for entry into mitosis [ XREF_BIBR , XREF_BIBR ] .	Cdc25B activates the cyclin dependent kinase Cdc2 for entry into mitosis [XREF_BIBR, XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25B	Cdc25B	Cdc25B	Cdc2	Cdc2	Cdc2	0	1	6	7
We also found that inactive Cdk1 is caused by the sustained inactivation of CDC25B , which removes the inhibitory phosphate from Cdk1 .	We also found that inactive Cdk1 is caused by the sustained inactivation of CDC25B, which removes the inhibitory phosphate from Cdk1.	4	16	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	Cdk1	Cdk1	Cdk1	13	14	5	6
A positive feedback model between FOXM1 and CDC25B has been proposed in which CDC25B phosphatase is a direct target for FOXM1 transcriptional activation XREF_BIBR , CDC25B protein activates CDK2 and cyclin E or CDK1 and cyclin B complexes through dephosphorylation , and the activation of CDK and cyclin complexes maintains phosphorylation of FOXM1 XREF_BIBR .	A positive feedback model between FOXM1 and CDC25B has been proposed in which CDC25B phosphatase is a direct target for FOXM1 transcriptional activation XREF_BIBR, CDC25B protein activates CDK2 and cyclin E or CDK1 and cyclin B complexes through dephosphorylation, and the activation of CDK and cyclin complexes maintains phosphorylation of FOXM1 XREF_BIBR.	25	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDK1	CDK1	CDK1	25	26	33	34
The mechanism of resistance to HCC proliferation was associated with nuclear accumulation of the cell-cycle inhibitor p27 Kip1 and reduced expression of the Cdk1 activator Cdc25B phosphatase [ XREF_BIBR ] .	The mechanism of resistance to HCC proliferation was associated with nuclear accumulation of the cell-cycle inhibitor p27 Kip1 and reduced expression of the Cdk1 activator Cdc25B phosphatase [XREF_BIBR].	23	28	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Cdc25B	Cdc25B	Cdc25B	Cdk1	Cdk1	Cdk1	25	26	23	24
Here we demonstrate biochemically that cdc2 and cyclin B1 accumulates at the centrosome in late G2 as the inactive , phosphotyrosine 15 form and that the centrosomal cdc2 and cyclin B1 can be activated in vitro by recombinant cdc25B .	Here we demonstrate biochemically that cdc2 and cyclin B1 accumulates at the centrosome in late G2 as the inactive, phosphotyrosine 15 form and that the centrosomal cdc2 and cyclin B1 can be activated in vitro by recombinant cdc25B.	25	39	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cdc25B	cdc25B	cdc25B	cdc2	cdc2	cdc2	38	39	27	28
Second , CDC25B activates the mitotic kinase CDK1 and cyclin B complex in the cytoplasm to stimulate cell cycle progression [ XREF_BIBR ] .	Second, CDC25B activates the mitotic kinase CDK1 and cyclin B complex in the cytoplasm to stimulate cell cycle progression [XREF_BIBR].	2	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDK1	CDK1	CDK1	2	3	7	8
Overexpression of Cdc25A or Cdc25B promotes earlier assembly and activation of Cdk1-cyclin B complexes , whereas repression of these phosphatases by short hairpin RNA has a reverse effect , leading to a substantial decrease in amounts of cyclin B bound Cdk1 in G ( 2 ) and mitosis .	Overexpression of Cdc25A or Cdc25B promotes earlier assembly and activation of Cdk1-cyclin B complexes, whereas repression of these phosphatases by short hairpin RNA has a reverse effect, leading to a substantial decrease in amounts of cyclin B bound Cdk1 in G (2) and mitosis.	0	47	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25B	Overexpression of Cdc25A or Cdc25B	cdc25b	Cdk1	Cdk1	cdk1	4	5	40	41
XREF_BIBR , XREF_BIBR It is well known that CDK1 can be activated by CDC25B through dephosphorylation at its Thr14 and Tyr15 site , 34 but it is unclear whether other molecules are involved in this process .	XREF_BIBR, XREF_BIBR It is well known that CDK1 can be activated by CDC25B through dephosphorylation at its Thr14 and Tyr15 site, 34 but it is unclear whether other molecules are involved in this process.	8	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDK1	CDK1	CDK1	13	14	8	9
In contrast , when the cellular miR-UL148D level in NR-1DeltamiR-UL148D-infected Kasumi-3 cells was increased by transfecting the cells with the miR-UL148D agomir , the CDC25B level increased , while the p-CDK ( Tyr15 ) level decreased ( XREF_FIG ) , supporting that hcmv-miR-UL-148D activates CDK1 through upregulating CDC25B .	In contrast, when the cellular miR-UL148D level in NR-1DeltamiR-UL148D-infected Kasumi-3 cells was increased by transfecting the cells with the miR-UL148D agomir, the CDC25B level increased, while the p-CDK (Tyr15) level decreased (XREF_FIG), supporting that hcmv-miR-UL-148D activates CDK1 through upregulating CDC25B.	24	45	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B level	cdc25b	CDK1	CDK1	cdk1	24	25	44	45
Moreover , cytoplasmic CDC25B may mediate the activation of centrosomal CDK1 ( CDC2 ) in late prophase [ XREF_BIBR ] .	Moreover, cytoplasmic CDC25B may mediate the activation of centrosomal CDK1 (CDC2) in late prophase [XREF_BIBR].	2	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDK1	CDK1	CDK1	3	4	10	11
CDC25B , a phosphatase that activates the cyclin dependent kinase CDC2 , was upregulated in NED DTC .	CDC25B, a phosphatase that activates the cyclin dependent kinase CDC2, was upregulated in NED DTC.	0	13	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDC2	CDC2	CDC2	0	1	10	11
Cdc25B dephosphorylate and activate CDK2 and cyclin A and Cdc2 and cyclin B , whereas , Cdc25C dephosphorylates and activates Cdc2 and cyclin B mitotic kinase complex and thereby permits cell entry into mitosis XREF_BIBR , XREF_BIBR .	Cdc25B dephosphorylate and activate CDK2 and cyclin A and Cdc2 and cyclin B, whereas, Cdc25C dephosphorylates and activates Cdc2 and cyclin B mitotic kinase complex and thereby permits cell entry into mitosis XREF_BIBR, XREF_BIBR.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25B	Cdc25B	Cdc25B	Cdc2	Cdc2	Cdc2	0	1	9	10
CDC25B has been demonstrated to activate the complex of CDK1 and Cyclin B and trigger mitosis .	CDC25B has been demonstrated to activate the complex of CDK1 and Cyclin B and trigger mitosis.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDK1	CDK1	CDK1	0	1	9	10
It was reported that CDC25B protein activates CDK1 and cyclin B complexes by dephosphorylation , allowing the CDK1 and cyclin B complex to maintain phosphorylation of FOXM1 , while activated FOXM1 allows transcription regulation of genes required to mediate the cell cycle transition ( 33 ) .	It was reported that CDC25B protein activates CDK1 and cyclin B complexes by dephosphorylation, allowing the CDK1 and cyclin B complex to maintain phosphorylation of FOXM1, while activated FOXM1 allows transcription regulation of genes required to mediate the cell cycle transition (33).	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDK1	CDK1	CDK1	4	5	7	8
Cdc25B activates the cyclin dependent kinase Cdc2 for entry into mitosis [ XREF_BIBR ] .	Cdc25B activates the cyclin dependent kinase Cdc2 for entry into mitosis [XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25B	Cdc25B	Cdc25B	Cdc2	Cdc2	Cdc2	0	1	6	7
The CDC25B phosphatase with polo like kinase 1 ( PLK1 ) activates CDC2 and regulates the G2 phase of the cell cycle progression .	The CDC25B phosphatase with polo like kinase 1 (PLK1) activates CDC2 and regulates the G2 phase of the cell cycle progression.	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDC2	CDC2	CDC2	1	2	12	13
Interference with nuclear export reduced the ability of CDC25B protein to induce GVBD suggesting that CDC25B is needed to activate CDC2 and CyclinB in the cytoplasm ( unpublished data , Yu B ) .	Interference with nuclear export reduced the ability of CDC25B protein to induce GVBD suggesting that CDC25B is needed to activate CDC2 and CyclinB in the cytoplasm (unpublished data, Yu B).	15	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDC2	CDC2	CDC2	15	16	20	21
Cdc25B Directly Activated p34 cdc2 / cyclin B. To address the question of whether Cdc25B directly activate p34 cdc2 / cyclin B , Cdc25B was immunoprecipitated from the extract of nontreated cells , and as a control , from the extract of cycloheximide treated cells .	Cdc25B Directly Activated p34 cdc2 / cyclin B. To address the question of whether Cdc25B directly activate p34 cdc2 / cyclin B, Cdc25B was immunoprecipitated from the extract of nontreated cells, and as a control, from the extract of cycloheximide treated cells.	14	19	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25B	Cdc25B	Cdc25B	p34 cdc2	p34 cdc2	p34 cdc2	14	15	17	19
Recent evidence suggests that in addition to other roles , CDC25B , the phosphatase that activates Cdk1 , plays an important role in synchronizing centrosome duplication to mitosis [ XREF_BIBR ] .	Recent evidence suggests that in addition to other roles, CDC25B, the phosphatase that activates Cdk1, plays an important role in synchronizing centrosome duplication to mitosis [XREF_BIBR].	10	18	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	Cdk1	Cdk1	Cdk1	10	11	16	17
Similarly , in liver Cdkn2a , which inhibits G1/S progression , is upregulated and Cdc25b , which activates Cdk1 and is required for G2/M progression , is downregulated .	Similarly, in liver Cdkn2a, which inhibits G1/S progression, is upregulated and Cdc25b, which activates Cdk1 and is required for G2/M progression, is downregulated.	14	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25b	Cdc25b	Cdc25b	Cdk1	Cdk1	Cdk1	14	15	18	19
Cyclin B1-Cdk1 is involved in the early events of mitosis and Cdc25B activates Cdc2 for the entry into mitosis [ XREF_BIBR ] .	Cyclin B1-Cdk1 is involved in the early events of mitosis and Cdc25B activates Cdc2 for the entry into mitosis [XREF_BIBR].	7	16	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdc25B	Cdc25B	Cdc25B	Cdc2	Cdc2	Cdc2	11	12	13	14
In hamster BHK21 cell , CDC25B can activate initially CDC2 and Cyclin B , also named the maturation promoting factor ( MPF ) , which initiates mitosis through the activation of CDC25C [ XREF_BIBR ] .	In hamster BHK21 cell, CDC25B can activate initially CDC2 and Cyclin B, also named the maturation promoting factor (MPF), which initiates mitosis through the activation of CDC25C [XREF_BIBR].	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDC2	CDC2	CDC2	5	6	9	10
A Dual-Specificity Phosphatase Cdc25B Is an Unstable Protein and Triggers p34 cdc2 / Cyclin B Activation in Hamster BHK21 Cells Arrested with Hydroxyurea .	A Dual-Specificity Phosphatase Cdc25B Is an Unstable Protein and Triggers p34 cdc2 / Cyclin B Activation in Hamster BHK21 Cells Arrested with Hydroxyurea.	0	12	Triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25B	Cdc25B	Cdc25B	p34 cdc2	p34 cdc2	p34 cdc2	3	4	10	12
CDC25B may mediate the activation of CDK1 and Cyclin B at the centrosome during prophase , while CDC25A may be required for the subsequent full activation of nuclear CDK1 and Cyclin B. CDC25C is dispensable for both mitotic and meiotic divisions , although it is highly regulated during the processes .	CDC25B may mediate the activation of CDK1 and Cyclin B at the centrosome during prophase, while CDC25A may be required for the subsequent full activation of nuclear CDK1 and Cyclin B. CDC25C is dispensable for both mitotic and meiotic divisions, although it is highly regulated during the processes.	0	9	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDK1	CDK1	CDK1	0	1	6	7
CDC25B activates the cyclin dependent kinase CDC2 ( CDK1 ) and is required for entry into mitosis ; REEP4 is a membrane receptor accessory protein about which little is known .	CDC25B activates the cyclin dependent kinase CDC2 (CDK1) and is required for entry into mitosis; REEP4 is a membrane receptor accessory protein about which little is known.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDC2	CDC2	CDC2	0	1	6	7
Previously , Chk1 was reported to localize to centrosomes and to be involved in the inhibition of CDC25B dependent activation of Cdk1 during metaphase XREF_BIBR .	Previously, Chk1 was reported to localize to centrosomes and to be involved in the inhibition of CDC25B dependent activation of Cdk1 during metaphase XREF_BIBR.	17	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	Cdk1	Cdk1	Cdk1	17	18	21	22
CDC25B may specifically activate CDK1 and Cyclin B at the centrosome , the microtubule organizing center for mitotic spindles .	CDC25B may specifically activate CDK1 and Cyclin B at the centrosome, the microtubule organizing center for mitotic spindles.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25B	CDC25B	CDC25B	CDK1	CDK1	CDK1	0	1	4	5
It is noteworthy that FoxM1 stimulates expression of Cdc25b and Cyclin B1 that activate Cdk1 XREF_BIBR .	It is noteworthy that FoxM1 stimulates expression of Cdc25b and Cyclin B1 that activate Cdk1 XREF_BIBR.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25b	FoxM1 stimulates expression of Cdc25b	cdc25b	Cdk1	Cdk1	cdk1	8	9	14	15
These findings may suggest that Cdc25B initially activates the p34 cdc2 / cyclin B complexes , which , in turn , phosphorylate Cdc25C , forming a positive feedback , mutual activation loop between Cdc25C and p34 cdc2 / cyclin B. Consistent with the notion that Cdc25B functions as a trigger for the initiation of mitosis , the in vitro activation of p34 cdc2 / cyclin B carried out by Cdc25B is lower compared to the activation of p34 cdc2 / cyclin B that is carried out by constitutively active E. coli produced Cdc25C .	These findings may suggest that Cdc25B initially activates the p34 cdc2 / cyclin B complexes, which, in turn, phosphorylate Cdc25C, forming a positive feedback, mutual activation loop between Cdc25C and p34 cdc2 / cyclin B. Consistent with the notion that Cdc25B functions as a trigger for the initiation of mitosis, the in vitro activation of p34 cdc2 / cyclin B carried out by Cdc25B is lower compared to the activation of p34 cdc2 / cyclin B that is carried out by constitutively active E. coli produced Cdc25C.	5	11	initially activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25B	Cdc25B	Cdc25B	p34 cdc2	p34 cdc2	p34 cdc2	5	6	9	11
Cdc25B plays a role in S- and G2-phases and activates Cdc2 and cyclin B at mitotic entry XREF_BIBR .	Cdc25B plays a role in S- and G2-phases and activates Cdc2 and cyclin B at mitotic entry XREF_BIBR.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25B	Cdc25B	Cdc25B	Cdc2	Cdc2	Cdc2	0	1	10	11
We also show that the phosphatase Cdc25A , which directly activates CDK2 , is downregulated in irradiated hESCs through the action of the checkpoint kinases Chk1 and/or Chk2 .	We also show that the phosphatase Cdc25A, which directly activates CDK2, is downregulated in irradiated hESCs through the action of the checkpoint kinases Chk1 and/or Chk2.	4	14	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	CDK2	CDK2	CDK2	6	7	11	12
This suggests that CDC25A mediated activation of Cdk2 is required for S-phase entry in human breast cancer .	This suggests that CDC25A mediated activation of Cdk2 is required for S-phase entry in human breast cancer.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	CDC25A	CDC25A	CDC25A	Cdk2	Cdk2	Cdk2	3	4	7	8
Cell-division-cycle 25 homolog A ( Cdc25A ) , which activates CDK2 and CDK4/6 [ XREF_BIBR - XREF_BIBR ] , showed strong upregulation suggesting enhancement of kinase activity that promotes G1/S phase progression .	Cell-division-cycle 25 homolog A (Cdc25A), which activates CDK2 and CDK4/6 [XREF_BIBR - XREF_BIBR], showed strong upregulation suggesting enhancement of kinase activity that promotes G1/S phase progression.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	CDK2	CDK2	CDK2	5	6	10	11
This inhibition occurs due to an accelerated proteolysis of Cdc25A leading to the inhibition of the cyclin and Cdk2 kinase complex through the persistence of inhibitory phosphorylation on T14 , Y15 of Cdk2 .	This inhibition occurs due to an accelerated proteolysis of Cdc25A leading to the inhibition of the cyclin and Cdk2 kinase complex through the persistence of inhibitory phosphorylation on T14, Y15 of Cdk2.	7	33	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	Cdk2	Cdk2	Cdk2	9	10	32	33
Following initiation of DNA damage signaling , the CHK1 or CHK2 kinases phosphorylate CDC25A , one of three CDC25 family members that dephosphorylate and activate the cyclin dependent kinases , CDK1 and CDK2 .	Following initiation of DNA damage signaling, the CHK1 or CHK2 kinases phosphorylate CDC25A, one of three CDC25 family members that dephosphorylate and activate the cyclin dependent kinases, CDK1 and CDK2.	8	33	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CDC25A	CHK1 or CHK2 kinases phosphorylate CDC25A	cdc25a	CDK2	CDK2	cdk2	13	14	32	33
24 The resultant stabilization of Cdc25a purportedly promotes increased Cdk2 activity and thus mESCs do not arrest in G1 .	24 The resultant stabilization of Cdc25a purportedly promotes increased Cdk2 activity and thus mESCs do not arrest in G1.	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25a	Cdc25a	Cdc25a	Cdk2	Cdk2	Cdk2	5	6	9	10
Cdc25A degradation and inhibition in response to DNA damage inactivates CDK2 and enforces intra-S phase cell cycle arrest critical for the repair of DNA damage prior to the resumption of DNA synthesis .	Cdc25A degradation and inhibition in response to DNA damage inactivates CDK2 and enforces intra-S phase cell cycle arrest critical for the repair of DNA damage prior to the resumption of DNA synthesis.	0	11	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	CDK2	CDK2	CDK2	0	1	10	11
The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2 , which increases the number of replication forks while reducing their stability .	The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability.	15	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CDC25A	CDC25A	CDC25A	CDK2	CDK2	CDK2	15	16	18	19
We found that treatment of PCK rats with VK3 decreased levels of Cdc25A and proteins known to be regulated by Cdc25A ; reduced the phosphorylated status of Rb , and increased the phosphorylated status of Cdk1 and Cdk2 .	We found that treatment of PCK rats with VK3 decreased levels of Cdc25A and proteins known to be regulated by Cdc25A; reduced the phosphorylated status of Rb, and increased the phosphorylated status of Cdk1 and Cdk2.	10	38	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25A	levels of Cdc25A	cdc25a	Cdk2	Cdk2	cdk2	12	13	37	38
Reduction of CDC25A activity in turn inactivates CDK2 and Cyclin E through inhibition of CDK2 tyrosine 15 dephosphorylation .	Reduction of CDC25A activity in turn inactivates CDK2 and Cyclin E through inhibition of CDK2 tyrosine 15 dephosphorylation.	2	10	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25A	CDC25A	CDC25A	CDK2	CDK2	CDK2	2	3	7	8
During S phase , CDC25A continuously activates CDK2 and Cyclin A as a driving force of DNA replication .	During S phase, CDC25A continuously activates CDK2 and Cyclin A as a driving force of DNA replication.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25A	CDC25A	CDC25A	CDK2	CDK2	CDK2	4	5	7	8
Cdc25a activates CDK2 by removing an inhibitory phosphate on CDK2 tyrosine 15 , so to determine the significance of cdc25a down-regulation in hypoxic cells we assessed the phosphorylation status of CDK2 .	Cdc25a activates CDK2 by removing an inhibitory phosphate on CDK2 tyrosine 15, so to determine the significance of cdc25a down-regulation in hypoxic cells we assessed the phosphorylation status of CDK2.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25a	Cdc25a	Cdc25a	CDK2	CDK2	CDK2	0	1	2	3
Thus , as the concentration of active APC ( Cdh1 ) decreases during G1 with the accumulation of cycD and Cdk4or6 , first Cdc25A appears and abruptly activates the newly p27-unbound cycE and Cdk2 ( causing the cycE and Cdk2-Cdc 25A cascade ) , then SCF appears and binds Fbw7 and ubiquitinates cycE .	Thus, as the concentration of active APC (Cdh1) decreases during G1 with the accumulation of cycD and Cdk4or6, first Cdc25A appears and abruptly activates the newly p27-unbound cycE and Cdk2 (causing the cycE and Cdk2-Cdc 25A cascade), then SCF appears and binds Fbw7 and ubiquitinates cycE.	22	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	Cdk2	Cdk2	Cdk2	23	24	33	34
We hypothesize that Cdc25A degradation does not inhibit Cdk2 activity because a considerable proportion of Cdk2 molecules localize to the cytoplasm and centrosomes in mESCs , where they may be sheltered from regulation by nuclear Cdc25A .	We hypothesize that Cdc25A degradation does not inhibit Cdk2 activity because a considerable proportion of Cdk2 molecules localize to the cytoplasm and centrosomes in mESCs, where they may be sheltered from regulation by nuclear Cdc25A.	3	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	Cdk2	Cdk2	Cdk2	3	4	8	9
Expression of cdc25A , a phosphatase that activates cdk2 , was reduced during 24-hr exposure to gnidimacrin .	Expression of cdc25A, a phosphatase that activates cdk2, was reduced during 24-hr exposure to gnidimacrin.	0	9	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	cdc25A	Expression of cdc25A	cdc25a	cdk2	cdk2	cdk2	2	3	8	9
In certain cell types , TGF-beta also upregulates p21 [ XREF_BIBR ] , a CDK2 inhibitor and downregulates cdc25A , a phosphatase that activates CDK2 [ XREF_BIBR ] .	In certain cell types, TGF-beta also upregulates p21 [XREF_BIBR], a CDK2 inhibitor and downregulates cdc25A, a phosphatase that activates CDK2 [XREF_BIBR].	17	26	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	cdc25A	cdc25A	cdc25A	CDK2	CDK2	CDK2	18	19	24	25
This results from the phosphorylation and subsequent inactivation of two inhibitory kinases ( WEE1 and MYT1 ) that tonically suppress CDK2 and CDC2 activity and activation of a phosphatase ( CDC25A ) that increases CDK2 activity .	This results from the phosphorylation and subsequent inactivation of two inhibitory kinases (WEE1 and MYT1) that tonically suppress CDK2 and CDC2 activity and activation of a phosphatase (CDC25A) that increases CDK2 activity.	28	35	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25A	CDC25A	CDC25A	CDK2	CDK2	CDK2	30	31	34	35
During normal replication , CDC25A activates CDK2 promoting the formation of the complex CDK2 and cyclin E/cyclin A necessary for the entry into the S phase and for the DNA synthesis .	During normal replication, CDC25A activates CDK2 promoting the formation of the complex CDK2 and cyclin E/cyclin A necessary for the entry into the S phase and for the DNA synthesis.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25A	CDC25A	CDC25A	CDK2	CDK2	CDK2	4	5	6	7
In both PI 3-kinase/Rac1 and ERK1/2 pathways , Ser10 of p27 is phosphorylated by KIS , confirmed by siRNA to KIS , which subsequently hampered the FGF-2-stimulated cell proliferation , while Thr187 of p27 was phosphorylated through Cdk2 activated by Cdc25A .	In both PI 3-kinase/Rac1 and ERK1/2 pathways, Ser10 of p27 is phosphorylated by KIS, confirmed by siRNA to KIS, which subsequently hampered the FGF-2-stimulated cell proliferation, while Thr187 of p27 was phosphorylated through Cdk2 activated by Cdc25A.	35	41	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	Cdk2	Cdk2	Cdk2	40	41	37	38
Whereas CDK2 , which is mainly activated by CDC25A XREF_BIBR , plays important roles in S-phase progression , transit from G2 to mitosis in normal cycling cells is governed by activity of the CDK1 ( also called cdc2 ) kinase in complex with its mitotic cyclin B1 XREF_BIBR .	Whereas CDK2, which is mainly activated by CDC25A XREF_BIBR, plays important roles in S-phase progression, transit from G2 to mitosis in normal cycling cells is governed by activity of the CDK1 (also called cdc2) kinase in complex with its mitotic cyclin B1 XREF_BIBR.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC25A	CDC25A	CDC25A	CDK2	CDK2	CDK2	8	9	1	2
Cdk2 kinase activity , in turn , is regulated by cyclin dependent kinase inhibitors and the cdc25A phosphatase which activates CDK2 .	Cdk2 kinase activity, in turn, is regulated by cyclin dependent kinase inhibitors and the cdc25A phosphatase which activates CDK2.	16	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdc25A	cdc25A	cdc25A	CDK2	CDK2	CDK2	16	17	20	21
In addition , Chk1 dependent degradation of Cdc25A further inhibits the CDK2 activity and suppresses the origin firing .	In addition, Chk1 dependent degradation of Cdc25A further inhibits the CDK2 activity and suppresses the origin firing.	5	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	CDK2	CDK2	CDK2	7	8	11	12
Once activated , the classical E2Fs drive transcription of Cyclin E and the phosphatase CDC25A which activates CDK2 , thus further increasing Rb phosphorylation.21 Overexpression of the RNA regulon repressed by ZFP36L1 and ZFP36L2 amplifies the sensitivity of the E2F pathway thus tipping the balance towards S phase entry and leading to activation of the mechanisms which prevent V ( D ) J recombination from occurring .	Once activated, the classical E2Fs drive transcription of Cyclin E and the phosphatase CDC25A which activates CDK2, thus further increasing Rb phosphorylation.21 Overexpression of the RNA regulon repressed by ZFP36L1 and ZFP36L2 amplifies the sensitivity of the E2F pathway thus tipping the balance towards S phase entry and leading to activation of the mechanisms which prevent V (D) J recombination from occurring.	6	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25A	CDC25A	CDC25A	CDK2	CDK2	CDK2	14	15	17	18
Rather , expression of cyclin A , which regulates cdk2 activity , and the cdc25A and cdc25B phosphatases , which are thought to activate cdk2 , was significantly reduced at both the RNA and protein levels in response to E2 expression .	Rather, expression of cyclin A, which regulates cdk2 activity, and the cdc25A and cdc25B phosphatases, which are thought to activate cdk2, was significantly reduced at both the RNA and protein levels in response to E2 expression.	2	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdc25A	expression of cyclin A, which regulates cdk2 activity, and the cdc25A	cdc25a	cdk2	cdk2	cdk2	14	15	24	25
It was found that CDC25A phosphatase activates CDK2 and CDK1 by dephosphorylating Tyr15 , which plays a key role in the RAS oncogenic pathway [ XREF_BIBR , XREF_BIBR ] .	It was found that CDC25A phosphatase activates CDK2 and CDK1 by dephosphorylating Tyr15, which plays a key role in the RAS oncogenic pathway [XREF_BIBR, XREF_BIBR].	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC25A	CDC25A	CDC25A	CDK2	CDK2	CDK2	4	5	7	8
Ectopic expression of Cdc25A activates Cdk2 in complex with cyclin E or cyclin A and accelerates S phase entry [ XREF_BIBR ] .	Ectopic expression of Cdc25A activates Cdk2 in complex with cyclin E or cyclin A and accelerates S phase entry [XREF_BIBR].	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25A	expression of Cdc25A	cdc25a	Cdk2	Cdk2	cdk2	3	4	5	6
Cdc45 loading requires Cdk2 activation , which is prevented by Chk1 dependent degradation of Cdc25A ( see section 3.3 ) .	Cdc45 loading requires Cdk2 activation, which is prevented by Chk1 dependent degradation of Cdc25A (see section 3.3).	3	15	prevented	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	Cdk2	Cdk2	Cdk2	14	15	3	4
The destruction of germinal centers due to inflammation and the lack of production of neutralizing antibodies have also been reported for another model of chronic viral infection , lymphocytic choriomeningitis virus , where chronic CD27 mediated stimulation of T cells by CD70 on B cells resulted in cytokine mediated germinal center destruction XREF_BIBR .	The destruction of germinal centers due to inflammation and the lack of production of neutralizing antibodies have also been reported for another model of chronic viral infection, lymphocytic choriomeningitis virus, where chronic CD27 mediated stimulation of T cells by CD70 on B cells resulted in cytokine mediated germinal center destruction XREF_BIBR.	34	44	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	41	42	34	35
The CD70 on medullary thymic epithelial cells ( mTECs ) and DCs in the thymic medulla triggers the CD27 signal on tTregs to promote their survival by inhibiting the mitochondrial apoptosis pathway .	The CD70 on medullary thymic epithelial cells (mTECs) and DCs in the thymic medulla triggers the CD27 signal on tTregs to promote their survival by inhibiting the mitochondrial apoptosis pathway.	0	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	1	2	18	19
These data indicate that CD70 on both DCs and epithelial cells contributes to T reg cell development by engaging CD27 on developing T reg cells .	These data indicate that CD70 on both DCs and epithelial cells contributes to T reg cell development by engaging CD27 on developing T reg cells.	4	20	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	4	5	19	20
While during primary T cell activation there seems to be a certain redundancy in CD80 and CD86 and CD70 costimulation , it is triggering of CD27 on T-lymphocytes by its ligand CD70 that enhances the magnitude of antigen specific cytotoxic T cell reponses [ XREF_BIBR , XREF_BIBR ] , which is required for effective immunotherapy .	While during primary T cell activation there seems to be a certain redundancy in CD80 and CD86 and CD70 costimulation, it is triggering of CD27 on T-lymphocytes by its ligand CD70 that enhances the magnitude of antigen specific cytotoxic T cell reponses [XREF_BIBR, XREF_BIBR], which is required for effective immunotherapy.	23	33	triggering	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	31	32	25	26
CD27 activity is induced by engagement of CD70 , a molecule that is found on activated T cells , B cells , and DCs .	CD27 activity is induced by engagement of CD70, a molecule that is found on activated T cells, B cells, and DCs.	0	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	7	8	0	1
We found that blocking of CD70 or CD40 or neutralization of IL-12 during AEP-expansion reduced the frequency of CD27 expressing CD8 + T cells and reduced T-cell viability after exposure to oxidative stress and apoptotic factors .	We found that blocking of CD70 or CD40 or neutralization of IL-12 during AEP-expansion reduced the frequency of CD27 expressing CD8 + T cells and reduced T-cell viability after exposure to oxidative stress and apoptotic factors.	3	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	5	6	18	19
The natural ligand for CD27 , CD70 , induces downregulation of CD27 in a process controlled by the common gamma-chain cytokine IL-15 .	The natural ligand for CD27, CD70, induces downregulation of CD27 in a process controlled by the common gamma-chain cytokine IL-15.	2	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	6	7	11	12
Interestingly , in alphaCD70 treated mice , human sCD27 levels were significantly lower than in controls , indicating that CD70 blockade specifically reduced CD27 signaling on human AML blasts in these mice ( XREF_FIG ) .	Interestingly, in alphaCD70 treated mice, human sCD27 levels were significantly lower than in controls, indicating that CD70 blockade specifically reduced CD27 signaling on human AML blasts in these mice (XREF_FIG).	19	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	19	20	23	24
Taken together , this study is the first to demonstrate that continuous CD70 triggering of CD27 on NK cells in vivo results in a severe reduction of NK cells .	Taken together, this study is the first to demonstrate that continuous CD70 triggering of CD27 on NK cells in vivo results in a severe reduction of NK cells.	12	18	triggering	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	12	13	15	16
This suggests that CD27 stimulation by CD70 , even when presented outside the viral or tumor environment , may prove useful as a strategy for enhancing CD8 + T cell responses to viruses and tumors .	This suggests that CD27 stimulation by CD70, even when presented outside the viral or tumor environment, may prove useful as a strategy for enhancing CD8 + T cell responses to viruses and tumors.	3	7	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	6	7	3	4
The resulting increase in CD70 triggered CD27 signaling and compensatory Wnt pathway activation .	The resulting increase in CD70 triggered CD27 signaling and compensatory Wnt pathway activation.	2	7	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	4	5	6	7
The ligand for CD27 , CD70 , is expressed on activated T and B cells and , for normal B cells , promotes the differentiation of CD27 + cells into plasma cells .	The ligand for CD27, CD70, is expressed on activated T and B cells and, for normal B cells, promotes the differentiation of CD27 + cells into plasma cells.	1	31	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	5	6	26	27
We further confirmed the inhibitory effect of lalphahCD70 on CD70-CD27 interaction in a functional assay where CD70 expressing cells ( U266 and Mino ) have been used to stimulate CD27 on HT1080 cells stably transfected with this receptor .	We further confirmed the inhibitory effect of lalphahCD70 on CD70-CD27 interaction in a functional assay where CD70 expressing cells (U266 and Mino) have been used to stimulate CD27 on HT1080 cells stably transfected with this receptor.	16	30	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	16	17	29	30
In addition , activated CD70 expressing lymphocytes may trigger CD27 on AML blasts or stem and progenitor cells .	In addition, activated CD70 expressing lymphocytes may trigger CD27 on AML blasts or stem and progenitor cells.	3	10	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70 expressing	cd70	CD27	CD27	cd27	4	5	9	10
Triggering via CD27 by CD27 ligand ( CD70 ) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 ( IL-10 ) .	Triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10).	0	6	Triggering	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CD27 ligand	CD27 ligand	CD27 ligand	CD27	CD27	CD27	4	6	2	3
Defective germinal center B cell differentiation was critically dependent on CD70 mediated CD27 signaling in T cells , and involved Fas dependent impairment of germinal center B cell differentiation .	Defective germinal center B cell differentiation was critically dependent on CD70 mediated CD27 signaling in T cells, and involved Fas dependent impairment of germinal center B cell differentiation.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	10	11	12	13
Ligation of CD70 to CD27 induces release of soluble CD27 ( sCD27 ) and it is indeed interesting that increased soluble CD27 level is a hallmark of diverse autoimmune conditions with a strong link to EBV , such as in cerebrospinal fluid in MS , in synovial tissue in RA and in serum in both systemic lupus erythematosus and Sjogren ' s syndrome .	Ligation of CD70 to CD27 induces release of soluble CD27 (sCD27) and it is indeed interesting that increased soluble CD27 level is a hallmark of diverse autoimmune conditions with a strong link to EBV, such as in cerebrospinal fluid in MS, in synovial tissue in RA and in serum in both systemic lupus erythematosus and Sjogren 's syndrome.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	2	3	9	10
The CD70 costimulatory molecules expressed on activated lymphocytes and DCs can increase activation of B and T cells through binding to CD27 .	The CD70 costimulatory molecules expressed on activated lymphocytes and DCs can increase activation of B and T cells through binding to CD27.	1	22	increase	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	1	2	21	22
Direct CD70 mediated downregulation of CD27 could provide real-time fine tuning of ongoing T cell activation processes necessary for controlling immune responses .	Direct CD70 mediated downregulation of CD27 could provide real-time fine tuning of ongoing T cell activation processes necessary for controlling immune responses.	0	7	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	1	2	5	6
127 Chronic CD70 overexpression in B cells continuously induced CD27 signaling on T cells , leading to a predominant , presumably pro atherogenic Th1 response .	127 Chronic CD70 overexpression in B cells continuously induced CD27 signaling on T cells, leading to a predominant, presumably pro atherogenic Th1 response.	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD70	CD70 overexpression	cd70	CD27	CD27	cd27	2	3	9	10
Constitutive expression of CD70 under the control of the CD19 promoter in transgenic mice leads to a persistent stimulation of CD27 .	Constitutive expression of CD70 under the control of the CD19 promoter in transgenic mice leads to a persistent stimulation of CD27.	1	21	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	CD70	expression of CD70	cd70	CD27	CD27	cd27	3	4	20	21
Continuous CD27 engagement , likely mediated by a subset of CD70 expressing B cells , led to T cell cytokine mediated splenic germinal center and marginal zone destruction , thus precluding the generation of a neutralizing antibody response .	Continuous CD27 engagement, likely mediated by a subset of CD70 expressing B cells, led to T cell cytokine mediated splenic germinal center and marginal zone destruction, thus precluding the generation of a neutralizing antibody response.	1	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	10	11	1	2
In line with the latter observations , CD70 + tumor cells in renal cell carcinoma and B cell lymphoma may promote depletion of naive CD27 + T cells and induce regulatory T cells in the tumor , respectively [ XREF_BIBR , XREF_BIBR ] .	In line with the latter observations, CD70 + tumor cells in renal cell carcinoma and B cell lymphoma may promote depletion of naive CD27 + T cells and induce regulatory T cells in the tumor, respectively [XREF_BIBR, XREF_BIBR].	7	27	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CD70	CD70	CD70	CD27	CD27	CD27	7	8	24	25
CD70 mediated stimulation of CD27 is an important cofactor of CD4 + T cell licensed dendritic cells .	CD70 mediated stimulation of CD27 is an important cofactor of CD4 + T cell licensed dendritic cells.	0	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	0	1	4	5
For example , T cell co-culture with B-cell lines expressing CD70 triggered CD27 downregulation , and even naive T cells in CD70 Tg mice had substantially lower CD27 levels .	For example, T cell co-culture with B-cell lines expressing CD70 triggered CD27 downregulation, and even naive T cells in CD70 Tg mice had substantially lower CD27 levels.	9	13	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	10	11	12	13
CD70 stimulates CD27 , which , among other functions , reduces activation induced [ XREF_BIBR ] and Fas-L mediated cell death [ XREF_BIBR ] .	CD70 stimulates CD27, which, among other functions, reduces activation induced [XREF_BIBR] and Fas-L mediated cell death [XREF_BIBR].	0	10	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	0	1	2	3
In this study we demonstrate that CD27 stimulation by soluble CD70 considerably enhances the magnitude and quality of the CD8 ( + ) T cell response .	In this study we demonstrate that CD27 stimulation by soluble CD70 considerably enhances the magnitude and quality of the CD8 (+) T cell response.	6	11	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD70	CD70	CD70	CD27	CD27	CD27	10	11	6	7
XREF_BIBR , XREF_BIBR Full-length PAK2 can be activated either by the small GTPases CDC42 and Rac or CASPs , which stimulates cell survival or induction of cell death in response to many apoptotic stimuli .	XREF_BIBR, XREF_BIBR Full-length PAK2 can be activated either by the small GTPases CDC42 and Rac or CASPs, which stimulates cell survival or induction of cell death in response to many apoptotic stimuli.	2	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK2	PAK2	PAK2	13	14	4	5
Cdc42 activates Pak2 and Pak4 .	Cdc42 activates Pak2 and Pak4.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak2	Pak2	Pak2	0	1	2	3
The constitutively active form of Cdc42 increases the association of Pak2 with Syk .	The constitutively active form of Cdc42 increases the association of Pak2 with Syk.	3	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak2	Pak2	Pak2	5	6	10	11
Other substrates such as the Rous sarcoma virus protein NC are phosphorylated by gamma-PAK following activation by Cdc42 ( GTPgammaS ) , but are not phosphorylated by T402A .	Other substrates such as the Rous sarcoma virus protein NC are phosphorylated by gamma-PAK following activation by Cdc42 (GTPgammaS), but are not phosphorylated by T402A.	13	19	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	gamma-PAK	gamma-PAK	gamma-PAK	17	18	13	14
SFKs and CDC42 and Rac1 , but not PI3K are upstream activators of PAK2 in pancreatic acinar cells .	SFKs and CDC42 and Rac1, but not PI3K are upstream activators of PAK2 in pancreatic acinar cells.	0	17	are upstream activators	Positive_activation_copula_1	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	PAK2	PAK2	PAK2	2	3	13	14
Pak2 is primarily inactive during growth , and is transiently activated by Cdc42 in response to moderate stress , and constitutively activated during apoptosis by caspase cleavage XREF_BIBR , XREF_BIBR .	Pak2 is primarily inactive during growth, and is transiently activated by Cdc42 in response to moderate stress, and constitutively activated during apoptosis by caspase cleavage XREF_BIBR, XREF_BIBR.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Pak2	Pak2	Pak2	12	13	0	1
However , in some cells , Cdc42 and its upstream activator DOCK10 can promote amoeboid motility , as Cdc42 activates PAK2 and consequently actomyosin contraction [ XREF_BIBR ] .	However, in some cells, Cdc42 and its upstream activator DOCK10 can promote amoeboid motility, as Cdc42 activates PAK2 and consequently actomyosin contraction [XREF_BIBR].	18	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK2	PAK2	PAK2	18	19	20	21
Pak2 deleted HSPCs was rescued by constitutive active CDC42 .	Pak2 deleted HSPCs was rescued by constitutive active CDC42.	0	9	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC42	CDC42	CDC42	Pak2	Pak2	Pak2	8	9	0	1
As stated above , Erbin expression had no impact on the activation of the upstream mediators of PAK2 activation Cdc42 and Rac1 or PI3K .	As stated above, Erbin expression had no impact on the activation of the upstream mediators of PAK2 activation Cdc42 and Rac1 or PI3K.	15	23	activation	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK2	PAK2	PAK2	19	20	17	18
Overall , eight autophosphorylation sites were identified in Cdc42 activated gamma-PAK , six of which are in common with those previously reported in alpha-PAK , while Ser 19 and Ser 165 appear to be uniquely phosphorylated in the gamma-form .	Overall, eight autophosphorylation sites were identified in Cdc42 activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser 19 and Ser 165 appear to be uniquely phosphorylated in the gamma-form.	6	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	gamma-PAK	gamma-PAK	gamma-PAK	8	9	10	11
PAK2 , when activated by the Cdc42 and Rac , was previously reported to catalyze phosphorylation and subsequent activation of intact nonmuscle MYO2 , which may be physiologically important in regulating cytoskeletal organization .	PAK2, when activated by the Cdc42 and Rac, was previously reported to catalyze phosphorylation and subsequent activation of intact nonmuscle MYO2, which may be physiologically important in regulating cytoskeletal organization.	0	14	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK2	PAK2	PAK2	6	7	0	1
Importantly , the combination of soluble CD40 agonist ( G28-5 mAb ) and Trx-1 inhibitor ( PX-12 ) triggered substantial induction of TRAF3 , which was equivalent to that observed with mCD40L , whereas agonist or inhibitor alone caused little or no TRAF3 induction , respectively ( XREF_FIG ) .	Importantly, the combination of soluble CD40 agonist (G28-5 mAb) and Trx-1 inhibitor (PX-12) triggered substantial induction of TRAF3, which was equivalent to that observed with mCD40L, whereas agonist or inhibitor alone caused little or no TRAF3 induction, respectively (XREF_FIG).	6	26	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	6	7	22	23
CD40 engagement triggers self degradation of TRAF2 and cIAP dependent degradation of TRAF3 , resulting in stabilization and accumulation of NIK .	CD40 engagement triggers self degradation of TRAF2 and cIAP dependent degradation of TRAF3, resulting in stabilization and accumulation of NIK.	0	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	0	1	12	13
In contrast to TNFR1 signaling , activation of CD40 signaling does not require the adapter TRADD but instead is initiated by binding of ubiquitin ligases TRAF2 , TRAF3 , and TRAF6 directly to the receptor .	In contrast to TNFR1 signaling, activation of CD40 signaling does not require the adapter TRADD but instead is initiated by binding of ubiquitin ligases TRAF2, TRAF3, and TRAF6 directly to the receptor.	8	28	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	8	9	27	28
CD40 induced TRAF3 dependent p38-MAPK activation can synergize with the TLR activated p38-MAPK-dependent IL-12 production and Th1 differentiation .	CD40 induced TRAF3 dependent p38-MAPK activation can synergize with the TLR activated p38-MAPK-dependent IL-12 production and Th1 differentiation.	0	11	induced	Positive_early_activation	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	0	1	2	3
In TRAF3 -/- cells , Wt-CD40 signaling resulted in ~ 2-fold more c-Jun phosphorylation than in TRAF3-sufficient cells ( XREF_FIG ) , supporting the role of TRAF3 as a negative regulator of Wt-CD40 signaling .	In TRAF3 -/- cells, Wt-CD40 signaling resulted in ~ 2-fold more c-Jun phosphorylation than in TRAF3-sufficient cells (XREF_FIG), supporting the role of TRAF3 as a negative regulator of Wt-CD40 signaling.	5	27	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wt-CD40	Wt-CD40	Wt-CD40	TRAF3	TRAF3	TRAF3	5	6	26	27
CD40 mutants with impaired binding to TRAF2 , TRAF3 , or both of these proteins completely retained the ability to activate NF-kappaB and Jun N-terminal kinase ( JNK ) , implying that CD40 can stimulate TRAF2- and TRAF3 independent pathways for NF-kappaB and JNK activation .	CD40 mutants with impaired binding to TRAF2, TRAF3, or both of these proteins completely retained the ability to activate NF-kappaB and Jun N-terminal kinase (JNK), implying that CD40 can stimulate TRAF2- and TRAF3 independent pathways for NF-kappaB and JNK activation.	32	39	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	32	33	37	38
To delineate CD40 induced TRAF3 dependent events , Ramos B cells stably transfected with a dominant negative TRAF3 were stimulated with membranes expressing recombinant CD154 and CD40 ligand .	To delineate CD40 induced TRAF3 dependent events, Ramos B cells stably transfected with a dominant negative TRAF3 were stimulated with membranes expressing recombinant CD154 and CD40 ligand.	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	2	3	4	5
Data shown in the present study provide additional support for the association between these post-translational modifications by demonstrating that Ubc9 knock-down significantly reduces CD40 mediated TRAF3 degradation and NF-kappaB2 processing .	Data shown in the present study provide additional support for the association between these post-translational modifications by demonstrating that Ubc9 knock-down significantly reduces CD40 mediated TRAF3 degradation and NF-kappaB2 processing.	22	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	23	24	25	26
The non canonical NF-kappaB pathway involves activation of MAP3K14 ( ' NIK ' ) by members of the TNF family , such as by CD40 activation of TRAF3 .	The non canonical NF-kappaB pathway involves activation of MAP3K14 (' NIK ') by members of the TNF family, such as by CD40 activation of TRAF3.	24	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	24	25	27	28
Detailed comparison of CD40 and LMP1 signaling between WT and TRAF3 -/- B cells has allowed us to delineate the specific roles of TRAF3 .	Detailed comparison of CD40 and LMP1 signaling between WT and TRAF3 -/- B cells has allowed us to delineate the specific roles of TRAF3.	3	24	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	3	4	23	24
In multiple myeloma , high-density oligonucleotide array CGH and gene expression profiling data revealed ten genes causing the inactivation of TRAF2 , TRAF3 , CYLD , and IAP1 and cIAP2 , and activation of NFKB1 , NFKB2 , CD40 , LTBR , TACI , and NIK was linked to constitutive activation of the noncanonical NF-kappaB pathway .	In multiple myeloma, high-density oligonucleotide array CGH and gene expression profiling data revealed ten genes causing the inactivation of TRAF2, TRAF3, CYLD, and IAP1 and cIAP2, and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK was linked to constitutive activation of the noncanonical NF-kappaB pathway.	16	39	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	38	39	22	23
However , LMP1 binds TRAF3 with markedly enhanced avidity , compared to CD40 , allowing LMP1 to sequester TRAF3 from the B-cell cytoplasm to the plasma membrane .	However, LMP1 binds TRAF3 with markedly enhanced avidity, compared to CD40, allowing LMP1 to sequester TRAF3 from the B-cell cytoplasm to the plasma membrane.	3	19	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	12	13	18	19
We therefore investigated TRAF2 and TRAF3 modifications induced by CD40 and LMP1 signaling in a panel of human cell lines of lymphoid and epithelial origins .	We therefore investigated TRAF2 and TRAF3 modifications induced by CD40 and LMP1 signaling in a panel of human cell lines of lymphoid and epithelial origins.	3	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	9	10	5	6
Strikingly , we also found that Nox itself could influence the fate of TRAF3 , as Nox inhibition prevented CD40 mediated TRAF3 induction ( XREF_FIG ) , thus suggesting the existence of a feedback loop between TRAF3 and Nox .	Strikingly, we also found that Nox itself could influence the fate of TRAF3, as Nox inhibition prevented CD40 mediated TRAF3 induction (XREF_FIG), thus suggesting the existence of a feedback loop between TRAF3 and Nox.	19	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	19	20	21	22
Strikingly , of the posttranslational regulators of Cdc2 , the Cdc2 activators Cdc25A and CCNB1 are both down-regulated , whereas the Cdc2 inhibitors BTG2 , p53 , GADD45 , Wee1 , ErbB2 , MCL1 , CDKN3 , and CDKN1B are all up-regulated , indicating that gene changes observed in Erk1/2 depleted keratinocytes may broadly contribute to G2/M arrest .	Strikingly, of the posttranslational regulators of Cdc2, the Cdc2 activators Cdc25A and CCNB1 are both down-regulated, whereas the Cdc2 inhibitors BTG2, p53, GADD45, Wee1, ErbB2, MCL1, CDKN3, and CDKN1B are all up-regulated, indicating that gene changes observed in Erk1/2 depleted keratinocytes may broadly contribute to G2/M arrest.	9	17	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	Cdc2	Cdc2	Cdc2	12	13	10	11
During the G2 --> M transition , CDK1 is activated by a group of dual-specificity phosphatases , Cdc25a , b and c ( herein collectively referred to as CDC25 ) , which themselves are subject to a complex regulatory network involving several kinases and phosphatases [ reviewed in XREF_BIBR ] .	During the G2 --> M transition, CDK1 is activated by a group of dual-specificity phosphatases, Cdc25a, b and c (herein collectively referred to as CDC25), which themselves are subject to a complex regulatory network involving several kinases and phosphatases [reviewed in XREF_BIBR].	7	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc25a	Cdc25a	Cdc25a	CDK1	CDK1	CDK1	17	18	7	8
In particular , Cdh1 completes the elimination of mitotic cyclins , induces degradation of the CDK1 activator Cdc25A and targets Skp2 and Cks1 for degradation , blocking degradation of the p27 and p21 CDK inhibitors by SCF Skp2 .	In particular, Cdh1 completes the elimination of mitotic cyclins, induces degradation of the CDK1 activator Cdc25A and targets Skp2 and Cks1 for degradation, blocking degradation of the p27 and p21 CDK inhibitors by SCF Skp2.	12	20	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	Cdc25A	Cdc25A	Cdc25A	CDK1	CDK1	CDK1	17	18	15	16
Furthermore , Cdc25A activates both Cdk1-2 and Cyclin A and Cdk1 and Cyclin B complexes while Cdc25B seems to be involved only in activation of Cdk1 and Cyclin B. Concomitantly , repression of Cdc25A led to a decrease in Cyclin A associated kinase activity and attenuated Cdk1 activation .	Furthermore, Cdc25A activates both Cdk1-2 and Cyclin A and Cdk1 and Cyclin B complexes while Cdc25B seems to be involved only in activation of Cdk1 and Cyclin B. Concomitantly, repression of Cdc25A led to a decrease in Cyclin A associated kinase activity and attenuated Cdk1 activation.	31	47	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	Cdk1	Cdk1	Cdk1	33	34	46	47
For instance , the Cdk1 activators Cdc25A and Cdc25B show higher activity in degenerating neurons in vivo , XREF_BIBR while a lower activity of the Cdk1 inhibitor Wee1 can be observed in these neurons .	For instance, the Cdk1 activators Cdc25A and Cdc25B show higher activity in degenerating neurons in vivo, XREF_BIBR while a lower activity of the Cdk1 inhibitor Wee1 can be observed in these neurons.	3	9	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Cdc25A	Cdc25A	Cdc25A	Cdk1	Cdk1	Cdk1	6	7	4	5
While both CD40 and LMP1 bind TRAF2 via their respective TBS , the sequence of the CD40 TBS induces TRAF2 to perform distinct functions compared to the TBS of LMP1 .	While both CD40 and LMP1 bind TRAF2 via their respective TBS, the sequence of the CD40 TBS induces TRAF2 to perform distinct functions compared to the TBS of LMP1.	16	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	16	17	19	20
To test whether CD40 induced TRAF2 and 3 degradation could be occurring independent of CD40 binding ( as an indirect effect of CD40 signaling ) , two mutants of CD40 were examined , a 22-amino acid deletion of the cytoplasmic tail of hCD40 ( hCD40Delta22 ) and a point mutant in the PXQXT motif of cytoplasmic hCD40 ( hCD40T234A ) .	To test whether CD40 induced TRAF2 and 3 degradation could be occurring independent of CD40 binding (as an indirect effect of CD40 signaling), two mutants of CD40 were examined, a 22-amino acid deletion of the cytoplasmic tail of hCD40 (hCD40Delta22) and a point mutant in the PXQXT motif of cytoplasmic hCD40 (hCD40T234A).	3	11	induced	Positive_early_activation	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	3	4	5	6
In this study , in TRAF1 -/- DCs , CD40 signaling in the short term ( up to 20 min ) on immature cells is intact and comparable to that of wild-type cells , enabling NF-kappaB activation and functional maturation , as well as depletion of TRAF2 from the soluble fraction ( XREF_FIG ) .	In this study, in TRAF1 -/- DCs, CD40 signaling in the short term (up to 20 min) on immature cells is intact and comparable to that of wild-type cells, enabling NF-kappaB activation and functional maturation, as well as depletion of TRAF2 from the soluble fraction (XREF_FIG).	9	47	enabling	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	9	10	46	47
We also observed transient CD40 induced membrane association of MEKK1 , TRAF2 , IKKgamma , and Ubc13 ( XREF_SUPPLEMENTARY ) .	We also observed transient CD40 induced membrane association of MEKK1, TRAF2, IKKgamma, and Ubc13 (XREF_SUPPLEMENTARY).	3	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	4	5	11	12
Immunoprecipitation of MEKK1 from whole cell lysates also revealed formation of a CD40 induced multiprotein complex containing CD40 , TRAF2 , c-IAP1/2 , Ubc13 , IKKgamma , and MEKK1 itself ( XREF_FIG ) .	Immunoprecipitation of MEKK1 from whole cell lysates also revealed formation of a CD40 induced multiprotein complex containing CD40, TRAF2, c-IAP1/2, Ubc13, IKKgamma, and MEKK1 itself (XREF_FIG).	9	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	12	13	19	20
CD40 induced activation of TRAF2 activates the cIAP proteins to ubiquitylate TRAF3 , promoting its degradation and releasing MEKK1 for downstream signaling .	CD40 induced activation of TRAF2 activates the cIAP proteins to ubiquitylate TRAF3, promoting its degradation and releasing MEKK1 for downstream signaling.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	0	1	4	5
Because LMP1 binds TRAF2 with less affinity than CD40 and TRAF2 is needed for inducing CD40 mediated TRAF2 and 3 degradation , it was thought that relative affinity for TRAF2 controls the disparate ways in which CD40 and LMP1 use and degrade TRAFs 2 and 3 , and that this in turn results from the different sequences of the TRAF2/3 binding sites of the two receptors .	Because LMP1 binds TRAF2 with less affinity than CD40 and TRAF2 is needed for inducing CD40 mediated TRAF2 and 3 degradation, it was thought that relative affinity for TRAF2 controls the disparate ways in which CD40 and LMP1 use and degrade TRAFs 2 and 3, and that this in turn results from the different sequences of the TRAF2/3 binding sites of the two receptors.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	15	16	17	18
Finally , inhibition of CDK1 and CDK9 decreased AR Ser 81 phosphorylation , chromatin binding , and transcriptional activity .	Finally, inhibition of CDK1 and CDK9 decreased AR Ser 81 phosphorylation, chromatin binding, and transcriptional activity.	2	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	AR	AR	AR	4	5	8	9
In addition , it may be of benefit to determine what phosphatases may counterbalance cdk1 mediated AR activity , whether cdk1 dependent phosphorylation events are up-regulated in human disease , and to assess whether or not this pathway could be developed as a means to suppress AR activity in human tumors .	In addition, it may be of benefit to determine what phosphatases may counterbalance cdk1 mediated AR activity, whether cdk1 dependent phosphorylation events are up-regulated in human disease, and to assess whether or not this pathway could be developed as a means to suppress AR activity in human tumors.	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	cdk1	cdk1	cdk1	AR	AR	AR	14	15	16	17
Overall these studies indicate that PP1alpha , CDK9 and CDK1 cooperate to drive AR transcriptional activity through a positive feedback loop and that agents targeting components of this loop may be effective in CRPC .	Overall these studies indicate that PP1alpha, CDK9 and CDK1 cooperate to drive AR transcriptional activity through a positive feedback loop and that agents targeting components of this loop may be effective in CRPC.	5	14	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	AR	AR	AR	9	10	13	14
The majority of genes that were induced both by androgen and by IGSF8 shRNA are well-known AR targets , including KLK3 ( PSA ) , KLK2 , KLK4 , PPAP2A , C19orf48 , cdc2 , and NFKB2 [ XREF_BIBR - XREF_BIBR ] .	The majority of genes that were induced both by androgen and by IGSF8 shRNA are well-known AR targets, including KLK3 (PSA), KLK2, KLK4, PPAP2A, C19orf48, cdc2, and NFKB2 [XREF_BIBR - XREF_BIBR].	16	34	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	cdc2	cdc2	cdc2	AR	AR	AR	33	34	16	17
The proteasome inhibitor , MG132 , could reverse the decrease in AR protein resulting from CDK1 inhibition although the S81A mutant was stabilized by over-expression of activated CDK1 similar to wild-type receptor suggesting that this phospho-site is not necessary for the CDK1 mediated stabilization of the AR .	The proteasome inhibitor, MG132, could reverse the decrease in AR protein resulting from CDK1 inhibition although the S81A mutant was stabilized by over-expression of activated CDK1 similar to wild-type receptor suggesting that this phospho-site is not necessary for the CDK1 mediated stabilization of the AR.	40	47	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	AR	AR	AR	41	42	46	47
Taken together our findings indicate that low levels of basal CDK1 mediated AR S81 phosphorylation are important to initiate transcription in response to androgen , which can then stimulate a positive feedback loop with recruitment PP1alpha and BRD4 , mobilization and recruitment of P-TEFb , and subsequent further AR S81 phosphorylation .	Taken together our findings indicate that low levels of basal CDK1 mediated AR S81 phosphorylation are important to initiate transcription in response to androgen, which can then stimulate a positive feedback loop with recruitment PP1alpha and BRD4, mobilization and recruitment of P-TEFb, and subsequent further AR S81 phosphorylation.	7	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	AR	AR	AR	10	11	12	13
This is in line with previous work which demonstrated that abolishment of pAR S81 in cell lines did not alter androgen dependent AR transcriptional activity , rapidly induced AR regulated genes or AR stabilisation mediated by Cdk1 .	This is in line with previous work which demonstrated that abolishment of pAR S81 in cell lines did not alter androgen dependent AR transcriptional activity, rapidly induced AR regulated genes or AR stabilisation mediated by Cdk1.	32	37	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	AR	AR	AR	36	37	32	33
Positive feedback loop mediated by protein phosphatase 1alpha mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer .	Positive feedback loop mediated by protein phosphatase 1alpha mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer.	13	17	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	androgen receptor	androgen receptor	androgen receptor	13	14	15	17
Together these results support a requirement for basal CDK1 mediated AR S81 phosphorylation , which may function to initiate a positive feedback loop through enhanced recruitment of p300 , BRD4 and P-TEFb , with subsequent amplification of the response through CDK9 mediated S81 phosphorylation .	Together these results support a requirement for basal CDK1 mediated AR S81 phosphorylation, which may function to initiate a positive feedback loop through enhanced recruitment of p300, BRD4 and P-TEFb, with subsequent amplification of the response through CDK9 mediated S81 phosphorylation.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	AR	AR	AR	8	9	10	11
Analysis of an S81A AR mutant demonstrated that this site is not required for transcriptional activity or Cdk1 mediated AR stabilization in transfected cells .	Analysis of an S81A AR mutant demonstrated that this site is not required for transcriptional activity or Cdk1 mediated AR stabilization in transfected cells.	12	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	AR	AR	AR	17	18	19	20
It has also been reported that CDK1 inhibition downregulates survivin , an inhibitor of apoptosis protein , and induces apoptosis .	It has also been reported that CDK1 inhibition downregulates survivin, an inhibitor of apoptosis protein, and induces apoptosis.	6	12	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	survivin	survivin	survivin	6	7	9	10
Additionally , CDK1 was able to not only enhance the anchorage independent growth ability of the cells , but also contribute to their further senescence escape by modulating the survivin and other pathways .	Additionally, CDK1 was able to not only enhance the anchorage independent growth ability of the cells, but also contribute to their further senescence escape by modulating the survivin and other pathways.	2	32	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	survivin	survivin	survivin	2	3	29	30
Studies have shown that elevated p34 cdc2 kinase activity can lead to increased survivin expression [ XREF_BIBR ] .	Studies have shown that elevated p34 cdc2 kinase activity can lead to increased survivin expression [XREF_BIBR].	5	15	lead	Positive_regulation_syntax_7_verb	Positive_activation	Positive_regulation	p34 cdc2	p34 cdc2	p34 cdc2	survivin	survivin expression	survivin	5	7	13	14
Cdk1 inhibition downregulates survivin , a known Cdk1 target required for the survival of cells overexpressing MYC .	Cdk1 inhibition downregulates survivin, a known Cdk1 target required for the survival of cells overexpressing MYC.	0	8	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	survivin	survivin	survivin	0	1	3	4
It was proposed that Cdc7 antagonizes the negative effect of the MCM4 N-terminal segment on initiation of DNA replication .	It was proposed that Cdc7 antagonizes the negative effect of the MCM4 N-terminal segment on initiation of DNA replication.	4	13	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc7	Cdc7	Cdc7	MCM4	MCM4	MCM4	4	5	11	12
Moreover , the MCM4 plasmid , unlike the empty vector , failed to yield transformed colonies in cdc7-4 mcm4 Delta2-174 or cdc7Delta mcm4 Delta2-174 cells , while CDC7 efficiently rescued cdc7Delta mcm4 Delta2-174 cells ( XREF_SUPPLEMENTARY ) .	Moreover, the MCM4 plasmid, unlike the empty vector, failed to yield transformed colonies in cdc7-4 mcm4 Delta2-174 or cdc7Delta mcm4 Delta2-174 cells, while CDC7 efficiently rescued cdc7Delta mcm4 Delta2-174 cells (XREF_SUPPLEMENTARY).	27	33	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC7	CDC7	CDC7	mcm4	mcm4	mcm4	27	28	31	32
13 During both maintenance of the prophase arrest and activation of the G 2 DNA damage checkpoint , CDC14B activates the CDH1 ( FZR1 ) regulatory component of the APC to reduce CDC2A activity via reduction of available CCNB1 .	13 During both maintenance of the prophase arrest and activation of the G 2 DNA damage checkpoint, CDC14B activates the CDH1 (FZR1) regulatory component of the APC to reduce CDC2A activity via reduction of available CCNB1.	18	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC14B	CDC14B	CDC14B	APC	APC	APC	18	19	29	30
However , when the superficial layer of cells in the animal caps was examined , in samples where all the deeper ( blastocelic roof ) cells had fallen off , E-cadherin was seen to be expressed at cell-cell contact sites and rescued the dissociation of alphaEC- depleted cells ( XREF_FIG D , E ) .	However, when the superficial layer of cells in the animal caps was examined, in samples where all the deeper (blastocelic roof) cells had fallen off, E-cadherin was seen to be expressed at cell-cell contact sites and rescued the dissociation of alphaEC- depleted cells (XREF_FIG D, E).	30	46	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	E-cadherin	E-cadherin	E-cadherin	alphaEC-	alphaEC-	alphaEC-	30	31	45	46
However , expression of both Cdc6 and Cdc7 fully rescued chromatin loading of Mcm2 in the presence of dominant negative Cdk2 .	However, expression of both Cdc6 and Cdc7 fully rescued chromatin loading of Mcm2 in the presence of dominant negative Cdk2.	2	14	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc7	expression of both Cdc6 and Cdc7	cdc7	Mcm2	Mcm2	mcm2	7	8	13	14
CDK14 and Cyclin Y activates LRP6 by phosphorylation at key residues during G2/M , promoting release of beta-catenin by Groucho , and induction of Wnt mediated gene transcription [ XREF_BIBR , XREF_BIBR ] .	CDK14 and Cyclin Y activates LRP6 by phosphorylation at key residues during G2/M, promoting release of beta-catenin by Groucho, and induction of Wnt mediated gene transcription [XREF_BIBR, XREF_BIBR].	0	6	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	CDK14	CDK14	CDK14	LRP6	LRP6	LRP6	0	1	5	6
Wnt and beta-catenin is potentially deregulated in PCas by loss of parafibromin , which is a member of the polymerase II complex interacting with beta-catenin [ XREF_BIBR ] .	Wnt and beta-catenin is potentially deregulated in PCas by loss of parafibromin, which is a member of the polymerase II complex interacting with beta-catenin [XREF_BIBR].	0	16	deregulated	Negative_activation_syntax_4_verb	Positive_activation	Negative_activation	parafibromin	loss of parafibromin	parafibromin	beta-catenin	beta-catenin	beta-catenin	11	12	2	3
As PP2A-B55delta is the major phosphatase that dephosphorylates CDK1 substrates , Greatwall and MASTL plays a pivotal role in maintaining CDK1 dependent phosphorylation during mitosis XREF_BIBR XREF_BIBR XREF_BIBR CDK1 activates Greatwall and MASTL during mitosis in a positive feedback loop XREF_BIBR .	As PP2A-B55delta is the major phosphatase that dephosphorylates CDK1 substrates, Greatwall and MASTL plays a pivotal role in maintaining CDK1 dependent phosphorylation during mitosis XREF_BIBR XREF_BIBR XREF_BIBR CDK1 activates Greatwall and MASTL during mitosis in a positive feedback loop XREF_BIBR.	27	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	MASTL	MASTL	MASTL	28	29	32	33
Cdk1 may contribute to regulate Gwl localization .	Cdk1 may contribute to regulate Gwl localization.	0	6	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Gwl	Gwl	Gwl	0	1	5	6
Gwl could be activated by a starter amount of activated Cdc2 .	Gwl could be activated by a starter amount of activated Cdc2.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdc2	amount of activated Cdc2	cdc2	Gwl	Gwl	gwl	10	11	0	1
This is because Cdk1 still drives Greatwall and MASTL activity .	This is because Cdk1 still drives Greatwall and MASTL activity.	3	9	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	MASTL	MASTL	MASTL	3	4	8	9
As Cdk1 dependent phosphorylation stimulates Gwl activity not only towards Ensa and ARPP19 but also towards Gwl itself at autoactivatory sites , by reversing Cdk1 dependent phosphorylation Fcp1 could also reduce Gwl autoactivatory strength , favouring this way PP1 action to stably switch off Gwl autoactivation and , along with directly reducing Gwl activity towards Ensa and ARPP19 , allow PP1 and PP2A-B55 to shut Gwl activity offdefinitively .	As Cdk1 dependent phosphorylation stimulates Gwl activity not only towards Ensa and ARPP19 but also towards Gwl itself at autoactivatory sites, by reversing Cdk1 dependent phosphorylation Fcp1 could also reduce Gwl autoactivatory strength, favouring this way PP1 action to stably switch off Gwl autoactivation and, along with directly reducing Gwl activity towards Ensa and ARPP19, allow PP1 and PP2A-B55 to shut Gwl activity offdefinitively.	23	33	reduce	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Gwl	Gwl	Gwl	24	25	31	32
Gwl is activated during M phase by Cdk1 and cyclin B ( MPF ) , but once activated , Gwl promotes PP2A and B55delta inhibition with no further requirement for MPF .	Gwl is activated during M phase by Cdk1 and cyclin B (MPF), but once activated, Gwl promotes PP2A and B55delta inhibition with no further requirement for MPF.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Gwl	Gwl	Gwl	7	8	0	1
Because Gwl is activated by Cdk1 phosphorylation , Cdk1 inhibits PP2A : B55 via this Gwl-ENSA pathway , allowing the high phosphorylation level of Cdk1 substrates in mitosis [ XREF_BIBR , XREF_BIBR ] .	Because Gwl is activated by Cdk1 phosphorylation, Cdk1 inhibits PP2A : B55 via this Gwl-ENSA pathway, allowing the high phosphorylation level of Cdk1 substrates in mitosis [XREF_BIBR, XREF_BIBR].	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdk1	Cdk1 phosphorylation	cdk1	Gwl	Gwl	gwl	5	6	1	2
Moreover , Cdk1 has been shown to activate Gwl kinase activity .	Moreover, Cdk1 has been shown to activate Gwl kinase activity.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Gwl	Gwl	Gwl	2	3	8	9
Cdk1 dependent activation of Gwl at mitotic entry leads to PP2A-B55 downregulation , which synergizes with Cdk1 activation to promote the phosphorylated states of several mitotic substrates .	Cdk1 dependent activation of Gwl at mitotic entry leads to PP2A-B55 downregulation, which synergizes with Cdk1 activation to promote the phosphorylated states of several mitotic substrates.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Gwl	Gwl	Gwl	0	1	4	5
And , Cdk1 directly induces the formation of BRCA1 foci during DNA damage response through phosphorylation of a number of serine residues in BRCA1 [ XREF_BIBR ] .	And, Cdk1 directly induces the formation of BRCA1 foci during DNA damage response through phosphorylation of a number of serine residues in BRCA1 [XREF_BIBR].	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	BRCA1	BRCA1	BRCA1	2	3	8	9
Because reduced cdk1 activity impairs BRCA1 function and HR repair , cdk1 inhibition represents a plausible strategy for expanding the utility of PARP inhibitors to the BRCA-proficient cancer population .	Because reduced cdk1 activity impairs BRCA1 function and HR repair, cdk1 inhibition represents a plausible strategy for expanding the utility of PARP inhibitors to the BRCA-proficient cancer population.	2	6	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	cdk1	cdk1	cdk1	BRCA1	BRCA1	BRCA1	2	3	5	6
These results indicate that the inhibition of Cdk1 activity or expression can decrease BRCA1 activity , resulting in reduced cellular recovery from DNA damage .	These results indicate that the inhibition of Cdk1 activity or expression can decrease BRCA1 activity, resulting in reduced cellular recovery from DNA damage.	7	14	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	BRCA1	BRCA1	BRCA1	7	8	13	14
Consequently , as reduced CDK1 expression impairs BRCA1 function and DNA repair , the inhibition of CDK1 represents a potential strategy for expanding the utility of poly-ADP ribose polymerase inhibitors to BRCA-competent cancers .	Consequently, as reduced CDK1 expression impairs BRCA1 function and DNA repair, the inhibition of CDK1 represents a potential strategy for expanding the utility of poly-ADP ribose polymerase inhibitors to BRCA-competent cancers.	4	8	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1 expression	cdk1	BRCA1	BRCA1	brca1	4	5	7	8
A further way to block HR is to inhibit CDK1 , which activates BRCA1 .	A further way to block HR is to inhibit CDK1, which activates BRCA1.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	BRCA1	BRCA1	BRCA1	9	10	13	14
In this particular case , selective cdk1 inhibition disrupts BRCA1 function without fully arresting the cancer cell cycle , blocking activation of the S phase checkpoint , as well as DNA repair .	In this particular case, selective cdk1 inhibition disrupts BRCA1 function without fully arresting the cancer cell cycle, blocking activation of the S phase checkpoint, as well as DNA repair.	6	10	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	cdk1	cdk1	cdk1	BRCA1	BRCA1	BRCA1	6	7	9	10
To explain this atypical mitotic activation in neurons we investigated the Cdc2 activating Cdc25A phosphatase in human brain .	To explain this atypical mitotic activation in neurons we investigated the Cdc2 activating Cdc25A phosphatase in human brain.	9	14	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdc2	Cdc2	Cdc2	Cdc25A	Cdc25A	Cdc25A	11	12	13	14
In the case of LNCaP cells , upregulated miR-449a directly downregulates c-Myc that is required to induce the cell cycle regulators Cdc25A and Cdc2 and CyclinB whose inactivation blocks G2 to M phase transition .	In the case of LNCaP cells, upregulated miR-449a directly downregulates c-Myc that is required to induce the cell cycle regulators Cdc25A and Cdc2 and CyclinB whose inactivation blocks G2 to M phase transition.	11	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc2	Cdc2	Cdc2	Cdc25A	Cdc25A	Cdc25A	23	24	21	22
Phosphorylation of Ser18 and Ser116 residues by CyclinB and Cdk1 results in mouse Cdc25A stabilization , thereby creating a positive feedback loop that allows Cdc25A to dephosphorylate and activate CyclinB and Cdk1 .	Phosphorylation of Ser18 and Ser116 residues by CyclinB and Cdk1 results in mouse Cdc25A stabilization, thereby creating a positive feedback loop that allows Cdc25A to dephosphorylate and activate CyclinB and Cdk1.	0	32	allows	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Cdk1	Phosphorylation of Ser18 and Ser116 residues by CyclinB and Cdk1	cdk1	Cdc25A	Cdc25A to dephosphorylate and activate CyclinB and Cdk1	cdc25a	9	10	24	25
This could be explained by the full activation of Eg5 by Cdk1 , which could be sufficient to overcome the resistant force .	This could be explained by the full activation of Eg5 by Cdk1, which could be sufficient to overcome the resistant force.	3	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Eg5	Eg5	Eg5	11	12	9	10
Together with the observation that cyclin B accumulates at spindle poles , Cdk1 and cyclin B might promote the interaction of Eg5 with dynein-dynactin toward the poles of spindles .	Together with the observation that cyclin B accumulates at spindle poles, Cdk1 and cyclin B might promote the interaction of Eg5 with dynein-dynactin toward the poles of spindles.	12	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Eg5	Eg5	Eg5	12	13	21	22
It is unclear , if Cdk1 contributes to disjunction , but Cdk1 is thought to trigger separation by activating Eg5 .	It is unclear, if Cdk1 contributes to disjunction, but Cdk1 is thought to trigger separation by activating Eg5.	11	20	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Eg5	Eg5	Eg5	11	12	19	20
We found that Cdk1 strongly enhances the binding of purified Eg5 to microtubules .	We found that Cdk1 strongly enhances the binding of purified Eg5 to microtubules.	3	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Eg5	Eg5	Eg5	3	4	10	11
These results demonstrate that phosphorylation of threonine 937 by Cdk1 in vitro strongly enhances the binding of Eg5 to microtubules .	These results demonstrate that phosphorylation of threonine 937 by Cdk1 in vitro strongly enhances the binding of Eg5 to microtubules.	4	18	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	phosphorylation of threonine 937 by Cdk1	cdk1	Eg5	Eg5	eg5	9	10	17	18
In turn , KIF11 is activated by CDC2 and CCNB ( XREF_FIG ) .	In turn, KIF11 is activated by CDC2 and CCNB (XREF_FIG).	3	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDC2	CDC2	CDC2	KIF11	KIF11	KIF11	7	8	3	4
It is thus likely that Cdk1 triggers fast separation by breaking the Eg5 opposing force .	It is thus likely that Cdk1 triggers fast separation by breaking the Eg5 opposing force.	5	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Eg5	Eg5	Eg5	5	6	12	13
Moreover , CRT0066101 downregulated the expression of Cdc25C , which dephosphorylates and activates CDK1 , but enhanced the activity of the checkpoint kinase Chk1 , which inhibits CDK1 by phosphorylating and inactivating Cdc25C .	Moreover, CRT0066101 downregulated the expression of Cdc25C, which dephosphorylates and activates CDK1, but enhanced the activity of the checkpoint kinase Chk1, which inhibits CDK1 by phosphorylating and inactivating Cdc25C.	2	33	enhanced	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	CDK1	CRT0066101 downregulated the expression of Cdc25C, which dephosphorylates and activates CDK1	cdk1	Chk1	Chk1, which inhibits CDK1 by phosphorylating and inactivating Cdc25C	chk1	13	14	23	24
In fact , Chk1 inactivation propagates in a wave like manner synchronized with the wave of Cdk1 activity ( XREF_FIG ) , arguing that Cdk1 triggers Chk1 inactivation , consistent with previous results .	In fact, Chk1 inactivation propagates in a wave like manner synchronized with the wave of Cdk1 activity (XREF_FIG), arguing that Cdk1 triggers Chk1 inactivation, consistent with previous results.	24	27	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Chk1	Chk1	Chk1	24	25	26	27
Since Cdc2 is not phosphorylated in this complex it is unlikely that Cdc2 is the target of Chk1 .	Since Cdc2 is not phosphorylated in this complex it is unlikely that Cdc2 is the target of Chk1.	12	18	is the target	Positive_activation_copula_1	Positive_activation	Positive_activation	Cdc2	Cdc2	Cdc2	Chk1	Chk1	Chk1	12	13	17	18
Once activated Chk1 prevents the activation of cyclin dependent kinase 1 ( Cdk1 ) which in complex with cyclin B is responsible for mitotic entry .	Once activated Chk1 prevents the activation of cyclin dependent kinase 1 (Cdk1) which in complex with cyclin B is responsible for mitotic entry.	1	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Chk1	Chk1	Chk1	12	13	2	3
Activated Chk1 inhibits Cdk1 activity by down-regulating Cdc25 phosphatases , which counteract inhibitory phosphorylation of Cdk1 by Wee1 kinase .	Activated Chk1 inhibits Cdk1 activity by down-regulating Cdc25 phosphatases, which counteract inhibitory phosphorylation of Cdk1 by Wee1 kinase.	0	4	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Chk1	Chk1	Chk1	3	4	1	2
These observations suggest a simple model whereby Mcl-1 is targeted for degradation during a mitotic arrest by Cdk1 dependent APC and C-Cdc 20 ubiquitination .	These observations suggest a simple model whereby Mcl-1 is targeted for degradation during a mitotic arrest by Cdk1 dependent APC and C-Cdc 20 ubiquitination.	7	24	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdk1	Cdk1 dependent APC and C-Cdc 20 ubiquitination	cdk1	Mcl-1	Mcl-1	mcl-1	17	18	7	8
CDK1 inhibition acts at multiple steps to inactivate MCL1 , both by inducing NOXA , as well as through inhibition of S64 phosphorylation in hESCs .	CDK1 inhibition acts at multiple steps to inactivate MCL1, both by inducing NOXA, as well as through inhibition of S64 phosphorylation in hESCs.	0	9	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	MCL1	MCL1	MCL1	0	1	8	9
Phosphorylation of S64 by CDK1 enhances its anti-apoptotic function of MCL1 without affecting protein stability .	Phosphorylation of S64 by CDK1 enhances its anti-apoptotic function of MCL1 without affecting protein stability.	0	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	Phosphorylation of S64 by CDK1	cdk1	MCL1	MCL1	mcl1	4	5	10	11
In the current study , CDK1 , but not CDK2 mediated the CDC25A enhanced FOXM1 transcriptional activity .	In the current study, CDK1, but not CDK2 mediated the CDC25A enhanced FOXM1 transcriptional activity.	5	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	FOXM1	FOXM1	FOXM1	5	6	14	15
Inhibition of Cdk1 , but not Plk1 , markedly reduced the binding of endogenous FoxM1 to GST-Plk1 PBD ( XREF_SUPPLEMENTARY ) .	Inhibition of Cdk1, but not Plk1, markedly reduced the binding of endogenous FoxM1 to GST-Plk1 PBD (XREF_SUPPLEMENTARY).	0	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	FoxM1	FoxM1	FoxM1	2	3	14	15
These results support a model in which CDK1 and cyclin protein complexes mediate CDC25A enhanced FOXM1 transcriptional activity via phosphorylation of T600 , T611 and T620 residues and the LXL docking motif .	These results support a model in which CDK1 and cyclin protein complexes mediate CDC25A enhanced FOXM1 transcriptional activity via phosphorylation of T600, T611 and T620 residues and the LXL docking motif.	7	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	FOXM1	FOXM1	FOXM1	7	8	15	16
Additionally , Cdk1 activates the acetyltransferase TIP60 , causing acetylation and activation of AURKB , which further contributes to abnormal aneuploidy and uncontrolled cell cycle progression .	Additionally, Cdk1 activates the acetyltransferase TIP60, causing acetylation and activation of AURKB, which further contributes to abnormal aneuploidy and uncontrolled cell cycle progression.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	TIP60	TIP60	TIP60	2	3	6	7
Our present study delineated the cellular function of TIP60 in mitosis but not earlier events by which CDK1 elicited activation of TIP60 orchestrated acetylation of Aurora B at the kinetochores for accurate chromosome alignment and segregation .	Our present study delineated the cellular function of TIP60 in mitosis but not earlier events by which CDK1 elicited activation of TIP60 orchestrated acetylation of Aurora B at the kinetochores for accurate chromosome alignment and segregation.	17	22	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	TIP60	TIP60	TIP60	17	18	21	22
E2F1 binding intensity to the MCL1 promoter was comparable to the known E2F1 target CDC2 , however only mildly altered by the addition of R1881 implying that other co-factors regulating E2F1 transcriptional activity might be involved .	E2F1 binding intensity to the MCL1 promoter was comparable to the known E2F1 target CDC2, however only mildly altered by the addition of R1881 implying that other co-factors regulating E2F1 transcriptional activity might be involved.	9	19	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	CDC2	CDC2	CDC2	E2F1	E2F1	E2F1	14	15	12	13
Thus , Cdk1 and Plx1 synergistically activate the kinase activity of BubR1 in a Thr 605 dependent manner .	Thus, Cdk1 and Plx1 synergistically activate the kinase activity of BubR1 in a Thr 605 dependent manner.	2	17	synergistically activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	BubR1	BubR1	BubR1	2	3	11	12
Cdk1 inhibition induced rapid securin degradation ( XREF_FIG B ) .	Cdk1 inhibition induced rapid securin degradation (XREF_FIG B).	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	securin	securin	securin	0	1	4	5
Thus , it is not clear how phosphorylation by cyclinB and Cdk1 activates SIRT1 activity .	Thus, it is not clear how phosphorylation by cyclinB and Cdk1 activates SIRT1 activity.	7	14	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	SIRT1	SIRT1	SIRT1	11	12	13	14
This model was confirmed in cells from p21Waf1 knockout mice where PGA2 was completely unable to block the activating phosphorylation of cdk2 , or inhibit cdk2 activity .	This model was confirmed in cells from p21Waf1 knockout mice where PGA2 was completely unable to block the activating phosphorylation of cdk2, or inhibit cdk2 activity.	11	26	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cdk2	PGA2 was completely unable to block the activating phosphorylation of cdk2	cdk2	cdk2	cdk2	cdk2	21	22	25	26
In contrast , cell adhesion does not have pronounced effects on ( a ) the levels of cyclin E or cdk2 , ( b ) formation of the cyclin E and cdk2 complex , or ( c ) the positive and negative regulatory phosphorylations that modulate cdk2 activity .	In contrast, cell adhesion does not have pronounced effects on (a) the levels of cyclin E or cdk2, (b) formation of the cyclin E and cdk2 complex, or (c) the positive and negative regulatory phosphorylations that modulate cdk2 activity.	15	47	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdk2	levels of cyclin E or cdk2	cdk2	cdk2	cdk2	cdk2	20	21	46	47
Reexpression of wild-type CDK2 in DN-CDK2-transfected cancer cells restored CDK2 activity but not paclitaxel sensitivity .	Reexpression of wild-type CDK2 in DN-CDK2-transfected cancer cells restored CDK2 activity but not paclitaxel sensitivity.	0	10	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK2	Reexpression of wild-type CDK2	cdk2	CDK2	CDK2	cdk2	3	4	9	10
One explanation for this phenomenon is that the overexpression of both CDK1 and CDK2 in the malignant state increases the ability of CDK2 to compensate for CDK1 loss .	One explanation for this phenomenon is that the overexpression of both CDK1 and CDK2 in the malignant state increases the ability of CDK2 to compensate for CDK1 loss.	8	23	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK2	overexpression of both CDK1 and CDK2	cdk2	CDK2	CDK2	cdk2	13	14	22	23
Dephosphorylation of Cdk2 by Cdc25A is required to activate cyclinA and Cdk2 in S phase [ XREF_BIBR ] .	Dephosphorylation of Cdk2 by Cdc25A is required to activate cyclinA and Cdk2 in S phase [XREF_BIBR].	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk2	Dephosphorylation of Cdk2	cdk2	Cdk2	Cdk2	cdk2	2	3	11	12
We first analyzed the phosphorylation of CDK2 at Thr 160 , which is known to activate CDK2 kinase activity and in turn promote the G 1 -S transition [ XREF_BIBR ] .	We first analyzed the phosphorylation of CDK2 at Thr 160, which is known to activate CDK2 kinase activity and in turn promote the G 1 -S transition [XREF_BIBR].	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK2	phosphorylation of CDK2 at Thr 160	cdk2	CDK2	CDK2	cdk2	6	7	16	17
Our data indicated that DOC-1R overexpression decreased CDK2 expression and inhibited CDK2 activation .	Our data indicated that DOC-1R overexpression decreased CDK2 expression and inhibited CDK2 activation.	4	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK2	DOC-1R overexpression decreased CDK2 expression	cdk2	CDK2	CDK2	cdk2	7	8	11	12
Phosphorylation of CDK2 at Thr 160 is known to activate CDK2 kinase activity , which in turn promotes G1-S transition .	Phosphorylation of CDK2 at Thr 160 is known to activate CDK2 kinase activity, which in turn promotes G1-S transition.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK2	Phosphorylation of CDK2 at Thr 160	cdk2	CDK2	CDK2	cdk2	2	3	10	11
CDK2 controls the G1/S transition by complexing with CYCLIN E , and is activated by CDC25A , which dephosphorylates CDK2 XREF_BIBR .	CDK2 controls the G1/S transition by complexing with CYCLIN E, and is activated by CDC25A, which dephosphorylates CDK2 XREF_BIBR.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CDK2	CDC25A, which dephosphorylates CDK2	cdk2	CDK2	CDK2	cdk2	19	20	0	1
Phosphorylation of CDK2 at Thr160 , which is required to activate CDK2 in G1-phase , 33 also did not show any significant changes with treatment , nor did phosphorylation of Thr821 on Rb , a CDK2 target .	Phosphorylation of CDK2 at Thr160, which is required to activate CDK2 in G1-phase, 33 also did not show any significant changes with treatment, nor did phosphorylation of Thr821 on Rb, a CDK2 target.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK2	Phosphorylation of CDK2 at Thr160	cdk2	CDK2	CDK2	cdk2	2	3	11	12
Although no direct MYBL2 inhibitor is available yet , CDK2 inhibition could be used to reduce MYBL2 activity in MYBL2 high expressing cancers .	Although no direct MYBL2 inhibitor is available yet, CDK2 inhibition could be used to reduce MYBL2 activity in MYBL2 high expressing cancers.	9	17	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK2	CDK2	CDK2	MYBL2	MYBL2	MYBL2	9	10	16	17
RO-3306 treatment significantly inhibited Nutlin induced transcriptional activation of p21 , suggesting that CDK1 inhibition blocks the transcriptional activity of p53 .	RO-3306 treatment significantly inhibited Nutlin induced transcriptional activation of p21, suggesting that CDK1 inhibition blocks the transcriptional activity of p53.	13	21	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	p53	p53	p53	13	14	20	21
These results indicate that ALS significantly downregulates the expression of CDC2 , cyclin B1 , and CDK2 but upregulates p21 Waf1 and Cip1 , p27 Kip1 , and p53 in both PANC-1 and BxPC-3 cells , which contributes , at least in part , to the observed cell cycle arrest phenomenon in both cell lines .	These results indicate that ALS significantly downregulates the expression of CDC2, cyclin B1, and CDK2 but upregulates p21 Waf1 and Cip1, p27 Kip1, and p53 in both PANC-1 and BxPC-3 cells, which contributes, at least in part, to the observed cell cycle arrest phenomenon in both cell lines.	4	29	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC2	ALS significantly downregulates the expression of CDC2	cdc2	p53	p53	p53	10	11	28	29
Suppression of Tpr and CDK1 Increases Virus Replication While Blockade of ATM , p53 , and Vimentin Reducing Virus Replication .	Suppression of Tpr and CDK1 Increases Virus Replication While Blockade of ATM, p53, and Vimentin Reducing Virus Replication.	2	14	Blockade	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	CDK1	CDK1	CDK1	p53	p53	p53	4	5	13	14
Further , Cdk1 inhibition and RO-3306 have been shown to not prevent DNA damage response or p53 induction .	Further, Cdk1 inhibition and RO-3306 have been shown to not prevent DNA damage response or p53 induction.	2	17	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	p53	p53	p53	2	3	16	17
Western blot analysis showed that beta-elemene down-regulated the protein expression of CDC2 , cyclin A , and cyclin B1 , and up-regulated the expression of p21 WAF1 and CIP1 and p53 in both A2780 and A2780/CP cells .	Western blot analysis showed that beta-elemene down-regulated the protein expression of CDC2, cyclin A, and cyclin B1, and up-regulated the expression of p21 WAF1 and CIP1 and p53 in both A2780 and A2780/CP cells.	5	36	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDC2	beta-elemene down-regulated the protein expression of CDC2	cdc2	p53	p53	p53	11	12	30	31
The enforced expression of both cyclin B1 and cdc2 leads to overriding p53 mediated G2-M arrest .	The enforced expression of both cyclin B1 and cdc2 leads to overriding p53 mediated G2-M arrest.	2	13	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	cdc2	expression of both cyclin B1 and cdc2	cdc2	p53	p53	p53	8	9	12	13
If p53 is inactivated due to complex formation with p34cdc2 protein , then attenuation of cdc2 by BPDE ( as we observed ) will relieve p53 inactivation resulting from complex formation ( increased free p53 ) and thereby cell growth inhibition by p53 will be augmented .	If p53 is inactivated due to complex formation with p34cdc2 protein, then attenuation of cdc2 by BPDE (as we observed) will relieve p53 inactivation resulting from complex formation (increased free p53) and thereby cell growth inhibition by p53 will be augmented.	13	26	relieve	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	cdc2	cdc2	cdc2	p53	p53	p53	15	16	25	26
Also , we localized cytoplasmic cdk2 to both the endoplasmic reticulum ( ER ) and Golgi compartments , and ER stress was blocked by specific cdk2 inhibition .	Also, we localized cytoplasmic cdk2 to both the endoplasmic reticulum (ER) and Golgi compartments, and ER stress was blocked by specific cdk2 inhibition.	19	26	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	cdk2	cdk2	cdk2	ER	ER	ER	25	26	19	20
In both ER + and ER - BCa cells diosgenin caused G 1 cell cycle arrest by downregulating cyclin D1 , cdk-2 and cdk-4 expression what resulted in cell proliferation inhibition and induced apoptosis .	In both ER + and ER - BCa cells diosgenin caused G 1 cell cycle arrest by downregulating cyclin D1, cdk-2 and cdk-4 expression what resulted in cell proliferation inhibition and induced apoptosis.	0	25	caused	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	cdk-2	cdk-2 and cdk-4 expression	cdk-2	ER	ER	er	21	22	2	3
Molecularly , DOC-1R inhibited CDK2 expression at the mRNA and protein levels , and there were decreased levels of G1-phase cyclins ( cyclin D1 and E ) and elevated levels of p21 , p27 , and p53 proteins .	Molecularly, DOC-1R inhibited CDK2 expression at the mRNA and protein levels, and there were decreased levels of G1-phase cyclins (cyclin D1 and E) and elevated levels of p21, p27, and p53 proteins.	2	37	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK2	DOC-1R inhibited CDK2 expression	cdk2	p53	p53	p53	4	5	36	37
Constitutive CCND1 and CDK2 activity caused accumulation of p53 except in cells expressing shp53 , and accumulation of p21 regardless of p53 expression ( XREF_FIG ) .	Constitutive CCND1 and CDK2 activity caused accumulation of p53 except in cells expressing shp53, and accumulation of p21 regardless of p53 expression (XREF_FIG).	3	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK2	CDK2	CDK2	p53	p53	p53	3	4	8	9
In addition , phosphorylation by CK2 strongly inhibits PKC induced activation of p53 DNA binding , while the activation of p53 by cdk2 and cyclin A is not affected by CK2 .	In addition, phosphorylation by CK2 strongly inhibits PKC induced activation of p53 DNA binding, while the activation of p53 by cdk2 and cyclin A is not affected by CK2.	18	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	cdk2	cdk2	cdk2	p53	p53	p53	22	23	20	21
Since Cdk2 inactivation also elicits p53 independent cellular senescence , Cdk2 may be another ideal target for treating cancers with p53 inactivation .	Since Cdk2 inactivation also elicits p53 independent cellular senescence, Cdk2 may be another ideal target for treating cancers with p53 inactivation.	1	8	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk2	Cdk2	Cdk2	p53	p53	p53	1	2	5	6
We show that , independently of p53 status , Cdk2 stimulates the ATR and Chk1 pathway and is required for an efficient DNA replication checkpoint response .	We show that, independently of p53 status, Cdk2 stimulates the ATR and Chk1 pathway and is required for an efficient DNA replication checkpoint response.	9	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk2	Cdk2	Cdk2	Chk1	Chk1	Chk1	9	10	14	15
Thus , Cdk2 stimulates Chk1 activation and promotes the replication stress response even in cells with functional p53 .	Thus, Cdk2 stimulates Chk1 activation and promotes the replication stress response even in cells with functional p53.	2	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk2	Cdk2	Cdk2	Chk1	Chk1	Chk1	2	3	4	5
We show that Cdk2 promotes Chk1 activation and cell cycle arrest induced by hydroxyurea .	We show that Cdk2 promotes Chk1 activation and cell cycle arrest induced by hydroxyurea.	3	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk2	Cdk2	Cdk2	Chk1	Chk1	Chk1	3	4	5	6
Although PNQALRE and CCRK was recently proposed to activate Cdk2 , we show that the monomeric protein has no intrinsic CAK activity .	Although PNQALRE and CCRK was recently proposed to activate Cdk2, we show that the monomeric protein has no intrinsic CAK activity.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCRK	CCRK	CCRK	Cdk2	Cdk2	Cdk2	3	4	9	10
CCRK activates Cdk2 , which controls the cell-cycle progression by phosphorylating a threonine residue conserved in Cdk2 .	CCRK activates Cdk2, which controls the cell-cycle progression by phosphorylating a threonine residue conserved in Cdk2.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCRK	CCRK	CCRK	Cdk2	Cdk2	Cdk2	0	1	2	3
On the other hand , CDC2 ( CDK1 ) and CDK2 have been shown to activate EZH2 by phosphorylation of its Thr350 residue [ XREF_BIBR - XREF_BIBR ] .	On the other hand, CDC2 (CDK1) and CDK2 have been shown to activate EZH2 by phosphorylation of its Thr350 residue [XREF_BIBR - XREF_BIBR].	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK2	CDK2	CDK2	EZH2	EZH2	EZH2	10	11	16	17
For example , phosphorylation of EZH2 on threonine 350 by CDK1 and CDK2 increases EZH2 recruitment to , and maintenance of , H3K27me3 levels at target loci , enhancing global gene silencing .	For example, phosphorylation of EZH2 on threonine 350 by CDK1 and CDK2 increases EZH2 recruitment to, and maintenance of, H3K27me3 levels at target loci, enhancing global gene silencing.	7	15	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CDK2	CDK2	CDK2	EZH2	EZH2	EZH2	12	13	14	15
Since CDK2 has been reported to phosphorylate and activate C/EBPbeta XREF_BIBR , GN could inhibit MCE during early adipogenesis through blocking the CDK2 mediated activation of C/EBPbeta .	Since CDK2 has been reported to phosphorylate and activate C/EBPbeta XREF_BIBR, GN could inhibit MCE during early adipogenesis through blocking the CDK2 mediated activation of C/EBPbeta.	22	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	CDK2	CDK2	CDK2	C/EBPbeta	C/EBPbeta	C/EBPbeta	22	23	26	27
CDK2 was reported to activate NF-YA by phosphorylating its Ser 291 and Ser 297 residues .	CDK2 was reported to activate NF-YA by phosphorylating its Ser 291 and Ser 297 residues.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK2	CDK2	CDK2	NF-YA	NF-YA	NF-YA	0	1	5	6
Resection is under cell cycle control and occurs during S and G2 phases when CDK2 activates the key resection protein CtIP via phosphorylation [ XREF_BIBR ] .	Resection is under cell cycle control and occurs during S and G2 phases when CDK2 activates the key resection protein CtIP via phosphorylation [XREF_BIBR].	14	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK2	CDK2	CDK2	CtIP	CtIP	CtIP	14	15	20	21
ICK can be activated by an upstream kinase CCRK ( cell cycle related kinase ) through phosphorylation of the essential Thr 157 residue in its MAPK like TDY motif XREF_BIBR .	ICK can be activated by an upstream kinase CCRK (cell cycle related kinase) through phosphorylation of the essential Thr 157 residue in its MAPK like TDY motif XREF_BIBR.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CCRK	CCRK	CCRK	ICK	ICK	ICK	8	9	0	1
Secondly , it has been demonstrated that Cyclin A-CDK2 complexes rapidly shuttle between the cytoplasm and the nucleus , allowing cytoplasmic targeting of CDC25C by CDK2 8 .	Secondly, it has been demonstrated that Cyclin A-CDK2 complexes rapidly shuttle between the cytoplasm and the nucleus, allowing cytoplasmic targeting of CDC25C by CDK2 8.	19	26	targeting	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CDK2	CDK2	CDK2	CDC25C	CDC25C	CDC25C	25	26	23	24
In addition , roscovitine could suppress expression of IL-6 by inhibiting CDK2 mediated activation of SP1 XREF_BIBR , a transcription factor that has been shown to be important in IL-6 gene expression XREF_BIBR , as well as in collagen expression XREF_BIBR , XREF_BIBR .	In addition, roscovitine could suppress expression of IL-6 by inhibiting CDK2 mediated activation of SP1 XREF_BIBR, a transcription factor that has been shown to be important in IL-6 gene expression XREF_BIBR, as well as in collagen expression XREF_BIBR, XREF_BIBR.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	CDK2	CDK2	CDK2	SP1	SP1	SP1	11	12	15	16
XREF_BIBR In another study , conditional disruption of Cdk7 in mouse embryonic fibroblasts ( MEFs ) blocked cell division and activation of Cdk1 , Cdk2 , Cdk4 , and Cdk6 .	XREF_BIBR In another study, conditional disruption of Cdk7 in mouse embryonic fibroblasts (MEFs) blocked cell division and activation of Cdk1, Cdk2, Cdk4, and Cdk6.	6	29	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk7	Cdk7	Cdk7	Cdk1	Cdk1	Cdk1	8	9	22	23
Additionally , myricetin treatment resulted in the up-regulation of Thr14 and Tyr15 phosphorylated ( inactive ) Cdc2 and p27 , and the down-regulation of CDK7 kinase protein , as well as CDK7 mediated Thr161 phosphorylated ( active ) Cdc2 .	Additionally, myricetin treatment resulted in the up-regulation of Thr14 and Tyr15 phosphorylated (inactive) Cdc2 and p27, and the down-regulation of CDK7 kinase protein, as well as CDK7 mediated Thr161 phosphorylated (active) Cdc2.	4	39	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK7	phosphorylated (inactive) Cdc2 and p27, and the down-regulation of CDK7 kinase protein, as well as CDK7	cdk7	Cdc2	Cdc2	cdc2	31	32	38	39
Cyclin H and CDK7 forms CAK complex that is able to activate CDK2 , CDK1 , CDK4 , and CDK6 by threonine phosphorylation , thus regulating cell cycle progression .	Cyclin H and CDK7 forms CAK complex that is able to activate CDK2, CDK1, CDK4, and CDK6 by threonine phosphorylation, thus regulating cell cycle progression.	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK7	CDK7	CDK7	CDK1	CDK1	CDK1	3	4	14	15
A two-step activation , in which Cdk1 was incubated with cyclin B , washed and treated with Cdk7 ( lane 14 ) , was less efficient ( < 1,000-fold ) , possibly due to the instability of Cdk1 and cyclin B complexes lacking T-loop phosphorylation .	A two-step activation, in which Cdk1 was incubated with cyclin B, washed and treated with Cdk7 (lane 14), was less efficient (< 1,000-fold), possibly due to the instability of Cdk1 and cyclin B complexes lacking T-loop phosphorylation.	6	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Cdk7	Cdk7	Cdk7	Cdk1	Cdk1	Cdk1	17	18	6	7
Because CDK1 activity mediated by CAK is involved in regulating cell cycle G 2 / M progression [ XREF_BIBR , XREF_BIBR ] , suggesting that pM9 expression suppresses CDK1 activity in regulating G 2 / M transition in the xenografted cells , as we observed in HL60R cells transduced with pM9 in vitro ( XREF_FIG ) .	Because CDK1 activity mediated by CAK is involved in regulating cell cycle G 2 / M progression [XREF_BIBR, XREF_BIBR], suggesting that pM9 expression suppresses CDK1 activity in regulating G 2 / M transition in the xenografted cells, as we observed in HL60R cells transduced with pM9 in vitro (XREF_FIG).	1	6	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CAK	CAK	CAK	CDK1	CDK1	CDK1	5	6	1	2
RNMT T77 phosphorylation was assessed following treatment with roscovitine , which targets CDK1 , CDK2 , CDK5 , CDK7 , and CDK9 , and RO-3306 , which targets CDK1 and CDK2 .	RNMT T77 phosphorylation was assessed following treatment with roscovitine, which targets CDK1, CDK2, CDK5, CDK7, and CDK9, and RO-3306, which targets CDK1 and CDK2.	11	30	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK7	CDK7	CDK7	CDK1	CDK1	CDK1	18	19	28	29
Cdc2-cyclin complexes isolated from the arrested cells could be activated in vitro by recombinant CAK , whereas complexes from wild-type cells or either of the single mutants were refractory to activation .	Cdc2-cyclin complexes isolated from the arrested cells could be activated in vitro by recombinant CAK, whereas complexes from wild-type cells or either of the single mutants were refractory to activation.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CAK	CAK	CAK	Cdc2-cyclin	Cdc2-cyclin	Cdc2-cyclin	14	15	0	1
Selective inhibition of Cdk7 , in HCT116 colon cancer cells in which wild-type Cdk7 was replaced with Cdk7 as , blocked activation of Cdk1 and Cdk2 and caused arrest at both G 1 / S and G 2 / M transitions .	Selective inhibition of Cdk7, in HCT116 colon cancer cells in which wild-type Cdk7 was replaced with Cdk7 as, blocked activation of Cdk1 and Cdk2 and caused arrest at both G 1 / S and G 2 / M transitions.	1	25	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk7	Cdk7	Cdk7	Cdk1	Cdk1	Cdk1	3	4	23	24
These results suggest that CDK7 and CCNH activate CDC2 by T161 phosphorylation and make up CAK , which is required for normal meiotic progression during porcine oocyte maturation .	These results suggest that CDK7 and CCNH activate CDC2 by T161 phosphorylation and make up CAK, which is required for normal meiotic progression during porcine oocyte maturation.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK7	CDK7	CDK7	CDC2	CDC2	CDC2	4	5	8	9
It is a general CAK that activates Cdk1 , Mcs6 and Cdk9 -- an essential homolog of positive transcription elongation factor b ( P-TEFb ) in metazoans XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR .	It is a general CAK that activates Cdk1, Mcs6 and Cdk9 -- an essential homolog of positive transcription elongation factor b (P-TEFb) in metazoans XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CAK	CAK	CAK	Cdk1	Cdk1	Cdk1	4	5	7	8
In this light , it is noteworthy that the Cdk1 activators CAK and Cdc25A are predominantly nuclear ( as is the Cdk1 inactivator Wee1 ) , and the Cdk1 inhibitor Myt1 is cytoplasmic .	In this light, it is noteworthy that the Cdk1 activators CAK and Cdc25A are predominantly nuclear (as is the Cdk1 inactivator Wee1), and the Cdk1 inhibitor Myt1 is cytoplasmic.	8	16	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	CAK	CAK	CAK	Cdk1	Cdk1	Cdk1	11	12	9	10
Immunoblotting experiments using monoclonal antibodies against cdc2 , cyclin B , and cdk7 ( an activator of cdc2 ) have revealed that the concentrations of cdc2 and cdk7 are almost constant during oogenesis .	Immunoblotting experiments using monoclonal antibodies against cdc2, cyclin B, and cdk7 (an activator of cdc2) have revealed that the concentrations of cdc2 and cdk7 are almost constant during oogenesis.	4	18	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	cdk7	cdk7	cdk7	cdc2	cdc2	cdc2	12	13	17	18
Cdk7 Activates Cdk2 but not Cdk1 by a CAK-First Mechanism In Vitro .	Cdk7 Activates Cdk2 but not Cdk1 by a CAK-First Mechanism In Vitro.	0	11	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk7	Cdk7	Cdk7	Cdk2	Cdk2	Cdk2	0	1	2	3
Activation of Cdk2 complexes requires dephosphorylation of Thr14 and Tyr15 on Cdk2 by cdc25 phosphatase and phosphorylation of Thr160 on Cdk2 XREF_BIBR , XREF_BIBR , which is mediated by CAK , a complex of Cdk7 and cyclin H XREF_BIBR .	Activation of Cdk2 complexes requires dephosphorylation of Thr14 and Tyr15 on Cdk2 by cdc25 phosphatase and phosphorylation of Thr160 on Cdk2 XREF_BIBR, XREF_BIBR, which is mediated by CAK, a complex of Cdk7 and cyclin H XREF_BIBR.	20	32	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CAK	CAK	CAK	Cdk2	Cdk2	Cdk2	29	30	20	21
We also demonstrated that IFN induced CKIs prevent CAK from activating the CDK-2 as immunodepletion of induced CKIs from the inhibitory extracts resulted in the restoration of CAK mediated activation of CDK-2 .	We also demonstrated that IFN induced CKIs prevent CAK from activating the CDK-2 as immunodepletion of induced CKIs from the inhibitory extracts resulted in the restoration of CAK mediated activation of CDK-2.	27	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	CAK	CAK	CAK	CDK-2	CDK-2	CDK-2	27	28	31	32
To further delineate the actions of MEK inhibition on CDK2 kinase activity , we asked whether PD0325901 potentiated CDK7-p27 Kip1 complex formation and thus blocked CDK activating kinase ( CAK )-dependent activation of CDK2 [ XREF_BIBR ] .	To further delineate the actions of MEK inhibition on CDK2 kinase activity, we asked whether PD0325901 potentiated CDK7-p27 Kip1 complex formation and thus blocked CDK activating kinase (CAK)-dependent activation of CDK2 [XREF_BIBR].	29	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CAK	CAK	CAK	CDK2	CDK2	CDK2	29	30	33	34
We created a Cdk7 as/as HCT116 human colon carcinoma cell line and showed that inhibition of Cdk7 in vivo prevented activation of Cdk2 , and blocked assembly and activation of Cdk1 and cyclin B.	We created a Cdk7 as/as HCT116 human colon carcinoma cell line and showed that inhibition of Cdk7 in vivo prevented activation of Cdk2, and blocked assembly and activation of Cdk1 and cyclin B.	14	23	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk7	Cdk7	Cdk7	Cdk2	Cdk2	Cdk2	16	17	22	23
These differences may accommodate the CAK independent activation of Cdk2 by Speedy and Ringo A2 and they raise the possibility that CDK-Speedy and Ringo A2 complexes could phosphorylate and regulate a subset of non canonical CDK substrates , such as Cdc25 protein phosphatases , to control cell cycle progression .	These differences may accommodate the CAK independent activation of Cdk2 by Speedy and Ringo A2 and they raise the possibility that CDK-Speedy and Ringo A2 complexes could phosphorylate and regulate a subset of non canonical CDK substrates, such as Cdc25 protein phosphatases, to control cell cycle progression.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CAK	CAK	CAK	Cdk2	Cdk2	Cdk2	5	6	9	10
CDK5R1 is an activator of CDK5 , a known gene that leads to the accumulation of aberrantly phosphorylated protein tau , a classic feature of AD pathology .	CDK5R1 is an activator of CDK5, a known gene that leads to the accumulation of aberrantly phosphorylated protein tau, a classic feature of AD pathology.	0	9	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	CDK5R1	CDK5R1	CDK5R1	CDK5	CDK5	CDK5	0	1	5	6
The mechanism of activation of Cdk5 by Nck5a differs from that of cyclin activation of Cdks in that full Cdk5 kinase activity can be achieved in the absence of phosphorylation of Cdk5 .	The mechanism of activation of Cdk5 by Nck5a differs from that of cyclin activation of Cdks in that full Cdk5 kinase activity can be achieved in the absence of phosphorylation of Cdk5.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Nck5a	Nck5a	Nck5a	Cdk5	Cdk5	Cdk5	7	8	5	6
CDK5RAP2 encodes the centrosomal protein CDK5RAP2 , which was originally identified in a yeast-two-hybrid screen of rat brain libraries to interact with the neuronal Cdk5 activator CDK5R1 .	CDK5RAP2 encodes the centrosomal protein CDK5RAP2, which was originally identified in a yeast-two-hybrid screen of rat brain libraries to interact with the neuronal Cdk5 activator CDK5R1.	20	27	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	CDK5R1	CDK5R1	CDK5R1	Cdk5	Cdk5	Cdk5	26	27	24	25
Here we delineate a complex consisting of the AMPK related kinase SIK2 , the CDK5 activator CDK5R1 and p35 , and the E3 ligase PJA2 essential for beta cell functional compensation .	Here we delineate a complex consisting of the AMPK related kinase SIK2, the CDK5 activator CDK5R1 and p35, and the E3 ligase PJA2 essential for beta cell functional compensation.	5	17	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	CDK5R1	CDK5R1	CDK5R1	CDK5	CDK5	CDK5	16	17	14	15
A few activators were also present ( CDK5R1 ( p35 ) activator of CDK5 , CDK7 that together with CCNH ( high in resting cells ) and MAT1 functions as a CDK activating kinase ( CAK ) and CCNC that interacts with CDK8 ) .	A few activators were also present (CDK5R1 (p35) activator of CDK5, CDK7 that together with CCNH (high in resting cells) and MAT1 functions as a CDK activating kinase (CAK) and CCNC that interacts with CDK8).	7	14	activator	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CDK5R1	CDK5R1	CDK5R1	CDK5	CDK5	CDK5	7	8	13	14
Given that Cdk5r1 activates the Cdk5 kinase complex , these data suggest that alpha-cells and other islet endocrine cells may not express appreciable levels of Cdk5 .	Given that Cdk5r1 activates the Cdk5 kinase complex, these data suggest that alpha-cells and other islet endocrine cells may not express appreciable levels of Cdk5.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5r1	Cdk5r1	Cdk5r1	Cdk5	Cdk5	Cdk5	2	3	5	6
Also atypical is the activation of Cdk5 by binding of a non cyclin activator protein , namely , the Cdk5 regulatory proteins Cdk5R1 ( p35 ) , truncated Cdk5R1 ( p25 ) , or Cdk5R2 ( p39 ) .	Also atypical is the activation of Cdk5 by binding of a non cyclin activator protein, namely, the Cdk5 regulatory proteins Cdk5R1 (p35), truncated Cdk5R1 (p25), or Cdk5R2 (p39).	2	27	is the activation	Positive_activation_copula_1	Positive_activation	Positive_activation	Cdk5R1	Cdk5R1	Cdk5R1	Cdk5	Cdk5	Cdk5	22	23	6	7
At the same time , Cdk5 is activated by the non cyclin proteins Cdk5R1 ( p35 , p25 ) or Cdk5R2 ( p39 ) , and phosphorylation in the T-loop is not required for its activation [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	At the same time, Cdk5 is activated by the non cyclin proteins Cdk5R1 (p35, p25) or Cdk5R2 (p39), and phosphorylation in the T-loop is not required for its activation [XREF_BIBR, XREF_BIBR - XREF_BIBR].	5	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdk5R1	Cdk5R1	Cdk5R1	Cdk5	Cdk5	Cdk5	13	14	5	6
In addition , as detected in NSC-p60 ( XREF_FIG ) , higher levels of activated Cdk5 and Cdk5r1 ( a neuron specific activator of Cdk5 ) ( XREF_FIG ) and enhanced activity of PP2A ( XREF_FIG ) were observed in p60TRP transgenic mice .	In addition, as detected in NSC-p60 (XREF_FIG), higher levels of activated Cdk5 and Cdk5r1 (a neuron specific activator of Cdk5) (XREF_FIG) and enhanced activity of PP2A (XREF_FIG) were observed in p60TRP transgenic mice.	12	25	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Cdk5r1	levels of activated Cdk5 and Cdk5r1	cdk5r1	Cdk5	Cdk5	cdk5	17	18	24	25
Conversely , the intracellular response machinery to extracellular cues was also altered , including downregulation of the cdk5r1 activator of CDK5 and microtubule associated proteins .	Conversely, the intracellular response machinery to extracellular cues was also altered, including downregulation of the cdk5r1 activator of CDK5 and microtubule associated proteins.	17	24	activator	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	cdk5r1	cdk5r1	cdk5r1	CDK5	CDK5	CDK5	17	18	20	21
In breast cancer cell lines treated with carboplatin , increased CDK5 activity can stimulate p53 stability and lead to cell death .	In breast cancer cell lines treated with carboplatin, increased CDK5 activity can stimulate p53 stability and lead to cell death.	10	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	p53	p53	p53	10	11	14	15
Moreover , Cdk5 ( cyclin dependent kinase 5 ) , a proline directed Ser/Thr kinase , additionally increases p53 stability via post-translational modification of p53 in response to hydrogen peroxide .	Moreover, Cdk5 (cyclin dependent kinase 5), a proline directed Ser/Thr kinase, additionally increases p53 stability via post-translational modification of p53 in response to hydrogen peroxide.	2	19	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	p53	p53	p53	2	3	18	19
Additionally , present data clearly indicates that activated Cdk5 modulates p53 transactivation in MCF-7 cells .	Additionally, present data clearly indicates that activated Cdk5 modulates p53 transactivation in MCF-7 cells.	7	11	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	p53	p53	p53	8	9	10	11
Furthermore , evidence is provided that increased Cdk5 activity increases p53 transcriptional activity significantly , suggesting that p53 is modulated in situ by Cdk5 .	Furthermore, evidence is provided that increased Cdk5 activity increases p53 transcriptional activity significantly, suggesting that p53 is modulated in situ by Cdk5.	7	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	p53	p53	p53	7	8	10	11
Cdk5 activates p53 by phosphorylation , inducing apoptosis .	Cdk5 activates p53 by phosphorylation, inducing apoptosis.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	p53	p53	p53	0	1	2	3
Hence , both c-Abl and Cdk5 cooperatively mediate p53 transcriptional activation resulting in neuronal death [ XREF_BIBR ] .	Hence, both c-Abl and Cdk5 cooperatively mediate p53 transcriptional activation resulting in neuronal death [XREF_BIBR].	3	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	p53	p53	p53	5	6	8	9
Collectively , these novel findings help define the mechanisms underlying neuronal apoptosis occurring as a result of Cdk5 mediated p53 stabilization and transcriptional activation .	Collectively, these novel findings help define the mechanisms underlying neuronal apoptosis occurring as a result of Cdk5 mediated p53 stabilization and transcriptional activation.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	p53	p53	p53	17	18	19	20
Following oxidative stress , c-Abl phosphorylates Cdk5 on Y15 , in return , Cdk5 promotes p53 accumulation and neuronal cell death [ XREF_BIBR ] .	Following oxidative stress, c-Abl phosphorylates Cdk5 on Y15, in return, Cdk5 promotes p53 accumulation and neuronal cell death [XREF_BIBR].	13	16	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	p53	p53	p53	13	14	15	16
These findings aid in clarifying the mechanism underlying the occurrence of neuronal apoptosis as a result of c-Abl and Cdk5 mediated p53 stabilization and transcriptional activation .	These findings aid in clarifying the mechanism underlying the occurrence of neuronal apoptosis as a result of c-Abl and Cdk5 mediated p53 stabilization and transcriptional activation.	2	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	p53	p53	p53	19	20	21	22
ATM mediates Cdk5 induced full activation of p53 activity , which requires S794 but not S1981 .	ATM mediates Cdk5 induced full activation of p53 activity, which requires S794 but not S1981.	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	p53	p53	p53	2	3	7	8
To explore the additional mechanisms by which CDK5 silencing inhibits wild type TP53 ovarian cancer cell growth and enhanced paclitaxel sensitivity , we examined the effect of CDK5 knockdown with or without paclitaxel treatment on induction of apoptosis and cell cycle arrest in Hey cells which is TP53 wild type .	To explore the additional mechanisms by which CDK5 silencing inhibits wild type TP53 ovarian cancer cell growth and enhanced paclitaxel sensitivity, we examined the effect of CDK5 knockdown with or without paclitaxel treatment on induction of apoptosis and cell cycle arrest in Hey cells which is TP53 wild type.	7	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	TP53	TP53	TP53	7	8	12	13
Knockdown of CDK5 significantly increased TP53 , p21 Cip1 and p27 Kip1 ( XREF_FIG ) .	Knockdown of CDK5 significantly increased TP53, p21 Cip1 and p27 Kip1 (XREF_FIG).	0	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK5	CDK5	CDK5	TP53	TP53	TP53	2	3	5	6
This gives RB-family-mediated G1 arrest , and potentially G2 arrest also through cessation of FOXM1 activation by CDK4 .	This gives RB-family-mediated G1 arrest, and potentially G2 arrest also through cessation of FOXM1 activation by CDK4.	14	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CDK4	CDK4	CDK4	FOXM1	FOXM1	FOXM1	17	18	14	15
It was recently reported that FOXM1 activation by CDK4 is lost in RB1 negative cells , but these findings rest on the expression of FOXM1 fragments lacking the N-terminal repression domain .	It was recently reported that FOXM1 activation by CDK4 is lost in RB1 negative cells, but these findings rest on the expression of FOXM1 fragments lacking the N-terminal repression domain.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CDK4	CDK4	CDK4	FOXM1	FOXM1	FOXM1	8	9	5	6
Overexpression of CDK4 or CDK6 could partially rescue the downregulation of FOXM1 ( XREF_FIG ) .	Overexpression of CDK4 or CDK6 could partially rescue the downregulation of FOXM1 (XREF_FIG).	0	13	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK4	Overexpression of CDK4	cdk4	FOXM1	FOXM1	foxm1	2	3	11	12
Moreover , over-expression of Cdk5 and p35 or Cdk5 and p25 in HEK293 cells led to a robust activation of endogenous ATM ( XREF_FIG ) .	Moreover, over-expression of Cdk5 and p35 or Cdk5 and p25 in HEK293 cells led to a robust activation of endogenous ATM (XREF_FIG).	2	22	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Cdk5	over-expression of Cdk5	cdk5	ATM	ATM	atm	4	5	21	22
Thus , it appears that under the experimental conditions tested , Cdk5 preferentially activates ATM in the nucleus .	Thus, it appears that under the experimental conditions tested, Cdk5 preferentially activates ATM in the nucleus.	11	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	ATM	ATM	ATM	11	12	14	15
Thus , we conclude that CDK5 is activated in response to DNA damage and that CDK5 inhibition prevents ATM and p53ser15 activation .	Thus, we conclude that CDK5 is activated in response to DNA damage and that CDK5 inhibition prevents ATM and p53ser15 activation.	15	21	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	ATM	ATM	ATM	15	16	18	19
Thus , activation of Cdk5 by DNA damage serves as a critical signal to initiate ATM response and regulate ATM dependent cellular processes .	Thus, activation of Cdk5 by DNA damage serves as a critical signal to initiate ATM response and regulate ATM dependent cellular processes.	2	16	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	ATM	ATM	ATM	4	5	15	16
Our findings in XREF_FIG suggested that Cdk5 mediated activation of ATM may be required for stress induced cell cycle re-entry of postmitotic neurons .	Our findings in XREF_FIG suggested that Cdk5 mediated activation of ATM may be required for stress induced cell cycle re-entry of postmitotic neurons.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	ATM	ATM	ATM	6	7	10	11
Co-expression of Cdk5 strongly activated wt ATM while S794A mutant lost the response to Cdk5 ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Co-expression of Cdk5 strongly activated wt ATM while S794A mutant lost the response to Cdk5 (XREF_FIG, XREF_SUPPLEMENTARY).	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Co-expression of Cdk5	cdk5	ATM	ATM	atm	2	3	6	7
Overexpression of CDK5 in LNCaP cells increased AR nuclear localization while knockdown increased AR cytoplasmic localization [ XREF_BIBR ] .	Overexpression of CDK5 in LNCaP cells increased AR nuclear localization while knockdown increased AR cytoplasmic localization [XREF_BIBR].	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	Overexpression of CDK5	cdk5	AR	AR	ar	2	3	7	8
As mentioned above , AR activation by CDK5 phosphorylation has been identified as a cancer driving mechanism in prostate tumors [ XREF_BIBR ] .	As mentioned above, AR activation by CDK5 phosphorylation has been identified as a cancer driving mechanism in prostate tumors [XREF_BIBR].	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CDK5	CDK5 phosphorylation	cdk5	AR	AR	ar	7	8	4	5
Interestingly , Cdk5 may regulate the interaction between STAT3 and AR through phosphorylation of Ser7 ( 2 ) 7-STAT3 and therefore upregulate AR protein stability and transactivation .	Interestingly, Cdk5 may regulate the interaction between STAT3 and AR through phosphorylation of Ser7 (2) 7-STAT3 and therefore upregulate AR protein stability and transactivation.	2	24	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	AR	AR	AR	2	3	22	23
In contrast , knockdown of CDK5 by siRNAs decreased AR half-life , and the proteasome inhibitor MG132 blocked this effect .	In contrast, knockdown of CDK5 by siRNAs decreased AR half-life, and the proteasome inhibitor MG132 blocked this effect.	3	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	AR	AR	AR	5	6	9	10
Our previous results indicated that Cdk5 activates androgen receptor ( AR ) and supports prostate cancer growth .	Our previous results indicated that Cdk5 activates androgen receptor (AR) and supports prostate cancer growth.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	androgen receptor	androgen receptor	androgen receptor	5	6	7	9
These findings demonstrate that Cdk5 is an important modulator of AR and contributes to prostate cancer growth .	These findings demonstrate that Cdk5 is an important modulator of AR and contributes to prostate cancer growth.	4	11	is an important modulator	Positive_activation_copula_1	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	AR	AR	AR	4	5	10	11
XREF_FIG shows that leptin treatment in cells overexpressing WT-Cdk5 induced pSTAT3 at both the Y 705 and S 727 sites , without changing the expression of the housekeeping gene beta-actin .	XREF_FIG shows that leptin treatment in cells overexpressing WT-Cdk5 induced pSTAT3 at both the Y 705 and S 727 sites, without changing the expression of the housekeeping gene beta-actin.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	WT-Cdk5	WT-Cdk5	WT-Cdk5	pSTAT3	pSTAT3	pSTAT3	8	9	10	11
Therefore , to determine whether Cdk5 modulates Stat3 function in T cells , we first immunoprecipitated Cdk5 from protein lysates prepared from T cells under various stimulation conditions , including either with or without anti-CD3 and anti-CD28 , in the presence or absence of TGF-beta and IL-6 , either alone or in combination .	Therefore, to determine whether Cdk5 modulates Stat3 function in T cells, we first immunoprecipitated Cdk5 from protein lysates prepared from T cells under various stimulation conditions, including either with or without anti-CD3 and anti-CD28, in the presence or absence of TGF-beta and IL-6, either alone or in combination.	5	8	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	Stat3	Stat3	Stat3	5	6	7	8
In other studies , CDK5 promoted medullary thyroid carcinoma cell growth by regulating STAT3 activation and cell proliferation [ XREF_BIBR ] .	In other studies, CDK5 promoted medullary thyroid carcinoma cell growth by regulating STAT3 activation and cell proliferation [XREF_BIBR].	4	14	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	STAT3	STAT3	STAT3	4	5	13	14
For example , expression of the DNA repair endonuclease , Eme1 , in genotoxic agent treated colorectal cancer cell lines is dependent on the activation of STAT-3 by Cdk5 [ XREF_BIBR , XREF_BIBR ] .	For example, expression of the DNA repair endonuclease, Eme1, in genotoxic agent treated colorectal cancer cell lines is dependent on the activation of STAT-3 by Cdk5 [XREF_BIBR, XREF_BIBR].	24	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	STAT-3	STAT-3	STAT-3	28	29	26	27
Cdk5 induces Stat3 function in T cells by physical interaction and Stat3 phosphorylation at Serine 727 .	Cdk5 induces Stat3 function in T cells by physical interaction and Stat3 phosphorylation at Serine 727.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	Stat3	Stat3	Stat3	0	1	2	3
Cdk3 enhances transactivation and transcriptional activity of ATF1 .	Cdk3 enhances transactivation and transcriptional activity of ATF1.	0	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk3	Cdk3	Cdk3	ATF1	ATF1	ATF1	0	1	7	8
Because c-Jun and c-Fos expression are regulated by ATF1 , we examined cdk3 mediated transcriptional activity of ATF1 using cells transfected with either a luciferase linked c-jun ( c-jun-luc ) or c-fos ( c-fos-luc ) promoter .	Because c-Jun and c-Fos expression are regulated by ATF1, we examined cdk3 mediated transcriptional activity of ATF1 using cells transfected with either a luciferase linked c-jun (c-jun-luc) or c-fos (c-fos-luc) promoter.	11	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdk3	cdk3	cdk3	ATF1	ATF1	ATF1	12	13	17	18
These results demonstrated that cdk3 positively regulated ATF1 transactivation activity through phosphorylation at serine 63 .	These results demonstrated that cdk3 positively regulated ATF1 transactivation activity through phosphorylation at serine 63.	4	9	positively regulated	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	cdk3	cdk3	cdk3	ATF1	ATF1	ATF1	4	5	7	8
The phosphorylation of ATF1 at serine 63 by cdk3 induced ATF1 transactivation and transcriptional activities .	The phosphorylation of ATF1 at serine 63 by cdk3 induced ATF1 transactivation and transcriptional activities.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	cdk3	cdk3	cdk3	ATF1	ATF1	ATF1	8	9	10	11
We found that ectopic expression of cdk3 in JB6 Cl41 cells stimulated EGF- induced cell transformation and ATF1 activation ( XREF_FIG ) .	We found that ectopic expression of cdk3 in JB6 Cl41 cells stimulated EGF- induced cell transformation and ATF1 activation (XREF_FIG).	4	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdk3	expression of cdk3	cdk3	ATF1	ATF1	atf1	6	7	17	18
Finally , we also assessed by immunoprecipitation the ability of E2F-4 transcription factors to associate with the Cdk4 activated pRb family member p107 .	Finally, we also assessed by immunoprecipitation the ability of E2F-4 transcription factors to associate with the Cdk4 activated pRb family member p107.	16	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk4	Cdk4	Cdk4	p107	p107	p107	17	18	22	23
We conclude that the contribution of CDK5 to the increase of TonEBP and OREBP transcriptional activity 4 h after NaCl is elevated occurs because CDK5 contributes to its increased nuclear localization , but that after 16 h , CDK5 no longer contributes to increased TonEBP and OREBP transcriptional activity because it no longer contributes to regulation of TonEBP and OREBP nuclear localization .	We conclude that the contribution of CDK5 to the increase of TonEBP and OREBP transcriptional activity 4 h after NaCl is elevated occurs because CDK5 contributes to its increased nuclear localization, but that after 16 h, CDK5 no longer contributes to increased TonEBP and OREBP transcriptional activity because it no longer contributes to regulation of TonEBP and OREBP nuclear localization.	38	48	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	TonEBP	TonEBP	TonEBP	38	39	44	45
Inhibition of CDK5 rapidly reduces high NaCl induced nuclear localization of TonEBP and OREBP ( XREF_FIG ) , but not its total abundance ( XREF_FIG ) , and this reduction is associated with decreased transcriptional activity ( XREF_FIG ) .	Inhibition of CDK5 rapidly reduces high NaCl induced nuclear localization of TonEBP and OREBP (XREF_FIG), but not its total abundance (XREF_FIG), and this reduction is associated with decreased transcriptional activity (XREF_FIG).	0	15	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	TonEBP	TonEBP	TonEBP	2	3	11	12
CDK5 activity contributes to the rapid high NaCl induced nuclear localization of TonEBP and OREBP .	CDK5 activity contributes to the rapid high NaCl induced nuclear localization of TonEBP and OREBP.	0	14	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	TonEBP	TonEBP	TonEBP	0	1	12	13
The induced Cdk5 increases DARPP-32 Thr75 phosphorylation and therefore decreases D 1 receptor and PKA signaling .	The induced Cdk5 increases DARPP-32 Thr75 phosphorylation and therefore decreases D 1 receptor and PKA signaling.	2	5	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	DARPP-32	DARPP-32	DARPP-32	2	3	4	5
Recently it was shown that Cdk5 modulates dopamine signaling in neurons by regulating DARPP-32 function .	Recently it was shown that Cdk5 modulates dopamine signaling in neurons by regulating DARPP-32 function.	5	14	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	DARPP-32	DARPP-32	DARPP-32	5	6	13	14
These results demonstrated that Cdk3 mediated c-Jun activation increases c-Jun/AP -1 transcriptional activity and induces proliferation .	These results demonstrated that Cdk3 mediated c-Jun activation increases c-Jun/AP -1 transcriptional activity and induces proliferation.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cdk3	Cdk3	Cdk3	c-Jun	c-Jun	c-Jun	4	5	6	7
However , when Cdk3 was co-expressed with cyclin E1 , phosphorylation of LIN-9 , cyclin E1 , and autophosphorylation of Cdk3 , was very strong ( XREF_FIG , upper panel , lane 3 ) indicating that cyclin E1 is a potent activator of Cdk3 and the Cdk3 and cyclin E1 complex targets LIN-9 for phosphorylation .	However, when Cdk3 was co-expressed with cyclin E1, phosphorylation of LIN-9, cyclin E1, and autophosphorylation of Cdk3, was very strong (XREF_FIG, upper panel, lane 3) indicating that cyclin E1 is a potent activator of Cdk3 and the Cdk3 and cyclin E1 complex targets LIN-9 for phosphorylation.	45	54	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk3	Cdk3	Cdk3	LIN-9	LIN-9	LIN-9	46	47	52	53
The enhanced p-NR2A S1232 was inhibited by roscovitine , but augmented by over-expression of Cdk5 .	The enhanced p-NR2A S1232 was inhibited by roscovitine, but augmented by over-expression of Cdk5.	2	15	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdk5	over-expression of Cdk5	cdk5	p-NR2A	p-NR2A	p-nr2a	14	15	2	3
In neuronal cells CDK5 can cause FAK activation via phosphorylation on Ser732 [ XREF_BIBR ] .	In neuronal cells CDK5 can cause FAK activation via phosphorylation on Ser732 [XREF_BIBR].	3	7	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	FAK	FAK	FAK	3	4	6	7
Indeed , p21 -/- cells showed increased multinucleation following Chk1 siRNA transfection , whereas Chk1 knockdown reverses the multinucleated phenotype of p53 -/- cells ( XREF_FIG ) .	Indeed, p21 -/- cells showed increased multinucleation following Chk1 siRNA transfection, whereas Chk1 knockdown reverses the multinucleated phenotype of p53 -/- cells (XREF_FIG).	14	23	reverses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	14	15	21	22
At the earliest stages of senescence , the p53 pathway is activated upon phosphorylation of the p53 protein by ATM and ATR , Chk1 and Chk2 and p19ARF ( a product of the p16 locus ) .	At the earliest stages of senescence, the p53 pathway is activated upon phosphorylation of the p53 protein by ATM and ATR, Chk1 and Chk2 and p19ARF (a product of the p16 locus).	8	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	23	24	8	9
In response to such stresses , cells activate an evolutionarily conserved kinase cascade involving the Chk1 and Chk2 checkpoint kinases , which in turn activate p53 to induce the transcription of genes that result in either G1 cell cycle arrest and DNA repair or apoptosis , depending on the cell type and physiological circumstance .	In response to such stresses, cells activate an evolutionarily conserved kinase cascade involving the Chk1 and Chk2 checkpoint kinases, which in turn activate p53 to induce the transcription of genes that result in either G1 cell cycle arrest and DNA repair or apoptosis, depending on the cell type and physiological circumstance.	12	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	15	16	25	26
Inhibition of ATM ( with KU55933 ) or both Chk1 and Chk2 ( with AZD7762 ) prevented p53 induction after B cell treatment with etoposide .	Inhibition of ATM (with KU55933) or both Chk1 and Chk2 (with AZD7762) prevented p53 induction after B cell treatment with etoposide.	0	18	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	9	10	17	18
During DNA replication stress enrichment of ATR at chromatin activates ATR and activated ATR phosphorylates checkpoint kinase-1 which subsequently activates and stabilizes p53 protein XREF_BIBR .	During DNA replication stress enrichment of ATR at chromatin activates ATR and activated ATR phosphorylates checkpoint kinase-1 which subsequently activates and stabilizes p53 protein XREF_BIBR.	6	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	checkpoint kinase-1	ATR at chromatin activates ATR and activated ATR phosphorylates checkpoint kinase-1	checkpoint kinase-1	p53	p53	p53	15	17	22	23
After a single exposure to UVB , normal epidermal cells from a p53 knockout mouse expressed a relatively high level of phospho-Chk1 ( Ser317 ) where as epidermal cells from a p53wild-type littermate induced p53 protein and expressed a relatively low level of phospho-Chk1 ( Ser317 ) .	After a single exposure to UVB, normal epidermal cells from a p53 knockout mouse expressed a relatively high level of phospho-Chk1 (Ser317) where as epidermal cells from a p53wild-type littermate induced p53 protein and expressed a relatively low level of phospho-Chk1 (Ser317).	19	35	induced	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	phospho-Chk1	level of phospho-Chk1	phospho-chk1	p53	p53	p53	21	22	34	35
Both CHK1 and CHK2 play a crucial role in cell cycle arrest and apoptosis , are part of the DDR mechanism , and can activate p53 [ XREF_BIBR ] .	Both CHK1 and CHK2 play a crucial role in cell cycle arrest and apoptosis, are part of the DDR mechanism, and can activate p53 [XREF_BIBR].	0	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	p53	p53	p53	1	2	25	26
The CHK1 and CHK2 also target p53 and MDM2 proteins .	The CHK1 and CHK2 also target p53 and MDM2 proteins.	0	9	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	p53	p53	p53	1	2	6	7
Notably , although CHK1 gene knock-out is lethal in embryos [ XREF_BIBR ] and induces apoptosis in embryonic stem cells [ XREF_BIBR ] , the depletion of CHK1 by siRNA in somatic cells on its own has been reported to cause little cytotoxicity and enhance the efficacy of DNA damaging drugs in p53 deficient cancer cell lines [ XREF_BIBR ] .	Notably, although CHK1 gene knock-out is lethal in embryos [XREF_BIBR] and induces apoptosis in embryonic stem cells [XREF_BIBR], the depletion of CHK1 by siRNA in somatic cells on its own has been reported to cause little cytotoxicity and enhance the efficacy of DNA damaging drugs in p53 deficient cancer cell lines [XREF_BIBR].	25	53	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK1	CHK1	CHK1	p53	p53	p53	27	28	52	53
XREF_BIBR , XREF_BIBR Ataxia telangiectasia mutated ( ATM ) and ataxia telangiectasia and Rad3 related ( ATR ) pathways sense DNA damage and phosphorylate the cell cycle checkpoint kinases CHK1 and CHK2 , resulting in p53 activation .	XREF_BIBR, XREF_BIBR Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) pathways sense DNA damage and phosphorylate the cell cycle checkpoint kinases CHK1 and CHK2, resulting in p53 activation.	3	37	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	CHK1	Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) pathways sense DNA damage and phosphorylate the cell cycle checkpoint kinases CHK1	chk1	p53	p53	p53	29	30	35	36
Upon DNA damage , p53 is activated via phosphorylation by Chk1 , Chk2 , ATM , and ATR , and may translocate into the nucleus , where it induces the transcription of pro apoptotic proteins such as Bax , as well as its antagonist MDM2 as a negative feedback loop ( Sionov and Haupt , 1999 ) .	Upon DNA damage, p53 is activated via phosphorylation by Chk1, Chk2, ATM, and ATR, and may translocate into the nucleus, where it induces the transcription of pro apoptotic proteins such as Bax, as well as its antagonist MDM2 as a negative feedback loop (Sionov and Haupt, 1999).	4	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	10	11	4	5
Once activated , ATM and ATR phosphorylate downstream checkpoint kinases Chk1 and Chk2 , which in turn phosphorylate and activate p53 to affect cell cycle progression .	Once activated, ATM and ATR phosphorylate downstream checkpoint kinases Chk1 and Chk2, which in turn phosphorylate and activate p53 to affect cell cycle progression.	3	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	ATM and ATR phosphorylate downstream checkpoint kinases Chk1	chk1	p53	p53	p53	10	11	20	21
Consistently , Chk1 knockdown reversed the multinucleated phenotype of p53 -/- cells , whereas cleavage of caspase 3 was increased .	Consistently, Chk1 knockdown reversed the multinucleated phenotype of p53 -/- cells, whereas cleavage of caspase 3 was increased.	2	11	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	2	3	9	10
Chk1 targets the TA domains of p53 and p73 to improve the TA of p53 and p73 .	Chk1 targets the TA domains of p53 and p73 to improve the TA of p53 and p73.	0	8	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	0	1	6	7
Inhibition of ATM and ATR , PI3-kinase and Chk1 and Chk2 by CGK733 , wortmannin and DBH , respectively , attenuated the apoptotic response in p53 ( wt ) but not p53 ( mt ) cells .	Inhibition of ATM and ATR, PI3-kinase and Chk1 and Chk2 by CGK733, wortmannin and DBH, respectively, attenuated the apoptotic response in p53 (wt) but not p53 (mt) cells.	0	27	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	8	9	25	26
Chk1 and Chk2 further cooperate with ATM and ATR to activate p53 , which inhibits cell cycle progression through induction of the cyclin dependent kinase inhibitor p21 [ XREF_BIBR ] .	Chk1 and Chk2 further cooperate with ATM and ATR to activate p53, which inhibits cell cycle progression through induction of the cyclin dependent kinase inhibitor p21 [XREF_BIBR].	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	0	1	11	12
In metazoan , telomere shortening and telomere uncapping activate ATM and ATR kinases to phosphorylate downstream kinases CHK1 and CHK2 , which initiates p53 dependent replicative senescence and apoptosis pathways to suppress tumorigenesis ( XREF_SUPPLEMENTARY ) .	In metazoan, telomere shortening and telomere uncapping activate ATM and ATR kinases to phosphorylate downstream kinases CHK1 and CHK2, which initiates p53 dependent replicative senescence and apoptosis pathways to suppress tumorigenesis (XREF_SUPPLEMENTARY).	9	24	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	ATM and ATR kinases to phosphorylate downstream kinases CHK1	chk1	p53	p53	p53	17	18	23	24
Depending on the type of lesion , DDR can cause activation of p53 via pathways involving the checkpoint kinases ATM and Chk2 or ATR and Chk1 , which in turn induces p53 [ XREF_BIBR , XREF_BIBR ] .	Depending on the type of lesion, DDR can cause activation of p53 via pathways involving the checkpoint kinases ATM and Chk2 or ATR and Chk1, which in turn induces p53 [XREF_BIBR, XREF_BIBR].	18	35	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	25	26	31	32
In the case of pluricellular organisms like humans , a key mediator of the cellular response is tumor suppressor p53 protein , which is activated by kinases ATR and ATM and Chk1 and Chk2 .	In the case of pluricellular organisms like humans, a key mediator of the cellular response is tumor suppressor p53 protein, which is activated by kinases ATR and ATM and Chk1 and Chk2.	17	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	31	32	17	20
In this DNA damage response , p53 is activated through phosphorylation on Ser15 by ATM and ATR and on Ser20 by Chk1 and Chk2 .	In this DNA damage response, p53 is activated through phosphorylation on Ser15 by ATM and ATR and on Ser20 by Chk1 and Chk2.	6	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	21	22	6	7
Verification of GFP-Chk1 D130A expression in Cl41 cells stably transfectant was shown in XREF_FIG and ectopic expression of kinase inactive GFP-Chk1 D130A attenuated induction of p53 protein phosphorylation at Ser15 and expression by Chel A ( XREF_FIG ) , strongly indicating that Chk1 mediated p53 stabilization .	Verification of GFP-Chk1 D130A expression in Cl41 cells stably transfectant was shown in XREF_FIG and ectopic expression of kinase inactive GFP-Chk1 D130A attenuated induction of p53 protein phosphorylation at Ser15 and expression by Chel A (XREF_FIG), strongly indicating that Chk1 mediated p53 stabilization.	42	45	mediated	Positive_early_activation	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	42	43	44	45
Highlighting the therapeutic potential of CHK1 ' s role in GOF p53 dependency , experiments in cell culture and mouse xenografts demonstrated that inhibition of CHK1 selectively blocked proliferation of cells and tumors expressing GOF p53 .	Highlighting the therapeutic potential of CHK1 's role in GOF p53 dependency, experiments in cell culture and mouse xenografts demonstrated that inhibition of CHK1 selectively blocked proliferation of cells and tumors expressing GOF p53.	23	36	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	p53	p53	p53	25	26	35	36
During transient mitotic arrest , p53 stabilization and activation is triggered by a pathway independent of ATM and ATR , Chk1 and Chk2 .	During transient mitotic arrest, p53 stabilization and activation is triggered by a pathway independent of ATM and ATR, Chk1 and Chk2.	5	21	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	20	21	5	6
Mammalian ATR and ATM phosphorylate checkpoint kinases 1 and 2 ( CHK1 and CHK2 ) and activate the p53 transcription factor .	Mammalian ATR and ATM phosphorylate checkpoint kinases 1 and 2 (CHK1 and CHK2) and activate the p53 transcription factor.	1	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	ATR and ATM phosphorylate checkpoint kinases 1 and 2 (CHK1	chk1	p53	p53	p53	11	12	18	19
A quick inspection of the genes identified known p53 targets , such as CDC20 , Aurora KinaseA and B , Chek1 , Topo IIalpha , CyclinB1 and B2 , CyclinA , CDC2 , p57 and Kip2 .	A quick inspection of the genes identified known p53 targets, such as CDC20, Aurora KinaseA and B, Chek1, Topo IIalpha, CyclinB1 and B2, CyclinA, CDC2, p57 and Kip2.	8	21	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Chek1	Chek1	Chek1	p53	p53	p53	20	21	8	9
p53-/- cells transplanted to nude mice treated with thymoquinone up-regulated CHEK1 expression and did not undergo apoptosis unlike p53 +/+ cells .	p53-/- cells transplanted to nude mice treated with thymoquinone up-regulated CHEK1 expression and did not undergo apoptosis unlike p53 +/+ cells.	0	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CHEK1	CHEK1	CHEK1	p53-/-	p53-/-	p53-/-	10	11	0	1
This branch depends on p53 , which is also targeted by ATM and ATR and CHK2 and CHK1 .	This branch depends on p53, which is also targeted by ATM and ATR and CHK2 and CHK1.	2	18	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	p53	p53	p53	17	18	4	5
Seven genes were engaged in G2/M transition with the majority negatively regulating the transition ( cyclin CCNB2 for promotion , negative regulator WEE1 and YWHAQ , genes associated with p53 signaling including MDM2 and CHEK1 , stress sensors GADD45B and GADD45G ) .	Seven genes were engaged in G2/M transition with the majority negatively regulating the transition (cyclin CCNB2 for promotion, negative regulator WEE1 and YWHAQ, genes associated with p53 signaling including MDM2 and CHEK1, stress sensors GADD45B and GADD45G).	29	35	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	CHEK1	CHEK1	CHEK1	p53	p53	p53	34	35	29	30
p53 could also be activated by Chk1 and Chk2 at Ser 20 .	p53 could also be activated by Chk1 and Chk2 at Ser 20.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	6	7	0	1
Chk1 can activate the tumor suppressor p53 directly to induce apoptotic response during various stress [ XREF_BIBR ] .	Chk1 can activate the tumor suppressor p53 directly to induce apoptotic response during various stress [XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	0	1	4	7
Chk1 mediated p53 stabilization and activation upon Chel A treatment .	Chk1 mediated p53 stabilization and activation upon Chel A treatment.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	0	1	2	3
Both CHK1 and CHK2 can activate p53 upon DNA damage and are important for cell cycle checkpoints , however , while CHK1 is crucial for intra-S and G2/S transition , CHK2 is more important for G1/S checkpoint .	Both CHK1 and CHK2 can activate p53 upon DNA damage and are important for cell cycle checkpoints, however, while CHK1 is crucial for intra-S and G2/S transition, CHK2 is more important for G1/S checkpoint.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	p53	p53	p53	1	2	6	7
Other signaling proteins viz , ATM , ATR , Chk1 , Chk2 kinases and cdc25 family of phosphatases also lie close to the pathway DDR and promote cell cycle arrest both in p53 dependent and independent manner .	Other signaling proteins viz, ATM, ATR, Chk1, Chk2 kinases and cdc25 family of phosphatases also lie close to the pathway DDR and promote cell cycle arrest both in p53 dependent and independent manner.	3	33	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	9	10	32	33
This response is initiated by the phosphatidylinositol 3-kinase-like protein kinases ATM and ATR , which phosphorylate proteins such as H2A.X and NBS1 , and downstream kinases CHK1 and CHK2 , which ultimately activate p53 and p21 proteins [ XREF_BIBR ] .	This response is initiated by the phosphatidylinositol 3-kinase-like protein kinases ATM and ATR, which phosphorylate proteins such as H2A.X and NBS1, and downstream kinases CHK1 and CHK2, which ultimately activate p53 and p21 proteins [XREF_BIBR].	3	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	initiated by the phosphatidylinositol 3-kinase-like protein kinases ATM and ATR, which phosphorylate proteins such as H2A.X and NBS1, and downstream kinases CHK1	chk1	p53	p53	p53	26	27	33	34
Since Chk1 activates p53 by phosphorylation , and p53 is a critical factor for senescence induction , we analyzed the phosphorylation states of p53 ( XREF_FIG ) .	Since Chk1 activates p53 by phosphorylation, and p53 is a critical factor for senescence induction, we analyzed the phosphorylation states of p53 (XREF_FIG).	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	1	2	3	4
To determine the effect of p53 status on caspase 2 and 3 cleavage in Chk1 depleted cells treated with thymidine , the cleaved forms of these caspases were analysed in HCT116 p53-/- cells treated with control or Chk1 siRNAs .	To determine the effect of p53 status on caspase 2 and 3 cleavage in Chk1 depleted cells treated with thymidine, the cleaved forms of these caspases were analysed in HCT116 p53-/- cells treated with control or Chk1 siRNAs.	31	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53-/-	p53-/-	p53-/-	37	38	31	32
When used in combination with chemotherapeutic agents or radiation , inhibition of CHK1 or WEE1 can cause selective sensitization of p53 negative cells .	When used in combination with chemotherapeutic agents or radiation, inhibition of CHK1 or WEE1 can cause selective sensitization of p53 negative cells.	10	22	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	p53	p53	p53	12	13	20	21
Examples of such effector proteins include checkpoint kinase 1 and 2 ( CHK1 and CHK2 , respectively ) that leads to cell cycle arrest and p53 influencing both cell cycle arrest and apoptosis .	Examples of such effector proteins include checkpoint kinase 1 and 2 (CHK1 and CHK2, respectively) that leads to cell cycle arrest and p53 influencing both cell cycle arrest and apoptosis.	6	26	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	checkpoint kinase 1	checkpoint kinase 1	checkpoint kinase 1	p53	p53	p53	6	9	25	26
P53 function can also be affected by loss of CDKN2A locus that encodes the P53 stabilizer ARF , overexpression of the P53 inhibitors MDM2 and MDM4 , and downregulation of the P53 activators CHK1 and CHK2 .	P53 function can also be affected by loss of CDKN2A locus that encodes the P53 stabilizer ARF, overexpression of the P53 inhibitors MDM2 and MDM4, and downregulation of the P53 activators CHK1 and CHK2.	28	35	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	P53	P53	P53	33	34	31	32
As Chk1 can also induce apoptosis by activating p53 , we next sought to determine whether RhoJ regulates cisplatin induced apoptosis in a p53 dependent manner .	As Chk1 can also induce apoptosis by activating p53, we next sought to determine whether RhoJ regulates cisplatin induced apoptosis in a p53 dependent manner.	1	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p53	p53	p53	1	2	8	9
ATM and CHK1 kinases induced by genotoxic stress signals activate p53 by driving dissociation of MDM2 and MDM4 through phophorylation [ XREF_BIBR ] .	ATM and CHK1 kinases induced by genotoxic stress signals activate p53 by driving dissociation of MDM2 and MDM4 through phophorylation [XREF_BIBR].	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	p53	p53	p53	2	3	10	11
Inhibition of phosphatidylinositol 3-kinase ( PI3K )/Akt with LY294002 ( LY ) and p38 kinase with SB203580 ( SB ) , respectively , decreased berberine induced p53 and p21 expression and restored cell proliferation and expression of cyclin B1 , cdc2 , cdc25c , and pRb cell cycle progression proteins .	Inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt with LY294002 (LY) and p38 kinase with SB203580 (SB), respectively, decreased berberine induced p53 and p21 expression and restored cell proliferation and expression of cyclin B1, cdc2, cdc25c, and pRb cell cycle progression proteins.	2	47	restored	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p21	phosphatidylinositol 3-kinase (PI3K)/Akt with LY294002 (LY) and p38 kinase with SB203580 (SB), respectively, decreased berberine induced p53 and p21 expression	p21	pRb	pRb	prb	28	29	45	46
Since cyclin D1-CDK4/6 complexes phosphorylate and inactivate Rb family proteins , p21 can indirectly activate Rb family proteins to inhibit the E2F1 dependent expression of mitotic regulators , thus halting the G2/M progression and resulting in the irreversible G2 arrest of cell cycle .	Since cyclin D1-CDK4/6 complexes phosphorylate and inactivate Rb family proteins, p21 can indirectly activate Rb family proteins to inhibit the E2F1 dependent expression of mitotic regulators, thus halting the G2/M progression and resulting in the irreversible G2 arrest of cell cycle.	11	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	Rb	Rb	Rb	11	12	15	16
p16 , p21 and p27 mediate Rb regulation in response to stressors like changes in growth factor availability and DNA damage [ XREF_BIBR , XREF_BIBR ] .	p16, p21 and p27 mediate Rb regulation in response to stressors like changes in growth factor availability and DNA damage [XREF_BIBR, XREF_BIBR].	0	7	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	Rb	Rb	Rb	2	3	6	7
These findings indicate that , in spite of the absence of Smad4 , growth inhibition in BxPC3 cells by TGF-beta1 is dependent on p21 upregulation and maintenance of RB in a hypophosphorylated , active state .	These findings indicate that, in spite of the absence of Smad4, growth inhibition in BxPC3 cells by TGF-beta1 is dependent on p21 upregulation and maintenance of RB in a hypophosphorylated, active state.	23	31	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p21	p21	p21	RB	RB	RB	23	24	28	29
p21 and p16 inhibit CDK2 and CDK4/6 activities , respectively , and result in the activation of the tumor suppressor Rb , which is inactivated by CDK2 and CDK4/6 through phosphorylation .	p21 and p16 inhibit CDK2 and CDK4/6 activities, respectively, and result in the activation of the tumor suppressor Rb, which is inactivated by CDK2 and CDK4/6 through phosphorylation.	0	24	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	p21	p21	p21	Rb	Rb	Rb	0	1	20	21
In addition , p21 also activates pRb through the inhibition of cyclin E/CDK2 [ XREF_BIBR ] .	In addition, p21 also activates pRb through the inhibition of cyclin E/CDK2 [XREF_BIBR].	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	pRb	pRb	pRb	3	4	6	7
However , a Rac1 and Cdc42 binding fragment of p21 activated protein kinase , RB without Tat peptide or TATHA protein A had no effect .	However, a Rac1 and Cdc42 binding fragment of p21 activated protein kinase, RB without Tat peptide or TATHA protein A had no effect.	3	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	RB	RB	RB	9	10	14	15
These results indicate that overexpression of cyclin D/cdk4 and cyclin E/cdk2 would phosphorylate pRB , and insufficient expression of p21 may accelerate pRB inactivation .	These results indicate that overexpression of cyclin D/cdk4 and cyclin E/cdk2 would phosphorylate pRB, and insufficient expression of p21 may accelerate pRB inactivation.	17	23	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	expression of p21	p21	pRB	pRB	prb	19	20	22	23
Subsequent increase in p21 stimulated pRb to repress E2F , blocking DNA synthesis to reduce ROS production , and inhibiting nucleotide synthesis to favor glutathione synthesis ( XREF_FIG ) .	Subsequent increase in p21 stimulated pRb to repress E2F, blocking DNA synthesis to reduce ROS production, and inhibiting nucleotide synthesis to favor glutathione synthesis (XREF_FIG).	1	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	pRb	pRb	pRb	3	4	5	6
More recently another role for p21 waf1 and cip1 was suggested in that p21 waf1 and cip1 can activate retinoblastoma protein ( Rb ) via dephosphorylation and yet inactivate Rb via degradation , suggesting it can regulate cell cycle progression and/or arrest XREF_BIBR .	More recently another role for p21 waf1 and cip1 was suggested in that p21 waf1 and cip1 can activate retinoblastoma protein (Rb) via dephosphorylation and yet inactivate Rb via degradation, suggesting it can regulate cell cycle progression and/or arrest XREF_BIBR.	16	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cip1	cip1	cip1	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	16	17	19	21
These results indicate that p21 both activates Rb through dephosphorylation and inactivates it through degradation , suggesting negative feedback regulation of damage induced cell-cycle checkpoint arrest .	These results indicate that p21 both activates Rb through dephosphorylation and inactivates it through degradation, suggesting negative feedback regulation of damage induced cell-cycle checkpoint arrest.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	Rb	Rb	Rb	4	5	7	8
Overexpression of p21 has been shown to activate Rb ( Agarwal et al , 1998 ; Keegan et al , 1998 ) .	Overexpression of p21 has been shown to activate Rb (Agarwal et al, 1998; Keegan et al, 1998).	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	Overexpression of p21	p21	Rb	Rb	rb	2	3	8	9
Subsequently p53 upregulates transcription of p21 , which activates Rb through the inhibition of cyclin E and Cdk2 complex , while activated Rb inhibits the transcription of E2F target genes , such as cyclin A and PCNA , causing a long-term cell cycle arrest [ XREF_BIBR ] .	Subsequently p53 upregulates transcription of p21, which activates Rb through the inhibition of cyclin E and Cdk2 complex, while activated Rb inhibits the transcription of E2F target genes, such as cyclin A and PCNA, causing a long-term cell cycle arrest [XREF_BIBR].	1	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p53 upregulates transcription of p21	p21	Rb	Rb	rb	5	6	9	10
p21 impedes progression through the cell cycle by blocking CDK dependent inactivation of the transcriptional repressor Rb , which in turn leads to repression of genes activated by E2F family of TFs XREF_BIBR , XREF_BIBR ( XREF_FIG ) , including genes previously described as directly repressed by p53 , such as BIRC5 ( Survivin ) and CDC25B-C .	p21 impedes progression through the cell cycle by blocking CDK dependent inactivation of the transcriptional repressor Rb, which in turn leads to repression of genes activated by E2F family of TFs XREF_BIBR, XREF_BIBR (XREF_FIG), including genes previously described as directly repressed by p53, such as BIRC5 (Survivin) and CDC25B-C.	0	21	impedes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	Rb	Rb	Rb	0	1	16	17
P53 down regulates the transcription of many genes indirectly through inducing p21 , which in turn activates the retinoblastoma protein and inhibits E2F transcription factors .	P53 down regulates the transcription of many genes indirectly through inducing p21, which in turn activates the retinoblastoma protein and inhibits E2F transcription factors.	10	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	11	12	18	20
The functional characterization of the inserting WAF1 gene implied that P21WAF1 and Cip1 expression could upregulate Rb gene and downregulate cyclin D1 gene at protein level .	The functional characterization of the inserting WAF1 gene implied that P21WAF1 and Cip1 expression could upregulate Rb gene and downregulate cyclin D1 gene at protein level.	10	17	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cip1	Cip1 expression	cip1	Rb	Rb	rb	12	13	16	17
In the p53 core regulatory module , p21 inhibits E2F [ XREF_BIBR ] , Cyclin D and Cyclin E [ XREF_BIBR ] , but p21 activates RB [ XREF_BIBR ] .	In the p53 core regulatory module, p21 inhibits E2F [XREF_BIBR], Cyclin D and Cyclin E [XREF_BIBR], but p21 activates RB [XREF_BIBR].	24	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	RB	RB	RB	24	25	26	27
p21 Cip1 can activate pRb which can regulate entry into replicative senescence [ XREF_BIBR , XREF_BIBR ] .	p21 Cip1 can activate pRb which can regulate entry into replicative senescence [XREF_BIBR, XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21 Cip1	p21 Cip1	p21 Cip1	pRb	pRb	pRb	0	2	4	5
In contrast , p21 activates pRb proteins by binding and inhibiting the activity of Cyclin-CDKs XREF_BIBR .	In contrast, p21 activates pRb proteins by binding and inhibiting the activity of Cyclin-CDKs XREF_BIBR.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	pRb	pRb	pRb	3	4	5	6
We speculated these effects might be through p21 mediated activation of pRb , which could bind E2F complexes and potentially inhibit CDC2 , Cyclin B1 , and Cyclin A expression as a result .	We speculated these effects might be through p21 mediated activation of pRb, which could bind E2F complexes and potentially inhibit CDC2, Cyclin B1, and Cyclin A expression as a result.	7	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	p21	p21	p21	pRb	pRb	pRb	7	8	11	12
Additionally , growing evidence supports that p21 mediates the activation of the DREAM complex , which is composed of DP , Rb like , E2F4 , and MuvB proteins , which leads to the specific binding of the DREAM complex to CHR .	Additionally, growing evidence supports that p21 mediates the activation of the DREAM complex, which is composed of DP, Rb like, E2F4, and MuvB proteins, which leads to the specific binding of the DREAM complex to CHR.	6	22	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	Rb	Rb	Rb	6	7	21	22
XREF_BIBR The dual effect of p21 on Sp is similar to its effect on Rb , where p21 activates Rb by dephosphorylation and concomitantly inactivates it by triggering its degradation .	XREF_BIBR The dual effect of p21 on Sp is similar to its effect on Rb, where p21 activates Rb by dephosphorylation and concomitantly inactivates it by triggering its degradation.	17	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	Rb	Rb	Rb	17	18	19	20
Among the connections between both senescence pathways , the p53 induced p21 can also activate RB ( XREF_FIG ) .	Among the connections between both senescence pathways, the p53 induced p21 can also activate RB (XREF_FIG).	9	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p53 induced p21	p21	RB	RB	rb	11	12	15	16
Depletion of Cdkn1a and Bbc3 , which were upregulated by Trp53 , rescued Rb1 deficient cells from undergoing cell cycle arrest and apoptosis .	Depletion of Cdkn1a and Bbc3, which were upregulated by Trp53, rescued Rb1 deficient cells from undergoing cell cycle arrest and apoptosis.	0	15	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdkn1a	Cdkn1a	Cdkn1a	Rb1	Rb1	Rb1	2	3	13	14
Since suprabasal epidermal layers in zebrafish larvae were proposed to contain TAC progenitors [ XREF_BIBR ] , it is possible that P21 mediated RB inactivation may promote higher levels of cell proliferation in zebrafish epidermal TACs ( XREF_TABLE ) .	Since suprabasal epidermal layers in zebrafish larvae were proposed to contain TAC progenitors [XREF_BIBR], it is possible that P21 mediated RB inactivation may promote higher levels of cell proliferation in zebrafish epidermal TACs (XREF_TABLE).	21	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	P21	P21	P21	RB	RB	RB	21	22	23	24
p53 or p16 activates p21 , which , in turn , can activate retinoblastoma protein ( Rb ) to shut down the transcription factor ( E 2 F ) target genes , thus inducing cell growth arrest and senescence [ XREF_BIBR ] .	p53 or p16 activates p21, which, in turn, can activate retinoblastoma protein (Rb) to shut down the transcription factor (E 2 F) target genes, thus inducing cell growth arrest and senescence [XREF_BIBR].	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	4	5	13	15
Markedly , loss of p38alpha leads to downregulation of p21 , and decreased activation of the p21 target Rb , both of which are important regulators of erythroblast enucleation .	Markedly, loss of p38alpha leads to downregulation of p21, and decreased activation of the p21 target Rb, both of which are important regulators of erythroblast enucleation.	13	25	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p21	p21	p21	Rb	Rb	Rb	16	17	18	19
The p53 protein represents the key regulator point for various signaling pathways of senescence : p53 phosphorylation and consequent activation inhibits cell division primarily inducing p21 expression , which , in turn , activates pRb through inhibition of a cyclin dependent kinase ( Cdk ) complex .	The p53 protein represents the key regulator point for various signaling pathways of senescence : p53 phosphorylation and consequent activation inhibits cell division primarily inducing p21 expression, which, in turn, activates pRb through inhibition of a cyclin dependent kinase (Cdk) complex.	25	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21 expression	p21	pRb	pRb	prb	25	26	34	35
XREF_BIBR An enhanced expression of p21 leads to hypophosphorylation , and thus activation , of retinoblastoma protein ( Rb ) what in turn results in cell cycle and proliferation arrest .	XREF_BIBR An enhanced expression of p21 leads to hypophosphorylation, and thus activation, of retinoblastoma protein (Rb) what in turn results in cell cycle and proliferation arrest.	0	17	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21	p21	p21	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	5	6	15	17
Biochemical analyses on CARF induced molecular signaling revealed that in p53-null cells , it caused transcriptional repression of p21 ( WAF1 ) leading to increase in CDK4 , CDK6 , pRb and E2F1 resulting in continued cell cycle progression .	Biochemical analyses on CARF induced molecular signaling revealed that in p53-null cells, it caused transcriptional repression of p21 (WAF1) leading to increase in CDK4, CDK6, pRb and E2F1 resulting in continued cell cycle progression.	16	31	leading	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p21	p21	p21	pRb	pRb	pRb	18	19	30	31
CHK-1 mediated Wee-1 activation and cdc25A inhibition result in inhibition of CDK2 catalytic activity and a slowing in the rate of DNA synthesis through late replication origin suppression [ XREF_BIBR ] .	CHK-1 mediated Wee-1 activation and cdc25A inhibition result in inhibition of CDK2 catalytic activity and a slowing in the rate of DNA synthesis through late replication origin suppression [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	CHK-1	CHK-1	CHK-1	Wee-1	Wee-1	Wee-1	0	1	2	3
Overall , the AMT-Chk2 and ATR-Chk1 pathways , together with the Wee1 like protein kinase ( Wee1 ) that is activated by Chk1 , are crucial for determining cell fate upon genotoxic injuries , being central in the G 1 -S , intra-S and G 2 -M cell cycle checkpoints XREF_BIBR , XREF_BIBR .	Overall, the AMT-Chk2 and ATR-Chk1 pathways, together with the Wee1 like protein kinase (Wee1) that is activated by Chk1, are crucial for determining cell fate upon genotoxic injuries, being central in the G 1 -S, intra-S and G 2 -M cell cycle checkpoints XREF_BIBR, XREF_BIBR.	14	23	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	22	23	16	17
In contrast , Chk1 is also able to activate the tyrosine kinase Wee1 , which phosphorylates and thereby inhibits the cyclin B and Cdk1 complex at the G2/M transition of the cell cycle .	In contrast, Chk1 is also able to activate the tyrosine kinase Wee1, which phosphorylates and thereby inhibits the cyclin B and Cdk1 complex at the G2/M transition of the cell cycle.	3	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	3	4	12	13
Chk1 has been shown to activate Wee1 in Xenopus extracts and yeast ; however such a relationship has not been recapitulated in higher eukaryotes [ XREF_BIBR , XREF_BIBR ] .	Chk1 has been shown to activate Wee1 in Xenopus extracts and yeast; however such a relationship has not been recapitulated in higher eukaryotes [XREF_BIBR, XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	0	1	6	7
CHK1 and CHK2 activated Wee 1 through phosphorylation .	CHK1 and CHK2 activated Wee 1 through phosphorylation.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	Wee 1	Wee 1	Wee 1	0	1	4	6
Overexpression of Chk1 in X. laevis embryos , which activates Wee1 and inhibits Cdc25A and Cdc25C , delays both the MBT and cyclin E degradation [ XREF_BIBR ] , suggesting that the cyclin E/Cdk2 timer is regulated by its phosphorylation state .	Overexpression of Chk1 in X. laevis embryos, which activates Wee1 and inhibits Cdc25A and Cdc25C, delays both the MBT and cyclin E degradation [XREF_BIBR], suggesting that the cyclin E/Cdk2 timer is regulated by its phosphorylation state.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Overexpression of Chk1	chk1	Wee1	Wee1	wee1	2	3	10	11
As Chk1 was previously shown to activate Wee1 during the G2/M checkpoint and the lack of Chk1 has a similar effect on the replication fork speed as Wee1 down-regulation , we down-regulated both Chk1 and Wee1 to test whether they could be functioning together or in parallel pathways .	As Chk1 was previously shown to activate Wee1 during the G2/M checkpoint and the lack of Chk1 has a similar effect on the replication fork speed as Wee1 down-regulation, we down-regulated both Chk1 and Wee1 to test whether they could be functioning together or in parallel pathways.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	1	2	7	8
On one hand CHK1 targets the Ser642 residue of Wee1 , favoring the Wee1 decision toward phosphorylation of CDK1 53 .	On one hand CHK1 targets the Ser642 residue of Wee1, favoring the Wee1 decision toward phosphorylation of CDK1 53.	2	10	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	Wee1	Wee1	Wee1	3	4	9	10
Work from a variety of labs has determined that the activity of Chk1 inhibits the Cdc25 phosphatase and activates the Wee1 and Mik1 protein kinases , two actions that favor phosphorylated , and thus inactive , cyclin dependent kinase , the engine that drives the cell cycle .	Work from a variety of labs has determined that the activity of Chk1 inhibits the Cdc25 phosphatase and activates the Wee1 and Mik1 protein kinases, two actions that favor phosphorylated, and thus inactive, cyclin dependent kinase, the engine that drives the cell cycle.	10	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	12	13	20	21
Furthermore , activated CHK1 directly increases the activity of Wee1 .	Furthermore, activated CHK1 directly increases the activity of Wee1.	2	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	Wee1	Wee1	Wee1	3	4	9	10
In addition , activation of Chk1 induces Wee-1 and also arrests the cells in G2/M .	In addition, activation of Chk1 induces Wee-1 and also arrests the cells in G2/M.	3	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee-1	Wee-1	Wee-1	5	6	7	8
This is accomplished in part by the activation of Wee1 by Chk1 , which is required for the low activity of Cdk1 observed in interphases of cell cycles 12 and 13 .	This is accomplished in part by the activation of Wee1 by Chk1, which is required for the low activity of Cdk1 observed in interphases of cell cycles 12 and 13.	2	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	11	12	9	10
To address stress induced DNA damage from various sources , CHK1 is phosphorylated by ATR at Ser345 , and pCHK1 subsequently activates WEE1 , maintaining CDK1 in its inactive Y15 phosphorylated form , which prevent cell cycle process and allow cells to repair DNA damage .	To address stress induced DNA damage from various sources, CHK1 is phosphorylated by ATR at Ser345, and pCHK1 subsequently activates WEE1, maintaining CDK1 in its inactive Y15 phosphorylated form, which prevent cell cycle process and allow cells to repair DNA damage.	10	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1 is phosphorylated by ATR at Ser345, and pCHK1	chk1	WEE1	WEE1	wee1	10	11	22	23
Like Chk1 , Cdr kinases phosphorylate Wee1 , but unlike the activation of Wee1 by Chk1 , Cdr kinases are Wee1 inhibitors [ XREF_BIBR - XREF_BIBR ] .	Like Chk1, Cdr kinases phosphorylate Wee1, but unlike the activation of Wee1 by Chk1, Cdr kinases are Wee1 inhibitors [XREF_BIBR - XREF_BIBR].	11	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	15	16	13	14
Chk1 downregulates the Cdc25 phosphatases and concomitantly upregulates the Wee1 kinases that control the phosphorylation of Cdc2 .	Chk1 downregulates the Cdc25 phosphatases and concomitantly upregulates the Wee1 kinases that control the phosphorylation of Cdc2.	0	10	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	0	1	9	10
CHK1 promotes the nuclear localization of Wee1 through phosphorylation on Ser642 and prepares CDC25C for cytoplasmic translocation through phosphorylation on Ser216 , thus enforcing G2 arrest through both primary regulatory nodes .	CHK1 promotes the nuclear localization of Wee1 through phosphorylation on Ser642 and prepares CDC25C for cytoplasmic translocation through phosphorylation on Ser216, thus enforcing G2 arrest through both primary regulatory nodes.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	Wee1	Wee1	Wee1	0	1	6	7
In addition , Chk1 has also been shown to directly target and activate Wee1 , the kinase directly responsible for the inhibitory phosphorylation of Cdk1 and 2 on Tyr 15 .	In addition, Chk1 has also been shown to directly target and activate Wee1, the kinase directly responsible for the inhibitory phosphorylation of Cdk1 and 2 on Tyr 15.	3	16	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	3	4	13	14
We also investigated the association between pWee1 and pChk1 in order to provide clues on whether Wee1 activation in cervical cancer is mediated by Chk1 .	We also investigated the association between pWee1 and pChk1 in order to provide clues on whether Wee1 activation in cervical cancer is mediated by Chk1.	16	25	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	24	25	16	17
The activation of Chk1 results in decreased function of Cdc25 and increased function of Wee1 .	The activation of Chk1 results in decreased function of Cdc25 and increased function of Wee1.	1	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	3	4	14	15
Additionally , Chk1 activates the kinase Wee1 , which is responsible for the inhibitory phosphorylation of Cdk1 at Y15 [ XREF_BIBR ] .	Additionally, Chk1 activates the kinase Wee1, which is responsible for the inhibitory phosphorylation of Cdk1 at Y15 [XREF_BIBR].	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	2	3	6	7
CHK1 and CHK2 in turn activates WEE1 and represses the CDC25 phosphatase family , thereby maintaining CDK1 in an inhibitory phosphorylated state XREF_BIBR .	CHK1 and CHK2 in turn activates WEE1 and represses the CDC25 phosphatase family, thereby maintaining CDK1 in an inhibitory phosphorylated state XREF_BIBR.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	WEE1	WEE1	WEE1	0	1	6	7
It is also proposed that the phosphorylation of CHK1 by CdK1 is at a site distinct from that activated by ATR ( Ser286 , Ser301 ) and triggers Crm-1-dependent nuclear export of CHK1 to mediate cell cycle transition of G2/M phase .	It is also proposed that the phosphorylation of CHK1 by CdK1 is at a site distinct from that activated by ATR (Ser286, Ser301) and triggers Crm-1-dependent nuclear export of CHK1 to mediate cell cycle transition of G2/M phase.	6	33	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	phosphorylation of CHK1	chk1	CHK1	CHK1	chk1	8	9	32	33
Consequently , ATX3 is essential for the maintenance of steady-state levels of Chk1 , and ATX3 mediated deubiquitination of Chk1 significantly prolongs the half-life of Chk1 , thus promoting checkpoint signaling and DNA repair upon genotoxic stress exposure .	Consequently, ATX3 is essential for the maintenance of steady-state levels of Chk1, and ATX3 mediated deubiquitination of Chk1 significantly prolongs the half-life of Chk1, thus promoting checkpoint signaling and DNA repair upon genotoxic stress exposure.	15	26	prolongs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	ATX3 mediated deubiquitination of Chk1	chk1	Chk1	Chk1	chk1	19	20	25	26
Overexpression of miR-424 inhibited the expression of CHEK1 and p-CHEK1 at residue Ser345 , and decreased the activity of the luciferase reporter containing the 3 '-untranslated region of CHEK1 .	Overexpression of miR-424 inhibited the expression of CHEK1 and p-CHEK1 at residue Ser345, and decreased the activity of the luciferase reporter containing the 3 '-untranslated region of CHEK1.	0	29	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p-CHEK1	Overexpression of miR-424 inhibited the expression of CHEK1 and p-CHEK1	p-chek1	CHEK1	CHEK1	chek1	9	10	28	29
Phosphorylation of Chk1 leads to an increase of Chk1 kinase activity [ XREF_BIBR ] and is often used as a convenient molecular marker for Chk1 dependent checkpoint activation .	Phosphorylation of Chk1 leads to an increase of Chk1 kinase activity [XREF_BIBR] and is often used as a convenient molecular marker for Chk1 dependent checkpoint activation.	0	10	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Chk1	Phosphorylation of Chk1	chk1	Chk1	Chk1	chk1	2	3	8	9
Phosphorylation of Chk1 at serine 317 and 345 by ATR promotes Chk1 activation but also induces the ubiquitin-proteasome dependent degradation of Chk1 [ XREF_BIBR - XREF_BIBR ] .	Phosphorylation of Chk1 at serine 317 and 345 by ATR promotes Chk1 activation but also induces the ubiquitin-proteasome dependent degradation of Chk1 [XREF_BIBR - XREF_BIBR].	0	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Phosphorylation of Chk1 at serine 317 and 345	chk1	Chk1	Chk1	chk1	2	3	21	22
Interestingly , these studies revealed that the phosphorylation of Chk1 at Ser 317 and Ser345 not only promotes full activation of Chk1 , but also induces degradation of Chk1 through the ubiquitin-proteasome pathway .	Interestingly, these studies revealed that the phosphorylation of Chk1 at Ser 317 and Ser345 not only promotes full activation of Chk1, but also induces degradation of Chk1 through the ubiquitin-proteasome pathway.	7	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	phosphorylation of Chk1 at Ser 317 and Ser345	chk1	Chk1	Chk1	chk1	9	10	28	29
The phosphorylation of Chk1 enhances Chk1 ' s kinase activity , which in turn phosphorylates downstream substrates ( e.g ., Cdc25 , BLM , and FANCD2 and FANCE ) and facilitates cell cycle arrest and DNA damage repair [ XREF_BIBR - XREF_BIBR ] .	The phosphorylation of Chk1 enhances Chk1 's kinase activity, which in turn phosphorylates downstream substrates (e.g., Cdc25, BLM, and FANCD2 and FANCE) and facilitates cell cycle arrest and DNA damage repair [XREF_BIBR - XREF_BIBR].	1	6	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Chk1	phosphorylation of Chk1	chk1	Chk1	Chk1	chk1	3	4	5	6
To determine whether overexpression of Chek1 R , a shChek1-4 resistant cDNA allele of Chek1 , could rescue the Chek1 knockdown phenotype , t4 Lkb1-null cells were first transduced with pCDH-Chek1 R co-expressing GFP and Chek1 R.	To determine whether overexpression of Chek1 R, a shChek1-4 resistant cDNA allele of Chek1, could rescue the Chek1 knockdown phenotype, t4 Lkb1-null cells were first transduced with pCDH-Chek1 R co-expressing GFP and Chek1 R.	3	21	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chek1	overexpression of Chek1	chek1	Chek1	Chek1	chek1	5	6	19	20
Phosphorylation of Chk1 and Chk2 on ATM and ATR mediated sites ( Chk1 pS345 and Chk2 pT68 ) increased following AZD7762 treatment ( XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY ) .	Phosphorylation of Chk1 and Chk2 on ATM and ATR mediated sites (Chk1 pS345 and Chk2 pT68) increased following AZD7762 treatment (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).	0	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Phosphorylation of Chk1	chk1	Chk1	Chk1	chk1	2	3	12	13
Chk1 phosphorylation triggers a release of Chk1 from chromatin upon DNA damage into the nucleoplasm and the cytoplasm .	Chk1 phosphorylation triggers a release of Chk1 from chromatin upon DNA damage into the nucleoplasm and the cytoplasm.	0	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1 phosphorylation	chk1	Chk1	Chk1	chk1	0	1	6	7
EA6 induced Chk1 activation and inhibition of Chk1 in CNE-1 cells by RNA interference ( RNAi ) markedly abrogated EA6 mediated G2/M arrest and abolished EA6 induced cytotoxicity .	EA6 induced Chk1 activation and inhibition of Chk1 in CNE-1 cells by RNA interference (RNAi) markedly abrogated EA6 mediated G2/M arrest and abolished EA6 induced cytotoxicity.	0	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Chk1	EA6 induced Chk1	chk1	Chk1	Chk1	chk1	2	3	7	8
In response to DNA damage or replicative stress , ATR induced phosphorylation of Chk1 at S317 and S345 activates Chk1 , thus regulating various signal pathways , such as DNA repair , cell cycle arrest and cell death in the case of excessive DNA damage , while dephosphorylation of activated Chk1 by PP1 and WIP1 promotes cell cycle recovery .	In response to DNA damage or replicative stress, ATR induced phosphorylation of Chk1 at S317 and S345 activates Chk1, thus regulating various signal pathways, such as DNA repair, cell cycle arrest and cell death in the case of excessive DNA damage, while dephosphorylation of activated Chk1 by PP1 and WIP1 promotes cell cycle recovery.	9	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	ATR induced phosphorylation of Chk1 at S317 and S345	chk1	Chk1	Chk1	chk1	13	14	19	20
Conversely , overexpression of USP7 wild type , but not a catalytic mutant version , elevates Chk1 levels and increases the half-life of Chk1 protein .	Conversely, overexpression of USP7 wild type, but not a catalytic mutant version, elevates Chk1 levels and increases the half-life of Chk1 protein.	2	24	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	overexpression of USP7 wild type, but not a catalytic mutant version, elevates Chk1 levels	chk1	Chk1	Chk1	chk1	16	17	23	24
Upon replication stress Chk1 is phosphorylated by ATR on S317 , which allows Chk1 to auto-phosphorylate , and initiate its downstream kinase cascade in the replication stress response that results in replication arrest .	Upon replication stress Chk1 is phosphorylated by ATR on S317, which allows Chk1 to auto-phosphorylate, and initiate its downstream kinase cascade in the replication stress response that results in replication arrest.	2	18	allows	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Chk1	Chk1 is phosphorylated by ATR on S317	chk1	Chk1	Chk1 to auto-phosphorylate	chk1	3	4	13	14
In response to genotoxic agents , Chk1 was phosphorylated on Serine 317 and 345 in an ATR dependent manner and mutations at these residues resulted in poor Chk1 activation .	In response to genotoxic agents, Chk1 was phosphorylated on Serine 317 and 345 in an ATR dependent manner and mutations at these residues resulted in poor Chk1 activation.	6	29	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Chk1	Chk1 was phosphorylated on Serine 317	chk1	Chk1	Chk1	chk1	6	7	27	28
Recent studies suggest that at least three mechanisms inactivate Chk1 in vertebrate cells : ( 1 ) SCF beta-Trcp1 -mediated degradation of Claspin , an essential mediator during the ATR induced Chk1 phosphorylation ; ( 2 ) dephosphorylation of activated Chk1 by PP1 , PP2A , or PP2C type phosphatases ; and ( 3 ) Cul1 or Cul4A dependent degradation of Chk1 , as described in this paper and elsewhere .	Recent studies suggest that at least three mechanisms inactivate Chk1 in vertebrate cells : (1) SCF beta-Trcp1 -mediated degradation of Claspin, an essential mediator during the ATR induced Chk1 phosphorylation; (2) dephosphorylation of activated Chk1 by PP1, PP2A, or PP2C type phosphatases; and (3) Cul1 or Cul4A dependent degradation of Chk1, as described in this paper and elsewhere.	37	62	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Chk1	dephosphorylation of activated Chk1 by PP1, PP2A, or PP2C type phosphatases; and (3) Cul1	chk1	Chk1	Chk1	chk1	40	41	61	62
It has been demonstrated that ATR mediated S345 phosphorylation of Chk1 not only activates Chk1 but also targets it for proteasomal destruction .	It has been demonstrated that ATR mediated S345 phosphorylation of Chk1 not only activates Chk1 but also targets it for proteasomal destruction.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	ATR mediated S345 phosphorylation of Chk1	chk1	Chk1	Chk1	chk1	10	11	14	15
Indeed , ectopic expression of Flag-ATX3 in A549 cells nicely upregulated the endogenous level of Chk1 , and promoted the stability of Chk1 after CHX treatment .	Indeed, ectopic expression of Flag-ATX3 in A549 cells nicely upregulated the endogenous level of Chk1, and promoted the stability of Chk1 after CHX treatment.	3	23	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	expression of Flag-ATX3 in A549 cells nicely upregulated the endogenous level of Chk1	chk1	Chk1	Chk1	chk1	15	16	22	23
Overexpression of Chk1 in control cells was sufficient to increase the etoposide induced DNA DSBs ( XREF_FIG ) and overexpression of the CMA-incompetent form of Chk1 that persisted at higher levels in the nucleus lead to even more pronounced accumulation of DNA damage ( XREF_FIG ) .	Overexpression of Chk1 in control cells was sufficient to increase the etoposide induced DNA DSBs (XREF_FIG) and overexpression of the CMA-incompetent form of Chk1 that persisted at higher levels in the nucleus lead to even more pronounced accumulation of DNA damage (XREF_FIG).	0	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Overexpression of Chk1	chk1	Chk1	Chk1	chk1	2	3	25	26
Phosphorylation of Chk1 at Ser317 is mediated by ATR and activates Chk1 [ XREF_BIBR ] .	Phosphorylation of Chk1 at Ser317 is mediated by ATR and activates Chk1 [XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Phosphorylation of Chk1 at Ser317	chk1	Chk1	Chk1	chk1	2	3	11	12
Western blot showed that ectopic expression of miR-497 suppressed the CHEK1 expression and inhibition of miR-497 led to significant upregulation of CHEK1 .	Western blot showed that ectopic expression of miR-497 suppressed the CHEK1 expression and inhibition of miR-497 led to significant upregulation of CHEK1.	10	22	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	CHEK1	CHEK1 expression	chek1	CHEK1	CHEK1	chek1	10	11	21	22
The ectopic overexpression of Chk1 in LMP1 exprssing cells enhanced Chk1 activation after gamma-ray irradiation .	The ectopic overexpression of Chk1 in LMP1 exprssing cells enhanced Chk1 activation after gamma-ray irradiation.	2	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	overexpression of Chk1	chk1	Chk1	Chk1	chk1	4	5	10	11
As expected , UV radiation increased phosphorylation of Chk1 at Ser317 ( p-Chk1 ) ( XREF_FIG ) , and roscovitine decreased Chk1 protein expression and abrogated UV induced p-Chk1 in both cytoplasm and nucleus ( XREF_FIG ) .	As expected, UV radiation increased phosphorylation of Chk1 at Ser317 (p-Chk1) (XREF_FIG), and roscovitine decreased Chk1 protein expression and abrogated UV induced p-Chk1 in both cytoplasm and nucleus (XREF_FIG).	19	29	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	roscovitine decreased Chk1 protein expression	chk1	p-Chk1	p-Chk1	p-chk1	21	22	28	29
The ATR mediated phosphorylation of Claspin promotes the phosphorylation of Chk1 by ATR and might directly stimulate the kinase activity of Chk1 .	The ATR mediated phosphorylation of Claspin promotes the phosphorylation of Chk1 by ATR and might directly stimulate the kinase activity of Chk1.	1	22	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	ATR mediated phosphorylation of Claspin promotes the phosphorylation of Chk1	chk1	Chk1	Chk1	chk1	10	11	21	22
The phosphorylation of Chk1 by ATR stimulates its kinase activity , and activated Chk1 in turn phosphorylates its downstream effectors , which influence cell cycle progression , DNA repair and cell survival .	The phosphorylation of Chk1 by ATR stimulates its kinase activity, and activated Chk1 in turn phosphorylates its downstream effectors, which influence cell cycle progression, DNA repair and cell survival.	1	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	phosphorylation of Chk1	chk1	Chk1	Chk1	chk1	3	4	13	14
Indeed , it has been reported that CHK1 can be activated by a hypothetical trans-regulatory protein independent of CHK1 Ser345 phosphorylation .	Indeed, it has been reported that CHK1 can be activated by a hypothetical trans-regulatory protein independent of CHK1 Ser345 phosphorylation.	7	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CHK1	CHK1 Ser345 phosphorylation	chk1	CHK1	CHK1	chk1	18	19	7	8
Given that S345 phosphorylation of Chk1 , mediated by ATR , targets Chk1 for degradation via the ubiquitin-proteasome pathway , we next assessed the impact of mutation of this phosphorylation site on the ATX3 and Chk1 interaction .	Given that S345 phosphorylation of Chk1, mediated by ATR, targets Chk1 for degradation via the ubiquitin-proteasome pathway, we next assessed the impact of mutation of this phosphorylation site on the ATX3 and Chk1 interaction.	2	14	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	S345 phosphorylation of Chk1	chk1	Chk1	Chk1	chk1	5	6	12	13
ATR mediated Chk1 phosphorylation at Ser317 and Ser345 stimulates Chk1 kinase and releases it from chromatin to carry out the intra-S checkpoint .	ATR mediated Chk1 phosphorylation at Ser317 and Ser345 stimulates Chk1 kinase and releases it from chromatin to carry out the intra-S checkpoint.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	ATR mediated Chk1 phosphorylation at Ser317	chk1	Chk1	Chk1	chk1	2	3	9	10
ATR mediated phosphorylation of CHK1 activates CHK1 kinase activity and thereby allows the protein to delay cell cycle progression [ XREF_BIBR - XREF_BIBR ] .	ATR mediated phosphorylation of CHK1 activates CHK1 kinase activity and thereby allows the protein to delay cell cycle progression [XREF_BIBR - XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	ATR mediated phosphorylation of CHK1	chk1	CHK1	CHK1	chk1	4	5	6	7
In DDR , ATR mediated Chk1 phosphorylation at serine 317 and serine 345 leads to the dissociation of Chk1-S from Chk1 , resulting in Chk1 activation and cell cycle arrest ( XREF_FIG ) .	In DDR, ATR mediated Chk1 phosphorylation at serine 317 and serine 345 leads to the dissociation of Chk1-S from Chk1, resulting in Chk1 activation and cell cycle arrest (XREF_FIG).	3	25	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	ATR mediated Chk1 phosphorylation at serine 317	chk1	Chk1	Chk1	chk1	5	6	24	25
Depleting AKT activity attenuated basal expression of p-Chk1 and HGF induced Chk1 activation .	Depleting AKT activity attenuated basal expression of p-Chk1 and HGF induced Chk1 activation.	5	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-Chk1	expression of p-Chk1	p-chk1	Chk1	Chk1	chk1	7	8	11	12
Interestingly , overexpression of miR-424 inhibited the expression of protein checkpoint kinase 1 ( Chk1 ) and phosphorylated Chk1 ( p-Chk1 ) at residues Ser345 and decreased the activity of luciferase reporter containing the 3 '-untranslated region ( UTR ) of Chk1 with predicted miR-424-binding site .	Interestingly, overexpression of miR-424 inhibited the expression of protein checkpoint kinase 1 (Chk1) and phosphorylated Chk1 (p-Chk1) at residues Ser345 and decreased the activity of luciferase reporter containing the 3 '-untranslated region (UTR) of Chk1 with predicted miR-424-binding site.	2	42	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	checkpoint kinase 1	overexpression of miR-424 inhibited the expression of protein checkpoint kinase 1	checkpoint kinase 1	Chk1	Chk1	chk1	10	13	41	42
The DNA damage effector kinase Chk1 on serine 280 can be directly phosphorylated by Akt , thereby stimulating the movement of Chk1 into the cytoplasm which blocks its function and promotes cell cycle progression from the G2 to the M phase .	The DNA damage effector kinase Chk1 on serine 280 can be directly phosphorylated by Akt, thereby stimulating the movement of Chk1 into the cytoplasm which blocks its function and promotes cell cycle progression from the G2 to the M phase.	0	22	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1 on serine 280 can be directly phosphorylated	chk1	Chk1	Chk1	chk1	5	6	21	22
These results are consistent with those of a study by Montano et al , in which the Chk1 inhibitor MK-8776 also inhibited DNA damaging agent and antimetabolite induced Chk1 ( Ser296 ) phosphorylation XREF_BIBR , XREF_BIBR .	These results are consistent with those of a study by Montano et al, in which the Chk1 inhibitor MK-8776 also inhibited DNA damaging agent and antimetabolite induced Chk1 (Ser296) phosphorylation XREF_BIBR, XREF_BIBR.	27	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1 (Ser296) phosphorylation	chk1	Chk1	Chk1	chk1	28	29	28	29
CHK2 ( the protein product of the CHEK2 gene ) is an effector protein conserved in eukaryotes and phosphorylated by the sensor kinases ATM and ATR in response to DNA damage ; upon phosphorylation by ATM and ATR , CHK2 phosphorylates and thus modifies the function of key targets of the checkpoint response [ XREF_BIBR ] .	CHK2 (the protein product of the CHEK2 gene) is an effector protein conserved in eukaryotes and phosphorylated by the sensor kinases ATM and ATR in response to DNA damage; upon phosphorylation by ATM and ATR, CHK2 phosphorylates and thus modifies the function of key targets of the checkpoint response [XREF_BIBR].	0	13	product	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	CHK2	CHK2	CHK2	CHEK2	CHEK2	CHEK2	0	1	7	8
As thymocytes predominantly reside in G0/G1 phase , we favour the possibility that DNA-PKcs , which can phosphorylate CHK2 in vitro and affect apoptosis independently of ATM , is an activator of CHK2 apoptotic activity XREF_BIBR , XREF_BIBR .	As thymocytes predominantly reside in G0/G1 phase, we favour the possibility that DNA-PKcs, which can phosphorylate CHK2 in vitro and affect apoptosis independently of ATM, is an activator of CHK2 apoptotic activity XREF_BIBR, XREF_BIBR.	13	33	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	CHK2	DNA-PKcs, which can phosphorylate CHK2	chk2	CHK2	CHK2	chk2	18	19	32	33
Thus , a model for Chk2 activation after DNA damage that embraces all of this data would suggest that Chk2 phosphorylation at T68 by ATM , causes Chk2 dimerization , which results in T-loop phosphorylation and activation of the kinase .	Thus, a model for Chk2 activation after DNA damage that embraces all of this data would suggest that Chk2 phosphorylation at T68 by ATM, causes Chk2 dimerization, which results in T-loop phosphorylation and activation of the kinase.	19	28	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	Chk2 phosphorylation at T68	chk2	Chk2	Chk2	chk2	19	20	27	28
Phosphorylation of CHK2 induces CHK2 dimerization , which is required for CHK2 activity .	Phosphorylation of CHK2 induces CHK2 dimerization, which is required for CHK2 activity.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK2	Phosphorylation of CHK2	chk2	CHK2	CHK2	chk2	2	3	4	5
Further they indicate that RPA4 expressing cells contain some type of abnormal DNA structure that is sufficient to cause elevated gamma-H2AX but not Chk2 activation ( low P-Chk2 ) .	Further they indicate that RPA4 expressing cells contain some type of abnormal DNA structure that is sufficient to cause elevated gamma-H2AX but not Chk2 activation (low P-Chk2).	13	28	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P-Chk2	P-Chk2	P-Chk2	Chk2	Chk2	Chk2	27	28	23	24
In response to irradiation , ATM phosphorylates Chk2 at its Thr68 residue promoting Chk2 dimerization and full activation [ XREF_BIBR ] .	In response to irradiation, ATM phosphorylates Chk2 at its Thr68 residue promoting Chk2 dimerization and full activation [XREF_BIBR].	5	14	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	ATM phosphorylates Chk2 at its Thr68	chk2	Chk2	Chk2	chk2	7	8	13	14
During the G2-M checkpoint , ATM phosphorylates monomers of CHK2 on Thr68 allowing the formation of CHK2 dimers that have as a main target the cell division cycle 25 homolog A ( CDC25A ) .	During the G2-M checkpoint, ATM phosphorylates monomers of CHK2 on Thr68 allowing the formation of CHK2 dimers that have as a main target the cell division cycle 25 homolog A (CDC25A).	5	17	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK2	ATM phosphorylates monomers of CHK2 on Thr68	chk2	CHK2	CHK2	chk2	9	10	16	17
In cell lacking ATM or expressing hypomorphic Mre11 complex alleles , Chk2 hyperphosphorylation is severely attenuated , suggesting impaired Chk2 kinase activity that has been proposed to underlie some features of the human genetic instability syndromes .	In cell lacking ATM or expressing hypomorphic Mre11 complex alleles, Chk2 hyperphosphorylation is severely attenuated, suggesting impaired Chk2 kinase activity that has been proposed to underlie some features of the human genetic instability syndromes.	11	21	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	Chk2 hyperphosphorylation	chk2	Chk2	Chk2	chk2	11	12	19	20
The TAp63alpha isoform we used here is usually expressed in oocytes where it forms an inactive conformation XREF_BIBR , XREF_BIBR , and must be activated first through phosphorylation by checkpoint kinase 2 ( CHK2 ) 36 .	The TAp63alpha isoform we used here is usually expressed in oocytes where it forms an inactive conformation XREF_BIBR, XREF_BIBR, and must be activated first through phosphorylation by checkpoint kinase 2 (CHK2) 36.	10	34	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	checkpoint kinase 2	checkpoint kinase 2	checkpoint kinase 2	CHK2	CHK2	CHK2	29	32	33	34
DNA damage signals the phosphorylation of CHK2 by DNA-PKcs at site T68 which stimulates CHK2 to hyper-phosphorylate Cabin1 targeting it for ubiquitination and degradation [ XREF_BIBR ] .	DNA damage signals the phosphorylation of CHK2 by DNA-PKcs at site T68 which stimulates CHK2 to hyper-phosphorylate Cabin1 targeting it for ubiquitination and degradation [XREF_BIBR].	4	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK2	phosphorylation of CHK2 by DNA-PKcs at site T68	chk2	CHK2	CHK2	chk2	6	7	14	15
In response to DNA damage , ataxia telangiectasia mutated ( ATM ) phosphorylates the Chk2 tumour suppressor kinase at threonine 68 ( Thr68 ) , allowing Chk2 kinase dimerization and activation by autophosphorylations in the T-loop .	In response to DNA damage, ataxia telangiectasia mutated (ATM) phosphorylates the Chk2 tumour suppressor kinase at threonine 68 (Thr68), allowing Chk2 kinase dimerization and activation by autophosphorylations in the T-loop.	6	28	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	ataxia telangiectasia mutated (ATM) phosphorylates the Chk2 tumour suppressor kinase at threonine	chk2	Chk2	Chk2	chk2	14	15	26	27
Tau phosphorylation has been investigated at AD related sites by using recombinant human tau phosphorylated by DNA damage activated checkpoint kinase 1 ( Chk1 ) and checkpoint kinase 2 ( Chk2 ) in vitro [ XREF_BIBR ] .	Tau phosphorylation has been investigated at AD related sites by using recombinant human tau phosphorylated by DNA damage activated checkpoint kinase 1 (Chk1) and checkpoint kinase 2 (Chk2) in vitro [XREF_BIBR].	18	31	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	Chk2	Chk2	checkpoint kinase 2	checkpoint kinase 2	checkpoint kinase 2	30	31	26	29
In turn , Mec1 and Tel1 phosphorylate Rad53 , thereby increasing the kinase activity of Rad53 .	In turn, Mec1 and Tel1 phosphorylate Rad53, thereby increasing the kinase activity of Rad53.	5	16	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad53	Tel1 phosphorylate Rad53	rad53	Rad53	Rad53	rad53	7	8	15	16
For example , the checkpoint kinase Chk2 is activated by ATM phosphorylation of Chk2 Thr68 in response to DSB .	For example, the checkpoint kinase Chk2 is activated by ATM phosphorylation of Chk2 Thr68 in response to DSB.	3	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Chk2	phosphorylation of Chk2	chk2	Chk2	Chk2	chk2	13	14	6	7
Among other substrates , ATM phosphorylates Chk2 on threonine 68 XREF_BIBR , XREF_BIBR , inducing dimerization of Chk2 and auto-phosphorylation of multiple sites , leading to full activation XREF_BIBR - XREF_BIBR .	Among other substrates, ATM phosphorylates Chk2 on threonine 68 XREF_BIBR, XREF_BIBR, inducing dimerization of Chk2 and auto-phosphorylation of multiple sites, leading to full activation XREF_BIBR - XREF_BIBR.	4	19	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	ATM phosphorylates Chk2 on threonine	chk2	Chk2	Chk2	chk2	6	7	17	18
In response to DNA double stranded breaks , DNA damage sensor kinase ataxia telangiectasia mutated ( ATM ) phosphorylates Chk2 at Thr68 residue promoting Chk2 homodimerization and full activation .	In response to DNA double stranded breaks, DNA damage sensor kinase ataxia telangiectasia mutated (ATM) phosphorylates Chk2 at Thr68 residue promoting Chk2 homodimerization and full activation.	10	25	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	sensor kinase ataxia telangiectasia mutated (ATM) phosphorylates Chk2 at Thr68	chk2	Chk2	Chk2	chk2	19	20	24	25
In the presence of HU , the Rad53 dependent intra-S phase checkpoint is activated by Rad53 phosphorylation that leads to fork stabilization and inhibition of late firing origins .	In the presence of HU, the Rad53 dependent intra-S phase checkpoint is activated by Rad53 phosphorylation that leads to fork stabilization and inhibition of late firing origins.	6	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rad53	Rad53 phosphorylation	rad53	Rad53	Rad53	rad53	15	16	7	8
However , both primary and tertiary structural differences between Cdk4 and Cdk2 support the idea that T-loop phosphorylation might be regulated differently for the two CDKs , and were invoked to suggest that Cdk4 might be activated by a CAK other than Cdk7 in metazoan cells .	However, both primary and tertiary structural differences between Cdk4 and Cdk2 support the idea that T-loop phosphorylation might be regulated differently for the two CDKs, and were invoked to suggest that Cdk4 might be activated by a CAK other than Cdk7 in metazoan cells.	33	42	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CAK	CAK	CAK	Cdk4	Cdk4	Cdk4	39	40	33	34
Collectively , these experiments together with our previous observations indicate that JNKs might activate cyclin D-CDK4 complexes stabilized by p21 , by acting as direct CDK4 activating kinases , and also by independently phosphorylating two critical residues of p21 involved in CAK dependent activation of CDK4 .	Collectively, these experiments together with our previous observations indicate that JNKs might activate cyclin D-CDK4 complexes stabilized by p21, by acting as direct CDK4 activating kinases, and also by independently phosphorylating two critical residues of p21 involved in CAK dependent activation of CDK4.	41	46	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CAK	CAK	CAK	CDK4	CDK4	CDK4	41	42	45	46
It had been suggested that Cdk4 was activated by another CAK , based on instances in which Cdk4 T-loop phosphorylation fluctuates while Cdk7 activity appears constant , and on structural differences between the Cdk4 T loop and those of other CDKs .	It had been suggested that Cdk4 was activated by another CAK, based on instances in which Cdk4 T-loop phosphorylation fluctuates while Cdk7 activity appears constant, and on structural differences between the Cdk4 T loop and those of other CDKs.	5	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CAK	CAK	CAK	Cdk4	Cdk4	Cdk4	10	11	5	6
These results are consistent with a model implying the cooperation of different kinases in the activation of CDK4 , including JNKs and CDK2 that allows the activation of CDK4 by CDK7 via S130 phosphorylation of p21 .	These results are consistent with a model implying the cooperation of different kinases in the activation of CDK4, including JNKs and CDK2 that allows the activation of CDK4 by CDK7 via S130 phosphorylation of p21.	24	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CDK7	CDK7	CDK7	CDK4	CDK4	CDK4	30	31	28	29
Cdk7 can activate Cdk4 and Cdk6 in vitro , and purified Cdk7 as phosphorylated endogenous Cdk4 selectively in crude extracts of human cells .	Cdk7 can activate Cdk4 and Cdk6 in vitro, and purified Cdk7 as phosphorylated endogenous Cdk4 selectively in crude extracts of human cells.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk7	Cdk7	Cdk7	Cdk4	Cdk4	Cdk4	0	1	3	4
These results are consistent with previous studies reporting that CDK4 activation is prevented by CDK7 inhibition [ XREF_BIBR ] .	These results are consistent with previous studies reporting that CDK4 activation is prevented by CDK7 inhibition [XREF_BIBR].	9	17	prevented	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	CDK7	CDK7	CDK7	CDK4	CDK4	CDK4	14	15	9	10
It was unknown if Cdk7 also activates Cdk4 and Cdk6 to promote passage of the Restriction ( R ) Point , when continued cell-cycle progression becomes mitogen independent ; or if CDK activating phosphorylation regulates G1 progression .	It was unknown if Cdk7 also activates Cdk4 and Cdk6 to promote passage of the Restriction (R) Point, when continued cell-cycle progression becomes mitogen independent; or if CDK activating phosphorylation regulates G1 progression.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk7	Cdk7	Cdk7	Cdk4	Cdk4	Cdk4	4	5	7	8
A recent study has shown that CDK7 activates CDK4 to regulate G1 progression [ XREF_BIBR ] .	A recent study has shown that CDK7 activates CDK4 to regulate G1 progression [XREF_BIBR].	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK7	CDK7	CDK7	CDK4	CDK4	CDK4	6	7	8	9
Interaction between MyoD and cdk4 disrupts MyoD DNA binding , muscle specific gene activation and myogenic conversion of 10T1/2 cells independently of cyclin D1 and the CAK activation of cdk4 .	Interaction between MyoD and cdk4 disrupts MyoD DNA binding, muscle specific gene activation and myogenic conversion of 10T1/2 cells independently of cyclin D1 and the CAK activation of cdk4.	26	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CAK	CAK	CAK	cdk4	cdk4	cdk4	26	27	29	30
XREF_BIBR We showed , however , that Cdk7 is responsible for activation of Cdk4 and Cdk6 through another distinct pathway .	XREF_BIBR We showed, however, that Cdk7 is responsible for activation of Cdk4 and Cdk6 through another distinct pathway.	7	15	is responsible for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	Cdk7	Cdk7	Cdk7	Cdk4	Cdk4	Cdk4	7	8	13	14
Indeed , in the presence of a motorless CENP-E fragment that can constitutively activate BubR1 , the majority of chromosomes congress to the metaphase plate in the Xenopus egg extracts depleted of endogenous CENP-E .	Indeed, in the presence of a motorless CENP-E fragment that can constitutively activate BubR1, the majority of chromosomes congress to the metaphase plate in the Xenopus egg extracts depleted of endogenous CENP-E.	8	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	8	9	14	15
Based on the observation that a phosphomimetic BubR1 mutant bypasses the requirement for CENP-E in metaphase chromosome alignment , Mao and colleagues proposed that the major function of CENP-E for the SAC and kinetochore-microtubule attachment is to activate BubR1 .	Based on the observation that a phosphomimetic BubR1 mutant bypasses the requirement for CENP-E in metaphase chromosome alignment, Mao and colleagues proposed that the major function of CENP-E for the SAC and kinetochore-microtubule attachment is to activate BubR1.	26	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	28	29	38	39
To test if CENP-E directly stimulates BubR1 kinase activity , recombinant human GSTHis-BubR1 ( 110 kD ; XREF_FIG C , lane 1 ) and human CENP-E ( 312 kD ; XREF_FIG C , lane 3 ) were expressed and purified from insect cells .	To test if CENP-E directly stimulates BubR1 kinase activity, recombinant human GSTHis-BubR1 (110 kD; XREF_FIG C, lane 1) and human CENP-E (312 kD; XREF_FIG C, lane 3) were expressed and purified from insect cells.	3	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	3	4	6	7
Because Cenp-E is thought to activate the checkpoint via BubR1 , perhaps this elevated level of Cenp-E is sufficient to activate the residual BubR1 and thus maintain mitotic arrest in the presence of nocodazole .	Because Cenp-E is thought to activate the checkpoint via BubR1, perhaps this elevated level of Cenp-E is sufficient to activate the residual BubR1 and thus maintain mitotic arrest in the presence of nocodazole.	14	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cenp-E	level of Cenp-E	cenp-e	BubR1	BubR1	bubr1	16	17	23	24
The key underlying difference between two systems could simply be the activation of BubR1 kinase by CENP-E .	The key underlying difference between two systems could simply be the activation of BubR1 kinase by CENP-E.	11	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	16	17	13	14
CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro .	CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro.	0	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	0	1	11	12
Moreover , CENP-E and BubR1 can form a stoichiometric complex , and the presence of CENP-E can greatly enhance the kinase activity of BubR1 toward itself or an exogenous substrate such as histone H1 .	Moreover, CENP-E and BubR1 can form a stoichiometric complex, and the presence of CENP-E can greatly enhance the kinase activity of BubR1 toward itself or an exogenous substrate such as histone H1.	13	29	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	15	16	23	24
Although such a feedback mechanism can link kinetochore attachments to the checkpoint , the threshold level of CENP-E activity that is required to activate or inactivate hBUBR1 activity remains to be determined .	Although such a feedback mechanism can link kinetochore attachments to the checkpoint, the threshold level of CENP-E activity that is required to activate or inactivate hBUBR1 activity remains to be determined.	17	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	hBUBR1	hBUBR1	hBUBR1	17	18	26	27
It has been proposed that CENP-E stimulates BUBR1 activity and that microtubule capture silences it .	It has been proposed that CENP-E stimulates BUBR1 activity and that microtubule capture silences it.	5	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BUBR1	BUBR1	BUBR1	5	6	7	8
Motorless CENP-E tail chronically activates BubR1 kinase and mitotic checkpoint signaling in Xenopus egg extracts .	Motorless CENP-E tail chronically activates BubR1 kinase and mitotic checkpoint signaling in Xenopus egg extracts.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	1	2	5	6
Furthermore , the kinetochore associated BubR1 autophosphorylation signals in cells also depend on the presence of CENP-E , just as in the previous results that CENP-E can stimulate BubR1 kinase activity in vitro and in Xenopus egg extracts .	Furthermore, the kinetochore associated BubR1 autophosphorylation signals in cells also depend on the presence of CENP-E, just as in the previous results that CENP-E can stimulate BubR1 kinase activity in vitro and in Xenopus egg extracts.	25	30	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	25	26	28	29
Therefore , with little correspondingly soluble CENP-E , it is most plausible that CENP-E stimulation of the BubR1 kinase is primarily at kinetochores , although the direct stimulation of BubR1 kinase by CENP-E in vitro demonstrates that such activity does not require kinetochore binding .	Therefore, with little correspondingly soluble CENP-E, it is most plausible that CENP-E stimulation of the BubR1 kinase is primarily at kinetochores, although the direct stimulation of BubR1 kinase by CENP-E in vitro demonstrates that such activity does not require kinetochore binding.	13	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	13	14	17	18
In addition , CENP-E directly stimulates the kinase ( and autokinase ) activity of BubR1 in vitro and in primary MEFs ( XREF_FIG ) .	In addition, CENP-E directly stimulates the kinase (and autokinase) activity of BubR1 in vitro and in primary MEFs (XREF_FIG).	3	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	3	4	14	15
After depletion of endogenous BubR1 and CENP-E , and restoration of normal BubR1 levels with purified GST tagged BubR1 , further addition of CENP-E tail activated the recombinant BubR1 kinase ( measured by affinity recovery of BubR1 with GST antibody beads ) to the same levels as endogenous BubR1 in mock depleted extracts ( XREF_FIG C , compare lanes 1 and 4 ) .	After depletion of endogenous BubR1 and CENP-E, and restoration of normal BubR1 levels with purified GST tagged BubR1, further addition of CENP-E tail activated the recombinant BubR1 kinase (measured by affinity recovery of BubR1 with GST antibody beads) to the same levels as endogenous BubR1 in mock depleted extracts (XREF_FIG C, compare lanes 1 and 4).	23	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	23	24	28	29
CENP-E stimulates mammalian BubR1 kinase activity .	CENP-E stimulates mammalian BubR1 kinase activity.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	0	1	3	4
Recombinant CENP-E tail lacking the rod and motor domains was found to activate BubR1 kinase in vitro as efficiently as did full-length CENP-E ( XREF_FIG A , compare lanes 3 and 6 ) .	Recombinant CENP-E tail lacking the rod and motor domains was found to activate BubR1 kinase in vitro as efficiently as did full-length CENP-E (XREF_FIG A, compare lanes 3 and 6).	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	1	2	13	14
Hydroxyurea induced replication stress induces nuclear accumulation of Rad51 foci in an ATR- and Chk1 dependent manner , and inhibition of Chk1 prevents localization of Rad51 to sites of HRR [ XREF_BIBR , XREF_BIBR ] .	Hydroxyurea induced replication stress induces nuclear accumulation of Rad51 foci in an ATR- and Chk1 dependent manner, and inhibition of Chk1 prevents localization of Rad51 to sites of HRR [XREF_BIBR, XREF_BIBR].	19	26	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Rad51	Rad51	Rad51	21	22	25	26
The results ( XREF_SUPPLEMENTARY ) showed that , as has been reported previously for inhibitors of Chk1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , inhibition of Chk1 by MK-8776 suppressed the formation of rad51 foci at 4 h after irradiation to a small extent .	The results (XREF_SUPPLEMENTARY) showed that, as has been reported previously for inhibitors of Chk1 [XREF_BIBR, XREF_BIBR, XREF_BIBR], inhibition of Chk1 by MK-8776 suppressed the formation of rad51 foci at 4 h after irradiation to a small extent.	25	35	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	rad51	rad51	rad51	27	28	34	35
Furthermore , Chk1 inhibition downregulated TH-302-induced upregulation of DNA repair protein Rad51 , a key component of the specific DNA repair pathway .	Furthermore, Chk1 inhibition downregulated TH-302-induced upregulation of DNA repair protein Rad51, a key component of the specific DNA repair pathway.	2	15	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Rad51	Rad51	Rad51	2	3	11	12
For instance , CHK1 contributes to homologous recombination ( HR ) by recruiting the HR components breast cancer 2 , early onset ( BRCA2 ) and RAD51 to DNA damage foci , 58,59 and to the Fanconi anemia ( FA ) pathway .	For instance, CHK1 contributes to homologous recombination (HR) by recruiting the HR components breast cancer 2, early onset (BRCA2) and RAD51 to DNA damage foci, 58,59 and to the Fanconi anemia (FA) pathway.	3	41	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	RAD51	RAD51	RAD51	3	4	26	27
Also CHK1 contributes to DDR by regulating the RAD51 mediated homologous recombination repair ( HRR ) 15 .	Also CHK1 contributes to DDR by regulating the RAD51 mediated homologous recombination repair (HRR) 15.	1	9	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	RAD51	RAD51	RAD51	1	2	8	9
Rad51 is a critical component of the HRR complex and , since it is known that Chk1 activates rad51 to facilitate its function in HRR [ XREF_BIBR ] , we assessed whether MK-8776 affected the formation of rad51 foci following irradiation .	Rad51 is a critical component of the HRR complex and, since it is known that Chk1 activates rad51 to facilitate its function in HRR [XREF_BIBR], we assessed whether MK-8776 affected the formation of rad51 foci following irradiation.	16	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	rad51	rad51	rad51	16	17	18	19
ATR also phosphorylates CHK1 during meiosis 66 , and CHK1 in turn promotes RAD51 loading at DSBs 67 .	ATR also phosphorylates CHK1 during meiosis 66, and CHK1 in turn promotes RAD51 loading at DSBs 67.	9	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	RAD51	RAD51	RAD51	9	10	13	14
Phosphorylation by Chk1 activates rad51 thereby coordinating its interaction with BRCA1 and facilitating HRR .	Phosphorylation by Chk1 activates rad51 thereby coordinating its interaction with BRCA1 and facilitating HRR.	0	5	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	rad51	rad51	rad51	2	3	4	5
While it ' s possible that Chk1 inhibition following DNA damage reduces or prevents the formation of Rad51 foci ( either by destabilizing existing Rad51 foci or by preventing the reformation of foci ) , cells that have progressed into mitosis have clearly lost these foci .	While it 's possible that Chk1 inhibition following DNA damage reduces or prevents the formation of Rad51 foci (either by destabilizing existing Rad51 foci or by preventing the reformation of foci), cells that have progressed into mitosis have clearly lost these foci.	6	18	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Rad51	Rad51	Rad51	6	7	17	18
In agreement with previous reports XREF_BIBR , we observed that depletion of ATR or chemical inhibition of CHK1 almost completely prevents RAD51 from nuclear foci assembly after HU treatment .	In agreement with previous reports XREF_BIBR, we observed that depletion of ATR or chemical inhibition of CHK1 almost completely prevents RAD51 from nuclear foci assembly after HU treatment.	15	22	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK1	CHK1	CHK1	RAD51	RAD51	RAD51	17	18	21	22
It had previously been reported that Chk1 directly activates Rad51 and HRR in response to replication stress [ XREF_BIBR ] .	It had previously been reported that Chk1 directly activates Rad51 and HRR in response to replication stress [XREF_BIBR].	6	13	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Rad51	Rad51	Rad51	6	7	9	10
Gemcitabine mediated DNA damage promotes the formation of Rad51 foci ; however , while Chk1 inhibition does not disrupt Rad51 foci that are formed in response to gemcitabine , these foci are lost as cells progress into mitosis .	Gemcitabine mediated DNA damage promotes the formation of Rad51 foci; however, while Chk1 inhibition does not disrupt Rad51 foci that are formed in response to gemcitabine, these foci are lost as cells progress into mitosis.	14	20	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Rad51	Rad51	Rad51	14	15	19	20
Previous studies suggested that Gas1 , Cdo and Boc promote Shh signaling during neural patterning .	Previous studies suggested that Gas1, Cdo and Boc promote Shh signaling during neural patterning.	4	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdo	Cdo	Cdo	Shh	Shh	Shh	6	7	10	11
The multifunctional coreceptor Cdo increases the signaling activity of Shh which is crucial for development of forebrain and neural tube .	The multifunctional coreceptor Cdo increases the signaling activity of Shh which is crucial for development of forebrain and neural tube.	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdo	Cdo	Cdo	Shh	Shh	Shh	3	4	9	10
One possibility is that Gas1 , Cdo and Boc act as necessary , but partially redundant co-factors to promote Shh signaling .	One possibility is that Gas1, Cdo and Boc act as necessary, but partially redundant co-factors to promote Shh signaling.	4	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdo	Cdo	Cdo	Shh	Shh	Shh	6	7	19	20
Of these , expression of CDO , BOC , or Gas1 increases Shh pathway activity , while Hhip negatively regulates the pathway .	Of these, expression of CDO, BOC, or Gas1 increases Shh pathway activity, while Hhip negatively regulates the pathway.	3	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDO	expression of CDO	cdo	Shh	Shh	shh	5	6	12	13
Gas1 , Cdo and Boc all promote ectopic Shh signaling during neural patterning .	Gas1, Cdo and Boc all promote ectopic Shh signaling during neural patterning.	0	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdo	Cdo	Cdo	Shh	Shh	Shh	2	3	8	9
A multifunctional receptor Cdo functions as a Shh coreceptor together with Boc and Gas1 to activate Shh signaling and these coreceptors seem to play compensatory roles in early heart development .	A multifunctional receptor Cdo functions as a Shh coreceptor together with Boc and Gas1 to activate Shh signaling and these coreceptors seem to play compensatory roles in early heart development.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdo	Cdo	Cdo	Shh	Shh	Shh	3	4	16	17
It has been experimentally shown that CDO and BOC both help to activate SHH ligand , whereas GAS1 inhibits it to bind with Patched proteins ( PTCH1/2 ) in the membrane XREF_BIBR .	It has been experimentally shown that CDO and BOC both help to activate SHH ligand, whereas GAS1 inhibits it to bind with Patched proteins (PTCH1/2) in the membrane XREF_BIBR.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDO	CDO	CDO	SHH	SHH	SHH	6	7	13	14
We show that Gas1 and Cdo cooperate to promote Shh signaling during neural tube patterning , craniofacial , and vertebral development .	We show that Gas1 and Cdo cooperate to promote Shh signaling during neural tube patterning, craniofacial, and vertebral development.	3	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdo	Cdo	Cdo	Shh	Shh	Shh	5	6	9	10
The enhanced mutant bladder mesenchyme responsiveness to Shh ( with no changes in ligand levels ) appears to be secondary to increased mesenchymal expression of Boc and Cdo , Patched-1 co-receptors that augment Shh activity .	The enhanced mutant bladder mesenchyme responsiveness to Shh (with no changes in ligand levels) appears to be secondary to increased mesenchymal expression of Boc and Cdo, Patched-1 co-receptors that augment Shh activity.	23	34	augment	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Cdo	expression of Boc and Cdo	cdo	Shh	Shh	shh	27	28	33	34
Shh target gene expression is reduced in the developing forebrains of Cdo-/- mice , and Cdo positively regulates Shh signaling in vitro .	Shh target gene expression is reduced in the developing forebrains of Cdo-/- mice, and Cdo positively regulates Shh signaling in vitro.	15	19	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Cdo	Cdo	Cdo	Shh	Shh	Shh	15	16	18	19
Activated ATM organizes repair of DSBs by phosphorylating numerous downstream targets , such as Chk2 , H2AX , p53 , mediator of DNA damage checkpoint protein 1 ( MDC1 ) , BRCA1 and the endonuclease CtIP [ XREF_BIBR , XREF_BIBR ] .	Activated ATM organizes repair of DSBs by phosphorylating numerous downstream targets, such as Chk2, H2AX, p53, mediator of DNA damage checkpoint protein 1 (MDC1), BRCA1 and the endonuclease CtIP [XREF_BIBR, XREF_BIBR].	14	32	mediator	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Chk2	Chk2	Chk2	BRCA1	BRCA1	BRCA1	14	15	31	32
A deficiency of Chk2 partially rescued the defective development and growth of BRCA1 deficient T-cells but enhanced tumour development .	A deficiency of Chk2 partially rescued the defective development and growth of BRCA1 deficient T-cells but enhanced tumour development.	1	14	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	Chk2	Chk2	BRCA1	BRCA1	BRCA1	3	4	12	13
Namely , while Chk2 inactivation promotes tumorigenesis of Brca1 , Nbs1 and Mre11 mutant strains , it remarkably suppresses cancer in Mus81 Deltaex3-4 and Deltaex3-4 mutant background .	Namely, while Chk2 inactivation promotes tumorigenesis of Brca1, Nbs1 and Mre11 mutant strains, it remarkably suppresses cancer in Mus81 Deltaex3-4 and Deltaex3-4 mutant background.	3	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	Chk2	Chk2	Brca1	Brca1	Brca1	3	4	8	9
After it gets phosphorylated , Chk2 further activates p53 and BRCA1 proteins .	After it gets phosphorylated, Chk2 further activates p53 and BRCA1 proteins.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	Chk2	Chk2	BRCA1	BRCA1	BRCA1	5	6	10	11
The decreased CHK2 phosphorylation that we observe in 53BP1 depleted Brca1 null cells could therefore result from decreased ATM signaling due to increased DNA resection , or from increased DSB repair .	The decreased CHK2 phosphorylation that we observe in 53BP1 depleted Brca1 null cells could therefore result from decreased ATM signaling due to increased DNA resection, or from increased DSB repair.	2	15	depleted	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK2	CHK2 phosphorylation	chk2	Brca1	Brca1	brca1	2	3	10	11
Nonetheless , reduced activation of Chk1 and Chk2 cause BRCA1 deficient cells to display aberrant checkpoint control , resulting in failure to inhibit cdk activity and cell cycle progression after DNA damage .	Nonetheless, reduced activation of Chk1 and Chk2 cause BRCA1 deficient cells to display aberrant checkpoint control, resulting in failure to inhibit cdk activity and cell cycle progression after DNA damage.	3	11	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	Chk2	Chk2	BRCA1	BRCA1	BRCA1	7	8	9	10
More recent mechanistic studies revealed that Nek11 is activated through phosphorylation on Ser 273 by Chk1 upon exposure of cells to ionizing radiation ( IR ) [ XREF_BIBR ] .	More recent mechanistic studies revealed that Nek11 is activated through phosphorylation on Ser 273 by Chk1 upon exposure of cells to ionizing radiation (IR) [XREF_BIBR].	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Nek11	Nek11	Nek11	15	16	6	7
The activity of NEK11 is in turn controlled by CHK1 that activates NEK11 via phosphorylation on serine 273 .	The activity of NEK11 is in turn controlled by CHK1 that activates NEK11 via phosphorylation on serine 273.	7	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	NEK11	NEK11	NEK11	9	10	12	13
This was mediated via activation of the DNA damage response ( DDR ) cascade , including phosphorylation of the checkpoint kinase 2 ( CHK2 ) , CHK2 mediated M-phase inducer phosphatase 3 depletion , and p53 activation .	This was mediated via activation of the DNA damage response (DDR) cascade, including phosphorylation of the checkpoint kinase 2 (CHK2), CHK2 mediated M-phase inducer phosphatase 3 depletion, and p53 activation.	23	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	CHK2	CHK2	CHK2	M-phase inducer phosphatase 3	M-phase inducer phosphatase 3	M-phase inducer phosphatase 3	26	27	28	32
In response to CDT treatment , CHK2 activation induces the sequestration of CDC25C phosphatase in the cytoplasm , making it unable to activate the CDK1 and Cyclin B complex [ XREF_BIBR ] .	In response to CDT treatment, CHK2 activation induces the sequestration of CDC25C phosphatase in the cytoplasm, making it unable to activate the CDK1 and Cyclin B complex [XREF_BIBR].	6	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK2	CHK2	CHK2	CDC25C	CDC25C	CDC25C	6	7	12	13
CHK2 also mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes XREF_BIBR .	CHK2 also mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes XREF_BIBR.	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK2	CHK2	CHK2	FoxM1	FoxM1	FoxM1	0	1	6	7
Chk2 also mediates stabilization of the FoxM1 transcription factor thereby stimulating expression of DNA repair genes .	Chk2 also mediates stabilization of the FoxM1 transcription factor thereby stimulating expression of DNA repair genes.	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	Chk2	Chk2	FoxM1	FoxM1	FoxM1	0	1	6	7
29 CHK2 stimulates expression of DNA repair genes by stabilizing the FoxM1 transcription factor .	29 CHK2 stimulates expression of DNA repair genes by stabilizing the FoxM1 transcription factor.	0	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK2	CHK2	CHK2	FoxM1	FoxM1	FoxM1	1	2	11	12
In addition , upon treatment with genotoxic agents , the checkpoint kinases Chk1 and Chk2 also phosphorylate and activate FOXM1 .	In addition, upon treatment with genotoxic agents, the checkpoint kinases Chk1 and Chk2 also phosphorylate and activate FOXM1.	12	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	Chk2	Chk2	FOXM1	FOXM1	FOXM1	14	15	19	20
FP elicited a p53 response and cell death , which were potentiated by a Cdk7 selective drug that by itself did not activate p53 .	FP elicited a p53 response and cell death, which were potentiated by a Cdk7 selective drug that by itself did not activate p53.	14	24	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Cdk7	Cdk7	Cdk7	p53	p53	p53	14	15	23	24
Mazumdar et al [ XREF_BIBR ] studied that , MTA1 restrained CAK induced ER alpha transcription by histone deacetylase in breast cancer cells , the cells deprived reaction to estrogen and possessed malignant phenotype .	Mazumdar et al [XREF_BIBR] studied that, MTA1 restrained CAK induced ER alpha transcription by histone deacetylase in breast cancer cells, the cells deprived reaction to estrogen and possessed malignant phenotype.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	CAK	CAK	CAK	ER	ER	ER	11	12	13	14
For example , MAPK and Cdk7 activates ERalpha by directly phosphorylating Ser 118 within the AF-1 domain .	For example, MAPK and Cdk7 activates ERalpha by directly phosphorylating Ser 118 within the AF-1 domain.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk7	Cdk7	Cdk7	ERalpha	ERalpha	ERalpha	5	6	7	8
Accordingly , MTA1 inhibited CAK stimulation of ER transactivation that was partially relieved by HDAC inhibitor trichostatin A , suggesting that MTA1 might inhibit CAK induced transactivation function of ER by recruiting HDAC .	Accordingly, MTA1 inhibited CAK stimulation of ER transactivation that was partially relieved by HDAC inhibitor trichostatin A, suggesting that MTA1 might inhibit CAK induced transactivation function of ER by recruiting HDAC.	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CAK	CAK	CAK	ER	ER	ER	4	5	7	8
Together , these results suggest that there is no persistent reprogramming of TLS and Chk1 signals in FANCD2 depleted cells .	Together, these results suggest that there is no persistent reprogramming of TLS and Chk1 signals in FANCD2 depleted cells.	12	18	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	FANCD2	FANCD2	FANCD2	14	15	17	18
Our data support the existence of a circuit in which CHK1 activates checkpoints , DNA repair and proliferating cell nuclear antigen and FANCD2 monoubiquitinylation .	Our data support the existence of a circuit in which CHK1 activates checkpoints, DNA repair and proliferating cell nuclear antigen and FANCD2 monoubiquitinylation.	10	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	FANCD2	FANCD2	FANCD2	10	11	22	23
While we can not further speculate on the signals leading to impaired ATM and Chk1 activation in UV irradiated FANCD2 depleted samples , it is evident that in agreement with our PFGE results , the lack of upregulated phosphorylation of KAP1 , ATM and Chk1 argues against a role of FANCD2 in the prevention of DSB accumulation after UV irradiation .	While we can not further speculate on the signals leading to impaired ATM and Chk1 activation in UV irradiated FANCD2 depleted samples, it is evident that in agreement with our PFGE results, the lack of upregulated phosphorylation of KAP1, ATM and Chk1 argues against a role of FANCD2 in the prevention of DSB accumulation after UV irradiation.	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	FANCD2	FANCD2	FANCD2	14	15	19	20
In accordance with the fact that ATR and not ATM is required for resistance to MMC , the result showed that CHK1 phosphorylated the peptide substrate specifically compared to CHK2 , further supporting that CHK1 targets FANCD2 at serine 331 ( XREF_FIG ) .	In accordance with the fact that ATR and not ATM is required for resistance to MMC, the result showed that CHK1 phosphorylated the peptide substrate specifically compared to CHK2, further supporting that CHK1 targets FANCD2 at serine 331 (XREF_FIG).	32	37	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	FANCD2	FANCD2	FANCD2	34	35	36	37
In addition , K-cyclin-induced p53 dependent growth arrest was rescued by the dn-Cdk9- or Cdk9 specific short hairpin RNA in SaOS2 cells .	In addition, K-cyclin-induced p53 dependent growth arrest was rescued by the dn-Cdk9- or Cdk9 specific short hairpin RNA in SaOS2 cells.	3	18	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Cdk9	Cdk9	Cdk9	p53	p53	p53	14	15	4	5
The Chk1 mediated phoshorylation events on BLM may mutually regulate each other temporarily and thereby modulate BLM functions during signal transduction cascades .	The Chk1 mediated phoshorylation events on BLM may mutually regulate each other temporarily and thereby modulate BLM functions during signal transduction cascades.	0	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	BLM	BLM	BLM	1	2	16	17
In this case , rather than modulating the protein interaction of BLM with TopBP1 , the constitutive phosphorylation of BLM at Ser 502 by checkpoint kinase 1 ( Chk1 ) enables BLM to localize to chromatin bridges where it is believed that the helicase inhibits HR or operates with another helicase known as Polo like kinase 1 interacting checkpoint helicase ( PICH ) to unravel chromatin and promote resolution of incompletely segregated chromosomal DNA ( i.e ., bridges ) that can form during anaphase [ XREF_BIBR ] ( XREF_FIG ) .	In this case, rather than modulating the protein interaction of BLM with TopBP1, the constitutive phosphorylation of BLM at Ser 502 by checkpoint kinase 1 (Chk1) enables BLM to localize to chromatin bridges where it is believed that the helicase inhibits HR or operates with another helicase known as Polo like kinase 1 interacting checkpoint helicase (PICH) to unravel chromatin and promote resolution of incompletely segregated chromosomal DNA (i.e., bridges) that can form during anaphase [XREF_BIBR] (XREF_FIG).	17	33	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	phosphorylation of BLM at Ser 502 by checkpoint kinase 1 (Chk1	chk1	BLM	BLM	blm	28	29	31	32
It has been shown that in p53 deficient cells , Chk1 , Chk2 and ABL upregulates p73 which restores the transactivation of p53 target genes [ XREF_BIBR , XREF_BIBR ] .	It has been shown that in p53 deficient cells, Chk1, Chk2 and ABL upregulates p73 which restores the transactivation of p53 target genes [XREF_BIBR, XREF_BIBR].	10	18	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	p73	p73	p73	10	11	16	17
CDKN2AIP activates the important tumour suppressor p53 XREF_BIBR , consequently its down-regulation could as well be important for mesothelioma progression .	CDKN2AIP activates the important tumour suppressor p53 XREF_BIBR, consequently its down-regulation could as well be important for mesothelioma progression.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDKN2AIP	CDKN2AIP	CDKN2AIP	p53	p53	p53	0	1	6	7
CARF , collaborator of ARF ( alternative reading frame ) , activates p53 functions by direct interacting and stabilizing of ARF as well as p53 proteins [ XREF_BIBR ] .	CARF, collaborator of ARF (alternative reading frame), activates p53 functions by direct interacting and stabilizing of ARF as well as p53 proteins [XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	collaborator of ARF	collaborator of ARF	collaborator of ARF	p53	p53	p53	2	5	12	13
Another recent study suggests that the Chk1 kinase contributes to the timing of mitosis by controlling the activity of centrosomal Cdc25B in an as yet undefined manner .	Another recent study suggests that the Chk1 kinase contributes to the timing of mitosis by controlling the activity of centrosomal Cdc25B in an as yet undefined manner.	6	26	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25B	Cdc25B	Cdc25B	6	7	20	21
Thus , CHK1 and MK2 mediate inactivation of CDC25B and induce a cell cycle arrest by blocking CDC25B dependent CDK activation [ XREF_BIBR ] .	Thus, CHK1 and MK2 mediate inactivation of CDC25B and induce a cell cycle arrest by blocking CDC25B dependent CDK activation [XREF_BIBR].	2	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	CDC25B	CDC25B	CDC25B	2	3	8	9
Our studies show that the human C/EBP alpha protein stimulates USF to bind to a USF consensus element within C/EBP alpha promoter and activates it by two- to threefold .	Our studies show that the human C/EBP alpha protein stimulates USF to bind to a USF consensus element within C/EBP alpha promoter and activates it by two- to threefold.	6	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	C/EBP alpha	C/EBP alpha	C/EBP alpha	USF	USF	USF	6	8	10	11
Consistent with our observation that the predominant action of cdr2 was to promote c-myc activity , we observed an increase in the incidence of apoptotic figures ( XREF_FIG ) in the EC2-1 tumors relative to EL4 tumors .	Consistent with our observation that the predominant action of cdr2 was to promote c-myc activity, we observed an increase in the incidence of apoptotic figures (XREF_FIG) in the EC2-1 tumors relative to EL4 tumors.	7	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdr2	cdr2	cdr2	c-myc	c-myc	c-myc	9	10	13	14
Aurora kinase B activity is enhanced through its phosphorylation by Chk1 and priming of its substrates by Plk1 and Mps1 .	Aurora kinase B activity is enhanced through its phosphorylation by Chk1 and priming of its substrates by Plk1 and Mps1.	0	15	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Chk1	Chk1	Chk1	Aurora kinase B	Aurora kinase B	Aurora kinase B	10	11	0	3
Depletion of CEP290 results in a significant decrease of Rab8a at the centrosome and at the cilium , raising the possibility that CEP290 first recruits Rab8a through direct protein protein interactions to the centrosome in cycling cells and later promotes ciliogenesis by allowing the entry of Rab8a into the cilium .	Depletion of CEP290 results in a significant decrease of Rab8a at the centrosome and at the cilium, raising the possibility that CEP290 first recruits Rab8a through direct protein protein interactions to the centrosome in cycling cells and later promotes ciliogenesis by allowing the entry of Rab8a into the cilium.	22	47	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CEP290	CEP290	CEP290	Rab8a	Rab8a	Rab8a	22	23	46	47
Ursolic acid blocks C/EBP-delta mediated activation of myostatin promoter .	Ursolic acid blocks C/EBP-delta mediated activation of myostatin promoter.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	C/EBP-delta	C/EBP-delta	C/EBP-delta	myostatin	myostatin	myostatin	3	4	7	8
Plk1 was shown to inhibit localization of 53BP1 to DNA damage foci , to promote the inhibition of Chk2 as well as the degradation of the Chk1 activator Claspin .	Plk1 was shown to inhibit localization of 53BP1 to DNA damage foci, to promote the inhibition of Chk2 as well as the degradation of the Chk1 activator Claspin.	23	29	activator	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Claspin	Claspin	Claspin	26	27	28	29
IKKalpha phosphorylation induces the polyubiquitination and proteasomal degradation of the NF-kappaB2 ( p100 ) precursor to the active form p52 ( Maruyama et al ., 2010 ) .	IKKalpha phosphorylation induces the polyubiquitination and proteasomal degradation of the NF-kappaB2 (p100) precursor to the active form p52 (Maruyama et al., 2010).	0	21	induces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha phosphorylation	ikkalpha	p52	p52	p52	0	1	19	20
Initially , we used the colon carcinoma cell line HT29 to monitor TNF induced phosphorylation and degradation of IkappaBalpha , two events crucially dependent on IKK2 activity , and of TWEAK induced processing of p100 , which is mediated by IKK1 , in order to determine functionally active inhibitor concentrations .	Initially, we used the colon carcinoma cell line HT29 to monitor TNF induced phosphorylation and degradation of IkappaBalpha, two events crucially dependent on IKK2 activity, and of TWEAK induced processing of p100, which is mediated by IKK1, in order to determine functionally active inhibitor concentrations.	32	41	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKK1	IKK1	IKK1	p100	p100	p100	40	41	34	35
Once activated by NIK , IKKalpha induces the processing of NF-kappaB2 and p100 to p52 .	Once activated by NIK, IKKalpha induces the processing of NF-kappaB2 and p100 to p52.	5	15	induces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p52	p52	p52	5	6	14	15
In contrast , the alternative NF-kappaB activation pathway is induced by a subset of TNFR family members ( e.g ., LTbetaR and BAFFR ) involving NIK and IKKalpha mediated p100 processing and generation of transcriptionally active p52 and RelB heterodimers [ XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	In contrast, the alternative NF-kappaB activation pathway is induced by a subset of TNFR family members (e.g., LTbetaR and BAFFR) involving NIK and IKKalpha mediated p100 processing and generation of transcriptionally active p52 and RelB heterodimers [XREF_BIBR, XREF_BIBR] (XREF_FIG).	25	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	27	28	29	30
However , the precise mechanisms by which NIK and IKKalpha induce p100 processing remain unclear .	However, the precise mechanisms by which NIK and IKKalpha induce p100 processing remain unclear.	7	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	9	10	11	12
However , both NIK and IKK1 target p100 for phosphorylation and subsequent processing of p100 by the proteasome .	However, both NIK and IKK1 target p100 for phosphorylation and subsequent processing of p100 by the proteasome.	3	8	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IKK1	IKK1	IKK1	p100	p100	p100	5	6	7	8
IKKalpha has been found to mediate the processing of the NF-kappaB p100 subunit from its latent form into an active conformation [ XREF_BIBR , XREF_BIBR ] .	IKKalpha has been found to mediate the processing of the NF-kappaB p100 subunit from its latent form into an active conformation [XREF_BIBR, XREF_BIBR].	0	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	0	1	11	12
Given that NEMO has recently been shown to target the IKK complex to IkappaBalpha [ XREF_BIBR ] , it may be that only IKKalpha that is free of NEMO can target p100 .	Given that NEMO has recently been shown to target the IKK complex to IkappaBalpha [XREF_BIBR], it may be that only IKKalpha that is free of NEMO can target p100.	22	32	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	23	24	31	32
In the non canonical pathway , NIK-mediated-phosphorylation of IKKalpha results in its activation and subsequent phosphorylation of p100 , which recruits a K48 E3 ligase to targetp100 for partial proteasomal degradation .	In the non canonical pathway, NIK-mediated-phosphorylation of IKKalpha results in its activation and subsequent phosphorylation of p100, which recruits a K48 E3 ligase to targetp100 for partial proteasomal degradation.	6	20	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IKKalpha	NIK-mediated-phosphorylation of IKKalpha	ikkalpha	p100	p100	p100	8	9	17	18
Constitutively active IKKalpha induced p52 , RelB , and cyclin D1 in untransformed mammary epithelial cells .	Constitutively active IKKalpha induced p52, RelB, and cyclin D1 in untransformed mammary epithelial cells.	1	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p52	p52	p52	2	3	4	5
Following activation of the noncanonical pathway , NIK ( NFkappaB inducing kinase ) phosphorylates IKKalpha , which subsequently activates p100 by phosphorylating two conserved serine residues ( Ser866 , Ser870 ) that prime the full-length inhibitory protein for ubiquitination ( at Lys855 ) and proteasomal cleavage to generate the active p52 fragment .	Following activation of the noncanonical pathway, NIK (NFkappaB inducing kinase) phosphorylates IKKalpha, which subsequently activates p100 by phosphorylating two conserved serine residues (Ser866, Ser870) that prime the full-length inhibitory protein for ubiquitination (at Lys855) and proteasomal cleavage to generate the active p52 fragment.	7	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	NIK (NFkappaB inducing kinase) phosphorylates IKKalpha	ikkalpha	p100	p100	p100	14	15	19	20
In contrast , activation of the noncanonical NF-kappaB pathway requires the activation of NF-kappaB-inducing kinase ( NIK ) and IKKalpha , leading to the phosphorylation and proteolytic processing of the p100 subunit to generate p52 .	In contrast, activation of the noncanonical NF-kappaB pathway requires the activation of NF-kappaB-inducing kinase (NIK) and IKKalpha, leading to the phosphorylation and proteolytic processing of the p100 subunit to generate p52.	11	35	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p52	p52	p52	19	20	34	35
Binding of these ligands to their appropriate receptors cause NIK to phosphorylate IkappaB kinase-alpha ( IKKalpha ) , which activates and targets IKKalpha to p100 , its substrate .	Binding of these ligands to their appropriate receptors cause NIK to phosphorylate IkappaB kinase-alpha (IKKalpha), which activates and targets IKKalpha to p100, its substrate.	11	27	activates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IkappaB kinase-alpha	phosphorylate IkappaB kinase-alpha	ikappab kinase-alpha	p100	p100	p100	12	14	24	25
NIK phosphorylation of IKKalpha leads phosphorylation of p100 in p100 : RelB heterodimers , and processing to p52 [ XREF_BIBR ] .	NIK phosphorylation of IKKalpha leads phosphorylation of p100 in p100 : RelB heterodimers, and processing to p52 [XREF_BIBR].	0	9	leads	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IKKalpha	NIK phosphorylation of IKKalpha	ikkalpha	p100	phosphorylation of p100	p100	3	4	7	8
In response to several specific extracellular inducers ( including LTbeta , CD40L and BAFF ) , NIK ( NF-kappaB inducing kinase ) activates IKKalpha , which targets p100 and NFkappaB2 for site specific phosphorylation , flagging it for ubiquitination and subsequent proteosomal processing .	In response to several specific extracellular inducers (including LTbeta, CD40L and BAFF), NIK (NF-kappaB inducing kinase) activates IKKalpha, which targets p100 and NFkappaB2 for site specific phosphorylation, flagging it for ubiquitination and subsequent proteosomal processing.	22	42	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	23	24	27	28
The alternative or non canonical pathways are triggered by activation of specific members of the TNF cytokine family , such as CD40 ligand , B cell activating factor ( BAFF ) and lymphotoxin-beta following IKKalpha mediated processing of precursor protein p100 to p52 forming active p52-RelB complexes .	The alternative or non canonical pathways are triggered by activation of specific members of the TNF cytokine family, such as CD40 ligand, B cell activating factor (BAFF) and lymphotoxin-beta following IKKalpha mediated processing of precursor protein p100 to p52 forming active p52-RelB complexes.	32	41	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	34	35	40	41
The mature p52 subunit is generated from its precursor protein p100 , whose processing is mediated by NIK ( NF-kappaB inducing kinase ) and IKKalpha after stimulation of cells ; TNFalpha does not activate this pool of NF-kappaB .	The mature p52 subunit is generated from its precursor protein p100, whose processing is mediated by NIK (NF-kappaB inducing kinase) and IKKalpha after stimulation of cells; TNFalpha does not activate this pool of NF-kappaB.	5	25	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	24	25	10	11
Mechanistically , we found that NF-kB2 p52 elevation in AMPKalpha1-KO MEFs was due to the increased NIK mediated phosphorylation of IkKalpha , which led to elevated p100 phosphorylation and enhanced the proteolytic processing of p100 precursor to p52 mediated by E3 ubiquitin ligase beta-TrCP .	Mechanistically, we found that NF-kB2 p52 elevation in AMPKalpha1-KO MEFs was due to the increased NIK mediated phosphorylation of IkKalpha, which led to elevated p100 phosphorylation and enhanced the proteolytic processing of p100 precursor to p52 mediated by E3 ubiquitin ligase beta-TrCP.	16	38	enhanced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IkKalpha	NIK mediated phosphorylation of IkKalpha	ikkalpha	p52	p52	p52	20	21	37	38
In contrast , the non canonical pathway depends on p100 processing induced by IKKalpha and NF-kappaB inducing kinase activation .	In contrast, the non canonical pathway depends on p100 processing induced by IKKalpha and NF-kappaB inducing kinase activation.	9	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	13	14	9	10
NIK in turn phosphorylates IKKalpha , which activates p100 and leads to its partial proteasomal processing to p52 .	NIK in turn phosphorylates IKKalpha, which activates p100 and leads to its partial proteasomal processing to p52.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	NIK in turn phosphorylates IKKalpha	ikkalpha	p100	p100	p100	4	5	8	9
These data also provide the first evidence for explaining why overexpression of IKKalpha or its activation by many other stimuli such as tumor necrosis factor and mitogens fails to induce p100 processing .	These data also provide the first evidence for explaining why overexpression of IKKalpha or its activation by many other stimuli such as tumor necrosis factor and mitogens fails to induce p100 processing.	10	31	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	overexpression of IKKalpha	ikkalpha	p100	p100	p100	12	13	30	31
pIKKalpha is crucial for phosphorylation of p100 , leading to proteosomal processing to p52 .	pIKKalpha is crucial for phosphorylation of p100, leading to proteosomal processing to p52.	0	14	leading	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	pIKKalpha	pIKKalpha	pIKKalpha	p52	p52	p52	0	1	13	14
Subsequently , accumulated NIK phosphorylates and activates IKKalpha , which induces partial degradation of p100 to p52 .	Subsequently, accumulated NIK phosphorylates and activates IKKalpha, which induces partial degradation of p100 to p52.	3	17	induces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IKKalpha	NIK phosphorylates and activates IKKalpha	ikkalpha	p52	p52	p52	7	8	16	17
IKKalpha enables p52 mediated gene repression and activation .	IKKalpha enables p52 mediated gene repression and activation.	0	3	enables	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p52	p52	p52	0	1	2	3
Importantly , IKKalpha forms homodimers , not associated with IKKgamma , that are required for phosphorylation induced p100 processing and activation of the alternative pathway .	Importantly, IKKalpha forms homodimers, not associated with IKKgamma, that are required for phosphorylation induced p100 processing and activation of the alternative pathway.	2	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	2	3	17	18
In macrophages , higher IKKalpha expression in conjunction with stabilization of the kinase NIK induces elevated p52 .	In macrophages, higher IKKalpha expression in conjunction with stabilization of the kinase NIK induces elevated p52.	4	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha expression	ikkalpha	p52	p52	p52	4	5	16	17
NIK activates NF-kappaB non canonical signaling by directly phosphorylating IKKalpha , which , in turn , phosphorylates p100 and induces its processing to p52 , facilitating the formation and nuclear translocation of RelB and p52 complexes .	NIK activates NF-kappaB non canonical signaling by directly phosphorylating IKKalpha, which, in turn, phosphorylates p100 and induces its processing to p52, facilitating the formation and nuclear translocation of RelB and p52 complexes.	8	24	induces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IKKalpha	phosphorylating IKKalpha	ikkalpha	p52	p52	p52	9	10	23	24
The p52 and RelB proteins are activated by the noncanonical NF-kappaB activation pathway , which depends on NIK and IKKalpha induced p100 processing .	The p52 and RelB proteins are activated by the noncanonical NF-kappaB activation pathway, which depends on NIK and IKKalpha induced p100 processing.	15	22	induced	Positive_early_activation	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	19	20	21	22
We recently showed that in B cells , IKKalpha inactivation causes increased p100 , a target of IKKalpha in the noncanonical NF-kappaB pathway [ XREF_BIBR ] .	We recently showed that in B cells, IKKalpha inactivation causes increased p100, a target of IKKalpha in the noncanonical NF-kappaB pathway [XREF_BIBR].	8	24	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	8	9	12	13
Finally , the decrease of Claspin in turns terminates Claspin mediated activation of Chk1 and turns off the DNA damage checkpoint .	Finally, the decrease of Claspin in turns terminates Claspin mediated activation of Chk1 and turns off the DNA damage checkpoint.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	9	10	13	14
In addition to its role during checkpoint recovery , betaTrCP dependent degradation of Claspin helps prevent inappropriate activation of Chk1 during mitosis .	In addition to its role during checkpoint recovery, betaTrCP dependent degradation of Claspin helps prevent inappropriate activation of Chk1 during mitosis.	11	20	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	13	14	19	20
A further understanding of how NEK9 activates CHK1 will require identifying its substrate ( s ) , which could include CHK1 , claspin , which can activate CHK1 independently of ATR , and other associated proteins .	A further understanding of how NEK9 activates CHK1 will require identifying its substrate (s), which could include CHK1, claspin, which can activate CHK1 independently of ATR, and other associated proteins.	20	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	claspin	claspin	claspin	CHK1	CHK1	CHK1	22	23	27	28
Furthermore , the Mrc1 human homolog CLASPIN is targeted for degradation in response to HU treatment , thereby promoting CHK1 inactivation .	Furthermore, the Mrc1 human homolog CLASPIN is targeted for degradation in response to HU treatment, thereby promoting CHK1 inactivation.	2	20	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CLASPIN	CLASPIN	CLASPIN	CHK1	CHK1	CHK1	6	7	19	20
To test if USP20 mediated stability of CLASPIN promotes CHK1 activation upon replication stress , we expressed wild-type FLAG-CLASPIN in USP20 depleted cells .	To test if USP20 mediated stability of CLASPIN promotes CHK1 activation upon replication stress, we expressed wild-type FLAG-CLASPIN in USP20 depleted cells.	5	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CLASPIN	CLASPIN	CLASPIN	CHK1	CHK1	CHK1	7	8	9	10
Claspin can stimulate ATR dependent CHK1 activation after genotoxic stress .	Claspin can stimulate ATR dependent CHK1 activation after genotoxic stress.	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	CHK1	CHK1	CHK1	0	1	5	6
Usp28 counteracts this process by deubiquitination of Claspin allowing it to activate Chk1 in response to DNA damage .	Usp28 counteracts this process by deubiquitination of Claspin allowing it to activate Chk1 in response to DNA damage.	5	14	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	deubiquitination of Claspin	claspin	Chk1	Chk1	chk1	7	8	12	13
Importantly , degradation of Claspin also reduces Chk1 kinase signaling , thus inhibiting checkpoint signaling .	Importantly, degradation of Claspin also reduces Chk1 kinase signaling, thus inhibiting checkpoint signaling.	2	9	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	4	5	7	8
We found that overexpression of FLAG-CLASPIN corrected the delay of USP20 depletion induced CHK1 activation in response to HU treatment .	We found that overexpression of FLAG-CLASPIN corrected the delay of USP20 depletion induced CHK1 activation in response to HU treatment.	3	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLAG-CLASPIN	overexpression of FLAG-CLASPIN	flag-claspin	CHK1	CHK1	chk1	5	6	13	14
BRCA1 and Claspin then function to activate the tumor suppressor Chk1 .	BRCA1 and Claspin then function to activate the tumor suppressor Chk1.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	2	3	10	11
Of these , claspin dependent activation of CHK1 is the best characterised and involves PIKK dependent phosphorylation of claspin itself XREF_BIBR , XREF_BIBR .	Of these, claspin dependent activation of CHK1 is the best characterised and involves PIKK dependent phosphorylation of claspin itself XREF_BIBR, XREF_BIBR.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	claspin	claspin	claspin	CHK1	CHK1	CHK1	3	4	7	8
Claspin degradation blocks further CHK1 activation during recovery from DNA damage , but phosphorylated ( active ) CHK1 is inactivated by CUL1 dependent degradation [ XREF_BIBR ] .	Claspin degradation blocks further CHK1 activation during recovery from DNA damage, but phosphorylated (active) CHK1 is inactivated by CUL1 dependent degradation [XREF_BIBR].	0	5	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	CHK1	CHK1	CHK1	0	1	4	5
In metazoans , Claspin mediates the activation of Chk1 XREF_BIBR , XREF_BIBR .	In metazoans, Claspin mediates the activation of Chk1 XREF_BIBR, XREF_BIBR.	3	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	3	4	8	9
Claspin was reported to be targeted by beta-TRCP and APC and Cdh1 to terminate Chk1 signaling in mitosis and during checkpoint recovery .	Claspin was reported to be targeted by beta-TRCP and APC and Cdh1 to terminate Chk1 signaling in mitosis and during checkpoint recovery.	0	15	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	0	1	14	15
Claspin mediates the activation of checkpoint kinase 1 ( Chk1 ) by ATM- and Rad3 related kinase ( ATR ) in response to genomic stress .	Claspin mediates the activation of checkpoint kinase 1 (Chk1) by ATM- and Rad3 related kinase (ATR) in response to genomic stress.	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	checkpoint kinase 1	checkpoint kinase 1	checkpoint kinase 1	0	1	5	8
There is , however , much crosstalk in the DNA damage response network , and CHK1 also is activated by Claspin following replication stress , independently of ATR .	There is, however, much crosstalk in the DNA damage response network, and CHK1 also is activated by Claspin following replication stress, independently of ATR.	15	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	CHK1	CHK1	CHK1	20	21	15	16
It has been established that ubiquitin hydrolase USP28 permits Claspin mediated activation of Chk1 in response to DNA damage in mammalian cells [ XREF_BIBR ] .	It has been established that ubiquitin hydrolase USP28 permits Claspin mediated activation of Chk1 in response to DNA damage in mammalian cells [XREF_BIBR].	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	9	10	13	14
In mammalian cells the orthologous protein , CLSPN , also mediates the activation of CHK1 following replicative stress or DNA damage .	In mammalian cells the orthologous protein, CLSPN, also mediates the activation of CHK1 following replicative stress or DNA damage.	5	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CLSPN	CLSPN	CLSPN	CHK1	CHK1	CHK1	7	8	14	15
However , this process is counteracted by the deubiquitylating enzyme Usp28 to permit Claspin mediated activation of Chk1 in response to DNA damage .	However, this process is counteracted by the deubiquitylating enzyme Usp28 to permit Claspin mediated activation of Chk1 in response to DNA damage.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	13	14	17	18
CHK1 is inhibited at the normal G2/M transition by Polo like kinase ( PLK ) 1 mediated phosphorylation and degradation of claspin XREF_BIBR , XREF_BIBR , a key regulator of CHK1 activity , as well as by CDK1 and CyclinB dependent inhibitory phosphorylation events in late G2 , triggering nuclear export of CHK1 and therefore limiting substrate accessibility 18 .	CHK1 is inhibited at the normal G2/M transition by Polo like kinase (PLK) 1 mediated phosphorylation and degradation of claspin XREF_BIBR, XREF_BIBR, a key regulator of CHK1 activity, as well as by CDK1 and CyclinB dependent inhibitory phosphorylation events in late G2, triggering nuclear export of CHK1 and therefore limiting substrate accessibility 18.	0	22	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	claspin	Polo like kinase (PLK) 1 mediated phosphorylation and degradation of claspin	claspin	CHK1	CHK1	chk1	21	22	0	1
This conclusion is supported by prior data in HeLa cells identifying that claspin dependent activation of CHEK1 is independent of RAD17 [ XREF_BIBR ] .	This conclusion is supported by prior data in HeLa cells identifying that claspin dependent activation of CHEK1 is independent of RAD17 [XREF_BIBR].	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	claspin	claspin	claspin	CHEK1	CHEK1	CHEK1	12	13	16	17
In particular , phosphorylation of Claspin on multiple residues in its CKAD mediates the binding of Chk1 .	In particular, phosphorylation of Claspin on multiple residues in its CKAD mediates the binding of Chk1.	3	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	phosphorylation of Claspin	claspin	Chk1	Chk1	chk1	5	6	16	17
When expressed in cells depleted of endogenous Claspin , both Claspin ( 1339 ) and Claspin ( 1332 ) are able to mediate Chk1 activation .	When expressed in cells depleted of endogenous Claspin, both Claspin (1339) and Claspin (1332) are able to mediate Chk1 activation.	9	24	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	10	11	23	24
Most of the intracellular proteins are degraded by the ubiquitin proteasome pathway ( UPP ) [ XREF_BIBR ] and proteins involved in Chk1 activation like Brca1 and Claspin are degraded by the UPP [ XREF_BIBR , XREF_BIBR ] .	Most of the intracellular proteins are degraded by the ubiquitin proteasome pathway (UPP) [XREF_BIBR] and proteins involved in Chk1 activation like Brca1 and Claspin are degraded by the UPP [XREF_BIBR, XREF_BIBR].	22	28	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	27	28	22	23
We found that mutant forms of Claspin incapable of interacting with DDK are still able to associate with and activate Chk1 in response to DNA replication blockages .	We found that mutant forms of Claspin incapable of interacting with DDK are still able to associate with and activate Chk1 in response to DNA replication blockages.	4	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	6	7	20	21
Conversely , neither phosphorylation of Claspin on these sites nor the presence of BRCA1 is necessary for activation of Chk1 in response to stalled replication forks .	Conversely, neither phosphorylation of Claspin on these sites nor the presence of BRCA1 is necessary for activation of Chk1 in response to stalled replication forks.	3	21	is necessary for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	Claspin	phosphorylation of Claspin	claspin	Chk1	Chk1	chk1	5	6	19	20
Among human mediators , Claspin dependent activation of CHK1 is best characterized , although BRCA1 and MDC1 also play undefined roles in this activation .	Among human mediators, Claspin dependent activation of CHK1 is best characterized, although BRCA1 and MDC1 also play undefined roles in this activation.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	CHK1	CHK1	CHK1	4	5	8	9
Claspin mediates CHK1 activation by ATR in response to genotoxic stress , and PLK1 dependent phosphorylation of Claspin leads to beta-TRCP-mediated degradation and termination of the DNA replication checkpoint , enabling checkpoint recovery [ XREF_BIBR - XREF_BIBR ] .	Claspin mediates CHK1 activation by ATR in response to genotoxic stress, and PLK1 dependent phosphorylation of Claspin leads to beta-TRCP-mediated degradation and termination of the DNA replication checkpoint, enabling checkpoint recovery [XREF_BIBR - XREF_BIBR].	0	3	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	CHK1	CHK1	CHK1	0	1	2	3
Since disruption of both Rad9A and Claspin has been shown to abolish Chk1 activation , we postulate that Rad9A mediated Claspin localization is a vital step during checkpoint activation .	Since disruption of both Rad9A and Claspin has been shown to abolish Chk1 activation, we postulate that Rad9A mediated Claspin localization is a vital step during checkpoint activation.	1	13	abolish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	6	7	12	13
Another prominent example is that SHP-2 negatively regulates gp130 signaling triggered by leukemia inhibitory factor , ciliary neurotrophic factor , and interleukin-6 ( IL-6 ) [ XREF_BIBR , XREF_BIBR ] .	Another prominent example is that SHP-2 negatively regulates gp130 signaling triggered by leukemia inhibitory factor, ciliary neurotrophic factor, and interleukin-6 (IL-6) [XREF_BIBR, XREF_BIBR].	8	19	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ciliary neurotrophic factor	ciliary neurotrophic factor	ciliary neurotrophic factor	gp130	gp130	gp130	16	19	8	9
Consistently , previous studies have demonstrated that administration of exogenous CNTF stimulates the two signal transducing subunits of the CNTFRalpha-leukemia inhibitory factor receptor beta ( LIFRbeta ) and gp130 and induces the differentiation of progenitor cells into astrocytes XREF_BIBR , XREF_BIBR , and that there was a significant reduction in the numbers of neurons and astrocytes within the central nervous system of CNTFRalpha XREF_BIBR , LIFRbeta XREF_BIBR or gp130 XREF_BIBR knockout mice .	Consistently, previous studies have demonstrated that administration of exogenous CNTF stimulates the two signal transducing subunits of the CNTFRalpha-leukemia inhibitory factor receptor beta (LIFRbeta) and gp130 and induces the differentiation of progenitor cells into astrocytes XREF_BIBR, XREF_BIBR, and that there was a significant reduction in the numbers of neurons and astrocytes within the central nervous system of CNTFRalpha XREF_BIBR, LIFRbeta XREF_BIBR or gp130 XREF_BIBR knockout mice.	7	29	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	gp130	gp130	gp130	10	11	28	29
In the late embryonic period and in the postnatal stage , STAT3 is activated through CNTF mediated gp130 receptor and entirely inhibits differentiation of rod photoreceptors .	In the late embryonic period and in the postnatal stage, STAT3 is activated through CNTF mediated gp130 receptor and entirely inhibits differentiation of rod photoreceptors.	13	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	gp130	gp130	gp130	15	16	17	18
Importantly , when mice that harbor a truncation of the COOH-terminal domain that eliminates these tyrosine residues on the gp130 receptor ( gp130 incrementSTAT mice ) are treated with CNTF , the phosphorylation of STAT3 is abolished , as is the activation of AMPK .	Importantly, when mice that harbor a truncation of the COOH-terminal domain that eliminates these tyrosine residues on the gp130 receptor (gp130 incrementSTAT mice) are treated with CNTF, the phosphorylation of STAT3 is abolished, as is the activation of AMPK.	19	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	gp130	gp130	gp130	29	30	19	20
Rat and human CNTF differ in their fine specificities : in addition to CNTFR , rat CNTF has been shown to activate the LIFR ( a heterodimer of LIFRbeta and gp130 ) , whereas human CNTF can bind and activate a tripartite receptor comprising the IL-6 receptor alpha chain ( IL-6Ralpha ) and LIFR .	Rat and human CNTF differ in their fine specificities : in addition to CNTFR, rat CNTF has been shown to activate the LIFR (a heterodimer of LIFRbeta and gp130), whereas human CNTF can bind and activate a tripartite receptor comprising the IL-6 receptor alpha chain (IL-6Ralpha) and LIFR.	15	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	gp130	gp130	gp130	16	17	30	31
LIF and CNTF stimulate the differentiation of neural stem and progenitor cells into astroglia by activating the gp130 , JAK , signal transducers and STAT pathway .	LIF and CNTF stimulate the differentiation of neural stem and progenitor cells into astroglia by activating the gp130, JAK, signal transducers and STAT pathway.	0	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	gp130	gp130	gp130	2	3	17	18
Cultures of neurons from wild type mice and from mice whose sympathetic neurons lack gp130 were treated with CNTF for 4 days , and TH activity was assayed .	Cultures of neurons from wild type mice and from mice whose sympathetic neurons lack gp130 were treated with CNTF for 4 days, and TH activity was assayed.	13	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	gp130	gp130	gp130	18	19	14	15
In the absence of CNTF receptor , CNTF can activate gp130 through a homodimer of IL6 receptor and leukaemia inhibitory factor receptor ( LIFR ) [ XREF_BIBR ] .	In the absence of CNTF receptor, CNTF can activate gp130 through a homodimer of IL6 receptor and leukaemia inhibitory factor receptor (LIFR) [XREF_BIBR].	7	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	gp130	gp130	gp130	7	8	10	11
Another transcription factor thought to be involved in the retrograde signal following a conditioning lesion is signal transducer and activator of transcription 3 ( STAT3 ) , which is activated via phosphorylation by tyrosine kinase Janus kinase ( JAKs ) associated with the receptor subunit glycoprotein 130 ( gp130 ) initiated by the growth factor ciliary neurotrophic factor ( CNTF ) .	Another transcription factor thought to be involved in the retrograde signal following a conditioning lesion is signal transducer and activator of transcription 3 (STAT3), which is activated via phosphorylation by tyrosine kinase Janus kinase (JAKs) associated with the receptor subunit glycoprotein 130 (gp130) initiated by the growth factor ciliary neurotrophic factor (CNTF).	40	58	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ciliary neurotrophic factor	ciliary neurotrophic factor	ciliary neurotrophic factor	gp130	gp130	gp130	55	58	48	49
CNTF in combination with sCNTFRalpha induces cyclooxygenase-2 ( Cox-2 ) and prostaglandin E2 ( PGE 2 ) in microglia that is gp130 independent .	CNTF in combination with sCNTFRalpha induces cyclooxygenase-2 (Cox-2) and prostaglandin E2 (PGE 2) in microglia that is gp130 independent.	0	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	gp130	gp130	gp130	0	1	21	22
However , IL6R can be activated by ciliary neurotrophic factor ( CNTF ) , and levels of CNTF are increased in NMDA damaged retinas .	However, IL6R can be activated by ciliary neurotrophic factor (CNTF), and levels of CNTF are increased in NMDA damaged retinas.	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ciliary neurotrophic factor	ciliary neurotrophic factor	ciliary neurotrophic factor	IL6R	IL6R	IL6R	7	10	2	3
Several studies have suggested that interleukin 6 ( IL-6 ) XREF_BIBR - XREF_BIBR and CC-chemokine ligand 2 ( CCL2 ) produced by macrophages 72 are responsible for gp130 activation in DRG neurons , whereas astrocytic expression of ciliary neurotrophic factor ( CNTF ) 73 and leukaemia inhibitory factor ( LIF ) 74 activate gp130 in RGCs .	Several studies have suggested that interleukin 6 (IL-6) XREF_BIBR - XREF_BIBR and CC-chemokine ligand 2 (CCL2) produced by macrophages 72 are responsible for gp130 activation in DRG neurons, whereas astrocytic expression of ciliary neurotrophic factor (CNTF) 73 and leukaemia inhibitory factor (LIF) 74 activate gp130 in RGCs.	35	55	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ciliary neurotrophic factor	expression of ciliary neurotrophic factor	ciliary neurotrophic factor	gp130	gp130	gp130	37	40	53	54
Here , we demonstrate that human CNTF can not directly induce a heterodimer of human gp130 and LIFR .	Here, we demonstrate that human CNTF can not directly induce a heterodimer of human gp130 and LIFR.	5	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	gp130	gp130	gp130	6	7	15	16
To investigate whether the enhanced tube formation was dependent on canonical or non canonical NF-kappaB signalling , we used siRNAs specifically targeting IKKbeta , the essential kinase in canonical NF-kappaB signalling , or NIK or IKKalpha , the main kinases of the non canonical NF-kappaB pathway ( siIKKbeta , siNIK or siIKKalpha ) .	To investigate whether the enhanced tube formation was dependent on canonical or non canonical NF-kappaB signalling, we used siRNAs specifically targeting IKKbeta, the essential kinase in canonical NF-kappaB signalling, or NIK or IKKalpha, the main kinases of the non canonical NF-kappaB pathway (siIKKbeta, siNIK or siIKKalpha).	19	36	targeting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	35	36	22	23
We now demonstrate that IKKbeta , the direct kinase of NF-kappaB , is activated not only by Akt and mTORC1 , but also by IKKalpha .	We now demonstrate that IKKbeta, the direct kinase of NF-kappaB, is activated not only by Akt and mTORC1, but also by IKKalpha.	4	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	24	25	4	5
Lastly , IKK1 can contribute to the canonical IKK2 and Nemo pathway , imparting important survival signals .	Lastly, IKK1 can contribute to the canonical IKK2 and Nemo pathway, imparting important survival signals.	2	16	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IKK1	IKK1	IKK1	IKK2	IKK2	IKK2	2	3	8	9
We found that 17-AAG preferentially inhibited IKKalpha expression in UM-SCC1 , and reduced a slower migrating IKKbeta band in both cell lines ( XREF_FIG ) .	We found that 17-AAG preferentially inhibited IKKalpha expression in UM-SCC1, and reduced a slower migrating IKKbeta band in both cell lines (XREF_FIG).	3	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	17-AAG preferentially inhibited IKKalpha expression	ikkalpha	IKKbeta	IKKbeta	ikkbeta	6	7	16	17
More importantly , constitutively active IKK2 induced robust osteoclastogenesis by IKK1 and RANK-null progenitors .	More importantly, constitutively active IKK2 induced robust osteoclastogenesis by IKK1 and RANK-null progenitors.	4	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKK1	IKK1	IKK1	IKK2	IKK2	IKK2	10	11	5	6
These results are consistent with previous reports that IKKalpha can enhance IKKbeta activity , though IKKbeta is the stronger , direct kinase for downstream canonical NF-kappaB activation .	These results are consistent with previous reports that IKKalpha can enhance IKKbeta activity, though IKKbeta is the stronger, direct kinase for downstream canonical NF-kappaB activation.	8	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	8	9	11	12
To determine whether defective IKKalpha activation or complete loss of IKKbeta affect osteoclastogenesis , we first used an in vitro differentiation system .	To determine whether defective IKKalpha activation or complete loss of IKKbeta affect osteoclastogenesis, we first used an in vitro differentiation system.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	4	5	10	11
These results indicate that IKKalpha , in addition to its previously described ability to phosphorylate IkappaBalpha , can increase the ability of IKKbeta to phosphorylate IkappaBalpha .	These results indicate that IKKalpha, in addition to its previously described ability to phosphorylate IkappaBalpha, can increase the ability of IKKbeta to phosphorylate IkappaBalpha.	4	23	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	4	5	22	23
Since phospho-IKKalpha and beta activates p65 through phosphorylation of residue 536 S in p65 , the level of phospho-p65 was analyzed using phospho- 536 S antibody .	Since phospho-IKKalpha and beta activates p65 through phosphorylation of residue 536 S in p65, the level of phospho-p65 was analyzed using phospho- 536 S antibody.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	phospho-IKKalpha	phospho-IKKalpha	phospho-IKKalpha	p65	p65	p65	1	2	5	6
In this regard , Lawrence and colleagues have demonstrated that IKK1 accelerates the turnover of RelA and cRel subunits and their removal from pro inflammatory gene promoters , resulting with suppression of NF-kappaB activity .	In this regard, Lawrence and colleagues have demonstrated that IKK1 accelerates the turnover of RelA and cRel subunits and their removal from pro inflammatory gene promoters, resulting with suppression of NF-kappaB activity.	10	18	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKK1	IKK1	IKK1	RelA	RelA	RelA	10	11	15	16
LTbetaR induced binding of RelB and p50 requires processing of p100 that is mediated by IKKalpha but is independent of IKKbeta , NEMO and IKKgamma , and RelA .	LTbetaR induced binding of RelB and p50 requires processing of p100 that is mediated by IKKalpha but is independent of IKKbeta, NEMO and IKKgamma, and RelA.	7	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	RelA	RelA	RelA	15	16	27	28
Nonetheless , IKKalpha also contributes to canonical NF-kappaB-dependent transcriptional responses by modulating the nuclear activities of RelA , histones and various transcriptional co-activators and co-repressors [ XREF_BIBR , XREF_BIBR ] .	Nonetheless, IKKalpha also contributes to canonical NF-kappaB-dependent transcriptional responses by modulating the nuclear activities of RelA, histones and various transcriptional co-activators and co-repressors [XREF_BIBR, XREF_BIBR].	2	24	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	RelA	RelA	RelA	2	3	16	17
In macrophages , the phosphorylation of p65 at S536 by IKKalpha increases p65 turnover , thereby reducing NF-kappaB activity and supporting the resolution of inflammation [ XREF_BIBR ] .	In macrophages, the phosphorylation of p65 at S536 by IKKalpha increases p65 turnover, thereby reducing NF-kappaB activity and supporting the resolution of inflammation [XREF_BIBR].	8	13	increases	Positive_activation_token_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	p65	p65	p65	10	11	12	13
IKKalpha contributes to suppression of NF-kappaB activity by accelerating both the turnover of the NF-kappaB subunits RelA and c-Rel , and their removal from pro inflammatory gene promoters .	IKKalpha contributes to suppression of NF-kappaB activity by accelerating both the turnover of the NF-kappaB subunits RelA and c-Rel, and their removal from pro inflammatory gene promoters.	0	18	contributes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	RelA	RelA	RelA	0	1	16	17
In this regard , XREF_BIBR have demonstrated that IKKalpha accelerates the turnover of RelA and c-Rel subunits and their removal from pro inflammatory gene promoters , resulting with suppression of NF-kappaB activity .	In this regard, XREF_BIBR have demonstrated that IKKalpha accelerates the turnover of RelA and c-Rel subunits and their removal from pro inflammatory gene promoters, resulting with suppression of NF-kappaB activity.	8	16	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	RelA	RelA	RelA	8	9	13	14
XREF_FIG , IKKalpha , IKKbeta and IkappaBalpha were detected out in the immunoprecipitates , but not activated NF-kappaB p65 .	XREF_FIG, IKKalpha, IKKbeta and IkappaBalpha were detected out in the immunoprecipitates, but not activated NF-kappaB p65.	0	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	2	3	17	19
Nuclear IKKalpha induces the post-translational modification of the p65 subunit of NF-kappaB at Ser536 , enhancing NF-kappaB activity through increasing its DNA binding activity [ XREF_BIBR ] .	Nuclear IKKalpha induces the post-translational modification of the p65 subunit of NF-kappaB at Ser536, enhancing NF-kappaB activity through increasing its DNA binding activity [XREF_BIBR].	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p65	p65	p65	1	2	8	9
IKK1 accelerates the removal of RelA and p50 subunits from proinflammatory gene promoters to limit NF-kB activation [ XREF_BIBR ] .	IKK1 accelerates the removal of RelA and p50 subunits from proinflammatory gene promoters to limit NF-kB activation [XREF_BIBR].	0	8	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKK1	IKK1	IKK1	RelA	RelA	RelA	0	1	5	6
Moreover , in the setting of LPS stimulation , EP4 activation decreased phosphorylation of IKKalpha and beta subunits and decreased nuclear translocation of the NF-kappaB subunits p65 and p50 , suggesting a possible mechanism for the reduced transcription of LPS induced pro inflammatory genes .	Moreover, in the setting of LPS stimulation, EP4 activation decreased phosphorylation of IKKalpha and beta subunits and decreased nuclear translocation of the NF-kappaB subunits p65 and p50, suggesting a possible mechanism for the reduced transcription of LPS induced pro inflammatory genes.	9	28	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	EP4 activation decreased phosphorylation of IKKalpha	ikkalpha	p65	p65	p65	14	15	26	27
Treatment of MEF wild type ( WT ) and IKKalpha -/- cells with LPS increased the nuclear content of RelA , to 4.0 and 3.2 times the baseline values , respectively ( p < 0.001 ) ( XREF_FIG ) .	Treatment of MEF wild type (WT) and IKKalpha -/- cells with LPS increased the nuclear content of RelA, to 4.0 and 3.2 times the baseline values, respectively (p < 0.001) (XREF_FIG).	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	RelA	RelA	RelA	9	10	19	20
Moreover , Lam et al have recently shown that IKKalpha can be recruited to activate p65 as a compensatory response in the absence of IKKbeta XREF_BIBR .	Moreover, Lam et al have recently shown that IKKalpha can be recruited to activate p65 as a compensatory response in the absence of IKKbeta XREF_BIBR.	9	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p65	p65	p65	9	10	15	16
In the absence of TCR stimulation , CD28 stimulation is able to drive IKKalpha and a non canonical NF-kB pathway leading to the activation of RelA and p52 80 .	In the absence of TCR stimulation, CD28 stimulation is able to drive IKKalpha and a non canonical NF-kB pathway leading to the activation of RelA and p52 80.	13	27	leading to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	RelA	RelA	RelA	13	14	25	26
IKKalpha accelerates turnover of the classical NF-kappaB subunits RelA and c-Rel in macrophages , and their removal from pro inflammatory gene promotors , thereby negatively regulating its own activation .	IKKalpha accelerates turnover of the classical NF-kappaB subunits RelA and c-Rel in macrophages, and their removal from pro inflammatory gene promotors, thereby negatively regulating its own activation.	0	9	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	RelA	RelA	RelA	0	1	8	9
IKK1 directly phosphorylates and stimulates CBP acetyl transferase activity after TNF stimulation [ XREF_BIBR ] .	IKK1 directly phosphorylates and stimulates CBP acetyl transferase activity after TNF stimulation [XREF_BIBR].	0	8	directly	Positive_regulation_token_1_verb	Positive_activation	Positive_regulation	IKK1	IKK1	ikk1	CBP	phosphorylates and stimulates CBP	cbp	0	1	5	6
For example , IKKalpha activates CREB binding protein ( CBP ) , a transcriptional co-activator of many neuronal signaling pathways including BDNF expression XREF_BIBR , XREF_BIBR .	For example, IKKalpha activates CREB binding protein (CBP), a transcriptional co-activator of many neuronal signaling pathways including BDNF expression XREF_BIBR, XREF_BIBR.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	CREB binding protein	CREB binding protein	CREB binding protein	3	4	5	8
Earlier work had shown that CNTF activates the LIF receptor to promote neuronal survival , and that Stat-3 is an important downstream effector of the LIF receptor .	Earlier work had shown that CNTF activates the LIF receptor to promote neuronal survival, and that Stat-3 is an important downstream effector of the LIF receptor.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	LIF receptor	LIF receptor	LIF receptor	5	6	8	10
At high concentrations , CNTF can also activate the LIFR and possibly other cross-reactive cytokine receptors in the absence of CNTFR alpha .	At high concentrations, CNTF can also activate the LIFR and possibly other cross-reactive cytokine receptors in the absence of CNTFR alpha.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	LIFR	LIFR	LIFR	4	5	9	10
However , phosphorylation of IKKalpha is normal in the absence of Viperin , suggesting that IKKalpha phosphorylation is insufficient to activate IRF7 .	However, phosphorylation of IKKalpha is normal in the absence of Viperin, suggesting that IKKalpha phosphorylation is insufficient to activate IRF7.	15	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha phosphorylation	ikkalpha	IRF7	IRF7	irf7	15	16	21	22
In the case of endosomal TLRs , IKKalpha can also promote IRF7 activation .	In the case of endosomal TLRs, IKKalpha can also promote IRF7 activation.	7	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	IRF7	IRF7	IRF7	7	8	11	12
Clk1 and Clk2 phosphorylate and activate the tyrosine phosphatase PTP-1B , suggesting that they are involved in signaling .	Clk1 and Clk2 phosphorylate and activate the tyrosine phosphatase PTP-1B, suggesting that they are involved in signaling.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Clk2	Clk2	Clk2	PTP-1B	PTP-1B	PTP-1B	2	3	9	10
We propose that hypothalamic CNTFR activation by CNTF regulates feeding related neurons , and modulates neuropeptide expression via JAK and STAT activation .	We propose that hypothalamic CNTFR activation by CNTF regulates feeding related neurons, and modulates neuropeptide expression via JAK and STAT activation.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CNTF	CNTF	CNTF	CNTFR	CNTFR	CNTFR	7	8	4	5
Since IKKalpha activated SRC3 is also required for transcriptional activity of NF-kappaB [ XREF_BIBR ] , SRC-3 coactivator , in addition to histone H3 and SMRT , may also be another target of nuclear IKKalpha to increase general gene transcriptions .	Since IKKalpha activated SRC3 is also required for transcriptional activity of NF-kappaB [XREF_BIBR], SRC-3 coactivator, in addition to histone H3 and SMRT, may also be another target of nuclear IKKalpha to increase general gene transcriptions.	1	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	SRC3	SRC3	SRC3	1	2	3	4
Since CLIP-170 tail also blocks the MT targeting of CAP-Gly domains of p150 Glued , dynactin is also removed from the MT plus ends in the CLIP-170 tail overexpressing cells , while the levels of plus-end bound EB1 are expected to remain unaffected .	Since CLIP-170 tail also blocks the MT targeting of CAP-Gly domains of p150 Glued, dynactin is also removed from the MT plus ends in the CLIP-170 tail overexpressing cells, while the levels of plus-end bound EB1 are expected to remain unaffected.	1	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CLIP-170	CLIP-170	CLIP-170	p150 Glued	p150 Glued	p150 Glued	1	2	12	14
Down-regulation of CLIP-170 did not cause any change in the expression level of p150 Glued ( XREF_FIG A ) .	Down-regulation of CLIP-170 did not cause any change in the expression level of p150 Glued (XREF_FIG A).	0	15	cause	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	CLIP-170	CLIP-170	clip-170	p150 Glued	level of p150 Glued	p150 glued	2	3	13	15
Data obtained regarding STAT3 phosphorylation , a key CNTFR signalling molecule activated by CLCF1 XREF_BIBR , XREF_BIBR indicate a significant modulation of the biological activity of CLCF1 by lipoproteins .	Data obtained regarding STAT3 phosphorylation, a key CNTFR signalling molecule activated by CLCF1 XREF_BIBR, XREF_BIBR indicate a significant modulation of the biological activity of CLCF1 by lipoproteins.	8	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CLCF1	CLCF1	CLCF1	CNTFR	CNTFR	CNTFR	13	14	8	9
Moreover , knockdown of CNK1 in Sbcl-2 cells abolished membrane localized CRAF in favor of cytoplasmic CRAF ( XREF_FIG , compare siControl and siCNK1-a ) .	Moreover, knockdown of CNK1 in Sbcl-2 cells abolished membrane localized CRAF in favor of cytoplasmic CRAF (XREF_FIG, compare siControl and siCNK1-a).	2	12	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CNK1	CNK1	CNK1	CRAF	CRAF	CRAF	4	5	11	12
Knockdown of endogenous CNK1 in MCF10A parental cells and in HeLa cells consistently demonstrated that the depletion of CNK1 is sufficient to prevent AKT mediated inhibition of CRAF and accompanied ERK inhibition ( XREF_SUPPLEMENTARY ) .	Knockdown of endogenous CNK1 in MCF10A parental cells and in HeLa cells consistently demonstrated that the depletion of CNK1 is sufficient to prevent AKT mediated inhibition of CRAF and accompanied ERK inhibition (XREF_SUPPLEMENTARY).	16	28	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CNK1	CNK1	CNK1	CRAF	CRAF	CRAF	18	19	27	28
Stimulation of cells bearing CNTF receptor alpha ( CNTFRalpha ) induces specific activation of the signal transducer and activator of transcription 3 ( STAT3 ) signalling system .	Stimulation of cells bearing CNTF receptor alpha (CNTFRalpha) induces specific activation of the signal transducer and activator of transcription 3 (STAT3) signalling system.	0	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CNTFRalpha	CNTFRalpha	CNTFRalpha	STAT3	STAT3	STAT3	8	9	23	24
Hypothalamic CLK2 Thr343 phosphorylation , which induces CLK2 activity , is regulated in vivo by refeeding , insulin and leptin , in a PI3K ( phosphoinositide 3-kinase )-dependent manner .	Hypothalamic CLK2 Thr343 phosphorylation, which induces CLK2 activity, is regulated in vivo by refeeding, insulin and leptin, in a PI3K (phosphoinositide 3-kinase)-dependent manner.	1	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CLK2	CLK2 Thr343 phosphorylation	clk2	CLK2	CLK2	clk2	1	2	7	8
We investigated the overall relationship with components of the canonical CIITA enhanceosome RFX5 , CREB1 , ATF1 , NFYA and -YB for CIITA BIs .	We investigated the overall relationship with components of the canonical CIITA enhanceosome RFX5, CREB1, ATF1, NFYA and -YB for CIITA BIs.	6	20	enhanceosome	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CIITA	CIITA	CIITA	RFX5	RFX5	RFX5	10	11	12	13
In melanocytes and fibroblasts CRH induced CRH-R1 stimulation upregulates POMC expression and production of ACTH through activation of cAMP dependent pathway ( s ) .	In melanocytes and fibroblasts CRH induced CRH-R1 stimulation upregulates POMC expression and production of ACTH through activation of cAMP dependent pathway (s).	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	CRH	CRH	CRH	CRH-R1	CRH-R1	CRH-R1	4	5	6	7
We have previously determined that CRH stimulation of CRHR1 leads to a rapid and sustained increase of intracellular cAMP levels using the HT22-CRHR1 cell line as a neuronal hippocampal model 9 .	We have previously determined that CRH stimulation of CRHR1 leads to a rapid and sustained increase of intracellular cAMP levels using the HT22-CRHR1 cell line as a neuronal hippocampal model 9.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	5	6	8	9
As indicated above , in addition to stimulating the HPA axis , activation of CRHR1 by CRH plays a major role coordinating stress responses , including sympathetic systems , central suppression of the immune system , arousal and other stress related behaviors .	As indicated above, in addition to stimulating the HPA axis, activation of CRHR1 by CRH plays a major role coordinating stress responses, including sympathetic systems, central suppression of the immune system, arousal and other stress related behaviors.	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	16	17	14	15
In this study , we demonstrate that sAC is a second source of cAMP in CRHR1 signaling mechanisms elicited by CRH in two physiologically relevant contexts of CRH action .	In this study, we demonstrate that sAC is a second source of cAMP in CRHR1 signaling mechanisms elicited by CRH in two physiologically relevant contexts of CRH action.	15	21	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	20	21	15	16
However , no differences were found between control and treated cells in the CRH mediated cAMP response , indicating that cAMP generated by CRH activated CRHR1 does not depend on ERK1/2 activation .	However, no differences were found between control and treated cells in the CRH mediated cAMP response, indicating that cAMP generated by CRH activated CRHR1 does not depend on ERK1/2 activation.	21	28	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	23	24	25	26
In HT22-CRHR1 cells , a significant fraction of CRH activated CRHR1 was internalized after 5min of stimulation and remained constant for at least 30min .	In HT22-CRHR1 cells, a significant fraction of CRH activated CRHR1 was internalized after 5min of stimulation and remained constant for at least 30min.	6	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	8	9	10	11
Our work in the hippocampal neuronal context , HT22 cells , also indicates that CRH activated CRHR1 continues to generate cAMP from endocytic compartments , as recently demonstrated for several GPCRs .	Our work in the hippocampal neuronal context, HT22 cells, also indicates that CRH activated CRHR1 continues to generate cAMP from endocytic compartments, as recently demonstrated for several GPCRs.	14	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	14	15	16	17
These results indicate that the cAMP response triggered by CRH activated CRHR1 in neurons and in HT22-CRHR1 cells follow a similar profile , validating the use of HT22-CRHR1 cells XREF_BIBR , XREF_BIBR as a reliable cellular model to study CRHR1 signalling .	These results indicate that the cAMP response triggered by CRH activated CRHR1 in neurons and in HT22-CRHR1 cells follow a similar profile, validating the use of HT22-CRHR1 cells XREF_BIBR, XREF_BIBR as a reliable cellular model to study CRHR1 signalling.	7	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	9	10	11	12
Together , it may be hypothesized that during the acute phase of the stress response , the increase in emotionality is evoked by CRH mediated CRHR1 activation and lienor Ucn IIl mediated CRHR2 activation , presumably in the amygdala , BNST , and/or iLS .	Together, it may be hypothesized that during the acute phase of the stress response, the increase in emotionality is evoked by CRH mediated CRHR1 activation and lienor Ucn IIl mediated CRHR2 activation, presumably in the amygdala, BNST, and/or iLS.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	23	24	25	26
CRH activates the surface receptors CRHR1 and CRHR2 which , along with AVP , is essential for the secretion of adrenocorticotropic hormone ( ACTH ) by the anterior pituitary ( Tsigos & Chrousos , 2002 ) .	CRH activates the surface receptors CRHR1 and CRHR2 which, along with AVP, is essential for the secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary (Tsigos & Chrousos, 2002).	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	0	1	5	6
Local Corticotropin releasing hormone ( CRH ) signals to its receptor CRHR1 during postnatal development of the mouse olfactory bulb .	Local Corticotropin releasing hormone (CRH) signals to its receptor CRHR1 during postnatal development of the mouse olfactory bulb.	3	12	signals	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	5	6	11	12
CRH , Unc , and ACTH stimulate all elements of the DHEAS synthetic pathway and activate CRH-R1 as well .	CRH, Unc, and ACTH stimulate all elements of the DHEAS synthetic pathway and activate CRH-R1 as well.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRH-R1	CRH-R1	CRH-R1	0	1	16	17
Thus , we hypothesized that locally secreted CRH activates CRHR1 to initiate circuit plasticity programs .	Thus, we hypothesized that locally secreted CRH activates CRHR1 to initiate circuit plasticity programs.	6	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	7	8	9	10
CRH and the urocortins mediate their effects via two distinct CRH receptors : CRH-R1 and CRH-R2 ( reviewed in ) .	CRH and the urocortins mediate their effects via two distinct CRH receptors : CRH-R1 and CRH-R2 (reviewed in).	0	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRH-R1	CRH-R1	CRH-R1	0	1	13	14
CRHR1 activation by CRH , which is not only released by the PVN , but also e.g ., by CRH expressing cells in the hippocampus and central amygdala ( CeA ) , is generally thought mediate stress initiation , whereas CRHR2 activation would moderate its termination , although recent work has emphasized that this dual , opposing role of CRHRs is overly simplified and highly brain-region specific .	CRHR1 activation by CRH, which is not only released by the PVN, but also e.g., by CRH expressing cells in the hippocampus and central amygdala (CeA), is generally thought mediate stress initiation, whereas CRHR2 activation would moderate its termination, although recent work has emphasized that this dual, opposing role of CRHRs is overly simplified and highly brain-region specific.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	3	4	0	1
As CRHR1 activation by CRH in the amygdala typically serves an activating , anxiogenic role , elevated expression levels match the overall increase in anxiety like behavior of ELS animals .	As CRHR1 activation by CRH in the amygdala typically serves an activating, anxiogenic role, elevated expression levels match the overall increase in anxiety like behavior of ELS animals.	1	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	4	5	1	2
In particular , CRH stimulated CRHR1 signals through extracellular signal regulated kinase 1/2 ( ERK1/2 ) to induce proopiomelanocortin ( Pomc ) transcription and activate the HPA axis in pituitary corticotrophs and in specific brain structures related to behavioral aspects of stress in response to intracerebroventricular CRH administration .	In particular, CRH stimulated CRHR1 signals through extracellular signal regulated kinase 1/2 (ERK1/2) to induce proopiomelanocortin (Pomc) transcription and activate the HPA axis in pituitary corticotrophs and in specific brain structures related to behavioral aspects of stress in response to intracerebroventricular CRH administration.	3	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	3	4	5	6
CRH stimulated CRHR1 leads to the activation of two members of the Ras family ( Ras and Rap1 ) and both proteins are part of the B and Raf complex responsible for ERK1/2 activation in a hippocampal neuronal context .	CRH stimulated CRHR1 leads to the activation of two members of the Ras family (Ras and Rap1) and both proteins are part of the B and Raf complex responsible for ERK1/2 activation in a hippocampal neuronal context.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	0	1	2	3
Because CRH activated CRHR1 has been shown to trigger an increase in calcium XREF_BIBR , XREF_BIBR which is critical for sAC activation , we investigated the involvement of calcium in the neuritogenic effect of CRH .	Because CRH activated CRHR1 has been shown to trigger an increase in calcium XREF_BIBR, XREF_BIBR which is critical for sAC activation, we investigated the involvement of calcium in the neuritogenic effect of CRH.	1	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	1	2	3	4
Also CRH or LPS , particularly CRH + LPS , stimulate TNF-alpha , IL-6 , and NO release in cultured primary microglia via CRH activated CRHR1 signaling PKA .	Also CRH or LPS, particularly CRH + LPS, stimulate TNF-alpha, IL-6, and NO release in cultured primary microglia via CRH activated CRHR1 signaling PKA.	21	27	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	23	24	25	26
In islets cultured under normoxia , CRH stimulated insulin release in a glucose- and CRH-level-dependent manner by activating CRHR1 and thus the cAMP dependent protein kinase pathway and calcium influx through L-type channels .	In islets cultured under normoxia, CRH stimulated insulin release in a glucose- and CRH-level-dependent manner by activating CRHR1 and thus the cAMP dependent protein kinase pathway and calcium influx through L-type channels.	6	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	6	7	18	19
Similar peak cAMP values were observed with CRH or UCN1 , ligands that activate both CRH-R1 and CRH-R2alpha .	Similar peak cAMP values were observed with CRH or UCN1, ligands that activate both CRH-R1 and CRH-R2alpha.	5	17	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRH-R1	CRH-R1	CRH-R1	7	8	15	16
The study of CRH activated CRHR1 uncovers a previously unanticipated link between sAC and endosome based GPCR signaling .	The study of CRH activated CRHR1 uncovers a previously unanticipated link between sAC and endosome based GPCR signaling.	1	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	3	4	5	6
Taken together , available data largely support the idea that the main source of the CRH that activates CRFR 1 within hippocampus is the hippocampus itself .	Taken together, available data largely support the idea that the main source of the CRH that activates CRFR 1 within hippocampus is the hippocampus itself.	12	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRFR 1	CRFR 1	CRFR 1	15	16	18	20
CRH activated CRHR1 was found to increase neuronal excitability of hippocampal CA1 pyramidal neurons through a mechanism dependent on L- and T-type calcium channels and voltage gated potassium channels but independent on intracellular calcium rise .	CRH activated CRHR1 was found to increase neuronal excitability of hippocampal CA1 pyramidal neurons through a mechanism dependent on L- and T-type calcium channels and voltage gated potassium channels but independent on intracellular calcium rise.	0	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	0	1	2	3
CRHR1 has been shown to mediate the CRH induced firing rate of ventral tegmental area ( VTA ) DA neurons , and CRHR1 antagonism has been shown to inhibit striatal DA release In addition , the activation of CRHR1 by CRH results in an increase in DA release in the nucleus accumbens , and midbrain CRHR1 blockade has been demonstrated to reduce cocaine induced DA release into the Acb .	CRHR1 has been shown to mediate the CRH induced firing rate of ventral tegmental area (VTA) DA neurons, and CRHR1 antagonism has been shown to inhibit striatal DA release In addition, the activation of CRHR1 by CRH results in an increase in DA release in the nucleus accumbens, and midbrain CRHR1 blockade has been demonstrated to reduce cocaine induced DA release into the Acb.	36	41	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	40	41	38	39
Notably , the calcium response elicited by CRH was not altered in HT22-CRHR1 cells preincubated with ddA or 2-HE ( XREF_FIG ) , suggesting that calcium , required for sAC activity , would not depend on cAMP stimulation by CRH activated CRHR1 .	Notably, the calcium response elicited by CRH was not altered in HT22-CRHR1 cells preincubated with ddA or 2-HE (XREF_FIG), suggesting that calcium, required for sAC activity, would not depend on cAMP stimulation by CRH activated CRHR1.	34	42	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	39	40	41	42
To determine if the increase in steroidogenic mRNA levels was due to CRHR1 receptor activation , GD15 mouse testis was treated with CRH and an antagonist specific for CRHR1 , NBI 27914 , for 24 hours ex vivo .	To determine if the increase in steroidogenic mRNA levels was due to CRHR1 receptor activation, GD15 mouse testis was treated with CRH and an antagonist specific for CRHR1, NBI 27914, for 24 hours ex vivo.	12	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	22	23	12	13
Together , these data provide a resource for discovering factors controlling fetal Leydig cell biology and suggest that CRHR1 activation by CRH stimulates rat and mouse fetal Leydig cell steroidogenesis in vivo .	Together, these data provide a resource for discovering factors controlling fetal Leydig cell biology and suggest that CRHR1 activation by CRH stimulates rat and mouse fetal Leydig cell steroidogenesis in vivo.	18	22	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	21	22	18	19
Enhanced serotonin signaling by CRH was shown to require CRH stimulated CRHR1 endocytosis and rapid recycling from endosomes , which resulted in increased cell surface expression of serotonin receptor ( 5-HT2R ) , in both HEK293 cells and mouse cortical neurons .	Enhanced serotonin signaling by CRH was shown to require CRH stimulated CRHR1 endocytosis and rapid recycling from endosomes, which resulted in increased cell surface expression of serotonin receptor (5-HT2R), in both HEK293 cells and mouse cortical neurons.	8	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	9	10	11	12
CRH activated CRHR1 has been shown to trigger an increase in calcium in several cellular contexts .	CRH activated CRHR1 has been shown to trigger an increase in calcium in several cellular contexts.	0	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	0	1	2	3
This increase was largely mediated by CRH activation of CRH-R1 located on NI neurons , as pre-treatment with the CRH antagonist , antalarmin , reduced the increase in relaxin-3 mRNA expression by 70-80 % .	This increase was largely mediated by CRH activation of CRH-R1 located on NI neurons, as pre-treatment with the CRH antagonist, antalarmin, reduced the increase in relaxin-3 mRNA expression by 70-80%.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CRH	CRH	CRH	CRH-R1	CRH-R1	CRH-R1	6	7	9	10
These studies indicate that activation of CRHR1 by CRH or Ucn I enhances intestinal inflammation .	These studies indicate that activation of CRHR1 by CRH or Ucn I enhances intestinal inflammation.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	8	9	6	7
Central CRH infusion has been demonstrated to activate NI neurons expressing CRH-R1 , and stress activated neurons in the NI express relaxin-3 .	Central CRH infusion has been demonstrated to activate NI neurons expressing CRH-R1, and stress activated neurons in the NI express relaxin-3.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRH-R1	CRH-R1	CRH-R1	1	2	11	12
Importantly , 2-HE did not affect CRH activated CRHR1 endocytosis , as shown by flow cytometry analysis and subcellular localization of CRHR1-GFP ( XREF_FIG ) .	Importantly, 2-HE did not affect CRH activated CRHR1 endocytosis, as shown by flow cytometry analysis and subcellular localization of CRHR1-GFP (XREF_FIG).	5	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	6	7	8	9
Our results indicate that CRH activated CRHR1 generates cAMP from endocytic compartments .	Our results indicate that CRH activated CRHR1 generates cAMP from endocytic compartments.	4	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	4	5	6	7
Direct infusion of CRH into the dorsal PVN was also shown to induce CRH-R1 mRNA in CRH positive neurons in the parvocellular part of the PVN , suggesting that CRH increases the amplitude of its own response to stress by increasing the number of CRH-R1 receptors in the hypothalamus of rats .	Direct infusion of CRH into the dorsal PVN was also shown to induce CRH-R1 mRNA in CRH positive neurons in the parvocellular part of the PVN, suggesting that CRH increases the amplitude of its own response to stress by increasing the number of CRH-R1 receptors in the hypothalamus of rats.	1	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRH-R1	CRH-R1	CRH-R1	3	4	13	14
Central administration of CRH increased CRH-R1 mRNA in the hypothalamus , and the effect of CRH was blocked by alpha-helical CRH .	Central administration of CRH increased CRH-R1 mRNA in the hypothalamus, and the effect of CRH was blocked by alpha-helical CRH.	1	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRH-R1	CRH-R1	CRH-R1	3	4	5	6
In response to stress , corticotropin releasing hormone ( CRH ) and vasopressin ( AVP ) are released from the hypothalamus , activate their receptors ( CRHR1 , CRHR2 or AVPr1b ) , and synergistically act to induce adrenocorticotropic hormone ( ACTH ) release from the anterior pituitary .	In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary.	5	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	corticotropin releasing hormone	corticotropin releasing hormone	corticotropin releasing hormone	CRHR1	CRHR1	CRHR1	5	8	26	27
The study of cAMP response elicited by CRH activated CRHR1 demonstrated that both tmACs and sAC are involved in two physiologically relevant scenarios , hippocampal HT22-CRHR1 and neuroendocrine AtT20 cells .	The study of cAMP response elicited by CRH activated CRHR1 demonstrated that both tmACs and sAC are involved in two physiologically relevant scenarios, hippocampal HT22-CRHR1 and neuroendocrine AtT20 cells.	5	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	7	8	9	10
This suggests that an autocrine loop is produced by which ovarian tumors can secrete CSF-1 stimulating the CSF-1R resulting in a more aggressive phenotype .	This suggests that an autocrine loop is produced by which ovarian tumors can secrete CSF-1 stimulating the CSF-1R resulting in a more aggressive phenotype.	13	18	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	14	15	17	18
The abundance of monocytes and tissue macrophages is controlled through the macrophage colony stimulating factor receptor ( CSF1R ) , which is activated by two ligands , CSF1 and IL34 .	The abundance of monocytes and tissue macrophages is controlled through the macrophage colony stimulating factor receptor (CSF1R), which is activated by two ligands, CSF1 and IL34.	15	28	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	CSF1	CSF1	CSF1	CSF1R	CSF1R	CSF1R	27	28	17	18
Non identical activation of the same CSF-1R receptor by CSF-1 and IL-34 .	Non identical activation of the same CSF-1R receptor by CSF-1 and IL-34.	2	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	9	10	6	7
We next asked whether CSF1 might activate CSF1R coupled intracellular pathways .	We next asked whether CSF1 might activate CSF1R coupled intracellular pathways.	4	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF1	CSF1	CSF1	CSF1R	CSF1R	CSF1R	4	5	7	8
Expressed by microglia , CSF1R is activated by two homodimeric glycoprotein ligands , CSF1 and Interleukin 34 .	Expressed by microglia, CSF1R is activated by two homodimeric glycoprotein ligands, CSF1 and Interleukin 34.	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF1	CSF1	CSF1	CSF1R	CSF1R	CSF1R	13	14	4	5
Macrophage colony stimulating factor ( CSF-1 ) increases the tissue invasive potential of the CSF-1 receptor bearing lung carcinoma cell lines A549 and Calu-1 by increasing the number of endogenously bound urokinase-type plasminogen activators ( u-PA ) s on these cells .	Macrophage colony stimulating factor (CSF-1) increases the tissue invasive potential of the CSF-1 receptor bearing lung carcinoma cell lines A549 and Calu-1 by increasing the number of endogenously bound urokinase-type plasminogen activators (u-PA) s on these cells.	3	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1 receptor	CSF-1 receptor	CSF-1 receptor	5	6	14	16
CSF-1 stimulation of the CSF-1R and FLT4 receptor chimera induced thymidine incorporation in serum starved NIH3T3 fibroblasts , but not in porcine aortic or murine lung capillary endothelial cells , although tyrosyl phosphorylation of the receptor and SHC occurred in these cells as well .	CSF-1 stimulation of the CSF-1R and FLT4 receptor chimera induced thymidine incorporation in serum starved NIH3T3 fibroblasts, but not in porcine aortic or murine lung capillary endothelial cells, although tyrosyl phosphorylation of the receptor and SHC occurred in these cells as well.	0	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	0	1	4	5
In this respect , activation of CSF-1R by its ligand is likely to occur in tumor cells in which CSF-1R and CSF-1 are co-expressed ( i.e. autocrine activation ) , or when CSF-1R is stimulated by CSF-1 released by cancer associated fibroblasts ( i.e. paracrine activation ) .	In this respect, activation of CSF-1R by its ligand is likely to occur in tumor cells in which CSF-1R and CSF-1 are co-expressed (i.e. autocrine activation), or when CSF-1R is stimulated by CSF-1 released by cancer associated fibroblasts (i.e. paracrine activation).	32	37	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	36	37	32	33
In support of our results , existing literature provides evidence that MCSF signaling activates its receptor the FMS tyrosine kinase which sequentially activates PI-3 kinase and Rac in microglia and bone marrow derived cells XREF_BIBR , XREF_BIBR .	In support of our results, existing literature provides evidence that MCSF signaling activates its receptor the FMS tyrosine kinase which sequentially activates PI-3 kinase and Rac in microglia and bone marrow derived cells XREF_BIBR, XREF_BIBR.	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MCSF	MCSF	MCSF	FMS	FMS	FMS	11	12	17	18
Thus , activation of M-CSFR and downstream ERK1/2 signals by M-CSF secreted from neurons and astroglia modulates microglial ET .	Thus, activation of M-CSFR and downstream ERK1/2 signals by M-CSF secreted from neurons and astroglia modulates microglial ET.	2	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	M-CSF	M-CSF	M-CSF	M-CSFR	M-CSFR	M-CSFR	10	11	4	5
Addition of CSF-1 to cells stimulates or stabilizes non covalent CSF-1R dimerization resulting in activation of the CSF-1R kinase and the tyrosine phosphorylation of the receptor and certain cytoplasmic proteins .	Addition of CSF-1 to cells stimulates or stabilizes non covalent CSF-1R dimerization resulting in activation of the CSF-1R kinase and the tyrosine phosphorylation of the receptor and certain cytoplasmic proteins.	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	2	3	10	11
Interestingly , TACE also cleaves the CSF1 receptor , c-fms , producing a soluble CSF1 receptor [ XREF_BIBR ] .	Interestingly, TACE also cleaves the CSF1 receptor, c-fms, producing a soluble CSF1 receptor [XREF_BIBR].	6	16	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF1	CSF1	CSF1	CSF1 receptor	CSF1 receptor	CSF1 receptor	6	7	14	16
CSF1R can be activated by CSF1 and interleukin-34 ( IL-34 ) , thus contributing to innate immunity by regulating the development of macrophage and microglia in the brain [ XREF_BIBR ] .	CSF1R can be activated by CSF1 and interleukin-34 (IL-34), thus contributing to innate immunity by regulating the development of macrophage and microglia in the brain [XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF1	CSF1	CSF1	CSF1R	CSF1R	CSF1R	5	6	0	1
In vivo studies of 125I-CSF-1 uptake and degradation and in vitro studies of 125I-CSF-1 binding by splenic cells demonstrated that within 24 h of the reaction the number of CSF-1 receptor+ cells had increased by 2-fold and their capacity to express the CSF-1 receptor by approximately 3-fold , resulting in a approximately 2.5-fold increase in the splenic clearance of CSF-1 from the circulation .	In vivo studies of 125I-CSF-1 uptake and degradation and in vitro studies of 125I-CSF-1 binding by splenic cells demonstrated that within 24 h of the reaction the number of CSF-1 receptor+ cells had increased by 2-fold and their capacity to express the CSF-1 receptor by approximately 3-fold, resulting in a approximately 2.5-fold increase in the splenic clearance of CSF-1 from the circulation.	29	44	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1 receptor	CSF-1 receptor	CSF-1 receptor	29	30	42	44
In addition , MDBMs expressed FMS , and exogenous M-CSF could activate FMS signaling pathways in MDBMs ( XREF_FIG ) .	In addition, MDBMs expressed FMS, and exogenous M-CSF could activate FMS signaling pathways in MDBMs (XREF_FIG).	8	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	M-CSF	M-CSF	M-CSF	FMS	FMS	FMS	9	10	12	13
M-CSF activates its receptor , Fms tyrosine kinase , and Fms sequentially activates a number of signaling molecules , including PI3K or phospholipase Cgamma ( PLCgamma ) .	M-CSF activates its receptor, Fms tyrosine kinase, and Fms sequentially activates a number of signaling molecules, including PI3K or phospholipase Cgamma (PLCgamma).	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	M-CSF	M-CSF	M-CSF	Fms	Fms	Fms	0	1	5	6
To ensure that CSF1 was responsible for this Tie2+ transition , we pre-treated freshly isolated CD14+ monocytes with a neutralizing antibody ( NAb ) to CSF1R for 30 minutes then treated with CSF1 and analyzed these cells for Tie2 expression .	To ensure that CSF1 was responsible for this Tie2+ transition, we pre-treated freshly isolated CD14+ monocytes with a neutralizing antibody (NAb) to CSF1R for 30 minutes then treated with CSF1 and analyzed these cells for Tie2 expression.	20	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CSF1	CSF1	CSF1	CSF1R	CSF1R	CSF1R	32	33	25	26
Since human CSF-1 stimulates secretion of alpha interferon from mononuclear cells and BARF1 encodes a soluble CSF-1 receptor , we examined whether recombinant BARF1 or BARF1 derived from EBV infected B cells could inhibit alpha interferon secretion .	Since human CSF-1 stimulates secretion of alpha interferon from mononuclear cells and BARF1 encodes a soluble CSF-1 receptor, we examined whether recombinant BARF1 or BARF1 derived from EBV infected B cells could inhibit alpha interferon secretion.	1	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1 receptor	CSF-1 receptor	CSF-1 receptor	2	3	16	18
Microglia , like other tissue macrophages , rely on sustained CSF1R signaling to survive , which in the CNS is driven by the secreted growth factors CSF-1 and IL-34 .	Microglia, like other tissue macrophages, rely on sustained CSF1R signaling to survive, which in the CNS is driven by the secreted growth factors CSF-1 and IL-34.	10	28	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF1R	CSF1R	CSF1R	26	27	10	11
As a possible example of this , IL-34 mediates development of Langerhans cells and microglia through CSF-1R , whereas CSF-1R signaling is mediated in most tissues by CSF-1 .	As a possible example of this, IL-34 mediates development of Langerhans cells and microglia through CSF-1R, whereas CSF-1R signaling is mediated in most tissues by CSF-1.	19	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	27	28	19	20
Thus , for example , bacteria or inflammatory stimuli can upregulate Pu.1 expression in hematopoietic stem cells through the activation of M-CSF , a cytokine that in turn activates the CSF-1 receptor .	Thus, for example, bacteria or inflammatory stimuli can upregulate Pu.1 expression in hematopoietic stem cells through the activation of M-CSF, a cytokine that in turn activates the CSF-1 receptor.	19	32	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	M-CSF	M-CSF	M-CSF	CSF-1 receptor	CSF-1 receptor	CSF-1 receptor	21	22	30	32
These results suggest that FBS can contain CSF-1 or other growth factors that stimulate CSF-1R .	These results suggest that FBS can contain CSF-1 or other growth factors that stimulate CSF-1R.	7	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	7	8	14	15
CSF-1 activates CSF-1R tyrosine residues , leading to a subsequent phosphorylation cascade [ XREF_BIBR ] .	CSF-1 activates CSF-1R tyrosine residues, leading to a subsequent phosphorylation cascade [XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	0	1	2	3
Conversely , mouse CSF-1 can activate porcine CSF-1R but not human CSF-1R .	Conversely, mouse CSF-1 can activate porcine CSF-1R but not human CSF-1R.	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	3	4	7	8
Moreover , while CSF-1 and IL-34 are able to activate CSF-1R in a similar fashion , a recent study indicates that CSF-1 and IL-34 may trigger nonoverlapping downstream signaling pathways in human monocytes [ XREF_BIBR ] , suggesting a potential functional specialization between these two cytokines .	Moreover, while CSF-1 and IL-34 are able to activate CSF-1R in a similar fashion, a recent study indicates that CSF-1 and IL-34 may trigger nonoverlapping downstream signaling pathways in human monocytes [XREF_BIBR], suggesting a potential functional specialization between these two cytokines.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	3	4	10	11
CSF1R , also known as cFMS and M-CSFR , is a member of the type III receptor tyrosine kinase family and is activated by binding of its ligands CSF-1 ( MCSF ) or IL-34 [ XREF_BIBR - XREF_BIBR ] .	CSF1R, also known as cFMS and M-CSFR, is a member of the type III receptor tyrosine kinase family and is activated by binding of its ligands CSF-1 (MCSF) or IL-34 [XREF_BIBR - XREF_BIBR].	0	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF1R	CSF1R	CSF1R	28	29	0	1
CSF-1 increased CSF-1R +/F4/80+ macrophage number by 34 % at P11 compared to Hyp+ PBS , but was not associated with growth or lung structural rescue .	CSF-1 increased CSF-1R +/F4/80+ macrophage number by 34% at P11 compared to Hyp+ PBS, but was not associated with growth or lung structural rescue.	0	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	0	1	2	3
Activation of CSF-1R by its ligand is likely to occur in an autocrine manner in tumor cells in which CSF-1R and CSF-1 are co-expressed , or in paracrine manner , when CSF-1R is stimulated by CSF-1 released by fibroblasts [ XREF_BIBR ] .	Activation of CSF-1R by its ligand is likely to occur in an autocrine manner in tumor cells in which CSF-1R and CSF-1 are co-expressed, or in paracrine manner, when CSF-1R is stimulated by CSF-1 released by fibroblasts [XREF_BIBR].	31	36	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	35	36	31	32
Compared to earlier results our data indicate that CSF-1R stimulation by IL-34 or CSF-1 produced similar types of responses by elderly postmortem brain derived microglia .	Compared to earlier results our data indicate that CSF-1R stimulation by IL-34 or CSF-1 produced similar types of responses by elderly postmortem brain derived microglia.	8	14	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	13	14	8	9
The development of macrophages requires signaling from the CSF1 receptor ( CSF1R ) initiated by one of two ligands , CSF1 and IL-34 .	The development of macrophages requires signaling from the CSF1 receptor (CSF1R) initiated by one of two ligands, CSF1 and IL-34.	8	21	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF1	CSF1	CSF1	CSF1 receptor	CSF1 receptor	CSF1 receptor	20	21	8	10
We previously showed that ' classical ' RTK signaling exists in breast cancer cells where CSF-1R is activated by its ligand CSF-1 , leading to CSF-1-induced proliferation and expression of genes involved in cell growth such as CCND1 , c-MYC and c-JUN .	We previously showed that ' classical ' RTK signaling exists in breast cancer cells where CSF-1R is activated by its ligand CSF-1, leading to CSF-1-induced proliferation and expression of genes involved in cell growth such as CCND1, c-MYC and c-JUN.	15	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	21	22	15	16
CSF-1R can be activated by both colony stimulating factor-1 ( CSF-1 ) and interleukin-34 and is known to regulate the development and maintenance of immune cells , such as monocytes and macrophage [ XREF_BIBR ] , as well as regulate neuron progenitor cells , such as myeloid cells [ XREF_BIBR , XREF_BIBR ] .	CSF-1R can be activated by both colony stimulating factor-1 (CSF-1) and interleukin-34 and is known to regulate the development and maintenance of immune cells, such as monocytes and macrophage [XREF_BIBR], as well as regulate neuron progenitor cells, such as myeloid cells [XREF_BIBR, XREF_BIBR].	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	10	11	0	1
Activation of CSF1R by CSF1 stimulates the proliferation , differentiation , and survival of macrophages and influences macrophage chemotaxis , phagocytosis , and synthesis and secretion of proteolytic enzymes and cytokines .	Activation of CSF1R by CSF1 stimulates the proliferation, differentiation, and survival of macrophages and influences macrophage chemotaxis, phagocytosis, and synthesis and secretion of proteolytic enzymes and cytokines.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CSF1	CSF1	CSF1	CSF1R	CSF1R	CSF1R	4	5	2	3
The CSF-1R is activated by two dimeric glycoprotein ligands , CSF-1 , and interleukin-34 ( IL-34 ) .	The CSF-1R is activated by two dimeric glycoprotein ligands, CSF-1, and interleukin-34 (IL-34).	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	10	11	1	2
CSF1R is activated by the binding of CSF1 , in the presence of or alternatively by IL-34 , and is required for microglial viability .	CSF1R is activated by the binding of CSF1, in the presence of or alternatively by IL-34, and is required for microglial viability.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CSF1	CSF1	CSF1	CSF1R	CSF1R	CSF1R	7	8	0	1
We have characterized the roles of Rho , Rac , and Cdc42 in macrophages stimulated with CSF-1 , which activates the CSF-1 receptor ( CSF-1R ) , 1 a receptor tyrosine kinase encoded by the protooncogene c-fms ( Allen et al ., 1997 ; Rohrschneider et al ., 1997 ) .	We have characterized the roles of Rho, Rac, and Cdc42 in macrophages stimulated with CSF-1, which activates the CSF-1 receptor (CSF-1R), 1 a receptor tyrosine kinase encoded by the protooncogene c-fms (Allen et al., 1997; Rohrschneider et al., 1997).	14	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1 receptor	CSF-1 receptor	CSF-1 receptor	16	17	21	23
Data reported in literature for solid tumors indicate that the oncogenic potential of CSF-1 and CSF-1R is due to the co-expression of this growth factor and receptor pair , rather than CSF-1R overexpression or mutations activating CSF-1R independently of ligand XREF_BIBR .	Data reported in literature for solid tumors indicate that the oncogenic potential of CSF-1 and CSF-1R is due to the co-expression of this growth factor and receptor pair, rather than CSF-1R overexpression or mutations activating CSF-1R independently of ligand XREF_BIBR.	11	37	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	13	14	36	37
Macrophages flocked to the tumour , the so called tumour associated macrophages ( TAMs ) , are generally recruited by the activation of CSF1R by CSF-1 or IL-34 , as well as by the chemokine CCL2 [ XREF_BIBR ] .	Macrophages flocked to the tumour, the so called tumour associated macrophages (TAMs), are generally recruited by the activation of CSF1R by CSF-1 or IL-34, as well as by the chemokine CCL2 [XREF_BIBR].	18	27	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF1R	CSF1R	CSF1R	25	26	23	24
This increase in Cbp phosphorylation causes additional recruitment of Csk , which may serve to control the amount of active Fyn and thus controls degranulation .	This increase in Cbp phosphorylation causes additional recruitment of Csk, which may serve to control the amount of active Fyn and thus controls degranulation.	3	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cbp	Cbp phosphorylation	cbp	Csk	Csk	csk	3	4	9	10
Two groups independently uncovered Cbp and PAG as the essential factor potentiating Csk localization at the plasmalemma .	Two groups independently uncovered Cbp and PAG as the essential factor potentiating Csk localization at the plasmalemma.	2	13	potentiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cbp	Cbp	Cbp	Csk	Csk	Csk	4	5	12	13
Unlike Cbp , which must be added to kinase assays in a phosphorylated form to activate Csk , YL2 was added to the assays in the present study as an unphosphorylated protein ( and was presumably phosphorylated in situ as shown in a separate in vitro assay [ XREF_FIG ] ) .	Unlike Cbp, which must be added to kinase assays in a phosphorylated form to activate Csk, YL2 was added to the assays in the present study as an unphosphorylated protein (and was presumably phosphorylated in situ as shown in a separate in vitro assay [XREF_FIG]).	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cbp	Cbp	Cbp	Csk	Csk	Csk	1	2	16	17
Recent theoretical models by Fuss et al [ XREF_BIBR - XREF_BIBR ] incorporated positive feedback that can occur owing to Src induced phosphorylation and activation of PTPalpha , and negative feedback that is exerted via the Csk binding protein Cbp , which when phosphorylated by SFKs can target Csk to Src , promoting inhibitory phosphorylation of Src .	Recent theoretical models by Fuss et al [XREF_BIBR - XREF_BIBR] incorporated positive feedback that can occur owing to Src induced phosphorylation and activation of PTPalpha, and negative feedback that is exerted via the Csk binding protein Cbp, which when phosphorylated by SFKs can target Csk to Src, promoting inhibitory phosphorylation of Src.	33	49	target	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Cbp	Cbp	Cbp	Csk	Csk	Csk	39	40	48	49
Phosphorylation of Cbp ( specifically at Y317 ) causes the recruitment and binding of Csk via its SH2 domain .	Phosphorylation of Cbp (specifically at Y317) causes the recruitment and binding of Csk via its SH2 domain.	0	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cbp	Phosphorylation of Cbp (specifically at Y317	cbp	Csk	Csk	csk	2	3	14	15
Thus , the loop elongation does not appear to have a significant effect on how CBP activates Csk via the phosphotyrosine-SH2 interaction .	Thus, the loop elongation does not appear to have a significant effect on how CBP activates Csk via the phosphotyrosine-SH2 interaction.	15	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CBP	CBP	CBP	Csk	Csk	Csk	15	16	17	18
Csk and the cytoplasmic domain of phosphorylated Cbp form a stable complex and enhance the affinity of Csk toward Src .	Csk and the cytoplasmic domain of phosphorylated Cbp form a stable complex and enhance the affinity of Csk toward Src.	6	18	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cbp	phosphorylated Cbp	cbp	Csk	Csk	csk	7	8	17	18
Binding of M-CSFR by M-CSF has been reported to activate the MAPK pathway .	Binding of M-CSFR by M-CSF has been reported to activate the MAPK pathway.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	M-CSFR	M-CSFR	M-CSFR	MAPK	MAPK	MAPK	2	3	11	12
Overexpression of CSF-1R activates the ERK1/2 signaling pathway leading to the stimulation of proliferation [ XREF_BIBR ] .	Overexpression of CSF-1R activates the ERK1/2 signaling pathway leading to the stimulation of proliferation [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1R	Overexpression of CSF-1R	csf-1r	ERK1/2	ERK1/2	erk1/2	2	3	5	6
CSF-1R not only mediates the ERK and AKT pathway , but is also regulated by the ERK and AKT dependent pathway [ XREF_BIBR , XREF_BIBR ] .	CSF-1R not only mediates the ERK and AKT pathway, but is also regulated by the ERK and AKT dependent pathway [XREF_BIBR, XREF_BIBR].	0	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1R	CSF-1R	CSF-1R	ERK	ERK	ERK	0	1	5	6
Overexpression and knockdown studies also showed that CSF-1R significantly promoted active AKT and ERK1/2 signalling pathways in cisplatin resistant cells .	Overexpression and knockdown studies also showed that CSF-1R significantly promoted active AKT and ERK1/2 signalling pathways in cisplatin resistant cells.	7	15	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1R	CSF-1R	CSF-1R	ERK1/2	ERK1/2	ERK1/2	7	8	13	14
CSF-1R inhibition also decreases the number of macrophages and inhibits activation of the MAPK pathway in mouse tumors .	CSF-1R inhibition also decreases the number of macrophages and inhibits activation of the MAPK pathway in mouse tumors.	0	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1R	CSF-1R	CSF-1R	MAPK	MAPK	MAPK	0	1	13	14
Subsequent to FMS * MAPK signaling activation , an increase in AP and MMP-14 mRNA is detected , which is also inhibited by PTX , suggesting that FMS * activation of MAPK signaling could be an early event required for the induction of these genes .	Subsequent to FMS * MAPK signaling activation, an increase in AP and MMP-14 mRNA is detected, which is also inhibited by PTX, suggesting that FMS * activation of MAPK signaling could be an early event required for the induction of these genes.	27	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FMS	FMS	FMS	MAPK	MAPK	MAPK	27	28	31	32
Previous studies have demonstrated that CSF-1R induces proliferation by activating ERK 29 .	Previous studies have demonstrated that CSF-1R induces proliferation by activating ERK 29.	5	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1R	CSF-1R	CSF-1R	ERK	ERK	ERK	5	6	10	11
Based on these combined results , it appears that acetylation is required for maximal activity of p65 , which is consistent with results showing that overexpression of CBP and p300 enhances the activation potential of p65 , whereas overexpression of histone deacetylases ( HDAC ) represses p65 activity .	Based on these combined results, it appears that acetylation is required for maximal activity of p65, which is consistent with results showing that overexpression of CBP and p300 enhances the activation potential of p65, whereas overexpression of histone deacetylases (HDAC) represses p65 activity.	25	36	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CBP	overexpression of CBP	cbp	p65	p65	p65	27	28	35	36
The p65 dependent repression of PPARdelta- but not PPARalpha- or PPARgamma mediated transactivation was partially relieved by forced expression of the coactivators p300 or CBP .	The p65 dependent repression of PPARdelta- but not PPARalpha- or PPARgamma mediated transactivation was partially relieved by forced expression of the coactivators p300 or CBP.	1	25	relieved	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	CBP	expression of the coactivators p300 or CBP	cbp	p65	p65	p65	24	25	1	2
HG treatment of THP-1 monocytes increased the transcriptional activity of NF-kappaB p65 , which was augmented by CBP and p300 and p/CAF .	HG treatment of THP-1 monocytes increased the transcriptional activity of NF-kappaB p65, which was augmented by CBP and p300 and p/CAF.	10	21	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CBP	CBP	CBP	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	17	18	10	12
The presence of CBP further enhanced p65 mediated activity by an additional three-fold over control levels .	The presence of CBP further enhanced p65 mediated activity by an additional three-fold over control levels.	1	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CBP	CBP	CBP	p65	p65	p65	3	4	6	7
Further , blockade of CBP prevented DNA binding of both CREB and NF-kappaB p65 .	Further, blockade of CBP prevented DNA binding of both CREB and NF-kappaB p65.	2	14	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CBP	CBP	CBP	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	4	5	12	14
TorC2 mediated activation of Akt was shown to be essential for regulating the dynamic remodeling of F-Actin at the leading edge of chemotaxing Dictyostelium cells .	TorC2 mediated activation of Akt was shown to be essential for regulating the dynamic remodeling of F-Actin at the leading edge of chemotaxing Dictyostelium cells.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	TorC2	TorC2	TorC2	Akt	Akt	Akt	0	1	4	5
Although the inverse activity relationship between Rac and RhoA remains to be established [ XREF_BIBR , XREF_BIBR ] , both Rac1 and RhoA activation seems to exist in Crk overexpressing lung cancer cells through Dock families [ XREF_BIBR , XREF_BIBR ] or other molecules such as Src , Fak , and Abl those can be activated by Crk .	Although the inverse activity relationship between Rac and RhoA remains to be established [XREF_BIBR, XREF_BIBR], both Rac1 and RhoA activation seems to exist in Crk overexpressing lung cancer cells through Dock families [XREF_BIBR, XREF_BIBR] or other molecules such as Src, Fak, and Abl those can be activated by Crk.	43	58	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Crk	Crk	Crk	Fak	Fak	Fak	57	58	48	49
Therefore , while FAK , p130Cas , and paxillin localization to FA is upstream of Crk , disruption of Crk activity by ExoT or by CrkI and R38K mutation could potentially disrupt FAK , p130Cas , and paxillin subcellular localization , and/or their maintenance , and/or their activation at FA sites .	Therefore, while FAK, p130Cas, and paxillin localization to FA is upstream of Crk, disruption of Crk activity by ExoT or by CrkI and R38K mutation could potentially disrupt FAK, p130Cas, and paxillin subcellular localization, and/or their maintenance, and/or their activation at FA sites.	19	39	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Crk	Crk	Crk	FAK	FAK	FAK	19	20	32	33
Given that MYOD1 is activated by CBP and p300 or PCAF mediated acetylation XREF_BIBR , XREF_BIBR , we speculate that BRD4 may analogously interact with acetylated-MYOD1 in order to facilitate polymerase elongation at muscle genes in a manner similar to BRD3-GATA1 .	Given that MYOD1 is activated by CBP and p300 or PCAF mediated acetylation XREF_BIBR, XREF_BIBR, we speculate that BRD4 may analogously interact with acetylated-MYOD1 in order to facilitate polymerase elongation at muscle genes in a manner similar to BRD3-GATA1.	2	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CBP	CBP	CBP	MYOD1	MYOD1	MYOD1	6	7	2	3
Luciferase reporter assays showed that the histone acetyltransferase p300 was able to counteract the HDAC4 and HDAC5 mediated repression and that p300 and CBP synergized with transcription factors Sp1 , c-Myb , and Ets-1 in activation of the WT1 reporter .	Luciferase reporter assays showed that the histone acetyltransferase p300 was able to counteract the HDAC4 and HDAC5 mediated repression and that p300 and CBP synergized with transcription factors Sp1, c-Myb, and Ets-1 in activation of the WT1 reporter.	21	31	synergized	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CBP	CBP	CBP	c-Myb	c-Myb	c-Myb	23	24	30	31
Cbp and p300 is a known co-activator of Myb .	Cbp and p300 is a known co-activator of Myb.	0	9	is a known co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Cbp	Cbp	Cbp	Myb	Myb	Myb	0	1	8	9
Crk and CrkL not only activated HPK1 but also synergized with HPK1 in the activation of JNK .	Crk and CrkL not only activated HPK1 but also synergized with HPK1 in the activation of JNK.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CrkL	CrkL	CrkL	HPK1	HPK1	HPK1	2	3	6	7
CRKL mediates p110beta dependent PI3K signaling in PTEN deficient cancer cells .	CRKL mediates p110beta dependent PI3K signaling in PTEN deficient cancer cells.	0	3	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRKL	CRKL	CRKL	p110beta	p110beta	p110beta	0	1	2	3
G-CSF induces physiologic HSC mobilization by binding the G-CSF receptor on monocyte-macrophage lineage cells that , in turn , modulate stromal levels of CXCL12 .	G-CSF induces physiologic HSC mobilization by binding the G-CSF receptor on monocyte-macrophage lineage cells that, in turn, modulate stromal levels of CXCL12.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSF receptor	G-CSF receptor	G-CSF receptor	0	1	8	10
The change in the receptor architecture limits G-CSF binding and dimerization which leads to an abnormal G-CSF mediated downstream signaling of G-CSFR .	The change in the receptor architecture limits G-CSF binding and dimerization which leads to an abnormal G-CSF mediated downstream signaling of G-CSFR.	12	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR	G-CSFR	G-CSFR	16	17	21	22
Collectively , these results suggest that high levels of G-CSF may mediate the G-CSF and G-CSFR signaling pathway to affect sensory neurons and contribute to the hypersensitivity characteristic of neuropathic pain .	Collectively, these results suggest that high levels of G-CSF may mediate the G-CSF and G-CSFR signaling pathway to affect sensory neurons and contribute to the hypersensitivity characteristic of neuropathic pain.	7	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	G-CSF	levels of G-CSF	g-csf	G-CSFR	G-CSFR	g-csfr	9	10	15	16
Since GSK-3beta activity is regulated by PI3K and Akt signaling , thus we examined if G-CSFR stimulation by G-CSF attenuates apoptosis via the PI3K and Akt pathway and downstream GSK-3beta inhibition .	Since GSK-3beta activity is regulated by PI3K and Akt signaling, thus we examined if G-CSFR stimulation by G-CSF attenuates apoptosis via the PI3K and Akt pathway and downstream GSK-3beta inhibition.	15	19	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR	G-CSFR	G-CSFR	18	19	15	16
Inhibition of G-CSF signaling either by a G-CSF blocking antibody or lack of the G-CSF receptor was sufficient to limit HSC accumulation in the spleen , indicating that G-CSF plays a crucial role downstream of PRR activation to promote HSC mobilization during infection .	Inhibition of G-CSF signaling either by a G-CSF blocking antibody or lack of the G-CSF receptor was sufficient to limit HSC accumulation in the spleen, indicating that G-CSF plays a crucial role downstream of PRR activation to promote HSC mobilization during infection.	2	16	blocking	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSF receptor	G-CSF receptor	G-CSF receptor	2	3	14	16
In vitro studies have shown that G-CSF causes expansion of small pre-existing monosomy 7 cells and up-regulation of the isoform IV G-CSF receptor , resulting in defective differentiation signalling and expansion of undifferentiated cells [ XREF_BIBR ] .	In vitro studies have shown that G-CSF causes expansion of small pre-existing monosomy 7 cells and up-regulation of the isoform IV G-CSF receptor, resulting in defective differentiation signalling and expansion of undifferentiated cells [XREF_BIBR].	6	23	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSF receptor	G-CSF receptor	G-CSF receptor	6	7	21	23
GCSF induced GCSFR dimerization 17 activates downstream signal transduction pathways involving Src kinases such as Lyn , Janus kinase ( JAK )/signal transducer and activator of transcription ( STAT ) , Ras and extracellular regulated kinase ( ERK ) and phosphatidylinositol 3-kinase/Akt ( PKB ) .	GCSF induced GCSFR dimerization 17 activates downstream signal transduction pathways involving Src kinases such as Lyn, Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Ras and extracellular regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt (PKB).	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	GCSF	GCSF	GCSF	GCSFR	GCSFR	GCSFR	0	1	2	3
Appearance of the proximal mutation with the hyper-responsive truncated receptor expressing clone strongly supports the concept that perturbed G-CSF mediated signaling of G-CSFR plays a seminal role in the leukemic transformation of SCN .	Appearance of the proximal mutation with the hyper-responsive truncated receptor expressing clone strongly supports the concept that perturbed G-CSF mediated signaling of G-CSFR plays a seminal role in the leukemic transformation of SCN.	18	23	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR	G-CSFR	G-CSFR	18	19	22	23
Surprisingly , the protective effects of G-CSF imparted during stem cell mobilization was entirely dependent on direct signalling through the T cell since WT but not G-CSFR -/- donor T cells were modulated by G-CSF , despite the presence of predominantly normal ( WT ) haematopoiesis ( XREF_FIG ) .	Surprisingly, the protective effects of G-CSF imparted during stem cell mobilization was entirely dependent on direct signalling through the T cell since WT but not G-CSFR -/- donor T cells were modulated by G-CSF, despite the presence of predominantly normal (WT) haematopoiesis (XREF_FIG).	14	35	modulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR -/-	G-CSFR -/-	G-CSFR -/-	34	35	26	28
As shown in XREF_FIG , phosphorylation of Akt on serine residues is readily detected at 10 min following G-CSF stimulation in both WT- and K762R and G-CSFR transfectants .	As shown in XREF_FIG, phosphorylation of Akt on serine residues is readily detected at 10 min following G-CSF stimulation in both WT- and K762R and G-CSFR transfectants.	18	27	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR	G-CSFR	G-CSFR	18	19	26	27
G-CSF-R activation by G-CSF not only induces proliferation and differentiation of neutrophils but also mobilizes BM hematopoietic progenitors cells to blood .	G-CSF-R activation by G-CSF not only induces proliferation and differentiation of neutrophils but also mobilizes BM hematopoietic progenitors cells to blood.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSF-R	G-CSF-R	G-CSF-R	3	4	0	1
G-CSF increases G-CSFR , p-STAT3 and TRPV1 expression in neuronal cells .	G-CSF increases G-CSFR, p-STAT3 and TRPV1 expression in neuronal cells.	0	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR	G-CSFR	G-CSFR	0	1	2	3
More simply , to elucidate the signalling pathways in skeletal muscle , overexpression of downstream signalling targets such as Jak1 and Jak2 may augment G-CSF biological activity in skeletal muscle cells in vitro and provide conclusive evidence that G-CSF activated G-CSFR signalling pathways in skeletal muscle .	More simply, to elucidate the signalling pathways in skeletal muscle, overexpression of downstream signalling targets such as Jak1 and Jak2 may augment G-CSF biological activity in skeletal muscle cells in vitro and provide conclusive evidence that G-CSF activated G-CSFR signalling pathways in skeletal muscle.	38	42	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR	G-CSFR	G-CSFR	38	39	40	41
By increasing the stimulation of G-CSFR signalling , G-CSF therapy induces compensatory mechanisms of granulopoiesis in patients with severe congenital neutropenia .	By increasing the stimulation of G-CSFR signalling, G-CSF therapy induces compensatory mechanisms of granulopoiesis in patients with severe congenital neutropenia.	5	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR	G-CSFR	G-CSFR	8	9	5	6
Activation of G-CSFR by G-CSF binding induces trans-phosphorylation of the receptor associated Jak1 and Jak2 proteins , which subsequently stimulate several signal cascades .	Activation of G-CSFR by G-CSF binding induces trans-phosphorylation of the receptor associated Jak1 and Jak2 proteins, which subsequently stimulate several signal cascades.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR	G-CSFR	G-CSFR	4	5	2	3
To test this hypothesis , we first isolated splenic cells from leukemic PML-RARalpha Csf3r wt/wt and PML-RARalpha Csf3r d715 and d715 mice ( no mice were treated with G-CSF at the time these analyses were performed ) and measured the basal level of phosphorylated STAT3 , STAT5 , and Erk1/2 in blasts ( Gr-1+ Kit+ ) by flow cytometry ( XREF_FIG ) .	To test this hypothesis, we first isolated splenic cells from leukemic PML-RARalpha Csf3r wt/wt and PML-RARalpha Csf3r d715 and d715 mice (no mice were treated with G-CSF at the time these analyses were performed) and measured the basal level of phosphorylated STAT3, STAT5, and Erk1/2 in blasts (Gr-1+ Kit+) by flow cytometry (XREF_FIG).	17	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	Csf3r	Csf3r	Csf3r	28	29	17	18
These data suggest that heightened expression of CXCL1 partially compensates for deficient G-CSF signaling in Csf3r -/- hosts .	These data suggest that heightened expression of CXCL1 partially compensates for deficient G-CSF signaling in Csf3r -/- hosts.	12	17	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	Csf3r	Csf3r	Csf3r	12	13	15	16
G-CSF caused the transformants expressing G-CSFR to display a morphological characteristic of mature granulocytes , upregulated CD11b on the cell surface , and improved NBT reduction activity .	G-CSF caused the transformants expressing G-CSFR to display a morphological characteristic of mature granulocytes, upregulated CD11b on the cell surface, and improved NBT reduction activity.	0	23	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR	G-CSFR	G-CSFR	0	1	5	6
This hypothesis was strengthened by the finding that in Lin - BM cells G-CSFR was co-IPed with CEACAM1 when treated with G-CSF , and that under this condition CEACAM1 was phosphorylated on its ITIMs and recruited SHP-1 .	This hypothesis was strengthened by the finding that in Lin - BM cells G-CSFR was co-IPed with CEACAM1 when treated with G-CSF, and that under this condition CEACAM1 was phosphorylated on its ITIMs and recruited SHP-1.	13	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	G-CSF	G-CSF	G-CSF	G-CSFR	G-CSFR	G-CSFR	21	22	13	14
Thus , we conclude that the overexpression of Csk in p210 Bcr-Abl Ba/F3 cells leads to the inhibition of Bcr-Abl and SFK signaling independently of the kinase activity of Csk , and likely depends on its function as an adaptor protein , potentially by recruitment of phosphatases , such as Ptpn18 , to the site of SFK activity ( XREF_FIG ) .	Thus, we conclude that the overexpression of Csk in p210 Bcr-Abl Ba/F3 cells leads to the inhibition of Bcr-Abl and SFK signaling independently of the kinase activity of Csk, and likely depends on its function as an adaptor protein, potentially by recruitment of phosphatases, such as Ptpn18, to the site of SFK activity (XREF_FIG).	6	30	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Csk	overexpression of Csk	csk	Csk	Csk	csk	8	9	29	30
Csk is directly activated by PKA mediated phosphorylation of Csk serine 364 [ XREF_BIBR ] .	Csk is directly activated by PKA mediated phosphorylation of Csk serine 364 [XREF_BIBR].	0	10	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Csk	PKA mediated phosphorylation of Csk	csk	Csk	Csk	csk	9	10	0	1
Importantly , blunting sulindac mediated Csk induction in the Csk shRNA construct resulted in mitigation of the p21 cip and waf1 up-regulation .	Importantly, blunting sulindac mediated Csk induction in the Csk shRNA construct resulted in mitigation of the p21 cip and waf1 up-regulation.	3	11	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Csk	sulindac mediated Csk	csk	Csk	Csk	csk	5	6	9	10
The absence of GM-CSF receptor signaling in Csf2ra -/- mice significantly increased growth of the DppIVA RNAi strain by 12,098-fold , while growth of the wild-type strain was increased by 1166-fold ( XREF_SUPPLEMENTARY ) .	The absence of GM-CSF receptor signaling in Csf2ra -/- mice significantly increased growth of the DppIVA RNAi strain by 12,098-fold, while growth of the wild-type strain was increased by 1166-fold (XREF_SUPPLEMENTARY).	3	8	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GM-CSF	GM-CSF	GM-CSF	Csf2ra	Csf2ra	Csf2ra	3	4	7	8
Furthermore , we found that inhibition of CKIdelta by inhibitors ( XREF_SUPPLEMENTARY ) or shRNA treatment ( XREF_SUPPLEMENTARY ) also attenuated the p53 pulse in response to continuous DNA damage .	Furthermore, we found that inhibition of CKIdelta by inhibitors (XREF_SUPPLEMENTARY) or shRNA treatment (XREF_SUPPLEMENTARY) also attenuated the p53 pulse in response to continuous DNA damage.	5	23	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CKIdelta	CKIdelta	CKIdelta	p53	p53	p53	7	8	22	23
Taken together , they deduced that SDF-1 and CXCR-4 may interact in ligand-receptor style leading to chemotaxis that SDF-1 would direct CXCR-4 positive cancer cells to lymph nodes with high concentration of SDF-1 [ XREF_BIBR ] .	Taken together, they deduced that SDF-1 and CXCR-4 may interact in ligand-receptor style leading to chemotaxis that SDF-1 would direct CXCR-4 positive cancer cells to lymph nodes with high concentration of SDF-1 [XREF_BIBR].	18	24	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR-4	CXCR-4	CXCR-4	18	19	21	22
For example , HMW-HA enhanced cell migration and angiogenesis of hepatocellular carcinoma through accelerating CXCL12 induced CXCR4 activation.42 Binding of HMW-HA to CD44 downregulated tumor suppressor protein PDCD4 , leading to anti-apoptosis and chemotherapy resistance43 and enhanced invasion44 in breast cancer cells .	For example, HMW-HA enhanced cell migration and angiogenesis of hepatocellular carcinoma through accelerating CXCL12 induced CXCR4 activation.42 Binding of HMW-HA to CD44 downregulated tumor suppressor protein PDCD4, leading to anti-apoptosis and chemotherapy resistance43 and enhanced invasion44 in breast cancer cells.	4	18	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	16	17
CXCL12 activated CXCR4 signaling in human CD34 + hematopoietic stem cells or Jurkat T cells requires Rho GTPase activated kinases 1/2 ( ROCK1/2 ) .	CXCL12 activated CXCR4 signaling in human CD34 + hematopoietic stem cells or Jurkat T cells requires Rho GTPase activated kinases 1/2 (ROCK1/2).	0	3	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	2	3
CXCL12 signals through either of two receptors , CXCR4 XREF_BIBR , XREF_BIBR or CXCR7 XREF_BIBR .	CXCL12 signals through either of two receptors, CXCR4 XREF_BIBR, XREF_BIBR or CXCR7 XREF_BIBR.	0	9	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	8	9
The significant increase in neural progenitors during early EAE onset suggests that the endogenous neural repair mechanisms are being activated and built up already with development of the inflammation in CNS , and that the CXCR4 dependent activation by CXCL12 secreted by inflammatory cells may further drive the NPCs and OPCs towards differentiation and maturation and remyelination and neuronal repair [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The significant increase in neural progenitors during early EAE onset suggests that the endogenous neural repair mechanisms are being activated and built up already with development of the inflammation in CNS, and that the CXCR4 dependent activation by CXCL12 secreted by inflammatory cells may further drive the NPCs and OPCs towards differentiation and maturation and remyelination and neuronal repair [XREF_BIBR, XREF_BIBR, XREF_BIBR].	35	40	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	39	40	35	36
We found that MMP-2 cleaves SDF-1alpha , yielding an N-terminally truncated SDF-1 ( 5-67 ) that losses its ability to induce CXCR4 signaling and chemotactic function in human NPCs .	We found that MMP-2 cleaves SDF-1alpha, yielding an N-terminally truncated SDF-1 (5-67) that losses its ability to induce CXCR4 signaling and chemotactic function in human NPCs.	10	22	induce	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	11	12	21	22
CXCL12 activating CXCR4 receptor has been involved in the OPCs maturation and remyelination failure [ XREF_BIBR ] .	CXCL12 activating CXCR4 receptor has been involved in the OPCs maturation and remyelination failure [XREF_BIBR].	0	6	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	2	3
CXCR4 activated by CXCL-12 is rapidly internalized and targeted into the degradative pathway by an ubiquitin dependent mechanism .	CXCR4 activated by CXCL-12 is rapidly internalized and targeted into the degradative pathway by an ubiquitin dependent mechanism.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL-12	CXCL-12	CXCL-12	CXCR4	CXCR4	CXCR4	3	4	0	1
CXCL12 could activate CXCR4 via binding and contribute to the generation of pain behavior [ XREF_BIBR ] .	CXCL12 could activate CXCR4 via binding and contribute to the generation of pain behavior [XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	3	4
Treatment with CCX771 , a specific CXCR7 antagonist , during demyelination and peak CXCR7 expression led to increased levels of CXCL12 , enhanced CXCR4 activation and augmented differentiation of OPCs , resulting in increased numbers of mature oligodendrocytes within the demyelinated CC .	Treatment with CCX771, a specific CXCR7 antagonist, during demyelination and peak CXCR7 expression led to increased levels of CXCL12, enhanced CXCR4 activation and augmented differentiation of OPCs, resulting in increased numbers of mature oligodendrocytes within the demyelinated CC.	6	24	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCR7 antagonist, during demyelination and peak CXCR7 expression led to increased levels of CXCL12	cxcl12	CXCR4	CXCR4	cxcr4	20	21	23	24
We found significant CXCL12 mediated CXCR4 internalization at all concentrations and in all B cell subsets ( not shown ) , and desensitization occurred with similar efficiency in SOCS3 deficient and sufficient B-lineage cell subsets ( XREF_FIG ) .	We found significant CXCL12 mediated CXCR4 internalization at all concentrations and in all B cell subsets (not shown), and desensitization occurred with similar efficiency in SOCS3 deficient and sufficient B-lineage cell subsets (XREF_FIG).	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	5	6
This study provides evidence for a novel role for NPM as a negative regulator of CXCR4 signaling induced by CXCL12 that may be relevant to the biology of AML .	This study provides evidence for a novel role for NPM as a negative regulator of CXCR4 signaling induced by CXCL12 that may be relevant to the biology of AML.	15	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	15	16
Mv-1-Lu-CD4 and CXCR4 cells were treated with SDF-1 for periods up to 1 h.	Mv-1-Lu-CD4 and CXCR4 cells were treated with SDF-1 for periods up to 1 h.	0	9	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	7	8	2	3
The reduced expression of CXCR4 on the cell surface can be justified by the high expression of the CXCL12 protein in the lymph nodes XREF_BIBR as CXCL12 stimulates the internalization and subsequent lysosomal degradation of CXCR4 .	The reduced expression of CXCR4 on the cell surface can be justified by the high expression of the CXCL12 protein in the lymph nodes XREF_BIBR as CXCL12 stimulates the internalization and subsequent lysosomal degradation of CXCR4.	26	36	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	26	27	35	36
CXCR7 regulates CXCL12 and CXCR4 mediated cell motility by scavenging CXCL12 , both during normal processes ( e.g ., development ) and in the diseased state ( e.g ., cancer ) .	CXCR7 regulates CXCL12 and CXCR4 mediated cell motility by scavenging CXCL12, both during normal processes (e.g., development) and in the diseased state (e.g., cancer).	2	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	4	5
Thus , to interfere with disease promoting activities of the MIF and CXCR4 axis , specifically tailored targeting strategies need to be established that block MIF- but not CXCL12 mediated CXCR4 functions .	Thus, to interfere with disease promoting activities of the MIF and CXCR4 axis, specifically tailored targeting strategies need to be established that block MIF- but not CXCL12 mediated CXCR4 functions.	25	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	28	29	30	31
Therefore , it is likely that CXCL12 induced CXCR4 internalization and/or degradation involves multiple lysine dependent mono-ubiquitination or poly-ubiquitination events .	Therefore, it is likely that CXCL12 induced CXCR4 internalization and/or degradation involves multiple lysine dependent mono-ubiquitination or poly-ubiquitination events.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	8	9
Differently , in basophils cultured for 24 hours SDF-1 induced strong migration responses via binding to CXCR4 on the basophil surface .	Differently, in basophils cultured for 24 hours SDF-1 induced strong migration responses via binding to CXCR4 on the basophil surface.	8	17	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	8	9	16	17
As stated previously , CXCR4 signaling activated by its ligand SDF-1 causes chemotaxis and migration of breast cancer cells .	As stated previously, CXCR4 signaling activated by its ligand SDF-1 causes chemotaxis and migration of breast cancer cells.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	10	11	4	5
CXCR4 activation by SDF-1 provides a key retention signal for hematopoietic cells in the bone marrow .	CXCR4 activation by SDF-1 provides a key retention signal for hematopoietic cells in the bone marrow.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	0	1
GPCR kinase-3 ( GRK3 ) , which regulates CXCL12 promoted internalization and desensitization of CXCR4 , was profoundly decreased in at least one CXCR4 mutation negative WHIM patient [ XREF_BIBR ] .	GPCR kinase-3 (GRK3), which regulates CXCL12 promoted internalization and desensitization of CXCR4, was profoundly decreased in at least one CXCR4 mutation negative WHIM patient [XREF_BIBR].	8	15	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	14	15
This result indicates that AMD3100 decreases ESCC proliferation by inhibiting the CXCL12 and CXCR4 signalling pathway artificially enhanced by TE4 CXCL12 .	This result indicates that AMD3100 decreases ESCC proliferation by inhibiting the CXCL12 and CXCR4 signalling pathway artificially enhanced by TE4 CXCL12.	13	21	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	20	21	13	14
SDF-1 treatment induced the endocytosis and trafficking of CXCR4-WT-YFP into the same Rab11+ endosomes ( XREF_FIG , green ) .	SDF-1 treatment induced the endocytosis and trafficking of CXCR4-WT-YFP into the same Rab11+ endosomes (XREF_FIG, green).	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4-WT-YFP	CXCR4-WT-YFP	CXCR4-WT-YFP	0	1	8	9
In addition , the activation of CXCR4 by SDF-1alpha promotes invasion and proliferation of tumor cells , enhances tumor associated neoangiogenesis , and assists in the degradation of the extracellular matrix and basement membrane .	In addition, the activation of CXCR4 by SDF-1alpha promotes invasion and proliferation of tumor cells, enhances tumor associated neoangiogenesis, and assists in the degradation of the extracellular matrix and basement membrane.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1alpha	SDF-1alpha	SDF-1alpha	CXCR4	CXCR4	CXCR4	8	9	6	7
It has been demonstrated that the activation of CXCR4 by CXCL12 promoted the migration and invasion of tumor cells XREF_BIBR .	It has been demonstrated that the activation of CXCR4 by CXCL12 promoted the migration and invasion of tumor cells XREF_BIBR.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	8	9
SDF-1 and CXCL12 , the sole known native ligand for CXCR4 , is expressed in the bone marrow and at other sites and directs CXCR4 expressing stem cells to home to the bone marrow .	SDF-1 and CXCL12, the sole known native ligand for CXCR4, is expressed in the bone marrow and at other sites and directs CXCR4 expressing stem cells to home to the bone marrow.	0	25	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1 and CXCL12, the sole known native ligand for CXCR4, is expressed	sdf-1	CXCR4	CXCR4	cxcr4	0	1	24	25
HMW-HA increased SDF1b induced CXCR4 signaling and cell motility , increased vessel sprouting , and angiogenesis .	HMW-HA increased SDF1b induced CXCR4 signaling and cell motility, increased vessel sprouting, and angiogenesis.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF1b	SDF1b	SDF1b	CXCR4	CXCR4	CXCR4	2	3	4	5
Taken together , CXCL12 derived from peripheral nerves enhanced the invasion and metastasis of the CXCR4 positive PCa cells .	Taken together, CXCL12 derived from peripheral nerves enhanced the invasion and metastasis of the CXCR4 positive PCa cells.	3	18	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	15	16
Both siRNA mediated reduction of CD44 expression and antibodies that block the interaction of CD44 with HA provided evidence that CXCL12 induced CXCR4 signaling depends on the binding of hHA to CD44 .	Both siRNA mediated reduction of CD44 expression and antibodies that block the interaction of CD44 with HA provided evidence that CXCL12 induced CXCR4 signaling depends on the binding of hHA to CD44.	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	20	21	22	23
AMD alone or in combination with DLS also failed to mediate CXCR4 internalization alone or interfere with CXCL12 induced CXCR4 internalization ( data not shown ) .	AMD alone or in combination with DLS also failed to mediate CXCR4 internalization alone or interfere with CXCL12 induced CXCR4 internalization (data not shown).	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	17	18	19	20
Finally , these data provide evidence that although ERK is indeed a downstream target of CXCL12 activation of CXCR4 , this pathway is not necessarily essential for CXCR4 evoked chemotaxis .	Finally, these data provide evidence that although ERK is indeed a downstream target of CXCL12 activation of CXCR4, this pathway is not necessarily essential for CXCR4 evoked chemotaxis.	15	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	18	19
In contrast , the presence of CXCL12 significantly enhanced motility of CXCR4 expressing cells ( NB8x4 and SHSYpMigr cells ) , as previously described XREF_BIBR .	In contrast, the presence of CXCL12 significantly enhanced motility of CXCR4 expressing cells (NB8x4 and SHSYpMigr cells), as previously described XREF_BIBR.	4	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	11	12
CXCR4 , one of 19 known human chemokine receptors , is activated exclusively by the chemokine CXCL12 ( also known as Stromal Cell Derived Factor-1 , SDF-1 ) and couples primarily through G i proteins .	CXCR4, one of 19 known human chemokine receptors, is activated exclusively by the chemokine CXCL12 (also known as Stromal Cell Derived Factor-1, SDF-1) and couples primarily through G i proteins.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	16	17	0	1
As an increase in threonine phosphorylation on ERK also can be initiated by CXCL12 induced CXCR4 activation , it is possible that changes in Thr ( P ) phosphorylation of ERK occurred in response to CXCL12 activation of the 3K/R CXCR4 , which we would not have detected using only an anti-Tyr antibody .	As an increase in threonine phosphorylation on ERK also can be initiated by CXCL12 induced CXCR4 activation, it is possible that changes in Thr (P) phosphorylation of ERK occurred in response to CXCL12 activation of the 3K/R CXCR4, which we would not have detected using only an anti-Tyr antibody.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	13	14	15	16
XREF_FIG ) , demonstrating that it is the result of CXCL12 specific activation of CXCR4 and Nluc .	XREF_FIG), demonstrating that it is the result of CXCL12 specific activation of CXCR4 and Nluc.	10	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	14	15
This CXCL12 induced calcium flux was CXCR4 specific , since CXCL12 did not elicit a calcium flux in U87.CD4 cells ( data not shown ) .	This CXCL12 induced calcium flux was CXCR4 specific, since CXCL12 did not elicit a calcium flux in U87.CD4 cells (data not shown).	0	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	1	2	6	7
Activation of CXCR4 by CXCL12 is involved in many biological functions such as cell migration , growth and survival .	Activation of CXCR4 by CXCL12 is involved in many biological functions such as cell migration, growth and survival.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	2	3
CXCR4 stimulation by CXCL12 activates pertussis toxin ( PTX )-sensitive G proteins which activate at least two distinct signaling pathways .	CXCR4 stimulation by CXCL12 activates pertussis toxin (PTX)-sensitive G proteins which activate at least two distinct signaling pathways.	0	4	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	0	1
This implies that excess CXCL12 and CXCR4 signaling causes the intracellular clustering of CXCR4 .	This implies that excess CXCL12 and CXCR4 signaling causes the intracellular clustering of CXCR4.	3	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	13	14
Our present studies reveal that CXCL12 activation of CXCR4 , a member of the G protein coupled receptor superfamily , results in reversible ubiquitination of the receptor ( XREF_FIG ) .	Our present studies reveal that CXCL12 activation of CXCR4, a member of the G protein coupled receptor superfamily, results in reversible ubiquitination of the receptor (XREF_FIG).	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	8	9
These findings suggest that CXCL12 contributed to tumor related inflammation by inducing the accumulation of CXCR4 expressing cells with regulatory T cell markers around MM .	These findings suggest that CXCL12 contributed to tumor related inflammation by inducing the accumulation of CXCR4 expressing cells with regulatory T cell markers around MM.	4	17	contributed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	15	16
Although the mechanism by which CXCL12 could enhance the behavioral effects of cocaine has not been elucidated , it is possible that CXCL12 is activating CXCR4 receptors on dopaminergic neurons within the ventral tegmental area , stimulating a calcium current within these neurons and thus increasing dopamine release in the terminal regions .	Although the mechanism by which CXCL12 could enhance the behavioral effects of cocaine has not been elucidated, it is possible that CXCL12 is activating CXCR4 receptors on dopaminergic neurons within the ventral tegmental area, stimulating a calcium current within these neurons and thus increasing dopamine release in the terminal regions.	22	45	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	22	23	25	26
As an example , CXCL12 activates CXCR4 both on the surface of immune cells and on hematopoetic and endothelial precursors .	As an example, CXCL12 activates CXCR4 both on the surface of immune cells and on hematopoetic and endothelial precursors.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	6	7
We found that Ulocuplumab ( BMS-936564 ) inhibited CXCL12 mediated CXCR4 activation migration of CLL cells at nanomolar concentrations .	We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation migration of CLL cells at nanomolar concentrations.	8	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	10	11
In contrast , CXCR4 activation by CXCL12 desensitizes signals from both mu and delta receptors .	In contrast, CXCR4 activation by CXCL12 desensitizes signals from both mu and delta receptors.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	3	4
In the present study we observed that i ) CXCR4 is expressed on the surface of endothelial cells in both the glomerular and peritubular compartments , ii ) chronic CXCR4 blockade accelerates capillary loss in rats with CKD and iii ) local SDF-1 delivery induces glomerular eNOS activation in a CXCR4 dependent manner .	In the present study we observed that i) CXCR4 is expressed on the surface of endothelial cells in both the glomerular and peritubular compartments, ii) chronic CXCR4 blockade accelerates capillary loss in rats with CKD and iii) local SDF-1 delivery induces glomerular eNOS activation in a CXCR4 dependent manner.	42	52	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	42	43	50	51
Of interest , N-terminal peptides of CXCL12 were able to trigger responses in CXCR4 expressing cells at > = 10 muM concentrations .	Of interest, N-terminal peptides of CXCL12 were able to trigger responses in CXCR4 expressing cells at> = 10 muM concentrations.	4	15	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	13	14
A previous report demonstrated that CXCL12 activates CXCR4 to induce G protein coupled signaling pathways , such as phosphoinositide 3-kinase ( PI3K )/Akt , Rac1 , Rho , mitogen activated protein kinase ( MAPK ) , and activator protein-1 ( AP-1 ) , which subsequently mediates cellular responses XREF_BIBR - XREF_BIBR .	A previous report demonstrated that CXCL12 activates CXCR4 to induce G protein coupled signaling pathways, such as phosphoinositide 3-kinase (PI3K)/Akt, Rac1, Rho, mitogen activated protein kinase (MAPK), and activator protein-1 (AP-1), which subsequently mediates cellular responses XREF_BIBR - XREF_BIBR.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	7	8
Autocrine CXCL12 secretion from tumor cells may activate CXCR-4 on the tumor cells , which may be related to of the viability of distant metastases .	Autocrine CXCL12 secretion from tumor cells may activate CXCR-4 on the tumor cells, which may be related to of the viability of distant metastases.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR-4	CXCR-4	CXCR-4	1	2	8	9
The CXCL12 induced CXCR4 mediated intracellular signaling enhances tumor growth , cancer cell survival , and metastasis [ XREF_BIBR ] .	The CXCL12 induced CXCR4 mediated intracellular signaling enhances tumor growth, cancer cell survival, and metastasis [XREF_BIBR].	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	1	2	3	4
CXCL12 also causes CXCR4 desensitization and uncoupling from G-proteins by GPCR kinase ( GRK )-dependent phosphorylation and subsequent interaction of CXCR4 with beta-arrestin that mediates internalization of the receptor and targets desensitized CXCR4 to clathrin coated pits for endocytosis .	CXCL12 also causes CXCR4 desensitization and uncoupling from G-proteins by GPCR kinase (GRK)-dependent phosphorylation and subsequent interaction of CXCR4 with beta-arrestin that mediates internalization of the receptor and targets desensitized CXCR4 to clathrin coated pits for endocytosis.	0	30	causes	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	CXCL12	CXCL12	cxcl12	CXCR4	phosphorylation and subsequent interaction of CXCR4	cxcr4	0	1	20	21
Once the CXCR4 receptor is stimulated by SDF-1 , it becomes internalized at which point it is either recycled or degraded .	Once the CXCR4 receptor is stimulated by SDF-1, it becomes internalized at which point it is either recycled or degraded.	2	8	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	7	8	2	3
Activation of CXCR4 by CXCL12 depends on two domains located at the N-terminal of the chemokine .	Activation of CXCR4 by CXCL12 depends on two domains located at the N-terminal of the chemokine.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	2	3
In contrast , the G protein uncoupled mutant BILF1-K ( 3.50 ) A affected CXCL12 induced CXCR4 signaling to a much lesser extent , indicating that BILF1 mediated CXCR4 inhibition is a consequence of its constitutive activity .	In contrast, the G protein uncoupled mutant BILF1-K (3.50) A affected CXCL12 induced CXCR4 signaling to a much lesser extent, indicating that BILF1 mediated CXCR4 inhibition is a consequence of its constitutive activity.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	16	17
CXCR4 in GSLCs isolated from glioma cell lines or primary human tumors is activated by the CXCR4 chemokine agonist CXCL12 to show intracellular calcium mobilization , an indicator of GPCR signaling , and to promote the production of VEGF [ XREF_BIBR , XREF_BIBR ] .	CXCR4 in GSLCs isolated from glioma cell lines or primary human tumors is activated by the CXCR4 chemokine agonist CXCL12 to show intracellular calcium mobilization, an indicator of GPCR signaling, and to promote the production of VEGF [XREF_BIBR, XREF_BIBR].	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	0	1
Moreover , SDF-1 overexpression increased survival and growth of CXCR4 expressing mesenchymal stem cells both in vitro [ XREF_BIBR ] and in vivo [ XREF_BIBR , XREF_BIBR ] .	Moreover, SDF-1 overexpression increased survival and growth of CXCR4 expressing mesenchymal stem cells both in vitro [XREF_BIBR] and in vivo [XREF_BIBR, XREF_BIBR].	2	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1 overexpression	sdf-1	CXCR4	CXCR4	cxcr4	2	3	9	10
CXCL12 induces CXCR4 internalization into the cytosol followed by lysosomal degradation [ XREF_BIBR , XREF_BIBR ] .	CXCL12 induces CXCR4 internalization into the cytosol followed by lysosomal degradation [XREF_BIBR, XREF_BIBR].	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	2	3
In BMC old , SDF-1 also caused significant CXCR4 receptor internalization .	In BMC old, SDF-1 also caused significant CXCR4 receptor internalization.	4	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	8	9
Together , these studies suggest that CXCL12 mediated CXCR4 activation is required for maintenance of NPCs in neurogenic zones of the adult CNS .	Together, these studies suggest that CXCL12 mediated CXCR4 activation is required for maintenance of NPCs in neurogenic zones of the adult CNS.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	8	9
Through its interaction with Gbeta , Tax1 affects SDF-1 dependent activation of the CXCR4 GPCR chemokine receptor .	Through its interaction with Gbeta, Tax1 affects SDF-1 dependent activation of the CXCR4 GPCR chemokine receptor.	8	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	8	9	13	14
SDF-1 treatment induced CXCR4-WT-YFP endocytosis and trafficking into tightly clustered endosomes .	SDF-1 treatment induced CXCR4-WT-YFP endocytosis and trafficking into tightly clustered endosomes.	0	4	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4-WT-YFP	CXCR4-WT-YFP	CXCR4-WT-YFP	0	1	3	4
As a result of this change , SDF-1 more robustly activates the CXCR4 receptor , which promotes chemotactic responses of RMS .	As a result of this change, SDF-1 more robustly activates the CXCR4 receptor, which promotes chemotactic responses of RMS.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	7	8	12	13
In contrast to MDA-MB-231 , MDA-MB-468 are weakly-metastatic TNBC cells with a low CXCR4 : GRK3 expression ratio ( XREF_FIG ) , suggesting that GRK3 may be mitigating migration and invasion through increased desensitization and internalization of CXCL12 activated CXCR4 .	In contrast to MDA-MB-231, MDA-MB-468 are weakly-metastatic TNBC cells with a low CXCR4 : GRK3 expression ratio (XREF_FIG), suggesting that GRK3 may be mitigating migration and invasion through increased desensitization and internalization of CXCL12 activated CXCR4.	33	40	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	37	38	39	40
Moreover , the chemoattractant SDF-1 ligand gradient may promote the migration and adhesion of CXCR4 + circulating cancer cells including cancer stem and progenitor cells to endothelium and stromal ECM components at distant metastatic sites by modulating intracellular signaling pathways mediated by adhesion molecules and ECM and integrins .	Moreover, the chemoattractant SDF-1 ligand gradient may promote the migration and adhesion of CXCR4 + circulating cancer cells including cancer stem and progenitor cells to endothelium and stromal ECM components at distant metastatic sites by modulating intracellular signaling pathways mediated by adhesion molecules and ECM and integrins.	4	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	14	15
Biological Processes and Signaling Triggered by CXCL12 through CXCR4 .	Biological Processes and Signaling Triggered by CXCL12 through CXCR4.	4	9	Triggered	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	8	9
We recently demonstrated that SDF-1 ( also known as CXCL12 ) , which is the sole endogenous ligand for the CXCR4 chemokine receptor , robustly induces apoptotic cell death through the intrinsic pathway in AML cell lines and a significant fraction of patient samples expressing CXCR4 on the cell surface [ XREF_BIBR ] .	We recently demonstrated that SDF-1 (also known as CXCL12), which is the sole endogenous ligand for the CXCR4 chemokine receptor, robustly induces apoptotic cell death through the intrinsic pathway in AML cell lines and a significant fraction of patient samples expressing CXCR4 on the cell surface [XREF_BIBR].	4	46	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	45	46
In this regard , it was recently demonstrated that CXCR7 can aid in the pro migratory , pro metastatic effects of CXCR4 by scavenging CXCL12 rather than ( or in addition to ) allosteric modulation of CXCR4 as suggested in the study by Levoye [ XREF_BIBR ] .	In this regard, it was recently demonstrated that CXCR7 can aid in the pro migratory, pro metastatic effects of CXCR4 by scavenging CXCL12 rather than (or in addition to) allosteric modulation of CXCR4 as suggested in the study by Levoye [XREF_BIBR].	11	34	aid	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	24	25	21	22
Indeed , a prior study showed that CXCL12 promotes the proliferation of CXCR4 positive Ewing sarcoma cells in vitro and the same study also identified a positive correlation between tumor volume and the presence of CXCR4 positive tumor cells in primary human tumors [ XREF_BIBR ] .	Indeed, a prior study showed that CXCL12 promotes the proliferation of CXCR4 positive Ewing sarcoma cells in vitro and the same study also identified a positive correlation between tumor volume and the presence of CXCR4 positive tumor cells in primary human tumors [XREF_BIBR].	7	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	12	13
In addition LSCs behave like normal HSCs and progenitors associating with BM stromal cells and extracellular matrix proteins via cell adhesion molecules [ XREF_BIBR ] , and rely on CXCL12 mediated CXCR4 signaling for homing and mobilization within the BM [ XREF_BIBR , XREF_BIBR ] .	In addition LSCs behave like normal HSCs and progenitors associating with BM stromal cells and extracellular matrix proteins via cell adhesion molecules [XREF_BIBR], and rely on CXCL12 mediated CXCR4 signaling for homing and mobilization within the BM [XREF_BIBR, XREF_BIBR].	27	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	29	30	31	32
We speculate that induction of CCR7 homo-oligomerization is coupled to direct receptor activation , as some chemokine receptors are activated through receptor dimerization upon ligand binding ; for example , CXCL12 induced CXCR4 dimerization activates CXCR4 ' s downstream signaling pathway [ XREF_BIBR ] .	We speculate that induction of CCR7 homo-oligomerization is coupled to direct receptor activation, as some chemokine receptors are activated through receptor dimerization upon ligand binding; for example, CXCL12 induced CXCR4 dimerization activates CXCR4 's downstream signaling pathway [XREF_BIBR].	30	33	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	30	31	32	33
Two splice variants of human CXCL12 ( CXCL12alpha and CXCL12beta ) induce chemotaxis of CXCR4 ( + ) cells and inhibit X4 infection .	Two splice variants of human CXCL12 (CXCL12alpha and CXCL12beta) induce chemotaxis of CXCR4 (+) cells and inhibit X4 infection.	2	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	14	15
To induce signaling in the CXCR4 + TNBC : HMF co-culture spheroids , the spheroids were treated with CXCL12 containing conditioned medium collected from a confluent monolayer of CAFs .	To induce signaling in the CXCR4 + TNBC : HMF co-culture spheroids, the spheroids were treated with CXCL12 containing conditioned medium collected from a confluent monolayer of CAFs.	2	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	18	19	5	6
SDF-1 further induced the occurrence of EMT in CD133 + CXCR4 + cells , with a previous report demonstrating that inhibition of the SDF-1 and CXCR4 axis could impede the invasive behavior of CXCR4 expressing cells in vitro and metastatic cancer formation in vivo [ XREF_BIBR ] .	SDF-1 further induced the occurrence of EMT in CD133 + CXCR4 + cells, with a previous report demonstrating that inhibition of the SDF-1 and CXCR4 axis could impede the invasive behavior of CXCR4 expressing cells in vitro and metastatic cancer formation in vivo [XREF_BIBR].	23	35	impede	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	23	24	33	34
The chemokine CXCL12 activates CXCR4 , initiating multiple pathways that control immune cell trafficking , angiogenesis and embryogenesis ; CXCR4 is also overexpressed in multiple tumors affecting metastatic dissemination .	The chemokine CXCL12 activates CXCR4, initiating multiple pathways that control immune cell trafficking, angiogenesis and embryogenesis; CXCR4 is also overexpressed in multiple tumors affecting metastatic dissemination.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	4	5
These results showed that blocking CXCR4 with AMD3100 decreases the CXCL12 induced survival of CXCR4 + OS cells , and this effect was not concentration dependent .	These results showed that blocking CXCR4 with AMD3100 decreases the CXCL12 induced survival of CXCR4 + OS cells, and this effect was not concentration dependent.	9	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	14	15
Furthermore , in bone tissue , CXCL12 activated CXCR4 signaling promoted by ANGPTL2 accelerated osteolysis and bone engraftment most likely by increasing MMP-13 activity ( XREF_FIG ) .	Furthermore, in bone tissue, CXCL12 activated CXCR4 signaling promoted by ANGPTL2 accelerated osteolysis and bone engraftment most likely by increasing MMP-13 activity (XREF_FIG).	6	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	8	9
Phorbol Esters and SDF-1 Induce Rapid Endocytosis and Down Modulation of the Chemokine Receptor CXCR4 .	Phorbol Esters and SDF-1 Induce Rapid Endocytosis and Down Modulation of the Chemokine Receptor CXCR4.	1	15	Induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	14	15
In relation to this , our data revealed that the CXCL12 mediated activation of CXCR4 counteracted DTX induced microtubule stabilization in PCa cells .	In relation to this, our data revealed that the CXCL12 mediated activation of CXCR4 counteracted DTX induced microtubule stabilization in PCa cells.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	14	15
We showed that Sdf-1 treatment increased the number of CXCR4 + BMCs able to bind the myofiber and occupy the satellite cell niche .	We showed that Sdf-1 treatment increased the number of CXCR4 + BMCs able to bind the myofiber and occupy the satellite cell niche.	3	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sdf-1	Sdf-1	Sdf-1	CXCR4	CXCR4	CXCR4	3	4	9	10
In fact , evidence has been provided that CXCR4 activation by SDF-1alpha ( either as soluble chemokine or as stromal cell bound chemokine ) reduces the sensitivity of AML blasts to various anti-leukemic drugs , whereas an opposite effect is elicited by CXCR4 inhibitors .	In fact, evidence has been provided that CXCR4 activation by SDF-1alpha (either as soluble chemokine or as stromal cell bound chemokine) reduces the sensitivity of AML blasts to various anti-leukemic drugs, whereas an opposite effect is elicited by CXCR4 inhibitors.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	SDF-1alpha	SDF-1alpha	SDF-1alpha	CXCR4	CXCR4	CXCR4	11	12	8	9
As a niche derived chemo attractant for CXCR4 + cells , SDF1 is able to enhance the entry of CXCR4 + cells into the bone marrow [ XREF_BIBR ] .	As a niche derived chemo attractant for CXCR4 + cells, SDF1 is able to enhance the entry of CXCR4 + cells into the bone marrow [XREF_BIBR].	11	27	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	11	12	19	20
CXCL12 activation of its cognate receptor CXCR4 stimulated E-cadherin localization and monolayer tightening through Rho associated protein kinase activation and F-actin reorganization .	CXCL12 activation of its cognate receptor CXCR4 stimulated E-cadherin localization and monolayer tightening through Rho associated protein kinase activation and F-actin reorganization.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	6	7
Hence , we conclude that activation of CXCR4 by SDF-1 up-regulates the Hh pathway through up-regulation of SMO expression .	Hence, we conclude that activation of CXCR4 by SDF-1 up-regulates the Hh pathway through up-regulation of SMO expression.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	9	10	7	8
CXCL12 activates the CXCR4 pathway that is necessary for stem cell survival ; therefore , pathway disruption results in less drug resistance .	CXCL12 activates the CXCR4 pathway that is necessary for stem cell survival; therefore, pathway disruption results in less drug resistance.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	3	4
We analyzed by QPCR expression of CXCL12 and of its cognate receptor CXCR4 in dissected tissue from either the tumor or normal brain of moribund tumor -bearing animals with newly generated tumors induced with either NRAS and LgT or SPN ( XREF_SUPPLEMENTARY ) .	We analyzed by QPCR expression of CXCL12 and of its cognate receptor CXCR4 in dissected tissue from either the tumor or normal brain of moribund tumor -bearing animals with newly generated tumors induced with either NRAS and LgT or SPN (XREF_SUPPLEMENTARY).	4	33	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CXCL12	expression of CXCL12	cxcl12	CXCR4	CXCR4	cxcr4	6	7	12	13
Here , we describe a protocol to detect chemokine receptor CXCR4 by confocal immunofluorescence microscopy in HeLa cells treated with its chemokine ligand CXCL12 .	Here, we describe a protocol to detect chemokine receptor CXCR4 by confocal immunofluorescence microscopy in HeLa cells treated with its chemokine ligand CXCL12.	7	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	23	24	10	11
The implication of rafts in the activation of CXCR4 by CXCL12 has also been shown in the context of prostate cancer XREF_BIBR .	The implication of rafts in the activation of CXCR4 by CXCL12 has also been shown in the context of prostate cancer XREF_BIBR.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	8	9
Basolateral CCL2 was used in all of the transmigration studies including basal migration where CXCL12 was omitted , with the exception of pertussis toxin ( PTX ) pretreatment experiments where basolateral CCL2 was not used to study direct activation of CXCR4 by CXCL12 .	Basolateral CCL2 was used in all of the transmigration studies including basal migration where CXCL12 was omitted, with the exception of pertussis toxin (PTX) pretreatment experiments where basolateral CCL2 was not used to study direct activation of CXCR4 by CXCL12.	36	43	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	42	43	40	41
To further substantiate the notion that binding of hHA to CD44 is required for CXCL12 induced CXCR4 signaling , we used the BU52 antibody that blocks the binding of HA to CD44 .	To further substantiate the notion that binding of hHA to CD44 is required for CXCL12 induced CXCR4 signaling, we used the BU52 antibody that blocks the binding of HA to CD44.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	16	17
These findings suggest that the CXCL12 induced CXCR4 mediated signaling is not the indispensable survival factor or essential inducer of cancer cell growth .	These findings suggest that the CXCL12 induced CXCR4 mediated signaling is not the indispensable survival factor or essential inducer of cancer cell growth.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	7	8
The natural chemokine ligand of CXCR4 is SDF-1alpha ( also known as CXCL12 ) , which activates CXCR4 via G-proteins ( XREF_TABLE ) [ XREF_BIBR - XREF_BIBR ] .	The natural chemokine ligand of CXCR4 is SDF-1alpha (also known as CXCL12), which activates CXCR4 via G-proteins (XREF_TABLE) [XREF_BIBR - XREF_BIBR].	3	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1alpha	SDF-1alpha	SDF-1alpha	CXCR4	CXCR4	CXCR4	7	8	17	18
These findings indicate that when the ubiquitination cycle is perturbed , the ability of CXCL12 stimulation of the CXCR4 to lead to receptor down-regulation also is perturbed , and suggest that ubiquitination of the receptor is perhaps involved in more than simply marking the receptor for degradation .	These findings indicate that when the ubiquitination cycle is perturbed, the ability of CXCL12 stimulation of the CXCR4 to lead to receptor down-regulation also is perturbed, and suggest that ubiquitination of the receptor is perhaps involved in more than simply marking the receptor for degradation.	14	20	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	18	19
Together , endothelial Cxcl12 is important for the recruitment of Wnt5a producing Cxcr4 + ILCs in the stomach .	Together, endothelial Cxcl12 is important for the recruitment of Wnt5a producing Cxcr4 + ILCs in the stomach.	2	17	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cxcl12	Cxcl12	Cxcl12	Cxcr4	Cxcr4	Cxcr4	3	4	12	13
However , pDC activation was not affected by the natural ligand CXCL12 , even at high concentrations , while CXCL12 induces G protein and beta-arrestin activation of CXCR4 and therefore its internalization XREF_BIBR XREF_BIBR .	However, pDC activation was not affected by the natural ligand CXCL12, even at high concentrations, while CXCL12 induces G protein and beta-arrestin activation of CXCR4 and therefore its internalization XREF_BIBR XREF_BIBR.	19	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	27	28
We therefore hypothesized that CXCL12 promotes HSC contraction in a CXCR4 dependent manner .	We therefore hypothesized that CXCL12 promotes HSC contraction in a CXCR4 dependent manner.	4	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	10	11
We observed a substantial increase in the levels of CXCR4 in beta 2 AR immunoprecipitates from cardiac myocyte lysates treated with both ISO and SDF-1 as compared to myocytes treated with either ligand alone ( XREF_FIG ) .	We observed a substantial increase in the levels of CXCR4 in beta 2 AR immunoprecipitates from cardiac myocyte lysates treated with both ISO and SDF-1 as compared to myocytes treated with either ligand alone (XREF_FIG).	7	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	24	25	9	10
Notably , considering the contribution of activation of CXCR4 by CXCL12 to nociceptive pain process [ XREF_BIBR ] , and CXCL2 as a regulating target of miRNA-23a [ XREF_BIBR ] , we intrathecally injected CXCL2 into the mice having pain like behavior induced by the knockdown of LV-miR-23a .	Notably, considering the contribution of activation of CXCR4 by CXCL12 to nociceptive pain process [XREF_BIBR], and CXCL2 as a regulating target of miRNA-23a [XREF_BIBR], we intrathecally injected CXCL2 into the mice having pain like behavior induced by the knockdown of LV-miR-23a.	2	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	8	9
These data show that SDF-1 , immobilized on activated human endothelium , induces polarization of CXCR4 to the leading edge of migrating cells , revealing co-operativity between chemokine and substrate in the control of cell migration .	These data show that SDF-1, immobilized on activated human endothelium, induces polarization of CXCR4 to the leading edge of migrating cells, revealing co-operativity between chemokine and substrate in the control of cell migration.	4	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	15	16
We analyzed primary myoblasts , WJ-MSCs , or ESCs which were treated with Sdf-1 alone or transfected with siRNA complementary to mRNAs encoding either Cxcr4 or Cxcr7 and treated with Sdf-1 , along with control , i.e. untreated cells .	We analyzed primary myoblasts, WJ-MSCs, or ESCs which were treated with Sdf-1 alone or transfected with siRNA complementary to mRNAs encoding either Cxcr4 or Cxcr7 and treated with Sdf-1, along with control, i.e. untreated cells.	22	31	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Sdf-1	Sdf-1	Sdf-1	Cxcr4	Cxcr4	Cxcr4	30	31	24	25
Similarly , CXCL12 and CXCR4 chemokine receptor axis provides resistance against anti-estrogen therapy in CXCR4 driven tumors when treated with exogenous CXCL12 .	Similarly, CXCL12 and CXCR4 chemokine receptor axis provides resistance against anti-estrogen therapy in CXCR4 driven tumors when treated with exogenous CXCL12.	12	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	21	22	14	15
Under abnormal tensile force , SDF-1 can upregulate its specific receptor CXCR4 , thus increasing its binding efficiency and resulting in the activation of the SDF-1 and CXCR4 axis .	Under abnormal tensile force, SDF-1 can upregulate its specific receptor CXCR4, thus increasing its binding efficiency and resulting in the activation of the SDF-1 and CXCR4 axis.	5	12	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	11	12
Cells stably expressing Myc-CXCR4 were treated with CXCL12 for varying times before immunoisolation of Myc-CXCR4 ; the extent of ubiquitination of the receptor at these various time points was assessed using an anti-ubiquitin antibody .	Cells stably expressing Myc-CXCR4 were treated with CXCL12 for varying times before immunoisolation of Myc-CXCR4; the extent of ubiquitination of the receptor at these various time points was assessed using an anti-ubiquitin antibody.	2	8	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	Myc-CXCR4	Myc-CXCR4	Myc-CXCR4	7	8	3	4
Concordantly , our results also showed the viability of serum starved CXCR4 + LM8 cells in the presence of CXCL12 for 7 days to increase by 87 % compared with the control groups , whereas this CXCL12 induced increased proliferation effect was not observed in CXCR4 - Dunn cells ( XREF_FIG ) .	Concordantly, our results also showed the viability of serum starved CXCR4 + LM8 cells in the presence of CXCL12 for 7 days to increase by 87% compared with the control groups, whereas this CXCL12 induced increased proliferation effect was not observed in CXCR4 - Dunn cells (XREF_FIG).	35	50	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	36	37	45	46
Further , the percentage of SDF-1 , that can activate CXCR4 , drive osteogenesis , and maintain the BMSC population , as part of the total pool of circulating SDF-1 may decline with age relative to partially N-terminal degraded SDF-1 that is inactive or may have altered bioactivity [ XREF_BIBR , XREF_BIBR ] .	Further, the percentage of SDF-1, that can activate CXCR4, drive osteogenesis, and maintain the BMSC population, as part of the total pool of circulating SDF-1 may decline with age relative to partially N-terminal degraded SDF-1 that is inactive or may have altered bioactivity [XREF_BIBR, XREF_BIBR].	3	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	10	11
The activation of CXCR4 by SDF-1 prior to ISO blocks beta 2 AR from entering the active , conformational state ( XREF_FIG ) indicating the ability of CXCR4 to affect the structural dynamics of the beta 2 -Adrenergic receptor .	The activation of CXCR4 by SDF-1 prior to ISO blocks beta 2 AR from entering the active, conformational state (XREF_FIG) indicating the ability of CXCR4 to affect the structural dynamics of the beta 2 -Adrenergic receptor.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	3	4
Although activation of CXCR4 by CXCL12 ( SDF-1 ) promotes OPC differentiation under demyelinating conditions , the functional significance of these changes after SCI is unknown .	Although activation of CXCR4 by CXCL12 (SDF-1) promotes OPC differentiation under demyelinating conditions, the functional significance of these changes after SCI is unknown.	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	3	4
In order to determine whether SDF-1 induced HA-CXCR4 downregulation is dependent on the ESCRT-I complex , cells were depleted of the critical ESCRT-I component , TSG101 .	In order to determine whether SDF-1 induced HA-CXCR4 downregulation is dependent on the ESCRT-I complex, cells were depleted of the critical ESCRT-I component, TSG101.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	HA-CXCR4	HA-CXCR4	HA-CXCR4	5	6	7	8
After different concentrations of CXCL12 ( 0 , 1 , 10 and 100ng/ml ) were used to stimulate the CXCR4 siRNA transfected , untransfected and control siRNA , and HT-29 for 15min , the effects of CXCL12 on phosphorylation of member proteins in MAPK/PI3K/AP -1 signaling pathway were detected by Western blot .	After different concentrations of CXCL12 (0, 1, 10 and 100ng/ml) were used to stimulate the CXCR4 siRNA transfected, untransfected and control siRNA, and HT-29 for 15min, the effects of CXCL12 on phosphorylation of member proteins in MAPK/PI3K/AP -1 signaling pathway were detected by Western blot.	2	20	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	19	20
Since we demonstrated that PDGFR activation is required for CXCL12 mediated CXCR4 signaling , we questioned whether PDGFR signaling functions to suppress specific GRK expression and/or activity that would normally act to inhibit CXCR4 .	Since we demonstrated that PDGFR activation is required for CXCL12 mediated CXCR4 signaling, we questioned whether PDGFR signaling functions to suppress specific GRK expression and/or activity that would normally act to inhibit CXCR4.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	11	12
SDF-1 induced rapid down modulation of CXCR4 on these cells with a very similar time course to that seen in T cells .	SDF-1 induced rapid down modulation of CXCR4 on these cells with a very similar time course to that seen in T cells.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	6	7
In vitro , SDF-1 induced CXCR4 positive colorectal cancer cell invasion and EMT by activation of the Wnt and beta-catenin signaling pathway .	In vitro, SDF-1 induced CXCR4 positive colorectal cancer cell invasion and EMT by activation of the Wnt and beta-catenin signaling pathway.	1	10	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	5	6
Aside from the shift in response kinetics , both cell types have a similar CXCL12 induced CXCR4 response profile .	Aside from the shift in response kinetics, both cell types have a similar CXCL12 induced CXCR4 response profile.	11	18	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	16	17
The transient availability of wild-type CXCL12 in the blood will allow efficient CXCR4 recycling ; indeed , it has been reported that this process can be 75 % complete within 2 h XREF_BIBR .	The transient availability of wild-type CXCL12 in the blood will allow efficient CXCR4 recycling; indeed, it has been reported that this process can be 75% complete within 2 h XREF_BIBR.	2	13	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	12	13
SDF-1 activates C-X-C chemokine receptor type 4 ( CXCR4 ) to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	SDF-1 activates C-X-C chemokine receptor type 4 (CXCR4) to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	C-X-C chemokine receptor type 4	C-X-C chemokine receptor type 4	C-X-C chemokine receptor type 4	0	1	2	7
CXCL12 , produced by meningeal cells , enhances the tangential migration of CXCR4 expressing Cajal-Retzius cells and restricts their trajectories to the superficial-most side of the MZ XREF_BIBR XREF_BIBR .	CXCL12, produced by meningeal cells, enhances the tangential migration of CXCR4 expressing Cajal-Retzius cells and restricts their trajectories to the superficial-most side of the MZ XREF_BIBR XREF_BIBR.	0	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	12	13
Inhibition of the SDF-1 and CXCR4 axis partially blocks the homing of CXCR4 expressing cells to the site of injury [ XREF_BIBR , XREF_BIBR ] .	Inhibition of the SDF-1 and CXCR4 axis partially blocks the homing of CXCR4 expressing cells to the site of injury [XREF_BIBR, XREF_BIBR].	3	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	12	13
SDF-1 treatment caused rapid down-modulation of CXCR4 in SH-SY5Y cells .	SDF-1 treatment caused rapid down-modulation of CXCR4 in SH-SY5Y cells.	0	7	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	6	7
In dopaminergic neurons of the rat substantia nigra , CXCR4 stimulation by CXCL12 induces an increase of release of presynaptic neurotransmitter , particularly of GABA .	In dopaminergic neurons of the rat substantia nigra, CXCR4 stimulation by CXCL12 induces an increase of release of presynaptic neurotransmitter, particularly of GABA.	9	13	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	9	10
Thus , accumulation of intracellular HA-CXCR4 did not result in altered SDF-1 induced CXCR4 signaling in Gag expressing cells .	Thus, accumulation of intracellular HA-CXCR4 did not result in altered SDF-1 induced CXCR4 signaling in Gag expressing cells.	8	14	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	11	12	13	14
Although increasing concentrations of SDF-1 enhance CXCR4 internalization , kinase activation is prolonged .	Although increasing concentrations of SDF-1 enhance CXCR4 internalization, kinase activation is prolonged.	2	7	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	6	7
In contrast , in a zebrafish model of WHIM syndrome , we recently demonstrated that SDF1 activation of CXCR4WHIM mediates neutrophil retention in the CHT , suggesting that SDF1 activation of CXCR4 can also restrict neutrophil motility .	In contrast, in a zebrafish model of WHIM syndrome, we recently demonstrated that SDF1 activation of CXCR4WHIM mediates neutrophil retention in the CHT, suggesting that SDF1 activation of CXCR4 can also restrict neutrophil motility.	28	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	28	29	31	32
CXCR4 activation by CXCL12 induces migration and/or survival of neuronal and glial tumors , neuroblastoma cells , colorectal cancer , head and neck , brain , bladder , esophagealcancer , melanoma , renal cell cancer , ovarian cancer , and rhabdomyosarcoma ( RMS ) [ XREF_BIBR ] .	CXCR4 activation by CXCL12 induces migration and/or survival of neuronal and glial tumors, neuroblastoma cells, colorectal cancer, head and neck, brain, bladder, esophagealcancer, melanoma, renal cell cancer, ovarian cancer, and rhabdomyosarcoma (RMS) [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	0	1
[ XREF_BIBR - XREF_BIBR ] SDF1 induced CXCR-4 ( seven-transmembrane domain G protein coupled receptor ) activation leads to beta-integrin expression and the binding of vascular cell adhesion molecule ( VCAM ) -1 to endothelial cells .	[XREF_BIBR - XREF_BIBR] SDF1 induced CXCR-4 (seven-transmembrane domain G protein coupled receptor) activation leads to beta-integrin expression and the binding of vascular cell adhesion molecule (VCAM) -1 to endothelial cells.	3	17	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR-4	CXCR-4	CXCR-4	5	6	7	8
CXCR4 stimulation by its ligand SDF-1 reduced MFE of the normal breast cells lines but increased the MFE in T47D and patient derived breast cancer cells .	CXCR4 stimulation by its ligand SDF-1 reduced MFE of the normal breast cells lines but increased the MFE in T47D and patient derived breast cancer cells.	0	6	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	0	1
MUC1 and Muc1 was expressed only at low levels in uninflamed cells and lungs ; however , MUC1 and Muc1 expression was upregulated by CXCL12 induced CXCR4 activation .	MUC1 and Muc1 was expressed only at low levels in uninflamed cells and lungs; however, MUC1 and Muc1 expression was upregulated by CXCL12 induced CXCR4 activation.	22	27	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	24	25	26	27
High , not low , levels of CXCL12 activate CXCR4 on microglia , initiating TNF-alpha release , which causes astrocytes to release glutamate ( excitotoxicity ) .	High, not low, levels of CXCL12 activate CXCR4 on microglia, initiating TNF-alpha release, which causes astrocytes to release glutamate (excitotoxicity).	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	levels of CXCL12	cxcl12	CXCR4	CXCR4	cxcr4	7	8	9	10
Because in the immune system and other organs , the dynamics of CXCR4 induced by CXCL12 signaling is involved in the function of CXCR4 XREF_BIBR , XREF_BIBR - XREF_BIBR , it is probable that the phosphorylation and internalization of CXCR4 in GCPs correlate with the differentiationand migration of GCPs .	Because in the immune system and other organs, the dynamics of CXCR4 induced by CXCL12 signaling is involved in the function of CXCR4 XREF_BIBR, XREF_BIBR - XREF_BIBR, it is probable that the phosphorylation and internalization of CXCR4 in GCPs correlate with the differentiationand migration of GCPs.	10	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	12	13
However , it has been debated whether this is indeed due to CXCL12 induced mobilization , or rather to a reduced CXCL12 and CXCR4 mediated retention of these cells in the bone marrow caused by CXCL12 induced downregulation of CXCR4 on their cell surface .	However, it has been debated whether this is indeed due to CXCL12 induced mobilization, or rather to a reduced CXCL12 and CXCR4 mediated retention of these cells in the bone marrow caused by CXCL12 induced downregulation of CXCR4 on their cell surface.	12	25	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	23	24
CXCL12 can cause CXCR4 ( + ) Treg cells to migrate into the pregnant uterus and establish a beneficial microenvironment for the fetus .	CXCL12 can cause CXCR4 (+) Treg cells to migrate into the pregnant uterus and establish a beneficial microenvironment for the fetus.	0	8	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	3	4
We examined whether CXCL12 mediates coupling of CXCR4 to Galpha i.	We examined whether CXCL12 mediates coupling of CXCR4 to Galpha i.	3	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	7	8
Dopaminergic neurons of the substantia nigra constitutively express the CXCR4 receptor for the chemokine stromal-cell-derived factor 1alpha ( CXCL12 ) but , to date , no direct effect of CXCR4 activation by CXCL12 on membrane conductance of dopaminergic neurons has been demonstrated .	Dopaminergic neurons of the substantia nigra constitutively express the CXCR4 receptor for the chemokine stromal-cell-derived factor 1alpha (CXCL12) but, to date, no direct effect of CXCR4 activation by CXCL12 on membrane conductance of dopaminergic neurons has been demonstrated.	29	35	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	32	33	29	30
We found that CF172 dose-dependently inhibited the SDF1 mediated signaling of human CXCR4 .	We found that CF172 dose-dependently inhibited the SDF1 mediated signaling of human CXCR4.	6	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	7	8	12	13
In order to examine the effects of Gag expression on endogenous CXCR4 , we monitored the kinetics of SDF-1 induced downregulation of CXCR4 in Jurkat T cells .	In order to examine the effects of Gag expression on endogenous CXCR4, we monitored the kinetics of SDF-1 induced downregulation of CXCR4 in Jurkat T cells.	16	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	18	19	22	23
In PC-3 cells , CXCR4 surface levels are relatively low , unless the cells are treated with the CXCL12 ligand , which also clearly increases the invasive properties of these cells [ XREF_BIBR - XREF_BIBR ] .	In PC-3 cells, CXCR4 surface levels are relatively low, unless the cells are treated with the CXCL12 ligand, which also clearly increases the invasive properties of these cells [XREF_BIBR - XREF_BIBR].	4	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	18	19	4	5
DPDPE , a ligand of DOR , induces DOR homodimers ; CXCL12 and SDF-1 , a ligand of CXCR4 , triggers the formation of CXCR4 homodimers ; and DPDPE and SDF-1 together promote assembly of heterodimeric CXCR4 : DOR complexes .	DPDPE, a ligand of DOR, induces DOR homodimers; CXCL12/SDF-1, a ligand of CXCR4, triggers the formation of CXCR4 homodimers; and DPDPE and SDF-1 together promote assembly of heterodimeric CXCR4 : DOR complexes.	28	37	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	30	31	36	37
The contribution of moesin to receptor internalization may differ according to receptor type , since CXCL12 induced CXCR4 internalization in moesin deficient cells did not differ significantly from that in WT cells ( XREF_SUPPLEMENTARY ) .	The contribution of moesin to receptor internalization may differ according to receptor type, since CXCL12 induced CXCR4 internalization in moesin deficient cells did not differ significantly from that in WT cells (XREF_SUPPLEMENTARY).	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	17	18
In general , CXCL12 mediated activation of CXCR4 on HSCs is an indispensable signal for retention of HSCs in bone marrow .	In general, CXCL12 mediated activation of CXCR4 on HSCs is an indispensable signal for retention of HSCs in bone marrow.	3	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	7	8
SDF1 mediated activation of CXCR4 is known to regulate chemotaxis of diverse cell types including primordial germ cells during development , leukocytes in inflammatory responses and the invasive movement of cancer cells in tumor metastasis .	SDF1 mediated activation of CXCR4 is known to regulate chemotaxis of diverse cell types including primordial germ cells during development, leukocytes in inflammatory responses and the invasive movement of cancer cells in tumor metastasis.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	0	1	4	5
In the developing nephron , SDF-1 producing podocytes and CXCR4 expressing endothelial cells appear to be aligned adjacent to each other .	In the developing nephron, SDF-1 producing podocytes and CXCR4 expressing endothelial cells appear to be aligned adjacent to each other.	5	16	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	9	10
We investigated whether binding of the ligand CXCL12 could activate CXCR4 signalling and whether these responses were be modulated by ECM binding .	We investigated whether binding of the ligand CXCL12 could activate CXCR4 signalling and whether these responses were be modulated by ECM binding.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	10	11
In fact , CXCL12 mediated activation of CXCR4 promotes the release of the alpha-subunit of heterotrimeric inhibitory G protein ( G i ) , thereby inhibiting adenylate cyclase activity .	In fact, CXCL12 mediated activation of CXCR4 promotes the release of the alpha-subunit of heterotrimeric inhibitory G protein (G i), thereby inhibiting adenylate cyclase activity.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	7	8
However , CXCL12 induced CXCR4 degradation was significantly reduced in cells from Wwp1 -/- mice ( XREF_FIG , lower panels ) .	However, CXCL12 induced CXCR4 degradation was significantly reduced in cells from Wwp1 -/- mice (XREF_FIG, lower panels).	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	4	5
Here , we show that the cross communication between human tumor cells and zebrafish ligands is maintained , because zebrafish Cxcl12 activates human CXCR4 signaling in vitro and supports the formation of TNBC early metastases in vivo .	Here, we show that the cross communication between human tumor cells and zebrafish ligands is maintained, because zebrafish Cxcl12 activates human CXCR4 signaling in vitro and supports the formation of TNBC early metastases in vivo.	19	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cxcl12	Cxcl12	Cxcl12	CXCR4	CXCR4	CXCR4	20	21	23	24
Moreover , SDF1 mediated CXCR4 activation induces resistance to chemotherapy drug Cytarabine , by downregulating microRNA let-7a and promoting transcriptional activation of Myc and BCL2 like 1 isoform 1 ( BCL-xL ) in acute myeloid leukemia ( AML ) cells [ XREF_BIBR ] .	Moreover, SDF1 mediated CXCR4 activation induces resistance to chemotherapy drug Cytarabine, by downregulating microRNA let-7a and promoting transcriptional activation of Myc and BCL2 like 1 isoform 1 (BCL-xL) in acute myeloid leukemia (AML) cells [XREF_BIBR].	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	2	3	4	5
In addition , CXCL12 causes activation of the PI3K pathway and promotes proliferation of CXCR4 + prostate CSCs [ XREF_BIBR ] .	In addition, CXCL12 causes activation of the PI3K pathway and promotes proliferation of CXCR4 + prostate CSCs [XREF_BIBR].	3	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	14	15
The finding that programmed neuronal death after global ischemia was not associated with SDF-1 upregulation or recruitment of CXCR4 expressing cells is in sharp contrast to SDF-1 and CXCR4 mediated infiltration of infarct tissue after focal ischemia .	The finding that programmed neuronal death after global ischemia was not associated with SDF-1 upregulation or recruitment of CXCR4 expressing cells is in sharp contrast to SDF-1 and CXCR4-mediated infiltration of infarct tissue after focal ischemia.	13	20	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	13	14	18	19
CXCR4 internalisation is induced by the CXCR4 ligand stromal cell derived factor-1 ( SDF-1 ) , phorbol esters and , in T cells , cellular activation .	CXCR4 internalisation is induced by the CXCR4 ligand stromal cell derived factor-1 (SDF-1), phorbol esters and, in T cells, cellular activation.	0	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	stromal cell derived factor-1	stromal cell derived factor-1	stromal cell derived factor-1	CXCR4	CXCR4	CXCR4	8	12	0	1
CXCL12 activates CXCR4 in an autocrine loop .	CXCL12 activates CXCR4 in an autocrine loop.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	2	3
Our present results are consistent with the previous results that the inhibition of the CXCL12 induced CXCR4 mediated signaling suppressed the growth of both primary and metastatic tumors [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Our present results are consistent with the previous results that the inhibition of the CXCL12 induced CXCR4 mediated signaling suppressed the growth of both primary and metastatic tumors [XREF_BIBR, XREF_BIBR, XREF_BIBR].	11	18	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	16	17
It has also been shown that a number of NSCLC cell lines express high levels of CXCR4 , which is associated with aggressive behavior , and that CXCL12 activated CXCR4 promotes migration and invasion of these cell lines in vitro XREF_BIBR .	It has also been shown that a number of NSCLC cell lines express high levels of CXCR4, which is associated with aggressive behavior, and that CXCL12 activated CXCR4 promotes migration and invasion of these cell lines in vitro XREF_BIBR.	27	30	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	27	28	29	30
Mesenchymal stromal cells ( MSCs ) are known to support the growth and differentiation of normal hematopoietic stem cells ( HSCs ) [ XREF_BIBR - XREF_BIBR ] through various molecular signals such as CXCL12 mediated CXCR4 signaling and Wnt induced beta-catenin signaling .	Mesenchymal stromal cells (MSCs) are known to support the growth and differentiation of normal hematopoietic stem cells (HSCs) [XREF_BIBR - XREF_BIBR] through various molecular signals such as CXCL12 mediated CXCR4 signaling and Wnt induced beta-catenin signaling.	30	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	33	34	35	36
This form of SDF-1 is unable to trigger CXCR4 signalling and prevent the chemoattractant function of SDF-1alpha and CXCR4 in human progenitor cells 15 .	This form of SDF-1 is unable to trigger CXCR4 signalling and prevent the chemoattractant function of SDF-1alpha and CXCR4 in human progenitor cells 15.	1	19	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	18	19
The CXCR4 ligand ( CXCL12 ) stimulates CXCR4 promoting cell survival and proliferation , and may contribute to the tropism of leukemia cells towards lymphoid tissues .	The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues.	2	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	7	8
CXCR4 localization at the plasma membrane and intracellular vesicle ( cytoplasm ) were observed in leukocyte cell lines with enforced CXCR4 expression and CXCL12 induced polarization of CXCR4 to the edge of migrating leukocyte cells [ XREF_BIBR ] .	CXCR4 localization at the plasma membrane and intracellular vesicle (cytoplasm) were observed in leukocyte cell lines with enforced CXCR4 expression and CXCL12 induced polarization of CXCR4 to the edge of migrating leukocyte cells [XREF_BIBR].	23	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	23	24	27	28
Pretreatment with AMD3100 , rescued the CXCL12 induced impairments , indicating that CXCL12 produced the effects by activating CXCR4 receptors .	Pretreatment with AMD3100, rescued the CXCL12 induced impairments, indicating that CXCL12 produced the effects by activating CXCR4 receptors.	12	19	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	18	19
The signaling mediated by the chemokine SDF-1 ( also called CXCL12 ) and its cognate receptor CXCR4 has a central role in BM homing and is also required for the quiescence and retention of hematopoietic stem cells in the BM [ XREF_BIBR ] .	The signaling mediated by the chemokine SDF-1 (also called CXCL12) and its cognate receptor CXCR4 has a central role in BM homing and is also required for the quiescence and retention of hematopoietic stem cells in the BM [XREF_BIBR].	1	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	6	7	16	17
We founded that CXCR4 was mainly present on the somata of DRG neurons , suggesting that CXCL12 might activate the CXCR4 on the DRG neuronal somata .	We founded that CXCR4 was mainly present on the somata of DRG neurons, suggesting that CXCL12 might activate the CXCR4 on the DRG neuronal somata.	16	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	16	17	20	21
CXCL12 stimulation had no impact on Caco-2 cells but significantly increased migration of CXCR4 bearing SW480 and HT-29 cells .	CXCL12 stimulation had no impact on Caco-2 cells but significantly increased migration of CXCR4 bearing SW480 and HT-29 cells.	0	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	13	14
In experiments not shown , we established that KG1a expressed similar levels of WT and WHIM CXCR4 , and that WHIM CXCR4 expressing KG1a displayed a delay in SDF1 induced CXCR4 internalization .	In experiments not shown, we established that KG1a expressed similar levels of WT and WHIM CXCR4, and that WHIM CXCR4 expressing KG1a displayed a delay in SDF1 induced CXCR4 internalization.	26	31	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	28	29	30	31
CXCR4 receptor is activated by the ligand CXCL12 that regulates T cell access and recruits immunosuppressive population to tumoral microenvironment including interleukin-10-producing plasmacytoid dendritic cells , Tregs and MDSCs .	CXCR4 receptor is activated by the ligand CXCL12 that regulates T cell access and recruits immunosuppressive population to tumoral microenvironment including interleukin-10-producing plasmacytoid dendritic cells, Tregs and MDSCs.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	0	1
It has been shown that a number of NSCLC cell lines express high levels of CXCR4 , which is associated with aggressive behavior , and that CXCL12 activated CXCR4 promotes migration and invasion of these cell lines in vitro .	It has been shown that a number of NSCLC cell lines express high levels of CXCR4, which is associated with aggressive behavior, and that CXCL12 activated CXCR4 promotes migration and invasion of these cell lines in vitro.	26	29	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	26	27	28	29
10 In this manuscript , CXCL12 activates CXCR4 and CXCR7 signaling through p38 and ERK1/2 MAPK .	10 In this manuscript, CXCL12 activates CXCR4 and CXCR7 signaling through p38 and ERK1/2 MAPK.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	7	8
However , it has also been reported that CXCL12 secreted by CXCL12-abundant reticular ( CAR ) cells that contact HSCs in the bone marrow niche is able to enhance HSC quiescence by stimulating CXCR4 signaling .	However, it has also been reported that CXCL12 secreted by CXCL12-abundant reticular (CAR) cells that contact HSCs in the bone marrow niche is able to enhance HSC quiescence by stimulating CXCR4 signaling.	8	34	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	33	34
The increase in intracellular CXCR4 induced by expression of HIV-1 Gag did not result in a change in SDF-1 mediated CXCR4 signaling , as judged by MAP kinase activation ( Fig XREF_FIG ) .	The increase in intracellular CXCR4 induced by expression of HIV-1 Gag did not result in a change in SDF-1 mediated CXCR4 signaling, as judged by MAP kinase activation (Fig XREF_FIG).	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	18	19	20	21
The chemokine receptor CXCR4 is activated by its unique chemokine ligand CXCL12 and regulates many physiological and developmental processes such as hematopoietic cell trafficking .	The chemokine receptor CXCR4 is activated by its unique chemokine ligand CXCL12 and regulates many physiological and developmental processes such as hematopoietic cell trafficking.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	3	4
WWP1 knockdown markedly decreased CXCL12 induced CXCR4 degradation and lysosomal trafficking .	WWP1 knockdown markedly decreased CXCL12 induced CXCR4 degradation and lysosomal trafficking.	4	7	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	6	7
CXCL12 derived from the peripheral nerves stimulated the invasion and chemotactic migration of CXCR4 positive cancer cells in a paracrine manner , eventually leading to PNI .	CXCL12 derived from the peripheral nerves stimulated the invasion and chemotactic migration of CXCR4 positive cancer cells in a paracrine manner, eventually leading to PNI.	0	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	13	14
43 In this scenario , CD44 would promote CXCL12 induced CXCR4 signaling by tethering hHA complexed with CXCL12 in the close vicinity of CXCR4 , thereby fostering the interaction between CXCR4 and its ligand .	43 In this scenario, CD44 would promote CXCL12 induced CXCR4 signaling by tethering hHA complexed with CXCL12 in the close vicinity of CXCR4, thereby fostering the interaction between CXCR4 and its ligand.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	10	11
We show that SDF-1 , the sole ligand for CXCR4 , induces the expected migration and ERK activation in the KG1a AML cell line transiently overexpressing CXCR4 , but ERK activation did not lead to survival .	We show that SDF-1, the sole ligand for CXCR4, induces the expected migration and ERK activation in the KG1a AML cell line transiently overexpressing CXCR4, but ERK activation did not lead to survival.	3	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	26	27
The rational for this is increased CXCL12 levels induce both cytoplasmic and nuclear CXCR4 internalization .	The rational for this is increased CXCL12 levels induce both cytoplasmic and nuclear CXCR4 internalization.	6	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12 levels	cxcl12	CXCR4	CXCR4	cxcr4	6	7	13	14
We were curious whether CXCL12 activation of CXCR4 might lead to redistribution of USP14 to CXCR4 containing membrane compartments , consistent with the ligand- and time dependent association of USP14 with CXCR4 noted in XREF_FIG .	We were curious whether CXCL12 activation of CXCR4 might lead to redistribution of USP14 to CXCR4 containing membrane compartments, consistent with the ligand- and time dependent association of USP14 with CXCR4 noted in XREF_FIG.	4	16	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	15	16
However , some other ligands XREF_BIBR , XREF_BIBR such as MIF XREF_BIBR can bind and activate CXCR4 , while CXCL12 activates not only CXCR4 but also CXCR7 .	However, some other ligands XREF_BIBR, XREF_BIBR such as MIF XREF_BIBR can bind and activate CXCR4, while CXCL12 activates not only CXCR4 but also CXCR7.	19	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	23	24
These results showed that CXCL12 and CXCR4 axis mediated proliferative responses were both CXCR4- and AR dependent , whereas androgen/AR axis mediated proliferative responses were solely AR dependent .	These results showed that CXCL12 and CXCR4 axis mediated proliferative responses were both CXCR4- and AR dependent, whereas androgen/AR axis mediated proliferative responses were solely AR dependent.	4	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4-	CXCR4-	CXCR4-	4	5	13	14
CXCL12 induced CXCR4 signaling is also involved in the recruitment of EPCs to sites of arterial injury , where they participate in regenerative re-endothelialization , 42 a step where CD44 and hHA may be relevant .	CXCL12 induced CXCR4 signaling is also involved in the recruitment of EPCs to sites of arterial injury, where they participate in regenerative re-endothelialization, 42 a step where CD44 and hHA may be relevant.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	2	3
Stimulation of CXCR4 by CXCL12 is known to activate heterotrimeric G-proteins resulting in the dissociation of the Galpha and Gbetagamma subunits , which then activate downstream effectors .	Stimulation of CXCR4 by CXCL12 is known to activate heterotrimeric G-proteins resulting in the dissociation of the Galpha and Gbetagamma subunits, which then activate downstream effectors.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	2	3
Although both treatments caused dramatic negative effects on the tumor invasion and EMT induced by activation of CXCR4 by SDF-1 , Gli-1 siRNA could not interrupt the SDF-1-mediated increase in SMO ; in contrast , blocking SMO function by cyclopamine suppressed the expression of the transcription factor Gli-1 .	Although both treatments caused dramatic negative effects on the tumor invasion and EMT induced by activation of CXCR4 by SDF-1, Gli-1 siRNA could not interrupt the SDF-1-mediated increase in SMO; in contrast, blocking SMO function by cyclopamine suppressed the expression of the transcription factor Gli-1.	13	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	19	20	17	18
Studies have also demonstrated that the activation of CXCR4 by CXCL12 stimulates a specific and significant proliferative response in GSCs , but not in differentiated tumor cells [ XREF_BIBR ] .	Studies have also demonstrated that the activation of CXCR4 by CXCL12 stimulates a specific and significant proliferative response in GSCs, but not in differentiated tumor cells [XREF_BIBR].	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	8	9
In conclusion , our study suggests that CXCL12 stimulates MUC1 and Muc1 production in airway epithelial cells , mainly through the activation of CXCR4 .	In conclusion, our study suggests that CXCL12 stimulates MUC1 and Muc1 production in airway epithelial cells, mainly through the activation of CXCR4.	7	24	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	23	24
Elevated plasma SDF-1 levels stimulates CXCR4 + BMDC mobilization .	Elevated plasma SDF-1 levels stimulates CXCR4 + BMDC mobilization.	2	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1 levels	sdf-1	CXCR4	CXCR4	cxcr4	2	3	5	6
For example , the MIF receptors CXCR4 and CXCR7 form a complex , thus modulating CXCL12 mediated CXCR4 dependent chemotaxis .	For example, the MIF receptors CXCR4 and CXCR7 form a complex, thus modulating CXCL12 mediated CXCR4 dependent chemotaxis.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	17	18
Further research has emphasized the key role of CXCR4 in tumor cell malignancy ; the activation of CXCR4 by CXCL12 has been shown to induce the migration , invasion and angiogenesis of tumor cells XREF_BIBR , XREF_BIBR .	Further research has emphasized the key role of CXCR4 in tumor cell malignancy; the activation of CXCR4 by CXCL12 has been shown to induce the migration, invasion and angiogenesis of tumor cells XREF_BIBR, XREF_BIBR.	15	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	17	18
Furthermore , B cells from IgD deficient mice show defects in CXCL12 mediated CXCR4 signaling and B-cell migration , whereas B cells from IgM deficient mice are normal in this respect .	Furthermore, B cells from IgD deficient mice show defects in CXCL12 mediated CXCR4 signaling and B-cell migration, whereas B cells from IgM deficient mice are normal in this respect.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	13	14
CXCR4 is activated by the exclusive binding of its ligand CXCL12 .	CXCR4 is activated by the exclusive binding of its ligand CXCL12.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	0	1
CXCR4 is considered to be the major chemokine receptor expressed on cancer cells and its expression is required for tumor metastasis to other organs ; CXCR4 activation by CXCL12 induces the migration of neoplastic cells .	CXCR4 is considered to be the major chemokine receptor expressed on cancer cells and its expression is required for tumor metastasis to other organs; CXCR4 activation by CXCL12 induces the migration of neoplastic cells.	25	29	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	28	29	25	26
These findings suggest that the CXCL12 and CXCR4 axis contributes to inflammation in UIP and f-NSIP by promoting the accumulation CXCR4 ( + ) lymphocytes , and a decrease of Treg is correlated with the severity of fibrosis in UIP .	These findings suggest that the CXCL12 and CXCR4 axis contributes to inflammation in UIP and f-NSIP by promoting the accumulation CXCR4 (+) lymphocytes, and a decrease of Treg is correlated with the severity of fibrosis in UIP.	5	32	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	20	21
Activation of CXCR4 by CXCL12 induces migration , angiogenesis , and/or survival of the neoplastic cells , including tumor cells from neuroblastoma cells , colorectal cancer , prostate cancer , melanoma , ovarian cancer , and PaCa .	Activation of CXCR4 by CXCL12 induces migration, angiogenesis, and/or survival of the neoplastic cells, including tumor cells from neuroblastoma cells, colorectal cancer, prostate cancer, melanoma, ovarian cancer, and PaCa.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	2	3
We previously demonstrated that SDF-1 induces CXCR4 to complex with the TCR in order to prolong ERK activation , and we showed that these events lead to gene expression and cytokine production in activated T cells .	We previously demonstrated that SDF-1 induces CXCR4 to complex with the TCR in order to prolong ERK activation, and we showed that these events lead to gene expression and cytokine production in activated T cells.	4	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	6	7
SDF-1 promoted CXCR4 high expression cells adhesion to the stroma cells ( MSC ) and induced these cells migration .	SDF-1 promoted CXCR4 high expression cells adhesion to the stroma cells (MSC) and induced these cells migration.	0	15	promoted	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	2	3
Accordingly , a very low expression of CXCL12 in MDA-MB-231-B argued against the generation of a potential autocrine loop to activate the receptor CXCR4 .	Accordingly, a very low expression of CXCL12 in MDA-MB-231-B argued against the generation of a potential autocrine loop to activate the receptor CXCR4.	5	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	expression of CXCL12	cxcl12	CXCR4	CXCR4	cxcr4	7	8	23	24
DAMGO did not affect CXCL12 induced internalization of CXCR4 .	DAMGO did not affect CXCL12 induced internalization of CXCR4.	3	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	8	9
A known example is the requirement for HS during the activation of CXCR4 by CXCL12 and SDF-1alpha [ XREF_BIBR ] .	A known example is the requirement for HS during the activation of CXCR4 by CXCL12 and SDF-1alpha [XREF_BIBR].	10	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	12	13
US27 increases CXCL12 induced CXCR4 internalization .	US27 increases CXCL12 induced CXCR4 internalization.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	4	5
In SCLC , SDF-1alpha activates CXCR4 and tumor associated integrin .	In SCLC, SDF-1alpha activates CXCR4 and tumor associated integrin.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1alpha	SDF-1alpha	SDF-1alpha	CXCR4	CXCR4	CXCR4	3	4	5	6
The opposing effects of CXCR4 and ACKR3 activation by CXCL12 could be dissected pharmacologically .	The opposing effects of CXCR4 and ACKR3 activation by CXCL12 could be dissected pharmacologically.	4	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	4	5
Several in vitro studies have demonstrated that CXCR4 activation by SDF-1 induces neuronal survival through Akt phosphorylation and FOXO3a activation .	Several in vitro studies have demonstrated that CXCR4 activation by SDF-1 induces neuronal survival through Akt phosphorylation and FOXO3a activation.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	10	11	7	8
Second , SDF1 activated CXCR4 upregulates integrin alpha 5 beta 1 expression and enhances prostate tumor cell adhesion , invasion and metastasis .	Second, SDF1 activated CXCR4 upregulates integrin alpha 5 beta 1 expression and enhances prostate tumor cell adhesion, invasion and metastasis.	2	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	2	3	4	5
It has been shown that CXCR4 is expressed by endothelial cells and stimulation of CXCR4 by CXCL12 has a proangiogenic effect XREF_BIBR .	It has been shown that CXCR4 is expressed by endothelial cells and stimulation of CXCR4 by CXCL12 has a proangiogenic effect XREF_BIBR.	12	17	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	16	17	14	15
Furthermore , we asked a question whether activation of CXCR4 by CXCL12 will result in changes of TWIST2 levels , or not .	Furthermore, we asked a question whether activation of CXCR4 by CXCL12 will result in changes of TWIST2 levels, or not.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	9	10
It is worth noting there was one cell line , NGP , in which some SDF-1 was detected via ELISA , however the maximum concentration detected ( 184 pg/ml ) was more than an order of magnitude below the minimum concentration of exogenous SDF-1 ( 10 ng/ml ) used to mediate CXCR4 down-regulation in neuroblastoma cells [ XREF_BIBR ] .	It is worth noting there was one cell line, NGP, in which some SDF-1 was detected via ELISA, however the maximum concentration detected (184 pg/ml) was more than an order of magnitude below the minimum concentration of exogenous SDF-1 (10 ng/ml) used to mediate CXCR4 down-regulation in neuroblastoma cells [XREF_BIBR].	40	52	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	43	44	51	52
Stromal CXCL12 expression might promote the survival of CXCR4 expressing cells in the circulation and cell migration into extravascular tissues , so called homing or self seeding , which belongs to major drivers of tumor progression XREF_BIBR , XREF_BIBR , XREF_BIBR .	Stromal CXCL12 expression might promote the survival of CXCR4 expressing cells in the circulation and cell migration into extravascular tissues, so called homing or self seeding, which belongs to major drivers of tumor progression XREF_BIBR, XREF_BIBR, XREF_BIBR.	1	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12 expression	cxcl12	CXCR4	CXCR4	cxcr4	1	2	8	9
This suggests that activation of CXCR4 induced by CXCL12 occurs either by cell-cell interactions with non leukemia CXCL12 expressing cells , likely located in lymphatic tissues , or mediated by soluble CXCL12 .	This suggests that activation of CXCR4 induced by CXCL12 occurs either by cell-cell interactions with non leukemia CXCL12 expressing cells, likely located in lymphatic tissues, or mediated by soluble CXCL12.	3	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	5	6
CXCL12 is produced by the BM microenvironment , binds and activates its cognate receptor CXCR4 on leukemic cells , facilitates leukemia cell trafficking and homing in the BM microenvironment , and keeps leukemic cells in close contact with the stromal cells and extracellular matrix that constitutively generate growth promoting and anti-apoptotic signals .	CXCL12 is produced by the BM microenvironment, binds and activates its cognate receptor CXCR4 on leukemic cells, facilitates leukemia cell trafficking and homing in the BM microenvironment, and keeps leukemic cells in close contact with the stromal cells and extracellular matrix that constitutively generate growth promoting and anti-apoptotic signals.	0	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	14	15
If CXCL12 enhances presynaptic GABA release by activating CXCR4 receptors on GABA terminals , CXCL12 should enhance mIPSC frequency .	If CXCL12 enhances presynaptic GABA release by activating CXCR4 receptors on GABA terminals, CXCL12 should enhance mIPSC frequency.	1	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	1	2	8	9
We found that SDF-1 dose-dependently induced chemotaxis of CD11b + CXCR4 + splenocytes , with a minimal effective concentration of 100 ng/ml ( XREF_FIG ) .	We found that SDF-1 dose-dependently induced chemotaxis of CD11b + CXCR4 + splenocytes, with a minimal effective concentration of 100 ng/ml (XREF_FIG).	3	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	10	11
Activation of CXCR4 by SDF1 stimulates a number of pathways involved in motility , chemotaxis , adhesion and secretion , via activation of a number of signaling cascades including : adhesion , PI-3K-AKT , MEK-MAPK p42/44 , and JAK and STAT .	Activation of CXCR4 by SDF1 stimulates a number of pathways involved in motility, chemotaxis, adhesion and secretion, via activation of a number of signaling cascades including : adhesion, PI-3K-AKT, MEK-MAPK p42/44, and JAK and STAT.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	4	5	2	3
These data indicate that the effects of HA on CXCL12 induced CXCR4 signaling are mediated by CD44 .	These data indicate that the effects of HA on CXCL12 induced CXCR4 signaling are mediated by CD44.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	11	12
Furthermore , insights into the mechanism for CXCR4 activation by CXCL12 were gained .	Furthermore, insights into the mechanism for CXCR4 activation by CXCL12 were gained.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	7	8
However , CXCL12 also induces the migration of CXCR4 - Dunn cells .	However, CXCL12 also induces the migration of CXCR4 - Dunn cells.	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	8	9
CXCL12 could promote the proliferation , migration and invasion of SKOV3 and CXCR4 cells in a dose dependent fashion ( P < 0.05 ) .	CXCL12 could promote the proliferation, migration and invasion of SKOV3 and CXCR4 cells in a dose dependent fashion (P < 0.05).	0	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	12	13
Stromal cells present in the tumor microenvironment express high levels of CXCL12 protein , directly stimulating proliferation and migration of CXCR4 expressing cancer cells .	Stromal cells present in the tumor microenvironment express high levels of CXCL12 protein, directly stimulating proliferation and migration of CXCR4 expressing cancer cells.	11	21	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	20	21
Alternatively , CXCL12 has been shown to stimulate a CXCR4 mediated increase in intracellular calcium via N-type calcium currents .	Alternatively, CXCL12 has been shown to stimulate a CXCR4 mediated increase in intracellular calcium via N-type calcium currents.	2	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	9	10
SDF-1 also modulates adhesion of CXCR4 positive cancer cells to endothelial cells , to fibrinogen and to fibronectin by activating specific integrins and other cell surface molecules including VCAM-1 , ICAM-1 on endothelial cells .	SDF-1 also modulates adhesion of CXCR4 positive cancer cells to endothelial cells, to fibrinogen and to fibronectin by activating specific integrins and other cell surface molecules including VCAM-1, ICAM-1 on endothelial cells.	0	8	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	5	6
In contrast , NCI-H82 showed a strong constitutive association of JAK2 to CXCR4 that could not be further increased by CXCL12 stimulation .	In contrast, NCI-H82 showed a strong constitutive association of JAK2 to CXCR4 that could not be further increased by CXCL12 stimulation.	4	21	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	20	21	12	13
[ XREF_BIBR - XREF_BIBR ] Activation of CXCR4 by CXCL12 also governs migration , homing , and retention of HSCs and leukemic blasts within the bone marrow .	[XREF_BIBR - XREF_BIBR] Activation of CXCR4 by CXCL12 also governs migration, homing, and retention of HSCs and leukemic blasts within the bone marrow.	5	10	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	7	8
Using both isolated primary islets and immortalized cell lines , researchers have discovered that beta cell injury induces SDF-1 expression , which subsequently activates its receptor CXCR4 that is expressed on alpha cells .	Using both isolated primary islets and immortalized cell lines, researchers have discovered that beta cell injury induces SDF-1 expression, which subsequently activates its receptor CXCR4 that is expressed on alpha cells.	18	30	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	SDF-1	SDF-1 expression	sdf-1	CXCR4	CXCR4 that is expressed	cxcr4	18	19	26	27
Four unrelated compounds bind the selected site , and one , 3-( naphthalene-2-carbonylthio carbamoylamino ) benzoic acid , inhibits CXCL12 activation of its receptor CXCR4 at micromolar concentrations .	Four unrelated compounds bind the selected site, and one, 3-(naphthalene-2-carbonylthio carbamoylamino) benzoic acid, inhibits CXCL12 activation of its receptor CXCR4 at micromolar concentrations.	19	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	24	25
The results show that osteoblasts derived SDF-1 activates CXCR4 receptor and results in the activation of extracellular signal regulated kinase ( ERK )/IkappaB kinase alphabeta ( IKKalphabeta ) and nuclear factor-kappa B ( NF-kappaB ) , leading to upregulation of IL-6 expression and promoting osteoclastogenesis .	The results show that osteoblasts derived SDF-1 activates CXCR4 receptor and results in the activation of extracellular signal regulated kinase (ERK)/IkappaB kinase alphabeta (IKKalphabeta) and nuclear factor-kappa B (NF-kappaB), leading to upregulation of IL-6 expression and promoting osteoclastogenesis.	5	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	6	7	8	9
Thus , the binding of CD44 to HA is necessary for CXCL12 induced CXCR4 signaling .	Thus, the binding of CD44 to HA is necessary for CXCL12 induced CXCR4 signaling.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	13	14
However , unlike other chemokines that interact with multiple G protein coupled receptors , CXCL12 mediates its effects via its only known receptor , chemokine ( C-X-C motif ) receptor 4 ( CXCR4 ) .	However, unlike other chemokines that interact with multiple G protein coupled receptors, CXCL12 mediates its effects via its only known receptor, chemokine (C-X-C motif) receptor 4 (CXCR4).	14	33	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	32	33
We recently demonstrated that wounded ATII cells secreted the chemokine CXCL12 which promoted cell migration and wound closure through binding to its receptor CXCR4 23 .	We recently demonstrated that wounded ATII cells secreted the chemokine CXCL12 which promoted cell migration and wound closure through binding to its receptor CXCR4 23.	7	24	promoted	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	23	24
CXCL12 stimulation had no impact on Caco-2 cells but significantly increased migration of CXCR4 bearing SW480 and HT-29 cells ( CXCR4 expression being less pronounced in HT-29 cells ) , and this effect was significantly abrogated by neutralizing anti-CXCR4 antibody as well as by CXCR4 siRNAs .	CXCL12 stimulation had no impact on Caco-2 cells but significantly increased migration of CXCR4 bearing SW480 and HT-29 cells (CXCR4 expression being less pronounced in HT-29 cells), and this effect was significantly abrogated by neutralizing anti-CXCR4 antibody as well as by CXCR4 siRNAs.	0	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	13	14
The mTOR-antagonist , RAD001 , impaired the CXCL12 dependent induction of CXCR4 downstream effectors .	The mTOR-antagonist, RAD001, impaired the CXCL12 dependent induction of CXCR4 downstream effectors.	7	13	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	11	12
Specifically , the autocrine activation of CXCR4 by CXCL12 triggers intracellular PI3K and beta-catenin signals to promote G1 to S phase transition in MPNST cells .	Specifically, the autocrine activation of CXCR4 by CXCL12 triggers intracellular PI3K and beta-catenin signals to promote G1 to S phase transition in MPNST cells.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	6	7
In those studies , fluorescence resonance energy transfer data showed that the HMGB1- CXCL12 heterocomplex promotes different conformational rearrangements of CXCR4 from that of CXCL12 alone and is responsible for mononuclear cell migration .	In those studies, fluorescence resonance energy transfer data showed that the HMGB1- CXCL12 heterocomplex promotes different conformational rearrangements of CXCR4 from that of CXCL12 alone and is responsible for mononuclear cell migration.	13	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	13	14	20	21
Recent data show that CXCR4 activation by either gp120 or CXCL12 significantly enhanced giant depolarizing potentials ( GDP ) in rat neonatal hippocampus [ XREF_BIBR ] .	Recent data show that CXCR4 activation by either gp120 or CXCL12 significantly enhanced giant depolarizing potentials (GDP) in rat neonatal hippocampus [XREF_BIBR].	4	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	4	5
With regard to phosphorylation of ERK , CXCL12 was able to induce activity in both CXCR4 WT - and CXCR4 R334X -transfected K562 and CHO cells with very similar kinetics , whereas untransfected cells were unresponsive ( data not shown ) .	With regard to phosphorylation of ERK, CXCL12 was able to induce activity in both CXCR4 WT - and CXCR4 R334X -transfected K562 and CHO cells with very similar kinetics, whereas untransfected cells were unresponsive (data not shown).	7	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	15	16
Additionally , the CXCR4 ligand SDF-1 down regulated CXCR4 on blood leukocytes in vitro through enhanced internalization 24 and , as such , displacement of SDF-1 with MEDI3185 could result in upregulation of CXCR4 .	Additionally, the CXCR4 ligand SDF-1 down regulated CXCR4 on blood leukocytes in vitro through enhanced internalization 24 and, as such, displacement of SDF-1 with MEDI3185 could result in upregulation of CXCR4.	2	34	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	33	34
CXCL12 derived from CAFs in tumor microenvironment stimulates CXCL12 and CXCR4 signaling in AEG cells and promotes their invasive ability , resulting in tumor progression .	CXCL12 derived from CAFs in tumor microenvironment stimulates CXCL12 and CXCR4 signaling in AEG cells and promotes their invasive ability, resulting in tumor progression.	0	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	10	11
It was shown in colon carcinoma cell lines and intestinal epithelial cell lines that CXCL12 activation of CXCR4 stimulates the restitution of wounded epithelium and migration of epithelial cells in human T84 colonic epithelial cells .	It was shown in colon carcinoma cell lines and intestinal epithelial cell lines that CXCL12 activation of CXCR4 stimulates the restitution of wounded epithelium and migration of epithelial cells in human T84 colonic epithelial cells.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	17	18
To investigate the mechanism for enhanced CXCL12 induced CXCR4 signaling by HCMV US27 , we hypothesized that US27 might affect the dynamics of CXCR4 receptor internalization .	To investigate the mechanism for enhanced CXCL12 induced CXCR4 signaling by HCMV US27, we hypothesized that US27 might affect the dynamics of CXCR4 receptor internalization.	3	9	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	8	9
Together , the results in XREF_FIG & XREF_FIG and additional controls described here indicate that SDF-1 stimulation causes CXCR4 and the TCR to move into close , physical proximity in both the Jurkat T cell line and normal human T cells .	Together, the results in XREF_FIG & XREF_FIG and additional controls described here indicate that SDF-1 stimulation causes CXCR4 and the TCR to move into close, physical proximity in both the Jurkat T cell line and normal human T cells.	15	23	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	15	16	18	19
The transwell invasion assay was performed to examine whether SDF-1 treatment could also enhance the invasive properties of the CD133 + CXCR4 + subpopulation rather than CD133 + CXCR4 - cells .	The transwell invasion assay was performed to examine whether SDF-1 treatment could also enhance the invasive properties of the CD133 + CXCR4 + subpopulation rather than CD133 + CXCR4 - cells.	9	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	9	10	21	22
Activation of CXCR4 by SDF-1 has been implicated in the homeostasis and activation of the immune system and influences a range of biological systems under both normal and pathological conditions XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Activation of CXCR4 by SDF-1 has been implicated in the homeostasis and activation of the immune system and influences a range of biological systems under both normal and pathological conditions XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	2	3
Gassmann and colleagues for instance , demonstrated that colon cell line extravasation into the liver parenchyma is regulated in vivo by CXCL12 activated CXCR4 [ XREF_BIBR ] .	Gassmann and colleagues for instance, demonstrated that colon cell line extravasation into the liver parenchyma is regulated in vivo by CXCL12 activated CXCR4 [XREF_BIBR].	17	24	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	21	22	23	24
We also determined the influence of exendin-4 on the expression of the chemokine receptor for SDF-1 CXCR-4 ; the expression of CXCR4 was not affected by exendin-4 in NB cells whereas in SK-N-AS cells SDF-1 induced an increase of CXCR4 mRNA ( XREF_FIG ) .	We also determined the influence of exendin-4 on the expression of the chemokine receptor for SDF-1 CXCR-4; the expression of CXCR4 was not affected by exendin-4 in NB cells whereas in SK-N-AS cells SDF-1 induced an increase of CXCR4 mRNA (XREF_FIG).	34	40	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	34	35	39	40
The effect was unique for SDF-1 stimulation of CXCR4 .	The effect was unique for SDF-1 stimulation of CXCR4.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	8	9
CXCL12 promoted CXCR4 internalization was then analyzed qualitatively by immunocytochemistry ( XREF_FIG ) and quantitatively by radioligand labeling ( XREF_FIG ) .	CXCL12 promoted CXCR4 internalization was then analyzed qualitatively by immunocytochemistry (XREF_FIG) and quantitatively by radioligand labeling (XREF_FIG).	0	3	promoted	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	2	3
In the case of neuroinflammation , for example , dramatic upregulation of SDF-1 levels may produce excessive stimulation of CXCR4 and desensitization of receptor signaling , resulting in downregulated CXCR4 signaling and consequent ectopic dispersion of newly born neurons in the DG as has been observed in a number of other situations .	In the case of neuroinflammation, for example, dramatic upregulation of SDF-1 levels may produce excessive stimulation of CXCR4 and desensitization of receptor signaling, resulting in downregulated CXCR4 signaling and consequent ectopic dispersion of newly born neurons in the DG as has been observed in a number of other situations.	12	24	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1 levels	sdf-1	CXCR4	CXCR4	cxcr4	12	13	19	20
Indeed , CXCL12 treated cells had comparable level of total biotinylated receptors measured with permeabilized samples at 37 degrees ( XREF_FIG ) , indicating the effect of CXCL12 induced CXCR4 endocytosis .	Indeed, CXCL12 treated cells had comparable level of total biotinylated receptors measured with permeabilized samples at 37 degrees (XREF_FIG), indicating the effect of CXCL12 induced CXCR4 endocytosis.	2	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	29	30
In the dorsal raphe nucleus , CXCR4 stimulation by CXCL12 stimulates spontaneous inhibitory post-synaptic potential ( sIPSC ) frequency , by a pre-synaptic mechanism on 5HT-neurons , but it acts on sIPSC amplitude by a post-synaptic mechanism in non 5HT neurons .	In the dorsal raphe nucleus, CXCR4 stimulation by CXCL12 stimulates spontaneous inhibitory post-synaptic potential (sIPSC) frequency, by a pre-synaptic mechanism on 5HT-neurons, but it acts on sIPSC amplitude by a post-synaptic mechanism in non 5HT neurons.	6	10	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	6	7
T140 analogs inhibited in dose dependent manners the migration of a CXCR4 positive human breast carcinoma cell line MDA-MB-231 induced by CXCL12 .	T140 analogs inhibited in dose dependent manners the migration of a CXCR4 positive human breast carcinoma cell line MDA-MB-231 induced by CXCL12.	8	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	21	22	11	12
CXCL12 mediated myofibroblast phenoconversion requires activation of CXCR4 .	CXCL12 mediated myofibroblast phenoconversion requires activation of CXCR4.	0	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	7	8
However , the rate and extent of CXCR4 modulation by CXCL12 was different in the subline cells , consistent with a differential stabilisation of CXCR4 on 5T4 positive cells ( XREF_FIG ) .	However, the rate and extent of CXCR4 modulation by CXCL12 was different in the subline cells, consistent with a differential stabilisation of CXCR4 on 5T4 positive cells (XREF_FIG).	7	11	modulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	7	8
Via its cognate receptor CXCR4 , CXCL12 promotes migration and invasion of human CCA cells in vitro through MEK1/2 and Akt pathway activation .	Via its cognate receptor CXCR4, CXCL12 promotes migration and invasion of human CCA cells in vitro through MEK1/2 and Akt pathway activation.	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	4	5
Histone deacetylase blockade with TSA in HGF treated MDA-MB231 cells partly relieved the inhibition of CXCL12 mediated chemoinvasion also by affecting CXCR4 .	Histone deacetylase blockade with TSA in HGF treated MDA-MB231 cells partly relieved the inhibition of CXCL12 mediated chemoinvasion also by affecting CXCR4.	13	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	21	22
Given that tonic activation of CXCR4 by SDF1 leads to internalization of both chemokine and receptor , it is entirely possible that the constitutive release of neuronal SDF1 and subsequent neuronal signaling via CXCR4 may result in diminished evidence of CXCR4-IR in the sensory ganglia of morphine treated rats ( XREF_FIG ) .	Given that tonic activation of CXCR4 by SDF1 leads to internalization of both chemokine and receptor, it is entirely possible that the constitutive release of neuronal SDF1 and subsequent neuronal signaling via CXCR4 may result in diminished evidence of CXCR4-IR in the sensory ganglia of morphine treated rats (XREF_FIG).	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	7	8	5	6
AMD3100 did not fully prevent the proliferation of the TE4 and TE4 CXCL12+ cell lines in our study , suggesting that CXCL12 may promote the proliferation of ESCC through other pathways in addition to CXCR4 .	AMD3100 did not fully prevent the proliferation of the TE4 and TE4 CXCL12+ cell lines in our study, suggesting that CXCL12 may promote the proliferation of ESCC through other pathways in addition to CXCR4.	21	35	promote	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	21	22	34	35
Interestingly , PKD involvement in BCR mediated CXCR4 and CXCR5 downregulation observed in our CLL samples appears to be different from the CXCL12 and CXCR4 signaling pathway , which leads to CXCR4 , but not CXCR5 and CD62L downregulation in the mouse model of TCL-1 CLL like disease [ XREF_BIBR ] .	Interestingly, PKD involvement in BCR mediated CXCR4 and CXCR5 downregulation observed in our CLL samples appears to be different from the CXCL12 and CXCR4 signaling pathway, which leads to CXCR4, but not CXCR5 and CD62L downregulation in the mouse model of TCL-1 CLL like disease [XREF_BIBR].	19	32	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	22	23	31	32
Thus , CXCL12 ligand induced activation of CXCR4 on malignant cancer cell lines and peripheral blood mononuclear cells triggered down-regulation of MHC class I from the cell surface .	Thus, CXCL12 ligand induced activation of CXCR4 on malignant cancer cell lines and peripheral blood mononuclear cells triggered down-regulation of MHC class I from the cell surface.	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	7	8
GBM cells , organized around neuron and blood vessels in subpial regions and in white matter express high levels of CXCR4 : VEGF dependent CXCL12 up-regulation in neuronal and endothelial cells induces the migration of CXCR4 positive GBM cells , representing the molecular mechanisms of Scherer ' s structure formation .	GBM cells, organized around neuron and blood vessels in subpial regions and in white matter express high levels of CXCR4 : VEGF dependent CXCL12 up-regulation in neuronal and endothelial cells induces the migration of CXCR4 positive GBM cells, representing the molecular mechanisms of Scherer 's structure formation.	24	38	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	24	25	35	36
The second study showed that migration of natural IFN producing cells , a subpopulation of murine and human lymphocytes , to the CXCR3 agonists requires stimulation of CXCR4 by CXCL12 .	The second study showed that migration of natural IFN producing cells, a subpopulation of murine and human lymphocytes, to the CXCR3 agonists requires stimulation of CXCR4 by CXCL12.	24	30	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	29	30	27	28
Thus while autocrine SDF-1 may trigger some ligand dependent CXCR4 internalization , this is not the principal mechanism responsible for intracellular localization of CXCR4 in fMSC .	Thus while autocrine SDF-1 may trigger some ligand dependent CXCR4 internalization, this is not the principal mechanism responsible for intracellular localization of CXCR4 in fMSC.	2	10	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	9	10
Activation of CXCR4 by CXCL12 leads to G-protein-coupled signaling through extracellular signal regulated kinases ( ERK1/2 ) , Akt effectors , and mitogen activated protein kinase ( MAPK ) pathways , promoting cell survival , proliferation , and chemotaxis [ XREF_BIBR ] .	Activation of CXCR4 by CXCL12 leads to G-protein-coupled signaling through extracellular signal regulated kinases (ERK1/2), Akt effectors, and mitogen activated protein kinase (MAPK) pathways, promoting cell survival, proliferation, and chemotaxis [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	2	3
The activation of CXCR4 by SDF-1 prior to ISO treatment reduced the levels of phosphorylated PLB ser16 compared to myocytes treated with ISO only .	The activation of CXCR4 by SDF-1 prior to ISO treatment reduced the levels of phosphorylated PLB ser16 compared to myocytes treated with ISO only.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	3	4
Moreover , following E2-treatment , the increased secretion of CXCL12 may modulate the internalization of both CXCR4 and CXCR7 ; and consequently may influence the expression of the chemokine receptors at the cell surface XREF_BIBR .	Moreover, following E2-treatment, the increased secretion of CXCL12 may modulate the internalization of both CXCR4 and CXCR7; and consequently may influence the expression of the chemokine receptors at the cell surface XREF_BIBR.	7	18	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	16	17
The functional activity of Ulocuplumab ( BMS-936564 ) was studied in CLL samples that underwent CXCR4 activation mediated by CXCL12 .	The functional activity of Ulocuplumab (BMS-936564) was studied in CLL samples that underwent CXCR4 activation mediated by CXCL12.	15	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	15	16
CXCL12 can activate its receptor CXCR4 to promote VEGF production in glioma cells 68 .	CXCL12 can activate its receptor CXCR4 to promote VEGF production in glioma cells 68.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	5	6
It has previously been shown that recombinant human SDF-1 can activate CXCR4 signalling on DT40 cells XREF_BIBR .	It has previously been shown that recombinant human SDF-1 can activate CXCR4 signalling on DT40 cells XREF_BIBR.	6	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	8	9	11	12
More importantly , an increase in CXCL12 mediated motility was not observed in CXCR4 knockdown cells despite an increase in CXCR7 protein .	More importantly, an increase in CXCL12 mediated motility was not observed in CXCR4 knockdown cells despite an increase in CXCR7 protein.	4	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	13	14
Furthermore , CXCL12 induced activation of CXCR4 causes phosphorylation of specific residues ( i.e. Ser339 and human , Ser338 and rat ) implicated in CXCR4 regulation .	Furthermore, CXCL12 induced activation of CXCR4 causes phosphorylation of specific residues (i.e. Ser339 and human, Ser338 and rat) implicated in CXCR4 regulation.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	6	7
Activation of CXCR4 by CXCL12 is involved in many biological functions such as cell migration , growth , and survival [ XREF_BIBR ] .	Activation of CXCR4 by CXCL12 is involved in many biological functions such as cell migration, growth, and survival [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	2	3
SDF-1 activated CXCR4 receptors modulate integrin signalling , promote chemotaxis towards SDF-1 secreting cells and induce major actin cytoskeletal rearrangements XREF_BIBR .	SDF-1 activated CXCR4 receptors modulate integrin signalling, promote chemotaxis towards SDF-1 secreting cells and induce major actin cytoskeletal rearrangements XREF_BIBR.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	2	3
SDF-1 induced CXCR4 signaling could potentially be beneficial to viral replication since it results in the activation of transcription factors such as NFkappaB [ XREF_BIBR ] , which are known to increase HIV-1 LTR promoter activity [ XREF_BIBR ] .	SDF-1 induced CXCR4 signaling could potentially be beneficial to viral replication since it results in the activation of transcription factors such as NFkappaB [XREF_BIBR], which are known to increase HIV-1 LTR promoter activity [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	2	3
PDGF , HGF and SDF1 can activate PDGFRbeta , MET and CXCR4 , respectively .	PDGF, HGF and SDF1 can activate PDGFRbeta, MET and CXCR4, respectively.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	4	5	11	12
RPA inhibited the CXCL12 triggered CXCR4 internalization in a dose dependent manner , and full inhibition was observed above 0.5 mug/mL ( XREF_SUPPLEMENTARY ) .	RPA inhibited the CXCL12 triggered CXCR4 internalization in a dose dependent manner, and full inhibition was observed above 0.5 mug/mL (XREF_SUPPLEMENTARY).	2	6	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	5	6
Previous in vitro studies have shown that NSCLC cell lines express high levels of CXCR4 and that CXCL12 activated CXCR4 promotes migration and invasion of these cell lines [ XREF_BIBR ] .	Previous in vitro studies have shown that NSCLC cell lines express high levels of CXCR4 and that CXCL12 activated CXCR4 promotes migration and invasion of these cell lines [XREF_BIBR].	17	20	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	17	18	19	20
Both CXCR7 and Rac1 are required for extracellular signal regulated kinases ( ERK ) 1/2 activation and subsequent NPC migration , indicating that CXCR7 could serve as a functional receptor in CXCL12 mediated NPC migration independent of CXCR4 .	Both CXCR7 and Rac1 are required for extracellular signal regulated kinases (ERK) 1/2 activation and subsequent NPC migration, indicating that CXCR7 could serve as a functional receptor in CXCL12 mediated NPC migration independent of CXCR4.	29	38	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	31	32	37	38
In some pancreatic cancer cell lines , stroma derived stromal cell derived factor 1 ( SDF-1 ) ligand activates chemokine receptor type 4 ( CXCR4 ) to increase Smo and Gli1 mRNA and protein levels in the absence of hedgehog ligands [ XREF_BIBR ] , although the intermediate steps have not been elucidated .	In some pancreatic cancer cell lines, stroma derived stromal cell derived factor 1 (SDF-1) ligand activates chemokine receptor type 4 (CXCR4) to increase Smo and Gli1 mRNA and protein levels in the absence of hedgehog ligands [XREF_BIBR], although the intermediate steps have not been elucidated.	9	27	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	stromal cell derived factor 1	stromal cell derived factor 1	stromal cell derived factor 1	CXCR4	CXCR4	CXCR4	9	14	24	25
The Epstein-Barr virus - encoded vGPCR BILF1 was found to attenuate CXCL12 induced CXCR4 signaling by scavenging Galpha i -proteins and impairing CXCL12 binding to CXCR4 .	The Epstein-Barr virus - encoded vGPCR BILF1 was found to attenuate CXCL12 induced CXCR4 signaling by scavenging Galpha i -proteins and impairing CXCL12 binding to CXCR4.	10	23	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	13	14
For example , the 324 SSLKILS 330 KGK 333 motif in the C-tail of C-X-C chemokine receptor-4 ( CXCR4 ) was critical for CXCL12 mediated internalization of CXCR4 and its lysosomal degradation [ XREF_BIBR ] .	For example, the 324 SSLKILS 330 KGK 333 motif in the C-tail of C-X-C chemokine receptor-4 (CXCR4) was critical for CXCL12 mediated internalization of CXCR4 and its lysosomal degradation [XREF_BIBR].	23	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	23	24	27	28
1 CXCR4 recognizes and is activated by the chemokine SDF-1 , also called CXCL12 .	1 CXCR4 recognizes and is activated by the chemokine SDF-1, also called CXCL12.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	9	10	1	2
CXCL12 enhanced the CCR7 induced chemotaxis of wild-type but not CXCR4 deficient T cells in vitro at suboptimal concentrations of a CCR7 ligand , but without affecting the expression level or ligand binding ability of CCR7 .	CXCL12 enhanced the CCR7 induced chemotaxis of wild-type but not CXCR4 deficient T cells in vitro at suboptimal concentrations of a CCR7 ligand, but without affecting the expression level or ligand binding ability of CCR7.	0	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	10	11
It is widely recognized that upon CXCL12 stimulation CXCR4 intracellular loop 3 ( ICL3 ) changes its conformation to permit Galpha i activation and release of free betagamma subunits , which in turn inhibit adenylyl cyclase , stimulate mitogen activated protein kinase ( MAPK ) pathway and initiate calcium dependent biochemical cascades [ XREF_BIBR ] .	It is widely recognized that upon CXCL12 stimulation CXCR4 intracellular loop 3 (ICL3) changes its conformation to permit Galpha i activation and release of free betagamma subunits, which in turn inhibit adenylyl cyclase, stimulate mitogen activated protein kinase (MAPK) pathway and initiate calcium dependent biochemical cascades [XREF_BIBR].	6	10	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	8	9
Furthermore , it was shown that HSCs express the chemokine receptor CXCR4 and that CXCR4 activation by CXCL12 is profibrogenic by increasing HSC activation and proliferation [ XREF_BIBR ] .	Furthermore, it was shown that HSCs express the chemokine receptor CXCR4 and that CXCR4 activation by CXCL12 is profibrogenic by increasing HSC activation and proliferation [XREF_BIBR].	14	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	17	18	14	15
Chemokine CXCL12 promotes CXCR4 dependent chemotaxis of cancer cells to characteristic organs and tissues , leading to metastatic disease .	Chemokine CXCL12 promotes CXCR4 dependent chemotaxis of cancer cells to characteristic organs and tissues, leading to metastatic disease.	0	5	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	1	2	3	4
Nonetheless , in EAC , SDF-1 was shown to mediate the migration of CXCR4 positive tumor cells in vitro and in vivo , where daily stimulation by SDF-1 led to the dose dependent development of liver , lung , peritoneal and retroperitoneal metastases in NMRI/nu mice 186 .	Nonetheless, in EAC, SDF-1 was shown to mediate the migration of CXCR4 positive tumor cells in vitro and in vivo, where daily stimulation by SDF-1 led to the dose dependent development of liver, lung, peritoneal and retroperitoneal metastases in NMRI/nu mice 186.	5	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	13	14
Hence , we show that zebrafish Cxcl12 ligands trigger CXCR4 signal activation in human TNBC cells .	Hence, we show that zebrafish Cxcl12 ligands trigger CXCR4 signal activation in human TNBC cells.	6	11	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cxcl12	Cxcl12	Cxcl12	CXCR4	CXCR4	CXCR4	6	7	9	10
Treatment with TNF-alpha , IFN-gamma , IL-1beta and LPS downregulated CXCL12 and CXCR4 expression and CXCL12 ligation induced internalization of CXCR4 .	Treatment with TNF-alpha, IFN-gamma, IL-1beta and LPS downregulated CXCL12 and CXCR4 expression and CXCL12 ligation induced internalization of CXCR4.	10	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12 and CXCR4 expression	cxcl12	CXCR4	CXCR4	cxcr4	10	11	20	21
CXCR4 activation by its ligand CXCL12 induces migration and/or survival of the neoplastic cells , including tumor cells from neuroblastoma [ XREF_BIBR ] , colorectal [ XREF_BIBR ] , prostate [ XREF_BIBR ] , melanoma [ XREF_BIBR ] and ovarian cancers [ XREF_BIBR ] .	CXCR4 activation by its ligand CXCL12 induces migration and/or survival of the neoplastic cells, including tumor cells from neuroblastoma [XREF_BIBR], colorectal [XREF_BIBR], prostate [XREF_BIBR], melanoma [XREF_BIBR] and ovarian cancers [XREF_BIBR].	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	0	1
We further found that CB 2 -specific agonist JWH-015 inhibits the CXCL12 induced chemotaxis and wound healing of MCF7 overexpressing CXCR4 ( MCF7 and CXCR4 ) , highly metastatic clone of MDA-MB-231 ( SCP2 ) and NT 2.5 cells ( derived from MMTV-neu ) by using chemotactic and wound healing assays .	We further found that CB 2 -specific agonist JWH-015 inhibits the CXCL12 induced chemotaxis and wound healing of MCF7 overexpressing CXCR4 (MCF7 and CXCR4), highly metastatic clone of MDA-MB-231 (SCP2) and NT 2.5 cells (derived from MMTV-neu) by using chemotactic and wound healing assays.	10	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	20	21
Given that chemokine CXCL12 promotes CXCR4 dependent chemotaxis of cancer cells ( MDA-MB-231 ) , a compartmentalized microfluidic system that consists of two layers of PDMS channels separated by a semi-permeable membrane was developed to study CXCR4 dependent chemotaxis of cancer cells ( MDA-MB-231 ) towards a CXCL12 producing source ( XREF_FIG A ) [ XREF_BIBR ] .	Given that chemokine CXCL12 promotes CXCR4 dependent chemotaxis of cancer cells (MDA-MB-231), a compartmentalized microfluidic system that consists of two layers of PDMS channels separated by a semi-permeable membrane was developed to study CXCR4 dependent chemotaxis of cancer cells (MDA-MB-231) towards a CXCL12 producing source (XREF_FIG A) [XREF_BIBR].	2	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	5	6
Finally , authors summarize the ( patho ) biological functions of CXCR4 signaling mediated by CXCL12 or MIF that are likely to be important in devising potential future therapies targeting this signaling axis .	Finally, authors summarize the (patho) biological functions of CXCR4 signaling mediated by CXCL12 or MIF that are likely to be important in devising potential future therapies targeting this signaling axis.	11	23	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	11	12
The results demonstrate that DLS by itself failed to induce CXCR4 internalization and does not interfere with CXCL12 induced CXCR4 internalization .	The results demonstrate that DLS by itself failed to induce CXCR4 internalization and does not interfere with CXCL12 induced CXCR4 internalization.	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	17	18	19	20
The data presented in the current study extends these findings and elucidates the signaling mechanisms through which activation of CXCR4 by CXCL12 induces a TGFbeta / TGFbetaR independent transactivation of EGFR .	The data presented in the current study extends these findings and elucidates the signaling mechanisms through which activation of CXCR4 by CXCL12 induces a TGFbeta / TGFbetaR independent transactivation of EGFR.	17	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	21	22	19	20
These results further confirm that CXCL12 induces migration and invasion of HMVP2 cells by signaling thorugh both of its receptors CXCR4 and CXCR7 .	These results further confirm that CXCL12 induces migration and invasion of HMVP2 cells by signaling thorugh both of its receptors CXCR4 and CXCR7.	5	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	20	21
As CXCR4 was activated by SDF-1 , we found no change in CXCR4 expression at the levels of mRNA and total protein , but SDF-1 itself was able to produce a significant decline of CXCR4 expression on the cell surface .	As CXCR4 was activated by SDF-1, we found no change in CXCR4 expression at the levels of mRNA and total protein, but SDF-1 itself was able to produce a significant decline of CXCR4 expression on the cell surface.	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	1	2
HIF-1 activates transcription of the gene encoding SDF-1 , and increased SDF-1 expression promotes vascular regeneration by enhancing recruitment of CXCR4 expressing angiogenic cells [ XREF_BIBR ] .	HIF-1 activates transcription of the gene encoding SDF-1, and increased SDF-1 expression promotes vascular regeneration by enhancing recruitment of CXCR4 expressing angiogenic cells [XREF_BIBR].	11	22	promotes	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	SDF-1	SDF-1 expression	sdf-1	CXCR4	CXCR4 expressing	cxcr4	11	12	20	21
C-X-C motif chemokine 12 stimulates CXCR4 and CXCR7 bearing cells in a paracrine manner .	C-X-C motif chemokine 12 stimulates CXCR4 and CXCR7 bearing cells in a paracrine manner.	0	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	C-X-C motif chemokine 12	C-X-C motif chemokine 12	C-X-C motif chemokine 12	CXCR4	CXCR4	CXCR4	0	4	5	6
CXCR4 activation by CXCL12 also induces expression of the MT1 membrane bound matrix metalloproteinase ( MT1-MMP ) , but this matrix metalloproteinase ( MMP ) remains intracellular until the cells come in contact with the appropriate basement membrane proteins , then MT1-MMP moves to the plasma membrane in a PI-3K dependent manner .	CXCR4 activation by CXCL12 also induces expression of the MT1 membrane bound matrix metalloproteinase (MT1-MMP), but this matrix metalloproteinase (MMP) remains intracellular until the cells come in contact with the appropriate basement membrane proteins, then MT1-MMP moves to the plasma membrane in a PI-3K dependent manner.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	0	1
As a GPCR , the mechanism of CXCR4 activation by CXCL12 is mediated by a heterotrimeric G protein which is activated through the exchange of GTP in place of previously bound GDP on its Galpha i subunit followed by dissociation of heterotrimeric Galphabetagamma protein into activated Galpha i and Gbetagamma subunit .	As a GPCR, the mechanism of CXCR4 activation by CXCL12 is mediated by a heterotrimeric G protein which is activated through the exchange of GTP in place of previously bound GDP on its Galpha i subunit followed by dissociation of heterotrimeric Galphabetagamma protein into activated Galpha i and Gbetagamma subunit.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	7	8
11 When CXCR4 is stimulated by its ligand SDF-1 , CXCR4 couples with Gi family proteins and activates a number of signaling pathways involved in a variety of biological responses .	11 When CXCR4 is stimulated by its ligand SDF-1, CXCR4 couples with Gi family proteins and activates a number of signaling pathways involved in a variety of biological responses.	2	17	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	8	9	2	3
For example , actin binding cortactin and plectrin have been shown to be involved in CXCL12 induced CXCR4 internalization and recycling in HEK293 cells overexpressing CXCR4 XREF_BIBR , XREF_BIBR .	For example, actin binding cortactin and plectrin have been shown to be involved in CXCL12 induced CXCR4 internalization and recycling in HEK293 cells overexpressing CXCR4 XREF_BIBR, XREF_BIBR.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	17	18
However , the above treatments were performed on cortical neurons grown in the presence of a glial feeder layer while glial cells were removed shortly before stimulation of CXCR4 by CXCL12 .	However, the above treatments were performed on cortical neurons grown in the presence of a glial feeder layer while glial cells were removed shortly before stimulation of CXCR4 by CXCL12.	23	31	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	30	31	28	29
CXCL12 elicited CXCR4 receptor endocytosis , actin polymerization , and a robust activation of phospho-p44/42 mitogen activated protein kinase in SCLC cells .	CXCL12 elicited CXCR4 receptor endocytosis, actin polymerization, and a robust activation of phospho-p44/42 mitogen activated protein kinase in SCLC cells.	0	4	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	2	3
In a word , we supply a novel pathway that CXCR4 pathway stimulated by CXCL12 regulated AKT activation , CREB phosphorylation and P53 level to affect the process of aging and AD .	In a word, we supply a novel pathway that CXCR4 pathway stimulated by CXCL12 regulated AKT activation, CREB phosphorylation and P53 level to affect the process of aging and AD.	10	15	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	10	11
Evidence obtained from neuronal studies showed that stimulation of CXCR4 by CXCL12 leads to the activation of intracellular pathways such as PI3K and Akt -1 and changes in cell cycle proteins affecting neuronal survival .	Evidence obtained from neuronal studies showed that stimulation of CXCR4 by CXCL12 leads to the activation of intracellular pathways such as PI3K and Akt -1 and changes in cell cycle proteins affecting neuronal survival.	7	12	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	9	10
CXCR4 is activated by the chemokine CXCL12 , and a two-site model of chemokine binding has been suggested separating the binding and signaling functions of chemokine ligands : the chemokine globular domain is thought to bind the receptor N-terminus and ECLs ( site one ) defining affinity and specificity , whereas the disordered N-terminal domain is thought to penetrate into the receptor helical core ( site two ) controlling receptor signaling .	CXCR4 is activated by the chemokine CXCL12, and a two-site model of chemokine binding has been suggested separating the binding and signaling functions of chemokine ligands : the chemokine globular domain is thought to bind the receptor N-terminus and ECLs (site one) defining affinity and specificity, whereas the disordered N-terminal domain is thought to penetrate into the receptor helical core (site two) controlling receptor signaling.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	0	1
In vitro , interference of CXCR4 with the urokinase-receptor ( uPAR ) reduces the adhesion of CXCL12 mediated CXCR4 + GBM cells to collagen , the main component of ECM [ XREF_BIBR ] .	In vitro, interference of CXCR4 with the urokinase-receptor (uPAR) reduces the adhesion of CXCL12 mediated CXCR4 + GBM cells to collagen, the main component of ECM [XREF_BIBR].	14	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	16	17	18	19
This data suggests that CXCL12 induces conformational changes in the CXCR4 homodimer and that disruption of this conformational change inhibits function , at least in the context of calcium mobilization [ XREF_BIBR ] .	This data suggests that CXCL12 induces conformational changes in the CXCR4 homodimer and that disruption of this conformational change inhibits function, at least in the context of calcium mobilization [XREF_BIBR].	4	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	10	11
This compound selectively inhibits SDF1 induced CXCR4 signaling in THP1 cells .	This compound selectively inhibits SDF1 induced CXCR4 signaling in THP1 cells.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	4	5	6	7
For HSC , activation of CXCR4 by CXCL12 triggers migration to the bone marrow .	For HSC, activation of CXCR4 by CXCL12 triggers migration to the bone marrow.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	5	6
These results suggest that knockout of Cxcl12 in the endothelium inhibited expansion of the Mist1 + Cxcr4 + cell population , but the loss of Mist1 + cells may have been partially compensated by CCK2R + stem cell expansion .	These results suggest that knockout of Cxcl12 in the endothelium inhibited expansion of the Mist1 + Cxcr4 + cell population, but the loss of Mist1 + cells may have been partially compensated by CCK2R + stem cell expansion.	4	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cxcl12	Cxcl12	Cxcl12	Cxcr4	Cxcr4	Cxcr4	6	7	16	17
This is indicated by the fact that during OIH there is an AMD3100 reversible decline in CXCR4-IR in the DRG , presumably resulting from SDF1 activation of CXCR4 receptors followed by their internalization and recycling mechanisms , as previously observed in the dentate gyrus .	This is indicated by the fact that during OIH there is an AMD3100 reversible decline in CXCR4-IR in the DRG, presumably resulting from SDF1 activation of CXCR4 receptors followed by their internalization and recycling mechanisms, as previously observed in the dentate gyrus.	24	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	24	25	27	28
To test this possibility we isolated plasma-membrane proteins by means of cell surface protein biotinylation and measured the levels of surface CXCR4 and pCXCR4 in neurons treated with CXCL12 and/or DAMGO .	To test this possibility we isolated plasma-membrane proteins by means of cell surface protein biotinylation and measured the levels of surface CXCR4 and pCXCR4 in neurons treated with CXCL12 and/or DAMGO.	18	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	pCXCR4	pCXCR4	pCXCR4	28	29	23	24
High-molecular-weight HA ( hHA ) was found to augment CXCL12 induced CXCR4 signaling in both HepG2iso cells and primary human umbilical vein endothelial cells , as evidenced by enhanced ERK phosphorylation and increased cell motility .	High-molecular-weight HA (hHA) was found to augment CXCL12 induced CXCR4 signaling in both HepG2iso cells and primary human umbilical vein endothelial cells, as evidenced by enhanced ERK phosphorylation and increased cell motility.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	11	12
In contrast , CXCL12 triggered CXCR4 signaling to early targets , such as Akt as well as CXCR4 mediated chemotaxis , is insensitive to identical CXCR7 blocking .	In contrast, CXCL12 triggered CXCR4 signaling to early targets, such as Akt as well as CXCR4 mediated chemotaxis, is insensitive to identical CXCR7 blocking.	3	6	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	5	6
In contrast , we found that the binding of LM CXCL12 increased the NOE magnitude for residues 5 to 10 of CXCR4 1-38 , in addition to that for residues 11 to 25 ( XREF_FIG ) , suggesting that residues near the CXCR4 N terminus interacted to a greater extent with the LM form than with the LD form of CXCL12 .	In contrast, we found that the binding of LM CXCL12 increased the NOE magnitude for residues 5 to 10 of CXCR4 1-38, in addition to that for residues 11 to 25 (XREF_FIG), suggesting that residues near the CXCR4 N terminus interacted to a greater extent with the LM form than with the LD form of CXCL12.	7	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	21	22
We provided here evidence that GPCR kinase-3 ( GRK3 ) specifically regulates CXCL12 promoted internalization and desensitization of CXCR4 .	We provided here evidence that GPCR kinase-3 (GRK3) specifically regulates CXCL12 promoted internalization and desensitization of CXCR4.	12	19	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	18	19
We have previously shown that aside from this activity , which in its nature could be proinflammatory , CXCL12 also drives the polarization of CXCR4 + macrophages into the IL-10 high M2c like macrophages that hold anti-inflammatory properties and also of effector CD4 + T cells ( CXCR4 + ) into IL-10 high Tr1 cells .	We have previously shown that aside from this activity, which in its nature could be proinflammatory, CXCL12 also drives the polarization of CXCR4 + macrophages into the IL-10 high M2c like macrophages that hold anti-inflammatory properties and also of effector CD4 + T cells (CXCR4 +) into IL-10 high Tr1 cells.	18	31	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	18	19	24	25
In the present study , SDF-1 increased CXCR4 mRNA and protein expression in human endplate chondrocytes in a dose dependent manner .	In the present study, SDF-1 increased CXCR4 mRNA and protein expression in human endplate chondrocytes in a dose dependent manner.	5	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	7	8
Interestingly , we also observed that pretreatment with IU-1 partially blocked CXCL12 mediated CXCR4 down-modulation and degradation in CD4 + T cells from young donors but not in those from the elderly , indicating an age associated defect in ligand induced degradation of CXCR4 in CD4 + T cells .	Interestingly, we also observed that pretreatment with IU-1 partially blocked CXCL12 mediated CXCR4 down-modulation and degradation in CD4 + T cells from young donors but not in those from the elderly, indicating an age associated defect in ligand induced degradation of CXCR4 in CD4 + T cells.	10	40	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	13	14
CXCL12 promoted migration of CD4+ T-cells from three different mouse models of NASH was increased and dependent of CXCR4 .	CXCL12 promoted migration of CD4+ T-cells from three different mouse models of NASH was increased and dependent of CXCR4.	0	19	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	18	19
Our results showing normal neutrophil counts in the peripheral blood of HuCXCR4KI mice suggest proper retention in bone marrow , mediated by functional mouse CXCL12 -to - human CXCR4 signaling .	Our results showing normal neutrophil counts in the peripheral blood of HuCXCR4KI mice suggest proper retention in bone marrow, mediated by functional mouse CXCL12 -to - human CXCR4 signaling.	20	29	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	24	25	28	29
Activation of CXCR4 by CXCL12 resulted in the association of CXCR4 with CD45 and activation of PLCbeta3 , AKT , RhoA , IkappaBalpha and ERK1/2 .	Activation of CXCR4 by CXCL12 resulted in the association of CXCR4 with CD45 and activation of PLCbeta3, AKT, RhoA, IkappaBalpha and ERK1/2.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	2	3
Our work further shows that estrogen activation of the ER increases SDF-1 gene expression , which may drive CXCR4 signaling and mediate estrogen independent tumor growth .	Our work further shows that estrogen activation of the ER increases SDF-1 gene expression, which may drive CXCR4 signaling and mediate estrogen independent tumor growth.	5	19	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	estrogen activation of the ER increases SDF-1 gene expression	sdf-1	CXCR4	CXCR4	cxcr4	11	12	18	19
Moreover , TQ significantly down-regulated CXCR4 expression and CXCL12 mediated CXCR4 and CD45 association in MM cells .	Moreover, TQ significantly down-regulated CXCR4 expression and CXCL12 mediated CXCR4 and CD45 association in MM cells.	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	10	11
As HepG2iso cells clearly synthesize HA ( XREF_FIG ) , this suggests that CXCL12 induced CXCR4 signaling is also regulated by CD44 through the action of endogenously produced HA .	As HepG2iso cells clearly synthesize HA (XREF_FIG), this suggests that CXCL12 induced CXCR4 signaling is also regulated by CD44 through the action of endogenously produced HA.	13	16	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	13	14	15	16
Events triggered by CXCL12 may play a part , as CXCL12 drives the migration of both CXCR4 positive cancer cells and macrophages and may promote a molecular crosstalk between them .	Events triggered by CXCL12 may play a part, as CXCL12 drives the migration of both CXCR4 positive cancer cells and macrophages and may promote a molecular crosstalk between them.	10	24	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	16	17
The lower CXCR4 expression levels at later time points suggested that SDF-1 induced CXCR4 is likely endocytosed from the cell surface for receptor degradation or recycling back to the cell surface [ XREF_BIBR ] .	The lower CXCR4 expression levels at later time points suggested that SDF-1 induced CXCR4 is likely endocytosed from the cell surface for receptor degradation or recycling back to the cell surface [XREF_BIBR].	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	11	12	13	14
A role for CXCL12 modulation of CXCR4 and CXCR7 was identified for most of the brain tumors including gliomas , meningiomas and even pituitary adenomas that frequently overexpress these receptors .	A role for CXCL12 modulation of CXCR4 and CXCR7 was identified for most of the brain tumors including gliomas, meningiomas and even pituitary adenomas that frequently overexpress these receptors.	3	8	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	6	7
[ XREF_BIBR ] Similar to its role in hematopoietic stem cell ( HSC ) regulation , activation of CXCR4 by SDF-1 is critical for the migration and retention of leukemia cells within the bone marrow and may play a role in extramedullary spread .	[XREF_BIBR] Similar to its role in hematopoietic stem cell (HSC) regulation, activation of CXCR4 by SDF-1 is critical for the migration and retention of leukemia cells within the bone marrow and may play a role in extramedullary spread.	16	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	20	21	18	19
Quite differently , CXCR4 signaling activated by CXCL12 governs B lymphocyte retention in bone marrow during development .	Quite differently, CXCR4 signaling activated by CXCL12 governs B lymphocyte retention in bone marrow during development.	3	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	3	4
In summary , our data uncover a novel regulatory network through which HA of different sizes has contrasting effects on CXCL12 induced CXCR4 signaling in a CD44 dependent manner .	In summary, our data uncover a novel regulatory network through which HA of different sizes has contrasting effects on CXCL12 induced CXCR4 signaling in a CD44 dependent manner.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	20	21	22	23
Furthermore , our findings suggest that in bone tissue , CXCL12 activated CXCR4 signaling in breast cancer cells induced by ANGPTL2 also accelerates osteolysis and bone engraftment .	Furthermore, our findings suggest that in bone tissue, CXCL12 activated CXCR4 signaling in breast cancer cells induced by ANGPTL2 also accelerates osteolysis and bone engraftment.	10	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	12	13
The presented CXCL12 activates CXCR4 on CD34+ progenitor cells , which leads to adhesion and to endothelial differentiation .	The presented CXCL12 activates CXCR4 on CD34+ progenitor cells, which leads to adhesion and to endothelial differentiation.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	4	5
HIV-1 Gag attenuates SDF-1 induced downregulation of endogenous CXCR4 in Jurkat T cells .	HIV-1 Gag attenuates SDF-1 induced downregulation of endogenous CXCR4 in Jurkat T cells.	3	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	8	9
SDF-1 increased the invasive potential of MCF-7 and CXCR4 cells by 100 % as compared with the non stimulated control ( no SDF-1 added to the bottom well and diluent treated , set as 100 % ) , and this effect was completely blocked by melatonin administration .	SDF-1 increased the invasive potential of MCF-7 and CXCR4 cells by 100% as compared with the non stimulated control (no SDF-1 added to the bottom well and diluent treated, set as 100%), and this effect was completely blocked by melatonin administration.	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	8	9
CXCL12 stimulation triggered CXCR4 ( R334X ) internalization in FLNA deficient M2 cells but not in the FLNA expressing M2 subclone A7 ; this suggests a role for FLNA in stabilization of WHIM like CXCR4 at the cell surface .	CXCL12 stimulation triggered CXCR4 (R334X) internalization in FLNA deficient M2 cells but not in the FLNA expressing M2 subclone A7; this suggests a role for FLNA in stabilization of WHIM like CXCR4 at the cell surface.	0	7	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	3	4
When indicated , the chemoattractant CXCL12 was added in the bottom chamber to induce CXCR4 positive breast cancer cell to invade through the Matrigel ( specific chemoinvasion ) .	When indicated, the chemoattractant CXCL12 was added in the bottom chamber to induce CXCR4 positive breast cancer cell to invade through the Matrigel (specific chemoinvasion).	3	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	14	15
Silencing of CXCL12 remarkably promoted cell proliferation , inhibited cell apoptosis and suppressed CXCL12 and CXCR4 , p-STAT3 and caspase 3 .	Silencing of CXCL12 remarkably promoted cell proliferation, inhibited cell apoptosis and suppressed CXCL12 and CXCR4, p-STAT3 and caspase 3.	0	16	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	15	16
Normally , SDF-1 induced CXCR4 internalization is regarded as a mark of receptor desensitization and also plays a role in the downstream signaling and cells functions such as MAPK activation and cells migration in the particular cell types XREF_BIBR XREF_BIBR .	Normally, SDF-1 induced CXCR4 internalization is regarded as a mark of receptor desensitization and also plays a role in the downstream signaling and cells functions such as MAPK activation and cells migration in the particular cell types XREF_BIBR XREF_BIBR.	2	16	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	2	3	4	5
Immunohistochemistry of primary tumor samples from SCLC patients has revealed high expression of the GPCR chemokine receptor CXCR4 ; the CXCL12 ligand can elicit endocytosis of CXCR4 , actin polymerization , and robust activation of phospho-ERK1/2 in SCLC cells , which correlates with a significant induction of invasive properties 63 .	Immunohistochemistry of primary tumor samples from SCLC patients has revealed high expression of the GPCR chemokine receptor CXCR4; the CXCL12 ligand can elicit endocytosis of CXCR4, actin polymerization, and robust activation of phospho-ERK1/2 in SCLC cells, which correlates with a significant induction of invasive properties 63.	20	33	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	20	21	26	27
CXCL12 activates CXC chemokine receptor 4 ( CXCR4 ) resulting in liver fibrosis , tumor growth , and HCC metastasis [ XREF_BIBR - XREF_BIBR ] .	CXCL12 activates CXC chemokine receptor 4 (CXCR4) resulting in liver fibrosis, tumor growth, and HCC metastasis [XREF_BIBR - XREF_BIBR].	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	7	8
The CXC chemokine receptor 4 ( CXCR4 ) can only be activated by a unique ligand , the CXC chemokine ligand 12 ( CXCL12 ) , also known as stromal cell derived factor 1 ( SDF-1 ) [ XREF_BIBR ] .	The CXC chemokine receptor 4 (CXCR4) can only be activated by a unique ligand, the CXC chemokine ligand 12 (CXCL12), also known as stromal cell derived factor 1 (SDF-1) [XREF_BIBR].	0	27	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	23	24	6	7
Thus , inhibition of USP14 results in increased surface expression of CXCR4 and negatively impacts CXCL12 mediated CXCR4 internalization and degradation , by regulating the ubiquitination and deubiquitination cycle .	Thus, inhibition of USP14 results in increased surface expression of CXCR4 and negatively impacts CXCL12 mediated CXCR4 internalization and degradation, by regulating the ubiquitination and deubiquitination cycle.	14	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	17	18
The grey line denotes the background subtracted fluorescence emission spectrum of Jurkat T cells expressing both CXCR4-YFP and TCR-zeta-CFP before these cells have been treated with SDF-1 .	The grey line denotes the background subtracted fluorescence emission spectrum of Jurkat T cells expressing both CXCR4-YFP and TCR-zeta-CFP before these cells have been treated with SDF-1.	14	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4-YFP	CXCR4-YFP	CXCR4-YFP	26	27	16	17
AMD3100 , a CXCR4 selective inhibitor , inhibited CXCL12 induced chemotaxis and invasion of both MTLn3 CXCR4 and MTLn3 CXCR4-CXCR7 cells , while inhibition of CXCL12 binding to CXCR7 using I-TAC , CCX733 or CCX771 had no effect on CXCL12 induced chemotaxis .	AMD3100, a CXCR4 selective inhibitor, inhibited CXCL12 induced chemotaxis and invasion of both MTLn3 CXCR4 and MTLn3 CXCR4-CXCR7 cells, while inhibition of CXCL12 binding to CXCR7 using I-TAC, CCX733 or CCX771 had no effect on CXCL12 induced chemotaxis.	8	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	16	17
CXCL12 upregulated CXCR4 in HDMECs whereas TNF-alpha upregulated both CXCR4 and CXCR7 ( XREF_FIG ) .	CXCL12 upregulated CXCR4 in HDMECs whereas TNF-alpha upregulated both CXCR4 and CXCR7 (XREF_FIG).	0	3	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	2	3
From this , we concluded that CXCL12 promotes CXCR4 internalization , a view that is consistent with current understanding of CXCR4 function XREF_BIBR , as well as stabilizes homodimers of CXCR4 .	From this, we concluded that CXCL12 promotes CXCR4 internalization, a view that is consistent with current understanding of CXCR4 function XREF_BIBR, as well as stabilizes homodimers of CXCR4.	6	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	8	9
These data demonstrate that in WT MEF a classical signal transduction pathway evoked by CXCL12 mediated activation of CXCR4 is functional .	These data demonstrate that in WT MEF a classical signal transduction pathway evoked by CXCL12 mediated activation of CXCR4 is functional.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	18	19
SDF-1 induced CXCR4 signaling is indispensable for embryonic development and crucial for immune cell homing and has been implicated in metastasis of numerous types of cancer .	SDF-1 induced CXCR4 signaling is indispensable for embryonic development and crucial for immune cell homing and has been implicated in metastasis of numerous types of cancer.	0	18	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	2	3
SDF-1 Down Modulates CXCR4 .	SDF-1 Down Modulates CXCR4.	0	4	Modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	3	4
Opposing effects of high- and low-molecular weight hyaluronan on CXCL12 induced CXCR4 signaling depend on CD44 .	Opposing effects of high- and low-molecular weight hyaluronan on CXCL12 induced CXCR4 signaling depend on CD44.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	11	12
Though unknown , CXCR7 activity may include signaling through alternative pathways or perhaps modulating CXCL12 induced CXCR4 activity by physical association .	Though unknown, CXCR7 activity may include signaling through alternative pathways or perhaps modulating CXCL12 induced CXCR4 activity by physical association.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	16	17
The data thus indicate that CXCL12 is able to activate CXCR4 under conditions in which SOCS3 is up-regulated , not only in vitro but also in vivo , as observed in bGH-Tg mice .	The data thus indicate that CXCL12 is able to activate CXCR4 under conditions in which SOCS3 is up-regulated, not only in vitro but also in vivo, as observed in bGH-Tg mice.	5	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	10	11
Although the biochemical mechanisms underlying this process are incompletely defined , there is compelling evidence that SDF-1 and CXCL12 stimulation of CXCR4 is a principal regulator for retention and stress induced mobilization of myeloid lineage cells from the bone marrow to the blood XREF_BIBR - XREF_BIBR .	Although the biochemical mechanisms underlying this process are incompletely defined, there is compelling evidence that SDF-1 and CXCL12 stimulation of CXCR4 is a principal regulator for retention and stress induced mobilization of myeloid lineage cells from the bone marrow to the blood XREF_BIBR - XREF_BIBR.	16	22	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	18	19	21	22
However whether the CXCL12 produced by these ligands was sufficient to induce CXCR4 activation was next assessed in the study .	However whether the CXCL12 produced by these ligands was sufficient to induce CXCR4 activation was next assessed in the study.	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	12	13
These data confirm that SDF-1 induces CXCR4 internalization and calcium stimulates the production of active CXCR4 receptors .	These data confirm that SDF-1 induces CXCR4 internalization and calcium stimulates the production of active CXCR4 receptors.	4	7	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	6	7
In addition , a high level of SDF-1 can induce the internalization and degradation of CXCR4 through the lysosome pathway [ XREF_BIBR , XREF_BIBR ] .	In addition, a high level of SDF-1 can induce the internalization and degradation of CXCR4 through the lysosome pathway [XREF_BIBR, XREF_BIBR].	5	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	level of SDF-1	sdf-1	CXCR4	CXCR4	cxcr4	7	8	15	16
SDF-1 alpha activation of neuronal CXCR4 differs from activation of CXCR4 in leukocytes in that SDF-1 alpha induced calcium flux is activity dependent , requiring predepolarization with KCl or pretreatment with glutamate .	SDF-1 alpha activation of neuronal CXCR4 differs from activation of CXCR4 in leukocytes in that SDF-1 alpha induced calcium flux is activity dependent, requiring predepolarization with KCl or pretreatment with glutamate.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	5	6
One study has also observed CXCR4 localization at the cytoplasm in leukocyte cell lines with enforced CXCR4 expression and CXCL12 induced polarization of CXCR4 to the edge of migrating leukocyte cells [ XREF_BIBR ] .	One study has also observed CXCR4 localization at the cytoplasm in leukocyte cell lines with enforced CXCR4 expression and CXCL12 induced polarization of CXCR4 to the edge of migrating leukocyte cells [XREF_BIBR].	19	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	23	24
We will discuss signaling pathways initiated by binding of CXCL12 vs. MIF to CXCR4 , elaborate on how ACKR3 affects CXCR4 signaling , and summarize biological functions of CXCR4 signaling mediated by CXCL12 or MIF .	We will discuss signaling pathways initiated by binding of CXCL12 vs. MIF to CXCR4, elaborate on how ACKR3 affects CXCR4 signaling, and summarize biological functions of CXCR4 signaling mediated by CXCL12 or MIF.	28	34	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	32	33	28	29
As mentioned previously , CXCR4 activation by CXCL12 increases pre-synaptic neurotransmitter release and particularly GABA release in several neuronal populations .	As mentioned previously, CXCR4 activation by CXCL12 increases pre-synaptic neurotransmitter release and particularly GABA release in several neuronal populations.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	4	5
As endothelial cell expression of CXCR7 functions to regulate CXCL12 mediated retention of CXCR4 + infiltrates , these results suggest that IL-1 signaling regulates CXCR7 mediated internalization of CXCL12 , which would impact the perivascular localization of CXCR4 + leukocytes .	As endothelial cell expression of CXCR7 functions to regulate CXCL12 mediated retention of CXCR4 + infiltrates, these results suggest that IL-1 signaling regulates CXCR7 mediated internalization of CXCL12, which would impact the perivascular localization of CXCR4 + leukocytes.	8	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	13	14
In recent years , the alarmin HMGB1 , which can be massively released within the tumor microenvironment , has also been described to form a complex with the chemokine CXCL12 enhancing CXCR4 mediated signaling , thus providing an additional regulation of the activity of the chemokine system .	In recent years, the alarmin HMGB1, which can be massively released within the tumor microenvironment, has also been described to form a complex with the chemokine CXCL12 enhancing CXCR4 mediated signaling, thus providing an additional regulation of the activity of the chemokine system.	23	33	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	29	30	31	32
It is also of interest to examine if transient and constitutive CXCL12 stimulation of either CXCR4 or CXCR7 elicits distinct cellular outcomes .	It is also of interest to examine if transient and constitutive CXCL12 stimulation of either CXCR4 or CXCR7 elicits distinct cellular outcomes.	11	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	15	16
The monomer form of SDF1 is known to produce internalization of its receptor , CXCR4 , and intracellular Ca 2+ mobilization .	The monomer form of SDF1 is known to produce internalization of its receptor, CXCR4, and intracellular Ca 2+ mobilization.	2	15	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	4	5	14	15
Conversely , it has previously been shown that CXCR4 stimulation by CXCL12 can increase GABA release .	Conversely, it has previously been shown that CXCR4 stimulation by CXCL12 can increase GABA release.	8	12	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	8	9
The present study showed that CXCL-12 stimulation induced the rapid internalization of CXCR4 and facilitated the formation of lamellipodia and uropod in acute leukemia cell line HL-60 .	The present study showed that CXCL-12 stimulation induced the rapid internalization of CXCR4 and facilitated the formation of lamellipodia and uropod in acute leukemia cell line HL-60.	5	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL-12	CXCL-12	CXCL-12	CXCR4	CXCR4	CXCR4	5	6	12	13
It is probable that the activation of CXCR4 by SDF-1 is one of the sources of maternofetal immune tolerance , enabling normal development of the pregnancy .	It is probable that the activation of CXCR4 by SDF-1 is one of the sources of maternofetal immune tolerance, enabling normal development of the pregnancy.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	9	10	7	8
Activation of CXCR4 by SDF1 can be measured by intracellular calcium flux , a secondary messenger involved in GPCR signaling .	Activation of CXCR4 by SDF1 can be measured by intracellular calcium flux, a secondary messenger involved in GPCR signaling.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	4	5	2	3
HSP27 was also selected due to spectral counts indicative of phosphorylation upon CXCL12 activation of CXCR4 ( XREF_FIG ) , its implications in cancer and protection from apoptosis , and the availability of a phospho specific antibody at the Ser82 phosphorylation site XREF_BIBR , XREF_BIBR , XREF_BIBR .	HSP27 was also selected due to spectral counts indicative of phosphorylation upon CXCL12 activation of CXCR4 (XREF_FIG), its implications in cancer and protection from apoptosis, and the availability of a phospho specific antibody at the Ser82 phosphorylation site XREF_BIBR, XREF_BIBR, XREF_BIBR.	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	15	16
Recent studies have identified a novel molecular mechanism whereby SDF-1alpha activation of its receptor CXCR4 in primary human monocytes enables transmigration across an endothelial BBB model .	Recent studies have identified a novel molecular mechanism whereby SDF-1alpha activation of its receptor CXCR4 in primary human monocytes enables transmigration across an endothelial BBB model.	9	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SDF-1alpha	SDF-1alpha	SDF-1alpha	CXCR4	CXCR4	CXCR4	9	10	14	15
Our data ( Figs XREF_FIG , XREF_FIG ) strongly suggest that SDF-1 induced CXCR4 downregulation is TSG101 and ESCRT-I dependent .	Our data (Figs XREF_FIG, XREF_FIG) strongly suggest that SDF-1 induced CXCR4 downregulation is TSG101 and ESCRT-I dependent.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	11	12	13	14
These results suggest that CXCL12 expression increases the proliferation of ESCC through signal transduction after binding to the CXCR4 , which in turn leads to an earlier recurrence after surgery .	These results suggest that CXCL12 expression increases the proliferation of ESCC through signal transduction after binding to the CXCR4, which in turn leads to an earlier recurrence after surgery.	4	23	increases	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CXCL12	CXCL12 expression	cxcl12	CXCR4	CXCR4	cxcr4	4	5	18	19
Studies have found that SDF-1 secreted from the synovium and bone marrow , especially when stimulated by inflammatory factors , integrates with CXCR4 and can trigger the SDF-1 and CXCR4 signaling pathway to induce cartilage matrix degradation .	Studies have found that SDF-1 secreted from the synovium and bone marrow, especially when stimulated by inflammatory factors, integrates with CXCR4 and can trigger the SDF-1 and CXCR4 signaling pathway to induce cartilage matrix degradation.	4	31	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	29	30
However , excessive CXCL12 in the injured or infected brain activates CXCR4 on microglia , which then release large amounts of TNFalpha .	However, excessive CXCL12 in the injured or infected brain activates CXCR4 on microglia, which then release large amounts of TNFalpha.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	11	12
We also examined the distribution of endogenous CXCR4 in HeLa cells treated with CXCL12 for 30 min , revealing that CXCR4 colocalized with endogenous STAM-1 ( XREF_FIG B ) and arrestin-2/3 ( XREF_FIG C ) on EEA1 positive early endosomes .	We also examined the distribution of endogenous CXCR4 in HeLa cells treated with CXCL12 for 30 min, revealing that CXCR4 colocalized with endogenous STAM-1 (XREF_FIG B) and arrestin-2/3 (XREF_FIG C) on EEA1 positive early endosomes.	4	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	13	14	7	8
An interfering regulatory role for BILF1 upon CXCL12 dependent activation of CXCR4 has been observed , which may also be true for other chemokine receptors bound by BILF1 [ XREF_BIBR ] .	An interfering regulatory role for BILF1 upon CXCL12 dependent activation of CXCR4 has been observed, which may also be true for other chemokine receptors bound by BILF1 [XREF_BIBR].	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	11	12
Together these results indicate that SDF-1 stimulates CXCR4 endocytosis and trafficking into the same clustered , Rab11+ recycling endosomes through which the TCR constitutively recycles .	Together these results indicate that SDF-1 stimulates CXCR4 endocytosis and trafficking into the same clustered, Rab11+ recycling endosomes through which the TCR constitutively recycles.	5	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	7	8
in vitro experiments showed that CXCR4 activation by SDF-1 regulates motility and metastatic potential of neoplastic epithelial cell lines [ XREF_BIBR , XREF_BIBR ] , while CXCR4 inhibitors are effective in reducing chemotactic and metastatic potential of this receptor [ XREF_BIBR ] .	in vitro experiments showed that CXCR4 activation by SDF-1 regulates motility and metastatic potential of neoplastic epithelial cell lines [XREF_BIBR, XREF_BIBR], while CXCR4 inhibitors are effective in reducing chemotactic and metastatic potential of this receptor [XREF_BIBR].	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	8	9	5	6
Furthermore , CXCL12 not only elicits migratory responses but also increases the proliferation XREF_BIBR and CXCR4 expression XREF_BIBR of grafted NSPCs .	Furthermore, CXCL12 not only elicits migratory responses but also increases the proliferation XREF_BIBR and CXCR4 expression XREF_BIBR of grafted NSPCs.	2	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	15	16
In addition , it has been reported that the activation of CXCR4 by CXCL12 induces cancer cell survival XREF_BIBR .	In addition, it has been reported that the activation of CXCR4 by CXCL12 induces cancer cell survival XREF_BIBR.	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	13	14	11	12
We therefore performed a comparative CXCL12 and CXCR4 expression analysis and investigated how external addition of CXCL12 would promote CXCR4 mediated migration of CRC cell lines with different metastatic capabilities and how inhibition of CXCR4 by either CXCR4 siRNAs or neutralizing anti-CXCR4 antibodies would influence their migration potential .	We therefore performed a comparative CXCL12 and CXCR4 expression analysis and investigated how external addition of CXCL12 would promote CXCR4 mediated migration of CRC cell lines with different metastatic capabilities and how inhibition of CXCR4 by either CXCR4 siRNAs or neutralizing anti-CXCR4 antibodies would influence their migration potential.	14	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	16	17	19	20
It therefore comes as a surprise that CXCR4 serine residues 324 and 325 , which are critical for CXCL12 promoted CXCR4 internalization and degradation XREF_BIBR , XREF_BIBR , XREF_BIBR , are intact in all described WHIM mutant receptors .	It therefore comes as a surprise that CXCR4 serine residues 324 and 325, which are critical for CXCL12 promoted CXCR4 internalization and degradation XREF_BIBR, XREF_BIBR, XREF_BIBR, are intact in all described WHIM mutant receptors.	16	21	promoted	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	18	19	20	21
In this paper , we show that hHA promotes CXCL12 induced CXCR4 activation , whereas sHA fragments of 6-10 disaccharides in length inhibit CXCR4 induced Erk phosphorylation .	In this paper, we show that hHA promotes CXCL12 induced CXCR4 activation, whereas sHA fragments of 6-10 disaccharides in length inhibit CXCR4 induced Erk phosphorylation.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	11	12
Collectively , these studies show that dimeric and monomeric CXCL12 secreted from mammalian cells preferentially activate distinct aspects of CXCR4 signaling and function in breast cancer .	Collectively, these studies show that dimeric and monomeric CXCL12 secreted from mammalian cells preferentially activate distinct aspects of CXCR4 signaling and function in breast cancer.	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	19	20
Application of CXCL12 during the 30 min interval caused robust internalization of wildtype CXCR4 ( XREF_FIG ) but little internalization of S346-8A-CXCR4 and E343K-CXCR4 ( XREF_FIG ) .	Application of CXCL12 during the 30 min interval caused robust internalization of wildtype CXCR4 (XREF_FIG) but little internalization of S346-8A-CXCR4 and E343K-CXCR4 (XREF_FIG).	0	15	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	13	14
High levels of CXCL12 in organs and tissues , such as lymph nodes , lung , liver , and bone and bone marrow ( BM ) , are thought to direct the metastasis of CXCR4 expressing tumor cells [ XREF_BIBR ] .	High levels of CXCL12 in organs and tissues, such as lymph nodes, lung, liver, and bone and bone marrow (BM), are thought to direct the metastasis of CXCR4 expressing tumor cells [XREF_BIBR].	1	35	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	levels of CXCL12	cxcl12	CXCR4	CXCR4	cxcr4	3	4	34	35
CXCR4 activation by CXCL12 has been shown to increase presynaptic neurotransmitter release and particularly GABA release in several neuronal populations .	CXCR4 activation by CXCL12 has been shown to increase presynaptic neurotransmitter release and particularly GABA release in several neuronal populations.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	0	1
CXCL12 activates the CXCR4 chemokine axis and induces migration along its gradient .	CXCL12 activates the CXCR4 chemokine axis and induces migration along its gradient.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	3	4
Effects of CXCL12 on multiple organs and tissues are mediated through its receptors CXCR4 and CXCR7 , which independently or collectively regulate chemotaxis and invasion of cells , increase cell adhesion , and activate intracellular signaling pathways that control cell proliferation and survival .	Effects of CXCL12 on multiple organs and tissues are mediated through its receptors CXCR4 and CXCR7, which independently or collectively regulate chemotaxis and invasion of cells, increase cell adhesion, and activate intracellular signaling pathways that control cell proliferation and survival.	0	33	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	13	14
Furthermore , elucidation of signaling mechanisms reveals that JWH-015 inhibits CXCL12 induced CXCR4 and ERK phosphorylation , focal adhesion formation and actin stress fiber polymerization .	Furthermore, elucidation of signaling mechanisms reveals that JWH-015 inhibits CXCL12 induced CXCR4 and ERK phosphorylation, focal adhesion formation and actin stress fiber polymerization.	10	19	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	12	13
Spinal injection of SDF-1 induces CXCR4 and PLC dependent CaMKII and CREB activation in naive rats .	Spinal injection of SDF-1 induces CXCR4 and PLC dependent CaMKII and CREB activation in naive rats.	1	7	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	5	6
CXCL12 increases anoikis in colon cancer XREF_BIBR , whereas CXCR4 activation by CXCL12 in breast cancer cells decreases their sensitivity to anoikis XREF_BIBR .	CXCL12 increases anoikis in colon cancer XREF_BIBR, whereas CXCR4 activation by CXCL12 in breast cancer cells decreases their sensitivity to anoikis XREF_BIBR.	9	16	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	9	10
These results demonstrate that : ( 1 ) HIV related receptors are widely expressed on human hematopoietic cell lines ; ( 2 ) stimulation of CXCR4 by SDF-1 induces calcium flux and chemotaxis in several hematopoietic cell lines more efficiently than stimulation of CCR5 by receptor specific beta-chemokines ; ( 3 ) chemokines do not regulate proliferation of the hematopoietic cells ; and finally ( 4 ) infectability of the hematopoietic cells by HIV-1 may be auto-modulated by endogenously secreted chemokines .	These results demonstrate that : (1) HIV related receptors are widely expressed on human hematopoietic cell lines; (2) stimulation of CXCR4 by SDF-1 induces calcium flux and chemotaxis in several hematopoietic cell lines more efficiently than stimulation of CCR5 by receptor specific beta-chemokines; (3) chemokines do not regulate proliferation of the hematopoietic cells; and finally (4) infectability of the hematopoietic cells by HIV-1 may be auto-modulated by endogenously secreted chemokines.	23	28	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	27	28	25	26
In addition , SDF-1 over-expression increased CXCR4 positive fibroblastic cells , especially alphaSMA positive myofibroblasts , probably through recruitment of Grem1 + MSCs .	In addition, SDF-1 over-expression increased CXCR4 positive fibroblastic cells, especially alphaSMA positive myofibroblasts, probably through recruitment of Grem1 + MSCs.	3	7	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1 over-expression	sdf-1	CXCR4	CXCR4	cxcr4	3	4	6	7
XREF_BIBR , XREF_BIBR There is growing evidence that in an inflammatory milieu , SDF-1 and BMPs may serve as important chemoattractant molecules and mediate homing of CXCR4 positive stem cells to sites of injury or hypoxia XREF_BIBR , XREF_BIBR - XREF_BIBR .	XREF_BIBR, XREF_BIBR There is growing evidence that in an inflammatory milieu, SDF-1 and BMPs may serve as important chemoattractant molecules and mediate homing of CXCR4 positive stem cells to sites of injury or hypoxia XREF_BIBR, XREF_BIBR - XREF_BIBR.	13	29	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	13	14	26	27
As expected , SDF-1 treatment induced CXCR4 endocytosis from the plasma membrane ( XREF_FIG ) .	As expected, SDF-1 treatment induced CXCR4 endocytosis from the plasma membrane (XREF_FIG).	3	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	6	7
Further , CXCR4 is stimulated by secretory inflammatory chemokine CXCL12 .	Further, CXCR4 is stimulated by secretory inflammatory chemokine CXCL12.	2	10	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	2	3
Activation of CXCR4 by CXCL12 plays a key role in regulating diverse cellular responses , including cell migration , chemotaxis , and expressions of inflammatory mediators through stimulating downstream signaling such as Rac1 XREF_BIBR - XREF_BIBR .	Activation of CXCR4 by CXCL12 plays a key role in regulating diverse cellular responses, including cell migration, chemotaxis, and expressions of inflammatory mediators through stimulating downstream signaling such as Rac1 XREF_BIBR - XREF_BIBR.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	2	3
Moreover , Sdf-1 significantly increased the number of CXCR4 + BMCs ( beta-gal + ) able to bind myofibers .	Moreover, Sdf-1 significantly increased the number of CXCR4 + BMCs (beta-gal +) able to bind myofibers.	2	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sdf-1	Sdf-1	Sdf-1	CXCR4	CXCR4	CXCR4	2	3	8	9
Similarly , SDF-1 and CXCL12 and RANTES and CCL5 were shown to induce oligomerization of CXCR4 and CCR5 , respectively [ XREF_BIBR , XREF_BIBR ] .	Similarly, SDF-1 and CXCL12 and RANTES and CCL5 were shown to induce oligomerization of CXCR4 and CCR5, respectively [XREF_BIBR, XREF_BIBR].	2	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	2	3	15	16
The stromal cells produce abundant SDF-1 , which activates CXCR4 in PC cells and results in enhanced chemotaxis , transendothelial migration , and invasion [ XREF_BIBR ] .	The stromal cells produce abundant SDF-1, which activates CXCR4 in PC cells and results in enhanced chemotaxis, transendothelial migration, and invasion [XREF_BIBR].	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	9	10
CXCL12 activation of CXCR4 has also been shown to transactivate HER2 in lipid rafts in prostate cancer cells and this HER2 activation promotes metastasis to the bone [ XREF_BIBR ] .	CXCL12 activation of CXCR4 has also been shown to transactivate HER2 in lipid rafts in prostate cancer cells and this HER2 activation promotes metastasis to the bone [XREF_BIBR].	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	3	4
Also , the chemokine CXCL12 activates the chemokine receptor CXCR4 on endothelial cells , which promotes endothelial cell migration and proliferation in ovarian cancer cells [ XREF_BIBR ] .	Also, the chemokine CXCL12 activates the chemokine receptor CXCR4 on endothelial cells, which promotes endothelial cell migration and proliferation in ovarian cancer cells [XREF_BIBR].	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	9	10
CXCL12 triggers dimerization of receptor CXCR4 which activates multiple signaling pathways including PDZ domain containing 1 ( PDZK1 ) , phosphoinositide 3 kinase-serine and threonine protein kinases ( PI3k-Akt ) and mitogen activated kinase-extracellular signal regulated kinase1/2 ( MAPK-ERK1/2 ) ( XREF_FIG ) .	CXCL12 triggers dimerization of receptor CXCR4 which activates multiple signaling pathways including PDZ domain containing 1 (PDZK1), phosphoinositide 3 kinase-serine and threonine protein kinases (PI3k-Akt) and mitogen activated kinase-extracellular signal regulated kinase1/2 (MAPK-ERK1/2) (XREF_FIG).	0	28	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	5	6
These results provide a structural basis for understanding the role of post-translational tyrosine sulfation in SDF-1 induced CXCR4 signaling .	These results provide a structural basis for understanding the role of post-translational tyrosine sulfation in SDF-1 induced CXCR4 signaling.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	15	16	17	18
CXCR7 and CXCL12 Mediates Migration in Cxcr4 KO NPCs .	CXCR7 and CXCL12 Mediates Migration in Cxcr4 KO NPCs.	0	8	Mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	Cxcr4	Cxcr4	Cxcr4	2	3	6	7
CXCR4 activation by CXCL12 or MIF can be potently inhibited by the antagonistic pharmacological inhibitor AMD3100 [ XREF_BIBR ] .	CXCR4 activation by CXCL12 or MIF can be potently inhibited by the antagonistic pharmacological inhibitor AMD3100 [XREF_BIBR].	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	0	1
CXCL12 activates CXCR4 on cancer cells to directly increase proliferation and indirectly enhances tumor growth by increasing angiogenesis and establishing an immunosuppressive tumor microenvironment XREF_BIBR - XREF_BIBR .	CXCL12 activates CXCR4 on cancer cells to directly increase proliferation and indirectly enhances tumor growth by increasing angiogenesis and establishing an immunosuppressive tumor microenvironment XREF_BIBR - XREF_BIBR.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	2	3
The mobilization of CD34 + VEGFR2 + and Sca1 + CXCR4 + CACs from bone marrow and other tissues into peripheral blood is induced by the production of VEGF and SDF-1 , respectively , in ischemic tissue .	The mobilization of CD34 + VEGFR2 + and Sca1 + CXCR4 + CACs from bone marrow and other tissues into peripheral blood is induced by the production of VEGF and SDF-1, respectively, in ischemic tissue.	1	31	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	30	31	10	11
Furthermore , HMGB1 ( High mobility group protein B1 ) protein was reported to form complexes with CXCL12 promoting different conformational rearrangements of CXCR4 from that of CXCL12 alone [ XREF_BIBR ] .	Furthermore, HMGB1 (High mobility group protein B1) protein was reported to form complexes with CXCL12 promoting different conformational rearrangements of CXCR4 from that of CXCL12 alone [XREF_BIBR].	14	24	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	17	18	23	24
Activation of CXCR4 by CXCL12 also promotes CD4 + T-cell survival and increases expression of cell survival genes while inactivating pro apoptosis genes such as Bcl2 [ XREF_BIBR ] .	Activation of CXCR4 by CXCL12 also promotes CD4 + T-cell survival and increases expression of cell survival genes while inactivating pro apoptosis genes such as Bcl2 [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	2	3
In Vitro Suppression of CXCL12 induced Leukocyte Trafficking by Blocking CXCR4 and CXCR7 .	In Vitro Suppression of CXCL12 induced Leukocyte Trafficking by Blocking CXCR4 and CXCR7.	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	10	11
For example , a cross talk between CXCL12 activated CXCR4 and epidermal growth factor receptor ( EGFR ) has been proposed to link cell proliferation signals in ovarian carcinoma [ XREF_BIBR , XREF_BIBR ] .	For example, a cross talk between CXCL12 activated CXCR4 and epidermal growth factor receptor (EGFR) has been proposed to link cell proliferation signals in ovarian carcinoma [XREF_BIBR, XREF_BIBR].	5	22	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	9	10
We describe below a phycobiliprotein FRET assay that we used to show that SDF-1 -dependent signaling increases the proximity of endogenous CXCR4 and TCR of T cells .	We describe below a phycobiliprotein FRET assay that we used to show that SDF-1 -dependent signaling increases the proximity of endogenous CXCR4 and TCR of T cells.	13	23	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	13	14	21	22
Interestingly , our data indicates that CXCL12 exposure transcriptionally augments CXCR4 in both MCF-10A and MCF-7 cells as we observed an 11-fold and 7.5-fold increase , respectively , in CXCR4 mRNA expression after 2hours .	Interestingly, our data indicates that CXCL12 exposure transcriptionally augments CXCR4 in both MCF-10A and MCF-7 cells as we observed an 11-fold and 7.5-fold increase, respectively, in CXCR4 mRNA expression after 2hours.	6	11	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	10	11
Thus , the activation of CXCR4 by CXCL12 promotes homing of hematopoietic stem cells to the bone marrow [ XREF_BIBR ] .	Thus, the activation of CXCR4 by CXCL12 promotes homing of hematopoietic stem cells to the bone marrow [XREF_BIBR].	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	5	6
In embryogenesis , the biologic relevance of the CXCR4 receptor and its natural ligand stromal cell derived factor 1 ( SDF-1 ) is supported by the established role in which SDF-1 gradients initiate lineage specific migration of CXCR4 positive progeny [ XREF_BIBR ] .	In embryogenesis, the biologic relevance of the CXCR4 receptor and its natural ligand stromal cell derived factor 1 (SDF-1) is supported by the established role in which SDF-1 gradients initiate lineage specific migration of CXCR4 positive progeny [XREF_BIBR].	30	39	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	30	31	37	38
SDF-1 activates C-X-C chemokine receptor type 4 to induce a rapid and transient rise in the level of chemotaxis and intracellular calcium ions [ XREF_BIBR - XREF_BIBR ] .	SDF-1 activates C-X-C chemokine receptor type 4 to induce a rapid and transient rise in the level of chemotaxis and intracellular calcium ions [XREF_BIBR - XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	C-X-C chemokine receptor type 4	C-X-C chemokine receptor type 4	C-X-C chemokine receptor type 4	0	1	2	7
The reporter measures CXCL12 activation of CXCR4 signaling based on recruitment of the cytosolic adapter protein beta-arrestin 2 to this receptor .	The reporter measures CXCL12 activation of CXCR4 signaling based on recruitment of the cytosolic adapter protein beta-arrestin 2 to this receptor.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	6	7
Altogether , the findings were consistent with the reported high metastatic activity of 143B compared to HOS cells and suggested that the CXCL12 stimulated CXCR4 signaling and migration activity of 143B cells contributed to their in vivo metastatic potential .	Altogether, the findings were consistent with the reported high metastatic activity of 143B compared to HOS cells and suggested that the CXCL12 stimulated CXCR4 signaling and migration activity of 143B cells contributed to their in vivo metastatic potential.	21	25	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	22	23	24	25
SDF-1 ( CXCL12 ) promoted colon carcinoma cell proliferation via CXCR7 , but not CXCR4 [ XREF_BIBR ] .	SDF-1 (CXCL12) promoted colon carcinoma cell proliferation via CXCR7, but not CXCR4 [XREF_BIBR].	0	16	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	14	15
The selective CXCR4 receptor antagonist AMD 3100 prevented CXCL12 from increasing cocaine induced activity indicating that CXCL12 potentiated the effects of cocaine by activating CXCR4 receptors .	The selective CXCR4 receptor antagonist AMD 3100 prevented CXCL12 from increasing cocaine induced activity indicating that CXCL12 potentiated the effects of cocaine by activating CXCR4 receptors.	16	25	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	16	17	24	25
We have also previously showed that exogenous SDF-1 could induce CXCR4 positive pancreatic cancer invasion and EMT through the activation of the non canonical Hh pathway [ XREF_BIBR ] .	We have also previously showed that exogenous SDF-1 could induce CXCR4 positive pancreatic cancer invasion and EMT through the activation of the non canonical Hh pathway [XREF_BIBR].	6	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	7	8	10	11
XREF_FIG C shows that although SDF-1 could down modulate CXCR4 , it did not induce CD4 internalization .	XREF_FIG C shows that although SDF-1 could down modulate CXCR4, it did not induce CD4 internalization.	5	10	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	9	10
Addition of the chemokine SDF-1 only or SDF-1 plus sICAM-1 did not promote FRET in the alpha L -mCFP and beta 2 + alpha L -mYFP and beta 2 + CXCR4 transfectants ( XREF_FIG C ) .	Addition of the chemokine SDF-1 only or SDF-1 plus sICAM-1 did not promote FRET in the alpha L -mCFP and beta 2 + alpha L -mYFP and beta 2 + CXCR4 transfectants (XREF_FIG C).	0	31	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	30	31
In matrigel three-dimensional culture , the CD133 + / CXCR4 + group treated with recombinant SDF-1 led to more and larger colonies compared with vehicle .	In matrigel three-dimensional culture, the CD133 + / CXCR4 + group treated with recombinant SDF-1 led to more and larger colonies compared with vehicle.	6	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	15	16	9	10
As shown in XREF_FIG , for pro B cells , CXCL12 treatment induced internalization of 35-40 % of cell surface WT CXCR4 within 5 min , and maximal internalization of 50 % was achieved at 60 min .	As shown in XREF_FIG, for pro B cells, CXCL12 treatment induced internalization of 35-40% of cell surface WT CXCR4 within 5 min, and maximal internalization of 50% was achieved at 60 min.	10	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	21	22
As a stem cell homing factor , SDF-1 contributes to tissue regeneration and healing by recruiting CXCR4 positive progenitors to the damaged area .	As a stem cell homing factor, SDF-1 contributes to tissue regeneration and healing by recruiting CXCR4 positive progenitors to the damaged area.	7	18	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	7	8	16	17
As little as 37 ng/mL CXCL12 increased association of CXCR4 and beta-arrestin 2 above basal levels , and 1000 ng/mL produced a 4-fold increase in bioluminescence .	As little as 37 ng/mL CXCL12 increased association of CXCR4 and beta-arrestin 2 above basal levels, and 1000 ng/mL produced a 4-fold increase in bioluminescence.	3	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	9	10
Furthermore , WWP1 knockdown significantly reduced CXCL12 induced CXCR4 lysosomal trafficking and degradation .	Furthermore, WWP1 knockdown significantly reduced CXCL12 induced CXCR4 lysosomal trafficking and degradation.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	8	9
The CD69 and CXCR4 effects were driven by SDF-1 , while CCL21 downregulated CCR7 .	The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7.	1	9	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	8	9	3	4
SDF-1 caused CXCR4 mRNA augmentation to approximately 3x10 3 fold in comparison to the non transfected ASCs .	SDF-1 caused CXCR4 mRNA augmentation to approximately 3x10 3 fold in comparison to the non transfected ASCs.	0	4	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	2	3
The CXCL12 concentration gradients then drive movement of CXCR4 positive tumor cells in circulation and are responsible for the process of extravasation and organ specific metastasis .	The CXCL12 concentration gradients then drive movement of CXCR4 positive tumor cells in circulation and are responsible for the process of extravasation and organ specific metastasis.	1	11	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	1	2	8	9
The direct effect of CXCL12 and CXCR4 in tumor metastasis is that CXCL12 increases CXCR4 mediated motility , and the cell surface expression of integrins is mediated by the phosphorylation of extracellular signal regulated kinase ( ERK ) and downstream activation of the IKKalphabeta/NFkappabeta/RELA signaling .	The direct effect of CXCL12 and CXCR4 in tumor metastasis is that CXCL12 increases CXCR4 mediated motility, and the cell surface expression of integrins is mediated by the phosphorylation of extracellular signal regulated kinase (ERK) and downstream activation of the IKKalphabeta/NFkappabeta/RELA signaling.	12	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	14	15
Others have shown that CXCL12 stimulation of CXCR4 on HeLa cells results in MHC class I ubiquitination and targeting to endosomal degradation [ XREF_BIBR ] .	Others have shown that CXCL12 stimulation of CXCR4 on HeLa cells results in MHC class I ubiquitination and targeting to endosomal degradation [XREF_BIBR].	4	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	7	8
Calcium flux , a secondary messenger to CXCL12 mediated activation of CXCR4 , measures the activation of CXCR4 .	Calcium flux, a secondary messenger to CXCL12 mediated activation of CXCR4, measures the activation of CXCR4.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	11	12
These results confirm that CXCL12 and SDF-1alpha is not a ligand for US27 since there is no calcium flux when CXCR4 is blocked , further supporting the notion that the presence of US27 enhances the signaling activity of CXCR4 .	These results confirm that CXCL12 and SDF-1alpha is not a ligand for US27 since there is no calcium flux when CXCR4 is blocked, further supporting the notion that the presence of US27 enhances the signaling activity of CXCR4.	4	39	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	38	39
Amino acids 1-17 of CXCL12 are sufficient to activate CXCR4 signaling with greatly reduced potency , and amino acids 9-17 also function as weak agonists of this receptor [ XREF_BIBR , XREF_BIBR ] .	Amino acids 1-17 of CXCL12 are sufficient to activate CXCR4 signaling with greatly reduced potency, and amino acids 9-17 also function as weak agonists of this receptor [XREF_BIBR, XREF_BIBR].	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	9	10
On the other hand , the CXCL12 scavenging function of CXCR7 may positively regulate CXCR4 mediated migration by preventing down-regulation of CXCR4 surface expression and function following the exposure to excessive CXCL12 concentrations .	On the other hand, the CXCL12 scavenging function of CXCR7 may positively regulate CXCR4 mediated migration by preventing down-regulation of CXCR4 surface expression and function following the exposure to excessive CXCL12 concentrations.	6	16	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	14	15
SDF-1 induced HA-CXCR4 degradation was significantly attenuated in TSG101 deficient cells , as indicated by the retention of receptors in punctate structures even after 3 hours of incubation with SDF-1 .	SDF-1 induced HA-CXCR4 degradation was significantly attenuated in TSG101 deficient cells, as indicated by the retention of receptors in punctate structures even after 3 hours of incubation with SDF-1.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	HA-CXCR4	HA-CXCR4	HA-CXCR4	0	1	2	3
SDF-1 induced CXCR4 downregulation is ESCRT-I dependent .	SDF-1 induced CXCR4 downregulation is ESCRT-I dependent.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	2	3
Since the antagonist also blocks TEM of the NC-37 cells towards CXCL12 alone [ XREF_BIBR ] , we conclude that CXCR7 can regulate both CXCL12 directed TEM and CXCL12 potentiated TEM of CXCR4 + CXCR7 + lymphoma cells .	Since the antagonist also blocks TEM of the NC-37 cells towards CXCL12 alone [XREF_BIBR], we conclude that CXCR7 can regulate both CXCL12 directed TEM and CXCL12 potentiated TEM of CXCR4 + CXCR7 + lymphoma cells.	23	37	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	24	25	32	33
XREF_BIBR Furthermore , BTK is involved in B-cell adhesion , chemotaxis , and migration to lymph nodes via CXCL12 and CXCL13 activation of the chemokine receptors CXCR4 and CXCR5 .	XREF_BIBR Furthermore, BTK is involved in B-cell adhesion, chemotaxis, and migration to lymph nodes via CXCL12 and CXCL13 activation of the chemokine receptors CXCR4 and CXCR5.	18	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	18	19	26	27
Both in two-dimensional and three-dimensional cell cultures , we established that bioluminescence from this reporter measures CXCL12 dependent activation of CXCR4 and inhibition of this pathway with AMD3100 , a clinically approved small molecule that blocks CXCL12-CXCR4 binding .	Both in two-dimensional and three-dimensional cell cultures, we established that bioluminescence from this reporter measures CXCL12 dependent activation of CXCR4 and inhibition of this pathway with AMD3100, a clinically approved small molecule that blocks CXCL12-CXCR4 binding.	16	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	16	17	20	21
Upregulation of CXCL12 expression has been reported to enhance LN metastasis of CXCR4 + tumor cells .	Upregulation of CXCL12 expression has been reported to enhance LN metastasis of CXCR4 + tumor cells.	2	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12 expression	cxcl12	CXCR4	CXCR4	cxcr4	2	3	12	13
Activation of CXC-motif-chemokine receptor 4 ( CXCR4 ) signaling by the chemokine CXCL12 ( also known as SDF-1alpha ) plays a key role in many physiological processes including organogenesis , hematopoiesis , and immune responses .	Activation of CXC-motif-chemokine receptor 4 (CXCR4) signaling by the chemokine CXCL12 (also known as SDF-1alpha) plays a key role in many physiological processes including organogenesis, hematopoiesis, and immune responses.	6	13	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	6	7
The transactivation of HER2 and neu through CXCL12 stimulation of CXCR4 and Src activation cells was also demonstrated , in breast and prostate cancers [ XREF_BIBR - XREF_BIBR ] .	The transactivation of HER2 and neu through CXCL12 stimulation of CXCR4 and Src activation cells was also demonstrated, in breast and prostate cancers [XREF_BIBR - XREF_BIBR].	7	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	10	11
To further test this finding , N1 cells knocked down for CXCR4 or TGFbetaRI were treated with CXCL12 and monitored for ACTA2 and COL1alpha1 gene expression .	To further test this finding, N1 cells knocked down for CXCR4 or TGFbetaRI were treated with CXCL12 and monitored for ACTA2 and COL1alpha1 gene expression.	11	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	17	18	11	12
In this work , we assessed the involvement of the motor protein nonmuscle myosin heavy chain IIA ( MIIA ) in the endocytosis of CXCR4 induced by SDF-1alpha ( also known as CXCL12 ) in T lymphocytes .	In this work, we assessed the involvement of the motor protein nonmuscle myosin heavy chain IIA (MIIA) in the endocytosis of CXCR4 induced by SDF-1alpha (also known as CXCL12) in T lymphocytes.	22	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1alpha	SDF-1alpha	SDF-1alpha	CXCR4	CXCR4	CXCR4	27	28	24	25
XREF_BIBR , XREF_BIBR CXCL12 activates CXCR4 and the derived signaling can transduce on the mTOR pathway in pancreatic cancer , gastric cancer and T-cell leukemia cells ; XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR antagonists targeting PI3K and/or mTOR inhibited CXCL12 mediated cell migration and this effect was primarily attributed to the inhibition of mTORC1 and consequent decrease in RhoA , Cdc42 and Rac1 in human gastric carcinoma cells .	XREF_BIBR, XREF_BIBR CXCL12 activates CXCR4 and the derived signaling can transduce on the mTOR pathway in pancreatic cancer, gastric cancer and T-cell leukemia cells; XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR antagonists targeting PI3K and/or mTOR inhibited CXCL12 mediated cell migration and this effect was primarily attributed to the inhibition of mTORC1 and consequent decrease in RhoA, Cdc42 and Rac1 in human gastric carcinoma cells.	2	11	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	5	6
CXCR4 , a member of the large family of 7-transmembrane domain receptors , is coupled with heterotrimeric Gi proteins and activated by its ligand CXCL12 ( SDF-1 ) .	CXCR4, a member of the large family of 7-transmembrane domain receptors, is coupled with heterotrimeric Gi proteins and activated by its ligand CXCL12 (SDF-1).	0	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	24	25	0	1
Our in vitro data demonstrated that high levels of SDF-1 can induce the internalization and degradation of CXCR4 through the lysosome pathway .	Our in vitro data demonstrated that high levels of SDF-1 can induce the internalization and degradation of CXCR4 through the lysosome pathway.	7	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	levels of SDF-1	sdf-1	CXCR4	CXCR4	cxcr4	9	10	17	18
Therefore , CXCL12 mediated activation of CXCR4 may favor resistance to therapy in CLL patients by promoting and maintaining minimal residual disease [ XREF_BIBR - XREF_BIBR ] .	Therefore, CXCL12 mediated activation of CXCR4 may favor resistance to therapy in CLL patients by promoting and maintaining minimal residual disease [XREF_BIBR - XREF_BIBR].	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	6	7
We conclude that CXCL12 on LECs in chronically inflamed skin is well positioned to mediate the tissue exit of CCR7 + and CCR7 - CXCR4 + T cells .	We conclude that CXCL12 on LECs in chronically inflamed skin is well positioned to mediate the tissue exit of CCR7 + and CCR7 - CXCR4 + T cells.	3	27	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	24	25
CXCL12 dependent signaling of CXCR4 and its role in cellular physiology , including cancer metastasis , should be evaluated in the context of potential functional hetero-oligomerization with CXCR7 .	CXCL12 dependent signaling of CXCR4 and its role in cellular physiology, including cancer metastasis, should be evaluated in the context of potential functional hetero-oligomerization with CXCR7.	0	7	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	4	5
The SDF-1 effect was blocked by a specific CXCR4 inhibitor , AMD3100 , or transfection of siRNA targeting CXCR4 .	The SDF-1 effect was blocked by a specific CXCR4 inhibitor, AMD3100, or transfection of siRNA targeting CXCR4.	1	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	1	2	18	19
CXCL12 ( 3-68 ) was inefficient to activate CXCR4 in Presto-Tango beta-arrestin2 recruitment assays ; CXCL12-S-S4V , CXCL12-R47E and CXCL12-K27A/R41A/R47A showed significantly reduced potencies to activate CXCR4 .	CXCL12 (3-68) was inefficient to activate CXCR4 in Presto-Tango beta-arrestin2 recruitment assays; CXCL12-S-S4V, CXCL12-R47E and CXCL12-K27A/R41A/R47A showed significantly reduced potencies to activate CXCR4.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	8	9
CXCL12 stimulates the invasion and chemotactic migration of CXCR4 expressing cells , and the CXCR4 and CXCL12 axis promotes angiogenesis [ XREF_BIBR , XREF_BIBR ] .	CXCL12 stimulates the invasion and chemotactic migration of CXCR4 expressing cells, and the CXCR4 and CXCL12 axis promotes angiogenesis [XREF_BIBR, XREF_BIBR].	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	8	9
SDF-1 Enhanced Cardiogenesis Requires CXCR4 Induction .	SDF-1 Enhanced Cardiogenesis Requires CXCR4 Induction.	0	5	Enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	4	5
High MW HA augments SDF1 induced CXCR4 signaling in tumor cells , which is accompanied by enhanced ERK phosphorylation and increased motility .	High MW HA augments SDF1 induced CXCR4 signaling in tumor cells, which is accompanied by enhanced ERK phosphorylation and increased motility.	4	20	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	4	5	6	7
This hematopoietic leukemic cell line served as a control cell type with > 90 % endogenous surface expression when untreated , whereas SDF-1 treatment induced rapid internalization of CXCR4 .	This hematopoietic leukemic cell line served as a control cell type with> 90% endogenous surface expression when untreated, whereas SDF-1 treatment induced rapid internalization of CXCR4.	22	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	22	23	28	29
We demonstrated previously that activation of CXCR4 by CXCL12 enhanced the adhesion of prostate cancer cells to bone marrow endothelial cells .	We demonstrated previously that activation of CXCR4 by CXCL12 enhanced the adhesion of prostate cancer cells to bone marrow endothelial cells.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	6	7
Effect of CXCR4 activation by CXCL12 on restricting the gemcitabine induced cytotoxicity and stimulating the survival signalling was examined in pancreatic cancer cells by MTT , DNA laddering , caspase activity , immunoblot , and promoter reporter assays .	Effect of CXCR4 activation by CXCL12 on restricting the gemcitabine induced cytotoxicity and stimulating the survival signalling was examined in pancreatic cancer cells by MTT, DNA laddering, caspase activity, immunoblot, and promoter reporter assays.	2	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	2	3
The results showed that 100 ng/ml CXCL12 significantly increased the survival rate of CXCR4 + LM8 cells compared with the controls ( P < 0.05 , XREF_FIG ) .	The results showed that 100 ng/ml CXCL12 significantly increased the survival rate of CXCR4 + LM8 cells compared with the controls (P < 0.05, XREF_FIG).	4	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	13	14
We will review and discuss current knowledge on intracellular signaling through CXCR4 and biological effects triggered by each of these CXCR4 ligands , and will elaborate on how ACKR3 modulates classical CXCR4 signaling triggered by CXCL12 .	We will review and discuss current knowledge on intracellular signaling through CXCR4 and biological effects triggered by each of these CXCR4 ligands, and will elaborate on how ACKR3 modulates classical CXCR4 signaling triggered by CXCL12.	31	36	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	35	36	31	32
Both SDF-1 as well as PMA induced rapid internalization of Wt CXCR4 .	Both SDF-1 as well as PMA induced rapid internalization of Wt CXCR4.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	1	2	11	12
However , our results indicate that phorbol esters and SDF-1 operate through different intracellular signaling pathways to induce CXCR4 internalization .	However, our results indicate that phorbol esters and SDF-1 operate through different intracellular signaling pathways to induce CXCR4 internalization.	7	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	9	10	18	19
All other compounds inhibited the CXCL12 induced CXCR4 internalization in a dose dependent manner .	All other compounds inhibited the CXCL12 induced CXCR4 internalization in a dose dependent manner.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	7	8
In chemotaxis , CKLF1 is an activator of CCR4 , and SDF1 is an activator of CXCR4 .	In chemotaxis, CKLF1 is an activator of CCR4, and SDF1 is an activator of CXCR4.	11	17	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	11	12	16	17
Additionally , despite reporting little to no basal surface expression of CXCR4 on the majority of neuroblastoma cells they examined one group has reported SDF-1 mediated chemotaxis and down-regulation of CXCR4 upon derivatizing one of their cell lines to overexpress CXCR4 [ XREF_BIBR ] .	Additionally, despite reporting little to no basal surface expression of CXCR4 on the majority of neuroblastoma cells they examined one group has reported SDF-1 mediated chemotaxis and down-regulation of CXCR4 upon derivatizing one of their cell lines to overexpress CXCR4 [XREF_BIBR].	23	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	24	25	30	31
Also , the endogenous , antimicrobial protein human beta3-defensin ( HBD-3 ) was identified as a novel antagonist of CXCR4 , blocking CXCL12 induced CXCR4 signaling .	Also, the endogenous, antimicrobial protein human beta3-defensin (HBD-3) was identified as a novel antagonist of CXCR4, blocking CXCL12 induced CXCR4 signaling.	22	25	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	22	23	24	25
Because prior studies also determined that TNFR2 activity is required for proliferation of OPCs within the CC during CPZ exposure [ XREF_BIBR ] , we hypothesized that impaired remyelination in TNFR2 deficient mice might be due to loss of CXCL12 mediated activation of CXCR4 in OPCs .	Because prior studies also determined that TNFR2 activity is required for proliferation of OPCs within the CC during CPZ exposure [XREF_BIBR], we hypothesized that impaired remyelination in TNFR2 deficient mice might be due to loss of CXCL12 mediated activation of CXCR4 in OPCs.	39	44	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	39	40	43	44
CXCR4 activation by CXCL12 also enhances integrin dependent adhesion of renal carcinoma and small-cell lung cancer cells to FN .	CXCR4 activation by CXCL12 also enhances integrin dependent adhesion of renal carcinoma and small-cell lung cancer cells to FN.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	0	1
Interestingly , a CXCR4 dependent activation of focal adhesion kinase ( FAK ) , a known upregulator of KLF8 , was highly induced by CXCL12 treatment in KLF8 overexpressing , but not KLF8 deficient cells .	Interestingly, a CXCR4 dependent activation of focal adhesion kinase (FAK), a known upregulator of KLF8, was highly induced by CXCL12 treatment in KLF8 overexpressing, but not KLF8 deficient cells.	3	25	induced	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	24	25	3	4
Previously , we and others have shown that activation of CXCR4 by CXCL12 results in activation of extracellular signal regulated kinase ( ERK ) and AKT pathways in PCa cells .	Previously, we and others have shown that activation of CXCR4 by CXCL12 results in activation of extracellular signal regulated kinase (ERK) and AKT pathways in PCa cells.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	10	11
In contrast , CNO stimulation of cells co-expressing G i RASSL and Galpha 13i5 stimulated their migration toward the agonist gradient , thereby mimicking SDF-1 activation of CXCR4 .	In contrast, CNO stimulation of cells co-expressing G i RASSL and Galpha 13i5 stimulated their migration toward the agonist gradient, thereby mimicking SDF-1 activation of CXCR4.	24	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	24	25	27	28
Consistent with other members of the homeostatic and constitutive chemokine group , CXCL12 activation of CXCR4 regulates trafficking of hematopoietic stem cells , naive lymphocytes and leukocytes XREF_BIBR ; XREF_BIBR and has roles in cell-type specific mitogenesis XREF_BIBR - XREF_BIBR , carcinoma metastasis XREF_BIBR ; XREF_BIBR ; XREF_BIBR , and rheumatoid arthritis 133 .	Consistent with other members of the homeostatic and constitutive chemokine group, CXCL12 activation of CXCR4 regulates trafficking of hematopoietic stem cells, naive lymphocytes and leukocytes XREF_BIBR; XREF_BIBR and has roles in cell-type specific mitogenesis XREF_BIBR - XREF_BIBR, carcinoma metastasis XREF_BIBR; XREF_BIBR; XREF_BIBR, and rheumatoid arthritis 133.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	15	16
Boyden chamber assays expose cells acutely to high levels of CXCL12 , which may cause rapid CXCR4 internalization and desensitization 21b .	Boyden chamber assays expose cells acutely to high levels of CXCL12, which may cause rapid CXCR4 internalization and desensitization 21b.	8	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	levels of CXCL12	cxcl12	CXCR4	CXCR4	cxcr4	10	11	16	17
Furthermore , we could not exclude that a less diminished CXCL12 concentration contributed at certain times to the neuroprotective effect of CCR5 ablation by reducing the availability of free CXCR4 to viral gp120 .	Furthermore, we could not exclude that a less diminished CXCL12 concentration contributed at certain times to the neuroprotective effect of CCR5 ablation by reducing the availability of free CXCR4 to viral gp120.	10	30	contributed	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	29	30
Our studies demonstrate activation of CXCR4 by SDF-1 leads to a decrease in betaAR induced PKA activity as assessed by cAMP accumulation and PKA dependent phosphorylation of phospholamban ( PLB ) , an inhibitor of SERCA2a .	Our studies demonstrate activation of CXCR4 by SDF-1 leads to a decrease in betaAR induced PKA activity as assessed by cAMP accumulation and PKA dependent phosphorylation of phospholamban (PLB), an inhibitor of SERCA2a.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	7	8	5	6
These data suggest that the CCX771 mediated increase in CXCL12 promotes CXCR4 activation within OPCs .	These data suggest that the CCX771 mediated increase in CXCL12 promotes CXCR4 activation within OPCs.	7	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	11	12
However , our results tended toward a different direction ; CXCR4 is strongly upregulated on the cell surface of SF B cells , a finding counter to the signaling by CXCL12 in these cells .	However, our results tended toward a different direction; CXCR4 is strongly upregulated on the cell surface of SF B cells, a finding counter to the signaling by CXCL12 in these cells.	10	33	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	30	31	10	11
Because CXCL12 mediated activation of the CXCR4 receptor on HSCs is a critical niche retention signal , these data provide a plausible explanation for the phenotype observed in these mice .	Because CXCL12 mediated activation of the CXCR4 receptor on HSCs is a critical niche retention signal, these data provide a plausible explanation for the phenotype observed in these mice.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	1	2	6	7
In the case of T-cells , CXCL12 mediated CXCR4 signaling resulted in prolonged activation of ERK [ XREF_BIBR , XREF_BIBR ] .	In the case of T-cells, CXCL12 mediated CXCR4 signaling resulted in prolonged activation of ERK [XREF_BIBR, XREF_BIBR].	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	8	9
Both the homing of hematopoietic stem cells ( HSCs ) to the bone marrow and their engraftment in recipients of bone marrow transplants are primarily mediated by the chemokine stromal derived factor-1 ( SDF-1 ) or CXCL12 , which activates CXCR4 , its cognate receptor on HSCs .	Both the homing of hematopoietic stem cells (HSCs) to the bone marrow and their engraftment in recipients of bone marrow transplants are primarily mediated by the chemokine stromal derived factor-1 (SDF-1) or CXCL12, which activates CXCR4, its cognate receptor on HSCs.	30	44	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	36	37	40	41
Agents that disrupt CXCL12 mediated chemoattraction of CXCR4 expressing cells mobilize PMNs and HSPCs into the peripheral circulation and are therapeutically useful for HSPC collection before autologous bone marrow transplantation ( ABMT ) .	Agents that disrupt CXCL12 mediated chemoattraction of CXCR4 expressing cells mobilize PMNs and HSPCs into the peripheral circulation and are therapeutically useful for HSPC collection before autologous bone marrow transplantation (ABMT).	3	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	7	8
Thus , Sdf-1 stimulated binding of CXCR4 + BMCs ( beta-gal + ) to myofibers but did not change the proportion of cells expressing MRFs .	Thus, Sdf-1 stimulated binding of CXCR4 + BMCs (beta-gal +) to myofibers but did not change the proportion of cells expressing MRFs.	2	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sdf-1	Sdf-1	Sdf-1	CXCR4	CXCR4	CXCR4	2	3	6	7
This agrees with previous demonstrations in which signals other than Notch1 activation ( i.e ., stimulation of CXCR4 by SDF1a and activation of the Wnt pathway ) are required to successfully pass through the beta-selection checkpoint [ XREF_BIBR , XREF_BIBR ] .	This agrees with previous demonstrations in which signals other than Notch1 activation (i.e., stimulation of CXCR4 by SDF1a and activation of the Wnt pathway) are required to successfully pass through the beta-selection checkpoint [XREF_BIBR, XREF_BIBR].	15	21	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF1a	SDF1a	SDF1a	CXCR4	CXCR4	CXCR4	19	20	17	18
Relative to CXCR7 + cells , bioluminescence from CXCR7-CBGN and beta-arrestin 2-CBC decreased minimally by 15 % in CXCR4 + -CXCR7 + cells treated with 1000 ng/mL CXCL12 ( XREF_FIG ) .	Relative to CXCR7 + cells, bioluminescence from CXCR7-CBGN and beta-arrestin 2-CBC decreased minimally by 15% in CXCR4 + -CXCR7 + cells treated with 1000 ng/mL CXCL12 (XREF_FIG).	16	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	27	28	18	19
In general , CXCL12 triggers CXCR4 to activate G protein coupled signaling pathways including mitogen activated protein kinase ( MAPK ) , which subsequently induce several cellular responses including gene expression and pulmonary fibrosis [ XREF_BIBR , XREF_BIBR ] .	In general, CXCL12 triggers CXCR4 to activate G protein coupled signaling pathways including mitogen activated protein kinase (MAPK), which subsequently induce several cellular responses including gene expression and pulmonary fibrosis [XREF_BIBR, XREF_BIBR].	1	6	triggers	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	5	6
Bone marrow is one of the major tissues that produce CXCL12 which activates CXCR4 XREF_BIBR .	Bone marrow is one of the major tissues that produce CXCL12 which activates CXCR4 XREF_BIBR.	9	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	13	14
Intraventricular infusion of the CXCR4-antagonist AMD3100 dramatically increased CXCR4 protein expression in SGL neurons , suggesting that CXCR4 is tonically activated and downregulated by endogenous SDF-1 .	Intraventricular infusion of the CXCR4-antagonist AMD3100 dramatically increased CXCR4 protein expression in SGL neurons, suggesting that CXCR4 is tonically activated and downregulated by endogenous SDF-1.	17	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	25	26	17	18
Next , we investigated whether human CXCL12 activates zebrafish Cxcr4 .	Next, we investigated whether human CXCL12 activates zebrafish Cxcr4.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	Cxcr4	Cxcr4	Cxcr4	6	7	9	10
We also found that CXCL12 enhanced HNSCC cell invasion through paracrine activated CXCR4 , which triggered MMP dependent cell invasion .	We also found that CXCL12 enhanced HNSCC cell invasion through paracrine activated CXCR4, which triggered MMP dependent cell invasion.	4	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	12	13
In contrast , the CCR7 TM4 peptide did not affect CXCL12 induced CXCR4 internalization , indicating that the peptide selectively acted on CCR7 .	In contrast, the CCR7 TM4 peptide did not affect CXCL12 induced CXCR4 internalization, indicating that the peptide selectively acted on CCR7.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	12	13
These results showed that CXCL12 prevents apoptosis in serum starved CXCR4 + OS cells via the activation of CXCR4 .	These results showed that CXCL12 prevents apoptosis in serum starved CXCR4 + OS cells via the activation of CXCR4.	4	13	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	10	11
This is the first report to demonstrate GPCR regulation of CK1alpha expression and GSK3beta via Y216 phosphorylation , specifically , SDF1 activation of CXCR4 , where both actions converge to facilitate quiescence of resident CSPCs through GSK3beta dependent cyclin D1 phosphorylation and Bmi-1 dependent downregulation ( see schematic XREF_FIG ) .	This is the first report to demonstrate GPCR regulation of CK1alpha expression and GSK3beta via Y216 phosphorylation, specifically, SDF1 activation of CXCR4, where both actions converge to facilitate quiescence of resident CSPCs through GSK3beta dependent cyclin D1 phosphorylation and Bmi-1 dependent downregulation (see schematic XREF_FIG).	20	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	20	21	23	24
N1 cells knocked down for the CXCR4 receptor then treated with CXCL12 demonstrated greatly reduced EGFR , Akt and ERK1/2 phosphorylation when compared to control scramble siRNA transfected cells ( XREF_FIG ) .	N1 cells knocked down for the CXCR4 receptor then treated with CXCL12 demonstrated greatly reduced EGFR, Akt and ERK1/2 phosphorylation when compared to control scramble siRNA transfected cells (XREF_FIG).	6	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	6	7
Our results showed that SDF-1 treatment significantly increased the trafficking of CXCR4-WT-YFP and CXCR4-KKK and AAA-YFP into clustered endosomes in SDF-1 - treated cells .	Our results showed that SDF-1 treatment significantly increased the trafficking of CXCR4-WT-YFP and CXCR4-KKK and AAA-YFP into clustered endosomes in SDF-1 - treated cells.	4	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4-WT-YFP	CXCR4-WT-YFP	CXCR4-WT-YFP	4	5	11	12
Our model of CXCL12 mediated CXCR4 activation draws parallels to analogous models of beta 2 -adrenergic receptor ( beta 2 AR ) and mu-opioid receptor ( muOR ) activation .	Our model of CXCL12 mediated CXCR4 activation draws parallels to analogous models of beta 2 -adrenergic receptor (beta 2 AR) and mu-opioid receptor (muOR) activation.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	5	6
For different CXC receptor : chemokine pairs , interactions in this region can explain a number of experimental observations that could not be explained by previous structures and models : ( i ) cross saturation NMR experiments suggested that the beta 1 strand of CXCL12 is in close proximity to the CXCR4 N terminus XREF_BIBR , ( ii ) truncation of residues 2-9 of CXCR4 affects both CXCL12 binding and activation of CXCR4 , ( iii ) D10 is critical for CXCL12 induced activation of CXCR4 , ( iv ) sulfation of residues Y7 and Y12 of CXCR4 affects CXCL12 induced signalling XREF_BIBR , ( v ) nuclear Overhauser effects have been measured in this region between CXCL12 and a peptide corresponding to residues 1-38 of the CXCR4 N terminus XREF_BIBR , ( vi ) mutation of CXCR2 residues 7 and/or 9 affects chemokine binding and signalling XREF_BIBR and ( vii ) mutations in the beta1 strand of CXCL8 reduce its affinity for CXCR1 .	For different CXC receptor : chemokine pairs, interactions in this region can explain a number of experimental observations that could not be explained by previous structures and models : (i) cross saturation NMR experiments suggested that the beta 1 strand of CXCL12 is in close proximity to the CXCR4 N terminus XREF_BIBR, (ii) truncation of residues 2-9 of CXCR4 affects both CXCL12 binding and activation of CXCR4, (iii) D10 is critical for CXCL12 induced activation of CXCR4, (iv) sulfation of residues Y7 and Y12 of CXCR4 affects CXCL12 induced signalling XREF_BIBR, (v) nuclear Overhauser effects have been measured in this region between CXCL12 and a peptide corresponding to residues 1-38 of the CXCR4 N terminus XREF_BIBR, (vi) mutation of CXCR2 residues 7 and/or 9 affects chemokine binding and signalling XREF_BIBR and (vii) mutations in the beta1 strand of CXCL8 reduce its affinity for CXCR1.	81	163	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	81	82	85	86
, indicate that SDF-1 can induce rapid endocytosis of CXCR4 , and that this chemokine is a more effective inhibitor of HIV-1 infection on cells expressing endocytosis-competent CXCR4 than on cells expressing CXCR4 DeltaCyt , suggest that endocytosis may make a significant contribution to chemokine protection .	, indicate that SDF-1 can induce rapid endocytosis of CXCR4, and that this chemokine is a more effective inhibitor of HIV-1 infection on cells expressing endocytosis-competent CXCR4 than on cells expressing CXCR4 DeltaCyt, suggest that endocytosis may make a significant contribution to chemokine protection.	3	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	9	10
Bioinformatic analysis predicted these miRNA to modulate CXCR4 signalling , leading us to hypothesize that CXCL12 mediated CXCR4 signalling is involved in the disrupted differentiation of gonocytes that underpins CIS formation .	Bioinformatic analysis predicted these miRNA to modulate CXCR4 signalling, leading us to hypothesize that CXCL12 mediated CXCR4 signalling is involved in the disrupted differentiation of gonocytes that underpins CIS formation.	14	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	17	18
An optimum dose gradient of CXCL12 conducted by the neurons and Schwann cells induces the chemotactic migration of CXCR4 bearing tumor cells toward the peripheral nerves , and simultaneously increases PCa cells metastasis and invasion , thereby establishing PNI .	An optimum dose gradient of CXCL12 conducted by the neurons and Schwann cells induces the chemotactic migration of CXCR4 bearing tumor cells toward the peripheral nerves, and simultaneously increases PCa cells metastasis and invasion, thereby establishing PNI.	3	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	18	19
In fact it has been reported that SDF1 not only stimulates CXCR4 signaling but also regulates its expression by positive feed back mechanism .	In fact it has been reported that SDF1 not only stimulates CXCR4 signaling but also regulates its expression by positive feed back mechanism.	7	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	7	8	11	12
Granulocytes are retained in the bone marrow by CXCL12 mediated CXCR4 signalling and exit in response to CXCR2 ligands , such as CXCL2 ( also known as MIP2 ) and CXCL1 ( also known as KC ) , which are produced during infection XREF_BIBR , XREF_BIBR .	Granulocytes are retained in the bone marrow by CXCL12 mediated CXCR4 signalling and exit in response to CXCR2 ligands, such as CXCL2 (also known as MIP2) and CXCL1 (also known as KC), which are produced during infection XREF_BIBR, XREF_BIBR.	2	40	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	10	11
The dual-function polycation prevents cancer cell invasion by inhibiting CXCL12 stimulated CXCR4 activation , while at the same time efficiently and safely delivers plasmid DNA into cancer cells .	The dual-function polycation prevents cancer cell invasion by inhibiting CXCL12 stimulated CXCR4 activation, while at the same time efficiently and safely delivers plasmid DNA into cancer cells.	9	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	11	12
Because PCs expressing the CXCR4 epitope have the ability to home to areas of ischemia with increased expression of its ligand , SDF-1alpha , our results suggest that the increased expression of SDF-1alpha from the ischemic myocardium promotes homing of the CD34 + / CXCR4 + PCs , resulting in a decrease in circulating levels of PCs .	Because PCs expressing the CXCR4 epitope have the ability to home to areas of ischemia with increased expression of its ligand, SDF-1alpha, our results suggest that the increased expression of SDF-1alpha from the ischemic myocardium promotes homing of the CD34 + / CXCR4 + PCs, resulting in a decrease in circulating levels of PCs.	30	46	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1alpha	expression of SDF-1alpha	sdf-1alpha	CXCR4	CXCR4	cxcr4	32	33	44	45
Together , CXCL12 acts on arterial endothelial cells of SMA to up-regulate CXCR4 and mediate the connection between the larger artery and neighboring capillary plexus in an organ specific manner .	Together, CXCL12 acts on arterial endothelial cells of SMA to up-regulate CXCR4 and mediate the connection between the larger artery and neighboring capillary plexus in an organ specific manner.	2	14	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	12	13
CXCL12 induced an increase in intracellular free Ca 2+ in DW34 cells and CXCR4 transfected Chinese hamster ovary ( CHO ) cells , suggesting that CXCR4 is a receptor for CXCL12 .	CXCL12 induced an increase in intracellular free Ca 2+ in DW34 cells and CXCR4 transfected Chinese hamster ovary (CHO) cells, suggesting that CXCR4 is a receptor for CXCL12.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	13	14
In addition , studies in various cancer cell lines , including breast cancer cells , established key roles for P-Rex1 in cell migration stimulated by growth factors such as HRG as well as GPCR ligands such as SDF-1 , a chemokine that activates CXCR4 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, studies in various cancer cell lines, including breast cancer cells, established key roles for P-Rex1 in cell migration stimulated by growth factors such as HRG as well as GPCR ligands such as SDF-1, a chemokine that activates CXCR4 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	34	49	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	37	38	43	44
Another interesting finding of our study was the observation that the time course of ERK activation by CXCL12 induced activation of CXCR4 was indistinguishable for the WT and 3K/R receptor structures , providing evidence that a signaling pathway independent of ERK activation links CXCL12 activation of the receptor to chemotaxis .	Another interesting finding of our study was the observation that the time course of ERK activation by CXCL12 induced activation of CXCR4 was indistinguishable for the WT and 3K/R receptor structures, providing evidence that a signaling pathway independent of ERK activation links CXCL12 activation of the receptor to chemotaxis.	15	22	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	17	18	21	22
Alternatively , if CXCL12 produces its effect by activating CXCR4 receptors on GABA cell bodies or dendrites , enhancing neuronal activity and subsequently GABA release , mIPSC frequency should be unaffected by CXCL12 .	Alternatively, if CXCL12 produces its effect by activating CXCR4 receptors on GABA cell bodies or dendrites, enhancing neuronal activity and subsequently GABA release, mIPSC frequency should be unaffected by CXCL12.	3	10	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	9	10
Its analog AMD3465 demonstrated remarkable activity in antagonizing CXCL12 induced CXCR4 signaling pathways , mobilizing AML cells into circulation and enhancing anti-leukemic effects of chemotherapy in vitro and in vivo XREF_BIBR XREF_BIBR .	Its analog AMD3465 demonstrated remarkable activity in antagonizing CXCL12 induced CXCR4 signaling pathways, mobilizing AML cells into circulation and enhancing anti-leukemic effects of chemotherapy in vitro and in vivo XREF_BIBR XREF_BIBR.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	10	11
To determine the effects of the SDF-1 and CXCR4 axis on the apoptosis of degenerative NPCs , cells were treated with 10 ng/ml SDF-1 for 24 h. qPCR and western blot analysis demonstrated that SDF-1 treatment resulted in an increase in CXCR4 expression at the protein and mRNA levels ( P = 0.034 and P = 0.022 , respectively ) , compared with untreated cells ( XREF_FIG ) .	To determine the effects of the SDF-1 and CXCR4 axis on the apoptosis of degenerative NPCs, cells were treated with 10 ng/ml SDF-1 for 24 h. qPCR and western blot analysis demonstrated that SDF-1 treatment resulted in an increase in CXCR4 expression at the protein and mRNA levels (P = 0.034 and P = 0.022, respectively), compared with untreated cells (XREF_FIG).	6	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	23	24	8	9
To test this hypothesis , the time course of pERK formation , a downstream readout of SDF-1 mediated CXCR4 signaling , was monitored .	To test this hypothesis, the time course of pERK formation, a downstream readout of SDF-1 mediated CXCR4 signaling, was monitored.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	16	17	18	19
Moreover , we found that CXCL12 induced the migration of CXCR4 positive macrophages ( Additional file XREF_SUPPLEMENTARY , Supplemental Figures 5B and 5C ) .	Moreover, we found that CXCL12 induced the migration of CXCR4 positive macrophages (Additional file XREF_SUPPLEMENTARY, Supplemental Figures 5B and 5C).	5	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	10	11
High-molecular weight HA binding to CD44 augmented the activation of CXCR4 by its ligand CXCL12 whereas small HA fragments completely abrogated the CXCL12 induced CXCR4 signaling .	High-molecular weight HA binding to CD44 augmented the activation of CXCR4 by its ligand CXCL12 whereas small HA fragments completely abrogated the CXCL12 induced CXCR4 signaling.	21	25	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	22	23	24	25
On the one hand , CXCL12 has been shown to induce secretion of VEGF in lymphohematopoietic CXCR4 + cell lines [ XREF_BIBR ] .	On the one hand, CXCL12 has been shown to induce secretion of VEGF in lymphohematopoietic CXCR4 + cell lines [XREF_BIBR].	5	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	16	17
These data indicate that endothelial cell secretion of CXCL12 is sufficient to induce the localization of CXCR4 expressing GBM cells .	These data indicate that endothelial cell secretion of CXCL12 is sufficient to induce the localization of CXCR4 expressing GBM cells.	6	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	16	17
Similarly , CXCL12 induced CXCR4 internalization was not significantly altered in any of the knockdown cell lines or in Syt7 -/- cells versus cells with shRNA mediated knockdown of eGFP or wild-type cells ( XREF_FIG ) .	Similarly, CXCL12 induced CXCR4 internalization was not significantly altered in any of the knockdown cell lines or in Syt7 -/- cells versus cells with shRNA mediated knockdown of eGFP or wild-type cells (XREF_FIG).	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	4	5
CXCL12 activates the chemokine receptor CXCR4 , which is overexpressed in 23 different cancers including breast cancer , and plays a role in cancer development through its promotion of cell growth , angiogenesis , and metastasis [ XREF_BIBR ] .	CXCL12 activates the chemokine receptor CXCR4, which is overexpressed in 23 different cancers including breast cancer, and plays a role in cancer development through its promotion of cell growth, angiogenesis, and metastasis [XREF_BIBR].	0	19	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	CXCL12	CXCL12	cxcl12	CXCR4	CXCR4, which is overexpressed	cxcr4	0	1	5	6
Results : Recruitment of eosinophils in the inflamed airway is selectively attenuated by short lived antagonists that block CXCL12 mediated activation of CXCR4 .	Results : Recruitment of eosinophils in the inflamed airway is selectively attenuated by short lived antagonists that block CXCL12 mediated activation of CXCR4.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	18	19	22	23
Using pharmacological and genetic approaches we demonstrated that hypoxic OPCs release in a HIF1 depended manner CXCL12 in the bloodstream , and that OPC derived CXCL12 activates CXCR4 to directly promote breast cancer cell proliferation and metastasis , in a systemic fashion .	Using pharmacological and genetic approaches we demonstrated that hypoxic OPCs release in a HIF1 depended manner CXCL12 in the bloodstream, and that OPC derived CXCL12 activates CXCR4 to directly promote breast cancer cell proliferation and metastasis, in a systemic fashion.	24	28	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	25	26	27	28
An alternative CXCL12 scavenger receptor , CXCR7 and ACKR3 ( CXCR7 ) , sequesters ligand for degradation , regulating CXCL12 mediated activation of CXCR4 .	An alternative CXCL12 scavenger receptor, CXCR7 and ACKR3 (CXCR7), sequesters ligand for degradation, regulating CXCL12 mediated activation of CXCR4.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	23	24
SDF-1 and CXCR4 may participate in corneal graft rejection in rats early after transplantation possibly through the mechanism that SDF-1 specifically induces CXCR4 + cell maturation and chemotaxis toward the allograft to promote corneal neovascularization .	SDF-1 and CXCR4 may participate in corneal graft rejection in rats early after transplantation possibly through the mechanism that SDF-1 specifically induces CXCR4 + cell maturation and chemotaxis toward the allograft to promote corneal neovascularization.	19	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	19	20	22	23
Using the murine MS model , experimental autoimmune encephalomyelitis ( EAE ) , we previously demonstrated that antagonism of the chemokine receptor CXCR7 blocks endothelial cell sequestration of CXCL12 , thereby enhancing the abluminal localization of CXCR4 expressing leukocytes .	Using the murine MS model, experimental autoimmune encephalomyelitis (EAE), we previously demonstrated that antagonism of the chemokine receptor CXCR7 blocks endothelial cell sequestration of CXCL12, thereby enhancing the abluminal localization of CXCR4 expressing leukocytes.	26	37	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	28	29	36	37
Because SDF1 triggers CXCR4 internalization and degradation , measuring the degree of CXCR4 internalization should be a readout of the levels of extracellular SDF1 ( XREF_FIG ) .	Because SDF1 triggers CXCR4 internalization and degradation, measuring the degree of CXCR4 internalization should be a readout of the levels of extracellular SDF1 (XREF_FIG).	1	4	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	1	2	3	4
A possible explanation for the phenotype could be that lack of CXCR7 gives rise to CXCL12 stimulated CXCR4 dependent hyperplasia .	A possible explanation for the phenotype could be that lack of CXCR7 gives rise to CXCL12 stimulated CXCR4 dependent hyperplasia.	13	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	17	18
In our previous work we demonstrated that metastasis of RMS cells to BM is mediated by BM stromal cells that secrete SDF-1 , a major chemoattractant for hematopoietic stem cells ( HSCs ) , that activates the CXCR4 receptor .	In our previous work we demonstrated that metastasis of RMS cells to BM is mediated by BM stromal cells that secrete SDF-1, a major chemoattractant for hematopoietic stem cells (HSCs), that activates the CXCR4 receptor.	20	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	21	22	37	38
SDF-1 triggers CXCR4 receptor dimerization and activate the intracellular signaling pathways of BMSCs , and the positive feedbacks from BMSC will change the behaviors of MICs .	SDF-1 triggers CXCR4 receptor dimerization and activate the intracellular signaling pathways of BMSCs, and the positive feedbacks from BMSC will change the behaviors of MICs.	0	6	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	2	3
Activation of CXCR4 by SDF1 will induce migration of these cells along the SDF1 track , bringing the next cells in contact with SDF1 .	Activation of CXCR4 by SDF1 will induce migration of these cells along the SDF1 track, bringing the next cells in contact with SDF1.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	4	5	2	3
SDF-1 causes internalization of CXCR4 in vitro and primary cells from MM patients showed higher surface expression of CXCR4 while circulating in the peripheral blood , when compared to BM resident MM cells , suggesting a potential negative feedback loop between SDF-1 and CXCR4 .	SDF-1 causes internalization of CXCR4 in vitro and primary cells from MM patients showed higher surface expression of CXCR4 while circulating in the peripheral blood, when compared to BM resident MM cells, suggesting a potential negative feedback loop between SDF-1 and CXCR4.	0	5	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	4	5
CXCL12 stimulated the invasion and migration of K1 cells overexpressing CXCR4 , but did not affect K1 cells overexpressing CXCR7 .	CXCL12 stimulated the invasion and migration of K1 cells overexpressing CXCR4, but did not affect K1 cells overexpressing CXCR7.	0	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	10	11
Thus , in ESCs expression of CD9 is regulated via Sdf-1 activating Cxcr4 , but not Cxcr7 , what was in agreement with our previous results documenting Sdf-1 dependent expression of CD9 in C2C12 myoblasts , bone marrow derived MSC , and ESCs .	Thus, in ESCs expression of CD9 is regulated via Sdf-1 activating Cxcr4, but not Cxcr7, what was in agreement with our previous results documenting Sdf-1 dependent expression of CD9 in C2C12 myoblasts, bone marrow derived MSC, and ESCs.	8	26	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Sdf-1	Sdf-1	Sdf-1	Cxcr4	Cxcr4	Cxcr4	10	11	12	13
Using flow cytometry to measure the rate of CXCL12 and SDF1 induced CXCR4 internalization , we found that WHIM mutant CXCR4 receptors show a slower rate of ligand induced internalization compared to WT receptor ( XREF_FIG ) .	Using flow cytometry to measure the rate of CXCL12 and SDF1 induced CXCR4 internalization, we found that WHIM mutant CXCR4 receptors show a slower rate of ligand induced internalization compared to WT receptor (XREF_FIG).	6	13	induced	Positive_early_activation	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	10	11	12	13
Interestingly , our recent studies demonstrate that Mu opioid receptor ( MOR ) agonists , such as morphine or DAMGO , inhibit CXCL12 induced activation of CXCR4 and stimulation of downstream signaling through ERK and Akt .	Interestingly, our recent studies demonstrate that Mu opioid receptor (MOR) agonists, such as morphine or DAMGO, inhibit CXCL12 induced activation of CXCR4 and stimulation of downstream signaling through ERK and Akt.	22	28	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	22	23	26	27
Perissinotto ' s study showed that high SDF-1 concentration contributed to the osteosarcoma metastatic development into the lung and inhibiting the SDF-1 and CXCR4 pathway by small-molecule inhibitors or anti-CXCR4 antibodies , T134 peptide , might prevent the dissemination of osteosarcoma cells.17 Liao et al20 found that blocking CXCR4 by AMD3100 could reduce primary tumor growth and lung metastasis .	Perissinotto 's study showed that high SDF-1 concentration contributed to the osteosarcoma metastatic development into the lung and inhibiting the SDF-1 and CXCR4 pathway by small-molecule inhibitors or anti-CXCR4 antibodies, T134 peptide, might prevent the dissemination of osteosarcoma cells.17 Liao et al20 found that blocking CXCR4 by AMD3100 could reduce primary tumor growth and lung metastasis.	7	24	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	7	8	23	24
Up-regulation of SDF-1 in the infarcted hearts causes massive influx of CXCR4 positive stem cells from the bone marrow XREF_BIBR , XREF_BIBR .	Up-regulation of SDF-1 in the infarcted hearts causes massive influx of CXCR4 positive stem cells from the bone marrow XREF_BIBR, XREF_BIBR.	0	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	2	3	11	12
CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem like cells and regulation of the tumor microenvironment .	CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem like cells and regulation of the tumor microenvironment.	0	6	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	3	4
In comparison , activation of CXCR4 by SDF-1 prior to ISO treatment substantially diminished cAMP accumulation ( XREF_FIG ) .	In comparison, activation of CXCR4 by SDF-1 prior to ISO treatment substantially diminished cAMP accumulation (XREF_FIG).	3	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	7	8	5	6
Pre-clinical studies indicate that SDF-1 increases stem cell homing by stimulating the CXCR4 receptor in these cells .	Pre-clinical studies indicate that SDF-1 increases stem cell homing by stimulating the CXCR4 receptor in these cells.	4	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	12	13
As expected , CXCL12 triggered internalization of its receptor CXCR4 but not CXCR3 ( data not shown ) .	As expected, CXCL12 triggered internalization of its receptor CXCR4 but not CXCR3 (data not shown).	3	10	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	9	10
GH pretreatment also prevents CXCL12 mediated CXCR4 internalization ( XREF_FIG A ) , indicating that GH interferes with CXCL12 signaling rather than with surface CXCR4 levels .	GH pretreatment also prevents CXCL12 mediated CXCR4 internalization (XREF_FIG A), indicating that GH interferes with CXCL12 signaling rather than with surface CXCR4 levels.	3	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	6	7
We previously demonstrated that direct stimulation of CXCR4 by CXCL12 activated two main signaling pathways in MM cells , PI3K and PLCbeta3 XREF_BIBR .	We previously demonstrated that direct stimulation of CXCR4 by CXCL12 activated two main signaling pathways in MM cells, PI3K and PLCbeta3 XREF_BIBR.	5	10	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	7	8
HeLa cells , which endogenously express CXCR4 , were transfected with HA-arrestin-2 and treated with CXCL12 ( 30 nM ) or vehicle ( 0.05 % BSA-PBS ) for various times followed by immunoprecipitation of tagged arrestin-2 and immunoblotting to detect bound endogenous STAM-1 .	HeLa cells, which endogenously express CXCR4, were transfected with HA-arrestin-2 and treated with CXCL12 (30 nM) or vehicle (0.05% BSA-PBS) for various times followed by immunoprecipitation of tagged arrestin-2 and immunoblotting to detect bound endogenous STAM-1.	5	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	6	7
In pregnant mice , CXCL12 causes migration of CXCR4 + T reg cells into the uterus and prevents embryo loss [ XREF_BIBR ] .	In pregnant mice, CXCL12 causes migration of CXCR4 + T reg cells into the uterus and prevents embryo loss [XREF_BIBR].	4	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	8	9
Our findings imply that interfering with the CXCL12 scavenging activity of CXCR7 causes loss of CXCR4 function as a consequence of excessive CXCL12 mediated CXCR4 activation and degradation .	Our findings imply that interfering with the CXCL12 scavenging activity of CXCR7 causes loss of CXCR4 function as a consequence of excessive CXCL12 mediated CXCR4 activation and degradation.	19	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	22	23	24	25
Our data clearly shows that tCXCR4 and CatCh was functionally expressed in NG108-15 and HEK293 cells , that the activation of CXCR4 by SDF1 in tCXCR4 and CatCh led to the internalization of the whole tandem construct by endocytosis via the clathrin mediated endosome pathway , and that the optophysiological tool could generate intracellular Ca 2+ -elevation upon light induced channel opening .	Our data clearly shows that tCXCR4 and CatCh was functionally expressed in NG108-15 and HEK293 cells, that the activation of CXCR4 by SDF1 in tCXCR4 and CatCh led to the internalization of the whole tandem construct by endocytosis via the clathrin mediated endosome pathway, and that the optophysiological tool could generate intracellular Ca 2+ -elevation upon light induced channel opening.	19	27	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	23	24	21	22
To investigate the role of MUC1 in CXCL12 activated CXCR4 signaling , immunoprecipitations were performed with anti-MUC1 antibodies ( XREF_FIG ) .	To investigate the role of MUC1 in CXCL12 activated CXCR4 signaling, immunoprecipitations were performed with anti-MUC1 antibodies (XREF_FIG).	1	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	9	10
Furthermore , our data demonstrate that the ligand of CXCR4 , SDF-1 induces CXCR4 positive pancreatic cancer invasion , epithelial-mesenchymal transition ( EMT ) process and activates the non canonical Hh pathway .	Furthermore, our data demonstrate that the ligand of CXCR4, SDF-1 induces CXCR4 positive pancreatic cancer invasion, epithelial-mesenchymal transition (EMT) process and activates the non canonical Hh pathway.	9	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	11	12	13	14
Tysseling et al [ XREF_BIBR ] demonstrated that SDF-1 induced the migration of CXCR4 positive macrophages to damaged regions following SCI , and several studies have verified that SDF-1 and CXCR4 regulates MSC migration to damaged sites in the central nervous system [ XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR ] .	Tysseling et al [XREF_BIBR] demonstrated that SDF-1 induced the migration of CXCR4 positive macrophages to damaged regions following SCI, and several studies have verified that SDF-1 and CXCR4 regulates MSC migration to damaged sites in the central nervous system [XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR].	8	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	8	9	13	14
Ectopic Sdf1 expression in the chick limb bud causes an aberrant accumulation of CXCR4 ( + ) myogenic cells near the source .	Ectopic Sdf1 expression in the chick limb bud causes an aberrant accumulation of CXCR4 (+) myogenic cells near the source.	1	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sdf1	Sdf1 expression	sdf1	CXCR4	CXCR4	cxcr4	1	2	13	14
SDF-1alpha activates CXCR4 , and this in turn mediates invasion and proliferation of tumor cells , enhances tumor associated neoangiogenesis , and assists in the degradation of the extracellular matrix and basement membrane [ XREF_BIBR , XREF_BIBR ] .	SDF-1alpha activates CXCR4, and this in turn mediates invasion and proliferation of tumor cells, enhances tumor associated neoangiogenesis, and assists in the degradation of the extracellular matrix and basement membrane [XREF_BIBR, XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1alpha	SDF-1alpha	SDF-1alpha	CXCR4	CXCR4	CXCR4	0	1	2	3
LSCs share certain features of self-renewal and differentiation with HSCs , and the molecules that mediate the interaction between LSCs and the BM niche , including adhesion molecules , and CXCL12 mediated CXCR4 signaling for homing and mobilization within the BM are similar to those of HSCs .	LSCs share certain features of self-renewal and differentiation with HSCs, and the molecules that mediate the interaction between LSCs and the BM niche, including adhesion molecules, and CXCL12 mediated CXCR4 signaling for homing and mobilization within the BM are similar to those of HSCs.	30	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	30	31	32	33
While full-length CXCL12 ( 68 amino acids ) activates CXCR4 , truncation of the N-terminus by 2-6 amino acids by enzymes such as dipeptidyl peptidase-IV ( CD26 ) abrogates receptor signaling and switches CXCL12 from an agonist to an antagonist [ XREF_BIBR ] .	While full-length CXCL12 (68 amino acids) activates CXCR4, truncation of the N-terminus by 2-6 amino acids by enzymes such as dipeptidyl peptidase-IV (CD26) abrogates receptor signaling and switches CXCL12 from an agonist to an antagonist [XREF_BIBR].	1	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	9	10
In those cells , it appears that activation of PI-3 kinase by Ga i is important in mediating activation of FAK in response to engagement of CXCR4 by CXCL12 , although exactly how the activation of PI-3 kinase leads to the activation of FAK was unclear [ XREF_BIBR , XREF_BIBR ] .	In those cells, it appears that activation of PI-3 kinase by Ga i is important in mediating activation of FAK in response to engagement of CXCR4 by CXCL12, although exactly how the activation of PI-3 kinase leads to the activation of FAK was unclear [XREF_BIBR, XREF_BIBR].	17	29	mediating	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	28	29	26	27
Naturally , CXCR4 is activated by its ligand CXCL12 , also known as stromal cell derived factor 1 ( SDF-1 ) , which represents a multifunctional cytokine .	Naturally, CXCR4 is activated by its ligand CXCL12, also known as stromal cell derived factor 1 (SDF-1), which represents a multifunctional cytokine.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	2	3
SDF-1 was also shown to elicit a CXCR4 dependent chemorepellent response from fetal SP thymocytes .	SDF-1 was also shown to elicit a CXCR4 dependent chemorepellent response from fetal SP thymocytes.	0	10	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	7	8
In these cells , the long-term treatment with Mu opioid receptor ( MOR ) agonists , such as morphine , inhibits CXCL12 induced activation of CXCR4 and the related downstream signalling through ERK and AKT [ XREF_BIBR ] .	In these cells, the long-term treatment with Mu opioid receptor (MOR) agonists, such as morphine, inhibits CXCL12 induced activation of CXCR4 and the related downstream signalling through ERK and AKT [XREF_BIBR].	21	30	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	21	22	25	26
We show that the activation of CXCR4 by CXCL12 is increased upon preincubation of cells with hHA .	We show that the activation of CXCR4 by CXCL12 is increased upon preincubation of cells with hHA.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	6	7
CXCL12 is cleaved by MMP-9 , causing its receptor CXCR4 to lose its binding ability [ XREF_BIBR , XREF_BIBR ] .	CXCL12 is cleaved by MMP-9, causing its receptor CXCR4 to lose its binding ability [XREF_BIBR, XREF_BIBR].	0	10	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	9	10
In the apoptosome , cytochrome c serves to allow oligomerisation of Apaf-1 and thereby of caspase-9 .	In the apoptosome, cytochrome c serves to allow oligomerisation of Apaf-1 and thereby of caspase-9.	4	12	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	4	6	11	12
Cytochrome C in turn stimulates Apaf-1 and Caspase-9 to form apoptosomes , and then activates Caspase-3 , leading to cell death XREF_BIBR , XREF_BIBR .	Cytochrome C in turn stimulates Apaf-1 and Caspase-9 to form apoptosomes, and then activates Caspase-3, leading to cell death XREF_BIBR, XREF_BIBR.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	Apaf-1	Apaf-1	Apaf-1	0	2	5	6
Then the release of cytochrome c causes apoptotic protease activating factor 1 ( Apaf1 ) oligomerization , resulting in apoptosome formation .	Then the release of cytochrome c causes apoptotic protease activating factor 1 (Apaf1) oligomerization, resulting in apoptosome formation.	4	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	apoptotic protease activating factor 1	apoptotic protease activating factor 1	apoptotic protease activating factor 1	4	6	7	12
In the presence of dATP , Cytochrome C complexes with and activates Apaf-1 that can begin caspase cascade leading to induction of apoptosis .	In the presence of dATP, Cytochrome C complexes with and activates Apaf-1 that can begin caspase cascade leading to induction of apoptosis.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	Apaf-1	Apaf-1	Apaf-1	6	8	12	13
To this end , we extended a previous deterministic ODE based model of the apoptosis execution phase that captures the interplay of the apoptosome ( cytochrome c induced APAF-1 oligomerisation and caspase-9 activation ) , SMAC , XIAP and caspase-3 .	To this end, we extended a previous deterministic ODE based model of the apoptosis execution phase that captures the interplay of the apoptosome (cytochrome c induced APAF-1 oligomerisation and caspase-9 activation), SMAC, XIAP and caspase-3.	25	29	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	APAF-1	APAF-1	APAF-1	25	27	28	29
This is achieved by stabilization of a strong interaction between Hsp90beta and apoptotic peptidase activating factor 1 ( Apaf-1 ) , which prevents cytochrome c induced Apaf-1 oligomerization and caspase-9 recruitment .	This is achieved by stabilization of a strong interaction between Hsp90beta and apoptotic peptidase activating factor 1 (Apaf-1), which prevents cytochrome c induced Apaf-1 oligomerization and caspase-9 recruitment.	23	27	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	23	25	26	27
However , a recent report showing CDC6 mediated inhibition of apoptosome formation through its binding onto cytochrome c activated Apaf-1 [ XREF_BIBR ] , probably explains why senescence emerges as the only tumor suppressor mechanism in our system .	However, a recent report showing CDC6 mediated inhibition of apoptosome formation through its binding onto cytochrome c activated Apaf-1 [XREF_BIBR], probably explains why senescence emerges as the only tumor suppressor mechanism in our system.	16	25	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	16	18	19	20
These data demonstrate that nsPEFs induce intrinsic apoptosis activate by cytochrome c release from mitochondria through an APAF-1- and caspase dependent pathway as well as through caspase independent mechanisms that remain to be defined .	These data demonstrate that nsPEFs induce intrinsic apoptosis activate by cytochrome c release from mitochondria through an APAF-1- and caspase dependent pathway as well as through caspase independent mechanisms that remain to be defined.	8	21	activate	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c release from mitochondria	cytochrome c	APAF-1-	APAF-1-	apaf-1-	10	12	17	18
Once in the cytosol , cytochrome c in the presence of ( d ) ATP initiates the oligomerisation of Apaf-1 ( apoptotic protease activating factor 1 ) into a large protein scaffold , the apoptosome , which recruits and processes pro caspase 9 into an active initiator caspase 9 .	Once in the cytosol, cytochrome c in the presence of (d) ATP initiates the oligomerisation of Apaf-1 (apoptotic protease activating factor 1) into a large protein scaffold, the apoptosome, which recruits and processes pro caspase 9 into an active initiator caspase 9.	5	20	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	5	7	19	20
Cytosolic cytochrome c activates Apaf-1 [ XREF_BIBR , XREF_BIBR ] which oligomerizes to form the apoptosome , a wheel like heptamer with angular symmetry [ XREF_BIBR , XREF_BIBR ] .	Cytosolic cytochrome c activates Apaf-1 [XREF_BIBR, XREF_BIBR] which oligomerizes to form the apoptosome, a wheel like heptamer with angular symmetry [XREF_BIBR, XREF_BIBR].	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	1	3	4	5
Accordingly , XIAP does not bind to Apaf-1 apoptosome in unactivated lysates but does so after cytochrome c triggered oligomerization of Apaf-1 .	Accordingly, XIAP does not bind to Apaf-1 apoptosome in unactivated lysates but does so after cytochrome c triggered oligomerization of Apaf-1.	16	22	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	16	18	21	22
The formation of Hsp90-Apaf-1 complexes negatively regulates cytochrome c mediated oligomerization of Apaf-1 , which prevents the assembly of the apoptosome [ XREF_BIBR , XREF_BIBR ] .	The formation of Hsp90-Apaf-1 complexes negatively regulates cytochrome c mediated oligomerization of Apaf-1, which prevents the assembly of the apoptosome [XREF_BIBR, XREF_BIBR].	7	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	7	9	12	13
Cytochrome c then causes aggregation of the adaptor molecule Apaf 1 , to form apoptosome along with procaspase-9 .	Cytochrome c then causes aggregation of the adaptor molecule Apaf 1, to form apoptosome along with procaspase-9.	0	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Apaf 1	Apaf 1	Apaf 1	0	2	9	11
It is known that the released cytochrome c promotes multimerization of Apaf-1 to form apoptosome complex , which sequentially recruits and activates initiator caspase9 that elicits downstream caspase cascade .	It is known that the released cytochrome c promotes multimerization of Apaf-1 to form apoptosome complex, which sequentially recruits and activates initiator caspase9 that elicits downstream caspase cascade.	6	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	6	8	11	12
In vivo , circumstances may arise where physiological cell death stimuli induce only a small subpopulation of mitochondria in cells to dump cytochrome c , necessitating that this small proportion of released cytochrome c activates Apaf-1 and secondarily triggers caspase dependent destruction of additional mitochondria , thereby committing the cell to death .	In vivo, circumstances may arise where physiological cell death stimuli induce only a small subpopulation of mitochondria in cells to dump cytochrome c, necessitating that this small proportion of released cytochrome c activates Apaf-1 and secondarily triggers caspase dependent destruction of additional mitochondria, thereby committing the cell to death.	32	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	32	34	35	36
Cytochrome C also triggers the oligomerization of Apaf-1 , which in turn recruits pro caspase 9 and pro caspase 3 into the apoptosome ( the caspase activation multiprotein complex ) .	Cytochrome C also triggers the oligomerization of Apaf-1, which in turn recruits pro caspase 9 and pro caspase 3 into the apoptosome (the caspase activation multiprotein complex).	0	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	Apaf-1	Apaf-1	Apaf-1	0	2	7	8
This idea only has validity if the common ancestor of platyhelminths , nematodes , and arthropods possessed an APAF1 that was activated by holocytochrome c ; the alternative proposal is that cytochrome c mediated APAF1 activation arose only after such a ' split ' .	This idea only has validity if the common ancestor of platyhelminths, nematodes, and arthropods possessed an APAF1 that was activated by holocytochrome c; the alternative proposal is that cytochrome c mediated APAF1 activation arose only after such a ' split '.	31	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	APAF1	APAF1	APAF1	31	33	34	35
While in chordates cytochrome c is required to activate APAF1 to form the activation platform for caspase-9 , this is not the case for nematodes , where the APAF1 homolog , CED-4 , lacks the region of the molecule required for cytochrome c interaction [ XREF_BIBR , XREF_BIBR ] .	While in chordates cytochrome c is required to activate APAF1 to form the activation platform for caspase-9, this is not the case for nematodes, where the APAF1 homolog, CED-4, lacks the region of the molecule required for cytochrome c interaction [XREF_BIBR, XREF_BIBR].	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	APAF1	APAF1	APAF1	3	5	9	10
It will be important to note that , while animal cytochrome c activates APAF1 , apocytochrome c , which lacks the heme group , does not activate APAF1 , nor does cytochrome c from non animal sources , such as yeast .	It will be important to note that, while animal cytochrome c activates APAF1, apocytochrome c, which lacks the heme group, does not activate APAF1, nor does cytochrome c from non animal sources, such as yeast.	10	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	APAF1	APAF1	APAF1	10	12	13	14
The release of cytochrome c into the cytosol triggers activation of caspase-3 via the formation of a large cytosolic complex , which is called the apoptosome and consists of cytochrome c , Apaf-1 , and caspase-9 [ XREF_BIBR ] .	The release of cytochrome c into the cytosol triggers activation of caspase-3 via the formation of a large cytosolic complex, which is called the apoptosome and consists of cytochrome c, Apaf-1, and caspase-9 [XREF_BIBR].	3	33	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	3	5	32	33
The key event in the intrinsic apoptotic pathway is the release of cytochrome c , a component of the mitochondrial respiratory chain , to the cytosol where it activates Apaf-1 leading to the subsequent activation of caspase-9 and caspase-3 .	The key event in the intrinsic apoptotic pathway is the release of cytochrome c, a component of the mitochondrial respiratory chain, to the cytosol where it activates Apaf-1 leading to the subsequent activation of caspase-9 and caspase-3.	10	30	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c, a component of the mitochondrial respiratory chain, to the cytosol	cytochrome c	Apaf-1	Apaf-1	apaf-1	12	14	29	30
Cytochrome c in turn activates APAF1 and triggers formation of the apoptosome , leading to caspase-9 autoactivation and initiation of the caspase cascade .	Cytochrome c in turn activates APAF1 and triggers formation of the apoptosome, leading to caspase-9 autoactivation and initiation of the caspase cascade.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	APAF1	APAF1	APAF1	0	2	5	6
Alternatively , ligand binding may allosterically activate NAIPs through rigid body rotation of the autoinhibitory LRR domain away from the NBD , reminiscent of the mechanism by which cytochrome C activates APAF-1 to trigger apoptosome assembly .	Alternatively, ligand binding may allosterically activate NAIPs through rigid body rotation of the autoinhibitory LRR domain away from the NBD, reminiscent of the mechanism by which cytochrome C activates APAF-1 to trigger apoptosome assembly.	28	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	APAF-1	APAF-1	APAF-1	28	30	31	32
Cytochrome c , once in the cytosol , induces the rearrangement and heptaoligomerization of Apaf-1 : each of these complexes can recruit up to seven caspase molecules , leading to their proteolytic self processing and consequent activation .	Cytochrome c, once in the cytosol, induces the rearrangement and heptaoligomerization of Apaf-1 : each of these complexes can recruit up to seven caspase molecules, leading to their proteolytic self processing and consequent activation.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Apaf-1	Apaf-1	Apaf-1	0	2	14	15
Cytochrome c activated Apaf-1 has been shown to undergo an ATP-hydrolysis-dependent conformational rearrangement in order to form heptamers through an interaction of its NACHT domains .	Cytochrome c activated Apaf-1 has been shown to undergo an ATP-hydrolysis-dependent conformational rearrangement in order to form heptamers through an interaction of its NACHT domains.	0	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Apaf-1	Apaf-1	Apaf-1	0	2	3	4
Bcr-Abl acted posttranslationally to prevent the cytochrome c induced binding of Apaf-1 to procaspase 9 .	Bcr-Abl acted posttranslationally to prevent the cytochrome c induced binding of Apaf-1 to procaspase 9.	6	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	6	8	11	12
Cytochrome c and dATP and ATP induce oligomerization of Apaf-1 into two distinct apoptosome complexes : an approximately 700 kDa complex , which recruits and activates caspases-9 , -3 and -7 , and an approximately 1.4 MDa complex , which recruits and processes caspase-9 , but does not efficiently activate effector caspases .	Cytochrome c and dATP and ATP induce oligomerization of Apaf-1 into two distinct apoptosome complexes : an approximately 700 kDa complex, which recruits and activates caspases-9, -3 and -7, and an approximately 1.4 MDa complex, which recruits and processes caspase-9, but does not efficiently activate effector caspases.	0	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Apaf-1	Apaf-1	Apaf-1	0	2	9	10
During apoptosis , release of cytochrome c initiates dATP dependent oligomerization of Apaf-1 and formation of the apoptosome .	During apoptosis, release of cytochrome c initiates dATP dependent oligomerization of Apaf-1 and formation of the apoptosome.	5	14	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	5	7	12	13
XREF_BIBR , XREF_BIBR , XREF_BIBR Released cytochrome c activates Apaf-1 , which assists in caspase activation .	XREF_BIBR, XREF_BIBR, XREF_BIBR Released cytochrome c activates Apaf-1, which assists in caspase activation.	6	12	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	6	8	9	10
XREF_BIBR Cytochrome c ( cyt-c ) activates apoptotic protease activating factor 1 ( Apaf-1 ) in the cytosol .	XREF_BIBR Cytochrome c (cyt-c) activates apoptotic protease activating factor 1 (Apaf-1) in the cytosol.	1	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	apoptotic protease activating factor 1	apoptotic protease activating factor 1	apoptotic protease activating factor 1	1	3	7	12
The release of cytochrome c triggers the assembly of Apaf-1 ( apoptotic protease activating factor ) and pro-caspase-9 to form an apoptosome .	The release of cytochrome c triggers the assembly of Apaf-1 (apoptotic protease activating factor) and pro-caspase-9 to form an apoptosome.	3	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	3	5	9	10
In cells expressing these kinases , the previously reported apoptosome inhibitor , Hsp90beta , bound strongly to Apaf-1 , preventing cytochrome c induced Apaf-1 oligomerization and caspase-9 recruitment .	In cells expressing these kinases, the previously reported apoptosome inhibitor, Hsp90beta, bound strongly to Apaf-1, preventing cytochrome c induced Apaf-1 oligomerization and caspase-9 recruitment.	20	24	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	20	22	23	24
The imbalance of Bax and Bcl -2 ratio has led to the disruption of mitochondrial inner transmembrane potential , and the release of Cytochrome C triggering the formation of cytochrome C , APAF-1 , and Caspase-9 complex and subsequently enhancing the activation of active Caspase-3 as a positive feedback effect .	The imbalance of Bax and Bcl -2 ratio has led to the disruption of mitochondrial inner transmembrane potential, and the release of Cytochrome C triggering the formation of cytochrome C, APAF-1, and Caspase-9 complex and subsequently enhancing the activation of active Caspase-3 as a positive feedback effect.	23	33	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	APAF-1	APAF-1	APAF-1	23	25	32	33
Once in the cytosol , cytochrome c triggers the olgomerization of apaf-1 with the cysteine aspartic protease caspase-9 to form the apoptosome , which goes on to activate the executioner caspases , caspase-3 and -7 .	Once in the cytosol, cytochrome c triggers the olgomerization of apaf-1 with the cysteine aspartic protease caspase-9 to form the apoptosome, which goes on to activate the executioner caspases, caspase-3 and -7.	5	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	apaf-1	apaf-1	apaf-1	5	7	11	12
Despite the fact that DAPK1 mediated apoptosis in response to TGF-beta is unclear ; it is well known that cytochrome c release from mitochondria causing apoptotic protease activating factor 1 ( Apaf1 ) activation and pro caspase 3 cleavage precedes TGF-beta-induced apoptosis .	Despite the fact that DAPK1 mediated apoptosis in response to TGF-beta is unclear; it is well known that cytochrome c release from mitochondria causing apoptotic protease activating factor 1 (Apaf1) activation and pro caspase 3 cleavage precedes TGF-beta-induced apoptosis.	19	30	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c release from mitochondria	cytochrome c	apoptotic protease activating factor 1	apoptotic protease activating factor 1	apoptotic protease activating factor 1	19	21	25	30
During apoptosis initiated by the intrinsic pathway cytochrome c is released by the mitochondria and causes heptamerization of Apaf-1 .	During apoptosis initiated by the intrinsic pathway cytochrome c is released by the mitochondria and causes heptamerization of Apaf-1.	7	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	7	9	18	19
The released cytochrome c activates Apaf-1 and procaspase-9 , resulting in the formation of apopto some [ XREF_BIBR ] .	The released cytochrome c activates Apaf-1 and procaspase-9, resulting in the formation of apopto some [XREF_BIBR].	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	2	4	5	6
Binding of the cytochrome c to the C-terminal WD domain induces oligomerization of APAF-1 into a ring shaped heptamer , in which the N-terminal CARD domains of the protein are clustered at the center of the ring .	Binding of the cytochrome c to the C-terminal WD domain induces oligomerization of APAF-1 into a ring shaped heptamer, in which the N-terminal CARD domains of the protein are clustered at the center of the ring.	3	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	APAF-1	APAF-1	APAF-1	3	5	13	14
In many forms of apoptosis , cytochrome c released from mitochondria induces the oligomerization of Apaf-1 to form a caspase activating apoptosome complex .	In many forms of apoptosis, cytochrome c released from mitochondria induces the oligomerization of Apaf-1 to form a caspase activating apoptosome complex.	6	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	6	8	15	16
XREF_BIBR Cytochrome c , a key protein in electron transport , activates apoptotic protease activating factor-1 , which triggers the activation of caspase 3 that will subsequently catalyze proteolytic cleavage of many key proteins , such as the PARP .	XREF_BIBR Cytochrome c, a key protein in electron transport, activates apoptotic protease activating factor-1, which triggers the activation of caspase 3 that will subsequently catalyze proteolytic cleavage of many key proteins, such as the PARP.	1	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	apoptotic protease activating factor-1	apoptotic protease activating factor-1	apoptotic protease activating factor-1	1	3	12	16
During oxidative stress , CYCS is released into the cytoplasm from mitochondria and activates Apaf1 ( apoptotic peptidase activating factor 1 ) , which in turn cleaves procaspase 9 into its active form of dimer p35 and p12 or p35 and p10 .	During oxidative stress, CYCS is released into the cytoplasm from mitochondria and activates Apaf1 (apoptotic peptidase activating factor 1), which in turn cleaves procaspase 9 into its active form of dimer p35 and p12 or p35 and p10.	4	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CYCS	CYCS	CYCS	Apaf1	Apaf1	Apaf1	4	5	14	15
In caspase dependent mitochondrial pathway , cytochrome c activates Apaf-1 and procaspase 9 , forming an apoptosome [ XREF_BIBR , XREF_BIBR ] .	In caspase dependent mitochondrial pathway, cytochrome c activates Apaf-1 and procaspase 9, forming an apoptosome [XREF_BIBR, XREF_BIBR].	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	6	8	9	10
The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c activated Apaf-1 ( apoptotic protease activating factor ) , dATP and procaspase-9 that link mitochondria disfunction with activation of the effector caspases and in turn is of interest for the development of apoptotic modulators .	The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c activated Apaf-1 (apoptotic protease activating factor), dATP and procaspase-9 that link mitochondria disfunction with activation of the effector caspases and in turn is of interest for the development of apoptotic modulators.	9	38	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	9	11	12	13
Once in the cytosol , cytochrome c initiates a cascade of caspase activation by promoting the oligomerization of APAF-1 and the activation of procaspase-9 .	Once in the cytosol, cytochrome c initiates a cascade of caspase activation by promoting the oligomerization of APAF-1 and the activation of procaspase-9.	5	19	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	APAF-1	APAF-1	APAF-1	5	7	18	19
We also show that Hsp90 inhibits cytochrome c mediated oligomerization of Apaf-1 and thereby activation of procaspase-9 .	We also show that Hsp90 inhibits cytochrome c mediated oligomerization of Apaf-1 and thereby activation of procaspase-9.	6	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	6	8	11	12
The evidence that cytochrome c can activate Apaf-1 is abundant , but the proof that cytochrome c is required for apoptosis is limited to two studies that used genetically modified mice .	The evidence that cytochrome c can activate Apaf-1 is abundant, but the proof that cytochrome c is required for apoptosis is limited to two studies that used genetically modified mice.	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	3	5	7	8
Upon release into the cytoplasm , cytochrome-c activates Apaf-1 and triggers the caspase cascade leading to the activation of executioner caspase , caspase-3 [ XREF_BIBR ] .	Upon release into the cytoplasm, cytochrome-c activates Apaf-1 and triggers the caspase cascade leading to the activation of executioner caspase, caspase-3 [XREF_BIBR].	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome-c	cytochrome-c	cytochrome-c	Apaf-1	Apaf-1	Apaf-1	6	7	8	9
In response to apoptotic stimuli , cytochrome c activates Apaf-1 by binding to its C-terminus .	In response to apoptotic stimuli, cytochrome c activates Apaf-1 by binding to its C-terminus.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	6	8	9	10
Alternatively , very low amounts of cytochrome c , accidently released during the preparation of cytosolic extracts , could have induced the formation of Apaf-1 apoptosome-XIAP complexes , which are particularly detectable in XIAP overexpressing cells .	Alternatively, very low amounts of cytochrome c, accidently released during the preparation of cytosolic extracts, could have induced the formation of Apaf-1 apoptosome-XIAP complexes, which are particularly detectable in XIAP overexpressing cells.	4	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	amounts of cytochrome c	cytochrome c	Apaf-1	Apaf-1	apaf-1	6	8	24	25
Among the various insults by chemical agents and UV radiation , induced damage or FasL-FADD induced activation of pro-caspase-8 or p53 --> Bax --> cytochrome c induced activation of Apaf-1 and caspase 9 ultimately leads to activation of caspase 3 and leads to death ( apoptosis ) .	Among the various insults by chemical agents and UV radiation, induced damage or FasL-FADD induced activation of pro-caspase-8 or p53 --> Bax --> cytochrome c induced activation of Apaf-1 and caspase 9 ultimately leads to activation of caspase 3 and leads to death (apoptosis).	24	31	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	24	26	29	30
Release of cytochrome c from mitochondria activates apaf-1 ( apoptosome ) , which in its turn cleaves the pro enzyme of Caspase-9 into its most active form .	Release of cytochrome c from mitochondria activates apaf-1 (apoptosome), which in its turn cleaves the pro enzyme of Caspase-9 into its most active form.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	Release of cytochrome c from mitochondria	cytochrome c	apaf-1	apaf-1	apaf-1	2	4	7	8
Cytochrome c is released into the cytoplasm to stimulate the assembly of the apoptosome ( consisting of Apaf-1 , cytochrome c , ATP , and procaspase-9 ) , activation of procaspase-9 , which in turn activates caspase-3 , DNA fragmentation , and cell death .	Cytochrome c is released into the cytoplasm to stimulate the assembly of the apoptosome (consisting of Apaf-1, cytochrome c, ATP, and procaspase-9), activation of procaspase-9, which in turn activates caspase-3, DNA fragmentation, and cell death.	0	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Apaf-1	Apaf-1	Apaf-1	0	2	17	18
Once released , cytochrome c activates Apaf-1 to assist the activation of caspases that cleave cellular proteins and thereby contribute to the morphological and biochemical changes associated with apoptosis .	Once released, cytochrome c activates Apaf-1 to assist the activation of caspases that cleave cellular proteins and thereby contribute to the morphological and biochemical changes associated with apoptosis.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	3	5	6	7
XREF_BIBR AIP contains an N-terminal caspase recruiting domain ( CARD ) , allowing direct binding to Apaf-1 upon its activation by cytosolic cytochrome c and disrupting the formation of apoptosome and subsequent activation of caspase-9 and caspase-3 .	XREF_BIBR AIP contains an N-terminal caspase recruiting domain (CARD), allowing direct binding to Apaf-1 upon its activation by cytosolic cytochrome c and disrupting the formation of apoptosome and subsequent activation of caspase-9 and caspase-3.	12	24	allowing	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	22	24	16	17
Once in the cytosol , cytochrome c activates Apaf-1 , which then activates procaspase-9 , which , in turn , activates caspase-3 , triggering apoptosis .	Once in the cytosol, cytochrome c activates Apaf-1, which then activates procaspase-9, which, in turn, activates caspase-3, triggering apoptosis.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	5	7	8	9
The first intrinsic sub-pathway is mediated by cytochrome c , which subsequently activates Apaf1 , caspase 9 , and caspase 3/7 .	The first intrinsic sub-pathway is mediated by cytochrome c, which subsequently activates Apaf1, caspase 9, and caspase 3/7.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf1	Apaf1	Apaf1	7	9	13	14
Upon its release , cytochrome c together with dATP promotes APAF-1 ( adaptor protein ) mediated activation of caspase 9 thereby unleashing the caspase cascade ( see above ; reviewed in ) .	Upon its release, cytochrome c together with dATP promotes APAF-1 (adaptor protein) mediated activation of caspase 9 thereby unleashing the caspase cascade (see above; reviewed in).	4	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	APAF-1	APAF-1	APAF-1	4	6	10	11
XREF_BIBR , XREF_BIBR However , the use of AIP may be advantageous over the conventional caspase inhibitors , as AIP inhibits specifically the cytochrome c activated Apaf-1 signaling pathway without interfering with the basal caspase activities in neurons .	XREF_BIBR, XREF_BIBR However, the use of AIP may be advantageous over the conventional caspase inhibitors, as AIP inhibits specifically the cytochrome c activated Apaf-1 signaling pathway without interfering with the basal caspase activities in neurons.	23	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	23	25	26	27
Cytochrome c triggers oligomerization of Apaf-1 , but is still detected in the holoenzyme , which raises the following question : Is this protein redundant in the apoptosome or does it have some specific but as-yet unidentified functions ?	Cytochrome c triggers oligomerization of Apaf-1, but is still detected in the holoenzyme, which raises the following question : Is this protein redundant in the apoptosome or does it have some specific but as-yet unidentified functions?	0	6	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Apaf-1	Apaf-1	Apaf-1	0	2	5	6
These observations are consistent with the notion that AIP binds to Apaf-1 and inhibits the caspase-9 pathway only when Apaf-1 is activated by cytochrome c XREF_BIBR , thus AIP is not an inhibitor for developmental neuronal apoptosis .	These observations are consistent with the notion that AIP binds to Apaf-1 and inhibits the caspase-9 pathway only when Apaf-1 is activated by cytochrome c XREF_BIBR, thus AIP is not an inhibitor for developmental neuronal apoptosis.	19	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	23	25	19	20
In the cytosol , cytochrome c activates apoptotic protease activating factor 1 ( Apaf1 ) , which assembles into the apoptosome structure ( XREF_FIG ) .	In the cytosol, cytochrome c activates apoptotic protease activating factor 1 (Apaf1), which assembles into the apoptosome structure (XREF_FIG).	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	apoptotic protease activating factor 1	apoptotic protease activating factor 1	apoptotic protease activating factor 1	4	6	7	12
Cytosolic cytochrome c mediates the oligomerization of Apaf-1 and the formation of the apoptosome complex , which cleave the initiator caspase 9 , thereby activating the terminal caspases such as caspase-3 , -6 , and -7 XREF_BIBR .	Cytosolic cytochrome c mediates the oligomerization of Apaf-1 and the formation of the apoptosome complex, which cleave the initiator caspase 9, thereby activating the terminal caspases such as caspase-3, -6, and -7 XREF_BIBR.	1	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	1	3	7	8
Once in the cytosol , cytochrome c induces the oligomerization of apoptotic protease activating factor 1 ( Apaf-1 ) and the subsequent recruitment of procaspase-9 .	Once in the cytosol, cytochrome c induces the oligomerization of apoptotic protease activating factor 1 (Apaf-1) and the subsequent recruitment of procaspase-9.	5	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	apoptotic protease activating factor 1	apoptotic protease activating factor 1	apoptotic protease activating factor 1	5	7	11	16
Cytosolic cytochrome c mediates the allosteric activation of Apaf-1 , and together they form the apoptosome .	Cytosolic cytochrome c mediates the allosteric activation of Apaf-1, and together they form the apoptosome.	1	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	1	3	8	9
Cytoplasmic cytochrome c triggers ATP dependent conformational change and oligomerization of the adaptor APAF-1 ( Apoptotic peptidase activating factor 1 ) in a high-molecular mass cytoplasmic complex referred to as Apoptosome .	Cytoplasmic cytochrome c triggers ATP dependent conformational change and oligomerization of the adaptor APAF-1 (Apoptotic peptidase activating factor 1) in a high-molecular mass cytoplasmic complex referred to as Apoptosome.	1	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	APAF-1	APAF-1	APAF-1	1	3	13	14
Mitochondrial dysfunction includes a change in the mitochondrial membrane potential , production of reactive oxygen species ( ROS ) , opening of the permeability transition pore ( PTP ) , and the release of the intermembrane space protein , cytochrome c. Released cytochrome c activates Apaf-1 , which in turn activates a downstream caspase program .	Mitochondrial dysfunction includes a change in the mitochondrial membrane potential, production of reactive oxygen species (ROS), opening of the permeability transition pore (PTP), and the release of the intermembrane space protein, cytochrome c. Released cytochrome c activates Apaf-1, which in turn activates a downstream caspase program.	42	50	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	42	44	45	46
Consistent with these researches , we found the cytoplasmic cytochrome C and Smac/DIABLO triggered the formation of the Apaf-1 and caspase-9 apoptosome as well as neutralizing the Xiap in the T-47D-CSCs co-treated with miR-519d and cisplatin .	Consistent with these researches, we found the cytoplasmic cytochrome C and Smac/DIABLO triggered the formation of the Apaf-1 and caspase-9 apoptosome as well as neutralizing the Xiap in the T-47D-CSCs co-treated with miR-519d and cisplatin.	9	21	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	Apaf-1	Apaf-1	Apaf-1	9	11	18	19
Cytochrome c activates Apaf-1 , which oligomerizes to form an approximately 700-1400-kDa caspase activating complex known as the Apaf-1 apoptosome .	Cytochrome c activates Apaf-1, which oligomerizes to form an approximately 700-1400-kDa caspase activating complex known as the Apaf-1 apoptosome.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Apaf-1	Apaf-1	Apaf-1	0	2	3	4
Besides performing prereplicative complex assembly and Cdk2 activation , Cdc6 obstructed apoptosome assembly by forming stable complexes very likely with a monomer of cytochrome c activated Apaf-1 molecules .	Besides performing prereplicative complex assembly and Cdk2 activation, Cdc6 obstructed apoptosome assembly by forming stable complexes very likely with a monomer of cytochrome c activated Apaf-1 molecules.	23	27	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	23	25	26	27
The release of cytochrome c from the inner mitochondrial membrane , where it is anchored by caridolipin , triggers the formation of the Apaf-1 apoptosome .	The release of cytochrome c from the inner mitochondrial membrane, where it is anchored by caridolipin, triggers the formation of the Apaf-1 apoptosome.	1	24	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from the inner mitochondrial membrane	cytochrome c	Apaf-1	Apaf-1	apaf-1	3	5	23	24
Previous studies using cell-free extracts of Jurkat , Hela , and HEK293 cells have shown that the addition of cytochrome c and dATP to these extracts is sufficient to trigger assembly of the Apaf-1 apoptosome , which recruits and activates caspase-9 .	Previous studies using cell-free extracts of Jurkat, Hela, and HEK293 cells have shown that the addition of cytochrome c and dATP to these extracts is sufficient to trigger assembly of the Apaf-1 apoptosome, which recruits and activates caspase-9.	19	34	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	19	21	33	34
By promoting Bax oligomerization and massive cytochrome c efflux , Drp1 could ensure that mitochondrial function is irreversibly altered during apoptosis , and that a sufficient amount of cytochrome c is released to activate APAF1 .	By promoting Bax oligomerization and massive cytochrome c efflux, Drp1 could ensure that mitochondrial function is irreversibly altered during apoptosis, and that a sufficient amount of cytochrome c is released to activate APAF1.	26	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	amount of cytochrome c	cytochrome c	APAF1	APAF1	apaf1	28	30	34	35
When apoptosis occurs , cytochrome c is released by the mitochondria into the cytosol , thus inducing the formation of the Apaf-1 : caspase-9 holoenzyme .	When apoptosis occurs, cytochrome c is released by the mitochondria into the cytosol, thus inducing the formation of the Apaf-1 : caspase-9 holoenzyme.	4	22	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	4	6	21	22
This leads to the efflux of Cytochrome C , which activates Apaf-1 [ XREF_BIBR , XREF_BIBR ] .	This leads to the efflux of Cytochrome C, which activates Apaf-1 [XREF_BIBR, XREF_BIBR].	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	Apaf-1	Apaf-1	Apaf-1	6	8	11	12
Cytochrome c promotes activation of caspases by forming a protein complex composed of cytochrome c , Apaf-1 , and caspase-9 , that leads to the activation of a caspase cascade .	Cytochrome c promotes activation of caspases by forming a protein complex composed of cytochrome c, Apaf-1, and caspase-9, that leads to the activation of a caspase cascade.	0	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Apaf-1	Apaf-1	Apaf-1	0	2	16	17
It has been proposed that cytochrome c and dATP may induce a conformational change in Apaf-1 that exposes its CARD , allowing it to bind to caspase-9 .	It has been proposed that cytochrome c and dATP may induce a conformational change in Apaf-1 that exposes its CARD, allowing it to bind to caspase-9.	5	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	5	7	15	16
This pathway is triggered by the release of cytochrome c from mitochondria and its binding to monomeric apoptotic protease activating factor-1 ( APAF-1 ) to form the apoptosome complex .	This pathway is triggered by the release of cytochrome c from mitochondria and its binding to monomeric apoptotic protease activating factor-1 (APAF-1) to form the apoptosome complex.	3	21	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	apoptotic protease activating factor-1	apoptotic protease activating factor-1	apoptotic protease activating factor-1	8	10	17	21
Each has a different function , but cytochrome c causes the oligomerization of Apaf-1 and the activation of Caspase-9 .	Each has a different function, but cytochrome c causes the oligomerization of Apaf-1 and the activation of Caspase-9.	7	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	7	9	13	14
Cytochrome c activates the cytosolic protein Apaf-1 and pro caspase- 9 to form the apoptosome , and its release is strictly regulated in the cell by the pro- and anti-apoptotic factor ratio .	Cytochrome c activates the cytosolic protein Apaf-1 and pro caspase- 9 to form the apoptosome, and its release is strictly regulated in the cell by the pro- and anti-apoptotic factor ratio.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Apaf-1	Apaf-1	Apaf-1	0	2	6	7
During apoptosis , cytochrome c released from mitochondria activates Apaf-1 , a cofactor of caspase-9 .	During apoptosis, cytochrome c released from mitochondria activates Apaf-1, a cofactor of caspase-9.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	3	5	9	10
Cytochrome c induces a conformational change in the adaptor protein Apaf-1 causing it to oligomerize and recruit procaspase-9 [ XREF_BIBR ] .	Cytochrome c induces a conformational change in the adaptor protein Apaf-1 causing it to oligomerize and recruit procaspase-9 [XREF_BIBR].	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Apaf-1	Apaf-1	Apaf-1	0	2	10	11
In the intrinsic apoptosis pathway for example , release of cytochrome c from the mitochondria into the cytoplasm induces Apaf-1 to recruit caspase-9 via a CARD-CARD interaction [ XREF_BIBR ] .	In the intrinsic apoptosis pathway for example, release of cytochrome c from the mitochondria into the cytoplasm induces Apaf-1 to recruit caspase-9 via a CARD-CARD interaction [XREF_BIBR].	8	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from the mitochondria	cytochrome c	Apaf-1	Apaf-1	apaf-1	10	12	19	20
Release of mitochondrial proapoptotic factors such as Smac/Diablo and cytochrome c activates Apaf-1 generating enough active caspase-3 for apoptosis to proceed .	Release of mitochondrial proapoptotic factors such as Smac/Diablo and cytochrome c activates Apaf-1 generating enough active caspase-3 for apoptosis to proceed.	9	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	9	11	12	13
Cytochrome C induces the oligomerization of Apaf-1 to form a caspase activating apoptosome complex , whereas Smac/DIABLO participates by eliminating the caspase inhibitory effect of the inhibitor of apoptosis proteins ( IAP ) [ XREF_BIBR ] .	Cytochrome C induces the oligomerization of Apaf-1 to form a caspase activating apoptosome complex, whereas Smac/DIABLO participates by eliminating the caspase inhibitory effect of the inhibitor of apoptosis proteins (IAP) [XREF_BIBR].	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	Apaf-1	Apaf-1	Apaf-1	0	2	6	7
Without nucleotide exchange , cytochrome c induces Apaf-1 to form non functional aggregates .	Without nucleotide exchange, cytochrome c induces Apaf-1 to form non functional aggregates.	4	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	4	6	7	8
Hsp90 has been shown to inhibit cytochrome c mediated oligomerization of Apaf-1 and subsequent activation of procaspase-9 .	Hsp90 has been shown to inhibit cytochrome c mediated oligomerization of Apaf-1 and subsequent activation of procaspase-9.	6	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	6	8	11	12
Upon release from the mitochondria cytochrome c binds to and triggers the oligomerization of Apaf-1 [ XREF_BIBR ] .	Upon release from the mitochondria cytochrome c binds to and triggers the oligomerization of Apaf-1 [XREF_BIBR].	5	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Apaf-1	Apaf-1	Apaf-1	5	7	14	15
MDA-MB-231 breast cancer cells stably transduced with the CXCR7 and beta-arrestin complementation reporter were treated with 300 ng/ml CXCL12 for 30 minutes to promote association of CXCR7 and beta-arrestin 2 .	MDA-MB-231 breast cancer cells stably transduced with the CXCR7 and beta-arrestin complementation reporter were treated with 300 ng/ml CXCL12 for 30 minutes to promote association of CXCR7 and beta-arrestin 2.	5	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	18	19	8	9
The addition of CXCL12 ( 100 ng/ml ) at 2.5 minutes appeared to enhance the movement of CXCR7 to the plasma membrane ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	The addition of CXCL12 (100 ng/ml) at 2.5 minutes appeared to enhance the movement of CXCR7 to the plasma membrane (XREF_FIG; XREF_SUPPLEMENTARY).	1	18	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	3	4	17	18
SDF-1 also activates its EC specific cognate receptor CXCR7 to modulate vascular patterning and angiocrine factor production .	SDF-1 also activates its EC specific cognate receptor CXCR7 to modulate vascular patterning and angiocrine factor production.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	0	1	8	9
We hypothesized that combined effects of selected peptides and CXCL12 would potentiate activation of CXCR7 signaling to beta-arrestin 2 at reduced concentrations of either peptide or CXCL12 ligand .	We hypothesized that combined effects of selected peptides and CXCL12 would potentiate activation of CXCR7 signaling to beta-arrestin 2 at reduced concentrations of either peptide or CXCL12 ligand.	4	15	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	9	10	14	15
Treatment of Daudi cells with bafilomycin A had no effect on ligand induced CXCR4 down regulation and CXCL12 induced CXCR7 internalization ( XREF_FIG ) .	Treatment of Daudi cells with bafilomycin A had no effect on ligand induced CXCR4 down regulation and CXCL12 induced CXCR7 internalization (XREF_FIG).	13	20	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	17	18	19	20
These data may be supported by recent findings that CXCL12 upregulates CXCR7 surface availability on platelets , as will be discussed in more detail later .	These data may be supported by recent findings that CXCL12 upregulates CXCR7 surface availability on platelets, as will be discussed in more detail later.	9	13	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	9	10	11	12
Recent studies in breast cancer cells have revealed that CXCR7 activation by SDF-1 increases components regulating cell adhesion and cell-matrix interaction , such as vascular adhesion molecule VCAM-1 and matrix metalloproteinases MMP-2 and MMP-9 ( Wani etal ., 2014 ) , and SDF-1 also promoted MMP-9 expression in OC cells ( Yu etal ., 2014 ) .	Recent studies in breast cancer cells have revealed that CXCR7 activation by SDF-1 increases components regulating cell adhesion and cell-matrix interaction, such as vascular adhesion molecule VCAM-1 and matrix metalloproteinases MMP-2 and MMP-9 (Wani etal., 2014), and SDF-1 also promoted MMP-9 expression in OC cells (Yu etal., 2014).	9	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	12	13	9	10
Similarly , CXCL12 enhanced the phagocytic capacity of CXCR7 positive macrophages observed in lesions .	Similarly, CXCL12 enhanced the phagocytic capacity of CXCR7 positive macrophages observed in lesions.	2	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	2	3	8	9
Another reason may be because unlike CXCR4 , CXCL12 activation of CXCR7 does not induce calcium mobilization and cell migration but rather results in a proliferative effect and increased adhesion properties .	Another reason may be because unlike CXCR4, CXCL12 activation of CXCR7 does not induce calcium mobilization and cell migration but rather results in a proliferative effect and increased adhesion properties.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	8	9	11	12
28 Based on current literature , in glioma , CXCR7 is a functional receptor for CXCL12 and mediates anti-apoptotic and survival effects ; 28 whereas in breast cancer , CXCL12 enhanced CXCR7 mediated tumorigenicity and invasiveness by activating proinflammatory STAT3 signaling .	28 Based on current literature, in glioma, CXCR7 is a functional receptor for CXCL12 and mediates anti-apoptotic and survival effects; 28 whereas in breast cancer, CXCL12 enhanced CXCR7 mediated tumorigenicity and invasiveness by activating proinflammatory STAT3 signaling.	29	33	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	29	30	31	32
However , transfection of siRNA pools targeting beta-arrestin1 and -2 , resulted in a significant knock-down of the endogenous levels of these proteins ( as shown by Western blot analysis in XREF_FIG ) and was able to completely inhibit CXCL12 mediated internalization of CXCR7 ( XREF_FIG ) .	However, transfection of siRNA pools targeting beta-arrestin1 and -2, resulted in a significant knock-down of the endogenous levels of these proteins (as shown by Western blot analysis in XREF_FIG) and was able to completely inhibit CXCL12 mediated internalization of CXCR7 (XREF_FIG).	38	45	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	39	40	43	44
[ XREF_BIBR ] SDF1 stimulates CXCR7 leading to proangiogenic cytokines secretions by EPCs to angiogenesis promotion .	[XREF_BIBR] SDF1 stimulates CXCR7 leading to proangiogenic cytokines secretions by EPCs to angiogenesis promotion.	1	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR7	CXCR7	CXCR7	3	4	5	6
On the other hand , CXCL12 stimulation of CXCR7 , but not CXCR4 , promoted MAP-kinase signaling .	On the other hand, CXCL12 stimulation of CXCR7, but not CXCR4, promoted MAP-kinase signaling.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	5	6	8	9
Moreover , the CXCR7 transfected HepG2 cells showed a substantial increase in cell numbers in the presence of CXCL12 ( 100ng/ml ) , compared with nontreatment ones ; but proliferation was not increased in HepG2-pBabe cells by CXCL12 stimulation .	Moreover, the CXCR7 transfected HepG2 cells showed a substantial increase in cell numbers in the presence of CXCL12 (100ng/ml), compared with nontreatment ones; but proliferation was not increased in HepG2-pBabe cells by CXCL12 stimulation.	2	38	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	37	38	3	4
A previous study on T cells demonstrated that CXCL12 can induce the internalization of CXCR7 in a dose dependent manner .	A previous study on T cells demonstrated that CXCL12 can induce the internalization of CXCR7 in a dose dependent manner.	8	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	8	9	14	15
NOX-A12 shows inhibition of SDF-1 mediated CXCR7 internalization dose dependently with an IC 50 of 3.0 +/- 0.9 nM .	NOX-A12 shows inhibition of SDF-1 mediated CXCR7 internalization dose dependently with an IC 50 of 3.0 +/- 0.9 nM.	2	8	mediated	Positive_early_activation	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	4	5	6	7
We also clearly show that activation of CXCR7 by SDF-1 or I-TAC increases internalization of the CXCR7 receptor .	We also clearly show that activation of CXCR7 by SDF-1 or I-TAC increases internalization of the CXCR7 receptor.	5	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	9	10	7	8
CXCR7 , another chemokine receptor , has also been shown to bind SDF-1 with high affinity [ XREF_BIBR ] ; however , the activation of CXCR7 by SDF-1 does not contribute to cell chemotaxis [ XREF_BIBR , XREF_BIBR ] .	CXCR7, another chemokine receptor, has also been shown to bind SDF-1 with high affinity [XREF_BIBR]; however, the activation of CXCR7 by SDF-1 does not contribute to cell chemotaxis [XREF_BIBR, XREF_BIBR].	23	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	27	28	25	26
Cxcr7 can then be stimulated by Sdf1a to down regulate fgf20a in parallel with Wnt 5b .	Cxcr7 can then be stimulated by Sdf1a to down regulate fgf20a in parallel with Wnt 5b.	0	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Sdf1a	Sdf1a	Sdf1a	Cxcr7	Cxcr7	Cxcr7	6	7	0	1
Thus , specific blockage of CXCR4 with AMD3100 and plerixafor may increase the functions of CXCR7 mediated by SDF-1 [ XREF_BIBR , XREF_BIBR ] .	Thus, specific blockage of CXCR4 with AMD3100 and plerixafor may increase the functions of CXCR7 mediated by SDF-1 [XREF_BIBR, XREF_BIBR].	13	22	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	18	19	15	16
The results of this study appear to support the co-receptor or decoy receptor hypothesis regarding CXCR7 function , because CXCL12 failed to stimulate the invasion of K1 cells overexpressing CXCR7 , but significantly induced K1-CXCR4 cell invasion .	The results of this study appear to support the co-receptor or decoy receptor hypothesis regarding CXCR7 function, because CXCL12 failed to stimulate the invasion of K1 cells overexpressing CXCR7, but significantly induced K1-CXCR4 cell invasion.	19	33	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	19	20	29	30
Although reports on the role of CXCR7 in OC are more limited , activation of CXCR7 by SDF-1 was recently shown to promote OC cell invasion ( Yu etal ., 2014 ) , whereas CXCR7 expression levels were found similar in normal and neoplastic ovaries ( Jaszczynska-Nowinka etal ., 2014 ) .	Although reports on the role of CXCR7 in OC are more limited, activation of CXCR7 by SDF-1 was recently shown to promote OC cell invasion (Yu etal., 2014), whereas CXCR7 expression levels were found similar in normal and neoplastic ovaries (Jaszczynska-Nowinka etal., 2014).	13	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	17	18	15	16
As shown in the present study , CXCR4 and CXCR7 are co-expressed in human first-trimester DECs and TC derived CXCL12 promotes the migration and invasion of DECs by binding to CXCR4 , rather than CXCR7 .	As shown in the present study, CXCR4 and CXCR7 are co-expressed in human first-trimester DECs and TC derived CXCL12 promotes the migration and invasion of DECs by binding to CXCR4, rather than CXCR7.	19	35	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	19	20	34	35
SDF-1 also activates the CXCR7 receptor , which modulates trafficking and adhesion of human malignant hematopoietic cells .	SDF-1 also activates the CXCR7 receptor, which modulates trafficking and adhesion of human malignant hematopoietic cells.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	0	1	4	5
The results from the present study provide the first evidence for CXCL12 induced CXCR7 polarization of HUVECs as a key event in its angiogenic effect on the ECs .	The results from the present study provide the first evidence for CXCL12 induced CXCR7 polarization of HUVECs as a key event in its angiogenic effect on the ECs.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	11	12	13	14
These data imply that SDF-1 stimulates CXCR7 in LSEC to trigger Akt dependent activation of Id1 angiocrine pathway .	These data imply that SDF-1 stimulates CXCR7 in LSEC to trigger Akt dependent activation of Id1 angiocrine pathway.	4	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	4	5	6	7
Our recent studies have demonstrated that CXCL12 activated CXCR7 for stem cell polarization , migration and prevention of apoptosis XREF_BIBR , XREF_BIBR .	Our recent studies have demonstrated that CXCL12 activated CXCR7 for stem cell polarization, migration and prevention of apoptosis XREF_BIBR, XREF_BIBR.	6	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	6	7	8	9
To explore the possible effects of CXCR7 on breast cancer cell proliferation , MDA-MB-231 cells were treated with CCX771 and/or CXCL12 , and proliferation rates were determined .	To explore the possible effects of CXCR7 on breast cancer cell proliferation, MDA-MB-231 cells were treated with CCX771 and/or CXCL12, and proliferation rates were determined.	4	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	20	21	6	7
Furthermore , and in agreement with the previous results indicating the lack of beta-arrestin recruitment , no internalization was observed after CXCL12 or CXCL11 stimulation of the CXCR7 DeltaC or the CXCR7 ST/A mutant receptors since the cell surface receptor levels detected by ELISA were not significantly different in the presence or absence of either CXCL11 or CXCL12 ( XREF_FIG ) .	Furthermore, and in agreement with the previous results indicating the lack of beta-arrestin recruitment, no internalization was observed after CXCL12 or CXCL11 stimulation of the CXCR7 DeltaC or the CXCR7 ST/A mutant receptors since the cell surface receptor levels detected by ELISA were not significantly different in the presence or absence of either CXCL11 or CXCL12 (XREF_FIG).	21	28	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	21	22	27	28
Of interest , the CXCR7 inhibitor CCX771 was recently described to interfere with CXCL12 directed migration of CXCR7 positive CD14 + CD16 + monocytes of HIV infected people into the CNS , which can result in a neurodegenerative disease termed NeuroAIDS XREF_BIBR .	Of interest, the CXCR7 inhibitor CCX771 was recently described to interfere with CXCL12 directed migration of CXCR7 positive CD14 + CD16 + monocytes of HIV infected people into the CNS, which can result in a neurodegenerative disease termed NeuroAIDS XREF_BIBR.	13	19	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	13	14	17	18
In this study , we observed that CXCL12 enhances CXCR7 mediated breast cancer migration .	In this study, we observed that CXCL12 enhances CXCR7 mediated breast cancer migration.	7	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	7	8	9	10
Overall , this study indicated that CXCL12 stimulated CXCR7 acts as a functional receptor to activate Akt for angiogenesis in HUVECs and that CXCR7 may be a potential target molecule for endothelial regeneration and repair after vascular injury .	Overall, this study indicated that CXCL12 stimulated CXCR7 acts as a functional receptor to activate Akt for angiogenesis in HUVECs and that CXCR7 may be a potential target molecule for endothelial regeneration and repair after vascular injury.	6	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	6	7	8	9
Stromal cell derived factor-1 ( SDF-1 ) activates CXC chemokine receptor ( CXCR ) 4 + and CXCR7 + cells and plays an important role in wound healing .	Stromal cell derived factor-1 (SDF-1) activates CXC chemokine receptor (CXCR) 4 + and CXCR7 + cells and plays an important role in wound healing.	1	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	5	6	17	18
For the boundary conditions , all surfaces were set to insulation except for the two regions which contain the CXCL12 producing cells and the CXCR7 cells .	For the boundary conditions, all surfaces were set to insulation except for the two regions which contain the CXCL12 producing cells and the CXCR7 cells.	17	25	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	19	20	24	25
CXCL12 induced the internalization of cell surface CXCR7 in the U937 cells ( XREF_FIG ) .	CXCL12 induced the internalization of cell surface CXCR7 in the U937 cells (XREF_FIG).	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	0	1	7	8
In cell lines , activation of CXCR7 by CXCL12 induced trans-endothelial migration , whereas CXCR7 antagonists and CXCL11 both inhibited cellular migration .	In cell lines, activation of CXCR7 by CXCL12 induced trans-endothelial migration, whereas CXCR7 antagonists and CXCL11 both inhibited cellular migration.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	8	9	6	7
Indeed , when CXCR7 is activated by CXCL12 , the classical GPCR mobilization of Ca 2+ is not observed .	Indeed, when CXCR7 is activated by CXCL12, the classical GPCR mobilization of Ca 2+ is not observed.	3	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	7	8	3	4
XREF_BIBR , XREF_BIBR Here our study has implied a paradigm in which platelet supplied SDF-1 activates CXCR7 on LSECs and initiates subsequent angiocrine signaling .	XREF_BIBR, XREF_BIBR Here our study has implied a paradigm in which platelet supplied SDF-1 activates CXCR7 on LSECs and initiates subsequent angiocrine signaling.	14	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	14	15	16	17
Moreover , SDF-1 induced dramatically upregulation of CXCR7 mRNA and protein levels , indicating that the SDF-1 and CXCR7 axis existed in ovarian cancer .	Moreover, SDF-1 induced dramatically upregulation of CXCR7 mRNA and protein levels, indicating that the SDF-1 and CXCR7 axis existed in ovarian cancer.	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	2	3	7	8
We can not rule out , of course , that in addition to an inhibition of CXCR4 signalling , CXCR7 activation by SDF1 also has a more direct effect on migration directionality .	We can not rule out, of course, that in addition to an inhibition of CXCR4 signalling, CXCR7 activation by SDF1 also has a more direct effect on migration directionality.	19	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR7	CXCR7	CXCR7	22	23	19	20
Investigating the functional role of CXCR7 in human cell lines ( HEK-293T and MDA-MB-231 ) two mechanisms have been suggested regarding the CXCL12 mediated action of CXCR7 .	Investigating the functional role of CXCR7 in human cell lines (HEK-293T and MDA-MB-231) two mechanisms have been suggested regarding the CXCL12 mediated action of CXCR7.	21	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	22	23	26	27
Unlike CXCR4 , CXCL12 activation of CXCR7 does not induce calcium mobilisation and cell migration ( Burns et al , 2006 ) but rather results in a proliferative effect and increased adhesion properties ( Miao et al , 2007 ; Sierro et al , 2007 ; Wang et al , 2008 ) .	Unlike CXCR4, CXCL12 activation of CXCR7 does not induce calcium mobilisation and cell migration (Burns et al, 2006) but rather results in a proliferative effect and increased adhesion properties (Miao et al, 2007; Sierro et al, 2007; Wang et al, 2008).	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	3	4	6	7
CXCR7 is the predominant chemokine receptor expressed in SCC cell lines , and activation of CXCR7 by CXCL12 promotes survival of SCC cells through the ERK pathway .	CXCR7 is the predominant chemokine receptor expressed in SCC cell lines, and activation of CXCR7 by CXCL12 promotes survival of SCC cells through the ERK pathway.	13	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	17	18	15	16
It is known that while CXCR4 binds SDF-1 only , CXCR7 is activated by both SDF-1 and I-TAC .	It is known that while CXCR4 binds SDF-1 only, CXCR7 is activated by both SDF-1 and I-TAC.	10	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	15	16	10	11
Generally , SDF-1 mediates these disparate processes predominantly through CXC receptor 4 ( CXCR4 ) and/or CXCR7 .	Generally, SDF-1 mediates these disparate processes predominantly through CXC receptor 4 (CXCR4) and/or CXCR7.	2	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	2	3	16	17
CXCL12 induces CXCR7 dependent migration of breast cancer cells .	CXCL12 induces CXCR7 dependent migration of breast cancer cells.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	0	1	2	3
This high affinity for CXCL12 allows CXCR7 to significantly reduce the overall magnitude of CXCL12 concentration in the device and can alter the gradient over distances on the order of millimeters .	This high affinity for CXCL12 allows CXCR7 to significantly reduce the overall magnitude of CXCL12 concentration in the device and can alter the gradient over distances on the order of millimeters.	2	9	allows	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	4	5	6	7
Furthermore , activation of CXCR7 by SDF-1 , TC14012 , or I-TAC all prompted macrophage migration , which was significantly suppressed by atorvastatin treatment , but not by the CXCR4 antagonist .	Furthermore, activation of CXCR7 by SDF-1, TC14012, or I-TAC all prompted macrophage migration, which was significantly suppressed by atorvastatin treatment, but not by the CXCR4 antagonist.	2	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	6	7	4	5
Furthermore , both CXCL12 and MIF can interact with ACKR3 , and , despite the initial view that ACKR3 merely serves as a chemokine decoy receptor , first reports have now indicated that both MIF- and CXCL12 induced ACKR3 signaling regulate important biological processes , and it can be expected that additional functions of these signaling pathways in both physiological as well as pathological conditions will be revealed .	Furthermore, both CXCL12 and MIF can interact with ACKR3, and, despite the initial view that ACKR3 merely serves as a chemokine decoy receptor, first reports have now indicated that both MIF- and CXCL12 induced ACKR3 signaling regulate important biological processes, and it can be expected that additional functions of these signaling pathways in both physiological as well as pathological conditions will be revealed.	34	39	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	ACKR3	ACKR3	ACKR3	36	37	38	39
Taken together , ectopic expression of IL-8 promoted the APC min -induced tumor development by activating the CXCR2 pathway .	Taken together, ectopic expression of IL-8 promoted the APC min -induced tumor development by activating the CXCR2 pathway.	4	18	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	expression of IL-8	il-8	CXCR2	CXCR2	cxcr2	6	7	17	18
The GAG bound CXCL8 can activate CXCR1 and CXCR2 , specific G protein coupled receptors , on travelling leukocytes .	The GAG bound CXCL8 can activate CXCR1 and CXCR2, specific G protein coupled receptors, on travelling leukocytes.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	3	4	8	9
In fact , in the absence of functional P53 , activation of CXCR2 by IL8 appears to stimulate cell growth ( XREF_FIG ) , suggesting that CXCR2 may elicit both growth inhibitory and growth stimulatory pathways .	In fact, in the absence of functional P53, activation of CXCR2 by IL8 appears to stimulate cell growth (XREF_FIG), suggesting that CXCR2 may elicit both growth inhibitory and growth stimulatory pathways.	10	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	14	15	12	13
Lastly , we have shown that pre-treatment of L1.2 cells with the proteasome inhibitor Lactacystin blocks CXCL8 induced internalization of the CXCR1 and CXCR2 receptors .	Lastly, we have shown that pre-treatment of L1.2 cells with the proteasome inhibitor Lactacystin blocks CXCL8 induced internalization of the CXCR1 and CXCR2 receptors.	16	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	16	17	23	24
In addition to blocking CXCR2 signaling mediated by CXCL1 ( growth related oncogene alpha ) and CXCL8 ( interleukin-8 ) , both classes of nanobodies displayed inverse agonist behavior .	In addition to blocking CXCR2 signaling mediated by CXCL1 (growth related oncogene alpha) and CXCL8 (interleukin-8), both classes of nanobodies displayed inverse agonist behavior.	4	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	16	17	4	5
The IL-8 and CXCL1 have been demonstrated to continually stimulate certain cells expressing the CXCR1 and CXCR2 by autocrine and paracine mechanism and leading to malignant and oncogenic transformation .	The IL-8 and CXCL1 have been demonstrated to continually stimulate certain cells expressing the CXCR1 and CXCR2 by autocrine and paracine mechanism and leading to malignant and oncogenic transformation.	0	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	1	2	16	17
CXCL8 ( previously termed interleukin-8 ) is produced by both macrophages and epithelial cells , and induces chemotaxis by binding the chemokine receptor CXCR2 .	CXCL8 (previously termed interleukin-8) is produced by both macrophages and epithelial cells, and induces chemotaxis by binding the chemokine receptor CXCR2.	0	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	0	1	23	24
Staphopain A did not inhibit neutrophil activation via CXCL8 , which activates both the CXCR1 and CXCR2 ( XREF_FIG ) .	Staphopain A did not inhibit neutrophil activation via CXCL8, which activates both the CXCR1 and CXCR2 (XREF_FIG).	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	8	9	16	17
As a major function of IL-8 is to induce chemotaxis of cells expressing its receptors ( CXCR1 and CXCR2 ) to sites of inflammation in the initial phases of an innate response , this data supports the potential for LAK/DC derived IL-8 to sustain additional endogenous effector cell trafficking into targeted tumour sites in vivo .	As a major function of IL-8 is to induce chemotaxis of cells expressing its receptors (CXCR1 and CXCR2) to sites of inflammation in the initial phases of an innate response, this data supports the potential for LAK/DC derived IL-8 to sustain additional endogenous effector cell trafficking into targeted tumour sites in vivo.	3	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	5	6	18	19
CXCL8 activates PMNs by binding the seven-transmembrane ( 7-TM ) G-protein-coupled receptors CXC chemokine receptor 1 ( CXCR1 ) and CXC chemokine receptor 2 ( CXCR2 ) .	CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2).	0	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	0	1	25	26
In addition , exogenous IL-8 was able to downregulate endocytic adaptor protein ( NUMB ) , and upregulate IL-8RA , IL-8RB and extracellular signal regulated protein kinases ( ERKs ) expression levels in HeLa cells .	In addition, exogenous IL-8 was able to downregulate endocytic adaptor protein (NUMB), and upregulate IL-8RA, IL-8RB and extracellular signal regulated protein kinases (ERKs) expression levels in HeLa cells.	3	23	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	IL-8RB	IL-8RB	IL-8RB	4	5	20	21
Our results show that CXCL8 mediates productive infection of HIV-1 in MDM and microglia via receptors CXCR1 and CXCR2 .	Our results show that CXCL8 mediates productive infection of HIV-1 in MDM and microglia via receptors CXCR1 and CXCR2.	4	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	4	5	18	19
As an important function of p53 is in the cell cycle control and growth inhibition , these results suggest that growth inhibition of LNCaP and CXCR2 cells after activation of CXCR2 by IL8 may involve the p53 pathway .	As an important function of p53 is in the cell cycle control and growth inhibition, these results suggest that growth inhibition of LNCaP and CXCR2 cells after activation of CXCR2 by IL8 may involve the p53 pathway.	28	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	32	33	30	31
Our results suggest that IL-8 release by glial cells in vivo may activate CXCR1 and CXCR2 receptors on cholinergic septal neurons and acutely modulate their excitability by closing calcium channels .	Our results suggest that IL-8 release by glial cells in vivo may activate CXCR1 and CXCR2 receptors on cholinergic septal neurons and acutely modulate their excitability by closing calcium channels.	4	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	4	5	15	16
It has been well established that ELR + chemokines including CXCL1 , CXCL2 , ( MGSAgamma and grogamma ( CXCL3 ) , CXCL5 , CXCL6 , NAP-2 ( CXCL7 ) , and CXCL8 enhance angiogenesis by directly activating CXCR2 on endothelial cells , while ELR - chemokines such as CXCL9 , CXCL10 , and ITAC ( CXCL11 ) are angiostatic factors [ XREF_BIBR ] .	It has been well established that ELR + chemokines including CXCL1, CXCL2, (MGSAgamma and grogamma (CXCL3), CXCL5, CXCL6, NAP-2 (CXCL7), and CXCL8 enhance angiogenesis by directly activating CXCR2 on endothelial cells, while ELR - chemokines such as CXCL9, CXCL10, and ITAC (CXCL11) are angiostatic factors [XREF_BIBR].	6	39	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	32	33	38	39
IL8 dose dependently ( 20-500 ng/ml ) enhanced migration of vehicle-control , AdNull , IL8RA , IL8RB and IL8RA/RB ECs .	IL8 dose dependently (20-500 ng/ml) enhanced migration of vehicle-control, AdNull, IL8RA, IL8RB and IL8RA/RB ECs.	0	17	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL8	IL8	IL8	IL8RB	IL8RB	IL8RB	0	1	16	17
CXCL8 monomer and dimer mediated CXCR1 and CXCR2 activation in RBL-2H3 cells .	CXCL8 monomer and dimer mediated CXCR1 and CXCR2 activation in RBL-2H3 cells.	0	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	0	1	7	8
IL-8 ( or CXCL8 ) activates the receptors CXCR1 ( IL-8RA ) and CXCR2 ( IL-8RB ) to induce chemotaxis in leukocytes , but only CXCR1 mediates cytotoxic and cross-regulatory signals .	IL-8 (or CXCL8) activates the receptors CXCR1 (IL-8RA) and CXCR2 (IL-8RB) to induce chemotaxis in leukocytes, but only CXCR1 mediates cytotoxic and cross-regulatory signals.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	0	1	13	14
CXCL8 ( also known as interleukin-8 ) activates CXCR1 and CXCR2 to mediate neutrophil recruitment and trigger cytotoxic effect at sites of infection .	CXCL8 (also known as interleukin-8) activates CXCR1 and CXCR2 to mediate neutrophil recruitment and trigger cytotoxic effect at sites of infection.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	0	1	10	11
As shown in XREF_FIG , suppression of AhR as well as IL-8 expression through gene silencing decreased the TCDD stimulated induction of VEGF indicating that this effect is AhR dependent and mediated through IL-8 which binds to and activate CXCR2 .	As shown in XREF_FIG, suppression of AhR as well as IL-8 expression through gene silencing decreased the TCDD stimulated induction of VEGF indicating that this effect is AhR dependent and mediated through IL-8 which binds to and activate CXCR2.	11	40	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8 expression	il-8	CXCR2	CXCR2	cxcr2	11	12	39	40
CXCL8 activated both the receptors CXCR1 and CXCR2 in human lung microvascular endothelial cells ( HLMECs ) and immortalized dermal human microvascular endothelial cells ( HMECs ) .	CXCL8 activated both the receptors CXCR1 and CXCR2 in human lung microvascular endothelial cells (HLMECs) and immortalized dermal human microvascular endothelial cells (HMECs).	0	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	0	1	7	8
Highly malignant human glioblastoma cells ( GBM ) express a classical chemoattractant GPCR , FPR1 , which recognizes a ligand , Annexin A1 , released by necrotic GBM cells that mediates the proliferation of live GBM cells to increase their invasiveness and the production of angiogenic factors vascular endothelial growth factor ( VEGF ) and CXCL8 ( IL-8 ) , which stimulate VEGF receptor ( VEGFR ) and CXCR1 and CXCR2 on vascular ECs to promote their migration and formation of new vasculature [ XREF_BIBR , XREF_BIBR ] .	Highly malignant human glioblastoma cells (GBM) express a classical chemoattractant GPCR, FPR1, which recognizes a ligand, Annexin A1, released by necrotic GBM cells that mediates the proliferation of live GBM cells to increase their invasiveness and the production of angiogenic factors vascular endothelial growth factor (VEGF) and CXCL8 (IL-8), which stimulate VEGF receptor (VEGFR) and CXCR1 and CXCR2 on vascular ECs to promote their migration and formation of new vasculature [XREF_BIBR, XREF_BIBR].	43	71	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	55	56	70	71
Expression of CXCR2 and CXCL8 increases in microglia and inhibition of CXCR2 reduced microgliosis and conferred neuroprotection in Abeta1-42 induced rat model of AD XREF_BIBR .	Expression of CXCR2 and CXCL8 increases in microglia and inhibition of CXCR2 reduced microgliosis and conferred neuroprotection in Abeta1-42 induced rat model of AD XREF_BIBR.	0	12	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL8	Expression of CXCR2 and CXCL8	cxcl8	CXCR2	CXCR2	cxcr2	4	5	11	12
IL-8 stimulates CXCR2 receptor through autocrine signaling to regulate the differentiation or function of neuroendocrine cells .	IL-8 stimulates CXCR2 receptor through autocrine signaling to regulate the differentiation or function of neuroendocrine cells.	0	3	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	0	1	2	3
Differential Activation and Regulation of CXCR1 and CXCR2 by CXCL8 monomer and dimer1 .	Differential Activation and Regulation of CXCR1 and CXCR2 by CXCL8 monomer and dimer1.	1	10	Activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	9	10	7	8
IL-8 is known to inhibit the HIV infection by blocking its specific receptor CXCR2 [ XREF_BIBR , XREF_BIBR ] .	IL-8 is known to inhibit the HIV infection by blocking its specific receptor CXCR2 [XREF_BIBR, XREF_BIBR].	0	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	0	1	13	14
By engaging CXCR2 and CXCR1 receptors , IL-8 activates and chemoattracts endothelial cells XREF_BIBR , XREF_BIBR .	By engaging CXCR2 and CXCR1 receptors, IL-8 activates and chemoattracts endothelial cells XREF_BIBR, XREF_BIBR.	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	7	8	2	3
Using HEK 293 cell transfectants , IL-8 was shown to induce significantly higher levels of CXCR2 internalization than NAP-2 .	Using HEK 293 cell transfectants, IL-8 was shown to induce significantly higher levels of CXCR2 internalization than NAP-2.	6	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	6	7	15	16
Interestingly , activation of CXCR2 by IL8 led to altered expression of many genes involved in p53 signaling .	Interestingly, activation of CXCR2 by IL8 led to altered expression of many genes involved in p53 signaling.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	6	7	4	5
Taken together , the results indicate that the CXCL8 monomer and dimer differentially activate and regulate CXCR1 and CXCR2 receptors .	Taken together, the results indicate that the CXCL8 monomer and dimer differentially activate and regulate CXCR1 and CXCR2 receptors.	8	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	8	9	18	19
Formation of heterodimers enhances the anti-proliferative effect of PF4 on endothelial cells in culture , as well as the IL8 induced migration of CXCR2 vector transfected Baf3 cells .	Formation of heterodimers enhances the anti-proliferative effect of PF4 on endothelial cells in culture, as well as the IL8 induced migration of CXCR2 vector transfected Baf3 cells.	6	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	19	20	23	24
These results indicated that CXCR1 and CXCR2 mediated migration induced by the IL-8 synergistically and only CXCR2 mediated migration induced by GROalpha in guinea pig neutrophils .	These results indicated that CXCR1 and CXCR2 mediated migration induced by the IL-8 synergistically and only CXCR2 mediated migration induced by GROalpha in guinea pig neutrophils.	9	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	12	13	16	17
However , CXCR1 , CXCR2 , and CXCR3 do not exhibit constitutive signaling , although like KSHV-GPCR they appear to signal via phospholipase C. For example , IL-8 activation of CXCR1 and CXCR2 stimulates formation of inositol phosphate second messenger molecules in a monkey kidney ( COS ) cell line , and HuIP-10 and HuMig activation of CXCR3 stimulates elevation of intracellular calcium , which is likely caused by phospholipase C mediated generation of inositol 1,4,5-trisphosphate , in several cell types .	However, CXCR1, CXCR2, and CXCR3 do not exhibit constitutive signaling, although like KSHV-GPCR they appear to signal via phospholipase C. For example, IL-8 activation of CXCR1 and CXCR2 stimulates formation of inositol phosphate second messenger molecules in a monkey kidney (COS) cell line, and HuIP-10 and HuMig activation of CXCR3 stimulates elevation of intracellular calcium, which is likely caused by phospholipase C mediated generation of inositol 1,4,5-trisphosphate, in several cell types.	27	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	27	28	32	33
In a genetic screen to identify molecules that are critical for replicative senescence , it was found that activation of CXCR2 by IL8 leads to cellular senescence , which is mediated by p53 .	In a genetic screen to identify molecules that are critical for replicative senescence, it was found that activation of CXCR2 by IL8 leads to cellular senescence, which is mediated by p53.	18	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	22	23	20	21
Although IL-8 induced a comparable down-modulation of CXCR1 and CXCR2 , TK inhibitors did not attenuate this effect .	Although IL-8 induced a comparable down-modulation of CXCR1 and CXCR2, TK inhibitors did not attenuate this effect.	1	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	1	2	9	10
IL-8 activates multiple intracellular signaling pathways downstream of two cell-surface receptors , CXCR1 and CXCR2 .	IL-8 activates multiple intracellular signaling pathways downstream of two cell-surface receptors, CXCR1 and CXCR2.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	0	1	14	15
Interestingly , while IL8 induced surface downregulation of CXCR1 and CXCR2 , GKY25 did not .	Interestingly, while IL8 induced surface downregulation of CXCR1 and CXCR2, GKY25 did not.	3	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	3	4	10	11
Monomer induced CXCR1 internalization was faster than that of the dimer ( ~ 70 % vs. 30 % after 15 min ; XREF_FIG ) , whereas both forms of CXCL8 induced rapid CXCR2 internalization ( ~ 95 % after 5 min ; XREF_FIG ) .	Monomer induced CXCR1 internalization was faster than that of the dimer (~ 70% vs. 30% after 15 min; XREF_FIG), whereas both forms of CXCL8 induced rapid CXCR2 internalization (~ 95% after 5 min; XREF_FIG).	27	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	29	30	32	33
The significant increase in steady state apoptosis rates due to IL-8 are consistent with reports of IL-8 activation of CXCR2 resulting in endothelial cell retraction , gap formation , and increased vascular permeability .	The significant increase in steady state apoptosis rates due to IL-8 are consistent with reports of IL-8 activation of CXCR2 resulting in endothelial cell retraction, gap formation, and increased vascular permeability.	16	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	16	17	19	20
An added complexity is that activation of CXCR2 by IL-8 requires an N-terminal ELR motif , of which there is a pseudo motif in huMIF composed of two nonadjacent but adequately spaced Asp and Arg residues .	An added complexity is that activation of CXCR2 by IL-8 requires an N-terminal ELR motif, of which there is a pseudo motif in huMIF composed of two nonadjacent but adequately spaced Asp and Arg residues.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	9	10	7	8
Whereas IL-8 caused 78 and 72 % of CXCR1 and CXCR2 internalization , respectively , fMLP had minimal effects on CXCR1 or CXCR2 ( < 15 % ) .	Whereas IL-8 caused 78 and 72% of CXCR1 and CXCR2 internalization, respectively, fMLP had minimal effects on CXCR1 or CXCR2 (< 15%).	1	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	1	2	10	11
Human IL-8 has been shown to bind to and activate mouse CXCR2 , although at a much lower efficiency compared to human CXCR2 17 .	Human IL-8 has been shown to bind to and activate mouse CXCR2, although at a much lower efficiency compared to human CXCR2 17.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	1	2	11	12
In a study of CXCL8 activation of CXCR2 and CXCR1 , Rajarathnam and colleagues identified an important Gly Pro ( GP ) sequence in the 30s-loop that had large conformational effects on CXCL8 when mutated , causing CXCL8 to activate CXCR1 and CXCR2 in unique ways [ XREF_BIBR ] .	In a study of CXCL8 activation of CXCR2 and CXCR1, Rajarathnam and colleagues identified an important Gly Pro (GP) sequence in the 30s-loop that had large conformational effects on CXCL8 when mutated, causing CXCL8 to activate CXCR1 and CXCR2 in unique ways [XREF_BIBR].	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	4	5	7	8
As CXCR2 driven senescence is mediated by IL-8 , this finding furthers the possibility that the CXCR2 axis acts as a tumor suppressive mechanism in lung cancer .	As CXCR2 driven senescence is mediated by IL-8, this finding furthers the possibility that the CXCR2 axis acts as a tumor suppressive mechanism in lung cancer.	1	8	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	7	8	1	2
Additionally , our results indicated that CF172 did not inhibit the CXCL8 mediated signaling of human CXCR2 , which was consistent with the observed binding specificity presented in Figure XREF_FIG .	Additionally, our results indicated that CF172 did not inhibit the CXCL8 mediated signaling of human CXCR2, which was consistent with the observed binding specificity presented in Figure XREF_FIG.	10	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	11	12	16	17
IL-8 activates neutrophils by binding to two distinct seven-transmembrane ( 7-TMR ) G protein coupled receptors CXCR1 ( IL-8RA ) and CXCR2 ( IL-8RB ) , while GROalpha , GRObeta , GROgamma , and ENA-78 bind to and activate only CXCR2 .	IL-8 activates neutrophils by binding to two distinct seven-transmembrane (7-TMR) G protein coupled receptors CXCR1 (IL-8RA) and CXCR2 (IL-8RB), while GROalpha, GRObeta, GROgamma, and ENA-78 bind to and activate only CXCR2.	0	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	0	1	40	41
Both CXCL8 monomer and dimer induced internalization of CXCR1 and CXCR2 in a time dependent manner ( XREF_FIG ) .	Both CXCL8 monomer and dimer induced internalization of CXCR1 and CXCR2 in a time dependent manner (XREF_FIG).	1	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	1	2	10	11
It clearly shows different F-actin distribution pattern in CXCR1 and/or CXCR2 knock-down cells treated with CXCL8 as compared to vector control transfected cells .	It clearly shows different F-actin distribution pattern in CXCR1 and/or CXCR2 knock-down cells treated with CXCL8 as compared to vector control transfected cells.	10	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	15	16	10	11
Furthermore , the erythrocyte bound CXCL8 was not able to activate the neutrophils by engaging CXCR2 but this process could be reversed by the addition of excess unlabeled CXCL8 .	Furthermore, the erythrocyte bound CXCL8 was not able to activate the neutrophils by engaging CXCR2 but this process could be reversed by the addition of excess unlabeled CXCL8.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	5	6	15	16
Interleukin-8 stimulation of CXCR1 or CXCR2 cross phosphorylated CCR1 and cross desensitized its ability to stimulate GTPase activity and Ca ( 2+ ) mobilization .	Interleukin-8 stimulation of CXCR1 or CXCR2 cross phosphorylated CCR1 and cross desensitized its ability to stimulate GTPase activity and Ca (2+) mobilization.	0	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Interleukin-8	Interleukin-8	Interleukin-8	CXCR2	CXCR2	CXCR2	0	1	5	6
Since the signaling in neutrophil like dHL-60 cells occurs rapidly , and most intracellular signaling molecules such as Akt , Rac2 , and Cdc42 were activated maximally by 1 min , we studied the CXCL8 stimulated molecular repertoire of CXCR2 chemosynapse at the 1-min time point .	Since the signaling in neutrophil like dHL-60 cells occurs rapidly, and most intracellular signaling molecules such as Akt, Rac2, and Cdc42 were activated maximally by 1 min, we studied the CXCL8 stimulated molecular repertoire of CXCR2 chemosynapse at the 1-min time point.	33	40	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	34	35	39	40
The results also suggest that in the absence of functional P53 , activation of CXCR2 by IL8 may stimulate cell proliferation via a different signaling pathway .	The results also suggest that in the absence of functional P53, activation of CXCR2 by IL8 may stimulate cell proliferation via a different signaling pathway.	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	16	17	14	15
CXCL1 , CXCL3 , CXCL5 , CXCL6 and CXCL8 all activate CXCR2 receptor , and CXCL8 can also activate CXCR1 .	CXCL1, CXCL3, CXCL5, CXCL6 and CXCL8 all activate CXCR2 receptor, and CXCL8 can also activate CXCR1.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	8	9	11	12
XREF_FIG also illustrates the range of their signaling pathways in tumor microenvironments , which are activated by , for example , IL-8 via chemokine receptors CXCR1 and CXCR2 , which activate signal transducers and activators of transcription-3 ( STAT3 ) and beta-catenin , which has been shown to promote cell proliferation and angiogenesis .	XREF_FIG also illustrates the range of their signaling pathways in tumor microenvironments, which are activated by, for example, IL-8 via chemokine receptors CXCR1 and CXCR2, which activate signal transducers and activators of transcription-3 (STAT3) and beta-catenin, which has been shown to promote cell proliferation and angiogenesis.	15	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	21	22	27	28
This study demonstrates that IL-8 recognizes and activates CXCR1 , CXCR2 , and the Duffy antigen by distinct mechanisms .	This study demonstrates that IL-8 recognizes and activates CXCR1, CXCR2, and the Duffy antigen by distinct mechanisms.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	4	5	10	11
Both IL8 and CXCL1 can activate their receptor CXCR2 which not only leads to a proliferative arrest , but also to the transcriptional activation of SASP genes .	Both IL8 and CXCL1 can activate their receptor CXCR2 which not only leads to a proliferative arrest, but also to the transcriptional activation of SASP genes.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	1	2	8	9
IL-8 is known to be a potent mediator of angiogenesis and has been reported to activate CXCR1 and CXCR2 receptors on endothelial cells [ XREF_BIBR ] , which contribute to increased vascular permeability [ XREF_BIBR , XREF_BIBR ] .	IL-8 is known to be a potent mediator of angiogenesis and has been reported to activate CXCR1 and CXCR2 receptors on endothelial cells [XREF_BIBR], which contribute to increased vascular permeability [XREF_BIBR, XREF_BIBR].	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	0	1	18	19
Previous work has demonstrated that IL-8 induces a time- and dose dependent internalization of CXCR1 and CXCR2 , with CXCR2 internalized more quickly than CXCR1 , but CXCR1 recovering more quickly .	Previous work has demonstrated that IL-8 induces a time- and dose dependent internalization of CXCR1 and CXCR2, with CXCR2 internalized more quickly than CXCR1, but CXCR1 recovering more quickly.	5	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	5	6	16	17
CXCL8 induced CXCR2 signaling , however , did not change CD11a expression or activate a high-affinity conformation of LFA-1 on CXCR2 transduced NK cells ( data not shown ) .	CXCL8 induced CXCR2 signaling, however, did not change CD11a expression or activate a high-affinity conformation of LFA-1 on CXCR2 transduced NK cells (data not shown).	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	0	1	2	3
The activation of GPCR ( CXCR1 and CXCR2 ) activated by IL-8 promotes the activation of a variety of downstream pathways , including but may not be limited to PLC-PKC , PI3K-AKT , Rho-GTPase family , FAK and Src of non receptor tyrosine kinases and MAPK cascade signals , which ultimately affect the progression of cancer , angiogenesis , metastasis , and cancer stem cell activation [ XREF_BIBR ] .	The activation of GPCR (CXCR1 and CXCR2) activated by IL-8 promotes the activation of a variety of downstream pathways, including but may not be limited to PLC-PKC, PI3K-AKT, Rho-GTPase family, FAK and Src of non receptor tyrosine kinases and MAPK cascade signals, which ultimately affect the progression of cancer, angiogenesis, metastasis, and cancer stem cell activation [XREF_BIBR].	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	11	12	7	8
Cell lysates were made of differentiated CXCR2 HL-60 cells not treated with CXCL8 and cells treated with CXCL8 for 1 min .	Cell lysates were made of differentiated CXCR2 HL-60 cells not treated with CXCL8 and cells treated with CXCL8 for 1 min.	6	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	17	18	6	7
Given the recent findings showing activation of CXCR2 by IL-8 leads to cellular senescence in a p53 dependent manner [ XREF_BIBR ] , we propose that the IL-8-CXCR2-p53 axis could be the major regulatory signaling pathway to maintain the neuroendocrine cells of benign prostate and adenocarcinoma in a quiescent state .	Given the recent findings showing activation of CXCR2 by IL-8 leads to cellular senescence in a p53 dependent manner [XREF_BIBR], we propose that the IL-8-CXCR2-p53 axis could be the major regulatory signaling pathway to maintain the neuroendocrine cells of benign prostate and adenocarcinoma in a quiescent state.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	9	10	7	8
These heterodimers enhance the anti-proliferative effect of CXCL4 on endothelial cells in culture , and the CXCL8 induced migration of CXCR2 transfected Baf3 cells as well .	These heterodimers enhance the anti-proliferative effect of CXCL4 on endothelial cells in culture, and the CXCL8 induced migration of CXCR2 transfected Baf3 cells as well.	15	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	16	17	20	21
beta-arrestins have been shown to mediate the internalization and desensitization of IL-8 induced CXCR1 XREF_BIBR ; XREF_BIBR , CXCR2 XREF_BIBR ; XREF_BIBR ; XREF_BIBR , and CXCL9- and CXCL10 induced CXCR3 75 .	beta-arrestins have been shown to mediate the internalization and desensitization of IL-8 induced CXCR1 XREF_BIBR; XREF_BIBR, CXCR2 XREF_BIBR; XREF_BIBR; XREF_BIBR, and CXCL9- and CXCL10 induced CXCR3 75.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	11	12	13	14
Furthermore , treatment of ALDH1 positive cells with recombinant CXCL8 promotes mammosphere ( in vitro assay for stemness ) formation in these cells , confirming the fact that CXCL8 mediated CXCR1 signaling plays an important role in sustaining the CSC population .	Furthermore, treatment of ALDH1 positive cells with recombinant CXCL8 promotes mammosphere (in vitro assay for stemness) formation in these cells, confirming the fact that CXCL8 mediated CXCR1 signaling plays an important role in sustaining the CSC population.	28	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR1	CXCR1	CXCR1	28	29	30	31
We conclude that in human renal PTCs , IL-8 upregulates ICAM-1 production by engaging the CXCR-1 receptor and p38 MAPK signaling pathway .	We conclude that in human renal PTCs, IL-8 upregulates ICAM-1 production by engaging the CXCR-1 receptor and p38 MAPK signaling pathway.	8	16	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR-1	CXCR-1	CXCR-1	8	9	15	16
IL-8 treatment induced intracellular clustering of CXCR1-GFP and the fluorescent signals partially overlapped with those of REEPs , suggesting that REEPs might be involved in CXCR1 translocation ( XREF_FIG ) .	IL-8 treatment induced intracellular clustering of CXCR1-GFP and the fluorescent signals partially overlapped with those of REEPs, suggesting that REEPs might be involved in CXCR1 translocation (XREF_FIG).	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1-GFP	CXCR1-GFP	CXCR1-GFP	0	1	6	7
While interleukin-8 stimulation promoted CXCR1 sequestration in RBL-2H3 cells , receptor internalization in HEK 293 cells required co-expression of G protein coupled receptor kinase 2 and beta-arrestin proteins .	While interleukin-8 stimulation promoted CXCR1 sequestration in RBL-2H3 cells, receptor internalization in HEK 293 cells required co-expression of G protein coupled receptor kinase 2 and beta-arrestin proteins.	1	5	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-8	interleukin-8	interleukin-8	CXCR1	CXCR1	CXCR1	1	2	4	5
Moreover , beta-arrestin 1 ( ARRB1 ) has been shown to be involved in IL8 mediated granule release in neutrophils and to regulate IL8 induced CXCR1 internalization in HEK 293 cells .	Moreover, beta-arrestin 1 (ARRB1) has been shown to be involved in IL8 mediated granule release in neutrophils and to regulate IL8 induced CXCR1 internalization in HEK 293 cells.	22	26	induced	Positive_early_activation	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR1	CXCR1	CXCR1	23	24	25	26
Consistent with our in vivo findings , these in vitro studies demonstrated that Cxcr1 -/- neutrophils were not impaired in migrating to CXCR1/2 chemokines , but even rather showed a tendency towards a more efficient chemotactic migration , particularly towards recombinant CXCL8 that has been previously described to unexpectedly activate Cxcr1 [ XREF_BIBR ] ( XREF_FIG ) .	Consistent with our in vivo findings, these in vitro studies demonstrated that Cxcr1 -/- neutrophils were not impaired in migrating to CXCR1/2 chemokines, but even rather showed a tendency towards a more efficient chemotactic migration, particularly towards recombinant CXCL8 that has been previously described to unexpectedly activate Cxcr1 [XREF_BIBR] (XREF_FIG).	28	55	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	Cxcr1	Cxcr1	Cxcr1	41	42	50	51
Interleukin-8 ( IL-8 , also known as CXCL8 ) , one of the best studied chemokines , plays a critical role in host immune response by binding and activating the CXCR1 receptor on neutrophils .	Interleukin-8 (IL-8, also known as CXCL8), one of the best studied chemokines, plays a critical role in host immune response by binding and activating the CXCR1 receptor on neutrophils.	0	31	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin-8	Interleukin-8	Interleukin-8	CXCR1	CXCR1	CXCR1	0	1	30	31
Cells were stimulated either with the CXCR2 specific agent growth related oncogene-alpha , or with IL-8 , which stimulates CXCR1 and CXRR2 .	Cells were stimulated either with the CXCR2 specific agent growth related oncogene-alpha, or with IL-8, which stimulates CXCR1 and CXRR2.	2	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	15	16	19	20
The cells were transfected with CXCR1 and SRE-luc in a 4:1 ratio and treated with IL-8 to examine receptor activation .	The cells were transfected with CXCR1 and SRE-luc in a 4:1 ratio and treated with IL-8 to examine receptor activation.	3	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	15	16	5	6
Interestingly , the levels of IL-8 are increased during HBV infection [ XREF_BIBR ] , which suggests that IL-8 might be causing an accumulation of CD181 + macrophages in the HBV infected liver .	Interestingly, the levels of IL-8 are increased during HBV infection [XREF_BIBR], which suggests that IL-8 might be causing an accumulation of CD181 + macrophages in the HBV infected liver.	18	32	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CD181	CD181	CD181	18	19	25	26
Similarly , the PDZ ligand is also required for interleukin-8 ( IL-8 ) activation of CXCR1 .	Similarly, the PDZ ligand is also required for interleukin-8 (IL-8) activation of CXCR1.	9	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	interleukin-8	interleukin-8	interleukin-8	CXCR1	CXCR1	CXCR1	9	10	15	16
At 10 nM and higher concentrations , GCP-2 and IL-8 induced significant activation of CXCR1 expressing cells , but no activity was found with GRO alpha and ENA-78 .	At 10 nM and higher concentrations, GCP-2 and IL-8 induced significant activation of CXCR1 expressing cells, but no activity was found with GRO alpha and ENA-78.	7	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	9	10	14	15
Finally , the ELR motif of CXCL8 binds to the EC loops of CXCR1 through electrostatic interactions ( Site II binding ) , triggering conformational changes of CXCR1 that result in downstream signal transduction .	Finally, the ELR motif of CXCL8 binds to the EC loops of CXCR1 through electrostatic interactions (Site II binding), triggering conformational changes of CXCR1 that result in downstream signal transduction.	4	28	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR1	CXCR1	CXCR1	6	7	27	28
XREF_BIBR - XREF_BIBR We and others have shown that CXCR1 activation by CXCL8 triggers mitogenic response in tumor cells , including that of CaP cells , and there is increased accumulation of CXCR1 intracellularly .	XREF_BIBR - XREF_BIBR We and others have shown that CXCR1 activation by CXCL8 triggers mitogenic response in tumor cells, including that of CaP cells, and there is increased accumulation of CXCR1 intracellularly.	9	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR1	CXCR1	CXCR1	12	13	9	10
However , IL-1beta also significantly induced IL8 production by purified MMIC , suggesting additional relevance of the identified ABCB5 driven cytokine circuit to autocrine IL8 mediated CXCR1 activation .	However, IL-1beta also significantly induced IL8 production by purified MMIC, suggesting additional relevance of the identified ABCB5 driven cytokine circuit to autocrine IL8 mediated CXCR1 activation.	19	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR1	CXCR1	CXCR1	24	25	26	27
However there are reports suggesting that mouse CXCR1 is activated by human IL-8 , hence permitting to some extent experiments in xenografts XREF_BIBR .	However there are reports suggesting that mouse CXCR1 is activated by human IL-8, hence permitting to some extent experiments in xenografts XREF_BIBR.	6	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	12	13	7	8
When CXCR1 is stimulated by IL8 , this loop is implicated in G protein binding and calcium signaling [ XREF_BIBR ] .	When CXCR1 is stimulated by IL8, this loop is implicated in G protein binding and calcium signaling [XREF_BIBR].	1	6	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL8	IL8	IL8	CXCR1	CXCR1	CXCR1	5	6	1	2
IL-8 contributes to liver inflammation and fibrosis by increasing the accumulation of CD181 + macrophages in the liver [ XREF_BIBR ] .	IL-8 contributes to liver inflammation and fibrosis by increasing the accumulation of CD181 + macrophages in the liver [XREF_BIBR].	0	19	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CD181	CD181	CD181	0	1	12	13
On the other hand , the nasal microbiota clusters had no impact on ( i ) CXCL8 response targeting CXCR1 and 2 on neutrophils , or ( ii ) on CXCL10 response targeting CXCR3A and B on natural killer and T cells 29 .	On the other hand, the nasal microbiota clusters had no impact on (i) CXCL8 response targeting CXCR1 and 2 on neutrophils, or (ii) on CXCL10 response targeting CXCR3A and B on natural killer and T cells 29.	16	20	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR1	CXCR1	CXCR1	16	17	19	20
CXCL8 induced CXCR1 activation in neutrophils also promotes respiratory burst and alpha-defensin release , which are key antibacterial host defense functions [ XREF_BIBR ] .	CXCL8 induced CXCR1 activation in neutrophils also promotes respiratory burst and alpha-defensin release, which are key antibacterial host defense functions [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR1	CXCR1	CXCR1	0	1	2	3
IL-8 activation of CXCR1 , but not the IL-8 receptor CXCR2 , cross phosphorylated CCR5 and CXCR4 and cross desensitized their responsiveness to RANTES ( regulated on activation normal T cell expressed and secreted ) ( CCL5 ) and stromal derived factor ( SDF-1 or CXCL12 ) , respectively .	IL-8 activation of CXCR1, but not the IL-8 receptor CXCR2, cross phosphorylated CCR5 and CXCR4 and cross desensitized their responsiveness to RANTES (regulated on activation normal T cell expressed and secreted) (CCL5) and stromal derived factor (SDF-1 or CXCL12), respectively.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	0	1	3	4
In one study , equal doses of IL-8 caused CXCR1 to be 70 % internalized in 30 minutes whereas CXCR2 was 95 % internalized within 5 minutes .	In one study, equal doses of IL-8 caused CXCR1 to be 70% internalized in 30 minutes whereas CXCR2 was 95% internalized within 5 minutes.	5	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	7	8	9	10
Previously , IL-8 was reported to induce proliferation , differentiation and CXCR1 dependent migration in Caco-2 BBE cells [ XREF_BIBR , XREF_BIBR ] .	Previously, IL-8 was reported to induce proliferation, differentiation and CXCR1 dependent migration in Caco-2 BBE cells [XREF_BIBR, XREF_BIBR].	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	2	3	11	12
IL-8 and granulocyte chemotactic protein-2 ( GCP-2 ) activate CXCR1 .	IL-8 and granulocyte chemotactic protein-2 (GCP-2) activate CXCR1.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	0	1	9	10
The present finding in concert with earlier reports establishes that external and internal stimulation of CXCR1 by IL-8 mediate autocrine growth stimulation .	The present finding in concert with earlier reports establishes that external and internal stimulation of CXCR1 by IL-8 mediate autocrine growth stimulation.	13	18	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	17	18	15	16
CXCR1 is activated by IL-8 and granulocyte chemotactic protein-2 ( GCP-2 )/CXCL6 [ XREF_BIBR ] .	CXCR1 is activated by IL-8 and granulocyte chemotactic protein-2 (GCP-2)/CXCL6 [XREF_BIBR].	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	4	5	0	1
Chemokine CXCL-8 plays a central role in human immune response by binding to and activate its cognate receptor CXCR1 , a member of the G protein coupled receptor ( GPCR ) family .	Chemokine CXCL-8 plays a central role in human immune response by binding to and activate its cognate receptor CXCR1, a member of the G protein coupled receptor (GPCR) family.	0	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL-8	CXCL-8	CXCL-8	CXCR1	CXCR1	CXCR1	1	2	18	19
We investigated changes in interleukin-8 ( IL-8 ) mediated neutrophil migration and associated changes in receptor expression , of the IL-8 receptors CXCR1 , the integrins CD11b and CD18 and platelet endothelial cell adhesion molecule-1 ( PECAM-1 ) in patients sustaining major trauma .	We investigated changes in interleukin-8 (IL-8) mediated neutrophil migration and associated changes in receptor expression, of the IL-8 receptors CXCR1, the integrins CD11b and CD18 and platelet endothelial cell adhesion molecule-1 (PECAM-1) in patients sustaining major trauma.	2	30	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-8	interleukin-8	interleukin-8	CXCR1	CXCR1	CXCR1	4	5	22	23
Furthermore , inhibition of ERK1/2 phosphorylation using an inhibitor abrogated CXCL8 mediated endothelial cell migration , demonstrating important role of ERK1/2 phosphorylation in CXCL8 mediated CXCR1 and/or CXCR2 dependent endothelial cell migration ( XREF_FIG ) .	Furthermore, inhibition of ERK1/2 phosphorylation using an inhibitor abrogated CXCL8 mediated endothelial cell migration, demonstrating important role of ERK1/2 phosphorylation in CXCL8 mediated CXCR1 and/or CXCR2 dependent endothelial cell migration (XREF_FIG).	16	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR1	CXCR1	CXCR1	23	24	25	26
IL8 stimulated cell migration was significantly greater in IL8RA and RB-EC ( 2 way ANOVA , p < 0.05 ) compared to the other 4 experimental groups ( XREF_FIG ) .	IL8 stimulated cell migration was significantly greater in IL8RA and RB-EC (2 way ANOVA, p < 0.05) compared to the other 4 experimental groups (XREF_FIG).	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL8	IL8	IL8	IL8RA	IL8RA	IL8RA	0	1	8	9
CXCR1 and CXCR2 receptors also exhibit a markedly distinct ligand binding pharmacology : CXCR1 is predominantly activated by CXCL8 and CXCL6 , whereas CXCR2 could be activated by CXCL1-3 and 5-8 [ XREF_BIBR ] .	CXCR1 and CXCR2 receptors also exhibit a markedly distinct ligand binding pharmacology : CXCR1 is predominantly activated by CXCL8 and CXCL6, whereas CXCR2 could be activated by CXCL1-3 and 5-8 [XREF_BIBR].	13	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CXCL8	CXCL8	CXCL8	CXCR1	CXCR1	CXCR1	18	19	13	14
Overexpression of p120ctn stimulates Cdc42 and Rac1 activation , but diminishes RhoA activity .	Overexpression of p120ctn stimulates Cdc42 and Rac1 activation, but diminishes RhoA activity.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120ctn	Overexpression of p120ctn	p120ctn	Rac1	Rac1	rac1	2	3	6	7
For example , in a context dependent manner , both p120 and plakophilin subfamily members can activate Rac1 and inhibit RhoA [ XREF_BIBR ] .	For example, in a context dependent manner, both p120 and plakophilin subfamily members can activate Rac1 and inhibit RhoA [XREF_BIBR].	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	10	11	17	18
For example , within the cytoplasm , p120-catenin modulates the opposing activity of the Rho and Rac families of GTPases , thus contributing to cytoskeletal organization [ XREF_BIBR ] .	For example, within the cytoplasm, p120-catenin modulates the opposing activity of the Rho and Rac families of GTPases, thus contributing to cytoskeletal organization [XREF_BIBR].	7	17	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120-catenin	p120-catenin	p120-catenin	Rac	Rac	Rac	7	8	16	17
This suggests that p120 , when phosphorylated on Y335 , interacts with VAV2 , probably through its SH2 domain to activate Rac1 at the leading edge to promote membrane protrusion and motility .	This suggests that p120, when phosphorylated on Y335, interacts with VAV2, probably through its SH2 domain to activate Rac1 at the leading edge to promote membrane protrusion and motility.	3	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120, when phosphorylated on Y335, interacts with VAV2, probably through its SH2 domain	p120	Rac1	Rac1	rac1	3	4	21	22
Previous studies in epithelial tumor cells have shown that mesenchymal cadherins ( i.e. N-cadherin and cadherin 11 ) can promote tumor cell growth and migration via p120 mediated activation of Rac1 signaling XREF_BIBR , XREF_BIBR .	Previous studies in epithelial tumor cells have shown that mesenchymal cadherins (i.e. N-cadherin and cadherin 11) can promote tumor cell growth and migration via p120 mediated activation of Rac1 signaling XREF_BIBR, XREF_BIBR.	26	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	26	27	30	31
How mesenchymal cadherins promote cell migration is currently unclear , but it may involve the p120 mediated activation of Rac1 signaling and subsequent actin reorganization [ XREF_BIBR - XREF_BIBR ] .	How mesenchymal cadherins promote cell migration is currently unclear, but it may involve the p120 mediated activation of Rac1 signaling and subsequent actin reorganization [XREF_BIBR - XREF_BIBR].	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	15	16	19	20
Combined , these data strongly argue that endogenous p120 promotes the growth of MDA-MB-231 cells by inducing Rac1 activation .	Combined, these data strongly argue that endogenous p120 promotes the growth of MDA-MB-231 cells by inducing Rac1 activation.	7	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	8	9	17	18
Once in the cytoplasm , p120-catenin represses RhoA activity and activates Rac and Cdc42 through Vav2 to promote actin cytoskeleton remodeling [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Once in the cytoplasm, p120-catenin represses RhoA activity and activates Rac and Cdc42 through Vav2 to promote actin cytoskeleton remodeling [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120-catenin	p120-catenin	p120-catenin	Rac	Rac	Rac	5	6	11	12
Overexpression of p120 enhances the activity of Rac1 and cdc42 while suppressing activity of RhoA .	Overexpression of p120 enhances the activity of Rac1 and cdc42 while suppressing activity of RhoA.	0	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	Overexpression of p120	p120	Rac1	Rac1	rac1	2	3	7	8
Cytoplasmic p120ctn promotes cell motility , and probably other activities , by modulating the activities of RhoA , Rac and Cdc42 .	Cytoplasmic p120ctn promotes cell motility, and probably other activities, by modulating the activities of RhoA, Rac and Cdc42.	0	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120ctn	p120ctn	p120ctn	Rac	Rac	Rac	1	2	18	19
p120ctn has been shown to stimulate Rac and/or Cdc42 activity and/or inhibit RhoA activity in cells lacking E-cadherin , including fibroblasts and cancer cell lines XREF_BIBR , XREF_BIBR .	p120ctn has been shown to stimulate Rac and/or Cdc42 activity and/or inhibit RhoA activity in cells lacking E-cadherin, including fibroblasts and cancer cell lines XREF_BIBR, XREF_BIBR.	0	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120ctn	p120ctn	p120ctn	Rac	Rac	Rac	0	1	6	7
These effects are apparently mediated by the ability of p120 to suppress RhoA activity and induce the activities of the related Rho GTPases Rac1 and Cdc42 .	These effects are apparently mediated by the ability of p120 to suppress RhoA activity and induce the activities of the related Rho GTPases Rac1 and Cdc42.	4	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	9	10	23	24
Binding of p120 to the juxtamembrane domain of cadherins is believed to locally activate the small GTPase Rac1 at the plasma membrane , which in turn induces membrane ruffling and allows for the extension of lamellipodia through the localized regulation of actin dynamics .	Binding of p120 to the juxtamembrane domain of cadherins is believed to locally activate the small GTPase Rac1 at the plasma membrane, which in turn induces membrane ruffling and allows for the extension of lamellipodia through the localized regulation of actin dynamics.	0	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	2	3	17	18
It is also possible that p120-catenin may be modulating the activity of Rho and Rac at the contact after activation of the PCP pathway .	It is also possible that p120-catenin may be modulating the activity of Rho and Rac at the contact after activation of the PCP pathway.	5	15	modulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120-catenin	p120-catenin	p120-catenin	Rac	Rac	Rac	5	6	14	15
Given mammalian cell line studies indicating that p120 inhibits RhoA and activates Rac and Cdc42 ( Introduction ) , we asked if this functionality is evident in vertebrate embryogenesis .	Given mammalian cell line studies indicating that p120 inhibits RhoA and activates Rac and Cdc42 (Introduction), we asked if this functionality is evident in vertebrate embryogenesis.	7	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac	Rac	Rac	7	8	12	13
However , upon E-cadherin loss during EMT or tumor progression , the negative regulation of Ras is relieved , endogenous p120 induces Rac1 activation , constitutive activation of the ERK MAP kinase signaling pathway , cell cycle progression , and anchorage independent growth [ XREF_BIBR ] .	However, upon E-cadherin loss during EMT or tumor progression, the negative regulation of Ras is relieved, endogenous p120 induces Rac1 activation, constitutive activation of the ERK MAP kinase signaling pathway, cell cycle progression, and anchorage independent growth [XREF_BIBR].	19	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	20	21	22	23
The current data suggest that understanding and targeting the ability of p120 to activate Rac1 may also block the transformed growth of these E-cadherin-deficient cells .	The current data suggest that understanding and targeting the ability of p120 to activate Rac1 may also block the transformed growth of these E-cadherin-deficient cells.	9	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	11	12	14	15
In the absence of E-cadherin ( control MDA-MB-231 cells ) , p120 promotes Rac1 activation and tumor growth .	In the absence of E-cadherin (control MDA-MB-231 cells), p120 promotes Rac1 activation and tumor growth.	11	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	11	12	13	14
Endogenous p120 promotes the transformed growth of E-cadherin-deficient tumors by promoting Rac1 activation and inducing MAPK signaling .	Endogenous p120 promotes the transformed growth of E-cadherin-deficient tumors by promoting Rac1 activation and inducing MAPK signaling.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	1	2	11	12
CAS and Crk mediated cell invasion and survival requires activation of the small GTPase Rac , whereas ERK induced cell invasion , but not survival requires myosin light chain kinase activation and myosin light chain phosphorylation .	CAS and Crk mediated cell invasion and survival requires activation of the small GTPase Rac, whereas ERK induced cell invasion, but not survival requires myosin light chain kinase activation and myosin light chain phosphorylation.	0	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CAS	CAS	CAS	Rac	Rac	Rac	0	1	14	15
Combined , our data support a model in which p120 mediated Rac1 activation cooperates with Ras-MAPK signaling to induce the transformed growth of MDA-MB-231 cells .	Combined, our data support a model in which p120 mediated Rac1 activation cooperates with Ras-MAPK signaling to induce the transformed growth of MDA-MB-231 cells.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	9	10	11	12
Rac1 physically interacts with M-cadherin [ XREF_BIBR ] and is activated by p120 [ XREF_BIBR , XREF_BIBR ] and M-cadherin [ XREF_BIBR ] .	Rac1 physically interacts with M-cadherin [XREF_BIBR] and is activated by p120 [XREF_BIBR, XREF_BIBR] and M-cadherin [XREF_BIBR].	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	12	13	0	1
Finally , association of p120 to the RhoGEF Vav2 induces the activation of Rac1 and Cdc42 35 , which may account for the essential role of the JMD in Rac1 activation following the ligation of E-cadherin extracellular domains at early stages of cell-cell contact 36 .	Finally, association of p120 to the RhoGEF Vav2 induces the activation of Rac1 and Cdc42 35, which may account for the essential role of the JMD in Rac1 activation following the ligation of E-cadherin extracellular domains at early stages of cell-cell contact 36.	2	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	4	5	13	14
Given that p120ctn stimulates Rac and Cdc42 activity and downregulates RhoA activity , we wanted to see if these biochemical effects correlated with biological responses that are known to be regulated by the Rho family GTPases .	Given that p120ctn stimulates Rac and Cdc42 activity and downregulates RhoA activity, we wanted to see if these biochemical effects correlated with biological responses that are known to be regulated by the Rho family GTPases.	2	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120ctn	p120ctn	p120ctn	Rac	Rac	Rac	2	3	4	5
p120 mediated Rac activation requires mesenchymal cadherin binding .	p120 mediated Rac activation requires mesenchymal cadherin binding.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac	Rac	Rac	0	1	2	3
p120ctn overexpression increased the activity of endogenous Cdc42 and Rac1 .	p120ctn overexpression increased the activity of endogenous Cdc42 and Rac1.	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120ctn	p120ctn overexpression	p120ctn	Rac1	Rac1	rac1	0	1	9	10
The reexpression of full-length murine p120 isoform 1A ( mp120 ) rescues both Rac1 and RhoA activities .	The reexpression of full-length murine p120 isoform 1A (mp120) rescues both Rac1 and RhoA activities.	1	16	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	reexpression of full-length murine p120	p120	Rac1	Rac1	rac1	5	6	13	14
We sought to determine the mechanism by which p120ctn could increase the activity of Rac1 and Cdc42 .	We sought to determine the mechanism by which p120ctn could increase the activity of Rac1 and Cdc42.	8	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120ctn	p120ctn	p120ctn	Rac1	Rac1	Rac1	8	9	14	15
Based on reports showing that p120 overexpression in fibroblasts or epithelial cells inhibits RhoA and activates Rac and Cdc42 GTPases , and on other reports showing that RhoA activation in endothelial cells is necessary for leukocyte TEM , we reasoned that p120 overexpression inhibited TEM through inhibition of RhoA .	Based on reports showing that p120 overexpression in fibroblasts or epithelial cells inhibits RhoA and activates Rac and Cdc42 GTPases, and on other reports showing that RhoA activation in endothelial cells is necessary for leukocyte TEM, we reasoned that p120 overexpression inhibited TEM through inhibition of RhoA.	5	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120 overexpression	p120	Rac	Rac	rac	5	6	16	17
In contrast , expression of the cadherin uncoupled p120-A1 mutant failed to restore Rac1 activation , suggesting that p120 mediated activation of Rac1 requires mesenchymal cadherin binding .	In contrast, expression of the cadherin uncoupled p120-A1 mutant failed to restore Rac1 activation, suggesting that p120 mediated activation of Rac1 requires mesenchymal cadherin binding.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	18	19	22	23
Collectively , these data strongly argue that the p120 mediated activation of Rac1 requires association of p120 with mesenchymal cadherins .	Collectively, these data strongly argue that the p120 mediated activation of Rac1 requires association of p120 with mesenchymal cadherins.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	8	9	12	13
Further investigation would be required to determine the significance of CD148 dephosphorylation and phosphorylation ( Y228 ) of p120 in E-cadherin mediated Rac1 activation .	Further investigation would be required to determine the significance of CD148 dephosphorylation and phosphorylation (Y228) of p120 in E-cadherin mediated Rac1 activation.	13	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	phosphorylation (Y228) of p120	p120	Rac1	Rac1	rac1	18	19	22	23
For example , p120 can inhibit RhoA directly XREF_BIBR , XREF_BIBR , or indirectly through p190RhoGAP XREF_BIBR , and has been shown to promote Rac1 activation XREF_BIBR , XREF_BIBR .	For example, p120 can inhibit RhoA directly XREF_BIBR, XREF_BIBR, or indirectly through p190RhoGAP XREF_BIBR, and has been shown to promote Rac1 activation XREF_BIBR, XREF_BIBR.	3	26	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	3	4	24	25
Cytoplasmic p120 was shown to interact with Vav2 and increase the Rac1 activity and cell motility XREF_BIBR , XREF_BIBR .	Cytoplasmic p120 was shown to interact with Vav2 and increase the Rac1 activity and cell motility XREF_BIBR, XREF_BIBR.	0	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	1	2	11	12
This is probably regulated by p120 , which after binding to the cadherin and catenin complexes inhibits RhoA and activates Rac and Cdc42 [ reviewed in XREF_BIBR ] .	This is probably regulated by p120, which after binding to the cadherin and catenin complexes inhibits RhoA and activates Rac and Cdc42 [reviewed in XREF_BIBR].	3	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac	Rac	Rac	5	6	20	21
Furthermore , experiments using cadherin 11 depleted cells or cadherin uncoupled p120 mutants indicate that the p120 induced Rac1 activation requires mesenchymal cadherin association and are in agreement with recent data suggesting that the p120 binding juxtamembrane domain is required for E-cadherin- or N-cadherin-induced Rac1 activation upon cell-cell adhesion .	Furthermore, experiments using cadherin 11 depleted cells or cadherin uncoupled p120 mutants indicate that the p120 induced Rac1 activation requires mesenchymal cadherin association and are in agreement with recent data suggesting that the p120 binding juxtamembrane domain is required for E-cadherin- or N-cadherin-induced Rac1 activation upon cell-cell adhesion.	15	19	induced	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	16	17	18	19
The increase in Cdc42 and Rac1 activity induced by p120ctn overexpression led us to look for GEFs that might interact with p120ctn .	The increase in Cdc42 and Rac1 activity induced by p120ctn overexpression led us to look for GEFs that might interact with p120ctn.	3	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p120ctn	p120ctn overexpression	p120ctn	Rac1	Rac1	rac1	9	10	5	6
The data suggest that , unlike p120 mediated Rac1 activation , the p120 mediated inhibition of RhoA is independent of mesenchymal cadherin expression in these cells .	The data suggest that, unlike p120 mediated Rac1 activation, the p120 mediated inhibition of RhoA is independent of mesenchymal cadherin expression in these cells.	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	6	7	8	9
In contrast , the expression of a p120 truncation mutant lacking 323 N-terminal amino acids ( DeltaN ) and resembling endogenous p120 isoform 4 can rescue Rac1 activation ( XREF_FIG ) but has no effect on RhoA .	In contrast, the expression of a p120 truncation mutant lacking 323 N-terminal amino acids (DeltaN) and resembling endogenous p120 isoform 4 can rescue Rac1 activation (XREF_FIG) but has no effect on RhoA.	4	27	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	expression of a p120	p120	Rac1	Rac1	rac1	7	8	26	27
In cancer cells , p120catenin has also been reported to activate Rac1 that in combination with reduced substrate adhesion due to RhoA inhibition , promotes cancer cell invasion [ XREF_BIBR ] .	In cancer cells, p120catenin has also been reported to activate Rac1 that in combination with reduced substrate adhesion due to RhoA inhibition, promotes cancer cell invasion [XREF_BIBR].	4	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120catenin	p120catenin	p120catenin	Rac1	Rac1	Rac1	4	5	11	12
In contrast , the mesenchymal specific p120 isoform 1 induces cell migration and invasiveness by inhibiting RHOA-ROCK signaling pathway and stimulating RAC1 activity [ XREF_BIBR ] .	In contrast, the mesenchymal specific p120 isoform 1 induces cell migration and invasiveness by inhibiting RHOA-ROCK signaling pathway and stimulating RAC1 activity [XREF_BIBR].	6	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	RAC1	RAC1	RAC1	6	7	21	22
The p120 accumulation stimulates Cdc42 - a cell-division control protein and a member of the family of Rho small guanosine triphosphatases ( GTPases ) - and activates Ras related C3 botulinum toxin substrate 1 ( Rac1 ) , decreasing thereby E-cadherin [ XREF_BIBR , XREF_BIBR ] , microtubule polymerization [ XREF_BIBR ] , and integrin clustering [ XREF_BIBR ] .	The p120 accumulation stimulates Cdc42 - a cell-division control protein and a member of the family of Rho small guanosine triphosphatases (GTPases) - and activates Ras related C3 botulinum toxin substrate 1 (Rac1), decreasing thereby E-cadherin [XREF_BIBR, XREF_BIBR], microtubule polymerization [XREF_BIBR], and integrin clustering [XREF_BIBR].	1	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	1	2	35	36
Our model ( XREF_FIG ) predicts that loss of E-cadherin or perturbations of the cell-cell junctions will increase the pool of p120ctn , which , in turn , will stimulate increased Cdc42 and Rac1 activity and decreased RhoA activity .	Our model (XREF_FIG) predicts that loss of E-cadherin or perturbations of the cell-cell junctions will increase the pool of p120ctn, which, in turn, will stimulate increased Cdc42 and Rac1 activity and decreased RhoA activity.	19	34	stimulate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p120ctn	p120ctn	p120ctn	Rac1	Rac1	Rac1	21	22	33	34
In the case of breast cancer cells expressing E-cadherin , p120 mediated Rac1 activation was required for HER2 and ErbB2 induced cell migration [ XREF_BIBR ] .	In the case of breast cancer cells expressing E-cadherin, p120 mediated Rac1 activation was required for HER2 and ErbB2 induced cell migration [XREF_BIBR].	10	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	10	11	12	13
Finally , if the ability of p120 to induce Rac1 activation requires cadherin association , depletion of endogenous cadherins should block p120 mediated Rac1 activation .	Finally, if the ability of p120 to induce Rac1 activation requires cadherin association, depletion of endogenous cadherins should block p120 mediated Rac1 activation.	20	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	21	22	23	24
FAK and Src mediated CAS phosphorylation activates the small GTPses Ras and Rac as well as JNK and Erk1/2 , which are known to trigger gene expression for cell survival and growth .	FAK and Src mediated CAS phosphorylation activates the small GTPses Ras and Rac as well as JNK and Erk1/2, which are known to trigger gene expression for cell survival and growth.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CAS	Src mediated CAS phosphorylation	cas	Rac	Rac	rac	4	5	12	13
Furthermore , p120 induced Rac activation requires binding of p120 to mesenchymal cadherins and promotes invasiveness .	Furthermore, p120 induced Rac activation requires binding of p120 to mesenchymal cadherins and promotes invasiveness.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac	Rac	Rac	2	3	4	5
Interestingly , in MDA-MB-231 breast cancer cells , activation of Rac by p120ctn requires cadherin binding XREF_BIBR , suggesting that mesenchymal cadherins could specifically contribute to Rac activity .	Interestingly, in MDA-MB-231 breast cancer cells, activation of Rac by p120ctn requires cadherin binding XREF_BIBR, suggesting that mesenchymal cadherins could specifically contribute to Rac activity.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	p120ctn	p120ctn	p120ctn	Rac	Rac	Rac	12	13	10	11
p120 mediated activation of Rac and cdc42 are proposed to occur through its association with the guanine exchange factor , VAV2 .	p120 mediated activation of Rac and cdc42 are proposed to occur through its association with the guanine exchange factor, VAV2.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac	Rac	Rac	0	1	4	5
In agreement , P-cadherin overexpression in pancreatic cancer cells induces p120 dependent activation of Rac1 and Cdc42 119 .	In agreement, P-cadherin overexpression in pancreatic cancer cells induces p120 dependent activation of Rac1 and Cdc42 119.	10	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	10	11	14	15
We have shown previously that p120 induces Rac1 in these cells via its association with mesenchymal cadherins .	We have shown previously that p120 induces Rac1 in these cells via its association with mesenchymal cadherins.	5	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	5	6	7	8
p120ctn Stimulates Rac1 and Cdc42 Activation but Decreases RhoA Activation .	p120ctn Stimulates Rac1 and Cdc42 Activation but Decreases RhoA Activation.	0	7	Stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120ctn	p120ctn	p120ctn	Rac1	Rac1	Rac1	0	1	2	3
Following up on the original observation that p120 is a transformation-relevant Src substrate , recent work has established that p120 is an essential mediator of the Src and Rac1 induced AIG [ XREF_BIBR ] ( XREF_FIG ) .	Following up on the original observation that p120 is a transformation-relevant Src substrate, recent work has established that p120 is an essential mediator of the Src and Rac1 induced AIG [XREF_BIBR] (XREF_FIG).	19	29	is an essential mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	19	20	28	29
Our data indicate that p120 binds to and cooperates with mesenchymal cadherins to activate Rac1 and promote motility and invasiveness .	Our data indicate that p120 binds to and cooperates with mesenchymal cadherins to activate Rac1 and promote motility and invasiveness.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	4	5	14	15
Finally , whereas overexpression of wild-type p120 enhanced Rac1 and decreased RhoA activity in HCT116 cells , expression of the Y335F mutant did not stimulate Rac1 activity and had a modest effect on RhoA ( XREF_FIG ) .	Finally, whereas overexpression of wild-type p120 enhanced Rac1 and decreased RhoA activity in HCT116 cells, expression of the Y335F mutant did not stimulate Rac1 activity and had a modest effect on RhoA (XREF_FIG).	3	9	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	overexpression of wild-type p120	p120	Rac1	Rac1	rac1	6	7	8	9
p120 catenin in the cytoplasm modulates the activities of small Rho family GTPases by inhibiting RhoA and activating Rac1 and Cdc42 , which together influence cytoskeletal dynamics and cell migration .	p120 catenin in the cytoplasm modulates the activities of small Rho family GTPases by inhibiting RhoA and activating Rac1 and Cdc42, which together influence cytoskeletal dynamics and cell migration.	0	24	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120 catenin	p120 catenin	p120 catenin	Rac1	Rac1	Rac1	0	2	18	19
Furthermore , p120-catenin depletion inactivated RhoA , but increased the activity of Cdc42 and Rac1 , and promoted proliferation and the invasive ability of lung cancer cells both in vitro and in vivo .	Furthermore, p120-catenin depletion inactivated RhoA, but increased the activity of Cdc42 and Rac1, and promoted proliferation and the invasive ability of lung cancer cells both in vitro and in vivo.	2	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p120-catenin	p120-catenin	p120-catenin	Rac1	Rac1	Rac1	2	3	14	15
p120ctn depleted cells also have increased migration speed and invasion , which correlates with increased Rap1 but not Rac1 or RhoA activity .	p120ctn depleted cells also have increased migration speed and invasion, which correlates with increased Rap1 but not Rac1 or RhoA activity.	0	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120ctn	p120ctn	p120ctn	Rac1	Rac1	Rac1	0	1	18	19
P120 catenin also modulates the activity and spatial distribution of Rac1 [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	P120 catenin also modulates the activity and spatial distribution of Rac1 [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	16	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P120 catenin	P120 catenin	P120 catenin	Rac1	Rac1	Rac1	0	2	10	11
Specifically , p120 activates Rac1 and inhibits RhoA .	Specifically, p120 activates Rac1 and inhibits RhoA.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	2	3	4	5
Our data show that p120 mediated activation of Rac1 is one of the mechanisms that E-cadherin-deficient tumor cells use to grow under conditions of anchorage independence .	Our data show that p120 mediated activation of Rac1 is one of the mechanisms that E-cadherin-deficient tumor cells use to grow under conditions of anchorage independence.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	4	5	8	9
These data are consistent with our previous observation that p120 mediated Rac1 activation in control MDA-MB-231 cells requires mesenchymal cadherin association and that E-cadherin expression competes p120 away from mesenchymal cadherins , leading to their destabilization .	These data are consistent with our previous observation that p120 mediated Rac1 activation in control MDA-MB-231 cells requires mesenchymal cadherin association and that E-cadherin expression competes p120 away from mesenchymal cadherins, leading to their destabilization.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	9	10	11	12
In addition , p120 overexpression promotes Rac1 activation in fibroblasts , whereas the recruitment and activation of Rac1 upon cadherin ligation requires p120 catenin binding to the cadherin complexes .	In addition, p120 overexpression promotes Rac1 activation in fibroblasts, whereas the recruitment and activation of Rac1 upon cadherin ligation requires p120 catenin binding to the cadherin complexes.	3	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120 overexpression	p120	Rac1	Rac1	rac1	3	4	6	7
p120 also modulates the activities of RhoA , Rac , and Cdc42 , suggesting that along with other Src substrates , p120 regulates actin dynamics .	p120 also modulates the activities of RhoA, Rac, and Cdc42, suggesting that along with other Src substrates, p120 regulates actin dynamics.	0	13	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac	Rac	Rac	0	1	8	9
These authors additionally demonstrated that Wt1 knockout resulted in an epicardium specific reduction in beta-catenin , with down-regulation of the Wnt / beta-catenin target Lef1 [ XREF_BIBR ] .	These authors additionally demonstrated that Wt1 knockout resulted in an epicardium specific reduction in beta-catenin, with down-regulation of the Wnt / beta-catenin target Lef1 [XREF_BIBR].	20	26	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef1	Lef1	Lef1	22	23	24	25
Cotransfection of beta-catenin and LEF-1 into Chinese hamster ovary cells induced transactivation of a LEF-1 reporter , which was blocked by the N-cadherin-derived molecules .	Cotransfection of beta-catenin and LEF-1 into Chinese hamster ovary cells induced transactivation of a LEF-1 reporter, which was blocked by the N-cadherin-derived molecules.	0	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	2	3	14	15
In the stem cell niche , Wnt signaling and beta-catenin stabilization are considered to activate the Lef1 and T-cell factor complex , which binds to its target genes and promotes stem cell activation and proliferation ; these constitute critical steps required to support hair growth .	In the stem cell niche, Wnt signaling and beta-catenin stabilization are considered to activate the Lef1 and T-cell factor complex, which binds to its target genes and promotes stem cell activation and proliferation; these constitute critical steps required to support hair growth.	9	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef1	Lef1	Lef1	9	10	16	17
The elimination of Wnt and beta-catenin signaling in either Lef1 or Wnt10b knockout mice resulted in down-regulation of Shh expression .	The elimination of Wnt and beta-catenin signaling in either Lef1 or Wnt10b knockout mice resulted in down-regulation of Shh expression.	3	13	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef1	Lef1	Lef1	5	6	9	10
It also showed that betacatenin relieves Tcf3 repression of Lef1 , and subsequently activate Wnt target genes through its interaction with Lef1 .	It also showed that betacatenin relieves Tcf3 repression of Lef1, and subsequently activate Wnt target genes through its interaction with Lef1.	4	13	relieves	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	betacatenin	betacatenin	betacatenin	Lef1	Lef1	Lef1	4	5	9	10
In reporter gene assays using the pGL3OT reporter containing LEF responsive elements , beta-catenin enhanced LEF1 activity , and coexpression of beta-catenin and DBC1 further enhanced LEF1 function in a synergistic manner ( XREF_FIG ) .	In reporter gene assays using the pGL3OT reporter containing LEF responsive elements, beta-catenin enhanced LEF1 activity, and coexpression of beta-catenin and DBC1 further enhanced LEF1 function in a synergistic manner (XREF_FIG).	13	16	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	13	14	15	16
Because scales develop in an invariant sequence we were also able to analyze expression of conserved Wnt and beta-catenin targets lef1 and axin2 in fixed specimens .	Because scales develop in an invariant sequence we were also able to analyze expression of conserved Wnt and beta-catenin targets lef1 and axin2 in fixed specimens.	15	22	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	lef1	lef1	lef1	18	19	20	21
Therefore , binding of beta-catenin to different interaction partners in the nucleus may direct both TCF and LEF1 dependent and -independent transcriptional regulation .	Therefore, binding of beta-catenin to different interaction partners in the nucleus may direct both TCF and LEF1 dependent and -independent transcriptional regulation.	2	22	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	4	5	17	18
By bioinformatics analyses , we discovered that the promoter regions of all RAS genes contained putative T-cell factor ( TCF )/lymphoid enhancer factor ( LEF )-binding sites , and beta-catenin induced the binding of LEF-1 to these sites in kidney tubular cells .	By bioinformatics analyses, we discovered that the promoter regions of all RAS genes contained putative T-cell factor (TCF)/lymphoid enhancer factor (LEF)-binding sites, and beta-catenin induced the binding of LEF-1 to these sites in kidney tubular cells.	17	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	29	30	34	35
Thus , Wnt signaling increases cytoplasmic levels of beta-catenin , which enters the nucleus and interacts with other factors to activate a TCF and LEF1 mediated transcriptional program 5 .	Thus, Wnt signaling increases cytoplasmic levels of beta-catenin, which enters the nucleus and interacts with other factors to activate a TCF and LEF1 mediated transcriptional program 5.	6	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	levels of beta-catenin	beta-catenin	LEF1	LEF1	lef1	8	9	24	25
Relationships between hypoxia and Wnt signaling have been explored in neural stem cells where HIF-1alpha enhances beta-catenin activation and expression of downstream effectors LEF-1 and TCF-1 XREF_BIBR .	Relationships between hypoxia and Wnt signaling have been explored in neural stem cells where HIF-1alpha enhances beta-catenin activation and expression of downstream effectors LEF-1 and TCF-1 XREF_BIBR.	16	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	16	17	23	24
This result strongly suggests that the most conserved ( by position and sequence similarity among five mammalian species ) and proximal ( relative to the TSS ) Lef1 and Tcf binding site ' c ' is the functionally most important of the three Lef1 and Tcf binding sites for Lef1 mediated activation of the murine Dkk3 gene by Wnt1 and beta-catenin signaling .	This result strongly suggests that the most conserved (by position and sequence similarity among five mammalian species) and proximal (relative to the TSS) Lef1 and Tcf binding site ' c ' is the functionally most important of the three Lef1 and Tcf binding sites for Lef1 mediated activation of the murine Dkk3 gene by Wnt1 and beta-catenin signaling.	49	61	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef1	Lef1	Lef1	60	61	49	50
Reporter assays revealed that ectopic expression of Sox17 suppresses Wnt3A and beta-catenin activation of the Lef-1 promoter in cell lines .	Reporter assays revealed that ectopic expression of Sox17 suppresses Wnt3A and beta-catenin activation of the Lef-1 promoter in cell lines.	9	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef-1	Lef-1	Lef-1	11	12	15	16
In situ hybridization experiments for the Wnt and beta-catenin targets lef1 and ctnnb2 revealed that lef1 and ctnnb2 are expressed in deposited interneuromast cells at 2 dpf ( XREF_FIG , arrowheads ) .	In situ hybridization experiments for the Wnt and beta-catenin targets lef1 and ctnnb2 revealed that lef1 and ctnnb2 are expressed in deposited interneuromast cells at 2 dpf (XREF_FIG, arrowheads).	3	11	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	lef1	lef1	lef1	8	9	10	11
We performed in situ hybridization with the Wnt and beta-catenin target lef1 and a dgfp probe for a transgenic Wnt and beta-catenin reporter line , Tg ( Tcf and Lef-miniP : dGFP ) that contains 6 copies of a consensus TCF/Lef binding site followed by destabilized EGFP .	We performed in situ hybridization with the Wnt and beta-catenin target lef1 and a dgfp probe for a transgenic Wnt and beta-catenin reporter line, Tg (Tcf and Lef-miniP : dGFP) that contains 6 copies of a consensus TCF/Lef binding site followed by destabilized EGFP.	1	12	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	lef1	lef1	lef1	9	10	11	12
Since LEF1 is strongly induced by Wnt and beta-catenin in Ewing sarcoma cells we speculate that this might lead to sequestration of EWS and ETS proteins by LEF1 and inhibition of EWS and ETS dependent transcription .	Since LEF1 is strongly induced by Wnt and beta-catenin in Ewing sarcoma cells we speculate that this might lead to sequestration of EWS and ETS proteins by LEF1 and inhibition of EWS and ETS dependent transcription.	1	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	8	9	1	2
Tcf7l1 forms a complex with beta-catenin and thereby loses chromatin occupancy in mouse embryonic stem cells and breast cancer cells XREF_BIBR , whereas recombinant beta-catenin strongly promotes binding of Lef1 to chromatin templates in vitro XREF_BIBR .	Tcf7l1 forms a complex with beta-catenin and thereby loses chromatin occupancy in mouse embryonic stem cells and breast cancer cells XREF_BIBR, whereas recombinant beta-catenin strongly promotes binding of Lef1 to chromatin templates in vitro XREF_BIBR.	23	30	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef1	Lef1	Lef1	24	25	29	30
Most importantly , the nuclear accumulation of beta-catenin activated T-cell factor and lymphocyte enhancer factor-1 ( TCF-1 and LEF-1 ) , which acts as a transcriptional activator .	Most importantly, the nuclear accumulation of beta-catenin activated T-cell factor and lymphocyte enhancer factor-1 (TCF-1 and LEF-1), which acts as a transcriptional activator.	5	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	7	8	18	19
In proximal tubular cells , constitutively activated beta-catenin promotes the binding of LEF-1 to these sites , and overexpression of beta-catenin or various Wnt ligands induces expression of multiple RAS genes ( XREF_FIG ) [ XREF_BIBR ] .	In proximal tubular cells, constitutively activated beta-catenin promotes the binding of LEF-1 to these sites, and overexpression of beta-catenin or various Wnt ligands induces expression of multiple RAS genes (XREF_FIG) [XREF_BIBR].	6	13	promotes	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	7	8	12	13
These findings indicate that beta-catenin alone can mediate the nuclear import of lef-1 through the direct binding .	These findings indicate that beta-catenin alone can mediate the nuclear import of lef-1 through the direct binding.	4	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	lef-1	lef-1	lef-1	4	5	12	13
Ten genes ( CCND1 , JUN , CCND2 , EGFR , LEF1 , MET , MMP7 , MYC , TCF3 , TERT , and beta-catenin itself ( CTNNB1 ) ) were up-regulated by beta-catenin and two ( FOS and CDH1 ) were down-regulated ; for the remaining genes , the directionality of the beta-catenin effect was not reported .	Ten genes (CCND1, JUN, CCND2, EGFR, LEF1, MET, MMP7, MYC, TCF3, TERT, and beta-catenin itself (CTNNB1)) were up-regulated by beta-catenin and two (FOS and CDH1) were down-regulated; for the remaining genes, the directionality of the beta-catenin effect was not reported.	1	34	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	33	34	11	12
69 Finally , HIF1alpha itself modulates Wnt and beta-catenin signaling in hypoxic embryonic stem ( ES ) cells by enhancing beta-catenin activation and expression of the downstream effectors LEF-1 and TCF-1 .	69 Finally, HIF1alpha itself modulates Wnt and beta-catenin signaling in hypoxic embryonic stem (ES) cells by enhancing beta-catenin activation and expression of the downstream effectors LEF-1 and TCF-1.	20	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	20	21	28	29
CTNNB1 activates Lef1 transcription and upregulates Lef1 promoter activity in vitro .	CTNNB1 activates Lef1 transcription and upregulates Lef1 promoter activity in vitro.	0	5	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	CTNNB1	CTNNB1	ctnnb1	Lef1	Lef1 transcription	lef1	0	1	2	3
Both VDR and 1,25 ( OH ) 2 D suppress beta-catenin stimulated LEF1 and TCF driven reporter activity .	Both VDR and 1,25 (OH) 2 D suppress beta-catenin stimulated LEF1 and TCF driven reporter activity.	10	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	10	11	12	13
Recently , for endometrial cancer similar observations have been described confirming promoter binding sites for the Wnt and beta-catenin inducing transcription factor LEF-1 and , interestingly , also for the EMT inducing transcription factors SNAI1 and SNAI2 XREF_BIBR .	Recently, for endometrial cancer similar observations have been described confirming promoter binding sites for the Wnt and beta-catenin inducing transcription factor LEF-1 and, interestingly, also for the EMT inducing transcription factors SNAI1 and SNAI2 XREF_BIBR.	10	37	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	18	19	22	23
Expression analysis of a selection of these transcripts demonstrates a similar profile , suggesting interaction and or co-regulation of Wnt and beta-catenin antagonists , Wnt and beta-catenin target element TCF4 , and EMT related transcription factors SNAI2 and LEF1 , which can be activated by both Wnt and beta-catenin and TGF-beta signalling ( XREF_FIG ) XREF_BIBR .	Expression analysis of a selection of these transcripts demonstrates a similar profile, suggesting interaction and or co-regulation of Wnt and beta-catenin antagonists, Wnt and beta-catenin target element TCF4, and EMT related transcription factors SNAI2 and LEF1, which can be activated by both Wnt and beta-catenin and TGF-beta signalling (XREF_FIG) XREF_BIBR.	13	49	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	48	49	38	39
It has been reported to target the mRNA of Lef1 , the transcription factor that is upregulated by beta-catenin [ XREF_BIBR ] .	It has been reported to target the mRNA of Lef1, the transcription factor that is upregulated by beta-catenin [XREF_BIBR].	7	20	upregulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef1	Lef1	Lef1	18	19	9	10
It has been shown that in chick neural cells , phosphorylation of beta-catenin at tyrosine 489 ( Y489 ) targets it to the nucleus where it binds to its partner ( s ) TCF and Lef1 and acts as a co-activator of transcription XREF_BIBR .	It has been shown that in chick neural cells, phosphorylation of beta-catenin at tyrosine 489 (Y489) targets it to the nucleus where it binds to its partner (s) TCF and Lef1 and acts as a co-activator of transcription XREF_BIBR.	10	36	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	phosphorylation of beta-catenin at tyrosine 489 (Y489	beta-catenin	Lef1	Lef1	lef1	12	13	35	36
For instance , PIASy directs the Wnt and beta-catenin mediator LEF1 to PML nuclear bodies , which results in repression of LEF1 activity .	For instance, PIASy directs the Wnt and beta-catenin mediator LEF1 to PML nuclear bodies, which results in repression of LEF1 activity.	4	11	mediator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	8	9	10	11
PITX2 isoforms regulate the LEF-1 promoter , and beta-catenin synergistically enhanced activation of the LEF-1 promoter in combination with PITX2 and Lef-1 isoforms .	PITX2 isoforms regulate the LEF-1 promoter, and beta-catenin synergistically enhanced activation of the LEF-1 promoter in combination with PITX2 and Lef-1 isoforms.	8	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	8	9	14	15
Also , for the first time we present evidence that TGFbeta 3 up-regulates LEF1 mRNA and that Smads , not beta-catenin , activate LEF1 in this embryonic EMT .	Also, for the first time we present evidence that TGFbeta 3 up-regulates LEF1 mRNA and that Smads, not beta-catenin, activate LEF1 in this embryonic EMT.	17	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	20	21	23	24
Thus , miR-26b is a tumor repressor that is a potent inhibitor of colon cancer cell proliferation that blocks Wnt and beta-catenin dependent activation of LEF-1 and a model for tumor suppressor like activity of miR-26b is illustrated in XREF_FIG .	Thus, miR-26b is a tumor repressor that is a potent inhibitor of colon cancer cell proliferation that blocks Wnt and beta-catenin dependent activation of LEF-1 and a model for tumor suppressor like activity of miR-26b is illustrated in XREF_FIG.	19	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	21	22	25	26
We observed that G-17 not only enhanced the expression of total cellular beta-catenin , but also increased nuclear beta-catenin accumulation and beta-catenin-dependent LEF-1 activity .	We observed that G-17 not only enhanced the expression of total cellular beta-catenin, but also increased nuclear beta-catenin accumulation and beta-catenin-dependent LEF-1 activity.	3	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	G-17 not only enhanced the expression of total cellular beta-catenin	beta-catenin	LEF-1	LEF-1	lef-1	12	13	22	23
We hypothesize that endothelial cells are responsive to Wnt signals and that Lef1 , a member of the vertebrate specific Wnt and beta-catenin throughput inducing transcription factors ' sub-family Lef1 and Tcf1 , mediates this responsiveness and promotes endothelial cell invasion .	We hypothesize that endothelial cells are responsive to Wnt signals and that Lef1, a member of the vertebrate specific Wnt and beta-catenin throughput inducing transcription factors ' sub-family Lef1 and Tcf1, mediates this responsiveness and promotes endothelial cell invasion.	22	31	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef1	Lef1	Lef1	22	23	29	30
Lymphoid enhance factor1 ( Lef1 ) is a transcriptional regulator of the Wnt and beta-catenin signaling cascade and is activated by nuclear beta-catenin .	Lymphoid enhance factor1 (Lef1) is a transcriptional regulator of the Wnt and beta-catenin signaling cascade and is activated by nuclear beta-catenin.	0	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lymphoid enhance factor1	Lymphoid enhance factor1	Lymphoid enhance factor1	22	23	0	3
In these clusters we observed the expression of cell survival and cell cycle genes CCND2 , NFKB1 , PLK1 , NAIP ; putative oncogenes JUNB , TOX , AHI1 ; novel cancer testis genes GTSF1 , SYCP1 as well as embryonic stem cell genes TCF3 , EVA1 , CHD1 ; genes promoting inflammatory T cell signaling ITK , LCK , FYB , GNLY , CCL18 , CCL26 , E-Selectin ; skin homing chemokine receptor CCR4 ; cytokines ( and their cognate receptors ) that were reported to be secreted by the Th17 cells IL-26 , IL-17A , IL-17F , IL-21 and IL-21R ; the IL-22 cytokine ; actin binding protein PLS3 ; matrix metalloproteinase MMP12 ; downstream positive regulator of WNT and beta-catenin signalling LEF1 ; transcription factors STAT5A , MXI and POU2AF ; markers of T cell activation TFRC , IRF4 ; and other signaling genes including T3JAM , FOSL1 , SHD1A , SERPINB4 ( XREF_FIG , XREF_FIG and XREF_SUPPLEMENTARY ) .	In these clusters we observed the expression of cell survival and cell cycle genes CCND2, NFKB1, PLK1, NAIP; putative oncogenes JUNB, TOX, AHI1; novel cancer testis genes GTSF1, SYCP1 as well as embryonic stem cell genes TCF3, EVA1, CHD1; genes promoting inflammatory T cell signaling ITK, LCK, FYB, GNLY, CCL18, CCL26, E-Selectin; skin homing chemokine receptor CCR4; cytokines (and their cognate receptors) that were reported to be secreted by the Th17 cells IL-26, IL-17A, IL-17F, IL-21 and IL-21R; the IL-22 cytokine; actin binding protein PLS3; matrix metalloproteinase MMP12; downstream positive regulator of WNT and beta-catenin signalling LEF1; transcription factors STAT5A, MXI and POU2AF; markers of T cell activation TFRC, IRF4; and other signaling genes including T3JAM, FOSL1, SHD1A, SERPINB4 (XREF_FIG, XREF_FIG and XREF_SUPPLEMENTARY).	122	156	signalling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	122	123	124	125
In the uninfected parental cell lines , stable expression full length LEF1 ( variant 1 ) led to beta-catenin activation of an LEF1 responsive luciferase reporter .	In the uninfected parental cell lines, stable expression full length LEF1 (variant 1) led to beta-catenin activation of an LEF1 responsive luciferase reporter.	18	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	18	19	22	23
Consistent with the model in which beta-catenin acetylation enhances its binding to LEF1 and leads to increased chromatin occupancy of LEF1 by stabilizing LEF1 , beta , and catenin complex , XREF_BIBR , XREF_BIBR our results further showed that DBC1 enhances the interaction of beta-catenin with LEF1 ( XREF_FIG ) and is required for efficient recruitment of LEF1 and beta-catenin to their target chromatin regions ( XREF_FIG ) , probably through protecting beta-catenin from SIRT1 mediated deacetylation ( XREF_FIG ) .	Consistent with the model in which beta-catenin acetylation enhances its binding to LEF1 and leads to increased chromatin occupancy of LEF1 by stabilizing LEF1, beta, and catenin complex, XREF_BIBR, XREF_BIBR our results further showed that DBC1 enhances the interaction of beta-catenin with LEF1 (XREF_FIG) and is required for efficient recruitment of LEF1 and beta-catenin to their target chromatin regions (XREF_FIG), probably through protecting beta-catenin from SIRT1 mediated deacetylation (XREF_FIG).	6	29	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin acetylation	beta-catenin	LEF1	LEF1	lef1	6	7	23	24
Furthermore , GRIP1 and beta-catenin can synergistically enhance the activity of both AR and Lef1 , and both coactivators are recruited specifically to AR driven and Lef1 driven promoters .	Furthermore, GRIP1 and beta-catenin can synergistically enhance the activity of both AR and Lef1, and both coactivators are recruited specifically to AR driven and Lef1 driven promoters.	2	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef1	Lef1	Lef1	4	5	14	15
Furthermore , co-expression of beta-catenin and DBC1 synergistically enhanced LEF1 activity .	Furthermore, co-expression of beta-catenin and DBC1 synergistically enhanced LEF1 activity.	2	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	co-expression of beta-catenin	beta-catenin	LEF1	LEF1	lef1	4	5	9	10
TCF-7 and LEF-1 transcription factors , which are represented by V $ LEF1TCF1_Q4 , can be activated by beta-catenin and are involved in canonical WNT signaling .	TCF-7 and LEF-1 transcription factors, which are represented by V$ LEF1TCF1_Q4, can be activated by beta-catenin and are involved in canonical WNT signaling.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	18	19	2	3
beta-Catenin stabilizes cell-cell junctions by anchoring cell adhesion molecules ( i.e ., Cadherins ) in the actin cytoskeleton , activates the LEF1 and TCF family of transcription factors , and is involved in the amplification and separation of centrosomes [ XREF_BIBR ] .	beta-Catenin stabilizes cell-cell junctions by anchoring cell adhesion molecules (i.e., Cadherins) in the actin cytoskeleton, activates the LEF1 and TCF family of transcription factors, and is involved in the amplification and separation of centrosomes [XREF_BIBR].	0	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Catenin	beta-Catenin	beta-Catenin	LEF1	LEF1	LEF1	0	1	21	22
We show with antisense beta-catenin oligonucleotides that up-regulated LEF1 is not activated by beta-catenin in palate EMT .	We show with antisense beta-catenin oligonucleotides that up-regulated LEF1 is not activated by beta-catenin in palate EMT.	8	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	13	14	8	9
After Wnt binds to cell-surface receptors Fzd and Lrp , beta-catenin is stabilized in the cytoplasm and translocated to the nucleus where it activates the Tcf and Lef1 transcription complex to regulate the promoter activity of Wnt signaling target genes [ XREF_BIBR , XREF_BIBR ] .	After Wnt binds to cell-surface receptors Fzd and Lrp, beta-catenin is stabilized in the cytoplasm and translocated to the nucleus where it activates the Tcf and Lef1 transcription complex to regulate the promoter activity of Wnt signaling target genes [XREF_BIBR, XREF_BIBR].	10	29	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin is stabilized in the cytoplasm and translocated to the nucleus	beta-catenin	Lef1	Lef1	lef1	10	11	27	28
Moreover , CK1 dependent phosphorylation in contrast to CK2 disrupts the association of beta-catenin and LEF-1 but does not impair DNA binding of LEF-1 .	Moreover, CK1 dependent phosphorylation in contrast to CK2 disrupts the association of beta-catenin and LEF-1 but does not impair DNA binding of LEF-1.	4	24	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	phosphorylation in contrast to CK2 disrupts the association of beta-catenin	beta-catenin	LEF-1	LEF-1	lef-1	13	14	23	24
This naturally occurring Lef-1 transcript was used in order to eliminate the effect of beta-catenin activating Lef-1 .	This naturally occurring Lef-1 transcript was used in order to eliminate the effect of beta-catenin activating Lef-1.	12	17	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef-1	Lef-1	Lef-1	14	15	16	17
Here , we show that Hypoxia Inducible Factor-1alpha ( HIF-1alpha ) , a principal mediator of hypoxic adaptations , modulates Wnt and beta-catenin signalling in hypoxic embryonic stem ( ES ) cells by enhancing beta-catenin activation and expression of downstream effectors LEF-1 and TCF-1 .	Here, we show that Hypoxia Inducible Factor-1alpha (HIF-1alpha), a principal mediator of hypoxic adaptations, modulates Wnt and beta-catenin signalling in hypoxic embryonic stem (ES) cells by enhancing beta-catenin activation and expression of downstream effectors LEF-1 and TCF-1.	34	43	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	LEF-1	LEF-1	LEF-1	34	35	41	42
Mazumdar et al ., have demonstrated that Hif1a modulates Wnt and beta-catenin signaling in hypoxic embryonic stem ( ES ) cells by enhancing beta-catenin activation and expression of the downstream effectors Lef-1 and Tcf-1 .	Mazumdar et al., have demonstrated that Hif1a modulates Wnt and beta-catenin signaling in hypoxic embryonic stem (ES) cells by enhancing beta-catenin activation and expression of the downstream effectors Lef-1 and Tcf-1.	23	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Lef-1	Lef-1	Lef-1	23	24	31	32
Genetic mutations or altered protein expression of beta-catenin and Apc have been implicated in human cancers , and all result in increased beta-catenin levels , which in turn lead to increased Lef-1 and Tcf-1 transcriptional activity and deregulated proliferation [ XREF_BIBR ] .	Genetic mutations or altered protein expression of beta-catenin and Apc have been implicated in human cancers, and all result in increased beta-catenin levels, which in turn lead to increased Lef-1 and Tcf-1 transcriptional activity and deregulated proliferation [XREF_BIBR].	22	40	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin levels	beta-catenin	Lef-1	Lef-1	lef-1	22	23	31	32
Ectopic overexpression of beta-catenin in 293 cells also induced the assembly of the beta , catenin , and LEF-1 complex and activated gene transcription from a LEF-1-dependent promotor .	Ectopic overexpression of beta-catenin in 293 cells also induced the assembly of the beta, catenin, and LEF-1 complex and activated gene transcription from a LEF-1-dependent promotor.	1	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	overexpression of beta-catenin	beta-catenin	LEF-1	LEF-1	lef-1	3	4	18	19
Fkn induced activation of CX3CR1 by ECs leads to in vivo angiogenesis through two sequential steps : the induction of HIF-1alpha and VEGF-A gene expression by CX3CR1 activation and the subsequent VEGF-A and KDR induced angiogenesis .	Fkn induced activation of CX3CR1 by ECs leads to in vivo angiogenesis through two sequential steps : the induction of HIF-1alpha and VEGF-A gene expression by CX3CR1 activation and the subsequent VEGF-A and KDR-induced angiogenesis.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	Fkn	Fkn	Fkn	CX3CR1	CX3CR1	CX3CR1	0	1	4	5
Membrane bound fractalkine on endothelial cells mediates adhesion of CX3CR1 + leukocytes , and proteolytic cleavage releases the soluble domain that confers fractalkine its chemotactic properties .	Membrane bound fractalkine on endothelial cells mediates adhesion of CX3CR1 + leukocytes, and proteolytic cleavage releases the soluble domain that confers fractalkine its chemotactic properties.	2	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	2	3	9	10
Although the chemokine system is thought to participate in the development of insulin resistance by sustaining adipose tissue inflammation , the CX3C chemokine ligand 1 ( CX3CL1 ) and its cognate chemokine receptor CX3CR1 were demonstrated to regulate pancreatic beta-cell insulin secretory pathway in which CX3CL1 stimulates CX3CR1 to increase insulin secretion .	Although the chemokine system is thought to participate in the development of insulin resistance by sustaining adipose tissue inflammation, the CX3C chemokine ligand 1 (CX3CL1) and its cognate chemokine receptor CX3CR1 were demonstrated to regulate pancreatic beta-cell insulin secretory pathway in which CX3CL1 stimulates CX3CR1 to increase insulin secretion.	45	48	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	45	46	47	48
We further demonstrated that the CX3CL1 soluble peptides released from stimulated HSC induced the activation of the CX3CR1 dependent signalling pathway and promoted chemoattraction of monocytes in vitro .	We further demonstrated that the CX3CL1 soluble peptides released from stimulated HSC induced the activation of the CX3CR1 dependent signalling pathway and promoted chemoattraction of monocytes in vitro.	5	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	5	6	17	18
Effect of activation of CX3CR1 by CX3CL1 on stimulation of the expression of various inflammatory cytokines and chemokines in PSCs .	Effect of activation of CX3CR1 by CX3CL1 on stimulation of the expression of various inflammatory cytokines and chemokines in PSCs.	0	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	6	7	4	5
CX3CL1 in turn activates its receptor CX3CR1 on microglia , which leads to phosphorylation of p38 MAPK in microglia XREF_BIBR , XREF_BIBR .	CX3CL1 in turn activates its receptor CX3CR1 on microglia, which leads to phosphorylation of p38 MAPK in microglia XREF_BIBR, XREF_BIBR.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	0	1	6	7
For instance , fractalkine activates the microglia specific CX3CR1 and induces a transient reduction of the amplitude of evoked excitatory postsynaptic currents ( PSCs ) in CA1 pyramidal neurons .	For instance, fractalkine activates the microglia specific CX3CR1 and induces a transient reduction of the amplitude of evoked excitatory postsynaptic currents (PSCs) in CA1 pyramidal neurons.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	3	4	8	9
CX3CL1 may activate CX3CR1 on microglia with following adenosine release that in turn , could activate Adenosine ( A ) 3 receptors ( R ) in neurons , inducing a signaling cascade which results in the modulation of GABA A receptors to increase their sensitivity to GABA [ XREF_BIBR ] .	CX3CL1 may activate CX3CR1 on microglia with following adenosine release that in turn, could activate Adenosine (A) 3 receptors (R) in neurons, inducing a signaling cascade which results in the modulation of GABA A receptors to increase their sensitivity to GABA [XREF_BIBR].	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	0	1	3	4
Increased FKN expression in the glomerulus and expression of CX3CR1 by glomerular CD16 + monocytes in murine proliferative lupus nephritis indicates that FKN induces homing of CX3CR1 positive mononuclear cells [ XREF_BIBR ] .	Increased FKN expression in the glomerulus and expression of CX3CR1 by glomerular CD16 + monocytes in murine proliferative lupus nephritis indicates that FKN induces homing of CX3CR1 positive mononuclear cells [XREF_BIBR].	22	31	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKN	FKN	FKN	CX3CR1	CX3CR1	CX3CR1	22	23	26	27
Microglial CX3CR1 activation by CX3CL1 ( fractalkine ) , which is secreted and/or cleaved from FMN , activates microglia and causes migration towards the injured FMN cell bodies , which they ensheath soon after axotomy .	Microglial CX3CR1 activation by CX3CL1 (fractalkine), which is secreted and/or cleaved from FMN, activates microglia and causes migration towards the injured FMN cell bodies, which they ensheath soon after axotomy.	1	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	4	5	1	2
Fractalkine has been extensively used to activate CX3CR1 on microglia , which induces migration , cytokine release and phagocytic activity [ XREF_BIBR , XREF_BIBR ] .	Fractalkine has been extensively used to activate CX3CR1 on microglia, which induces migration, cytokine release and phagocytic activity [XREF_BIBR, XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fractalkine	Fractalkine	Fractalkine	CX3CR1	CX3CR1	CX3CR1	0	1	7	8
Fractalkine can be produced by endothelial cells in the context of CMV infection , thus possibly attracting differentiated CX3CR1 + fetal gammadelta T cells to the site of infection .	Fractalkine can be produced by endothelial cells in the context of CMV infection, thus possibly attracting differentiated CX3CR1 + fetal gammadelta T cells to the site of infection.	0	23	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fractalkine	Fractalkine	Fractalkine	CX3CR1	CX3CR1	CX3CR1	0	1	18	19
Increased L-Selectin Surface Expression Follows Fractalkine Mediated CX3CR1 Endocytosis on CD8 + T Cells .	Increased L-Selectin Surface Expression Follows Fractalkine Mediated CX3CR1 Endocytosis on CD8 + T Cells.	4	8	Mediated	Positive_early_activation	Positive_activation	Positive_activation	Fractalkine	Fractalkine	Fractalkine	CX3CR1	CX3CR1	CX3CR1	5	6	7	8
In turn fractalkine activates CX3CR1 receptors on microglia leading to a further release of micro-glial mediators thus establishing a positive feed back which may contribute to a chronic pain state .	In turn fractalkine activates CX3CR1 receptors on microglia leading to a further release of micro-glial mediators thus establishing a positive feed back which may contribute to a chronic pain state.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	2	3	4	5
By contrast , the secreted form of CX3CL1 has been shown to promote chemotaxis of CX3CR1 + monocytes , T cells and NK cells by a conventional mechanism of integrin mediated adhesion .	By contrast, the secreted form of CX3CL1 has been shown to promote chemotaxis of CX3CR1 + monocytes, T cells and NK cells by a conventional mechanism of integrin mediated adhesion.	5	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	7	8	15	16
First , fractalkine as chemokine from vascular endothelial cells stimulated via TLR3 or TLR4 induce CX3CR1 positive monocytes or NK cells .	First, fractalkine as chemokine from vascular endothelial cells stimulated via TLR3 or TLR4 induce CX3CR1 positive monocytes or NK cells.	2	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	2	3	15	16
CX3CL1 induced pain hypersensitivity is abrogated in CX3CR1 knockout mice .	CX3CL1 induced pain hypersensitivity is abrogated in CX3CR1 knockout mice.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	0	1	7	8
A recent report has indicated that when CX3CR1 are expressed by neurons , their ligand sensitivity is smaller than those expressed by microglia [ XREF_BIBR ] and that a higher concentration of fractalkine would be required to activate CX3CR1 in this non microglial cell-type [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	A recent report has indicated that when CX3CR1 are expressed by neurons, their ligand sensitivity is smaller than those expressed by microglia [XREF_BIBR] and that a higher concentration of fractalkine would be required to activate CX3CR1 in this non microglial cell-type [XREF_BIBR, XREF_BIBR, XREF_BIBR].	30	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	32	33	38	39
In regard with obesity and T2D , the emerging data support that CX3CL1 and CX3CR1 axis promotes inflammation and , therefore , therapeutic targeting of this axis represents a promising translational approach which can be achieved , in principle , by : ( 1 ) controlling ligand ( CX3CL1 ) shedding by using antagonists of ADAM-10/17 or cathepsin S ; and/or ( 2 ) blocking cognate receptor ( CX3CR1 ) by using specific antibodies or clinical grade CX3CR1 antagonists .	In regard with obesity and T2D, the emerging data support that CX3CL1 and CX3CR1 axis promotes inflammation and, therefore, therapeutic targeting of this axis represents a promising translational approach which can be achieved, in principle, by : (1) controlling ligand (CX3CL1) shedding by using antagonists of ADAM-10/17 or cathepsin S; and/or (2) blocking cognate receptor (CX3CR1) by using specific antibodies or clinical grade CX3CR1 antagonists.	12	78	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	12	13	77	78
Fractalkine and CX3CL1 expression on inflamed endothelium along with the coexpression of intercellular adhesion molecule ( ICAM ) -1 and vascular cell adhesion molecule ( VCAM )-1, greatly enhances cell adhesion function by capturing CX3CR1 expressing cells from the blood and promoting migration into tissue .	Fractalkine and CX3CL1 expression on inflamed endothelium along with the coexpression of intercellular adhesion molecule (ICAM) -1 and vascular cell adhesion molecule (VCAM)-1, greatly enhances cell adhesion function by capturing CX3CR1 expressing cells from the blood and promoting migration into tissue.	0	36	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fractalkine	Fractalkine and CX3CL1 expression	fractalkine	CX3CR1	CX3CR1	cx3cr1	0	1	34	35
CX3CL1 is expressed in atherosclerotic plaques in a transmembrane form and can initiate the arrest of CX3CR1 + NK cells , subsets of T lymphocytes , and monocytes .	CX3CL1 is expressed in atherosclerotic plaques in a transmembrane form and can initiate the arrest of CX3CR1 + NK cells, subsets of T lymphocytes, and monocytes.	0	19	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1 is expressed	cx3cl1	CX3CR1	CX3CR1	cx3cr1	0	1	16	17
Together , these studies describe a novel pathway regulating beta cell secretory function in which FKN stimulates CX3CR1 to promote increased insulin secretory responses .	Together, these studies describe a novel pathway regulating beta cell secretory function in which FKN stimulates CX3CR1 to promote increased insulin secretory responses.	15	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKN	FKN	FKN	CX3CR1	CX3CR1	CX3CR1	15	16	17	18
Although there were no differences in survival between vehicle + control versus fractalkine + control neurons , there is some possibility that fractalkine enhances baseline neuron survival in the Cx3cr1 -/- glial co-cultures .	Although there were no differences in survival between vehicle + control versus fractalkine + control neurons, there is some possibility that fractalkine enhances baseline neuron survival in the Cx3cr1 -/- glial co-cultures.	22	32	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	Cx3cr1	Cx3cr1	Cx3cr1	22	23	29	30
For example , the disruption of fractalkine and CX3CR1 signaling in adult CX3CR1 deficient mice causes a disturbance in adult hippocampal neurogenesis .	For example, the disruption of fractalkine and CX3CR1 signaling in adult CX3CR1 deficient mice causes a disturbance in adult hippocampal neurogenesis.	6	14	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	6	7	12	13
We found that E6130 inhibited the fractalkine induced chemotaxis of human peripheral blood natural killer cells ( IC 50 4.9 nM ) , most likely via E6130 induced down-regulation of CX3CR1 on the cell surface .	We found that E6130 inhibited the fractalkine induced chemotaxis of human peripheral blood natural killer cells (IC 50 4.9 nM), most likely via E6130 induced down-regulation of CX3CR1 on the cell surface.	5	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	6	7	30	31
Human CX3CL1 has been modified at the N-terminus to produce a CX3CR1 antagonist named F1 .	Human CX3CL1 has been modified at the N-terminus to produce a CX3CR1 antagonist named F1.	0	12	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	1	2	11	12
Thus , locally produced CX3CL1 can promote PF development primarily by attracting CX3CR1 expressing M2 macrophages and fibrocytes into the lungs .	Thus, locally produced CX3CL1 can promote PF development primarily by attracting CX3CR1 expressing M2 macrophages and fibrocytes into the lungs.	4	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	4	5	12	13
Building on these data , we sought to determine the potential for pre-clinical antitumor effects generated by the pharmacologic targeting of CX3CR1 and proceeded with synthesizing a novel small-molecule compound directed to impair CX3CR1 functional activation by FKN .	Building on these data, we sought to determine the potential for pre-clinical antitumor effects generated by the pharmacologic targeting of CX3CR1 and proceeded with synthesizing a novel small-molecule compound directed to impair CX3CR1 functional activation by FKN.	33	38	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FKN	FKN	FKN	CX3CR1	CX3CR1	CX3CR1	37	38	33	34
CX3CL1 may activate CX3CR1 on microglia to directly prevent microglial activation under neuroinflammatory conditions .	CX3CL1 may activate CX3CR1 on microglia to directly prevent microglial activation under neuroinflammatory conditions.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	0	1	3	4
This suggests that FKN induced chemotaxis is CX3CR1 dependent and FKN-CD-integrin interaction may not be involved in chemotaxis .	This suggests that FKN induced chemotaxis is CX3CR1 dependent and FKN-CD-integrin interaction may not be involved in chemotaxis.	3	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKN	FKN	FKN	CX3CR1	CX3CR1	CX3CR1	3	4	7	8
Thus , CX3CL1 and FKN could induce CX3CR1 expressing macrophages to express HO-1 , thereby ameliorating toxin A induced enteritis .	Thus, CX3CL1 and FKN could induce CX3CR1 expressing macrophages to express HO-1, thereby ameliorating toxin A induced enteritis.	2	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	2	3	7	8
Our results suggest the following bidirectional mechanism for MPCs on to neuronal dendrites : after increased glutamate release , ( 1 ) neuronal NMDARs activation results in ( 2 ) the release of CX3CL1 from neuronal membranes that ( 3 ) activates microglial CX3CR1 .	Our results suggest the following bidirectional mechanism for MPCs on to neuronal dendrites : after increased glutamate release, (1) neuronal NMDARs activation results in (2) the release of CX3CL1 from neuronal membranes that (3) activates microglial CX3CR1.	31	44	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	release of CX3CL1 from neuronal membranes	cx3cl1	CX3CR1	CX3CR1	cx3cr1	33	34	43	44
Fractalkine Mediates CX3CR1 INT to CX3CR1 NEG Conversion in Peripheral Blood Derived CD8 + T Cells via Receptor Endocytosis .	Fractalkine Mediates CX3CR1 INT to CX3CR1 NEG Conversion in Peripheral Blood Derived CD8 + T Cells via Receptor Endocytosis.	0	3	Mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fractalkine	Fractalkine	Fractalkine	CX3CR1	CX3CR1	CX3CR1	0	1	2	3
We identified WT ( CX3CR1-WT/WT ) , CX3CR1-WT and M280 heterozygous , and CX3CR1-M280 and M280 homozygous healthy donors of European descent , and we show that CX3CL1 rescues serum starvation induced cell death in CX3CR1-WT/WT and CX3CR1-WT and M280 but not in CX3CR1-M280 and M280 monocytes .	We identified WT (CX3CR1-WT/WT), CX3CR1-WT and M280 heterozygous, and CX3CR1-M280 and M280 homozygous healthy donors of European descent, and we show that CX3CL1 rescues serum starvation induced cell death in CX3CR1-WT/WT and CX3CR1-WT and M280 but not in CX3CR1-M280 and M280 monocytes.	27	38	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1-WT	CX3CR1-WT	CX3CR1-WT	27	28	37	38
In addition , CX3CL1 may stimulate CX3CR1 positive cells for survival , production of cytokines , and release of granules in the lung .	In addition, CX3CL1 may stimulate CX3CR1 positive cells for survival, production of cytokines, and release of granules in the lung.	3	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	3	4	6	7
When cleaved from the membrane , soluble fractalkine ( sCX3CL1 ) activates the receptor CX3CR1 .	When cleaved from the membrane, soluble fractalkine (sCX3CL1) activates the receptor CX3CR1.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	7	8	14	15
We recently discovered that fractalkine activates integrins in the absence of CX3CR1 through the direct binding of fractalkine to a ligand binding site in the integrin headpiece ( site 2 ) that is distinct from the classical RGD binding site ( site 1 ) .	We recently discovered that fractalkine activates integrins in the absence of CX3CR1 through the direct binding of fractalkine to a ligand binding site in the integrin headpiece (site 2) that is distinct from the classical RGD binding site (site 1).	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	4	5	11	12
Under neuropathic pain conditions , neuronal CX3CL1 activates the microglial CX3CR1 receptor following proteolytic liberation of the chemokine extracellular domain .	Under neuropathic pain conditions, neuronal CX3CL1 activates the microglial CX3CR1 receptor following proteolytic liberation of the chemokine extracellular domain.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1	CX3CL1	CX3CR1	CX3CR1	CX3CR1	6	7	10	11
Upregulation of fractalkine and its receptor CX3CR1 in inflammatory cells ( monocyte , T cells and NK cells ) and target tissue expression may contribute to immune related inflammatory diseases and promote trafficking and retention of CX3CR1 expressing cells to the site of inflammation [ XREF_BIBR ] .	Upregulation of fractalkine and its receptor CX3CR1 in inflammatory cells (monocyte, T cells and NK cells) and target tissue expression may contribute to immune related inflammatory diseases and promote trafficking and retention of CX3CR1 expressing cells to the site of inflammation [XREF_BIBR].	0	38	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	2	3	36	37
Second , fractalkine as cell adhesion molecule from TLR4 stimulated BEC recruit CX3CR1 positive cells around target cells .	Second, fractalkine as cell adhesion molecule from TLR4 stimulated BEC recruit CX3CR1 positive cells around target cells.	2	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	2	3	12	13
Although not directly tested in our studies , it is likely that CD40 induced CX3CL1 upregulation could promote adhesion of CX3CR1 + monocytes .	Although not directly tested in our studies, it is likely that CD40 induced CX3CL1 upregulation could promote adhesion of CX3CR1 + monocytes.	12	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CD40 induced CX3CL1	cx3cl1	CX3CR1	CX3CR1	cx3cr1	14	15	20	21
Therefore , we postulate that tumor derived fractalkine release stimulates mobilization of CD11b + CX3CR1 + monocytes through fractalkine and CX3CR1 interaction , and these mobilized CD11b + CX3CR1 + monocytes in the PB have angiogenic and/or immunosuppressive activity in the tumor microenvironment .	Therefore, we postulate that tumor derived fractalkine release stimulates mobilization of CD11b + CX3CR1 + monocytes through fractalkine and CX3CR1 interaction, and these mobilized CD11b + CX3CR1 + monocytes in the PB have angiogenic and/or immunosuppressive activity in the tumor microenvironment.	7	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fractalkine	fractalkine	fractalkine	CX3CR1	CX3CR1	CX3CR1	7	8	14	15
In detail , a higher level of neuronal chemokine Cx3cl1 , which mediates neuronal-microglial communication through binding to its specific receptor CX3CR1 on microglia , was observed in NPC mice derived cerebrospinal fluid ( NPC-CSF ) than in wild-type mice .	In detail, a higher level of neuronal chemokine Cx3cl1, which mediates neuronal-microglial communication through binding to its specific receptor CX3CR1 on microglia, was observed in NPC mice derived cerebrospinal fluid (NPC-CSF) than in wild-type mice.	5	23	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Cx3cl1	level of neuronal chemokine Cx3cl1	cx3cl1	CX3CR1	CX3CR1	cx3cr1	9	10	21	22
Chemotaxis assays performed in vitro by other researchers have demonstrated that increased CX3CL1 levels initiate and augment the migration of specific CX3CR1 positive subpopulations of inflammatory cells [ XREF_BIBR ] .	Chemotaxis assays performed in vitro by other researchers have demonstrated that increased CX3CL1 levels initiate and augment the migration of specific CX3CR1 positive subpopulations of inflammatory cells [XREF_BIBR].	12	23	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CX3CL1	CX3CL1 levels	cx3cl1	CX3CR1	CX3CR1	cx3cr1	12	13	21	22
These data suggest that the high level of endogenous CX3CL1 expressed in neurons in the adult CNS leads to a tonic activation of CX3CR1 on microglia and acts as a neuronal off signal maintaining microglia in a quiescent state [ XREF_BIBR , XREF_BIBR ] , thus mediating a neuroprotective role for CX3CL1-CX3CR1 signaling .	These data suggest that the high level of endogenous CX3CL1 expressed in neurons in the adult CNS leads to a tonic activation of CX3CR1 on microglia and acts as a neuronal off signal maintaining microglia in a quiescent state [XREF_BIBR, XREF_BIBR], thus mediating a neuroprotective role for CX3CL1-CX3CR1 signaling.	6	24	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	CX3CL1	level of endogenous CX3CL1	cx3cl1	CX3CR1	CX3CR1	cx3cr1	9	10	23	24
XREF_BIBR It was also proposed that Akt phosphorylated FOXO is prevented from binding beta-catenin , allowing beta-catenin and TCF4 to initiate transcription .	XREF_BIBR It was also proposed that Akt phosphorylated FOXO is prevented from binding beta-catenin, allowing beta-catenin and TCF4 to initiate transcription.	10	20	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	13	14	18	19
In another study , Wu et al showed that beta-catenin increased T-cell factor 4 ( TCF4 ) transcription activity and expression of its target genes , including cyclin D1 and c-Myc , in CRC cells .	In another study, Wu et al showed that beta-catenin increased T-cell factor 4 (TCF4) transcription activity and expression of its target genes, including cyclin D1 and c-Myc, in CRC cells.	9	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	9	10	15	16
beta-catenin upregulates TCF-4 transcript and protein expression [ XREF_BIBR ] .	beta-catenin upregulates TCF-4 transcript and protein expression [XREF_BIBR].	0	3	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF-4	TCF-4	TCF-4	0	1	2	3
Expression of Axin or AxinDeltap53 downregulates beta-catenin and TCF-4 , and knock-down of beta-catenin upregulates TCF-4 in BE1 cells .	Expression of Axin or AxinDeltap53 downregulates beta-catenin and TCF-4, and knock-down of beta-catenin upregulates TCF-4 in BE1 cells.	11	18	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF-4	TCF-4	TCF-4	13	14	15	16
Moreover , HIF-1alpha disruption of hARD1 and beta-catenin repressed TCF4 activity , resulting in c-Myc suppression and p21 ( cip1 ) induction .	Moreover, HIF-1alpha disruption of hARD1 and beta-catenin repressed TCF4 activity, resulting in c-Myc suppression and p21 (cip1) induction.	3	10	repressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	7	8	9	10
PAK1 also interacts with beta-catenin to promote beta-catenin and TCF4 activation in gastric epithelial cells and it phosphorylates beta-catenin at Serine 675 , which increases the stability and transcriptional activity of beta-catenin in colon cancer cells XREF_BIBR .	PAK1 also interacts with beta-catenin to promote beta-catenin and TCF4 activation in gastric epithelial cells and it phosphorylates beta-catenin at Serine 675, which increases the stability and transcriptional activity of beta-catenin in colon cancer cells XREF_BIBR.	6	22	promote	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	beta-catenin	phosphorylates beta-catenin at Serine 675	beta-catenin	TCF4	TCF4	tcf4	18	19	9	10
It was reported that beta-catenin is needed to activate TCF4 activity .	It was reported that beta-catenin is needed to activate TCF4 activity.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	4	5	9	10
These include inhibitors of differentiation ( Ids ) , the Wnt and beta-catenin target Tcf4 , Sox5/6 , Notch and one of its downstream effectors Hes5 .	These include inhibitors of differentiation (Ids), the Wnt and beta-catenin target Tcf4, Sox5/6, Notch and one of its downstream effectors Hes5.	4	15	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Tcf4	Tcf4	Tcf4	12	13	14	15
c-Myc was identified as a target of the Wnt signalling pathway , with its expression being repressed by wild-type APC and activated by beta-catenin via inappropriate complex formation with TCF4 ( He et al , 1998 ) .	c-Myc was identified as a target of the Wnt signalling pathway, with its expression being repressed by wild-type APC and activated by beta-catenin via inappropriate complex formation with TCF4 (He et al, 1998).	21	31	activated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	23	24	29	30
Furthermore , Reg4 mediated increase in nuclear beta-Catenin induced TCF-4 transcriptional activities to increase expression of cell cycle regulatory genes Cyclin D1 and D3 and associated Cyclin dependent kinases ( CDK4 and CDK6 ) .	Furthermore, Reg4 mediated increase in nuclear beta-Catenin induced TCF-4 transcriptional activities to increase expression of cell cycle regulatory genes Cyclin D1 and D3 and associated Cyclin dependent kinases (CDK4 and CDK6).	3	11	induced	Positive_early_activation	Positive_activation	Positive_activation	beta-Catenin	beta-Catenin	beta-Catenin	TCF-4	TCF-4	TCF-4	7	8	9	10
These findings raised the possibility that the redistribution of beta-catenin from the membrane to the nucleus may enhance TCF4 and beta-catenin transcriptional activity .	These findings raised the possibility that the redistribution of beta-catenin from the membrane to the nucleus may enhance TCF4 and beta-catenin transcriptional activity.	7	22	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	9	10	18	19
In contrast , beta-catenin in HT1080 cancer cells enhanced the activity of MT1-MMP by entering the nucleus and activating transcription factor Tcf-4 and Lef , and elevating the level of MT1-MMP protein .	In contrast, beta-catenin in HT1080 cancer cells enhanced the activity of MT1-MMP by entering the nucleus and activating transcription factor Tcf-4 and Lef, and elevating the level of MT1-MMP protein.	3	23	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Tcf-4	Tcf-4	Tcf-4	3	4	21	22
This is consistent with our earlier finding that inhibition of the beta-catenin : T-cell factor 4 ( Tcf-4 ) pathway by the adenomatous polyposis coli protein down-regulates survivin expression and with recent evidence that sulindac induces beta-catenin degradation , which would reduce Tcf-4 activation .	This is consistent with our earlier finding that inhibition of the beta-catenin : T-cell factor 4 (Tcf-4) pathway by the adenomatous polyposis coli protein down-regulates survivin expression and with recent evidence that sulindac induces beta-catenin degradation, which would reduce Tcf-4 activation.	36	43	reduce	Negative_activation_syntax_5_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Tcf-4	Tcf-4	Tcf-4	36	37	42	43
In the canonical Wnt pathway , Wnt3a induces axon growth from developing sensory neurons via accumulation of beta-catenin and subsequent activation of TCF4 ( XREF_FIG ) 113 , providing evidence for GSK3 and beta-catenin signaling in axon growth .	In the canonical Wnt pathway, Wnt3a induces axon growth from developing sensory neurons via accumulation of beta-catenin and subsequent activation of TCF4 (XREF_FIG) 113, providing evidence for GSK3 and beta-catenin signaling in axon growth.	17	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	17	18	22	23
We observed that knockdown of beta-catenin strikingly reduced the binding of TCF4 with the Nherf1 promoter , while promoting the association with TCF1 in both CRC cell lines .	We observed that knockdown of beta-catenin strikingly reduced the binding of TCF4 with the Nherf1 promoter, while promoting the association with TCF1 in both CRC cell lines.	3	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	5	6	11	12
Wnt / beta-catenin pathway inhibitors might suppress ITF-2 more effectively and may provide a novel combination approach for MEK inhibitors .	Wnt / beta-catenin pathway inhibitors might suppress ITF-2 more effectively and may provide a novel combination approach for MEK inhibitors.	2	8	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	ITF-2	ITF-2	ITF-2	2	3	7	8
The dual luciferase assay performed on LUST overexpressing cells , showed that the lncRNA alone as well as beta-catenin , is able to activate the TCF-4 reporter mini gene .	The dual luciferase assay performed on LUST overexpressing cells, showed that the lncRNA alone as well as beta-catenin, is able to activate the TCF-4 reporter mini gene.	13	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF-4	TCF-4	TCF-4	18	19	25	26
Mutations in APC or beta-catenin inappropriately activate the transcription factor Tcf4 , thereby transforming intestinal epithelial cells .	Mutations in APC or beta-catenin inappropriately activate the transcription factor Tcf4, thereby transforming intestinal epithelial cells.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Tcf4	Tcf4	Tcf4	4	5	10	11
Inactivation of APC causes nuclear translocation of normally membrane bound beta-catenin and subsequent activation of the beta , catenin , and TCF4 complex with resultant increased proliferation [ XREF_BIBR - XREF_BIBR ] .	Inactivation of APC causes nuclear translocation of normally membrane bound beta-catenin and subsequent activation of the beta, catenin, and TCF4 complex with resultant increased proliferation [XREF_BIBR - XREF_BIBR].	10	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	10	11	21	22
Tcf4 is constitutively activated by mutations in the adenomatous polyposis coli and beta-catenin genes in virtually all colon tumors and is constitutively repressed by Groucho and CtBP in normal tissue .	Tcf4 is constitutively activated by mutations in the adenomatous polyposis coli and beta-catenin genes in virtually all colon tumors and is constitutively repressed by Groucho and CtBP in normal tissue.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Tcf4	Tcf4	Tcf4	12	13	0	1
Results further suggest that Reg4-Akt-GSK-3beta-mediated nuclear translocation of beta-Catenin induces TCF-4 transcriptional activities , and establishes a crucial event to regulate the expression of genes associated with human CRC cell division .	Results further suggest that Reg4-Akt-GSK-3beta-mediated nuclear translocation of beta-Catenin induces TCF-4 transcriptional activities, and establishes a crucial event to regulate the expression of genes associated with human CRC cell division.	6	12	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-Catenin	beta-Catenin	beta-Catenin	TCF-4	TCF-4	TCF-4	8	9	10	11
Overexpression of EphA2 resulted in the upregulation of the EMT molecular markers N-cadherin and Snail , as well as the Wnt and beta-catenin targets TCF4 , Cyclin-D1 and c-Myc , while silencing EphA2 using short hairpin RNA had the opposite effect .	Overexpression of EphA2 resulted in the upregulation of the EMT molecular markers N-cadherin and Snail, as well as the Wnt and beta-catenin targets TCF4, Cyclin-D1 and c-Myc, while silencing EphA2 using short hairpin RNA had the opposite effect.	6	25	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	22	23	24	25
Thus , our data indicate that signaling initiated by the beta-catenin / TCF4 pathway in DCs promotes both tumor growth and immune suppression .	Thus, our data indicate that signaling initiated by the beta-catenin / TCF4 pathway in DCs promotes both tumor growth and immune suppression.	7	13	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	10	11	12	13
Under activation of the Wnt pathway , beta-catenin relocates to the nucleus and induces the unhooking of TCF4 corepressors allowing the functional remodeling of TCF4 that becomes a transcriptional activator .	Under activation of the Wnt pathway, beta-catenin relocates to the nucleus and induces the unhooking of TCF4 corepressors allowing the functional remodeling of TCF4 that becomes a transcriptional activator.	7	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	7	8	17	18
12 In XREF_FIG , the target t is a beta-catenin activation TCF4 reporter 13 assayed across 83 cancer cell lines whose mutations and copy number profiles have previously been reported .	12 In XREF_FIG, the target t is a beta-catenin activation TCF4 reporter 13 assayed across 83 cancer cell lines whose mutations and copy number profiles have previously been reported.	0	14	activation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	9	10	11	12
c-myc , Cyclin D1 and Axin2 are three major regulators of the progression of cells into the proliferative stage of the cell cycle and these factors also represent classic down-stream activation factors following beta-catenin activation of tcf-4 transcription [ XREF_BIBR , XREF_BIBR ] .	c-myc, Cyclin D1 and Axin2 are three major regulators of the progression of cells into the proliferative stage of the cell cycle and these factors also represent classic down-stream activation factors following beta-catenin activation of tcf-4 transcription [XREF_BIBR, XREF_BIBR].	33	38	activation	Positive_regulation_syntax_3_noun	Positive_activation	Positive_regulation	beta-catenin	beta-catenin	beta-catenin	tcf-4	tcf-4 transcription	tcf-4	33	34	36	37
It is evident from our results that the occupancy of beta-catenin on this promoter depends on the level of beta-catenin , thus supporting the involvement of the beta , catenin , and TCF4 complex in p68 promoter activation .	It is evident from our results that the occupancy of beta-catenin on this promoter depends on the level of beta-catenin, thus supporting the involvement of the beta, catenin, and TCF4 complex in p68 promoter activation.	8	33	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	10	11	32	33
PAK1 is also required for activation of the beta-catenin signaling pathway in CRC cells , as PAK1 knockdown reduced beta-catenin expression and inhibited the transcriptional activity of beta-catenin and TCF4 .	PAK1 is also required for activation of the beta-catenin signaling pathway in CRC cells, as PAK1 knockdown reduced beta-catenin expression and inhibited the transcriptional activity of beta-catenin and TCF4.	16	30	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	PAK1 knockdown reduced beta-catenin expression	beta-catenin	TCF4	TCF4	tcf4	19	20	29	30
Targeting of beta-catenin to the nucleus during IRI was also completely blocked in Muc1 KO mice , as was induction of the beta-catenin protective pathway including stimulation of prosurvival factors ( activated Akt , survivin , transcription factor T cell factor 4 ( TCF4 ) and downstream target cyclin D1 ) , and repression of proapoptotoc factors ( p53 , active Bax and cleaved caspase-3 ) [ XREF_BIBR ] .	Targeting of beta-catenin to the nucleus during IRI was also completely blocked in Muc1 KO mice, as was induction of the beta-catenin protective pathway including stimulation of prosurvival factors (activated Akt, survivin, transcription factor T cell factor 4 (TCF4) and downstream target cyclin D1), and repression of proapoptotoc factors (p53, active Bax and cleaved caspase-3) [XREF_BIBR].	0	44	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	2	3	43	44
Our model provides a mechanism for the observation that beta-catenin can stimulate the transcriptional activity of Oct4 in pluripotency , even though it is difficult to detect beta-catenin at Oct4 targets : it acts by ensuring limiting amounts of Oct4 for interaction with its preferred partners : Nanog and Sox2 .	Our model provides a mechanism for the observation that beta-catenin can stimulate the transcriptional activity of Oct4 in pluripotency, even though it is difficult to detect beta-catenin at Oct4 targets : it acts by ensuring limiting amounts of Oct4 for interaction with its preferred partners : Nanog and Sox2.	9	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Oct4	Oct4	Oct4	9	10	16	17
At the same time , the stabilized beta-catenin by GSK-3 inhibition enhances Oct-4 activity and reinforces pluripotency through a TCF independent mechanism XREF_BIBR .	At the same time, the stabilized beta-catenin by GSK-3 inhibition enhances Oct-4 activity and reinforces pluripotency through a TCF independent mechanism XREF_BIBR.	5	15	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Oct-4	Oct-4	Oct-4	7	8	12	13
beta-Catenin then suppresses TCF3 mediated repression of OCT4 , SOX2 , and Nanog homeobox ( NANOG ) target genes to mediate signaling for self-renewal [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	beta-Catenin then suppresses TCF3 mediated repression of OCT4, SOX2, and Nanog homeobox (NANOG) target genes to mediate signaling for self-renewal [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	13	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Catenin	beta-Catenin	beta-Catenin	OCT4	OCT4	OCT4	0	1	7	8
XREF_BIBR An activated Wnt and beta-catenin pathway , which in A540 cells up-regulates the stem marker OCT-4 , XREF_BIBR predicts increased risk of tumor recurrence .	XREF_BIBR An activated Wnt and beta-catenin pathway, which in A540 cells up-regulates the stem marker OCT-4, XREF_BIBR predicts increased risk of tumor recurrence.	5	18	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	OCT-4	OCT-4	OCT-4	5	6	16	17
Second , our work , and that of others indicate that Tcf proteins are required for occupancy at Oct4 dependent promoter XREF_BIBR - XREF_BIBR and engagement of beta-catenin can enhance Oct4 promoter activity XREF_BIBR - XREF_BIBR .	Second, our work, and that of others indicate that Tcf proteins are required for occupancy at Oct4 dependent promoter XREF_BIBR - XREF_BIBR and engagement of beta-catenin can enhance Oct4 promoter activity XREF_BIBR - XREF_BIBR.	23	33	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Oct4	Oct4	Oct4	27	28	30	31
It is known that beta-catenin enhances Oct4 activity and plays an important role in the regulation of self-renewal of ESCs .	It is known that beta-catenin enhances Oct4 activity and plays an important role in the regulation of self-renewal of ESCs.	4	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Oct4	Oct4	Oct4	4	5	6	7
Furthermore , overexpression of the beta-catenin in the SGSCs by knockin increased the expression of downstream target signals ( TCF , AXIN2 , NANOG , SOX2 , and POU5F1 ) .	Furthermore, overexpression of the beta-catenin in the SGSCs by knockin increased the expression of downstream target signals (TCF, AXIN2, NANOG, SOX2, and POU5F1).	2	29	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	overexpression of the beta-catenin	beta-catenin	POU5F1	POU5F1	pou5f1	5	6	28	29
Studies with embryonic stem cells revealed that overexpression of beta-catenin prolongs the retention of Oct4 protein XREF_BIBR , XREF_BIBR , whereas knockdown of beta-catenin with siRNA decreased Oct4 expression 47 .	Studies with embryonic stem cells revealed that overexpression of beta-catenin prolongs the retention of Oct4 protein XREF_BIBR, XREF_BIBR, whereas knockdown of beta-catenin with siRNA decreased Oct4 expression 47.	21	29	decreased	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	beta-catenin	beta-catenin	beta-catenin	Oct4	Oct4 expression	oct4	23	24	27	28
Oct4 is transcriptionally activated by beta-Catenin , and has been shown to determine the direction of ESC differentiation , and this molecule was downregulated by Rbm46 in our study .	Oct4 is transcriptionally activated by beta-Catenin, and has been shown to determine the direction of ESC differentiation, and this molecule was downregulated by Rbm46 in our study.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-Catenin	beta-Catenin	beta-Catenin	Oct4	Oct4	Oct4	5	6	0	1
Increases in beta-catenin or addition of Wnt3A to the culture medium promotes pluripotency and aids the activity of Nanog and Oct4 .	Increases in beta-catenin or addition of Wnt3A to the culture medium promotes pluripotency and aids the activity of Nanog and Oct4.	0	21	aids	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Oct4	Oct4	Oct4	2	3	20	21
Moreover , beta-catenin is able to enhance Oct4 activity and reinforce pluripotency in mESCs XREF_BIBR .	Moreover, beta-catenin is able to enhance Oct4 activity and reinforce pluripotency in mESCs XREF_BIBR.	2	10	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Oct4	Oct4	Oct4	2	3	7	8
This analysis reveals a correlation between Nanog and Oct4 at the level of single cells that is increased by Wnt and beta-catenin signaling ( XREF_FIG ; supplementary material Fig .	This analysis reveals a correlation between Nanog and Oct4 at the level of single cells that is increased by Wnt and beta-catenin signaling (XREF_FIG; supplementary material Fig.	2	22	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Oct4	Oct4	Oct4	21	22	8	9
It has been reported that activation of beta-catenin upregulates its downstream molecule RUNX2 , which subsequently exaggerates the IVD degeneration phenotype XREF_BIBR .	It has been reported that activation of beta-catenin upregulates its downstream molecule RUNX2, which subsequently exaggerates the IVD degeneration phenotype XREF_BIBR.	5	16	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	RUNX2	RUNX2	RUNX2	7	8	12	13
Both the PKCdelta-ERK and MAPK axis and the beta-catenin pathways stimulate RUNX2 , which in turn , activates the transcription of cartilage degrading enzymes , including MMP-13 and ADAMTS-5 in chondrocytes or chondrocyte like cells .	Both the PKCdelta-ERK and MAPK axis and the beta-catenin pathways stimulate RUNX2, which in turn, activates the transcription of cartilage degrading enzymes, including MMP-13 and ADAMTS-5 in chondrocytes or chondrocyte like cells.	8	20	stimulate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	beta-catenin	beta-catenin	beta-catenin	RUNX2	RUNX2, which in turn, activates the transcription	runx2	8	9	11	12
Elevated beta-catenin signaling induces Runx2 , resulting in osteoblast differentiation , whereas reduced beta-catenin signaling has the opposite effect on gene expression , inducing chondrogenesis [ XREF_BIBR ] .	Elevated beta-catenin signaling induces Runx2, resulting in osteoblast differentiation, whereas reduced beta-catenin signaling has the opposite effect on gene expression, inducing chondrogenesis [XREF_BIBR].	1	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Runx2	Runx2	Runx2	1	2	4	5
Because beta-catenin binds the Runx2 promoter and control its transcription XREF_BIBR , in this study , we aim to define the role of beta-catenin in odontoblastic differentiation during reparative dentin formation and determine if such a role is fulfilled through activation of Runx2 by beta-catenin .	Because beta-catenin binds the Runx2 promoter and control its transcription XREF_BIBR, in this study, we aim to define the role of beta-catenin in odontoblastic differentiation during reparative dentin formation and determine if such a role is fulfilled through activation of Runx2 by beta-catenin.	38	45	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Runx2	Runx2	Runx2	44	45	42	43
Compared with IL-1alpha only , IL-1alpha plus SOST treatment decreased beta-catenin and LRP5/6 mRNA expression levels in healthy ( P = 0.002 , 0.012 , 0.012 ) and OA chondrocytes ( P = 0.022 , 0.002 , 0.015 ) and decreased RUNX-2 , MMP-13 and ADAMTS4/5 , and increased COL2A1 in healthy ( P = 0.023 , 0.009 , 0.013 , 0.016 ; XREF_FIG ) but not OA ( P = 0.68 , 0.57 , 0.55 ; XREF_FIG ) chondrocytes .	Compared with IL-1alpha only, IL-1alpha plus SOST treatment decreased beta-catenin and LRP5/6 mRNA expression levels in healthy (P = 0.002, 0.012, 0.012) and OA chondrocytes (P = 0.022, 0.002, 0.015) and decreased RUNX-2, MMP-13 and ADAMTS4/5, and increased COL2A1 in healthy (P = 0.023, 0.009, 0.013, 0.016; XREF_FIG) but not OA (P = 0.68, 0.57, 0.55; XREF_FIG) chondrocytes.	5	45	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	IL-1alpha plus SOST treatment decreased beta-catenin and LRP5/6 mRNA expression levels	beta-catenin	RUNX-2	RUNX-2	runx-2	10	11	41	42
Increasing beta-catenin did not upregulate RUNX2 , which contradicts the results of a previous study .	Increasing beta-catenin did not upregulate RUNX2, which contradicts the results of a previous study.	0	8	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	RUNX2	RUNX2	RUNX2	1	2	5	6
Myxomatous valves demonstrated activation of canonical BMP and Wnt and beta-catenin signaling and upregulation of their common target Runx2 .	Myxomatous valves demonstrated activation of canonical BMP and Wnt and beta-catenin signaling and upregulation of their common target Runx2.	10	19	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Runx2	Runx2	Runx2	10	11	18	19
Furthermore , the inhibition of beta-catenin significantly repressed osteogenic differential markers ( Runx2 and ColI ) ( XREF_FIG ) , while inducing neural linage markers ( MAP2 and NFL ) on the stiff ECM ( XREF_FIG ) .	Furthermore, the inhibition of beta-catenin significantly repressed osteogenic differential markers (Runx2 and ColI) (XREF_FIG), while inducing neural linage markers (MAP2 and NFL) on the stiff ECM (XREF_FIG).	3	14	repressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Runx2	Runx2	Runx2	5	6	12	13
This led Kawaguchi [ XREF_BIBR ] to hypothesize that beta-catenin induces chondrocyte maturation similarly to Runx2 , whereas it suppresses chondrocyte apoptosis similarly to osteoprotegerin .	This led Kawaguchi [XREF_BIBR] to hypothesize that beta-catenin induces chondrocyte maturation similarly to Runx2, whereas it suppresses chondrocyte apoptosis similarly to osteoprotegerin.	9	16	induces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Runx2	Runx2	Runx2	9	10	15	16
These data together suggested that miR-203 inhibited the ERK and beta-catenin signaling in a Runx2 dependent manner .	These data together suggested that miR-203 inhibited the ERK and beta-catenin signaling in a Runx2 dependent manner.	8	16	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Runx2	Runx2	Runx2	10	11	14	15
Canonical WNT and beta-catenin signaling through Frizzled and LRP5/6 receptors promotes RUNX2 dependent osteoblastic differentiation of mesenchymal stem or progenitor cells .	Canonical WNT and beta-catenin signaling through Frizzled and LRP5/6 receptors promotes RUNX2 dependent osteoblastic differentiation of mesenchymal stem or progenitor cells.	3	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	RUNX2	RUNX2	RUNX2	3	4	11	12
Also , beta-catenin reportedly enhances the level and transcription activity of Notch1 .	Also, beta-catenin reportedly enhances the level and transcription activity of Notch1.	2	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Notch1	Notch1	Notch1	2	3	11	12
This proposed enhancement of the canonical Wnt pathway is further supported by the recent observation that beta-catenin ( the central protein that also ties PS1 to the pathway ) modulates the level and transcriptional activity of Notch1 and NICD through their direct interaction XREF_BIBR .	This proposed enhancement of the canonical Wnt pathway is further supported by the recent observation that beta-catenin (the central protein that also ties PS1 to the pathway) modulates the level and transcriptional activity of Notch1 and NICD through their direct interaction XREF_BIBR.	16	39	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	NICD	NICD	NICD	16	17	38	39
beta-catenin can prevent NICD degradation , possibly by competing with CDC4 and Fbw7 dependent degradation [ XREF_BIBR ] .	beta-catenin can prevent NICD degradation, possibly by competing with CDC4 and Fbw7 dependent degradation [XREF_BIBR].	0	4	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	NICD	NICD	NICD	0	1	3	4
Moreover , beta-catenin increases the transcriptional activity of NICD , and the effects of beta-catenin on Notch1 are noticeably reduced by overexpression of the lymphocyte enhancer binding factor 1 , LEF1 .	Moreover, beta-catenin increases the transcriptional activity of NICD, and the effects of beta-catenin on Notch1 are noticeably reduced by overexpression of the lymphocyte enhancer binding factor 1, LEF1.	2	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	NICD	NICD	NICD	2	3	8	9
In addition , beta-catenin enhanced the transcriptional activity of NICD on the hairy and enhancer of split 1 ( HES1 ) and CSL through its C-terminal transactivation domain .	In addition, beta-catenin enhanced the transcriptional activity of NICD on the hairy and enhancer of split 1 (HES1) and CSL through its C-terminal transactivation domain.	3	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	NICD	NICD	NICD	3	4	9	10
beta-catenin could also modulate the transcriptional activity of Notch1 and NICD [ XREF_BIBR ] .	beta-catenin could also modulate the transcriptional activity of Notch1 and NICD [XREF_BIBR].	0	12	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	NICD	NICD	NICD	0	1	10	11
These results suggested that the beta-catenin signaling pathway was involved in the anti-proliferative effect of beta-elemene and mediated the regulation of E-cadherin , GFAP , Notch1 and vimentin expression .	These results suggested that the beta-catenin signaling pathway was involved in the anti-proliferative effect of beta-elemene and mediated the regulation of E-cadherin, GFAP, Notch1 and vimentin expression.	5	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Notch1	Notch1	Notch1	5	6	25	26
Moreover , silencing Ctnnb1 increased Notch1 activation in TSB treated ECs .	Moreover, silencing Ctnnb1 increased Notch1 activation in TSB treated ECs.	2	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ctnnb1	Ctnnb1	Ctnnb1	Notch1	Notch1	Notch1	3	4	5	6
Moreover , DAPT reduced the proliferation of ECs treated with siCtnnb1 and TSB , demonstrating that beta-catenin can inhibit EC proliferation by limiting Notch1 activation .	Moreover, DAPT reduced the proliferation of ECs treated with siCtnnb1 and TSB, demonstrating that beta-catenin can inhibit EC proliferation by limiting Notch1 activation.	16	24	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	Notch1	Notch1	Notch1	16	17	23	24
Mutations in beta-catenin enhance its stability and promote the subsequent transactivation of TCF7L2 ; such transactivation is found in a wide variety of human tumors XREF_BIBR .	Mutations in beta-catenin enhance its stability and promote the subsequent transactivation of TCF7L2; such transactivation is found in a wide variety of human tumors XREF_BIBR.	0	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF7L2	TCF7L2	TCF7L2	2	3	12	13
To validate the transcriptional activity of beta-catenin involved in azoramide inhibition , a Wnt agonist was applied that was known to induce Wnt and beta-catenin transcriptional activation of downstream target gene TCF7L2 mRNA expression [ XREF_BIBR ] .	To validate the transcriptional activity of beta-catenin involved in azoramide inhibition, a Wnt agonist was applied that was known to induce Wnt and beta-catenin transcriptional activation of downstream target gene TCF7L2 mRNA expression [XREF_BIBR].	22	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF7L2	TCF7L2	TCF7L2	24	25	31	32
These data suggest that beta-catenin may mediate its negative effect on OPC differentiation at least in part by recruiting TCF7L2 to regulate the transcription of important Wnt pathway target genes .	These data suggest that beta-catenin may mediate its negative effect on OPC differentiation at least in part by recruiting TCF7L2 to regulate the transcription of important Wnt pathway target genes.	4	20	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF7L2	TCF7L2	TCF7L2	4	5	19	20
Each isoform regulates the expression of distinct sets of genes and recruits , colocalizes , and competes in a distinct fashion with the Wnt and beta-catenin mediator T-cell factor 4 ( TCF4 ) at CTTTG motifs as well as at AP-1 motifs ( TGAXTCA ) .	Each isoform regulates the expression of distinct sets of genes and recruits, colocalizes, and competes in a distinct fashion with the Wnt and beta-catenin mediator T-cell factor 4 (TCF4) at CTTTG motifs as well as at AP-1 motifs (TGAXTCA).	25	31	mediator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	T-cell factor 4	T-cell factor 4	T-cell factor 4	25	26	27	30
Wnt and beta-catenin signalling supports transcriptional repression of Bace1 by promoting the binding of T-cell factor-4 at Bace1 genetic promoters .	Wnt and beta-catenin signalling supports transcriptional repression of Bace1 by promoting the binding of T-cell factor-4 at Bace1 genetic promoters.	0	16	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	T-cell factor-4	T-cell factor-4	T-cell factor-4	2	3	14	16
Of these six proteins , only beta-catenin ( CTNNB1 ) has previously been shown to modulate TCF7L2 in gastrin mediated intracellular signaling .	Of these six proteins, only beta-catenin (CTNNB1) has previously been shown to modulate TCF7L2 in gastrin mediated intracellular signaling.	5	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF7L2	TCF7L2	TCF7L2	6	7	16	17
beta-catenin has previously been reported to activate Myod1 [ XREF_BIBR ] , and we had observed that activation of Wnt in JARID2 depleted cells both activated MYOD and enhanced nuclear translocation of beta-catenin to the nucleus .	beta-catenin has previously been reported to activate Myod1 [XREF_BIBR], and we had observed that activation of Wnt in JARID2 depleted cells both activated MYOD and enhanced nuclear translocation of beta-catenin to the nucleus.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Myod1	Myod1	Myod1	0	1	7	8
Our data show that beta-catenin directly activates Myod1 under control of the JARID2 and PRC2 complex .	Our data show that beta-catenin directly activates Myod1 under control of the JARID2 and PRC2 complex.	4	8	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Myod1	Myod1	Myod1	4	5	7	8
MiR-100 regulates cell differentiation and survival via its target RBSP3 , which in turn modulates the cell cycle effector pRB and E2F1 in myeloid cells .	MiR-100 regulates cell differentiation and survival via its target RBSP3, which in turn modulates the cell cycle effector pRB and E2F1 in myeloid cells.	3	24	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RBSP3	RBSP3	RBSP3	pRB	pRB	pRB	9	10	19	20
If the truncated CTDSPL and CTDSPL2 proteins can no longer activate pRb through dephosphorylation , then pRb may become phosphorylated and thus inactive , allowing for evasion of senescence as observed in our cell culture system .	If the truncated CTDSPL and CTDSPL2 proteins can no longer activate pRb through dephosphorylation, then pRb may become phosphorylated and thus inactive, allowing for evasion of senescence as observed in our cell culture system.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CTDSPL	CTDSPL	CTDSPL	pRb	pRb	pRb	3	4	11	12
beta-Catenin Directs Nuclear Factor-kappaB p65 Output via CREB Binding Protein and p300 in Human Airway Smooth Muscle .	beta-Catenin Directs Nuclear Factor-kappaB p65 Output via CREB Binding Protein and p300 in Human Airway Smooth Muscle.	0	16	Directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Catenin	beta-Catenin	beta-Catenin	p300	p300	p300	0	1	11	12
As previously shown ( XREF_FIG ) , FLAP1 and p300 synergistically enhanced transcriptional activation by beta-catenin fused to GAL4 DBD ( bar 8 , XREF_FIG ) .	As previously shown (XREF_FIG), FLAP1 and p300 synergistically enhanced transcriptional activation by beta-catenin fused to GAL4 DBD (bar 8, XREF_FIG).	7	16	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	p300	p300	p300	15	16	9	10
However , our evidence indicates that CBP and p300 is associated with the Wnt enhanceosome prior to Wnt signaling , possibly via direct binding to B9L as suggested by RIME ( XREF_FIG ) , and that the docking of Armadillo and beta-catenin to the Wnt enhanceosome strengthens its association with CBP and p300 , and/or directs the histone acetyltransferase activity of CBP and p300 towards its substrates , primarily the histone tails .	However, our evidence indicates that CBP and p300 is associated with the Wnt enhanceosome prior to Wnt signaling, possibly via direct binding to B9L as suggested by RIME (XREF_FIG), and that the docking of Armadillo and beta-catenin to the Wnt enhanceosome strengthens its association with CBP and p300, and/or directs the histone acetyltransferase activity of CBP and p300 towards its substrates, primarily the histone tails.	37	64	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	p300	p300	p300	41	42	63	64
We identified a novel cis element in the Klf4 gene that was activated by beta-catenin in J1 mESCs .	We identified a novel cis element in the Klf4 gene that was activated by beta-catenin in J1 mESCs.	8	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Klf4	Klf4	Klf4	14	15	8	9
We further identified Klf4 as a missing target of CHIR , and demonstrated that CHIR treatment or transient beta-catenin expression effectively enhanced Klf4 activity .	We further identified Klf4 as a missing target of CHIR, and demonstrated that CHIR treatment or transient beta-catenin expression effectively enhanced Klf4 activity.	18	23	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin expression	beta-catenin	Klf4	Klf4	klf4	18	19	22	23
Though Ctnnb1 is a direct target of Klf4 , it is unaffected in the Klf4CN lens unlike Egr1 and Atf4 .	Though Ctnnb1 is a direct target of Klf4, it is unaffected in the Klf4CN lens unlike Egr1 and Atf4.	1	8	is a direct target	Positive_activation_copula_1	Positive_activation	Positive_activation	Ctnnb1	Ctnnb1	Ctnnb1	Klf4	Klf4	Klf4	1	2	7	8
TCF7 is enhanced by beta-catenin and TCF7L2 ( also known as TCF4 ) as a downstream target gene of Wnt pathway .	TCF7 is enhanced by beta-catenin and TCF7L2 (also known as TCF4) as a downstream target gene of Wnt pathway.	0	6	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF7	TCF7	TCF7	4	5	0	1
Knock-down of CCN2 also induced the down-regulation of p-LRP6 , CD90 and ALDH , but resulted in the up-regulation of E-cadherin .	Knock-down of CCN2 also induced the down-regulation of p-LRP6, CD90 and ALDH, but resulted in the up-regulation of E-cadherin.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CCN2	CCN2	CCN2	p-LRP6	p-LRP6	p-LRP6	2	3	8	9
Furthermore , p120 localization is enhanced at actin rich protrusions and lamellipodia and has an increased association with the guanine nucleotide exchange factor , VAV2 , and cortactin .	Furthermore, p120 localization is enhanced at actin rich protrusions and lamellipodia and has an increased association with the guanine nucleotide exchange factor, VAV2, and cortactin.	2	25	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	VAV2	VAV2	VAV2	2	3	24	25
The release of cytochrome c from mitochondria leads to the activation of caspase 9 , and subsequently caspases 3 and 7 .	The release of cytochrome c from mitochondria leads to the activation of caspase 9, and subsequently caspases 3 and 7.	1	14	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from mitochondria	cytochrome c	caspase 9	caspase 9	caspase 9	3	5	12	14
In addition , it promotes the localization of the Bcl-2-associated X protein ( BaX ) and Bcl-2-associated death promoter ( BaD ) proapoptotic proteins to the mitochondria ; this damages the mitochondrial membrane , leading to release of cytochrome C , which consequently activates the caspase-9 and -3 , inducing cell death .	In addition, it promotes the localization of the Bcl-2-associated X protein (BaX) and Bcl-2-associated death promoter (BaD) proapoptotic proteins to the mitochondria; this damages the mitochondrial membrane, leading to release of cytochrome C, which consequently activates the caspase-9 and -3, inducing cell death.	38	47	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	38	40	45	46
In the intrinsic pathway , the release of cytochrome c activates caspase-9 , which subsequently induces the activation of caspase-3 .	In the intrinsic pathway, the release of cytochrome c activates caspase-9, which subsequently induces the activation of caspase-3.	8	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	11	12
However , the apoptotic process requires Smac/DIABLO , but not cytochrome c mediated caspase-9 activation .	However, the apoptotic process requires Smac/DIABLO, but not cytochrome c mediated caspase-9 activation.	10	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	10	12	13	14
The released cytochrome c triggered the activation of caspase-9 .	The released cytochrome c triggered the activation of caspase-9.	2	9	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	8	9
During apoptosis , the released cytochrome c from mitochondria triggers caspase-9 activation whereas ligation of death receptors on the plasma membrane activates caspase-8 [ XREF_BIBR ] .	During apoptosis, the released cytochrome c from mitochondria triggers caspase-9 activation whereas ligation of death receptors on the plasma membrane activates caspase-8 [XREF_BIBR].	5	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	10	11
Cytochrome c activates caspase-9 and subsequently results in the cleavage of caspase-3 as the cell death executioner [ XREF_BIBR ] .	Cytochrome c activates caspase-9 and subsequently results in the cleavage of caspase-3 as the cell death executioner [XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	3	4
The BIM of cell death is a potent pro apoptotic member of the Bcl2 family , 11 essential for induction of cell death and to mediate cytochrome c release from mitochondria which in turn activates apoptosome formation and the effector caspase-9 .	The BIM of cell death is a potent pro apoptotic member of the Bcl2 family, 11 essential for induction of cell death and to mediate cytochrome c release from mitochondria which in turn activates apoptosome formation and the effector caspase-9.	26	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c release from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	26	28	40	41
We have previously showed that neuroglobin protects neuronal cells from the mitochondrial pathway of apoptosis induced by the BH3 mimetic , by preventing cytochrome c triggered activation of caspase 9 .	We have previously showed that neuroglobin protects neuronal cells from the mitochondrial pathway of apoptosis induced by the BH3 mimetic, by preventing cytochrome c triggered activation of caspase 9.	23	30	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	23	25	28	30
Cytochrome c , the protein that shuttles electrons between complex III and complex IV in oxidative phosphorylation [ XREF_BIBR ] is an effector of apoptosis by interacting with cytosolic Apaf-1 to form the apoptosome and activate caspase-9 .	Cytochrome c, the protein that shuttles electrons between complex III and complex IV in oxidative phosphorylation [XREF_BIBR] is an effector of apoptosis by interacting with cytosolic Apaf-1 to form the apoptosome and activate caspase-9.	0	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	36	37
Finally , cytochrome c activated caspase-3 and caspase-9 , and induced the apoptosis in the HepG2 cells .	Finally, cytochrome c activated caspase-3 and caspase-9, and induced the apoptosis in the HepG2 cells.	2	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	7	8
The ' apoptosome ' cascade or intrinsic pathway involves activation of pro-caspase-9 by cytochrome C released from the mitochondria , leading to the activation of the executioner pro caspases ( caspase-3 , -6 and -7 ) that cleave poly ( adenosine diphosphate ribose ) polymerase ( PARP ) and other apoptotic protein substrates .	The ' apoptosome ' cascade or intrinsic pathway involves activation of pro-caspase-9 by cytochrome C released from the mitochondria, leading to the activation of the executioner pro caspases (caspase-3, -6 and -7) that cleave poly (adenosine diphosphate ribose) polymerase (PARP) and other apoptotic protein substrates.	9	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	pro-caspase-9	pro-caspase-9	pro-caspase-9	13	15	11	12
An alteration in the permeability of mitochondrial membranes promotes translocation of the mitochondrial apoptogenic proteins which included SMAC ( an inhibitor of XIAP ) and cytochrome c ( an activator of caspase 9 ) into the cytoplasm .	An alteration in the permeability of mitochondrial membranes promotes translocation of the mitochondrial apoptogenic proteins which included SMAC (an inhibitor of XIAP) and cytochrome c (an activator of caspase 9) into the cytoplasm.	25	33	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	25	27	31	33
This triggers release of cytochrome c complex ( cyt c ) which induces calcium release from endoplasmic reticulum and activates caspase 9 which in turn activates caspase 3 and 7 leading to cell death ( XREF_FIG ) [ XREF_BIBR ] .	This triggers release of cytochrome c complex (cyt c) which induces calcium release from endoplasmic reticulum and activates caspase 9 which in turn activates caspase 3 and 7 leading to cell death (XREF_FIG) [XREF_BIBR].	4	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	4	6	20	22
19 Cytochrome-c release in the cytosol in turn activates caspase 9 after binding to Apaf-1 through formation of the apoptosome .	19 Cytochrome-c release in the cytosol in turn activates caspase 9 after binding to Apaf-1 through formation of the apoptosome.	1	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome-c	Cytochrome-c	Cytochrome-c	caspase 9	caspase 9	caspase 9	1	2	9	11
Cytosolic cytochrome c activates caspase-9 , causing caspase dependent apoptosis .	Cytosolic cytochrome c activates caspase-9, causing caspase dependent apoptosis.	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	4	5
Caspase-9 is activated by cytochrome C released from mitochondria and thus crucial for the execution of the mitochondria dependent apoptosis , which in turn activates caspase-3 .	Caspase-9 is activated by cytochrome C released from mitochondria and thus crucial for the execution of the mitochondria dependent apoptosis, which in turn activates caspase-3.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	Caspase-9	Caspase-9	Caspase-9	4	6	0	1
The release of cytochrome c can then activate downstream caspase-9 and caspase-3 , leading to an amplification of the caspase cascade reaction , and ultimately to enhanced cell apoptosis .	The release of cytochrome c can then activate downstream caspase-9 and caspase-3, leading to an amplification of the caspase cascade reaction, and ultimately to enhanced cell apoptosis.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	9	10
Additionally , we observed the release of proapoptotic mitochondrial factors such as cytochrome c , which activate caspase-9 to form an apoptosome complex , as well as the activation of caspase-3 and cleavage of PARP-1 to execute apoptosis .	Additionally, we observed the release of proapoptotic mitochondrial factors such as cytochrome c, which activate caspase-9 to form an apoptosome complex, as well as the activation of caspase-3 and cleavage of PARP-1 to execute apoptosis.	12	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	12	14	17	18
This intrinsic pathway leads to release of mitochondrial cytochrome c that sequentially activates caspase 9 , 3 , 6 and 7 , triggering apoptosis .	This intrinsic pathway leads to release of mitochondrial cytochrome c that sequentially activates caspase 9, 3, 6 and 7, triggering apoptosis.	8	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	8	10	13	15
The mitochondrial apoptotic cascade requires the release of the inter-mitochondrial membrane protein cytochrome c into the cytosol ; an increased cytosolic level of cytochrome c induces activation of caspase-9 and caspase-3 and , subsequently , neuronal death XREF_BIBR .	The mitochondrial apoptotic cascade requires the release of the inter-mitochondrial membrane protein cytochrome c into the cytosol; an increased cytosolic level of cytochrome c induces activation of caspase-9 and caspase-3 and, subsequently, neuronal death XREF_BIBR.	21	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	level of cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	23	25	28	29
Bax protein , as a crucial component of mitochondrial membrane ion channels , induces the transfer of cytochrome c across mitochondrial membranes and the formation of apoptotic bodies ; activates caspase-9 andcaspase-3 , which consequently leads to apoptosis .	Bax protein, as a crucial component of mitochondrial membrane ion channels, induces the transfer of cytochrome c across mitochondrial membranes and the formation of apoptotic bodies; activates caspase-9 andcaspase-3, which consequently leads to apoptosis.	17	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	17	19	30	31
It is likely that HuP10 enhances caspase-3 activity by both the cytochrome c mediated activation of caspase-9 and by the auto-cleavage of pro domain of caspase-3 mediated by the XIAP and SMAC interaction .	It is likely that HuP10 enhances caspase-3 activity by both the cytochrome c mediated activation of caspase-9 and by the auto-cleavage of pro domain of caspase-3 mediated by the XIAP and SMAC interaction.	11	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	11	13	16	17
Once in the cytoplasm , cytochrome C triggers the activation of caspase-9 that activates the intrinsic pathway of apoptosis [ XREF_BIBR ] .	Once in the cytoplasm, cytochrome C triggers the activation of caspase-9 that activates the intrinsic pathway of apoptosis [XREF_BIBR].	5	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	5	7	11	12
[ XREF_BIBR XREF_BIBR ] The apoptosome , a complex of cytochrome C and apoptosis protease activating factor-1 activates caspase 9 by cleavage of its zymogen ( pro caspase 9 ) .	[XREF_BIBR XREF_BIBR] The apoptosome, a complex of cytochrome C and apoptosis protease activating factor-1 activates caspase 9 by cleavage of its zymogen (pro caspase 9).	10	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase 9	caspase 9	caspase 9	10	12	18	20
Cytochrome c triggers the formation of apoptosome and activation of initiator caspase-9 .	Cytochrome c triggers the formation of apoptosome and activation of initiator caspase-9.	0	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	11	12
The cytochrome C , which was released from mitochondria to cytoplasm activated Caspase-9 ; Caspases-9 further activated Caspase-3 and others [ XREF_BIBR , XREF_BIBR ] .	The cytochrome C, which was released from mitochondria to cytoplasm activated Caspase-9; Caspases-9 further activated Caspase-3 and others [XREF_BIBR, XREF_BIBR].	1	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C, which was released from mitochondria to cytoplasm	cytochrome c	Caspase-9	Caspase-9	caspase-9	1	3	12	13
The fact that JWH-015 induced cytochrome c release into cytosol and activated caspase 9 in prostate PC-3 cells confirms the involvement of apoptosis and points to an activation of the intrinsic apoptotic pathway .	The fact that JWH-015 induced cytochrome c release into cytosol and activated caspase 9 in prostate PC-3 cells confirms the involvement of apoptosis and points to an activation of the intrinsic apoptotic pathway.	3	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	JWH-015 induced cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	5	7	12	14
Cytochrome c triggers the proteolytic activity of caspase-3 and caspase-9 in the cytosol , then the activation of caspases degrade ( poly [ ADP-ribose ] polymerase PARP ) and caspase-activated-DNase , which initiates DNA degradation XREF_BIBR .	Cytochrome c triggers the proteolytic activity of caspase-3 and caspase-9 in the cytosol, then the activation of caspases degrade (poly [ADP-ribose] polymerase PARP) and caspase-activated-DNase, which initiates DNA degradation XREF_BIBR.	0	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	9	10
Cytochrome c activates caspase-9 , which activates downstream effector caspases resulting in apoptosis ( Luo et al , 1998 ) .	Cytochrome c activates caspase-9, which activates downstream effector caspases resulting in apoptosis (Luo et al, 1998).	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	3	4
The release of cytochrome c is shown to trigger the activation of caspase-9 to form an apoptosome , and this culminates in the initiation of the apoptosis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The release of cytochrome c is shown to trigger the activation of caspase-9 to form an apoptosome, and this culminates in the initiation of the apoptosis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	13	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	12	13
These studies demonstrate that XIAP , cIAP1 and cIAP2 can prevent the proteolytic processing of pro caspases -3 , -6 and -7 by blocking the cytochrome c induced activation of pro-caspase-9 .	These studies demonstrate that XIAP, cIAP1 and cIAP2 can prevent the proteolytic processing of pro caspases -3, -6 and -7 by blocking the cytochrome c induced activation of pro-caspase-9.	25	31	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	pro-caspase-9	pro-caspase-9	pro-caspase-9	25	27	30	31
To further explore the mechanism that mda-7 and IL-24 utilized in tumor cell apoptosis , we examined molecules and pathways involved in apoptotic regulation and found that Ad-IL24 induced the down-regulation of anti-apoptotic gene Bcl-2 and the release of cytochrome c , which subsequently activated caspase-9 , caspase-3 and PARP to induce apoptosis .	To further explore the mechanism that mda-7 and IL-24 utilized in tumor cell apoptosis, we examined molecules and pathways involved in apoptotic regulation and found that Ad-IL24 induced the down-regulation of anti-apoptotic gene Bcl-2 and the release of cytochrome c, which subsequently activated caspase-9, caspase-3 and PARP to induce apoptosis.	39	49	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	39	41	45	46
In line with these findings , a recent study provided evidence that salinomycin at the micromolar range ( 1-10 microm ) cause in vitro a cytotoxic effect on murine dorsal root ganglia neurons by means of calpain and cytochrome c mediated caspase 9 and subsequent caspase 3 activation XREF_BIBR .	In line with these findings, a recent study provided evidence that salinomycin at the micromolar range (1-10 microm) cause in vitro a cytotoxic effect on murine dorsal root ganglia neurons by means of calpain and cytochrome c mediated caspase 9 and subsequent caspase 3 activation XREF_BIBR.	36	45	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	38	40	41	43
As shown by the results of the western blotting ( XREF_FIG B and C ) , caspase independent and caspase dependent apoptosis related proteins were released , including HtrA 2 , AIF , Endo G , and cytochrome c ; cytochrome c activated caspase-9 and caspase-3 , and cut downstream protein PARP , ultimately leading to cell apoptosis .	As shown by the results of the western blotting (XREF_FIG B and C), caspase independent and caspase dependent apoptosis related proteins were released, including HtrA 2, AIF, Endo G, and cytochrome c; cytochrome c activated caspase-9 and caspase-3, and cut downstream protein PARP, ultimately leading to cell apoptosis.	40	45	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	40	42	43	44
Cytosolic cytochrome c activates caspase-9 cleavages , triggering the activation of caspase 3 and apoptosis [ XREF_BIBR ] .	Cytosolic cytochrome c activates caspase-9 cleavages, triggering the activation of caspase 3 and apoptosis [XREF_BIBR].	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	4	5
XREF_BIBR In this assay , addition of dATP and cytochrome c into cell lysates activates caspase-9 , and recombinant XIAP BIR3 protein inhibits the activity of caspase-9 in a dose dependent manner .	XREF_BIBR In this assay, addition of dATP and cytochrome c into cell lysates activates caspase-9, and recombinant XIAP BIR3 protein inhibits the activity of caspase-9 in a dose dependent manner.	7	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	9	11	15	16
Redistribution of cytochrome-c to the cytoplasm is an important step in apoptosome formation and greatly enhances the enzymatic activity of caspase 9 [ XREF_BIBR , XREF_BIBR ] .	Redistribution of cytochrome-c to the cytoplasm is an important step in apoptosome formation and greatly enhances the enzymatic activity of caspase 9 [XREF_BIBR, XREF_BIBR].	0	23	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome-c	cytochrome-c	cytochrome-c	caspase 9	caspase 9	caspase 9	2	3	20	22
Cytochrome-c released from mitochondria combines with pro-caspase-9 in the cytosol to produce active caspase-9 , which cleaves procaspase-3 to activate caspase-3 and initiates apoptosis [ XREF_BIBR , XREF_BIBR ] .	Cytochrome-c released from mitochondria combines with pro-caspase-9 in the cytosol to produce active caspase-9, which cleaves procaspase-3 to activate caspase-3 and initiates apoptosis [XREF_BIBR, XREF_BIBR].	0	22	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome-c	Cytochrome-c	Cytochrome-c	caspase-9	caspase-9	caspase-9	0	1	13	14
The intrinsic pathway involves mitochondrial changes and triggers the release of cytochrome C , which in turn activates caspase-9 and then caspase-3 .	The intrinsic pathway involves mitochondrial changes and triggers the release of cytochrome C, which in turn activates caspase-9 and then caspase-3.	11	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	11	13	18	19
Third , an inhibitor of 12-LOX has been found effective against metastatic prostate tumor growth by inducing the release of cytochrome C from mitochondia which activates caspase 9 , 7 , 3 and eventually leads to apoptosis .	Third, an inhibitor of 12-LOX has been found effective against metastatic prostate tumor growth by inducing the release of cytochrome C from mitochondia which activates caspase 9, 7, 3 and eventually leads to apoptosis.	20	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase 9	caspase 9	caspase 9	20	22	26	28
In our study , t-BID was translocated in the presence of xanthurenic acid from the cytoplasm to mitochondria indicating that caspase-8 activation is an upstream event leading to the observed cytochrome C release , which in turn can activate caspase-9 by apoptosome formation [ XREF_BIBR ] .	In our study, t-BID was translocated in the presence of xanthurenic acid from the cytoplasm to mitochondria indicating that caspase-8 activation is an upstream event leading to the observed cytochrome C release, which in turn can activate caspase-9 by apoptosome formation [XREF_BIBR].	29	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	30	32	39	40
These proteins cause mitochondrial disruption and the release of pro apoptotic mitochondrial factors such as cytochrome-c , which interacts with Apaf-1 and activates caspase-9 , which in turn proteolytically activates caspase-3 down-stream [ XREF_BIBR , XREF_BIBR ] .	These proteins cause mitochondrial disruption and the release of pro apoptotic mitochondrial factors such as cytochrome-c, which interacts with Apaf-1 and activates caspase-9, which in turn proteolytically activates caspase-3 down-stream [XREF_BIBR, XREF_BIBR].	12	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome-c	cytochrome-c, which interacts with Apaf-1	cytochrome-c	caspase-9	caspase-9	caspase-9	15	16	23	24
Cytosolic cytochrome c complexes with apoptotic protease activating factor 1 ( APAF1 ) , uveal autoantigen with coiled-coil domains and ankyrin repeats ( UACA ) and pro-caspase-9 to form the apoptosome .	Cytosolic cytochrome c complexes with apoptotic protease activating factor 1 (APAF1), uveal autoantigen with coiled-coil domains and ankyrin repeats (UACA) and pro-caspase-9 to form the apoptosome.	1	28	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	pro-caspase-9	pro-caspase-9	pro-caspase-9	1	3	26	27
In particular , the release of cytochrome c and other apoptogenic factors from these organelles trigger sequential maturation of caspase-9 and caspase-3 , as well as caspase independent cell death events .	In particular, the release of cytochrome c and other apoptogenic factors from these organelles trigger sequential maturation of caspase-9 and caspase-3, as well as caspase independent cell death events.	6	21	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	19	20
Changes in DeltaPsim may initiate cytochrome c release from mitochondria , which may additionally activate caspase-9 and caspase-3 .	Changes in DeltaPsim may initiate cytochrome c release from mitochondria, which may additionally activate caspase-9 and caspase-3.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c release from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	15	16
Release of cytochrome c from mitochondria triggered the activation of caspase-9 and the subsequent activation of the executioner caspase , caspase-3 .	Release of cytochrome c from mitochondria triggered the activation of caspase-9 and the subsequent activation of the executioner caspase, caspase-3.	0	11	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	Release of cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	10	11
Caspase-9 is activated very early in the apoptotic cascade by cytochrome C , which is released from the mitochondria in response to apoptotic stimuli [ XREF_BIBR ] .	Caspase-9 is activated very early in the apoptotic cascade by cytochrome C, which is released from the mitochondria in response to apoptotic stimuli [XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	Caspase-9	Caspase-9	Caspase-9	10	12	0	1
Under physiological conditions , caspase 9 is activated by the release of cytochrome C from damaged mitochondria .	Under physiological conditions, caspase 9 is activated by the release of cytochrome C from damaged mitochondria.	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase 9	caspase 9	caspase 9	12	14	4	6
Cytochrome c in turn promotes the assembly of the apoptosome and caspase 9 activation .	Cytochrome c in turn promotes the assembly of the apoptosome and caspase 9 activation.	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	11	13
Western blot analysis of apoptosis related proteins revealed that 1 induces HepG2 cell apoptosis through mitochondrial cytochrome c dependent activation of the caspase-9 and caspase-3 cascade pathway ( intrinsic pathway ) .	Western blot analysis of apoptosis related proteins revealed that 1 induces HepG2 cell apoptosis through mitochondrial cytochrome c dependent activation of the caspase-9 and caspase-3 cascade pathway (intrinsic pathway).	16	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	16	18	22	23
Following release from the mitochondria , cytochrome C is known to complex with Apaf-1 to initiate cleavage of pro-caspase-9 thus activating caspase dependent apoptosis through executioner caspase-3 .	Following release from the mitochondria, cytochrome C is known to complex with Apaf-1 to initiate cleavage of pro-caspase-9 thus activating caspase dependent apoptosis through executioner caspase-3.	6	20	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	pro-caspase-9	pro-caspase-9	pro-caspase-9	6	8	18	19
Apoptotic stimuli induce the release of cytochrome c from the mitochondria to the cytosol , and this released cytochrome c promotes the formation of the apoptosome , which contains cytochrome c , Apaf-1 and caspase-9 , resulting in the activation of caspase-9 and the promotion of apoptotic cell death .	Apoptotic stimuli induce the release of cytochrome c from the mitochondria to the cytosol, and this released cytochrome c promotes the formation of the apoptosome, which contains cytochrome c, Apaf-1 and caspase-9, resulting in the activation of caspase-9 and the promotion of apoptotic cell death.	29	42	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	29	31	41	42
HSP90 depletes Apaf-1 and inhibits cytochrome c mediated activation of pro apoptotic caspase-9 XREF_BIBR ) .	HSP90 depletes Apaf-1 and inhibits cytochrome c mediated activation of pro apoptotic caspase-9 XREF_BIBR).	5	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	12	13
The assembly of cytochrome c and apoptotic protease activating factor-1 ( Apaf-1 ) activates caspase-9 which in turn activates the effectors caspase-3 , -6 , and -7 , leading to apoptosis [ XREF_BIBR ] .	The assembly of cytochrome c and apoptotic protease activating factor-1 (Apaf-1) activates caspase-9 which in turn activates the effectors caspase-3, -6, and -7, leading to apoptosis [XREF_BIBR].	3	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	14	15
The release of cytochrome c and other pro apoptotic factors , such as apaf-1 from mitochondria , activates caspase-9 [ XREF_BIBR , XREF_BIBR ] .	The release of cytochrome c and other pro apoptotic factors, such as apaf-1 from mitochondria, activates caspase-9 [XREF_BIBR, XREF_BIBR].	3	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	18	19
As our study showed , HLE at lower concentrations ( 0.1-0.5 mg/mL ) inhibited cell migration and invasion via a sustained inactivation of the PI3K and Akt signal in LNCaP cells ( XREF_FIG , XREF_FIG and XREF_FIG ) , and , alternately , a higher dosage ( 2.5 mg/mL ) induced apoptosis via both intrinsic ( Bax and cytochrome c mediated caspase 9 ) and extrinsic ( Fas mediated caspase 8/t-Bid ) apoptotic pathways [ XREF_BIBR ] .	As our study showed, HLE at lower concentrations (0.1-0.5 mg/mL) inhibited cell migration and invasion via a sustained inactivation of the PI3K and Akt signal in LNCaP cells (XREF_FIG, XREF_FIG and XREF_FIG), and, alternately, a higher dosage (2.5 mg/mL) induced apoptosis via both intrinsic (Bax and cytochrome c mediated caspase 9) and extrinsic (Fas mediated caspase 8/t-Bid) apoptotic pathways [XREF_BIBR].	56	63	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	58	60	61	63
In a cell-free functional assay , addition of cytochrome c and dATP into the MDA-MB-231 cell lysates robustly activates caspase-9 , as measured with Z-LEHD-AFC , a substrate specific to caspase-9 .	In a cell-free functional assay, addition of cytochrome c and dATP into the MDA-MB-231 cell lysates robustly activates caspase-9, as measured with Z-LEHD-AFC, a substrate specific to caspase-9.	8	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	19	20
Furthermore , GC treatment downregulated Bcl-2 expression with an increase in expression level of Bax resulting in collapse of mitochondrial integrity with release of cytochrome c. Released cytochrome c caused activation of pro-caspase-9 , -3 , and cleavage of PARP resulting in activation of intrinsic apoptotic pathways in leukemic cells .	Furthermore, GC treatment downregulated Bcl-2 expression with an increase in expression level of Bax resulting in collapse of mitochondrial integrity with release of cytochrome c. Released cytochrome c caused activation of pro-caspase-9, -3, and cleavage of PARP resulting in activation of intrinsic apoptotic pathways in leukemic cells.	27	33	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	pro-caspase-9	pro-caspase-9	pro-caspase-9	27	29	32	33
Thus , release of cytochrome c induced activation of caspase-9 and caspase-3 which subsequently cleaved 116 kDa PARP protein into an 85 kDa fragment .	Thus, release of cytochrome c induced activation of caspase-9 and caspase-3 which subsequently cleaved 116 kDa PARP protein into an 85 kDa fragment.	4	11	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	9	10
Cytochrome c then activates caspase-9 family members and the caspase cascade through the apoptosome formation XREF_BIBR .	Cytochrome c then activates caspase-9 family members and the caspase cascade through the apoptosome formation XREF_BIBR.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	4	5
Accordingly , the apoptotic cascade downstream of cytochrome C including activated caspase 3 , activated caspase 9 and cleaved PARP-1 were also increased .	Accordingly, the apoptotic cascade downstream of cytochrome C including activated caspase 3, activated caspase 9 and cleaved PARP-1 were also increased.	7	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase 9	caspase 9	caspase 9	7	9	15	17
Cytochrome c , with the help of apoptotic protease activating factor-1 , activates caspase-9 and in turn activates caspase-3 [ XREF_BIBR ] , which is also transmitted in type I cells [ XREF_BIBR ] .	Cytochrome c, with the help of apoptotic protease activating factor-1, activates caspase-9 and in turn activates caspase-3 [XREF_BIBR], which is also transmitted in type I cells [XREF_BIBR].	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	13	14
Caspse-8 is activated by a combined cell death receptor , such as Fas , with a cell death receptor ligand in the external pathway , whereas caspase-9 is activated by the release of cytochrome c from the mitochondrial membrane , which activates the internal pathway [ XREF_BIBR - XREF_BIBR ] .	Caspse-8 is activated by a combined cell death receptor, such as Fas, with a cell death receptor ligand in the external pathway, whereas caspase-9 is activated by the release of cytochrome c from the mitochondrial membrane, which activates the internal pathway [XREF_BIBR - XREF_BIBR].	26	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	33	35	26	27
Cytochrome c compounds in cytoplasm can activate caspase-9 followed by activation of Caspase-3 promoting the apoptosis process [ XREF_BIBR ] .	Cytochrome c compounds in cytoplasm can activate caspase-9 followed by activation of Caspase-3 promoting the apoptosis process [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	7	8
In summary ( XREF_FIG ) , corilagin upregulates the expression of p53 leading to the release of cytochrome c from the mitochondria to the cytoplasm and then cytochrome c activates caspase-9 , caspase-3 and cleavage of PARP consequently resulting in the apoptosis of HCC cells .	In summary (XREF_FIG), corilagin upregulates the expression of p53 leading to the release of cytochrome c from the mitochondria to the cytoplasm and then cytochrome c activates caspase-9, caspase-3 and cleavage of PARP consequently resulting in the apoptosis of HCC cells.	27	36	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	27	29	30	31
In the cytosol , cytochrome c activated caspase-9 and then caspase-9 directly cleaved and activated caspase-3 .	In the cytosol, cytochrome c activated caspase-9 and then caspase-9 directly cleaved and activated caspase-3.	4	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	7	8
When released from the mitochondria , cytochrome c activates caspase-9 , which then cleaves caspase-3 and induces apoptosis .	When released from the mitochondria, cytochrome c activates caspase-9, which then cleaves caspase-3 and induces apoptosis.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	9	10
Thus , in certain settings the pools of cytochrome c and Smac in the peripheral IMS might be sufficient to activate Caspase-9 , and in such cases apoptosis might not depend on Opa1 mediated crista junction opening .	Thus, in certain settings the pools of cytochrome c and Smac in the peripheral IMS might be sufficient to activate Caspase-9, and in such cases apoptosis might not depend on Opa1 mediated crista junction opening.	8	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Caspase-9	Caspase-9	Caspase-9	8	10	21	22
Moreover , Bcl-2 family members regulate the mitochondrial cytochrome c release that initiates caspase 9 activation .	Moreover, Bcl-2 family members regulate the mitochondrial cytochrome c release that initiates caspase 9 activation.	8	15	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	8	10	13	15
In the cytosol , cytochrome c causes sequential activation of caspase-9 , caspase-3 , PARP cleavage and apoptosis .	In the cytosol, cytochrome c causes sequential activation of caspase-9, caspase-3, PARP cleavage and apoptosis.	4	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	10	11
Caspase-9 is activated by cytochrome c released from mitochondria .	Caspase-9 is activated by cytochrome c released from mitochondria.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Caspase-9	Caspase-9	Caspase-9	4	6	0	1
The latter allows the apoptosis cascade to proceed through different and complementary mechanisms : cytochrome c promotes caspase-9 activation through the assembly of the apoptosome ; and Smac/Diablo antagonizes inhibitors of caspases , such as XIAP .	The latter allows the apoptosis cascade to proceed through different and complementary mechanisms : cytochrome c promotes caspase-9 activation through the assembly of the apoptosome; and Smac/Diablo antagonizes inhibitors of caspases, such as XIAP.	14	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	14	16	17	18
Manumycin induced cytochrome C release from the mitochondria into the cytosol after 6 h treatment , and activated caspase-9 , caspase-8 , and caspase-3 after a 16h treatment .	Manumycin induced cytochrome C release from the mitochondria into the cytosol after 6 h treatment, and activated caspase-9, caspase-8, and caspase-3 after a 16h treatment.	0	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	Manumycin induced cytochrome C release from the mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	18	19
The cytochrome c complex activates caspase 9 followed by the cleavage and subsequent activation of caspase 3 .	The cytochrome c complex activates caspase 9 followed by the cleavage and subsequent activation of caspase 3.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	1	3	5	7
Immunodepletion of Hsp90 depletes Apaf-1 and thereby inhibits cytochrome c mediated activation of caspase-9 .	Immunodepletion of Hsp90 depletes Apaf-1 and thereby inhibits cytochrome c mediated activation of caspase-9.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	13	14
The release of cytochrome c induces the cleavage of caspase-9 , which contributes to the activation of effector caspases such as caspase-3 .	The release of cytochrome c induces the cleavage of caspase-9, which contributes to the activation of effector caspases such as caspase-3.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	9	10
The Apaf-1 protein is essential for cytochrome c mediated caspase-9 activation in the intrinsic mammalian pathway of apoptosis .	The Apaf-1 protein is essential for cytochrome c mediated caspase-9 activation in the intrinsic mammalian pathway of apoptosis.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	9	10
This release of cytochrome c into the cytosol triggers caspase-9 activation XREF_BIBR .	This release of cytochrome c into the cytosol triggers caspase-9 activation XREF_BIBR.	3	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	9	10
The increased level of cytochrome c in the cytosol results in the initiation of caspase-9 and caspase-3 and the subsequent activation of PARP and induces the morphological changes of the dying cell [ XREF_BIBR - XREF_BIBR ] .	The increased level of cytochrome c in the cytosol results in the initiation of caspase-9 and caspase-3 and the subsequent activation of PARP and induces the morphological changes of the dying cell [XREF_BIBR - XREF_BIBR].	2	16	initiation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	cytochrome c	level of cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	14	15
Whereas cytochrome c results in activation of initiator caspase 9 XREF_BIBR , apoptosis by AIF was reported as caspase independent XREF_BIBR .	Whereas cytochrome c results in activation of initiator caspase 9 XREF_BIBR, apoptosis by AIF was reported as caspase independent XREF_BIBR.	1	10	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	1	3	8	10
Release of cytochrome c from mitochondria to cytosol triggers the formation of the apoptosome , activation of caspase 9 and subsequent activation of the caspase cascade leading to activation of the executioner caspase-3 and apoptotic cell death XREF_BIBR .	Release of cytochrome c from mitochondria to cytosol triggers the formation of the apoptosome, activation of caspase 9 and subsequent activation of the caspase cascade leading to activation of the executioner caspase-3 and apoptotic cell death XREF_BIBR.	0	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	Release of cytochrome c from mitochondria to cytosol	cytochrome c	caspase 9	caspase 9	caspase 9	2	4	17	19
The intrinsic apoptosis pathway is induced by cellular events , such as DNA damage , and is mediated by mitochondrial depolarization ; this induces the release in the cytosol of cytochrome c , which promotes caspase-9 cleavage and the subsequent activation of effector caspases , and of the pro apoptotic protein Second mitochondria derived activator of caspases and direct IAP binding protein with low pI ( Smac/DIABLO ) .	The intrinsic apoptosis pathway is induced by cellular events, such as DNA damage, and is mediated by mitochondrial depolarization; this induces the release in the cytosol of cytochrome c, which promotes caspase-9 cleavage and the subsequent activation of effector caspases, and of the pro apoptotic protein Second mitochondria derived activator of caspases and direct IAP binding protein with low pI (Smac/DIABLO).	30	36	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	30	32	35	36
Neuroglobin prevents cytochrome c induced caspase 9 activation , significantly blocking cell death triggered by a BH3 mimetic HA14-1 .	Neuroglobin prevents cytochrome c induced caspase 9 activation, significantly blocking cell death triggered by a BH3 mimetic HA14-1.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	2	4	5	7
When compared with the WKY group , the protein levels of t-Bid , Bak , Bad , Bax , cytochrome c , activated caspase 9 and activated caspase 3 were significantly increased in the SHR-Sham group , and even further increases were observed in the SHR-OVX group when compared with the SHR-Sham group ( XREF_FIG ) .	When compared with the WKY group, the protein levels of t-Bid, Bak, Bad, Bax, cytochrome c, activated caspase 9 and activated caspase 3 were significantly increased in the SHR-Sham group, and even further increases were observed in the SHR-OVX group when compared with the SHR-Sham group (XREF_FIG).	9	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	levels of t-Bid, Bak, Bad, Bax, cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	19	21	23	25
Cytochrome c , together with apoptosis activating factor 1 ( Apaf-1 ) , promotes activation of caspase-9 , which then activates downstream caspases , such as caspase-3 and -7 .	Cytochrome c, together with apoptosis activating factor 1 (Apaf-1), promotes activation of caspase-9, which then activates downstream caspases, such as caspase-3 and -7.	0	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	16	17
MPT triggers apoptosis via the cytochrome c mediated activation of caspase 9 through the formation of the apoptosome .	MPT triggers apoptosis via the cytochrome c mediated activation of caspase 9 through the formation of the apoptosome.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	5	7	10	12
In mitochondria dependent apoptotic signaling pathway , cytochrome c , which is released by the mitochondria in response to pro apoptotic stimuli , activates caspase-9 followed by activation of caspase-3 , resulting in apoptosis .	In mitochondria dependent apoptotic signaling pathway, cytochrome c, which is released by the mitochondria in response to pro apoptotic stimuli, activates caspase-9 followed by activation of caspase-3, resulting in apoptosis.	7	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	7	9	24	25
Subsequently , mitochondrial release of cytochrome c activates caspase-9 and casaspe-3 , eventually resulting in cell death [ XREF_BIBR ] .	Subsequently, mitochondrial release of cytochrome c activates caspase-9 and casaspe-3, eventually resulting in cell death [XREF_BIBR].	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	8	9
We found that the human myeloid leukemic K562 cells were more resistant to cytochrome c induced activation of caspase-9 and -3 in a cell-free system compared with the human T-lymphoblastic subclone CEM and VLB ( 100 ) cells .	We found that the human myeloid leukemic K562 cells were more resistant to cytochrome c induced activation of caspase-9 and -3 in a cell-free system compared with the human T-lymphoblastic subclone CEM and VLB (100) cells.	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	13	15	18	19
After that we decomposed the model into modules corresponding to three biological steps : activation of caspase-8 , cytochrome C induced activation of caspase-9 and PARP cleavage down-regulated by these caspases .	After that we decomposed the model into modules corresponding to three biological steps : activation of caspase-8, cytochrome C induced activation of caspase-9 and PARP cleavage down-regulated by these caspases.	18	24	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	18	20	23	24
While cytochrome c release did result in activation of caspase-9 and subsequent activation of caspase-3 , calpain was shown to cleave both caspases-3 and 9 rendering this pathway inactive [ XREF_BIBR ] .	While cytochrome c release did result in activation of caspase-9 and subsequent activation of caspase-3, calpain was shown to cleave both caspases-3 and 9 rendering this pathway inactive [XREF_BIBR].	1	10	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	9	10
Another pathway is the mitochondrial pathway , in which oxygen free radicals , calcium overload and other apoptosis stimulating factors increase mitochondrial permeability to reduce mitochondrial transmembrane potential , and release cytochrome c. Cytochrome c activates caspase-9 and caspase-3 to induce cell apoptosis .	Another pathway is the mitochondrial pathway, in which oxygen free radicals, calcium overload and other apoptosis stimulating factors increase mitochondrial permeability to reduce mitochondrial transmembrane potential, and release cytochrome c. Cytochrome c activates caspase-9 and caspase-3 to induce cell apoptosis.	33	38	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	33	35	36	37
Moreover , concentrations of apoptosome inhibitors such as XIAP could also vary , in effect raising or lowering the threshold amounts of cytochrome c and Smac/DIABLO needed to activate caspase-9 .	Moreover, concentrations of apoptosome inhibitors such as XIAP could also vary, in effect raising or lowering the threshold amounts of cytochrome c and Smac/DIABLO needed to activate caspase-9.	20	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	amounts of cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	22	24	29	30
The cytochrome c ( cyt c ) released from mitochondria activates caspase-9 and -3 , and this mechanism is regulated by Bcl-2 .	The cytochrome c (cyt c) released from mitochondria activates caspase-9 and -3, and this mechanism is regulated by Bcl-2.	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	11	12
Cytochrome c facilitates the formation of an apoptosome complex with apoptotic protease activating factor-1 , dATP , and caspase-9 and leads to caspase-3 activation .	Cytochrome c facilitates the formation of an apoptosome complex with apoptotic protease activating factor-1, dATP, and caspase-9 and leads to caspase-3 activation.	0	19	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	18	19
Results showed that PCC enhanced the release of mitochondrial cytochrome c which activates caspase 9 by 4.8-5.0 folds in both liver cancer cells .	Results showed that PCC enhanced the release of mitochondrial cytochrome c which activates caspase 9 by 4.8-5.0 folds in both liver cancer cells.	9	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	9	11	13	15
As cytochrome c leads to caspase-9 activation via apoptosome formation , we determined whether suppression of cytochrome c release was associated with a concomitant decrease in As3 +-induced activation of caspase-9 .	As cytochrome c leads to caspase-9 activation via apoptosome formation, we determined whether suppression of cytochrome c release was associated with a concomitant decrease in As3 +-induced activation of caspase-9.	1	6	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	5	6
It is regulated by cytochrome c release from mitochondria , promoting the activation of caspase-9 through Apaf1 and then caspase-3 activation .	It is regulated by cytochrome c release from mitochondria, promoting the activation of caspase-9 through Apaf1 and then caspase-3 activation.	4	15	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	14	15
Caspase-9 can be activated by cytochrome C from the chondriosome , which can activate caspase-3 and trigger apoptosis .	Caspase-9 can be activated by cytochrome C from the chondriosome, which can activate caspase-3 and trigger apoptosis.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	Caspase-9	Caspase-9	Caspase-9	5	7	0	1
Upon receiving apoptotic stimuli , cytochrome c is release from the mitochondrial inner membrane and leads to the formation of the apoptosome , which in turn cleaves and activates caspase-9 .	Upon receiving apoptotic stimuli, cytochrome c is release from the mitochondrial inner membrane and leads to the formation of the apoptosome, which in turn cleaves and activates caspase-9.	5	30	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	29	30
The released cytochrome c can then activate caspase-9 and trigger intrinsic apoptosis .	The released cytochrome c can then activate caspase-9 and trigger intrinsic apoptosis.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	7	8
The released cytochrome c then activates the initiator caspase-9 , thereby initiating the sequential activation of downstream caspases leading to apoptosis XREF_BIBR , XREF_BIBR .	The released cytochrome c then activates the initiator caspase-9, thereby initiating the sequential activation of downstream caspases leading to apoptosis XREF_BIBR, XREF_BIBR.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	8	9
Truncated Bid acts on the mitochondria to cause the release of cytochrome c , which further activates caspase-9 .	Truncated Bid acts on the mitochondria to cause the release of cytochrome c, which further activates caspase-9.	9	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	11	13	17	18
In the intrinsic pathway , Cytochrome C released by the mitochondria due to DNA damage or ROS activates Caspase 9 .	In the intrinsic pathway, Cytochrome C released by the mitochondria due to DNA damage or ROS activates Caspase 9.	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	Caspase 9	Caspase 9	Caspase 9	5	7	18	20
XREF_BIBR , XREF_BIBR Cytochrome C initiates formation of the apoptosome and activation of initiator caspase-9 which in turn activates caspase-3 , eventually leading to the execution of apoptotic cell death .	XREF_BIBR, XREF_BIBR Cytochrome C initiates formation of the apoptosome and activation of initiator caspase-9 which in turn activates caspase-3, eventually leading to the execution of apoptotic cell death.	3	15	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	caspase-9	caspase-9	caspase-9	3	5	14	15
Cytochrome c release into cytosol activates caspase-9 , then caspase-3 completes the apoptotic program [ XREF_BIBR , XREF_BIBR ] .	Cytochrome c release into cytosol activates caspase-9, then caspase-3 completes the apoptotic program [XREF_BIBR, XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	6	7
Caspase 3 can be activated by several routes , these include ligation of cell surface receptors , such as Fas ( Enari et al , 1996 ) , which are associated with caspase 8 ; or by factors released from mitochondria , that is , cytochrome c ( Liu et al , 1996 ) , in response to cellular stress , which in turn activate caspase 9 ( Liu et al , 1996 ) .	Caspase 3 can be activated by several routes, these include ligation of cell surface receptors, such as Fas (Enari et al, 1996), which are associated with caspase 8; or by factors released from mitochondria, that is, cytochrome c (Liu et al, 1996), in response to cellular stress, which in turn activate caspase 9 (Liu et al, 1996).	45	68	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	45	47	65	67
Cytochrome c release after mitochondrial damage induces caspase 9 release , which mediates apoptotic signals .	Cytochrome c release after mitochondrial damage induces caspase 9 release, which mediates apoptotic signals.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	7	9
Cytochrome c activates caspase 9 , leading to activation of several downstream caspases and induces apoptosis in caspase dependent manner .	Cytochrome c activates caspase 9, leading to activation of several downstream caspases and induces apoptosis in caspase dependent manner.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	3	5
Cytochrome c , deoxyadenosine triphosphate , and apoptotic protease activating factor 1 , which are key components of the apoptosome , activate caspase-9 .	Cytochrome c, deoxyadenosine triphosphate, and apoptotic protease activating factor 1, which are key components of the apoptosome, activate caspase-9.	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	22	23
The release of cytochrome c from damaged mitochondria may activate caspase 9 and downstream caspases .	The release of cytochrome c from damaged mitochondria may activate caspase 9 and downstream caspases.	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from damaged mitochondria	cytochrome c	caspase 9	caspase 9	caspase 9	3	5	10	12
Casein kinase 2 ( CK2 ) enable caspase-9 to be phosphorylated at Ser348 site in murine cells ( equivalent to human Ser310 ) , blocking its cleavage at Asp353 by caspase-8 , which is irrelevant to cytochrome c mediated activation of caspase-9 , incurred by tumor necrosis factor-alpha [ XREF_BIBR ] .	Casein kinase 2 (CK2) enable caspase-9 to be phosphorylated at Ser348 site in murine cells (equivalent to human Ser310), blocking its cleavage at Asp353 by caspase-8, which is irrelevant to cytochrome c mediated activation of caspase-9, incurred by tumor necrosis factor-alpha [XREF_BIBR].	36	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	36	38	41	42
Initiator caspase-8 is known to be activated through the death receptors , whereas caspase-9 is activated by cytochrome c leakage from the mitochondria .	Initiator caspase-8 is known to be activated through the death receptors, whereas caspase-9 is activated by cytochrome c leakage from the mitochondria.	13	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	17	19	13	14
Once inactivation of mitochondria occurs , cytochrome c is released into the cytoplasm and activates caspase-3 and caspase-9 , which consequently causes apoptosis .	Once inactivation of mitochondria occurs, cytochrome c is released into the cytoplasm and activates caspase-3 and caspase-9, which consequently causes apoptosis.	6	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	17	18
In neuronal N18 cells , JEV infection triggered cytochrome c release from mitochondria , which in turn activated caspase-9 and -3 .	In neuronal N18 cells, JEV infection triggered cytochrome c release from mitochondria, which in turn activated caspase-9 and -3.	8	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c release from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	18	19
Cytochrome c activates caspase-9 , which subsequently activates caspase-3 [ XREF_BIBR ] .	Cytochrome c activates caspase-9, which subsequently activates caspase-3 [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	3	4
CASP9 , an important initiator CASP of the intrinsic pathway , is activated by the release of cytochrome c from mitochondria , activates downstream the effector CASP3 and CASP7 [ XREF_BIBR - XREF_BIBR ] .	CASP9, an important initiator CASP of the intrinsic pathway, is activated by the release of cytochrome c from mitochondria, activates downstream the effector CASP3 and CASP7 [XREF_BIBR - XREF_BIBR].	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	CASP9	CASP9	CASP9	17	19	0	1
The released cytochrome c from the mitochondria cleaves and activates caspase-3 and caspase-9 to trigger a series of downstream apoptotic events XREF_BIBR , XREF_BIBR , XREF_BIBR .	The released cytochrome c from the mitochondria cleaves and activates caspase-3 and caspase-9 to trigger a series of downstream apoptotic events XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	12	13
Cytochrome c released from the mitochondria can activate the initiator caspase-9 and the effector caspase-3 , which is an important step in the apoptotic pathway .	Cytochrome c released from the mitochondria can activate the initiator caspase-9 and the effector caspase-3, which is an important step in the apoptotic pathway.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	10	11
Our findings that substantial activation of caspase-9 occur earlier than caspase-8 activation , and that caspase-8 activation was inhibited in the presence of caspase-9 inhibitor in AVO treated cells strongly suggest that the AVO induced apoptosis occurs mainly through cytochrome c dependent activation of caspase-9 and that activation of caspase-8 is a subsequent event to activation of the caspase cascade .	Our findings that substantial activation of caspase-9 occur earlier than caspase-8 activation, and that caspase-8 activation was inhibited in the presence of caspase-9 inhibitor in AVO treated cells strongly suggest that the AVO induced apoptosis occurs mainly through cytochrome c dependent activation of caspase-9 and that activation of caspase-8 is a subsequent event to activation of the caspase cascade.	39	45	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	39	41	44	45
In the cytosol , cytochrome c , together with apoptotic protease activating factor 1 ( APAF1 ) and pro-caspase-9 , forms a multi protein complex apoptosome , which cleaves zymogen pro-caspase-9 into active caspase-9 .	In the cytosol, cytochrome c, together with apoptotic protease activating factor 1 (APAF1) and pro-caspase-9, forms a multi protein complex apoptosome, which cleaves zymogen pro-caspase-9 into active caspase-9.	4	19	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	pro-caspase-9	pro-caspase-9	pro-caspase-9	4	6	18	19
The release of endogenous mitochondrial cytochrome C into the cell cytosol activates caspase 9 , which in turn cleaves caspase 3 , a key mediator of programmed cell death ( apoptosis ) into its biologically active form [ XREF_BIBR ] .	The release of endogenous mitochondrial cytochrome C into the cell cytosol activates caspase 9, which in turn cleaves caspase 3, a key mediator of programmed cell death (apoptosis) into its biologically active form [XREF_BIBR].	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase 9	caspase 9	caspase 9	5	7	12	14
In the absence of tRNA , cytochrome c induced activation of caspase-9 at a concentration as low as 2 mug/ml .	In the absence of tRNA, cytochrome c induced activation of caspase-9 at a concentration as low as 2 mug/ml.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	11	12
Cytochrome C activates caspase9 which , in turn , cleaves caspase3 .	Cytochrome C activates caspase9 which, in turn, cleaves caspase3.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	caspase9	caspase9	caspase9	0	2	3	4
In mammals , the apoptosome assembles when cytochrome c is released from mitochondria , binding Apaf1 in an ATP dependent manner and activating caspase 9 to execute apoptosis .	In mammals, the apoptosome assembles when cytochrome c is released from mitochondria, binding Apaf1 in an ATP dependent manner and activating caspase 9 to execute apoptosis.	7	25	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	7	9	23	25
Cytochrome c and dATP were added into the cell lysates , and incubated at 30 degreesC in a water bath for 60 minutes to activate caspase-9 .	Cytochrome c and dATP were added into the cell lysates, and incubated at 30 degreesC in a water bath for 60 minutes to activate caspase-9.	0	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	25	26
Cytochrome c release activates caspase-9 which in turn initiates the cleavage of caspase-3 .	Cytochrome c release activates caspase-9 which in turn initiates the cleavage of caspase-3.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	4	5
In contrast , the intrinsic pathway is triggered by the release of cytochrome c from mitochondria , thereby activating caspase-9 .	In contrast, the intrinsic pathway is triggered by the release of cytochrome c from mitochondria, thereby activating caspase-9.	7	20	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	12	14	19	20
Cytochrome C is an upstream activator of caspase-9 .	Cytochrome C is an upstream activator of caspase-9.	0	8	is an upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	caspase-9	caspase-9	caspase-9	0	2	7	8
TNFalpha induced ASK1 activation also increases mitochondrial cytochrome C levels to activate caspase 9 .	TNFalpha induced ASK1 activation also increases mitochondrial cytochrome C levels to activate caspase 9.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	TNFalpha induced ASK1 activation also increases mitochondrial cytochrome C levels	cytochrome c	caspase 9	caspase 9	caspase 9	7	9	12	14
Cytochrome c induces the cleavage of the initiator caspase 9 , which in turn cleaves effector caspase 3 .	Cytochrome c induces the cleavage of the initiator caspase 9, which in turn cleaves effector caspase 3.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	8	10
Evidence indicates that the release of cytochrome c into the cytosol induces cleavage of caspase-9 .	Evidence indicates that the release of cytochrome c into the cytosol induces cleavage of caspase-9.	6	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	14	15
Upon its release , cytochrome c , in concert with Apaf-1 and dATP , activates caspase-9 , leading to the subsequent activation of caspase-3 .	Upon its release, cytochrome c, in concert with Apaf-1 and dATP, activates caspase-9, leading to the subsequent activation of caspase-3.	4	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	15	16
It has been reported that Cytochrome-C ( Cyt-C ) , released from the mitochondria upon apoptotic stimuli , can activate caspase-9 [ XREF_BIBR ] .	It has been reported that Cytochrome-C (Cyt-C), released from the mitochondria upon apoptotic stimuli, can activate caspase-9 [XREF_BIBR].	5	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome-C	Cytochrome-C	Cytochrome-C	caspase-9	caspase-9	caspase-9	5	6	20	21
On the basis of these studies it was generally accepted that ATP and cytochrome c together activate caspase-9 .	On the basis of these studies it was generally accepted that ATP and cytochrome c together activate caspase-9.	11	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	13	15	17	18
17 In the intrinsic pathway of apoptosis conformationally activated Bax and Bak induces mitochondrial release of intermembrane space proteins such as cytochrome c that immediately initiates the activation of procaspase 9 to caspase 9 .	17 In the intrinsic pathway of apoptosis conformationally activated Bax and Bak induces mitochondrial release of intermembrane space proteins such as cytochrome c that immediately initiates the activation of procaspase 9 to caspase 9.	21	34	initiates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	21	23	32	34
Taken together , these results are consistent with a model in which Smac/DIABLO mediated inhibition of IAPs , rather than cytochrome c mediated activation of caspase-9 , is the key event responsible for mitochondrial augmentation of reovirus induced apoptosis .	Taken together, these results are consistent with a model in which Smac/DIABLO mediated inhibition of IAPs, rather than cytochrome c mediated activation of caspase-9, is the key event responsible for mitochondrial augmentation of reovirus induced apoptosis.	20	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	20	22	25	26
However , comparing cytosolic extracts from cells in which the level of GSK3beta was knocked down with cytosol from wild-type cells demonstrated that knocking down GSK3beta reduced cytochrome c induced caspase-9 and caspase-3 activation ( XREF_FIG ) and the association of XIAP with Apaf-1 , active caspase-9 , and active caspase-3 ( XREF_FIG ) .	However, comparing cytosolic extracts from cells in which the level of GSK3beta was knocked down with cytosol from wild-type cells demonstrated that knocking down GSK3beta reduced cytochrome c induced caspase-9 and caspase-3 activation (XREF_FIG) and the association of XIAP with Apaf-1, active caspase-9, and active caspase-3 (XREF_FIG).	27	33	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	27	29	30	31
Release of cytochrome C from mitochondria leads to Caspase-9 activation ( cysteine aspartate proteases ) and the downstream caspase cascade by cleaving at specific sites and hetero-dimerizing to produce the active caspases that play a central role in the execution-phase of cell apoptosis ( XREF_FIG ) .	Release of cytochrome C from mitochondria leads to Caspase-9 activation (cysteine aspartate proteases) and the downstream caspase cascade by cleaving at specific sites and hetero-dimerizing to produce the active caspases that play a central role in the execution-phase of cell apoptosis (XREF_FIG).	0	9	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	cytochrome C	Release of cytochrome C from mitochondria	cytochrome c	Caspase-9	Caspase-9	caspase-9	2	4	8	9
Cytochrome C release from mitochondrial inter-membrane spaces initiates subsequent activation of caspase-9 as the downstream effector caspase-3 is further activated [ XREF_BIBR , XREF_BIBR ] .	Cytochrome C release from mitochondrial inter-membrane spaces initiates subsequent activation of caspase-9 as the downstream effector caspase-3 is further activated [XREF_BIBR, XREF_BIBR].	0	12	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	caspase-9	caspase-9	caspase-9	0	2	11	12
Cytochrome c released from mitochondria stimulates caspase-9 and caspase-3 , which causes apoptosis of cells .	Cytochrome c released from mitochondria stimulates caspase-9 and caspase-3, which causes apoptosis of cells.	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	6	7
The increased cytosolic cytochrome c level induces caspase-9 and caspase-3 activities that trigger destruction of structural and specific proteins leading to DNA fragmentation and thereby oocyte apoptosis .	The increased cytosolic cytochrome c level induces caspase-9 and caspase-3 activities that trigger destruction of structural and specific proteins leading to DNA fragmentation and thereby oocyte apoptosis.	3	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c level	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	7	8
Cytochrome c release from the mitochondria to the cytoplasm activated the caspase-9 and caspase-3 at early postmortem aging and the activation of caspase-9 occurs before the activation of caspase-3 .	Cytochrome c release from the mitochondria to the cytoplasm activated the caspase-9 and caspase-3 at early postmortem aging and the activation of caspase-9 occurs before the activation of caspase-3.	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c release from the mitochondria to the cytoplasm	cytochrome c	caspase-9	caspase-9	caspase-9	0	2	11	12
During mitochondrial mediated apoptosis , cytochrome c is released from mitochondrial into cytosol and subsequently activates caspase-9 .	During mitochondrial mediated apoptosis, cytochrome c is released from mitochondrial into cytosol and subsequently activates caspase-9.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	16	17
In concert with these results , MUC1 attenuated ( i ) the loss of mitochondrial transmembrane potential , ( ii ) mitochondrial cytochrome c release , ( iii ) activation of caspase-9 , and ( iv ) induction of apoptosis by the antimetabolite , 1-beta-d-arabinofuranosylcytosine .	In concert with these results, MUC1 attenuated (i) the loss of mitochondrial transmembrane potential, (ii) mitochondrial cytochrome c release, (iii) activation of caspase-9, and (iv) induction of apoptosis by the antimetabolite, 1-beta-d-arabinofuranosylcytosine.	22	32	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	22	24	31	32
Release of cytochrome c from mitochondria results in activation of caspase-9 and the effector caspases XREF_BIBR .	Release of cytochrome c from mitochondria results in activation of caspase-9 and the effector caspases XREF_BIBR.	0	15	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	cytochrome c	Release of cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	10	11
The released cytochrome c stimulated cleavage of caspase 9 which was more significant after 48 h of treatment and was maximum in case of the lec-pac-MNPs ( XREF_FIG C ) .	The released cytochrome c stimulated cleavage of caspase 9 which was more significant after 48 h of treatment and was maximum in case of the lec-pac-MNPs (XREF_FIG C).	2	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	2	4	7	9
Furthermore , 1 induced G2/M cell cycle arrest and promoted apoptosis through mitochondrial cytochrome c dependent activation of the caspase-9 and caspase-3 cascade pathway in ESCC cell lines .	Furthermore, 1 induced G2/M cell cycle arrest and promoted apoptosis through mitochondrial cytochrome c dependent activation of the caspase-9 and caspase-3 cascade pathway in ESCC cell lines.	13	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	13	15	19	20
The release of cytochrome c from the mitochondria activates caspase-9 and subsequently activates caspase-3 .	The release of cytochrome c from the mitochondria activates caspase-9 and subsequently activates caspase-3.	1	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from the mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	9	10
Resultantly , cytochrome c is released from mitochondria , causing the activations of caspase-9 and effector caspases , and eventually apoptotic cell death .	Resultantly, cytochrome c is released from mitochondria, causing the activations of caspase-9 and effector caspases, and eventually apoptotic cell death.	2	16	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	13	14
This release of cytochrome c in turn activates Caspase-9 , and subsequently Caspase-3 , which are responsible for the ultimate cell death 42 ] .	This release of cytochrome c in turn activates Caspase-9, and subsequently Caspase-3, which are responsible for the ultimate cell death 42].	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Caspase-9	Caspase-9	Caspase-9	3	5	8	9
The released cytochrome c activates caspase-9 which in turn triggers the activation of caspase-3 , which induces cell death [ XREF_BIBR ] .	The released cytochrome c activates caspase-9 which in turn triggers the activation of caspase-3, which induces cell death [XREF_BIBR].	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	5	6
Once released to the cytosol , cytochrome c could activate caspase-9 to initiate cysteine proteases cascade reaction [ XREF_BIBR , XREF_BIBR ] .	Once released to the cytosol, cytochrome c could activate caspase-9 to initiate cysteine proteases cascade reaction [XREF_BIBR, XREF_BIBR].	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	10	11
The proapoptotic proteins induce mitochondria to release cytochrome c , which through a series of events activates caspase-9 .	The proapoptotic proteins induce mitochondria to release cytochrome c, which through a series of events activates caspase-9.	7	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	7	9	17	18
Release of cytochrome c would then activate caspase 9 and then caspase 3 to initiate apoptosis .	Release of cytochrome c would then activate caspase 9 and then caspase 3 to initiate apoptosis.	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	2	4	7	9
In contrast , cytochrome c failed to activate caspase-9 and -3 in ARCM ( XREF_FIG ) .	In contrast, cytochrome c failed to activate caspase-9 and -3 in ARCM (XREF_FIG).	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	8	9
Mitochondrial proteins that cause caspase dependent cell death include cytochrome c which triggers caspase-9 activation through Apaf-1 .	Mitochondrial proteins that cause caspase dependent cell death include cytochrome c which triggers caspase-9 activation through Apaf-1.	9	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	9	11	13	14
In the cytosol , cytochrome c can activate caspase-9 , and activated caspase-9 in turn cleaves and activates executioner caspase-3 .	In the cytosol, cytochrome c can activate caspase-9, and activated caspase-9 in turn cleaves and activates executioner caspase-3.	4	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	12	13
For example , XIAP , cIAP1 and cIAP2 can prevent the proteolytic processing of pro caspases -3 , -6 and -7 by blocking the cytochrome c induced activation of pro-caspase-9 .	For example, XIAP, cIAP1 and cIAP2 can prevent the proteolytic processing of pro caspases -3, -6 and -7 by blocking the cytochrome c induced activation of pro-caspase-9.	24	30	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	pro-caspase-9	pro-caspase-9	pro-caspase-9	24	26	29	30
Caspase 9 is activated by cytochrome c released from mitochondria and is thus crucial for the execution of mitochondria dependent apoptosis , whereas caspase 8 is activated largely through a mitochondria independent mechanism [ XREF_BIBR ] .	Caspase 9 is activated by cytochrome c released from mitochondria and is thus crucial for the execution of mitochondria dependent apoptosis, whereas caspase 8 is activated largely through a mitochondria independent mechanism [XREF_BIBR].	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Caspase 9	Caspase 9	Caspase 9	5	7	0	2
This report shows that the induction of apoptosis by trimidox occurs through a cytochrome c dependent pathway , which sequentially activates caspase-3 and caspase-9 .	This report shows that the induction of apoptosis by trimidox occurs through a cytochrome c dependent pathway, which sequentially activates caspase-3 and caspase-9.	13	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	13	15	23	24
Cytochrome c induced caspase-9 activation is regulated at multiple levels involving various protein factors , cations such as potassium and calcium , and perhaps most notably , nucleotides .	Cytochrome c induced caspase-9 activation is regulated at multiple levels involving various protein factors, cations such as potassium and calcium, and perhaps most notably, nucleotides.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	3	4
Cytochrome c induced caspase-9 activation is regulated at multiple levels , and tRNA was reported recently to bind to cytochrome c , blocking formation of the apoptosome and the subsequent activation of caspase-9 .	Cytochrome c induced caspase-9 activation is regulated at multiple levels, and tRNA was reported recently to bind to cytochrome c, blocking formation of the apoptosome and the subsequent activation of caspase-9.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	3	4
GLP-1 increased Bcl-2 and Bax ratio , reduced cytochrome c levels in the cytoplasm , and reduced the activity of caspase-9 and -3 in AGEs treated HUVECs .	GLP-1 increased Bcl-2 and Bax ratio, reduced cytochrome c levels in the cytoplasm, and reduced the activity of caspase-9 and -3 in AGEs treated HUVECs.	0	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cytochrome c	GLP-1 increased Bcl-2 and Bax ratio, reduced cytochrome c levels	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	20	21
The release of cytochrome C in mitochondria caused by apoptotic signals could activate caspase-9 and caspase-3 , leading to cell apoptosis .	The release of cytochrome C in mitochondria caused by apoptotic signals could activate caspase-9 and caspase-3, leading to cell apoptosis.	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	3	5	13	14
Caspase-9 is activated in the upstream of the apoptotic process by the release of cytochrome c by the mitochondria as a response to an apoptotic stimulus .	Caspase-9 is activated in the upstream of the apoptotic process by the release of cytochrome c by the mitochondria as a response to an apoptotic stimulus.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Caspase-9	Caspase-9	Caspase-9	14	16	0	1
This is characterized by leakage of cytochrome c from the mitochondria , causing the activation of caspase 9 which in turn activates caspase-3 XREF_BIBR .	This is characterized by leakage of cytochrome c from the mitochondria, causing the activation of caspase 9 which in turn activates caspase-3 XREF_BIBR.	6	18	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	6	8	16	18
Cytochrome c promotes the aggregation of caspase-9 together with Apaf-1 in the cytosol to form a multi protein complex , i.e ., the apoptosome that results in caspase-9 activation .	Cytochrome c promotes the aggregation of caspase-9 together with Apaf-1 in the cytosol to form a multi protein complex, i.e., the apoptosome that results in caspase-9 activation.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	6	7
Cytochrome c and other different factors recruit and process procaspase-9 and lead to the activation of caspase-9 , which then processes and activates the effector caspases to orchestrate the biochemical execution of apoptosis [ XREF_BIBR , XREF_BIBR ] .	Cytochrome c and other different factors recruit and process procaspase-9 and lead to the activation of caspase-9, which then processes and activates the effector caspases to orchestrate the biochemical execution of apoptosis [XREF_BIBR, XREF_BIBR].	0	22	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	16	17
Permeabilization of the mitochondrial outer membrane results in the release of the intermediate apoptosis signaling molecule cytochrome c causing activation of caspase-9 , which then cleaves and activates caspase-3 , followed by cleavage of caspase-6 and -7 resulting in downstream apoptosis and DNA fragmentation .	Permeabilization of the mitochondrial outer membrane results in the release of the intermediate apoptosis signaling molecule cytochrome c causing activation of caspase-9, which then cleaves and activates caspase-3, followed by cleavage of caspase-6 and -7 resulting in downstream apoptosis and DNA fragmentation.	16	27	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	16	18	21	22
Interestingly , when HeLa S100 extracts were pre-treated with increasing amounts of RNase A , cytochrome c induced caspase-9 activation was progressively enhanced ( XREF_FIG ) .	Interestingly, when HeLa S100 extracts were pre-treated with increasing amounts of RNase A, cytochrome c induced caspase-9 activation was progressively enhanced (XREF_FIG).	15	19	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	15	17	18	19
Overexpression of BRG1 elevated CYCS , activated CASP3 and CASP9 , and inhibited BCL2 , while these effects were abrogated when p53 was knocked down .	Overexpression of BRG1 elevated CYCS, activated CASP3 and CASP9, and inhibited BCL2, while these effects were abrogated when p53 was knocked down.	0	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CYCS	Overexpression of BRG1 elevated CYCS	cycs	CASP9	CASP9	casp9	4	5	9	10
Caspase-9 activity assays showed that activation of caspase-9 by cytochrome c and dATP was inhibited in extracts prepared from Akt-stable lines compared with those in vector-control cell extracts , indicating that expressing active Akt effectively inhibits the cytochrome c initiated caspase activation cascade .	Caspase-9 activity assays showed that activation of caspase-9 by cytochrome c and dATP was inhibited in extracts prepared from Akt-stable lines compared with those in vector-control cell extracts, indicating that expressing active Akt effectively inhibits the cytochrome c initiated caspase activation cascade.	5	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	9	11	7	8
Since our results are in agreement with the induction of the intrinsic apoptotic pathway in tumor biopsies from mice injected subcutaneously with HCMV infected HepG2 cells , we assessed cytochrome c induced caspase-9 activation in our xenografted murine model .	Since our results are in agreement with the induction of the intrinsic apoptotic pathway in tumor biopsies from mice injected subcutaneously with HCMV infected HepG2 cells, we assessed cytochrome c induced caspase-9 activation in our xenografted murine model.	29	33	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	29	31	32	33
Therefore , the ratio of Bax to Bcl-2 is vital for determining the release of many apoptogenic proteins from the mitochondrial intermembrane space , such as cytochrome c which can further activate caspase-9 .	Therefore, the ratio of Bax to Bcl-2 is vital for determining the release of many apoptogenic proteins from the mitochondrial intermembrane space, such as cytochrome c which can further activate caspase-9.	26	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	26	28	32	33
Indeed , others have reported that TcdB can alter mitochondrial function by activating membrane channels that trigger hyperpolarization , mitochondrial swelling and cytochrome C release , the latter of which drives caspase-9 dependent apoptosis in this system [ XREF_BIBR ] .	Indeed, others have reported that TcdB can alter mitochondrial function by activating membrane channels that trigger hyperpolarization, mitochondrial swelling and cytochrome C release, the latter of which drives caspase-9 dependent apoptosis in this system [XREF_BIBR].	22	33	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	22	24	31	32
Cytochrome c in turn activated caspase-9 and caspase-3 .	Cytochrome c in turn activated caspase-9 and caspase-3.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	5	6
Cytochrome c release induces activation of caspase-9 , and subsequent cleavage of caspase-3 , which in turn induces apoptosis in most mononucleated cell types .	Cytochrome c release induces activation of caspase-9, and subsequent cleavage of caspase-3, which in turn induces apoptosis in most mononucleated cell types.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	6	7
As the activation of caspase-9 by cytochrome-C release from the mitochondrium does not seem to lead to consequently higher caspase-3 and -7 engagement , one could assume that caspase-9 was also involved in induction of autophagy via a cross-talk mechanism .	As the activation of caspase-9 by cytochrome-C release from the mitochondrium does not seem to lead to consequently higher caspase-3 and -7 engagement, one could assume that caspase-9 was also involved in induction of autophagy via a cross-talk mechanism.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	cytochrome-C	cytochrome-C	cytochrome-C	caspase-9	caspase-9	caspase-9	6	7	4	5
It has also been reported that cytochrome c release can activate initiator caspase-9 , which eventually activates executioner caspases like caspase-3 via cleavage XREF_BIBR .	It has also been reported that cytochrome c release can activate initiator caspase-9, which eventually activates executioner caspases like caspase-3 via cleavage XREF_BIBR.	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	12	13
Caspase-8 is activated in response to death receptors ( such as Fas ) whereas caspase-9 is activated by the release of cytochrome c via the intrinsic mitochondrial stress pathway .	Caspase-8 is activated in response to death receptors (such as Fas) whereas caspase-9 is activated by the release of cytochrome c via the intrinsic mitochondrial stress pathway.	14	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	21	23	14	15
Two main mechanisms for caspase-7 activation have been proposed : ( i ) caspase-8 recruitment to death receptors ( Fas or tumour necrosis factor ) ; and ( ii ) changes in mitochondrial membrane permeability and cytochrome c release , which activate caspase-9 .	Two main mechanisms for caspase-7 activation have been proposed : (i) caspase-8 recruitment to death receptors (Fas or tumour necrosis factor); and (ii) changes in mitochondrial membrane permeability and cytochrome c release, which activate caspase-9.	36	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	36	38	42	43
In the cytosol , cytochrome c combines with APAF-1 in the presence of ATP to activate caspase-9 that , in turn , activates effectors caspases such as caspase-3 .	In the cytosol, cytochrome c combines with APAF-1 in the presence of ATP to activate caspase-9 that, in turn, activates effectors caspases such as caspase-3.	4	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	16	17
Cytochrome c activates caspase-9 , which cleaves and activates downstream effector proteases , such as caspase-3 , leading to apoptosis XREF_BIBR .	Cytochrome c activates caspase-9, which cleaves and activates downstream effector proteases, such as caspase-3, leading to apoptosis XREF_BIBR.	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	3	4
Therefore it is hypothesized that activation of caspase-7 , the primary executioner caspase , was not wholly dependent on the activation of caspase-9 by cytochrome c release , but also via caspase-8 activation mediated by TNF family during the programmed cell death .	Therefore it is hypothesized that activation of caspase-7, the primary executioner caspase, was not wholly dependent on the activation of caspase-9 by cytochrome c release, but also via caspase-8 activation mediated by TNF family during the programmed cell death.	20	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	24	26	22	23
The released cytochrome c triggered the activation of caspase-9 followed by the executioner caspase-3/7 and then cleaved the PARP protein .	The released cytochrome c triggered the activation of caspase-9 followed by the executioner caspase-3/7 and then cleaved the PARP protein.	2	9	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	8	9
Recently , we showed that MG-132 induces cytochrome c release from the mitochondria and activates caspase-9 and caspase-3 in a time dependent manner [ 19 ] , demonstrating mitochondria dependent apoptotic cell death in dopaminergic cells .	Recently, we showed that MG-132 induces cytochrome c release from the mitochondria and activates caspase-9 and caspase-3 in a time dependent manner [19], demonstrating mitochondria dependent apoptotic cell death in dopaminergic cells.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	MG-132 induces cytochrome c release from the mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	7	9	15	16
In this response , BH3 domain-only family members such as Bid are activated and interact with Bax-type proteins ( Bax , Bak , Bok ) to form or interact with mitochondrial pores , release cytochrome c , activate caspase-9 and induce cell death .	In this response, BH3 domain-only family members such as Bid are activated and interact with Bax-type proteins (Bax, Bak, Bok) to form or interact with mitochondrial pores, release cytochrome c, activate caspase-9 and induce cell death.	34	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	34	36	38	39
Meanwhile , bax initiates the mitochondrial apoptotic pathway by triggering the loss of mitochondrial membrane integrity , which releases cytochrome c from mitochondria into cytoplasm , activating caspase-9 and in turn , its downstream caspase-3 , resulting in apoptosis [ XREF_BIBR , XREF_BIBR ] .	Meanwhile, bax initiates the mitochondrial apoptotic pathway by triggering the loss of mitochondrial membrane integrity, which releases cytochrome c from mitochondria into cytoplasm, activating caspase-9 and in turn, its downstream caspase-3, resulting in apoptosis [XREF_BIBR, XREF_BIBR].	18	28	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	releases cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	19	21	27	28
Apoptosomes containing APAF1 and cytochrome C mediate caspase-9 activation , which cleaves executioner caspase-3 or -7 .	Apoptosomes containing APAF1 and cytochrome C mediate caspase-9 activation, which cleaves executioner caspase-3 or -7.	2	8	mediate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	4	6	7	8
These stimuli lead to the release of several factors into cytosol including cytochrome c , which activates the initiator caspase-9 via the apoptosome followed by the activation of effector caspases .	These stimuli lead to the release of several factors into cytosol including cytochrome c, which activates the initiator caspase-9 via the apoptosome followed by the activation of effector caspases.	12	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	12	14	19	20
Amongst the escaping molecules are cytochrome c and dATP , which together activate caspase 9 , held in this microenvironment by its association with a protein ( with remarkable , seven-fold symmetry ) called apaf-1 .	Amongst the escaping molecules are cytochrome c and dATP, which together activate caspase 9, held in this microenvironment by its association with a protein (with remarkable, seven-fold symmetry) called apaf-1.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	5	7	13	15
Cytosolic cytochrome c promoted the activation of caspase-9 after Taxol treatment ( XREF_FIG ) .	Cytosolic cytochrome c promoted the activation of caspase-9 after Taxol treatment (XREF_FIG).	1	8	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	7	8
The released cytochrome c then activates the initiator active caspase-9 .	The released cytochrome c then activates the initiator active caspase-9.	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	9	10
The cytochrome c triggers the proteolytic activity of caspase-3 and caspase-9 in the cytosol , and these activated caspases degrade ( poly [ ADP-ribose ] polymerase ) and caspase-activated-DNase , which initiates DNA degradation [ XREF_BIBR ] .	The cytochrome c triggers the proteolytic activity of caspase-3 and caspase-9 in the cytosol, and these activated caspases degrade (poly [ADP-ribose] polymerase) and caspase-activated-DNase, which initiates DNA degradation [XREF_BIBR].	1	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	10	11
They observed that treatment of mammalian S100 extracts with RNase strongly increased cytochrome c induced caspase-9 activation , while the addition of RNA to the extracts impaired caspase-9 activation .	They observed that treatment of mammalian S100 extracts with RNase strongly increased cytochrome c induced caspase-9 activation, while the addition of RNA to the extracts impaired caspase-9 activation.	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	12	14	15	16
This promotes cytochrome C release , which subsequently activates caspase-9 and -3 [ XREF_BIBR ] .	This promotes cytochrome C release, which subsequently activates caspase-9 and -3 [XREF_BIBR].	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	2	4	9	10
These events are then associated with mitochondrial swelling , outer membrane disruption , and the release of cytochrome c , which , in turn , activates caspase-9 and , subsequently , the entire apoptotic cascade ( XREF_FIG ) .	These events are then associated with mitochondrial swelling, outer membrane disruption, and the release of cytochrome c, which, in turn, activates caspase-9 and, subsequently, the entire apoptotic cascade (XREF_FIG).	17	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	17	19	26	27
The induction of apoptosis by realgar is mediated through a cytochrome c dependent pathway , which sequentially activates caspase-9 and caspase-3 .	The induction of apoptosis by realgar is mediated through a cytochrome c dependent pathway, which sequentially activates caspase-9 and caspase-3.	10	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	10	12	18	19
Cytochrome c mediated caspase-9 activation triggers the activation of the executioner caspase-3 that leads to cell death XREF_BIBR , XREF_BIBR .	Cytochrome c mediated caspase-9 activation triggers the activation of the executioner caspase-3 that leads to cell death XREF_BIBR, XREF_BIBR.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	3	4
Alcohol may induce mitochondrial stress through disruption of Ca 2+ homeostasis , the release of cytochrome c occurred from mitochondria , which then interacts with Apaf-1 , causing self-cleavage and activation of caspase-9 .	Alcohol may induce mitochondrial stress through disruption of Ca 2+ homeostasis, the release of cytochrome c occurred from mitochondria, which then interacts with Apaf-1, causing self-cleavage and activation of caspase-9.	15	33	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	15	17	32	33
Similarly , cIAP-2 is another kind of effective inhibitor of apoptosis by blocking the activity of caspase-9 induced by cytochrome c [ XREF_BIBR ] .	Similarly, cIAP-2 is another kind of effective inhibitor of apoptosis by blocking the activity of caspase-9 induced by cytochrome c [XREF_BIBR].	14	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	19	21	16	17
Fas engagement also triggers mitochondrial cytochrome c release that , in conjunction with apoptotic protease activating factor ( APAF ) -1 and dATP , activates caspase 9 and downstream caspases .	Fas engagement also triggers mitochondrial cytochrome c release that, in conjunction with apoptotic protease activating factor (APAF) -1 and dATP, activates caspase 9 and downstream caspases.	5	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	5	7	25	27
By activating two key enzymes of the apoptotic pathway -- caspase-9 and caspase-3 -- cytochrome C triggers a signaling cascade that results in cell death .	By activating two key enzymes of the apoptotic pathway -- caspase-9 and caspase-3 -- cytochrome C triggers a signaling cascade that results in cell death.	8	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	14	16	10	11
Because osteoclasts contain abundant mitochondria that are involved in cytochrome c mediated caspase-9 activation , we investigated whether mitochondrial pathways are involved in osteoclast apoptosis .	Because osteoclasts contain abundant mitochondria that are involved in cytochrome c mediated caspase-9 activation, we investigated whether mitochondrial pathways are involved in osteoclast apoptosis.	9	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	9	11	12	13
One important event in the apoptotic cascade is the release of cytochrome c by mitochondria into the cytoplasm , activating caspase-9 , leading to the subsequent activation of downstream executioner caspases .	One important event in the apoptotic cascade is the release of cytochrome c by mitochondria into the cytoplasm, activating caspase-9, leading to the subsequent activation of downstream executioner caspases.	11	21	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	11	13	20	21
In the intrinsic pathway induced by chemotherapeutic agents , cytochrome C released from mitochondria in conjunction with Apaf-1 causes the activation of initiator caspase-9 .	In the intrinsic pathway induced by chemotherapeutic agents, cytochrome C released from mitochondria in conjunction with Apaf-1 causes the activation of initiator caspase-9.	9	24	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	9	11	23	24
Cooperating with Apaf-1 , the cytochrome C released into cytoplasm may activate caspase-9 and therefore induce activation of caspase cascade , including caspases-3 , -6 and -7 , resulting in cell apoptosis XREF_BIBR .	Cooperating with Apaf-1, the cytochrome C released into cytoplasm may activate caspase-9 and therefore induce activation of caspase cascade, including caspases-3, -6 and -7, resulting in cell apoptosis XREF_BIBR.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	5	7	12	13
Once released cytochrome c promotes Caspase-9 activation on a cytosolic scaffold protein ( APAF-1 , apoptotic protease activating factor 1 ) and SMAC concomitantly lifts the effect of the caspase inhibitor XIAP ( X linked inhibitor of caspases ) .	Once released cytochrome c promotes Caspase-9 activation on a cytosolic scaffold protein (APAF-1, apoptotic protease activating factor 1) and SMAC concomitantly lifts the effect of the caspase inhibitor XIAP (X linked inhibitor of caspases).	2	6	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Caspase-9	Caspase-9	Caspase-9	2	4	5	6
To further understand the cardiac mitochondria dependent apoptotic signaling pathways in the coexistence of hypertension and ovariectomy , we measured the protein levels of t-Bid , Bak , Bad , Bax , cytochrome c , activated caspase 9 and activated caspase 3 in the left ventricles excised from the WKY , SHR-Sham and SHR-OVX groups by Western blotting .	To further understand the cardiac mitochondria dependent apoptotic signaling pathways in the coexistence of hypertension and ovariectomy, we measured the protein levels of t-Bid, Bak, Bad, Bax, cytochrome c, activated caspase 9 and activated caspase 3 in the left ventricles excised from the WKY, SHR-Sham and SHR-OVX groups by Western blotting.	22	38	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	levels of t-Bid, Bak, Bad, Bax, cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	32	34	36	38
We can also recover the details of caspase-9 activation mediated by cytochrome C and Smac release from mitochondria but with altered kinetics of release .	We can also recover the details of caspase-9 activation mediated by cytochrome C and Smac release from mitochondria but with altered kinetics of release.	7	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	11	13	7	8
Cytoplasmic cytochrome c then activates caspase-9 , which in turn triggers the activation of caspase-3 and leads to cell death .	Cytoplasmic cytochrome c then activates caspase-9, which in turn triggers the activation of caspase-3 and leads to cell death.	1	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	5	6
In the presence of 0.1 and 0.2 mug and mul tRNA , the minimal amount of cytochrome c required to induce caspase-9 activation increased to 10 and 20 mug/ml , respectively ( XREF_FIG ) .	In the presence of 0.1 and 0.2 mug and mul tRNA, the minimal amount of cytochrome c required to induce caspase-9 activation increased to 10 and 20 mug/ml, respectively (XREF_FIG).	14	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	amount of cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	16	18	21	22
XREF_BIBR Release of cytochrome c from mitochondria through stress stimuli , induces activation of caspase 9 , which in turn leads to activation of caspase 3 enzyme .	XREF_BIBR Release of cytochrome c from mitochondria through stress stimuli, induces activation of caspase 9, which in turn leads to activation of caspase 3 enzyme.	1	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	Release of cytochrome c from mitochondria	cytochrome c	caspase 9	caspase 9	caspase 9	3	5	14	16
Expression of the BIR2 domain in cells also partially suppressed Fas induced apoptosis and blocked cytochrome c induced processing of caspase-9 in cytosolic extracts , whereas BIR1 and BIR3 did not .	Expression of the BIR2 domain in cells also partially suppressed Fas induced apoptosis and blocked cytochrome c induced processing of caspase-9 in cytosolic extracts, whereas BIR1 and BIR3 did not.	15	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	15	17	20	21
It is regulated by cytochrome c release from mitochondria , promoting the activation of caspase-9 through Apaf1 , and then caspase-3 activation ( XREF_FIG and XREF_FIG ) .	It is regulated by cytochrome c release from mitochondria, promoting the activation of caspase-9 through Apaf1, and then caspase-3 activation (XREF_FIG and XREF_FIG).	4	15	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	14	15
Once in the cytoplasm , cytochrome c activates caspase-9 by inducing formation of the apoptosome XREF_BIBR .	Once in the cytoplasm, cytochrome c activates caspase-9 by inducing formation of the apoptosome XREF_BIBR.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	8	9
Literature data indicated that the release of cytochrome c from the mitochondria into the cytosol , may result in the caspase-9 activation , which subsequently activates effector caspase , such as caspase-3 , which causes DNA fragmentation and eventually -- cell death [ XREF_BIBR ] .	Literature data indicated that the release of cytochrome c from the mitochondria into the cytosol, may result in the caspase-9 activation, which subsequently activates effector caspase, such as caspase-3, which causes DNA fragmentation and eventually -- cell death [XREF_BIBR].	5	22	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from the mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	7	9	20	21
We conclude that the ATP and cytochrome c dependent activation of caspase-9 is increased during hypoxia .	We conclude that the ATP and cytochrome c dependent activation of caspase-9 is increased during hypoxia.	4	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	11	12
Once released to the cytoplasm , cytochrome c acts as a cofactor in conjunction with Apaf-1 , procaspase-9 , and ATP and dATP to induce activation of caspase-9 and subsequently caspase-3 2122 .	Once released to the cytoplasm, cytochrome c acts as a cofactor in conjunction with Apaf-1, procaspase-9, and ATP and dATP to induce activation of caspase-9 and subsequently caspase-3 2122.	6	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	27	28
In this system caspases are activated by the addition of cytochrome c , triggering Apaf-1-dependent activation of caspase-9 and -3 [ XREF_BIBR ] .	In this system caspases are activated by the addition of cytochrome c, triggering Apaf-1-dependent activation of caspase-9 and -3 [XREF_BIBR].	5	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	10	12	17	18
One of the consequences of cytochrome C release is formation of apoptosome containing cytochrome C , Apaf-1 and procaspase-9 in the cytosol of the cells , leading to activation of caspase 9 through an intrinsic autocatalytic cleavage of procaspase 9 .	One of the consequences of cytochrome C release is formation of apoptosome containing cytochrome C, Apaf-1 and procaspase-9 in the cytosol of the cells, leading to activation of caspase 9 through an intrinsic autocatalytic cleavage of procaspase 9.	13	32	leading to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase 9	caspase 9	caspase 9	13	15	30	32
XREF_BIBR , XREF_BIBR When apoptotic signals overcome inhibition and protection by Bcl-2 and Bcl-x L , Bax translocates from the cytosol to mitochondria , 112 releasing mitochondrial cytochrome c that in turn activates caspase-9 .	XREF_BIBR, XREF_BIBR When apoptotic signals overcome inhibition and protection by Bcl-2 and Bcl-x L, Bax translocates from the cytosol to mitochondria, 112 releasing mitochondrial cytochrome c that in turn activates caspase-9.	27	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	27	29	33	34
Excessive ROS causes the release of Cytochrome c from mitochondria to the cytosol and triggers caspase-9 activation and apoptosis [ XREF_BIBR ] .	Excessive ROS causes the release of Cytochrome c from mitochondria to the cytosol and triggers caspase-9 activation and apoptosis [XREF_BIBR].	1	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	ROS causes the release of Cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	15	16
MOMP leads to the release of mitochondrial apoptotic inducing factors cytochrome C and SMAC/DIABLO , thereby activating casp9 and downstream effector caspases .	MOMP leads to the release of mitochondrial apoptotic inducing factors cytochrome C and SMAC/DIABLO, thereby activating casp9 and downstream effector caspases.	10	21	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	casp9	casp9	casp9	10	12	17	18
Cytochrome C further activates caspase9 , leading activation of effector caspases and execution of apoptosis In addition , caspase8 can also directly target effector caspases , depending on cell type and pathological conditions .	Cytochrome C further activates caspase9, leading activation of effector caspases and execution of apoptosis In addition, caspase8 can also directly target effector caspases, depending on cell type and pathological conditions.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	caspase9	caspase9	caspase9	0	2	4	5
APIP and MTNB also inhibits cytochrome c induced activation of caspase-9 [ XREF_BIBR , XREF_BIBR ] .	APIP and MTNB also inhibits cytochrome c induced activation of caspase-9 [XREF_BIBR, XREF_BIBR].	5	14	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	10	11
Moreover , immunoblots revealed a strongly reduced expression of the adaptor molecule APAF-1 , which is required for cytochrome c dependent activation of caspase-9 and subsequently caspase-3 .	Moreover, immunoblots revealed a strongly reduced expression of the adaptor molecule APAF-1, which is required for cytochrome c dependent activation of caspase-9 and subsequently caspase-3.	18	24	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	18	20	23	24
The pro apoptotic proteins activate cytochrome C release from the mitochondria , which then activate caspase 9 and caspase-3 , leading to cell apoptosis .	The pro apoptotic proteins activate cytochrome C release from the mitochondria, which then activate caspase 9 and caspase-3, leading to cell apoptosis.	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C release from the mitochondria	cytochrome c	caspase 9	caspase 9	caspase 9	5	7	15	17
Cathepsin B causes mitochondrial release of cytochrome c. Cytochrome c activates caspase 9 , which activates caspases 3 and 7 .	Cathepsin B causes mitochondrial release of cytochrome c. Cytochrome c activates caspase 9, which activates caspases 3 and 7.	8	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	8	10	11	13
Cytosolic cytochrome c promotes apoptosis by contributing to the formation of the apoptosome , which also includes ATP and Apoptotic Peptidase Activating Factor 1 ( APAF-1 ) , and results in activation of caspase 9 [ XREF_BIBR , XREF_BIBR ] .	Cytosolic cytochrome c promotes apoptosis by contributing to the formation of the apoptosome, which also includes ATP and Apoptotic Peptidase Activating Factor 1 (APAF-1), and results in activation of caspase 9 [XREF_BIBR, XREF_BIBR].	1	36	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	1	3	33	35
Results showed that NTC enhanced the release of mitochondrial cytochrome c which activated caspase 9 by 3-folds in colon cancer cells .	Results showed that NTC enhanced the release of mitochondrial cytochrome c which activated caspase 9 by 3-folds in colon cancer cells.	9	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	9	11	13	15
Cytochrome c leads to activation of caspase 9 which then triggers a cascade of caspases ( caspase 3 , caspase 6 and caspase 7 ) [ XREF_BIBR ] .	Cytochrome c leads to activation of caspase 9 which then triggers a cascade of caspases (caspase 3, caspase 6 and caspase 7) [XREF_BIBR].	0	8	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	6	8
Upon activated by tBid , the pores open to release cytochrome C , which , in turn , activates caspase-9 in the cytoplasm .	Upon activated by tBid, the pores open to release cytochrome C, which, in turn, activates caspase-9 in the cytoplasm.	10	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	10	12	19	20
In a previous study , cytochrome c induced activation of caspase-9 was inhibited by either z-VAD .	In a previous study, cytochrome c induced activation of caspase-9 was inhibited by either z-VAD.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	10	11
Mammalian cells contain multiple caspases with caspase-9 being activated by mitochondrial depolarization and cytochrome C ( Intrinsic apoptosis ) , and caspase-8 being activated by Fas Associated protein with Death Domain ( FADD ) receptor ( Extrinsic apoptosis ) .	Mammalian cells contain multiple caspases with caspase-9 being activated by mitochondrial depolarization and cytochrome C (Intrinsic apoptosis), and caspase-8 being activated by Fas Associated protein with Death Domain (FADD) receptor (Extrinsic apoptosis).	2	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	13	15	6	7
Cytochrome c promotes activation of caspase-9 , which in turn promotes activation of caspase-3 , leading to apoptosis of the tumor cell [ XREF_BIBR - XREF_BIBR ] .	Cytochrome c promotes activation of caspase-9, which in turn promotes activation of caspase-3, leading to apoptosis of the tumor cell [XREF_BIBR - XREF_BIBR].	0	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	5	6
Apoptosis inducing small molecules typically engage the intrinsic pathway , in which release of mitochondrial cytochrome c induces activation of caspase-9 , followed by activation of caspase-3 .	Apoptosis inducing small molecules typically engage the intrinsic pathway, in which release of mitochondrial cytochrome c induces activation of caspase-9, followed by activation of caspase-3.	15	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	15	17	20	21
In normal cells , caspase-9 is activated by cytochrome c , following its release from mitochondria .	In normal cells, caspase-9 is activated by cytochrome c, following its release from mitochondria.	4	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	4	5
Cytochrome c release triggered caspase-9 activation , which then activated caspase-7 , leading to apoptotic changes .	Cytochrome c release triggered caspase-9 activation, which then activated caspase-7, leading to apoptotic changes.	0	5	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	4	5
An increase of the pro apoptotic bax and anti-apoptotic bcl-2 ratio enhances the permeability of the mitochondrial membrane , causes the release of cytochrome c from mitochondria to cytosol and , in turn , results in the activation of caspase-9 and the downstream target caspase-3 XREF_BIBR .	An increase of the pro apoptotic bax and anti-apoptotic bcl-2 ratio enhances the permeability of the mitochondrial membrane, causes the release of cytochrome c from mitochondria to cytosol and, in turn, results in the activation of caspase-9 and the downstream target caspase-3 XREF_BIBR.	6	45	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	cytochrome c	bax and anti-apoptotic bcl-2 ratio enhances the permeability of the mitochondrial membrane, causes the release of cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	23	25	39	40
JNK activation facilitates the decrease of mitochondrial membrane potential followed by release of cytochrome c , which then activates caspase-9 and caspase-3 , eventually leading to cell death [ XREF_BIBR ] .	JNK activation facilitates the decrease of mitochondrial membrane potential followed by release of cytochrome c, which then activates caspase-9 and caspase-3, eventually leading to cell death [XREF_BIBR].	13	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	13	15	19	20
Western blots of lysates from TQ treated TNBC cells showed cytochrome c and apoptosis inducing factor in the cytoplasm , as well as caspase-9 activation consistent with the mitochondrial pathway of apoptosis .	Western blots of lysates from TQ treated TNBC cells showed cytochrome c and apoptosis inducing factor in the cytoplasm, as well as caspase-9 activation consistent with the mitochondrial pathway of apoptosis.	10	24	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	10	12	23	24
Interestingly , apoptosis induction of these type II cells is strongly dependent on the mitochondrial release of Smac , rather than cytochrome c mediated activation of caspase-9 .	Interestingly, apoptosis induction of these type II cells is strongly dependent on the mitochondrial release of Smac, rather than cytochrome c mediated activation of caspase-9.	21	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	21	23	26	27
The extrinsic pathway requires the activation of plasma membrane Fas receptor and the activation of caspase 8 by Fas associated death domain signal transduction , and the intrinsic pathway requires the translocation of Bcl-2-associated X protein ( Bax ) to the mitochondria , in which Bax forms pores that release cytochrome C and activate caspase 9 XREF_BIBR .	The extrinsic pathway requires the activation of plasma membrane Fas receptor and the activation of caspase 8 by Fas associated death domain signal transduction, and the intrinsic pathway requires the translocation of Bcl-2-associated X protein (Bax) to the mitochondria, in which Bax forms pores that release cytochrome C and activate caspase 9 XREF_BIBR.	49	56	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase 9	caspase 9	caspase 9	50	52	54	56
Biochemical studies have shown that in the Bcl-2-regulated pathway release of cytochrome c from mitochondria promotes activation of caspase-9 by its adaptor Apaf-1 .	Biochemical studies have shown that in the Bcl-2-regulated pathway release of cytochrome c from mitochondria promotes activation of caspase-9 by its adaptor Apaf-1.	9	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	11	13	18	19
Cytochrome c induced caspase-9 activation is regulated by nucleotides .	Cytochrome c induced caspase-9 activation is regulated by nucleotides.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	3	4
In the cytosol , cytochrome c complexes with the adapter protein Apaf-1 and activates the cysteine protease caspase-9 .	In the cytosol, cytochrome c complexes with the adapter protein Apaf-1 and activates the cysteine protease caspase-9.	4	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	17	18
The released cytosolic cytochrome c activates caspase-9 , which in turn activates caspases cascade including caspase-3 that leads to activation of ultimate biochemical events in apoptosis XREF_BIBR - XREF_BIBR .	The released cytosolic cytochrome c activates caspase-9, which in turn activates caspases cascade including caspase-3 that leads to activation of ultimate biochemical events in apoptosis XREF_BIBR - XREF_BIBR.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	6	7
Both cytochrome C and Smac/Diablo are known mediators leading to apoptosis ; where cytochrome C acts to activate caspase-9 while Smac/Diablo suppresses IAP expression in cytosol .	Both cytochrome C and Smac/Diablo are known mediators leading to apoptosis; where cytochrome C acts to activate caspase-9 while Smac/Diablo suppresses IAP expression in cytosol.	13	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	13	15	18	19
The mitochondrial release of cytochrome c into the cytosol could cause activation of caspase-9 .	The mitochondrial release of cytochrome c into the cytosol could cause activation of caspase-9.	4	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	13	14
XREF_BIBR In the intrinsic pathway , the release of cytochrome c from mitochondria into the cytosol leads to the formation of apoptosome and activates caspase-9 , resulting in the activation of effector caspases such as caspase-3 , caspase-6 and caspase-7 .	XREF_BIBR In the intrinsic pathway, the release of cytochrome c from mitochondria into the cytosol leads to the formation of apoptosome and activates caspase-9, resulting in the activation of effector caspases such as caspase-3, caspase-6 and caspase-7.	7	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	9	11	24	25
However , unlike staurosporine induced apoptosis , cytochrome c , which activates caspase-9 , was not detected in the cytosol of RA/BMP-4-treated cells .	However, unlike staurosporine induced apoptosis, cytochrome c, which activates caspase-9, was not detected in the cytosol of RA/BMP-4-treated cells.	7	13	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	7	9	12	13
Cytochrome c released from mitochondria together with other proteins leads to the production of active caspase-9 that again induces caspase-3 activation and results in apoptosis .	Cytochrome c released from mitochondria together with other proteins leads to the production of active caspase-9 that again induces caspase-3 activation and results in apoptosis.	0	16	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	15	16
The cytochrome c release triggers the activation of caspase-9 in DRCKD , which was effectively suppressed by exercise trainings ( XREF_FIG ) , and in the next step , caspase-3 is activated by active cleaved caspase-9 ( XREF_FIG ) .	The cytochrome c release triggers the activation of caspase-9 in DRCKD, which was effectively suppressed by exercise trainings (XREF_FIG), and in the next step, caspase-3 is activated by active cleaved caspase-9 (XREF_FIG).	1	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	8	9
These changes are likely to be a consequence of the reduction of mitochondrial membrane potential and release of mitochondria cytochrome c , which subsequently activates caspase 9 and then caspase 3 24 .	These changes are likely to be a consequence of the reduction of mitochondrial membrane potential and release of mitochondria cytochrome c, which subsequently activates caspase 9 and then caspase 3 24.	19	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	19	21	25	27
Cytochrome c activates caspase 9 and caspase 3 activity .	Cytochrome c activates caspase 9 and caspase 3 activity.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	3	5
Cytochrome c mediate formation of apoptosome by recruiting apoptotic protease activating factor ( Apaf-1 ) and pro-caspase-9 where caspase-9 get cleaved and become activated and cleaved .	Cytochrome c mediate formation of apoptosome by recruiting apoptotic protease activating factor (Apaf-1) and pro-caspase-9 where caspase-9 get cleaved and become activated and cleaved.	0	25	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	pro-caspase-9	pro-caspase-9	pro-caspase-9	0	2	16	17
Here we demonstrate that the enhanced nitration of specific tyrosine residues of cytochrome c , which are induced by continuous peroxynitrite exposure , attenuates cytochrome c induced caspase-9 activation in vitro .	Here we demonstrate that the enhanced nitration of specific tyrosine residues of cytochrome c, which are induced by continuous peroxynitrite exposure, attenuates cytochrome c induced caspase-9 activation in vitro.	24	28	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	24	26	27	28
In the cytoplasm , cytochrome c , in combination with Apaf-1 , activates caspase-9 , leading to the activation of caspase-3 and subsequent apoptosis [ XREF_BIBR ] .	In the cytoplasm, cytochrome c, in combination with Apaf-1, activates caspase-9, leading to the activation of caspase-3 and subsequent apoptosis [XREF_BIBR].	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	13	14
Cytochrome c induced the activation of caspase-9 in permeabilized H9c2 cardiomyocytes that increased further upon adding Smac-N7 peptide ( XREF_FIG ) .	Cytochrome c induced the activation of caspase-9 in permeabilized H9c2 cardiomyocytes that increased further upon adding Smac-N7 peptide (XREF_FIG).	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	6	7
In the intrinsic apoptotic pathway , cytochrome c is released from the mitochondrial intermembrane space into the cytosol , initiating the formation of the apoptosome complex and the activation of caspase-9 as the apical caspase .	In the intrinsic apoptotic pathway, cytochrome c is released from the mitochondrial intermembrane space into the cytosol, initiating the formation of the apoptosome complex and the activation of caspase-9 as the apical caspase.	6	31	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	30	31
The released cytochrome c activates caspase-9 and sequentially activates caspase-3 .	The released cytochrome c activates caspase-9 and sequentially activates caspase-3.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	5	6
Cytochrome c promotes the assembly of apoptosome and subsequent activation of caspase 9 , which is facilitated by SMAC/Diablo and HtrA2 and Omi , which antagonize the inhibitors of apoptosis ( IAP ) family of proteins .	Cytochrome c promotes the assembly of apoptosome and subsequent activation of caspase 9, which is facilitated by SMAC/Diablo and HtrA2 and Omi, which antagonize the inhibitors of apoptosis (IAP) family of proteins.	0	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	11	13
[ XREF_BIBR ] The released cytochrome c could recruit Apaf-1 and activate caspase-9 and caspase-3 , resulting in apoptosis .	[XREF_BIBR] The released cytochrome c could recruit Apaf-1 and activate caspase-9 and caspase-3, resulting in apoptosis.	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	12	13
As shown in XREF_FIG , incubation of permeabilized H9c2 cardiomyoblasts with exogenous cytochrome c activated caspase-9 and -3 .	As shown in XREF_FIG, incubation of permeabilized H9c2 cardiomyoblasts with exogenous cytochrome c activated caspase-9 and -3.	12	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	12	14	15	16
During the initiation of apoptosis , cytochrome c released from the mitochondria activates the proapoptotic caspase-9 , which ultimately causes apoptotic cell death [ XREF_BIBR - XREF_BIBR ] .	During the initiation of apoptosis, cytochrome c released from the mitochondria activates the proapoptotic caspase-9, which ultimately causes apoptotic cell death [XREF_BIBR - XREF_BIBR].	6	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	15	16
Activation of death receptors triggers the cleavage of caspase 8 , whereas release of cytochrome c from mitochondria activates caspase 9 ; both pathways eventually converge to activate the execution caspase , caspase 3 .	Activation of death receptors triggers the cleavage of caspase 8, whereas release of cytochrome c from mitochondria activates caspase 9; both pathways eventually converge to activate the execution caspase, caspase 3.	12	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from mitochondria	cytochrome c	caspase 9	caspase 9	caspase 9	14	16	19	21
In naive cell lysates , the addition of bovine cytochrome c , but not yeast cytochrome c , induced significant processing of caspase-9 and caspase-3 ( XREF_FIG D ) .	In naive cell lysates, the addition of bovine cytochrome c, but not yeast cytochrome c, induced significant processing of caspase-9 and caspase-3 (XREF_FIG D).	9	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	9	11	22	23
This releases apoptogenic factors into the cytosol , particularly cytochrome c , which promotes the activation of procaspase 9 on APAF1 ; activated caspase 9 in turn processes and activates the effector caspases i.e ., caspase 3 [ XREF_BIBR ] .	This releases apoptogenic factors into the cytosol, particularly cytochrome c, which promotes the activation of procaspase 9 on APAF1; activated caspase 9 in turn processes and activates the effector caspases i.e., caspase 3 [XREF_BIBR].	9	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	9	11	23	25
The Pd complex inflicted mitochondrial dysfunction leading to mitochondrial membrane potential loss , reactive oxygen species generation and release of cytosolic cytochrome c that activated caspase-9 and caspase-3 proteins which finally caused programmed cell death .	The Pd complex inflicted mitochondrial dysfunction leading to mitochondrial membrane potential loss, reactive oxygen species generation and release of cytosolic cytochrome c that activated caspase-9 and caspase-3 proteins which finally caused programmed cell death.	21	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	21	23	25	26
RNA hydrolysis enhances cytochrome c induced caspase-9 activation .	RNA hydrolysis enhances cytochrome c induced caspase-9 activation.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	6	7
The released cytochrome c triggered the activation of caspase-9 followed by caspase-3 .	The released cytochrome c triggered the activation of caspase-9 followed by caspase-3.	2	9	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	8	9
Cytosolic cytochrome C increased , formed a complex with , and activated caspase 9 .	Cytosolic cytochrome C increased, formed a complex with, and activated caspase 9.	1	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase 9	caspase 9	caspase 9	1	3	12	14
This release of cytochrome c , in turn , activates caspase-9 in the cytosol .	This release of cytochrome c, in turn, activates caspase-9 in the cytosol.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	10	11
The release of cytochrome c could activate caspase-9 , a cysteine protease .	The release of cytochrome c could activate caspase-9, a cysteine protease.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	7	8
After losing the mitochondrial membrane potential , caspase independent and caspase dependent apoptosis related proteins were released , including HtrA 2 , apoptotic induced factor , endonuclease G , and cytochrome c. Cytochrome c activated caspase-9 and caspase-3 , and cut downstream protein PARP , ultimately leading to cell apoptosis .	After losing the mitochondrial membrane potential, caspase independent and caspase dependent apoptosis related proteins were released, including HtrA 2, apoptotic induced factor, endonuclease G, and cytochrome c. Cytochrome c activated caspase-9 and caspase-3, and cut downstream protein PARP, ultimately leading to cell apoptosis.	32	37	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	32	34	35	36
There are two major apoptotic pathways : one is the mitochondrial and cytochrome C ( endogenous ) pathway , in which the endogenous signal ultimately activates Caspase-9 and Caspase-3 ; the other pathway is the cell membrane surface death receptor ( exogenous ) pathway , which finally activates Caspase-8 and Caspase-3 [ XREF_BIBR ] .	There are two major apoptotic pathways : one is the mitochondrial and cytochrome C (endogenous) pathway, in which the endogenous signal ultimately activates Caspase-9 and Caspase-3; the other pathway is the cell membrane surface death receptor (exogenous) pathway, which finally activates Caspase-8 and Caspase-3 [XREF_BIBR].	10	28	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	Caspase-9	Caspase-9	Caspase-9	12	14	26	27
Cytochrome c released from mitochondria to cytoplasm induces subsequent activation of caspase-9 .	Cytochrome c released from mitochondria to cytoplasm induces subsequent activation of caspase-9.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	11	12
Upon activation , BAX penetrates the mitochondrial outer membrane and elicits a release of cytochrome c from the intermembrane space to the cytosol , activating caspase-9 , which in turn activates caspase-3 , a key factor of apoptosis .	Upon activation, BAX penetrates the mitochondrial outer membrane and elicits a release of cytochrome c from the intermembrane space to the cytosol, activating caspase-9, which in turn activates caspase-3, a key factor of apoptosis.	3	26	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	BAX penetrates the mitochondrial outer membrane and elicits a release of cytochrome c from the intermembrane space to the cytosol	cytochrome c	caspase-9	caspase-9	caspase-9	14	16	25	26
Cytosolic cytochrome c , together with APAF-1 , activates caspase-9 and subsequently caspase-3 .	Cytosolic cytochrome c, together with APAF-1, activates caspase-9 and subsequently caspase-3.	1	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	9	10
In the intrinsic pathway , when the Deltapsim is decreased , cytochrome c released from the mitochondrial intermembrane space will lead to activation of caspase-9 , which is regulated by anti-apoptotic Bcl-2 and pro apoptotic Bax .	In the intrinsic pathway, when the Deltapsim is decreased, cytochrome c released from the mitochondrial intermembrane space will lead to activation of caspase-9, which is regulated by anti-apoptotic Bcl-2 and pro apoptotic Bax.	11	28	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	11	13	24	25
In the intrinsic pathway , cytochrome c releases from damaged mitochondria and causes apoptosome dependent activation of caspase 9 .	In the intrinsic pathway, cytochrome c releases from damaged mitochondria and causes apoptosome dependent activation of caspase 9.	5	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	5	7	17	19
In addition , phosphorylation of pro caspase 9 by Akt abrogates cytochrome c induced proteolytic processing of pro caspase 9 , which in turn prevents the activation of downstream executor caspases .	In addition, phosphorylation of pro caspase 9 by Akt abrogates cytochrome c induced proteolytic processing of pro caspase 9, which in turn prevents the activation of downstream executor caspases.	11	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	11	13	18	20
Caspase activation during apoptosis can involve receptor mediated death pathways where the TNF family of death receptors activate initiator Caspase-8 ( i.e. extrinsic pathway ) or can involve the mitochondrial mediated apoptosis pathway where Cytochrome C is released from the mitochondria and activates initiator Caspase-9 XREF_BIBR - XREF_BIBR .	Caspase activation during apoptosis can involve receptor mediated death pathways where the TNF family of death receptors activate initiator Caspase-8 (i.e. extrinsic pathway) or can involve the mitochondrial mediated apoptosis pathway where Cytochrome C is released from the mitochondria and activates initiator Caspase-9 XREF_BIBR - XREF_BIBR.	34	45	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	Caspase-9	Caspase-9	Caspase-9	34	36	44	45
The release of cytochrome c from mitochondria can activate caspase-9 and caspase-3 .	The release of cytochrome c from mitochondria can activate caspase-9 and caspase-3.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	9	10
Cytochrome c ( in the presence of ATP ) is known to activate caspase-9 .	Cytochrome c (in the presence of ATP) is known to activate caspase-9.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	13	14
Since previous reports have shown that G-CSF prolong neutrophil survival by inhibiting mitochondria initiated pathways of apoptosis , we examined whether mitochondrial outer membrane permeabilization ( MOMP ) and cytochrome c dependent activation of caspase 9 play a role in inhibition of neutrophil apoptosis induced by IL-17-activated PCs .	Since previous reports have shown that G-CSF prolong neutrophil survival by inhibiting mitochondria initiated pathways of apoptosis, we examined whether mitochondrial outer membrane permeabilization (MOMP) and cytochrome c dependent activation of caspase 9 play a role in inhibition of neutrophil apoptosis induced by IL-17-activated PCs.	29	36	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	29	31	34	36
The compound caused cell cycle arrest in the sub-G0 phase and induced apoptosis in MCF-7 by Bcl-2 downregulation ; Bax upregulation and cytochrome-c release resulted in caspase-9 and caspase-7 activation .	The compound caused cell cycle arrest in the sub-G0 phase and induced apoptosis in MCF-7 by Bcl-2 downregulation; Bax upregulation and cytochrome-c release resulted in caspase-9 and caspase-7 activation.	22	30	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	cytochrome-c	cytochrome-c	cytochrome-c	caspase-9	caspase-9	caspase-9	22	23	26	27
Further results showed that swainsonine treatment up-regulated Bax , downregulated Bcl-2 expression , triggered Bax translocation to mitochondria , destructed mitochondria integrity and activated mitochondria mediated apoptotic pathway , followed by the release of cytochrome c , which in turn activated caspase-9 and caspase-3 , promoted the cleavage of PARP , resulting in Eca-109 cell apoptosis .	Further results showed that swainsonine treatment up-regulated Bax, downregulated Bcl-2 expression, triggered Bax translocation to mitochondria, destructed mitochondria integrity and activated mitochondria mediated apoptotic pathway, followed by the release of cytochrome c, which in turn activated caspase-9 and caspase-3, promoted the cleavage of PARP, resulting in Eca-109 cell apoptosis.	34	43	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	34	36	41	42
XREF_BIBR , XREF_BIBR In turn , the released cytochrome c ultimately leads to the cleavage and activation of caspase-9 and caspase-3 , 23 representing the final steps of the intrinsic caspase pathway that has been previously shown to regulate ischemic cell death .	XREF_BIBR, XREF_BIBR In turn, the released cytochrome c ultimately leads to the cleavage and activation of caspase-9 and caspase-3, 23 representing the final steps of the intrinsic caspase pathway that has been previously shown to regulate ischemic cell death.	8	22	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	18	19
Importantly , incubation of purified Apaf-1 and caspase 9 together with T. gondii extract dose-dependently prevented subsequent activation of caspase 9 triggered by cytochrome c and ATP .	Importantly, incubation of purified Apaf-1 and caspase 9 together with T. gondii extract dose-dependently prevented subsequent activation of caspase 9 triggered by cytochrome c and ATP.	17	25	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	23	25	19	21
Since activation of caspase-9 by release of cytochrome-C from mitochondria plays a central role in ischemia induced apoptosis XREF_BIBR , XREF_BIBR , we looked at the potential interactions of IL-1Ra with caspase-9 and with caspases -3 , -6 , and -7 , acting downstream caspase-9 activation in this cell death pathway .	Since activation of caspase-9 by release of cytochrome-C from mitochondria plays a central role in ischemia induced apoptosis XREF_BIBR, XREF_BIBR, we looked at the potential interactions of IL-1Ra with caspase-9 and with caspases -3, -6, and -7, acting downstream caspase-9 activation in this cell death pathway.	1	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	cytochrome-C	release of cytochrome-C from mitochondria	cytochrome-c	caspase-9	caspase-9	caspase-9	7	8	3	4
The intrinsic pathway ( mitochondria pathway ) involves a decrease in mitochondrial membrane potential and release of cytochrome c XREF_BIBR , which activates caspase-9 through the apoptosome .	The intrinsic pathway (mitochondria pathway) involves a decrease in mitochondrial membrane potential and release of cytochrome c XREF_BIBR, which activates caspase-9 through the apoptosome.	17	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	17	19	23	24
Cytochrome C activates caspase-9 and then caspase-3 , which leads to cell apoptosis .	Cytochrome C activates caspase-9 and then caspase-3, which leads to cell apoptosis.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	caspase-9	caspase-9	caspase-9	0	2	3	4
This releases cytochrome c , which provokes Apaf-1 ( apoptotic protease activating factor 1 ) to activate caspase-9 [ XREF_BIBR ] .	This releases cytochrome c, which provokes Apaf-1 (apoptotic protease activating factor 1) to activate caspase-9 [XREF_BIBR].	2	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	17	18
This event , in conjunction with a favorable ratio of pro apoptotic to anti-apoptotic Bcl-2 family members , causes the release of cytochrome c from the mitochondria into the cytosol ; cytochrome c , upon forming a complex with the apoptotic protease activating factor 1 ( Apaf-1 ) , leads to the activation of CASP-9 and the downstream CASP-3 , eventually resulting in cell death .	This event, in conjunction with a favorable ratio of pro apoptotic to anti-apoptotic Bcl-2 family members, causes the release of cytochrome c from the mitochondria into the cytosol; cytochrome c, upon forming a complex with the apoptotic protease activating factor 1 (Apaf-1), leads to the activation of CASP-9 and the downstream CASP-3, eventually resulting in cell death.	31	58	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	CASP-9	CASP-9	CASP-9	31	33	54	55
IAPs are also able to inhibit the cytochrome c induced activation of caspase-9 [ XREF_BIBR ] .	IAPs are also able to inhibit the cytochrome c induced activation of caspase-9 [XREF_BIBR].	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	7	9	12	13
Activation of caspase-8 induces cytochrome c release from mitochondria , which then activates caspase-9 and -3 XREF_BIBR .	Activation of caspase-8 induces cytochrome c release from mitochondria, which then activates caspase-9 and -3 XREF_BIBR.	2	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	caspase-8 induces cytochrome c release from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	13	14
We also find , in this reconstituted in vitro system , that caspase 9 activation by exogenous cytochrome c depends on the redox state of the added cytochrome c.	We also find, in this reconstituted in vitro system, that caspase 9 activation by exogenous cytochrome c depends on the redox state of the added cytochrome c.	12	19	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	17	19	12	14
In the former pathway , proapoptotic signals provoke release from mitochondrial inter-membranous space into cytosol of cytochrome c , which forms a complex with Apaf-1 and dATP , known as apoptosome , and triggers caspase-9 activation .	In the former pathway, proapoptotic signals provoke release from mitochondrial inter-membranous space into cytosol of cytochrome c, which forms a complex with Apaf-1 and dATP, known as apoptosome, and triggers caspase-9 activation.	16	35	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c, which forms a complex with Apaf-1	cytochrome c	caspase-9	caspase-9	caspase-9	16	18	34	35
Cytochrome c promotes the aggregation of caspase-9 together with Apaf-1 in the cytosol to form a multi protein complex called an apoptosome , which results in caspase-9 activation .	Cytochrome c promotes the aggregation of caspase-9 together with Apaf-1 in the cytosol to form a multi protein complex called an apoptosome, which results in caspase-9 activation.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	6	7
In addition , cytochrome-c , together with apoptotic protease activating factor-1 and homodimers of initiator caspase 9 , form the apoptosome that is responsible for procaspase 3 cleavage and further destruction of the cell ( XREF_FIG ) .	In addition, cytochrome-c, together with apoptotic protease activating factor-1 and homodimers of initiator caspase 9, form the apoptosome that is responsible for procaspase 3 cleavage and further destruction of the cell (XREF_FIG).	3	18	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome-c	cytochrome-c	cytochrome-c	caspase 9	caspase 9	caspase 9	3	4	15	17
Lack of cytokine signaling has been shown to cause an increase in mitochondrial permeability and cytochrome c release ; along with apoptotic protease activating factor 1 ( APAF1 ) , cytochrome c activates caspase-9 and downstream effector caspases .	Lack of cytokine signaling has been shown to cause an increase in mitochondrial permeability and cytochrome c release; along with apoptotic protease activating factor 1 (APAF1), cytochrome c activates caspase-9 and downstream effector caspases.	30	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	30	32	33	34
Cytochrome c is thus released from mitochondria into cytosol and subsequently triggers hierarchical activation of caspase-9 , caspase-3 and caspase-7 .	Cytochrome c is thus released from mitochondria into cytosol and subsequently triggers hierarchical activation of caspase-9, caspase-3 and caspase-7.	0	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	15	16
Previous studies have revealed the means by which EGCG or other natural agents cause the mitochondria to release cytochrome c : one direct means is mediated by Bcl-2 family proteins ; the other is through Fas aggregated caspase-8 , not directly activating the caspase-3 cascade but followed by cleaving of Bid to tBid and subsequent cytochrome c release that activates caspase-9 and caspase-3 .	Previous studies have revealed the means by which EGCG or other natural agents cause the mitochondria to release cytochrome c : one direct means is mediated by Bcl-2 family proteins; the other is through Fas aggregated caspase-8, not directly activating the caspase-3 cascade but followed by cleaving of Bid to tBid and subsequent cytochrome c release that activates caspase-9 and caspase-3.	55	62	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	55	57	60	61
In the intrinsic pathway , mitochondrial permeabilization causes cytochrome c release , which activates caspase 9 and in turn caspase 3 .	In the intrinsic pathway, mitochondrial permeabilization causes cytochrome c release, which activates caspase 9 and in turn caspase 3.	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	8	10	14	16
The intrinsic cell death pathway involves the permeabilization of mitochondria , resulting in release of proapoptotic factors such as cytochrome c and Smac/Diablo XREF_BIBR - XREF_BIBR into the cytosol , in which cytochrome c initiates apoptosome formation and activation of caspase-9 whereas second mitochondria derived activator of caspase ( Smac ) relieves the inhibition of caspase by the inhibitors of apoptosis proteins ( IAPs ) .	The intrinsic cell death pathway involves the permeabilization of mitochondria, resulting in release of proapoptotic factors such as cytochrome c and Smac/Diablo XREF_BIBR - XREF_BIBR into the cytosol, in which cytochrome c initiates apoptosome formation and activation of caspase-9 whereas second mitochondria derived activator of caspase (Smac) relieves the inhibition of caspase by the inhibitors of apoptosis proteins (IAPs).	32	41	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	32	34	40	41
XREF_BIBR In the present study , our findings suggest that the increased cytosolic level of cytochrome c subsequently activates caspase 9 .	XREF_BIBR In the present study, our findings suggest that the increased cytosolic level of cytochrome c subsequently activates caspase 9.	13	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	level of cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	15	17	19	21
The latter is controlled by pro- and anti-apoptotic Bcl-2 family proteins where , upon an apoptotic stimulus , changes in intrafamily protein interactions at the mitochondrial surface determine the release of cytochrome c. Cytosolic cytochrome c activates the apoptosome complex , initiator caspase 9 and the effector caspases .	The latter is controlled by pro- and anti-apoptotic Bcl-2 family proteins where, upon an apoptotic stimulus, changes in intrafamily protein interactions at the mitochondrial surface determine the release of cytochrome c. Cytosolic cytochrome c activates the apoptosome complex, initiator caspase 9 and the effector caspases.	34	44	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	34	36	42	44
Mitochondrial release of Cytochrome C and other molecules activates Caspase-9 and is an integral part of intrinsic apoptotic pathways XREF_BIBR - XREF_BIBR .	Mitochondrial release of Cytochrome C and other molecules activates Caspase-9 and is an integral part of intrinsic apoptotic pathways XREF_BIBR - XREF_BIBR.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	Caspase-9	Caspase-9	Caspase-9	3	5	9	10
Physiological and pathological regulation of cytochrome c mediated caspase-9 activation .	Physiological and pathological regulation of cytochrome c mediated caspase-9 activation.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	8	9
Mitochondrial dysfunction causes the release of cytochrome c , which activates caspase-9 , in turn fueling apoptosis .	Mitochondrial dysfunction causes the release of cytochrome c, which activates caspase-9, in turn fueling apoptosis.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	6	8	11	12
These findings suggest that the binding of ABRA to AOP-1 promotes apoptosis by inhibiting the mitochondrial antioxidant protein AOP-1 , resulting in the increase of intracellular ROS and the release of cytochrome c from the mitochondria to the cytosol , which activates caspase-9 and caspase-3 .	These findings suggest that the binding of ABRA to AOP-1 promotes apoptosis by inhibiting the mitochondrial antioxidant protein AOP-1, resulting in the increase of intracellular ROS and the release of cytochrome c from the mitochondria to the cytosol, which activates caspase-9 and caspase-3.	29	44	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from the mitochondria to the cytosol	cytochrome c	caspase-9	caspase-9	caspase-9	31	33	42	43
The release of cytochrome c activated caspase-9 , which consequently activated caspase-3/7 with the cleaved poly ( ADP-ribose ) polymerase protein , thereby resulting in apoptosis alteration .	The release of cytochrome c activated caspase-9, which consequently activated caspase-3/7 with the cleaved poly (ADP-ribose) polymerase protein, thereby resulting in apoptosis alteration.	3	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	6	7
Oxidative stress induces the mitochondrial membrane to release cytochrome c , which activates caspase-9 activity and triggers the downstream caspase cascade including the activation of caspase-3 [ XREF_BIBR ] .	Oxidative stress induces the mitochondrial membrane to release cytochrome c, which activates caspase-9 activity and triggers the downstream caspase cascade including the activation of caspase-3 [XREF_BIBR].	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	13	14
The mitochondrial release of cytochrome c into the cytosol could cause activation of caspase-9 ( XREF_FIG ) .	The mitochondrial release of cytochrome c into the cytosol could cause activation of caspase-9 (XREF_FIG).	4	15	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	13	14
The cytochrome C protein then activates caspase-9 as well as the downstream effector caspase-3 , subsequently cleaving poly ( ADP-ribose ) polymerase-1 ( PARP-1 ) , inducing chromatin condensation and DNA chromatin fragmentation [ XREF_BIBR ] .	The cytochrome C protein then activates caspase-9 as well as the downstream effector caspase-3, subsequently cleaving poly (ADP-ribose) polymerase-1 (PARP-1), inducing chromatin condensation and DNA chromatin fragmentation [XREF_BIBR].	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	1	3	6	7
XREF_BIBR , XREF_BIBR , XREF_BIBR Cytochrome c may induce activation of initiator caspase-9 , and the different initiator caspases cleave and activate the executioner caspases (-3, -6 and -7 ) , which irreversibly trigger apoptosis by cleavage of a multitude of death substrates .	XREF_BIBR, XREF_BIBR, XREF_BIBR Cytochrome c may induce activation of initiator caspase-9, and the different initiator caspases cleave and activate the executioner caspases (-3, -6 and -7), which irreversibly trigger apoptosis by cleavage of a multitude of death substrates.	5	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	5	7	12	13
The internal pathway for apoptosis destabilizes the mitochondrial membrane and releases apoptosis associated proteins , such as cytochrome c. Cytochrome c together with apaf-1 induces the activation of Caspase-9 which in turn activate Caspase-3 , causing cell apoptosis XREF_BIBR , XREF_BIBR .	The internal pathway for apoptosis destabilizes the mitochondrial membrane and releases apoptosis associated proteins, such as cytochrome c. Cytochrome c together with apaf-1 induces the activation of Caspase-9 which in turn activate Caspase-3, causing cell apoptosis XREF_BIBR, XREF_BIBR.	19	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Caspase-9	Caspase-9	Caspase-9	19	21	28	29
One of these molecules , cytochrome c , is necessary to activate caspase 9 , 12 which activates the effector caspases 3 and 7 by cleavage .	One of these molecules, cytochrome c, is necessary to activate caspase 9, 12 which activates the effector caspases 3 and 7 by cleavage.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	5	7	12	14
This leads to release of pro apoptotic factors including cytochrome c , that activates caspase 9 and hence caspase 3 XREF_BIBR .	This leads to release of pro apoptotic factors including cytochrome c, that activates caspase 9 and hence caspase 3 XREF_BIBR.	9	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	9	11	14	16
The release of cytochrome c from the mitochondria triggers the activation of caspase 9 in a complex with dATP and Apaf-1 to form the apoptosome .	The release of cytochrome c from the mitochondria triggers the activation of caspase 9 in a complex with dATP and Apaf-1 to form the apoptosome.	1	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from the mitochondria	cytochrome c	caspase 9	caspase 9	caspase 9	3	5	12	14
The release of cytochrome c from mitochondria into the cytoplasm activates caspases by binding to apoptotic protease activating factor 1 ( Apaf-1 ) , inducing it to associate with pro-caspase-9 , thereby triggering caspase-9 activation and initiating the proteolytic cascade that culminates in apoptosis .	The release of cytochrome c from mitochondria into the cytoplasm activates caspases by binding to apoptotic protease activating factor 1 (Apaf-1), inducing it to associate with pro-caspase-9, thereby triggering caspase-9 activation and initiating the proteolytic cascade that culminates in apoptosis.	1	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	33	34
Addition of cytochrome c caused the activation of caspase-9 and -3 in permeabilized NRCM and H9c2 cardiomyoblasts but not in permeabilized ARCM .	Addition of cytochrome c caused the activation of caspase-9 and -3 in permeabilized NRCM and H9c2 cardiomyoblasts but not in permeabilized ARCM.	2	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	8	9
Cytochrome c activates caspase 9 , which cleaves and activates downstream effector proteases including caspase 3 , leading to apoptosis .	Cytochrome c activates caspase 9, which cleaves and activates downstream effector proteases including caspase 3, leading to apoptosis.	0	17	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	3	5
Treatment of SK-N-BE2 and IMR-32 cells with 75 muMu wogonin for 48 h significantly promoted apoptosis , the release of cytochrome c , altered the expression of certain members of Bcl-2 family ( Bcl-2 , Bax and Bid ) , and increased the activation of caspase-3 , caspase-8 , caspase-9 , and PARP-1 , which demonstrated that the cytotoxic effect of wogonin in SK-N-BE2 and IMR-32 cells is mediated by mitochondrial dysfunction .	Treatment of SK-N-BE2 and IMR-32 cells with 75 muMu wogonin for 48 h significantly promoted apoptosis, the release of cytochrome c, altered the expression of certain members of Bcl-2 family (Bcl-2, Bax and Bid), and increased the activation of caspase-3, caspase-8, caspase-9, and PARP-1, which demonstrated that the cytotoxic effect of wogonin in SK-N-BE2 and IMR-32 cells is mediated by mitochondrial dysfunction.	20	55	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	20	22	49	50
Some studies showed that overexpression of Hsp27 and Hsp20 prevents the cytochrome c activation of Caspase 9 and 3 playing a central role in the execution of apoptosis [ XREF_BIBR ] .	Some studies showed that overexpression of Hsp27 and Hsp20 prevents the cytochrome c activation of Caspase 9 and 3 playing a central role in the execution of apoptosis [XREF_BIBR].	11	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Caspase 9	Caspase 9	Caspase 9	11	13	15	17
Cytosolic cytochrome c activates caspase 9 and 3/7 , which triggers the apoptotic machinery ( XREF_FIG ) .	Cytosolic cytochrome c activates caspase 9 and 3/7, which triggers the apoptotic machinery (XREF_FIG).	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	1	3	4	6
The release of cytochrome c from apoptotic cells triggers sequential maturation of caspase-9 and caspase-3 in caspase dependent cell death events .	The release of cytochrome c from apoptotic cells triggers sequential maturation of caspase-9 and caspase-3 in caspase dependent cell death events.	3	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	12	13
Liberated cytochrome c , in turn , initiates caspase-9 activation via apoptosome formation .	Liberated cytochrome c, in turn, initiates caspase-9 activation via apoptosome formation.	1	9	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	8	9
Cytochrome c triggers the activation of caspase-9 by forming the cytochrome c/apoptotic protease activating factor ( Apaf-1 )/caspase-9-containing apoptosome complex .	Cytochrome c triggers the activation of caspase-9 by forming the cytochrome c/apoptotic protease activating factor (Apaf-1)/caspase-9-containing apoptosome complex.	0	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	6	7
Cytochrome c , which activates caspase-9 XREF_BIBR , may contribute to the sensitization of A-375-TS and A-375 .	Cytochrome c, which activates caspase-9 XREF_BIBR, may contribute to the sensitization of A-375-TS and A-375.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	5	6
Release of cytochrome c activates caspase-9 followed by activation of caspase-3 , which ensures the execution of apoptosis by PARP cleavage XREF_BIBR .	Release of cytochrome c activates caspase-9 followed by activation of caspase-3, which ensures the execution of apoptosis by PARP cleavage XREF_BIBR.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	5	6
In addition , cytochrome c released from depolarized mitochondria directly activates caspase 9 .	In addition, cytochrome c released from depolarized mitochondria directly activates caspase 9.	3	13	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	3	5	11	13
Either the duration or the amount of cytochrome c transduced into the cell was insufficient to trigger detectable caspase-9 cleavage .	Either the duration or the amount of cytochrome c transduced into the cell was insufficient to trigger detectable caspase-9 cleavage.	5	19	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	amount of cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	7	9	18	19
Release of cytochrome-c from the mitochondria to the cytoplasm initiates a caspase-9 cascade .	Release of cytochrome-c from the mitochondria to the cytoplasm initiates a caspase-9 cascade.	0	12	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome-c	Release of cytochrome-c from the mitochondria to the cytoplasm	cytochrome-c	caspase-9	caspase-9	caspase-9	2	3	11	12
Then , the released cytochrome c activates caspase 9 , which causes caspase 3 cleavage and eventually apoptosis 43 .	Then, the released cytochrome c activates caspase 9, which causes caspase 3 cleavage and eventually apoptosis 43.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	4	6	7	9
Similarly , both cytochrome c and Smac-N7 peptide increased the activity of caspase-9 and -3 in permeabilized NRCM ( XREF_FIG ) .	Similarly, both cytochrome c and Smac-N7 peptide increased the activity of caspase-9 and -3 in permeabilized NRCM (XREF_FIG).	3	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	12	13
The release of cytochrome C could activate caspase-9 and increase apoptosis .	The release of cytochrome C could activate caspase-9 and increase apoptosis.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	3	5	7	8
Second , addition of cytochrome c failed to induce caspase-9 activation , caspase-3 processing , or PARP cleavage in extracts from cells expressing active Akt .	Second, addition of cytochrome c failed to induce caspase-9 activation, caspase-3 processing, or PARP cleavage in extracts from cells expressing active Akt.	4	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	4	6	9	10
Cytochrome c in the cytosol is thought to activate downstream caspase-9 and caspase-3 , leading to apoptosis .	Cytochrome c in the cytosol is thought to activate downstream caspase-9 and caspase-3, leading to apoptosis.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	10	11
In cell-free systems supplemented with ATP caspase-9 activation is induced by addition of cytochrome c and we show that in this process PP1alpha is indispensable for triggering caspase-9 as well as caspase-3 cleavage and activation .	In cell-free systems supplemented with ATP caspase-9 activation is induced by addition of cytochrome c and we show that in this process PP1alpha is indispensable for triggering caspase-9 as well as caspase-3 cleavage and activation.	6	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	13	15	6	7
Silencing of cytochrome c inhibited the activation of pro caspase 3 and pro caspase 9 in SL-1 cells induced by AfMNPV .	Silencing of cytochrome c inhibited the activation of pro caspase 3 and pro caspase 9 in SL-1 cells induced by AfMNPV.	2	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	2	4	13	15
ZD55-ST13 induced the upregulation of Hsp70 , the downregulation of antiapoptotic gene Bcl-2 , and the release of cytochrome c. Cytochrome c triggered apoptosis by activating caspase-9 and caspase-3 , which cleave the enzyme poly ( ADP-ribose ) polymerase in ZD55-ST13-infected SW620 cells .	ZD55-ST13 induced the upregulation of Hsp70, the downregulation of antiapoptotic gene Bcl-2, and the release of cytochrome c. Cytochrome c triggered apoptosis by activating caspase-9 and caspase-3, which cleave the enzyme poly (ADP-ribose) polymerase in ZD55-ST13-infected SW620 cells.	20	31	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	20	22	26	27
In general , cytochrome C release from the mitochondria to the cytosol activates caspase-9 , which has been established as a major step in apoptosis .	In general, cytochrome C release from the mitochondria to the cytosol activates caspase-9, which has been established as a major step in apoptosis.	3	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C release from the mitochondria to the cytosol	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	13	14
The cytochrome C release results in the formation of the apoptosome and the activation of caspase-9 , which in turn cleaves and activates the effector caspases .	The cytochrome C release results in the formation of the apoptosome and the activation of caspase-9, which in turn cleaves and activates the effector caspases.	1	16	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	1	3	15	16
In turn , cytochrome c induced the processing of pro-caspase-9 and pro-caspase-3 , followed by the cleavage of poly-( ADP-ribose ) polymerase ( PARP ) and DNA fragmentation factor ( DFF-45 ) .	In turn, cytochrome c induced the processing of pro-caspase-9 and pro-caspase-3, followed by the cleavage of poly-(ADP-ribose) polymerase (PARP) and DNA fragmentation factor (DFF-45).	3	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	pro-caspase-9	pro-caspase-9	pro-caspase-9	3	5	9	10
Interacting with Bcl-xl and Mcl-1 , Bim initiates cytochrome c release from mitochondria , activates Caspase 9 and consequently triggers mitochondrial apoptotic pathway [ XREF_BIBR ] .	Interacting with Bcl-xl and Mcl-1, Bim initiates cytochrome c release from mitochondria, activates Caspase 9 and consequently triggers mitochondrial apoptotic pathway [XREF_BIBR].	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	Bim initiates cytochrome c release from mitochondria	cytochrome c	Caspase 9	Caspase 9	caspase 9	8	10	15	17
Cytochrome c then joins the holoenzyme , known as the apoptosome , to promote the self-cleavage of caspase-9 .	Cytochrome c then joins the holoenzyme, known as the apoptosome, to promote the self-cleavage of caspase-9.	0	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	17	18
Upon mitochondrial stress through disruption of Ca 2+ homeostasis , the release of cytochrome c may interact with Apaf-1 , causing self-cleavage and activation of caspase-9 .	Upon mitochondrial stress through disruption of Ca 2+ homeostasis, the release of cytochrome c may interact with Apaf-1, causing self-cleavage and activation of caspase-9.	13	26	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	13	15	25	26
Cytochrome c released from the mitochondria triggering the activation of caspase-9 by association with APAF-1 in an ATP dependent manner [ XREF_BIBR , XREF_BIBR ] .	Cytochrome c released from the mitochondria triggering the activation of caspase-9 by association with APAF-1 in an ATP dependent manner [XREF_BIBR, XREF_BIBR].	0	11	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c released from the mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	0	2	10	11
Cytosolic cytochrome c and Smac/Diablo released from the mitochondria promote the activation of caspase-9 [ XREF_BIBR , XREF_BIBR ] .	Cytosolic cytochrome c and Smac/Diablo released from the mitochondria promote the activation of caspase-9 [XREF_BIBR, XREF_BIBR].	1	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	13	14
Treatment of mammalian S100 extracts with RNase strongly increased cytochrome c induced caspase-9 activation , while the addition of RNA to the extracts impaired caspase-9 activation .	Treatment of mammalian S100 extracts with RNase strongly increased cytochrome c induced caspase-9 activation, while the addition of RNA to the extracts impaired caspase-9 activation.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	9	11	12	13
The granulosa cells go through the mitochondria dependent apoptosis pathway ; the indicated pro apoptosis protein Bax was expressed and induced cytochrome c release from mitochondria , which then activated caspase-9 and caspase-3 until cell death occurred .	The granulosa cells go through the mitochondria dependent apoptosis pathway; the indicated pro apoptosis protein Bax was expressed and induced cytochrome c release from mitochondria, which then activated caspase-9 and caspase-3 until cell death occurred.	21	32	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c release from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	21	23	30	31
Cyc combined with Apaf-1 and subsequently activated caspase-9 to initiate downstream effector caspases to cause the cell apoptosis [ XREF_BIBR , XREF_BIBR ] .	Cyc combined with Apaf-1 and subsequently activated caspase-9 to initiate downstream effector caspases to cause the cell apoptosis [XREF_BIBR, XREF_BIBR].	0	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cyc	Cyc	Cyc	caspase-9	caspase-9	caspase-9	0	1	7	8
Cytochrome c promotes the activation of the initiator caspase-9 in a direct fashion via the assembly of the apoptosome , whereas Smac/Diablo favors the caspase cascade indirectly by antagonizing the activity of endogenous inhibitors of caspases , such as Inhibitor of Apoptosis Proteins .	Cytochrome c promotes the activation of the initiator caspase-9 in a direct fashion via the assembly of the apoptosome, whereas Smac/Diablo favors the caspase cascade indirectly by antagonizing the activity of endogenous inhibitors of caspases, such as Inhibitor of Apoptosis Proteins.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	8	9
The released cytochrome c triggered the activation of caspase 9 followed by the executioner caspase 3/7 .	The released cytochrome c triggered the activation of caspase 9 followed by the executioner caspase 3/7.	2	10	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	2	4	8	10
Another possible pathway is the release of cytochrome c , which subsequently activates caspase-9 and caspase-3 .	Another possible pathway is the release of cytochrome c, which subsequently activates caspase-9 and caspase-3.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	7	9	13	14
The complex formation between phosphorylated BIM EL and BAX triggers a conformational change in BAX , leading to the dysfunction of MOMP and the release of cytochrome c. Finally , ATO and BSO treated cells undergo apoptosis via activation of cytochrome c mediated caspase 9 , caspase 3 and PARP .	The complex formation between phosphorylated BIM EL and BAX triggers a conformational change in BAX, leading to the dysfunction of MOMP and the release of cytochrome c. Finally, ATO and BSO treated cells undergo apoptosis via activation of cytochrome c mediated caspase 9, caspase 3 and PARP.	40	49	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	40	42	43	45
Cytochrome c along with apoptosis protease activating factor ( APAF-1 ) and pro caspase 9 form an apoptosome which activates caspase 9 .	Cytochrome c along with apoptosis protease activating factor (APAF-1) and pro caspase 9 form an apoptosome which activates caspase 9.	0	15	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	13	15
AM significantly stimulated the cells to release cytochrome c from mitochondria into cytosol during early apoptosis , cytochrome c release to the cytosol stimulates caspase-9 , which in turn leads to activation of the downstream caspase-3/7 .	AM significantly stimulated the cells to release cytochrome c from mitochondria into cytosol during early apoptosis, cytochrome c release to the cytosol stimulates caspase-9, which in turn leads to activation of the downstream caspase-3/7.	17	29	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c release to the cytosol	cytochrome c	caspase-9	caspase-9	caspase-9	17	19	24	25
The intrinsic pathway occurs when cytochrome c released from mitochondria to the cytosol acts with Apaf-1 to promote the activation of caspase-9 and the downstream members caspase-3 and -7 .	The intrinsic pathway occurs when cytochrome c released from mitochondria to the cytosol acts with Apaf-1 to promote the activation of caspase-9 and the downstream members caspase-3 and -7.	5	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	21	22
The other involves cytochrome c release dependent activation of caspase 9 through Apaf-1 [ XREF_BIBR , XREF_BIBR ] .	The other involves cytochrome c release dependent activation of caspase 9 through Apaf-1 [XREF_BIBR, XREF_BIBR].	3	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	3	5	9	11
Intrinsic pathway activation may have mitochondrial damage as a pre-requisite , leading to the activation of pro apoptotic members of the Bcl-2 family and/or inactivation of anti-apoptotic Bcl-2 and results in the mitochondrial release of cytochrome C which in turn activates initiator caspase-9 [ XREF_BIBR ] as seen in SKOV-3 cells following HNTMB treatment .	Intrinsic pathway activation may have mitochondrial damage as a pre-requisite, leading to the activation of pro apoptotic members of the Bcl-2 family and/or inactivation of anti-apoptotic Bcl-2 and results in the mitochondrial release of cytochrome C which in turn activates initiator caspase-9 [XREF_BIBR] as seen in SKOV-3 cells following HNTMB treatment.	33	44	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	35	37	42	43
Furthermore , Bcl-2 overexpression significantly improved cellular viability through inhibition of hypoxia or cotreatment with CRP induced Bax and Bcl -2 ratio changes and cytochrome c release from mitochondria to cytosol , and significantly blocked the activity of Caspase-9 and Caspase-3 .	Furthermore, Bcl-2 overexpression significantly improved cellular viability through inhibition of hypoxia or cotreatment with CRP induced Bax and Bcl -2 ratio changes and cytochrome c release from mitochondria to cytosol, and significantly blocked the activity of Caspase-9 and Caspase-3.	15	40	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cytochrome c	CRP induced Bax and Bcl -2 ratio changes and cytochrome c release from mitochondria	cytochrome c	Caspase-9	Caspase-9	caspase-9	24	26	38	39
Interestingly , the release of cytochrome c did not activate caspase-9 and -3 , the main caspases involved in apoptosis .	Interestingly, the release of cytochrome c did not activate caspase-9 and -3, the main caspases involved in apoptosis.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	10	11
GA triggered cytosolic release of apoptotic molecules , cytochrome c , promoted activation of caspase-9 and caspase-3 , and ultimately apoptotic cell death .	GA triggered cytosolic release of apoptotic molecules, cytochrome c, promoted activation of caspase-9 and caspase-3, and ultimately apoptotic cell death.	8	16	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	14	15
It is widely accepted that Abeta mediated loss of mitochondrial membrane potential promotes mitochondrial apoptosis , during which cytoplasmic release of cytochrome c activates caspase-9 and downstream caspase-3 47 .	It is widely accepted that Abeta mediated loss of mitochondrial membrane potential promotes mitochondrial apoptosis, during which cytoplasmic release of cytochrome c activates caspase-9 and downstream caspase-3 47.	21	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	21	23	24	25
Our results revealed that C1 controls the MMP via the up regulation of Bax and Bad , and the down regulation of Bcl2 in addition to the control of cytochrome c release from the mitochondria to the cytosol , which then triggers caspase 9 .	Our results revealed that C1 controls the MMP via the up regulation of Bax and Bad, and the down regulation of Bcl2 in addition to the control of cytochrome c release from the mitochondria to the cytosol, which then triggers caspase 9.	29	44	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c release from the mitochondria to the cytosol	cytochrome c	caspase 9	caspase 9	caspase 9	29	31	42	44
In the apoptosis process , the release of cytochrome c induced the activation of caspase-9 and then activates caspase-3 [ XREF_BIBR ] .	In the apoptosis process, the release of cytochrome c induced the activation of caspase-9 and then activates caspase-3 [XREF_BIBR].	8	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	14	15
Bak also regulates the release of cytochrome c. Cytochrome c release , in turn , activates caspase-9 and -3 .	Bak also regulates the release of cytochrome c. Cytochrome c release, in turn, activates caspase-9 and -3.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	8	10	16	17
In addition , combined treatment with IR and beta-lap also caused the release of cytochrome c , expected to initiate activation of caspase-9 ( XREF_FIG ) .	In addition, combined treatment with IR and beta-lap also caused the release of cytochrome c, expected to initiate activation of caspase-9 (XREF_FIG).	14	24	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	14	16	22	23
Release of mitochondrial cytochrome c triggers assembly of a caspase-9 and activating complex and subsequent activation of the downstream caspase cascade .	Release of mitochondrial cytochrome c triggers assembly of a caspase-9 and activating complex and subsequent activation of the downstream caspase cascade.	3	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	9	10
Cytochrome c forms complexes with apaf-1 and procaspase 9 to form a large multicomponent structure known as the apoptosome , causing the activation of caspase 9 [ XREF_BIBR , XREF_BIBR ] .	Cytochrome c forms complexes with apaf-1 and procaspase 9 to form a large multicomponent structure known as the apoptosome, causing the activation of caspase 9 [XREF_BIBR, XREF_BIBR].	0	27	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	24	26
One such factor is cytochrome c ( Cyto c ) , which upon its release from the mitochondria , leads to the conversion of Pro-Caspase-9 ( Pro-Casp-9 ) to Caspase-9 ( Casp-9 ) , which in turn cleaves Pro-Caspase-3 ( Pro-Casp-3 ) to Caspase-3 ( Casp-3 ) XREF_BIBR .	One such factor is cytochrome c (Cyto c), which upon its release from the mitochondria, leads to the conversion of Pro-Caspase-9 (Pro-Casp-9) to Caspase-9 (Casp-9), which in turn cleaves Pro-Caspase-3 (Pro-Casp-3) to Caspase-3 (Casp-3) XREF_BIBR.	4	37	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	Casp-9	Casp-9	Casp-9	4	6	31	32
As shown in XREF_FIG and XREF_TABLE , FZQJ remarkably increased the levels of cytoplasm cytochrome c , activated caspase 9 and 3 , and increased the cleavage of PARP .	As shown in XREF_FIG and XREF_TABLE, FZQJ remarkably increased the levels of cytoplasm cytochrome c, activated caspase 9 and 3, and increased the cleavage of PARP.	7	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	FZQJ remarkably increased the levels of cytoplasm cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	14	16	18	20
Cytochrome c in turn activates the apoptotic cascade of caspase-9 and -3 , leading to cell death .	Cytochrome c in turn activates the apoptotic cascade of caspase-9 and -3, leading to cell death.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	9	10
Cytochrome c leads to the activation of caspase-9 , which then triggers a cascade of caspase activation ( caspase-3 , caspase-6 , caspase-7 ) , resulting in the morphological and biochemical changes associated with apoptosis [ XREF_BIBR , XREF_BIBR ] .	Cytochrome c leads to the activation of caspase-9, which then triggers a cascade of caspase activation (caspase-3, caspase-6, caspase-7), resulting in the morphological and biochemical changes associated with apoptosis [XREF_BIBR, XREF_BIBR].	0	11	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	7	8
Cytochrome c in the cytosol can activate Caspase-9 , which in turn cleaves and activates the key executioner , Caspase-3 , and the sequential activation of Caspase-9 and Caspase-3 leads to apoptosis XREF_BIBR , XREF_BIBR .	Cytochrome c in the cytosol can activate Caspase-9, which in turn cleaves and activates the key executioner, Caspase-3, and the sequential activation of Caspase-9 and Caspase-3 leads to apoptosis XREF_BIBR, XREF_BIBR.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	Caspase-9	Caspase-9	Caspase-9	0	2	7	8
Results showed that PCC enhanced the release of mitochondrial cytochrome c which activated caspase 9 by 4.8-5.0 fold in both liver cancer cells XREF_BIBR .	Results showed that PCC enhanced the release of mitochondrial cytochrome c which activated caspase 9 by 4.8-5.0 fold in both liver cancer cells XREF_BIBR.	9	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	9	11	13	15
The delivery of cytochrome C from the mitochondrial intermembrane to the cytosol will cause the activation of caspase-9 , which targets critical cellular death substrates and contributes to apoptosis .	The delivery of cytochrome C from the mitochondrial intermembrane to the cytosol will cause the activation of caspase-9, which targets critical cellular death substrates and contributes to apoptosis.	3	26	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	3	5	17	18
During malaria , the depletion of cardiolipin and formation of the mitochondrial permeability transition pore favor cytochrome c release to activate caspase-9 .	During malaria, the depletion of cardiolipin and formation of the mitochondrial permeability transition pore favor cytochrome c release to activate caspase-9.	6	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	16	18	21	22
In addition , following reovirus infection , the mitochondrial pro apoptotic proteins cytochrome c and second mitochondrion derived activator of caspase ( Smac/DIABLO ) are released , without disturbance of the mitochondrial membrane potential or release of apoptosis inducing factor ( AIF ) , and eventually activate downstream effector caspases with or without caspase-9 ( caspase-9 is activated by cytochrome c but has been shown to be dispensable in the mitochondrial associated pathway ) .	In addition, following reovirus infection, the mitochondrial pro apoptotic proteins cytochrome c and second mitochondrion derived activator of caspase (Smac/DIABLO) are released, without disturbance of the mitochondrial membrane potential or release of apoptosis inducing factor (AIF), and eventually activate downstream effector caspases with or without caspase-9 (caspase-9 is activated by cytochrome c but has been shown to be dispensable in the mitochondrial associated pathway).	55	67	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	59	61	55	56
Oxidation of cytochrome c by cytochrome c oxidase activates the apoptosome and caspase-9 cascade .	Oxidation of cytochrome c by cytochrome c oxidase activates the apoptosome and caspase-9 cascade.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	12	13
Since caspase-9 is the initiator caspase for cleaving and activating caspase-3 , we examined whether caspase-9 activation by cytochrome c and dATP was inhibited in extracts prepared from Akt-stable lines ( XREF_FIG D ) .	Since caspase-9 is the initiator caspase for cleaving and activating caspase-3, we examined whether caspase-9 activation by cytochrome c and dATP was inhibited in extracts prepared from Akt-stable lines (XREF_FIG D).	15	20	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	18	20	15	16
Mistletoe extract seems to induce apoptosis via activation of death pathways , possibly through activation of caspase 8 and subsequently activation of other cascade of caspases in apoptotic process and by loss of mitochondrial potential which , in turn , release cytochrome C into cytosol and activate caspase 9 .	Mistletoe extract seems to induce apoptosis via activation of death pathways, possibly through activation of caspase 8 and subsequently activation of other cascade of caspases in apoptotic process and by loss of mitochondrial potential which, in turn, release cytochrome C into cytosol and activate caspase 9.	40	49	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase 9	caspase 9	caspase 9	41	43	47	49
Regulation of cytochrome c mediated caspase-9 activation occurs both before and after cytochrome c release .	Regulation of cytochrome c mediated caspase-9 activation occurs both before and after cytochrome c release.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	5	6
The released cytochrome c from mitochondria promotes caspase 9 activation , which then activates downstream caspase proteins such as caspase 3 XREF_BIBR .	The released cytochrome c from mitochondria promotes caspase 9 activation, which then activates downstream caspase proteins such as caspase 3 XREF_BIBR.	2	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	2	4	7	9
Upon entering the cytosol , cytochrome c activates caspase-9 , then triggers activation of caspase-7 , and consequently cleaves specific substrates leading to apoptosis through the intrinsic pathway .	Upon entering the cytosol, cytochrome c activates caspase-9, then triggers activation of caspase-7, and consequently cleaves specific substrates leading to apoptosis through the intrinsic pathway.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	8	9
Our current observation of an increase in cytosolic level of cytochrome c ( XREF_FIG ) is in agreement with our previous study demonstrating that the release of cytochrome c from mitochondria to cytosol can activate caspase-9 for apoptosis .	Our current observation of an increase in cytosolic level of cytochrome c (XREF_FIG) is in agreement with our previous study demonstrating that the release of cytochrome c from mitochondria to cytosol can activate caspase-9 for apoptosis.	25	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from mitochondria to cytosol	cytochrome c	caspase-9	caspase-9	caspase-9	27	29	35	36
Caspase 2 is activated , which in turn signals the mitochondria to decrease the membrane potential and trigger the release of cytochrome c. Cytochrome c activates caspase 9 causing the executioner caspases 3 and 7 to initiate programed cell death .	Caspase 2 is activated, which in turn signals the mitochondria to decrease the membrane potential and trigger the release of cytochrome c. Cytochrome c activates caspase 9 causing the executioner caspases 3 and 7 to initiate programed cell death.	23	28	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	23	25	26	28
Due to the changes in permeability of the mitochondrial membrane , cytochrome c , one of the pro apoptotic molecules , is released from the mitochondria in order to trigger caspase-9 activation , leading to caspase-3 activation .	Due to the changes in permeability of the mitochondrial membrane, cytochrome c, one of the pro apoptotic molecules, is released from the mitochondria in order to trigger caspase-9 activation, leading to caspase-3 activation.	11	31	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	11	13	30	31
The release of cytochrome c from mitochondria in turn causes activation of caspase-9 [ XREF_BIBR , XREF_BIBR ] .	The release of cytochrome c from mitochondria in turn causes activation of caspase-9 [XREF_BIBR, XREF_BIBR].	1	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	release of cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	3	5	12	13
Treatment of cancer cells with COX inhibitors induces cytochrome C release from mitochondria , which in turn activates caspase-9 and then caspase-3 [ XREF_BIBR - XREF_BIBR ] .	Treatment of cancer cells with COX inhibitors induces cytochrome C release from mitochondria, which in turn activates caspase-9 and then caspase-3 [XREF_BIBR - XREF_BIBR].	5	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	COX inhibitors induces cytochrome C release from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	18	19
Upon release from the mitochondria into the cytoplasm , cytochrome c combines with Apaf-1 to promote caspase-9 activation , which , in turn , activates effector caspases XREF_BIBR , XREF_BIBR to trigger a cascade of proteolytic events .	Upon release from the mitochondria into the cytoplasm, cytochrome c combines with Apaf-1 to promote caspase-9 activation, which, in turn, activates effector caspases XREF_BIBR, XREF_BIBR to trigger a cascade of proteolytic events.	9	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	9	11	16	17
Cytosolic cytochrome c activates caspase-9 and subsequently , it cleaves and activates caspase-3 and caspase-7 .	Cytosolic cytochrome c activates caspase-9 and subsequently, it cleaves and activates caspase-3 and caspase-7.	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	4	5
Finally , we checked whether NEK7 had any effect on the cleavage of caspase-9 which it did not , nor did it affect the cleavage of caspase-9 triggered by the addition of cytochrome c ( XREF_FIG ) .	Finally, we checked whether NEK7 had any effect on the cleavage of caspase-9 which it did not, nor did it affect the cleavage of caspase-9 triggered by the addition of cytochrome c (XREF_FIG).	24	34	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	32	34	26	27
In mitochondrion dependent apoptosis , cytochrome c released from the mitochondria can activate the initiator caspase-9 and the effector caspase-3 , which play key roles in both intrinsic and extrinsic pathways [ XREF_BIBR , XREF_BIBR ] .	In mitochondrion dependent apoptosis, cytochrome c released from the mitochondria can activate the initiator caspase-9 and the effector caspase-3, which play key roles in both intrinsic and extrinsic pathways [XREF_BIBR, XREF_BIBR].	5	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	15	16
Together , these data indicate that a parasite effector can directly prevent cytochrome c triggered caspase 9 activation both during and after onset of apoptosome assembly .	Together, these data indicate that a parasite effector can directly prevent cytochrome c triggered caspase 9 activation both during and after onset of apoptosome assembly.	12	17	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	12	14	15	17
Chemotherapeutic agents and UV irradiation cause release of mitochondrial cytochrome c , which then binds the adapter molecule apoptotic proteinase activating factor-1 ( Apaf-1 ) , and this complex along with adenine nucleotides promotes caspase-9 autoactivation .	Chemotherapeutic agents and UV irradiation cause release of mitochondrial cytochrome c, which then binds the adapter molecule apoptotic proteinase activating factor-1 (Apaf-1), and this complex along with adenine nucleotides promotes caspase-9 autoactivation.	9	35	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	9	11	34	35
Cytochrome c release mediates caspase-9 activation , while the apoptosis inhibitors from Bcl-2 family prevent the efflux of cytochrome c from mitochondria .	Cytochrome c release mediates caspase-9 activation, while the apoptosis inhibitors from Bcl-2 family prevent the efflux of cytochrome c from mitochondria.	0	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	4	5
Cytochrome c subsequently activates caspase 9 and downstream executioner caspase-3/7 , leading to apoptotic changes .	Cytochrome c subsequently activates caspase 9 and downstream executioner caspase-3/7, leading to apoptotic changes.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase 9	caspase 9	caspase 9	0	2	4	6
Cytochrome c , which is included among the main initiator factors of apoptosis , mediates the activation of caspase-9 promoting the chain activation of caspases , including caspase-3 which leads cellular suicide .	Cytochrome c, which is included among the main initiator factors of apoptosis, mediates the activation of caspase-9 promoting the chain activation of caspases, including caspase-3 which leads cellular suicide.	0	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	18	19
Cytochrome C release from mitochondrial inter-membrane spaces then activates caspase-9 , further activating the downstream effector caspase-3 in order to cleave poly ( ADP-ribose ) polymerase-1 ( PARP-1 ) that is further activated [ XREF_BIBR ] .	Cytochrome C release from mitochondrial inter-membrane spaces then activates caspase-9, further activating the downstream effector caspase-3 in order to cleave poly (ADP-ribose) polymerase-1 (PARP-1) that is further activated [XREF_BIBR].	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cytochrome C	Cytochrome C	Cytochrome C	caspase-9	caspase-9	caspase-9	0	2	9	10
Cytosolic cytochrome c activates caspase-9 in the Apaf-1apoptosome , which subsequently triggers activation of the downstream executioner caspase-3 [ XREF_BIBR , XREF_BIBR ] .	Cytosolic cytochrome c activates caspase-9 in the Apaf-1apoptosome, which subsequently triggers activation of the downstream executioner caspase-3 [XREF_BIBR, XREF_BIBR].	1	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	1	3	4	5
DAAM1 activates small G protein Rho and then Rho associated kinase ( ROCK ) .	DAAM1 activates small G protein Rho and then Rho associated kinase (ROCK).	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAAM1	DAAM1	DAAM1	Rho	Rho	Rho	0	1	5	6
Similarly , the complex of Dishevelled and Daam1 can upregulate RhoA , ROCK and Myosin II activity .	Similarly, the complex of Dishevelled and Daam1 can upregulate RhoA, ROCK and Myosin II activity.	3	16	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	RhoA	RhoA	RhoA	7	8	10	11
Together , these data strongly suggested that Daam1 was required to induce RhoA activation and participated in Wnt5a induced MDA-MB-231 and MCF-7 migration .	Together, these data strongly suggested that Daam1 was required to induce RhoA activation and participated in Wnt5a induced MDA-MB-231 and MCF-7 migration.	7	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	RhoA	RhoA	RhoA	7	8	12	13
In addition to its direct role in Actin polymerization , Daam1 also independently activates RhoA GTPase activity [ XREF_BIBR ] .	In addition to its direct role in Actin polymerization, Daam1 also independently activates RhoA GTPase activity [XREF_BIBR].	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	RhoA	RhoA	RhoA	10	11	14	15
While early studies indicated that DAAM1 was necessary and sufficient for Wnt ligands to activate RhoA , RhoA signaling was unaffected in the hearts of Daam1 beta-geo and betageo mice .	While early studies indicated that DAAM1 was necessary and sufficient for Wnt ligands to activate RhoA, RhoA signaling was unaffected in the hearts of Daam1 beta-geo and betageo mice.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAAM1	DAAM1	DAAM1	RhoA	RhoA	RhoA	5	6	15	16
Then , we examined whether Daam1 could activate RhoA in other human breast cancer cells .	Then, we examined whether Daam1 could activate RhoA in other human breast cancer cells.	5	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	RhoA	RhoA	RhoA	5	6	8	9
Daam1 mediated nucleation of actin filaments , activated by Rho , may contribute to filament assembly at this step ; a positive feedback loop involving Daam1 activation of Rho and Rho activation of Daam1 to further promote actin assembly , may also be triggered as well .	Daam1 mediated nucleation of actin filaments, activated by Rho, may contribute to filament assembly at this step; a positive feedback loop involving Daam1 activation of Rho and Rho activation of Daam1 to further promote actin assembly, may also be triggered as well.	25	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	Rho	Rho	Rho	25	26	28	29
Rac1 activates c-Jun N-terminal kinase , leading to actin polymerization , 22 while DAAM1 activates Rho , which in turn activates Rho associated kinase ( ROCK ) to regulate cellular cytoskeletal arrangements .	Rac1 activates c-Jun N-terminal kinase, leading to actin polymerization, 22 while DAAM1 activates Rho, which in turn activates Rho associated kinase (ROCK) to regulate cellular cytoskeletal arrangements.	13	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAAM1	DAAM1	DAAM1	Rho	Rho	Rho	13	14	15	16
This included not only the genes encoding core PCP transmembrane proteins such as Vangl2 , Frizzled-3 ( Fzd3 ) and Frizzled-6 ( Fzd6 ) , and flamingo homologue Celsr-1 , but also intracellular intermediates dishevelled-1 ( Dvl1 ) , dishevelled-2 ( Dvl2 ) and dishevelled-3 ( Dvl3 ) , DAAM1 and downstream mediators of signalling , RhoA , protein tyrosine kinase 7 ( Ptk7 ) , ROCK1 and ROCK2 .	This included not only the genes encoding core PCP transmembrane proteins such as Vangl2, Frizzled-3 (Fzd3) and Frizzled-6 (Fzd6), and flamingo homologue Celsr-1, but also intracellular intermediates dishevelled-1 (Dvl1), dishevelled-2 (Dvl2) and dishevelled-3 (Dvl3), DAAM1 and downstream mediators of signalling, RhoA, protein tyrosine kinase 7 (Ptk7), ROCK1 and ROCK2.	49	57	mediators	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	DAAM1	DAAM1	DAAM1	RhoA	RhoA	RhoA	49	50	56	57
Although studies performed in frog embryos and cultured cells indicated that DAAM1 is required for Wnt ligands to activate RhoA signaling , genetic interaction studies of the Drosophila Daam1 homolog suggest that DAAM proteins acts downstream of RhoA in a manner consistent with other FH proteins .	Although studies performed in frog embryos and cultured cells indicated that DAAM1 is required for Wnt ligands to activate RhoA signaling, genetic interaction studies of the Drosophila Daam1 homolog suggest that DAAM proteins acts downstream of RhoA in a manner consistent with other FH proteins.	11	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAAM1	DAAM1	DAAM1	RhoA	RhoA	RhoA	11	12	19	20
Daam1 activates RhoA to regulate Wnt5a induced glioblastoma cell invasion .	Daam1 activates RhoA to regulate Wnt5a induced glioblastoma cell invasion.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	RhoA	RhoA	RhoA	0	1	2	3
In the PCP pathway , Wnt mediated activation of Fzd and Dvl promotes the formation of the scaffold protein and Daam1 complex , which in turn activates the G protein Rho .	In the PCP pathway, Wnt mediated activation of Fzd and Dvl promotes the formation of the scaffold protein and Daam1 complex, which in turn activates the G protein Rho.	20	31	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	Rho	Rho	Rho	20	21	30	31
Because NPHP4 can target Dvl for degradation , NPHP4 could antagonize Dvl2 and Daam1 mediated Rho activation to redirect the function of Daam1 in a spatially restricted manner .	Because NPHP4 can target Dvl for degradation, NPHP4 could antagonize Dvl2 and Daam1 mediated Rho activation to redirect the function of Daam1 in a spatially restricted manner.	10	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	Rho	Rho	Rho	13	14	15	16
In our study , specific downregulation of Dvl2 and Daam1 signaling in MDA-MB-231 cells suppresses Wnt5a induced activation of RhoA , and upregulation of Daam1 in MCF-7 cells induces RhoA activation .	In our study, specific downregulation of Dvl2 and Daam1 signaling in MDA-MB-231 cells suppresses Wnt5a induced activation of RhoA, and upregulation of Daam1 in MCF-7 cells induces RhoA activation.	22	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	RhoA	RhoA	RhoA	24	25	29	30
Subsequently , Daam1 activates Rho protein and can interact with the actin binding proteins profilin 1 and 2 .	Subsequently, Daam1 activates Rho protein and can interact with the actin binding proteins profilin 1 and 2.	2	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	Rho	Rho	Rho	2	3	4	5
Rho appears to promote Daam1 actin nucleation activity , whereas Dsh appears to induce Daam1 activation of Rho in the PCP pathway .	Rho appears to promote Daam1 actin nucleation activity, whereas Dsh appears to induce Daam1 activation of Rho in the PCP pathway.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	Rho	Rho	Rho	14	15	17	18
Cytoplasmic Daxx activates Ask-1 in a positive feedback loop to initiate apoptosis [ XREF_BIBR ] .	Cytoplasmic Daxx activates Ask-1 in a positive feedback loop to initiate apoptosis [XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	Ask-1	Ask-1	Ask-1	1	2	3	4
Daxx enhances apoptosis on cells by interacting with and activating ASK1 , which activates the JNK and p38 pathway .	Daxx enhances apoptosis on cells by interacting with and activating ASK1, which activates the JNK and p38 pathway.	0	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	ASK1	ASK1	ASK1	0	1	10	11
gambiae MAP3K4 would be predicted to lie downstream of TGF-beta activation of GADD45 ( AGAP007651 ) , while MAP3K5 could be activated by TGF-beta-mediated activation of DAXX ( AGAP009432 ) or TNF and TNFR activation of TRAF2 .	gambiae MAP3K4 would be predicted to lie downstream of TGF-beta activation of GADD45 (AGAP007651), while MAP3K5 could be activated by TGF-beta-mediated activation of DAXX (AGAP009432) or TNF and TNFR activation of TRAF2.	18	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DAXX	DAXX	DAXX	MAP3K5	MAP3K5	MAP3K5	26	27	18	19
As mentioned previously , Daxx mediated ASK1 oligomerization may act as a positive feedback loop for ASK1-MEK-MAPK signal transduction by maintaining and promoting ASK1 activity .	As mentioned previously, Daxx mediated ASK1 oligomerization may act as a positive feedback loop for ASK1-MEK-MAPK signal transduction by maintaining and promoting ASK1 activity.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	ASK1	ASK1	ASK1	4	5	6	7
Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1 .	Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1.	19	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	ASK1	ASK1	ASK1	20	21	23	24
This accumulated Daxx , in turn , further activates ASK1 which reinforces the amplification of downstream kinase activations including JNK and p38 .	This accumulated Daxx, in turn, further activates ASK1 which reinforces the amplification of downstream kinase activations including JNK and p38.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	ASK1	ASK1	ASK1	2	3	9	10
Over-expression of both Daxx and ASK1 in SH-SY5Y and COS-7 cells increases ASK1 activation and cell death compared with ASK1 over-expression alone .	Over-expression of both Daxx and ASK1 in SH-SY5Y and COS-7 cells increases ASK1 activation and cell death compared with ASK1 over-expression alone.	0	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Over-expression of both Daxx	daxx	ASK1	ASK1	ask1	3	4	12	13
Daxx activates apoptosis signal regulating kinase 1 ( ASK1 ) , which in turn increases c-Jun N-terminal kinase ( JNK ) activity leading to apoptosis XREF_BIBR , XREF_BIBR .	Daxx activates apoptosis signal regulating kinase 1 (ASK1), which in turn increases c-Jun N-terminal kinase (JNK) activity leading to apoptosis XREF_BIBR, XREF_BIBR.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	ASK1	ASK1	ASK1	0	1	8	9
ASK1 phosphorylation of Daxx , an ASK1 activator protein , increases Daxx accumulation in cells and further enhances ASK1 activity through a positive feedback mechanism .	ASK1 phosphorylation of Daxx, an ASK1 activator protein, increases Daxx accumulation in cells and further enhances ASK1 activity through a positive feedback mechanism.	11	19	enhances	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	ASK1	ASK1	ASK1	11	12	18	19
The null phosphorylation mutant FLAG Daxx ST0 failed to be accumulated by ASK1-DeltaN ( XREF_FIG , lane 8 ) , whereas the revertant mutant FLAG Daxx ST0-176/184S , phosphorylatable by ASK1-DeltaN , restored its ASK1 dependent accumulation to the similar extent of that of wild type FLAG-Daxx ( XREF_FIG , lanes 5 and 2 ) .	The null phosphorylation mutant FLAG Daxx ST0 failed to be accumulated by ASK1-DeltaN (XREF_FIG, lane 8), whereas the revertant mutant FLAG Daxx ST0-176/184S, phosphorylatable by ASK1-DeltaN, restored its ASK1 dependent accumulation to the similar extent of that of wild type FLAG-Daxx (XREF_FIG, lanes 5 and 2).	25	36	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	ASK1	ASK1	ASK1	25	26	34	35
Upon stress situations , Daxx , which is a nuclear protein under basal conditions , translocates to the cytoplasm , interacts and activates ASK1 leading to cell death .	Upon stress situations, Daxx, which is a nuclear protein under basal conditions, translocates to the cytoplasm, interacts and activates ASK1 leading to cell death.	4	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Daxx, which is a nuclear protein under basal conditions, translocates to the cytoplasm	daxx	ASK1	ASK1	ask1	4	5	23	24
On the other hand , the Smac released from mitochondria activates caspase-9 via binding to IAP [ XREF_BIBR ] .	On the other hand, the Smac released from mitochondria activates caspase-9 via binding to IAP [XREF_BIBR].	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	6	7	11	12
Smac mimetic compounds targeting the inhibitor of apoptosis proteins ( IAP ) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression .	Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression.	0	29	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	0	1	28	29
Notably , Smac did not induce caspase-9 processing in the absence of caspase-3 .	Notably, Smac did not induce caspase-9 processing in the absence of caspase-3.	2	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	2	3	6	7
All of these new Smac mimetics 5 , 6 and 7 can dose-dependently restore the activity of caspase-9 .	All of these new Smac mimetics 5, 6 and 7 can dose-dependently restore the activity of caspase-9.	4	18	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	4	5	17	18
Smac disrupts the inhibitor of apoptosis X linked inhibitor of apoptosis protein and caspase -9 complex and thereby allows activation of caspase-9 , caspase-3 cleavage and apoptosis .	Smac disrupts the inhibitor of apoptosis X linked inhibitor of apoptosis protein and caspase -9 complex and thereby allows activation of caspase-9, caspase-3 cleavage and apoptosis.	0	24	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	0	1	21	22
SMAC inactivation of XIAP also activates caspase-9 .	SMAC inactivation of XIAP also activates caspase-9.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMAC	SMAC	SMAC	caspase-9	caspase-9	caspase-9	0	1	6	7
Consistent with this finding , binding of the caspase-9 linker peptide and Smac to the BIR3 domain of XIAP is mutually exclusive , suggesting that Smac potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3 .	Consistent with this finding, binding of the caspase-9 linker peptide and Smac to the BIR3 domain of XIAP is mutually exclusive, suggesting that Smac potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3.	25	28	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	25	26	27	28
H2O2 ( 0.5 mmol/L ) activated caspase-3 , caspase-9 8 h after the treatment and specific morphological changes of apoptosis 12 h after the treatment , and overexpression of Smac significantly promoted H2O2 induced activation of caspase-3 , caspase-9 and apoptosis in C2C12 myogenic cells .	H2O2 (0.5 mmol/L) activated caspase-3, caspase-9 8 h after the treatment and specific morphological changes of apoptosis 12 h after the treatment, and overexpression of Smac significantly promoted H2O2 induced activation of caspase-3, caspase-9 and apoptosis in C2C12 myogenic cells.	27	39	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	overexpression of Smac	smac	caspase-9	caspase-9	caspase-9	29	30	38	39
23 We found that both WT-Smac and truncated Smac expression enhanced caspase-9 and -3 cleavage to XIAP depletion ( XREF_FIG ) .	23 We found that both WT-Smac and truncated Smac expression enhanced caspase-9 and -3 cleavage to XIAP depletion (XREF_FIG).	8	14	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Smac	Smac expression	smac	caspase-9	caspase-9	caspase-9	8	9	11	12
Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins , IAPs , and removing their inhibitory activity .	Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, IAPs, and removing their inhibitory activity.	0	3	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	0	1	2	3
XREF_BIBR , XREF_BIBR Through direct binding , Smac antagonizes XIAP and abrogates the inhibition of caspase-3/-7 and caspase-9 by XIAP .	XREF_BIBR, XREF_BIBR Through direct binding, Smac antagonizes XIAP and abrogates the inhibition of caspase-3/-7 and caspase-9 by XIAP.	7	18	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	7	8	17	18
In conjunction with other observations , our results reveal how Smac may relieve IAP inhibition of caspase-9 activity .	In conjunction with other observations, our results reveal how Smac may relieve IAP inhibition of caspase-9 activity.	10	17	relieve	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	10	11	16	17
Immunoblot analysis revealed that forced expression of miR-34a and Smac activated the cleavage of caspase-3 , caspase-9 and PARP-1 ( XREF_FIG ) .	Immunoblot analysis revealed that forced expression of miR-34a and Smac activated the cleavage of caspase-3, caspase-9 and PARP-1 (XREF_FIG).	5	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	expression of miR-34a and Smac	smac	caspase-9	caspase-9	caspase-9	9	10	16	17
While AIF , Endo G and HtrA2 may cause cell death independent of caspases [ XREF_BIBR ] , Smac promotes caspase activation by releasing caspase-9 and caspase-3 from inhibition by the inhibitor of apoptosis ( IAP ) proteins [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	While AIF, Endo G and HtrA2 may cause cell death independent of caspases [XREF_BIBR], Smac promotes caspase activation by releasing caspase-9 and caspase-3 from inhibition by the inhibitor of apoptosis (IAP) proteins [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	18	26	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	18	19	24	25
Bivalent Smac mimetics 16 , 18-21 , 24 and 29 have similar potencies and can restore 60-80 % of caspase-9 activity at concentrations of 1.5 muM .	Bivalent Smac mimetics 16, 18-21, 24 and 29 have similar potencies and can restore 60-80% of caspase-9 activity at concentrations of 1.5 muM.	1	20	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	1	2	19	20
Since it has been reported that p53 induction and apoptosis is stimulated by the adhesion-inhibitory activity of DAPK [ XREF_BIBR ] , we next evaluated the effect of DANGER on DAPK induced p53 activation and apoptosis .	Since it has been reported that p53 induction and apoptosis is stimulated by the adhesion-inhibitory activity of DAPK [XREF_BIBR], we next evaluated the effect of DANGER on DAPK induced p53 activation and apoptosis.	6	19	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DAPK	DAPK	DAPK	p53	p53	p53	17	18	6	7
The beta subunit of AMPK ( AMPK beta ) , DRAM and DAPK are transcriptional targets of p53 that are commonly implicated in autophagy .	The beta subunit of AMPK (AMPK beta), DRAM and DAPK are transcriptional targets of p53 that are commonly implicated in autophagy.	10	18	are transcriptional targets	Positive_activation_copula_1	Positive_activation	Positive_activation	DAPK	DAPK	DAPK	p53	p53	p53	12	13	17	18
DAPk1 is a transcriptional target of p53 and the activation of DAPk1 eventually promotes its function by a positive feedback regulation between DAPk1 and p53 [ XREF_BIBR ] .	DAPk1 is a transcriptional target of p53 and the activation of DAPk1 eventually promotes its function by a positive feedback regulation between DAPk1 and p53 [XREF_BIBR].	0	7	is a transcriptional target	Positive_activation_copula_1	Positive_activation	Positive_activation	DAPk1	DAPk1	DAPk1	p53	p53	p53	0	1	6	7
Both DAPK1 and p14 ( ARF ) positively regulate p53 whereas miR-34a and -34 b/c are direct transcriptional targets of p53 .	Both DAPK1 and p14 (ARF) positively regulate p53 whereas miR-34a and -34 b/c are direct transcriptional targets of p53.	0	10	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	DAPK1	DAPK1	DAPK1	p53	p53	p53	1	2	9	10
In addition , DAPK1 indirectly induces p53 activation by activating the ARF tumor suppressor , which inhibits MDM2 , an inhibitor of p53 [ XREF_BIBR ] .	In addition, DAPK1 indirectly induces p53 activation by activating the ARF tumor suppressor, which inhibits MDM2, an inhibitor of p53 [XREF_BIBR].	3	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK1	DAPK1	DAPK1	p53	p53	p53	3	4	6	7
DAPK is able to activate the p19ARF and p53 dependent apoptotic pathway through phosphorylation of p19ARF .	DAPK is able to activate the p19ARF and p53 dependent apoptotic pathway through phosphorylation of p19ARF.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK	DAPK	DAPK	p53	p53	p53	0	1	8	9
DAPK1 overexpression results in upregulation of p53 , suggesting a signaling feedback loop in which DAPK1 and p53 regulate each other ' s expression .	DAPK1 overexpression results in upregulation of p53, suggesting a signaling feedback loop in which DAPK1 and p53 regulate each other 's expression.	0	7	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	DAPK1	DAPK1 overexpression	dapk1	p53	p53	p53	0	1	6	7
In normal cells , DAPK1 can activate p53 , leading to p53 target gene transcription and apoptosis under death related signaling .	In normal cells, DAPK1 can activate p53, leading to p53 target gene transcription and apoptosis under death related signaling.	4	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK1	DAPK1	DAPK1	p53	p53	p53	4	5	7	8
IR increases DAPK activity , which enhances p53 transcriptional activity , which leads to anoikis .	IR increases DAPK activity, which enhances p53 transcriptional activity, which leads to anoikis.	2	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK	DAPK	DAPK	p53	p53	p53	2	3	7	8
In addition , DAPK1 functioned as an upstream protein kinase triggering p53 and Ets-1-dependent IKKbeta and MDM2 reduction and GADD45alpha accumulation , thus promoting apoptosis in HepG2 cells .	In addition, DAPK1 functioned as an upstream protein kinase triggering p53 and Ets-1-dependent IKKbeta and MDM2 reduction and GADD45alpha accumulation, thus promoting apoptosis in HepG2 cells.	3	14	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK1	DAPK1	DAPK1	p53	p53	p53	3	4	11	12
In this connection , methylation of DAPK1 gene , which triggers TP53 activation upon oncogenic cellular transformation , was first reported as a TSG methylated in CLL [ XREF_BIBR ] , and subsequently shown to contribute to CLL progression by blocking the apoptosis of leukemia cells [ XREF_BIBR ] .	In this connection, methylation of DAPK1 gene, which triggers TP53 activation upon oncogenic cellular transformation, was first reported as a TSG methylated in CLL [XREF_BIBR], and subsequently shown to contribute to CLL progression by blocking the apoptosis of leukemia cells [XREF_BIBR].	4	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK1	methylation of DAPK1	dapk1	TP53	TP53	tp53	6	7	11	12
DAPK1 leads to p53 activation and apoptosis through DAPK1 phosphorylation of tetrametric p53 on Ser20 , which is located within the transactivation domain that binds p300 [ XREF_BIBR ] .	DAPK1 leads to p53 activation and apoptosis through DAPK1 phosphorylation of tetrametric p53 on Ser20, which is located within the transactivation domain that binds p300 [XREF_BIBR].	0	4	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	DAPK1	DAPK1	DAPK1	p53	p53	p53	0	1	3	4
It has been reported that DAPK1 activates the p53 pathway via p19 ARF through an undetermined mechanism .	It has been reported that DAPK1 activates the p53 pathway via p19 ARF through an undetermined mechanism.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK1	DAPK1	DAPK1	p53	p53	p53	5	6	8	9
We have previously found that protein expression of DAPK3 increases in the mesenteric artery from spontaneously hypertensive rats ( SHRs ) and that DAPK3 mediates the development of hypertension in SHRs partly through promoting reactive oxygen species dependent vascular inflammation .	We have previously found that protein expression of DAPK3 increases in the mesenteric artery from spontaneously hypertensive rats (SHRs) and that DAPK3 mediates the development of hypertension in SHRs partly through promoting reactive oxygen species dependent vascular inflammation.	6	24	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	DAPK3	expression of DAPK3	dapk3	DAPK3	DAPK3	dapk3	8	9	23	24
In addition , phosphorylation of DLK itself by JNK prevents the ubiquitination and proteasomal degradation of DLK , resulting in a feed-forward loop [ XREF_BIBR , XREF_BIBR ] .	In addition, phosphorylation of DLK itself by JNK prevents the ubiquitination and proteasomal degradation of DLK, resulting in a feed-forward loop [XREF_BIBR, XREF_BIBR].	3	17	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DLK	phosphorylation of DLK	dlk	DLK	DLK	dlk	5	6	16	17
DAPk is able to trans-phosphorylate ZIPk on six distinct sites in the extra-catalytic domain , thus increasing the cytoplasmic localization of ZIPk and the homo-trimerization towards a more potent cell death inducer .	DAPk is able to trans-phosphorylate ZIPk on six distinct sites in the extra-catalytic domain, thus increasing the cytoplasmic localization of ZIPk and the homo-trimerization towards a more potent cell death inducer.	0	22	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ZIPk	DAPk is able to trans-phosphorylate ZIPk	zipk	ZIPk	ZIPk	zipk	5	6	21	22
Interestingly , in addition to reducing JNK activation upon potassium deprivation , LZK depletion also diminished DLK protein levels ( XREF_FIG ) , possibly due to decreased JNK activity under these conditions , as JNK dependent phosphorylation of DLK promotes DLK stability XREF_BIBR .	Interestingly, in addition to reducing JNK activation upon potassium deprivation, LZK depletion also diminished DLK protein levels (XREF_FIG), possibly due to decreased JNK activity under these conditions, as JNK dependent phosphorylation of DLK promotes DLK stability XREF_BIBR.	34	42	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLK	JNK dependent phosphorylation of DLK	dlk	DLK	DLK	dlk	38	39	40	41
Hence , overexpression of DLK is sufficient to stimulate the catalytic activity of DLK .	Hence, overexpression of DLK is sufficient to stimulate the catalytic activity of DLK.	2	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLK	overexpression of DLK	dlk	DLK	DLK	dlk	4	5	13	14
Similarly , DAB2ip promotes endoplasmic reticulum stress induced activation of ASK1 and apoptosis in both blood vessel ECs and fibroblasts .	Similarly, DAB2ip promotes endoplasmic reticulum stress induced activation of ASK1 and apoptosis in both blood vessel ECs and fibroblasts.	2	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAB2ip	DAB2ip	DAB2ip	ASK1	ASK1	ASK1	2	3	10	11
Overexpression of DAB2IP into SNU449 cells resulted in ASK1 activation and suppression of the VEGFR2/Akt/PLC-gamma axis , whereas opposite results where obtained when silencing DAB2IP in HuH6 cells ( XREF_FIG , and XREF_SUPPLEMENTARY ) .	Overexpression of DAB2IP into SNU449 cells resulted in ASK1 activation and suppression of the VEGFR2/Akt/PLC-gamma axis, whereas opposite results where obtained when silencing DAB2IP in HuH6 cells (XREF_FIG, and XREF_SUPPLEMENTARY).	0	10	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	DAB2IP	Overexpression of DAB2IP	dab2ip	ASK1	ASK1	ask1	2	3	8	9
DAB2IP activates ASK1 by allowing its release from the inactive complex with 14-3-3 [ XREF_BIBR ] .	DAB2IP activates ASK1 by allowing its release from the inactive complex with 14-3-3 [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAB2IP	DAB2IP	DAB2IP	ASK1	ASK1	ASK1	0	1	2	3
DAB2IP can suppress the PI3K and Akt pathway and enhance ASK1 activation leading to cell apoptosis .	DAB2IP can suppress the PI3K and Akt pathway and enhance ASK1 activation leading to cell apoptosis.	0	11	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAB2IP	DAB2IP	DAB2IP	ASK1	ASK1	ASK1	0	1	10	11
Dab2IP causes dissociation of ASK1 from its inhibitor and activation of c-Jun Kinase ( JNK ) signaling , while at the same time activating IKK NF-kB signaling via TRAF2 XREF_BIBR , XREF_BIBR .	Dab2IP causes dissociation of ASK1 from its inhibitor and activation of c-Jun Kinase (JNK) signaling, while at the same time activating IKK NF-kB signaling via TRAF2 XREF_BIBR, XREF_BIBR.	0	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dab2IP	Dab2IP	Dab2IP	ASK1	ASK1	ASK1	0	1	4	5
DAPK is reported to promote Vps34 activation by promoting the release of BECN1 from inhibitory complexes .	DAPK is reported to promote Vps34 activation by promoting the release of BECN1 from inhibitory complexes.	0	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK	DAPK	DAPK	BECN1	BECN1	BECN1	0	1	12	13
DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain , and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy .	DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy.	0	29	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK	DAPK	DAPK	beclin 1	beclin 1	beclin 1	0	1	23	25
DAPK phosphorylates Beclin-1 on Thr119 located at a crucial position in its BH3 domain , and thus promoted the dissociation of Beclin-1 from its inhibitor Bcl-X L , resulting in the induction of autophagy XREF_BIBR , XREF_BIBR .	DAPK phosphorylates Beclin-1 on Thr119 located at a crucial position in its BH3 domain, and thus promoted the dissociation of Beclin-1 from its inhibitor Bcl-X L, resulting in the induction of autophagy XREF_BIBR, XREF_BIBR.	0	22	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK	DAPK	DAPK	Beclin-1	Beclin-1	Beclin-1	0	1	21	22
DAPk ( Death Associated Protein kinase )-mediated phosphorylation in the BH3 domain of Beclin1 promotes dissociation of Beclin1 from Bcl-x L to induce autophagy [ XREF_BIBR ] .	DAPk (Death Associated Protein kinase)-mediated phosphorylation in the BH3 domain of Beclin1 promotes dissociation of Beclin1 from Bcl-x L to induce autophagy [XREF_BIBR].	0	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPk	DAPk	DAPk	Beclin1	Beclin1	Beclin1	0	1	17	18
These data suggest that Dlk and ZIP kinase is able to trigger the mitochondrial apoptosis pathway independent of the p19ARF and p53 signalling pathway .	These data suggest that Dlk and ZIP kinase is able to trigger the mitochondrial apoptosis pathway independent of the p19ARF and p53 signalling pathway.	4	23	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dlk	Dlk	Dlk	p53	p53	p53	4	5	21	22
However , Dlk and ZIP kinase triggered cell death was also observed in p19ARF deficient and p53 deficient mouse fibroblast cells .	However, Dlk and ZIP kinase triggered cell death was also observed in p19ARF deficient and p53 deficient mouse fibroblast cells.	2	20	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dlk	Dlk	Dlk	p53	p53	p53	2	3	16	17
These results may support our finding that over-expression of DAPK3 in p53 and PTEN null PC-3 cells causes growth inhibition independent of p53 status .	These results may support our finding that over-expression of DAPK3 in p53 and PTEN null PC-3 cells causes growth inhibition independent of p53 status.	7	23	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK3	over-expression of DAPK3	dapk3	p53	p53	p53	9	10	22	23
A recent study demonstrated that activation of DAPK3 causes genome instability independent of p53 status in cancer cells XREF_BIBR .	A recent study demonstrated that activation of DAPK3 causes genome instability independent of p53 status in cancer cells XREF_BIBR.	5	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAPK3	DAPK3	DAPK3	p53	p53	p53	7	8	13	14
These findings reveal that Daxx modulates the function of Mdm2 at multiple levels and suggest that the disruption of the Mdm2-Daxx interaction may be important for p53 activation in response to DNA damage .	These findings reveal that Daxx modulates the function of Mdm2 at multiple levels and suggest that the disruption of the Mdm2-Daxx interaction may be important for p53 activation in response to DNA damage.	4	14	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	Mdm2	Mdm2	Mdm2	4	5	9	10
DAXX enhances the intrinsic activity of MDM2 towards p53 and functions as a scaffolding protein to recruit the deubiquitylating enzyme HAUSP , which protects MDM2 from degradation [ XREF_BIBR ] by removing ubiquitin chains that were formed by MDM2 autoubiquitylation [ XREF_BIBR ] .	DAXX enhances the intrinsic activity of MDM2 towards p53 and functions as a scaffolding protein to recruit the deubiquitylating enzyme HAUSP, which protects MDM2 from degradation [XREF_BIBR] by removing ubiquitin chains that were formed by MDM2 autoubiquitylation [XREF_BIBR].	0	16	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DAXX	DAXX	DAXX	MDM2	MDM2	MDM2	0	1	6	7
In addition , Daxx enhances the intrinsic E3 activity of Mdm2 towards p53 .	In addition, Daxx enhances the intrinsic E3 activity of Mdm2 towards p53.	3	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	Mdm2	Mdm2	Mdm2	3	4	10	11
The function of Mdm2 is critically dependent on Daxx , which prevents Mdm2 degradation and also enhances E3 activity of Mdm2 towards p53 .	The function of Mdm2 is critically dependent on Daxx, which prevents Mdm2 degradation and also enhances E3 activity of Mdm2 towards p53.	6	16	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Daxx	Daxx	Daxx	Mdm2	Mdm2	Mdm2	8	9	12	13
Conversely , knockdown of DDX5 by shRNA reduced cell division of Arf -/- and p53 -/- MEFs .	Conversely, knockdown of DDX5 by shRNA reduced cell division of Arf -/- and p53 -/- MEFs.	2	16	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DDX5	DDX5	DDX5	p53	p53	p53	4	5	14	15
The RNA helicase p68 modulates expression and function of the Delta133 isoform ( s ) of p53 , and is inversely associated with Delta133p53 expression in breast cancer .	The RNA helicase p68 modulates expression and function of the Delta133 isoform (s) of p53, and is inversely associated with Delta133p53 expression in breast cancer.	1	17	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RNA helicase p68	RNA helicase p68	RNA helicase p68	p53	p53	p53	1	4	16	17
DDX5 is a transcriptional co-activator of p53 , a function that would be impeded by its relocalization to the cytoplasm .	DDX5 is a transcriptional co-activator of p53, a function that would be impeded by its relocalization to the cytoplasm.	0	9	is a transcriptional co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	DDX5	DDX5	DDX5	p53	p53	p53	0	1	6	7
Functionally , Ddx5 augmented Runx2 transcriptional activity while CoAA repressed Runx factor driven expression of reporter plasmids .	Functionally, Ddx5 augmented Runx2 transcriptional activity while CoAA repressed Runx factor driven expression of reporter plasmids.	2	6	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ddx5	Ddx5	Ddx5	Runx2	Runx2	Runx2	2	3	4	5
Interestingly , Ddx5 augmented Runx2 transcriptional activity while CoAA prevented Runx2 from binding DNA .	Interestingly, Ddx5 augmented Runx2 transcriptional activity while CoAA prevented Runx2 from binding DNA.	2	6	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ddx5	Ddx5	Ddx5	Runx2	Runx2	Runx2	2	3	4	5
It seems likely , therefore , that DDX5 enhances RUNX2 transcriptional activity in chondrocytes and thus enhances RUNX2 ' s stimulation of hypertrophy .	It seems likely, therefore, that DDX5 enhances RUNX2 transcriptional activity in chondrocytes and thus enhances RUNX2 's stimulation of hypertrophy.	7	18	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DDX5	DDX5	DDX5	RUNX2	RUNX2	RUNX2	7	8	17	18
Of particular interest is that DAB2IP differentially regulates GSK3beta activity in hMSCs and prostate cancer cells ; DAB2IP activates GSK3beta in prostate cancer cells but represses GSK3beta in hMSCs .	Of particular interest is that DAB2IP differentially regulates GSK3beta activity in hMSCs and prostate cancer cells; DAB2IP activates GSK3beta in prostate cancer cells but represses GSK3beta in hMSCs.	17	27	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	GSK3beta	GSK3beta	GSK3beta	17	18	26	27
Furthermore , IBP mediates Rac1 , RhoA and Cdc42 activation in breast cancer cells and regulates Rho GTPase dependent processes , including actin cytoskeleton rearrangement and matrix metalloprotease ( MMP ) production .	Furthermore, IBP mediates Rac1, RhoA and Cdc42 activation in breast cancer cells and regulates Rho GTPase dependent processes, including actin cytoskeleton rearrangement and matrix metalloprotease (MMP) production.	2	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IBP	IBP	IBP	Cdc42	Cdc42	Cdc42	2	3	8	9
We also observed that DISC1 increases the accumulation of NDEL1 to the centrosome .	We also observed that DISC1 increases the accumulation of NDEL1 to the centrosome.	4	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DISC1	DISC1	DISC1	NDEL1	NDEL1	NDEL1	4	5	9	10
The knockdown of DISC1 by RNA interference or the dominant negative form of DISC1 inhibited the accumulation of NUDEL , LIS1 , and 14-3-3epsilon at the axons and axon elongation .	The knockdown of DISC1 by RNA interference or the dominant negative form of DISC1 inhibited the accumulation of NUDEL, LIS1, and 14-3-3epsilon at the axons and axon elongation.	1	23	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DISC1	DISC1	DISC1	NUDEL	NUDEL	NUDEL	3	4	18	19
DDB1 modulates the transcription factor E2F1 , which , in turn , regulates cell proliferation and telomerase .	DDB1 modulates the transcription factor E2F1, which, in turn, regulates cell proliferation and telomerase.	0	6	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DDB1	DDB1	DDB1	transcription factor E2F1	transcription factor E2F1	transcription factor E2F1	0	1	3	6
We showed that expression of DDB1 and DDB2 stimulated the activity of the cell cycle regulatory transcription factor E2F1 .	We showed that expression of DDB1 and DDB2 stimulated the activity of the cell cycle regulatory transcription factor E2F1.	3	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DDB1	expression of DDB1	ddb1	transcription factor E2F1	transcription factor E2F1	transcription factor e2f1	5	6	16	19
Furthermore , collagen I could induce DDR1 expression , and activated DDR1 promoted NSCLC cell migration and invasion , while knockdown of DDR1 by transfection with siRNA resulted in a significant decrease in cell migrativeness and invasiveness .	Furthermore, collagen I could induce DDR1 expression, and activated DDR1 promoted NSCLC cell migration and invasion, while knockdown of DDR1 by transfection with siRNA resulted in a significant decrease in cell migrativeness and invasiveness.	2	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DDR1	collagen I could induce DDR1 expression	ddr1	DDR1	DDR1	ddr1	6	7	11	12
In Jag1 expressing domains , control of neurogenesis can be achieved by either Jag1- or Dll1 mediated Notch signalling .	In Jag1 expressing domains, control of neurogenesis can be achieved by either Jag1- or Dll1 mediated Notch signalling.	10	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	15	16	17	18
This effect was significantly decreased in the presence of gsi ( XREF_SUPPLEMENTARY ) , thus confirming the direct involvement of Dll1 triggered Notch signaling in the early differentiation step of murine and human MABs .	This effect was significantly decreased in the presence of gsi (XREF_SUPPLEMENTARY), thus confirming the direct involvement of Dll1 triggered Notch signaling in the early differentiation step of murine and human MABs.	18	23	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	20	21	22	23
In contrast , activation of the RBP-J mediated canonical Notch pathway , potentially promoted by Dll1 ligand expressed by proliferating NSCs and IPs , preserves the quiescent NSC pool .	In contrast, activation of the RBP-J mediated canonical Notch pathway, potentially promoted by Dll1 ligand expressed by proliferating NSCs and IPs, preserves the quiescent NSC pool.	9	16	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	15	16	9	10
Endothelial Notch activation induced by Dll1 is involved in regulation of arteriogenesis 132 while Dll4 binding is considered the principle mechanism controlling the extent of branching XREF_BIBR - XREF_BIBR .	Endothelial Notch activation induced by Dll1 is involved in regulation of arteriogenesis 132 while Dll4 binding is considered the principle mechanism controlling the extent of branching XREF_BIBR - XREF_BIBR.	1	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	5	6	1	2
Moreover , MaSC expressed Dll1 activates Notch signaling in stromal macrophages , increasing their expression of Wnt family ligands such as Wnt3 , Wnt10A , and Wnt16 , thereby initiating a feed back loop that promotes the function of Dll1 + MaSCs .	Moreover, MaSC expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feed back loop that promotes the function of Dll1 + MaSCs.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	4	5	6	7
However , as they were distributed in the white matter in which immature glial cells are known to preponderate , the upregulation and concomitant release of Delta-1 could function to promote Notch signaling in early oligodendrocytes and astrocytes .	However, as they were distributed in the white matter in which immature glial cells are known to preponderate, the upregulation and concomitant release of Delta-1 could function to promote Notch signaling in early oligodendrocytes and astrocytes.	24	32	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Delta-1	Delta-1	Delta-1	Notch	Notch	Notch	26	27	31	32
We show that activation of Notch signaling by its ligands Delta-1 or Delta-4 potentiates IL-7-driven proliferation and survival of CD34 ( + ) TN and to a lesser extent of CD4 ( + ) ISP precursors .	We show that activation of Notch signaling by its ligands Delta-1 or Delta-4 potentiates IL-7-driven proliferation and survival of CD34 (+) TN and to a lesser extent of CD4 (+) ISP precursors.	5	12	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Delta-1	Delta-1	Delta-1	Notch	Notch	Notch	10	11	5	6
Dll1 expression then leads to activation of notch signaling between adjacent NSCs .	Dll1 expression then leads to activation of notch signaling between adjacent NSCs.	0	8	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1 expression	dll1	notch	notch	notch	0	1	7	8
Furthermore , DLL1 induced monocyte conversion was impaired by incubation with a gamma-secretase inhibitor , N-( N-( 3,5-difluorophenacetyl )-L-alanyl )-S-phenylglycine t-butyl ester ( DAPT ) , which blocks the generation of the active intracellular Notch domain XREF_BIBR , thus indicating that DLL1 induced Notch receptor cleavage is required for this process ( XREF_FIG ) .	Furthermore, DLL1 induced monocyte conversion was impaired by incubation with a gamma-secretase inhibitor, N-(N-(3,5-difluorophenacetyl)-L-alanyl)-S-phenylglycine t-butyl ester (DAPT), which blocks the generation of the active intracellular Notch domain XREF_BIBR, thus indicating that DLL1 induced Notch receptor cleavage is required for this process (XREF_FIG).	41	45	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	41	42	43	44
Taken together , DLL1 mediated Notch signaling appeared to act as a regulatory switch for at least two critical points in the osteoblast differentiation : a positive regulator for the expansion of bone forming cells and a negative regulator for the functional maturation of osteoblasts .	Taken together, DLL1 mediated Notch signaling appeared to act as a regulatory switch for at least two critical points in the osteoblast differentiation : a positive regulator for the expansion of bone forming cells and a negative regulator for the functional maturation of osteoblasts.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	3	4	5	6
Taken together , these data suggest that Dll1 deficiency in CD4 + T cells does not affect the expression of Notch and Rbpj mediated Notch signaling .	Taken together, these data suggest that Dll1 deficiency in CD4 + T cells does not affect the expression of Notch and Rbpj mediated Notch signaling.	7	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	7	8	24	25
Thus , Dll1 mediated Notch activation regulates ephrin-B2 expression and postnatal arteriogenesis .	Thus, Dll1 mediated Notch activation regulates ephrin-B2 expression and postnatal arteriogenesis.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	2	3	4	5
This result is in line with the observation that DLL1 induced Notch signaling has suppressive effect on tumor growth in B16 melanoma model due to the attenuated vascularization .	This result is in line with the observation that DLL1 induced Notch signaling has suppressive effect on tumor growth in B16 melanoma model due to the attenuated vascularization.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	9	10	11	12
Taken together , Notch signaling mediated by Dll1 and Dll4 is essential for arterial differentiation via VEGF-A during vascular morphogenesis .	Taken together, Notch signaling mediated by Dll1 and Dll4 is essential for arterial differentiation via VEGF-A during vascular morphogenesis.	3	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	7	8	3	4
Here we show , using chimeric embryos composed of wild-type cells and Delta like 1 ( Dll1 )-null cells , that Dll1 mediated Notch signalling is responsible for the synchronization mechanism .	Here we show, using chimeric embryos composed of wild-type cells and Delta like 1 (Dll1)-null cells, that Dll1 mediated Notch signalling is responsible for the synchronization mechanism.	21	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	21	22	23	24
However , cleavage products of Dll1 were remarkably increased by co-culture with Notch1 expressing COS7 cells ( Notch and COS7 ) .	However, cleavage products of Dll1 were remarkably increased by co-culture with Notch1 expressing COS7 cells (Notch and COS7).	3	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	5	6	17	18
Underscoring the importance of ligand ubiquitination in signaling activity , the Dll1 and Dll3 chimera did not activate Notch signaling and this also correlated with a loss in fractionation to lipid microdomains .	Underscoring the importance of ligand ubiquitination in signaling activity, the Dll1 and Dll3 chimera did not activate Notch signaling and this also correlated with a loss in fractionation to lipid microdomains.	11	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	11	12	18	19
The oscillatory expression between Ngn2 or Ascl1 and Dll1 in the complementary phase leads to mutual activation of Notch signaling within neighboring progenitors , and enables the progenitors to maintain the proliferative state of NPCs .	The oscillatory expression between Ngn2 or Ascl1 and Dll1 in the complementary phase leads to mutual activation of Notch signaling within neighboring progenitors, and enables the progenitors to maintain the proliferative state of NPCs.	2	19	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	8	9	18	19
In addition , Geffers et al recently reported that DLL3 does not activate Notch in D. melanogaster nor repress DLL1 mediated Notch activation in vivo .	In addition, Geffers et al recently reported that DLL3 does not activate Notch in D. melanogaster nor repress DLL1 mediated Notch activation in vivo.	18	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	19	20	21	22
DLL1 and DLL4 activate Notch similarly in vitro .	DLL1 and DLL4 activate Notch similarly in vitro.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	0	1	4	5
Expression of DLL1 enhanced Notch activation ~ 15-fold whereas expression of DLL4 increased Notch activation only < 5-fold which was not significantly different from HeLa-N1 cells without transgenic ligand ( XREF_FIG ; n = 6 ; numbers in XREF_FIG are normalised to the left bar in 5Ec , i.e. culture of HeLa-N1 without transgenic DLL , set to 1 ) .	Expression of DLL1 enhanced Notch activation ~ 15-fold whereas expression of DLL4 increased Notch activation only < 5-fold which was not significantly different from HeLa-N1 cells without transgenic ligand (XREF_FIG; n = 6; numbers in XREF_FIG are normalised to the left bar in 5Ec, i.e. culture of HeLa-N1 without transgenic DLL, set to 1).	0	6	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	Expression of DLL1	dll1	Notch	Notch	notch	2	3	4	5
Here we propose a positive feedback loop between STAT3 and DLL1 activated Notch signaling after TLR mediated inflammation .	Here we propose a positive feedback loop between STAT3 and DLL1 activated Notch signaling after TLR mediated inflammation.	6	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	10	11	12	13
In another study in which Notch signaling was initiated by the ligand Dll1 , Hes1 expression was found to oscillate , yet signaling led to a rapid , sustained disappearance of MyoD RNA , rendering any specific effects of Notch or of Hes1 on MyoD activity irrelevant .	In another study in which Notch signaling was initiated by the ligand Dll1, Hes1 expression was found to oscillate, yet signaling led to a rapid, sustained disappearance of MyoD RNA, rendering any specific effects of Notch or of Hes1 on MyoD activity irrelevant.	5	13	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	12	13	5	6
It has been found that activation of Notch by Dll1 induces T-bet expression in activated CD4 + T cells early after stimulation 22,15 .	It has been found that activation of Notch by Dll1 induces T-bet expression in activated CD4 + T cells early after stimulation 22,15.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	9	10	7	8
Note that our model describes preservation of the NSCs in two contexts : in the resting state , Lfng boosted Dll1 mediated Notch signaling preserves the NSCs at the population level ( i.e ., prevents global NSC activation to undergo division ) , while in the context of active division , Jag1 mediated inhibition of Notch signaling preserves the NSC on the single-cell level ( prevents its perpetual division ) .	Note that our model describes preservation of the NSCs in two contexts : in the resting state, Lfng boosted Dll1 mediated Notch signaling preserves the NSCs at the population level (i.e., prevents global NSC activation to undergo division), while in the context of active division, Jag1 mediated inhibition of Notch signaling preserves the NSC on the single-cell level (prevents its perpetual division).	19	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	20	21	22	23
This is in agreement with biochemical data reported by Yang et al ., who showed that , in the absence of Fringe , the levels of Notch activity elicited by Dll1 or Jag1 are identical XREF_BIBR .	This is in agreement with biochemical data reported by Yang et al., who showed that, in the absence of Fringe, the levels of Notch activity elicited by Dll1 or Jag1 are identical XREF_BIBR.	26	32	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	30	31	26	27
Additional effects of the pharmacological DLL1 mediated Notch activation in tumor bearing host associate with remarkably higher ( 2.65-fold ) T cell infiltration into tumors as assessed by CD3e immunostaining of D459 tumor sections ( XREF_FIG ) , a factor known to correlate with the improved prognosis in human patients .	Additional effects of the pharmacological DLL1 mediated Notch activation in tumor bearing host associate with remarkably higher (2.65-fold) T cell infiltration into tumors as assessed by CD3e immunostaining of D459 tumor sections (XREF_FIG), a factor known to correlate with the improved prognosis in human patients.	1	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	5	6	7	8
In the presence of Dll1 , the relative luciferase activity of the CSL reporter gene increased 20-fold ( XREF_FIG , Lanes A , B ) , showing that Notch was indeed activated by Dll1 .	In the presence of Dll1, the relative luciferase activity of the CSL reporter gene increased 20-fold (XREF_FIG, Lanes A, B), showing that Notch was indeed activated by Dll1.	28	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	33	34	28	29
Collectively , these observations demonstrated that immobilized Dll1 activated Notch signaling is able to regulate ECFC gene expression patterns in vitro over several days of exposure .	Collectively, these observations demonstrated that immobilized Dll1 activated Notch signaling is able to regulate ECFC gene expression patterns in vitro over several days of exposure.	6	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	7	8	9	10
Ascl1 is presumed to drive expression of Dll1 , which would activate Notch receptors on adjacent cells .	Ascl1 is presumed to drive expression of Dll1, which would activate Notch receptors on adjacent cells.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Ascl1 is presumed to drive expression of Dll1	dll1	Notch	Notch	notch	7	8	12	13
By using a Notch reporter construct , we show that Dll1 processing by ADAM12 increases Notch signaling in a cell-autonomous manner .	By using a Notch reporter construct, we show that Dll1 processing by ADAM12 increases Notch signaling in a cell-autonomous manner.	10	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	10	11	15	16
In these mice , the residual Notch activity within HSPCs suggested complementary mechanisms of Notch activation , likely contributed by other Notch ligands , including jagged-2 , DLL1 , and DLL4 .	In these mice, the residual Notch activity within HSPCs suggested complementary mechanisms of Notch activation, likely contributed by other Notch ligands, including jagged-2, DLL1, and DLL4.	14	28	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	27	28	14	15
Notch signaling is mediated by the interaction of transmembrane receptors ( NOTCH1-4 ) and ligands ( JAGGED1 and 2 and DLL1 , 3 , and 4 ) expressed on the surface of neighboring cells .	Notch signaling is mediated by the interaction of transmembrane receptors (NOTCH1-4) and ligands (JAGGED1 and 2 and DLL1, 3, and 4) expressed on the surface of neighboring cells.	0	25	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	20	21	0	1
The authors concluded that Notch signaling by Dll1 could release an inhibitory signal that otherwise maintains B cells in a non secreting state .	The authors concluded that Notch signaling by Dll1 could release an inhibitory signal that otherwise maintains B cells in a non secreting state.	4	8	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	7	8	4	5
This may explain that Dll1 or Dll4 activation of Notch signaling induce T-bet expression independent of IL-12 22,15 .	This may explain that Dll1 or Dll4 activation of Notch signaling induce T-bet expression independent of IL-12 22,15.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	4	5	9	10
In this study , we investigated the effects of DLL1 induced Notch signaling in the differentiation and function of bone cells .	In this study, we investigated the effects of DLL1 induced Notch signaling in the differentiation and function of bone cells.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	9	10	11	12
Cell culture assays that measure Notch activation by DLL1 or DLL4 demonstrate that DLL4 trans-activates Notch signalling similarly to DLL1 but cis-inhibits Notch signalling much more efficiently than DLL1 , partly overruling the activation by interactions in trans .	Cell culture assays that measure Notch activation by DLL1 or DLL4 demonstrate that DLL4 trans-activates Notch signalling similarly to DLL1 but cis-inhibits Notch signalling much more efficiently than DLL1, partly overruling the activation by interactions in trans.	5	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	8	9	5	6
Our results demonstrate that Dll1 mediated Notch signaling is essential for generation of left-right asymmetry , and that the Notch pathway acts upstream of Nodal expression during left-right asymmetry determination in mice .	Our results demonstrate that Dll1 mediated Notch signaling is essential for generation of left-right asymmetry, and that the Notch pathway acts upstream of Nodal expression during left-right asymmetry determination in mice.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	4	5	6	7
JAG1- but not DLL1 induced Notch signaling is permissive for the generation of thymic CDPs from bipotent T/DC ETPs .	JAG1- but not DLL1 induced Notch signaling is permissive for the generation of thymic CDPs from bipotent T/DC ETPs.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	3	4	5	6
At the crypt base , Rfng expressed in Paneth cells modulates DLL1 and DLL4 , which enhances Notch signalling and self-renewal of neighbouring CBCs .	At the crypt base, Rfng expressed in Paneth cells modulates DLL1 and DLL4, which enhances Notch signalling and self-renewal of neighbouring CBCs.	10	18	enhances	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	11	12	17	18
These observations suggest that Dll1 mediated activation of Notch signaling may have some effects in facilitating tumor cell adhesion .	These observations suggest that Dll1 mediated activation of Notch signaling may have some effects in facilitating tumor cell adhesion.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	4	5	8	9
In conclusion , the ubiquitous expression of three DICD variants at levels higher than endogenous DICD had no measurable effect on patterning processes that depend on DLL1 and Notch signaling or expression of selected Notch target genes in vivo .	In conclusion, the ubiquitous expression of three DICD variants at levels higher than endogenous DICD had no measurable effect on patterning processes that depend on DLL1 and Notch signaling or expression of selected Notch target genes in vivo.	26	36	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	26	27	34	35
The ubiquitin ligase Mindbomb is required in Dll1 expressing cells for the Dll1 induced activation of Notch signaling .	The ubiquitin ligase Mindbomb is required in Dll1 expressing cells for the Dll1 induced activation of Notch signaling.	9	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	12	13	16	17
Functionally , activation of Notch signalling by Dll1 in CD4 ( + ) T cells enhanced the expression of a T helper type 1 ( Th1 ) cytokine IFN-gamma , while Notch activation in macrophages had no direct effect on replication of DENV .	Functionally, activation of Notch signalling by Dll1 in CD4 (+) T cells enhanced the expression of a T helper type 1 (Th1) cytokine IFN-gamma, while Notch activation in macrophages had no direct effect on replication of DENV.	4	9	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	7	8	4	5
DLL1 mediated NOTCH activation induced a marked expression of GATA4 , NKX2.5 , MEF2C , and TBX5 ( XREF_SUPPLEMENTARY ) .	DLL1 mediated NOTCH activation induced a marked expression of GATA4, NKX2.5, MEF2C, and TBX5 (XREF_SUPPLEMENTARY).	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NOTCH	NOTCH	NOTCH	0	1	2	3
However , this data does not rule out that Dll1 signalling from cells located in adjacent domains can activate Notch in V1 and dI6 progenitors , as the endogenous expression of Jag1 in electroporated cells can result in cis-inhibition of the ectopically expressed Dll1 .	However, this data does not rule out that Dll1 signalling from cells located in adjacent domains can activate Notch in V1 and dI6 progenitors, as the endogenous expression of Jag1 in electroporated cells can result in cis-inhibition of the ectopically expressed Dll1.	9	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	9	10	19	20
STAT3 induces DLL1 expression that activates Notch signaling and boosts NF-kappaB-induced IL-6 which transduces stabilization of STAT3 activation .	STAT3 induces DLL1 expression that activates Notch signaling and boosts NF-kappaB-induced IL-6 which transduces stabilization of STAT3 activation.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	STAT3 induces DLL1 expression	dll1	Notch	Notch	notch	2	3	6	7
Importantly , Dll1 + cells were detected in close proximity ( within a distance of 10mum between nuclei ) to most ( 84.4 +/-7.2 % ) NICD + LRCs ( XREF_FIG ) , suggesting that Dll1 might activate Notch in NSCs .	Importantly, Dll1 + cells were detected in close proximity (within a distance of 10mum between nuclei) to most (84.4 +/-7.2%) NICD + LRCs (XREF_FIG), suggesting that Dll1 might activate Notch in NSCs.	35	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	35	36	38	39
Here , we show that activin A induces Delta-1 , Delta-2 and Notch expression and then activates Notch signaling in animal caps .	Here, we show that activin A induces Delta-1, Delta-2 and Notch expression and then activates Notch signaling in animal caps.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Delta-1	activin A induces Delta-1, Delta-2 and Notch expression	delta-1	Notch	Notch	notch	8	9	17	18
An allelic series in mice that carried the same point mutations in endogenous Dll1 , generated using a mini gene strategy , showed that early developmental processes depending on DLL1 mediated NOTCH activation were differently sensitive to mutation of individual EGF repeats in DLL1 .	An allelic series in mice that carried the same point mutations in endogenous Dll1, generated using a mini gene strategy, showed that early developmental processes depending on DLL1 mediated NOTCH activation were differently sensitive to mutation of individual EGF repeats in DLL1.	26	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NOTCH	NOTCH	NOTCH	29	30	31	32
Cranial-caudal somite patterning critically depends on DLL1 mediated Notch signalling [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Cranial-caudal somite patterning critically depends on DLL1 mediated Notch signalling [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	6	7	8	9
Here we show that DLL1 induced NOTCH signaling in CHO cells was enhanced by LFNG , but this did not occur in either Lec8 or Lec20 CHO mutants lacking Gal on O-fucose glycans .	Here we show that DLL1 induced NOTCH signaling in CHO cells was enhanced by LFNG, but this did not occur in either Lec8 or Lec20 CHO mutants lacking Gal on O-fucose glycans.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NOTCH	NOTCH	NOTCH	4	5	6	7
To verify that the addition of Dll1 to co-cultures of macrophages and T cells was activating Notch pathways , we used quantitative real-time PCR to examine Hes1 expression .	To verify that the addition of Dll1 to co-cultures of macrophages and T cells was activating Notch pathways, we used quantitative real-time PCR to examine Hes1 expression.	4	17	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	6	7	16	17
These data suggest that , in the absence of Dll1 mediated Notch signaling , cells are diverted from an epithelial fate to a neuronal fate .	These data suggest that, in the absence of Dll1 mediated Notch signaling, cells are diverted from an epithelial fate to a neuronal fate.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	9	10	11	12
During this event , scattered cells expressing Dll1 activate Notch in their neighbouring cells inducing the expression of the transcriptional repressors of the Hes and Hey family genes .	During this event, scattered cells expressing Dll1 activate Notch in their neighbouring cells inducing the expression of the transcriptional repressors of the Hes and Hey family genes.	6	13	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	7	8	9	10
Overexpression of Dll1 activated Notch signaling in B16 cells .	Overexpression of Dll1 activated Notch signaling in B16 cells.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Overexpression of Dll1	dll1	Notch	Notch	notch	2	3	4	5
The first reaction is the cleavage of NICD from Notch under the condition of activation of the Dll1 ligand , which is represented using a mass action equation because the rate of NICD synthesis is proportional to the concentration of the Notch receptor , while the activation of Dll1 to the cleavage of NICD is represented using a Hill equation with Hill coefficient 1 because Dll1 catalyzes Notch at only one site ; also , the inhibition of the cleavage of NICD by Lfng is represented using a Hill equation with Hill coefficient -2 because Lfng binds to Notch at two sites .	The first reaction is the cleavage of NICD from Notch under the condition of activation of the Dll1 ligand, which is represented using a mass action equation because the rate of NICD synthesis is proportional to the concentration of the Notch receptor, while the activation of Dll1 to the cleavage of NICD is represented using a Hill equation with Hill coefficient 1 because Dll1 catalyzes Notch at only one site; also, the inhibition of the cleavage of NICD by Lfng is represented using a Hill equation with Hill coefficient -2 because Lfng binds to Notch at two sites.	65	101	catalyzes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	65	66	67	68
Apart from a putative effect on cell apoptosis , another possibility is that Notch triggering by Delta-1 ( but not by Jagged-1 ) might deliver a B cell differentiation inhibitory signal to a common lymphoid precursor which would then choose the alternative T/NK-cell fate .	Apart from a putative effect on cell apoptosis, another possibility is that Notch triggering by Delta-1 (but not by Jagged-1) might deliver a B cell differentiation inhibitory signal to a common lymphoid precursor which would then choose the alternative T/NK-cell fate.	13	19	triggering	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Delta-1	Delta-1	Delta-1	Notch	Notch	Notch	16	17	13	14
Here , we report that DLL1 mediated Notch signaling regulates the differentiation and function of both osteoblast and osteoclast lineage cells during bone remodeling .	Here, we report that DLL1 mediated Notch signaling regulates the differentiation and function of both osteoblast and osteoclast lineage cells during bone remodeling.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	5	6	7	8
Effects of DLL1 mediated Notch signal activation on osteoclast differentiation in vivo and in vitro .	Effects of DLL1 mediated Notch signal activation on osteoclast differentiation in vivo and in vitro.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	2	3	4	5
Gal enhances the effect of LFNG but inhibits the effect of MFNG on DLL1 induced NOTCH signaling , with functional consequences for regulating the strength of NOTCH signaling .	Gal enhances the effect of LFNG but inhibits the effect of MFNG on DLL1 induced NOTCH signaling, with functional consequences for regulating the strength of NOTCH signaling.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NOTCH	NOTCH	NOTCH	13	14	15	16
However , DLL3 can cis-inhibit Notch signaling activated by DLL1 19 .	However, DLL3 can cis-inhibit Notch signaling activated by DLL1 19.	5	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	9	10	5	6
In summary , Dll1 and Jag1 can similarly activate Notch signalling in neural progenitors of the embryonic spinal cord to regulate their commitment to differentiation , although the two ligands are differently restricted in their range of action : while Jag1 is effectively prevented from signalling to progenitors located in adjacent Dll1 expressing domains , Dll1 can efficiently signal to progenitors in Jag1 expressing domains and regulate their differentiation .	In summary, Dll1 and Jag1 can similarly activate Notch signalling in neural progenitors of the embryonic spinal cord to regulate their commitment to differentiation, although the two ligands are differently restricted in their range of action : while Jag1 is effectively prevented from signalling to progenitors located in adjacent Dll1 expressing domains, Dll1 can efficiently signal to progenitors in Jag1 expressing domains and regulate their differentiation.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	3	4	9	10
In those cells undergoing neuronal differentiation , notch ligands such as Delta-like1 ( Dll1 ) are up-regulated , which in turn activate notch signaling in neighboring cells .	In those cells undergoing neuronal differentiation, notch ligands such as Delta-like1 (Dll1) are up-regulated, which in turn activate notch signaling in neighboring cells.	8	23	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	notch	notch	notch	13	14	22	23
To confirm that the action of miR-34a on DLL1 modulated Notch signaling , we examined the expression of the Notch signaling target gene Hairy Enhancer of Split-1 protein ( Hes-1 ) and found that it was reduced upon force expression of miR-34a in both cell lines .	To confirm that the action of miR-34a on DLL1 modulated Notch signaling, we examined the expression of the Notch signaling target gene Hairy Enhancer of Split-1 protein (Hes-1) and found that it was reduced upon force expression of miR-34a in both cell lines.	6	11	modulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	8	9	10	11
Nevertheless , they have reduced binding of Notch ligands and low levels of Delta1- and Jagged1 induced Notch signaling .	Nevertheless, they have reduced binding of Notch ligands and low levels of Delta1- and Jagged1 induced Notch signaling.	11	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Delta1-	levels of Delta1-	delta1-	Notch	Notch	notch	13	14	17	18
Co-transfection of Dll1 into signal receiving cells decreased the Notch activity due to cis-inhibition by Dll1 .	Co-transfection of Dll1 into signal receiving cells decreased the Notch activity due to cis-inhibition by Dll1.	0	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	2	3	9	10
Based on the known function of Fringe proteins to enhance Delta ligand mediated signaling , these data suggest that Dll1 , expressed in myoepithelial cells , functions to activate Notch in Lfng expressing MaSCs or bipotent progenitors .	Based on the known function of Fringe proteins to enhance Delta ligand mediated signaling, these data suggest that Dll1, expressed in myoepithelial cells, functions to activate Notch in Lfng expressing MaSCs or bipotent progenitors.	19	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1, expressed	dll1	Notch	Notch	notch	19	20	29	30
Taken together , we found that Notch activation induced by Delta-1 partially inhibited GM-CSF-induced differentiation , growth suppression , and apoptosis , along with reducing the GM-CSF-induced cleavage of PARP .	Taken together, we found that Notch activation induced by Delta-1 partially inhibited GM-CSF-induced differentiation, growth suppression, and apoptosis, along with reducing the GM-CSF-induced cleavage of PARP.	6	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Delta-1	Delta-1	Delta-1	Notch	Notch	Notch	10	11	6	7
Altogether , our results demonstrate the significance of DLL1 mediated Notch signaling in osteoblast-osteoclast coupling during bone remodeling .	Altogether, our results demonstrate the significance of DLL1 mediated Notch signaling in osteoblast-osteoclast coupling during bone remodeling.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	8	9	10	11
Notch signaling in SC and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SC .	Notch signaling in SC and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SC.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	9	10	0	1
Therefore , these observations imply that Notch triggering by Delta-1 , but not Jagged-1 , induces the emergence of two cell populations ; a predominant one bearing a phenotype of T and NK cell precursors and a minor one , with a phenotype similar to that observed in developing CD4 + CD8 + thymocytes .	Therefore, these observations imply that Notch triggering by Delta-1, but not Jagged-1, induces the emergence of two cell populations; a predominant one bearing a phenotype of T and NK cell precursors and a minor one, with a phenotype similar to that observed in developing CD4 + CD8 + thymocytes.	6	10	triggering	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Delta-1	Delta-1	Delta-1	Notch	Notch	Notch	9	10	6	7
By contrast , MFNG promoted DLL1 induced NOTCH signaling better in the absence of Gal than in its presence .	By contrast, MFNG promoted DLL1 induced NOTCH signaling better in the absence of Gal than in its presence.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NOTCH	NOTCH	NOTCH	5	6	7	8
Interestingly , arsenic induced an upregulation of Dll1 , a ligand that promotes Notch signaling , which enhances proliferation of progenitor cells .	Interestingly, arsenic induced an upregulation of Dll1, a ligand that promotes Notch signaling, which enhances proliferation of progenitor cells.	5	14	promotes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	7	8	13	14
Accordingly , strong DLL1 mediated signaling leads to GATA2 down-regulation in ETPs developing in culture , whereas GATA2 expression is maintained in ETPs receiving JAG1 mediated Notch signaling .	Accordingly, strong DLL1 mediated signaling leads to GATA2 down-regulation in ETPs developing in culture, whereas GATA2 expression is maintained in ETPs receiving JAG1 mediated Notch signaling.	2	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	3	4	26	27
There are four Notch receptors ( Notch1-4 ) , which can be activated by ligands that belong to either the Delta like ( DLL1 , 3 , 4 ) or Jagged family ( Jagged 1 and 2 ) of proteins .	There are four Notch receptors (Notch1-4), which can be activated by ligands that belong to either the Delta like (DLL1, 3, 4) or Jagged family (Jagged 1 and 2) of proteins.	3	27	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	23	24	3	4
Our results showed that over-expression of Dll1 could activate Notch signaling in tumor cells , and promote tumor cell proliferation in vitro .	Our results showed that over-expression of Dll1 could activate Notch signaling in tumor cells, and promote tumor cell proliferation in vitro.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	over-expression of Dll1	dll1	Notch	Notch	notch	6	7	9	10
According to our results , STAT3 induces DLL1 and DLL1 mediated Notch signaling boosts TLRL stimulated IL-6 .	According to our results, STAT3 induces DLL1 and DLL1 mediated Notch signaling boosts TLRL stimulated IL-6.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	9	10	11	12
In a similar vein , it was reported that in the ventricular zone , DLL1 is linked with adherens junction through interaction with MAGI1 at the apical termini of processes to activate Notch on neighboring cells in the developing central nervous system [ XREF_BIBR ] .	In a similar vein, it was reported that in the ventricular zone, DLL1 is linked with adherens junction through interaction with MAGI1 at the apical termini of processes to activate Notch on neighboring cells in the developing central nervous system [XREF_BIBR].	14	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	14	15	32	33
In mammals , Notch signals are transmitted when transmembrane ligands Jagged1 ( Jag1 ) , Jagged2 ( Jag2 ) , Delta like 1 ( DLL1 ) or Delta like 4 ( DLL4 ) stimulate Notch receptor paralogs ( Notch1-4 ) on the surface of adjacent cells .	In mammals, Notch signals are transmitted when transmembrane ligands Jagged1 (Jag1), Jagged2 (Jag2), Delta like 1 (DLL1) or Delta like 4 (DLL4) stimulate Notch receptor paralogs (Notch1-4) on the surface of adjacent cells.	20	36	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	24	25	34	35
Dll3 does not compensate for Dll1 ; DLL1 activates Notch in Drosophila wing discs , but DLL3 does not .	Dll3 does not compensate for Dll1; DLL1 activates Notch in Drosophila wing discs, but DLL3 does not.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	7	8	9	10
In the anterior PSM , every cell expresses both Notch receptors and ligands , and DLL1 is the only activator of Notch while DLL4 is not endogenously expressed .	In the anterior PSM, every cell expresses both Notch receptors and ligands, and DLL1 is the only activator of Notch while DLL4 is not endogenously expressed.	15	22	is the only activator	Positive_activation_copula_1	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	15	16	21	22
These data strongly suggest that the multivalent DLL1 mediated Notch activation possesses functional capacity to induce tumor specific T cell responses and memory resulting in the significant therapeutic benefit in tumor models .	These data strongly suggest that the multivalent DLL1 mediated Notch activation possesses functional capacity to induce tumor specific T cell responses and memory resulting in the significant therapeutic benefit in tumor models.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	7	8	9	10
Of note , only iNs expressed factors that are involved in Notch signaling such as Dll1 , Dll3 , Hes5 , and Mfng .	Of note, only iNs expressed factors that are involved in Notch signaling such as Dll1, Dll3, Hes5, and Mfng.	11	22	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	15	16	11	12
Because DLL1 overexpression produced a stronger effect on the postnatal bone phenotype than did JAG1 overexpression , we evaluated the roles of DLL1 mediated Notch signal activation in bone physiology .	Because DLL1 overexpression produced a stronger effect on the postnatal bone phenotype than did JAG1 overexpression, we evaluated the roles of DLL1 mediated Notch signal activation in bone physiology.	20	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	22	23	24	25
Conversely , the selective activation of Dll1 mediated Notch signaling in BM precursors in tumor bearing mice resulted in the increase of tumor infiltrating T cells and enhanced activation of Th1-type IFNgamma producing T cells , resulting in tumor growth inhibition .	Conversely, the selective activation of Dll1 mediated Notch signaling in BM precursors in tumor bearing mice resulted in the increase of tumor infiltrating T cells and enhanced activation of Th1-type IFNgamma producing T cells, resulting in tumor growth inhibition.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	6	7	8	9
In the simple mathematical model described above , d = 0 represents complete Dll1 deficiency ( no Notch signalling ) , and d x = I 1 ( x )/[ P+ I 1 ( x ) + I 2 + N ] when there is ' x ' fraction of I 1 than in wild-type embryos , an estimation of the Dll1 level triggering Notch signalling in P ; for instance , x in Dll1 heterozygous embryos might equal ( 1/2 ) .	In the simple mathematical model described above, d = 0 represents complete Dll1 deficiency (no Notch signalling), and d x = I 1 (x)/[P+I 1 (x) + I 2 + N] when there is ' x ' fraction of I 1 than in wild-type embryos, an estimation of the Dll1 level triggering Notch signalling in P; for instance, x in Dll1 heterozygous embryos might equal (1/2).	61	65	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1 level	dll1	Notch	Notch	notch	61	62	64	65
Nevertheless , Dll1 and Jag1 could activate Notch receptors differently , and some evidence suggests that Dll1 induces stronger Notch signalling than Jag1 in the inner ear , possibly due to modifications of the Notch receptor by Fringe proteins .	Nevertheless, Dll1 and Jag1 could activate Notch receptors differently, and some evidence suggests that Dll1 induces stronger Notch signalling than Jag1 in the inner ear, possibly due to modifications of the Notch receptor by Fringe proteins.	16	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	16	17	19	20
Furthermore , in contrast to wildtype B cells , ADAM10-null cells were completely unresponsive to Dll1 induced Notch stimulation .	Furthermore, in contrast to wildtype B cells, ADAM10-null cells were completely unresponsive to Dll1 induced Notch stimulation.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	15	16	17	18
On the contrary , no significant changes were detected in Runx2 transcription in either DLL1 or Dll1 floxed mice compared with their respective littermates , implying that DLL1 mediated Notch signaling was not involved in a Runx2 transcription dependent process of osteoblast commitment from MSCs .	On the contrary, no significant changes were detected in Runx2 transcription in either DLL1 or Dll1 floxed mice compared with their respective littermates, implying that DLL1 mediated Notch signaling was not involved in a Runx2 transcription dependent process of osteoblast commitment from MSCs.	27	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	27	28	29	30
Since there is no evidence for any physical boundary separating the various progenitor domains along the D-V axis of the embryonic spinal cord , it is conceivable that Dll1 expressing cells , in direct contact with V1 and dI6 progenitors , may activate Notch in these cells , enabling neurogenesis to proceed at normal pace in the absence of Jag1 .	Since there is no evidence for any physical boundary separating the various progenitor domains along the D-V axis of the embryonic spinal cord, it is conceivable that Dll1 expressing cells, in direct contact with V1 and dI6 progenitors, may activate Notch in these cells, enabling neurogenesis to proceed at normal pace in the absence of Jag1.	28	46	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	28	29	43	44
Together our optical tweezers and biochemical analyses suggest Dll1 recycling modulates Notch signaling by regulating the level of ligand at the cell surface , rather than enhancing Dll1-N1 bond strength as previously proposed .	Together our optical tweezers and biochemical analyses suggest Dll1 recycling modulates Notch signaling by regulating the level of ligand at the cell surface, rather than enhancing Dll1-N1 bond strength as previously proposed.	8	12	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	8	9	11	12
It is also worth noting that Notch signaling activated by Dll1 regulates the Nrp1 promoter , indicating direct control of VEGF responsiveness by Notch .	It is also worth noting that Notch signaling activated by Dll1 regulates the Nrp1 promoter, indicating direct control of VEGF responsiveness by Notch.	6	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	10	11	6	7
Evidently , it is only in the crypts that cells interact via the Notch pathway , and only there that Dll1 can be serving to activate Notch .	Evidently, it is only in the crypts that cells interact via the Notch pathway, and only there that Dll1 can be serving to activate Notch.	20	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	20	21	26	27
To test whether the DSL domain and distal two EGF repeats of DLL1 are sufficient to activate Notch , we replaced the six proximal EGF repeats of DLL1 by the EGF repeats of DLL3 ( XREF_FIG , construct G ) .	To test whether the DSL domain and distal two EGF repeats of DLL1 are sufficient to activate Notch, we replaced the six proximal EGF repeats of DLL1 by the EGF repeats of DLL3 (XREF_FIG, construct G).	10	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	12	13	17	18
In contrast , in the diffuse type of GC , DLL1 epigenetic silencing represses the activation of Notch and is associated with high level of HATH1 , which is a specific feature of diffuse of mixed type of gastric cancer .	In contrast, in the diffuse type of GC, DLL1 epigenetic silencing represses the activation of Notch and is associated with high level of HATH1, which is a specific feature of diffuse of mixed type of gastric cancer.	10	18	represses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	10	11	17	18
Dll1 is expressed by cells peripheral to the vasculature , and acts as an extrinsic signal to activate Notch signaling in presumptive tip cells , which reinforces VEGF-A action by further inducing Dll4 expression to promote tip cell specification .	Dll1 is expressed by cells peripheral to the vasculature, and acts as an extrinsic signal to activate Notch signaling in presumptive tip cells, which reinforces VEGF-A action by further inducing Dll4 expression to promote tip cell specification.	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1 is expressed	dll1	Notch	Notch	notch	0	1	18	19
Recently , cis-inhibition of Notch signaling by the DLL1 ligand has been described in Drosophila and mice [ XREF_BIBR ] .	Recently, cis-inhibition of Notch signaling by the DLL1 ligand has been described in Drosophila and mice [XREF_BIBR].	4	9	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	8	9	4	5
Since Lfng normally enhances cis-inhibition between Delta ligands and Notch receptors expressed in the same cell , we predict that loss of Lfng would partially relieve cis-inhibition of Dll1 expressed at the boundary and allow it to deliver more Notch signal to compensate for the loss of Jag2 .	Since Lfng normally enhances cis-inhibition between Delta ligands and Notch receptors expressed in the same cell, we predict that loss of Lfng would partially relieve cis-inhibition of Dll1 expressed at the boundary and allow it to deliver more Notch signal to compensate for the loss of Jag2.	20	40	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	loss of Lfng would partially relieve cis-inhibition of Dll1 expressed	dll1	Notch	Notch	notch	28	29	39	40
64 Notch mediated progenitor expansion was perfected by the demonstration that immobilization of Dll1 ligands was necessary to efficiently induce Notch signaling .	64 Notch mediated progenitor expansion was perfected by the demonstration that immobilization of Dll1 ligands was necessary to efficiently induce Notch signaling.	13	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	13	14	20	21
At later stages ( neurogenic phase ) , many differentiating neurons express Dll1 in a sustained manner , thereby activating Notch signaling in neural stem and progenitor cells .	At later stages (neurogenic phase), many differentiating neurons express Dll1 in a sustained manner, thereby activating Notch signaling in neural stem and progenitor cells.	11	21	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	12	13	20	21
In light of these data , we predict that enhanced expression of both DLL1 and Notch2 on the HEK-TERST cells would increase activation of Notch signaling via cell-cell interactions between adjacent HEK-TERST cells .	In light of these data, we predict that enhanced expression of both DLL1 and Notch2 on the HEK-TERST cells would increase activation of Notch signaling via cell-cell interactions between adjacent HEK-TERST cells.	10	25	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	expression of both DLL1	dll1	Notch	Notch	notch	13	14	24	25
The strong immune stimulatory effect of pharmacologically enhanced DLL1 mediated Notch signaling supports the concept that multivalent DLL1 could be employed as a novel immunotherapeutic to induce robust immune responses , provide effective tumor surveillance and prolong tumor-free survival when combined with tumor oncogene targeted therapies .	The strong immune stimulatory effect of pharmacologically enhanced DLL1 mediated Notch signaling supports the concept that multivalent DLL1 could be employed as a novel immunotherapeutic to induce robust immune responses, provide effective tumor surveillance and prolong tumor-free survival when combined with tumor oncogene targeted therapies.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	8	9	10	11
Since DLL1 expressing mice recapitulated the phenotypes of osteoblast specific Notch gain-of-function mice ( Engin et al ., 2008 ) , we sought to determine the roles of DLL1 mediated Notch signaling activation in the maintenance of bone homeostasis .	Since DLL1 expressing mice recapitulated the phenotypes of osteoblast specific Notch gain-of-function mice (Engin et al., 2008), we sought to determine the roles of DLL1 mediated Notch signaling activation in the maintenance of bone homeostasis.	26	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	28	29	30	31
In DLL1 activated NOTCH limbs , the pool of PAX7+ cells was maintained at E9.5 , despite inhibition of muscle differentiation ( XREF_FIG ) , which is consistent with the maintenance of PAX7+ progenitors in NICD expressing cells in mouse fetuses .	In DLL1 activated NOTCH limbs, the pool of PAX7+ cells was maintained at E9.5, despite inhibition of muscle differentiation (XREF_FIG), which is consistent with the maintenance of PAX7+ progenitors in NICD expressing cells in mouse fetuses.	0	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NOTCH	NOTCH	NOTCH	1	2	3	4
This Notch mediated immune suppression could be reversed by the enhanced DLL1 mediated Notch signaling in hematopoietic microenvironment .	This Notch mediated immune suppression could be reversed by the enhanced DLL1 mediated Notch signaling in hematopoietic microenvironment.	7	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	11	12	13	14
Pharmacological enhancement of DLL1 mediated Notch signaling supports effector T cell differentiation and survival in tumor bearing mice .	Pharmacological enhancement of DLL1 mediated Notch signaling supports effector T cell differentiation and survival in tumor bearing mice.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	3	4	5	6
Although Rab11 dependent Dll1 recycling does not strengthen Notch binding , depletion of Rab11A and B by more than 80 % significantly reduced Notch reporter activity induced by Dll1 cells in coculture assays ( XREF_FIG ) .	Although Rab11 dependent Dll1 recycling does not strengthen Notch binding, depletion of Rab11A and B by more than 80% significantly reduced Notch reporter activity induced by Dll1 cells in coculture assays (XREF_FIG).	23	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	28	29	23	24
On the other hand , Delta-1 activation of Notch signaling is known to result in HES-1 transactivation 32 , an effect that could explain the accumulation of cells with a phenotype of T/NK progenitors in Delta-1-expressing stromas as described in this paper .	On the other hand, Delta-1 activation of Notch signaling is known to result in HES-1 transactivation 32, an effect that could explain the accumulation of cells with a phenotype of T/NK progenitors in Delta-1-expressing stromas as described in this paper.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Delta-1	Delta-1	Delta-1	Notch	Notch	Notch	5	6	8	9
To further clarify the roles of DLL1 mediated Notch signaling in osteoblast-osteoclast coupling , we measured the concentrations of cytokines important for osteoclastogenesis in the plasma , BM liquid , and culture supernatant of DLL1 and non transgenic littermates .	To further clarify the roles of DLL1 mediated Notch signaling in osteoblast-osteoclast coupling, we measured the concentrations of cytokines important for osteoclastogenesis in the plasma, BM liquid, and culture supernatant of DLL1 and non transgenic littermates.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	6	7	8	9
Dll1 mediated Notch activation induced N-cadherin expression .	Dll1 mediated Notch activation induced N-cadherin expression.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	0	1	2	3
Fng proteins enhance Dll1 activated Notch signalling and block Notch activation mediated by Jag1 .	Fng proteins enhance Dll1 activated Notch signalling and block Notch activation mediated by Jag1.	3	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	3	4	5	6
Delta-Like1 ( DLL1 ) can combine with Notch receptor and activate the Notch signal pathway , then made a decision to cell differentiation and regulate the development of many tissues .	Delta-Like1 (DLL1) can combine with Notch receptor and activate the Notch signal pathway, then made a decision to cell differentiation and regulate the development of many tissues.	0	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Delta-Like1	Delta-Like1	Delta-Like1	Notch	Notch	Notch	0	1	12	13
For example , siRNA knockdown of the Notch receptor decreased Notch availability ( XREF_FIG ) and reduced Notch activation by Dll1 ligands adhered to cell culture plate surfaces ( XREF_FIG ) .	For example, siRNA knockdown of the Notch receptor decreased Notch availability (XREF_FIG) and reduced Notch activation by Dll1 ligands adhered to cell culture plate surfaces (XREF_FIG).	17	21	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	20	21	17	18
DLL3 does not repress DLL1 mediated Notch activation in vivo .	DLL3 does not repress DLL1 mediated Notch activation in vivo.	3	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	4	5	6	7
The canonical Notch pathway is activated by the interaction of DSL ligands ( DLL1 , DLL3 , DLL4 , JAG1 and JAG2 ) and Notch receptors ( NOTCH1-NOTCH4 ) leading to two sequential proteolytic cleavages of the receptors .	The canonical Notch pathway is activated by the interaction of DSL ligands (DLL1, DLL3, DLL4, JAG1 and JAG2) and Notch receptors (NOTCH1-NOTCH4) leading to two sequential proteolytic cleavages of the receptors.	2	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	13	14	2	3
The activation of NOTCH signalling by DELTA-1 in the adjacent progenitors inhibits neurogenesis and is required to maintain proliferation .	The activation of NOTCH signalling by DELTA-1 in the adjacent progenitors inhibits neurogenesis and is required to maintain proliferation.	3	10	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	DELTA-1	DELTA-1	DELTA-1	NOTCH	NOTCH	NOTCH	6	7	3	4
Recently , LFNG has been shown to repress DLL1 function in NIH3T3 cells that simultaneously express DLL3 and Notch1 , whereas coexpression of DLL3 with DLL1 in L cells had no effect on DLL1 mediated Notch activation [ XREF_BIBR ] .	Recently, LFNG has been shown to repress DLL1 function in NIH3T3 cells that simultaneously express DLL3 and Notch1, whereas coexpression of DLL3 with DLL1 in L cells had no effect on DLL1 mediated Notch activation [XREF_BIBR].	31	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	33	34	35	36
This is an intriguing result , as in Jag1 mutants , the maculae ( particularly the saccular macula ) are the least affected sensory organs [ XREF_BIBR , XREF_BIBR ] , indicating that Dll1 mediated Notch activation may play an important role in the specification of these organs .	This is an intriguing result, as in Jag1 mutants, the maculae (particularly the saccular macula) are the least affected sensory organs [XREF_BIBR, XREF_BIBR], indicating that Dll1 mediated Notch activation may play an important role in the specification of these organs.	33	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	33	34	35	36
In those experiments , both DLL1 and DLL4 were able to activate Drosophila Notch , and DLL3 had no effect .	In those experiments, both DLL1 and DLL4 were able to activate Drosophila Notch, and DLL3 had no effect.	4	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	5	6	13	14
Functionally , we found that dual inactivation of DLL1 and DLL3 was sufficient to upregulate Notch signalling in epidermal progenitors , as visualized by induction of the direct Notch targets HES1 , HES5 and NOTCH3 mRNAs ( XREF_FIG ) .	Functionally, we found that dual inactivation of DLL1 and DLL3 was sufficient to upregulate Notch signalling in epidermal progenitors, as visualized by induction of the direct Notch targets HES1, HES5 and NOTCH3 mRNAs (XREF_FIG).	6	16	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	8	9	15	16
When BM hematopoietic cells of DLL1 mice and non transgenic littermates were cultured in the presence of M-CSF and RANKL , osteoclasts were formed in similar numbers , confirming that the number and the functionality of osteoclast precursors within the hematopoietic population were not altered by osteoblast specific activation of DLL1 mediated Notch signaling .	When BM hematopoietic cells of DLL1 mice and non transgenic littermates were cultured in the presence of M-CSF and RANKL, osteoclasts were formed in similar numbers, confirming that the number and the functionality of osteoclast precursors within the hematopoietic population were not altered by osteoblast specific activation of DLL1 mediated Notch signaling.	48	53	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	50	51	52	53
To verify if DLL1 increased levels leads to an effective Notch pathway activation , the expression of NICD protein ( Notch Intracellular Domain , Notch 1 activated form ) in SH-SY5Y and IMR-32 neuroblastoma cells was analyzed .	To verify if DLL1 increased levels leads to an effective Notch pathway activation, the expression of NICD protein (Notch Intracellular Domain, Notch 1 activated form) in SH-SY5Y and IMR-32 neuroblastoma cells was analyzed.	3	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	3	4	10	11
To determine the endogenous function of DLL1 mediated Notch signaling in the physiology of osteoblast development , in vitro osteoblast differentiation experiments were conducted without adding any cytokines or osteogenic agents using MSC enriched BM cells obtained from DLL1 mice , mice with conditional deletion of the DLL1 gene ( Dll1 floxed ) , and their respective littermates .	To determine the endogenous function of DLL1 mediated Notch signaling in the physiology of osteoblast development, in vitro osteoblast differentiation experiments were conducted without adding any cytokines or osteogenic agents using MSC enriched BM cells obtained from DLL1 mice, mice with conditional deletion of the DLL1 gene (Dll1 floxed), and their respective littermates.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	6	7	8	9
Dll1 overexpression activated Notch signaling in B16 tumor cells and significantly enhanced the adhering capacity of B16 tumor cells both in vitro and in vivo .	Dll1 overexpression activated Notch signaling in B16 tumor cells and significantly enhanced the adhering capacity of B16 tumor cells both in vitro and in vivo.	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1 overexpression	dll1	Notch	Notch	notch	0	1	3	4
It is known that Notch signaling , in which Notch in a cell can be activated by Dll1 in neighboring cells ( trans-activation ) and can also be inhibited by Dll1 within the same cell ( cis-inhibition ) , is important for neural fate decisions .	It is known that Notch signaling, in which Notch in a cell can be activated by Dll1 in neighboring cells (trans-activation) and can also be inhibited by Dll1 within the same cell (cis-inhibition), is important for neural fate decisions.	4	20	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	17	18	4	5
Our expression analysis in the mammary gland reveals a similar boundary at the TEB-ductal junction , where Lfng may differentially regulate Notch activation induced by Dll1 and/or Jagged1 .	Our expression analysis in the mammary gland reveals a similar boundary at the TEB-ductal junction, where Lfng may differentially regulate Notch activation induced by Dll1 and/or Jagged1.	21	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	25	26	21	22
Because the number of Dll1-immunopositive cells appeared to be fewer than that of NICD + cells , it is possible that one Dll1 positive cell communicates with a number of adjacent NSCs to activate Notch signalling .	Because the number of Dll1-immunopositive cells appeared to be fewer than that of NICD + cells, it is possible that one Dll1 positive cell communicates with a number of adjacent NSCs to activate Notch signalling.	22	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	22	23	34	35
Roles of DLL1 mediated Notch signal activation in osteoblast development in vitro .	Roles of DLL1 mediated Notch signal activation in osteoblast development in vitro.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	2	3	4	5
Taken together , the combined data provide strong evidence that EOGT regulates DLL1 induced Notch signaling .	Taken together, the combined data provide strong evidence that EOGT regulates DLL1 induced Notch signaling.	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	12	13	14	15
In summary , these results confirms that Notch signaling is activated by DLL1 in CD4 + T cells , yet this is insufficient to instruct either Th1 or Th2 fate specification , nor can NICD act to redirect CD4 + T cell differentiation under these conditions ( XREF_FIG ) .	In summary, these results confirms that Notch signaling is activated by DLL1 in CD4 + T cells, yet this is insufficient to instruct either Th1 or Th2 fate specification, nor can NICD act to redirect CD4 + T cell differentiation under these conditions (XREF_FIG).	7	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	12	13	7	8
These results indicate that DLL1 expression in osteoblasts must be regulated properly to ensure both the early and late phases of the physiological development of osteoblast To further delineate the mechanisms by which DLL1 mediated Notch signaling regulates osteoblast differentiation and maturation , expression levels of transcriptional regulators were analyzed .	These results indicate that DLL1 expression in osteoblasts must be regulated properly to ensure both the early and late phases of the physiological development of osteoblast To further delineate the mechanisms by which DLL1 mediated Notch signaling regulates osteoblast differentiation and maturation, expression levels of transcriptional regulators were analyzed.	33	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	33	34	35	36
To exclude the possibility that other members of the Wnt family or factors released by fibroblasts may influence these results , we used an experimental system where Notch signaling was activated by Delta-1 immobilized on plastic , thereby removing the involvement of stromal cells .	To exclude the possibility that other members of the Wnt family or factors released by fibroblasts may influence these results, we used an experimental system where Notch signaling was activated by Delta-1 immobilized on plastic, thereby removing the involvement of stromal cells.	27	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Delta-1	Delta-1	Delta-1	Notch	Notch	Notch	32	33	27	28
Delta-1 substantially activated the Notch pathway ( p < 0.01 ) , determined by activation of CBF-1 transcription factor ( XREF_FIG ) and by the increased expression of the Notch targeted gene Hes 5 ( XREF_FIG ) .	Delta-1 substantially activated the Notch pathway (p < 0.01), determined by activation of CBF-1 transcription factor (XREF_FIG) and by the increased expression of the Notch targeted gene Hes 5 (XREF_FIG).	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Delta-1	Delta-1	Delta-1	Notch	Notch	Notch	0	1	4	5
In the normal gut Dll4 acts redundantly with Dll1 mediating the Notch signaling regulation of the intestinal stem cells proliferation and their commitment towards de secretory cell fate [ XREF_BIBR ] .	In the normal gut Dll4 acts redundantly with Dll1 mediating the Notch signaling regulation of the intestinal stem cells proliferation and their commitment towards de secretory cell fate [XREF_BIBR].	5	13	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	8	9	11	12
Effects of DLL1 mediated Notch signaling on osteoblast differentiation in vivo .	Effects of DLL1 mediated Notch signaling on osteoblast differentiation in vivo.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	2	3	4	5
Taken together , DLL1 mediated Notch signaling is critical for proper bone remodeling as it regulates the differentiation and function of both osteoblasts and osteoclasts .	Taken together, DLL1 mediated Notch signaling is critical for proper bone remodeling as it regulates the differentiation and function of both osteoblasts and osteoclasts.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	3	4	5	6
Our data show that basal Dll1 expression in resting microglial cells can be potently induced by curcumin , which could potentially trigger Notch signaling to prevent migration associated with pro inflammatory priming of BV-2 cells .	Our data show that basal Dll1 expression in resting microglial cells can be potently induced by curcumin, which could potentially trigger Notch signaling to prevent migration associated with pro inflammatory priming of BV-2 cells.	5	23	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1 expression in resting microglial cells can be potently induced by curcumin	dll1	Notch	Notch	notch	5	6	22	23
Since the expression of Dll1 activates the Notch signaling pathway in neighboring cells , these factors , i.e ., Notch and Dll1 , Hes1 , Ngn2 , form a regulatory loop including both positive and negative regulatory interactions .	Since the expression of Dll1 activates the Notch signaling pathway in neighboring cells, these factors, i.e., Notch and Dll1, Hes1, Ngn2, form a regulatory loop including both positive and negative regulatory interactions.	2	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	expression of Dll1	dll1	Notch	Notch	notch	4	5	19	20
Mutation of its conserved tryptophan residue results in a Dll1 molecule which is rapidly inactivated by shedding and degradation , does not recycle to the cell surface and does not activate Notch signaling .	Mutation of its conserved tryptophan residue results in a Dll1 molecule which is rapidly inactivated by shedding and degradation, does not recycle to the cell surface and does not activate Notch signaling.	9	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	9	10	31	32
Although our genetic studies confirm that ablation of Dll4 in the intestinal epithelium does not perturb proliferation or goblet cell differentiation in the crypt , they show that Dll4 mediated Notch signaling is indeed occurring in the intestine and that the absence of a measurable phenotype in Dll4 mutant mice is due to redundant Dll1 mediated Notch signaling .	Although our genetic studies confirm that ablation of Dll4 in the intestinal epithelium does not perturb proliferation or goblet cell differentiation in the crypt, they show that Dll4 mediated Notch signaling is indeed occurring in the intestine and that the absence of a measurable phenotype in Dll4 mutant mice is due to redundant Dll1 mediated Notch signaling.	51	57	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	54	55	56	57
Therefore , although weak JAG1- and strong DLL1 induced Notch signaling either support or inhibit , respectively , GATA2 expression in ETPs ( XREF_FIG ) , once ETPs have undergone the myeloid/DC developmental program , GATA2 transcription is preserved in committed CDPs , even upon strong Notch signaling provided by DLL1 .	Therefore, although weak JAG1- and strong DLL1 induced Notch signaling either support or inhibit, respectively, GATA2 expression in ETPs (XREF_FIG), once ETPs have undergone the myeloid/DC developmental program, GATA2 transcription is preserved in committed CDPs, even upon strong Notch signaling provided by DLL1.	4	10	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	7	8	9	10
Thus , Dll4 mediated Notch signaling occurs downstream of VEGF during arterial specification , whereas Dll1 mediated Notch signaling acts upstream of VEGF to maintain arterial identity .	Thus, Dll4 mediated Notch signaling occurs downstream of VEGF during arterial specification, whereas Dll1 mediated Notch signaling acts upstream of VEGF to maintain arterial identity.	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	15	16	17	18
To test whether O fucosylation is important for DLL1 mediated activation of Notch , wild type and POFUT1 deficient cells expressing wt DLL1 were cocultured with HeLa cells stably expressing NOTCH1 ( HeLaN1 ) and activated Notch was determined by Western Blot analysis using antibodies specifically recognizing NICD after S3 cleavage .	To test whether O fucosylation is important for DLL1 mediated activation of Notch, wild type and POFUT1 deficient cells expressing wt DLL1 were cocultured with HeLa cells stably expressing NOTCH1 (HeLaN1) and activated Notch was determined by Western Blot analysis using antibodies specifically recognizing NICD after S3 cleavage.	8	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	8	9	12	13
Our study revealed unique roles of DLL1 mediated Notch signaling in the process of bone remodeling .	Our study revealed unique roles of DLL1 mediated Notch signaling in the process of bone remodeling.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	6	7	8	9
Given that Dll1 activates Notch in neighbouring cells ( trans activation ) and inhibits Notch within the same cell ( cis inhibition ) , asymmetric segregation of Dll1 during NSC division would be expected to promote the activation of Notch signalling in the daughter NSC not only by providing a Dll1 signal to its sister cell but also by excluding Dll1 from the daughter NSC .	Given that Dll1 activates Notch in neighbouring cells (trans activation) and inhibits Notch within the same cell (cis inhibition), asymmetric segregation of Dll1 during NSC division would be expected to promote the activation of Notch signalling in the daughter NSC not only by providing a Dll1 signal to its sister cell but also by excluding Dll1 from the daughter NSC.	2	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	2	3	14	15
These data further suggest a cellular mechanism for INP mediated Dll1 activation of Notch signaling , whereby INPs extend long-range dynamic processes containing punctate Dll1 protein to contact and activate Notch signaling in RG .	These data further suggest a cellular mechanism for INP mediated Dll1 activation of Notch signaling, whereby INPs extend long-range dynamic processes containing punctate Dll1 protein to contact and activate Notch signaling in RG.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Dll1	INP mediated Dll1	dll1	Notch	Notch	notch	10	11	13	14
As NOTCH2NLB can block DLL1 function when co-expressed in the same cell , it could prevent DLL1 mediated cis-inhibition , thereby leading tor a higher tone of Notch signaling and progenitor self-renewal cell-autonomously .	As NOTCH2NLB can block DLL1 function when co-expressed in the same cell, it could prevent DLL1 mediated cis-inhibition, thereby leading tor a higher tone of Notch signaling and progenitor self-renewal cell-autonomously.	15	28	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	16	17	27	28
In this study , we demonstrate that Dll1 can activate Notch signaling mostly through Notch2 receptor and can contribute to drug resistance to bortezomib , both in murine and human MM cells .	In this study, we demonstrate that Dll1 can activate Notch signaling mostly through Notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human MM cells.	7	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	7	8	10	11
We asked whether DLL1 mediated Notch signaling functioned in perinatal bone formation .	We asked whether DLL1 mediated Notch signaling functioned in perinatal bone formation.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	3	4	5	6
Exclusion of Dll1 by asymmetric segregation , in addition to Notch activation by the Dll1 inheriting sister cell , thus results in the ' initialization ' of the quiescent and undifferentiated state in activated NSCs .	Exclusion of Dll1 by asymmetric segregation, in addition to Notch activation by the Dll1 inheriting sister cell, thus results in the ' initialization ' of the quiescent and undifferentiated state in activated NSCs.	10	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	14	15	10	11
Therefore , Notch signaling induced by DLL1 , and to a lesser extent by JAG1 , supports the survival of CD123 + CDPs generated in vitro from ETPs .	Therefore, Notch signaling induced by DLL1, and to a lesser extent by JAG1, supports the survival of CD123 + CDPs generated in vitro from ETPs.	2	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	6	7	2	3
Dll1 shedding changes the receptor and ligand ratio and modulates the level of Notch signaling .	Dll1 shedding changes the receptor and ligand ratio and modulates the level of Notch signaling.	0	14	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	0	1	13	14
DLL1 induced Notch signaling was responsible for the expansion of the bone forming cell pool by promoting the proliferation of committed but immature osteoblasts .	DLL1 induced Notch signaling was responsible for the expansion of the bone forming cell pool by promoting the proliferation of committed but immature osteoblasts.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	0	1	2	3
Jag1 and Dll1 alone as well as in combination with each other induced Notch activation in control cells ( XREF_FIG , lanes 3 , 5 & 7 ) .	Jag1 and Dll1 alone as well as in combination with each other induced Notch activation in control cells (XREF_FIG, lanes 3, 5 & 7).	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	2	3	13	14
Maintenance of Bone Homeostasis by DLL1 Mediated Notch Signaling .	Maintenance of Bone Homeostasis by DLL1 Mediated Notch Signaling.	3	8	Mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	5	6	7	8
Therefore , the presence of Gal on O-fucose glycans differentially affects DLL1 induced NOTCH signaling modulated by LFNG versus MFNG .	Therefore, the presence of Gal on O-fucose glycans differentially affects DLL1 induced NOTCH signaling modulated by LFNG versus MFNG.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NOTCH	NOTCH	NOTCH	11	12	13	14
These results demonstrate that , in transfected cells , ADAM mediated processing of Dll1 indeed increases Notch signaling in a cell-autonomous manner ( XREF_FIG ) .	These results demonstrate that, in transfected cells, ADAM mediated processing of Dll1 indeed increases Notch signaling in a cell-autonomous manner (XREF_FIG).	11	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	13	14	16	17
Both of the Notch ligands Jagged1 and Dll1 can activate Notch signaling in DCs , but their effect on DC differentiation is different .	Both of the Notch ligands Jagged1 and Dll1 can activate Notch signaling in DCs, but their effect on DC differentiation is different.	5	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	7	8	10	11
Dll1 and Jag1 activated the Notch pathway as was measured by the activity of CBF-1 reporter and expression of hes5 ( XREF_FIG ) , suggesting that both ligands are able to activate the conventional Notch signaling .	Dll1 and Jag1 activated the Notch pathway as was measured by the activity of CBF-1 reporter and expression of hes5 (XREF_FIG), suggesting that both ligands are able to activate the conventional Notch signaling.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	0	1	5	6
Ngn3 infection activated transcription of Dll1 and Dll4 and thus increased Notch signaling in neighboring pairs , which is expected to limit overall endocrine differentiation .	Ngn3 infection activated transcription of Dll1 and Dll4 and thus increased Notch signaling in neighboring pairs, which is expected to limit overall endocrine differentiation.	0	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Ngn3 infection activated transcription of Dll1	dll1	Notch	Notch	notch	5	6	11	12
Loss of the ligands Dll1 and Dll4 could induce the silencing of Notch activation in intestinal epithelial cells .	Loss of the ligands Dll1 and Dll4 could induce the silencing of Notch activation in intestinal epithelial cells.	0	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Loss of the ligands Dll1	dll1	Notch	Notch	notch	4	5	12	13
A primary role of DLL1 mediated Notch signaling is to induce proliferation of osteoblast progenitors to expand the pool of bone forming cells .	A primary role of DLL1 mediated Notch signaling is to induce proliferation of osteoblast progenitors to expand the pool of bone forming cells.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	4	5	6	7
On the contrary , kinetic analysis of cell cultures set up from CD123 + p as above ( XREF_FIG ) showed that numbers of cells keeping the CD123 + CD13 lo CDP phenotype ( XREF_FIG ) increased significantly along time in OP9-DLL1 cultures compared with OP9-GFP controls but less so in OP9-JAG1 cultures , suggesting that Notch activation induced by Notch ligands , particularly DLL1 , support the expansion of developing CDPs ( XREF_FIG ) .	On the contrary, kinetic analysis of cell cultures set up from CD123 + p as above (XREF_FIG) showed that numbers of cells keeping the CD123 + CD13 lo CDP phenotype (XREF_FIG) increased significantly along time in OP9-DLL1 cultures compared with OP9-GFP controls but less so in OP9-JAG1 cultures, suggesting that Notch activation induced by Notch ligands, particularly DLL1, support the expansion of developing CDPs (XREF_FIG).	56	65	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	64	65	56	57
A Dll1 overexpression vector was transfected into the cells to activate Notch signaling , and the results revealed that the activation of Notch signaling attenuated the effects of OSM on MC3T3-E1 cell proliferation and differentiation .	A Dll1 overexpression vector was transfected into the cells to activate Notch signaling, and the results revealed that the activation of Notch signaling attenuated the effects of OSM on MC3T3-E1 cell proliferation and differentiation.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	1	2	11	12
Additionally , DLL4 induces Notch-1 , -2 , -3 cleavages [ XREF_BIBR ] .	Additionally, DLL4 induces Notch-1, -2, -3 cleavages [XREF_BIBR].	2	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch-1	Notch-1	Notch-1	2	3	4	5
When Dll4 activates Notch1 , a portion of the intracellular domain of Notch1 ( NotchICD ) is cleaved through a gamma-secretase-dependent mechanism .	When Dll4 activates Notch1, a portion of the intracellular domain of Notch1 (NotchICD) is cleaved through a gamma-secretase-dependent mechanism.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	1	2	3	4
Consistently , it was demonstrated that Jagged1 and Dll4 expressed by lung carcinoma and melanoma cells and Jagged1 expressed by neutrophils triggers Notch1 activation in endothelial cells inducing their senescence along with the expression of chemokines and the adhesion molecule VCAM1 , that favor neutrophil infiltration , tumor cell intravasation in tumor vessels and metastasis .	Consistently, it was demonstrated that Jagged1 and Dll4 expressed by lung carcinoma and melanoma cells and Jagged1 expressed by neutrophils triggers Notch1 activation in endothelial cells inducing their senescence along with the expression of chemokines and the adhesion molecule VCAM1, that favor neutrophil infiltration, tumor cell intravasation in tumor vessels and metastasis.	6	23	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4 expressed	dll4	Notch1	Notch1	notch1	8	9	22	23
A similar role for SENP1 was observed in Dll4 mediated NOTCH1 cleavage , which resulted in an even higher level of N1ICD ( XREF_FIG , lanes 3 and 4 ) .	A similar role for SENP1 was observed in Dll4 mediated NOTCH1 cleavage, which resulted in an even higher level of N1ICD (XREF_FIG, lanes 3 and 4).	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	NOTCH1	NOTCH1	NOTCH1	8	9	10	11
On the other hand , recent work from another group showed that the DLL4 mediated NOTCH1 activation in endothelial cells derived from LLC ( Lewis lung carcinoma cells ) tumor xenografts was also involved in the negative regulation of tumor angiogenesis and growth [ XREF_BIBR ] , suggesting that NOTCH1 signaling in both tumor cells and tumor microenvironment may cooperatively suppress tumor growth .	On the other hand, recent work from another group showed that the DLL4 mediated NOTCH1 activation in endothelial cells derived from LLC (Lewis lung carcinoma cells) tumor xenografts was also involved in the negative regulation of tumor angiogenesis and growth [XREF_BIBR], suggesting that NOTCH1 signaling in both tumor cells and tumor microenvironment may cooperatively suppress tumor growth.	12	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	13	14	15	16
Conversely , Dll4 mediated Notch activation in macrophages may have an antitumor effect as shown by the evidence that Dll4 mediated Notch1 activation hampers IL-4-induced M2 polarization and promotes M1 macrophage apoptosis ; the authors suggest that the interaction between Notch and IL-4 pathway may involve HES1 ability to bind STAT3 , finally inhibiting IL-4R signaling .	Conversely, Dll4 mediated Notch activation in macrophages may have an antitumor effect as shown by the evidence that Dll4 mediated Notch1 activation hampers IL-4-induced M2 polarization and promotes M1 macrophage apoptosis; the authors suggest that the interaction between Notch and IL-4 pathway may involve HES1 ability to bind STAT3, finally inhibiting IL-4R signaling.	19	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	19	20	21	22
Collectively , these results suggested a model in which Dll4 expressing tumor infiltrating WT myeloid cells , stimulate Notch1 and Notch4 signaling in LLC1 cells inducing Hey2 expression ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Collectively, these results suggested a model in which Dll4 expressing tumor infiltrating WT myeloid cells, stimulate Notch1 and Notch4 signaling in LLC1 cells inducing Hey2 expression (XREF_FIG and XREF_SUPPLEMENTARY).	9	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4 expressing	dll4	Notch1	Notch1	notch1	9	10	18	19
Notch1 activation by DLL4 variants .	Notch1 activation by DLL4 variants.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	3	4	0	1
Our analysis suggests that Dll4 activates Notch1 and Notch4 in decidual capillaries , whereas both Dll4 and Jag1 activate Notch1 in spiral arteries .	Our analysis suggests that Dll4 activates Notch1 and Notch4 in decidual capillaries, whereas both Dll4 and Jag1 activate Notch1 in spiral arteries.	14	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	15	16	19	20
N1 10-24 and N1 10-36 decoys did not inhibit DLL4 mediated Notch1 signaling , indicating EGF like repeats 1-9 are required for DLL4 and Notch interactions ( XREF_FIG ) .	N1 10-24 and N1 10-36 decoys did not inhibit DLL4 mediated Notch1 signaling, indicating EGF like repeats 1-9 are required for DLL4 and Notch interactions (XREF_FIG).	8	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	9	10	11	12
These novel findings demonstrating enhanced Th17 skewing with Dll4 induced N-ICD release are likely influenced by the immune environment created by the TLR stimuli that would include the generation of high levels of IL-6 .	These novel findings demonstrating enhanced Th17 skewing with Dll4 induced N-ICD release are likely influenced by the immune environment created by the TLR stimuli that would include the generation of high levels of IL-6.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	N-ICD	N-ICD	N-ICD	8	9	10	11
Overrepresentation of the FOXC2 gene , a known transcriptional regulator of CXCR4 and Delta like 4 ( DLL4 ) implies the down regulation of the Notch inhibitor Deltex1 to promote constitutive activation of NOTCH1 activity in HRS cells .	Overrepresentation of the FOXC2 gene, a known transcriptional regulator of CXCR4 and Delta like 4 (DLL4) implies the down regulation of the Notch inhibitor Deltex1 to promote constitutive activation of NOTCH1 activity in HRS cells.	0	34	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	17	18	33	34
Overall , these results support a model in which WT myeloid cells recruited to the tumor accelerate tumor progression by secreting mitogenic TGF-beta and enhancing TGF-beta signaling in the tumor cells via expression of the ligand Dll4 , which activates Notch1 and Notch4 ( XREF_FIG ) .	Overall, these results support a model in which WT myeloid cells recruited to the tumor accelerate tumor progression by secreting mitogenic TGF-beta and enhancing TGF-beta signaling in the tumor cells via expression of the ligand Dll4, which activates Notch1 and Notch4 (XREF_FIG).	32	44	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	expression of the ligand Dll4	dll4	Notch1	Notch1	notch1	36	37	40	41
To gain an insight into the molecular mechanism leading to Dll4 upregulation and activation of Notch1 , we treated HepG2.2.15 with various specific signalling pathway inhibitors and measured the level of Notch1 , Dll4 and cleaved Notch1 .	To gain an insight into the molecular mechanism leading to Dll4 upregulation and activation of Notch1, we treated HepG2.2.15 with various specific signalling pathway inhibitors and measured the level of Notch1, Dll4 and cleaved Notch1.	10	16	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	10	11	15	16
In the stem cell zone , the Dll1 + Dll4 + Paneth cells trigger Notch1 and Notch2 on stem cells , thus keeping the stem cells from terminal differentiation into the secretory lineage .	In the stem cell zone, the Dll1 + Dll4 + Paneth cells trigger Notch1 and Notch2 on stem cells, thus keeping the stem cells from terminal differentiation into the secretory lineage.	9	16	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	9	10	14	15
To further investigate whether Jag1 negatively regulates the endothelial programme by competing with Dll4 mediated Notch1 signalling , we evaluated the effect of anti-Dll4 and anti-Jag1-blocking antibodies on the in vitro generation of haematopoietic cells from E10.5 AGMs CD31 + CD45 - progenitors ( XREF_FIG ) .	To further investigate whether Jag1 negatively regulates the endothelial programme by competing with Dll4 mediated Notch1 signalling, we evaluated the effect of anti-Dll4 and anti-Jag1-blocking antibodies on the in vitro generation of haematopoietic cells from E10.5 AGMs CD31 + CD45 - progenitors (XREF_FIG).	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	13	14	15	16
By contrast , Dll4 activates Notch1 in a sustained , amplitude modulated manner that predominantly upregulates Hey1 and HeyL .	By contrast, Dll4 activates Notch1 in a sustained, amplitude modulated manner that predominantly upregulates Hey1 and HeyL.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	3	4	5	6
When Dll4 activates Notch1 , a portion of the intracellular domain of Notch1 is cleaved through a gamma-secretase dependent mechanism .	When Dll4 activates Notch1, a portion of the intracellular domain of Notch1 is cleaved through a gamma-secretase dependent mechanism.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	1	2	3	4
Shear stress triggers Dll4 dependent proteolytic activation of Notch1 to reveal the Notch1 transmembrane domain - the key domain that mediates barrier establishment .	Shear stress triggers Dll4 dependent proteolytic activation of Notch1 to reveal the Notch1 transmembrane domain - the key domain that mediates barrier establishment.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	3	4	8	9
Sprouting cells at the tip of the developing vessel express Dll4 , which activates Notch1 and Notch4 receptors in the adjacent endothelial cells in the stem of the new vessel .	Sprouting cells at the tip of the developing vessel express Dll4, which activates Notch1 and Notch4 receptors in the adjacent endothelial cells in the stem of the new vessel.	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	10	11	14	15
Taken together , these experiments indicate that E2 enhances Dll4 mediated Notch1 activation downstream of VEGF-A and suggest that estrogen receptors ERalpha or ERbeta play a role in this modulation .	Taken together, these experiments indicate that E2 enhances Dll4 mediated Notch1 activation downstream of VEGF-A and suggest that estrogen receptors ERalpha or ERbeta play a role in this modulation.	8	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	9	10	11	12
The RCC cell lines 786-O , 769-P , and caki-1 ( all cell lines express Notch1 , Notch2 , XREF_SUPPLEMENTARY ) were treated with recombinant DLL4 ; 786-O and caki-1 were further analyzed using a co-culture assay .	The RCC cell lines 786-O, 769-P, and caki-1 (all cell lines express Notch1, Notch2, XREF_SUPPLEMENTARY) were treated with recombinant DLL4; 786-O and caki-1 were further analyzed using a co-culture assay.	14	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	25	26	15	16
These results are consistent with the hypothesis that Jag1 outcompetes Dll4 for binding to the receptor but elicits a weaker activation of Notch1 in the endothelial cells of the AGM .	These results are consistent with the hypothesis that Jag1 outcompetes Dll4 for binding to the receptor but elicits a weaker activation of Notch1 in the endothelial cells of the AGM.	8	23	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	10	11	22	23
Some studies found that overexpression of Notch1 inhibited lung carcinogenesis , XREF_BIBR , XREF_BIBR or that DLL4 activated Notch1 , which reduced lung tumor cell growth via PTEN signaling .	Some studies found that overexpression of Notch1 inhibited lung carcinogenesis, XREF_BIBR, XREF_BIBR or that DLL4 activated Notch1, which reduced lung tumor cell growth via PTEN signaling.	16	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	16	17	18	19
N1 1-24 decoy protein was able to inhibit both DLL4 and JAG1 activation of Notch1 at all concentrations ( XREF_SUPPLEMENTARY ) .	N1 1-24 decoy protein was able to inhibit both DLL4 and JAG1 activation of Notch1 at all concentrations (XREF_SUPPLEMENTARY).	9	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	9	10	14	15
9 Emerging data from recent studies indicate that DLL4 activation of Notch1 signaling is also important for proliferation of antigen activated CD8 + T cells .	9 Emerging data from recent studies indicate that DLL4 activation of Notch1 signaling is also important for proliferation of antigen activated CD8 + T cells.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	8	9	11	12
Disruption of Dll4 or endothelium specific loss of Notch1 increases the superficial plexus vascular density and causes an excess of angiogenic sprouts .	Disruption of Dll4 or endothelium specific loss of Notch1 increases the superficial plexus vascular density and causes an excess of angiogenic sprouts.	2	9	loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	2	3	8	9
DLL4 knockdown also blocked the Notch-1 pathway , weakening invasion ability and resistance to 5-FU chemotherapy .	DLL4 knockdown also blocked the Notch-1 pathway, weakening invasion ability and resistance to 5-FU chemotherapy.	0	6	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch-1	Notch-1	Notch-1	0	1	5	6
However , Notch1 domains 8 through 10 are required for maximal DLL4 mediated Notch1 activation in cellular assays .	However, Notch1 domains 8 through 10 are required for maximal DLL4 mediated Notch1 activation in cellular assays.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	11	12	13	14
As reported previously , activation of Notch1 or 2 by Dll1 and Dll4 is enhanced by Lfng , whereas Notch1 or 2 activation by Jag1 is reduced XREF_BIBR - XREF_BIBR .	As reported previously, activation of Notch1 or 2 by Dll1 and Dll4 is enhanced by Lfng, whereas Notch1 or 2 activation by Jag1 is reduced XREF_BIBR - XREF_BIBR.	4	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	12	13	6	7
DLL4 mediated NOTCH1 signaling represents an essential pathway for vascular development and has emerged as an attractive target for angiogenesis based cancer therapies .	DLL4 mediated NOTCH1 signaling represents an essential pathway for vascular development and has emerged as an attractive target for angiogenesis based cancer therapies.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	0	1	2	3
N1 1-13 decoy interfered with DLL1 and DLL4 mediated NOTCH1 signaling and caused endothelial hypersprouting in vitro , in retinal angiogenesis and in tumors .	N1 1-13 decoy interfered with DLL1 and DLL4 mediated NOTCH1 signaling and caused endothelial hypersprouting in vitro, in retinal angiogenesis and in tumors.	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	7	8	9	10
Collectively , our data show that DLL4 preferentially activates NOTCH1 over NOTCH2 , whereas DLL1 is equally effective in activating NOTCH1 and NOTCH2 , establishing that the ectodomains dictate selective ligand function in vivo , and that features outside the known binding interface contribute to their differences .	Collectively, our data show that DLL4 preferentially activates NOTCH1 over NOTCH2, whereas DLL1 is equally effective in activating NOTCH1 and NOTCH2, establishing that the ectodomains dictate selective ligand function in vivo, and that features outside the known binding interface contribute to their differences.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	6	7	9	10
XREF_BIBR , XREF_BIBR Interestingly , a recent report demonstrated that laminar shear stress triggers Dll4 dependent proteolytic activation of Notch1 to reveal the Notch1 transmembrane domain , the key domain that mediates barrier establishment .	XREF_BIBR, XREF_BIBR Interestingly, a recent report demonstrated that laminar shear stress triggers Dll4 dependent proteolytic activation of Notch1 to reveal the Notch1 transmembrane domain, the key domain that mediates barrier establishment.	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	14	15	19	20
DLL1 and DLL4 activate NOTCH1 and NOTCH2 differently in cell based assays and this discriminating potential lies in the region between the N-terminus and EGF repeat three .	DLL1 and DLL4 activate NOTCH1 and NOTCH2 differently in cell based assays and this discriminating potential lies in the region between the N-terminus and EGF repeat three.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	2	3	4	5
These Dll4 expressing tip cells activate Notch1 signaling in adjacent cells .	These Dll4 expressing tip cells activate Notch1 signaling in adjacent cells.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4 expressing	dll4	Notch1	Notch1	notch1	1	2	6	7
XREF_BIBR Despite the multiple NOTCH ligands and receptors in the vascular system , DLL4 mediated NOTCH1 signaling appears to be an essential pathway for vascular development .	XREF_BIBR Despite the multiple NOTCH ligands and receptors in the vascular system, DLL4 mediated NOTCH1 signaling appears to be an essential pathway for vascular development.	13	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	13	14	15	16
We show here that EOGT catalyzed O-GlcNAc modification potentiates DLL1- and DLL4 mediated NOTCH1 signaling in co-culture assays and is required in vivo during retinal angiogenesis and the maintenance of retinal vascular integrity in mice .	We show here that EOGT catalyzed O-GlcNAc modification potentiates DLL1- and DLL4 mediated NOTCH1 signaling in co-culture assays and is required in vivo during retinal angiogenesis and the maintenance of retinal vascular integrity in mice.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	11	12	13	14
Recent work from the de La Pompa lab suggested that Manic Fringe ( Mfng ) activity within the endocardium favors Dll4 mediated activation of Notch1 over myocardial derived Jag1 in the early heart , and subsequent downregulation of Dll4 and Mfng coupled with upregulation of Jag1 and Jag2 favors myocardial cell activation of endocardial Notch1 later in heart development .	Recent work from the de La Pompa lab suggested that Manic Fringe (Mfng) activity within the endocardium favors Dll4 mediated activation of Notch1 over myocardial derived Jag1 in the early heart, and subsequent downregulation of Dll4 and Mfng coupled with upregulation of Jag1 and Jag2 favors myocardial cell activation of endocardial Notch1 later in heart development.	20	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	20	21	24	25
However , as the alterations were moderated with no macroscopic repercussions ( no observed increase of mucus secretion ) in the ubiquitous Dll4 mutants ' gut , Dll1 may partially compensate the lack of Dll4 in this setting and/or Dll4 may not activate both Notch1 and 2 receptors .	However, as the alterations were moderated with no macroscopic repercussions (no observed increase of mucus secretion) in the ubiquitous Dll4 mutants ' gut, Dll1 may partially compensate the lack of Dll4 in this setting and/or Dll4 may not activate both Notch1 and 2 receptors.	30	47	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	39	40	44	45
Similarly , Dll4 induced Notch1 and Dll1- and Dll4 induced Notch2 signaling were all significantly inhibited by compounds 10 and 11 relative to DMSO and compound 9 treated controls ( XREF_FIG ) .	Similarly, Dll4 induced Notch1 and Dll1- and Dll4 induced Notch2 signaling were all significantly inhibited by compounds 10 and 11 relative to DMSO and compound 9 treated controls (XREF_FIG).	2	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	2	3	4	5
Altogether , our results indicate that Dll4 induced Notch1 activity is required to specify the arterial programme , while Jag1 induced Notch activity and the subsequent ( or concomitant ) downregulation of the Dll4 mediated signalling are both required for generating HSC in the embryo .	Altogether, our results indicate that Dll4 induced Notch1 activity is required to specify the arterial programme, while Jag1 induced Notch activity and the subsequent (or concomitant) downregulation of the Dll4 mediated signalling are both required for generating HSC in the embryo.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	6	7	8	9
VEGF induced Dll4 activates Notch1 on the neighboring cell , leading to the down-regulation of VEGF receptor levels ( XREF_FIG ) ,.	VEGF induced Dll4 activates Notch1 on the neighboring cell, leading to the down-regulation of VEGF receptor levels (XREF_FIG),.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	VEGF induced Dll4	dll4	Notch1	Notch1	notch1	2	3	4	5
DLL4 acting as a specific trigger for Tfh cells would also be consistent with our Mib1 results , as Mib1 has the highest affinity for DLL4 and is known to play a key role in DLL4 mediated Notch1 signaling during T cell lineage development XREF_BIBR , XREF_BIBR .	DLL4 acting as a specific trigger for Tfh cells would also be consistent with our Mib1 results, as Mib1 has the highest affinity for DLL4 and is known to play a key role in DLL4 mediated Notch1 signaling during T cell lineage development XREF_BIBR, XREF_BIBR.	30	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	35	36	37	38
DLL4 knockdown inhibits Notch-1 signaling pathway activation in GCSPCs .	DLL4 knockdown inhibits Notch-1 signaling pathway activation in GCSPCs.	0	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch-1	Notch-1	Notch-1	0	1	3	4
Since DLL4 upregulates Notch1 mRNA during polarization , we speculated that DLL4 might signal through Notch1 in these cells .	Since DLL4 upregulates Notch1 mRNA during polarization, we speculated that DLL4 might signal through Notch1 in these cells.	1	4	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	1	2	3	4
In agreement with our previous data , increased Notch1 or Notch3 activation by DLL4 slightly increased the generation of gammadelta T cells ( XREF_FIG ) .	In agreement with our previous data, increased Notch1 or Notch3 activation by DLL4 slightly increased the generation of gammadelta T cells (XREF_FIG).	8	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	13	14	8	9
However , VEGFR2 signalling also upregulates DLL4 expression , which activates the Notch1 receptor on neighbouring cells .	However, VEGFR2 signalling also upregulates DLL4 expression, which activates the Notch1 receptor on neighbouring cells.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	VEGFR2 signalling also upregulates DLL4 expression	dll4	Notch1	Notch1	notch1	6	7	12	13
A dose response analysis of N1 1-13 decoy protein purified from conditioned media produced by Chinese hamster ovary ( CHO ) cell clones showed that N1 1-13 decoy preferentially inhibited DLL4 activation of Notch1 , and only inhibited JAG1 activation of Notch1 at a high dose of 50mug/mL ( XREF_SUPPLEMENTARY ) .	A dose response analysis of N1 1-13 decoy protein purified from conditioned media produced by Chinese hamster ovary (CHO) cell clones showed that N1 1-13 decoy preferentially inhibited DLL4 activation of Notch1, and only inhibited JAG1 activation of Notch1 at a high dose of 50mug/mL (XREF_SUPPLEMENTARY).	30	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	30	31	33	34
N1 1-13 decoy inhibited DLL4 induced Notch1 signaling but not JAG1 mediated Notch1 signaling ( XREF_FIG ) .	N1 1-13 decoy inhibited DLL4 induced Notch1 signaling but not JAG1 mediated Notch1 signaling (XREF_FIG).	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	4	5	6	7
Using antibodies specific to the cleaved , activated forms of Notch1 , Notch2 , and Notch4 in immunoblot , we confirmed that only Notch1 was activated by DLL4 in HAEC ( XREF_FIG ) .	Using antibodies specific to the cleaved, activated forms of Notch1, Notch2, and Notch4 in immunoblot, we confirmed that only Notch1 was activated by DLL4 in HAEC (XREF_FIG).	22	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	27	28	23	24
XREF_BIBR - XREF_BIBR Tip cells expressing Delta like 4 ( DLL4 ) activate NOTCH1 in adjoining cells to suppress the tip cell phenotype , thus committing them to stalk cell specification .	XREF_BIBR - XREF_BIBR Tip cells expressing Delta like 4 (DLL4) activate NOTCH1 in adjoining cells to suppress the tip cell phenotype, thus committing them to stalk cell specification.	0	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	10	11	13	14
Moreover , in endothelial and tumor cells ' coculture model , it was shown that the expression of a NOTCH ligand DLL4 ( Delta like ligand 4 ) in HUVEC endothelial cells increased NOTCH1 and suppressed the proliferation of cocultured A549 and H460 NSCLC cells [ XREF_BIBR , XREF_BIBR ] .	Moreover, in endothelial and tumor cells ' coculture model, it was shown that the expression of a NOTCH ligand DLL4 (Delta like ligand 4) in HUVEC endothelial cells increased NOTCH1 and suppressed the proliferation of cocultured A549 and H460 NSCLC cells [XREF_BIBR, XREF_BIBR].	16	34	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	expression of a NOTCH ligand DLL4	dll4	NOTCH1	NOTCH1	notch1	21	22	33	34
Thus , aberrant expression of the NOTCH ligand delta like 4 ( DLL4 ) may contribute to NOTCH1 driven leukemias [ XREF_BIBR ] .	Thus, aberrant expression of the NOTCH ligand delta like 4 (DLL4) may contribute to NOTCH1 driven leukemias [XREF_BIBR].	3	18	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	12	13	17	18
Therefore , we assessed the ability of all four candidate lipids to influence Dll4 stimulated Notch activity and the generation of the NICD .	Therefore, we assessed the ability of all four candidate lipids to influence Dll4 stimulated Notch activity and the generation of the NICD.	12	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	NICD	NICD	NICD	13	14	22	23
These indicated that the low-oxygen environment , with the high expression of HIF-1a , leads to up-regulation of the ligand Dll4 , while Dll4 mediated activation of Notch1 receptors in a neighboring cell activate VEGFR2 expression then promote the angiogenesis .	These indicated that the low-oxygen environment, with the high expression of HIF-1a, leads to up-regulation of the ligand Dll4, while Dll4 mediated activation of Notch1 receptors in a neighboring cell activate VEGFR2 expression then promote the angiogenesis.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	23	24	27	28
In U87MG cells , the activation of Notch1 by DLL4 stimulation or by the overexpression of Notch intracellular domain ( NICD ) resulted in AKT activation and thereby promoted beta-catenin activity and NF-kappaB signaling .	In U87MG cells, the activation of Notch1 by DLL4 stimulation or by the overexpression of Notch intracellular domain (NICD) resulted in AKT activation and thereby promoted beta-catenin activity and NF-kappaB signaling.	5	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	9	10	7	8
Thereby EGFL7 promoted Notch1 activation induced by Dll4 at the expense of Jagged1 .	Thereby EGFL7 promoted Notch1 activation induced by Dll4 at the expense of Jagged1.	3	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	7	8	3	4
HD105 also suppressed Dll4 induced Notch1 dependent activation of the luciferase gene .	HD105 also suppressed Dll4 induced Notch1 dependent activation of the luciferase gene.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	3	4	5	6
The Notch1 decoy can reduce Notch1 signaling stimulated by the action of at least three distinct Notch ligands ; Dll1 , Dll4 and Jagged1 .	The Notch1 decoy can reduce Notch1 signaling stimulated by the action of at least three distinct Notch ligands; Dll1, Dll4 and Jagged1.	5	22	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	21	22	5	6
Of the three mammalian Fringe proteins , it has been shown that only LFng can enhance Notch1 signaling induced by Dll1 and suppress the signaling induced by Jag1 in coculture reporter assays [ XREF_BIBR ] .	Of the three mammalian Fringe proteins, it has been shown that only LFng can enhance Notch1 signaling induced by Dll1 and suppress the signaling induced by Jag1 in coculture reporter assays [XREF_BIBR].	16	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch1	Notch1	Notch1	20	21	16	17
Actin cytoskeleton regulator Arp2/3 complex is required for DLL1 activating Notch1 signaling to maintain the stem cell phenotype of glioma initiating cells .	Actin cytoskeleton regulator Arp2/3 complex is required for DLL1 activating Notch1 signaling to maintain the stem cell phenotype of glioma initiating cells.	6	11	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch1	Notch1	Notch1	8	9	10	11
The aforementioned observations , in combination with the IP and luciferase analyses at days 3 and 5 of differentiation , suggest a time dependent threshold effect of Dll1 activated NICD interplay with Mef2C and Maml1 ( XREF_FIG ) .	The aforementioned observations, in combination with the IP and luciferase analyses at days 3 and 5 of differentiation, suggest a time dependent threshold effect of Dll1 activated NICD interplay with Mef2C and Maml1 (XREF_FIG).	25	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	NICD	NICD	NICD	27	28	29	30
The plausible mechanism mediating the dynamism is progressive weakening of the Dll1 drive of Notch1 signaling .	The plausible mechanism mediating the dynamism is progressive weakening of the Dll1 drive of Notch1 signaling.	11	15	drive	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch1	Notch1	Notch1	11	12	14	15
In the case of a traditional feedback mechanism , continuous Dll1 signaling would result in widespread NICD activation and reduced numbers of hair cells .	In the case of a traditional feedback mechanism, continuous Dll1 signaling would result in widespread NICD activation and reduced numbers of hair cells.	10	18	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	NICD	NICD	NICD	10	11	16	17
Quantitative single-cell imaging revealed that Dll1 activates Notch1 in discrete , frequency modulated pulses that specifically upregulate the Notch target gene Hes1 .	Quantitative single-cell imaging revealed that Dll1 activates Notch1 in discrete, frequency modulated pulses that specifically upregulate the Notch target gene Hes1.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch1	Notch1	Notch1	5	6	7	8
In order to confirm that DLL1 would trigger Notch1 activation , we transiently transfected SNU601 with the full DLL1 coding sequence .	In order to confirm that DLL1 would trigger Notch1 activation, we transiently transfected SNU601 with the full DLL1 coding sequence.	5	9	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch1	Notch1	Notch1	5	6	8	9
DLL1 activates Notch1 signaling in GC cell lines .	DLL1 activates Notch1 signaling in GC cell lines.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch1	Notch1	Notch1	0	1	2	3
For example , in the Drosophila wing disc Fringe potentiates a cell ' s ability to respond to Delta and inhibits its ability to respond to Serrate [ XREF_BIBR ] , whereas in the presomitic mesoderm of mouse embryos Lunatic fringe ( LFNG ) appears to attenuate Delta1 like ( DLL1 )-mediated activation of Notch1 [ XREF_BIBR ] .	For example, in the Drosophila wing disc Fringe potentiates a cell 's ability to respond to Delta and inhibits its ability to respond to Serrate [XREF_BIBR], whereas in the presomitic mesoderm of mouse embryos Lunatic fringe (LFNG) appears to attenuate Delta1 like (DLL1)-mediated activation of Notch1 [XREF_BIBR].	50	55	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch1	Notch1	Notch1	50	51	54	55
To further evaluate the effect that incorporation of inhibitory fucose analogs into Notch EGF repeats has on Notch signaling , we used a cell based co-culture Notch reporter assay where Dll1 and Jag1 activated Notch1 to nearly identical levels relative to controls ( XREF_SUPPLEMENTARY ) .	To further evaluate the effect that incorporation of inhibitory fucose analogs into Notch EGF repeats has on Notch signaling, we used a cell based co-culture Notch reporter assay where Dll1 and Jag1 activated Notch1 to nearly identical levels relative to controls (XREF_SUPPLEMENTARY).	30	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch1	Notch1	Notch1	30	31	34	35
Importantly , Notch1 ligands Dll1 and Jag1 expressed in B cells and pre-coated Notch1 protein promotes Notch1 knocked down B cells to produce antibody in LPS stimulated B cells suggesting that Notch1 in other cells may promote antibody production by binding its ligands Dll1 and Jag1 in B cells .	Importantly, Notch1 ligands Dll1 and Jag1 expressed in B cells and pre-coated Notch1 protein promotes Notch1 knocked down B cells to produce antibody in LPS stimulated B cells suggesting that Notch1 in other cells may promote antibody production by binding its ligands Dll1 and Jag1 in B cells.	4	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1 and Jag1 expressed	dll1	Notch1	Notch1	notch1	4	5	16	17
To investigate specificity , HeLa cells expressing GAPDH or TA197 shRNA against the 3 ' UTR of EOGT , were transfected with empty vector or a human EOGT cDNA , and DLL1 induced activation of NOTCH1 was determined .	To investigate specificity, HeLa cells expressing GAPDH or TA197 shRNA against the 3 ' UTR of EOGT, were transfected with empty vector or a human EOGT cDNA, and DLL1 induced activation of NOTCH1 was determined.	31	36	induced	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NOTCH1	NOTCH1	NOTCH1	31	32	35	36
Here , we showed that Delta-like1 ( DLL1 ) activated Notch1 signaling to maintain the stem cell phenotype of GICs .	Here, we showed that Delta-like1 (DLL1) activated Notch1 signaling to maintain the stem cell phenotype of GICs.	5	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch1	Notch1	Notch1	7	8	10	11
In conclusion , we demonstrated that DLL1 is epigenetically regulated in GC cell lines and DLL1 expression activates Notch1 signaling .	In conclusion, we demonstrated that DLL1 is epigenetically regulated in GC cell lines and DLL1 expression activates Notch1 signaling.	15	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1 expression	dll1	Notch1	Notch1	notch1	15	16	18	19
Taken altogether , our data suggest that Dll1 triggered Notch1 activation plays a pivotal role in the myogenic commitment of post-natal murine and human MABs .	Taken altogether, our data suggest that Dll1 triggered Notch1 activation plays a pivotal role in the myogenic commitment of post-natal murine and human MABs.	7	10	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch1	Notch1	Notch1	7	8	9	10
Since treatment with 50 muM analogs completely inhibited Dll1 mediated Notch1 activation ( XREF_FIG ) , we used a lower concentration to achieve partial inhibition in these studies ( 100 nM , XREF_SUPPLEMENTARY ) .	Since treatment with 50 muM analogs completely inhibited Dll1 mediated Notch1 activation (XREF_FIG), we used a lower concentration to achieve partial inhibition in these studies (100 nM, XREF_SUPPLEMENTARY).	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch1	Notch1	Notch1	8	9	10	11
N1 1-24 decoy and N1 1-36 inhibited both DLL1 and JAG2 activation of Notch1 ( XREF_SUPPLEMENTARY ) .	N1 1-24 decoy and N1 1-36 inhibited both DLL1 and JAG2 activation of Notch1 (XREF_SUPPLEMENTARY).	8	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch1	Notch1	Notch1	8	9	13	14
It has been reported that Dll1 induced Notch1 signaling induces down-regulation of Spi-B in plasmacytoid DCs [ XREF_BIBR ] .	It has been reported that Dll1 induced Notch1 signaling induces down-regulation of Spi-B in plasmacytoid DCs [XREF_BIBR].	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch1	Notch1	Notch1	5	6	7	8
In GC cell lines , DLL1 expression is epigenetically regulated by promoter methylation although DLL1 activates Notch1 signaling pathway .	In GC cell lines, DLL1 expression is epigenetically regulated by promoter methylation although DLL1 activates Notch1 signaling pathway.	14	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch1	Notch1	Notch1	14	15	16	17
Loss of DLL1 function abolishes formation of NICD in the PSM , indicating that DLL1 is the major activator of Notch1 in the PSM .	Loss of DLL1 function abolishes formation of NICD in the PSM, indicating that DLL1 is the major activator of Notch1 in the PSM.	2	10	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NICD	NICD	NICD	2	3	7	8
As HES7 represses Dll1 , which induces NICD , which in turn co-induces Hes1/7 and Lfng , we expect the expression pattern in the posterior end of the tail bud to change , if one would include this .	As HES7 represses Dll1, which induces NICD, which in turn co-induces Hes1/7 and Lfng, we expect the expression pattern in the posterior end of the tail bud to change, if one would include this.	2	31	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	NICD	NICD	NICD	3	4	7	8
Importantly , while DLL1 mediated NOTCH1 signalling is required for intestinal stem-cell homeostasis XREF_BIBR , the binding to JAG1 is associated with colon carcinogenesis XREF_BIBR .	Importantly, while DLL1 mediated NOTCH1 signalling is required for intestinal stem-cell homeostasis XREF_BIBR, the binding to JAG1 is associated with colon carcinogenesis XREF_BIBR.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NOTCH1	NOTCH1	NOTCH1	3	4	5	6
MuSK IgG1-3 could also have an effect on Lrp4 , though it is not clear how , or MuSK antibodies may affect Dok7 mediated MuSK activation , perhaps by altering MuSK conformation , MuSK kinase activity and/or preventing binding of Dok7 to MuSK , as observed in CMS with a MuSK mutation .	MuSK IgG1-3 could also have an effect on Lrp4, though it is not clear how, or MuSK antibodies may affect Dok7 mediated MuSK activation, perhaps by altering MuSK conformation, MuSK kinase activity and/or preventing binding of Dok7 to MuSK, as observed in CMS with a MuSK mutation.	21	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	22	23	24	25
The muscle protein Dok-7 is essential for activation of the receptor kinase MuSK , which governs NMJ formation , and DOK7 mutations underlie familial limb-girdle myasthenia ( DOK7 myasthenia ) , a neuromuscular disease characterized by small NMJs .	The muscle protein Dok-7 is essential for activation of the receptor kinase MuSK, which governs NMJ formation, and DOK7 mutations underlie familial limb-girdle myasthenia (DOK7 myasthenia), a neuromuscular disease characterized by small NMJs.	2	15	is essential for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	protein Dok-7	protein Dok-7	protein Dok-7	MuSK	MuSK	MuSK	2	4	12	13
It is possible that Dok7 triggered MuSK activation , which would be independent of agrin binding , could facilitate the pre-patterning of MuSK and AChRs [ XREF_BIBR ] .	It is possible that Dok7 triggered MuSK activation, which would be independent of agrin binding, could facilitate the pre-patterning of MuSK and AChRs [XREF_BIBR].	4	7	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	4	5	6	7
Activated MuSK phosphorylates the two tyrosine residues ( Y396 and Y406 ) of Dok-7 , which are essential for activating downstream signaling leading to AChR clustering 26 .	Activated MuSK phosphorylates the two tyrosine residues (Y396 and Y406) of Dok-7, which are essential for activating downstream signaling leading to AChR clustering 26.	0	14	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dok-7	Dok-7	Dok-7	MuSK	MuSK	MuSK	13	14	1	2
We previously demonstrated that activation of muscle specific kinase MuSK by the cytoplasmic protein Dok-7 is essential for NMJ formation , and forced expression of Dok-7 in muscle activates MuSK and enlarges NMJs .	We previously demonstrated that activation of muscle specific kinase MuSK by the cytoplasmic protein Dok-7 is essential for NMJ formation, and forced expression of Dok-7 in muscle activates MuSK and enlarges NMJs.	4	15	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	protein Dok-7	protein Dok-7	protein Dok-7	MuSK	MuSK	MuSK	13	15	9	10
The Cytoplasmic Adapter Protein Dok7 Activates the Receptor Tyrosine Kinase MuSK via Dimerization .	The Cytoplasmic Adapter Protein Dok7 Activates the Receptor Tyrosine Kinase MuSK via Dimerization.	0	12	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	4	5	10	11
Taken together , these results indicate that MuSK activation by Dok7 does not alter MuSK internalization but favours a localization of MuSK in caveolin positive structures .	Taken together, these results indicate that MuSK activation by Dok7 does not alter MuSK internalization but favours a localization of MuSK in caveolin positive structures.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	10	11	7	8
This Dok7 mediated MuSK activation mechanism is premised on the assumption that Tyr553 in the MuSK juxtamembrane region is autophosphorylated ( in trans , to create a docking site for Dok7 ) prior to activation-loop phosphorylation and full kinase activation .	This Dok7 mediated MuSK activation mechanism is premised on the assumption that Tyr553 in the MuSK juxtamembrane region is autophosphorylated (in trans, to create a docking site for Dok7) prior to activation-loop phosphorylation and full kinase activation.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	1	2	3	4
One is the adaptor protein Dok7 , which activates the muscle specific RTK MuSK and controls neuromuscular junction formation .	One is the adaptor protein Dok7, which activates the muscle specific RTK MuSK and controls neuromuscular junction formation.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	5	6	13	14
As mentioned , we previously demonstrated that DOK7 gene therapy activates muscle specific kinase MuSK to enlarge NMJs , and ameliorates myopathies characterized by NMJ defects in mouse models irrespective of the presence or absence of a dok-7 gene mutation , attesting to its potential in a range of neuromuscular diseases ( Arimura etal , 2014 ) .	As mentioned, we previously demonstrated that DOK7 gene therapy activates muscle specific kinase MuSK to enlarge NMJs, and ameliorates myopathies characterized by NMJ defects in mouse models irrespective of the presence or absence of a dok-7 gene mutation, attesting to its potential in a range of neuromuscular diseases (Arimura etal, 2014).	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DOK7	DOK7	DOK7	MuSK	MuSK	MuSK	7	8	14	15
MuSK activation by Dok7 mildly affects the localization of MuSK on the cell surface but has no effect on the rate of MuSK internalization .	MuSK activation by Dok7 mildly affects the localization of MuSK on the cell surface but has no effect on the rate of MuSK internalization.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	3	4	0	1
The crystal structure of Dok7 ( PH-PTB )-MuSK ( pTyr553 ) and the SEC results suggest a mechanism by which Dok7 might stimulate the kinase activity of MuSK : Dimerization of Dok7 bound to the juxtamembrane region of MuSK juxtaposes the two kinase domains for trans-autophosphorylation on the activation loop .	The crystal structure of Dok7 (PH-PTB)-MuSK (pTyr553) and the SEC results suggest a mechanism by which Dok7 might stimulate the kinase activity of MuSK : Dimerization of Dok7 bound to the juxtamembrane region of MuSK juxtaposes the two kinase domains for trans-autophosphorylation on the activation loop.	20	28	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	20	21	27	28
Downstream of the agrin/LRP4/MuSK pathway , Dok7 is believed to promote MuSK activity and rapsyn is believed to bridge the AChR with the cytoskeleton .	Downstream of the agrin/LRP4/MuSK pathway, Dok7 is believed to promote MuSK activity and rapsyn is believed to bridge the AChR with the cytoskeleton.	4	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	6	7	11	12
MuSK is activated by Dok-7 and Lrp4 ( agrin receptor ) and contributes to AChR clustering at the postsynaptic membrane via various kinase cascades in collaboration with Wnt-MuSK and Frizzled Dishevelled signaling .	MuSK is activated by Dok-7 and Lrp4 (agrin receptor) and contributes to AChR clustering at the postsynaptic membrane via various kinase cascades in collaboration with Wnt-MuSK and Frizzled-Dishevelled signaling.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dok-7	Dok-7	Dok-7	MuSK	MuSK	MuSK	4	5	0	1
First , Dok7 may be required for agrin function ; either as an effector through an unknown intermediate or in concert with agrin to activate MuSK .	First, Dok7 may be required for agrin function; either as an effector through an unknown intermediate or in concert with agrin to activate MuSK.	2	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	2	3	25	26
The observation that Dok-7 is a muscle-intrinsic activator of MuSK 61 prompted a search for CMS caused by mutations DOK7 .	The observation that Dok-7 is a muscle-intrinsic activator of MuSK 61 prompted a search for CMS caused by mutations DOK7.	3	10	is a muscle-intrinsic activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Dok-7	Dok-7	Dok-7	MuSK	MuSK	MuSK	3	4	9	10
Now that the basic molecular mechanism by which Dok7 mediates MuSK activation is in hand , the next challenge will be to determine how Agrin and LRP4 work in concert with Dok7 to activate MuSK during neuromuscular synaptogenesis .	Now that the basic molecular mechanism by which Dok7 mediates MuSK activation is in hand, the next challenge will be to determine how Agrin and LRP4 work in concert with Dok7 to activate MuSK during neuromuscular synaptogenesis.	8	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	8	9	10	11
Dok7 Mediated MuSK Activation in Cells .	Dok7 Mediated MuSK Activation in Cells.	0	3	Mediated	Positive_early_activation	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	0	1	2	3
Dok7 dependent activation of MuSK does not alter the rate of internalization but favours a localization of MuSK in caveolin specific structures .	Dok7 dependent activation of MuSK does not alter the rate of internalization but favours a localization of MuSK in caveolin specific structures.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	0	1	4	5
However , this inhibition is not dependent on MuSK activation because we find the same degree of inhibition when MuSK has been activated by Dok7 .	However, this inhibition is not dependent on MuSK activation because we find the same degree of inhibition when MuSK has been activated by Dok7.	19	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	24	25	19	20
Our structural and biochemical studies are consistent with a Dok7 mediated MuSK activation mechanism in which Dok7 binds to the phosphorylated juxtamembrane region of MuSK and , through dimerization of its PH-PTB domains , juxtaposes two MuSK kinase domains for trans-autophosphorylation on their activation loops ( XREF_FIG ) .	Our structural and biochemical studies are consistent with a Dok7 mediated MuSK activation mechanism in which Dok7 binds to the phosphorylated juxtamembrane region of MuSK and, through dimerization of its PH-PTB domains, juxtaposes two MuSK kinase domains for trans-autophosphorylation on their activation loops (XREF_FIG).	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	9	10	11	12
Although these observations demonstrate potential for DOK7 gene therapy in these myopathies with NMJ defects , we suspected that this therapy might also benefit motor neurodegenerative diseases , because muscle specific overexpression of Dok-7 activates MuSK and enlarges not only the postsynaptic apparatus but also presynaptic motor nerve terminals at NMJs , which might counteract degeneration , or size reduction in particular , of the terminal ( Inoue etal , 2009 ; Arimura etal , 2014 ) .	Although these observations demonstrate potential for DOK7 gene therapy in these myopathies with NMJ defects, we suspected that this therapy might also benefit motor neurodegenerative diseases, because muscle specific overexpression of Dok-7 activates MuSK and enlarges not only the postsynaptic apparatus but also presynaptic motor nerve terminals at NMJs, which might counteract degeneration, or size reduction in particular, of the terminal (Inoue etal, 2009; Arimura etal, 2014).	31	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dok-7	overexpression of Dok-7	dok-7	MuSK	MuSK	musk	33	34	35	36
DOK7 is not only a substrate of MuSK , but can also activate MuSK kinase activity .	DOK7 is not only a substrate of MuSK, but can also activate MuSK kinase activity.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DOK7	DOK7	DOK7	MuSK	MuSK	MuSK	0	1	13	14
Once recruited to MuSK , Dok-7 directly stimulates MuSK kinase activity .	Once recruited to MuSK, Dok-7 directly stimulates MuSK kinase activity.	5	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dok-7	Dok-7	Dok-7	MuSK	MuSK	MuSK	5	6	8	9
From pioneering studies by XREF_BIBR and XREF_BIBR , we learned that Dok-7 is a muscle-intrinsic activator of MuSK and important in synaptogenesis and that mutations in Dok-7 cause a CMS that preferentially affects the limb-girdle and axial rather than cranial muscles .	From pioneering studies by XREF_BIBR and XREF_BIBR, we learned that Dok-7 is a muscle-intrinsic activator of MuSK and important in synaptogenesis and that mutations in Dok-7 cause a CMS that preferentially affects the limb-girdle and axial rather than cranial muscles.	11	19	is a muscle-intrinsic activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Dok-7	Dok-7	Dok-7	MuSK	MuSK	MuSK	11	12	17	18
Dok7 induced MuSK endocytosis in heterologous cells .	Dok7 induced MuSK endocytosis in heterologous cells.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Dok7	Dok7	Dok7	MuSK	MuSK	MuSK	0	1	2	3
Recent studies have elucidated the roles of several key molecules , including the cytoplasmic adaptor protein Dok-7 and LDL receptor related protein 4 ( Lrp4 ) , in agrin induced MuSK activation .	Recent studies have elucidated the roles of several key molecules, including the cytoplasmic adaptor protein Dok-7 and LDL receptor related protein 4 (Lrp4), in agrin induced MuSK activation.	15	31	induced	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	protein Dok-7	protein Dok-7	protein Dok-7	MuSK	MuSK	MuSK	15	17	30	31
The apparently identical somite phenotypes of Dll3 and Lfng mutant embryos and their reported inhibitory activity in the PSM raise the possibility that there both gene products together modulate Notch activity .	The apparently identical somite phenotypes of Dll3 and Lfng mutant embryos and their reported inhibitory activity in the PSM raise the possibility that there both gene products together modulate Notch activity.	6	30	raise	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	6	7	29	30
In contrast , the related ligand delta like 3 ( DLL3 ) predominantly localizes to the Golgi apparatus and is unable to activate Notch signaling .	In contrast, the related ligand delta like 3 (DLL3) predominantly localizes to the Golgi apparatus and is unable to activate Notch signaling.	6	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	10	11	23	24
The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands .	The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	4	5	8	9
Dunwoodie et al reported that injection of DLL3 RNA into Xenopus oocytes is able to inhibit primary neuron formation , as observed in ectopic expression of constitutively active Notch1 , suggesting that DLL3 is able to activate Notch signaling .	Dunwoodie et al reported that injection of DLL3 RNA into Xenopus oocytes is able to inhibit primary neuron formation, as observed in ectopic expression of constitutively active Notch1, suggesting that DLL3 is able to activate Notch signaling.	32	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	32	33	37	38
However , Ladi et al reported that DLL3 does not bind or activate any of the known mammalian Notch receptors when presented in trans , although DLL3 inhibited ligand induced Notch signaling when coexpressed with Notch at the cell surface in cis .	However, Ladi et al reported that DLL3 does not bind or activate any of the known mammalian Notch receptors when presented in trans, although DLL3 inhibited ligand induced Notch signaling when coexpressed with Notch at the cell surface in cis.	26	31	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	26	27	30	31
Unlike other ligands , DLL3 is unable to activate Notch in cultured cells and seems to inhibit Notch signaling .	Unlike other ligands, DLL3 is unable to activate Notch in cultured cells and seems to inhibit Notch signaling.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	4	5	9	10
Even under that condition , Dll3 did not activate any of the four Notch receptors on neighboring cells XREF_BIBR , XREF_BIBR .	Even under that condition, Dll3 did not activate any of the four Notch receptors on neighboring cells XREF_BIBR, XREF_BIBR.	5	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	5	6	13	14
Support for this notion comes from a recent study that showed that DLL3 can not activate Notch in vitro and suggested that DLL3 acts as an antagonist to DLL1 on the cell surface .	Support for this notion comes from a recent study that showed that DLL3 can not activate Notch in vitro and suggested that DLL3 acts as an antagonist to DLL1 on the cell surface.	12	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	12	13	16	17
However , homozygous Dll1 Dll3HAki or Dll1 Dll3ki embryos were virtually indistinguishable from Dll1 null mutant embryos ( XREF_FIG ) , indicating that DLL3 can not substitute for DLL1 and activate Notch in vivo .	However, homozygous Dll1 Dll3HAki or Dll1 Dll3ki embryos were virtually indistinguishable from Dll1 null mutant embryos (XREF_FIG), indicating that DLL3 can not substitute for DLL1 and activate Notch in vivo.	23	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	23	24	31	32
There also is a Dll3 gene , which can not activate Notch receptors in trans and appears to encode a decoy receptor , as phenotypes observed in Dll3 deficient mice are consistent with Notch gain-of-function .	There also is a Dll3 gene, which can not activate Notch receptors in trans and appears to encode a decoy receptor, as phenotypes observed in Dll3 deficient mice are consistent with Notch gain-of-function.	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	4	5	11	12
With hypofractionated radiotherapy regimen in mind , it was remarkable that DLL3 , a divergent Notch ligand family member that does not activate Notch signaling in adjacent cells but inhibits Notch receptors when expressed in the same cell [ XREF_BIBR ] , was consistently induced after higher doses of 6 and 8 Gy , suggesting that signaling relevant for breast cancer stem cells at these large fractions differs from signaling seen after conventional fractions of 2 Gy .	With hypofractionated radiotherapy regimen in mind, it was remarkable that DLL3, a divergent Notch ligand family member that does not activate Notch signaling in adjacent cells but inhibits Notch receptors when expressed in the same cell [XREF_BIBR], was consistently induced after higher doses of 6 and 8 Gy, suggesting that signaling relevant for breast cancer stem cells at these large fractions differs from signaling seen after conventional fractions of 2 Gy.	11	44	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	11	12	30	31
Consistent with this idea , Dll1 is a potent activating Notch ligand , while Dll3 lacks structural characteristics important for DSL ligands to bind to Notch in trans and thereby activate Notch signaling .	Consistent with this idea, Dll1 is a potent activating Notch ligand, while Dll3 lacks structural characteristics important for DSL ligands to bind to Notch in trans and thereby activate Notch signaling.	14	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	14	15	31	32
Dll3 has a unique function in that unlike Dll1 , which functions as a classic Delta protein by stimulating Notch signaling and inhibiting neural differentiation , Dll3 does not stimulate Notch signaling .	Dll3 has a unique function in that unlike Dll1, which functions as a classic Delta protein by stimulating Notch signaling and inhibiting neural differentiation, Dll3 does not stimulate Notch signaling.	26	31	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	26	27	30	31
Unlike all other known DSL ligands , Dll3 was unable to activate Notch in apposing cells .	Unlike all other known DSL ligands, Dll3 was unable to activate Notch in apposing cells.	7	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	7	8	12	13
This is because in vitro DLL3 did not activate Notch in trans , but rather inhibited Notch signaling when expressed in the same cell as Notch .	This is because in vitro DLL3 did not activate Notch in trans, but rather inhibited Notch signaling when expressed in the same cell as Notch.	1	15	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	5	6	9	10
Remarkably , addition of DLL3 enhanced Th17 differentiation in vitro , although it was shown that DLL3 can not activate Notch in adjacent cells , but inhibits signaling when expressed in the same cell as the Notch receptor .	Remarkably, addition of DLL3 enhanced Th17 differentiation in vitro, although it was shown that DLL3 can not activate Notch in adjacent cells, but inhibits signaling when expressed in the same cell as the Notch receptor.	16	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	16	17	20	21
DLL3 predominantly localizes to the Golgi apparatus and is unable to activate Notch signaling .	DLL3 predominantly localizes to the Golgi apparatus and is unable to activate Notch signaling.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	0	1	12	13
Dll3 is unable to replace Dll1 in vivo and is unable to activate Notch in cellulo ; the in cellulo experiments may need to be repeated in the presence of DLK1 and/or DLK2 to rule out Dll3 as a Notch activator .	Dll3 is unable to replace Dll1 in vivo and is unable to activate Notch in cellulo; the in cellulo experiments may need to be repeated in the presence of DLK1 and/or DLK2 to rule out Dll3 as a Notch activator.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	0	1	13	14
However , in contrast to DLL1 ( and the other Notch ligands ) , DLL3 expressed in cultured cells can not activate Notch on adjacent cells in vitro [ XREF_BIBR , XREF_BIBR ] and , in vivo DLL3 protein expressed instead of DLL1 in mouse embryos did not activate Notch under physiological conditions and failed to compensate for the loss of DLL1 [ XREF_BIBR ] .	However, in contrast to DLL1 (and the other Notch ligands), DLL3 expressed in cultured cells can not activate Notch on adjacent cells in vitro [XREF_BIBR, XREF_BIBR] and, in vivo DLL3 protein expressed instead of DLL1 in mouse embryos did not activate Notch under physiological conditions and failed to compensate for the loss of DLL1 [XREF_BIBR].	14	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL3	DLL3 expressed	dll3	Notch	Notch	notch	14	15	22	23
Although there is a consensus that Dll3 in unable to activate Notch , its Golgi localization is inconsistent with cis-inhibition by DSL ligands requiring cell surface expression .	Although there is a consensus that Dll3 in unable to activate Notch, its Golgi localization is inconsistent with cis-inhibition by DSL ligands requiring cell surface expression.	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	6	7	11	12
We show that Dll3 can not activate Notch when expressed in trans but like other Notch ligands it can inhibit Notch signalling when expressed in cis with the receptor .	We show that Dll3 can not activate Notch when expressed in trans but like other Notch ligands it can inhibit Notch signalling when expressed in cis with the receptor.	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	3	4	7	8
We have shown previously that DC specific deletion of RBPJ caused partial reduction of the splenic CD11b + DCs , which express Notch target Dtx1 in an RBPJ dependent manner .	We have shown previously that DC specific deletion of RBPJ caused partial reduction of the splenic CD11b + DCs, which express Notch target Dtx1 in an RBPJ dependent manner.	21	29	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Dtx1	Dtx1	Dtx1	Notch	Notch	Notch	24	25	22	23
In addition , a study of the neuroepithelial cell line MNS-70 showed that mouse DTX1 mediates Notch signaling to block neural progenitor cell differentiation [ XREF_BIBR ] .	In addition, a study of the neuroepithelial cell line MNS-70 showed that mouse DTX1 mediates Notch signaling to block neural progenitor cell differentiation [XREF_BIBR].	13	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DTX1	DTX1	DTX1	Notch	Notch	Notch	14	15	16	17
In particular , known Notch targets such as Hes1 and Dtx1 were decreased in expression in Notch2 cKO CD11b + cDCs , as were cDC specific genes such as Lphn3 , Spint1 and Dnase1l3 ( XREF_FIG ) .	In particular, known Notch targets such as Hes1 and Dtx1 were decreased in expression in Notch2 cKO CD11b + cDCs, as were cDC specific genes such as Lphn3, Spint1 and Dnase1l3 (XREF_FIG).	4	11	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Dtx1	Dtx1	Dtx1	Notch	Notch	Notch	10	11	4	5
To determine if HES1 was sufficient to reproduce the Notch mediated effects in AML , we expressed human HES1 , compared with another well described Notch target Deltex1 .	To determine if HES1 was sufficient to reproduce the Notch mediated effects in AML, we expressed human HES1, compared with another well described Notch target Deltex1.	24	28	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Deltex1	Deltex1	Deltex1	Notch	Notch	Notch	27	28	25	26
A study of the neuroepithelial cell line MNS-70 showed that mouse DTX1 mediates Notch signaling , blocking neural progenitor cell differentiation [ XREF_BIBR ] .	A study of the neuroepithelial cell line MNS-70 showed that mouse DTX1 mediates Notch signaling, blocking neural progenitor cell differentiation [XREF_BIBR].	10	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DTX1	DTX1	DTX1	Notch	Notch	Notch	11	12	13	14
Although the pro migratory factors Snail-1 and Akt2 and PKBbeta are influenced by DTX1 in both lines , high Notch activity appears to saturate the migratory behavior and can not be further induced by over-expressing DTX1 whereas low Notch levels readily induce migration .	Although the pro migratory factors Snail-1 and Akt2 and PKBbeta are influenced by DTX1 in both lines, high Notch activity appears to saturate the migratory behavior and can not be further induced by over-expressing DTX1 whereas low Notch levels readily induce migration.	19	36	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DTX1	DTX1	DTX1	Notch	Notch	Notch	35	36	19	20
The T-cell differentiation block was as profound as that produced by enforced expression of the Notch modulator Deltex1 .	The T-cell differentiation block was as profound as that produced by enforced expression of the Notch modulator Deltex1.	12	18	modulator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Deltex1	Deltex1	Deltex1	Notch	Notch	Notch	17	18	15	16
Although Hes1 was induced , an overall increase in Notch signaling was not observed after forced expression of GATA-3 , because Dtx1 transcripts ( another downstream target of Notch signaling pathway ) were reduced in this experiment .	Although Hes1 was induced, an overall increase in Notch signaling was not observed after forced expression of GATA-3, because Dtx1 transcripts (another downstream target of Notch signaling pathway) were reduced in this experiment.	21	30	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Dtx1	Dtx1	Dtx1	Notch	Notch	Notch	21	22	28	29
In contrast , only the Ebf1 +/- Pax5 +/- cells responded by induction of the Notch target Deltex1 .	In contrast, only the Ebf1 +/- Pax5 +/- cells responded by induction of the Notch target Deltex1.	12	18	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Deltex1	Deltex1	Deltex1	Notch	Notch	Notch	17	18	15	16
In agreement , Notch target genes that require the highest level of Notch activation ( such as NRARP and DTX1 ) are repressed during the commitment process , while others ( such as HES1 and MYC ) remain expressed until the cells have passed through the beta-selection checkpoint XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	In agreement, Notch target genes that require the highest level of Notch activation (such as NRARP and DTX1) are repressed during the commitment process, while others (such as HES1 and MYC) remain expressed until the cells have passed through the beta-selection checkpoint XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	12	20	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	DTX1	DTX1	DTX1	Notch	Notch	Notch	19	20	12	13
The few genes sharply up-regulated between multipotent progenitors and Pro T cell stages included those encoding transcription factors Bcl11b , TCF-1 ( Tcf7 ) , and HEBalt , Notch target Deltex1 , Deltex3L , Fkbp5 , Eva1 , and Tmem131 .	The few genes sharply up-regulated between multipotent progenitors and Pro T cell stages included those encoding transcription factors Bcl11b, TCF-1 (Tcf7), and HEBalt, Notch target Deltex1, Deltex3L, Fkbp5, Eva1, and Tmem131.	28	39	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Deltex1	Deltex1	Deltex1	Notch	Notch	Notch	30	31	28	29
We show that Deltex-1 ( DTX1 ) , a mammalian homolog of Drosophila Deltex , mediates a Notch signal to block differentiation of neural progenitor cells .	We show that Deltex-1 (DTX1), a mammalian homolog of Drosophila Deltex, mediates a Notch signal to block differentiation of neural progenitor cells.	3	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DTX1	DTX1	DTX1	Notch	Notch	Notch	5	6	17	18
We found that Satb1 -/- CD150 + LSK HSCs , as well as highly purified CD150 + CD48 - LSK HSCs , showed significantly reduced levels of Notch targets , including Hes1 ( by 60 +/- 13 % ) , Hes5 ( by 82.5 +/- 6.6 % ) , Dtx1 ( by 88.5 +/- 19.4 % ) and Hey1 ( by 83.4 +/- 9.2 % ) in comparison to wild-type HSCs ( XREF_FIG , XREF_SUPPLEMENTARY ) .	We found that Satb1 -/- CD150 + LSK HSCs, as well as highly purified CD150 + CD48 - LSK HSCs, showed significantly reduced levels of Notch targets, including Hes1 (by 60 +/- 13%), Hes5 (by 82.5 +/- 6.6%), Dtx1 (by 88.5 +/- 19.4%) and Hey1 (by 83.4 +/- 9.2%) in comparison to wild-type HSCs (XREF_FIG, XREF_SUPPLEMENTARY).	27	55	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Dtx1	Dtx1	Dtx1	Notch	Notch	Notch	49	50	27	28
However , its selective requirement in CD8 - DCs is correlated with the specific and RBP-Jk-dependent expression of Notch target Deltex1 by this population .	However, its selective requirement in CD8 - DCs is correlated with the specific and RBP-Jk-dependent expression of Notch target Deltex1 by this population.	16	21	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Deltex1	Deltex1	Deltex1	Notch	Notch	Notch	20	21	18	19
This revealed that the induction of TCF7 and GATA3 is delayed compared with the direct Notch targets DTX1 and HES1 , when sequential stages of T cell development are evaluated ( XREF_FIG ) , consistent with earlier findings in both mouse and human XREF_BIBR XREF_BIBR .	This revealed that the induction of TCF7 and GATA3 is delayed compared with the direct Notch targets DTX1 and HES1, when sequential stages of T cell development are evaluated (XREF_FIG), consistent with earlier findings in both mouse and human XREF_BIBR XREF_BIBR.	10	34	targets	Positive_activation_token_1_noun	Positive_activation	Positive_activation	DTX1	DTX1	DTX1	Notch	Notch	Notch	17	18	15	16
These included the well-known direct Notch targets Dtx1 , Myc , Notch3 , NRarp , Notch1 and IL2RA ( XREF_FIG and XREF_SUPPLEMENTARY ; XREF_SUPPLEMENTARY ) .	These included the well-known direct Notch targets Dtx1, Myc, Notch3, NRarp, Notch1 and IL2RA (XREF_FIG and XREF_SUPPLEMENTARY; XREF_SUPPLEMENTARY).	1	21	targets	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Dtx1	Dtx1	Dtx1	Notch	Notch	Notch	7	8	5	6
Levels of RNA encoding Notch ligands Jagged1 , Jagged2 and Delta-like-ligand 1 were equal between WT and IL-7Ralpha 449F/449F spleens ( XREF_FIG ) ; however , levels of the negative regulator of notch signaling Deltex1 were notably higher in T1 cells from IL-7Ralpha 449F/449F mice ( XREF_FIG ) .	Levels of RNA encoding Notch ligands Jagged1, Jagged2 and Delta-like-ligand 1 were equal between WT and IL-7Ralpha 449F/449F spleens (XREF_FIG); however, levels of the negative regulator of notch signaling Deltex1 were notably higher in T1 cells from IL-7Ralpha 449F/449F mice (XREF_FIG).	30	35	signaling	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Deltex1	Deltex1	Deltex1	notch	notch	notch	34	35	32	33
This non canonical notch activation was found to be exclusively dependent on F3/Contactin/NB3 , and was mediated by Deltex1 ( DTX1 ) , an E3 ligase also known to antagonize c-Jun N-terminal kinase ( JNK ) , and promote the degradation of NICD , as well as MAPK and ERK kinase kinase 1 .	This non canonical notch activation was found to be exclusively dependent on F3/Contactin/NB3, and was mediated by Deltex1 (DTX1), an E3 ligase also known to antagonize c-Jun N-terminal kinase (JNK), and promote the degradation of NICD, as well as MAPK and ERK kinase kinase 1.	3	25	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Deltex1	Deltex1	Deltex1	notch	notch	notch	18	19	3	4
In contrast , CD11b + DC specific genes including the Notch target Dtx1 were preferentially expressed in the Esam hi subset .	In contrast, CD11b + DC specific genes including the Notch target Dtx1 were preferentially expressed in the Esam hi subset.	7	13	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Dtx1	Dtx1	Dtx1	Notch	Notch	Notch	12	13	10	11
Activation of Notch signalling was confirmed by increased expression of Notch targets such as DTX1 , FOS , HEY1 , HEY2 and HES1 ( XREF_SUPPLEMENTARY , Fig .	Activation of Notch signalling was confirmed by increased expression of Notch targets such as DTX1, FOS, HEY1, HEY2 and HES1 (XREF_SUPPLEMENTARY, Fig.	10	26	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	DTX1	DTX1	DTX1	Notch	Notch	Notch	14	15	10	11
If this interpretation is correct , DTX1 depletion should promote Notch signaling for both CD8-NDeltaE and the dileucine mutant , as observed following clathrin depletion ( XREF_FIG ) .	If this interpretation is correct, DTX1 depletion should promote Notch signaling for both CD8-NDeltaE and the dileucine mutant, as observed following clathrin depletion (XREF_FIG).	6	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	DTX1	DTX1	DTX1	Notch	Notch	Notch	6	7	10	11
This selective requirement for Notch-RBP-J signaling in CD8 - DCs correlated with the specific and RBP-J-dependent expression of Notch target Dtx1 by this DC population .	This selective requirement for Notch-RBP-J signaling in CD8 - DCs correlated with the specific and RBP-J-dependent expression of Notch target Dtx1 by this DC population.	16	21	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Dtx1	Dtx1	Dtx1	Notch	Notch	Notch	20	21	18	19
Depending on the cellular context , DTX1 , a downstream gene in the Notch pathway , either acts as an oncogene to promote the Notch pathway by activating the downstream HLH family genes to inhibit cell differentiation or acts as a suppressed gene to inhibit this pathway by forming the Notch-Deltex-Kurz protein complexes that mediate Notch receptor degradation through a ubiquitination dependent pathway [ XREF_BIBR , XREF_BIBR ] .	Depending on the cellular context, DTX1, a downstream gene in the Notch pathway, either acts as an oncogene to promote the Notch pathway by activating the downstream HLH family genes to inhibit cell differentiation or acts as a suppressed gene to inhibit this pathway by forming the Notch-Deltex-Kurz protein complexes that mediate Notch receptor degradation through a ubiquitination dependent pathway [XREF_BIBR, XREF_BIBR].	6	44	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DTX1	DTX1	DTX1	Notch	Notch	Notch	6	7	24	25
The activity of the V306A mutant in NIH3T3 cells was then measured using Dyrk1A driven Gli 1 dependent synthesis of luciferase as the reporter [ XREF_BIBR ] .	The activity of the V306A mutant in NIH3T3 cells was then measured using Dyrk1A driven Gli 1 dependent synthesis of luciferase as the reporter [XREF_BIBR].	12	17	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dyrk1A	Dyrk1A	Dyrk1A	Gli	Gli	Gli	13	14	15	16
In the testing system using MNB and DYRK1A promoted Gli 1 dependent transcription as the readout , NIH3T3 cells expressing EGCG resistant MNB and DYRK1A mutant R21 were found to acquire EGCG resistance for a wide range of drug concentrations .	In the testing system using MNB and DYRK1A promoted Gli 1 dependent transcription as the readout, NIH3T3 cells expressing EGCG resistant MNB and DYRK1A mutant R21 were found to acquire EGCG resistance for a wide range of drug concentrations.	5	11	promoted	Positive_activation_token_1_verb	Positive_activation	Positive_activation	DYRK1A	DYRK1A	DYRK1A	Gli	Gli	Gli	7	8	9	10
The kinase DYRK1A ( dual-specificity tyrosine phosphorylation regulated kinase 1a ) has been shown to activate GLI1 via a phosphorylation event , leading to the translocation of GLI1 from the cytoplasm to the nucleus [ XREF_BIBR - XREF_BIBR ] .	The kinase DYRK1A (dual-specificity tyrosine phosphorylation regulated kinase 1a) has been shown to activate GLI1 via a phosphorylation event, leading to the translocation of GLI1 from the cytoplasm to the nucleus [XREF_BIBR - XREF_BIBR].	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1A	DYRK1A	DYRK1A	GLI1	GLI1	GLI1	2	3	16	17
Although the conditions of these experiments would suggest that DYRK1A induced GLI1 stimulation would primarily occur in artificial transfection situations , we can not rule out that endogenous situations exist in which DYRK1A would exert a positive role on Hh signalling ( as , for example , in XREF_SUPPLEMENTARY ) .	Although the conditions of these experiments would suggest that DYRK1A induced GLI1 stimulation would primarily occur in artificial transfection situations, we can not rule out that endogenous situations exist in which DYRK1A would exert a positive role on Hh signalling (as, for example, in XREF_SUPPLEMENTARY).	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	DYRK1A	DYRK1A	DYRK1A	GLI1	GLI1	GLI1	9	10	11	12
For instance , DYRK2 can directly phosphorylate GLI2 thereby promoting its degradation , while overexpression of DYRK1A can enhance GLI transcriptional activity .	For instance, DYRK2 can directly phosphorylate GLI2 thereby promoting its degradation, while overexpression of DYRK1A can enhance GLI transcriptional activity.	14	21	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1A	overexpression of DYRK1A	dyrk1a	GLI	GLI	gli	16	17	19	20
However , when both the S102/104 and S130/132 SPS clusters were mutated , DYRK1A was unable to enhance the transcriptional activity of GLI1 as measured in a luminometric Hh reporter assay ( XREF_FIG ) .	However, when both the S102/104 and S130/132 SPS clusters were mutated, DYRK1A was unable to enhance the transcriptional activity of GLI1 as measured in a luminometric Hh reporter assay (XREF_FIG).	13	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1A	DYRK1A	DYRK1A	GLI1	GLI1	GLI1	13	14	22	23
In initial studies Dyrk1A enhanced Gli1 dependent gene transcription and acted synergistically with Sonic hedgehog to induce transcription [ XREF_BIBR ] .	In initial studies Dyrk1A enhanced Gli1 dependent gene transcription and acted synergistically with Sonic hedgehog to induce transcription [XREF_BIBR].	3	16	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Dyrk1A	Dyrk1A	Dyrk1A	Gli1	Gli1	Gli1	3	4	5	6
Further , when both SPS clusters were mutated , GLI transcriptional activity was not enhanced by DYRK1A [ XREF_BIBR ] .	Further, when both SPS clusters were mutated, GLI transcriptional activity was not enhanced by DYRK1A [XREF_BIBR].	9	18	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DYRK1A	DYRK1A	DYRK1A	GLI	GLI	GLI	16	17	9	10
We went on to verify the DYRK1A induced stimulation of GLI1 in various knockout mouse embryonic fibroblast ( MEF ) cell lines and could find the expected increase in transfected GLI1 activity in Ptch1-/- and Smo-/- cells , but surprisingly not in Sufu-/- MEF cells , suggesting that the dissociation from SUFU might play a functional role in this process ( XREF_SUPPLEMENTARY ) .	We went on to verify the DYRK1A induced stimulation of GLI1 in various knockout mouse embryonic fibroblast (MEF) cell lines and could find the expected increase in transfected GLI1 activity in Ptch1-/- and Smo-/- cells, but surprisingly not in Sufu-/- MEF cells, suggesting that the dissociation from SUFU might play a functional role in this process (XREF_SUPPLEMENTARY).	5	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1A	DYRK1A	DYRK1A	GLI1	GLI1	GLI1	6	7	10	11
With DYRK1A phosphorylation predicted to activate GLI1 [ XREF_BIBR ] , this phospho-site ( Ser408 ) has the potential to be a targetable site for cancers mediated by high levels of GLI1 transcriptional activity .	With DYRK1A phosphorylation predicted to activate GLI1 [XREF_BIBR], this phospho-site (Ser408) has the potential to be a targetable site for cancers mediated by high levels of GLI1 transcriptional activity.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1A	DYRK1A phosphorylation	dyrk1a	GLI1	GLI1	gli1	1	2	6	7
Here we find that DYRK1A stimulates GLI transcription factor activity through phosphorylation of general nuclear localization clusters .	Here we find that DYRK1A stimulates GLI transcription factor activity through phosphorylation of general nuclear localization clusters.	4	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1A	DYRK1A	DYRK1A	GLI	GLI	GLI	4	5	6	7
In C3H10/T1/2 cells , Dyrk1a activated only GLI1 , while in NIH3T3 cells , the activity of both variants was increased , but to a lesser extent for GLI1-701G ( XREF_FIG ) .	In C3H10/T1/2 cells, Dyrk1a activated only GLI1, while in NIH3T3 cells, the activity of both variants was increased, but to a lesser extent for GLI1-701G (XREF_FIG).	4	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dyrk1a	Dyrk1a	Dyrk1a	GLI1	GLI1	GLI1	4	5	7	8
However , DYRK1A mediated stimulation of GLI1 was mostly observed under conditions of very high DYRK1A expression levels and in many cases in combination with transiently transfected GLI1 ( which typically yields very high expression levels as well ) .	However, DYRK1A mediated stimulation of GLI1 was mostly observed under conditions of very high DYRK1A expression levels and in many cases in combination with transiently transfected GLI1 (which typically yields very high expression levels as well).	2	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1A	DYRK1A	DYRK1A	GLI1	GLI1	GLI1	2	3	27	28
Notch2 activation may also be triggered by Dll1 on surrounding stromal cells resulting in the development of bortezomib resistance [ XREF_BIBR ] .	Notch2 activation may also be triggered by Dll1 on surrounding stromal cells resulting in the development of bortezomib resistance [XREF_BIBR].	0	8	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch2	Notch2	Notch2	7	8	0	1
However , both Jag1 and Dll1 activated Notch2 in the HSC enriched population that inhibited myeloid differentiation and enhanced the generation of myeloid progenitors during stress hematopoiesis .	However, both Jag1 and Dll1 activated Notch2 in the HSC enriched population that inhibited myeloid differentiation and enhanced the generation of myeloid progenitors during stress hematopoiesis.	3	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch2	Notch2	Notch2	5	6	7	8
The aberrantly elevated levels of NOTCH2 protein in IRF4 deficient FO B cells may lead to DLL1 mediated activation of NOTCH2 signaling that is sufficient to temporarily retain those cells in the MZ during their entry or egress from the spleen .	The aberrantly elevated levels of NOTCH2 protein in IRF4 deficient FO B cells may lead to DLL1 mediated activation of NOTCH2 signaling that is sufficient to temporarily retain those cells in the MZ during their entry or egress from the spleen.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	NOTCH2	NOTCH2	NOTCH2	16	17	20	21
Similarly , the immunofluorescence staining showed that none of over-expressions of DVL1 , DVL2 , and DVL3 triggered nuclear translocation of beta-catenin in HCT-8 cells .	Similarly, the immunofluorescence staining showed that none of over-expressions of DVL1, DVL2, and DVL3 triggered nuclear translocation of beta-catenin in HCT-8 cells.	9	22	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DVL1	over-expressions of DVL1	dvl1	beta-catenin	beta-catenin	beta-catenin	11	12	21	22
Stable overexpression of Dvl-1 caused beta-catenin and NANOG to accumulate .	Stable overexpression of Dvl-1 caused beta-catenin and NANOG to accumulate.	1	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dvl-1	overexpression of Dvl-1	dvl-1	beta-catenin	beta-catenin	beta-catenin	3	4	5	6
Expression of Dvl-1 in L cells induced the nuclear accumulation of beta-catenin , and deletion of the DIX domain abolished this activity .	Expression of Dvl-1 in L cells induced the nuclear accumulation of beta-catenin, and deletion of the DIX domain abolished this activity.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dvl-1	Expression of Dvl-1	dvl-1	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
Coexpression of Dvl-1 and Frat-1 caused accumulation of beta-catenin synergistically in L cells .	Coexpression of Dvl-1 and Frat-1 caused accumulation of beta-catenin synergistically in L cells.	0	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dvl-1	Coexpression of Dvl-1	dvl-1	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
Most notably , the protective LRRK2 variant , R1398H , has the opposite effect , actually enhancing DVL1 driven beta-catenin activation [ XREF_BIBR ] .	Most notably, the protective LRRK2 variant, R1398H, has the opposite effect, actually enhancing DVL1 driven beta-catenin activation [XREF_BIBR].	16	20	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DVL1	DVL1	DVL1	beta-catenin	beta-catenin	beta-catenin	17	18	19	20
An initial study suggests a gain of Wnt and beta-Catenin activity in ADRS , thus it is conceivable that ADRS mutations in DVL1 and DVL3 might result in defective beta-Catenin independent Wnt signaling and concomitantly upregulate Wnt and beta-Catenin activity .	An initial study suggests a gain of Wnt and beta-Catenin activity in ADRS, thus it is conceivable that ADRS mutations in DVL1 and DVL3 might result in defective beta-Catenin independent Wnt signaling and concomitantly upregulate Wnt and beta-Catenin activity.	20	39	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DVL1	DVL1	DVL1	beta-Catenin	beta-Catenin	beta-Catenin	22	23	38	39
We found that the appropriate concentrations and time-points of CsA induced the expression of Dvl-1 and subsequent up-regulation of beta-catenin and c-Myc , which is consistent with previously demonstrated concentrations and time-points when H9c2 cells apoptosis occurred .	We found that the appropriate concentrations and time-points of CsA induced the expression of Dvl-1 and subsequent up-regulation of beta-catenin and c-Myc, which is consistent with previously demonstrated concentrations and time-points when H9c2 cells apoptosis occurred.	9	21	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Dvl-1	CsA induced the expression of Dvl-1	dvl-1	beta-catenin	beta-catenin	beta-catenin	14	15	19	20
In addition , previous studies indicated that dishevelled-1 could upregulate and activate beta-catenin during the wound healing process after MI [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, previous studies indicated that dishevelled-1 could upregulate and activate beta-catenin during the wound healing process after MI [XREF_BIBR, XREF_BIBR, XREF_BIBR].	7	17	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	dishevelled-1	dishevelled-1	dishevelled-1	beta-catenin	beta-catenin	beta-catenin	7	8	12	13
Here we show that Lfng/Mfng/Rfng triple knockout ( Fng tKO ) mice exhibited reduced binding of DLL4 Notch ligand to CD4 and CD8 double negative ( DN ) T cell progenitors , and reduced expression of NOTCH1 targets Deltex1 and CD25 .	Here we show that Lfng/Mfng/Rfng triple knockout (Fng tKO) mice exhibited reduced binding of DLL4 Notch ligand to CD4 and CD8 double negative (DN) T cell progenitors, and reduced expression of NOTCH1 targets Deltex1 and CD25.	34	40	targets	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Deltex1	Deltex1	Deltex1	NOTCH1	NOTCH1	NOTCH1	38	39	36	37
Finally , in the T6E cells treated with antagomir-181a , we observed increased Nrarp and DUSP6 protein expression ( XREF_FIG ) , down-regulation of expression from Notch1 controlled targets including c-Myc , Dtx1 , Hes1 and Hey1 ( XREF_FIG ) , a decrease in proliferation ( XREF_FIG ) , and an increase apoptosis ( XREF_FIG ) .	Finally, in the T6E cells treated with antagomir-181a, we observed increased Nrarp and DUSP6 protein expression (XREF_FIG), down-regulation of expression from Notch1 controlled targets including c-Myc, Dtx1, Hes1 and Hey1 (XREF_FIG), a decrease in proliferation (XREF_FIG), and an increase apoptosis (XREF_FIG).	26	33	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Dtx1	Dtx1	Dtx1	Notch1	Notch1	Notch1	32	33	26	27
Established direct Notch1 gene targets such as Ptcra and Deltex1 19 failed to be upregulated , confirming that these T-lineage cells arose independently of Notch1 signals ( XREF_FIG ) .	Established direct Notch1 gene targets such as Ptcra and Deltex1 19 failed to be upregulated, confirming that these T-lineage cells arose independently of Notch1 signals (XREF_FIG).	2	10	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Deltex1	Deltex1	Deltex1	Notch1	Notch1	Notch1	9	10	2	3
In addition , loss of CD147 in thymocytes impairs Notch signaling , as we detected inhibited expression of Notch1 in CD147 T-KO DN3 cells , as well as in genes directly regulated by Notch1 signaling such as HES1 , DTX1 , and TCF1 .	In addition, loss of CD147 in thymocytes impairs Notch signaling, as we detected inhibited expression of Notch1 in CD147 T-KO DN3 cells, as well as in genes directly regulated by Notch1 signaling such as HES1, DTX1, and TCF1.	33	40	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	DTX1	DTX1	DTX1	Notch1	Notch1	Notch1	39	40	33	34
Surprisingly , we discovered that DTX1 depletion also elevates Notch1 activity mediated by a mutant form of the receptor that lacks lysine residues for ubiquitination , suggesting that DTX1 targets additional factors .	Surprisingly, we discovered that DTX1 depletion also elevates Notch1 activity mediated by a mutant form of the receptor that lacks lysine residues for ubiquitination, suggesting that DTX1 targets additional factors.	5	10	elevates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	DTX1	DTX1	DTX1	Notch1	Notch1	Notch1	5	6	9	10
Furthermore , the cell that remained basally displayed elevated levels of Notch3 while the apical cell expressed the Dll-1 , suggesting that activation of Notch3 by Dll-1 positively selects the basal cells to maintain the stem cell fate .	Furthermore, the cell that remained basally displayed elevated levels of Notch3 while the apical cell expressed the Dll-1, suggesting that activation of Notch3 by Dll-1 positively selects the basal cells to maintain the stem cell fate.	22	27	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Dll-1	Dll-1	Dll-1	Notch3	Notch3	Notch3	26	27	24	25
Dll1 produced by endothelial cells activates Notch3 on mural cells , thereby promoting mural-cell maturation XREF_BIBR .	Dll1 produced by endothelial cells activates Notch3 on mural cells, thereby promoting mural-cell maturation XREF_BIBR.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch3	Notch3	Notch3	0	1	6	7
Interestingly , knockdown of Notch canonical ligands JAG1 or DLL1 in RMS cell lines decreases Notch3 activity and reduces cell proliferation .	Interestingly, knockdown of Notch canonical ligands JAG1 or DLL1 in RMS cell lines decreases Notch3 activity and reduces cell proliferation.	2	16	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch3	Notch3	Notch3	9	10	15	16
Notch3 , the predominant Notch receptor in vascular smooth muscle cells , can be activated in endothelial cells by Dll1 and Jagged1 , thereby promoting mural cell maturation XREF_BIBR , XREF_BIBR , XREF_BIBR .	Notch3, the predominant Notch receptor in vascular smooth muscle cells, can be activated in endothelial cells by Dll1 and Jagged1, thereby promoting mural cell maturation XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	21	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch3	Notch3	Notch3	19	20	0	1
Low concentrations of a recombinant form of DLL1 enhanced cleavage of Notch3 , and congruently increased proliferation of MCF10A-HER2 cells ( XREF_SUPPLEMENTARY ) .	Low concentrations of a recombinant form of DLL1 enhanced cleavage of Notch3, and congruently increased proliferation of MCF10A-HER2 cells (XREF_SUPPLEMENTARY).	5	12	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch3	Notch3	Notch3	7	8	11	12
The coordinated expression of DYRK1A and REST in mouse brain further supports the cross-interaction of DYRK1A and REST during neurodevelopment .	The coordinated expression of DYRK1A and REST in mouse brain further supports the cross-interaction of DYRK1A and REST during neurodevelopment.	2	17	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1A	expression of DYRK1A	dyrk1a	DYRK1A	DYRK1A	dyrk1a	4	5	15	16
LATS2 can also phosphorylate DYRK1A ( dual-specificity tyrosine-( Y )-phosphorylation-regulated kinase 1A ) , which enhances DYRK1A kinase activity and thereby possibly plays a role in RB mediated senescence [ XREF_BIBR ] .	LATS2 can also phosphorylate DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A), which enhances DYRK1A kinase activity and thereby possibly plays a role in RB mediated senescence [XREF_BIBR].	0	22	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1A	LATS2 can also phosphorylate DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A	dyrk1a	DYRK1A	DYRK1A	dyrk1a	4	5	16	17
Finally , if the therapeutic effects of EGCG are mechanistically caused by inhibition of Dyrk1a , then it will be important to demonstrate conclusively that Dyrk1a overexpression and/or increased Dyrk1a activity in specific tissues or specific brain regions can be causally linked to specific trisomic phenotypes .	Finally, if the therapeutic effects of EGCG are mechanistically caused by inhibition of Dyrk1a, then it will be important to demonstrate conclusively that Dyrk1a overexpression and/or increased Dyrk1a activity in specific tissues or specific brain regions can be causally linked to specific trisomic phenotypes.	25	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dyrk1a	Dyrk1a overexpression	dyrk1a	Dyrk1a	Dyrk1a	dyrk1a	25	26	29	30
We also reported that MKP-3 can activate FOXO1 by at least dephosphorylating Ser 256 , one of the Akt phosphorylation sites XREF_BIBR .	We also reported that MKP-3 can activate FOXO1 by at least dephosphorylating Ser 256, one of the Akt phosphorylation sites XREF_BIBR.	4	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKP-3	MKP-3	MKP-3	FOXO1	FOXO1	FOXO1	4	5	7	8
Reduced hepatic MKP-3 expression by shMKP-3 decreased 71 % of FOXO1 and FOXO1 3A to co-immunoprecipitate with MKP-3 in FOXO1 3A overexpression mice ( XREF_FIG , the second graph , bar 4 vs. 3 ) .	Reduced hepatic MKP-3 expression by shMKP-3 decreased 71% of FOXO1 and FOXO1 3A to co-immunoprecipitate with MKP-3 in FOXO1 3A overexpression mice (XREF_FIG, the second graph, bar 4 vs. 3).	2	13	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MKP-3	MKP-3 expression	mkp-3	FOXO1	FOXO1	foxo1	2	3	10	11
Although our results are consistent with DLL3 activating Notch1 in the neural stem cell compartment at mid gestation , in other systems DLL3 might also behave as inhibitor of Notch1 , possibly through competition with other Notch ligands .	Although our results are consistent with DLL3 activating Notch1 in the neural stem cell compartment at mid gestation, in other systems DLL3 might also behave as inhibitor of Notch1, possibly through competition with other Notch ligands.	22	30	behave as inhibitor	Negative_activation_copula_1	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch1	Notch1	Notch1	22	23	29	30
Recent data show that Dll3 interacts with full length NOTCH1 in the late endocytic compartment and that high levels of Dll3 expression are correlated with low levels of Notch1 suggesting that Dll3 targets Notch1 for lysosomal degradation [ XREF_BIBR ] .	Recent data show that Dll3 interacts with full length NOTCH1 in the late endocytic compartment and that high levels of Dll3 expression are correlated with low levels of Notch1 suggesting that Dll3 targets Notch1 for lysosomal degradation [XREF_BIBR].	29	38	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch1	Notch1	Notch1	31	32	33	34
In this context , theWP component , Disheveled has been proposed as one of the candidates as an upstream regulator of RAC1 activity as the overexpression of Dishevelled-2 , but not Dishevelled-1 upregulated RAC1 in a different context [ XREF_BIBR ] .	In this context, theWP component, Disheveled has been proposed as one of the candidates as an upstream regulator of RAC1 activity as the overexpression of Dishevelled-2, but not Dishevelled-1 upregulated RAC1 in a different context [XREF_BIBR].	30	34	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dishevelled-1	Dishevelled-1	Dishevelled-1	RAC1	RAC1	RAC1	31	32	33	34
Myotonic dystrophy protein kinase ( DMPK ) , a muscle- and neuron restricted kinase , enhanced SRF mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells .	Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron restricted kinase, enhanced SRF mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells.	3	18	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DMPK	DMPK	DMPK	SRF	SRF	SRF	5	6	16	17
Dner , a gene that activates the NOTCH1 signaling pathway ( involved in cell differentiation ) was up regulated 7.1-fold in V clones .	Dner, a gene that activates the NOTCH1 signaling pathway (involved in cell differentiation) was up regulated 7.1-fold in V clones.	0	18	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Dner	Dner	Dner	NOTCH1	NOTCH1	NOTCH1	0	1	7	8
While deficiency of Dok-4 induces Src localization to extra-mitochondria , overexpression of Dok-4 causes Src localization to mitochondria [ XREF_BIBR ] .	While deficiency of Dok-4 induces Src localization to extra-mitochondria, overexpression of Dok-4 causes Src localization to mitochondria [XREF_BIBR].	10	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dok-4	overexpression of Dok-4	dok-4	Src	Src	src	12	13	14	15
Soluble monomeric ephrin-A1 , found in the conditioned media of U-251 MG GBM cells , was able to induce EphA2 receptor internalization and down-regulation ; the same was observed for recombinant monomeric forms of ephrin-A1 and ephrin-A5 .	Soluble monomeric ephrin-A1, found in the conditioned media of U-251 MG GBM cells, was able to induce EphA2 receptor internalization and down-regulation; the same was observed for recombinant monomeric forms of ephrin-A1 and ephrin-A5.	0	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	2	3	19	20
EphA2 receptor tyrosine kinase ( RTK ) is activated by ephrin-A1 ligand , which harbors a GPI-anchor that enhances lipid raft localization .	EphA2 receptor tyrosine kinase (RTK) is activated by ephrin-A1 ligand, which harbors a GPI-anchor that enhances lipid raft localization.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	10	11	0	1
In this study , we used ephrinA1 fusion protein and verified that ephrinA1 can activate EphA1 but not EphA2 receptors in an EphA1 negative HCC cell line of HLE cells ( Additional file 2 : Figure S2 ) , which was similar to Iida ' s findings [ XREF_BIBR ] .	In this study, we used ephrinA1 fusion protein and verified that ephrinA1 can activate EphA1 but not EphA2 receptors in an EphA1 negative HCC cell line of HLE cells (Additional file 2 : Figure S2), which was similar to Iida 's findings [XREF_BIBR].	12	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	12	13	18	19
Since ephrin-B3 is not an activating ligand for EphA2 [ XREF_BIBR ] , an explanation for these findings could be that ephrin-B3 interacting in cis prevents EphA2 activation and degradation induced by ephrin-A1 in trans [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Since ephrin-B3 is not an activating ligand for EphA2 [XREF_BIBR], an explanation for these findings could be that ephrin-B3 interacting in cis prevents EphA2 activation and degradation induced by ephrin-A1 in trans [XREF_BIBR, XREF_BIBR, XREF_BIBR].	26	40	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	32	33	26	27
As expected , EphrinA1 , when presented as a Fc-fusion protein , induced significant activation of EphA2 in endothelial cells ( XREF_FIG ) , as did thrombin .	As expected, EphrinA1, when presented as a Fc-fusion protein, induced significant activation of EphA2 in endothelial cells (XREF_FIG), as did thrombin.	3	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphrinA1	EphrinA1	EphrinA1	EphA2	EphA2	EphA2	3	4	16	17
We previously showed that EphA2 is activated by ephrin-A ligand in a contact dependent manner in keratinocytes and that delivery of additional , soluble ephrin-A1 peptide mimetic ( i.e. EfnA1-Fc ) enhances EphA2 activation and subsequent receptor down-regulation , leading to increased differentiation .	We previously showed that EphA2 is activated by ephrin-A ligand in a contact dependent manner in keratinocytes and that delivery of additional, soluble ephrin-A1 peptide mimetic (i.e. EfnA1-Fc) enhances EphA2 activation and subsequent receptor down-regulation, leading to increased differentiation.	24	33	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	24	25	32	33
In psoriatic lesions , we suspect that impaired keratinocyte differentiation , reduced ephrin-A1 ligand expression and the integrated actions of growth factors and pro inflammatory cytokines work collectively to up-regulate EphA2 .	In psoriatic lesions, we suspect that impaired keratinocyte differentiation, reduced ephrin-A1 ligand expression and the integrated actions of growth factors and pro inflammatory cytokines work collectively to up-regulate EphA2.	12	31	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1 ligand expression	ephrin-a1	EphA2	EphA2	epha2	12	13	30	31
In HUVECs , addition of exogenous soluble EphA2-Fc blocks VEGF induced angiogenesis , suggesting forward signaling through EphA2 receptor triggered by the interacting Ephrin-A1 ligand mediates the VEGF induced response [ XREF_BIBR ] .	In HUVECs, addition of exogenous soluble EphA2-Fc blocks VEGF induced angiogenesis, suggesting forward signaling through EphA2 receptor triggered by the interacting Ephrin-A1 ligand mediates the VEGF induced response [XREF_BIBR].	17	24	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ephrin-A1	Ephrin-A1	Ephrin-A1	EphA2	EphA2	EphA2	23	24	17	18
Recent studies provide evidence that ephrin-A1 promotes the motility of EphA2 positive cardiac stem cells , resulting in enhanced regeneration and cardiac function after myocardial infarction .	Recent studies provide evidence that ephrin-A1 promotes the motility of EphA2 positive cardiac stem cells, resulting in enhanced regeneration and cardiac function after myocardial infarction.	5	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	5	6	10	11
This suggests that Akt is not constitutively dephosphorylated by a calyculin sensitive phosphatase in PC3 cells , but becomes a target of the phosphatase when EphA2 is activated by ephrin-A1 .	This suggests that Akt is not constitutively dephosphorylated by a calyculin sensitive phosphatase in PC3 cells, but becomes a target of the phosphatase when EphA2 is activated by ephrin-A1.	25	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	29	30	25	26
Soluble ephrin-A1 fails to activate EphA2 and only if the ligand is chemically cross linked or surface bound is its activity rescued 14 .	Soluble ephrin-A1 fails to activate EphA2 and only if the ligand is chemically cross linked or surface bound is its activity rescued 14.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	1	2	5	6
Since HeLa cells express endogenous EfnA1 , this constitutive turnover may be due to autocrine activation of EphA2 by EfnA1 made in the same cell or neighboring cells .	Since HeLa cells express endogenous EfnA1, this constitutive turnover may be due to autocrine activation of EphA2 by EfnA1 made in the same cell or neighboring cells.	12	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EfnA1	EfnA1	EfnA1	EphA2	EphA2	EphA2	19	20	17	18
Soluble , monomeric ephrinA1 induces internalization and downregulation of EphA2 .	Soluble, monomeric ephrinA1 induces internalization and downregulation of EphA2.	2	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	3	4	9	10
Importantly , we found that FVIIa potentiated the cellular response to ephrin-A1 as measured by increased cell rounding and retraction fiber formation upon stimulation , demonstrating that FVIIa and ephrin-A1 act synergistically to enhance ligand dependent EphA2 signaling .	Importantly, we found that FVIIa potentiated the cellular response to ephrin-A1 as measured by increased cell rounding and retraction fiber formation upon stimulation, demonstrating that FVIIa and ephrin-A1 act synergistically to enhance ligand dependent EphA2 signaling.	27	37	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	29	30	36	37
Elevated levels of ephrin-A1 may contribute to diabetic keratopathies by persistently engaging EphA2 and prohibiting Akt dependent corneal epithelial repair processes .	Elevated levels of ephrin-A1 may contribute to diabetic keratopathies by persistently engaging EphA2 and prohibiting Akt dependent corneal epithelial repair processes.	1	13	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	levels of ephrin-A1	ephrin-a1	EphA2	EphA2	epha2	3	4	12	13
Here we show that ephrin-A1 ligand dependent activation of EphA2 decreases the growth of PC3 prostate cancer cells and profoundly inhibits the Akt-mTORC1 pathway , which is hyperactivated due to loss of the PTEN tumor suppressor .	Here we show that ephrin-A1 ligand dependent activation of EphA2 decreases the growth of PC3 prostate cancer cells and profoundly inhibits the Akt-mTORC1 pathway, which is hyperactivated due to loss of the PTEN tumor suppressor.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	4	5	9	10
Ephrin-A1 induced activation of EphA2 in breast cancer cells was shown to decrease in vivo tumorigenicity in mouse models .	Ephrin-A1 induced activation of EphA2 in breast cancer cells was shown to decrease in vivo tumorigenicity in mouse models.	0	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Ephrin-A1	Ephrin-A1	Ephrin-A1	EphA2	EphA2	EphA2	0	1	4	5
Along this line , in both glioma stem cells ( shown in this report ) and established glioma cells lines , EphA2 can be readily activated by exogenous ligand ephrin-A1 , leading to the inhibition of both Akt and Erk1/2 activities .	Along this line, in both glioma stem cells (shown in this report) and established glioma cells lines, EphA2 can be readily activated by exogenous ligand ephrin-A1, leading to the inhibition of both Akt and Erk1/2 activities.	21	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	29	30	21	22
We have previously demonstrated in vitro study that EphrinA1 could induce EphA2 activation in human fallopian tubal epithelial cells , accompanied by the up-regulation of Pho-EphA2 [ XREF_BIBR ] .	We have previously demonstrated in vitro study that EphrinA1 could induce EphA2 activation in human fallopian tubal epithelial cells, accompanied by the up-regulation of Pho-EphA2 [XREF_BIBR].	8	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphrinA1	EphrinA1	EphrinA1	EphA2	EphA2	EphA2	8	9	11	12
This effect is indirect : SOCS2 induces EfnA1 expression , and EfnA1 induces EphA2 down-regulation .	This effect is indirect : SOCS2 induces EfnA1 expression, and EfnA1 induces EphA2 down-regulation.	11	14	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EfnA1	EfnA1	EfnA1	EphA2	EphA2	EphA2	11	12	13	14
We previously reported that activation of EphA2 by ephrinA1 induces compaction and enhanced polarization of Madin-Darby canine kidney ( MDCK ) epithelial cells .	We previously reported that activation of EphA2 by ephrinA1 induces compaction and enhanced polarization of Madin-Darby canine kidney (MDCK) epithelial cells.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	8	9	6	7
Moreover , ephrin-A1 targeting of EphA2 leads to its activation and down-regulation to promote keratinocyte differentiation .	Moreover, ephrin-A1 targeting of EphA2 leads to its activation and down-regulation to promote keratinocyte differentiation.	2	6	targeting	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	2	3	5	6
As it is known that Tiam1 is involved in Rac1 activity and EphA8 and ephrinA5 endocytosis , we investigated whether Tiam1 would play a role in ephrinA1 induced EphA2 endocytosis .	As it is known that Tiam1 is involved in Rac1 activity and EphA8 and ephrinA5 endocytosis, we investigated whether Tiam1 would play a role in ephrinA1 induced EphA2 endocytosis.	24	29	induced	Positive_early_activation	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	26	27	28	29
Notably , mobile EphrinA1 on supported membranes can effectively trigger EphA2 activation in human breast cancer cells .	Notably, mobile EphrinA1 on supported membranes can effectively trigger EphA2 activation in human breast cancer cells.	2	11	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphrinA1	EphrinA1	EphrinA1	EphA2	EphA2	EphA2	3	4	10	11
A recent study by Lin et al further reinforced that EphA2 activation by ephrin-A1 stimulation strengthens inter-keratinocyte adhesion and induces stratification and terminal differentiation .	A recent study by Lin et al further reinforced that EphA2 activation by ephrin-A1 stimulation strengthens inter-keratinocyte adhesion and induces stratification and terminal differentiation.	10	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	13	14	10	11
We found that compound 76D10 inhibits EphA2 tyrosine phosphorylation in response to stimulation with the angiogenic factor TNFalpha ( XREF_FIG ) , which is known to rapidly upregulate expression of endogenous ephrin-A1 thus causing EphA2 activation in endothelial cells .	We found that compound 76D10 inhibits EphA2 tyrosine phosphorylation in response to stimulation with the angiogenic factor TNFalpha (XREF_FIG), which is known to rapidly upregulate expression of endogenous ephrin-A1 thus causing EphA2 activation in endothelial cells.	17	35	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	TNFalpha (XREF_FIG), which is known to rapidly upregulate expression of endogenous ephrin-A1	ephrin-a1	EphA2	EphA2	epha2	31	32	34	35
In contrast , ephrin-A1 induced a robust EphA2 dependent increase in NFAT activation , and mutation of the NF-kappaB and NFAT binding sites in the VCAM-1 promoter blunted ephrin-A1-induced promoter activity .	In contrast, ephrin-A1 induced a robust EphA2 dependent increase in NFAT activation, and mutation of the NF-kappaB and NFAT-binding sites in the VCAM-1 promoter blunted ephrin-A1-induced promoter activity.	3	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	3	4	7	8
Activation of EPHA2 by ephrin-A1 can change the cytoskeletal morphology and cellular morphogenesis by controlling disassembly of the cytoskeleton XREF_BIBR , XREF_BIBR .	Activation of EPHA2 by ephrin-A1 can change the cytoskeletal morphology and cellular morphogenesis by controlling disassembly of the cytoskeleton XREF_BIBR, XREF_BIBR.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EPHA2	EPHA2	EPHA2	4	5	2	3
EphrinA1 conditioned media treatment caused EphA2 to internalize and relocate from the plasma membrane to the cytoplasmic and perinuclear regions of cells after 2 h , followed by a gradual decrease in the receptor level at 4 and 8 h ( XREF_FIG ) .	EphrinA1 conditioned media treatment caused EphA2 to internalize and relocate from the plasma membrane to the cytoplasmic and perinuclear regions of cells after 2 h, followed by a gradual decrease in the receptor level at 4 and 8 h (XREF_FIG).	0	6	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphrinA1	EphrinA1	EphrinA1	EphA2	EphA2	EphA2	0	1	5	6
Thus , further studies are required to determine the endogenous EphA2 signaling cascade triggered by ephrin-A1 stimulation that acts to promote cell adhesion via integrins in leukocytes as well as other cell types .	Thus, further studies are required to determine the endogenous EphA2 signaling cascade triggered by ephrin-A1 stimulation that acts to promote cell adhesion via integrins in leukocytes as well as other cell types.	10	16	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	15	16	10	11
We next demonstrated that EphA2 was profoundly downregulated in U-251MG and A-172MG GBM cells treated with ephrinA1 conditioned media obtained from either U-251 [ ephrinA1 ] ( + ) cells or SK-Br-3 cells ( XREF_FIG ) .	We next demonstrated that EphA2 was profoundly downregulated in U-251MG and A-172MG GBM cells treated with ephrinA1 conditioned media obtained from either U-251 [ephrinA1] (+) cells or SK-Br-3 cells (XREF_FIG).	4	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	16	17	4	5
EphA2 activation by ephrin-A1 decreases cell attachment to ECM and counteracts integrin signalling in multiple cells types leading to Rac mediated upregulation of Rho activity [ XREF_BIBR , XREF_BIBR ] .	EphA2 activation by ephrin-A1 decreases cell attachment to ECM and counteracts integrin signalling in multiple cells types leading to Rac mediated upregulation of Rho activity [XREF_BIBR, XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	3	4	0	1
The particular example highlighted here uses supported membranes that incorporate the cyclic peptide [ Arg-Gly-Asp-d-Phe-Lys ( Biotin-PEG-PEG ) ] ( cRGD ) that specifically targets integrin receptors , and ephrin-A1 , which targets the EphA2 receptor tyrosine kinase .	The particular example highlighted here uses supported membranes that incorporate the cyclic peptide [Arg-Gly-Asp-d-Phe-Lys (Biotin-PEG-PEG)] (cRGD) that specifically targets integrin receptors, and ephrin-A1, which targets the EphA2 receptor tyrosine kinase.	7	35	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	29	30	34	35
Both studies are consistent with previous report that EphA2 activation by ephrin-A1 simulation in primary keratinocytes results in the inhibition of Ras and ERK activities and cell growth .	Both studies are consistent with previous report that EphA2 activation by ephrin-A1 simulation in primary keratinocytes results in the inhibition of Ras and ERK activities and cell growth.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	11	12	8	9
Ephrin-A1 activation of receptor EphA2 down regulated the expression of claudin-2 in NSCLC cells .	Ephrin-A1 activation of receptor EphA2 down regulated the expression of claudin-2 in NSCLC cells.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Ephrin-A1	Ephrin-A1	Ephrin-A1	EphA2	EphA2	EphA2	0	1	4	5
Silencing the expression of EphA2 receptor also increases the expression of cdx-2 which indicates that knockdown of EphA2 either by ephrin-A1 activation or by silencing interference RNA could be potential in inhibiting the oncogenic effect of receptor EphA2 and tumor growth .	Silencing the expression of EphA2 receptor also increases the expression of cdx-2 which indicates that knockdown of EphA2 either by ephrin-A1 activation or by silencing interference RNA could be potential in inhibiting the oncogenic effect of receptor EphA2 and tumor growth.	15	21	knockdown	Negative_activation_syntax_1_noun	Positive_activation	Negative_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	20	21	17	18
Ligand dependent forward signaling by EphA2 frequently targets the cytoskeleton , with EphA2 activation by ephrin-A1 leading to cytoskeletal rearrangements and cell rounding [ XREF_BIBR ] .	Ligand dependent forward signaling by EphA2 frequently targets the cytoskeleton, with EphA2 activation by ephrin-A1 leading to cytoskeletal rearrangements and cell rounding [XREF_BIBR].	12	24	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	15	16	12	13
EphA2 overexpressing U-251 MG GBM cells treated with recombinant dimeric ephrin-A1 showed a decrease in migration and proliferation potential .	EphA2 overexpressing U-251 MG GBM cells treated with recombinant dimeric ephrin-A1 showed a decrease in migration and proliferation potential.	0	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	10	11	0	1
In vivo studies demonstrate that EphA2 activation by systemically administered ephrin-A1 decreases tumorigenicity and invasiveness of carcinoma xenografts XREF_BIBR , XREF_BIBR .	In vivo studies demonstrate that EphA2 activation by systemically administered ephrin-A1 decreases tumorigenicity and invasiveness of carcinoma xenografts XREF_BIBR, XREF_BIBR.	5	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	10	11	5	6
For example , ephrinA1 induced activation of EphA2 stimulates the MAP and ERK kinase signaling cascade [ XREF_BIBR ] , EphB4 receptor signaling mediates endothelial cell migration and proliferation via the PI 3 K/Akt pathway [ XREF_BIBR ] , and the mTOR pathway is a crucial mediator of EphA signaling in neurons [ XREF_BIBR ] .	For example, ephrinA1 induced activation of EphA2 stimulates the MAP and ERK kinase signaling cascade [XREF_BIBR], EphB4 receptor signaling mediates endothelial cell migration and proliferation via the PI 3 K/Akt pathway [XREF_BIBR], and the mTOR pathway is a crucial mediator of EphA signaling in neurons [XREF_BIBR].	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	3	4	7	8
For instance , EFNA1 mediated EPHA2 activation is required for maximal neoangiogenesis by VEGF in vivo XREF_BIBR .	For instance, EFNA1 mediated EPHA2 activation is required for maximal neoangiogenesis by VEGF in vivo XREF_BIBR.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	EFNA1	EFNA1	EFNA1	EPHA2	EPHA2	EPHA2	3	4	5	6
This result provided additional evidence that E119 of EphrinA1 contributed its EphA2 activating function , which is consistent with previous study 13 .	This result provided additional evidence that E119 of EphrinA1 contributed its EphA2 activating function, which is consistent with previous study 13.	6	13	contributed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphrinA1	EphrinA1	EphrinA1	EphA2	EphA2	EphA2	8	9	11	12
A number of studies have shown that stimulation of EphA2 by ephrin-A1 resulted in inhibition of Akt activity in certain cell lines ( U87 , U251 , A172 , MCF7 , G48a , ES2 , HEYA8 and corneal epithelial cells ) XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	A number of studies have shown that stimulation of EphA2 by ephrin-A1 resulted in inhibition of Akt activity in certain cell lines (U87, U251, A172, MCF7, G48a, ES2, HEYA8 and corneal epithelial cells) XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	7	12	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	11	12	9	10
The EphA2 receptor tyrosine kinase is overexpressed in a number of malignancies and is activated by ephrin ligands , most commonly by ephrin-A1 .	The EphA2 receptor tyrosine kinase is overexpressed in a number of malignancies and is activated by ephrin ligands, most commonly by ephrin-A1.	1	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	22	23	1	2
Conditioned media containing a soluble monomer of ephrinA1 caused EphA2 internalization and downregulation , dramatic alteration of cell morphology and suppression of the Ras-MAPK pathway .	Conditioned media containing a soluble monomer of ephrinA1 caused EphA2 internalization and downregulation, dramatic alteration of cell morphology and suppression of the Ras-MAPK pathway.	5	10	caused	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	7	8	9	10
Ephrin-A1 is shown to activate the EphA2 receptor tyrosine kinase in PC3 cells .	Ephrin-A1 is shown to activate the EphA2 receptor tyrosine kinase in PC3 cells.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ephrin-A1	Ephrin-A1	Ephrin-A1	EphA2	EphA2	EphA2	0	1	6	7
Membrane bound ephrin-A1 triggered the EphA2 RTK pathway and ultimately led to its degradation , as measured by western blotting ( XREF_FIG ) , confirming that the ligand was active on the supported membrane surface .	Membrane bound ephrin-A1 triggered the EphA2 RTK pathway and ultimately led to its degradation, as measured by western blotting (XREF_FIG), confirming that the ligand was active on the supported membrane surface.	2	10	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	2	3	5	6
EphA2 was activated and phosphorylated by ephrinA1 in GBM cells .	EphA2 was activated and phosphorylated by ephrinA1 in GBM cells.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	6	7	0	1
Using a combination of biochemical and imaging approaches , we provide evidence that ephrin-A1 and a ligand activated form of EphA2 partition outside of lipid raft domains in response to calcium mediated cell-cell contact stabilization in normal human epidermal keratinocytes ( NHEKs ) .	Using a combination of biochemical and imaging approaches, we provide evidence that ephrin-A1 and a ligand activated form of EphA2 partition outside of lipid raft domains in response to calcium mediated cell-cell contact stabilization in normal human epidermal keratinocytes (NHEKs).	13	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	13	14	20	21
In this study , EphA2 activation by ligand ephrin-A1 stimulation in MDCK cells suppresses Arf6 , a GTPase primarily regulates recycling of plasma membrane components and remodeling of the membrane and actin cytoskeleton at the cell peripheries , and induces cell compaction , which is accompanied by the enhanced accumulation of E-cadherin to cell-cell contacts .	In this study, EphA2 activation by ligand ephrin-A1 stimulation in MDCK cells suppresses Arf6, a GTPase primarily regulates recycling of plasma membrane components and remodeling of the membrane and actin cytoskeleton at the cell peripheries, and induces cell compaction, which is accompanied by the enhanced accumulation of E-cadherin to cell-cell contacts.	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	8	9	4	5
This suggests that the effect of over-expressed SOCS2 on EphA2 is quite indirect , involving induction of EfnA1 and increased EfnA1 induced internalization and degradation of EphA2 .	This suggests that the effect of over-expressed SOCS2 on EphA2 is quite indirect, involving induction of EfnA1 and increased EfnA1 induced internalization and degradation of EphA2.	20	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EfnA1	EfnA1	EfnA1	EphA2	EphA2	EphA2	20	21	26	27
These data suggest that Tiam1 is required for ephrinA1 induced EphA2 endocytosis .	These data suggest that Tiam1 is required for ephrinA1 induced EphA2 endocytosis.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	8	9	10	11
These results suggest that EFNA1 mediated EPHA2 stimulation can lead to phosphorylation of CEACAM1-L ITIM associated Tyr residues , with recruitment of its SHP-1 phosphatase partner resulting in EPHA2 downstream signaling modulation , as reported for other CEACAM1-L-mediated processes downstream other RTKs [ XREF_BIBR ] .	These results suggest that EFNA1 mediated EPHA2 stimulation can lead to phosphorylation of CEACAM1-L ITIM associated Tyr residues, with recruitment of its SHP-1 phosphatase partner resulting in EPHA2 downstream signaling modulation, as reported for other CEACAM1-L-mediated processes downstream other RTKs [XREF_BIBR].	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	EFNA1	EFNA1	EFNA1	EPHA2	EPHA2	EPHA2	4	5	6	7
This might be explained by the pro oncogenic function of EPHA2 in the absence of EFNA1 XREF_BIBR , whereas activation of EPHA2 by EFNA1 promoted tumor suppression by triggering receptor degradation XREF_BIBR .	This might be explained by the pro oncogenic function of EPHA2 in the absence of EFNA1 XREF_BIBR, whereas activation of EPHA2 by EFNA1 promoted tumor suppression by triggering receptor degradation XREF_BIBR.	19	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EFNA1	EFNA1	EFNA1	EPHA2	EPHA2	EPHA2	23	24	21	22
Therefore , we considered the possibility that growth factor signaling pathways impacted by ephrin-A1 ligand stimulation of EphA2 may contribute to the regulation E-cadherin at heterotypic contacts .	Therefore, we considered the possibility that growth factor signaling pathways impacted by ephrin-A1 ligand stimulation of EphA2 may contribute to the regulation E-cadherin at heterotypic contacts.	13	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	13	14	17	18
So it is possible that the increasing EphA2 activation by both membrane bound and soluble ephrin-A1 in SCC-9 cells had resulted in the down-regulation of ephrin-A1 .	So it is possible that the increasing EphA2 activation by both membrane bound and soluble ephrin-A1 in SCC-9 cells had resulted in the down-regulation of ephrin-A1.	7	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	15	16	7	8
EFNA1 initiation of EPHA2 forward signaling in breast cancer cells results in increased caspase-3 activity , reduced ERK activation and attenuated Ras and MAPK pathway activation in response to EGF ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	EFNA1 initiation of EPHA2 forward signaling in breast cancer cells results in increased caspase-3 activity, reduced ERK activation and attenuated Ras and MAPK pathway activation in response to EGF (XREF_FIG) [XREF_BIBR, XREF_BIBR].	0	5	initiation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EFNA1	EFNA1	EFNA1	EPHA2	EPHA2	EPHA2	0	1	3	4
We have previously demonstrated that EphA2 stimulation by ephrin-A1 promotes cell adhesion through interaction with integrins and integrin ligands in two monocyte and macrophage cell lines .	We have previously demonstrated that EphA2 stimulation by ephrin-A1 promotes cell adhesion through interaction with integrins and integrin ligands in two monocyte and macrophage cell lines.	5	9	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	8	9	5	6
Therefore , a single set of signals from EphA2 induced by Ephrin-A1 is not sufficient .	Therefore, a single set of signals from EphA2 induced by Ephrin-A1 is not sufficient.	6	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ephrin-A1	Ephrin-A1	Ephrin-A1	EphA2	EphA2	EphA2	11	12	8	9
Therefore , EphA2 activation by thrombin in our system was not mediated by EphrinA1 or other ephrins .	Therefore, EphA2 activation by thrombin in our system was not mediated by EphrinA1 or other ephrins.	2	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EphrinA1	EphrinA1	EphrinA1	EphA2	EphA2	EphA2	13	14	2	3
Since EphrinA1 expression in atherosclerotic plaques in vivo may induce endothelial EphA2 activation , we measured EphA2 and ephrinA1 staining in healthy and atherosclerotic vessels harvested from ApoE null mice .	Since EphrinA1 expression in atherosclerotic plaques in vivo may induce endothelial EphA2 activation, we measured EphA2 and ephrinA1 staining in healthy and atherosclerotic vessels harvested from ApoE null mice.	1	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphrinA1	EphrinA1 expression	ephrina1	EphA2	EphA2	epha2	1	2	11	12
In addition , forskolin did not detectably affect EphA2 endocytosis induced by ephrin-A1 Fc stimulation ( Supplemental Figure S2D ) .	In addition, forskolin did not detectably affect EphA2 endocytosis induced by ephrin-A1 Fc stimulation (Supplemental Figure S2D).	8	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	12	13	8	9
Furthermore , stimulation of EphA2 by ephrin-A1 in PTEN null PC3 cell line demonstrated inhibition of the Akt-mTORC1 pathway [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Furthermore, stimulation of EphA2 by ephrin-A1 in PTEN null PC3 cell line demonstrated inhibition of the Akt-mTORC1 pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	12	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	6	7	4	5
EphA2 activation by ephrin-A1 simulation in primary keratinocytes results in the inhibition of Erk and MAP kinase activation .	EphA2 activation by ephrin-A1 simulation in primary keratinocytes results in the inhibition of Erk and MAP kinase activation.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	3	4	0	1
Because ephrinA1 is similarly expressed in epithelial and endothelial cells to EphA2 , ephrinA1 induces EphA2 activation upon cell-cell contacts .	Because ephrinA1 is similarly expressed in epithelial and endothelial cells to EphA2, ephrinA1 induces EphA2 activation upon cell-cell contacts.	13	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	13	14	15	16
P52 however , did not block EphrinA1 mediated activation of EphA2 ( XREF_FIG ) .	P52 however, did not block EphrinA1 mediated activation of EphA2 (XREF_FIG).	6	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	EphrinA1	EphrinA1	EphrinA1	EphA2	EphA2	EphA2	6	7	10	11
Furthermore , ephrinA1 induced a prominent , dose dependent inhibitory effect on the anchorage independent growth and invasiveness of GBM cells highly overexpressing EphA2 , which was not seen in cells expressing low levels of the receptor .	Furthermore, ephrinA1 induced a prominent, dose dependent inhibitory effect on the anchorage independent growth and invasiveness of GBM cells highly overexpressing EphA2, which was not seen in cells expressing low levels of the receptor.	2	28	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	2	3	23	24
Our data also indicate that Tiam1 is required for ephrinA1 induced EphA2 endocytosis .	Our data also indicate that Tiam1 is required for ephrinA1 induced EphA2 endocytosis.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	9	10	11	12
The existence of soluble EFNA1 in HeLa cells raises the possibility that it can affect EPHA2 signaling .	The existence of soluble EFNA1 in HeLa cells raises the possibility that it can affect EPHA2 signaling.	1	16	raises	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EFNA1	EFNA1	EFNA1	EPHA2	EPHA2	EPHA2	4	5	15	16
Ephrin-A1 ligand targeting of EphA2 restricted the ability of corneal epithelial cells to seal linear scratch wounds in a manner that was associated with a transient reduction in Erk1/2 and Akt activation state .	Ephrin-A1 ligand targeting of EphA2 restricted the ability of corneal epithelial cells to seal linear scratch wounds in a manner that was associated with a transient reduction in Erk1/2 and Akt activation state.	0	5	targeting	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Ephrin-A1	Ephrin-A1	Ephrin-A1	EphA2	EphA2	EphA2	0	1	4	5
However , in prostate cancer and endothelial cells , ephrin-A1 stimulation of EphA2 leads to the inhibition of both basal and EGF induced MAPK activity ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	However, in prostate cancer and endothelial cells, ephrin-A1 stimulation of EphA2 leads to the inhibition of both basal and EGF induced MAPK activity (XREF_FIG) [XREF_BIBR, XREF_BIBR].	9	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	9	10	12	13
In their study , ET-1 induced significant increases in airway and tissue resistance as well as H and eta .	In their study, ET-1 induced significant increases in airway and tissue resistance as well as H and eta.	4	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	eta	eta	eta	4	5	18	19
It is suggested that differential sensitivity to BQ-123 is an intrinsic property of Et-1 and Et-3 activated ETA receptors and that there is no need to postulate the existence of new ETA receptor isoforms to account for singular actions of BQ-123 .	It is suggested that differential sensitivity to BQ-123 is an intrinsic property of Et-1 and Et-3 activated ETA receptors and that there is no need to postulate the existence of new ETA receptor isoforms to account for singular actions of BQ-123.	11	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Et-1	Et-1	Et-1	ETA	ETA	ETA	13	14	17	18
We conclude that centrally administered ET-1 stimulates ETA receptors to produce systemic and regional circulatory changes mediated by the sympathetic nervous system .	We conclude that centrally administered ET-1 stimulates ETA receptors to produce systemic and regional circulatory changes mediated by the sympathetic nervous system.	4	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	5	6	7	8
This mode of non cell autonomous action of EDN1 matches that of its normal mode of action during mandibular arch patterning , when EDN1 from primarily the ectoderm drives EDNRA signaling .	This mode of non cell autonomous action of EDN1 matches that of its normal mode of action during mandibular arch patterning, when EDN1 from primarily the ectoderm drives EDNRA signaling.	23	30	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EDN1	EDN1	EDN1	EDNRA	EDNRA	EDNRA	23	24	29	30
ET-1 also induced AA release in CHO cells expressing ETAR truncated at the carboxyl terminal downstream of Cys385 ( CHO-ETARDelta385 ) or an unpalmitoylated ( Cys383 Cys385-388 --> Ser383Ser385-388 ) ETAR ( CHO-SerETAR ) , each of which is coupled with Gq or Gs/G12 , respectively .	ET-1 also induced AA release in CHO cells expressing ETAR truncated at the carboxyl terminal downstream of Cys385 (CHO-ETARDelta385) or an unpalmitoylated (Cys383 Cys385-388 --> Ser383Ser385-388) ETAR (CHO-SerETAR), each of which is coupled with Gq or Gs/G12, respectively.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETAR	ETAR	ETAR	0	1	9	10
In summary , our in vivo and in vitro data suggest that ET-1 mediated activation of ETA receptors in the renal pelvic wall contributes to the suppressed responsiveness of renal mechanosensory nerves in heart failure .	In summary, our in vivo and in vitro data suggest that ET-1 mediated activation of ETA receptors in the renal pelvic wall contributes to the suppressed responsiveness of renal mechanosensory nerves in heart failure.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	12	13	16	17
Using the cell-substrate impedance based assay , we observed that ET-1 induces opposing morphological changes in CHO ETA and CHO ETB cells with ETB causing an increase in the cell footprint and ETA a decrease .	Using the cell-substrate impedance based assay, we observed that ET-1 induces opposing morphological changes in CHO ETA and CHO ETB cells with ETB causing an increase in the cell footprint and ETA a decrease.	10	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	10	11	17	18
The enhanced endothelin-1 may activate the endothelin-A receptor , which would , in turn , result in reduced cerebral blood flow .	The enhanced endothelin-1 may activate the endothelin-A receptor, which would, in turn, result in reduced cerebral blood flow.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	endothelin-1	endothelin-1	endothelin-1	endothelin-A receptor	endothelin-A receptor	endothelin-A receptor	2	3	6	8
In vascular tissue , ET-1 activation of ETA in smooth muscle cells leads to blood vessel contraction and proliferative regulation , while the activation of ETB in endothelial cells leads to vessel dilation and production of anti-proliferative effectors .	In vascular tissue, ET-1 activation of ETA in smooth muscle cells leads to blood vessel contraction and proliferative regulation, while the activation of ETB in endothelial cells leads to vessel dilation and production of anti-proliferative effectors.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	4	5	7	8
Moreover , ETAR activation by ET-1 affects cell proliferation , survival , angiogenesis , and invasion .	Moreover, ETAR activation by ET-1 affects cell proliferation, survival, angiogenesis, and invasion.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETAR	ETAR	ETAR	5	6	2	3
Contraction was potentiated by the ETA receptor antagonist BQ 123 ( 10 microM ) and the mixed antagonist bosentan ( 10 microM ) , suggesting that ET-1 also activates ETA and ETB receptors that inhibit contraction .	Contraction was potentiated by the ETA receptor antagonist BQ 123 (10 microM) and the mixed antagonist bosentan (10 microM), suggesting that ET-1 also activates ETA and ETB receptors that inhibit contraction.	26	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	26	27	29	30
These results indicate that ET-1 activation of ETA receptors de-stabilizes vascular integrity through canonical mechanisms including cell contraction and disruption of adherens junctions between adjacent ECs .	These results indicate that ET-1 activation of ETA receptors de-stabilizes vascular integrity through canonical mechanisms including cell contraction and disruption of adherens junctions between adjacent ECs.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	4	5	7	8
These results support that a ROS dependent release of ET-1 , which activates the ET-A receptor is involved in the potentiation of the CB chemosensory responses to hypoxia elicited by CIH in neonatal rats .	These results support that a ROS dependent release of ET-1, which activates the ET-A receptor is involved in the potentiation of the CB chemosensory responses to hypoxia elicited by CIH in neonatal rats.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ET-A	ET-A	ET-A	9	10	14	15
Endothelin-1 ( EDN1 ) activates specific ETA receptors ( EDNRA ) on vascular smooth muscle cells to cause vasoconstriction and cell proliferation .	Endothelin-1 (EDN1) activates specific ETA receptors (EDNRA) on vascular smooth muscle cells to cause vasoconstriction and cell proliferation.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Endothelin-1	Endothelin-1	Endothelin-1	ETA	ETA	ETA	0	1	6	7
Rosano et al determined that endothelin-1 ( ET-1 ) activates endothelin-A receptor ( ETAR ) and promotes ovarian cancer cell invasion and metastasis due to its interaction with beta-arrestin scaffold proteins .	Rosano et al determined that endothelin-1 (ET-1) activates endothelin-A receptor (ETAR) and promotes ovarian cancer cell invasion and metastasis due to its interaction with beta-arrestin scaffold proteins.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	endothelin-A receptor	endothelin-A receptor	endothelin-A receptor	7	8	10	12
Activation of ETAR by ET-1 dose-dependently promoted cell migration and invasion of HCC cells , while silencing of ETAR by siRNA or blocking of ETAR by specific inhibitor resulted in significant reduction in ET-1-mediated migration and invasion .	Activation of ETAR by ET-1 dose-dependently promoted cell migration and invasion of HCC cells, while silencing of ETAR by siRNA or blocking of ETAR by specific inhibitor resulted in significant reduction in ET-1-mediated migration and invasion.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETAR	ETAR	ETAR	4	5	2	3
Initial studies demonstrated that ET-1 increases Na/H exchange in OKP cells transfected with ETB , but not ETA .	Initial studies demonstrated that ET-1 increases Na/H exchange in OKP cells transfected with ETB, but not ETA.	4	18	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	4	5	17	18
First , we show that in stably transfected CHO cells expressing ETA , binding of an ET-1 ligand induces rapid endocytosis of cell surface ETA .	First, we show that in stably transfected CHO cells expressing ETA, binding of an ET-1 ligand induces rapid endocytosis of cell surface ETA.	16	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	16	17	24	25
These results demonstrate that ET-1 induces dose- and ETA receptor dependent release of Ca2+ in in nociceptor like neurons , and permit further examination of the pathways that underlie ET-1-induced pain signaling .	These results demonstrate that ET-1 induces dose- and ETA receptor dependent release of Ca2+ in in nociceptor like neurons, and permit further examination of the pathways that underlie ET-1-induced pain signaling.	4	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	4	5	8	9
This is mediated by tumor secreted ET-1 , which activates the osteoblast endothelin A receptor ( ETAR ) and down-regulates osteoblast DKK1 XREF_BIBR .	This is mediated by tumor secreted ET-1, which activates the osteoblast endothelin A receptor (ETAR) and down-regulates osteoblast DKK1 XREF_BIBR.	5	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	endothelin A receptor	endothelin A receptor	endothelin A receptor	6	7	12	15
Therefore , we hypothesize that similar mechanisms may contribute to the ETA-R mediated reduction of the PGE 2 -mediated activation of renal sensory nerves in conditions of increased ET-1 mediated activation of renal pelvic ETA-R in physiological and pathophysiological conditions of sodium retention .	Therefore, we hypothesize that similar mechanisms may contribute to the ETA-R mediated reduction of the PGE 2 -mediated activation of renal sensory nerves in conditions of increased ET-1 mediated activation of renal pelvic ETA-R in physiological and pathophysiological conditions of sodium retention.	28	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA-R	ETA-R	ETA-R	28	29	34	35
ET-1 stimulates ETA -mediated NADPH oxidase dependent ROS generation , which inhibits endothelial NO bioavailability and contributes to ET-1-induced contraction in healthy penile arteries .	ET-1 stimulates ETA -mediated NADPH oxidase dependent ROS generation, which inhibits endothelial NO bioavailability and contributes to ET-1-induced contraction in healthy penile arteries.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	0	1	2	3
Taken together , our findings suggest that activation of ETAR by ET-1 promotes HCC cell migration and invasion via activating ERK1/2 and AKT signaling pathways and upregulating MMP-3 expression .	Taken together, our findings suggest that activation of ETAR by ET-1 promotes HCC cell migration and invasion via activating ERK1/2 and AKT signaling pathways and upregulating MMP-3 expression.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETAR	ETAR	ETAR	11	12	9	10
Endothelin-1 ( ET-1 ) autocrine and paracrine signaling modulate cell proliferation of tumor cells by activating its receptors , endothelin A receptor ( ET A R ) and endothelin B receptor ( ET B R ) .	Endothelin-1 (ET-1) autocrine and paracrine signaling modulate cell proliferation of tumor cells by activating its receptors, endothelin A receptor (ET A R) and endothelin B receptor (ET B R).	0	22	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Endothelin-1	Endothelin-1	Endothelin-1	endothelin A receptor	endothelin A receptor	endothelin A receptor	0	1	19	22
Pigmentation can be induced , however , by treatment with tetradecanoyl phorbol acetate , which mimics EDNRB signaling , but not by treatment with endothelin 1 , which stimulates the paralogous receptor EDNRA .	Pigmentation can be induced, however, by treatment with tetradecanoyl phorbol acetate, which mimics EDNRB signaling, but not by treatment with endothelin 1, which stimulates the paralogous receptor EDNRA.	22	33	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	endothelin 1	endothelin 1	endothelin 1	EDNRA	EDNRA	EDNRA	24	26	32	33
ET-1 activates ETA and ETB receptors , leading to an augmented ROS production in vasculature , which results in endothelial dysfunction [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	ET-1 activates ETA and ETB receptors, leading to an augmented ROS production in vasculature, which results in endothelial dysfunction [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	0	1	2	3
ET-1 from these cells could activate ETAR on adjacent osteoprogenitor cells .	ET-1 from these cells could activate ETAR on adjacent osteoprogenitor cells.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETAR	ETAR	ETAR	0	1	6	7
Taken together , these results indicate that ET-1 activates primarily ETA receptors at moderately low doses to produce renal vasoconstriction while higher doses also involve non ETA receptors .	Taken together, these results indicate that ET-1 activates primarily ETA receptors at moderately low doses to produce renal vasoconstriction while higher doses also involve non ETA receptors.	7	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	7	8	10	11
The response to MOR activation was significantly inhibited by Et-1 activation of HETAR in homomeric channels composed of either Kir3.2 or Kir3.4 .	The response to MOR activation was significantly inhibited by Et-1 activation of HETAR in homomeric channels composed of either Kir3.2 or Kir3.4.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Et-1	Et-1	Et-1	HETAR	HETAR	HETAR	9	10	12	13
Based on these results and data in the literature , a link between ET-1 stimulation of ETA receptors may be established by E4BP4 binding to the promoters and consequent inhibition of gene expression .	Based on these results and data in the literature, a link between ET-1 stimulation of ETA receptors may be established by E4BP4 binding to the promoters and consequent inhibition of gene expression.	13	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	13	14	16	17
ET-1 contributes to the regulation of vascular tone through two major receptors : endothelin-A ( ET-A ) and endothelin-B ( ET-B ) .	ET-1 contributes to the regulation of vascular tone through two major receptors : endothelin-A (ET-A) and endothelin-B (ET-B).	0	16	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ET-A	ET-A	ET-A	0	1	15	16
ET-1 and ET-RA are overexpressed in canine ovary tumors [ XREF_BIBR ] , which is consistent with the function of ET-RA signaling induced by ET-1 that is involved in cell proliferation .	ET-1 and ET-RA are overexpressed in canine ovary tumors [XREF_BIBR], which is consistent with the function of ET-RA signaling induced by ET-1 that is involved in cell proliferation.	20	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ET-RA	ET-RA	ET-RA	24	25	20	21
ET-1 is primarily produced by endothelial cells and manifests effects through 2 G-protein-coupled receptors ET-A and ET-B .	ET-1 is primarily produced by endothelial cells and manifests effects through 2 G-protein-coupled receptors ET-A and ET-B.	0	16	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ET-A	ET-A	ET-A	0	1	14	15
Data based on pharmacological and siRNA approaches indicate that ETA and ETB receptors contributed to the activation of MAPK14 by ET-1 through a mechanism involving Gi protein , but not PI3-kinase .	Data based on pharmacological and siRNA approaches indicate that ETA and ETB receptors contributed to the activation of MAPK14 by ET-1 through a mechanism involving Gi protein, but not PI3-kinase.	9	21	contributed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	20	21	9	10
Endothelin-1 activates receptors ETA , ETB1 and ETB2 [ XREF_BIBR ] .	Endothelin-1 activates receptors ETA, ETB1 and ETB2 [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Endothelin-1	Endothelin-1	Endothelin-1	ETA	ETA	ETA	0	1	3	4
In summary , we determined that ET-1 activation of ETAR signalled through ARF6 , which is crucial for lipolysis .	In summary, we determined that ET-1 activation of ETAR signalled through ARF6, which is crucial for lipolysis.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETAR	ETAR	ETAR	6	7	9	10
Increased ET-1 that activated ETA receptors accentuated expression on vascular smooth muscle cells will result in renal cortex ischemia .	Increased ET-1 that activated ETA receptors accentuated expression on vascular smooth muscle cells will result in renal cortex ischemia.	0	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	1	2	4	5
Likewise , in pulmonary artery smooth muscle cells , which express both ETA and ETB receptors , ET-1 induces an ETA dependent contraction and an ETB dependent dilation .	Likewise, in pulmonary artery smooth muscle cells, which express both ETA and ETB receptors, ET-1 induces an ETA dependent contraction and an ETB dependent dilation.	17	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	17	18	20	21
These findings suggest that ET-1 could induce contraction by stimulating either ETA or ETB receptors .	These findings suggest that ET-1 could induce contraction by stimulating either ETA or ETB receptors.	4	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	4	5	11	12
From targeted inactivation studies in mice and analysis of mutant and morphant zebrafish , EDN1 mediated EDNRA signaling is now known to establish the identity of NCCs in the mandibular portion of the first pharyngeal arch .	From targeted inactivation studies in mice and analysis of mutant and morphant zebrafish, EDN1 mediated EDNRA signaling is now known to establish the identity of NCCs in the mandibular portion of the first pharyngeal arch.	14	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	EDN1	EDN1	EDN1	EDNRA	EDNRA	EDNRA	14	15	16	17
Therefore , cold exposure increased ET-1 production , upregulated ETA receptors , and downregulated ETB receptors .	Therefore, cold exposure increased ET-1 production, upregulated ETA receptors, and downregulated ETB receptors.	5	10	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	5	6	9	10
The constriction was inhibited by BQ-123 , an ETA receptor antagonist , but the equipotency of ET-1 and ET-3 did not support the presence of the ETA receptor ( tentatively called ETR-m ) .	The constriction was inhibited by BQ-123, an ETA receptor antagonist, but the equipotency of ET-1 and ET-3 did not support the presence of the ETA receptor (tentatively called ETR-m).	14	27	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	16	17	26	27
Therefore , we assessed the effect of endothelin-A receptor antagonism in the response of pulmonary arteries from rats treated with lipopolysaccharide to endothelin-1 , and determined the vasomotor role of the endothelin-B receptors that are known to be located on rat pulmonary artery smooth muscle and endothelium .	Therefore, we assessed the effect of endothelin-A receptor antagonism in the response of pulmonary arteries from rats treated with lipopolysaccharide to endothelin-1, and determined the vasomotor role of the endothelin-B receptors that are known to be located on rat pulmonary artery smooth muscle and endothelium.	7	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	endothelin-1	endothelin-1	endothelin-1	endothelin-A receptor	endothelin-A receptor	endothelin-A receptor	22	23	7	9
XREF_BIBR , XREF_BIBR Importantly , ET-1 activation of the ETA receptor is known to increase collagen production in isolated human CFs .	XREF_BIBR, XREF_BIBR Importantly, ET-1 activation of the ETA receptor is known to increase collagen production in isolated human CFs.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	5	6	9	10
We have previously demonstrated that endothelin ( ET ) -1 and its subtype A receptor ( ET-AR ) expression are increased in lung under hypoxic conditions and that activation of ET-AR by ET-1 is a major mediator of hypoxia induced pulmonary hypertension in the rat .	We have previously demonstrated that endothelin (ET) -1 and its subtype A receptor (ET-AR) expression are increased in lung under hypoxic conditions and that activation of ET-AR by ET-1 is a major mediator of hypoxia induced pulmonary hypertension in the rat.	28	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ET-AR	ET-AR	ET-AR	32	33	30	31
In murine DRG neurons , ET-1 induced internalization of ETAR within ECE-1-containing endosomes .	In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes.	5	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETAR	ETAR	ETAR	5	6	9	10
S6c ( an ETB selective agonist ) and ET-1 caused marked ETA and/or ETB receptor mediated potentiation of EFS induced contraction in tracheal tissue from both groups .	S6c (an ETB selective agonist) and ET-1 caused marked ETA and/or ETB receptor mediated potentiation of EFS induced contraction in tracheal tissue from both groups.	0	14	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	8	9	11	12
Interestingly , a role for ET-1 induced activation of ETA receptors in the increased ERSNA in heart failure was suggested by the fall in ERSNA by chronic administration of the ETA receptor antagonist BQ123 in rabbits with heart failure , most likely by a mechanism ( s ) involving improvement of the carotid baroreceptor function .	Interestingly, a role for ET-1 induced activation of ETA receptors in the increased ERSNA in heart failure was suggested by the fall in ERSNA by chronic administration of the ETA receptor antagonist BQ123 in rabbits with heart failure, most likely by a mechanism (s) involving improvement of the carotid baroreceptor function.	3	10	induced	Positive_early_activation	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	5	6	9	10
By ligating the ETRA , ET-1 intracellular calcium concentrations increase and activates the protein kinase C pathway [ XREF_BIBR ] .	By ligating the ETRA, ET-1 intracellular calcium concentrations increase and activates the protein kinase C pathway [XREF_BIBR].	1	10	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETRA	ETRA	ETRA	5	6	3	4
Ednra ( found on all cranial NCCs ) is stimulated by Edn1 , a 21 amino acid peptide [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	Ednra (found on all cranial NCCs) is stimulated by Edn1, a 21 amino acid peptide [XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR].	0	17	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Edn1	Edn1	Edn1	Ednra	Ednra	Ednra	11	12	0	1
Both CHO ETA cells and hSMC show contraction when treated with ET-1 ( XREF_FIG ) .	Both CHO ETA cells and hSMC show contraction when treated with ET-1 (XREF_FIG).	2	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	11	12	2	3
We conclude that 1 ) ET-1 can stimulate ANP secretion by direct action on the atrial myocytes ; 2 ) primary cultures of adult rat atrial myocytes express only the ETA receptor subtype ; 3 ) the ANP secretory response to ET-1 desensitizes rapidly but recovers slowly ; and 4 ) occupation of the ETA receptors by ET-1 initiates the unidirectional sequence of receptor activation , signal transduction , ANP secretion , and finally , desensitization .	We conclude that 1) ET-1 can stimulate ANP secretion by direct action on the atrial myocytes; 2) primary cultures of adult rat atrial myocytes express only the ETA receptor subtype; 3) the ANP secretory response to ET-1 desensitizes rapidly but recovers slowly; and 4) occupation of the ETA receptors by ET-1 initiates the unidirectional sequence of receptor activation, signal transduction, ANP secretion, and finally, desensitization.	5	55	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	5	6	54	55
Taken together these studies suggest that ET-1 mediated activation of ETA receptors contributes to the impaired responsiveness of renal mechanosensory nerves in CHF .	Taken together these studies suggest that ET-1 mediated activation of ETA receptors contributes to the impaired responsiveness of renal mechanosensory nerves in CHF.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	6	7	10	11
These data suggested that ET-1 mediated activation of ETA receptors suppressed the responsiveness of the renal mechanosensory nerves in CHF by a mechanism involving the peripheral renal sensory nerve fibers .	These data suggested that ET-1 mediated activation of ETA receptors suppressed the responsiveness of the renal mechanosensory nerves in CHF by a mechanism involving the peripheral renal sensory nerve fibers.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	4	5	8	9
ET-1 activates the endothelin A receptor on primary afferent nocicetpors but also has vasoactive properties in the cancer microenvironment and contributes to angiogenesis [ XREF_BIBR ] .	ET-1 activates the endothelin A receptor on primary afferent nocicetpors but also has vasoactive properties in the cancer microenvironment and contributes to angiogenesis [XREF_BIBR].	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	endothelin A receptor	endothelin A receptor	endothelin A receptor	0	1	3	6
These results indicate that ET-1 increases lymphatic vasomotion by acting on smooth muscle ETA receptors and activation of G-protein-PLC-IP3 cascade , which is known to cause pacemaker Ca2+ release and resultant pacemaker potentials .	These results indicate that ET-1 increases lymphatic vasomotion by acting on smooth muscle ETA receptors and activation of G-protein-PLC-IP3 cascade, which is known to cause pacemaker Ca2+ release and resultant pacemaker potentials.	4	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	4	5	13	14
Therefore , we tested the idea that ET-1 mediated activation of ETA receptors modulates the PGE 2 -mediated release of substance P in an isolated renal pelvic wall preparation by comparing the substance P release from renal pelvic wall tissue incubated in the presence and absence of BQ123 .	Therefore, we tested the idea that ET-1 mediated activation of ETA receptors modulates the PGE 2 -mediated release of substance P in an isolated renal pelvic wall preparation by comparing the substance P release from renal pelvic wall tissue incubated in the presence and absence of BQ123.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	7	8	11	12
Endothelin-1 ( ET-1 ) mediates hypoxia mediated pulmonary vascular remodeling ( HPVR ) , and endothelin-A receptor ( ET-AR ) blockade prevents HPVR in newborn mice .	Endothelin-1 (ET-1) mediates hypoxia mediated pulmonary vascular remodeling (HPVR), and endothelin-A receptor (ET-AR) blockade prevents HPVR in newborn mice.	0	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Endothelin-1	Endothelin-1	Endothelin-1	endothelin-A receptor	endothelin-A receptor	endothelin-A receptor	0	1	15	17
Thus , investigating the pathway downstream to ET-1 protein , i.e ., ET-1 action mediating receptors , ETAR and ETBR , were essential in this study to detect a deleterious response to hyperinsulinemia that might explain impaired FID in LHCs .	Thus, investigating the pathway downstream to ET-1 protein, i.e., ET-1 action mediating receptors, ETAR and ETBR, were essential in this study to detect a deleterious response to hyperinsulinemia that might explain impaired FID in LHCs.	12	18	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETAR	ETAR	ETAR	12	13	17	18
Next , we used a pharmacological approach to show that ETA receptors are activated by ET-1 during oligodendrocyte myelination .	Next, we used a pharmacological approach to show that ETA receptors are activated by ET-1 during oligodendrocyte myelination.	10	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	15	16	10	11
Although modulation of ETAR by ET-1 was not strong , ETAR expression was significantly correlated with ETBR protein expression .	Although modulation of ETAR by ET-1 was not strong, ETAR expression was significantly correlated with ETBR protein expression.	1	6	modulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETAR	ETAR	ETAR	5	6	3	4
These results suggest that ET-1 enhances nervous acetylcholine release by simultaneously activating the ET-1-selective ETA receptor and the isopeptide-nonselective ETB receptor ( ETB1 subtype that is sensitive to both RES-701-1 and BQ-788 and the ETB2 subtype that is sensitive only to BQ-788 ) .	These results suggest that ET-1 enhances nervous acetylcholine release by simultaneously activating the ET-1-selective ETA receptor and the isopeptide-nonselective ETB receptor (ETB1 subtype that is sensitive to both RES-701-1 and BQ-788 and the ETB2 subtype that is sensitive only to BQ-788).	4	15	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	4	5	14	15
Normal tone results from the balance between ET-1 stimulation of ET-A and ET-B receptors [ XREF_BIBR ] .	Normal tone results from the balance between ET-1 stimulation of ET-A and ET-B receptors [XREF_BIBR].	7	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ET-A	ET-A	ET-A	7	8	10	11
Using a modified inositol phosphate accumulation assay , we found that stimulation of ETA by endothelin-1 results in sustained activation of the subtype , retaining > 30 % of its initial activity even 20 min after agonist administration , whereas the ETB rapidly deactivated after agonist stimulation , losing > 80 % of its initial activity within 5 min after endothelin application .	Using a modified inositol phosphate accumulation assay, we found that stimulation of ETA by endothelin-1 results in sustained activation of the subtype, retaining> 30% of its initial activity even 20 min after agonist administration, whereas the ETB rapidly deactivated after agonist stimulation, losing> 80% of its initial activity within 5 min after endothelin application.	11	16	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	endothelin-1	endothelin-1	endothelin-1	ETA	ETA	ETA	15	16	13	14
Edn1 secreted from surrounding tissues in the pharyngeal arch environment activates Ednra in cranial NCCs .	Edn1 secreted from surrounding tissues in the pharyngeal arch environment activates Ednra in cranial NCCs.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Edn1	Edn1	Edn1	Ednra	Ednra	Ednra	0	1	11	12
In diabetes , ET-1 levels are elevated and upregulation of ETA and ETB occurs in the vasculature , along with a reduction in NO bioavailability .	In diabetes, ET-1 levels are elevated and upregulation of ETA and ETB occurs in the vasculature, along with a reduction in NO bioavailability.	3	12	are elevated and upregulation	Positive_activation_copula_1	Positive_activation	Positive_activation	ET-1	ET-1 levels	et-1	ETA	ETA	eta	3	4	10	11
It is concluded that endothelin-1 at low concentrations activates prejunctional endothelin ETA receptors and inhibits adrenergic nerve mediated contractions by an inhibition of amine release , whereas the peptide at high concentrations potentiates the neurally induced contractions by a postjunctional enhancement , via endothelin ETA receptors , of the action of norepinephrine .	It is concluded that endothelin-1 at low concentrations activates prejunctional endothelin ETA receptors and inhibits adrenergic nerve mediated contractions by an inhibition of amine release, whereas the peptide at high concentrations potentiates the neurally induced contractions by a postjunctional enhancement, via endothelin ETA receptors, of the action of norepinephrine.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	endothelin-1	endothelin-1	endothelin-1	ETA	ETA	ETA	4	5	11	12
In this study , ET-1 induced a contracted short-term morphological change in CHO ETA and a more expanded short-term morphological change in CHO ETB .	In this study, ET-1 induced a contracted short-term morphological change in CHO ETA and a more expanded short-term morphological change in CHO ETB.	4	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETA	ETA	ETA	4	5	13	14
When down-regulation of ETB was required , astrocytes were treated with ET-1 ( 100 nM ) and cycloheximide ( 20 mug/mL ) by adding these reagents into their normal culture media .	When down-regulation of ETB was required, astrocytes were treated with ET-1 (100 nM) and cycloheximide (20 mug/mL) by adding these reagents into their normal culture media.	1	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETB	ETB	ETB	11	12	3	4
These differences may be explained by our recent report , where we describe that ET-1 activates endothelial ET-B receptors and increases NO concentrations , which in turn decreases Na , K-ATPase activity in AEC , reducing AFC .	These differences may be explained by our recent report, where we describe that ET-1 activates endothelial ET-B receptors and increases NO concentrations, which in turn decreases Na, K-ATPase activity in AEC, reducing AFC.	14	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ET-B	ET-B	ET-B	14	15	17	18
In contrast , intramedullary administration of ET-1 causes a natriuresis in ETB deficient rats that is prevented by ETA blockade .	In contrast, intramedullary administration of ET-1 causes a natriuresis in ETB deficient rats that is prevented by ETA blockade.	4	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETB	ETB	ETB	6	7	11	12
Previous data show that activation of ETB by ET-1 leads to hypernociception induced by mechanical stimulation via activation of the PKC pathway XREF_BIBR .	Previous data show that activation of ETB by ET-1 leads to hypernociception induced by mechanical stimulation via activation of the PKC pathway XREF_BIBR.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETB	ETB	ETB	8	9	6	7
Therefore , in response to a high salt diet , renal medullary production of endothelin-1 is enhanced , thus activating mainly ET-B receptors located on the medullary thick ascending loop of Henle and collecting ducts .	Therefore, in response to a high salt diet, renal medullary production of endothelin-1 is enhanced, thus activating mainly ET-B receptors located on the medullary thick ascending loop of Henle and collecting ducts.	12	22	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	endothelin-1	endothelin-1	endothelin-1	ET-B	ET-B	ET-B	14	15	21	22
XREF_BIBR Dissociated ET-B receptors in oral carcinoma cells might be more readily activated by ET-1 , which is produced in abundance by carcinoma cells , leading to opioid secretion in the cancer microenvironment .	XREF_BIBR Dissociated ET-B receptors in oral carcinoma cells might be more readily activated by ET-1, which is produced in abundance by carcinoma cells, leading to opioid secretion in the cancer microenvironment.	2	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ET-B	ET-B	ET-B	14	15	2	3
In the present study in HeLa cells , we have found that ET-1 induced signalling activates the NF-kappaB transcription complex ( TC ) in the nucleus at 6 h specifically via ET-A - but not ET-B receptor .	In the present study in HeLa cells, we have found that ET-1 induced signalling activates the NF-kappaB transcription complex (TC) in the nucleus at 6 h specifically via ET-A - but not ET-B receptor.	12	36	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ET-B	ET-B	ET-B	12	13	35	36
Given the evidence , ET-1 activation of ETB likely leads to intracellular pathways , which directly and not through secreted effectors , cause both the dilatory and growth inhibitory effects of CHO ETB cells .	Given the evidence, ET-1 activation of ETB likely leads to intracellular pathways, which directly and not through secreted effectors, cause both the dilatory and growth inhibitory effects of CHO ETB cells.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETB	ETB	ETB	4	5	7	8
Contractions induced by endothelin-1 , endothelin-3 and the selective ETB agonist , sarafotoxin S6c , were studied in segments of human temporal artery .	Contractions induced by endothelin-1, endothelin-3 and the selective ETB agonist, sarafotoxin S6c, were studied in segments of human temporal artery.	1	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	endothelin-1	endothelin-1	endothelin-1	ETB	ETB	ETB	3	4	9	10
Thus , CD derived ET-1 autocrine activation of ETB exerts a natriuretic and diuretic effect .	Thus, CD derived ET-1 autocrine activation of ETB exerts a natriuretic and diuretic effect.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETB	ETB	ETB	4	5	8	9
However , it has to be noted that EDN1 not only activates EDNRB but is also a strong activator of EDNRA .	However, it has to be noted that EDN1 not only activates EDNRB but is also a strong activator of EDNRA.	8	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EDN1	EDN1	EDN1	EDNRB	EDNRB	EDNRB	8	9	12	13
CD derived ET-1 activates ETB , which , through a variety of signaling mechanisms , decreases both ENaC open probability and number .	CD derived ET-1 activates ETB, which, through a variety of signaling mechanisms, decreases both ENaC open probability and number.	1	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETB	ETB	ETB	2	3	4	5
TAL derived ET-1 activates autocrine ETB leading to increased NO production and inhibition of Cl - transport .	TAL derived ET-1 activates autocrine ETB leading to increased NO production and inhibition of Cl - transport.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETB	ETB	ETB	2	3	5	6
Results in AA : ET-1 induced similar constrictions in ETB (-/-) and ETB ( +/+ ) mice .	Results in AA : ET-1 induced similar constrictions in ETB (-/-) and ETB (+/+) mice.	0	16	induced	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ET-1	ET-1	ET-1	ETB	ETB	ETB	4	5	12	13
In addition , EphA4 activation by the ephrin-A3 ligand in hippocampal slices promotes dendritic spine retraction and pruning XREF_BIBR , XREF_BIBR .	In addition, EphA4 activation by the ephrin-A3 ligand in hippocampal slices promotes dendritic spine retraction and pruning XREF_BIBR, XREF_BIBR.	3	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	7	8	3	4
Thus , EphA4 activation by ephrin-A3 inhibits beta1-integrin activity and adhesion to fibronectin in neurons .	Thus, EphA4 activation by ephrin-A3 inhibits beta1-integrin activity and adhesion to fibronectin in neurons.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	5	6	2	3
EphA4 activation by ephrin-A3 inhibits integrin adhesion pathways and therefore destabilizes dendritic spines .	EphA4 activation by ephrin-A3 inhibits integrin adhesion pathways and therefore destabilizes dendritic spines.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	3	4	0	1
EphA4 activation by ephrin-A3 induces spine retraction , and inhibition of the interaction between ephrin and EphA4 alters spine shape and organisation in hippocampal slices XREF_BIBR and in activity dependent synaptic wiring in the mouse cerebellar cortex XREF_BIBR .	EphA4 activation by ephrin-A3 induces spine retraction, and inhibition of the interaction between ephrin and EphA4 alters spine shape and organisation in hippocampal slices XREF_BIBR and in activity dependent synaptic wiring in the mouse cerebellar cortex XREF_BIBR.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	3	4	0	1
In human T cells , for example , EphA4 activation by ephrin-A1 and ephrin-A3 has been shown to inhibit beta1 and beta2 integrin adhesion to fibronectin- and ICAM1 coated surfaces .	In human T cells, for example, EphA4 activation by ephrin-A1 and ephrin-A3 has been shown to inhibit beta1 and beta2 integrin adhesion to fibronectin- and ICAM1 coated surfaces.	8	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	13	14	8	9
In contrast , EphA4 receptor tyrosine kinase was demonstrated to have opposing effects on dendritic spine morphology within cultured hippocampal neurons by inhibiting integrin beta1 signaling , which suggests that EphA4 activation by ephrin-A3 promotes spine shortening at least partially by inhibiting integrin beta1 induced spine elongation .	In contrast, EphA4 receptor tyrosine kinase was demonstrated to have opposing effects on dendritic spine morphology within cultured hippocampal neurons by inhibiting integrin beta1 signaling, which suggests that EphA4 activation by ephrin-A3 promotes spine shortening at least partially by inhibiting integrin beta1 induced spine elongation.	30	34	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	33	34	30	31
Activation of EphA4 by ephrin-A3 was found to induce spine retraction , whereas inhibiting ephrin and EphA4 interactions distorted spine shape and organization in hippocampal slices .	Activation of EphA4 by ephrin-A3 was found to induce spine retraction, whereas inhibiting ephrin and EphA4 interactions distorted spine shape and organization in hippocampal slices.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	4	5	2	3
Astrocytic ephrin-A3 is likely to mediate the effect of EphA4 signaling on hippocampal dendritic spine shape , although it is unclear whether such an interaction has an effect on synapse formation per se .	Astrocytic ephrin-A3 is likely to mediate the effect of EphA4 signaling on hippocampal dendritic spine shape, although it is unclear whether such an interaction has an effect on synapse formation per se.	0	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	1	2	9	10
In addition , activation of EphA4 by ephrinA3 has been shown to induce spine retraction .	In addition, activation of EphA4 by ephrinA3 has been shown to induce spine retraction.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ephrinA3	ephrinA3	ephrinA3	EphA4	EphA4	EphA4	7	8	5	6
In this study , we show that EphA4 activation by ephrin-A3 in hippocampal slices inhibits integrin downstream signaling pathways .	In this study, we show that EphA4 activation by ephrin-A3 in hippocampal slices inhibits integrin downstream signaling pathways.	7	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	10	11	7	8
Here we report that ephrin-A3 activates EphA4 to suppress Wnt3a and beta-catenin signaling , and that addition of Wnt3a alone is sufficient to promote cell proliferation .	Here we report that ephrin-A3 activates EphA4 to suppress Wnt3a and beta-catenin signaling, and that addition of Wnt3a alone is sufficient to promote cell proliferation.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	4	5	6	7
Interestingly in a semi-in vivo setting , activation of EphA4 by ephrin-A3 in hippocampal slices also inhibits integrin downstream signaling , including FAK , Pyk2 and Crk dephosphorylation .	Interestingly in a semi-in vivo setting, activation of EphA4 by ephrin-A3 in hippocampal slices also inhibits integrin downstream signaling, including FAK, Pyk2 and Crk dephosphorylation.	7	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	11	12	9	10
Activation of EphA4 by ephrin-A3 may disrupt critical integrin mediated attachment to the extracellular matrix and cell surface integrin ligands , thus inhibiting integrin signaling to Cas and other downstream signaling proteins .	Activation of EphA4 by ephrin-A3 may disrupt critical integrin mediated attachment to the extracellular matrix and cell surface integrin ligands, thus inhibiting integrin signaling to Cas and other downstream signaling proteins.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA4	EphA4	EphA4	4	5	2	3
In cells transfected with the control oligos , ephrin-A1 activated EphA4 normally , whereas the tyrosine phosphorylation of EphA4 was greatly decreased when the expression of ARMS and alpha-syntrophin was reduced by siRNA transfection ( XREF_FIG ) .	In cells transfected with the control oligos, ephrin-A1 activated EphA4 normally, whereas the tyrosine phosphorylation of EphA4 was greatly decreased when the expression of ARMS and alpha-syntrophin was reduced by siRNA transfection (XREF_FIG).	8	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA4	EphA4	EphA4	8	9	10	11
Consistent with this hypothesis , treating neurons with ephrin-A1 , which activates the receptor EphA4 and induces spine retraction via Cdk5 and RhoA activation XREF_BIBR , also increased CaMKv phosphorylation at Thr345 ( XREF_SUPPLEMENTARY ) .	Consistent with this hypothesis, treating neurons with ephrin-A1, which activates the receptor EphA4 and induces spine retraction via Cdk5 and RhoA activation XREF_BIBR, also increased CaMKv phosphorylation at Thr345 (XREF_SUPPLEMENTARY).	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA4	EphA4	EphA4	8	9	14	15
In conclusion , the present study provides evidence that the activation of EphA4 induced by EphrinA1 contributes to BBB damage following ischemic stroke through the Rho and ROCK signaling pathway , which highlights a potential therapeutic strategy for ischemic stroke and may help the development of preventative interventions for VD .	In conclusion, the present study provides evidence that the activation of EphA4 induced by EphrinA1 contributes to BBB damage following ischemic stroke through the Rho and ROCK signaling pathway, which highlights a potential therapeutic strategy for ischemic stroke and may help the development of preventative interventions for VD.	10	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EphrinA1	EphrinA1	EphrinA1	EphA4	EphA4	EphA4	15	16	12	13
Two recent reports have shown that activation of EphA4 by ephrin-A1 or activation of EphB2 by ephrin-B1 caused the reduction of Rap1-GTP in neurons or colon cancer cells , respectively .	Two recent reports have shown that activation of EphA4 by ephrin-A1 or activation of EphB2 by ephrin-B1 caused the reduction of Rap1-GTP in neurons or colon cancer cells, respectively.	6	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA4	EphA4	EphA4	10	11	8	9
The activation of cyclin dependent kinase 5 ( Cdk5 ) and ephexin1 by ephrin-A1 promotes EphA4 dependent spine retraction , followed by a scaling-down of excitatory synaptic strength .	The activation of cyclin dependent kinase 5 (Cdk5) and ephexin1 by ephrin-A1 promotes EphA4 dependent spine retraction, followed by a scaling-down of excitatory synaptic strength.	11	20	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA4	EphA4	EphA4	13	14	15	16
When EphA4 is stimulated by ephrinA1 , it activates Cdk5 , which regulates Src phosphorylation of ephexin , which collapses spines and dendrites via activation of RhoA XREF_BIBR .	When EphA4 is stimulated by ephrinA1, it activates Cdk5, which regulates Src phosphorylation of ephexin, which collapses spines and dendrites via activation of RhoA XREF_BIBR.	1	6	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA4	EphA4	EphA4	5	6	1	2
Chronic neuronal activity or application of ephrin-A1 stimulates the EphA4 receptor , which recruits Cdh1-APC to target the AMPA receptor ( AMPAR ) subunit GluA1 for turnover and thus reduces synaptic strength .	Chronic neuronal activity or application of ephrin-A1 stimulates the EphA4 receptor, which recruits Cdh1-APC to target the AMPA receptor (AMPAR) subunit GluA1 for turnover and thus reduces synaptic strength.	4	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA4	EphA4	EphA4	6	7	9	10
Vascular smooth muscle cells also express EphA4 receptors , which can be activated by EphrinA1 and by many EphrinB ligands .	Vascular smooth muscle cells also express EphA4 receptors, which can be activated by EphrinA1 and by many EphrinB ligands.	6	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EphrinA1	EphrinA1	EphrinA1	EphA4	EphA4	EphA4	14	15	6	7
These findings suggest that ephrin-A1 promotes EphA4 dependent spine retraction through the activation of Cdk5 and ephexin1 , which in turn modulates actin cytoskeletal dynamics .	These findings suggest that ephrin-A1 promotes EphA4 dependent spine retraction through the activation of Cdk5 and ephexin1, which in turn modulates actin cytoskeletal dynamics.	4	7	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA4	EphA4	EphA4	4	5	6	7
In the case of ephrinA1 induced EphA4 growth cone collapse , phosphorylation of the GEF ephexin leads to increased specificity for RhoA compared with Rac1 and Cdc42 .	In the case of ephrinA1 induced EphA4 growth cone collapse, phosphorylation of the GEF ephexin leads to increased specificity for RhoA compared with Rac1 and Cdc42.	2	9	induced	Positive_early_activation	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA4	EphA4	EphA4	4	5	6	7
Multivalent ephrin-A5 triggers the assembly of large EphA3 receptor signaling clusters .	Multivalent ephrin-A5 triggers the assembly of large EphA3 receptor signaling clusters.	0	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A5	ephrin-A5	ephrin-A5	EphA3	EphA3	EphA3	1	2	7	8
In agreement with confocal microscopic analysis ( XREF_FIG ) , these experiments suggest that both EphA3 dephosphorylation by elevated w/t PTP1B , as well as binding of the PTP1B-[ D-A ]-trapping mutant likely blocking access to EphA3-phospho-tyrosines , markedly attenuate ephrinA5 induced EphA3 trafficking .	In agreement with confocal microscopic analysis (XREF_FIG), these experiments suggest that both EphA3 dephosphorylation by elevated w/t PTP1B, as well as binding of the PTP1B-[D-A]-trapping mutant likely blocking access to EphA3-phospho-tyrosines, markedly attenuate ephrinA5 induced EphA3 trafficking.	39	43	induced	Positive_early_activation	Positive_activation	Positive_activation	ephrinA5	ephrinA5	ephrinA5	EphA3	EphA3	EphA3	40	41	42	43
On the other hand , EphA3 activation by ephrin-A5 stimulation resulted in a reduced integrin mediated cell adhesion .	On the other hand, EphA3 activation by ephrin-A5 stimulation resulted in a reduced integrin mediated cell adhesion.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A5	ephrin-A5	ephrin-A5	EphA3	EphA3	EphA3	8	9	5	6
Ephrin-A5 stimulation of EphA3 resulted in a significant decrease in k T / acceptor values ( XREF_FIG ) , indicating an increased GFP-RFP distance .	Ephrin-A5 stimulation of EphA3 resulted in a significant decrease in k T / acceptor values (XREF_FIG), indicating an increased GFP-RFP distance.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Ephrin-A5	Ephrin-A5	Ephrin-A5	EphA3	EphA3	EphA3	0	1	3	4
Furthermore , unclustered IIIA4 and ephrin-A5 Fc applied in combination initiate greatly enhanced EphA3 signaling .	Furthermore, unclustered IIIA4 and ephrin-A5 Fc applied in combination initiate greatly enhanced EphA3 signaling.	5	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A5	ephrin-A5	ephrin-A5	EphA3	EphA3	EphA3	5	6	13	14
Ephrin-A5 induces growth cone collapse in EphA3 transfected lateral hippocampal neurons .	Ephrin-A5 induces growth cone collapse in EphA3 transfected lateral hippocampal neurons.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ephrin-A5	Ephrin-A5	Ephrin-A5	EphA3	EphA3	EphA3	0	1	6	7
An example of ephrin modulation of cell morphology and attachment is seen in melanoma and human embryonic kidney cells , wherein the activation of EphA3 by EphrinA5 activates Rho , causing acto-myosin rearrangement , cell rounding , blebbing , and detachment [ XREF_BIBR ] .	An example of ephrin modulation of cell morphology and attachment is seen in melanoma and human embryonic kidney cells, wherein the activation of EphA3 by EphrinA5 activates Rho, causing acto-myosin rearrangement, cell rounding, blebbing, and detachment [XREF_BIBR].	22	27	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EphrinA5	EphrinA5	EphrinA5	EphA3	EphA3	EphA3	26	27	24	25
Here , we have found that ephrinA5 stimulates EphA3 kinase and ADAM10 activity to promote PSA-NCAM cleavage at a site in its second FNIII repeat , which regulates ephrinA5 induced growth cone collapse in GABAergic and non GABAergic neurons .	Here, we have found that ephrinA5 stimulates EphA3 kinase and ADAM10 activity to promote PSA-NCAM cleavage at a site in its second FNIII repeat, which regulates ephrinA5 induced growth cone collapse in GABAergic and non GABAergic neurons.	6	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrinA5	ephrinA5	ephrinA5	EphA3	EphA3	EphA3	6	7	8	9
Ephrin-A5 induced co-clustering of surface bound NCAM and EphA3 in GABAergic cortical interneurons in culture .	Ephrin-A5 induced co-clustering of surface bound NCAM and EphA3 in GABAergic cortical interneurons in culture.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ephrin-A5	Ephrin-A5	Ephrin-A5	EphA3	EphA3	EphA3	0	1	8	9
S1 D ) , which indicates a consistent reduction in levels of ephrinA5 activated EphA3 receptors ( XREF_FIG ) .	S1 D), which indicates a consistent reduction in levels of ephrinA5 activated EphA3 receptors (XREF_FIG).	10	15	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ephrinA5	levels of ephrinA5	ephrina5	EphA3	EphA3	epha3	12	13	14	15
NG108-15 neurites disappeared when wild type EphA3 transfected cells were treated with ephrin-A5 , whereas cells transfected with the non functional EphA3 mutants ( K653R , Y596F ) retained these neurites ( XREF_FIG ) .	NG108-15 neurites disappeared when wild type EphA3 transfected cells were treated with ephrin-A5, whereas cells transfected with the non functional EphA3 mutants (K653R, Y596F) retained these neurites (XREF_FIG).	4	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ephrin-A5	ephrin-A5	ephrin-A5	EphA3	EphA3	EphA3	12	13	6	7
35 Ephrin-A1 ligand induces carcinoma cell retraction through EPHA2 , a paralog of EPHA1 , and downstream SRC and FAK , a paralog of PTK2B .	35 Ephrin-A1 ligand induces carcinoma cell retraction through EPHA2, a paralog of EPHA1, and downstream SRC and FAK, a paralog of PTK2B.	1	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ephrin-A1	Ephrin-A1	Ephrin-A1	EPHA1	EPHA1	EPHA1	1	2	13	14
RET and EDNRB are activated by members of the GDNF family of ligands and endothelin-3 , respectively , which are produced by the intestinal mesenchyme , highlighting the key role of the cellular microenvironment on the development of ENS lineages .	RET and EDNRB are activated by members of the GDNF family of ligands and endothelin-3, respectively, which are produced by the intestinal mesenchyme, highlighting the key role of the cellular microenvironment on the development of ENS lineages.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	endothelin-3	endothelin-3	endothelin-3	EDNRB	EDNRB	EDNRB	14	15	2	3
Ednrb is activated by the Endothelin 3 ( Edn3 ) ligand XREF_BIBR .	Ednrb is activated by the Endothelin 3 (Edn3) ligand XREF_BIBR.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Endothelin 3	Endothelin 3	Endothelin 3	Ednrb	Ednrb	Ednrb	5	7	0	1
These results suggest that epilation induces EDN3 , which then stimulates its receptor EDNRB to regulate McSCs and melanocytes .	These results suggest that epilation induces EDN3, which then stimulates its receptor EDNRB to regulate McSCs and melanocytes.	5	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EDN3	EDN3	EDN3	EDNRB	EDNRB	EDNRB	6	7	13	14
EDNRB belongs to a super-family of G protein coupled receptors and is activated by the EDN3 ligand .	EDNRB belongs to a super-family of G protein coupled receptors and is activated by the EDN3 ligand.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EDN3	EDN3	EDN3	EDNRB	EDNRB	EDNRB	15	16	0	1
One important note is that the activation of EDNRB by EDN3 also leads to loss of expression of the cell adhesion molecule E-cadherin and associated catenin proteins , while increasing Snail and N-cadherin expression .	One important note is that the activation of EDNRB by EDN3 also leads to loss of expression of the cell adhesion molecule E-cadherin and associated catenin proteins, while increasing Snail and N-cadherin expression.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EDN3	EDN3	EDN3	EDNRB	EDNRB	EDNRB	10	11	8	9
Ephrin-A5 activates EphA2 , leading to the increased recruitment of beta-catenin to N-cadherin .	Ephrin-A5 activates EphA2, leading to the increased recruitment of beta-catenin to N-cadherin.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ephrin-A5	Ephrin-A5	Ephrin-A5	EphA2	EphA2	EphA2	0	1	2	3
Using these ' nanocalipers ' to present ephrin ligands , we showed that the nanoscale spacing of ephrin-A5 directs the levels of EphA2 receptor activation in human breast cancer cells .	Using these ' nanocalipers ' to present ephrin ligands, we showed that the nanoscale spacing of ephrin-A5 directs the levels of EphA2 receptor activation in human breast cancer cells.	15	24	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A5	ephrin-A5	ephrin-A5	EphA2	EphA2	EphA2	17	18	22	23
We have shown here that activation of EPHA2 by ephrin-A5 in both alphaTN4-1 and HEK293 cells resulted in Akt activation , which correlates with inhibition of cell migration .	We have shown here that activation of EPHA2 by ephrin-A5 in both alphaTN4-1 and HEK293 cells resulted in Akt activation, which correlates with inhibition of cell migration.	5	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ephrin-A5	ephrin-A5	ephrin-A5	EPHA2	EPHA2	EPHA2	9	10	7	8
In this study , suppression of fibulin-4 or fibulin-5 , but not fibulin-2 , reduced tropoelastin deposition in an in vitro culture system .	In this study, suppression of fibulin-4 or fibulin-5, but not fibulin-2, reduced tropoelastin deposition in an in vitro culture system.	4	16	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-4	fibulin-4	fibulin-4	tropoelastin	tropoelastin	tropoelastin	6	7	15	16
Instead , Fibulin-4 R/R aortas show increased ECM remodeling , and increased collagen and elastin structures .	Instead, Fibulin-4 R/R aortas show increased ECM remodeling, and increased collagen and elastin structures.	2	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fibulin-4	Fibulin-4	Fibulin-4	elastin	elastin	elastin	2	3	14	15
Due to the lack of such a complex , despite formation of a normal microfibril network , fibulin-4 suppression may inhibit the deposition of tropoelastin .	Due to the lack of such a complex, despite formation of a normal microfibril network, fibulin-4 suppression may inhibit the deposition of tropoelastin.	17	25	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-4	fibulin-4	fibulin-4	tropoelastin	tropoelastin	tropoelastin	17	18	24	25
On the other hand , fibulin-4 suppression reduced the level of tropoelastin deposition to 10 % of the control ( scrambled siRNA transfected cells ) .	On the other hand, fibulin-4 suppression reduced the level of tropoelastin deposition to 10% of the control (scrambled siRNA transfected cells).	5	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-4	fibulin-4	fibulin-4	tropoelastin	tropoelastin	tropoelastin	5	6	11	12
The results showed the same tendency , i.e. that suppression of each of fibulin-4 or -5 inhibited tropoelastin deposition , whereas suppression of fibulin-2 did not .	The results showed the same tendency, i.e. that suppression of each of fibulin-4 or -5 inhibited tropoelastin deposition, whereas suppression of fibulin-2 did not.	11	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-4	fibulin-4	fibulin-4	tropoelastin	tropoelastin	tropoelastin	13	14	17	18
Mirk enhanced HNF1alpha transcriptional activity in a dose dependent manner , whereas two kinase-inactive Mirk mutants and a Mirk N-terminal deletion mutant did not .	Mirk enhanced HNF1alpha transcriptional activity in a dose dependent manner, whereas two kinase-inactive Mirk mutants and a Mirk N-terminal deletion mutant did not.	0	4	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mirk	Mirk	Mirk	HNF1alpha	HNF1alpha	HNF1alpha	0	1	2	3
MKK3 enhanced Mirk kinase activity and the transcriptional activation of HNF1alpha by Mirk , suggesting that Mirk , like p38 , is activated by certain environmental stress agents .	MKK3 enhanced Mirk kinase activity and the transcriptional activation of HNF1alpha by Mirk, suggesting that Mirk, like p38, is activated by certain environmental stress agents.	1	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Mirk	Mirk	Mirk	HNF1alpha	HNF1alpha	HNF1alpha	12	13	10	11
p38alphaMAPK blocked Mirk activation of HNF1alpha in a dose dependent manner , with high levels of kinase-inactive p38alphaAF completely suppressing the activity of Mirk .	p38alphaMAPK blocked Mirk activation of HNF1alpha in a dose dependent manner, with high levels of kinase-inactive p38alphaAF completely suppressing the activity of Mirk.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mirk	Mirk	Mirk	HNF1alpha	HNF1alpha	HNF1alpha	2	3	5	6
This strongly suggests that Eda is not a major determinant of NFkappaB activation in SMG branching morphogenesis , and presages the existence of an additional Eda initiated transcriptional control of the 4 genes : Edar , Fgf8 , Shh , Egf .	This strongly suggests that Eda is not a major determinant of NFkappaB activation in SMG branching morphogenesis, and presages the existence of an additional Eda initiated transcriptional control of the 4 genes : Edar, Fgf8, Shh, Egf.	21	40	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Eda	Eda	Eda	Edar	Edar	Edar	25	26	34	35
EDA activates EDAR on the surface of follicular cells in mesenchyme , which in turn binds to EDARADD and TRAF6 to induce downstream signaling .	EDA activates EDAR on the surface of follicular cells in mesenchyme, which in turn binds to EDARADD and TRAF6 to induce downstream signaling.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EDA	EDA	EDA	EDAR	EDAR	EDAR	0	1	2	3
At the same time , ephrinA5 mediated EphA4 forward signaling triggers axonal growth cone collapse via the downstream RacGAP alpha2-chimaerin-dependent signaling pathway ( Wegmeyer et al ., 2007 ) .	At the same time, ephrinA5 mediated EphA4 forward signaling triggers axonal growth cone collapse via the downstream RacGAP alpha2-chimaerin-dependent signaling pathway (Wegmeyer et al., 2007).	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	ephrinA5	ephrinA5	ephrinA5	EphA4	EphA4	EphA4	5	6	7	8
Thus , ephrin-A5 induced EphA4 activation by paracrine interactions of neighboring progenitors or feedback signaling from the cortical plate seems rather unlikely .	Thus, ephrin-A5 induced EphA4 activation by paracrine interactions of neighboring progenitors or feedback signaling from the cortical plate seems rather unlikely.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	ephrin-A5	ephrin-A5	ephrin-A5	EphA4	EphA4	EphA4	2	3	4	5
A recent study shows that while EphA2 ephrin-A5 and EphA4 ephrin-A5 have similar binding affinities , ephrin-A5 induces smaller EphA4 clusters than EphA2 and with different , circular versus array organizations , respectively [ XREF_BIBR ] .	A recent study shows that while EphA2 ephrin-A5 and EphA4 ephrin-A5 have similar binding affinities, ephrin-A5 induces smaller EphA4 clusters than EphA2 and with different, circular versus array organizations, respectively [XREF_BIBR].	16	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A5	ephrin-A5	ephrin-A5	EphA4	EphA4	EphA4	16	17	19	20
In a separate study , EphA4 stimulation by ephrin-A5 resulted in inhibition of PC3 cell migration by impairment of cell-cell contact [ XREF_BIBR ] .	In a separate study, EphA4 stimulation by ephrin-A5 resulted in inhibition of PC3 cell migration by impairment of cell-cell contact [XREF_BIBR].	5	9	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ephrin-A5	ephrin-A5	ephrin-A5	EphA4	EphA4	EphA4	8	9	5	6
As the particular form under which E2F1 is able to regulate CDC2 ' s expression is not known , we first considered that E2F1 could upregulate CDC2 when associated only to DP1 or when associated to a phosphorylated form of RB , as we know that unphosphorylated RB is an inhibitor of E2F1 .	As the particular form under which E2F1 is able to regulate CDC2 's expression is not known, we first considered that E2F1 could upregulate CDC2 when associated only to DP1 or when associated to a phosphorylated form of RB, as we know that unphosphorylated RB is an inhibitor of E2F1.	23	27	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	E2F1	E2F1	E2F1	CDC2	CDC2	CDC2	23	24	26	27
We further show that E2F1 is important for E6 to upregulate Cdk1 .	We further show that E2F1 is important for E6 to upregulate Cdk1.	4	12	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	E2F1	E2F1	E2F1	Cdk1	Cdk1	Cdk1	4	5	11	12
Necdin interacts with E2F transcription factors and suppresses E2F1 dependent transcriptional activation of the cyclin dependent kinase Cdk1 gene .	Necdin interacts with E2F transcription factors and suppresses E2F1 dependent transcriptional activation of the cyclin dependent kinase Cdk1 gene.	8	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	E2F1	E2F1	E2F1	Cdk1	Cdk1	Cdk1	8	9	17	18
Mirk also increases the length of G1 by stabilizing p27kip1 by phosphorylation at S10 [ XREF_BIBR ] , [ XREF_BIBR ] .	Mirk also increases the length of G1 by stabilizing p27kip1 by phosphorylation at S10 [XREF_BIBR], [XREF_BIBR].	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mirk	Mirk	Mirk	p27kip1	p27kip1	p27kip1	0	1	9	10
DYRK1B can induce reversible cell arrest in a quiescent G 0 state by targeting cyclin D1 for proteasomal degradation and stabilizing p27 Kip1 .	DYRK1B can induce reversible cell arrest in a quiescent G 0 state by targeting cyclin D1 for proteasomal degradation and stabilizing p27 Kip1.	0	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1B	DYRK1B	DYRK1B	p27 Kip1	p27 Kip1	p27 Kip1	0	1	21	23
On the other hand , lapatinib treatment resulted in increased DYRK1B expression , which correlated with increased p27 phosphorylation at Ser10 and decreased p27 degradation .	On the other hand, lapatinib treatment resulted in increased DYRK1B expression, which correlated with increased p27 phosphorylation at Ser10 and decreased p27 degradation.	10	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DYRK1B	DYRK1B expression	dyrk1b	p27	p27	p27	10	11	23	24
SBDS and its interacting partner elongation factor like GTPase 1 ( EFL1 ) , promote the dissociation of eukaryotic initiation factor 6 ( EIF6 ) from the LSU .	SBDS and its interacting partner elongation factor like GTPase 1 (EFL1), promote the dissociation of eukaryotic initiation factor 6 (EIF6) from the LSU.	5	27	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	elongation factor like GTPase 1	elongation factor like GTPase 1	elongation factor like GTPase 1	EIF6	EIF6	EIF6	5	10	23	24
SBDS protein ( deficient in the inherited leukemia-predisposition disorder Shwachman-Diamond syndrome ) and the GTPase EFL1 ( an EF-G homolog ) activate nascent 60S ribosomal subunits for translation by catalyzing eviction of the antiassociation factor eIF6 from nascent 60S ribosomal subunits .	SBDS protein (deficient in the inherited leukemia-predisposition disorder Shwachman-Diamond syndrome) and the GTPase EFL1 (an EF-G homolog) activate nascent 60S ribosomal subunits for translation by catalyzing eviction of the antiassociation factor eIF6 from nascent 60S ribosomal subunits.	1	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EFL1	EFL1	EFL1	eIF6	eIF6	eIF6	15	16	35	36
Ephrin-A3 coexpression also attenuated ephrin-A3 Fc induced activation of endogenous EphA2 in A549 cells ( XREF_FIG ) .	Ephrin-A3 coexpression also attenuated ephrin-A3 Fc induced activation of endogenous EphA2 in A549 cells (XREF_FIG).	4	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA2	EphA2	EphA2	4	5	10	11
Ephrin-A1 stimulation of Jurkat cells was also found to cause down-regulation of endogenous EphA3 receptors from the cell surface and their degradation .	Ephrin-A1 stimulation of Jurkat cells was also found to cause down-regulation of endogenous EphA3 receptors from the cell surface and their degradation.	0	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ephrin-A1	Ephrin-A1	Ephrin-A1	EphA3	EphA3	EphA3	0	1	13	14
Mirk antagonized the inhibition of MEF2C by MITR , whereas kinase-inactive Mirk was ineffective .	Mirk antagonized the inhibition of MEF2C by MITR, whereas kinase-inactive Mirk was ineffective.	0	6	antagonized	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mirk	Mirk	Mirk	MEF2C	MEF2C	MEF2C	0	1	5	6
Dyrk1b enhances MEF2C induction of myog promoter reporter constructs in C2C12 cells XREF_BIBR .	Dyrk1b enhances MEF2C induction of myog promoter reporter constructs in C2C12 cells XREF_BIBR.	0	3	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dyrk1b	Dyrk1b	Dyrk1b	MEF2C	MEF2C	MEF2C	0	1	2	3
EDA isoform1 binds to EDAR , whereas XEDAR is activated by isoform2 of the EDA protein .	EDA isoform1 binds to EDAR, whereas XEDAR is activated by isoform2 of the EDA protein.	7	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EDA protein	EDA protein	EDA protein	XEDAR	XEDAR	XEDAR	14	16	7	8
This mechanism entails the activation of the E2F1 protein by the HMGA2 mediated displacement of HDAC1 from pRB protein .	This mechanism entails the activation of the E2F1 protein by the HMGA2 mediated displacement of HDAC1 from pRB protein.	7	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	E2F1	E2F1	E2F1	HDAC1	HDAC1	HDAC1	7	8	15	16
The two lentivirally infected cancer cell lines , which do not express detectable endogenous EphA3 or ephrin-A3 ( XREF_FIG ) , were then treated with ephrin-A3 Fc ( a soluble form of the ephrin-A3 ligand fused to the Fc portion of human IgG 1 ) to activate EphA3 through ephrin binding in trans .	The two lentivirally infected cancer cell lines, which do not express detectable endogenous EphA3 or ephrin-A3 (XREF_FIG), were then treated with ephrin-A3 Fc (a soluble form of the ephrin-A3 ligand fused to the Fc portion of human IgG 1) to activate EphA3 through ephrin binding in trans.	11	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA3	EphA3	EphA3	25	26	14	15
XREF_BIBR , XREF_BIBR Likewise , in response to a DNA double-strand break , DYRK2 targets p53 to phosphorylate ser46 to induce pro apoptotic genes .	XREF_BIBR, XREF_BIBR Likewise, in response to a DNA double-strand break, DYRK2 targets p53 to phosphorylate ser46 to induce pro apoptotic genes.	0	17	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	DYRK2	DYRK2	DYRK2	p53	p53	p53	13	14	15	16
Eph and ephrins also act as negative modulators in the nervous system as shown by the involvement of EphA7 and ephrin-A2 on progenitor cell proliferation in mice [ XREF_BIBR ] , influence of ephrin-B3 [ XREF_BIBR ] , and EphB3 [ XREF_BIBR ] in the adult subventricular zone , and regulation of hippocampus neural progenitor growth by ephrin-A2 and A3 mediated activation of EphA7 [ XREF_BIBR ] .	Eph and ephrins also act as negative modulators in the nervous system as shown by the involvement of EphA7 and ephrin-A2 on progenitor cell proliferation in mice [XREF_BIBR], influence of ephrin-B3 [XREF_BIBR], and EphB3 [XREF_BIBR] in the adult subventricular zone, and regulation of hippocampus neural progenitor growth by ephrin-A2 and A3-mediated activation of EphA7 [XREF_BIBR].	57	65	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ephrin-A2	ephrin-A2	ephrin-A2	EphA7	EphA7	EphA7	57	58	63	64
More importantly , small interfering RNA mediated Odin silencing significantly diminished ephrinA5 induced EphA8 signaling effects , which inhibit cell migration in HEK293 cells and retract growing neurites of Neuro2a cells .	More importantly, small interfering RNA mediated Odin silencing significantly diminished ephrinA5 induced EphA8 signaling effects, which inhibit cell migration in HEK293 cells and retract growing neurites of Neuro2a cells.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	ephrinA5	ephrinA5	ephrinA5	EphA8	EphA8	EphA8	11	12	13	14
EGF induces dimerization of EGFR by binding to the extracellular region of the receptor to form a 2:2 EGF : EGFR complex [ XREF_BIBR , XREF_BIBR ] .	EGF induces dimerization of EGFR by binding to the extracellular region of the receptor to form a 2:2 EGF : EGFR complex [XREF_BIBR, XREF_BIBR].	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
We investigated EGF induced auto-transphosphorylation of EGFR in both cell lines .	We investigated EGF induced auto-transphosphorylation of EGFR in both cell lines.	2	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	6	7
In co-immunoprecipitation studies , EGF stimulation of NIH3T3 and hEGFR fibroblasts induced 1.38-fold increase in Stat3 : EGFR complexation ( XREF_FIG , lanes 3 vs 2 , Stat3 ) , which was associated with pY705Stat3 induction ( XREF_FIG , lanes 2 vs 1 , pY705Stat3 ) .	In co-immunoprecipitation studies, EGF stimulation of NIH3T3 and hEGFR fibroblasts induced 1.38-fold increase in Stat3 : EGFR complexation (XREF_FIG, lanes 3 vs 2, Stat3), which was associated with pY705Stat3 induction (XREF_FIG, lanes 2 vs 1, pY705Stat3).	4	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	17	18
Both PRL and EGF caused robust signaling in T47D cells ; PRL acutely activated JAK2 , signal transducer and activator of transcription-5 ( STAT5 ) , and extracellular signal regulated kinase-1 and -2 ( ERK1 and ERK2 ) , whereas EGF caused EGFR activation and consequent src homology collagen ( SHC ) activation and ERK activation .	Both PRL and EGF caused robust signaling in T47D cells; PRL acutely activated JAK2, signal transducer and activator of transcription-5 (STAT5), and extracellular signal regulated kinase-1 and -2 (ERK1 and ERK2), whereas EGF caused EGFR activation and consequent src homology collagen (SHC) activation and ERK activation.	40	43	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	40	41	42	43
3.2 EGF induced EGFR downregulation is enhanced in CHO cells expressing EGFR T669A compared to WT EGFR .	3.2 EGF induced EGFR downregulation is enhanced in CHO cells expressing EGFR T669A compared to WT EGFR.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR Our data demonstrate that , [ i ] activation of ORs by analgesic morphine co-activates EGFR in highly resistant NSCLC cells , [ ii ] ORs are involved with EGF induced EGFR , MAPK and ERK- and Aktphosphorylation , proliferation and invasiveness and [ iii ] the self-supportive tumor microenvironment created by NSCLC cells may be associated with increased expression of MOR on tumor cells .	XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR Our data demonstrate that, [i] activation of ORs by analgesic morphine co-activates EGFR in highly resistant NSCLC cells, [ii] ORs are involved with EGF induced EGFR, MAPK and ERK- and Aktphosphorylation, proliferation and invasiveness and [iii] the self-supportive tumor microenvironment created by NSCLC cells may be associated with increased expression of MOR on tumor cells.	34	42	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	36	37	38	39
We demonstrated that suppression of endophilin B1 increased EGFR levels via delaying EGFR internalization triggered by EGF and its intracellular degradation .	We demonstrated that suppression of endophilin B1 increased EGFR levels via delaying EGFR internalization triggered by EGF and its intracellular degradation.	12	20	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	12	13
Unlike the ATP-competitive TKIs , PTUPB treatment does not deplete EGF induced phosphorylation of EGFR ( p-EGFR Tyr1173 ) until 6 h post dose , while Gefitinib , a widely used EGFR TKI , inhibits EGF induced p-EGFR in early phase ( 30 min ) in glioblastoma cells [ XREF_BIBR ] .	Unlike the ATP-competitive TKIs, PTUPB treatment does not deplete EGF induced phosphorylation of EGFR (p-EGFR Tyr1173) until 6 h post dose, while Gefitinib, a widely used EGFR TKI, inhibits EGF induced p-EGFR in early phase (30 min) in glioblastoma cells [XREF_BIBR].	35	38	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	p-EGFR	p-EGFR	p-EGFR	35	36	37	38
A recent study suggested that EGF induced the formation of a G i alpha , GIV , Girdin , and EGFR complex activating the PI3K-Akt pathway , and the interaction of G i3 alpha with EGFR was dependent on the guanine exchange factor ( GEF ) motif in GIV [ XREF_BIBR ] .	A recent study suggested that EGF induced the formation of a G i alpha, GIV, Girdin, and EGFR complex activating the PI3K-Akt pathway, and the interaction of G i3 alpha with EGFR was dependent on the guanine exchange factor (GEF) motif in GIV [XREF_BIBR].	5	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	20	21
Although EGF also elevated the activity of EGFR tyrosine kinase in both sham operated and DOCA-salt hypertensive rats , the expression and the magnitude of activation did not differ between strips .	Although EGF also elevated the activity of EGFR tyrosine kinase in both sham operated and DOCA-salt hypertensive rats, the expression and the magnitude of activation did not differ between strips.	1	9	elevated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	7	8
For example , conjugation of EGF to 5-ALA can target EGFR + gliomas , ultimately improving their visualization and resection ( XREF_FIG ) .	For example, conjugation of EGF to 5-ALA can target EGFR + gliomas, ultimately improving their visualization and resection (XREF_FIG).	3	21	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	10	11
Afatinib promoted cell cycle arrest at the S and G2/M phases , and it significantly inhibited epidermal growth factor ( EGF )-induced activation of EGFR and its downstream signaling factors .	Afatinib promoted cell cycle arrest at the S and G2/M phases, and it significantly inhibited epidermal growth factor (EGF)-induced activation of EGFR and its downstream signaling factors.	20	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	24	25
The EGF induced effect requires interaction of the EGFR and its cognate ligand because cell lines that lack EGFR can not be shown to phosphorylate p185 , even when exposed to large amounts of EGF .	The EGF induced effect requires interaction of the EGFR and its cognate ligand because cell lines that lack EGFR can not be shown to phosphorylate p185, even when exposed to large amounts of EGF.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	8	9
Wound repair after injury was significantly hastened by application of exogenous EGF ( 13.3 microm and hour , +/-2.63 ) compared to absence of exogenous EGF ( 7.1 microm and hour +/-2.84 ) , but inhibited with concurrent addition of Gefitinib ( 5.2 microm and hour , +/-2.23 ) , indicating that EGF mediates wound healing in an EGFR dependent manner .	Wound repair after injury was significantly hastened by application of exogenous EGF (13.3 microm and hour, +/-2.63) compared to absence of exogenous EGF (7.1 microm and hour +/-2.84), but inhibited with concurrent addition of Gefitinib (5.2 microm and hour, +/-2.23), indicating that EGF mediates wound healing in an EGFR dependent manner.	52	60	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	52	53	58	59
Collectively these findings suggest that EGF ligand , radiation and cetuximab enhance nuclear accumulation of the EGFR .	Collectively these findings suggest that EGF ligand, radiation and cetuximab enhance nuclear accumulation of the EGFR.	5	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	16	17
In contrast , EGF ligand treatment caused robust EGFR-GFP internalization but had little or no effect on HER2 distribution .	In contrast, EGF ligand treatment caused robust EGFR-GFP internalization but had little or no effect on HER2 distribution.	3	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR-GFP	EGFR-GFP	EGFR-GFP	3	4	8	9
A subsequent study described the successful modification of polymer coated , wild-type Ad5 , through the incorporation of murine epidermal growth factor ( mEGF ) , which selectively targets the EGF receptor [ XREF_BIBR ] .	A subsequent study described the successful modification of polymer coated, wild-type Ad5, through the incorporation of murine epidermal growth factor (mEGF), which selectively targets the EGF receptor [XREF_BIBR].	19	32	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	19	22	30	32
However , EGFR was co-IP ' ed with endogenous ERbeta in A549 cells treated with EGF or EGF plus E 2 .	However, EGFR was co-IP ' ed with endogenous ERbeta in A549 cells treated with EGF or EGF plus E 2.	2	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	2	3
EGF induced the formation of ErbB1 dimers as well as larger clusters ( up to pentamers ) that colocalized with clathrin coated pits .	EGF induced the formation of ErbB1 dimers as well as larger clusters (up to pentamers) that colocalized with clathrin coated pits.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	0	1	5	6
Interestingly , the activation of STAT5b downstream of DeltaEGFR was dependent on SFKs , while the signal from acutely EGF stimulated EGFR to STAT5b involved other kinases .	Interestingly, the activation of STAT5b downstream of DeltaEGFR was dependent on SFKs, while the signal from acutely EGF stimulated EGFR to STAT5b involved other kinases.	16	22	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
Moreover , activation of EGFR by EGF increased COX-2 promoter activity and protein expression in Hep3B and Huh-7 cells , whereas blocking PGE ( 2 ) synthesis or EP ( 1 ) attenuated EGFR phosphorylation induced by EGF , suggesting that the COX-2 and PGE ( 2 )/EP ( 1 ) pathway also modulate the activation of EGFR by its cognate ligand .	Moreover, activation of EGFR by EGF increased COX-2 promoter activity and protein expression in Hep3B and Huh-7 cells, whereas blocking PGE (2) synthesis or EP (1) attenuated EGFR phosphorylation induced by EGF, suggesting that the COX-2 and PGE (2)/EP (1) pathway also modulate the activation of EGFR by its cognate ligand.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	4	5
Here we present a complementary study using two different cell lines , LNZ308 and LN428 , and including novel comparisons of the DeltaEGFR signal with a kinase inactive DeltaEGFR ( DeltaEGFR-ki ) and acutely EGF stimulated EGFR .	Here we present a complementary study using two different cell lines, LNZ308 and LN428, and including novel comparisons of the DeltaEGFR signal with a kinase inactive DeltaEGFR (DeltaEGFR-ki) and acutely EGF stimulated EGFR.	28	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	34	35	36	37
The steroid hormone also seemingly promotes EGF induced internalization of apical and basolateral membrane EGFR .	The steroid hormone also seemingly promotes EGF induced internalization of apical and basolateral membrane EGFR.	6	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	14	15
Border cells migrate tens of cell diameters through a complex tissue environment in response to signaling by the Pvf1 and EGF ligands and their corresponding Pvr and epidermal growth factor receptor receptors .	Border cells migrate tens of cell diameters through a complex tissue environment in response to signaling by the Pvf1 and EGF ligands and their corresponding Pvr and epidermal growth factor receptor receptors.	15	31	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	20	21	27	31
Further , pretreatment with the MEK1 and ERK inhibitor PD98059 enhanced EGF induced EGFR loss in cells expressing WT EGFR , but not EGFR T669A , suggesting that the ERK dependent effects on EGFR downregulation required phosphorylation of 669 T.	Further, pretreatment with the MEK1 and ERK inhibitor PD98059 enhanced EGF induced EGFR loss in cells expressing WT EGFR, but not EGFR T669A, suggesting that the ERK dependent effects on EGFR downregulation required phosphorylation of 669 T.	10	14	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
To assess whether Crk and Nck were associated with the induction of EGFR mediated carcinoma cell migration , lysates from FG cells treated with or without EGF were subjected to immunoprecipitation with anti-CAS followed by immunoblotting for Nck1 , Nck2 , CrkL and CrkI .	To assess whether Crk and Nck were associated with the induction of EGFR mediated carcinoma cell migration, lysates from FG cells treated with or without EGF were subjected to immunoprecipitation with anti-CAS followed by immunoblotting for Nck1, Nck2, CrkL and CrkI.	10	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	12	13
As the ATPase functional domain of dynein , which utilizes ATP to generate energy for this movement , is usually used as a target to inhibit dynein ' s function , we used dynein inhibitors to determine if dynein has a role in EGF induced EGFR trafficking to Golgi .	As the ATPase functional domain of dynein, which utilizes ATP to generate energy for this movement, is usually used as a target to inhibit dynein 's function, we used dynein inhibitors to determine if dynein has a role in EGF induced EGFR trafficking to Golgi.	41	46	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	43	44	45	46
Accumulated evidence reveals the association between EGF activated EGFR and c-Src that leads to activation of both kinases .	Accumulated evidence reveals the association between EGF activated EGFR and c-Src that leads to activation of both kinases.	0	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Here we report that at high concentrations , EGF can induce cell growth and differentiation in the absence of ErbB-1 .	Here we report that at high concentrations, EGF can induce cell growth and differentiation in the absence of ErbB-1.	8	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	8	9	19	20
Endogenous Ankrd 13A and 13D bind to EGF activated EGFR .	Endogenous Ankrd 13A and 13D bind to EGF activated EGFR.	5	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
In contrast , epidermal growth factor rapidly induced EGFR , but not IGF-IR , phosphorylation in Tam-R cells .	In contrast, epidermal growth factor rapidly induced EGFR, but not IGF-IR, phosphorylation in Tam-R cells.	3	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	3	6	8	9
XREF_BIBR The activation of EGFR by EGF can upregulate the production of VEGF in human cancer cells ; conversely , EGFR blockade can inhibit the secretion of VEGF and other angiogenic growth factors .	XREF_BIBR The activation of EGFR by EGF can upregulate the production of VEGF in human cancer cells; conversely, EGFR blockade can inhibit the secretion of VEGF and other angiogenic growth factors.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	4	5
An epidermal growth factor ( EGF ) receptor cDNA clone was obtained by screening of the expression library with a rabbit polyclonal antibody ( IgG ) , raised to the purified A431 EGF receptor , in combination with [ 125I ] protein A of S. aureus .	An epidermal growth factor (EGF) receptor cDNA clone was obtained by screening of the expression library with a rabbit polyclonal antibody (IgG), raised to the purified A431 EGF receptor, in combination with [125I] protein A of S. aureus.	1	34	raised	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	1	4	32	34
Genistein at cytostatic concentration ( less than 40 microM ) did not prevent the induction of c-myc mRNA synthesis caused by the activation of EGF receptor by EGF .	Genistein at cytostatic concentration (less than 40 microM) did not prevent the induction of c-myc mRNA synthesis caused by the activation of EGF receptor by EGF.	19	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	27	28	24	26
In this study , we found in both A549 and H1975 cells that EGFR activation stimulated by EGF can be blocked by the EGFR-TKI gefitinib ; however , TOPK phosphorylation occurred downstream of EGF and EGFR and was only partially inhibited by gefitinib .	In this study, we found in both A549 and H1975 cells that EGFR activation stimulated by EGF can be blocked by the EGFR-TKI gefitinib; however, TOPK phosphorylation occurred downstream of EGF and EGFR and was only partially inhibited by gefitinib.	13	18	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	13	14
Following injury , the process of EMT which is associated with decreased expression of E-cadherin promotes uncoupling and redistribution of EGFR from the apicolateral junctional complexes to the apical cell surface [ XREF_BIBR ] , where EGF ligands secreted by either resident epithelial or infiltrated inflammatory cells activates EGFR readily .	Following injury, the process of EMT which is associated with decreased expression of E-cadherin promotes uncoupling and redistribution of EGFR from the apicolateral junctional complexes to the apical cell surface [XREF_BIBR], where EGF ligands secreted by either resident epithelial or infiltrated inflammatory cells activates EGFR readily.	36	49	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	36	37	48	49
Additional inhibition of EGF mediated EGFR dimerization and activation by soluble Decorin has been reported .	Additional inhibition of EGF mediated EGFR dimerization and activation by soluble Decorin has been reported.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
High doses of EGF seem to promote the sorting of EGFR to late endosomes through a raft and cholesterol dependant mechanism , implicating them in EGFR degradation .	High doses of EGF seem to promote the sorting of EGFR to late endosomes through a raft and cholesterol dependant mechanism, implicating them in EGFR degradation.	1	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	10	11
Furthermore , we examined nuclear EGFR levels in ovarian cancer cell lines treated with EGF , and primary ovarian tumor tissue using immunofluorescence analysis .	Furthermore, we examined nuclear EGFR levels in ovarian cancer cell lines treated with EGF, and primary ovarian tumor tissue using immunofluorescence analysis.	5	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	5	6
Unexpectedly , activation of EGFR by EGF in isolated cortical precursor cells resulted in a robust transactivation of TrkB and also TrkC .	Unexpectedly, activation of EGFR by EGF in isolated cortical precursor cells resulted in a robust transactivation of TrkB and also TrkC.	2	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	4	5
In another study the authors showed by scoring gamma-H2AX foci that activation of EGFR signaling by its natural ligand EGF enhanced the overall capacity of cells to repair DSBs .	In another study the authors showed by scoring gamma-H2AX foci that activation of EGFR signaling by its natural ligand EGF enhanced the overall capacity of cells to repair DSBs.	13	20	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	13	14
PS2-TAT blocks the EGF induced migration of EGFR and c-erbB-2-positive MDA-HER2 cells .	PS2-TAT blocks the EGF induced migration of EGFR and c-erbB-2-positive MDA-HER2 cells.	2	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	7	8
As predicted from previous results we also found that the extent of EGF induced EGFR degradation at 90 min was significantly reduced in cells expressing the Dyn2 mutants compared to WT cells ( XREF_FIG ) .	As predicted from previous results we also found that the extent of EGF induced EGFR degradation at 90 min was significantly reduced in cells expressing the Dyn2 mutants compared to WT cells (XREF_FIG).	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
EGF activated EGFR is rapidly internalized into early endosomes .	EGF activated EGFR is rapidly internalized into early endosomes.	0	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
We observed that EGF treatment down to 2.5 ngml -1 was sufficient to activate EGFR signalling in these cells as evidenced by optimal pERK1/2 induction .	We observed that EGF treatment down to 2.5 ngml -1 was sufficient to activate EGFR signalling in these cells as evidenced by optimal pERK1/2 induction.	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	14	15
Almost 50 percent of the total pool of alpha-adaptins was coimmunoprecipitated with the EGF receptor when A-431 cells were treated with EGF at 37 degrees C , but not at 4 degrees C. Partial proteolysis of alpha-adaptin suggested that the amino-terminal domain is the region that associates with the EGF receptor .	Almost 50 percent of the total pool of alpha-adaptins was coimmunoprecipitated with the EGF receptor when A-431 cells were treated with EGF at 37 degrees C, but not at 4 degrees C. Partial proteolysis of alpha-adaptin suggested that the amino-terminal domain is the region that associates with the EGF receptor.	13	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	21	22	13	15
First , they comigrate with cancer cells using a chemotactic paracrine signaling loop consisting of macrophage secreted EGF [ which activates EGFR ( EGF receptor ) on cancer cells ] and cancer cell secreted CSF-1 ( which activates CSF-1R on macrophage ) .	First, they comigrate with cancer cells using a chemotactic paracrine signaling loop consisting of macrophage secreted EGF [which activates EGFR (EGF receptor) on cancer cells] and cancer cell secreted CSF-1 (which activates CSF-1R on macrophage).	13	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	21	22
In turn , blocking sodium influx reduced tubulin acetylation and EGF induced EGFR turnover .	In turn, blocking sodium influx reduced tubulin acetylation and EGF induced EGFR turnover.	8	13	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
Furthermore , the EGF induced activation of EGFR , ERK , and AKT increased YAP expression and subsequently proliferation .	Furthermore, the EGF induced activation of EGFR, ERK, and AKT increased YAP expression and subsequently proliferation.	2	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	7	8
The initial observation that the Cbl protein couples only to EGF activated ErbB1 but not to ErbB1 transactivated by NRG induced heterodimerization with ErbB3 or ErbB4 [ XREF_BIBR ] suggested that the phosphorylation pattern on a given receptor might be modulated by the dimerization partner .	The initial observation that the Cbl protein couples only to EGF activated ErbB1 but not to ErbB1 transactivated by NRG induced heterodimerization with ErbB3 or ErbB4 [XREF_BIBR] suggested that the phosphorylation pattern on a given receptor might be modulated by the dimerization partner.	8	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	10	11	12	13
Interestingly , the flow cytometry studies of Szabo et al showed that while EGF induced larger ErbB1 clusters in A431 cells , it led to a substantial decrease in the size of ErbB2 homoclusters in SKBR-3 cells .	Interestingly, the flow cytometry studies of Szabo et al showed that while EGF induced larger ErbB1 clusters in A431 cells, it led to a substantial decrease in the size of ErbB2 homoclusters in SKBR-3 cells.	13	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	13	14	16	17
To determine if the growth-inhibitory effects of SEC61gamma knockdown might be mediated through the EGFR and AKT signaling pathway , we evaluated the consequence of SEC61gamma knockdown on the EGFR and AKT pathway activity and found that EGF mediated activation of EGFR and AKT was significantly inhibited in SEC61gamma siRNA transfected cells ( XREF_SUPPLEMENTARY ) .	To determine if the growth-inhibitory effects of SEC61gamma knockdown might be mediated through the EGFR and AKT signaling pathway, we evaluated the consequence of SEC61gamma knockdown on the EGFR and AKT pathway activity and found that EGF mediated activation of EGFR and AKT was significantly inhibited in SEC61gamma siRNA transfected cells (XREF_SUPPLEMENTARY).	37	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	37	38	41	42
It is known that EGF induces activation of EGFR , followed by degradation and attenuation of EGFR and downstream signaling pathways .	It is known that EGF induces activation of EGFR, followed by degradation and attenuation of EGFR and downstream signaling pathways.	4	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	8	9
We show further that third generation DM EGFR selective TKIs alter JM structure via allostery to restore the conformation found when WT EGFR is activated by the growth factors EGF and HB-EGF .	We show further that third generation DM EGFR selective TKIs alter JM structure via allostery to restore the conformation found when WT EGFR is activated by the growth factors EGF and HB-EGF.	21	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	22	23
Transfection of GCF expression vector interfered with the mRNA accumulation for EGFR and TGF-beta induced by epidermal growth factor in gastric carcinoma cell lines .	Transfection of GCF expression vector interfered with the mRNA accumulation for EGFR and TGF-beta induced by epidermal growth factor in gastric carcinoma cell lines.	5	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	16	19	11	12
These results strongly suggest that O GlcNAcylation of MIF at Ser 112/Thr 113 , which are the residues in the C-terminal beta-strand and part of a looped structure composed of two beta-strands 22 , is required for MIF to bind to the extracellular domain of EGFR and to inhibit EGF induced EGFR activation .	These results strongly suggest that O GlcNAcylation of MIF at Ser 112/Thr 113, which are the residues in the C-terminal beta-strand and part of a looped structure composed of two beta-strands 22, is required for MIF to bind to the extracellular domain of EGFR and to inhibit EGF induced EGFR activation.	48	52	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	49	50	51	52
In hamsters , EGF and transforming growth factor alpha ( TGF-alpha ) can activate the EGF receptor ( EGFR ) , and infusion of either ligand into the hamster ICV suppresses locomotion and feeding in an EGFR dependent fashion [ XREF_BIBR ] .	In hamsters, EGF and transforming growth factor alpha (TGF-alpha) can activate the EGF receptor (EGFR), and infusion of either ligand into the hamster ICV suppresses locomotion and feeding in an EGFR dependent fashion [XREF_BIBR].	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	3	4	15	17
Standard EGFR activation ( referred as SD activation ) , serving as a control , was achieved by normal EGF stimulation of wild type EGFR in CHO-EGFR cells .	Standard EGFR activation (referred as SD activation), serving as a control, was achieved by normal EGF stimulation of wild type EGFR in CHO-EGFR cells.	19	27	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	24	25
As observed above ( XREF_FIG ) , EGF stimulation of control and EGFR expressing NMuMG cells readily promoted the formation of normal and dysmorphic branching structures , respectively ( XREF_FIG ) .	As observed above (XREF_FIG), EGF stimulation of control and EGFR expressing NMuMG cells readily promoted the formation of normal and dysmorphic branching structures, respectively (XREF_FIG).	7	15	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	12	13
A five and ten second PLIMB treatment of micros-long pulses was used , and oxidation was mapped and quantified in amino acids throughout EGFR treated with and without added EGF .	A five and ten second PLIMB treatment of micros-long pulses was used, and oxidation was mapped and quantified in amino acids throughout EGFR treated with and without added EGF.	16	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	23	24
These data suggest therefore that the peroxide induced redistribution of EGFR occurs through a qualitatively similar process to that of EGF induced EGFR internalization .	These data suggest therefore that the peroxide induced redistribution of EGFR occurs through a qualitatively similar process to that of EGF induced EGFR internalization.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
Spermine prevented EGF induced binding of the EGFR with integrin beta3 , Src , and FAK .	Spermine prevented EGF induced binding of the EGFR with integrin beta3, Src, and FAK.	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	7	8
In line with this , simultaneously mutating two AP-2 interaction sites in EGFR affected p38 MAPK induced internalization much more than EGF induced EGFR internalization .	In line with this, simultaneously mutating two AP-2 interaction sites in EGFR affected p38 MAPK induced internalization much more than EGF induced EGFR internalization.	21	24	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	23	24
Translocation of pEGFR to the nucleus occurred independent of phosphorylation at Y1110 in LNCaP cells as shown by strongly increased pEGFR Y1068 in the nuclear fraction of both EGF stimulated WT-EGFR and MT-EGFR transfected LNCaP cells ( XREF_FIG ) .	Translocation of pEGFR to the nucleus occurred independent of phosphorylation at Y1110 in LNCaP cells as shown by strongly increased pEGFR Y1068 in the nuclear fraction of both EGF stimulated WT-EGFR and MT-EGFR transfected LNCaP cells (XREF_FIG).	25	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	WT-EGFR	WT-EGFR	WT-EGFR	28	29	30	31
Cells with high ST6Gal-I expression were found to have elevated levels of basal and EGF induced EGFR activation .	Cells with high ST6Gal-I expression were found to have elevated levels of basal and EGF induced EGFR activation.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
The results from fluorescence resonance energy transfer ( FRET ) assay also support the EGF stimulated transport of EGFR to the Golgi ( XREF_FIG ) .	The results from fluorescence resonance energy transfer (FRET) assay also support the EGF stimulated transport of EGFR to the Golgi (XREF_FIG).	13	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	18	19
NEU1 overexpression diminished EGF stimulated EGFR Tyr 1068 autophosphorylation by up to 44 % but enhanced MUC1 dependent Pseudomonas aeruginosa adhesion by 1.6-1.7-fold and flagellin stimulated ERK1/2 activation by 1.7-1.9-fold .	NEU1 overexpression diminished EGF stimulated EGFR Tyr 1068 autophosphorylation by up to 44% but enhanced MUC1 dependent Pseudomonas aeruginosa adhesion by 1.6-1.7-fold and flagellin stimulated ERK1/2 activation by 1.7-1.9-fold.	2	6	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
CDRI-85/287 inhibits EGF- EGFR interaction and antagonises EGF- induced EGFR activation .	CDRI-85/287 inhibits EGF- EGFR interaction and antagonises EGF- induced EGFR activation.	1	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF-	EGF-	EGF-	EGFR	EGFR	EGFR	7	8	9	10
Phenobarbital represses EGF activation of EGFR .	Phenobarbital represses EGF activation of EGFR.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	5	6
Further study in our laboratory showed that PKG II could inhibit the proliferation of gastric cancer cell lines and block EGF induced signal transduction of MAPK and ERK mediated pathway through preventing the activation of EGFR by EGF XREF_BIBR , XREF_BIBR .	Further study in our laboratory showed that PKG II could inhibit the proliferation of gastric cancer cell lines and block EGF induced signal transduction of MAPK and ERK mediated pathway through preventing the activation of EGFR by EGF XREF_BIBR, XREF_BIBR.	33	38	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	37	38	35	36
The observation that ExoS ADP ribosylated Rab5 , together with the ability of constitutively active Rab5 protein to reverse ExoS inhibition of EGF activated EGFR trafficking out of CCVs , suggests that ExoS ADPr inhibits Rab5 activity in cells .	The observation that ExoS ADP ribosylated Rab5, together with the ability of constitutively active Rab5 protein to reverse ExoS inhibition of EGF activated EGFR trafficking out of CCVs, suggests that ExoS ADPr inhibits Rab5 activity in cells.	20	25	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
It has since been demonstrated that while PKC phosphorylation of EGFR inhibits subsequent EGF induced EGFR activation , pretreatment with EGF prevents the inhibitory effects of phorbol esters on EGFR signaling [ XREF_BIBR ] .	It has since been demonstrated that while PKC phosphorylation of EGFR inhibits subsequent EGF induced EGFR activation, pretreatment with EGF prevents the inhibitory effects of phorbol esters on EGFR signaling [XREF_BIBR].	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
This activity was counteracted by EGF induced activation of EGF receptor signaling .	This activity was counteracted by EGF induced activation of EGF receptor signaling.	3	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	5	6	9	11
We performed parallel immunofluorescence ( XREF_FIG ) and Western blot analyses ( XREF_FIG ) using Tu212 cells in the presence or absence of EGF to examine whether EGCG affects EGF induced EGFR activation , internalization and degradation .	We performed parallel immunofluorescence (XREF_FIG) and Western blot analyses (XREF_FIG) using Tu212 cells in the presence or absence of EGF to examine whether EGCG affects EGF induced EGFR activation, internalization and degradation.	28	32	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	31	32
We can not exclude the possibility that EGF receptor activation by systemic TGF-alpha or EGF occurs primarily outside the central nervous and that the activation of cells in the hypothalamus is caused by secondary events .	We can not exclude the possibility that EGF receptor activation by systemic TGF-alpha or EGF occurs primarily outside the central nervous and that the activation of cells in the hypothalamus is caused by secondary events.	7	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	14	15	7	9
EGF stimulated EGFR downregulation was accelerated in RVH6849 cells when Odin expression was knocked down ( XREF_FIG , lanes 7-12 ) , with EGFR levels falling to approximately 50 % by the 60 min time point , consistent with what was observed in the HEK293 background .	EGF stimulated EGFR downregulation was accelerated in RVH6849 cells when Odin expression was knocked down (XREF_FIG, lanes 7-12), with EGFR levels falling to approximately 50% by the 60 min time point, consistent with what was observed in the HEK293 background.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Moreover , the EGFR Y1045F mutant and z-cbl , both of which presumably increase the duration of EGF induced EGFR signaling , increase the intrinsic activity of EGF but not of AR .	Moreover, the EGFR Y1045F mutant and z-cbl, both of which presumably increase the duration of EGF induced EGFR signaling, increase the intrinsic activity of EGF but not of AR.	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
As shown in Figure XREF_FIG , C225 effectively blocked EGF induced EGFR activation but failed to inhibit the constitutive activation of EGFR .	As shown in Figure XREF_FIG, C225 effectively blocked EGF induced EGFR activation but failed to inhibit the constitutive activation of EGFR.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
XREF_BIBR In a parallel pathway , the EGF like molecule LIN-3 induces quiescence by activating the EGF receptor LET-23 in the ALA interneuron .	XREF_BIBR In a parallel pathway, the EGF like molecule LIN-3 induces quiescence by activating the EGF receptor LET-23 in the ALA interneuron.	6	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	7	8	16	18
In conclusion these results suggest that caveolin-1 overexpression in MCF-7 breast cancer cell line modulates EGFR activation levels and EGF induced EGFR signalling .	In conclusion these results suggest that caveolin-1 overexpression in MCF-7 breast cancer cell line modulates EGFR activation levels and EGF induced EGFR signalling.	14	22	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
This study demonstrates that in breast cancer cells EGF promotes nuclear accumulation of EGFR and is dependent on clathrin coated pits , EGFR kinase activity , caveolae microdomains and cytoskeleton integrity .	This study demonstrates that in breast cancer cells EGF promotes nuclear accumulation of EGFR and is dependent on clathrin coated pits, EGFR kinase activity, caveolae microdomains and cytoskeleton integrity.	8	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	13	14
We have reported that galectin-3 stabilizes Neu1-MMP9 crosstalk in alliance with neuromedin B GPCR tethered to EGFR at the ectodomain on the cell surface , which is required for EGF induced activation of EGFR [ XREF_BIBR ] .	We have reported that galectin-3 stabilizes Neu1-MMP9 crosstalk in alliance with neuromedin B GPCR tethered to EGFR at the ectodomain on the cell surface, which is required for EGF induced activation of EGFR [XREF_BIBR].	27	35	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	33	34
In addition , because EGF induces homodimerization of the EGFR to activate its tyrosine kinase activity , the present study , which shows EGF dependent activation of the EGFR and Jak2 chimera , implies that Jak2 may also become activated by homodimerization .	In addition, because EGF induces homodimerization of the EGFR to activate its tyrosine kinase activity, the present study, which shows EGF dependent activation of the EGFR and Jak2 chimera, implies that Jak2 may also become activated by homodimerization.	23	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	28	29
EGF induced activation of EGFR , HER2 , and HER3 , as well as a reduced level of ALK activation , was associated with sustained downstream signaling in the presence of ALK inhibitors , indicative of a shift in survival dependency from the ALK signaling pathway to HER family pathways in ALK-TKI-resistant cells XREF_BIBR .	EGF induced activation of EGFR, HER2, and HER3, as well as a reduced level of ALK activation, was associated with sustained downstream signaling in the presence of ALK inhibitors, indicative of a shift in survival dependency from the ALK signaling pathway to HER family pathways in ALK-TKI-resistant cells XREF_BIBR.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
Polyoma middle T antigen or v-src appears to modulate EGF induced down-regulation of EGF-R , possibly through interaction of the receptor with the viral oncogenes , and this interaction may be altered in the mutant .	Polyoma middle T antigen or v-src appears to modulate EGF induced down-regulation of EGF-R, possibly through interaction of the receptor with the viral oncogenes, and this interaction may be altered in the mutant.	8	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	9	10	13	14
An EGF mimetic peptide ( GE11 ) has been used to enhance transduction of EGFR overexpressing tumors , which is known to be overexpressed on approximately 60 % of solid tumors .	An EGF mimetic peptide (GE11) has been used to enhance transduction of EGFR overexpressing tumors, which is known to be overexpressed on approximately 60% of solid tumors.	1	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	14	15
We detected increased EGFR activity in EGFR-wt but not -DeltaAP2 cells upon UVC exposure , whereas EGF triggered similar EGFR activation in EGFR-DeltaAP2 and -wt cells ( XREF_FIG ) .	We detected increased EGFR activity in EGFR-wt but not -DeltaAP2 cells upon UVC exposure, whereas EGF triggered similar EGFR activation in EGFR-DeltaAP2 and -wt cells (XREF_FIG).	16	20	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	19	20
Overall , the data collected so far demonstrate that , in the post-surgical setting , EGF is produced as a consequence of the wound response and locally promotes activation of EGFR and downstream pro survival signaling pathways .	Overall, the data collected so far demonstrate that, in the post-surgical setting, EGF is produced as a consequence of the wound response and locally promotes activation of EGFR and downstream pro survival signaling pathways.	15	36	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	30	31
To confirm that EGF stimulated EGFR signaling , a western blot of extracts from cells treated with EGF or IR showed the expected increase in ERK phosphorylation , and the ability of AG1478 to block these responses ( XREF_SUPPLEMENTARY ) .	To confirm that EGF stimulated EGFR signaling, a western blot of extracts from cells treated with EGF or IR showed the expected increase in ERK phosphorylation, and the ability of AG1478 to block these responses (XREF_SUPPLEMENTARY).	3	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Rather than instructing lamina neuronal differentiation directly , EGF secreted from photoreceptor axons activates the EGFR pathway in glia ( XREF_FIG ) ; in turn , glia induce lamina precursors to differentiate into L1-L4 through local Insulin and MAPK signaling ( XREF_FIG ) .	Rather than instructing lamina neuronal differentiation directly, EGF secreted from photoreceptor axons activates the EGFR pathway in glia (XREF_FIG); in turn, glia induce lamina precursors to differentiate into L1-L4 through local Insulin and MAPK signaling (XREF_FIG).	8	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	15	16
For example , monoclonal antibodies that bind the EGFR extracellular domain can promote downregulation [ XREF_BIBR , XREF_BIBR ] , and the endocytosis of EGFR induced by EGF is closely related to the sensitivity to the tyrosine kinase inhibitor gefitinib in non small cell lung cancer cell lines [ XREF_BIBR ] .	For example, monoclonal antibodies that bind the EGFR extracellular domain can promote downregulation [XREF_BIBR, XREF_BIBR], and the endocytosis of EGFR induced by EGF is closely related to the sensitivity to the tyrosine kinase inhibitor gefitinib in non small cell lung cancer cell lines [XREF_BIBR].	22	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	24	25
Other members of the TGF-alpha and EGF family also activate the EGFR or structurally closely related tyrosine kinase receptors ( Alroy and Yarden 1997 ; Riese and Stern 1998 ) .	Other members of the TGF-alpha and EGF family also activate the EGFR or structurally closely related tyrosine kinase receptors (Alroy and Yarden 1997; Riese and Stern 1998).	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	11	12
At low EGF doses , EGFR endocytosis is mediated by clathrin dependent pathway , whereas high doses of EGF trigger EGFR internalization through both clathrin dependent and clathrin independent pathways .	At low EGF doses, EGFR endocytosis is mediated by clathrin dependent pathway, whereas high doses of EGF trigger EGFR internalization through both clathrin dependent and clathrin independent pathways.	16	21	trigger	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
We investigated the time course of the internalization fate of EGF induced pEGFR via the early and late endocytic pathway in human fibrosarcoma cell line HT1080 cells using Y-27632 , a selective Rho-kinase inhibitor .	We investigated the time course of the internalization fate of EGF induced pEGFR via the early and late endocytic pathway in human fibrosarcoma cell line HT1080 cells using Y-27632, a selective Rho-kinase inhibitor.	8	19	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	10	11	12	13
However , EGFR activation by uPAR stimuli mediated cellular invasion rather than proliferation , while EGFR activation by EGF led to a proliferative response .	However, EGFR activation by uPAR stimuli mediated cellular invasion rather than proliferation, while EGFR activation by EGF led to a proliferative response.	15	19	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	15	16
EGF chronic treatment induced internalization and degradation of EGFR with the consequent decrease of both surface and total EGFR levels .	EGF chronic treatment induced internalization and degradation of EGFR with the consequent decrease of both surface and total EGFR levels.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	8	9
Our data suggest that luteolin may inhibit EGF induced activities of EGFR signaling pathway in human breast cancer cell lines , and PI3K and Akt , MAPK/Erk1/2 , STAT3 signal pathways may be the major pathways that mediate the inhibitory effect of luteolin on EGFR signaling .	Our data suggest that luteolin may inhibit EGF induced activities of EGFR signaling pathway in human breast cancer cell lines, and PI3K and Akt, MAPK/Erk1/2, STAT3 signal pathways may be the major pathways that mediate the inhibitory effect of luteolin on EGFR signaling.	6	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	11	12
We also determined during our characterization of DCA mediated signaling that its activation of EGFR did not trigger degradation of the receptor as is observed when EGFR is activated by EGF .	We also determined during our characterization of DCA mediated signaling that its activation of EGFR did not trigger degradation of the receptor as is observed when EGFR is activated by EGF.	26	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	30	31	26	27
The discordant responses of inactivation of the ESCRT pathway on EGFR degradation by EGF and LDLR degradation by PCSK9 is most consistent with the notion that the PCSK9 and LDLR complex traffics to lysosomes independently of the ESCRT pathway , or at least ESCRT-0 or ESCRT-I .	The discordant responses of inactivation of the ESCRT pathway on EGFR degradation by EGF and LDLR degradation by PCSK9 is most consistent with the notion that the PCSK9 and LDLR complex traffics to lysosomes independently of the ESCRT pathway, or at least ESCRT-0 or ESCRT-I.	10	16	degradation	Negative_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	10	11
The above mentioned aberrant trafficking of mutant EGF-R was observed in a setting where mutant EGF-R was stimulated by EGF , the natural ligand .	The above mentioned aberrant trafficking of mutant EGF-R was observed in a setting where mutant EGF-R was stimulated by EGF, the natural ligand.	14	23	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	mutant EGF-R	mutant EGF-R	mutant EGF-R	19	20	14	16
EGF ligand causes rapid activation of EGF receptor , which in turn leads to activation of the ACK1 kinase ( XREF_FIG , lane 2 , top panel ) .	EGF ligand causes rapid activation of EGF receptor, which in turn leads to activation of the ACK1 kinase (XREF_FIG, lane 2, top panel).	0	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	6	8
We identified that As 2 O 3 activates EGFR and promotes phosphorylation of p66 ShcA and its interaction with the Grb2 adaptor protein with slower kinetics compared to EGF mediated EGFR activation .	We identified that As 2 O 3 activates EGFR and promotes phosphorylation of p66 ShcA and its interaction with the Grb2 adaptor protein with slower kinetics compared to EGF mediated EGFR activation.	28	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	28	29	30	31
By altering the spatial distribution of EGFR activity , EGF promoted Akt signaling from the plasma membrane was suppressed , thereby inhibiting cell migration .	By altering the spatial distribution of EGFR activity, EGF promoted Akt signaling from the plasma membrane was suppressed, thereby inhibiting cell migration.	6	11	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	6	7
Interestingly EGF and IL15 cooperate to induce activation of the EGFR and IL15-R alpha pathway in CaCo2 cells , an intestinal epithelial cell line responsive to gliadin XREF_BIBR .	Interestingly EGF and IL15 cooperate to induce activation of the EGFR and IL15-R alpha pathway in CaCo2 cells, an intestinal epithelial cell line responsive to gliadin XREF_BIBR.	1	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	10	11
EGF stimulated intestinal cell migration requires intact EGF receptor tyrosine kinase , phospholipase , and protein kinase C activities .	EGF stimulated intestinal cell migration requires intact EGF receptor tyrosine kinase, phospholipase, and protein kinase C activities.	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	7	9
Because EGF stimulation results in activation of both EGFR and Src , we asked whether ligand dependent tyrosine phosphorylation of GIV is mediated by both receptor and non receptor kinases .	Because EGF stimulation results in activation of both EGFR and Src, we asked whether ligand dependent tyrosine phosphorylation of GIV is mediated by both receptor and non receptor kinases.	1	10	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	8	9
The prosurvival pathway of Fas is upregulated upon the EGF induced activation of EGFR .	The prosurvival pathway of Fas is upregulated upon the EGF induced activation of EGFR.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	13	14
Src kinase can also stimulate membrane bound epidermal growth factor ( EGF ) , which activates a tyrosine kinase EGF receptor that can activate the MAP kinase pathway .	Src kinase can also stimulate membrane bound epidermal growth factor (EGF), which activates a tyrosine kinase EGF receptor that can activate the MAP kinase pathway.	9	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	11	12	19	21
Although the initial step of endocytosis has been investigated for both ligand stimulated and stress induced EGFR , the majority of studies of the post-endocytic traffic of EGFR to the nucleus have focused on EGF stimulated EGFR .	Although the initial step of endocytosis has been investigated for both ligand stimulated and stress induced EGFR, the majority of studies of the post-endocytic traffic of EGFR to the nucleus have focused on EGF stimulated EGFR.	32	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	34	35	36	37
Twenty-four hour prior treatment of fibroblasts with agents decreased EGF stimulated Stat3 : EGFR co-immunoprecipitation ( XREF_FIG , lanes 4 and 5 vs 3 , Stat3 ) , in parallel with decreased EGF induced pY705Stat3 ( XREF_FIG , lanes 3 and 4 vs 2 , pY705Stat3 ) , without inhibiting pY1068EGFR or pERK1/2 induction ( XREF_FIG ) .	Twenty-four hour prior treatment of fibroblasts with agents decreased EGF stimulated Stat3 : EGFR co-immunoprecipitation (XREF_FIG, lanes 4 and 5 vs 3, Stat3), in parallel with decreased EGF induced pY705Stat3 (XREF_FIG, lanes 3 and 4 vs 2, pY705Stat3), without inhibiting pY1068EGFR or pERK1/2 induction (XREF_FIG).	9	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	13	14
Previously , the E5 and the E6 oncoproteins of the high risk genital HPV16 belonging to the genus alpha were found to interfere with EGF stimulated EGFR signaling pathways and thus protect cells from apoptosis and induce migration , respectively .	Previously, the E5 and the E6 oncoproteins of the high risk genital HPV16 belonging to the genus alpha were found to interfere with EGF stimulated EGFR signaling pathways and thus protect cells from apoptosis and induce migration, respectively.	24	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
Accelerated internalization and degradation of activated EGFR lead to the decreased number of receptors at the cell surface , a phenomenon referred to as EGF induced down-regulation of EGFR .	Accelerated internalization and degradation of activated EGFR lead to the decreased number of receptors at the cell surface, a phenomenon referred to as EGF induced down-regulation of EGFR.	24	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	28	29
Using the pY291 Fas proxy , we found that it was the phosphorylated , pro survival form of Fas that coupled Fas pathway to the EGFR pathway by acting as the signaling hub for the complex assembly that included EGFR , Src family kinases , Yes-1 and Src , and STAT3 , and permitting a robust EGF induced EGFR signaling .	Using the pY291 Fas proxy, we found that it was the phosphorylated, pro survival form of Fas that coupled Fas pathway to the EGFR pathway by acting as the signaling hub for the complex assembly that included EGFR, Src family kinases, Yes-1 and Src, and STAT3, and permitting a robust EGF induced EGFR signaling.	53	59	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	56	57	58	59
Taken together , these results indicate that the interaction between PLD1 and mu2 is a key determinant for the EGF induced internalization rate of EGFR in cells .	Taken together, these results indicate that the interaction between PLD1 and mu2 is a key determinant for the EGF induced internalization rate of EGFR in cells.	18	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	24	25
The combination of the ErbB1-4 subunits during heterodimerization does not appear to be limited ; NRG1 bound ErbB4 can associate with ErbB1 to form a heterodimer , even though ErbB1 is not activated by EGF .	The combination of the ErbB1-4 subunits during heterodimerization does not appear to be limited; NRG1 bound ErbB4 can associate with ErbB1 to form a heterodimer, even though ErbB1 is not activated by EGF.	29	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	34	35	29	30
Participation of Tom1L1 in EGF stimulated endocytosis of EGF receptor .	Participation of Tom1L1 in EGF stimulated endocytosis of EGF receptor.	2	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	4	5	8	10
Here we report a mechanism of Golgi translocation of epidermal growth factor receptor ( EGFR ) in which EGF induced EGFR travels to the Golgi via microtubule dependent movement by interacting with dynein and fuses with the Golgi through syntaxin 6 mediated membrane fusion .	Here we report a mechanism of Golgi translocation of epidermal growth factor receptor (EGFR) in which EGF induced EGFR travels to the Golgi via microtubule dependent movement by interacting with dynein and fuses with the Golgi through syntaxin 6 mediated membrane fusion.	18	34	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
We then validated the results obtained by RPPA with results previously obtained using Western blot and ELISA , observing similar trends in EGF activation or gefitinib inhibition of EGFR and downstream molecules .	We then validated the results obtained by RPPA with results previously obtained using Western blot and ELISA, observing similar trends in EGF activation or gefitinib inhibition of EGFR and downstream molecules.	22	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	28	29
EGF mediated EGFR endocytosis plays a crucial role in the attenuation of EGFR activation by sorting from early endosomes to late endosomes and transporting them into lysosomes for the final proteolytic degradation .	EGF mediated EGFR endocytosis plays a crucial role in the attenuation of EGFR activation by sorting from early endosomes to late endosomes and transporting them into lysosomes for the final proteolytic degradation.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
As shown in XREF_FIG , the EGF receptor is activated by the EGF targeted phage and targeted cells appear immunopositive for phospho-EGF receptor thereby supporting our hypothesis that the EGFR is the portal of entry for EGF displaying phage in the CP .	As shown in XREF_FIG, the EGF receptor is activated by the EGF targeted phage and targeted cells appear immunopositive for phospho-EGF receptor thereby supporting our hypothesis that the EGFR is the portal of entry for EGF displaying phage in the CP.	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	12	13	6	8
Psoralidin down-regulates EGF induced EGFR signaling in AIPC .	Psoralidin down-regulates EGF induced EGFR signaling in AIPC.	1	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
The binding of EGF to the extracellular domain ( also known as domains I and III ) causes a single EGF receptor to undergo a more extended conformation , due to the severing of intramolecular bonds acting upon domains II and IV [ XREF_BIBR ] .	The binding of EGF to the extracellular domain (also known as domains I and III) causes a single EGF receptor to undergo a more extended conformation, due to the severing of intramolecular bonds acting upon domains II and IV [XREF_BIBR].	1	22	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	3	4	20	22
The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors ( EGFR-TKIs ; e.g ., AZD9291 ) , which selectively and irreversibly inhibit EGFR activating and T790M mutants , represent very promising therapeutic options for patients with non small cell lung cancer ( NSCLC ) that has become resistant to 1st generation EGFR-TKIs due to T790M mutation .	The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs; e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants, represent very promising therapeutic options for patients with non small cell lung cancer (NSCLC) that has become resistant to 1st generation EGFR-TKIs due to T790M mutation.	3	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	3	6	22	23
AG1478 , an inhibitor of EGFR , also attenuated EGF induced activation of EGFR , JNK2 , ERK1/2 , and Akt .	AG1478, an inhibitor of EGFR, also attenuated EGF induced activation of EGFR, JNK2, ERK1/2, and Akt.	9	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	13	14
Knockdown or inhibition of EGFR abolished the suppressive effect of YAP on apoptosis , whereas activation of EGFR by EGF significantly reduced apoptosis caused by the knockdown of YAP .	Knockdown or inhibition of EGFR abolished the suppressive effect of YAP on apoptosis, whereas activation of EGFR by EGF significantly reduced apoptosis caused by the knockdown of YAP.	15	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	17	18
The activation of EGFR by EGF , results in the activation of multiple pathways including ERK-1/2 , PI3K and Stat3 via phosphorylation [ XREF_BIBR ] .	The activation of EGFR by EGF, results in the activation of multiple pathways including ERK-1/2, PI3K and Stat3 via phosphorylation [XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	3	4
Therefore , Axl is a direct substrate of EGFR kinase in vitro , as well as in vivo in intact cells following activation of EGFR by EGF .	Therefore, Axl is a direct substrate of EGFR kinase in vitro, as well as in vivo in intact cells following activation of EGFR by EGF.	22	27	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	24	25
EGFR is activated by its soluble ligand EGF , which triggers the formation of homo- and hetero-dimers with other ErbB receptor tyrosine kinases , activating the auto-phosphorylation of several cytoplasmic proteins [ XREF_BIBR ] .	EGFR is activated by its soluble ligand EGF, which triggers the formation of homo- and hetero-dimers with other ErbB receptor tyrosine kinases, activating the auto-phosphorylation of several cytoplasmic proteins [XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	0	1
Here , we show that LAPTM4B , an endosomal transmembrane oncoprotein , inhibits EGF induced EGFR intraluminal sorting and lysosomal degradation , leading to enhanced and prolonged EGFR signaling .	Here, we show that LAPTM4B, an endosomal transmembrane oncoprotein, inhibits EGF induced EGFR intraluminal sorting and lysosomal degradation, leading to enhanced and prolonged EGFR signaling.	13	22	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
EGF has also been fused to the diphtheria toxin to target EGFR in brain tumors .	EGF has also been fused to the diphtheria toxin to target EGFR in brain tumors.	0	12	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	11	12
Twenty-two statistically significant common pathways were related to Cell growth and death , among which the 9 most significant common pathways were related to signalling mediated by EGF ( 3 databases ) , ERbB , PDGFR , FGF , hepatocyte growth factor ( 2 databases ) , and also apoptosis signalling .	Twenty-two statistically significant common pathways were related to Cell growth and death, among which the 9 most significant common pathways were related to signalling mediated by EGF (3 databases), ERbB, PDGFR, FGF, hepatocyte growth factor (2 databases), and also apoptosis signalling.	25	41	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ERbB	ERbB	ERbB	27	28	33	34
It has been previously shown that EGF stimulates EGFR mitochondrial import leading to mitochondrial interaction of EGFR with Cox II ; the cellular consequence of the interaction , however , remains unclear [ XREF_BIBR , XREF_BIBR ] .	It has been previously shown that EGF stimulates EGFR mitochondrial import leading to mitochondrial interaction of EGFR with Cox II; the cellular consequence of the interaction, however, remains unclear [XREF_BIBR, XREF_BIBR].	6	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
We next tested whether EGF stimulation induced plasma membrane EGFR depletion leads to new synthesis of EGFR , accounting for the EGFR observed at the ER .	We next tested whether EGF stimulation induced plasma membrane EGFR depletion leads to new synthesis of EGFR, accounting for the EGFR observed at the ER.	4	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	9	10
Furthermore , this article presents results showing that EGF stimulated cell migration and EGFR internalization are regulated by RhoG .	Furthermore, this article presents results showing that EGF stimulated cell migration and EGFR internalization are regulated by RhoG.	8	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	13	14
Transferrin uptake was unaffected in the presence of all of the SH3 domain mutants , consistent with the EGF stimulated EGFR internalization pathway being clathrin independent .	Transferrin uptake was unaffected in the presence of all of the SH3 domain mutants, consistent with the EGF stimulated EGFR internalization pathway being clathrin independent.	15	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
Trapped EGFR Dimers Are Phosphorylated to a Similar Extent as EGF Activated EGFR .	Trapped EGFR Dimers Are Phosphorylated to a Similar Extent as EGF Activated EGFR.	4	13	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
Meanwhile , 8d can significantly block EGF induced EGFR activation and the phosphorylation of its downstream proteins such as Akt and Erk1/2 in human NSCLC cells .	Meanwhile, 8d can significantly block EGF induced EGFR activation and the phosphorylation of its downstream proteins such as Akt and Erk1/2 in human NSCLC cells.	5	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
To test this , we performed a cross linking assay , finding that EGF predominately triggered EGFR homodimerization with a lesser degree of EGFR : GPNMB heterodimerization while HB-EGF stimulated EGFR : GPNMB heterodimerization with less EGFR homodimerization ( XREF_FIG ) .	To test this, we performed a cross linking assay, finding that EGF predominately triggered EGFR homodimerization with a lesser degree of EGFR : GPNMB heterodimerization while HB-EGF stimulated EGFR : GPNMB heterodimerization with less EGFR homodimerization (XREF_FIG).	13	17	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	16	17
Epidermal growth factor ( EGF ) increases Twist transcripts and protein in EGFR expressing lines .	Epidermal growth factor (EGF) increases Twist transcripts and protein in EGFR expressing lines.	2	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	12	13
The mRNA concentration of EGFR in embryos treated with 0.1 ng/ml of EGF was significantly higher than those of the control and other EGF treatment groups .	The mRNA concentration of EGFR in embryos treated with 0.1 ng/ml of EGF was significantly higher than those of the control and other EGF treatment groups.	2	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	4	5
Upon binding , EGF activates the EGF receptor ( EGFR ) , which further activates several intracellular signaling pathways , including the Src kinase which mediates the assembly of the invadopodium precursor and the phosphoinositide-3 kinase ( PI-3K ) , necessary for anchoring the precursor to the cell membrane .	Upon binding, EGF activates the EGF receptor (EGFR), which further activates several intracellular signaling pathways, including the Src kinase which mediates the assembly of the invadopodium precursor and the phosphoinositide-3 kinase (PI-3K), necessary for anchoring the precursor to the cell membrane.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	3	4	6	8
EGF stimulation causes rapid proteolysis of EGFR , which is almost complete in 2 h.	EGF stimulation causes rapid proteolysis of EGFR, which is almost complete in 2 h.	0	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	6	7
Thus , it appears that the effects of ouabain on EGF induced EGFR signaling are not due to nonspecific cytotoxicity but indeed due to inhibition of EGFR signaling .	Thus, it appears that the effects of ouabain on EGF induced EGFR signaling are not due to nonspecific cytotoxicity but indeed due to inhibition of EGFR signaling.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
EGF and TGFalpha elicit distinct biological phenotypes , signalling and receptor trafficking responses downstream of EGFR activation .	EGF and TGFalpha elicit distinct biological phenotypes, signalling and receptor trafficking responses downstream of EGFR activation.	0	16	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	15	16
In this review , we will examine our knowledge on how the mitogen EGF activates the EGFR and its signaling pathways .	In this review, we will examine our knowledge on how the mitogen EGF activates the EGFR and its signaling pathways.	11	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	16	17
Activation of EGFR by EGF enhanced cell proliferation in vitro , but erlotinib decreased proliferation of the U-CH1 and C24 human chordoma cell lines in a dose dependent fashion [ XREF_BIBR , XREF_BIBR ] .	Activation of EGFR by EGF enhanced cell proliferation in vitro, but erlotinib decreased proliferation of the U-CH1 and C24 human chordoma cell lines in a dose dependent fashion [XREF_BIBR, XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	2	3
However , the activated p185neu tyrosine kinases are not able to mimic the EGF stimulated EGF receptor tyrosine kinase in triggering oocyte maturation , which suggests that the EGF receptor and the p185neu tyrosine kinase do not input into identical signal transduction pathways in these cells .	However, the activated p185neu tyrosine kinases are not able to mimic the EGF stimulated EGF receptor tyrosine kinase in triggering oocyte maturation, which suggests that the EGF receptor and the p185neu tyrosine kinase do not input into identical signal transduction pathways in these cells.	12	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	13	14	15	17
In carcinoma cells , a gradient of epidermal growth factor ( EGF ) stimulates EGF receptor ( EGFR ) internalization such that internalized EGFR preferentially accumulates at the side of the cell facing the EGF source .	In carcinoma cells, a gradient of epidermal growth factor (EGF) stimulates EGF receptor (EGFR) internalization such that internalized EGFR preferentially accumulates at the side of the cell facing the EGF source.	7	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	7	10	14	16
Previous studies concluded that stimulation with 100 ng/mL EGF caused EGFR aggregation on the plasma membrane , followed by receptor internalization after longer stimulation times [ XREF_BIBR , XREF_BIBR ] .	Previous studies concluded that stimulation with 100 ng/mL EGF caused EGFR aggregation on the plasma membrane, followed by receptor internalization after longer stimulation times [XREF_BIBR, XREF_BIBR].	4	11	caused	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
The net effect in certain cell types is that GH and EGF can synergize in terms of the pace and extent of signal transduction that they elicit , at least in part by virtue of GH ' s ability to potentiate and sustain EGF induced EGFR signaling [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The net effect in certain cell types is that GH and EGF can synergize in terms of the pace and extent of signal transduction that they elicit, at least in part by virtue of GH 's ability to potentiate and sustain EGF induced EGFR signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR].	40	52	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	43	44	45	46
Interestingly , the content of the acceptor channel is exclusively constituted by the subpopulation of EGFR dimers activated by two EGF molecules ( an EGF-Atto532 and an EGF-Cy5 ) .	Interestingly, the content of the acceptor channel is exclusively constituted by the subpopulation of EGFR dimers activated by two EGF molecules (an EGF-Atto532 and an EGF-Cy5).	15	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	15	16
The activation of EGFR by EGF was unaffected by these inhibitors [ XREF_FIG ] .	The activation of EGFR by EGF was unaffected by these inhibitors [XREF_FIG].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	3	4
This study defines an essential role for the EGF mediated EGFR and ERK signaling in promoting germinative cell proliferation in E. multilocularis .	This study defines an essential role for the EGF mediated EGFR and ERK signaling in promoting germinative cell proliferation in E. multilocularis.	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
This indicated that delta-catenin failed to block the endocytosis of EGFR induced by EGF .	This indicated that delta-catenin failed to block the endocytosis of EGFR induced by EGF.	8	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	10	11
Interestingly , we found that EGF induced EGFR endocytosis is existed differently between gefitinib sensitive and -insensitive lung cancer cell lines .	Interestingly, we found that EGF induced EGFR endocytosis is existed differently between gefitinib sensitive and -insensitive lung cancer cell lines.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
In support of this , we demonstrated that although a single injection of EGF ( 10 microg/kg ) or TGF-alpha ( 5 microg/kg ) in young ( 4-6 mo old ) rats greatly increased membrane associated EGFR tyrosine kinase activity , the same treatment slightly inhibited the enzyme activity in aged ( 24 mo old ) rats .	In support of this, we demonstrated that although a single injection of EGF (10 microg/kg) or TGF-alpha (5 microg/kg) in young (4-6 mo old) rats greatly increased membrane associated EGFR tyrosine kinase activity, the same treatment slightly inhibited the enzyme activity in aged (24 mo old) rats.	11	39	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	36	37
The missing beneficial effect of exogenous EGF administration in these mice further underlines the importance of an intact ligand and EGF-R pathway .	The missing beneficial effect of exogenous EGF administration in these mice further underlines the importance of an intact ligand and EGF-R pathway.	6	21	underlines	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	6	7	20	21
Previously , we and others have shown that epidermal growth factor ( EGF ) stimulates the synthesis of its own receptor and the accumulation of EGF receptor mRNA .	Previously, we and others have shown that epidermal growth factor (EGF) stimulates the synthesis of its own receptor and the accumulation of EGF receptor mRNA.	8	27	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	8	11	25	27
This model system allowed the comparison of EGF activated ErbB-1 with ErbB-1 activated by Neu differentiation factor ( NDF )-induced heterodimerization with ErbB-4 .	This model system allowed the comparison of EGF activated ErbB-1 with ErbB-1 activated by Neu differentiation factor (NDF)-induced heterodimerization with ErbB-4.	5	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	7	8	9	10
Previous reports have indicated that tethering of EGF can inhibit degradation of EGFR [ XREF_BIBR ] , which we observe here .	Previous reports have indicated that tethering of EGF can inhibit degradation of EGFR [XREF_BIBR], which we observe here.	5	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	12	13
To extend the role of TIP30 in the mouse lung to human lung adenocarcinoma cells , we knocked down TIP30 expression in human lung adenocarcinoma A549 cells using two shRNAs that specifically target TIP30 ( XREF_FIG ) and performed endocytic degradation assays to examine EGF induced EGFR endocytic degradation and signaling .	To extend the role of TIP30 in the mouse lung to human lung adenocarcinoma cells, we knocked down TIP30 expression in human lung adenocarcinoma A549 cells using two shRNAs that specifically target TIP30 (XREF_FIG) and performed endocytic degradation assays to examine EGF induced EGFR endocytic degradation and signaling.	43	50	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	44	45	46	47
Because EGF induces both degradation and the recycling of EGFR , we also assayed EGFR recycling in response to TGFalpha , an EGFR ligand that promotes EGFR recycling without substantial degradation .	Because EGF induces both degradation and the recycling of EGFR, we also assayed EGFR recycling in response to TGFalpha, an EGFR ligand that promotes EGFR recycling without substantial degradation.	1	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	9	10
We found that depolymerizing the F-actin and microtubule networks by treating cells with Latrunculin A XREF_BIBR or Nocodazol XREF_BIBR , or altering the size of plasma membrane domains by treating cells with Nystatin or MbetaCD , have significant effects on the size of the plasma membrane compartments in which EGFR diffuses ( XREF_SUPPLEMENTARY ) , the rate of EGF induced oligomerisation ( XREF_SUPPLEMENTARY ) , and the half-life of EGFR complexes ( XREF_SUPPLEMENTARY ) .	We found that depolymerizing the F-actin and microtubule networks by treating cells with Latrunculin A XREF_BIBR or Nocodazol XREF_BIBR, or altering the size of plasma membrane domains by treating cells with Nystatin or MbetaCD, have significant effects on the size of the plasma membrane compartments in which EGFR diffuses (XREF_SUPPLEMENTARY), the rate of EGF induced oligomerisation (XREF_SUPPLEMENTARY), and the half-life of EGFR complexes (XREF_SUPPLEMENTARY).	56	70	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	58	59	69	70
EGFR may be activated by EGF family ligands such as EGF and epiregulin ( EREG ) .	EGFR may be activated by EGF family ligands such as EGF and epiregulin (EREG).	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	0	1
The epidermal growth factor receptor ( EGFR ) is activated by extracellular ligands of the epidermal growth factor ( EGF ) family , resulting in a cascade of cytoplasmic signaling events .	The epidermal growth factor receptor (EGFR) is activated by extracellular ligands of the epidermal growth factor (EGF) family, resulting in a cascade of cytoplasmic signaling events.	1	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	15	18	1	5
In addition , we found that the treatments significantly inhibited mRNA levels of ErbB1 ligands , EGF and HB-EGF ( XREF_FIG ) , indicating ligand induced transactivation of ErbB2 and ErbB1 as a critical target of the treatment .	In addition, we found that the treatments significantly inhibited mRNA levels of ErbB1 ligands, EGF and HB-EGF (XREF_FIG), indicating ligand induced transactivation of ErbB2 and ErbB1 as a critical target of the treatment.	14	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	16	17	30	31
EGF stimulation increases EGFR tyrosine kinase activity and ERK1/2 activity , resulting in increased ADAM17 mediated cleavage of LAR [ XREF_BIBR ] .	EGF stimulation increases EGFR tyrosine kinase activity and ERK1/2 activity, resulting in increased ADAM17 mediated cleavage of LAR [XREF_BIBR].	0	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	3	4
Although further work is needed to define the precise molecular mechanisms of EGFR internalization and degradation , the accumulated evidence suggests the following model of EGF induced EGFR endocytosis : EGFR that is autophosphorylated at Y1045 within its C-terminal domain recruits and interacts with the TKB domain of c-Cbl .	Although further work is needed to define the precise molecular mechanisms of EGFR internalization and degradation, the accumulated evidence suggests the following model of EGF induced EGFR endocytosis : EGFR that is autophosphorylated at Y1045 within its C-terminal domain recruits and interacts with the TKB domain of c-Cbl.	23	28	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	27	28
To determine the effect of EGF and EGF mediated activation of EGFR on viable cell numbers we again used AG1478 .	To determine the effect of EGF and EGF mediated activation of EGFR on viable cell numbers we again used AG1478.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	11	12
These data obtained from the TR-EGF trafficking assays are in agreement with the results of our 125 I-EGF degradation assays ( XREF_FIG ) , and suggest that Trak1 regulates EGF induced EGFR trafficking from the early endosome to the lysosome in an Hrs dependent manner .	These data obtained from the TR-EGF trafficking assays are in agreement with the results of our 125 I-EGF degradation assays (XREF_FIG), and suggest that Trak1 regulates EGF induced EGFR trafficking from the early endosome to the lysosome in an Hrs dependent manner.	28	32	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	31	32
Morphine and EGF induced EGFR co-activation and downstream signaling are abrogated by naloxone and erlotinib .	Morphine and EGF induced EGFR co-activation and downstream signaling are abrogated by naloxone and erlotinib.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
Interestingly , PKC dependent phosphorylation of EGFR T654 blocks EGF induced EGFR activation [ XREF_BIBR ] .	Interestingly, PKC dependent phosphorylation of EGFR T654 blocks EGF induced EGFR activation [XREF_BIBR].	8	12	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
However , our present study indeed finds Lycorine reduces the mRNA level of EGF and EGFR in vivo and down-regulates both total EGFR and p-EGFR in vitro .	However, our present study indeed finds Lycorine reduces the mRNA level of EGF and EGFR in vivo and down-regulates both total EGFR and p-EGFR in vitro.	7	24	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	Lycorine reduces the mRNA level of EGF	egf	EGFR	EGFR	egfr	13	14	22	23
Epithelium renewal of the Drosophila gut is stimulated by the release of secreted ligands of the Unpaired and EGF families , which activate respectively the JAK and STAT and EGFR pathways in stem-cell like progenitor cells to promote their division and differentiation , thereby establishing compensatory homeostatic regulatory loops XREF_BIBR , XREF_BIBR .	Epithelium renewal of the Drosophila gut is stimulated by the release of secreted ligands of the Unpaired and EGF families, which activate respectively the JAK and STAT and EGFR pathways in stem-cell like progenitor cells to promote their division and differentiation, thereby establishing compensatory homeostatic regulatory loops XREF_BIBR, XREF_BIBR.	18	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	29	30
HDAC6 becomes phosphorylated at Y570 by EGFR following activation by the EGF ligand .	HDAC6 becomes phosphorylated at Y570 by EGFR following activation by the EGF ligand.	6	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	6	7
A requirement for ERalpha in EGF stimulated EGFR activation and DNA-synthesis is also demonstrated in MCF7 breast cancer cells [ XREF_BIBR ] .	A requirement for ERalpha in EGF stimulated EGFR activation and DNA-synthesis is also demonstrated in MCF7 breast cancer cells [XREF_BIBR].	3	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Immunoprecipitation experiments further confirmed that there is a preferential interaction of PTPRG-mCitrine with ligandless EGFR over liganded EGFR activated by EGF , whereas PTPRJ constitutively interacts with both species ( XREF_SUPPLEMENTARY H ) .	Immunoprecipitation experiments further confirmed that there is a preferential interaction of PTPRG-mCitrine with ligandless EGFR over liganded EGFR activated by EGF, whereas PTPRJ constitutively interacts with both species (XREF_SUPPLEMENTARY H).	14	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	17	18
Furthermore , these effects appear to be Src specific because CD2 expression had no effect on EGF induced activation of EGF receptor and ERK .	Furthermore, these effects appear to be Src specific because CD2 expression had no effect on EGF induced activation of EGF receptor and ERK.	14	22	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	16	17	20	22
Three lines of evidence suggest that EGFR activation by EGF is responsible for the protective effects of breast milk on enterocyte apoptosis and proliferation .	Three lines of evidence suggest that EGFR activation by EGF is responsible for the protective effects of breast milk on enterocyte apoptosis and proliferation.	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	6	7
To analyze the influence of Fas survival pathways on the EGFR signaling in cancer , we examined the EGF induced activation of EGFR in two KRAS mutated , cetuximab resistant colorectal cancer cells , SW480 and HCT116 .	To analyze the influence of Fas survival pathways on the EGFR signaling in cancer, we examined the EGF induced activation of EGFR in two KRAS mutated, cetuximab resistant colorectal cancer cells, SW480 and HCT116.	17	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	22	23
EGF stimulation induced interactions of DOK2 and wild-type EGFR and RASA1 ( XREF_FIG ) .	EGF stimulation induced interactions of DOK2 and wild-type EGFR and RASA1 (XREF_FIG).	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	8	9
Consistent with previous data , we observed that overexpression of PTPRS in HK2 cells using an adenoviral vector dampened basal EGFR phosphorylation and weakly antagonized EGF induced activation of EGFR ( XREF_SUPPLEMENTARY ) .	Consistent with previous data, we observed that overexpression of PTPRS in HK2 cells using an adenoviral vector dampened basal EGFR phosphorylation and weakly antagonized EGF induced activation of EGFR (XREF_SUPPLEMENTARY).	25	31	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	29	30
Furthermore , boehmenan concentration-dependently inhibited EGF induced activation of EGFR and its downstream signaling molecules , including MEK , Akt , ERK1/2 , and STAT3 .	Furthermore, boehmenan concentration-dependently inhibited EGF induced activation of EGFR and its downstream signaling molecules, including MEK, Akt, ERK1/2, and STAT3.	5	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	9	10
Addition of cholesterol was found to reduce EGF binding and reduce EGF induced EGFR activation .	Addition of cholesterol was found to reduce EGF binding and reduce EGF induced EGFR activation.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
In the present study , we examined EGF induced internalization , degradation and trafficking of the epidermal growth factor receptor ( EGFR ) mutated at serines 1046 , 1047 , 1057 and 1142 located in its cytoplasmic carboxy-terminal region .	In the present study, we examined EGF induced internalization, degradation and trafficking of the epidermal growth factor receptor (EGFR) mutated at serines 1046, 1047, 1057 and 1142 located in its cytoplasmic carboxy-terminal region.	7	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	7	8	16	20
We conclude that contrary to the dogma , EGFR is activated by EGF during mitosis .	We conclude that contrary to the dogma, EGFR is activated by EGF during mitosis.	8	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	8	9
EGF stimulated EGF receptor ( EGFR ) auto-phosphorylation was very similar across the relevant knockdown and knockout cell lines ( XREF_SUPPLEMENTARY C ) .	EGF stimulated EGF receptor (EGFR) auto-phosphorylation was very similar across the relevant knockdown and knockout cell lines (XREF_SUPPLEMENTARY C).	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	2	4
While EGF first stimulates the activation of the EGFR and subsequently increases cancer cell proliferation , EGF concurrently induces the activation of ROCK , which then turns off the activated EGFR pathway via a negative feedback system .	While EGF first stimulates the activation of the EGFR and subsequently increases cancer cell proliferation, EGF concurrently induces the activation of ROCK, which then turns off the activated EGFR pathway via a negative feedback system.	1	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	8	9
These previous study showed that various EGFR signaling pathways including ERK pathway is well activated following the stimulation of EGFR by EGF in CHO cells XREF_BIBR , XREF_BIBR .	These previous study showed that various EGFR signaling pathways including ERK pathway is well activated following the stimulation of EGFR by EGF in CHO cells XREF_BIBR, XREF_BIBR.	17	25	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	19	20
In the presence of CTEN , we found that EGF treatment elevated the level of EGFR protein but not mRNA .	In the presence of CTEN, we found that EGF treatment elevated the level of EGFR protein but not mRNA.	9	16	elevated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	15	16
XREF_BIBR Enhanced microtubule stability leads to the recruitment of molecular motors kinesin-1 and cytoplasmic dynein to microtubules thereby stimulating anterograde and retrograde vesicle transport including EGF stimulated EGFR .	XREF_BIBR Enhanced microtubule stability leads to the recruitment of molecular motors kinesin-1 and cytoplasmic dynein to microtubules thereby stimulating anterograde and retrograde vesicle transport including EGF stimulated EGFR.	23	28	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	27	28
EGF and HB-EGF were tested for their potential to activate ERBB receptors in purified EGFR ( + ) and HLA-G ( + ) trophoblasts .	EGF and HB-EGF were tested for their potential to activate ERBB receptors in purified EGFR (+) and HLA-G (+) trophoblasts.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ERBB	ERBB	ERBB	0	1	10	11
JM Cys Cys EGFR Variants are Present at the Cell Surface and Activated by EGF .	JM Cys Cys EGFR Variants are Present at the Cell Surface and Activated by EGF.	3	15	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	3	4
The Vav family of RhoGEFs is an example of a group of GEFs that are activated in response to EGF stimulation of EGFR [ XREF_BIBR , XREF_BIBR ] .	The Vav family of RhoGEFs is an example of a group of GEFs that are activated in response to EGF stimulation of EGFR [XREF_BIBR, XREF_BIBR].	19	26	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	22	23
Endocytosis of EGFR triggered by the binding of EGF continues during the maturation of early endosomes into either late endosomes or lysosomes , resulting in a dramatic decrease in cell surface EGFR and total cellular EGFR as part of the mechanism of ligand induced receptor downregulation XREF_BIBR .	Endocytosis of EGFR triggered by the binding of EGF continues during the maturation of early endosomes into either late endosomes or lysosomes, resulting in a dramatic decrease in cell surface EGFR and total cellular EGFR as part of the mechanism of ligand induced receptor downregulation XREF_BIBR.	0	9	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	2	3
To mechanistically evaluate the role of MOR on EGF induced EGFR dynamics , we treated H358 cells with EGF at various times and immunoprecipitated the EGFR to determine potential MOR association .	To mechanistically evaluate the role of MOR on EGF induced EGFR dynamics, we treated H358 cells with EGF at various times and immunoprecipitated the EGFR to determine potential MOR association.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
EGF is a well known ligand of EGFR and has been shown to stimulate the activity of EGFR ; therefore , the head and neck cutaneous SCC13 cells were treated with EGF ( 10 ng/ml ) for EGFR stimulation , and thereafter determined the effect of EGF on the invasion of SCC13 cells .	EGF is a well known ligand of EGFR and has been shown to stimulate the activity of EGFR; therefore, the head and neck cutaneous SCC13 cells were treated with EGF (10 ng/ml) for EGFR stimulation, and thereafter determined the effect of EGF on the invasion of SCC13 cells.	0	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	17	18
Mutations in the N-lobe ( I706Q ) or C-lobe ( V948R ) region of the asymmetric kinase dimer interface have been shown to impair EGF induced activation of WT EGFR in cells XREF_BIBR , XREF_BIBR .	Mutations in the N-lobe (I706Q) or C-lobe (V948R) region of the asymmetric kinase dimer interface have been shown to impair EGF induced activation of WT EGFR in cells XREF_BIBR, XREF_BIBR.	24	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	29	30
Cotransfection of EGFR resulted in an increase of reporter activity , with DeltaEGFR and with EGF stimulated EGFR resulting in higher levels than EGFR under serum starved condition .	Cotransfection of EGFR resulted in an increase of reporter activity, with DeltaEGFR and with EGF stimulated EGFR resulting in higher levels than EGFR under serum starved condition.	14	18	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
To begin to explore the basis for the oncogenic signaling network mediated by AREG and EGFR in our model cell lines , we studied the influence of AREG versus EGF activation of EGFR in MCF-10A cells and SUM-149 cells on proliferation , signaling properties , and gene expression .	To begin to explore the basis for the oncogenic signaling network mediated by AREG and EGFR in our model cell lines, we studied the influence of AREG versus EGF activation of EGFR in MCF-10A cells and SUM-149 cells on proliferation, signaling properties, and gene expression.	29	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	32	33
Second , it is demonstrated that expression of the NCAM-180 isoform induces EGFR down-regulation in transfected cells and promotes EGFR down-regulation induced by EGF stimulation .	Second, it is demonstrated that expression of the NCAM-180 isoform induces EGFR down-regulation in transfected cells and promotes EGFR down-regulation induced by EGF stimulation.	19	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	19	20
In this report we show that EGF and EGF-dextran differentially activate the EGFR .	In this report we show that EGF and EGF-dextran differentially activate the EGFR.	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	12	13
In addition to potentiating effects on signaling offered by ErbB-2 , heterodimerization of EGFR with ErbB-2 is known to dampen EGF induced EGFR downregulation [ XREF_BIBR , XREF_BIBR ] .	In addition to potentiating effects on signaling offered by ErbB-2, heterodimerization of EGFR with ErbB-2 is known to dampen EGF induced EGFR downregulation [XREF_BIBR, XREF_BIBR].	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
However , EGF dependent activation of the EGFR ( i.e ., autophosphorylation ) has not been detected in yeast cells , probably because the yeast cell wall prevents EGF from accessing the ligand binding domain of the EGFR .	However, EGF dependent activation of the EGFR (i.e., autophosphorylation) has not been detected in yeast cells, probably because the yeast cell wall prevents EGF from accessing the ligand binding domain of the EGFR.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	7	8
EGF induced EGFR activation has been shown to promote tumor cell migration .	EGF induced EGFR activation has been shown to promote tumor cell migration.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
EGF stimulation increases EGFR transport efficiency .	EGF stimulation increases EGFR transport efficiency.	0	5	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	3	4
These studies demonstrate that the EGF- and TGF-alpha-induced upregulation of EGFR mRNA and protein in human prostate cancer cell lines is complex and occurs at multiple , transcriptional and post-transcriptional levels .	These studies demonstrate that the EGF- and TGF-alpha-induced upregulation of EGFR mRNA and protein in human prostate cancer cell lines is complex and occurs at multiple, transcriptional and post-transcriptional levels.	5	11	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF-	EGF-	EGF-	EGFR	EGFR	EGFR	5	6	10	11
Although we previously showed that ECM1 enhanced EGF dependent activation of EGFR , we needed to check the effect of ECM1 on EGFR and HER3 expression because we found that EGFR and HER3 expression were increased in BT-474 TR cells compared with parental BT-474 cells ( Additional file 3 : Figure S2C ) .	Although we previously showed that ECM1 enhanced EGF dependent activation of EGFR, we needed to check the effect of ECM1 on EGFR and HER3 expression because we found that EGFR and HER3 expression were increased in BT-474 TR cells compared with parental BT-474 cells (Additional file 3 : Figure S2C).	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	11	12
The EGF like repeats of TSP1 activate the epidermal growth factor receptor ( EGFR ) and ErbB2 and these two receptor protein tyrosine kinase ( PTK ) s participate in ZA protein tyrosine phosphorylation and barrier disruption in response to the TSP1 stimulus .	The EGF like repeats of TSP1 activate the epidermal growth factor receptor (EGFR) and ErbB2 and these two receptor protein tyrosine kinase (PTK) s participate in ZA protein tyrosine phosphorylation and barrier disruption in response to the TSP1 stimulus.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	1	2	8	12
However , it is notable that even in the context of ErbB-2 coexpression , blockade of ERK activity in C14 cells enhanced EGF induced EGFR downregulation significantly .	However, it is notable that even in the context of ErbB-2 coexpression, blockade of ERK activity in C14 cells enhanced EGF induced EGFR downregulation significantly.	22	25	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
Epidermal growth factor ( EGF )/DNA complexes targeted to cancer cells overexpressing the EGF receptor resulted in efficient transduction of several lung cancer cell lines in vitro .	Epidermal growth factor (EGF)/DNA complexes targeted to cancer cells overexpressing the EGF receptor resulted in efficient transduction of several lung cancer cell lines in vitro.	0	15	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epidermal growth factor	Epidermal growth factor	Epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	0	3	13	15
In XREF_FIG , the data show that ligand production was inhibited by exposure to a 0.4 mT power frequency MF , indicating that all of the above effects we observed were not simply due to increased EGF production in the EGFR upstream pathway .	In XREF_FIG, the data show that ligand production was inhibited by exposure to a 0.4 mT power frequency MF, indicating that all of the above effects we observed were not simply due to increased EGF production in the EGFR upstream pathway.	36	42	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	36	37	40	41
In these cells , EGFR was constitutively detected with the ERK consensus site phosphorylation specific antibody and EGF induced EGFR downregulation was modest , but was substantially enhanced by pretreatment with MEK1 and ERK inhibitor .	In these cells, EGFR was constitutively detected with the ERK consensus site phosphorylation specific antibody and EGF induced EGFR downregulation was modest, but was substantially enhanced by pretreatment with MEK1 and ERK inhibitor.	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
Tyr1068 is a common residue of EGFR that is phosphorylated when EGFR is activated by EGF [ XREF_BIBR - XREF_BIBR ] .	Tyr1068 is a common residue of EGFR that is phosphorylated when EGFR is activated by EGF [XREF_BIBR - XREF_BIBR].	11	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	11	12
We showed that graduate truncation of EGFR from C-terminus to 1044 did not affect EGF induced EGFR endocytosis with or without kinase activation .	We showed that graduate truncation of EGFR from C-terminus to 1044 did not affect EGF induced EGFR endocytosis with or without kinase activation.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
Cross linking experiments confirm that EGF but not nucleolin can induce dimerization of the ErbB1 DeltaNLS receptor mutant ( XREF_FIG ) .	Cross linking experiments confirm that EGF but not nucleolin can induce dimerization of the ErbB1 DeltaNLS receptor mutant (XREF_FIG).	5	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	5	6	14	15
17 Together these data confirm that EGF mediated activation of EGFR results in its redistribution to the detergent-insoluble fraction and are consistent with EGFR being tethered to the actin cytoskeleton upon activation .	17 Together these data confirm that EGF mediated activation of EGFR results in its redistribution to the detergent-insoluble fraction and are consistent with EGFR being tethered to the actin cytoskeleton upon activation.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	10	11
XREF_BIBR Similar findings have been reported in MCF7 cells in which moderate doses of luteolin abolished EGF induced increased pEGFR , Akt , and ERK kinase activity , as well as the transcription factor STAT3 .	XREF_BIBR Similar findings have been reported in MCF7 cells in which moderate doses of luteolin abolished EGF induced increased pEGFR, Akt, and ERK kinase activity, as well as the transcription factor STAT3.	16	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	16	17	19	20
Significant EGFR down-regulation in cells treated with high EGF concentrations ( 20 to 100 ng/ml ) is observed beginning at 15 to 20 min after EGF stimulation .	Significant EGFR down-regulation in cells treated with high EGF concentrations (20 to 100 ng/ml) is observed beginning at 15 to 20 min after EGF stimulation.	1	9	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	1	2
Furthermore , pretreatment of murine 3T3-F442A preadipocytes with GH [ XREF_BIBR , XREF_BIBR ] or human T47D breast cancer cells with PRL [ XREF_BIBR ] blunted EGFR downregulation induced by subsequent EGF treatment and these effects of GH or PRL were also prevented by ERK inhibitors .	Furthermore, pretreatment of murine 3T3-F442A preadipocytes with GH [XREF_BIBR, XREF_BIBR] or human T47D breast cancer cells with PRL [XREF_BIBR] blunted EGFR downregulation induced by subsequent EGF treatment and these effects of GH or PRL were also prevented by ERK inhibitors.	26	32	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	31	32	26	27
Indeed , administration of non toxic doses of chloroquine ( i.e ., 10 microM ) ( XREF_FIG ) , which are effective in blocking the lysosomal dependent EGF induced EGF-R degradation { ( XREF_FIG ) and XREF_BIBR } , partially prevents the dose- ( XREF_FIG ) and time dependent ( XREF_FIG and XREF_SUPPLEMENTARY ) E2 induced ERalpha degradation in breast cancer cells .	Indeed, administration of non toxic doses of chloroquine (i.e., 10 microM) (XREF_FIG), which are effective in blocking the lysosomal dependent EGF induced EGF-R degradation {(XREF_FIG) and XREF_BIBR}, partially prevents the dose- (XREF_FIG) and time dependent (XREF_FIG and XREF_SUPPLEMENTARY) E2 induced ERalpha degradation in breast cancer cells.	23	30	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	27	28	29	30
At 10 min after EGF stimulation EGFR had reached EEA1 endosomes scattered throughout the cytoplasm in both controls and Galphas depleted cells ( XREF_FIG ) .	At 10 min after EGF stimulation EGFR had reached EEA1 endosomes scattered throughout the cytoplasm in both controls and Galphas depleted cells (XREF_FIG).	2	8	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
In this report , EGF stimulation of the EGFR resulted in endocytosis of the EGFR and interaction with importin beta , via its tripartite NLS .	In this report, EGF stimulation of the EGFR resulted in endocytosis of the EGFR and interaction with importin beta, via its tripartite NLS.	4	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	8	9
39 Similarly , resistance to Raf inhibition can result from upregulated levels of EGF , which activates EGFR , and drives downstream pathway activation in BRAF V600E mutant lung adenocarcinoma .	39 Similarly, resistance to Raf inhibition can result from upregulated levels of EGF, which activates EGFR, and drives downstream pathway activation in BRAF V600E mutant lung adenocarcinoma.	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	levels of EGF	egf	EGFR	EGFR	egfr	13	14	17	18
Here we used monoclonal antibody as the targeting ligand , which is much slower than the EGF targeted EGFR endocytosis [ XREF_BIBR ] .	Here we used monoclonal antibody as the targeting ligand, which is much slower than the EGF targeted EGFR endocytosis [XREF_BIBR].	12	19	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
The levels were slightly higher in cKO relative to WT P2 epidermis , and this and/or other EGF signaling molecules could enhance the effects of elevated EGFR in neonatal cKO mice .	The levels were slightly higher in cKO relative to WT P2 epidermis, and this and/or other EGF signaling molecules could enhance the effects of elevated EGFR in neonatal cKO mice.	17	27	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	26	27
We report here that SEPW1 is required for EGF induced EGFR activation and that it functions by suppressing EGFR ubiquitination and receptor degradation .	We report here that SEPW1 is required for EGF induced EGFR activation and that it functions by suppressing EGFR ubiquitination and receptor degradation.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
EGF stimulated EGFR , which is also endocytosed into EEA1 + early endosomes and then delivered to the lysosome for degradation , shows little costaining with lysosomal markers unless the cells are incubated with lysosomal enzyme inhibitors to prevent receptor degradation .	EGF stimulated EGFR, which is also endocytosed into EEA1 + early endosomes and then delivered to the lysosome for degradation, shows little costaining with lysosomal markers unless the cells are incubated with lysosomal enzyme inhibitors to prevent receptor degradation.	0	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Here , we describe an association of 14-3-3zeta with the epidermal growth factor receptor ( EGFR ) that is rapidly induced by EGF .	Here, we describe an association of 14-3-3zeta with the epidermal growth factor receptor (EGFR) that is rapidly induced by EGF.	10	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	22	23	10	14
The EGF activated EGFR is distributed over the entire cellular surface .	The EGF activated EGFR is distributed over the entire cellular surface.	0	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
EGF drives EGFR internalization and activates its downstream signaling pathways , so we examined whether EGF treatment could increase PS-ASO activity in A431 cells .	EGF drives EGFR internalization and activates its downstream signaling pathways, so we examined whether EGF treatment could increase PS-ASO activity in A431 cells.	0	3	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
EGFR positive MDA-MB-468 and BT-20 cells were treated with EGF for 24 h. Immunoblotting showed that EGF treatment induced FOXC1 protein expression ( XREF_FIG ) .	EGFR positive MDA-MB-468 and BT-20 cells were treated with EGF for 24 h. Immunoblotting showed that EGF treatment induced FOXC1 protein expression (XREF_FIG).	0	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	0	1
First , in co-immune-precipitation experiment we observed that EGF stimulation of quiescent HT1080 cells induces association of EGF-R with AR and Src ( lower panel in XREF_FIG ) .	First, in co-immune-precipitation experiment we observed that EGF stimulation of quiescent HT1080 cells induces association of EGF-R with AR and Src (lower panel in XREF_FIG).	8	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	8	9	17	18
Cells treated with EGF alone showed a significant increase in the level of phosphorylated EGFR ; nevertheless , after the addition of mS100A4 , the EGFR phosphorylation level was higher than that observed in cells treated with EGF alone .	Cells treated with EGF alone showed a significant increase in the level of phosphorylated EGFR; nevertheless, after the addition of mS100A4, the EGFR phosphorylation level was higher than that observed in cells treated with EGF alone.	25	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	37	38	25	26
Ectopically expressed Ankrd 13A , 13B , and 13D bind to EGF activated EGFR directly in a UIM dependent manner .	Ectopically expressed Ankrd 13A, 13B, and 13D bind to EGF activated EGFR directly in a UIM dependent manner.	9	14	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Given the critical role of endosome-to-lysosome trafficking in the attenuation of EGFR signaling , we examined whether SIMPLE depletion could affect the mitogen activated protein ( MAP ) kinase signaling downstream of EGF activated EGFR .	Given the critical role of endosome-to-lysosome trafficking in the attenuation of EGFR signaling, we examined whether SIMPLE depletion could affect the mitogen activated protein (MAP) kinase signaling downstream of EGF activated EGFR.	29	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	32	33	34	35
Consistently , endocytosis of EGFR induced by 15 ng/ml of EGF was similarly inhibited by Tom1L1 and Y460 ( XREF_SUPPLEMENTARY , second panel ) to a level comparable to the inhibition observed in cells stimulated with 100 ng/ml of EGF ( XREF_SUPPLEMENTARY , third panel ) .	Consistently, endocytosis of EGFR induced by 15 ng/ml of EGF was similarly inhibited by Tom1L1 and Y460 (XREF_SUPPLEMENTARY, second panel) to a level comparable to the inhibition observed in cells stimulated with 100 ng/ml of EGF (XREF_SUPPLEMENTARY, third panel).	2	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	4	5
Anisomycin and EGF employ different mechanisms to promote EGFR endocytosis as anisomycin induced internalization does not require tyrosine kinase activity or ubiquitination of the receptor .	Anisomycin and EGF employ different mechanisms to promote EGFR endocytosis as anisomycin induced internalization does not require tyrosine kinase activity or ubiquitination of the receptor.	0	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	8	9
The bond of EGF with its receptor stimulates tyrosine kinase domain of EGFR and allows transduction of an activating signal .	The bond of EGF with its receptor stimulates tyrosine kinase domain of EGFR and allows transduction of an activating signal.	1	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	12	13
These turnover rates can be dramatically accelerated if EGFR is activated by EGF or other ligands .	These turnover rates can be dramatically accelerated if EGFR is activated by EGF or other ligands.	8	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	8	9
ST6Gal-I overexpression in OV4 ovarian cancer cells increases basal and EGF induced EGFR activation .	ST6Gal-I overexpression in OV4 ovarian cancer cells increases basal and EGF induced EGFR activation.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
EGF induced activation of ErbB1 receptors leads to the formation of receptor homo- and heterodimers [ XREF_BIBR , XREF_BIBR ] .	EGF induced activation of ErbB1 receptors leads to the formation of receptor homo- and heterodimers [XREF_BIBR, XREF_BIBR].	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	0	1	4	5
EGFR activation by EGF did not induce cell proliferation .	EGFR activation by EGF did not induce cell proliferation.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	0	1
While this experiment does show that clusters form when EGFR expressing cells are treated with soluble EGF , any further comparison is not possible due to the inherent differences between tethered and soluble ligand .	While this experiment does show that clusters form when EGFR expressing cells are treated with soluble EGF, any further comparison is not possible due to the inherent differences between tethered and soluble ligand.	9	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	9	10
Recently , Anks1a was shown to increase EGF induced EGFR internalization from the plasma membrane into recycling endosomes while blocking its routing to the lysosome XREF_BIBR .	Recently, Anks1a was shown to increase EGF induced EGFR internalization from the plasma membrane into recycling endosomes while blocking its routing to the lysosome XREF_BIBR.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
EGFR was however activated by its specific ligand EGF .	EGFR was however activated by its specific ligand EGF.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	0	1
In their seminal analysis of the activation of EGFR by EGF , Yarden and Schlessinger showed that the addition of EGF to EGFR results in the formation of dimers or higher-order multimers in cells .	In their seminal analysis of the activation of EGFR by EGF, Yarden and Schlessinger showed that the addition of EGF to EGFR results in the formation of dimers or higher-order multimers in cells.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	8	9
We found that overexpression of Hrs was unable to rescue the EGF induced EGFR degradation defect in SIMPLE depleted cells .	We found that overexpression of Hrs was unable to rescue the EGF induced EGFR degradation defect in SIMPLE depleted cells.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
On the other hand , EGF induced activation of the EGF-R in C9 cells was found to cause phosphorylation of the AT ( 1 )-R .	On the other hand, EGF induced activation of the EGF-R in C9 cells was found to cause phosphorylation of the AT (1)-R.	5	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	5	6	10	11
Anyhow , our findings prove that Lycorine inhibits EGF activation of EGFR kinase activity .	Anyhow, our findings prove that Lycorine inhibits EGF activation of EGFR kinase activity.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	11	12
VJ downregulates EGF induced EGFR signaling in lung cancer .	VJ downregulates EGF induced EGFR signaling in lung cancer.	1	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
However , purified His MIF was unable to block EGF induced EGFR activation ( XREF_SUPPLEMENTARY ) , suggesting that bacterially expressed His MIF may not have the same structure or post-translational modification as its mammalian homologue from cells .	However, purified His MIF was unable to block EGF induced EGFR activation (XREF_SUPPLEMENTARY), suggesting that bacterially expressed His MIF may not have the same structure or post-translational modification as its mammalian homologue from cells.	8	17	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
EGF induces dimerization of EGFR by binding to the extracellular region of the receptor , which leads to a 2:2 EGF-EGFR ( XREF_FIG ) .	EGF induces dimerization of EGFR by binding to the extracellular region of the receptor, which leads to a 2:2 EGF-EGFR (XREF_FIG).	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
However , the mechanism ( s ) involved in EGF mediated EGFR stability and endocytic trafficking in cystic epithelial cells is unknown .	However, the mechanism (s) involved in EGF mediated EGFR stability and endocytic trafficking in cystic epithelial cells is unknown.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
The mechanism through which PKGII blocks the EGF induced activation of EGFR was preliminarily investigated in this experiment .	The mechanism through which PKGII blocks the EGF induced activation of EGFR was preliminarily investigated in this experiment.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	11	12
As expected , the antiparallel structure for EGF activated EGFR that was proposed by Jura et al ..	As expected, the antiparallel structure for EGF activated EGFR that was proposed by Jura et al..	5	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Moreover , in non small cell lung cancer , EGFR activation by EGF resulted in cell migration stimulation but it did not promote cell proliferation [ XREF_BIBR ] .	Moreover, in non small cell lung cancer, EGFR activation by EGF resulted in cell migration stimulation but it did not promote cell proliferation [XREF_BIBR].	9	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	9	10
The EGF dependent activation of the EGFR has been reported to be inhibited in an E-cadherin adhesion dependent manner , which inhibits the ligand dependent activation of diverse receptor tyrosine kinases .	The EGF dependent activation of the EGFR has been reported to be inhibited in an E-cadherin adhesion dependent manner, which inhibits the ligand dependent activation of diverse receptor tyrosine kinases.	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	6	7
Moreover , TFV ORF080L interacted with human and zebrafish LITAF and impaired EGF induced EGFR degradation , thereby indicating that TFV ORF080L played a role in endosome-to-lysosome trafficking .	Moreover, TFV ORF080L interacted with human and zebrafish LITAF and impaired EGF induced EGFR degradation, thereby indicating that TFV ORF080L played a role in endosome-to-lysosome trafficking.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
In contrast , EGF- or HGF activated growth of HT29 and BcPAP cells was suppressed by MEDICA , with decrease in EGF activated phospho-EGFR ( Tyr1068 ) , phospho-ErbB2 ( Tyr1248 ) , phospho-Akt ( Ser473 ) and phospho-Erk ( Tyr204 ) , as well as in HGF activated phospho-Met ( Tyr1234 ) .	In contrast, EGF- or HGF activated growth of HT29 and BcPAP cells was suppressed by MEDICA, with decrease in EGF activated phospho-EGFR (Tyr1068), phospho-ErbB2 (Tyr1248), phospho-Akt (Ser473) and phospho-Erk (Tyr204), as well as in HGF activated phospho-Met (Tyr1234).	19	40	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	phospho-EGFR	phospho-EGFR	phospho-EGFR	21	22	23	24
Furthermore , GH cotreatment with EGF markedly slowed EGF induced EGFR degradation and down-regulation , thereby potentiating EGF induced EGFR signaling .	Furthermore, GH cotreatment with EGF markedly slowed EGF induced EGFR degradation and down-regulation, thereby potentiating EGF induced EGFR signaling.	16	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
In addition to EGF activating EGFR , other factors , such as HB-EGF , Ang II , and aldosterone , are known to transactivate EGFR XREF_BIBR , XREF_BIBR , XREF_BIBR .	In addition to EGF activating EGFR, other factors, such as HB-EGF, Ang II, and aldosterone, are known to transactivate EGFR XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	21	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Furthermore , increased CXCR7 expression also led to , constitutively and rapidly , EGF induced increase of p-EGFR ( XREF_FIG ) .	Furthermore, increased CXCR7 expression also led to, constitutively and rapidly, EGF induced increase of p-EGFR (XREF_FIG).	13	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	p-EGFR	p-EGFR	p-EGFR	13	14	17	18
EGF induces cell proliferation by activating the tyrosine kinase receptor EGFR , which transiently activates the ERK and AKT pathways XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	EGF induces cell proliferation by activating the tyrosine kinase receptor EGFR, which transiently activates the ERK and AKT pathways XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	10	11
In contrast , when EGFR was reactivated by the addition of EGF , the level of autophagy was reduced which led to decreased cell death .	In contrast, when EGFR was reactivated by the addition of EGF, the level of autophagy was reduced which led to decreased cell death.	4	12	reactivated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	4	5
The ligand EGF activates EGFR to regulate cell proliferation , XREF_BIBR , XREF_BIBR and some studies have reported that EGF stimulates SK-BR-3 cells and regulates proliferation .	The ligand EGF activates EGFR to regulate cell proliferation, XREF_BIBR, XREF_BIBR and some studies have reported that EGF stimulates SK-BR-3 cells and regulates proliferation.	0	17	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
Mimura et al also demonstrated p-Akt expression was enhanced to a large extent by EGF , whereas p-Erk expression was marginally increased in response to EGF when the EGFR overexpressing ESCC cell line KYSE30 was treated with EGF [ XREF_BIBR ] .	Mimura et al also demonstrated p-Akt expression was enhanced to a large extent by EGF, whereas p-Erk expression was marginally increased in response to EGF when the EGFR overexpressing ESCC cell line KYSE30 was treated with EGF [XREF_BIBR].	27	39	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	37	38	28	29
To investigate the mechanisms by which GALNT1 knockdown suppresses EGF induced HCC cell migration and invasion , EGF induced EGFR activation and degradation were analyzed .	To investigate the mechanisms by which GALNT1 knockdown suppresses EGF induced HCC cell migration and invasion, EGF induced EGFR activation and degradation were analyzed.	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
Furthermore , neural stem cells from GD3 synthase deficient mice have reduced level of EGFR expression and accelerated EGF induced EGFR degradation consistent with decreased self-renewal capacity [ XREF_BIBR ] .	Furthermore, neural stem cells from GD3 synthase deficient mice have reduced level of EGFR expression and accelerated EGF induced EGFR degradation consistent with decreased self-renewal capacity [XREF_BIBR].	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
EGF activated the EGFR as demonstrated by the detection of tyrosine phosphorylated EGFR ( XREF_SUPPLEMENTARY ) .	EGF activated the EGFR as demonstrated by the detection of tyrosine phosphorylated EGFR (XREF_SUPPLEMENTARY).	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	3	4
A simple interpretation of these data would be that EGFR signalling and OA1 signalling upregulate the numbers of separate populations of MVBs , EGF stimulation promoting the formation of an EGFR containing subset , and OA1 activity inhibiting the lysosomal delivery of a different subset of MVBs .	A simple interpretation of these data would be that EGFR signalling and OA1 signalling upregulate the numbers of separate populations of MVBs, EGF stimulation promoting the formation of an EGFR containing subset, and OA1 activity inhibiting the lysosomal delivery of a different subset of MVBs.	23	31	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	30	31
Importantly , unprecedented increase in the sensitivity of microscopy imaging systems provides an opportunity to follow endocytosis of EGFR activated by low , physiological concentrations of fluorescent EGF in living cells and in real time .	Importantly, unprecedented increase in the sensitivity of microscopy imaging systems provides an opportunity to follow endocytosis of EGFR activated by low, physiological concentrations of fluorescent EGF in living cells and in real time.	16	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	18	19
Although EGF treatment activated the EGFR signaling pathway ( XREF_SUPPLEMENTARY ) , the VEGF production in HepG2 cells was not promoted significantly ( XREF_SUPPLEMENTARY ) .	Although EGF treatment activated the EGFR signaling pathway (XREF_SUPPLEMENTARY), the VEGF production in HepG2 cells was not promoted significantly (XREF_SUPPLEMENTARY).	1	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	5	6
It is interesting to note that 1ngml -1 concentration of EGF predominantly activates EGFR pathway alone .	It is interesting to note that 1ngml -1 concentration of EGF predominantly activates EGFR pathway alone.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	13	14
To test whether EGF directly mediates the binding of nuclear EGFR to either pri-miR-1-1 or pri-miR-1-2 , we performed a chromatin immunoprecipitation ( ChIP ) assay on RasB1 cells following quantitative PCR analyses .	To test whether EGF directly mediates the binding of nuclear EGFR to either pri-miR-1-1 or pri-miR-1-2, we performed a chromatin immunoprecipitation (ChIP) assay on RasB1 cells following quantitative PCR analyses.	3	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	10	11
EGF activated EGF receptor tyrosine kinase activity was completely inhibited by 3 muM ZM 252868 in PE01 , SKOV-3 and PE01 CDDP cells .	EGF activated EGF receptor tyrosine kinase activity was completely inhibited by 3 muM ZM 252868 in PE01, SKOV-3 and PE01 CDDP cells.	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	2	4
Hypoxic-induction of arginase II requires EGF mediated EGFR activation in human pulmonary microvascular endothelial cells .	Hypoxic-induction of arginase II requires EGF mediated EGFR activation in human pulmonary microvascular endothelial cells.	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Whereas EGF targets EGFR to the degradative pathway , TGFalpha allows receptor recycling .	Whereas EGF targets EGFR to the degradative pathway, TGFalpha allows receptor recycling.	0	10	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
The rapid turnover of EGF activated EGFR is believed to decrease the stimulation of cellular proliferation pathways , permitting a balance with various differentiation inducing stimuli present in normal tissue [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The rapid turnover of EGF activated EGFR is believed to decrease the stimulation of cellular proliferation pathways, permitting a balance with various differentiation inducing stimuli present in normal tissue [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	10	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
Furthermore , EGF stimulation promoted EGFR internalization , as reflected by the reduction in EGFR levels following lysosomal degradation 31 .	Furthermore, EGF stimulation promoted EGFR internalization, as reflected by the reduction in EGFR levels following lysosomal degradation 31.	2	6	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	5	6
Importantly , these authors also showed PIC mediated PDT decreased EGF induced activation of pEGFR , pAKT ( Ser473 ) , and pMAPK and pERK , all of which can be involved in the induction of angiogenesis .	Importantly, these authors also showed PIC mediated PDT decreased EGF induced activation of pEGFR, pAKT (Ser473), and pMAPK and pERK, all of which can be involved in the induction of angiogenesis.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	10	11	14	15
Furthermore , Tom1L1 and Y460 or Tom1L1 knockdown also inhibited endocytosis of EGFR triggered by 1.5 ng/ml of EGF in HeLa cells ( XREF_SUPPLEMENTARY ) .	Furthermore, Tom1L1 and Y460 or Tom1L1 knockdown also inhibited endocytosis of EGFR triggered by 1.5 ng/ml of EGF in HeLa cells (XREF_SUPPLEMENTARY).	10	21	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	12	13
EGF stimulated pinocytosis was increased XREF_BIBR and EGFR trafficking and degradation were delayed XREF_BIBR suggesting that phosphorylation and/or ubiquitination of the EGFR were altered by TBC1D3 expression .	EGF stimulated pinocytosis was increased XREF_BIBR and EGFR trafficking and degradation were delayed XREF_BIBR suggesting that phosphorylation and/or ubiquitination of the EGFR were altered by TBC1D3 expression.	0	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	7	8
In quiescent cells , EGF pretreatment potentiated both EGFR and ERK activation in response to radiation , whereas erlotinib abrogated this activation ( XREF_FIG ) .	In quiescent cells, EGF pretreatment potentiated both EGFR and ERK activation in response to radiation, whereas erlotinib abrogated this activation (XREF_FIG).	4	11	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	8	9
Consistent with these findings , EGF stimulated EGF receptor and MAP kinase pathway signaling is prolonged .	Consistent with these findings, EGF stimulated EGF receptor and MAP kinase pathway signaling is prolonged.	3	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	5	6	7	9
Early work demonstrated the presence of an EGF activated PI 4-kinase activity at in membrane fractions that was associated with a decreased apparent K m for PI substrate but with no increase in the V max for PI phosphorylation activated EGFR XREF_BIBR .	Early work demonstrated the presence of an EGF activated PI 4-kinase activity at in membrane fractions that was associated with a decreased apparent K m for PI substrate but with no increase in the V max for PI phosphorylation activated EGFR XREF_BIBR.	4	41	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	40	41
However , we have shown here that inhibition of EGFR kinase activation by mutation or by chemical inhibitors did not block EGF induced EGFR internalization .	However, we have shown here that inhibition of EGFR kinase activation by mutation or by chemical inhibitors did not block EGF induced EGFR internalization.	20	24	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	23	24
Moreover , rosiglitazone stimulates EGFR phosphorylation , while direct activation of EGFR by EGF up-regulates caveolin-1 mRNA .	Moreover, rosiglitazone stimulates EGFR phosphorylation, while direct activation of EGFR by EGF up-regulates caveolin-1 mRNA.	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	11	12
In cells intoxicated with ExoS G - A - or ExoS G + , EGF stimulated the EGFR to traffic to lysosomes ( ICQs = ~ 0.2 , indicating partial co-localization ) , while in cells intoxicated with ExoS A + , upon EGF stimulation EGFR was excluded from lysosomes ( ICQ = ~ -0.1 , indicating segmentation ) ( XREF_FIG ) .	In cells intoxicated with ExoS G - A - or ExoS G +, EGF stimulated the EGFR to traffic to lysosomes (ICQs = ~ 0.2, indicating partial co-localization), while in cells intoxicated with ExoS A +, upon EGF stimulation EGFR was excluded from lysosomes (ICQ = ~ -0.1, indicating segmentation) (XREF_FIG).	35	47	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	43	44	45	46
Later , internalization of EGFR by large vesicular structures lacking clathrin in cells treated with high concentrations of EGF was also observed by fluorescence microscopy in COS cells that express a much lesser level of EGFR [ XREF_BIBR ] .	Later, internalization of EGFR by large vesicular structures lacking clathrin in cells treated with high concentrations of EGF was also observed by fluorescence microscopy in COS cells that express a much lesser level of EGFR [XREF_BIBR].	2	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	4	5
114 Ho and colleagues confirmed these findings , but found that the EGF stimulated proliferation was the result of EGFR activation of the PI3K and AKT pathway .	114 Ho and colleagues confirmed these findings, but found that the EGF stimulated proliferation was the result of EGFR activation of the PI3K and AKT pathway.	11	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	19	20
Instead , the tyrosine residues in EGFRvIII are phosphorylated independently of ligand engagement , but at a much lower level compared with EGF stimulated wild-type EGFR .	Instead, the tyrosine residues in EGFRvIII are phosphorylated independently of ligand engagement, but at a much lower level compared with EGF stimulated wild-type EGFR.	8	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	25	26
It has been previously shown that various ligands can induce specific heterodimerization , for example EGF can induce heterodimerization of EGFR with HER2 , HER3 or HER4 .	It has been previously shown that various ligands can induce specific heterodimerization, for example EGF can induce heterodimerization of EGFR with HER2, HER3 or HER4.	14	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	20	21
For example , Odin level is correlated with the degree of increased EGF induced EGFR trafficking to recycle endosomes and recycle back to the cell surface .	For example, Odin level is correlated with the degree of increased EGF induced EGFR trafficking to recycle endosomes and recycle back to the cell surface.	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Treatment with either compound significantly blocked levels of EGF stimulated pEGFR in the highly sensitive and moderate groups , but not in the resistant group ( XREF_FIG ) .	Treatment with either compound significantly blocked levels of EGF stimulated pEGFR in the highly sensitive and moderate groups, but not in the resistant group (XREF_FIG).	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	levels of EGF	egf	pEGFR	pEGFR	pegfr	8	9	10	11
Therefore , we determined binding of integrin beta3 and FAK with the EGFR in cells treated with EGF .	Therefore, we determined binding of integrin beta3 and FAK with the EGFR in cells treated with EGF.	3	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	12	13
Confocal immunofluorescence analysis revealed that EGF initiates rapid internalization of both the EGF receptor and PLSCR1 , with trafficking into both distinct and common endosomal pools .	Confocal immunofluorescence analysis revealed that EGF initiates rapid internalization of both the EGF receptor and PLSCR1, with trafficking into both distinct and common endosomal pools.	5	14	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	5	6	12	14
The Grb2 protein bound only to EGF activated ErbB1 in this cellular system , and not to NRG activated ErbB1 in a heterodimer with ErbB4 .	The Grb2 protein bound only to EGF activated ErbB1 in this cellular system, and not to NRG activated ErbB1 in a heterodimer with ErbB4.	3	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	6	7	8	9
To demonstrate that EGFR activation by EGF specifically regulates MMP-1 expression , the activation of EGFR was inhibited using the small molecule inhibitor ZD1839 .	To demonstrate that EGFR activation by EGF specifically regulates MMP-1 expression, the activation of EGFR was inhibited using the small molecule inhibitor ZD1839.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	3	4
Expression of the integrin alpha2 subunit was selectively increased upon EGF mediated EGFR activation in both A431 cells and A549 cells XREF_BIBR .	Expression of the integrin alpha2 subunit was selectively increased upon EGF mediated EGFR activation in both A431 cells and A549 cells XREF_BIBR.	10	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
A potential role of gefitinib efficacy , radiation efficacy and gefitinib- or EGF modulated EGFR and/or pEGFR expression in the prediction of interaction between gefitinib and radiation is supported .	A potential role of gefitinib efficacy, radiation efficacy and gefitinib- or EGF modulated EGFR and/or pEGFR expression in the prediction of interaction between gefitinib and radiation is supported.	5	15	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Biotinylating platelet surface proteins showed ADAMDEC1 hydrolyzed surface pro EGF to HMW-EGF that stimulated HeLa EGF receptor ( EGFR ) reporter cells and EGFR dependent tumor cell migration .	Biotinylating platelet surface proteins showed ADAMDEC1 hydrolyzed surface pro EGF to HMW-EGF that stimulated HeLa EGF receptor (EGFR) reporter cells and EGFR dependent tumor cell migration.	5	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	ADAMDEC1 hydrolyzed surface pro EGF	egf	EGF receptor	EGF receptor	egf receptor	9	10	15	17
Indeed p38 kinase is not required for EGF stimulated EGFR internalization but is required subsequently for CBL mediated ubiquitination and degradation of internalized EGFR .	Indeed p38 kinase is not required for EGF stimulated EGFR internalization but is required subsequently for CBL mediated ubiquitination and degradation of internalized EGFR.	7	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
At the same time , the unexpected site specific phosphorylation patterns of EGF induced EGFR on the cell membrane ( XREF_FIG ) , which had been veiled in ensemble results so far , can also be verified .	At the same time, the unexpected site specific phosphorylation patterns of EGF induced EGFR on the cell membrane (XREF_FIG), which had been veiled in ensemble results so far, can also be verified.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Chronic withdrawal of HC/EGF from MCF-10A cell cultures seems to strongly facilitate the formation of this putative ERalpha/ERbeta/EGFR ternary complex , a possible manifestation of the ER and EGFR upregulation induced by increased ROS and EGF deficiency in the microenvironment , thereby conferring both EGF and E2 hypersensitivity to cells .	Chronic withdrawal of HC/EGF from MCF-10A cell cultures seems to strongly facilitate the formation of this putative ERalpha/ERbeta/EGFR ternary complex, a possible manifestation of the ER and EGFR upregulation induced by increased ROS and EGF deficiency in the microenvironment, thereby conferring both EGF and E2 hypersensitivity to cells.	26	36	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	35	36	28	29
We then examined the ability of EFEMP1 to block EGF mediated activation of EGFR signaling pathways by immunoblotting whole cell lysates of EFEMP1 infected U251 cells .	We then examined the ability of EFEMP1 to block EGF mediated activation of EGFR signaling pathways by immunoblotting whole cell lysates of EFEMP1 infected U251 cells.	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	13	14
Furthermore , the immunofluorescence staining also indicated that the endogenous EGFR can be detected in the mitochondria and EGF treatment induces mitochondrial localization of EGFR in H1299 cells .	Furthermore, the immunofluorescence staining also indicated that the endogenous EGFR can be detected in the mitochondria and EGF treatment induces mitochondrial localization of EGFR in H1299 cells.	18	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	24	25
These results show that EGF is able to stimulate EGFR at Tyr1068 in IFI6 expressing cells in a similar manner to control cells , and that the inhibition of EGFR phosphorylation in an IFI6 expressing cells is confined to those interactions involving CD81 .	These results show that EGF is able to stimulate EGFR at Tyr1068 in IFI6 expressing cells in a similar manner to control cells, and that the inhibition of EGFR phosphorylation in an IFI6 expressing cells is confined to those interactions involving CD81.	4	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	9	10
In addition , overexpression of caveolin-1 in the MCF-7 breast cancer cell line has been shown to modulate EGFR activation levels and EGF induced EGFR signaling [ XREF_BIBR ] .	In addition, overexpression of caveolin-1 in the MCF-7 breast cancer cell line has been shown to modulate EGFR activation levels and EGF induced EGFR signaling [XREF_BIBR].	22	25	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
Therefore , the use of this novel Ab , directly demonstrates that the active conformation of EGFR under ox-stress differs from that of the EGFR stimulated by EGF .	Therefore, the use of this novel Ab, directly demonstrates that the active conformation of EGFR under ox-stress differs from that of the EGFR stimulated by EGF.	21	28	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	24	25
Interestingly , stimulation of EGFR by EGF does not result in a [ Ca 2+ ] i ( XREF_FIG ) .	Interestingly, stimulation of EGFR by EGF does not result in a [Ca 2+] i (XREF_FIG).	2	7	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	4	5
Compared to the rapid internalization of EGF activated ErbB-1 , NDF activated ErbB-1 showed delayed internalization characteristics .	Compared to the rapid internalization of EGF activated ErbB-1, NDF activated ErbB-1 showed delayed internalization characteristics.	4	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	6	7	8	9
Furthermore , IS effectively inhibited the EGF induced activation of the EGFR pathways .	Furthermore, IS effectively inhibited the EGF induced activation of the EGFR pathways.	5	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	11	12
It has been recently shown that neoblast clonal expansion in the free living flatworm planarian is regulated by its own EGF mediated EGFR signaling [ XREF_BIBR ] .	It has been recently shown that neoblast clonal expansion in the free living flatworm planarian is regulated by its own EGF mediated EGFR signaling [XREF_BIBR].	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
To further understand the mechanism of fusion kinase re-phosphorylation , we tested whether EGF induced activation of EGFR resulted in the dissociation of the FKI .	To further understand the mechanism of fusion kinase re-phosphorylation, we tested whether EGF induced activation of EGFR resulted in the dissociation of the FKI.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	17	18
Our data suggest that PRL synergistically augments EGF signaling in T47D breast cancer cells at least in part by lessening EGF induced EGFR downregulation and that this effect requires PRL induced ERK activity and threonine phosphorylation of EGFR .	Our data suggest that PRL synergistically augments EGF signaling in T47D breast cancer cells at least in part by lessening EGF induced EGFR downregulation and that this effect requires PRL induced ERK activity and threonine phosphorylation of EGFR.	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
Previous study showed that a phosphorylation of EGFR was induced by ionizing radiation in a ligand independent manner and ionizing radiation or cisplatin without EGF induced EGFR transport into the nucleus XREF_BIBR .	Previous study showed that a phosphorylation of EGFR was induced by ionizing radiation in a ligand independent manner and ionizing radiation or cisplatin without EGF induced EGFR transport into the nucleus XREF_BIBR.	19	27	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
By enhancing the ubiquitination of Hrs by the E3 ubiquitin ligase Nedd4 , LAPTM4B could inhibit the function of Hrs so that EGF stimulated EGFR signaling could be prolonged .	By enhancing the ubiquitination of Hrs by the E3 ubiquitin ligase Nedd4, LAPTM4B could inhibit the function of Hrs so that EGF stimulated EGFR signaling could be prolonged.	22	25	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
In both shCtl and shEcad , the phosphorylation levels of EGFR , ERK and Akt promptly increased upon EGF stimulation and then gradually decreased , while the total EGFR expression decreased after EGF stimulation , which might be the consequence of EGF stimulated EGFR endocytosis [ XREF_BIBR ] .	In both shCtl and shEcad, the phosphorylation levels of EGFR, ERK and Akt promptly increased upon EGF stimulation and then gradually decreased, while the total EGFR expression decreased after EGF stimulation, which might be the consequence of EGF stimulated EGFR endocytosis [XREF_BIBR].	39	44	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	41	42	43	44
HRG induced strong and persistent activation ( phosphorylation ) in EGFR , ErbB2 , ERK , JNK , p38 MAPK and Akt , while EGF induced only weak ( EGFR , ErbB2 and Akt ) and transient ( ERK , JNK and p38 MAPK ) signals ( XREF_FIG , XREF_SUPPLEMENTARY ) .	HRG induced strong and persistent activation (phosphorylation) in EGFR, ErbB2, ERK, JNK, p38 MAPK and Akt, while EGF induced only weak (EGFR, ErbB2 and Akt) and transient (ERK, JNK and p38 MAPK) signals (XREF_FIG, XREF_SUPPLEMENTARY).	24	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	29	30
The process is EGF dependent and involves a protease mediated liberation of EGF , which subsequently activates the EGFR .	The process is EGF dependent and involves a protease mediated liberation of EGF, which subsequently activates the EGFR.	3	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	18	19
Altogether these results demonstrated that the presence of CTEN significantly diminished EGF induced EGFR down-regulation , sustained activated receptor , and therefore prolonged EGFR signaling .	Altogether these results demonstrated that the presence of CTEN significantly diminished EGF induced EGFR down-regulation, sustained activated receptor, and therefore prolonged EGFR signaling.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Correlation analyses revealed a significant correlation between the median combination index ( CI ) and gefitinib IC50 , radiation ID50 , gefitinib- or EGF modulated EGFR and/or pEGFR expression ( all p < = 0.05 ) .	Correlation analyses revealed a significant correlation between the median combination index (CI) and gefitinib IC50, radiation ID50, gefitinib- or EGF modulated EGFR and/or pEGFR expression (all p < = 0.05).	10	31	modulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	25	26
Because ductal cells do not express EGF , EGF in the sweat secreted from the secretory cells should activate EGFR in the ductal cells in a paracrine manner .	Because ductal cells do not express EGF, EGF in the sweat secreted from the secretory cells should activate EGFR in the ductal cells in a paracrine manner.	8	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	19	20
NE enhanced EGF induced DNA synthesis , EGF induced EGFR dimerization , and its phosphorylation in PVH but not in PPH .	NE enhanced EGF induced DNA synthesis, EGF induced EGFR dimerization, and its phosphorylation in PVH but not in PPH.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
17 EGF binding the EGFR leads to dimerization and activation of the EGFR .	17 EGF binding the EGFR leads to dimerization and activation of the EGFR.	0	13	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	12	13
On the other hand , EGF induced signalling relies more on activation of the RAS/RAF/MEK/MAPK/ELK1 and PI3K and Akt pathways because phosphorylation of MAPK1/3 and Akt were greatly increased after EGF stimulation of MCF7 and EGFR cells .	On the other hand, EGF induced signalling relies more on activation of the RAS/RAF/MEK/MAPK/ELK1 and PI3K and Akt pathways because phosphorylation of MAPK1/3 and Akt were greatly increased after EGF stimulation of MCF7 and EGFR cells.	30	36	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	30	31	35	36
To evaluate the secondary mediator like response of IL-6 in response to ligand stimulation of EGFR , both OVCA 433 and SKOV3 cell lines were treated with EGF , and the mRNA expression of IL-6 , IL-6R , LIF , LIFR and GP130 receptor were analysed within 1h .	To evaluate the secondary mediator like response of IL-6 in response to ligand stimulation of EGFR, both OVCA 433 and SKOV3 cell lines were treated with EGF, and the mRNA expression of IL-6, IL-6R, LIF, LIFR and GP130 receptor were analysed within 1h.	13	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	15	16
EGF stimulates the proliferation of breast cancer cells by binding to EGFR which is one of the oncogenes of breast cancer .	EGF stimulates the proliferation of breast cancer cells by binding to EGFR which is one of the oncogenes of breast cancer.	0	17	stimulates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	11	12
Addition of mab225 , which blocks EGF dependent activation of EGFR but not its intrinsic kinase activity , had no effect on haptotaxis or velocity ( XREF_FIG ) , suggesting that the requirement for EGFR kinase activity revealed by sensitivity to erlotinib was not dependent on activation of EGFR by ligand .	Addition of mab225, which blocks EGF dependent activation of EGFR but not its intrinsic kinase activity, had no effect on haptotaxis or velocity (XREF_FIG), suggesting that the requirement for EGFR kinase activity revealed by sensitivity to erlotinib was not dependent on activation of EGFR by ligand.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	10	11
EGF ligands can induce the homodimerization of EGFR as well as the heterodimerization with other members of the family : HER2 , HER3 and HER4 [ XREF_BIBR ] .	EGF ligands can induce the homodimerization of EGFR as well as the heterodimerization with other members of the family : HER2, HER3 and HER4 [XREF_BIBR].	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	7	8
Activation of EGFR by EGF and HB-EGF was also inhibited by AG1478 [ XREF_FIG ] .	Activation of EGFR by EGF and HB-EGF was also inhibited by AG1478 [XREF_FIG].	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	2	3
EGF activated EGFR in CL1-5 wt cells or constitutively activated EGFR in PC9 d19 cells was inactivated by treatment with Gefitinib , a potent EGFR inhibitor ( XREF_FIG ) .	EGF activated EGFR in CL1-5 wt cells or constitutively activated EGFR in PC9 d19 cells was inactivated by treatment with Gefitinib, a potent EGFR inhibitor (XREF_FIG).	0	3	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Also for NHEJ activity , there was a substantial increase , when EGFR was activated by EGF as determined for two different reporter cell lines ( A549.EJ and H1299.EJ ) and , vice versa , a reduction was seen when EGFR signalling was blocked by Cetuximab or erlotinib .	Also for NHEJ activity, there was a substantial increase, when EGFR was activated by EGF as determined for two different reporter cell lines (A549.EJ and H1299.EJ) and, vice versa, a reduction was seen when EGFR signalling was blocked by Cetuximab or erlotinib.	12	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	12	13
Next , to establish EGF induced EGFR signaling ; serum starved AIPC cells were stimulated with EGF and pEGFR expression was studied .	Next, to establish EGF induced EGFR signaling; serum starved AIPC cells were stimulated with EGF and pEGFR expression was studied.	3	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
Heparin binding epidermal growth factor activates EGFR , and the activated EGFR enhances the activity of phospholipase D , which in turn causes the production of LPA ( Yeo and Exton , 1995 ) .	Heparin binding epidermal growth factor activates EGFR, and the activated EGFR enhances the activity of phospholipase D, which in turn causes the production of LPA (Yeo and Exton, 1995).	2	7	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	2	5	6	7
This process is similar to EGF induced EGFR endocytosis that depends upon the clathrin pathway , but it is different from that induced by decorin , another member of the small leucine rich proteoglycan family .	This process is similar to EGF induced EGFR endocytosis that depends upon the clathrin pathway, but it is different from that induced by decorin, another member of the small leucine rich proteoglycan family.	3	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
As expected , EGF activated EGFR as well as the Raf/MEK/ERK and PI3K and AKT pathways ( see in lane 2 ) .	As expected, EGF activated EGFR as well as the Raf/MEK/ERK and PI3K and AKT pathways (see in lane 2).	3	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Under both culture conditions ( EGF plus bFGF or bFGF only ) the status of these two genes did not change , suggesting that absence of EGF per se is not sufficient to drive EGFR amplification ( Additional file XREF_SUPPLEMENTARY : Figure S2 ) .	Under both culture conditions (EGF plus bFGF or bFGF only) the status of these two genes did not change, suggesting that absence of EGF per se is not sufficient to drive EGFR amplification (Additional file XREF_SUPPLEMENTARY : Figure S2).	24	35	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	34	35
Activation of EGFR signaling , by EGF , in A549 lung adenocarcinoma cells ( overexpressing EGFR ) significantly enhanced the function of the mTOR autoamplification loop , consisting of S6K , mTOR , CK1alpha , and betaTrCP1 , which resulted in downregulation of DEPTOR expression .	Activation of EGFR signaling, by EGF, in A549 lung adenocarcinoma cells (overexpressing EGFR) significantly enhanced the function of the mTOR autoamplification loop, consisting of S6K, mTOR, CK1alpha, and betaTrCP1, which resulted in downregulation of DEPTOR expression.	0	7	Activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	2	3
Similar findings were observed with direct labeling of EGFR in SC4MOL deficient cells treated with EGF for 30 and 60 minutes , which showed substantial depletion of EGFR in SC4MOL deficient cells ( XREF_SUPPLEMENTARY ) .	Similar findings were observed with direct labeling of EGFR in SC4MOL deficient cells treated with EGF for 30 and 60 minutes, which showed substantial depletion of EGFR in SC4MOL deficient cells (XREF_SUPPLEMENTARY).	6	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	8	9
Members of the EGF family stimulate the EGF receptor to varying extents and in different manners [ XREF_BIBR , XREF_BIBR ] .	Members of the EGF family stimulate the EGF receptor to varying extents and in different manners [XREF_BIBR, XREF_BIBR].	3	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	3	4	7	9
Trafficking studies suggest that ~ 50 % of EGF stimulated EGFR is degraded in the lysosome , while the remainder is recycled back to the plasma membrane [ XREF_BIBR ] .	Trafficking studies suggest that ~ 50% of EGF stimulated EGFR is degraded in the lysosome, while the remainder is recycled back to the plasma membrane [XREF_BIBR].	4	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
Furthermore , the finding that the EGF neutralizing antibody prevented the hypoxia induced increase in viable cell numbers supports the notion that hypoxia induced EGF production serves as an autocrine loop to activate EGFR in cancers .	Furthermore, the finding that the EGF neutralizing antibody prevented the hypoxia induced increase in viable cell numbers supports the notion that hypoxia induced EGF production serves as an autocrine loop to activate EGFR in cancers.	24	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	33	34
EGF also stimulates rapid EGFR endocytosis and its eventual degradation in lysosomes .	EGF also stimulates rapid EGFR endocytosis and its eventual degradation in lysosomes.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
Further studies revealed that epidermal growth factor ( EGF )-induced activation of epidermal growth factor receptor ( EGFR ) and MAPK could be potently inhibited by LC-X in both NPC-TW02 and A431cells in a dose dependent manner .	Further studies revealed that epidermal growth factor (EGF)-induced activation of epidermal growth factor receptor (EGFR) and MAPK could be potently inhibited by LC-X in both NPC-TW02 and A431cells in a dose dependent manner.	4	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	4	7	12	16
Data generated using mice genetic models perturbing ovulation and fertility indicates that the EGF like growth factors amphiregulin , epiregulin , and betacellulin are induced by LH and activate the EGF receptor pathway in granulosa cells of preovulatory follicles to impact ovulation [ XREF_BIBR , XREF_BIBR ] .	Data generated using mice genetic models perturbing ovulation and fertility indicates that the EGF like growth factors amphiregulin, epiregulin, and betacellulin are induced by LH and activate the EGF receptor pathway in granulosa cells of preovulatory follicles to impact ovulation [XREF_BIBR, XREF_BIBR].	12	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	13	14	30	32
The EGFR signaling cascade is initiated by the binding of EGF to the transmembrane EGFR at its extracellular domain .	The EGFR signaling cascade is initiated by the binding of EGF to the transmembrane EGFR at its extracellular domain.	1	11	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	1	2
In contrast , ALIX depletion had no clear effect on MVBs containing EGF stimulated EGFR .	In contrast, ALIX depletion had no clear effect on MVBs containing EGF stimulated EGFR.	11	15	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Furthermore , Icariside II inhibited epidermal growth factor ( EGF )-induced activation of EGFR and mTOR signaling pathway .	Furthermore, Icariside II inhibited epidermal growth factor (EGF)-induced activation of EGFR and mTOR signaling pathway.	5	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	5	8	13	14
Clathrin independent endocytosis has been involved in several cellular processes , recently including the endocytosis of EGFR stimulated by high EGF concentration that conduces to receptor degradation and signal attenuation .	Clathrin independent endocytosis has been involved in several cellular processes, recently including the endocytosis of EGFR stimulated by high EGF concentration that conduces to receptor degradation and signal attenuation.	14	21	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	16	17
Short-term activation of EGFR stimulation by EGF is accompanied by ERK phosphorylation .	Short-term activation of EGFR stimulation by EGF is accompanied by ERK phosphorylation.	3	7	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	3	4
As mentioned previously , the addition of EGF for 15 min induced a clear redistribution of EGFR-GFP to intracellular vesicles .	As mentioned previously, the addition of EGF for 15 min induced a clear redistribution of EGFR-GFP to intracellular vesicles.	5	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR-GFP	EGFR-GFP	EGFR-GFP	7	8	16	17
We concluded that MAP1A and LC2 is critical for RhoB function in EGF induced EGF receptor regulation .	We concluded that MAP1A and LC2 is critical for RhoB function in EGF induced EGF receptor regulation.	10	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	12	13	14	16
It would appear that , unlike cultures with soluble EGF on collagen I or peptide gels , DNA synthesis is stimulated via tethered EGF activating EGFR and ERK1/2 without altering levels of EGFR or ErbB2 .	It would appear that, unlike cultures with soluble EGF on collagen I or peptide gels, DNA synthesis is stimulated via tethered EGF activating EGFR and ERK1/2 without altering levels of EGFR or ErbB2.	20	27	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	25	26
In RVH6849 with or without Odin knockdown EGF stimulated EGFR activation as measured by phosphorylation at Y 1092 was rapidly achieved , in both cases reaching an approximate maximum by 1-min ( XREF_FIG , middle panel ) .	In RVH6849 with or without Odin knockdown EGF stimulated EGFR activation as measured by phosphorylation at Y 1092 was rapidly achieved, in both cases reaching an approximate maximum by 1-min (XREF_FIG, middle panel).	7	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
EGF induced activation of EGFR , Ras , extracellular-signal-regulated kinase and S6K with or without inhibitors was measured by FRET imaging , and analyzed by semi-automatic image processing .	EGF induced activation of EGFR, Ras, extracellular-signal-regulated kinase and S6K with or without inhibitors was measured by FRET imaging, and analyzed by semi-automatic image processing.	0	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
Here we found extensive co-localization of stress internalized , but not EGF stimulated EGFR with LBPA in serum starved cells ( XREF_FIG ) .	Here we found extensive co-localization of stress internalized, but not EGF stimulated EGFR with LBPA in serum starved cells (XREF_FIG).	10	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Although both EGF and TGFalpha activate the EGF receptor and induce receptor endocytosis , EGF preferentially targets the receptor to multi-vesicular bodies and lysosomal degradation , while TGFalpha enhances receptor recycling and surface availability [ XREF_BIBR , XREF_BIBR ] .	Although both EGF and TGFalpha activate the EGF receptor and induce receptor endocytosis, EGF preferentially targets the receptor to multi-vesicular bodies and lysosomal degradation, while TGFalpha enhances receptor recycling and surface availability [XREF_BIBR, XREF_BIBR].	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	2	3	7	9
13 It can be observed that EGF , HGF or HRG stimulation induce very specific homo and heterodimerization patterns of EGFR and EGFR and HER2 respectively .	13 It can be observed that EGF, HGF or HRG stimulation induce very specific homo and heterodimerization patterns of EGFR and EGFR and HER2 respectively.	6	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	20	21
Over the past decade , the knowledge of EGF overexpression in these tumors has led to the introduction of antibodies targeting EGFR for the treatment of head and neck cancer .	Over the past decade, the knowledge of EGF overexpression in these tumors has led to the introduction of antibodies targeting EGFR for the treatment of head and neck cancer.	8	22	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF overexpression	egf	EGFR	EGFR	egfr	8	9	21	22
We then performed immune-electron microscopy to examine EGF stimulated EGFR to transport to the Golgi apparatus .	We then performed immune-electron microscopy to examine EGF stimulated EGFR to transport to the Golgi apparatus.	6	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Epidermal growth factor receptor activated by EGF and other ligands triggers signaling cascades leading to cancer cell proliferation , target gene expression [ XREF_BIBR - XREF_BIBR ] .	Epidermal growth factor receptor activated by EGF and other ligands triggers signaling cascades leading to cancer cell proliferation, target gene expression [XREF_BIBR - XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	Epidermal growth factor receptor	Epidermal growth factor receptor	Epidermal growth factor receptor	6	7	0	4
Similarly , EGF stimulation of the EGF receptor has been shown to be upstream of NOX1 activation in vascular SMCs [ XREF_BIBR ] .	Similarly, EGF stimulation of the EGF receptor has been shown to be upstream of NOX1 activation in vascular SMCs [XREF_BIBR].	2	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	2	3	6	8
We found that EGF induced EGFR degradation was significantly decreased in SIMPLE depleted cells compared with the control cells ( XREF_FIG ) , which indicates that SIMPLE is required for ligand induced lysosomal degradation of EGFR .	We found that EGF induced EGFR degradation was significantly decreased in SIMPLE depleted cells compared with the control cells (XREF_FIG), which indicates that SIMPLE is required for ligand induced lysosomal degradation of EGFR.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
XREF_BIBR Initially , it was shown that vandetanib blocks the enzymatic activity of RET derived oncoproteins and in vivo phosphorylation and signaling of the RET and PTC3 and RET and MEN2B oncoproteins and of an epidermal growth factor activated EGFR and RET chimeric receptor .	XREF_BIBR Initially, it was shown that vandetanib blocks the enzymatic activity of RET derived oncoproteins and in vivo phosphorylation and signaling of the RET and PTC3 and RET and MEN2B oncoproteins and of an epidermal growth factor activated EGFR and RET chimeric receptor.	8	43	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	35	38	39	40
Further studies revealed that CBD inhibits EGF induced activation of EGFR , ERK , AKT and NF-kB signaling pathways as well as MMP2 and MMP9 secretion .	Further studies revealed that CBD inhibits EGF induced activation of EGFR, ERK, AKT and NF-kB signaling pathways as well as MMP2 and MMP9 secretion.	6	18	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	10	11
GALNT1 knockdown suppressed EGF induced EGFR activation where a decrease in p-Y1068 levels in both HA22T and PLC5 cells is clearly evident at 3 min .	GALNT1 knockdown suppressed EGF induced EGFR activation where a decrease in p-Y1068 levels in both HA22T and PLC5 cells is clearly evident at 3 min.	2	6	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
ALIX is recruited to MVBs by binding to the rare lipid lyso-bisphosphatidic acid ( LBPA ) XREF_BIBR , which we previously showed to be absent from EGF stimulated EGFR containing MVBs XREF_BIBR , but present in MVBs containing OA1 .	ALIX is recruited to MVBs by binding to the rare lipid lyso-bisphosphatidic acid (LBPA) XREF_BIBR, which we previously showed to be absent from EGF stimulated EGFR containing MVBs XREF_BIBR, but present in MVBs containing OA1.	24	29	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
The aim of this study was to determine whether EGF promotes EGFR nuclear accumulation and the role of clathrin coated pits , EGFR kinase activity , caveolae microdomains and cytoskeleton integrity in breast cancer cells .	The aim of this study was to determine whether EGF promotes EGFR nuclear accumulation and the role of clathrin coated pits, EGFR kinase activity, caveolae microdomains and cytoskeleton integrity in breast cancer cells.	9	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
NDRG1 reduces EGFR expression and abrogates EGF induced EGFR activation , subsequently inhibiting the EGFR-c-Src association and c-Src activation .	NDRG1 reduces EGFR expression and abrogates EGF induced EGFR activation, subsequently inhibiting the EGFR-c-Src association and c-Src activation.	5	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
A recent report that inhibition of EGFR activation by EGCG is mediated by altering lipid order , thus preventing EGF induced EGFR from dimerization in HT29 colon cancer cells , further strengthens our findings .	A recent report that inhibition of EGFR activation by EGCG is mediated by altering lipid order, thus preventing EGF induced EGFR from dimerization in HT29 colon cancer cells, further strengthens our findings.	18	22	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
This suggested that HDN-1 facilitated EGF induced EGFR downregulation independent of the EGFR mutation status .	This suggested that HDN-1 facilitated EGF induced EGFR downregulation independent of the EGFR mutation status.	4	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Incubation with pertuzumab also increased the amount of EGF induced EGFR homodimers , and under these conditions , endocytosis of radiolabeled EGF was increased .	Incubation with pertuzumab also increased the amount of EGF induced EGFR homodimers, and under these conditions, endocytosis of radiolabeled EGF was increased.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
We further note that : i ) Even though the HRG concentration used here is 2.5 times that of EGF and the ligand doses are equivalent when their receptor binding affinities are accounted for ( see above ) , HER2 receptors are activated at a much lower levels through the HRG stimulated HER3 pathway than through the EGF stimulated EGFR pathway .	We further note that : i) Even though the HRG concentration used here is 2.5 times that of EGF and the ligand doses are equivalent when their receptor binding affinities are accounted for (see above), HER2 receptors are activated at a much lower levels through the HRG stimulated HER3 pathway than through the EGF stimulated EGFR pathway.	54	60	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	57	58	59	60
By using high-pressure liquid chromatography with electrochemical detection , we found that tyrphostin was readily incorporated into A431 cells , reaching maximal levels within 1 h. Although tyrphostin ( 50 to 100 microM ) had no effect on high-affinity binding of EGF to its receptor in A431 cells for up to 24 h , the compound partially inhibited EGF stimulated EGF receptor tyrosine kinase activity .	By using high-pressure liquid chromatography with electrochemical detection, we found that tyrphostin was readily incorporated into A431 cells, reaching maximal levels within 1 h. Although tyrphostin (50 to 100 microM) had no effect on high-affinity binding of EGF to its receptor in A431 cells for up to 24 h, the compound partially inhibited EGF stimulated EGF receptor tyrosine kinase activity.	57	62	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	58	59	60	62
Galphas depleted HeLa cells and controls were stimulated with 300 ng/ml EGF and stained for EGFR and EEA1 .	Galphas depleted HeLa cells and controls were stimulated with 300 ng/ml EGF and stained for EGFR and EEA1.	7	17	stimulated	Positive_activation_token_experimental_results_1	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	15	16
We found that EGF induced EGFR activation significantly activated Fas survival signals , as indicated by the increase in the level of phosphorylated Y291 ( pY291 ) Fas upon EGF treatment ( Figs XREF_FIG , and S1 ) .	We found that EGF induced EGFR activation significantly activated Fas survival signals, as indicated by the increase in the level of phosphorylated Y291 (pY291) Fas upon EGF treatment (Figs XREF_FIG, and S1).	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
58 On the other side , LAPTM4B could promote active EGFR signaling by blocking EGF stimulated EGFR intraluminal sorting and lysosomal degradation to inhibit autophagy .	58 On the other side, LAPTM4B could promote active EGFR signaling by blocking EGF stimulated EGFR intraluminal sorting and lysosomal degradation to inhibit autophagy.	14	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
Thus , the ~ 48 kDa ERK in male worms may play a specific role in growth and development and/or host-interactions , particularly given that human EGF activates EGFR in S. mansoni XREF_BIBR and influences ERK signalling and proliferation in other parasites , including Echinococcus multilocularis XREF_BIBR and Trypanosoma cruzi XREF_BIBR .	Thus, the ~ 48 kDa ERK in male worms may play a specific role in growth and development and/or host-interactions, particularly given that human EGF activates EGFR in S. mansoni XREF_BIBR and influences ERK signalling and proliferation in other parasites, including Echinococcus multilocularis XREF_BIBR and Trypanosoma cruzi XREF_BIBR.	25	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
Simultaneous PDGF-BB and EGF stimulation induces macropinocytosis of EGFR .	Simultaneous PDGF-BB and EGF stimulation induces macropinocytosis of EGFR.	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	8	9
However , EGFR activation by EGF resulted in cell migration stimulation in both cell lines .	However, EGFR activation by EGF resulted in cell migration stimulation in both cell lines.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	2	3
Interestingly , activation of EGFR by EGF induced production of matrix metalloproteinase-9 ( MMP-9 ) and soluble E-cadherin ( sE-cad ) , and knockdown of MMP-9 by siRNA inhibited sE-cad production induced by EGF in SCC10A .	Interestingly, activation of EGFR by EGF induced production of matrix metalloproteinase-9 (MMP-9) and soluble E-cadherin (sE-cad), and knockdown of MMP-9 by siRNA inhibited sE-cad production induced by EGF in SCC10A.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	4	5
We have previously shown that expression of HIV-1 Gag decreases the rate of EGF induced EGFR degradation [ XREF_BIBR ] .	We have previously shown that expression of HIV-1 Gag decreases the rate of EGF induced EGFR degradation [XREF_BIBR].	11	16	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Conversely , when the expression of miR-214 was repressed in HLF cells by LNA-antimiR-214 , their proliferation was significantly repressed and the levels of EGF mediated p-EGFR ( Y1173 and Y845 ) and p-Met ( Tyr1234/1235 ) were substantially decreased .	Conversely, when the expression of miR-214 was repressed in HLF cells by LNA-antimiR-214, their proliferation was significantly repressed and the levels of EGF mediated p-EGFR (Y1173 and Y845) and p-Met (Tyr1234/1235) were substantially decreased.	22	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	p-EGFR	p-EGFR	p-EGFR	24	25	26	27
Our results show that EGF induced EGFR activation increases GC transmigration , opposite of the effect of the EGFR kinase inhibitor that blocks EGFR activation and decreases GC transmigration , supporting the hypothesis that GC induced EGFR transactivation is involved in GC transmigration .	Our results show that EGF induced EGFR activation increases GC transmigration, opposite of the effect of the EGFR kinase inhibitor that blocks EGFR activation and decreases GC transmigration, supporting the hypothesis that GC induced EGFR transactivation is involved in GC transmigration.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
Interestingly although p38 kinase is not required for EGF induced EGFR internalization , it is required for CBL dependent receptor degradation .	Interestingly although p38 kinase is not required for EGF induced EGFR internalization, it is required for CBL dependent receptor degradation.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
However , EGF drives EGFR internalization , resulting in downregulation of EGFR and ligand desensitization when cells are exposed to moderately high ligand concentrations ( i.e ., above the K D for ligand-receptor interactions , ~ 1nM ) [ XREF_BIBR , XREF_BIBR ] .	However, EGF drives EGFR internalization, resulting in downregulation of EGFR and ligand desensitization when cells are exposed to moderately high ligand concentrations (i.e., above the K D for ligand-receptor interactions, ~ 1nM) [XREF_BIBR, XREF_BIBR].	2	5	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
To further examine the role of p130Cas in EGFR internalization , we tested the effect of p130Cas on EGF induced EGFR internalization and subsequent degradation .	To further examine the role of p130Cas in EGFR internalization, we tested the effect of p130Cas on EGF induced EGFR internalization and subsequent degradation.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
In vitro experiments demonstrate that EGF stimulation of EGFR positive NSCLC cell lines can result in the upregulation of MMP-9 and , likewise , inhibition of EGFR in vivo reduces tumour cell MMP-9 expression ( Perrotte et al , 1999 ; O'Byrne et al , 2001 ) .	In vitro experiments demonstrate that EGF stimulation of EGFR positive NSCLC cell lines can result in the upregulation of MMP-9 and, likewise, inhibition of EGFR in vivo reduces tumour cell MMP-9 expression (Perrotte et al, 1999; O'Byrne et al, 2001).	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	8	9
Treatment of the control cells with the general proteosome inhibitor MG-132 completely blocked EGF induced EGFR degradation , which suggested that HER2 confers EGFR resistance by interfering with proteosomal degradation ( XREF_FIG ) .	Treatment of the control cells with the general proteosome inhibitor MG-132 completely blocked EGF induced EGFR degradation, which suggested that HER2 confers EGFR resistance by interfering with proteosomal degradation (XREF_FIG).	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
In this way , EGF will not stimulate the EGFR and ERK1/2 signaling pathways in those cumulus cells implying a low developmental potential of the oocyte [ XREF_BIBR ] ( XREF_FIG ) .	In this way, EGF will not stimulate the EGFR and ERK1/2 signaling pathways in those cumulus cells implying a low developmental potential of the oocyte [XREF_BIBR] (XREF_FIG).	4	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	9	10
H. pylori upregulates the expression of EGF related growth factors , which activate EGFR and other tyrosine kinase receptors , and then stimulate proliferation and survival through PI3K-AKT and mitogen activated protein kinases ( MAPK ) pathways .	H. pylori upregulates the expression of EGF related growth factors, which activate EGFR and other tyrosine kinase receptors, and then stimulate proliferation and survival through PI3K-AKT and mitogen activated protein kinases (MAPK) pathways.	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	expression of EGF	egf	EGFR	EGFR	egfr	6	7	13	14
Moreover , HER2 inhibits EGF induced EGFR internalization by forming EGFR and ErbB2 heterodimerization without affecting the phosphorylation or ubiquitination of EGFR ( Haslekas etal ., 2005 ; Wang etal ., 1999 ) , and by having a negative effect on the formation of CCP ( Cortese etal ., 2013 ) .	Moreover, HER2 inhibits EGF induced EGFR internalization by forming EGFR and ErbB2 heterodimerization without affecting the phosphorylation or ubiquitination of EGFR (Haslekas etal., 2005; Wang etal., 1999), and by having a negative effect on the formation of CCP (Cortese etal., 2013).	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
Neutralization of positively charged amino acids abolished EGFR and PIP 2 interaction in the context of this peptide and down-regulated epidermal growth factor ( EGF )-induced EGFR autophosphorylation and EGF induced EGFR signaling to ion channels in the context of the full-length receptor .	Neutralization of positively charged amino acids abolished EGFR and PIP 2 interaction in the context of this peptide and down-regulated epidermal growth factor (EGF)-induced EGFR autophosphorylation and EGF induced EGFR signaling to ion channels in the context of the full-length receptor.	20	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor (EGF)-induced EGFR autophosphorylation	epidermal growth factor	EGFR	EGFR	egfr	20	23	31	32
Further study revealed that CKAP4 could associate with EGFR at basal status and the complex was reduced upon EGF stimulation , leading to release EGFR into cytoplasm .	Further study revealed that CKAP4 could associate with EGFR at basal status and the complex was reduced upon EGF stimulation, leading to release EGFR into cytoplasm.	18	25	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	24	25
In addition cholinergic agonists activate matrix metalloproteinases of the ADAM family that release EGF or an EGF family member that in turn activates the EGFR .	In addition cholinergic agonists activate matrix metalloproteinases of the ADAM family that release EGF or an EGF family member that in turn activates the EGFR.	16	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	24	25
EGF like repeats of tenascin-C directly activate EGFR .	EGF like repeats of tenascin-C directly activate EGFR.	0	8	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	7	8
Colony dispersal in TGF-beta1+ EGF stimulated HaCaT II-4 keratinocytes involves p38 , MEK and ERK , and upstream EGFR signaling .	Colony dispersal in TGF-beta1+ EGF stimulated HaCaT II-4 keratinocytes involves p38, MEK and ERK, and upstream EGFR signaling.	1	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	18	19
Moreover , the phosphorylation pattern of LZ-EGFR-GFP is very similar to that of EGF stimulated EGFR .	Moreover, the phosphorylation pattern of LZ-EGFR-GFP is very similar to that of EGF stimulated EGFR.	11	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
These results indicate that the activation of EGFR induced by EGF preceded the phosphorylation of cofilin , which reflects the activation of ROCK in Panc1 cells .	These results indicate that the activation of EGFR induced by EGF preceded the phosphorylation of cofilin, which reflects the activation of ROCK in Panc1 cells.	5	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	7	8
Notably , PD98059 pretreatment of the fibrosarcoma cells also significantly hastened and enhanced EGF induced EGFR downregulation and significantly augmented acute EGF induced EGFR 1068 Y phosphorylation .	Notably, PD98059 pretreatment of the fibrosarcoma cells also significantly hastened and enhanced EGF induced EGFR downregulation and significantly augmented acute EGF induced EGFR 1068 Y phosphorylation.	3	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
When epithelial cells are stimulated by EGF , c-Src is activated by EGF induced EGF receptor activation [ XREF_BIBR ] .	When epithelial cells are stimulated by EGF, c-Src is activated by EGF induced EGF receptor activation [XREF_BIBR].	10	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	12	13	14	16
EGF stimulated human and rat conjunctival goblet cell proliferation by activating the EGFR .	EGF stimulated human and rat conjunctival goblet cell proliferation by activating the EGFR.	0	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	12	13
Thus , pharmacologic blunting of basal and EGF induced ERK activity in C14 cells augmented early EGF induced EGFR activation ; however , the overall 1068 Y phosphorylation signal at later EGF stimulation time points in PD98059 pretreated cells was not enhanced , likely in part because EGFR abundance was lessened at these later points in the inhibitor pretreated cells .	Thus, pharmacologic blunting of basal and EGF induced ERK activity in C14 cells augmented early EGF induced EGFR activation; however, the overall 1068 Y phosphorylation signal at later EGF stimulation time points in PD98059 pretreated cells was not enhanced, likely in part because EGFR abundance was lessened at these later points in the inhibitor pretreated cells.	15	19	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
Single amino acid substitutions in EGF decreased its binding to the receptor and as a result , decreased the degradation rate of EGFR compared with EGFR activated by wild type EGF [ XREF_BIBR ] .	Single amino acid substitutions in EGF decreased its binding to the receptor and as a result, decreased the degradation rate of EGFR compared with EGFR activated by wild type EGF [XREF_BIBR].	22	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	30	31	25	26
Meanwhile , the connection between Fas and EGFR through which the pro survival mode of Fas heightens the EGF induced EGFR signaling in cancer was never addressed .	Meanwhile, the connection between Fas and EGFR through which the pro survival mode of Fas heightens the EGF induced EGFR signaling in cancer was never addressed.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
RCE in passage number 12-20 are a physiologically relevant model for studies on growth factor receptor mediated control of cell cycle progression and differentiation in its parent tissue as each of these phenomena were conserved : 1 ) EGF induced EGF receptor activation ; 2 ) EGF activated ERK signaling ; 3 ) expression of cornea specific differentiation markers ; 4 ) karyotype profile ; and 5 ) cell cycle control and progression .	RCE in passage number 12-20 are a physiologically relevant model for studies on growth factor receptor mediated control of cell cycle progression and differentiation in its parent tissue as each of these phenomena were conserved : 1) EGF induced EGF receptor activation; 2) EGF activated ERK signaling; 3) expression of cornea specific differentiation markers; 4) karyotype profile; and 5) cell cycle control and progression.	38	42	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	38	39	40	42
EGF stimulated EGFR is internalized and the process of endocytic degradation of EGFR mediates its signaling which is frequently dysregulated in many kinds of cancer .	EGF stimulated EGFR is internalized and the process of endocytic degradation of EGFR mediates its signaling which is frequently dysregulated in many kinds of cancer.	0	4	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Since we previously had shown that EGF stimulates EGF receptor synthesis in these cells , we tested whether hormones that stimulate PtdIns ( 4,5 ) P2 hydrolysis would increase EGF receptor protein synthesis and mRNA levels .	Since we previously had shown that EGF stimulates EGF receptor synthesis in these cells, we tested whether hormones that stimulate PtdIns (4,5) P2 hydrolysis would increase EGF receptor protein synthesis and mRNA levels.	6	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	6	7	8	10
Our previous study demonstrated that EGF activated EGFR and Ras to enhance TBP expression and RNA Pol III reporter transcription .	Our previous study demonstrated that EGF activated EGFR and Ras to enhance TBP expression and RNA Pol III reporter transcription.	5	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Whereas ErbB-1 receptor ( known as epidermal growth factor receptor , EGFR ) , is activated by EGF and EGF like ligands , ErbB-3 and ErbB-4 receptors are activated by NRG and neuregulin isoforms and ErbB-2 receptor has no known ligand XREF_BIBR .	Whereas ErbB-1 receptor (known as epidermal growth factor receptor, EGFR), is activated by EGF and EGF like ligands, ErbB-3 and ErbB-4 receptors are activated by NRG and neuregulin isoforms and ErbB-2 receptor has no known ligand XREF_BIBR.	1	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1 receptor	ErbB-1 receptor	ErbB-1 receptor	17	18	1	3
The epidermal growth factor ( EGF ) , which induces TK activity of EGFR , and monoclonal antibody Mab 108 , which does not , have been exploited as ligands to stimulate endocytosis of EGFR .	The epidermal growth factor (EGF), which induces TK activity of EGFR, and monoclonal antibody Mab 108, which does not, have been exploited as ligands to stimulate endocytosis of EGFR.	1	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	1	4	13	14
While EGF stimulation monotonically increased the activities of EGFR , ERK and STAT3 , it instead induced a biphasic response of c-Met where c-Met level was initially decreased but then dramatically increased beyond its basal level ( XREF_FIG ) .	While EGF stimulation monotonically increased the activities of EGFR, ERK and STAT3, it instead induced a biphasic response of c-Met where c-Met level was initially decreased but then dramatically increased beyond its basal level (XREF_FIG).	1	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	8	9
EGF had no significant effect on the rate of general protein synthesis in these cells , yet stimulated the synthesis of the EGF receptor 1.8-fold over the unstimulated rate .	EGF had no significant effect on the rate of general protein synthesis in these cells, yet stimulated the synthesis of the EGF receptor 1.8-fold over the unstimulated rate.	0	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	22	24
Tyrosine phosphorylations that showed an increase that was predominantly associated with EGF stimulation of EGFR were on MAPK proteins , Tensin 3 and male germ cell associated kinase at Y159 ( XREF_TABLE ) .	Tyrosine phosphorylations that showed an increase that was predominantly associated with EGF stimulation of EGFR were on MAPK proteins, Tensin 3 and male germ cell associated kinase at Y159 (XREF_TABLE).	11	15	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	14	15
In that setting , both wild-type and mutant EGFRs coimmunoprecipitated with ErbB-2 , but EGF induced EGFR downregulation was augmented for EGFR T669A compared to WT EGFR .	In that setting, both wild-type and mutant EGFRs coimmunoprecipitated with ErbB-2, but EGF induced EGFR downregulation was augmented for EGFR T669A compared to WT EGFR.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
Transforming growth factor-alpha or heparin binding epidermal growth factor induced activation of EGFR and HER-2 was inhibited by ERRP in colon and breast cancer cells expressing high levels of EGFR or HER-2 .	Transforming growth factor-alpha or heparin binding epidermal growth factor induced activation of EGFR and HER-2 was inhibited by ERRP in colon and breast cancer cells expressing high levels of EGFR or HER-2.	6	14	induced	Positive_early_activation	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	6	9	12	13
Moreover , Rho down regulation and EGF up-regulation in the dSur KD link EGFR signalling pathway to the ABCC9 K ATP potassium channel .	Moreover, Rho down regulation and EGF up-regulation in the dSur KD link EGFR signalling pathway to the ABCC9 K ATP potassium channel.	4	15	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	13	14
Db-scTRAIL is capable to also modify EGF signaling in EGF receptor ( EGFR ) positive and responsive cells , but the latter can be excluded in NCI-H460 cells , because these carry a KRAS mutation and have been shown to be unresponsive to EGF ( M. Olayioye , unpublished data ) .	Db-scTRAIL is capable to also modify EGF signaling in EGF receptor (EGFR) positive and responsive cells, but the latter can be excluded in NCI-H460 cells, because these carry a KRAS mutation and have been shown to be unresponsive to EGF (M. Olayioye, unpublished data).	6	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	6	7	9	11
The model was then simulated in The Cell Collective , and the activity levels of EGF activated EGFR homodimer on i ) the plasma membrane , ii ) in clathrin coated pits , iii ) clathrin coated vesicles , and iv ) the endosome were measured .	The model was then simulated in The Cell Collective, and the activity levels of EGF activated EGFR homodimer on i) the plasma membrane, ii) in clathrin coated pits, iii) clathrin coated vesicles, and iv) the endosome were measured.	13	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	levels of EGF	egf	EGFR	EGFR	egfr	15	16	17	18
Several studies have shown that EGF induces the EGFR and MAPK signal transduction pathway and contributes to the survival , proliferation and migration of RPE cells [ XREF_BIBR - XREF_BIBR ] .	Several studies have shown that EGF induces the EGFR and MAPK signal transduction pathway and contributes to the survival, proliferation and migration of RPE cells [XREF_BIBR - XREF_BIBR].	5	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	8	9
BMS-536924 up to a concentration of 1muM ( which was maximal for blocking IGF-IR - see XREF_FIG ) had no effect upon EGF mediated activation of EGFR ( XREF_FIG ) .	BMS-536924 up to a concentration of 1muM (which was maximal for blocking IGF-IR - see XREF_FIG) had no effect upon EGF mediated activation of EGFR (XREF_FIG).	22	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	26	27
Also in agreement with previous reports , we saw activation of several MAP kinases by EGFR stimulated by EGF ( see XREF_TABLE ) , but did not see these events in cells expressing DeltaEGFR XREF_BIBR , XREF_BIBR .	Also in agreement with previous reports, we saw activation of several MAP kinases by EGFR stimulated by EGF (see XREF_TABLE), but did not see these events in cells expressing DeltaEGFR XREF_BIBR, XREF_BIBR.	8	20	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	15	16
Of note , EGF stimulation also induces palmitoylation of mitochondrial EGFR , which , in turn , favors fusion of mitochondria ( Bollu etal ., 2014 ) .	Of note, EGF stimulation also induces palmitoylation of mitochondrial EGFR, which, in turn, favors fusion of mitochondria (Bollu etal., 2014).	3	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	10	11
EGFR activation by EGF or EGF like factors is known to induce resumption of meiosis in oocytes and cumulus cell expansion in pigs [ XREF_BIBR , XREF_BIBR ] , rats [ XREF_BIBR ] , mice [ XREF_BIBR ] , humans [ XREF_BIBR ] , and cattle [ XREF_BIBR ] .	EGFR activation by EGF or EGF like factors is known to induce resumption of meiosis in oocytes and cumulus cell expansion in pigs [XREF_BIBR, XREF_BIBR], rats [XREF_BIBR], mice [XREF_BIBR], humans [XREF_BIBR], and cattle [XREF_BIBR].	0	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	0	1
The result demonstrated that EGF treatment ( 100 ng/ml , 5 min ) led to significant increase of Tyr1068 and Tyr1173 phosphorylation of EGFR , and pre-treatment with CHAG ( 1000 mug/ml , 1 h ) efficiently hindered the EGF induced phosphorylation of EGFR , indicating that CHAG inhibited EGF induced activation of EGFR .	The result demonstrated that EGF treatment (100 ng/ml, 5 min) led to significant increase of Tyr1068 and Tyr1173 phosphorylation of EGFR, and pre-treatment with CHAG (1000 mug/ml, 1 h) efficiently hindered the EGF induced phosphorylation of EGFR, indicating that CHAG inhibited EGF induced activation of EGFR.	49	54	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	49	50	53	54
U87 glioma cells were first infected with lenti-AS-566 and then EGF was introduced to activate EGFR signaling .	U87 glioma cells were first infected with lenti-AS-566 and then EGF was introduced to activate EGFR signaling.	10	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	15	16
Panitumumab and Trastuzumab Inhibit the EGF Dependent Activation of EGFR and HER2 and Blunt the Feedback Activation of AKT by Trametinib .	Panitumumab and Trastuzumab Inhibit the EGF Dependent Activation of EGFR and HER2 and Blunt the Feedback Activation of AKT by Trametinib.	5	11	Activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	9	10
The conjugate blocks EGF mediated EGFR activation with higher efficacy than that of both modalities alone ; a phenomenon that is caused by both effective receptor blockade and internalization .	The conjugate blocks EGF mediated EGFR activation with higher efficacy than that of both modalities alone; a phenomenon that is caused by both effective receptor blockade and internalization.	2	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
To ensure the inhibitors were specific for the EGFR , CASMC were treated with the ligands EGF , bFGF , and PDGF-BB .	To ensure the inhibitors were specific for the EGFR, CASMC were treated with the ligands EGF, bFGF, and PDGF-BB.	5	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	8	9
EGF induced EGFR homodimer signaling .	EGF induced EGFR homodimer signaling.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
We next tested the hypothesis that the function of EHD3 might be different in presence of EGFR ligand activation , by assessing the impact of EHD3 expression on EGF mediated activation of EGFR .	We next tested the hypothesis that the function of EHD3 might be different in presence of EGFR ligand activation, by assessing the impact of EHD3 expression on EGF mediated activation of EGFR.	28	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	28	29	32	33
The above findings suggest that psoralidin inhibits EGF induced EGFR and MAPK signaling in AIPC cells .	The above findings suggest that psoralidin inhibits EGF induced EGFR and MAPK signaling in AIPC cells.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Particularly , nuclear EGFR induced by EGF or PGE 2 or the combination of treatments , promotes CCND1 , PTGS2 , MYC and NOS2 upregulation and sustains tumor growth , supporting the hypothesis that the gene signature associated with nuclear EGFR is correlated with poor prognosis in NSCLC and may serve as a biomarker for patients outcome and treatment selection .	Particularly, nuclear EGFR induced by EGF or PGE 2 or the combination of treatments, promotes CCND1, PTGS2, MYC and NOS2 upregulation and sustains tumor growth, supporting the hypothesis that the gene signature associated with nuclear EGFR is correlated with poor prognosis in NSCLC and may serve as a biomarker for patients outcome and treatment selection.	2	26	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	3	4
Altogether , these results indicate that EGF treatment can result in EGFR activation and increased expression of Aurora-A .	Altogether, these results indicate that EGF treatment can result in EGFR activation and increased expression of Aurora-A.	6	13	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	11	12
The implication of c-Cbl in EGF induced EGFR downregulation [ XREF_BIBR , XREF_BIBR ] raises the question whether EGF stimulation regulates alphaPIX : : c and Cbl complex formation and/or alphaPIX and c-Cbl protein turnover .	The implication of c-Cbl in EGF induced EGFR downregulation [XREF_BIBR, XREF_BIBR] raises the question whether EGF stimulation regulates alphaPIX : : c and Cbl complex formation and/or alphaPIX and c-Cbl protein turnover.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
It is important to stress that in these cells EGF stimulation activates the endogenous EGFR , as well as chEGFR when present , but not chDeltaEGFR ; AP20187 activates the two chimeric receptors selectively .	It is important to stress that in these cells EGF stimulation activates the endogenous EGFR, as well as chEGFR when present, but not chDeltaEGFR; AP20187 activates the two chimeric receptors selectively.	9	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	14	15
EGF at nanomolar or subnanomolar concentration induces EGFR activation and accurately regulates signal transduction and gene expression in cells 30 .	EGF at nanomolar or subnanomolar concentration induces EGFR activation and accurately regulates signal transduction and gene expression in cells 30.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	7	8
Among four EGF-receptor ( EGFR ) family members , the EGFR was solely activated by EGF , heparin binding EGF ( HB-EGF ) , transforming growth factor alpha ( TGF alpha ) , epiregulin ( ER ) , and betacellulin ( BTC ) , resulting in induction of phenotypic modulation of SMCs .	Among four EGF-receptor (EGFR) family members, the EGFR was solely activated by EGF, heparin binding EGF (HB-EGF), transforming growth factor alpha (TGF alpha), epiregulin (ER), and betacellulin (BTC), resulting in induction of phenotypic modulation of SMCs.	9	39	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	10	11
Growth factors such as transforming growth factor alpha and epidermal growth factor induce EGFR homodimerization or heterodimerization with other members of the erbB family , including HER2 and neu ( erbB2 ) , HER3 ( erbB3 ) , and HER4 ( erbB4 ) , followed by EGFR autophosphorylation at specific tyrosine sites .	Growth factors such as transforming growth factor alpha and epidermal growth factor induce EGFR homodimerization or heterodimerization with other members of the erbB family, including HER2 and neu (erbB2), HER3 (erbB3), and HER4 (erbB4), followed by EGFR autophosphorylation at specific tyrosine sites.	6	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	9	12	13	14
EGF stimulated EGFR activation induces receptor internalization and degradation , which plays an important role in EGFR signaling .	EGF stimulated EGFR activation induces receptor internalization and degradation, which plays an important role in EGFR signaling.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Activation of EGFR by epidermal growth factor ( EGF ) or transforming growth factor-alpha ( TGFalpha ) leads to an activation of an intracellular tyrosine kinase unit which induces several proliferative pathways .	Activation of EGFR by epidermal growth factor (EGF) or transforming growth factor-alpha (TGFalpha) leads to an activation of an intracellular tyrosine kinase unit which induces several proliferative pathways.	0	13	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	4	7	2	3
GH- or PRL induced EGFR phosphorylation alters subsequent EGF induced EGFR downregulation and signal characteristics in an ERK dependent fashion .	GH- or PRL induced EGFR phosphorylation alters subsequent EGF induced EGFR downregulation and signal characteristics in an ERK dependent fashion.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
Moreover , a high concentration of EGF ( 100 ng/ml ) fails to increase the accumulation of EGFR in caveolae in HEp2 cells [ XREF_BIBR ] .	Moreover, a high concentration of EGF (100 ng/ml) fails to increase the accumulation of EGFR in caveolae in HEp2 cells [XREF_BIBR].	4	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	17	18
Addition of TGF beta enhances the accumulation of EGF receptor mRNA induced by EGF .	Addition of TGF beta enhances the accumulation of EGF receptor mRNA induced by EGF.	8	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	13	14	8	10
Taken together with the data of the present study , we may conclude that in a simplified model of in vitro culture of COCs isolated from growing follicles , both cAMP-PKA signaling induced by gonadotropins and action of oocyte derived paracrine signaling are required for proper function of the EGFR activated by EGF like peptides .	Taken together with the data of the present study, we may conclude that in a simplified model of in vitro culture of COCs isolated from growing follicles, both cAMP-PKA signaling induced by gonadotropins and action of oocyte derived paracrine signaling are required for proper function of the EGFR activated by EGF like peptides.	46	54	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	52	53	49	50
Resistance to EGFR inhibitors : EGFR receptors , activated by the EGF ligands , induce three main pro survival signaling pathways : SRC/JAK/STAT signaling , RAS/RAF/MEK/ERK signaling , and PI3K/AKT/mTOR signaling .	Resistance to EGFR inhibitors : EGFR receptors, activated by the EGF ligands, induce three main pro survival signaling pathways : SRC/JAK/STAT signaling, RAS/RAF/MEK/ERK signaling, and PI3K/AKT/mTOR signaling.	5	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	5	6
Because Ankrd 13A , 13B , and 13D bound maximally to EGFR when cells were treated with EGF for 5 min ( XREF_FIG ) , they should colocalize with EGFR in these cells .	Because Ankrd 13A, 13B, and 13D bound maximally to EGFR when cells were treated with EGF for 5 min (XREF_FIG), they should colocalize with EGFR in these cells.	8	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	11	12
In that regard , our results suggest that when EGF and AR are applied in concentrations that result in equivalent levels of short-term EGFR phosphorylation , EGF targets EGFR to degradation , whereas AR targets EGFR to a recycling pathway .	In that regard, our results suggest that when EGF and AR are applied in concentrations that result in equivalent levels of short-term EGFR phosphorylation, EGF targets EGFR to degradation, whereas AR targets EGFR to a recycling pathway.	24	34	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
EGF induced activation of EGFR stimulates cells to rapidly acquire an invasive or metastatic phenotype .	EGF induced activation of EGFR stimulates cells to rapidly acquire an invasive or metastatic phenotype.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
In HMECs pretreated with DMSO , EGF stimulation caused more than 80 % of EGFR to be degraded within 120 min ( XREF_FIG ) .	In HMECs pretreated with DMSO, EGF stimulation caused more than 80% of EGFR to be degraded within 120 min (XREF_FIG).	6	15	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	14	15
Pre-treatment of the PC-3 cells with LPA decreases the dose of EGF required to elicit maximal activation of EGFR .	Pre-treatment of the PC-3 cells with LPA decreases the dose of EGF required to elicit maximal activation of EGFR.	9	19	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	18	19
A search for SCAMP kinase activities has shown that SCAMPs 1 and 3 , but not SCAMP2 , are tyrosine phosphorylated in EGF stimulated murine fibroblasts overexpressing the EGF receptor ( EGFR ) .	A search for SCAMP kinase activities has shown that SCAMPs 1 and 3, but not SCAMP2, are tyrosine phosphorylated in EGF stimulated murine fibroblasts overexpressing the EGF receptor (EGFR).	20	30	overexpressing	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGF	phosphorylated in EGF	egf	EGF receptor	EGF receptor	egf receptor	22	23	28	30
These effects were also MEK1 dependent and suggested ERK pathway dependent influence of GH on EGF induced EGFR postendocytic trafficking and signaling .	These effects were also MEK1 dependent and suggested ERK pathway dependent influence of GH on EGF induced EGFR postendocytic trafficking and signaling.	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
For example , EGF activates EGFR and its two major downstream signaling pathways , PI3K and MAPK , resulting in CREB phosphorylation [ XREF_BIBR , XREF_BIBR ] .	For example, EGF activates EGFR and its two major downstream signaling pathways, PI3K and MAPK, resulting in CREB phosphorylation [XREF_BIBR, XREF_BIBR].	3	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
11 We also show that third generation , DM EGFR selective TKIs , as a group , alter JM structure via allostery to restore the conformation seen when WT EGFR is activated by the growth factors EGF and HB-EGF .	11 We also show that third generation, DM EGFR selective TKIs, as a group, alter JM structure via allostery to restore the conformation seen when WT EGFR is activated by the growth factors EGF and HB-EGF.	28	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	36	37	29	30
Soluble EGF ( sEGF ) causes internalization and degradation of EGFR , a phenomenon that can result in acute or chronic EGFR downregulation when high ( > > K D ) concentrations are used for stimulation .	Soluble EGF (sEGF) causes internalization and degradation of EGFR, a phenomenon that can result in acute or chronic EGFR downregulation when high (>> K D) concentrations are used for stimulation.	0	22	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	10	11
EGFR could be activated by two ligands : Epidermal Growth Factor ( EGF ) and Transforming Growth Factor-alpha ( TGFalpha ) .	EGFR could be activated by two ligands : Epidermal Growth Factor (EGF) and Transforming Growth Factor-alpha (TGFalpha).	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Epidermal Growth Factor	Epidermal Growth Factor	Epidermal Growth Factor	EGFR	EGFR	EGFR	8	11	0	1
We showed that AG1478 reduced BrdU incorporation level to 9 % in cells expressing LZ-EGFR-GFP and to 11 % in EGF stimulated cells expressing EGFR-GFP ( XREF_FIG ) .	We showed that AG1478 reduced BrdU incorporation level to 9% in cells expressing LZ-EGFR-GFP and to 11% in EGF stimulated cells expressing EGFR-GFP (XREF_FIG).	18	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR-GFP	EGFR-GFP	EGFR-GFP	20	21	24	25
Pretreatment with PD98059 to inhibit both basal and EGF induced ERK activity resulted in significantly enhanced EGF induced EGFR loss compared to cells not pretreated ( XREF_FIG ) .	Pretreatment with PD98059 to inhibit both basal and EGF induced ERK activity resulted in significantly enhanced EGF induced EGFR loss compared to cells not pretreated (XREF_FIG).	12	19	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
Neutralization mutations of the positively charged amino acids abolishes EGFR and PIP 2 interaction , suppresses EGF induced EGFR auto-phosphorylation and down-regulates EGF induced EGFR signaling to ion channels .	Neutralization mutations of the positively charged amino acids abolishes EGFR and PIP 2 interaction, suppresses EGF induced EGFR auto-phosphorylation and down-regulates EGF induced EGFR signaling to ion channels.	22	25	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
Activation of EGFR by EGF leads to an expressional switch from tensin 3 ( TNS3 ) to CTEN , and this up-regulation of CTEN with reduced tensin 3 contributes to EGF promoted mammary cell migration .	Activation of EGFR by EGF leads to an expressional switch from tensin 3 (TNS3) to CTEN, and this up-regulation of CTEN with reduced tensin 3 contributes to EGF promoted mammary cell migration.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	2	3
Administration of EGF after SBR induced a similar expression of EGF receptor protein .	Administration of EGF after SBR induced a similar expression of EGF receptor protein.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	2	3	10	12
These data demonstrate the contribution of EGF mediated EGFR and ERK signaling to the regulation of germinative cells in E. multilocularis , and suggest the EGFR and ERK signaling as a potential therapeutic target for AE and perhaps other human cestodiasis .	These data demonstrate the contribution of EGF mediated EGFR and ERK signaling to the regulation of germinative cells in E. multilocularis, and suggest the EGFR and ERK signaling as a potential therapeutic target for AE and perhaps other human cestodiasis.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Activation of EGFR by EGF involves the formation of a specific dimer of the extracellular ligand binding regions XREF_BIBR - XREF_BIBR , which appears to promote an asymmetric dimer interaction between the kinase domains in which the activity of one kinase subunit ( acceptor kinase ) is stimulated by another ( donor kinase ) 19 .	Activation of EGFR by EGF involves the formation of a specific dimer of the extracellular ligand binding regions XREF_BIBR - XREF_BIBR, which appears to promote an asymmetric dimer interaction between the kinase domains in which the activity of one kinase subunit (acceptor kinase) is stimulated by another (donor kinase) 19.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	2	3
To test this possibility , we assessed the effects of overexpressing wild-type and mutant Trak1 on EGF induced EGFR internalization and degradation , using the overexpression of Hrs as a positive control .	To test this possibility, we assessed the effects of overexpressing wild-type and mutant Trak1 on EGF induced EGFR internalization and degradation, using the overexpression of Hrs as a positive control.	10	19	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
Therefore , IP , FRET and immunoelectron microscopy assays indicate that EGF stimulates EGFR to localize around microtubules and suggest that EGFR travels along microtubules upon EGF stimulation .	Therefore, IP, FRET and immunoelectron microscopy assays indicate that EGF stimulates EGFR to localize around microtubules and suggest that EGFR travels along microtubules upon EGF stimulation.	11	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
The manner in which EGF induces internalization and intracellular trafficking of the EGF receptor has been described in detail .	The manner in which EGF induces internalization and intracellular trafficking of the EGF receptor has been described in detail.	4	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	4	5	12	14
The results confirmed rapid , EGF induced ubiquitinylation of EGFR ( XREF_FIG ) .	The results confirmed rapid, EGF induced ubiquitinylation of EGFR (XREF_FIG).	5	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	9	10
Our findings suggest that HB-EGF is relatively abundant in human gastric cancers and that co-expression of the EGF ligand family may lead to excessive activation of EGF-R in this disorder .	Our findings suggest that HB-EGF is relatively abundant in human gastric cancers and that co-expression of the EGF ligand family may lead to excessive activation of EGF-R in this disorder.	14	27	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	EGF	co-expression of the EGF	egf	EGF-R	EGF-R	egf-r	17	18	26	27
EGFR activation is caused by the release of epidermal growth factor ( EGF )-family ligands by proteases belonging to the a disintegrin and metalloproteinase ( ADAM ) enzyme family .	EGFR activation is caused by the release of epidermal growth factor (EGF)-family ligands by proteases belonging to the a disintegrin and metalloproteinase (ADAM) enzyme family.	0	14	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	0	1
In addition , in vivo activation of ErbB1 by epidermal growth factor ( EGF ) protects the heart against acute stress induced damage .	In addition, in vivo activation of ErbB1 by epidermal growth factor (EGF) protects the heart against acute stress induced damage.	5	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	ErbB1	ErbB1	ErbB1	9	12	7	8
These low-molecular-weight compounds block EGF induced EGFR activation and proliferation of tumor endothelial cells .	These low-molecular-weight compounds block EGF induced EGFR activation and proliferation of tumor endothelial cells.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
In order to evaluate the role of epidermal growth factor ( EGF ) and transforming growth factor alpha ( TGF-alpha ) in colorectal cancer , the present investigation examines changes in EGF and TGF-alpha-mediated activation of overall and EGF receptor ( EGF-R ) associated tyrosine kinase activity in isolated rat colonocytes after administration of the colonic carcinogen azoxymethane .	In order to evaluate the role of epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) in colorectal cancer, the present investigation examines changes in EGF and TGF-alpha-mediated activation of overall and EGF receptor (EGF-R) associated tyrosine kinase activity in isolated rat colonocytes after administration of the colonic carcinogen azoxymethane.	31	40	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	31	32	38	40
Along these lines , our observations that both T669A mutation and pharmacologic ERK inhibition also allowed greater acute EGF induced EGFR activation ( as assessed by blotting of 992 Y and 1068 Y phosphorylation ) and ubiquitination are of substantial interest .	Along these lines, our observations that both T669A mutation and pharmacologic ERK inhibition also allowed greater acute EGF induced EGFR activation (as assessed by blotting of 992 Y and 1068 Y phosphorylation) and ubiquitination are of substantial interest.	15	21	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
Prior to internalization , EGF stimulated EGFR accumulated ubiquitin at 7 K residues and phosphorylation at 7 Y sites and at S ( 1104 ) .	Prior to internalization, EGF stimulated EGFR accumulated ubiquitin at 7 K residues and phosphorylation at 7 Y sites and at S (1104).	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
The EGFR signaling pathway is activated by binding of ligands , EGF , or TGF-alpha which is closely associated with cancer [ XREF_BIBR ] .	The EGFR signaling pathway is activated by binding of ligands, EGF, or TGF-alpha which is closely associated with cancer [XREF_BIBR].	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	1	2
As shown in XREF_FIG , EGF induced significant endocytosis of EGFR but did not dramatically affect the localization of delta-catenin .	As shown in XREF_FIG, EGF induced significant endocytosis of EGFR but did not dramatically affect the localization of delta-catenin.	5	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	10	11
Pro EGF is cleaved to yield EGF , activating the EGF receptor ( EGFR ) , which in turn triggers an intracellular cascade that regulates TRPM6 activity [ XREF_BIBR ] .	Pro EGF is cleaved to yield EGF, activating the EGF receptor (EGFR), which in turn triggers an intracellular cascade that regulates TRPM6 activity [XREF_BIBR].	0	12	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	1	2	10	12
Whereas 1 or 2 muM gefitinib blocked EGF induced activation of EGFR in T98G cells ( XREF_FIG ) , it had no effect on the total abundance ( XREF_FIG ) or cell surface expression ( XREF_SUPPLEMENTARY ) of xCT , suggesting that EGFR promotes xCT expression in a manner independent of its kinase activity .	Whereas 1 or 2 muM gefitinib blocked EGF induced activation of EGFR in T98G cells (XREF_FIG), it had no effect on the total abundance (XREF_FIG) or cell surface expression (XREF_SUPPLEMENTARY) of xCT, suggesting that EGFR promotes xCT expression in a manner independent of its kinase activity.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	11	12
However , despite this , EGF activation of the COC EGFR remained significantly lower at 3 and 6 h of IVM than in vivo , and levels were similar to those observed during FSH supplemented IVM .	However, despite this, EGF activation of the COC EGFR remained significantly lower at 3 and 6 h of IVM than in vivo, and levels were similar to those observed during FSH supplemented IVM.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	10	11
Binding of EGF ligand promotes dimerization of the EGFR [ XREF_BIBR ] .	Binding of EGF ligand promotes dimerization of the EGFR [XREF_BIBR].	2	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	8	9
Gallic acid repressed the EGF induced activation of EGFR and Src ; furthermore , inactivation of Akt and p65 and ERK and c-Jun was a result of the inhibitory effect of gallic acid on the EGF induced MMP-9 up-regulation .	Gallic acid repressed the EGF induced activation of EGFR and Src; furthermore, inactivation of Akt and p65 and ERK and c-Jun was a result of the inhibitory effect of gallic acid on the EGF induced MMP-9 up-regulation.	3	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	8	9
Furthermore , knockdown of p130Cas enhanced EGF induced EGFR internalization and degradation , while overexpression of p130Cas inhibited EGF uptake , indicating that EGFR internalization is likely regulated by p130Cas ( XREF_FIG and XREF_FIG ) .	Furthermore, knockdown of p130Cas enhanced EGF induced EGFR internalization and degradation, while overexpression of p130Cas inhibited EGF uptake, indicating that EGFR internalization is likely regulated by p130Cas (XREF_FIG and XREF_FIG).	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
EGF treatment induced ERK activation as well as the rapid assembly of SHP2 , EGFR , and Gab1 .	EGF treatment induced ERK activation as well as the rapid assembly of SHP2, EGFR, and Gab1.	0	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	14	15
This secondary signal relies on EGF induced EGFR self association and switches suppressive recycling to directional trafficking .	This secondary signal relies on EGF induced EGFR self association and switches suppressive recycling to directional trafficking.	3	9	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
In the case of EGFR , Src mediates EGF independent transactivation , which promotes differential biological effects than EGF stimulation of EGFR This is similar to the observations reported here on the MSP independent activation of RON .	In the case of EGFR, Src mediates EGF independent transactivation, which promotes differential biological effects than EGF stimulation of EGFR This is similar to the observations reported here on the MSP independent activation of RON.	18	24	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	21	22
We used the same concentrations of EGF and ( DNA-BG ) 2 as in our earlier assays and confirmed that , while EGF and ( DNA-BG ) 2 stimulated similar levels of Y1068 phosphorylation after 5 min , only EGF activated EGFR was capable of activating Erk signaling .	We used the same concentrations of EGF and (DNA-BG) 2 as in our earlier assays and confirmed that, while EGF and (DNA-BG) 2 stimulated similar levels of Y1068 phosphorylation after 5 min, only EGF activated EGFR was capable of activating Erk signaling.	38	43	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	39	40	41	42
In contrast , the reductants N-acetyl-L-cysteine [ Cys ( Ac ) ] and dithiothreitol markedly suppressed EGF induced dimerization and activation of the EGF receptor in cells .	In contrast, the reductants N-acetyl-L-cysteine [Cys (Ac)] and dithiothreitol markedly suppressed EGF induced dimerization and activation of the EGF receptor in cells.	16	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	16	17	23	25
The MET and EGFR RTKs when signaled by their ligands , HGF and EGF , respectively , through a cascade of signaling reactions , modulate the ERK and PI3K intracellular regulatory pathways .	The MET and EGFR RTKs when signaled by their ligands, HGF and EGF, respectively, through a cascade of signaling reactions, modulate the ERK and PI3K intracellular regulatory pathways.	1	14	signaled	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	3	4
We previously showed that LAPTM4B inhibits EGF stimulated EGFR lysosomal sorting ( unpublished data ) .	We previously showed that LAPTM4B inhibits EGF stimulated EGFR lysosomal sorting (unpublished data).	5	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
EGFR signaling is stimulated by members of the epidermal growth factor ( EGF ) family of peptide growth factors , whose roles in stimulating ErbB receptor signaling and coupling to biological responses have been intensively studied [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	EGFR signaling is stimulated by members of the epidermal growth factor (EGF) family of peptide growth factors, whose roles in stimulating ErbB receptor signaling and coupling to biological responses have been intensively studied [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	14	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	8	11	0	1
A significant finding is that PKG II is able to inhibit EGF induced activation of EGFR , which is the starting event of the signal transduction of EGF and EGFR mediated pathways .	A significant finding is that PKG II is able to inhibit EGF induced activation of EGFR, which is the starting event of the signal transduction of EGF and EGFR mediated pathways.	11	21	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	15	16
As hypothesized , the addition of EGF to the assembly mixture increased the yield of EGFR and pEGFR incorporated into the NLPs .	As hypothesized, the addition of EGF to the assembly mixture increased the yield of EGFR and pEGFR incorporated into the NLPs.	4	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	6	7	17	18
DAOY clones expressing different EGF-R levels were treated with EGF .	DAOY clones expressing different EGF-R levels were treated with EGF.	4	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	9	10	4	5
To verify whether there were discernible differences in the degradation and recycling of the activated receptor in the control and AnxA6 depleted BT-549 cells , we examined the co-localization of EGF activated EGFR with either LAMP1 ( a late endosomal marker ) or Rab11 ( a recycling endosomal marker ) .	To verify whether there were discernible differences in the degradation and recycling of the activated receptor in the control and AnxA6 depleted BT-549 cells, we examined the co-localization of EGF activated EGFR with either LAMP1 (a late endosomal marker) or Rab11 (a recycling endosomal marker).	28	33	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	30	31	32	33
The EGF activated EGFR is also associated with Cbl in early endosomes , resulting in continued ubiquitination of EGFR .	The EGF activated EGFR is also associated with Cbl in early endosomes, resulting in continued ubiquitination of EGFR.	0	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
Even though the activation level of EGFR was comparable under EGF or GO treatment , as assessed by the tyrosine phosphorylation level ( alphap-Y20 ) ( XREF_FIG ) , the alpha4-2 Ab pulled down the EGF stimulated EGFR with an affinity ~ 3.5 folds higher than that observed under ox-stress ( GO ) activation ( XREF_FIG ) .	Even though the activation level of EGFR was comparable under EGF or GO treatment, as assessed by the tyrosine phosphorylation level (alphap-Y20) (XREF_FIG), the alpha4-2 Ab pulled down the EGF stimulated EGFR with an affinity ~ 3.5 folds higher than that observed under ox-stress (GO) activation (XREF_FIG).	34	38	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	35	36	37	38
We therefore investigated whether membrane anchored EGF can stimulate the EGF receptor .	We therefore investigated whether membrane anchored EGF can stimulate the EGF receptor.	6	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	6	7	10	12
Both EGF treatment and 50 Hz MF exposure could induce EGFR clustering ; however , nystatin pretreatment disrupted this effect .	Both EGF treatment and 50 Hz MF exposure could induce EGFR clustering; however, nystatin pretreatment disrupted this effect.	1	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	10	11
This result prompts us to speculate whether traditional EGFR signalling pathway regulates the protein expression of Aurora-A in the early stage of EGF stimulus in EGFR overexpressed cells .	This result prompts us to speculate whether traditional EGFR signalling pathway regulates the protein expression of Aurora-A in the early stage of EGF stimulus in EGFR overexpressed cells.	22	27	stimulus	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	25	26
Similar results were also observed in the EmER expressing oocytes ( XREF_FIG ) , suggesting that addition of exogenous EGF could activate the parasite EGFR in the oocytes and induce GVBD .	Similar results were also observed in the EmER expressing oocytes (XREF_FIG), suggesting that addition of exogenous EGF could activate the parasite EGFR in the oocytes and induce GVBD.	16	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	24	25
Furthermore , GPRC5A knockdown enhanced EGF induced EGFR and its downstream signaling activation .	Furthermore, GPRC5A knockdown enhanced EGF induced EGFR and its downstream signaling activation.	4	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
The itinerary of EGF induced EGFR trafficking has been intensely studied [ XREF_BIBR ] .	The itinerary of EGF induced EGFR trafficking has been intensely studied [XREF_BIBR].	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
EGF activates EGFR by binding to a cavity between EGFR domain I and III , with binding sites existing on both domain I and III [ XREF_BIBR ] .	EGF activates EGFR by binding to a cavity between EGFR domain I and III, with binding sites existing on both domain I and III [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
11 Epidermal growth factor mediated EGFR activation upregulates MUC5AC there by activating Ras and Raf pathway , which in turn leads to cancer cell proliferation .	11 Epidermal growth factor mediated EGFR activation upregulates MUC5AC there by activating Ras and Raf pathway, which in turn leads to cancer cell proliferation.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Epidermal growth factor	Epidermal growth factor	Epidermal growth factor	EGFR	EGFR	EGFR	1	4	5	6
It has been shown that activation of EGFR by EGF resulted in rapid internalization and degradation of the receptor [ XREF_BIBR , XREF_BIBR ] .	It has been shown that activation of EGFR by EGF resulted in rapid internalization and degradation of the receptor [XREF_BIBR, XREF_BIBR].	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	7	8
The activation of EGFR by EGF can also induce epithelial-mesenchymal transition ( EMT ) , which usually corresponds to increased cell motility [ XREF_BIBR ] .	The activation of EGFR by EGF can also induce epithelial-mesenchymal transition (EMT), which usually corresponds to increased cell motility [XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	3	4
As the objective of tethering EGF to the hydrogels is to stimulate the EGF receptor of cells adhering to the hydrogel on a sustained basis , thus influencing downstream phenotypic responses , we further characterized the EGF tethered to the hydrogel using a direct ELISA approach to quantify the relative amounts of accessible EGF tethered under the different substrate conditions .	As the objective of tethering EGF to the hydrogels is to stimulate the EGF receptor of cells adhering to the hydrogel on a sustained basis, thus influencing downstream phenotypic responses, we further characterized the EGF tethered to the hydrogel using a direct ELISA approach to quantify the relative amounts of accessible EGF tethered under the different substrate conditions.	2	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	5	6	13	15
The epidermal growth factor ( EGF ) ( 10 nM ) promoted growth of A431 cells ( +25 +/-4.6 % ) and mediated epidermal growth factor receptor ( EGFR ) tyrosine kinase activity and autophosphorylation of EGFR were inhibited by Lu and Qu .	The epidermal growth factor (EGF) (10 nM) promoted growth of A431 cells (+25 +/-4.6%) and mediated epidermal growth factor receptor (EGFR) tyrosine kinase activity and autophosphorylation of EGFR were inhibited by Lu and Qu.	3	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	5	6	23	27
In the present study , simultaneous depletion of HRS and TSG101 disrupted the ESCRT pathway , as indicated by the inhibition of EGF stimulated EGFR degradation in Hela cells ( XREF_FIG ) and the enlargement of early endosomes in HEK293 cells ( XREF_FIG ) , but failed to block PCSK9 mediated LDLR degradation in multiple cell types , including cultured hepatocytes ( HuH7 , HepG2 ) , embryonic kidney cells ( HEK293 ) , and primary fibroblasts .	In the present study, simultaneous depletion of HRS and TSG101 disrupted the ESCRT pathway, as indicated by the inhibition of EGF stimulated EGFR degradation in Hela cells (XREF_FIG) and the enlargement of early endosomes in HEK293 cells (XREF_FIG), but failed to block PCSK9 mediated LDLR degradation in multiple cell types, including cultured hepatocytes (HuH7, HepG2), embryonic kidney cells (HEK293), and primary fibroblasts.	20	25	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
Epidermal growth factor ( EGF ) ( PeproTech , Rocky Hill , NJ , US ) was used at a dose of 50ng/mL to stimulate the EGF receptor and mitogen activated protein kinase ( EGFR and MAPK ) pathway .	Epidermal growth factor (EGF) (PeproTech, Rocky Hill, NJ, US) was used at a dose of 50ng/mL to stimulate the EGF receptor and mitogen activated protein kinase (EGFR and MAPK) pathway.	2	28	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	4	5	26	28
As shown in our recent studies [ XREF_BIBR ] , EGF stimulation of HEK293 cells for 30min increased the percentage of the proteinase K-insensitive EGFR from ~ 5 to ~ 60 % ( XREF_SUPPLEMENTARY ) .	As shown in our recent studies [XREF_BIBR], EGF stimulation of HEK293 cells for 30min increased the percentage of the proteinase K-insensitive EGFR from ~ 5 to ~ 60% (XREF_SUPPLEMENTARY).	10	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	24	25
EGF induced EGFR stimulation did not affect the association of integrin alpha 2 beta 1 and EGFR .	EGF induced EGFR stimulation did not affect the association of integrin alpha 2 beta 1 and EGFR.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
EGCG dose-dependently inhibited anchorage independent growth and short-term EGCG exposure substantially decreased EGF induced EGF receptor ( EGFR ) , Akt and ERK1/2 activation , as well as the downregulation of hexokinase 2 ( HK2 ) .	EGCG dose-dependently inhibited anchorage independent growth and short-term EGCG exposure substantially decreased EGF induced EGF receptor (EGFR), Akt and ERK1/2 activation, as well as the downregulation of hexokinase 2 (HK2).	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	12	13	14	16
In MKN1 cells , the EGF induced activation of EGFR that was inhibited by cetuximab in a concentration dependent manner was detected at all stimulation times .	In MKN1 cells, the EGF induced activation of EGFR that was inhibited by cetuximab in a concentration dependent manner was detected at all stimulation times.	4	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	9	10
Thus , significant intracellular pools of activated receptor can accumulate and it has been demonstrated that the majority of EGF stimulated EGFR is localized in the endosomes of many cell types [ XREF_BIBR , XREF_BIBR ] .	Thus, significant intracellular pools of activated receptor can accumulate and it has been demonstrated that the majority of EGF stimulated EGFR is localized in the endosomes of many cell types [XREF_BIBR, XREF_BIBR].	17	23	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
To visualize basal p-EGFR levels , which are lower than levels of EGF induced p-EGFR , we optimized blotting conditions by increasing the total amount of protein loaded ( > 40mug ) and prolonging film exposure times .	To visualize basal p-EGFR levels, which are lower than levels of EGF induced p-EGFR, we optimized blotting conditions by increasing the total amount of protein loaded (> 40mug) and prolonging film exposure times.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	p-EGFR	p-EGFR	p-EGFR	12	13	14	15
Thus , whether referring to extranuclear androgen signaling prostate cancer cells or extranuclear estrogen signaling in breast cancer cells , an important concept to be taken from both examples is that steroid triggered kinase signaling is essentially the same as EGF triggered kinase signaling , only steroids indirectly activate the EGFR through released EGFR ligands , while EGF directly activates the EGFR .	Thus, whether referring to extranuclear androgen signaling prostate cancer cells or extranuclear estrogen signaling in breast cancer cells, an important concept to be taken from both examples is that steroid triggered kinase signaling is essentially the same as EGF triggered kinase signaling, only steroids indirectly activate the EGFR through released EGFR ligands, while EGF directly activates the EGFR.	57	62	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	57	58	61	62
On the other hand , no significant alterations were observed when EGFR was activated by EGF except for TIMP-2 , which exhibited a strong down-regulation .	On the other hand, no significant alterations were observed when EGFR was activated by EGF except for TIMP-2, which exhibited a strong down-regulation.	11	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	11	12
Densitometric analysis of the individual bands relative to beta-actin and total EGFR show that BPD-PDT treated samples were more responsive to EGF stimulation of EGFR activity than control cells ; for BPD-PDT treated samples , the addition of EGF stimulated phosphorylation of EGFR to 180 % of that observed in the no treatment control ( XREF_FIG ) .	Densitometric analysis of the individual bands relative to beta-actin and total EGFR show that BPD-PDT treated samples were more responsive to EGF stimulation of EGFR activity than control cells; for BPD-PDT treated samples, the addition of EGF stimulated phosphorylation of EGFR to 180% of that observed in the no treatment control (XREF_FIG).	21	25	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	24	25
Of interest , EGF can stimulate the contraction of vascular and nonvascular smooth muscles , including the rat aorta , rabbit aorta , and guinea pig gastric smooth muscle , raising the possibility that the direct stimulation of EGFR by EGF related growth factors also could induce smooth muscle contraction in a Rho-kinase-dependent manner .	Of interest, EGF can stimulate the contraction of vascular and nonvascular smooth muscles, including the rat aorta, rabbit aorta, and guinea pig gastric smooth muscle, raising the possibility that the direct stimulation of EGFR by EGF related growth factors also could induce smooth muscle contraction in a Rho-kinase-dependent manner.	36	43	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	40	41	38	39
EGF treatment has been shown to stimulate the formation of ILVs and EGFR sorting into ILVs .	EGF treatment has been shown to stimulate the formation of ILVs and EGFR sorting into ILVs.	0	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	12	13
These results argue that EGF from photoreceptor axons activates EGFR in wrapping glia , which is both necessary and sufficient to induce L1-L4 differentiation .	These results argue that EGF from photoreceptor axons activates EGFR in wrapping glia, which is both necessary and sufficient to induce L1-L4 differentiation.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	9	10
Our results confirmed that EGF rapidly induces the disappearance of EGFR from MCF-10A cell membranes .	Our results confirmed that EGF rapidly induces the disappearance of EGFR from MCF-10A cell membranes.	4	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	10	11
EGFR activation induced by the addition of EGF increased transepithelial electrical resistance ( TER ) in AECs .	EGFR activation induced by the addition of EGF increased transepithelial electrical resistance (TER) in AECs.	0	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	0	1
Ras proteins are very important in the controlling of the MAPK pathway and are activated following EGF stimulation of EGFR .	Ras proteins are very important in the controlling of the MAPK pathway and are activated following EGF stimulation of EGFR.	16	20	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	19	20
Overexpression of ErbB2 has been demonstrated to inhibit epidermal growth factor induced internalization and degradation of epidermal growth factor receptor .	Overexpression of ErbB2 has been demonstrated to inhibit epidermal growth factor induced internalization and degradation of epidermal growth factor receptor.	8	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	8	11	16	20
Because the maximal number of small molecules displayed on the yeast cell surface is estimated to be about 10 6 per yeast cell XREF_BIBR XREF_BIBR , the maximal concentration of cell wall anchored EGF is estimated at 146muM , which implies that a 1.2 x 10 5 -fold of the EC 50 of EGF ( 1.2 nM ) to activate the EGFR in mammalian cells XREF_BIBR .	Because the maximal number of small molecules displayed on the yeast cell surface is estimated to be about 10 6 per yeast cell XREF_BIBR XREF_BIBR, the maximal concentration of cell wall anchored EGF is estimated at 146muM, which implies that a 1.2 x 10 5 -fold of the EC 50 of EGF (1.2 nM) to activate the EGFR in mammalian cells XREF_BIBR.	50	65	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	53	54	61	62
Compared to the effect of EGCG , erlotinib substantially inhibited EGF induced pEGFR , pERK and pAKT .	Compared to the effect of EGCG, erlotinib substantially inhibited EGF induced pEGFR, pERK and pAKT.	10	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	10	11	12	13
In PC cell lines , PA inhibited both constitutive and EGF stimulated EGFR activation , decreasing EGFR phosphorylation .	In PC cell lines, PA inhibited both constitutive and EGF stimulated EGFR activation, decreasing EGFR phosphorylation.	8	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
We found that AKT inhibition reduced the rate of EGF induced EGFR recycling ( XREF_FIG ) .	We found that AKT inhibition reduced the rate of EGF induced EGFR recycling (XREF_FIG).	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
Epidermal growth factor receptor is one of the first reported growth factor receptors that exhibit raft affinity , and EGF induced the coalescence of EGF receptor containing rafts with different type of lipid rafts that contain GPI anchored proteins .	Epidermal growth factor receptor is one of the first reported growth factor receptors that exhibit raft affinity, and EGF induced the coalescence of EGF receptor containing rafts with different type of lipid rafts that contain GPI anchored proteins.	19	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	19	20	24	26
To further investigate how Arg 1175 methylation affects EGFR functionality , we compared tyrosine phosphorylation of EGF stimulated EGFR ( WT ) and EGFR ( R1175K ) with site specific antibodies against phospho-Tyr 845 , Tyr 992 , Tyr 1045 , Tyr 1068 , Tyr 1086 , Tyr 1148 and Tyr 1173 .	To further investigate how Arg 1175 methylation affects EGFR functionality, we compared tyrosine phosphorylation of EGF stimulated EGFR (WT) and EGFR (R1175K) with site specific antibodies against phospho-Tyr 845, Tyr 992, Tyr 1045, Tyr 1068, Tyr 1086, Tyr 1148 and Tyr 1173.	13	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	tyrosine phosphorylation of EGF	egf	EGFR	EGFR	egfr	16	17	18	19
Specifically , we believe that rho may function in the R8 cell to cleave an EGF ligand , that activates EGFR in the R7 cell .	Specifically, we believe that rho may function in the R8 cell to cleave an EGF ligand, that activates EGFR in the R7 cell.	15	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	20	21
We therefore asked whether rapid inactivation of EGF stimulated ErbB1 by gefitinib would propagate to receptors such as ErbB2 and ErbB3 that are phosphorylated by ErbB1 in trans and also to cytosolic kinases that transduce signals downstream of ErbB1 such as ERK , Akt , JNK , and p38 .	We therefore asked whether rapid inactivation of EGF stimulated ErbB1 by gefitinib would propagate to receptors such as ErbB2 and ErbB3 that are phosphorylated by ErbB1 in trans and also to cytosolic kinases that transduce signals downstream of ErbB1 such as ERK, Akt, JNK, and p38.	5	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	7	8	9	10
Glucose transport in the c ' 973 EGFR adipocytes was stimulated by insulin , but not by EGF .	Glucose transport in the c ' 973 EGFR adipocytes was stimulated by insulin, but not by EGF.	7	18	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	7	8
Importantly , in these cells EGFR activity is low under basal conditions , but is greatly enhanced by EGF treatment .	Importantly, in these cells EGFR activity is low under basal conditions, but is greatly enhanced by EGF treatment.	5	19	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	5	6
Pull-down experiments have shown that DJ-1 binds directly to the kinase domain of c-Raf , and this interaction is enhanced upon EGF treatment XREF_BIBR , which augments EGFR and c-Raf activation .	Pull-down experiments have shown that DJ-1 binds directly to the kinase domain of c-Raf, and this interaction is enhanced upon EGF treatment XREF_BIBR, which augments EGFR and c-Raf activation.	21	30	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	27	28
Significantly , we find that ST6Gal-I-mediated sialylation of EGFR stimulates both the basal and EGF induced activation of EGFR .	Significantly, we find that ST6Gal-I-mediated sialylation of EGFR stimulates both the basal and EGF induced activation of EGFR.	12	19	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	18	19
We show , by confocal microscopy analysis , that illumination of adenocarcinomic human alveolar basal epithelial cells ( Human A549 - EGFR biosensor cell line ) with 280 nm at irradiance levels up to 20 times weaker than the UVB solar output for short periods of time ( 15-45 min ) prevents EGF mediated activation of EGFR located on the cell membrane , preventing or reducing cellular disaggregation , formation of filopodia and cell migration .	We show, by confocal microscopy analysis, that illumination of adenocarcinomic human alveolar basal epithelial cells (Human A549 - EGFR biosensor cell line) with 280 nm at irradiance levels up to 20 times weaker than the UVB solar output for short periods of time (15-45 min) prevents EGF mediated activation of EGFR located on the cell membrane, preventing or reducing cellular disaggregation, formation of filopodia and cell migration.	52	57	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	52	53	56	57
In addition , we observed that dynamin2 regulated EGF mediated EGFR downstream Ras/ERK1/2 signaling and p-ERK1/2 accumulation in nucleus .	In addition, we observed that dynamin2 regulated EGF mediated EGFR downstream Ras/ERK1/2 signaling and p-ERK1/2 accumulation in nucleus.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
To test this prediction , we determined the effect of ALG-2 knockdown or overexpression on the kinetics of EGF induced EGFR degradation .	To test this prediction, we determined the effect of ALG-2 knockdown or overexpression on the kinetics of EGF induced EGFR degradation.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
However , unlike the EGF activated ErbB-1 , which is destined primarily to degradation in lysosomes , NDF and TGF-alpha direct their receptors to recycling , probably because these ligands dissociate from their receptors earlier along the endocytic pathway .	However, unlike the EGF activated ErbB-1, which is destined primarily to degradation in lysosomes, NDF and TGF-alpha direct their receptors to recycling, probably because these ligands dissociate from their receptors earlier along the endocytic pathway.	2	20	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	4	5	6	7
In fact , EGF induces association of EGFR , AR and Src and inhibition of Src/AR complex assembly by Casodex suppresses Src activation and mitogenesis induced by EGF [ XREF_BIBR ] .	In fact, EGF induces association of EGFR, AR and Src and inhibition of Src/AR complex assembly by Casodex suppresses Src activation and mitogenesis induced by EGF [XREF_BIBR].	3	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	7	8
Recent findings indicate that FSH induces the expression of epidermal growth factor ( EGF )-like factors [ XREF_BIBR , XREF_BIBR ] and activates the epidermal growth factor receptor ( EGFR ) , which further activates MAPK3/1 [ XREF_BIBR ] .	Recent findings indicate that FSH induces the expression of epidermal growth factor (EGF)-like factors [XREF_BIBR, XREF_BIBR] and activates the epidermal growth factor receptor (EGFR), which further activates MAPK3/1 [XREF_BIBR].	4	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	FSH induces the expression of epidermal growth factor	epidermal growth factor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	9	12	24	28
We therefore , examined the binding of Src with the EGFR in cells treated with EGF for various time intervals in the presence and absence of spermine .	We therefore, examined the binding of Src with the EGFR in cells treated with EGF for various time intervals in the presence and absence of spermine.	7	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	10	11
For example , EGF stimulation of EGFR in A431 cells or in mouse embryo fibroblasts enhanced the degradation of IkappaBalpha and resulted in NFkappaB activation XREF_BIBR .	For example, EGF stimulation of EGFR in A431 cells or in mouse embryo fibroblasts enhanced the degradation of IkappaBalpha and resulted in NFkappaB activation XREF_BIBR.	3	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	6	7
EGF receptor activation of AGS human gastric adenocarcinoma cell line stimulated gastrin gene expression nearly fourfold ; and gastrin reporter constructs transfected into AGS cells were stimulated more than fourfold by EGF .	EGF receptor activation of AGS human gastric adenocarcinoma cell line stimulated gastrin gene expression nearly fourfold; and gastrin reporter constructs transfected into AGS cells were stimulated more than fourfold by EGF.	0	32	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	31	32	0	2
In addition , we have shown that the functionally distinct EGFR ligands , EGF and transforming growth factor-alpha ( TGFalpha ) , exert differing effects on EGFR downregulation and hence on the duration of ErbB2 co-activation : high concentrations of EGF initially cause prolonged EGFR activation associated with ErbB2 heterodimerisation , followed by eventual EGFR downregulation and signal cessation ; whereas TGFalpha fails to downregulate EGFR , leading to sustained signalling ( Gulliford et al , 1997 ; Ouyang et al , 1999a ) .	In addition, we have shown that the functionally distinct EGFR ligands, EGF and transforming growth factor-alpha (TGFalpha), exert differing effects on EGFR downregulation and hence on the duration of ErbB2 co-activation : high concentrations of EGF initially cause prolonged EGFR activation associated with ErbB2 heterodimerisation, followed by eventual EGFR downregulation and signal cessation; whereas TGFalpha fails to downregulate EGFR, leading to sustained signalling (Gulliford et al, 1997; Ouyang et al, 1999a).	38	45	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	40	41	44	45
Moreover , EGF induced transient expression of EGF receptor mRNA followed by the de novo synthesis of EGF receptor protein .	Moreover, EGF induced transient expression of EGF receptor mRNA followed by the de novo synthesis of EGF receptor protein.	2	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	2	3	7	9
As EGF is known to specifically activate the EGF receptor ( EGFR ) , we investigated whether the activation of the EGFR complex as well as the activation of its downstream effectors , ERK1/2 and AKT , is modulated by NPM1 expression level .	As EGF is known to specifically activate the EGF receptor (EGFR), we investigated whether the activation of the EGFR complex as well as the activation of its downstream effectors, ERK1/2 and AKT, is modulated by NPM1 expression level.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	1	2	8	10
EGF activated epidermal growth factor receptor ( EGFR ) and triggered resistance to sunitinib , E7080 , vandetanib , and sorafenib by transducing bypass survival signaling through ERK and AKT .	EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT.	0	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	2	6
One explanation for these results could be that IGF induced nuclear RNF11 is not sufficient to mediate the up-regulation of SEC23/SEC24 components on its own , and factors additional to RNF11 are necessary to mediate the EGF stimulated up-regulation of SEC23/24 and EGFR transport .	One explanation for these results could be that IGF induced nuclear RNF11 is not sufficient to mediate the up-regulation of SEC23/SEC24 components on its own, and factors additional to RNF11 are necessary to mediate the EGF stimulated up-regulation of SEC23/24 and EGFR transport.	35	43	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	36	37	42	43
This study investigated a recombinant protein called epidermal growth factor bispecific angiotoxin ( eBAT ) , which is designed to target the epidermal growth factor receptor ( EGFR ) on cancer cells and the urokinase plasminogen activator receptor ( uPAR ) on cancer cells and associated tumor vasculature .	This study investigated a recombinant protein called epidermal growth factor bispecific angiotoxin (eBAT), which is designed to target the epidermal growth factor receptor (EGFR) on cancer cells and the urokinase plasminogen activator receptor (uPAR) on cancer cells and associated tumor vasculature.	7	26	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	7	10	22	26
In contrast to transforming growth factor-alpha and E4T , which each enhanced EGFR recycling , EGF stimulation was shown to promote EGFR degradation XREF_BIBR .	In contrast to transforming growth factor-alpha and E4T, which each enhanced EGFR recycling, EGF stimulation was shown to promote EGFR degradation XREF_BIBR.	15	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	21	22
In addition , treatment of these activated primary HSC with EGF increases phospho-EGFR , decreases total EGFR and increases phospho-ERK consistent with the DEN rat tissue western blots ( XREF_FIG ) .	In addition, treatment of these activated primary HSC with EGF increases phospho-EGFR, decreases total EGFR and increases phospho-ERK consistent with the DEN rat tissue western blots (XREF_FIG).	8	13	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	phospho-EGFR	phospho-EGFR	phospho-EGFR	10	11	12	13
In contrast , EGF , when added for several hours , did not cause accumulation of the EGF receptor at this site .	In contrast, EGF, when added for several hours, did not cause accumulation of the EGF receptor at this site.	3	19	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	3	4	17	19
It has also been shown that EGF activation of EGFR further accentuates CDCP1 induced pro cancer effects by inhibiting proteasome mediated , palmitoylation dependent constitutive degradation of CDCP1 .	It has also been shown that EGF activation of EGFR further accentuates CDCP1 induced pro cancer effects by inhibiting proteasome mediated, palmitoylation dependent constitutive degradation of CDCP1.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	9	10
This study reveals that the expression of cell surface MUC1 is a critical enhancer of EGF induced EGFR activation in human breast and colon cancer cells .	This study reveals that the expression of cell surface MUC1 is a critical enhancer of EGF induced EGFR activation in human breast and colon cancer cells.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
Taken together , these results suggest that microtubule formation is required for EGF induced EGFR trafficking from the cell surface to the Golgi .	Taken together, these results suggest that microtubule formation is required for EGF induced EGFR trafficking from the cell surface to the Golgi.	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Altogether these results indicate that EGF treatment can result in EGFR activation and consequentially in an increased expression of ZNF216 .	Altogether these results indicate that EGF treatment can result in EGFR activation and consequentially in an increased expression of ZNF216.	5	12	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	10	11
This cytokine receptor mediated transactivation event effectively modulates EGF induced EGFR trafficking and signaling [ XREF_BIBR ] .	This cytokine receptor mediated transactivation event effectively modulates EGF induced EGFR trafficking and signaling [XREF_BIBR].	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
To investigate whether any of the genes in the 194 gene signature were regulated in an EGFR dependent manner , we queried a publicly available database of MCF-7 breast cancer cells that had been stably transfected with constitutively active kinases ( Raf1 , MEK1 , ErbB2 ) or with wild-type EGFR , which was activated by short-term EGF treatment XREF_BIBR .	To investigate whether any of the genes in the 194 gene signature were regulated in an EGFR dependent manner, we queried a publicly available database of MCF-7 breast cancer cells that had been stably transfected with constitutively active kinases (Raf1, MEK1, ErbB2) or with wild-type EGFR, which was activated by short-term EGF treatment XREF_BIBR.	35	59	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	57	58	50	51
This suggests that EGFR and PAFR , stimulated by EGF , can potentially activate common downstream intracellular signaling pathways .	This suggests that EGFR and PAFR, stimulated by EGF, can potentially activate common downstream intracellular signaling pathways.	3	13	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	3	4
This suggests that LZ-EGFR-GFP functions similarly to EGF activated EGFR-GFP in promoting cell proliferation .	This suggests that LZ-EGFR-GFP functions similarly to EGF activated EGFR-GFP in promoting cell proliferation.	5	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR-GFP	EGFR-GFP	EGFR-GFP	7	8	9	10
Biologically , the presence of EGF often increases the formation of EGFR dimers , so we hypothesized that adding EGF to the NLP assembly mixture would produce a higher yield of EGFR-NLPs containing homodimers as well as multimers compared to the assembly mixtures made without EGF supplementation .	Biologically, the presence of EGF often increases the formation of EGFR dimers, so we hypothesized that adding EGF to the NLP assembly mixture would produce a higher yield of EGFR-NLPs containing homodimers as well as multimers compared to the assembly mixtures made without EGF supplementation.	3	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	11	12
The downstream branch of the EGF pathway involving phospholipase Cgamma PLC-3 and IP3 receptor ITR-1 promotes healthy aging outcomes of EGFR activation .	The downstream branch of the EGF pathway involving phospholipase Cgamma PLC-3 and IP3 receptor ITR-1 promotes healthy aging outcomes of EGFR activation.	5	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	20	21
In the Drosophila intestine , VMs act as the stem cell niche and produce growth factors , such as the EGF family member Vein , that stimulates EGFR signaling in stem cells and contribute to their maintenance and proliferation .	In the Drosophila intestine, VMs act as the stem cell niche and produce growth factors, such as the EGF family member Vein, that stimulates EGFR signaling in stem cells and contribute to their maintenance and proliferation.	20	28	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	27	28
After serum starvation overnight , EGFR activation by EGF was suppressed by pre-treatment with belinostat .	After serum starvation overnight, EGFR activation by EGF was suppressed by pre-treatment with belinostat.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	5	6
Thus , EGF treatment caused transient activation of EGFR and MAPK in MKN1 cells that was reverted by concomitant cetuximab treatment to some extent but had only marginal effects on AKT signaling .	Thus, EGF treatment caused transient activation of EGFR and MAPK in MKN1 cells that was reverted by concomitant cetuximab treatment to some extent but had only marginal effects on AKT signaling.	2	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	8	9
We speculate that the inconsistencies between the literature and our findings stem from comparing EGFR stimulation triggered by exogenous EGF to a blockade of endogenous AREG-EGFR signaling .	We speculate that the inconsistencies between the literature and our findings stem from comparing EGFR stimulation triggered by exogenous EGF to a blockade of endogenous AREG-EGFR signaling.	14	20	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	14	15
In the three characteristic episodes of the generic model of epidermal growth factor induced EGFR endocytosis that we use for our analysis we state that the vesicle-episode comprises single and early endosomes and the cluster-episode comprises clustered and late endosomes .	In the three characteristic episodes of the generic model of epidermal growth factor induced EGFR endocytosis that we use for our analysis we state that the vesicle-episode comprises single and early endosomes and the cluster-episode comprises clustered and late endosomes.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	10	13	14	15
Tethered EGF induces sustained EGFR mediated signaling in immortalized and primary human MSCs .	Tethered EGF induces sustained EGFR mediated signaling in immortalized and primary human MSCs.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	4	5
While EGF first stimulates the activation of EGFR , and subsequently induces pancreatic cancer cell proliferation , concurrent EGF induced the activation of ROCK then turns off the activated EGFR pathway .	While EGF first stimulates the activation of EGFR, and subsequently induces pancreatic cancer cell proliferation, concurrent EGF induced the activation of ROCK then turns off the activated EGFR pathway.	17	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	29	30
Since we had already linked Endo II to EGFR signaling in TNBC cells [ XREF_BIBR ] , we selected SK-BR-3 and HCC1954 cells that highly express both EGFR and HER2 to study the effects of Endo II KD on EGF induced EGFR and HER2 signaling .	Since we had already linked Endo II to EGFR signaling in TNBC cells [XREF_BIBR], we selected SK-BR-3 and HCC1954 cells that highly express both EGFR and HER2 to study the effects of Endo II KD on EGF induced EGFR and HER2 signaling.	31	44	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	39	40	41	42
Similarly , EGF treatment of A431 cells induces concomitant hetero-oligomerization of active ErbB2 with inactive EGFR , of active EGFR with inactive ErbB2 , and of inactive ErbB2 with kinase defective ErbB3 .	Similarly, EGF treatment of A431 cells induces concomitant hetero-oligomerization of active ErbB2 with inactive EGFR, of active EGFR with inactive ErbB2, and of inactive ErbB2 with kinase defective ErbB3.	2	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	19	20
Furthermore , Eps15 is recruited to the plasma membrane upon EGF stimulation of EGFR , and expression of dominant negative Eps15 as well as siRNA mediated knockdown of Eps15 has been shown to inhibit EGFR endocytosis .	Furthermore, Eps15 is recruited to the plasma membrane upon EGF stimulation of EGFR, and expression of dominant negative Eps15 as well as siRNA mediated knockdown of Eps15 has been shown to inhibit EGFR endocytosis.	10	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	13	14
EGF stimulated a time dependent increase in EGF receptor associated PI kinase activity measured in EGF receptor immunoprecipitates .	EGF stimulated a time dependent increase in EGF receptor associated PI kinase activity measured in EGF receptor immunoprecipitates.	0	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	7	9
To assess the role of these ligands in mediating TCDD dependent EGFR down-regulation , NHEKs were treated with TCDD or EGF in the presence or absence of batimastat ( 3 muM ) or neutralizing antibodies for AREG , EREG , or TGF-alpha , alone or in combination .	To assess the role of these ligands in mediating TCDD dependent EGFR down-regulation, NHEKs were treated with TCDD or EGF in the presence or absence of batimastat (3 muM) or neutralizing antibodies for AREG, EREG, or TGF-alpha, alone or in combination.	11	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	11	12
We showed that GroA ( nucleolin inhibitor ) reduced ErbB1 and nucleolin interaction , affected EGF induced ErbB1 activation and facilitated the degradation of ErbB1 .	We showed that GroA (nucleolin inhibitor) reduced ErbB1 and nucleolin interaction, affected EGF induced ErbB1 activation and facilitated the degradation of ErbB1.	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	15	16	17	18
EGF+ D eguelin treatment showed EGFR expression pattern similar to those cells treated with EGF only ( data not shown for 10 min ) .	EGF+D eguelin treatment showed EGFR expression pattern similar to those cells treated with EGF only (data not shown for 10 min).	5	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	5	6
If caveolae were involved in EGFR internalization stimulated by high concentrations of EGF to any significant degree , two possible mechanisms can be envisioned : either the EGFR containing caveolae become internalized in a single-wave process , leading to depletion of the plasma membrane for caveolae as has been reported for SV40 virus , or activation of EGFR stimulates an increased mobility or turnover of caveolae so that internalized caveolae become replaced by new caveolae at the plasma membrane .	If caveolae were involved in EGFR internalization stimulated by high concentrations of EGF to any significant degree, two possible mechanisms can be envisioned : either the EGFR containing caveolae become internalized in a single-wave process, leading to depletion of the plasma membrane for caveolae as has been reported for SV40 virus, or activation of EGFR stimulates an increased mobility or turnover of caveolae so that internalized caveolae become replaced by new caveolae at the plasma membrane.	5	13	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	5	6
It is well established that the EGF triggers dimerization of the epidermal growth factor receptor ( EGFR ) , followed by recruitment and activation of intracellular signal transducers such as proteins containing SH2 ( src homology domain 2 ) or PTB ( phosphotyrosine binding ) domain XREF_BIBR , XREF_BIBR .	It is well established that the EGF triggers dimerization of the epidermal growth factor receptor (EGFR), followed by recruitment and activation of intracellular signal transducers such as proteins containing SH2 (src homology domain 2) or PTB (phosphotyrosine binding) domain XREF_BIBR, XREF_BIBR.	5	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	6	7	11	15
In other studies , EGF induced a rapid association of EGF receptor with Triton X-100-insoluble ( cytoskeletal ) elements .	In other studies, EGF induced a rapid association of EGF receptor with Triton X-100-insoluble (cytoskeletal) elements.	4	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	4	5	10	12
The influence of gravity on EGF induced EGF receptor clustering and gene expression as well as on actin polymerization and cell rounding have been investigated in adherent A431 epithelial cells with the use of sounding rockets to create microgravity conditions .	The influence of gravity on EGF induced EGF receptor clustering and gene expression as well as on actin polymerization and cell rounding have been investigated in adherent A431 epithelial cells with the use of sounding rockets to create microgravity conditions.	3	9	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	5	6	7	9
As expected , EGF stimulation of WT-EGFR activated MAPK and Erk and WNK1 in BE2C and IMR32 cells respectively ( XREF_FIG ) .	As expected, EGF stimulation of WT-EGFR activated MAPK and Erk and WNK1 in BE2C and IMR32 cells respectively (XREF_FIG).	3	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	WT-EGFR	WT-EGFR	WT-EGFR	3	4	6	7
Surprisingly , we have found that B1SP is not only able to inhibit SEMA3C induced RTK activation but B1SP is also able to suppress RTK activation by its cognate ligands , that is , EGF induced EGFR activation and HGF induced MET activation .	Surprisingly, we have found that B1SP is not only able to inhibit SEMA3C induced RTK activation but B1SP is also able to suppress RTK activation by its cognate ligands, that is, EGF induced EGFR activation and HGF induced MET activation.	34	37	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	34	35	36	37
Taken together , these data indicate that 225 mAb induces internalization and downregulation of EGFR via a mechanism distinct from that underlying EGF induced EGFR internalization and downregulation .	Taken together, these data indicate that 225 mAb induces internalization and downregulation of EGFR via a mechanism distinct from that underlying EGF induced EGFR internalization and downregulation.	18	25	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
The signaling pathways transmitted at endosomes can be qualitatively different from those originated at the plasma membrane , as has been shown for EGF activated ErbB1 and EGFR [ XREF_BIBR ] .	The signaling pathways transmitted at endosomes can be qualitatively different from those originated at the plasma membrane, as has been shown for EGF activated ErbB1 and EGFR [XREF_BIBR].	21	27	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	23	24	25	26
In order to assess whether EGF stimulated anterograde lysosome trafficking is EGFR specific , we treated cells with the EGFR inhibitor AG1478 or the c-Met inhibitor SU11274 in the presence or absence of EGF and observed the redistribution of LAMP-1 positive vesicles ( red ) by immunofluorescence microscopy .	In order to assess whether EGF stimulated anterograde lysosome trafficking is EGFR specific, we treated cells with the EGFR inhibitor AG1478 or the c-Met inhibitor SU11274 in the presence or absence of EGF and observed the redistribution of LAMP-1 positive vesicles (red) by immunofluorescence microscopy.	5	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	11	12
Without EGF stimulation EGFR was randomly distributed while after stimulation with EGF for 30 min , EGFR was accumulated around alpha-tubulin labeled microtubule bundles .	Without EGF stimulation EGFR was randomly distributed while after stimulation with EGF for 30 min, EGFR was accumulated around alpha-tubulin labeled microtubule bundles.	0	6	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
EGF treatment of cells led to transient association of Cbl and the epidermal growth factor receptor ( EGFR ) with a constitutive CD2AP and endophilin complex .	EGF treatment of cells led to transient association of Cbl and the epidermal growth factor receptor (EGFR) with a constitutive CD2AP and endophilin complex.	0	16	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	12	16
As EGF can be secreted by lung epithelial cancer and/or stromal cells , we investigated whether an autocrine-paracrine EGF mediated activation of the EGFR signaling in H2228 cells could explain their partial resistance to ALK inhibition and overcome ALK inhibition of ALK sensitive cells .	As EGF can be secreted by lung epithelial cancer and/or stromal cells, we investigated whether an autocrine-paracrine EGF mediated activation of the EGFR signaling in H2228 cells could explain their partial resistance to ALK inhibition and overcome ALK inhibition of ALK sensitive cells.	18	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	23	24
EGF also induced significant downregulation of EGFR to undetectable levels after 3 hr of treatment .	EGF also induced significant downregulation of EGFR to undetectable levels after 3 hr of treatment.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	6	7
In summary , we have demonstrated in MCF10A cells and SUM149 breast cancer cells that AR activation of EGFR results in increased steady-state levels of EGFR protein , less EGFR phosphorylation at Y1045 and less ubiquitination of the receptor compared with EGFR that is activated by EGF .	In summary, we have demonstrated in MCF10A cells and SUM149 breast cancer cells that AR activation of EGFR results in increased steady-state levels of EGFR protein, less EGFR phosphorylation at Y1045 and less ubiquitination of the receptor compared with EGFR that is activated by EGF.	38	47	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	46	47	41	42
EGF enhances the transfection efficiency of dendriplexes in human breast cancer cell line MCF-7 and EGFR .	EGF enhances the transfection efficiency of dendriplexes in human breast cancer cell line MCF-7 and EGFR.	0	16	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	15	16
The AC expresses and secretes the epidermal growth factor ( EGF )-like ligand LIN-3 that activates the EGF receptor LET-23 in the underlying VPCs .	The AC expresses and secretes the epidermal growth factor (EGF)-like ligand LIN-3 that activates the EGF receptor LET-23 in the underlying VPCs.	10	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	10	11	17	19
Although the activation fails to trigger the dimerization of EGFR typically induced by EGF , it increases phosphorylation , which is accompanied by a loss of PTP activity .	Although the activation fails to trigger the dimerization of EGFR typically induced by EGF, it increases phosphorylation, which is accompanied by a loss of PTP activity.	7	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	9	10
To assess the functional role of TGF-alpha in colonic carcinogenesis the present investigation examines the changes in TGF-alpha-and EGF induced activation of intrinsic tyrosine kinase ( Tyr k ) activity of EGFR in the colonic mucosa of rats after administration of the colonic carcinogen azoxymethane ( AOM ; 20 mg/kg body wt ) .	To assess the functional role of TGF-alpha in colonic carcinogenesis the present investigation examines the changes in TGF-alpha-and EGF induced activation of intrinsic tyrosine kinase (Tyr k) activity of EGFR in the colonic mucosa of rats after administration of the colonic carcinogen azoxymethane (AOM; 20 mg/kg body wt).	15	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	31	32
Surprisingly , despite the pronounced impact of in situ Sia editing on EGF induced EGFR dimerization and activation , little influence of this treatment on EGF induced EGFR degradation was observed ( XREF_SUPPLEMENTARY ) .	Surprisingly, despite the pronounced impact of in situ Sia editing on EGF induced EGFR dimerization and activation, little influence of this treatment on EGF induced EGFR degradation was observed (XREF_SUPPLEMENTARY).	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Fixed cell immunofluorescence revealed that EGF stimulated COS-7 cells expressing endogenous EGF-R with either wt GFP-Cbl or the F434A mutant contained enlarged , EEA1/EGF-R/GFP-positive early endosomes ( XREF_FIG ) .	Fixed cell immunofluorescence revealed that EGF stimulated COS-7 cells expressing endogenous EGF-R with either wt GFP-Cbl or the F434A mutant contained enlarged, EEA1/EGF-R/GFP-positive early endosomes (XREF_FIG).	5	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	5	6	11	12
In panels A1 , B1 and C1 it can be observed that EGF has induced EGFR internalization , alone and when conjugated with the HAOA coated gold nanoparticles .	In panels A1, B1 and C1 it can be observed that EGF has induced EGFR internalization, alone and when conjugated with the HAOA coated gold nanoparticles.	12	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	15	16
We have demonstrated previously that the human picornavirus Echovirus 1 ( EV1 ) triggers an infectious internalization pathway that follows closely , but seems to stay separate , from the epidermal growth factor receptor ( EGFR ) pathway triggered by epidermal growth factor ( EGF ) .	We have demonstrated previously that the human picornavirus Echovirus 1 (EV1) triggers an infectious internalization pathway that follows closely, but seems to stay separate, from the epidermal growth factor receptor (EGFR) pathway triggered by epidermal growth factor (EGF).	30	43	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	40	43	30	34
For example , KLK1 cleaved pro epidermal growth factor ( EGF ) into mature EGF , which finally activated EGF receptor ( EGFR ) signaling pathway and led to hypertrophy of primary cultured tracheal submucosal gland cells XREF_BIBR .	For example, KLK1 cleaved pro epidermal growth factor (EGF) into mature EGF, which finally activated EGF receptor (EGFR) signaling pathway and led to hypertrophy of primary cultured tracheal submucosal gland cells XREF_BIBR.	4	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	14	15	19	21
Increased internalization of Texas Red-EGF in S2VP10 cells corresponded to increased levels of EGF induced EGFR internalization with colocalization of the probe and EEA1 .	Increased internalization of Texas Red-EGF in S2VP10 cells corresponded to increased levels of EGF induced EGFR internalization with colocalization of the probe and EEA1.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
We previously reported that metabolites of the nonsteroidal anti-inflammatory drug sulindac downregulate the expression of EGFR and inhibit basal and EGF induced EGFR signaling through extracellular signal regulated kinase 1/2 .	We previously reported that metabolites of the nonsteroidal anti-inflammatory drug sulindac downregulate the expression of EGFR and inhibit basal and EGF induced EGFR signaling through extracellular signal regulated kinase 1/2.	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
Transforming growth factor-alpha ( TGF-alpha ) is a member of the epidermal growth factor family that binds to and activates EGF receptor ( EGFR ) .	Transforming growth factor-alpha (TGF-alpha) is a member of the epidermal growth factor family that binds to and activates EGF receptor (EGFR).	11	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	11	14	20	22
P. aeruginosa ExoS ADPr inhibits EGF activated EGFR trafficking to lysosomes .	P. aeruginosa ExoS ADPr inhibits EGF activated EGFR trafficking to lysosomes.	4	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Immunoblots using antibodies against phosphotyrosine ( p-Tyr ) demonstrated that EGF treatment of intact cells increased the p-Tyr content of at least seven proteins ( EGF-R , 115 , 100 , 75 , 66 , 57 , and 52 kDa ) within 5 s. Incubation of intact cells with EGF at 0 degrees C to prevent endocytosis still resulted in tyrosine phosphorylation of these seven proteins .	Immunoblots using antibodies against phosphotyrosine (p-Tyr) demonstrated that EGF treatment of intact cells increased the p-Tyr content of at least seven proteins (EGF-R, 115, 100, 75, 66, 57, and 52 kDa) within 5 s. Incubation of intact cells with EGF at 0 degrees C to prevent endocytosis still resulted in tyrosine phosphorylation of these seven proteins.	10	39	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	10	11	25	26
To examine EGF induced EGFR downregulation ( XREF_FIG ) , CHO-GHR cells were cotransfected with FLAG tagged ErbB2 or a vector control and either WT EGFR or EGFR T669A , as indicated , and treated with EGF for 3h in the presence of CHX , as in XREF_FIG .	To examine EGF induced EGFR downregulation (XREF_FIG), CHO-GHR cells were cotransfected with FLAG tagged ErbB2 or a vector control and either WT EGFR or EGFR T669A, as indicated, and treated with EGF for 3h in the presence of CHX, as in XREF_FIG.	1	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
EGF at 20 ng/mL , which maximally stimulated EGFR activation ( data not shown ) , markedly decreased AR protein at 24 hours in hormone depleted medium ( XREF_FIG , left ) or in FBS medium ( XREF_FIG , right ) , with a corresponding decrease in PSA protein .	EGF at 20 ng/mL, which maximally stimulated EGFR activation (data not shown), markedly decreased AR protein at 24 hours in hormone depleted medium (XREF_FIG, left) or in FBS medium (XREF_FIG, right), with a corresponding decrease in PSA protein.	0	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	8	9
These data demonstrate that the Aurora-A promoter is activated by EGF stimulation in EGFR expressing cultured cell lines .	These data demonstrate that the Aurora-A promoter is activated by EGF stimulation in EGFR expressing cultured cell lines.	10	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	13	14
In addition , EGFR-GFP immunoprecipitates from HeLa cells treated with EGF or anisomycin were immunoblotted with the anti-phosphotyrosine antibody 4G10 confirming that EGF , but not anisomycin , induced tyrosine phosphorylation of the receptor ( XREF_FIG ) .	In addition, EGFR-GFP immunoprecipitates from HeLa cells treated with EGF or anisomycin were immunoblotted with the anti-phosphotyrosine antibody 4G10 confirming that EGF, but not anisomycin, induced tyrosine phosphorylation of the receptor (XREF_FIG).	3	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR-GFP	EGFR-GFP	EGFR-GFP	10	11	3	4
Furthermore , EGF stimulation of EGFR induces PLCgamma1 and calcium dependent signaling responsible for the selective internalization of the receptor by CDE [ XREF_BIBR ] .	Furthermore, EGF stimulation of EGFR induces PLCgamma1 and calcium dependent signaling responsible for the selective internalization of the receptor by CDE [XREF_BIBR].	2	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	5	6
As appositive control , EGF stimulated EGFR and Akt activation in YAMC cells ( XREF_FIG ) .	As appositive control, EGF stimulated EGFR and Akt activation in YAMC cells (XREF_FIG).	4	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
Wild-type EGFR is normally activated by binding of the epidermal growth factor ( EGF ) to the extracellular domain of EGFR .	Wild-type EGFR is normally activated by binding of the epidermal growth factor (EGF) to the extracellular domain of EGFR.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	9	12	1	2
Spry2 can stabilize EGFR by binding and sequestering c-Cbl , which mediates EGFR degradation , and suppression of Spry2 impairs EGF mediated EGFR signaling XREF_BIBR .	Spry2 can stabilize EGFR by binding and sequestering c-Cbl, which mediates EGFR degradation, and suppression of Spry2 impairs EGF mediated EGFR signaling XREF_BIBR.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
Instead of lysosomal degradation or plasma membrane recycling , EGFR accumulates in a subset of LBPA rich perinuclear multivesicular bodies ( MVBs ) distinct from those carrying EGF stimulated EGFR .	Instead of lysosomal degradation or plasma membrane recycling, EGFR accumulates in a subset of LBPA rich perinuclear multivesicular bodies (MVBs) distinct from those carrying EGF stimulated EGFR.	23	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	29	30
Multiple signaling pathways are stimulated when a member of the EGF family binds to and activates EGFR .	Multiple signaling pathways are stimulated when a member of the EGF family binds to and activates EGFR.	10	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	16	17
Within 2 min , EGF elicits EGFR dependent activation of phospholipase C gamma ( PLCgamma ) , producing inositol triphosphate ( IP 3 ) , which binds to IP 3 receptor ( IP 3 R ) , opening the endoplasmic reticulum IP 3 R Ca 2+ channels , resulting in increased intracellular Ca 2+ .	Within 2 min, EGF elicits EGFR dependent activation of phospholipase C gamma (PLCgamma), producing inositol triphosphate (IP 3), which binds to IP 3 receptor (IP 3 R), opening the endoplasmic reticulum IP 3 R Ca 2+ channels, resulting in increased intracellular Ca 2+.	4	8	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
These were evaluated for their ability to inhibit the tyrosine phosphorylating action of EGF stimulated full-length EGFR enzyme and for inhibition of autophosphorylation of the EGFR in A431 human epidermoid carcinoma cells in culture .	These were evaluated for their ability to inhibit the tyrosine phosphorylating action of EGF stimulated full-length EGFR enzyme and for inhibition of autophosphorylation of the EGFR in A431 human epidermoid carcinoma cells in culture.	11	29	stimulated	Positive_regulation_syntax_1_verb	Positive_activation	Negative_regulation	EGF	EGF	egf	EGFR	autophosphorylation of the EGFR	egfr	13	14	25	26
Whereas EGFR is activated by EGF and related growth factors , ErbB-3 and -4 are receptors for the neuregulins ( NRGs ) [ XREF_BIBR ] .	Whereas EGFR is activated by EGF and related growth factors, ErbB-3 and -4 are receptors for the neuregulins (NRGs) [XREF_BIBR].	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	1	2
Compound 2 , but not compound 1 , prevented EGF induced activation of EGFR ( Tyr1173 ) .	Compound 2, but not compound 1, prevented EGF induced activation of EGFR (Tyr1173).	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	13	14
It is well known that activation of EGFR by EGF or elevation of intra-spermatozoal [ Ca 2+ ] using Ca 2+ -ionophore activates PLCgamma .	It is well known that activation of EGFR by EGF or elevation of intra-spermatozoal [Ca 2+] using Ca 2+ -ionophore activates PLCgamma.	5	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	7	8
In contrast , we observed EGF induced in vivo association of nuclear EGFR to the B-Myb promoter and the association is only detected at the G1/S phase and is abolished by EGFR kinase inhibitor .	In contrast, we observed EGF induced in vivo association of nuclear EGFR to the B-Myb promoter and the association is only detected at the G1/S phase and is abolished by EGFR kinase inhibitor.	5	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	12	13
Here we studied the role of EGFR C-terminus in EGF induced EGFR internalization with or without EGFR kinase activation .	Here we studied the role of EGFR C-terminus in EGF induced EGFR internalization with or without EGFR kinase activation.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
Moreover , we found that the PRMT5-EGFR association ( XREF_SUPPLEMENTARY , top ) and the Arg 1175 methylation status ( XREF_SUPPLEMENTARY , bottom ) remained consistent before and after EGF mediated EGFR activation , indicating that EGF stimulation and EGFR kinase activity are not required for Arg 1175 methylation .	Moreover, we found that the PRMT5-EGFR association (XREF_SUPPLEMENTARY, top) and the Arg 1175 methylation status (XREF_SUPPLEMENTARY, bottom) remained consistent before and after EGF mediated EGFR activation, indicating that EGF stimulation and EGFR kinase activity are not required for Arg 1175 methylation.	29	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	31	32
Importantly , our studies in the presence of monensin or chloroquine demonstrated clear , predominant co-localization of AR stimulated EGFRs in Rab11 positive vesicles , and EGF stimulated EGFR in LAMP positive lysosomes , respectively ( XREF_FIG , AR 60 min/M and EGF 60 min/Ch ) .	Importantly, our studies in the presence of monensin or chloroquine demonstrated clear, predominant co-localization of AR stimulated EGFRs in Rab11 positive vesicles, and EGF stimulated EGFR in LAMP positive lysosomes, respectively (XREF_FIG, AR 60 min/M and EGF 60 min/Ch).	26	29	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
Meanwhile , the EGFR activation induced by EGF in MCF-12A and MCF-10A cells was prevented in the presence of baicalein .	Meanwhile, the EGFR activation induced by EGF in MCF-12A and MCF-10A cells was prevented in the presence of baicalein.	3	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	3	4
In particular , GH activation of the ERK signaling pathway causes phosphorylation of EGFR at the intracellular residue Thr 669 , resulting in modulation of EGF induced EGFR tyrosine phopshorylation and downregulation .	In particular, GH activation of the ERK signaling pathway causes phosphorylation of EGFR at the intracellular residue Thr 669, resulting in modulation of EGF induced EGFR tyrosine phopshorylation and downregulation.	23	29	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	27	28
EGF beads simultaneously activate the EGFR while blocking its endocytosis and allow analysis of EGFR signaling from the plasma membrane .	EGF beads simultaneously activate the EGFR while blocking its endocytosis and allow analysis of EGFR signaling from the plasma membrane.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
SOCS-4 can be induced by epidermal growth factor ( EGF ) and regulates EGF receptor ( EGFR ) by competitively binding to phosphotyrosine sites with STAT3 .	SOCS-4 can be induced by epidermal growth factor (EGF) and regulates EGF receptor (EGFR) by competitively binding to phosphotyrosine sites with STAT3.	3	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	9	10	13	15
EGFR is activated by its ligands ( EGF , TGF-alpha , amphiregulin , betacellulin , heparin or epiregulin ) that bind to the extracellular domain , causing a conformational change and promoting homo- or hetero-dimerization .	EGFR is activated by its ligands (EGF, TGF-alpha, amphiregulin, betacellulin, heparin or epiregulin) that bind to the extracellular domain, causing a conformational change and promoting homo- or hetero-dimerization.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	0	1
We show here that both the MUC1 extracellular and intracellular domains contribute to EGF induced EGFR activation in human colon and breast cancer cells with the predominate contribution from the MUC1 extracellular domain .	We show here that both the MUC1 extracellular and intracellular domains contribute to EGF induced EGFR activation in human colon and breast cancer cells with the predominate contribution from the MUC1 extracellular domain.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
The EGF induced EGFR signaling involves EGFR auto-phosphorylation , and effective EGFR/Grb2/Gab1/Shp2 cascades complex formation .	The EGF induced EGFR signaling involves EGFR auto-phosphorylation, and effective EGFR/Grb2/Gab1/Shp2 cascades complex formation.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
As a receptor tyrosine protein kinase , EGFR can be activated by epidermal growth factor and then induce activation of Phosphoinositide 3-kinases ( PI3K ) , resulting in the formation of a PtdIns ( 3,4,5 ) P3 molecule ( PIP3 in XREF_FIG ) .	As a receptor tyrosine protein kinase, EGFR can be activated by epidermal growth factor and then induce activation of Phosphoinositide 3-kinases (PI3K), resulting in the formation of a PtdIns (3,4,5) P3 molecule (PIP3 in XREF_FIG).	7	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	12	15	7	8
We infer from these results that presentation of EGF tethered via neutravidin to the peptide gels is sufficient to allow homodimerization of the EGFR , although we do not rule out release of autocrine EGFR ligands as a means of homodimerization as hepatocytes make abundant TGF-alpha [ XREF_BIBR ] .	We infer from these results that presentation of EGF tethered via neutravidin to the peptide gels is sufficient to allow homodimerization of the EGFR, although we do not rule out release of autocrine EGFR ligands as a means of homodimerization as hepatocytes make abundant TGF-alpha [XREF_BIBR].	6	24	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	23	24
Although EGFR kinase is activated by EGF , we did not see a substantial increase in cell survival in the presence of EGF probably because EGFR can also be activated by cisplatin .	Although EGFR kinase is activated by EGF, we did not see a substantial increase in cell survival in the presence of EGF probably because EGFR can also be activated by cisplatin.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	1	2
We also determined that the increased CXCR7 expression in prostate cancer cells during ADT enhances EGF induced EGFR and ERK1/2 activation .	We also determined that the increased CXCR7 expression in prostate cancer cells during ADT enhances EGF induced EGFR and ERK1/2 activation.	14	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
Because EGF causes both EGFR recycling and lysosomal sorting , we also repeated the degradation assay with betacellulin , an EGFR ligand that induces lysosomal sorting and degradation of EGFR without detectable recycling .	Because EGF causes both EGFR recycling and lysosomal sorting, we also repeated the degradation assay with betacellulin, an EGFR ligand that induces lysosomal sorting and degradation of EGFR without detectable recycling.	1	5	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	4	5
The net effect is that brief pretreatment with GH or PRL , via ERK dependent EGFR phosphorylation , blunts subsequent EGF induced EGFR downregulation and prolongs EGFR downstream signaling [ XREF_BIBR - XREF_BIBR ] .	The net effect is that brief pretreatment with GH or PRL, via ERK dependent EGFR phosphorylation, blunts subsequent EGF induced EGFR downregulation and prolongs EGFR downstream signaling [XREF_BIBR - XREF_BIBR].	19	25	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
Taken together , these results suggest that EGF promoted-ADAM10 cleavage of E-cadherin may contribute to proliferative disorders by allowing sE-cad to bind EGFR and alter downstream signaling and proliferation in prostate epithelium .	Taken together, these results suggest that EGF promoted-ADAM10 cleavage of E-cadherin may contribute to proliferative disorders by allowing sE-cad to bind EGFR and alter downstream signaling and proliferation in prostate epithelium.	7	23	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	22	23
This is a significant advantage compared to EGFR targeting using endogenous molecules like EGF , which may trigger EGFR based signaling cascades that are known to promote tumor cell survival and growth .	This is a significant advantage compared to EGFR targeting using endogenous molecules like EGF, which may trigger EGFR based signaling cascades that are known to promote tumor cell survival and growth.	9	19	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	18	19
We have shown that LAPTM4B blocks EGF stimulated EGFR intraluminal sorting and lysosomal degradation , resulting in enhanced and prolonged EGFR signaling ( unpublished data ) .	We have shown that LAPTM4B blocks EGF stimulated EGFR intraluminal sorting and lysosomal degradation, resulting in enhanced and prolonged EGFR signaling (unpublished data).	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
However , EGF induced EGFR degradation was effectively reduced when the cells were pretreated with 6r or ZFL .	However, EGF induced EGFR degradation was effectively reduced when the cells were pretreated with 6r or ZFL.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
The results demonstrated that EGFR activation by EGF specifically regulates MMP-1 expression at the mRNA and protein levels .	The results demonstrated that EGFR activation by EGF specifically regulates MMP-1 expression at the mRNA and protein levels.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	4	5
Because of the difference in their affinities to EGFR , EGF induces strong activation of EGFR and the downstream molecule , ERK , whereas the extent of AREG induced EGFR-ERK activation is comparatively weak .	Because of the difference in their affinities to EGFR, EGF induces strong activation of EGFR and the downstream molecule, ERK, whereas the extent of AREG induced EGFR-ERK activation is comparatively weak.	10	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	15	16
We noticed that the ReAsH fluorescence associated with CC 858 -1 EGFR ( 1.5-fold ) was lower than that observed for EGF stimulated cells expressing CC H -1 EGFR ( 2.0-fold ) ( XREF_FIG ) .	We noticed that the ReAsH fluorescence associated with CC 858 -1 EGFR (1.5-fold) was lower than that observed for EGF stimulated cells expressing CC H -1 EGFR (2.0-fold) (XREF_FIG).	19	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	28	29
The released EGF activates the EGF receptor dimer to attract and phosphorylate the adapter proteins Grb2 and Shc .	The released EGF activates the EGF receptor dimer to attract and phosphorylate the adapter proteins Grb2 and Shc.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	2	3	5	7
In experiments whereby the EGFR is stimulated by either administration of various EGFR ligands or transgenic EGF overexpression , the magnitude of adaptation ( increased villus growth ) is augmented .	In experiments whereby the EGFR is stimulated by either administration of various EGFR ligands or transgenic EGF overexpression, the magnitude of adaptation (increased villus growth) is augmented.	3	18	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF overexpression	egf	EGFR	EGFR	egfr	16	17	4	5
Moreover , EGF dependent activation of EGFR and cell growth were inhibited by Chk1 depletion , and were rescued by co-depletion of Mig-6 .	Moreover, EGF dependent activation of EGFR and cell growth were inhibited by Chk1 depletion, and were rescued by co-depletion of Mig-6.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	6	7
Notably , protection from EGF induced degradation and inhibition of EGF induced intracellular redistribution afforded by GH were both prevented by a MEK1 inhibitor , suggesting a role for GH induced ERK activation in regulating the trafficking itinerary of the EGF stimulated EGFR .	Notably, protection from EGF induced degradation and inhibition of EGF induced intracellular redistribution afforded by GH were both prevented by a MEK1 inhibitor, suggesting a role for GH induced ERK activation in regulating the trafficking itinerary of the EGF stimulated EGFR.	37	43	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	40	41	42	43
NF1 MPNST lines show a strong transactivation of ErbB2 in response to activation of EGFR by EGF .	NF1 MPNST lines show a strong transactivation of ErbB2 in response to activation of EGFR by EGF.	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	14	15
The conformation of the erbB2 : EGFR heterodimer interface changes when the cells are treated with epidermal growth factor ( EGF ) .	The conformation of the erbB2 : EGFR heterodimer interface changes when the cells are treated with epidermal growth factor (EGF).	6	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	16	19	6	7
ST6Gal-I activity regulates basal and EGF induced EGFR activation in SKOV3 ovarian cancer cells .	ST6Gal-I activity regulates basal and EGF induced EGFR activation in SKOV3 ovarian cancer cells.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
EGFR immunoprecipitates from EGF stimulated cells expressing WT and variant EGFR proteins were prepared by using anti-FLAG antibodies and analyzed by LC-MS/MS for associated proteins similar to previously published methods involving gel-free , LC-MS/MS analysis of trypsin digested , anti-FLAG immunoprecipitates .	EGFR immunoprecipitates from EGF stimulated cells expressing WT and variant EGFR proteins were prepared by using anti-FLAG antibodies and analyzed by LC-MS/MS for associated proteins similar to previously published methods involving gel-free, LC-MS/MS analysis of trypsin digested, anti-FLAG immunoprecipitates.	1	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	10	11
In intestinal epithelial cells ( IECs ) , EGF induced EGF receptor ( EGFR ) activation and recruitment of PI3K play a key role in regulating many cellular functions including Ca ( 2+ )-dependent Cl (-) secretion .	In intestinal epithelial cells (IECs), EGF induced EGF receptor (EGFR) activation and recruitment of PI3K play a key role in regulating many cellular functions including Ca (2+)-dependent Cl (-) secretion.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	8	9	10	12
Activation of ErbB-1 signaling by EGF and EGF like growth factors plays an important role in prostate cancer cell proliferation and addition of EGF to cultures of prostate cancer cells stimulates their growth XREF_BIBR .	Activation of ErbB-1 signaling by EGF and EGF like growth factors plays an important role in prostate cancer cell proliferation and addition of EGF to cultures of prostate cancer cells stimulates their growth XREF_BIBR.	2	10	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	5	6	2	3
EGF activated EGFR degradation was inhibited by lysosome inhibitors , bafilomycin A1 and chloroquine , but not the proteasome inhibitor , clasto-lactacyctin beta-lactone ( data not shown ) , supporting a lysosomal pathway for EGFR degradation .	EGF activated EGFR degradation was inhibited by lysosome inhibitors, bafilomycin A1 and chloroquine, but not the proteasome inhibitor, clasto-lactacyctin beta-lactone (data not shown), supporting a lysosomal pathway for EGFR degradation.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Subsequent testing of this possibility showed that EGF induced trafficking of ErbB-1 to the endoplasmic reticulum where it interacted with the Sec61 translocon that then mediated receptor retrotranslocation to the cytoplasm and import into the nucleus [ XREF_BIBR ] .	Subsequent testing of this possibility showed that EGF induced trafficking of ErbB-1 to the endoplasmic reticulum where it interacted with the Sec61 translocon that then mediated receptor retrotranslocation to the cytoplasm and import into the nucleus [XREF_BIBR].	7	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	7	8	11	12
Also , there is an interesting crosstalk between MET and EGFR : the EGFR variant III ( EGFRvIII ) stimulates expression of both MET and its ligand HGF , possibly contributing to oncogenicity of EGFRvIII [ XREF_BIBR ] , but this phenomenon is counteracted by EGF mediated activation of wild-type EGFR in the same complex [ XREF_BIBR ] .	Also, there is an interesting crosstalk between MET and EGFR : the EGFR variant III (EGFRvIII) stimulates expression of both MET and its ligand HGF, possibly contributing to oncogenicity of EGFRvIII [XREF_BIBR], but this phenomenon is counteracted by EGF mediated activation of wild-type EGFR in the same complex [XREF_BIBR].	45	51	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	45	46	50	51
In HEK293 lacking Odin there was less EGF induced EGFR recycling , and consequently more trafficking of receptors to the lysosome compartment and degradation ( XREF_FIG - XREF_FIG ) .	In HEK293 lacking Odin there was less EGF induced EGFR recycling, and consequently more trafficking of receptors to the lysosome compartment and degradation (XREF_FIG - XREF_FIG).	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
We conclude that EGFR C-terminal sequences 1005-1017 and the 1010LL1011 motif are essential for EGF induced EGFR endoytosis independent of EGFR kinase activation and autophosphorylation .	We conclude that EGFR C-terminal sequences 1005-1017 and the 1010LL1011 motif are essential for EGF induced EGFR endoytosis independent of EGFR kinase activation and autophosphorylation.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
The specification and patterning of vulval precursor cells ( VPCs ) in Caenorhabditiselegans is achieved using a conserved EGFR and RAS signaling pathway that is activated by the ligand lin-3 and EGF , which is secreted by the neighboring somatic gonad .	The specification and patterning of vulval precursor cells (VPCs) in Caenorhabditiselegans is achieved using a conserved EGFR and RAS signaling pathway that is activated by the ligand lin-3 and EGF, which is secreted by the neighboring somatic gonad.	15	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	31	32	18	19
BACE1 is required for the processing of neuregulin 1 type III , an EGF like factor that activates the EGF receptor in Schwann cells , thereby regulating the myelination of axons in the peripheral and central nervous system .	BACE1 is required for the processing of neuregulin 1 type III, an EGF like factor that activates the EGF receptor in Schwann cells, thereby regulating the myelination of axons in the peripheral and central nervous system.	5	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	13	14	19	21
XREF_BIBR , XREF_BIBR However , this does not seem to be solely responsible for this phenomenon as EGF induced inhibition of cell-growth occurs in various non EGFR amplified cell-lines .	XREF_BIBR, XREF_BIBR However, this does not seem to be solely responsible for this phenomenon as EGF induced inhibition of cell-growth occurs in various non EGFR amplified cell-lines.	17	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	26	27
In the present study , to investigate the role of SNX1 on EGF stimulated EGFR and pEGFR endocytosis via the endocytic pathway , we examined the effect of depletion of SNX1 expression by siRNA in human NSCLC cell lines .	In the present study, to investigate the role of SNX1 on EGF stimulated EGFR and pEGFR endocytosis via the endocytic pathway, we examined the effect of depletion of SNX1 expression by siRNA in human NSCLC cell lines.	6	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
The siRNA library screening experiments showed that treatment of cells for 72h with siRNA targeting Uev1A resulted in a 20 % and 65 % reduction in the amount of EGFR at the surface of cells untreated and treated with EGF , respectively ( XREF_FIG ) .	The siRNA library screening experiments showed that treatment of cells for 72h with siRNA targeting Uev1A resulted in a 20% and 65% reduction in the amount of EGFR at the surface of cells untreated and treated with EGF, respectively (XREF_FIG).	27	40	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	39	40	29	30
In polyoma middle T antigen ( PyMT ) transgenic mouse mammary tumours , TAMs comigrate with tumour cells in a paracrine loop dependent manner in which EGF that is produced by TAMs increases the migration of EGFR expressing breast cancer cells .	In polyoma middle T antigen (PyMT) transgenic mouse mammary tumours, TAMs comigrate with tumour cells in a paracrine loop dependent manner in which EGF that is produced by TAMs increases the migration of EGFR expressing breast cancer cells.	26	37	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	36	37
Note that rhMATN2 does not activate EGFR ( XREF_FIG ) , but it strongly enhances EGFR activation when the cells are stimulated by EGF ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Note that rhMATN2 does not activate EGFR (XREF_FIG), but it strongly enhances EGFR activation when the cells are stimulated by EGF (XREF_FIG, XREF_SUPPLEMENTARY).	15	25	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	15	16
EGF and NRG1-beta1 induced efficient homo-oligomerization of the erbB1 and erbB4 extracellular domains , respectively .	EGF and NRG1-beta1 induced efficient homo-oligomerization of the erbB1 and erbB4 extracellular domains, respectively.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	erbB1	erbB1	erbB1	0	1	8	9
In this review we outline the molecular mechanisms of EGF induced endocytic downregulation of EGFR .	In this review we outline the molecular mechanisms of EGF induced endocytic downregulation of EGFR.	7	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	14	15
B1SP inhibited EGF induced EGFR pathway activation in LNCaP ( Fig XREF_FIG G ) , C4-2 ( Fig XREF_FIG H ) , CWR22Rv1 ( XREF_SUPPLEMENTARY ) , and MR49F ( XREF_SUPPLEMENTARY ) .	B1SP inhibited EGF induced EGFR pathway activation in LNCaP (Fig XREF_FIG G), C4-2 (Fig XREF_FIG H), CWR22Rv1 (XREF_SUPPLEMENTARY), and MR49F (XREF_SUPPLEMENTARY).	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
EGF or other EGF like ligands trigger homo- and hetero-dimerization of EGFR with other ErbB members , which activates a mitogenic and antiapoptotic signaling cascade via several pathways , including not only the RAS-RAF-MEK-ERK and the PI3K-AKT-mTOR axes but also SRC family kinases , PLCgamma-PKC , and STATs [ XREF_BIBR , XREF_BIBR ] .	EGF or other EGF like ligands trigger homo- and hetero-dimerization of EGFR with other ErbB members, which activates a mitogenic and antiapoptotic signaling cascade via several pathways, including not only the RAS-RAF-MEK-ERK and the PI3K-AKT-mTOR axes but also SRC family kinases, PLCgamma-PKC, and STATs [XREF_BIBR, XREF_BIBR].	0	12	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	11	12
These signaling data suggest that ERK mediated 669 T phosphorylation negatively modulates EGF induced EGFR kinase activity .	These signaling data suggest that ERK mediated 669 T phosphorylation negatively modulates EGF induced EGFR kinase activity.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Since EGFR signaling was triggered by EGF ligands via EGFR phosphorylation , we further detected the phosphorylation status of EGFR in the presence or absence of EBP50 expression .	Since EGFR signaling was triggered by EGF ligands via EGFR phosphorylation, we further detected the phosphorylation status of EGFR in the presence or absence of EBP50 expression.	1	7	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	1	2
Thus , we speculate that EGF induced ASCs ' proliferation and maintained ASCs ' differentiation through STAT signal pathway by activating EGFR .	Thus, we speculate that EGF induced ASCs ' proliferation and maintained ASCs ' differentiation through STAT signal pathway by activating EGFR.	5	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	21	22
In control cells , FN mediated cell adhesion increased total EGFR levels and attenuated EGF induced EGFR degradation .	In control cells, FN mediated cell adhesion increased total EGFR levels and attenuated EGF induced EGFR degradation.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
Clearly , compared to EGF treatment , nocodazole treatment significantly reduced the EGF induced movement of EGFR in parallel with microtubules .	Clearly, compared to EGF treatment, nocodazole treatment significantly reduced the EGF induced movement of EGFR in parallel with microtubules.	11	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	16	17
In agreement with the role of MIG6 protein as a negative regulator of EGFR signaling we found that M-110 treatment inhibits EGF induced EGFR activation and the activation of the downstream ERK MAPkinase pathway .	In agreement with the role of MIG6 protein as a negative regulator of EGFR signaling we found that M-110 treatment inhibits EGF induced EGFR activation and the activation of the downstream ERK MAPkinase pathway.	20	27	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	23	24
We have compared the activation and trafficking of epidermal growth factor receptor ( EGFR ) induced by UV light and EGF .	We have compared the activation and trafficking of epidermal growth factor receptor (EGFR) induced by UV light and EGF.	8	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	20	21	8	12
To address this question , we monitored the process of EGF stimulated endocytic transport and lysosomal degradation of EGFR in HEK293T cells after transient overexpression of wild-type UVRAG and the Leu-to-Glu mutants .	To address this question, we monitored the process of EGF stimulated endocytic transport and lysosomal degradation of EGFR in HEK293T cells after transient overexpression of wild-type UVRAG and the Leu-to-Glu mutants.	8	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	18	19
Moreover , EGF was shown to induce the formation of EGFR nanoclusters depending on the activity of phospholipase D2 .	Moreover, EGF was shown to induce the formation of EGFR nanoclusters depending on the activity of phospholipase D2.	2	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	10	11
For EGFR activation induced by 1 ng/ml EGF , 0.2 mM GM3 caused ~ 40 % inhibition and 0.1 mM GM3 exhibited no significant effect ( XREF_FIG , columns c and d ) .	For EGFR activation induced by 1 ng/ml EGF, 0.2 mM GM3 caused ~ 40% inhibition and 0.1 mM GM3 exhibited no significant effect (XREF_FIG, columns c and d).	1	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	1	2
In related studies , EGF activated the EGF receptor , which , in turn , stimulated ERK1/2 activity to induce proliferation in goblet cells from both species .	In related studies, EGF activated the EGF receptor, which, in turn, stimulated ERK1/2 activity to induce proliferation in goblet cells from both species.	4	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	4	5	7	9
This lack of effect of gefitinib on EGFR activity was not due to receptor dysfunction as EGF challenge substantially increased EGFR activity , together with Akt and ERK1/2 activity indicating that the EGFR signalling pathway was intact .	This lack of effect of gefitinib on EGFR activity was not due to receptor dysfunction as EGF challenge substantially increased EGFR activity, together with Akt and ERK1/2 activity indicating that the EGFR signalling pathway was intact.	16	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	20	21
We used two different doses ( 20 ng and 100 ng ) of EGF , which are known to stimulate EGFR activated signaling .	We used two different doses (20 ng and 100 ng) of EGF, which are known to stimulate EGFR activated signaling.	4	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	20	21
We found that treatment with AG1478 clearly inhibited EGFR downregulation induced by both cisplatin and EGF stimulation ( XREF_FIG ) .	We found that treatment with AG1478 clearly inhibited EGFR downregulation induced by both cisplatin and EGF stimulation (XREF_FIG).	8	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	8	9
Because TGHQ , but not epidermal growth factor ( EGF ) , induces histone H3 phosphorylation and cell death in LLC-PK ( 1 ) cells , we hypothesized that there are differences in the mechanisms by which TGHQ and EGF induce activation of the EGF receptor ( EGFR ) .	Because TGHQ, but not epidermal growth factor (EGF), induces histone H3 phosphorylation and cell death in LLC-PK (1) cells, we hypothesized that there are differences in the mechanisms by which TGHQ and EGF induce activation of the EGF receptor (EGFR).	37	46	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	39	40	44	46
In these cells , which express low levels of uPAR and malignancy , both ATF and EGF stimuli induced an interaction of the EGFR with uPAR and ERK activation .	In these cells, which express low levels of uPAR and malignancy, both ATF and EGF stimuli induced an interaction of the EGFR with uPAR and ERK activation.	16	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	23	24
In addition , though both EGF and anisomycin caused EGFR internalization , the EGFR internalized by anisomycin was not associated with an ubiquitin ligase , c-Cbl .	In addition, though both EGF and anisomycin caused EGFR internalization, the EGFR internalized by anisomycin was not associated with an ubiquitin ligase, c-Cbl.	4	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	9	10
This report was followed soon after with evidence that EGF induced EGF-R dimerization on living cells .	This report was followed soon after with evidence that EGF induced EGF-R dimerization on living cells.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	9	10	11	12
To further test the role of PT in suppressing vimentin expression , wild-type EGFR over-expressing U251 cells were treated with 15 ng/mL EGF in the presence or absence of 0.1 mug/mL PT for up to 18 h.	To further test the role of PT in suppressing vimentin expression, wild-type EGFR over-expressing U251 cells were treated with 15 ng/mL EGF in the presence or absence of 0.1 mug/mL PT for up to 18 h.	13	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	13	14
Further experiments investigated the endocytic degradation of EGFR stimulated by EGF treatment in RTN3 depleted HCC827 cells , and RTN3 silencing did not alter the rate of EGFR degradation .	Further experiments investigated the endocytic degradation of EGFR stimulated by EGF treatment in RTN3 depleted HCC827 cells, and RTN3 silencing did not alter the rate of EGFR degradation.	5	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	7	8
EGF modulates cell morphology and EGFR trafficking .	EGF modulates cell morphology and EGFR trafficking.	0	6	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
EGFR could be activated by EGF , hence we added EGF into the glioma cells to observe the potential involvement of EGFR and VEGF-A pathway .	EGFR could be activated by EGF, hence we added EGF into the glioma cells to observe the potential involvement of EGFR and VEGF-A pathway.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	0	1
Once EGF activates c-Src downstream of EGFR concomitantly with NRG-1-induced ErbB4 activation , c-Src associates with phospho-Tyr950 and phospho-Tyr1056 on 4ICD , thereby decreasing nuclear accumulation of 4ICD and inhibiting an increase of H3K9me3 levels .	Once EGF activates c-Src downstream of EGFR concomitantly with NRG-1-induced ErbB4 activation, c-Src associates with phospho-Tyr950 and phospho-Tyr1056 on 4ICD, thereby decreasing nuclear accumulation of 4ICD and inhibiting an increase of H3K9me3 levels.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	6	7
Retrograde directed transport of EGF activated erbB1 on filopodia was not unique to A431 cells expressing high levels of receptors but also occurred on HeLa cells with only 60,000 endogenous erbB1 receptors or on MCF7 cells transfected with erbB1 ( velocity data for these cell types are included in XREF_TABLE ) .	Retrograde directed transport of EGF activated erbB1 on filopodia was not unique to A431 cells expressing high levels of receptors but also occurred on HeLa cells with only 60,000 endogenous erbB1 receptors or on MCF7 cells transfected with erbB1 (velocity data for these cell types are included in XREF_TABLE).	2	11	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	erbB1	erbB1	erbB1	4	5	6	7
Both epidermal growth factor ( EGF ) and nerve growth factor ( NGF ) activate RTKs in the neuroendocrine PC12 cell line ( EGF receptor and TrkA , respectively ) , which in turn activate Erk through the Ras pathway .	Both epidermal growth factor (EGF) and nerve growth factor (NGF) activate RTKs in the neuroendocrine PC12 cell line (EGF receptor and TrkA, respectively), which in turn activate Erk through the Ras pathway.	3	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	5	6	23	25
These studies demonstrate that NDRG1 modulates c-Src activation which is achieved by down-regulation of both the expression and EGF induced activation of EGFR , preventing its interaction with c-Src .	These studies demonstrate that NDRG1 modulates c-Src activation which is achieved by down-regulation of both the expression and EGF induced activation of EGFR, preventing its interaction with c-Src.	12	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	22	23
Recently , it has been shown that although both TGFA- and EGF induced internalization of EGFR into EEA1 positive endosomes ( early endosomes ) , only EGF stimulation led to colocalization of EGFR with Lamp1 positive endosomes ( lysosomes ) [ XREF_BIBR ] .	Recently, it has been shown that although both TGFA- and EGF induced internalization of EGFR into EEA1 positive endosomes (early endosomes), only EGF stimulation led to colocalization of EGFR with Lamp1 positive endosomes (lysosomes) [XREF_BIBR].	9	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	15	16
The O GlcNAcylation of MIF is required for MIF to bind to EGFR and to inhibit EGF induced EGFR activation .	The O GlcNAcylation of MIF is required for MIF to bind to EGFR and to inhibit EGF induced EGFR activation.	15	19	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
The presence of galectin-3 with EGF also increased EGFR internalization in comparison to the cells treated with EGF alone and caused a more clustered pattern of internalized EGFR .	The presence of galectin-3 with EGF also increased EGFR internalization in comparison to the cells treated with EGF alone and caused a more clustered pattern of internalized EGFR.	8	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	8	9
Dacomitinib but not Cetuximab Inhibits EGF Stimulated EGFR Downstream Pathways .	Dacomitinib but not Cetuximab Inhibits EGF Stimulated EGFR Downstream Pathways.	5	9	Stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
HER-1 is activated by several EGF family ligands including heparin binding epidermal growth factor like growth factor ( HB-EGF ) , a mitogenic and chemotactic molecule that participates in tissue repair , tumor growth , and other tissue modeling phenomena , such as angiogenesis and fibrogenesis .	HER-1 is activated by several EGF family ligands including heparin binding epidermal growth factor like growth factor (HB-EGF), a mitogenic and chemotactic molecule that participates in tissue repair, tumor growth, and other tissue modeling phenomena, such as angiogenesis and fibrogenesis.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER-1	HER-1	HER-1	5	6	0	1
We show that EGF induces palmitoylation of EGFR and that palmitoylation facilitates receptor inactivation through two distinct mechanisms .	We show that EGF induces palmitoylation of EGFR and that palmitoylation facilitates receptor inactivation through two distinct mechanisms.	3	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	7	8
It has been reported that EGF concentrations of 100-200 ng/ml ( corresponding to 16.1-32.2 nM ) can induce macropinocytosis in A431 and MCF7 cells XREF_BIBR , XREF_BIBR , and that EGF treatment induces EGFR uptake by circular ruffling in NR6 , COS7 and PANC1 cells XREF_BIBR .	It has been reported that EGF concentrations of 100-200 ng/ml (corresponding to 16.1-32.2 nM) can induce macropinocytosis in A431 and MCF7 cells XREF_BIBR, XREF_BIBR, and that EGF treatment induces EGFR uptake by circular ruffling in NR6, COS7 and PANC1 cells XREF_BIBR.	30	34	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	30	31	33	34
Taken together , ExoS ADPr blocks EGF activated EGFR trafficking to lysosomes , rather than blocking EGFR internalization .	Taken together, ExoS ADPr blocks EGF activated EGFR trafficking to lysosomes, rather than blocking EGFR internalization.	5	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
We noted that the phosphotyrosine staining of the EGFR induced by EGF was greater intensity than the internal pTyr standards .	We noted that the phosphotyrosine staining of the EGFR induced by EGF was greater intensity than the internal pTyr standards.	5	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	8	9
They found a discrepancy between EGF induced EGFR activation and hydrogen peroxide induced EGFR activation , in that hydrogen peroxide might preferentially induce EGFR Tyr phosphorylation , whereas EGF stimulation would trigger both serine/threonine ( Ser/Thr ) and Tyr receptor phosphorylation [ XREF_BIBR ] .	They found a discrepancy between EGF induced EGFR activation and hydrogen peroxide induced EGFR activation, in that hydrogen peroxide might preferentially induce EGFR Tyr phosphorylation, whereas EGF stimulation would trigger both serine/threonine (Ser/Thr) and Tyr receptor phosphorylation [XREF_BIBR].	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Furthermore , EGFR activity was strongly associated with BL stimulation in cells with WT-EGFR and receptors with Thr654 substitutions , in contrast to cells with nonpolarizing EGFR ( 658-AA ) where Ap EGF also elicited robust EGFR activation .	Furthermore, EGFR activity was strongly associated with BL stimulation in cells with WT-EGFR and receptors with Thr654 substitutions, in contrast to cells with nonpolarizing EGFR (658-AA) where Ap EGF also elicited robust EGFR activation.	31	37	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	32	33	36	37
Exogenous TGF-alpha activated EGFR , ErbB-2 and MAPK , whereas EGF activated only the EGFR .	Exogenous TGF-alpha activated EGFR, ErbB-2 and MAPK, whereas EGF activated only the EGFR.	10	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	14	15
have shown that overexpression of UVRAG leads to enhanced endolysosomal trafficking as confirmed by assays that measure EGF stimulated endocytic transport and lysosomal degradation of the EGF receptor ( EGFR ) .	have shown that overexpression of UVRAG leads to enhanced endolysosomal trafficking as confirmed by assays that measure EGF stimulated endocytic transport and lysosomal degradation of the EGF receptor (EGFR).	16	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	17	18	26	28
Berberine also inhibited EGF stimulated EGFR activation ( XREF_FIG ) .	Berberine also inhibited EGF stimulated EGFR activation (XREF_FIG).	2	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
EGFR phosphorylation in keratinocytes cultured with no EGF or treated with soluble EGF remained relatively unchanged from the 1-hour time point .	EGFR phosphorylation in keratinocytes cultured with no EGF or treated with soluble EGF remained relatively unchanged from the 1-hour time point.	0	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	0	1
The activation of EGFR by EGF was suppressed by MARC and MPML treatment in EGFR ( +/+ ) cells , but not in EGFR (-/-) cells .	The activation of EGFR by EGF was suppressed by MARC and MPML treatment in EGFR (+/+) cells, but not in EGFR (-/-) cells.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	3	4
To test the effect of MUC1 on EGFR signaling , HEC50 cells were serum starved and then treated with EGF for 5 min .	To test the effect of MUC1 on EGFR signaling, HEC50 cells were serum starved and then treated with EGF for 5 min.	7	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	7	8
We then use our method to study EGF mediated signaling in the ERBB pathway .	We then use our method to study EGF mediated signaling in the ERBB pathway.	7	13	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ERBB	ERBB	ERBB	7	8	12	13
Next , we show that pharmacological inhibition of ERK ( but not Akt ) signaling enhances EGF induced EGFR activation , ubiquitination and downregulation , and may lead to enhanced receptor turnover .	Next, we show that pharmacological inhibition of ERK (but not Akt) signaling enhances EGF induced EGFR activation, ubiquitination and downregulation, and may lead to enhanced receptor turnover.	15	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
As shown in Figure XREF_FIG , the initial rate of EGF induced EGFR degradation was significantly slower in the CMTM7-knockdown compared with the control cells .	As shown in Figure XREF_FIG, the initial rate of EGF induced EGFR degradation was significantly slower in the CMTM7-knockdown compared with the control cells.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
Here we report that treatment of prostate cancer cells with M-110 or a structurally unrelated PIM kinase inhibitor SGI-1776 increases the expression of MIG6 RNA and protein and inhibits EGF induced activation of the EGFR and the downstream ERK MAPkinase pathway .	Here we report that treatment of prostate cancer cells with M-110 or a structurally unrelated PIM kinase inhibitor SGI-1776 increases the expression of MIG6 RNA and protein and inhibits EGF induced activation of the EGFR and the downstream ERK MAPkinase pathway.	29	40	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	34	35
In a well designed study Weinstein and co-workers show that the green tea polyphenol epigallocatechin gallate ( EGCG ) and extract polyphenon E can inhibit the EGF induced dimerization of EGFR in HT29 cells by disruption of lipid-order in the plasma membrane .	In a well designed study Weinstein and co-workers show that the green tea polyphenol epigallocatechin gallate (EGCG) and extract polyphenon E can inhibit the EGF induced dimerization of EGFR in HT29 cells by disruption of lipid-order in the plasma membrane.	25	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	30	31
It is well described that EGF induces the active sorting of the EGFR at the endosomal membranes where it can be either directed to the lysosomal degradation pathway or recycled back to the plasma membrane [ XREF_BIBR ] .	It is well described that EGF induces the active sorting of the EGFR at the endosomal membranes where it can be either directed to the lysosomal degradation pathway or recycled back to the plasma membrane [XREF_BIBR].	5	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	12	13
Incubation with an antibody against HB-EGF blocked the ATF but not the EGF mediated activation of EGFR ( XREF_FIG ) .	Incubation with an antibody against HB-EGF blocked the ATF but not the EGF mediated activation of EGFR (XREF_FIG).	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	16	17
Both previous findings and our own strongly suggest that EGF , which activates the EGFR signal transduction pathway , plays a key role in the pathogenesis of PVR .	Both previous findings and our own strongly suggest that EGF, which activates the EGFR signal transduction pathway, plays a key role in the pathogenesis of PVR.	9	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	14	15
Substantial degradation of WT EGFR occurred within two hours of EGF induced activation of EGFR .	Substantial degradation of WT EGFR occurred within two hours of EGF induced activation of EGFR.	8	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	14	15
Cetuximab partially inhibited the EGFR and MAPK pathway induced by EGF , TGF-alpha , and IGF .	Cetuximab partially inhibited the EGFR and MAPK pathway induced by EGF, TGF-alpha, and IGF.	4	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	4	5
Our earlier findings have shown that flotillin-1 regulates EGF induced EGFR and MAPK signaling at two levels [ XREF_BIBR ] .	Our earlier findings have shown that flotillin-1 regulates EGF induced EGFR and MAPK signaling at two levels [XREF_BIBR].	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
EGF induced EGFR nuclear translocalization in T98G cells was confirmed using immunofluorescence staining and confocal microscopy ( XREF_SUPPLEMENTARY ) .	EGF induced EGFR nuclear translocalization in T98G cells was confirmed using immunofluorescence staining and confocal microscopy (XREF_SUPPLEMENTARY).	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Epidermal growth factor ( EGF ) activation of the EGF receptor ( EGFR ) is an important mediator of cell migration , and aberrant signaling via this system promotes a number of malignancies including ovarian cancer .	Epidermal growth factor (EGF) activation of the EGF receptor (EGFR) is an important mediator of cell migration, and aberrant signaling via this system promotes a number of malignancies including ovarian cancer.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	4	5	9	11
Results suggest that compound 1G may interact and interfere with epidermal growth factor ( EGF ) which well along bind and activates the cell membrane EGFR receptor , and later activate the nuclear C-Jun and SP1 transcription factors .	Results suggest that compound 1G may interact and interfere with epidermal growth factor (EGF) which well along bind and activates the cell membrane EGFR receptor, and later activate the nuclear C-Jun and SP1 transcription factors.	10	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	10	13	25	26
Myofibroblast derived EGF induced EGFR activation with enhanced migratory and invasive properties in CCA cells .	Myofibroblast derived EGF induced EGFR activation with enhanced migratory and invasive properties in CCA cells.	1	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
To further evaluate the effect of HDN-1 on EGFR degradation , we examined EGFR levels in the cells treated with EGF for 1 to 5 h.	To further evaluate the effect of HDN-1 on EGFR degradation, we examined EGFR levels in the cells treated with EGF for 1 to 5 h.	8	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	8	9
When cells are incubated with a high concentration of EGF , EGF induces EGFR aggregation and receptor clustering .	When cells are incubated with a high concentration of EGF, EGF induces EGFR aggregation and receptor clustering.	11	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
IGFBP-3 potentiated EGF stimulated EGF receptor activation and DNA synthesis , and this was blocked by inhibitors of SphK activity or small interference RNA mediated silencing of SphK1 , but not SphK2 , expression .	IGFBP-3 potentiated EGF stimulated EGF receptor activation and DNA synthesis, and this was blocked by inhibitors of SphK activity or small interference RNA mediated silencing of SphK1, but not SphK2, expression.	1	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	2	3	4	6
Our data also suggest that delta-T interferes with the EGF induced EGFR internalization , which leads to the inhibition of the receptor tyrosine kinase dependent activation of AKT .	Our data also suggest that delta-T interferes with the EGF induced EGFR internalization, which leads to the inhibition of the receptor tyrosine kinase dependent activation of AKT.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
Clathrin Knockdown Abolishes EGF induced EGFR Localization to Endosomes , Whereas HB-EGF- and BTC induced Endosomal Localization is Only Partly Reduced .	Clathrin Knockdown Abolishes EGF induced EGFR Localization to Endosomes, Whereas HB-EGF- and BTC induced Endosomal Localization is Only Partly Reduced.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
EGF stimulated EGFR activation leads to receptor internalization and endocytic degradation to control EGFR mediated signaling .	EGF stimulated EGFR activation leads to receptor internalization and endocytic degradation to control EGFR mediated signaling.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
EGF increased activities of both Drosha- and Malat1 specific PS-ASOs in control cells with the decrease in IC 50 values ~ 2- to 3-fold , as in Figures XREF_FIG and XREF_FIG , but that EGF effect was eliminated in EGFR depleted cells .	EGF increased activities of both Drosha- and Malat1 specific PS-ASOs in control cells with the decrease in IC 50 values ~ 2- to 3-fold, as in Figures XREF_FIG and XREF_FIG, but that EGF effect was eliminated in EGFR depleted cells.	0	40	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	39	40
Finally , we observed that ERK inhibitor pretreatment alone enhanced EGF dependent EGFR downregulation [ XREF_BIBR ] , strongly suggesting that ERK mediated EGFR threonine phosphorylation , whether accomplished by PRL or GH before EGF stimulation or resulting from EGF induced ERK activation , can modulate EGF induced EGFR downregulation .	Finally, we observed that ERK inhibitor pretreatment alone enhanced EGF dependent EGFR downregulation [XREF_BIBR], strongly suggesting that ERK mediated EGFR threonine phosphorylation, whether accomplished by PRL or GH before EGF stimulation or resulting from EGF induced ERK activation, can modulate EGF induced EGFR downregulation.	45	49	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	46	47	48	49
In contrast , dampening of elicited lamellipodial protrusion by Mena11a likely arises as a consequence of reduced actin assembly rather than dysregulated signal transduction , as acute EGF elicited EGFR activation and downstream signaling were unaffected in Mena11a expressing cells .	In contrast, dampening of elicited lamellipodial protrusion by Mena11a likely arises as a consequence of reduced actin assembly rather than dysregulated signal transduction, as acute EGF elicited EGFR activation and downstream signaling were unaffected in Mena11a expressing cells.	26	30	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	29	30
EGF activated EGFR transiently , whereas Cpd 5 induced an intense and sustained activation .	EGF activated EGFR transiently, whereas Cpd 5 induced an intense and sustained activation.	0	3	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
PDGFRB knock-down in both DAOY ( XREF_FIG ) and D556 did not affect EGF induced EGFR activation ( XREF_SUPPLEMENTARY ) , but significantly reduced PDGF-BB-mediated transactivation of EGFR similar to imatinib ( P < 0.05 ) ( XREF_FIG ) .	PDGFRB knock-down in both DAOY (XREF_FIG) and D556 did not affect EGF induced EGFR activation (XREF_SUPPLEMENTARY), but significantly reduced PDGF-BB-mediated transactivation of EGFR similar to imatinib (P < 0.05) (XREF_FIG).	12	18	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Colocalization was also not observed when EGF was overexpressed in WT and MZspg embryos to enhance EGFR-GFP endocytosis ( XREF_SUPPLEMENTARY ) .	Colocalization was also not observed when EGF was overexpressed in WT and MZspg embryos to enhance EGFR-GFP endocytosis (XREF_SUPPLEMENTARY).	6	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF was overexpressed	egf	EGFR-GFP	EGFR-GFP	egfr-gfp	6	7	16	17
We performed this in HeLa cells transiently transfected with EGFR-GFP , and treated with two concentrations of EGF reported to direct EGFR internalization distinctly [ XREF_BIBR , XREF_BIBR ] : a low EGF dose ( 2 ng/ml ) induces EGFR internalization via the clathrin mediated route , while a high EGF dose ( 20 ng/ml ) directs EGFR internalization through both clathrin coated pits and caveolae .	We performed this in HeLa cells transiently transfected with EGFR-GFP, and treated with two concentrations of EGF reported to direct EGFR internalization distinctly [XREF_BIBR, XREF_BIBR] : a low EGF dose (2 ng/ml) induces EGFR internalization via the clathrin mediated route, while a high EGF dose (20 ng/ml) directs EGFR internalization through both clathrin coated pits and caveolae.	7	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR-GFP	EGFR-GFP	EGFR-GFP	17	18	9	10
EGF induced EGFR activation destabilises E-cadherin adhesions [ XREF_BIBR ] .	EGF induced EGFR activation destabilises E-cadherin adhesions [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Since EphA2 is also regulated by EGFR signaling in the EGFR overexpressing human head and neck carcinoma derived cell line , HN5 , and the human epidermoid derived cell line , A-431 , EphA2 levels are increased when EGFR is activated by EGF .	Since EphA2 is also regulated by EGFR signaling in the EGFR overexpressing human head and neck carcinoma derived cell line, HN5, and the human epidermoid derived cell line, A-431, EphA2 levels are increased when EGFR is activated by EGF.	38	43	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	42	43	38	39
Furthermore , spermine decreased EGF induced internalization and degradation of EGFR and consequently led to the accumulation of pY-EGFR .	Furthermore, spermine decreased EGF induced internalization and degradation of EGFR and consequently led to the accumulation of pY-EGFR.	4	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	10	11
In cultured cumulus-oocyte complexes , the activation of EGF receptor by EGF mobilized intracellular calcium of cumulus cells to decrease NPR2 affinity and cGMP levels , resulting in meiotic resumption .	In cultured cumulus-oocyte complexes, the activation of EGF receptor by EGF mobilized intracellular calcium of cumulus cells to decrease NPR2 affinity and cGMP levels, resulting in meiotic resumption.	6	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	11	12	8	10
Surprisingly , the abundance of phosphorylated EGFRvIII was strongly increased when LN-229 : EGFR and EGFRvIII cells were treated with EGF ( XREF_FIG ) , evident at Y1068 and Y1173 tyrosine residues ( XREF_SUPPLEMENTARY ) .	Surprisingly, the abundance of phosphorylated EGFRvIII was strongly increased when LN-229 : EGFR and EGFRvIII cells were treated with EGF (XREF_FIG), evident at Y1068 and Y1173 tyrosine residues (XREF_SUPPLEMENTARY).	13	31	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	13	14
For example , EGF stimulation of EGFR activates the Ras > Raf > MEK pathway , which in turn regulates expression of both EGFR and its ligands XREF_BIBR .	For example, EGF stimulation of EGFR activates the Ras> Raf> MEK pathway, which in turn regulates expression of both EGFR and its ligands XREF_BIBR.	3	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	6	7
In this regard , further experiments are necessary to determine if there is any effect of prolonged EGF stimulation of wild-type EGFR on receptor internalization and further signaling processes .	In this regard, further experiments are necessary to determine if there is any effect of prolonged EGF stimulation of wild-type EGFR on receptor internalization and further signaling processes.	17	28	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	21	22
Our results showed EGF mediated activation of EGFR , Erk , and p70s6k was suppressed in pancreatic cancer cells treated with belinostat , most likely through the loss of EGFR expression .	Our results showed EGF mediated activation of EGFR, Erk, and p70s6k was suppressed in pancreatic cancer cells treated with belinostat, most likely through the loss of EGFR expression.	3	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	7	8
By contrast , EGF activates ErbB-1 and ErbB-1 or ErbB-1 and ErbB-2 dimers and induces cell growth and survival .	By contrast, EGF activates ErbB-1 and ErbB-1 or ErbB-1 and ErbB-2 dimers and induces cell growth and survival.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	3	4	5	6
Introducing EGFR in these cells showed no effect on exosomal-PTEN ( XREF_FIG ) , however when the introduced EGFR was activated by EGF treatment we saw an increase in exosomal-PTEN expression ( XREF_FIG ) .	Introducing EGFR in these cells showed no effect on exosomal-PTEN (XREF_FIG), however when the introduced EGFR was activated by EGF treatment we saw an increase in exosomal-PTEN expression (XREF_FIG).	16	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	18	19
This correlated with Sos2 binding less efficiently than Sos1 to EGFR and Shc in cells treated with EGF for > or = 90 min or to v-Src and Shc in v-Src-expressing cells , and with less ERK activity .	This correlated with Sos2 binding less efficiently than Sos1 to EGFR and Shc in cells treated with EGF for> or = 90 min or to v-Src and Shc in v-Src-expressing cells, and with less ERK activity.	8	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	10	11
Moreover , in the light of the report showing that 1,25-dihydroxyvitamin D inhibited EGF induced EGFR nuclear transport , vitamin D1 may in part exert its anticancer effect via blocking the nuclear EGFR pathway ( Cordero et al , 2002 ) .	Moreover, in the light of the report showing that 1,25-dihydroxyvitamin D inhibited EGF induced EGFR nuclear transport, vitamin D1 may in part exert its anticancer effect via blocking the nuclear EGFR pathway (Cordero et al, 2002).	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Mimic-miR-214 decreased the expression of Mig-6 and increased the levels of EGF mediated p-EGFR ( Y1173 and Y845 ) and p-Met ( Tyr1234/1235 ; Fig .	Mimic-miR-214 decreased the expression of Mig-6 and increased the levels of EGF mediated p-EGFR (Y1173 and Y845) and p-Met (Tyr1234/1235; Fig.	9	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	p-EGFR	p-EGFR	p-EGFR	11	12	13	14
Further study showed that oxymatrine treatment strikingly inhibited EGF induced EGFR , Akt , and ERK1/2 activation in HCC827 cells .	Further study showed that oxymatrine treatment strikingly inhibited EGF induced EGFR, Akt, and ERK1/2 activation in HCC827 cells.	7	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
Therefore , we analyzed whether , the supplementation of EGF would increase viability and proliferation of EGFR positive tissue samples .	Therefore, we analyzed whether, the supplementation of EGF would increase viability and proliferation of EGFR positive tissue samples.	7	19	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	16	17
EGF induced EGFR signaling regulated HCC proliferation , metastasis and production of inflammatory cytokine [ XREF_BIBR ] .	EGF induced EGFR signaling regulated HCC proliferation, metastasis and production of inflammatory cytokine [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
EGF induced EGFR activation is controlled , at least in part , by a negative feedback transcriptional program [ XREF_BIBR , XREF_BIBR ] .	EGF induced EGFR activation is controlled, at least in part, by a negative feedback transcriptional program [XREF_BIBR, XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
EGF also stimulates rapid EGFR endocytosis into endosomes ( EN ) and its eventual degradation in lysosomes [ XREF_BIBR , XREF_BIBR ] .	EGF also stimulates rapid EGFR endocytosis into endosomes (EN) and its eventual degradation in lysosomes [XREF_BIBR, XREF_BIBR].	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
EGF stimulation and forced expression of EGFR significantly increase B-Myb gene activity and such increase occurs in the G1 phase .	EGF stimulation and forced expression of EGFR significantly increase B-Myb gene activity and such increase occurs in the G1 phase.	0	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	6	7
More recently , a study uncovered that EGF induced EGFR signaling enhances production of intracellular reactive oxygen species ( ROS ) by dual oxidase 1 ( DUOX1 ) 10 .	More recently, a study uncovered that EGF induced EGFR signaling enhances production of intracellular reactive oxygen species (ROS) by dual oxidase 1 (DUOX1) 10.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Addition of EGF activated EGFR within minutes and this signal was transmitted downstream to signaling cascades measured .	Addition of EGF activated EGFR within minutes and this signal was transmitted downstream to signaling cascades measured.	0	11	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
Despite a lower level of phosphorylated EGFR at both phosphorylation sites , EGF was able to activate EGFR downstream signaling in contrast to imgatuzumab or cetuximab .	Despite a lower level of phosphorylated EGFR at both phosphorylation sites, EGF was able to activate EGFR downstream signaling in contrast to imgatuzumab or cetuximab.	12	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	17	18
Epidermal growth factor ( EGF ) and TGFalpha significantly increased EGFR and MAPK pathway activity in both cell lines .	Epidermal growth factor (EGF) and TGFalpha significantly increased EGFR and MAPK pathway activity in both cell lines.	0	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epidermal growth factor	Epidermal growth factor	Epidermal growth factor	EGFR	EGFR	EGFR	0	3	10	11
EGF activates the EGF receptor ( EGFR/ErbB ) , which initiates , in turn , intracellular signaling .	EGF activates the EGF receptor (EGFR/ErbB), which initiates, in turn, intracellular signaling.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	3	5
These EGF like peptides stimulate EGFR in the mural and cumulus cell compartment , concomitant with a positive autocrine feedback loop on their own expression [ XREF_BIBR ] .	These EGF like peptides stimulate EGFR in the mural and cumulus cell compartment, concomitant with a positive autocrine feedback loop on their own expression [XREF_BIBR].	0	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	5	6
Internalized EGFR however can not be activated by EGF and this observation may explain growth inhibitory effects of Erbitux .	Internalized EGFR however can not be activated by EGF and this observation may explain growth inhibitory effects of Erbitux.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	1	2
Our previous studies used ICS and saturating concentrations of EGF to establish that EGF induces increased aggregation of EGFR-eGFP in BaF/3 cells , with a predominantly dimeric EGFR population ( > 90 % dimer ) in the absence of EGF transitioning to higher-order oligomers in the presence of EGF .	Our previous studies used ICS and saturating concentrations of EGF to establish that EGF induces increased aggregation of EGFR-eGFP in BaF/3 cells, with a predominantly dimeric EGFR population (> 90% dimer) in the absence of EGF transitioning to higher-order oligomers in the presence of EGF.	13	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR-eGFP	EGFR-eGFP	EGFR-eGFP	13	14	18	19
EGF and TGF alpha , which trigger the mammalian EGF receptor , did not increase the kinase activity of DER .	EGF and TGF alpha, which trigger the mammalian EGF receptor, did not increase the kinase activity of DER.	0	11	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	9	11
A multiscale NSCLC model was first developed , with a revised EGF induced EGFR mediated signaling pathway implemented at the molecular level and a 2D heterogeneous biochemical tumor growth environment implemented at the microscopic level .	A multiscale NSCLC model was first developed, with a revised EGF induced EGFR mediated signaling pathway implemented at the molecular level and a 2D heterogeneous biochemical tumor growth environment implemented at the microscopic level.	9	17	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Overexpression of this dominant negative mutant induces a delay in EGF induced EGF receptor transport to the LAMP1 positive late endosomal/lysosomal compartment and impairs ligand induced EGF receptor degradation .	Overexpression of this dominant negative mutant induces a delay in EGF induced EGF receptor transport to the LAMP1 positive late endosomal/lysosomal compartment and impairs ligand induced EGF receptor degradation.	8	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	10	11	12	14
Flies have a single EGF receptor family member that can be stimulated by four EGF like growth factors .	Flies have a single EGF receptor family member that can be stimulated by four EGF like growth factors.	4	17	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	14	15	4	6
Thus , results in pigs [ XREF_BIBR ] showing that EGFR activation by EGF like growth factors produced under the FSH stimulus is involved in initiating the ovulatory events in porcine OCC are consistent with the results obtained in mice and rats [ XREF_BIBR , XREF_BIBR ] .	Thus, results in pigs [XREF_BIBR] showing that EGFR activation by EGF like growth factors produced under the FSH stimulus is involved in initiating the ovulatory events in porcine OCC are consistent with the results obtained in mice and rats [XREF_BIBR, XREF_BIBR].	10	16	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	10	11
Using tetramethylrhodamine labeled EGF , we established assays for quantifying EGF triggered EGFR internalization by both high resolution confocal microscopy and flow cytometry .	Using tetramethylrhodamine labeled EGF, we established assays for quantifying EGF triggered EGFR internalization by both high resolution confocal microscopy and flow cytometry.	7	13	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
In HEY and OVCA 433 ovarian carcinoma cells , ET-1 or EGF induced rapid activation of EGFR , p42/44 mitogen activated protein kinase ( MAPK ) , and AKT .	In HEY and OVCA 433 ovarian carcinoma cells, ET-1 or EGF induced rapid activation of EGFR, p42/44 mitogen activated protein kinase (MAPK), and AKT.	7	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	16	17
Furthermore , EGF activated EGFR , Erk and Akt in both SKpcDNA and SKCOX-1 cells , but aspirin inhibited EGFR , Erk and Akt activation in SKCOX-1 cells but not in SKpcDNA cells .	Furthermore, EGF activated EGFR, Erk and Akt in both SKpcDNA and SKCOX-1 cells, but aspirin inhibited EGFR, Erk and Akt activation in SKCOX-1 cells but not in SKpcDNA cells.	2	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
EGF induced EGFR activation in human epidermoid carcinoma A431 cells was shown to be strongly inhibited by GM3 , but to a much lesser degree by various other gangliosides and neutral GSLs .	EGF induced EGFR activation in human epidermoid carcinoma A431 cells was shown to be strongly inhibited by GM3, but to a much lesser degree by various other gangliosides and neutral GSLs.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
The results showed that EGF stimulated EGFR degradation was significantly slowed down in FLCN silencing HeLa cells , and knockdown of FLCN resulted in persisting activation of p-AKT and p-ERK .	The results showed that EGF stimulated EGFR degradation was significantly slowed down in FLCN silencing HeLa cells, and knockdown of FLCN resulted in persisting activation of p-AKT and p-ERK.	4	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
PIKfyve siRNA studies of EGF induced EGFR downregulation have not revealed any defect in EGFR downregulation XREF_BIBR .	PIKfyve siRNA studies of EGF induced EGFR downregulation have not revealed any defect in EGFR downregulation XREF_BIBR.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
EGF mediated activation of the EGFR produces a rapid and transient phosphorylation of multiple downstream signaling proteins , and a STAT3-Twist signaling pathway has been implicated in EGF induced EMT in these cells .	EGF mediated activation of the EGFR produces a rapid and transient phosphorylation of multiple downstream signaling proteins, and a STAT3-Twist signaling pathway has been implicated in EGF induced EMT in these cells.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
Binding of EGF induces dimerization of EGFR monomers , followed by trans-autophosphorylation of key tyrosine residues on the EGFR intracellular tails , which up-regulates their intrinsic RTK activity [ XREF_BIBR ] .	Binding of EGF induces dimerization of EGFR monomers, followed by trans-autophosphorylation of key tyrosine residues on the EGFR intracellular tails, which up-regulates their intrinsic RTK activity [XREF_BIBR].	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	6	7
Using antibodies directed against the active form of the EGF receptor , we show that in HaCaT cells EGF and thrombin triggered a rapid activation of the EGF receptor , followed by the phosphorylation and activation of the extracellular signal regulated protein kinase ( ERK ) .	Using antibodies directed against the active form of the EGF receptor, we show that in HaCaT cells EGF and thrombin triggered a rapid activation of the EGF receptor, followed by the phosphorylation and activation of the extracellular signal regulated protein kinase (ERK).	18	29	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	18	19	27	29
To confirm whether CTSS was involved in EGFR degradation , the EGF mediated EGFR degradation rates were determined in vector- and CTSS overexpressing cells .	To confirm whether CTSS was involved in EGFR degradation, the EGF mediated EGFR degradation rates were determined in vector- and CTSS overexpressing cells.	1	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
EGFR signaling is induced by various EGF like growth factor family ligands such as EGF and amphiregulin .	EGFR signaling is induced by various EGF like growth factor family ligands such as EGF and amphiregulin.	0	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	0	1
When the EGFR was activated by EGF , yeast cells survived even at 37degreesC due to complementation of the function of CDC25 ts by Grb2-Sos or Shc1-Sos ( XREF_SUPPLEMENTARY ) .	When the EGFR was activated by EGF, yeast cells survived even at 37degreesC due to complementation of the function of CDC25 ts by Grb2-Sos or Shc1-Sos (XREF_SUPPLEMENTARY).	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	2	3
The data in XREF_FIG - XREF_FIG indicate that endogenous ( wild-type ) EGFR present along with endogenous ErbB-2 in fibrosarcoma cells undergoes EGF induced PTP-101-reactive phosphorylation and that in that setting pharmacologic prevention of ERK activity augments EGF induced EGFR downregulation and EGF induced EGFR tyrosine phosphorylation .	The data in XREF_FIG - XREF_FIG indicate that endogenous (wild-type) EGFR present along with endogenous ErbB-2 in fibrosarcoma cells undergoes EGF induced PTP-101-reactive phosphorylation and that in that setting pharmacologic prevention of ERK activity augments EGF induced EGFR downregulation and EGF induced EGFR tyrosine phosphorylation.	36	40	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	37	38	39	40
While EGF induced EGFR activation in BC was rapid , the effect of AREG was detected only after 7 days , and BC continued to respond to AREG with robust EGFR activation till day 14 of ALI culture , when the stimulatory effect of EGF on EGFR activation was no longer significant .	While EGF induced EGFR activation in BC was rapid, the effect of AREG was detected only after 7 days, and BC continued to respond to AREG with robust EGFR activation till day 14 of ALI culture, when the stimulatory effect of EGF on EGFR activation was no longer significant.	1	4	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
In this model , EGF stimulation activates EGFR , which activates AKT .	In this model, EGF stimulation activates EGFR, which activates AKT.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	7	8
SF767 , which show high basal expression of EGFR , and LN229ER , cells engineered to overexpress EGFR , were treated with EGF for varying times after culturing overnight in serum-free media .	SF767, which show high basal expression of EGFR, and LN229ER, cells engineered to overexpress EGFR, were treated with EGF for varying times after culturing overnight in serum-free media.	16	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	17	18
EGF induces rapid ubiquitinylation and lysosomal trafficking of EGFR .	EGF induces rapid ubiquitinylation and lysosomal trafficking of EGFR.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	8	9
Functional studies on PC3 prostate adenocarcinoma cells revealed that active extracts antagonized ephrinA1-Fc-induced EphA2 phosphorylation at non cytotoxic concentrations ( IC50 0.31-11.3 mug/ml ) without interfering with EGF induced EGFR activation , suggesting a specific effect .	Functional studies on PC3 prostate adenocarcinoma cells revealed that active extracts antagonized ephrinA1-Fc-induced EphA2 phosphorylation at non cytotoxic concentrations (IC50 0.31-11.3 mug/ml) without interfering with EGF induced EGFR activation, suggesting a specific effect.	25	30	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	29	30
The activation of EGFR by EGF was detected by p-EGFR presence in both cell lines and did not promote cell proliferation when compared to unstimulated cells .	The activation of EGFR by EGF was detected by p-EGFR presence in both cell lines and did not promote cell proliferation when compared to unstimulated cells.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	3	4
As microtubule motor protein dynein is required for Golgi translocation of EGFR ( XREF_FIG ) upon EGF stimulation , we further investigated whether EGF induces the association of EGFR with dynein .	As microtubule motor protein dynein is required for Golgi translocation of EGFR (XREF_FIG) upon EGF stimulation, we further investigated whether EGF induces the association of EGFR with dynein.	23	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	28	29
However , CSPG did not enhance EGF stimulation of EGFR .	However, CSPG did not enhance EGF stimulation of EGFR.	6	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	9	10
( Although comparison between different cell systems may not be entirely valid , EGF treatment of CHO cells stably expressing WT EGFR for 3 h caused a slightly greater degree of receptor loss than that seen in C14 cells treated for 4 h. ) Similarly enhanced EGF induced EGFR downregulation in C14 cells was observed when U0126 , a distinct ERK pathway inhibitor , was used instead of PD98059 ( XREF_FIG ) .	(Although comparison between different cell systems may not be entirely valid, EGF treatment of CHO cells stably expressing WT EGFR for 3 h caused a slightly greater degree of receptor loss than that seen in C14 cells treated for 4 h.) Similarly enhanced EGF induced EGFR downregulation in C14 cells was observed when U0126, a distinct ERK pathway inhibitor, was used instead of PD98059 (XREF_FIG).	19	49	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	46	47	48	49
This observation indicates the requirement of the prosurvival form of Fas for the formation of a signaling platform where Src , Yes-1 , and STAT3 may couple the pro survival signal of Fas to EGF induced EGFR signaling .	This observation indicates the requirement of the prosurvival form of Fas for the formation of a signaling platform where Src, Yes-1, and STAT3 may couple the pro survival signal of Fas to EGF induced EGFR signaling.	26	37	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	34	35	36	37
EGF does not interact with EGFRvIII and in our study EGFRvIII expressing cells treated with EGF continued to proliferate without any interruption .	EGF does not interact with EGFRvIII and in our study EGFRvIII expressing cells treated with EGF continued to proliferate without any interruption.	3	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFRvIII	EGFRvIII	EGFRvIII	15	16	5	6
IL17RD increases EGF induced colon cancer cell proliferation and EGFR signaling .	IL17RD increases EGF induced colon cancer cell proliferation and EGFR signaling.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	9	10
In contrast , EGF greatly prolongs the half-life of EGF receptor mRNA suggesting a possible mechanism for the stimulatory effect of EGF on EGF receptor mRNA levels .	In contrast, EGF greatly prolongs the half-life of EGF receptor mRNA suggesting a possible mechanism for the stimulatory effect of EGF on EGF receptor mRNA levels.	3	11	prolongs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	3	4	9	11
All of the compounds were evaluated for their ability to inhibit the tyrosine phosphorylating action of EGF stimulated full-length EGFR enzyme .	All of the compounds were evaluated for their ability to inhibit the tyrosine phosphorylating action of EGF stimulated full-length EGFR enzyme.	14	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	19	20
Here , we show that EGF stimulates activation of EGFR and transactivation of ErbB-2 in quiescent HASM cells .	Here, we show that EGF stimulates activation of EGFR and transactivation of ErbB-2 in quiescent HASM cells.	5	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	9	10
When OECM1 cells were treated with EGF , which activates EGFR , the amount of nuclear beta-catenin increased over time .	When OECM1 cells were treated with EGF, which activates EGFR, the amount of nuclear beta-catenin increased over time.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	10	11
While epidermal growth factor ( EGF ) is a well known mitogen , high doses of EGF result in a paradoxical apoptotic response in the cells that overexpress EGF receptor such as A431 epidermoid carcinoma cells .	While epidermal growth factor (EGF) is a well known mitogen, high doses of EGF result in a paradoxical apoptotic response in the cells that overexpress EGF receptor such as A431 epidermoid carcinoma cells.	16	30	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	16	17	28	30
Collectively , these data revealed that NDRG1 over-expression abrogates EGF induced EGFR activation and attenuates its effect on c-Src activation .	Collectively, these data revealed that NDRG1 over-expression abrogates EGF induced EGFR activation and attenuates its effect on c-Src activation.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
Different EGF family ligands do not elicit EGFR downregulation in an identical fashion .	Different EGF family ligands do not elicit EGFR downregulation in an identical fashion.	1	8	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	7	8
These results are very similar to those published for EGF induced trafficking of EGF receptor to the ER .	These results are very similar to those published for EGF induced trafficking of EGF receptor to the ER.	9	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	9	10	13	15
[ XREF_BIBR ] Similar to lithocholic acid , cholanic and isolithocholic acids at concentrations up to 100 muM also did not interfere with EGF receptor activation induced by EGF ( XREF_FIG ) .	[XREF_BIBR] Similar to lithocholic acid, cholanic and isolithocholic acids at concentrations up to 100 muM also did not interfere with EGF receptor activation induced by EGF (XREF_FIG).	23	30	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	28	29	23	25
Surprisingly , EGF and TGF-alpha induced full activation of MAPK in duration and intensity and stimulated association of the EGFR with Shc and Grb2 .	Surprisingly, EGF and TGF-alpha induced full activation of MAPK in duration and intensity and stimulated association of the EGFR with Shc and Grb2.	2	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	19	20
Indeed , activation of EGFR by EGF has been found to induce tumorigenesis through upregulation of signaling pathways , including PI3K and Akt , STAT , Ras/Raf/MAPK XREF_BIBR , XREF_BIBR and members of Rho GTPase family such as Rac1 XREF_BIBR .	Indeed, activation of EGFR by EGF has been found to induce tumorigenesis through upregulation of signaling pathways, including PI3K and Akt, STAT, Ras/Raf/MAPK XREF_BIBR, XREF_BIBR and members of Rho GTPase family such as Rac1 XREF_BIBR.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	4	5
In PIPKIgammai5-knockdown cells , the degradation of EGFR induced by low EGF was also blocked , and EGFR activation and downstream AKT signaling were enhanced and prolonged ( XREF_SUPPLEMENTARY ) .	In PIPKIgammai5-knockdown cells, the degradation of EGFR induced by low EGF was also blocked, and EGFR activation and downstream AKT signaling were enhanced and prolonged (XREF_SUPPLEMENTARY).	5	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	7	8
At saturating doses , EGF and EE activated EGFR in a comparable fashion in HeLa cells , but activation of HER2 was diminished by ~ 50 % in cells stimulated with EE compared with EGF ( XREF_FIG E ) .	At saturating doses, EGF and EE activated EGFR in a comparable fashion in HeLa cells, but activation of HER2 was diminished by ~ 50% in cells stimulated with EE compared with EGF (XREF_FIG E).	4	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	8	9
As afatinib potently inhibits the activity of both wild-type and mutant ( L858R and T790M ) EGFR [ XREF_BIBR ] , we hypothesized that the inhibitor may block EGF induced activation of EGFR and its downstream signaling .	As afatinib potently inhibits the activity of both wild-type and mutant (L858R and T790M) EGFR [XREF_BIBR], we hypothesized that the inhibitor may block EGF induced activation of EGFR and its downstream signaling.	28	36	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	28	29	32	33
With EGF induced activation of EGFR , we demonstrated phosphorylation in PI3K and Akt , MEK and ERK , and p38 MAPK pathways ; with pathway inhibitors ( LY294002 , U0126 , SB203580 ) the EGF mediated decrease in papillae was reversed , and synergistic actions were shown .	With EGF induced activation of EGFR, we demonstrated phosphorylation in PI3K and Akt, MEK and ERK, and p38 MAPK pathways; with pathway inhibitors (LY294002, U0126, SB203580) the EGF mediated decrease in papillae was reversed, and synergistic actions were shown.	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	5	6
This study finds that the two most common EGFR mutations in non small cell lung cancer ( L858R and Delta746-750 ) result in EGF independent tEGFR activities comparable to , or greater than , the activity of EGF stimulated WT EGFR , and that tEGFR activation resulting from these mutations remains strongly coupled to asymmetric kinase dimer formation ( XREF_FIG ) .	This study finds that the two most common EGFR mutations in non small cell lung cancer (L858R and Delta746-750) result in EGF independent tEGFR activities comparable to, or greater than, the activity of EGF stimulated WT EGFR, and that tEGFR activation resulting from these mutations remains strongly coupled to asymmetric kinase dimer formation (XREF_FIG).	35	41	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	37	38	40	41
In addition , EGF triggered the internalization of the EGFR which notably colocalized with endocytosed Kv1.3 ( XREF_FIG ) .	In addition, EGF triggered the internalization of the EGFR which notably colocalized with endocytosed Kv1.3 (XREF_FIG).	3	17	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	9	10
We initially observed that BK- and EGF dependent activation of Src , EGFR , Akt , and p42 and p44 MAPK and [ 3H ] thymidine incorporation were mediated by Src and EGFR , because the Src inhibitor PP1 and EGFR kinase inhibitor AG1478 abrogated BK- and EGF dependent effects .	We initially observed that BK- and EGF dependent activation of Src, EGFR, Akt, and p42 and p44 MAPK and [3H] thymidine incorporation were mediated by Src and EGFR, because the Src inhibitor PP1 and EGFR kinase inhibitor AG1478 abrogated BK- and EGF dependent effects.	4	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	12	13
Conversely , treatment with retinoic acid , an inducer of TG2 , significantly decreased EGF induced EGFR dimerization and its phosphorylation with a significant increase in TG2 expression and its catalysed products , isopeptide bonds , in both subpopulations .	Conversely, treatment with retinoic acid, an inducer of TG2, significantly decreased EGF induced EGFR dimerization and its phosphorylation with a significant increase in TG2 expression and its catalysed products, isopeptide bonds, in both subpopulations.	13	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
found that EGFR and c-MET co-immunoprecipitated in cancer cells and suggested that their association facilitates the HGF independent phosphorylation of c-MET through TGFalpha and EGF mediated EGFR activation .	found that EGFR and c-MET co-immunoprecipitated in cancer cells and suggested that their association facilitates the HGF independent phosphorylation of c-MET through TGFalpha and EGF mediated EGFR activation.	22	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
The rate of EGF stimulated EGFR degradation was slower in the KD cells compared to the control cells ( XREF_FIG ) .	The rate of EGF stimulated EGFR degradation was slower in the KD cells compared to the control cells (XREF_FIG).	1	6	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Bipartite Tetracysteine Display Confirms the Antiparallel JM Interaction is Present when EGFR is Activated by EGF .	Bipartite Tetracysteine Display Confirms the Antiparallel JM Interaction is Present when EGFR is Activated by EGF.	11	16	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	11	12
As shown in XREF_FIG , disruption of microtubule and dynein by nocodazole and EHNA , respectively , blocked EGF induced binding of EGFR to the CCND1 promoter , a known target of nuclear EGFR 18 by chromatin-IP ( ChIP ) analysis ( XREF_FIG ) .	As shown in XREF_FIG, disruption of microtubule and dynein by nocodazole and EHNA, respectively, blocked EGF induced binding of EGFR to the CCND1 promoter, a known target of nuclear EGFR 18 by chromatin-IP (ChIP) analysis (XREF_FIG).	18	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	22	23
In addition to GH using EGFR as a docking molecule to facilitate downstream GHR signal propagation and GH modulating EGF induced EGFR trafficking to potentiate EGFR signaling , our data indicate that GH also sensitizes the EGF induced EGFR mediated ERK pathway such that it is more activatable at a post receptor ( and , specifically , post-Raf ) level .	In addition to GH using EGFR as a docking molecule to facilitate downstream GHR signal propagation and GH modulating EGF induced EGFR trafficking to potentiate EGFR signaling, our data indicate that GH also sensitizes the EGF induced EGFR mediated ERK pathway such that it is more activatable at a post receptor (and, specifically, post-Raf) level.	35	39	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	36	37	38	39
We predicted that if the level of EGF expression in the 32D/EGFR/EGF mature cell line is insufficient to stimulate EGFR coupling to cell proliferation , then the response of the 32D/EGFR/EGF mature cell line to soluble EGF should be roughly equivalent to the response of the 32D/EGFR/pLenti6 vector control cell line to soluble EGF .	We predicted that if the level of EGF expression in the 32D/EGFR/EGF mature cell line is insufficient to stimulate EGFR coupling to cell proliferation, then the response of the 32D/EGFR/EGF mature cell line to soluble EGF should be roughly equivalent to the response of the 32D/EGFR/pLenti6 vector control cell line to soluble EGF.	7	20	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF expression	egf	EGFR	EGFR	egfr	7	8	19	20
MET is required for EGF induced cell invasion and motility in EGFR wild-type NSCLC cells but it was unclear if this is true in cells with EGFR activating mutations .	MET is required for EGF induced cell invasion and motility in EGFR wild-type NSCLC cells but it was unclear if this is true in cells with EGFR activating mutations.	4	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	11	12
Taken together , these findings support our hypotheses , that hypoxia results in HeLa cell proliferation due to arginase induction , and that the hypoxia induced arginase II induction and proliferation depends on EGF mediated activation of EGFR .	Taken together, these findings support our hypotheses, that hypoxia results in HeLa cell proliferation due to arginase induction, and that the hypoxia induced arginase II induction and proliferation depends on EGF mediated activation of EGFR.	33	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	33	34	37	38
However , neither microgravity nor clinostatting affect EGF induced EGF receptor clustering , suggesting that inhibition of EGF induced signal transduction by microgravity and clinostatting is independent of EGF receptor clustering .	However, neither microgravity nor clinostatting affect EGF induced EGF receptor clustering, suggesting that inhibition of EGF induced signal transduction by microgravity and clinostatting is independent of EGF receptor clustering.	3	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	7	8	9	11
A new bispecific ligand directed toxin ( BLT ) was created in which 2 human cytokines-epidermal growth factor ( [ EGF ] , targeting overexpressed EGF receptor ) and amino acid terminal fragment ( [ ATF ] , targeting urokinase plasminogen activator receptor )-were cloned onto the same single-chain molecule with truncated Pseudomonas exotoxin with a terminal lysyl-aspartyl-glutamyl-leucine ( KDEL ) sequence .	A new bispecific ligand directed toxin (BLT) was created in which 2 human cytokines-epidermal growth factor ([EGF], targeting overexpressed EGF receptor) and amino acid terminal fragment ([ATF], targeting urokinase plasminogen activator receptor)-were cloned onto the same single-chain molecule with truncated Pseudomonas exotoxin with a terminal lysyl-aspartyl-glutamyl-leucine (KDEL) sequence.	20	27	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	20	21	25	27
Unlike EGF activated EGFR , CS activated EGFR binds c-Src and caveolin-1 and does not undergo canonical dimerization .	Unlike EGF activated EGFR, CS activated EGFR binds c-Src and caveolin-1 and does not undergo canonical dimerization.	0	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
Thus , activation of EGFR by EGF directly stimulates a myriad of intricate cellular signaling pathways , many of which converge on elements of the ERK and MAPK pathway ( see XREF_FIG ) .	Thus, activation of EGFR by EGF directly stimulates a myriad of intricate cellular signaling pathways, many of which converge on elements of the ERK and MAPK pathway (see XREF_FIG).	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	4	5
Cetuximab in the PIC formulation blocked EGF induced activation of the EGFR and downstream signaling pathways .	Cetuximab in the PIC formulation blocked EGF induced activation of the EGFR and downstream signaling pathways.	6	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	11	12
On the other hand , EGFR stimulation by EGF decreased the levels of mature miR-23b .	On the other hand, EGFR stimulation by EGF decreased the levels of mature miR-23b.	5	9	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	5	6
Untransfected cells showed an increase in pY1086 EGFR phosphorylation treated with 10 ng/mL EGF and 1 muM 3,6-BPQ , 5.6-fold and 4.8-fold respectively ( p < 0.05 ) .	Untransfected cells showed an increase in pY1086 EGFR phosphorylation treated with 10 ng/mL EGF and 1 muM 3,6-BPQ, 5.6-fold and 4.8-fold respectively (p < 0.05).	7	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	7	8
Since ErbB2 is the preferred heterodimerization partner of EGF activated ErbB1 XREF_BIBR , the investigation of the effect of the dipole potential on clusters of ErbB1 and ErbB2 would be incomplete without measuring their heteroassociation .	Since ErbB2 is the preferred heterodimerization partner of EGF activated ErbB1 XREF_BIBR, the investigation of the effect of the dipole potential on clusters of ErbB1 and ErbB2 would be incomplete without measuring their heteroassociation.	6	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	8	9	10	11
TGFalpha and EGF stimulate GnRH release by activating erbB1 receptors .	TGFalpha and EGF stimulate GnRH release by activating erbB1 receptors.	0	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	erbB1	erbB1	erbB1	2	3	8	9
Because EGFR is activated both by exogenous EGF and autocrine TGF-alpha we modeled the effect of C225 addition by disabling the MAX function downstream of TNF and EGF ( recall that this gate is present to model activation of EGFR not only by exogenous EGF but also by TNF dependent release of TGFalpha , which acts in an autocrine manner ) .	Because EGFR is activated both by exogenous EGF and autocrine TGF-alpha we modeled the effect of C225 addition by disabling the MAX function downstream of TNF and EGF (recall that this gate is present to model activation of EGFR not only by exogenous EGF but also by TNF dependent release of TGFalpha, which acts in an autocrine manner).	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	1	2
It is well established that Cbl directly and specifically determines the rate of EGFR degradation by triggering EGF induced EGFR downregulation , which results in attenuation of EGFR promoted signaling [ XREF_BIBR ] .	It is well established that Cbl directly and specifically determines the rate of EGFR degradation by triggering EGF induced EGFR downregulation, which results in attenuation of EGFR promoted signaling [XREF_BIBR].	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
Epidermal growth factor ( EGF )-like factors [ amphiregulin ( AREG ) , betacellulin , and epiregulin ] are induced by LH and activate the EGF receptor ( ERBB1 )/ERK1/2 pathway in granulosa cells and cumulus cells of preovulatory follicles to impact ovulation .	Epidermal growth factor (EGF)-like factors [amphiregulin (AREG), betacellulin, and epiregulin] are induced by LH and activate the EGF receptor (ERBB1)/ERK1/2 pathway in granulosa cells and cumulus cells of preovulatory follicles to impact ovulation.	0	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epidermal growth factor	Epidermal growth factor	Epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	0	3	25	27
EGFR stimulation by treatment with the receptor ligands , including EGF , induces signal transduction pathways for macropinocytotic cellular uptake via the activation of Rac , a member of the Rho family of small GTPases , which leads to actin cytoskeletal organisation containing lamellipodial extensions XREF_BIBR XREF_BIBR .	EGFR stimulation by treatment with the receptor ligands, including EGF, induces signal transduction pathways for macropinocytotic cellular uptake via the activation of Rac, a member of the Rho family of small GTPases, which leads to actin cytoskeletal organisation containing lamellipodial extensions XREF_BIBR XREF_BIBR.	0	11	stimulation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	0	1
EGF mediated activation of EGFR and the downstream signalling kinase ERK2 were monitored in Western blots with activation-state specific anti-phospho-site antibodies .	EGF mediated activation of EGFR and the downstream signalling kinase ERK2 were monitored in Western blots with activation-state specific anti-phospho-site antibodies.	0	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
In line with this , the aberrant expression of NeuGcGM3 in NSCLC probably causes a disruption in the mechanism of EGFR tyrosine kinase inhibition by GM3 , permitting an uncontrolled EGFR system activation mediated by the ligand EGF .	In line with this, the aberrant expression of NeuGcGM3 in NSCLC probably causes a disruption in the mechanism of EGFR tyrosine kinase inhibition by GM3, permitting an uncontrolled EGFR system activation mediated by the ligand EGF.	30	38	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	37	38	30	31
EGF does not directly trigger EGFR dimerization , as observed for other growth factors , but induces a conformational change of the single receptor favoring dimerization .	EGF does not directly trigger EGFR dimerization, as observed for other growth factors, but induces a conformational change of the single receptor favoring dimerization.	0	16	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
In contrast , the present investigation revealed that NDRG1 expression decreased the level of EGFR and abrogated EGF induced EGFR activation , leading to decreased c-Src activation regardless of EGF treatment .	In contrast, the present investigation revealed that NDRG1 expression decreased the level of EGFR and abrogated EGF induced EGFR activation, leading to decreased c-Src activation regardless of EGF treatment.	16	22	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
In contrast , EGF activates the EGFR pathway , that , via AKT , promotes beta-catenin detachment from the Plasma Membrane and its nuclear translocation .	In contrast, EGF activates the EGFR pathway, that, via AKT, promotes beta-catenin detachment from the Plasma Membrane and its nuclear translocation.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	6	7
Consequently , this intracellular peptide inhibited EGF induced EGFR and Grb2 associations but not EGFR and Shc or Shc and Grb2 associations .	Consequently, this intracellular peptide inhibited EGF induced EGFR and Grb2 associations but not EGFR and Shc or Shc and Grb2 associations.	5	21	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Here , we report that a cell wall anchored form of EGF can access the EGFR expressed on the yeast cell surface , and EGF activates the EGFR in an autocrine manner .	Here, we report that a cell wall anchored form of EGF can access the EGFR expressed on the yeast cell surface, and EGF activates the EGFR in an autocrine manner.	24	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	27	28
As both repeated peroxide and EGF mediated an effective redistribution of EGFR from the plasma membrane fraction , we also found that exogenous EGF application ( 10ng/mL , 30 minutes ) was able to partially blunt the subsequent ERK1/2 response to peroxide stimulation ( % peroxide induced ERK1/2 phosphorylation after EGF treatment , compared to non EGF pre-exposed control , was 52 +/- 5.7 % ( n = 3 ) ) .	As both repeated peroxide and EGF mediated an effective redistribution of EGFR from the plasma membrane fraction, we also found that exogenous EGF application (10ng/mL, 30 minutes) was able to partially blunt the subsequent ERK1/2 response to peroxide stimulation (% peroxide induced ERK1/2 phosphorylation after EGF treatment, compared to non EGF pre-exposed control, was 52 +/- 5.7% (n = 3)).	3	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	11	12
It is also interesting to note that MMP1 activation in all genetic combinations except Ras V12 , scrib - does not co-relate with invasion suggesting that invasive potential of scrib mutant cells is not just dependent on JNK activation but alteration of cell survival due to increased Epidermal Growth Factor / Mitogen Activated Protein Kinases ( EGFR and MAPK ) or Yki activity in case of Ras V12 or loss of wts respectively .	It is also interesting to note that MMP1 activation in all genetic combinations except Ras V12, scrib - does not co-relate with invasion suggesting that invasive potential of scrib mutant cells is not just dependent on JNK activation but alteration of cell survival due to increased Epidermal Growth Factor / Mitogen Activated Protein Kinases (EGFR and MAPK) or Yki activity in case of Ras V12 or loss of wts respectively.	47	58	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epidermal Growth Factor	Epidermal Growth Factor	Epidermal Growth Factor	EGFR	EGFR	EGFR	47	50	56	57
The EGF like growth factors are released from the cell surface as mature , soluble peptides by proteolytic cleavage of the ectodomain , and when added to cumulus-oocyte complexes or follicles in culture , activate the EGFR on the surfaces of the somatic cells to promote oocyte meiotic resumption and cumulus expansion .	The EGF like growth factors are released from the cell surface as mature, soluble peptides by proteolytic cleavage of the ectodomain, and when added to cumulus-oocyte complexes or follicles in culture, activate the EGFR on the surfaces of the somatic cells to promote oocyte meiotic resumption and cumulus expansion.	0	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	36	37
These data point to a paracrine signal transduction between CAFs and tumor epithelium in that FGFs secreted by CAFs can activate FGFR expressed on tumor epithelial cells , and EGF secreted by tumor cells can , in turn , activate EGFR on CAFs .	These data point to a paracrine signal transduction between CAFs and tumor epithelium in that FGFs secreted by CAFs can activate FGFR expressed on tumor epithelial cells, and EGF secreted by tumor cells can, in turn, activate EGFR on CAFs.	29	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	40	41
In addition , we found that without EGF stimulation EGFR was randomly distributed in Pkd1 wild type and mutant MEK cells as well as in postnatal Pkd1 heterozygous PH2 and homozygous PN24 cells stained with anti-EGFR antibody ( XREF_FIG ) .	In addition, we found that without EGF stimulation EGFR was randomly distributed in Pkd1 wild type and mutant MEK cells as well as in postnatal Pkd1 heterozygous PH2 and homozygous PN24 cells stained with anti-EGFR antibody (XREF_FIG).	6	12	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
In both control and chronically Morphine treated cells , activation of ErbB1 by EGF leads to stimulation of ERK1/2 and Akt activities , as previously observed for Heregulin .	In both control and chronically Morphine treated cells, activation of ErbB1 by EGF leads to stimulation of ERK1/2 and Akt activities, as previously observed for Heregulin.	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	13	14	11	12
Pretreatment with gefitinib inhibits EGF induced stimulation of both EGFR and downstream Akt and MAPK more efficiently in MCF-7 and CAV1 than in MCF-7 cells .	Pretreatment with gefitinib inhibits EGF induced stimulation of both EGFR and downstream Akt and MAPK more efficiently in MCF-7 and CAV1 than in MCF-7 cells.	4	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	9	10
Also treatment with phorbol esters ( TPA ) , lysophosphatic acid ( LPA ) or EGF and subsequent activation of the EGF receptor induced a phosphorylation of Ser255 , Ser262 , Ser278/282 of Cx43 leading to a rapid disruption of GJIC [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Also treatment with phorbol esters (TPA), lysophosphatic acid (LPA) or EGF and subsequent activation of the EGF receptor induced a phosphorylation of Ser255, Ser262, Ser278/282 of Cx43 leading to a rapid disruption of GJIC [XREF_BIBR, XREF_BIBR, XREF_BIBR].	15	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	15	16	21	23
The overall DSB repair capacity was clearly enhanced when EGFR was activated by its natural ligand EGF and , vice versa , was reduced when EGFR was blocked either by the specific antibody Cetuximab or the tyrosine kinase inhibitor erlotinib , whereby reduction was clearly stronger for erlotinib .	The overall DSB repair capacity was clearly enhanced when EGFR was activated by its natural ligand EGF and, vice versa, was reduced when EGFR was blocked either by the specific antibody Cetuximab or the tyrosine kinase inhibitor erlotinib, whereby reduction was clearly stronger for erlotinib.	9	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	9	10
This finding indicates that c-Cbl-mediated ubiquitination is not required for EGF induced EGFR endocytosis .	This finding indicates that c-Cbl-mediated ubiquitination is not required for EGF induced EGFR endocytosis.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
In A549 cells , incubated with increasing concentration of MbetaCD ( 1 , 5 , 10 mM ) before EGF or PGE 2 treatment , we found no effect on EGF mediated EGFR nuclear translocation , whereas a reduced EGFR nuclear accumulation was observed after PGE 2 stimulation , demonstrating that Caveolin mediated endocytosis plays a role in PGE 2 -induced EGFR nuclear translocation .	In A549 cells, incubated with increasing concentration of MbetaCD (1, 5, 10 mM) before EGF or PGE 2 treatment, we found no effect on EGF mediated EGFR nuclear translocation, whereas a reduced EGFR nuclear accumulation was observed after PGE 2 stimulation, demonstrating that Caveolin mediated endocytosis plays a role in PGE 2 -induced EGFR nuclear translocation.	28	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	30	31	32	33
SphK1 expression and activity were stimulated by IGFBP-3 approximately 2-fold over 24 h. Silencing of sphingosine 1-phosphate receptor 1 ( S1P1 ) or S1P3 , but not S1P2 , abolished the effect of IGFBP-3 on EGF stimulated EGFR activation .	SphK1 expression and activity were stimulated by IGFBP-3 approximately 2-fold over 24 h. Silencing of sphingosine 1-phosphate receptor 1 (S1P1) or S1P3, but not S1P2, abolished the effect of IGFBP-3 on EGF stimulated EGFR activation.	33	38	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	35	36	37	38
Microinjection of an ErbB2 expression plasmid into BT20 cells significantly inhibited EGF stimulated EGFR endocytosis .	Microinjection of an ErbB2 expression plasmid into BT20 cells significantly inhibited EGF stimulated EGFR endocytosis.	10	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Importantly , exotic addition of EGF reactivated the downstream pathway of EGFR and reversed the apoptosis as well as cell cycle arrest induced by PA ..	Importantly, exotic addition of EGF reactivated the downstream pathway of EGFR and reversed the apoptosis as well as cell cycle arrest induced by PA..	3	12	reactivated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	11	12
Indeed , activation of EGFR by EGF stimulation of MDA-MB-231 cells led to both MET and AXL phosphorylation but not vice versa .	Indeed, activation of EGFR by EGF stimulation of MDA-MB-231 cells led to both MET and AXL phosphorylation but not vice versa.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	4	5
DYN pretreatment of NSCLC cells blocked the nuclear import of EGFR induced by either EGF ( 10 min ) or PGE 2 ( 60 min ) , whereas EIPA treatment failed to affect the EGFR internalization and nuclear translocation process .	DYN pretreatment of NSCLC cells blocked the nuclear import of EGFR induced by either EGF (10 min) or PGE 2 (60 min), whereas EIPA treatment failed to affect the EGFR internalization and nuclear translocation process.	8	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	10	11
Recombinant ALP inhibits EGF activation of EGFR pathway .	Recombinant ALP inhibits EGF activation of EGFR pathway.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	6	7
Increasing the PKG II activity of AGS cells by infecting them with Ad-PKG II and stimulating them with 8-pCPT-cGMP inhibited the EGF induced activation of EGFR , PI3K , Akt , mTOR and NF-kappaB ; caused an increase in caspase 9 breakdown ( activation ) and DFF levels ; and reversed the anti-apoptotic effect of EGF .	Increasing the PKG II activity of AGS cells by infecting them with Ad-PKG II and stimulating them with 8-pCPT-cGMP inhibited the EGF induced activation of EGFR, PI3K, Akt, mTOR and NF-kappaB; caused an increase in caspase 9 breakdown (activation) and DFF levels; and reversed the anti-apoptotic effect of EGF.	20	33	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	25	26
Immunohistochemistry shows that EGF causes activation of the EGFr signaling pathway , suggesting that prior to use as a targeting , diagnostic agent , potential deleterious effects should be considered .	Immunohistochemistry shows that EGF causes activation of the EGFr signaling pathway, suggesting that prior to use as a targeting, diagnostic agent, potential deleterious effects should be considered.	3	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFr	EGFr	EGFr	3	4	8	9
Compared with the respective controls , addition of EGF caused the dimerisation of EGFR in both cell types ( XREF_FIG ) .	Compared with the respective controls, addition of EGF caused the dimerisation of EGFR in both cell types (XREF_FIG).	6	14	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	13	14
As RTK substrates including phospholipase C-gamma , Src , GAP , and p85 and PI3K were identified , it became apparent that EGF activated EGFR is tightly bound to stable signaling complexes .	As RTK substrates including phospholipase C-gamma, Src, GAP, and p85 and PI3K were identified, it became apparent that EGF activated EGFR is tightly bound to stable signaling complexes.	22	27	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
EGF induced intense activation of pEGFR ( tyr1173 , tyr 1045 ) and pERK .	EGF induced intense activation of pEGFR (tyr1173, tyr 1045) and pERK.	0	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	0	1	5	6
However , efficient knockdown of SNX1 or SNX2 resulted in loss of SNX5 ( but not SNX6 ) , resulting in a block of EGF stimulated EGFR degradation ( unpublished data ) .	However, efficient knockdown of SNX1 or SNX2 resulted in loss of SNX5 (but not SNX6), resulting in a block of EGF stimulated EGFR degradation (unpublished data).	22	27	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
These results suggest that EGFR activated by EGF and its downstream signaling pathways proteins could be downregulated by taspine in a dose dependent manner .	These results suggest that EGFR activated by EGF and its downstream signaling pathways proteins could be downregulated by taspine in a dose dependent manner.	4	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	4	5
From the independency between autophosphorylation sites , we conjecture that EGFR kinase activity has no inherent selectivity to recognize prior autophosphorylation of EGFR , explaining why EGF induced EGFR on cell membrane was mostly mono-phosphorylated and rarely multi phosphorylated ( XREF_FIG ) .	From the independency between autophosphorylation sites, we conjecture that EGFR kinase activity has no inherent selectivity to recognize prior autophosphorylation of EGFR, explaining why EGF induced EGFR on cell membrane was mostly mono-phosphorylated and rarely multi phosphorylated (XREF_FIG).	26	37	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
Gefitinib , one kind of TKIs for advanced non-small-cell lung cancer therapy , was reported to inhibit EGF induced stimulation of both EGFR and downstream Akt and MAPK more efficiently in MCF-7 cells overexpressing Cav-1 than in parental cells [ XREF_BIBR ] .	Gefitinib, one kind of TKIs for advanced non-small-cell lung cancer therapy, was reported to inhibit EGF induced stimulation of both EGFR and downstream Akt and MAPK more efficiently in MCF-7 cells overexpressing Cav-1 than in parental cells [XREF_BIBR].	17	27	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	22	23
Overexpression of Mig-7 increased gamma 2 chain domain III fragments known to contain epidermal growth factor ( EGF )-like repeats that can activate EGF receptor .	Overexpression of Mig-7 increased gamma 2 chain domain III fragments known to contain epidermal growth factor (EGF)-like repeats that can activate EGF receptor.	13	25	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	13	16	23	25
Regarding the regulation of AQP-3 expression , a previous report had shown that EGF could trigger the activation of EGFR , PI3K , and ERK signaling pathways to regulate the AQP-3 expression in dermal fibroblasts , which is involved in fibroblast migration [ XREF_BIBR ] .	Regarding the regulation of AQP-3 expression, a previous report had shown that EGF could trigger the activation of EGFR, PI3K, and ERK signaling pathways to regulate the AQP-3 expression in dermal fibroblasts, which is involved in fibroblast migration [XREF_BIBR].	13	26	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	19	20
EGF like growth factors bind to the extracellular region of EGFR causing EGFR dimerization ( homo and hetero ) and activation of the intrinsic protein kinase activity of the EGFR .	EGF like growth factors bind to the extracellular region of EGFR causing EGFR dimerization (homo and hetero) and activation of the intrinsic protein kinase activity of the EGFR.	0	13	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	12	13
During the ovulatory cascade , expression of EGF like peptides such as amphiregulin ( AREG ) , epiregulin , and betacellulin on mural granulosa cells is induced in rapid response to the FSH and LH surges , and then the EGF like peptides activate the EGFR on cumulus cells XREF_BIBR - XREF_BIBR .	During the ovulatory cascade, expression of EGF like peptides such as amphiregulin (AREG), epiregulin, and betacellulin on mural granulosa cells is induced in rapid response to the FSH and LH surges, and then the EGF like peptides activate the EGFR on cumulus cells XREF_BIBR - XREF_BIBR.	39	49	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	40	41	45	46
These results suggest that expression of MUC1 is critical to EGF induced EGFR activation and that both the MUC1 intra- and extra-cellular domains contribute to the MUC1 associated increase of EGFR activity but with predominate influence from the MUC1 extracellular domain .	These results suggest that expression of MUC1 is critical to EGF induced EGFR activation and that both the MUC1 intra- and extra-cellular domains contribute to the MUC1 associated increase of EGFR activity but with predominate influence from the MUC1 extracellular domain.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
Indeed , over expression of c-Cbl significantly increases EGF induced EGFR degradation [ XREF_BIBR ] .	Indeed, over expression of c-Cbl significantly increases EGF induced EGFR degradation [XREF_BIBR].	7	11	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
These findings confirm the importance of Tyr 998 and reveal a role for Ser 991 in EGF mediated EGFR internalization possibly involving cross-talk with the p38 kinase dependent EGFR recycling pathway .	These findings confirm the importance of Tyr 998 and reveal a role for Ser 991 in EGF mediated EGFR internalization possibly involving cross-talk with the p38 kinase dependent EGFR recycling pathway.	16	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
In particular , whereas EGFR S1046/1047A exhibited enhanced EGF induced signaling and decreased EGF induced EGFR downregulation and EGFR T654A manifested primarily enhanced EGF induced signaling , EGFR T669A in our study displayed both enhanced acute EGF induced EGFR activation and enhanced EGF induced EGFR downregulation .	In particular, whereas EGFR S1046/1047A exhibited enhanced EGF induced signaling and decreased EGF induced EGFR downregulation and EGFR T654A manifested primarily enhanced EGF induced signaling, EGFR T669A in our study displayed both enhanced acute EGF induced EGFR activation and enhanced EGF induced EGFR downregulation.	41	45	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	42	43	44	45
As is seen in XREF_FIG , both HB-EGF and EGF produced a rapid and similar increase of activation of the EGFR , but whereas the activity of the EGFR reverted to background levels 2 hours after stimulation with EGF , the EGFR was still detectably activated 8 hours after stimulation with HB-EGF .	As is seen in XREF_FIG, both HB-EGF and EGF produced a rapid and similar increase of activation of the EGFR, but whereas the activity of the EGFR reverted to background levels 2 hours after stimulation with EGF, the EGFR was still detectably activated 8 hours after stimulation with HB-EGF.	7	21	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	20	21
Thus , it was concluded that phosphorylation of 1046 S and 1047 S in the receptor tail facilitated several negative regulatory events in the itinerary of the EGF stimulated EGFR , including receptor internalization and downregulation and desensitization of the kinase to further EGF stimulation [ XREF_BIBR , XREF_BIBR ] .	Thus, it was concluded that phosphorylation of 1046 S and 1047 S in the receptor tail facilitated several negative regulatory events in the itinerary of the EGF stimulated EGFR, including receptor internalization and downregulation and desensitization of the kinase to further EGF stimulation [XREF_BIBR, XREF_BIBR].	24	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	29	30
Contrary to resting cells , an elevated dipole potential significantly and systematically promoted the EGF induced homoassociation of ErbB1 and ErbB2 according to FRET and N & B measurements ( XREF_FIG A , B and XREF_FIG ) .	Contrary to resting cells, an elevated dipole potential significantly and systematically promoted the EGF induced homoassociation of ErbB1 and ErbB2 according to FRET and N&B measurements (XREF_FIG A, B and XREF_FIG).	13	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	14	15	18	19
Activation of EGFR by EGF stimulation of MDA-MB-231 cells was shown to lead to both Axl and MET phosphorylation but not vice versa .	Activation of EGFR by EGF stimulation of MDA-MB-231 cells was shown to lead to both Axl and MET phosphorylation but not vice versa.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	2	3
Loss of SNX5 blocked EGF stimulated EGFR degradation ( XREF_FIG ) demonstrating that SNX5 is required .	Loss of SNX5 blocked EGF stimulated EGFR degradation (XREF_FIG) demonstrating that SNX5 is required.	3	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
The identified USP8 mutants increase EGFR deubiquitination to inhibit EGF induced EGFR downregulation , leading to augmented and more sustained EGFR signaling .	The identified USP8 mutants increase EGFR deubiquitination to inhibit EGF induced EGFR downregulation, leading to augmented and more sustained EGFR signaling.	8	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
For NSCs , EGF induced activation of EGFR increases proliferation , survival , and migration , while inhibiting differentiation , whereas withdrawal of EGF from NSC cultures leads to differentiation and cell death ( XREF_FIG ) [ XREF_BIBR ] .	For NSCs, EGF induced activation of EGFR increases proliferation, survival, and migration, while inhibiting differentiation, whereas withdrawal of EGF from NSC cultures leads to differentiation and cell death (XREF_FIG) [XREF_BIBR].	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	7	8
EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na +/H+ exchanger regulatory factor 1 , engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1 .	EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na +/H+ exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1.	0	6	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
To investigate the binding of Eps15 to the truncated EGF receptor , cells were treated with EGF , and the EGF receptor was immunoprecipitated using an anti-EGF receptor antibody directed against the extracellular domain of the EGF receptor .	To investigate the binding of Eps15 to the truncated EGF receptor, cells were treated with EGF, and the EGF receptor was immunoprecipitated using an anti-EGF receptor antibody directed against the extracellular domain of the EGF receptor.	9	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	16	17	9	11
Investigation of the activation status of EGFR , MAPK and AKT by Western blot analysis showed transient activation of EGFR by EGF treatment in the cetuximab sensitive cell line MKN1 , which was reverted by concomitant cetuximab treatment .	Investigation of the activation status of EGFR, MAPK and AKT by Western blot analysis showed transient activation of EGFR by EGF treatment in the cetuximab sensitive cell line MKN1, which was reverted by concomitant cetuximab treatment.	17	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	19	20
EGF induced activation of EGFR tyrosine kinase is known to be inhibited by ganglioside GM3 , its dimer , and other mimetics .	EGF induced activation of EGFR tyrosine kinase is known to be inhibited by ganglioside GM3, its dimer, and other mimetics.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
Constitutive EGFR activation can be elicited by EGF related growth factors produced either by the tumor cells themselves or by the surrounding stromal cells [ XREF_BIBR ] .	Constitutive EGFR activation can be elicited by EGF related growth factors produced either by the tumor cells themselves or by the surrounding stromal cells [XREF_BIBR].	1	11	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	1	2
Recent studies have shown that early growth response-1 ( EGR-1 ) is highly expressed in MSC , and that EGF strongly upregulates EGR-1 and also EGF receptor in a protein kinase C-and/or mitogen activated protein kinase-extracellular-signal-regulated kinase dependent manner XREF_BIBR .	Recent studies have shown that early growth response-1 (EGR-1) is highly expressed in MSC, and that EGF strongly upregulates EGR-1 and also EGF receptor in a protein kinase C-and/or mitogen activated protein kinase-extracellular-signal-regulated kinase dependent manner XREF_BIBR.	19	27	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	19	20	25	27
In the experiments in XREF_FIG , we reverted to the CHO-GHR system ( in which neither EGFR nor ErbB-2 is endogenously expressed ) to probe the effects of coexpression or ErbB-2 on EGF induced EGFR downregulation of EGFR T669A compared to WT EGFR .	In the experiments in XREF_FIG, we reverted to the CHO-GHR system (in which neither EGFR nor ErbB-2 is endogenously expressed) to probe the effects of coexpression or ErbB-2 on EGF induced EGFR downregulation of EGFR T669A compared to WT EGFR.	24	35	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	32	33	34	35
EGF induced activation of EGFR in keratinocytes stimulates the MAPK signaling pathway , leading to growth stimulation ( XREF_FIG ) XREF_BIBR , XREF_BIBR .	EGF induced activation of EGFR in keratinocytes stimulates the MAPK signaling pathway, leading to growth stimulation (XREF_FIG) XREF_BIBR, XREF_BIBR.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
Cloning of EGF activated receptors also identified the human EGF receptor ( EGFR )-related gene 2 , called HER2 or ErbB2 .	Cloning of EGF activated receptors also identified the human EGF receptor (EGFR)-related gene 2, called HER2 or ErbB2.	0	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	2	3	9	11
To investigate whether the expression of ANGPTL4 is associated with the activation of EGFR signalling in HNSCC , cells were treated with EGF for varying periods of time .	To investigate whether the expression of ANGPTL4 is associated with the activation of EGFR signalling in HNSCC, cells were treated with EGF for varying periods of time.	13	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	13	14
In normal cells , EGFR that has been activated by EGF passes through the endosomal pathway and is degraded within lysosomes .	In normal cells, EGFR that has been activated by EGF passes through the endosomal pathway and is degraded within lysosomes.	4	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	4	5
In glioma , EGF or substance P can activate EGFR , which activates ERK and EGR1 biosynthesis [ XREF_BIBR ] .	In glioma, EGF or substance P can activate EGFR, which activates ERK and EGR1 biosynthesis [XREF_BIBR].	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	9	10
XREF_FIG A , EGFR and HER2 kinase activity and their downstream Akt and ERK signaling were dramatically induced by EGF and achieved the maximum after 30min , but were declined after three hours .	XREF_FIG A, EGFR and HER2 kinase activity and their downstream Akt and ERK signaling were dramatically induced by EGF and achieved the maximum after 30min, but were declined after three hours.	3	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	3	4
Epiregulin is an epidermal growth factor ( EGF ) member that activates ErBB1 and ErBB4 homodimers and all possible heterodimeric ErbB complexes .	Epiregulin is an epidermal growth factor (EGF) member that activates ErBB1 and ErBB4 homodimers and all possible heterodimeric ErbB complexes.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErBB1	ErBB1	ErBB1	7	8	12	13
Pollard and Vlaicu et al , have shown through cell line research and mouse models , that in breast cancer , macrophage production of EGF induces EGFR activation on tumor cells , which in turn leads to M-CSF ( CSF-1 ) production , consequently attracting more macrophages .	Pollard and Vlaicu et al, have shown through cell line research and mouse models, that in breast cancer, macrophage production of EGF induces EGFR activation on tumor cells, which in turn leads to M-CSF (CSF-1) production, consequently attracting more macrophages.	22	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
delta-Catenin failed to block the EGFR endocytosis induced by EGF but affected the EGFR expression pattern in CWR22Rv-1 cell membrane .	delta-Catenin failed to block the EGFR endocytosis induced by EGF but affected the EGFR expression pattern in CWR22Rv-1 cell membrane.	5	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	5	6
As EGFR activating mutations are known to remain at least partially ligand dependent in inducing oncogenic signals XREF_BIBR , we next examined whether EGFR activation by EGF might induce TWIST1 , restore its nuclear localization and contribute to the induction of EMT .	As EGFR activating mutations are known to remain at least partially ligand dependent in inducing oncogenic signals XREF_BIBR, we next examined whether EGFR activation by EGF might induce TWIST1, restore its nuclear localization and contribute to the induction of EMT.	23	27	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	23	24
These studies provide a novel regulatory mechanism to attenuate EGFR signaling in which EGF modulates EGFR trafficking through intracellular sodium mediated HDAC6 inactivation and tubulin acetylation .	These studies provide a novel regulatory mechanism to attenuate EGFR signaling in which EGF modulates EGFR trafficking through intracellular sodium mediated HDAC6 inactivation and tubulin acetylation.	13	16	modulates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Interestingly , ERBB2 and ERBB3 capable of binding the EGFR ( but not EGF ) in the membranes , also underwent similar rapid elimination in SC4MOL targeted cells following EGF induced EGFR internalization to endosomes ( XREF_FIG ) , while an unrelated surface protein , E-cadherin , did not ( XREF_FIG ) .	Interestingly, ERBB2 and ERBB3 capable of binding the EGFR (but not EGF) in the membranes, also underwent similar rapid elimination in SC4MOL targeted cells following EGF induced EGFR internalization to endosomes (XREF_FIG), while an unrelated surface protein, E-cadherin, did not (XREF_FIG).	27	32	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	31	32
This suggests that even though ErbB-2 is known to dampen EGF induced EGFR downregulation ( further discussed below ) , the difference between the WT EGFR and EGFR T669A is still maintained in the setting of ErbB-2 expression .	This suggests that even though ErbB-2 is known to dampen EGF induced EGFR downregulation (further discussed below), the difference between the WT EGFR and EGFR T669A is still maintained in the setting of ErbB-2 expression.	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
We showed that EGFR was strongly activated by EGF during mitosis as all the five major tyrosine residues including Y992 , Y1045 , Y1068 , Y1086 , and Y1173 were phosphorylated to a level similar to that in the interphase .	We showed that EGFR was strongly activated by EGF during mitosis as all the five major tyrosine residues including Y992, Y1045, Y1068, Y1086, and Y1173 were phosphorylated to a level similar to that in the interphase.	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	3	4
The models included the activation of EGFR by EGF , its effect on Class I PI3K activity , the phosphorylation and dephosphorylation PI ( 4,5 ) P2 , PI ( 3,4 ) P2 and PI ( 3,4,5 ) P3 .	The models included the activation of EGFR by EGF, its effect on Class I PI3K activity, the phosphorylation and dephosphorylation PI (4,5) P2, PI (3,4) P2 and PI (3,4,5) P3.	2	34	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	6	7
However , when the EGFR is activated by EGF exposure , the MCF7-EGFR cells were no longer sensitive to TAM .	However, when the EGFR is activated by EGF exposure, the MCF7-EGFR cells were no longer sensitive to TAM.	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	4	5
Our previous study has shown that EGF induces the indirect association of EGFR and c-Src and activation of c-Src in A431 cells .	Our previous study has shown that EGF induces the indirect association of EGFR and c-Src and activation of c-Src in A431 cells.	6	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	12	13
To then establish the connection between EGFR induced H 2 O 2 production and PTPRG inhibition , we determined whether the catalytic PTPRG cysteine is oxidized upon activation of EGFR by EGF .	To then establish the connection between EGFR induced H 2 O 2 production and PTPRG inhibition, we determined whether the catalytic PTPRG cysteine is oxidized upon activation of EGFR by EGF.	25	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	31	32	29	30
In addition , EGF can induce apoptosis by activating the EGFR in A431 cells , which can be abrogated by tyrosine kinase inhibition [ XREF_BIBR ] .	In addition, EGF can induce apoptosis by activating the EGFR in A431 cells, which can be abrogated by tyrosine kinase inhibition [XREF_BIBR].	3	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	10	11
EGFR signaling is triggered by the binding of EGF and EGF like growth factors , resulting in the homodimerization of EGFR molecules or heterodimerization of EGFR with other closely related receptors such as c-erbB2 [ XREF_BIBR ] .	EGFR signaling is triggered by the binding of EGF and EGF like growth factors, resulting in the homodimerization of EGFR molecules or heterodimerization of EGFR with other closely related receptors such as c-erbB2 [XREF_BIBR].	0	10	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	0	1
The specific activity of the kinase domain was low compared to purified , EGF activated EGF receptor .	The specific activity of the kinase domain was low compared to purified, EGF activated EGF receptor.	13	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	13	14	15	17
XREF_BIBR , XREF_BIBR The most proximal oocyte is thought to secrete LIN-3 , an epidermal growth factor ( EGF )-like ligand that activates LET-23 and EGF receptor on the sheath cells .	XREF_BIBR, XREF_BIBR The most proximal oocyte is thought to secrete LIN-3, an epidermal growth factor (EGF)-like ligand that activates LET-23 and EGF receptor on the sheath cells.	14	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	14	17	25	27
Together , these results indicate that EGF activates EGFR signaling to induce H3S28ph , which , in turn , upregulates tRNA Leu and 5S rRNA transcription through Brf1 and TBP and promotes cell transformation .	Together, these results indicate that EGF activates EGFR signaling to induce H3S28ph, which, in turn, upregulates tRNA Leu and 5S rRNA transcription through Brf1 and TBP and promotes cell transformation.	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Taken together , these data show that EGFR and HER2 signaling can be activated by EGF in DAOY cells and thus , DAOY cells may serve as a suitable model to test the effect of cardiac glycosides on EGFR signaling in medulloblastoma .	Taken together, these data show that EGFR and HER2 signaling can be activated by EGF in DAOY cells and thus, DAOY cells may serve as a suitable model to test the effect of cardiac glycosides on EGFR signaling in medulloblastoma.	7	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	7	8
Small-molecule EGFR inhibitors reduced the EGF induced activation of EGFR and its downstream signaling molecules at nanomolar doses , but cell viability was reduced , and caspase-3/7 was activated in GCT cells only at micromolar doses .	Small-molecule EGFR inhibitors reduced the EGF induced activation of EGFR and its downstream signaling molecules at nanomolar doses, but cell viability was reduced, and caspase-3/7 was activated in GCT cells only at micromolar doses.	4	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	9	10
ERK is maximally inhibited after one hour of vemurafenib treatment but EGF activation of EGFR did not activate downstream effectors at this time .	ERK is maximally inhibited after one hour of vemurafenib treatment but EGF activation of EGFR did not activate downstream effectors at this time.	11	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	14	15
The Km of progesterone receptor for phosphorylation by EGF activated EGF receptor was 100 nM and the Vmax was 2.5 nmol and min per mg of EGF receptor protein at 0 degrees C.	The Km of progesterone receptor for phosphorylation by EGF activated EGF receptor was 100 nM and the Vmax was 2.5 nmol and min per mg of EGF receptor protein at 0 degrees C.	6	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	8	9	10	12
Furthermore , both trastuzumab mediated down-regulation of ErbB2 and epidermal growth factor induced down-regulation of epidermal growth factor receptor are impaired in the trastuzumab resistant SKBR3 cells , indicating that the endocytic down-regulation of ErbB receptors is compromised in the resistant cells .	Furthermore, both trastuzumab mediated down-regulation of ErbB2 and epidermal growth factor induced down-regulation of epidermal growth factor receptor are impaired in the trastuzumab resistant SKBR3 cells, indicating that the endocytic down-regulation of ErbB receptors is compromised in the resistant cells.	7	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	9	12	15	19
In parallel , phosphorylation of STAT3 was significantly suppressed in the presence of Dasatinib and WP1066 in both DeltaEGFR and EGF stimulated EGFR cells ( as revealed by quantification , XREF_SUPPLEMENTARY ) .	In parallel, phosphorylation of STAT3 was significantly suppressed in the presence of Dasatinib and WP1066 in both DeltaEGFR and EGF stimulated EGFR cells (as revealed by quantification, XREF_SUPPLEMENTARY).	20	23	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
The EGFR can be activated by EGF , TGF-alpha , amphiregulin and heparin binding EGF .	The EGFR can be activated by EGF, TGF-alpha, amphiregulin and heparin binding EGF.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	1	2
However , EGF induced EGFR degradation was strikingly attenuated in Pkd1 wild type and mutant MEK cells treated with nocodazole for 2 hours ( XREF_FIG ) .	However, EGF induced EGFR degradation was strikingly attenuated in Pkd1 wild type and mutant MEK cells treated with nocodazole for 2 hours (XREF_FIG).	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
These methods were used to map phosphorylation on epidermal growth factor stimulated epidermal growth factor receptor to gauge the sensitivity of the proposed method .	These methods were used to map phosphorylation on epidermal growth factor stimulated epidermal growth factor receptor to gauge the sensitivity of the proposed method.	8	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	8	11	12	16
Knockdown of PI3KC3 expression in U-251 cells does not affect internalization of the epidermal growth factor receptor ( EGFR ) , but reduces the rate of dephosphorylation and degradation of EGFR induced by EGF stimulation .	Knockdown of PI3KC3 expression in U-251 cells does not affect internalization of the epidermal growth factor receptor (EGFR), but reduces the rate of dephosphorylation and degradation of EGFR induced by EGF stimulation.	24	34	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	33	34	30	31
We first confirmed our previously published observations that tethered EGF ( tEGF ) stimulates EGFR mediated signaling in human MSCs immortalized with telomerase reverse-transcriptase ( htMSC ) .	We first confirmed our previously published observations that tethered EGF (tEGF) stimulates EGFR mediated signaling in human MSCs immortalized with telomerase reverse-transcriptase (htMSC).	8	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	14	15
Recently , it was reported that MSCs stimulated by soluble EGF induced EGFR signaling and promoted the upregulation of migration and proliferation [ XREF_BIBR ] .	Recently, it was reported that MSCs stimulated by soluble EGF induced EGFR signaling and promoted the upregulation of migration and proliferation [XREF_BIBR].	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
Under steady state conditions , the exon 19 deleted EGFR forms a number of intracellular punctae that colocalize with endocytic compartments ; while the amounts of intracellular EGFR punctae reversely correlate with the efficiency of EGF induced EGFR downregulation .	Under steady state conditions, the exon 19 deleted EGFR forms a number of intracellular punctae that colocalize with endocytic compartments; while the amounts of intracellular EGFR punctae reversely correlate with the efficiency of EGF induced EGFR downregulation.	33	38	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	35	36	37	38
EGF-R , similar to other growth factor receptors , is activated by EGF , heparin binding-EGF ( HB-EGF ) and tumor growth factor-alpha ( TGF-alpha ) [ XREF_BIBR ] b Since the first report of transactivation of EGF-R by LPA in fibroblast [ XREF_BIBR ] , recent studies have established EGF-R transactivation by LPA in airway epithelial cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	EGF-R, similar to other growth factor receptors, is activated by EGF, heparin binding-EGF (HB-EGF) and tumor growth factor-alpha (TGF-alpha) [XREF_BIBR] b Since the first report of transactivation of EGF-R by LPA in fibroblast [XREF_BIBR], recent studies have established EGF-R transactivation by LPA in airway epithelial cells [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	12	13	0	1
These results suggest that endogenous PLD1 facilitates the EGF induced internalization of EGFR in HeLa cells in a lipase activity dependent manner .	These results suggest that endogenous PLD1 facilitates the EGF induced internalization of EGFR in HeLa cells in a lipase activity dependent manner.	7	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	12	13
These calculations yielded the half-life of EGF activated EGFR protein of ~ 5 h. 4.4.4 Considerations .	These calculations yielded the half-life of EGF activated EGFR protein of ~ 5 h. 4.4.4 Considerations.	4	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Pulse-chase experiments with [ 35 S ]-methionine revealed that EGFR half-life was ~ 8 h when treated with EGF , whereas H 2 O 2 treatment extended receptor half-life to 18 h ( combined treatment with EGF and H 2 O 2 yielded a half-life of 12 h ) .	Pulse-chase experiments with [35 S]-methionine revealed that EGFR half-life was ~ 8 h when treated with EGF, whereas H 2 O 2 treatment extended receptor half-life to 18 h (combined treatment with EGF and H 2 O 2 yielded a half-life of 12 h).	9	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	9	10
Given the robust interaction of HOPS subunits with RILP and that VPS41 is primarily responsible for the interaction , we interfered the function of HOPS complex by depleting VPS41 , using pSuper mediated shRNA targeting VPS41 and then examined the EGF stimulated EGFR internalization and degradation .	Given the robust interaction of HOPS subunits with RILP and that VPS41 is primarily responsible for the interaction, we interfered the function of HOPS complex by depleting VPS41, using pSuper mediated shRNA targeting VPS41 and then examined the EGF stimulated EGFR internalization and degradation.	39	43	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	40	41	42	43
Boehmenan Inhibited EGF Induced EGFR and Its Related Signaling Activation .	Boehmenan Inhibited EGF Induced EGFR and Its Related Signaling Activation.	1	9	Induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
EGF receptor was also induced by its ligand EGF .	EGF receptor was also induced by its ligand EGF.	0	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	8	9	0	2
Topical EGF was successfully applied as an experimental treatment to antagonize the inhibitory effect of the EGF receptor antibody .	Topical EGF was successfully applied as an experimental treatment to antagonize the inhibitory effect of the EGF receptor antibody.	0	18	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	1	2	16	18
So far through a series of three studies [ XREF_BIBR - XREF_BIBR ] we found that ( 1 ) EGCG alters lipid organization on the plasma membrane , ( 2 ) EGCG promote the internalization of nonactivated monomer EGFR into cytosol , thus , inhibiting the activation of EGFR by EGF , ( 3 ) as a result , treatment with EGCG causes marked reduction of phosphorylated ( activated ) EGFRs , that are otherwise preferentially present in lipid rafts , ( 4 ) EGCG induced EGFR internalization requires neither the binding of c-Cbl to EGFR nor a phosphorylation of EGFR at tyrosine residue , suggesting that this internalization is mediated by a different mechanism that is observed in EGF treated cells , and ( 5 ) phosphorylation of EGFR at serine1046/1047 mediated by p38MAPK is essential for EGCG induced EGFR internalization ( XREF_FIG ) .	So far through a series of three studies [XREF_BIBR - XREF_BIBR] we found that (1) EGCG alters lipid organization on the plasma membrane, (2) EGCG promote the internalization of nonactivated monomer EGFR into cytosol, thus, inhibiting the activation of EGFR by EGF, (3) as a result, treatment with EGCG causes marked reduction of phosphorylated (activated) EGFRs, that are otherwise preferentially present in lipid rafts, (4) EGCG induced EGFR internalization requires neither the binding of c-Cbl to EGFR nor a phosphorylation of EGFR at tyrosine residue, suggesting that this internalization is mediated by a different mechanism that is observed in EGF treated cells, and (5) phosphorylation of EGFR at serine1046/1047 mediated by p38MAPK is essential for EGCG induced EGFR internalization (XREF_FIG).	46	143	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	50	51	48	49
The data show that EGFR is activated by ox-stress only at 37degreesC whereas EGF activates EGFR even at 4degreesC ( XREF_FIG ) .	The data show that EGFR is activated by ox-stress only at 37degreesC whereas EGF activates EGFR even at 4degreesC (XREF_FIG).	13	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Very recently , Chung and colleagues [ XREF_BIBR ] have shown that NF-kB binds to the promoter region of FOXC1 once EGFR is activated by EGF .	Very recently, Chung and colleagues [XREF_BIBR] have shown that NF-kB binds to the promoter region of FOXC1 once EGFR is activated by EGF.	21	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	21	22
In both stable cell lines , the canonical pathway of EGF induced EGFR activity was unaltered , as attested by the proper phosphorylation of MAPK ERK1/2 .	In both stable cell lines, the canonical pathway of EGF induced EGFR activity was unaltered, as attested by the proper phosphorylation of MAPK ERK1/2.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
Additionally , a previous study revealed that EGF induced EGFR activation is able to reduce IGFBP-3 levels .	Additionally, a previous study revealed that EGF induced EGFR activation is able to reduce IGFBP-3 levels.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Although GH did not discernibly affect EGF induced EGFR tyrosine phosphorylation , we observed by immunoblotting a substantial decrease of EGF induced EGFR degradation in the presence of GH .	Although GH did not discernibly affect EGF induced EGFR tyrosine phosphorylation, we observed by immunoblotting a substantial decrease of EGF induced EGFR degradation in the presence of GH.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
In contrast , 1 muM erlotinib ( XREF_FIG A ) or gefitinib ( unpublished data ) did not inhibit anchorage independent growth of EGF treated cells overexpressing the wild-type EGFR .	In contrast, 1 muM erlotinib (XREF_FIG A) or gefitinib (unpublished data) did not inhibit anchorage independent growth of EGF treated cells overexpressing the wild-type EGFR.	21	30	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	29	30
NSCLC cell line H1792 was selected for two reasons : 1 ) H1792 cells express a low level of endogenous GPRC5A , thus expression of exogenous GPRC5A-WT and GPRC5A-4F could be detected and evaluated ; and 2 ) this cell line expresses endogenous EGFR , thus EGFR activity can be induced by EGF .	NSCLC cell line H1792 was selected for two reasons : 1) H1792 cells express a low level of endogenous GPRC5A, thus expression of exogenous GPRC5A-WT and GPRC5A-4F could be detected and evaluated; and 2) this cell line expresses endogenous EGFR, thus EGFR activity can be induced by EGF.	46	53	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	52	53	46	47
Since phosphorylation of Tyr1068 and Tyr1086 are functionally linked to the activation of Akt and ERK signaling pathways , next we examined whether the blunted EGF induced activation of EGFR seen in SCD5 expressors would be translated to its downstream effectors .	Since phosphorylation of Tyr1068 and Tyr1086 are functionally linked to the activation of Akt and ERK signaling pathways, next we examined whether the blunted EGF induced activation of EGFR seen in SCD5 expressors would be translated to its downstream effectors.	23	30	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	29	30
Both MAPK and ERK kinase inhibition and HIF-1alpha knockdown under normoxic conditions reduced EGF dependent VEGF-A secretion in HK-2 cells confirming that EGF mediated stimulation of EGFR regulates VEGF-A secretion in HK-2 cells via MAPK ( ERK1/2 ) signaling and the transcription factor HIF-1alpha .	Both MAPK and ERK kinase inhibition and HIF-1alpha knockdown under normoxic conditions reduced EGF dependent VEGF-A secretion in HK-2 cells confirming that EGF mediated stimulation of EGFR regulates VEGF-A secretion in HK-2 cells via MAPK (ERK1/2) signaling and the transcription factor HIF-1alpha.	22	27	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	26	27
We found that expression of exogenous SIMPLE W116G or P135T mutant , but not SIMPLE WT , significantly impaired EGF induced EGFR degradation ( XREF_FIG ) and TR-EGF trafficking in cells ( XREF_FIG ) , which indicates a dominant negative role for the CMT1C linked SIMPLE mutants in endosome-to-lysosome trafficking .	We found that expression of exogenous SIMPLE W116G or P135T mutant, but not SIMPLE WT, significantly impaired EGF induced EGFR degradation (XREF_FIG) and TR-EGF trafficking in cells (XREF_FIG), which indicates a dominant negative role for the CMT1C linked SIMPLE mutants in endosome-to-lysosome trafficking.	15	22	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
Coexpression of ErbB2 with EGFR in 293T cells also significantly inhibited EGF stimulated EGFR endocytosis .	Coexpression of ErbB2 with EGFR in 293T cells also significantly inhibited EGF stimulated EGFR endocytosis.	10	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
EGF , transforming growth factor-alpha ( TGFalpha ) , and amphiregulin are specific for EGFR and primarily induce the formation of EGFR and EGFR homodimers and EGFR and ErbB2 heterodimers [ XREF_BIBR ] .	EGF, transforming growth factor-alpha (TGFalpha), and amphiregulin are specific for EGFR and primarily induce the formation of EGFR and EGFR homodimers and EGFR and ErbB2 heterodimers [XREF_BIBR].	0	30	induce	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	EGF	EGF	egf	EGFR	EGFR and ErbB2 heterodimers	egfr	0	1	26	27
Addition of EGF to DMSO treated cells caused a rapid down-regulation of the EGF receptor , but did not alter their proliferation rate .	Addition of EGF to DMSO treated cells caused a rapid down-regulation of the EGF receptor, but did not alter their proliferation rate.	0	15	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	2	3	13	15
Indeed , EGF activated EGFR signaling increased the self-renewal potential of WT BM-MSCs that have intact AR .	Indeed, EGF activated EGFR signaling increased the self-renewal potential of WT BM-MSCs that have intact AR.	2	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
While EGF stimulated EGFR internalization is tyrosine kinase dependent and requires autophosphorylation of multiple tyrosines , UV stimulated internalization is tyrosine kinase independent [ XREF_BIBR ] .	While EGF stimulated EGFR internalization is tyrosine kinase dependent and requires autophosphorylation of multiple tyrosines, UV stimulated internalization is tyrosine kinase independent [XREF_BIBR].	1	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
Epidermal growth factor stimulates human sperm capacitation by activating the tyrosine kinase of the EGF receptor which is regulated by multisite phosphorylation .	Epidermal growth factor stimulates human sperm capacitation by activating the tyrosine kinase of the EGF receptor which is regulated by multisite phosphorylation.	0	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epidermal growth factor	Epidermal growth factor	Epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	0	3	14	16
Depletion of NEU1 increases EGF stimulated EGFR Tyr 1068 auto-phosphorylation and activation , decreases MUC1 mediated Pseudomonas aeruginosa adhesion and flagellin stimulated ERK1/2 activation .	Depletion of NEU1 increases EGF stimulated EGFR Tyr 1068 auto-phosphorylation and activation, decreases MUC1 mediated Pseudomonas aeruginosa adhesion and flagellin stimulated ERK1/2 activation.	3	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
EGF could not cause activation of EGFR because of the dephosphorylation of p44/42 MAPK and AKT in HL-SMCs , which caused p27 expression insufficiently and cell cycle dysregulation .	EGF could not cause activation of EGFR because of the dephosphorylation of p44/42 MAPK and AKT in HL-SMCs, which caused p27 expression insufficiently and cell cycle dysregulation.	0	7	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	6	7
In control cells cultured without Dox , there was canonical EGFR signal activation by EGF , with time dependent reduction of EGFR and a rapid increase and maintenance of high phosphorylation levels for ERK and AKT ( solid lines in Figure XREF_FIG ) .	In control cells cultured without Dox, there was canonical EGFR signal activation by EGF, with time dependent reduction of EGFR and a rapid increase and maintenance of high phosphorylation levels for ERK and AKT (solid lines in Figure XREF_FIG).	10	15	signal activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	10	11
UVB prevented EGF induced activation of EGFR , abolishing phosphorylation of the EGFR intracellular domain and of other key downstream signaling proteins such as AKT ( Protein Kinase B ) and the mitogen activated protein kinases ( ERK1 and 2 ) .	UVB prevented EGF induced activation of EGFR, abolishing phosphorylation of the EGFR intracellular domain and of other key downstream signaling proteins such as AKT (Protein Kinase B) and the mitogen activated protein kinases (ERK1 and 2).	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	6	7
Our studies have demonstrated that EGF activation of EGFR through the intrinsic tyrosine kinase activity of the receptor and the activation of downstream signal transduction pathways ( MAPK and ERK and PI3K and AKT ) , up-regulates the human prolactin receptor .	Our studies have demonstrated that EGF activation of EGFR through the intrinsic tyrosine kinase activity of the receptor and the activation of downstream signal transduction pathways (MAPK and ERK and PI3K and AKT), up-regulates the human prolactin receptor.	5	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	8	9
As shown in XREF_FIG , EGF initiated the activation of EGFR signaling pathways as the fluorescent signal of phosphorylated EGFR increased significantly .	As shown in XREF_FIG, EGF initiated the activation of EGFR signaling pathways as the fluorescent signal of phosphorylated EGFR increased significantly.	5	12	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	10	11
Unlike EGF activated EGFR , CS stimulated EGFR triggers aberrant Src phosphorylation in lung cancer cells .	Unlike EGF activated EGFR, CS stimulated EGFR triggers aberrant Src phosphorylation in lung cancer cells.	0	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
To further examine whether the differential status of EGFR distribution between gefitinib sensitive and -insensitive cells resulted from dysregulation of EGFR endocytosis , we determined the frequencies of EGF induced EGFR endocytosis by flow cytometry with fluorescent conjugated EGF .	To further examine whether the differential status of EGFR distribution between gefitinib sensitive and -insensitive cells resulted from dysregulation of EGFR endocytosis, we determined the frequencies of EGF induced EGFR endocytosis by flow cytometry with fluorescent conjugated EGF.	26	31	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	28	29	30	31
This antibody potently antagonizes the binding of the EGF ligand to EGFR , inhibits EGF stimulated activation of both EGFR and the downstream p44 and p42 MAP kinases , and neutralizes EGF induced DiFi cell proliferation .	This antibody potently antagonizes the binding of the EGF ligand to EGFR, inhibits EGF stimulated activation of both EGFR and the downstream p44 and p42 MAP kinases, and neutralizes EGF induced DiFi cell proliferation.	14	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	19	20
We observed that GCs express mRNAs for the epithelial growth factor receptor ( EGFR ) ( XREF_FIG and XREF_SUPPLEMENTARY ) , and consistent with this pathway blocking secretion and GAP formation , EGF activated the EGFR and p42 and p44 MAPK and inhibited cholinergic agonist induced secretion in a cell intrinsic manner in the LS174T GC line ( XREF_SUPPLEMENTARY ) .	We observed that GCs express mRNAs for the epithelial growth factor receptor (EGFR) (XREF_FIG and XREF_SUPPLEMENTARY), and consistent with this pathway blocking secretion and GAP formation, EGF activated the EGFR and p42 and p44 MAPK and inhibited cholinergic agonist induced secretion in a cell intrinsic manner in the LS174T GC line (XREF_SUPPLEMENTARY).	32	42	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	32	33	35	36
Finally , EGFR activated by ox-stress could not bind to a new Ab that recognizes only the EGF induced active conformation of EGFR because the epitopes recognized by this Ab are in the intracellular domain of EGFR , which are exposed only in these active conformations .	Finally, EGFR activated by ox-stress could not bind to a new Ab that recognizes only the EGF induced active conformation of EGFR because the epitopes recognized by this Ab are in the intracellular domain of EGFR, which are exposed only in these active conformations.	16	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	22	23
EGF Directs the Association of EGFR , NHERF1 , and NHE1 into Protein Protein Complexes .	EGF Directs the Association of EGFR, NHERF1, and NHE1 into Protein Protein Complexes.	0	14	Directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
Moreover , EGF treated NR6 fibroblasts can stimulate EGFR activation leading to the loss of focal adhesions and a concomitant reduction in cell adhesion strength .	Moreover, EGF treated NR6 fibroblasts can stimulate EGFR activation leading to the loss of focal adhesions and a concomitant reduction in cell adhesion strength.	2	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	8	9
On the other hand , EGCG induced internalization of EGFR in the absence of activated EGFR ( tyr 1173 ) and pEGFR ( tyr1045 ) , a critical tyrosine phosphorylation site for EGF induced EGFR internalization .	On the other hand, EGCG induced internalization of EGFR in the absence of activated EGFR (tyr 1173) and pEGFR (tyr1045), a critical tyrosine phosphorylation site for EGF induced EGFR internalization.	30	35	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	32	33	34	35
EGF stimulates EGFR neddylation , which requires the RING and TKB domains of Cbl , as well as Y1045 of EGFR .	EGF stimulates EGFR neddylation, which requires the RING and TKB domains of Cbl, as well as Y1045 of EGFR.	0	3	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Thus , AR stimulation of EGFR results in greater steady-state EGFR expression than does EGF stimulation of EGFR .	Thus, AR stimulation of EGFR results in greater steady-state EGFR expression than does EGF stimulation of EGFR.	14	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	17	18
EGF did not stimulate tyrosine phosphorylation of CAIX , although EGFR and down-stream signaling pathways were activated by EGF .	EGF did not stimulate tyrosine phosphorylation of CAIX, although EGFR and down-stream signaling pathways were activated by EGF.	10	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	10	11
Binding of EGF to its receptor , the epidermal growth factor receptor ( EGFR ) , induces dimerization and activation of EGFR .	Binding of EGF to its receptor, the epidermal growth factor receptor (EGFR), induces dimerization and activation of EGFR.	0	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	21	22
We quantified EGF dependent activation of EGFR by probing tyrosine phosphorylation of immobilized proteins ( XREF_FIG ) .	We quantified EGF dependent activation of EGFR by probing tyrosine phosphorylation of immobilized proteins (XREF_FIG).	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	6	7
Conversely EGF has an extremely large N terminal extension whose cleavage may regulate the efficiency of EGF activation of EGFR .	Conversely EGF has an extremely large N terminal extension whose cleavage may regulate the efficiency of EGF activation of EGFR.	16	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	19	20
EGF rapidly triggers internalization of the fluorescent EGF receptor type 1 , but we failed to observe any sequestration of this receptor type upon exposure of cells to an opioid , since opioids most likely trigger stimulation of a different EGF receptor type .	EGF rapidly triggers internalization of the fluorescent EGF receptor type 1, but we failed to observe any sequestration of this receptor type upon exposure of cells to an opioid, since opioids most likely trigger stimulation of a different EGF receptor type.	0	9	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	7	9
The time dependent activation of EGFR was investigated in conventional T cells after they were treated with epidermal growth factor ( EGF ) for various periods .	The time dependent activation of EGFR was investigated in conventional T cells after they were treated with epidermal growth factor (EGF) for various periods.	3	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	17	20	5	6
Using this technique , we have studied the process of early signal transduction of epidermal growth factor ( EGF ) in single molecules : binding of EGF to its receptor ( EGFR ) on the cell surface , dimerization of EGFR induced by binding of EGF , fluctuation of the structure of EGFR clusters , activation of EGFR through tyrosine phosphorylations on its cytoplasmic domain , and recognition of activated EGFR by a cytoplasmic adaptor protein , Grb2 .	Using this technique, we have studied the process of early signal transduction of epidermal growth factor (EGF) in single molecules : binding of EGF to its receptor (EGFR) on the cell surface, dimerization of EGFR induced by binding of EGF, fluctuation of the structure of EGFR clusters, activation of EGFR through tyrosine phosphorylations on its cytoplasmic domain, and recognition of activated EGFR by a cytoplasmic adaptor protein, Grb2.	38	67	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	45	46	40	41
Src is responsible for activation of STAT transcription factors after activation of ErbB1 by EGF , suggesting that EGF induced mitogenesis might be mediated by the Src-STAT pathway which is independent of Jak [ XREF_BIBR ] .	Src is responsible for activation of STAT transcription factors after activation of ErbB1 by EGF, suggesting that EGF induced mitogenesis might be mediated by the Src-STAT pathway which is independent of Jak [XREF_BIBR].	10	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	14	15	12	13
In the absence of EGF , Kv1.3 and EGFR were primarily localized at the cell surface ( XREF_FIG ) ; EGF incubation triggered the co-internalization of Kv1.3 and the EGFR ( XREF_FIG ) .	In the absence of EGF, Kv1.3 and EGFR were primarily localized at the cell surface (XREF_FIG); EGF incubation triggered the co-internalization of Kv1.3 and the EGFR (XREF_FIG).	20	31	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	29	30
We therefore hypothesized that phenobarbital may stimulate the dephosphorylation of CAR by antagonizing EGF induced activation of EGFR .	We therefore hypothesized that phenobarbital may stimulate the dephosphorylation of CAR by antagonizing EGF induced activation of EGFR.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	17	18
Pretreatment with EGCG inhibited the binding of Alexa Fluor 488 labeled EGF to the cells and also inhibited EGF induced dimerization of the EGFR .	Pretreatment with EGCG inhibited the binding of Alexa Fluor 488 labeled EGF to the cells and also inhibited EGF induced dimerization of the EGFR.	18	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	23	24
Exposure of U87-EGFR cells to EGF induced activation of EGFR , c-Src , and p38 ( XREF_FIG ) .	Exposure of U87-EGFR cells to EGF induced activation of EGFR, c-Src, and p38 (XREF_FIG).	3	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	9	10
Interestingly , we further found that EGF induced EGFR endocytosis and EGFR signaling were different between gefitinib sensitive and gefitinib-insensitive ESCC cell lines .	Interestingly, we further found that EGF induced EGFR endocytosis and EGFR signaling were different between gefitinib sensitive and gefitinib-insensitive ESCC cell lines.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
The effect of exogenous IGFBP-3 on EGFR activation was blocked by pharmacologic inhibition or siRNA mediated silencing of SphK1 , and silencing of endogenous IGFBP-3 also suppressed EGF stimulated EGFR activation .	The effect of exogenous IGFBP-3 on EGFR activation was blocked by pharmacologic inhibition or siRNA mediated silencing of SphK1, and silencing of endogenous IGFBP-3 also suppressed EGF stimulated EGFR activation.	26	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	29	30
It was observed that EGF rapidly induced a > 7 fold increase of pEGFR that was maximal at 10 min .	It was observed that EGF rapidly induced a> 7 fold increase of pEGFR that was maximal at 10 min.	4	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	4	5	13	14
The latter correlated with impaired EGF induced EGFR degradation .	The latter correlated with impaired EGF induced EGFR degradation.	2	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Activation of EGF receptor by EGF or other high-affinity ligands often results in increased migration of cells in physiological and pathological situations .	Activation of EGF receptor by EGF or other high-affinity ligands often results in increased migration of cells in physiological and pathological situations.	0	9	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	5	6	2	4
It has been demonstrated that EGFR Y1045 is phosphorylated after EGF activation of EGFR and the E3 ubiquitin ligase c-Cbl binds this phosphorylated residue , thereby mediating EGFR ubiquitination and degradation [ XREF_BIBR ] .	It has been demonstrated that EGFR Y1045 is phosphorylated after EGF activation of EGFR and the E3 ubiquitin ligase c-Cbl binds this phosphorylated residue, thereby mediating EGFR ubiquitination and degradation [XREF_BIBR].	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	13	14
The higher levels of EGF observed in miR-223 KO mice resulted in slightly higher phosphorylation of EGFR in mammary glands of miR-223 KO mice than in WT littermates ( XREF_SUPPLEMENTARY ) , supporting the possibility that miR-223 regulated the EGF and EGFR pathway also under physiological conditions .	The higher levels of EGF observed in miR-223 KO mice resulted in slightly higher phosphorylation of EGFR in mammary glands of miR-223 KO mice than in WT littermates (XREF_SUPPLEMENTARY), supporting the possibility that miR-223 regulated the EGF and EGFR pathway also under physiological conditions.	2	42	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	levels of EGF	egf	EGFR	EGFR	egfr	4	5	41	42
Soluble EGF can activate EGFR on distant cells via an endocrine and paracrine pathway or cells of its origin via an autocrine action .	Soluble EGF can activate EGFR on distant cells via an endocrine and paracrine pathway or cells of its origin via an autocrine action.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	4	5
This has implications for spontaneously versus EGF activated EGFR- signaling .	This has implications for spontaneously versus EGF activated EGFR- signaling.	1	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR-	EGFR-	EGFR-	6	7	8	9
Before EGF stimulation EGFR was primarily located along the cell surface .	Before EGF stimulation EGFR was primarily located along the cell surface.	0	6	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
Vertebrate EGF activates S. mansoni EGFR and the downstream classical ERK pathway , indicating the conservation of EGFR function in S. mansoni [ XREF_BIBR ] .	Vertebrate EGF activates S. mansoni EGFR and the downstream classical ERK pathway, indicating the conservation of EGFR function in S. mansoni [XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	5	6
Previously , it was demonstrated that NRG activates ErbB-2 and ErbB-3 heterodimers to induce LNCaP cell death , whereas , EGF activates ErbB-1 and ErbB-1 or ErbB-1 and ErbB-2 dimers to induce cell growth and survival .	Previously, it was demonstrated that NRG activates ErbB-2 and ErbB-3 heterodimers to induce LNCaP cell death, whereas, EGF activates ErbB-1 and ErbB-1 or ErbB-1 and ErbB-2 dimers to induce cell growth and survival.	20	31	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	20	21	22	23
Moreover , when expressed in BT20 cells by microinjection , a chimeric receptor composed of the ErbB2 extracellular domain and the EGFR intracellular domain underwent normal endocytosis in response to EGF , and this chimera did not block EGF induced EGFR endocytosis .	Moreover, when expressed in BT20 cells by microinjection, a chimeric receptor composed of the ErbB2 extracellular domain and the EGFR intracellular domain underwent normal endocytosis in response to EGF, and this chimera did not block EGF induced EGFR endocytosis.	37	41	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	38	39	40	41
The canonical process of EGF mediated activation of EGFR includes EGFR internalization , hence reduction of membrane level of EGFR , and increase of AKT phosphorylation ( pAKT ) , which normally occur in synchronized cells by serum starvation for 1-2 days .	The canonical process of EGF mediated activation of EGFR includes EGFR internalization, hence reduction of membrane level of EGFR, and increase of AKT phosphorylation (pAKT), which normally occur in synchronized cells by serum starvation for 1-2 days.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	8	9
In EGF induced EGFR activation , EGFR dimerization occurs followed by EGFR auto-phosphorylation and internalization .	In EGF induced EGFR activation, EGFR dimerization occurs followed by EGFR auto-phosphorylation and internalization.	0	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
Furthermore , the p85 subunit of phosphatidylinositol kinase ( PI3-K ) associated with EGF activated ErbB-1 in a biphasic manner , whereas association with ErbB-1 transactivated by ErbB-4 was monophasic .	Furthermore, the p85 subunit of phosphatidylinositol kinase (PI3-K) associated with EGF activated ErbB-1 in a biphasic manner, whereas association with ErbB-1 transactivated by ErbB-4 was monophasic.	11	16	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	13	14	15	16
EGF significantly increases TWIST transcripts and protein in EGFR expressing lines .	EGF significantly increases TWIST transcripts and protein in EGFR expressing lines.	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	8	9
Moreover , fluorescence microscopy revealed that p38 MAPK activated by UVC radiation triggered EGFR internalization and that this was not correlated with c-Cbl , an ubiquitin ligase , which plays an important role in EGF induced EGFR downregulation .	Moreover, fluorescence microscopy revealed that p38 MAPK activated by UVC radiation triggered EGFR internalization and that this was not correlated with c-Cbl, an ubiquitin ligase, which plays an important role in EGF induced EGFR downregulation.	32	37	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	34	35	36	37
In contrast , expression of an inactive dominant negative ( DN ) form of AMSH in the same cells inhibited EGF induced EGFR degradation [ XREF_BIBR ] .	In contrast, expression of an inactive dominant negative (DN) form of AMSH in the same cells inhibited EGF induced EGFR degradation [XREF_BIBR].	20	23	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
The dynamics of Shc1 phosphorylation at six residues and its association with 41 binding partners was followed over multiple time points after activation of EGFR by EGF .	The dynamics of Shc1 phosphorylation at six residues and its association with 41 binding partners was followed over multiple time points after activation of EGFR by EGF.	16	27	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	24	25
This is in accordance with our results showing that stimulation of EGFR by EGF rescued loss of cell viability by dasatinib .	This is in accordance with our results showing that stimulation of EGFR by EGF rescued loss of cell viability by dasatinib.	9	14	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	11	12
Taken together , this data clearly highlighted that USP17 is required for EGFR internalisation and indicated that the induction of USP17 by EGF allows EGFR internalisation .	Taken together, this data clearly highlighted that USP17 is required for EGFR internalisation and indicated that the induction of USP17 by EGF allows EGFR internalisation.	20	25	allows	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
These approaches provided consistent results indicating that EGF induced rapid dimerization of EGF receptor in living cells , suggesting that this process may play a role in transmembrane signalling mediated by EGF .	These approaches provided consistent results indicating that EGF induced rapid dimerization of EGF receptor in living cells, suggesting that this process may play a role in transmembrane signalling mediated by EGF.	7	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	7	8	12	14
Similarly , EGF increased STAT3 promoter activity in vector transfected controls , while EGF was unable to augment the already elevated levels of STAT3 promoter activation in HNSCC cells expressing EGFRvIII .	Similarly, EGF increased STAT3 promoter activity in vector transfected controls, while EGF was unable to augment the already elevated levels of STAT3 promoter activation in HNSCC cells expressing EGFRvIII.	13	31	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFRvIII	EGFRvIII	EGFRvIII	13	14	30	31
To address how EGFR moves from cell surface to the Golgi , we first asked whether EGF could stimulate EGFR transport to the Golgi .	To address how EGFR moves from cell surface to the Golgi, we first asked whether EGF could stimulate EGFR transport to the Golgi.	16	20	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	19	20
Further studies showed that PD153035 , which does not reverse ligand induced EGFR down-regulation , blocks EGF induced EGFR activation as well as EGFR ' s binding to c-cbl and Grb2 .	Further studies showed that PD153035, which does not reverse ligand induced EGFR down-regulation, blocks EGF induced EGFR activation as well as EGFR 's binding to c-cbl and Grb2.	16	25	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
Interestingly , we observed that EGF induced EGFR endocytosis progressed continuously in gefitinib-insensitive cells regardless of gefitinib treatment , whereas it was suppressed by gefitinib in gefitinib sensitive cells .	Interestingly, we observed that EGF induced EGFR endocytosis progressed continuously in gefitinib-insensitive cells regardless of gefitinib treatment, whereas it was suppressed by gefitinib in gefitinib sensitive cells.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Our data indicate , in goat cumulus cells , that activation of EGF-R by EGF triggers signaling through the MAP kinase pathway during in vitro maturation .	Our data indicate, in goat cumulus cells, that activation of EGF-R by EGF triggers signaling through the MAP kinase pathway during in vitro maturation.	10	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	14	15	12	13
Moreover , EGF can activate EGFR to stimulate cell proliferation , differentiation , invasion and metastasis via stimulation of downstream JAK , Src , Ras and MAPKs and PI3K and Akt signaling [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Moreover, EGF can activate EGFR to stimulate cell proliferation, differentiation, invasion and metastasis via stimulation of downstream JAK, Src, Ras and MAPKs and PI3K and Akt signaling [XREF_BIBR, XREF_BIBR - XREF_BIBR].	2	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	5	6
Since EGF can activate the EGFR and HER2 , the lack of tyrosine phosphorylated proteins indicates that neither EGFR nor HER2 interact with MTK1 , while HRG selectively activates HER3 to interact with MTK1 ( lane b ) .	Since EGF can activate the EGFR and HER2, the lack of tyrosine phosphorylated proteins indicates that neither EGFR nor HER2 interact with MTK1, while HRG selectively activates HER3 to interact with MTK1 (lane b).	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	5	6
Ligand dependent turnover of the EGFR can be assessed by initially maintaining U251 GBM cells in serum-free medium without EGF , which attenuates receptor internalization and allows EGFR to accumulate on the cell surface .	Ligand dependent turnover of the EGFR can be assessed by initially maintaining U251 GBM cells in serum-free medium without EGF, which attenuates receptor internalization and allows EGFR to accumulate on the cell surface.	11	29	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	27	28
Activation of EGFR signaling by EGF results in secretion of proangiogenic growth factors such as vascular endothelial growth factor ( VEGF ) ; blockade of EGFR inhibits the secretion of VEGF .	Activation of EGFR signaling by EGF results in secretion of proangiogenic growth factors such as vascular endothelial growth factor (VEGF); blockade of EGFR inhibits the secretion of VEGF.	2	6	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	2	3
While all EGFR ligands effectively activated EGFR ( XREF_SUPPLEMENTARY ) , HB-EGF robustly induced the specific interaction between EGFR and GPNMB ( XREF_FIG ) , indicating that EGF ligands could differentially trigger the formation of the EGFR homodimer or the heterodimer between EGFR and other receptors 45 .	While all EGFR ligands effectively activated EGFR (XREF_SUPPLEMENTARY), HB-EGF robustly induced the specific interaction between EGFR and GPNMB (XREF_FIG), indicating that EGF ligands could differentially trigger the formation of the EGFR homodimer or the heterodimer between EGFR and other receptors 45.	27	37	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	36	37
Eps15 ubiquitination but not tyrosine phosphorylation was inhibited under conditions that blocked EGF induced internalization of the EGF receptor .	Eps15 ubiquitination but not tyrosine phosphorylation was inhibited under conditions that blocked EGF induced internalization of the EGF receptor.	12	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	12	13	17	19
In both control and heat inactivated AnxA2 antibody pretreated cells , EGF was internalised and showed a similar intracellular distribution , as evidenced by the colocalisation ( yellow dots ) of EGF with EEA1 , while cells pretreated with AnxA2 ( D1/274.5 ) antibody showed significantly less fluorescent EGF and colocalisation with EEA1 in both cell types , suggesting that AnxA2 antibody pretreatment inhibits the EGF induced EGFR internalisation in MDA-MB-231 ( XREF_FIG ) and JIMT-1 ( XREF_FIG ) cells .	In both control and heat inactivated AnxA2 antibody pretreated cells, EGF was internalised and showed a similar intracellular distribution, as evidenced by the colocalisation (yellow dots) of EGF with EEA1, while cells pretreated with AnxA2 (D1/274.5) antibody showed significantly less fluorescent EGF and colocalisation with EEA1 in both cell types, suggesting that AnxA2 antibody pretreatment inhibits the EGF induced EGFR internalisation in MDA-MB-231 (XREF_FIG) and JIMT-1 (XREF_FIG) cells.	64	68	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	65	66	67	68
These results suggest that EGF triggers a transient Grb2 and Shc mediated association of EGFR with Tyr phosphorylated Tom1L1 to engage the endocytic machinery for endocytosis of the ligand and receptor complex .	These results suggest that EGF triggers a transient Grb2 and Shc mediated association of EGFR with Tyr phosphorylated Tom1L1 to engage the endocytic machinery for endocytosis of the ligand and receptor complex.	4	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	14	15
Both T669A mutation and pharmacologic ERK inhibition substantially enhanced EGF induced EGFR downregulation in this system ; the ERK inhibitor effect is consistent with our observations ( mentioned above ) in T47D cells [ XREF_BIBR ] and the T669A mutation result furthers the argument that it is the EGF induced ERK dependent phosphorylation at 669 T that tends to negatively regulate the receptor ' s own downregulation .	Both T669A mutation and pharmacologic ERK inhibition substantially enhanced EGF induced EGFR downregulation in this system; the ERK inhibitor effect is consistent with our observations (mentioned above) in T47D cells [XREF_BIBR] and the T669A mutation result furthers the argument that it is the EGF induced ERK dependent phosphorylation at 669 T that tends to negatively regulate the receptor 's own downregulation.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
Functionally , EGFR activation by EGF stimulation mitigates hypoxia induced PC12 cells apoptosis in both dose- and time dependent manner .	Functionally, EGFR activation by EGF stimulation mitigates hypoxia induced PC12 cells apoptosis in both dose- and time dependent manner.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	2	3
It is possible that retrograde motion of vaccinia virus involves a signaling receptor , since many poxviruses express EGF like growth factors that target ErbB-1 , and infection of animals can be blocked with ErbB-1 inhibitors XREF_BIBR .	It is possible that retrograde motion of vaccinia virus involves a signaling receptor, since many poxviruses express EGF like growth factors that target ErbB-1, and infection of animals can be blocked with ErbB-1 inhibitors XREF_BIBR.	17	25	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	18	19	24	25
These findings suggest that addition of exogenous GD1a may help maintain EGF induced activation of EGFR signaling .	These findings suggest that addition of exogenous GD1a may help maintain EGF induced activation of EGFR signaling.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	15	16
Continuous EGF stimulation increased EGFP-EGFR transport efficiency with a maximum of 3.7-fold at 18 h , whereas pulse stimulation reached a maximum of 2.2-fold at 12 h.	Continuous EGF stimulation increased EGFP-EGFR transport efficiency with a maximum of 3.7-fold at 18 h, whereas pulse stimulation reached a maximum of 2.2-fold at 12 h.	1	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFP-EGFR	EGFP-EGFR	EGFP-EGFR	1	2	4	5
EGFR activation by EGF increased the production of H 2 O 2 in MCF7 cells ( XREF_SUPPLEMENTARY B and S4C ) .	EGFR activation by EGF increased the production of H 2 O 2 in MCF7 cells (XREF_SUPPLEMENTARY B and S4C).	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	0	1
EGFR ubiquitination can be detected in cells treated with EGF at 4 degreesC .	EGFR ubiquitination can be detected in cells treated with EGF at 4 degreesC.	0	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	0	1
To further investigate the role of SNX1 in EGF stimulated pEGFR endocytosis , followed by downstream signaling leading to the activation of phosphatidylinositol 3-kinase ( PI3K ) -- the serine/threonine kinase AKT pathway , we examined the effect of depletion of SNX1 knock-down expression by siRNA and an inhibition of targeting membrane recycling using monensin .	To further investigate the role of SNX1 in EGF stimulated pEGFR endocytosis, followed by downstream signaling leading to the activation of phosphatidylinositol 3-kinase (PI3K) -- the serine/threonine kinase AKT pathway, we examined the effect of depletion of SNX1 knock-down expression by siRNA and an inhibition of targeting membrane recycling using monensin.	6	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	8	9	10	11
It was found that PD-L1 expression was induced significantly in an EGFR dependent manner when EGFR signaling pathways were activated by EGF in ESCC cells .	It was found that PD-L1 expression was induced significantly in an EGFR dependent manner when EGFR signaling pathways were activated by EGF in ESCC cells.	15	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	15	16
As shown in XREF_FIG , 100ng/mL EGF maximally activated the EGFR and RSK2 in these cells .	As shown in XREF_FIG, 100ng/mL EGF maximally activated the EGFR and RSK2 in these cells.	5	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	10	11
We further found that EGF increased EGFR homodimerization in association with induction of EGFR autophosphorylation in NSCLC cells WT for EGFR .	We further found that EGF increased EGFR homodimerization in association with induction of EGFR autophosphorylation in NSCLC cells WT for EGFR.	4	7	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
However , they also found that overexpression of Neu1 using recombinant adenovirus ( Ad ) encoding FLAG tagged human NEU1 ( Ad-NEU1 ) diminished EGF stimulated EGFR Tyr 1068 autophosphorylation by up to 44 % but instead , enhanced MUC1 dependent Pseudomonas aeruginosa adhesion by about 2-fold and flagellin stimulated ERK1/2 activation by nearly 2-fold .	However, they also found that overexpression of Neu1 using recombinant adenovirus (Ad) encoding FLAG tagged human NEU1 (Ad-NEU1) diminished EGF stimulated EGFR Tyr 1068 autophosphorylation by up to 44% but instead, enhanced MUC1 dependent Pseudomonas aeruginosa adhesion by about 2-fold and flagellin stimulated ERK1/2 activation by nearly 2-fold.	23	27	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
Mig6 segment 1 thus physically obstructs asymmetric dimer formation , thereby inhibiting EGF mediated EGFR activation .	Mig6 segment 1 thus physically obstructs asymmetric dimer formation, thereby inhibiting EGF mediated EGFR activation.	11	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
To rule out the possibility that EGF stimulation induces EGFR synthesis in the ER and post-translational modification at the Golgi , we used cycloheximide ( CHX ) to inhibit protein synthesis and found that EGF still can enhance colocalization of EGFR and GalNac T2 ( XREF_SUPPLEMENTARY ; the colocalization of EGFR with the Golgi was quantitated by counting the number of yellow spots representing merged green ( EGFR ) and red ( GalNac T2 ) channels in about 30 cells ) , suggesting that EGF induced EGFR on the Golgi is not from protein synthesis .	To rule out the possibility that EGF stimulation induces EGFR synthesis in the ER and post-translational modification at the Golgi, we used cycloheximide (CHX) to inhibit protein synthesis and found that EGF still can enhance colocalization of EGFR and GalNac T2 (XREF_SUPPLEMENTARY; the colocalization of EGFR with the Golgi was quantitated by counting the number of yellow spots representing merged green (EGFR) and red (GalNac T2) channels in about 30 cells), suggesting that EGF induced EGFR on the Golgi is not from protein synthesis.	6	10	induces	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	9	10
We next compared the specific tyrosine phosphorylation status of LZ-EGFR-GFP and EGF activated EGFR-GFP .	We next compared the specific tyrosine phosphorylation status of LZ-EGFR-GFP and EGF activated EGFR-GFP.	7	14	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR-GFP	EGFR-GFP	EGFR-GFP	11	12	13	14
A 45-minute incubation of cells with phorbol 12-myristate 13-acetate caused a concentration dependent decrease in EGF binding that was prevented by a 40-hour , 2 mumol/L pre-exposure to phorbol 12-myristate 13-acetate ; 10 (-8) mol/L EGF also caused a downregulation of the EGF receptor that was not prevented by phorbol 12-myristate 13-acetate or retinoic acid .	A 45-minute incubation of cells with phorbol 12-myristate 13-acetate caused a concentration dependent decrease in EGF binding that was prevented by a 40-hour, 2 mumol/L pre-exposure to phorbol 12-myristate 13-acetate; 10 (-8) mol/L EGF also caused a downregulation of the EGF receptor that was not prevented by phorbol 12-myristate 13-acetate or retinoic acid.	32	44	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	35	36	42	44
The non specific ADAM inhibitors TAPI-0 and TAPI-1 also reduced EGFR activation in response to CTF but did not interrupt EGF activation of EGFR [ XREF_FIG ] .	The non specific ADAM inhibitors TAPI-0 and TAPI-1 also reduced EGFR activation in response to CTF but did not interrupt EGF activation of EGFR [XREF_FIG].	20	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	23	24
An alternate conjugate of EGF targeting the EGF receptor ( EGFR ) that is also overexpressed on A764 cells bound and displaced with a comparable affinity ( data not shown ) .	An alternate conjugate of EGF targeting the EGF receptor (EGFR) that is also overexpressed on A764 cells bound and displaced with a comparable affinity (data not shown).	2	16	targeting	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	EGF	EGF	egf	EGF receptor	EGF receptor (EGFR) that is also overexpressed	egf receptor	4	5	7	9
We show SphK1 overexpression increased EGF induced EGFR and ERK and AKT activity , increased matrix metalloproteinase ( MMP )-2/9 mRNA and reduced E-cadherin .	We show SphK1 overexpression increased EGF induced EGFR and ERK and AKT activity, increased matrix metalloproteinase (MMP)-2/9 mRNA and reduced E-cadherin.	4	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
In keratinocytes , ErbB1 activation by EGF requires the presence of urokinase receptor and leads to an increase in cell proliferation , migration , and laminin ( gamma2 chain ) deposition via activation of MAPK/ERK1/2 pathway .	In keratinocytes, ErbB1 activation by EGF requires the presence of urokinase receptor and leads to an increase in cell proliferation, migration, and laminin (gamma2 chain) deposition via activation of MAPK/ERK1/2 pathway.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	6	7	3	4
We showed that constitutively activated LZ-EGFR , and EGF activated EGFR , phosphorylated PLC-gamma1 , ERK , and Akt ( XREF_FIG A , B ) .	We showed that constitutively activated LZ-EGFR, and EGF activated EGFR, phosphorylated PLC-gamma1, ERK, and Akt (XREF_FIG A, B).	8	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
Earlier studies demonstrated that EGF activated EGFR , Ras , and MAP kinases to increase TBP expression , resulting in RNA Pol I and III transcription .	Earlier studies demonstrated that EGF activated EGFR, Ras, and MAP kinases to increase TBP expression, resulting in RNA Pol I and III transcription.	4	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
At least seven distinct epidermal growth factor ( EGF ) ligands bind to and activate the EGF receptor ( EGFR ) .	At least seven distinct epidermal growth factor (EGF) ligands bind to and activate the EGF receptor (EGFR).	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	8	9	16	18
To determine if the EGFR signaling cascade was altered in EGFR-inhibitor resistant lines , we investigated the active EGFR , AKT , MAPK & STAT3 , Using immunoblotting analysis , we found that treatment with EGFR inhibitors efficiently blocked EGF stimulated activation of EGFR , AKT , MAPK & STAT3 in a dose dependent manner in parental cells but not in Cet-R , Gef-R and Erl-R cells ( XREF_FIG ) .	To determine if the EGFR signaling cascade was altered in EGFR-inhibitor resistant lines, we investigated the active EGFR, AKT, MAPK & STAT3, Using immunoblotting analysis, we found that treatment with EGFR inhibitors efficiently blocked EGF stimulated activation of EGFR, AKT, MAPK & STAT3 in a dose dependent manner in parental cells but not in Cet-R, Gef-R and Erl-R cells (XREF_FIG).	39	54	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	39	40	43	44
The EGFR protein remained on the plasma membrane when the cells were treated with the GNP conjugated EGF at low temperature .	The EGFR protein remained on the plasma membrane when the cells were treated with the GNP conjugated EGF at low temperature.	1	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	1	2
Fourthly , co-immunoprecipitation experiments using cell lysates from 3T3-hEGFR cells demonstrated that MMP9 forms a complex with naive and EGF stimulated EGFRs , and western blot analyses clearly showed that MMP9i inhibited EGF induced pEGFR in these cell lysates .	Fourthly, co-immunoprecipitation experiments using cell lysates from 3T3-hEGFR cells demonstrated that MMP9 forms a complex with naive and EGF stimulated EGFRs, and western blot analyses clearly showed that MMP9i inhibited EGF induced pEGFR in these cell lysates.	32	35	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	32	33	34	35
Intracranial infusion of EGF into the striatum of adult male rats activated ErbB1 and induced neurobehavioral impairments observed in several schizophrenia models .	Intracranial infusion of EGF into the striatum of adult male rats activated ErbB1 and induced neurobehavioral impairments observed in several schizophrenia models.	1	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	3	4	12	13
These results indicated that vesicular trafficking mediated by ARF1 activation plays a critical role in the EGF induced EGFR transport to the ER .	These results indicated that vesicular trafficking mediated by ARF1 activation plays a critical role in the EGF induced EGFR transport to the ER.	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
Our data suggests that , at least in Capan-1 cells , this autocrine mechanism may need to be refined so that cell-cell interactions between membrane expressed but non secreted EGF stimulates EGF-R on adjacent cells .	Our data suggests that, at least in Capan-1 cells, this autocrine mechanism may need to be refined so that cell-cell interactions between membrane expressed but non secreted EGF stimulates EGF-R on adjacent cells.	28	34	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	29	30	31	32
This study provides evidence of interaction between GM3 and N-glycans inhibits EGF induced EGFR activity .	This study provides evidence of interaction between GM3 and N-glycans inhibits EGF induced EGFR activity.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
In agreement with previous findings , besides decreased EGFR protein levels , EGF induced EGFR activation was abrogated by nimotuzumab treatment in ACC-M and ACC-2 cell lines , resulting in pERK down-regulation [ XREF_BIBR ] .	In agreement with previous findings, besides decreased EGFR protein levels, EGF induced EGFR activation was abrogated by nimotuzumab treatment in ACC-M and ACC-2 cell lines, resulting in pERK down-regulation [XREF_BIBR].	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Because Ras activation by EGF involves EGF stimulated association of EGF-R with Grb2 , the EGF-R was immunoprecipitated and a Western blot was probed for Grb2 .	Because Ras activation by EGF involves EGF stimulated association of EGF-R with Grb2, the EGF-R was immunoprecipitated and a Western blot was probed for Grb2.	5	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	6	7	10	11
We have shown previously that NS5A impaired epidermal growth factor ( EGF ) receptor ( EGFR ) endocytosis , thereby inhibiting EGF stimulated EGFR degradation by a mechanism that remained unclear .	We have shown previously that NS5A impaired epidermal growth factor (EGF) receptor (EGFR) endocytosis, thereby inhibiting EGF stimulated EGFR degradation by a mechanism that remained unclear.	20	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	23	24
EGF induced EGFR activation was enhanced in OE cells , but diminished in KD cells .	EGF induced EGFR activation was enhanced in OE cells, but diminished in KD cells.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
At each step of EGF induced EGFR endocytosis and downregulation , multiply monoubiquitinated EGFR associates with ubiquitin interacting motif containing proteins [ XREF_BIBR ] .	At each step of EGF induced EGFR endocytosis and downregulation, multiply monoubiquitinated EGFR associates with ubiquitin interacting motif containing proteins [XREF_BIBR].	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
Activation of EGFR by EGF was blocked by the addition of gefitinib .	Activation of EGFR by EGF was blocked by the addition of gefitinib.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	2	3
The selectivity of Disruptin toward EGFR driven cancer cells is due to the high level of EGF stimulation of EGFR in EGFR dependent tumor cells relative to normal cells .	The selectivity of Disruptin toward EGFR driven cancer cells is due to the high level of EGF stimulation of EGFR in EGFR dependent tumor cells relative to normal cells.	16	25	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	19	20
Interestingly , recent studies have identified that EGF induced activation of the EGFR can promote adipogenesis cells when administered in low concentrations ( < 1 nM ; 38 ) ; however , at higher doses EGF inhibits this differentiation .	Interestingly, recent studies have identified that EGF induced activation of the EGFR can promote adipogenesis cells when administered in low concentrations (< 1 nM; 38); however, at higher doses EGF inhibits this differentiation.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	12	13
In parallel experiments to assay for EGF induced EGFR uptake , trafficking and degradation , it was found that overexpression of MGRN1 could not rescue blocked clearance of vesicular cargo after TSG101 depletion ( XREF_FIG ) .	In parallel experiments to assay for EGF induced EGFR uptake, trafficking and degradation, it was found that overexpression of MGRN1 could not rescue blocked clearance of vesicular cargo after TSG101 depletion (XREF_FIG).	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
To determine that CFF-1-induced inhibition of PI3K and AKT and Raf/MEK/Erk signal pathways was via CFF-1 inhibiting EGFR auto-phosphorylation and inactivating EGF and EGFR signal pathway , LNCaP and PC3 cells were cultured and treated with different concentrations of EGF and/or CFF-1 ( 5mg/mL ) or different concentrations of CFF-1 and/or EGF ( 30ng/mL ) as indicated in Figure XREF_FIG .	To determine that CFF-1-induced inhibition of PI3K and AKT and Raf/MEK/Erk signal pathways was via CFF-1 inhibiting EGFR auto-phosphorylation and inactivating EGF and EGFR signal pathway, LNCaP and PC3 cells were cultured and treated with different concentrations of EGF and/or CFF-1 (5mg/mL) or different concentrations of CFF-1 and/or EGF (30ng/mL) as indicated in Figure XREF_FIG.	21	40	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	39	40	23	24
However , our data could not exclude the possibility that EGFR inhibitors may also impair the parasite ' s EGFR activation mediated by its own EGF molecules .	However, our data could not exclude the possibility that EGFR inhibitors may also impair the parasite 's EGFR activation mediated by its own EGF molecules.	19	26	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	19	20
No EGF receptor could be detected by immunoprecipitation after fibroblasts were treated with EGF or conditioned medium from the melanoma cells which secrete EGF like TGF ( alpha TGF ) .	No EGF receptor could be detected by immunoprecipitation after fibroblasts were treated with EGF or conditioned medium from the melanoma cells which secrete EGF like TGF (alpha TGF).	1	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	13	14	1	3
Both EGF treatment and 50-Hz MF exposure could induce EGFR clustering .	Both EGF treatment and 50-Hz MF exposure could induce EGFR clustering.	1	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	9	10
Binding of EGF to its receptor , EGFR , activates the intrinsic protein tyrosine kinase of EGFR , which regulates downstream cascades , including MAPKs [ XREF_BIBR ] .	Binding of EGF to its receptor, EGFR, activates the intrinsic protein tyrosine kinase of EGFR, which regulates downstream cascades, including MAPKs [XREF_BIBR].	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	16	17
Since receptor dimers have been implicated in the EGF induced activation of EGF receptor , hyperosmotic shock may activate EGF receptor by a different mechanism .	Since receptor dimers have been implicated in the EGF induced activation of EGF receptor, hyperosmotic shock may activate EGF receptor by a different mechanism.	8	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	8	9	12	14
Our results showing c-Cbl-CTEN interaction suggest that the effect of CTEN on EGF induced EGFR down-regulation may depend on CTEN SH2 domain binding to phosphorylated Y774 on c-Cbl .	Our results showing c-Cbl-CTEN interaction suggest that the effect of CTEN on EGF induced EGFR down-regulation may depend on CTEN SH2 domain binding to phosphorylated Y774 on c-Cbl.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
The EGFR can be activated by EGF to generate an intracellular signaling pathway leading to the phosphorylation of several downstream effector proteins such as Erk1/2 .	The EGFR can be activated by EGF to generate an intracellular signaling pathway leading to the phosphorylation of several downstream effector proteins such as Erk1/2.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	1	2
ST-2 cells expressed relatively high levels of EGF-R protein ( XREF_FIG ) when treated with EGF for 4 or 24h .	ST-2 cells expressed relatively high levels of EGF-R protein (XREF_FIG) when treated with EGF for 4 or 24h.	7	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R protein	EGF-R protein	EGF-R protein	15	16	7	9
EGF increased the activation of EGFR in rat conjunctival goblet cells .	EGF increased the activation of EGFR in rat conjunctival goblet cells.	0	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
It was found that , as expected , treatment of the cells with EGF induced EGFR dimerization in the MUC1 positive HCT116 MUC1Full ( XREF_FIG ) and HCA1.7+ ( XREF_FIG ) cells .	It was found that, as expected, treatment of the cells with EGF induced EGFR dimerization in the MUC1 positive HCT116 MUC1Full (XREF_FIG) and HCA1.7+ (XREF_FIG) cells.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
This fits with the EGFR endocytosis process during which EGF exposure is causing a gradual EGFR re-distribution from the plasma-membrane into vesicles .	This fits with the EGFR endocytosis process during which EGF exposure is causing a gradual EGFR re-distribution from the plasma-membrane into vesicles.	9	16	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	15	16
As expected , following plasma membrane retention of the EGFR upon Dynasore treatment , EGF stimulated cells exhibited both sustained EGFR phosphorylation and reduced EGFR degradation .	As expected, following plasma membrane retention of the EGFR upon Dynasore treatment, EGF stimulated cells exhibited both sustained EGFR phosphorylation and reduced EGFR degradation.	14	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	24	25
Our observation that EGF stimulation induces new synthesis of EGFR in a concentration dependent manner is in agreement with earlier work .	Our observation that EGF stimulation induces new synthesis of EGFR in a concentration dependent manner is in agreement with earlier work.	3	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	9	10
As P-s207 LysRS has been shown to translocate to the nucleus [ XREF_BIBR ] , a nuclear and cytoplasmic fractionation assay was carried out following EGF activation of EGFR .	As P-s207 LysRS has been shown to translocate to the nucleus [XREF_BIBR], a nuclear and cytoplasmic fractionation assay was carried out following EGF activation of EGFR.	25	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	28	29
We showed by both methods that SD activation of EGFR by EGF in CHO-EGFR cells result in stronger cell proliferation than PM activation of EGFR by EGF in CHO-LL/AA cells and the differences are statistically significant ( XREF_FIG ) .	We showed by both methods that SD activation of EGFR by EGF in CHO-EGFR cells result in stronger cell proliferation than PM activation of EGFR by EGF in CHO-LL/AA cells and the differences are statistically significant (XREF_FIG).	15	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	24	25
XREF_BIBR Farhan et al have shown that anti-Lewis Y antibody inhibited the EGF stimulated EGFR signaling in A431 cells and prevented cell peoliferation .	XREF_BIBR Farhan et al have shown that anti-Lewis Y antibody inhibited the EGF stimulated EGFR signaling in A431 cells and prevented cell peoliferation.	11	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
To compare the temporal relationship between EGF , cetuximab and radiation induced nuclear translocation of the EGFR , cells were treated with EGF , cetuximab or radiation for the indicated times ( XREF_FIG ) .	To compare the temporal relationship between EGF, cetuximab and radiation induced nuclear translocation of the EGFR, cells were treated with EGF, cetuximab or radiation for the indicated times (XREF_FIG).	13	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	16	17
In these cells , constitutive PTP101-reactive phosphorylation of EGFR was detected and EGF induced EGFR downregulation was modest , but was substantially enhanced by pretreatment with MEK1 and ERK inhibitor .	In these cells, constitutive PTP101-reactive phosphorylation of EGFR was detected and EGF induced EGFR downregulation was modest, but was substantially enhanced by pretreatment with MEK1 and ERK inhibitor.	12	22	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Third , 2-5 muM sphingosine , an amphipathic , membrane-permeable weak base , activates ErbB1 in WI-38 fibroblasts , provided the receptor is in an intact membrane ; in contrast , EGF can activate ErbB1 both in membranes and in solubilized form .	Third, 2-5 muM sphingosine, an amphipathic, membrane-permeable weak base, activates ErbB1 in WI-38 fibroblasts, provided the receptor is in an intact membrane; in contrast, EGF can activate ErbB1 both in membranes and in solubilized form.	31	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	31	32	34	35
The result demonstrated both A2780 and SKOV3 expressed EGFR ( Additional file 1 : Figure S1 ) , andEGF treatment ( 100ng/mL , 5min ) led to an increase of Tyr1068 and Tyr1173 phosphorylation of EGFR , and pre-treatment with CHAG ( 500 and 1000mug/mL ) efficiently inhibited the EGF induced phosphorylation of EGFR , indicating that CHAG inhibited EGF induced activation of EGFR .	The result demonstrated both A2780 and SKOV3 expressed EGFR (Additional file 1 : Figure S1), andEGF treatment (100ng/mL, 5min) led to an increase of Tyr1068 and Tyr1173 phosphorylation of EGFR, and pre-treatment with CHAG (500 and 1000mug/mL) efficiently inhibited the EGF induced phosphorylation of EGFR, indicating that CHAG inhibited EGF induced activation of EGFR.	59	64	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	59	60	63	64
EGF stimulates the interaction of EGFR with RHA in the nucleus of cancer cells .	EGF stimulates the interaction of EGFR with RHA in the nucleus of cancer cells.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
EGFR-NLS clones maintained the EGF induced EGFR canonical signaling , such as receptor phosphorylation on Tyr 1068 and AKT activation , as did the EGFR WT clones .	EGFR-NLS clones maintained the EGF induced EGFR canonical signaling, such as receptor phosphorylation on Tyr 1068 and AKT activation, as did the EGFR WT clones.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
3Y1 rat fibroblasts overexpressing the epidermal growth factor ( EGF ) receptor ( EGFR cells ) become transformed when treated with EGF .	3Y1 rat fibroblasts overexpressing the epidermal growth factor (EGF) receptor (EGFR cells) become transformed when treated with EGF.	13	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	13	14
All together these data suggest that EGF delivery via infiltration stimulates the EGFR in a manner that meets the classic academic paradigms , prerequisites for cell proliferation .	All together these data suggest that EGF delivery via infiltration stimulates the EGFR in a manner that meets the classic academic paradigms, prerequisites for cell proliferation.	6	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	12	13
Sensitivity to gefitinib correlated with overexpression and constitutive phosphorylation of HER2 and HER3 , but not EGFR , altered HER ligand expression , and enhanced activation of EGF triggered EGFR pathway .	Sensitivity to gefitinib correlated with overexpression and constitutive phosphorylation of HER2 and HER3, but not EGFR, altered HER ligand expression, and enhanced activation of EGF triggered EGFR pathway.	25	30	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	29	30
These results allow us to propose a working model for Tom1L1 to act as a regulated adaptor in mediating EGF stimulated endocytosis of EGFR ( XREF_FIG ) .	These results allow us to propose a working model for Tom1L1 to act as a regulated adaptor in mediating EGF stimulated endocytosis of EGFR (XREF_FIG).	16	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	23	24
When cholesterol was depleted in plasma membranes using MbetaCD , both basal and EGF stimulated EGFR site specific phosphorylation were enhanced .	When cholesterol was depleted in plasma membranes using MbetaCD, both basal and EGF stimulated EGFR site specific phosphorylation were enhanced.	11	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Furthermore , VDR deficiency led to the activation of the epidermal growth factor receptor ( EGFR ) pathway , while EGFR activation by EGF induced both calpain 1 activation and E-cadherin cleavage in these cells .	Furthermore, VDR deficiency led to the activation of the epidermal growth factor receptor (EGFR) pathway, while EGFR activation by EGF induced both calpain 1 activation and E-cadherin cleavage in these cells.	20	24	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	20	21
It is probable that these EGF like domains might direct heterodimerization with ErbB receptors and mediate EGFR signaling .	It is probable that these EGF like domains might direct heterodimerization with ErbB receptors and mediate EGFR signaling.	4	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	16	17
However , this spatial change of EGFR induced by EGF stimulation was suppressed after gefitinib treatment in gefitinib sensitive H358 cells but not in gefitinib-insensitive H1703 cells .	However, this spatial change of EGFR induced by EGF stimulation was suppressed after gefitinib treatment in gefitinib sensitive H358 cells but not in gefitinib-insensitive H1703 cells.	4	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	6	7
EGF induced EGF receptor ( EGFR ) tyrosine phosphorylation and extracellular signal regulated kinase phosphorylation were enhanced by miR-10b , and these effects were mimicked by TIP30 silencing .	EGF induced EGF receptor (EGFR) tyrosine phosphorylation and extracellular signal regulated kinase phosphorylation were enhanced by miR-10b, and these effects were mimicked by TIP30 silencing.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	2	4
Notably , knockdown of TRAF6 impairs the interaction between CD147 and EGFR and attenuates EGF induced EGFR activation , in agreement with previous results .	Notably, knockdown of TRAF6 impairs the interaction between CD147 and EGFR and attenuates EGF induced EGFR activation, in agreement with previous results.	13	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
To further examine whether AnxA2 antibody treatment also regulates the internalisation of the EGFR and ligand complex , we analysed EGF induced EGFR internalisation using immunofluorescence microscopy .	To further examine whether AnxA2 antibody treatment also regulates the internalisation of the EGFR and ligand complex, we analysed EGF induced EGFR internalisation using immunofluorescence microscopy.	19	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
The protocols in this unit describe methodologies to measure the rates of EGFR synthesis and degradation , to monitor EGF induced down-regulation of surface EGFR , to measure the kinetic rate parameters of internalization , recycling , and degradation of radiolabeled EGF , and to perform radioiodination of EGF by the chloramine T method .	The protocols in this unit describe methodologies to measure the rates of EGFR synthesis and degradation, to monitor EGF induced down-regulation of surface EGFR, to measure the kinetic rate parameters of internalization, recycling, and degradation of radiolabeled EGF, and to perform radioiodination of EGF by the chloramine T method.	18	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	24	25
The EGFR ( Epidermal Growth Factor Receptor ) signalling pathway mediated by EGF ligands is associated with cell proliferation , apoptosis , angiogenesis and metastasis occurrence .	The EGFR (Epidermal Growth Factor Receptor) signalling pathway mediated by EGF ligands is associated with cell proliferation, apoptosis, angiogenesis and metastasis occurrence.	3	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	Epidermal Growth Factor Receptor	Epidermal Growth Factor Receptor	Epidermal Growth Factor Receptor	12	13	3	7
Besides the endosome and lysosome system , EGF activated EGFR has been detected in the nuclei of several types of cells .	Besides the endosome and lysosome system, EGF activated EGFR has been detected in the nuclei of several types of cells.	7	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Such phosphorylation reduces EGF induced EGFR degradation , thus modulating EGFR trafficking and signaling .	Such phosphorylation reduces EGF induced EGFR degradation, thus modulating EGFR trafficking and signaling.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Activation of G protein coupled receptors increases the activity of metalloproteases that release bound EGF ( HB-EGF ) , which activates the EGF receptor .	Activation of G protein coupled receptors increases the activity of metalloproteases that release bound EGF (HB-EGF), which activates the EGF receptor.	13	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	14	15	22	24
We found that epidermal growth factor ( EGF )-induced activation of epidermal growth factor receptor ( EGFR ) in A-172 cells activated MMP9 , resulting in an increase in cancer invasiveness .	We found that epidermal growth factor (EGF)-induced activation of epidermal growth factor receptor (EGFR) in A-172 cells activated MMP9, resulting in an increase in cancer invasiveness.	7	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	7	8	11	15
Furthermore , the same signalling capacity of the transactivated and EGF activated EGFR [ XREF_BIBR * ] , carbachol induced EGFR dimerization [ XREF_BIBR ] and the critical dependence on the intrinsic tyrosine kinase activity of the EGFR [ XREF_BIBR , XREF_BIBR * , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] points to an analogous mechanism of EGFR activation by G-proteins or exogenous EGF .	Furthermore, the same signalling capacity of the transactivated and EGF activated EGFR [XREF_BIBR *], carbachol induced EGFR dimerization [XREF_BIBR] and the critical dependence on the intrinsic tyrosine kinase activity of the EGFR [XREF_BIBR, XREF_BIBR *, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] points to an analogous mechanism of EGFR activation by G-proteins or exogenous EGF.	5	14	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
On the other hand , EGF increased the Vmax of the EGF receptor for progesterone receptor subunits as substrates .	On the other hand, EGF increased the Vmax of the EGF receptor for progesterone receptor subunits as substrates.	5	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	5	6	11	13
Considering the requirement of EGFR kinase activity for EGF induced EGFR endocytosis XREF_BIBR , XREF_BIBR these results imply that virus attachment should induce EGFR kinase activation .	Considering the requirement of EGFR kinase activity for EGF induced EGFR endocytosis XREF_BIBR, XREF_BIBR these results imply that virus attachment should induce EGFR kinase activation.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
EGF induced EGFR endocytosis is delayed and inhibited for a few minutes and is slower in M phase , especially at metaphase .	EGF induced EGFR endocytosis is delayed and inhibited for a few minutes and is slower in M phase, especially at metaphase.	0	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Treatment of cells with EGF stimulates EGFR , and we observed that treatment of SCC13 cells with EGF enhances cell invasion ability , and that this EGF induced cell invasion was blocked by the treatment of cells with GSPs .	Treatment of cells with EGF stimulates EGFR, and we observed that treatment of SCC13 cells with EGF enhances cell invasion ability, and that this EGF induced cell invasion was blocked by the treatment of cells with GSPs.	2	7	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
In MDA-MB-231 breast cancer cells stably overexpressing H19 , EGF strongly activated EGFR , Akt and Erk compared to parental cells .	In MDA-MB-231 breast cancer cells stably overexpressing H19, EGF strongly activated EGFR, Akt and Erk compared to parental cells.	9	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	12	13
This , together with the discovery that galectin-3 alone did not induce EGFR dimerization , suggests that galectin-3-MUC1 interaction is essential for galectin-3-associated , EGF induced EGFR activation .	This, together with the discovery that galectin-3 alone did not induce EGFR dimerization, suggests that galectin-3-MUC1 interaction is essential for galectin-3-associated, EGF induced EGFR activation.	24	27	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
The mRNA obtained from EGF stimulated NIH-3T3 cells expressing chimaeric EGFR-ErbB3 receptors provided the tester amplicons ( small PCR amplified fragments ) which were subtracted against driver amplicons derived from unstimulated NIH-3T3 cells expressing the EGFR-ErbB3 chimaera or EGF stimulated NIH-3T3 cells overexpressing the EGFR .	The mRNA obtained from EGF stimulated NIH-3T3 cells expressing chimaeric EGFR-ErbB3 receptors provided the tester amplicons (small PCR amplified fragments) which were subtracted against driver amplicons derived from unstimulated NIH-3T3 cells expressing the EGFR-ErbB3 chimaera or EGF stimulated NIH-3T3 cells overexpressing the EGFR.	36	45	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	38	39	44	45
The cross correlation values for EGF stimulated EGFR are , on average , less than expected for a constitutive dimer , based on comparison to Myr-GCN4-ICM .	The cross correlation values for EGF stimulated EGFR are, on average, less than expected for a constitutive dimer, based on comparison to Myr-GCN4-ICM.	3	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
In marked contrast , the association between c-Cbl and EGFR was more stable in cells treated with EGF , persisting without diminishing for 15 min .	In marked contrast, the association between c-Cbl and EGFR was more stable in cells treated with EGF, persisting without diminishing for 15 min.	5	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	9	10
These results suggest that afatinib effectively inhibits EGF induced activation of EGFR and its downstream PI3K/AKT/mTOR signaling pathway in NB cells .	These results suggest that afatinib effectively inhibits EGF induced activation of EGFR and its downstream PI3K/AKT/mTOR signaling pathway in NB cells.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	11	12
Numerous studies have shown that EGF stimulation of EGFR promotes cell invasion and motility in various cancers including glioblastoma , squamous cell carcinoma , bladder , gastric , renal , prostate , and breast cancer .	Numerous studies have shown that EGF stimulation of EGFR promotes cell invasion and motility in various cancers including glioblastoma, squamous cell carcinoma, bladder, gastric, renal, prostate, and breast cancer.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	8	9
Moreover , KIAA1199 , as an EGFR binding protein , promotes EGF mediated EGFR , Src and MEK1 phosphorylations , thus suggesting that KIAA1199 connects EGFR to downstream kinases .	Moreover, KIAA1199, as an EGFR binding protein, promotes EGF mediated EGFR, Src and MEK1 phosphorylations, thus suggesting that KIAA1199 connects EGFR to downstream kinases.	10	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Hence , we sought to compare EGF induced WT EGFR kinase activation with that of EGFR T669A ( XREF_FIG ) .	Hence, we sought to compare EGF induced WT EGFR kinase activation with that of EGFR T669A (XREF_FIG).	5	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	9	10
AnxA2 antibody inhibits the EGF induced EGFR internalisation .	AnxA2 antibody inhibits the EGF induced EGFR internalisation.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
Epidermal growth factor receptor ( EGFR ) can be activated through an autocrine loop by expression of EGFR ligands , EGF , and TGF-alpha ( transforming growth factor alpha ; increased expression linked to aggressive meningioma proliferation ) .	Epidermal growth factor receptor (EGFR) can be activated through an autocrine loop by expression of EGFR ligands, EGF, and TGF-alpha (transforming growth factor alpha; increased expression linked to aggressive meningioma proliferation).	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	expression of EGFR ligands, EGF	egf	Epidermal growth factor receptor	Epidermal growth factor receptor	epidermal growth factor receptor	20	21	0	4
Furthermore , in T47D cells , EGF itself caused EGFR PTP101-reactive phosphorylation and blockade of MEK1 resulted in enhanced EGF induced EGFR downregulation , suggesting that EGF induced ERK mediated threonine phosphorylation may serve as a brake on receptor downregulation [ XREF_BIBR ] .	Furthermore, in T47D cells, EGF itself caused EGFR PTP101-reactive phosphorylation and blockade of MEK1 resulted in enhanced EGF induced EGFR downregulation, suggesting that EGF induced ERK mediated threonine phosphorylation may serve as a brake on receptor downregulation [XREF_BIBR].	16	22	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
EGF activated the epidermal growth factor receptor to the same extent in SPP-1-expressing cells , yet ERK1/2 activation was impaired .	EGF activated the epidermal growth factor receptor to the same extent in SPP-1-expressing cells, yet ERK1/2 activation was impaired.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	3	7
Although CDRs significantly contribute to EGF mediated ERBB1 internalization [ XREF_BIBR ] , here we observed poor ERBB2 internalization upon Tz-treatment as reported by others [ XREF_BIBR ] [ XREF_BIBR ] .	Although CDRs significantly contribute to EGF mediated ERBB1 internalization [XREF_BIBR], here we observed poor ERBB2 internalization upon Tz-treatment as reported by others [XREF_BIBR] [XREF_BIBR].	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	ERBB1	ERBB1	ERBB1	5	6	7	8
We showed in Figures XREF_FIG and XREF_FIG that Y27632 remarkably prolonged the EGF induced activation of EGFR and subsequent signaling via MEK1/2 and Akt .	We showed in Figures XREF_FIG and XREF_FIG that Y27632 remarkably prolonged the EGF induced activation of EGFR and subsequent signaling via MEK1/2 and Akt.	11	17	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	16	17
EGF was chosen to activate EGFR selectively , whereas NRG1 was chosen to activate ebB3/4 selectively .	EGF was chosen to activate EGFR selectively, whereas NRG1 was chosen to activate ebB3/4 selectively.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
To achieve complete EGFR endocytosis and avoid endosome arrest and EGFR recycling via EGFR inhibited autophagy 30 , we stimulated A549 human non small cell lung carcinoma cells with EGF under normal serum conditions , analyzed the canonical EGF induced pathways of active EGFR in whole-cell lysate ( WCL ) , and investigated whether EGF stimulation promoted the interaction between EGFR and sortilin .	To achieve complete EGFR endocytosis and avoid endosome arrest and EGFR recycling via EGFR inhibited autophagy 30, we stimulated A549 human non small cell lung carcinoma cells with EGF under normal serum conditions, analyzed the canonical EGF induced pathways of active EGFR in whole-cell lysate (WCL), and investigated whether EGF stimulation promoted the interaction between EGFR and sortilin.	36	44	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	38	39	43	44
We also observed cognate ligand , EGF mediated complex formation of EGFR and Plexin B1 ( Fig XREF_FIG G ) .	We also observed cognate ligand, EGF mediated complex formation of EGFR and Plexin B1 (Fig XREF_FIG G).	6	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	11	12
However , in contrast to our studies , alpha2-6 sialylation appeared to inhibit EGF induced EGFR tyrosine phosphorylation [ XREF_BIBR ] .	However, in contrast to our studies, alpha2-6 sialylation appeared to inhibit EGF induced EGFR tyrosine phosphorylation [XREF_BIBR].	13	18	induced	Positive_early_regulation	Positive_activation	Positive_regulation	EGF	EGF	egf	EGFR	EGFR tyrosine phosphorylation	egfr	13	14	15	16
Consistent with activation of Cdc42 in fibroblasts in response to EGF 19 , activation of EGFR signaling by EGF in G-CSF-treated mice further increased Cdc42 activity in low-density bone marrow ( LDBM ) cells compared to G-CSF treatment alone ( XREF_FIG ) .	Consistent with activation of Cdc42 in fibroblasts in response to EGF 19, activation of EGFR signaling by EGF in G-CSF-treated mice further increased Cdc42 activity in low-density bone marrow (LDBM) cells compared to G-CSF treatment alone (XREF_FIG).	15	21	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	15	16
Therefore , we sought to investigate EGFR signaling in mock- and ERbeta transfected REN cells treated with EGF .	Therefore, we sought to investigate EGFR signaling in mock- and ERbeta transfected REN cells treated with EGF.	6	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	6	7
Both HCMV and EGF activated the EGF receptor ( EGFR ) , inducing receptor tyrosine phosphorylation at specific residues .	Both HCMV and EGF activated the EGF receptor (EGFR), inducing receptor tyrosine phosphorylation at specific residues.	1	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	3	4	6	8
Pretreatment with LY294002 ( a phosphatidylinositol 3-kinase ( PI3K ) inhibitor ) , EGF ( an EGFR agonist ) and AG1478 ( an EGFR inhibitor ) partially reversed the icariside II induced decrease in cell viability , indicating icariside II effectively inhibited the EGF induced activation of the EGFR pathway [ XREF_BIBR ] .	Pretreatment with LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor), EGF (an EGFR agonist) and AG1478 (an EGFR inhibitor) partially reversed the icariside II induced decrease in cell viability, indicating icariside II effectively inhibited the EGF induced activation of the EGFR pathway [XREF_BIBR].	42	49	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	43	44	48	49
EGCG alters the topology of EGFR TMD and activates the receptor in the absence of EGF , but inhibits EGF induced EGFR activation .	EGCG alters the topology of EGFR TMD and activates the receptor in the absence of EGF, but inhibits EGF induced EGFR activation.	18	22	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
One promising target of interest is the epidermal growth factor receptor ( EGFr ) , which is activated by the ligands EGF and TGF-alpha .	One promising target of interest is the epidermal growth factor receptor (EGFr), which is activated by the ligands EGF and TGF-alpha.	10	23	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFr	EGFr	EGFr	21	22	12	13
Moreover , the model is consistent with observed negative cooperativity in EGF binding to intact EGFR as well as positive linkage between EGF dose and the size of EGF induced EGFR clusters .	Moreover, the model is consistent with observed negative cooperativity in EGF binding to intact EGFR as well as positive linkage between EGF dose and the size of EGF induced EGFR clusters.	26	31	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	28	29	30	31
EGF triggered both Akt and ERK phosphorylation in HCT116 cells and induced ERK activation in SW480 cells ( XREF_FIG ) , indicating that KRAS mutation does not fully take over the ligand mediated ERK activation and also impling the significance of EGFR in KRAS mutant cells .	EGF triggered both Akt and ERK phosphorylation in HCT116 cells and induced ERK activation in SW480 cells (XREF_FIG), indicating that KRAS mutation does n't fully take over the ligand mediated ERK activation and also impling the significance of EGFR in KRAS mutant cells.	0	45	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	41	42
The activation of EGFR by EGF leads to the binding and ubiquitylation of the receptor by c-Cbl , which then recruits CIN85 to EGFR and Cbl complex to initiate the receptor endocytosis [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	The activation of EGFR by EGF leads to the binding and ubiquitylation of the receptor by c-Cbl, which then recruits CIN85 to EGFR and Cbl complex to initiate the receptor endocytosis [XREF_BIBR, XREF_BIBR - XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	3	4
The combination of EGF and PGE 2 prolongs nuclear EGFR transcriptional activity manifested by the upregulation of CCND1 , PTGS2 , MYC and NOS2 mRNA levels and potentiates nuclear EGFR induced NSCLC cell proliferation .	The combination of EGF and PGE 2 prolongs nuclear EGFR transcriptional activity manifested by the upregulation of CCND1, PTGS2, MYC and NOS2 mRNA levels and potentiates nuclear EGFR induced NSCLC cell proliferation.	1	11	prolongs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	9	10
We have previously observed that EGF stimulation of ErbB1 receptors lacking an NLS sequence resulted in receptor dimerization , but not in its consequent phosphorylation [ XREF_BIBR ] ; since ErbB1 and ErbB2 possess highly similar structures [ XREF_BIBR ] , the lack of phosphorylation of the ErbB2 DeltaNLS mutant in the presence of nucleolin could stem from some additional reasons , besides ablation of its nucleolin binding abilities .	We have previously observed that EGF stimulation of ErbB1 receptors lacking an NLS sequence resulted in receptor dimerization, but not in its consequent phosphorylation [XREF_BIBR]; since ErbB1 and ErbB2 possess highly similar structures [XREF_BIBR], the lack of phosphorylation of the ErbB2 DeltaNLS mutant in the presence of nucleolin could stem from some additional reasons, besides ablation of its nucleolin binding abilities.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	5	6	8	9
Active EGFR Mutants and EGF Stimulation of Wild-Type EGFR Alter the Beclin 1 Interactome .	Active EGFR Mutants and EGF Stimulation of Wild-Type EGFR Alter the Beclin 1 Interactome.	4	9	Stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	8	9
Consistent with these observations , endocytosis of EGFR elicited by 100 ng/ml of EGF in A431 was potently suppressed by knockdown of CHC ( XREF_SUPPLEMENTARY ) .	Consistent with these observations, endocytosis of EGFR elicited by 100 ng/ml of EGF in A431 was potently suppressed by knockdown of CHC (XREF_SUPPLEMENTARY).	5	14	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	7	8
Binding of EGF induces a conformational change in the extracellular domain of EGFR that facilitates its dimerization 12 .	Binding of EGF induces a conformational change in the extracellular domain of EGFR that facilitates its dimerization 12.	0	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	12	13
We then examined the effect of transient EFEMP1 overexpression on EGF mediated activation of the EGFR signaling pathway .	We then examined the effect of transient EFEMP1 overexpression on EGF mediated activation of the EGFR signaling pathway.	10	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	15	16
Cross linked products , probably involving EGFR and SHC , were successfully detected when cells were treated with EGF ( XREF_FIG , red arrow and XREF_FIG , blue arrows , respectively ) .	Cross linked products, probably involving EGFR and SHC, were successfully detected when cells were treated with EGF (XREF_FIG, red arrow and XREF_FIG, blue arrows, respectively).	5	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	6	7
In a dose dependent study , the compound inhibited both basal as well as EGF induced activation of EGFR .	In a dose dependent study, the compound inhibited both basal as well as EGF induced activation of EGFR.	10	19	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	18	19
Thus EGFR activation by EGF recapitulates the effect of Dsc2 down-regulation on beta-catenin-dependent transcription and strongly supports a role for EGFR in the activation of Akt and beta-catenin signaling in Dsc2 deficient cells .	Thus EGFR activation by EGF recapitulates the effect of Dsc2 down-regulation on beta-catenin-dependent transcription and strongly supports a role for EGFR in the activation of Akt and beta-catenin signaling in Dsc2 deficient cells.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	1	2
Using pharmacological and RNA interference inhibition of p38 mitogen activated protein kinase , we show that p38 is required for efficient EGF induced EGFR destruction but not internalization .	Using pharmacological and RNA interference inhibition of p38 mitogen activated protein kinase, we show that p38 is required for efficient EGF induced EGFR destruction but not internalization.	20	24	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	23	24
EGFR signaling induced by EGF and TGFalpha is highly important in the regulation of endochondral ossification during the formation of bone .	EGFR signaling induced by EGF and TGFalpha is highly important in the regulation of endochondral ossification during the formation of bone.	0	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	0	1
We found that centrosome clustering is not affected by epidermal growth factor activation of EGFR ( XREF_FIG , left ) , EGFR inhibition by erlotinib ( XREF_FIG , right ) or Jak2 inhibition by ruxolitinib ( XREF_FIG ) , suggesting that Stat3 regulation of centrosome clustering is independent of canonical Stat3 upstream signalling .	We found that centrosome clustering is not affected by epidermal growth factor activation of EGFR (XREF_FIG, left), EGFR inhibition by erlotinib (XREF_FIG, right) or Jak2 inhibition by ruxolitinib (XREF_FIG), suggesting that Stat3 regulation of centrosome clustering is independent of canonical Stat3 upstream signalling.	9	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	9	12	14	15
Whereas Grb2 and Cbl directly and specifically determine the rates of EGFR turnover , internalization and degradation , a number of other proteins have been identified that can have a modulatory effect on the rate of EGF induced EGFR down-regulation .	Whereas Grb2 and Cbl directly and specifically determine the rates of EGFR turnover, internalization and degradation, a number of other proteins have been identified that can have a modulatory effect on the rate of EGF induced EGFR down-regulation.	34	39	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	36	37	38	39
In addition we assessed whether loss of ITSN affects EGF induced EGFR internalization .	In addition we assessed whether loss of ITSN affects EGF induced EGFR internalization.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
The function of Tom1L1 in EGFR endocytosis is specific as knockdown of Tom1 or Tom1L2 did not affect EGF stimulated endocytosis of EGFR ( XREF_FIG ) .	The function of Tom1L1 in EGFR endocytosis is specific as knockdown of Tom1 or Tom1L2 did not affect EGF stimulated endocytosis of EGFR (XREF_FIG).	17	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	22	23
Pretreatment of serum starved cells with GSE resulted in 70 % to almost complete inhibition of EGF induced EGFR activation and 50 % to complete inhibition of Shc activation , which corroborated with a comparable decrease in EGF induced Shc binding to EGFR .	Pretreatment of serum starved cells with GSE resulted in 70% to almost complete inhibition of EGF induced EGFR activation and 50% to complete inhibition of Shc activation, which corroborated with a comparable decrease in EGF induced Shc binding to EGFR.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
First , the extent of EGFR endocytosis correlates well with Tyr phosphorylation of EGFR and Tom1L1 , and interaction of Tom1L1 with EGFR when cells were treated with different concentrations of EGF ( XREF_SUPPLEMENTARY ) .	First, the extent of EGFR endocytosis correlates well with Tyr phosphorylation of EGFR and Tom1L1, and interaction of Tom1L1 with EGFR when cells were treated with different concentrations of EGF (XREF_SUPPLEMENTARY).	7	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	31	32	22	23
However , AnxA2 ( D1/274.5 ) antibody pretreatment hindered the dimerisation of EGFR induced by EGF as compared with EGF alone or EGF with heat inactivated AnxA2 ( D1/274.5 ) antibody pretreatment .	However, AnxA2 (D1/274.5) antibody pretreatment hindered the dimerisation of EGFR induced by EGF as compared with EGF alone or EGF with heat inactivated AnxA2 (D1/274.5) antibody pretreatment.	10	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	12	13
We hypothesized that in GBM cells , EGFR activation by its main ligand EGF may act as a negative regulator of 5-ALA-induced PpIX fluorescence , through induction of the enzyme HO-1 .	We hypothesized that in GBM cells, EGFR activation by its main ligand EGF may act as a negative regulator of 5-ALA-induced PpIX fluorescence, through induction of the enzyme HO-1.	7	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	7	8
But these in vitro experiments did not confirm the importance of EGF system in primary epithelial cells , so we investigated whether EGF or Pseudomonas stimulate the EGF-R activation and mucin secretion by way of MUC5AC gene expression in rat tracheal epithelial cells .	But these in vitro experiments did not confirm the importance of EGF system in primary epithelial cells, so we investigated whether EGF or Pseudomonas stimulate the EGF-R activation and mucin secretion by way of MUC5AC gene expression in rat tracheal epithelial cells.	22	28	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	22	23	27	28
In COS7 cells expressing CIN85 null function mutant ( CIN85-DeltaCC or CIN85-A4m ) , EGF stimulated EGFR degradation was decreased , whereas in cells expressing neutral mutant ( CIN85-B4m ) or wild type CIN85 the ligand stimulated receptor degradation was not affected .	In COS7 cells expressing CIN85 null function mutant (CIN85-DeltaCC or CIN85-A4m), EGF stimulated EGFR degradation was decreased, whereas in cells expressing neutral mutant (CIN85-B4m) or wild type CIN85 the ligand stimulated receptor degradation was not affected.	14	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
The EGFR is activated by TGFalpha , EGF , and other ligands , but no specific ligand for HER2 has yet been identified [ XREF_BIBR ] .	The EGFR is activated by TGFalpha, EGF, and other ligands, but no specific ligand for HER2 has yet been identified [XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	1	2
Thirdly , M. amurensis lectin MAL-2 ( specific for alpha-2 ,3 sialic acid linked to terminal beta-galactose ) significantly blocked EGF induced pEGFR dose-dependently , but had no effect on Neu1 activation .	Thirdly, M. amurensis lectin MAL-2 (specific for alpha-2,3 sialic acid linked to terminal beta-galactose) significantly blocked EGF induced pEGFR dose-dependently, but had no effect on Neu1 activation.	20	26	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	20	21	22	23
To assure that any further work with the inhibitor was not due non specific blockade of EGFR , we examined EGF activation of EGFR in the presence of increasing concentrations of BMS-536924 .	To assure that any further work with the inhibitor was not due non specific blockade of EGFR, we examined EGF activation of EGFR in the presence of increasing concentrations of BMS-536924.	20	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	23	24
At the same time , EGFR activation by EGF was just slightly changed by the addition of the MbetaCD and cholesterol complex ( XREF_FIG ) .	At the same time, EGFR activation by EGF was just slightly changed by the addition of the MbetaCD and cholesterol complex (XREF_FIG).	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	5	6
Next we determined the effect of CTTN on EGF induced EGFR down-regulation in CRC cells .	Next we determined the effect of CTTN on EGF induced EGFR down-regulation in CRC cells.	2	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
In addition , we assessed whether EGF directly activates TRPM7 channels ( independently of the EGFR ) using N1E-115 cells that stably express plasmalemmal TRPM7 channels but do not express the EGFR .	In addition, we assessed whether EGF directly activates TRPM7 channels (independently of the EGFR) using N1E-115 cells that stably express plasmalemmal TRPM7 channels but do not express the EGFR.	6	16	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	15	16
EGFR activation by its ligand EGF leads to signal transduction through three main pathways : Mitogen activated protein ( MAP ) kinase cascade , phosphotidylinositol-3 kinase ( PI3K ) pathway and the signal transducer and activator of transcription ( STAT ) pathway , promoting cell division and survival [ XREF_BIBR ] .	EGFR activation by its ligand EGF leads to signal transduction through three main pathways : Mitogen activated protein (MAP) kinase cascade, phosphotidylinositol-3 kinase (PI3K) pathway and the signal transducer and activator of transcription (STAT) pathway, promoting cell division and survival [XREF_BIBR].	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	0	1
EGF upregulates MMP-9 , MMP-1 , and EGFR .	EGF upregulates MMP-9, MMP-1, and EGFR.	0	8	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	7	8
However , the major histocompatibility complex ( MHC ) peptides did not affect EGF stimulated internalization of EGF receptor , in contrast to their effect on the insulin receptors .	However, the major histocompatibility complex (MHC) peptides did not affect EGF stimulated internalization of EGF receptor, in contrast to their effect on the insulin receptors.	12	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	13	14	17	19
We wondered that whether a higher dosage of EGF could enhance the downregulation of EGFR in HCC827 cells .	We wondered that whether a higher dosage of EGF could enhance the downregulation of EGFR in HCC827 cells.	6	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	14	15
We have investigated whether CIN85 plays a role in EGF induced EGF receptor ( EGFR ) internalization , as previously suggested , or whether CIN85 is rather involved in endosomal sorting of the EGFR .	We have investigated whether CIN85 plays a role in EGF induced EGF receptor (EGFR) internalization, as previously suggested, or whether CIN85 is rather involved in endosomal sorting of the EGFR.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	9	10	11	13
To further prove migration and invasion of EGFR mediated EMT in propolin C suppressed lung cancer cells , EGF induced EGFR wild-type A549 lung cancer cell model was examined .	To further prove migration and invasion of EGFR mediated EMT in propolin C suppressed lung cancer cells, EGF induced EGFR wild-type A549 lung cancer cell model was examined.	18	28	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
EGFR family members can also be activated by other signaling proteins independent of exogenous EGF ligands .	EGFR family members can also be activated by other signaling proteins independent of exogenous EGF ligands.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	0	1
28 The present study shows that MUC1 expression increases EGF induced EGFR activation in human breast and colon cancer cells .	28 The present study shows that MUC1 expression increases EGF induced EGFR activation in human breast and colon cancer cells.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
EGF induced EGFR endocytosis in FaDu cells was proven not to be affected by AvidinOX conjugation ( XREF_SUPPLEMENTARY ) .	EGF induced EGFR endocytosis in FaDu cells was proven not to be affected by AvidinOX conjugation (XREF_SUPPLEMENTARY).	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
These data suggest that EGFR activation by EGF destabilized FKI binding to ROS1 and ALK .	These data suggest that EGFR activation by EGF destabilized FKI binding to ROS1 and ALK.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	4	5
Prior studies using epidermal growth factor ( EGF ) stimulation of an EGFR and Axl chimeric receptor determined that EGF-EGFR and Axl chimera binding activates the PI3 kinase pathway .	Prior studies using epidermal growth factor (EGF) stimulation of an EGFR and Axl chimeric receptor determined that EGF-EGFR and Axl chimera binding activates the PI3 kinase pathway.	7	16	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	12	13
Mimic-miR-214 decreased the expression of Mig-6 and increased the levels of EGF mediated p-EGFR ( Y1173 and Y845 ) and p-Met ( Tyr1234/1235 ) in Huh-7 cells .	Mimic-miR-214 decreased the expression of Mig-6 and increased the levels of EGF mediated p-EGFR (Y1173 and Y845) and p-Met (Tyr1234/1235) in Huh-7 cells.	9	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	p-EGFR	p-EGFR	p-EGFR	11	12	13	14
We recently showed that Fhit protein levels can be regulated by Fhit proteasome degradation mediated by EGF dependent activation of EGFR family members , including HER2 , whose overexpression is linked to poor prognosis in breast cancer .	We recently showed that Fhit protein levels can be regulated by Fhit proteasome degradation mediated by EGF dependent activation of EGFR family members, including HER2, whose overexpression is linked to poor prognosis in breast cancer.	16	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	20	21
To determine if hypoxia resulted in EGF mediated activation of EGFR , we utilized immunoprecipitation with 4G10 ( anti-phosphotyrosine antibody ) and Western blotting with an antibody against phospho-EGFR ( pEGFRTyr845 ) .	To determine if hypoxia resulted in EGF mediated activation of EGFR, we utilized immunoprecipitation with 4G10 (anti-phosphotyrosine antibody) and Western blotting with an antibody against phospho-EGFR (pEGFRTyr845).	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	10	11
EGF and HB-EGF activate EGFR , ERBB4 , AKT and extracellular signal regulated kinase 1/2 in EGFR ( + ) primary trophoblasts ; however , they do not show an effect on HLA-G ( + ) EVTs .	EGF and HB-EGF activate EGFR, ERBB4, AKT and extracellular signal regulated kinase 1/2 in EGFR (+) primary trophoblasts; however, they do not show an effect on HLA-G (+) EVTs.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
Our results suggest that increased HER2 and HER3 expression potentiates ligand induced autocrine and paracrine signaling resulting from EGF activation of HER1 .	Our results suggest that increased HER2 and HER3 expression potentiates ligand induced autocrine and paracrine signaling resulting from EGF activation of HER1.	18	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	HER1	HER1	HER1	18	19	21	22
These findings may well reflect a reduced availability of EGF in these cells , especially as exogenous intake of EGF partially rescues EGFR activation as attested by its phosphorylation status .	These findings may well reflect a reduced availability of EGF in these cells, especially as exogenous intake of EGF partially rescues EGFR activation as attested by its phosphorylation status.	17	23	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	22	23
Both positive and negative effects of EGF mediated EGFR activation on OPG expression have been reported with , EGF stimulating OPG expression in prostate LNCaP cells [ XREF_BIBR ] , but inhibiting OPG expression in oesteoblastic cells [ XREF_BIBR ] .	Both positive and negative effects of EGF mediated EGFR activation on OPG expression have been reported with, EGF stimulating OPG expression in prostate LNCaP cells [XREF_BIBR], but inhibiting OPG expression in oesteoblastic cells [XREF_BIBR].	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Although these findings are seemingly at odds with the preceding studies , one possible explanation is that EGF causes internalization and degradation of the EGF receptor and therefore a decrease in net EGF receptor activity .	Although these findings are seemingly at odds with the preceding studies, one possible explanation is that EGF causes internalization and degradation of the EGF receptor and therefore a decrease in net EGF receptor activity.	17	34	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	17	18	32	34
In these models , EGFR was shown to be a direct substrate for ST6Gal-I-mediated sialylation , and in every case , alpha2-6-sialylation of EGFR increased both the basal and EGF induced activation of EGFR .	In these models, EGFR was shown to be a direct substrate for ST6Gal-I-mediated sialylation, and in every case, alpha2-6-sialylation of EGFR increased both the basal and EGF induced activation of EGFR.	27	34	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	33	34
In normal cells , binding of EGF causes activation of the EGFR , leading to receptor dimerization and autophosphorylation .	In normal cells, binding of EGF causes activation of the EGFR, leading to receptor dimerization and autophosphorylation.	4	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	11	12
In the presence of primaquine ( a receptor recycling inhibitor ) , immuno precipitation for NHS-S-S-biotin-labelled EGFR showed increased levels of intracellular EGFR and HER2 in SPRY2 KD DU145 cells treated with EGF for 15 , 30 and 60 min , an observation not seen for HER3 ( XREF_FIG ) .	In the presence of primaquine (a receptor recycling inhibitor), immuno precipitation for NHS-S-S-biotin-labelled EGFR showed increased levels of intracellular EGFR and HER2 in SPRY2 KD DU145 cells treated with EGF for 15, 30 and 60 min, an observation not seen for HER3 (XREF_FIG).	19	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	32	33	22	23
It has been reported that EGF stimulation can induce the accumulation of EGFR in the nucleus .	It has been reported that EGF stimulation can induce the accumulation of EGFR in the nucleus.	5	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	12	13
Although catecholamine stimulation mediates the retention of beta1AR-EGFR interaction throughout receptor internalization , direct EGF ligand stimulation initiates the internalization of EGFR alone .	Although catecholamine stimulation mediates the retention of beta1AR-EGFR interaction throughout receptor internalization, direct EGF ligand stimulation initiates the internalization of EGFR alone.	14	22	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	21	22
The EGF dependent activation of the EGFR has been reported to be inhibited in an E-cadherin adhesion dependent manner , which inhibits the ligand dependent activation of diverse receptor tyrosine kinases XREF_BIBR .	The EGF dependent activation of the EGFR has been reported to be inhibited in an E-cadherin adhesion dependent manner, which inhibits the ligand dependent activation of diverse receptor tyrosine kinases XREF_BIBR.	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	6	7
Ectopic expression of HIF-1alpha prevented EGF ( 100ngml -1 , 1h ) induced EGFR endocytosis , whereas overexpression of PLD1 promoted EGF induced EGFR endocytosis and recovered endocytosis decelerated by HIF-1alpha ( XREF_FIG ) .	Ectopic expression of HIF-1alpha prevented EGF (100ngml -1, 1h) induced EGFR endocytosis, whereas overexpression of PLD1 promoted EGF induced EGFR endocytosis and recovered endocytosis decelerated by HIF-1alpha (XREF_FIG).	21	24	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	23	24
Given the heterogeneous nature of human tumours and the fact that individual glioblastoma tumours express both amplified EGFR and EGFRvIII and undergo tumour promoting effects from EGFRvIII expressing cells through paracrine mechanisms 24 , EGFRvIII expression in some tumour cells downregulates extracellular MIF , which , in turn , is likely to promote EGF induced WT EGFR activation in the tumour cells expressing WT EGFR .	Given the heterogeneous nature of human tumours and the fact that individual glioblastoma tumours express both amplified EGFR and EGFRvIII and undergo tumour promoting effects from EGFRvIII expressing cells through paracrine mechanisms 24, EGFRvIII expression in some tumour cells downregulates extracellular MIF, which, in turn, is likely to promote EGF induced WT EGFR activation in the tumour cells expressing WT EGFR.	52	57	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	53	54	56	57
PLIMB was used to map the dimerization of EGF induced EGFR dimerization , yielding results consistent with published crystal structures and demonstrating its promising utility for quick mapping of protein protein interactions for applications in the clinical protein therapeutics field , as well as for basic research on the three-dimensional structure of proteins in solution under a wide number of conditions .	PLIMB was used to map the dimerization of EGF induced EGFR dimerization, yielding results consistent with published crystal structures and demonstrating its promising utility for quick mapping of protein protein interactions for applications in the clinical protein therapeutics field, as well as for basic research on the three-dimensional structure of proteins in solution under a wide number of conditions.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
Here we studied EGF induced EGFR activation and the activation of major signaling pathways downstream of EGFR during mitosis .	Here we studied EGF induced EGFR activation and the activation of major signaling pathways downstream of EGFR during mitosis.	2	9	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Clathrin Knockdown Fully Inhibits EGF induced EGFR Internalization , but Internalization Upon HB-EGF and BTC Binding is Only Partly Inhibited .	Clathrin Knockdown Fully Inhibits EGF induced EGFR Internalization, but Internalization Upon HB-EGF and BTC Binding is Only Partly Inhibited.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
Moreover , since pertuzumab does not block EGF induced EGFR activation [ XREF_BIBR ] , liganded EGFR monomers are induced to form endocytosis-competent EGFR homodimers .	Moreover, since pertuzumab does not block EGF induced EGFR activation [XREF_BIBR], liganded EGFR monomers are induced to form endocytosis-competent EGFR homodimers.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
EGF treatment of SHIP2 RNAi cells led to the following : enhanced EGF receptor ( EGFR ) degradation ; increased EGFR ubiquitination ; and increased association of EGFR with c-Cbl ubiquitin ligase .	EGF treatment of SHIP2 RNAi cells led to the following : enhanced EGF receptor (EGFR) degradation; increased EGFR ubiquitination; and increased association of EGFR with c-Cbl ubiquitin ligase.	0	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	27	28
In addition , overexpression of its ligand EGF , which activates EGFR , plays an important role in tumorigenesis of NSCLC [ XREF_BIBR ] .	In addition, overexpression of its ligand EGF, which activates EGFR, plays an important role in tumorigenesis of NSCLC [XREF_BIBR].	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	overexpression of its ligand EGF	egf	EGFR	EGFR	egfr	7	8	11	12
To further examine endogenous ERbeta-EGFR interaction , and to assess whether subcellular localization is important in ligand dependent interaction between ERbeta and EGFR detected in co-IP studies , we performed immunofluorescent staining for ERbeta and EGFR in EtOH treated cells or in cells treated with E 2 , EGF , or both E 2 and EGF for 1 h.	To further examine endogenous ERbeta-EGFR interaction, and to assess whether subcellular localization is important in ligand dependent interaction between ERbeta and EGFR detected in co-IP studies, we performed immunofluorescent staining for ERbeta and EGFR in EtOH treated cells or in cells treated with E 2, EGF, or both E 2 and EGF for 1 h.	29	49	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	48	49	35	36
The signal from the maturing oocyte that controls dilation of the distal spermatheca is thought to be LIN-3 and EGF , which triggers LET-23 and EGF receptor signaling in the distal spermatheca and possibly the sheath cells .	The signal from the maturing oocyte that controls dilation of the distal spermatheca is thought to be LIN-3 and EGF, which triggers LET-23 and EGF receptor signaling in the distal spermatheca and possibly the sheath cells.	14	27	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	19	20	25	27
Exposure of cells to PMA resulted in a decrease in the EGF stimulated EGFr phosphotyrosine content from 96 +/- 5 U in control to 66 +/- 6 U in PMA ( P < 0.01 ) .	Exposure of cells to PMA resulted in a decrease in the EGF stimulated EGFr phosphotyrosine content from 96 +/- 5 U in control to 66 +/- 6 U in PMA (P < 0.01).	10	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFr	EGFr	EGFr	11	12	13	14
To determine how ADP ribosylation inhibited EGFR degradation , EGF activated EGFR localization was measured in HeLa cells intoxicated with P. aeruginosa expressing ExoS derivatives .	To determine how ADP ribosylation inhibited EGFR degradation, EGF activated EGFR localization was measured in HeLa cells intoxicated with P. aeruginosa expressing ExoS derivatives.	9	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
Flow cytometry and Western blot methods were used to assess PD-L1 expression on ESCC cells when EGFR signaling pathway was activated by epidermal growth factor ( EGF ) with or without EGFR specific inhibitor AG-1478 , and then EGFR signaling array was applied to analyze the potential signaling pathways involved .	Flow cytometry and Western blot methods were used to assess PD-L1 expression on ESCC cells when EGFR signaling pathway was activated by epidermal growth factor (EGF) with or without EGFR specific inhibitor AG-1478, and then EGFR signaling array was applied to analyze the potential signaling pathways involved.	16	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	22	25	16	17
In BxPC-3 , ERL appropriately reduced EGF stimulated pEGFR and pERK at 10 ng/ml , whereas BYL reduced IGF stimulated pAkt signals at 50 ng/ml .	In BxPC-3, ERL appropriately reduced EGF stimulated pEGFR and pERK at 10 ng/ml, whereas BYL reduced IGF stimulated pAkt signals at 50 ng/ml.	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	6	7	8	9
If cells were stimulated by EGF first to induce EGFR kinase activity herein express high level of p-EGFR , then Lycorine could downregulate EGF induced EGFR phosphorylation and its downstream signals .	If cells were stimulated by EGF first to induce EGFR kinase activity herein express high level of p-EGFR, then Lycorine could downregulate EGF induced EGFR phosphorylation and its downstream signals.	3	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	9	10
Whereas immunohistochemistry revealed no substantial effect of EGF on the pattern of EGFR expression in HCC827 or A549 cells , PLA analysis showed that EGF induced EGFR homodimerization in A549 and H2228 cells ( both of which are WT for EGFR ) but not in EGFR mutation positive HCC827 cells .	Whereas immunohistochemistry revealed no substantial effect of EGF on the pattern of EGFR expression in HCC827 or A549 cells, PLA analysis showed that EGF induced EGFR homodimerization in A549 and H2228 cells (both of which are WT for EGFR) but not in EGFR mutation positive HCC827 cells.	24	27	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
Additionally , EGF induced EGFR signalling is indispensable for the initiation of hair growth 15 .	Additionally, EGF induced EGFR signalling is indispensable for the initiation of hair growth 15.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
EGF ( 100 ng/ml ) treatment resulted in EGFR and STAT3 activation .	EGF (100 ng/ml) treatment resulted in EGFR and STAT3 activation.	0	12	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	8	9
To ensure that EGF is activating EGFR to stimulate high molecular weight secretion , goblet cells were preincubated with AG1478 ( 10 -6 and 10 -5 M ) and stimulated with EGF ( 10 -7 M ) for 1 h. EGF significantly increased high molecular weight glycoconjugate secretion 1.4 +/- 0.1 fold above basal ( XREF_FIG ) .	To ensure that EGF is activating EGFR to stimulate high molecular weight secretion, goblet cells were preincubated with AG1478 (10 -6 and 10 -5 M) and stimulated with EGF (10 -7 M) for 1 h. EGF significantly increased high molecular weight glycoconjugate secretion 1.4 +/- 0.1 fold above basal (XREF_FIG).	3	7	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	6	7
The unconventional E3 ubiquitin ligase Rabex-5 has been reported to bind to EGF activated EGFR through its two ubiquitin binding domains .	The unconventional E3 ubiquitin ligase Rabex-5 has been reported to bind to EGF activated EGFR through its two ubiquitin binding domains.	10	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Several lines of evidence indicate that sortilin is involved in EGFR trafficking , independently of EGF induced EGFR internalization .	Several lines of evidence indicate that sortilin is involved in EGFR trafficking, independently of EGF induced EGFR internalization.	1	18	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
These data suggest that EGF , already known to be present in the cytoplasm of secretory cells in eccrine and apocrine sweat glands , activates EGFR in the nuclei of secretory cells themselves in an intracrine manner .	These data suggest that EGF, already known to be present in the cytoplasm of secretory cells in eccrine and apocrine sweat glands, activates EGFR in the nuclei of secretory cells themselves in an intracrine manner.	4	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	25	26
We studied ( a ) nicotine induced increase in the cellular expression of EGF-R in human papillomavirus ( HPV )-positive ME-180 and HPV negative HT-3 cervical cancer cell line cultures , using a semi-quantitative immunofluorescent antibody assay ; ( b ) alterations in cellular proliferation in association with changes in EGF-R levels ; and ( c ) the EGF-R mediation by EGF .	We studied (a) nicotine induced increase in the cellular expression of EGF-R in human papillomavirus (HPV)-positive ME-180 and HPV negative HT-3 cervical cancer cell line cultures, using a semi-quantitative immunofluorescent antibody assay; (b) alterations in cellular proliferation in association with changes in EGF-R levels; and (c) the EGF-R mediation by EGF.	58	62	mediation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	61	62	58	59
Specifically , in this regulatory circuit , EGF activated EGFR functions as a negative regulator of NHERF1 expression by committing NHERF1 to proteosomal degradation ( XREF_FIG ) , and NHERF1 functions to regulate the duration of the EGFR signal by inducing receptor internalization and its rapid recycling to the plasma membrane after a short EGF stimulation while sorting the majority , but not all , of the EGFRs to lysosomal degradation after a persistent EGF stimulation ( XREF_FIG , XREF_FIG ) .	Specifically, in this regulatory circuit, EGF activated EGFR functions as a negative regulator of NHERF1 expression by committing NHERF1 to proteosomal degradation (XREF_FIG), and NHERF1 functions to regulate the duration of the EGFR signal by inducing receptor internalization and its rapid recycling to the plasma membrane after a short EGF stimulation while sorting the majority, but not all, of the EGFRs to lysosomal degradation after a persistent EGF stimulation (XREF_FIG, XREF_FIG).	7	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Ubiquitinated cargo , such as EGF stimulated EGFR , is targeted onto ILVs for later delivery to the lysosome by a series of protein complexes that comprise the endosomal sorting complex required for transport ( ESCRT ) machinery [ XREF_BIBR ] .	Ubiquitinated cargo, such as EGF stimulated EGFR, is targeted onto ILVs for later delivery to the lysosome by a series of protein complexes that comprise the endosomal sorting complex required for transport (ESCRT) machinery [XREF_BIBR].	1	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
In CRC cells , CTTN expression attenuates EGF induced down-regulation of EGFR .	In CRC cells, CTTN expression attenuates EGF induced down-regulation of EGFR.	7	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	11	12
The experimental data described above demonstrated the tumor suppressive function of EFEMP1 , which operates by attenuating and blocking EGF stimulated EGFR signaling activities , and is consistent with the patient outcomes predicted based on the EGFR level in the subset of gliomas expressing a low level of EFEMP1 .	The experimental data described above demonstrated the tumor suppressive function of EFEMP1, which operates by attenuating and blocking EGF stimulated EGFR signaling activities, and is consistent with the patient outcomes predicted based on the EGFR level in the subset of gliomas expressing a low level of EFEMP1.	16	23	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
This indicates that EGF induces actin polymerization as well as additional association of the EGFR with similar sites on the membrane-skeleton .	This indicates that EGF induces actin polymerization as well as additional association of the EGFR with similar sites on the membrane-skeleton.	3	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	14	15
However , no role for ALIX has been demonstrated in sorting of EGF stimulated EGFR onto ILVs or its targeting to lysosomes for degradation XREF_BIBR .	However, no role for ALIX has been demonstrated in sorting of EGF stimulated EGFR onto ILVs or its targeting to lysosomes for degradation XREF_BIBR.	10	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
We further hypothesized that hypoxia would result in EGF mediated EGFR activation , which is necessary for arginase II induction and proliferation .	We further hypothesized that hypoxia would result in EGF mediated EGFR activation, which is necessary for arginase II induction and proliferation.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
Other patterns are discernible here , such as HGF induced MET , or EGF- induced EGFR and Her2 , in both BT549 and BT20 cell lines .	Other patterns are discernible here, such as HGF induced MET, or EGF- induced EGFR and Her2, in both BT549 and BT20 cell lines.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF-	EGF-	EGF-	EGFR	EGFR	EGFR	13	14	15	16
Furthermore , glaziovianin A inhibited the transport of endosomes containing EGF stimulated EGFR and prolonged the EGFR activation .	Furthermore, glaziovianin A inhibited the transport of endosomes containing EGF stimulated EGFR and prolonged the EGFR activation.	9	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
Similar , but fainter bands can be seen in EGF stimulated EGFR and chEGFR , but not in any of the other samples where DeltaEGFR was expressed .	Similar, but fainter bands can be seen in EGF stimulated EGFR and chEGFR, but not in any of the other samples where DeltaEGFR was expressed.	7	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
Thus , we also sought to determine the changes in EGFR-erbB2 and Akt-FoxO survival pathways after global ischemia and following activation of EGFR signaling by EGF in both normal and diabetic hearts .	Thus, we also sought to determine the changes in EGFR-erbB2 and Akt-FoxO survival pathways after global ischemia and following activation of EGFR signaling by EGF in both normal and diabetic hearts.	20	26	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	22	23
Both exogenous and endogenous NO impaired the EGF induced activation of the EGF receptor ( EGFR ) tyrosine kinase and prevented the EGF induced Akt phosphorylation in neurosphere cells .	Both exogenous and endogenous NO impaired the EGF induced activation of the EGF receptor (EGFR) tyrosine kinase and prevented the EGF induced Akt phosphorylation in neurosphere cells.	6	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	7	8	12	14
EGF binds to a homodimer or heterodimer receptor of EGFR to activate EGFR .	EGF binds to a homodimer or heterodimer receptor of EGFR to activate EGFR.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	12	13
Under similar conditions of TSG101 knockdown , EGF induced EGFR degradation was dramatically inhibited .	Under similar conditions of TSG101 knockdown, EGF induced EGFR degradation was dramatically inhibited.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
In the signaling network presented here ( XREF_FIG ) , EGF induced activation of EGFR occurs through two parallel phosphorylation pathways corresponding to tyrosine 1068 ( Y1068 ) and tyrosine 1173 ( Y1173 ) .	In the signaling network presented here (XREF_FIG), EGF induced activation of EGFR occurs through two parallel phosphorylation pathways corresponding to tyrosine 1068 (Y1068) and tyrosine 1173 (Y1173).	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	14	15
Then EGFR internalisation and its lysosomal degradation were stimulated by addition of EGF .	Then EGFR internalisation and its lysosomal degradation were stimulated by addition of EGF.	1	13	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	1	2
In summary , we identified a novel trafficking mechanism of nuclear EGFR in which EGF induces EGFR to travel along microtubule cytoskeleton to Golgi via syntaixn 6 mediated membrane fusion and to the nucleus to control the nuclear functions of EGFR ( XREF_FIG ) .	In summary, we identified a novel trafficking mechanism of nuclear EGFR in which EGF induces EGFR to travel along microtubule cytoskeleton to Golgi via syntaixn 6 mediated membrane fusion and to the nucleus to control the nuclear functions of EGFR (XREF_FIG).	14	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
In this study , EGF promoted activation of EGFR and induced MMP-9 to enhance the ability of OS cells to metastasize .	In this study, EGF promoted activation of EGFR and induced MMP-9 to enhance the ability of OS cells to metastasize.	4	10	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	8	9
In contrast , p-EGFR is readily detected in EGF treated cells , indicating that EGF efficiently activated EGFR in these cells .	In contrast, p-EGFR is readily detected in EGF treated cells, indicating that EGF efficiently activated EGFR in these cells.	14	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	17	18
Early studies demonstrated that EGF dependent lysosomal targeting of EGFR was a saturable process , suggesting the likelihood that certain key regulatory proteins were rate limiting [ XREF_BIBR ] .	Early studies demonstrated that EGF dependent lysosomal targeting of EGFR was a saturable process, suggesting the likelihood that certain key regulatory proteins were rate limiting [XREF_BIBR].	4	10	targeting	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	9	10
Continuous 200-ng/ml EGF stimulation for 24 h increased EGFP-EGFR transport efficiency from the ER to the plasma membrane in cells on average by 2.8-fold , whereas PDGF- and IGF stimulated cells did not show any changes ( XREF_FIG ) .	Continuous 200-ng/ml EGF stimulation for 24 h increased EGFP-EGFR transport efficiency from the ER to the plasma membrane in cells on average by 2.8-fold, whereas PDGF- and IGF stimulated cells did not show any changes (XREF_FIG).	2	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFP-EGFR	EGFP-EGFR	EGFP-EGFR	2	3	8	9
To gain further insight into the differential signaling properties of AREG-versus EGF stimulated EGFR in MCF-10A and SUM-149 cells , we performed experiments using reverse phase protein arrays ( RPPAs ) .	To gain further insight into the differential signaling properties of AREG-versus EGF stimulated EGFR in MCF-10A and SUM-149 cells, we performed experiments using reverse phase protein arrays (RPPAs).	8	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Together , these data establish ubiquitination as a form of EGF stimulated covalent modification of the EGF-R .	Together, these data establish ubiquitination as a form of EGF stimulated covalent modification of the EGF-R.	7	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	10	11	16	17
As expected we found that EGF stimulated an association of EGF-R with Grb2 , PRL , however , blocked this association .	As expected we found that EGF stimulated an association of EGF-R with Grb2, PRL, however, blocked this association.	5	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	5	6	10	11
As a control , EGF induced EGFR nuclear translocation was not modified in cells with siRNA ablated EP3 receptor expression ( XREF_SUPPLEMENTARY ) .	As a control, EGF induced EGFR nuclear translocation was not modified in cells with siRNA ablated EP3 receptor expression (XREF_SUPPLEMENTARY).	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
When cells cotransfected with Kv1.3 and the EGFr are treated with EGF during patch recording , the inactivation rate of the current increases .	When cells cotransfected with Kv1.3 and the EGFr are treated with EGF during patch recording, the inactivation rate of the current increases.	2	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFr	EGFr	EGFr	11	12	7	8
The results of in vitro experiments showed that CHAG suppressed both basic and EGF induced migration and invasion of OC cells , blocked the activation of EGF initiated EGFR activation , inhibited downstream signal transduction of EGFR , and decreased expression of proliferation and migration and invasion related proteins .	The results of in vitro experiments showed that CHAG suppressed both basic and EGF induced migration and invasion of OC cells, blocked the activation of EGF initiated EGFR activation, inhibited downstream signal transduction of EGFR, and decreased expression of proliferation and migration and invasion related proteins.	24	29	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
Furthermore , immunofluorescence staining of Grb2 adaptor , known to be associated with the EGF activated EGFR in endosomes , was used to compare the localization of EGFR signaling complexes with MEK2-GFP .	Furthermore, immunofluorescence staining of Grb2 adaptor, known to be associated with the EGF activated EGFR in endosomes, was used to compare the localization of EGFR signaling complexes with MEK2-GFP.	11	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
Regarding angiogenesis , AF was shown to disrupt EGF induced EGFR activation [ XREF_BIBR ] , PI3K/Akt/mTOR activation , and HIF-1 expression in MDA-MB-231 cells [ XREF_BIBR ] .	Regarding angiogenesis, AF was shown to disrupt EGF induced EGFR activation [XREF_BIBR], PI3K/Akt/mTOR activation, and HIF-1 expression in MDA-MB-231 cells [XREF_BIBR].	7	11	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
The result showed EGF mediated activation of EGFR signaling in un treated cells .	The result showed EGF mediated activation of EGFR signaling in un treated cells.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	7	8
RPE cells do not detectably express HER2 levels , and thus EGF stimulation of these cells results in activation of EGFR homodimers .	RPE cells do not detectably express HER2 levels, and thus EGF stimulation of these cells results in activation of EGFR homodimers.	11	21	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	20	21
In myometrial SMCs , however , EGF induced sustained activation of EGFR , Akt , and p44/42 MAPK with up-regulation of p27 .	In myometrial SMCs, however, EGF induced sustained activation of EGFR, Akt, and p44/42 MAPK with up-regulation of p27.	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	11	12
Tethered EGF induced higher levels of activation of EGFR and ERK1/2 on various peptide gel compositions at later time-points compared to soluble EGF .	Tethered EGF induced higher levels of activation of EGFR and ERK1/2 on various peptide gel compositions at later time-points compared to soluble EGF.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	8	9
To test the hypothesis that EGFR activation promotes sensitivity to CC214-1 , we examined the impact of EGFRvIII or EGF stimulation of wild type EGFR , in isogenic GBM cell lines .	To test the hypothesis that EGFR activation promotes sensitivity to CC214-1, we examined the impact of EGFRvIII or EGF stimulation of wild type EGFR, in isogenic GBM cell lines.	17	25	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	24	25
C2-ceramide and PLA2 inhibits EGF induced activation of EGFR , which is associated with arachidonic acid release and an increase in intracellular ceramide formation , leading to inhibition of proliferation in human epidermoid carcinoma cells [ XREF_BIBR ] .	C2-ceramide and PLA2 inhibits EGF induced activation of EGFR, which is associated with arachidonic acid release and an increase in intracellular ceramide formation, leading to inhibition of proliferation in human epidermoid carcinoma cells [XREF_BIBR].	4	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	8	9
These findings suggest that 20ng/ml EGF optimally stimulates EGFR tyrosine kinase activity and cell motility in our RPC population .	These findings suggest that 20ng/ml EGF optimally stimulates EGFR tyrosine kinase activity and cell motility in our RPC population.	4	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	8	9
Following HTATIP2 and TIP30-knockout , EGF induced EGFR degradation was inhibited , possibly due to the fact that HTATIP2 and TIP30 , ACSL4 and endophilin B1 formed a complex protein , which promoted EGFR from early endosomes into liposomal sorting , and then accelerated the degradation of EGFR in liver cells in mice and mammary cells .	Following HTATIP2 and TIP30-knockout, EGF induced EGFR degradation was inhibited, possibly due to the fact that HTATIP2 and TIP30, ACSL4 and endophilin B1 formed a complex protein, which promoted EGFR from early endosomes into liposomal sorting, and then accelerated the degradation of EGFR in liver cells in mice and mammary cells.	5	43	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
It is well established that EGF activates EGFR .	It is well established that EGF activates EGFR.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
We further pursued EGF induced EGFR downregulation by exploring the effect of pharmacological inhibition of the ERK pathway ( XREF_FIG ) .	We further pursued EGF induced EGFR downregulation by exploring the effect of pharmacological inhibition of the ERK pathway (XREF_FIG).	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
EGF activation of EGFR signaling in OSCC results in the increased expression of miR-31 , miR-181b and miR-222 expression .	EGF activation of EGFR signaling in OSCC results in the increased expression of miR-31, miR-181b and miR-222 expression.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	3	4
EGFR activation by EGF promotes cell proliferation and survival .	EGFR activation by EGF promotes cell proliferation and survival.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	0	1
Additionally , EGF activated EGFR and downstream EGFR signaling was not depleted under conditions of c-Met inhibition .	Additionally, EGF activated EGFR and downstream EGFR signaling was not depleted under conditions of c-Met inhibition.	2	11	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
In both High Na + and Low Na + buffers , EGF activated EGFR , Erk1/2 and Akt to a similar extend suggesting that activation of canonical EGFR signaling is independent of the EGF induced sodium influx .	In both High Na + and Low Na + buffers, EGF activated EGFR, Erk1/2 and Akt to a similar extend suggesting that activation of canonical EGFR signaling is independent of the EGF induced sodium influx.	11	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Western blot analysis showed that , indeed , MCT1 KD reduced levels of phosphorylated c-Met ( pMet ) , as well as downstream phosphorylated Akt ( pAkt ) in DU145 cells exposed to HGF ; however , there was no decrease in activation of EGFR in DU145 cells treated with EGF .	Western blot analysis showed that, indeed, MCT1 KD reduced levels of phosphorylated c-Met (pMet), as well as downstream phosphorylated Akt (pAkt) in DU145 cells exposed to HGF; however, there was no decrease in activation of EGFR in DU145 cells treated with EGF.	42	51	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	50	51	44	45
However , a recent study with NSCLC cells expressing wild-type Met and EGFR showed delayed Met phosphorylation in response to EGF stimulation of EGFR beginning at 24 h and that Met signalling was required for maximal EGFR induced invasion and motility .	However, a recent study with NSCLC cells expressing wild-type Met and EGFR showed delayed Met phosphorylation in response to EGF stimulation of EGFR beginning at 24 h and that Met signalling was required for maximal EGFR induced invasion and motility.	20	24	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	23	24
The Akt signal was specific to ErbB3 activation by heregulin , and was not observed in response to EGF activation of EGFR .	The Akt signal was specific to ErbB3 activation by heregulin, and was not observed in response to EGF activation of EGFR.	18	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	21	22
Although degradation is widely accepted as the ultimate fate of EGF activated EGFR , the rate of receptor degradation has been found to be significantly slower than the rate of internalization [ XREF_BIBR ] .	Although degradation is widely accepted as the ultimate fate of EGF activated EGFR, the rate of receptor degradation has been found to be significantly slower than the rate of internalization [XREF_BIBR].	8	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
Through EGF induced EGFR receptor internalisation , CD9 attenuates EGFR signalling by reducing cell surface EGFR expression .	Through EGF induced EGFR receptor internalisation, CD9 attenuates EGFR signalling by reducing cell surface EGFR expression.	0	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
In our own solution biophysical studies , we observed weak heterodimerization of ErbB2 with the neuregulin bound extracellular regions of ErbB3 or ErbB4 [ XREF_BIBR ] , but failed to detect EGF induced association of the EGFR and ErbB2 extracellular regions ( or other anticipated heterodimers ) .	In our own solution biophysical studies, we observed weak heterodimerization of ErbB2 with the neuregulin bound extracellular regions of ErbB3 or ErbB4 [XREF_BIBR], but failed to detect EGF induced association of the EGFR and ErbB2 extracellular regions (or other anticipated heterodimers).	30	43	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	31	32	36	37
The impact of ExoS ADPr activity on host vesicle trafficking was further tested by measuring EGF activated EGF receptor ( EGFR ) degradation , a pathway involving clathrin mediated uptake of activated EGFR dimer , maturation to early and late endosomes and final degradation of the EGFR in lysosomes .	The impact of ExoS ADPr activity on host vesicle trafficking was further tested by measuring EGF activated EGF receptor (EGFR) degradation, a pathway involving clathrin mediated uptake of activated EGFR dimer, maturation to early and late endosomes and final degradation of the EGFR in lysosomes.	14	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	15	16	17	19
In these experiments , the in vivo inhibition of the EGFR kinase domain prevented the EGF induced internalization of EGFR .	In these experiments, the in vivo inhibition of the EGFR kinase domain prevented the EGF induced internalization of EGFR.	14	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	19	20
We found that EGF conjugated dendrimers did not stimulate growth of EGFR expressing cells at the selected concentration .	We found that EGF conjugated dendrimers did not stimulate growth of EGFR expressing cells at the selected concentration.	3	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	11	12
Correspondingly , EBP50 overexpression inhibited EGF induced EGFR and downstream molecules ( ERK1/2 and AKT ) phosphorylation , and EBP50 knockdown enhanced EGF induced EGFR and downstream molecules ( ERK1/2 and AKT ) phosphorylation ( Figs .	Correspondingly, EBP50 overexpression inhibited EGF induced EGFR and downstream molecules (ERK1/2 and AKT) phosphorylation, and EBP50 knockdown enhanced EGF induced EGFR and downstream molecules (ERK1/2 and AKT) phosphorylation (Figs.	21	27	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
Therefore , to rule out that the effect of STI571 on SHP-2 phosphorylation was not due to inhibition of PDGFR , which may affect EGFR activation via receptor crosstalk , we assessed whether STI571 inhibited EGF induced EGFR activation .	Therefore, to rule out that the effect of STI571 on SHP-2 phosphorylation was not due to inhibition of PDGFR, which may affect EGFR activation via receptor crosstalk, we assessed whether STI571 inhibited EGF induced EGFR activation.	34	38	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	35	36	37	38
The lapatinib result on EGF stimulation of HER1 seems to confirm this .	The lapatinib result on EGF stimulation of HER1 seems to confirm this.	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	HER1	HER1	HER1	4	5	7	8
Except for IKK and NFkappaB , JNK and p38 were also activated following EGF stimulation of EGFR f/f Kupffer cells ( XREF_SUPPLEMENTARY ) .	Except for IKK and NFkappaB, JNK and p38 were also activated following EGF stimulation of EGFR f/f Kupffer cells (XREF_SUPPLEMENTARY).	13	19	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	16	17
Lycorine suppresses EGF induced EGFR signaling pathway .	Lycorine suppresses EGF induced EGFR signaling pathway.	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
We thus investigated whether an exogenous intake of EGF could rescue the activation of the EGF and EGFR pathway effectors and subsequently increase LNCaP cells proliferation and migration .	We thus investigated whether an exogenous intake of EGF could rescue the activation of the EGF and EGFR pathway effectors and subsequently increase LNCaP cells proliferation and migration.	6	19	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	17	18
EGF activates EGFR tyrosine kinases and plays an important role in the regulation of mucus secretion in asthma patients [ XREF_BIBR ] .	EGF activates EGFR tyrosine kinases and plays an important role in the regulation of mucus secretion in asthma patients [XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
EGF induced activation of EGFR in a human glioblastoma line , A-172 cells , increased MMP9 expression through activation of phosphatidylinositol 3-kinase ( PI3K )/Akt pathway , without affecting expression of miRNA-181c .	EGF induced activation of EGFR in a human glioblastoma line, A-172 cells, increased MMP9 expression through activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway, without affecting expression of miRNA-181c.	0	9	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
As EGF stimulation has been shown to enhance the mitochondrial localization of EGFR , we examined whether Tid1 appeared to be involved in this process .	As EGF stimulation has been shown to enhance the mitochondrial localization of EGFR, we examined whether Tid1 appeared to be involved in this process.	1	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	12	13
When the expression of Mig-6 was repressed using two different siRNA ( siMig-6-1 and siMig-6-2 ) , the growth of Huh-7 cells was significantly increased and the levels of EGF mediated p-EGFR ( Y1173 and Y845 ) and p-Met ( Tyr1234/1235 ) were substantially increased .	When the expression of Mig-6 was repressed using two different siRNA (siMig-6-1 and siMig-6-2), the growth of Huh-7 cells was significantly increased and the levels of EGF mediated p-EGFR (Y1173 and Y845) and p-Met (Tyr1234/1235) were substantially increased.	27	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	p-EGFR	p-EGFR	p-EGFR	29	30	31	32
We hypothesized that exogenous EGF would increase EGFR activation and cell proliferation resulting in more rapid wound closure .	We hypothesized that exogenous EGF would increase EGFR activation and cell proliferation resulting in more rapid wound closure.	3	8	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	7	8
We conducted EGF induced EGF receptor ( EGFR ) degradation assays to examine the effects of monoubiquitinated Rab5 on the endocytic trafficking pathway .	We conducted EGF induced EGF receptor (EGFR) degradation assays to examine the effects of monoubiquitinated Rab5 on the endocytic trafficking pathway.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	2	3	4	6
Although EGF activated the EGF receptor ( EGFR ) , as measured by EGFR-Y845 phosphorylation , whether or not the cells had been treated with DLC1 siRNAs , EGF increased RhoA-GTP only under conditions with continued expression of DLC1 ( XREF_FIG ; Fig .	Although EGF activated the EGF receptor (EGFR), as measured by EGFR-Y845 phosphorylation, whether or not the cells had been treated with DLC1 siRNAs, EGF increased RhoA-GTP only under conditions with continued expression of DLC1 (XREF_FIG; Fig.	1	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	1	2	4	6
We have previously reported that GALNT1 and GALNT2 are the two major polypeptide GalNAc-transferases in liver and HCC tissues ; and overexpression of GALNT2 suppresses EGF induced EGFR activation and enhances EGFR degradation [ XREF_BIBR ] .	We have previously reported that GALNT1 and GALNT2 are the two major polypeptide GalNAc-transferases in liver and HCC tissues; and overexpression of GALNT2 suppresses EGF induced EGFR activation and enhances EGFR degradation [XREF_BIBR].	24	28	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	27	28
In this study , we observed that both Ang II and EGF could increase the phospohorylation of EGFR and protein kinase B ( AKT )/extracellular signal regulated kinase ( ERK ) , and then induce cell hypertrophy in H9c2 cells .	In this study, we observed that both Ang II and EGF could increase the phospohorylation of EGFR and protein kinase B (AKT)/extracellular signal regulated kinase (ERK), and then induce cell hypertrophy in H9c2 cells.	9	21	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	17	18
Due to the constitutive membrane anchorage of Spry1 ( XREF_FIG ) , it is also possible that Spry1 somehow interferes EGF mediated EGFR activation .	Due to the constitutive membrane anchorage of Spry1 (XREF_FIG), it is also possible that Spry1 somehow interferes EGF mediated EGFR activation.	19	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
In C. elegans , cellular stress induces sleep through Epidermal Growth Factor ( EGF )-dependent activation of the EGF receptor in the ALA neuron .	In C. elegans, cellular stress induces sleep through Epidermal Growth Factor (EGF)-dependent activation of the EGF receptor in the ALA neuron.	9	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Epidermal Growth Factor	Epidermal Growth Factor	Epidermal Growth Factor	EGF receptor	EGF receptor	EGF receptor	9	12	18	20
Several studies have shown that EGF induces the EGFR and mitogen activated protein kinase ( MAPK )/AKT signal transduction pathway and contributes to the proliferation and migration of RPE cells .	Several studies have shown that EGF induces the EGFR and mitogen activated protein kinase (MAPK)/AKT signal transduction pathway and contributes to the proliferation and migration of RPE cells.	5	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	8	9
These results suggest that GALNT1 knockdown suppresses EGF induced EGFR activation and enhances EGF induced EGFR degradation in HCC cells .	These results suggest that GALNT1 knockdown suppresses EGF induced EGFR activation and enhances EGF induced EGFR degradation in HCC cells.	13	16	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Activation of the ERK1/2 pathway in response to epidermal growth factor ( EGF ) stimulation of the EGF receptor falls into three major regulatory loops : immediate , delayed , and late ( secondary ) [ XREF_BIBR - XREF_BIBR ] .	Activation of the ERK1/2 pathway in response to epidermal growth factor (EGF) stimulation of the EGF receptor falls into three major regulatory loops : immediate, delayed, and late (secondary) [XREF_BIBR - XREF_BIBR].	12	19	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	12	13	17	19
As known , EGF stimulates activation of the EGFR signaling pathway .	As known, EGF stimulates activation of the EGFR signaling pathway.	3	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	8	9
Epidermal growth factor ( EGF ) activates the EGF receptor ( EGFR ) and stimulates its internalization and trafficking to lysosomes for degradation .	Epidermal growth factor (EGF) activates the EGF receptor (EGFR) and stimulates its internalization and trafficking to lysosomes for degradation.	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	4	5	8	10
EGF stimulated EGFR initiates a signaling cascade culminating in its transient phosphorylation and cell proliferation .	EGF stimulated EGFR initiates a signaling cascade culminating in its transient phosphorylation and cell proliferation.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
In those cells , prolactin caused substantial PKC dependent EGFR threonine phosphorylation ( although the residue was not mapped ) and subsequent desensitization of EGF induced EGFR tyrosine kinase activity .	In those cells, prolactin caused substantial PKC dependent EGFR threonine phosphorylation (although the residue was not mapped) and subsequent desensitization of EGF induced EGFR tyrosine kinase activity.	22	29	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
Pretreatment with Triptorelin or [ d-Lys ( 6 ) ] GnRH-II blocked EGF induced autophosphoryla-tion of EGF receptor and activation of mitogen activated protein kinase ( extracellular-signal-regulated kinase 1/2 ( ERK1/2 ) ) in these cells .	Pretreatment with Triptorelin or [d-Lys (6)] GnRH-II blocked EGF induced autophosphoryla-tion of EGF receptor and activation of mitogen activated protein kinase (extracellular-signal-regulated kinase 1/2 (ERK1/2)) in these cells.	12	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	12	13	16	18
Consistent with the known functions of MIG6 , down regulation of MIG6 by siRNA increased EGF induced activation of EGFR .	Consistent with the known functions of MIG6, down regulation of MIG6 by siRNA increased EGF induced activation of EGFR.	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	19	20
In the present study , we generated protein based PLC-gamma1 inhibitors consisting of PLC-gamma1-SH2 domains fused to the TAT leader sequence as highly specific inhibitors to block PLC-gamma1 tyrosine phosphorylation , thereby inhibiting the EGF induced migration of EGFR and c-erbB-2-positive breast cancer cells .	In the present study, we generated protein based PLC-gamma1 inhibitors consisting of PLC-gamma1-SH2 domains fused to the TAT leader sequence as highly specific inhibitors to block PLC-gamma1 tyrosine phosphorylation, thereby inhibiting the EGF induced migration of EGFR and c-erbB-2-positive breast cancer cells.	33	43	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	34	35	38	39
Notably , EGF induced EGFR downregulation in C14 cells was relatively blunted .	Notably, EGF induced EGFR downregulation in C14 cells was relatively blunted.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
As shown in XREF_FIG , SbS completely blocked EGF induced EGFR activation and attenuated NRG1 induced HER-2 and HER-3 activation .	As shown in XREF_FIG, SbS completely blocked EGF induced EGFR activation and attenuated NRG1 induced HER-2 and HER-3 activation.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
In the above studies , we demonstrated that AnxA2 ( D1/274.5 ) antibody preincubation inhibits EGF induced EGFR dimerisation , tyrosine phosphorylation , internalisation , and its downstream signalling pathways PI3K-AKT , and Raf-MEK-ERK that leads to inhibition of cancer cell proliferation and migration .	In the above studies, we demonstrated that AnxA2 (D1/274.5) antibody preincubation inhibits EGF induced EGFR dimerisation, tyrosine phosphorylation, internalisation, and its downstream signalling pathways PI3K-AKT, and Raf-MEK-ERK that leads to inhibition of cancer cell proliferation and migration.	14	33	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
We now show that the MDA468 breast cancer cells express the mRNA for the EGF like molecule , transforming growth factor-alpha ( TGF-alpha ) , and demonstrate that TPA or EGF cause an accumulation of both EGF receptor and TGF-alpha mRNA .	We now show that the MDA468 breast cancer cells express the mRNA for the EGF like molecule, transforming growth factor-alpha (TGF-alpha), and demonstrate that TPA or EGF cause an accumulation of both EGF receptor and TGF-alpha mRNA.	28	38	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	30	31	36	38
These data indicate that GH , by activating ERKs , can modulate EGF induced EGFR trafficking and signaling and expand our understanding of mechanisms of cross-talk between the GH and EGF signaling systems .	These data indicate that GH, by activating ERKs, can modulate EGF induced EGFR trafficking and signaling and expand our understanding of mechanisms of cross-talk between the GH and EGF signaling systems.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Localized activation of EGFR induced by EGF coated magnetic microspheres ( ~ 1 microm ) has been shown to occur exclusively at the attachment loci on the cell membrane XREF_BIBR , XREF_BIBR , XREF_BIBR .	Localized activation of EGFR induced by EGF coated magnetic microspheres (~ 1 microm) has been shown to occur exclusively at the attachment loci on the cell membrane XREF_BIBR, XREF_BIBR, XREF_BIBR.	1	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	3	4
Cells treated with both XY3-3-Tat and EGF contained higher levels of EGFR than those treated with Tat and EGF , with EGFR levels approaching that of cells treated with Tat alone ( XREF_FIG ) .	Cells treated with both XY3-3-Tat and EGF contained higher levels of EGFR than those treated with Tat and EGF, with EGFR levels approaching that of cells treated with Tat alone (XREF_FIG).	9	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	11	12
Taken together , these findings indicate that p130Cas expression negatively regulates EGF induced EGFR internalization .	Taken together, these findings indicate that p130Cas expression negatively regulates EGF induced EGFR internalization.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
We found that the levels of phosphorylation of the major EGFR downstream signaling mediators including STAT3 , STAT5 , Shc and Akt were increased in the cells expressing EGF stimulated EGFR CTD deletion mutants , suggesting that the enzymatic activity of these mutants are able to be further enhanced by ligand unlike EGFRvIII mutant in the absence of autophosphorylation ( XREF_SUPPLEMENTARY ) .	We found that the levels of phosphorylation of the major EGFR downstream signaling mediators including STAT3, STAT5, Shc and Akt were increased in the cells expressing EGF stimulated EGFR CTD deletion mutants, suggesting that the enzymatic activity of these mutants are able to be further enhanced by ligand unlike EGFRvIII mutant in the absence of autophosphorylation (XREF_SUPPLEMENTARY).	27	33	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	28	29	30	31
AF interferes with EGFR and MAPK signaling induced by EGF in ARPE-19 cells .	AF interferes with EGFR and MAPK signaling induced by EGF in ARPE-19 cells.	3	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	3	4
Transactivation of EGFR by beta2-adrenergic receptor signaling requires the phosphorylation of Y845 by Src to exert the full range of EGFR activation that is comparable to EGF induced EGFR activation .	Transactivation of EGFR by beta2-adrenergic receptor signaling requires the phosphorylation of Y845 by Src to exert the full range of EGFR activation that is comparable to EGF induced EGFR activation.	24	29	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
If the goal of the experiment is to measure the degradation rates of EGF activated EGFR , the length of the longest chase incubation can be reduced to 2 and 10 hr in cells with low and high EGFR levels , respectively .	If the goal of the experiment is to measure the degradation rates of EGF activated EGFR, the length of the longest chase incubation can be reduced to 2 and 10 hr in cells with low and high EGFR levels, respectively.	11	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
This EGF displaying BNC can target EGFR overexpressing cells in vitro .	This EGF displaying BNC can target EGFR overexpressing cells in vitro.	0	8	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	6	7
Because multiple facets of EGFR trafficking remain unresolved 19 , and EGFR internalization represents a crucial step for signal termination , we investigated the role of sortilin XREF_BIBR - XREF_BIBR in EGFR regulation following EGF induced EGFR internalization .	Because multiple facets of EGFR trafficking remain unresolved 19, and EGFR internalization represents a crucial step for signal termination, we investigated the role of sortilin XREF_BIBR - XREF_BIBR in EGFR regulation following EGF induced EGFR internalization.	32	37	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	34	35	36	37
These results suggest that GALNT1 knockdown accelerates EGF induced EGFR internalization and co-localization with EEA1 and promotes receptor trafficking to the late endosome and lysosomal pathway leading to enhanced EGFR degradation .	These results suggest that GALNT1 knockdown accelerates EGF induced EGFR internalization and co-localization with EEA1 and promotes receptor trafficking to the late endosome and lysosomal pathway leading to enhanced EGFR degradation.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Gefitinib at IC 50 concentrations significantly suppressed EGF induced activation of p-EGFR , phospho-mitogen-activated protein kinase ( p-MAPK ) and p-STAT3 , but p-AKT showed persistent activation in HK1 and HONE-1 cells .	Gefitinib at IC 50 concentrations significantly suppressed EGF induced activation of p-EGFR, phospho-mitogen-activated protein kinase (p-MAPK) and p-STAT3, but p-AKT showed persistent activation in HK1 and HONE-1 cells.	7	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	p-EGFR	p-EGFR	p-EGFR	7	8	11	12
EGFR activation by EGF attenuated PP2A activity , whereas mutation of Y307 to phenylalanine abolished the effect .	EGFR activation by EGF attenuated PP2A activity, whereas mutation of Y307 to phenylalanine abolished the effect.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	0	1
These data indicate that enhanced tumorigenesis occurs through increase in EGF induced EGFR activation in FLNa expressing melanoma cells and that high FLNa levels are predictors of negative outcome for patients with melanoma tumors .	These data indicate that enhanced tumorigenesis occurs through increase in EGF induced EGFR activation in FLNa expressing melanoma cells and that high FLNa levels are predictors of negative outcome for patients with melanoma tumors.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
EGFR downregulation is also more efficiently induced by EGF , suggesting that ligand dependent modification of ErbB2 may be required to terminate EGFR signalling in cells expressing both receptor types .	EGFR downregulation is also more efficiently induced by EGF, suggesting that ligand dependent modification of ErbB2 may be required to terminate EGFR signalling in cells expressing both receptor types.	0	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	0	1
Notably , we show for the first time that the activation of EGFR induced by its cognate ligand EGF is abolished by knocking down GPER expression or in the presence of MIBE , which is an inhibitor of GPER as ascertained in the present study .	Notably, we show for the first time that the activation of EGFR induced by its cognate ligand EGF is abolished by knocking down GPER expression or in the presence of MIBE, which is an inhibitor of GPER as ascertained in the present study.	10	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	12	13
Indeed , inhibition of EGF induced EGFR degradation in alphaPIX WT cells was rescued by coexpression of c-Cbl ( XREF_FIG ) indicating that this effect is not mediated by other alphaPIX interacting proteins , such as p21 activated kinases which also bind to the SH3 domain of alphaPIX [ XREF_BIBR , XREF_BIBR ] .	Indeed, inhibition of EGF induced EGFR degradation in alphaPIX WT cells was rescued by coexpression of c-Cbl (XREF_FIG) indicating that this effect is not mediated by other alphaPIX interacting proteins, such as p21 activated kinases which also bind to the SH3 domain of alphaPIX [XREF_BIBR, XREF_BIBR].	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
The results suggest that the cytoskeleton is not obligatorily involved in EGF induced EGF receptor down regulation .	The results suggest that the cytoskeleton is not obligatorily involved in EGF induced EGF receptor down regulation.	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	11	12	13	15
Experiments with an anti-EGF receptor antibody that specifically blocks the binding of EGF to low affinity receptors indicated that EGF induces a shift in the EGF receptor from low to high affinity .	Experiments with an anti-EGF receptor antibody that specifically blocks the binding of EGF to low affinity receptors indicated that EGF induces a shift in the EGF receptor from low to high affinity.	19	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	19	20	25	27
These results suggest that in MCF10A cells , EGF activation of EGFR induces a predominantly intracellular localization .	These results suggest that in MCF10A cells, EGF activation of EGFR induces a predominantly intracellular localization.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	11	12
Moreover , Y27632 retarded the internalization of the EGFR induced by EGF , suggesting that ROCK is involved in the trafficking of the EGFR .	Moreover, Y27632 retarded the internalization of the EGFR induced by EGF, suggesting that ROCK is involved in the trafficking of the EGFR.	5	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	8	9
We also did not find evidence that EGF is more beneficial in tumor samples overexpressing EGFR .	We also did not find evidence that EGF is more beneficial in tumor samples overexpressing EGFR.	7	16	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	15	16
Western blotting revealed that the inhibition of CTSS activities in various cell lines delayed the EGF mediated EGFR degradation process ( XREF_SUPPLEMENTARY ) .	Western blotting revealed that the inhibition of CTSS activities in various cell lines delayed the EGF mediated EGFR degradation process (XREF_SUPPLEMENTARY).	15	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
Whereas on EGF stimulation EGFR homodimers are sorted for degradation , heterodimers fail to recruit Cbl , thereby evading degradation and are instead recycled .	Whereas on EGF stimulation EGFR homodimers are sorted for degradation, heterodimers fail to recruit Cbl, thereby evading degradation and are instead recycled.	2	5	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
In a recent study , a panel of peptides was developed to bind to EGF and block activation of EGFR signaling pathways .	In a recent study, a panel of peptides was developed to bind to EGF and block activation of EGFR signaling pathways.	14	21	block activation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	19	20
These data are consistent with the expected pattern of EGF stimulated EGFR endocytic trafficking .	These data are consistent with the expected pattern of EGF stimulated EGFR endocytic trafficking.	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
We recently showed that EGF induced EGFR internalization is directly controlled by receptor dimerization , rather than kinase activation .	We recently showed that EGF induced EGFR internalization is directly controlled by receptor dimerization, rather than kinase activation.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
It is known that epidermal growth factor ( EGF ) causes downregulation of EGFR by ubiquitination .	It is known that epidermal growth factor (EGF) causes downregulation of EGFR by ubiquitination.	6	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	13	14
Consistent with EGFR activation by nanoconjugated EGF , we detected robust EGFR phosphorylation levels after 25 min of incubation with NP-EGF ( 8 pM , effective EGF concentration = 8 pM x 124 EGF/NP = ~ 1 nM ) ( XREF_FIG ) .	Consistent with EGFR activation by nanoconjugated EGF, we detected robust EGFR phosphorylation levels after 25 min of incubation with NP-EGF (8 pM, effective EGF concentration = 8 pM x 124 EGF/NP = ~ 1 nM) (XREF_FIG).	2	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	2	3
Over-expression of Odin increased EGF induced EGFR trafficking to recycling endosomes and recycling back to the cell surface , and decreased trafficking to lysosomes and degradation .	Over-expression of Odin increased EGF induced EGFR trafficking to recycling endosomes and recycling back to the cell surface, and decreased trafficking to lysosomes and degradation.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
In normal lung tissue , EGF triggers homodimerization of EGFR or heterodimerization with other ErbB members , leading to receptor phosphorylation and activation of downstream effectors such as ERK , PI3K and STAT3 [ XREF_BIBR ] , providing a robust signal for epithelial cell proliferation and survival .	In normal lung tissue, EGF triggers homodimerization of EGFR or heterodimerization with other ErbB members, leading to receptor phosphorylation and activation of downstream effectors such as ERK, PI3K and STAT3 [XREF_BIBR], providing a robust signal for epithelial cell proliferation and survival.	5	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	9	10
Human EGF ( hEGF ) has been reported to bind to and activate EGFR , which leads to activation of the PI3K/AKT/mTOR signaling pathway [ XREF_BIBR ] .	Human EGF (hEGF) has been reported to bind to and activate EGFR, which leads to activation of the PI3K/AKT/mTOR signaling pathway [XREF_BIBR].	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	13	14
However , the mutant of EGFR does not affect EGF induced downstream signaling transduction ( XREF_FIG , EGFR and STAT [ signal transducer and activator of transcription ] phosphorylation ) and/or EGF stimulated EGFR endocytotic degradation .	However, the mutant of EGFR does not affect EGF induced downstream signaling transduction (XREF_FIG, EGFR and STAT [signal transducer and activator of transcription] phosphorylation) and/or EGF stimulated EGFR endocytotic degradation.	31	35	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	31	32	33	34
EGFR is activated by EGF and TGF-alpha on its external domain , and its intracellular TK domain is afterward phosphorylated to initiate downstream cell proliferation , transformation and division .	EGFR is activated by EGF and TGF-alpha on its external domain, and its intracellular TK domain is afterward phosphorylated to initiate downstream cell proliferation, transformation and division.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	0	1
The p-EGFR and p-Erk1/2 were examined to see whether EGFR signaling was activated upon EGF addition and we found that addition of EGF activates EGFR and Erk1/2 signaling ( XREF_FIG ) .	The p-EGFR and p-Erk1/2 were examined to see whether EGFR signaling was activated upon EGF addition and we found that addition of EGF activates EGFR and Erk1/2 signaling (XREF_FIG).	20	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
Epidermal growth factor ( EGF ) binding to the ECD induces dimerization of EGFR , which leads to activation of the cytoplasmic tyrosine kinase domain and subsequent stimulation of cell growth and differentiation [ XREF_BIBR ] .	Epidermal growth factor (EGF) binding to the ECD induces dimerization of EGFR, which leads to activation of the cytoplasmic tyrosine kinase domain and subsequent stimulation of cell growth and differentiation [XREF_BIBR].	2	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	13	14
In order to investigate EREG signaling , we established the anti-EREG antibody that inhibits EGFR downstream signaling stimulated by EREG but not by EGF .	In order to investigate EREG signaling, we established the anti-EREG antibody that inhibits EGFR downstream signaling stimulated by EREG but not by EGF.	14	24	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	14	15
Thus , it is conceivable that EGF activated EGFR in MCF10A cells is signaling predominantly from the endosomes rather than from the membrane .	Thus, it is conceivable that EGF activated EGFR in MCF10A cells is signaling predominantly from the endosomes rather than from the membrane.	6	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
To assess EGFR signaling , cells were treated with 100ng/mL EGF in the presence or absence of the p38 inhibitor SB203580 or with decreasing concentrations of EGF and assessed by western blot .	To assess EGFR signaling, cells were treated with 100ng/mL EGF in the presence or absence of the p38 inhibitor SB203580 or with decreasing concentrations of EGF and assessed by western blot.	2	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	2	3
Specifically , PTPN2 knockdown in T 84 colonic epithelial cells accentuated epidermal growth factor ( EGF ) inhibition of Ca 2+ -stimulated chloride secretion thus promoting EGFR suppression of electrolyte secretion .	Specifically, PTPN2 knockdown in T 84 colonic epithelial cells accentuated epidermal growth factor (EGF) inhibition of Ca 2+ -stimulated chloride secretion thus promoting EGFR suppression of electrolyte secretion.	15	27	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	26	27
EGF like repeats from TSP2 and TSP4 also activated EGFR .	EGF like repeats from TSP2 and TSP4 also activated EGFR.	0	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	9	10
The obtained data demonstrated that pmAb is a specific blocker of EGF mediated EGFR activation , resulting in a significant inhibition of colon cancer cell proliferation in early stages of growth , migration and invasiveness as well as of matrix effector implicated in cancer progression .	The obtained data demonstrated that pmAb is a specific blocker of EGF mediated EGFR activation, resulting in a significant inhibition of colon cancer cell proliferation in early stages of growth, migration and invasiveness as well as of matrix effector implicated in cancer progression.	11	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Phosphorylation rate of EGFR induced by EGF was analyzed in A431 cells in presence of either cetuximab Fab fragment ( CT Fab ) , EGFR binding regions of cetuximab , or MI061 .	Phosphorylation rate of EGFR induced by EGF was analyzed in A431 cells in presence of either cetuximab Fab fragment (CT Fab), EGFR binding regions of cetuximab, or MI061.	1	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	3	4
EGF activates EGF receptor ( EGFR ) tyrosine kinase and stimulates a variety of intracellular signaling pathways .	EGF activates EGF receptor (EGFR) tyrosine kinase and stimulates a variety of intracellular signaling pathways.	0	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	2	4
First , EGF mediated activation of EGFR blunted fusion kinase inhibitor binding and restored fusion kinase signaling complexes .	First, EGF mediated activation of EGFR blunted fusion kinase inhibitor binding and restored fusion kinase signaling complexes.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	6	7
In EGF mediated signaling , which induces EGFR homo and hetero-dimerization , gefitinib in combination with Tam decreased the levels of pAKT and pMAPK much more effectively than lapatinib , a weaker EGFR inhibitor .	In EGF mediated signaling, which induces EGFR homo and hetero-dimerization, gefitinib in combination with Tam decreased the levels of pAKT and pMAPK much more effectively than lapatinib, a weaker EGFR inhibitor.	1	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	7	8
The EGFR pathway is activated by the EGF ligands , Spitz , Keren and Vein , the latter being induced in the surrounding visceral muscles in part under the control of the Janus kinase and signal transducer and activator of transcription ( JAK and STAT ) pathway .	The EGFR pathway is activated by the EGF ligands, Spitz, Keren and Vein, the latter being induced in the surrounding visceral muscles in part under the control of the Janus kinase and signal transducer and activator of transcription (JAK and STAT) pathway.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	1	2
For example , endothelial derived EGF activating EGFR in epidermal cells has been described as a mechanism supporting alveologenesis ( Ding etal .	For example, endothelial derived EGF activating EGFR in epidermal cells has been described as a mechanism supporting alveologenesis (Ding etal.	4	18	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Unlike IGF-1R , EGFR can be stimulated by numerous EGF like factors , which macrophages produce in a tissue and disease specific manner [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Unlike IGF-1R, EGFR can be stimulated by numerous EGF like factors, which macrophages produce in a tissue and disease specific manner [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	10	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	3	4
EGFR in cells was rapidly activated by EGF stimulation within 15min , an effect that was abolished by the EGFR specific SMI gefitinib .	EGFR in cells was rapidly activated by EGF stimulation within 15min, an effect that was abolished by the EGFR specific SMI gefitinib.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	0	1
The EGF stimulation driving the EGFR kinase activity increased the abundance of phosphorylated tyrosines , not all of which associated with the EGFR and thus were unlikely to be involved in FRET ( XREF_FIG a and Supporting Information Fig .	The EGF stimulation driving the EGFR kinase activity increased the abundance of phosphorylated tyrosines, not all of which associated with the EGFR and thus were unlikely to be involved in FRET (XREF_FIG a and Supporting Information Fig.	1	7	driving	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	5	6
We did not see significant changes in the degradation rate of EGFR in HeLa cells treated with 1 ng/ml EGF upon loss of HRS compared with WT cells ( XREF_FIG ) .	We did not see significant changes in the degradation rate of EGFR in HeLa cells treated with 1 ng/ml EGF upon loss of HRS compared with WT cells (XREF_FIG).	9	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	11	12
In A431 epidermoid cells , it was shown that 1,25 ( OH ) 2 D 3 impaired EGF induced EGFR nuclear translocation and , consequently , its binding to AT rich DNA sequences and the transcriptional activation of the cyclin D1 promoter .	In A431 epidermoid cells, it was shown that 1,25 (OH) 2 D 3 impaired EGF induced EGFR nuclear translocation and, consequently, its binding to AT rich DNA sequences and the transcriptional activation of the cyclin D1 promoter.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
However , MET was stabilized by co-expression of EGFR and further stabilized when EGFR was activated by EGF ( XREF_FIG ) .	However, MET was stabilized by co-expression of EGFR and further stabilized when EGFR was activated by EGF (XREF_FIG).	13	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	13	14
The human EGFR is activated by EGF family ligand proteins , such as human EGF and transforming growth factor alpha ( TGFalpha ) [ XREF_BIBR ] .	The human EGFR is activated by EGF family ligand proteins, such as human EGF and transforming growth factor alpha (TGFalpha) [XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	2	3
And since EGF not only activates EGFR but also sodium influx , our data do not exclude that both direct phosphorylation of HDAC6 by EGFR , and sodium influx induced inactivation may contribute to the increase in tubulin acetylation upon activation of EGFR .	And since EGF not only activates EGFR but also sodium influx, our data do not exclude that both direct phosphorylation of HDAC6 by EGFR, and sodium influx induced inactivation may contribute to the increase in tubulin acetylation upon activation of EGFR.	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	6	7
The epidermal growth factor receptor ( EGFR ) is activated by three EGF ligands : Spitz and Keren ( produced within the intestinal epithelium ) and Vein , which is produced by the visceral muscles [ XREF_BIBR , XREF_BIBR ] .	The epidermal growth factor receptor (EGFR) is activated by three EGF ligands : Spitz and Keren (produced within the intestinal epithelium) and Vein, which is produced by the visceral muscles [XREF_BIBR, XREF_BIBR].	1	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	12	13	1	5
EGF stimulates receptor neddylation , which enhances subsequent ubiquitylation , as well as sorting of EGFR for degradation .	EGF stimulates receptor neddylation, which enhances subsequent ubiquitylation, as well as sorting of EGFR for degradation.	0	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	15	16
Manuela Campiglio ' s group had previously shown that FHIT protein levels could be regulated by FHIT proteasome degradation mediated by EGF dependent activation of EGFR family members , including HER2 , whose overexpression is linked to poor prognosis in breast cancer [ XREF_BIBR ] .	Manuela Campiglio 's group had previously shown that FHIT protein levels could be regulated by FHIT proteasome degradation mediated by EGF dependent activation of EGFR family members, including HER2, whose overexpression is linked to poor prognosis in breast cancer [XREF_BIBR].	21	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	25	26
At 0 degrees C , binding of EGF induced tyrosine phosphorlyation of EGFR and , when the cells were subsequently broken by scraping and warmed in the presence of exogenous cytosol , activation of ERK2 occurred .	At 0 degrees C, binding of EGF induced tyrosine phosphorlyation of EGFR and, when the cells were subsequently broken by scraping and warmed in the presence of exogenous cytosol, activation of ERK2 occurred.	5	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	12	13
This study shows that EGF induced EGFR activation is substantially increased by expression of MUC1 in human breast and colon epithelial cells .	This study shows that EGF induced EGFR activation is substantially increased by expression of MUC1 in human breast and colon epithelial cells.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
In a study currently published in Molecular Systems Biology , XREF_BIBR make an important contribution to elucidation of this mechanism by studying the effects of HER2 overexpression on EGF- and HRG mediated signaling of erbB receptors .	In a study currently published in Molecular Systems Biology, XREF_BIBR make an important contribution to elucidation of this mechanism by studying the effects of HER2 overexpression on EGF- and HRG mediated signaling of erbB receptors.	28	35	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF-	EGF-	EGF-	erbB	erbB	erbB	28	29	34	35
Under in vivo conditions , the EGFR can be directly activated by its known ligand epidermal growth factor ( EGF ) , and indirectly by activating PKA or by transactivation mediated by G protein coupled receptors ( GPCRs ) activation or by ouabain .	Under in vivo conditions, the EGFR can be directly activated by its known ligand epidermal growth factor (EGF), and indirectly by activating PKA or by transactivation mediated by G protein coupled receptors (GPCRs) activation or by ouabain.	5	18	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	15	18	6	7
It is well known that EGF induces the internalization of the EGFR , and this is associated with subsequent ubiquitin mediated degradation of the EGFR [ XREF_BIBR ] .	It is well known that EGF induces the internalization of the EGFR, and this is associated with subsequent ubiquitin mediated degradation of the EGFR [XREF_BIBR].	5	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	11	12
Peptides EGFR-L1 and EGFR-L2 were designed to act as a substitute for the natural ligand EGF , which has reported mitogenic and neoangiogenic activity , and has been shown to specifically target EGFR over-expressing tumor cells both in vitro and in vivo .	Peptides EGFR-L1 and EGFR-L2 were designed to act as a substitute for the natural ligand EGF, which has reported mitogenic and neoangiogenic activity, and has been shown to specifically target EGFR over-expressing tumor cells both in vitro and in vivo.	10	35	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	32	33
Others previously have shown that EGF and TGF-alpha induce differential fates of the internalized EGFR , with the former resulting in EGFR degradation and the latter in EGFR recycling .	Others previously have shown that EGF and TGF-alpha induce differential fates of the internalized EGFR, with the former resulting in EGFR degradation and the latter in EGFR recycling.	5	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	14	15
Further , it is not yet known if the EGF like repeats in TN-C can activate the EGFR when present in the intact TN-C sequence .	Further, it is not yet known if the EGF like repeats in TN-C can activate the EGFR when present in the intact TN-C sequence.	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	17	18
As we and others have previously reported , overexpression of Hrs caused an inhibition of EGF induced EGFR degradation in control cells .	As we and others have previously reported, overexpression of Hrs caused an inhibition of EGF induced EGFR degradation in control cells.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
Binding of EGF activates EGFR and initiates signal transduction pathways , including the phosphatidylinositol 3-kinase ( PI3K )-Akt and Ras-Erk , resulting in cell proliferation and survival [ XREF_BIBR ] .	Binding of EGF activates EGFR and initiates signal transduction pathways, including the phosphatidylinositol 3-kinase (PI3K)-Akt and Ras-Erk, resulting in cell proliferation and survival [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
PRL has similar effects on EGF induced EGFR signaling and trafficking in human breast cancer cells [ XREF_BIBR ] .	PRL has similar effects on EGF induced EGFR signaling and trafficking in human breast cancer cells [XREF_BIBR].	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Furthermore , PKM2 promotes the Warburg effect through EGF stimulated EGFR activation and the MAPK signaling pathway .	Furthermore, PKM2 promotes the Warburg effect through EGF stimulated EGFR activation and the MAPK signaling pathway.	6	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
In contrast , treatment of ARPE-19 cells with the dynamin inhibitor dynasore or dyngo4A was without effect on EGF stimulated EGFR ( pY1068 ) , Gab1 ( pY627 ) , or Akt ( pS473 ) phosphorylation ( Supplemental Figure S5 ) .	In contrast, treatment of ARPE-19 cells with the dynamin inhibitor dynasore or dyngo4A was without effect on EGF stimulated EGFR (pY1068), Gab1 (pY627), or Akt (pS473) phosphorylation (Supplemental Figure S5).	1	38	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
Moreover , EGFR on tumor cells was also activated by EGF , which in turn upregulated the VEGF and VEGFR signaling in tumor cells and ultimately led to the tumor growth and migration .	Moreover, EGFR on tumor cells was also activated by EGF, which in turn upregulated the VEGF and VEGFR signaling in tumor cells and ultimately led to the tumor growth and migration.	2	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	2	3
Concentration of EGF in the culture media modulated the anti-proliferative and proapoptotic effects of honokiol and expression and activation of EGFR and its downstream effectors .	Concentration of EGF in the culture media modulated the anti-proliferative and proapoptotic effects of honokiol and expression and activation of EGFR and its downstream effectors.	0	24	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	20	21
We demonstrated that EGF disrupted cell-cell adhesion and caused epithelial-to-mesenchymal transition ( EMT ) in human tumor cells overexpressing EGFR , and also induced caveolin dependent endocytosis of E-cadherin , a cell-cell adhesion protein .	We demonstrated that EGF disrupted cell-cell adhesion and caused epithelial-to-mesenchymal transition (EMT) in human tumor cells overexpressing EGFR, and also induced caveolin dependent endocytosis of E-cadherin, a cell-cell adhesion protein.	3	23	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	19	20
Conventionally , EGFR degradation is a physiological protein recycling mechanism triggered by first EGF stimulation , followed by activation of EGFR Y1045 phosphorylation site and docking of cbl , and then EGFR internalization via the proteosomal degradation pathway .	Conventionally, EGFR degradation is a physiological protein recycling mechanism triggered by first EGF stimulation, followed by activation of EGFR Y1045 phosphorylation site and docking of cbl, and then EGFR internalization via the proteosomal degradation pathway.	10	32	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	31	32
Activation of EGFR by EGF in inflammatory conditions reverses this finding .	Activation of EGFR by EGF in inflammatory conditions reverses this finding.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	2	3
Using immunofluorescence staining , we confirmed that EGF induces activation of EGFR , visualized by its phosphorylation on Tyr845 with the same antibody as used in ChIP assay .	Using immunofluorescence staining, we confirmed that EGF induces activation of EGFR, visualized by its phosphorylation on Tyr845 with the same antibody as used in ChIP assay.	7	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	11	12
To assess the effects of EGFR sialylation on EGFR activation , cells were treated with EGF for up to 30min , and then lysates were immunoblotted for p-EGFR ( representative blot in Fig .	To assess the effects of EGFR sialylation on EGFR activation, cells were treated with EGF for up to 30min, and then lysates were immunoblotted for p-EGFR (representative blot in Fig.	5	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	5	6
Further , in agreement with its ability to bind Calu1 and A431 cells , CL4 strongly inhibited EGF induced activation of EGFR and STAT3 in these cells ( XREF_FIG ) .	Further, in agreement with its ability to bind Calu1 and A431 cells, CL4 strongly inhibited EGF induced activation of EGFR and STAT3 in these cells (XREF_FIG).	17	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	21	22
Analysis of the mechanism underlying this trans-potentiation implied that EGF driven homodimers of ErbB-1 are destined for intracellular degradation , whereas the corresponding heterodimers with ErbB-2 or with ErbB-3 , dissociate in the early endosome .	Analysis of the mechanism underlying this trans-potentiation implied that EGF driven homodimers of ErbB-1 are destined for intracellular degradation, whereas the corresponding heterodimers with ErbB-2 or with ErbB-3, dissociate in the early endosome.	9	15	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-1	ErbB-1	ErbB-1	9	10	13	14
As expected , EGF stimulated EGFR activation was alleviated and , thus , activation of STAT3 and ERK1/2 were decreased in the REP1 knockdown cells compared with siNC transfected cells ( XREF_FIG ) .	As expected, EGF stimulated EGFR activation was alleviated and, thus, activation of STAT3 and ERK1/2 were decreased in the REP1 knockdown cells compared with siNC transfected cells (XREF_FIG).	3	6	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
By activating the EGFR receptor , EGF stimulates the trafficking of TRPM6 channels to the luminal membrane , increasing the reabsorption of Mg 2+ through TRPM6 [ XREF_BIBR ] .	By activating the EGFR receptor, EGF stimulates the trafficking of TRPM6 channels to the luminal membrane, increasing the reabsorption of Mg 2+ through TRPM6 [XREF_BIBR].	3	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	3	4
EGFR was stimulated only by EGF ( 10 nM for 5 min ) .	EGFR was stimulated only by EGF (10 nM for 5 min).	0	8	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	0	1
To determine whether EGF induced EGFR signalling resulting in tamoxifen resistance involves ERalpha or not , we introduced a siRNA targeting ERalpha in both parental MCF7 and MCF7-EGFR cells , which resulted in 70 % ERalpha knock down .	To determine whether EGF induced EGFR signalling resulting in tamoxifen resistance involves ERalpha or not, we introduced a siRNA targeting ERalpha in both parental MCF7 and MCF7-EGFR cells, which resulted in 70% ERalpha knock down.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
EGF Stimulation Causes Redistribution of EGFR to the Cytoskeleton .	EGF Stimulation Causes Redistribution of EGFR to the Cytoskeleton.	0	6	Causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
We also examined the endocytosis of EGFR induced by low-dose EGF , which is dependent on CME , by observing localization of the transfected EGFR-GFP .	We also examined the endocytosis of EGFR induced by low-dose EGF, which is dependent on CME, by observing localization of the transfected EGFR-GFP.	4	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	6	7
For example , E-cadherin-mediated , cell-cell adhesion has been shown to repress EGF induced epidermal growth factor receptor activation .	For example, E-cadherin-mediated, cell-cell adhesion has been shown to repress EGF induced epidermal growth factor receptor activation.	11	18	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	12	13	14	18
EGF binds to the monomeric form of EGFR and induces EGFR dimerization for signaling transduction [ XREF_BIBR ] .	EGF binds to the monomeric form of EGFR and induces EGFR dimerization for signaling transduction [XREF_BIBR].	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	10	11
Such phosphorylation reduces EGF induced EGFR degradation , thus modulating EGFR trafficking and signaling [ XREF_BIBR ] .	Such phosphorylation reduces EGF induced EGFR degradation, thus modulating EGFR trafficking and signaling [XREF_BIBR].	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
GALNT1 knockdown reduces EGF induced EGFR activation and facilitates EGFR degradation .	GALNT1 knockdown reduces EGF induced EGFR activation and facilitates EGFR degradation.	2	6	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Using a combination of mutagenesis and vesicle binding studies , it was revealed that the asymmetric EGFR kinase dimer is critical for the mechanisms of EGF ligand induced activation of EGFR .	Using a combination of mutagenesis and vesicle binding studies, it was revealed that the asymmetric EGFR kinase dimer is critical for the mechanisms of EGF ligand induced activation of EGFR.	25	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	30	31
Although the mechanism by which EGF sensitized cells to cisplatin was not elucidated , we would hypothesize that EGF increased EGFR activation and subsequent degradation .	Although the mechanism by which EGF sensitized cells to cisplatin was not elucidated, we would hypothesize that EGF increased EGFR activation and subsequent degradation.	18	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
Co-incubating EGF stimulated cells with an antibody to the EGFR extracellular domain coupled to gold allows EGFR containing and non-EGFR-containing MVB subpopulations to be distinguished ( XREF_FIG A ) .	Co-incubating EGF stimulated cells with an antibody to the EGFR extracellular domain coupled to gold allows EGFR containing and non-EGFR-containing MVB subpopulations to be distinguished (XREF_FIG A).	0	21	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	16	17
The ErbB inhibitors gefitinib ( 168 nM ) and lapatinib ( 102 nM ) also inhibited EGF induced autophophorylation of the EGFR in LNCaP C4-2B cells .	The ErbB inhibitors gefitinib (168 nM) and lapatinib (102 nM) also inhibited EGF induced autophophorylation of the EGFR in LNCaP C4-2B cells.	16	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	21	22
We next explored whether SWNT functionalized with EGF targets EGFR on HNSCC cultures in vitro ( XREF_FIG ) .	We next explored whether SWNT functionalized with EGF targets EGFR on HNSCC cultures in vitro (XREF_FIG).	5	12	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
EGF stimulation induced pEGFR in all cell lines , while pEGFR was undetectable and weak in the absence of EGF .	EGF stimulation induced pEGFR in all cell lines, while pEGFR was undetectable and weak in the absence of EGF.	0	4	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	0	1	3	4
Overexpression of EGFR increased the MET half-life from 3.5 to 5.5 hours , while EGF stimulation of EGFR further increased the half-life to 6.3 hours ( XREF_FIG ) .	Overexpression of EGFR increased the MET half-life from 3.5 to 5.5 hours, while EGF stimulation of EGFR further increased the half-life to 6.3 hours (XREF_FIG).	14	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	17	18
To illustrate the use of SteinerNet , we applied it to phosphoproteomic data from the EGF stimulated ERBB pathway .	To illustrate the use of SteinerNet, we applied it to phosphoproteomic data from the EGF stimulated ERBB pathway.	8	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ERBB	ERBB	ERBB	15	16	17	18
Thus , we conclude that MATN2 binds to , but does not activate the EGFR ; rather MATN2 potentiates EGFR activation stimulated by EGF .	Thus, we conclude that MATN2 binds to, but does not activate the EGFR; rather MATN2 potentiates EGFR activation stimulated by EGF.	19	24	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	19	20
Flow cytometry experiments show that GRK2 overexpression has no effect on EGF induced EGFR internalization , however , it increases agonist induced G protein coupled delta opioid receptor internalization by approximately 40 % ( P < 0.01 ) .	Flow cytometry experiments show that GRK2 overexpression has no effect on EGF induced EGFR internalization, however, it increases agonist induced G protein coupled delta opioid receptor internalization by approximately 40% (P < 0.01).	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Expression of this receptor in EGF receptor deficient , PDGF responsive NIH 3T3 cells allows the activation of PDGF signalling pathways by EGF .	Expression of this receptor in EGF receptor deficient, PDGF responsive NIH 3T3 cells allows the activation of PDGF signalling pathways by EGF.	5	23	allows	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	22	23	5	7
EGF stimulation did not affect the LAPTM4B interaction with EGFR-KD ( XREF_FIG ) that is not activated by EGF ( XREF_SUPPLEMENTARY ) .	EGF stimulation did not affect the LAPTM4B interaction with EGFR-KD (XREF_FIG) that is not activated by EGF (XREF_SUPPLEMENTARY).	4	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR-KD	EGFR-KD	EGFR-KD	18	19	9	10
EGF induced EGF receptor degradation was slower in F3 cells ( t1/2 = 4 h ) than in wild-type cells ( t1/2 = 1 h ) .	EGF induced EGF receptor degradation was slower in F3 cells (t1/2 = 4 h) than in wild-type cells (t1/2 = 1 h).	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	2	4
In this study , we showed that activation of EGFR by EGF in HNSCC cell line SCC10A enhanced cell migration and invasion , and induced loss of epitheloid phenotype in parallel with downregulation of E-cadherin and upregulation of N-cadherin and vimentin , indicating that EGFR promoted SCC10A cell migration and invasion possibly by an epithelial to mesenchymal transition ( EMT )-like phenotype change .	In this study, we showed that activation of EGFR by EGF in HNSCC cell line SCC10A enhanced cell migration and invasion, and induced loss of epitheloid phenotype in parallel with downregulation of E-cadherin and upregulation of N-cadherin and vimentin, indicating that EGFR promoted SCC10A cell migration and invasion possibly by an epithelial to mesenchymal transition (EMT)-like phenotype change.	7	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	9	10
Pretreatment of A431 or NA cells with the EGFR inhibitor CGP52411 prevented EGF induced actin cytoskeletal rearrangements and cell rounding ( data not shown ) indicating that EGF stimulated EGFR tyrosine kinase activity was required to initiate these rapid changes .	Pretreatment of A431 or NA cells with the EGFR inhibitor CGP52411 prevented EGF induced actin cytoskeletal rearrangements and cell rounding (data not shown) indicating that EGF stimulated EGFR tyrosine kinase activity was required to initiate these rapid changes.	27	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	29	30
While structural and biochemical studies identified this EGF induced allosteric activation , imaging collective EGFR activation in cells and molecular dynamics simulations pointed at additional catalytic EGFR activation mechanisms .	While structural and biochemical studies identified this EGF induced allosteric activation, imaging collective EGFR activation in cells and molecular dynamics simulations pointed at additional catalytic EGFR activation mechanisms.	6	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	14	15
Furthermore , it has been shown that high or low doses of extracellular EGF induce EGF and EGFR endocytosis in non clathrin or clathrin coated vesicles , respectively .	Furthermore, it has been shown that high or low doses of extracellular EGF induce EGF and EGFR endocytosis in non clathrin or clathrin coated vesicles, respectively.	10	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	17	18
EGF stimulation promotes the formation of large ILVs in EGFR containing MVBs .	EGF stimulation promotes the formation of large ILVs in EGFR containing MVBs.	0	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	9	10
In HeLa cells intoxicated with ExoS G + or ExoS A + , EGF activated the internalization of the EGFR , indicating movement of the EGFR off the plasma membrane and into the endocytic pathway .	In HeLa cells intoxicated with ExoS G + or ExoS A +, EGF activated the internalization of the EGFR, indicating movement of the EGFR off the plasma membrane and into the endocytic pathway.	13	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	19	20
Exogenous EGF stimulated EGFR , ERK1/2 , and Akt activation and the EGFR inhibitor blocked phosphorylation of ERK1/2 and Akt .	Exogenous EGF stimulated EGFR, ERK1/2, and Akt activation and the EGFR inhibitor blocked phosphorylation of ERK1/2 and Akt.	0	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
In the absence of p38 activity , EGF fails to stimulate the ubiquitin ligase Cbl or ubiquitinylation of EGFR , and internalized EGFR accumulates in intracellular vesicles containing caveolin-1 .	In the absence of p38 activity, EGF fails to stimulate the ubiquitin ligase Cbl or ubiquitinylation of EGFR, and internalized EGFR accumulates in intracellular vesicles containing caveolin-1.	7	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	18	19
EGF stimulation elicited co-localization between EGFR and the early endosome antigen 1 ( EEA1 ) , whereas dynamin inhibition impaired EGF induced EGFR endocytosis , as confirmed by the presence of EGFR clusters at the cell surface and a reduction in the overlap between the EGFR and EEA1 signals ) .	EGF stimulation elicited co-localization between EGFR and the early endosome antigen 1 (EEA1), whereas dynamin inhibition impaired EGF induced EGFR endocytosis, as confirmed by the presence of EGFR clusters at the cell surface and a reduction in the overlap between the EGFR and EEA1 signals).	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
EGF mediated EGFR and ERK signaling pathway promotes germinative cell proliferation in Echinococcus multilocularis that contributes to larval growth and development .	EGF mediated EGFR and ERK signaling pathway promotes germinative cell proliferation in Echinococcus multilocularis that contributes to larval growth and development.	0	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
In conclusion , our findings prove that Lycorine inhibits EGF activated EGFR kinase activity .	In conclusion, our findings prove that Lycorine inhibits EGF activated EGFR kinase activity.	8	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
To examine the interaction between endogenous Ankrd 13 proteins and EGFR , untransfected HeLa cells were treated with EGF for 5 or 30 min , and EGFR was immunoprecipitated from the cells .	To examine the interaction between endogenous Ankrd 13 proteins and EGFR, untransfected HeLa cells were treated with EGF for 5 or 30 min, and EGFR was immunoprecipitated from the cells.	3	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	10	11
In addition , few studies have shown that EGF itself is the growth factor that is shed and is responsible for transactivation of the EGF receptor .	In addition, few studies have shown that EGF itself is the growth factor that is shed and is responsible for transactivation of the EGF receptor.	8	26	is responsible for transactivation	Positive_activation_copula_1	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	8	9	24	26
The present study also demonstrated that the EGFR signaling pathway could be activated by the addition of EGF in the parental UROtsa cells and the As +3 -transformed isolates .	The present study also demonstrated that the EGFR signaling pathway could be activated by the addition of EGF in the parental UROtsa cells and the As +3 -transformed isolates.	7	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	7	8
We detected the effects of these inhibitors on EGFR signalling induced by EGF in H9c2 cells .	We detected the effects of these inhibitors on EGFR signalling induced by EGF in H9c2 cells.	8	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	8	9
Thirty minutes after the addition of dacomitinib , EGFR was stimulated by the addition of 20 ng/ml recombinant human EGF ( Shenandoah Biotechnology ) .	Thirty minutes after the addition of dacomitinib, EGFR was stimulated by the addition of 20 ng/ml recombinant human EGF (Shenandoah Biotechnology).	8	20	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	8	9
Thus , EGF may stimulate Src kinase to phosphorylate Tyr 52 of RACK1 , thereby blocking the interaction between RACK1 , CAR , and PP2Ac ; however , phenobarbital represses this mechanism by blocking the EGF induced activation of EGFR .	Thus, EGF may stimulate Src kinase to phosphorylate Tyr 52 of RACK1, thereby blocking the interaction between RACK1, CAR, and PP2Ac; however, phenobarbital represses this mechanism by blocking the EGF induced activation of EGFR.	34	40	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	35	36	39	40
Here , we examined EGF mediated EGFR internalization and determined that it occurred more rapidly in JAKi treated cells compared to vehicle treated cells ( XREF_FIG and XREF_SUPPLEMENTARY ) , suggesting that JAKi may increase the abundance of specifically wild-type EGFR .	Here, we examined EGF mediated EGFR internalization and determined that it occurred more rapidly in JAKi treated cells compared to vehicle treated cells (XREF_FIG and XREF_SUPPLEMENTARY), suggesting that JAKi may increase the abundance of specifically wild-type EGFR.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
There was no effect on EGF and HB-EGF activation of EGFR [ XREF_FIG ] .	There was no effect on EGF and HB-EGF activation of EGFR [XREF_FIG].	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	10	11
Activation of EGFR by EGF ( 100ng/ml ) or 10 % FBS treatment was inhibited by MHYs in Caco2 and HT29 cells .	Activation of EGFR by EGF (100ng/ml) or 10% FBS treatment was inhibited by MHYs in Caco2 and HT29 cells.	0	12	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	2	3
Further , we analyzed whether VJ overcome EGF induced EGFR activation , both cell lines treated with EGF and EGFR activation were measured by western blot analysis .	Further, we analyzed whether VJ overcome EGF induced EGFR activation, both cell lines treated with EGF and EGFR activation were measured by western blot analysis.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Cancer cell binding and inhibition of EGF mediated EGFR tyrosine phosphorylation by mAbs .	Cancer cell binding and inhibition of EGF mediated EGFR tyrosine phosphorylation by mAbs.	2	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
The E5 mediated , sorbitol dependent increase in ERK1/2 activation is EGF independent and is only partially inhibited by tyrphostin AG1478 , which is known to inhibit specifically EGF receptor activation .	The E5 mediated, sorbitol dependent increase in ERK1/2 activation is EGF independent and is only partially inhibited by tyrphostin AG1478, which is known to inhibit specifically EGF receptor activation.	11	30	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	11	12	28	30
Therefore , it was highly likely that EGF induced EGFR dimerization and endocytosis which in turn , reduced the interaction of EGFR to delta-catenin .	Therefore, it was highly likely that EGF induced EGFR dimerization and endocytosis which in turn, reduced the interaction of EGFR to delta-catenin.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
These results strongly suggest that the inhibition of ROCK delayed the internalization of the EGFR induced by EGF in Panc1 cells .	These results strongly suggest that the inhibition of ROCK delayed the internalization of the EGFR induced by EGF in Panc1 cells.	11	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	14	15
After 10 min of EGF stimulation EGFR was localized in the nucleus in Scramble siRNA treated cells , but was excluded from the nucleus in the CHC2 siRNA treated cells ( XREF_FIG ) .	After 10 min of EGF stimulation EGFR was localized in the nucleus in Scramble siRNA treated cells, but was excluded from the nucleus in the CHC2 siRNA treated cells (XREF_FIG).	2	20	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
We also found that activation of EGFR by EGF correlated with a reduction in the percentage of HPCs in the S phase of mitosis ( XREF_SUPPLEMENTARY ) , suggesting that changes in cell cycle parameters may also contribute to inhibition of mobilization by EGF XREF_BIBR , XREF_BIBR .	We also found that activation of EGFR by EGF correlated with a reduction in the percentage of HPCs in the S phase of mitosis (XREF_SUPPLEMENTARY), suggesting that changes in cell cycle parameters may also contribute to inhibition of mobilization by EGF XREF_BIBR, XREF_BIBR.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	6	7
EGF activated EGFR kinase was not able to restore insulin dependent rapid endocytosis to InsR .	EGF activated EGFR kinase was not able to restore insulin dependent rapid endocytosis to InsR.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Receptor-receptor interaction has been proposed as an essential initial mechanism for EGF dependent activation of EGF receptor kinase ( EGF-RK ) ( Schlessinger , J. ( 1988 ) Trends Biochem .	Receptor-receptor interaction has been proposed as an essential initial mechanism for EGF dependent activation of EGF receptor kinase (EGF-RK) (Schlessinger, J. (1988) Trends Biochem.	11	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	11	12	15	17
EGF is known to cause EGFR receptor internalization and recycling in epithelial cells .	EGF is known to cause EGFR receptor internalization and recycling in epithelial cells.	0	7	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
XREF_FIG shows that at l0 ng/ml , EGF strongly induced association of EGFR with Shc and Src , which was significantly decreased when treated with 500 ng/ml of EGF ( XREF_FIG ) .	XREF_FIG shows that at l0 ng/ml, EGF strongly induced association of EGFR with Shc and Src, which was significantly decreased when treated with 500 ng/ml of EGF (XREF_FIG).	7	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	12	13
In contrast to EGF induced EGFR down-regulation , the antibody combination efficiently degraded the EGFR without initiating downstream proliferative signaling .	In contrast to EGF induced EGFR down-regulation, the antibody combination efficiently degraded the EGFR without initiating downstream proliferative signaling.	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
The G i alphaPCR mediated shedding of HB-EGF is PTX sensitive , whereas EGFR mediated activation of the PI3K/Akt/mTORC1 and ERK1/2 pathways by EGF is PTX insensitive [ XREF_BIBR , XREF_BIBR ] .	The G i alphaPCR mediated shedding of HB-EGF is PTX sensitive, whereas EGFR mediated activation of the PI3K/Akt/mTORC1 and ERK1/2 pathways by EGF is PTX insensitive [XREF_BIBR, XREF_BIBR].	13	24	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	13	14
Our results showed that CHAG suppressed the migration and invasion of ovarian cancer cells , and delayed the development OC implantation tumor through blocking EGF stimulated activation of EGFR and its downstream signal transduction .	Our results showed that CHAG suppressed the migration and invasion of ovarian cancer cells, and delayed the development OC implantation tumor through blocking EGF stimulated activation of EGFR and its downstream signal transduction.	24	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	28	29
Consistent with this , our previous finding also suggests the association of AnxA2 and EGFR in the membrane complex and knock-down of AnxA2 inhibits EGF induced EGFR mediated downstream signalling .	Consistent with this, our previous finding also suggests the association of AnxA2 and EGFR in the membrane complex and knock-down of AnxA2 inhibits EGF induced EGFR mediated downstream signalling.	24	27	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
Both EGF and TGFbeta mediate their effects through activation of the epidermal growth factor receptor ( EGFR ) , a member of the ErbB family of receptor tyrosine kinases ; EGF activates EGFR by binding directly to the receptor while TGFbeta1 activates or inhibits EGFR indirectly via a signaling pathway XREF_BIBR .	Both EGF and TGFbeta mediate their effects through activation of the epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases; EGF activates EGFR by binding directly to the receptor while TGFbeta1 activates or inhibits EGFR indirectly via a signaling pathway XREF_BIBR.	30	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	30	31	32	33
We found that EGF induced EGFR endocytosis still occurs during M phase , but follows different kinetics .	We found that EGF induced EGFR endocytosis still occurs during M phase, but follows different kinetics.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
In this study , the removal of surface sialylation facilitated the formation of EGF induced EGFR dimers .	In this study, the removal of surface sialylation facilitated the formation of EGF induced EGFR dimers.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Previous studies have demonstrated that the autocrine expression of EGF in HMEC can lead to constant activation of the EGFR , which can drive in vitro cellular motility but have no effect of proliferation rates even though the EGFR gets downregulated as a consequence of receptor activation .	Previous studies have demonstrated that the autocrine expression of EGF in HMEC can lead to constant activation of the EGFR, which can drive in vitro cellular motility but have no effect of proliferation rates even though the EGFR gets downregulated as a consequence of receptor activation.	7	29	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	EGF	expression of EGF	egf	EGFR	EGFR	egfr	9	10	19	20
Gefitinib suppresses EGF mediated EGFR and ERK activation in MPNSTs .	Gefitinib suppresses EGF mediated EGFR and ERK activation in MPNSTs.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
EGFR is activated by the ligand EGF which in turn activates multiple cell signaling pathways and modulates tumor cell division , invasion and apoptosis [ XREF_BIBR ] .	EGFR is activated by the ligand EGF which in turn activates multiple cell signaling pathways and modulates tumor cell division, invasion and apoptosis [XREF_BIBR].	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	0	1
Similarly , we found that EGF- or IR induced association of EGFR and histone H4 requires the tyrosine kinase activity of EGFR ( XREF_FIG ) .	Similarly, we found that EGF- or IR induced association of EGFR and histone H4 requires the tyrosine kinase activity of EGFR (XREF_FIG).	5	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF-	EGF-	EGF-	EGFR	EGFR	EGFR	5	6	21	22
We also tested our hypothesis that encapsulated EGF in exosomes releases EGF from endosomes after cellular uptake , and recycled EGF stimulates the EGFR , leading to an enhanced macropinocytosis pathway and exosome uptake by cells .	We also tested our hypothesis that encapsulated EGF in exosomes releases EGF from endosomes after cellular uptake, and recycled EGF stimulates the EGFR, leading to an enhanced macropinocytosis pathway and exosome uptake by cells.	19	24	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	23	24
Similarly to direct activation of EGFR by EGF [ XREF_BIBR ] , the cholinergic EGFR transactivation and its downstream signaling to MAP kinases also depends on flotillin-1 .	Similarly to direct activation of EGFR by EGF [XREF_BIBR], the cholinergic EGFR transactivation and its downstream signaling to MAP kinases also depends on flotillin-1.	3	9	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	5	6
Because EGF induces internalization and degradation of the Ala 654 EGF receptor , at least two independent mechanisms can serve to signal loss of functional EGF receptors .	Because EGF induces internalization and degradation of the Ala 654 EGF receptor, at least two independent mechanisms can serve to signal loss of functional EGF receptors.	1	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	1	2	10	12
These results are consistent with reports that EGF treatment triggers transport of the EGFR to lysosomes and subsequent receptor degradation .	These results are consistent with reports that EGF treatment triggers transport of the EGFR to lysosomes and subsequent receptor degradation.	7	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	13	14
Because phenobarbital antagonized EGF activation of EGFR ( XREF_FIG ) and repressed Src kinase mediated phosphorylation of RACK1 ( XREF_FIG ) , we next investigated whether phenobarbital directly bound to EGFR .	Because phenobarbital antagonized EGF activation of EGFR (XREF_FIG) and repressed Src kinase mediated phosphorylation of RACK1 (XREF_FIG), we next investigated whether phenobarbital directly bound to EGFR.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	6	7
EGF treatment of NIH3T3 cells overexpressing both EGFR and ZNF216 ( NIH3T3-EGFR and ZNF216 ) , induced a long lasting activation of EGFR in the cytosolic fraction and an accumulation of phosphorylated EGFR ( pEGFR ) more in the nuclear than in the cytosolic fraction compared to NIH3T3-EGFR cells .	EGF treatment of NIH3T3 cells overexpressing both EGFR and ZNF216 (NIH3T3-EGFR and ZNF216), induced a long lasting activation of EGFR in the cytosolic fraction and an accumulation of phosphorylated EGFR (pEGFR) more in the nuclear than in the cytosolic fraction compared to NIH3T3-EGFR cells.	0	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	22	23
This report is the first to show that overexpression of Cav-1significantly inhibits the proliferation , migration , and invasion potential of SW480 cells , possibly through reducing EGF induced EGFR activation .	This report is the first to show that overexpression of Cav-1significantly inhibits the proliferation, migration, and invasion potential of SW480 cells, possibly through reducing EGF induced EGFR activation.	27	30	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	29	30
Both groups concluded that the bulk of EGF induced EGFR signaling occurs through multiple pathways initiated mostly by receptors at the plasma membrane .	Both groups concluded that the bulk of EGF induced EGFR signaling occurs through multiple pathways initiated mostly by receptors at the plasma membrane.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
The binding of EGF causes a rapid , temperature sensitive dimerization of the EGF receptor .	The binding of EGF causes a rapid, temperature sensitive dimerization of the EGF receptor.	1	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	3	4	13	15
We found that EGF induced activation of EGFR in A549 cells activated MMP9 , resulting in an increase in cancer invasiveness .	We found that EGF induced activation of EGFR in A549 cells activated MMP9, resulting in an increase in cancer invasiveness.	3	10	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	7	8
We decided to investigate whether the EGF like repeats in tenascin-C activate EGFR , as tenascin-C is restricted to sites of tissue development and regeneration and is up-regulated in tumor cells , all of which are sites of EGFR functioning .	We decided to investigate whether the EGF like repeats in tenascin-C activate EGFR, as tenascin-C is restricted to sites of tissue development and regeneration and is up-regulated in tumor cells, all of which are sites of EGFR functioning.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	12	13
In order to test whether the peptide has an effect on EGFR levels , MDA-MB-231 cells were treated with EGF for two minutes followed by treatment with 10 microM TE-64562 for 5 , 10 , 30 , 60 and 180 minutes , then analyzed for the presence of EGFR .	In order to test whether the peptide has an effect on EGFR levels, MDA-MB-231 cells were treated with EGF for two minutes followed by treatment with 10 microM TE-64562 for 5, 10, 30, 60 and 180 minutes, then analyzed for the presence of EGFR.	11	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	11	12
EGF stimulation causes a rapid ( 0-5 min ) increase in EGFR concentration in the insoluble cytoskeletal fraction , which is sustained with receptor activation ( XREF_FIG ) .	EGF stimulation causes a rapid (0-5 min) increase in EGFR concentration in the insoluble cytoskeletal fraction, which is sustained with receptor activation (XREF_FIG).	0	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	11	12
ROR1 kinases activity was thought to be required to fully sustain downstream signaling of EGF stimulated EGFR .	ROR1 kinases activity was thought to be required to fully sustain downstream signaling of EGF stimulated EGFR.	12	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
Although S100A7 has been reported to increase EGF mRNA levels in MDA-MB-231 cells XREF_BIBR , not much is known about its role in EGF induced EGFR signaling .	Although S100A7 has been reported to increase EGF mRNA levels in MDA-MB-231 cells XREF_BIBR, not much is known about its role in EGF induced EGFR signaling.	18	26	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	25	26
Already , 10 ng/ml EGF stimulation was sufficient to increase EGFP-EGFR transport efficiency by 1.4-fold .	Already, 10 ng/ml EGF stimulation was sufficient to increase EGFP-EGFR transport efficiency by 1.4-fold.	4	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFP-EGFR	EGFP-EGFR	EGFP-EGFR	4	5	10	11
Endogenous Spry1 constitutively anchors to the cell membrane , stabilizes EGFR protein , or facilitates EGF mediated EGFR activation and EGFR/Grb2/Gab1/Shp2 cascade complexes formation and signaling .	Endogenous Spry1 constitutively anchors to the cell membrane, stabilizes EGFR protein, or facilitates EGF mediated EGFR activation and EGFR/Grb2/Gab1/Shp2 cascade complexes formation and signaling.	14	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
The reconstituted EGFR tyrosine kinase was well activated by EGF .	The reconstituted EGFR tyrosine kinase was well activated by EGF.	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	2	3
Binding of the EGF ligand induces EGFR dimerization and receptor aggregation in the plasma membrane .	Binding of the EGF ligand induces EGFR dimerization and receptor aggregation in the plasma membrane.	3	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	6	7
In contrast , EGF induces a strong increase in the binding of the EGF receptor to both Eps15 and alpha-adaptin .	In contrast, EGF induces a strong increase in the binding of the EGF receptor to both Eps15 and alpha-adaptin.	3	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	3	4	13	15
These cells displayed EGF mediated EGFR homodimerization , increased basal ligand independent EGFR dimerization and , HRGbeta1 mediated HER2-HER3 heterodimerization comparable to 20GS cells .	These cells displayed EGF mediated EGFR homodimerization, increased basal ligand independent EGFR dimerization and, HRGbeta1 mediated HER2-HER3 heterodimerization comparable to 20GS cells.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
These two effects are combined in the case of heparin binding epidermal growth factor ( HB-EGF ) , which activates both EGFR and ERBB4 at high affinity and similarly leads to cetuximab resistance XREF_BIBR .	These two effects are combined in the case of heparin binding epidermal growth factor (HB-EGF), which activates both EGFR and ERBB4 at high affinity and similarly leads to cetuximab resistance XREF_BIBR.	11	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	11	14	21	22
In this report , we show that growth-inhibitory concentrations of the dietary phytochemical resveratrol suppress EGFR dependent Erk1/2 activation pathways stimulated by EGF and phorbol ester ( 12- O -tetradecanoyl phorbol 13-acetate , TPA ) in human AI PrCa PC-3 cells in vitro .	In this report, we show that growth-inhibitory concentrations of the dietary phytochemical resveratrol suppress EGFR dependent Erk1/2 activation pathways stimulated by EGF and phorbol ester (12- O -tetradecanoyl phorbol 13-acetate, TPA) in human AI PrCa PC-3 cells in vitro.	14	25	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	15	16
It should be noted that consistent with previous studies , pretreatment with monensin also blocked EGF induced EGFR degradation , whereas chloroquine had negligible effects on AR induced EGFR recycling ( XREF_SUPPLEMENTARY ) .	It should be noted that consistent with previous studies, pretreatment with monensin also blocked EGF induced EGFR degradation, whereas chloroquine had negligible effects on AR induced EGFR recycling (XREF_SUPPLEMENTARY).	15	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGF induced EGFR	egfr	EGFR	EGFR	egfr	17	18	28	29
EGFR antagonists target the EGFR family , also known as the ErbB protein family , which is comprised of four receptor tyrosine kinases ( ErbB1/EGFR/HER1 , ErbB2/HER2/neu , ErbB3 and HER3 and ErbB4 and HER4 ) [ XREF_BIBR ] .	EGFR antagonists target the EGFR family, also known as the ErbB protein family, which is comprised of four receptor tyrosine kinases (ErbB1/EGFR/HER1, ErbB2/HER2/neu, ErbB3 and HER3 and ErbB4 and HER4) [XREF_BIBR].	0	5	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFR	EGFR	EGFR	0	1	4	5
IGF-I or high-dose insulin transmodulates keratinocyte EGF receptor expression via the IGF-I receptor in a dose- and time dependent manner , increasing EGF receptor binding an average of 1.8 times up to a maximum of fourfold without altering EGF binding affinity .	IGF-I or high-dose insulin transmodulates keratinocyte EGF receptor expression via the IGF-I receptor in a dose- and time dependent manner, increasing EGF receptor binding an average of 1.8 times up to a maximum of fourfold without altering EGF binding affinity.	6	24	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor expression	egf receptor	EGF receptor	EGF receptor	egf receptor	6	8	22	24
Montgomery found that the EGFR specific quinazoline inhibitor AG1478 at a concentration of 0.1 muM stimulated colony formation of EGFRvIII expressing cells ( Montgomery , 2002 ) .	Montgomery found that the EGFR specific quinazoline inhibitor AG1478 at a concentration of 0.1 muM stimulated colony formation of EGFRvIII expressing cells (Montgomery, 2002).	4	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	4	5	19	20
We suggest that the prolonged stress associated with PTX treatment stimulates the p38 MAPK and p53 network and induces EGFR transcription , which activates the EGFR pathway and PTX resistance in NSCLC .	We suggest that the prolonged stress associated with PTX treatment stimulates the p38 MAPK and p53 network and induces EGFR transcription, which activates the EGFR pathway and PTX resistance in NSCLC.	19	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR transcription	egfr	EGFR	EGFR	egfr	19	20	25	26
EGFR expression identifies tumor initiating cells with different tumorigenic capacities in human glioblastoma multiforme XREF_BIBR ; enforced EGFR expression in CSCs enhanced their tumorigenic potential , while ectopic EGFR expression increased the in vivo tumorigenic capacity of EGFR negative CSC lines .	EGFR expression identifies tumor initiating cells with different tumorigenic capacities in human glioblastoma multiforme XREF_BIBR; enforced EGFR expression in CSCs enhanced their tumorigenic potential, while ectopic EGFR expression increased the in vivo tumorigenic capacity of EGFR negative CSC lines.	28	38	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR expression	egfr	EGFR	EGFR	egfr	28	29	37	38
Other EGFR downstream signals activated constitutively by EGFRvIII were not obviously affected .	Other EGFR downstream signals activated constitutively by EGFRvIII were not obviously affected.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	7	8	1	2
Our results found that curcumin can decrease EGFR protein expression might through down-regulated EGFR protein in gefitinib resistant NSCLC cells .	Our results found that curcumin can decrease EGFR protein expression might through down-regulated EGFR protein in gefitinib resistant NSCLC cells.	4	14	down-regulated	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	EGFR	curcumin can decrease EGFR protein expression	egfr	EGFR	EGFR	egfr	7	8	13	14
Core fucosylation of the EGF receptor can clearly promote EGFR signaling , yet other forms of glycosylation inhibit EGFR signaling .	Core fucosylation of the EGF receptor can clearly promote EGFR signaling, yet other forms of glycosylation inhibit EGFR signaling.	4	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	EGFR	EGFR	EGFR	4	6	9	10
In further support of this strategy , a recent study shows that intracranial delivery of toxin conjugated scFv from an EGFR antibody targeting both wtEGFR and EGFRvIII results in strong anti-neoplastic effects against intracranial glioblastoma xenografts expressing wtEGFR or co-expressing wtEGFR and EGFRvIII .	In further support of this strategy, a recent study shows that intracranial delivery of toxin conjugated scFv from an EGFR antibody targeting both wtEGFR and EGFRvIII results in strong anti-neoplastic effects against intracranial glioblastoma xenografts expressing wtEGFR or co-expressing wtEGFR and EGFRvIII.	20	27	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	20	21	26	27
Structural changes in extracellular EGFR are hypothesized to affect the intracellular domain conformation and the ATP pocket leading to the constitutive activation by EGFRvIII and its resistance to EGFR targeted therapy by monoclonal antibodies against the extracellular domain of EGFR .	Structural changes in extracellular EGFR are hypothesized to affect the intracellular domain conformation and the ATP pocket leading to the constitutive activation by EGFRvIII and its resistance to EGFR targeted therapy by monoclonal antibodies against the extracellular domain of EGFR.	17	29	leading	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	23	24	28	29
Since EGFRvIII and c-Met may signal cooperatively to drive tumor growth , U87GM cells expressing EGFRvIII were treated with the EGFR kinase inhibitor AG1478 and the c-Met inhibitor PHA665752 .	Since EGFRvIII and c-Met may signal cooperatively to drive tumor growth, U87GM cells expressing EGFRvIII were treated with the EGFR kinase inhibitor AG1478 and the c-Met inhibitor PHA665752.	14	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	20	21	15	16
EGFR activation was also examined and here the BCA2 siRNA increased EGFR phosphorylation and promoted association of EGFR with the signalling protein SHC1 .	EGFR activation was also examined and here the BCA2 siRNA increased EGFR phosphorylation and promoted association of EGFR with the signalling protein SHC1.	8	18	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	BCA2 siRNA increased EGFR phosphorylation	egfr	EGFR	EGFR	egfr	11	12	17	18
We examined the glycosylation status of EGFR protein using Western blotting in HCT116 and HT-29 cells with tunicamycin treatment , and observed that tunicamycin reduced the total EGFR expression and decreased the molecular weight of EGFR compared to control .	We examined the glycosylation status of EGFR protein using Western blotting in HCT116 and HT-29 cells with tunicamycin treatment, and observed that tunicamycin reduced the total EGFR expression and decreased the molecular weight of EGFR compared to control.	23	36	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	tunicamycin reduced the total EGFR expression	egfr	EGFR	EGFR	egfr	27	28	35	36
To strengthen these findings , we then modulated EGFR function genetically expressing either EGFRvIII or CD533 that would stimulate or block EGFR signaling , respectively .	To strengthen these findings, we then modulated EGFR function genetically expressing either EGFRvIII or CD533 that would stimulate or block EGFR signaling, respectively.	11	22	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	13	14	21	22
We propose that Grb2 mediates transient anchoring of the EGFR to an Eps15 containing molecular complex at the rim of coated pits and that Cbl induced ubiquitination of the EGFR allows relocation of EGFR from the rim to the center of clathrin coated pits .	We propose that Grb2 mediates transient anchoring of the EGFR to an Eps15 containing molecular complex at the rim of coated pits and that Cbl induced ubiquitination of the EGFR allows relocation of EGFR from the rim to the center of clathrin coated pits.	24	34	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Cbl induced ubiquitination of the EGFR	egfr	EGFR	EGFR	egfr	29	30	33	34
Analysis of human glioblastoma tumors demonstrated alignment among EGFR , EGFRvIII and STAT signaling in tumors , supporting a model in which EGFR activation of EGFRvIII leads to transphosphorylation of both kinases , converging on STAT signaling .	Analysis of human glioblastoma tumors demonstrated alignment among EGFR, EGFRvIII and STAT signaling in tumors, supporting a model in which EGFR activation of EGFRvIII leads to transphosphorylation of both kinases, converging on STAT signaling.	22	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	22	23	25	26
Moreover , a recent study in a model of colitis associated colon cancer showed that ginseng reduced levels of phospho-active EGFR and phospho-active ErbB2 as well as ERK , a down stream effector of EGFR , indicating ginseng could suppress EGFR signals in colonic tumorigenesis [ XREF_BIBR ] .	Moreover, a recent study in a model of colitis associated colon cancer showed that ginseng reduced levels of phospho-active EGFR and phospho-active ErbB2 as well as ERK, a down stream effector of EGFR, indicating ginseng could suppress EGFR signals in colonic tumorigenesis [XREF_BIBR].	17	41	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	levels of phospho-active EGFR	egfr	EGFR	EGFR	egfr	20	21	40	41
In our study there was tumor overexpression of EGFR ( 2 times more ) and KRAS ( 5 times more ) compared to tumor-free lungs .	In our study there was tumor overexpression of EGFR (2 times more) and KRAS (5 times more) compared to tumor-free lungs.	4	18	was tumor overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	overexpression of EGFR	egfr	EGFR	EGFR	egfr	8	9	8	9
It is known that EGFR overexpression results in tyrosine phosphorylation and constitutive activation of the EGFR .	It is known that EGFR overexpression results in tyrosine phosphorylation and constitutive activation of the EGFR.	4	16	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	EGFR	EGFR	egfr	4	5	15	16
Using chemical genetic approaches , we found that EGFR promoted unidirectional EGFRvIII signaling in glioblastoma cells , driving further phosphorylation of STAT proteins , and enhanced malignancy .	Using chemical genetic approaches, we found that EGFR promoted unidirectional EGFRvIII signaling in glioblastoma cells, driving further phosphorylation of STAT proteins, and enhanced malignancy.	8	12	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	8	9	11	12
One such example is the development of a CAR against epidermal growth factor receptor variant III ( EGFRvIII ) , a common variant of EGFR that results from an in-frame deletion of multiple exons and produces a modified EGFR protein that is only found in human tumors and is immunogenic .	One such example is the development of a CAR against epidermal growth factor receptor variant III (EGFRvIII), a common variant of EGFR that results from an in-frame deletion of multiple exons and produces a modified EGFR protein that is only found in human tumors and is immunogenic.	8	39	produces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	17	18	38	39
Methylation of EGFR at Arg1175 increases the association of EGFR with a tyrosine phosphatase , SHP1 , leading to dephosphorylation of Tyr1173 , which is involved in the activation of MAPK [ XREF_BIBR , XREF_BIBR ] .	Methylation of EGFR at Arg1175 increases the association of EGFR with a tyrosine phosphatase, SHP1, leading to dephosphorylation of Tyr1173, which is involved in the activation of MAPK [XREF_BIBR, XREF_BIBR].	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Methylation of EGFR at Arg1175	egfr	EGFR	EGFR	egfr	2	3	9	10
Thus , given the EGFR overexpression associated with TNBC , the ability to target EGFR using the GE11 peptide , and the anti-cancer properties of AF in models of TNBC , we hypothesize that AF loaded NPs conjugated with GE11 have therapeutic potential in TNBC .	Thus, given the EGFR overexpression associated with TNBC, the ability to target EGFR using the GE11 peptide, and the anti-cancer properties of AF in models of TNBC, we hypothesize that AF loaded NPs conjugated with GE11 have therapeutic potential in TNBC.	4	23	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	EGFR	EGFR	egfr	4	5	14	15
Our current study found that suppression of CXCR4 in EGFRvIII expressing breast cancer cells decreased the invasive potential and the proliferation of EGFRvIII expressing breast cancer cells .	Our current study found that suppression of CXCR4 in EGFRvIII expressing breast cancer cells decreased the invasive potential and the proliferation of EGFRvIII expressing breast cancer cells.	7	23	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII expressing	egfrviii	EGFRvIII	EGFRvIII	egfrviii	9	10	22	23
Various epithelial tumors are linked to EGFR overexpression or expression of variant forms , such as the EGFR1 variant , EGFRvIII .	Various epithelial tumors are linked to EGFR overexpression or expression of variant forms, such as the EGFR1 variant, EGFRvIII.	6	21	overexpression	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	20	21	6	7
Development , production , and purification of the Mel-14 monoclonal antibody targeting human chondroitin sulfate proteoglycan 4 ( CSGP4 ) , the D2C7 monoclonal antibody targeting human wild-type epidermal growth factor receptor ( EGFRwt ) and human mutant EGFR variant III ( EGFRvIII ) , and the NZ-1 monoclonal antibody targeting human podoplanin have been previously described [ XREF_BIBR - XREF_BIBR ] .	Development, production, and purification of the Mel-14 monoclonal antibody targeting human chondroitin sulfate proteoglycan 4 (CSGP4), the D2C7 monoclonal antibody targeting human wild-type epidermal growth factor receptor (EGFRwt) and human mutant EGFR variant III (EGFRvIII), and the NZ-1 monoclonal antibody targeting human podoplanin have been previously described [XREF_BIBR - XREF_BIBR].	24	43	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	42	43	28	32
Differences in the sites of ligand induced EGFR tyrosine phosphorylation may underlie divergent ligand induced EGFR coupling to signaling effectors and biological responses .	Differences in the sites of ligand induced EGFR tyrosine phosphorylation may underlie divergent ligand induced EGFR coupling to signaling effectors and biological responses.	7	16	underlie	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR tyrosine phosphorylation	egfr	EGFR	EGFR	egfr	7	8	15	16
STA-2842 reduced expression of total EGFR , and additionally reduced the ratio of phY 1068 / total and phY 1173 / total EGFR at the effective 100 mg/kg dose ( XREF_FIG ) .	STA-2842 reduced expression of total EGFR, and additionally reduced the ratio of phY 1068 / total and phY 1173 / total EGFR at the effective 100 mg/kg dose (XREF_FIG).	0	28	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	STA-2842 reduced expression of total EGFR	egfr	EGFR	EGFR	egfr	5	6	22	23
In addition , we investigated whether EGFR activation by diesel exposure could be mediated by Src activation and phosphorylation of Src Tyr 416 and leading to transactivation of EGFR at Tyr 845 and whether activation of EGFR would increase the downstream MEK-ERK pathway signalling , linked to proliferation and differentiation .	In addition, we investigated whether EGFR activation by diesel exposure could be mediated by Src activation and phosphorylation of Src Tyr 416 and leading to transactivation of EGFR at Tyr 845 and whether activation of EGFR would increase the downstream MEK-ERK pathway signalling, linked to proliferation and differentiation.	6	32	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	Src activation and phosphorylation of Src Tyr 416 and leading to transactivation of EGFR at Tyr 845	egfr	EGFR	EGFR	egfr	28	29	6	7
In parallel , NOX1 induced ROS stimulate p38 and Akt activation , which in turn induce TGF-alpha and EGFR expression and consequently activate the EGFR pathway to induce cell growth .	In parallel, NOX1 induced ROS stimulate p38 and Akt activation, which in turn induce TGF-alpha and EGFR expression and consequently activate the EGFR pathway to induce cell growth.	3	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	NOX1 induced ROS stimulate p38 and Akt activation, which in turn induce TGF-alpha and EGFR expression	egfr	EGFR	EGFR	egfr	18	19	24	25
WHSC1L1 mediated mono-methylation of EGFR at lysine K721 enhances activating phosphorylation marks of EGFR .	WHSC1L1 mediated mono-methylation of EGFR at lysine K721 enhances activating phosphorylation marks of EGFR.	0	14	enhances activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	WHSC1L1 mediated mono-methylation of EGFR at lysine K721	egfr	EGFR	EGFR	egfr	4	5	13	14
FGF and FcgammaR share several components with EGFR pathway which is activated by the EGFR family of receptors , two of which are targets of lapatinib .	FGF and FcgammaR share several components with EGFR pathway which is activated by the EGFR family of receptors, two of which are targets of lapatinib.	7	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFR	EGFR	EGFR	14	15	7	8
Overexpression and ectopic expression of sim and components of the EGFR signaling pathway in the ventral neuroectoderm induced the formation of extra RP2s and their sibling cells by activating EGFR signaling .	Overexpression and ectopic expression of sim and components of the EGFR signaling pathway in the ventral neuroectoderm induced the formation of extra RP2s and their sibling cells by activating EGFR signaling.	3	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	expression of sim and components of the EGFR	egfr	EGFR	EGFR	egfr	10	11	29	30
Furthermore , ectoine in CNP treated cells not only increased the amount of EGFR in the non raft fractions but also appeared to enhance EGFR stability in the non raft fractions .	Furthermore, ectoine in CNP treated cells not only increased the amount of EGFR in the non raft fractions but also appeared to enhance EGFR stability in the non raft fractions.	2	25	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	ectoine in CNP treated cells not only increased the amount of EGFR	egfr	EGFR	EGFR	egfr	13	14	24	25
Interestingly , we recently reported that 4-HNE inhibits tropoelastin synthesis in fibroblasts , by forming adducts on the EGF receptor , which stimulates EGFR signaling , this counteracting the elastogenic activity of TGF-beta XREF_BIBR .	Interestingly, we recently reported that 4-HNE inhibits tropoelastin synthesis in fibroblasts, by forming adducts on the EGF receptor, which stimulates EGFR signaling, this counteracting the elastogenic activity of TGF-beta XREF_BIBR.	18	24	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	EGFR	EGFR	EGFR	18	20	23	24
Further , Winograd-Katz and Levitzki ( Winograd-Katz and Levitzki , 2006 ) proposed that cisplatin induced EGFR T669 phosphorylation similarly increased EGFR endocytosis , which might switch signaling pathways from proliferation to survival .	Further, Winograd-Katz and Levitzki (Winograd-Katz and Levitzki, 2006) proposed that cisplatin induced EGFR T669 phosphorylation similarly increased EGFR endocytosis, which might switch signaling pathways from proliferation to survival.	14	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	cisplatin induced EGFR T669 phosphorylation	egfr	EGFR	EGFR	egfr	16	17	21	22
In GBMs , a low-frequency EGFRvIII containing subpopulation of cancer cells was found to enhance the activation of the wild-type EGFR in adjacent cancer cells to facilitate the growth of the major clones through an interleukin 6 and leukemia inhibitory factor paracrine mechanism 91 .	In GBMs, a low-frequency EGFRvIII containing subpopulation of cancer cells was found to enhance the activation of the wild-type EGFR in adjacent cancer cells to facilitate the growth of the major clones through an interleukin 6 and leukemia inhibitory factor paracrine mechanism 91.	3	24	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	5	6	20	21
EGF did not induce MET phosphorylation and HGF did not induce EGFR phosphorylation , verifying specificity of ligands for their receptors ( XREF_SUPPLEMENTARY ) .	EGF did not induce MET phosphorylation and HGF did not induce EGFR phosphorylation, verifying specificity of ligands for their receptors (XREF_SUPPLEMENTARY).	10	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR phosphorylation	egfr	EGFR	EGFR	egfr	11	12	11	12
( Nishimura etal ., 2009 ) showed that tumor necrosis factor alpha ( TNF-alpha )-induced EGFR phosphorylation at T669 and S1046/1047 stimulated EGFR endocytosis , leading to the survival of cells exposed to TNF-alpha receptor death signal .	(Nishimura etal., 2009) showed that tumor necrosis factor alpha (TNF-alpha)-induced EGFR phosphorylation at T669 and S1046/1047 stimulated EGFR endocytosis, leading to the survival of cells exposed to TNF-alpha receptor death signal.	15	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR phosphorylation at T669	egfr	EGFR	EGFR	egfr	15	16	22	23
We examined the glycosylation status of EGFR protein using Western blotting in HCT116-shRPN2 and HT-29-shRPN2 cells with 90 % RPN2 inhibition , and observed that RPN2 knockdown reduced the total EGFR expression by approximately 25 % and decreased the molecular weight of EGFR compared to negative control .	We examined the glycosylation status of EGFR protein using Western blotting in HCT116-shRPN2 and HT-29-shRPN2 cells with 90% RPN2 inhibition, and observed that RPN2 knockdown reduced the total EGFR expression by approximately 25% and decreased the molecular weight of EGFR compared to negative control.	25	43	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	RPN2 knockdown reduced the total EGFR expression	egfr	EGFR	EGFR	egfr	30	31	42	43
In fact , in one study of 57 patients , ERBB signaling ( including EGFR , ERBB2 , ERBB3 , ERBB4 , and their downstream targets , such as NRG1 ) was mutated in 36.8 % of tumors [ XREF_BIBR ] .	In fact, in one study of 57 patients, ERBB signaling (including EGFR, ERBB2, ERBB3, ERBB4, and their downstream targets, such as NRG1) was mutated in 36.8% of tumors [XREF_BIBR].	10	29	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERBB	ERBB	ERBB	14	15	10	11
Specially appealing is the overexpression of EGFR in tumors such as lung , colon , kidney and head and neck carcinomas which are mostly resistant to current chemotherapy .	Specially appealing is the overexpression of EGFR in tumors such as lung, colon, kidney and head and neck carcinomas which are mostly resistant to current chemotherapy.	2	7	is the overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	overexpression of EGFR	egfr	EGFR	EGFR	egfr	6	7	6	7
However , phosphorylation of EGFR at Tyr1045 enables the binding of the ubiquitin ligase c-cbl to EGFR , resulting in EGFR ubiquitination and degradation .	However, phosphorylation of EGFR at Tyr1045 enables the binding of the ubiquitin ligase c-cbl to EGFR, resulting in EGFR ubiquitination and degradation.	2	17	enables	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFR	phosphorylation of EGFR at Tyr1045	egfr	EGFR	EGFR	egfr	4	5	16	17
However , in other cases binding of the ligand induces conformational change in the receptor and dimerization takes place purely via receptor domain interactions , for example , in the epidermal growth factor receptor family ( EGFRs ) .	However, in other cases binding of the ligand induces conformational change in the receptor and dimerization takes place purely via receptor domain interactions, for example, in the epidermal growth factor receptor family (EGFRs).	9	34	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	30	34	30	34
Given that curcumin suppresses EGFR mRNA expression , promotes EGFR protein degradation , and precludes EGFR-TKIs toxicity of intestines injury , curcumin might offer another way to attenuate EGFR related signals regardless of EGFR mutation status .	Given that curcumin suppresses EGFR mRNA expression, promotes EGFR protein degradation, and precludes EGFR-TKIs toxicity of intestines injury, curcumin might offer another way to attenuate EGFR related signals regardless of EGFR mutation status.	2	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	curcumin suppresses EGFR mRNA expression	egfr	EGFR	EGFR	egfr	4	5	9	10
The increase in EGFR , Src and AnxA2 levels upon Her-2 downregulation and inhibition led us to investigate the role of AnxA2 in EGFR signaling in TNBC subset of breast cancer , where EGFR plays a major role in survival , growth , migration and invasion of cancer cells XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	The increase in EGFR, Src and AnxA2 levels upon Her-2 downregulation and inhibition led us to investigate the role of AnxA2 in EGFR signaling in TNBC subset of breast cancer, where EGFR plays a major role in survival, growth, migration and invasion of cancer cells XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	24	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR, Src and AnxA2 levels	egfr	EGFR	EGFR	egfr	3	4	23	24
There was a rapid induction of radiation induced epidermal growth factor receptor Y phosphorylation , starting within 2 min , with maximum values between 0.5 and 5 min after radiation exposure followed by a slower decline to baseline levels after 20 min .	There was a rapid induction of radiation induced epidermal growth factor receptor Y phosphorylation, starting within 2 min, with maximum values between 0.5 and 5 min after radiation exposure followed by a slower decline to baseline levels after 20 min.	7	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor Y phosphorylation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	8	12	8	12
We show that PD153035 inhibits EGF dependent EGF receptor phosphorylation and suppresses the proliferation and clonogenicity of a wide panel of EGF receptor overexpressing human cancer cell lines .	We show that PD153035 inhibits EGF dependent EGF receptor phosphorylation and suppresses the proliferation and clonogenicity of a wide panel of EGF receptor overexpressing human cancer cell lines.	3	23	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF receptor	PD153035 inhibits EGF dependent EGF receptor phosphorylation	egf receptor	EGF receptor	EGF receptor	egf receptor	7	9	21	23
In contrast to that of the normal prostate , in which androgens decrease EGFR expression , in ALVA101 cells androgen induced EGFR expression resulted in increased cell division and upregulation of EGFR , thus enhancing proliferation of PCa cells ( Liu et al , 1993 ) .	In contrast to that of the normal prostate, in which androgens decrease EGFR expression, in ALVA101 cells androgen induced EGFR expression resulted in increased cell division and upregulation of EGFR, thus enhancing proliferation of PCa cells (Liu et al, 1993).	21	32	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	EGFR	EGFR expression	egfr	EGFR	EGFR	egfr	21	22	31	32
EGF receptor ubiquitination is mediated at least in part by the RING finger E3 ubiquitin ligase cbl , which is recruited to ligand stimulated EGFR by binding to phosphorylated receptor tyrosine 1045 .	EGF receptor ubiquitination is mediated at least in part by the RING finger E3 ubiquitin ligase cbl, which is recruited to ligand stimulated EGFR by binding to phosphorylated receptor tyrosine 1045.	0	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor ubiquitination	egf receptor	EGFR	EGFR	egfr	0	2	24	25
RNF144A promotes EGFR ubiquitination , maintains EGFR protein and prolongs EGF and EGFR signaling during EGF stimulation .	RNF144A promotes EGFR ubiquitination, maintains EGFR protein and prolongs EGF and EGFR signaling during EGF stimulation.	0	13	prolongs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	RNF144A promotes EGFR ubiquitination	egfr	EGFR	EGFR	egfr	2	3	12	13
Earlier studies have indicated co-overexpression of PPAR NR heterodimers increased EGFR protein expression and more importantly increased EGFR promoter transactivation [ XREF_BIBR ] .	Earlier studies have indicated co-overexpression of PPAR NR heterodimers increased EGFR protein expression and more importantly increased EGFR promoter transactivation [XREF_BIBR].	4	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	co-overexpression of PPAR NR heterodimers increased EGFR protein expression	egfr	EGFR	EGFR	egfr	10	11	17	18
Sulindac metabolites block EGF induced phosphorylation of EGFR and ERK1/2 , downregulate total EGFR protein , and induce apoptotic cell death .	Sulindac metabolites block EGF induced phosphorylation of EGFR and ERK1/2, downregulate total EGFR protein, and induce apoptotic cell death.	0	14	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	Sulindac metabolites block EGF induced phosphorylation of EGFR	egfr	EGFR	EGFR	egfr	7	8	13	14
In addition , we showed that cells expressing high levels of wild-type EGFR ( mimicking the amplification and/or overexpression of EGFR observed in most malignant gliomas ) are receptive to infection by Delta-24-RIVER , albeit with less efficiency than the ones expressing the mutant form , but enough to induce an anti-glioma effect .	In addition, we showed that cells expressing high levels of wild-type EGFR (mimicking the amplification and/or overexpression of EGFR observed in most malignant gliomas) are receptive to infection by Delta-24-RIVER, albeit with less efficiency than the ones expressing the mutant form, but enough to induce an anti-glioma effect.	9	21	overexpression	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	EGFR	levels of wild-type EGFR	egfr	EGFR	EGFR	egfr	12	13	20	21
Then we measured the activation of EGFR and its downstream signaling , the phosphorylation levels of EGFR , AKT and ERK1/2 were increased in the TAZ rescued HDAC9-knockdown cells and xenograft tumors .	Then we measured the activation of EGFR and its downstream signaling, the phosphorylation levels of EGFR, AKT and ERK1/2 were increased in the TAZ rescued HDAC9-knockdown cells and xenograft tumors.	4	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	levels of EGFR	egfr	EGFR	EGFR	egfr	16	17	6	7
Panitumumab is a fully human monoclonal IgG ( 2 ) antibody targeting the EGF receptor ( EGFR ) .	Panitumumab is a fully human monoclonal IgG (2) antibody targeting the EGF receptor (EGFR).	10	17	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGF receptor	EGF receptor	EGF receptor	16	17	13	15
While EGFR overexpression could be targeted using anti EGFR drugs , the effects on endosome trafficking and protein turnover represents a more elusive target and should be taken into account for any long-term therapy with Celecoxib .	While EGFR overexpression could be targeted using anti EGFR drugs, the effects on endosome trafficking and protein turnover represents a more elusive target and should be taken into account for any long-term therapy with Celecoxib.	1	9	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	EGFR	EGFR	egfr	1	2	8	9
While it is a difficult task distinguish the effects of EGFR and GPCR activation from the effects of EGFR transactivation by GPCR in a clinical setting , it is very feasible to at least collect significant data to determine whether there is the co-overexpression of EGFR and GPCR in patients and whether this co-overexpression correlates with poor prognosis .	While it is a difficult task distinguish the effects of EGFR and GPCR activation from the effects of EGFR transactivation by GPCR in a clinical setting, it is very feasible to at least collect significant data to determine whether there is the co-overexpression of EGFR and GPCR in patients and whether this co-overexpression correlates with poor prognosis.	41	47	is the co-overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	co-overexpression of EGFR	egfr	EGFR	EGFR	egfr	45	46	45	46
We also found that stimulation with either ANG or SII induced EGFR phosphorylation at Tyr 845 by Src kinase , which is known to activate EGFR .	We also found that stimulation with either ANG or SII induced EGFR phosphorylation at Tyr 845 by Src kinase, which is known to activate EGFR.	10	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	induced EGFR phosphorylation at Tyr 845 by Src	egfr	EGFR	EGFR	egfr	11	12	25	26
Discovery of EGFR overexpression in cancer has led to substantial efforts over the last four decades to target the EGFR as a cancer treatment strategy .	Discovery of EGFR overexpression in cancer has led to substantial efforts over the last four decades to target the EGFR as a cancer treatment strategy.	2	20	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	EGFR	EGFR	egfr	2	3	19	20
Furthermore , FSH endogenously stimulated EGFR activators expression , which activated EGFR signaling pathway and then FEOs meiotic resumption .	Furthermore, FSH endogenously stimulated EGFR activators expression, which activated EGFR signaling pathway and then FEOs meiotic resumption.	2	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	FSH endogenously stimulated EGFR activators expression	egfr	EGFR	EGFR	egfr	5	6	11	12
Therefore , it is likely that the activation of Src by OVA induces the transactivation of EGFR via pro-HB-EGF shedding and the direct phosphorylation of EGFR at Tyr 845 , both of which activate EGFR , resulting in the activation of Rho-kinase in VSMCs through unidentified pathway .	Therefore, it is likely that the activation of Src by OVA induces the transactivation of EGFR via pro-HB-EGF shedding and the direct phosphorylation of EGFR at Tyr 845, both of which activate EGFR, resulting in the activation of Rho-kinase in VSMCs through unidentified pathway.	23	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	phosphorylation of EGFR at Tyr 845	egfr	EGFR	EGFR	egfr	25	26	34	35
Gefitinib is a broad EGFR family member inhibitor which has been shown to inhibit EGFR signaling and HER2 signaling through heterodimerization with EGFR [ XREF_BIBR ] .	Gefitinib is a broad EGFR family member inhibitor which has been shown to inhibit EGFR signaling and HER2 signaling through heterodimerization with EGFR [XREF_BIBR].	4	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFR	EGFR	EGFR	4	5	14	15
EGFR is the expression product of the proto-oncogene c-erbB-1 and possesses tyrosine kinase ( TK ) activity .	EGFR is the expression product of the proto-oncogene c-erbB-1 and possesses tyrosine kinase (TK) activity.	0	10	is the expression product	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	proto-oncogene c-erbB-1	proto-oncogene c-erbB-1	proto-oncogene c-erbB-1	0	1	7	9
There is overexpression of EGFR in up to 90 % of PDACs [ XREF_BIBR , XREF_BIBR ] , with males expressing more than female patients [ XREF_BIBR ] .	There is overexpression of EGFR in up to 90% of PDACs [XREF_BIBR, XREF_BIBR], with males expressing more than female patients [XREF_BIBR].	1	20	is overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	overexpression of EGFR	egfr	EGFR	EGFR	egfr	4	5	4	5
First , the over-expression of EGFR monomers may increase the probability ligand independent dimerization of EGFR resulting in potentially higher basal EGFR signaling and a rescue of cardiac function XREF_BIBR , XREF_BIBR .	First, the over-expression of EGFR monomers may increase the probability ligand independent dimerization of EGFR resulting in potentially higher basal EGFR signaling and a rescue of cardiac function XREF_BIBR, XREF_BIBR.	3	25	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	over-expression of EGFR	egfr	EGFR	EGFR	egfr	5	6	15	16
OA induced EGFR autophosphorylation triggered EGFR signaling pathway activation ( as assessed through coimmunoprecipitation of SH2 proteins such as SHC , GRB2 , and SHP-2 ) and subsequent p42 and p44 mitogen activated protein kinase ( as shown by the use of EGFR- deficient B82L and EGFR- transduced B82LK ( + ) cell lines ) .	OA induced EGFR autophosphorylation triggered EGFR signaling pathway activation (as assessed through coimmunoprecipitation of SH2 proteins such as SHC, GRB2, and SHP-2) and subsequent p42 and p44 mitogen activated protein kinase (as shown by the use of EGFR- deficient B82L and EGFR- transduced B82LK (+) cell lines).	0	8	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	OA induced EGFR autophosphorylation	egfr	EGFR	EGFR	egfr	2	3	5	6
This opens the possibility that one of the consequences of EGFR ubiquitination may be , via recruitment of Rabex-5 , to activate RAB5 and RAB22 dependent EGFR trafficking through the early-endocytic pathway .	This opens the possibility that one of the consequences of EGFR ubiquitination may be, via recruitment of Rabex-5, to activate RAB5 and RAB22 dependent EGFR trafficking through the early-endocytic pathway.	10	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR ubiquitination	egfr	EGFR	EGFR	egfr	10	11	26	27
Autocrine loop with ERBB2 ( EGFR family of tyrosine kinase receptors ) induced by YAP to bypass EGFR ( epidermal growth factor receptor ) inactivation regulates ovarian cancer initiation and progression through Hippo kinases inhibition [ XREF_BIBR ] .	Autocrine loop with ERBB2 (EGFR family of tyrosine kinase receptors) induced by YAP to bypass EGFR (epidermal growth factor receptor) inactivation regulates ovarian cancer initiation and progression through Hippo kinases inhibition [XREF_BIBR].	5	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFR	EGFR	EGFR	5	6	17	18
[ XREF_BIBR ] Le y glycosylation of EGFR has been found to modulate the function of EGFR .	[XREF_BIBR] Le y glycosylation of EGFR has been found to modulate the function of EGFR.	5	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	glycosylation of EGFR	egfr	EGFR	EGFR	egfr	7	8	16	17
These mutations lead to a higher rate of USP8 induced EGFR deubiquitination , increasing EGFR pathway stimulation , and ultimately increasing ACTH secretion .	These mutations lead to a higher rate of USP8 induced EGFR deubiquitination, increasing EGFR pathway stimulation, and ultimately increasing ACTH secretion.	8	16	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	USP8 induced EGFR deubiquitination	egfr	EGFR	EGFR	egfr	10	11	14	15
High glucose stimulates EGFR phosphorylation and blocks EGFR degradation .	High glucose stimulates EGFR phosphorylation and blocks EGFR degradation.	1	8	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	glucose stimulates EGFR phosphorylation	egfr	EGFR	EGFR	egfr	3	4	7	8
Dual targeting of EGFR and Notch3 increases both EGFR internalization and dephosphorylation , and decreases the EGFR nuclear localization .	Dual targeting of EGFR and Notch3 increases both EGFR internalization and dephosphorylation, and decreases the EGFR nuclear localization.	1	12	increases	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	EGFR	EGFR	egfr	EGFR	EGFR internalization and dephosphorylation	egfr	3	4	8	9
We hypothesized that inhibiting the phosphorylation of the EGFR and VEGFR by ZD6474 , a dual tyrosine kinase inhibitor of EGFR and VEGFR , in combination with paclitaxel or radiation would inhibit breast cancer cell growth .	We hypothesized that inhibiting the phosphorylation of the EGFR and VEGFR by ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel or radiation would inhibit breast cancer cell growth.	5	22	inhibitor	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGFR	phosphorylation of the EGFR and VEGFR by ZD6474, a dual tyrosine	egfr	EGFR	EGFR	egfr	8	9	20	21
Mechanistically , ZD6474 inhibits autotyrosine phosphorylation of EGFR and EGFRvIII , suppresses EGFR dependent and EGFRvIII dependent phosphorylation of Stat3 , Akt , and ERK1 / 2 , and reduces expression of Bcl-X L in EGFRvIII expressing glioma cells .	Mechanistically, ZD6474 inhibits autotyrosine phosphorylation of EGFR and EGFRvIII, suppresses EGFR dependent and EGFRvIII dependent phosphorylation of Stat3, Akt, and ERK1 / 2, and reduces expression of Bcl-X L in EGFRvIII expressing glioma cells.	2	25	suppresses	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	EGFR	ZD6474 inhibits autotyrosine phosphorylation of EGFR	egfr	EGFRvIII	EGFRvIII dependent phosphorylation of Stat3, Akt, and ERK1	egfrviii	7	8	15	16
The HPV-16 E6 and E7 proteins stimulate EGFR expression on epithelial cells and the HPV E5 protein increases recycling of the EGFR to the cell surface and alters EGF endocytic trafficking .	The HPV-16 E6 and E7 proteins stimulate EGFR expression on epithelial cells and the HPV E5 protein increases recycling of the EGFR to the cell surface and alters EGF endocytic trafficking.	7	22	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR expression	egfr	EGFR	EGFR	egfr	7	8	21	22
EGFR mutations , increased EGFR gene copy number , k-ras mutations , and overexpression of the EGFR protein have been explored as predictive markers for the response to treatment response with EGFR-TKIs .	EGFR mutations, increased EGFR gene copy number, k-ras mutations, and overexpression of the EGFR protein have been explored as predictive markers for the response to treatment response with EGFR-TKIs.	3	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	overexpression of the EGFR	egfr	EGFR	EGFR	egfr	16	17	4	5
There is overexpression of EGFR in MDS cases .	There is overexpression of EGFR in MDS cases.	1	7	is overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	overexpression of EGFR	egfr	EGFR	EGFR	egfr	4	5	4	5
The combination of increased EGFR expression , decreased downstream signaling of EGFR , reduced proliferation , and maintenance of the undifferentiated state , all resulting from inhibition of the p38 pathway is suggestive of a quiescent state .	The combination of increased EGFR expression, decreased downstream signaling of EGFR, reduced proliferation, and maintenance of the undifferentiated state, all resulting from inhibition of the p38 pathway is suggestive of a quiescent state.	4	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR expression	egfr	EGFR	EGFR	egfr	4	5	11	12
Our results , however , show that reggie-1 down-regulation inhibits EGFR phosphorylation at various residues ( particularly at Y845 and Y1045 ) , impairs EGFR endocytosis and degradation , and affects the downstream targets PI3K and Akt and Erk1/2 , which are known to require receptor endocytosis .	Our results, however, show that reggie-1 down-regulation inhibits EGFR phosphorylation at various residues (particularly at Y845 and Y1045), impairs EGFR endocytosis and degradation, and affects the downstream targets PI3K and Akt and Erk1/2, which are known to require receptor endocytosis.	7	25	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	reggie-1 down-regulation inhibits EGFR phosphorylation	egfr	EGFR	EGFR	egfr	10	11	24	25
Knockdown of src by specific siRNA blocked EGFR phosphorylation at Y845 , phosphorylation of caveolin-1 at Y14 and abolished EGFR transport into the nucleus and phosphorylation of DNA-PK .	Knockdown of src by specific siRNA blocked EGFR phosphorylation at Y845, phosphorylation of caveolin-1 at Y14 and abolished EGFR transport into the nucleus and phosphorylation of DNA-PK.	2	20	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	src by specific siRNA blocked EGFR phosphorylation at Y845	egfr	EGFR	EGFR	egfr	7	8	19	20
CFF-1 induced inhibition of auto-phosphorylation of EGFR and inhibited activation of EGFR .	CFF-1 induced inhibition of auto-phosphorylation of EGFR and inhibited activation of EGFR.	0	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	CFF-1 induced inhibition of auto-phosphorylation of EGFR	egfr	EGFR	EGFR	egfr	6	7	11	12
The EGFR selective tyrosine kinase inhibitors , erlotinib and gefitinib , blocked not only EGFRvIII signaling to ERK but also uPAR dependent STAT5b activation .	The EGFR selective tyrosine kinase inhibitors, erlotinib and gefitinib, blocked not only EGFRvIII signaling to ERK but also uPAR dependent STAT5b activation.	1	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	1	2	14	15
Combination of fulv and EGFR family tyrosine kinase inhibitors ( erlotinib and lapatinib ) significantly decreased EGFR signaling and cell survival .	Combination of fulv and EGFR family tyrosine kinase inhibitors (erlotinib and lapatinib) significantly decreased EGFR signaling and cell survival.	2	17	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFR	EGFR	EGFR	4	5	16	17
The EGF receptor is the product of the c-erb-B proto-oncogene ( also known as EGFR ) .	The EGF receptor is the product of the c-erb-B proto-oncogene (also known as EGFR).	1	10	is the product	Positive_activation_copula_1	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	c-erb-B proto-oncogene	c-erb-B proto-oncogene	c-erb-B proto-oncogene	1	3	8	10
We show that sunitinib treatment does not inhibit EGF induced EGFR phosphorylation , confirming the specificity of sunitinib to block PDGFR activation , and as a result , prevents PDGF-BB mediated transactivation of EGFR ( XREF_FIG ) .	We show that sunitinib treatment does not inhibit EGF induced EGFR phosphorylation, confirming the specificity of sunitinib to block PDGFR activation, and as a result, prevents PDGF-BB mediated transactivation of EGFR (XREF_FIG).	3	35	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	sunitinib treatment does not inhibit EGF induced EGFR phosphorylation	egfr	EGFR	EGFR	egfr	10	11	33	34
In conclusion , the inhibition of CD44 by shRNA-CD44 following stimulation with TGF-beta1 abolished the expression of CD44 and EGFR , deactivated the EGF and EGFR signaling pathways and inhibited the process of EMT , suggesting that there is a link between TGF-beta1 and CD44 and EGFR in the process of EMT .	In conclusion, the inhibition of CD44 by shRNA-CD44 following stimulation with TGF-beta1 abolished the expression of CD44 and EGFR, deactivated the EGF and EGFR signaling pathways and inhibited the process of EMT, suggesting that there is a link between TGF-beta1 and CD44 and EGFR in the process of EMT.	6	27	deactivated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	CD44 by shRNA-CD44 following stimulation with TGF-beta1 abolished the expression of CD44 and EGFR	egfr	EGFR	EGFR	egfr	19	20	25	26
EGFR overexpression partially restored EGFR signaling and liver regeneration .	EGFR overexpression partially restored EGFR signaling and liver regeneration.	0	5	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	EGFR	EGFR	egfr	0	1	4	5
SFKs phosphorylate EGFR on Y845 and Y1101 , enhancing EGFR signaling .	SFKs phosphorylate EGFR on Y845 and Y1101, enhancing EGFR signaling.	1	10	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	phosphorylate EGFR on Y845 and Y1101	egfr	EGFR	EGFR	egfr	2	3	9	10
It was also reported that PKM2 induces EGFR phosphorylation and activates downstream EGFR signalling in triple negative breast cancer cells 51 .	It was also reported that PKM2 induces EGFR phosphorylation and activates downstream EGFR signalling in triple negative breast cancer cells 51.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	PKM2 induces EGFR phosphorylation	egfr	EGFR	EGFR	egfr	7	8	12	13
Our finding , that EGFRvIII stimulates the repair of radiation induced DNA damage , is not completely unexpected given that EGFR is activated by radiation and EGFRvIII displays even higher levels of radiation induced activation compared to the wild type receptor .	Our finding, that EGFRvIII stimulates the repair of radiation induced DNA damage, is not completely unexpected given that EGFR is activated by radiation and EGFRvIII displays even higher levels of radiation induced activation compared to the wild type receptor.	20	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	26	27	20	21
The development of new agents that can target the EGFR deletion mutant , EGFRvIII , can permit direct targeting of glioblastoma cells while sparing the normal brain .	The development of new agents that can target the EGFR deletion mutant, EGFRvIII, can permit direct targeting of glioblastoma cells while sparing the normal brain.	1	14	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	13	14	9	10
The peptide mimics and antipeptide Abs to all three epitopes inhibited cancer cell growth , prevented EGFR specific phosphorylation , downregulated EGFR signaling pathways , and caused increased apoptosis and ADCC in EGFR expressing cells .	The peptide mimics and antipeptide Abs to all three epitopes inhibited cancer cell growth, prevented EGFR specific phosphorylation, downregulated EGFR signaling pathways, and caused increased apoptosis and ADCC in EGFR expressing cells.	5	23	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	Abs to all three epitopes inhibited cancer cell growth, prevented EGFR specific phosphorylation	egfr	EGFR	EGFR	egfr	16	17	21	22
Since there was immunohistochemical overexpression of epidermal growth factor receptor , the patient was treated with gefitinib .	Since there was immunohistochemical overexpression of epidermal growth factor receptor, the patient was treated with gefitinib.	2	10	was immunohistochemical overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	epidermal growth factor receptor	overexpression of epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	6	10	6	10
In an NSCLC model , high-level expression of the ErbB ligands including EGF , amphiregulin , and others , and action of the SRC family kinases were found to promote nuclear EGFR expression ; further , induced expression of nuclear EGFR promoted resistance to EGFR targeting agents such as cetuximab .	In an NSCLC model, high-level expression of the ErbB ligands including EGF, amphiregulin, and others, and action of the SRC family kinases were found to promote nuclear EGFR expression; further, induced expression of nuclear EGFR promoted resistance to EGFR targeting agents such as cetuximab.	37	45	promoted	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFR	expression of nuclear EGFR	egfr	EGFR	EGFR	egfr	40	41	44	45
In a similar fashion , EGF receptor ( EGFR ) agonists induce heterodimers of EGFR and ErbB2 .	In a similar fashion, EGF receptor (EGFR) agonists induce heterodimers of EGFR and ErbB2.	5	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	EGFR	EGFR	EGFR	5	7	14	15
The overexpression of epidermal growth factor receptor ( EGFR ) in tumors underlines the recent interest in EGFR as attractive target for the development of new cancer imaging agents .	The overexpression of epidermal growth factor receptor (EGFR) in tumors underlines the recent interest in EGFR as attractive target for the development of new cancer imaging agents.	1	18	underlines	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	overexpression of epidermal growth factor receptor	epidermal growth factor receptor	EGFR	EGFR	egfr	3	7	17	18
This is not surprising , since high HB-EGF or EGFR protein levels do not inevitably lead to the activation of EGFR unless a sheddase , i.e ., ADAM12L , is also expressed at high level .	This is not surprising, since high HB-EGF or EGFR protein levels do not inevitably lead to the activation of EGFR unless a sheddase, i.e., ADAM12L, is also expressed at high level.	9	21	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR protein levels	egfr	EGFR	EGFR	egfr	9	10	20	21
By contrast , HIF-1 accumulation did not contribute to EGF-R expression and FGF-2 only modestly induced EGF-R .	By contrast, HIF-1 accumulation did not contribute to EGF-R expression and FGF-2 only modestly induced EGF-R.	3	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF-R	HIF-1 accumulation did not contribute to EGF-R expression	egf-r	EGF-R	EGF-R	egf-r	9	10	16	17
However , in a subset of patients with non-small-cell-lung cancer ( NSCLC ) , there is overexpression of epidermal growth factor receptor ( EGFR ) .	However, in a subset of patients with non-small-cell-lung cancer (NSCLC), there is overexpression of epidermal growth factor receptor (EGFR).	15	22	is overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	epidermal growth factor receptor	overexpression of epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	18	22	18	22
Its variant III mutation ( EGFRvIII ) , characterized by an in-frame deletion in exons 2-7 , is common ( 25 %-50% ) in GBM and produces a truncated EGFR protein without the extracellular ligand binding domain , leading to its ligand independent constitutive activation [ XREF_BIBR ] .	Its variant III mutation (EGFRvIII), characterized by an in-frame deletion in exons 2-7, is common (25%-50%) in GBM and produces a truncated EGFR protein without the extracellular ligand binding domain, leading to its ligand independent constitutive activation [XREF_BIBR].	3	30	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	5	6	29	30
In fact , this agent could be used in resistant-tumors to anti-EGFR therapies , since a recent study of GBM patients found that EGFRvIII in combination with the loss of the PTEN tumor suppressor gene resulted in resistance to second generation cancer therapeutics targeting EGFR 34 .	In fact, this agent could be used in resistant-tumors to anti-EGFR therapies, since a recent study of GBM patients found that EGFRvIII in combination with the loss of the PTEN tumor suppressor gene resulted in resistance to second generation cancer therapeutics targeting EGFR 34.	23	45	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	23	24	44	45
We have examined an archival series of cases of pancreatic pathology for expression of the EGFR using the anti-EGFR antiserum 12E and found that there is almost ubiquitous overexpression of EGFR in pancreatic cancer and in chronic pancreatitis .	We have examined an archival series of cases of pancreatic pathology for expression of the EGFR using the anti-EGFR antiserum 12E and found that there is almost ubiquitous overexpression of EGFR in pancreatic cancer and in chronic pancreatitis.	25	37	is almost ubiquitous overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	overexpression of EGFR	egfr	EGFR	EGFR	egfr	30	31	30	31
Src siRNA decreased phosphorylation of cytoplasmic EGFR at Y845 , reduced EGFR transport into nucleus and impaired phosphorylation of DNA-PK at T2609 after irradiation .	Src siRNA decreased phosphorylation of cytoplasmic EGFR at Y845, reduced EGFR transport into nucleus and impaired phosphorylation of DNA-PK at T2609 after irradiation.	3	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	phosphorylation of cytoplasmic EGFR at Y845	egfr	EGFR	EGFR	egfr	6	7	11	12
The increased EGFR signaling by amplified EGFR expression with PTEN loss promotes increased angiogenesis , and increased TBV is a measure of microvasculature density and has previously been shown to reflect an underlying angiogenetic mechanism XREF_BIBR ; thus , tumors with EGFR overexpression with PTEN loss can have increased TBV .	The increased EGFR signaling by amplified EGFR expression with PTEN loss promotes increased angiogenesis, and increased TBV is a measure of microvasculature density and has previously been shown to reflect an underlying angiogenetic mechanism XREF_BIBR; thus, tumors with EGFR overexpression with PTEN loss can have increased TBV.	2	8	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGFR	EGFR expression	egfr	EGFR	EGFR	egfr	6	7	2	3
There is overexpression of EGFR and HER2 in carcinomas of the salivary glands .	There is overexpression of EGFR and HER2 in carcinomas of the salivary glands.	1	6	is overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	overexpression of EGFR	egfr	EGFR	EGFR	egfr	4	5	4	5
EGFRvIII expressing cells displayed elevated levels of Tyr1068 phosphorylation ( EGFR-P ) and ERK activation ( Thr202 and Tyr204 phosphorylation on ERK1/2 ; ERK1/2-P ) in SF media ( XREF_FIG ) , demonstrating that ectopic EGFRvIII expression resulted in constitutive EGFR signaling .	EGFRvIII expressing cells displayed elevated levels of Tyr1068 phosphorylation (EGFR-P) and ERK activation (Thr202 and Tyr204 phosphorylation on ERK1/2; ERK1/2-P) in SF media (XREF_FIG), demonstrating that ectopic EGFRvIII expression resulted in constitutive EGFR signaling.	35	42	signaling	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII expression	egfrviii	EGFR	EGFR	egfr	35	36	40	41
However , overexpression of EGFR in TNBC tissues supports the potential development of EGFR targeted nanoparticles , imaging probes , and drug carriers that selectively deliver nanoparticles into EGFR expressing tumor cells to enhance imaging specificity and the effectiveness of cancer therapeutics .	However, overexpression of EGFR in TNBC tissues supports the potential development of EGFR targeted nanoparticles, imaging probes, and drug carriers that selectively deliver nanoparticles into EGFR expressing tumor cells to enhance imaging specificity and the effectiveness of cancer therapeutics.	2	14	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	overexpression of EGFR	egfr	EGFR	EGFR	egfr	4	5	13	14
Collectively , these data present a novel S1P regulated feed-forward signaling pathway , i.e ., S1P 3 transcriptionally up-regulates EGFR expression , which consequently augments EGFR stimulated carcinogenic responses .	Collectively, these data present a novel S1P regulated feed-forward signaling pathway, i.e., S1P 3 transcriptionally up-regulates EGFR expression, which consequently augments EGFR stimulated carcinogenic responses.	19	26	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR expression	egfr	EGFR	EGFR	egfr	19	20	25	26
Subsequent proteasome independent ubiquitination of EGFR and endocytic adaptor proteins mediate the EGFR internalization .	Subsequent proteasome independent ubiquitination of EGFR and endocytic adaptor proteins mediate the EGFR internalization.	1	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	proteasome independent ubiquitination of EGFR	egfr	EGFR	EGFR	egfr	5	6	12	13
The latter study found that AKT dependent phosphorylation of membrane EGFR caused EGFR to translocate to the nucleus where it interacted with the BCRP promoter to enhance transcription of BCRP in gefitinib resistant cells [ XREF_BIBR ] .	The latter study found that AKT dependent phosphorylation of membrane EGFR caused EGFR to translocate to the nucleus where it interacted with the BCRP promoter to enhance transcription of BCRP in gefitinib resistant cells [XREF_BIBR].	5	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	AKT dependent phosphorylation of membrane EGFR	egfr	EGFR	EGFR	egfr	10	11	12	13
Our results showed that HB-EGF plays no role in the growth of NSCLC , and that there was no significant overexpression of EGFR in tumor tissue .	Our results showed that HB-EGF plays no role in the growth of NSCLC, and that there was no significant overexpression of EGFR in tumor tissue.	17	25	was no significant overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	overexpression of EGFR	egfr	EGFR	EGFR	egfr	22	23	22	23
In TKI sensitive HCC827 cells ( but not in TKI resistant H1975 cells ) , erlotinib led to EGFR dephosphorylation , disruption of EGFR and Beclin 1 binding , disruption of Beclin 1/Rubicon binding , increased Beclin 1/VPS34 binding , decreased Beclin 1/Bcl -2 binding , and increased Beclin 1 associated VPS34 kinase activity ( XREF_FIG ) .	In TKI sensitive HCC827 cells (but not in TKI resistant H1975 cells), erlotinib led to EGFR dephosphorylation, disruption of EGFR and Beclin 1 binding, disruption of Beclin 1/Rubicon binding, increased Beclin 1/VPS34 binding, decreased Beclin 1/Bcl -2 binding, and increased Beclin 1 associated VPS34 kinase activity (XREF_FIG).	16	20	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFR	EGFR dephosphorylation	egfr	EGFR	EGFR	egfr	18	19	18	19
How does EGFR activate EGFRvIII ?	How does EGFR activate EGFRvIII?	2	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	2	3	4	5
In a similar study that specifically examined beta 1 -adrenergic receptor mediated EGFR transactivation -- a process that was previously shown in the heart to be dependent upon beta-arrestins XREF_BIBR -- only alprenolol and carvedilol induced EGFR internalization XREF_BIBR .	In a similar study that specifically examined beta 1 -adrenergic receptor mediated EGFR transactivation -- a process that was previously shown in the heart to be dependent upon beta-arrestins XREF_BIBR -- only alprenolol and carvedilol induced EGFR internalization XREF_BIBR.	7	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	beta 1 -adrenergic receptor mediated EGFR	egfr	EGFR	EGFR	egfr	12	13	36	37
Hence , indeed CRC rarely express high levels of membranous EGFR protein , which are not directly regulated by EGFR promoter methylation and mRNA expression ( XREF_SUPPLEMENTARY ) .	Hence, indeed CRC rarely express high levels of membranous EGFR protein, which are not directly regulated by EGFR promoter methylation and mRNA expression (XREF_SUPPLEMENTARY).	10	22	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR promoter methylation	egfr	EGFR	EGFR	egfr	19	20	10	11
EGFR overexpression in tumor cells can produce up to 2 million EGFR molecules per cell , and has been correlated to a more malignant tumor grade as well as a reduced patient survival [ XREF_BIBR , XREF_BIBR ] .	EGFR overexpression in tumor cells can produce up to 2 million EGFR molecules per cell, and has been correlated to a more malignant tumor grade as well as a reduced patient survival [XREF_BIBR, XREF_BIBR].	0	12	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	EGFR	EGFR	egfr	0	1	11	12
Additionally , at concentration of 2.0 micromol/L , although ZD6474 inhibits phosphorylation of EGFR , Akt , Stat3 , ERK1/2 , and Bcl-X L expression in EGF stimulated U87MG and EGFR or nonstimulated GBM12 cells that only overexpress WT EGFR , lesser inhibition of cell growth and survival was seen compared with U87MG and EGFRvIII and GBM6 cells that only express EGFRvIII .	Additionally, at concentration of 2.0 micromol/L, although ZD6474 inhibits phosphorylation of EGFR, Akt, Stat3, ERK1/2, and Bcl-X L expression in EGF stimulated U87MG and EGFR or nonstimulated GBM12 cells that only overexpress WT EGFR, lesser inhibition of cell growth and survival was seen compared with U87MG and EGFRvIII and GBM6 cells that only express EGFRvIII.	9	31	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGFR	ZD6474 inhibits phosphorylation of EGFR	egfr	EGFR	EGFR	egfr	13	14	30	31
EGFR activity is enhanced by upregulation of EGFR protein expression , inhibition and deletion of downstream pathway inhibitors , constitutively active EGFR ( EGFRvIII ) , and EGFR amplification .	EGFR activity is enhanced by upregulation of EGFR protein expression, inhibition and deletion of downstream pathway inhibitors, constitutively active EGFR (EGFRvIII), and EGFR amplification.	0	10	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR protein expression	egfr	EGFR	EGFR	egfr	7	8	0	1
NEU3 appears to be indispensable for the survival of cancer cells , since small interfering RNA mediated knock down of NEU3 in cancer cell lines leads to decreased epidermal growth factor receptor ( EGFR ) phosphorylation and the suppression of Ras and extracellular signal regulated kinase ( ERK ) activation , which in turn results in apoptosis of the cells XREF_BIBR .	NEU3 appears to be indispensable for the survival of cancer cells, since small interfering RNA mediated knock down of NEU3 in cancer cell lines leads to decreased epidermal growth factor receptor (EGFR) phosphorylation and the suppression of Ras and extracellular signal regulated kinase (ERK) activation, which in turn results in apoptosis of the cells XREF_BIBR.	25	36	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor (EGFR) phosphorylation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	28	32	28	32
Our data also showed that HDACi mediated loss of EGFR , and the concurrent reduction of SGLT1 expression and glucose uptake would eliminate the overall pro survival functions of EGFR .	Our data also showed that HDACi mediated loss of EGFR, and the concurrent reduction of SGLT1 expression and glucose uptake would eliminate the overall pro survival functions of EGFR.	5	30	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	HDACi mediated loss of EGFR	egfr	EGFR	EGFR	egfr	9	10	29	30
Ligands which activate the EGF receptor ( EGFR ) have been shown to increase HCV cellular entry [ XREF_BIBR ] .	Ligands which activate the EGF receptor (EGFR) have been shown to increase HCV cellular entry [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGF receptor	EGF receptor	EGF receptor	7	8	4	6
Inhibition of EGF receptor tyrosine kinase activity did not reduce the proportion of EGFR high precursors after infection with either control or Akt1 viruses .	Inhibition of EGF receptor tyrosine kinase activity did not reduce the proportion of EGFR high precursors after infection with either control or Akt1 viruses.	2	15	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	EGFR	EGFR	EGFR	2	4	13	14
Systematic analysis of EGFR family phosphorylation dependent protein interactions has been assessed , and many of the known EGFR interacting proteins can be categorized as functioning in cellular processes such as EGF induced signal transduction and EGFR endocytosis and trafficking .	Systematic analysis of EGFR family phosphorylation dependent protein interactions has been assessed, and many of the known EGFR interacting proteins can be categorized as functioning in cellular processes such as EGF induced signal transduction and EGFR endocytosis and trafficking.	3	37	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR family phosphorylation	egfr	EGFR	EGFR	egfr	3	4	36	37
While the EGFR mRNA level was indistinguishable from that in control cells , the observed increase in cell surface area and total amount of EGFR ( XREF_FIG and XREF_FIG ) and enhanced stability of EGFR , relative to control cells ( XREF_FIG ) , are suggestive of defective EGFR endocytosis in SPIN90 knockdown cells .	While the EGFR mRNA level was indistinguishable from that in control cells, the observed increase in cell surface area and total amount of EGFR (XREF_FIG and XREF_FIG) and enhanced stability of EGFR, relative to control cells (XREF_FIG), are suggestive of defective EGFR endocytosis in SPIN90 knockdown cells.	2	35	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR mRNA level	egfr	EGFR	EGFR	egfr	2	3	34	35
XREF_BIBR The role of adaptor proteins Nck1 and Grb2 in recruiting PAK to phospho-Tyr containing signaling complexes such as the ligand activated EGF receptor ( ErbB1 ) has not yet been tested in the relevant knockout cells .	XREF_BIBR The role of adaptor proteins Nck1 and Grb2 in recruiting PAK to phospho-Tyr containing signaling complexes such as the ligand activated EGF receptor (ErbB1) has not yet been tested in the relevant knockout cells.	0	26	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ErbB1	ErbB1	ErbB1	EGF receptor	EGF receptor	EGF receptor	25	26	22	24
Cezanne-1 deubiquitinates and stabilizes EGFR , enhancing EGFR signaling and cancer progression [ XREF_BIBR ] .	Cezanne-1 deubiquitinates and stabilizes EGFR, enhancing EGFR signaling and cancer progression [XREF_BIBR].	0	8	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Cezanne-1 deubiquitinates and stabilizes EGFR	egfr	EGFR	EGFR	egfr	4	5	7	8
Estrogen can induce phosphorylation of EGFR , and can directly interact with signal transduction pathways , to activate MAPK , JAK and STAT , SRC , and PI3K signaling pathways downstream of EGFR .	Estrogen can induce phosphorylation of EGFR, and can directly interact with signal transduction pathways, to activate MAPK, JAK and STAT, SRC, and PI3K signaling pathways downstream of EGFR.	0	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Estrogen can induce phosphorylation of EGFR	egfr	EGFR	EGFR	egfr	5	6	32	33
Cetuximab combined with radiation inhibited radiation induced autophosphorylation of EGFR , and inhibited radiation induced homo-dimerization of EGFR .	Cetuximab combined with radiation inhibited radiation induced autophosphorylation of EGFR, and inhibited radiation induced homo-dimerization of EGFR.	0	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	Cetuximab combined with radiation inhibited radiation induced autophosphorylation of EGFR	egfr	EGFR	EGFR	egfr	9	10	17	18
To assess whether EGFR K721 mono-methylation enhances the activating phosphorylation marks of EGFR independently of EGF stimulation , we cotransfected 293T cells with HA-WHSC1L1 and FLAG-EGFR-WT , HA-WHSC1L1 and FLAG-EGFR-K721A , or an enzyme dead variant of WHSC1L1 ( HA-WHSC1L1 1-1073 ) and FLAG-EGFR-WT .	To assess whether EGFR K721 mono-methylation enhances the activating phosphorylation marks of EGFR independently of EGF stimulation, we cotransfected 293T cells with HA-WHSC1L1 and FLAG-EGFR-WT, HA-WHSC1L1 and FLAG-EGFR-K721A, or an enzyme dead variant of WHSC1L1 (HA-WHSC1L1 1-1073) and FLAG-EGFR-WT.	3	16	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR K721 mono-methylation	egfr	EGFR	EGFR	egfr	3	4	12	13
Taken together , these data indicated that AZD8055 induced EGFR up-regulation through an AKT dependent pathway and then activated the EGFR and AKT signaling pathways , which might contribute to cell resistance to AZD8055 in pancreatic cancers .	Taken together, these data indicated that AZD8055 induced EGFR up-regulation through an AKT dependent pathway and then activated the EGFR and AKT signaling pathways, which might contribute to cell resistance to AZD8055 in pancreatic cancers.	7	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	AZD8055 induced EGFR	egfr	EGFR	EGFR	egfr	9	10	20	21
In addition , administration of nNOSi , a highly selective inhibitor of nNOS , prior to hypoxia prevented the hypoxia induced increased activity and phosphorylation of EGFR kinase active site Tyr 418 , an index of Src kinase activation .	In addition, administration of nNOSi, a highly selective inhibitor of nNOS, prior to hypoxia prevented the hypoxia induced increased activity and phosphorylation of EGFR kinase active site Tyr 418, an index of Src kinase activation.	20	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	phosphorylation of EGFR kinase active site Tyr 418	egfr	EGFR	EGFR	egfr	26	27	26	27
There was an overexpression of epidermal growth factor receptor ( EGFR ) in > 50 % of patients with TNBC [ XREF_BIBR , XREF_BIBR ] , and it was found from a tumor microarray study that patients with significantly elevated expression of EGFR were more prone to lung metastasis [ XREF_BIBR ] .	There was an overexpression of epidermal growth factor receptor (EGFR) in> 50% of patients with TNBC [XREF_BIBR, XREF_BIBR], and it was found from a tumor microarray study that patients with significantly elevated expression of EGFR were more prone to lung metastasis [XREF_BIBR].	1	9	was an overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	epidermal growth factor receptor	overexpression of epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	5	9	5	9
EGFR is an expression product of proto-oncogene c-erbB1 , a member of the human epidermal receptor family .	EGFR is an expression product of proto-oncogene c-erbB1, a member of the human epidermal receptor family.	0	8	is an expression product	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	proto-oncogene c-erbB1	proto-oncogene c-erbB1	proto-oncogene c-erbB1	0	1	6	8
This increased cbl activation would then promote a more complete EGFR ubiquitination that promotes EGFR sorting into MVBs and targeting to the lysosome for degradation .	This increased cbl activation would then promote a more complete EGFR ubiquitination that promotes EGFR sorting into MVBs and targeting to the lysosome for degradation.	2	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	cbl activation would then promote a more complete EGFR ubiquitination	egfr	EGFR	EGFR	egfr	10	11	14	15
Whether EGFR expression levels , the nature of EGFR mutations , and/or activities of EGFR regulatory factors such as Src , Cbl or PTEN , which has been shown to be absent in the H1650 cell line [ XREF_BIBR ] , might contribute to the differences in the localization of mutant EGFR and their endocytic trafficking remain open questions .	Whether EGFR expression levels, the nature of EGFR mutations, and/or activities of EGFR regulatory factors such as Src, Cbl or PTEN, which has been shown to be absent in the H1650 cell line [XREF_BIBR], might contribute to the differences in the localization of mutant EGFR and their endocytic trafficking remain open questions.	1	43	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR expression levels	egfr	EGFR	EGFR	egfr	1	2	14	15
p38 mediated EGFR T669 phosphorylation may induce a conformational change in the EGFR cytoplasmic domain , revealing the AP2 interaction sites that are necessary for p38 dependent endocytosis .	p38 mediated EGFR T669 phosphorylation may induce a conformational change in the EGFR cytoplasmic domain, revealing the AP2 interaction sites that are necessary for p38 dependent endocytosis.	0	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	p38 mediated EGFR T669 phosphorylation	egfr	EGFR	EGFR	egfr	2	3	12	13
The parallel growth pattern of both the EGFR expressing cell lines as compared to the EGFR negative , 20GS cell line , supports the dominant role of EGFR for growth .	The parallel growth pattern of both the EGFR expressing cell lines as compared to the EGFR negative, 20GS cell line, supports the dominant role of EGFR for growth.	7	29	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR expressing	egfr	EGFR	EGFR	egfr	7	8	27	28
This possible redundant pathway might explain why the inhibition of EGFR ubiquitination by v-Cbl , a dominant negative form of c-Cbl , is not able to inhibit the internalization of EGFR XREF_BIBR , XREF_BIBR .	This possible redundant pathway might explain why the inhibition of EGFR ubiquitination by v-Cbl, a dominant negative form of c-Cbl, is not able to inhibit the internalization of EGFR XREF_BIBR, XREF_BIBR.	8	31	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	inhibition of EGFR ubiquitination by v-Cbl	egfr	EGFR	EGFR	egfr	10	11	30	31
Following treatment with erlotinib , P-EGFR and P-MAPK levels were reduced in both Cal33 and HSC-6 cells , demonstrating inhibition of EGFR under experimental conditions .	Following treatment with erlotinib, P-EGFR and P-MAPK levels were reduced in both Cal33 and HSC-6 cells, demonstrating inhibition of EGFR under experimental conditions.	5	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	P-EGFR	P-EGFR and P-MAPK levels	p-egfr	EGFR	EGFR	egfr	5	6	21	22
Therapies that target the EGF receptor ( EGFR ) , such as gefitinib ( IRESSA ) , are effective in a subset of patients with advanced non small cell lung cancer ( NSCLC ) .	Therapies that target the EGF receptor (EGFR), such as gefitinib (IRESSA), are effective in a subset of patients with advanced non small cell lung cancer (NSCLC).	0	8	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGF receptor	EGF receptor	EGF receptor	7	8	4	6
However , re-expression of either WT or KD EGFR rescued autophagic flux in EGFR knockdown cells ( XREF_FIG , left panels ) , and treatment of EGFR-WT re-expressing cells with the EGFR TKI gefitinib enhanced the rescue of autophagy initiation ( XREF_FIG , right panels ) , indicating the role for EGFR in autophagy initiation is kinase independent .	However, re-expression of either WT or KD EGFR rescued autophagic flux in EGFR knockdown cells (XREF_FIG, left panels), and treatment of EGFR-WT re-expressing cells with the EGFR TKI gefitinib enhanced the rescue of autophagy initiation (XREF_FIG, right panels), indicating the role for EGFR in autophagy initiation is kinase independent.	2	15	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	re-expression of either WT or KD EGFR	egfr	EGFR	EGFR	egfr	8	9	13	14
Thus , Src kinases may phosphorylate other residues in EGFR or other proteins that then mediate EGFR activation .	Thus, Src kinases may phosphorylate other residues in EGFR or other proteins that then mediate EGFR activation.	5	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	phosphorylate other residues in EGFR	egfr	EGFR	EGFR	egfr	9	10	16	17
Finally , we confirmed that ectopic expression of EGFR in CHO cells resulted in EGFR activation in response to radiation only in quiescent cells and not in proliferating cells ( XREF_FIG ) .	Finally, we confirmed that ectopic expression of EGFR in CHO cells resulted in EGFR activation in response to radiation only in quiescent cells and not in proliferating cells (XREF_FIG).	6	16	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	EGFR	expression of EGFR	egfr	EGFR	EGFR	egfr	8	9	14	15
Overexpression of EGFR leads to EGFR dimerization , auto-phosphorylation and downstream activation of the PI3K , STAT and MAPK pathways .	Overexpression of EGFR leads to EGFR dimerization, auto-phosphorylation and downstream activation of the PI3K, STAT and MAPK pathways.	0	6	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	EGFR	Overexpression of EGFR	egfr	EGFR	EGFR	egfr	2	3	5	6
Using an IR stimulated mouse lung tumorigenesis model , we explain that IR enhances the EGFR transcription , which causes a moderate EGFR protein increase in LBE cells , whereas , loss of translational suppression in Gprc5a -/- LBE cells markedly amplifies the increase of the EGFR protein level after IR exposure .	Using an IR stimulated mouse lung tumorigenesis model, we explain that IR enhances the EGFR transcription, which causes a moderate EGFR protein increase in LBE cells, whereas, loss of translational suppression in Gprc5a -/- LBE cells markedly amplifies the increase of the EGFR protein level after IR exposure.	12	24	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	IR enhances the EGFR transcription	egfr	EGFR	EGFR	egfr	15	16	22	23
Antibodies and antibody fragments targeting the extracellular EGF receptor and small molecules targeting the intracellular tyrosine kinase ( TK ) part of EGFR have been developed as possible diagnostic EGFR imaging agents .	Antibodies and antibody fragments targeting the extracellular EGF receptor and small molecules targeting the intracellular tyrosine kinase (TK) part of EGFR have been developed as possible diagnostic EGFR imaging agents.	7	23	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	EGFR	EGFR	EGFR	7	9	22	23
For example , it has been reported that mutant EGFR , especially EGFRvIII , contributes to the resistance to EGFR targeted therapy .	For example, it has been reported that mutant EGFR, especially EGFRvIII, contributes to the resistance to EGFR targeted therapy.	9	20	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	12	13	19	20
In addition , radiation triggers PKCepsilon mediated EGFR phosphorylation at Thr654 [ XREF_BIBR ] , which blocks CBL mediated EGFR ubiquitination and lysosomal degradation and promotes EGFR nuclear transport [ XREF_BIBR ] .	In addition, radiation triggers PKCepsilon mediated EGFR phosphorylation at Thr654 [XREF_BIBR], which blocks CBL mediated EGFR ubiquitination and lysosomal degradation and promotes EGFR nuclear transport [XREF_BIBR].	5	21	blocks	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	EGFR	PKCepsilon mediated EGFR phosphorylation at Thr654	egfr	EGFR	CBL mediated EGFR ubiquitination	egfr	7	8	19	20
Insights into the role of EGFR sensitizing mutations and acquired and de novo T790M resistance mutations followed , and differences in progression-free survival for patients with EGFR Del19- and L858R mutated tumors treated with reversible first generation EGF receptor tyrosine kinase inhibitors were reported .	Insights into the role of EGFR sensitizing mutations and acquired and de novo T790M resistance mutations followed, and differences in progression-free survival for patients with EGFR Del19- and L858R mutated tumors treated with reversible first generation EGF receptor tyrosine kinase inhibitors were reported.	26	41	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	EGFR	EGFR	EGFR	37	39	26	27
Specifically , TCPTP regulation of EGFR phosphorylation was studied in response to direct versus indirect activation of the EGFR by epidermal growth factor ( EGF ) and IFN-gamma , that can transactivate the EGFR , respectively .	Specifically, TCPTP regulation of EGFR phosphorylation was studied in response to direct versus indirect activation of the EGFR by epidermal growth factor (EGF) and IFN-gamma, that can transactivate the EGFR, respectively.	5	22	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR phosphorylation	egfr	EGFR	EGFR	egfr	5	6	18	19
Using HaCaT keratinocytes , knockdown of Dsg2 decreases EGFR expression and abrogates the activation of EGFR , c-Src and Stat3 , but not Erk1/2 or Akt , in response to EGF ligand stimulation .	Using HaCaT keratinocytes, knockdown of Dsg2 decreases EGFR expression and abrogates the activation of EGFR, c-Src and Stat3, but not Erk1/2 or Akt, in response to EGF ligand stimulation.	6	19	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Dsg2 decreases EGFR expression	egfr	EGFR	EGFR	egfr	8	9	15	16
In addition , patients suffering from recurrent glioblastoma with EGFR amplification and those lacking EGFRvIII expression have been treated with the EGFR targeted monoclonal antibody cetuximab with a significantly superior progression-free and overall survival XREF_BIBR .	In addition, patients suffering from recurrent glioblastoma with EGFR amplification and those lacking EGFRvIII expression have been treated with the EGFR targeted monoclonal antibody cetuximab with a significantly superior progression-free and overall survival XREF_BIBR.	14	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	21	22	14	15
EGFR overexpression enhances EGFR signaling in the adult SVZ ( data not shown ) and expands the NPC pool XREF_BIBR - XREF_BIBR ( XREF_SUPPLEMENTARY ) .	EGFR overexpression enhances EGFR signaling in the adult SVZ (data not shown) and expands the NPC pool XREF_BIBR - XREF_BIBR (XREF_SUPPLEMENTARY).	0	4	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	EGFR	EGFR	egfr	0	1	3	4
Since restoration of EGFR signaling by transgenic expression of sSpi or EGFR rescued the abnormal cardiac phenotypes observed in rho3 deficiencies and the ru 1 homozygotes , the effects of inhibiting EGFR signaling in the adult Drosophila heart were evaluated using a well characterized dominant negative EGFR ( EGFR.DN ) XREF_BIBR .	Since restoration of EGFR signaling by transgenic expression of sSpi or EGFR rescued the abnormal cardiac phenotypes observed in rho3 deficiencies and the ru 1 homozygotes, the effects of inhibiting EGFR signaling in the adult Drosophila heart were evaluated using a well characterized dominant negative EGFR (EGFR.DN) XREF_BIBR.	3	12	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGFR	expression of sSpi or EGFR	egfr	EGFR	EGFR	egfr	11	12	3	4
Phosphorylation of Y845 of EGFR by SRC stimulates the mitochondrial trafficking of EGFR .	Phosphorylation of Y845 of EGFR by SRC stimulates the mitochondrial trafficking of EGFR.	0	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Phosphorylation of Y845 of EGFR	egfr	EGFR	EGFR	egfr	4	5	12	13
Growth was inhibited in tumors expressing barely detectable levels of EGFR and in tumors overexpressing wild-type EGFR or the constitutively active EGFRvIII mutant , suggesting that the effect is at least partially independent of ligand activation or the type and level of EGFR expression .	Growth was inhibited in tumors expressing barely detectable levels of EGFR and in tumors overexpressing wild-type EGFR or the constitutively active EGFRvIII mutant, suggesting that the effect is at least partially independent of ligand activation or the type and level of EGFR expression.	14	44	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR expression	egfr	EGFR	EGFR	egfr	42	43	16	17
We demonstrate that GOF p53 upregulates EGFR expression and activates the EGFR pathway .	We demonstrate that GOF p53 upregulates EGFR expression and activates the EGFR pathway.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	p53 upregulates EGFR expression	egfr	EGFR	EGFR	egfr	6	7	11	12
For example , the dephosphorylation of epidermal growth factor receptor ( EGFR ) by PTP1B occurs at regions of close contact between the ER and multivesicular bodies , causing EGFR to become sequestered with multivesicular bodies .	For example, the dephosphorylation of epidermal growth factor receptor (EGFR) by PTP1B occurs at regions of close contact between the ER and multivesicular bodies, causing EGFR to become sequestered with multivesicular bodies.	4	30	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	dephosphorylation of epidermal growth factor receptor (EGFR	egfr	EGFR	EGFR	egfr	11	12	29	30
This may be due to enhanced ligand induced internalization of EGF receptor ( EGFR ) .	This may be due to enhanced ligand induced internalization of EGF receptor (EGFR).	7	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGF receptor	EGF receptor	EGF receptor	13	14	10	12
Increased EGFR expression and its association with advanced disease in NSCLC XREF_BIBR prompted early efforts toward clinical development of agents targeting the EGFR pathway .	Increased EGFR expression and its association with advanced disease in NSCLC XREF_BIBR prompted early efforts toward clinical development of agents targeting the EGFR pathway.	1	23	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR expression	egfr	EGFR	EGFR	egfr	1	2	22	23
Lapatinib is an oral dual erbB 1/2 tyrosine kinase inhibitor that inhibits human EGF receptor 2 ( HER2 ) and blocks the EGF receptor .	Lapatinib is an oral dual erbB 1/2 tyrosine kinase inhibitor that inhibits human EGF receptor 2 (HER2) and blocks the EGF receptor.	5	24	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	erbB	erbB	erbB	EGF receptor	EGF receptor	EGF receptor	5	6	22	24
Overexpression of epidermal growth factor receptor ( EGFR ) and mutation of pten tumor suppressor gene in human cancer cells leads to activated EGFR downstream signaling including PI3-kinase and AKT ( PI3K and AKT ) and/or mitogen activated protein kinases ( RAS/RAF/MAPK ) and have been linked to resistance to anti-EGFR targeted therapies .	Overexpression of epidermal growth factor receptor (EGFR) and mutation of pten tumor suppressor gene in human cancer cells leads to activated EGFR downstream signaling including PI3-kinase and AKT (PI3K and AKT) and/or mitogen activated protein kinases (RAS/RAF/MAPK) and have been linked to resistance to anti-EGFR targeted therapies.	0	25	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	Overexpression of epidermal growth factor receptor	epidermal growth factor receptor	EGFR	EGFR	egfr	2	6	23	24
Western blot analysis revealed that the phosphorylation levels of p44/42 and Akt were both reduced in AsPC-1 and CFPAC-1 SMAD4 reconstituted cells , but phosphatase and tensin homolog ( PTEN ) protein expression was not increased in SMAD4 transfected cells compared to cells with the control vectors , implying that SMAD4 loss not only increased the protein and phosphorylation levels of EGFR , but also activated the EGFR downstream signaling .	Western blot analysis revealed that the phosphorylation levels of p44/42 and Akt were both reduced in AsPC-1 and CFPAC-1 SMAD4 reconstituted cells, but phosphatase and tensin homolog (PTEN) protein expression was not increased in SMAD4 transfected cells compared to cells with the control vectors, implying that SMAD4 loss not only increased the protein and phosphorylation levels of EGFR, but also activated the EGFR downstream signaling.	50	69	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	SMAD4 loss not only increased the protein and phosphorylation levels of EGFR	egfr	EGFR	EGFR	egfr	61	62	67	68
Collectively , these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIII expressing tumors , and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity .	Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIII expressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity.	13	30	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII expressing	egfrviii	EGFR	EGFR	egfr	15	16	29	30
The down-regulation of HDAC3 increased the expression of pEGFR Y845 and induced interaction of EGFR with FAK and Src ( XREF_FIG ) .	The down-regulation of HDAC3 increased the expression of pEGFR Y845 and induced interaction of EGFR with FAK and Src (XREF_FIG).	3	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pEGFR	HDAC3 increased the expression of pEGFR	pegfr	EGFR	EGFR	egfr	8	9	14	15
In addition , upon activation by EGFR , Brk directly phosphorylated Y845 in the EGFR kinase domain , thereby further potentiating EGFR kinase activity .	In addition, upon activation by EGFR, Brk directly phosphorylated Y845 in the EGFR kinase domain, thereby further potentiating EGFR kinase activity.	8	23	potentiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Brk directly phosphorylated Y845 in the EGFR	egfr	EGFR	EGFR	egfr	14	15	21	22
Ultimately , the question remains as to whether dual EGFR and ERBB2 inhibition will itself be limited by de novo or induced upregulation of the remaining ERBB receptors .	Ultimately, the question remains as to whether dual EGFR and ERBB2 inhibition will itself be limited by de novo or induced upregulation of the remaining ERBB receptors.	8	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERBB	ERBB	ERBB	9	10	26	27
Re-expression of either WT or KD EGFR fully rescued the starvation induced formation of GFP-LC3 puncta in EGFR knockdown cells ( XREF_FIG ) .	Re-expression of either WT or KD EGFR fully rescued the starvation induced formation of GFP-LC3 puncta in EGFR knockdown cells (XREF_FIG).	0	19	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Re-expression of either WT or KD EGFR	egfr	EGFR	EGFR	egfr	6	7	17	18
The low levels of ubiquinated EGFR we observed in AR stimulated cells could be explained by the ability of c-Cbl to target EGFR indirectly for degradation by binding to Grb2 .	The low levels of ubiquinated EGFR we observed in AR stimulated cells could be explained by the ability of c-Cbl to target EGFR indirectly for degradation by binding to Grb2.	2	23	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	levels of ubiquinated EGFR	egfr	EGFR	EGFR	egfr	5	6	22	23
EGFR is overexpressed in more than 60 % of NSCLC cases and considered as a driving force in lung adenocarcinomas [ XREF_BIBR ] , so targeting EGFR to inhibit EGFR mediated pro survival and anti-apoptotic signals through the MAPK and ERK and PI3K and AKT pathways would be an effective lung cancer treatment .	EGFR is overexpressed in more than 60% of NSCLC cases and considered as a driving force in lung adenocarcinomas [XREF_BIBR], so targeting EGFR to inhibit EGFR mediated pro survival and anti-apoptotic signals through the MAPK and ERK and PI3K and AKT pathways would be an effective lung cancer treatment.	0	27	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR is overexpressed	egfr	EGFR	EGFR	egfr	0	1	26	27
In contrast , here we report that knockdown of GALNT1 suppresses EGF induced EGFR phosphorylation , accelerates EGFR internalization , and enhances EGFR degradation .	In contrast, here we report that knockdown of GALNT1 suppresses EGF induced EGFR phosphorylation, accelerates EGFR internalization, and enhances EGFR degradation.	9	18	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	GALNT1 suppresses EGF induced EGFR phosphorylation	egfr	EGFR	EGFR	egfr	13	14	17	18
The EGFR tyrosine kinase inhibitor , AG1478 , and the MEK inhibitor , U0126 , blocked these cellular effects of EGFRvIII .	The EGFR tyrosine kinase inhibitor, AG1478, and the MEK inhibitor, U0126, blocked these cellular effects of EGFRvIII.	1	21	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	1	2	20	21
Subsequently researchers identified that AKT phosphorylates EGFR directly at serine 229 in A431 gefitinib resistant cells , inducing the nuclear localization of EGFR ; inhibition of AKT with the pharmacological inhibitor API-2 , or through siRNA directed towards AKT1/2/3 reduced nuclear EGFR localization .	Subsequently researchers identified that AKT phosphorylates EGFR directly at serine 229 in A431 gefitinib resistant cells, inducing the nuclear localization of EGFR; inhibition of AKT with the pharmacological inhibitor API-2, or through siRNA directed towards AKT1/2/3 reduced nuclear EGFR localization.	4	23	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	AKT phosphorylates EGFR directly at serine 229	egfr	EGFR	EGFR	egfr	6	7	22	23
There is also loss of chromosome-10 , CDKN2A deletion and amplification of EGFR all linked to HGGs XREF_BIBR .	There is also loss of chromosome-10, CDKN2A deletion and amplification of EGFR all linked to HGGs XREF_BIBR.	1	14	is also loss	Negative_activation_copula_1	Positive_activation	Negative_activation	EGFR	loss of chromosome-10, CDKN2A deletion and amplification of EGFR	egfr	EGFR	EGFR	egfr	12	13	12	13
For example , GD1a increases EGFR dimerization and phosphorylation and increases activation of downstream EGFR signaling pathways , which results in cell proliferation .	For example, GD1a increases EGFR dimerization and phosphorylation and increases activation of downstream EGFR signaling pathways, which results in cell proliferation.	3	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	GD1a increases EGFR dimerization and phosphorylation	egfr	EGFR	EGFR	egfr	5	6	14	15
We hypothesized that inhibiting the phosphorylation of the EGFR and vascular endothelial growth factor receptor ( VEGFR ) by AEE788 , a dual tyrosine kinase inhibitor of EGFR and VEGFR , in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure .	We hypothesized that inhibiting the phosphorylation of the EGFR and vascular endothelial growth factor receptor (VEGFR) by AEE788, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure.	5	29	inhibitor	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGFR	phosphorylation of the EGFR and vascular endothelial growth factor receptor (VEGFR) by AEE788, a dual tyrosine	egfr	EGFR	EGFR	egfr	8	9	27	28
EGF receptor ( EGFR ) responsiveness to EGF is mediated by the surface expression of high affinity EGFR , which is associated with the cytoskeleton ( CSK ) .	EGF receptor (EGFR) responsiveness to EGF is mediated by the surface expression of high affinity EGFR, which is associated with the cytoskeleton (CSK).	0	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	expression of high affinity EGFR	egfr	EGF receptor	EGF receptor	egf receptor	17	18	0	2
Ectopic expression of EGFR in the 32D mouse myeloid cell line permits a saturating concentration of EGF to stimulate EGFR coupling to survival .	Ectopic expression of EGFR in the 32D mouse myeloid cell line permits a saturating concentration of EGF to stimulate EGFR coupling to survival.	1	20	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	expression of EGFR	egfr	EGFR	EGFR	egfr	3	4	19	20
Expression of EGFRvIII leads to recruitment of the ubiqitin ligases , TRAF2 and cIAP2 , to RIP1 and to EGFRvIII resulting in K63 linked ubiquitination of RIP1 and NF-kappaB activation .	Expression of EGFRvIII leads to recruitment of the ubiqitin ligases, TRAF2 and cIAP2, to RIP1 and to EGFRvIII resulting in K63 linked ubiquitination of RIP1 and NF-kappaB activation.	0	20	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFRvIII	Expression of EGFRvIII	egfrviii	EGFRvIII	EGFRvIII	egfrviii	2	3	19	20
In addition , MMP14 cleaves laminin5 gamma2 chain , which generates the EGF like fragment that activates EGF receptor ( EGFR ) .	In addition, MMP14 cleaves laminin5 gamma2 chain, which generates the EGF like fragment that activates EGF receptor (EGFR).	14	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGF receptor	EGF receptor	EGF receptor	20	21	17	19
Accordingly , inhibitor resistant lung cancer lines remain susceptible to EGFR and ErbB1 knockdown as well as irreversible EGFR and ErbB1 inhibitors that effectively reduce EGFR and ErbB1 abundance in cells .	Accordingly, inhibitor resistant lung cancer lines remain susceptible to EGFR and ErbB1 knockdown as well as irreversible EGFR and ErbB1 inhibitors that effectively reduce EGFR and ErbB1 abundance in cells.	8	28	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ErbB1	ErbB1	ErbB1	18	19	27	28
Overexpression of EGFR and its ligands is frequently observed in pancreatic cancer and correlates with poor prognosis , disease progression , and metastasis ( Oliveira-Cunha etal ., 2011 ; Xie and Xie , 2015 ) , supporting the prominent role of the EGFR family for malignant transformation , prevention of apoptosis , and drug resistance .	Overexpression of EGFR and its ligands is frequently observed in pancreatic cancer and correlates with poor prognosis, disease progression, and metastasis (Oliveira-Cunha etal., 2011; Xie and Xie, 2015), supporting the prominent role of the EGFR family for malignant transformation, prevention of apoptosis, and drug resistance.	0	43	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Overexpression of EGFR	egfr	EGFR	EGFR	egfr	2	3	42	43
We have previously shown the diabetes and/or hyperglycemia induces upregulation of EGFR and ErbB2 expression and phosphorylation that leads to vascular dysfunction via pathways involving ERK1/2 , p38 MAPK and ROCKs [ XREF_BIBR - XREF_BIBR ] .	We have previously shown the diabetes and/or hyperglycemia induces upregulation of EGFR and ErbB2 expression and phosphorylation that leads to vascular dysfunction via pathways involving ERK1/2, p38 MAPK and ROCKs [XREF_BIBR - XREF_BIBR].	8	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR and ErbB2 expression and phosphorylation	egfr	EGFR	EGFR	egfr	11	12	11	12
Overexpression of EGFR instantly leads to constitutive activation of EGFR in the absence of ligands [ XREF_BIBR ] .	Overexpression of EGFR instantly leads to constitutive activation of EGFR in the absence of ligands [XREF_BIBR].	0	10	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	EGFR	Overexpression of EGFR	egfr	EGFR	EGFR	egfr	2	3	9	10
Direct phosphorylation of EGFR by c-Src might allow transactivation of EGFR in the absence of growth factors .	Direct phosphorylation of EGFR by c-Src might allow transactivation of EGFR in the absence of growth factors.	1	11	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	phosphorylation of EGFR	egfr	EGFR	EGFR	egfr	3	4	10	11
As erlotinib has chiefly been reported to block EGFR phosphorylation rather than cause EGFR degradation , we conducted cell culture studies to better understand these clinical observations .	As erlotinib has chiefly been reported to block EGFR phosphorylation rather than cause EGFR degradation, we conducted cell culture studies to better understand these clinical observations.	1	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	erlotinib has chiefly been reported to block EGFR phosphorylation	egfr	EGFR	EGFR	egfr	8	9	13	14
To the best of our knowledge , this is the first study to evaluate the role of EGFRvIII in a cohort of patients with R/M SCCHN treated with or without EGFR TKI .	To the best of our knowledge, this is the first study to evaluate the role of EGFRvIII in a cohort of patients with R/M SCCHN treated with or without EGFR TKI.	15	31	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	30	31	17	18
Based on these data , we conclude that most HNSCC cell lines express activated EGFR levels driving EGFR dependent cell growth but certain cell lines may have features that weaken the dependence on EGFR .	Based on these data, we conclude that most HNSCC cell lines express activated EGFR levels driving EGFR dependent cell growth but certain cell lines may have features that weaken the dependence on EGFR.	14	29	driving	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR levels	egfr	EGFR	EGFR	egfr	14	15	17	18
EGFRvIII increases STAT3 activation .	EGFRvIII increases STAT3 activation.	0	3	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT3	STAT3	STAT3	0	1	2	3
Indeed , time dependent simulations backed up by experiments helped reveal that while inhibition of EGFR or PYK2 alone ( by Gefitinib or PF396 , respectively ) only temporarily suppressed the activities of ERK and STAT3 which were subsequently restored to basal levels ; this activity recovery was abolished by the combined treatment .	Indeed, time dependent simulations backed up by experiments helped reveal that while inhibition of EGFR or PYK2 alone (by Gefitinib or PF396, respectively) only temporarily suppressed the activities of ERK and STAT3 which were subsequently restored to basal levels; this activity recovery was abolished by the combined treatment.	13	36	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	15	16	35	36
As shown above , HAb18G and CD147 and EGFR activate STAT3 signaling , contributing to gemcitabine enhanced invasion .	As shown above, HAb18G and CD147 and EGFR activate STAT3 signaling, contributing to gemcitabine enhanced invasion.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	8	9	10	11
More recently , it has been shown that in a subset of glioblastomas the EGFR driven activation of STAT3 requires : a. the phosphorylation of EGFRvIII by EFGR , b. the nuclear entrance of EGFRvIII , and b. the formation of an EGFRvIII and STAT3 complex in the nucleus [ XREF_BIBR ] .	More recently, it has been shown that in a subset of glioblastomas the EGFR driven activation of STAT3 requires : a. the phosphorylation of EGFRvIII by EFGR, b. the nuclear entrance of EGFRvIII, and b. the formation of an EGFRvIII and STAT3 complex in the nucleus [XREF_BIBR].	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	14	15	18	19
We have previously shown that in the GBM cell line U87 , Stat3 is activated by EGFR and that activated Stat3 suppresses the spontaneous apoptosis of U87 cells by upregulating the expression of the pro survival protein Mcl-1 in vitro .	We have previously shown that in the GBM cell line U87, Stat3 is activated by EGFR and that activated Stat3 suppresses the spontaneous apoptosis of U87 cells by upregulating the expression of the pro survival protein Mcl-1 in vitro.	12	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	16	17	12	13
IL-13Ralpha2 and EGFRvIII enhances activation of MAPK and STAT3 .	IL-13Ralpha2 and EGFRvIII enhances activation of MAPK and STAT3.	0	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT3	STAT3	STAT3	2	3	8	9
Increased EGFR activity has been demonstrated to promote persistent activation of STAT3 , which leads to tumor progression .	Increased EGFR activity has been demonstrated to promote persistent activation of STAT3, which leads to tumor progression.	1	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	1	2	11	12
XREF_BIBR - XREF_BIBR Notably , the activation of EGFR finally triggers PI3K/Akt/mTOR and STAT3 signaling pathways , resulting in increased cell survival by activating antiapoptotic proteins .	XREF_BIBR - XREF_BIBR Notably, the activation of EGFR finally triggers PI3K/Akt/mTOR and STAT3 signaling pathways, resulting in increased cell survival by activating antiapoptotic proteins.	6	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	8	9	13	14
Since EGFR induced STAT3 activation has been shown to promote resistance to proteasome inhibitors in MM cells [ XREF_BIBR ] , we asked if the STAT3 activation in MM-3D cells contributes to resistance to bortezomib , a proteasome inhibitor commonly used in treating MM patients .	Since EGFR induced STAT3 activation has been shown to promote resistance to proteasome inhibitors in MM cells [XREF_BIBR], we asked if the STAT3 activation in MM-3D cells contributes to resistance to bortezomib, a proteasome inhibitor commonly used in treating MM patients.	1	4	induced	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	1	2	3	4
After being phosphorylated , EGFR is activated and then in turn activates multiple downstream intracellular signaling pathways , mainly PI3K-Akt , STAT3 , and Ras-Raf-MAPK pathways .	After being phosphorylated, EGFR is activated and then in turn activates multiple downstream intracellular signaling pathways, mainly PI3K-Akt, STAT3, and Ras-Raf-MAPK pathways.	4	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	4	5	21	22
Multiple signaling pathways converge on STAT3 activation , such as IL-6 and JAKs , EGFR , Src , and is overexpressed in a variety of tumor cells and tissues .	Multiple signaling pathways converge on STAT3 activation, such as IL-6 and JAKs, EGFR, Src, and is overexpressed in a variety of tumor cells and tissues.	5	16	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	14	15	5	6
In cancer cells with high MET activity , inhibition of EGFR activity alone likely is not sufficient to abrogate STAT3 activity .	In cancer cells with high MET activity, inhibition of EGFR activity alone likely is not sufficient to abrogate STAT3 activity.	10	20	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	10	11	19	20
To examine whether IL-6 and EGFR activate STAT3 in podocytes , we blocked IL-6 and EGFR in cultured primary podocytes and performed western blotting to determine STAT3 phosphorylation ( Tyr705 ) , which is a marker of STAT3 activation .	To examine whether IL-6 and EGFR activate STAT3 in podocytes, we blocked IL-6 and EGFR in cultured primary podocytes and performed western blotting to determine STAT3 phosphorylation (Tyr705), which is a marker of STAT3 activation.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	7	8
Inhibition of EGFRvIII phosphorylation by lapatinib and carnatinib strongly impaired the EGFRvIII-OSMR interaction and STAT3 activation .	Inhibition of EGFRvIII phosphorylation by lapatinib and carnatinib strongly impaired the EGFRvIII-OSMR interaction and STAT3 activation.	2	15	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII phosphorylation	egfrviii	STAT3	STAT3	stat3	2	3	14	15
Blockade of uPAR and MMP9 Inhibited EGFR Mediated Activation of STAT3 .	Blockade of uPAR and MMP9 Inhibited EGFR Mediated Activation of STAT3.	5	11	Mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	6	7	10	11
53 As AKT is also downstream of EGFR , EGFR can activate STAT3 through multiple downstream effectors .	53 As AKT is also downstream of EGFR, EGFR can activate STAT3 through multiple downstream effectors.	9	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	9	10	12	13
This soluble form of HB-EGF then binds to and initiates phosphorylation of EGFR and subsequently activates STAT1 and STAT3 ( XREF_FIG ) .	This soluble form of HB-EGF then binds to and initiates phosphorylation of EGFR and subsequently activates STAT1 and STAT3 (XREF_FIG).	4	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	HB-EGF then binds to and initiates phosphorylation of EGFR	egfr	STAT3	STAT3	stat3	12	13	18	19
While it is well established that EGFR can activate STAT3 , STAT1 activation by EGFR has been reported rarely in the literature and primarily in cells that overexpress EGFR .	While it is well established that EGFR can activate STAT3, STAT1 activation by EGFR has been reported rarely in the literature and primarily in cells that overexpress EGFR.	6	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	6	7	9	10
It is worth mentioning that prior studies have shown that there is cross-talk between JAK and STAT and EGFR signalling in the regulation of hyperproliferation [ XREF_BIBR ] , and that EGFR is an upstream activator of STAT3 that can mediate EGFR signalling [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] ; therefore , EGFR-TKIs may be able to inhibit STAT3 activation .	It is worth mentioning that prior studies have shown that there is cross-talk between JAK and STAT and EGFR signalling in the regulation of hyperproliferation [XREF_BIBR], and that EGFR is an upstream activator of STAT3 that can mediate EGFR signalling [XREF_BIBR, XREF_BIBR, XREF_BIBR]; therefore, EGFR-TKIs may be able to inhibit STAT3 activation.	31	38	is an upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	31	32	37	38
Moreover , EGFR reduction represses IKKalpha deletion induced excessive ERK , Stat3 and c-Jun activities , and skin inflammation .	Moreover, EGFR reduction represses IKKalpha deletion induced excessive ERK, Stat3 and c-Jun activities, and skin inflammation.	2	14	represses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	2	3	11	12
As STAT3 is activated by EGFR [ XREF_BIBR ] , we examined whether EGFR is involved in gemcitabine enhanced invasion by activating STAT3 .	As STAT3 is activated by EGFR [XREF_BIBR], we examined whether EGFR is involved in gemcitabine enhanced invasion by activating STAT3.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	1	2
EGFR signaling in myeloid cells promoted activation of STAT3 and expression of survivin in intestinal tumor cells .	EGFR signaling in myeloid cells promoted activation of STAT3 and expression of survivin in intestinal tumor cells.	0	10	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	0	1	8	9
EGFR amplifies EGF signals to activate MMP-9 and the ERK1/2 , PI3K and AKT , STAT3 , and STAT5 pathways .	EGFR amplifies EGF signals to activate MMP-9 and the ERK1/2, PI3K and AKT, STAT3, and STAT5 pathways.	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	0	1	15	16
Activation of the EGF receptor ( EGFR ) induces activation of STAT3 and AKT signaling pathways .	Activation of the EGF receptor (EGFR) induces activation of STAT3 and AKT signaling pathways.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	6	7	11	12
Similarly , an inhibitor of EGFR was shown to inhibit Stat3 activation and it was shown that high EGFR was positively correlated with Stat3 in breast cancer [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Similarly, an inhibitor of EGFR was shown to inhibit Stat3 activation and it was shown that high EGFR was positively correlated with Stat3 in breast cancer [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	5	6	10	11
In addition , p-STAT3 expression has been positively correlated to cyclin D1 expression , while the activation of epidermal growth factor receptor in glioma cells can cause excessive activation of STAT3 , and the resulting increased expression of cyclin D1 drives the accelerated proliferation of tumor cells .	In addition, p-STAT3 expression has been positively correlated to cyclin D1 expression, while the activation of epidermal growth factor receptor in glioma cells can cause excessive activation of STAT3, and the resulting increased expression of cyclin D1 drives the accelerated proliferation of tumor cells.	18	31	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	STAT3	STAT3	STAT3	18	22	30	31
For example , whereas the direct activation of STAT3 by EGFR has been clearly shown in HNSCC cells , STAT3 can also be activated by an EGFR independent mechanism .	For example, whereas the direct activation of STAT3 by EGFR has been clearly shown in HNSCC cells, STAT3 can also be activated by an EGFR independent mechanism.	19	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	26	27	19	20
In addition to IL-6 , STAT3 can be activated by EGFR in many cancer types .	In addition to IL-6, STAT3 can be activated by EGFR in many cancer types.	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	10	11	5	6
XREF_BIBR , XREF_BIBR It has been reported that EGFR activates Stat3 in various types of cancers including PC .	XREF_BIBR, XREF_BIBR It has been reported that EGFR activates Stat3 in various types of cancers including PC.	8	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	8	9	10	11
These findings suggest the involvement of EGFR in alpha 1 -AR induced Stat3 activation .	These findings suggest the involvement of EGFR in alpha 1 -AR induced Stat3 activation.	4	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	6	7	12	13
Aberrant EGFR signaling in GBM mediates STAT3 transcriptional activation to promote tumorigenesis , progression and invasion of glioblastoma XREF_BIBR , XREF_BIBR .	Aberrant EGFR signaling in GBM mediates STAT3 transcriptional activation to promote tumorigenesis, progression and invasion of glioblastoma XREF_BIBR, XREF_BIBR.	1	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	1	2	6	7
As the CD147 activation and knock-down influenced the pEGFR levels accordingly , EGFR activated pSTAT3 signaling depended on HAb18G and CD147 levels .	As the CD147 activation and knock-down influenced the pEGFR levels accordingly, EGFR activated pSTAT3 signaling depended on HAb18G and CD147 levels.	12	15	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	pSTAT3	pSTAT3	pSTAT3	12	13	14	15
Thus , we examined whether Src and EGFR Y845 mediate rapid STAT3 activation in T. gondii infected cells .	Thus, we examined whether Src and EGFR Y845 mediate rapid STAT3 activation in T. gondii infected cells.	5	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	7	8	11	12
Likewise , Bild and colleagues recently observed that STAT-3 signaling initiated by EGFR activation localized to endocytic vesicles that moved from the plasma membrane to the nucleus , and they found that inhibition of EGFR endocytosis prevented STAT-3 nuclear translocation and abrogated STAT-3-mediated gene transcription [ XREF_BIBR ] .	Likewise, Bild and colleagues recently observed that STAT-3 signaling initiated by EGFR activation localized to endocytic vesicles that moved from the plasma membrane to the nucleus, and they found that inhibition of EGFR endocytosis prevented STAT-3 nuclear translocation and abrogated STAT-3-mediated gene transcription [XREF_BIBR].	8	13	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT-3	STAT-3	STAT-3	12	13	8	9
Src kinase plays a vital role in EGFR mediated STAT3 and STAT5 activation in HNSCC .	Src kinase plays a vital role in EGFR mediated STAT3 and STAT5 activation in HNSCC.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	7	8	9	10
Specific inhibition of EGFR failed to prevent STAT3 activation in some HNSCC cell lines ; rather , an autocrine and paracrine IL-6 and gp130 loop was demonstrated in these cell lines [ XREF_BIBR ] .	Specific inhibition of EGFR failed to prevent STAT3 activation in some HNSCC cell lines; rather, an autocrine and paracrine IL-6 and gp130 loop was demonstrated in these cell lines [XREF_BIBR].	1	8	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	3	4	7	8
XREF_BIBR , XREF_BIBR , XREF_BIBR In addition to IL-6 , STAT3 can also be activated by EGFR that is often overexpressed in head and neck cancer cells .	XREF_BIBR, XREF_BIBR, XREF_BIBR In addition to IL-6, STAT3 can also be activated by EGFR that is often overexpressed in head and neck cancer cells.	10	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR that is often overexpressed	egfr	STAT3	STAT3	stat3	16	17	10	11
In addition , EGFR signaling has been shown to activate signal transducer and activator of transcription proteins ( STAT ) XREF_BIBR , particularly STAT3 mediated signaling XREF_BIBR .	In addition, EGFR signaling has been shown to activate signal transducer and activator of transcription proteins (STAT) XREF_BIBR, particularly STAT3 mediated signaling XREF_BIBR.	3	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	3	4	23	24
STAT3 can be activated by EGFR or IL-6 .	STAT3 can be activated by EGFR or IL-6.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	0	1
XREF_BIBR , XREF_BIBR EGFR activation results in downstream STAT3 activation in a JAK dependent manner , presumably through FGFR and IL-6 signaling .	XREF_BIBR, XREF_BIBR EGFR activation results in downstream STAT3 activation in a JAK dependent manner, presumably through FGFR and IL-6 signaling.	3	10	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	3	4	8	9
Inhibiting EGFR can enhance STAT1 signaling , hence stimulating TAA presentation , and inhibit STAT3 , hence favoring the conversion of an immunosuppressive tumor microenvironment into an immunostimulatory one .	Inhibiting EGFR can enhance STAT1 signaling, hence stimulating TAA presentation, and inhibit STAT3, hence favoring the conversion of an immunosuppressive tumor microenvironment into an immunostimulatory one.	0	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	1	2	14	15
EGFR is also known to activate STAT-3 and thus its downstream target genes involved in cell proliferation and survival ( such as c-Myc and survivin ) .	EGFR is also known to activate STAT-3 and thus its downstream target genes involved in cell proliferation and survival (such as c-Myc and survivin).	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT-3	STAT-3	STAT-3	0	1	6	7
In contrast , malignant progression of the keratinocyte towards SCC is associated with negative MAPK regulation and EGFR induced STAT3 activation [ XREF_BIBR - XREF_BIBR ] , which drives expression of multiple antiapoptotic molecules [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	In contrast, malignant progression of the keratinocyte towards SCC is associated with negative MAPK regulation and EGFR induced STAT3 activation [XREF_BIBR - XREF_BIBR], which drives expression of multiple antiapoptotic molecules [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	17	18	19	20
In HeLa cells , along with c-Src , Pyk2 can facilitate EGFR mediated STAT3 activation [ XREF_BIBR ] .	In HeLa cells, along with c-Src, Pyk2 can facilitate EGFR mediated STAT3 activation [XREF_BIBR].	10	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	11	12	13	14
In this case , the signal from hTERT to STAT3 can be transduced by the previously mentioned EGFR , which phosphorylates and thereby activates STAT3 [ XREF_BIBR ] .	In this case, the signal from hTERT to STAT3 can be transduced by the previously mentioned EGFR, which phosphorylates and thereby activates STAT3 [XREF_BIBR].	12	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	17	18	24	25
In H1650 cells , where mutated epidermal growth factor receptor ( EGFR ) constitutively activated STAT3 via SFKs , this compound reduced STAT3 phosphorylation without reduction of SFK phosphorylation , indicating that this compound could inhibit STAT3 phosphorylation independently of the type of upstream kinases ( XREF_FIG ) .	In H1650 cells, where mutated epidermal growth factor receptor (EGFR) constitutively activated STAT3 via SFKs, this compound reduced STAT3 phosphorylation without reduction of SFK phosphorylation, indicating that this compound could inhibit STAT3 phosphorylation independently of the type of upstream kinases (XREF_FIG).	6	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	STAT3	STAT3	STAT3	6	10	15	16
We propose that IRF3 is activated at the cell membrane and then translocates to the nucleus , partly analogous to the model described for EGFR mediated activation of STAT3 38 .	We propose that IRF3 is activated at the cell membrane and then translocates to the nucleus, partly analogous to the model described for EGFR mediated activation of STAT3 38.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	24	25	28	29
To determine the effects of cetuximab on EGFRvIII mediated STAT3 activation , HNSCC cells expressing EGFRvIII were treated with cetuximab followed by STAT3 promoter assays .	To determine the effects of cetuximab on EGFRvIII mediated STAT3 activation, HNSCC cells expressing EGFRvIII were treated with cetuximab followed by STAT3 promoter assays.	1	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT3	STAT3	STAT3	7	8	9	10
In this regard , epidermal growth factor receptor mediated activation of Stat3 occurrs in mouse epidermis following topical treatment of diverse classes of tumor promoters , including TPA , okadaic acid , and chrysarobin .	In this regard, epidermal growth factor receptor mediated activation of Stat3 occurrs in mouse epidermis following topical treatment of diverse classes of tumor promoters, including TPA, okadaic acid, and chrysarobin.	4	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	Stat3	Stat3	Stat3	4	8	11	12
These results suggest that EGFR and EGFRvIII driven STAT3 activation depends on TRIM24 linked histone modification .	These results suggest that EGFR and EGFRvIII driven STAT3 activation depends on TRIM24 linked histone modification.	4	10	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	4	5	8	9
The combination treatment of TG101348 and erlotinib obviously decreased the expressions of EGFR , p-EGFR , Bcl-xL and survivin , suppressed the activation of STAT3 , induced apoptosis and inhibited tumor growth of EGFR-mutant NSCLC cells in vivo .	The combination treatment of TG101348 and erlotinib obviously decreased the expressions of EGFR, p-EGFR, Bcl-xL and survivin, suppressed the activation of STAT3, induced apoptosis and inhibited tumor growth of EGFR-mutant NSCLC cells in vivo.	4	25	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p-EGFR	TG101348 and erlotinib obviously decreased the expressions of EGFR, p-EGFR	p-egfr	STAT3	STAT3	stat3	14	15	24	25
As noted above , Jak kinases can phosphorylate Stat3 , reinforcing Egfr mediated Stat3 activation .	As noted above, Jak kinases can phosphorylate Stat3, reinforcing Egfr mediated Stat3 activation.	11	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Egfr	Egfr	Egfr	Stat3	Stat3	Stat3	11	12	13	14
In this study , we demonstrated in stably transfected NIH-3T3 cells that activation of Stat3 by EGFR was eliminated by mutation of all five EGFR tyrosines to phenylalanine and that activation was restored with return of two of the mutated tyrosine sites , Y1068 and Y1086 , to wild-type .	In this study, we demonstrated in stably transfected NIH-3T3 cells that activation of Stat3 by EGFR was eliminated by mutation of all five EGFR tyrosines to phenylalanine and that activation was restored with return of two of the mutated tyrosine sites, Y1068 and Y1086, to wild-type.	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	16	17	14	15
These findings together suggest the EGFR and Src kinase activities promote the association of Stat3 with EGFR in the nuclear heteromeric complex , while the inhibition of EGFR or Src kinase alone does not preclude the interaction between EGFR and Src .	These findings together suggest the EGFR and Src kinase activities promote the association of Stat3 with EGFR in the nuclear heteromeric complex, while the inhibition of EGFR or Src kinase alone does not preclude the interaction between EGFR and Src.	4	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	5	6	14	15
XREF_BIBR , XREF_BIBR The observations herein would be consistent with the Gef-NArg conjugates preventing EGFR mediated STAT3 activation , while both molecules are in the nucleus , but a more complete mechanistic understanding would require further studies .	XREF_BIBR, XREF_BIBR The observations herein would be consistent with the Gef-NArg conjugates preventing EGFR mediated STAT3 activation, while both molecules are in the nucleus, but a more complete mechanistic understanding would require further studies.	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	14	15	16	17
This suggests the presence of an EGFR independent activation of Stat3 in HSC-1 cells .	This suggests the presence of an EGFR independent activation of Stat3 in HSC-1 cells.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	6	7	10	11
Stat3 activation by the EGFR has been mapped to the COOH-terminal region of the EGFR between amino acid residues 1061 and 1123 , which contains Y1068 and Y1086 .	Stat3 activation by the EGFR has been mapped to the COOH-terminal region of the EGFR between amino acid residues 1061 and 1123, which contains Y1068 and Y1086.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	4	5	0	1
It was reported that in tumor cells , EGFR is capable of activating STAT3 ; compared with IL-6 , which mediates STAT3 activation rapidly and transiently , EGFR mediated STAT3 activation is persistent 13 .	It was reported that in tumor cells, EGFR is capable of activating STAT3; compared with IL-6, which mediates STAT3 activation rapidly and transiently, EGFR mediated STAT3 activation is persistent 13.	27	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	27	28	29	30
Whether EGFRvIII triggers a transcriptional switch in STAT3 function outside of the brain will be an important question for future studies .	Whether EGFRvIII triggers a transcriptional switch in STAT3 function outside of the brain will be an important question for future studies.	1	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT3	STAT3	STAT3	1	2	7	8
STAT1 and STAT3 play opposing roles in the course of oncogenesis and tumor progression , and an imbalance in STAT1 vs STAT3 signaling is observed in many epithelial cancers , in particular in settings in which EGFR simultaneously activates STAT3 while inhibiting STAT1 via SHP2 .	STAT1 and STAT3 play opposing roles in the course of oncogenesis and tumor progression, and an imbalance in STAT1 vs STAT3 signaling is observed in many epithelial cancers, in particular in settings in which EGFR simultaneously activates STAT3 while inhibiting STAT1 via SHP2.	36	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	36	37	39	40
S1C ) , we investigated whether basal EGFR activity in the presence of the PDGFR inhibitor-IV contributes to cell shape change and STAT3 ( Y705 ) nuclear translocation .	S1C), we investigated whether basal EGFR activity in the presence of the PDGFR inhibitor-IV contributes to cell shape change and STAT3 (Y705) nuclear translocation.	7	27	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	7	8	22	23
In addition , the existence of EGFR independent signaling for Stat3 activation has been reported , enhancing the importance of Stat3 activation in tumor growth [ XREF_BIBR ] .	In addition, the existence of EGFR independent signaling for Stat3 activation has been reported, enhancing the importance of Stat3 activation in tumor growth [XREF_BIBR].	6	21	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	6	7	20	21
Collectively , in this work , we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3 , whereas treatment targeting EGFR only could not sufficiently repress NF-kappaB and STAT3 pathways for lung cancers harboring mutant EGFR .	Collectively, in this work, we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3, whereas treatment targeting EGFR only could not sufficiently repress NF-kappaB and STAT3 pathways for lung cancers harboring mutant EGFR.	21	32	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	23	24	31	32
Inhibitor of EGFR Downregulates the Constitutive Activation of Stat3 in HSC-1 Cells , and a Combination of Inhibitors of EGFR and PI3K and Akt Abrogates Stat3 Activation .	Inhibitor of EGFR Downregulates the Constitutive Activation of Stat3 in HSC-1 Cells, and a Combination of Inhibitors of EGFR and PI3K and Akt Abrogates Stat3 Activation.	0	11	Downregulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	2	3	8	9
TGFbeta and/or EGF and EGFR mediated STAT3 activation also has been observed to possess a pivotal role in EMT through increased TWIST1 expression in MC cells [ XREF_BIBR ] , [ XREF_BIBR ] .	TGFbeta and/or EGF and EGFR mediated STAT3 activation also has been observed to possess a pivotal role in EMT through increased TWIST1 expression in MC cells [XREF_BIBR], [XREF_BIBR].	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	4	5	6	7
Protein expression analysis demonstrated that immature testis xenografts were able to establish angiogenesis either through eNOS activation via VEGF and PI3K and AKT or through EGFR mediated STAT3 pathway .	Protein expression analysis demonstrated that immature testis xenografts were able to establish angiogenesis either through eNOS activation via VEGF and PI3K and AKT or through EGFR mediated STAT3 pathway.	11	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	25	26	27	28
However , endothelial growth factor receptor ( EGFR ) , which could activate STAT3 , has been implicated both in the inherent and acquired resistance to sorafenib [ XREF_BIBR , XREF_BIBR ] .	However, endothelial growth factor receptor (EGFR), which could activate STAT3, has been implicated both in the inherent and acquired resistance to sorafenib [XREF_BIBR, XREF_BIBR].	5	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	7	8	13	14
How JSRV Env activates STAT3 is not known , but since the EGFR activated STAT3 pathway XREF_BIBR is important in NSCLC cell survival XREF_BIBR , Env induced activation of EGFR could be one mechanism .	How JSRV Env activates STAT3 is not known, but since the EGFR activated STAT3 pathway XREF_BIBR is important in NSCLC cell survival XREF_BIBR, Env induced activation of EGFR could be one mechanism.	11	16	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	12	13	14	15
As IL6 promotes JAK2 and STAT3 activation , we hypothesized that NF-kappaB may be required for EGFR TKI induced STAT3 activation .	As IL6 promotes JAK2 and STAT3 activation, we hypothesized that NF-kappaB may be required for EGFR TKI induced STAT3 activation.	16	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	16	17	19	20
Previous studies have shown that EGFRvIII can promote EMT or cell invasion by activating STAT3 XREF_BIBR , XREF_BIBR or regulating myristoylated alanine rich protein kinase C substrate overexpression XREF_BIBR .	Previous studies have shown that EGFRvIII can promote EMT or cell invasion by activating STAT3 XREF_BIBR, XREF_BIBR or regulating myristoylated alanine rich protein kinase C substrate overexpression XREF_BIBR.	5	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT3	STAT3	STAT3	5	6	14	15
Using the knowledge that EGFRvIII activates the transcription factor STAT3 , they simultaneously performed RNA-seq on mouse astrocytes ( one of the normal cells of origin for HGG ) expressing EGFRvIII in the presence or absence of Stat3 .	Using the knowledge that EGFRvIII activates the transcription factor STAT3, they simultaneously performed RNA-seq on mouse astrocytes (one of the normal cells of origin for HGG) expressing EGFRvIII in the presence or absence of Stat3.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT3	STAT3	STAT3	4	5	9	10
The angiogenesis in testis graft could be established either through eNOS activation via VEGF and PI3K and AKT or via EGFR- mediated STAT3 pathway .	The angiogenesis in testis graft could be established either through eNOS activation via VEGF and PI3K and AKT or via EGFR- mediated STAT3 pathway.	7	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR-	EGFR-	EGFR-	STAT3	STAT3	STAT3	20	21	22	23
To confirm that EGFR driven STAT3 signaling is one of the key mechanisms , we added an EGFR specific inhibitor to Panc02 cell media .	To confirm that EGFR driven STAT3 signaling is one of the key mechanisms, we added an EGFR specific inhibitor to Panc02 cell media.	3	8	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	3	4	5	6
EGFR induced STAT3 activity has a well established role in the growth of primary human tumors that express high levels of EGFR including TNBC .	EGFR induced STAT3 activity has a well established role in the growth of primary human tumors that express high levels of EGFR including TNBC.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	0	1	2	3
EGFR and IL-6 have both been shown to activate STAT3 ( XREF_FIG ) , and the relative role of these ligands and their receptors may depend on epigenetic inactivation of SOCS-1 , a gene involved in negative feedback of IL-6R-janus kinase mediated STAT3 activation [ XREF_BIBR , XREF_BIBR ] .	EGFR and IL-6 have both been shown to activate STAT3 (XREF_FIG), and the relative role of these ligands and their receptors may depend on epigenetic inactivation of SOCS-1, a gene involved in negative feedback of IL-6R-janus kinase mediated STAT3 activation [XREF_BIBR, XREF_BIBR].	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	0	1	9	10
The proliferation and survival of myeloma cells may be suppressed by PD153035 due to the blockage of phosphatation of STAT3 induced by the activation of EGFR .	The proliferation and survival of myeloma cells may be suppressed by PD153035 due to the blockage of phosphatation of STAT3 induced by the activation of EGFR.	17	26	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	25	26	19	20
Src mediated EGFR transactivation is not required for Akt activation triggered by T. gondii but mediates ROP16 independent STAT3 activation .	Src mediated EGFR transactivation is not required for Akt activation triggered by T. gondii but mediates ROP16 independent STAT3 activation.	0	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Src mediated EGFR	egfr	STAT3	STAT3	stat3	2	3	18	19
STAT3 can be activated by EGFR , JAK2 , and other tyrosine kinases whose activation can be mediated by EGF , leukemia inhibitory factor ( LIF ) , and other cytokines .	STAT3 can be activated by EGFR, JAK2, and other tyrosine kinases whose activation can be mediated by EGF, leukemia inhibitory factor (LIF), and other cytokines.	0	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	0	1
In conclusion , our findings identify TRIM24 as an oncogenic transcriptional co-activator in EGFR driven GBM and also demonstrate a previously unknown signal relay by which H3K23ac and TRIM24 mediates EGFR stimulation of STAT3 activation , thereby enhancing the oncogenic activity of the EGFR and STAT3 pathway in human cancers .	In conclusion, our findings identify TRIM24 as an oncogenic transcriptional co-activator in EGFR driven GBM and also demonstrate a previously unknown signal relay by which H3K23ac and TRIM24 mediates EGFR stimulation of STAT3 activation, thereby enhancing the oncogenic activity of the EGFR and STAT3 pathway in human cancers.	30	34	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	30	31	33	34
AG1478 , an inhibitor of the EGFR , downregulated Stat3 activation in HSC-1 human SCC cells .	AG1478, an inhibitor of the EGFR, downregulated Stat3 activation in HSC-1 human SCC cells.	3	10	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	6	7	9	10
While inhibition of Src or EGFR signaling pathways temporarily reduces constitutive STAT3 in pancreatic cancer cell lines , reactivation of STAT3 occurs rapidly XREF_BIBR , XREF_BIBR .	While inhibition of Src or EGFR signaling pathways temporarily reduces constitutive STAT3 in pancreatic cancer cell lines, reactivation of STAT3 occurs rapidly XREF_BIBR, XREF_BIBR.	3	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	11	12
Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of EGFR , which subsequently activates STAT3 signaling .	Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of EGFR, which subsequently activates STAT3 signaling.	16	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	18	19	23	24
Myeloid cell expression of EGFR increases activation of STAT3 and expression of survivin in intestinal epithelial cells andexpression of IL6 in colon tissues .	Myeloid cell expression of EGFR increases activation of STAT3 and expression of survivin in intestinal epithelial cells andexpression of IL6 in colon tissues.	2	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	expression of EGFR	egfr	STAT3	STAT3	stat3	4	5	8	9
40 Here , we show EGFR expression is relevant to sphere formation , a surrogate of tumour initiation ( XREF_FIG ) , and that EGFR levels and activity mediate downstream activation of Stat3 in vivo and in vitro ( XREF_FIG ) .	40 Here, we show EGFR expression is relevant to sphere formation, a surrogate of tumour initiation (XREF_FIG), and that EGFR levels and activity mediate downstream activation of Stat3 in vivo and in vitro (XREF_FIG).	24	37	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR levels	egfr	Stat3	Stat3	stat3	24	25	32	33
This warrants exploration into the significance of EGFR mediated STAT3 activation in the dissemination of ovarian carcinoma .	This warrants exploration into the significance of EGFR mediated STAT3 activation in the dissemination of ovarian carcinoma.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	7	8	9	10
15d-PGJ 2 does not inhibit EGFR mediated Stat3 signalling .	15d-PGJ 2 does not inhibit EGFR mediated Stat3 signalling.	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	5	6	7	8
EGFR independent constitutive activation of STAT3 in head and neck cancers can also be mediated by IL-6 48 .	EGFR independent constitutive activation of STAT3 in head and neck cancers can also be mediated by IL-6 48.	0	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	0	1	5	6
Moreover , mutations in EGFR kinase domain have been shown to mediate STAT3 activation by IL-6 production in human lung carcinomas ( Gao et al , 2007 ) , suggesting that EGFR like STAT3 activation can be mediated by IL-6R or GP130 receptors in an autocrine manner .	Moreover, mutations in EGFR kinase domain have been shown to mediate STAT3 activation by IL-6 production in human lung carcinomas (Gao et al, 2007), suggesting that EGFR like STAT3 activation can be mediated by IL-6R or GP130 receptors in an autocrine manner.	4	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	4	5	12	13
SI-2 markedly reduced phosphorylation of EGFR and inhibited activation of AKT and STAT3 .	SI-2 markedly reduced phosphorylation of EGFR and inhibited activation of AKT and STAT3.	0	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	SI-2 markedly reduced phosphorylation of EGFR	egfr	STAT3	STAT3	stat3	5	6	12	13
But our results did not show if STAT3 was directly activated by EGFR during carcinogenesis .	But our results did not show if STAT3 was directly activated by EGFR during carcinogenesis.	7	13	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	12	13	7	8
These studies support the role of Stat3 as an oncogene , which is activated early in SCCHN carcinogenesis , and efforts to understand EGFR mediated Stat3 signaling could facilitate novel strategies that will interfere with this growth promoting pathway .	These studies support the role of Stat3 as an oncogene, which is activated early in SCCHN carcinogenesis, and efforts to understand EGFR mediated Stat3 signaling could facilitate novel strategies that will interfere with this growth promoting pathway.	22	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	23	24	25	26
Furthermore , continuous EGFR signalling from late endosomes contributes to sustained downstream AKT and STAT3 but not ERK1/2 or p38 signalling cascades .	Furthermore, continuous EGFR signalling from late endosomes contributes to sustained downstream AKT and STAT3 but not ERK1/2 or p38 signalling cascades.	3	15	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	3	4	14	15
Moreover , the EGFR activates STAT3 in lung cancer cell lines XREF_BIBR and can promote tumor survival in vivo in NSCLC by signaling through STAT3 XREF_BIBR .	Moreover, the EGFR activates STAT3 in lung cancer cell lines XREF_BIBR and can promote tumor survival in vivo in NSCLC by signaling through STAT3 XREF_BIBR.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	3	4	5	6
Interestingly , EGF receptor ( EGFR ) signaling contributes to tumor progression in the mouse AOM model 46 , and the ability of EGFR to activate STAT3 signaling would be impaired in the Ptk6 -/- mice .	Interestingly, EGF receptor (EGFR) signaling contributes to tumor progression in the mouse AOM model 46, and the ability of EGFR to activate STAT3 signaling would be impaired in the Ptk6 -/- mice.	3	27	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	26	27
Thus , our data also suggest that MALT1 contributes to the EGFR dependent activation of STAT3 in vivo .	Thus, our data also suggest that MALT1 contributes to the EGFR dependent activation of STAT3 in vivo.	11	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	11	12	15	16
To determine whether STAT3 is differentially activated by EGFRvIII , we analyzed expression of tyrosine phosphorylated STAT3 by immunoblotting in addition to STAT3 transcriptional activity in the EGFRvIII expressing HNSCC cells compared with vector-controls .	To determine whether STAT3 is differentially activated by EGFRvIII, we analyzed expression of tyrosine phosphorylated STAT3 by immunoblotting in addition to STAT3 transcriptional activity in the EGFRvIII expressing HNSCC cells compared with vector-controls.	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT3	STAT3	STAT3	8	9	3	4
According to our previous study , 7 EGFR , functioning as a REG3A receptor , mediated the REG3A signal promoting human pancreatic cancer cell growth and JAK2 and STAT3 activation .	According to our previous study, 7 EGFR, functioning as a REG3A receptor, mediated the REG3A signal promoting human pancreatic cancer cell growth and JAK2 and STAT3 activation.	6	29	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	7	8	28	29
To examine whether EGFR Y845 phosphorylation promotes STAT3 activation triggered by T. gondii , human epithelial cells were transfected with a plasmid encoding WT EGFR or Y845F EGFR .	To examine whether EGFR Y845 phosphorylation promotes STAT3 activation triggered by T. gondii, human epithelial cells were transfected with a plasmid encoding WT EGFR or Y845F EGFR.	3	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR Y845 phosphorylation	egfr	STAT3	STAT3	stat3	3	4	7	8
These gain and loss of function of EGFR results demonstrate that EGFR is a significant activator of STAT3 in MPNST cells .	These gain and loss of function of EGFR results demonstrate that EGFR is a significant activator of STAT3 in MPNST cells.	11	20	is a significant activator	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	11	12	17	18
An example of STAT activation independently of JAK is the activation of STAT3 by epidermal growth factor receptor ( EGFR ) most notably by c-Src XREF_BIBR , XREF_BIBR .	An example of STAT activation independently of JAK is the activation of STAT3 by epidermal growth factor receptor (EGFR) most notably by c-Src XREF_BIBR, XREF_BIBR.	10	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	STAT3	STAT3	STAT3	14	18	12	13
NO induced EGFR and Src activation subsequently activated Akt , c-Myc , STAT3 and beta-catenin pathways .	NO induced EGFR and Src activation subsequently activated Akt, c-Myc, STAT3 and beta-catenin pathways.	0	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	NO induced EGFR	egfr	STAT3	STAT3	stat3	2	3	12	13
EGF-R mediated signaling is upstream of Stat3 activation and involved in the postnatal maintenance of the thymic medulla .	EGF-R mediated signaling is upstream of Stat3 activation and involved in the postnatal maintenance of the thymic medulla.	0	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF-R	EGF-R	EGF-R	Stat3	Stat3	Stat3	0	1	6	7
An early hypothesis suggested that pStat3 is activated by deregulation of EGFR and aberrant IL-6 expression [ XREF_BIBR ] .	An early hypothesis suggested that pStat3 is activated by deregulation of EGFR and aberrant IL-6 expression [XREF_BIBR].	5	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	pStat3	pStat3	pStat3	11	12	5	6
Reduction of EGFR activation decreased STAT3 activation , which could attenuate the development of fibrotic progress .	Reduction of EGFR activation decreased STAT3 activation, which could attenuate the development of fibrotic progress.	2	6	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	2	3	5	6
EGFR overexpression can activate NF-kappaB and STAT3 , which leads to chemoresistance and poor outcome .	EGFR overexpression can activate NF-kappaB and STAT3, which leads to chemoresistance and poor outcome.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	STAT3	STAT3	stat3	0	1	6	7
These results clearly demonstrated that MET- and EGFR mediated STAT3 signalings cooperatively contribute to liver regeneration and could provide new insights into tissue homeostasis .	These results clearly demonstrated that MET- and EGFR mediated STAT3 signalings cooperatively contribute to liver regeneration and could provide new insights into tissue homeostasis.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	7	8	9	10
SIE reporter assays showed that PIAS3 served as a potent inhibitor for STAT3 by not only inhibiting constitutive STAT3 activity but also impairing EGFR induced STAT3 transcription activation .	SIE reporter assays showed that PIAS3 served as a potent inhibitor for STAT3 by not only inhibiting constitutive STAT3 activity but also impairing EGFR induced STAT3 transcription activation.	22	27	induced	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	23	24	25	26
XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR Growth promoting signaling pathways including mitogen activated protein kinase and extracellular signal regulated kinase ( MAPK and ERK ) and Stat3 , activated by EGFR , VEGFR2 and PDGFRs are key mediators of the normal healing process .	XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR Growth promoting signaling pathways including mitogen activated protein kinase and extracellular signal regulated kinase (MAPK and ERK) and Stat3, activated by EGFR, VEGFR2 and PDGFRs are key mediators of the normal healing process.	6	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	29	30	25	26
Given that STAT3 is activated by EGFR and IL-6 , we selected two NSCLC cell lines ( H1650 and A549 ) with different PIAS3 expression levels to determine the effect of EGFR and IL-6 stimulation on PIAS3 interaction with STAT3 .	Given that STAT3 is activated by EGFR and IL-6, we selected two NSCLC cell lines (H1650 and A549) with different PIAS3 expression levels to determine the effect of EGFR and IL-6 stimulation on PIAS3 interaction with STAT3.	2	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	6	7	2	3
Unlike ligand activated wild-type EGFR , however , EGFRvIII also activates the c-Jun N-terminal kinase through PI3K , but can not activate the signal transducers and activators of transcription 1 ( STAT1 ) and STAT3 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Unlike ligand activated wild-type EGFR, however, EGFRvIII also activates the c-Jun N-terminal kinase through PI3K, but can not activate the signal transducers and activators of transcription 1 (STAT1) and STAT3 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT3	STAT3	STAT3	8	9	34	35
The apoptosis induced by targeting MMP-9 and uPAR was initiated by inhibiting epidermal growth factor receptor ( EGFR ) mediated activation of STAT3 and NF-kappaB related signaling molecules .	The apoptosis induced by targeting MMP-9 and uPAR was initiated by inhibiting epidermal growth factor receptor (EGFR) mediated activation of STAT3 and NF-kappaB related signaling molecules.	17	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	17	18	22	23
Although VEGF and EGFR can activate JAK and STAT3 signaling pathway , a variety of extracellular stimuli especially IL6 expression , is necessary for the activation of STAT3 signaling [ XREF_BIBR - XREF_BIBR ] .	Although VEGF and EGFR can activate JAK and STAT3 signaling pathway, a variety of extracellular stimuli especially IL6 expression, is necessary for the activation of STAT3 signaling [XREF_BIBR - XREF_BIBR].	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	3	4	8	9
Thus II-6 mediated activation of P-Jak2 depends on EGFR mediated Stat3 activation in SCPs , and maintains viability of SCPs .	Thus II-6 mediated activation of P-Jak2 depends on EGFR mediated Stat3 activation in SCPs, and maintains viability of SCPs.	6	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	8	9	10	11
We observed STAT3 phosphorylation in these cells , confirming that EGFR knockdown impairs STAT3 activation by IGFBP2 without compromising alternate STAT3 activation pathways ( XREF_SUPPLEMENTARY ) .	We observed STAT3 phosphorylation in these cells, confirming that EGFR knockdown impairs STAT3 activation by IGFBP2 without compromising alternate STAT3 activation pathways (XREF_SUPPLEMENTARY).	10	14	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	10	11	13	14
STAT3 is activated by receptor tyrosine kinases EGFR , HER2 , fibroblast growth factor receptor ( FGFR ) , IGFR , HGFR and platelet derived growth factor receptor ( PDGFR ) , receptor associated kinases ( JAK ) and non receptor kinases ( Src and Abl ) through phosphorylation [ XREF_BIBR , XREF_BIBR ] .	STAT3 is activated by receptor tyrosine kinases EGFR, HER2, fibroblast growth factor receptor (FGFR), IGFR, HGFR and platelet derived growth factor receptor (PDGFR), receptor associated kinases (JAK) and non receptor kinases (Src and Abl) through phosphorylation [XREF_BIBR, XREF_BIBR].	0	41	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	7	8	0	1
EGFR activation induces the constitutive activation of signal transducer and activator of transcription 3 ( STAT3 ) , a known oncogenic transcription factor .	EGFR activation induces the constitutive activation of signal transducer and activator of transcription 3 (STAT3), a known oncogenic transcription factor.	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	0	1	15	16
As a membrane protein , EGFR can activate intracellular signaling molecule STAT3 , which functions as a transcription factor to carry EGFR signal to the nuclear and regulate target gene expression .	As a membrane protein, EGFR can activate intracellular signaling molecule STAT3, which functions as a transcription factor to carry EGFR signal to the nuclear and regulate target gene expression.	5	27	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	11	12
It has been reported that Bcl-xL is regulated by EGFR activated STAT3 to promote survival in head and neck cancer XREF_BIBR .	It has been reported that Bcl-xL is regulated by EGFR activated STAT3 to promote survival in head and neck cancer XREF_BIBR.	7	12	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	9	10	11	12
Butaprost also induced the activation of AKT , ERK1/2 , and STAT3 , all of which were inhibited by beta-arrestin deficiency or EGFR inhibition .	Butaprost also induced the activation of AKT, ERK1/2, and STAT3, all of which were inhibited by beta-arrestin deficiency or EGFR inhibition.	2	23	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	22	23	11	12
The relationship between LIF- and EGFR induced STAT3 activation is also found in various types of cells , such as lung carcinoma cells [ XREF_BIBR ] and ovarian cancer cell lines [ XREF_BIBR ] .	The relationship between LIF- and EGFR induced STAT3 activation is also found in various types of cells, such as lung carcinoma cells [XREF_BIBR] and ovarian cancer cell lines [XREF_BIBR].	1	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	7	8
Mechanistically , EGFR kinase activity mediated activation of ERK1/2 and STAT3 signaling pathways to induce inflammation and renal cell injury .	Mechanistically, EGFR kinase activity mediated activation of ERK1/2 and STAT3 signaling pathways to induce inflammation and renal cell injury.	2	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	2	3	10	11
In addition , EGFR is known to activate STAT3 signaling .	In addition, EGFR is known to activate STAT3 signaling.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	3	4	8	9
Although a large body of knowledge has established the mechanisms by which EGFR activates STAT3 through JAK or Src 48 , in this study , we show a novel mechanism by which activated EGFR enhances H3K23 acetylation and TRIM24 expression , promoting the association of TRIM24 with H3K23ac and STAT3 , and facilitating STAT3 interaction with chromatin , leading to downstream signaling activation to drive glioma tumorigenesis .	Although a large body of knowledge has established the mechanisms by which EGFR activates STAT3 through JAK or Src 48, in this study, we show a novel mechanism by which activated EGFR enhances H3K23 acetylation and TRIM24 expression, promoting the association of TRIM24 with H3K23ac and STAT3, and facilitating STAT3 interaction with chromatin, leading to downstream signaling activation to drive glioma tumorigenesis.	12	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	12	13	14	15
Our data reveal that in basal conditions expression of 247R genetic variant of alpha 1a AR leads to STAT3 activation that is inhibited by EGFR- and MMP- specific inhibitors , demonstrating EGFR transactivation dependent STAT3 activation .	Our data reveal that in basal conditions expression of 247R genetic variant of alpha 1a AR leads to STAT3 activation that is inhibited by EGFR- and MMP- specific inhibitors, demonstrating EGFR transactivation dependent STAT3 activation.	22	35	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR-	EGFR-	EGFR-	STAT3	STAT3	STAT3	24	25	34	35
Combined inhibition of Src and EGFR with gemcitabine inhibits constitutively activated STAT3 .	Combined inhibition of Src and EGFR with gemcitabine inhibits constitutively activated STAT3.	1	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	11	12
In vitro data show that EGFR blockade decreased STAT3 activation .	In vitro data show that EGFR blockade decreased STAT3 activation.	5	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	8	9
Signatures scoring different pathways were also concordant ; for instance , Myc mediated regulation of E2F signaling 33 was identified by the association between the RB-LOH 16 and Myc 15 signatures ( R = 0.79 ) , while EGFR mediated activation of Stat3 signaling 34 was recapitulated by the EGFR XREF_BIBR , XREF_BIBR and Stat3 XREF_BIBR , XREF_BIBR ( R = 0.72 ) signatures .	Signatures scoring different pathways were also concordant; for instance, Myc mediated regulation of E2F signaling 33 was identified by the association between the RB-LOH 16 and Myc 15 signatures (R = 0.79), while EGFR mediated activation of Stat3 signaling 34 was recapitulated by the EGFR XREF_BIBR, XREF_BIBR and Stat3 XREF_BIBR, XREF_BIBR (R = 0.72) signatures.	38	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	38	39	42	43
In epithelial tumors , STAT3 activation is mediated by EGFR , erythropoietin receptor , IL-6 receptor , PDGFR , c-Met , and IGF1R .	In epithelial tumors, STAT3 activation is mediated by EGFR, erythropoietin receptor, IL-6 receptor, PDGFR, c-Met, and IGF1R.	4	22	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	9	10	4	5
Present data also suggest that only a portion of the intracellular EGFR , Src and Stat3 protein pools are utilized in the formation of the nuclear complex , raising the possibility that there may be diverse cellular pools of EGFR , Src , or Stat3 with different accessibility limitations .	Present data also suggest that only a portion of the intracellular EGFR, Src and Stat3 protein pools are utilized in the formation of the nuclear complex, raising the possibility that there may be diverse cellular pools of EGFR, Src, or Stat3 with different accessibility limitations.	11	45	raising	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	11	12	44	45
Because the EGFR makes major contributions to STAT3 activation during tumor promotion , loss of CD151-integrin regulation of the EGFR should contribute to diminished STAT3 activation .	Because the EGFR makes major contributions to STAT3 activation during tumor promotion, loss of CD151-integrin regulation of the EGFR should contribute to diminished STAT3 activation.	16	25	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	19	20	24	25
EGFR Signaling in Myeloid Cells Promotes STAT3 Activation in Colorectal Tumor Cells .	EGFR Signaling in Myeloid Cells Promotes STAT3 Activation in Colorectal Tumor Cells.	0	7	Promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	0	1	6	7
In addition , epidermal growth factor receptor ( EGFR ) , which is known to activate STAT3 , is critical for lung cancer metastasis XREF_BIBR .	In addition, epidermal growth factor receptor (EGFR), which is known to activate STAT3, is critical for lung cancer metastasis XREF_BIBR.	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	8	9	16	17
The role of STAT3 in HPV positive and negative oral lesions was evaluated further by examining level of pEGFR ( Y1092 ) that activates STAT3 28 and p16 , a negative regulator of STAT3 29 and an established surrogate marker for HPV infection 7 .	The role of STAT3 in HPV positive and negative oral lesions was evaluated further by examining level of pEGFR (Y1092) that activates STAT3 28 and p16, a negative regulator of STAT3 29 and an established surrogate marker for HPV infection 7.	16	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pEGFR	level of pEGFR	pegfr	STAT3	STAT3	stat3	18	19	24	25
Sustained STAT3 activation in this process may be mediated by EGFR .	Sustained STAT3 activation in this process may be mediated by EGFR.	1	11	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	10	11	1	2
Although high levels of activated STAT3 occur in cells with activating mutation of EGFR , we did not believe that STAT3 activity is driven directly by EGFR kinase activity .	Although high levels of activated STAT3 occur in cells with activating mutation of EGFR, we did not believe that STAT3 activity is driven directly by EGFR kinase activity.	20	28	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	26	27	20	21
XREF_BIBR , XREF_BIBR , XREF_BIBR In this regard , the previously demonstrated overexpression of EGFR and its ligands in the tumor cells of specific subtypes of SGTs , including salivary duct carcinoma , mucoepidermoid carcinoma , and adenoid cystic carcinoma , may drive constitutive Stat3 signaling in these tumors .	XREF_BIBR, XREF_BIBR, XREF_BIBR In this regard, the previously demonstrated overexpression of EGFR and its ligands in the tumor cells of specific subtypes of SGTs, including salivary duct carcinoma, mucoepidermoid carcinoma, and adenoid cystic carcinoma, may drive constitutive Stat3 signaling in these tumors.	12	45	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	overexpression of EGFR	egfr	Stat3	Stat3	stat3	14	15	44	45
However , recent evidence points to the contribution of Src in EGFR mediated Stat3 activation ( Xi et al , 2003 ) and supports the existence of EGFR independent Stat3 oncogenic properties ( Kijima et al , 2002 ) .	However, recent evidence points to the contribution of Src in EGFR mediated Stat3 activation (Xi et al, 2003) and supports the existence of EGFR independent Stat3 oncogenic properties (Kijima et al, 2002).	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	11	12	13	14
12 Interleukin 6 ( IL-6 ) , Janus activated kinases ( JAK ) , EGFR , and Src family kinases are among the activators of Stat3 .	12 Interleukin 6 (IL-6), Janus activated kinases (JAK), EGFR, and Src family kinases are among the activators of Stat3.	1	26	are among the activators	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	14	15	25	26
We therefore hypothesize that perhaps EGFR mediated STAT3 activation kinetics differ from those of IL-6 to account for their differential effect on proteasome subunit induction .	We therefore hypothesize that perhaps EGFR mediated STAT3 activation kinetics differ from those of IL-6 to account for their differential effect on proteasome subunit induction.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	7	8
ROS produced by this oxidase activates Src , enable that in turn , transactivates EGFR that activates Stat3 in tyrosine , allowing its dimerization .	ROS produced by this oxidase activates Src, enable that in turn, transactivates EGFR that activates Stat3 in tyrosine, allowing its dimerization.	13	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	14	15	17	18
IL6 was consistently and significantly increased by EGFR TKI treatment in two distinct EGFR-mutant NSCLC model ( XREF_FIG ) , and was recently implicated as a mediator of EGFR TKI induced STAT3 activation .	IL6 was consistently and significantly increased by EGFR TKI treatment in two distinct EGFR-mutant NSCLC model (XREF_FIG), and was recently implicated as a mediator of EGFR TKI induced STAT3 activation.	28	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	28	29	31	32
To assess the effect of 15d-PGJ 2 on EGFR mediated activation of Stat3 , oral SCC cells were stimulated with exogenous TGF-alpha in the presence or absence of 15d-PGJ 2 .	To assess the effect of 15d-PGJ 2 on EGFR mediated activation of Stat3, oral SCC cells were stimulated with exogenous TGF-alpha in the presence or absence of 15d-PGJ 2.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	8	9	12	13
In the present study , we further confirmed that STAT3 could be activated by EGFRvIII , and inhibition of STAT3 activation or knock down of STAT3 could inhibit S100A11 expression and S100A11 promoter activity .	In the present study, we further confirmed that STAT3 could be activated by EGFRvIII, and inhibition of STAT3 activation or knock down of STAT3 could inhibit S100A11 expression and S100A11 promoter activity.	9	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT3	STAT3	STAT3	14	15	9	10
In this study , we aimed to investigate the activity of Stat3 related activators such as EGFR and PI3K and Akt in the proliferation of a cutaneous malignant tumor , SCC , and evaluate the therapeutic value of inhibition of the signaling pathways .	In this study, we aimed to investigate the activity of Stat3 related activators such as EGFR and PI3K and Akt in the proliferation of a cutaneous malignant tumor, SCC, and evaluate the therapeutic value of inhibition of the signaling pathways.	11	20	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	16	17	11	12
We provided evidence of a novel link among NADPH oxidase and Stat3 signaling , mediated by Src , EGFR , and Erk1/2 .	We provided evidence of a novel link among NADPH oxidase and Stat3 signaling, mediated by Src, EGFR, and Erk1/2.	11	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	18	19	11	12
It has been shown that the crosstalk between TAMs and tumor cells can regulate the induction of pluripotency gene SOX-2 through EGF receptor mediated activation of STAT3 signaling [ XREF_BIBR ] .	It has been shown that the crosstalk between TAMs and tumor cells can regulate the induction of pluripotency gene SOX-2 through EGF receptor mediated activation of STAT3 signaling [XREF_BIBR].	21	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	STAT3	STAT3	STAT3	21	23	26	27
We observed a two-fold increase in nuclear p-STAT3 in PDX tumors treated with erlotinib ( XREF_FIG ) , consistent with the STAT3 activation observed in EGFR-mutant NSCLC cell lines treated with an EGFR TKI .	We observed a two-fold increase in nuclear p-STAT3 in PDX tumors treated with erlotinib (XREF_FIG), consistent with the STAT3 activation observed in EGFR-mutant NSCLC cell lines treated with an EGFR TKI.	21	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	32	33	21	22
In addition to IL-6 signaling , STAT3 can be activated by EGFR , PDGFR , and Src kinase .	In addition to IL-6 signaling, STAT3 can be activated by EGFR, PDGFR, and Src kinase.	6	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	11	12	6	7
The EGFR- and CSF-1-mediated activation of STAT3 in tumor cells and tumor associated immune cells is one of the key mechanisms by which TAMs provide support to tumors.32 Although expression of EGFR in the peripheral area of the pLSCCs was not different compared with the central area , phospho-EGFR ( pY1068 ) and phospho-STAT3 ( Tyr705 ) expression in the peripheral area of pLSCCs were higher than in the central area .	The EGFR- and CSF-1-mediated activation of STAT3 in tumor cells and tumor associated immune cells is one of the key mechanisms by which TAMs provide support to tumors.32 Although expression of EGFR in the peripheral area of the pLSCCs was not different compared with the central area, phospho-EGFR (pY1068) and phospho-STAT3 (Tyr705) expression in the peripheral area of pLSCCs were higher than in the central area.	1	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR-	EGFR-	EGFR-	STAT3	STAT3	STAT3	1	2	6	7
Importantly , iNOS mediates EGFRvIII induced STAT3 dependent proliferation of astrocytes .	Importantly, iNOS mediates EGFRvIII induced STAT3 dependent proliferation of astrocytes.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT3	STAT3	STAT3	4	5	6	7
Firstly , we determined whether EGFR is responsible for activation of ERK and STAT3 and expression of COX-2 and eNOS in CLP induced AKI mice model .	Firstly, we determined whether EGFR is responsible for activation of ERK and STAT3 and expression of COX-2 and eNOS in CLP induced AKI mice model.	5	14	is responsible for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	13	14
For example , small molecule inhibitors of JAK , Src , Bcr-Abl , and EGFR have all been shown to block STAT3 signaling and induce tumor cell apoptosis ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	For example, small molecule inhibitors of JAK, Src, Bcr-Abl, and EGFR have all been shown to block STAT3 signaling and induce tumor cell apoptosis (XREF_FIG) [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	22	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	14	15	21	22
In response to irradiation , EGFR also functions anti-apoptotically , especially in heterodimers with ERBB2 [ XREF_BIBR ] , and transcriptionally activates anti-apoptotic BCL2L1 via SRC and STAT3 ( signal transducer and activator of transcription 3 ) signaling [ XREF_BIBR ] .	In response to irradiation, EGFR also functions anti-apoptotically, especially in heterodimers with ERBB2 [XREF_BIBR], and transcriptionally activates anti-apoptotic BCL2L1 via SRC and STAT3 (signal transducer and activator of transcription 3) signaling [XREF_BIBR].	5	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	27	28
XREF_BIBR , XREF_BIBR EGFR induced STAT3 signaling initiates transcription of genes necessary for cell growth ( Cyclin D1 ) , survival ( Bcl-X L ) and angiogenesis ( VEGF ) .	XREF_BIBR, XREF_BIBR EGFR induced STAT3 signaling initiates transcription of genes necessary for cell growth (Cyclin D1), survival (Bcl-X L) and angiogenesis (VEGF).	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	3	4	5	6
And repressed GPRC5A correlates with activated EGFR and STAT3 signaling in lung cancer [ XREF_BIBR ] , which explains dysregulated STAT3 induced by aberrantly activated EGFR in lung cancer .	And repressed GPRC5A correlates with activated EGFR and STAT3 signaling in lung cancer [XREF_BIBR], which explains dysregulated STAT3 induced by aberrantly activated EGFR in lung cancer.	18	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	25	26	20	21
We showed that in SCP , EGFR driven P-Stat3 stimulates II-6 secretion , and Il6 reinforced EGFR and Stat signalling ( XREF_FIG ) .	We showed that in SCP, EGFR driven P-Stat3 stimulates II-6 secretion, and Il6 reinforced EGFR and Stat signalling (XREF_FIG).	6	9	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	P-Stat3	P-Stat3	P-Stat3	6	7	8	9
A newly identified EGFR variant , termed EGFRvA [ XREF_BIBR ] , also drives STAT3 activation , as does a reported EGFR-SEPT14 chimera [ XREF_BIBR ] .	A newly identified EGFR variant, termed EGFRvA [XREF_BIBR], also drives STAT3 activation, as does a reported EGFR-SEPT14 chimera [XREF_BIBR].	3	15	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	3	4	14	15
Expression of miR-21 can be influenced by gene amplification 12 , transcriptional silencing 39 , genotoxic stress ( i.e. H 2 O 2 or ionizing radiation ) 40 , and various other transcriptional mechanisms including activation by EGFR pathway 41 , STAT3 dependent regulation through interleukin 6 ( IL-6 ) 42 or interferon ( IFN ) 43 and transcriptional repression by FOXO3A 44 .	Expression of miR-21 can be influenced by gene amplification 12, transcriptional silencing 39, genotoxic stress (i.e. H 2 O 2 or ionizing radiation) 40, and various other transcriptional mechanisms including activation by EGFR pathway 41, STAT3 dependent regulation through interleukin 6 (IL-6) 42 or interferon (IFN) 43 and transcriptional repression by FOXO3A 44.	35	43	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	37	38	41	42
EGFR stimulation has been shown to activate STAT3 .	EGFR stimulation has been shown to activate STAT3.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	0	1	7	8
STAT3 can be also activated by EGFR , JAK2 , and other tyrosine kinases activated by EGF , leukemia inhibitory factor ( LIF ) , and other cytokines .	STAT3 can be also activated by EGFR, JAK2, and other tyrosine kinases activated by EGF, leukemia inhibitory factor (LIF), and other cytokines.	0	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	6	7	0	1
Blockade of EGFR activation inhibited the activation of both AKT and Stat3 in U87 and D54 GBM cells and induced spontaneous apoptosis , which were associated with reduction in the steady-state level of Mcl-1 .	Blockade of EGFR activation inhibited the activation of both AKT and Stat3 in U87 and D54 GBM cells and induced spontaneous apoptosis, which were associated with reduction in the steady-state level of Mcl-1.	2	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	2	3	11	12
Inhibition of epidermal growth factor receptor ( EGFR ) and Src activities by the inhibitors PD-153035 and PP2 , respectively , abolished the activation of Stat3 by DEP , suggesting that Stat3 activation by DEP requires EGFR and Src kinase activation .	Inhibition of epidermal growth factor receptor (EGFR) and Src activities by the inhibitors PD-153035 and PP2, respectively, abolished the activation of Stat3 by DEP, suggesting that Stat3 activation by DEP requires EGFR and Src kinase activation.	5	26	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	7	8	25	26
EGFR activation induces STAT3 signaling .	EGFR activation induces STAT3 signaling.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	0	1	3	4
XREF_BIBR Indeed , the activation of STAT3 by EGF receptor ( EGFR ) requires Src to phosphorylate the catalytic domain of EGFR at Tyr845 , as well as at two EGFR autophosphorylation sites located at Tyr1068 and Tyr1086 , both of which serve as docking sites for STAT3 .	XREF_BIBR Indeed, the activation of STAT3 by EGF receptor (EGFR) requires Src to phosphorylate the catalytic domain of EGFR at Tyr845, as well as at two EGFR autophosphorylation sites located at Tyr1068 and Tyr1086, both of which serve as docking sites for STAT3.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	STAT3	STAT3	STAT3	8	10	6	7
Since STAT3 is activated by EGFR and IL-6R , EGFR inhibition in combination with IL-6 antagonists [ XREF_BIBR ] or STAT decoy oligonucleotides [ XREF_BIBR ] holds potential for synergistic activity .	Since STAT3 is activated by EGFR and IL-6R, EGFR inhibition in combination with IL-6 antagonists [XREF_BIBR] or STAT decoy oligonucleotides [XREF_BIBR] holds potential for synergistic activity.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	5	6	1	2
Here , we provide evidence that Pyk2 , along with c-Src , facilitates EGFR mediated Stat3 activation .	Here, we provide evidence that Pyk2, along with c-Src, facilitates EGFR mediated Stat3 activation.	12	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	13	14	15	16
Next , we evaluated the importance of the specific interactions between PTPN18 and HER2 Y 1196 and Y 1248 phosphorylated sites in EGF induced HER2 signaling , utilizing information derived from complex crystal structures .	Next, we evaluated the importance of the specific interactions between PTPN18 and HER2 Y 1196 and Y 1248 phosphorylated sites in EGF induced HER2 signaling, utilizing information derived from complex crystal structures.	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	22	23	24	25
The efficient internalization of both HER2 and EGFR within 10 minutes of EGF stimulation in the HER2 cells clearly demonstrates that HER2 ' s primary role is not sequestering EGFR and itself at the PM .	The efficient internalization of both HER2 and EGFR within 10 minutes of EGF stimulation in the HER2 cells clearly demonstrates that HER2 's primary role is not sequestering EGFR and itself at the PM.	12	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	12	13	16	17
When we treated with wortmannin , another PI3K inhibitor , or we knocked down PI3K or AKT isoforms in the presence of EGF , ErbB2 up-regulation was not observed , suggesting that the increase of ErbB2 induced by EGF plus LY294002 is not mediated by the PI3K-Akt pathway .	When we treated with wortmannin, another PI3K inhibitor, or we knocked down PI3K or AKT isoforms in the presence of EGF, ErbB2 up-regulation was not observed, suggesting that the increase of ErbB2 induced by EGF plus LY294002 is not mediated by the PI3K-Akt pathway.	33	40	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	38	39	35	36
Luminal breast cancer cells usually do not exhibit amplification of the EGF signaling HER2 receptor or show only low over-expression of this receptor ; nevertheless , they bind EGF and respond to its tumor promoting stimuli [ XREF_BIBR - XREF_BIBR ] .	Luminal breast cancer cells usually do not exhibit amplification of the EGF signaling HER2 receptor or show only low over-expression of this receptor; nevertheless, they bind EGF and respond to its tumor promoting stimuli [XREF_BIBR - XREF_BIBR].	11	15	signaling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2 receptor	HER2 receptor	HER2 receptor	11	12	13	15
Our results imply that activation of ErbB2 by EGF preferentially takes place outside lipid raft domains and an increased dipole potential mimics this effect .	Our results imply that activation of ErbB2 by EGF preferentially takes place outside lipid raft domains and an increased dipole potential mimics this effect.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	8	9	6	7
Her2 and Her3 are also activated by EGF and BTC providing additional means for these ligands to support cell signaling and growth .	Her2 and Her3 are also activated by EGF and BTC providing additional means for these ligands to support cell signaling and growth.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	Her2	Her2	Her2	7	8	0	1
Together , these findings demonstrated that the CI values measured indeed resulted from changes in the status of NRG1b- and EGF elicited HER2 signaling activities .	Together, these findings demonstrated that the CI values measured indeed resulted from changes in the status of NRG1b- and EGF elicited HER2 signaling activities.	20	24	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	20	21	22	23
Since inhibition of EGF signaling in ErbB2 positive breast cancers has been associated with glucose deprivation and energetic stress , we hypothesized that lapatinib mediated cell toxicity may be associated with inhibition of glucose uptake and subsequent energetic stress .	Since inhibition of EGF signaling in ErbB2 positive breast cancers has been associated with glucose deprivation and energetic stress, we hypothesized that lapatinib mediated cell toxicity may be associated with inhibition of glucose uptake and subsequent energetic stress.	3	9	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	3	4	6	7
Neu differentiation factor ( NDF ) , a member of the epidermal growth factor ( EGF )-related peptide family , activates ErbB2 via heterodimerization with the NDF receptors ErbB3 and ErbB4 .	Neu differentiation factor (NDF), a member of the epidermal growth factor (EGF)-related peptide family, activates ErbB2 via heterodimerization with the NDF receptors ErbB3 and ErbB4.	11	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	ErbB2	ErbB2	ErbB2	11	14	21	22
The p-value for the comparison of HER2 phosphorylation by both ligands EGF+ HRG in HER2 +/3+ and by EGF activation in HER2 +/3- cells is 0.019 .	The p-value for the comparison of HER2 phosphorylation by both ligands EGF+HRG in HER2 +/3+ and by EGF activation in HER2 +/3- cells is 0.019.	18	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	18	19	21	22
The authors evaluated HER2 over-expressed breast cancer cell lines ( SK-BR3 ) treated with TGF-b or EGF with induction of SMAD3 phosphorylation and CEACAM6 expression .	The authors evaluated HER2 over-expressed breast cancer cell lines (SK-BR3) treated with TGF-b or EGF with induction of SMAD3 phosphorylation and CEACAM6 expression.	2	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	16	17	3	4
EGF induced Y1068F-EGFR trafficking resembles that of WT-EGFR in presence of HER2 .	EGF induced Y1068F-EGFR trafficking resembles that of WT-EGFR in presence of HER2.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	0	1	11	12
Western blot analysis of the immunoprecipitates using anti-PY antibody revealed that HER2 and Neu was activated by H. pylori infection and EGF treatment in AGS cells .	Western blot analysis of the immunoprecipitates using anti-PY antibody revealed that HER2 and Neu was activated by H. pylori infection and EGF treatment in AGS cells.	11	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	Neu	Neu	Neu	21	22	13	14
Cells that expressed ErbB2 and treated with EGF showed prolonged activation of Raf-1 and MAP kinase compared with cells that expressed low levels of ErbB2 .	Cells that expressed ErbB2 and treated with EGF showed prolonged activation of Raf-1 and MAP kinase compared with cells that expressed low levels of ErbB2.	2	8	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	7	8	3	4
EGF treatment of Nsi cells resulted in a mild activation of EGFR , HER2 , and MET receptors .	EGF treatment of Nsi cells resulted in a mild activation of EGFR, HER2, and MET receptors.	0	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	0	1	13	14
EGF stimulation of HER2 overexpressing cells promoted migration by phosphorylation of proteins that belong to different pathways , including PI3K , MAPK , catenins and FAK .	EGF stimulation of HER2 overexpressing cells promoted migration by phosphorylation of proteins that belong to different pathways, including PI3K, MAPK, catenins and FAK.	0	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	0	1	3	4
In contrast , EGF , which can signal through an ErbB-1 and ErbB-2 heterodimer , induced phosphorylation of tyrosines 1112 , 1139 , and 1248 of ErbB-2 in the same cells .	In contrast, EGF, which can signal through an ErbB-1 and ErbB-2 heterodimer, induced phosphorylation of tyrosines 1112, 1139, and 1248 of ErbB-2 in the same cells.	3	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-2	ErbB-2	ErbB-2	3	4	26	27
Since A431 cells over-express EGFR , we expected AG 1478 to prevent activation of HER2 by EGF stimulation .	Since A431 cells over-express EGFR, we expected AG 1478 to prevent activation of HER2 by EGF stimulation.	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	16	17	14	15
Since we did not detect nuclear EGFR-HER2 heterodimers , EGF induced HER2 nuclear transport may potentially be a result of nuclear transport of Her-3 .	Since we did not detect nuclear EGFR-HER2 heterodimers, EGF induced HER2 nuclear transport may potentially be a result of nuclear transport of Her-3.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	9	10	11	12
Different Her-2 targeting drugs may involve different mechanisms , such as pertuzumab inhibits the dimerization of Her-2 with other human epidermal growth factor receptors , while lapatinib , a dual tyrosine kinase inhibitor , interrupts the Her-2 and neu and epidermal growth factor receptor ( EGFR ) pathways .	Different Her-2 targeting drugs may involve different mechanisms, such as pertuzumab inhibits the dimerization of Her-2 with other human epidermal growth factor receptors, while lapatinib, a dual tyrosine kinase inhibitor, interrupts the Her-2 and neu and epidermal growth factor receptor (EGFR) pathways.	12	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	Her-2	Her-2	Her-2	20	23	16	17
More specifically , EGF stimulation of HER2 overexpressing cells promoted migration by the phosphorylation of proteins from multiple pathways ( e.g ., PI3K , MAPK , catenins , and FAK ) , whereas HRG stimulation of HER2 overexpressing cells activated only a very specific subset of proteins in the canonical migration pathway , in particular FAK , Src , paxillin , and p130Cas .	More specifically, EGF stimulation of HER2 overexpressing cells promoted migration by the phosphorylation of proteins from multiple pathways (e.g., PI3K, MAPK, catenins, and FAK), whereas HRG stimulation of HER2 overexpressing cells activated only a very specific subset of proteins in the canonical migration pathway, in particular FAK, Src, paxillin, and p130Cas.	3	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	3	4	6	7
Herceptin , a humanized anti-human epidermal growth factor receptor-2 ( HER2 ) monoclonal antibody , is used for treatment of metastatic breast cancer patients overexpressing HER2 on tumor cells , and is being studied in clinical trials for therapy of other types of cancer .	Herceptin, a humanized anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody, is used for treatment of metastatic breast cancer patients overexpressing HER2 on tumor cells, and is being studied in clinical trials for therapy of other types of cancer.	5	26	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	HER2	HER2	HER2	5	8	25	26
Although substrate stiffness did not increase the levels of Akt pS473 in unstimulated MECs , ECM stiffness potentiated the magnitude of EGF activated Akt pS473 ( XREF_FIG ) and increased ErbB2 activated Akt pS473 ( XREF_FIG ) .	Although substrate stiffness did not increase the levels of Akt pS473 in unstimulated MECs, ECM stiffness potentiated the magnitude of EGF activated Akt pS473 (XREF_FIG) and increased ErbB2 activated Akt pS473 (XREF_FIG).	19	33	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	21	22	30	31
EGF and NRG1b activated the HER2 pathway by initially increasing the impedance values in a ligand concentration dependent manner .	EGF and NRG1b activated the HER2 pathway by initially increasing the impedance values in a ligand concentration dependent manner.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	0	1	5	6
The results suggested that PKG II inhibits EGF induced activation of HER2 through binding with and causing threonine 686 phosphorylation of this oncogenic protein .	The results suggested that PKG II inhibits EGF induced activation of HER2 through binding with and causing threonine 686 phosphorylation of this oncogenic protein.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	7	8	11	12
This closes the paracrine positive feedback loop and can strengthen the feedback , since the increased EGF level can induce upregulation of Her2 and Neu , a member of the EGFR family , which in turn strengthens signaling via the EGF pathway .	This closes the paracrine positive feedback loop and can strengthen the feedback, since the increased EGF level can induce upregulation of Her2 and Neu, a member of the EGFR family, which in turn strengthens signaling via the EGF pathway.	16	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF level	egf	Neu	Neu	neu	16	17	24	25
As expected , neither EGF nor NRG-1 ( ligands of other ErbBs ) activated ErbB2 in CHO-K1 and ErbB2 cells ( XREF_SUPPLEMENTARY ) .	As expected, neither EGF nor NRG-1 (ligands of other ErbBs) activated ErbB2 in CHO-K1 and ErbB2 cells (XREF_SUPPLEMENTARY).	3	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	4	5	14	15
Moreover , rapid phospho-turnover is not restricted to ErbB1 and the same phenomenon can be observed ( or inferred ) for EGF activated ErbB2 and ErbB3 , and for IGF1R and FGFR1 .	Moreover, rapid phospho-turnover is not restricted to ErbB1 and the same phenomenon can be observed (or inferred) for EGF activated ErbB2 and ErbB3, and for IGF1R and FGFR1.	21	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	21	22	23	24
Amplification of the human epidermal growth factor receptor-2 gene ( HER2 ) leads to an overabundance of the Her-2 protein on the cell surface , enhances dimerization of Her-2 with itself or with other members of the epidermal growth factor receptor ( egfr ) family , and triggers intracellular tyrosine kinase activity and signal transduction pathways .	Amplification of the human epidermal growth factor receptor-2 gene (HER2) leads to an overabundance of the Her-2 protein on the cell surface, enhances dimerization of Her-2 with itself or with other members of the epidermal growth factor receptor (egfr) family, and triggers intracellular tyrosine kinase activity and signal transduction pathways.	3	29	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	Her-2	Her-2	Her-2	4	7	28	29
Although EGF induced a phosphorylation of ErbB-2 in HEK293 cells , activation of ErbB-2 by EGF via the ErbB-1 and ErbB-2 heterodimer did not result in tyrosine phosphorylation of plexin B1 or activation of RhoA ( XREF_FIG B ) .	Although EGF induced a phosphorylation of ErbB-2 in HEK293 cells, activation of ErbB-2 by EGF via the ErbB-1 and ErbB-2 heterodimer did not result in tyrosine phosphorylation of plexin B1 or activation of RhoA (XREF_FIG B).	11	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB-2	ErbB-2	ErbB-2	15	16	13	14
Stimulation of SKBR3 cells and HCII RI # 11 mouse mammary epithelial cells expressing the human erbB-2 with EGF led to an increase in scFv ( FRP5 )-ETA activity , showing that the EGF induced activation of erbB-2 can potentiate the action of the erbB-2-directed toxin .	Stimulation of SKBR3 cells and HCII RI # 11 mouse mammary epithelial cells expressing the human erbB-2 with EGF led to an increase in scFv (FRP5)-ETA activity, showing that the EGF induced activation of erbB-2 can potentiate the action of the erbB-2-directed toxin.	32	38	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	erbB-2	erbB-2	erbB-2	33	34	37	38
Stable HER2 transfectants derived from wt p53 line treated with heregulin-beta1 or epidermal growth factor showed a decrease in proliferation due to a G ( 2 )/M cell cycle block despite normal mitogen activated protein kinase activation .	Stable HER2 transfectants derived from wt p53 line treated with heregulin-beta1 or epidermal growth factor showed a decrease in proliferation due to a G (2)/M cell cycle block despite normal mitogen activated protein kinase activation.	1	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	HER2	HER2	HER2	12	15	1	2
In contrast , EGFR truncation did not impair EGF mitogenic signaling , and in c ' 1000 cells EGF was able to stimulate the association of ErbB2 with GRB2 and SHC .	In contrast, EGFR truncation did not impair EGF mitogenic signaling, and in c ' 1000 cells EGF was able to stimulate the association of ErbB2 with GRB2 and SHC.	16	27	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	18	19	26	27
Treatment with trastuzumab modestly inhibited growth and invasiveness of HER2 YVMA but not EGF stimulated HER2 WT acini in 3D co-culture ( XREF_FIG ) .	Treatment with trastuzumab modestly inhibited growth and invasiveness of HER2 YVMA but not EGF stimulated HER2 WT acini in 3D co-culture (XREF_FIG).	5	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	13	14	15	16
Activation of ERBB2 by EGF or HRG could be found in Jones et al ..	Activation of ERBB2 by EGF or HRG could be found in Jones et al..	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ERBB2	ERBB2	ERBB2	4	5	2	3
Ligand dependent activation of HER1 , HER3 , and HER4 by EGF or heregulin results in heterodimerization and , thereby , HER2 activation .	Ligand dependent activation of HER1, HER3, and HER4 by EGF or heregulin results in heterodimerization and, thereby, HER2 activation.	2	22	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	11	12	21	22
Like with leptin , the best stimulation of HER2 was seen with the 200 ng/mL dose and high EGF concentrations produced HER2 downregulation .	Like with leptin, the best stimulation of HER2 was seen with the 200 ng/mL dose and high EGF concentrations produced HER2 downregulation.	18	22	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	18	19	21	22
EGF induces heparanase nucleolar localization in high HER2 - expressing 231BR3 cells .	EGF induces heparanase nucleolar localization in high HER2 - expressing 231BR3 cells.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	0	1	7	8
Although ErbB2 was not present in freshly isolated hepatocytes , EGF and insulin independently induced ErbB2 while suppressing ErbB3 expression .	Although ErbB2 was not present in freshly isolated hepatocytes, EGF and insulin independently induced ErbB2 while suppressing ErbB3 expression.	10	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	10	11	15	16
Our study suggests that residual ErbB2 activation by EGF , despite EGFR blockade , is responsible for persistent downstream activation of Stat-3 .	Our study suggests that residual ErbB2 activation by EGF, despite EGFR blockade, is responsible for persistent downstream activation of Stat-3.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	8	9	5	6
In this plot , the sum of NRG1b- and EGF driven HER2 signals that can be inhibited by pertuzumab in the same CELx HSF test was used to calculate the net CELx HSF test value ( an indicator of HER2 signaling activity ) for each cell line , as described in the Methods .	In this plot, the sum of NRG1b- and EGF driven HER2 signals that can be inhibited by pertuzumab in the same CELx HSF test was used to calculate the net CELx HSF test value (an indicator of HER2 signaling activity) for each cell line, as described in the Methods.	5	12	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	9	10	11	12
A panel of pharmacological inhibitors that specifically inhibit different points in the PI3K and MAPK pathways was tested in order to determine which pathway ( s ) was critically involved in NRG1b- and EGF directed HER2 signals in breast cancer and thereby specific cellular responses in our CELx HSF tests .	A panel of pharmacological inhibitors that specifically inhibit different points in the PI3K and MAPK pathways was tested in order to determine which pathway (s) was critically involved in NRG1b- and EGF directed HER2 signals in breast cancer and thereby specific cellular responses in our CELx HSF tests.	29	36	directed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	33	34	35	36
EGF induced migratory potential is closely related to the activation of EGFR and ErbB3 by autophosphorylation , whereas HER2 is not directly activated by EGF [ XREF_BIBR ] .	EGF induced migratory potential is closely related to the activation of EGFR and ErbB3 by autophosphorylation, whereas HER2 is not directly activated by EGF [XREF_BIBR].	18	26	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	24	25	18	19
Data generated from this analysis reveal that EGF stimulation of HER2 overexpressing cells activates multiple signaling pathways to stimulate migration , whereas HRG stimulation of these cells results in amplification of a specific subset of the migration signaling network .	Data generated from this analysis reveal that EGF stimulation of HER2 overexpressing cells activates multiple signaling pathways to stimulate migration, whereas HRG stimulation of these cells results in amplification of a specific subset of the migration signaling network.	7	12	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	7	8	10	11
Rapid phospho-turnover is also observed for EGF activated ErbB2 and ErbB3 , unrelated RTKs , and multiple intracellular adaptor proteins and signaling kinases .	Rapid phospho-turnover is also observed for EGF activated ErbB2 and ErbB3, unrelated RTKs, and multiple intracellular adaptor proteins and signaling kinases.	4	22	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	6	7	8	9
Lapatinib inhibited both EGF- and NRG1b driven HER2 signals to the same level in SKBr3 ( IC 50 = 97nM for EGF driven signal and IC 50 = 175nM for NRG1b driven signal ) .	Lapatinib inhibited both EGF- and NRG1b driven HER2 signals to the same level in SKBr3 (IC 50 = 97nM for EGF driven signal and IC 50 = 175nM for NRG1b driven signal).	1	16	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF-	EGF-	EGF-	HER2	HER2	HER2	3	4	7	8
Among various potential domains of MUC4 , epidermal growth factor ( EGF ) -like domains are hypothesized to interact with and activate the ErbB2 receptors , suggesting an intramembrane-growth factor function for MUC4 .	Among various potential domains of MUC4, epidermal growth factor (EGF) -like domains are hypothesized to interact with and activate the ErbB2 receptors, suggesting an intramembrane-growth factor function for MUC4.	7	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	ErbB2	ErbB2	ErbB2	7	10	23	24
These data demonstrated that inhibition of PI3K significantly reduced both EGF- and NRG1b directed HER2 signals detected by CELx HSF tests in a drug dose dependent manner .	These data demonstrated that inhibition of PI3K significantly reduced both EGF- and NRG1b directed HER2 signals detected by CELx HSF tests in a drug dose dependent manner.	9	15	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF-	EGF-	EGF-	HER2	HER2	HER2	10	11	14	15
Indeed , increased expression of EGFR ligands EGF , TGF ( transforming growth factor )-alpha , and betacellulin , and HER3 ligand heregulin ( HRG ) reduced trastuzumab mediated growth inhibition in HER2 overexpressing breast cancer cells [ XREF_BIBR - XREF_BIBR ] .	Indeed, increased expression of EGFR ligands EGF, TGF (transforming growth factor)-alpha, and betacellulin, and HER3 ligand heregulin (HRG) reduced trastuzumab mediated growth inhibition in HER2 overexpressing breast cancer cells [XREF_BIBR - XREF_BIBR].	3	34	reduced	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	EGF	expression of EGFR ligands EGF	egf	HER2	HER2 overexpressing	her2	7	8	32	33
This presumes a significant contribution of MAPK in cell survival , since it is also activated by EGF stimulation independent of epidermal receptor growth factor 2 ( ErbB2 ) and epidermal receptor growth factor 3 ( ErbB3 ) signaling in human colon cancer ( GEO ) cells .	This presumes a significant contribution of MAPK in cell survival, since it is also activated by EGF stimulation independent of epidermal receptor growth factor 2 (ErbB2) and epidermal receptor growth factor 3 (ErbB3) signaling in human colon cancer (GEO) cells.	17	38	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	17	18	27	28
EGF stimulated both tyrosine phosphorylation and autokinase activity of p185erbB-2 down-regulates p185erbB-2 at a post-translational level .	EGF stimulated both tyrosine phosphorylation and autokinase activity of p185erbB-2 down-regulates p185erbB-2 at a post-translational level.	0	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	p185erbB-2	p185erbB-2	p185erbB-2	0	1	11	12
Comparing the magnitude of IGF-1 and IGF-1R signals , NRG1b- and EGF induced HER2 signals were much larger in these cells ( Delta CI = 0.8 to 1.2 ; Fig .	Comparing the magnitude of IGF-1 and IGF-1R signals, NRG1b- and EGF induced HER2 signals were much larger in these cells (Delta CI = 0.8 to 1.2; Fig.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	HER2	HER2	HER2	11	12	13	14
Western blot analysis was performed on to determine the effect of DIM and/or paclitaxel on the proteins involved in apoptosis , and epidermal growth factor induced activation of HER2 and neu and ERK1/2 signaling proteins .	Western blot analysis was performed on to determine the effect of DIM and/or paclitaxel on the proteins involved in apoptosis, and epidermal growth factor induced activation of HER2 and neu and ERK1/2 signaling proteins.	22	34	induced	Positive_early_activation	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	HER2	HER2	HER2	22	25	28	29
ErbB2 can be activated by EGF through the formation of heterodimers with EGFR or by neuregulin through heterodimerization with ErbB3 and ErbB4 .	ErbB2 can be activated by EGF through the formation of heterodimers with EGFR or by neuregulin through heterodimerization with ErbB3 and ErbB4.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	5	6	0	1
Since EGFR and Her2 TKIs target EGFR and Her2 with high specificity , we hypothesized that down-regulation of EGFR and Her2 may be critical to potentiate the efficacy of lapatinib and afatinib in SCC15 and miR -124 cells .	Since EGFR and Her2 TKIs target EGFR and Her2 with high specificity, we hypothesized that down-regulation of EGFR and Her2 may be critical to potentiate the efficacy of lapatinib and afatinib in SCC15 and miR -124 cells.	1	9	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Her2	Her2	Her2	1	2	8	9
In breast cancer , EGFRvIII is frequently co-expressed with ErbB2 , and defective degradation pathways of EGFRvIII can lead to prolonged and enhanced EGFRvIII and ErbB2 signaling [ XREF_BIBR ; XREF_BIBR ] .	In breast cancer, EGFRvIII is frequently co-expressed with ErbB2, and defective degradation pathways of EGFRvIII can lead to prolonged and enhanced EGFRvIII and ErbB2 signaling [XREF_BIBR; XREF_BIBR].	14	30	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	ErbB2	ErbB2	ErbB2	16	17	25	26
One explanation is that pHER2 is induced by other members of the EGFR network including EGFR XREF_BIBR , so it is possible that patients without HER2 over expression could still benefit from Trastuzumab XREF_BIBR .	One explanation is that pHER2 is induced by other members of the EGFR network including EGFR XREF_BIBR, so it is possible that patients without HER2 over expression could still benefit from Trastuzumab XREF_BIBR.	4	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	pHER2	pHER2	pHER2	12	13	4	5
Whereas lapatinib , a supposed equipotent HER2 and EGFR kinase inhibitor , based on data from in vitro kinase assays , appropriately inhibited HER2 signaling , EGFR conversely was incompletely inactivated .	Whereas lapatinib, a supposed equipotent HER2 and EGFR kinase inhibitor, based on data from in vitro kinase assays, appropriately inhibited HER2 signaling, EGFR conversely was incompletely inactivated.	8	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	8	9	23	24
Expression of ERRalpha positively correlates with HER2 status in breast tumors and ERRalpha transcriptional activity is positively modulated by EGFR and HER2 signaling in breast cancer cells .	Expression of ERRalpha positively correlates with HER2 status in breast tumors and ERRalpha transcriptional activity is positively modulated by EGFR and HER2 signaling in breast cancer cells.	6	22	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	19	20	6	7
Gene amplification and over-expression of human erythroblastosis oncogene B ( ERBB ) up-regulates the HER2 receptor on the surface of breast cancer cells , which further induces the activation of the ER co-activator , amplified in breast cancer 1 ( AIB-1 )/steroid receptor coactivator-3 ( SRC-3 ) , which can reduce the efficacy of tamoxifen therapy [ XREF_BIBR ] .	Gene amplification and over-expression of human erythroblastosis oncogene B (ERBB) up-regulates the HER2 receptor on the surface of breast cancer cells, which further induces the activation of the ER co-activator, amplified in breast cancer 1 (AIB-1)/steroid receptor coactivator-3 (SRC-3), which can reduce the efficacy of tamoxifen therapy [XREF_BIBR].	1	16	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB	ERBB	ERBB	HER2 receptor	HER2 receptor	HER2 receptor	10	11	14	16
Additional studies confirmed FAM83A also conferred resistance to lapatinib , another EGFR TKI that also targets HER2 [ XREF_BIBR ] .	Additional studies confirmed FAM83A also conferred resistance to lapatinib, another EGFR TKI that also targets HER2 [XREF_BIBR].	11	18	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	11	12	16	17
Cross signaling from EGFR activates HER2 and could theoretically limit response to HER2 inhibition .	Cross signaling from EGFR activates HER2 and could theoretically limit response to HER2 inhibition.	1	6	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	3	4	5	6
In this regard , bicalutamide increased p-EGFR levels 3.3-fold ( OR 3.3 ; 95 % CI 1.3 to 8.2 ; P = 0.0016 ) and increased p-Her2 and neu 2.8-fold ( OR 2.8 ; 95 % CI 1.2 to 6.3 ; P = 0.025 ) .	In this regard, bicalutamide increased p-EGFR levels 3.3-fold (OR 3.3; 95% CI 1.3 to 8.2; P = 0.0016) and increased p-Her2 and neu 2.8-fold (OR 2.8; 95% CI 1.2 to 6.3; P = 0.025).	4	29	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-EGFR	bicalutamide increased p-EGFR levels	p-egfr	neu	neu	neu	6	7	28	29
HKI-272 , a second generation irreversible EGFR TKI that also inhibits HER2 , has completed accrual of a phase II trial in both untreated patients and patients with acquired resistance to erlotinib or gefitinib .	HKI-272, a second generation irreversible EGFR TKI that also inhibits HER2, has completed accrual of a phase II trial in both untreated patients and patients with acquired resistance to erlotinib or gefitinib.	6	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	6	7	11	12
In a recent study of breast cancer patients , 35 % of 306 HER2 overexpressing tumours were found to express EGFR Conversely , 87 % of EGFR overexpressing tumours were found to overexpress HER2 as well ( DiGiovanna et al , 2005 ) .	In a recent study of breast cancer patients, 35% of 306 HER2 overexpressing tumours were found to express EGFR Conversely, 87% of EGFR overexpressing tumours were found to overexpress HER2 as well (DiGiovanna et al, 2005).	26	34	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	26	27	33	34
MDA-MB-231 ( abbreviated as MM231 ) cells are triple negative ( ER - / PR - / HER2 - ) and can not be treated with hormone receptor and EGFR ( HER2 ) inhibitors , making cancer cells such as these refractory to most treatment strategies .	MDA-MB-231 (abbreviated as MM231) cells are triple negative (ER - / PR - / HER2 -) and can not be treated with hormone receptor and EGFR (HER2) inhibitors, making cancer cells such as these refractory to most treatment strategies.	14	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	29	30	17	18
Whereas overexpression of ErbB1 , -3 , or -4 was sufficient to induce ErbB2 activation and MCF7 cell migration , it failed to stimulate these events in MCF7-5R cells devoid of cell surface ErbB2 receptors ( XREF_FIG and XREF_FIG ) .	Whereas overexpression of ErbB1, -3, or -4 was sufficient to induce ErbB2 activation and MCF7 cell migration, it failed to stimulate these events in MCF7-5R cells devoid of cell surface ErbB2 receptors (XREF_FIG and XREF_FIG).	1	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB1	overexpression of ErbB1	erbb1	ErbB2	ErbB2	erbb2	3	4	13	14
Research shows that curcumin inhibits EGFR kinase activity and EGFR induced tyrosine phosphorylation of EGFR in A431cells and degrades cells of Her2 and neu protein in-vitro .	Research shows that curcumin inhibits EGFR kinase activity and EGFR induced tyrosine phosphorylation of EGFR in A431cells and degrades cells of Her2 and neu protein in-vitro.	3	24	degrades	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	curcumin inhibits EGFR kinase activity and EGFR induced tyrosine phosphorylation of EGFR	egfr	Her2	Her2	her2	9	10	21	22
Recent progress in the development of molecular cancer therapy has revealed new molecular targeting drugs , such as EGFR targeting drug ZD1839 ( Iressa ) and HER2 targeting anti-HER2 monoclonal antibody trastuzumab ( Herceptin ) , to be potent therapies for specific cancers [ XREF_BIBR - XREF_BIBR ] .	Recent progress in the development of molecular cancer therapy has revealed new molecular targeting drugs, such as EGFR targeting drug ZD1839 (Iressa) and HER2 targeting anti-HER2 monoclonal antibody trastuzumab (Herceptin), to be potent therapies for specific cancers [XREF_BIBR - XREF_BIBR].	14	27	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	18	19	26	27
Inhibition of the normally expressed EGFR significantly suppressed the ability of overexpressed HER2 to induce enhanced signaling and cell transformation , suggesting that HER2 requires the EGFR and potentially other members to maximize its signaling and transformation potency .	Inhibition of the normally expressed EGFR significantly suppressed the ability of overexpressed HER2 to induce enhanced signaling and cell transformation, suggesting that HER2 requires the EGFR and potentially other members to maximize its signaling and transformation potency.	0	13	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	5	6	12	13
That suppression of CD44 is able to deplete heregulin induced activation of erbB signalling and also depletes HA promoted erbB2 : erbB3 association suggest a potential value of therapeutically targeting CD44 in breast cancer , potentially to improve the effect of current targeted therapies .	That suppression of CD44 is able to deplete heregulin induced activation of erbB signalling and also depletes HA promoted erbB2 : erbB3 association suggest a potential value of therapeutically targeting CD44 in breast cancer, potentially to improve the effect of current targeted therapies.	3	20	depletes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	erbB	CD44 is able to deplete heregulin induced activation of erbB	erbb	erbB2	erbB2	erbb2	12	13	19	20
Anti-human epidermal growth factor receptor 2 ( HER2 ) antibodies were conjugated to TGA-QDs to target HER2 overexpressing cancer cells .	Anti-human epidermal growth factor receptor 2 (HER2) antibodies were conjugated to TGA-QDs to target HER2 overexpressing cancer cells.	1	17	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	HER2	HER2	HER2	1	5	16	17
Moreover , EGFR and HER2 dimerization status could explain the different type of toxicity induced by EGFR targeted vs HER2 targeted therapies [ XREF_BIBR ] .	Moreover, EGFR and HER2 dimerization status could explain the different type of toxicity induced by EGFR targeted vs HER2 targeted therapies [XREF_BIBR].	14	20	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	16	17	19	20
Suppression of EGFR signaling downregulates HER2 signaling and proliferation of NCI-N87 cells .	Suppression of EGFR signaling downregulates HER2 signaling and proliferation of NCI-N87 cells.	2	6	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	2	3	5	6
Levels of these proteins were decreased compared to non treated controls , indicating that EGFR activation contributes upregulation of Her2 and Her3 , increased downstream signaling , and consequent resistance to antibodies [ XREF_BIBR ] .	Levels of these proteins were decreased compared to non treated controls, indicating that EGFR activation contributes upregulation of Her2 and Her3, increased downstream signaling, and consequent resistance to antibodies [XREF_BIBR].	14	21	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Her2	Her2	Her2	14	15	19	20
Preclinical glioma CAR studies targeting HER2 and the previously described EGFRvIII reported impressive results .	Preclinical glioma CAR studies targeting HER2 and the previously described EGFRvIII reported impressive results.	3	11	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	HER2	HER2	HER2	10	11	5	6
We found that all EGFR exon 20 insertions tested were activating mutations ( XREF_SUPPLEMENTARY ) , and six HER2 exon 20 mutations and HER2 L755P , which is located in exon 19 , were activating mutations ( XREF_SUPPLEMENTARY ) .	We found that all EGFR exon 20 insertions tested were activating mutations (XREF_SUPPLEMENTARY), and six HER2 exon 20 mutations and HER2 L755P, which is located in exon 19, were activating mutations (XREF_SUPPLEMENTARY).	4	19	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	4	5	18	19
Nevertheless , second generation CARs employing a composite CD28-CD3zeta signaling domain have been shown to be functional in NK-92 cells targeting EpCAM and ErbB2 on breast cancer cells , epidermal growth factor receptor ( EGFR ) on glioblastoma cells and breast cancer brain metastases , EGFRvIII , a glioblastoma specific mutant form of EGFR arising from an in-frame deletion of exons 2-7 of the receptor , CD19 on B-cell malignancies , CS1 on multiple myeloma cells , and CD33 on acute myeloid leukemia cells .	Nevertheless, second generation CARs employing a composite CD28-CD3zeta signaling domain have been shown to be functional in NK-92 cells targeting EpCAM and ErbB2 on breast cancer cells, epidermal growth factor receptor (EGFR) on glioblastoma cells and breast cancer brain metastases, EGFRvIII, a glioblastoma specific mutant form of EGFR arising from an in-frame deletion of exons 2-7 of the receptor, CD19 on B-cell malignancies, CS1 on multiple myeloma cells, and CD33 on acute myeloid leukemia cells.	20	46	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	ErbB2	ErbB2	ErbB2	45	46	23	24
We report a patient with metastatic gastric linitis plastica harboring human epidermal growth factor receptor 2 ( HER2 ) activating mutation and HER2 amplification .	We report a patient with metastatic gastric linitis plastica harboring human epidermal growth factor receptor 2 (HER2) activating mutation and HER2 amplification.	11	23	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	HER2	HER2	HER2	11	15	22	23
Although activation of EGFR and HER3 signaling significantly abrogates IFNgamma/TNFalpha/trastuzumab induced class I restoration , EGFR and HER3 receptor blockade rescues class I expression as well as HER2 369-377 -CD8 + cytotoxicity of HER2 and neu expressing cells .	Although activation of EGFR and HER3 signaling significantly abrogates IFNgamma/TNFalpha/trastuzumab induced class I restoration, EGFR and HER3 receptor blockade rescues class I expression as well as HER2 369-377 -CD8 + cytotoxicity of HER2 and neu expressing cells.	15	37	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	neu	neu	neu	15	16	35	36
Their data demonstrated the dysregulation of EGFR internalization and degradation and the subsequent EGFR dependent activation of HER2 and HER3 .	Their data demonstrated the dysregulation of EGFR internalization and degradation and the subsequent EGFR dependent activation of HER2 and HER3.	13	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	13	14	17	18
This pathway is triggered by EGFR activation via binding to its ligand EGF resulting in activation of EGFR and ERBB2 downstream target proteins including the serine/threonine kinase AKT and extracellular signal regulated kinase ( ERK ) .	This pathway is triggered by EGFR activation via binding to its ligand EGF resulting in activation of EGFR and ERBB2 downstream target proteins including the serine/threonine kinase AKT and extracellular signal regulated kinase (ERK).	3	20	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERBB2	ERBB2	ERBB2	5	6	19	20
On the other hand , heterodimers of HER2 and EGFR are able to induce invasive growth of HER2 overexpressing MCF10A spheroids .	On the other hand, heterodimers of HER2 and EGFR are able to induce invasive growth of HER2 overexpressing MCF10A spheroids.	5	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	9	10	17	18
These data indicate that gefitinib can inhibit the EGFR induced transactivation of erbB2 receptor molecule which is overexpressed in about 40 % of medulloblastomas and associated with a poor outcome of the patients .	These data indicate that gefitinib can inhibit the EGFR induced transactivation of erbB2 receptor molecule which is overexpressed in about 40% of medulloblastomas and associated with a poor outcome of the patients.	7	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	erbB2	erbB2	erbB2	8	9	12	13
In accordance , EGFR promoted dimerisation and strong activation of HER2 in cells , which acquired cetuximab resistance , with consequent activation of downstream cascades and sustained proliferation ( Wheeler et al , 2008 ) .	In accordance, EGFR promoted dimerisation and strong activation of HER2 in cells, which acquired cetuximab resistance, with consequent activation of downstream cascades and sustained proliferation (Wheeler et al, 2008).	3	11	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	3	4	10	11
, who found that 87 % of EGFR positive primary breast tumors also overexpressed HER2 and that 97 % of tumors with p-HER2 expression co-overexpressed also overex pressed EGFR .	, who found that 87% of EGFR positive primary breast tumors also overexpressed HER2 and that 97% of tumors with p-HER2 expression co-overexpressed also overex pressed EGFR.	7	15	overexpressed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	7	8	14	15
Recently , the first case of acquired resistance to HER2 therapies driven by an active EGFR sensitizing mutation was documented in an IBC patient who clinically benefited from Erlotinib therapy .	Recently, the first case of acquired resistance to HER2 therapies driven by an active EGFR sensitizing mutation was documented in an IBC patient who clinically benefited from Erlotinib therapy.	9	16	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	15	16	9	10
Glioblastoma cells ( LN-18 , LN-229 ) with different co-expression levels of EGFR and HER2 were treated with specific EGFR and bispecific EGFR and HER2 tyrosine kinase inhibitors ( TKIs ) ( AG1478 , AEE788 ) and experimental radiotherapy , followed by assessment of growth inhibition .	Glioblastoma cells (LN-18, LN-229) with different co-expression levels of EGFR and HER2 were treated with specific EGFR and bispecific EGFR and HER2 tyrosine kinase inhibitors (TKIs) (AG1478, AEE788) and experimental radiotherapy, followed by assessment of growth inhibition.	10	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	19	20	14	15
Co-expression of EGFRvIII with ErbB2 has been detected in a subset of breast tumors , and furthermore , co-expression of EGFRvIII with ErbB2 enhances ErbB2 activation , and amplifies the down-stream signaling pathways observed in both EGFRvIII expressing 32D cells and in breast cancer cells .	Co-expression of EGFRvIII with ErbB2 has been detected in a subset of breast tumors, and furthermore, co-expression of EGFRvIII with ErbB2 enhances ErbB2 activation, and amplifies the down-stream signaling pathways observed in both EGFRvIII expressing 32D cells and in breast cancer cells.	18	25	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	co-expression of EGFRvIII	egfrviii	ErbB2	ErbB2	erbb2	20	21	24	25
Such efforts have yielded several FDA approved drugs , including the EGFR kinase inhibitors erlotinib , gefitinib , and afatinib , the HER2 kinase inhibitor lapatinib , the EGFR directed antibodies cetuximab and panitumumab , and the HER2 targeted antibodies trastuzumab and pertuzumab .	Such efforts have yielded several FDA approved drugs, including the EGFR kinase inhibitors erlotinib, gefitinib, and afatinib, the HER2 kinase inhibitor lapatinib, the EGFR directed antibodies cetuximab and panitumumab, and the HER2 targeted antibodies trastuzumab and pertuzumab.	27	38	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	28	29	37	38
Here , we report that Plexin B1 also associates with EGFR and SEMA3C can stimulate activation of EGFR pathway as well as HER2 and ErbB2 and MET pathways via binding to Plexin B1/NRP1 .	Here, we report that Plexin B1 also associates with EGFR and SEMA3C can stimulate activation of EGFR pathway as well as HER2 and ErbB2 and MET pathways via binding to Plexin B1/NRP1.	10	27	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB2	ErbB2	ErbB2	10	11	24	25
Inhibition of EGFR kinase activity with AG1478 did not block the increase in EGFR or HER2 between days 4 and 7 , suggesting that the increase in total EGFR protein is not EGFR phosphorylation dependent ( XREF_FIG ) .	Inhibition of EGFR kinase activity with AG1478 did not block the increase in EGFR or HER2 between days 4 and 7, suggesting that the increase in total EGFR protein is not EGFR phosphorylation dependent (XREF_FIG).	2	16	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	2	3	15	16
We also revealed that the clinicopathologic characteristics of EGFR overexpressing HER2 positive breast cancers were same irrespective of the cutoff value used .	We also revealed that the clinicopathologic characteristics of EGFR overexpressing HER2 positive breast cancers were same irrespective of the cutoff value used.	6	13	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	8	9	10	11
Effectiveness of EGFR and HER2 targeted drugs is influenced by the downstream interaction shifts of PTPIP51 in HER2 amplified breast cancer cells .	Effectiveness of EGFR and HER2 targeted drugs is influenced by the downstream interaction shifts of PTPIP51 in HER2 amplified breast cancer cells.	0	18	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	2	3	17	18
Resistance to trastuzumab and the emergence of multiple new HER1 and HER2 targeted therapies support a need for assays which directly measure not only total amounts of HER1 and HER2 receptors , but more specifically HER1 and HER2 activation .	Resistance to trastuzumab and the emergence of multiple new HER1 and HER2 targeted therapies support a need for assays which directly measure not only total amounts of HER1 and HER2 receptors, but more specifically HER1 and HER2 activation.	5	38	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER1	HER1	HER1	HER2	HER2	HER2	9	10	37	38
The orphan receptor tyrosine kinase ErbB2 is activated by each of the EGFR family members upon ligand binding .	The orphan receptor tyrosine kinase ErbB2 is activated by each of the EGFR family members upon ligand binding.	2	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB2	ErbB2	ErbB2	12	13	5	6
Biologically , why might a HER2 directed antibody be more effective than an oral TKI , especially one like lapatinib which doubly targets both HER2 and the epidermal growth factor receptor ( EGFR ) ?	Biologically, why might a HER2 directed antibody be more effective than an oral TKI, especially one like lapatinib which doubly targets both HER2 and the epidermal growth factor receptor (EGFR)?	19	33	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	32	33	24	25
Consequently , it is not entirely surprising that NRG2beta and Q43L competitively antagonizes agonist stimulation of EGFR signaling and agonist stimulation of ErbB2 and ErbB3 signaling .	Consequently, it is not entirely surprising that NRG2beta and Q43L competitively antagonizes agonist stimulation of EGFR signaling and agonist stimulation of ErbB2 and ErbB3 signaling.	16	25	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB2	ErbB2	ErbB2	16	17	22	23
Our data demonstrate that the constitutive activity of EGFRvIII is sufficient to trigger endocytosis and trafficking of wtEGFR and erbB2 , which may play a role in activating signaling pathways that are triggered during receptor endocytosis .	Our data demonstrate that the constitutive activity of EGFRvIII is sufficient to trigger endocytosis and trafficking of wtEGFR and erbB2, which may play a role in activating signaling pathways that are triggered during receptor endocytosis.	6	23	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	erbB2	erbB2	erbB2	8	9	19	20
Therefore , EGFR driven HCC827 and HER2 driven MDA-MB-453 cells were treated with a MEK inhibitor , lipids were isolated , and PIP 3 levels were quantified .	Therefore, EGFR driven HCC827 and HER2 driven MDA-MB-453 cells were treated with a MEK inhibitor, lipids were isolated, and PIP 3 levels were quantified.	2	11	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	2	3	6	7
Therefore , HER2 induced tumorigenesis is dependent on EGFR , suggesting that the normally expressed EGFR may potentiate the oncogenic property of HER2 in HER2 positive breast cancer .	Therefore, HER2 induced tumorigenesis is dependent on EGFR, suggesting that the normally expressed EGFR may potentiate the oncogenic property of HER2 in HER2 positive breast cancer.	12	23	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	15	16	22	23
That finding enabled us to elucidate , in molecular terms , the directionality observed in the activation process of ErbB heterodimers ; it can explain , for example , the preferential activation of ErbB2 by ErbB1 over activation of ErbB1 by ErbB2 .	That finding enabled us to elucidate, in molecular terms, the directionality observed in the activation process of ErbB heterodimers; it can explain, for example, the preferential activation of ErbB2 by ErbB1 over activation of ErbB1 by ErbB2.	24	37	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ErbB1	ErbB1	ErbB1	ErbB2	ErbB2	ErbB2	35	36	33	34
In 447 HER2 positive primary breast cancer patients treated with adjuvant trastuzumab , EGFR overexpression was also an independent poor prognostic factor .	In 447 HER2 positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor.	2	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	13	14	2	3
There is biological rationale and clinical evidence to support the use of dual EGFR and HER2 targeted agents in HER-2 positive disease .	There is biological rationale and clinical evidence to support the use of dual EGFR and HER2 targeted agents in HER-2 positive disease.	10	21	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER-2	HER-2	HER-2	13	14	19	20
Another example comes from the identification of HER2-enriched/TN tumors that do not amplify ERBB2 , some of which might be driven by high EGFR .	Another example comes from the identification of HER2-enriched/TN tumors that do not amplify ERBB2, some of which might be driven by high EGFR.	12	24	driven	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERBB2	ERBB2	ERBB2	23	24	13	14
Specific examples are antibodies that target the HER2 protein ( trastuzumab ) and VEGF receptor 2 ( VEGFR2 ; ramucirumab ) approved in gastric cancer and antibodies that target VEGF ( bevacizumab ) and epidermal growth factor receptor ( cetuximab , panitumumab ) approved in CRC .	Specific examples are antibodies that target the HER2 protein (trastuzumab) and VEGF receptor 2 (VEGFR2; ramucirumab) approved in gastric cancer and antibodies that target VEGF (bevacizumab) and epidermal growth factor receptor (cetuximab, panitumumab) approved in CRC.	5	38	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	HER2	HER2	HER2	34	38	7	8
The human HER2 and neu ( c-erbB2 ) gene product , like the epidermal growth factor receptor , is a transmembrane receptor protein that includes a cysteine rich extracellular ligand binding domain , a hydrophobic membrane spanning region , and an intracellular tyrosine kinase domain [ XREF_BIBR ] .	The human HER2 and neu (c-erbB2) gene product, like the epidermal growth factor receptor, is a transmembrane receptor protein that includes a cysteine rich extracellular ligand binding domain, a hydrophobic membrane spanning region, and an intracellular tyrosine kinase domain [XREF_BIBR].	2	17	product	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	neu	neu	neu	13	17	4	5
Furthermore , we have presented data that show that EGFR contributes significantly to HER2 induced tumorigenesis in xenograft mice models .	Furthermore, we have presented data that show that EGFR contributes significantly to HER2 induced tumorigenesis in xenograft mice models.	9	14	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	9	10	13	14
This observation fits well with the poor prognosis of cases with primary tumors expressing the phosphorylated receptors and , worthy of note , it indicates that pHER1 and pHER3 may be important activators of HER2 in metastatic tumor cell growth .	This observation fits well with the poor prognosis of cases with primary tumors expressing the phosphorylated receptors and, worthy of note, it indicates that pHER1 and pHER3 may be important activators of HER2 in metastatic tumor cell growth.	26	39	be important activators	Positive_activation_copula_1	Positive_activation	Positive_activation	pHER1	pHER1	pHER1	HER2	HER2	HER2	26	27	34	35
These results identify erbB2 mediated dominant trapping of phosphorylated EGFR at the PM as a mechanism that prolongs EGFR signaling , by sequestration of activated EGFR away from intracellular sites of high PTP activity .	These results identify erbB2 mediated dominant trapping of phosphorylated EGFR at the PM as a mechanism that prolongs EGFR signaling, by sequestration of activated EGFR away from intracellular sites of high PTP activity.	3	29	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	erbB2	erbB2	erbB2	25	26	3	4
BIBW2992 is an irreversible EGFR TKI that also inhibits HER2 and vascular epidermal growth factor receptors .	BIBW2992 is an irreversible EGFR TKI that also inhibits HER2 and vascular epidermal growth factor receptors.	4	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	4	5	9	10
However , there is little information on CTL directed epitopes of EGFR , although such CTL directed peptides of HER2 and neu , a family of EGFR , have been reported over the past decade ( Fisk et al , 1995 ; Peoples et al , 1995 ; Kawashima et al , 1999 ; Okugawa et al , 2000 ) .	However, there is little information on CTL directed epitopes of EGFR, although such CTL directed peptides of HER2 and neu, a family of EGFR, have been reported over the past decade (Fisk et al, 1995; Peoples et al, 1995; Kawashima et al, 1999; Okugawa et al, 2000).	16	27	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	neu	neu	neu	26	27	21	22
We used basal markers CK5/6 and CK14 instead of CK5/6 and EGFR for four reasons : i ) Based on the recent progress in TNBC gene subtyping by Prat et al , expression of EGFR was observed to be significantly increased in HER2-enriched/TN tumors compared with HER2 enriched and non TN tumors , thus suggesting that certain HER2 enriched tumors , which are at gene level in line with HER2 enriched tumors but are HER2- by IHC , may be driven by EGFR as discussed above .	We used basal markers CK5/6 and CK14 instead of CK5/6 and EGFR for four reasons : i) Based on the recent progress in TNBC gene subtyping by Prat et al, expression of EGFR was observed to be significantly increased in HER2-enriched/TN tumors compared with HER2-enriched and non-TN tumors, thus suggesting that certain HER2 enriched tumors, which are at gene level in line with HER2 enriched tumors but are HER2- by IHC, may be driven by EGFR as discussed above.	57	83	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	82	83	57	58
S4 in XREF_SUPPLEMENTARY , EGFR and HER2 targeted drugs , Erlotinib [ EGFR ] , CL387 [ EGFR ] , HKI272 [ EGFR , HER2 ] , and Lapatinib [ ERBB1/2 ] , clustered together with a correlation coefficient of 0.66 for the EGFR subcluster .	S4 in XREF_SUPPLEMENTARY, EGFR and HER2 targeted drugs, Erlotinib [EGFR], CL387 [EGFR], HKI272 [EGFR, HER2], and Lapatinib [ERBB1/2], clustered together with a correlation coefficient of 0.66 for the EGFR subcluster.	0	25	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	4	5	24	25
EGFR suppression downregulated HER2 , pHER2 and pERK as well as FUT1 suppression in NCI-N87 cells ( XREF_FIG ) .	EGFR suppression downregulated HER2, pHER2 and pERK as well as FUT1 suppression in NCI-N87 cells (XREF_FIG).	0	6	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	pHER2	pHER2	pHER2	0	1	5	6
Interestingly , the dual EGFR and HER2 kinase inhibitor lapatinib 26 which inhibited the phosphorylation of HER2 also reduced antibody induced internalization and degradation of HER2 , indicating that the HER2 kinase activity is crucial for these processes .	Interestingly, the dual EGFR and HER2 kinase inhibitor lapatinib 26 which inhibited the phosphorylation of HER2 also reduced antibody induced internalization and degradation of HER2, indicating that the HER2 kinase activity is crucial for these processes.	2	20	inhibited	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	EGFR	EGFR	egfr	HER2	phosphorylation of HER2	her2	4	5	16	17
Our observations suggest that EGFR triggered and/or HER2 triggered PI3K and Akt activation may be involved in the regulation of the malignant and metastatic potential of CTCs .	Our observations suggest that EGFR triggered and/or HER2 triggered PI3K and Akt activation may be involved in the regulation of the malignant and metastatic potential of CTCs.	4	8	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	4	5	7	8
The effect of inhibiting HER2 dimerization on HER3 activation in response to EGF is also presented in Figure XREF_FIG and Figure XREF_FIG , and this data can be used to validate the role of HER2 in EGFR mediated HER3 transactivation .	The effect of inhibiting HER2 dimerization on HER3 activation in response to EGF is also presented in Figure XREF_FIG and Figure XREF_FIG, and this data can be used to validate the role of HER2 in EGFR mediated HER3 transactivation.	30	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	36	37	38	39
A recently characterized , ErbB3 specific humanized antibody MM-121 blocked ligand dependent ErbB3 activation induced by the ErbB1 , ErbB2 or MET receptors [ XREF_BIBR ] .	A recently characterized, ErbB3 specific humanized antibody MM-121 blocked ligand dependent ErbB3 activation induced by the ErbB1, ErbB2 or MET receptors [XREF_BIBR].	12	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ErbB1	ErbB1	ErbB1	ErbB3	ErbB3	ErbB3	17	18	12	13
Our data shows that inhibition of both EGFR and HER2 is required to prevent ErbB3 signaling , likely by preventing its dimerization .	Our data shows that inhibition of both EGFR and HER2 is required to prevent ErbB3 signaling, likely by preventing its dimerization.	4	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB3	ErbB3	ErbB3	7	8	14	15
On-treatment pharmacodynamic analysis demonstrated targeted inhibition of EGFR and/or HER3 in a number of patients who had previously been treated with EGFR targeted therapies .	On-treatment pharmacodynamic analysis demonstrated targeted inhibition of EGFR and/or HER3 in a number of patients who had previously been treated with EGFR targeted therapies.	2	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	21	22	9	10
In hepatocellular carcinoma cell lines , HER3 activation by EGFR in response to IGR-1R inhibition seems to be one potential mechanism of resistance [ XREF_BIBR ] .	In hepatocellular carcinoma cell lines, HER3 activation by EGFR in response to IGR-1R inhibition seems to be one potential mechanism of resistance [XREF_BIBR].	6	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	9	10	6	7
HER3 is upregulated in a compensatory manner by EGFR TKI exposure due to AKT mediated negative feedback signaling , which consequently causes EGFR TKI resistance [ XREF_BIBR ] .	HER3 is upregulated in a compensatory manner by EGFR TKI exposure due to AKT mediated negative feedback signaling, which consequently causes EGFR TKI resistance [XREF_BIBR].	0	10	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	8	9	0	1
XREF_BIBR The results from our previous work suggest that acquired resistance to cetuximab reflects dysregulation of EGFR internalization and degradation and subsequent EGFR dependent activation of HER3 .	XREF_BIBR The results from our previous work suggest that acquired resistance to cetuximab reflects dysregulation of EGFR internalization and degradation and subsequent EGFR dependent activation of HER3.	22	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	22	23	26	27
Using the vesicle based assay , we found that the presence of the EGFR JM-latch sequence potentiated HER3 dependent activation of the kinase domain of EGFR to a similar extent as observed for the homodimeric EGFR and EGFR interaction ( XREF_FIG ) , indicating that the interaction between the JM-latch of EGFR and the C-lobe of the HER3 pseudokinase domain contributes to kinase activation .	Using the vesicle based assay, we found that the presence of the EGFR JM-latch sequence potentiated HER3 dependent activation of the kinase domain of EGFR to a similar extent as observed for the homodimeric EGFR and EGFR interaction (XREF_FIG), indicating that the interaction between the JM-latch of EGFR and the C-lobe of the HER3 pseudokinase domain contributes to kinase activation.	13	19	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	13	14	17	18
Further investigations of this model of acquired resistance to cetuximab indicated that Src family kinases ( SFKs ) are highly activated in cetuximab resistant cells and enhance EGFR activation of HER3 and PI ( 3 ) K/Akt .	Further investigations of this model of acquired resistance to cetuximab indicated that Src family kinases (SFKs) are highly activated in cetuximab resistant cells and enhance EGFR activation of HER3 and PI (3) K/Akt.	27	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	27	28	30	31
In our first report of this model of acquired resistance we showed that EGFR and HER2 activation of HER3 is a critical mechanism for escaping cetuximab therapy .	In our first report of this model of acquired resistance we showed that EGFR and HER2 activation of HER3 is a critical mechanism for escaping cetuximab therapy.	13	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	13	14	18	19
XREF_BIBR In this work , cells with acquired resistance to cetuximab exhibited robust expression of active SFKs , and this activity enhanced EGFR activation of HER3 and the PI3K and AKT pathway , leading to enhanced survival .	XREF_BIBR In this work, cells with acquired resistance to cetuximab exhibited robust expression of active SFKs, and this activity enhanced EGFR activation of HER3 and the PI3K and AKT pathway, leading to enhanced survival.	22	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	22	23	25	26
We found that MM-121 effectively blocked ligand dependent activation of ErbB3 induced by either EGFR , HER2 , or MET .	We found that MM-121 effectively blocked ligand dependent activation of ErbB3 induced by either EGFR, HER2, or MET.	8	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB3	ErbB3	ErbB3	14	15	10	11
It was also shown that Ctx R clones had increased EGFR dependent activation of HER3 [ XREF_BIBR ] .	It was also shown that Ctx R clones had increased EGFR dependent activation of HER3 [XREF_BIBR].	10	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	10	11	14	15
Furthermore , our clinical analysis suggests that HER3 abundance and activation are induced in TNBC patients by EGFR targeted therapies and that this change may prevent therapy induced tumor regression .	Furthermore, our clinical analysis suggests that HER3 abundance and activation are induced in TNBC patients by EGFR targeted therapies and that this change may prevent therapy induced tumor regression.	7	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	17	18	7	8
As expected , the irreversible EGFR and ErbB2 inhibitor PD168393 effectively blocked both EGFR ( pTyr 845 ) and ErbB3 ( pTyr 1289 ) activation in response to EGF and heregulin-beta1 , respectively ( XREF_FIG , bottom ) .	As expected, the irreversible EGFR and ErbB2 inhibitor PD168393 effectively blocked both EGFR (pTyr 845) and ErbB3 (pTyr 1289) activation in response to EGF and heregulin-beta1, respectively (XREF_FIG, bottom).	3	24	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ErbB3	ErbB3	ErbB3	5	6	19	20
These data suggest that acquired-resistance to cetuximab is accompanied by dysregulation of EGFR internalization and degradation and subsequent EGFR dependent activation of HER3 .	These data suggest that acquired-resistance to cetuximab is accompanied by dysregulation of EGFR internalization and degradation and subsequent EGFR dependent activation of HER3.	18	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	18	19	22	23
This increased SFK activity led to prolonged EGFR activity and was critical for EGFR activation of HER3 and subsequent activation of PI ( 3 ) K/Akt and other survival signals .	This increased SFK activity led to prolonged EGFR activity and was critical for EGFR activation of HER3 and subsequent activation of PI (3) K/Akt and other survival signals.	13	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	13	14	16	17
62 Cetuximab resistant cells with high Src activation were found to have increased EGFR activation of HER3 and PI3K and Akt .	62 Cetuximab resistant cells with high Src activation were found to have increased EGFR activation of HER3 and PI3K and Akt.	13	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	13	14	16	17
Pancreatic cancer cell lines lacking ErbB3 were reported to be less dependent on EGFR signaling and were resistant to erlotinib [ XREF_BIBR ] whilst in another in vitro study , ErbB3 was activated by EGFR through AKT and was a determinant of erlotinib sensitivity [ XREF_BIBR ] .	Pancreatic cancer cell lines lacking ErbB3 were reported to be less dependent on EGFR signaling and were resistant to erlotinib [XREF_BIBR] whilst in another in vitro study, ErbB3 was activated by EGFR through AKT and was a determinant of erlotinib sensitivity [XREF_BIBR].	30	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB3	ErbB3	ErbB3	34	35	30	31
These cells were particularly sensitive to the EGFR and HER2 TKI lapatinib , suggesting NRG1 driven tumors depend on HER3 activated by HER2 and/or EGFR .	These cells were particularly sensitive to the EGFR and HER2 TKI lapatinib, suggesting NRG1 driven tumors depend on HER3 activated by HER2 and/or EGFR.	17	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	24	25	19	20
These results demonstrate that EGFR T669 phosphorylation is necessary for MEK and ERK to suppress EGFR mediated activation of ERBB3 .	These results demonstrate that EGFR T669 phosphorylation is necessary for MEK and ERK to suppress EGFR mediated activation of ERBB3.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERBB3	ERBB3	ERBB3	15	16	19	20
In addition , as inhibition of HER-2 or downstream pathways may lead to transcriptional and posttranslational upregulation of HER-3 , dual inhibition of EGFR and HER-2 with lapatinib does not eliminate the compensatory upregulation of HER-3 .	In addition, as inhibition of HER-2 or downstream pathways may lead to transcriptional and posttranslational upregulation of HER-3, dual inhibition of EGFR and HER-2 with lapatinib does not eliminate the compensatory upregulation of HER-3.	21	36	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER-3	HER-3	HER-3	23	24	35	36
Acquired resistance to therapy has been attributed to dysregulation of EGFR internalization or degradation , EGFR dependent activation of human epidermal growth factor receptor 2 ( HER2 ; ErbB2 ) and ErbB3 , and increased signaling of alternative receptor tyrosine kinases , such as cMET [ XREF_BIBR ] .	Acquired resistance to therapy has been attributed to dysregulation of EGFR internalization or degradation, EGFR dependent activation of human epidermal growth factor receptor 2 (HER2; ErbB2) and ErbB3, and increased signaling of alternative receptor tyrosine kinases, such as cMET [XREF_BIBR].	15	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB3	ErbB3	ErbB3	15	16	31	32
This confirms the derived role of HER2 in EGFR mediated HER3 transactivation in HME cells .	This confirms the derived role of HER2 in EGFR mediated HER3 transactivation in HME cells.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	8	9	10	11
We now present data that Src family kinases ( SFKs ) are highly activated in cetuximab resistant cells and enhance EGFR activation of HER3 and PI ( 3 ) K/Akt .	We now present data that Src family kinases (SFKs) are highly activated in cetuximab resistant cells and enhance EGFR activation of HER3 and PI (3) K/Akt.	20	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	20	21	23	24
Increased EGFR and ERBB2 activation , in turn , promotes ERBB3 upregulation and signaling that buffers the cells against the effects of MEK inhibition .	Increased EGFR and ERBB2 activation, in turn, promotes ERBB3 upregulation and signaling that buffers the cells against the effects of MEK inhibition.	0	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERBB3	ERBB3	ERBB3	1	2	10	11
High levels of ERBB3 is strongly associated with tumor progression and poor prognosis of patients with GC XREF_BIBR - XREF_BIBR and the EGFR kinase inhibitors gefitinib could prevent EGFR and ERBB2 activation of ERBB3 .	High levels of ERBB3 is strongly associated with tumor progression and poor prognosis of patients with GC XREF_BIBR - XREF_BIBR and the EGFR kinase inhibitors gefitinib could prevent EGFR and ERBB2 activation of ERBB3.	22	34	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ERBB3	ERBB3	ERBB3	22	23	33	34
Acquired resistance to cetuximab has been linked to dysregulation of EGFR internalization or degradation , EGFR dependent activation of human epidermal growth factor receptor 2 ( HER2 ; ErbB2 ) and ErbB3 , and increased signalling of alternative receptor tyrosine kinases , such as cMET [ XREF_BIBR ] .	Acquired resistance to cetuximab has been linked to dysregulation of EGFR internalization or degradation, EGFR dependent activation of human epidermal growth factor receptor 2 (HER2; ErbB2) and ErbB3, and increased signalling of alternative receptor tyrosine kinases, such as cMET [XREF_BIBR].	15	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB3	ErbB3	ErbB3	15	16	31	32
These data suggest that acquired resistance to cetuximab is accompanied by dysregulation of EGFR internalization and degradation and subsequent EGFR dependent activation of HER3 .	These data suggest that acquired resistance to cetuximab is accompanied by dysregulation of EGFR internalization and degradation and subsequent EGFR dependent activation of HER3.	19	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	19	20	23	24
AZD8931 is an equipotent , reversible inhibitor of signaling by epidermal growth factor receptor ( EGFR ) , human EGFR 2 ( HER2 ) and HER3 .	AZD8931 is an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), human EGFR 2 (HER2) and HER3.	6	26	inhibitor	Negative_activation_syntax_2_noun	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	HER3	HER3	HER3	10	14	25	26
Thus , our quantitative phosphoproteomics data point to various anti-apoptotic signaling mechanisms triggered upon ERBB3 and ERBB4 activation in the absence of any contributions by other EGFR family members .	Thus, our quantitative phosphoproteomics data point to various anti-apoptotic signaling mechanisms triggered upon ERBB3 and ERBB4 activation in the absence of any contributions by other EGFR family members.	12	28	triggered	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERBB3	ERBB3	ERBB3	26	27	14	15
Interestingly , apicidin induced phosphorylation of phospholipase Cgamma1 ( PLCgamma1 ) and epidermal growth factor receptor ( EGFR ) , and inhibition of PLCgamma1 and EGFR reduced cell death and ER stress .	Interestingly, apicidin induced phosphorylation of phospholipase Cgamma1 (PLCgamma1) and epidermal growth factor receptor (EGFR), and inhibition of PLCgamma1 and EGFR reduced cell death and ER stress.	21	31	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	25	26	30	31
We have shown that EGFR activation in ERalpha - breast cell lines is associated with Jab1 nuclear localization and that these changes relate to activation of both AKT and ERK pathways and modulation of Jab1 downstream genes .	We have shown that EGFR activation in ERalpha - breast cell lines is associated with Jab1 nuclear localization and that these changes relate to activation of both AKT and ERK pathways and modulation of Jab1 downstream genes.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERalpha	ERalpha	ERalpha	4	5	7	8
Our recent in vitro studies also suggest that EGFR signalling productively cross-talks with insulin like growth factor receptor ( IGF-1R ) and , where present , activates ER on key AF-1 serine residues to facilitate acquired tamoxifen resistant growth .	Our recent in vitro studies also suggest that EGFR signalling productively cross-talks with insulin like growth factor receptor (IGF-1R) and, where present, activates ER on key AF-1 serine residues to facilitate acquired tamoxifen resistant growth.	8	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	8	9	27	28
EGFR and MAPK signaling can induce a switch in MCF-7 cells , from an ERalpha positive , Luminal-A phenotype , to an ERalpha negative , basal like phenotype .	EGFR and MAPK signaling can induce a switch in MCF-7 cells, from an ERalpha positive, Luminal-A phenotype, to an ERalpha negative, basal like phenotype.	0	25	induce	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERalpha	ERalpha	ERalpha	0	1	22	23
Some oestrogen-receptor ( ER ) positive breast cancers express epidermal growth factor receptor ( EGFR ) , but whether inhibition of EGFR can suppress proliferation of breast cancer cells and ER function is not known .	Some oestrogen-receptor (ER) positive breast cancers express epidermal growth factor receptor (EGFR), but whether inhibition of EGFR can suppress proliferation of breast cancer cells and ER function is not known.	19	31	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	21	22	30	31
In the last years , a number of studies demonstrated an ER mediated activation of growth factors receptors , such as EGFR , HER2 and Neu and IGFR [ XREF_BIBR , XREF_BIBR ] , and it is known that the EGF/Ras/MAPK signalling pathway is able to activate ERalpha through phosphorylation at Ser118 , as well as E2 [ XREF_BIBR ] .	In the last years, a number of studies demonstrated an ER mediated activation of growth factors receptors, such as EGFR, HER2 and Neu and IGFR [XREF_BIBR, XREF_BIBR], and it is known that the EGF/Ras/MAPK signalling pathway is able to activate ERalpha through phosphorylation at Ser118, as well as E2 [XREF_BIBR].	11	25	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	21	22	11	12
It has been demonstrated that cisplatin and inhibition of EGFR signaling may induce endoplasmic reticulum ( ER ) stress associated apoptosis .	It has been demonstrated that cisplatin and inhibition of EGFR signaling may induce endoplasmic reticulum (ER) stress associated apoptosis.	9	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	9	10	16	17
The ER-EGFR signaling axis appears to be reciprocal , with ER signaling promoting the activation of EGFR , and EGFR signaling promoting the actvation of ER .	The ER-EGFR signaling axis appears to be reciprocal, with ER signaling promoting the activation of EGFR, and EGFR signaling promoting the actvation of ER.	19	26	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	19	20	25	26
Thus , NF-kappaB is a potential target for therapy of EGFR family receptor overexpressing ER- breast cancers .	Thus, NF-kappaB is a potential target for therapy of EGFR family receptor overexpressing ER- breast cancers.	10	16	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER-	ER-	ER-	10	11	14	15
In a follow-up study the same group has demonstrated that AngII induces vascular remodelling by EGFR mediated ER stress activation [ XREF_BIBR ] .	In a follow-up study the same group has demonstrated that AngII induces vascular remodelling by EGFR mediated ER stress activation [XREF_BIBR].	11	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	15	16	17	18
Taken together , these data support the combination of mTORC1 blockade with inhibition of ERBB signalling and ER function in ER + BC , highlighting the potential clinical utility .	Taken together, these data support the combination of mTORC1 blockade with inhibition of ERBB signalling and ER function in ER + BC, highlighting the potential clinical utility.	14	22	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERBB	ERBB	ERBB	ER	ER	ER	14	15	20	21
Based on the ability of Wnt1 to activate EGFR and ERK1/2 signaling in the ER + T47D and MCF-7 breast tumor cells , we examined the effect of Wnt1 treatment on their response to 4-HT .	Based on the ability of Wnt1 to activate EGFR and ERK1/2 signaling in the ER + T47D and MCF-7 breast tumor cells, we examined the effect of Wnt1 treatment on their response to 4-HT.	8	15	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	8	9	14	15
In parallel , EGFR can , in turn , phosphorylate and activate ER and PR .	In parallel, EGFR can, in turn, phosphorylate and activate ER and PR.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	3	4	12	13
Since the majority of breast cancers express ER , and since Rac1 is a downstream mediator of EGFR , which activates ER , we wanted to determine if there is crosstalk between Rac1 and ER in breast cancer cells .	Since the majority of breast cancers express ER, and since Rac1 is a downstream mediator of EGFR, which activates ER, we wanted to determine if there is crosstalk between Rac1 and ER in breast cancer cells.	15	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	17	18	21	22
Stimulation of ER has been reported to increase the activity of the EGFR signal , and EGFR signal increases the activity of the ER [ XREF_BIBR ] .	Stimulation of ER has been reported to increase the activity of the EGFR signal, and EGFR signal increases the activity of the ER [XREF_BIBR].	16	25	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	16	17	23	24
Recently , we reported that ER-alpha36 mediates mitogenic estrogen signaling through the EGFR and Src signaling in ER negative breast cancer MDA-MB-231 and MDA-MB-436 cells .	Recently, we reported that ER-alpha36 mediates mitogenic estrogen signaling through the EGFR and Src signaling in ER negative breast cancer MDA-MB-231 and MDA-MB-436 cells.	12	24	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	12	13	17	18
EGFR and Vav3 , a growth factor activated Rho GTPase GEF , both enhance ER transcriptional activity in breast cancer cells .	EGFR and Vav3, a growth factor activated Rho GTPase GEF, both enhance ER transcriptional activity in breast cancer cells.	0	16	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	0	1	14	15
Inhibition of EGFR signaling does not inhibit the autocrine action of ERalpha .	Inhibition of EGFR signaling does not inhibit the autocrine action of ERalpha.	2	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERalpha	ERalpha	ERalpha	2	3	11	12
In previous studies , five bispecific and enediyne energized fusion proteins with enhanced antitumor efficacy have been prepared and evaluated by our lab , such as EGFR and HER2 specific fusion protein Ec-LDP-Hr-AE , anti-gelatinases tandem scFv format dFv-LDP-AE , EGFR and CD13 targeting fusion protein ER ( Fv )-LDP-NGR-AE , Ec-LDP-TRAIL which consisted of an oligopeptide against EGFR and tumor necrosis factor related apoptosis inducing ligand ( TRAIL ) , and the tuftsin based , EGFR targeting fusion protein Ec-LDM-TF [ XREF_BIBR - XREF_BIBR ] .	In previous studies, five bispecific and enediyne energized fusion proteins with enhanced antitumor efficacy have been prepared and evaluated by our lab, such as EGFR and HER2 specific fusion protein Ec-LDP-Hr-AE, anti-gelatinases tandem scFv format dFv-LDP-AE, EGFR and CD13 targeting fusion protein ER (Fv)-LDP-NGR-AE, Ec-LDP-TRAIL which consisted of an oligopeptide against EGFR and tumor necrosis factor related apoptosis inducing ligand (TRAIL), and the tuftsin based, EGFR targeting fusion protein Ec-LDM-TF [XREF_BIBR - XREF_BIBR].	32	73	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	40	41	46	47
Jab1 is a target of EGFR signaling in ERalpha - cell lines and breast tumors and therefore may be a common central factor and potential therapeutic target for important cell signaling pathways in ERalpha - breast cancer .	Jab1 is a target of EGFR signaling in ERalpha - cell lines and breast tumors and therefore may be a common central factor and potential therapeutic target for important cell signaling pathways in ERalpha - breast cancer.	5	9	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERalpha	ERalpha	ERalpha	5	6	8	9
These residues were found to be phosphorylated in 87.5 % of ER positive lung tumors examined , suggesting that EGFR activation of ER is common in lung cancer .	These residues were found to be phosphorylated in 87.5% of ER positive lung tumors examined, suggesting that EGFR activation of ER is common in lung cancer.	19	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	19	20	22	23
EGFR overexpression potentiated ER stress as measured by XBP1s and GRP78 expression at an intermediate ( 18 hr ) time point .	EGFR overexpression potentiated ER stress as measured by XBP1s and GRP78 expression at an intermediate (18 hr) time point.	0	4	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	ER	ER	er	0	1	3	4
Data from the Slingerland lab suggest that both EGFR and Her2 signaling can cooperate with estrogen to activate ER proteolysis ( I Chu , A Alkarain , J Sun , manuscript submitted ) .	Data from the Slingerland lab suggest that both EGFR and Her2 signaling can cooperate with estrogen to activate ER proteolysis (I Chu, A Alkarain, J Sun, manuscript submitted).	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	8	9	18	19
Furthermore , Wnt1 rescues estrogen receptor positive ( ER + ) breast cancer cells from the anti-proliferative effects of 4-hydroxytamoxifen ( 4-HT ) and this activity can be blocked by an EGFR tyrosine kinase inhibitor .	Furthermore, Wnt1 rescues estrogen receptor positive (ER +) breast cancer cells from the anti-proliferative effects of 4-hydroxytamoxifen (4-HT) and this activity can be blocked by an EGFR tyrosine kinase inhibitor.	4	34	blocked	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	estrogen receptor	estrogen receptor	estrogen receptor	31	32	4	6
AR and EGFR Promote ERalpha Activation and Tam Agonist Activity .	AR and EGFR Promote ERalpha Activation and Tam Agonist Activity.	0	5	Promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERalpha	ERalpha	ERalpha	2	3	4	5
The direct inhibition of EGFR by Tyrphostin AG537 , and its downstream signal transducer , MKK1 kinase , by UO126 or PD98589 reduces EGF activation of ER , as determined by the proportion of responsive cells in our assays .	The direct inhibition of EGFR by Tyrphostin AG537, and its downstream signal transducer, MKK1 kinase, by UO126 or PD98589 reduces EGF activation of ER, as determined by the proportion of responsive cells in our assays.	2	27	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	4	5	26	27
Notably , EGFR ligands rescue ductal development in ovariectomized [ XREF_BIBR ] and ER-alpha-deficient mice [ XREF_BIBR ] , and exogenous estrogen elicits EGFR activation in ovariecto mized mice [ XREF_BIBR ] , suggesting that EGFR promotes mammary branching downstream of ER-alpha .	Notably, EGFR ligands rescue ductal development in ovariectomized [XREF_BIBR] and ER-alpha-deficient mice [XREF_BIBR], and exogenous estrogen elicits EGFR activation in ovariecto mized mice [XREF_BIBR], suggesting that EGFR promotes mammary branching downstream of ER-alpha.	35	42	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER-alpha	ER-alpha	ER-alpha	35	36	41	42
Taken together , this information suggests that both the EGF-R and IGF-R pathways can mediate ERalpha signaling .	Taken together, this information suggests that both the EGF-R and IGF-R pathways can mediate ERalpha signaling.	7	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF-R	EGF-R	EGF-R	ERalpha	ERalpha	ERalpha	9	10	15	16
DDAs are chemically and mechanistically distinct from other classes of anticancer agents and selectively exacerbate the ER stress caused by the aberrantly high expression of EGFR and HER2 that occurs in breast cancers .	DDAs are chemically and mechanistically distinct from other classes of anticancer agents and selectively exacerbate the ER stress caused by the aberrantly high expression of EGFR and HER2 that occurs in breast cancers.	16	27	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	expression of EGFR	egfr	ER	ER	er	25	26	16	17
It has been shown that S100A7 downregulation inhibits EGFR mediated signaling in ERalpha - cells [ XREF_BIBR ] .	It has been shown that S100A7 downregulation inhibits EGFR mediated signaling in ERalpha - cells [XREF_BIBR].	8	13	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERalpha	ERalpha	ERalpha	8	9	12	13
EGFR overexpression induces S167 phosphorylation , increases binding of ERalpha to DNA , enhances the binding of coactivator SRC3 to ERalpha in the presence of E2 , and consequently enhances transcription .	EGFR overexpression induces S167 phosphorylation, increases binding of ERalpha to DNA, enhances the binding of coactivator SRC3 to ERalpha in the presence of E2, and consequently enhances transcription.	0	23	enhances	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	ERalpha	ERalpha	eralpha	0	1	20	21
However , whether EGFR mediated ER stress and ROS generation contribute to DN progression remains unexplored .	However, whether EGFR mediated ER stress and ROS generation contribute to DN progression remains unexplored.	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	3	4	5	6
Constitutive ERalpha phosphorylation and transcriptional activity was inhibited by Enzalutamide and the EGFR inhibitor gefitinib , demonstrating that AR mediated EGFR signaling activated ER .	Constitutive ERalpha phosphorylation and transcriptional activity was inhibited by Enzalutamide and the EGFR inhibitor gefitinib, demonstrating that AR mediated EGFR signaling activated ER.	18	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	AR mediated EGFR	egfr	ER	ER	er	20	21	23	24
XREF_BIBR Pathways emanating from growth factor receptors such as the Epidermal Growth Factor Receptor ( EGFR ) family and Insulin like Growth Factor Receptor ( IGF-IR ) family as well as Notch and leptin signaling may promote ER signaling independent of ligands and also favor resistance to agents targeting it .	XREF_BIBR Pathways emanating from growth factor receptors such as the Epidermal Growth Factor Receptor (EGFR) family and Insulin like Growth Factor Receptor (IGF-IR) family as well as Notch and leptin signaling may promote ER signaling independent of ligands and also favor resistance to agents targeting it.	13	38	promote	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	15	16	37	38
This ER-EGFR signaling axis appears to be reciprocal : ER signaling promotes the activation of EGFR , while EGFR signaling promotes the activation of ER .	This ER-EGFR signaling axis appears to be reciprocal : ER signaling promotes the activation of EGFR, while EGFR signaling promotes the activation of ER.	18	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER	ER	ER	18	19	24	25
Therefore we examined the effect of NOS2 activity on EGFR activation in MDA-MB-468 human ER- breast cancer cell lines .	Therefore we examined the effect of NOS2 activity on EGFR activation in MDA-MB-468 human ER- breast cancer cell lines.	9	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ER-	ER-	ER-	9	10	14	15
Over-expression of GRP78 also prevented the drug combination induced rapid declines in the expression of EDG-1 , ERBB1 , IL6R , IGF1R , and the PDGFRalpha and beta , as well as drug efflux and blood-brain-barrier ABC transporters , suggesting that the reduction in receptor expression and transporter expression is also a result of reduced GRP78 levels and enhanced ER stress signaling ( XREF_FIG ) .	Over-expression of GRP78 also prevented the drug combination induced rapid declines in the expression of EDG-1, ERBB1, IL6R, IGF1R, and the PDGFRalpha and beta, as well as drug efflux and blood-brain-barrier ABC transporters, suggesting that the reduction in receptor expression and transporter expression is also a result of reduced GRP78 levels and enhanced ER stress signaling (XREF_FIG).	0	61	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB1	Over-expression of GRP78 also prevented the drug combination induced rapid declines in the expression of EDG-1, ERBB1	erbb1	ER	ER	er	17	18	59	60
EGFR activates PLC-gamma1 directly and activates Akt indirectly through phosphatidylinositol 3-kinase ( PI3K ) .	EGFR activates PLC-gamma1 directly and activates Akt indirectly through phosphatidylinositol 3-kinase (PI3K).	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLC-gamma1	PLC-gamma1	PLC-gamma1	0	1	2	3
PLCgamma1 is activated by the EGF receptor , where it hydrolyzes PI ( 4,5 ) P 2 to activate cofilin .	PLCgamma1 is activated by the EGF receptor, where it hydrolyzes PI (4,5) P 2 to activate cofilin.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	PLCgamma1	PLCgamma1	PLCgamma1	5	7	0	1
The D1019K mutation also potentiated the EGFR dependent activation of PLC-gamma1 in cells ( XREF_FIG ) .	The D1019K mutation also potentiated the EGFR dependent activation of PLC-gamma1 in cells (XREF_FIG).	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLC-gamma1	PLC-gamma1	PLC-gamma1	6	7	10	11
Similarly , PLCgamma1 and phosphoinositide 3-kinase ( PI3K ) signalling by EGFR is inhibited by receptor internalization owing to the lack of their lipid substrate , PtdIns ( 4,5 ) P 2 , in endosomes XREF_BIBR .	Similarly, PLCgamma1 and phosphoinositide 3-kinase (PI3K) signalling by EGFR is inhibited by receptor internalization owing to the lack of their lipid substrate, PtdIns (4,5) P 2, in endosomes XREF_BIBR.	2	12	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLCgamma1	PLCgamma1	PLCgamma1	11	12	2	3
EGFR stimulation increased the association of PLCgamma-1 and c-Src in HNSCC cells expressing c-Src or PLCgamma-1 , but not in dominant negative c-Src or PLCgamma-1 expressing cells suggesting that c-Src and PLCgamma-1 may interact with each other downstream of EGFR in HNSCC cells ( XREF_FIG ) .	EGFR stimulation increased the association of PLCgamma-1 and c-Src in HNSCC cells expressing c-Src or PLCgamma-1, but not in dominant negative c-Src or PLCgamma-1 expressing cells suggesting that c-Src and PLCgamma-1 may interact with each other downstream of EGFR in HNSCC cells (XREF_FIG).	0	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLCgamma-1	PLCgamma-1	PLCgamma-1	0	1	6	7
Among the activations of key molecules within the four signaling pathways , overexpression of Migfilin up-regulated both EGFR mediated activations of PLC-gamma1 and STAT3 but not ERK and AKT .	Among the activations of key molecules within the four signaling pathways, overexpression of Migfilin up-regulated both EGFR mediated activations of PLC-gamma1 and STAT3 but not ERK and AKT.	15	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLC-gamma1	PLC-gamma1	PLC-gamma1	17	18	21	22
EGFR have been reported to activate ras-mitogen activated protein kinase kinase ( MEK ) , extracellular signal regulated kinase ( ERK ) , phosphatidylinositol-3-kinase ( PI3K )-Akt , c-Src , Stat3 , c-Met , and phospholipase Cgamma-1 ( PLCgamma-1 ) .	EGFR have been reported to activate ras-mitogen activated protein kinase kinase (MEK), extracellular signal regulated kinase (ERK), phosphatidylinositol-3-kinase (PI3K)-Akt, c-Src, Stat3, c-Met, and phospholipase Cgamma-1 (PLCgamma-1).	0	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	phospholipase Cgamma-1	phospholipase Cgamma-1	phospholipase Cgamma-1	0	1	35	37
The activation of the EGFR kinase in meningioma cells further activates PLC-gamma1 and increases its catalytic activity , leading to another mechanism that promotes meningioma cell growth ; additional evidences indicate that PLCgamma expression does not differ significantly between meningiomas of different histopathological grades [ XREF_BIBR ] .	The activation of the EGFR kinase in meningioma cells further activates PLC-gamma1 and increases its catalytic activity, leading to another mechanism that promotes meningioma cell growth; additional evidences indicate that PLCgamma expression does not differ significantly between meningiomas of different histopathological grades [XREF_BIBR].	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLC-gamma1	PLC-gamma1	PLC-gamma1	4	5	11	12
Complete epidermal growth factor receptor inhibition only partly reduced the activation of phospholipase Cgamma1 and NOS3 .	Complete epidermal growth factor receptor inhibition only partly reduced the activation of phospholipase Cgamma1 and NOS3.	1	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	phospholipase Cgamma1	phospholipase Cgamma1	phospholipase Cgamma1	1	5	12	14
These results systematically revealed that PKG II inhibited EGF induced migration of gastric cancer cells through blocking EGF and EGFR initiated signal transduction of PLCgamma1 and MAP and ERK mediated pathways .	These results systematically revealed that PKG II inhibited EGF induced migration of gastric cancer cells through blocking EGF and EGFR initiated signal transduction of PLCgamma1 and MAP and ERK mediated pathways.	17	30	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLCgamma1	PLCgamma1	PLCgamma1	19	20	24	25
EGFR stimulation increased activation of PLCgamma-1 in vector control transfected HNSCC cells , but not in dominant negative PLCgamma-1 expressing cells ( XREF_FIG ) .	EGFR stimulation increased activation of PLCgamma-1 in vector control transfected HNSCC cells, but not in dominant negative PLCgamma-1 expressing cells (XREF_FIG).	0	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLCgamma-1	PLCgamma-1	PLCgamma-1	0	1	5	6
This mutant lacks Y783 which is essential for EGFR mediated PLCgamma1 activation [ XREF_BIBR ] .	This mutant lacks Y783 which is essential for EGFR mediated PLCgamma1 activation [XREF_BIBR].	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLCgamma1	PLCgamma1	PLCgamma1	8	9	10	11
Taken together , our data suggest ADAM17 and EGFR driven PLCgamma1 and PKC pathways as important promoters of TG1 expression during terminal keratinocyte differentiation and skin barrier formation .	Taken together, our data suggest ADAM17 and EGFR driven PLCgamma1 and PKC pathways as important promoters of TG1 expression during terminal keratinocyte differentiation and skin barrier formation.	5	13	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLCgamma1	PLCgamma1	PLCgamma1	8	9	10	11
Our data provides the novel finding that the ADAM17 and EGFR axis in terminal differentiating keratinocytes mainly promotes PLCgamma1 signalling .	Our data provides the novel finding that the ADAM17 and EGFR axis in terminal differentiating keratinocytes mainly promotes PLCgamma1 signalling.	8	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLCgamma1	PLCgamma1	PLCgamma1	10	11	18	19
The activation of PLC-gamma1 by EGFR regulates cell mitogenesis and migration [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The activation of PLC-gamma1 by EGFR regulates cell mitogenesis and migration [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLC-gamma1	PLC-gamma1	PLC-gamma1	5	6	3	4
The EGFR specifically activates phospholipase C-gamma1 ( PLC-gamma1 ) .	The EGFR specifically activates phospholipase C-gamma1 (PLC-gamma1).	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	phospholipase C-gamma1	phospholipase C-gamma1	phospholipase C-gamma1	1	2	4	6
Our results suggest ADAM17 and EGFR driven PLCgamma1 and PKC pathways as important promoters of TG1 expression during terminal keratinocyte differentiation .	Our results suggest ADAM17 and EGFR driven PLCgamma1 and PKC pathways as important promoters of TG1 expression during terminal keratinocyte differentiation.	2	10	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLCgamma1	PLCgamma1	PLCgamma1	5	6	7	8
In this study , we have followed-up on EGFR dependent activation of PLCgamma1 .	In this study, we have followed-up on EGFR dependent activation of PLCgamma1.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLCgamma1	PLCgamma1	PLCgamma1	8	9	12	13
Activation of PLC-gamma1 by EGFR requires the EGFR to bind to PLC-gamma1 after its translocation from cytosol to cytoskeleton .	Activation of PLC-gamma1 by EGFR requires the EGFR to bind to PLC-gamma1 after its translocation from cytosol to cytoskeleton.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLC-gamma1	PLC-gamma1	PLC-gamma1	4	5	2	3
Our results suggest that in vitro the EGF receptor can increase PLC-gamma 1 activity independently of tyrosine phosphorylation .	Our results suggest that in vitro the EGF receptor can increase PLC-gamma 1 activity independently of tyrosine phosphorylation.	7	17	increase	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	PLC-gamma 1	PLC-gamma 1	PLC-gamma 1	7	9	11	13
The constitutively activated EGFR variant , EGFRvIII , also cooperates with STAT3 to activate the STAT1 gene promoter through the identified STAT3-bindings sites within the promoter .	The constitutively activated EGFR variant, EGFRvIII, also cooperates with STAT3 to activate the STAT1 gene promoter through the identified STAT3-bindings sites within the promoter.	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	3	4	15	16
This is in contrast to the results indicating that nuclear activity is required for EGFR mediated STAT1 gene upregulation ( XREF_FIG ) .	This is in contrast to the results indicating that nuclear activity is required for EGFR mediated STAT1 gene upregulation (XREF_FIG).	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	14	15	16	17
Therefore , approaches that boost IFN-gamma signalling and STAT1 activation , such as EGFR antagonism , may be significant in restoring antigen presentation through increased expression of HLA class I molecules and proinflammatory cytokines [ XREF_BIBR , XREF_BIBR ] .	Therefore, approaches that boost IFN-gamma signalling and STAT1 activation, such as EGFR antagonism, may be significant in restoring antigen presentation through increased expression of HLA class I molecules and proinflammatory cytokines [XREF_BIBR, XREF_BIBR].	6	14	signalling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	13	14	8	9
The engagement of this pathway in constitutive EGFR signaling is suggested by experiments demonstrating that EGFR upregulates IFNbeta and IFNalpha and results in activation of STAT1 .	The engagement of this pathway in constitutive EGFR signaling is suggested by experiments demonstrating that EGFR upregulates IFNbeta and IFNalpha and results in activation of STAT1.	15	26	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	15	16	25	26
Moreover , Lapatinib , an EGFR and ErbB2 tyrosine kinase inhibitor , potentiates STAT1 dependent activation of immune surveillance XREF_BIBR .	Moreover, Lapatinib, an EGFR and ErbB2 tyrosine kinase inhibitor, potentiates STAT1 dependent activation of immune surveillance XREF_BIBR.	2	15	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	5	6	13	14
EGFRvIII cooperates with STAT3 to activate the STAT1 gene promoter .	EGFRvIII cooperates with STAT3 to activate the STAT1 gene promoter.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT1	STAT1	STAT1	0	1	7	8
Thus , we determined whether EGFR synergizes with STAT3 to activate the STAT1 gene promoter .	Thus, we determined whether EGFR synergizes with STAT3 to activate the STAT1 gene promoter.	5	14	synergizes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	5	6	12	13
Together , these results demonstrate that the human STAT1 gene is transcriptionally activated by nuclear EGFR .	Together, these results demonstrate that the human STAT1 gene is transcriptionally activated by nuclear EGFR.	8	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	15	16	8	9
Studies have shown that in cell lines that hyper-express EGFR , the EGFR activates STAT1 , which recognizes responsive elements of and upregulates p21 [ XREF_BIBR , XREF_BIBR ] .	Studies have shown that in cell lines that hyper-express EGFR, the EGFR activates STAT1, which recognizes responsive elements of and upregulates p21 [XREF_BIBR, XREF_BIBR].	11	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	12	13	14	15
Collectively , these results indicate that EGFRvIII cooperates with STAT3 to activate the STAT1 promoter and that nuclear EGFRvIII does not play a significant role in this cooperation .	Collectively, these results indicate that EGFRvIII cooperates with STAT3 to activate the STAT1 promoter and that nuclear EGFRvIII does not play a significant role in this cooperation.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT1	STAT1	STAT1	6	7	13	14
We further investigated whether the constitutively active EGFR variant , EGFRvIII , activates STAT1 promoter and whether the activation requires cooperation with STAT3 .	We further investigated whether the constitutively active EGFR variant, EGFRvIII, activates STAT1 promoter and whether the activation requires cooperation with STAT3.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT1	STAT1	STAT1	10	11	13	14
As shown in XREF_FIG , we observed that EGFRvIII alone did not significantly enhance STAT1 promoter activity , but that the activity was greatly increased by the combination of EGFRvIII and STAT3CA .	As shown in XREF_FIG, we observed that EGFRvIII alone did not significantly enhance STAT1 promoter activity, but that the activity was greatly increased by the combination of EGFRvIII and STAT3CA.	8	16	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	STAT1	STAT1	STAT1	8	9	14	15
EGFR synergizes with STAT3 to activate the STAT1 gene promoter .	EGFR synergizes with STAT3 to activate the STAT1 gene promoter.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	0	1	7	8
As shown in XREF_FIG , transient co-expression of EGFR with constitutively activated STAT3 ( STAT3CA ) greatly enhanced STAT1 promoter activity in U87MG cells with very low levels of endogenous EGFR .	As shown in XREF_FIG, transient co-expression of EGFR with constitutively activated STAT3 (STAT3CA) greatly enhanced STAT1 promoter activity in U87MG cells with very low levels of endogenous EGFR.	6	20	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	co-expression of EGFR	egfr	STAT1	STAT1	stat1	8	9	18	19
Consistent with these results , we further show in XREF_FIG that STAT1 promoter activity is enhanced by ectopic EGFR in two breast cancer cell lines , MDA-MB-231 and MCF-7 cells with low levels of endogenous EGFR .	Consistent with these results, we further show in XREF_FIG that STAT1 promoter activity is enhanced by ectopic EGFR in two breast cancer cell lines, MDA-MB-231 and MCF-7 cells with low levels of endogenous EGFR.	11	29	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	18	19	11	12
Altogether , these results indicate that EGFR synergizes with STAT3 to activate the STAT1 gene promoter and that nuclear EGFR plays an important role in this synergy .	Altogether, these results indicate that EGFR synergizes with STAT3 to activate the STAT1 gene promoter and that nuclear EGFR plays an important role in this synergy.	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	6	7	13	14
Furthermore , EGFR siRNA increased STAT1 activation in STAT1 +/+ cells , but not in STAT1 -/- cells ( XREF_SUPPLEMENTARY ) .	Furthermore, EGFR siRNA increased STAT1 activation in STAT1 +/+ cells, but not in STAT1 -/- cells (XREF_SUPPLEMENTARY).	2	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	2	3	5	6
Our data suggest that HCMV utilizes EGFR- and integrin dependent ( but IFN independent ) signaling pathways to induce STAT1 activation , which may allow the virus to specifically dictate the biological activity of STAT1 during infection .	Our data suggest that HCMV utilizes EGFR- and integrin dependent (but IFN independent) signaling pathways to induce STAT1 activation, which may allow the virus to specifically dictate the biological activity of STAT1 during infection.	6	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR-	EGFR-	EGFR-	STAT1	STAT1	STAT1	6	7	19	20
Finally , in order to determine whether phosphorylation of PKR at Y162 also modulates PKR dimerization we decided to carry out a GST-PKR pulldown assay in the presence of dsRNA with in vitro translated [ 35 S ] methionine labeled PKR-WT or PKR-Y162D proteins previously subjected to an in vitro SUMOylation assay in the presence or absence of SUMO1 .	Finally, in order to determine whether phosphorylation of PKR at Y162 also modulates PKR dimerization we decided to carry out a GST-PKR pulldown assay in the presence of dsRNA with in vitro translated [35 S] methionine labeled PKR-WT or PKR-Y162D proteins previously subjected to an in vitro SUMOylation assay in the presence or absence of SUMO1.	7	15	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	phosphorylation of PKR at Y162	pkr	PKR	PKR	pkr	9	10	14	15
Furthermore , enhanced phosphorylation of PKR observed upon transfection of siRNA into human tissue culture cells is reduced by N 2 -benzyl modifications shown to block PKR activation in vitro .	Furthermore, enhanced phosphorylation of PKR observed upon transfection of siRNA into human tissue culture cells is reduced by N 2 -benzyl modifications shown to block PKR activation in vitro.	3	27	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKR	phosphorylation of PKR observed upon transfection of siRNA into human tissue culture cells is reduced by N 2	pkr	PKR	PKR	pkr	5	6	26	27
We found that PKRi and isohymenialdisine ( 3 ) inhibited autophosphorylation of PKR-KD ( XREF_FIG , compare lanes 4-7 to lanes 2 and 3 ) consistent with isohymenialdisine being able to directly inhibit PKR activation .	We found that PKRi and isohymenialdisine (3) inhibited autophosphorylation of PKR-KD (XREF_FIG, compare lanes 4-7 to lanes 2 and 3) consistent with isohymenialdisine being able to directly inhibit PKR activation.	3	34	inhibit	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	PKR-KD	PKRi and isohymenialdisine (3) inhibited autophosphorylation of PKR-KD	pkr-kd	PKR	PKR	pkr	12	13	33	34
Ectopic expression of wildtype PKR restored MAPK activation and IFN-beta induction in PKR deficient human cells .	Ectopic expression of wildtype PKR restored MAPK activation and IFN-beta induction in PKR deficient human cells.	1	15	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	expression of wildtype PKR	pkr	PKR	PKR	pkr	4	5	12	13
These authors also observed that ER stress does not induce PKR expression but rather activates the pre-existing PKR via the induction of the PKR activating protein PACT .	These authors also observed that ER stress does not induce PKR expression but rather activates the pre-existing PKR via the induction of the PKR activating protein PACT.	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	ER stress does not induce PKR expression	pkr	PKR	PKR	pkr	10	11	17	18
We also reconstituted PKR expression in the Pkr -/- MEFs since increased PKR expression itself induces PKR activity thus allowing comparisons in the same cellular background without stimulation of other signaling pathways ( XREF_SUPPLEMENTARY ) .	We also reconstituted PKR expression in the Pkr -/- MEFs since increased PKR expression itself induces PKR activity thus allowing comparisons in the same cellular background without stimulation of other signaling pathways (XREF_SUPPLEMENTARY).	2	14	increased	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	PKR	Pkr	pkr	PKR	PKR expression	pkr	7	8	12	13
The large amount of PKR did not allow appropriate quantification of the P-PKR and PKR ratio , but the P-eIF2alpha and eIF2alpha ratio clearly indicated that low amounts of PACT prevented the phosphorylation of eIF2alpha and increasing amounts restored HIV-1 protein expression and virion production .	The large amount of PKR did not allow appropriate quantification of the P-PKR and PKR ratio, but the P-eIF2alpha and eIF2alpha ratio clearly indicated that low amounts of PACT prevented the phosphorylation of eIF2alpha and increasing amounts restored HIV-1 protein expression and virion production.	2	15	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	amount of PKR	pkr	P-PKR	P-PKR	p-pkr	4	5	12	13
Strikingly , proteosome inhibition by MG132 restored LPS induced PKR activation in endotoxin tolerized macrophages and prevented the inducible loss of PKR protein ( XREF_FIG , top and middle , respectively ) .	Strikingly, proteosome inhibition by MG132 restored LPS induced PKR activation in endotoxin tolerized macrophages and prevented the inducible loss of PKR protein (XREF_FIG, top and middle, respectively).	5	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	MG132 restored LPS induced PKR	pkr	PKR	PKR	pkr	9	10	21	22
Lrig knockout mouse induces upregulation of EGFR , ErbB2 , and ErbB3 promoting downstream activation of c-Myc within intestinal stem and progenitor cells [ XREF_BIBR , XREF_BIBR ] .	Lrig knockout mouse induces upregulation of EGFR, ErbB2, and ErbB3 promoting downstream activation of c-Myc within intestinal stem and progenitor cells [XREF_BIBR, XREF_BIBR].	4	17	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	c-Myc	c-Myc	c-Myc	6	7	16	17
EGFRvIII activates c-Myc signaling through the control of alternative splicing of Max , a Myc binding partner , and mTORC2 dependent upregulation of c-Myc expression level [ XREF_BIBR , XREF_BIBR ] .	EGFRvIII activates c-Myc signaling through the control of alternative splicing of Max, a Myc binding partner, and mTORC2 dependent upregulation of c-Myc expression level [XREF_BIBR, XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	c-Myc	c-Myc	c-Myc	0	1	2	3
First , EGFRvIII promotes the oncogenic activity of c-Myc by inducing mTORC1 dependent , hnRNA1 dependent splicing of the c-Myc interacting protein MAX , to form the gain of function variant Delta MAX .	First, EGFRvIII promotes the oncogenic activity of c-Myc by inducing mTORC1 dependent, hnRNA1 dependent splicing of the c-Myc interacting protein MAX, to form the gain of function variant Delta MAX.	2	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	c-Myc	c-Myc	c-Myc	2	3	8	9
In tumors , dietary fat and Egfr wt up-regulated TGF-alpha , amphiregulin , CTNNB1 , MYC , and CCND1 , whereas PTGS2 was only increased in Egfr wt mice and further up-regulated by dietary fat .	In tumors, dietary fat and Egfr wt up-regulated TGF-alpha, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfr wt mice and further up-regulated by dietary fat.	4	30	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Egfr	Egfr	Egfr	MYC	MYC	MYC	6	7	15	16
In addition , they showed that this dietary pattern can down-regulate tumor suppressor miRNA-143 and miRNA-145 through EGFR signaling , which further up-regulated their target oncogenes , MYC and KRAS , resulting in increased tumorigenesis [ XREF_BIBR ] .	In addition, they showed that this dietary pattern can down-regulate tumor suppressor miRNA-143 and miRNA-145 through EGFR signaling, which further up-regulated their target oncogenes, MYC and KRAS, resulting in increased tumorigenesis [XREF_BIBR].	17	28	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	MYC	MYC	MYC	17	18	27	28
This is consistent with findings that , in flies and mammals , EGFR-Ras , PI3K , and Tor signaling upregulate Myc protein levels XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	This is consistent with findings that, in flies and mammals, EGFR-Ras, PI3K, and Tor signaling upregulate Myc protein levels XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	12	23	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR-Ras	EGFR-Ras	EGFR-Ras	Myc	Myc	Myc	12	13	20	21
In the presence of a Western diet , EGFR signals increased proto-oncogene MYC and pro inflammatory cyclooxygenase-2 ( Cox-2 ) .	In the presence of a Western diet, EGFR signals increased proto-oncogene MYC and pro inflammatory cyclooxygenase-2 (Cox-2).	8	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	MYC	MYC	MYC	8	9	12	13
Similarly , stimulation of either TLR2 or EGFR in a non transformed IEC line derived from the small intestine ( RIE-1 ) also activated ERK and c-myc ( XREF_SUPPLEMENTARY ) .	Similarly, stimulation of either TLR2 or EGFR in a non transformed IEC line derived from the small intestine (RIE-1) also activated ERK and c-myc (XREF_SUPPLEMENTARY).	2	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	c-myc	c-myc	c-myc	7	8	26	27
We previously observed that CCND1 , PTGS2 , MYC and NOS2 were highly modulated by PGE 2 -induced nuclear EGFR [ XREF_BIBR ] .	We previously observed that CCND1, PTGS2, MYC and NOS2 were highly modulated by PGE 2 -induced nuclear EGFR [XREF_BIBR].	4	21	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	MYC	MYC	MYC	19	20	8	9
Prior studies have shown that c-MYC can be upregulated by EGFR through pathways such as the Ras-Raf-Erk pathway and therefore result in the promotion of angiogenesis through HIF-1alpha and VEGF XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Prior studies have shown that c-MYC can be upregulated by EGFR through pathways such as the Ras-Raf-Erk pathway and therefore result in the promotion of angiogenesis through HIF-1alpha and VEGF XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	20	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	c-MYC	c-MYC	c-MYC	10	11	5	6
The combination of DETANO and PP2 resulted in serum starved control levels of c-Myc actvation , indicating that EGFR and/or Src activity is required for DETANO to increase c-Myc signaling ( XREF_FIG ) .	The combination of DETANO and PP2 resulted in serum starved control levels of c-Myc actvation, indicating that EGFR and/or Src activity is required for DETANO to increase c-Myc signaling (XREF_FIG).	18	29	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	c-Myc	c-Myc	c-Myc	18	19	28	29
We have previously demonstrated that EGFRvIII signaling through mTORC1 enhances c-MYC activity through the alternative splicing of the c-MYC heterodimerization partner Max to generate Delta Max , a gain of function variant , and we have found that EGFRvIII controls c-MYC protein level through a FOXO 1 , 3- acetylation signaling cascade .	We have previously demonstrated that EGFRvIII signaling through mTORC1 enhances c-MYC activity through the alternative splicing of the c-MYC heterodimerization partner Max to generate Delta Max, a gain of function variant, and we have found that EGFRvIII controls c-MYC protein level through a FOXO 1, 3- acetylation signaling cascade.	5	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	c-MYC	c-MYC	c-MYC	5	6	10	11
The results showed that inhibition of EGFR with erlotinib in breast cancer MDA-MB-231 and HBL100 cell lines significant downregulated p-AKT , p-ERK , CD44 , KLF4 , Myc , Slug and Snail in these cells ( XREF_FIG ) .	The results showed that inhibition of EGFR with erlotinib in breast cancer MDA-MB-231 and HBL100 cell lines significant downregulated p-AKT, p-ERK, CD44, KLF4, Myc, Slug and Snail in these cells (XREF_FIG).	4	28	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Myc	Myc	Myc	6	7	27	28
It is known that EGFR activates c-myc and CREB .	It is known that EGFR activates c-myc and CREB.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	c-myc	c-myc	c-myc	4	5	6	7
This supports that EGFR may be able to induce the up-regulation of c-MYC and HIF-1alpha .	This supports that EGFR may be able to induce the up-regulation of c-MYC and HIF-1alpha.	3	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	c-MYC	c-MYC	c-MYC	3	4	12	13
Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro proliferative transcription factor c-MYC .	Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro proliferative transcription factor c-MYC.	7	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	c-MYC	c-MYC	c-MYC	7	8	20	21
Of note , both BRAF V600E and EGFRvIII promoted the stability of MYC either singly phosphorylated at T58 or doubly phosphorylated at T58 and S62 .	Of note, both BRAF V600E and EGFRvIII promoted the stability of MYC either singly phosphorylated at T58 or doubly phosphorylated at T58 and S62.	5	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	MYC	MYC	MYC	7	8	12	13
EGFR mediated FAK signalling are key regulators of invasion and metastasis in cancer cells , and the meta-analysis studies reveal EGFR signalling as a key pathway involving the majority of differentially regulated genes in preeclamptic placenta XREF_BIBR .	EGFR mediated FAK signalling are key regulators of invasion and metastasis in cancer cells, and the meta-analysis studies reveal EGFR signalling as a key pathway involving the majority of differentially regulated genes in preeclamptic placenta XREF_BIBR.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	FAK	FAK	FAK	0	1	2	3
28 Our current results confirmed that EGFR blockade not only inhibited HB-EGF-induced cell migration , but also reversed HB-EGF-induced F-actin reorganization and FAK activation .	28 Our current results confirmed that EGFR blockade not only inhibited HB-EGF-induced cell migration, but also reversed HB-EGF-induced F-actin reorganization and FAK activation.	6	23	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	FAK	FAK	FAK	6	7	22	23
EGFR and EGFR mediated FAK signaling are key regulators of invasion and metastasis in cancer cells .	EGFR and EGFR mediated FAK signaling are key regulators of invasion and metastasis in cancer cells.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	FAK	FAK	FAK	2	3	4	5
The anti-tumor effects of quercetin 3-O-glucoside were mediated by selectively inhibiting the EGFR mediated FAK , AKT , MEK1/2 , and ERK1/2 signaling pathway .	The anti-tumor effects of quercetin 3-O-glucoside were mediated by selectively inhibiting the EGFR mediated FAK, AKT, MEK1/2, and ERK1/2 signaling pathway.	11	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	FAK	FAK	FAK	12	13	14	15
Recent researchers found EGFRvIII promoted glioma cell migration was closely linked to high levels of tyrosine phosphorylation in FAK Y397 .	Recent researchers found EGFRvIII promoted glioma cell migration was closely linked to high levels of tyrosine phosphorylation in FAK Y397.	3	19	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	FAK	FAK	FAK	3	4	18	19
Oncogenic Receptor Tyrosine Kinases HER2 and EGFR reactivate FAK in FAK-kinase inhibited cancer cells and activate AKT and ERK independent of FAK-kinase activity .	Oncogenic Receptor Tyrosine Kinases HER2 and EGFR reactivate FAK in FAK-kinase inhibited cancer cells and activate AKT and ERK independent of FAK-kinase activity.	4	10	reactivate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	FAK	FAK	FAK	6	7	8	9
RHBDL2 Mediates Anoikis Resistance through EGFR Activated FAK Pathway .	RHBDL2 Mediates Anoikis Resistance through EGFR Activated FAK Pathway.	1	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	FAK	FAK	FAK	5	6	7	8
For instance , EGFR is predicted to target GAB1 ( EGFR ---> GAB1 ) , GRB2 ( EGFR ---> GRB2 ) , etc ..	For instance, EGFR is predicted to target GAB1 (EGFR ---> GAB1), GRB2 (EGFR ---> GRB2), etc..	3	15	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	GAB1	GAB1	GAB1	3	4	8	9
These observations provide evidence that efficient ErbB-2-induced mammary tumor progression requires EGFR dependent activation of Gab1 .	These observations provide evidence that efficient ErbB-2-induced mammary tumor progression requires EGFR dependent activation of Gab1.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Gab1	Gab1	Gab1	11	12	15	16
In addition , we searched for ser473 p-Akt ( p-Akt ) , which is activated by EGFR , and Epithelial Membrane Antigen ( EMA ) , which is generally used as differential diagnosis marker of mesothelial cells .	In addition, we searched for ser473 p-Akt (p-Akt), which is activated by EGFR, and Epithelial Membrane Antigen (EMA), which is generally used as differential diagnosis marker of mesothelial cells.	14	24	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EMA	EMA	EMA	16	17	23	24
We compared the size and selectivity of vapor nanobubbles generated from MUC1- and EGFR targeted AuNPs in HES ( MUC1 +/EGFR+ ) and HS-5 ( MUC1- and EGFR+ ) cells .	We compared the size and selectivity of vapor nanobubbles generated from MUC1- and EGFR targeted AuNPs in HES (MUC1 +/EGFR+) and HS-5 (MUC1- and EGFR+) cells.	9	27	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	MUC1-	MUC1-	MUC1-	13	14	25	26
XREF_BIBR , XREF_BIBR Without the presence of EGF , introduction of galectin-3 had no significant effect on EGFR activation in either MUC1 positive or -negative cells of breast origin ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR Without the presence of EGF, introduction of galectin-3 had no significant effect on EGFR activation in either MUC1 positive or -negative cells of breast origin (XREF_FIG).	17	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	MUC1	MUC1	MUC1	17	18	21	22
Endosomal transport has been established only for internalization of MUC1 C-terminal subunit initiated by ligand engagement of EGF receptor [ XREF_BIBR ; XREF_BIBR ] .	Endosomal transport has been established only for internalization of MUC1 C-terminal subunit initiated by ligand engagement of EGF receptor [XREF_BIBR; XREF_BIBR].	9	20	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	MUC1	MUC1	MUC1	17	19	9	10
The EGFR directed monoclonal antibody , cetuximab , is FDA- and EMA approved for the treatment of HNSCC .	The EGFR directed monoclonal antibody, cetuximab, is FDA- and EMA approved for the treatment of HNSCC.	0	12	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	EMA	EMA	EMA	1	2	11	12
To determine whether EGFR signaling induces cleavage of MUC1 , whole cell lysates from FG cells treated with or without a pulse of EGF were probed for the 15 kDa MUC1 cytoplasmic domain by immunoblotting .	To determine whether EGFR signaling induces cleavage of MUC1, whole cell lysates from FG cells treated with or without a pulse of EGF were probed for the 15 kDa MUC1 cytoplasmic domain by immunoblotting.	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	MUC1	MUC1	MUC1	3	4	8	9
XREF_BIBR , XREF_BIBR , XREF_BIBR However , the discovery that EGF showed a much weaker effect on EGFR activation in the MUC1 negative cells ( XREF_FIG - XREF_FIG ) , irrespective of the presence of galectin-3 , indicates that exposure of cell surface EGFR for easy EGF access is unlikely to be the mechanism of the MUC1-galectin-3 interaction associated EGFR activation .	XREF_BIBR, XREF_BIBR, XREF_BIBR However, the discovery that EGF showed a much weaker effect on EGFR activation in the MUC1 negative cells (XREF_FIG - XREF_FIG), irrespective of the presence of galectin-3, indicates that exposure of cell surface EGFR for easy EGF access is unlikely to be the mechanism of the MUC1-galectin-3 interaction associated EGFR activation.	17	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	MUC1	MUC1	MUC1	17	18	21	22
In this study , evidence is presented that MUC1 expression disrupts TLR5-MyD88 interaction and downstream proinflammatory signaling , and that EGFR activation promotes this anti-inflammatory effect of MUC1 through tyrosine phosphorylation of the MUC1 CT ..	In this study, evidence is presented that MUC1 expression disrupts TLR5-MyD88 interaction and downstream proinflammatory signaling, and that EGFR activation promotes this anti-inflammatory effect of MUC1 through tyrosine phosphorylation of the MUC1 CT..	20	28	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	MUC1	MUC1	MUC1	20	21	27	28
In hepatocytes at 24 h of culturing ( mid and late G ( 1 ) ) with 20,000 cells per cm ( 2 ) , EGF induced strong phosphorylation of the EGF receptor , as well as Shc and ERK , and stimulated DNA synthesis , but did not activate Stat5b , although the Stat5b response to GH or PRL was retained .	In hepatocytes at 24 h of culturing (mid and late G (1)) with 20,000 cells per cm (2), EGF induced strong phosphorylation of the EGF receptor, as well as Shc and ERK, and stimulated DNA synthesis, but did not activate Stat5b, although the Stat5b response to GH or PRL was retained.	25	51	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF receptor	EGF induced strong phosphorylation of the EGF receptor	egf receptor	Stat5b	Stat5b	stat5b	31	33	50	51
In particular , STAT5b , which is a crucial factor for controlling cell survival , cell cycle arrest , and cell death , can be activated by the phosphorylated Y845 kinase domain of EGFR in EGF stimulated tumor cells [ XREF_BIBR ] .	In particular, STAT5b, which is a crucial factor for controlling cell survival, cell cycle arrest, and cell death, can be activated by the phosphorylated Y845 kinase domain of EGFR in EGF stimulated tumor cells [XREF_BIBR].	3	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT5b	STAT5b	STAT5b	33	34	3	4
EGF is capable of activating STAT5b , signaling of which is mediated by the EGF receptor .	EGF is capable of activating STAT5b, signaling of which is mediated by the EGF receptor.	2	16	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	STAT5b	STAT5b	STAT5b	14	16	5	6
Cell-cycle analysis upon EfnB1 ligand stimulation of EphB1 high cells revealed an increase in the number of cells in G 2 -M phase of the cell cycle after which these cells were prone to go into apoptosis ( XREF_FIG , paired samples t test , P = 0.028 ) .	Cell-cycle analysis upon EfnB1 ligand stimulation of EphB1 high cells revealed an increase in the number of cells in G 2 -M phase of the cell cycle after which these cells were prone to go into apoptosis (XREF_FIG, paired samples t test, P = 0.028).	3	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EfnB1	EfnB1	EfnB1	EphB1	EphB1	EphB1	3	4	7	8
These data indicate that ephrin-B1 expressed in the SC midline acts as ligand to mediate EphB1 and EphB2 forward signal driven VT RGC axon retinocollicular mapping , although the incomplete penetrance of the defect suggests additional ephrin-B molecules likely participate .	These data indicate that ephrin-B1 expressed in the SC midline acts as ligand to mediate EphB1 and EphB2 forward signal driven VT RGC axon retinocollicular mapping, although the incomplete penetrance of the defect suggests additional ephrin-B molecules likely participate.	4	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-B1	ephrin-B1 expressed	ephrin-b1	EphB1	EphB1	ephb1	4	5	15	16
Ephrin-B1 activation of EphB1 promotes assembly of these cells into capillary like structures .	Ephrin-B1 activation of EphB1 promotes assembly of these cells into capillary like structures.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Ephrin-B1	Ephrin-B1	Ephrin-B1	EphB1	EphB1	EphB1	0	1	3	4
As expected , the phosphorylation of cell-cycle regulators p27 , p38 and p53 was increased upon EfnB1 stimulation of EphB1 high AML cells .	As expected, the phosphorylation of cell-cycle regulators p27, p38 and p53 was increased upon EfnB1 stimulation of EphB1 high AML cells.	16	22	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EfnB1	EfnB1	EfnB1	EphB1	EphB1	EphB1	16	17	19	20
For instance , ephrin-B1 can activate EphB1 and stimulate the production of TNF-alpha in PBLs and IL-6 in synovial cells [ XREF_BIBR ] .	For instance, ephrin-B1 can activate EphB1 and stimulate the production of TNF-alpha in PBLs and IL-6 in synovial cells [XREF_BIBR].	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-B1	ephrin-B1	ephrin-B1	EphB1	EphB1	EphB1	3	4	6	7
The tyrphostin AG1478 , known to inhibit EGF receptor phosphorylation , also inhibited the angiotensin II and EGF induced activation of ERK , the phosphorylation of the EGF receptor , and the subsequent association of Shc and Grb2 .	The tyrphostin AG1478, known to inhibit EGF receptor phosphorylation, also inhibited the angiotensin II and EGF induced activation of ERK, the phosphorylation of the EGF receptor, and the subsequent association of Shc and Grb2.	2	38	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF receptor	AG1478, known to inhibit EGF receptor phosphorylation	egf receptor	Grb2	Grb2	grb2	7	9	37	38
EGFR : GRB2 PLA was found not to be correlated with total EGFR expression indicating that EGFR : GRB2 PLA was not solely driven by the abundance of EGFR ( XREF_FIG ) .	EGFR : GRB2 PLA was found not to be correlated with total EGFR expression indicating that EGFR : GRB2 PLA was not solely driven by the abundance of EGFR (XREF_FIG).	18	30	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	GRB2	GRB2	GRB2	28	29	18	19
To test whether nicotine activated EGFR was able to bind to Grb2 , MCF10A cells were treated with nicotine or EGFR and immunoprecipitation was then performed .	To test whether nicotine activated EGFR was able to bind to Grb2, MCF10A cells were treated with nicotine or EGFR and immunoprecipitation was then performed.	9	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Grb2	Grb2	Grb2	20	21	11	12
We asked if the increased amount of EGFR in the endosomal pool actively signals in shDHHC20 cells by examining endogenous Grb2 localization by IF .	We asked if the increased amount of EGFR in the endosomal pool actively signals in shDHHC20 cells by examining endogenous Grb2 localization by IF.	5	21	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	amount of EGFR	egfr	Grb2	Grb2	grb2	7	8	20	21
Phosphorylation of Y1068 on EGFR allows binding of Grb2 .	Phosphorylation of Y1068 on EGFR allows binding of Grb2.	0	9	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Phosphorylation of Y1068 on EGFR	egfr	Grb2	Grb2	grb2	4	5	8	9
JAK2 activation can be mediated by EGFR and EGFRvIII .	JAK2 activation can be mediated by EGFR and EGFRvIII.	0	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFRvIII	EGFRvIII	EGFRvIII	JAK2	JAK2	JAK2	8	9	0	1
Thus , acute , physiologically relevant doses of cisplatin initiates EGFR signaling and activation of JAK2 and AKT .	Thus, acute, physiologically relevant doses of cisplatin initiates EGFR signaling and activation of JAK2 and AKT.	10	17	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	JAK2	JAK2	JAK2	10	11	15	16
With AG1478 treatment , the activation of JAK2 in the suprabasal layer was significantly reduced as compared to mutants treated with DMSO ( compare XREF_FIG ) , suggesting that inhibition of EGFR signaling is sufficient to block JAK2 activation regardless of the presence of cytokines .	With AG1478 treatment, the activation of JAK2 in the suprabasal layer was significantly reduced as compared to mutants treated with DMSO (compare XREF_FIG), suggesting that inhibition of EGFR signaling is sufficient to block JAK2 activation regardless of the presence of cytokines.	31	38	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	JAK2	JAK2	JAK2	31	32	37	38
NE increased tyrosine phosphorylation of focal adhesion related kinase Pyk2 and a 70 kDa protein , probably paxillin , whereas EGF strongly stimulated tyrosine phosphorylation of the EGF receptor and cytokine activated kinase Jak2 .	NE increased tyrosine phosphorylation of focal adhesion related kinase Pyk2 and a 70 kDa protein, probably paxillin, whereas EGF strongly stimulated tyrosine phosphorylation of the EGF receptor and cytokine activated kinase Jak2.	23	34	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF receptor	tyrosine phosphorylation of the EGF receptor	egf receptor	Jak2	Jak2	jak2	27	29	33	34
Moreover , Cbl loss not only uncouples Met from Cbl mediated negative regulation but also releases other Cbl targets , such as the EGF receptor , from Cbl mediated signal attenuation .	Moreover, Cbl loss not only uncouples Met from Cbl mediated negative regulation but also releases other Cbl targets, such as the EGF receptor, from Cbl mediated signal attenuation.	17	25	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	Cbl	Cbl	Cbl	23	25	17	18
Collectively , these data suggest that the ubiquitination resulting from direct binding of Cbl to pTyr1045 of the EGFR is critical for lysosomal sorting of the EGFR in contrast to ubiquitination resulting from Grb2 mediated binding of Cbl to the EGFR .	Collectively, these data suggest that the ubiquitination resulting from direct binding of Cbl to pTyr1045 of the EGFR is critical for lysosomal sorting of the EGFR in contrast to ubiquitination resulting from Grb2 mediated binding of Cbl to the EGFR.	23	38	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Cbl	Cbl	Cbl	26	27	37	38
In addition , EGFR also functions as a transcription factor and enhances cell proliferation by activating and stabilizing PCNA [ XREF_BIBR ] .	In addition, EGFR also functions as a transcription factor and enhances cell proliferation by activating and stabilizing PCNA [XREF_BIBR].	3	20	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PCNA	PCNA	PCNA	3	4	18	19
Inside the nucleus , EGFR functions as a co-transcription factor for several genes involved in cell proliferation and angiogenesis , and as a tyrosine kinase to activate and stabilize proliferating cell nuclear antigen and DNA dependent protein kinase .	Inside the nucleus, EGFR functions as a co-transcription factor for several genes involved in cell proliferation and angiogenesis, and as a tyrosine kinase to activate and stabilize proliferating cell nuclear antigen and DNA dependent protein kinase.	4	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	4	5	29	33
Prolonged induction of p21Cip1 , WAF1 , CDK2 , and PCNA complex by epidermal growth factor receptor activation mediates ligand induced A431 cell growth inhibition .	Prolonged induction of p21Cip1, WAF1, CDK2, and PCNA complex by epidermal growth factor receptor activation mediates ligand induced A431 cell growth inhibition.	1	17	induction	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	PCNA	PCNA	PCNA	13	17	10	11
We speculate that inhibition of TIP30 may block EGFR trafficking to the lysosome and increase EGFR nuclear import , thereby increasing EGFR nuclear localization and expression of its two direct targets , CyclinD1 and PCNA .	We speculate that inhibition of TIP30 may block EGFR trafficking to the lysosome and increase EGFR nuclear import, thereby increasing EGFR nuclear localization and expression of its two direct targets, CyclinD1 and PCNA.	7	35	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PCNA	PCNA	PCNA	15	16	34	35
XREF_BIBR Nuclear EGFR can also activate and stabilize PCNA and DNA-PK to enhance DNA replication and DNA repair .	XREF_BIBR Nuclear EGFR can also activate and stabilize PCNA and DNA-PK to enhance DNA replication and DNA repair.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PCNA	PCNA	PCNA	2	3	8	9
In contrast , fibroblasts express high level of ephrin-B2 , which activates EphB3 and EphB4 on PC3 cells to induce Cdc42 activation , lamellipodia formation and cell migration .	In contrast, fibroblasts express high level of ephrin-B2, which activates EphB3 and EphB4 on PC3 cells to induce Cdc42 activation, lamellipodia formation and cell migration.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-B2	level of ephrin-B2	ephrin-b2	EphB3	EphB3	ephb3	8	9	12	13
For instance , Vav2 and can be directly activated by the receptor protein tyrosine kinase activity of EphA receptor and epidermal growth factor receptor .	For instance, Vav2 and can be directly activated by the receptor protein tyrosine kinase activity of EphA receptor and epidermal growth factor receptor.	3	24	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	Vav2	Vav2	Vav2	20	24	3	4
It appears that CadF does not only act as a canonical adhesin for bacterial attachment to fibronectin , but could also stimulate integrins as well as FAK , EGFR and PDGFR kinase activity , which subsequently may activate Vav2 and Cdc42 , important for maximal C. jejuni invasion .	It appears that CadF does not only act as a canonical adhesin for bacterial attachment to fibronectin, but could also stimulate integrins as well as FAK, EGFR and PDGFR kinase activity, which subsequently may activate Vav2 and Cdc42, important for maximal C. jejuni invasion.	26	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Vav2	Vav2	Vav2	28	29	38	39
To determine whether ephrinB3 can stimulate EphB3 and EphA4 to regulate D-serine levels in the adult hippocampus , we first examined whether hippocampal astrocytes expressed Eph receptors .	To determine whether ephrinB3 can stimulate EphB3 and EphA4 to regulate D-serine levels in the adult hippocampus, we first examined whether hippocampal astrocytes expressed Eph receptors.	3	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrinB3	ephrinB3	ephrinB3	EphB3	EphB3	EphB3	3	4	6	7
It is conceivable that ephrinB3 expressed in the striatum bordering the germinal zone could signal on NSPC expressing EphB3 .	It is conceivable that ephrinB3 expressed in the striatum bordering the germinal zone could signal on NSPC expressing EphB3.	4	19	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrinB3	ephrinB3 expressed	ephrinb3	EphB3	EphB3	ephb3	4	5	18	19
EphrinB3 activate EphB3 and EphA4 receptors to stimulate D-serine release from cultured astrocytes .	EphrinB3 activate EphB3 and EphA4 receptors to stimulate D-serine release from cultured astrocytes.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphrinB3	EphrinB3	EphrinB3	EphB3	EphB3	EphB3	0	1	2	3
This provides support to our previous gain-of-function studies showing that ephrinB3 stimulation of EphB3 could increase d-serine levels in hippocampal slices and cultured astrocytes .	This provides support to our previous gain-of-function studies showing that ephrinB3 stimulation of EphB3 could increase d-serine levels in hippocampal slices and cultured astrocytes.	10	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ephrinB3	ephrinB3	ephrinB3	EphB3	EphB3	EphB3	10	11	13	14
Ephrin-B3 can also reduce cell death by inhibiting the functions of EphA4 receptors during adult neurogenesis in the subventricular zone of the brain .	Ephrin-B3 can also reduce cell death by inhibiting the functions of EphA4 receptors during adult neurogenesis in the subventricular zone of the brain.	0	12	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ephrin-B3	Ephrin-B3	Ephrin-B3	EphA4	EphA4	EphA4	0	1	11	12
Interestingly the same guidance mechanism , namely ephrinB3 induced EphA4 forward signaling , is required for the guidance of both ascending and descending axon tracts .	Interestingly the same guidance mechanism, namely ephrinB3 induced EphA4 forward signaling, is required for the guidance of both ascending and descending axon tracts.	4	10	induced	Positive_early_activation	Positive_activation	Positive_activation	ephrinB3	ephrinB3	ephrinB3	EphA4	EphA4	EphA4	7	8	9	10
EphrinB3 induced EphA4 signaling has been shown to regulate CPG development by detering the axons of ipsilaterally projecting excitatory spinal interneurons from inappropriately crossing the midline , preventing aberrant innervation of the contralateral CPG XREF_BIBR .	EphrinB3 induced EphA4 signaling has been shown to regulate CPG development by detering the axons of ipsilaterally projecting excitatory spinal interneurons from inappropriately crossing the midline, preventing aberrant innervation of the contralateral CPG XREF_BIBR.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	EphrinB3	EphrinB3	EphrinB3	EphA4	EphA4	EphA4	0	1	2	3
PLD-1 may be activated via protein kinase Calpha [ XREF_BIBR ] , while PLD-2 can be activated directly by the EGFR [ XREF_BIBR ] .	PLD-1 may be activated via protein kinase Calpha [XREF_BIBR], while PLD-2 can be activated directly by the EGFR [XREF_BIBR].	13	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLD-2	PLD-2	PLD-2	20	21	13	14
PLD2 is activated by EGFR and mediates MAPK activation [ XREF_BIBR , XREF_BIBR ] , implying that it is the source of EGFR generated PA ..	PLD2 is activated by EGFR and mediates MAPK activation [XREF_BIBR, XREF_BIBR], implying that it is the source of EGFR generated PA..	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLD2	PLD2	PLD2	4	5	0	1
Previous studies have shown that EGFR stimulates PLD2 activity , and that PLD2 and EGFR co-localize [ XREF_BIBR , XREF_BIBR ] .	Previous studies have shown that EGFR stimulates PLD2 activity, and that PLD2 and EGFR co-localize [XREF_BIBR, XREF_BIBR].	5	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PLD2	PLD2	PLD2	5	6	7	8
Recently , EGFR mediated Nck1 and Rap1 activation has been shown to upregulate metastasis in a model of metastatic pancreatic carcinoma without affecting primary tumor growth [ XREF_BIBR ] .	Recently, EGFR mediated Nck1 and Rap1 activation has been shown to upregulate metastasis in a model of metastatic pancreatic carcinoma without affecting primary tumor growth [XREF_BIBR].	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Nck1	Nck1	Nck1	2	3	4	5
XREF_BIBR , XREF_BIBR EGFR homodimerization and heterodimerization with other EGFR family members leads to enhanced tyrosine kinase activity of the receptor complexes and activation of multiple signaling pathways , such as mitogen activated protein kinase ( MAPK ) , p38 MAPK , phosphatidylinositol 3 '-kinase ( PI3K ) , Src , Crk and Nck .	XREF_BIBR, XREF_BIBR EGFR homodimerization and heterodimerization with other EGFR family members leads to enhanced tyrosine kinase activity of the receptor complexes and activation of multiple signaling pathways, such as mitogen activated protein kinase (MAPK), p38 MAPK, phosphatidylinositol 3 '-kinase (PI3K), Src, Crk and Nck.	3	54	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Nck	Nck	Nck	3	4	53	54
As expected , this was due to the upregulation of EGFR signaling in ERRFI1 knockdown cells relative to siNeg control ( Fig XREF_FIG A , right panel ) .	As expected, this was due to the upregulation of EGFR signaling in ERRFI1 knockdown cells relative to siNeg control (Fig XREF_FIG A, right panel).	10	15	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERRFI1	ERRFI1	ERRFI1	10	11	13	14
Pathways downstream of EGFR activation stimulate the induction of Mig6 , which then acts as a negative-feedback response and attenuates EGFR signaling .	Pathways downstream of EGFR activation stimulate the induction of Mig6, which then acts as a negative-feedback response and attenuates EGFR signaling.	3	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Mig6	Mig6	Mig6	3	4	9	10
Several interesting genes such as the transcriptional repressor HESX1 , a negative regulator of EGFR signaling ERRFI1 and the lymphoid specific helicase HELLS were repressed by SNF5 .	Several interesting genes such as the transcriptional repressor HESX1, a negative regulator of EGFR signaling ERRFI1 and the lymphoid specific helicase HELLS were repressed by SNF5.	12	22	signaling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ERRFI1	ERRFI1	ERRFI1	14	15	16	17
Apparently , SHC1 , Erk and PI3K activation is initiated by EGFR activation and may together lead to FAK activation .	Apparently, SHC1, Erk and PI3K activation is initiated by EGFR activation and may together lead to FAK activation.	2	12	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	SHC1	SHC1	SHC1	11	12	2	3
Hence , abolition of the kinase activity of EGFR by a specific tyrosine kinase inhibitor prevented the inhibitory effect of PTP-1B to dephosphorylate tyrosine residues of the receptor in the cells exposed to NBD compounds or to the cognate ligand .	Hence, abolition of the kinase activity of EGFR by a specific tyrosine kinase inhibitor prevented the inhibitory effect of PTP-1B to dephosphorylate tyrosine residues of the receptor in the cells exposed to NBD compounds or to the cognate ligand.	6	21	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	PTP-1B	PTP-1B	PTP-1B	8	9	20	21
Coexpression of ERBB4 and STAT5A , however , resulted in a > 40-fold increase in beta-casein reporter activity ( XREF_FIG ) demonstrating for the first time that an ERBB receptor directly regulates STAT5A transactivation .	Coexpression of ERBB4 and STAT5A, however, resulted in a> 40-fold increase in beta-casein reporter activity (XREF_FIG) demonstrating for the first time that an ERBB receptor directly regulates STAT5A transactivation.	28	33	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB	ERBB	ERBB	STAT5A	STAT5A	STAT5A	28	29	32	33
Hrs overexpression enhances the ubiquitination of EGFR and leads to translocation of EGFR to Hrs containing endosomes , both of which depend on the integrity of the lipid binding motif of Hrs .	Hrs overexpression enhances the ubiquitination of EGFR and leads to translocation of EGFR to Hrs containing endosomes, both of which depend on the integrity of the lipid binding motif of Hrs.	0	15	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EGFR	Hrs overexpression enhances the ubiquitination of EGFR	egfr	Hrs	Hrs	hrs	6	7	14	15
Therefore , our results indicate that EGFR Del19 may promote Fn14 and JAK1 and STAT1 expression in NSCLC and Fn14 may serve as a prognostic biomarker in NSCLC with EGFR Del19 .	Therefore, our results indicate that EGFR Del19 may promote Fn14 and JAK1 and STAT1 expression in NSCLC and Fn14 may serve as a prognostic biomarker in NSCLC with EGFR Del19.	6	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	JAK1	JAK1	JAK1	6	7	12	13
Notably , treatment of cardiac myocytes with Dox decreased the protein levels of p300 but markedly increased those of p53 .	Notably, treatment of cardiac myocytes with Dox decreased the protein levels of p300 but markedly increased those of p53.	11	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	levels of p300	p300	p53	p53	p53	13	14	19	20
Also , many of the same sites that are ubiquitinated by Hdm2 can also be acetylated by p300 and CBP to promote p53 activation .	Also, many of the same sites that are ubiquitinated by Hdm2 can also be acetylated by p300 and CBP to promote p53 activation.	15	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	17	18	22	23
This acetylation is brought about by p300 , which in this way aids to direct p53 towards specific target genes .	This acetylation is brought about by p300, which in this way aids to direct p53 towards specific target genes.	3	16	aids	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	6	7	15	16
For example , it has been reported that PRMT1 , CARM1 and PRMT4 and p300 function cooperatively to promote p53 transcriptional activity on the cell cycle controlling gene GADD45 XREF_BIBR .	For example, it has been reported that PRMT1, CARM1 and PRMT4 and p300 function cooperatively to promote p53 transcriptional activity on the cell cycle controlling gene GADD45 XREF_BIBR.	14	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	14	15	19	20
Because p300 is well-known to activate p53 through acetylation XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , and increased p53-p300 interaction is associated with enhanced acetylation XREF_BIBR , the effect of the C462A mutation on p300-p53 binding provides an explanation for the excess p53 activity observed in Mdm2 m/m MEFs compared to Mdm2-null MEFs .	Because p300 is well-known to activate p53 through acetylation XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, and increased p53-p300 interaction is associated with enhanced acetylation XREF_BIBR, the effect of the C462A mutation on p300-p53 binding provides an explanation for the excess p53 activity observed in Mdm2 m/m MEFs compared to Mdm2-null MEFs.	1	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	1	2	6	7
These results suggest that induction of p21 Waf1 and CIP1 in early differentiation is regulated by p300 dependent activation of p53 .	These results suggest that induction of p21 Waf1 and CIP1 in early differentiation is regulated by p300 dependent activation of p53.	16	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	16	17	20	21
Indeed , the fact that p300 functions to destabilize wild-type p53 in certain conditions is supported by multiple lines of evidence , including demonstration that p300 enhances MDM2 mediated destruction of p53 XREF_BIBR , XREF_BIBR .	Indeed, the fact that p300 functions to destabilize wild-type p53 in certain conditions is supported by multiple lines of evidence, including demonstration that p300 enhances MDM2 mediated destruction of p53 XREF_BIBR, XREF_BIBR.	25	32	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	25	26	31	32
Studies indicate that depletion of p300 down-regulates the acetylation and expression of p53 , and chromatin immunoprecipitation ( ChIP ) analysis shows that induction of p21 Waf1 and CIP1 in early differentiation is a result of p300 dependent activation of p53 and that depletion of p21 Waf1 and CIP1 results in the delay of differentiation and a phenotype similar to p300 depletion .	Studies indicate that depletion of p300 down-regulates the acetylation and expression of p53, and chromatin immunoprecipitation (ChIP) analysis shows that induction of p21 Waf1 and CIP1 in early differentiation is a result of p300 dependent activation of p53 and that depletion of p21 Waf1 and CIP1 results in the delay of differentiation and a phenotype similar to p300 depletion.	36	41	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	36	37	40	41
Nevertheless , a role for p53 is not completely eliminated ; it is possible that loss of p300 impairs p53 function only partially and , despite giving the cell a selective advantage , there would still be selective pressure to lose p53 function completely .	Nevertheless, a role for p53 is not completely eliminated; it is possible that loss of p300 impairs p53 function only partially and, despite giving the cell a selective advantage, there would still be selective pressure to lose p53 function completely.	15	20	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	loss of p300	p300	p53	p53	p53	17	18	19	20
CBP and p300 are essential coactivators of p53 mediated transcriptional processes and are required for functioning of the p53 mediated checkpoint in the G1 phase of the cell cycle [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	CBP and p300 are essential coactivators of p53 mediated transcriptional processes and are required for functioning of the p53 mediated checkpoint in the G1 phase of the cell cycle [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	13	are essential coactivators	Positive_activation_copula_1	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	2	3	7	8
MDM2 is a negative regulator of TP53 whereas EP300 stimulates TP53 ' s transcriptional activity .	MDM2 is a negative regulator of TP53 whereas EP300 stimulates TP53 's transcriptional activity.	8	11	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EP300	EP300	EP300	TP53	TP53	TP53	8	9	10	11
In contrast , a p300 fragment , which binds to p53 but not to HIF-1 , prevents p53 dependent repression of HIF activity .	In contrast, a p300 fragment, which binds to p53 but not to HIF-1, prevents p53 dependent repression of HIF activity.	4	19	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300 fragment, which binds to p53	p300	p53	p53	p53	4	5	17	18
p300 and CBP modulate the p53 pathway at multiple levels .	p300 and CBP modulate the p53 pathway at multiple levels.	0	6	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	0	1	5	6
PQ exposure increases expression of the p300 and CREB binding protein ( p300 and CBP ) and phosphorylation of p53 at Ser 15 , which stimulates p53 dependent transactivation through increased binding with p300 .	PQ exposure increases expression of the p300 and CREB binding protein (p300 and CBP) and phosphorylation of p53 at Ser 15, which stimulates p53 dependent transactivation through increased binding with p300.	0	28	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	PQ exposure increases expression of the p300	p300	p53	p53	p53	6	7	26	27
Conversely , ectopic expression of p300 rescues the transactivation function of p53 in cells overexpressing Skp2 .	Conversely, ectopic expression of p300 rescues the transactivation function of p53 in cells overexpressing Skp2.	3	13	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	expression of p300	p300	p53	p53	p53	5	6	11	12
Since there are previous reports of competition of p53 and Notch for p300 and MAML1 functions at least in part by recruiting p300 to the Notch transcriptional complex ( NTC ) , we also determined whether p300 may relieve p53 mediated inhibition of Notch-1 transcriptional activity .	Since there are previous reports of competition of p53 and Notch for p300 and MAML1 functions at least in part by recruiting p300 to the Notch transcriptional complex (NTC), we also determined whether p300 may relieve p53 mediated inhibition of Notch-1 transcriptional activity.	36	41	relieve	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	36	37	39	40
A plausible explanation for the delay in acetylation is the slow accumulation and nuclear transport of co-factors like Strap that are necessary for p300 and CBP mediated modification of p53 .	A plausible explanation for the delay in acetylation is the slow accumulation and nuclear transport of co-factors like Strap that are necessary for p300 and CBP mediated modification of p53.	23	30	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	23	24	29	30
In fact , p300 knockdown by hammerhead ribozymes inhibits apoptosis , probably by disrupting the p53 mediated response to DNA damage .	In fact, p300 knockdown by hammerhead ribozymes inhibits apoptosis, probably by disrupting the p53 mediated response to DNA damage.	3	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300	p300	p53	p53	p53	3	4	15	16
An example is the interaction between p300 and Sirt2 , for which a model has been proposed stating that p300 indirectly increases the transcriptional activity of p53 through acetylation and subsequent attenuation of the deacetylase function of Sirt2 .	An example is the interaction between p300 and Sirt2, for which a model has been proposed stating that p300 indirectly increases the transcriptional activity of p53 through acetylation and subsequent attenuation of the deacetylase function of Sirt2.	19	27	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	19	20	26	27
The aim of the present study is ( i ) to understand some of the basic issues of p53 autoregulation induced by regulators p300 and HDAC1 , ( ii ) to elucidate the functional relationship of p300 and HDAC1 in regulating p53 function , ( iii ) how do these regulators lifts the normal p53-Mdm2 network to different stress states and ( iv ) what could be the role of noise in such situations .	The aim of the present study is (i) to understand some of the basic issues of p53 autoregulation induced by regulators p300 and HDAC1, (ii) to elucidate the functional relationship of p300 and HDAC1 in regulating p53 function, (iii) how do these regulators lifts the normal p53-Mdm2 network to different stress states and (iv) what could be the role of noise in such situations.	18	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	23	24	18	19
Importantly , an in-frame deletion of CR2 within the full-length p300 protein strongly compromises p300 mediated p53 transcriptional activation from a chromatin template in vitro .	Importantly, an in-frame deletion of CR2 within the full-length p300 protein strongly compromises p300 mediated p53 transcriptional activation from a chromatin template in vitro.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	14	15	16	17
Together , the overall balance of p300- and SIRT1-activities modulate p53 transcriptional function .	Together, the overall balance of p300- and SIRT1-activities modulate p53 transcriptional function.	4	12	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300-	p300-	p300-	p53	p53	p53	6	7	10	11
In addition , expression of exogenous p300 in H1299 cells allows full recovery of p53 transactivation in the presence of Tax .	In addition, expression of exogenous p300 in H1299 cells allows full recovery of p53 transactivation in the presence of Tax.	3	15	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	expression of exogenous p300	p300	p53	p53	p53	6	7	14	15
[ XREF_BIBR ] It seems that P300 is able to acetylated and activate P53 and induce apoptosis in response to DNA damage in some cancer cells .	[XREF_BIBR] It seems that P300 is able to acetylated and activate P53 and induce apoptosis in response to DNA damage in some cancer cells.	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P300	P300	P300	P53	P53	P53	6	7	13	14
According to their results , p300 acted as a positive regulator to increase p53 stability in the presence of lower level of MDM2 , whereas p300 became a negative regulator for p53 to induce MDM2 dependent degradation in the presence of higher level of MDM2 .	According to their results, p300 acted as a positive regulator to increase p53 stability in the presence of lower level of MDM2, whereas p300 became a negative regulator for p53 to induce MDM2 dependent degradation in the presence of higher level of MDM2.	5	14	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	5	6	13	14
The transcriptional coactivator p300 binds to and mediates the transcriptional functions of the tetrameric tumor suppressor p53 .	The transcriptional coactivator p300 binds to and mediates the transcriptional functions of the tetrameric tumor suppressor p53.	0	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	3	4	14	17
Overexpression of p300 relieves p53 mediated repression of the Rad51core promoter .	Overexpression of p300 relieves p53 mediated repression of the Rad51core promoter.	0	6	relieves	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	Overexpression of p300	p300	p53	p53	p53	2	3	4	5
These results suggest that the effects of shCITED2 are independent of direct CBP and p300 mediated p53 activation .	These results suggest that the effects of shCITED2 are independent of direct CBP and p300 mediated p53 activation.	9	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	14	15	16	17
Interestingly , p85alpha is also required for the autoacetylation of p53 associated p300 ( XREF_FIG ) , which events may be helpful to upregulate HATs activity of p300 and then increase p53 transcriptional activity by promoting histone acetylation in the vicinity of p53-RE , and therefore altering the chromatin structure for the access of p53 .	Interestingly, p85alpha is also required for the autoacetylation of p53 associated p300 (XREF_FIG), which events may be helpful to upregulate HATs activity of p300 and then increase p53 transcriptional activity by promoting histone acetylation in the vicinity of p53-RE, and therefore altering the chromatin structure for the access of p53.	8	32	increase	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p300	autoacetylation of p53 associated p300	p300	p53	p53	p53	12	13	31	32
Therefore , loss of CREB and p300 could disrupt p53 activation , stability , and transactivation of target genes and alter the cell fate in response to p53 activation .	Therefore, loss of CREB and p300 could disrupt p53 activation, stability, and transactivation of target genes and alter the cell fate in response to p53 activation.	2	10	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	loss of CREB and p300	p300	p53	p53	p53	6	7	9	10
Transfection of full-length p300 stimulates both p53 dependent and HIF dependent transcription but does not relieve p53 mediated inhibition of HIF .	Transfection of full-length p300 stimulates both p53 dependent and HIF dependent transcription but does not relieve p53 mediated inhibition of HIF.	0	18	relieve	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300 stimulates both p53 dependent and HIF dependent transcription	p300	p53	p53	p53	3	4	16	17
Mechanistically , we showed that conversion of a minimal four of these lysines to alanines but not arginines mimics p300 mediated p53 nuclear export , and these lysine neutralizing mutations effectively prevent p53 tetramerization , thus exposing the oligomerization regulated nuclear export signal .	Mechanistically, we showed that conversion of a minimal four of these lysines to alanines but not arginines mimics p300 mediated p53 nuclear export, and these lysine neutralizing mutations effectively prevent p53 tetramerization, thus exposing the oligomerization regulated nuclear export signal.	5	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	19	20	21	22
Consistently , it has been reported that downregulation of p300 histone acetyltransferase activity induces senescence independent of the p53 and p16 INK4a pathway XREF_BIBR .	Consistently, it has been reported that downregulation of p300 histone acetyltransferase activity induces senescence independent of the p53 and p16 INK4a pathway XREF_BIBR.	9	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	9	10	18	19
For example , CARM1 and p300 synergistically enhance the activity of NR , beta-catenin , p53 , NFkB and other transcription factors .	For example, CARM1 and p300 synergistically enhance the activity of NR, beta-catenin, p53, NFkB and other transcription factors.	3	21	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	5	6	15	16
It has been suggested that the ability of CBP and p300 to modulate p53 function underlies p53 ' s regulation of cell proliferation and tumorigenesis .	It has been suggested that the ability of CBP and p300 to modulate p53 function underlies p53 's regulation of cell proliferation and tumorigenesis.	6	14	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	10	11	13	14
For example , acetylation of Lys320 by CBP and p300 promotes the interaction of p53 with high-affinity binding sites regulating genes that support cell cycle arrest and survival .	For example, acetylation of Lys320 by CBP and p300 promotes the interaction of p53 with high-affinity binding sites regulating genes that support cell cycle arrest and survival.	3	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	acetylation of Lys320 by CBP and p300	p300	p53	p53	p53	9	10	14	15
It has been also reported that p300 acetylates and activates p53 in response to DNA damage XREF_BIBR , XREF_BIBR .	It has been also reported that p300 acetylates and activates p53 in response to DNA damage XREF_BIBR, XREF_BIBR.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	6	7	10	11
Moreover , p300 and CBP functions as the bridge molecule to increase the binding of p53 to the DNA responsive elements , which subsequently enhances the transcriptional activity of p53 .	Moreover, p300 and CBP functions as the bridge molecule to increase the binding of p53 to the DNA responsive elements, which subsequently enhances the transcriptional activity of p53.	2	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	2	3	15	16
In particular , as acetylation of p53 C-terminal lysines at position 373 and 382 by p300 stimulates these activities [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , we tested whether ectopic p300 was able to restore p53 apoptotic transcriptional activity in siHIPK2 cells .	In particular, as acetylation of p53 C-terminal lysines at position 373 and 382 by p300 stimulates these activities [XREF_BIBR, XREF_BIBR, XREF_BIBR], we tested whether ectopic p300 was able to restore p53 apoptotic transcriptional activity in siHIPK2 cells.	30	39	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	31	32	36	37
In addition to directly modifying p53 , p300 contributes to p53 mediated transcriptional activation via its coactivator function and through histone acetylation at promoters bound by p53 .	In addition to directly modifying p53, p300 contributes to p53 mediated transcriptional activation via its coactivator function and through histone acetylation at promoters bound by p53.	7	11	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	7	8	10	11
Of note , p300 overexpression reactivated p53 apoptotic transcription in response to ADR , while it did not induce p21 and BTG2 gene expression .	Of note, p300 overexpression reactivated p53 apoptotic transcription in response to ADR, while it did not induce p21 and BTG2 gene expression.	3	8	reactivated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300 overexpression	p300	p53	p53	p53	3	4	6	7
These observations suggest a mechanism whereby HDM2 and CBP and p300 function synergistically to regulate the p53 response .	These observations suggest a mechanism whereby HDM2 and CBP and p300 function synergistically to regulate the p53 response.	10	17	synergistically	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	10	11	16	17
p300 promotes apoptosis and positively regulates p53 in response to DNA damage .	p300 promotes apoptosis and positively regulates p53 in response to DNA damage.	0	7	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	0	1	6	7
During cellular stress , GAPDH associates with the E3 ligase Siah1 and shuttles to the nucleus , where it enhances p300 autoacetylation , which in turn activates the p53 mediated apoptotic pathway .	During cellular stress, GAPDH associates with the E3 ligase Siah1 and shuttles to the nucleus, where it enhances p300 autoacetylation, which in turn activates the p53 mediated apoptotic pathway.	20	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300 autoacetylation	p300	p53	p53	p53	20	21	28	29
Cytoplasmic compartmentalization of p300 and CBP ' s ubiquitination function reconciles seemingly opposed functions and explains how a futile cycle is avoided cytoplasmic p300 and CBP E4 activities ubiquitinate and destabilize p53 , while physically separate nuclear p300 and CBP activities , such as p53 acetylation , activate p53 .	Cytoplasmic compartmentalization of p300 and CBP 's ubiquitination function reconciles seemingly opposed functions and explains how a futile cycle is avoided cytoplasmic p300 and CBP E4 activities ubiquitinate and destabilize p53, while physically separate nuclear p300 and CBP activities, such as p53 acetylation, activate p53.	34	49	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	37	38	48	49
Dasatinib inhibits EphA2 tyrosine phosphorylation in human melanoma cells and blocks EphA2 kinase activity in vitro .	Dasatinib inhibits EphA2 tyrosine phosphorylation in human melanoma cells and blocks EphA2 kinase activity in vitro.	0	13	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EphA2	Dasatinib inhibits EphA2 tyrosine phosphorylation	epha2	EphA2	EphA2	epha2	2	3	11	12
EphA2 overexpression , functional alterations and gain of oncogenic function provide an opportunity to target EphA2 for therapeutic intervention .	EphA2 overexpression, functional alterations and gain of oncogenic function provide an opportunity to target EphA2 for therapeutic intervention.	0	16	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphA2	EphA2 overexpression	epha2	EphA2	EphA2	epha2	0	1	15	16
However , the same study showed that P36 interferes with Ephrin A1 mediated EphA2 phosphorylation , raising the possibility that P36 may affect EphA2 signalling indirectly , for example via SR-BI and the SRC pathway .	However, the same study showed that P36 interferes with Ephrin A1 mediated EphA2 phosphorylation, raising the possibility that P36 may affect EphA2 signalling indirectly, for example via SR-BI and the SRC pathway.	10	24	raising	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphA2	Ephrin A1 mediated EphA2 phosphorylation	epha2	EphA2	EphA2	epha2	13	14	23	24
Importantly , expression of EphA2-GFP or GFP-RCP restored the scattered morphology of EPHA2 -/- and RCP -/- PDAC cells respectively , whereas EphA2-GFP 897A and GFP-RCP 435A were ineffective in this regard ( XREF_FIG ) .	Importantly, expression of EphA2-GFP or GFP-RCP restored the scattered morphology of EPHA2 -/- and RCP -/- PDAC cells respectively, whereas EphA2-GFP 897A and GFP-RCP 435A were ineffective in this regard (XREF_FIG).	2	13	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphA2-GFP	expression of EphA2-GFP	epha2-gfp	EPHA2	EPHA2	epha2	4	5	12	13
Carles-Kinch and colleagues exploited the mechanism by which EphA2 overexpression potentiates malignant transformation by developing an agonistic EphA2 antibody that mimics the actions of the ligand ephrin-A1 .	Carles-Kinch and colleagues exploited the mechanism by which EphA2 overexpression potentiates malignant transformation by developing an agonistic EphA2 antibody that mimics the actions of the ligand ephrin-A1.	8	18	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphA2	EphA2 overexpression	epha2	EphA2	EphA2	epha2	8	9	17	18
Protein kinase A can block EphA2 receptor mediated cell repulsion by increasing EphA2 S897 phosphorylation .	Protein kinase A can block EphA2 receptor mediated cell repulsion by increasing EphA2 S897 phosphorylation.	5	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EphA2	EphA2 S897 phosphorylation	epha2	EphA2	EphA2	epha2	12	13	5	6
In contrast to its role in non transformed cells , dysregulation in EphA2 expression and function causes EphA2 to support tumor progression and metastasis .	In contrast to its role in non transformed cells, dysregulation in EphA2 expression and function causes EphA2 to support tumor progression and metastasis.	12	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphA2	EphA2 expression	epha2	EphA2	EphA2	epha2	12	13	17	18
Collectively , our data support a model in which increased ROS levels enhance EphA2 phosphorylation by inactivating PTP1B and thereby promote the sorting of EphA2 into sEVs in DXR induced senescent cells .	Collectively, our data support a model in which increased ROS levels enhance EphA2 phosphorylation by inactivating PTP1B and thereby promote the sorting of EphA2 into sEVs in DXR induced senescent cells.	10	26	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphA2	ROS levels enhance EphA2 phosphorylation	epha2	EphA2	EphA2	epha2	13	14	24	25
For instance , in U937 cells , it seems that PKR dependent activation of p53 is necessary for TNFalpha induced apoptosis [ XREF_BIBR ] .	For instance, in U937 cells, it seems that PKR dependent activation of p53 is necessary for TNFalpha induced apoptosis [XREF_BIBR].	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PKR	PKR	PKR	p53	p53	p53	10	11	14	15
In addition , PKR activates p53 via interaction with the C-terminal which may initiate apoptotic signaling cascades .	In addition, PKR activates p53 via interaction with the C-terminal which may initiate apoptotic signaling cascades.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PKR	PKR	p53	p53	p53	3	4	5	6
Since both PKR and Hck inhibition suppress DON induced p53 activation , caspase-3 activity and apoptosis , these kinases are also likely to be upstream transducers in MAPK regulated apoptosis [ XREF_BIBR , XREF_BIBR ] .	Since both PKR and Hck inhibition suppress DON induced p53 activation, caspase-3 activity and apoptosis, these kinases are also likely to be upstream transducers in MAPK regulated apoptosis [XREF_BIBR, XREF_BIBR].	2	10	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PKR	PKR	p53	p53	p53	2	3	9	10
Since a cross talk between IFN inducible proteins and p53 had already been established , we investigated whether and how p53 function was modulated by PKR .	Since a cross talk between IFN inducible proteins and p53 had already been established, we investigated whether and how p53 function was modulated by PKR.	20	26	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKR	PKR	PKR	p53	p53	p53	25	26	20	21
These findings also further elucidate chronic EtOH responsive PKR signaling pathways , one of which subsequently activates p53 .	These findings also further elucidate chronic EtOH responsive PKR signaling pathways, one of which subsequently activates p53.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PKR	PKR	p53	p53	p53	8	9	17	18
PKR also mediates the activation of several transcription factors ( STAT1 , p53 , and NFkappaB ) regulating both pro- and antiapoptotic mechanisms .	PKR also mediates the activation of several transcription factors (STAT1, p53, and NFkappaB) regulating both pro- and antiapoptotic mechanisms.	0	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PKR	PKR	p53	p53	p53	0	1	12	13
These novel findings suggest that PKR enhances p53 transcriptional function and implicate PKR in cell signaling elicited by a specific type of DNA damage that leads to p53 phosphorylation , possibly through a PI-3 kinase pathway .	These novel findings suggest that PKR enhances p53 transcriptional function and implicate PKR in cell signaling elicited by a specific type of DNA damage that leads to p53 phosphorylation, possibly through a PI-3 kinase pathway.	5	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PKR	PKR	p53	p53	p53	5	6	7	8
Therefore , p53 up-regulation , mediated by EtOH induced PKR signaling , may serve as a key contributor to ROS production associated with EtOH exposure and may likely elicit many other ROS related secondary effects , which could collectively result in cell death .	Therefore, p53 up-regulation, mediated by EtOH induced PKR signaling, may serve as a key contributor to ROS production associated with EtOH exposure and may likely elicit many other ROS related secondary effects, which could collectively result in cell death.	2	10	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKR	EtOH induced PKR	pkr	p53	p53	p53	9	10	2	3
However the molecular mechanisms underlying PKR dependent upregulation of P53 remain unknown .	However the molecular mechanisms underlying PKR dependent upregulation of P53 remain unknown.	5	10	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PKR	PKR	PKR	P53	P53	P53	5	6	9	10
Strikingly , the ablation of PKR expression fully restored etoposide induced accumulation of p53 ( XREF_FIG ) in addition to restoring global protein synthesis ( XREF_FIG and XREF_FIG ) .	Strikingly, the ablation of PKR expression fully restored etoposide induced accumulation of p53 (XREF_FIG) in addition to restoring global protein synthesis (XREF_FIG and XREF_FIG).	5	27	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PKR expression	pkr	p53	p53	p53	5	6	13	14
As PKR activates p53 and counteracts TCTP , it adds another layer of antagonistic control between TCTP and p53 .	As PKR activates p53 and counteracts TCTP, it adds another layer of antagonistic control between TCTP and p53.	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PKR	PKR	p53	p53	p53	1	2	3	4
Clustered regularly interspaced short palindromic repeat ( CRISPR )/Cas9-mediated ablation of double stranded RNA ( dsRNA )-activated protein kinase R ( PKR ) restored p53 responses while boosting HCV replication , showing that p53 inhibition results directly from viral activation of PKR .	Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated ablation of double stranded RNA (dsRNA)-activated protein kinase R (PKR) restored p53 responses while boosting HCV replication, showing that p53 inhibition results directly from viral activation of PKR.	19	25	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PKR	PKR	p53	p53	p53	21	22	24	25
AKT mediated phosphorylation of p300 dramatically increases its acetyltransferase activity and can increase acetylation and full transcriptional activation of p65 [ XREF_BIBR , XREF_BIBR ] .	AKT mediated phosphorylation of p300 dramatically increases its acetyltransferase activity and can increase acetylation and full transcriptional activation of p65 [XREF_BIBR, XREF_BIBR].	0	23	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	AKT mediated phosphorylation of p300	p300	p65	p65	p65	4	5	19	20
It is known that p300 dependent RelA acetylation increases RelA nuclear retention and transcriptional activity .	It is known that p300 dependent RelA acetylation increases RelA nuclear retention and transcriptional activity.	4	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	RelA	RelA	RelA	4	5	9	10
Overexpression of p160 and cAMP response element binding protein binding protein and p300 co-activators failed to relieve repression of RelA , which is consistent with the demonstration that RelA inhibition can occur independently of these co-activators .	Overexpression of p160 and cAMP response element binding protein binding protein and p300 co-activators failed to relieve repression of RelA, which is consistent with the demonstration that RelA inhibition can occur independently of these co-activators.	0	23	relieve	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	Overexpression of p160 and cAMP response element binding protein binding protein and p300	p300	RelA	RelA	rela	12	13	19	20
Our data indicate that histone acetylation at the Myod1 enhancer by p300 is required for MyoD gene expression and myogenic differentiation .	Our data indicate that histone acetylation at the Myod1 enhancer by p300 is required for MyoD gene expression and myogenic differentiation.	8	12	enhancer	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	p300	p300	p300	Myod1	Myod1	Myod1	11	12	8	9
NFATc1 inhibits MyoD function by physically interacting with and blocking the essential interaction of the MyoD N-terminal activation domain with p300 and subsequent activation of MyoD target genes .	NFATc1 inhibits MyoD function by physically interacting with and blocking the essential interaction of the MyoD N-terminal activation domain with p300 and subsequent activation of MyoD target genes.	20	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p300	p300	p300	MyoD	MyoD	MyoD	20	21	25	26
Moreover , p300 potentiates MyoD- and myogenin dependent activation of transcription from E-box-containing reporter genes .	Moreover, p300 potentiates MyoD- and myogenin dependent activation of transcription from E-box-containing reporter genes.	2	8	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	MyoD-	MyoD-	MyoD-	2	3	4	5
Acetylation of histone 3 lysine 27 ( H3K27 ) , a mark often associated with open chromatin , has also been achieved using a fusion of dCas9 with human acetyltransferase p300 targeting the promoters of the following genes : MYOD ( Myogenic Differentiation 1 ) , IL1R ( Interleukin 1 Receptor Type 1 ) , OCT4 ( Octamer Binding Protein 4 ) , which provoked transcriptional activation of the downstream genes .	Acetylation of histone 3 lysine 27 (H3K27), a mark often associated with open chromatin, has also been achieved using a fusion of dCas9 with human acetyltransferase p300 targeting the promoters of the following genes : MYOD (Myogenic Differentiation 1), IL1R (Interleukin 1 Receptor Type 1), OCT4 (Octamer Binding Protein 4), which provoked transcriptional activation of the downstream genes.	22	64	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	MYOD	MYOD	MYOD	30	31	39	40
IGF-1-elicited Akt activation leads to phosphorylation of p300 , causing an association of MyoD with p300 and PCAF acetyltransferases 45 .	IGF-1-elicited Akt activation leads to phosphorylation of p300, causing an association of MyoD with p300 and PCAF acetyltransferases 45.	1	14	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	Akt activation leads to phosphorylation of p300	p300	MyoD	MyoD	myod	7	8	13	14
Consistent with its role as a coactivator , p300 potentiates MyoD activated transcription .	Consistent with its role as a coactivator, p300 potentiates MyoD activated transcription.	6	11	potentiates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p300	p300	p300	MyoD	MyoD	MyoD	8	9	10	11
RT-PCR analysis showed that the p300 core upregulated the IL1RN gene 9,920 fold , the MYOD gene 50 fold , and the OCT4 gene 32 fold .	RT-PCR analysis showed that the p300 core upregulated the IL1RN gene 9,920 fold, the MYOD gene 50 fold, and the OCT4 gene 32 fold.	5	16	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	MYOD	MYOD	MYOD	5	6	15	16
Along with EGF , amphiregulin , transforming growth factor ( TGF ) alpha , epiregulin , betacellulin , heparin binding EGF , and epigen activate EGFR XREF_BIBR .	Along with EGF, amphiregulin, transforming growth factor (TGF) alpha, epiregulin, betacellulin, heparin binding EGF, and epigen activate EGFR XREF_BIBR.	14	26	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	epigen	epigen	epigen	EGFR	EGFR	EGFR	23	24	25	26
Gene expression profiling of mammary epithelium revealed that CUZD1 regulates the expression of a subset of the EGF family growth factors , epiregulin , neuregulin-1 , and epigen , which act in an autocrine fashion to activate ErbB1 and ErbB4 receptors .	Gene expression profiling of mammary epithelium revealed that CUZD1 regulates the expression of a subset of the EGF family growth factors, epiregulin, neuregulin-1, and epigen, which act in an autocrine fashion to activate ErbB1 and ErbB4 receptors.	20	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epigen	epigen	epigen	ErbB1	ErbB1	ErbB1	27	28	37	38
The PERK pathway is activated by PERK autophosphorylation , PERK then phosphorylates eukaryotic initiation factor-2alpha ( eIF2alpha ) .	The PERK pathway is activated by PERK autophosphorylation, PERK then phosphorylates eukaryotic initiation factor-2alpha (eIF2alpha).	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PERK	PERK autophosphorylation	perk	PERK	PERK	perk	6	7	1	2
In agreement with PERK mediated modulation of proinsulin levels , we demonstrated that overexpression of PERK at low levels ( transfection of 0.5-2.0 mug ) in MIN6 cells slightly enhanced PERK activation and proinsulin content ( Supplemental FigureS4 ) .	In agreement with PERK mediated modulation of proinsulin levels, we demonstrated that overexpression of PERK at low levels (transfection of 0.5-2.0 mug) in MIN6 cells slightly enhanced PERK activation and proinsulin content (Supplemental FigureS4).	13	31	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PERK	overexpression of PERK	perk	PERK	PERK	perk	15	16	30	31
To determine whether PERK phosphorylation at Y 561 modulates ER stress induced PERK activation and signaling , we followed pThr-980 PERK and peIF2alphaS 51 in ER stressed MIN6 cells pretreated or not with PV ( XREF_FIG ) .	To determine whether PERK phosphorylation at Y 561 modulates ER stress induced PERK activation and signaling, we followed pThr-980 PERK and peIF2alphaS 51 in ER stressed MIN6 cells pretreated or not with PV (XREF_FIG).	3	13	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PERK	PERK phosphorylation	perk	PERK	PERK	perk	3	4	12	13
Interestingly , sustained expression of p-PERK , activated form of PERK , was observed in 10-1RXG8 and 10-1RXG23 and is consistent with the reduced VCDs observed in these cultures .	Interestingly, sustained expression of p-PERK, activated form of PERK, was observed in 10-1RXG8 and 10-1RXG23 and is consistent with the reduced VCDs observed in these cultures.	3	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-PERK	expression of p-PERK	p-perk	PERK	PERK	perk	5	6	10	11
Phosphorylation of PERK at Y 561 modulates PERK activity .	Phosphorylation of PERK at Y 561 modulates PERK activity.	0	8	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PERK	Phosphorylation of PERK	perk	PERK	PERK	perk	2	3	7	8
Interaction of Nck1 and PERK phosphorylated at Y 561 negatively modulates PERK activity and PERK regulation of pancreatic beta-cell proinsulin content .	Interaction of Nck1 and PERK phosphorylated at Y 561 negatively modulates PERK activity and PERK regulation of pancreatic beta-cell proinsulin content.	0	12	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PERK	PERK phosphorylated	perk	PERK	PERK	perk	4	5	11	12
The stronger EphB2 expression levels could stimulate EphB2 kinase activity , potentially desensitizing these EphB2 + axons to ephrin-B2 .	The stronger EphB2 expression levels could stimulate EphB2 kinase activity, potentially desensitizing these EphB2 + axons to ephrin-B2.	2	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphB2	EphB2 expression levels	ephb2	EphB2	EphB2	ephb2	2	3	7	8
In a parallel experiment , we confirmed that similarly high expression levels of Wt EphA3 notably enhanced ephrin-B1- as well as IIIA4 stimulated EphB2 activation , whereas , by comparison , COS7 cells expressing mutant EphA3 [ K653M ] revealed strongly reduced EphB2 phosphorylation ( XREF_FIG ) .	In a parallel experiment, we confirmed that similarly high expression levels of Wt EphA3 notably enhanced ephrin-B1- as well as IIIA4 stimulated EphB2 activation, whereas, by comparison, COS7 cells expressing mutant EphA3 [K653M] revealed strongly reduced EphB2 phosphorylation (XREF_FIG).	22	44	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphB2	EphB2 phosphorylation	ephb2	EphB2	EphB2	ephb2	42	43	23	24
And there was an overexpression of ERK-p for G+ E as compared to gemcitabine ( p = 0.016 ) .	And there was an overexpression of ERK-p for G+ E as compared to gemcitabine (p = 0.016).	2	9	was an overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	ERK-p	overexpression of ERK-p	erk-p	ERK-p	ERK-p	erk-p	6	7	6	7
Kal7 or EphB2 expression was reduced with shRNA sequences targeting mouse Kal7 or EphB2 under the U6 promoter .	Kal7 or EphB2 expression was reduced with shRNA sequences targeting mouse Kal7 or EphB2 under the U6 promoter.	0	14	targeting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EphB2	EphB2 expression	ephb2	EphB2	EphB2	ephb2	2	3	13	14
Our data show that absence of PS1 affects both , the levels of EphB2 and TrkB at neuronal cell surface and the ligand induced metabolism of surface EphB2 and TrkB .	Our data show that absence of PS1 affects both, the levels of EphB2 and TrkB at neuronal cell surface and the ligand induced metabolism of surface EphB2 and TrkB.	11	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphB2	levels of EphB2	ephb2	EphB2	EphB2	ephb2	13	14	27	28
EphrinB2 not only increased the phosphorylation of EphB2 and EphB4 in a time dependent manner but also increased recruitment of p120-Ras-GTPase-activating protein ( p120-RasGAP ) to EphB2 and EphB4 .	EphrinB2 not only increased the phosphorylation of EphB2 and EphB4 in a time dependent manner but also increased recruitment of p120-Ras-GTPase-activating protein (p120-RasGAP) to EphB2 and EphB4.	0	28	increased	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EphB2	EphrinB2 not only increased the phosphorylation of EphB2	ephb2	EphB2	EphB2	ephb2	7	8	26	27
Silencing of p300 with a specific siRNA partially reduced Smad7 content , suggesting the existence of further mechanisms and factors involved in the control of Smad7 protein stability .	Silencing of p300 with a specific siRNA partially reduced Smad7 content, suggesting the existence of further mechanisms and factors involved in the control of Smad7 protein stability.	0	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	Smad7	Smad7	Smad7	2	3	9	10
To test the role of p300 I1395G mutant in transcriptional regulation in a more physiologically relevant context , we first established conditions that simultaneous knockdown of CBP and p300 by siRNAs significantly impaired TGF-beta1-induced transcriptional activation of TGF-beta1 target genes PAI1 and SMAD7 [ XREF_BIBR ] ( XREF_FIG ) .	To test the role of p300 I1395G mutant in transcriptional regulation in a more physiologically relevant context, we first established conditions that simultaneous knockdown of CBP and p300 by siRNAs significantly impaired TGF-beta1-induced transcriptional activation of TGF-beta1 target genes PAI1 and SMAD7 [XREF_BIBR] (XREF_FIG).	24	44	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	SMAD7	SMAD7	SMAD7	28	29	42	43
In the present study , we aimed to ascertain whether EphA3 is induced by PC-1 and the functional significance of EphA3 expression in PCa .	In the present study, we aimed to ascertain whether EphA3 is induced by PC-1 and the functional significance of EphA3 expression in PCa.	10	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EphA3	EphA3 expression	epha3	EphA3	EphA3	epha3	20	21	10	11
Activated Src and FAK engage Etk , a tyrosine kinase shown to be involved in prostate carcinogenesis .	Activated Src and FAK engage Etk, a tyrosine kinase shown to be involved in prostate carcinogenesis.	0	9	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Etk	Etk	Etk	Src	Src	Src	5	6	1	2
That said , Etk is able to activate FAK and Src , and as such , the entire complex is involved in CRPC development .	That said, Etk is able to activate FAK and Src, and as such, the entire complex is involved in CRPC development.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Etk	Etk	Etk	Src	Src	Src	3	4	10	11
In contrast , forward EphB2 signalling promoted MSC migration by activating the Src kinase- and Abl dependent signalling pathways .	In contrast, forward EphB2 signalling promoted MSC migration by activating the Src kinase- and Abl dependent signalling pathways.	4	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EphB2	EphB2	EphB2	Src	Src	Src	4	5	12	13
Epigen is unable to activate HER3 and HER4 in the absence of ErbB2 expression .	Epigen is unable to activate HER3 and HER4 in the absence of ErbB2 expression.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epigen	Epigen	Epigen	HER4	HER4	HER4	0	1	7	8
We also show that Lys4 acetylation plays a prominent role in the p300 dependent activation of MEF2C .	We also show that Lys4 acetylation plays a prominent role in the p300 dependent activation of MEF2C.	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p300	p300	p300	MEF2C	MEF2C	MEF2C	12	13	16	17
These results suggest that eIF3f is specifically involved in an ubiquitination and deubiquitination process targeting activated Notch .	These results suggest that eIF3f is specifically involved in an ubiquitination and deubiquitination process targeting activated Notch.	4	17	targeting activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	eIF3f	eIF3f	eIF3f	Notch	Notch	Notch	4	5	16	17
The translation initiation factor 3f ( EIF3F ) is recruited to activate Notch on endocytic vesicles by the Deltex1 serving as a bridging factor .	The translation initiation factor 3f (EIF3F) is recruited to activate Notch on endocytic vesicles by the Deltex1 serving as a bridging factor.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EIF3F	EIF3F	EIF3F	Notch	Notch	Notch	6	7	12	13
MEF-2D , but not other MEFs , significantly potentiated cardiac specific transcription by p300 .	MEF-2D, but not other MEFs, significantly potentiated cardiac specific transcription by p300.	0	14	potentiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p300	p300	p300	MEF-2D	MEF-2D	MEF-2D	13	14	0	1
The Ras dependent cofactors include Elk-1 and SAP , which are activated by ERK .	The Ras dependent cofactors include Elk-1 and SAP, which are activated by ERK.	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	13	14	5	6
The inhibition of IL-1beta-induced activation of ERK1/2 by PD-98059 ( 100 muM ) inhibited the activation of Elk-1 ( XREF_FIG ) .	The inhibition of IL-1beta-induced activation of ERK1/2 by PD-98059 (100 muM) inhibited the activation of Elk-1 (XREF_FIG).	4	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk-1	Elk-1	Elk-1	6	7	17	18
Both TGF-beta1 and p38 and p42/44 MAPK signal pathways target nuclear receptors ATF-2 and Elk-1 .	Both TGF-beta1 and p38 and p42/44 MAPK signal pathways target nuclear receptors ATF-2 and Elk-1.	6	15	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Elk-1	Elk-1	Elk-1	6	7	14	15
Although a lot is known about ERK mediated ELK1 activation , comparatively less is known about the inactivation mechanisms which extinguish ELK1 activity and hence immediate-early gene induction .	Although a lot is known about ERK mediated ELK1 activation, comparatively less is known about the inactivation mechanisms which extinguish ELK1 activity and hence immediate-early gene induction.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	ELK1	ELK1	ELK1	6	7	8	9
ERK1/2 , which can activate ELK-1 , is a well characterised common nuclear substrate that belongs to the family of Ets domain containing transcription factors .	ERK1/2, which can activate ELK-1, is a well characterised common nuclear substrate that belongs to the family of Ets domain containing transcription factors.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ELK-1	ELK-1	ELK-1	0	1	5	6
Estrogen induces Egr1 via ERK1/2 dependent activation of ELK-1 in MCF-7 breast cancer cells .	Estrogen induces Egr1 via ERK1/2 dependent activation of ELK-1 in MCF-7 breast cancer cells.	4	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ELK-1	ELK-1	ELK-1	4	5	8	9
To confirm that the dominant negative effect of this ELK1Delta308-321 on androgen dependent growth was not due to dependence on activation of ELK1 by ERK , we demonstrate that LNCaP growth is insensitive to inhibition of MEK by trametinib ( XREF_FIG E ) ; as a control in XREF_FIG E , the AKT inhibitor AKTi-1/2 completely inhibited androgen dependent growth .	To confirm that the dominant negative effect of this ELK1Delta308-321 on androgen dependent growth was not due to dependence on activation of ELK1 by ERK, we demonstrate that LNCaP growth is insensitive to inhibition of MEK by trametinib (XREF_FIG E); as a control in XREF_FIG E, the AKT inhibitor AKTi-1/2 completely inhibited androgen dependent growth.	16	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	ELK1	ELK1	ELK1	24	25	22	23
The decrease of active ERK in the nucleus inhibited the activation of Elk1 , c-fos , and Fra1 , the ERK nuclear targets , leading to decreased proliferation of HCC1806 cells .	The decrease of active ERK in the nucleus inhibited the activation of Elk1, c-fos, and Fra1, the ERK nuclear targets, leading to decreased proliferation of HCC1806 cells.	1	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk1	Elk1	Elk1	4	5	12	13
Our studies also indicated that ERK1/2 activation caused a downstream activation of Elk-1 .	Our studies also indicated that ERK1/2 activation caused a downstream activation of Elk-1.	5	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk-1	Elk-1	Elk-1	5	6	12	13
In this well documented pathway [ XREF_BIBR - XREF_BIBR ] , ERK activated ELK-1 stimulates the expression of c-Fos which binds to pre-existing c-Jun proteins leading to the activation of AP-1 and AP-1 target genes [ XREF_BIBR ] .	In this well documented pathway [XREF_BIBR - XREF_BIBR], ERK activated ELK-1 stimulates the expression of c-Fos which binds to pre-existing c-Jun proteins leading to the activation of AP-1 and AP-1 target genes [XREF_BIBR].	11	19	activated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ERK	ERK	erk	ELK-1	ELK-1 stimulates the expression of c-Fos	elk-1	11	12	13	14
We determined the activation and expression levels of ERK , its cytoplasmic target RSK2 and the nuclear ERK target Elk-1 .	We determined the activation and expression levels of ERK, its cytoplasmic target RSK2 and the nuclear ERK target Elk-1.	6	20	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	17	18	19	20
Furthermore , we demonstrated that gal-1 induces the activation of Elk1 , a transcription factor that is activated by MAPK pathways .	Furthermore, we demonstrated that gal-1 induces the activation of Elk1, a transcription factor that is activated by MAPK pathways.	8	20	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Elk1	Elk1	Elk1	19	20	10	11
The activation of Elk-1 by ERK is directly associated with the transcriptional induction of MMP-13 via Elk-1 binding to the proximal DNA recognition sequence in the MMP-13 promoter .	The activation of Elk-1 by ERK is directly associated with the transcriptional induction of MMP-13 via Elk-1 binding to the proximal DNA recognition sequence in the MMP-13 promoter.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	5	6	3	4
The Pio mediated activation of MAPK is transmitted to activate ELK-1 and the related anti-proliferation is blocked by MEK inhibitor ( PD-184352 ) .	The Pio mediated activation of MAPK is transmitted to activate ELK-1 and the related anti-proliferation is blocked by MEK inhibitor (PD-184352).	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ELK-1	ELK-1	ELK-1	5	6	10	11
EGF induced EGFR and ERK1/2 phosphorylation was followed by rapid MAPK kinase and ERK kinase dependent activation of Elk-1 and c-Fos .	EGF induced EGFR and ERK1/2 phosphorylation was followed by rapid MAPK kinase and ERK kinase dependent activation of Elk-1 and c-Fos.	13	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	13	14	18	19
Here , induction of structural LTP in a few ( 3-7 ) spines led to nuclear ERK activation and subsequent regulation of downstream transcription factors CREB and Elk-1 .	Here, induction of structural LTP in a few (3-7) spines led to nuclear ERK activation and subsequent regulation of downstream transcription factors CREB and Elk-1.	16	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	16	17	27	28
It has also been reported that DUSP5 expression is regulated mainly at the transcriptional level by the transcription factor Elk-1 38 , and that Elk-1 is phosphorylated and thus activated by ERK 39 , suggesting that LPS induces ERK mediated Elk-1 activation and thus DUSP5 activity .	It has also been reported that DUSP5 expression is regulated mainly at the transcriptional level by the transcription factor Elk-1 38, and that Elk-1 is phosphorylated and thus activated by ERK 39, suggesting that LPS induces ERK mediated Elk-1 activation and thus DUSP5 activity.	37	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	38	39	40	41
It was hypothesized the expression was controlled by MEK1 activating ERK1/2 , which in turn activated the transcription factor Elk1 .	It was hypothesized the expression was controlled by MEK1 activating ERK1/2, which in turn activated the transcription factor Elk1.	6	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk1	Elk1	Elk1	10	11	19	20
Pharmacological inhibitor studies as well as reporter assays for ERK dependent activation of the transcription factor Elk1 revealed that the PP2A holoenzymes ABalphaC and ABdeltaC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade .	Pharmacological inhibitor studies as well as reporter assays for ERK dependent activation of the transcription factor Elk1 revealed that the PP2A holoenzymes ABalphaC and ABdeltaC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade.	9	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk1	Elk1	Elk1	9	10	16	17
The ELK1 polypeptide motifs required for co-activation by AR versus those required for activation of ELK1 by ERK were systematically mapped using a mammalian two-hybrid system and confirmed using a co-immunoprecipitation assay .	The ELK1 polypeptide motifs required for co-activation by AR versus those required for activation of ELK1 by ERK were systematically mapped using a mammalian two-hybrid system and confirmed using a co-immunoprecipitation assay.	11	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	ELK1	ELK1	ELK1	17	18	15	16
In this hypothetical model , bFGF through FGFR1 activates ERK , which in turn activates Elk-1 via reciprocal phosphorylation and desumoylation .	In this hypothetical model, bFGF through FGFR1 activates ERK, which in turn activates Elk-1 via reciprocal phosphorylation and desumoylation.	8	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	9	10	15	16
ERK1/2 activates Elk-1 , a transcription cofactor that forms a ternary complex with a dimer of SRF , which recruits and activates the basal transcriptional machinery .	ERK1/2 activates Elk-1, a transcription cofactor that forms a ternary complex with a dimer of SRF, which recruits and activates the basal transcriptional machinery.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk-1	Elk-1	Elk-1	0	1	2	3
Elk-1 is activated by MAPK and ERK via phosphorylation of serine residues 383 and 389 within the transactivation domain XREF_BIBR , XREF_BIBR , leading to an enhanced association between Elk-1 and the histone actyltransferase ( HAT ) , p300 XREF_BIBR .	Elk-1 is activated by MAPK and ERK via phosphorylation of serine residues 383 and 389 within the transactivation domain XREF_BIBR, XREF_BIBR, leading to an enhanced association between Elk-1 and the histone actyltransferase (HAT), p300 XREF_BIBR.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	6	7	0	1
These studies provide an interesting mechanism by which WFA induced ERK and RSK , in a concerted action , results in concomitant upregulation and activation of CHOP and Elk1 ( ETS like transcription factor 1 ) .	These studies provide an interesting mechanism by which WFA induced ERK and RSK, in a concerted action, results in concomitant upregulation and activation of CHOP and Elk1 (ETS like transcription factor 1).	10	29	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk1	Elk1	Elk1	10	11	28	29
The data demonstrate that EV71 infection triggers ERK1/2 dependent activation of c-Fos , c-Jun , c-myc and Elk1 .	The data demonstrate that EV71 infection triggers ERK1/2 dependent activation of c-Fos, c-Jun, c-myc and Elk1.	7	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk1	Elk1	Elk1	7	8	17	18
In vivo and in vitro studies have demonstrated a specific interaction between mammalian Med23 and the ternary complex factor Elk1 , which is activated by MAPK signaling .	In vivo and in vitro studies have demonstrated a specific interaction between mammalian Med23 and the ternary complex factor Elk1, which is activated by MAPK signaling.	7	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Elk1	Elk1	Elk1	25	26	19	20
The ETS domain transcription factor ELK1 is in a repressive association with growth genes and is transiently activated through phosphorylation by ERK1/2 .	The ETS domain transcription factor ELK1 is in a repressive association with growth genes and is transiently activated through phosphorylation by ERK1/2.	2	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ELK1	ELK1	ELK1	21	22	5	6
We used GAL-Elk-1 expression plasmids to detect ERK dependent activation of Elk-1 .	We used GAL-Elk-1 expression plasmids to detect ERK dependent activation of Elk-1.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	7	8	11	12
Since ERK phosphorylates and thereby activates ELK-1 and CREB in the nucleus , abundance of P-ELK-1 and P-CREB was analyzed .	Since ERK phosphorylates and thereby activates ELK-1 and CREB in the nucleus, abundance of P-ELK-1 and P-CREB was analyzed.	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ELK-1	ELK-1	ELK-1	1	2	6	7
MED23 , one of the components which interacts with MAPK activated ELK1 and adenovirus E1A , is a highly hydrophobic protein and is difficult to be purified in a soluble form .	MED23, one of the components which interacts with MAPK activated ELK1 and adenovirus E1A, is a highly hydrophobic protein and is difficult to be purified in a soluble form.	9	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ELK1	ELK1	ELK1	9	10	11	12
LIN-1 is related to the mammalian ERK target Elk1 .	LIN-1 is related to the mammalian ERK target Elk1.	2	9	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk1	Elk1	Elk1	6	7	8	9
Stat3 activity is typically induced by Receptor Tyrosine Kinases ( RTKs ) or by the interleukin-6 ( IL-6 )-Janus kinases ( JAK ) pathway , whereas Elk-1 is activated by the MAPK pathway .	Stat3 activity is typically induced by Receptor Tyrosine Kinases (RTKs) or by the interleukin-6 (IL-6)-Janus kinases (JAK) pathway, whereas Elk-1 is activated by the MAPK pathway.	26	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Elk-1	Elk-1	Elk-1	31	32	26	27
In addition , in vivo intestinal perfusion studies also indicated that the TNF-alpha-induced increase in mouse intestinal permeability requires ERK1/2 dependent activation of Elk-1 .	In addition, in vivo intestinal perfusion studies also indicated that the TNF-alpha-induced increase in mouse intestinal permeability requires ERK1/2 dependent activation of Elk-1.	19	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk-1	Elk-1	Elk-1	19	20	23	24
The activation of ERK1/2 also stimulates Elk1 and leads to SRE ( serum responsive element )-mediated transcription .	The activation of ERK1/2 also stimulates Elk1 and leads to SRE (serum responsive element)-mediated transcription.	1	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk1	Elk1	Elk1	3	4	6	7
In the CNS , Elk1 is activated by ERKs and these kinases respond to neurotrophins and neurotransmitters .	In the CNS, Elk1 is activated by ERKs and these kinases respond to neurotrophins and neurotransmitters.	4	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	Elk1	Elk1	Elk1	8	9	4	5
Elevated AngII is associated with the fibrosis in the heart XREF_BIBR , and the stimulation of AngII type 1 receptor ( AT 1 R ) activates ERK1/2 by uncoupling G protein dependent and beta-arrestin2-dependent pathways XREF_BIBR , by which ERK1/2 can further activate ERK dependent transcriptional responsiveness of Elk1 , GATA4 , and the ANP factor promoter XREF_BIBR .	Elevated AngII is associated with the fibrosis in the heart XREF_BIBR, and the stimulation of AngII type 1 receptor (AT 1 R) activates ERK1/2 by uncoupling G protein dependent and beta-arrestin2-dependent pathways XREF_BIBR, by which ERK1/2 can further activate ERK dependent transcriptional responsiveness of Elk1, GATA4, and the ANP factor promoter XREF_BIBR.	39	57	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk1	Elk1	Elk1	39	40	48	49
Endogenous Rlf expression was detected with two different commercial antibodies in MCF-7 cells , but only one of them revealed very faint bands in HeLa or HEK 293T cells in which we were unable to detect MEK and ERK independent activation of Elk1 ( XREF_FIG ) .	Endogenous Rlf expression was detected with two different commercial antibodies in MCF-7 cells, but only one of them revealed very faint bands in HeLa or HEK 293T cells in which we were unable to detect MEK and ERK independent activation of Elk1 (XREF_FIG).	36	44	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk1	Elk1	Elk1	38	39	42	43
The differential spatio-temporal dynamics of phosphorylated ERK cause the differential activations of two downstream substrates ELK1 and RSK .	The differential spatio-temporal dynamics of phosphorylated ERK cause the differential activations of two downstream substrates ELK1 and RSK.	5	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	phosphorylated ERK	erk	ELK1	ELK1	elk1	6	7	15	16
Additionally , as expected , both ERK inhibition ( U0126 , XREF_FIG ) and Elk-1 depletion ( XREF_FIG ) also reduced p-Elk-1 and Ac-H4K5 enrichment at c-Fos promoter following EGF stimulation .	Additionally, as expected, both ERK inhibition (U0126, XREF_FIG) and Elk-1 depletion (XREF_FIG) also reduced p-Elk-1 and Ac-H4K5 enrichment at c-Fos promoter following EGF stimulation.	6	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	p-Elk-1	p-Elk-1	p-Elk-1	6	7	21	22
Previous studies have shown that interactions between MED23 and the MAPK phosphorylated serines increase the affinity of ELK1 for mediator .	Previous studies have shown that interactions between MED23 and the MAPK phosphorylated serines increase the affinity of ELK1 for mediator.	5	19	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK phosphorylated	mapk	ELK1	ELK1	elk1	10	11	17	18
The basal level of phosphorylation of the Erk1/2 targets p90RSK , p70S6K , Elk1 , MSK1 , and c-Myc was similar in all Erk2T188-mutant mouse lines examined suggested that Thr188 phosphorylation is not sufficient to activate ERK1/2 , or that the phosphomimetic mutation did not fully mimic phosphorylation at Thr188 position .	The basal level of phosphorylation of the Erk1/2 targets p90RSK, p70S6K, Elk1, MSK1, and c-Myc was similar in all Erk2T188-mutant mouse lines examined suggested that Thr188 phosphorylation is not sufficient to activate ERK1/2, or that the phosphomimetic mutation did not fully mimic phosphorylation at Thr188 position.	4	14	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk1/2	phosphorylation of the Erk1/2	erk1/2	Elk1	Elk1	elk1	7	8	13	14
The molecular mechanism may be involved in suppressing MAPK signaling and inactivation of Elk-1 and activation of PPARgamma .	The molecular mechanism may be involved in suppressing MAPK signaling and inactivation of Elk-1 and activation of PPARgamma.	8	15	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Elk-1	Elk-1	Elk-1	8	9	13	14
Furthermore , Egr1 is induced by estrogen via ERK1/2 dependent activation of ELK-1 in MCF-7 breast cancer cells .	Furthermore, Egr1 is induced by estrogen via ERK1/2 dependent activation of ELK-1 in MCF-7 breast cancer cells.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ELK-1	ELK-1	ELK-1	8	9	12	13
Recently , we designed a synthetic cell penetrating peptide which specifically interferes with ERK dependent activation of Elk-1 in vitro .	Recently, we designed a synthetic cell penetrating peptide which specifically interferes with ERK dependent activation of Elk-1 in vitro.	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	13	14	17	18
The ERK dependent activation of Elk-1 has been clearly demonstrated in neuronal cells in which phosphorylation of Elk-1 at S383/389 by ERK is tightly linked to its activation and nuclear translocation and inhibition of phosphorylation results in cytoplasmic Elk-1 retention , limiting its transcriptional properties XREF_BIBR .	The ERK dependent activation of Elk-1 has been clearly demonstrated in neuronal cells in which phosphorylation of Elk-1 at S383/389 by ERK is tightly linked to its activation and nuclear translocation and inhibition of phosphorylation results in cytoplasmic Elk-1 retention, limiting its transcriptional properties XREF_BIBR.	1	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	1	2	5	6
The finding that ERK1/2 activates the transcription factors ELK1 and SP1 is in line with our data showing that binding sites for these factors are enriched amongst thegenes deregulated in aged Fmn2 -/- mice ( Fig XREF_FIG G ) .	The finding that ERK1/2 activates the transcription factors ELK1 and SP1 is in line with our data showing that binding sites for these factors are enriched amongst thegenes deregulated in aged Fmn2 -/- mice (Fig XREF_FIG G).	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ELK1	ELK1	ELK1	3	4	8	9
Importantly , these current findings are consistent with our previous results in which we observed that the activation of Elk-1 by ERK MAP kinase is critical for transcriptional stimulation of MMP-13 , and that the hyper-activation of ERK MAP kinase and Elk-1 is persistent in OA cartilage tissues compared to normal articular cartilage .	Importantly, these current findings are consistent with our previous results in which we observed that the activation of Elk-1 by ERK MAP kinase is critical for transcriptional stimulation of MMP-13, and that the hyper-activation of ERK MAP kinase and Elk-1 is persistent in OA cartilage tissues compared to normal articular cartilage.	17	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	21	22	19	20
The translocation of Erk1/2 activated Elk1 and sequentially promoted superoxide dismutase1 ( SOD1 ) expression .	The translocation of Erk1/2 activated Elk1 and sequentially promoted superoxide dismutase1 (SOD1) expression.	1	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	Elk1	Elk1	Elk1	3	4	5	6
Elk-1 is activated by the MAPK and ERK pathway , which is stimulated during HCMV infection XREF_BIBR .	Elk-1 is activated by the MAPK and ERK pathway, which is stimulated during HCMV infection XREF_BIBR.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	7	8	0	1
The ERK , JNK , and p38 groups of mitogen activated protein ( MAP ) kinases phosphorylate and activate Elk-1 in response to a variety of extracellular stimuli .	The ERK, JNK, and p38 groups of mitogen activated protein (MAP) kinases phosphorylate and activate Elk-1 in response to a variety of extracellular stimuli.	0	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	1	2	19	20
Elk-1 , another transcription factor involved in the regulation of c-Fos gene expression , can be modulated by ERK1/2 , JNK , and p38 .	Elk-1, another transcription factor involved in the regulation of c-Fos gene expression, can be modulated by ERK1/2, JNK, and p38.	0	23	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk-1	Elk-1	Elk-1	18	19	0	1
Having shown that ELK-1 is activated by ERK1/2 in response to EGF stimulation , we checked whether the promoter of ZFP36 is the target of ELK-1 regulation .	Having shown that ELK-1 is activated by ERK1/2 in response to EGF stimulation, we checked whether the promoter of ZFP36 is the target of ELK-1 regulation.	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ELK-1	ELK-1	ELK-1	7	8	3	4
As SUMO imparts repressive properties on Elk-1 , ERK mediated SUMO loss leads to de-repression at the same time as the ERK pathway promotes activation of Elk-1 .	As SUMO imparts repressive properties on Elk-1, ERK mediated SUMO loss leads to de-repression at the same time as the ERK pathway promotes activation of Elk-1.	21	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	21	22	26	27
In addition , ERK mediated Elk-1 activation ( which targets SRE ) takes place in the cytoplasm , while ERK mediated CREB activation ( which targets CRE ) takes place in the nucleus .	In addition, ERK mediated Elk-1 activation (which targets SRE) takes place in the cytoplasm, while ERK mediated CREB activation (which targets CRE) takes place in the nucleus.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	3	4	5	6
Thus , ERK activated Elk-1 and/or CREB may underlie cocaine induced gene expression in both CPu and NAc .	Thus, ERK activated Elk-1 and/or CREB may underlie cocaine induced gene expression in both CPu and NAc.	2	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	2	3	4	5
The inhibition of ERK1/2 activation prevented the IL-1beta-induced activation of Elk-1 .	The inhibition of ERK1/2 activation prevented the IL-1beta-induced activation of Elk-1.	3	11	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk-1	Elk-1	Elk-1	3	4	10	11
Taken together these results demonstrate that S1P activates multiple signaling pathways in SMC and regulates proliferation by ERK dependent activation of Elk-1 and differentiation by RhoA dependent activation of MRTF-A .	Taken together these results demonstrate that S1P activates multiple signaling pathways in SMC and regulates proliferation by ERK dependent activation of Elk-1 and differentiation by RhoA dependent activation of MRTF-A.	17	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	17	18	21	22
ERK can activate both ELK-1 and CREB ( via RSK2 ) , whereas RSK2 can activate only CREB .	ERK can activate both ELK-1 and CREB (via RSK2), whereas RSK2 can activate only CREB.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ELK-1	ELK-1	ELK-1	0	1	4	5
It was possible that the PI3K and Akt pathway promotes ERK1/2 independent activation of Elk1 in MCF-7 cells .	It was possible that the PI3K and Akt pathway promotes ERK1/2 independent activation of Elk1 in MCF-7 cells.	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk1	Elk1	Elk1	10	11	14	15
Further evidence that Snail may promote activation of ERK1/2 , which subsequently activates Elk-1 was supported by the fact that Snail knockdown in MDA-MB-231 cells led to translocation of p-Elk-1 from the nucleus into the cytosol ( XREF_SUPPLEMENTARY ) .	Further evidence that Snail may promote activation of ERK1/2, which subsequently activates Elk-1 was supported by the fact that Snail knockdown in MDA-MB-231 cells led to translocation of p-Elk-1 from the nucleus into the cytosol (XREF_SUPPLEMENTARY).	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk-1	Elk-1	Elk-1	8	9	13	14
ERK and MAPK directly activates Elk-1 through phosphorylation .	ERK and MAPK directly activates Elk-1 through phosphorylation.	0	6	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Elk-1	Elk-1	Elk-1	2	3	5	6
To test whether KRC had any effect on MAPK activity , we used a sensitive assay ( the PathDetect reporting system ) to evaluate the effect of KRC on ERK mediated ELK-1 transactivation and p38 mediated ATF2 transactivation .	To test whether KRC had any effect on MAPK activity, we used a sensitive assay (the PathDetect reporting system) to evaluate the effect of KRC on ERK mediated ELK-1 transactivation and p38 mediated ATF2 transactivation.	23	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	ELK-1	ELK-1	ELK-1	29	30	31	32
Probably best characterized is ERK activation of Elk-1 and c-Myc , p38 activation of ATF-2 and MEF2 , and JNK activation of c-Jun .	Probably best characterized is ERK activation of Elk-1 and c-Myc, p38 activation of ATF-2 and MEF2, and JNK activation of c-Jun.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	4	5	7	8
Together , these data indicate that , in this setting , Elk-1 is specifically activated by ERK .	Together, these data indicate that, in this setting, Elk-1 is specifically activated by ERK.	11	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	16	17	11	12
In cancer cells , the active ERK1/2 protein will activate RSK2 and Elk1 proteins that subsequently activate c-Jun and c-Fos proteins .	In cancer cells, the active ERK1/2 protein will activate RSK2 and Elk1 proteins that subsequently activate c-Jun and c-Fos proteins.	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk1	Elk1	Elk1	6	7	12	13
In H. pylori infected gastric cells , the villin promoter has been shown to be increased by Elk-1 , a downstream nuclear transcription factor which is activated by ERK1/2 phosphorylation .	In H. pylori infected gastric cells, the villin promoter has been shown to be increased by Elk-1, a downstream nuclear transcription factor which is activated by ERK1/2 phosphorylation.	15	30	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2 phosphorylation	erk1/2	Elk-1	Elk-1	elk-1	28	29	17	18
To confirm that PI3K and Akt was not responsible for the ERK1/2 independent activation of Elk1 , we investigated the effect of the PI3K inhibitor , LY294002 , on M-Ras-induced Elk1 activation .	To confirm that PI3K and Akt was not responsible for the ERK1/2 independent activation of Elk1, we investigated the effect of the PI3K inhibitor, LY294002, on M-Ras-induced Elk1 activation.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk1	Elk1	Elk1	11	12	15	16
E2 stimulated MAPK mediated Elk-1 transcriptional activity .	E2 stimulated MAPK mediated Elk-1 transcriptional activity.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Elk-1	Elk-1	Elk-1	2	3	4	5
Phosphorylation of ERK allows translocation from the cytoplasm to the nucleus , and mediates transcriptional activation of Elk-1 , ATF , NF-kappaB , Ap-1 , c-fos and c-Jun .	Phosphorylation of ERK allows translocation from the cytoplasm to the nucleus, and mediates transcriptional activation of Elk-1, ATF, NF-kappaB, Ap-1, c-fos and c-Jun.	0	27	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	Phosphorylation of ERK	erk	Elk-1	Elk-1	elk-1	2	3	17	18
Moreover , nuclear ERK can activate ELK-1 , ETS , SP-1 , and c-JUN [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Moreover, nuclear ERK can activate ELK-1, ETS, SP-1, and c-JUN [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ELK-1	ELK-1	ELK-1	3	4	6	7
Furthermore , both Elk1 and SRF are usually activated by MAPK pathway .	Furthermore, both Elk1 and SRF are usually activated by MAPK pathway.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Elk1	Elk1	Elk1	10	11	3	4
Phosphorylation activated ERK1/2 translocates from the cytoplasm to the nucleus and thereby mediates the transcriptional activation of Elk-1 , ATF , NF-kappaB , AP-1 , and c-fos , which in turn regulate cell proliferation and differentiation , the maintenance of cell shape , the construction of the cytoskeleton , apoptosis , and the malignant transformation of cells , among other biological functions .	Phosphorylation activated ERK1/2 translocates from the cytoplasm to the nucleus and thereby mediates the transcriptional activation of Elk-1, ATF, NF-kappaB, AP-1, and c-fos, which in turn regulate cell proliferation and differentiation, the maintenance of cell shape, the construction of the cytoskeleton, apoptosis, and the malignant transformation of cells, among other biological functions.	2	23	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2 translocates from the cytoplasm to the nucleus	erk1/2	Elk-1	Elk-1	elk-1	2	3	17	18
To further investigate the regulation of ERK1/2 signalling , we examined the expression and activation of MEKs , the interaction of MEK with ERKs , MEK mediated activation of ERK1/2 , and ERK1/2 mediated activation of nuclear substrate Elk-1 in the prefrontal cortex and hippocampus of suicide subjects .	To further investigate the regulation of ERK1/2 signalling, we examined the expression and activation of MEKs, the interaction of MEK with ERKs, MEK mediated activation of ERK1/2, and ERK1/2 mediated activation of nuclear substrate Elk-1 in the prefrontal cortex and hippocampus of suicide subjects.	32	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Elk-1	Elk-1	Elk-1	32	33	38	39
We discovered an interesting pathway where WA induced ERK and RSK led to a concomitant activation of ELK1 and DR5 in HCC cells .	We discovered an interesting pathway where WA induced ERK and RSK led to a concomitant activation of ELK1 and DR5 in HCC cells.	6	19	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	ERK	WA induced ERK	erk	ELK1	ELK1	elk1	8	9	17	18
In the CNS , Elk-1 is activated by ERKs in response to neurotrophins and neurotransmitters .	In the CNS, Elk-1 is activated by ERKs in response to neurotrophins and neurotransmitters.	4	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	Elk-1	Elk-1	Elk-1	8	9	4	5
ERK dependent activation of Elk-1 is observed in response to glutamate in striatal slices , after an acute administration of cocaine , or amphetamine .	ERK dependent activation of Elk-1 is observed in response to glutamate in striatal slices, after an acute administration of cocaine, or amphetamine.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	0	1	4	5
ELK1 is directly activated through its phosphorylation by MAPK on growth factors stimulation .	ELK1 is directly activated through its phosphorylation by MAPK on growth factors stimulation.	0	12	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ELK1	ELK1	ELK1	8	9	0	1
Although ELK-1 was activated by ERK , JNK , and p38 MAPK in response to NaASO ( 2 ) , ELK-1-mediated activation of the p21 promoter was largely dependent on ERK .	Although ELK-1 was activated by ERK, JNK, and p38 MAPK in response to NaASO (2), ELK-1-mediated activation of the p21 promoter was largely dependent on ERK.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ELK-1	ELK-1	ELK-1	5	6	1	2
Finally we asked whether UBE3A depletion caused phosphorylation of the ERK targeted transcription factor ELK1 upon translocation to the nucleus .	Finally we asked whether UBE3A depletion caused phosphorylation of the ERK targeted transcription factor ELK1 upon translocation to the nucleus.	4	16	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	UBE3A depletion caused phosphorylation of the ERK	erk	ELK1	ELK1	elk1	10	11	14	15
Unstimulated cells have low MMP expression , but expression can be increased by MAPK modulation of c-Jun and c-Fos .	Unstimulated cells have low MMP expression, but expression can be increased by MAPK modulation of c-Jun and c-Fos.	13	18	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	13	14	16	17
FGF2 signaling results in the phosphorylation of Erk1/2 , and activation of c-Fos and c-Jun that lead to elevated cyclin D mRNA levels .	FGF2 signaling results in the phosphorylation of Erk1/2, and activation of c-Fos and c-Jun that lead to elevated cyclin D mRNA levels.	0	15	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Erk1/2	FGF2 signaling results in the phosphorylation of Erk1/2	erk1/2	c-Jun	c-Jun	c-jun	7	8	14	15
The MAPK pathway activates the transcription factor activator protein-1 ( AP-1 ) , which is also responsible for the expression of the pro inflammatory cytokines .	The MAPK pathway activates the transcription factor activator protein-1 (AP-1), which is also responsible for the expression of the pro inflammatory cytokines.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	activator protein-1	activator protein-1	activator protein-1	1	2	7	9
Besides JNK , c-Jun can also be activated by ERK1/2 .	Besides JNK, c-Jun can also be activated by ERK1/2.	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	9	10	3	4
However , a recent study suggested that additional cell-type-specific factors could determine which MAPK module linked to c-Jun , and there have been accumulating studies to demonstrate that c-Jun can also be activated by other MAPKs , ERK1/2 and p38 .	However, a recent study suggested that additional cell-type-specific factors could determine which MAPK module linked to c-Jun, and there have been accumulating studies to demonstrate that c-Jun can also be activated by other MAPKs, ERK1/2 and p38.	28	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	37	38	28	29
DHAvD also suppressed activation of mitogen activated protein kinase ( MAPK ) , and MAPK mediated nuclear factor-kappa B ( NF-kappaB ) and activator protein-1 ( AP-1 ) activations in TPA treated MCF-7 cells .	DHAvD also suppressed activation of mitogen activated protein kinase (MAPK), and MAPK mediated nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) activations in TPA treated MCF-7 cells.	14	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	activator protein-1	activator protein-1	activator protein-1	14	15	23	25
EGF activates different mitogen activated protein kinases including ERK , JNK , and p38 , which , in turn , activate c-Jun and c-Fos , leading to cell growth and differentiation XREF_BIBR .	EGF activates different mitogen activated protein kinases including ERK, JNK, and p38, which, in turn, activate c-Jun and c-Fos, leading to cell growth and differentiation XREF_BIBR.	8	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	8	9	21	22
The MAPK and ERK kinase kinae ( MEKK ) mediates Ras-Raf signal transduction to JNK and c-Jun , and p21ras is reported to act both downstream and upstream of insulin receptor substrate-1 ( IRS-1 ) in the insulin signaling cascade .	The MAPK and ERK kinase kinae (MEKK) mediates Ras-Raf signal transduction to JNK and c-Jun, and p21ras is reported to act both downstream and upstream of insulin receptor substrate-1 (IRS-1) in the insulin signaling cascade.	0	17	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	1	2	16	17
Ha-RasV12 and activated proteins in both the extra-cellular regulated kinase ( ERK ) and the stress activated protein kinase ( SAPK ) or Jun N-terminal kinase ( JNK ) cascades independently stimulated PEA3 mediated gene expression .	Ha-RasV12 and activated proteins in both the extra-cellular regulated kinase (ERK) and the stress activated protein kinase (SAPK) or Jun N-terminal kinase (JNK) cascades independently stimulated PEA3 mediated gene expression.	3	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Jun	Jun	Jun	11	12	23	24
Although c-Jun indeed is a canonical downstream target of JNK , accumulated data has shown that c-Jun can also be activated by other MAPK signaling axes such as by p38MAPK and Erk1/2 .	Although c-Jun indeed is a canonical downstream target of JNK, accumulated data has shown that c-Jun can also be activated by other MAPK signaling axes such as by p38MAPK and Erk1/2.	16	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	23	24	16	17
Subsequent induction of c-Jun led by ERK and JNK activation was essential for this EGF response .	Subsequent induction of c-Jun led by ERK and JNK activation was essential for this EGF response.	1	9	led	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	6	7	3	4
Furthermore , numerous studies identified that the action of ERK and other members of the MAPK family , including p38 and JNK , subsequently activates activator protein-1 and NF-kappaB , and are thus pivotal for the induction of MMPs and other inflammatory factors in macrophages .	Furthermore, numerous studies identified that the action of ERK and other members of the MAPK family, including p38 and JNK, subsequently activates activator protein-1 and NF-kappaB, and are thus pivotal for the induction of MMPs and other inflammatory factors in macrophages.	9	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	activator protein-1	activator protein-1	activator protein-1	9	10	25	27
While c-myb and c-jun can be activated by MAPK , Foxo expression is negatively regulated by Akt phosphorylation .	While c-myb and c-jun can be activated by MAPK, Foxo expression is negatively regulated by Akt phosphorylation.	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-jun	c-jun	c-jun	8	9	3	4
In further study , we found that ERK activity promoted the expression of AP1 components Fra-1 and c-Jun , both of which were necessary for cell migration .	In further study, we found that ERK activity promoted the expression of AP1 components Fra-1 and c-Jun, both of which were necessary for cell migration.	7	23	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	7	8	17	18
Members of the MAPK family phosphorylate and activate components of the transcription factor AP-1 .	Members of the MAPK family phosphorylate and activate components of the transcription factor AP-1.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	3	4	11	14
MAPK pathway activation induces another transcription factor AP-1 which also plays a role in proinflammatory cytokine expression XREF_BIBR , XREF_BIBR .	MAPK pathway activation induces another transcription factor AP-1 which also plays a role in proinflammatory cytokine expression XREF_BIBR, XREF_BIBR.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	0	1	5	8
ERK also activated c-Jun through phosphorylation .	ERK also activated c-Jun through phosphorylation.	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	0	1	3	4
Of the three major mammalian MAPK proteins , the extracellular regulated kinase and MAPK ( ERK and MAPK ) pathway is commonly associated with survival XREF_BIBR , whereas p38 and MAPK XREF_BIBR and stress activated protein kinase and Jun N-terminal kinase ( SAPK and JNK ) pathways are often implicated in cell death XREF_BIBR , XREF_BIBR .	Of the three major mammalian MAPK proteins, the extracellular regulated kinase and MAPK (ERK and MAPK) pathway is commonly associated with survival XREF_BIBR, whereas p38 and MAPK XREF_BIBR and stress activated protein kinase and Jun N-terminal kinase (SAPK and JNK) pathways are often implicated in cell death XREF_BIBR, XREF_BIBR.	28	40	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Jun	Jun	Jun	30	31	38	39
The Gallo laboratory recently reported that ERK activation in OPC up-regulated c-Jun , which in turn has a negative effect on myelin gene expression .	The Gallo laboratory recently reported that ERK activation in OPC up-regulated c-Jun, which in turn has a negative effect on myelin gene expression.	6	16	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	6	7	11	12
We observed activation of 3 mitogen activated protein kinases ( MAPKs ) , p44/42 MAPK , p38 MAPK , and stress activated MAPK and Jun N-terminal kinase , by DOX , but only a specific inhibitor of the p44/42 MAPK kinase suppressed the effects of DOX on Egr-1 and SERCA2 mRNA expression .	We observed activation of 3 mitogen activated protein kinases (MAPKs), p44/42 MAPK, p38 MAPK, and stress activated MAPK and Jun N-terminal kinase, by DOX, but only a specific inhibitor of the p44/42 MAPK kinase suppressed the effects of DOX on Egr-1 and SERCA2 mRNA expression.	2	26	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Jun	Jun	Jun	14	15	24	25
Signaling that originated , at least in part , from DUOX2 mediated H 2 O 2 production was responsible for ERK related activation of activator protein 1 [ AP-1 ] , which appeared to play a role in the up-regulation of VEGF-A .	Signaling that originated, at least in part, from DUOX2 mediated H 2 O 2 production was responsible for ERK related activation of activator protein 1 [AP-1], which appeared to play a role in the up-regulation of VEGF-A.	20	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	activator protein 1	activator protein 1	activator protein 1	20	21	24	27
Mammals express at least four distinctly regulated groups of MAPKs : extracellular signal related kinases ( Erk )-1/2 , Jun amino-terminal kinases ( Jnk1/2/3 ) , p38 proteins ( p38alpha/beta/gamma/delta ) and Erk5 , all of which are activated by specific MAPK kinases : Mek1/2 ( for Erk1/2 ) , Mkk3/6 ( for the p38 ) , Mkk4/7 ( also known as Jnkk1/2 ; for the JNKs ) and Mek5 ( for Erk5 ) .	Mammals express at least four distinctly regulated groups of MAPKs : extracellular signal related kinases (Erk)-1/2, Jun amino-terminal kinases (Jnk1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and Erk5, all of which are activated by specific MAPK kinases : Mek1/2 (for Erk1/2), Mkk3/6 (for the p38), Mkk4/7 (also known as Jnkk1/2; for the JNKs) and Mek5 (for Erk5).	19	42	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Jun	Jun	Jun	41	42	19	20
The MAPK signaling pathway can activate the transcription factor activator protein-1 ( AP-1 ) .	The MAPK signaling pathway can activate the transcription factor activator protein-1 (AP-1).	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	activator protein-1	activator protein-1	activator protein-1	1	2	9	11
It is , therefore , plausible to suggest that activated ERK1/2 can induce c-Jun and in turn recruit transcription factor AP-1 for increased expression of TGFbeta1 .	It is, therefore, plausible to suggest that activated ERK1/2 can induce c-Jun and in turn recruit transcription factor AP-1 for increased expression of TGFbeta1.	9	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	10	11	13	14
XREF_BIBR ERK dependent upregulation of c-Jun leads to suppression of PTEN expression and concomitant activation of the PI3K/AKT/mTOR pathway .	XREF_BIBR ERK dependent upregulation of c-Jun leads to suppression of PTEN expression and concomitant activation of the PI3K/AKT/mTOR pathway.	1	6	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	1	2	5	6
Furthermore , transcriptional factor AP-1 and c-Jun , activated by Ca 2+ -provoked ERK1/2 signalling , was involved in the stretch enhanced miR-34c transcription .	Furthermore, transcriptional factor AP-1 and c-Jun, activated by Ca 2+ -provoked ERK1/2 signalling, was involved in the stretch enhanced miR-34c transcription.	4	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	13	14	6	7
Several MAPK regulated host transcription factors such as c-Jun , STAT1alpha , MEF2 , c-Myc , ATF-2 and c-Fos were induced early during infection , and ERK inhibition significantly blocked the c-Fos , c-Jun , c-Myc , and STAT1alpha activation in the infected cells .	Several MAPK regulated host transcription factors such as c-Jun, STAT1alpha, MEF2, c-Myc, ATF-2 and c-Fos were induced early during infection, and ERK inhibition significantly blocked the c-Fos, c-Jun, c-Myc, and STAT1alpha activation in the infected cells.	26	34	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	26	27	33	34
To determine whether the radiation activated ERK1/2 signaling pathway modulates c-Jun transcriptional function , c-Jun DNA binding ability was examined using a EMSA assay .	To determine whether the radiation activated ERK1/2 signaling pathway modulates c-Jun transcriptional function, c-Jun DNA binding ability was examined using a EMSA assay.	6	11	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	6	7	10	11
Interestingly , however , ERK did not stimulate c-Jun .	Interestingly, however, ERK did not stimulate c-Jun.	4	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	4	5	8	9
HBV was believed to target mitochondrial calcium regulation , leading to the activation of Pyk and FAK ( Proline rich tyrosine kinase and Focal adhesion kinase ) , Src XREF_BIBR , and the signal was then passed into nucleus through Ras-Raf-MAPK-JNK ( MAPK , mitogen activated protein kinase ; JNK , Jun N-terminal protein kinase ) XREF_BIBR , in turn MMPs ( Matrix metalloproteinase ) XREF_BIBR - XREF_BIBR , Myc and Cyclin were trans-activated , resulting the change of cell movements and cell cycle regulation .	HBV was believed to target mitochondrial calcium regulation, leading to the activation of Pyk and FAK (Proline rich tyrosine kinase and Focal adhesion kinase), Src XREF_BIBR, and the signal was then passed into nucleus through Ras-Raf-MAPK-JNK (MAPK, mitogen activated protein kinase; JNK, Jun N-terminal protein kinase) XREF_BIBR, in turn MMPs (Matrix metalloproteinase) XREF_BIBR - XREF_BIBR, Myc and Cyclin were trans-activated, resulting the change of cell movements and cell cycle regulation.	42	54	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Jun	Jun	Jun	42	43	51	52
The MAPK pathways activate the transcription factor AP-1 , which is a homo- or heterodimer of c-Jun , c-Fos and ATF2 .	The MAPK pathways activate the transcription factor AP-1, which is a homo- or heterodimer of c-Jun, c-Fos and ATF2.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	1	2	5	8
Conversely , our data show that FGF-1 increases ERK phosphorylation in ENU1564 cells , increases c-jun and c-fos mRNA expression in a time dependent manner , and triggers nuclear translocation of c-jun .	Conversely, our data show that FGF-1 increases ERK phosphorylation in ENU1564 cells, increases c-jun and c-fos mRNA expression in a time dependent manner, and triggers nuclear translocation of c-jun.	6	20	increases	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ERK	FGF-1 increases ERK phosphorylation	erk	c-jun	c-jun and c-fos mRNA expression	c-jun	8	9	15	16
As previously mentioned , the transcriptional activity of PPAR-gamma is regulated by phosphorylation ( by kinases such as the mitogen activated protein kinase ( MAPK ) , which activate Jun N-terminal kinase , or JNK , and extracellular signal regulated kinase 2 , or ERK 2 ) , and GILZ can directly interact with Raf1 , one of the MAPK members , resulting in the inhibition of Raf-1 phosphorylation and , subsequently , the suppression of both MEK/ERK-1/2 phosphorylation and AP-1-dependent transcription [ XREF_BIBR ] .	As previously mentioned, the transcriptional activity of PPAR-gamma is regulated by phosphorylation (by kinases such as the mitogen activated protein kinase (MAPK), which activate Jun N-terminal kinase, or JNK, and extracellular signal regulated kinase 2, or ERK 2), and GILZ can directly interact with Raf1, one of the MAPK members, resulting in the inhibition of Raf-1 phosphorylation and, subsequently, the suppression of both MEK/ERK-1/2 phosphorylation and AP-1-dependent transcription [XREF_BIBR].	22	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Jun	Jun	Jun	24	25	29	30
Specifically in HeLa cells photosensitisation with hypericin resulted in the rapid and sustained activation of Jun N-terminal kinase-1 and MAPK ( Assefa et al , 1999 ) .	Specifically in HeLa cells photosensitisation with hypericin resulted in the rapid and sustained activation of Jun N-terminal kinase-1 and MAPK (Assefa et al, 1999).	7	20	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Jun	Jun	Jun	19	20	15	16
Their stimulation by soluble CXCL16 induces the PI3-kinase and Akt and Erk pathways resulting in the activation of the transcription factor AP-1 .	Their stimulation by soluble CXCL16 induces the PI3-kinase and Akt and Erk pathways resulting in the activation of the transcription factor AP-1.	9	22	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Erk	Erk	Erk	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	11	12	19	22
It has been shown that MAPK mediated activation of transcription factor AP-1 increased MMP-9 expression in response to tumor necrosis factor a ( TNF-a ) in human vascular smooth muscle cells [ XREF_BIBR ] .	It has been shown that MAPK mediated activation of transcription factor AP-1 increased MMP-9 expression in response to tumor necrosis factor a (TNF-a) in human vascular smooth muscle cells [XREF_BIBR].	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	5	6	9	12
IL-17 activates MAPK pathway is shown to activate activator protein 1 ( AP1 ) , but the exact mechanism by which IL-17 regulates mRNA stability needs to be clarified .	IL-17 activates MAPK pathway is shown to activate activator protein 1 (AP1), but the exact mechanism by which IL-17 regulates mRNA stability needs to be clarified.	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	activator protein 1	activator protein 1	activator protein 1	2	3	8	11
The activated ERK1/2 then induced a sequential activation of p90RSK , and increase in phosphorylation of transcription factors c-fos and c-jun leading to transcriptional activation of AP-1 .	The activated ERK1/2 then induced a sequential activation of p90RSK, and increase in phosphorylation of transcription factors c-fos and c-jun leading to transcriptional activation of AP-1.	0	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-jun	c-jun	c-jun	2	3	20	21
Together with c-Jun N-terminal kinase , Erk1/2 may activate c-Jun .	Together with c-Jun N-terminal kinase, Erk1/2 may activate c-Jun.	6	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	c-Jun	c-Jun	c-Jun	6	7	9	10
The full-length human TSP1 promoter contains binding sites for many transcription factors such as MAPK targets of c-jun , c-fos , CREB , and c-myc .	The full-length human TSP1 promoter contains binding sites for many transcription factors such as MAPK targets of c-jun, c-fos, CREB, and c-myc.	14	24	targets	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-jun	c-jun	c-jun	14	15	17	18
Several intracellular signals elicited by ET-1 via ET receptors and even Epidermal Growth Factor Receptor ( EGFR ) contributed to the up-regulation of CTGF , including ERK activation and induction of the AP-1 components c-fos and c-jun , as also evaluated by ChIP analysis .	Several intracellular signals elicited by ET-1 via ET receptors and even Epidermal Growth Factor Receptor (EGFR) contributed to the up-regulation of CTGF, including ERK activation and induction of the AP-1 components c-fos and c-jun, as also evaluated by ChIP analysis.	26	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-jun	c-jun	c-jun	26	27	36	37
Protein VacA ( Vacuolating cytotoxin A ) also stimulates ERK and p38 pathways XREF_BIBR which activate transcription factor AP-1 XREF_BIBR , XREF_BIBR - XREF_BIBR .	Protein VacA (Vacuolating cytotoxin A) also stimulates ERK and p38 pathways XREF_BIBR which activate transcription factor AP-1 XREF_BIBR, XREF_BIBR - XREF_BIBR.	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	9	10	16	19
Dependent on its transmembrane helices , TMME174 overexpression is able to promote the transcriptional activity of activator protein 1 ( AP-1 ) , which is partly mediated by the ERK pathway .	Dependent on its transmembrane helices, TMME174 overexpression is able to promote the transcriptional activity of activator protein 1 (AP-1), which is partly mediated by the ERK pathway.	16	30	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	activator protein 1	activator protein 1	activator protein 1	29	30	16	19
LPS and TNF-alpha activate the MAPK pathway , which proceeds to activate nuclear factor kappa-B ( NF-kappaB ) and activator protein-1 ( AP1 ) , key proinflammatory transcription factors [ XREF_BIBR , XREF_BIBR ] .	LPS and TNF-alpha activate the MAPK pathway, which proceeds to activate nuclear factor kappa-B (NF-kappaB) and activator protein-1 (AP1), key proinflammatory transcription factors [XREF_BIBR, XREF_BIBR].	5	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	activator protein-1	activator protein-1	activator protein-1	5	6	19	21
The precise mechanism by which csHsp90 facilitates ERK mediated KSHV gene expression remains to be determined , although ERK activation of the transcription factor AP-1 is one possibility .	The precise mechanism by which csHsp90 facilitates ERK mediated KSHV gene expression remains to be determined, although ERK activation of the transcription factor AP-1 is one possibility.	18	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	18	19	22	25
Taken together , these results demonstrate that the FABP4 induced DNA synthesis and cell migration are mediated primarily through a MAPK dependent pathway that activates the transcription factors c-jun and c-myc in HCASMCs .	Taken together, these results demonstrate that the FABP4 induced DNA synthesis and cell migration are mediated primarily through a MAPK dependent pathway that activates the transcription factors c-jun and c-myc in HCASMCs.	20	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-jun	c-jun	c-jun	20	21	28	29
Considering our results , this inhibition might be explained by ERK activated Jun , which could then inhibit miR-22 .	Considering our results, this inhibition might be explained by ERK activated Jun, which could then inhibit miR-22.	8	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Jun	Jun	Jun	10	11	12	13
In the human ex vivo organ culture model , angiotensin II induces MAPK , which activates transcription factor AP-1 ( activator protein-1 ) .	In the human ex vivo organ culture model, angiotensin II induces MAPK, which activates transcription factor AP-1 (activator protein-1).	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	12	13	16	19
Additionally , p38gamma MAPK activates c-Jun , and activated c-Jun recruits p38gamma to the MMP-9 promoter as a cofactor to induce MMP-9 promoter trans-activation and cell invasion [ XREF_BIBR ] .	Additionally, p38gamma MAPK activates c-Jun, and activated c-Jun recruits p38gamma to the MMP-9 promoter as a cofactor to induce MMP-9 promoter trans-activation and cell invasion [XREF_BIBR].	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	3	4	5	6
Moreover , c-Fos and c-Jun , the major downstream components of MAPKs , were up-regulated by ERK and JNK , respectively .	Moreover, c-Fos and c-Jun, the major downstream components of MAPKs, were up-regulated by ERK and JNK, respectively.	2	18	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	16	17	4	5
ERKs activated c-Jun during PC12 cell differentiation , in oncogenic transformation via epidermal growth factor mediated activation , and during iron chelator induced IL-8 generation in human epithelial cells .	ERKs activated c-Jun during PC12 cell differentiation, in oncogenic transformation via epidermal growth factor mediated activation, and during iron chelator induced IL-8 generation in human epithelial cells.	0	3	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	c-Jun	c-Jun	c-Jun	0	1	2	3
ERK activation induced c-Jun , a member of the AP-1 transcription factor family .	ERK activation induced c-Jun, a member of the AP-1 transcription factor family.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	0	1	3	4
In addition , TGF-beta1-induced phosphorylation of ERK1/2 without affecting p38 mitogen activated protein kinases and Jun N-terminal kinase .	In addition, TGF-beta1-induced phosphorylation of ERK1/2 without affecting p38 mitogen activated protein kinases and Jun N-terminal kinase.	4	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	phosphorylation of ERK1/2	erk1/2	Jun	Jun	jun	6	7	15	16
Because Elk-1 controls egr-1 , which in turn controls c-Jun activation , we hypothesize that ERK may indirectly activate c-Jun via the intermediate targets Elk-1 and Egr-1 .	Because Elk-1 controls egr-1, which in turn controls c-Jun activation, we hypothesize that ERK may indirectly activate c-Jun via the intermediate targets Elk-1 and Egr-1.	15	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	15	16	19	20
Recently , we also identified a novel cross-talk mechanism , by which pharmacologic or genetic inhibition of MEK restores PTEN expression , thus leading to cross-inhibition of downstream signaling through AKT and mTOR : more specifically , ERK dependent upregulation of c-Jun and miR-25 leads to suppression of PTEN expression ( XREF_FIG ) [ XREF_BIBR ] .	Recently, we also identified a novel cross-talk mechanism, by which pharmacologic or genetic inhibition of MEK restores PTEN expression, thus leading to cross-inhibition of downstream signaling through AKT and mTOR : more specifically, ERK dependent upregulation of c-Jun and miR-25 leads to suppression of PTEN expression (XREF_FIG) [XREF_BIBR].	37	43	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	37	38	41	42
Ras is known to stimulate at least two mitogen activated protein kinase ( MAPK ) cascades , the extracellular regulated kinase ( ERK ) cascade and the stress activated kinase ( SAPK ) or Jun kinase ( JNK ) cascade .	Ras is known to stimulate at least two mitogen activated protein kinase (MAPK) cascades, the extracellular regulated kinase (ERK) cascade and the stress activated kinase (SAPK) or Jun kinase (JNK) cascade.	22	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Jun	Jun	Jun	22	23	34	35
These include mitogen activated protein kinases ERK1/2 that activate transcription factor AP-1 and promotes cell proliferation ; phosphatidylinositol 3-kinase ( PI3-K ) that activates AKT and nuclear factor-kappa B ( NF-kappaB )/RELA ; and JAK-STAT3 , all of which promote cancer cell survival .	These include mitogen activated protein kinases ERK1/2 that activate transcription factor AP-1 and promotes cell proliferation; phosphatidylinositol 3-kinase (PI3-K) that activates AKT and nuclear factor-kappa B (NF-kappaB)/RELA; and JAK-STAT3, all of which promote cancer cell survival.	1	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	6	7	9	12
MAPK pathways activate nuclear factor ( NF )-kappaB and activator protein-1 ( AP-1 ) , which enhances the release of inflammatory cytokines such as tumor necrosis factor-alpha , IL-1beta , IL-6 , and IL-8 [ XREF_BIBR , XREF_BIBR ] .	MAPK pathways activate nuclear factor (NF)-kappaB and activator protein-1 (AP-1), which enhances the release of inflammatory cytokines such as tumor necrosis factor-alpha, IL-1beta, IL-6, and IL-8 [XREF_BIBR, XREF_BIBR].	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	activator protein-1	activator protein-1	activator protein-1	0	1	9	11
Erk induces increases in activator protein-1 ( AP-1 ) transcription factor activity which may augment mesangial cell proliferation and ECM protein production .	Erk induces increases in activator protein-1 (AP-1) transcription factor activity which may augment mesangial cell proliferation and ECM protein production.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	activator protein-1	activator protein-1	activator protein-1	0	1	4	6
Phosphorylation by JNK enhances protein stability via protection from ubiquitination XREF_BIBR , whereas constitutively active p44/42 MAPK increases c-Jun stability via inactivation of glycogen kinase 2 in melanoma cells XREF_BIBR .	Phosphorylation by JNK enhances protein stability via protection from ubiquitination XREF_BIBR, whereas constitutively active p44/42 MAPK increases c-Jun stability via inactivation of glycogen kinase 2 in melanoma cells XREF_BIBR.	14	19	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	16	17	18	19
ERK and JNK are known to target c-Jun , which is a critical component of AP-1 , thereby affecting HIV-1 replication 19 .	ERK and JNK are known to target c-Jun, which is a critical component of AP-1, thereby affecting HIV-1 replication 19.	0	13	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	0	1	7	8
Here , we show that the transcription factor c-Jun is activated by p38gamma MAPK , and the activated c-Jun then recruits p38gamma as a cofactor into the matrix metalloproteinase 9 ( MMP9 ) promoter to induce its trans-activation and cell invasion .	Here, we show that the transcription factor c-Jun is activated by p38gamma MAPK, and the activated c-Jun then recruits p38gamma as a cofactor into the matrix metalloproteinase 9 (MMP9) promoter to induce its trans-activation and cell invasion.	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	13	14	8	9
ERK and JNK induce accumulation and activation of activator protein-1 ( AP-1 ) , causing apoptosis .	ERK and JNK induce accumulation and activation of activator protein-1 (AP-1), causing apoptosis.	0	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	activator protein-1	activator protein-1	activator protein-1	0	1	8	10
In addition , when AP-1 was blocked using pharmacological inhibitors during BGP treatment , PD-98059 ( PD ) , which inhibits phosphorylation of ERK 1/2 by MEK and subsequently c-Fos , and SP-600125 ( SP ) , which inhibits JNK and prevents c-Jun activation ; we found that they were able to block endothelial senescence induced by BGP , measured as SA-beta-GAL activity and p16 protein expression .	In addition, when AP-1 was blocked using pharmacological inhibitors during BGP treatment, PD-98059 (PD), which inhibits phosphorylation of ERK 1/2 by MEK and subsequently c-Fos, and SP-600125 (SP), which inhibits JNK and prevents c-Jun activation; we found that they were able to block endothelial senescence induced by BGP, measured as SA-beta-GAL activity and p16 protein expression.	14	43	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK 1/2	PD-98059 (PD), which inhibits phosphorylation of ERK 1/2 by MEK and subsequently c-Fos, and SP-600125	erk 1/2	c-Jun	c-Jun	c-jun	23	25	42	43
Together , our data suggest that ERK1/2 mediated c-Jun activation may be responsible for TLR2 agonist induced SPLUNC1 gene expression .	Together, our data suggest that ERK1/2 mediated c-Jun activation may be responsible for TLR2 agonist induced SPLUNC1 gene expression.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	6	7	8	9
In fact , TNF induced MAPK activation can mediate the nuclear translocation and enhancement of the transcriptional activity of NF-kappaB and c-Jun later being known as AP-1 , once heterodimerize with c-fos [ XREF_BIBR ] .	In fact, TNF induced MAPK activation can mediate the nuclear translocation and enhancement of the transcriptional activity of NF-kappaB and c-Jun later being known as AP-1, once heterodimerize with c-fos [XREF_BIBR].	3	22	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	TNF induced MAPK	mapk	c-Jun	c-Jun	c-jun	5	6	21	22
c-Jun was activated by ERK1/2 signalling in response to stretch .	c-Jun was activated by ERK1/2 signalling in response to stretch.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	4	5	0	1
Taken together , these data support the conclusion that GSK3beta activation is a pre-requisite signal for the MAPK dependent activation of c-Jun and ATF2 and also NF-kappaB p65 activity which in turn regulates SCF/SA induced cytokine production .	Taken together, these data support the conclusion that GSK3beta activation is a pre-requisite signal for the MAPK dependent activation of c-Jun and ATF2 and also NF-kappaB p65 activity which in turn regulates SCF/SA induced cytokine production.	17	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	17	18	21	22
MAPK activation induces c-jun and c-fos and triggers , among others , genes related to metal trafficking and antioxidant defense .	MAPK activation induces c-jun and c-fos and triggers, among others, genes related to metal trafficking and antioxidant defense.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-jun	c-jun	c-jun	0	1	3	4
Results of protein binding assays suggest that ERK1/2 may potentially mediate JNK independent c-Jun activation .	Results of protein binding assays suggest that ERK1/2 may potentially mediate JNK independent c-Jun activation.	7	14	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	7	8	13	14
The expression of the transcription factors c-Jun and ATF-2 were decreased in 2-ABP treated cells in the presence of ERK and JNK inhibitors , suggesting that the expression of ERK and JNK pathways leads to the downstream activation of c-Jun and ATF-2 .	The expression of the transcription factors c-Jun and ATF-2 were decreased in 2-ABP treated cells in the presence of ERK and JNK inhibitors, suggesting that the expression of ERK and JNK pathways leads to the downstream activation of c-Jun and ATF-2.	27	41	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	ERK	expression of ERK	erk	c-Jun	c-Jun	c-jun	29	30	39	40
Our siRNA screen identified a number of transcription factors as hits , including c-Jun and Sp1 , both of which can be activated by JNK and MAPK signaling .	Our siRNA screen identified a number of transcription factors as hits, including c-Jun and Sp1, both of which can be activated by JNK and MAPK signaling.	3	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	26	27	13	14
Moreover , phosphorylation of MAPK activates the transcription factor AP-1 in responses to multiple TLRs activation .	Moreover, phosphorylation of MAPK activates the transcription factor AP-1 in responses to multiple TLRs activation.	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	phosphorylation of MAPK	mapk	transcription factor AP-1	transcription factor AP-1	transcription factor ap-1	4	5	7	10
Taken together , these experiments indicate that NF-kappa B can rapidly transduce hypoxic signals through increased DNA binding and transactivation activities , whereas specific AP-1 ( ATF-2 and c-Jun ) complexes may be activated under the same hypoxic conditions by a stress-reponsive MAPK pathway .	Taken together, these experiments indicate that NF-kappa B can rapidly transduce hypoxic signals through increased DNA binding and transactivation activities, whereas specific AP-1 (ATF-2 and c-Jun) complexes may be activated under the same hypoxic conditions by a stress-reponsive MAPK pathway.	26	43	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	42	43	28	29
Interestingly , TPA induces c-Jun in alphaT3 cells , and it is not clear whether ERK1/2 can activate c-Jun , or PKC can activate JNK in alphaT3 cells .	Interestingly, TPA induces c-Jun in alphaT3 cells, and it is not clear whether ERK1/2 can activate c-Jun, or PKC can activate JNK in alphaT3 cells.	15	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	15	16	18	19
c-Jun is mainly activated by MAPK pathway .	c-Jun is mainly activated by MAPK pathway.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	5	6	0	1
The presence of C. albicans yeast or hyphae triggers the NF-kappaB signaling and an early response of the MAPK activation through ERK1/2 and JNK signaling which induces the c-Jun activity .	The presence of C. albicans yeast or hyphae triggers the NF-kappaB signaling and an early response of the MAPK activation through ERK1/2 and JNK signaling which induces the c-Jun activity.	21	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	21	22	28	29
Our data indicate that MMP-2 and MMP-9 downregulation in gallic acid treated K562 cells are mediated through suppression of JNK1 mediated c-Jun and ATF -2 and Akt and ERK mediated c-Jun and c-Fos pathways , respectively .	Our data indicate that MMP-2 and MMP-9 downregulation in gallic acid treated K562 cells are mediated through suppression of JNK1 mediated c-Jun and ATF -2 and Akt and ERK mediated c-Jun and c-Fos pathways, respectively.	23	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	28	29	30	31
53 MAPK signaling pathways can activate the transcription factor activator protein-1 ( AP-1 ) .	53 MAPK signaling pathways can activate the transcription factor activator protein-1 (AP-1).	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	activator protein-1	activator protein-1	activator protein-1	1	2	9	11
ERK dependent activation of c-Jun results in the recruitment of Tet1 to the Zta promoter to facilitate Zta promoter hypomethylation , Zta gene expression , and eventually EBV reactivation .	ERK dependent activation of c-Jun results in the recruitment of Tet1 to the Zta promoter to facilitate Zta promoter hypomethylation, Zta gene expression, and eventually EBV reactivation.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	0	1	4	5
It has been suggested by others that the MAP kinase , ERK1/2 signalling pathway may result in activation of Activator protein-1 ( AP-1 ) , a transcription factor which is critical for auto-induction of TGFbeta1 [ XREF_BIBR ] .	It has been suggested by others that the MAP kinase, ERK1/2 signalling pathway may result in activation of Activator protein-1 (AP-1), a transcription factor which is critical for auto-induction of TGFbeta1 [XREF_BIBR].	11	21	result in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Activator protein-1	Activator protein-1	Activator protein-1	11	12	19	21
In agreement with our result , Helicobacter pylori induces apoptosis in macrophages via ERK dependent activation of c-Jun .	In agreement with our result, Helicobacter pylori induces apoptosis in macrophages via ERK dependent activation of c-Jun.	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	13	14	17	18
When triggered by inflammatory cytokines such as TNF-alpha , MAPK cascades are initiated via p38 and JNK pathways to regulate activator protein-1 , which subsequently leads to inflammatory responses and cell apoptosis .	When triggered by inflammatory cytokines such as TNF-alpha, MAPK cascades are initiated via p38 and JNK pathways to regulate activator protein-1, which subsequently leads to inflammatory responses and cell apoptosis.	9	22	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	activator protein-1	activator protein-1	activator protein-1	9	10	20	22
Knockdown of Naa10 significantly decreases phorbol ester TPA induced phosphorylation of Erk1/2 , attenuates c-Jun and c-Fos activation , decreases AP-1-recruitment to the cyclin D1 promoter and results in a repression of the AP-1 target genes including cyclin D1 .	Knockdown of Naa10 significantly decreases phorbol ester TPA induced phosphorylation of Erk1/2, attenuates c-Jun and c-Fos activation, decreases AP-1-recruitment to the cyclin D1 promoter and results in a repression of the AP-1 target genes including cyclin D1.	7	17	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Erk1/2	TPA induced phosphorylation of Erk1/2	erk1/2	c-Jun	c-Jun	c-jun	11	12	14	15
The c-fos and c-jun , components of activator protein-1 ( AP-1 ) , were mediated by MAPK pathways .	The c-fos and c-jun, components of activator protein-1 (AP-1), were mediated by MAPK pathways.	1	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-jun	c-jun	c-jun	16	17	3	4
The transcription factor AP-1 plays a major role in the regulation of CXCL8 transcription and is activated by MAPK signaling .	The transcription factor AP-1 plays a major role in the regulation of CXCL8 transcription and is activated by MAPK signaling.	1	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	18	19	1	4
Given that there is important crosstalk between AR and mitogen activated protein kinase ( MAPK ) signaling , we also investigated whether genistein activates the MAPK end targets c-Jun N-terminal kinase ( JNK ) and c-Jun .	Given that there is important crosstalk between AR and mitogen activated protein kinase (MAPK) signaling, we also investigated whether genistein activates the MAPK end targets c-Jun N-terminal kinase (JNK) and c-Jun.	25	36	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	25	26	35	36
One could surmise that RAGE may serve to stabilize the activation of NF-kappaB over time ( e.g ., by promoting endosomal signal complex formation with TLR9 ) or could activate other signaling pathways that serve to amplify the effects of NF-kappaB ( e.g ., ERK related activation of transcription factor AP-1 ) , but further investigation would be needed to clarify this mechanism .	One could surmise that RAGE may serve to stabilize the activation of NF-kappaB over time (e.g., by promoting endosomal signal complex formation with TLR9) or could activate other signaling pathways that serve to amplify the effects of NF-kappaB (e.g., ERK related activation of transcription factor AP-1), but further investigation would be needed to clarify this mechanism.	44	51	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	44	45	48	51
These actions were dependent upon the activation of multiple MAPK signal pathways , including ERK5 kinase ; transactivation of the epidermal growth factor receptor ; and the increased expression and activities of transcription factors ELK-1 , activating transcription factor-2 , c-Fos , c-Jun , activator protein-1 , and myocyte enhancer factor-2 .	These actions were dependent upon the activation of multiple MAPK signal pathways, including ERK5 kinase; transactivation of the epidermal growth factor receptor; and the increased expression and activities of transcription factors ELK-1, activating transcription factor-2, c-Fos, c-Jun, activator protein-1, and myocyte enhancer factor-2.	9	46	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	activator protein-1	activator protein-1	activator protein-1	9	10	44	46
Also , p38gamma MAPK activates c-Jun , and the activated c-Jun recruits p38gamma as a cofactor into MMP-9 promoter to induce its trans-activation and cell invasion [ XREF_BIBR ] .	Also, p38gamma MAPK activates c-Jun, and the activated c-Jun recruits p38gamma as a cofactor into MMP-9 promoter to induce its trans-activation and cell invasion [XREF_BIBR].	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	3	4	5	6
This is in line with the observation that NF-kappaB is strongly induced by MRPs , on the other hand , efficient induction of AP-1 might be due to the fact that ERK and JNK are up-stream activators of c-Jun and c-Fos which dimerize to form active AP-1 complexes XREF_BIBR .	This is in line with the observation that NF-kappaB is strongly induced by MRPs, on the other hand, efficient induction of AP-1 might be due to the fact that ERK and JNK are up-stream activators of c-Jun and c-Fos which dimerize to form active AP-1 complexes XREF_BIBR.	31	40	are up-stream activators	Positive_activation_copula_1	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	31	32	38	39
Numerous in vitro studies using human epithelial cystic fibrosis and control cell lines confirmed increased NF-kappaB signaling XREF_BIBR , XREF_BIBR - XREF_BIBR and the involvement of several proinflammatory cascades , including activation of Ca 2+ -dependent signaling XREF_BIBR , XREF_BIBR , increased nuclear factor of activated T cells ( NFAT ) transcription 29 and mitogen activated protein kinase ( MAPK )-dependent activation of activator protein 1 ( AP-1 ) , in cystic fibrosis epithelia compared to control epithelia XREF_BIBR , XREF_BIBR .	Numerous in vitro studies using human epithelial cystic fibrosis and control cell lines confirmed increased NF-kappaB signaling XREF_BIBR, XREF_BIBR - XREF_BIBR and the involvement of several proinflammatory cascades, including activation of Ca 2+ -dependent signaling XREF_BIBR, XREF_BIBR, increased nuclear factor of activated T cells (NFAT) transcription 29 and mitogen activated protein kinase (MAPK)-dependent activation of activator protein 1 (AP-1), in cystic fibrosis epithelia compared to control epithelia XREF_BIBR, XREF_BIBR.	41	66	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MAPK	increased nuclear factor of activated T cells (NFAT) transcription 29 and mitogen activated protein kinase (MAPK	mapk	activator protein 1	activator protein 1	activator protein 1	59	60	63	66
Taken together , our data indicate that Fas and FasL up-regulation in piceatannol treated U937 cells is elicited by Ca ( 2+ )/p38alpha MAPK mediated activation of c-Jun and ATF-2 , and suggest that autocrine Fas mediated apoptotic mechanism is involved in piceatannol induced cell death .	Taken together, our data indicate that Fas and FasL up-regulation in piceatannol treated U937 cells is elicited by Ca (2+)/p38alpha MAPK mediated activation of c-Jun and ATF-2, and suggest that autocrine Fas mediated apoptotic mechanism is involved in piceatannol induced cell death.	23	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	23	24	27	28
Because there is an active cross-talk between c-Jun/AP -1 and beta-catenin and Wnt signaling XREF_BIBR and p38gamma binds both c-Jun and beta-catenin proteins XREF_BIBR , XREF_BIBR , p38gamma MAPK may mediate the c-Jun and beta-catenin signaling crosstalk through a complex formation to promote colon tumorigenesis ( XREF_FIG ) .	Because there is an active cross-talk between c-Jun/AP -1 and beta-catenin and Wnt signaling XREF_BIBR and p38gamma binds both c-Jun and beta-catenin proteins XREF_BIBR, XREF_BIBR, p38gamma MAPK may mediate the c-Jun and beta-catenin signaling crosstalk through a complex formation to promote colon tumorigenesis (XREF_FIG).	25	36	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	28	29	32	33
bAgNP Induced Activation of Jun N-Terminal Kinase ( JNK ) and Extracellular Signal Regulated Kinase ( ERK ) Mitogen Activated Protein Kinase ( MAPK ) Signaling Act Antagonistically .	bAgNP Induced Activation of Jun N-Terminal Kinase (JNK) and Extracellular Signal Regulated Kinase (ERK) Mitogen Activated Protein Kinase (MAPK) Signaling Act Antagonistically.	0	17	Induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Jun	Jun	Jun	16	17	4	5
For instance , c-Jun is activated by JNK , XREF_BIBR TPA , XREF_BIBR PDCD4 , XREF_BIBR MAPK , XREF_BIBR and cytokines .	For instance, c-Jun is activated by JNK, XREF_BIBR TPA, XREF_BIBR PDCD4, XREF_BIBR MAPK, XREF_BIBR and cytokines.	3	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	16	17	3	4
This observation strongly supports the concept that the EPO ligand induces dimerization of EPOR and thus results in downstream activation through this mechanism ( XREF_FIG ) .	This observation strongly supports the concept that the EPO ligand induces dimerization of EPOR and thus results in downstream activation through this mechanism (XREF_FIG).	8	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	8	9	13	14
This report supports the idea that EPOR is important in phase 2 IVNV and can be activated by erythropoietin or VEGF .	This report supports the idea that EPOR is important in phase 2 IVNV and can be activated by erythropoietin or VEGF.	6	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	erythropoietin	erythropoietin	erythropoietin	EPOR	EPOR	EPOR	18	19	6	7
Human EpoR was activated in these cells by erythropoietin but was resistant to gp55 .	Human EpoR was activated in these cells by erythropoietin but was resistant to gp55.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	erythropoietin	erythropoietin	erythropoietin	EpoR	EpoR	EpoR	8	9	1	2
Unexpectedly , Epo induced EpoR internalization does not require PI3K kinase activity .	Unexpectedly, Epo induced EpoR internalization does not require PI3K kinase activity.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	2	3	4	5
In mice , EpoR expression increased with ischemic stroke along with increased EPO production , and EPO treatment reduced infarct size [ XREF_BIBR ] , suggesting that in ischemic injury , EpoR increases EPO response and the increase of EPO availability contributes to neuroprotection .	In mice, EpoR expression increased with ischemic stroke along with increased EPO production, and EPO treatment reduced infarct size [XREF_BIBR], suggesting that in ischemic injury, EpoR increases EPO response and the increase of EPO availability contributes to neuroprotection.	31	34	increases	Positive_activation_token_1_noun	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	33	34	31	32
EPO mediated upregulation of EPO-R , but not EPO , mRNA was observed within 4 h of the excitotoxic insult .	EPO mediated upregulation of EPO-R, but not EPO, mRNA was observed within 4 h of the excitotoxic insult.	0	5	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPO-R	EPO-R	EPO-R	0	1	4	5
Another consequence is an additional increase in Epo levels , thus activating the EpoR and Jak2 pathway .	Another consequence is an additional increase in Epo levels, thus activating the EpoR and Jak2 pathway.	7	16	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo levels	epo	EpoR	EpoR	epor	7	8	13	14
Altogether , these findings suggest that in skeletal muscle in vivo , EPO may not activate the EPO-R or the established EPO signaling cascades , such as JAK2 and STAT5 or PI3-K and Akt .	Altogether, these findings suggest that in skeletal muscle in vivo, EPO may not activate the EPO-R or the established EPO signaling cascades, such as JAK2 and STAT5 or PI3-K and Akt.	12	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPO-R	EPO-R	EPO-R	12	13	17	18
Here we show that addition of EPO or interleukin-3 ( IL-3 ) to an IL-3-dependent cell line expressing the wild-type EPOR causes a small fraction ( less than 5 % ) of total cellular EPOR to shift in gel mobility from 66 to 72 kDa , due at least in part to phosphorylation .	Here we show that addition of EPO or interleukin-3 (IL-3) to an IL-3-dependent cell line expressing the wild-type EPOR causes a small fraction (less than 5%) of total cellular EPOR to shift in gel mobility from 66 to 72 kDa, due at least in part to phosphorylation.	4	35	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	6	7	34	35
Our results demonstrate that treatment with EPO elicits EPO-R downstream signalling in cultured KCs and increases the capacity of cultured and sorted primary KCs to phagocytose .	Our results demonstrate that treatment with EPO elicits EPO-R downstream signalling in cultured KCs and increases the capacity of cultured and sorted primary KCs to phagocytose.	4	10	elicits	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPO-R	EPO-R	EPO-R	6	7	8	9
XREF_BIBR Thus , we demonstrated that chronic Epo deficiency induces a cardiac angiogenesis probably mediated by HIF-1alpha and VEGF ( XREF_FIG ) and Epo-R pathways , which could optimize O 2 supply and limit the consequences of chronic anemia on cardiac cells .	XREF_BIBR Thus, we demonstrated that chronic Epo deficiency induces a cardiac angiogenesis probably mediated by HIF-1alpha and VEGF (XREF_FIG) and Epo-R pathways, which could optimize O 2 supply and limit the consequences of chronic anemia on cardiac cells.	7	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	Epo-R	Epo-R	Epo-R	7	8	23	24
Thus , two novel pathways of Epo induced EpoR down-regulation have been identified .	Thus, two novel pathways of Epo induced EpoR down-regulation have been identified.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	6	7	8	9
EPO significantly increased the number of KCs in the control Epor fl/fl mice , but had no effect on KC numbers in the LysM cre -Epor fl/fl mice .	EPO significantly increased the number of KCs in the control Epor fl/fl mice, but had no effect on KC numbers in the LysM cre -Epor fl/fl mice.	0	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	Epor	Epor	Epor	0	1	10	11
Small peptides , or EPO mimetics with sequences unrelated to EPO , can activate the EPOR homodimer .	Small peptides, or EPO mimetics with sequences unrelated to EPO, can activate the EPOR homodimer.	4	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	4	5	15	16
One important negative regulatory mechanism to terminate Epo signaling is Epo induced EpoR endocytosis and degradation .	One important negative regulatory mechanism to terminate Epo signaling is Epo induced EpoR endocytosis and degradation.	4	13	induced	Positive_early_activation	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	10	11	12	13
Increased EPO signaling activity is also suggested by the increased pEPO-R in S-HBs as the JAK-2 mediated STAT5 phosphorylation would also auto-phosphorylate both JAK2 and EPO-R XREF_BIBR .	Increased EPO signaling activity is also suggested by the increased pEPO-R in S-HBs as the JAK-2 mediated STAT5 phosphorylation would also auto-phosphorylate both JAK2 and EPO-R XREF_BIBR.	1	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPO-R	EPO-R	EPO-R	1	2	25	26
These results suggest that endogenous EPO secretion induced by high glucose activates EPOR in rat GECs .	These results suggest that endogenous EPO secretion induced by high glucose activates EPOR in rat GECs.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	5	6	12	13
Simultaneously , activation of EPOR by EPO binding promotes degradation of the formed complex via two pathways [ XREF_BIBR ] : ( 1 ) proteolysis by proteosomes at the cell surface ; and ( 2 ) internalization followed by targeting to lysosomes .	Simultaneously, activation of EPOR by EPO binding promotes degradation of the formed complex via two pathways [XREF_BIBR] : (1) proteolysis by proteosomes at the cell surface; and (2) internalization followed by targeting to lysosomes.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	6	7	4	5
Studies in our laboratory have shown that Epo induces internalization of EpoR via CME , and we identified a novel function of p85 in EpoR endocytosis and downregulation .	Studies in our laboratory have shown that Epo induces internalization of EpoR via CME, and we identified a novel function of p85 in EpoR endocytosis and downregulation.	7	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	7	8	11	12
The expression of epor mRNA in goldfish tissues , cell populations and cells treated with recombinant goldfish EPO ( rgEPO ) were evaluated by quantitative PCR revealing that goldfish epor mRNA is transcribed in both erythropoietic tissues ( blood , kidney and spleen ) and non hematopoietic tissues ( brain , heart and gill ) , as well as in immature erythrocytes .	The expression of epor mRNA in goldfish tissues, cell populations and cells treated with recombinant goldfish EPO (rgEPO) were evaluated by quantitative PCR revealing that goldfish epor mRNA is transcribed in both erythropoietic tissues (blood, kidney and spleen) and non hematopoietic tissues (brain, heart and gill), as well as in immature erythrocytes.	3	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EPO	EPO	EPO	epor	epor	epor	17	18	3	4
The endogenous EPO could then activate EPOR in a paracrine or autocrine fashion , 29 avoiding the rheological consequences of high doses of exogenous EPO .	The endogenous EPO could then activate EPOR in a paracrine or autocrine fashion, 29 avoiding the rheological consequences of high doses of exogenous EPO.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	2	3	6	7
Binding of EPO to the cell surface induces dimerization of two EPOR molecules , which , in turn , initiates the Janus kinase intracellular signal transduction required for erythropoiesis [ XREF_BIBR ] .	Binding of EPO to the cell surface induces dimerization of two EPOR molecules, which, in turn, initiates the Janus kinase intracellular signal transduction required for erythropoiesis [XREF_BIBR].	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	2	3	11	12
eNOS has also a major role in EPO mediated vascular protection ; EPO activation of EPOR increased expression of phosphorylated Ser1177-eNOS and normalized the vasodilator reaction to acetylcholine .	eNOS has also a major role in EPO mediated vascular protection; EPO activation of EPOR increased expression of phosphorylated Ser1177-eNOS and normalized the vasodilator reaction to acetylcholine.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	12	13	15	16
EPOR is not directly regulated by HIF ; however , we and others have demonstrated that EPO induces EPOR expression XREF_BIBR XREF_BIBR .	EPOR is not directly regulated by HIF; however, we and others have demonstrated that EPO induces EPOR expression XREF_BIBR XREF_BIBR.	16	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	16	17	18	19
Assuming a hyperbolic binding curve for Epo , basal Epo levels ( 0.010-0.020 U/ml ) would occupy only 1 %-2% of the cell surface EpoR , and an Epo concentration of 0.1 U/ml , generating half the maximal p-Stat5 response , would increase EpoR occupancy to 10 % .	Assuming a hyperbolic binding curve for Epo, basal Epo levels (0.010-0.020 U/ml) would occupy only 1%-2% of the cell surface EpoR, and an Epo concentration of 0.1 U/ml, generating half the maximal p-Stat5 response, would increase EpoR occupancy to 10%.	28	44	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	28	29	43	44
A statistically significant positive correlation was observed between EpoR and Flt-1 expression in DLD-1 xenografts treated with Epo ( r = 0.688 , p = 0.028 ) , as well as between VEGF and Flt-1 expression in DLD-1 xenografts treated with Epo ( r = 0.734 , p = 0.016 ) .	A statistically significant positive correlation was observed between EpoR and Flt-1 expression in DLD-1 xenografts treated with Epo (r = 0.688, p = 0.028), as well as between VEGF and Flt-1 expression in DLD-1 xenografts treated with Epo (r = 0.734, p = 0.016).	8	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	17	18	8	9
We observed augmented phosphorylation of the mTOR downstream target 4EBP1 and activation of the p44/42 MAPK ( Erk1/2 ) signaling pathway upon EPO stimulation in EPOR rearranged PDX cells but not in Ba/F3 cells expressing truncated EPOR ( XREF_SUPPLEMENTARY ) , indicating these pathways may also be inhibited to reduce leukemic cell proliferation .	We observed augmented phosphorylation of the mTOR downstream target 4EBP1 and activation of the p44/42 MAPK (Erk1/2) signaling pathway upon EPO stimulation in EPOR rearranged PDX cells but not in Ba/F3 cells expressing truncated EPOR (XREF_SUPPLEMENTARY), indicating these pathways may also be inhibited to reduce leukemic cell proliferation.	22	26	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	22	23	25	26
Erythropoietin activates the erythropoietin receptor on immature red blood cell precursors to promote their survival and differentiation .	Erythropoietin activates the erythropoietin receptor on immature red blood cell precursors to promote their survival and differentiation.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erythropoietin	Erythropoietin	Erythropoietin	erythropoietin receptor	erythropoietin receptor	erythropoietin receptor	0	1	3	5
EPO administration elicited an early enhanced expression of EpoR 1day after TAI+ H x compared with a 7-day peak in vehicle controls .	EPO administration elicited an early enhanced expression of EpoR 1day after TAI+H x compared with a 7-day peak in vehicle controls.	0	9	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	0	1	8	9
Although Pyr41 protects Epo activated EpoR from proteasome degradation as efficiently as MLN or LLnL ( XREF_FIG B ) , Pim2 degradation was not modified by this inhibitor in the same UT7 cells ( XREF_FIG C ) .	Although Pyr41 protects Epo activated EpoR from proteasome degradation as efficiently as MLN or LLnL (XREF_FIG B), Pim2 degradation was not modified by this inhibitor in the same UT7 cells (XREF_FIG C).	2	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	3	4	5	6
EPO also enhanced the differentiation of neural progenitor cells expressing EpoR at high level toward the oligodendrocyte-lineage cells through activation of cyclin E and Janus kinase 2 pathways .	EPO also enhanced the differentiation of neural progenitor cells expressing EpoR at high level toward the oligodendrocyte-lineage cells through activation of cyclin E and Janus kinase 2 pathways.	0	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	0	1	10	11
However , in subcutaneous and visceral white primary adipocytes isolated from WT mice treated with EPO and from EpoR aP2KO mice , CS activity was affected by EPO and EpoR signaling , increasing in WT mice treated with EPO and decreasing in EpoR aP2KO mice with or without EPO treatment compared with WT control mice ( XREF_FIG ) .	However, in subcutaneous and visceral white primary adipocytes isolated from WT mice treated with EPO and from EpoR aP2KO mice, CS activity was affected by EPO and EpoR signaling, increasing in WT mice treated with EPO and decreasing in EpoR aP2KO mice with or without EPO treatment compared with WT control mice (XREF_FIG).	27	39	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	38	39	29	30
Moreover , we found that Epo increases the expression of Epo receptor ( EpoR ) in hBMSC but fails to induce EpoR in ST2 cells , although both cell types express EpoR at the same level ( Figs .	Moreover, we found that Epo increases the expression of Epo receptor (EpoR) in hBMSC but fails to induce EpoR in ST2 cells, although both cell types express EpoR at the same level (Figs.	5	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo increases the expression of Epo	epo	EpoR	EpoR	epor	5	6	21	22
EPO activates the EPOR to induce cellular signaling and block apoptosis [ XREF_BIBR , XREF_BIBR ] .	EPO activates the EPOR to induce cellular signaling and block apoptosis [XREF_BIBR, XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	0	1	3	4
This indicates that EPO might not only have an effect on erythroid progenitor cells , but also could induce EPO mediated survival signaling in other cells expressing the EPOR , including tumor cells .	This indicates that EPO might not only have an effect on erythroid progenitor cells, but also could induce EPO mediated survival signaling in other cells expressing the EPOR, including tumor cells.	18	29	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	19	20	28	29
These results indicate that both gp55 and Epo stimulate EpoR and that the Fv-2 gene encodes a protein that controls response to these ligands .	These results indicate that both gp55 and Epo stimulate EpoR and that the Fv-2 gene encodes a protein that controls response to these ligands.	5	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	7	8	9	10
It has been reported that EPO mediates the dimerization of EPOR via asymmetric binding , followed by the activation of a signaling pathway XREF_BIBR .	It has been reported that EPO mediates the dimerization of EPOR via asymmetric binding, followed by the activation of a signaling pathway XREF_BIBR.	5	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	5	6	10	11
Knockdown of Cbl , expression of its dominant negative forms , or expression of an epsin-1 mutant devoid of ubiquitin interacting motifs all compromise Epo induced EpoR internalization .	Knockdown of Cbl, expression of its dominant negative forms, or expression of an epsin-1 mutant devoid of ubiquitin interacting motifs all compromise Epo induced EpoR internalization.	22	27	induced	Positive_early_activation	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	24	25	26	27
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR EPO stimulates EpoR operated Ca 2+ channels in rat mesangial cells .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR EPO stimulates EpoR operated Ca 2+ channels in rat mesangial cells.	0	12	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	9	10	11	12
In mouse models of infection and colitis , EPO activation of EpoR on macrophages was reported to increase JAK2 signaling , inhibit NF-kappaB p65 signaling pathway and interfere with innate immune response resulting in increased deterioration of a Salmonella infection mouse model for sepsis but ameliorating chemically induced colitis in mice [ XREF_BIBR ] .	In mouse models of infection and colitis, EPO activation of EpoR on macrophages was reported to increase JAK2 signaling, inhibit NF-kappaB p65 signaling pathway and interfere with innate immune response resulting in increased deterioration of a Salmonella infection mouse model for sepsis but ameliorating chemically induced colitis in mice [XREF_BIBR].	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	8	9	11	12
We thus suggest that PTP1B dephosphorylates EPO stimulated EPO-R and participates in the down-regulation cascade of EPO mediated signal transduction .	We thus suggest that PTP1B dephosphorylates EPO stimulated EPO-R and participates in the down-regulation cascade of EPO mediated signal transduction.	5	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EPO	dephosphorylates EPO	epo	EPO-R	EPO-R	epo-r	6	7	8	9
One hypothesis is that Epo or exogenous ESAs could stimulate tumor growth by activating EpoR on endothelial cells to facilitate angiogenesis near tumors .	One hypothesis is that Epo or exogenous ESAs could stimulate tumor growth by activating EpoR on endothelial cells to facilitate angiogenesis near tumors.	4	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	4	5	14	15
We next asked whether the EPO induced increase in the chondrocyte proliferation was EPOR dependent by looking at the effect of EPO on the chondrocytes following EPOR knockdown .	We next asked whether the EPO induced increase in the chondrocyte proliferation was EPOR dependent by looking at the effect of EPO on the chondrocytes following EPOR knockdown.	4	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	5	6	13	14
Epo is a glycosylated cytokine that promotes erythropoiesis by binding and activating the cell membrane receptor EpoR .	Epo is a glycosylated cytokine that promotes erythropoiesis by binding and activating the cell membrane receptor EpoR.	0	17	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	0	1	16	17
Although it is unlikely that American ginseng exerts a similar effect in VSMCs since the activation of EpoR by Epo hardly affected Jak2 and Stat5 signaling in RASMCs , cell or tissue type specific actions of American ginseng extract need to be carefully dissected .	Although it is unlikely that American ginseng exerts a similar effect in VSMCs since the activation of EpoR by Epo hardly affected Jak2 and Stat5 signaling in RASMCs, cell or tissue type specific actions of American ginseng extract need to be carefully dissected.	7	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	19	20	17	18
Upon binding to its receptor , EPO triggers conformational changes in EPOR that activates the Janus family tyrosine protein kinase 2 ( JAK-2 ) and MAP kinase pathways , leading to downstream activation of ERK1/2 , PI3K and AKT , NFK-B , and STAT-5 [ XREF_BIBR ] .	Upon binding to its receptor, EPO triggers conformational changes in EPOR that activates the Janus family tyrosine protein kinase 2 (JAK-2) and MAP kinase pathways, leading to downstream activation of ERK1/2, PI3K and AKT, NFK-B, and STAT-5 [XREF_BIBR].	6	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	6	7	11	12
Local blockage of EPO signaling could suppress the growth of dual EPO and EPOR positive NSCLC tumor and prolong survivals of xenograft mice .	Local blockage of EPO signaling could suppress the growth of dual EPO and EPOR positive NSCLC tumor and prolong survivals of xenograft mice.	3	16	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	3	4	13	14
Erythropoietin does not activate erythropoietin receptor signaling or lipolytic pathways in human subcutaneous white adipose tissue in vivo .	Erythropoietin does not activate erythropoietin receptor signaling or lipolytic pathways in human subcutaneous white adipose tissue in vivo.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erythropoietin	Erythropoietin	Erythropoietin	erythropoietin receptor	erythropoietin receptor	erythropoietin receptor	0	1	4	6
EPO downregulated EPOR and vitamin C and upregulated EPOR .	EPO downregulated EPOR and vitamin C and upregulated EPOR.	0	7	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	0	1	2	3
In diabetic rats , intravitreal injection of EPO upregulated EPOR in the neurosensory retina and had a protective effect on vascular and photoreceptor cells [ XREF_BIBR ] .	In diabetic rats, intravitreal injection of EPO upregulated EPOR in the neurosensory retina and had a protective effect on vascular and photoreceptor cells [XREF_BIBR].	5	10	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	7	8	9	10
DFMO also caused G 0 / G 1 arrest of Epo stimulated EpoR cells and WT/EpoR cells , and spermidine counteracted the effect of DFMO ( XREF_FIG ) .	DFMO also caused G 0 / G 1 arrest of Epo stimulated EpoR cells and WT/EpoR cells, and spermidine counteracted the effect of DFMO (XREF_FIG).	8	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	10	11	12	13
The binding of Epo induces a conformational change in EpoR that brings the transmembrane and intracellular regions of the receptor in close proximity .	The binding of Epo induces a conformational change in EpoR that brings the transmembrane and intracellular regions of the receptor in close proximity.	1	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	3	4	9	10
As a result of viral transformation , these cells express the spleen focus forming env related glycoprotein gp55 , which can bind to the erythropoietin receptor ( EPO-R ) and mimics many aspects of EPO induced EPO-R signaling .	As a result of viral transformation, these cells express the spleen focus forming env related glycoprotein gp55, which can bind to the erythropoietin receptor (EPO-R) and mimics many aspects of EPO induced EPO-R signaling.	32	37	induced	Positive_early_activation	Positive_activation	Positive_activation	EPO	EPO	EPO	EPO-R	EPO-R	EPO-R	34	35	36	37
These alterations in metabolism and tumorigenicity caused by the EPOR with activating point mutations are similar to those observed in erythropoietin independent activation of the wild type EPOR by association with gp55 , the Friend spleen focus forming virus glycoprotein .	These alterations in metabolism and tumorigenicity caused by the EPOR with activating point mutations are similar to those observed in erythropoietin independent activation of the wild type EPOR by association with gp55, the Friend spleen focus forming virus glycoprotein.	20	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	erythropoietin	erythropoietin	erythropoietin	EPOR	EPOR	EPOR	20	21	27	28
In erythroid progenitor cells , Epo stimulates induction of transcription factor GATA-1 and EpoR ; in C2C12 cells , GATA-3 and EpoR expression are induced .	In erythroid progenitor cells, Epo stimulates induction of transcription factor GATA-1 and EpoR; in C2C12 cells, GATA-3 and EpoR expression are induced.	5	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	5	6	13	14
Erythropoietin stimulates angiogenesis in EpoR positive xenografts .	Erythropoietin stimulates angiogenesis in EpoR positive xenografts.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erythropoietin	Erythropoietin	Erythropoietin	EpoR	EpoR	EpoR	0	1	4	5
This result suggests that the neuroprotective effect of post-treated EPO on the GABAergic neurons can be related to the EPO mediated EpoR upregulation following KA-excitotoxicity .	This result suggests that the neuroprotective effect of post-treated EPO on the GABAergic neurons can be related to the EPO mediated EpoR upregulation following KA-excitotoxicity.	16	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	19	20	21	22
EPO mediated enhancement of EpoR and STAT3 and beta-adrenergic receptor/Mef2c/miR -133 pathways dramatically increases total uncoupling protein 1 ( UCP1 ) , an essential enzyme for BAT thermogenesis .	EPO mediated enhancement of EpoR and STAT3 and beta-adrenergic receptor/Mef2c/miR -133 pathways dramatically increases total uncoupling protein 1 (UCP1), an essential enzyme for BAT thermogenesis.	0	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	0	1	4	5
The gene expression analysis shows that EPO action increases EPO-R , while exercise stimulates myoglobin ( MB ) , probably due to the increased oxygen demand .	The gene expression analysis shows that EPO action increases EPO-R, while exercise stimulates myoglobin (MB), probably due to the increased oxygen demand.	6	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPO-R	EPO-R	EPO-R	6	7	9	10
One model suggests EPO induces dimerization of the EpoR and this is essential for signaling [ XREF_BIBR ] .	One model suggests EPO induces dimerization of the EpoR and this is essential for signaling [XREF_BIBR].	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	3	4	8	9
EPO can stimulate proliferation of myoblasts in culture through binding to EpoR to expand the progenitor population during differentiation and may have a potential role in muscle maintenance or repair [ XREF_BIBR , XREF_BIBR ] .	EPO can stimulate proliferation of myoblasts in culture through binding to EpoR to expand the progenitor population during differentiation and may have a potential role in muscle maintenance or repair [XREF_BIBR, XREF_BIBR].	0	21	stimulate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	0	1	11	12
However , EPO treatment not only reverted the number of EPOR+ endothelial cells , but also increased the intensity of EPOR signals .	However, EPO treatment not only reverted the number of EPOR+ endothelial cells, but also increased the intensity of EPOR signals.	2	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	2	3	20	21
In our study , we detected EPOR protein expression by immunofluorescence and and western blot in skeletal muscle isolated from type 2 diabetic mice , and systemic EPO stimulation activated EPOR protein , as confirmed by immunofluorescence and Western blot .	In our study, we detected EPOR protein expression by immunofluorescence and and western blot in skeletal muscle isolated from type 2 diabetic mice, and systemic EPO stimulation activated EPOR protein, as confirmed by immunofluorescence and Western blot.	27	31	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	27	28	30	31
These data are in accordance with previous reports demonstrating EPO mediated EPO-R endocytosis and internalization in various cell types XREF_BIBR - XREF_BIBR .	These data are in accordance with previous reports demonstrating EPO mediated EPO-R endocytosis and internalization in various cell types XREF_BIBR - XREF_BIBR.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	EPO	EPO	EPO	EPO-R	EPO-R	EPO-R	9	10	11	12
Together , these data suggest that paracrine and autocrine EPO contributes to patient outcome by stimulating EPOR present on GSCs .	Together, these data suggest that paracrine and autocrine EPO contributes to patient outcome by stimulating EPOR present on GSCs.	6	17	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	9	10	16	17
EPO tended to increase pEpoR and EpoR ratio under a high-fat diet ( XREF_FIG ) .	EPO tended to increase pEpoR and EpoR ratio under a high-fat diet (XREF_FIG).	0	7	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	pEpoR	pEpoR	pEpoR	0	1	4	5
In these studies we show that induction of EpoR signaling by either exogenous Epo treatment or over-expression of EpoR-R129C leads to the activation of MAP kinase pathway in MCF-7 breast cancer cells .	In these studies we show that induction of EpoR signaling by either exogenous Epo treatment or over-expression of EpoR-R129C leads to the activation of MAP kinase pathway in MCF-7 breast cancer cells.	8	14	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	13	14	8	9
Moreover , they demonstrated time- and concentration dependent manner of EPO induced MCF-7 proliferation and EGR1 , FOS , and EPOR as transcription targets of the EPO-EPOR signaling loop .	Moreover, they demonstrated time- and concentration dependent manner of EPO induced MCF-7 proliferation and EGR1, FOS, and EPOR as transcription targets of the EPO-EPOR signaling loop.	8	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	10	11	20	21
Also , we observed a significant difference in EpoR expression in DLD-1 xenografts treated with Epo compared with Ht-29 xenografts .	Also, we observed a significant difference in EpoR expression in DLD-1 xenografts treated with Epo compared with Ht-29 xenografts.	8	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	15	16	8	9
We observed that EPO ( 5 U/ml ) induced EPOR mRNA in lung endothelial cells at normal oxygen tension ( XREF_FIG ) .	We observed that EPO (5 U/ml) induced EPOR mRNA in lung endothelial cells at normal oxygen tension (XREF_FIG).	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	3	4	9	10
Next , we asked whether mutation of the F595 residue to Ala , Lys , Val or Ile critically influenced the ability of wild-type JAK2 or of JAK2 V617F to respond to Epo activated EpoR .	Next, we asked whether mutation of the F595 residue to Ala, Lys, Val or Ile critically influenced the ability of wild-type JAK2 or of JAK2 V617F to respond to Epo activated EpoR.	30	35	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	32	33	34	35
XREF_BIBR In vitro studies show that peginesatide and human recombinant erythropoietin activate similar erythropoietin receptor mediated pathways , leading to proliferation and differentiation of erythroid progenitor cells .	XREF_BIBR In vitro studies show that peginesatide and human recombinant erythropoietin activate similar erythropoietin receptor mediated pathways, leading to proliferation and differentiation of erythroid progenitor cells.	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	erythropoietin	erythropoietin	erythropoietin	erythropoietin receptor	erythropoietin receptor	erythropoietin receptor	10	11	13	15
Western blotting showed that EPO treatment of HMVEC-L , under hypoxic condition , induced the EPOR protein more than three fold compared to cultures at 21 % O 2 with and without EPO ( XREF_FIG ) .	Western blotting showed that EPO treatment of HMVEC-L, under hypoxic condition, induced the EPOR protein more than three fold compared to cultures at 21% O 2 with and without EPO (XREF_FIG).	4	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	4	5	15	16
In summary , we found that : 1 ) EPO facilitates energy expenditure by increasing classical BAT mass ; 2 ) EPO stimulates EpoR and STAT3 and beta-adrenergic receptor/Mef2c/miR -133 pathways , resulting in enhancement of PRDM16 of classical BAT ; 3 ) EPO promoted secretion of classical BAT ' s derived-FGF21 ; and 4 ) EPO ameliorated obesity and glucose homeostasis in high-fat diet induced obese mice .	In summary, we found that : 1) EPO facilitates energy expenditure by increasing classical BAT mass; 2) EPO stimulates EpoR and STAT3 and beta-adrenergic receptor/Mef2c/miR -133 pathways, resulting in enhancement of PRDM16 of classical BAT; 3) EPO promoted secretion of classical BAT 's derived-FGF21; and 4) EPO ameliorated obesity and glucose homeostasis in high-fat diet induced obese mice.	21	28	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	21	22	23	24
While the erythropoietic action of EPO is mediated by the homodimeric EPO receptor ( EPOR 2 ) , EPO also activates a heterodimeric EPOR and beta-common receptor ( betaCR ) , which is believed to be responsible for the tissue protective effects of EPO ( Leist etal .	While the erythropoietic action of EPO is mediated by the homodimeric EPO receptor (EPOR 2), EPO also activates a heterodimeric EPOR and beta-common receptor (betaCR), which is believed to be responsible for the tissue protective effects of EPO (Leist etal.	18	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	18	19	23	24
For example , erythropoietin ( EPO ) stimulates erythropoietin receptor ( EPOR )-JAK2-STAT5 signaling , which is responsible for cell proliferation and terminal differentiation into mature , oxygen carrying red blood cells [ XREF_BIBR , XREF_BIBR ] .	For example, erythropoietin (EPO) stimulates erythropoietin receptor (EPOR)-JAK2-STAT5 signaling, which is responsible for cell proliferation and terminal differentiation into mature, oxygen carrying red blood cells [XREF_BIBR, XREF_BIBR].	3	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	erythropoietin receptor	erythropoietin receptor	erythropoietin receptor	5	6	8	10
Epo mediated tissue protection under conditions such as hypoxia occurs in an EpoR independent manner .	Epo mediated tissue protection under conditions such as hypoxia occurs in an EpoR independent manner.	0	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	0	1	12	13
More recently , another erythropoietin related molecule has been produced called Continuous Erythropoietin Receptor Activator with an even greater half-life , and other molecules are in development or are being licensed , including biosimilar epoetin products and Hematide .	More recently, another erythropoietin related molecule has been produced called Continuous Erythropoietin Receptor Activator with an even greater half-life, and other molecules are in development or are being licensed, including biosimilar epoetin products and Hematide.	4	14	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	erythropoietin	erythropoietin	erythropoietin	Erythropoietin Receptor	Erythropoietin Receptor	Erythropoietin Receptor	4	5	12	14
In addition , EPO and F-gp55 stimulation of the EPO-R elicit different biological responses .	In addition, EPO and F-gp55 stimulation of the EPO-R elicit different biological responses.	3	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EPO	EPO	EPO	EPO-R	EPO-R	EPO-R	3	4	9	10
Even more interestingly , EPO accelerated the tumor growth of MMQ pituitary adenoma xenografts lacking EPOR via enhancement of angiogenesis in vivo , without a direct EPO effect on MMQ cells in vitro .	Even more interestingly, EPO accelerated the tumor growth of MMQ pituitary adenoma xenografts lacking EPOR via enhancement of angiogenesis in vivo, without a direct EPO effect on MMQ cells in vitro.	4	17	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	4	5	15	16
For example , several years of research from multiple laboratories suggested that erythropoietin activates the erythropoietin receptor ( EpoR ) in tumor cells ; a follow-up study , however , showed that only one of the four EpoR antibodies used in these studies detected EpoR and none of the four antibodies were suitable for immunohistochemistry .	For example, several years of research from multiple laboratories suggested that erythropoietin activates the erythropoietin receptor (EpoR) in tumor cells; a follow-up study, however, showed that only one of the four EpoR antibodies used in these studies detected EpoR and none of the four antibodies were suitable for immunohistochemistry.	12	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	erythropoietin	erythropoietin	erythropoietin	erythropoietin receptor	erythropoietin receptor	erythropoietin receptor	12	13	15	17
In endothelial cell cultures , EPO upregulated EPOR and increased endothelial cell sensitivity and response to EPO .	In endothelial cell cultures, EPO upregulated EPOR and increased endothelial cell sensitivity and response to EPO.	5	9	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	5	6	7	8
We explored the biological activity of these peptides using EpoR reporter cells we developed that gave us the ability to test EpoR signaling by receptor phosphorylation , but importantly , also using a beta-galactosidase complementation system that is a sensitive reporter of EPO induced EpoR oligomerization in physiologic conditions at 37 degreesC , which directly informs on early signaling and internalization .	We explored the biological activity of these peptides using EpoR reporter cells we developed that gave us the ability to test EpoR signaling by receptor phosphorylation, but importantly, also using a beta-galactosidase complementation system that is a sensitive reporter of EPO induced EpoR oligomerization in physiologic conditions at 37 degreesC, which directly informs on early signaling and internalization.	40	45	induced	Positive_early_activation	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	42	43	44	45
As predicted , S1P controlled EPO expression through activation of HIF1alpha , but EPOR was shown to be upregulated by EPO itself as part of a positive feedback loop .	As predicted, S1P controlled EPO expression through activation of HIF1alpha, but EPOR was shown to be upregulated by EPO itself as part of a positive feedback loop.	4	21	upregulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	20	21	13	14
Erythropoietin induces dimerization of the erythropoietin receptor on the surface of erythroid progenitor cells , promoting the differentiation of these cells into mature red blood cells .	Erythropoietin induces dimerization of the erythropoietin receptor on the surface of erythroid progenitor cells, promoting the differentiation of these cells into mature red blood cells.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erythropoietin	Erythropoietin	Erythropoietin	erythropoietin receptor	erythropoietin receptor	erythropoietin receptor	0	1	5	7
The common drug targeting EpoR , recombinant erythropoietin ( produced by Amgen and Janssen ) , has historically been the highest-expenditure drug by Medicare .	The common drug targeting EpoR, recombinant erythropoietin (produced by Amgen and Janssen), has historically been the highest-expenditure drug by Medicare.	2	9	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	erythropoietin	erythropoietin	erythropoietin	EpoR	EpoR	EpoR	7	8	4	5
It is possible that EPO stimulates other EPOR expressing cell type ( s ) , thereby indirectly promoting the survival of oligodendrocytes .	It is possible that EPO stimulates other EPOR expressing cell type (s), thereby indirectly promoting the survival of oligodendrocytes.	4	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	4	5	7	8
Thus EPO can induce EPOR dependent activation of the AKT signaling pathway in MDA-MB-231 cells .	Thus EPO can induce EPOR dependent activation of the AKT signaling pathway in MDA-MB-231 cells.	1	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	1	2	4	5
In hematopoietic cells , EPO activates the EpoR homodimer to induce downstream signaling and block apoptosis .	In hematopoietic cells, EPO activates the EpoR homodimer to induce downstream signaling and block apoptosis.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	4	5	7	8
Moreover , erythropoietin pretreatment could further activate the PI3K and Akt signalling and induced EPOR activity .	Moreover, erythropoietin pretreatment could further activate the PI3K and Akt signalling and induced EPOR activity.	2	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	erythropoietin	erythropoietin	erythropoietin	EPOR	EPOR	EPOR	2	3	14	15
In the present study , we have identified a cellular context ( the interleukin-2 [ IL-2 ]-dependent HT-2 line ) in which the EPO stimulation of the EPOR fails to support cellular proliferation , STAT-5 induction , or MAPK activation , despite efficient phosphorylation of the EPOR and JAK2 and inhibition of apoptosis after withdrawal of IL-2 .	In the present study, we have identified a cellular context (the interleukin-2 [IL-2]-dependent HT-2 line) in which the EPO stimulation of the EPOR fails to support cellular proliferation, STAT-5 induction, or MAPK activation, despite efficient phosphorylation of the EPOR and JAK2 and inhibition of apoptosis after withdrawal of IL-2.	23	28	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	23	24	27	28
EPO increased VEGF and EPOR mRNA and protein expression in diabetic myocardial tissue .	EPO increased VEGF and EPOR mRNA and protein expression in diabetic myocardial tissue.	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	0	1	4	5
The results of this study , together with those of previous reports , further demonstrate that EPOR can be induced by EPO XREF_BIBR XREF_BIBR , which could enhance the sensitivity of the macrophage EPOR to local EPO .	The results of this study, together with those of previous reports, further demonstrate that EPOR can be induced by EPO XREF_BIBR XREF_BIBR, which could enhance the sensitivity of the macrophage EPOR to local EPO.	16	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	21	22	16	17
EPO induced intracellular signaling in erythroid progenitor and precursor cells is mediated via EPOR homodimerization triggered by picomolar concentrations of EPO .	EPO induced intracellular signaling in erythroid progenitor and precursor cells is mediated via EPOR homodimerization triggered by picomolar concentrations of EPO.	13	21	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	20	21	13	14
Notably , without ligand present , unbound EPOR triggers neural cell death and exogenous EPO restores balanced EPOR signaling supporting neural cell development .	Notably, without ligand present, unbound EPOR triggers neural cell death and exogenous EPO restores balanced EPOR signaling supporting neural cell development.	11	18	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	14	15	17	18
In visceral epididymal white adipocytes , cells from EPO treated WT mice only showed increased expression of Ucp3 , Pparalpha , and Pgc-1alpha , and the expression of these genes was reduced in adipocytes from EpoR aP2KO mice and remained unchanged in EpoR aP2KO mice treated with EPO ( XREF_FIG ) .	In visceral epididymal white adipocytes, cells from EPO treated WT mice only showed increased expression of Ucp3, Pparalpha, and Pgc-1alpha, and the expression of these genes was reduced in adipocytes from EpoR aP2KO mice and remained unchanged in EpoR aP2KO mice treated with EPO (XREF_FIG).	42	49	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	47	48	42	43
We found that EPO caused a downregulation of GSK-3beta and an upregulation of EPOR , PI3K and p-Akt2 and Akt2 , and eventually led to improvements in the learning and memory deficits of diabetic rats , cell damage and oxidative stress .	We found that EPO caused a downregulation of GSK-3beta and an upregulation of EPOR, PI3K and p-Akt2 and Akt2, and eventually led to improvements in the learning and memory deficits of diabetic rats, cell damage and oxidative stress.	3	23	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	3	4	13	14
Also , an increased expression of EpoR has been reported in ischemic brain regions in animals treated with different doses of Epo ( Yu et al ., 2005 ; Castaneda-Arellano et al ., 2014 ) .	Also, an increased expression of EpoR has been reported in ischemic brain regions in animals treated with different doses of Epo (Yu et al., 2005; Castaneda-Arellano et al., 2014).	4	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	21	22	6	7
EPO can stimulate proliferation of myoblasts in culture through binding to EpoR to expand the progenitor population during differentiation and may have a potential role in muscle maintenance or repair .	EPO can stimulate proliferation of myoblasts in culture through binding to EpoR to expand the progenitor population during differentiation and may have a potential role in muscle maintenance or repair.	0	21	stimulate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	0	1	11	12
Erythropoietin ( Epo ) , a known hematopoietic growth factor , has been reported to promote tumor growth and angiogenesis in Epo receptor ( EpoR )-positive tumors , but its effects on EpoR negative tumors have not been clearly shown .	Erythropoietin (Epo), a known hematopoietic growth factor, has been reported to promote tumor growth and angiogenesis in Epo receptor (EpoR)-positive tumors, but its effects on EpoR negative tumors have not been clearly shown.	0	26	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erythropoietin	Erythropoietin	Erythropoietin	EpoR	EpoR	EpoR	0	1	24	25
Importantly , HER2-EGFR heterodimers have prolonged signaling compared to EGFR homodimers because HER2 induces recycling of its EGFR binding partner as opposed to degradation , thereby relieving negative feedback at the level of receptor internalization .	Importantly, HER2-EGFR heterodimers have prolonged signaling compared to EGFR homodimers because HER2 induces recycling of its EGFR binding partner as opposed to degradation, thereby relieving negative feedback at the level of receptor internalization.	12	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	12	13	17	18
We previously showed that ErbB2 expression causes constitutive EGF signalling by retarding downregulation of hetero-oligomerised EGFR ( Huang et al , 1999 ) .	We previously showed that ErbB2 expression causes constitutive EGF signalling by retarding downregulation of hetero-oligomerised EGFR (Huang et al, 1999).	4	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2 expression	erbb2	EGFR	EGFR	egfr	4	5	15	16
Thus , HER2 is the preferred partner for all of the HER family members , including EGFR , and is able to regulate and diversify EGFR downstream signaling ; in addition , EGFR mitotic signals can be augmented by the coexpression of HER2 .	Thus, HER2 is the preferred partner for all of the HER family members, including EGFR, and is able to regulate and diversify EGFR downstream signaling; in addition, EGFR mitotic signals can be augmented by the coexpression of HER2.	32	43	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HER2	coexpression of HER2	her2	EGFR	EGFR	egfr	42	43	32	33
In terms of trafficking processes , HER2 overexpression reduces the EGFR internalization rate constant and increases the fraction of EGFR recycled .	In terms of trafficking processes, HER2 overexpression reduces the EGFR internalization rate constant and increases the fraction of EGFR recycled.	6	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2 overexpression	her2	EGFR	EGFR	egfr	6	7	19	20
Activated ( p ) tyr 1248 Her-2 and neu was detected in 9 of 46 breast cancers ( 20 % ) , and activated ( p ) tyr 845 and ( p ) tyr 1173 EGFR were both present in 6 tumors ( 13 % ) while EGFR was present in 16 cases ( 35 % ) .	Activated (p) tyr 1248 Her-2 and neu was detected in 9 of 46 breast cancers (20%), and activated (p) tyr 845 and (p) tyr 1173 EGFR were both present in 6 tumors (13%) while EGFR was present in 16 cases (35%).	6	36	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neu	neu	neu	EGFR	EGFR	EGFR	8	9	35	36
Perhaps not by coincidence , it was observed that ErbB2 blocks lysosomal EGFR degradation by activating Mek [ XREF_BIBR ] .	Perhaps not by coincidence, it was observed that ErbB2 blocks lysosomal EGFR degradation by activating Mek [XREF_BIBR].	9	13	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	9	10	12	13
Three humanized mAbs targeting this family of receptors have been approved for clinical use , trastuzumab which targets HER2 and cetuximab or panitumumab which target the EGFR .	Three humanized mAbs targeting this family of receptors have been approved for clinical use, trastuzumab which targets HER2 and cetuximab or panitumumab which target the EGFR.	17	27	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	18	19	26	27
HER2 enriched tumors do not express HR , but overexpress human epidermal growth factor receptor 2 ( HER2 ) .	HER2 enriched tumors do not express HR, but overexpress human epidermal growth factor receptor 2 (HER2).	0	17	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	11	15
Moreover , ErbB2 expression may increase EGFR recycling to the membrane and prevent its degradation , a process that may also make a significant contribution to ErbB2 function .	Moreover, ErbB2 expression may increase EGFR recycling to the membrane and prevent its degradation, a process that may also make a significant contribution to ErbB2 function.	2	7	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2 expression	erbb2	EGFR	EGFR	egfr	2	3	6	7
Therefore , the dynamics of EGF induced Y1068F-EGFR processing resembles HER2 overexpression induced EGFR recycling .	Therefore, the dynamics of EGF induced Y1068F-EGFR processing resembles HER2 overexpression induced EGFR recycling.	10	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2 overexpression	her2	EGFR	EGFR	egfr	10	11	13	14
The differences in EGF consumption rate among the three HMEC lines clearly imply that the presence of HER2 or HER3 accelerates HER1 ligand consumption .	The differences in EGF consumption rate among the three HMEC lines clearly imply that the presence of HER2 or HER3 accelerates HER1 ligand consumption.	15	23	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER1	HER1	HER1	17	18	21	22
Rather , HER2 promotes the sorting of EGFR and itself to Rab11 positive ( recycling ) while suppressing sorting to LAMP1 positive ( lysosome targeting ) endosomes , which is consistent with enhanced receptor recycling ( Figs .	Rather, HER2 promotes the sorting of EGFR and itself to Rab11 positive (recycling) while suppressing sorting to LAMP1 positive (lysosome targeting) endosomes, which is consistent with enhanced receptor recycling (Figs.	2	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	2	3	7	8
In addition , co-activation of ErbB2 and the TGF-beta receptor in MCF-10As causes secretion of EGF receptor dependent factors that stimulate migration [ XREF_BIBR ] .	In addition, co-activation of ErbB2 and the TGF-beta receptor in MCF-10As causes secretion of EGF receptor dependent factors that stimulate migration [XREF_BIBR].	3	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	EGF receptor	EGF receptor	EGF receptor	5	6	15	17
The response to current anti-EGFR therapy can be modified by factors such as : the type of somatic EGFR mutations , EGFR gene amplification , increased autocrine EGFR ligands , and mutations in EGFR signaling pathway proteins ERBB2 , K-RAS , B-RAF , PI3KCA , PTEN , and BIM .	The response to current anti-EGFR therapy can be modified by factors such as : the type of somatic EGFR mutations, EGFR gene amplification, increased autocrine EGFR ligands, and mutations in EGFR signaling pathway proteins ERBB2, K-RAS, B-RAF, PI3KCA, PTEN, and BIM.	25	48	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	EGFR	EGFR	EGFR	37	38	33	34
The examples include estrogen and progesterone receptor status determination for the use of endocrine therapy , HER2 assessment for the administration of HER2 targeting agents , EGFR and ALK gene testing for lung cancer treatment , BRAF analysis in melanoma , etc ..	The examples include estrogen and progesterone receptor status determination for the use of endocrine therapy, HER2 assessment for the administration of HER2 targeting agents, EGFR and ALK gene testing for lung cancer treatment, BRAF analysis in melanoma, etc..	20	30	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	22	23	26	27
The ' HER2 positive ' subtype of breast cancer overexpresses the human epidermal growth factor receptor 2 ( HER2 ) .	The ' HER2 positive ' subtype of breast cancer overexpresses the human epidermal growth factor receptor 2 (HER2).	2	18	overexpresses	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	2	3	12	16
The Luminal subtype is characterized by the expression of estrogen and/or progesterone receptors ( ER and PR , respectively ) ; HER2 enriched overexpresses HER2 and neu ( human epidermal growth factor receptor 2 ) ; and TNBC shows negative expression for ER , PR and HER2 [ XREF_BIBR , XREF_BIBR ] .	The Luminal subtype is characterized by the expression of estrogen and/or progesterone receptors (ER and PR, respectively); HER2 enriched overexpresses HER2 and neu (human epidermal growth factor receptor 2); and TNBC shows negative expression for ER, PR and HER2 [XREF_BIBR, XREF_BIBR].	21	33	overexpresses	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	21	22	29	33
Clinical examples of this include HER2 targeted treatments of breast cancer , inhibitors of BRAF in melanoma , or antagonists of the epidermal growth factor receptor ( EGFR ) and its tyrosine kinase in lung cancer , to cite a few of many possible ones .	Clinical examples of this include HER2 targeted treatments of breast cancer, inhibitors of BRAF in melanoma, or antagonists of the epidermal growth factor receptor (EGFR) and its tyrosine kinase in lung cancer, to cite a few of many possible ones.	4	26	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	5	6	22	26
Specifically , ErbB-2 dimerization with ErbB-1 increases the affinity for binding of epidermal growth factor ( EGF ) to ErbB-1 , and the binding of EGF to ErbB-1 subsequently increases the activation of ErbB-2 .	Specifically, ErbB-2 dimerization with ErbB-1 increases the affinity for binding of epidermal growth factor (EGF) to ErbB-1, and the binding of EGF to ErbB-1 subsequently increases the activation of ErbB-2.	2	20	increases	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ErbB-2	ErbB-2	ErbB-2	ErbB-1	ErbB-1	ErbB-1	2	3	19	20
Therefore , our data suggest that the reduction in HER2 Thr701 phosphorylation by ERK inhibition may specifically inhibit CME of EGFR through increasing the clathrin binding and sequestering by HER2 , and thereby enhances the retention of EGFR at plasma membrane for the dimerization with HER2 , explaining the sustained and augmented Akt activity in response to the treatment with MEK inhibitor .	Therefore, our data suggest that the reduction in HER2 Thr701 phosphorylation by ERK inhibition may specifically inhibit CME of EGFR through increasing the clathrin binding and sequestering by HER2, and thereby enhances the retention of EGFR at plasma membrane for the dimerization with HER2, explaining the sustained and augmented Akt activity in response to the treatment with MEK inhibitor.	9	21	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2 Thr701 phosphorylation	her2	EGFR	EGFR	egfr	9	10	20	21
Since it is the preferred dimerisation partner of the other members of the family , a higher concentration of ERBB2 protein probably increases EGFR signalling .	Since it is the preferred dimerisation partner of the other members of the family, a higher concentration of ERBB2 protein probably increases EGFR signalling.	19	24	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	EGFR	EGFR	EGFR	19	20	23	24
In addition , ErbB2 heterodimers were determined to enhance the mitogenic signal of ErbB1 and ErbB3 [ XREF_BIBR ] .	In addition, ErbB2 heterodimers were determined to enhance the mitogenic signal of ErbB1 and ErbB3 [XREF_BIBR].	3	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB1	ErbB1	ErbB1	3	4	13	14
Constitutive activation of PI3K pathway by PTEN mutation and loss or PIK3CA mutation could render tumor cells independent of RTKs for malignant transformation and maintenance , which leads to resistance to HER2 targeted therapies in BC and EGFR targeted therapies in glioma [ XREF_BIBR - XREF_BIBR ] .	Constitutive activation of PI3K pathway by PTEN mutation and loss or PIK3CA mutation could render tumor cells independent of RTKs for malignant transformation and maintenance, which leads to resistance to HER2 targeted therapies in BC and EGFR targeted therapies in glioma [XREF_BIBR - XREF_BIBR].	27	38	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	31	32	37	38
This might be due to the fact that EGFR can be activated by ErbB2 since it is its main partner .	This might be due to the fact that EGFR can be activated by ErbB2 since it is its main partner.	8	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	13	14	8	9
Amplification of ErbB-2 , then , would be predicted to increase the fraction of EGFR in heterodimers upon activation , decrease the degradation of the activated EGFR , and increase the potency of the signal upon ligand binding .	Amplification of ErbB-2, then, would be predicted to increase the fraction of EGFR in heterodimers upon activation, decrease the degradation of the activated EGFR, and increase the potency of the signal upon ligand binding.	0	27	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB-2	ErbB-2	ErbB-2	EGFR	EGFR	EGFR	2	3	26	27
Since genetic activation of therapy targets such as ABL , C-KIT , Her2 and neu , and EGFR has been successfully demonstrated to be essential for treatment response [ XREF_BIBR ] , our finding of 5p gene targets such as RNASEN , SKP2 , and OSMR emphasize the need for functional analysis and dissecting signaling cascades involving these genes in ultimately obtaining therapeutic targets needed for cure and prevention of this devastating cancer .	Since genetic activation of therapy targets such as ABL, C-KIT, Her2 and neu, and EGFR has been successfully demonstrated to be essential for treatment response [XREF_BIBR], our finding of 5p gene targets such as RNASEN, SKP2, and OSMR emphasize the need for functional analysis and dissecting signaling cascades involving these genes in ultimately obtaining therapeutic targets needed for cure and prevention of this devastating cancer.	2	18	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	neu	neu	neu	EGFR	EGFR	EGFR	14	15	17	18
Activating mutations in the EGFR are found in 25 % of non small cell lung carcinomas ( NSCLC ) , and ErbB2 amplifications in 20 % of metastatic breast cancer .	Activating mutations in the EGFR are found in 25% of non small cell lung carcinomas (NSCLC), and ErbB2 amplifications in 20% of metastatic breast cancer.	0	22	Activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	21	22	4	5
Furthermore , ErbB2 deficient cells overexpressing ErbB1 , -3 , or -4 show strong receptor activation , but impaired migration in response to EGF like peptides .	Furthermore, ErbB2 deficient cells overexpressing ErbB1, -3, or -4 show strong receptor activation, but impaired migration in response to EGF like peptides.	2	19	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB1	ErbB1	ErbB1	2	3	6	7
HER2 expression as a potential marker for response to therapy targeted to the EGFR .	HER2 expression as a potential marker for response to therapy targeted to the EGFR.	0	14	targeted	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	HER2	HER2 expression	her2	EGFR	EGFR	egfr	0	1	13	14
We found that amplification of erbB-2 caused constitutive activation of erbB-2 as well as ligand independent activation of the EGFR .	We found that amplification of erbB-2 caused constitutive activation of erbB-2 as well as ligand independent activation of the EGFR.	3	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	erbB-2	erbB-2	erbB-2	EGFR	EGFR	EGFR	5	6	19	20
Approximately 20-25 % of early-stage BCs over-express human epidermal growth factor receptor 2 ( HER2 ) and can be treated with HER2 targeted agents ( e.g ., trastuzumab and lapatinib ) .	Approximately 20-25% of early-stage BCs over-express human epidermal growth factor receptor 2 (HER2) and can be treated with HER2 targeted agents (e.g., trastuzumab and lapatinib).	8	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	21	22	8	12
These data suggest that these co-occurring mutations in ERBB2 and ERBB3 enhance ERBB signaling output which , in turn , can be blocked by neratinib .	These data suggest that these co-occurring mutations in ERBB2 and ERBB3 enhance ERBB signaling output which, in turn, can be blocked by neratinib.	6	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	ERBB	ERBB	ERBB	8	9	12	13
18 Indeed , a previous study showed that ERBB2 could slow the degradation of EGFR molecules that were bound to ligand .	18 Indeed, a previous study showed that ERBB2 could slow the degradation of EGFR molecules that were bound to ligand.	8	15	slow	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	EGFR	EGFR	EGFR	8	9	14	15
Because of its 3 EGF domains , MUC13 may influence expression , stabilization , recycling , and activation of EGF receptors , such as HER2 , which in turn may modulate the EGF receptor cascade and its downstream signaling .	Because of its 3 EGF domains, MUC13 may influence expression, stabilization, recycling, and activation of EGF receptors, such as HER2, which in turn may modulate the EGF receptor cascade and its downstream signaling.	17	34	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGF receptor	EGF receptor	EGF receptor	24	25	32	34
These drugs include the HER2 targeted monoclonal antibodies Trastuzumab [ XREF_BIBR - XREF_BIBR ] and Pertuzumab [ XREF_BIBR - XREF_BIBR ] and the HER2 and Epidermal Growth Factor Receptor ( EGFR and HER1 ) tyrosine kinase inhibitor Lapatinib [ XREF_BIBR - XREF_BIBR ] .	These drugs include the HER2 targeted monoclonal antibodies Trastuzumab [XREF_BIBR - XREF_BIBR] and Pertuzumab [XREF_BIBR - XREF_BIBR] and the HER2 and Epidermal Growth Factor Receptor (EGFR and HER1) tyrosine kinase inhibitor Lapatinib [XREF_BIBR - XREF_BIBR].	2	33	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER1	HER1	HER1	4	5	32	33
This enhanced EGFR signaling was rather caused by erbB2 mediated retention of phosphorylated EGFR at the plasma membrane ( PM ) , thereby preventing EGFR dephosphorylation and signal termination by endomembrane bound protein tyrosine phosphatases ( PTPs ) .	This enhanced EGFR signaling was rather caused by erbB2 mediated retention of phosphorylated EGFR at the plasma membrane (PM), thereby preventing EGFR dephosphorylation and signal termination by endomembrane bound protein tyrosine phosphatases (PTPs).	2	9	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	erbB2	erbB2	erbB2	EGFR	EGFR	EGFR	8	9	2	3
Patients that express ERalpha can be successfully treated with antiestrogens and aromatase inhibitors , and more aggressive tumors that overexpress the epidermal growth factor receptor 2 ( ErbB2 ) oncogene can be treated with the ErbB2 neutralizing antibody in combination therapies [ XREF_BIBR ] .	Patients that express ERalpha can be successfully treated with antiestrogens and aromatase inhibitors, and more aggressive tumors that overexpress the epidermal growth factor receptor 2 (ErbB2) oncogene can be treated with the ErbB2 neutralizing antibody in combination therapies [XREF_BIBR].	21	37	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	35	36	21	25
Among the remaining learned activations with lower edge weights , the activations of ERBB1 by ERBB2 and vice versa are worth mentioning , since the two kinases are known to form heterodimers XREF_BIBR , XREF_BIBR .	Among the remaining learned activations with lower edge weights, the activations of ERBB1 by ERBB2 and vice versa are worth mentioning, since the two kinases are known to form heterodimers XREF_BIBR, XREF_BIBR.	11	17	activations	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	ERBB1	ERBB1	ERBB1	15	16	13	14
For example , the HER2 targeting drug Lapatinib also targets EGFR and could thus be considered beneficial in the two patients who expressed both HER2 and EGFR in close proximity to progression .	For example, the HER2 targeting drug Lapatinib also targets EGFR and could thus be considered beneficial in the two patients who expressed both HER2 and EGFR in close proximity to progression.	3	15	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	4	5	10	11
We examined whether lapatinib which binds both HER2 and EGFR could induce depletion of the EGFR positive pool of CTCs , which may in turn lead to clinical benefits .	We examined whether lapatinib which binds both HER2 and EGFR could induce depletion of the EGFR positive pool of CTCs, which may in turn lead to clinical benefits.	6	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	7	8	15	16
The HER2 positive BT-474 breast cancer cell line overexpressing SHP2 [ XREF_BIBR ] and the MCF-10A cells and MEFs ectopically overexpressing HER2 and EGFR were used as positive controls , while parental MCF-10A cells and MEFs as well as HMLE cells were used as negative controls for overexpression .	The HER2 positive BT-474 breast cancer cell line overexpressing SHP2 [XREF_BIBR] and the MCF-10A cells and MEFs ectopically overexpressing HER2 and EGFR were used as positive controls, while parental MCF-10A cells and MEFs as well as HMLE cells were used as negative controls for overexpression.	0	25	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2 positive BT-474 breast cancer cell line overexpressing	her2	EGFR	EGFR	egfr	1	2	23	24
As targeting moieties we used three IgG antibodies ; trastuzumab and chFRP5 that target ErbB2 and cetuximab that target the EGFR .	As targeting moieties we used three IgG antibodies; trastuzumab and chFRP5 that target ErbB2 and cetuximab that target the EGFR.	13	21	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	14	15	20	21
Evidence suggests that HER2 acts as the preferred dimerization partner for other family members as well , and could even enhance EGFR mediated signaling [ XREF_BIBR - XREF_BIBR ] .	Evidence suggests that HER2 acts as the preferred dimerization partner for other family members as well, and could even enhance EGFR mediated signaling [XREF_BIBR - XREF_BIBR].	3	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	3	4	21	22
These data represent the first identification of an ERBB2 specific signaling activity in an ERBB heterodimer context .	These data represent the first identification of an ERBB2 specific signaling activity in an ERBB heterodimer context.	8	16	signaling activity	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	ERBB	ERBB	ERBB	8	9	14	15
For example , this model was used to show that the small molecule tyrosine kinase inhibitors lapatinib that targets both ErbB2 and EGFR and gefitinib that targets EGFR inhibited mammary tumorigenesis .	For example, this model was used to show that the small molecule tyrosine kinase inhibitors lapatinib that targets both ErbB2 and EGFR and gefitinib that targets EGFR inhibited mammary tumorigenesis.	18	28	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	20	21	27	28
The data presented here suggest that EGFR activation and thereby the activation of downstream signaling cascades can only be prevented by combined inhibition of ERBB2 and EGFR in ERBB2 positive breast cancer with high-level expression of EGFR .	The data presented here suggest that EGFR activation and thereby the activation of downstream signaling cascades can only be prevented by combined inhibition of ERBB2 and EGFR in ERBB2 positive breast cancer with high-level expression of EGFR.	6	26	prevented	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	EGFR	EGFR	EGFR	24	25	6	7
Advanced or metastatic breast cancer is an incurable disease with high mortality rate worldwide and about 20 % of breast cancers overexpress and amplify the human epidermal growth factor receptor 2 ( HER2 ) .	Advanced or metastatic breast cancer is an incurable disease with high mortality rate worldwide and about 20% of breast cancers overexpress and amplify the human epidermal growth factor receptor 2 (HER2).	21	33	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	32	33	26	30
Elevated levels of HER2 or HER3 expression increased HER1 ligand secretion , suggesting an increase in the autocrine positive feedback loop that is associated with HER1 activation .	Elevated levels of HER2 or HER3 expression increased HER1 ligand secretion, suggesting an increase in the autocrine positive feedback loop that is associated with HER1 activation.	3	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2 or HER3 expression	her2	HER1	HER1	her1	3	4	8	9
EGFR : ERBB2 heterodimers more potently activate EGFR tyrosine kinase than do EGFR homodimers .	EGFR : ERBB2 heterodimers more potently activate EGFR tyrosine kinase than do EGFR homodimers.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	EGFR	EGFR	EGFR	2	3	7	8
Interestingly , ErbB2 deficient cells overexpressing ErbB1 showed a moderate level of ligand induced migration , although it was not as prominent as cells with functional ErbB2 receptors ( XREF_FIG C ) .	Interestingly, ErbB2 deficient cells overexpressing ErbB1 showed a moderate level of ligand induced migration, although it was not as prominent as cells with functional ErbB2 receptors (XREF_FIG C).	2	7	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB1	ErbB1	ErbB1	2	3	6	7
As HER2 overexpression is found to potentiate EGFR signalling , dual inhibition of these two receptors is considered to be of great potential clinical interest .	As HER2 overexpression is found to potentiate EGFR signalling, dual inhibition of these two receptors is considered to be of great potential clinical interest.	1	8	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2 overexpression	her2	EGFR	EGFR	egfr	1	2	7	8
Thus ErbB2 is a modulator of ErbB1 ( or 4 ) function leading to different MAPK response profiles to GF or radiation exposure .	Thus ErbB2 is a modulator of ErbB1 (or 4) function leading to different MAPK response profiles to GF or radiation exposure.	1	7	is a modulator	Positive_activation_copula_1	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB1	ErbB1	ErbB1	1	2	6	7
Patients with breast cancer whose tumors test positive for human epidermal growth factor receptor 2 ( HER2 ) are treated with HER2 targeted therapies such as trastuzumab , but limitations with HER2 testing may lead to false positive ( FP ) or false negative ( FN ) results .	Patients with breast cancer whose tumors test positive for human epidermal growth factor receptor 2 (HER2) are treated with HER2 targeted therapies such as trastuzumab, but limitations with HER2 testing may lead to false positive (FP) or false negative (FN) results.	10	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	21	22	10	14
Pre-clinical studies evaluating the use of other anti-estrogens alone and in combination with therapeutic agents targeting EGFRvIII and/or ErbB-2 , such as antibodies or tyrosine kinase inhibitors , is also warranted .	Pre-clinical studies evaluating the use of other anti-estrogens alone and in combination with therapeutic agents targeting EGFRvIII and/or ErbB-2, such as antibodies or tyrosine kinase inhibitors, is also warranted.	1	30	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB-2	ErbB-2	ErbB-2	EGFRvIII	EGFRvIII	EGFRvIII	18	19	16	17
Pertuzumab ( rhuMAb 2C4 ) , a humanized HER2 antibody , represents a new class of targeted therapeutics that inhibit dimerization of HER2 with ligand activated EGFR ( HER1 ) , HER3 , and HER-4 .	Pertuzumab (rhuMAb 2C4), a humanized HER2 antibody, represents a new class of targeted therapeutics that inhibit dimerization of HER2 with ligand activated EGFR (HER1), HER3, and HER-4.	20	34	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	22	23	26	27
Cancers that overexpress human EGF receptor 2 ( HER2 ) are treated with an anti-HER2 antibody , such as trastuzumab , or a tyrosine kinase inhibitor , such as lapatinib .	Cancers that overexpress human EGF receptor 2 (HER2) are treated with an anti-HER2 antibody, such as trastuzumab, or a tyrosine kinase inhibitor, such as lapatinib.	0	9	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGF receptor	EGF receptor	EGF receptor	8	9	4	6
More recently , HER-3 phosphorylation in colorectal cancer cells was shown to be strictly dependent on association with HER-2 , and that HER-2 and HER-3 signalling reversed the effect of EGFR blockade on inhibiting colorectal cancer cell growth .	More recently, HER-3 phosphorylation in colorectal cancer cells was shown to be strictly dependent on association with HER-2, and that HER-2 and HER-3 signalling reversed the effect of EGFR blockade on inhibiting colorectal cancer cell growth.	22	31	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HER-2	HER-2	HER-2	EGFR	EGFR	EGFR	22	23	30	31
Interestingly , recent studies have demonstrated that herceptin mediated blockade of ERBB2 also enhances nerve regeneration after injury in vivo by inhibiting transactivation of the EGFR .	Interestingly, recent studies have demonstrated that herceptin mediated blockade of ERBB2 also enhances nerve regeneration after injury in vivo by inhibiting transactivation of the EGFR.	9	26	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERBB2	ERBB2	ERBB2	EGFR	EGFR	EGFR	11	12	25	26
26 Their data further showed that HER3 phosphorylation is strictly dependent on association with HER2 but not EGFR , and that activation of HER2 and HER3 signaling by heregulin ( neuregulin 1 ) abolishes the effect of EGFR blockade on the growth of colorectal cancer .	26 Their data further showed that HER3 phosphorylation is strictly dependent on association with HER2 but not EGFR, and that activation of HER2 and HER3 signaling by heregulin (neuregulin 1) abolishes the effect of EGFR blockade on the growth of colorectal cancer.	23	38	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	23	24	37	38
In addition , erbB-2 overexpression promoted rapid recycling of activated EGFR back to the cell surface and decreased ligand dissociation from the EGFR .	In addition, erbB-2 overexpression promoted rapid recycling of activated EGFR back to the cell surface and decreased ligand dissociation from the EGFR.	3	11	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	erbB-2	erbB-2 overexpression	erbb-2	EGFR	EGFR	egfr	3	4	10	11
Phosphoproteins that were identified included many known Her2 signaling molecules as well as known EGFR signaling proteins that had not been previously linked to Her2 , such as Stat1 , Dok1 , and delta-catenin .	Phosphoproteins that were identified included many known Her2 signaling molecules as well as known EGFR signaling proteins that had not been previously linked to Her2, such as Stat1, Dok1, and delta-catenin.	4	16	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Her2	Her2	Her2	EGFR	EGFR	EGFR	7	8	14	15
HER2 activation likely contributes to downstream signaling events and enhances EGF receptor action .	HER2 activation likely contributes to downstream signaling events and enhances EGF receptor action.	0	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGF receptor	EGF receptor	EGF receptor	0	1	10	12
By contrast , our previous analysis conducted in the same cohort of patients demonstrated that HER2 gene increased copy number enhances gefitinib sensitivity in EGFR+ patients ( Cappuzzo et al , 2005b ) , with a significant difference in outcome for patients EGFR +/HER2+ and EGFR +/HER2-.	By contrast, our previous analysis conducted in the same cohort of patients demonstrated that HER2 gene increased copy number enhances gefitinib sensitivity in EGFR+ patients (Cappuzzo et al, 2005b), with a significant difference in outcome for patients EGFR +/HER2+ and EGFR +/HER2-.	15	46	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	15	16	45	46
Modulation of EGFR signaling network by HER2 .	Modulation of EGFR signaling network by HER2.	0	7	Modulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	6	7	2	3
The EGFR family protein , HER2 , does not bind ligand on its own but instead modulates the activity of other EGFR family members through heterodimerization .	The EGFR family protein, HER2, does not bind ligand on its own but instead modulates the activity of other EGFR family members through heterodimerization.	3	23	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	5	6	21	22
Amplification of the HER2 gene leading to human epidermal growth factor receptor 2 ( HER2 ) protein overexpression occurs in 20-30 % of breast cancers and is associated with an aggressive natural history and decreased overall survival [ XREF_BIBR , XREF_BIBR ] .	Amplification of the HER2 gene leading to human epidermal growth factor receptor 2 (HER2) protein overexpression occurs in 20-30% of breast cancers and is associated with an aggressive natural history and decreased overall survival [XREF_BIBR, XREF_BIBR].	3	14	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	3	4	8	12
HER2 and HER3 aptamers will direct EGFR siRNA to internalize to the HER2- and HER3 expressing cells through receptor mediated endocytosis .	HER2 and HER3 aptamers will direct EGFR siRNA to internalize to the HER2- and HER3 expressing cells through receptor mediated endocytosis.	0	7	direct	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	0	1	6	7
The ability of ErbB2 to potentiate EGF receptor signalling , due to the formation of EGF receptor-ErbB2 heterodimers , would provide tumour cells with a more potent growth stimulus and might lead to the activation of additional intracellular pathways .	The ability of ErbB2 to potentiate EGF receptor signalling, due to the formation of EGF receptor-ErbB2 heterodimers, would provide tumour cells with a more potent growth stimulus and might lead to the activation of additional intracellular pathways.	1	8	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	EGF receptor	EGF receptor	EGF receptor	3	4	6	8
On the cell surface , the presence of erythroblastosis B2 ( erbB2 ) increases the binding of mAb806 to the EGFR .	On the cell surface, the presence of erythroblastosis B2 (erbB2) increases the binding of mAb806 to the EGFR.	6	21	increases	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	erbB2	erbB2	erbB2	EGFR	EGFR	EGFR	11	12	20	21
HER2 overexpression is known to cause increased activation of EGFR .	HER2 overexpression is known to cause increased activation of EGFR.	0	10	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2 overexpression	her2	EGFR	EGFR	egfr	0	1	9	10
Indeed , ErbB2 expression caused a striking stabilization of EGFR following ECM detachment ( XREF_FIG ) that was critical for the rescue of ATP ( XREF_FIG ) .	Indeed, ErbB2 expression caused a striking stabilization of EGFR following ECM detachment (XREF_FIG) that was critical for the rescue of ATP (XREF_FIG).	2	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2 expression	erbb2	EGFR	EGFR	egfr	2	3	9	10
We measured drug induced heterodimerisation of HER2 and HER3 , as we have done previously in the case of drug induced dimerisation of the EGF receptor .	We measured drug induced heterodimerisation of HER2 and HER3, as we have done previously in the case of drug induced dimerisation of the EGF receptor.	4	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGF receptor	EGF receptor	EGF receptor	6	7	24	26
Tumors overexpressing the epidermal growth factor receptor 2 are treated with anti HER2 monoclonal antibodies as trastuzumab and pertuzumab or with immunoconjugates as TDM1 or kinase inhibitors as lapatinib or neratinib , mostly combined [ XREF_BIBR ] , whereas the triple negative breast cancer that is treated with conventional and moderately successful chemotherapies displays a poor prognosis and a high risk of relapse [ XREF_BIBR , XREF_BIBR ] .	Tumors overexpressing the epidermal growth factor receptor 2 are treated with anti HER2 monoclonal antibodies as trastuzumab and pertuzumab or with immunoconjugates as TDM1 or kinase inhibitors as lapatinib or neratinib, mostly combined [XREF_BIBR], whereas the triple negative breast cancer that is treated with conventional and moderately successful chemotherapies displays a poor prognosis and a high risk of relapse [XREF_BIBR, XREF_BIBR].	3	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	12	13	3	7
We found in tumors from the unsupplemented group that EGFR signals , including pEGFR , pErbB2 , pERK and pAKT were significantly increased .	We found in tumors from the unsupplemented group that EGFR signals, including pEGFR, pErbB2, pERK and pAKT were significantly increased.	9	16	signals	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	pErbB2	pErbB2	pErbB2	EGFR	EGFR	EGFR	15	16	9	10
However , a number of observations suggest that ErbB-2 may potentiate ErbB-1 signaling .	However, a number of observations suggest that ErbB-2 may potentiate ErbB-1 signaling.	8	12	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB-2	ErbB-2	ErbB-2	ErbB-1	ErbB-1	ErbB-1	8	9	11	12
Therapy with humanized HER2 mAb targeting different members of the epidermal growth factor receptor ( EGFR ) family combined with cytostatic agents e.g ., docetaxel and potentially tyrosine kinase inhibitors such as , e.g ., lapatinib or neratanib and afatinib has clearly improved the outcome of patients with metastatic breast or gastric cancer .	Therapy with humanized HER2 mAb targeting different members of the epidermal growth factor receptor (EGFR) family combined with cytostatic agents e.g., docetaxel and potentially tyrosine kinase inhibitors such as, e.g., lapatinib or neratanib and afatinib has clearly improved the outcome of patients with metastatic breast or gastric cancer.	3	14	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	3	4	10	14
Tumours from bitransgenic mice overexpress the myr-Akt1 and ErbB2 transgenes , but there was dramatically less overexpression and phosphorylation of ErbB3 , diminished phosphorylation of ErbB2 , decreased level of EGFR protein and undetectable ErbB4 protein .	Tumours from bitransgenic mice overexpress the myr-Akt1 and ErbB2 transgenes, but there was dramatically less overexpression and phosphorylation of ErbB3, diminished phosphorylation of ErbB2, decreased level of EGFR protein and undetectable ErbB4 protein.	16	31	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	overexpression and phosphorylation of ErbB3, diminished phosphorylation of ErbB2	erbb2	EGFR	EGFR	egfr	25	26	30	31
92 In the second , larger study , 230 patients were randomly assigned to one of three arms : pazopanib alone , lapatinib ( a tyrosine kinase targeting EGFR and HER2 and neu ) alone , or a combination of the two agents .	92 In the second, larger study, 230 patients were randomly assigned to one of three arms : pazopanib alone, lapatinib (a tyrosine kinase targeting EGFR and HER2 and neu) alone, or a combination of the two agents.	26	33	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neu	neu	neu	EGFR	EGFR	EGFR	32	33	28	29
Human epidermal growth factor receptor 2 ( HER2 )-positive breast cancer is treated with HER2 targeted agents , such as trastuzumab and lapatinib , that suppress signaling by phosphatidylinositol 3-kinase ( PI3K )-Akt and MAPK pathways .	Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is treated with HER2 targeted agents, such as trastuzumab and lapatinib, that suppress signaling by phosphatidylinositol 3-kinase (PI3K)-Akt and MAPK pathways.	1	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	14	15	1	5
Recent studies exemplifying both the basic and clinical importance of ITR include ERBB2 and PIK3CA , in which co-occurring PIK3CA mutations in ERBB2 positive breast cancers can modulate clinical responses to trastuzumab , XREF_BIBR and EGFR and MET , in which clinical resistance to gefitinib in EGFR mutated lung cancers can be caused by co-existing MET gene amplifications .	Recent studies exemplifying both the basic and clinical importance of ITR include ERBB2 and PIK3CA, in which co-occurring PIK3CA mutations in ERBB2 positive breast cancers can modulate clinical responses to trastuzumab, XREF_BIBR and EGFR and MET, in which clinical resistance to gefitinib in EGFR mutated lung cancers can be caused by co-existing MET gene amplifications.	11	37	modulate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	EGFR	EGFR	EGFR	12	13	35	36
As examples , the prometastatic SNF1 and AMPK related kinase hormonally upregulated Neu kinase was found to support EGFR activation in response to ligand binding , whereas the enigmatic kinase MGC16169 selectively supports coupling of active EGFR to ERK1/2 regulation .	As examples, the prometastatic SNF1 and AMPK related kinase hormonally upregulated Neu kinase was found to support EGFR activation in response to ligand binding, whereas the enigmatic kinase MGC16169 selectively supports coupling of active EGFR to ERK1/2 regulation.	12	19	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Neu	Neu	Neu	EGFR	EGFR	EGFR	12	13	18	19
The emergence of the HER2 targeted antibody drug Herceptin and trastuzumab and the small dual molecule EGFR and HER2 kinase inhibitor Tykerb and lapatinib has remarkably improved the survival of patients with breast cancer ; therefore , these drugs have been incorporated into the standard protocols for breast cancer treatment [ XREF_BIBR ] .	The emergence of the HER2 targeted antibody drug Herceptin and trastuzumab and the small dual molecule EGFR and HER2 kinase inhibitor Tykerb and lapatinib has remarkably improved the survival of patients with breast cancer; therefore, these drugs have been incorporated into the standard protocols for breast cancer treatment [XREF_BIBR].	1	23	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	4	5	16	17
Lapatinib ( Tykerb ; GlaxoSmithKline ) is a dual EGFR and HER2 kinase inhibitor that reduces EGFR and HER2 signaling and induces apoptosis in multiple models of HER2 overexpressing breast cancer [ XREF_BIBR , XREF_BIBR ] .	Lapatinib (Tykerb; GlaxoSmithKline) is a dual EGFR and HER2 kinase inhibitor that reduces EGFR and HER2 signaling and induces apoptosis in multiple models of HER2 overexpressing breast cancer [XREF_BIBR, XREF_BIBR].	11	19	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	11	12	16	17
ERK dependent upregulation of the immediate early genes egr-1 and c-fos has been shown in cell culture and in vivo in the hypothalamus XREF_BIBR , XREF_BIBR .	ERK dependent upregulation of the immediate early genes egr-1 and c-fos has been shown in cell culture and in vivo in the hypothalamus XREF_BIBR, XREF_BIBR.	0	11	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	0	1	10	11
These results suggested that the hyperactive ERK signaling and high level of c-fos in the breeding season may promote the proliferation of epithelial cells and glandular cells .	These results suggested that the hyperactive ERK signaling and high level of c-fos in the breeding season may promote the proliferation of epithelial cells and glandular cells.	6	16	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	6	7	12	13
Inhibition of Erk activation with PD98059 only partially inhibited c-fos induction , indicating that additional pathways are involved .	Inhibition of Erk activation with PD98059 only partially inhibited c-fos induction, indicating that additional pathways are involved.	2	10	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	c-fos	c-fos	c-fos	2	3	9	10
ERK1/2 induces c-Fos and JunB , which confer resistance to T cells against suppression by TGF-beta and IL-10 and against anergy induction .	ERK1/2 induces c-Fos and JunB, which confer resistance to T cells against suppression by TGF-beta and IL-10 and against anergy induction.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	0	1	2	3
PD98059 inhibited MAPK activation and induction stabilization of c-Fos .	PD98059 inhibited MAPK activation and induction stabilization of c-Fos.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Fos	c-Fos	c-Fos	2	3	8	9
LPA may regulate ESC maintenance , self-renewal and somatic cell reprogramming to iPSCs via ERK mediated activation of c-fos or by overexpression of pluripotent transcription factors , such as c-Myc XREF_BIBR .	LPA may regulate ESC maintenance, self-renewal and somatic cell reprogramming to iPSCs via ERK mediated activation of c-fos or by overexpression of pluripotent transcription factors, such as c-Myc XREF_BIBR.	12	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	14	15	18	19
Induction of miR-146b by PDGF-BB is modulated via MAPK dependent induction of c-fos .	Induction of miR-146b by PDGF-BB is modulated via MAPK dependent induction of c-fos.	8	13	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-fos	c-fos	c-fos	8	9	12	13
Our results show that MSK1 is an important ERK activated mediator of mitogen induced c-fos activation .	Our results show that MSK1 is an important ERK activated mediator of mitogen induced c-fos activation.	8	15	mediator	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	8	9	14	15
Our findings also revealed that LTP inducing stimulation of thalamo-LA synapses regulates the expression of the ERK driven IEGs Arc and Arg3.1 , c-Fos , and EGR-1 in both the LA and MGm and PIN .	Our findings also revealed that LTP inducing stimulation of thalamo-LA synapses regulates the expression of the ERK driven IEGs Arc and Arg3.1, c-Fos, and EGR-1 in both the LA and MGm and PIN.	13	24	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	expression of the ERK	erk	c-Fos	c-Fos	c-fos	16	17	23	24
Thus , ERK dependent activation of c-fos reflects a summation of activity dependent calcium influx over seconds to minutes .	Thus, ERK dependent activation of c-fos reflects a summation of activity dependent calcium influx over seconds to minutes.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	2	3	6	7
In particular , inhibition of p38 MAPK did not rescue differentiation or alter the Erk1/2 pathway other than the expected down-regulation of the common MAPK target c-Fos ( XREF_FIG ) .	In particular, inhibition of p38 MAPK did not rescue differentiation or alter the Erk1/2 pathway other than the expected down-regulation of the common MAPK target c-Fos (XREF_FIG).	20	28	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Fos	c-Fos	c-Fos	24	25	26	27
XREF_BIBR , XREF_BIBR Furthermore , in hepatocytes , the generation of ROS triggers apoptosis by promoting the Erk dependent induction of c-Fos and increased Bim transcription through this same AP-1 site .	XREF_BIBR, XREF_BIBR Furthermore, in hepatocytes, the generation of ROS triggers apoptosis by promoting the Erk dependent induction of c-Fos and increased Bim transcription through this same AP-1 site.	17	22	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Erk	Erk	Erk	c-Fos	c-Fos	c-Fos	17	18	21	22
In renal cell carcinoma , MAPK activation correlated with MAPK kinase activation and Raf-1 activation ( Oka et al , 1995 ) , while for hepatocarcinomas a relationship was reported between ERK1/2 activation and expression of the transcription factor c-Fos and cyclin D1 ( Ito et al , 1998 ) .	In renal cell carcinoma, MAPK activation correlated with MAPK kinase activation and Raf-1 activation (Oka et al, 1995), while for hepatocarcinomas a relationship was reported between ERK1/2 activation and expression of the transcription factor c-Fos and cyclin D1 (Ito et al, 1998).	31	44	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	31	32	39	40
Significantly , MAPK has been implicated to trigger the induction of c-Fos [ XREF_BIBR ] , and c-Fos is a key transcription factor of osteoclastogenesis [ XREF_BIBR ] .	Significantly, MAPK has been implicated to trigger the induction of c-Fos [XREF_BIBR], and c-Fos is a key transcription factor of osteoclastogenesis [XREF_BIBR].	2	13	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Fos	c-Fos	c-Fos	2	3	11	12
Inhibition of ERKs by PD098059 suppressed induction of c-fos without affecting early induction of c-jun , leading to attenuated activation of AP-1 in response to H2O2 .	Inhibition of ERKs by PD098059 suppressed induction of c-fos without affecting early induction of c-jun, leading to attenuated activation of AP-1 in response to H2O2.	0	9	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	c-fos	c-fos	c-fos	2	3	8	9
In addition , inhibition of MAPK activation or TGF-beta1 receptor by pharmacological agents prevented TGF-beta1-induced c-Fos and Lewis y expression .	In addition, inhibition of MAPK activation or TGF-beta1 receptor by pharmacological agents prevented TGF-beta1-induced c-Fos and Lewis y expression.	5	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Fos	c-Fos	c-Fos	5	6	15	16
A specific inhibitor of the MAPK kinases , PD98059 , partially inhibited the induction of c-fos by Cd2+ .	A specific inhibitor of the MAPK kinases, PD98059, partially inhibited the induction of c-fos by Cd2+.	5	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-fos	c-fos	c-fos	5	6	15	16
Thus , we report a novel function for PKG II in osteoblast mechanotransduction , and we propose a model whereby NO/cGMP/PKG II mediated Erk activation and induction of c-fos , fra-1 , fra-2 , and fosB and DeltafosB play a key role in the osteoblast anabolic response to mechanical stimulation .	Thus, we report a novel function for PKG II in osteoblast mechanotransduction, and we propose a model whereby NO/cGMP/PKG II mediated Erk activation and induction of c-fos, fra-1, fra-2, and fosB and DeltafosB play a key role in the osteoblast anabolic response to mechanical stimulation.	21	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Erk	II mediated Erk	erk	c-fos	c-fos	c-fos	23	24	28	29
Among the MAP kinases , tumor progression locus 2 ( Tpl2 and MAP3K8 ) , a MAP3 kinase , plays an important role in regulating IFN production by promoting the ERK dependent induction of c-fos , a component of AP-1 heterodimeric transcription factors [ XREF_BIBR ] .	Among the MAP kinases, tumor progression locus 2 (Tpl2 and MAP3K8), a MAP3 kinase, plays an important role in regulating IFN production by promoting the ERK dependent induction of c-fos, a component of AP-1 heterodimeric transcription factors [XREF_BIBR].	30	37	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	30	31	34	35
Intriguingly , these transcription factors are all known to be activated by the three kinases , of which c-Jun can be activated by JNK , c-Fos can be activated by ERK and p38 , and GATA2 can be activated by p38 .	Intriguingly, these transcription factors are all known to be activated by the three kinases, of which c-Jun can be activated by JNK, c-Fos can be activated by ERK and p38, and GATA2 can be activated by p38.	25	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	30	31	25	26
We show that c-Fos and JunB are specifically induced by ERK1/2 .	We show that c-Fos and JunB are specifically induced by ERK1/2.	3	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	10	11	3	4
In addition , important downstream transcriptional targets of ERK5 and ERK1/2 overlap , such as immediate-early gene Fra1 and oncogene c-Myc , whereas c-Fos and Egr1 were specifically induced by ERK1/2 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	In addition, important downstream transcriptional targets of ERK5 and ERK1/2 overlap, such as immediate-early gene Fra1 and oncogene c-Myc, whereas c-Fos and Egr1 were specifically induced by ERK1/2 (XREF_FIG and XREF_SUPPLEMENTARY).	23	34	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	30	31	23	24
Functional receptor binding studies by this group confirmed high levels of VEGF-VEGFR interaction only in Capan-1 cells ; VEGF dose-dependently enhanced proliferation , promoted MAPK phosphorylation , and induced c-fos activity only in these Capan-1 cells [ XREF_BIBR ] .	Functional receptor binding studies by this group confirmed high levels of VEGF-VEGFR interaction only in Capan-1 cells; VEGF dose-dependently enhanced proliferation, promoted MAPK phosphorylation, and induced c-fos activity only in these Capan-1 cells [XREF_BIBR].	18	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	VEGF dose-dependently enhanced proliferation, promoted MAPK phosphorylation	mapk	c-fos	c-fos	c-fos	24	25	29	30
ERK activates c-fos , while JNK increases AP-1 transcriptional activity through the phosphorylation of c-Jun [ XREF_BIBR ] .	ERK activates c-fos, while JNK increases AP-1 transcriptional activity through the phosphorylation of c-Jun [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	0	1	2	3
The activation of ERK1/2 causes c-Fos release and turns on the transcription of target genes necessary for cell spreading [ XREF_BIBR ] .	The activation of ERK1/2 causes c-Fos release and turns on the transcription of target genes necessary for cell spreading [XREF_BIBR].	1	6	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	3	4	5	6
MCF-7 cells show similar signaling input-output relationships : sustained ERK activity induces cellular differentiation and a significant c-Fos response , while transient ERK activity induces proliferation and a negligible c-Fos response .	MCF-7 cells show similar signaling input-output relationships : sustained ERK activity induces cellular differentiation and a significant c-Fos response, while transient ERK activity induces proliferation and a negligible c-Fos response.	22	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	22	23	29	30
Upon DC stimulation with TLR2 ligands such as yeast zymosan , JNK and p38 activation was correlated with strong IL-12 production , whereas ERK stimulation induced c-Fos , which acted to suppress IL-12 and upregulate IL-10 .	Upon DC stimulation with TLR2 ligands such as yeast zymosan, JNK and p38 activation was correlated with strong IL-12 production, whereas ERK stimulation induced c-Fos, which acted to suppress IL-12 and upregulate IL-10.	23	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	23	24	26	27
In parallel to the findings of the present study , rats given intra-LA infusion of Ifenprodil , 7-Ni , or Rp-8-Br-PET-cGMPS exhibit significant decreases in training induced expression of phosphorylated ERK and the ERK driven immediate early genes Arc and Arg3.1 , EGR-1 , and c-Fos in both the LA and the MGm and PIN , while those rats infused with 8-Br-cGMP exhibit a significant increase in the same proteins at both sites XREF_BIBR .	In parallel to the findings of the present study, rats given intra-LA infusion of Ifenprodil, 7-Ni, or Rp-8-Br-PET-cGMPS exhibit significant decreases in training induced expression of phosphorylated ERK and the ERK driven immediate early genes Arc and Arg3.1, EGR-1, and c-Fos in both the LA and the MGm and PIN, while those rats infused with 8-Br-cGMP exhibit a significant increase in the same proteins at both sites XREF_BIBR.	29	46	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	33	34	45	46
The induction of c-fos by ERK1/2 was proposed as a mechanism to explain the inhibition of IFNbeta and IL-12 production by ERK1/2 XREF_BIBR .	The induction of c-fos by ERK1/2 was proposed as a mechanism to explain the inhibition of IFNbeta and IL-12 production by ERK1/2 XREF_BIBR.	1	6	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-fos	c-fos	c-fos	5	6	3	4
Immunoblotting demonstrated that ERK inhibition suppressed the c-Fos increase but did not affect c-Jun expression ( XREF_FIG ) .	Immunoblotting demonstrated that ERK inhibition suppressed the c-Fos increase but did not affect c-Jun expression (XREF_FIG).	3	8	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	3	4	7	8
ERK is known to induce c-Fos during osteoclastogenesis with its inhibition shown to decrease osteoclast formation [ XREF_BIBR ] .	ERK is known to induce c-Fos during osteoclastogenesis with its inhibition shown to decrease osteoclast formation [XREF_BIBR].	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	0	1	5	6
Recent work in fibroblasts demonstrated that activation of ERK was required for basic calcium phosphate crystals to stimulate c-fos which is a regulator of MMP expression in these cells [ XREF_BIBR ] .	Recent work in fibroblasts demonstrated that activation of ERK was required for basic calcium phosphate crystals to stimulate c-fos which is a regulator of MMP expression in these cells [XREF_BIBR].	6	22	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	8	9	18	19
Supporting this hypothesis , we also found that inhibition of ERK1/2 by PD 198306 prevented the GP 1a induced activation of c-fos ( XREF_FIG ) .	Supporting this hypothesis, we also found that inhibition of ERK1/2 by PD 198306 prevented the GP 1a induced activation of c-fos (XREF_FIG).	8	23	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-fos	c-fos	c-fos	10	11	21	22
Specifically , we previously showed in striatal cultures XREF_BIBR XREF_BIBR XREF_BIBR that cell surface mGluR5 stimulates CAMKIV , p-CREB and c-jun , while intracellular mGluR5 phosphorylates ERK1/2 and Elk-1 , and enhances c-fos , erg-1 and Arc and Arg3.1 .	Specifically, we previously showed in striatal cultures XREF_BIBR XREF_BIBR XREF_BIBR that cell surface mGluR5 stimulates CAMKIV, p-CREB and c-jun, while intracellular mGluR5 phosphorylates ERK1/2 and Elk-1, and enhances c-fos, erg-1 and Arc and Arg3.1.	24	38	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	mGluR5 phosphorylates ERK1/2	erk1/2	c-fos	c-fos	c-fos	26	27	32	33
This ERK1/2 activation may therefore underlie the upregulated c-fos that we have previously observed in these animals , both at baseline and after amphetamine challenge .	This ERK1/2 activation may therefore underlie the upregulated c-fos that we have previously observed in these animals, both at baseline and after amphetamine challenge.	1	9	underlie	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-fos	c-fos	c-fos	1	2	8	9
Previous work has shown that c-Fos is activated via phosphorylation by the kinases ERK or JNK and enters the nucleus to regulate target gene expression .	Previous work has shown that c-Fos is activated via phosphorylation by the kinases ERK or JNK and enters the nucleus to regulate target gene expression.	5	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	13	14	5	6
Furthermore , c-fos induction by ERK is well characterised XREF_BIBR , XREF_BIBR and in the current study we have shown that c-fos is activated by M-CSF .	Furthermore, c-fos induction by ERK is well characterised XREF_BIBR, XREF_BIBR and in the current study we have shown that c-fos is activated by M-CSF.	2	6	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	5	6	2	3
Second , it is known that ERK induces and activates c-Fos for AP-1 activation [ XREF_BIBR ] .	Second, it is known that ERK induces and activates c-Fos for AP-1 activation [XREF_BIBR].	6	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	6	7	10	11
The new pool of c-fos induced by an initial activation of MAPK only appears after 30 minutes of sequential gene induction , transcription and translation .	The new pool of c-fos induced by an initial activation of MAPK only appears after 30 minutes of sequential gene induction, transcription and translation.	2	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-fos	c-fos	c-fos	11	12	4	5
To further corroborate that the ERK pathway mediates c-fos induction by FCS and LPA , Ro318220 was used to inhibit MAPKAP-K1 and RSK and MSK1 [ XREF_BIBR , XREF_BIBR ] , two downstream targets of ERK1 and ERK2 .	To further corroborate that the ERK pathway mediates c-fos induction by FCS and LPA, Ro318220 was used to inhibit MAPKAP-K1 and RSK and MSK1 [XREF_BIBR, XREF_BIBR], two downstream targets of ERK1 and ERK2.	5	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	5	6	8	9
Activated or overexpressive MAPK activates the immediately-early oncogenes ( c-fos , c-jun ) , which might play an important role in carcinogenesis of breast cancer and be an early event of oncogenesis of breast cancer .	Activated or overexpressive MAPK activates the immediately-early oncogenes (c-fos, c-jun), which might play an important role in carcinogenesis of breast cancer and be an early event of oncogenesis of breast cancer.	2	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-fos	c-fos	c-fos	3	4	9	10
One mechanism of ERK mediated c-fos induction by MSK1 could be phosphorylation of CREB bound to the CRE of the c-fos promoter .	One mechanism of ERK mediated c-fos induction by MSK1 could be phosphorylation of CREB bound to the CRE of the c-fos promoter.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	3	4	5	6
In human articular cartilage , c-Fos was activated by ERK1/2 signaling upon transactivation of the IL-11 gene [ XREF_BIBR ] .	In human articular cartilage, c-Fos was activated by ERK1/2 signaling upon transactivation of the IL-11 gene [XREF_BIBR].	5	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	9	10	5	6
Of interest , of the hyperfilamentous mutants , only Deltanrg1 and not Deltatup1 induced cytokines , suggesting that cytokine production is , in part , independent of MAPK induced c-Fos activation ( i.e ., probably NF-kappaB mediated ) .	Of interest, of the hyperfilamentous mutants, only Deltanrg1 and not Deltatup1 induced cytokines, suggesting that cytokine production is, in part, independent of MAPK induced c-Fos activation (i.e., probably NF-kappaB mediated).	25	33	induced	Positive_early_activation	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-Fos	c-Fos	c-Fos	27	28	29	30
ERK would induced c-Fos to combine with serum response factors through phosphorylation of tertiary complex factors and Ets like kinase-1 .	ERK would induced c-Fos to combine with serum response factors through phosphorylation of tertiary complex factors and Ets like kinase-1.	0	4	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	0	1	3	4
Former investigators have implicated p38 regulated microphthalmia associated transcription factor , ERK induced activation of c-fos , and JNK phosphorylated down-stream factors , including c-fos and c-Jun , which combine to form the activator protein-1 ( AP-1 ) heterodimer .	Former investigators have implicated p38 regulated microphthalmia associated transcription factor, ERK induced activation of c-fos, and JNK phosphorylated down-stream factors, including c-fos and c-Jun, which combine to form the activator protein-1 (AP-1) heterodimer.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	11	12	15	16
Furthermore , we provide evidence that the ERK dependent activation of c-Fos is an integral component of the mitogenic pathway by which PDGF regulates normal and aberrant cell growth .	Furthermore, we provide evidence that the ERK dependent activation of c-Fos is an integral component of the mitogenic pathway by which PDGF regulates normal and aberrant cell growth.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	7	8	11	12
In turn , in cell lines , ERK appears to mediate the activation of c-fos and ribosomal S6 kinase and S6 by the leptin receptor .	In turn, in cell lines, ERK appears to mediate the activation of c-fos and ribosomal S6 kinase and S6 by the leptin receptor.	7	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	7	8	14	15
It will be also of interest to examine whether A-type lamins serve a scaffolding function only for ERK1/2 dependent activation of c-Fos , or whether induction of other transcription factors also requires the activity of NE associated signal transducers .	It will be also of interest to examine whether A-type lamins serve a scaffolding function only for ERK1/2 dependent activation of c-Fos, or whether induction of other transcription factors also requires the activity of NE associated signal transducers.	17	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	17	18	21	22
Fluid shear stress has been shown to elicit multiple intra-cellular signaling pathways involving elevation in intracellular calcium as well as ERK1/2 activation of c-Fos and nuclear factor ( NF )-kappaB translocation [ XREF_BIBR , XREF_BIBR ] .	Fluid shear stress has been shown to elicit multiple intra-cellular signaling pathways involving elevation in intracellular calcium as well as ERK1/2 activation of c-Fos and nuclear factor (NF)-kappaB translocation [XREF_BIBR, XREF_BIBR].	20	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	20	21	23	24
Msk-1 ( Rps6ka4 ) is an important ERK activated mediator of mitogen induced c-fos activation , and c-fos is a cellular proto-oncogene belonging to the immediate early gene family of transcription factors XREF_BIBR , XREF_BIBR .	Msk-1 (Rps6ka4) is an important ERK activated mediator of mitogen induced c-fos activation, and c-fos is a cellular proto-oncogene belonging to the immediate early gene family of transcription factors XREF_BIBR, XREF_BIBR.	7	14	mediator	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	7	8	13	14
Among this , phosphorylation of ERK would later promote the induction of c-Fos , which is an essential member of AP-1 transcription factor complex 41 , and this is of vital importance to NFATc1 induction and osteoclast differentiation .	Among this, phosphorylation of ERK would later promote the induction of c-Fos, which is an essential member of AP-1 transcription factor complex 41, and this is of vital importance to NFATc1 induction and osteoclast differentiation.	3	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	phosphorylation of ERK	erk	c-Fos	c-Fos	c-fos	5	6	12	13
A recent study using rat mesenchymal stem cells traced the entire chain of events : rapid rise of intracellular calcium and prostaglandin E ( PGE ) release activated MAP kinases Erk1/2 and p38 , which in turn induced c-fos , vascular endothelial growth factor , and cyclooxygenase 2 ( COX2 ) [ XREF_BIBR ] .	A recent study using rat mesenchymal stem cells traced the entire chain of events : rapid rise of intracellular calcium and prostaglandin E (PGE) release activated MAP kinases Erk1/2 and p38, which in turn induced c-fos, vascular endothelial growth factor, and cyclooxygenase 2 (COX2) [XREF_BIBR].	27	52	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	c-fos	c-fos	c-fos	30	31	38	39
Given a prior finding that SKF-82958 does not differentially stimulate adenylyl cyclase in CPu or NAc of food restricted versus ad libitum fed subjects , the present results suggest that increased D-1 DA receptor mediated ERK1/2 MAP kinase signaling may mediate the enhanced downstream activation of CREB , c-fos , and behavioral responses in food restricted subjects .	Given a prior finding that SKF-82958 does not differentially stimulate adenylyl cyclase in CPu or NAc of food restricted versus ad libitum fed subjects, the present results suggest that increased D-1 DA receptor mediated ERK1/2 MAP kinase signaling may mediate the enhanced downstream activation of CREB, c-fos, and behavioral responses in food restricted subjects.	32	49	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	DA receptor mediated ERK1/2	erk1/2	c-fos	c-fos	c-fos	35	36	48	49
XREF_BIBR , XREF_BIBR Mouse ESCs express receptor subtypes LPAR 1-3 ,5 and S1PR 1-5 XREF_BIBR , XREF_BIBR while hESCs express LPAR 1-5 and S1PR 1-3 XREF_BIBR - XREF_BIBR The LPA signaling pathway that effects mouse ES maintenance is the ERK activation of c-fos .	XREF_BIBR, XREF_BIBR Mouse ESCs express receptor subtypes LPAR 1-3,5 and S1PR 1-5 XREF_BIBR, XREF_BIBR while hESCs express LPAR 1-5 and S1PR 1-3 XREF_BIBR - XREF_BIBR The LPA signaling pathway that effects mouse ES maintenance is the ERK activation of c-fos.	39	43	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	39	40	42	43
The observed phosphorylation of MAPK is postulated to upregulate the activity of c-fos , which dimerize with c-jun to promote AP-1 transcription activity in cell proliferation , differentiation , survival and apoptosis .	The observed phosphorylation of MAPK is postulated to upregulate the activity of c-fos, which dimerize with c-jun to promote AP-1 transcription activity in cell proliferation, differentiation, survival and apoptosis.	2	19	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	phosphorylation of MAPK	mapk	c-fos	c-fos	c-fos	4	5	12	13
In addition , the YXXQ-signal and an Erk signal co-operatively cause c-Fos activation in the nucleus .	In addition, the YXXQ-signal and an Erk signal co-operatively cause c-Fos activation in the nucleus.	7	12	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	c-Fos	c-Fos	c-Fos	7	8	11	12
In contrast , acute haloperidol injection activated phosphorylation of ERK , MSK1 , and H3 only in D2R neurons and induced c-fos and zif268 predominantly in these neurons .	In contrast, acute haloperidol injection activated phosphorylation of ERK, MSK1, and H3 only in D2R neurons and induced c-fos and zif268 predominantly in these neurons.	4	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	haloperidol injection activated phosphorylation of ERK	erk	c-fos	c-fos	c-fos	9	10	21	22
The insulin and ERK pathway dependent induction of the c-fos and Pip92 genes is under tonic inhibition by GGTase , since inhibition of GGTase activity increased the insulin effect .	The insulin and ERK pathway dependent induction of the c-fos and Pip92 genes is under tonic inhibition by GGTase, since inhibition of GGTase activity increased the insulin effect.	1	12	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	3	4	9	10
As to fucodiphloroethol G , this compound inhibit angiogenesis on ECV-304 and EA.hy926 cells when induced with VEGF , as well as the transcriptional factor c-fos and its targets AP-N , MMP-2 , by MAPK , and Akt signaling pathways inhibition .	As to fucodiphloroethol G, this compound inhibit angiogenesis on ECV-304 and EA.hy926 cells when induced with VEGF, as well as the transcriptional factor c-fos and its targets AP-N, MMP-2, by MAPK, and Akt signaling pathways inhibition.	15	40	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-fos	c-fos	c-fos	34	35	25	26
Thus , we report a novel function for PKG II in osteoblast mechanotransduction , and propose a model whereby NO/cGMP/PKG II mediated Erk activation and induction of c-fos , fra-1 , fra-2 , and fosB and DeltafosB play a key role in the osteoblast anabolic response to mechanical stimulation .	Thus, we report a novel function for PKG II in osteoblast mechanotransduction, and propose a model whereby NO/cGMP/PKG II mediated Erk activation and induction of c-fos, fra-1, fra-2, and fosB and DeltafosB play a key role in the osteoblast anabolic response to mechanical stimulation.	20	36	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Erk	II mediated Erk	erk	c-fos	c-fos	c-fos	22	23	27	28
The purpose of the present investigation was to define the role of mitogen activated protein kinase ( MAPK ) in Ang II induced DNA synthesis , migration , and c-fos induction in VSMCs .	The purpose of the present investigation was to define the role of mitogen activated protein kinase (MAPK) in Ang II induced DNA synthesis, migration, and c-fos induction in VSMCs.	15	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	c-fos	c-fos	c-fos	17	18	29	30
In the present experiments , we used a combination of Western blotting and immunohistochemistry to examine whether LTP inducing stimulation of thalamic input synapses to the LA regulate the ERK driven IEGs Arc and Arg3.1 , EGR-1 and c-Fos in the LA and the MGm and PIN .	In the present experiments, we used a combination of Western blotting and immunohistochemistry to examine whether LTP inducing stimulation of thalamic input synapses to the LA regulate the ERK driven IEGs Arc and Arg3.1, EGR-1 and c-Fos in the LA and the MGm and PIN.	27	39	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	29	30	38	39
Strikingly , histone H3 phosphorylation was demonstrated to accompany ERK and MAPK pathway mediated activation of c-Fos by agonists of dopamine ( DA ) , muscarinic acetylcholine ( mACh ) and glutamate ( GLU ) receptor in hippocampal neurons , suggesting an important role of nucleosomal response in memory formation XREF_BIBR .	Strikingly, histone H3 phosphorylation was demonstrated to accompany ERK and MAPK pathway mediated activation of c-Fos by agonists of dopamine (DA), muscarinic acetylcholine (mACh) and glutamate (GLU) receptor in hippocampal neurons, suggesting an important role of nucleosomal response in memory formation XREF_BIBR.	9	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Fos	c-Fos	c-Fos	9	10	16	17
HepG2 cells were pretreated with the potent MEK inhibitor , PD184352 , which prevents ERK1/2 phosphorylation ( activation ) , followed by treatment with tunicamycin to induce ER stress .	HepG2 cells were pretreated with the potent MEK inhibitor, PD184352, which prevents ERK1/2 phosphorylation (activation), followed by treatment with tunicamycin to induce ER stress.	7	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	MEK inhibitor, PD184352, which prevents ERK1/2 phosphorylation	erk1/2	ER	ER	er	14	15	27	28
Pretreatment with 17beta-estradiol prevented testosterone induced podocyte apoptosis , an estrogen receptor dependent effect mediated by activation of the ERK signaling pathway , and protected podocytes from TGF-beta1- or TNF-alpha-induced apoptosis .	Pretreatment with 17beta-estradiol prevented testosterone induced podocyte apoptosis, an estrogen receptor dependent effect mediated by activation of the ERK signaling pathway, and protected podocytes from TGF-beta1- or TNF-alpha-induced apoptosis.	10	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	estrogen receptor	estrogen receptor	estrogen receptor	19	20	10	12
Under estrogen deprivation , linc-RoR causes the upregulation of phosphorylated MAPK and ERK pathway which in turn activates ER signaling .	Under estrogen deprivation, linc-RoR causes the upregulation of phosphorylated MAPK and ERK pathway which in turn activates ER signaling.	10	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ER	ER	ER	12	13	18	19
Collectively , these data indicate that the MAPK stimulation of ERalpha activity involves the phosphorylation not only of S118 but also of S104 and S106 , and that MAPK mediated hyperphosphorylation of ERalpha at these sites may contribute to resistance to tamoxifen in breast cancer .	Collectively, these data indicate that the MAPK stimulation of ERalpha activity involves the phosphorylation not only of S118 but also of S104 and S106, and that MAPK mediated hyperphosphorylation of ERalpha at these sites may contribute to resistance to tamoxifen in breast cancer.	7	11	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	7	8	10	11
Data from the above studies suggest that oestrogen can initiate rapid MAPK signalling in an ER dependent and ER independent manner .	Data from the above studies suggest that oestrogen can initiate rapid MAPK signalling in an ER dependent and ER independent manner.	11	20	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	11	12	15	16
ERKs pathway participated in the protective action of baicalein against PA induced ER stress .	ERKs pathway participated in the protective action of baicalein against PA induced ER stress.	0	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	ER	ER	ER	0	1	12	13
The kinetic profiles of MAPK activation and inhibition show a relationship between the duration and magnitude of MAPK activation and cell migration in both ER positive and ER negative human breast cancer cells .	The kinetic profiles of MAPK activation and inhibition show a relationship between the duration and magnitude of MAPK activation and cell migration in both ER positive and ER negative human breast cancer cells.	17	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	17	18	24	25
The MAPK cascade induces ER stress and NFkappaB .	The MAPK cascade induces ER stress and NFkappaB.	1	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	1	2	4	5
MAPK and pAKT may cause a ligandless activation of the AF-1 domain of membrane bound and cytoplasmatic ER .	MAPK and pAKT may cause a ligandless activation of the AF-1 domain of membrane bound and cytoplasmatic ER.	0	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	0	1	17	18
This response is replicated in vitro and involves ERK mediated activation of the estrogen receptor ( ER ) alpha and upregulation of estrogen response element activity .	This response is replicated in vitro and involves ERK mediated activation of the estrogen receptor (ER) alpha and upregulation of estrogen response element activity.	8	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	estrogen receptor	estrogen receptor	estrogen receptor	8	9	13	15
Immunohistochemical staining demonstrates that progesterone receptor ( PR ) and pS2 , two E ( 2 )-regulated gene products , are significantly increased in MEK and MCF -7 cell tumors compared to those of MCF-7 control tumors , suggesting that activation of ERalpha by MAPK enhances the expression of E ( 2 )-regulated genes and accelerates tumor growth .	Immunohistochemical staining demonstrates that progesterone receptor (PR) and pS2, two E (2)-regulated gene products, are significantly increased in MEK and MCF -7 cell tumors compared to those of MCF-7 control tumors, suggesting that activation of ERalpha by MAPK enhances the expression of E (2)-regulated genes and accelerates tumor growth.	40	45	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	44	45	42	43
In addition , some reports suggest that CAV1 mediates mitogen activated protein kinase ( MAPK )-dependent CREB phosphorylation activating ERalpha and ERbeta through its scaffolding domain similarly to ERalpha and ERbeta activation by RES [ XREF_BIBR - XREF_BIBR , XREF_BIBR ] .	In addition, some reports suggest that CAV1 mediates mitogen activated protein kinase (MAPK)-dependent CREB phosphorylation activating ERalpha and ERbeta through its scaffolding domain similarly to ERalpha and ERbeta activation by RES [XREF_BIBR - XREF_BIBR, XREF_BIBR].	7	21	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	CAV1 mediates mitogen activated protein kinase (MAPK)-dependent CREB phosphorylation	mapk	ERalpha	ERalpha	eralpha	14	15	19	20
In addition , the induction of ER-alpha by MAPK also enhances ER signaling and promotes tumor growth in the presence of estradiol , and such tumors have been shown to be responsive still to antiestrogen therapy [ XREF_BIBR ] .	In addition, the induction of ER-alpha by MAPK also enhances ER signaling and promotes tumor growth in the presence of estradiol, and such tumors have been shown to be responsive still to antiestrogen therapy [XREF_BIBR].	4	9	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER-alpha	ER-alpha	ER-alpha	8	9	6	7
A new article by Holloway and colleagues [ XREF_BIBR ] sheds light on this mechanism of ERalpha negativity , revealing that exaggerated ERK1/2 MAPK signalling promotes ERalpha downregulation via its impact on cytoplasmic substrates that include the transcription factor nuclear factor kappa B ( NFkappaB ) .	A new article by Holloway and colleagues [XREF_BIBR] sheds light on this mechanism of ERalpha negativity, revealing that exaggerated ERK1/2 MAPK signalling promotes ERalpha downregulation via its impact on cytoplasmic substrates that include the transcription factor nuclear factor kappa B (NFkappaB).	22	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2 MAPK	ERK1/2 MAPK	ERK1/2 MAPK	ERalpha	ERalpha	ERalpha	22	24	26	27
In breast cancer , ERK1/2 is known to activate the ER at the S118 phosphorylation site , which results in enhanced proliferation and tumorigenesis .	In breast cancer, ERK1/2 is known to activate the ER at the S118 phosphorylation site, which results in enhanced proliferation and tumorigenesis.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	4	5	10	11
In particular , E2 induced a similar time course of MAPK activation in ERalpha or ERbeta expressing cells ( maximal activation at 15min ) which was necessary for neuroprotection against beta-amyloid toxicity .	In particular, E2 induced a similar time course of MAPK activation in ERalpha or ERbeta expressing cells (maximal activation at 15min) which was necessary for neuroprotection against beta-amyloid toxicity.	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	10	11	13	14
This suggests that the previously observed anti-tumor effects of sorafenib are mediated by a combination of inhibition of RAF family kinases and the ERK1/2 pathway ; receptor tyrosine kinases that signal angiogenesis ; and the induction of ER stress signaling .	This suggests that the previously observed anti-tumor effects of sorafenib are mediated by a combination of inhibition of RAF family kinases and the ERK1/2 pathway; receptor tyrosine kinases that signal angiogenesis; and the induction of ER stress signaling.	23	39	induction	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	23	24	37	38
In the present study , we first report that receptor Gb3 dependent Stx endocytosis activates the MAPK mediated ribotoxic stress response and apoptotic and ER stress pathways , triggering caspase-3/7/8 cleavage as well as disrupting the mitochondrial membrane potential in the newly identified toxin sensitive RPE cell line ARPE-19 .	In the present study, we first report that receptor Gb3 dependent Stx endocytosis activates the MAPK mediated ribotoxic stress response and apoptotic and ER stress pathways, triggering caspase-3/7/8 cleavage as well as disrupting the mitochondrial membrane potential in the newly identified toxin sensitive RPE cell line ARPE-19.	15	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	16	17	24	25
In conclusion , this result shows that luteolin and apigenin activate MAPK and Nrf2 signaling , which elicit adaptive cellular stress response pathways , restore 4-HNE-induced ER homeostasis and inhibit cytotoxicity .	In conclusion, this result shows that luteolin and apigenin activate MAPK and Nrf2 signaling, which elicit adaptive cellular stress response pathways, restore 4-HNE-induced ER homeostasis and inhibit cytotoxicity.	11	27	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	11	12	26	27
The formation of this multiprotein complex leads , via c-Src , to MAPK activation , which is abrogated in the presence of specific RNA silencers targeting ERalpha or IGF-IR .	The formation of this multiprotein complex leads, via c-Src, to MAPK activation, which is abrogated in the presence of specific RNA silencers targeting ERalpha or IGF-IR.	12	28	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	12	13	26	27
Moreover , these data also support others ' which suggest presence of the Her2 can limit endocrine response through MAPK signalling and modulation of ER function [ XREF_BIBR ] .	Moreover, these data also support others ' which suggest presence of the Her2 can limit endocrine response through MAPK signalling and modulation of ER function [XREF_BIBR].	19	27	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	19	20	24	25
Inhibition of ERK1/2 reduced ER stress caused by nefazodone .	Inhibition of ERK1/2 reduced ER stress caused by nefazodone.	0	5	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	2	3	4	5
Regardless , the finding that ER stress can switch between ERK1/2 regulated and ERK1/2 independent cell death pathways may be relevant to attempts to target ER stress signalling in certain pathologies .	Regardless, the finding that ER stress can switch between ERK1/2 regulated and ERK1/2 independent cell death pathways may be relevant to attempts to target ER stress signalling in certain pathologies.	3	27	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	13	14	25	26
Since we found that D1R activation restores LTP in the absence of endogenous E2 , but does not restore it in the presence of ER blockade , we explored whether the D1R- and ER dependent MSN LTP could also be mediated by ERK activation .	Since we found that D1R activation restores LTP in the absence of endogenous E2, but does not restore it in the presence of ER blockade, we explored whether the D1R- and ER dependent MSN LTP could also be mediated by ERK activation.	33	43	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ER	ER	ER	42	43	33	34
Since , it is well established that ERalpha can be activated in a ligand independent manner by MAPK [ XREF_BIBR ] at serine 118 ( S118 ) , we also evaluated the levels of phospho-S118 in WT ERalpha or K303R ERalpha overexpressing cells under the same conditions described above .	Since, it is well established that ERalpha can be activated in a ligand independent manner by MAPK [XREF_BIBR] at serine 118 (S118), we also evaluated the levels of phospho-S118 in WT ERalpha or K303R ERalpha overexpressing cells under the same conditions described above.	7	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	17	18	7	8
The increased activity and expression of MAPK may contribute to the estrogen nonresponsive growth phenotype and ligand independent activity of ER in T5-PRF cells .	The increased activity and expression of MAPK may contribute to the estrogen nonresponsive growth phenotype and ligand independent activity of ER in T5-PRF cells.	2	23	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	6	7	20	21
PYP ( 250 pg/ml ) treatment downregulated the PFOS induced increase in ER stress , mediated by phosphorylation of ERK1/2 .	PYP (250 pg/ml) treatment downregulated the PFOS induced increase in ER stress, mediated by phosphorylation of ERK1/2.	12	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	phosphorylation of ERK1/2	erk1/2	ER	ER	er	19	20	12	13
Furthermore , active MAPK signaling can phosphorylate serine in NH2-terminal region of the ER- AF1 , and thereby increase ER activation [ XREF_BIBR ] .	Furthermore, active MAPK signaling can phosphorylate serine in NH2-terminal region of the ER- AF1, and thereby increase ER activation [XREF_BIBR].	3	20	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	3	4	19	20
PI3K and Akt sensitive MEK independent compensatory circuit of ERK activation in ER positive PI3K-mutant T47D breast cancer cells .	PI3K and Akt sensitive MEK independent compensatory circuit of ERK activation in ER positive PI3K-mutant T47D breast cancer cells.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	ER	ER	ER	9	10	12	13
First , pharmacological inhibition of the MAPK pathway ( by PD98054 for 30 min ) reduced ER to Golgi transport of alpha1-antitrypsin ( XREF_FIG ) .	First, pharmacological inhibition of the MAPK pathway (by PD98054 for 30 min) reduced ER to Golgi transport of alpha1-antitrypsin (XREF_FIG).	6	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	6	7	16	17
Our results thus indicated that ER-alpha36 is the estrogen receptor that mediates estrogen induction of the MAPK and ERK signaling in ER positive breast cancer cells .	Our results thus indicated that ER-alpha36 is the estrogen receptor that mediates estrogen induction of the MAPK and ERK signaling in ER positive breast cancer cells.	16	22	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	ER	ER	ER	18	19	21	22
Work by Hayashi et al [ XREF_BIBR ] in estrogen dependent cancers provides an example where the constitutively activated MAPK signaling pathway in endometrial cancer cells might enhance the transcriptional activity of ERalpha via phosphorylation of its AF-1 domain .	Work by Hayashi et al [XREF_BIBR] in estrogen dependent cancers provides an example where the constitutively activated MAPK signaling pathway in endometrial cancer cells might enhance the transcriptional activity of ERalpha via phosphorylation of its AF-1 domain.	19	34	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	19	20	32	33
ER alpha is involved in the transient activation of ERK and mitogen activated protein kinase ( MAPK ) by genistein via its early association with IGF-IR , leading to hyper-responsiveness of LM cells and confirming that ER signaling is enhanced by activation of ERK and MAPK in LM cells .	ER alpha is involved in the transient activation of ERK and mitogen activated protein kinase (MAPK) by genistein via its early association with IGF-IR, leading to hyper-responsiveness of LM cells and confirming that ER signaling is enhanced by activation of ERK and MAPK in LM cells.	36	45	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ER	ER	ER	43	44	36	37
Linc-RoR is required for MAPK and ERK mediated activation of ER .	Linc-RoR is required for MAPK and ERK mediated activation of ER.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	ER	ER	ER	6	7	10	11
Leptin can also affect the growth of estrogen receptor ( ER )-positive breast cancer cells , by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens , and by inducing MAPK dependent activation of ER .	Leptin can also affect the growth of estrogen receptor (ER)-positive breast cancer cells, by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens, and by inducing MAPK dependent activation of ER.	34	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	34	35	38	39
Importantly , inhibition of ERK abolished ROS generation and ER stress , whereas inhibition of JNK did not , indicating that positive feedback regulation between ERK activation and ROS generation triggers ER stress in response to combined treatment .	Importantly, inhibition of ERK abolished ROS generation and ER stress, whereas inhibition of JNK did not, indicating that positive feedback regulation between ERK activation and ROS generation triggers ER stress in response to combined treatment.	2	10	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ER	ER	ER	4	5	9	10
This activity of genistein was independent of the ER mediated signaling and was not inhibited by PKA and ERK1/2 blockade .	This activity of genistein was independent of the ER mediated signaling and was not inhibited by PKA and ERK1/2 blockade.	5	19	inhibited	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	18	19	8	9
Persistent activation of ERK and MAPK leads to Med1 overexpression , resulting in ER positive breast cancer cells resistant to tamoxifen .	Persistent activation of ERK and MAPK leads to Med1 overexpression, resulting in ER positive breast cancer cells resistant to tamoxifen.	1	14	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	5	6	13	14
Inhibition of the ERK1/2 pathway prevented the down-regulation of Bim ( EL ) but caused only a partial reversion of the cyto-protective effect of DeltaMEKK3 : ER * .	Inhibition of the ERK1/2 pathway prevented the down-regulation of Bim (EL) but caused only a partial reversion of the cyto-protective effect of DeltaMEKK3 : ER *.	3	27	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	3	4	26	27
Patients whose melanoma tumors showed higher levels of autophagosomes after BRAF or BRAF and MEK inhibition experienced lower response rates and shorter progression free survival , and this autophagy activation in preclinical models was dependent on MAPK driven expansion of the ER stress response that can be abrogated with combined BRAF and autophagy inhibition .	Patients whose melanoma tumors showed higher levels of autophagosomes after BRAF or BRAF and MEK inhibition experienced lower response rates and shorter progression free survival, and this autophagy activation in preclinical models was dependent on MAPK driven expansion of the ER stress response that can be abrogated with combined BRAF and autophagy inhibition.	34	43	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	36	37	41	42
The role of MAPK on BP induced ER stress and cell death .	The role of MAPK on BP induced ER stress and cell death.	1	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	3	4	7	8
In addition to estrogens , ER could be activated via phosphorylation at Ser118 by MAPK to induce its target gene expression .	In addition to estrogens, ER could be activated via phosphorylation at Ser118 by MAPK to induce its target gene expression.	5	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	14	15	5	6
Here , our results are unique to show estrogen stimulated rapid ERalpha signaling mediated by ERK activation in aortic tissue , as well as VSMCs and ECs in vitro , in regulating vascular function by employing side-by-side comparisons in male and ovary-intact female mice in response to E2 or PPT .	Here, our results are unique to show estrogen stimulated rapid ERalpha signaling mediated by ERK activation in aortic tissue, as well as VSMCs and ECs in vitro, in regulating vascular function by employing side-by-side comparisons in male and ovary-intact female mice in response to E2 or PPT.	11	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ERalpha	ERalpha	ERalpha	15	16	11	12
Leptin can also affect the growth of ER positive breast cancer cells by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens , and by inducing MAPK dependent activation of ER [ XREF_BIBR , XREF_BIBR ] .	Leptin can also affect the growth of ER positive breast cancer cells by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens, and by inducing MAPK dependent activation of ER [XREF_BIBR, XREF_BIBR].	30	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	30	31	34	35
It was then shown that stromal derived FGFs act in a paracrine fashion , stimulating their receptors in the luminal epithelium and thus resulting in an ERK 1/2 mediated activation of ERalpha via phosphorylation [ XREF_BIBR ] .	It was then shown that stromal derived FGFs act in a paracrine fashion, stimulating their receptors in the luminal epithelium and thus resulting in an ERK 1/2 mediated activation of ERalpha via phosphorylation [XREF_BIBR].	26	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK 1/2	ERK 1/2	ERK 1/2	ERalpha	ERalpha	ERalpha	26	28	31	32
This suggests that the previously observed anti-tumor effects of sorafenib are partially mediated by a complex combination of inhibition of Raf family kinases and the ERK1/2 pathway ; receptor tyrosine kinases that signal angiogenesis ; and the induction of ER stress signaling .	This suggests that the previously observed anti-tumor effects of sorafenib are partially mediated by a complex combination of inhibition of Raf family kinases and the ERK1/2 pathway; receptor tyrosine kinases that signal angiogenesis; and the induction of ER stress signaling.	25	41	induction	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	25	26	39	40
Previous studies suggested that the ER could activate the MAPK pathway and in turn ERK could activate the ER .	Previous studies suggested that the ER could activate the MAPK pathway and in turn ERK could activate the ER.	13	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ER	ER	ER	14	15	18	19
Whereas STAT3 induces the expression of aromatase and upregulates estradiol production , MAPK inhibits the proteasomal degradation of ERalpha .	Whereas STAT3 induces the expression of aromatase and upregulates estradiol production, MAPK inhibits the proteasomal degradation of ERalpha.	12	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	12	13	18	19
These findings suggest that Cbl contributes to regulate RBP4 expression in adipose of female mice through ERK1/2 mediated activation of ERalpha .	These findings suggest that Cbl contributes to regulate RBP4 expression in adipose of female mice through ERK1/2 mediated activation of ERalpha.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ERalpha	ERalpha	ERalpha	16	17	20	21
By examining potential MAPK substrates ( again using appropriate dominant negatives ) , they demonstrate that activator protein-1 ( AP-1 ) and 90 kDa ribsosomal S6 kinase 1 ( RSK1 ) are not responsible for the ER downregulation promoted by MAPK hyperactivation .	By examining potential MAPK substrates (again using appropriate dominant negatives), they demonstrate that activator protein-1 (AP-1) and 90 kDa ribsosomal S6 kinase 1 (RSK1) are not responsible for the ER downregulation promoted by MAPK hyperactivation.	36	41	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	40	41	36	37
The activation of ERK1/2 through 17beta-estradiol triggered simultaneous association of endogenous androgen receptor , estrogen receptor alpha and Src .	The activation of ERK1/2 through 17beta-estradiol triggered simultaneous association of endogenous androgen receptor, estrogen receptor alpha and Src.	1	16	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	estrogen receptor	estrogen receptor	estrogen receptor	3	4	14	16
Inhibition of ERK-1/2 by PD98059 prevented PEP-1-GRX-1-induced dedifferentiation and inhibited ER stress .	Inhibition of ERK-1/2 by PD98059 prevented PEP-1-GRX-1-induced dedifferentiation and inhibited ER stress.	0	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK-1/2	ERK-1/2	ERK-1/2	ER	ER	ER	2	3	10	11
Given the interactions between MAPK signaling and ERalpha in ovarian cancer , we hypothesized that deregulation of MAPK modulates the intrinsic activity of ERalpha , and contributes to endocrine resistance in EOC .	Given the interactions between MAPK signaling and ERalpha in ovarian cancer, we hypothesized that deregulation of MAPK modulates the intrinsic activity of ERalpha, and contributes to endocrine resistance in EOC.	15	24	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	17	18	23	24
Substitution of S104/S106/S118 by alanine prevented ERalpha activation by Ras and Raf , indicating that these sites are required for MAPK stimulation of ERalpha activity .	Substitution of S104/S106/S118 by alanine prevented ERalpha activation by Ras and Raf, indicating that these sites are required for MAPK stimulation of ERalpha activity.	20	24	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	20	21	23	24
In resistant cells , vemurafenib did not inhibit phosphorylation of ERK , suppress the ER chaperone protein GRP78 after 72 hours , trigger phosphorylation of eIF2alpha , increase the abundance of pro apoptotic Bim isoform , inhibit growth , or induce apoptosis .	In resistant cells, vemurafenib did not inhibit phosphorylation of ERK, suppress the ER chaperone protein GRP78 after 72 hours, trigger phosphorylation of eIF2alpha, increase the abundance of pro apoptotic Bim isoform, inhibit growth, or induce apoptosis.	4	17	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	vemurafenib did not inhibit phosphorylation of ERK	erk	ER	ER	er	10	11	14	15
Thus , T ( 4 ) , like E ( 2 ) , causes phosphorylation by MAPK of nuclear ERalpha at serine 118 in MCF-7 cells and promotes cell proliferation through the ER by a MAPK dependent pathway .	Thus, T (4), like E (2), causes phosphorylation by MAPK of nuclear ERalpha at serine 118 in MCF-7 cells and promotes cell proliferation through the ER by a MAPK dependent pathway.	13	37	causes	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ER	ER	ER	16	17	32	33
Although both ER-alpha and ER-beta have been suggested to mediate both genomic and non genomic estrogen signaling , rapid estrogen signaling such as activation of the MAPK and ERK signaling in ER positive breast cancer MCF7 cells has been controversial .	Although both ER-alpha and ER-beta have been suggested to mediate both genomic and non genomic estrogen signaling, rapid estrogen signaling such as activation of the MAPK and ERK signaling in ER positive breast cancer MCF7 cells has been controversial.	26	36	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	ER	ER	ER	28	29	31	32
Although Her-3 is a kinase defective protein , heterodimerization with Her-2 and neu enables Her-3 response to extracellular ligand and the ability to directly couple to the PI3K ( phosphatidylinositol 3-kinase )-Akt cell survival pathway .	Although Her-3 is a kinase defective protein, heterodimerization with Her-2 and neu enables Her-3 response to extracellular ligand and the ability to directly couple to the PI3K (phosphatidylinositol 3-kinase)-Akt cell survival pathway.	8	15	enables	Positive_activation_token_1_verb	Positive_activation	Positive_activation	neu	neu	neu	Her-3	Her-3	Her-3	12	13	14	15
HER2 forms heterodimers with HER3 and transphosphorylation of HER3 by HER2 allows HER3 to interact with the p85 regulatory subunit of PI3K ( XREF_FIG ) , thereby causing activation of PI3K and Akt .	HER2 forms heterodimers with HER3 and transphosphorylation of HER3 by HER2 allows HER3 to interact with the p85 regulatory subunit of PI3K (XREF_FIG), thereby causing activation of PI3K and Akt.	0	14	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	0	1	12	13
Additional studies revealed that overexpression of erbB2 downregulated three erbB3 targeting miRNAs , miR-125a , miR-125b , and miR-205 , whereas the erbB2 kinase inhibitor ( lapatinib ) significantly enhanced expression of the three miRNAs in breast cancer cells , suggesting that erbB2 might regulate erbB3 expression through a miRNA dependent mechanism .	Additional studies revealed that overexpression of erbB2 downregulated three erbB3 targeting miRNAs, miR-125a, miR-125b, and miR-205, whereas the erbB2 kinase inhibitor (lapatinib) significantly enhanced expression of the three miRNAs in breast cancer cells, suggesting that erbB2 might regulate erbB3 expression through a miRNA dependent mechanism.	4	11	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	erbB2	overexpression of erbB2	erbb2	erbB3	erbB3	erbb3	6	7	9	10
Altogether , these results indicate that hMENA ( 11a ) in HER2 overexpressing breast cancer cells sustains HER3 and AKT axis activation and contributes to HER3 mediated resistance mechanisms to PI3K inhibitors .	Altogether, these results indicate that hMENA (11a) in HER2 overexpressing breast cancer cells sustains HER3 and AKT axis activation and contributes to HER3 mediated resistance mechanisms to PI3K inhibitors.	11	26	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	11	12	25	26
In tumor cells , ErbB2 activates ErbB3 , which stimulates several intracellular signaling proteins and pathways , including MAPK , PI3K and Akt and Src kinase .	In tumor cells, ErbB2 activates ErbB3, which stimulates several intracellular signaling proteins and pathways, including MAPK, PI3K and Akt and Src kinase.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	4	5	6	7
erbB2 activation of erbB3 is not dependent on equal surface levels of these receptors , since it occurs even in erbB3 transfected CHO cells with disproportionally small amounts of erbB2 .	erbB2 activation of erbB3 is not dependent on equal surface levels of these receptors, since it occurs even in erbB3 transfected CHO cells with disproportionally small amounts of erbB2.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	erbB2	erbB2	erbB2	erbB3	erbB3	erbB3	0	1	3	4
Phosphatidylinositol 3-kinase ( PI3K ) is activated by p185 ( erbB-2 ) / erbB-3 heterodimers in cells stimulated by HRG , and PI3K is constitutively activated by p185 ( erbB-2 ) / erbB-3 in breast carcinoma cells that overexpress c-erbB-2 .	Phosphatidylinositol 3-kinase (PI3K) is activated by p185 (erbB-2) / erbB-3 heterodimers in cells stimulated by HRG, and PI3K is constitutively activated by p185 (erbB-2) / erbB-3 in breast carcinoma cells that overexpress c-erbB-2.	6	39	activated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	erbB-2	erbB-2	erbb-2	erbB-3	erbB-3 in breast carcinoma cells that overexpress	erbb-3	10	11	32	33
Recent findings from our group and other group show that HER2 is a direct target of miR-199a and HER3 is a direct target of both miR-199a and miR-125b in A2780 and OVCAR-3 cells XREF_BIBR , XREF_BIBR .	Recent findings from our group and other group show that HER2 is a direct target of miR-199a and HER3 is a direct target of both miR-199a and miR-125b in A2780 and OVCAR-3 cells XREF_BIBR, XREF_BIBR.	10	19	is a direct target	Positive_activation_copula_1	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	10	11	18	19
Interestingly , ErbB2 overexpression induced mouse mammary tumors also markedly overexpress endogenous ErbB3 protein relative to uninvolved tissue , underscoring synergistic roles of the two receptors in promoting tumor onset and growth .	Interestingly, ErbB2 overexpression induced mouse mammary tumors also markedly overexpress endogenous ErbB3 protein relative to uninvolved tissue, underscoring synergistic roles of the two receptors in promoting tumor onset and growth.	2	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2 overexpression	erbb2	ErbB3	ErbB3	erbb3	2	3	12	13
Expression of the H1047R PIK3CA mutation in cells that overexpress HER2 upregulates the HER3 and HER4 ligand heregulin ( HRG ) and knockdown of HER3 inhibits growth of HER2 +/PI3K mutant cells .	Expression of the H1047R PIK3CA mutation in cells that overexpress HER2 upregulates the HER3 and HER4 ligand heregulin (HRG) and knockdown of HER3 inhibits growth of HER2 +/PI3K mutant cells.	10	22	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	10	11	13	14
These results suggest that the extracellular region of Necl-4 inhibits the HRG induced ErbB2 mediated activation of ErbB3 .	These results suggest that the extracellular region of Necl-4 inhibits the HRG induced ErbB2 mediated activation of ErbB3.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	13	14	17	18
Overexpression of HER2 or interaction with the ligand , neuroregulin1 ( NRG1 ) , promotes HER2 : HER3 heterodimerization and subsequent phosphoinositide 3-kinase signaling , driving tumor cell proliferation and tumor growth [ XREF_BIBR , XREF_BIBR ] .	Overexpression of HER2 or interaction with the ligand, neuroregulin1 (NRG1), promotes HER2 : HER3 heterodimerization and subsequent phosphoinositide 3-kinase signaling, driving tumor cell proliferation and tumor growth [XREF_BIBR, XREF_BIBR].	0	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	Overexpression of HER2	her2	HER3	HER3	her3	2	3	17	18
The HER2-HER3 signaling pair is an oncogenic unit in many HER2 driven breast cancers XREF_BIBR , XREF_BIBR , XREF_BIBR and upregulation of the HER3 receptor has been shown to play a role in resistance to several currently approved drugs XREF_BIBR , XREF_BIBR , XREF_BIBR .	The HER2-HER3 signaling pair is an oncogenic unit in many HER2 driven breast cancers XREF_BIBR, XREF_BIBR, XREF_BIBR and upregulation of the HER3 receptor has been shown to play a role in resistance to several currently approved drugs XREF_BIBR, XREF_BIBR, XREF_BIBR.	7	24	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	10	11	23	24
We describe here the existence of a heregulin-HER3 autocrine loop , and the contribution of heregulin dependent , HER2 mediated HER3 activation to gefitinib insensitivity in non small cell lung cancer ( NSCLC ) .	We describe here the existence of a heregulin-HER3 autocrine loop, and the contribution of heregulin dependent, HER2 mediated HER3 activation to gefitinib insensitivity in non small cell lung cancer (NSCLC).	18	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	18	19	20	21
This notion is consistent with the results of previous studies , which demonstrated that increased HER2 and HER3 dimerization leads to the activation of both HER2 and HER3 as well as their downstream signalling pathway in cancer [ XREF_BIBR , XREF_BIBR ] .	This notion is consistent with the results of previous studies, which demonstrated that increased HER2 and HER3 dimerization leads to the activation of both HER2 and HER3 as well as their downstream signalling pathway in cancer [XREF_BIBR, XREF_BIBR].	14	28	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	15	16	27	28
Although the putative phosphorylation site that activates ErbB3 has not yet been identified , the ErbB2 mediated activation of ErbB3 is a major assumption in our mathematical model .	Although the putative phosphorylation site that activates ErbB3 has not yet been identified, the ErbB2 mediated activation of ErbB3 is a major assumption in our mathematical model.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	15	16	19	20
Sublines of HER2 + breast cancer with acquired resistance to Tz ( BT474-TR and SKBR3-TR ) display increased cell surface HER3 compared to parental counterparts ( XREF_FIG ; XREF_SUPPLEMENTARY ) and correspondingly augmented sensitivity to H3-G and H3-D ( XREF_FIG ) .	Sublines of HER2 + breast cancer with acquired resistance to Tz (BT474-TR and SKBR3-TR) display increased cell surface HER3 compared to parental counterparts (XREF_FIG; XREF_SUPPLEMENTARY) and correspondingly augmented sensitivity to H3-G and H3-D (XREF_FIG).	0	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	2	3	20	21
In tumor cells , ErbB2 activates ErbB3 by stimulating several intracellular signaling proteins , such as MAPK , PI3K and Akt and Src kinase .	In tumor cells, ErbB2 activates ErbB3 by stimulating several intracellular signaling proteins, such as MAPK, PI3K and Akt and Src kinase.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	4	5	6	7
Our results in Figure XREF_FIG lend moderate support to this finding : a higher HER2 expression level leads to a slightly higher HER3 activation upon EGF stimulation .	Our results in Figure XREF_FIG lend moderate support to this finding : a higher HER2 expression level leads to a slightly higher HER3 activation upon EGF stimulation.	12	23	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	14	15	22	23
The experiments with ERBB2 gene amplified and ERBB2 dependent SKBR3 cells suggest that cytohesins can also fine tune signaling by ( asymmetric ) ERBB2 and ERBB3 dimers , where the potent ERBB2 kinase activates the catalytically deficient kinase domain of ERBB3 .	The experiments with ERBB2 gene amplified and ERBB2 dependent SKBR3 cells suggest that cytohesins can also fine tune signaling by (asymmetric) ERBB2 and ERBB3 dimers, where the potent ERBB2 kinase activates the catalytically deficient kinase domain of ERBB3.	31	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	ERBB3	ERBB3	ERBB3	31	32	40	41
AV-203 also shows potent tumor growth inhibition in a number of xenograft models where HER3 is activated by ligand NRG1 or HER2 overexpression [ XREF_BIBR ] .	AV-203 also shows potent tumor growth inhibition in a number of xenograft models where HER3 is activated by ligand NRG1 or HER2 overexpression [XREF_BIBR].	14	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	21	22	14	15
In the setting of ErbB2 positive breast cancer , preclinical data suggests that complete blockade of ErbB2 is insufficient to inhibit ErbB3 signaling ; ErbB2 blockade leads to both transcriptional upregulation and mobilization of cytoplasmic stores of ErbB3 that promote activation of downstream signaling and circumvent ErbB2 inhibition .	In the setting of ErbB2 positive breast cancer, preclinical data suggests that complete blockade of ErbB2 is insufficient to inhibit ErbB3 signaling; ErbB2 blockade leads to both transcriptional upregulation and mobilization of cytoplasmic stores of ErbB3 that promote activation of downstream signaling and circumvent ErbB2 inhibition.	14	22	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	16	17	21	22
This property may be particularly advantageous in HER2 amplified breast cancers , in which HER2 appears to activate HER3 in a ligand independent manner .	This property may be particularly advantageous in HER2 amplified breast cancers, in which HER2 appears to activate HER3 in a ligand independent manner.	7	19	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	7	8	18	19
LJM716 therefore possesses a novel mechanism of action ; it prevents the structural rearrangements required for ErbB3 activation induced by either HER2 or NRG .	LJM716 therefore possesses a novel mechanism of action; it prevents the structural rearrangements required for ErbB3 activation induced by either HER2 or NRG.	16	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ErbB3	ErbB3	ErbB3	21	22	16	17
Dual blockade of HER2 with trastuzumab and lapatinib does not eliminate the compensatory upregulation of HER3 .	Dual blockade of HER2 with trastuzumab and lapatinib does not eliminate the compensatory upregulation of HER3.	1	16	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	3	4	15	16
Treatment of HER2 +/ER-/AR+ BC cells ( LAR-BC cells ) , MDA-MB453 , with DHT stimulates cell growth by activating the oncogenic Wnt and the HER3 signaling pathway .	Treatment of HER2 +/ER-/AR+ BC cells (LAR-BC cells), MDA-MB453, with DHT stimulates cell growth by activating the oncogenic Wnt and the HER3 signaling pathway.	2	27	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	2	3	25	26
XREF_BIBR A resistance mechanism to lapatinib belongs to this same category , since lapatinib induced HER2 inhibition causes a compensatory PI3K and Akt- and FoxO3A dependent upregulation of HER3 .	XREF_BIBR A resistance mechanism to lapatinib belongs to this same category, since lapatinib induced HER2 inhibition causes a compensatory PI3K and Akt- and FoxO3A dependent upregulation of HER3.	13	29	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	lapatinib induced HER2	her2	HER3	HER3	her3	15	16	28	29
These studies suggest that 1 ) dual blockade of HER2 does not eliminate HER3 function completely , and 2 ) HER3 inhibitors sensitize HER2 overexpressing breast cancers to dual blockade of HER2 .	These studies suggest that 1) dual blockade of HER2 does not eliminate HER3 function completely, and 2) HER3 inhibitors sensitize HER2 overexpressing breast cancers to dual blockade of HER2.	7	14	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	9	10	13	14
Immunoblotting analysis indicated that HRG1 re-activated HER3 and AKT in the presence of lapatinib , which persisted for at least 72 h. Activation of HER3 and downstream AKT was mediated by residual activity of HER2 .	Immunoblotting analysis indicated that HRG1 re-activated HER3 and AKT in the presence of lapatinib, which persisted for at least 72 h. Activation of HER3 and downstream AKT was mediated by residual activity of HER2.	4	35	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	34	35	6	7
Several new HER2 targeted therapies and HER2 and HER3 antibodies have now been developed for metastatic disease ( S54 ) .	Several new HER2 targeted therapies and HER2 and HER3 antibodies have now been developed for metastatic disease (S54).	0	13	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	2	3	8	9
These pharmacodynamic studies demonstrate that LJM716 is capable of inhibiting both HER2 and ligand mediated HER3 signaling in vivo as evidenced by decreased pHER3 / pAKT in both xenograft models .	These pharmacodynamic studies demonstrate that LJM716 is capable of inhibiting both HER2 and ligand mediated HER3 signaling in vivo as evidenced by decreased pHER3 / pAKT in both xenograft models.	10	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	11	12	15	16
These data may indicate that HER2 can activate PI3K signaling in a HER3 dependent and independent manner , and that modulation of pAKT may be a key predictor of single-agent activity for both LJM716 and trastuzumab .	These data may indicate that HER2 can activate PI3K signaling in a HER3 dependent and independent manner, and that modulation of pAKT may be a key predictor of single-agent activity for both LJM716 and trastuzumab.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	5	6	12	13
In fact , ErbB2 deficient cells overexpressing ErbB3 and -4 showed little capacity to migrate in response to EGF ligands , compared with cells with functional ErbB2 receptors ( XREF_FIG and XREF_FIG ) .	In fact, ErbB2 deficient cells overexpressing ErbB3 and -4 showed little capacity to migrate in response to EGF ligands, compared with cells with functional ErbB2 receptors (XREF_FIG and XREF_FIG).	3	9	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	3	4	7	8
ErbB2 heterodimerizes with and activates the ErbB3 receptor , and the two receptors synergize in promoting growth factor induced cell proliferation , transformation , and invasiveness .	ErbB2 heterodimerizes with and activates the ErbB3 receptor, and the two receptors synergize in promoting growth factor induced cell proliferation, transformation, and invasiveness.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	0	1	6	7
Since Tz inhibited the RAD001 induced increases in P-HER3 and P-AKT , we deduce that mTOR inhibition increased PI3K signaling via HER2 activated HER3 .	Since Tz inhibited the RAD001 induced increases in P-HER3 and P-AKT, we deduce that mTOR inhibition increased PI3K signaling via HER2 activated HER3.	19	24	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	21	22	23	24
We next examined whether the HRG induced ErbB2 mediated activation of ErbB3 is inhibited by the extracellular region of Necl-4 .	We next examined whether the HRG induced ErbB2 mediated activation of ErbB3 is inhibited by the extracellular region of Necl-4.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	7	8	11	12
Dual blockade of HER2 in HER2 overexpressing tumor cells does not completely eliminate HER3 function .	Dual blockade of HER2 in HER2 overexpressing tumor cells does not completely eliminate HER3 function.	3	14	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2 overexpressing	her2	HER3	HER3	her3	5	6	13	14
To investigate whether over-expression and relocalization of ErbB2 causes the relocalization of ErbB3 to the apical domain as well , we assessed ErbB3 polarity in the same surface biotinylation experiments described above .	To investigate whether over-expression and relocalization of ErbB2 causes the relocalization of ErbB3 to the apical domain as well, we assessed ErbB3 polarity in the same surface biotinylation experiments described above.	3	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	over-expression and relocalization of ErbB2	erbb2	ErbB3	ErbB3	erbb3	7	8	12	13
The antibody shows potent inhibition of tumor growth in a broad spectrum of xenograft models in which ErbB3 is activated by its ligand NRG1 or by HER2 overexpression .	The antibody shows potent inhibition of tumor growth in a broad spectrum of xenograft models in which ErbB3 is activated by its ligand NRG1 or by HER2 overexpression.	17	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HER2	HER2 overexpression	her2	ErbB3	ErbB3	erbb3	26	27	17	18
In summary , dual blockade of HER2 does not eliminate HER3 function completely .	In summary, dual blockade of HER2 does not eliminate HER3 function completely.	4	11	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	6	7	10	11
Preliminary results show that HER-2 over-expression might not be necessary and activation of HER-3 and/or HER-4 by HRGs might be enough to subsequently activate HER-2 [ XREF_BIBR - XREF_BIBR ] .	Preliminary results show that HER-2 over-expression might not be necessary and activation of HER-3 and/or HER-4 by HRGs might be enough to subsequently activate HER-2 [XREF_BIBR - XREF_BIBR].	4	14	be necessary and activation	Positive_activation_copula_1	Positive_activation	Positive_activation	HER-2	HER-2 over-expression	her-2	HER-3	HER-3	her-3	4	5	13	14
Although ligand blocking HER3 antibodies inhibit NRG1 driven tumor growth , they are ineffective against HER2-drive tumor growth because HER2 activates HER3 in a ligand independent manner .	Although ligand blocking HER3 antibodies inhibit NRG1 driven tumor growth, they are ineffective against HER2-drive tumor growth because HER2 activates HER3 in a ligand independent manner.	19	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	19	20	21	22
Pharmacologic strategies to block HER2-HER3 signaling include antibodies that directly target HER3 , or HER2 monoclonal antibodies that sterically hinder receptor dimerization .	Pharmacologic strategies to block HER2-HER3 signaling include antibodies that directly target HER3, or HER2 monoclonal antibodies that sterically hinder receptor dimerization.	10	16	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	14	15	11	12
Thus , HER2 mediated activation of HER3 is essential for stimulation of the PI3K and AKT pathway .	Thus, HER2 mediated activation of HER3 is essential for stimulation of the PI3K and AKT pathway.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	2	3	6	7
Overexpression of ErbB2 , which may activate the ErbB2 and ErbB3 pathway , is often detected in breast cancer and associated with malignancy .	Overexpression of ErbB2, which may activate the ErbB2 and ErbB3 pathway, is often detected in breast cancer and associated with malignancy.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	Overexpression of ErbB2	erbb2	ErbB3	ErbB3	erbb3	2	3	10	11
We report herein that ErbB3 drives ErbB2 mediated preneoplastic hyperplasia , the transition of DCIS to malignant adenocarcinoma , and the response of ErbB2 overexpressing breast cancers to ErbB2 inhibitors .	We report herein that ErbB3 drives ErbB2 mediated preneoplastic hyperplasia, the transition of DCIS to malignant adenocarcinoma, and the response of ErbB2 overexpressing breast cancers to ErbB2 inhibitors.	4	7	drives	Positive_activation_token_1_noun	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	6	7	4	5
ErbB2 and ErbB3 transactivation by oxidative stress was supported by enhanced ErbB2 and ErbB3 Tyr phosphorylation , coupled to increased association with PI3K and Akt activation ( XREF_FIG ) .	ErbB2 and ErbB3 transactivation by oxidative stress was supported by enhanced ErbB2 and ErbB3 Tyr phosphorylation, coupled to increased association with PI3K and Akt activation (XREF_FIG).	0	16	supported	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ErbB2	ErbB2 and ErbB3 Tyr phosphorylation	erbb2	ErbB3	ErbB3	erbb3	11	12	2	3
With these techniques they demonstrated that ErbB2 inactivation blocked proliferation in ErbB2 overexpressing cells and that this was associated with a decrease in the phosphotyrosine content of ErbB3 , confirming that ErbB2 activity was required to activate ErbB3 .	With these techniques they demonstrated that ErbB2 inactivation blocked proliferation in ErbB2 overexpressing cells and that this was associated with a decrease in the phosphotyrosine content of ErbB3, confirming that ErbB2 activity was required to activate ErbB3.	31	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	31	32	37	38
22 Inhibition of HER2 using tyrosine kinase inhibitors ( TKIs ) suppresses HER3 mediated downstream activation of PI3K signaling in HER2 overexpressing cells .	22 Inhibition of HER2 using tyrosine kinase inhibitors (TKIs) suppresses HER3 mediated downstream activation of PI3K signaling in HER2 overexpressing cells.	1	15	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	3	4	12	13
Mammary glands harvested from 12-week-old virgin female NIC mice revealed ErbB2 induced diffuse hyperplasia and focal neoplasia in ErbB3 FL / + X NIC samples , but not ErbB3 FL / + X NIC ( XREF_FIG ) .	Mammary glands harvested from 12-week-old virgin female NIC mice revealed ErbB2 induced diffuse hyperplasia and focal neoplasia in ErbB3 FL / + X NIC samples, but not ErbB3 FL / + X NIC (XREF_FIG).	10	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	10	11	18	19
However , once ErbB3 receptors are activated by ErbB2 , they can go on to homodimerize and activate other ErbB3 receptors .	However, once ErbB3 receptors are activated by ErbB2, they can go on to homodimerize and activate other ErbB3 receptors.	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	8	9	3	4
In tumors that highly overexpress HER2 through gene amplification , ErbB3 can also be activated directly by HER2 through mass action in a ligand independent fashion [ XREF_BIBR - XREF_BIBR ] .	In tumors that highly overexpress HER2 through gene amplification, ErbB3 can also be activated directly by HER2 through mass action in a ligand independent fashion [XREF_BIBR - XREF_BIBR].	10	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ErbB3	ErbB3	ErbB3	17	18	10	11
Importantly , EREG neutralizing antibody , but not normal IgG , blocked the autocrine EREG induced EGFR phosphorylation and the migration of SACC cells , suggesting that EREG induced EGFR activation is essential for induction of cell migration and invasion by SACC cells .	Importantly, EREG neutralizing antibody, but not normal IgG, blocked the autocrine EREG induced EGFR phosphorylation and the migration of SACC cells, suggesting that EREG induced EGFR activation is essential for induction of cell migration and invasion by SACC cells.	27	30	induced	Positive_early_activation	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	27	28	29	30
EREG , as a ligand of EGFR , stimulates the EGFR signaling pathway , which promotes the metastasis of breast cancer cells .	EREG, as a ligand of EGFR, stimulates the EGFR signaling pathway, which promotes the metastasis of breast cancer cells.	0	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	0	1	10	11
We have demonstrated two novel and important functions of CX 3 CL1 on primary human SMCs : anti-apoptosis and proliferation , both mediated via epiregulin induced EGFR signalling .	We have demonstrated two novel and important functions of CX 3 CL1 on primary human SMCs : anti-apoptosis and proliferation, both mediated via epiregulin induced EGFR signalling.	22	27	induced	Positive_early_activation	Positive_activation	Positive_activation	epiregulin	epiregulin	epiregulin	EGFR	EGFR	EGFR	24	25	26	27
At the molecular level , EREG activates ErbB1 and ErbB4 homodimers as well as heterodimeric combinations of these two proteins and other EGF receptors [ XREF_BIBR , XREF_BIBR ] .	At the molecular level, EREG activates ErbB1 and ErbB4 homodimers as well as heterodimeric combinations of these two proteins and other EGF receptors [XREF_BIBR, XREF_BIBR].	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	ErbB1	ErbB1	ErbB1	5	6	7	8
In summary , we demonstrate that autocrine EREG activated EGFR can stabilize Snail and Slug , induce EMT and metastatic features in SACC cells .	In summary, we demonstrate that autocrine EREG activated EGFR can stabilize Snail and Slug, induce EMT and metastatic features in SACC cells.	6	11	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	7	8	9	10
Thus , autocrine EREG induced EGFR activation , even without a genetic mutation , in metastatic SACC patients may be suitable for EGFR targeting therapy .	Thus, autocrine EREG induced EGFR activation, even without a genetic mutation, in metastatic SACC patients may be suitable for EGFR targeting therapy.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	3	4	5	6
Importantly , a neutralizing anti-EREG antibody , but not normal Ig G , abrogated auto-phosphorylation of EGFR in SACC-LM cell , which suggests that EGFR activation in SACC-LM cells is caused by the autocrine EREG .	Importantly, a neutralizing anti-EREG antibody, but not normal Ig G, abrogated auto-phosphorylation of EGFR in SACC-LM cell, which suggests that EGFR activation in SACC-LM cells is caused by the autocrine EREG.	24	35	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	34	35	24	25
XREF_BIBR In addition , EREG not only stimulates homodimers of both ErbB1 and ErbB4 , but also activates all possible heterodimers of ErbB complexes .	XREF_BIBR In addition, EREG not only stimulates homodimers of both ErbB1 and ErbB4, but also activates all possible heterodimers of ErbB complexes.	4	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	ErbB1	ErbB1	ErbB1	4	5	11	12
XREF_BIBR EREG is capable of binding to EGFR and ErbB4 receptor and stimulates homodimers of EGFR and ErbB4 in addition to heterodimers of ErbB2 and ErbB3 , leading to the activation of their intrinsic kinase domain and the phosphorylation of specific tyrosine residues in the cytoplasmic tail of their receptors ( XREF_FIG ) .	XREF_BIBR EREG is capable of binding to EGFR and ErbB4 receptor and stimulates homodimers of EGFR and ErbB4 in addition to heterodimers of ErbB2 and ErbB3, leading to the activation of their intrinsic kinase domain and the phosphorylation of specific tyrosine residues in the cytoplasmic tail of their receptors (XREF_FIG).	0	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	1	2	15	16
EREG activated EGFR signaling stabilized Snail and Slug and induced EMT program in SACC-LM cells .	EREG activated EGFR signaling stabilized Snail and Slug and induced EMT program in SACC-LM cells.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	0	1	2	3
In a colon cancer xenograft model , EREG expression correlated with a positive response to the anti-EGFR monoclonal antibody cetuximab , suggesting the tumors were dependent on the EGFR signaling pathway activated by EREG .	In a colon cancer xenograft model, EREG expression correlated with a positive response to the anti-EGFR monoclonal antibody cetuximab, suggesting the tumors were dependent on the EGFR signaling pathway activated by EREG.	28	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	33	34	28	29
Together , these results support a promiscuous role of MUC1 in lung cancer development that may be related to cell-type specific functions of MUC1 in the tumor microenvironment , and MUC1 deficiency in fibroblasts and malignant cells results in increased EREG production that activates the EGFR pathway for lung carcinogenesis .	Together, these results support a promiscuous role of MUC1 in lung cancer development that may be related to cell-type specific functions of MUC1 in the tumor microenvironment, and MUC1 deficiency in fibroblasts and malignant cells results in increased EREG production that activates the EGFR pathway for lung carcinogenesis.	40	46	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	40	41	45	46
Supporting this notion , EREG activation of EGFR was delayed as compared to AREG .	Supporting this notion, EREG activation of EGFR was delayed as compared to AREG.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	4	5	7	8
Additionally , upregulation of EREG expression through promoter demethylation might activate the EGFR pathway during the genesis of CRC [ XREF_BIBR ] , which also emphasize the role of aberrant methylation in EGFR pathway .	Additionally, upregulation of EREG expression through promoter demethylation might activate the EGFR pathway during the genesis of CRC [XREF_BIBR], which also emphasize the role of aberrant methylation in EGFR pathway.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EREG	EREG expression	ereg	EGFR	EGFR	egfr	4	5	12	13
Moreover , EREG activated EGFR stabilized Snail and Slug , which promoted EMT and metastatic features in SACC cells .	Moreover, EREG activated EGFR stabilized Snail and Slug, which promoted EMT and metastatic features in SACC cells.	2	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	2	3	4	5
Because epiregulin can stimulate multiple members of the EGFR receptor family , activation of both EGFR and EGFR3 signaling may contribute to carcinogenesis .	Because epiregulin can stimulate multiple members of the EGFR receptor family, activation of both EGFR and EGFR3 signaling may contribute to carcinogenesis.	1	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epiregulin	epiregulin	epiregulin	EGFR	EGFR	EGFR	1	2	8	9
Mechanistically , we found EREG mediated activation of the EGFR pathway in CRC to be associated with demethylation of its promoter .	Mechanistically, we found EREG mediated activation of the EGFR pathway in CRC to be associated with demethylation of its promoter.	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	4	5	9	10
The EMT like and metastatic features of SACC were promoted by autocrine EREG activated EGFR signaling pathway .	The EMT like and metastatic features of SACC were promoted by autocrine EREG activated EGFR signaling pathway.	9	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	12	13	14	15
This lowered concentration of EPR would then be unable to induce any significant down-regulation of EGFR .	This lowered concentration of EPR would then be unable to induce any significant down-regulation of EGFR.	2	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPR	EPR	EPR	EGFR	EGFR	EGFR	4	5	15	16
Autocrine EREG activates EGFR pathway in high metastatic SACC-LM cells .	Autocrine EREG activates EGFR pathway in high metastatic SACC-LM cells.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	1	2	3	4
TLR4 signaling in IECs also induces expression and release of amphyregulin and epiregulin that activate epidermal growth factor receptor ( EGFR ) .	TLR4 signaling in IECs also induces expression and release of amphyregulin and epiregulin that activate epidermal growth factor receptor (EGFR).	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epiregulin	TLR4 signaling in IECs also induces expression and release of amphyregulin and epiregulin	epiregulin	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	12	13	15	19
In addition , epiregulin caused rapid EGF receptor activation in RASM cells .	In addition, epiregulin caused rapid EGF receptor activation in RASM cells.	3	8	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epiregulin	epiregulin	epiregulin	EGF receptor	EGF receptor	EGF receptor	3	4	6	8
EREG is downregulated by siRNA mediated EGFR knockdown and EGFR inhibitors in EGFR-mutant NSCLC cells .	EREG is downregulated by siRNA mediated EGFR knockdown and EGFR inhibitors in EGFR-mutant NSCLC cells.	0	7	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	0	1	6	7
Epiregulin induced a more prolonged activation of EGF receptor ( EGFR ) and p42/44 mitogen activated protein kinase ( MAPK ) than EGF .	Epiregulin induced a more prolonged activation of EGF receptor (EGFR) and p42/44 mitogen activated protein kinase (MAPK) than EGF.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epiregulin	Epiregulin	Epiregulin	EGF receptor	EGF receptor	EGF receptor	0	1	7	9
Activation of EGFR by EPR can lead to activation of downstream Ras-Raf-mitogen activated protein kinase ( MAPK )-extracellular signal regulated kinase ( ERK ) as well as the phosphatidylinositol-3-kinase ( PI3K )-Akt pathways to increase cellular proliferation [ XREF_BIBR - XREF_BIBR ] .	Activation of EGFR by EPR can lead to activation of downstream Ras-Raf-mitogen activated protein kinase (MAPK)-extracellular signal regulated kinase (ERK) as well as the phosphatidylinositol-3-kinase (PI3K)-Akt pathways to increase cellular proliferation [XREF_BIBR - XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EPR	EPR	EPR	EGFR	EGFR	EGFR	4	5	2	3
CX3CL1 induced shedding of epiregulin , which acted in an autocrine and paracrine manner to activate the epidermal growth factor receptor , leading to PI3K activation and Akt phosphorylation [ XREF_BIBR ] .	CX3CL1 induced shedding of epiregulin, which acted in an autocrine and paracrine manner to activate the epidermal growth factor receptor, leading to PI3K activation and Akt phosphorylation [XREF_BIBR].	2	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epiregulin	epiregulin	epiregulin	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	4	5	17	21
We found that epiregulin induced EGFR activation in both primary osteoblasts and osteoblast like MC3T3-E1 cells .	We found that epiregulin induced EGFR activation in both primary osteoblasts and osteoblast like MC3T3-E1 cells.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	epiregulin	epiregulin	epiregulin	EGFR	EGFR	EGFR	3	4	5	6
Epiregulin may stimulate EGFR through an autocrine loop with positive feedback , and elevated EREG may indicate tumour dependence on the EGFR pathway .	Epiregulin may stimulate EGFR through an autocrine loop with positive feedback, and elevated EREG may indicate tumour dependence on the EGFR pathway.	0	4	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epiregulin	Epiregulin	Epiregulin	EGFR	EGFR	EGFR	0	1	3	4
We show here that EPR activates two members of the ErbB family of receptor tyrosine kinases , epidermal growth factor receptor ( EGFR ) and ErbB4 .	We show here that EPR activates two members of the ErbB family of receptor tyrosine kinases, epidermal growth factor receptor (EGFR) and ErbB4.	4	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EPR	EPR	EPR	EGFR	EGFR	EGFR	4	5	22	23
Finally , in the two cell lines expressing ErbB receptors , we demonstrated that only EGFR and ErbB1 was activated by epiregulin .	Finally, in the two cell lines expressing ErbB receptors, we demonstrated that only EGFR and ErbB1 was activated by epiregulin.	15	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	epiregulin	epiregulin	epiregulin	ErbB1	ErbB1	ErbB1	21	22	17	18
Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma .	Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epiregulin	epiregulin	epiregulin	EGFR	EGFR	EGFR	1	2	3	4
Epiregulin induced activation of the EGF receptor ( EGFR ) , Akt , a downstream kinase of phosphoinositide 3-kinase ( PI3K ) , and extracellular signaling regulated kinase 1/2 ( ERK1/2 ) .	Epiregulin induced activation of the EGF receptor (EGFR), Akt, a downstream kinase of phosphoinositide 3-kinase (PI3K), and extracellular signaling regulated kinase 1/2 (ERK1/2).	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Epiregulin	Epiregulin	Epiregulin	EGF receptor	EGF receptor	EGF receptor	0	1	5	7
EREG mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9 .	EREG mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	0	1	4	5
When signaling pathways were included in the network analysis , the network now included HB-EGF and EREG mediated EGFR signaling through C/EBPbeta , c-Src and AP-1 .	When signaling pathways were included in the network analysis, the network now included HB-EGF and EREG mediated EGFR signaling through C/EBPbeta, c-Src and AP-1.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	16	17	18	19
With these two SACC lines , we found that autocrine EREG induced EGFR activation promotes lung metastasis via EMT .	With these two SACC lines, we found that autocrine EREG induced EGFR activation promotes lung metastasis via EMT.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	10	11	12	13
We have previously shown that the ERK dependent activation of the Bcl-2 family can have a pro apoptotic effect on HSCs .	We have previously shown that the ERK dependent activation of the Bcl-2 family can have a pro apoptotic effect on HSCs.	6	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	6	7	11	12
Through the ESR1 specific agonist , propylpyrazole , the receptor ' s activity has been shown to protect against Abeta accumulation [ XREF_BIBR ] and from glutamate excitotoxicity through ERK signaling and upregulation of Bcl-2 at the gene level [ XREF_BIBR , XREF_BIBR ] .	Through the ESR1 specific agonist, propylpyrazole, the receptor 's activity has been shown to protect against Abeta accumulation [XREF_BIBR] and from glutamate excitotoxicity through ERK signaling and upregulation of Bcl-2 at the gene level [XREF_BIBR, XREF_BIBR].	29	35	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	29	30	34	35
Several clinical and experimental studies have shown that the activation of the Akt / ERK1/2 pathways directly regulates P-gp , Bcl-2 , and CXCR4 in colorectal cancer MDR cells associated with many physiologic and pathologic processes involving inflammation [ XREF_BIBR - XREF_BIBR ] .	Several clinical and experimental studies have shown that the activation of the Akt / ERK1/2 pathways directly regulates P-gp, Bcl-2, and CXCR4 in colorectal cancer MDR cells associated with many physiologic and pathologic processes involving inflammation [XREF_BIBR - XREF_BIBR].	14	21	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	14	15	20	21
Since activation of the ERK pathway has been shown to enhance Bcl-2 expression XREF_BIBR , XREF_BIBR , XREF_BIBR , we assessed whether the increased ERK1/2 phosphorylation in RanBPM shRNA cells was responsible for the elevated Bcl-2 protein levels observed in these cells .	Since activation of the ERK pathway has been shown to enhance Bcl-2 expression XREF_BIBR, XREF_BIBR, XREF_BIBR, we assessed whether the increased ERK1/2 phosphorylation in RanBPM shRNA cells was responsible for the elevated Bcl-2 protein levels observed in these cells.	4	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	4	5	11	12
Inhibition of ERK , but not PI3K and Akt , abrogates Cdk5 medidated Bcl-2 upregulation and the protection of the differentiated cells .	Inhibition of ERK, but not PI3K and Akt, abrogates Cdk5 medidated Bcl-2 upregulation and the protection of the differentiated cells.	0	14	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	2	3	13	14
Inhibition of ERKs inhibited the BDNF stimulated up-regulation of p35 and Bcl2 .	Inhibition of ERKs inhibited the BDNF stimulated up-regulation of p35 and Bcl2.	0	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	Bcl2	Bcl2	Bcl2	2	3	11	12
The inhibition of ERK activation with ERK inhibitor ( U0126 ) abolishes Bcl-2 activation .	The inhibition of ERK activation with ERK inhibitor (U0126) abolishes Bcl-2 activation.	3	13	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	3	4	12	13
Bcl-2 levels were increased in male mice treated with methamphetamine , whereas ERK1/2 and BAD levels were unchanged .	Bcl-2 levels were increased in male mice treated with methamphetamine, whereas ERK1/2 and BAD levels were unchanged.	0	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	12	13	0	1
ERK1/2 inhibition prevented doxorubicin induced upregulation of Bcl-2 and Bcl-xL , thereby increasing doxorubicin sensitivity in osteosarcoma cells .	ERK1/2 inhibition prevented doxorubicin induced upregulation of Bcl-2 and Bcl-xL, thereby increasing doxorubicin sensitivity in osteosarcoma cells.	0	9	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	0	1	7	8
In contrast to Rho signaling pathways , ERK dependent pathways stimulate Bcl-2 family proteins , such as Bcl-2 , as a pro survival protein ( Stankiewicz et al ., 2014 ) or as an anti-apoptotic protein working through several pathways , including CREB ( Hetman et al ., 2004 ) .	In contrast to Rho signaling pathways, ERK dependent pathways stimulate Bcl-2 family proteins, such as Bcl-2, as a pro survival protein (Stankiewicz et al., 2014) or as an anti-apoptotic protein working through several pathways, including CREB (Hetman et al., 2004).	7	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	7	8	11	12
This protection is associated with decreased apoptosis and involves ERK1/2 activation and alterations in antiapoptotic Bcl-2 and proapoptotic Bax proteins .	This protection is associated with decreased apoptosis and involves ERK1/2 activation and alterations in antiapoptotic Bcl-2 and proapoptotic Bax proteins.	9	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	9	10	15	16
Erk1/2 also upregulates Bcl-2 and Bcl-xL , as well as heat-shock proteins ( HSP90 and HSP70 ) through signal transducers and activators of transcription-3 ( STAT-3 ) [ XREF_BIBR , XREF_BIBR ] .	Erk1/2 also upregulates Bcl-2 and Bcl-xL, as well as heat-shock proteins (HSP90 and HSP70) through signal transducers and activators of transcription-3 (STAT-3) [XREF_BIBR, XREF_BIBR].	0	11	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	Bcl-2	Bcl-2	Bcl-2	0	1	3	4
In this regard , extracellular-signal-regulated kinase ( ERK ) and p38 from mitogen activated protein kinase family and Bcl-2 , Bim and Bax from Bcl-2 protein family were investigated .	In this regard, extracellular-signal-regulated kinase (ERK) and p38 from mitogen activated protein kinase family and Bcl-2, Bim and Bax from Bcl-2 protein family were investigated.	5	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	7	8	18	19
We had previously demonstrated that autophagy inhibited the activation of the ROS and ERK pathway [ XREF_BIBR ] , and there is abundant evidence that activation of the ERK pathway can increase the expression of several pro survival proteins , notably Bcl-2 , Bcl-xl and Mcl-1 , in a variety of cell types [ XREF_BIBR - XREF_BIBR ] .	We had previously demonstrated that autophagy inhibited the activation of the ROS and ERK pathway [XREF_BIBR], and there is abundant evidence that activation of the ERK pathway can increase the expression of several pro survival proteins, notably Bcl-2, Bcl-xl and Mcl-1, in a variety of cell types [XREF_BIBR - XREF_BIBR].	28	45	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	28	29	41	42
Indeed , the MAPK activated Bcl-2 protein family has been shown to directly affect the release of cytochrome c from mitochondria , offering a possible explanation for the observed cell apoptosis alteration .	Indeed, the MAPK activated Bcl-2 protein family has been shown to directly affect the release of cytochrome c from mitochondria, offering a possible explanation for the observed cell apoptosis alteration.	2	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Bcl-2	Bcl-2	Bcl-2	3	4	5	6
Furthermore , inhibition of Erk1/2 phosphorylation by MEK1/2 inhibitors increased sensitivity of GNAQ wild type cells to enzastaurin and was associated with similar alterations in the expression of p27 Kip1 , cyclin D1 , Bcl-2 and/or survivin to GNAQ mutant cells treated with enzastaurin .	Furthermore, inhibition of Erk1/2 phosphorylation by MEK1/2 inhibitors increased sensitivity of GNAQ wild type cells to enzastaurin and was associated with similar alterations in the expression of p27 Kip1, cyclin D1, Bcl-2 and/or survivin to GNAQ mutant cells treated with enzastaurin.	4	35	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Erk1/2	Erk1/2 phosphorylation	erk1/2	Bcl-2	Bcl-2	bcl-2	4	5	34	35
This study suggests that ERK mediated Bcl-2 upregulation contributes to BDNF induced Cdk5 mediated neuronal survival .	This study suggests that ERK mediated Bcl-2 upregulation contributes to BDNF induced Cdk5 mediated neuronal survival.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	4	5	6	7
Stimulation of cells with LIF increased the Bcl-2 and Bax ratio , whereas ERK1/2 inhibition decreased the Bcl-2 and Bax ratio , even after LIF stimulation .	Stimulation of cells with LIF increased the Bcl-2 and Bax ratio, whereas ERK1/2 inhibition decreased the Bcl-2 and Bax ratio, even after LIF stimulation.	13	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	13	14	17	18
ERK mediated signals and Bcl-2 both inhibit radiation induced changes in the mitochondrial membrane and the subsequent cell death in lymphocytic leukemia cells [ XREF_BIBR ] .	ERK mediated signals and Bcl-2 both inhibit radiation induced changes in the mitochondrial membrane and the subsequent cell death in lymphocytic leukemia cells [XREF_BIBR].	0	5	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	0	1	4	5
For example , ERK1/2 activation has been shown to promote the anti-apoptotic functions of Bcl-2 and cell survival in neuronal PC12 cells , whereas the activation of JNKs results in cell death via the apoptotic signaling pathway .	For example, ERK1/2 activation has been shown to promote the anti-apoptotic functions of Bcl-2 and cell survival in neuronal PC12 cells, whereas the activation of JNKs results in cell death via the apoptotic signaling pathway.	3	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	3	4	14	15
Furthermore , by Western blotting with antibodies specific for EGFR , Erk 1/2 ( p-Erk 1/2 ) , Mek ( p-Mek ) , Bcl-2 , and Bax , it was demonstrated that EGCG could reduce the expression of EGFR , inhibit phosphorylation of Erk 1/2 and Mek , downregulate Bcl-2 , and upregulate Bax .	Furthermore, by Western blotting with antibodies specific for EGFR, Erk 1/2 (p-Erk 1/2), Mek (p-Mek), Bcl-2, and Bax, it was demonstrated that EGCG could reduce the expression of EGFR, inhibit phosphorylation of Erk 1/2 and Mek, downregulate Bcl-2, and upregulate Bax.	32	50	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Erk 1/2	EGCG could reduce the expression of EGFR, inhibit phosphorylation of Erk 1/2	erk 1/2	Bcl-2	Bcl-2	bcl-2	43	45	49	50
Both PD98059 and U0126 , MAPK and ERK kinase inhibitors significantly prevented Bcl-2 induction suggesting regulation of Bcl-2 through the MEK and ERK pathway .	Both PD98059 and U0126, MAPK and ERK kinase inhibitors significantly prevented Bcl-2 induction suggesting regulation of Bcl-2 through the MEK and ERK pathway.	3	13	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	7	8	12	13
As shown in XREF_FIG , inhibition of ERK1/2 and p53 prevented the Dox induced upregulation of Bax and the downregulation of Bcl-2 .	As shown in XREF_FIG, inhibition of ERK1/2 and p53 prevented the Dox induced upregulation of Bax and the downregulation of Bcl-2.	5	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	7	8	21	22
RA treatment activates Cdk5 mediated PI3K and Akt and ERK pathways which cause Bcl-2 upregulation and prevent apoptosis during neuronal differentiation [ XREF_BIBR ] .	RA treatment activates Cdk5 mediated PI3K and Akt and ERK pathways which cause Bcl-2 upregulation and prevent apoptosis during neuronal differentiation [XREF_BIBR].	7	14	cause	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	9	10	13	14
We report that : ( 1 ) Anoikis causes a down-activation of Fak , Src , Akt-1 and Erk1/2 , a loss of Fak-Src association , and a sustained and enhanced activation of p38beta , which is required as apoptosis and anoikis driver ; ( 2 ) PI3-K and Akt -1 up-regulates the expression of Bcl-X ( L ) and Mcl-1 , down-regulates Bax and Bak , drives Bad phosphorylation ( both serine112/136 residues ) and antagonizes p38beta activation ; ( 3 ) MEK and Erk up-regulates Bcl-2 , drives Bad phosphorylation ( serine112 residue ) , but does not antagonize p38bactivation ; ( 4 ) PI3-K and Akt -1 is required for survival , whereas MEK and Erk is not ; ( 5 ) Src acts as a cornerstone in the engagement of both pathways by beta1 integrins and Fak , and is crucial for survival ; and ( 6 ) beta1 integrins and Fak and/or Src regulate Bcl-2 homologs as both PI3-K and Atk -1 and MEK and Erk combined .	We report that : (1) Anoikis causes a down-activation of Fak, Src, Akt-1 and Erk1/2, a loss of Fak-Src association, and a sustained and enhanced activation of p38beta, which is required as apoptosis and anoikis driver; (2) PI3-K and Akt -1 up-regulates the expression of Bcl-X (L) and Mcl-1, down-regulates Bax and Bak, drives Bad phosphorylation (both serine112/136 residues) and antagonizes p38beta activation; (3) MEK and Erk up-regulates Bcl-2, drives Bad phosphorylation (serine112 residue), but does not antagonize p38bactivation; (4) PI3-K and Akt -1 is required for survival, whereas MEK and Erk is not; (5) Src acts as a cornerstone in the engagement of both pathways by beta1 integrins and Fak, and is crucial for survival; and (6) beta1 integrins and Fak and/or Src regulate Bcl-2 homologs as both PI3-K and Atk -1 and MEK and Erk combined.	85	171	up-regulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	Bcl-2	Bcl-2	Bcl-2	85	86	87	88
Inhibition of the ERK1/2 by PD98059 could downregulate Bcl-2 and upregulate Bax and was associated with restoration of sensitivity to gemcitabine in BXPC-3 cells .	Inhibition of the ERK1/2 by PD98059 could downregulate Bcl-2 and upregulate Bax and was associated with restoration of sensitivity to gemcitabine in BXPC-3 cells.	0	9	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	3	4	8	9
However , inhibitors of PI3K and MAPK ( data not shown ) as well as PKC ( XREF_FIG ) failed to block the increase in Xiap and Bcl-2 at 16 hours .	However, inhibitors of PI3K and MAPK (data not shown) as well as PKC (XREF_FIG) failed to block the increase in Xiap and Bcl-2 at 16 hours.	2	30	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Bcl-2	Bcl-2	Bcl-2	6	7	27	28
Therefore , the ERK1/2 and ICER mediated incoherent feed-forward loop differentially regulates the Bcl-2 response depending on the concentration range of ISO , which enables the cell to choose a different cell fate depending on the strength of the external stimulus .	Therefore, the ERK1/2 and ICER mediated incoherent feed-forward loop differentially regulates the Bcl-2 response depending on the concentration range of ISO, which enables the cell to choose a different cell fate depending on the strength of the external stimulus.	2	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	3	4	13	14
In most cases ERK1/2 signalling promotes cell survival by activating prosurvival BCL2 proteins ( BCL2 , BCL-x L and MCL1 ) and repressing prodeath proteins ( BAD , BIM , BMF and PUMA ) .	In most cases ERK1/2 signalling promotes cell survival by activating prosurvival BCL2 proteins (BCL2, BCL-x L and MCL1) and repressing prodeath proteins (BAD, BIM, BMF and PUMA).	3	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	BCL2	BCL2	BCL2	3	4	11	12
Also , the MEK and ERKs pathway activity can upregulate the pro apoptotic members of Bcl-2 family such as Bax , PUMA , and Bak as well as down regulate the anti-apoptotic members of the family such as Bcl-2 and Bcl-XL .	Also, the MEK and ERKs pathway activity can upregulate the pro apoptotic members of Bcl-2 family such as Bax, PUMA, and Bak as well as down regulate the anti-apoptotic members of the family such as Bcl-2 and Bcl-XL.	5	16	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	Bcl-2	Bcl-2	Bcl-2	5	6	15	16
In addition , ERK1/2 phosphorylation has been shown to upregulate Bcl-2 and enhanced survival of human macrophages .	In addition, ERK1/2 phosphorylation has been shown to upregulate Bcl-2 and enhanced survival of human macrophages.	3	11	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2 phosphorylation	erk1/2	Bcl-2	Bcl-2	bcl-2	3	4	10	11
Cell survival in MDCK ARF6-Q cysts induced at least in part by ERK dependent up-regulation of Bcl-2 , may sterically hinder lumen fusion .	Cell survival in MDCK ARF6-Q cysts induced at least in part by ERK dependent up-regulation of Bcl-2, may sterically hinder lumen fusion.	12	17	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	12	13	16	17
Several studies have found that constitutive activation of the extracellular signaling regulated kinase ( ERK ) could induce Bcl-2 upregulation and Bax downregulation [ XREF_BIBR - XREF_BIBR ] .	Several studies have found that constitutive activation of the extracellular signaling regulated kinase (ERK) could induce Bcl-2 upregulation and Bax downregulation [XREF_BIBR - XREF_BIBR].	12	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	14	15	18	19
Furthermore , previous studies have shown that the c-Abl-PKCdelta-p38 MAPK signaling pathway may trigger the mitochondrial apoptotic signaling pathway by activating the proapoptotic Bcl-2 proteins , Bax and Bak .	Furthermore, previous studies have shown that the c-Abl-PKCdelta-p38 MAPK signaling pathway may trigger the mitochondrial apoptotic signaling pathway by activating the proapoptotic Bcl-2 proteins, Bax and Bak.	9	24	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Bcl-2	Bcl-2	Bcl-2	9	10	23	24
We also observed that ILK increases the phosphorylation of ERK and AKT , which are involved in the regulation of adhesion mediated cell survival signaling in hypoxic MSCs , and also increases the Bcl-2 and Bax ratio and inhibits caspase-3 activation .	We also observed that ILK increases the phosphorylation of ERK and AKT, which are involved in the regulation of adhesion mediated cell survival signaling in hypoxic MSCs, and also increases the Bcl-2 and Bax ratio and inhibits caspase-3 activation.	4	36	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ILK increases the phosphorylation of ERK	erk	Bcl-2	Bcl-2	bcl-2	9	10	33	34
In the present study , GPR30 activation promoted Akt and ERK phosphorylation levels , increased Bcl-2 and BDNF , and decreased the levels of cleaved caspase-3 , BAX and the ratio of BAX and Bcl-2in the G-1 and E2 groups .	In the present study, GPR30 activation promoted Akt and ERK phosphorylation levels, increased Bcl-2 and BDNF, and decreased the levels of cleaved caspase-3, BAX and the ratio of BAX and Bcl-2in the G-1 and E2 groups.	5	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	GPR30 activation promoted Akt and ERK phosphorylation levels	erk	Bcl-2	Bcl-2	bcl-2	10	11	15	16
GPR30 activation regulated phosphatidylinositol 3-kinase ( PI3K )/Akt and MAPK and extracellular signal regulated kinase ( ERK ) signalling pathways , increased GPR30 and anti-apoptosis proteins Bcl-2 and brain derived neurotrophic factor ( BDNF ) , but decreased the pro apoptosis factor Bax and cleaved caspase-3 .	GPR30 activation regulated phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK and extracellular signal regulated kinase (ERK) signalling pathways, increased GPR30 and anti-apoptosis proteins Bcl-2 and brain derived neurotrophic factor (BDNF), but decreased the pro apoptosis factor Bax and cleaved caspase-3.	14	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	16	17	26	27
Thus , cisplatin and ARHI induced the occurrence of apoptosis that results from decreasing ERK and HER2 activation and downregulation of their downstream targets , Bcl-2 and XIAP , the known inhibitors of apoptosis .	Thus, cisplatin and ARHI induced the occurrence of apoptosis that results from decreasing ERK and HER2 activation and downregulation of their downstream targets, Bcl-2 and XIAP, the known inhibitors of apoptosis.	14	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	14	15	25	26
Previous studies show that activation of the MEK and ERK pathway increases pro apoptotic BCL-2 family members , such as BNIP3 .	Previous studies show that activation of the MEK and ERK pathway increases pro apoptotic BCL-2 family members, such as BNIP3.	7	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	BCL-2	BCL-2	BCL-2	9	10	14	15
HGF stimulated the downstream targets of Akt , glycogen synthase kinase ( GSK-3 ) , and Bad , a proapoptotic member of the Bcl-2 family , an effect that was blocked by PI-3K inhibitors but not by ERK1/2 inhibition .	HGF stimulated the downstream targets of Akt, glycogen synthase kinase (GSK-3), and Bad, a proapoptotic member of the Bcl-2 family, an effect that was blocked by PI-3K inhibitors but not by ERK1/2 inhibition.	23	38	blocked	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	37	38	23	24
MAPK associated extracellular signal regulated kinases ( ERK1/2 ) can also activate bcl-2 XREF_BIBR , p90RSK XREF_BIBR , m-calpains and micro-calpains XREF_BIBR , XREF_BIBR , cyclin D/cdk4 and cyclin E/cdk2 XREF_BIBR , XREF_BIBR cascades .	MAPK associated extracellular signal regulated kinases (ERK1/2) can also activate bcl-2 XREF_BIBR, p90RSK XREF_BIBR, m-calpains and micro-calpains XREF_BIBR, XREF_BIBR, cyclin D/cdk4 and cyclin E/cdk2 XREF_BIBR, XREF_BIBR cascades.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	bcl-2	bcl-2	bcl-2	7	8	12	13
ERK signaling can induce the intrinsic pathway of apoptosis and transcription of proapoptotic Bcl-2 family members Bax , Bak , and PUMA .	ERK signaling can induce the intrinsic pathway of apoptosis and transcription of proapoptotic Bcl-2 family members Bax, Bak, and PUMA.	0	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	0	1	13	14
Inhibition of ERK down-regulated BCL-2 and was associated with restoration of sensitivity to anoikis .	Inhibition of ERK down-regulated BCL-2 and was associated with restoration of sensitivity to anoikis.	0	5	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	BCL-2	BCL-2	BCL-2	2	3	4	5
We found that blockade of ERK activation not only suppressed Foxp3 generation , but Bcl-2 upregulation as well .	We found that blockade of ERK activation not only suppressed Foxp3 generation, but Bcl-2 upregulation as well.	5	15	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	5	6	14	15
The rationale for co-administration was that some melanomas respond poorly to MAPK inhibition , possibly through ERK mediated upregulation of the anti-apoptotic Bcl-2 family of proteins .	The rationale for co-administration was that some melanomas respond poorly to MAPK inhibition, possibly through ERK mediated upregulation of the anti-apoptotic Bcl-2 family of proteins.	8	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	16	17	22	23
ERK signaling has been shown to transcriptionally activate the pro survival genes BCL-2 and BCL-xL , as well as stabilize MCL-1 through phosphorylation [ XREF_BIBR , XREF_BIBR ] .	ERK signaling has been shown to transcriptionally activate the pro survival genes BCL-2 and BCL-xL, as well as stabilize MCL-1 through phosphorylation [XREF_BIBR, XREF_BIBR].	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	BCL-2	BCL-2	BCL-2	0	1	12	13
O GlcNAcylation at S209 of Lsp1 is a prerequisite for the recruitment of its kinase , PKC-beta1 , to induce S243 phosphorylation , leading to ERK activation and downregulation of BCL-2 and BCL-xL .	O GlcNAcylation at S209 of Lsp1 is a prerequisite for the recruitment of its kinase, PKC-beta1, to induce S243 phosphorylation, leading to ERK activation and downregulation of BCL-2 and BCL-xL.	25	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	BCL-2	BCL-2	BCL-2	25	26	30	31
Moreover , inhibition of ERK1/2 activity by the MAP kinase and ERK kinase ( MEK ) inhibitor PD98059 triggered the degradation of Bcl-2 and induced apoptotic cell death ( data not shown ) , suggesting that inhibition of ERK1/2 may trigger the degradation of Bcl-2 .	Moreover, inhibition of ERK1/2 activity by the MAP kinase and ERK kinase (MEK) inhibitor PD98059 triggered the degradation of Bcl-2 and induced apoptotic cell death (data not shown), suggesting that inhibition of ERK1/2 may trigger the degradation of Bcl-2.	36	45	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	38	39	44	45
We have reported that inhibition of MEK-1 , the upstream kinase of ERK1/2 , attenuates PKCepsilon mediated induction of A1 , A20 , and Bcl-2 , 15 whereas the PI-3K antagonist LY290042 prevents celecoxib induction of HO-1 .	We have reported that inhibition of MEK-1, the upstream kinase of ERK1/2, attenuates PKCepsilon mediated induction of A1, A20, and Bcl-2, 15 whereas the PI-3K antagonist LY290042 prevents celecoxib induction of HO-1.	10	25	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	12	13	24	25
Both MAPK and Akt pathways have been reported to induce Bcl-2 and survivin expression XREF_BIBR - XREF_BIBR .	Both MAPK and Akt pathways have been reported to induce Bcl-2 and survivin expression XREF_BIBR - XREF_BIBR.	1	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Bcl-2	Bcl-2	Bcl-2	1	2	10	11
Significant factors in the multivariate model included HER2 directed therapy ( HR = 0.38 , 95 % CI 0.17-0.84 , P = 0.02 ) and estrogen receptor positivity ( HR = 0.32 , 95 % CI 0.14-0.74 , P = 0.01 ) .	Significant factors in the multivariate model included HER2 directed therapy (HR = 0.38, 95% CI 0.17-0.84, P = 0.02) and estrogen receptor positivity (HR = 0.32, 95% CI 0.14-0.74, P = 0.01).	6	27	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	estrogen receptor	estrogen receptor	estrogen receptor	7	8	25	27
In HR +/HER2+ breast cancer cell lines , ER signaling and ER transcriptional activity are upregulated following treatment with HER2 targeted agents trastuzumab and lapatinib and ER functions as the key survival pathway reducing sensitivity to HER2-blockade [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In HR +/HER2+ breast cancer cell lines, ER signaling and ER transcriptional activity are upregulated following treatment with HER2 targeted agents trastuzumab and lapatinib and ER functions as the key survival pathway reducing sensitivity to HER2-blockade [XREF_BIBR, XREF_BIBR, XREF_BIBR].	17	27	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	19	20	26	27
XREF_BIBR - XREF_BIBR Due to the absence of ER and lack of HER2 over-expression , TNBCs are not treated with endocrine or HER2 targeted therapies .	XREF_BIBR - XREF_BIBR Due to the absence of ER and lack of HER2 over-expression, TNBCs are not treated with endocrine or HER2 targeted therapies.	0	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	22	23	8	9
Overexpression of HER-2 and Neu signaling pathway induces phosphorylation and constitutive activation of ERalpha leading to aberrant cell proliferation .	Overexpression of HER-2 and Neu signaling pathway induces phosphorylation and constitutive activation of ERalpha leading to aberrant cell proliferation.	0	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER-2	Overexpression of HER-2	her-2	ERalpha	ERalpha	eralpha	2	3	13	14
To examine whether Src axis plays a role in HER2 mediated ERalpha extranuclear actions , we have down regulated Src kinase using shRNA delivery .	To examine whether Src axis plays a role in HER2 mediated ERalpha extranuclear actions, we have down regulated Src kinase using shRNA delivery.	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	9	10	11	12
NVP-AUY922 exhibits potent antitumor activity at well tolerated dose levels against an ERBB2 overexpressing ER positive breast cancer xenograft .	NVP-AUY922 exhibits potent antitumor activity at well tolerated dose levels against an ERBB2 overexpressing ER positive breast cancer xenograft.	9	15	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	ER	ER	ER	12	13	14	15
Whilst breast tumors that express estrogen receptor ( ER ) are responsive to ER antagonists and aromatase inhibitors and HER2 positive tumors are effectively treated with HER2 blocking antibodies and/or HER2 kinase inhibitors [ XREF_BIBR ] , TNBC lacks a targeted therapy .	Whilst breast tumors that express estrogen receptor (ER) are responsive to ER antagonists and aromatase inhibitors and HER2 positive tumors are effectively treated with HER2 blocking antibodies and/or HER2 kinase inhibitors [XREF_BIBR], TNBC lacks a targeted therapy.	13	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	26	27	13	14
Another feature of interest is that MEKK1 , a downstream Her-2 signalling mediator activates ER and potentiates the agonist effect of tamoxifen [ XREF_BIBR ] .	Another feature of interest is that MEKK1, a downstream Her-2 signalling mediator activates ER and potentiates the agonist effect of tamoxifen [XREF_BIBR].	10	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Her-2	Her-2	Her-2	ER	ER	ER	10	11	14	15
However primary vMCF-7 DeltaRaf-1 1GX cells displayed higher resistance to chemo-endocrine therapy ( XREF_FIG ) indicating that aberrant activation of Raf-1/MEK/MAPK pathway and HER-2 and Neu overexpression activates ERalpha pathway and confers higher resistance to conventional anti-cancer therapy during in vivo growth .	However primary vMCF-7 DeltaRaf-1 1GX cells displayed higher resistance to chemo-endocrine therapy (XREF_FIG) indicating that aberrant activation of Raf-1/MEK/MAPK pathway and HER-2 and Neu overexpression activates ERalpha pathway and confers higher resistance to conventional anti-cancer therapy during in vivo growth.	23	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Neu	Neu overexpression	neu	ERalpha	ERalpha	eralpha	25	26	28	29
Preclinical models of HER2 overexpression have provided insights into possible mechanisms underlying tamoxifen resistance ; however , only the occasional HER2 overexpressing ERalpha positive cell line exhibits at best partial tamoxifen resistance , and in contrast to a significant percentage of primary breast tumors , HER2 overexpressing ERalpha positive breast tumor cell lines remain estrogen dependent .	Preclinical models of HER2 overexpression have provided insights into possible mechanisms underlying tamoxifen resistance; however, only the occasional HER2 overexpressing ERalpha positive cell line exhibits at best partial tamoxifen resistance, and in contrast to a significant percentage of primary breast tumors, HER2 overexpressing ERalpha positive breast tumor cell lines remain estrogen dependent.	43	48	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	45	46	47	48
Since ErbB2 has been found to decrease ER-alpha protein expression , these results are likely a consequence of ErbB2 mediated ERalpha downregulation .	Since ErbB2 has been found to decrease ER-alpha protein expression, these results are likely a consequence of ErbB2 mediated ERalpha downregulation.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ERalpha	ERalpha	ERalpha	18	19	20	21
Our results demonstrated that pRNA-HER2apt-siMED1 nanoparticles were specifically delivered to HER2 overexpressing ERalpha positive breast cancer cells both in vitro and in vivo .	Our results demonstrated that pRNA-HER2apt-siMED1 nanoparticles were specifically delivered to HER2 overexpressing ERalpha positive breast cancer cells both in vitro and in vivo.	8	16	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	10	11	12	13
Collectively , these results suggest that functional Src axis is necessary for HER2 mediated ER extranuclear actions and proliferation .	Collectively, these results suggest that functional Src axis is necessary for HER2 mediated ER extranuclear actions and proliferation.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	12	13	14	15
Moreover , ER can activate HER2 by membrane non genomic estrogen signaling , while HER2 activates ligand-independently ER by mitogen activated protein kinase ( MAPK )-/protein kinase B ( AKT )-mediated phosphorylation [ XREF_BIBR ] .	Moreover, ER can activate HER2 by membrane non genomic estrogen signaling, while HER2 activates ligand-independently ER by mitogen activated protein kinase (MAPK)-/protein kinase B (AKT)-mediated phosphorylation [XREF_BIBR].	14	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	14	15	17	18
Another ER transcriptional coactivator , mediator subunit 1 ( MED1 ) is overexpressed in circulating tumor cells and primary breast tumor tissues following tamoxifen treatment leading to HER2 mediated ER resistance .	Another ER transcriptional coactivator, mediator subunit 1 (MED1) is overexpressed in circulating tumor cells and primary breast tumor tissues following tamoxifen treatment leading to HER2 mediated ER resistance.	27	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	27	28	29	30
11 Importantly , MED1 can be phosphorylated and activated by an HER2 signaling pathway , while knockdown of MED1 by small interference RNA ( siRNA ) significantly sensitized HER2 overexpressing ERalpha positive breast cancer cells to tamoxifen treatment .	11 Importantly, MED1 can be phosphorylated and activated by an HER2 signaling pathway, while knockdown of MED1 by small interference RNA (siRNA) significantly sensitized HER2 overexpressing ERalpha positive breast cancer cells to tamoxifen treatment.	27	34	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	28	29	30	31
Factors that remained significantly associated with OS included receipt of neoadjuvant HER2 directed therapy ( HR 0.38 , 95 % CI 0.17-0.84 , P = 0.02 ) and positive ER status ( HR 0.32 , 95 % CI 0.14-0.74 , P = 0.01 ) .	Factors that remained significantly associated with OS included receipt of neoadjuvant HER2 directed therapy (HR 0.38, 95% CI 0.17-0.84, P = 0.02) and positive ER status (HR 0.32, 95% CI 0.14-0.74, P = 0.01).	8	30	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	11	12	29	30
Altered genes included PgR ( a known target of ERalpha and mTOR signaling ) and PLAU ( both decreased ) and BCL2 , ERBB2 , TFF1 , and SERPINA3 ( all increased ) .	Altered genes included PgR (a known target of ERalpha and mTOR signaling) and PLAU (both decreased) and BCL2, ERBB2, TFF1, and SERPINA3 (all increased).	7	24	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	ERalpha	ERalpha	ERalpha	23	24	9	10
In ER positive operable breast cancer treated with adjuvant tamoxifen , HER2 overexpression was associated with poor prognosis .	In ER positive operable breast cancer treated with adjuvant tamoxifen, HER2 overexpression was associated with poor prognosis.	1	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	11	12	1	2
Although suppression of oxidant repressed genes was not shown to be associated with ERBB2 over-expression , there was an enrichment of oxidant induced genes among the ERBB2 over-expressing ER positive breast tumors , suggesting that elevated oxidative stress is associated with ERBB2 overexpression and may contribute to the loss of PR co-expression seen in ERBB2 overexpressing ER positive breast cancers .	Although suppression of oxidant repressed genes was not shown to be associated with ERBB2 over-expression, there was an enrichment of oxidant induced genes among the ERBB2 over-expressing ER positive breast tumors, suggesting that elevated oxidative stress is associated with ERBB2 overexpression and may contribute to the loss of PR co-expression seen in ERBB2 overexpressing ER positive breast cancers.	52	59	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERBB2	ERBB2	ERBB2	ER	ER	ER	54	55	56	57
In the present study , we demonstrate that ERbeta activity can be modulated by ErbB2 signaling in ER expressing breast cancer cells .	In the present study, we demonstrate that ERbeta activity can be modulated by ErbB2 signaling in ER expressing breast cancer cells.	14	18	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ER	ER	ER	14	15	17	18
The crosstalk between MED1 and HER2 plays an important role in the tamoxifen resistance of human breast cancer , rendering targeted MED1 silencing in HER2 overexpressing ERalpha positive human breast cancer a promising strategy to overcome tamoxifen resistance .	The crosstalk between MED1 and HER2 plays an important role in the tamoxifen resistance of human breast cancer, rendering targeted MED1 silencing in HER2 overexpressing ERalpha positive human breast cancer a promising strategy to overcome tamoxifen resistance.	22	27	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	24	25	26	27
In this regard , HER-2 and neu vaccination appeared to alter tumor phenotype , causing ER pos HER-2 and neu pos DCIS to become ER pos HER-2 neg in 43.8 % of patients , and ER neg HER-2 and neu pos DCIS to become triple negative , ( 6.3 % ) , as shown in XREF_TABLE .	In this regard, HER-2 and neu vaccination appeared to alter tumor phenotype, causing ER pos HER-2 and neu pos DCIS to become ER pos HER-2 neg in 43.8% of patients, and ER neg HER-2 and neu pos DCIS to become triple negative, (6.3%), as shown in XREF_TABLE.	4	17	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neu	neu	neu	ER	ER	ER	6	7	15	16
HER2 mediated ER extranuclear actions requires Src kinase .	HER2 mediated ER extranuclear actions requires Src kinase.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	0	1	2	3
In this study , we found that ; ( a ) functional Src axis is needed for optimal activation of ERalpha extranuclear actions , ( b ) Src plays a key role in PELP1 and HER2 oncogene mediated ERalpha extranuclear actions and proliferation , ( c ) Excessive ERalpha extranuclear signaling in therapy resistant cells is inhibited by pharmacological inhibition of Src , ( d ) Functional Src axis is needed for PELP1 mediated oncogenic functions in vivo , and ( e ) Combination therapy of Src inhibitor with antiestrogens is more effective in blocking therapy resistance .	In this study, we found that; (a) functional Src axis is needed for optimal activation of ERalpha extranuclear actions, (b) Src plays a key role in PELP1 and HER2 oncogene mediated ERalpha extranuclear actions and proliferation, (c) Excessive ERalpha extranuclear signaling in therapy resistant cells is inhibited by pharmacological inhibition of Src, (d) Functional Src axis is needed for PELP1 mediated oncogenic functions in vivo, and (e) Combination therapy of Src inhibitor with antiestrogens is more effective in blocking therapy resistance.	35	84	mediated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	35	36	38	39
For long-term prognosis the phenotype of HR positive tumors cells ( higher differentiation , slower proliferation , etc. ) seems to be more relevant in receptor co-expressing tumors and may even be amplified by HER2 mediated ER activation .	For long-term prognosis the phenotype of HR positive tumors cells (higher differentiation, slower proliferation, etc.) seems to be more relevant in receptor co-expressing tumors and may even be amplified by HER2 mediated ER activation.	34	37	mediated	Positive_early_activation	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	34	35	36	37
Her2 overexpression in MCF-7 and Her2 cells promotes the relocalization of ER from the nucleus to the cytoplasm , enhances interactions of ER with Her2 , inhibits ER transactivation function , and induces resistance to tamoxifen mediated growth inhibition of breast cancer cells .	Her2 overexpression in MCF-7 and Her2 cells promotes the relocalization of ER from the nucleus to the cytoplasm, enhances interactions of ER with Her2, inhibits ER transactivation function, and induces resistance to tamoxifen mediated growth inhibition of breast cancer cells.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Her2	Her2 overexpression	her2	ER	ER	er	0	1	11	12
Preclinical data demonstrate that HER2 overexpression can lead to ligand independent activation of the ER and a reduction in the oestrogen binding capacity of the cells ( ie , to decreased ER levels ) and to a decrease in ER as well as PR transcripts ( Pietras et al , 1995 ) .	Preclinical data demonstrate that HER2 overexpression can lead to ligand independent activation of the ER and a reduction in the oestrogen binding capacity of the cells (ie, to decreased ER levels) and to a decrease in ER as well as PR transcripts (Pietras et al, 1995).	4	17	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	HER2	HER2 overexpression	her2	ER	ER	er	4	5	14	15
Our multivariate analysis showed that in patients without HER2 overexpression ER + PR- tumors were associated with an increased risk of recurrence and death compared with ER + PR+ tumors , with a hazard ratio of 2.12 for disease-free survival ( DFS ) and 4.79 for overall survival ( OS ) .	Our multivariate analysis showed that in patients without HER2 overexpression ER + PR- tumors were associated with an increased risk of recurrence and death compared with ER + PR+ tumors, with a hazard ratio of 2.12 for disease-free survival (DFS) and 4.79 for overall survival (OS).	6	13	overexpression	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	8	9	10	11
Overall , this study describes the delivery of MED1 siRNAs via the pRNA nanoparticle specifically to HER2 overexpressing ERalpha positive human breast cancer cells to overcome tamoxifen resistance , and our findings provide a highly promising perspective for potential clinical treatment of advanced metastatic and tamoxifen resistant human breast cancer .	Overall, this study describes the delivery of MED1 siRNAs via the pRNA nanoparticle specifically to HER2 overexpressing ERalpha positive human breast cancer cells to overcome tamoxifen resistance, and our findings provide a highly promising perspective for potential clinical treatment of advanced metastatic and tamoxifen resistant human breast cancer.	4	25	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	16	17	18	19
This study focused on patients with ER +/HER2+ breast cancer treated with neoadjuvant chemotherapy and HER2 targeted therapy and was designed to identify novel biomarkers predictive of pathologic response .	This study focused on patients with ER +/HER2+ breast cancer treated with neoadjuvant chemotherapy and HER2 targeted therapy and was designed to identify novel biomarkers predictive of pathologic response.	2	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	15	16	6	7
Because of the importance of membrane growth factor receptor HER2 signaling in ER positive breast cancer , we assessed relationship between Beclin 1 and HER2 and the role of Beclin 1 in ER positive breast cancer .	Because of the importance of membrane growth factor receptor HER2 signaling in ER positive breast cancer, we assessed relationship between Beclin 1 and HER2 and the role of Beclin 1 in ER positive breast cancer.	9	15	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	9	10	12	13
Examples specifically pertinent to breast cancer include Her2 and Neu receptor activated pathways as well as ER and PR receptors , discussed in subsequent sections .	Examples specifically pertinent to breast cancer include Her2 and Neu receptor activated pathways as well as ER and PR receptors, discussed in subsequent sections.	7	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Her2	Her2	Her2	ER	ER	ER	7	8	16	17
Taken together , these results support the requirement of RBP2 in aggressive breast cancers and provide the rationale for novel treatment methods targeting RBP2 in ER - and HER2 + patients .	Taken together, these results support the requirement of RBP2 in aggressive breast cancers and provide the rationale for novel treatment methods targeting RBP2 in ER - and HER2 + patients.	15	30	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	28	29	25	26
Several groups have demonstrated that the therapeutic usage of HER2 blocking agents , such as lapatinib , upregulates ERalpha , the ERalpha regulators FOXO3a and caveolin1 , and ER regulated genes , such as PgR and Bcl-2 , in HR+ HER2+ cell lines [ XREF_BIBR , XREF_BIBR ] .	Several groups have demonstrated that the therapeutic usage of HER2 blocking agents, such as lapatinib, upregulates ERalpha, the ERalpha regulators FOXO3a and caveolin1, and ER regulated genes, such as PgR and Bcl-2, in HR+ HER2+ cell lines [XREF_BIBR, XREF_BIBR].	7	30	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	9	10	18	19
Activated membrane ER can then activate adjacent EGFR and/or HER2 , which may then stimulate tumor growth .	Activated membrane ER can then activate adjacent EGFR and/or HER2, which may then stimulate tumor growth.	0	14	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	9	10	2	3
However , HER2 overexpressing ER positive tumors can develop resistance to tamoxifen by the acquisition of tamoxifen stimulated growth [ XREF_BIBR ] .	However, HER2 overexpressing ER positive tumors can develop resistance to tamoxifen by the acquisition of tamoxifen stimulated growth [XREF_BIBR].	2	8	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	2	3	4	5
Pak1 has been specifically linked to ErbB2 signaling in estrogen receptor ( ER ) negative tumors .	Pak1 has been specifically linked to ErbB2 signaling in estrogen receptor (ER) negative tumors.	6	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	estrogen receptor	estrogen receptor	estrogen receptor	6	7	9	11
Earlier studies have shown that both PELP1 and HER2 oncogenes promote activation of ERalpha target genes as well as local estrogen synthesis via upregulation of aromatase [ XREF_BIBR , XREF_BIBR ] .	Earlier studies have shown that both PELP1 and HER2 oncogenes promote activation of ERalpha target genes as well as local estrogen synthesis via upregulation of aromatase [XREF_BIBR, XREF_BIBR].	8	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	8	9	13	14
Based on these findings , we hypothesized that activators of the HER2 pathway might cause parabens to stimulate ERalpha at lower doses than suspected given the results of studies that examined their effects in isolation .	Based on these findings, we hypothesized that activators of the HER2 pathway might cause parabens to stimulate ERalpha at lower doses than suspected given the results of studies that examined their effects in isolation.	11	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	11	12	18	19
Diagnostic biomarkers were observed to fall into distinct groups : HER2 and neu co-clustered in group II with pro survival signaling molecules such as pAkt1 , pPI3K , pRSK3 , pGSK3beta , PDGFRbeta and insulin receptor ; progesterone receptor co-clustered in group X with Vav1 , peIF4G , pPLA2 ; and ER clustered by itself ( group XI ) .	Diagnostic biomarkers were observed to fall into distinct groups : HER2 and neu co-clustered in group II with pro survival signaling molecules such as pAkt1, pPI3K, pRSK3, pGSK3beta, PDGFRbeta and insulin receptor; progesterone receptor co-clustered in group X with Vav1, peIF4G, pPLA2; and ER clustered by itself (group XI).	10	57	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neu	neu	neu	ER	ER	ER	12	13	51	52
Second , the ER pathway can be activated by HER2 in the absence of estrogen and HER2 +/ER+ tumors are reported to be resistant to endocrine therapy XREF_BIBR .	Second, the ER pathway can be activated by HER2 in the absence of estrogen and HER2 +/ER+ tumors are reported to be resistant to endocrine therapy XREF_BIBR.	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	9	10	3	4
We showed that the expression of HER2 or HRG activated HER3 in breast cancer cell lines lead to phosphorylation and thus activation of ER ( XREF_FIG ) , confirming the direct cross talk between these receptors .	We showed that the expression of HER2 or HRG activated HER3 in breast cancer cell lines lead to phosphorylation and thus activation of ER (XREF_FIG), confirming the direct cross talk between these receptors.	4	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	expression of HER2	her2	ER	ER	er	6	7	23	24
XREF_BIBR , XREF_BIBR - XREF_BIBR In the current study , we exploited the 3-WJ pRNA structure to construct AlexaFluor647 labeled multifunctional pRNA-HER2apt-siMED1 nanoparticles bearing an HER2 targeting RNA aptamer and two different MED1 siRNAs to silence MED1 expression in HER2 overexpressing ERalpha positive breast cancer cells .	XREF_BIBR, XREF_BIBR - XREF_BIBR In the current study, we exploited the 3-WJ pRNA structure to construct AlexaFluor647 labeled multifunctional pRNA-HER2apt-siMED1 nanoparticles bearing an HER2 targeting RNA aptamer and two different MED1 siRNAs to silence MED1 expression in HER2 overexpressing ERalpha positive breast cancer cells.	37	45	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	39	40	41	42
These results reveal a mechanism of ER regulation mediated by HER2 , which suggests a new strategy to improve responses to endocrine therapy in breast cancer .	These results reveal a mechanism of ER regulation mediated by HER2, which suggests a new strategy to improve responses to endocrine therapy in breast cancer.	6	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	ER	ER	ER	10	11	6	7
Dual epidermal growth factor receptor ( EGFR ) and HER2 targeting with the tyrosine kinase inhibitor lapatinib is approved for treating advanced HER2 positive breast cancer and can prevent estrogen receptor ( ER )-negative mammary tumors in HER2 transgenic mouse models .	Dual epidermal growth factor receptor (EGFR) and HER2 targeting with the tyrosine kinase inhibitor lapatinib is approved for treating advanced HER2 positive breast cancer and can prevent estrogen receptor (ER)-negative mammary tumors in HER2 transgenic mouse models.	9	31	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	estrogen receptor	estrogen receptor	estrogen receptor	9	10	29	31
P2X7 Receptor Induced Intracellular Ca 2+ and MAPK Activation Modulates TACE .	P2X7 Receptor Induced Intracellular Ca 2+ and MAPK Activation Modulates TACE.	7	11	Modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	TACE	TACE	TACE	7	8	10	11
These results establish a mechanism for downregulating TGF-beta signaling through TACE activation by the Erk MAP kinase pathway , and a strategy for evasion of tumor suppression and modulation of epithelial to mesenchymal transition , during cancer progression .	These results establish a mechanism for downregulating TGF-beta signaling through TACE activation by the Erk MAP kinase pathway, and a strategy for evasion of tumor suppression and modulation of epithelial to mesenchymal transition, during cancer progression.	10	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Erk	Erk	Erk	TACE	TACE	TACE	14	15	10	11
VEGF enhances VEGFR2 shedding via ADAM17 , which is activated by the ERK and MAPK pathways .	VEGF enhances VEGFR2 shedding via ADAM17, which is activated by the ERK and MAPK pathways.	2	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ADAM17	ADAM17	ADAM17	14	15	5	6
At the same time , TACE production is positively induced by ERK which is activated by the cleaved ligands .	At the same time, TACE production is positively induced by ERK which is activated by the cleaved ligands.	5	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	TACE	TACE	TACE	11	12	5	6
The major cell surface sheddases in hematopoietic cells are ADAM10 and ADAM17 ( also termed TACE ) ; ADAM17 is activated by TLRs and the ERK MAPKs .	The major cell surface sheddases in hematopoietic cells are ADAM10 and ADAM17 (also termed TACE); ADAM17 is activated by TLRs and the ERK MAPKs.	18	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ADAM17	ADAM17	ADAM17	25	26	18	19
ERK activation increases cleavage activity of ADAM17 in vitro , and mutating the putative ERK phosphorylation site blocks this increase [ XREF_BIBR ] .	ERK activation increases cleavage activity of ADAM17 in vitro, and mutating the putative ERK phosphorylation site blocks this increase [XREF_BIBR].	0	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ADAM17	ADAM17	ADAM17	0	1	6	7
Interestingly , TACE , activated by ERK signaling , induced cleavage of TbetaRI was also shown to reduce the cell surface receptor amount and negatively regulate TGF-beta signaling on anti-proliferation and epithelial-mesenchymal transition [ XREF_BIBR ] .	Interestingly, TACE, activated by ERK signaling, induced cleavage of TbetaRI was also shown to reduce the cell surface receptor amount and negatively regulate TGF-beta signaling on anti-proliferation and epithelial-mesenchymal transition [XREF_BIBR].	2	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	TACE	TACE	TACE	6	7	2	3
Moreover , ERK can activate TACE , while binding of Staphylococcus aureus derived protein A to EGFR leads to TACE phosphorylation in a c-Src-ERK1/2-dependent manner .	Moreover, ERK can activate TACE, while binding of Staphylococcus aureus derived protein A to EGFR leads to TACE phosphorylation in a c-Src-ERK1/2-dependent manner.	2	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	TACE	TACE	TACE	2	3	5	6
ADAM = a disintegrin and metalloprotease ; AKT = protein kinase B ; AR = amphiregulin ; EGF = epidermal growth factor ; EGFR = epidermal growth factor receptor ; GPCR = G protein coupled receptor ; HB-EGF = heparin binding epidermal growth factor ; IGFR = insulin like growth factor receptor ; MAPK = mitogen activated protein kinase ; MMP = matrix metallo protease ; TACE = tumour necrosis factor alpha converting enzyme ; TGFalpha = transforming growth factor alpha .	ADAM = a disintegrin and metalloprotease; AKT = protein kinase B; AR = amphiregulin; EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; GPCR = G protein coupled receptor; HB-EGF = heparin binding epidermal growth factor; IGFR = insulin like growth factor receptor; MAPK = mitogen activated protein kinase; MMP = matrix metallo protease; TACE = tumour necrosis factor alpha converting enzyme; TGFalpha = transforming growth factor alpha.	53	70	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	TACE	TACE	TACE	53	54	66	67
Although not tested in the present study , the mechanism by which Tpl2 regulates post-transcriptional expression of TNFalpha may involve mRNA translation , translocation and/or ERK induced activation of TACE as in macrophages .	Although not tested in the present study, the mechanism by which Tpl2 regulates post-transcriptional expression of TNFalpha may involve mRNA translation, translocation and/or ERK induced activation of TACE as in macrophages.	23	30	induced	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	TACE	TACE	TACE	25	26	29	30
TACE dependent ectodomain shedding of cell-surface proteins is increased by ERK and p38 MAP kinase , which phosphorylate threonine 735 in the cytoplasmic tail of TACE [ XREF_BIBR , XREF_BIBR ] .	TACE dependent ectodomain shedding of cell-surface proteins is increased by ERK and p38 MAP kinase, which phosphorylate threonine 735 in the cytoplasmic tail of TACE [XREF_BIBR, XREF_BIBR].	0	14	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	TACE	TACE	TACE	10	11	0	1
Taken together , the present data reveal that PLA2 suppresses ERK mediated ADAM17 maturation , thus reducing sTNF-alpha production in U937 cells .	Taken together, the present data reveal that PLA2 suppresses ERK mediated ADAM17 maturation, thus reducing sTNF-alpha production in U937 cells.	9	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	ADAM17	ADAM17	ADAM17	10	11	12	13
Role of TIMP3 in MAPK activated TACE activation .	Role of TIMP3 in MAPK activated TACE activation.	2	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	TACE	TACE	TACE	4	5	6	7
In breast carcinoma cells , ERK or p38 signalling induces TACE activation by increasing the presentation of TACE on cell surfaces and decreasing the inhibition of TACE activation by tissue inhibitor of metalloproteinase-3 ( TIMP3 ) [ XREF_BIBR ] .	In breast carcinoma cells, ERK or p38 signalling induces TACE activation by increasing the presentation of TACE on cell surfaces and decreasing the inhibition of TACE activation by tissue inhibitor of metalloproteinase-3 (TIMP3) [XREF_BIBR].	5	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	TACE	TACE	TACE	5	6	26	27
Furthermore , we showed that substantial more phospho-ERK was coimmunoprecipitated with ADAM17 in wounded or PMA treated HCECs ( XREF_FIG ) , confirming a role of ERK1/2 in wounding induced ADAM17 activation .	Furthermore, we showed that substantial more phospho-ERK was coimmunoprecipitated with ADAM17 in wounded or PMA treated HCECs (XREF_FIG), confirming a role of ERK1/2 in wounding induced ADAM17 activation.	24	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ADAM17	ADAM17	ADAM17	26	27	30	31
SpA stimulates EGFR and ERK phosphorylation and stimulates ADAM17 ( or TACE-TNF alpha converting enzyme ) , the TNFR1 sheddase [ XREF_BIBR ] .	SpA stimulates EGFR and ERK phosphorylation and stimulates ADAM17 (or TACE-TNF alpha converting enzyme), the TNFR1 sheddase [XREF_BIBR].	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	SpA stimulates EGFR and ERK phosphorylation	erk	ADAM17	ADAM17	adam17	4	5	8	9
TACE Activation by MAPK Mediated Regulation of Cell Surface Dimerization and TIMP3 Association .	TACE Activation by MAPK Mediated Regulation of Cell Surface Dimerization and TIMP3 Association.	0	4	Activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	TACE	TACE	TACE	3	4	0	1
Previous work has shown that TACE , which can be activated by either p38 or ERKs , participates in the cleavage of M-CSF receptor , and our results show that IL-1beta-induced shedding of the M-CSF receptor is at least in part dependent on matrix metalloproteinases ( MMPs ) .	Previous work has shown that TACE, which can be activated by either p38 or ERKs, participates in the cleavage of M-CSF receptor, and our results show that IL-1beta-induced shedding of the M-CSF receptor is at least in part dependent on matrix metalloproteinases (MMPs).	5	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	TACE	TACE	TACE	15	16	5	6
ADAM-17 is activated by the Mitogenic Protein Kinase ERK in a Model of Kidney Fibrosis .	ADAM-17 is activated by the Mitogenic Protein Kinase ERK in a Model of Kidney Fibrosis.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ADAM-17	ADAM-17	ADAM-17	8	9	0	1
Our results indicate that in addition to its EGFR effector function , the ERK pathway also contributes to corneal epithelial wound healing by regulating ADAM17 activity , HB-EGF shedding , and EGFR activation .	Our results indicate that in addition to its EGFR effector function, the ERK pathway also contributes to corneal epithelial wound healing by regulating ADAM17 activity, HB-EGF shedding, and EGFR activation.	13	25	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ADAM17	ADAM17	ADAM17	13	14	24	25
We now present evidence for a novel mode of regulation of TGF-beta signaling : the cell surface presentation of TbetaRI , but not TbetaRII , is downregulated by TACE mediated ectodomain shedding , which is activated by Erk MAP kinase signaling .	We now present evidence for a novel mode of regulation of TGF-beta signaling : the cell surface presentation of TbetaRI, but not TbetaRII, is downregulated by TACE mediated ectodomain shedding, which is activated by Erk MAP kinase signaling.	26	40	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	TACE	TACE	TACE	37	38	28	29
PKCalpha is antiproliferative and causes G1 cell-cycle arrest associated with ERK activation and inhibition of p21 and p27 in the intestinal epithelial cells [ XREF_BIBR ] .	PKCalpha is antiproliferative and causes G1 cell-cycle arrest associated with ERK activation and inhibition of p21 and p27 in the intestinal epithelial cells [XREF_BIBR].	10	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	p27	p27	p27	10	11	17	18
At the molecular level , Rottlerin hampered the NFkB activation process , causing loss of cyclin D1 and promoting , in a PKCdelta dependent pathway , ERK activation , which , in turn induced the cell cycle inhibitor p21 Cip1 and Kip1 .	At the molecular level, Rottlerin hampered the NFkB activation process, causing loss of cyclin D1 and promoting, in a PKCdelta dependent pathway, ERK activation, which, in turn induced the cell cycle inhibitor p21 Cip1 and Kip1.	26	42	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Kip1	Kip1	Kip1	26	27	41	42
It was shown in this study that chemical inhibition of ERK reduced the ability of Nodal to increase c-myc and downregulate p27 , suggesting that Nodal was acting to regulate aspects of the cell cycle through ERK , independent of Smad signaling .	It was shown in this study that chemical inhibition of ERK reduced the ability of Nodal to increase c-myc and downregulate p27, suggesting that Nodal was acting to regulate aspects of the cell cycle through ERK, independent of Smad signaling.	8	22	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	p27	p27	p27	10	11	21	22
Consistently , we found that inhibition of either Erk1/2 or protein kinase C almost completely abrogated PDGF dependent down-regulation of p27 Kip1 ( not shown ) , suggesting a prominent role for these PLCgamma effectors for the regulation of p27 Kip1 .	Consistently, we found that inhibition of either Erk1/2 or protein kinase C almost completely abrogated PDGF dependent down-regulation of p27 Kip1 (not shown), suggesting a prominent role for these PLCgamma effectors for the regulation of p27 Kip1.	5	22	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	p27 Kip1	p27 Kip1	p27 Kip1	8	9	20	22
The mechanism involves in increased expression of cyclin D1 , cyclin E , CDK 2 , CDK 4 , and pRb , and decreased level of cyclin dependent kinases inhibitors p21 and p27 , which are blocked by the inhibitors of upstream signal molecules , MAPK and PI3K and Akt .	The mechanism involves in increased expression of cyclin D1, cyclin E, CDK 2, CDK 4, and pRb, and decreased level of cyclin dependent kinases inhibitors p21 and p27, which are blocked by the inhibitors of upstream signal molecules, MAPK and PI3K and Akt.	23	46	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	p27	p27	p27	45	46	32	33
These findings suggest that degradation of p27 ( KIP1 ) mediated by phosphorylation of ERK 1/2 is correlated with proliferation of the epithelial cells after the extraction of the lens fiber cells .	These findings suggest that degradation of p27 (KIP1) mediated by phosphorylation of ERK 1/2 is correlated with proliferation of the epithelial cells after the extraction of the lens fiber cells.	4	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	ERK 1/2	phosphorylation of ERK 1/2	erk 1/2	p27	p27	p27	14	16	6	7
Moreover , blockade of the activity of c-SRC , ERK1/2 , or NFkappaB prevented FA induced increases in TP53 , CDKN1A and CDKN1B protein .	Moreover, blockade of the activity of c-SRC, ERK1/2, or NFkappaB prevented FA induced increases in TP53, CDKN1A and CDKN1B protein.	5	23	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	CDKN1B	CDKN1B	CDKN1B	9	10	22	23
Additionally , ERK1/2 also targets the cyclin and cdk inhibitor p27 kip1 for degradation .	Additionally, ERK1/2 also targets the cyclin and cdk inhibitor p27 kip1 for degradation.	2	12	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	p27 kip1	p27 kip1	p27 kip1	2	3	10	12
Genetic or chemical blockade of the ERK pathway prevented down-regulation and cytoplasmic localization of p27Kip1 in response to estrogen .	Genetic or chemical blockade of the ERK pathway prevented down-regulation and cytoplasmic localization of p27Kip1 in response to estrogen.	6	15	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	p27Kip1	p27Kip1	p27Kip1	6	7	14	15
Many studies have shown that ERK1/2 contributes to p27 KIP1 down-regulation [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Many studies have shown that ERK1/2 contributes to p27 KIP1 down-regulation [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	10	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	KIP1	KIP1	KIP1	5	6	9	10
In the presence of diabetes mellitus , ERK activity is increased , destabilizing p27 Kip1 mRNA and abolishes the check on VSMC proliferation and migration under basal conditions .	In the presence of diabetes mellitus, ERK activity is increased, destabilizing p27 Kip1 mRNA and abolishes the check on VSMC proliferation and migration under basal conditions.	7	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	p27 Kip1	p27 Kip1	p27 Kip1	7	8	13	15
This study sought to probe the mechanisms underlying ERK1/2 mediated p27 ( Kip1 ) regulation in mitogenically stimulated cardiac fibroblasts .	This study sought to probe the mechanisms underlying ERK1/2 mediated p27 (Kip1) regulation in mitogenically stimulated cardiac fibroblasts.	7	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	p27	p27	p27	8	9	10	11
This mechanism appears particularly pertinent to the anti-mitogenic effects of NO , sodium salicylate and relaxin , all of which elicit ERK 1/2 -dependent up-regulation of p21 waf1 and cip1 and p27 kip1 to inhibit mitogenesis .	This mechanism appears particularly pertinent to the anti-mitogenic effects of NO, sodium salicylate and relaxin, all of which elicit ERK 1/2 -dependent up-regulation of p21 waf1 and cip1 and p27 kip1 to inhibit mitogenesis.	21	33	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK 1/2	ERK 1/2	ERK 1/2	p27 kip1	p27 kip1	p27 kip1	21	23	31	33
We found that inhibition of ERK activity reversed the PDGF induced upregulation of cell cycle regulatory proteins and downregulation of CDK inhibitor p27 kip1 .	We found that inhibition of ERK activity reversed the PDGF induced upregulation of cell cycle regulatory proteins and downregulation of CDK inhibitor p27 kip1.	5	24	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	p27 kip1	p27 kip1	p27 kip1	5	6	22	24
The effect results at least in part via enhanced MAPK mediated modulation of p27 and CDK4 .	The effect results at least in part via enhanced MAPK mediated modulation of p27 and CDK4.	6	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	p27	p27	p27	9	10	13	14
We propose that excess HA produced by HAS3 has the two-fold effect of increasing E-cadherin homotypic interaction and suppressing S-phase entry , as well as elevating unliganded EGF receptor , sustained ERK activation and elevation of p21 and p27 protein .	We propose that excess HA produced by HAS3 has the two-fold effect of increasing E-cadherin homotypic interaction and suppressing S-phase entry, as well as elevating unliganded EGF receptor, sustained ERK activation and elevation of p21 and p27 protein.	31	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	p27	p27	p27	31	32	38	39
MAPK signaling increased the phosphorylation of the transcription factors Ets2 , C/EBPalpha , and C/EBPbeta , and rapidly increased transcription from the p21 promoter via multiple Ets- and C/EBP-elements within the enhancer region .	MAPK signaling increased the phosphorylation of the transcription factors Ets2, C/EBPalpha, and C/EBPbeta, and rapidly increased transcription from the p21 promoter via multiple Ets- and C/EBP-elements within the enhancer region.	0	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	C/EBPbeta	C/EBPbeta	C/EBPbeta	0	1	14	15
C/EBPbeta activity is primarily activated by ERK in response to insulin XREF_BIBR , XREF_BIBR , XREF_BIBR .	C/EBPbeta activity is primarily activated by ERK in response to insulin XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	C/EBPbeta	C/EBPbeta	C/EBPbeta	6	7	0	1
Moreover , in line with data showing that activated ERK can phosphorylate and thereby activate C/EBP-beta , we showed that DIRAS3 inhibits ERK phosphorylation in ASCs and this correlates with reduced C/EBPbeta activation .	Moreover, in line with data showing that activated ERK can phosphorylate and thereby activate C/EBP-beta, we showed that DIRAS3 inhibits ERK phosphorylation in ASCs and this correlates with reduced C/EBPbeta activation.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	C/EBP-beta	C/EBP-beta	C/EBP-beta	9	10	15	16
Based on our results , we propose a possible signal transduction pathway in DLD-1 cells in which SDF-1 induces ERK , JNK and p38 phosphorylation , which activates NF-kappaB , Sp1 and C/EBP-beta to lead to their binding to respective sites in the ICAM-1 promoter , thus resulting in ICAM-1 transcriptional activation .	Based on our results, we propose a possible signal transduction pathway in DLD-1 cells in which SDF-1 induces ERK, JNK and p38 phosphorylation, which activates NF-kappaB, Sp1 and C/EBP-beta to lead to their binding to respective sites in the ICAM-1 promoter, thus resulting in ICAM-1 transcriptional activation.	17	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	SDF-1 induces ERK, JNK and p38 phosphorylation	erk	C/EBP-beta	C/EBP-beta	c/ebp-beta	19	20	32	33
Increased PGRN expression from HCC cells in response to IL-6 stimulation was via MEK and Erk signaling activating the transcriptional factor C/EBPbeta .	Increased PGRN expression from HCC cells in response to IL-6 stimulation was via MEK and Erk signaling activating the transcriptional factor C/EBPbeta.	13	22	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	C/EBPbeta	C/EBPbeta	C/EBPbeta	15	16	21	22
XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR - XREF_BIBR IL1 stimulates MMP-1 transcription through ERK dependent activation of C/EBPbeta .	XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR - XREF_BIBR IL1 stimulates MMP-1 transcription through ERK dependent activation of C/EBPbeta.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	C/EBPbeta	C/EBPbeta	C/EBPbeta	11	12	15	16
XREF_BIBR found that thrombin induced C/EBP beta activation was blocked by the ERK inhibitor PD98059 , and ERK signaling promoted the formation of a C/EBP beta specific DNA complex .	XREF_BIBR found that thrombin induced C/EBP beta activation was blocked by the ERK inhibitor PD98059, and ERK signaling promoted the formation of a C/EBP beta specific DNA complex.	17	28	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	C/EBP beta	C/EBP beta	C/EBP beta	17	18	24	26
16 IL-6 treatment increased the phosphorylation and hence activation of C/EBPbeta , which could be blocked by inhibitors of the ERK1/2 and RSK1 pathway ( XREF_FIG ) .	16 IL-6 treatment increased the phosphorylation and hence activation of C/EBPbeta, which could be blocked by inhibitors of the ERK1/2 and RSK1 pathway (XREF_FIG).	8	23	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	C/EBPbeta	C/EBPbeta	C/EBPbeta	20	21	10	11
The mitotic clonal expansion of 3T3-L1 cells involves the sequential activation of C/EBPbeta protein by MAPK and glycogen synthase kinase 3beta ( GSK3beta ) .	The mitotic clonal expansion of 3T3-L1 cells involves the sequential activation of C/EBPbeta protein by MAPK and glycogen synthase kinase 3beta (GSK3beta).	7	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	C/EBPbeta protein	C/EBPbeta protein	C/EBPbeta protein	15	16	12	14
Further , by knocking down the expression of p38alpha MAPK or p38beta MAPK utilizing specific siRNAs , we confirmed that p38beta MAPK , not p38alpha MAPK , mediates C/EBPbeta activation induced by activin A.	Further, by knocking down the expression of p38alpha MAPK or p38beta MAPK utilizing specific siRNAs, we confirmed that p38beta MAPK, not p38alpha MAPK, mediates C/EBPbeta activation induced by activin A.	20	29	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	C/EBPbeta	C/EBPbeta	C/EBPbeta	21	22	28	29
Our data identify CCL2 as a cytokine induced robustly by vGPCR in endothelial cells , determine that MAPK activated C/EBPbeta is necessary for the induction , and demonstrate the relevance of vGPCR and C/EBPbeta for CCL2 induction during HHV-8 infection of endothelial cells .	Our data identify CCL2 as a cytokine induced robustly by vGPCR in endothelial cells, determine that MAPK activated C/EBPbeta is necessary for the induction, and demonstrate the relevance of vGPCR and C/EBPbeta for CCL2 induction during HHV-8 infection of endothelial cells.	17	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	C/EBPbeta	C/EBPbeta	C/EBPbeta	17	18	19	20
A breast cancer study reported that upregulation of the ERK signaling pathway initiated further C/EBP beta activation XREF_BIBR .	A breast cancer study reported that upregulation of the ERK signaling pathway initiated further C/EBP beta activation XREF_BIBR.	9	17	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	C/EBP beta	C/EBP beta	C/EBP beta	9	10	14	16
The transcriptional induction of MKPs , which deactivate ERK by dephosphorylation , ensures that C/EBP-beta activation by ERK also ceases .	The transcriptional induction of MKPs, which deactivate ERK by dephosphorylation, ensures that C/EBP-beta activation by ERK also ceases.	14	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	C/EBP-beta	C/EBP-beta	C/EBP-beta	17	18	14	15
It has been reported that MAPK and GSK3beta mediates C/EBPbeta activity via sequential phosphorylation of on T188 and T179 , respectively .	It has been reported that MAPK and GSK3beta mediates C/EBPbeta activity via sequential phosphorylation of on T188 and T179, respectively.	5	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	C/EBPbeta	C/EBPbeta	C/EBPbeta	5	6	9	10
Based on these observations , we propose a model where the activation of MKK6b and p38alpha MAPK activity by IL-1beta can further activate C/EBP-beta to result in sustained induction of C3 ( XREF_FIG ) .	Based on these observations, we propose a model where the activation of MKK6b and p38alpha MAPK activity by IL-1beta can further activate C/EBP-beta to result in sustained induction of C3 (XREF_FIG).	16	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	C/EBP-beta	C/EBP-beta	C/EBP-beta	16	17	23	24
Dexras1 translocates to the membrane through the C-terminal domain ( XREF_FIG ) and in the absence of Dexras1 , MAPK or MAPK directed C/EBPbeta activation was not accomplished , even in the full differentiation medium , indicating that insulin and IGF -1 signaling to MAPK is clearly associated with Dexras1 .	Dexras1 translocates to the membrane through the C-terminal domain (XREF_FIG) and in the absence of Dexras1, MAPK or MAPK directed C/EBPbeta activation was not accomplished, even in the full differentiation medium, indicating that insulin and IGF -1 signaling to MAPK is clearly associated with Dexras1.	15	24	directed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	C/EBPbeta	C/EBPbeta	C/EBPbeta	21	22	23	24
Ereg is promiscuous , binds and activates the Egfr family member Erbb4 via heterodimeric interactions with Erbb2 XREF_BIBR .	Ereg is promiscuous, binds and activates the Egfr family member Erbb4 via heterodimeric interactions with Erbb2 XREF_BIBR.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ereg	Ereg	Ereg	Erbb4	Erbb4	Erbb4	0	1	11	12
Thus , it appears that epiregulin and other high-affinity ErbB4 ligands share a common binding site on ErbB4 and that epiregulin and other efficacious ErbB4 ligands stimulate ErbB4 signaling in essentially the same manner .	Thus, it appears that epiregulin and other high-affinity ErbB4 ligands share a common binding site on ErbB4 and that epiregulin and other efficacious ErbB4 ligands stimulate ErbB4 signaling in essentially the same manner.	20	28	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epiregulin	epiregulin	epiregulin	ErbB4	ErbB4	ErbB4	20	21	27	28
On the other hand , it is unclear whether activation of ErbB4 by EPR stimulates increased cellular proliferation although one study did show that another EGF family member , NRG-1beta , increased proliferation by coupling MAPK to ErbB4 [ XREF_BIBR ] .	On the other hand, it is unclear whether activation of ErbB4 by EPR stimulates increased cellular proliferation although one study did show that another EGF family member, NRG-1beta, increased proliferation by coupling MAPK to ErbB4 [XREF_BIBR].	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EPR	EPR	EPR	ErbB4	ErbB4	ErbB4	13	14	11	12
In addition , ERBB4 may indirectly modulate STAT5A transactivation through nuclear translocation of 4ICD associated transcriptional coactivators .	In addition, ERBB4 may indirectly modulate STAT5A transactivation through nuclear translocation of 4ICD associated transcriptional coactivators.	3	8	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB4	ERBB4	ERBB4	STAT5A	STAT5A	STAT5A	3	4	7	8
Whereas , the JAK2 and STAT5a cascade is only induced by WT HER4 homodimers .	Whereas, the JAK2 and STAT5a cascade is only induced by WT HER4 homodimers.	3	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HER4	HER4	HER4	STAT5a	STAT5a	STAT5a	12	13	5	6
Our studies demonstrate that phosphorylation of STAT5A at Ser 127 and Ser 128 and Ser 779 are obligatory events regulating ERBB4 mediated activation of STAT5A .	Our studies demonstrate that phosphorylation of STAT5A at Ser-127 and Ser-128 and Ser 779 are obligatory events regulating ERBB4 mediated activation of STAT5A.	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERBB4	ERBB4	ERBB4	STAT5A	STAT5A	STAT5A	20	21	24	25
We incorporate JAK2 into the model in this way to reflect that it is required for the HER4 mediated activation of STAT5a , though the mechanism is currently unknown .	We incorporate JAK2 into the model in this way to reflect that it is required for the HER4 mediated activation of STAT5a, though the mechanism is currently unknown.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	HER4	HER4	HER4	STAT5a	STAT5a	STAT5a	17	18	21	22
As an extension of these observations we next determined if ERBB4 stimulates STAT5A transactivation of a bovine beta-casein promoter positioned upstream of the luciferase reporter gene .	As an extension of these observations we next determined if ERBB4 stimulates STAT5A transactivation of a bovine beta-casein promoter positioned upstream of the luciferase reporter gene.	10	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB4	ERBB4	ERBB4	STAT5A	STAT5A	STAT5A	10	11	12	13
This was confirmed in experiments in which ErbB4 upregulation rescued Akt and STAT5A dysregulation in response to ErbB3 ablation , whereas ErbB4 knock-down exacerbated the defects in Akt and STAT5A signaling caused by ErbB3 depletion .	This was confirmed in experiments in which ErbB4 upregulation rescued Akt and STAT5A dysregulation in response to ErbB3 ablation, whereas ErbB4 knock-down exacerbated the defects in Akt and STAT5A signaling caused by ErbB3 depletion.	7	13	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB4	ErbB4	ErbB4	STAT5A	STAT5A	STAT5A	7	8	12	13
Independent serine-to-alanine residue substitutions in full-length STAT5A revealed that although STAT5A Ser 779 phosphorylation was dispensable for phosphorylation of STAT5A at Tyr 694 and subsequent DNA binding , Ser 779 was required to stabilize an interaction with ERBB4 and mediate ERBB4 induced STAT5A stimulation of gene expression .	Independent serine-to-alanine residue substitutions in full-length STAT5A revealed that although STAT5A Ser 779 phosphorylation was dispensable for phosphorylation of STAT5A at Tyr 694 and subsequent DNA binding, Ser 779 was required to stabilize an interaction with ERBB4 and mediate ERBB4 induced STAT5A stimulation of gene expression.	39	43	induced	Positive_early_activation	Positive_activation	Positive_activation	ERBB4	ERBB4	ERBB4	STAT5A	STAT5A	STAT5A	40	41	42	43
ERBB4 activation in the mammary gland in turn activates the Signal Transducer and Activator of Transcription STAT5A , and conditional deletion of either Erbb4 or Stat5a induces lactation failure which appears histologically similar to the phenotype we observe following basal p63 deletion .	ERBB4 activation in the mammary gland in turn activates the Signal Transducer and Activator of Transcription STAT5A, and conditional deletion of either Erbb4 or Stat5a induces lactation failure which appears histologically similar to the phenotype we observe following basal p63 deletion.	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB4	ERBB4	ERBB4	STAT5A	STAT5A	STAT5A	0	1	16	17
Functionally , ERBB4-CA exhibited higher levels of nuclear translocation than wild-type ERBB4 , leading to significantly enhanced ERBB4 induced STAT5A simulation of the beta-casein promoter .	Functionally, ERBB4-CA exhibited higher levels of nuclear translocation than wild-type ERBB4, leading to significantly enhanced ERBB4 induced STAT5A simulation of the beta-casein promoter.	13	20	induced	Positive_early_activation	Positive_activation	Positive_activation	ERBB4	ERBB4	ERBB4	STAT5A	STAT5A	STAT5A	17	18	19	20
These findings suggest that the NRG receptors , ErbB3 and ErbB4 , cooperatively enhance STAT5A and P-Akt signaling during lactogenic expansion and differentiation of the mouse mammary epithelium , and that loss of ErbB3 can be compensated for , at least partially , by increased signaling through ErbB4 .	These findings suggest that the NRG receptors, ErbB3 and ErbB4, cooperatively enhance STAT5A and P-Akt signaling during lactogenic expansion and differentiation of the mouse mammary epithelium, and that loss of ErbB3 can be compensated for, at least partially, by increased signaling through ErbB4.	6	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB4	ErbB4	ErbB4	STAT5A	STAT5A	STAT5A	10	11	14	15
ERBB4 mediated activation of STAT5A in the pregnant and lactating breast results in STAT5A transactivation of milk genes with gamma-interferon activation sites ( GAS ) within their promoters , including beta-casein and whey acidic protein .	ERBB4 mediated activation of STAT5A in the pregnant and lactating breast results in STAT5A transactivation of milk genes with gamma-interferon activation sites (GAS) within their promoters, including beta-casein and whey acidic protein.	0	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERBB4	ERBB4	ERBB4	STAT5A	STAT5A	STAT5A	0	1	4	5
ERBB4 activities in the breast are mediated through the signal transducer and activator of transcription ( STAT ) family member STAT5A , and ERBB4 directly activates STAT5A , in part , through phosphorylation of STAT5A at the regulatory Tyr 694 .	ERBB4 activities in the breast are mediated through the signal transducer and activator of transcription (STAT) family member STAT5A, and ERBB4 directly activates STAT5A, in part, through phosphorylation of STAT5A at the regulatory Tyr 694.	23	27	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERBB4	ERBB4	ERBB4	STAT5A	STAT5A	STAT5A	23	24	26	27
We suggest that HER4 mediated STAT5a activation may constitute a cellular shift from a program of proliferation to a program of differentiation : precisely the same shift that can potentially be modulated to bias tumor cells toward the HER4 differentiation pathway for therapeutic purposes .	We suggest that HER4 mediated STAT5a activation may constitute a cellular shift from a program of proliferation to a program of differentiation : precisely the same shift that can potentially be modulated to bias tumor cells toward the HER4 differentiation pathway for therapeutic purposes.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	HER4	HER4	HER4	STAT5a	STAT5a	STAT5a	3	4	5	6
Our recent in vivo data indicates that ERBB4 activation of STAT5A in the mammary gland regulates lactational expression of the essential milk-genes beta-casein and whey acidic protein .	Our recent in vivo data indicates that ERBB4 activation of STAT5A in the mammary gland regulates lactational expression of the essential milk-genes beta-casein and whey acidic protein.	7	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERBB4	ERBB4	ERBB4	STAT5A	STAT5A	STAT5A	7	8	10	11
Our findings suggest that the ERK mediated Cdk2 and cyclin-A signaling pathway is an important regulator of pemetrexed induced S-phase arrest and apoptotic cell death .	Our findings suggest that the ERK mediated Cdk2 and cyclin-A signaling pathway is an important regulator of pemetrexed induced S-phase arrest and apoptotic cell death.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	Cdk2	Cdk2	Cdk2	5	6	7	8
A novel arylbenzofuran induces cervical cancer cell apoptosis and G1/S arrest through ERK mediated Cdk2 and cyclin-A signaling pathway .	A novel arylbenzofuran induces cervical cancer cell apoptosis and G1/S arrest through ERK mediated Cdk2 and cyclin-A signaling pathway.	7	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	Cdk2	Cdk2	Cdk2	12	13	14	15
Importantly , our study sets a remarkable example of cancer plasticity that underlies melanoma primary resistance to drug therapies : upon BRAFi treatment , the resistance is accompanied by MAPK pathway activation , which triggers cell cycle progression and CDK2 activation ( Lents etal , 2002 ) .	Importantly, our study sets a remarkable example of cancer plasticity that underlies melanoma primary resistance to drug therapies : upon BRAFi treatment, the resistance is accompanied by MAPK pathway activation, which triggers cell cycle progression and CDK2 activation (Lents etal, 2002).	29	40	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	CDK2	CDK2	CDK2	29	30	39	40
Taken together , these results suggest that the MEK and ERK pathway act in a positive regulatory fashion to activate Cdk2 in IGF-1-induced mitogenesis in osteoblasts .	Taken together, these results suggest that the MEK and ERK pathway act in a positive regulatory fashion to activate Cdk2 in IGF-1-induced mitogenesis in osteoblasts.	10	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Cdk2	Cdk2	Cdk2	10	11	20	21
Abolishing ERK activity by MEK inhibition or expression of dominant negative ERK significantly reduces cdk2 activity in mammalian cells .	Abolishing ERK activity by MEK inhibition or expression of dominant negative ERK significantly reduces cdk2 activity in mammalian cells.	2	15	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	cdk2	cdk2	cdk2	11	12	14	15
Versican G3 domain promotes cell cycle entry through EGFR and ERK signaling and expression of CDK2 and Glycogen synthase kinase-3beta serine 9 phosphorylation ( GSK-3beta , S9P ) .	Versican G3 domain promotes cell cycle entry through EGFR and ERK signaling and expression of CDK2 and Glycogen synthase kinase-3beta serine 9 phosphorylation (GSK-3beta, S9P).	8	16	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	CDK2	CDK2	CDK2	10	11	15	16
Blockade of ERK activation suppressed synthesis of CyE and A as well as CDK2 activation .	Blockade of ERK activation suppressed synthesis of CyE and A as well as CDK2 activation.	2	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	CDK2	CDK2	CDK2	2	3	13	14
Overall , our data reveal that in our employed model cell line SK-Mel 28 , the inherent resistance to BRAFi is accompanied by activation of the MAPK pathway , which promotes cell cycle progression and CDK2 activation .	Overall, our data reveal that in our employed model cell line SK-Mel 28, the inherent resistance to BRAFi is accompanied by activation of the MAPK pathway, which promotes cell cycle progression and CDK2 activation.	26	36	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	CDK2	CDK2	CDK2	26	27	35	36
These findings also suggest that ERK mediated Cdk2 and cyclin A signaling pathway is involved in Ary induced G1/S-phase arrest .	These findings also suggest that ERK mediated Cdk2 and cyclin A signaling pathway is involved in Ary induced G1/S-phase arrest.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	Cdk2	Cdk2	Cdk2	5	6	7	8
There is considerable evidence to indicate that adipocyte maturation requires a precise proliferative step , called mitotic clonal expansion ( MCE ) , with ERK activation in the beginning stage ; ERK inhibition blocks MCE and the expression of cell cycle markers ( cyclin A and cdk2 ) in the middle stage , whereas ERK activation returned to a low level accompanying PPARgamma expression during terminal differentiation .	There is considerable evidence to indicate that adipocyte maturation requires a precise proliferative step, called mitotic clonal expansion (MCE), with ERK activation in the beginning stage; ERK inhibition blocks MCE and the expression of cell cycle markers (cyclin A and cdk2) in the middle stage, whereas ERK activation returned to a low level accompanying PPARgamma expression during terminal differentiation.	31	47	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	cdk2	cdk2	cdk2	31	32	46	47
In contrast with these findings , prolonged activation of the MAPK pathway in hepatocytes from p21Cip-1 and WAF1-null mice enhanced cdk2 and cdk4 activities and caused a large increase in DNA synthesis , despite elevated expression of p16INK4a .	In contrast with these findings, prolonged activation of the MAPK pathway in hepatocytes from p21Cip-1 and WAF1-null mice enhanced cdk2 and cdk4 activities and caused a large increase in DNA synthesis, despite elevated expression of p16INK4a.	10	23	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	cdk2	cdk2	cdk2	10	11	20	21
Furthermore , CSB was co-immunoprecipitated and co-localized with NEIL1 in HeLa cells and stimulated NEIL1 activity in vitro .	Furthermore, CSB was co-immunoprecipitated and co-localized with NEIL1 in HeLa cells and stimulated NEIL1 activity in vitro.	2	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSB	CSB	CSB	NEIL1	NEIL1	NEIL1	2	3	14	15
In addition , we have shown that CSB stimulates NEIL1 incision of FapyG , FapyA and 5OHU in duplex DNA structures whereas the incision of 8oxoG is not affected .	In addition, we have shown that CSB stimulates NEIL1 incision of FapyG, FapyA and 5OHU in duplex DNA structures whereas the incision of 8oxoG is not affected.	7	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSB	CSB	CSB	NEIL1	NEIL1	NEIL1	7	8	9	10
In addition , CSB has not been found to stimulate NEIL1 activity on a bubble structure .	In addition, CSB has not been found to stimulate NEIL1 activity on a bubble structure.	3	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSB	CSB	CSB	NEIL1	NEIL1	NEIL1	3	4	10	11
XREF_BIBR , XREF_BIBR It has also been shown in vitro that CSB stimulates NEIL1 glycosylase activity , and that CSB and NEIL1 co ; immunoprecipitate and co ; localize in HeLa cells .	XREF_BIBR, XREF_BIBR It has also been shown in vitro that CSB stimulates NEIL1 glycosylase activity, and that CSB and NEIL1 co; immunoprecipitate and co; localize in HeLa cells.	11	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSB	CSB	CSB	NEIL1	NEIL1	NEIL1	11	12	13	14
CSB stimulates both incision and AP lyase activities of NEIL1 , and the N-terminal part of CSB ( CSB 2-341 ) is responsible for the stimulation of NEIL1 incision activity , thus reflecting a direct stimulation of a BER protein by a specific domain of CSB .	CSB stimulates both incision and AP lyase activities of NEIL1, and the N-terminal part of CSB (CSB 2-341) is responsible for the stimulation of NEIL1 incision activity, thus reflecting a direct stimulation of a BER protein by a specific domain of CSB.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSB	CSB	CSB	NEIL1	NEIL1	NEIL1	0	1	9	10
In addition , CSB stimulates NEIL1 incision activity in vitro , and CSB and NEIL1 co-immunoprecipitate and co-localize in HeLa cells .	In addition, CSB stimulates NEIL1 incision activity in vitro, and CSB and NEIL1 co-immunoprecipitate and co-localize in HeLa cells.	3	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSB	CSB	CSB	NEIL1	NEIL1	NEIL1	3	4	5	6
Amongst its interactions with BER proteins , CSB stimulates the incision and AP lyase activity of Neil1 , a DNA glycosylase involved in BER .	Amongst its interactions with BER proteins, CSB stimulates the incision and AP lyase activity of Neil1, a DNA glycosylase involved in BER.	7	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSB	CSB	CSB	Neil1	Neil1	Neil1	7	8	16	17
Moreover , CSB was found to stimulate NEIL1 dependent removal of these lesions .	Moreover, CSB was found to stimulate NEIL1 dependent removal of these lesions.	2	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSB	CSB	CSB	NEIL1	NEIL1	NEIL1	2	3	7	8
CSB appears to stimulate both NEIL1 and NEIL2 in their repair of FapyA .	CSB appears to stimulate both NEIL1 and NEIL2 in their repair of FapyA.	0	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSB	CSB	CSB	NEIL1	NEIL1	NEIL1	0	1	5	6
In vitro , CSB stimulated enzymatic activity of NEIL1 ( 26 ) and has been shown to interact with other BER enzymes , including AP endonuclease 1 [ XREF_BIBR ] and poly ( ADP-ribose ) polymerase ( PARP1 ) [ XREF_BIBR ] .	In vitro, CSB stimulated enzymatic activity of NEIL1 (26) and has been shown to interact with other BER enzymes, including AP endonuclease 1 [XREF_BIBR] and poly (ADP-ribose) polymerase (PARP1) [XREF_BIBR].	3	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSB	CSB	CSB	NEIL1	NEIL1	NEIL1	3	4	8	9
Surprisingly , we found that an ERK1/2 kinase inhibitor , but not an ALK5 inhibitor , blocked the stimulation of p300 by TGF-beta .	Surprisingly, we found that an ERK1/2 kinase inhibitor, but not an ALK5 inhibitor, blocked the stimulation of p300 by TGF-beta.	6	21	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	p300	p300	p300	6	7	20	21
Indeed , stimulation of CBP and Ep300 or SRC-1 dependent transcriptional activity by MAPK signaling elucidates that phosphorylation exerts a positive regulatory effect on certain coactivator functions [ XREF_BIBR - XREF_BIBR ] .	Indeed, stimulation of CBP and Ep300 or SRC-1 dependent transcriptional activity by MAPK signaling elucidates that phosphorylation exerts a positive regulatory effect on certain coactivator functions [XREF_BIBR - XREF_BIBR].	2	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Ep300	Ep300	Ep300	13	14	6	7
In line , inhibition of ERK1/2 signaling abolished the effects of p300 .	In line, inhibition of ERK1/2 signaling abolished the effects of p300.	5	12	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	p300	p300	p300	5	6	11	12
In vascular smooth muscle cells , angiotensin II induced IL-6 expression is known to require activation of NF-kB and CREB as well as ERK dependent histone acetylation mediated p300 and SRC-1 .	In vascular smooth muscle cells, angiotensin II induced IL-6 expression is known to require activation of NF-kB and CREB as well as ERK dependent histone acetylation mediated p300 and SRC-1.	14	30	mediated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	p300	p300	p300	23	24	28	29
Although the precise mechanism of repression remains to be established , ERK and MAPK signalling is known to activate p300 , and ERK signalling could repress miR-142 through this mechanism .	Although the precise mechanism of repression remains to be established, ERK and MAPK signalling is known to activate p300, and ERK signalling could repress miR-142 through this mechanism.	11	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	p300	p300	p300	13	14	19	20
Both ERK and MAPK and p38MAPK phosphorylate and modulate the activity of p300 .	Both ERK and MAPK and p38MAPK phosphorylate and modulate the activity of p300.	1	13	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	p300	p300	p300	3	4	12	13
To clarify whether ErbB2 directly activates Dock7 and whether Tyr 1118 is critical for ErbB2 dependent GEF activity , we incubated the purified wild-type or Y1118F Dock7 with the ErbB2 kinase and performed guanine nucleotide release assays in vitro .	To clarify whether ErbB2 directly activates Dock7 and whether Tyr 1118 is critical for ErbB2 dependent GEF activity, we incubated the purified wild-type or Y1118F Dock7 with the ErbB2 kinase and performed guanine nucleotide release assays in vitro.	3	7	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	Dock7	Dock7	Dock7	3	4	6	7
It is clear that ErbB2 phosphorylates and activates Dock7 in vitro ; however , the question of whether Dock7 can be activated by an alternative mechanism remains .	It is clear that ErbB2 phosphorylates and activates Dock7 in vitro; however, the question of whether Dock7 can be activated by an alternative mechanism remains.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	Dock7	Dock7	Dock7	4	5	8	9
ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration .	ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration.	0	8	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	Dock7	Dock7	Dock7	0	1	6	7
ErbB2 stimulated guanine nucleotide release of Dock7 for Rac1 and Cdc42 , whereas the Y1118F mutation in Dock7 abolished the release ( XREF_FIG ) .	ErbB2 stimulated guanine nucleotide release of Dock7 for Rac1 and Cdc42, whereas the Y1118F mutation in Dock7 abolished the release (XREF_FIG).	0	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	Dock7	Dock7	Dock7	0	1	6	7
To investigate whether NRG1 activation of the ErbB2 and 3 heterodimer stimulates the GEF activity of Dock7 , we cotransfected the plasmids encoding wild-type Dock7 , ErbB2 , and ErbB3 into 293T cells and measured the exchange of the guanine nucleotide from immunoprecipitated Dock7 for Rac1 and Cdc42 .	To investigate whether NRG1 activation of the ErbB2 and 3 heterodimer stimulates the GEF activity of Dock7, we cotransfected the plasmids encoding wild-type Dock7, ErbB2, and ErbB3 into 293T cells and measured the exchange of the guanine nucleotide from immunoprecipitated Dock7 for Rac1 and Cdc42.	4	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	Dock7	Dock7	Dock7	7	8	16	17
In addition , elucidation of the 3D structures of Dock7 and the other Dock180 related GEFs should provide valuable information concerning how the phosphorylation by ErbB2 activates Dock7 in Schwann cells .	In addition, elucidation of the 3D structures of Dock7 and the other Dock180 related GEFs should provide valuable information concerning how the phosphorylation by ErbB2 activates Dock7 in Schwann cells.	23	30	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	Dock7	Dock7	Dock7	25	26	27	28
We furthermore find that the E2f1 transcription factor is required and sufficient to drive EB/EC endocycles , and that E2f1 is posttranscriptionally induced by Ras and MAPK signalling .	We furthermore find that the E2f1 transcription factor is required and sufficient to drive EB/EC endocycles, and that E2f1 is posttranscriptionally induced by Ras and MAPK signalling.	19	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	E2f1	E2f1	E2f1	26	27	19	20
CREB and E2F1 TFBSs were under and over-represented ( respectively ) in HMCs treated with both TGFbeta and CCN2 ; ERK inhibition restored migration and inhibited E2F1 .	CREB and E2F1 TFBSs were under and over-represented (respectively) in HMCs treated with both TGFbeta and CCN2; ERK inhibition restored migration and inhibited E2F1.	20	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	E2F1	E2F1	E2F1	20	21	26	27
As discussed below , how Ras and MAPK might increase the translation of E2f1 remains an open question .	As discussed below, how Ras and MAPK might increase the translation of E2f1 remains an open question.	5	14	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	E2f1	E2f1	E2f1	7	8	13	14
Inhibition of MAPK and ERK signaling caused the activation of pRb tumor suppressive activity and suppressed E2F1 and E2F3 activity suggesting the influence of this signaling on E2F1 activity in melanoma cells .	Inhibition of MAPK and ERK signaling caused the activation of pRb tumor suppressive activity and suppressed E2F1 and E2F3 activity suggesting the influence of this signaling on E2F1 activity in melanoma cells.	2	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	E2F1	E2F1	E2F1	4	5	16	17
A MAPK dependent increase in E2f1 stability would therefore have to be mediated by an unknown Gap-phase-specific degradation pathway .	A MAPK dependent increase in E2f1 stability would therefore have to be mediated by an unknown Gap-phase-specific degradation pathway.	1	6	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	E2f1	E2f1	E2f1	1	2	5	6
Furthermore , the ERK signaling pathway can activate E2F1 , which is highly expressed in various tumors [ XREF_BIBR ] .	Furthermore, the ERK signaling pathway can activate E2F1, which is highly expressed in various tumors [XREF_BIBR].	3	14	activate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ERK	ERK	erk	E2F1	E2F1, which is highly expressed	e2f1	3	4	8	9
XREF_BIBR , XREF_BIBR The expression of BNIP3 has also been reported to be regulated by E2F-1 , 26 which is activated by Ras induced ERK and MAPK .	XREF_BIBR, XREF_BIBR The expression of BNIP3 has also been reported to be regulated by E2F-1, 26 which is activated by Ras induced ERK and MAPK.	13	26	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ERK	Ras induced ERK	erk	E2F-1	E2F-1	e2f-1	24	25	15	16
In cell line experiments , when HER-2 positive cancer cells were transfected to overexpress HER-4 , a reduction in proliferation and an increase in apoptosis were observed , suggesting that HER-4 antagonizes HER-2 signaling activity .	In cell line experiments, when HER-2 positive cancer cells were transfected to overexpress HER-4, a reduction in proliferation and an increase in apoptosis were observed, suggesting that HER-4 antagonizes HER-2 signaling activity.	6	15	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER-2	HER-2	HER-2	HER-4	HER-4	HER-4	6	7	14	15
It may be possible that patients believed to be HER2 positive would receive HER2 targeted therapy while in fact being only HER4 positive .	It may be possible that patients believed to be HER2 positive would receive HER2 targeted therapy while in fact being only HER4 positive.	13	22	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER4	HER4	HER4	13	14	21	22
In cell line experiments , when HER2 positive cancer cells were transfected to overexpress HER4 , a reduction in proliferation and an increase in apoptosis was noted [ XREF_BIBR ] .	In cell line experiments, when HER2 positive cancer cells were transfected to overexpress HER4, a reduction in proliferation and an increase in apoptosis was noted [XREF_BIBR].	6	15	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER4	HER4	HER4	6	7	14	15
In cell line experiments , when HER2 positive cancer cells were transfected to overexpress HER4 , a reduction in proliferation and an increase in apoptosis was observed ( Sartor et al , 2001 ) .	In cell line experiments, when HER2 positive cancer cells were transfected to overexpress HER4, a reduction in proliferation and an increase in apoptosis was observed (Sartor et al, 2001).	6	15	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER4	HER4	HER4	6	7	14	15
Through phosphorylation of hnRNP K , Erk1/2 increases hnRNP K cytoplasmic accumulation and thereby silences the translation of DICE containing genes .	Through phosphorylation of hnRNP K, Erk1/2 increases hnRNP K cytoplasmic accumulation and thereby silences the translation of DICE containing genes.	6	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	hnRNP K	hnRNP K	hnRNP K	6	7	8	10
However , the inhibition of the MEK and ERK pathway or addition of growth factors did not seem to decrease the cytoplasmic accumulation of hnRNP K in the BxPC3 and MiaPaCa-2 cells .	However, the inhibition of the MEK and ERK pathway or addition of growth factors did not seem to decrease the cytoplasmic accumulation of hnRNP K in the BxPC3 and MiaPaCa-2 cells.	6	26	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	hnRNP K	hnRNP K	hnRNP K	8	9	24	26
ERK modulates movement of hnRNP K within carcinoma cells XREF_BIBR and in response to T-cell activation XREF_BIBR .	ERK modulates movement of hnRNP K within carcinoma cells XREF_BIBR and in response to T-cell activation XREF_BIBR.	0	6	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	hnRNP K	hnRNP K	hnRNP K	0	1	4	6
Thus , enhanced phosphorylation of extracellular-signal-regulated kinase ( ERK ) is frequently observed in MM downstream NRAS and BRAF and , importantly , induces cytoplasmic accumulation of hnRNP K [ XREF_BIBR , XREF_BIBR ] .	Thus, enhanced phosphorylation of extracellular-signal-regulated kinase (ERK) is frequently observed in MM downstream NRAS and BRAF and, importantly, induces cytoplasmic accumulation of hnRNP K [XREF_BIBR, XREF_BIBR].	3	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	phosphorylation of extracellular-signal-regulated kinase (ERK	erk	hnRNP K	hnRNP K	hnrnp k	8	9	27	29
Our results collectively establish the regulation and role of ERK mediated cytoplasmic accumulation of hnRNP K as an upstream modulator of TP , suggesting that hnRNP K may be an attractive candidate as a future therapeutic target for cancer .	Our results collectively establish the regulation and role of ERK mediated cytoplasmic accumulation of hnRNP K as an upstream modulator of TP, suggesting that hnRNP K may be an attractive candidate as a future therapeutic target for cancer.	5	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	hnRNP K	hnRNP K	hnRNP K	9	10	14	16
The results reveal distinct characters of R2N1d cells that can be ascribed to HER2 : 1 ) development of fast growing tumors ; 2 ) high frequency of CD44 + / CD24 - cells ( ~ 50 % for R2N1d vs. ~ 10 % for R2d ) ; 3 ) enhanced expression of COX-2 , HDAC6 mediated , respectively , by MAPK and PI3K and Akt pathways , and many genes associated with inflammation , metastasis , and angiogenesis .	The results reveal distinct characters of R2N1d cells that can be ascribed to HER2 : 1) development of fast growing tumors; 2) high frequency of CD44 + / CD24 - cells (~ 50% for R2N1d vs. ~ 10% for R2d); 3) enhanced expression of COX-2, HDAC6 mediated, respectively, by MAPK and PI3K and Akt pathways, and many genes associated with inflammation, metastasis, and angiogenesis.	50	66	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	HDAC6	HDAC6	HDAC6	61	62	55	56
As shown in Figure XREF_FIG , both SAHA and U0126 exhibited similar effects on colony formation inhibition , and the combination of SAHA and U0126 gave the additive effect , suggesting that MAPK could also activate a HDAC6 independent pathway to promote cell growth in K-ras mutant cancer cells .	As shown in Figure XREF_FIG, both SAHA and U0126 exhibited similar effects on colony formation inhibition, and the combination of SAHA and U0126 gave the additive effect, suggesting that MAPK could also activate a HDAC6 independent pathway to promote cell growth in K-ras mutant cancer cells.	32	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	HDAC6	HDAC6	HDAC6	32	33	37	38
These findings clearly indicate the importance of EGFR-HER3 heteromerization in HER3 mediated Grb2 dependent signaling pathways and supports the central role of HER3 in the diversity and regulation of HER family functioning .	These findings clearly indicate the importance of EGFR-HER3 heteromerization in HER3 mediated Grb2 dependent signaling pathways and supports the central role of HER3 in the diversity and regulation of HER family functioning.	8	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	HER3	HER3	HER3	Grb2	Grb2	Grb2	10	11	12	13
Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2 , provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade , thereby causing unrestricted cellular proliferation .	Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation.	8	21	stimulates	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	ErbB-2	tyrosine phosphorylation of ErbB-2 by Jak2	erbb-2	Grb2	Grb2	grb2	12	13	20	21
Instead , engagement of the HER2 homodimer primarily activates the GRB2 and SHC adaptor proteins that initiate RAS and MAPK signaling .	Instead, engagement of the HER2 homodimer primarily activates the GRB2 and SHC adaptor proteins that initiate RAS and MAPK signaling.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	GRB2	GRB2	GRB2	5	6	10	11
A previous study suggests that p110delta is signaling downstream of ErbB4 [ XREF_BIBR ] , but so far it is unknown if p110delta controls protein synthesis mediated by ErbB4 or other neurotransmitter receptors .	A previous study suggests that p110delta is signaling downstream of ErbB4 [XREF_BIBR], but so far it is unknown if p110delta controls protein synthesis mediated by ErbB4 or other neurotransmitter receptors.	22	32	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ErbB4	ErbB4	ErbB4	p110delta	p110delta	p110delta	28	29	22	23
ErbB4 activation significantly promoted YAP and PIK3CB activity and increased the expression of tight junction proteins Occludin and Claudin-5 .	ErbB4 activation significantly promoted YAP and PIK3CB activity and increased the expression of tight junction proteins Occludin and Claudin-5.	0	7	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB4	ErbB4	ErbB4	PIK3CB	PIK3CB	PIK3CB	0	1	6	7
Initially , we considered the rTM ' s thrombin inhibitory effects with thrombin activated PAR-1 signal downregulation and reduced endothelial inflammation were the major mechanisms 19 .	Initially, we considered the rTM 's thrombin inhibitory effects with thrombin activated PAR-1 signal downregulation and reduced endothelial inflammation were the major mechanisms 19.	3	18	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	14	15
Besides subcellular localization , the differential PAR 1 -dependent cellular responses induced by thrombin and APC may also be explained by their distinct cleavage sites .	Besides subcellular localization, the differential PAR 1 -dependent cellular responses induced by thrombin and APC may also be explained by their distinct cleavage sites.	4	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	13	14	6	8
The goal of these studies is to determine the kinetics of thrombin activation of PAR1 and PAR4 and to relate the individual inputs from each receptor to platelet Ca ( 2+ ) signaling , secondary autocrine stimulation , and aggregation .	The goal of these studies is to determine the kinetics of thrombin activation of PAR1 and PAR4 and to relate the individual inputs from each receptor to platelet Ca (2+) signaling, secondary autocrine stimulation, and aggregation.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	14	15
Although the EPCR-APC-PAR1 paradigm is broadly useful and supported [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR , XREF_BIBR - XREF_BIBR ] , there is a paradox of how PAR1 can be activated by both APC and thrombin with such contrasting outcomes [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Although the EPCR-APC-PAR1 paradigm is broadly useful and supported [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR, XREF_BIBR - XREF_BIBR], there is a paradox of how PAR1 can be activated by both APC and thrombin with such contrasting outcomes [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	31	40	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	39	40	31	32
Further studies demonstrated that when EPCR was occupied by protein C , similar to APC , the thrombin activation of PAR-1 inhibits the activation of RhoA and enhances the activation of Rac1 pathways in the TNF-alpha-stimulated endothelial cells [ XREF_BIBR ] .	Further studies demonstrated that when EPCR was occupied by protein C, similar to APC, the thrombin activation of PAR-1 inhibits the activation of RhoA and enhances the activation of Rac1 pathways in the TNF-alpha-stimulated endothelial cells [XREF_BIBR].	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	17	18	20	21
Activation of PAR-1 by thrombin or thrombin agonist peptides induces rapid endothelial cell contraction and vascular permeability , however thrombin does not activate PAR-2 47 .	Activation of PAR-1 by thrombin or thrombin agonist peptides induces rapid endothelial cell contraction and vascular permeability, however thrombin does not activate PAR-2 47.	0	8	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	2	3
PAR-1 expression is minimal or absent in benign and normal breast tissue and noninvasive carcinoma , but thrombin activation of PAR-1 has been implicated in tumour cell growth , in invasion and metastasis of breast cancer and in other human malignant diseases [ XREF_BIBR ] .	PAR-1 expression is minimal or absent in benign and normal breast tissue and noninvasive carcinoma, but thrombin activation of PAR-1 has been implicated in tumour cell growth, in invasion and metastasis of breast cancer and in other human malignant diseases [XREF_BIBR].	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	17	18	20	21
Interestingly , PAR-1 activation by thrombin did not affect macrophage migration towards control medium , but did potentiate directed migration towards conditioned medium of injured epithelial cells .	Interestingly, PAR-1 activation by thrombin did not affect macrophage migration towards control medium, but did potentiate directed migration towards conditioned medium of injured epithelial cells.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	2	3
These results suggest that functional PAR1 is expressed by SVZ neural stem cells derived from the adult brain , and that both thrombin and PAR1-AP specifically activate PAR1 in NSCs to gate Ca 2+ signaling .	These results suggest that functional PAR1 is expressed by SVZ neural stem cells derived from the adult brain, and that both thrombin and PAR1-AP specifically activate PAR1 in NSCs to gate Ca 2+ signaling.	21	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	22	23	27	28
PAR1 , PAR3 and PAR4 are activated by thrombin , whereas PAR2 is activated by trypsin , mast cell tryptase and coagulation factor VIIa/Xa .	PAR1, PAR3 and PAR4 are activated by thrombin, whereas PAR2 is activated by trypsin, mast cell tryptase and coagulation factor VIIa/Xa.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	0	1
PAR1 , PAR3 and PAR4 can be activated by thrombin , a serine protease and a member of coagulation cascade ; PAR2 is activated by trypsin like enzymes such as trypsin , mast cell tryptase , neutrophil proteinase 3 as well as Porphyromonas gingivalis proteases [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	PAR1, PAR3 and PAR4 can be activated by thrombin, a serine protease and a member of coagulation cascade; PAR2 is activated by trypsin like enzymes such as trypsin, mast cell tryptase, neutrophil proteinase 3 as well as Porphyromonas gingivalis proteases [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	0	1
The contribution of thrombin mediated activation of PAR-1 to myocardial infarction is less clear .	The contribution of thrombin mediated activation of PAR-1 to myocardial infarction is less clear.	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	7	8
Other platelet activation pathways , including the PAR-1 pathway activated by thrombin ( the most potent platelet activator ) , remain active in the presence of current antiplatelet agents .	Other platelet activation pathways, including the PAR-1 pathway activated by thrombin (the most potent platelet activator), remain active in the presence of current antiplatelet agents.	7	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	11	12	7	8
Since aPC bound to EPCR and thrombin are potent activators of endothelial PAR1 ( XREF_SUPPLEMENTARY ) , we first characterized PAR1 expression by HSC and found that PAR1 was highly expressed by bone marrow EPCR + LT-HSC populations ( XREF_FIG ) .	Since aPC bound to EPCR and thrombin are potent activators of endothelial PAR1 (XREF_SUPPLEMENTARY), we first characterized PAR1 expression by HSC and found that PAR1 was highly expressed by bone marrow EPCR + LT-HSC populations (XREF_FIG).	6	14	are potent activators	Positive_activation_copula_1	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	12	13
We used voltage- and calcium sensitive dye recordings to study the effects of PAR1-AP , PAR2-AP , PAR4-AP , the PAR1 activator thrombin , and the PAR2 activator tryptase on neurons and glia in human and guinea pig submucous plexus .	We used voltage- and calcium sensitive dye recordings to study the effects of PAR1-AP, PAR2-AP, PAR4-AP, the PAR1 activator thrombin, and the PAR2 activator tryptase on neurons and glia in human and guinea pig submucous plexus.	11	23	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	22	23	20	21
These data indicate that activation of PAR-1 by MMP-1 results in a disparate gene expression profile , compared to PAR-1 activation by thrombin .	These data indicate that activation of PAR-1 by MMP-1 results in a disparate gene expression profile, compared to PAR-1 activation by thrombin.	19	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	22	23	19	20
A promising candidate is the PAR-1 receptor , which is activated by thrombin and represents a validated therapeutic target mediating thrombosis without being critical for hemostasis in preclinical models .	A promising candidate is the PAR-1 receptor, which is activated by thrombin and represents a validated therapeutic target mediating thrombosis without being critical for hemostasis in preclinical models.	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	12	13	5	6
XREF_BIBR , XREF_BIBR PAR-1 , PAR-3 , and PAR-4 are activated by thrombin , whereas PAR-2 is activated by trypsin and trypsin like proteases and not by thrombin .	XREF_BIBR, XREF_BIBR PAR-1, PAR-3, and PAR-4 are activated by thrombin, whereas PAR-2 is activated by trypsin and trypsin like proteases and not by thrombin.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	12	13	3	4
PAR1 is activated by thrombin and PAR2 is activated by trypsin like enzymes , including trypsin , mast cell tryptase and neutrophil proteinse-3 [ XREF_BIBR ] .	PAR1 is activated by thrombin and PAR2 is activated by trypsin like enzymes, including trypsin, mast cell tryptase and neutrophil proteinse-3 [XREF_BIBR].	0	8	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	0	1
PAR1 activation by 30 nM thrombin significantly increased the amplitude of field EPSPs compared to slices recorded in ACSF alone .	PAR1 activation by 30 nM thrombin significantly increased the amplitude of field EPSPs compared to slices recorded in ACSF alone.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	0	1
These data suggest , albeit indirectly , that TF mediated PAR1 signaling may primarily drive tumor growth , whereas thrombin mediated PAR1 signaling may contribute to tumor cell adhesion and initial seeding of tumor cells .	These data suggest, albeit indirectly, that TF mediated PAR1 signaling may primarily drive tumor growth, whereas thrombin mediated PAR1 signaling may contribute to tumor cell adhesion and initial seeding of tumor cells.	19	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	19	20	21	22
PAR-1 activation by thrombin or TRAP in vitro results in the production of proinflammatory mediators , including IL-8 15 , E-selectin , and platelet derived growth factor 16 by endothelial cells and monocyte chemoattractant protein 1 17 by mesangial cells .	PAR-1 activation by thrombin or TRAP in vitro results in the production of proinflammatory mediators, including IL-8 15, E-selectin, and platelet derived growth factor 16 by endothelial cells and monocyte chemoattractant protein 1 17 by mesangial cells.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	0	1
Thus , because PAR1 was shown to be a biased receptor , application of the biased signalling paradigm to PAR1 activation by APC and thrombin provides a comprehensive , conceptual explanation why phenomena such as receptor occupancy of EPCR and localisation of PAR1 and EPCR in caveolae result in such remarkable differences in functional selectivity when PAR1 is activated by two different proteases [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Thus, because PAR1 was shown to be a biased receptor, application of the biased signalling paradigm to PAR1 activation by APC and thrombin provides a comprehensive, conceptual explanation why phenomena such as receptor occupancy of EPCR and localisation of PAR1 and EPCR in caveolae result in such remarkable differences in functional selectivity when PAR1 is activated by two different proteases [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	19	25	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	24	25	19	20
It has been suggested that thrombin indirectly induces cellular rearrangements by activating PAR1 and transactivating the epidermal growth factor receptor ( EGFR and/or HER2 ) poor prognosis factors for breast cancer patients , which exerts its effects exclusively through intracellular signals .	It has been suggested that thrombin indirectly induces cellular rearrangements by activating PAR1 and transactivating the epidermal growth factor receptor (EGFR and/or HER2) poor prognosis factors for breast cancer patients, which exerts its effects exclusively through intracellular signals.	5	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	12	13
Previous studies have indicated that , unlike the barrier protective activity of APC , thrombin and proinflammatory cytokines enhance permeability by cleaving PAR-1 on the surface of endothelial cells .	Previous studies have indicated that, unlike the barrier protective activity of APC, thrombin and proinflammatory cytokines enhance permeability by cleaving PAR-1 on the surface of endothelial cells.	12	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	14	15	22	23
The coagulant protease thrombin is the physiological activator of PAR-1 , PAR-3 , and PAR-4 .	The coagulant protease thrombin is the physiological activator of PAR-1, PAR-3, and PAR-4.	0	14	is the physiological activator	Positive_activation_copula_1	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	9	10
PAR1 activation by APC and thrombin results in the activation of distinct intracellular signaling cascades .	PAR1 activation by APC and thrombin results in the activation of distinct intracellular signaling cascades.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	0	1
After PAR-1 activation by thrombin or TFLLR-NH2 , secretory responses to EFS but not those to forskolin or carbachol were significantly reduced .	After PAR-1 activation by thrombin or TFLLR-NH2, secretory responses to EFS but not those to forskolin or carbachol were significantly reduced.	1	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	1	2
There are four known members in the family , in which PAR-1 and PAR-3 are activated mainly by thrombin , PAR-2 is activated by trypsin and PAR-4 is activated by both enzymes XREF_BIBR , XREF_BIBR .	There are four known members in the family, in which PAR-1 and PAR-3 are activated mainly by thrombin, PAR-2 is activated by trypsin and PAR-4 is activated by both enzymes XREF_BIBR, XREF_BIBR.	11	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	18	19	11	12
In contrast , PAR1 and PAR3 activation by thrombin results in barrier disruption .	In contrast, PAR1 and PAR3 activation by thrombin results in barrier disruption.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	3	4
Since PAR1 activation by thrombin influences astrocytic inflammation , neuronal electrophysiology and pain , we hypothesize that human and salmon thrombin may activate this receptor differently contributing to possible differences in pain and cellular responses .	Since PAR1 activation by thrombin influences astrocytic inflammation, neuronal electrophysiology and pain, we hypothesize that human and salmon thrombin may activate this receptor differently contributing to possible differences in pain and cellular responses.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	1	2
In particular , activation of PAR1 triggers astrogliosis after brain injury XREF_BIBR , and low doses of thrombin activate PAR1 to mediate proliferation of astrocytes via MAPK signaling pathways XREF_BIBR .	In particular, activation of PAR1 triggers astrogliosis after brain injury XREF_BIBR, and low doses of thrombin activate PAR1 to mediate proliferation of astrocytes via MAPK signaling pathways XREF_BIBR.	15	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	17	18	19	20
We found that thrombin and thrombin agonist peptides induce homologous internalization of thrombin receptor in a dose dependent manner .	We found that thrombin and thrombin agonist peptides induce homologous internalization of thrombin receptor in a dose dependent manner.	3	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	3	4	12	14
In the disarmed state the PAR1 can be still activated by the tethered ligand , but not by thrombin .	In the disarmed state the PAR1 can be still activated by the tethered ligand, but not by thrombin.	4	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	18	19	5	6
Thus , thrombin mediated activation of PAR1 on tumor cells also did not account for enhanced metastasis in TM Pro mice .	Thus, thrombin mediated activation of PAR1 on tumor cells also did not account for enhanced metastasis in TM Pro mice.	2	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	6	7
Our results suggest heterogeneous mechanisms in the NO independent relaxation to thrombin and peptide activators of PAR1 in the porcine coronary artery .	Our results suggest heterogeneous mechanisms in the NO independent relaxation to thrombin and peptide activators of PAR1 in the porcine coronary artery.	11	21	activators	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	16	17
Here we have investigated the effect of aprotinin on thrombin induced PAR1 activation of platelets .	Here we have investigated the effect of aprotinin on thrombin induced PAR1 activation of platelets.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	11	12
PAR1 , PAR3 , and PAR4 are activated mainly by thrombin .	PAR1, PAR3, and PAR4 are activated mainly by thrombin.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	0	1
These observations suggest modulation of APC mediated signalling by PAR3 , consistent with modulation of thrombin mediated PAR1 signalling by PAR3 due to PAR1 and PAR3 heterodimer formation that enhances barrier disruptive effects of thrombin [ XREF_BIBR ] .	These observations suggest modulation of APC mediated signalling by PAR3, consistent with modulation of thrombin mediated PAR1 signalling by PAR3 due to PAR1 and PAR3 heterodimer formation that enhances barrier disruptive effects of thrombin [XREF_BIBR].	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	15	16	17	18
The inhibition of thrombin associated effects was mostly observed at thrombin concentrations that caused complete PAR-1 proteolysis and secretion of all ADP .	The inhibition of thrombin associated effects was mostly observed at thrombin concentrations that caused complete PAR-1 proteolysis and secretion of all ADP.	10	16	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	15	16
To verify whether doxycycline plays its inhibitory function in breast cancer cells through PAR1 , thrombin was used to activate PAR1 in MCF-7 cells , E-Cadherin ( a classical and most well studied member of the cadherin superfamily , acting as a canonical epithelial marker ) and Vimentin were detected with immunofluorescence assay [ XREF_BIBR ] .	To verify whether doxycycline plays its inhibitory function in breast cancer cells through PAR1, thrombin was used to activate PAR1 in MCF-7 cells, E-Cadherin (a classical and most well studied member of the cadherin superfamily, acting as a canonical epithelial marker) and Vimentin were detected with immunofluorescence assay [XREF_BIBR].	15	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	15	16	20	21
In contrast , thrombin activation of PAR1 results in coupling to G 12/13 signaling when examined in human dermal microvascular endothelial cells [ XREF_BIBR ] .	In contrast, thrombin activation of PAR1 results in coupling to G 12/13 signaling when examined in human dermal microvascular endothelial cells [XREF_BIBR].	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	6	7
The thrombin activated PAR1 and RAP1 signaling pathway is important for platelet aggregation , as it partially increases cell adhesion while reducing migration and thus plays roles in hemostasis and thrombosis .	The thrombin activated PAR1 and RAP1 signaling pathway is important for platelet aggregation, as it partially increases cell adhesion while reducing migration and thus plays roles in hemostasis and thrombosis.	0	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	1	2	3	4
We further demonstrate that the activation of PAR-1 by thrombin induces intracellular calcium movements that are blocked by 2-APB , an inhibitor of inositol 1,4,5-triphosphate ( IP3 )-induced calcium release .	We further demonstrate that the activation of PAR-1 by thrombin induces intracellular calcium movements that are blocked by 2-APB, an inhibitor of inositol 1,4,5-triphosphate (IP3)-induced calcium release.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	7	8
This study demonstrates that PAR-1 is the only known PAR family member functionally expressed by cardiac fibroblasts and that PAR-1 activation by thrombin leads to increased DNA synthesis in cardiac fibroblasts .	This study demonstrates that PAR-1 is the only known PAR family member functionally expressed by cardiac fibroblasts and that PAR-1 activation by thrombin leads to increased DNA synthesis in cardiac fibroblasts.	19	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	22	23	19	20
After ischemic cardiac injury , it has been proposed that prothrombin from the blood leaks into the myocardium through the damaged endothelial barrier , and the subsequent generation of thrombin leads to pathological PAR1 signaling in the heart 7 .	After ischemic cardiac injury, it has been proposed that prothrombin from the blood leaks into the myocardium through the damaged endothelial barrier, and the subsequent generation of thrombin leads to pathological PAR1 signaling in the heart 7.	10	34	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	prothrombin	prothrombin	prothrombin	PAR1	PAR1	PAR1	10	11	33	34
Secondly , PAR-1 activation by thrombin protects non silenced and beta-arrestin 1 deficient astrocytes from staurosporine induced chemical toxicity .	Secondly, PAR-1 activation by thrombin protects non silenced and beta-arrestin 1 deficient astrocytes from staurosporine induced chemical toxicity.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	2	3
Large quantities of high TF expressing tumor derived EV in the circulation are likely to generate thrombin , which will activate PAR-1 more strongly than FXa and override any observed FXa mediated responses .	Large quantities of high TF expressing tumor derived EV in the circulation are likely to generate thrombin, which will activate PAR-1 more strongly than FXa and override any observed FXa mediated responses.	15	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	16	17	21	22
Motility and migration of melanoma cells is also regulated by thrombin mediated PAR-1 activation [ XREF_BIBR , XREF_BIBR ] .	Motility and migration of melanoma cells is also regulated by thrombin mediated PAR-1 activation [XREF_BIBR, XREF_BIBR].	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	12	13
24 The effects of interactions of PAR-1 and PAR-4 on platelet mediated thrombin generation were reported by Thomas et al , 25 who found that thrombin treatment of human platelets resulted in PAR-1- and PAR-4-dependent production of phosphatidylethanolamine or phosphatidylcholine esterified 12S-HETE .	24 The effects of interactions of PAR-1 and PAR-4 on platelet mediated thrombin generation were reported by Thomas et al, 25 who found that thrombin treatment of human platelets resulted in PAR-1- and PAR-4-dependent production of phosphatidylethanolamine or phosphatidylcholine esterified 12S-HETE.	25	36	production	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1-	PAR-1-	PAR-1-	25	26	32	33
While thrombin activation of PAR1 induces an NMDAR mediated slow onset LTP , which saturates the ability to induce further LTP in the exposed network , aPC stimulation of PAR1 enhances tetanus induced LTP through a voltage gated calcium channels mediated mechanism .	While thrombin activation of PAR1 induces an NMDAR mediated slow onset LTP, which saturates the ability to induce further LTP in the exposed network, aPC stimulation of PAR1 enhances tetanus induced LTP through a voltage gated calcium channels mediated mechanism.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	1	2	4	5
In contrast to thrombin activated PAR 1 , APC cleaved PAR 1 fails to activate extracellular signal regulated kinase ( ERK ) 1/2 .	In contrast to thrombin activated PAR 1, APC cleaved PAR 1 fails to activate extracellular signal regulated kinase (ERK) 1/2.	1	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	3	4	5	7
In addition to thrombin ' s role in converting fibrinogen to fibrin , thrombin is known to activate PAR-1 .	In addition to thrombin 's role in converting fibrinogen to fibrin, thrombin is known to activate PAR-1.	13	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	13	14	18	19
We demonstrated that following PAR-1 activation thrombin ' s mitogenic effect on fibroblasts is critically dependent on induction of both PDGF-AA and the PDGF alpha-receptor .	We demonstrated that following PAR-1 activation thrombin 's mitogenic effect on fibroblasts is critically dependent on induction of both PDGF-AA and the PDGF alpha-receptor.	4	8	activation	Positive_activation_token_1_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	6	7	4	5
Remarkably , thrombin activated PAR1 NA ECL2 mutant displayed an enhanced maximal signaling response compared with wild-type receptor .	Remarkably, thrombin activated PAR1 NA ECL2 mutant displayed an enhanced maximal signaling response compared with wild-type receptor.	2	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	4	5
Therefore , thrombin may indirectly promote fracture healing by activating PAR-1 .	Therefore, thrombin may indirectly promote fracture healing by activating PAR-1.	2	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	10	11
PAR-1 , PAR-3 , and PAR-4 can be activated by thrombin , and PAR-2 can be mainly activated by trypsin and numerous studies have demonstrated that PAR-2 is highly expressed in ECs [ XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	PAR-1, PAR-3, and PAR-4 can be activated by thrombin, and PAR-2 can be mainly activated by trypsin and numerous studies have demonstrated that PAR-2 is highly expressed in ECs [XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	0	1
PAR1 activation by thrombin occurs after cleavage of the canonical Arg41 site after which the tethered-ligand starting at Ser42 promotes G protein dependent signaling that includes activation of barrier disruptive Ras homolog gene family member A ( RhoA ) .	PAR1 activation by thrombin occurs after cleavage of the canonical Arg41 site after which the tethered-ligand starting at Ser42 promotes G protein dependent signaling that includes activation of barrier disruptive Ras homolog gene family member A (RhoA).	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	0	1
Human PAR1 , PAR3 , and PAR4 are activated by thrombin , whereas PAR2 is activated by trypsin but not by thrombin .	Human PAR1, PAR3, and PAR4 are activated by thrombin, whereas PAR2 is activated by trypsin but not by thrombin.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	1	2
This study demonstrates that platelet PAR1 activation by thrombin can be inhibited by aprotinin .	This study demonstrates that platelet PAR1 activation by thrombin can be inhibited by aprotinin.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	5	6
While the pharmacological approach used here suggests that the regulation of PAR1 and PAR4 activation by thrombin could be subtle in human intestinal epithelial cells , depending on the concentration of surrounding thrombin , all our data point to a detrimental effect of thrombin and its receptors on epithelial growth and potential healing .	While the pharmacological approach used here suggests that the regulation of PAR1 and PAR4 activation by thrombin could be subtle in human intestinal epithelial cells, depending on the concentration of surrounding thrombin, all our data point to a detrimental effect of thrombin and its receptors on epithelial growth and potential healing.	11	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	16	17	11	12
However , it is unclear at present whether a direct TF-PAR1-mediated signaling or thrombin induced PAR-1 mediated signaling is responsible for this tumor growth .	However, it is unclear at present whether a direct TF-PAR1-mediated signaling or thrombin induced PAR-1 mediated signaling is responsible for this tumor growth.	11	17	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	13	14	15	16
This may be due to thrombin activating PAR-1 with a 3-4 orders of magnitude higher catalytic efficiency than APC [ XREF_BIBR ] .	This may be due to thrombin activating PAR-1 with a 3-4 orders of magnitude higher catalytic efficiency than APC [XREF_BIBR].	3	11	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	7	8
A significant increase in TAB1 expression was also induced after thrombin stimulation of endogenous PAR1 in endothelial cells ( XREF_FIG ) .	A significant increase in TAB1 expression was also induced after thrombin stimulation of endogenous PAR1 in endothelial cells (XREF_FIG).	10	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	14	15
PAR-1 conformational changes mediated by thrombin result in receptor coupling to Galpha protein ( Galphaq , Galphai , and Galpha 12/13 ) and Gbetagamma .	PAR-1 conformational changes mediated by thrombin result in receptor coupling to Galpha protein (Galphaq, Galphai, and Galpha 12/13) and Gbetagamma.	0	6	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	0	1
Furthermore , we suppose that this binding may interfere with thrombin mediated cleavage of PAR-1 since the cleavage site ( Ser 42 ) is located in the vicinity to hypothetical heparin binding site and can be masked by heparin molecule .	Furthermore, we suppose that this binding may interfere with thrombin mediated cleavage of PAR-1 since the cleavage site (Ser 42) is located in the vicinity to hypothetical heparin binding site and can be masked by heparin molecule.	10	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	14	15
These results suggest that catalytic activation of thrombin receptor by thrombin results in GRO alpha and MGSA production , at least in part , via a pathway involving PKC in HUVEC .	These results suggest that catalytic activation of thrombin receptor by thrombin results in GRO alpha and MGSA production, at least in part, via a pathway involving PKC in HUVEC.	5	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	10	11	7	9
It is well known that not the same concentrations of thrombin are required to activate PAR1 and PAR4 on platelets ( Kahn et al ., 1998 ; Ramachandran and Hollenberg , 2008 ) .	It is well known that not the same concentrations of thrombin are required to activate PAR1 and PAR4 on platelets (Kahn et al., 1998; Ramachandran and Hollenberg, 2008).	8	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	15	16
Thus , non canonical activation of PAR1 by APC at Arg46 and canonical activation of PAR1 by thrombin at Arg41 can understandably mediate the often opposite effects of thrombin and APC because each protease generates different tethered-ligand agonists that utilize different signaling pathways with different functional consequences .	Thus, non canonical activation of PAR1 by APC at Arg46 and canonical activation of PAR1 by thrombin at Arg41 can understandably mediate the often opposite effects of thrombin and APC because each protease generates different tethered-ligand agonists that utilize different signaling pathways with different functional consequences.	13	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	17	18	15	16
It is generally thought that thrombin induces proinflammatory responses by cleaving PAR-1 at the surface of endothelial cells XREF_BIBR , XREF_BIBR - XREF_BIBR .	It is generally thought that thrombin induces proinflammatory responses by cleaving PAR-1 at the surface of endothelial cells XREF_BIBR, XREF_BIBR - XREF_BIBR.	5	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	11	12
Interestingly , this study also showed that while high concentrations of thrombin induced increased permeability through the classical activation of the PAR-1 receptor , low concentrations of thrombin ( ~ 40 pM ) activated the PAR-1 receptor in a fashion similar to aPC and mediated barrier enhancement through S1P1 transactivation [ XREF_BIBR ] .	Interestingly, this study also showed that while high concentrations of thrombin induced increased permeability through the classical activation of the PAR-1 receptor, low concentrations of thrombin (~ 40 pM) activated the PAR-1 receptor in a fashion similar to aPC and mediated barrier enhancement through S1P1 transactivation [XREF_BIBR].	25	36	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	27	28	35	36
Collectively , our findings define a detrimental role of thrombin activated PAR-1 in wound healing and further validate APC , also acting through the PAR-1 by biased agonism , as a promising therapeutic target for spinal cord injury .	Collectively, our findings define a detrimental role of thrombin activated PAR-1 in wound healing and further validate APC, also acting through the PAR-1 by biased agonism, as a promising therapeutic target for spinal cord injury.	7	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	11	12
Interestingly PAR1 in fish are activated by thrombin while PAR2 is activated by trypsin .	Interestingly PAR1 in fish are activated by thrombin while PAR2 is activated by trypsin.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	1	2
Moreover , thrombin activated PAR-1 in the endothelium not only induces pro inflammatory signaling but also alters the cell shape , increases vascular permeability , and modulates leukocyte trafficking [ XREF_BIBR , XREF_BIBR ] .	Moreover, thrombin activated PAR-1 in the endothelium not only induces pro inflammatory signaling but also alters the cell shape, increases vascular permeability, and modulates leukocyte trafficking [XREF_BIBR, XREF_BIBR].	2	26	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	4	5
Furthermore , there is in vitro evidence that the reduction of thrombin production results in less thrombin induced PAR-1 mediated proliferation of osteoblasts [ XREF_BIBR ] .	Furthermore, there is in vitro evidence that the reduction of thrombin production results in less thrombin induced PAR-1 mediated proliferation of osteoblasts [XREF_BIBR].	13	20	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	16	17	18	19
Noting the phenotypic differences between venous and arterial endothelial cells and the observation that PAR-1 activation by thrombin elicits potent proinflammatory responses in both cell types , we decided to evaluate the PAR-1-dependent signaling function of thrombin in human pulmonary artery endothelial cells ( HPAECs ) under culture conditions in which EPCR has been occupied with a physiological concentration of the zymogen protein C. To make the analysis straightforward , we used the catalytically inactive S195A mutant of protein C ( PC-S195A ) in the experiments .	Noting the phenotypic differences between venous and arterial endothelial cells and the observation that PAR-1 activation by thrombin elicits potent proinflammatory responses in both cell types, we decided to evaluate the PAR-1-dependent signaling function of thrombin in human pulmonary artery endothelial cells (HPAECs) under culture conditions in which EPCR has been occupied with a physiological concentration of the zymogen protein C. To make the analysis straightforward, we used the catalytically inactive S195A mutant of protein C (PC-S195A) in the experiments.	14	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	17	18	14	15
Thus , it has been demonstrated that the thrombin activation of PAR-1 promotes the interaction of leukocytes with endothelial cells and up-regulates the expression of cell adhesion molecules through the activation of the NF-kappaB pathway .	Thus, it has been demonstrated that the thrombin activation of PAR-1 promotes the interaction of leukocytes with endothelial cells and up-regulates the expression of cell adhesion molecules through the activation of the NF-kappaB pathway.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	11	12
Although the signal transduction pathways induced by thrombin activation of PAR1 in endothelial cells have been extensively studied , the key regulatory mechanisms remain poorly understood .	Although the signal transduction pathways induced by thrombin activation of PAR1 in endothelial cells have been extensively studied, the key regulatory mechanisms remain poorly understood.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	10	11
The activation of PAR1 by thrombin increased the amplitude of NMDA receptor mediated component of EPSPs .	The activation of PAR1 by thrombin increased the amplitude of NMDA receptor mediated component of EPSPs.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	3	4
Hence , high concentrations of thrombin saturate the ability of neurons to express further LTP via direct PAR1 activation , while at low concentration thrombin mediates metaplasticity by enhancing LTP via aPC-EPCR mediated PAR1 signaling .	Hence, high concentrations of thrombin saturate the ability of neurons to express further LTP via direct PAR1 activation, while at low concentration thrombin mediates metaplasticity by enhancing LTP via aPC-EPCR mediated PAR1 signaling.	24	34	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	24	25	33	34
Thus , it is conceivable that activation of PAR1 by thrombin or APC in tumor cells lacking EPCR could result in pro tumor growth signaling whereas activation of PAR1 by thrombin in tumor cells expressing EPCR may initiate pro apoptotic cell signaling .	Thus, it is conceivable that activation of PAR1 by thrombin or APC in tumor cells lacking EPCR could result in pro tumor growth signaling whereas activation of PAR1 by thrombin in tumor cells expressing EPCR may initiate pro apoptotic cell signaling.	26	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	30	31	28	29
Activation of PAR-1 by thrombin and of PAR-2 by factor leads to a rapid expression and exposure on the membrane of endothelial cells of both adhesive proteins that mediate an acute inflammatory reaction and of the tissue factor that initiates the blood coagulation cascade .	Activation of PAR-1 by thrombin and of PAR-2 by factor leads to a rapid expression and exposure on the membrane of endothelial cells of both adhesive proteins that mediate an acute inflammatory reaction and of the tissue factor that initiates the blood coagulation cascade.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	2	3
Activation of PAR-1 by the APC and PAR-1 complex leads to different cellular signaling than when thrombin activates PAR-1 despite cleaving the same site on the receptor [ XREF_BIBR ] .	Activation of PAR-1 by the APC and PAR-1 complex leads to different cellular signaling than when thrombin activates PAR-1 despite cleaving the same site on the receptor [XREF_BIBR].	16	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	16	17	18	19
Among the four members of PAR family ( PAR1 to PAR4 ) , three receptor subtypes ( PAR1 , PAR3 , and PAR4 ) are activated by thrombin .	Among the four members of PAR family (PAR1 to PAR4), three receptor subtypes (PAR1, PAR3, and PAR4) are activated by thrombin.	15	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	27	28	17	18
For many of the functional studies we used thrombin , a protease which activates PAR1 , 3 and 4 but not PAR2 receptors .	For many of the functional studies we used thrombin, a protease which activates PAR1, 3 and 4 but not PAR2 receptors.	7	22	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	14	15
PAR1 activation by both thrombin and an agonist peptide stimulated renal cancer cell invasion through Matrigel .	PAR1 activation by both thrombin and an agonist peptide stimulated renal cancer cell invasion through Matrigel.	0	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	0	1
Our recent work demonstrates a role for TAB1 dependent autophosphorylation and activation of p38 MAP kinase mediated induction of endothelial barrier permeability initiated by thrombin activation of PAR1 .	Our recent work demonstrates a role for TAB1 dependent autophosphorylation and activation of p38 MAP kinase mediated induction of endothelial barrier permeability initiated by thrombin activation of PAR1.	24	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	24	25	27	28
CCL2 is present in increased amounts in the bronchoalveolar lavage fluid of IPF patients [ XREF_BIBR ] , and may be induced in the AECs themselves by thrombin activation of the major thrombin receptor , proteinase activated receptor-1 ( PAR1 ) [ XREF_BIBR ] .	CCL2 is present in increased amounts in the bronchoalveolar lavage fluid of IPF patients [XREF_BIBR], and may be induced in the AECs themselves by thrombin activation of the major thrombin receptor, proteinase activated receptor-1 (PAR1) [XREF_BIBR].	27	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	27	28	32	34
Experimental studies on gastric cancer cell lines revealed that thrombin mediated PAR-1 activation leads to reprogramming of gene expression by stimulation of transcription factors like SNAIL1 that is known to drive EMT in the embryo [ XREF_BIBR ] .	Experimental studies on gastric cancer cell lines revealed that thrombin mediated PAR-1 activation leads to reprogramming of gene expression by stimulation of transcription factors like SNAIL1 that is known to drive EMT in the embryo [XREF_BIBR].	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	11	12
Not only does thrombin induce PAR1 dependent proinflammatory and endothelial barrier disruptive effects that contrast APC ' s cytoprotective and endothelial barrier protective effects , the requirement for thrombin to activate protein C seemed incompatible with a role for PAR1 mediated cytoprotective effects of endogenously generated APC [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Not only does thrombin induce PAR1 dependent proinflammatory and endothelial barrier disruptive effects that contrast APC 's cytoprotective and endothelial barrier protective effects, the requirement for thrombin to activate protein C seemed incompatible with a role for PAR1 mediated cytoprotective effects of endogenously generated APC [XREF_BIBR, XREF_BIBR - XREF_BIBR].	3	6	induce	Positive_activation_token_1_verb	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	5	6
Similarly , fibronectin deposition was increased after thrombin mediated PAR-1 signaling in mesangial cells in vitro whereas it was reduced in glomeruli of diabetic PAR-1 deficient mice .	Similarly, fibronectin deposition was increased after thrombin mediated PAR-1 signaling in mesangial cells in vitro whereas it was reduced in glomeruli of diabetic PAR-1 deficient mice.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	9	10
In numerous cancers , the response to thrombin induced PAR-1 activation increases cell proliferation , as well as motility and migration in Matrigel barrier assays [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In numerous cancers, the response to thrombin induced PAR-1 activation increases cell proliferation, as well as motility and migration in Matrigel barrier assays [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	9	10
Robust evidence states that thrombin can canonically activate , unmasking via cleavage their tethered ligand , PAR1 , PAR3 , and PAR4 [ XREF_BIBR ] .	Robust evidence states that thrombin can canonically activate, unmasking via cleavage their tethered ligand, PAR1, PAR3, and PAR4 [XREF_BIBR].	2	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	16	17
Receptor activation by thrombin , or the thrombin receptor ( proteinase activated receptor 1 ) agonist peptide , leads to an early increase in stress fiber formation followed by cortical actin accumulation and cell rounding .	Receptor activation by thrombin, or the thrombin receptor (proteinase activated receptor 1) agonist peptide, leads to an early increase in stress fiber formation followed by cortical actin accumulation and cell rounding.	1	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	3	4	7	9
Similarly , internalization of mammalian PAR1 is triggered by thrombin , and the previous study of zebrafish Par proteins had shown that human thrombin can stimulate zebrafish Par1 to induce a Ca 2+ response in Xenopus oocytes .	Similarly, internalization of mammalian PAR1 is triggered by thrombin, and the previous study of zebrafish Par proteins had shown that human thrombin can stimulate zebrafish Par1 to induce a Ca 2+ response in Xenopus oocytes.	22	28	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	Par1	Par1	Par1	23	24	27	28
Finally , the observation that thrombin mediated PAR-1 activation interferes and abrogates docetaxel mediated cancer cell apoptosis through upregulation of BcL-xL protein expression in advanced prostate cancer has profound therapeutic potential , as direct thrombin inhibition during docetaxel chemotherapy could enhance docetaxel cytotoxicty .	Finally, the observation that thrombin mediated PAR-1 activation interferes and abrogates docetaxel mediated cancer cell apoptosis through upregulation of BcL-xL protein expression in advanced prostate cancer has profound therapeutic potential, as direct thrombin inhibition during docetaxel chemotherapy could enhance docetaxel cytotoxicty.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	7	8
In our studies using primary astrocytes , we observed that thrombin , which activates PAR1 , stimulates transient Ras activation but leads to sustained activation of Rap1 .	In our studies using primary astrocytes, we observed that thrombin, which activates PAR1, stimulates transient Ras activation but leads to sustained activation of Rap1.	10	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	14	15
One of the reasons that PAR1 mediated cytoprotective signalling by APC initially drew considerable scepticism was based on the major question of how APC could induce relevant PAR1 mediated signalling when thrombin , the archetypal PAR1 activator , activates PAR1 so much more efficiently .	One of the reasons that PAR1 mediated cytoprotective signalling by APC initially drew considerable scepticism was based on the major question of how APC could induce relevant PAR1 mediated signalling when thrombin, the archetypal PAR1 activator, activates PAR1 so much more efficiently.	31	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	31	32	39	40
Vorapaxar is a protease activated receptor-1 ( PAR-1 ) antagonist , and prevents thrombin activation of PAR-1 receptors on platelets .	Vorapaxar is a protease activated receptor-1 (PAR-1) antagonist, and prevents thrombin activation of PAR-1 receptors on platelets.	13	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	13	14	16	17
Moreover , PAR1 activation by thrombin in human microvascular endothelial cells displayed dual effects on tube formation on Matrigel , with low concentrations stimulating and high concentrations inhibiting tubulogenesis XREF_BIBR .	Moreover, PAR1 activation by thrombin in human microvascular endothelial cells displayed dual effects on tube formation on Matrigel, with low concentrations stimulating and high concentrations inhibiting tubulogenesis XREF_BIBR.	2	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	2	3
Activation of distinct subtypes of PARs is cancer specific , for example , gene regulation elicited by TF/FVIIa through PAR-2 in MDA-MB-231 cells may occur in glioblastoma cell lines through thrombin mediated activation of PAR-1 [ XREF_BIBR ] .	Activation of distinct subtypes of PARs is cancer specific, for example, gene regulation elicited by TF/FVIIa through PAR-2 in MDA-MB-231 cells may occur in glioblastoma cell lines through thrombin mediated activation of PAR-1 [XREF_BIBR].	30	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	30	31	34	35
These in vitro studies have suggested that S1P 1 plays a role in aPC mediated endothelial barrier protection , either by SphK1 mediated S1P production or by EPCR mediated direct trans-activation of S1P 1 ( XREF_FIG ) , whereas a differential coupling of thrombin activated PAR1 with S1P 3 leads to endothelial barrier disruption ( XREF_FIG ) .	These in vitro studies have suggested that S1P 1 plays a role in aPC mediated endothelial barrier protection, either by SphK1 mediated S1P production or by EPCR mediated direct trans-activation of S1P 1 (XREF_FIG), whereas a differential coupling of thrombin activated PAR1 with S1P 3 leads to endothelial barrier disruption (XREF_FIG).	41	49	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	43	44	45	46
PAR1 is activated by thrombin , and when thrombin binds the receptor on platelets , it stimulates clot formation .	PAR1 is activated by thrombin, and when thrombin binds the receptor on platelets, it stimulates clot formation.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	0	1
Contributions of other PAR receptors and modulation of PAR1 signalling via formation of heterodimers provides additional selectivity between APC and thrombin mediated PAR1 signalling .	Contributions of other PAR receptors and modulation of PAR1 signalling via formation of heterodimers provides additional selectivity between APC and thrombin mediated PAR1 signalling.	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	20	21	22	23
Activation of PAR1 by thrombin on tumour cells has also been linked to the facilitation of tumour metastasis [ XREF_BIBR ] .	Activation of PAR1 by thrombin on tumour cells has also been linked to the facilitation of tumour metastasis [XREF_BIBR].	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	2	3
Importantly , both the primary and the secondary Ca2+ release induced by thrombin and epinephrine in PAR1- and PAR4 desensitized platelets were abrogated upon cleavage of GPIbalpha by the metalloproteinase mocarhagin .	Importantly, both the primary and the secondary Ca2+ release induced by thrombin and epinephrine in PAR1- and PAR4 desensitized platelets were abrogated upon cleavage of GPIbalpha by the metalloproteinase mocarhagin.	10	22	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1-	PAR1-	PAR1-	12	13	16	17
Based on these results we conclude that the activation of PAR-1 by thrombin would initiate a protective response in intact arterial vascular cells expressing EPCR .	Based on these results we conclude that the activation of PAR-1 by thrombin would initiate a protective response in intact arterial vascular cells expressing EPCR.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	12	13	10	11
PAR1 activation by thrombin , or the CNS expressed serine protease , neurosin ( kallikrein 6 ) , suppresses expression of the major myelin genes PLP and MBP in primary oligodendrocytes in vitro .	PAR1 activation by thrombin, or the CNS expressed serine protease, neurosin (kallikrein 6), suppresses expression of the major myelin genes PLP and MBP in primary oligodendrocytes in vitro.	0	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	0	1
PAR1 , PAR3 , and PAR4 can all be activated by thrombin .	PAR1, PAR3, and PAR4 can all be activated by thrombin.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	0	1
Thus , similar to APC , the activation of PAR-1 by thrombin initiated potent anti-inflammatory responses in endothelial cells .	Thus, similar to APC, the activation of PAR-1 by thrombin initiated potent anti-inflammatory responses in endothelial cells.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	11	12	9	10
Although PAR1 [ XREF_BIBR ] , PAR3 [ XREF_BIBR ] , and PAR4 [ XREF_BIBR ] are activated by thrombin , PAR2 is activated by mast cell tryptase [ XREF_BIBR ] and trypsin [ XREF_BIBR ] .	Although PAR1 [XREF_BIBR], PAR3 [XREF_BIBR], and PAR4 [XREF_BIBR] are activated by thrombin, PAR2 is activated by mast cell tryptase [XREF_BIBR] and trypsin [XREF_BIBR].	1	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	19	20	1	2
Consequently , PAR-1 activation by MMP-1 vs thrombin could differentially influence cell behavior and pathological outcome .	Consequently, PAR-1 activation by MMP-1 vs thrombin could differentially influence cell behavior and pathological outcome.	2	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	2	3
PAR1 , PAR3 , and PAR4 , but not PAR2 , are activated by thrombin , whereas trypsin can activate PAR2 and PAR4 .	PAR1, PAR3, and PAR4, but not PAR2, are activated by thrombin, whereas trypsin can activate PAR2 and PAR4.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	14	15	0	1
PAR1 activation by thrombin stimulates Rho dependent cytoskeletal responses involved in the permeability and migration of endothelial cells [ XREF_BIBR ] .	PAR1 activation by thrombin stimulates Rho dependent cytoskeletal responses involved in the permeability and migration of endothelial cells [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	0	1
We also found that dexamethasone produced a significant decrease in PAR-1 , which was increased by thrombin plus dexamethasone ; nexin-1 , the most abundant , potent endogenous thrombin inhibitor in brain [ XREF_BIBR ] , was not also affected by dexamethasone alone but was increased by thrombin ; the effect was greater and in the same direction when thrombin and dexamethasone were used together .	We also found that dexamethasone produced a significant decrease in PAR-1, which was increased by thrombin plus dexamethasone; nexin-1, the most abundant, potent endogenous thrombin inhibitor in brain [XREF_BIBR], was not also affected by dexamethasone alone but was increased by thrombin; the effect was greater and in the same direction when thrombin and dexamethasone were used together.	5	18	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	16	17	10	11
In our model , thrombin activates PAR-1 which enables signaling eventually promoting tumor progression .	In our model, thrombin activates PAR-1 which enables signaling eventually promoting tumor progression.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	6	7
99 These observations paved the way for the hypothesis that stress induced , accelerated thrombin generation may promote PAR1 + HSPC exit from the BM , and that the higher PAR1 surface expression by the mobilized human CD34 + stem and progenitor cells has motility supporting functions .	99 These observations paved the way for the hypothesis that stress induced, accelerated thrombin generation may promote PAR1 + HSPC exit from the BM, and that the higher PAR1 surface expression by the mobilized human CD34 + stem and progenitor cells has motility supporting functions.	14	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	14	15	18	19
Previous studies have demonstrated that intracellular signaling mediated by the thrombin activation of PAR1 increases the expression of proinflammatory cytokines ( Naldini et al ., 2000 ; Fan et al ., 2005 ) .	Previous studies have demonstrated that intracellular signaling mediated by the thrombin activation of PAR1 increases the expression of proinflammatory cytokines (Naldini et al., 2000; Fan et al., 2005).	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	13	14
Beside this direct activity of thrombin in control of haemostasis , thrombin can activate four different protease activated receptors ( PAR-1 , PAR-2 , PAR-3 , and PAR-4 ) that belong to the seven transmembrane G-protein-coupled receptor family .	Beside this direct activity of thrombin in control of haemostasis, thrombin can activate four different protease activated receptors (PAR-1, PAR-2, PAR-3, and PAR-4) that belong to the seven transmembrane G-protein-coupled receptor family.	11	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	11	12	20	21
We found that thrombin activation of PAR1 caused a significant approximately twofold increase in TAB1 expression ( XREF_FIG , lanes 1 and 2 ) , whereas TAB2 expression remained unchanged , suggesting that TAB1 protein stability is dynamically regulated .	We found that thrombin activation of PAR1 caused a significant approximately twofold increase in TAB1 expression (XREF_FIG, lanes 1 and 2), whereas TAB2 expression remained unchanged, suggesting that TAB1 protein stability is dynamically regulated.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	6	7
S1P 1 plays a role in activated protein C ( aPC )-mediated endothelial barrier protection , either by SphK1 mediated S1P production or by EPCR mediated direct trans-activation of S1P 1 , while a differential coupling of thrombin activated PAR-1 with S1P 3 leads to endothelial barrier disruption .	S1P 1 plays a role in activated protein C (aPC)-mediated endothelial barrier protection, either by SphK1 mediated S1P production or by EPCR mediated direct trans-activation of S1P 1, while a differential coupling of thrombin activated PAR-1 with S1P 3 leads to endothelial barrier disruption.	35	43	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	37	38	39	40
Moreover , thrombin activated PAR1-PAR2 heterodimers enhance beta-arrestin-mediated ERK1/2 activation in the cytoplasm , whereas activated ERK1/2 induced by the thrombin activated PAR1 protomer redistributes to the nucleus .	Moreover, thrombin activated PAR1-PAR2 heterodimers enhance beta-arrestin-mediated ERK1/2 activation in the cytoplasm, whereas activated ERK1/2 induced by the thrombin activated PAR1 protomer redistributes to the nucleus.	17	23	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	20	21	22	23
PAR 1 , PAR 3 , and PAR 4 are activated by thrombin ; PAR 2 mediates the cellular effects of trypsin and trypsin like enzymes , including several microbial proteinases .	PAR 1, PAR 3, and PAR 4 are activated by thrombin; PAR 2 mediates the cellular effects of trypsin and trypsin like enzymes, including several microbial proteinases.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	12	13	0	2
Interestingly , thrombin induced PAR-1 signaling leads to increased mesangial proliferation in vitro .	Interestingly, thrombin induced PAR-1 signaling leads to increased mesangial proliferation in vitro.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	4	5
It appears that thrombin induced PAR1 activation in the hippocampus and CNS cell types modulates synaptic transmission and plasticity through the enhancement of NMDA receptor currents and Ca 2+ flux XREF_BIBR XREF_BIBR .	It appears that thrombin induced PAR1 activation in the hippocampus and CNS cell types modulates synaptic transmission and plasticity through the enhancement of NMDA receptor currents and Ca 2+ flux XREF_BIBR XREF_BIBR.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	5	6
Indeed , although APC and thrombin can both activate PAR-1 , APC affects the vascular endothelium in a way that clearly is distinct from thrombin signaling .	Indeed, although APC and thrombin can both activate PAR-1, APC affects the vascular endothelium in a way that clearly is distinct from thrombin signaling.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	9	10
Furthermore , APC activated PAR1 remains on the cell surface and fails to internalize in contrast to thrombin activated PAR1 [ XREF_BIBR , XREF_BIBR ] .	Furthermore, APC activated PAR1 remains on the cell surface and fails to internalize in contrast to thrombin activated PAR1 [XREF_BIBR, XREF_BIBR].	13	20	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	17	18	19	20
These results suggest thatthe hypertrophic remodeling of atrial myocardium is partly due to an over activation of PAR-1 by thrombin .	These results suggest thatthe hypertrophic remodeling of atrial myocardium is partly due to an over activation of PAR-1 by thrombin.	11	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	19	20	17	18
While PAR1 , PAR3 , and PAR4 are preferentially activated by thrombin , PAR2 is preferentially activated by trypsin and trypsin like proteinases [ XREF_BIBR ] .	While PAR1, PAR3, and PAR4 are preferentially activated by thrombin, PAR2 is preferentially activated by trypsin and trypsin like proteinases [XREF_BIBR].	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	1	2
Of the four family members , PAR1 , PAR3 , and PAR4 are primarily activated by thrombin while PAR2 is activated by trypsin , mast cell tryptase , and clotting factors VIIa and Xa .	Of the four family members, PAR1, PAR3, and PAR4 are primarily activated by thrombin while PAR2 is activated by trypsin, mast cell tryptase, and clotting factors VIIa and Xa.	6	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	16	17	6	7
In addition , sufficient thrombin can enter brain tissue in pathological conditions such as ischemia or hemorrhage and activate PAR1 receptor , which in multiple animal models has been shown to enhance neuronal damage [ XREF_BIBR - XREF_BIBR ] .	In addition, sufficient thrombin can enter brain tissue in pathological conditions such as ischemia or hemorrhage and activate PAR1 receptor, which in multiple animal models has been shown to enhance neuronal damage [XREF_BIBR - XREF_BIBR].	3	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	19	20
XREF_BIBR , XREF_BIBR PAR-1 , -3 , and -4 are activated by thrombin , whereas PAR-2 is activated by trypsin like serine proteases such as kallikrein .	XREF_BIBR, XREF_BIBR PAR-1, -3, and -4 are activated by thrombin, whereas PAR-2 is activated by trypsin like serine proteases such as kallikrein.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	12	13	3	4
The expression of integrin alpha v beta 3 is regulated by thrombin mediated PAR-1 activity .	The expression of integrin alpha v beta 3 is regulated by thrombin mediated PAR-1 activity.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	11	12	13	14
GzmA can also proteolytically activate macrophages to secrete cytokines , cause neurite retraction of astrocytes , and inhibit thrombin induced platelet aggregation by cleaving the thrombin receptor .	GzmA can also proteolytically activate macrophages to secrete cytokines, cause neurite retraction of astrocytes, and inhibit thrombin induced platelet aggregation by cleaving the thrombin receptor.	18	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	18	19	25	27
PAR-1 is proteolytically activated by thrombin by cleavage at its extracellular domain , unmasking a new amino terminus , which internally binds to the proximal receptor , eliciting cellular activation .	PAR-1 is proteolytically activated by thrombin by cleavage at its extracellular domain, unmasking a new amino terminus, which internally binds to the proximal receptor, eliciting cellular activation.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	0	1
PAR1 , PAR3 , and PAR4 are activated by thrombin , and PAR2 is activated by serine proteases , including trypsin , tissue kallikreins , coagulation factors VIIa and Xa , mast cell tryptase , and transmembrane serine proteases XREF_BIBR .	PAR1, PAR3, and PAR4 are activated by thrombin, and PAR2 is activated by serine proteases, including trypsin, tissue kallikreins, coagulation factors VIIa and Xa, mast cell tryptase, and transmembrane serine proteases XREF_BIBR.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	0	1
The thrombin receptor on human platelets is activated by thrombin to stimulate platelet aggregation through the tethered ligand SFLLRN .	The thrombin receptor on human platelets is activated by thrombin to stimulate platelet aggregation through the tethered ligand SFLLRN.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	9	10	1	3
We speculate that TAB1 is protected from proteasomal degradation after thrombin activation of PAR1 possibly through recruitment into the TAB1-TAB2-p38 endosomal signaling complex .	We speculate that TAB1 is protected from proteasomal degradation after thrombin activation of PAR1 possibly through recruitment into the TAB1-TAB2-p38 endosomal signaling complex.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	13	14
In terms of selectivity of certain GRKs over others , in endothelial cells GRK5 is the critical isoform that mediates thrombin induced desensitization of PAR 1 .	In terms of selectivity of certain GRKs over others, in endothelial cells GRK5 is the critical isoform that mediates thrombin induced desensitization of PAR 1.	20	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	20	21	24	26
In addition , thrombin activation of its receptor PAR-1 results in S1P secretion and autocrine activation of S1P 1 receptor which allows the recovery of the barrier dysfunction .	In addition, thrombin activation of its receptor PAR-1 results in S1P secretion and autocrine activation of S1P 1 receptor which allows the recovery of the barrier dysfunction.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	8	9
Although data from several studies indicate that PAR-1 signaling is required for APC mediated barrier stabilization , it is interesting to note that PAR-1 signaling can mediate opposite biological effects on the endothelial barrier depending on whether PAR-1 is activated by thrombin or APC .	Although data from several studies indicate that PAR-1 signaling is required for APC mediated barrier stabilization, it is interesting to note that PAR-1 signaling can mediate opposite biological effects on the endothelial barrier depending on whether PAR-1 is activated by thrombin or APC.	37	43	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	41	42	37	38
Compared with the human enzyme , murine thrombin cleaves fibrinogen and protein C with similar k ( cat )/K ( m ) values but activates PAR1 and PAR4 with k ( cat )/K ( m ) values 4- and 26-fold higher , respectively .	Compared with the human enzyme, murine thrombin cleaves fibrinogen and protein C with similar k (cat)/K (m) values but activates PAR1 and PAR4 with k (cat)/K (m) values 4- and 26-fold higher, respectively.	6	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	25	26
In our cellular and tissue models , we have shown that thrombin activated PAR1 and its downstream profibrotic activities .	In our cellular and tissue models, we have shown that thrombin activated PAR1 and its downstream profibrotic activities.	11	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	13	14
We then injected thrombin intracerebrally and found that thrombin induced increases of brain phospho-MAPK were much less in PAR-1 knockout mice ( phospho-p44/42 : 158 +/-121 vs. 6531 +/-3710 pixels in the wild type mice , p < 0.01 ; phospho-p38 : 47 +/-54 vs. 3772 +/-3133 pixels , p < 0.01 ) .	We then injected thrombin intracerebrally and found that thrombin induced increases of brain phospho-MAPK were much less in PAR-1 knockout mice (phospho-p44/42 : 158 +/-121 vs. 6531 +/-3710 pixels in the wild type mice, p < 0.01; phospho-p38 : 47 +/-54 vs. 3772 +/-3133 pixels, p < 0.01).	8	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	18	19
Whereas PAR-1 , -3 , and -4 are activated in vivo by the secreted serine protease thrombin and appear to primarily function as part of the blood coagulation cascade , PAR-2 is expressed by a majority of epithelial and endothelial cells and can be activated by a number of soluble and membrane anchored proteases with trypsin like activity , but is not efficiently activated by thrombin XREF_BIBR .	Whereas PAR-1, -3, and -4 are activated in vivo by the secreted serine protease thrombin and appear to primarily function as part of the blood coagulation cascade, PAR-2 is expressed by a majority of epithelial and endothelial cells and can be activated by a number of soluble and membrane anchored proteases with trypsin like activity, but is not efficiently activated by thrombin XREF_BIBR.	1	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	16	17	1	2
Further studies demonstrated that when EPCR is occupied by protein C , thrombin activation of PAR-1 inhibited the activation of RhoA GTPase and enhanced the activation of Rac1 GTPase in the TNF-alpha-stimulated endothelial cells , which is similar to the response observed with APC .	Further studies demonstrated that when EPCR is occupied by protein C, thrombin activation of PAR-1 inhibited the activation of RhoA GTPase and enhanced the activation of Rac1 GTPase in the TNF-alpha-stimulated endothelial cells, which is similar to the response observed with APC.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	12	13	15	16
Thus , while activation of PAR1 by thrombin promotes endothelial cell contractility through multiple G protein subtypes resulting in interendothelial cell gaps and barrier disruption , the G q/11 pathway appears to be the predominate regulator of endothelial barrier permeability in vivo at least in mouse models .	Thus, while activation of PAR1 by thrombin promotes endothelial cell contractility through multiple G protein subtypes resulting in interendothelial cell gaps and barrier disruption, the G q/11 pathway appears to be the predominate regulator of endothelial barrier permeability in vivo at least in mouse models.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	5	6
Dissecting the precise contribution , if any , of thrombin mediated PAR-1 activation to colonic epithelial cell transformational changes is complicated by the fact that this receptor is expressed on numerous cell types capable of influencing CAC pathogenesis through distinct , and potentially opposing , mechanisms .	Dissecting the precise contribution, if any, of thrombin mediated PAR-1 activation to colonic epithelial cell transformational changes is complicated by the fact that this receptor is expressed on numerous cell types capable of influencing CAC pathogenesis through distinct, and potentially opposing, mechanisms.	3	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	11	12
In particular , thrombin can modulate this force balance XREF_BIBR - XREF_BIBR , XREF_BIBR , acting near the site of its generation XREF_BIBR through protease activated receptors ( PAR-1 , PAR-3 , and PAR-4 ) .	In particular, thrombin can modulate this force balance XREF_BIBR - XREF_BIBR, XREF_BIBR, acting near the site of its generation XREF_BIBR through protease activated receptors (PAR-1, PAR-3, and PAR-4).	3	33	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	28	29
Among the four types of PAR ( PAR1-4 ; cloned and named in order of their discovery ) , PAR1 , PAR3 and PAR4 are activated by thrombin , unlike PAR2 , which is activated by trypsin like serine proteases .	Among the four types of PAR (PAR1-4; cloned and named in order of their discovery), PAR1, PAR3 and PAR4 are activated by thrombin, unlike PAR2, which is activated by trypsin like serine proteases.	19	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	27	28	19	20
50 The reduction of microparticle shedding is additionally revealing because MG132 suppressed shedding after stimulation by LPS activation of TLR4 , thrombin activation of PAR1 , and ADP activation of P2Y12 .	50 The reduction of microparticle shedding is additionally revealing because MG132 suppressed shedding after stimulation by LPS activation of TLR4, thrombin activation of PAR1, and ADP activation of P2Y12.	21	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	21	22	24	25
Human platelets express two types of thrombin triggered PARs , namely the high-affinity PAR-1 and low-affinity PAR-4 .	Human platelets express two types of thrombin triggered PARs, namely the high-affinity PAR-1 and low-affinity PAR-4.	4	14	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	6	7	13	14
PAR1 , PAR3 , and PAR4 can be activated by thrombin , and PAR2 can be activated by trypsin , mast cell tryptase , neutrophil protease 3 , tissue factor and factor VIIa and factor Xa , membrane tethered serine proteinase-1 , or proteases from Porphyromonas gingivalis [ XREF_BIBR ] .	PAR1, PAR3, and PAR4 can be activated by thrombin, and PAR2 can be activated by trypsin, mast cell tryptase, neutrophil protease 3, tissue factor and factor VIIa and factor Xa, membrane tethered serine proteinase-1, or proteases from Porphyromonas gingivalis [XREF_BIBR].	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	0	1
APC and thrombin both triggered PAR1 mediated responses in endothelial cells including expression of antiapoptotic ( tumor necrosis factor-alpha-induced a20 and iap-1 ) and chemokine ( interleukin-8 ( il-8 ) and cxcl3 ) genes , but again , APC was approximately 10 ( 4 )-fold less potent than thrombin .	APC and thrombin both triggered PAR1 mediated responses in endothelial cells including expression of antiapoptotic (tumor necrosis factor-alpha-induced a20 and iap-1) and chemokine (interleukin-8 (il-8) and cxcl3) genes, but again, APC was approximately 10 (4)-fold less potent than thrombin.	0	7	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	5	6
PAR1 , PAR3 , and PAR4 are activated by thrombin , reviewed in [ XREF_BIBR , XREF_BIBR ] , while PAR2 is not activated by thrombin but is activated by trypsin and mast cell tryptase [ XREF_BIBR - XREF_BIBR ] .	PAR1, PAR3, and PAR4 are activated by thrombin, reviewed in [XREF_BIBR, XREF_BIBR], while PAR2 is not activated by thrombin but is activated by trypsin and mast cell tryptase [XREF_BIBR - XREF_BIBR].	0	28	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	0	1
Both thrombin and APC activate cells by cleaving PAR-1 [ XREF_BIBR , XREF_BIBR ] , though the efficiency of cleavage by the former exceeds the latter by 3-4 orders of magnitude [ XREF_BIBR ] .	Both thrombin and APC activate cells by cleaving PAR-1 [XREF_BIBR, XREF_BIBR], though the efficiency of cleavage by the former exceeds the latter by 3-4 orders of magnitude [XREF_BIBR].	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	1	2	8	9
We propose that these effects are mediated , at least in part , via thrombin induced PAR-1 signalling in human chondrocytes .	We propose that these effects are mediated, at least in part, via thrombin induced PAR-1 signalling in human chondrocytes.	6	17	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	14	15	16	17
Nanomolar enterokinase concentrations are required to activate this new receptor , in contrast to the picomolar thrombin concentrations that activate wild-type thrombin receptor .	Nanomolar enterokinase concentrations are required to activate this new receptor, in contrast to the picomolar thrombin concentrations that activate wild-type thrombin receptor.	16	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	16	17	21	23
We conclude that thrombin induced activation of PAR-1 mediates PAR-1 expression by signaling through Gi1/2 coupled to Src and phosphoinositide 3-kinase , and thereby activating the downstream Ras and MAPK cascade .	We conclude that thrombin induced activation of PAR-1 mediates PAR-1 expression by signaling through Gi1/2 coupled to Src and phosphoinositide 3-kinase, and thereby activating the downstream Ras and MAPK cascade.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	7	8
In HUVECs , plasma induced transcriptional changes are mediated by thrombin induced PAR-1 activation .	In HUVECs, plasma induced transcriptional changes are mediated by thrombin induced PAR-1 activation.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	12	13
Activation of PAR-1 by thrombin and of PAR-2 by factor X a leads to a rapid expression and exposure on the membrane of endothelial cells of both adhesive proteins that mediate an acute inflammatory reaction and of the tissue factor that initiates the blood coagulation cascade .	Activation of PAR-1 by thrombin and of PAR-2 by factor X a leads to a rapid expression and exposure on the membrane of endothelial cells of both adhesive proteins that mediate an acute inflammatory reaction and of the tissue factor that initiates the blood coagulation cascade.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	2	3
Human platelets possess two distinct thrombin activated receptors , PAR-1 ( protease activated receptor-1 ) and PAR-4 , whereas human vascular smooth muscle cells possess only PAR-1 .	Human platelets possess two distinct thrombin activated receptors, PAR-1 (protease activated receptor-1) and PAR-4, whereas human vascular smooth muscle cells possess only PAR-1.	3	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	26	27
The idea that APC ' s cell signaling activities involve direct activation of PAR1 was quite enigmatic for a decade because thrombin activation of PAR1 involving canonical cleavage of PAR1 at Arg41 63 ( XREF_FIG ) was known to be proinflammatory and disruptive of endothelial barrier integrity whereas APC ' s actions were anti-inflammatory and promoted vascular integrity .	The idea that APC 's cell signaling activities involve direct activation of PAR1 was quite enigmatic for a decade because thrombin activation of PAR1 involving canonical cleavage of PAR1 at Arg41 63 (XREF_FIG) was known to be proinflammatory and disruptive of endothelial barrier integrity whereas APC 's actions were anti-inflammatory and promoted vascular integrity.	21	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	21	22	24	25
However , it does not affect the stimulation of DNA synthesis by the synthetic thrombin receptor peptide Ser-Phe-Phe-Leu-Arg-Asn-Pro ( SFFLRNP ) , which mimics the amino-terminus of thrombin receptor proteolytically activated by thrombin .	However, it does not affect the stimulation of DNA synthesis by the synthetic thrombin receptor peptide Ser-Phe-Phe-Leu-Arg-Asn-Pro (SFFLRNP), which mimics the amino-terminus of thrombin receptor proteolytically activated by thrombin.	27	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	32	33	27	29
These studies suggest that thrombin activation of PAR1 contributes to the anti-viral response in mice .	These studies suggest that thrombin activation of PAR1 contributes to the anti-viral response in mice.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	7	8
PAR1 signaling by thrombin .	PAR1 signaling by thrombin.	0	4	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	0	1
Thus , not only are the functional effects of PAR1 signalling by APC and thrombin different but also the PAR1 signalling itself is qualitatively different .	Thus, not only are the functional effects of PAR1 signalling by APC and thrombin different but also the PAR1 signalling itself is qualitatively different.	9	15	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	14	15	9	10
There is considerable evidence that elevated levels of thrombin mediate neurotoxicity in a PAR1 dependent fashion and this was confirmed here using primary cerebellar granule neurons as a model .	There is considerable evidence that elevated levels of thrombin mediate neurotoxicity in a PAR1 dependent fashion and this was confirmed here using primary cerebellar granule neurons as a model.	6	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	levels of thrombin	thrombin	PAR1	PAR1	par1	8	9	13	14
PAR-1 , the prototypic member of the PAR family , is activated by thrombin following cleavage of its extracellular amino terminus domain .	PAR-1, the prototypic member of the PAR family, is activated by thrombin following cleavage of its extracellular amino terminus domain.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	13	14	0	1
It has been reported that tumor cells upregulate the expression of tissue factor ( TF ) leading to an increase in thrombin , which activates platelet PAR1 or PAR4 .	It has been reported that tumor cells upregulate the expression of tissue factor (TF) leading to an increase in thrombin, which activates platelet PAR1 or PAR4.	19	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	21	22	26	27
We excluded a potential involvement of thrombin in this process as hirudin ( 2.5 U/mL ) , a specific inhibitor of thrombin , was unable to prevent the ISO dependent PAR1 cleavage ( XREF_SUPPLEMENTARY ) .	We excluded a potential involvement of thrombin in this process as hirudin (2.5 U/mL), a specific inhibitor of thrombin, was unable to prevent the ISO dependent PAR1 cleavage (XREF_SUPPLEMENTARY).	19	31	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	21	22	30	31
Unlike typical ligand-receptor interactions , thrombin does not activate PAR-1 upon N-terminus binding .	Unlike typical ligand-receptor interactions, thrombin does not activate PAR-1 upon N-terminus binding.	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	9	10
5 Activation of PAR-1 by thrombin initiates a signaling cascade that promotes proinflammatory , vasomotor , and cellular proliferative effects in various cell types , including endothelial cells , smooth muscle cells , and macrophages , among others .	5 Activation of PAR-1 by thrombin initiates a signaling cascade that promotes proinflammatory, vasomotor, and cellular proliferative effects in various cell types, including endothelial cells, smooth muscle cells, and macrophages, among others.	1	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	3	4
This appeared to be a possibility , since earlier work demonstrated that thrombin mediated PAR1 activation induces neurite retraction in neuroblastoma derived cell lines .	This appeared to be a possibility, since earlier work demonstrated that thrombin mediated PAR1 activation induces neurite retraction in neuroblastoma derived cell lines.	12	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	12	13	14	15
A previous study showed that the small molecule benzimidazole derivate Q94 selectively blocks thrombin activated PAR1 coupling to G q signaling important for mouse lung fibroblast proliferation and fibroblast-to-myofibroblast differentiation [ XREF_BIBR , XREF_BIBR ] .	A previous study showed that the small molecule benzimidazole derivate Q94 selectively blocks thrombin activated PAR1 coupling to G q signaling important for mouse lung fibroblast proliferation and fibroblast-to-myofibroblast differentiation [XREF_BIBR, XREF_BIBR].	12	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	13	14	15	16
Furthermore , contrary to PAR1 activation by thrombin , activation by APC does not lead to PAR2 transactivation [ XREF_BIBR ] .	Furthermore, contrary to PAR1 activation by thrombin, activation by APC does not lead to PAR2 transactivation [XREF_BIBR].	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	4	5
PAR-1 , PAR-3 and PAR-4 are mainly activated by thrombin , while PAR-2 is preferentially activated by trypsin .	PAR-1, PAR-3 and PAR-4 are mainly activated by thrombin, while PAR-2 is preferentially activated by trypsin.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	0	1
PAR-1 and -3 are activated by thrombin , so all thrombin inhibitors mentioned in regard to coagulation may also be mentioned here .	PAR-1 and -3 are activated by thrombin, so all thrombin inhibitors mentioned in regard to coagulation may also be mentioned here.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	6	7	0	1
Based on the published data , a low concentration of thrombin ( < 2 nM ) is sufficient to activate cell surface PAR1 , thus one should be cautious not to attribute PAR4 signaling by higher concentrations of thrombin to PAR1 signaling in endothelial cells .	Based on the published data, a low concentration of thrombin (< 2 nM) is sufficient to activate cell surface PAR1, thus one should be cautious not to attribute PAR4 signaling by higher concentrations of thrombin to PAR1 signaling in endothelial cells.	8	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	22	23
PAR-1 , a G-protein-coupled receptor , is directly activated by the serine protease activity of thrombin .	PAR-1, a G-protein-coupled receptor, is directly activated by the serine protease activity of thrombin.	0	16	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	15	16	0	1
Previous findings that thrombin activation of PAR-1 leads to VEGF secretion from platelets , while activation of PAR-4 results in the release of an inhibitor of angiogenesis-endostatin , were recently disputed [ XREF_BIBR ] .	Previous findings that thrombin activation of PAR-1 leads to VEGF secretion from platelets, while activation of PAR-4 results in the release of an inhibitor of angiogenesis-endostatin, were recently disputed [XREF_BIBR].	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	6	7
The coagulation protease thrombin activates PAR1 , inducing pro inflammatory and pro apoptotic responses 13 .	The coagulation protease thrombin activates PAR1, inducing pro inflammatory and pro apoptotic responses 13.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	5	6
In the coagulation cascade , coagulation factor II ( thrombin ) can activate the coagulation factor II receptor ( also known as the protease activated receptor , PAR ) .	In the coagulation cascade, coagulation factor II (thrombin) can activate the coagulation factor II receptor (also known as the protease activated receptor, PAR).	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	coagulation factor II	coagulation factor II	coagulation factor II	coagulation factor II receptor	coagulation factor II receptor	coagulation factor II receptor	5	8	14	18
PAR1 is activated by thrombin whereas the upstream coagulant protease VIIa bound to tissue factor and Xa can activate both PAR1 and PAR2 .	PAR1 is activated by thrombin whereas the upstream coagulant protease VIIa bound to tissue factor and Xa can activate both PAR1 and PAR2.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	0	1
The thrombin + PC-S195A mediated down-regulation of cell adhesion molecules required the activation of PAR-1 by thrombin since a function blocking anti-PAR-1 antibody abrogated the effect of thrombin ( XREF_FIG ) .	The thrombin + PC-S195A mediated down-regulation of cell adhesion molecules required the activation of PAR-1 by thrombin since a function blocking anti-PAR-1 antibody abrogated the effect of thrombin (XREF_FIG).	10	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	16	17	14	15
19 The study suggested that direct thrombin mediated PAR-1 signaling events led to HSC mobilization .	19 The study suggested that direct thrombin mediated PAR-1 signaling events led to HSC mobilization.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	6	7	8	9
Moreover , the activation of PAR-1 or -2 by thrombin or trypsin caused accelerated aggregation and formation of smaller , presumably more viable clusters .	Moreover, the activation of PAR-1 or -2 by thrombin or trypsin caused accelerated aggregation and formation of smaller, presumably more viable clusters.	3	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	5	6
Dabigatran inhibits thrombin mediated PAR1 function by inhibiting N-terminal cleavage and internalization [ XREF_BIBR ] .	Dabigatran inhibits thrombin mediated PAR1 function by inhibiting N-terminal cleavage and internalization [XREF_BIBR].	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	4	5
In addition the endogenous PAR1 activator thrombin evoked spike discharge in 26 % of human myenteric neurons .	In addition the endogenous PAR1 activator thrombin evoked spike discharge in 26% of human myenteric neurons.	2	7	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	4	5
68 RWJ-56110 , a potent PAR-1 antagonist , inhibited low ( 0.05 U/mL ) but not high concentration thrombin induced platelet aggregation , whereas YD-3 , alone , had little or no effect on thrombin induced platelet aggregation , but significantly enhanced the antiaggregatory activity of a PAR-1 antagonist .	68 RWJ-56110, a potent PAR-1 antagonist, inhibited low (0.05 U/mL) but not high concentration thrombin induced platelet aggregation, whereas YD-3, alone, had little or no effect on thrombin induced platelet aggregation, but significantly enhanced the antiaggregatory activity of a PAR-1 antagonist.	9	48	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	18	19	47	48
Thus , catalytically inactive thrombin appears to modulate PAR1 function in vitro by stabilizing receptor cell-surface expression ; but given the high clearance rate of thrombin , the high concentration of dabigatran required to achieve this effect the in vivo physiologic relevance is unknown .	Thus, catalytically inactive thrombin appears to modulate PAR1 function in vitro by stabilizing receptor cell-surface expression; but given the high clearance rate of thrombin, the high concentration of dabigatran required to achieve this effect the in vivo physiologic relevance is unknown.	3	9	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	8	9
The endogenous PAR1 activator thrombin evoked in 26 % ( 16 of 61 neurons ) of human myenteric neurons a median spike discharge of 1.3 ( 0.8/2.5 ) Hz .	The endogenous PAR1 activator thrombin evoked in 26% (16 of 61 neurons) of human myenteric neurons a median spike discharge of 1.3 (0.8/2.5) Hz.	0	5	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	2	3
Following activation of PAR1 by thrombin for example , PAR1 is rapidly internalized , while after activation by activated protein C , PAR1 remains on the cell surface .	Following activation of PAR1 by thrombin for example, PAR1 is rapidly internalized, while after activation by activated protein C, PAR1 remains on the cell surface.	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	3	4
However , we showed that when endothelial cells are pretreated with a catalytically inactive S195A mutant of the zymogen protein C so that to occupy EPCR , the activation of PAR-1 by thrombin can no longer activate the NF-kappaB pathway , but rather it elicits a protective response thus inhibiting the activation of the proinflammatory pathways in the cytokine stimulated endothelial cells [ XREF_BIBR ] .	However, we showed that when endothelial cells are pretreated with a catalytically inactive S195A mutant of the zymogen protein C so that to occupy EPCR, the activation of PAR-1 by thrombin can no longer activate the NF-kappaB pathway, but rather it elicits a protective response thus inhibiting the activation of the proinflammatory pathways in the cytokine stimulated endothelial cells [XREF_BIBR].	28	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	32	33	30	31
It is known that thrombin enhances permeability of endothelial cells by activating PAR1 .	It is known that thrombin enhances permeability of endothelial cells by activating PAR1.	4	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	12	13
PAR-1 , PAR-3 and PAR-4 are activated physiologically by thrombin , whereas PAR-2 activation is associated with a proinflammatory response .	PAR-1, PAR-3 and PAR-4 are activated physiologically by thrombin, whereas PAR-2 activation is associated with a proinflammatory response.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	0	1
PAR-1 , -3 and -4 are activated via cleavage by thrombin .	PAR-1, -3 and -4 are activated via cleavage by thrombin.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	0	1
Since salmon thrombin activates the synthetic PAR1 peptides at a slower rate than human thrombin , it is possible that salmon thrombin signals through PAR1 at the nerve root and initiates neuroprotection , whereas higher levels of PAR1 activation by human thrombin may exacerbate injury .	Since salmon thrombin activates the synthetic PAR1 peptides at a slower rate than human thrombin, it is possible that salmon thrombin signals through PAR1 at the nerve root and initiates neuroprotection, whereas higher levels of PAR1 activation by human thrombin may exacerbate injury.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	6	7
All these genes were expressed at high levels by EPCs and were over-expressed 4 hrs after PAR-1 activation by thrombin or by the SFLLRN peptide ( XREF_TABLE ) .	All these genes were expressed at high levels by EPCs and were over-expressed 4 hrs after PAR-1 activation by thrombin or by the SFLLRN peptide (XREF_TABLE).	16	20	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	19	20	16	17
For instance , thrombin can promote the proliferation of osteoblastic cells by activating PAR-1 and inhibit their apoptosis XREF_BIBR .	For instance, thrombin can promote the proliferation of osteoblastic cells by activating PAR-1 and inhibit their apoptosis XREF_BIBR.	3	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	13	14
Until now , four PARs have been discovered , PAR-1 , PAR-2 , PAR-3 and PAR-4 XREF_BIBR , among which PAR-1 , PAR-3 and PAR-4 can be activated by thrombin , whereas PAR-2 is activated by trypsin XREF_BIBR .	Until now, four PARs have been discovered, PAR-1, PAR-2, PAR-3 and PAR-4 XREF_BIBR, among which PAR-1, PAR-3 and PAR-4 can be activated by thrombin, whereas PAR-2 is activated by trypsin XREF_BIBR.	20	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	29	30	20	21
PAR-1 , PAR-3 and PAR-4 are activated by thrombin , whereas PAR-2 activation is believed to be the result of other proteases such as PMN derived pr3 , coagulation associated factor Xa or Gingipain ( RgpB , HRgpA and Kgp ) from Porphyromonas gingivalis ,.	PAR-1, PAR-3 and PAR-4 are activated by thrombin, whereas PAR-2 activation is believed to be the result of other proteases such as PMN derived pr3, coagulation associated factor Xa or Gingipain (RgpB, HRgpA and Kgp) from Porphyromonas gingivalis,.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	0	1
We have previously shown that the stimulation of PAR1 by thrombin promotes intracellular signaling leading to RPE cell transformation , proliferation , and migration which characterize fibroproliferative eye diseases leading to blindness .	We have previously shown that the stimulation of PAR1 by thrombin promotes intracellular signaling leading to RPE cell transformation, proliferation, and migration which characterize fibroproliferative eye diseases leading to blindness.	6	11	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	8	9
Curiously , although APC and thrombin can both activate PAR1 , APC affects the vascular endothelium in a way that clearly is distinct from thrombin signaling .	Curiously, although APC and thrombin can both activate PAR1, APC affects the vascular endothelium in a way that clearly is distinct from thrombin signaling.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	9	10
PAR1 is activated in a similar manner to PAR2 by proteases ( thrombin , other coagulation proteases , different activating hexapeptides ) .	PAR1 is activated in a similar manner to PAR2 by proteases (thrombin, other coagulation proteases, different activating hexapeptides).	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	12	13	0	1
Several thrombin cellular effects are dependent upon stimulation of proteinase activated receptor-1 ( PAR-1 ) localized over the cellular surface .	Several thrombin cellular effects are dependent upon stimulation of proteinase activated receptor-1 (PAR-1) localized over the cellular surface.	0	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	1	2	13	14
Of the four mammalian PARs , PAR1 , PAR3 and PAR4 can be activated by thrombin , whereas PAR2 can be activated by coagulation proteases FVIIa and FXa but not thrombin [ XREF_BIBR - XREF_BIBR ] .	Of the four mammalian PARs, PAR1, PAR3 and PAR4 can be activated by thrombin, whereas PAR2 can be activated by coagulation proteases FVIIa and FXa but not thrombin [XREF_BIBR - XREF_BIBR].	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	15	16	6	7
Under these conditions , thrombin can activate all cell surface PAR-1 [ XREF_BIBR - XREF_BIBR ] .	Under these conditions, thrombin can activate all cell surface PAR-1 [XREF_BIBR - XREF_BIBR].	4	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	10	11
In an early phase , thrombin activates PAR-1 , which increases intracellular Ca 2+ + and subsequent scramblase activation , cell contraction , and cytoskeletal reorganization additionally mediated by Rho-kinase and caspase 2 activation of ROCK-II .	In an early phase, thrombin activates PAR-1, which increases intracellular Ca 2+ + and subsequent scramblase activation, cell contraction, and cytoskeletal reorganization additionally mediated by Rho-kinase and caspase 2 activation of ROCK-II.	5	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	7	8
Interestingly , blockage to PAR-1 and PAR-2 had little effect on the phosphorylation of NFkappaB , though PAR-1- and PAR-2-mediated NFkappaB activation by thrombin has been reported in epithelial and endothelial cells [ XREF_BIBR , XREF_BIBR ] .	Interestingly, blockage to PAR-1 and PAR-2 had little effect on the phosphorylation of NFkappaB, though PAR-1- and PAR-2-mediated NFkappaB activation by thrombin has been reported in epithelial and endothelial cells [XREF_BIBR, XREF_BIBR].	17	24	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1-	PAR-1-	PAR-1-	23	24	17	18
The human platelet thrombin receptor is activated by thrombin cleavage to create a new NH2 terminus that acts as a tethered ligand , and peptides based on the tethered ligand can activate the receptor independently of thrombin .	The human platelet thrombin receptor is activated by thrombin cleavage to create a new NH2 terminus that acts as a tethered ligand, and peptides based on the tethered ligand can activate the receptor independently of thrombin.	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	8	9	3	5
Four members of this family have been identified : PAR1 , PAR3 , and PAR4 activated by thrombin and PAR2 mainly activated by trypsin , tryptase , and other trypsin like proteases , in addition to high concentrations of thrombin [ XREF_BIBR ] .	Four members of this family have been identified : PAR1, PAR3, and PAR4 activated by thrombin and PAR2 mainly activated by trypsin, tryptase, and other trypsin like proteases, in addition to high concentrations of thrombin [XREF_BIBR].	9	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	17	18	9	10
PAR-1 activation by thrombin rapidly inhibited GJ-channels , which coincided with the internalization of gap junctions in porcine pulmonary artery endothelial cells .	PAR-1 activation by thrombin rapidly inhibited GJ-channels, which coincided with the internalization of gap junctions in porcine pulmonary artery endothelial cells.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	0	1
Lastly , thrombin mediated activation of PAR-1 mediates the surface exposure of TF .	Lastly, thrombin mediated activation of PAR-1 mediates the surface exposure of TF.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	6	7
We propose that in the early stage of an ischemic event , thrombin may be the main activator of PAR1 in the heart .	We propose that in the early stage of an ischemic event, thrombin may be the main activator of PAR1 in the heart.	12	22	be the main activator	Positive_activation_copula_1	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	12	13	19	20
The mechanism of PAR1 activation by the coagulant protease thrombin has been most extensively studied [ XREF_BIBR , XREF_BIBR ] .	The mechanism of PAR1 activation by the coagulant protease thrombin has been most extensively studied [XREF_BIBR, XREF_BIBR].	3	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	3	4
PAR-1 can be activated by thrombin , and is known as a thrombin receptor 8 .	PAR-1 can be activated by thrombin, and is known as a thrombin receptor 8.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	0	1
Interestingly , EPCR occupation by active site blocked APC FVII -82 was , like FVII , unable to mimic EC barrier stabilization induced by PC upon PAR1 proteolysis by thrombin .	Interestingly, EPCR occupation by active site blocked APC FVII -82 was, like FVII, unable to mimic EC barrier stabilization induced by PC upon PAR1 proteolysis by thrombin.	22	30	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	29	30	26	27
PAR-1 is irreversibly activated by thrombin , tissue factor ( TF ) , endothelial protein C receptor ( EPCR ) , MMPs , and so on .	PAR-1 is irreversibly activated by thrombin, tissue factor (TF), endothelial protein C receptor (EPCR), MMPs, and so on.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	0	1
In addition , previous data indicate that thrombin induced a sustained contraction in normal pulmonary arteries by activating PAR-1 XREF_BIBR .	In addition, previous data indicate that thrombin induced a sustained contraction in normal pulmonary arteries by activating PAR-1 XREF_BIBR.	7	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	18	19
Rather , thrombin activation of PAR-1 and PAR-4 appears central to exacerbation of early APAP induced liver injury in mice .	Rather, thrombin activation of PAR-1 and PAR-4 appears central to exacerbation of early APAP induced liver injury in mice.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	5	6
Vorapaxar and atopaxar are novel antiplatelet drugs that inhibit the thrombin induced platelet activation by antagonizing the PAR-1 .	Vorapaxar and atopaxar are novel antiplatelet drugs that inhibit the thrombin induced platelet activation by antagonizing the PAR-1.	9	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	17	18
These studies suggest that in endothelial cells APC targets a distinct subpopulation of PAR1 residing in caveolae that undergo differential activation and signal termination processes compared to thrombin activated PAR1 .	These studies suggest that in endothelial cells APC targets a distinct subpopulation of PAR1 residing in caveolae that undergo differential activation and signal termination processes compared to thrombin activated PAR1.	18	30	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	27	28	29	30
XREF_BIBR have demonstrated that thrombin activated PAR 1 preferentially couples to G 12/13 proteins while PAR 1 -APs favor activation of G q signaling leading to [ Ca 2+ ] i increase .	XREF_BIBR have demonstrated that thrombin activated PAR 1 preferentially couples to G 12/13 proteins while PAR 1 -APs favor activation of G q signaling leading to [Ca 2+] i increase.	4	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	4	5	6	8
It is likely that the protective effects of the exogenously administered signaling form of APC are also mediated , in part , via disrupting pathological thrombin dependent activation of PAR-1 .	It is likely that the protective effects of the exogenously administered signaling form of APC are also mediated, in part, via disrupting pathological thrombin dependent activation of PAR-1.	25	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	25	26	29	30
However , PAR2 , PAR3 and PAR4 are often co-expressed with PAR1 in endothelial cells and can influence thrombin activated PAR1 signaling .	However, PAR2, PAR3 and PAR4 are often co-expressed with PAR1 in endothelial cells and can influence thrombin activated PAR1 signaling.	17	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	18	19	20	21
We demonstrated that stimulation of PAR1 by thrombin or thrombin receptor activating peptide ( TRAP6 ) , in androgen independent DU145 and PC-3 cells resulted in increased DNA binding activity of the NFkappaB p65 subunit .	We demonstrated that stimulation of PAR1 by thrombin or thrombin receptor activating peptide (TRAP6), in androgen independent DU145 and PC-3 cells resulted in increased DNA binding activity of the NFkappaB p65 subunit.	3	11	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	5	6
Due to the irreversible nature of PAR1 activation by thrombin , PAR1 signaling and inactivation must be tightly regulated [ XREF_BIBR , XREF_BIBR ] .	Due to the irreversible nature of PAR1 activation by thrombin, PAR1 signaling and inactivation must be tightly regulated [XREF_BIBR, XREF_BIBR].	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	6	7
In conclusion , we have demonstrated a detrimental role for thrombin activated PAR-1 in wound healing and locomotor recovery after spinal cord injury .	In conclusion, we have demonstrated a detrimental role for thrombin activated PAR-1 in wound healing and locomotor recovery after spinal cord injury.	8	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	12	13
It is observed that activation of PAR-1 by thrombin stimulates directed migration of human eosinophils and thereby affects eosinophils in tissue and allergic inflammation [ XREF_BIBR ] .	It is observed that activation of PAR-1 by thrombin stimulates directed migration of human eosinophils and thereby affects eosinophils in tissue and allergic inflammation [XREF_BIBR].	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	6	7
Cultured vascular endothelial cells express all four PARs and the traditional view is that the activation of PAR-1 by thrombin up-regulates proinflammatory responses in endothelial cells .	Cultured vascular endothelial cells express all four PARs and the traditional view is that the activation of PAR-1 by thrombin up-regulates proinflammatory responses in endothelial cells.	15	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	19	20	17	18
In a series of recent studies we provided some insight into the nature of this problem and demonstrated that the occupancy of EPCR by protein C in cultured endothelial cells can switch the PAR-1-dependent signaling specificity of thrombin , thus the activation of PAR-1 by thrombin elicited only cytoprotective responses similar to those observed with APC if cells were pretreated with a sub-physiological concentration of the zymogen protein C ( 10 nM ) immediately prior to their stimulation by thrombin .	In a series of recent studies we provided some insight into the nature of this problem and demonstrated that the occupancy of EPCR by protein C in cultured endothelial cells can switch the PAR-1-dependent signaling specificity of thrombin, thus the activation of PAR-1 by thrombin elicited only cytoprotective responses similar to those observed with APC if cells were pretreated with a sub-physiological concentration of the zymogen protein C (10 nM) immediately prior to their stimulation by thrombin.	31	46	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	45	46	43	44
It is known that both APC and thrombin elicit cellular responses in endothelial cells by activating PAR-1 [ XREF_BIBR , XREF_BIBR ] .	It is known that both APC and thrombin elicit cellular responses in endothelial cells by activating PAR-1 [XREF_BIBR, XREF_BIBR].	5	20	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	16	17
The serine protease thrombin , which activates PAR-1 during the first hours after stroke , appears to be associated with the cytotoxicity .	The serine protease thrombin, which activates PAR-1 during the first hours after stroke, appears to be associated with the cytotoxicity.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	7	8
Such competition between APC and thrombin is well-known and APC- or thrombin induced PAR-1 cleavage leads to distinct or even opposite downstream signalling events .	Such competition between APC and thrombin is well-known and APC- or thrombin induced PAR-1 cleavage leads to distinct or even opposite downstream signalling events.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	11	12	13	14
PAR-2 induced gene regulation by TF / FVIIa in glioblastoma cell line is mediated by thrombin mediated activation of PAR-1 [ XREF_BIBR ] .	PAR-2 induced gene regulation by TF / FVIIa in glioblastoma cell line is mediated by thrombin mediated activation of PAR-1 [XREF_BIBR].	15	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	15	16	19	20
Although PAR-1 activation by thrombin promotes pulmonary fibrosis through fibroblast proliferation and differentiation , no reports have implicated thrombin in EMT until now .	Although PAR-1 activation by thrombin promotes pulmonary fibrosis through fibroblast proliferation and differentiation, no reports have implicated thrombin in EMT until now.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	1	2
These results indicate that activation of PAR-1 by thrombin or TRAP amplifies crescentic GN .	These results indicate that activation of PAR-1 by thrombin or TRAP amplifies crescentic GN.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	6	7
PAR1 activating peptide TFLLR-NH 2 and thrombin stimulated PAR1 related intracellular Ca 2+ release .	PAR1 activating peptide TFLLR-NH 2 and thrombin stimulated PAR1 related intracellular Ca 2+ release.	3	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	8	9
XREF_BIBR PAR-1 activation by the serine protease thrombin can lead to increased endothelial cell permeability , while conversely , PAR-1 activation by activated protein C ( APC ) can lead to endothelial cell barrier protection .	XREF_BIBR PAR-1 activation by the serine protease thrombin can lead to increased endothelial cell permeability, while conversely, PAR-1 activation by activated protein C (APC) can lead to endothelial cell barrier protection.	1	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	1	2
PAR 1 , PAR 3 , and PAR 4 are activated by thrombin and PAR 3 has been reported to be a co-factor for the activation of PAR 4 by thrombin .	PAR 1, PAR 3, and PAR 4 are activated by thrombin and PAR 3 has been reported to be a co-factor for the activation of PAR 4 by thrombin.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	12	13	0	2
In this respect , the novel direct thrombin inhibitor , dabigatran , which blocks the proteolytic activity of thrombin , might mimic the antiepileptic effect of alpha-NAPAP by preventing the thrombin dependent activation of PAR-1 .	In this respect, the novel direct thrombin inhibitor, dabigatran, which blocks the proteolytic activity of thrombin, might mimic the antiepileptic effect of alpha-NAPAP by preventing the thrombin dependent activation of PAR-1.	30	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	30	31	34	35
XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR Our results suggest that thrombin induced PAR-1 , -4 stimulation up-regulates detrimental signaling : exacerbating inflammatory ( i.e. COX-2 mediated ) and proliferative responses ( i.e. p-mTOR mediated ) that are potentially upstream of ECM protein dysregulation .	XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR Our results suggest that thrombin induced PAR-1, -4 stimulation up-regulates detrimental signaling : exacerbating inflammatory (i.e. COX-2 mediated) and proliferative responses (i.e. p-mTOR mediated) that are potentially upstream of ECM protein dysregulation.	13	16	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	13	14	15	16
Neurons , smooth muscle cells , immune cells , epithelial cells , and fibroblasts among others all undergo substantial phenotypic changes following thrombin mediated activation of PAR1 .	Neurons, smooth muscle cells, immune cells, epithelial cells, and fibroblasts among others all undergo substantial phenotypic changes following thrombin mediated activation of PAR1.	22	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	22	23	26	27
Indeed , APC induced PAR-1 activation leads to a decrease in podocyte apoptosis XREF_BIBR , whereas thrombin induced PAR-1 activation leads to an increase in podocyte apoptosis XREF_BIBR .	Indeed, APC induced PAR-1 activation leads to a decrease in podocyte apoptosis XREF_BIBR, whereas thrombin induced PAR-1 activation leads to an increase in podocyte apoptosis XREF_BIBR.	16	19	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	16	17	18	19
However , the mechanism by which thrombin activation of PAR1 leads to induction of p38 MAP kinase activity in endothelial cells is not clear .	However, the mechanism by which thrombin activation of PAR1 leads to induction of p38 MAP kinase activity in endothelial cells is not clear.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	9	10
The complexity of this question is underscored by the observation that thrombin activates PAR-1 with at least three orders of magnitude higher catalytic efficiency to initiates disruptive , hyperpermeability and proinflammatory responses in endothelial cells [ XREF_BIBR , XREF_BIBR ] .	The complexity of this question is underscored by the observation that thrombin activates PAR-1 with at least three orders of magnitude higher catalytic efficiency to initiates disruptive, hyperpermeability and proinflammatory responses in endothelial cells [XREF_BIBR, XREF_BIBR].	11	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	11	12	13	14
However , this would not be the case if the vessel wall lacks EPCR ( due to either damage or down-regulation by cytokines ) in which case the activation of PAR-1 by thrombin would elicit proinflammatory responses as has been reported .	However, this would not be the case if the vessel wall lacks EPCR (due to either damage or down-regulation by cytokines) in which case the activation of PAR-1 by thrombin would elicit proinflammatory responses as has been reported.	28	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	32	33	30	31
P4pal-10 inhibited 85 % of human platelet aggregation in response to 20 nM thrombin conditions where normally both PAR1 and PAR4 would be fully activated by thrombin [ XREF_BIBR ] .	P4pal-10 inhibited 85% of human platelet aggregation in response to 20 nM thrombin conditions where normally both PAR1 and PAR4 would be fully activated by thrombin [XREF_BIBR].	17	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	26	27	18	19
In contrast , PAR1 activation by thrombin can result in proinflammatory effects such as disruption of endothelial barrier integrity [ XREF_BIBR ] .	In contrast, PAR1 activation by thrombin can result in proinflammatory effects such as disruption of endothelial barrier integrity [XREF_BIBR].	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	3	4
To address the process of cell-cell junction recovery , we used the model of thrombin induced PAR-1 activation , which is known to rapidly disrupt cell-cell junctions and reduce endothelial monolayer resistance .	To address the process of cell-cell junction recovery, we used the model of thrombin induced PAR-1 activation, which is known to rapidly disrupt cell-cell junctions and reduce endothelial monolayer resistance.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	14	15	16	17
On the other hand , we also showed that gyroxin is able to interfere with the activation of PAR-1 by thrombin or by synthetic PAR-1 agonist in cultured astrocytes .	On the other hand, we also showed that gyroxin is able to interfere with the activation of PAR-1 by thrombin or by synthetic PAR-1 agonist in cultured astrocytes.	13	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	20	21	18	19
Notably , thrombin activation of PAR1 can differentiate normal lung fibroblasts into a myofibroblast phenotype , inducing fibrogenic cytokine release and increased expression of extracellular matrix proteins .	Notably, thrombin activation of PAR1 can differentiate normal lung fibroblasts into a myofibroblast phenotype, inducing fibrogenic cytokine release and increased expression of extracellular matrix proteins.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	5	6
During thrombosis , platelets respond simultaneously to collagen activation of GPVI and alpha 2 beta 1 , ADP activation of P2Y 1 , P2Y 12 , and P2X 1 , thromboxane activation of TP , and thrombin activation of PAR1 and PAR4 , while NO and PGI 2 dampen responsiveness .	During thrombosis, platelets respond simultaneously to collagen activation of GPVI and alpha 2 beta 1, ADP activation of P2Y 1, P2Y 12, and P2X 1, thromboxane activation of TP, and thrombin activation of PAR1 and PAR4, while NO and PGI 2 dampen responsiveness.	36	41	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	36	37	39	40
Although inhibitors of thrombin failed to block PAR-1 transforming activity , a PAR-1 mutant that can not be cleaved by thrombin was nontransforming .	Although inhibitors of thrombin failed to block PAR-1 transforming activity, a PAR-1 mutant that can not be cleaved by thrombin was nontransforming.	1	9	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	7	8
Experimental studies on breast cancer have shown that PAR-1 is activated by thrombin , MMPs and TF , while PAR-2 is activated by coagulation factors VIIa , Xa , or their complexes with TF [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Experimental studies on breast cancer have shown that PAR-1 is activated by thrombin, MMPs and TF, while PAR-2 is activated by coagulation factors VIIa, Xa, or their complexes with TF [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	12	13	8	9
Activation of p38 MAP kinase by thrombin activated PAR1 via the non canonical pathway increases endothelial barrier permeability ( XREF_FIG ) .	Activation of p38 MAP kinase by thrombin activated PAR1 via the non canonical pathway increases endothelial barrier permeability (XREF_FIG).	4	14	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	8	9
Since thrombin is the main activator of PAR-1 , it too is implicated in promoting melanoma progression .	Since thrombin is the main activator of PAR-1, it too is implicated in promoting melanoma progression.	1	8	is the main activator	Positive_activation_copula_1	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	1	2	7	8
By 16 hours of TGFbeta exposure , PAR-1 protein levels are also increased and subsequent thrombin mediated PAR-1 stimulation led to increased ERK phosphorylation at 10 minutes when compared to control cells .	By 16 hours of TGFbeta exposure, PAR-1 protein levels are also increased and subsequent thrombin mediated PAR-1 stimulation led to increased ERK phosphorylation at 10 minutes when compared to control cells.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	15	16	17	18
PAR1 is activated by thrombin .	PAR1 is activated by thrombin.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	0	1
Given the pro- and anti-inflammatory effects mediated by PAR1 activation by thrombin and APC respectively , one attractive possibility is the selective inhibition of thrombin mediated PAR1 dependent vascular endothelial inflammatory effects in conditions such as sepsis .	Given the pro- and anti-inflammatory effects mediated by PAR1 activation by thrombin and APC respectively, one attractive possibility is the selective inhibition of thrombin mediated PAR1 dependent vascular endothelial inflammatory effects in conditions such as sepsis.	22	27	mediated	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	24	25	26	27
We have studied the involvement of the thrombin receptor [ protease activated receptor-1 ( PAR-1 ) ] in astrogliosis , because extravasation of PAR-1 activators , such as thrombin , into brain parenchyma can occur after blood-brain barrier breakdown in a number of CNS disorders .	We have studied the involvement of the thrombin receptor [protease activated receptor-1 (PAR-1)] in astrogliosis, because extravasation of PAR-1 activators, such as thrombin, into brain parenchyma can occur after blood-brain barrier breakdown in a number of CNS disorders.	23	29	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	28	29	23	24
For instance , it has been shown that activation of PAR1 by thrombin induces proinflammatory signaling responses , whereas the activation of the same receptor by activated protein C ( APC ) elicits antiinflammatory responses in cultured HUVECs .	For instance, it has been shown that activation of PAR1 by thrombin induces proinflammatory signaling responses, whereas the activation of the same receptor by activated protein C (APC) elicits antiinflammatory responses in cultured HUVECs.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	12	13	10	11
Recent study also showed that thrombin could induce platelet activation in dependent of PAR1 and PAR4 and GPIbalpha .	Recent study also showed that thrombin could induce platelet activation in dependent of PAR1 and PAR4 and GPIbalpha.	5	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	13	14
The prototype of this signaling is found in thrombin , which activates PAR 1 , resulting in vascular biological and inflammatory responses , especially those involving platelet aggregation [ XREF_BIBR ] .	The prototype of this signaling is found in thrombin, which activates PAR 1, resulting in vascular biological and inflammatory responses, especially those involving platelet aggregation [XREF_BIBR].	6	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	8	9	12	14
The present study was undertaken to investigate whether dabigatran interferes with signal transduction in human lung fibroblasts induced by thrombin and mediated via PAR-1 .	The present study was undertaken to investigate whether dabigatran interferes with signal transduction in human lung fibroblasts induced by thrombin and mediated via PAR-1.	17	24	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	19	20	23	24
First , thrombin mediated activation of PAR-1 is responsible for the production of nitric oxide and prostacyclin , which limits platelet activation .	First, thrombin mediated activation of PAR-1 is responsible for the production of nitric oxide and prostacyclin, which limits platelet activation.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	6	7
MMP-1 has been demonstrated to have agonist activity for PAR1 , which is a G-protein-coupled receptor that is classically activated through cleavage of the N-terminal exodomain by the serine protease thrombin .	MMP-1 has been demonstrated to have agonist activity for PAR1, which is a G-protein-coupled receptor that is classically activated through cleavage of the N-terminal exodomain by the serine protease thrombin.	7	31	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	30	31	9	10
Thrombin is an excellent activator of PAR1 , and picomolar concentrations of thrombin may produce similar PAR1 activation as pharmacologic concentrations of APC , which is a poor activator of PAR1 .	Thrombin is an excellent activator of PAR1, and picomolar concentrations of thrombin may produce similar PAR1 activation as pharmacologic concentrations of APC, which is a poor activator of PAR1.	10	17	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	12	13	16	17
We then measured brain IL-1beta levels in WT and PAR-1 KO mice and found that thrombin induced upregulation of brain IL-1beta was basically absent in PAR-1 KO mice ( p < 0.01 , XREF_FIG ) .	We then measured brain IL-1beta levels in WT and PAR-1 KO mice and found that thrombin induced upregulation of brain IL-1beta was basically absent in PAR-1 KO mice (p < 0.01, XREF_FIG).	15	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	15	16	25	26
PAR 1 , PAR 3 and PAR 4 are activated principally by thrombin , while PAR 2 is activated by trypsin like proteases such as mast cell tryptase and coagulation Factor Xa .	PAR 1, PAR 3 and PAR 4 are activated principally by thrombin, while PAR 2 is activated by trypsin like proteases such as mast cell tryptase and coagulation Factor Xa.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	12	13	0	2
We reported that PAR1 activation by thrombin induced epithelial-mesenchymal transition ( EMT ) via Snail [ XREF_BIBR ] .	We reported that PAR1 activation by thrombin induced epithelial-mesenchymal transition (EMT) via Snail [XREF_BIBR].	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	3	4
XREF_BIBR Four PAR members have been identified : PAR-1 , -3 , and -4 are activated by thrombin and are involved in homeostasis and thrombosis , whereas PAR-2 is activated by trypsin like serine proteases , but not by thrombin .	XREF_BIBR Four PAR members have been identified : PAR-1, -3, and -4 are activated by thrombin and are involved in homeostasis and thrombosis, whereas PAR-2 is activated by trypsin like serine proteases, but not by thrombin.	6	20	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	17	18	8	9
Interestingly , a previous report showed that thrombin mediated activation of PAR-1 induced CDKN1A and p21 upregulation via the JAK and STAT pathway in various types of cells .	Interestingly, a previous report showed that thrombin mediated activation of PAR-1 induced CDKN1A and p21 upregulation via the JAK and STAT pathway in various types of cells.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	11	12
Using human derived ARPE-19 cells as a model for RPE , in the present study we investigated the mechanism responsible for the termination of thrombin induced PAR1 signaling and demonstrated that activation of PAR1 by thrombin decreases PAR1 membrane expression through the Ca 2+ -dependent activation of calpain .	Using human derived ARPE-19 cells as a model for RPE, in the present study we investigated the mechanism responsible for the termination of thrombin induced PAR1 signaling and demonstrated that activation of PAR1 by thrombin decreases PAR1 membrane expression through the Ca 2+ -dependent activation of calpain.	22	27	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	24	25	26	27
Thus , the activation of PAR-1 by thrombin initiated protective signaling responses in HUVECs stimulated by proinflammatory cytokines XREF_BIBR .	Thus, the activation of PAR-1 by thrombin initiated protective signaling responses in HUVECs stimulated by proinflammatory cytokines XREF_BIBR.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	5	6
In addition , thrombin activation of PAR1 induces RhoA signaling through G 12/13 coupling to Rho guanine nucleotide exchange factors ( GEFs ) .	In addition, thrombin activation of PAR1 induces RhoA signaling through G 12/13 coupling to Rho guanine nucleotide exchange factors (GEFs).	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	6	7
PAR-1 is activated by thrombin , which is an inflammatory factor that mediates contraction of endothelial cells leading to increased permeability of the vascular endothelium and vascular edema .	PAR-1 is activated by thrombin, which is an inflammatory factor that mediates contraction of endothelial cells leading to increased permeability of the vascular endothelium and vascular edema.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	0	1
Unlike activated protein C ( APC ) , the activation of PAR-1 by thrombin is known to elicit proinflammatory responses .	Unlike activated protein C (APC), the activation of PAR-1 by thrombin is known to elicit proinflammatory responses.	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	13	14	11	12
Based on our and previous findings , the activation of PAR-1 by thrombin may allow tumor cell to increase their motility and therefore to acquire a more metastatic phenotype .	Based on our and previous findings, the activation of PAR-1 by thrombin may allow tumor cell to increase their motility and therefore to acquire a more metastatic phenotype.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	12	13	10	11
121 While the EPCR and PAR1 signaling has anticoagulant and anti-inflammatory effects in endothelial cells , thrombin induced activation of PAR1 promotes coagulation and inflammation .	121 While the EPCR and PAR1 signaling has anticoagulant and anti-inflammatory effects in endothelial cells, thrombin induced activation of PAR1 promotes coagulation and inflammation.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	16	17	20	21
Particularly in HMC-1 cell line , it was found that curcumin inhibits PAR-2 and PAR-4 mediated human mast cell activation , not by inhibition of trypsin activity but by the blocking of extracellular signal regulated kinase ( ERK ) pathway [ XREF_BIBR ] , and thrombin mediates PAR-1 mediated mast cell adhesion through the activation of G ( i ) proteins , phosphoinositol 3-kinase , protein kinase C , and mitogen activated protein kinase ( MAPK ) pathways [ XREF_BIBR ] .	Particularly in HMC-1 cell line, it was found that curcumin inhibits PAR-2 and PAR-4 mediated human mast cell activation, not by inhibition of trypsin activity but by the blocking of extracellular signal regulated kinase (ERK) pathway [XREF_BIBR], and thrombin mediates PAR-1 mediated mast cell adhesion through the activation of G (i) proteins, phosphoinositol 3-kinase, protein kinase C, and mitogen activated protein kinase (MAPK) pathways [XREF_BIBR].	33	48	mediates	Positive_activation_token_1_verb	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	45	46	47	48
PAR1 , a G-protein-coupled receptor , is proteolytically activated by thrombin , internalized , sorted predominantly to lysosomes , and efficiently degraded .	PAR1, a G-protein-coupled receptor, is proteolytically activated by thrombin, internalized, sorted predominantly to lysosomes, and efficiently degraded.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	0	1
However , P1pal-12 ( PAR-1 antagonist ) does not prevent thrombin induced PAR-1 cleavage .	However, P1pal-12 (PAR-1 antagonist) does not prevent thrombin induced PAR-1 cleavage.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	12	13
In this study , we report that proteolytic activation of PAR1 by thrombin induces persistent transactivation of EGFR and ErbB2 and HER2 in invasive breast carcinoma , but not in normal mammary epithelial cells .	In this study, we report that proteolytic activation of PAR1 by thrombin induces persistent transactivation of EGFR and ErbB2 and HER2 in invasive breast carcinoma, but not in normal mammary epithelial cells.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	12	13	10	11
Among the four PARs identified to date , PAR-2 is a unique one activated by trypsin and mast cell tryptase while others ( PAR-1 , -3 , and -4 ) activated by thrombin [ XREF_BIBR ] .	Among the four PARs identified to date, PAR-2 is a unique one activated by trypsin and mast cell tryptase while others (PAR-1, -3, and -4) activated by thrombin [XREF_BIBR].	21	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	32	33	23	24
Our data confirms the role of thrombin activated PAR-1 in mediating ischemic cell death .	Our data confirms the role of thrombin activated PAR-1 in mediating ischemic cell death.	4	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	6	7	8	9
14 In CU , some authors have demonstrated that generation of thrombin could potentially be contributing to an increased vascular permeability , because thrombin may activate PAR-1 on endothelial cells , amplifying the inflammatory response in urticaria 8 .	14 In CU, some authors have demonstrated that generation of thrombin could potentially be contributing to an increased vascular permeability, because thrombin may activate PAR-1 on endothelial cells, amplifying the inflammatory response in urticaria 8.	23	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	23	24	26	27
Short peptides corresponding to the thrombin ( R41 ) generated neo-N-terminus have been used to activate PAR1 albeit peptide and thrombin activated PAR1 have been shown to mediate distinct and different coupling to G-adaptor proteins [ XREF_BIBR ] .	Short peptides corresponding to the thrombin (R41) generated neo-N-terminus have been used to activate PAR1 albeit peptide and thrombin activated PAR1 have been shown to mediate distinct and different coupling to G-adaptor proteins [XREF_BIBR].	18	27	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	20	21	22	23
Predictably , a significant reduction in mean fluorescence intensity ( as determined by flow cytometry using an antibody detecting PAR-1 activation ) was observed following incubation of EA.hy926 endothelial cells with thrombin , as a consequence of thrombin mediated activation of the PAR-1 extracellular domain .	Predictably, a significant reduction in mean fluorescence intensity (as determined by flow cytometry using an antibody detecting PAR-1 activation) was observed following incubation of EA.hy926 endothelial cells with thrombin, as a consequence of thrombin mediated activation of the PAR-1 extracellular domain.	37	44	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	37	38	42	43
Several in vitro models show thrombin activation of PAR1 to be neuroprotective .	Several in vitro models show thrombin activation of PAR1 to be neuroprotective.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	8	9
Taken together , our data suggest that the heparin and ODSH can interfere with thrombin activated PAR1 mediated signaling in the EC possibly via interaction of heparin and ODSH with thrombin receptors .	Taken together, our data suggest that the heparin and ODSH can interfere with thrombin activated PAR1 mediated signaling in the EC possibly via interaction of heparin and ODSH with thrombin receptors.	14	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	14	15	16	17
Second , thrombin mediated activation of PAR-1 induces the activation of Weibel-Palade bodies , releasing VWF and t-PA .	Second, thrombin mediated activation of PAR-1 induces the activation of Weibel-Palade bodies, releasing VWF and t-PA.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	6	7
Moreover , thrombin mediated activation of PAR-1 and NF-kappaB has also been shown to increase VCAM-1 and ICAM-1 expression - two key adhesion molecules implicated in leukocyte adhesion in diabetic retinopathy [ XREF_BIBR ; XREF_BIBR ] .	Moreover, thrombin mediated activation of PAR-1 and NF-kappaB has also been shown to increase VCAM-1 and ICAM-1 expression - two key adhesion molecules implicated in leukocyte adhesion in diabetic retinopathy [XREF_BIBR; XREF_BIBR].	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	6	7
In lung microvascular endothelial cells , thrombin , which activates PAR-1 by cleaving its N-terminal , stimulates PLC and thereby evokes Ca 2+ release through IP 3 Rs .	In lung microvascular endothelial cells, thrombin, which activates PAR-1 by cleaving its N-terminal, stimulates PLC and thereby evokes Ca 2+ release through IP 3 Rs.	6	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	6	7	10	11
Localization of PAR1 in caveolin-1 rafts is required for cytoprotective signaling on endothelial cells by APC but this is not the case for thrombin activation of PAR1 [ XREF_BIBR ] .	Localization of PAR1 in caveolin-1 rafts is required for cytoprotective signaling on endothelial cells by APC but this is not the case for thrombin activation of PAR1 [XREF_BIBR].	23	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	23	24	26	27
We have recently shown that thrombin activates PAR-1 , which induces transactivation of PAR-2 , resulting in increased plasminogen activator inhibitor-1 ( PAI-1 ) expression in 4T1 murine mammary adenocarcinoma cells .	We have recently shown that thrombin activates PAR-1, which induces transactivation of PAR-2, resulting in increased plasminogen activator inhibitor-1 (PAI-1) expression in 4T1 murine mammary adenocarcinoma cells.	5	24	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	7	8
These results suggested that the activation of PAR-1 by thrombin on intact vascular endothelial cells expressing EPCR would initiate potent protective intracellular signaling responses in the presence of physiological concentrations of the zymogen protein C.	These results suggested that the activation of PAR-1 by thrombin on intact vascular endothelial cells expressing EPCR would initiate potent protective intracellular signaling responses in the presence of physiological concentrations of the zymogen protein C.	5	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	7	8
Activation of PAR1 by thrombin at high concentrations contributes to the transient focal cerebral ischemia injury XREF_BIBR .	Activation of PAR1 by thrombin at high concentrations contributes to the transient focal cerebral ischemia injury XREF_BIBR.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	2	3
Taken together , these data suggest that functional , procoagulant TF is required for the generation of thrombin , which in turn activates PAR1 to promote phosphorylation of the cytoplasmic domain of TF in enterocytes .	Taken together, these data suggest that functional, procoagulant TF is required for the generation of thrombin, which in turn activates PAR1 to promote phosphorylation of the cytoplasmic domain of TF in enterocytes.	15	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	17	18	23	24
XREF_BIBR , XREF_BIBR , XREF_BIBR The Hir sequence allows PAR1 to compete with the much more abundant fibrinogen , and as a result , PAR1 is activated by thrombin at sub-nanomolar concentrations .	XREF_BIBR, XREF_BIBR, XREF_BIBR The Hir sequence allows PAR1 to compete with the much more abundant fibrinogen, and as a result, PAR1 is activated by thrombin at sub-nanomolar concentrations.	24	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	28	29	24	25
Enhanced activity of the TF-FVIIa-PAR-2 axis may contribute to the EOC progression via PAR-2 dependent signaling that supports an angiogenic and invasive phenotype and local thrombin generation supporting PAR-1 dependent proliferation .	Enhanced activity of the TF-FVIIa-PAR-2 axis may contribute to the EOC progression via PAR-2 dependent signaling that supports an angiogenic and invasive phenotype and local thrombin generation supporting PAR-1 dependent proliferation.	25	30	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	25	26	28	29
PAR-1 is activated by the thrombin , and it is overexpressed in the alveolar macrophages from smokers with normal lung function .	PAR-1 is activated by the thrombin, and it is overexpressed in the alveolar macrophages from smokers with normal lung function.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	0	1
Endogenous PAR activators are serine proteases such as thrombin which mainly activates PAR1 or the mast cell derived tryptase which acts as a PAR2 activator .	Endogenous PAR activators are serine proteases such as thrombin which mainly activates PAR1 or the mast cell derived tryptase which acts as a PAR2 activator.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	12	13
Tryptase , a serine protease released from mast cell granules in response to an allergen challenge can activate protease activated receptor -2 ( PAR-2 ) in a manner similar to thrombin activation of PAR-1 .	Tryptase, a serine protease released from mast cell granules in response to an allergen challenge can activate protease activated receptor -2 (PAR-2) in a manner similar to thrombin activation of PAR-1.	30	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	30	31	33	34
To date four PAR family members have been identified : PAR1 , PAR3 and PAR4 are cleaved and activated predominantly by thrombin whereas PAR2 is activated primarily by trypsin and mast cell tryptase [ XREF_BIBR ] .	To date four PAR family members have been identified : PAR1, PAR3 and PAR4 are cleaved and activated predominantly by thrombin whereas PAR2 is activated primarily by trypsin and mast cell tryptase [XREF_BIBR].	10	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	21	22	10	11
Therefore , thrombin may activate PAR1 receptors in the urothelium to elicit MIF release from urothelial cells and thus continue and/or augment inflammation in the bladder .	Therefore, thrombin may activate PAR1 receptors in the urothelium to elicit MIF release from urothelial cells and thus continue and/or augment inflammation in the bladder.	2	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	5	6
The other evidence that links PAR 1 action to bone metabolism comes from the fact that in periodontal ligament cells , PAR 1 activation by thrombin induces the synthesis of osteoprotegerin , which is one of the key molecules that regulate bone homeostasis and prevent osteoclastogenesis [ XREF_BIBR ] .	The other evidence that links PAR 1 action to bone metabolism comes from the fact that in periodontal ligament cells, PAR 1 activation by thrombin induces the synthesis of osteoprotegerin, which is one of the key molecules that regulate bone homeostasis and prevent osteoclastogenesis [XREF_BIBR].	21	26	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	25	26	21	23
Based on these lines of evidence , we speculated that thrombin directly activated PAR1 in the course of ICH , leading to the activation of a series of downstream signaling pathways that mediate ICH injuries .	Based on these lines of evidence, we speculated that thrombin directly activated PAR1 in the course of ICH, leading to the activation of a series of downstream signaling pathways that mediate ICH injuries.	10	14	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	13	14
Likewise , activation of PAR 1 by thrombin induces persistent EGFR and ErbB-2 transactivation , sustained p42 and p44 MAPK signalling , and invasion in breast cancer cells [ XREF_BIBR ] .	Likewise, activation of PAR 1 by thrombin induces persistent EGFR and ErbB-2 transactivation, sustained p42 and p44 MAPK signalling, and invasion in breast cancer cells [XREF_BIBR].	2	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	7	8	4	6
Since thrombin is the prototypical activator of PAR1 , and known to mediate neurotoxicity , possible transcriptional changes in this serine protease were also examined in parallel , although possibly the greatest source of thrombin in acute SCI will be extravasation .	Since thrombin is the prototypical activator of PAR1, and known to mediate neurotoxicity, possible transcriptional changes in this serine protease were also examined in parallel, although possibly the greatest source of thrombin in acute SCI will be extravasation.	1	8	is the prototypical activator	Positive_activation_copula_1	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	1	2	7	8
Therefore , a conceivable framework of the molecular mechanism of thrombin induced lung cancer cell Glc-82 function could be as follows : thrombin activates PAR1 on the cell membrane ; the activated PAR1 transfers some signal to downregulate PTEN expression ; the negative regulation of PTEN on PI3K is attenuated , which activates the AKT signaling pathway and changes the expression of Skp2 and p27 ; finally , the cell function is affected by AKT signaling pathway .	Therefore, a conceivable framework of the molecular mechanism of thrombin induced lung cancer cell Glc-82 function could be as follows : thrombin activates PAR1 on the cell membrane; the activated PAR1 transfers some signal to downregulate PTEN expression; the negative regulation of PTEN on PI3K is attenuated, which activates the AKT signaling pathway and changes the expression of Skp2 and p27; finally, the cell function is affected by AKT signaling pathway.	22	28	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	22	23	24	25
PAR1 is activated by the coagulation factors thrombin and factor Xa ( fXa ) , endothelial protein C receptor ( EPCR )-bound activated protein C ( APC ) , matrix metalloproteinases ( MMPs ) and plasmin , whereas trypsin , mast cell tryptase , fXa and the coagulation factor complex tissue factor ( TF ) : factor VIIa ( fVIIa ) cleave PAR2 XREF_BIBR .	PAR1 is activated by the coagulation factors thrombin and factor Xa (fXa), endothelial protein C receptor (EPCR)-bound activated protein C (APC), matrix metalloproteinases (MMPs) and plasmin, whereas trypsin, mast cell tryptase, fXa and the coagulation factor complex tissue factor (TF) : factor VIIa (fVIIa) cleave PAR2 XREF_BIBR.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	0	1
In endothelial cells for example the recruitment of distinct PAR1 mediated downstream signaling pathways has been reported : while thrombin mediated PAR1 activation recruits G q / G 12/13 , aPC seems to act via PAR1 mediated G i.	In endothelial cells for example the recruitment of distinct PAR1 mediated downstream signaling pathways has been reported : while thrombin mediated PAR1 activation recruits G q / G 12/13, aPC seems to act via PAR1 mediated G i.	19	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	19	20	21	22
We have shown that salmon thrombin uniquely inhibits the development of neuropathic pain after a nerve root compression injury and activates PAR1 to a lower degree than human thrombin .	We have shown that salmon thrombin uniquely inhibits the development of neuropathic pain after a nerve root compression injury and activates PAR1 to a lower degree than human thrombin.	4	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	21	22
Furthermore it had been shown that proteolytic activation of PAR1 by thrombin induces persistent transactivation of EGFR and ErbB2 and HER2 in invasive breast carcinoma ( 23 ) .	Furthermore it had been shown that proteolytic activation of PAR1 by thrombin induces persistent transactivation of EGFR and ErbB2 and HER2 in invasive breast carcinoma (23).	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	9	10
While thrombin can effectively activate PAR-1 , downstream effects of this activation process are in direct opposition to that of aPC [ XREF_BIBR ] .	While thrombin can effectively activate PAR-1, downstream effects of this activation process are in direct opposition to that of aPC [XREF_BIBR].	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	1	2	5	6
Thus , thrombin activates human platelets independently of PAR-1 , i.e ., through PAR-4 , which we confirmed by PCR analysis .	Thus, thrombin activates human platelets independently of PAR-1, i.e., through PAR-4, which we confirmed by PCR analysis.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	8	9
While PAR2 represents a class of trypsin and tryptase activated receptors , PAR1 , PAR3 , and PAR4 are effectively activated by thrombin .	While PAR2 represents a class of trypsin and tryptase activated receptors, PAR1, PAR3, and PAR4 are effectively activated by thrombin.	12	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	22	23	12	13
To date , four PARs have been cloned ; PAR 1 , PAR 3 and PAR 4 are preferentially activated by thrombin , while PAR 2 are selectively activated by trypsin [ XREF_BIBR ] .	To date, four PARs have been cloned; PAR 1, PAR 3 and PAR 4 are preferentially activated by thrombin, while PAR 2 are selectively activated by trypsin [XREF_BIBR].	9	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	21	22	9	11
Thrombin receptor activation , by thrombin or SFLLR containing peptides , stimulates GTPase activity in platelet and CHRF-288 membranes .	Thrombin receptor activation, by thrombin or SFLLR containing peptides, stimulates GTPase activity in platelet and CHRF-288 membranes.	0	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	Thrombin receptor	Thrombin receptor	Thrombin receptor	5	6	0	2
For example , in human brain microvascular endothelial cells , thrombin activation of PAR 1 triggers endothelial barrier permeability , whereas PAR1-AP ( SFLLRN-NH 2 ) has no significant effect .	For example, in human brain microvascular endothelial cells, thrombin activation of PAR 1 triggers endothelial barrier permeability, whereas PAR1-AP (SFLLRN-NH 2) has no significant effect.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	10	11	13	15
The activation of PAR-1 by thrombin is known to have a bimodal effect in endothelial cell permeability with a low concentration ( pM levels ) eliciting a barrier protective and a high concentration ( nM levels ) eliciting a barrier disruptive response .	The activation of PAR-1 by thrombin is known to have a bimodal effect in endothelial cell permeability with a low concentration (pM levels) eliciting a barrier protective and a high concentration (nM levels) eliciting a barrier disruptive response.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	3	4
Whereas PAR-1 , PAR-3 and PAR-4 are activated by thrombin , PAR-2 is activated by multiple trypsin like enzymes XREF_BIBR and is suggested to be involved in pancreatic cancer progression .	Whereas PAR-1, PAR-3 and PAR-4 are activated by thrombin, PAR-2 is activated by multiple trypsin like enzymes XREF_BIBR and is suggested to be involved in pancreatic cancer progression.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	1	2
There are intriguing findings from an animal model that thrombin mediated PAR-1 and PAR-2 activation plays a role in the pathogenesis of acute side effects of radiotherapy , e.g ., enteritis , where PAR mediated signaling activates inflammatory , mitogenic , and proliferative processes in cells of the gut after radiotherapy .	There are intriguing findings from an animal model that thrombin mediated PAR-1 and PAR-2 activation plays a role in the pathogenesis of acute side effects of radiotherapy, e.g., enteritis, where PAR mediated signaling activates inflammatory, mitogenic, and proliferative processes in cells of the gut after radiotherapy.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	11	12
Interestingly , effects mediated by thrombin dependent activation of PAR-1 are in sharp contrast to the protective effects mediated by activated protein C dependent ( APC dependent ) activation of PAR-1 , which results in the improvement of blood-brain barrier function and activation of prosurvival pathways in neurons .	Interestingly, effects mediated by thrombin dependent activation of PAR-1 are in sharp contrast to the protective effects mediated by activated protein C dependent (APC dependent) activation of PAR-1, which results in the improvement of blood-brain barrier function and activation of prosurvival pathways in neurons.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	9	10
There is no study addressing the effects of new classes of antiplatelet agents , such as vorapaxar ( a thrombin protease activated receptor-1 ( PAR-1 ) antagonist ) or the thromboxane receptor antagonist terutroban , on pMV formation .	There is no study addressing the effects of new classes of antiplatelet agents, such as vorapaxar (a thrombin protease activated receptor-1 (PAR-1) antagonist) or the thromboxane receptor antagonist terutroban, on pMV formation.	19	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	19	20	24	25
PAR-1 , PAR-3 and PAR-4 are activated by thrombin and PAR-2 by trypsin or tryptase .	PAR-1, PAR-3 and PAR-4 are activated by thrombin and PAR-2 by trypsin or tryptase.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	0	1
Thus , we hypothesize that either MMP-1 or thrombin activates PAR-1 , which further stimulates the invasion of oral SCC cells .	Thus, we hypothesize that either MMP-1 or thrombin activates PAR-1, which further stimulates the invasion of oral SCC cells.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	10	11
Together , our data identify Tpl2 as a component of a Galpha i -mediated pathway that regulates the release of Ca 2+ from the ER into the cytosol in response to thrombin activation of PAR1 .	Together, our data identify Tpl2 as a component of a Galpha i -mediated pathway that regulates the release of Ca 2+ from the ER into the cytosol in response to thrombin activation of PAR1.	31	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	31	32	34	35
In addition , the activation of PAR-1 by thrombin after the injury could be a key adjustment for cyclooxygenase-2 expression .	In addition, the activation of PAR-1 by thrombin after the injury could be a key adjustment for cyclooxygenase-2 expression.	4	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	6	7
In astrocytes , activation of PAR-1 by thrombin leads to increased MMP-9 expression through regulation of ERK1/2 [ XREF_BIBR ] .	In astrocytes, activation of PAR-1 by thrombin leads to increased MMP-9 expression through regulation of ERK1/2 [XREF_BIBR].	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	5	6
Wild-type rTMD23 , but not rTMD23 ( I425A ) , decreased both the thrombin induced surface PAR-1 internalization and the increase in cytoplasmic Ca ( 2+ ) concentrations in endothelial cells ( ECs ) .	Wild-type rTMD23, but not rTMD23 (I425A), decreased both the thrombin induced surface PAR-1 internalization and the increase in cytoplasmic Ca (2+) concentrations in endothelial cells (ECs).	12	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	13	14	16	17
In line with this hypothesis , thrombin induced PAR-1 activation can lead to VSMC migration and proliferation ( XREF_FIG b ) .	In line with this hypothesis, thrombin induced PAR-1 activation can lead to VSMC migration and proliferation (XREF_FIG b).	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	6	7	8	9
We next addressed whether increased thrombin levels in TM Pro mice increased metastasis through signaling involving PAR1 on tumor cells , using thrombin-insensitive breast cancer cell lines from PyMT-PAR1 -/- mice [ XREF_BIBR ] .	We next addressed whether increased thrombin levels in TM Pro mice increased metastasis through signaling involving PAR1 on tumor cells, using thrombin-insensitive breast cancer cell lines from PyMT-PAR1 -/- mice [XREF_BIBR].	5	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin levels	thrombin	PAR1	PAR1	par1	5	6	16	17
The serine protease inhibitor aprotinin protects platelets against thrombin mediated PAR1 activation in vitro and in vivo .	The serine protease inhibitor aprotinin protects platelets against thrombin mediated PAR1 activation in vitro and in vivo.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	10	11
The result also found that PAR1 and PAR3 receptors activation by MMP-13 is increased by thrombin via a mechanism involving EGFR transactivation and activation of PKCdelta , c-Src , PI3K , Akt , and finally AP-1 on the MMP-13 promoter , thereby contributing to cartilage destruction during arthritis [ XREF_BIBR ] .	The result also found that PAR1 and PAR3 receptors activation by MMP-13 is increased by thrombin via a mechanism involving EGFR transactivation and activation of PKCdelta, c-Src, PI3K, Akt, and finally AP-1 on the MMP-13 promoter, thereby contributing to cartilage destruction during arthritis [XREF_BIBR].	5	18	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	15	16	5	6
In addition to platelet aggregation , thrombin mediated PAR-1 and PAR-4 cleavage induces selective release of platelet proangiogenic and mitogenic regulators ( PDGF , VEGF , and angiopoietin-1 ) that facilitate migration of endothelial progenitor cells and new capillary net formation , which is a pivotal step to metastases [ XREF_BIBR ] .	In addition to platelet aggregation, thrombin mediated PAR-1 and PAR-4 cleavage induces selective release of platelet proangiogenic and mitogenic regulators (PDGF, VEGF, and angiopoietin-1) that facilitate migration of endothelial progenitor cells and new capillary net formation, which is a pivotal step to metastases [XREF_BIBR].	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	6	7	8	9
Taken together , these results indicated that the specificity of PAR1 signaling by thrombin and APC is determined by the occupancy of EPCR by its natural ligand independent of the protease cleaving the receptor .	Taken together, these results indicated that the specificity of PAR1 signaling by thrombin and APC is determined by the occupancy of EPCR by its natural ligand independent of the protease cleaving the receptor.	10	15	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	13	14	10	11
Stimulation of PAR1 by thrombin causes proliferation of glia and produces reactive gliosis , infiltration of inflammatory cells , and angiogenesis .	Stimulation of PAR1 by thrombin causes proliferation of glia and produces reactive gliosis, infiltration of inflammatory cells, and angiogenesis.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	2	3
In this study now , for the first time , we demonstrate that the cleavage of PAR-1 by thrombin also inhibits the release of proinflammatory molecules , P-selectin and Ang2 from WPBs , suggesting that thrombin activation of PAR-1 on the healthy vasculature expressing EPCR would only initiate protective anti-inflammatory and anticoagulant responses under normal physiological conditions .	In this study now, for the first time, we demonstrate that the cleavage of PAR-1 by thrombin also inhibits the release of proinflammatory molecules, P-selectin and Ang2 from WPBs, suggesting that thrombin activation of PAR-1 on the healthy vasculature expressing EPCR would only initiate protective anti-inflammatory and anticoagulant responses under normal physiological conditions.	35	42	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	35	36	38	39
It has been reported that unlike a disruptive G-protein-mediated PAR1 signaling by thrombin , APC induces a protective beta-arrestin-2 biased PAR1 signaling by unknown mechanisms .	It has been reported that unlike a disruptive G-protein-mediated PAR1 signaling by thrombin, APC induces a protective beta-arrestin-2 biased PAR1 signaling by unknown mechanisms.	9	13	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	12	13	9	10
For example , PAR1 activation by thrombin in endothelial cells can induce vascular protection or vascular leakage depending on which sphingosine 1-phosphate ( S1P ) receptor PAR1 is coupled to , S1P 1 or S1P 3 XREF_BIBR .	For example, PAR1 activation by thrombin in endothelial cells can induce vascular protection or vascular leakage depending on which sphingosine 1-phosphate (S1P) receptor PAR1 is coupled to, S1P 1 or S1P 3 XREF_BIBR.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	3	4
Importantly however , PAR-1 activation by thrombin stimulates the expression of TGF-beta with subsequent extracellular matrix production by proximal tubular epithelial cells XREF_BIBR which would suggest PAR-1 activation on tubular epithelial cells may potentiate tubular atrophy directly .	Importantly however, PAR-1 activation by thrombin stimulates the expression of TGF-beta with subsequent extracellular matrix production by proximal tubular epithelial cells XREF_BIBR which would suggest PAR-1 activation on tubular epithelial cells may potentiate tubular atrophy directly.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	6	7	3	4
These experiments demonstrated that iLTP is mediated by PAR1 , which can be activated by thrombin following OGD in vitro .	These experiments demonstrated that iLTP is mediated by PAR1, which can be activated by thrombin following OGD in vitro.	6	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	15	16	8	9
There are four PARs identified to date : PAR 1 , PAR 3 and PAR 4 , activated specifically by thrombin , and PAR 2 activated by trypsin or human mast cell tryptase .	There are four PARs identified to date : PAR 1, PAR 3 and PAR 4, activated specifically by thrombin, and PAR 2 activated by trypsin or human mast cell tryptase.	3	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	20	21	8	10
For example , TF itself activates protease activated receptor ( PAR ) 2 and , to a lesser extent , PAR1 , whereas thrombin is known to activate PAR1 , 3 , and 4 .	For example, TF itself activates protease activated receptor (PAR) 2 and, to a lesser extent, PAR1, whereas thrombin is known to activate PAR1, 3, and 4.	23	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	23	24	28	29
Our studies suggest that both thrombin and matrix metalloproteinase 13 activate PAR1 during CVB3 infection [ XREF_BIBR ] .	Our studies suggest that both thrombin and matrix metalloproteinase 13 activate PAR1 during CVB3 infection [XREF_BIBR].	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	11	12
Differential antibody binding was used to demonstrate rapid and near complete thrombin induced PAR-1 cleavage and internalization , with protein synthesis dependent replacement of intact receptors occurring over longer time intervals , but only minimal recycling of cleaved receptors .	Differential antibody binding was used to demonstrate rapid and near complete thrombin induced PAR-1 cleavage and internalization, with protein synthesis dependent replacement of intact receptors occurring over longer time intervals, but only minimal recycling of cleaved receptors.	6	14	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	11	12	13	14
It is generally thought that the activation of PAR-1 by thrombin initiates proinflammatory signaling responses on vascular endothelial cells XREF_BIBR , XREF_BIBR - XREF_BIBR .	It is generally thought that the activation of PAR-1 by thrombin initiates proinflammatory signaling responses on vascular endothelial cells XREF_BIBR, XREF_BIBR - XREF_BIBR.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	8	9
PAR1 activation by thrombin contributes to thrombosis while also increasing endothelial barrier permeability ; however , PAR1 activation by APC in concert with EPCR elicits an opposite barrier-protective effect .	PAR1 activation by thrombin contributes to thrombosis while also increasing endothelial barrier permeability; however, PAR1 activation by APC in concert with EPCR elicits an opposite barrier-protective effect.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	0	1
Using 125I labeled ATAP2 , a monoclonal antibody against the functional thrombin receptor , we found that thrombin and thrombin receptor agonist peptide ( TRAP ) induce homologous internalization of thrombin receptor in a dose dependent manner .	Using 125I labeled ATAP2, a monoclonal antibody against the functional thrombin receptor, we found that thrombin and thrombin receptor agonist peptide (TRAP) induce homologous internalization of thrombin receptor in a dose dependent manner.	17	32	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	17	18	30	32
To examine this possibility , we used the model system of stromal human microvessel endothelial cells ( HMVECs ) in which PAR-1 was activated by purified thrombin or MMP-1 [ XREF_BIBR ] .	To examine this possibility, we used the model system of stromal human microvessel endothelial cells (HMVECs) in which PAR-1 was activated by purified thrombin or MMP-1 [XREF_BIBR].	21	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	26	27	21	22
Here , we report that thrombin activation of PAR1 induces noncanonical p38 activation through autophosphorylation via a ubiquitin and TAB1-TAB2-dependent pathway on endosomes .	Here, we report that thrombin activation of PAR1 induces noncanonical p38 activation through autophosphorylation via a ubiquitin and TAB1-TAB2-dependent pathway on endosomes.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	8	9
Accordingly , thrombin induced activation of PAR 1 on M24met melanoma cells enhanced their migration and metastasis .	Accordingly, thrombin induced activation of PAR 1 on M24met melanoma cells enhanced their migration and metastasis.	2	11	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	2	3	6	8
Neither bradykinin nor bradykinin 1-5 affected thrombin receptor activating peptide induced platelet aggregation , consistent with the hypothesis that bradykinin and bradykinin 1-5 inhibit thrombin induced platelet aggregation by preventing cleavage of the thrombin receptor and liberation of thrombin receptor activating peptide .	Neither bradykinin nor bradykinin 1-5 affected thrombin receptor activating peptide induced platelet aggregation, consistent with the hypothesis that bradykinin and bradykinin 1-5 inhibit thrombin induced platelet aggregation by preventing cleavage of the thrombin receptor and liberation of thrombin receptor activating peptide.	24	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	24	25	33	35
PAR1 can be activated by thrombin within the endometriotic stroma in response to recurrent bleeding from highly vascularized lesions .	PAR1 can be activated by thrombin within the endometriotic stroma in response to recurrent bleeding from highly vascularized lesions.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	0	1
In contrast , the PARs have been shown , following platelet activation by thrombin or the PAR1 peptide agonist SFLLRN , to be internalized or shed into membrane microparticles , resulting in a decrease in the number of receptors detected at the platelet surface .	In contrast, the PARs have been shown, following platelet activation by thrombin or the PAR1 peptide agonist SFLLRN, to be internalized or shed into membrane microparticles, resulting in a decrease in the number of receptors detected at the platelet surface.	11	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	13	14	16	17
Our model suggests that increased thrombin levels directly activate PAR1 signaling cascades in bone marrow LT-HSCs as well as in stromal cells ( XREF_SUPPLEMENTARY ) , inducing stem cell egress and recruitment to the blood circulation as part of host defense and repair .	Our model suggests that increased thrombin levels directly activate PAR1 signaling cascades in bone marrow LT-HSCs as well as in stromal cells (XREF_SUPPLEMENTARY), inducing stem cell egress and recruitment to the blood circulation as part of host defense and repair.	5	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin levels	thrombin	PAR1	PAR1	par1	5	6	9	10
Whereas thrombin mediated activation of PAR 1 leads to disruption of the BBB , vascular leakage , neurotoxicity , apoptosis , and neuroinflammation , APC mediated activation of PAR1 produces the opposite effects .	Whereas thrombin mediated activation of PAR 1 leads to disruption of the BBB, vascular leakage, neurotoxicity, apoptosis, and neuroinflammation, APC mediated activation of PAR1 produces the opposite effects.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	1	2	5	7
Although R67A-thrombin binds to PAR1 with 10 5 -fold-less affinity than native thrombin , and therefore would be ineffective as a competitive inhibitor to block endogenous thrombin activation of PAR1 , it has been engineered to have limited proinflammatory activity while retaining selectivity for protein C activation , and as shown here , it retains potential PfEMP1 cleavage function .	Although R67A-thrombin binds to PAR1 with 10 5 -fold-less affinity than native thrombin, and therefore would be ineffective as a competitive inhibitor to block endogenous thrombin activation of PAR1, it has been engineered to have limited proinflammatory activity while retaining selectivity for protein C activation, and as shown here, it retains potential PfEMP1 cleavage function.	26	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	26	27	29	30
PAR-1 is activated by thrombin and trypsin , PAR-2 is a receptor for trypsin and mast cell tryptase , and PAR-3 and PAR-4 are receptors for thrombin XREF_BIBR , XREF_BIBR , XREF_BIBR .	PAR-1 is activated by thrombin and trypsin, PAR-2 is a receptor for trypsin and mast cell tryptase, and PAR-3 and PAR-4 are receptors for thrombin XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	0	1
PAR-1 , -3 , and -4 are activated by thrombin , while PAR-2 can be activated by trypsin and tryptase .	PAR-1, -3, and -4 are activated by thrombin, while PAR-2 can be activated by trypsin and tryptase.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	0	1
Strikingly , this study showed that thrombin activated PAR 1 / PAR 2 heterodimers signal via a beta-arrestin-scaffold-mediated activation of MAPK in the cytoplasm , whereas the activation of the PAR 1 monomer by thrombin promotes its redistribution to the nucleus , presumably for a signalling function .	Strikingly, this study showed that thrombin activated PAR 1 / PAR 2 heterodimers signal via a beta-arrestin-scaffold-mediated activation of MAPK in the cytoplasm, whereas the activation of the PAR 1 monomer by thrombin promotes its redistribution to the nucleus, presumably for a signalling function.	6	46	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	6	7	8	10
The differentially expressed genes regulated via PAR-1 mediated transactivation of the EGFR were obtained when CASMCs were treated with thrombin in the presence of EGFR antagonist , AG1478 .	The differentially expressed genes regulated via PAR-1 mediated transactivation of the EGFR were obtained when CASMCs were treated with thrombin in the presence of EGFR antagonist, AG1478.	6	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	19	20	6	7
While platelet activation can persist despite antiplatelet treatment via thrombin induced activation of PAR1 and PAR4 , activation of PAR2 by factor Xa and the TF and VIIa complex may promote a pro inflammatory condition in the vessel wall .	While platelet activation can persist despite antiplatelet treatment via thrombin induced activation of PAR1 and PAR4, activation of PAR2 by factor Xa and the TF and VIIa complex may promote a pro inflammatory condition in the vessel wall.	7	15	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	13	14
Given that both human and rat urothelial cells were shown to express both MIF and PAR1 we consider it likely that thrombin stimulated PAR1 receptors on rat urothelial cells to elicit MIF release .	Given that both human and rat urothelial cells were shown to express both MIF and PAR1 we consider it likely that thrombin stimulated PAR1 receptors on rat urothelial cells to elicit MIF release.	21	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	21	22	23	24
Activation of PAR-1 by thrombin and of PAR-2 by factor Xa leads to a rapid expression and exposure on the membrane of endothelial cells of both adhesive proteins that mediate an acute inflammatory reaction and of the tissue factor that initiates the blood coagulation cascade .	Activation of PAR-1 by thrombin and of PAR-2 by factor Xa leads to a rapid expression and exposure on the membrane of endothelial cells of both adhesive proteins that mediate an acute inflammatory reaction and of the tissue factor that initiates the blood coagulation cascade.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	2	3
Early thrombin generation in sepsis activates PAR1 , which promotes RHOA GTPase signalling and induces endothelial barrier breakdown .	Early thrombin generation in sepsis activates PAR1, which promotes RHOA GTPase signalling and induces endothelial barrier breakdown.	1	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	1	2	6	7
Using antibody specific for cleaved ( S42 ) PAR-1 , we can detect thrombin activated PAR-1 by Western blotting and compare the levels of thrombin activated receptor in presence or absence of heparin or ODSH .	Using antibody specific for cleaved (S42) PAR-1, we can detect thrombin activated PAR-1 by Western blotting and compare the levels of thrombin activated receptor in presence or absence of heparin or ODSH.	12	18	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	13	14	15	16
For instance , triggering of PAR 1 localized in the caveolae by APC can signal via set of downstream effectors that are distinct from those regulated when thrombin activates PAR 1 in a non caveolar environment [ XREF_BIBR ] .	For instance, triggering of PAR 1 localized in the caveolae by APC can signal via set of downstream effectors that are distinct from those regulated when thrombin activates PAR 1 in a non caveolar environment [XREF_BIBR].	27	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	27	28	29	31
Of the four known human PARs , PAR1 , PAR3 , and PAR4 are activated by thrombin .	Of the four known human PARs, PAR1, PAR3, and PAR4 are activated by thrombin.	7	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	16	17	7	8
In platelets , thrombin mediated activation of PAR1 results in aggregation , granule release , activation of adhesion proteins , and profound shape change .	In platelets, thrombin mediated activation of PAR1 results in aggregation, granule release, activation of adhesion proteins, and profound shape change.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	7	8
Of particular relevance to the first therapeutic strategy targeting PARs is the temporal difference in intracellular calcium signaling elicited by thrombin activating PAR1 versus PAR4 .	Of particular relevance to the first therapeutic strategy targeting PARs is the temporal difference in intracellular calcium signaling elicited by thrombin activating PAR1 versus PAR4.	18	24	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	20	21	22	23
Here , we discuss the mechanism by which thrombin activation of PAR1 promotes endothelial barrier breakdown and highlight recent advances that have provided new insight into molecular mechanisms that control of endothelial barrier integrity .	Here, we discuss the mechanism by which thrombin activation of PAR1 promotes endothelial barrier breakdown and highlight recent advances that have provided new insight into molecular mechanisms that control of endothelial barrier integrity.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	11	12
PAR1 is activated differentially by distinct canonical ( thrombin ) and noncanonical ( MMP-1 ) generated tethered ligands within the extracellular N-terminal domain that result in subtle differences in the allosteric mechanisms of activation and transmembrane signaling to a variety of unique downstream integrators ( XREF_FIG ) .	PAR1 is activated differentially by distinct canonical (thrombin) and noncanonical (MMP-1) generated tethered ligands within the extracellular N-terminal domain that result in subtle differences in the allosteric mechanisms of activation and transmembrane signaling to a variety of unique downstream integrators (XREF_FIG).	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	0	1
PAR1 , PAR3 and PAR4 are all stimulated by thrombin 13 .	PAR1, PAR3 and PAR4 are all stimulated by thrombin 13.	0	10	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	0	1
As recently reviewed by XREF_BIBR , XREF_BIBR ) and XREF_BIBR , PARs are present within the nervous system and whereas PAR-2 acts as a class of trypsin and tryptase activated receptors , PAR-1 , PAR-3 , and PAR-4 are most efficiently triggered by thrombin .	As recently reviewed by XREF_BIBR, XREF_BIBR) and XREF_BIBR, PARs are present within the nervous system and whereas PAR-2 acts as a class of trypsin and tryptase activated receptors, PAR-1, PAR-3, and PAR-4 are most efficiently triggered by thrombin.	30	44	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	43	44	32	33
PAR-1 , PAR-3 , and PAR-4 are activated by thrombin and are responsible for thrombin induced platelet activation .	PAR-1, PAR-3, and PAR-4 are activated by thrombin and are responsible for thrombin induced platelet activation.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	0	1
PAR1 is activated by thrombin and Factor 10a .	PAR1 is activated by thrombin and Factor 10a.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	0	1
PAR1 then has an intriguing dual function : PAR1 activation by thrombin results in a proinflammatory and endothelial-permeability enhancing response , while the same receptor activated by APC and endothelial protein C receptor results in an anti-inflammatory , endothelial-integrity preserving response [ XREF_BIBR ] .	PAR1 then has an intriguing dual function : PAR1 activation by thrombin results in a proinflammatory and endothelial-permeability enhancing response, while the same receptor activated by APC and endothelial protein C receptor results in an anti-inflammatory, endothelial-integrity preserving response [XREF_BIBR].	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	8	9
PAR1 , PAR3 , and PAR4 can be stimulated by thrombin and PAR2 can be activated by trypsin , tissue factor and factor VIIa and factor Xa , neutrophil proteinase 3 , mast cell tryptase , and membrane tethered serine proteinase-1 [ XREF_BIBR - XREF_BIBR ] .	PAR1, PAR3, and PAR4 can be stimulated by thrombin and PAR2 can be activated by trypsin, tissue factor and factor VIIa and factor Xa, neutrophil proteinase 3, mast cell tryptase, and membrane tethered serine proteinase-1 [XREF_BIBR - XREF_BIBR].	0	15	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	0	1
The PAR1-AP response was mimicked by the endogenous PAR1 activator thrombin and blocked by the PAR1 antagonists SCH79797 .	The PAR1-AP response was mimicked by the endogenous PAR1 activator thrombin and blocked by the PAR1 antagonists SCH79797.	4	11	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	8	9
In addition , the activation of PAR1 by thrombin results in the generation of proinflammatory cytokines and disruption of barrier integrity .	In addition, the activation of PAR1 by thrombin results in the generation of proinflammatory cytokines and disruption of barrier integrity.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	6	7
Persistent activation of thrombin receptor by thrombin led to homologous down-regulation of thrombin receptor protein .	Persistent activation of thrombin receptor by thrombin led to homologous down-regulation of thrombin receptor protein.	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	6	7	3	5
Therefore , even in the presence of these agents , other platelet activation pathways , including the PAR-1 pathway activated by thrombin , remain functional , allowing continued platelet aggregation and thrombosis .	Therefore, even in the presence of these agents, other platelet activation pathways, including the PAR-1 pathway activated by thrombin, remain functional, allowing continued platelet aggregation and thrombosis.	17	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	21	22	17	18
At 1 ng/ml , RANTES can abolish tryptase induced IL-13 release , but enhance trypsin , tryptase and thrombin induced PAR-1 , -2 and -4 expression .	At 1 ng/ml, RANTES can abolish tryptase induced IL-13 release, but enhance trypsin, tryptase and thrombin induced PAR-1, -2 and -4 expression.	13	25	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	18	19	20	21
In general , PAR 1 is activated by thrombin ; PAR 2 is activated by trypsin and mast cell tryptase ; PAR 3 is activated by thrombin ; and PAR 4 can be activated by thrombin , trypsin , elastase , and cathepsin G [ XREF_BIBR ] .	In general, PAR 1 is activated by thrombin; PAR 2 is activated by trypsin and mast cell tryptase; PAR 3 is activated by thrombin; and PAR 4 can be activated by thrombin, trypsin, elastase, and cathepsin G [XREF_BIBR].	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	8	9	3	5
All experiments were performed in the presence of hirudin to block ( ectopic ) thrombin activation of PAR1 .	All experiments were performed in the presence of hirudin to block (ectopic) thrombin activation of PAR1.	12	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	14	15	17	18
As was observed with MMP-1 , thrombin stimulation of PAR1 caused the secretion of IL-8 and GRO-alpha , and gave only a slight induction in VEGF-A-165 in OVCAR-4 and OVCAR-3 cells ( XREF_SUPPLEMENTARY ) .	As was observed with MMP-1, thrombin stimulation of PAR1 caused the secretion of IL-8 and GRO-alpha, and gave only a slight induction in VEGF-A-165 in OVCAR-4 and OVCAR-3 cells (XREF_SUPPLEMENTARY).	6	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	9	10
First , thrombin cleavage of PAR-1 can be re-directed by APC , or mutant protease deficient APC , such that thrombin no longer induces barrier disruption by cleaving PAR-1 at Arg 41 but rather by barrier protective cleavage at Arg 46 .	First, thrombin cleavage of PAR-1 can be re-directed by APC, or mutant protease deficient APC, such that thrombin no longer induces barrier disruption by cleaving PAR-1 at Arg 41 but rather by barrier protective cleavage at Arg 46.	20	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	20	21	28	29
We provide direct evidence that thrombin activates PAR-1 , PKC , and ERK1/2 in A549 alveolar epithelial cells and that these pathways are associated with the epithelial to myofibroblast transition and collagen secretion .	We provide direct evidence that thrombin activates PAR-1, PKC, and ERK1/2 in A549 alveolar epithelial cells and that these pathways are associated with the epithelial to myofibroblast transition and collagen secretion.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	7	8
Evidence has been provided that thrombin induced PAR1 mediated LTP saturates and thus occludes the ability of neurons to express synaptic plasticity .	Evidence has been provided that thrombin induced PAR1 mediated LTP saturates and thus occludes the ability of neurons to express synaptic plasticity.	5	13	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	7	8
For example , APC switches thrombin induced PAR-1 signalling from a disruptive to a protective effect in human umbilical vein endothelial cells 21 , 38 .	For example, APC switches thrombin induced PAR-1 signalling from a disruptive to a protective effect in human umbilical vein endothelial cells 21, 38.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	7	8
While both thrombin and activated protein C activate PAR1 on endothelial cells , thrombin induces changes in endothelial cells which promote breakdown of the blood brain barrier , while activated protein C promotes blood brain barrier integrity .	While both thrombin and activated protein C activate PAR1 on endothelial cells, thrombin induces changes in endothelial cells which promote breakdown of the blood brain barrier, while activated protein C promotes blood brain barrier integrity.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	8	9
PAR1 , PAR3 , and PAR4 can all be activated by thrombin whereas PAR2 is activated by trypsin and few other proteases .	PAR1, PAR3, and PAR4 can all be activated by thrombin whereas PAR2 is activated by trypsin and few other proteases.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	0	1
The aim of the present study was to examine the relative contributions of GPIbalpha and ADP receptors in response to thrombin induced PAR1 and PAR4 stimulation .	The aim of the present study was to examine the relative contributions of GPIbalpha and ADP receptors in response to thrombin induced PAR1 and PAR4 stimulation.	8	25	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	20	21	22	23
It is known that the activation of PAR-1 by thrombin elicits proinflammatory responses through the activation of the NF-kappaB pathway in cultured endothelial cells .	It is known that the activation of PAR-1 by thrombin elicits proinflammatory responses through the activation of the NF-kappaB pathway in cultured endothelial cells.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	7	8
Four members of PARs have been characterized , PAR1 , PAR3 and PAR4 are activated by thrombin , whereas PAR2 is activated by other proteases such as trypsin and tryptase , but not by thrombin [ XREF_BIBR , XREF_BIBR ] .	Four members of PARs have been characterized, PAR1, PAR3 and PAR4 are activated by thrombin, whereas PAR2 is activated by other proteases such as trypsin and tryptase, but not by thrombin [XREF_BIBR, XREF_BIBR].	8	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	16	17	8	9
PAR1 activation by thrombin and other trypsin like serine like proteases is based on protease cleaving of the N-terminal domain of the receptor and the release of a tethered ligand binding to an extracellular loop of the receptor , subsequently activating the G-protein-coupled signal transduction [ XREF_BIBR ] .	PAR1 activation by thrombin and other trypsin like serine like proteases is based on protease cleaving of the N-terminal domain of the receptor and the release of a tethered ligand binding to an extracellular loop of the receptor, subsequently activating the G-protein-coupled signal transduction [XREF_BIBR].	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	0	1
Conversely , salmon thrombin activates a PAR1 derived peptide more weakly than human thrombin .	Conversely, salmon thrombin activates a PAR1 derived peptide more weakly than human thrombin.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	6	7
PAR-1 signaling is activated by TF , MMPs and thrombin , mediates tumor progression , PAR-1 and PAR-2 cooperate functionally in breast cancer [ XREF_BIBR , XREF_BIBR ] .	PAR-1 signaling is activated by TF, MMPs and thrombin, mediates tumor progression, PAR-1 and PAR-2 cooperate functionally in breast cancer [XREF_BIBR, XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	0	1
This is consistent with other studies that demonstrate PAR3 heterodimerization with PAR1 allosterically modulates thrombin mediated PAR1 activation in endothelial cells [ XREF_BIBR ] .	This is consistent with other studies that demonstrate PAR3 heterodimerization with PAR1 allosterically modulates thrombin mediated PAR1 activation in endothelial cells [XREF_BIBR].	13	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	14	15	16	17
Physiological concentrations of thrombin that stimulate PAR1 have been shown to induce myocyte hypertrophy [ XREF_BIBR ] .	Physiological concentrations of thrombin that stimulate PAR1 have been shown to induce myocyte hypertrophy [XREF_BIBR].	1	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	6	7
Our results indicate that thrombin induced activation of PAR-1 and PAR-4 evokes Ca2+ release from both Ca2+ stores , while activation of GPIb-IX-V by thrombin releases Ca2+ solely from the acidic compartments in human platelets .	Our results indicate that thrombin induced activation of PAR-1 and PAR-4 evokes Ca2+ release from both Ca2+ stores, while activation of GPIb-IX-V by thrombin releases Ca2+ solely from the acidic compartments in human platelets.	4	10	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	8	9
We show that upon thrombin receptor stimulation by low-dose thrombin or the peptide ligand YFLLRNP , or upon thromboxane receptor activation by U46619 , shape change and MLC phosphorylation in human platelets proceed through a pathway that does not involve an increase in cytosolic Ca ( 2+ ) .	We show that upon thrombin receptor stimulation by low-dose thrombin or the peptide ligand YFLLRNP, or upon thromboxane receptor activation by U46619, shape change and MLC phosphorylation in human platelets proceed through a pathway that does not involve an increase in cytosolic Ca (2+).	4	14	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	9	10	4	6
XREF_BIBR At the beginning , thrombin locally activates its PAR-1 receptor on the EC and couples it to the members of small G proteins ( G12/13 , Gq , and Gi/z ) .	XREF_BIBR At the beginning, thrombin locally activates its PAR-1 receptor on the EC and couples it to the members of small G proteins (G12/13, Gq, and Gi/z).	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	9	10
The mechanisms responsible for PAR1 activation by thrombin have been extensively studied .	The mechanisms responsible for PAR1 activation by thrombin have been extensively studied.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	4	5
Among these , the PAR1 , a GPCR , is activated by proteolytic cleavage of the N-terminus by thrombin and trypsin ( Dery et al ., 1998 ) .	Among these, the PAR1, a GPCR, is activated by proteolytic cleavage of the N-terminus by thrombin and trypsin (Dery et al., 1998).	3	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	18	19	4	5
In this study , we aimed to explore if dabigatran may affect mechanisms favoring tumor growth by interfering with thrombin induced PAR-1 activation .	In this study, we aimed to explore if dabigatran may affect mechanisms favoring tumor growth by interfering with thrombin induced PAR-1 activation.	19	22	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	19	20	21	22
During viral infection , thrombin mediated PAR-1 activation was linked to increased susceptibility to herpes viruses of endothelial cells in vitro [ XREF_BIBR ] .	During viral infection, thrombin mediated PAR-1 activation was linked to increased susceptibility to herpes viruses of endothelial cells in vitro [XREF_BIBR].	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	6	7
At low concentrations thrombin activates PAR-1 on platelets through a hirudin like site and at high concentrations additional PAR-4 .	At low concentrations thrombin activates PAR-1 on platelets through a hirudin like site and at high concentrations additional PAR-4.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	5	6
However , it is also known that PAR-1 activation by thrombin elicits potent proinflammatory responses in endothelial cells [ XREF_BIBR , XREF_BIBR ] .	However, it is also known that PAR-1 activation by thrombin elicits potent proinflammatory responses in endothelial cells [XREF_BIBR, XREF_BIBR].	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	7	8
PAR-1 , PAR-3 and PAR-4 are activated by thrombin , whereas PAR-2 is activated by serine proteases , such as trypsin and tryptase .	PAR-1, PAR-3 and PAR-4 are activated by thrombin, whereas PAR-2 is activated by serine proteases, such as trypsin and tryptase.	0	22	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	0	1
PAR-1 , PAR-3 , and PAR-4 are activated mainly by thrombin , whereas PAR-2 is activated by trypsin , tryptase , factor VIIa , and factor Xa .	PAR-1, PAR-3, and PAR-4 are activated mainly by thrombin, whereas PAR-2 is activated by trypsin, tryptase, factor VIIa, and factor Xa.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	0	1
PAR-1 activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand .	PAR-1 activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	0	1
Among the four PARs identified to date , PAR 1 , PAR 3 , and PAR 4 can be activated by thrombin , whereas trypsin and mast cell tryptase can activate PAR 2 .	Among the four PARs identified to date, PAR 1, PAR 3, and PAR 4 can be activated by thrombin, whereas trypsin and mast cell tryptase can activate PAR 2.	8	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	21	22	8	10
While evidence for direct acute action of thrombin to increase permeability in intact vascular beds is limited XREF_BIBR , it has been previously shown that human thrombin can stimulate zebrafish Par1 to induce a Ca 2+ response in Xenopus oocytes XREF_BIBR .	While evidence for direct acute action of thrombin to increase permeability in intact vascular beds is limited XREF_BIBR, it has been previously shown that human thrombin can stimulate zebrafish Par1 to induce a Ca 2+ response in Xenopus oocytes XREF_BIBR.	25	31	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	Par1	Par1	Par1	26	27	30	31
Unlike typical ligand receptor interactions , thrombin does not activate PAR-1 upon binding .	Unlike typical ligand receptor interactions, thrombin does not activate PAR-1 upon binding.	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	6	7	10	11
In the intestine , collagen formation is largely regulated by thrombin mediated PAR-1 activation on smooth muscle cells and myofibroblasts .	In the intestine, collagen formation is largely regulated by thrombin mediated PAR-1 activation on smooth muscle cells and myofibroblasts.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	12	13
However , in epithelial cancers and melanoma cells thrombin mediated PAR-1 activation triggers prosurvival pathways [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	However, in epithelial cancers and melanoma cells thrombin mediated PAR-1 activation triggers prosurvival pathways [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	10	11
Given that thrombin activates PAR1 , PAR3 , and PAR4 13 , we investigated whether the effects of thrombin on basal and LPS induced HEEC inflammation was mediated in a PAR dependent mechanism .	Given that thrombin activates PAR1, PAR3, and PAR4 13, we investigated whether the effects of thrombin on basal and LPS induced HEEC inflammation was mediated in a PAR dependent mechanism.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	4	5
As shown in XREF_FIG , an initial proteolytic activation of PAR-1 by thrombin prior to incubation with GrK decreased IL-6 , IL-8 and MCP-1 production .	As shown in XREF_FIG, an initial proteolytic activation of PAR-1 by thrombin prior to incubation with GrK decreased IL-6, IL-8 and MCP-1 production.	8	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	12	13	10	11
In the present study , tetracyclines , especially doxycycline , inhibit calcium influx caused by thrombin mediated activation of PAR1 , which results in decreased inhibition efficacy upon PAR1 knockdown .	In the present study, tetracyclines, especially doxycycline, inhibit calcium influx caused by thrombin mediated activation of PAR1, which results in decreased inhibition efficacy upon PAR1 knockdown.	15	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	15	16	19	20
PAR 1 , PAR 3 and PAR 4 are stimulated by thrombin , whereas PAR 2 can be activated by trypsin .	PAR 1, PAR 3 and PAR 4 are stimulated by thrombin, whereas PAR 2 can be activated by trypsin.	0	12	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	11	12	0	2
In our experiment , thrombin activated the PAR1 and PAR3 receptor , PKCdelta , c-Src , and Nrf2 pathways , leading to the upregulation of HO-1 expression .	In our experiment, thrombin activated the PAR1 and PAR3 receptor, PKCdelta, c-Src, and Nrf2 pathways, leading to the upregulation of HO-1 expression.	4	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	7	8
PAR-1 , PAR-3 , and PAR-4 are activated by thrombin , whereas PAR-2 is activated mainly by trypsin but also by mast cell tryptase .	PAR-1, PAR-3, and PAR-4 are activated by thrombin, whereas PAR-2 is activated mainly by trypsin but also by mast cell tryptase.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	0	1
The difference in the magnitude of the Ca 2+ response between cells stimulated with thrombin and TFLLRN-NH2 could be due to differences in the conformation of proteolytically activated PAR1 ( thrombin ) versus peptide activated PAR1 .	The difference in the magnitude of the Ca 2+ response between cells stimulated with thrombin and TFLLRN-NH2 could be due to differences in the conformation of proteolytically activated PAR1 (thrombin) versus peptide activated PAR1.	28	36	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	30	31	35	36
A well studied system is PAR1 activation by thrombin .	A well studied system is PAR1 activation by thrombin.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	5	6
Since PAR1 mRNA is itself upregulated by thrombin [ XREF_BIBR ] , PAR1 may be part of a positive-feedback loop that potentiates the coagulation cascade .	Since PAR1 mRNA is itself upregulated by thrombin [XREF_BIBR], PAR1 may be part of a positive-feedback loop that potentiates the coagulation cascade.	1	9	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	1	2
In the same cells metalloprotease dependent shedding of HB-EGF is required for H 2 O 2 -induced EGFR transactivation [ XREF_BIBR ] , and PAR1 and PAR3 stimulation by thrombin induces Nox1 dependent generation of ROS , which results in EGFR transactivation via metalloprotease shedding of EGF like ligands [ XREF_BIBR , XREF_BIBR ] .	In the same cells metalloprotease dependent shedding of HB-EGF is required for H 2 O 2 -induced EGFR transactivation [XREF_BIBR], and PAR1 and PAR3 stimulation by thrombin induces Nox1 dependent generation of ROS, which results in EGFR transactivation via metalloprotease shedding of EGF like ligands [XREF_BIBR, XREF_BIBR].	24	30	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	29	30	24	25
Our results showed that thrombin activation of PAR-1 induces RPE cell proliferation through Ras independent activation of the Raf/MEK/ERK1/2 MAPK signalling cascade .	Our results showed that thrombin activation of PAR-1 induces RPE cell proliferation through Ras independent activation of the Raf/MEK/ERK1/2 MAPK signalling cascade.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	7	8
Here , we discuss the mechanisms by which thrombin activation of PAR1 regulates endothelial barrier integrity and highlight new work implicating a role for ubiquitin in integrating p38 MAP kinase signaling and endothelial barrier dysfunction .	Here, we discuss the mechanisms by which thrombin activation of PAR1 regulates endothelial barrier integrity and highlight new work implicating a role for ubiquitin in integrating p38 MAP kinase signaling and endothelial barrier dysfunction.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	11	12
None of the mutants known to prevent thrombin mediated cleavage of PAR-1 resisted SpeB ( XREF_FIG ) .	None of the mutants known to prevent thrombin mediated cleavage of PAR-1 resisted SpeB (XREF_FIG).	6	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	11	12
PAR-1 activation by thrombin destabilizes the endothelial barrier , while activation of PAR-1 by APC enhances barrier function .	PAR-1 activation by thrombin destabilizes the endothelial barrier, while activation of PAR-1 by APC enhances barrier function.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	0	1
PAR-1 activation by thrombin involves the anion binding exosite of thrombin binding to the PAR-1 amino terminus in an acidic region spanning amino acids 51 to 63 [ XREF_BIBR ] .	PAR-1 activation by thrombin involves the anion binding exosite of thrombin binding to the PAR-1 amino terminus in an acidic region spanning amino acids 51 to 63 [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	0	1
As mentioned in the introduction , each type of PAR receptor is activated by its special protease , for instance , thrombin activate PAR-1 while PAR-2 is cleft and activated by trypsin on the macrophages .	As mentioned in the introduction, each type of PAR receptor is activated by its special protease, for instance, thrombin activate PAR-1 while PAR-2 is cleft and activated by trypsin on the macrophages.	21	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	21	22	23	24
Thus the strength of PAR1 and PAR2 activation by thrombin , factor Xa , and activated protein C can either promote or protect against changes in vascular permeability depending on the status of the endothelium .	Thus the strength of PAR1 and PAR2 activation by thrombin, factor Xa, and activated protein C can either promote or protect against changes in vascular permeability depending on the status of the endothelium.	4	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	4	5
PAR-1 activation by thrombin , further , diminished ceramide induced astrocyte death via upregulation of JUN N-terminal kinase ( Wang , Luo , Stricker , & Reiser , 2006 ) , and rescued astrocytes through the PI3K and Akt signaling pathway from chemically induced apoptosis ( Zhu and Reiser , 2014 ) .	PAR-1 activation by thrombin, further, diminished ceramide induced astrocyte death via upregulation of JUN N-terminal kinase (Wang, Luo, Stricker, & Reiser, 2006), and rescued astrocytes through the PI3K and Akt signaling pathway from chemically induced apoptosis (Zhu and Reiser, 2014).	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	0	1
Thus , unlike the activation of the NF-kappaB pathway , the activation of PAR-1 by thrombin does not lead to up-regulation of sPLA 2 -IIA in HUVECs .	Thus, unlike the activation of the NF-kappaB pathway, the activation of PAR-1 by thrombin does not lead to up-regulation of sPLA 2 -IIA in HUVECs.	11	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	15	16	13	14
Our results indicate that both the C-tail and the third intracellular loop are involved in PAR-1 internalisation induced by thrombin while only the C-tail plays a role in the PMA induced and in the agonist independent PAR-1 internalisation .	Our results indicate that both the C-tail and the third intracellular loop are involved in PAR-1 internalisation induced by thrombin while only the C-tail plays a role in the PMA induced and in the agonist independent PAR-1 internalisation.	15	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	19	20	15	16
A family of protease activated receptors ( PAR ) has been identified , of which PAR-1 , PAR-3 , and PAR-4 are activated by thrombin 3 .	A family of protease activated receptors (PAR) has been identified, of which PAR-1, PAR-3, and PAR-4 are activated by thrombin 3.	15	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	24	25	15	16
Activation of c-Met by hepatocyte growth factor ( HGF ) , or PAR1 activation by thrombin also results in receptor degradation in the lysosome .	Activation of c-Met by hepatocyte growth factor (HGF), or PAR1 activation by thrombin also results in receptor degradation in the lysosome.	12	16	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	15	16	12	13
This article is focused on briefly reviewing the literature with respect to determinants of the specificity of PAR signaling by coagulation proteases with special emphasis on the mechanism of PAR1 signaling by thrombin and activated protein C in endothelial cells .	This article is focused on briefly reviewing the literature with respect to determinants of the specificity of PAR signaling by coagulation proteases with special emphasis on the mechanism of PAR1 signaling by thrombin and activated protein C in endothelial cells.	29	33	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	32	33	29	30
As previously observed with EDTA treated PRP activated by PAR1 agonist peptide and U46619 [ XREF_BIBR ] , thrombin activation of PAR1 and PAR4 and the thromboxane mimetic U46619 were synergistic ( S ij = 0.1127 at medium dose of thrombin and low dose U46619 ) , and especially at medium doses of thrombin and U46619 ( S ij = 0.1766 ) .	As previously observed with EDTA treated PRP activated by PAR1 agonist peptide and U46619 [XREF_BIBR], thrombin activation of PAR1 and PAR4 and the thromboxane mimetic U46619 were synergistic (S ij = 0.1127 at medium dose of thrombin and low dose U46619), and especially at medium doses of thrombin and U46619 (S ij = 0.1766).	18	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	18	19	21	22
XREF_BIBR , XREF_BIBR In line with this mechanism , our findings implicate thrombin induced PAR-1 activation as the most likely mechanism for the increased Ang-2 found in patients with LVADs .	XREF_BIBR, XREF_BIBR In line with this mechanism, our findings implicate thrombin induced PAR-1 activation as the most likely mechanism for the increased Ang-2 found in patients with LVADs.	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	12	13	14	15
In human brain microvascular endothelial cells , thrombin activation of PAR1 induced rapid and transient calcium responses and triggered endothelial barrier permeability , whereas agonist peptide caused sustained calcium responses with minimal effects on endothelial barrier permeability [ XREF_BIBR ] .	In human brain microvascular endothelial cells, thrombin activation of PAR1 induced rapid and transient calcium responses and triggered endothelial barrier permeability, whereas agonist peptide caused sustained calcium responses with minimal effects on endothelial barrier permeability [XREF_BIBR].	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	10	11
PAR1 and PAR4 are activated by thrombin and play a major role in activation of human platelets .	PAR1 and PAR4 are activated by thrombin and play a major role in activation of human platelets.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	0	1
In contrast , PAR1 activation by thrombin does not result in S1P1 activation [ XREF_BIBR ] .	In contrast, PAR1 activation by thrombin does not result in S1P1 activation [XREF_BIBR].	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	3	4
Our data are consistent with the following cascade of events on activation of PAR1 by thrombin or specific activating peptide : ( a ) a matrix metalloproteinase dependent release of transforming growth factor-alpha ( TGF-alpha ) as shown with TGF-alpha blocking antibodies and measurement of TGF-alpha in culture medium ; ( b ) TGF-alpha-mediated activation of epidermal growth factor receptor ( EGFR ) and subsequent EGFR phosphorylation ; and ( c ) activation of extracellular signal regulated protein kinase 1/2 ( ERK1/2 ) and subsequent cell proliferation .	Our data are consistent with the following cascade of events on activation of PAR1 by thrombin or specific activating peptide : (a) a matrix metalloproteinase dependent release of transforming growth factor-alpha (TGF-alpha) as shown with TGF-alpha blocking antibodies and measurement of TGF-alpha in culture medium; (b) TGF-alpha-mediated activation of epidermal growth factor receptor (EGFR) and subsequent EGFR phosphorylation; and (c) activation of extracellular signal regulated protein kinase 1/2 (ERK1/2) and subsequent cell proliferation.	3	86	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	15	16	13	14
Of the four mammalian PAR , PAR1 , PAR3 , and PAR4 are activated by thrombin , while PAR2 can be activated by coagulation proteases FVIIa and FXa but not thrombin [ XREF_BIBR - XREF_BIBR ] .	Of the four mammalian PAR, PAR1, PAR3, and PAR4 are activated by thrombin, while PAR2 can be activated by coagulation proteases FVIIa and FXa but not thrombin [XREF_BIBR - XREF_BIBR].	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	15	16	6	7
Notably , 6 h thrombin treatment significantly upregulated thrombin receptor Par4 and down-regulated thrombin receptor Par 3 while there was no change in the expression of thrombin receptor Par 1 .	Notably, 6 h thrombin treatment significantly upregulated thrombin receptor Par4 and down-regulated thrombin receptor Par 3 while there was no change in the expression of thrombin receptor Par 1.	4	15	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	4	5	13	15
While PAR1 , PAR3 , and PAR4 activation is driven by thrombin , PAR2 is activated by serine proteases such as tryptase , factor Xa , trypsin and the TF and FVIIa complex .	While PAR1, PAR3, and PAR4 activation is driven by thrombin, PAR2 is activated by serine proteases such as tryptase, factor Xa, trypsin and the TF and FVIIa complex.	1	12	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	1	2
PAR1 is triggered by very low concentrations of thrombin , but it also rapidly desensitizes .	PAR1 is triggered by very low concentrations of thrombin, but it also rapidly desensitizes.	0	9	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	0	1
Thrombin stimulates PAR-1-mediated proliferative responses in osteoblasts , chondrocytes and myoblasts , and in developing muscle , PAR-1 activation by thrombin appears to mediate activity dependent polyneuronal synapse reduction .	Thrombin stimulates PAR-1-mediated proliferative responses in osteoblasts, chondrocytes and myoblasts, and in developing muscle, PAR-1 activation by thrombin appears to mediate activity dependent polyneuronal synapse reduction.	17	21	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	20	21	17	18
PAR-1 , -3 , and , -4 are activated by thrombin , and PAR-2 is activated by trypsin and tryptase .	PAR-1, -3, and, -4 are activated by thrombin, and PAR-2 is activated by trypsin and tryptase.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	0	1
However , no published work has demonstrated that a direct thrombin activation of PAR-1 on stellate cells increases fibrosis in vivo .	However, no published work has demonstrated that a direct thrombin activation of PAR-1 on stellate cells increases fibrosis in vivo.	10	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	13	14
This study elucidated the Ca ( 2 ) ( + ) - and MLC20 phosphorylation independent ROS mediated noncanonical mechanism as well as Ca ( 2 ) ( + ) - and MLC20 phosphorylation dependent canonical mechanism that are involved in the thrombin induced PAR1 mediated pulmonary vasoconstriction .	This study elucidated the Ca (2) (+) - and MLC20 phosphorylation independent ROS mediated noncanonical mechanism as well as Ca (2) (+) - and MLC20 phosphorylation dependent canonical mechanism that are involved in the thrombin induced PAR1 mediated pulmonary vasoconstriction.	39	45	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	42	43	44	45
In line with biased agonism and allosteric modulation of PAR1 by thrombin and APC , drug discovery efforts to identify compounds that antagonise PAR1 ' s G protein dependent signalling but not beta-arrestin 2 dependent signalling may prove fruitful for treating a variety of diseases where thrombosis , inflammation and barrier disruption play a key role .	In line with biased agonism and allosteric modulation of PAR1 by thrombin and APC, drug discovery efforts to identify compounds that antagonise PAR1 's G protein dependent signalling but not beta-arrestin 2 dependent signalling may prove fruitful for treating a variety of diseases where thrombosis, inflammation and barrier disruption play a key role.	7	17	modulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	9	10
However , the roles of PAR1 signaling triggered by aPC-EPCR or thrombin in adult bone marrow LT-HSC function are not clear .	However, the roles of PAR1 signaling triggered by aPC-EPCR or thrombin in adult bone marrow LT-HSC function are not clear.	5	12	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	11	12	5	6
Several studies link coagulation cascade activation to exacerbation of early ( 6 hours ) APAP hepatotoxicity in mice with thrombin activation of PAR-1 and PAR-4 being identified as the primary mechanism [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Several studies link coagulation cascade activation to exacerbation of early (6 hours) APAP hepatotoxicity in mice with thrombin activation of PAR-1 and PAR-4 being identified as the primary mechanism [XREF_BIBR, XREF_BIBR, XREF_BIBR].	19	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	19	20	22	23
In part , this is because although both thrombin and APC are capable of cleaving and activating PAR1 , thrombin induces PAR1 cleavage and subsequent intracellular signaling in vascular endothelial cells with ~ 10,000-fold greater efficiency than does APC [ XREF_BIBR ] .	In part, this is because although both thrombin and APC are capable of cleaving and activating PAR1, thrombin induces PAR1 cleavage and subsequent intracellular signaling in vascular endothelial cells with ~ 10,000-fold greater efficiency than does APC [XREF_BIBR].	19	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	19	20	21	22
Considering that TF can initiate thrombin mediated PAR1 signaling as well as direct signaling through PAR2 , we used the PyMT model as an unbiased approach to study contributions of PARs to spontaneous breast cancer development .	Considering that TF can initiate thrombin mediated PAR1 signaling as well as direct signaling through PAR2, we used the PyMT model as an unbiased approach to study contributions of PARs to spontaneous breast cancer development.	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	7	8
Indeed , thrombin is the prototypical PAR1 agonist and thrombin inhibition will thus inhibit PAR1 signaling on tumor cells , suppress mesenchymal transition , and enhance tumor cell proliferation .	Indeed, thrombin is the prototypical PAR1 agonist and thrombin inhibition will thus inhibit PAR1 signaling on tumor cells, suppress mesenchymal transition, and enhance tumor cell proliferation.	9	15	inhibit	Negative_activation_syntax_5_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	14	15
The protease activated family of G protein coupled receptors includes PAR-1 and PAR-3 , which are activated by thrombin , and PAR-2 , which is activated by trypsin and tryptase .	The protease activated family of G protein coupled receptors includes PAR-1 and PAR-3, which are activated by thrombin, and PAR-2, which is activated by trypsin and tryptase.	9	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	18	19	10	11
This study indicates that the activation of 2 thrombin receptors , protease activated receptor type 1 ( PAR-1 ) and PAR-4 on the platelet surface [ XREF_BIBR ] occurred within 5 min .	This study indicates that the activation of 2 thrombin receptors, protease activated receptor type 1 (PAR-1) and PAR-4 on the platelet surface [XREF_BIBR] occurred within 5 min.	8	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	17	18
Furthermore , we used this assay to develop a PAR1 receptor activating probe [ Ala-parafluoroPhe-Arg-Cha-Cit-Tyr-NH2 ( Cit-NH2 ) ] , which displays a high degree of specificity for PAR1 over PAR2 , and we used the assay to quantitate the ability of trypsin to disarm the activation of PAR1 by thrombin .	Furthermore, we used this assay to develop a PAR1 receptor activating probe [Ala-parafluoroPhe-Arg-Cha-Cit-Tyr-NH2 (Cit-NH2)], which displays a high degree of specificity for PAR1 over PAR2, and we used the assay to quantitate the ability of trypsin to disarm the activation of PAR1 by thrombin.	44	51	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	50	51	48	49
Data suggest that activation of PAR1 by thrombin stimulates directed migration of human eosinophils and thereby may affect eosinophils in tissue and allergic inflammation .	Data suggest that activation of PAR1 by thrombin stimulates directed migration of human eosinophils and thereby may affect eosinophils in tissue and allergic inflammation.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	5	6
These observations raised the possibility that , contrary to the traditional view , the thrombin activation of PAR-1 may actually play a protective role in vascular endothelial cells expressing EPCR under normal physiological conditions .	These observations raised the possibility that, contrary to the traditional view, the thrombin activation of PAR-1 may actually play a protective role in vascular endothelial cells expressing EPCR under normal physiological conditions.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	14	15	17	18
Activation of PAR-1 by thrombin or SFFL inhibited endogenous alkaline phosphatase ( ALP ) activity and caused a transient elevation of intracellular calcium in the osteoblast like cells .	Activation of PAR-1 by thrombin or SFFL inhibited endogenous alkaline phosphatase (ALP) activity and caused a transient elevation of intracellular calcium in the osteoblast like cells.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	2	3
Research has shown that thrombin triggered activation of PAR-1 results in disassembly of endothelial adhering junctions , altered endothelial morphology , and formation of inter-endothelial gaps [ XREF_BIBR , XREF_BIBR ] , giving rise to compromised barrier to circulating proteins and the evolution of vasogenic edema and neutrophil infiltration [ XREF_BIBR , XREF_BIBR ] .	Research has shown that thrombin triggered activation of PAR-1 results in disassembly of endothelial adhering junctions, altered endothelial morphology, and formation of inter-endothelial gaps [XREF_BIBR, XREF_BIBR], giving rise to compromised barrier to circulating proteins and the evolution of vasogenic edema and neutrophil infiltration [XREF_BIBR, XREF_BIBR].	4	9	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	8	9
PAR-1 stimulation by thrombin results in platelet aggregation and PAR-1 inhibitors are potential anti-platelet agents .	PAR-1 stimulation by thrombin results in platelet aggregation and PAR-1 inhibitors are potential anti-platelet agents.	0	4	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	0	1
Recent work has shown that thrombin activation of PAR1 causes induction of GRO-alpha in breast carcinoma and melanoma .	Recent work has shown that thrombin activation of PAR1 causes induction of GRO-alpha in breast carcinoma and melanoma.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	5	6	8	9
These results strongly suggest that catalytic activation of thrombin receptor by thrombin results in PKC dependent IL-8 production accompanied by an increase in IL-8 mRNA level .	These results strongly suggest that catalytic activation of thrombin receptor by thrombin results in PKC dependent IL-8 production accompanied by an increase in IL-8 mRNA level.	6	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	11	12	8	10
PAR1 and PAR3 are activated by thrombin , PAR2 is activated by tryptase or trypsin , and PAR4 is activated by both thrombin and tryptase or trypsin .	PAR1 and PAR3 are activated by thrombin, PAR2 is activated by tryptase or trypsin, and PAR4 is activated by both thrombin and tryptase or trypsin.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	0	1
These data suggest that PAR-1 and PAR-4 are activated by thrombin at distinct concentrations and with distinct kinetics .	These data suggest that PAR-1 and PAR-4 are activated by thrombin at distinct concentrations and with distinct kinetics.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	10	11	4	5
It is recognized that MAP kinases and Akt and PKB are involved in the intracellular signaling of thrombin activated PAR1 [ XREF_BIBR ] .	It is recognized that MAP kinases and Akt and PKB are involved in the intracellular signaling of thrombin activated PAR1 [XREF_BIBR].	15	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	17	18	19	20
We hypothesize that the increase in the level of thrombin after SE could activate PAR1 , which will result in the decrease of PAR1 immunoreactivity .	We hypothesize that the increase in the level of thrombin after SE could activate PAR1, which will result in the decrease of PAR1 immunoreactivity.	7	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	level of thrombin	thrombin	PAR1	PAR1	par1	9	10	14	15
XREF_BIBR PAR-1 and PAR-3 are activated by thrombin , PAR-2 is activated by tryptase or trypsin , and PAR-4 is activated by both thrombin and tryptase or trypsin .	XREF_BIBR PAR-1 and PAR-3 are activated by thrombin, PAR-2 is activated by tryptase or trypsin, and PAR-4 is activated by both thrombin and tryptase or trypsin.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	1	2
PAR1 , PAR3 , and PAR4 are activated by thrombin , but PAR2 is activated by trypsin .	PAR1, PAR3, and PAR4 are activated by thrombin, but PAR2 is activated by trypsin.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	0	1
Stimulation of PAR-1 by thrombin causes proliferation of glia and potentially produces reactive gliosis , infiltration of inflammatory cells , and angiogenesis .	Stimulation of PAR-1 by thrombin causes proliferation of glia and potentially produces reactive gliosis, infiltration of inflammatory cells, and angiogenesis.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	2	3
The importance of thrombin induced PAR-1 activation in liver fibrosis has been established recently ; however , the role of PAR-2 and the cellular consequences of its activation by coagulation FXa has remained remarkably underexplored in the context of liver fibrosis .	The importance of thrombin induced PAR-1 activation in liver fibrosis has been established recently; however, the role of PAR-2 and the cellular consequences of its activation by coagulation FXa has remained remarkably underexplored in the context of liver fibrosis.	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	5	6
Previous reports suggest that proteolytic activation of PAR1 by thrombin dependent MMP activity resulted in the persistent activation of EGFR and ErbB2 and HER2 through extracellular signal regulated kinase-1 and kinase-2 ( ERK1/2 ) in invasive breast carcinoma [ XREF_BIBR , XREF_BIBR ] .	Previous reports suggest that proteolytic activation of PAR1 by thrombin dependent MMP activity resulted in the persistent activation of EGFR and ErbB2 and HER2 through extracellular signal regulated kinase-1 and kinase-2 (ERK1/2) in invasive breast carcinoma [XREF_BIBR, XREF_BIBR].	5	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	7	8
29 Interestingly , thrombin but not Xa activated the PAR1 and PAR2 response in breast cancer cells suggesting that the receptor complexes may reside in different membrane micro-domains .	29 Interestingly, thrombin but not Xa activated the PAR1 and PAR2 response in breast cancer cells suggesting that the receptor complexes may reside in different membrane micro-domains.	0	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	9	10
Increased thrombin production during IVH results in PAR-1 activation which can damage the ependymal wall and lead to the induction of hydrocephalus 13 .	Increased thrombin production during IVH results in PAR-1 activation which can damage the ependymal wall and lead to the induction of hydrocephalus 13.	1	9	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	1	2	7	8
It is clear that thrombin mediated PAR1 activation results in activation of barrier disruptive RhoA , Rho kinase mediated inactivation of myosin light chain phosphatase , and actin-myosin contractility due to increased myosin light chain phosphorylation , whereas APC prevents such morphologic transformations and maintains endothelial barrier functions both in vitro and in vivo [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	It is clear that thrombin mediated PAR1 activation results in activation of barrier disruptive RhoA, Rho kinase mediated inactivation of myosin light chain phosphatase, and actin-myosin contractility due to increased myosin light chain phosphorylation, whereas APC prevents such morphologic transformations and maintains endothelial barrier functions both in vitro and in vivo [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	6	7
Proteasome protease was required by the high affinity thrombin receptor because epoxomicin inhibited platelet aggregation by low thrombin concentrations , but not high thrombin concentrations that stimulate PAR1 ( XREF_SUPPLEMENTARY ) .	Proteasome protease was required by the high affinity thrombin receptor because epoxomicin inhibited platelet aggregation by low thrombin concentrations, but not high thrombin concentrations that stimulate PAR1 (XREF_SUPPLEMENTARY).	23	29	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	23	24	27	28
Moreover , the fluorescence intensity measured in cells incubated with thrombin ( 1nmol/L ; 10minutes ) following pre-incubation with tinzaparin was similar to that measured in cells treated with thrombin alone , suggesting that LMWH does not impair thrombin mediated activation of PAR-1 .	Moreover, the fluorescence intensity measured in cells incubated with thrombin (1nmol/L; 10minutes) following pre-incubation with tinzaparin was similar to that measured in cells treated with thrombin alone, suggesting that LMWH does not impair thrombin mediated activation of PAR-1.	38	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	38	39	42	43
Although they are specific for activation of PAR1 , they signal preferentially through G q proteins , whereas thrombin activation of PAR1 signals preferentially through G 12/13 proteins and rho activation .	Although they are specific for activation of PAR1, they signal preferentially through G q proteins, whereas thrombin activation of PAR1 signals preferentially through G 12/13 proteins and rho activation.	18	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	18	19	21	22
Activation of PAR1 by thrombin increases phospholipase C-beta activity that leads to the generation of inositol phosphates and diacylglycerol and increases intracellular Ca 2+ concentrations and protein kinase C ( PKC ) activation .	Activation of PAR1 by thrombin increases phospholipase C-beta activity that leads to the generation of inositol phosphates and diacylglycerol and increases intracellular Ca 2+ concentrations and protein kinase C (PKC) activation.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	2	3
Different from thrombin mediated PAR 1 activation , APC activation of PAR 1 requires colocalization of PAR 1 with EPCR in caveolae microdomains in the form of a signaling complex with caveolin-1 .	Different from thrombin mediated PAR 1 activation, APC activation of PAR 1 requires colocalization of PAR 1 with EPCR in caveolae microdomains in the form of a signaling complex with caveolin-1.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 1	PAR 1	PAR 1	2	3	4	6
In addition , the lack of an inhibitory effect of SCH79797 , a potent inhibitor of thrombin mediated PAR-1 activation , on C5b-9 formation argues against a PAR-1-mediated action of thrombin in this process .	In addition, the lack of an inhibitory effect of SCH79797, a potent inhibitor of thrombin mediated PAR-1 activation, on C5b-9 formation argues against a PAR-1-mediated action of thrombin in this process.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	16	17	18	19
We investigated arachidonic acid and prostaglandin E2 release in the human urothelial carcinoma cell line RT4 in response to stimulation with thrombin , which activates PAR-1 , and tryptase , which activates PAR-2 .	We investigated arachidonic acid and prostaglandin E2 release in the human urothelial carcinoma cell line RT4 in response to stimulation with thrombin, which activates PAR-1, and tryptase, which activates PAR-2.	1	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	21	22	25	26
In contrast to thrombin activated PAR1 , endothelial cells stimulated with APC do not exhibit changes in RhoA signaling but rather APC activated PAR1 appears to couple preferentially to Rac1 activation [ XREF_BIBR , XREF_BIBR ] .	In contrast to thrombin activated PAR1, endothelial cells stimulated with APC do not exhibit changes in RhoA signaling but rather APC activated PAR1 appears to couple preferentially to Rac1 activation [XREF_BIBR, XREF_BIBR].	1	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	5	6
The underlying mechanism by which PAR-1 modifies chemotaxis remains unclear although a recent study elegantly shows that PAR-1 activation by thrombin on human monocytes ( THP-1 cells ) leads to cytoskeletal remodeling and migration [ XREF_BIBR ] .	The underlying mechanism by which PAR-1 modifies chemotaxis remains unclear although a recent study elegantly shows that PAR-1 activation by thrombin on human monocytes (THP-1 cells) leads to cytoskeletal remodeling and migration [XREF_BIBR].	17	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	20	21	17	18
In nasopharyngeal cancer , thrombin induced PAR-1 activation leads to increased expression of MMP-2 and MMP-9 , which are closely associated with tumor metastasis as they can degrade the extracellular matrix and disrupt the basement membrane [ XREF_BIBR , XREF_BIBR ] .	In nasopharyngeal cancer, thrombin induced PAR-1 activation leads to increased expression of MMP-2 and MMP-9, which are closely associated with tumor metastasis as they can degrade the extracellular matrix and disrupt the basement membrane [XREF_BIBR, XREF_BIBR].	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	6	7
An interaction between thrombin induced PAR-1 signaling and the S1P system via enhanced expression of SphK1 and elevated S1P synthesis has first been observed in epithelial and in endothelial cells [ XREF_BIBR ] .	An interaction between thrombin induced PAR-1 signaling and the S1P system via enhanced expression of SphK1 and elevated S1P synthesis has first been observed in epithelial and in endothelial cells [XREF_BIBR].	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	5	6
In breast cancer , proteolytic activation of PAR1 by thrombin promotes cell invasion by stimulating the induction of persistent transactivation of EGFR and ErbB2 and HER2 and subsequently , a prolonged ERK1/2 signaling .	In breast cancer, proteolytic activation of PAR1 by thrombin promotes cell invasion by stimulating the induction of persistent transactivation of EGFR and ErbB2 and HER2 and subsequently, a prolonged ERK1/2 signaling.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	9	10	7	8
Physiologically thrombin activates PAR1 , PAR3 and PAR4 , whereas trypsin activates PAR2 XREF_BIBR - XREF_BIBR .	Physiologically thrombin activates PAR1, PAR3 and PAR4, whereas trypsin activates PAR2 XREF_BIBR - XREF_BIBR.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	1	2	3	4
We have investigated the potential mechanism of thrombin induced fibroblast proliferation and roles of PAR-1 and NF-kappaB signalling in this process .	We have investigated the potential mechanism of thrombin induced fibroblast proliferation and roles of PAR-1 and NF-kappaB signalling in this process.	5	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	14	15
The purpose of this study was to characterize how the expression of innate immune markers is modulated when PAR1 and PAR2 are activated by their agonist enzymes , thrombin and trypsin , respectively .	The purpose of this study was to characterize how the expression of innate immune markers is modulated when PAR1 and PAR2 are activated by their agonist enzymes, thrombin and trypsin, respectively.	18	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	28	29	18	19
Consequently , the reduced fibrotic response might not be solely FXa-PAR-2 dependent but also due to diminished thrombin induced PAR-1 signalling as this latter signalling pathway is known to be profibrogenic as well [ XREF_BIBR ] .	Consequently, the reduced fibrotic response might not be solely FXa-PAR-2 dependent but also due to diminished thrombin induced PAR-1 signalling as this latter signalling pathway is known to be profibrogenic as well [XREF_BIBR].	16	34	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	17	18	19	20
These data suggest that thrombin dependent activation of PAR-1 might contribute to PAH by downregulating nitric oxide-cGMP pathway and causing vasoconstriction .	These data suggest that thrombin dependent activation of PAR-1 might contribute to PAH by downregulating nitric oxide-cGMP pathway and causing vasoconstriction.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	4	5	8	9
The study showed that thrombin activation of PAR1 results in the quick increase in intracellular Ca 2+ which is directly followed by PAR4 mediated sustained Ca 2+ response .	The study showed that thrombin activation of PAR1 results in the quick increase in intracellular Ca 2+ which is directly followed by PAR4 mediated sustained Ca 2+ response.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	4	5	7	8
These discordant effects of PAR1 activation by thrombin versus APC raises the question how PAR1 activation by different proteases can result in opposite effects ?	These discordant effects of PAR1 activation by thrombin versus APC raises the question how PAR1 activation by different proteases can result in opposite effects?	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	7	8	4	5
At a functional level direct activation of PAR-1 by thrombin enhances tumorigenesis by increased tumor cell motility and metastasis and VEGF family proteins expression as well as EGFR transactivation leading to cancer cell proliferation .	At a functional level direct activation of PAR-1 by thrombin enhances tumorigenesis by increased tumor cell motility and metastasis and VEGF family proteins expression as well as EGFR transactivation leading to cancer cell proliferation.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	9	10	7	8
Aprotinin inhibits thrombin induced platelet activation by preventing proteolysis of the PAR1 receptor .	Aprotinin inhibits thrombin induced platelet activation by preventing proteolysis of the PAR1 receptor.	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	11	12
An understanding of how endothelial barrier permeability is regulated by thrombin activation of PAR1 is important for the discovery of new drug targets that can be manipulated to control endothelial barrier permeability and prevent progression of vascular inflammation .	An understanding of how endothelial barrier permeability is regulated by thrombin activation of PAR1 is important for the discovery of new drug targets that can be manipulated to control endothelial barrier permeability and prevent progression of vascular inflammation.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	13	14
CD95 ligand ( CD95L ) potently induces apoptosis by activating CD95 on target cells .	CD95 ligand (CD95L) potently induces apoptosis by activating CD95 on target cells.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95 ligand	CD95 ligand	CD95 ligand	CD95	CD95	CD95	0	2	10	11
For example , several studies have shown that cytotoxic T cells , which express FASL in membrane bound form ( mFASL ) on their surface , can kill FAS + target cells and neutralization of FASL with specific antibodies or FAS-Fc fusion proteins proved that this killing is mediated by FASL induced activation of FAS .	For example, several studies have shown that cytotoxic T cells, which express FASL in membrane bound form (mFASL) on their surface, can kill FAS + target cells and neutralization of FASL with specific antibodies or FAS-Fc fusion proteins proved that this killing is mediated by FASL induced activation of FAS.	48	55	induced	Positive_early_activation	Positive_activation	Positive_activation	FASL	FASL	FASL	FAS	FAS	FAS	50	51	54	55
Recent evidence for a FasL independent activation of Fas suggests that the death receptor can also be activated intracellularly , in the absence of its ligand XREF_BIBR .	Recent evidence for a FasL independent activation of Fas suggests that the death receptor can also be activated intracellularly, in the absence of its ligand XREF_BIBR.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	4	5	8	9
XREF_BIBR , XREF_BIBR , XREF_BIBR For this reason , mFasL but not sFasL induces apoptosis in Fas positive cells .	XREF_BIBR, XREF_BIBR, XREF_BIBR For this reason, mFasL but not sFasL induces apoptosis in Fas positive cells.	0	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	12	13	16	17
NF-kappaB can also directly activate Fas ligand expression to induce Fas cascade death .	NF-kappaB can also directly activate Fas ligand expression to induce Fas cascade death.	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	NF-kappaB can also directly activate Fas ligand expression	fas ligand	Fas	Fas	fas	5	7	10	11
The level of serum sFasL correlated with disease progression suggesting that sFasL induces the apoptosis of Fas + T cells to evade immune surveillance .	The level of serum sFasL correlated with disease progression suggesting that sFasL induces the apoptosis of Fas + T cells to evade immune surveillance.	11	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	11	12	16	17
Thus , FasL induced Fas activation might be responsible for increased IL-6 secretion of portal transplanted fat pads , ultimately inducing hepatic insulin resistance .	Thus, FasL induced Fas activation might be responsible for increased IL-6 secretion of portal transplanted fat pads, ultimately inducing hepatic insulin resistance.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	2	3	4	5
Fas ligand ( FasL , CD95L , Apo-1L ) , a type II membrane protein belonging to the tumour necrosis factor family , induces apoptosis in Fas bearing cells .	Fas ligand (FasL, CD95L, Apo-1L), a type II membrane protein belonging to the tumour necrosis factor family, induces apoptosis in Fas bearing cells.	0	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	0	2	26	27
Upon stimulation with cytokines , appropriate target cells , or FcgammaRIIIA ligands , functional FasL is induced on NK cells at significant levels and in appropriate configuration to cross-link Fas on positive target cells ( e.g ., Jurkat ) and induce their death .	Upon stimulation with cytokines, appropriate target cells, or FcgammaRIIIA ligands, functional FasL is induced on NK cells at significant levels and in appropriate configuration to cross-link Fas on positive target cells (e.g., Jurkat) and induce their death.	13	40	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	14	15	29	30
FasL activates Fas , which forms a complex with FADD and procaspase-8 , to activate caspase-8 [ XREF_BIBR ] .	FasL activates Fas, which forms a complex with FADD and procaspase-8, to activate caspase-8 [XREF_BIBR].	0	14	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	FasL	FasL	fasl	Fas	Fas, which forms a complex with FADD and procaspase-8	fas	0	1	2	3
FasL overexpression in the context of Fas down-regulation in SCLC predicts the ability of SCLC cells to induce paracrine killing of Fas expressing cytotoxic T cells .	FasL overexpression in the context of Fas down-regulation in SCLC predicts the ability of SCLC cells to induce paracrine killing of Fas expressing cytotoxic T cells.	0	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL overexpression	fasl	Fas	Fas	fas	0	1	21	22
We also examined the relative importance of mitochondrial damage and direct cleavage of the executioner caspases by activated initiator caspase 8 in the propagation of FasL and Fas signaling activated by either recombinant membrane FasL or H/R .	We also examined the relative importance of mitochondrial damage and direct cleavage of the executioner caspases by activated initiator caspase 8 in the propagation of FasL and Fas signaling activated by either recombinant membrane FasL or H/R.	25	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	34	35	27	28
In the Fas mediated apoptotic pathway , binding of FasL drives Fas clustering and binding of Fas to FADD .	In the Fas mediated apoptotic pathway, binding of FasL drives Fas clustering and binding of Fas to FADD.	9	12	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	9	10	11	12
To analyze membrane FasL induced Fas clustering in living cells by confocal microscopy we have used YFP and CFP fusion proteins of FasL and Fas ( XREF_FIG A ) .	To analyze membrane FasL induced Fas clustering in living cells by confocal microscopy we have used YFP and CFP fusion proteins of FasL and Fas (XREF_FIG A).	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	5	6
Upon treatment CD95 ligand ( CD95-L ) was induced that stimulated the CD95 pathway by crosslinking CD95 via an autocrine and paracrine loop .	Upon treatment CD95 ligand (CD95-L) was induced that stimulated the CD95 pathway by crosslinking CD95 via an autocrine and paracrine loop.	3	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95-L	CD95-L	CD95-L	CD95	CD95	CD95	5	6	12	13
Our previous work demonstrated that the Fas pathway in thyrocytes can be activated by Fas ligand in the presence of combinations of pro inflammatory cytokines such as IL-1beta , IFNgamma and TNFalpha [ XREF_BIBR , XREF_BIBR ] .	Our previous work demonstrated that the Fas pathway in thyrocytes can be activated by Fas ligand in the presence of combinations of pro inflammatory cytokines such as IL-1beta, IFNgamma and TNFalpha [XREF_BIBR, XREF_BIBR].	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	14	16	6	7
Therefore , the optimization of the FasL conformation has to be considered for the development of efficient FasL derived anti-cancer drugs targeting Fas .	Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL derived anti-cancer drugs targeting Fas.	14	23	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	17	18	22	23
We have previously shown , that FasL induces Fas + BMDCs to transcribe and produce both IL-1beta and IL-18 .	We have previously shown, that FasL induces Fas + BMDCs to transcribe and produce both IL-1beta and IL-18.	6	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	6	7	8	9
In CLD , activated cytotoxic T lymphocytes ( CTLs ) have elevated expression of FasL [ XREF_BIBR ] , which triggers Fas signaling and apoptosis in Fas ( receptor ) bearing hepatocytes .	In CLD, activated cytotoxic T lymphocytes (CTLs) have elevated expression of FasL [XREF_BIBR], which triggers Fas signaling and apoptosis in Fas (receptor) bearing hepatocytes.	14	22	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	14	15	21	22
Interaction of Fas-ligand ( Fas-L ) with the extracytoplasmic domain of the Fas receptor can induce Fas trimerization and activation of the apoptotic cell death process .	Interaction of Fas-ligand (Fas-L) with the extracytoplasmic domain of the Fas receptor can induce Fas trimerization and activation of the apoptotic cell death process.	2	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas-L	Fas-L	Fas-L	Fas	Fas	Fas	4	5	16	17
Within the seminiferous epithelium , increasing expression of FAS ligand by Sertoli cells will activate apoptosis in Fas positive germ cells such as spermatocytes and round spermatids .	Within the seminiferous epithelium, increasing expression of FAS ligand by Sertoli cells will activate apoptosis in Fas positive germ cells such as spermatocytes and round spermatids.	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAS ligand	expression of FAS ligand	fas ligand	Fas	Fas	fas	8	10	17	18
CTL kill target cells largely by one of two methods : 1 ) perforin mediated granzyme delivery following exocytosis of cytotoxic granules and/or 2 ) Fas ligand ( FasL ) mediated coupling of target cell Fas death receptors .	CTL kill target cells largely by one of two methods : 1) perforin mediated granzyme delivery following exocytosis of cytotoxic granules and/or 2) Fas ligand (FasL) mediated coupling of target cell Fas death receptors.	3	37	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	28	29	35	36
It has also been reported that in Jurkat cells , Fas activation by Fas ligand causes activation of K v 1.3 channels via FADD recruitment .	It has also been reported that in Jurkat cells, Fas activation by Fas ligand causes activation of K v 1.3 channels via FADD recruitment.	10	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	13	15	10	11
Our results show that surface expression of Fas ligand by tumor cells does not always induce killing of adjoining Fas sensitive cells and that tumor cells may induce a protective immune response or an active tolerance independently of Fas ligand expression .	Our results show that surface expression of Fas ligand by tumor cells does not always induce killing of adjoining Fas sensitive cells and that tumor cells may induce a protective immune response or an active tolerance independently of Fas ligand expression.	5	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	expression of Fas ligand	fas ligand	Fas	Fas	fas	7	9	19	20
However Fas expression per se does not lead to cell death as ligation of Fas by FasL is required to trigger apoptosis .	However Fas expression per se does not lead to cell death as ligation of Fas by FasL is required to trigger apoptosis.	7	17	lead	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	16	17	14	15
Initial activation of Fas by FasL leads to caspase-8-mediated SMase translocation into membrane rafts and its subsequent activation generating ceramide , which in turn promotes Fas clustering in ceramide enriched membrane platforms and further Fas activation .	Initial activation of Fas by FasL leads to caspase-8-mediated SMase translocation into membrane rafts and its subsequent activation generating ceramide, which in turn promotes Fas clustering in ceramide enriched membrane platforms and further Fas activation.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	5	6	3	4
Fas is one of the death receptors ; binding of FasL induces Fas trimerization , which recruits caspase-8 via the adaptor protein Fas associated death domain protein ( FADD ) .	Fas is one of the death receptors; binding of FasL induces Fas trimerization, which recruits caspase-8 via the adaptor protein Fas associated death domain protein (FADD).	8	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	10	11	12	13
In conclusion , we identify EGFR-CD95 interaction and phosphorylation of critical CD95 tyrosine residues as important early events in hyperosmotic and CD95L induced CD95 activation and apoptosis induction .	In conclusion, we identify EGFR-CD95 interaction and phosphorylation of critical CD95 tyrosine residues as important early events in hyperosmotic and CD95L induced CD95 activation and apoptosis induction.	17	24	induced	Positive_early_activation	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	21	22	23	24
These results suggest that the greater numbers of FasL expressing T cells infiltrating into SCC compared with AK are targeting Fas expressing tumour cells .	These results suggest that the greater numbers of FasL expressing T cells infiltrating into SCC compared with AK are targeting Fas expressing tumour cells.	6	21	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL expressing	fasl	Fas	Fas	fas	8	9	20	21
CD95 dependent apoptosis is triggered by CD95L ( FasL , APO-1L , TNFSF6 ) binding and clustering of surface CD95 .	CD95 dependent apoptosis is triggered by CD95L (FasL, APO-1L, TNFSF6) binding and clustering of surface CD95.	0	16	triggered	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	6	7	0	1
The expression of FasL is upregulated in colon cancer and the functionally expressed FasL can induce apoptosis of Fas expressing T lymphocytes .	The expression of FasL is upregulated in colon cancer and the functionally expressed FasL can induce apoptosis of Fas expressing T lymphocytes.	10	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	13	14	18	19
There exists a soluble form of FasL ( sFasL ) , and sFasL also induces apoptosis of Fas bearing cells .	There exists a soluble form of FasL (sFasL), and sFasL also induces apoptosis of Fas bearing cells.	12	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	12	13	17	18
This suggests that the formation of higher order complexes of Fas and FasL is an essential step in membrane FasL induced Fas activation .	This suggests that the formation of higher order complexes of Fas and FasL is an essential step in membrane FasL induced Fas activation.	16	22	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	19	20	21	22
Emerging evidence suggest that the introduction of Fas ligand ( FasL ) can enhance the Fas dependent apoptosis and induce durable immune responses against tumor .	Emerging evidence suggest that the introduction of Fas ligand (FasL) can enhance the Fas dependent apoptosis and induce durable immune responses against tumor.	7	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	7	9	15	16
In fact , Fas activation by FasL in cell lines resistant to apoptosis increases motility and invasiveness XREF_BIBR .	In fact, Fas activation by FasL in cell lines resistant to apoptosis increases motility and invasiveness XREF_BIBR.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	6	7	3	4
In addition to the granule exocytosis pathway , CTLs can also induce target cell proteolysis and apoptosis through ligation of target cell Fas by CTL Fas ligand 32 .	In addition to the granule exocytosis pathway, CTLs can also induce target cell proteolysis and apoptosis through ligation of target cell Fas by CTL Fas ligand 32.	11	27	induce	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	25	27	22	23
Activation of CD95 by FasL , a trimeric cell surface protein , leads to rapid induction of apoptosis XREF_BIBR .	Activation of CD95 by FasL, a trimeric cell surface protein, leads to rapid induction of apoptosis XREF_BIBR.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	CD95	CD95	CD95	4	5	2	3
To test the influence of FasL mediated signaling on the virulence of Y. pestis in the presence or absence of Pla , we utilized C57BL/6 FasL gld mice , which lack functional FasL and are unable to activate Fas .	To test the influence of FasL mediated signaling on the virulence of Y. pestis in the presence or absence of Pla, we utilized C57BL/6 FasL gld mice, which lack functional FasL and are unable to activate Fas.	25	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	25	26	38	39
It represents important apoptotic signaling in many cell types and the pathway of FasL mediated FAS death has been extensively investigated in the interplay between immune cells , cancer cells and MSC based immunomodulation XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	It represents important apoptotic signaling in many cell types and the pathway of FasL mediated FAS death has been extensively investigated in the interplay between immune cells, cancer cells and MSC based immunomodulation XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	FAS	FAS	FAS	13	14	15	16
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR In contrast , soluble CD95L induced CD95 mediated cell migration and proliferation are independent from FADD and occur by help of tyrosine kinases that directly interact with CD95 .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR In contrast, soluble CD95L induced CD95 mediated cell migration and proliferation are independent from FADD and occur by help of tyrosine kinases that directly interact with CD95.	12	26	induced	Positive_early_activation	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	13	14	15	16
Stimulation of the CD95 ( Apo-1 and Fas ) molecule either by the CD95 ligand or by monoclonal antibodies induces programmed cell death by apoptosis in a variety of cell lines and primary cells .	Stimulation of the CD95 (Apo-1 and Fas) molecule either by the CD95 ligand or by monoclonal antibodies induces programmed cell death by apoptosis in a variety of cell lines and primary cells.	0	15	Stimulation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	CD95 ligand	CD95 ligand	CD95 ligand	CD95	CD95	CD95	13	15	3	4
The current model of death ligand-receptor dynamics assumes that FasL activates Fas by direct crosslinking , producing a DISC concentration that varies smoothly with the ligand input XREF_BIBR .	The current model of death ligand-receptor dynamics assumes that FasL activates Fas by direct crosslinking, producing a DISC concentration that varies smoothly with the ligand input XREF_BIBR.	9	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	9	10	11	12
Because FAS associated apoptosis , mediated by FAS-L expressing cytotoxic T lymphocytes , is thought to play a key role in HCV associated liver disease [ XREF_BIBR - XREF_BIBR ] , the level of apoptosis was examined using both Caspase-3 activation immunohistochemistry and lobular apoptotic body count .	Because FAS associated apoptosis, mediated by FAS-L expressing cytotoxic T lymphocytes, is thought to play a key role in HCV associated liver disease [XREF_BIBR - XREF_BIBR], the level of apoptosis was examined using both Caspase-3 activation immunohistochemistry and lobular apoptotic body count.	1	8	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FAS-L	FAS-L	FAS-L	FAS	FAS	FAS	7	8	1	2
These results suggest that Fas targeting by FasL but not by alpha-Fas antibodies may provide a promising approach for locoregional glioma treatment .	These results suggest that Fas targeting by FasL but not by alpha-Fas antibodies may provide a promising approach for locoregional glioma treatment.	4	8	targeting	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	4	5
However , recent evidence for FasL independent activation of Fas suggests that the death receptor can also be activated intracellularly , in the absence of its ligand .	However, recent evidence for FasL independent activation of Fas suggests that the death receptor can also be activated intracellularly, in the absence of its ligand.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	5	6	9	10
Fas activation by Fas ligand induced a hypertrophic response in cultured cardiomyocytes , which was dependent on the inactivation of glycogen synthase kinase 3 beta ( GSK3 beta ) by phosphorylation .	Fas activation by Fas ligand induced a hypertrophic response in cultured cardiomyocytes, which was dependent on the inactivation of glycogen synthase kinase 3 beta (GSK3 beta) by phosphorylation.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	3	5	0	1
The ligand of CD95 , CD95L , induces apoptosis in CD95 expressing cells through activation of caspases .	The ligand of CD95, CD95L, induces apoptosis in CD95 expressing cells through activation of caspases.	1	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	5	6	10	11
Fas ligand ( FasL ) induces apoptosis in Fas bearing cells , and its expression on activated T cells contributes to the regulation of the immune response and physiological cell turnover .	Fas ligand (FasL) induces apoptosis in Fas bearing cells, and its expression on activated T cells contributes to the regulation of the immune response and physiological cell turnover.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	0	2	8	9
On the other hand , expression of FasL on T-cells and NK-cells induces cell death in Fas bearing tumour cells .	On the other hand, expression of FasL on T-cells and NK-cells induces cell death in Fas bearing tumour cells.	5	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	expression of FasL	fasl	Fas	Fas	fas	7	8	16	17
In contrast to lethal dose IAV infections , during sublethal infections LNDC downregulate FasL expression allowing the developing Fas + IAV specific CD8 T cells to escape apoptosis and traffic into the lungs in sufficient numbers to clear the infection .	In contrast to lethal dose IAV infections, during sublethal infections LNDC downregulate FasL expression allowing the developing Fas + IAV specific CD8 T cells to escape apoptosis and traffic into the lungs in sufficient numbers to clear the infection.	11	20	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	LNDC downregulate FasL expression	fasl	Fas	Fas	fas	13	14	18	19
Importantly , membrane bound FasL is sufficient to induce Fas internalization , formation of a Death Inducing Signaling Complex , and apoptosis .	Importantly, membrane bound FasL is sufficient to induce Fas internalization, formation of a Death Inducing Signaling Complex, and apoptosis.	4	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	4	5	9	10
By contrast , when implanted into nonprivileged sites , CD95L + tumor cells activate CD95 + neutrophils and are rejected by these innate immune effectors ( the activated neutrophils ) , permitting recipient survival .	By contrast, when implanted into nonprivileged sites, CD95L + tumor cells activate CD95 + neutrophils and are rejected by these innate immune effectors (the activated neutrophils), permitting recipient survival.	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	9	10	14	15
In certain pathological conditions , such as alcoholic hepatitis and Wilson ' s disease , FasL can also be expressed by hepatocytes and induce fratricide cell death of Fas expressing hepatocytes , amplifying the tissue damage .	In certain pathological conditions, such as alcoholic hepatitis and Wilson 's disease, FasL can also be expressed by hepatocytes and induce fratricide cell death of Fas expressing hepatocytes, amplifying the tissue damage.	15	29	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL can also be expressed	fasl	Fas	Fas	fas	15	16	28	29
Overall , these data suggested that IFNgamma ( a ) facilitated both Ag dependent and Ag independent events as a prerequisite for efficient CTL and target interactions , FasL up-regulation and triggering of Fas dependent , as well as Fas independent lysis ( perforin ) ; and ( b ) enhanced or restored a Fas sensitive phenotype in SW480 cells , reflecting modulation of cell-surface and intracellular elements of the Fas pathway .	Overall, these data suggested that IFNgamma (a) facilitated both Ag dependent and Ag independent events as a prerequisite for efficient CTL and target interactions, FasL up-regulation and triggering of Fas dependent, as well as Fas independent lysis (perforin); and (b) enhanced or restored a Fas sensitive phenotype in SW480 cells, reflecting modulation of cell-surface and intracellular elements of the Fas pathway.	28	48	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	28	29	33	34
XREF_BIBR The Fas pathway becomes activated after ligation of Fas by Fas ligand ( FasL )-expressing effector cells , or by soluble FasL .	XREF_BIBR The Fas pathway becomes activated after ligation of Fas by Fas ligand (FasL)-expressing effector cells, or by soluble FasL.	5	17	activated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	14	15	9	10
Expression of FasL potentially enables colon tumors to counterattack Fas sensitive anti-tumor immune effector cells through Fas mediated death .	Expression of FasL potentially enables colon tumors to counterattack Fas sensitive anti-tumor immune effector cells through Fas mediated death.	0	19	enables	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	FasL	Expression of FasL	fasl	Fas	Fas mediated death	fas	2	3	16	17
These two populations differed in their susceptibility to Fas killing induced by FasL bearing Th1 effector cells : at each effector and target cell ratio tested , specific lysis of cDNA transfected BAL-17 B cells , detected by Cr-release assay , was reduced by half or more in comparison to cells transfected with vector alone , despite equivalent levels of surface Fas expression ( data not shown ) .	These two populations differed in their susceptibility to Fas killing induced by FasL bearing Th1 effector cells : at each effector and target cell ratio tested, specific lysis of cDNA transfected BAL-17 B cells, detected by Cr-release assay, was reduced by half or more in comparison to cells transfected with vector alone, despite equivalent levels of surface Fas expression (data not shown).	8	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	12	13	8	9
The death receptor Fas , activated by FasL , recruits the adaptor protein Fas associated death domain protein ( FADD ) to aggregate procaspase-8 , that cleaves one other to initiate an active form of caspase-8 , causing activation of the effector caspase-3 [ XREF_BIBR ] .	The death receptor Fas, activated by FasL, recruits the adaptor protein Fas associated death domain protein (FADD) to aggregate procaspase-8, that cleaves one other to initiate an active form of caspase-8, causing activation of the effector caspase-3 [XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	3	4
Fas , a tumor necrosis factor family receptor , is activated by the membrane protein Fas ligand ( FasL ) expressed on various immune cells .	Fas, a tumor necrosis factor family receptor, is activated by the membrane protein Fas ligand (FasL) expressed on various immune cells.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand (FasL) expressed	fas ligand	Fas	Fas	fas	15	17	0	1
Edelfosine was the first antitumor drug reported to promote an apoptotic response through FasL and CD95L independent activation of Fas and CD95 by its recruitment in lipid rafts XREF_BIBR , linking for the first time membrane rafts and Fas and CD95 mediated apoptosis in cancer chemotherapy .	Edelfosine was the first antitumor drug reported to promote an apoptotic response through FasL and CD95L independent activation of Fas and CD95 by its recruitment in lipid rafts XREF_BIBR, linking for the first time membrane rafts and Fas and CD95 mediated apoptosis in cancer chemotherapy.	13	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	13	14	19	20
Due to the complex and presumably cell type specific role of lipid rafts in Fas activation , we have clarified here the relationship between lipid rafts and the formation of membrane FasL induced Fas clusters .	Due to the complex and presumably cell type specific role of lipid rafts in Fas activation, we have clarified here the relationship between lipid rafts and the formation of membrane FasL induced Fas clusters.	28	34	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	31	32	33	34
Since no cross linking antibody was used in the experiments shown in XREF_FIG , the recombinant sFasL ( R & D Systems ) is less likely to induce trimerization of Fas which is known to be important for mediating apoptosis [ XREF_BIBR , XREF_BIBR ] .	Since no cross linking antibody was used in the experiments shown in XREF_FIG, the recombinant sFasL (R&D Systems) is less likely to induce trimerization of Fas which is known to be important for mediating apoptosis [XREF_BIBR, XREF_BIBR].	14	31	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	16	17	30	31
The membrane bound death ligands CD95L and FasL and TRAIL , which activate the corresponding death receptors CD95 and Fas , TRAILR1 and TRAILR2 , induce apoptosis in many tumour cells , but can also elicit an inflammatory response .	The membrane bound death ligands CD95L and FasL and TRAIL, which activate the corresponding death receptors CD95 and Fas, TRAILR1 and TRAILR2, induce apoptosis in many tumour cells, but can also elicit an inflammatory response.	5	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	19	20
Moreover , S. aureus induced apoptosis of monocytes has been proposed to involve CD95 signaling caused by the upregulation of CD95 ligand expression .	Moreover, S. aureus induced apoptosis of monocytes has been proposed to involve CD95 signaling caused by the upregulation of CD95 ligand expression.	13	23	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD95 ligand	CD95 ligand expression	cd95 ligand	CD95	CD95	cd95	20	22	13	14
These data suggest that survival and differentiation of HIV specific CD8+ T cells may be compromised by Fas apoptosis induced by FasL expressing HIV infected cells [ XREF_BIBR ] .	These data suggest that survival and differentiation of HIV specific CD8+ T cells may be compromised by Fas apoptosis induced by FasL expressing HIV infected cells [XREF_BIBR].	17	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	21	22	17	18
By engaging Fas , Fas ligand ( FasL ) on activated T lymphocytes induces activation induced cell death ( AICD ) , and also triggers apoptosis of target cells during immune downregulation .	By engaging Fas, Fas ligand (FasL) on activated T lymphocytes induces activation induced cell death (AICD), and also triggers apoptosis of target cells during immune downregulation.	1	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	4	6	2	3
Activation of FasL and Fas signaling by either recombinant membrane FasL under normal culture conditions or H/R causes cardiomyocyte death mainly through the mitochondrial damage and caspase 9 activation pathway .	Activation of FasL and Fas signaling by either recombinant membrane FasL under normal culture conditions or H/R causes cardiomyocyte death mainly through the mitochondrial damage and caspase 9 activation pathway.	2	16	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	10	11	4	5
CD95L addition under normoosmotic conditions caused CD95 membrane trafficking , which was sensitive to JNK inhibition , but not to cyclic adenosine monophosphate or inhibition of PKC , Erks , and p38 ( MAPK ) .	CD95L addition under normoosmotic conditions caused CD95 membrane trafficking, which was sensitive to JNK inhibition, but not to cyclic adenosine monophosphate or inhibition of PKC, Erks, and p38 (MAPK).	0	8	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	0	1	6	7
Fas-L transfectants induced 20 +/- 4.2 % apoptosis of Fas sensitive T cells , while controls induced 3.47 +/- 2.3 % by flow cytometry ( P = 0.04 , n = 3 ) .	Fas-L transfectants induced 20 +/- 4.2% apoptosis of Fas sensitive T cells, while controls induced 3.47 +/- 2.3% by flow cytometry (P = 0.04, n = 3).	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas-L	Fas-L	Fas-L	Fas	Fas	Fas	0	1	9	10
In conclusion , we have shown that inactivation of the Fas mediated cell death pathway by mutation of Fas or Fasl accelerates the development and greatly increases the incidence of B cell lymphomas .	In conclusion, we have shown that inactivation of the Fas mediated cell death pathway by mutation of Fas or Fasl accelerates the development and greatly increases the incidence of B cell lymphomas.	7	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fasl	Fasl	Fasl	Fas	Fas	Fas	20	21	10	11
Mouse WR19L transformants expressing Fas ( W3 cells ) were treated with Fas ligand ( FasL ) for 30 min , washed , and then further incubated for 60 min .	Mouse WR19L transformants expressing Fas (W3 cells) were treated with Fas ligand (FasL) for 30 min, washed, and then further incubated for 60 min.	3	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	15	16	4	5
XREF_BIBR , XREF_BIBR Activation of Fas by FasL is a major trigger of the extrinsic pathway of apoptosis .	XREF_BIBR, XREF_BIBR Activation of Fas by FasL is a major trigger of the extrinsic pathway of apoptosis.	3	8	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	5	6
Fas stimulation by Fas-ligand ( CD95 and Apo-1 , Jo2 antibody as a mouse Fas-ligand ) activates caspase-3 via caspase-8 in liver cells .	Fas stimulation by Fas-ligand (CD95/Apo-1, Jo2 antibody as a mouse Fas-ligand) activates caspase-3 via caspase-8 in liver cells.	0	7	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Fas-ligand	Fas-ligand	Fas-ligand	Fas	Fas	Fas	3	4	0	1
Fas ligand ( FasL ) , a member of the TNF protein family , potently induces cell death by activating its matching receptor Fas .	Fas ligand (FasL), a member of the TNF protein family, potently induces cell death by activating its matching receptor Fas.	0	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	0	2	23	24
However , at 72 h p.i ., cells infected with strains Merlin or AD169 became less sensitive to Fas signalling induced by either FasL or Fas mAb ( XREF_FIG ) .	However, at 72 h p.i., cells infected with strains Merlin or AD169 became less sensitive to Fas signalling induced by either FasL or Fas mAb (XREF_FIG).	18	26	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	23	24	18	19
Apoptotic signaling is initiated by Fas clustering induced by trimeric Fas ligand ( FasL ) engagement , a signaling complex formation containing FasL , Fas , FADD , and procaspase-8 XREF_BIBR .	Apoptotic signaling is initiated by Fas clustering induced by trimeric Fas ligand (FasL) engagement, a signaling complex formation containing FasL, Fas, FADD, and procaspase-8 XREF_BIBR.	5	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	10	12	5	6
Activation of Fas by Fas ligand induces apoptosis via activation of the caspase cascade [ XREF_BIBR ] .	Activation of Fas by Fas ligand induces apoptosis via activation of the caspase cascade [XREF_BIBR].	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	4	6	2	3
The death receptors TRAIL-R1 ( DR4 ) , TRAIL-R2 ( DR5 ) and CD95 ( Fas ) are specialised members of the TNF receptor superfamily and are key mediators of apoptosis triggered by ligands expressed by cells of the immune system , namely TRAIL ( TNF related apoptosis inducing ligand ) , which activates TRAIL-R1 and TRAIL-R2 , and CD95L ( FasL ) , which activates CD95 .	The death receptors TRAIL-R1 (DR4), TRAIL-R2 (DR5) and CD95 (Fas) are specialised members of the TNF receptor superfamily and are key mediators of apoptosis triggered by ligands expressed by cells of the immune system, namely TRAIL (TNF related apoptosis inducing ligand), which activates TRAIL-R1 and TRAIL-R2, and CD95L (FasL), which activates CD95.	28	67	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	59	60	66	67
For example , TNFalpha activates TNF-R1 while FasL and TL1A activate Fas and DR3 respectively .	For example, TNFalpha activates TNF-R1 while FasL and TL1A activate Fas and DR3 respectively.	7	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	11	12
Normal synthesis of surfactant lipids and proteins , including SP-A , SP-B , SP-C , SP-D , ABCA3 ( a lamellar body associated protein ) and FAS ( precursor of fatty acid synthesis ) were dependent upon expression of the C/EBPalpha in respiratory epithelial cells .	Normal synthesis of surfactant lipids and proteins, including SP-A, SP-B, SP-C, SP-D, ABCA3 (a lamellar body associated protein) and FAS (precursor of fatty acid synthesis) were dependent upon expression of the C/EBPalpha in respiratory epithelial cells.	1	35	synthesis	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	SP-A	SP-A	SP-A	FAS	FAS	FAS	9	10	26	27
This observation raises an intriguing question regarding the role of FasL expressed by thymocytes : is thymocyte FasL able to trigger Fas by an autocrine manner ?	This observation raises an intriguing question regarding the role of FasL expressed by thymocytes : is thymocyte FasL able to trigger Fas by an autocrine manner?	16	22	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	17	18	21	22
Increased activation of CD95 and Fas by Fas ligand in viral hepatitis and autoimmunity is involved in pathogenesis of fulminant hepatitis and liver failure .	Increased activation of CD95 and Fas by Fas ligand in viral hepatitis and autoimmunity is involved in pathogenesis of fulminant hepatitis and liver failure.	1	9	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	CD95	CD95	CD95	7	9	3	4
Binding of Fas ligand ( FasL ) induces Fas trimerization , which results in recruitment of adapter protein Fas associated death domain ( FADD ) through DD-DD interactions .	Binding of Fas ligand (FasL) induces Fas trimerization, which results in recruitment of adapter protein Fas associated death domain (FADD) through DD-DD interactions.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	5	6	8	9
Fas ligand upregulation in melanoma cells induces Fas bearing cytotoxic T lymphocytes and natural killer cells to undergo apoptosis .	Fas ligand upregulation in melanoma cells induces Fas bearing cytotoxic T lymphocytes and natural killer cells to undergo apoptosis.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	0	2	7	8
The activation of Fas by Fas ligand ( FasL ) affects caspase-8 activation .	The activation of Fas by Fas ligand (FasL) affects caspase-8 activation.	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	5	7	3	4
The Fas ligand ( FasL ) , a member of the tumor necrosis factor family , induces apoptosis in Fas expressing cells .	The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas expressing cells.	1	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	1	3	19	20
Several functional studies have shown that FasL positive colon tumour cells can induce apoptosis of Fas sensitive lymphocytes in vitro [ XREF_BIBR , XREF_BIBR ] .	Several functional studies have shown that FasL positive colon tumour cells can induce apoptosis of Fas sensitive lymphocytes in vitro [XREF_BIBR, XREF_BIBR].	6	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	6	7	15	16
In contrast , hexameric soluble FasL or antibody cross linked soluble FasL are sufficient to induce Fas signaling .	In contrast, hexameric soluble FasL or antibody cross linked soluble FasL are sufficient to induce Fas signaling.	9	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	11	12	16	17
Promotion of FasL translocation to the cell surface by lysophosphatidic acid evoked a FasL activated Fas death pathway in MCF-7 cells .	Promotion of FasL translocation to the cell surface by lysophosphatidic acid evoked a FasL activated Fas death pathway in MCF-7 cells.	12	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	13	14	15	16
These receptors include TNF related apoptosis inducing ligand-receptor ( TRAIL-R ) and Fas ( CD95 ) which are activated by their cognate ligands , Fas ligand ( FasL ) ( CD95L ) and TRAIL , present on NK cells .	These receptors include TNF related apoptosis inducing ligand-receptor (TRAIL-R) and Fas (CD95) which are activated by their cognate ligands, Fas ligand (FasL) (CD95L) and TRAIL, present on NK cells.	9	26	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	CD95	CD95	CD95	24	26	14	15
When human Jurkat , or its transformants , expressing mouse Fas were treated with Fas ligand or anti-mouse Fas antibodies , the cells died , showing characteristics of apoptosis .	When human Jurkat, or its transformants, expressing mouse Fas were treated with Fas ligand or anti-mouse Fas antibodies, the cells died, showing characteristics of apoptosis.	8	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	14	16	10	11
However , we also found that Fas ligand treatment stimulated Fas expressing Kupffer cells or macrophages to produce active IL-18 in a caspase-1-independent manner , indicating the presence of some other caspase mediated pathways for IL-18 secretion .	However, we also found that Fas ligand treatment stimulated Fas expressing Kupffer cells or macrophages to produce active IL-18 in a caspase-1-independent manner, indicating the presence of some other caspase mediated pathways for IL-18 secretion.	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	6	8	10	11
These results show that CD95L either from autocrine or from paracrine sources - for example , the tumour microenvironment - can trigger proinvasive CD95 signalling .	These results show that CD95L either from autocrine or from paracrine sources - for example, the tumour microenvironment - can trigger proinvasive CD95 signalling.	4	24	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	4	5	23	24
Moreover , expression of FasL in nonlymphoid and tumor cells contributes to the maintenance of immune privilege of tissues by preventing the infiltration of Fas sensitive lymphocytes ( 8- 12 ) .	Moreover, expression of FasL in nonlymphoid and tumor cells contributes to the maintenance of immune privilege of tissues by preventing the infiltration of Fas sensitive lymphocytes (8- 12).	2	26	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	expression of FasL	fasl	Fas	Fas	fas	4	5	24	25
The Fas ligand ( FasL ) , a member of the tumor necrosis factor family , induces apoptosis in Fas bearing cells .	The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas bearing cells.	2	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	4	5	19	20
However , sFasL does not activate Fas , and it competes with mFasL reducing its cytotoxic activity .	However, sFasL does not activate Fas, and it competes with mFasL reducing its cytotoxic activity.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	2	3	6	7
We previously reported that Fas activation by FasL treatment induced secretion of IL-6 in 3T3-L1 adipocytes .	We previously reported that Fas activation by FasL treatment induced secretion of IL-6 in 3T3-L1 adipocytes.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	4	5
Similar results were obtained when Fas ligand or an agonistic Fas antibody initiated the Fas apoptosis pathway .	Similar results were obtained when Fas ligand or an agonistic Fas antibody initiated the Fas apoptosis pathway.	5	16	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	5	7	14	15
Perhaps , the spatial orientation and mobility reduction of membrane FasL in the plasma membrane facilitates Fas aggregation , making cytosolic events dispensable for membrane FasL induced Fas clustering .	Perhaps, the spatial orientation and mobility reduction of membrane FasL in the plasma membrane facilitates Fas aggregation, making cytosolic events dispensable for membrane FasL induced Fas clustering.	24	28	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	25	26	27	28
FASL mediated FAS death pathway has been extensively investigated in the interplay between immune cells , cancer cells and MSC based immunomodulation XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	FASL mediated FAS death pathway has been extensively investigated in the interplay between immune cells, cancer cells and MSC based immunomodulation XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	FASL	FASL	FASL	FAS	FAS	FAS	0	1	2	3
Binding of Fas ligand or an agonistic anti-Fas antibody induces apoptosis in Fas bearing cells .	Binding of Fas ligand or an agonistic anti-Fas antibody induces apoptosis in Fas bearing cells.	2	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	2	4	12	13
The fact that substitution of Y by other amino acids allowed Fas and FasL uptake by CDE suggests that the FasL induced Fas uptake did not depend on Y291 as a part of the Y based sorting motif but possibly of other motifs such as the acidic LL motif .	The fact that substitution of Y by other amino acids allowed Fas and FasL uptake by CDE suggests that the FasL induced Fas uptake did not depend on Y291 as a part of the Y based sorting motif but possibly of other motifs such as the acidic LL motif.	19	23	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	20	21	22	23
To confirm the pro apoptotic activity , we tested whether 6xHisLys 145 FasL activated Fas by examining the presence of Fas and FADD complexes in lysates of HBMEC exposed to FLAG-sFasL or to 6xHisLys 145 FasL .	To confirm the pro apoptotic activity, we tested whether 6xHisLys 145 FasL activated Fas by examining the presence of Fas and FADD complexes in lysates of HBMEC exposed to FLAG-sFasL or to 6xHisLys 145 FasL.	10	15	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	12	13	14	15
Insertion of Fas-L into betaTC was characterized by reverse transcription polymerase chain reaction ( RT-PCR ) and the ability of transfectants ( betaTC-3 and Fas-L ) to induce apoptosis of Fas sensitive T cells .	Insertion of Fas-L into betaTC was characterized by reverse transcription polymerase chain reaction (RT-PCR) and the ability of transfectants (betaTC-3 and Fas-L) to induce apoptosis of Fas sensitive T cells.	0	33	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas-L	Fas-L	Fas-L	Fas	Fas	Fas	2	3	30	31
Binding of Fas ligand ( FasL ) or an agonistic anti-Fas receptor ( Fas and CD95 ) antibody induces apoptosis in Fas bearing target cells .	Binding of Fas ligand (FasL) or an agonistic anti-Fas receptor (Fas and CD95) antibody induces apoptosis in Fas bearing target cells.	2	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	2	4	21	22
In susceptible cells , membrane FasL , agonistic Fas specific antibodies , and secondarily aggregated soluble FasL induce reorganization of inactive , preassembled Fas complexes to supramolecular Fas clusters having the capacity to signal apoptosis .	In susceptible cells, membrane FasL, agonistic Fas specific antibodies, and secondarily aggregated soluble FasL induce reorganization of inactive, preassembled Fas complexes to supramolecular Fas clusters having the capacity to signal apoptosis.	4	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	5	6	23	24
Variants of human TRAIL ( hTRAIL ) and human CD95L ( hCD95L ) , encompassing the TNF homology domain ( THD ) , interact with the corresponding receptors and stimulate CD95 and TRAILR2 signaling after cross linking .	Variants of human TRAIL (hTRAIL) and human CD95L (hCD95L), encompassing the TNF homology domain (THD), interact with the corresponding receptors and stimulate CD95 and TRAILR2 signaling after cross linking.	0	33	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	9	10	30	31
Moreover , it is worth noting that these cytoplasmic changes occurred early ( 30 min ) after FasL induced CD95 triggering in cells that do not yet display ultrastructural signs of apoptosis and increased with time ( up to 1 h ) .	Moreover, it is worth noting that these cytoplasmic changes occurred early (30 min) after FasL induced CD95 triggering in cells that do not yet display ultrastructural signs of apoptosis and increased with time (up to 1 h).	17	33	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	CD95	CD95	CD95	17	18	19	20
Moreover , membrane FasL induced Fas cluster formation at the cell membrane resulted in gene induction or was followed by rapid cell death in the absence of the caspase inhibitor zVAD-fmk ( XREF_FIG B ; Fig .	Moreover, membrane FasL induced Fas cluster formation at the cell membrane resulted in gene induction or was followed by rapid cell death in the absence of the caspase inhibitor zVAD-fmk (XREF_FIG B; Fig.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	5	6
Photoactivation of HA and HB enhanced both CD95 and CD95L expression and induced CD95 signaling dependent cell death in all tumor cell lines studied .	Photoactivation of HA and HB enhanced both CD95 and CD95L expression and induced CD95 signaling dependent cell death in all tumor cell lines studied.	2	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	HA and HB enhanced both CD95 and CD95L expression	cd95l	CD95	CD95	cd95	9	10	13	14
Emerging evidence suggests that Fas ligand activation enhances Fas dependent apoptosis and induces robust immune responses against tumors [ XREF_BIBR ] .	Emerging evidence suggests that Fas ligand activation enhances Fas dependent apoptosis and induces robust immune responses against tumors [XREF_BIBR].	4	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	4	6	8	9
According to the current model of type I apoptosis , binding of either the FasL or an agonistic antibody induces aggregation of Fas followed by a conformational change in its cytoplasmic domain that results in formation of the DISC .	According to the current model of type I apoptosis, binding of either the FasL or an agonistic antibody induces aggregation of Fas followed by a conformational change in its cytoplasmic domain that results in formation of the DISC.	10	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	14	15	22	23
Fas ligand ( FasL ) triggers apoptosis of Fas positive cells , and previous reports described FasL induced cell death of Fas positive photoreceptors following a retinal detachment .	Fas ligand (FasL) triggers apoptosis of Fas positive cells, and previous reports described FasL induced cell death of Fas positive photoreceptors following a retinal detachment.	1	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	8	9
It has been suggested that the up-regulation of FasL in CRC cells can induce apoptosis of Fas expressing T lymphocytes in the tumour [ XREF_BIBR ] .	It has been suggested that the up-regulation of FasL in CRC cells can induce apoptosis of Fas expressing T lymphocytes in the tumour [XREF_BIBR].	6	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	8	9	16	17
The Fas and TRAIL receptors are activated by the Fas ligand ( FasL ) and TRAIL , respectively , and these events result in the clustering of death receptors and the recruitment of the Fas associated death domain ( FADD ) molecule [ XREF_BIBR ] .	The Fas and TRAIL receptors are activated by the Fas ligand (FasL) and TRAIL, respectively, and these events result in the clustering of death receptors and the recruitment of the Fas associated death domain (FADD) molecule [XREF_BIBR].	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	9	11	1	2
Photosensitization of HY enhanced both CD95 and CD95L expression and induced CD95 signaling dependent cell death in all tumor cell lines studied .	Photosensitization of HY enhanced both CD95 and CD95L expression and induced CD95 signaling dependent cell death in all tumor cell lines studied.	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	HY enhanced both CD95 and CD95L expression	cd95l	CD95	CD95	cd95	7	8	11	12
Fas and CD95 raft coclustering is also promoted by Fas and CD95 ligand , agonistic Fas and CD95 antibodies , and additional antitumor drugs .	Fas and CD95 raft coclustering is also promoted by Fas and CD95 ligand, agonistic Fas and CD95 antibodies, and additional antitumor drugs.	2	13	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD95 ligand	CD95 ligand	CD95 ligand	CD95	CD95	CD95	11	13	2	3
Soluble CD95L induces CD95 internalization in type I cells .	Soluble CD95L induces CD95 internalization in type I cells.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	1	2	3	4
Doxorubicin induced caspase-8 activation was found to be mediated through Akt and ERK inactivation and FasL independent Fas pathway in MCF-7 cells , while caspase-8 activation in MCF-7 and Dox cells depended exclusively on FasL stimulated Fas pathway .	Doxorubicin induced caspase-8 activation was found to be mediated through Akt and ERK inactivation and FasL independent Fas pathway in MCF-7 cells, while caspase-8 activation in MCF-7 and Dox cells depended exclusively on FasL stimulated Fas pathway.	15	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	15	16	36	37
Stimulation of Fas by Fas ligand or agonistic antibodies results in the activation of interleukin-1 beta converting enzyme like ( ICE like ) proteases , and proteolytic cleavage of poly ( ADP-ribose ) polymerase ( PARP ) .	Stimulation of Fas by Fas ligand or agonistic antibodies results in the activation of interleukin-1 beta converting enzyme like (ICE like) proteases, and proteolytic cleavage of poly (ADP-ribose) polymerase (PARP).	0	8	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	4	6	2	3
The mechanisms through which stimulation of Fas by FasL initiate apoptosis have been extensively investigated .	The mechanisms through which stimulation of Fas by FasL initiate apoptosis have been extensively investigated.	4	10	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	8	9	6	7
The pathogenic role of Fas and FasL in APAP induced ALI is likewise well established , detectable in Fas- or FasL deficient as well as in wild-type mice , and apparently mediated by non canonical Fas action .	The pathogenic role of Fas and FasL in APAP induced ALI is likewise well established, detectable in Fas- or FasL deficient as well as in wild-type mice, and apparently mediated by non canonical Fas action.	2	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas-	Fas-	Fas-	6	7	18	19
The Fas signaling system is composed of the interacting proteins Fas ( CD95 and APO-1 ) and Fas ligand ( FasL , CD95L , APO-1L ) and is proposed to act in the testis as a paracrine signaling mechanism by which FasL expressing Sertoli cells initiate apoptosis of Fas bearing germ cells .	The Fas signaling system is composed of the interacting proteins Fas (CD95/APO-1) and Fas ligand (FasL, CD95L, APO-1L) and is proposed to act in the testis as a paracrine signaling mechanism by which FasL expressing Sertoli cells initiate apoptosis of Fas bearing germ cells.	41	51	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL expressing	fasl	Fas	Fas	fas	41	42	48	49
The group of Martin-Villalba links the activation of Fas by FasL to glioblastoma invasion mediated by PI3K and AKT and regulated by the Src family protein Yes .	The group of Martin-Villalba links the activation of Fas by FasL to glioblastoma invasion mediated by PI3K and AKT and regulated by the Src family protein Yes.	4	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	10	11	8	9
Simultaneously , an antiapoptotic signaling is triggered by CD95L induced CD95 tyrosine nitration .	Simultaneously, an antiapoptotic signaling is triggered by CD95L induced CD95 tyrosine nitration.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	8	9	10	11
Neither CD95L nor CHX alone induced CD95 membrane trafficking and HSC apoptosis .	Neither CD95L nor CHX alone induced CD95 membrane trafficking and HSC apoptosis.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	1	2	6	7
Tumor Necrosis Factor Receptor 1 ( TNFR1 ) , and Fas ( CD95 ) , are activated by their ligands TRAIL , TNF , and FasL , respectively .	Tumor Necrosis Factor Receptor 1 (TNFR1), and Fas (CD95), are activated by their ligands TRAIL, TNF, and FasL, respectively.	6	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	25	26	10	11
FasL positive astrocytes were often situated in close vicinity to cerebral blood vessels in vivo and induced apoptosis of Fas expressing Jurkat cells in vitro .	FasL positive astrocytes were often situated in close vicinity to cerebral blood vessels in vivo and induced apoptosis of Fas expressing Jurkat cells in vitro.	0	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	0	1	19	20
These results overall confirm our reported finding that FasL and antibodies do not stimulate identically the Fas signalling machinery XREF_BIBR , and confirm the requirement of minimal Fas aggregation by a multimeric ligand trigger XREF_BIBR .	These results overall confirm our reported finding that FasL and antibodies do not stimulate identically the Fas signalling machinery XREF_BIBR, and confirm the requirement of minimal Fas aggregation by a multimeric ligand trigger XREF_BIBR.	8	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	8	9	16	17
Usually , the combination of FASLG with Fas death receptor , induces the polymerization of Fas to form death inducing signaling , and is complicated by recruiting the death domain adapter protein FADD , caspase-8 , and caspase-2 [ XREF_BIBR , XREF_BIBR ] .	Usually, the combination of FASLG with Fas death receptor, induces the polymerization of Fas to form death inducing signaling, and is complicated by recruiting the death domain adapter protein FADD, caspase-8, and caspase-2 [XREF_BIBR, XREF_BIBR].	3	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FASLG	FASLG	FASLG	Fas	Fas	Fas	5	6	15	16
Our results suggest , together with previous reports using T cell hybridomas or clones , that apoptosis has occurred by triggering of Fas by FasL expressing neighboring T cells .	Our results suggest, together with previous reports using T cell hybridomas or clones, that apoptosis has occurred by triggering of Fas by FasL expressing neighboring T cells.	18	25	triggering	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	24	25	22	23
TGFbeta1 can also induce apoptosis through the FasL independent activation of the Fas death pathway in human gastric SNU-620 carcinoma cells [ XREF_BIBR ] .	TGFbeta1 can also induce apoptosis through the FasL independent activation of the Fas death pathway in human gastric SNU-620 carcinoma cells [XREF_BIBR].	7	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	12	13
XREF_BIBR , XREF_BIBR Importantly , the ex-vivo use of MegaFasL allows to circumvent any potential in-vivo toxicity issues of Fas agonists in humans , because stem cell transplants would be treated with MegaFasL , then washed to remove MegaFasL before re-infusion into a patient , ensuring the safety of the procedure .	XREF_BIBR, XREF_BIBR Importantly, the ex-vivo use of MegaFasL allows to circumvent any potential in-vivo toxicity issues of Fas agonists in humans, because stem cell transplants would be treated with MegaFasL, then washed to remove MegaFasL before re-infusion into a patient, ensuring the safety of the procedure.	19	45	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	MegaFasL	MegaFasL	MegaFasL	Fas	Fas	Fas	32	33	19	20
Moreover , since FasL upregulates Fas [ XREF_BIBR , XREF_BIBR ] , we propose that the release of the secreted form of the death ligand from effector cells is able to boost the expression of death receptors on bystander cells .	Moreover, since FasL upregulates Fas [XREF_BIBR, XREF_BIBR], we propose that the release of the secreted form of the death ligand from effector cells is able to boost the expression of death receptors on bystander cells.	3	9	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	5	6
Membrane FasL induced Fas clusters were formed in caspase-8- or FADD deficient cells or when a cytoplasmic deletion mutant of Fas was used suggesting that cluster formation is independent of the assembly of the cytoplasmic Fas signaling complex and downstream activated signaling pathways .	Membrane FasL induced Fas clusters were formed in caspase-8- or FADD deficient cells or when a cytoplasmic deletion mutant of Fas was used suggesting that cluster formation is independent of the assembly of the cytoplasmic Fas signaling complex and downstream activated signaling pathways.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	1	2	3	4
Our data suggest that the survival and differentiation of HIV specific CD8 ( + ) T cells may be compromised by CD95 and Fas apoptosis induced by FasL expressing HIV infected cells .	Our data suggest that the survival and differentiation of HIV specific CD8 (+) T cells may be compromised by CD95 and Fas apoptosis induced by FasL expressing HIV infected cells.	21	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	CD95	CD95	CD95	27	28	21	22
In contrast to the conventional paradigm , which holds that Fas dependent apoptosis is initiated by the binding of lymphocyte Fas ligand to target cell Fas , our data suggest that up-regulated RTC Fas binds to Fas ligand on adjacent RTC , which then leads to RTC death by fratricide .	In contrast to the conventional paradigm, which holds that Fas dependent apoptosis is initiated by the binding of lymphocyte Fas ligand to target cell Fas, our data suggest that up-regulated RTC Fas binds to Fas ligand on adjacent RTC, which then leads to RTC death by fratricide.	10	22	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	20	22	10	11
Fas death receptor stimulation by FasL bearing cells is important for the elimination of unwanted or damaged cells , particularly in the lymphoid system .	Fas death receptor stimulation by FasL bearing cells is important for the elimination of unwanted or damaged cells, particularly in the lymphoid system.	0	7	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	5	6	0	1
Collectively our data argue that vorinostat contributes to sorafenib -induced activation of CD95 shortly following drug exposure by elevating ROS levels that inhibit PTPase function and promote CD95 activation whereas at later time points vorinostat promotes CD95 signaling and tumor cell death by increasing FAS-L expression in an NFkappaB -dependent fashion .	Collectively our data argue that vorinostat contributes to sorafenib -induced activation of CD95 shortly following drug exposure by elevating ROS levels that inhibit PTPase function and promote CD95 activation whereas at later time points vorinostat promotes CD95 signaling and tumor cell death by increasing FAS-L expression in an NFkappaB -dependent fashion.	36	46	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FAS-L	FAS-L expression	fas-l	CD95	CD95	cd95	44	45	36	37
First , if FAS is activated by soluble FasL following its shedding from the surface of immune effector cell in the tumor microenvironment .	First, if FAS is activated by soluble FasL following its shedding from the surface of immune effector cell in the tumor microenvironment.	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	FAS	FAS	FAS	8	9	3	4
Tumors may also directly inhibit immune responses by producing immunosuppressive factors such as IL-10 and TGF-beta or by the expression of CD95L ( FasL ) which promotes tumor specific CD95 ( Fas ) + immune cells to undergo apoptosis .	Tumors may also directly inhibit immune responses by producing immunosuppressive factors such as IL-10 and TGF-beta or by the expression of CD95L (FasL) which promotes tumor specific CD95 (Fas) + immune cells to undergo apoptosis.	19	35	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	expression of CD95L	cd95l	CD95	CD95	cd95	21	22	29	30
Altogether , our results highlight the putative role of both membrane bound and soluble FasL in oxLDL induced Fas and FADD dependent apoptosis of T lymphocytes and suggest an involvement of ROS , ERK , and JNK in this process .	Altogether, our results highlight the putative role of both membrane bound and soluble FasL in oxLDL induced Fas and FADD dependent apoptosis of T lymphocytes and suggest an involvement of ROS, ERK, and JNK in this process.	13	27	induced	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	14	15	18	19
Interestingly , the ectopic expression of CD95L by endothelial cells also promotes transmigration of CD95 expressing myeloid cells by tethering cells and slowing cell rolling .	Interestingly, the ectopic expression of CD95L by endothelial cells also promotes transmigration of CD95 expressing myeloid cells by tethering cells and slowing cell rolling.	4	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	expression of CD95L	cd95l	CD95	CD95	cd95	6	7	14	15
Besides membrane FasL , Fas can also be activated by agonistic antibodies or secondarily aggregated soluble FasL .	Besides membrane FasL, Fas can also be activated by agonistic antibodies or secondarily aggregated soluble FasL.	4	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	16	17	4	5
They remain functionally suppressive but are susceptible to apoptosis via the Fas pathway mediated by FASL on bile ducts , and this can be inhibited by exogenous IL-2 .	They remain functionally suppressive but are susceptible to apoptosis via the Fas pathway mediated by FASL on bile ducts, and this can be inhibited by exogenous IL-2.	11	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FASL	FASL	FASL	Fas	Fas	Fas	15	16	11	12
Death Domain Tyrosine Phosphorylation Is Vital to FasL Induced Non Death Signaling of Fas .	Death Domain Tyrosine Phosphorylation Is Vital to FasL Induced Non Death Signaling of Fas.	5	14	Induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	13	14
Fas ligand ( FasL/CD95L/TNFSF6 ) , a member of the tumor necrosis factor family , initiates apoptosis in lymphoid and nonlymphoid tissues by binding to its receptor Fas ( CD95 and TNFRSF6 ) .	Fas ligand (FasL/CD95L/TNFSF6), a member of the tumor necrosis factor family, initiates apoptosis in lymphoid and nonlymphoid tissues by binding to its receptor Fas (CD95 and TNFRSF6).	0	32	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	TNFRSF6	TNFRSF6	TNFRSF6	0	2	31	32
This soluble human FasL efficiently induces apoptosis in some Fas expressing cells .	This soluble human FasL efficiently induces apoptosis in some Fas expressing cells.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	9	10
It has been demonstrated that upregulation of Fas and FasL in breast cancer cells induces T-cell apoptosis in Fas bearing T cells .	It has been demonstrated that upregulation of Fas and FasL in breast cancer cells induces T-cell apoptosis in Fas bearing T cells.	5	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	9	10	18	19
Vitamin D. Considerable verification suggests that pretreatment with 1,25-dihydroxyvitamin D3 repressed apoptosis induced by TRAIL and Fas ligand by up-regulating decoy receptor and death receptor 4 and repressing Fas .	Vitamin D. Considerable verification suggests that pretreatment with 1,25-dihydroxyvitamin D3 repressed apoptosis induced by TRAIL and Fas ligand by up-regulating decoy receptor and death receptor 4 and repressing Fas.	10	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	16	18	28	29
Other studies demonstrated that activation of Fas signaling mediated by the administration of recombinant FasL protein or an anti-Fas agonistic antibody causes acute lung inflammation XREF_BIBR - XREF_BIBR .	Other studies demonstrated that activation of Fas signaling mediated by the administration of recombinant FasL protein or an anti-Fas agonistic antibody causes acute lung inflammation XREF_BIBR - XREF_BIBR.	6	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	14	15	6	7
In contrast , the newly synthesized later wave of FasL mediated extensive Fas dependent bystander killing .	In contrast, the newly synthesized later wave of FasL mediated extensive Fas dependent bystander killing.	7	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	9	10	12	13
It has been shown that downregulation of FAS may protect tumor cells from elimination by antitumor immune responses , whereas up-regulation of FASLG may increase the ability of tumor cells to counterattack the immune system by inducing apoptosis of FAS sensitive lymphocytes .	It has been shown that downregulation of FAS may protect tumor cells from elimination by antitumor immune responses, whereas up-regulation of FASLG may increase the ability of tumor cells to counterattack the immune system by inducing apoptosis of FAS sensitive lymphocytes.	20	41	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FASLG	FASLG	FASLG	FAS	FAS	FAS	22	23	39	40
In contrast to early , soluble FasL induced Fas aggregates , recently named signaling protein oligomeric transduction structures ( SPOTS ) , membrane FasL induced Fas clusters form independently of the intracellular domain of Fas and occur in the absence of FADD or caspase-8 suggesting that the formation of supramolecular FasL-Fas clusters precedes and is independent of recruitment and activation of downstream signaling components .	In contrast to early, soluble FasL induced Fas aggregates, recently named signaling protein oligomeric transduction structures (SPOTS), membrane FasL induced Fas clusters form independently of the intracellular domain of Fas and occur in the absence of FADD or caspase-8 suggesting that the formation of supramolecular FasL-Fas clusters precedes and is independent of recruitment and activation of downstream signaling components.	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	6	7	8	9
Membrane bound Fas ligand ( FasL , Apo-1L , CD95L ) induces rapid apoptosis of Fas ( CD95 )-sensitive cells on interaction with Fas , and is an important effector molecule of cytolytic T lymphocytes ( CTLs ) .	Membrane bound Fas ligand (FasL, Apo-1L, CD95L) induces rapid apoptosis of Fas (CD95)-sensitive cells on interaction with Fas, and is an important effector molecule of cytolytic T lymphocytes (CTLs).	3	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	Fas	Fas	Fas	9	10	15	16
CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase ( PI3K ) and metalloproteinase-9 ( MMP-9 ) via recruitment and activation of Syk kinase , ultimately leading to increased migration .	CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase (PI3K) and metalloproteinase-9 (MMP-9) via recruitment and activation of Syk kinase, ultimately leading to increased migration.	0	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	0	1	3	4
Binding of FasL induces the oligomerization of Fas , and Fas recruits its downstream cytosolic adaptor protein Fadd , which in turn recruits procaspase-8 .	Binding of FasL induces the oligomerization of Fas, and Fas recruits its downstream cytosolic adaptor protein Fadd, which in turn recruits procaspase-8.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	2	3	7	8
Previous studies have reported that immune cells in malignancies have aberrant Fas and FasL genes , which induced downregulated Fas and upregulated FasL expressions .	Previous studies have reported that immune cells in malignancies have aberrant Fas and FasL genes, which induced downregulated Fas and upregulated FasL expressions.	13	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	13	14	19	20
This plasmin generated soluble FasL activates Fas and is a potent inducer of apoptosis in EC .	This plasmin generated soluble FasL activates Fas and is a potent inducer of apoptosis in EC.	2	7	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	4	5	6	7
FasL molecule expressed on activated T cells induces apoptosis in Fas expressing cells .	FasL molecule expressed on activated T cells induces apoptosis in Fas expressing cells.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	0	1	10	11
Fas can be activated by FasL , and we found that the expression of FasL and TNF-alpha increased in the depigmented compared to that in the normally pigmented epidermis XREF_BIBR .	Fas can be activated by FasL, and we found that the expression of FasL and TNF-alpha increased in the depigmented compared to that in the normally pigmented epidermis XREF_BIBR.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	5	6	0	1
Fas Ligand ( FasL ) can induce apoptosis of Fas bearing cells .	Fas Ligand (FasL) can induce apoptosis of Fas bearing cells.	0	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas Ligand	Fas Ligand	Fas Ligand	Fas	Fas	Fas	0	2	9	10
Fas , a member of the TNF receptor superfamily , plays a vital role in regulating apoptosis in many cell types and is typically stimulated by FasL or agonistic Fas mAb XREF_BIBR , XREF_BIBR .	Fas, a member of the TNF receptor superfamily, plays a vital role in regulating apoptosis in many cell types and is typically stimulated by FasL or agonistic Fas mAb XREF_BIBR, XREF_BIBR.	0	31	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	26	27	0	1
By immunoprecipitation , CD95L was physically bound to CD95 , suggesting that AICD and doxorubicin induced apoptosis involve CD95L mediated CD95 aggregation , thereby triggering the CD95 death pathway .	By immunoprecipitation, CD95L was physically bound to CD95, suggesting that AICD and doxorubicin induced apoptosis involve CD95L mediated CD95 aggregation, thereby triggering the CD95 death pathway.	17	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	18	19	20	21
Soluble FasL does not cause Fas aggregation and may block binding of membrane associated FasL with death inducing capacity .	Soluble FasL does not cause Fas aggregation and may block binding of membrane associated FasL with death inducing capacity.	0	9	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	1	2	5	6
The T cells were examined for Fas ligand mediated cytotoxicity in a 51Cr release assay using Fas expressing normal T cells as target cells .	The T cells were examined for Fas ligand mediated cytotoxicity in a 51Cr release assay using Fas expressing normal T cells as target cells.	6	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	6	8	16	17
The present results suggested that the sFasL released by cumulus cells activates Fas on the oocyte by activating NOX and increasing ROS .	The present results suggested that the sFasL released by cumulus cells activates Fas on the oocyte by activating NOX and increasing ROS.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	6	7	12	13
Thus , we hypothesize that sFasL released by cumulus cells activates Fas on the oocyte by activating NOX and increasing ROS .	Thus, we hypothesize that sFasL released by cumulus cells activates Fas on the oocyte by activating NOX and increasing ROS.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	5	6	11	12
Crosslinked Soluble FasL , which also occurs physiologically , behaves similarly to the CH11 antibody , and may therefore be more likely to initiate non apoptotic Fas signaling due to less RIP1 in the receptor complex .	Crosslinked Soluble FasL, which also occurs physiologically, behaves similarly to the CH11 antibody, and may therefore be more likely to initiate non apoptotic Fas signaling due to less RIP1 in the receptor complex.	0	27	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	2	3	26	27
In these cases , FasL attacks activated Fas expressing immune cells , and is therefore crucial for the immune privilege of the tissues expressing it .	In these cases, FasL attacks activated Fas expressing immune cells, and is therefore crucial for the immune privilege of the tissues expressing it.	4	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	4	5	7	8
It is currently also unclear whether membrane FasL , cross linked sFasL and anti-Fas antibodies induce Fas clustering in a similar fashion .	It is currently also unclear whether membrane FasL, cross linked sFasL and anti-Fas antibodies induce Fas clustering in a similar fashion.	6	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	16	17
These findings indicate that the FasL and Fas signal should be triggered by the induction of expression of FasL rather than Fas in mice infected with influenza A viruses , and this induction was regulated by type-I IFN mediated signal .	These findings indicate that the FasL and Fas signal should be triggered by the induction of expression of FasL rather than Fas in mice infected with influenza A viruses, and this induction was regulated by type-I IFN mediated signal.	5	19	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	expression of FasL	fasl	Fas	Fas	fas	18	19	7	8
Their progressive disappearance may be due to an indirect mechanism , which involves FASL mediated killing of FAS + cells that deliver critical survival signals to T lymphocytes .	Their progressive disappearance may be due to an indirect mechanism, which involves FASL mediated killing of FAS + cells that deliver critical survival signals to T lymphocytes.	12	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FASL	FASL	FASL	FAS	FAS	FAS	13	14	17	18
Here we show that in Jurkat T lymphocytes , RIP1 is also necessary for the most efficient activation of downstream caspases by Fas when treated with membrane bound Fas Ligand ( memFasL ) , but not with agonistic antibodies or crosslinked soluble Fas Ligand .	Here we show that in Jurkat T lymphocytes, RIP1 is also necessary for the most efficient activation of downstream caspases by Fas when treated with membrane bound Fas Ligand (memFasL), but not with agonistic antibodies or crosslinked soluble Fas Ligand.	20	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Fas Ligand	Fas Ligand	Fas Ligand	Fas	Fas	Fas	28	30	22	23
FasL bearing vesicles induce apoptosis of Fas expressing cancer cells at the same level as observed by treatment with monoclonal anti-Fas antibody .	FasL bearing vesicles induce apoptosis of Fas expressing cancer cells at the same level as observed by treatment with monoclonal anti-Fas antibody.	0	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	0	1	6	7
When the cell surface molecule Fas is triggered by its agonist Fas ligand the result is apoptosis of these cells and tissue destruction .	When the cell surface molecule Fas is triggered by its agonist Fas ligand the result is apoptosis of these cells and tissue destruction.	1	13	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	11	13	5	6
Our data suggest that the impairment of the Na + -K + -ATPase activity during apoptosis is linked to perturbations in cell Ca 2+ homeostasis that modulate apoptosis induced by the activation of Fas by FasL .	Our data suggest that the impairment of the Na + -K + -ATPase activity during apoptosis is linked to perturbations in cell Ca 2+ homeostasis that modulate apoptosis induced by the activation of Fas by FasL.	28	36	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	35	36	33	34
Using ST6Gal-I knockdown and forced overexpression colon carcinoma cell models , we find that alpha2-6 sialylation of Fas prevents apoptosis stimulated by FasL as well as the Fas activating antibody , CH11 , as evidenced by decreased activation of caspases 8 and 3 .	Using ST6Gal-I knockdown and forced overexpression colon carcinoma cell models, we find that alpha2-6 sialylation of Fas prevents apoptosis stimulated by FasL as well as the Fas activating antibody, CH11, as evidenced by decreased activation of caspases 8 and 3.	20	29	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	22	23	27	28
Moreover , the expression of FasL on B cells of individuals infected by human immunodeficiency virus ( HIV ) and the induction of Epstein-Barr virus of FasL expression by B cells markedly increases the sensitivity of Th cells to Fas mediated T cell apoptosis .	Moreover, the expression of FasL on B cells of individuals infected by human immunodeficiency virus (HIV) and the induction of Epstein-Barr virus of FasL expression by B cells markedly increases the sensitivity of Th cells to Fas mediated T cell apoptosis.	3	40	increases	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	FasL	expression of FasL	fasl	Fas	Fas	fas	5	6	39	40
The results indicated that sFasL released by cumulus cells activated Fas on the oocyte by increasing reactive oxygen species via activating NADPH oxidase .	The results indicated that sFasL released by cumulus cells activated Fas on the oocyte by increasing reactive oxygen species via activating NADPH oxidase.	4	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	4	5	10	11
Caspase-8 can be activated by ligation of cell surface death receptors and their ligands , such as TNF , TNF related apoptosis inducing ligand ( TRAIL ) and FAS ( TNF receptor superfamily , member 6 ) ligand ( CD95L ) .	Caspase-8 can be activated by ligation of cell surface death receptors and their ligands, such as TNF, TNF related apoptosis inducing ligand (TRAIL) and FAS (TNF receptor superfamily, member 6) ligand (CD95L).	21	40	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	FAS	FAS	FAS	39	40	28	29
Fas ( CD95 , APO-1 ) is a member of the TNF receptor family , and engagement of Fas by its ligand , Fas ligand ( FasL ) , can induce apoptotic death of Fas expressing cells .	Fas (CD95, APO-1) is a member of the TNF receptor family, and engagement of Fas by its ligand, Fas ligand (FasL), can induce apoptotic death of Fas expressing cells.	24	36	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	26	27	34	35
IFNs induce apoptosis indirectly by upregulating the expression of death ligands , such as TRAIL and Fas ligand , which activate the extrinsic Fas associated death domain ( FADD )/Caspase-8 signaling pathway .	IFNs induce apoptosis indirectly by upregulating the expression of death ligands, such as TRAIL and Fas ligand, which activate the extrinsic Fas associated death domain (FADD)/Caspase-8 signaling pathway.	14	24	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	16	18	23	24
Many publications have highlighted the role of the Fas and FasL system in chemotherapy induced apoptosis of tumors by up-regulating Fas and APO -1 or FasL [ XREF_BIBR ] .	Many publications have highlighted the role of the Fas and FasL system in chemotherapy induced apoptosis of tumors by up-regulating Fas and APO -1 or FasL [XREF_BIBR].	8	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	10	11	20	21
Fas ( CD95 ) is a death-domain-containing receptor , and can be activated by its corresponding ligand , FasL ( CD178 ) or agonistic antibodies .	Fas (CD95) is a death-domain-containing receptor, and can be activated by its corresponding ligand, FasL (CD178) or agonistic antibodies.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	18	19	0	1
8 Specific viral infections have been shown to increase CD95 ( Fas ) and/or Fas Ligand expression and increase sensitivity to Fas and Fas Ligand dependent apoptosis .	8 Specific viral infections have been shown to increase CD95 (Fas) and/or Fas Ligand expression and increase sensitivity to Fas and Fas Ligand dependent apoptosis.	8	17	increase	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Fas Ligand	Fas Ligand expression	fas ligand	CD95	CD95	cd95	14	16	9	10
Taking into account the primary , proapoptotic function of Fas and FasL signalling , its possible role in IBD initially appeared to be similar to TNF and TNFR1 signalling : intestinal epithelial cells expressing Fas targeted by FasL ( + ) lymphocytes undergo apoptosis which may lead to the increased permeability of intestinal epithelium [ XREF_BIBR ] .	Taking into account the primary, proapoptotic function of Fas and FasL signalling, its possible role in IBD initially appeared to be similar to TNF and TNFR1 signalling : intestinal epithelial cells expressing Fas targeted by FasL (+) lymphocytes undergo apoptosis which may lead to the increased permeability of intestinal epithelium [XREF_BIBR].	33	38	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	37	38	34	35
In particular , some studies reported that Fas clustering induced by cross linked sFasL or anti-Fas antibodies is a delayed event occurring in an actin- and caspase dependent , but lipid raft independent manner , whereas other reports found rapid Fas capping under involvement of lipid rafts .	In particular, some studies reported that Fas clustering induced by cross linked sFasL or anti-Fas antibodies is a delayed event occurring in an actin- and caspase dependent, but lipid raft independent manner, whereas other reports found rapid Fas capping under involvement of lipid rafts.	7	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	13	14	7	8
Significantly higher levels of soluble Fas and FasL were observed in ARDS patients with worse clinical outcomes and in those who died , suggesting that sFasL and sFas released in the airspaces of patients with acute lung injury leads to activation of the Fas and FasL pathway , which contributes to the severe epithelial damage that occurs in ARDS .	Significantly higher levels of soluble Fas and FasL were observed in ARDS patients with worse clinical outcomes and in those who died, suggesting that sFasL and sFas released in the airspaces of patients with acute lung injury leads to activation of the Fas and FasL pathway, which contributes to the severe epithelial damage that occurs in ARDS.	25	46	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	25	26	43	44
For instance , FasL expressed by non lymphoid cells in the eye was shown to induce apoptosis of Fas + lymphoid cells entering in response to viral infection , thus protecting the eye from inflammatory damage .	For instance, FasL expressed by non lymphoid cells in the eye was shown to induce apoptosis of Fas + lymphoid cells entering in response to viral infection, thus protecting the eye from inflammatory damage.	3	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL expressed	fasl	Fas	Fas	fas	3	4	18	19
Fas ligand ( FasL ) induces apoptosis in Fas bearing target cells , such as leukocytes , and up-regulation of FasL expression on the endothelium may contribute to anti-inflammatory reactions that attenuate leukocyte extravasation during inflammation .	Fas ligand (FasL) induces apoptosis in Fas bearing target cells, such as leukocytes, and up-regulation of FasL expression on the endothelium may contribute to anti-inflammatory reactions that attenuate leukocyte extravasation during inflammation.	1	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	8	9
Activated cytotoxic T lymphocytes ( CTLs ) induce and express high levels of FasL , but the effects of Fas activation initiated by FasL in CTLs on apoptosis resistant tumor cells remain largely unclear .	Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis resistant tumor cells remain largely unclear.	19	24	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	23	24	19	20
There is further evidence that membrane FasL , soluble FasL , and anti-Fas antibodies do not use exactly the same mechanisms to activate Fas .	There is further evidence that membrane FasL, soluble FasL, and anti-Fas antibodies do not use exactly the same mechanisms to activate Fas.	5	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	6	7	23	24
The results of the present study demonstrated that there was significant overexpression of Fas and FasL in PBMCs from patients with sepsis compared with healthy controls ( XREF_FIG ) .	The results of the present study demonstrated that there was significant overexpression of Fas and FasL in PBMCs from patients with sepsis compared with healthy controls (XREF_FIG).	9	16	was significant overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	FasL	overexpression of Fas and FasL	fasl	Fas	Fas	fas	15	16	13	14
Induction of apoptosis by Fas ligand ( FasL ) of Fas containing cells is a known mechanism involved in the eradication of inappropriate cells during normal development .	Induction of apoptosis by Fas ligand (FasL) of Fas containing cells is a known mechanism involved in the eradication of inappropriate cells during normal development.	0	11	Induction	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	4	6	10	11
Since BMMSCs express FasL and activated T cells express elevated levels of Fas , we hypothesized that FasL mediated Fas signaling might play a critical role in BMMSC based immunomodulation .	Since BMMSCs express FasL and activated T cells express elevated levels of Fas, we hypothesized that FasL mediated Fas signaling might play a critical role in BMMSC based immunomodulation.	17	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	17	18	19	20
In mice , antigen stimulated CD8 + T cells secrete exosomes that enhance the metastasis of melanoma cells to the lung via Fas signaling triggered by the exosome protein FasL 20 .	In mice, antigen stimulated CD8 + T cells secrete exosomes that enhance the metastasis of melanoma cells to the lung via Fas signaling triggered by the exosome protein FasL 20.	22	30	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	29	30	22	23
In both BMSCs injection and L-A injection treating group , FASL mediated FAS death pathway had been activated and thus may protect the bone metabolism through regulating the immune function and maintain the balance of osteoblast and osteoclast XREF_BIBR XREF_BIBR XREF_BIBR .	In both BMSCs injection and L-A injection treating group, FASL mediated FAS death pathway had been activated and thus may protect the bone metabolism through regulating the immune function and maintain the balance of osteoblast and osteoclast XREF_BIBR XREF_BIBR XREF_BIBR.	10	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	FASL	FASL	FASL	FAS	FAS	FAS	10	11	12	13
In fact , some studies have found that Fas ligand independent pathways could activate the Fas death pathway by recruiting the adaptor protein FADD or depletion of membrane cholesterol .	In fact, some studies have found that Fas ligand independent pathways could activate the Fas death pathway by recruiting the adaptor protein FADD or depletion of membrane cholesterol.	8	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	8	10	15	16
Activation of Fas by FasL or certain antibodies initiates activation induced cell death ( AICD ) , involving the formation of the death inducing signaling complex ( DISC ) and downstream activation of apoptotic caspases .	Activation of Fas by FasL or certain antibodies initiates activation induced cell death (AICD), involving the formation of the death inducing signaling complex (DISC) and downstream activation of apoptotic caspases.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	4	5	2	3
FasL is predominantly expressed on activated T and NK cells , and mediates Fas divided by target cell lysis by these effector cells .	FasL is predominantly expressed on activated T and NK cells, and mediates Fas divided by target cell lysis by these effector cells.	0	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL is predominantly expressed	fasl	Fas	Fas	fas	0	1	13	14
This suggested that endogenous FasL was activating Fas in these neurons , thereby triggering the cell death process .	This suggested that endogenous FasL was activating Fas in these neurons, thereby triggering the cell death process.	3	10	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	4	5	7	8
Lipid rafts and the cytoplasmic domain of Fas have a major role in soluble FasL induced SPOTS formation , but are dispensable for membrane FasL induced Fas cluster formation .	Lipid rafts and the cytoplasmic domain of Fas have a major role in soluble FasL induced SPOTS formation, but are dispensable for membrane FasL induced Fas cluster formation.	23	28	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	24	25	26	27
Furthermore , morphine enhanced the mRNA expression of Fas , FasL and TRAIL and promoted Fas mediated AICD of CD4 ( + ) T cells .	Furthermore, morphine enhanced the mRNA expression of Fas, FasL and TRAIL and promoted Fas mediated AICD of CD4 (+) T cells.	2	17	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	morphine enhanced the mRNA expression of Fas, FasL	fasl	Fas	Fas	fas	10	11	15	16
In the death receptor pathway , Fas-Fas ligand ( FasL ) interaction can activate Fas associated death domain ( FADD ) and FADD may induce pro caspase 8 .	In the death receptor pathway, Fas-Fas ligand (FasL) interaction can activate Fas associated death domain (FADD) and FADD may induce pro caspase 8.	7	15	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	9	10	14	15
The down-regulation of FAS may protect tumor cells from elimination by antitumor immune responses , whereas up-regulation of FASL may increase the ability of tumor cells to counterattack the immune system by inducing apoptosis of FAS sensitive lymphocytes [ XREF_BIBR - XREF_BIBR ] .	The down-regulation of FAS may protect tumor cells from elimination by antitumor immune responses, whereas up-regulation of FASL may increase the ability of tumor cells to counterattack the immune system by inducing apoptosis of FAS sensitive lymphocytes [XREF_BIBR - XREF_BIBR].	16	37	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FASL	FASL	FASL	FAS	FAS	FAS	18	19	35	36
Similarly , Fas-FasL signaling may be studied using Fas lpr mice , which lack a functional Fas receptor and thus can not be activated by FasL XREF_BIBR .	Similarly, Fas-FasL signaling may be studied using Fas lpr mice, which lack a functional Fas receptor and thus can not be activated by FasL XREF_BIBR.	8	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	25	26	8	9
In our study , statin-Dex carried higher level of FasL compared with control-Dex and statin-Dex treatment increased the number of Fas + cells on lymph node MNC .	In our study, statin-Dex carried higher level of FasL compared with control-Dex and statin-Dex treatment increased the number of Fas + cells on lymph node MNC.	7	26	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	level of FasL	fasl	Fas	Fas	fas	9	10	20	21
The core protein induces apoptosis in a target T cell expressing Fas , which is mediated by FasL that is upregulated in hepatoblastoma cell line [ XREF_BIBR ] .	The core protein induces apoptosis in a target T cell expressing Fas, which is mediated by FasL that is upregulated in hepatoblastoma cell line [XREF_BIBR].	10	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	17	18	11	12
It is possible that the single amino acid mutant form of FasL in gld mice retains a limited ability to bind to and trigger Fas mediated apoptosis but can not activate Fas signaling robustly after toxicant induced Sertoli cell injury .	It is possible that the single amino acid mutant form of FasL in gld mice retains a limited ability to bind to and trigger Fas mediated apoptosis but can not activate Fas signaling robustly after toxicant induced Sertoli cell injury.	9	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	11	12	31	32
After transfection of various forms of Fas into Fas deficient Jurkat cells , FasL induced robust apoptosis of cells expressing WT Fas in a dose dependent manner , while cells harboring the TM trimer defective mutants ( C178R , L180F , P183L , P183A , and P185A ) were significantly resistant to FasL induced apoptosis ( XREF_FIG ) .	After transfection of various forms of Fas into Fas deficient Jurkat cells, FasL induced robust apoptosis of cells expressing WT Fas in a dose dependent manner, while cells harboring the TM trimer defective mutants (C178R, L180F, P183L, P183A, and P185A) were significantly resistant to FasL induced apoptosis (XREF_FIG).	13	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	13	14	21	22
FasL expressing cells may contribute to immune privilege by inducing apoptosis of Fas bearing lymphocytes .	FasL expressing cells may contribute to immune privilege by inducing apoptosis of Fas bearing lymphocytes.	0	14	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	0	1	12	13
Further studies found that soluble Fas ligand ( sFasL ) secreted by cumulus cells could activate Fas on the oocyte by increasing reactive oxygen species ( ROS ) and glucose metabolism in cumulus cells prevented oocyte aging by producing pyruvate and NADPH through glycolysis and pentose phosphate pathway ( PPP ) [ XREF_BIBR - XREF_BIBR ] .	Further studies found that soluble Fas ligand (sFasL) secreted by cumulus cells could activate Fas on the oocyte by increasing reactive oxygen species (ROS) and glucose metabolism in cumulus cells prevented oocyte aging by producing pyruvate and NADPH through glycolysis and pentose phosphate pathway (PPP) [XREF_BIBR - XREF_BIBR].	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	8	9	16	17
These findings revealed the precise function of Fas and FasL mediated as well as Fas and FasL independent AICD in the regulation of helper T cell responses .	These findings revealed the precise function of Fas and FasL mediated as well as Fas and FasL independent AICD in the regulation of helper T cell responses.	5	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	9	10	14	15
Together , these data suggest that the extracellular domains of Fas and FasL alone are sufficient to drive membrane FasL induced formation of supramolecular Fas-FasL complexes , whereas soluble FasL induced Fas aggregation is dependent on lipid rafts and mechanisms associated with the intracellular domain of Fas .	Together, these data suggest that the extracellular domains of Fas and FasL alone are sufficient to drive membrane FasL induced formation of supramolecular Fas-FasL complexes, whereas soluble FasL induced Fas aggregation is dependent on lipid rafts and mechanisms associated with the intracellular domain of Fas.	28	32	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	29	30	31	32
Fas ligand ( FasL ) mediates apoptosis of susceptible Fas expressing lymphocytes , and may contribute to the maintenance of peripheral tolerance .	Fas ligand (FasL) mediates apoptosis of susceptible Fas expressing lymphocytes, and may contribute to the maintenance of peripheral tolerance.	1	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	9	10
TNF receptor family genes Tnfrs5 ( Cd40 ) , Tnfrsf6 ( Fas ) and Tnfrsf11b and 12awere upregulated by 2.3 to 7.7 fold , and TNF ligand family genes Tnfsf5 ( Cd40L ) , Tnfsf6 ( FasL ) and Tnfsf9 were upregulated by 2.9-8.4 fold in the retina from poor glycemic control group compared to the retina obtained from age matched normal rats .	TNF receptor family genes Tnfrs5 (Cd40), Tnfrsf6 (Fas) and Tnfrsf11b and 12awere upregulated by 2.3 to 7.7 fold, and TNF ligand family genes Tnfsf5 (Cd40L), Tnfsf6 (FasL) and Tnfsf9 were upregulated by 2.9-8.4 fold in the retina from poor glycemic control group compared to the retina obtained from age matched normal rats.	4	41	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tnfsf6	Tnfsf6	Tnfsf6	Tnfrsf6	Tnfrsf6	Tnfrsf6	34	35	9	10
In particular , stimulation of Fas by FasL induces receptor trimerization at the surface membrane , which allows the recruitment of the adapter protein FADD which , with the initiator procaspase-8 , forms the death inducing signaling complex .	In particular, stimulation of Fas by FasL induces receptor trimerization at the surface membrane, which allows the recruitment of the adapter protein FADD which, with the initiator procaspase-8, forms the death inducing signaling complex.	3	8	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	5	6
XREF_BIBR , XREF_BIBR , XREF_BIBR Although Fas signaling is mainly associated with this apoptotic cell death pathway , it has also been reported that , when FasL triggers Fas receptors in cells that inhibit or lack caspase 8 , an alternative death pathway is activated that is mediated by receptor interacting protein ( RIP ) kinase , leading to necrotic cell death .	XREF_BIBR, XREF_BIBR, XREF_BIBR Although Fas signaling is mainly associated with this apoptotic cell death pathway, it has also been reported that, when FasL triggers Fas receptors in cells that inhibit or lack caspase 8, an alternative death pathway is activated that is mediated by receptor interacting protein (RIP) kinase, leading to necrotic cell death.	26	29	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	26	27	28	29
Currently , both pro apoptotic and pro survival roles of Fas are bases of therapeutics that aim either to activate Fas signaling ( APO010 agent targeting extracellular domain of Fas ) [ XREF_BIBR ] or to inhibit Fas signaling triggered by FasL ( APG101 targeting FasL ) [ XREF_BIBR ] .	Currently, both pro apoptotic and pro survival roles of Fas are bases of therapeutics that aim either to activate Fas signaling (APO010 agent targeting extracellular domain of Fas) [XREF_BIBR] or to inhibit Fas signaling triggered by FasL (APG101 targeting FasL) [XREF_BIBR].	37	42	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	41	42	37	38
Combination of CD95L in the form of a trimer with CD95 would cause trimerization of CD95 , and subsequently the CD95 complex would enter cells via internalization , where it formed a death inducing signaling complex or DISC , causing programmed cell death or apoptosis .	Combination of CD95L in the form of a trimer with CD95 would cause trimerization of CD95, and subsequently the CD95 complex would enter cells via internalization, where it formed a death inducing signaling complex or DISC, causing programmed cell death or apoptosis.	0	16	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	2	3	15	16
Studies with perforin deficient mice have demonstrated that two independent mechanisms account for T cell mediated cytotoxicity : A main pathway is mediated by the secretion of the pore forming protein perforin by the cytotoxic T cell , whereas an alternative nonsecretory pathway relies on the interaction of the Fas ligand that is upregulated during T cell activation with the apoptosis inducing Fas molecule on the target cell .	Studies with perforin deficient mice have demonstrated that two independent mechanisms account for T cell mediated cytotoxicity : A main pathway is mediated by the secretion of the pore forming protein perforin by the cytotoxic T cell, whereas an alternative nonsecretory pathway relies on the interaction of the Fas ligand that is upregulated during T cell activation with the apoptosis inducing Fas molecule on the target cell.	49	63	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	49	51	62	63
These findings confirm the results of Lee and colleagues and demonstrate that CD95L induces the CD95 internalization .	These findings confirm the results of Lee and colleagues and demonstrate that CD95L induces the CD95 internalization.	12	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	12	13	15	16
Four of the six death receptors ( DR1-6 ) - TNFR-1 ( DR1 ) , the Fas ligand activated Fas ( CD95 and DR2 ) and the two TNF related apoptosis inducing ligand ( TRAIL )-activated DR4 and DR5 XREF_BIBR , XREF_BIBR - have been studied extensively .	Four of the six death receptors (DR1-6) - TNFR-1 (DR1), the Fas ligand activated Fas (CD95 and DR2) and the two TNF related apoptosis inducing ligand (TRAIL)-activated DR4 and DR5 XREF_BIBR, XREF_BIBR - have been studied extensively.	16	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	16	18	19	20
The fact that the caspase inhibitor z-VAD-fmk does not interfere with the formation of FasL-Fas clusters in our experiments argues against a crucial role of caspase-8 in FasL induced Fas aggregation .	The fact that the caspase inhibitor z-VAD-fmk does not interfere with the formation of FasL-Fas clusters in our experiments argues against a crucial role of caspase-8 in FasL induced Fas aggregation.	19	30	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	27	28	29	30
Together , these data suggested that the in vivo growth of FasL bearing tumor cells can induce significant apoptosis and toxicity in Fas ( + ) tissues of the host .	Together, these data suggested that the in vivo growth of FasL bearing tumor cells can induce significant apoptosis and toxicity in Fas (+) tissues of the host.	11	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	11	12	22	23
FasL activates Fas , and TRAIL activates DR4 ( TRAILR1 ) and DR5 ( TRAILR2 ) XREF_BIBR .	FasL activates Fas, and TRAIL activates DR4 (TRAILR1) and DR5 (TRAILR2) XREF_BIBR.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	0	1	2	3
Thus , the expression of CD95L by trophoblast may induce apoptosis of CD95 expressing activated cytotoxic maternal T cells at the maternal-fetal interface .	Thus, the expression of CD95L by trophoblast may induce apoptosis of CD95 expressing activated cytotoxic maternal T cells at the maternal-fetal interface.	3	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95L	expression of CD95L	cd95l	CD95	CD95	cd95	5	6	12	13
In contrast , when FasL is used to trigger the Fas pathway , wild-type Fas and the deletion mutant are similarly sensitive , whereas the chimera is 100-fold less susceptible to ligand mediated killing than Fas .	In contrast, when FasL is used to trigger the Fas pathway, wild-type Fas and the deletion mutant are similarly sensitive, whereas the chimera is 100-fold less susceptible to ligand mediated killing than Fas.	4	11	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	4	5	10	11
The requirement of EGFR mediated CD95 tyrosine phosphorylation for hyperosmotic and CD95L induced CD95 membrane targeting and DISC formation was also shown in CD95 mutagenesis experiments .	The requirement of EGFR mediated CD95 tyrosine phosphorylation for hyperosmotic and CD95L induced CD95 membrane targeting and DISC formation was also shown in CD95 mutagenesis experiments.	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	11	12	13	14
FasL expressed on ocular tissues induces apoptosis in Fas + lymphoid cells that invade the eye in response to viral infection or corneal grafting .	FasL expressed on ocular tissues induces apoptosis in Fas + lymphoid cells that invade the eye in response to viral infection or corneal grafting.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL expressed	fasl	Fas	Fas	fas	0	1	8	9
Membrane bound FasL induces powerful Fas mediated signals because it possesses both Fas focusing and signal transducing functions .	Membrane bound FasL induces powerful Fas mediated signals because it possesses both Fas focusing and signal transducing functions.	2	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	2	3	5	6
A similar argumentation may also explain the differential relevance of lipid rafts in membrane FasL induced Fas clustering and soluble FasL induced SPOTS formation .	A similar argumentation may also explain the differential relevance of lipid rafts in membrane FasL induced Fas clustering and soluble FasL induced SPOTS formation.	11	17	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	14	15	16	17
Contrary to previous experience XREF_BIBR XREF_BIBR XREF_BIBR , we found that blocking sFasL in plasma inhibited Fas mediated apoptosis in healthy donor memory B-cells exposed to cirrhotic plasma suggesting that sFasL can indeed activate Fas in human B-cells .	Contrary to previous experience XREF_BIBR XREF_BIBR XREF_BIBR, we found that blocking sFasL in plasma inhibited Fas mediated apoptosis in healthy donor memory B-cells exposed to cirrhotic plasma suggesting that sFasL can indeed activate Fas in human B-cells.	30	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	30	31	34	35
The expression of Fas-L on the plasma membrane of numerous tumor cells allow them , in vitro , to kill Fas expressing immune cells .	The expression of Fas-L on the plasma membrane of numerous tumor cells allow them, in vitro, to kill Fas expressing immune cells.	1	21	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas-L	expression of Fas-L	fas-l	Fas	Fas	fas	3	4	20	21
In the presence of neurotrophic factors , exogenous Fas activators such as soluble FasL or anti-Fas antibodies triggered PCD of 40-50 % of purified motoneurons over the following 3-5 d ; this treatment led to activation of caspase-3 , and was blocked by IETD .	In the presence of neurotrophic factors, exogenous Fas activators such as soluble FasL or anti-Fas antibodies triggered PCD of 40-50% of purified motoneurons over the following 3-5 d; this treatment led to activation of caspase-3, and was blocked by IETD.	8	16	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	13	14	8	9
CD95 can be activated by its natural ligand CD95L or agonistic antibodies , such as anti-APO-1 [ XREF_BIBR ] .	CD95 can be activated by its natural ligand CD95L or agonistic antibodies, such as anti-APO-1 [XREF_BIBR].	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	8	9	0	1
FasL knockout ( gld and gld ) mice , Fas knockout ( lpr and lpr ) mice , and mice treated with neutralizing FasL antibody were protected against liver injury induced by a hepatotoxic dose ( 15mg/kg ) of Con A.	FasL knockout (gld and gld) mice, Fas knockout (lpr and lpr) mice, and mice treated with neutralizing FasL antibody were protected against liver injury induced by a hepatotoxic dose (15mg/kg) of Con A.	9	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	23	24	9	10
Potential mechanisms include : ( i ) contact independent inhibition of CD4+ T-cell proliferation [ XREF_BIBR ] via a TGFbeta mediated inhibition of dendritic cells [ XREF_BIBR ] , ( ii ) local immunosuppressive cell-cell paracrine factors , i.e. Serpin-6 ( serine protease inhibitor 6 )-mediated resistance of mESC and EBs to CTL mediated lysis [ XREF_BIBR ] and ( iii ) tolerance induction via Fas ligand activation of CD95 and inducted apoptosis in recipient T cells ( lack of ESC engraftment in Fas deficient mice ) [ XREF_BIBR ] .	Potential mechanisms include : (i) contact independent inhibition of CD4+ T-cell proliferation [XREF_BIBR] via a TGFbeta mediated inhibition of dendritic cells [XREF_BIBR], (ii) local immunosuppressive cell-cell paracrine factors, i.e. Serpin-6 (serine protease inhibitor 6)-mediated resistance of mESC and EBs to CTL mediated lysis [XREF_BIBR] and (iii) tolerance induction via Fas ligand activation of CD95 and inducted apoptosis in recipient T cells (lack of ESC engraftment in Fas deficient mice) [XREF_BIBR].	65	70	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	CD95	CD95	CD95	65	67	69	70
The Fas death pathway , mediated by FasL or TGFbeta , is one of two apoptotic pathways .	The Fas death pathway, mediated by FasL or TGFbeta, is one of two apoptotic pathways.	1	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	1	2
HeLa cells and CD95 depleted HeLa cells were both treated with CD95L : in the membrane fractions the phosphorylation at T273 of procaspase-8 and p43/41 was weak without CD95L stimulation , but 1 h later a strong phospho-signal intensity was visible , which was clearly reduced at 2 h of stimulation , likely due to further procaspase-8 processing ( XREF_FIG ) .	HeLa cells and CD95 depleted HeLa cells were both treated with CD95L : in the membrane fractions the phosphorylation at T273 of procaspase-8 and p43/41 was weak without CD95L stimulation, but 1 h later a strong phospho-signal intensity was visible, which was clearly reduced at 2 h of stimulation, likely due to further procaspase-8 processing (XREF_FIG).	1	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	11	12	3	4
The extrinsic pathway involves activation of FAS by FASL and culminates with Caspase 8 and subsequent Caspase 3 activation .	The extrinsic pathway involves activation of FAS by FASL and culminates with Caspase 8 and subsequent Caspase 3 activation.	3	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FASL	FASL	FASL	FAS	FAS	FAS	8	9	6	7
We next exposed cultured pancreatic INS-1 beta-cells to Il-beta , FasL and TNF-alpha and found that only FasL stimulated the release of TNFR-1 , TRAILR-2 and Fas from the cells ( XREF_FIG ) .	We next exposed cultured pancreatic INS-1 beta-cells to Il-beta, FasL and TNF-alpha and found that only FasL stimulated the release of TNFR-1, TRAILR-2 and Fas from the cells (XREF_FIG).	16	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	17	18	26	27
Both human and mouse recombinant FasL expressed in COS induced apoptosis in the cells expressing either human Fas or mouse Fas , indicating that FasL fully cross-reacts between human and mouse .	Both human and mouse recombinant FasL expressed in COS induced apoptosis in the cells expressing either human Fas or mouse Fas, indicating that FasL fully cross-reacts between human and mouse.	1	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL expressed	fasl	Fas	Fas	fas	5	6	17	18
Moreover , membrane FasL induced Fas cluster formation occurred in the presence of the lipid raft destabilizing component methyl-beta-cyclodextrin , whereas Fas aggregation by soluble FasL was blocked .	Moreover, membrane FasL induced Fas cluster formation occurred in the presence of the lipid raft destabilizing component methyl-beta-cyclodextrin, whereas Fas aggregation by soluble FasL was blocked.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	5	6
Fas activation by FasL and its receptor FADD activate caspases-3 , -8 and -9 , leading to apoptosis .	Fas activation by FasL and its receptor FADD activate caspases-3, -8 and -9, leading to apoptosis.	0	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	0	1
Human , but not mouse sFasL promoted apoptosis of Fas bearing W4 cells .	Human, but not mouse sFasL promoted apoptosis of Fas bearing W4 cells.	0	12	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	5	6	9	10
The interaction of the cell membrance protein , Fas , with its ligand , Fas ligand , induces apoptosis in Fas bearing cells .	The interaction of the cell membrance protein, Fas, with its ligand, Fas ligand, induces apoptosis in Fas bearing cells.	14	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	14	16	20	21
The activation of Fas by FasL or by agonistic antibody leads to the trimerization of FasDD , which consequently recruits FADD ( Fas associated protein with death domain ) or MORT1 , and caspase-8 , forming the so called death inducing signal complex ( DISC ) [ XREF_BIBR ] .	The activation of Fas by FasL or by agonistic antibody leads to the trimerization of FasDD, which consequently recruits FADD (Fas associated protein with death domain) or MORT1, and caspase-8, forming the so called death inducing signal complex (DISC) [XREF_BIBR].	1	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	5	6	3	4
Autocrine stimulation of Fas by FasL triggers the death pathway via the recruitment of adaptors to the cytoplasmic tail of Fas 5 .	Autocrine stimulation of Fas by FasL triggers the death pathway via the recruitment of adaptors to the cytoplasmic tail of Fas 5.	1	6	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	5	6	3	4
CD95 activation by the CD95L prodrugs was preceded by prodrug processing .	CD95 activation by the CD95L prodrugs was preceded by prodrug processing.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD95L	CD95L	CD95L	CD95	CD95	CD95	4	5	0	1
Fas ligand ( FasL ) binding to death receptor Fas triggers apoptosis of Fas expressing cells including tumour infiltrating immune cells .	Fas ligand (FasL) binding to death receptor Fas triggers apoptosis of Fas expressing cells including tumour infiltrating immune cells.	0	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	0	2	13	14
Since Fas ligand ( FasL ) can induce apoptosis of Fas bearing cells , Fas and FasL interactions can play a critical role in maintaining self-tolerance .	Since Fas ligand (FasL) can induce apoptosis of Fas bearing cells, Fas and FasL interactions can play a critical role in maintaining self-tolerance.	1	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	1	3	10	11
FADD mediates FasL induced apoptotic signals by binding to Fas through its DD and recruits pro-caspase-8 through its DED , thus forming the DISC to transduce apoptotic signals .	FADD mediates FasL induced apoptotic signals by binding to Fas through its DD and recruits pro-caspase-8 through its DED, thus forming the DISC to transduce apoptotic signals.	2	14	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	2	3	9	10
It has also been advocated that FasL expressing tumor cells might induce the killing of Fas expressing normal tissue cells including immune cells such as T lymphocytes .	It has also been advocated that FasL expressing tumor cells might induce the killing of Fas expressing normal tissue cells including immune cells such as T lymphocytes.	6	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL expressing	fasl	Fas	Fas	fas	6	7	15	16
The long persistence of membrane FasL-Fas clusters could be of special relevance when FasL expressing cells stimulate apoptosis in resistant Fas expressing cells that can however become sensitive by regulatory mechanisms .	The long persistence of membrane FasL-Fas clusters could be of special relevance when FasL expressing cells stimulate apoptosis in resistant Fas expressing cells that can however become sensitive by regulatory mechanisms.	13	22	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FasL	FasL	FasL	Fas	Fas	Fas	13	14	20	21
We now show that CD95 stimulation of multiple apoptosis resistant tumor cells by CD95 ligand induces increased motility and invasiveness , a response much less efficiently triggered by TNFalpha or TRAIL .	We now show that CD95 stimulation of multiple apoptosis resistant tumor cells by CD95 ligand induces increased motility and invasiveness, a response much less efficiently triggered by TNFalpha or TRAIL.	4	15	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	CD95 ligand	CD95 ligand	CD95 ligand	CD95	CD95	CD95	13	15	4	5
The adaptor protein , FADD recruits and activates caspase-8 to initiate apoptosis and this pathway can be blocked by FLICE like inhibitory protein long ( FLIP L ) .	The adaptor protein, FADD recruits and activates caspase-8 to initiate apoptosis and this pathway can be blocked by FLICE like inhibitory protein long (FLIP L).	4	9	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	4	5	8	9
This in turn orchestrates the assembly of the death inducing signaling complex ( DISC ) that contains adapter components such as Fas associated death domain ( FADD ) that activates initiator caspases , caspase-8 and -10 , leading eventually to activation of effector caspases such as caspase-3 and to apoptosis [ XREF_BIBR - XREF_BIBR ] .	This in turn orchestrates the assembly of the death inducing signaling complex (DISC) that contains adapter components such as Fas associated death domain (FADD) that activates initiator caspases, caspase-8 and -10, leading eventually to activation of effector caspases such as caspase-3 and to apoptosis [XREF_BIBR - XREF_BIBR].	24	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	26	27	33	34
In innate immune cells , the Fas-FasL dependent , caspase-1 independent , activation of pro-IL-1 and pro-IL-18 results from TLR mediated upregulation of Fas expression , leading to FADD dependent activation of caspase-8 and subsequently caspase-3 ( XREF_FIG ) .	In innate immune cells, the Fas-FasL dependent, caspase-1 independent, activation of pro-IL-1 and pro-IL-18 results from TLR mediated upregulation of Fas expression, leading to FADD dependent activation of caspase-8 and subsequently caspase-3 (XREF_FIG).	28	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	28	29	32	33
Thus , two distinct apoptotic pathways : one triggered by Fas-L and the other initiated by TRAIL , converge to activate FADD , which in turn activates caspase 8 ( XREF_FIG ) .	Thus, two distinct apoptotic pathways : one triggered by Fas-L and the other initiated by TRAIL, converge to activate FADD, which in turn activates caspase 8 (XREF_FIG).	20	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	21	22	27	29
The absence of c-FLIP induces FADD mediated caspase-8 activation and apoptosis in the DISC of breast cancer cells [ XREF_BIBR ] .	The absence of c-FLIP induces FADD mediated caspase-8 activation and apoptosis in the DISC of breast cancer cells [XREF_BIBR].	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	5	6	7	8
After TRAIL bound to these receptors , the death receptor adaptor protein FADD ( Fas Associated protein with death domain ) induce the activation of caspase-8 and subsequently triggered both extrinsic and intrinsic apoptotic signaling pathways .	After TRAIL bound to these receptors, the death receptor adaptor protein FADD (Fas Associated protein with death domain) induce the activation of caspase-8 and subsequently triggered both extrinsic and intrinsic apoptotic signaling pathways.	11	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein FADD	protein FADD	protein FADD	caspase-8	caspase-8	caspase-8	11	13	25	26
These two pathways result in two different situations that are TRADD and FADD activates caspase-8 and induces apoptosis , while TRADD/RIP/TRAF2 activates NF-kappaB and prosurvival pathway [ XREF_BIBR ] .	These two pathways result in two different situations that are TRADD and FADD activates caspase-8 and induces apoptosis, while TRADD/RIP/TRAF2 activates NF-kappaB and prosurvival pathway [XREF_BIBR].	7	15	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	12	13	14	15
Interestingly , coincubation of FADD and FLICE caused the appearance of a 21-kD band that was not detectable in individually in vitro translated FADD or FLICE .	Interestingly, coincubation of FADD and FLICE caused the appearance of a 21-kD band that was not detectable in individually in vitro translated FADD or FLICE.	2	26	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	FLICE	FLICE	FLICE	4	5	25	26
It is well known that activation of Fas by extracellular FasL triggers the recruitment of FADD , which directly activates caspase-8 .	It is well known that activation of Fas by extracellular FasL triggers the recruitment of FADD, which directly activates caspase-8.	13	21	directly activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	15	16	20	21
FADD activation , in turn , activates caspase-8 , initiating activation of the caspase cascade .	FADD activation, in turn, activates caspase-8, initiating activation of the caspase cascade.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	0	1	7	8
Our group has previously shown a similar pattern of caspase activation and cleavage of PARP with bortezomib in human melanoma cell lines which demonstrated bortezomib induced apoptosis as a result of FADD induced caspase-8 activation [ XREF_BIBR ] .	Our group has previously shown a similar pattern of caspase activation and cleavage of PARP with bortezomib in human melanoma cell lines which demonstrated bortezomib induced apoptosis as a result of FADD induced caspase-8 activation [XREF_BIBR].	29	34	induced	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	31	32	33	34
Fas associated death domain ( FADD ) , a signaling molecule that directly interacts with Fas , triggers caspase-8 ( CASP8 ) activation .	Fas associated death domain (FADD), a signaling molecule that directly interacts with Fas, triggers caspase-8 (CASP8) activation.	3	22	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	5	6	18	19
Overall , our data show that p38 activation by TGFbeta induced an apoptotic pathway via FADD independent activation of caspase-8 .	Overall, our data show that p38 activation by TGFbeta induced an apoptotic pathway via FADD independent activation of caspase-8.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	15	16	19	20
FADD signals to activate caspase 8 , leading to apoptosis .	FADD signals to activate caspase 8, leading to apoptosis.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	0	1	4	6
Since in death receptor signaling , FADD mediates activation of caspase-8 , which in turn cleaves BID , and since caspase-8 is activated in PTEN mediated apoptosis , we examined BID cleavage in PTEN mediated apoptosis .	Since in death receptor signaling, FADD mediates activation of caspase-8, which in turn cleaves BID, and since caspase-8 is activated in PTEN mediated apoptosis, we examined BID cleavage in PTEN mediated apoptosis.	6	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	6	7	10	11
DR5 induces extrinsic apoptosis pathways by recruiting the adaptor protein FADD , which activates caspase-8 .	DR5 induces extrinsic apoptosis pathways by recruiting the adaptor protein FADD, which activates caspase-8.	9	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein FADD	protein FADD	protein FADD	caspase-8	caspase-8	caspase-8	9	11	14	15
Next , the N terminal death effect structure of FADD raised by DD was unable to activate Caspase-8 , a member of the cysteine aspartic acid protease ( caspase ) family which executes cell apoptosis , as described by Jackson and Park [ XREF_BIBR - XREF_BIBR ] .	Next, the N terminal death effect structure of FADD raised by DD was unable to activate Caspase-8, a member of the cysteine aspartic acid protease (caspase) family which executes cell apoptosis, as described by Jackson and Park [XREF_BIBR - XREF_BIBR].	7	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	Caspase-8	Caspase-8	Caspase-8	9	10	17	18
The combination of Fas and FasL recruits the adaptor protein FADD and pro caspase 8 , which together form the death inducing signaling complex ( DISC ) and activates caspase 8 .	The combination of Fas and FasL recruits the adaptor protein FADD and pro caspase 8, which together form the death inducing signaling complex (DISC) and activates caspase 8.	9	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein FADD	protein FADD	protein FADD	caspase 8	caspase 8	caspase 8	9	11	29	31
Consequently , FADD activates caspase-8 which leading to form of the death inducing signaling complex ( DISC ) .	Consequently, FADD activates caspase-8 which leading to form of the death inducing signaling complex (DISC).	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	2	3	4	5
This produces a conformational change in FADD to expose its DED , leading to the binding of FADD ' s DED to a similar domain on caspase-8 to induce caspase-8 dimerization and activation .	This produces a conformational change in FADD to expose its DED, leading to the binding of FADD 's DED to a similar domain on caspase-8 to induce caspase-8 dimerization and activation.	4	30	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	6	7	29	30
( 2 ) The activity of the cardiac Fas receptor dependent apoptotic pathway in mice with chronic intermittent hypoxia was significantly decreased with treatment of Rhodiola Crenulata , which data is based on decreases in Fas , FADD , activated caspase 8 , activated caspase 3 compared to the Hypoxia group .	(2) The activity of the cardiac Fas receptor dependent apoptotic pathway in mice with chronic intermittent hypoxia was significantly decreased with treatment of Rhodiola Crenulata, which data is based on decreases in Fas, FADD, activated caspase 8, activated caspase 3 compared to the Hypoxia group.	37	43	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	37	38	40	42
TRADD then recruits a protein called Fas associated protein with death domain ( FADD ) , which then sequentially activates caspase-8 , caspase-3 , and , thus , apoptosis [ XREF_BIBR ] .	TRADD then recruits a protein called Fas associated protein with death domain (FADD), which then sequentially activates caspase-8, caspase-3, and, thus, apoptosis [XREF_BIBR].	11	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	13	14	20	21
FADD can also induced caspase-8 and -10 activation in cytoplasmic platforms such as Complexes-II or Ripoptosome [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	FADD can also induced caspase-8 and -10 activation in cytoplasmic platforms such as Complexes-II or Ripoptosome [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	0	1	4	5
Interaction of FADD with caspase-8 stimulates activation of caspase-8 , which activates effector caspases , such as caspase-9 and -3 .	Interaction of FADD with caspase-8 stimulates activation of caspase-8, which activates effector caspases, such as caspase-9 and -3.	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	2	3	8	9
Fas and FasL interaction recruits the adaptor protein Fas associated death domain ( FADD ) , which activates caspase-8 and initiates the apoptotic cascade .	Fas and FasL interaction recruits the adaptor protein Fas associated death domain (FADD), which activates caspase-8 and initiates the apoptotic cascade.	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	13	14	18	19
FADD activates caspase 8 , leading to either mitochondria independent ( extrinsic ) or mitochondrial dependent ( intrinsic ) death of Eos .	FADD activates caspase 8, leading to either mitochondria independent (extrinsic) or mitochondrial dependent (intrinsic) death of Eos.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	0	1	2	4
A combination of FADD and procaspase-8 in this pathway results in the formation of the death inducing signaling complex ( DISC ) and tends to activate caspase-8 , after which the execution phase of apoptosis is triggered [ XREF_BIBR ] .	A combination of FADD and procaspase-8 in this pathway results in the formation of the death inducing signaling complex (DISC) and tends to activate caspase-8, after which the execution phase of apoptosis is triggered [XREF_BIBR].	1	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	3	4	26	27
However , it remains unclear how this modification facilitates FADD mediated activation of caspase 8 or leads to FADD ' s accumulation in the nucleus .	However, it remains unclear how this modification facilitates FADD mediated activation of caspase 8 or leads to FADD 's accumulation in the nucleus.	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	9	10	13	15
The activated FADD or TRADD leads to the formation and activation of DISC activating caspase-8 .	The activated FADD or TRADD leads to the formation and activation of DISC activating caspase-8.	0	15	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	2	3	14	15
Since IETDase is the preferred substrate for caspase 8 , which is activated by FADD induced aggregation of its proenzyme 34 , its early activation is consistent with current ideas about this pathway .	Since IETDase is the preferred substrate for caspase 8, which is activated by FADD induced aggregation of its proenzyme 34, its early activation is consistent with current ideas about this pathway.	5	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	14	15	7	9
In this process , oligomerized DR5 death domain ( DD ) binding to Fas associated death domain ( FADD ) leads to FADD activating caspase-8 , which marks the formation of the death inducing signaling complex ( DISC ) that initiates apoptosis .	In this process, oligomerized DR5 death domain (DD) binding to Fas associated death domain (FADD) leads to FADD activating caspase-8, which marks the formation of the death inducing signaling complex (DISC) that initiates apoptosis.	20	27	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	22	23	24	25
Factors that were critical in drug induced apoptosis were activation of caspases , with caspase-8 being activated by diverse drugs in a FADD independent manner .	Factors that were critical in drug induced apoptosis were activation of caspases, with caspase-8 being activated by diverse drugs in a FADD independent manner.	9	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	22	23	14	15
DISC results in recruitment of the adapter molecule Fas associated death domain ( FADD ) , which in turn recruits and activates caspase-8 to execute apoptosis .	DISC results in recruitment of the adapter molecule Fas associated death domain (FADD), which in turn recruits and activates caspase-8 to execute apoptosis.	11	23	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	13	14	22	23
Moreover , in response to poly I : C , caspase-8 or caspase-10 is activated by FADD , and the cleaved form of caspases activates NF-kappaB .	Moreover, in response to poly I : C, caspase-8 or caspase-10 is activated by FADD, and the cleaved form of caspases activates NF-kappaB.	10	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	16	17	10	11
As a result , FADD activates caspase-3 and caspase-8 .	As a result, FADD activates caspase-3 and caspase-8.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	4	5	8	9
In this study , we observed silencing of the FADD attenuated cell death and caspase-8 activation ( XREF_FIG ) .	In this study, we observed silencing of the FADD attenuated cell death and caspase-8 activation (XREF_FIG).	6	15	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	9	10	14	15
Also , activated TRADD has been shown to recruit a second adaptor ( FADD ) , which in turn activates caspase-8 .	Also, activated TRADD has been shown to recruit a second adaptor (FADD), which in turn activates caspase-8.	11	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	13	14	20	21
Accordingly , reconstitution of FADD deficient cells with FKBP-FADD , but neither FKBP-AHALL nor FKBP-RHDAA , restored cleavage of caspase-8 , FLIP L ( FLICE like inhibitory protein long ) or RIP1 ( XREF_FIG ) .	Accordingly, reconstitution of FADD deficient cells with FKBP-FADD, but neither FKBP-AHALL nor FKBP-RHDAA, restored cleavage of caspase-8, FLIP L (FLICE like inhibitory protein long) or RIP1 (XREF_FIG).	4	31	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	4	5	19	20
Cytoplasmic TRADD activates apoptosis through Fas associated death domain protein ( FADD ) and caspase-8 activation that was blocked by caspase inhibitors or dominant negative FADD .	Cytoplasmic TRADD activates apoptosis through Fas associated death domain protein (FADD) and caspase-8 activation that was blocked by caspase inhibitors or dominant negative FADD.	14	26	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	25	26	14	15
This activates the adaptor protein Fas associated death domain ( FADD ) protein , which in turn activates caspase-8 , an initiator protein , to form a signal complex .	This activates the adaptor protein Fas associated death domain (FADD) protein, which in turn activates caspase-8, an initiator protein, to form a signal complex.	8	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	10	11	18	19
Further studies are also necessary to determine the mechanism involved in the regulation of RIP1 and RIP3 mediated necroptosis by FADD and caspase 8 .	Further studies are also necessary to determine the mechanism involved in the regulation of RIP1 and RIP3 mediated necroptosis by FADD and caspase 8.	17	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	20	21	22	24
We also observed a dose dependent up-regulation of Fas and its downstream adaptor protein , FADD , which can activate caspase-8 , the main enzyme responsible for truncation of Bid .	We also observed a dose dependent up-regulation of Fas and its downstream adaptor protein, FADD, which can activate caspase-8, the main enzyme responsible for truncation of Bid.	13	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	15	16	20	21
As this cytosolic RIP1 , FADD , caspase-8 , and containing complex has been described to drive caspase-8 activation , XREF_BIBR , XREF_BIBR we next monitored activation of the caspase cascade by western blotting .	As this cytosolic RIP1, FADD, caspase-8, and containing complex has been described to drive caspase-8 activation, XREF_BIBR, XREF_BIBR we next monitored activation of the caspase cascade by western blotting.	5	18	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	5	6	17	18
After Fas activation , the FADD complex activates Caspase 8 , which after a downstream network of reactions converts pro-Caspase-3 to effector active Caspase-3 in the apoptosome [ XREF_BIBR ] .	After Fas activation, the FADD complex activates Caspase 8, which after a downstream network of reactions converts pro-Caspase-3 to effector active Caspase-3 in the apoptosome [XREF_BIBR].	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	Caspase 8	Caspase 8	Caspase 8	5	6	8	10
FADD mediates caspase-8 maturation with canonical and non canonical Nlrp3 inflammasome stimuli .	FADD mediates caspase-8 maturation with canonical and non canonical Nlrp3 inflammasome stimuli.	0	3	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	0	1	2	3
These similar findings suggest that ixazomib and bortezomib may both initiate tumor cell death through activation of the extrinsic pathway of apoptosis via FADD induced caspase-8 activation .	These similar findings suggest that ixazomib and bortezomib may both initiate tumor cell death through activation of the extrinsic pathway of apoptosis via FADD induced caspase-8 activation.	21	26	induced	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	23	24	25	26
Accepting that FADD mediated activation of caspase-8 is essential for the aforementioned non apoptotic processes , one must ask the following two questions : ( 1 ) how are FADD and caspase-8 activated during these processes ?	Accepting that FADD mediated activation of caspase-8 is essential for the aforementioned non apoptotic processes, one must ask the following two questions : (1) how are FADD and caspase-8 activated during these processes?	0	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	2	3	6	7
FADD can combine with receptors through the interaction between two DDs and increase the precursor of caspase-8 , which is the initiator of apoptosis ( pro-caspase-8 ) , via the interaction between DED , and finally form the death signal complex DISC ( death inducing signaling complex ) .	FADD can combine with receptors through the interaction between two DDs and increase the precursor of caspase-8, which is the initiator of apoptosis (pro-caspase-8), via the interaction between DED, and finally form the death signal complex DISC (death inducing signaling complex).	0	21	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	0	1	16	17
FADD activates caspase-8 following activation of executioner caspases ( caspase 3 , 6 and 7 ) , either directly ( type I pathway ) or indirectly through mitochondrial dysfunction ( type II pathway ) .	FADD activates caspase-8 following activation of executioner caspases (caspase 3, 6 and 7), either directly (type I pathway) or indirectly through mitochondrial dysfunction (type II pathway).	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	0	1	2	3
Labeling biotinylated FADD by 10 nm streptavidin-gold particles showed that the Fas DD / FADD complex is localized at one end of the filaments ( XREF_FIG ) , supporting that the Fas and FADD complex nucleates directional polymerization of Casp-8 .	Labeling biotinylated FADD by 10 nm streptavidin-gold particles showed that the Fas DD / FADD complex is localized at one end of the filaments (XREF_FIG), supporting that the Fas and FADD complex nucleates directional polymerization of Casp-8.	14	40	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	Casp-8	Casp-8	Casp-8	14	15	39	40
Although a definite connection between PKR and FADD mediated caspase 8 activation remains to be determined , apoptosis is induced by the over-expression of PKR XREF_BIBR .	Although a definite connection between PKR and FADD mediated caspase 8 activation remains to be determined, apoptosis is induced by the over-expression of PKR XREF_BIBR.	3	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	7	8	9	11
In conclusion , laminarin upregulates DR4 , DR5 , TRAIL and FADD expression levels in LoVo cells , downregulates procaspase-8 and -3 expression levels and increases the activity of caspase-8 , -3 , -6 and -7 .	In conclusion, laminarin upregulates DR4, DR5, TRAIL and FADD expression levels in LoVo cells, downregulates procaspase-8 and -3 expression levels and increases the activity of caspase-8, -3, -6 and -7.	3	30	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	laminarin upregulates DR4, DR5, TRAIL and FADD expression levels	fadd	caspase-8	caspase-8	caspase-8	11	12	29	30
The death domain of TRADD binds to that of FADD , which transmits apoptotic signaling , activates caspase 8 , and then activates downstream caspase 3 , resulting in cell apoptosis ( Tang et al ., 2009 ) .	The death domain of TRADD binds to that of FADD, which transmits apoptotic signaling, activates caspase 8, and then activates downstream caspase 3, resulting in cell apoptosis (Tang et al., 2009).	7	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	9	10	17	19
The FADD in turn activates caspase 8 via its death effector domain ( DED ) and then the activated caspase-8 subsequently triggers the activation of downstream caspases that participate in the execution of the apoptotic process [ XREF_BIBR , XREF_BIBR ] .	The FADD in turn activates caspase 8 via its death effector domain (DED) and then the activated caspase-8 subsequently triggers the activation of downstream caspases that participate in the execution of the apoptotic process [XREF_BIBR, XREF_BIBR].	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	1	2	5	7
FADD , in turn , recruits and activates caspase-8 through forced dimerization via its death effector domain .	FADD, in turn, recruits and activates caspase-8 through forced dimerization via its death effector domain.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	0	1	8	9
The observation that the developmental abnormalities of caspase-8 deficient mice are shared by mice lacking the dimerization adapter FADD or the caspase paralog FLIP L has led to the hypothesis that FADD dependent formation of heterodimers between caspase-8 and FLIP L could mediate the developmental role of caspase-8 .	The observation that the developmental abnormalities of caspase-8 deficient mice are shared by mice lacking the dimerization adapter FADD or the caspase paralog FLIP L has led to the hypothesis that FADD dependent formation of heterodimers between caspase-8 and FLIP L could mediate the developmental role of caspase-8.	31	48	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	31	32	47	48
To further understand the relationship between FADD induced caspase-8 maturation and Nlrp3 inflammasome activation , we monitored caspase-8 activation status in inflammasome deficient macrophages .	To further understand the relationship between FADD induced caspase-8 maturation and Nlrp3 inflammasome activation, we monitored caspase-8 activation status in inflammasome deficient macrophages.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	6	7	8	9
Fas and Fasl signaling transduction involved in FADD activating Caspase-8 and Caspase-3 .	Fas and Fasl signaling transduction involved in FADD activating Caspase-8 and Caspase-3.	5	11	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	Caspase-8	Caspase-8	Caspase-8	7	8	9	10
FADD Mediated Unidirectional Casp-8 Polymerization Using Three Types of Interactions .	FADD Mediated Unidirectional Casp-8 Polymerization Using Three Types of Interactions.	0	4	Mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	Casp-8	Casp-8	Casp-8	0	1	3	4
However , FADD , which mediates the Fas signal to caspase 8 , can kill cells without caspase 8 .	However, FADD, which mediates the Fas signal to caspase 8, can kill cells without caspase 8.	2	14	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	2	3	10	12
Apoptosis was characterized by FADD expression , activated caspase-8 , caspase-3 and induction of Bax , Bak , and Bid as revealed by GEArray and protein fractionation assays .	Apoptosis was characterized by FADD expression, activated caspase-8, caspase-3 and induction of Bax, Bak, and Bid as revealed by GEArray and protein fractionation assays.	4	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD expression	fadd	caspase-8	caspase-8	caspase-8	4	5	8	9
Bortezomib and IFN-alpha induce apoptosis via FADD mediated caspase-8 activation .	Bortezomib and IFN-alpha induce apoptosis via FADD mediated caspase-8 activation.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	6	7	8	9
7 This data suggested that bortezomib and IFN-alpha acted through the extrinsic pathway of apoptosis via FADD induced caspase-8 activation to initiate melanoma tumor cell death .	7 This data suggested that bortezomib and IFN-alpha acted through the extrinsic pathway of apoptosis via FADD induced caspase-8 activation to initiate melanoma tumor cell death.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	16	17	18	19
We demonstrate here that E1B 19K and Bcl-x L are able to inhibit apoptosis induced by FADD , but not FLICE .	We demonstrate here that E1B 19K and Bcl-x L are able to inhibit apoptosis induced by FADD, but not FLICE.	12	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	FLICE	FLICE	FLICE	16	17	20	21
RIPK1 binds to FADD via a death domain ( DD ) homotypic interaction , whereupon FADD activates caspase-8 .	RIPK1 binds to FADD via a death domain (DD) homotypic interaction, whereupon FADD activates caspase-8.	14	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	15	16	17	18
Thus , this study shows that Hid engages with conserved components of cellular death machinery and suggests that apoptotic paradigms characterized by FADD independent activation of caspase-8 may involve a Hid like molecule in mammalian cells .	Thus, this study shows that Hid engages with conserved components of cellular death machinery and suggests that apoptotic paradigms characterized by FADD independent activation of caspase-8 may involve a Hid like molecule in mammalian cells.	22	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	22	23	26	27
However , we found that HSP70i over-expression did not affect TNFalpha induced activation of caspase 8 ( data not shown ) , indicating that HSP70 may not affect FADD induced caspase 8 activation .	However, we found that HSP70i over-expression did not affect TNFalpha induced activation of caspase 8 (data not shown), indicating that HSP70 may not affect FADD induced caspase 8 activation.	27	32	induced	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	28	29	30	32
Thus , FADD mediated caspase 8 activation involves intracellular ExoS in an ADPRT dependent manner .	Thus, FADD mediated caspase 8 activation involves intracellular ExoS in an ADPRT dependent manner.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	2	3	4	6
In addition , trifolin increased the levels of the death receptor involving the Fas and Fas ligand ( FasL ) and Fas associated protein with the death domain ( FADD ) , which consequently activated caspase-8 , caspase-9 , caspase-3 , and the proteolytic cleavage of poly ( ADP-ribose ) polymerase ( PARP ) .	In addition, trifolin increased the levels of the death receptor involving the Fas and Fas ligand (FasL) and Fas associated protein with the death domain (FADD), which consequently activated caspase-8, caspase-9, caspase-3, and the proteolytic cleavage of poly (ADP-ribose) polymerase (PARP).	27	44	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	29	30	35	36
Thus , bortezomib can sensitize tumors to cell death by amplifying the extrinsic pathway of apoptosis via FADD induced caspase-8 activation .	Thus, bortezomib can sensitize tumors to cell death by amplifying the extrinsic pathway of apoptosis via FADD induced caspase-8 activation.	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	17	18	19	20
122 An additional step necessary for NF-kappaB activation is FADD mediated engagement of caspase-8 and/or caspase-10 .	122 An additional step necessary for NF-kappaB activation is FADD mediated engagement of caspase-8 and/or caspase-10.	0	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	9	10	13	14
E2 protein of HR-HPV18 has been found to be involved in novel FADD independent activation of caspase-8 , however , the molecular basis of this unique non-death-fold E2 mediated apoptosis is poorly understood .	E2 protein of HR-HPV18 has been found to be involved in novel FADD independent activation of caspase-8, however, the molecular basis of this unique non-death-fold E2 mediated apoptosis is poorly understood.	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	12	13	16	17
FADD transduces death signals by binding to ligand activated Fas via its DD and recruiting and activating caspase-8 via its death-effector domain ( DED ; XREF_FIG ) .	FADD transduces death signals by binding to ligand activated Fas via its DD and recruiting and activating caspase-8 via its death-effector domain (DED; XREF_FIG).	0	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	0	1	17	18
For both assays , Fas and FADD mediated activation of Caspase-8 and NLRP1DeltaLRR and Asc mediated activation of Caspase-1 resulted in activation of the cleavable transcription factor , producing beta-galactosidase , which was measured using a colorimetric substrate .	For both assays, Fas and FADD mediated activation of Caspase-8 and NLRP1DeltaLRR and Asc mediated activation of Caspase-1 resulted in activation of the cleavable transcription factor, producing beta-galactosidase, which was measured using a colorimetric substrate.	4	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	Caspase-8	Caspase-8	Caspase-8	6	7	10	11
However , if caspase-8 is inactivated by pharmacological inhibitors ( e.g ., zVAD ) , endogenous inhibitors ( e.g ., c-FLIP S ) , or genetic caspase-8 or FADD inhibition and deletion , it loses its capacity to cleave RIP1 and RIP3 , leading to the phosphorylation of these two kinases and the formation of the filamentous like RIP1 and RIP3 complex , or the necrosome .	However, if caspase-8 is inactivated by pharmacological inhibitors (e.g., zVAD), endogenous inhibitors (e.g., c-FLIP S), or genetic caspase-8 or FADD inhibition and deletion, it loses its capacity to cleave RIP1 and RIP3, leading to the phosphorylation of these two kinases and the formation of the filamentous like RIP1 and RIP3 complex, or the necrosome.	3	29	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	28	29	3	4
These data suggest that bortezomib and IFN-alpha act through the extrinsic pathway of apoptosis via FADD induced caspase-8 activation to initiate cell death .	These data suggest that bortezomib and IFN-alpha act through the extrinsic pathway of apoptosis via FADD induced caspase-8 activation to initiate cell death.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	15	16	17	18
For example , TNF-alpha signaling can lead to the generation of an apoptotic signal via FADD mediated activation of caspase 8 , whereas TRADD and TRAF -2 ( TNF receptor associated factor-2 ) activation can lead to activation of NF-kappaB and triggering of downstream events that result in increased gene expression leading to an anti-apoptotic or a proliferative response 16 , 17 , 18 , 19 , 20 .	For example, TNF-alpha signaling can lead to the generation of an apoptotic signal via FADD mediated activation of caspase 8, whereas TRADD and TRAF -2 (TNF receptor associated factor-2) activation can lead to activation of NF-kappaB and triggering of downstream events that result in increased gene expression leading to an anti-apoptotic or a proliferative response 16, 17, 18, 19, 20.	15	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	15	16	19	21
As illustrated in Figures XREF_FIG and XREF_FIG , our results show that the silencing of FADD could partially recover the cell viability and repress caspase-8 activation .	As illustrated in Figures XREF_FIG and XREF_FIG, our results show that the silencing of FADD could partially recover the cell viability and repress caspase-8 activation.	13	25	repress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	15	16	24	25
The results were consistent with a block in the apoptotic signaling pathways of glioma cells between caspase-8 and caspase-3 activation , and that inducible Fadd could induce caspase-8 independent apoptosis in some cells .	The results were consistent with a block in the apoptotic signaling pathways of glioma cells between caspase-8 and caspase-3 activation, and that inducible Fadd could induce caspase-8 independent apoptosis in some cells.	23	29	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fadd	Fadd	Fadd	caspase-8	caspase-8	caspase-8	24	25	27	28
FADD is subsequently activated to improve caspase 8 activity .	FADD is subsequently activated to improve caspase 8 activity.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	0	1	6	8
Similarly , Hsp70 may promote TNF dependent FADD mediated activation of caspase-8 , by limiting anti-apoptotic proteins FLIP ( FLICE inhibitory protein ) and RIP1 ( receptor interacting protein 1 ) recruitment at the plasma membrane , or by inhibiting IKK mediated phosphorylation and proteasomal degradation of NF-kB inhibitor IkB and , thus , NF-kappaB pro survival signaling [ XREF_BIBR - XREF_BIBR ] .	Similarly, Hsp70 may promote TNF dependent FADD mediated activation of caspase-8, by limiting anti-apoptotic proteins FLIP (FLICE inhibitory protein) and RIP1 (receptor interacting protein 1) recruitment at the plasma membrane, or by inhibiting IKK mediated phosphorylation and proteasomal degradation of NF-kB inhibitor IkB and, thus, NF-kappaB pro survival signaling [XREF_BIBR - XREF_BIBR].	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	7	8	11	12
The pathway of PKR induced apoptosis involves FADD activation of caspase 8 by a mechanism independent of Fas and TNFR .	The pathway of PKR induced apoptosis involves FADD activation of caspase 8 by a mechanism independent of Fas and TNFR.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	7	8	10	12
FADD mediates caspase-8 activation downstream of Fas , TNF and death receptors .	FADD mediates caspase-8 activation downstream of Fas, TNF and death receptors.	0	3	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	0	1	2	3
Caspase-8 is usually activated upon its dimerization in intracellular or membrane DISCs through recruitment by the adapter molecule FADD in response to the interaction of death ligands with death receptors .	Caspase-8 is usually activated upon its dimerization in intracellular or membrane DISCs through recruitment by the adapter molecule FADD in response to the interaction of death ligands with death receptors.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	Caspase-8	Caspase-8	Caspase-8	18	19	0	1
In effect , stimulation of cytokine receptors including TNFalphaR1 signals the extrinsic cascade of apoptosis , which is mediated by FADD protein signaling the activation of caspase-8 with self-cleavage [ XREF_BIBR ] .	In effect, stimulation of cytokine receptors including TNFalphaR1 signals the extrinsic cascade of apoptosis, which is mediated by FADD protein signaling the activation of caspase-8 with self-cleavage [XREF_BIBR].	18	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	20	21	26	27
In its kinase active form , it also recruits the adapter molecule , FADD , which in turn activates caspase-8 to promote apoptosis induced by TLR signaling or DNA damage .	In its kinase active form, it also recruits the adapter molecule, FADD, which in turn activates caspase-8 to promote apoptosis induced by TLR signaling or DNA damage.	11	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	13	14	19	20
If NF-kappaB activation is inadequate , apoptosis , a late response to TNF-alpha can be mediated by the activation of caspase-8 by FADD , and lead to the accumulation of intracellular reactive oxygen ( ROS ) , sustained Jun amino-terminal kinase ( JNK ) activation and mitochondrial pathways activation .	If NF-kappaB activation is inadequate, apoptosis, a late response to TNF-alpha can be mediated by the activation of caspase-8 by FADD, and lead to the accumulation of intracellular reactive oxygen (ROS), sustained Jun amino-terminal kinase (JNK) activation and mitochondrial pathways activation.	15	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	22	23	20	21
Thus , we propose a mechanism in which FADD needs to be multimerized at the DISC , similar to Fas , to activate FLICE .	Thus, we propose a mechanism in which FADD needs to be multimerized at the DISC, similar to Fas, to activate FLICE.	8	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	FLICE	FLICE	FLICE	8	9	23	24
Coexpression of FADD and FLICE without E1B 19K caused increased FLICE activation as indicated by the disappearance of full-length FLICE .	Coexpression of FADD and FLICE without E1B 19K caused increased FLICE activation as indicated by the disappearance of full-length FLICE.	0	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	Coexpression of FADD	fadd	FLICE	FLICE	flice	2	3	10	11
For example , the FAS associated protein with death domain ( FADD ) activates caspase 8 and the BH3-interacting-domain death agonist ( BID ) .	For example, the FAS associated protein with death domain (FADD) activates caspase 8 and the BH3-interacting-domain death agonist (BID).	4	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	11	12	14	16
In addition , it has been reported that Eif2ak2 is able to trigger apoptosis through the FADD mediated activation of caspase 8 in a manner independent of Fas and ApoI and TNFR1 receptors [ XREF_BIBR ] .	In addition, it has been reported that Eif2ak2 is able to trigger apoptosis through the FADD mediated activation of caspase 8 in a manner independent of Fas and ApoI and TNFR1 receptors [XREF_BIBR].	16	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	16	17	20	22
In the present study , we have demonstrated that treatment of melanoma cells with bortezomib and IFN-alpha synergistically induced apoptotic cell death via FADD dependent activation of caspase-8 .	In the present study, we have demonstrated that treatment of melanoma cells with bortezomib and IFN-alpha synergistically induced apoptotic cell death via FADD dependent activation of caspase-8.	23	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	23	24	27	28
The apoptosis in DR5- and c-FLIP-siRNA treated cells as compared to DR5- and non targeting siRNA treated cells is probably due to the FADD induced activation of caspase-8 ( see XREF_FIG ) , as well as the incomplete knockdown of DR5 gene expression ( XREF_FIG ) .	The apoptosis in DR5- and c-FLIP-siRNA treated cells as compared to DR5- and non targeting siRNA treated cells is probably due to the FADD induced activation of caspase-8 (see XREF_FIG), as well as the incomplete knockdown of DR5 gene expression (XREF_FIG).	22	29	induced	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	23	24	27	28
Importantly , it was associated with TNFR1 and FADD mediated caspase 8 activation and mitochondrial dysfunction ( XREF_FIG ) .	Importantly, it was associated with TNFR1 and FADD mediated caspase 8 activation and mitochondrial dysfunction (XREF_FIG).	4	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	8	9	10	12
TNF-alpha signaling can stimulate the generation of an apoptotic signal via FADD mediated activation of caspase-8 , whereas TRADD activation can lead to activation of NF-kappaB and trigger downstream events that result in increased gene expression leading to an anti-apoptotic response [ XREF_BIBR ] .	TNF-alpha signaling can stimulate the generation of an apoptotic signal via FADD mediated activation of caspase-8, whereas TRADD activation can lead to activation of NF-kappaB and trigger downstream events that result in increased gene expression leading to an anti-apoptotic response [XREF_BIBR].	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	11	12	15	16
FADD then activates caspase 8 ( also known as FLICE or MACH ) through an interaction between the death-effector domains of FADD and caspase 8 .	FADD then activates caspase 8 (also known as FLICE or MACH) through an interaction between the death-effector domains of FADD and caspase 8.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	0	1	3	5
Rip is activated by Ripk1 and stimulates a pathway leading to the activation of Nf-kappab , whereas Fadd mediates the activation of apoptosis by recruiting and oligmerizing caspase 8 .	Rip is activated by Ripk1 and stimulates a pathway leading to the activation of Nf-kappab, whereas Fadd mediates the activation of apoptosis by recruiting and oligmerizing caspase 8.	17	29	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fadd	Fadd	Fadd	caspase 8	caspase 8	caspase 8	17	18	27	29
This signaling event leads to the recruitment of Fas associated death receptor ( FADD ) which in turn activates caspase 8 .	This signaling event leads to the recruitment of Fas associated death receptor (FADD) which in turn activates caspase 8.	11	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	13	14	19	21
Consequently the intracellular domain of Fas is able to bind to the adaptor FADD which in turn activates caspase 8 in the cytosol from pro caspase 8 .	Consequently the intracellular domain of Fas is able to bind to the adaptor FADD which in turn activates caspase 8 in the cytosol from pro caspase 8.	9	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	13	14	18	20
The involvement of the death adaptor protein FADD and apoptosis initiating caspase-8 in death signaling by DR4 and DR5 are controversial .	The involvement of the death adaptor protein FADD and apoptosis initiating caspase-8 in death signaling by DR4 and DR5 are controversial.	6	14	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein FADD	protein FADD	protein FADD	caspase-8	caspase-8	caspase-8	6	8	11	12
In the death signaling , activated TNFR1 induces the binding of adaptor protein tumor necrosis factor receptor type 1 associated death domain protein ( TRADD ) to Fas associated protein with death domain ( FADD ) , which activates caspase-8 .	In the death signaling, activated TNFR1 induces the binding of adaptor protein tumor necrosis factor receptor type 1 associated death domain protein (TRADD) to Fas associated protein with death domain (FADD), which activates caspase-8.	32	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	34	35	39	40
The FADD activates caspase 8 , cleaves pro caspase 3 and undergoes autocatalysis forming active caspase 3 , an effector caspase of apoptosis [ XREF_BIBR , XREF_BIBR ] .	The FADD activates caspase 8, cleaves pro caspase 3 and undergoes autocatalysis forming active caspase 3, an effector caspase of apoptosis [XREF_BIBR, XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	1	2	3	5
Interestingly , Fadd -/-, Trif -/- and Ripk1 -/- BMDCs also failed to activate caspase 8 in response to TLR4 stimulation , suggesting that these adaptors are required for RIPK3 dependent caspase 8 activation .	Interestingly, Fadd -/-, Trif -/- and Ripk1 -/- BMDCs also failed to activate caspase 8 in response to TLR4 stimulation, suggesting that these adaptors are required for RIPK3 dependent caspase 8 activation.	2	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fadd	Fadd	Fadd	caspase 8	caspase 8	caspase 8	2	3	14	16
Detachment induces extrinsic apoptosis through FADD dependent activation of caspase 8 and FOXO1/3a suppression of the caspase 8 antagonist c-Flip , which may or may not involve Fas and FasL interactions .	Detachment induces extrinsic apoptosis through FADD dependent activation of caspase 8 and FOXO1/3a suppression of the caspase 8 antagonist c-Flip, which may or may not involve Fas and FasL interactions.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	5	6	9	11
cFLIP , the mammalian homologue of the previously described family of viral inhibitors ( v-FLIPs ) [ XREF_BIBR ] , blocks cell death receptor signaling by interfering with the recruitment and activation of caspase-8 by FADD [ XREF_BIBR ] .	cFLIP, the mammalian homologue of the previously described family of viral inhibitors (v-FLIPs) [XREF_BIBR], blocks cell death receptor signaling by interfering with the recruitment and activation of caspase-8 by FADD [XREF_BIBR].	29	37	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	35	36	33	34
The FADD mediated caspase 8 activation results in the cleavage and activation of Bid , which destabilizes the mitochondrial membrane leading to apoptosis .	The FADD mediated caspase 8 activation results in the cleavage and activation of Bid, which destabilizes the mitochondrial membrane leading to apoptosis.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	1	2	3	5
FADD promotes Casp8 activation within the death inducing signaling complex ( DISC ) , a process subject to regulation by cFLIP .	FADD promotes Casp8 activation within the death inducing signaling complex (DISC), a process subject to regulation by cFLIP.	0	3	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	Casp8	Casp8	Casp8	0	1	2	3
However , high FADD was sufficient to activate Caspase-8 and -10 , with addition of death receptors only modestly further increasing reporter gene activity ( XREF_FIG ) .	However, high FADD was sufficient to activate Caspase-8 and -10, with addition of death receptors only modestly further increasing reporter gene activity (XREF_FIG).	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	Caspase-8	Caspase-8	Caspase-8	3	4	8	9
Intracellular adaptors , TRADD ( TNFR associated death domain ) , and FADD ( Fas associated death domain ) are used by the TNFR superfamily to activate the caspase 8 cascade , JNK , and NFkappaB , accounting for the diverse biological effects of TNFalpha including apoptosis , cell activation , coagulation , inflammation , and host defense [ XREF_BIBR ] .	Intracellular adaptors, TRADD (TNFR associated death domain), and FADD (Fas associated death domain) are used by the TNFR superfamily to activate the caspase 8 cascade, JNK, and NFkappaB, accounting for the diverse biological effects of TNFalpha including apoptosis, cell activation, coagulation, inflammation, and host defense [XREF_BIBR].	1	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 8	caspase 8	caspase 8	12	13	28	30
PAR2 is not directly activated by thrombin , but appears to be a less selective sensor for several proteases , including trypsin and mast cell tryptase .	PAR2 is not directly activated by thrombin, but appears to be a less selective sensor for several proteases, including trypsin and mast cell tryptase.	0	15	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	6	7	0	1
XREF_BIBR Thrombin exerts it cell activity partially through the G protein coupled PAR receptors ( PAR 1 , 3 , and 4 ) ; TF : VIIa and factor Xa and Trypsin , but not thrombin activate PAR 2 .	XREF_BIBR Thrombin exerts it cell activity partially through the G protein coupled PAR receptors (PAR 1, 3, and 4); TF : VIIa and factor Xa and Trypsin, but not thrombin activate PAR 2.	24	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 2	PAR 2	PAR 2	35	36	37	39
Combinations of several PARs can exist ; PAR-2 can be activated by thrombin cleaved PAR-1 [ XREF_BIBR ] , suggesting a link between MrgprC11 and PAR-2 [ XREF_BIBR ] .	Combinations of several PARs can exist; PAR-2 can be activated by thrombin cleaved PAR-1 [XREF_BIBR], suggesting a link between MrgprC11 and PAR-2 [XREF_BIBR].	7	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	12	13	7	8
Moreover , conditioned medium of thrombin treated fibroblasts did not induce PAR-2 dependent fibrotic effects ( data not shown ) .	Moreover, conditioned medium of thrombin treated fibroblasts did not induce PAR-2 dependent fibrotic effects (data not shown).	5	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	5	6	11	12
Until now , four members of the PAR family were discovered : PAR 1 , PAR 3 , and PAR 4 which are activated by thrombin and PAR 2 that can be activated by trypsin , neutrophil proteinase 3 , tissue factor and factor VIIa and factor Xa , mast cell tryptase , membrane tethered serine proteinase-1 , or gingipains [ XREF_BIBR , XREF_BIBR ] .	Until now, four members of the PAR family were discovered : PAR 1, PAR 3, and PAR 4 which are activated by thrombin and PAR 2 that can be activated by trypsin, neutrophil proteinase 3, tissue factor and factor VIIa and factor Xa, mast cell tryptase, membrane tethered serine proteinase-1, or gingipains [XREF_BIBR, XREF_BIBR].	12	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 2	PAR 2	PAR 2	25	26	27	29
For example , thrombin ligation of PAR1 was shown to induce the transactivation of PAR2 in COS7 and human umbilical vein endothelial cells ( HUVECs ) which in turn regulated thrombin responses .	For example, thrombin ligation of PAR1 was shown to induce the transactivation of PAR2 in COS7 and human umbilical vein endothelial cells (HUVECs) which in turn regulated thrombin responses.	3	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	3	4	14	15
PAR-2 is not activated by thrombin .	PAR-2 is not activated by thrombin.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	5	6	0	1
5 Multiple proteases found in the microenvironment of an injured blood vessel wall including thrombin 6 , plasmin 7 , and matrix metalloprotease-1 ( MMP-1 ) XREF_BIBR , XREF_BIBR can activate PAR1 , whereas PAR2 can be activated by tryptase , matriptase ( MT-SP1 ) , FVIIa and FXa , and PAR4 by thrombin .	5 Multiple proteases found in the microenvironment of an injured blood vessel wall including thrombin 6, plasmin 7, and matrix metalloprotease-1 (MMP-1) XREF_BIBR, XREF_BIBR can activate PAR1, whereas PAR2 can be activated by tryptase, matriptase (MT-SP1), FVIIa and FXa, and PAR4 by thrombin.	34	54	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	53	54	34	35
Different from these PARs , PAR2 , which is not expressed in platelets , is activated by trypsin , mast cell tryptase and coagulation factors VIIa and Xa , but not by thrombin .	Different from these PARs, PAR2, which is not expressed in platelets, is activated by trypsin, mast cell tryptase and coagulation factors VIIa and Xa, but not by thrombin.	5	33	activated	Positive_regulation_syntax_2_verb	Positive_activation	Positive_regulation	thrombin	thrombin	thrombin	PAR2	PAR2, which is not expressed	par2	32	33	5	6
PAR2 is activated by trypsin and by trypsin like proteases but not by thrombin .	PAR2 is activated by trypsin and by trypsin like proteases but not by thrombin.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	13	14	0	1
PAR2 is not activated effectively by thrombin but can be activated by a variety of serine proteases with trypsin like specificity including the coagulation proteases tissue factor and factor VIIa and factor Xa .	PAR2 is not activated effectively by thrombin but can be activated by a variety of serine proteases with trypsin like specificity including the coagulation proteases tissue factor and factor VIIa and factor Xa.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	6	7	0	1
Thrombin has the highest affinity for PAR-1 , but also activates PAR-3 and PAR-4 , whereas PAR-2 is activated by trypsin and other proteases , but not by thrombin .	Thrombin has the highest affinity for PAR-1, but also activates PAR-3 and PAR-4, whereas PAR-2 is activated by trypsin and other proteases, but not by thrombin.	16	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	28	29	16	17
Four different PARs are known : PAR-1 , -3 , and -4 show responsible for thrombin signaling whereas PAR-2 is activated by trypsin like serine proteases , FVIIa , and matriptase but not by thrombin .	Four different PARs are known : PAR-1, -3, and -4 show responsible for thrombin signaling whereas PAR-2 is activated by trypsin like serine proteases, FVIIa, and matriptase but not by thrombin.	18	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	34	35	18	19
Although able to activate PARs 1 and 4 , thrombin is not able to activate PAR2 , which is a target for trypsin [ XREF_BIBR ] .	Although able to activate PARs 1 and 4, thrombin is not able to activate PAR2, which is a target for trypsin [XREF_BIBR].	9	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	9	10	15	16
Whereas PAR-1 , PAR-3 and PAR-4 are targets for thrombin , cathepsin G , and trypsin , PAR-2 is activated by trypsin , tryptase , acrosin and coagulation factors Xa and Vlla but not by thrombin .	Whereas PAR-1, PAR-3 and PAR-4 are targets for thrombin, cathepsin G, and trypsin, PAR-2 is activated by trypsin, tryptase, acrosin and coagulation factors Xa and Vlla but not by thrombin.	17	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	35	36	17	18
PARs-1 , -3 and -4 are activated by thrombin , while PAR-2 is activated by trypsin or mast cell tryptase , but not by thrombin .	PARs-1, -3 and -4 are activated by thrombin, while PAR-2 is activated by trypsin or mast cell tryptase, but not by thrombin.	11	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	24	25	11	12
PAR2 is not activated by thrombin but by multiple trypsin like serine proteases , including trypsin itself and tryptase .	PAR2 is not activated by thrombin but by multiple trypsin like serine proteases, including trypsin itself and tryptase.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	5	6	0	1
Although thrombin is able to activate PAR3 and PAR4 , and even PAR2 at higher concentrations 8 , in NSC monolayers grown in the presence of EGF and bFGF , genetic knockout of PAR1 completely blocked the ability of thrombin to gate intracellular Ca 2+ flux .	Although thrombin is able to activate PAR3 and PAR4, and even PAR2 at higher concentrations 8, in NSC monolayers grown in the presence of EGF and bFGF, genetic knockout of PAR1 completely blocked the ability of thrombin to gate intracellular Ca 2+ flux.	1	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	1	2	12	13
Although PAR2 is not directly activated by thrombin , the N-terminus of PAR1 formed by thrombin cleavage can bind to an adjacent PAR2 in trans to activate the receptor in endothelial cells .	Although PAR2 is not directly activated by thrombin, the N-terminus of PAR1 formed by thrombin cleavage can bind to an adjacent PAR2 in trans to activate the receptor in endothelial cells.	1	8	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	7	8	1	2
Recently , however , it was shown that thrombin , at concentrations achievable at injury sites or in cancer pabulum , can also directly activate PAR2 [ XREF_BIBR ] .	Recently, however, it was shown that thrombin, at concentrations achievable at injury sites or in cancer pabulum, can also directly activate PAR2 [XREF_BIBR].	8	27	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	8	9	25	26
MKN-1 cells expressed both proteinase activated receptor-1 ( PAR-1 ) and PAR-2 , which are activated by thrombin and trypsin , respectively .	MKN-1 cells expressed both proteinase activated receptor-1 (PAR-1) and PAR-2, which are activated by thrombin and trypsin, respectively.	2	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	17	18	11	12
Indeed , thrombin signals through PAR-1 , -3 and -4 , FVIIa in association with tissue factor activates PAR-2 , while FXa activates both PAR-1 and PAR-2 [ XREF_BIBR ] .	Indeed, thrombin signals through PAR-1, -3 and -4, FVIIa in association with tissue factor activates PAR-2, while FXa activates both PAR-1 and PAR-2 [XREF_BIBR].	2	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	2	3	18	19
This result is not compatible with an action of SFLLRN at a distinct protease activated receptor ( PAR-2 ; which is activated by SFLLRN , but not by thrombin ) , since SLIGRL ( a ligand which is selective for PAR-2 , but not the thrombin receptor ) has no effect .	This result is not compatible with an action of SFLLRN at a distinct protease activated receptor (PAR-2; which is activated by SFLLRN, but not by thrombin), since SLIGRL (a ligand which is selective for PAR-2, but not the thrombin receptor) has no effect.	15	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	28	29	17	18
Compensation for PAR1 by PAR2 , but not vice versa , may be particularly effective for thrombin induced tumour cell chemokinesis and metastasis that involves cross activation of PAR2 by thrombin cleaved PAR1 [ XREF_BIBR ] .	Compensation for PAR1 by PAR2, but not vice versa, may be particularly effective for thrombin induced tumour cell chemokinesis and metastasis that involves cross activation of PAR2 by thrombin cleaved PAR1 [XREF_BIBR].	24	31	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	30	31	28	29
PAR-2 can be proteolytically activated by thrombin , granzyme-B , cathepsin-S , and possibly other proteases .	PAR-2 can be proteolytically activated by thrombin, granzyme-B, cathepsin-S, and possibly other proteases.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	6	7	0	1
Nystedt and co-workers cloned in 1994 a second protease activatable receptor ( PAR-2 ) that could be activated by trypsin but not by thrombin ( 1 ) .	Nystedt and co-workers cloned in 1994 a second protease activatable receptor (PAR-2) that could be activated by trypsin but not by thrombin (1).	10	25	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	23	24	12	13
Since thrombin does not activate PAR2 13 , a specific agonist for this receptor was also tested to serve as a negative control .	Since thrombin does not activate PAR2 13, a specific agonist for this receptor was also tested to serve as a negative control.	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	1	2	5	6
PAR2 can be activated by factor VIIa , factor Xa , tryptase , and trypsin , but not thrombin .	PAR2 can be activated by factor VIIa, factor Xa, tryptase, and trypsin, but not thrombin.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	18	19	0	1
Thrombin enhances migration in the presence of a cleavage blocking anti-PAR2 antibody , suggesting that thrombin activates PAR2 indirectly and independent of receptor cleavage .	Thrombin enhances migration in the presence of a cleavage blocking anti-PAR2 antibody, suggesting that thrombin activates PAR2 indirectly and independent of receptor cleavage.	15	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	15	16	17	18
In contrast , PAR 2 is activated by multiple trypsin like serine proteases including the upstream coagulant proteases VIIa -- tissue factor ( TF ) and Xa , but not by thrombin .	In contrast, PAR 2 is activated by multiple trypsin like serine proteases including the upstream coagulant proteases VIIa -- tissue factor (TF) and Xa, but not by thrombin.	3	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 2	PAR 2	PAR 2	31	32	3	5
Among the 3 types of PARs expressed by HAoSMCs , PAR-1 and -3 will be associated with CCL11 expression in response to thrombin because PAR-2 is activated by trypsin , but not by thrombin [ XREF_BIBR ] .	Among the 3 types of PARs expressed by HAoSMCs, PAR-1 and -3 will be associated with CCL11 expression in response to thrombin because PAR-2 is activated by trypsin, but not by thrombin [XREF_BIBR].	24	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	33	34	24	25
In line with a theory that thrombin activates PAR2 via the intermolecular transactivation of PAR2 XREF_BIBR , a peptide mimicking the PAR1 tethered ligand , TRAP , stimulated both phosphorylation sites in a concentration dependent manner ( 10-100 mumol/L ) .	In line with a theory that thrombin activates PAR2 via the intermolecular transactivation of PAR2 XREF_BIBR, a peptide mimicking the PAR1 tethered ligand, TRAP, stimulated both phosphorylation sites in a concentration dependent manner (10-100 mumol/L).	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	6	7	8	9
29 Activation of signaling pathways within the cell , including PKC and MAPKs- Recent investigations have shown that thrombin leads to increase in the intracellular Ca 2 + level by stimulating the PAR-2 in the murine astrocytes and C6 glioma cells in a dose and concentration dependent manner .	29 Activation of signaling pathways within the cell, including PKC and MAPKs- Recent investigations have shown that thrombin leads to increase in the intracellular Ca 2 + level by stimulating the PAR-2 in the murine astrocytes and C6 glioma cells in a dose and concentration dependent manner.	18	40	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	18	19	32	33
PAR-2 , however , is not efficiently activated by thrombin , but systematic profiling revealed that a surprisingly large number of membrane anchored serine proteases with PAR-2-activating potential are expressed at the site of neural tube closure .	PAR-2, however, is not efficiently activated by thrombin, but systematic profiling revealed that a surprisingly large number of membrane anchored serine proteases with PAR-2-activating potential are expressed at the site of neural tube closure.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	9	10	0	1
Neutrophils ( PMNs ) and endothelial cells are reported to express PAR-2 ; however , thrombin does not activate the PAR-2 receptor , although other serine proteases , including plasmin , have this capacity .	Neutrophils (PMNs) and endothelial cells are reported to express PAR-2; however, thrombin does not activate the PAR-2 receptor, although other serine proteases, including plasmin, have this capacity.	15	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	15	16	20	21
The fourth ( PAR2 ) is not activated by thrombin , but can be activated by other proteases , including trypsin , tryptase and Factor Xa .	The fourth (PAR2) is not activated by thrombin, but can be activated by other proteases, including trypsin, tryptase and Factor Xa.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	9	10	3	4
PAR2 is activated by several proteases , such as trypsin and tryptase , but not by thrombin [ XREF_BIBR ] .	PAR2 is activated by several proteases, such as trypsin and tryptase, but not by thrombin [XREF_BIBR].	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	16	17	0	1
PAR-1 , -3 , and -4 are known to be activated by thrombin , and thereby involved in homeostasis and thrombosis , whereas PAR-2 is activated by trypsin like serine proteases , but not by thrombin .	PAR-1, -3, and -4 are known to be activated by thrombin, and thereby involved in homeostasis and thrombosis, whereas PAR-2 is activated by trypsin like serine proteases, but not by thrombin.	23	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-2	PAR-2	PAR-2	35	36	23	24
We now show that thrombin , at concentrations that can be achieved at sites of acute injury or in a tumor microenvironment , can directly activate PAR2 vasorelaxation and signaling , stimulating calcium and mitogen activated protein kinase responses along with triggeringbeta-arrestin recruitment .	We now show that thrombin, at concentrations that can be achieved at sites of acute injury or in a tumor microenvironment, can directly activate PAR2 vasorelaxation and signaling, stimulating calcium and mitogen activated protein kinase responses along with triggeringbeta-arrestin recruitment.	4	27	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	4	5	26	27
20 Although PAR2 is not directly activated by thrombin , the thrombin generated PAR1 tethered ligand , SFLLRN , serves as a full agonist of PAR2 .	20 Although PAR2 is not directly activated by thrombin, the thrombin generated PAR1 tethered ligand, SFLLRN, serves as a full agonist of PAR2.	2	9	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	8	9	2	3
XREF_BIBR , XREF_BIBR , XREF_BIBR Unlike other PAR family members , PAR2 is not activated by thrombin but can be cleaved by proteases including trypsin , chitinase , and activated FVIIa and FXa .	XREF_BIBR, XREF_BIBR, XREF_BIBR Unlike other PAR family members, PAR2 is not activated by thrombin but can be cleaved by proteases including trypsin, chitinase, and activated FVIIa and FXa.	11	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR2	PAR2	PAR2	16	17	11	12
Conversely , inhibition of ERalpha with 0.1 mum MPP significantly down-regulated ERbeta ( XREF_FIG D ) .	Conversely, inhibition of ERalpha with 0.1 mum MPP significantly down-regulated ERbeta (XREF_FIG D).	2	14	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	4	5	11	12
Ginsenoside protopanaxadiol and g-PPT increased [ Ca ( 2+ ) ] ( i ) , eNOS phosphorylation and NO production in HUVECs , which were inhibited by the GR antagonist , RU486 , the ER antagonist , ICI 182,780 and siRNA targeting GR or ERbeta .	Ginsenoside protopanaxadiol and g-PPT increased [Ca (2+)] (i), eNOS phosphorylation and NO production in HUVECs, which were inhibited by the GR antagonist, RU486, the ER antagonist, ICI 182,780 and siRNA targeting GR or ERbeta.	1	45	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ER	protopanaxadiol and g-PPT increased [Ca (2+)] (i), eNOS phosphorylation and NO production in HUVECs, which were inhibited by the GR antagonist, RU486, the ER	er	ERbeta	ERbeta	erbeta	34	35	44	45
Meanwhile , 1 x 10 (-5) mol x L (-1) or 1 x 10 (-6) mol x L (-1) carnosol could significantly increase ERalpha and ERbeta expressions of T47D cells , and remarkably increase ERalpha and ERbeta ratio .	Meanwhile, 1 x 10 (-5) mol x L (-1) or 1 x 10 (-6) mol x L (-1) carnosol could significantly increase ERalpha and ERbeta expressions of T47D cells, and remarkably increase ERalpha and ERbeta ratio.	19	37	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	carnosol could significantly increase ERalpha and ERbeta expressions	eralpha	ERbeta	ERbeta	erbeta	23	24	36	37
Selectively targeting ERs can provide effective cancer treatments and new techniques to inhibit ERalpha and selectively activate ERbeta are emerging to improve the effectiveness of identifying tissue and subtype selective ER ligands for cancer therapy .	Selectively targeting ERs can provide effective cancer treatments and new techniques to inhibit ERalpha and selectively activate ERbeta are emerging to improve the effectiveness of identifying tissue and subtype selective ER ligands for cancer therapy.	1	31	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	30	31	17	18
Transcriptional effects of estrogen result from its activation of two estrogen receptor ( ER ) isoforms ; ERalpha that drives proliferation and ERbeta that is antiproliferative .	Transcriptional effects of estrogen result from its activation of two estrogen receptor (ER) isoforms; ERalpha that drives proliferation and ERbeta that is antiproliferative.	1	25	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	17	18	22	23
We investigated ligand specific effects on ER activation in HeLa-ERalpha and ERbeta reporter cells ; on proliferation , genome-wide gene regulation and non-ER-mediated effects in MCF7 breast cancer cells ; and how coexposure influenced these effects .	We investigated ligand specific effects on ER activation in HeLa-ERalpha and ERbeta reporter cells; on proliferation, genome-wide gene regulation and non-ER-mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	6	7	11	12
To determine , in preclinical in vivo animal and in clinical studies , whether raloxifene ( a selective oestrogen-receptor ( ER ) modulator that targets ER-beta and induces apoptosis in vitro in androgen independent prostate cancer , AIPC cells ) affects prostate cell differentiation , proliferation and carcinogenesis , and in the pilot phase II clinical trial , the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene .	To determine, in preclinical in vivo animal and in clinical studies, whether raloxifene (a selective oestrogen-receptor (ER) modulator that targets ER-beta and induces apoptosis in vitro in androgen independent prostate cancer, AIPC cells) affects prostate cell differentiation, proliferation and carcinogenesis, and in the pilot phase II clinical trial, the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene.	20	26	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ER	ER	ER	ER-beta	ER-beta	ER-beta	20	21	25	26
Which estrogen receptor mediates memory effects , ERalpha or ERbeta ?	Which estrogen receptor mediates memory effects, ERalpha or ERbeta?	0	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	estrogen receptor	estrogen receptor	estrogen receptor	ERbeta	ERbeta	ERbeta	1	3	9	10
As expected , DPN showed a selective activation of ERbeta when used at a concentration less than 10 nM , with an EC 50 of 2.7 nM and PPT activated only ERalpha ( EC50 = 0.15 nM ) .	As expected, DPN showed a selective activation of ERbeta when used at a concentration less than 10 nM, with an EC 50 of 2.7 nM and PPT activated only ERalpha (EC50 = 0.15 nM).	7	33	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	31	32	9	10
Moreover , ERalpha mediated the protection afforded by estrogen since only the ERalpha agonist , HPTE , but not the ERbeta agonist , DPN , protected against dopamine cell loss .	Moreover, ERalpha mediated the protection afforded by estrogen since only the ERalpha agonist, HPTE, but not the ERbeta agonist, DPN, protected against dopamine cell loss.	2	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	2	3	20	21
Thus , both estrogen receptors have been proposed to play opposite roles in cell proliferation , with estrogen receptor alpha promoting proliferation and estrogen receptor beta having an antiproliferative effect .	Thus, both estrogen receptors have been proposed to play opposite roles in cell proliferation, with estrogen receptor alpha promoting proliferation and estrogen receptor beta having an antiproliferative effect.	17	26	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	estrogen receptor	estrogen receptor	estrogen receptor	estrogen receptor beta	estrogen receptor beta	estrogen receptor beta	17	19	23	26
We demonstrated that E2 increased expression of both ER-alpha , and ER-beta in heart tissues , consistent with other reports showing E2 replacement increases expression of ER-alpha , and ER-beta in heart tissues from aged rats .	We demonstrated that E2 increased expression of both ER-alpha, and ER-beta in heart tissues, consistent with other reports showing E2 replacement increases expression of ER-alpha, and ER-beta in heart tissues from aged rats.	3	32	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ER-alpha	E2 increased expression of both ER-alpha	er-alpha	ER-beta	ER-beta	er-beta	8	9	29	30
In contrast , ovariectomized ( OVX ) rats treated with an ERbeta agonist exhibited significantly less depressive behavior than rats treated with vehicle or an ERalpha agonist ; an effect that was absent in ERbeta -/- mice , indicating that ERbeta signaling may play a key role in the mechanism of ET in depression .	In contrast, ovariectomized (OVX) rats treated with an ERbeta agonist exhibited significantly less depressive behavior than rats treated with vehicle or an ERalpha agonist; an effect that was absent in ERbeta -/- mice, indicating that ERbeta signaling may play a key role in the mechanism of ET in depression.	11	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	25	26	11	12
The sense variants may encode functional ERalpha or related proteins that modulate ERalpha or ERbeta activity .	The sense variants may encode functional ERalpha or related proteins that modulate ERalpha or ERbeta activity.	4	15	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	6	7	14	15
In the present study , we have generated rats harboring a dominant negative ERalpha , which inhibits the actions of not only ERalpha but also recently identified ERbeta .	In the present study, we have generated rats harboring a dominant negative ERalpha, which inhibits the actions of not only ERalpha but also recently identified ERbeta.	9	28	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	13	14	27	28
ER-alpha and ER-beta share more than 96 % similarity in DNA binding region , but only 53 % similarity in ligand binding region [ XREF_BIBR ] , consequently inducing different signal pathways activated by ER-alpha and ER-beta .	ER-alpha and ER-beta share more than 96% similarity in DNA binding region, but only 53% similarity in ligand binding region [XREF_BIBR], consequently inducing different signal pathways activated by ER-alpha and ER-beta.	0	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ER-alpha	ER-alpha	ER-alpha	ER-beta	ER-beta	ER-beta	34	35	2	3
In the case of SM6Met the desired positive estrogenic attributes are more complex in that ERbeta agonism , ERalpha antagonism and antagonism of E 2 -induced breast cancer cell proliferation were simultaneously targeted .	In the case of SM6Met the desired positive estrogenic attributes are more complex in that ERbeta agonism, ERalpha antagonism and antagonism of E 2 -induced breast cancer cell proliferation were simultaneously targeted.	15	33	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	18	19	15	16
Overall , the preclinical research suggests that selective ER modulators targeting ERbeta may be an attractive alternative or adjunct treatment to currently prescribed antidepressants or anxiolytics .	Overall, the preclinical research suggests that selective ER modulators targeting ERbeta may be an attractive alternative or adjunct treatment to currently prescribed antidepressants or anxiolytics.	8	12	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	8	9	11	12
In the present study we explored the roles of ERalpha and ERbeta in estrogen induced disruption of avian sex differentiation by exposing Japanese quail embryos to the ERalpha selective agonist 16alphaLE 2 and the ERbeta selective agonist WAY .	In the present study we explored the roles of ERalpha and ERbeta in estrogen induced disruption of avian sex differentiation by exposing Japanese quail embryos to the ERalpha selective agonist 16alphaLE 2 and the ERbeta selective agonist WAY.	7	37	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	9	10	34	35
The identification of a second oestrogen receptor , oestrogen receptor ( ER ) beta , has led to a need to assess the relative importance of the classical ERalpha and ERbeta in human breast and breast carcinomas .	The identification of a second oestrogen receptor, oestrogen receptor (ER) beta, has led to a need to assess the relative importance of the classical ERalpha and ERbeta in human breast and breast carcinomas.	9	31	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	11	12	30	31
However , both ERalpha and ERbeta are capable of exerting non genomic activity , and they appear to be acting through different signaling pathways and elicit opposite affects , with the ERalpha activating the extracellular signal regulated kinase ( ERK ) pathway possible in association with IGF-IR-matrix metalloproteinases- heparin binding epidermal growth factor to stimulate growth and the ERbeta activating the p38 MAPK to increase apoptosis .	However, both ERalpha and ERbeta are capable of exerting non genomic activity, and they appear to be acting through different signaling pathways and elicit opposite affects, with the ERalpha activating the extracellular signal regulated kinase (ERK) pathway possible in association with IGF-IR-matrix metalloproteinases- heparin binding epidermal growth factor to stimulate growth and the ERbeta activating the p38 MAPK to increase apoptosis.	16	59	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	31	32	58	59
The present study confirms and extends these previous studies by showing that central activation of either ERalpha or ERbeta by icv chronic infusions of selective ER agonists attenuate the pressor effects in Aldo and NaCl treated OVX female rats .	The present study confirms and extends these previous studies by showing that central activation of either ERalpha or ERbeta by icv chronic infusions of selective ER agonists attenuate the pressor effects in Aldo and NaCl treated OVX female rats.	13	26	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	25	26	18	19
EAE was induced in wild-type , ERalpha-, or ERbeta deficient mice , and each was treated with the highly selective ERalpha agonist , propyl pyrazole triol , to determine the effect on clinical outcomes , as well as on inflammatory and neurodegenerative changes .	EAE was induced in wild-type, ERalpha-, or ERbeta deficient mice, and each was treated with the highly selective ERalpha agonist, propyl pyrazole triol, to determine the effect on clinical outcomes, as well as on inflammatory and neurodegenerative changes.	6	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	20	21	8	9
Tissue specific effects of 17beta-estradiol ( E ( 2 ) ) and synthetic estrogen receptor ( ER ) ligands on target gene regulation might , at least partly , be explained by a selective ligand induced conformational change of their receptors ( ERalpha and ERbeta ) .	Tissue specific effects of 17beta-estradiol (E (2)) and synthetic estrogen receptor (ER) ligands on target gene regulation might, at least partly, be explained by a selective ligand induced conformational change of their receptors (ERalpha and ERbeta).	13	45	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	estrogen receptor	estrogen receptor	estrogen receptor	ERbeta	ERbeta	ERbeta	13	15	44	45
ER agonists that selectively target ERalpha , ERbeta and perhaps GPR30 may modify specific vascular signaling pathways .	ER agonists that selectively target ERalpha, ERbeta and perhaps GPR30 may modify specific vascular signaling pathways.	0	8	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	0	1	7	8
Thus , mitogenic effects of E2 in these OVCA models are mediated by ERalpha and not dependent on ERbeta .	Thus, mitogenic effects of E2 in these OVCA models are mediated by ERalpha and not dependent on ERbeta.	11	19	mediated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	13	14	18	19
Transcriptome analysis in human ductal breast epithelial tumour cell line , T47D , following either stimulation with either estrogen receptor ( ER ) alpha which induces proliferation or ERbeta which has antiproliferative effects showed that K 2P 5.1 mRNA was upregulated by ERalpha signalling XREF_BIBR .	Transcriptome analysis in human ductal breast epithelial tumour cell line, T47D, following either stimulation with either estrogen receptor (ER) alpha which induces proliferation or ERbeta which has antiproliferative effects showed that K 2P 5.1 mRNA was upregulated by ERalpha signalling XREF_BIBR.	18	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	estrogen receptor	estrogen receptor	estrogen receptor	ERbeta	ERbeta	ERbeta	18	20	28	29
Ligands for the estrogen receptor ( ER ) that have the capacity to selectively bind to or activate the ER subtypes ERalpha or ERbeta would be useful in elucidating the biology of these two receptors and might assist in the development of estrogen pharmaceuticals with improved tissue selectivity .	Ligands for the estrogen receptor (ER) that have the capacity to selectively bind to or activate the ER subtypes ERalpha or ERbeta would be useful in elucidating the biology of these two receptors and might assist in the development of estrogen pharmaceuticals with improved tissue selectivity.	3	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	estrogen receptor	estrogen receptor	estrogen receptor	ERbeta	ERbeta	ERbeta	3	5	23	24
Rzemieniec et al confirmed a pivotal involvement of ERalpha , but not ERbeta or the recently identified membrane ER G-protein-coupled receptor 30 ( GPER ) , in the neuroprotective potential of raloxifene , a type of selective estrogen receptor modulator ( SERM ) , against hypoxia induced damage of mouse hippocampal cells .	Rzemieniec et al confirmed a pivotal involvement of ERalpha, but not ERbeta or the recently identified membrane ER G-protein-coupled receptor 30 (GPER), in the neuroprotective potential of raloxifene, a type of selective estrogen receptor modulator (SERM), against hypoxia induced damage of mouse hippocampal cells.	3	47	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	estrogen receptor	estrogen receptor	estrogen receptor	ERbeta	ERbeta	ERbeta	37	39	12	13
There is general agreement that ERs function as dimers , and co-expression of ERalpha and ERbeta in the same cell causes the formation of homodimers ( ERalpha and ERalpha and ERbeta and ERbeta ) or heterodimers ( ERalpha and ERbeta ) , which affect ligand-specificity .	There is general agreement that ERs function as dimers, and co-expression of ERalpha and ERbeta in the same cell causes the formation of homodimers (ERalpha and ERalpha and ERbeta and ERbeta) or heterodimers (ERalpha and ERbeta), which affect ligand-specificity.	11	32	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	co-expression of ERalpha	eralpha	ERbeta	ERbeta	erbeta	13	14	30	31
In addition , we observed that E2 elevated HIF-1alpha is likely mediated by ERalpha and not ERbeta .	In addition, we observed that E2 elevated HIF-1alpha is likely mediated by ERalpha and not ERbeta.	10	17	mediated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	13	14	16	17
We proposed a non additive non multiplicative oligogenic model including ESR2 AG genotype modulated by NRIP1 A+ or ESR1 TT genotypes involved in osteoporosis .	We proposed a non additive non multiplicative oligogenic model including ESR2 AG genotype modulated by NRIP1 A+ or ESR1 TT genotypes involved in osteoporosis.	10	20	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ESR1	ESR1	ESR1	ESR2	ESR2	ESR2	18	19	10	11
The lack of ERalpha expression enabled us to examine the ability of ERbeta and hPMC2 to recruit ER associated coactivators and for inducing antioxidative genes in the absence of ERalpha .	The lack of ERalpha expression enabled us to examine the ability of ERbeta and hPMC2 to recruit ER associated coactivators and for inducing antioxidative genes in the absence of ERalpha.	3	14	enabled	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha expression	eralpha	ERbeta	ERbeta	erbeta	3	4	12	13
Although the E2 induced proliferation with full expression of ERbeta was reached at 3nM of PPT ( 153 % ) , no considerable reduction of proliferation compared with E2 ( 124 % ) was observed under all ERalpha and ERbeta ratios studied due to the inability of PPT to activate ERbeta .	Although the E2 induced proliferation with full expression of ERbeta was reached at 3nM of PPT (153%), no considerable reduction of proliferation compared with E2 (124%) was observed under all ERalpha and ERbeta ratios studied due to the inability of PPT to activate ERbeta.	37	51	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	37	38	50	51
Previously , we have shown that mice treated neonatally with genistein , the primary soy phytoestrogen , have multi-oocyte follicles ( MOFs ) , an effect apparently mediated by estrogen receptor 2 ( ESR2 , more commonly known as ERbeta ) .	Previously, we have shown that mice treated neonatally with genistein, the primary soy phytoestrogen, have multi-oocyte follicles (MOFs), an effect apparently mediated by estrogen receptor 2 (ESR2, more commonly known as ERbeta).	19	35	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	estrogen receptor	estrogen receptor	estrogen receptor	ESR2	ESR2	ESR2	29	31	33	34
Substitution performed on the carborane moiety in the ortho position was found to decrease the binding affinity of the analogues to both ERalpha and ERbeta , but more so to ERalpha , thus increasing ERbeta selectivity .	Substitution performed on the carborane moiety in the ortho position was found to decrease the binding affinity of the analogues to both ERalpha and ERbeta, but more so to ERalpha, thus increasing ERbeta selectivity.	28	35	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	30	31	34	35
In transcription assays , ERbeta is less active than ERalpha and in cotransfection assays , ERbeta inhibits the activity of ERalpha supporting the opposing effects of ERalpha and ERbeta .	In transcription assays, ERbeta is less active than ERalpha and in cotransfection assays, ERbeta inhibits the activity of ERalpha supporting the opposing effects of ERalpha and ERbeta.	18	29	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	20	21	28	29
The two isoforms of estrogen receptor ( ER ) alpha and beta play opposite roles in regulating proliferation and differentiation of breast cancers , with ER-alpha mediating mitogenic effects and ER-beta acting as a tumor suppressor .	The two isoforms of estrogen receptor (ER) alpha and beta play opposite roles in regulating proliferation and differentiation of breast cancers, with ER-alpha mediating mitogenic effects and ER-beta acting as a tumor suppressor.	12	31	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ER-alpha	ER-alpha	ER-alpha	ER-beta	ER-beta	ER-beta	25	26	30	31
Clinical trials have failed to demonstrate cardioprotective benefit from chronic estrogen ( E 2 ) replacement therapy , yet protective effects of E 2 have been demonstrated in adult animal models and are mediated by the estrogen receptor ( ER ) subtypes ERalpha and ERbeta .	Clinical trials have failed to demonstrate cardioprotective benefit from chronic estrogen (E 2) replacement therapy, yet protective effects of E 2 have been demonstrated in adult animal models and are mediated by the estrogen receptor (ER) subtypes ERalpha and ERbeta.	5	45	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	estrogen receptor	estrogen receptor	estrogen receptor	ERbeta	ERbeta	ERbeta	36	38	44	45
In this report , forty-nine pesticides were tested for ERalpha and beta activation or inhibition in stable reporter cell lines , HELN ERalpha and ERbeta .	In this report, forty-nine pesticides were tested for ERalpha and beta activation or inhibition in stable reporter cell lines, HELN ERalpha and ERbeta.	9	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	9	10	24	25
Both AR and ERalpha can independently mediate the cancellous bone sparing effects of sex steroids in male mice , but not ERbeta .	Both AR and ERalpha can independently mediate the cancellous bone sparing effects of sex steroids in male mice, but not ERbeta.	1	22	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	3	4	21	22
Studies in ERalpha or ERbeta knockout mice indicated that ERalpha is the major mediator of OBHS effectiveness and ERbeta is dominant in CLI actions , implying involvement of both ERs in endometriosis .	Studies in ERalpha or ERbeta knockout mice indicated that ERalpha is the major mediator of OBHS effectiveness and ERbeta is dominant in CLI actions, implying involvement of both ERs in endometriosis.	9	19	is the major mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	9	10	18	19
The ER is regulated primarily by the endogenous estrogen , estradiol ( E2 , XREF_FIG ) , but it is also the target of pharmaceutical agents , including estrogen agonists , antagonists , and selective estrogen receptor modulators ( SERMs ) that activate the subtypes ERalpha and ERbeta .	The ER is regulated primarily by the endogenous estrogen, estradiol (E2, XREF_FIG), but it is also the target of pharmaceutical agents, including estrogen agonists, antagonists, and selective estrogen receptor modulators (SERMs) that activate the subtypes ERalpha and ERbeta.	35	48	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	estrogen receptor	estrogen receptor	estrogen receptor	ERbeta	ERbeta	ERbeta	35	37	47	48
On the other hand , the lack of ERalpha expression would allow the investigation of ERbeta genomic function without the interference from the former receptor .	On the other hand, the lack of ERalpha expression would allow the investigation of ERbeta genomic function without the interference from the former receptor.	8	17	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	ERalpha expression	eralpha	ERbeta	ERbeta	erbeta	8	9	15	16
Alternatively , in the absence of MK2 and MK3 the signal may circumvent the p38 MAPK pathway altogether and instead use the ERK1/2 pathway , which also activates MNK1 and MSK1 XREF_BIBR .	Alternatively, in the absence of MK2 and MK3 the signal may circumvent the p38 MAPK pathway altogether and instead use the ERK1/2 pathway, which also activates MNK1 and MSK1 XREF_BIBR.	22	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MSK1	MSK1	MSK1	22	23	30	31
A combination of both greatly reduced ( 86.1 % ) MSK1 activation suggesting that p38 MAPK and ERK act synergistically to activate MSK1 ( XREF_FIG ) .	A combination of both greatly reduced (86.1%) MSK1 activation suggesting that p38 MAPK and ERK act synergistically to activate MSK1 (XREF_FIG).	15	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	17	18	22	23
OspF alters HP1gamma phosphorylation mainly by inactivating the Erk activated kinase MSK1 , spotlighting it as a new HP1 kinase .	OspF alters HP1gamma phosphorylation mainly by inactivating the Erk activated kinase MSK1, spotlighting it as a new HP1 kinase.	7	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	MSK1	MSK1	MSK1	8	9	11	12
Eleven mammalian MAPK activated protein kinases have been identified , and they are divided into five subgroups : the ribosomal-S6-kinases RSK1-4 , the MAPK interacting kinases MNK1 and 2 , the mitogen- and stress activated kinases MSK1 and 2 , the MAPK activated protein kinases MK2 and 3 , and the MAPK activated protein kinase MK5 ( also referred to as PRAK ) .	Eleven mammalian MAPK activated protein kinases have been identified, and they are divided into five subgroups : the ribosomal-S6-kinases RSK1-4, the MAPK interacting kinases MNK1 and 2, the mitogen- and stress activated kinases MSK1 and 2, the MAPK activated protein kinases MK2 and 3, and the MAPK activated protein kinase MK5 (also referred to as PRAK).	20	51	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	MSK1	MSK1	MSK1	23	24	36	37
We found that , as a result of selective pressure by PI3K and mTOR inhibition , MSK1 was up-regulated and phosphorylated by ERK signaling .	We found that, as a result of selective pressure by PI3K and mTOR inhibition, MSK1 was up-regulated and phosphorylated by ERK signaling.	16	23	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	22	23	16	17
We also sought to determine whether our TLR agonists activate MSK1 , a protein kinase that is similarly activated by ERK1/2 .	We also sought to determine whether our TLR agonists activate MSK1, a protein kinase that is similarly activated by ERK1/2.	9	21	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MSK1	MSK1	MSK1	20	21	10	11
SB203580 , PD98059 , and H89 are inhibitors of p38 activation of MSK1 , MAPK activation of MSK1 and the ability of activate MSK1 to phosphorylate NF-kappaB p65 , respectively .	SB203580, PD98059, and H89 are inhibitors of p38 activation of MSK1, MAPK activation of MSK1 and the ability of activate MSK1 to phosphorylate NF-kappaB p65, respectively.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	MSK1	MSK1	MSK1	14	15	17	18
In conclusion , we show that histone H3S28 phosphorylation through ERK and p38 MAPK activation of MSK1 kinase represents a critical step that links signal transduction pathways that are responsive to external stimuli to help in evicting the Polycomb complexes that induce INK4AB and ARF gene expression and senescence .	In conclusion, we show that histone H3S28 phosphorylation through ERK and p38 MAPK activation of MSK1 kinase represents a critical step that links signal transduction pathways that are responsive to external stimuli to help in evicting the Polycomb complexes that induce INK4AB and ARF gene expression and senescence.	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	10	11	16	17
CREB is the physiological substrate for MAPKs and stress activated protein kinases-1 ( MSK1 ) , which is activated by ERK and p38 MAPK mediated signaling in response to LPS .	CREB is the physiological substrate for MAPKs and stress activated protein kinases-1 (MSK1), which is activated by ERK and p38 MAPK mediated signaling in response to LPS.	11	21	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	20	21	13	14
MSK1 and -2 are activated in cells via phosphorylation by either ERK1/2 or p38alpha and can therefore serve to integrate signals downstream of these two pathways .	MSK1 and -2 are activated in cells via phosphorylation by either ERK1/2 or p38alpha and can therefore serve to integrate signals downstream of these two pathways.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MSK1	MSK1	MSK1	11	12	0	1
Although MSK1 can be activated by either the ERK1/2 or p38alpha MAPK pathways 42 , we have previously shown in BDNF stimulated cortical neuronal cultures that the ERK1/2 , but not the p38 pathway , is responsible for MSK1 activation 18 .	Although MSK1 can be activated by either the ERK1/2 or p38alpha MAPK pathways 42, we have previously shown in BDNF stimulated cortical neuronal cultures that the ERK1/2, but not the p38 pathway, is responsible for MSK1 activation 18.	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	MSK1	MSK1	MSK1	11	12	1	2
Another protein kinase substrate of p38alpha MAPK is mitogen and stress activated protein kinase 1 ( MSK1 ) , which is activated upon phosphorylation by p38alpha MAPK .	Another protein kinase substrate of p38alpha MAPK is mitogen and stress activated protein kinase 1 (MSK1), which is activated upon phosphorylation by p38alpha MAPK.	8	27	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	MSK1	MSK1	MSK1	26	27	16	17
RPS6KA5 is activated by ERK .	RPS6KA5 is activated by ERK.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	RPS6KA5	RPS6KA5	RPS6KA5	4	5	0	1
The activated ERK1/2 can activate the p90RSK ( 90-kDa ribosomal S6 kinase ) and MSK1 ( mitogen and stress activated protein kinase ) [ XREF_BIBR , XREF_BIBR ] .	The activated ERK1/2 can activate the p90RSK (90-kDa ribosomal S6 kinase) and MSK1 (mitogen and stress activated protein kinase) [XREF_BIBR, XREF_BIBR].	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MSK1	MSK1	MSK1	2	3	14	15
Chromatin immunoprecipitation ( ChIP ) analysis showed that ERK mediated activation of MSK1 leads to the accumulation of histone H3 phosphorylated on Ser10 , at the promoter of fosB .	Chromatin immunoprecipitation (ChIP) analysis showed that ERK mediated activation of MSK1 leads to the accumulation of histone H3 phosphorylated on Ser10, at the promoter of fosB.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	8	9	12	13
Notably , the CTD MSK1 is activated by either p38 or ERK1/2 .	Notably, the CTD MSK1 is activated by either p38 or ERK1/2.	2	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MSK1	MSK1	MSK1	11	12	4	5
The second group includes 13 proteins comprising the transcription factors : p53 ( S15 and S46 ) controlling cell cycle arrest , DNA repair or apoptosis ; MSK-1 ( S360 ) activated by ERK and p38 ; anti-apoptotic STAT3 ( S727 ) activated through the MAPK or mTOR pathways ; ATF2 ( T69/71 ) activated by SAPK and JNK and p38 MAPK ; NF-kB p65 ( S536 ) playing a pivotal role in inflammatory and immune responses ; and CREB ( S133 ) mediating numerous cellular responses .	The second group includes 13 proteins comprising the transcription factors : p53 (S15 and S46) controlling cell cycle arrest, DNA repair or apoptosis; MSK-1 (S360) activated by ERK and p38; anti-apoptotic STAT3 (S727) activated through the MAPK or mTOR pathways; ATF2 (T69/71) activated by SAPK and JNK and p38 MAPK; NF-kB p65 (S536) playing a pivotal role in inflammatory and immune responses; and CREB (S133) mediating numerous cellular responses.	3	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK-1	MSK-1	MSK-1	33	34	27	28
These signaling adaptors include ERK and JNK MAPKs and PI3K , which subsequently activated MSK1 and AKT , respectively .	These signaling adaptors include ERK and JNK MAPKs and PI3K, which subsequently activated MSK1 and AKT, respectively.	4	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	4	5	14	15
Furthermore , we find that histone H3 phosphorylation is induced by BDNF in this region via the ERK1/2 activated kinase MSK1 , and that this , as opposed to the phosphorylation of CREB S133 , is associated with the induction of Arc and Arg3.1 .	Furthermore, we find that histone H3 phosphorylation is induced by BDNF in this region via the ERK1/2 activated kinase MSK1, and that this, as opposed to the phosphorylation of CREB S133, is associated with the induction of Arc and Arg3.1.	14	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MSK1	MSK1	MSK1	17	18	20	21
A recent study has reported that the mechanism of increased breast cancer migration and invasiveness involves MAPK induced MSK1 recruitment to the Snail promoter , via activation of the CXCL5-CXCR2 chemotaxis ligand-receptor pathway XREF_BIBR .	A recent study has reported that the mechanism of increased breast cancer migration and invasiveness involves MAPK induced MSK1 recruitment to the Snail promoter, via activation of the CXCL5-CXCR2 chemotaxis ligand-receptor pathway XREF_BIBR.	16	19	induced	Positive_early_activation	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	MSK1	MSK1	MSK1	16	17	18	19
42 There were no upstream changes in ERK activation after administration of SB747651A , supporting the targeted specificity of MSK1 inhibition .	42 There were no upstream changes in ERK activation after administration of SB747651A, supporting the targeted specificity of MSK1 inhibition.	7	20	supporting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	7	8	19	20
MSK1 , activated by both p38 and ERK , is supposed to be a key inflammatory regulator XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	MSK1, activated by both p38 and ERK, is supposed to be a key inflammatory regulator XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	7	8	0	1
Nevertheless , we found that MSK1 was activated by ERK in response to PI3K and mTOR inhibition .	Nevertheless, we found that MSK1 was activated by ERK in response to PI3K and mTOR inhibition.	5	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	9	10	5	6
MAPK activated kinases MK2 and MK3 are uniquely activated by p38 MAPK , whereas the mitogen- and stress activated kinases MSK1 and MSK2 can be activated by either p38 MAPK or ERK .	MAPK activated kinases MK2 and MK3 are uniquely activated by p38 MAPK, whereas the mitogen- and stress activated kinases MSK1 and MSK2 can be activated by either p38 MAPK or ERK.	20	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	31	32	20	21
Stimulation by TNF also activates p38 kinase and ERK MAPK kinases , both of which can activate MSK1 independently , with maximal activation requiring phosphorylation of MSK1 by both kinases .	Stimulation by TNF also activates p38 kinase and ERK MAPK kinases, both of which can activate MSK1 independently, with maximal activation requiring phosphorylation of MSK1 by both kinases.	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK MAPK	ERK MAPK	ERK MAPK	MSK1	MSK1	MSK1	8	10	17	18
In contrast , PMA induced ERK dependent activation of MSK1 is not impaired .	In contrast, PMA induced ERK dependent activation of MSK1 is not impaired.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	MSK1	MSK1	MSK1	5	6	9	10
These included genes that were activated by ERK ( RPS6KA5 ) or that mediate apoptosis ( BIRC1 ) , cell cycle regulation ( C9orf127 ) , or ubiquitin dependent protein catabolic process ( USP34 ) .	These included genes that were activated by ERK (RPS6KA5) or that mediate apoptosis (BIRC1), cell cycle regulation (C9orf127), or ubiquitin dependent protein catabolic process (USP34).	2	10	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	RPS6KA5	RPS6KA5	RPS6KA5	7	8	9	10
In addition to PAR-1 , thrombin activates PAR-3 and PAR-4 , whereas trypsin , factor VIIa , Xa , mast cell tryptase , and neutrophil elastase all activate PAR-2 [ XREF_BIBR ] .	In addition to PAR-1, thrombin activates PAR-3 and PAR-4, whereas trypsin, factor VIIa, Xa, mast cell tryptase, and neutrophil elastase all activate PAR-2 [XREF_BIBR].	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-3	PAR-3	PAR-3	5	6	7	8
While PAR-3 and PAR-4 can be proteolytically activated by thrombin , evidence suggests that PAR-3 acts as a cofactor for PAR-4 at low concentrations of thrombin and is a non signaling receptor XREF_BIBR .	While PAR-3 and PAR-4 can be proteolytically activated by thrombin, evidence suggests that PAR-3 acts as a cofactor for PAR-4 at low concentrations of thrombin and is a non signaling receptor XREF_BIBR.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-3	PAR-3	PAR-3	9	10	1	2
Moreover , persistent thrombin signalling in Par3 deficient platelets led to the identification of Par4 XREF_BIBR .	Moreover, persistent thrombin signalling in Par3 deficient platelets led to the identification of Par4 XREF_BIBR.	3	8	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	Par3	Par3	Par3	3	4	6	7
Dental pulp fibroblasts express the thrombin receptors protease activated receptor-1 ( PAR-1 ) , PAR-3 and PAR-4 .	Dental pulp fibroblasts express the thrombin receptors protease activated receptor-1 (PAR-1), PAR-3 and PAR-4.	5	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-3	PAR-3	PAR-3	5	6	14	15
It appeared that thrombin induced proMMP-9 release was most likely through activation of PAR-1 as HDFs express PAR-1 , PAR-2 and PAR-3 , PAR-2 is not a receptor for thrombin and PAR-3 could not be activated by thrombin alone [ XREF_BIBR ] .	It appeared that thrombin induced proMMP-9 release was most likely through activation of PAR-1 as HDFs express PAR-1, PAR-2 and PAR-3, PAR-2 is not a receptor for thrombin and PAR-3 could not be activated by thrombin alone [XREF_BIBR].	29	40	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-3	PAR-3	PAR-3	37	38	31	32
The receptor subfamily also includes PAR 2 which is activated by trypsin , and two other thrombin activated receptors , PAR 3 and PAR 4 XREF_BIBR - XREF_BIBR .	The receptor subfamily also includes PAR 2 which is activated by trypsin, and two other thrombin activated receptors, PAR 3 and PAR 4 XREF_BIBR - XREF_BIBR.	14	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 3	PAR 3	PAR 3	16	17	20	22
Recently , it was shown that thrombin activation of PAR-3 in human lung epithelial cells led to Rho- and calcium dependent ATP release which was PAR-1 and PAR-4 independent .	Recently, it was shown that thrombin activation of PAR-3 in human lung epithelial cells led to Rho- and calcium dependent ATP release which was PAR-1 and PAR-4 independent.	6	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-3	PAR-3	PAR-3	6	7	9	10
PAR-2 is activated by trypsin , tryptase , factor Xa , or factor VIIa , but it can not be activated by thrombin , PAR-3 and PAR-4 can also be activated by thrombin .	PAR-2 is activated by trypsin, tryptase, factor Xa, or factor VIIa, but it can not be activated by thrombin, PAR-3 and PAR-4 can also be activated by thrombin.	24	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-3	PAR-3	PAR-3	32	33	24	25
PAR-3 and PAR-4 are mainly activated by thrombin , but PAR-4 can also be activated by cathepsin G , a protease secreted by neutrophils [ XREF_BIBR , XREF_BIBR ] .	PAR-3 and PAR-4 are mainly activated by thrombin, but PAR-4 can also be activated by cathepsin G, a protease secreted by neutrophils [XREF_BIBR, XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-3	PAR-3	PAR-3	7	8	0	1
However thrombin can also activate PAR-3 and PAR-4 , whereas PAR-2 is primarily a receptor for trypsin and the trypsin like enzymes , factors Xa and VIIa [ XREF_BIBR - XREF_BIBR ] .	However thrombin can also activate PAR-3 and PAR-4, whereas PAR-2 is primarily a receptor for trypsin and the trypsin like enzymes, factors Xa and VIIa [XREF_BIBR - XREF_BIBR].	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-3	PAR-3	PAR-3	1	2	5	6
PAR-3 , also activated by thrombin , although relatively well expressed in numerous tissues , is a special case .	PAR-3, also activated by thrombin, although relatively well expressed in numerous tissues, is a special case.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-3	PAR-3	PAR-3	5	6	0	1
Protease activated receptors Par4 ( 5,200 +/- 1,500 ) and Par3 ( 3,900 +/- 1,400 ) , which reside on mouse platelets ( in contrast to human platelets , where PAR1 and PAR4 are expressed ) , are activated by thrombin , one of the most potent platelet agonists .	Protease activated receptors Par4 (5,200 +/- 1,500) and Par3 (3,900 +/- 1,400), which reside on mouse platelets (in contrast to human platelets, where PAR1 and PAR4 are expressed), are activated by thrombin, one of the most potent platelet agonists.	10	48	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	Par3	Par3	Par3	40	41	10	11
PAR-1 is the prototypical receptor of thrombin ( and FXa ) ( XREF_FIG ) , although PAR-3 and -4 can be activated by thrombin also .	PAR-1 is the prototypical receptor of thrombin (and FXa) (XREF_FIG), although PAR-3 and -4 can be activated by thrombin also.	16	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-3	PAR-3	PAR-3	23	24	16	17
This suggests that APC and thrombin activation of PAR 3 mediates different signaling profile , and thus is involved in different cellular response , respectively .	This suggests that APC and thrombin activation of PAR 3 mediates different signaling profile, and thus is involved in different cellular response, respectively.	3	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR 3	PAR 3	PAR 3	5	6	8	10
Constitutive activation of the ERK1/2 pathways increased the activity of both RSK1 and RSK2 , whereas constitutive activation of ERK5 only activated RSK2 ( XREF_FIG ) .	Constitutive activation of the ERK1/2 pathways increased the activity of both RSK1 and RSK2, whereas constitutive activation of ERK5 only activated RSK2 (XREF_FIG).	4	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	4	5	13	14
Furthermore , our previous results have demonstrated that ERK1/2 mediated RSK2 activation modulates NF-kappaB activity by phosphorylation of IkappaBalpha at Ser32 [ XREF_BIBR ] .	Furthermore, our previous results have demonstrated that ERK1/2 mediated RSK2 activation modulates NF-kappaB activity by phosphorylation of IkappaBalpha at Ser32 [XREF_BIBR].	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	8	9	10	11
More recently we have found that PEA-15 forms a complex with both ERK and RSK2 and is essential for ERK activation of RSK2 [ XREF_BIBR ] .	More recently we have found that PEA-15 forms a complex with both ERK and RSK2 and is essential for ERK activation of RSK2 [XREF_BIBR].	19	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	19	20	22	23
Indeed PEA-15 acts as a scaffold to enhance ERK activation of RSK2 and subsequent CREB transcription [ XREF_BIBR ] .	Indeed PEA-15 acts as a scaffold to enhance ERK activation of RSK2 and subsequent CREB transcription [XREF_BIBR].	8	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	8	9	11	12
RSK2 , a protein kinase A/protein kinase G/protein kinase C ( AGC ) family member , is activated by ERK phosphorylation .	RSK2, a protein kinase A/protein kinase G/protein kinase C (AGC) family member, is activated by ERK phosphorylation.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK phosphorylation	erk	RSK2	RSK2	rsk2	19	20	0	1
XREF_BIBR These results indicate that ERKs mediated RSK2 signaling pathway induces not only cell proliferation but also cell survival .	XREF_BIBR These results indicate that ERKs mediated RSK2 signaling pathway induces not only cell proliferation but also cell survival.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	RSK2	RSK2	RSK2	5	6	7	8
Recently , it was shown that PEA-15 may act as a scaffold for ERK and RSK2 molecules , resulting in increasing ERK activation of RSK2 leading to a specific physiological outcome .	Recently, it was shown that PEA-15 may act as a scaffold for ERK and RSK2 molecules, resulting in increasing ERK activation of RSK2 leading to a specific physiological outcome.	21	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	21	22	24	25
Indeed , high levels of PEA15 prevent ERK activation of RSK2 29 .	Indeed, high levels of PEA15 prevent ERK activation of RSK2 29.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	7	8	10	11
The ERK cascade activates RSK2 , an S6 kinase which activates transcription factors , including CREB , that bind to the promoter region of the c-fos gene , and mediate synaptic plasticity underlying diverse learning and memory related processes , including CPP .	The ERK cascade activates RSK2, an S6 kinase which activates transcription factors, including CREB, that bind to the promoter region of the c-fos gene, and mediate synaptic plasticity underlying diverse learning and memory related processes, including CPP.	1	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	1	2	4	5
ERK1/2 mediated RSK2 signaling in cell transformation .	ERK1/2 mediated RSK2 signaling in cell transformation.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	0	1	2	3
Erk and MAPK activates Rsk2 , the major kinase for CREB .	Erk and MAPK activates Rsk2, the major kinase for CREB.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	Rsk2	Rsk2	Rsk2	0	1	4	5
As expected , inhibition of ERK1/2 activity in the Rsk2 knockdown PC12 cells with the U0126 inhibitor reversed the effect of RSK2 depletion on GluR2 expression , clearly implicating ERK1/2 in the elevated GluR2 expression .	As expected, inhibition of ERK1/2 activity in the Rsk2 knockdown PC12 cells with the U0126 inhibitor reversed the effect of RSK2 depletion on GluR2 expression, clearly implicating ERK1/2 in the elevated GluR2 expression.	5	22	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	5	6	21	22
This association is thought to increase the subsequent activation of RSK2 by ERK1/2 [ XREF_BIBR ] .	This association is thought to increase the subsequent activation of RSK2 by ERK1/2 [XREF_BIBR].	8	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	12	13	10	11
The ERK target RSK2 directly acts on the third intracellular ( i3 ) loop of 5-HT 2A R protein , leading to direct phosphorylation of the i3 loop at the conserved residue Ser 314 to suppress 5-HT 2A R signaling .	The ERK target RSK2 directly acts on the third intracellular (i3) loop of 5-HT 2A R protein, leading to direct phosphorylation of the i3 loop at the conserved residue Ser 314 to suppress 5-HT 2A R signaling.	0	35	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	1	2	3	4
Interestingly , in this malignancy RSK2 activity is tightly regulated by PEA-15 , a protein scaffold that supports ERK activation of RSK2 .	Interestingly, in this malignancy RSK2 activity is tightly regulated by PEA-15, a protein scaffold that supports ERK activation of RSK2.	18	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	18	19	21	22
RSK2 is a member of the p90 RSK family and is activated by ERK1/2 and phosphoinositide dependent kinase 1 .	RSK2 is a member of the p90 RSK family and is activated by ERK1/2 and phosphoinositide dependent kinase 1.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	13	14	0	1
ERKs , but not p38 , activate RSK2 .	ERKs, but not p38, activate RSK2.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	RSK2	RSK2	RSK2	0	1	7	8
ERK1/2 mediated RSK2 activation .	ERK1/2 mediated RSK2 activation.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	0	1	2	3
We demonstrate for the first time that in FGF2 and FGFR2 signalling , p38 but not MEK and ERK , indirectly activated RSK2 at Tyr529 , which facilitated phosphorylation of its other residues ( Thr359 and Ser363 , Thr573 and Ser380 ) .	We demonstrate for the first time that in FGF2 and FGFR2 signalling, p38 but not MEK and ERK, indirectly activated RSK2 at Tyr529, which facilitated phosphorylation of its other residues (Thr359 and Ser363, Thr573 and Ser380).	13	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	18	19	22	23
Both the ERK and PI3K signaling cascades can also signal to ribosomal S6 kinase 2 ( RSK2 ) and c-jun N-terminal kinase ( JNK ) , which have also been implicated in cancer development although their specific role requires further verification .	Both the ERK and PI3K signaling cascades can also signal to ribosomal S6 kinase 2 (RSK2) and c-jun N-terminal kinase (JNK), which have also been implicated in cancer development although their specific role requires further verification.	0	21	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	2	3	16	17
Four isoforms of RSK have been described , of which RSK1 , RSK2 , and RSK3 are activated by the ERK1/2 pathway .	Four isoforms of RSK have been described, of which RSK1, RSK2, and RSK3 are activated by the ERK1/2 pathway.	10	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	20	21	12	13
Moreover , the ERK cascade activates RSK2 , an S6 kinase that activates transcription factors , including CREB , that bind to the promoter region of the c-fos gene .	Moreover, the ERK cascade activates RSK2, an S6 kinase that activates transcription factors, including CREB, that bind to the promoter region of the c-fos gene.	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	3	4	6	7
Therefore , PEA-15 functions as a scaffold to enhance ERK activation of RSK2 , and this activity is regulated by phosphorylation .	Therefore, PEA-15 functions as a scaffold to enhance ERK activation of RSK2, and this activity is regulated by phosphorylation.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK2	RSK2	RSK2	9	10	12	13
MK2 is exclusively activated by p38 and the CTD RSK2 is activated by ERK1/2 .	MK2 is exclusively activated by p38 and the CTD RSK2 is activated by ERK1/2.	7	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	13	14	9	10
Because the ERK1/2 mediated activation of RSK2 and MSK1 may lead to phosphorylation of CREB at Ser 133 XREF_BIBR , XREF_BIBR , XREF_BIBR , dnCaMKI may suppress CREB activity and CRE and CaRE3 mediated transcription through the ERK1/2-RSK 2/MSK1 cascade in NMDA stimulated neurons .	Because the ERK1/2 mediated activation of RSK2 and MSK1 may lead to phosphorylation of CREB at Ser 133 XREF_BIBR, XREF_BIBR, XREF_BIBR, dnCaMKI may suppress CREB activity and CRE and CaRE3 mediated transcription through the ERK1/2-RSK 2/MSK1 cascade in NMDA stimulated neurons.	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	2	3	6	7
Intriguingly , butein sensitizes cells to tumor necrosis factor related apoptosis inducing ligand induced apoptosis via ERK mediated Sp1 activation , which promotes the transcription of specific death receptor 5 .	Intriguingly, butein sensitizes cells to tumor necrosis factor related apoptosis inducing ligand induced apoptosis via ERK mediated Sp1 activation, which promotes the transcription of specific death receptor 5.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	Sp1	Sp1	Sp1	16	17	18	19
Moreover , this response depended upon both activation of Sp1 by MAPK and NFATc1 transcriptional activity consistent with the predicted molecular signaling .	Moreover, this response depended upon both activation of Sp1 by MAPK and NFATc1 transcriptional activity consistent with the predicted molecular signaling.	4	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Sp1	Sp1	Sp1	11	12	9	10
Taken together , our observations showed that , independently of insulin action , leptin exerts an inhibitory effect on SCD1 transcription via a signaling pathway implicating Jak2 , ERK1/2 , and p90RSK which probably targets the downstream transcription factor Sp1 on the SCD1 promoter .	Taken together, our observations showed that, independently of insulin action, leptin exerts an inhibitory effect on SCD1 transcription via a signaling pathway implicating Jak2, ERK1/2, and p90RSK which probably targets the downstream transcription factor Sp1 on the SCD1 promoter.	25	40	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	transcription factor Sp1	transcription factor Sp1	transcription factor Sp1	28	29	37	40
The ERK pathway could modulate CA9 at three different levels : by stimulating activities of HIF-1 , SP1 and SP3 [ XREF_BIBR ] , and also AP1 [ XREF_BIBR ] .	The ERK pathway could modulate CA9 at three different levels : by stimulating activities of HIF-1, SP1 and SP3 [XREF_BIBR], and also AP1 [XREF_BIBR].	1	21	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	SP1	SP1	SP1	1	2	17	18
These results may indicate that ERK activates Sp1 , which in turn regulates MMP9 transcription .	These results may indicate that ERK activates Sp1, which in turn regulates MMP9 transcription.	5	15	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ERK	ERK	erk	Sp1	Sp1, which in turn regulates MMP9 transcription	sp1	5	6	7	8
Because Sp1 is activated by both the MAP kinase and ERK kinase and p38 kinase pathways , we postulate that synergistic activation of these pathways by GM-CSF and LPS induced sufficient levels of Sp1 to activate the HIV-1 LTR in a Tat independent manner and induced HIV-1 production by JR-CSF mouse monocytes .	Because Sp1 is activated by both the MAP kinase and ERK kinase and p38 kinase pathways, we postulate that synergistic activation of these pathways by GM-CSF and LPS induced sufficient levels of Sp1 to activate the HIV-1 LTR in a Tat independent manner and induced HIV-1 production by JR-CSF mouse monocytes.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Sp1	Sp1	Sp1	10	11	1	2
As an upstream factor , ERK1/2 can modulate Sp1 activation and mediates TGF-beta1 regulation for target genes XREF_BIBR .	As an upstream factor, ERK1/2 can modulate Sp1 activation and mediates TGF-beta1 regulation for target genes XREF_BIBR.	5	11	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Sp1	Sp1	Sp1	5	6	8	9
Collectively , these results demonstrate that morin reduced cyclin D1 , cyclin E , CDK2 and CDK4 expression via the induction of p21WAF1 expression , increased ERK1/2 phosphorylation and decreased JNK , and AKT phosphorylation , and prevented MMP-9 expression via the inhibition of transcription factors AP-1 , Sp-1 , and NF-kappaB , thereby resulting in the inhibition of growth , migration , and invasion of bladder cancer EJ cells .	Collectively, these results demonstrate that morin reduced cyclin D1, cyclin E, CDK2 and CDK4 expression via the induction of p21WAF1 expression, increased ERK1/2 phosphorylation and decreased JNK, and AKT phosphorylation, and prevented MMP-9 expression via the inhibition of transcription factors AP-1, Sp-1, and NF-kappaB, thereby resulting in the inhibition of growth, migration, and invasion of bladder cancer EJ cells.	6	54	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	morin reduced cyclin D1, cyclin E, CDK2 and CDK4 expression via the induction of p21WAF1 expression, increased ERK1/2 phosphorylation	erk1/2	Sp-1	Sp-1	sp-1	26	27	48	49
These observations indicate that Rac1 inhibits MMP-9 gene expression in alveolar macrophages by attenuating the activation of ERK and ERK mediated stabilization of SP-1 at the S586 residue within its PEST domain .	These observations indicate that Rac1 inhibits MMP-9 gene expression in alveolar macrophages by attenuating the activation of ERK and ERK mediated stabilization of SP-1 at the S586 residue within its PEST domain.	15	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	SP-1	SP-1	SP-1	17	18	23	24
ERK can activate Ap-1 , Notch1 , and Sp-1 , and these transcription factors have been associated with ABCC1 expression .	ERK can activate Ap-1, Notch1, and Sp-1, and these transcription factors have been associated with ABCC1 expression.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Sp-1	Sp-1	Sp-1	0	1	8	9
M-CSF also induced the nuclear localization of Sp1 , which was blocked by ERK inhibition .	M-CSF also induced the nuclear localization of Sp1, which was blocked by ERK inhibition.	5	14	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Sp1	Sp1	Sp1	13	14	7	8
The other transcription factors recruited to the TNFalpha promoter involve Sp1 , the ERK targets Egr-1 , Ets and Elk-1 [ XREF_BIBR ] , as well as the JNK targets c-Jun and ATF-2 [ XREF_BIBR ] .	The other transcription factors recruited to the TNFalpha promoter involve Sp1, the ERK targets Egr-1, Ets and Elk-1 [XREF_BIBR], as well as the JNK targets c-Jun and ATF-2 [XREF_BIBR].	9	15	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Sp1	Sp1	Sp1	13	14	10	11
ERK inhibition significantly decreased the abundance of SP-1 in the absence of protein synthesis in Rac1 null cells suggesting that ERK activation increases SP-1 stability ( XREF_FIG ) .	ERK inhibition significantly decreased the abundance of SP-1 in the absence of protein synthesis in Rac1 null cells suggesting that ERK activation increases SP-1 stability (XREF_FIG).	20	24	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	SP-1	SP-1	SP-1	20	21	23	24
The transcription factor Sp1 is activated by ERK and induces VEGF production in other cells .	The transcription factor Sp1 is activated by ERK and induces VEGF production in other cells.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	transcription factor Sp1	transcription factor Sp1	transcription factor Sp1	7	8	1	4
In addition , ERK activation increased the stability and abundance of SP-1 , an effect that was mediated at the S586 residue .	In addition, ERK activation increased the stability and abundance of SP-1, an effect that was mediated at the S586 residue.	3	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	SP-1	SP-1	SP-1	3	4	11	12
Further investigation identified Sp1 as a critical transcriptional activator in TIMP-3 regulation , and Sp1 activity is modulated by ERK1/2 , not Akt .	Further investigation identified Sp1 as a critical transcriptional activator in TIMP-3 regulation, and Sp1 activity is modulated by ERK1/2, not Akt.	14	22	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Sp1	Sp1	Sp1	19	20	14	15
H. pylori also stimulates host VEGF gene expression via MEK and ERK dependent activation of Sp1 and Sp3 [ XREF_BIBR ] .	H. pylori also stimulates host VEGF gene expression via MEK and ERK dependent activation of Sp1 and Sp3 [XREF_BIBR].	9	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Sp1	Sp1	Sp1	11	12	15	16
Our results showed that targetgene SP1 of miR-124 activated EGFR of miR-133a by MAPK cascade .	Our results showed that targetgene SP1 of miR-124 activated EGFR of miR-133a by MAPK cascade.	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	SP1	SP1	SP1	13	14	5	6
Whether ERK1/2 further activates other kinases to modulate Sp1 activity also requires investigation .	Whether ERK1/2 further activates other kinases to modulate Sp1 activity also requires investigation.	1	9	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Sp1	Sp1	Sp1	1	2	8	9
Mithramycin attenuated ANG II stimulated Sp1 and collagen I over-production ( XREF_FIG ) , as well as TGF-beta and ERK activation ( XREF_FIG ) , in a dose dependent manner ; however , mithramycin did not affect JNK or p38 activation ( XREF_FIG ) .	Mithramycin attenuated ANG II stimulated Sp1 and collagen I over-production (XREF_FIG), as well as TGF-beta and ERK activation (XREF_FIG), in a dose dependent manner; however, mithramycin did not affect JNK or p38 activation (XREF_FIG).	4	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Sp1	Sp1	Sp1	19	20	5	6
Taken together , our data suggest that PRL1 promotes the activation of the Src and ERK1/2 pathways , which drive the AP1 and Sp1 dependent transcriptional up-regulation of MMP2 and MMP9 .	Taken together, our data suggest that PRL1 promotes the activation of the Src and ERK1/2 pathways, which drive the AP1 and Sp1 dependent transcriptional up-regulation of MMP2 and MMP9.	13	26	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Sp1	Sp1	Sp1	15	16	23	24
It has been reported that NF-kappaB and Sp1 can be activated by MAPK family members , depending on the target gene in different cells [ XREF_BIBR ] .	It has been reported that NF-kappaB and Sp1 can be activated by MAPK family members, depending on the target gene in different cells [XREF_BIBR].	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Sp1	Sp1	Sp1	12	13	7	8
Thus , we investigated whether LfcinB induction of SMAD activity occurs through ERK activation of Sp1 in human primary articular chondrocytes .	Thus, we investigated whether LfcinB induction of SMAD activity occurs through ERK activation of Sp1 in human primary articular chondrocytes.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Sp1	Sp1	Sp1	12	13	15	16
We report a novel finding that ERK activation increases SP-1 stability at S586 and , thereby , increases MMP-9 promoter activity .	We report a novel finding that ERK activation increases SP-1 stability at S586 and, thereby, increases MMP-9 promoter activity.	6	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	SP-1	SP-1	SP-1	6	7	9	10
We then demonstrated a Ras-Raf-MEK and ERK signalling pathway was exclusively activated upstream of Sp1 activating the promoter and confirmed the requirement for matrix metalloproteinase activation leading to a ligand dependent activation of the epidermal growth factor receptor .	We then demonstrated a Ras-Raf-MEK and ERK signalling pathway was exclusively activated upstream of Sp1 activating the promoter and confirmed the requirement for matrix metalloproteinase activation leading to a ligand dependent activation of the epidermal growth factor receptor.	6	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Sp1	Sp1	Sp1	6	7	14	15
In contrast , the transcription factor Sp1 can be activated by the MAPK cascades induced by vanadium compounds [ XREF_BIBR , XREF_BIBR ] .	In contrast, the transcription factor Sp1 can be activated by the MAPK cascades induced by vanadium compounds [XREF_BIBR, XREF_BIBR].	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	transcription factor Sp1	transcription factor Sp1	transcription factor Sp1	12	13	4	7
ERK increases the stability of SP-1 at S586 .	ERK increases the stability of SP-1 at S586.	0	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	SP-1	SP-1	SP-1	0	1	5	6
In the presence of ERK pathway specific inhibitor ( ERKi ) , LfcinB mediated Sp1-DNA binding activity was abolished , suggesting that the LfcinB-ERK and MAPK axis activates Sp1 in human articular chondrocytes ( XREF_FIG ; lane 7 ) .	In the presence of ERK pathway specific inhibitor (ERKi), LfcinB mediated Sp1-DNA binding activity was abolished, suggesting that the LfcinB-ERK and MAPK axis activates Sp1 in human articular chondrocytes (XREF_FIG; lane 7).	23	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Sp1	Sp1	Sp1	25	26	28	29
Growth factors activate a rapamycin sensitive pathway involving the activation of p70S6K by mTOR and a rapamycin resistant pathway where ERK1/2 activate p90RSK [ XREF_BIBR ] .	Growth factors activate a rapamycin sensitive pathway involving the activation of p70S6K by mTOR and a rapamycin resistant pathway where ERK1/2 activate p90RSK [XREF_BIBR].	20	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	p90RSK	p90RSK	p90RSK	20	21	22	23
For example , we recently reported that an early phase of activated MAPK translocates to the nucleus , activates the CREB kinase p90rsk , regulates apc and ebp expression , and is required for Two-Trial LTM .	For example, we recently reported that an early phase of activated MAPK translocates to the nucleus, activates the CREB kinase p90rsk, regulates apc and ebp expression, and is required for Two-Trial LTM.	9	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	p90rsk	p90rsk	p90rsk	12	13	22	23
While AKT stimulates mTOR pathway through PRAS40 and further activates p70S6 , S6 , and 4E-BP1 , PDK1 may play a role in activating MEK mediated MAPK pathway , where PDK1 interacts with and activates MEK and also p90RSK to activate the MAPK signaling pathway .	While AKT stimulates mTOR pathway through PRAS40 and further activates p70S6, S6, and 4E-BP1, PDK1 may play a role in activating MEK mediated MAPK pathway, where PDK1 interacts with and activates MEK and also p90RSK to activate the MAPK signaling pathway.	24	39	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MAPK	MEK mediated MAPK	mapk	p90RSK	p90RSK	p90rsk	26	27	38	39
Phosphorylation of in MAPK pathway signaling molecules c-Raf , MEK1/2 , ERK1/2 , and p90RSK was determined by Western blot .	Phosphorylation of in MAPK pathway signaling molecules c-Raf, MEK1/2, ERK1/2, and p90RSK was determined by Western blot.	0	15	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	Phosphorylation of in MAPK	mapk	p90RSK	p90RSK	p90rsk	3	4	14	15
In addition , we demonstrate that the MEK and ERK pathway activated by CCL2 treatment mediate p90RSK activation in BV2 cells .	In addition, we demonstrate that the MEK and ERK pathway activated by CCL2 treatment mediate p90RSK activation in BV2 cells.	7	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	p90RSK	p90RSK	p90RSK	9	10	16	17
Here we review our current knowledge on the Mos and MAPK signalling pathway and a recently found connection between MAPK activated p90rsk and the p34cdc2 inhibitory kinase Myt1 .	Here we review our current knowledge on the Mos and MAPK signalling pathway and a recently found connection between MAPK activated p90rsk and the p34cdc2 inhibitory kinase Myt1.	17	27	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	p90rsk	p90rsk	p90rsk	19	20	21	22
Aripiprazole and quetiapine effects on the downstream ERK targets p90RSK and c-Fos .	Aripiprazole and quetiapine effects on the downstream ERK targets p90RSK and c-Fos.	0	11	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	p90RSK	p90RSK	p90RSK	7	8	9	10
Previous study revealed that p90RSK , activated by ERK1/2 in response to growth factors , was involved in regulation of apoptotic cell death and considered as a new therapeutic approach for preventing brain injury .	Previous study revealed that p90RSK, activated by ERK1/2 in response to growth factors, was involved in regulation of apoptotic cell death and considered as a new therapeutic approach for preventing brain injury.	4	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	p90RSK	p90RSK	p90RSK	8	9	4	5
Moreover , our findings suggest that the activation of Erk1/2 signaling and subsequent activation of p90RSK , inhibition of Bad , and inhibition of GSK3beta are responsible for the anti-apoptotic and infarct lowering effects of Na 2 S therapy .	Moreover, our findings suggest that the activation of Erk1/2 signaling and subsequent activation of p90RSK, inhibition of Bad, and inhibition of GSK3beta are responsible for the anti-apoptotic and infarct lowering effects of Na 2 S therapy.	9	16	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	p90RSK	p90RSK	p90RSK	9	10	15	16
Several evidence suggests that p90RSK is activated by MAPK .	Several evidence suggests that p90RSK is activated by MAPK.	4	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	p90RSK	p90RSK	p90RSK	8	9	4	5
p90RSK is located downstream of the Raf-MEK-ERK1/2 signaling pathway 85 , and ERK1/2 activates the C-terminus kinase of p90RSK , leading to full activation of the N-terminus kinase and subsequent substrate phosphorylation .	p90RSK is located downstream of the Raf-MEK-ERK1/2 signaling pathway 85, and ERK1/2 activates the C-terminus kinase of p90RSK, leading to full activation of the N-terminus kinase and subsequent substrate phosphorylation.	12	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	p90RSK	p90RSK	p90RSK	12	13	18	19
Arrestin-2-mediated ERK activation resulted in the activation of the P90RSK , leading to phosphorylation of Bad at Ser 112 .	Arrestin-2-mediated ERK activation resulted in the activation of the P90RSK, leading to phosphorylation of Bad at Ser 112.	1	10	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	ERK	ERK	ERK	P90RSK	P90RSK	P90RSK	1	2	9	10
ERK1/2 is a downstream factor of IL-17 belonging to the p44 and p42 MAPK signaling pathway that can activate p90RSK and CREB to induce the expression of BCL-2 [ XREF_BIBR - XREF_BIBR ] .	ERK1/2 is a downstream factor of IL-17 belonging to the p44 and p42 MAPK signaling pathway that can activate p90RSK and CREB to induce the expression of BCL-2 [XREF_BIBR - XREF_BIBR].	13	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	p90RSK	p90RSK	p90RSK	13	14	19	20
A possible mechanism is suggested by the interesting observation that ERK signaling can activate PARP-1 which has a role in NHEJ .	A possible mechanism is suggested by the interesting observation that ERK signaling can activate PARP-1 which has a role in NHEJ.	10	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PARP-1	PARP-1	PARP-1	10	11	14	15
Multiple studies have also indicated c-Jun N-terminal kinases ( JNKs ) and extracellular signal regulated kinases ( ERKs ) in PARP-1-induced cytotoxicity [ XREF_BIBR - XREF_BIBR ] : JNK1 can mediate PARP-1-induced mitochondrial impairments and cell death [ XREF_BIBR , XREF_BIBR ] ; and ERK1/2 has also been shown to induce PARP-1 activation by phosphorylating directly the enzyme [ XREF_BIBR ] .	Multiple studies have also indicated c-Jun N-terminal kinases (JNKs) and extracellular signal regulated kinases (ERKs) in PARP-1-induced cytotoxicity [XREF_BIBR - XREF_BIBR] : JNK1 can mediate PARP-1-induced mitochondrial impairments and cell death [XREF_BIBR, XREF_BIBR]; and ERK1/2 has also been shown to induce PARP-1 activation by phosphorylating directly the enzyme [XREF_BIBR].	44	52	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	PARP-1	PARP-1	PARP-1	44	45	51	52
Pharmacological inhibitors of MAPK and ERK kinase and p38 MAPK suppressed caspase 3 activation and PARP cleavage .	Pharmacological inhibitors of MAPK and ERK kinase and p38 MAPK suppressed caspase 3 activation and PARP cleavage.	3	16	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PARP	PARP	PARP	5	6	15	16
More interestingly , ERK knockdown significantly suppressed VacA induced cleavages of PARP and caspase-9 ( XREF_FIG ) .	More interestingly, ERK knockdown significantly suppressed VacA induced cleavages of PARP and caspase-9 (XREF_FIG).	3	15	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PARP	PARP	PARP	3	4	11	12
Unrelated to Mycoplasma infection , it was shown that PARP-1 is activated by ERK and its activity is up-regulated by ERK catalyzed phosphorylation XREF_BIBR .	Unrelated to Mycoplasma infection, it was shown that PARP-1 is activated by ERK and its activity is up-regulated by ERK catalyzed phosphorylation XREF_BIBR.	9	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PARP-1	PARP-1	PARP-1	13	14	9	10
A possible role of this Erk induced PARP1 activation in stimulation induced IEG expression was examined by measuring PARP1 dependent recruitment of phosphorylated Erk2 to the promoters of c-fos and zif268 [ XREF_BIBR ] .	A possible role of this Erk induced PARP1 activation in stimulation induced IEG expression was examined by measuring PARP1 dependent recruitment of phosphorylated Erk2 to the promoters of c-fos and zif268 [XREF_BIBR].	2	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Erk	Erk	Erk	PARP1	PARP1	PARP1	5	6	7	8
Western blot analysis showed that Zey substantially decreased phosphorylation of PI3K and ERK , meanwhile , increased the cleavage of PARP compared with the control group .	Western blot analysis showed that Zey substantially decreased phosphorylation of PI3K and ERK, meanwhile, increased the cleavage of PARP compared with the control group.	8	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	phosphorylation of PI3K and ERK	erk	PARP	PARP	parp	12	13	20	21
In our test , all of p38 ( SB202190 ) , c-Jun ( SP600125 ) , and ERK ( PD98059 ) inhibitors had no inhibitory effect on combined treatment induced PARP cleavage ( XREF_SUPPLEMENTARY ) .	In our test, all of p38 (SB202190), c-Jun (SP600125), and ERK (PD98059) inhibitors had no inhibitory effect on combined treatment induced PARP cleavage (XREF_SUPPLEMENTARY).	4	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PARP	PARP	PARP	17	18	30	31
The extracellular signal activated kinase , or Erk , has been shown to modulate PARP-1 activity , including the phosphorylation of PARP-1 and the PARylation of NFkappaB ( p65 ) in an inflammatory response model .	The extracellular signal activated kinase, or Erk, has been shown to modulate PARP-1 activity, including the phosphorylation of PARP-1 and the PARylation of NFkappaB (p65) in an inflammatory response model.	4	15	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	PARP-1	PARP-1	PARP-1	7	8	14	15
Our findings are thus in line with EPO induced polyADP ribosylation via ERK phosphorylation activating PARP-1 .	Our findings are thus in line with EPO induced polyADP ribosylation via ERK phosphorylation activating PARP-1.	12	16	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK phosphorylation	erk	PARP-1	PARP-1	parp-1	12	13	15	16
Signaling through ERK1/2 enhances PARP-1 activity , although phosphorylation of PARP-1 does not occur in all contexts .	Signaling through ERK1/2 enhances PARP-1 activity, although phosphorylation of PARP-1 does not occur in all contexts.	0	5	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	PARP-1	PARP-1	PARP-1	2	3	4	5
The mechanism underlying this event remains to be determined , as we failed to detect activation of PARP1 by ERK through protein protein interactions , both in vitro and in living cells ( Martinez-Zamudio and Ha , manuscript in preparation ) .	The mechanism underlying this event remains to be determined, as we failed to detect activation of PARP1 by ERK through protein protein interactions, both in vitro and in living cells (Martinez-Zamudio and Ha, manuscript in preparation).	14	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	PARP1	PARP1	PARP1	19	20	17	18
Results indicated that the PARP inhibitor ABT-888 did not interfere with the phosphorylation of EPO-R , ERK or STAT5 , which are all activated by EPO , upstream to PARP .	Results indicated that the PARP inhibitor ABT-888 did not interfere with the phosphorylation of EPO-R, ERK or STAT5, which are all activated by EPO, upstream to PARP.	12	30	activated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ERK	phosphorylation of EPO-R, ERK	erk	PARP	PARP	parp	16	17	29	30
As a result , ERK1/2 inhibition by PD98059 attenuated GL mediated cleavage of PARP in HCT116 cells .	As a result, ERK1/2 inhibition by PD98059 attenuated GL mediated cleavage of PARP in HCT116 cells.	4	14	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	PARP	PARP	PARP	4	5	13	14
In addition , in 20 % O2 , but not in 2 % O2 , 4-HPR obviously downregulated the protein expression of procaspase-3 , ERK1/2 and XIAP , and increased the cleavage of PARP .	In addition, in 20% O2, but not in 2% O2, 4-HPR obviously downregulated the protein expression of procaspase-3, ERK1/2 and XIAP, and increased the cleavage of PARP.	15	34	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	4-HPR obviously downregulated the protein expression of procaspase-3, ERK1/2	erk1/2	PARP	PARP	parp	24	25	33	34
In an in vitro model of ischemia , ERK1/2 mediated PARP-1 activation was involved in OL death in a caspase independent manner XREF_BIBR .	In an in vitro model of ischemia, ERK1/2 mediated PARP-1 activation was involved in OL death in a caspase independent manner XREF_BIBR.	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	PARP-1	PARP-1	PARP-1	8	9	10	11
ERK1/2 and JNK1/2 MAPK can mediate the downstream signals of PARP-1 .	ERK1/2 and JNK1/2 MAPK can mediate the downstream signals of PARP-1.	0	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	PARP-1	PARP-1	PARP-1	0	1	10	11
It is known that the PARP activity is mediated by ERK dependent phosphorylation [ XREF_BIBR - XREF_BIBR ] and persistent ERK activation has been shown in many complication-prone tissues in diabetes , including vascular smooth muscle cells , endothelial cells , peripheral nerves , and pericytes [ XREF_BIBR - XREF_BIBR ] .	It is known that the PARP activity is mediated by ERK dependent phosphorylation [XREF_BIBR - XREF_BIBR] and persistent ERK activation has been shown in many complication-prone tissues in diabetes, including vascular smooth muscle cells, endothelial cells, peripheral nerves, and pericytes [XREF_BIBR - XREF_BIBR].	5	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK dependent phosphorylation	erk	PARP	PARP	parp	10	11	5	6
Thus , Erk induced PARP1 activation mediated IEG expression implicated in long-term memory .	Thus, Erk induced PARP1 activation mediated IEG expression implicated in long-term memory.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Erk	Erk	Erk	PARP1	PARP1	PARP1	2	3	4	5
Inactivation of ERK1/2 signaling and attenuation of caspase-3 activation and PARP cleavage were revealed with RGE against H. pylori infection .	Inactivation of ERK1/2 signaling and attenuation of caspase-3 activation and PARP cleavage were revealed with RGE against H. pylori infection.	2	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	PARP	PARP	PARP	2	3	10	11
High frequency stimulation induced binding of phosphrylated Erk2 to PARP1 in the chromatin of cerebral neurons ( XREF_FIG and XREF_FIG ) , concomitantly with Erk induced PARP1 activation XREF_BIBR ( XREF_FIG and XREF_FIG , XREF_SUPPLEMENTARY ) , polyADP ribosylated linker histone H1 ( XREF_FIG ) , and facilitated access of PARP1 bound phosphorylated Erk2 and acetylated histone H4 to promoters of immediate early genes cfos and zif268 XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR ( XREF_FIG ) .	High frequency stimulation induced binding of phosphrylated Erk2 to PARP1 in the chromatin of cerebral neurons (XREF_FIG and XREF_FIG), concomitantly with Erk induced PARP1 activation XREF_BIBR (XREF_FIG and XREF_FIG, XREF_SUPPLEMENTARY), polyADP ribosylated linker histone H1 (XREF_FIG), and facilitated access of PARP1 bound phosphorylated Erk2 and acetylated histone H4 to promoters of immediate early genes cfos and zif268 XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR (XREF_FIG).	4	28	induced	Positive_early_activation	Positive_activation	Positive_activation	Erk	Erk	Erk	PARP1	PARP1	PARP1	24	25	26	27
A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk induced PARP1 activation , rendering transcription factors and promoters of immediate early genes ( IEG ) accessible to PARP1 bound phosphorylated Erk2 .	A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1 bound phosphorylated Erk2.	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	Erk	Erk	Erk	PARP1	PARP1	PARP1	15	16	17	18
Inactivation of ERK1/2 signaling and attenuation of caspase-3 activation and PARP cleavage were revealed with red ginseng extracts against H. pylori infection .	Inactivation of ERK1/2 signaling and attenuation of caspase-3 activation and PARP cleavage were revealed with red ginseng extracts against H. pylori infection.	2	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	PARP	PARP	PARP	2	3	10	11
We found that IL6 , TNF , CXCL8 , IL1B and ERK1/2 were the top genes in terms of the number of connections in platinum induced neuropathy and TP53 , MYC , PARP1 , P38 MAPK and TNF for combined taxane-platinum-induced neuropathy .	We found that IL6, TNF, CXCL8, IL1B and ERK1/2 were the top genes in terms of the number of connections in platinum induced neuropathy and TP53, MYC, PARP1, P38 MAPK and TNF for combined taxane-platinum-induced neuropathy.	3	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	PARP1	PARP1	PARP1	11	12	32	33
We observed that silencing HAS2 , CD44 or RHAMM genes suppressed the expression and activation of EGFR , Akt , and ERK and activated the pro apoptotic proteins caspase 3 and PARP , indicating that the interaction between HA and CD44 and RHAMM regulate the EGFR/Akt/ERK pathway and thereby enhancing cell proliferation and survival .	We observed that silencing HAS2, CD44 or RHAMM genes suppressed the expression and activation of EGFR, Akt, and ERK and activated the pro apoptotic proteins caspase 3 and PARP, indicating that the interaction between HA and CD44 and RHAMM regulate the EGFR/Akt/ERK pathway and thereby enhancing cell proliferation and survival.	4	33	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	HAS2, CD44 or RHAMM genes suppressed the expression and activation of EGFR, Akt, and ERK	erk	PARP	PARP	parp	21	22	31	32
Consistently , the exposure of SH-SY5Y cells to ONE led to a proteolytic cleavage of PARP , one of the molecular hallmarks for apoptosis , resulting in the accumulation of the 85 kDa fragment and ERK inhibition significantly reduced the level of this PARP fragment ( XREF_FIG ) in line with its neuroprotective actions .	Consistently, the exposure of SH-SY5Y cells to ONE led to a proteolytic cleavage of PARP, one of the molecular hallmarks for apoptosis, resulting in the accumulation of the 85 kDa fragment and ERK inhibition significantly reduced the level of this PARP fragment (XREF_FIG) in line with its neuroprotective actions.	35	44	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PARP	PARP	PARP	35	36	43	44
FAS expression in renal tubular epithelial cells and accumulation of FASL expressing lymphocytes during reperfusion contributes to the FAS mediated tissue damage [ XREF_BIBR ] .	FAS expression in renal tubular epithelial cells and accumulation of FASL expressing lymphocytes during reperfusion contributes to the FAS mediated tissue damage [XREF_BIBR].	0	19	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	FAS	FAS expression	fas	FAS	FAS	fas	0	1	18	19
The antibodies that trigger the receptor Fas ( CD95 ) unfortunately showed high toxicity to liver [ XREF_BIBR ] , while TRAIL and agonistic antibodies that bind TRAIL receptors appear to be well tolerated in vivo .	The antibodies that trigger the receptor Fas (CD95) unfortunately showed high toxicity to liver [XREF_BIBR], while TRAIL and agonistic antibodies that bind TRAIL receptors appear to be well tolerated in vivo.	1	9	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95	CD95	CD95	Fas	Fas	Fas	8	9	6	7
Ceramide mediated CD95 clustering then amplifies the primary CD95 signaling and drives the second step of CD95 signaling , that is , formation of the DISC yielding 100 % caspase activity and apoptosis .	Ceramide mediated CD95 clustering then amplifies the primary CD95 signaling and drives the second step of CD95 signaling, that is, formation of the DISC yielding 100% caspase activity and apoptosis.	0	17	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95	Ceramide mediated CD95	cd95	CD95	CD95	cd95	2	3	16	17
Cell death mediated by the TNF receptor family member Fas ( TNFRSF6 and CD95 ) is required for normal lymphocyte homeostasis and peripheral immune tolerance .	Cell death mediated by the TNF receptor family member Fas (TNFRSF6 and CD95) is required for normal lymphocyte homeostasis and peripheral immune tolerance.	1	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	CD95	CD95	CD95	9	10	13	14
Because the TNF type 1 ( p55 ) receptor shares a common signaling pathway with Fas ( CD95 ) , NOD and B6 mice were treated with the Fas agonist antibody , Jo-2 .	Because the TNF type 1 (p55) receptor shares a common signaling pathway with Fas (CD95), NOD and B6 mice were treated with the Fas agonist antibody, Jo-2.	13	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Fas	Fas	Fas	CD95	CD95	CD95	28	29	17	18
As TNF-alpha has been demonstrated to upregulate Fas expression and induce Fas responsiveness on more committed progenitor cells 183740 , we next investigated whether TNF-alpha could upregulate Fas expression on Lin - Sca1 + c-kit + cells .	As TNF-alpha has been demonstrated to upregulate Fas expression and induce Fas responsiveness on more committed progenitor cells 183740, we next investigated whether TNF-alpha could upregulate Fas expression on Lin - Sca1 + c-kit + cells.	1	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	TNF-alpha has been demonstrated to upregulate Fas expression	fas	Fas	Fas	fas	7	8	11	12
FasL interacts with Fas expressed on target cells , inducing the apoptosis of the Fas expressing cells .	FasL interacts with Fas expressed on target cells, inducing the apoptosis of the Fas expressing cells.	1	16	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas expressed	fas	Fas	Fas	fas	3	4	14	15
For instance , the autoimmune lymphoproliferative syndrome ( ALPS ) caused by a complete expression defect of CD95 ( Fas , APO-1 ) can be cured by allogeneic BMT .	For instance, the autoimmune lymphoproliferative syndrome (ALPS) caused by a complete expression defect of CD95 (Fas, APO-1) can be cured by allogeneic BMT.	6	21	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD95	CD95	CD95	Fas	Fas	Fas	17	18	19	20
IL-1 beta , TNF-alpha , and combining both of them can up-regulate Fas protein expression , which may contribute to more Fas ( + ) cells in proliferative vitreoretinopathy ( PVR ) .	IL-1 beta, TNF-alpha, and combining both of them can up-regulate Fas protein expression, which may contribute to more Fas (+) cells in proliferative vitreoretinopathy (PVR).	0	23	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Fas	IL-1 beta, TNF-alpha, and combining both of them can up-regulate Fas protein expression	fas	Fas	Fas	fas	12	13	21	22
Aerosol Gemcitabine ( GCB ) upregulated Fas expression and induced tumor regression in wild-type Balb/c mice but not Fas L deficient mice .	Aerosol Gemcitabine (GCB) upregulated Fas expression and induced tumor regression in wild-type Balb/c mice but not Fas L deficient mice.	1	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Gemcitabine (GCB) upregulated Fas expression	fas	Fas	Fas	fas	6	7	18	19
5-aza-2-deoxycytidine failed to increase Fas mRNA ( XREF_SUPPLEMENTARY ) and Fas promoter was actually not hypermethylated in Miapaca-2 cells ( XREF_SUPPLEMENTARY ) .	5-aza-2-deoxycytidine failed to increase Fas mRNA (XREF_SUPPLEMENTARY) and Fas promoter was actually not hypermethylated in Miapaca-2 cells (XREF_SUPPLEMENTARY).	3	16	increase	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Fas	Fas promoter was actually not hypermethylated	fas	Fas	Fas	fas	10	11	4	5
Anti-CD95 ( Fas ) Ab that induces Fas + tumor apoptosis in vitro has been investigated as a potential reagent for this purpose [ XREF_BIBR ] .	Anti-CD95 (Fas) Ab that induces Fas + tumor apoptosis in vitro has been investigated as a potential reagent for this purpose [XREF_BIBR].	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Anti-CD95	Anti-CD95	Anti-CD95	Fas	Fas	Fas	0	1	7	8
Anoikis Mediated by Fas and CD95 Signaling , Triggers Association of RIP with Fas and Dissociation of RIP from FAK .	Anoikis Mediated by Fas and CD95 Signaling, Triggers Association of RIP with Fas and Dissociation of RIP from FAK.	1	17	Mediated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	CD95	CD95	CD95	Fas	Fas	Fas	5	6	13	14
Here , we report that MS-275 upregulates the expression of Fas mRNA and protein and induces the redistribution of Fas to membrane lipid rafts .	Here, we report that MS-275 upregulates the expression of Fas mRNA and protein and induces the redistribution of Fas to membrane lipid rafts.	5	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	MS-275 upregulates the expression of Fas	fas	Fas	Fas	fas	10	11	19	20
Activated EGFR then associates in a JNK dependent way with CD95 and catalyzes CD95 tyrosine phosphorylation , which triggers CD95 membrane trafficking , death inducing signaling complex ( DISC ) formation , i.e. association of Fas associated death domain ( FADD ) and caspase 8 to the death receptor , followed by caspase 8 dependent mitochondrial amplification of pro apoptotic signaling , which finally leads to apoptotic cell death [ XREF_BIBR ] .	Activated EGFR then associates in a JNK dependent way with CD95 and catalyzes CD95 tyrosine phosphorylation, which triggers CD95 membrane trafficking, death inducing signaling complex (DISC) formation, i.e. association of Fas associated death domain (FADD) and caspase 8 to the death receptor, followed by caspase 8 dependent mitochondrial amplification of pro apoptotic signaling, which finally leads to apoptotic cell death [XREF_BIBR].	13	21	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95	CD95 tyrosine phosphorylation	cd95	CD95	CD95	cd95	13	14	19	20
Although the protease cascade initiated by Fas ( CD95 , Apo-1 ) is well characterized , there remains little known about how kinase pathways may impact on Fas mediated apoptosis .	Although the protease cascade initiated by Fas (CD95, Apo-1) is well characterized, there remains little known about how kinase pathways may impact on Fas mediated apoptosis.	3	10	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	CD95	CD95	CD95	6	7	8	9
Additional evidence supporting the involvement of Fas pY in human cancer comes from our observation that pY291 Fas levels decreased while pY232 Fas levels increased in the majority of rectal tumors after radiotherapy ( +/- concurrent chemotherapy , XREF_FIG ) , suggesting distinct regulation and functions of pY232 and pY291 in Fas signaling in rectal cancer in response to cancer therapy .	Additional evidence supporting the involvement of Fas pY in human cancer comes from our observation that pY291 Fas levels decreased while pY232 Fas levels increased in the majority of rectal tumors after radiotherapy (+/- concurrent chemotherapy, XREF_FIG), suggesting distinct regulation and functions of pY232 and pY291 in Fas signaling in rectal cancer in response to cancer therapy.	22	52	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas levels	fas	Fas	Fas	fas	22	23	51	52
ESC , ESC-1 , ESC-2 significantly increased Fas expression and ESC significantly increased Fas and Fas-L ratio .	ESC, ESC-1, ESC-2 significantly increased Fas expression and ESC significantly increased Fas and Fas-L ratio.	7	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas expression	fas	Fas	Fas	fas	7	8	13	14
Interestingly , avicin D induced activation of the Fas pathway is not dependent on the linkage of extracellular Fas ligands or the application of agonist Fas antibodies , suggesting that avicin D may incorporate into cell membrane rafts , promoting their clustering as well as the translocation of Fas and its downstream signaling molecules into clustered rafts .	Interestingly, avicin D induced activation of the Fas pathway is not dependent on the linkage of extracellular Fas ligands or the application of agonist Fas antibodies, suggesting that avicin D may incorporate into cell membrane rafts, promoting their clustering as well as the translocation of Fas and its downstream signaling molecules into clustered rafts.	2	49	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	avicin D induced activation of the Fas	fas	Fas	Fas	fas	8	9	48	49
Knock down of PDGFRbeta enhanced Src Y416 and CD95 tyrosine phosphorylation that correlated with elevated CD95 plasma membrane levels and autophagy , and with a reduced ability of sorafenib to promote CD95 membrane localization .	Knock down of PDGFRbeta enhanced Src Y416 and CD95 tyrosine phosphorylation that correlated with elevated CD95 plasma membrane levels and autophagy, and with a reduced ability of sorafenib to promote CD95 membrane localization.	8	33	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95	CD95 tyrosine phosphorylation	cd95	CD95	CD95	cd95	8	9	31	32
The appearance of apoptosis , expression of Fas , activation of caspases-3 , -8 , -9 , SAPK and JNK and AP-1 , the release of mitochondrial cytochrome-C and the formation of death induced signalling complex ( DISC ) between Fas and the Fas associated death domain ( FADD ) were measured by fluorescence microscopy , Western blotting , flow cytometry , gel shift assay and immunoprecipitation , respectively .	The appearance of apoptosis, expression of Fas, activation of caspases-3, -8, -9, SAPK and JNK and AP-1, the release of mitochondrial cytochrome-C and the formation of death induced signalling complex (DISC) between Fas and the Fas associated death domain (FADD) were measured by fluorescence microscopy, Western blotting, flow cytometry, gel shift assay and immunoprecipitation, respectively.	5	44	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	expression of Fas	fas	Fas	Fas	fas	7	8	43	44
Taken together , these data indicate that LMP2A requires signaling through the ITAM motif in the cytoplasmic tail to increase the sensitivity of the A20 cell line to Fas mediated signaling and apoptosis by increasing Fas expression .	Taken together, these data indicate that LMP2A requires signaling through the ITAM motif in the cytoplasmic tail to increase the sensitivity of the A20 cell line to Fas mediated signaling and apoptosis by increasing Fas expression.	19	37	increase	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Fas	Fas expression	fas	Fas	Fas	fas	35	36	28	29
Alpha-mangostin could effectively suppress FAS expression and inhibit intracellular FAS activity , and result in decrease of intracellular fatty acid accumulation .	Alpha-mangostin could effectively suppress FAS expression and inhibit intracellular FAS activity, and result in decrease of intracellular fatty acid accumulation.	0	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAS	Alpha-mangostin could effectively suppress FAS expression	fas	FAS	FAS	fas	4	5	9	10
This process is achieved via the following two pathways : ( 1 ) exogenous pathway , where stimuli activate the death receptors Fas or CD95 on the cell surface ; and ( 2 ) endogenous pathway , where increased permeability of the mitochondrial membrane and ER stress occurs [ XREF_BIBR ] .	This process is achieved via the following two pathways : (1) exogenous pathway, where stimuli activate the death receptors Fas or CD95 on the cell surface; and (2) endogenous pathway, where increased permeability of the mitochondrial membrane and ER stress occurs [XREF_BIBR].	3	28	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CD95	CD95	CD95	Fas	Fas	Fas	24	25	22	23
Induction of apoptosis by hydrophobic bile salts involves EGF-R activation and EGF-R-dependent CD95 tyrosine phosphorylation , which triggers CD95 membrane targeting and Fas associated death domain and caspase -8 recruitment .	Induction of apoptosis by hydrophobic bile salts involves EGF-R activation and EGF-R-dependent CD95 tyrosine phosphorylation, which triggers CD95 membrane targeting and Fas associated death domain and caspase -8 recruitment.	12	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95	CD95 tyrosine phosphorylation	cd95	CD95	CD95	cd95	12	13	18	19
In our previous research discovered , HFD treatment will increase FAS expression and cause FAS induced cardiac apoptosis [ XREF_BIBR ] .	In our previous research discovered, HFD treatment will increase FAS expression and cause FAS induced cardiac apoptosis [XREF_BIBR].	6	15	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAS	HFD treatment will increase FAS expression	fas	FAS	FAS	fas	10	11	14	15
Estrogen decreases expression of Fas and abrogates in vitro effect of Fas activation in osteoblast lineage cells .	Estrogen decreases expression of Fas and abrogates in vitro effect of Fas activation in osteoblast lineage cells.	0	12	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fas	Estrogen decreases expression of Fas	fas	Fas	Fas	fas	4	5	11	12
Thus , Fas signaling in PD patients may be diminished by reduced cell surface Fas expression and by the presence of soluble Fas .	Thus, Fas signaling in PD patients may be diminished by reduced cell surface Fas expression and by the presence of soluble Fas.	2	16	diminished	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas	Fas expression	fas	Fas	Fas	fas	14	15	2	3
A bispecific CD95 and anti-tenascin-C antibody that activated the Fas and Apo -1 death receptor efficiently caused glioma cell lysis that was strongly enhanced in combination with topoisomerase inhibitors or doxorubicin .	A bispecific CD95 and anti-tenascin-C antibody that activated the Fas and Apo -1 death receptor efficiently caused glioma cell lysis that was strongly enhanced in combination with topoisomerase inhibitors or doxorubicin.	0	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95	CD95	CD95	Fas	Fas	Fas	2	3	9	10
CD95 expression was also increased in these cells , suggesting an up-regulation in the FAS pathway in WAS lymphocytes .	CD95 expression was also increased in these cells, suggesting an up-regulation in the FAS pathway in WAS lymphocytes.	0	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95	CD95 expression	cd95	FAS	FAS	fas	0	1	14	15
XREF_BIBR , XREF_BIBR , XREF_BIBR The structurally related MSK1/2 and RSK1 , 2 are both activated by the ERK1/2 signaling pathway .	XREF_BIBR, XREF_BIBR, XREF_BIBR The structurally related MSK1/2 and RSK1, 2 are both activated by the ERK1/2 signaling pathway.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK1	RSK1	RSK1	18	19	10	11
There is also evidence that the MEK and Erk pathway is activated by the Type III IFN receptor and mediates IFNlambda dependent activation of the kinase RSK1 and downstream upregulation of p21 WAF1 and CIP1 , suggesting a mechanism for the generation of IFNlambda- inducible growth inhibitory responses .	There is also evidence that the MEK and Erk pathway is activated by the Type III IFN receptor and mediates IFNlambda dependent activation of the kinase RSK1 and downstream upregulation of p21 WAF1 and CIP1, suggesting a mechanism for the generation of IFNlambda- inducible growth inhibitory responses.	6	27	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	RSK1	RSK1	RSK1	8	9	26	27
Activation of ERK by phosphorylation ( pERK ) induces p90 ribosomal S6 kinase 1 ( RSK1 ) to translocate to the nucleus and phosphorylate transcription factors such as cAMP response element binding protein ( CREB ) and ETS domain containing protein 1 ( Elk1 ) , which regulate transcription [ XREF_BIBR , XREF_BIBR ] .	Activation of ERK by phosphorylation (pERK) induces p90 ribosomal S6 kinase 1 (RSK1) to translocate to the nucleus and phosphorylate transcription factors such as cAMP response element binding protein (CREB) and ETS domain containing protein 1 (Elk1), which regulate transcription [XREF_BIBR, XREF_BIBR].	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK1	RSK1	RSK1	2	3	15	16
Control of the TSC1 and TSC2 complex principally occurs though the phosphorylation of TSC2 by Akt , extracellular signal regulated kinases ( ERKs ) , activating protein p90 ribosomal S6 kinase 1 ( RSK1 ) , AMPK , and glycogen synthase kinase -3 beta ( GSK-3beta ) .	Control of the TSC1 and TSC2 complex principally occurs though the phosphorylation of TSC2 by Akt, extracellular signal regulated kinases (ERKs), activating protein p90 ribosomal S6 kinase 1 (RSK1), AMPK, and glycogen synthase kinase -3 beta (GSK-3beta).	20	36	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERKs	ERKs	ERKs	RSK1	RSK1	RSK1	22	23	33	34
RSK1 , 2 , and 3 are activated in cells by ERK1/2 , whereas RSK4 has been suggested to be constitutively active .	RSK1, 2, and 3 are activated in cells by ERK1/2, whereas RSK4 has been suggested to be constitutively active.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK1	RSK1	RSK1	11	12	0	1
Because RSK1 is also activated by MAPK , the increased cell motility and metastatic potential of cancer cells with PI3K and/or MAPK pathway activation may result in part from RSK1 activation , leading to accumulation of p27T198 in the cytoplasm , p27 : RhoA binding , inhibition of RhoA and Rock pathway activation , and loss of actomyosin stability .	Because RSK1 is also activated by MAPK, the increased cell motility and metastatic potential of cancer cells with PI3K and/or MAPK pathway activation may result in part from RSK1 activation, leading to accumulation of p27T198 in the cytoplasm, p27 : RhoA binding, inhibition of RhoA and Rock pathway activation, and loss of actomyosin stability.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	RSK1	RSK1	RSK1	6	7	1	2
These data show that the naive transcription factor circuitry collapses more rapidly in response to ERK1/2 activation in the RSK1 * 23 mutants .	These data show that the naive transcription factor circuitry collapses more rapidly in response to ERK1/2 activation in the RSK1 * 23 mutants.	15	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK1	RSK1	RSK1	15	16	19	20
Apart from ERK itself , the ERK target p90RSK1 has been shown to phosphorylate S409 downstream of activated KIT ( Wu etal ., 2000 ) .	Apart from ERK itself, the ERK target p90RSK1 has been shown to phosphorylate S409 downstream of activated KIT (Wu etal., 2000).	5	19	target	Positive_regulation_token_1_verb	Positive_activation	Positive_regulation	ERK	ERK	erk	p90RSK1	p90RSK1 has been shown to phosphorylate S409 downstream of activated KIT	p90rsk1	6	7	8	9
Activation of RSK1 by ERK1/2 leads to its subsequent translocation to the nucleus , phosphorylation of downstream substrates , and growth factor induced proliferation [ XREF_BIBR ] .	Activation of RSK1 by ERK1/2 leads to its subsequent translocation to the nucleus, phosphorylation of downstream substrates, and growth factor induced proliferation [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK1	RSK1	RSK1	4	5	2	3
RSK1 is activated by MAP kinases of the ERK family in response to growth factors , hormones , and other stimuli 21 .	RSK1 is activated by MAP kinases of the ERK family in response to growth factors, hormones, and other stimuli 21.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	RSK1	RSK1	RSK1	8	9	0	1
Both ERK1/2 and p38 are able to activate downstream kinases ; p38alpha activates the related kinases MK2 and MK3 , whereas ERK1/2 is able to activate RSK1 , 2 , and 3 .	Both ERK1/2 and p38 are able to activate downstream kinases; p38alpha activates the related kinases MK2 and MK3, whereas ERK1/2 is able to activate RSK1, 2, and 3.	21	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK1	RSK1	RSK1	21	22	26	27
In addition , there was a decrease in RSK1 activity in the Mz-IL-6 shRNA cell line compared with the Mz-neo neg cells ( XREF_FIG ) , further supporting the concept that IL-6 may be increasing PGRN expression by activating a signal-transduction pathway involving ERK1/2 dependent activation of RSK1 .	In addition, there was a decrease in RSK1 activity in the Mz-IL-6 shRNA cell line compared with the Mz-neo neg cells (XREF_FIG), further supporting the concept that IL-6 may be increasing PGRN expression by activating a signal-transduction pathway involving ERK1/2 dependent activation of RSK1.	43	48	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	RSK1	RSK1	RSK1	43	44	47	48
In particular , ERK1 and ERK2 , which are activated by the MAPK and ERK kinase-1/2 ( MEK1/2 ) , are emerging as important regulators of cellular responses to various stimuli [ XREF_BIBR ] .	In particular, ERK1 and ERK2, which are activated by the MAPK and ERK kinase-1/2 (MEK1/2), are emerging as important regulators of cellular responses to various stimuli [XREF_BIBR].	3	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ERK1	ERK1	ERK1	14	15	3	4
These data imply that the ICP0 and ERK1/2 nuclear localization coincides temporally , underlining that the virus could probably requires ERK1 functions or that ICP0 requires ERK1 activity .	These data imply that the ICP0 and ERK1/2 nuclear localization coincides temporally, underlining that the virus could probably requires ERK1 functions or that ICP0 requires ERK1 activity.	7	21	underlining	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	ERK1	ERK1	ERK1	7	8	20	21
As shown in XREF_FIG A , ERK1 , or ERK2 , or ERK1/2 expression were almost diminished by siERK1 , or ERK2 , or siERK1 +2 , which resulted in the activation inhibition of ERK1 , ERK2 , or ERK1/2 by about 80 % to 90 % .	As shown in XREF_FIG A, ERK1, or ERK2, or ERK1/2 expression were almost diminished by siERK1, or ERK2, or siERK1 +2, which resulted in the activation inhibition of ERK1, ERK2, or ERK1/2 by about 80% to 90%.	12	39	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2 expression	erk1/2	ERK1	ERK1	erk1	12	13	34	35
ERK1 could also be activated by the ERK activator to the same extent .	ERK1 could also be activated by the ERK activator to the same extent.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ERK1	ERK1	ERK1	7	8	0	1
ERK1 and ERK2 , which are activated by the MAPK and ERK kinase-1/2 ( MEK1/2 ) , play a beneficial , neuroprotective role in many systems .	ERK1 and ERK2, which are activated by the MAPK and ERK kinase-1/2 (MEK1/2), play a beneficial, neuroprotective role in many systems.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ERK1	ERK1	ERK1	11	12	0	1
A recent study using Erk1 -/- and Erk2 flox and flox mice reported that Erk1 positively regulated osteoclast function , providing grounds for our proposal that the increased bone resorbing activity of Stat5 KO osteoclasts is , at least in part , caused by the increased activity of ERK .	A recent study using Erk1 -/- and Erk2 flox and flox mice reported that Erk1 positively regulated osteoclast function, providing grounds for our proposal that the increased bone resorbing activity of Stat5 KO osteoclasts is, at least in part, caused by the increased activity of ERK.	14	49	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Erk1	Erk1	Erk1	48	49	14	15
In this study , we investigated a novel 50-kDa ERK like protein ( ERK-50 ) that is up-regulated significantly in addition to ERK1 ,2 after treatment with the dual APL .	In this study, we investigated a novel 50-kDa ERK like protein (ERK-50) that is up-regulated significantly in addition to ERK1,2 after treatment with the dual APL.	5	23	up-regulated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ERK1	ERK1	ERK1	9	10	22	23
ERK1 and ERK2 are directly regulated and phosphorylated by two MAPK kinases , MKK1 and MKK2 .	ERK1 and ERK2 are directly regulated and phosphorylated by two MAPK kinases, MKK1 and MKK2.	0	11	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERK1	ERK1	ERK1	10	11	0	1
We show that DNR increased phosphorylation of extracellular regulated kinases ( ERKs ) and stimulated activities of both Raf-1 and extracellular regulated kinase 1 ( ERK1 ) within 10 to 30 minutes in U937 cells .	We show that DNR increased phosphorylation of extracellular regulated kinases (ERKs) and stimulated activities of both Raf-1 and extracellular regulated kinase 1 (ERK1) within 10 to 30 minutes in U937 cells.	3	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERKs	DNR increased phosphorylation of extracellular regulated kinases (ERKs	erks	ERK1	ERK1	erk1	11	12	25	26
In turn , the MAPK kinases activate ERK 1 and ERK 2 .	In turn, the MAPK kinases activate ERK 1 and ERK 2.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	ERK 1	ERK 1	ERK 1	4	5	7	9
Knockdown of Shp2 in these cells impaired EGF stimulated Erk1 and Erk2 ( Erk1/2 ) activation .	Knockdown of Shp2 in these cells impaired EGF stimulated Erk1 and Erk2 (Erk1/2) activation.	8	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	Erk1	Erk1	Erk1	13	14	9	10
FR180204 is a novel ERK selective inhibitor that can permeate the cell , and has been reported to inhibit ERK1 and ERK2 XREF_BIBR .	FR180204 is a novel ERK selective inhibitor that can permeate the cell, and has been reported to inhibit ERK1 and ERK2 XREF_BIBR.	4	22	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ERK1	ERK1	ERK1	4	5	19	20
ERK1 and ERK2 , which are activated by the MAPK and ERK kinase-1/2 ( MEK1/2 ) , are emerging as important regulators of neuronal responses to both functional and pathologic stimuli , which play a beneficial , neuroprotective role in many systems .	ERK1 and ERK2, which are activated by the MAPK and ERK kinase-1/2 (MEK1/2), are emerging as important regulators of neuronal responses to both functional and pathologic stimuli, which play a beneficial, neuroprotective role in many systems.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ERK1	ERK1	ERK1	11	12	0	1
ERK1 and ERK2 are activated by MAPK and ERK kinase ( MEK ) 1 and MEK2 15 .	ERK1 and ERK2 are activated by MAPK and ERK kinase (MEK) 1 and MEK2 15.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ERK1	ERK1	ERK1	8	9	0	1
Surprisingly , attenuation of ERK and MAP kinase signaling by genetic inactivation of Erk2 , RNAi mediated knockdown of ERK1 or ERK2 , or MEK inhibitors prevented the activation of the senescence mechanism , allowing oncogenic ras to transform primary cells .	Surprisingly, attenuation of ERK and MAP kinase signaling by genetic inactivation of Erk2, RNAi mediated knockdown of ERK1 or ERK2, or MEK inhibitors prevented the activation of the senescence mechanism, allowing oncogenic ras to transform primary cells.	4	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ERK1	ERK1	ERK1	4	5	19	20
Activated Raf phosphorylates and activates the mitogen activated ERK kinases , MEK1 and MEK2 , which in turn phosphorylate and activate the extracellular signal activated kinases , ERK1 and ERK2 .	Activated Raf phosphorylates and activates the mitogen activated ERK kinases, MEK1 and MEK2, which in turn phosphorylate and activate the extracellular signal activated kinases, ERK1 and ERK2.	8	28	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	ERK1	ERK1	ERK1	8	9	27	28
Moreover , the Ser36 residue located in the transactivating N-terminal domain of YB-1 may be a target for the extracellular-signal-regulated kinase 1 ( ERK1 ) , which is activated by MAPK in response to growth factor stimulation resulting in cell proliferation and survival .	Moreover, the Ser36 residue located in the transactivating N-terminal domain of YB-1 may be a target for the extracellular-signal-regulated kinase 1 (ERK1), which is activated by MAPK in response to growth factor stimulation resulting in cell proliferation and survival.	19	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	extracellular-signal-regulated kinase 1	extracellular-signal-regulated kinase 1	extracellular-signal-regulated kinase 1	30	31	19	22
Taken together , it is likely that eIF4E phosphosphorylation is regulated in two different ways ; either through MAPK activated Mnk1 or through mTOR and PI3K activated Mnk2 ( see XREF_FIG ) .	Taken together, it is likely that eIF4E phosphosphorylation is regulated in two different ways; either through MAPK activated Mnk1 or through mTOR and PI3K activated Mnk2 (see XREF_FIG).	14	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Mnk1	Mnk1	Mnk1	18	19	20	21
The same effect on cap dependent translation was observed when MNK1 was activated by the Erk or p38 pathway .	The same effect on cap dependent translation was observed when MNK1 was activated by the Erk or p38 pathway.	10	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	MNK1	MNK1	MNK1	15	16	10	11
This challenges a prior dogma , as so far it was generally accepted that induction of eIF4E phosphorylation is mainly triggered by MAPK activated Mnk1 , while Mnk2 is responsible for basal eIF4E phosphorylation [ XREF_BIBR ] .	This challenges a prior dogma, as so far it was generally accepted that induction of eIF4E phosphorylation is mainly triggered by MAPK activated Mnk1, while Mnk2 is responsible for basal eIF4E phosphorylation [XREF_BIBR].	20	29	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Mnk1	Mnk1	Mnk1	22	23	24	25
Immunohistochemical analysis revealed that the PKA- and ERK dependent increases in Mnk1 activation induced by NMDA also occurred in dendrites .	Immunohistochemical analysis revealed that the PKA- and ERK dependent increases in Mnk1 activation induced by NMDA also occurred in dendrites.	7	12	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	Mnk1	Mnk1	Mnk1	7	8	11	12
In addition , the ERK activated protein kinases MNK1 and MNK2 ( MAPK interacting protein kinase 1 and 2 ) directly phosphorylate eIF4E [ XREF_BIBR , XREF_BIBR ] .	In addition, the ERK activated protein kinases MNK1 and MNK2 (MAPK interacting protein kinase 1 and 2) directly phosphorylate eIF4E [XREF_BIBR, XREF_BIBR].	3	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	MNK1	MNK1	MNK1	4	5	8	9
A docking domain in extracellular-signal-regulated kinase ( ERK ) , a MAPK , serves as a common site for binding to the MAPK kinase MEK1 , the MAPK activated protein kinase MNK1 and the MAPK phosphatase MKP3 .	A docking domain in extracellular-signal-regulated kinase (ERK), a MAPK, serves as a common site for binding to the MAPK kinase MEK1, the MAPK activated protein kinase MNK1 and the MAPK phosphatase MKP3.	24	36	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	MNK1	MNK1	MNK1	27	28	31	32
The MAP kinases p38 and ERK1/2 can activate Mnk1 to regulate the phosphorylation of eIF4E .	The MAP kinases p38 and ERK1/2 can activate Mnk1 to regulate the phosphorylation of eIF4E.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Mnk1	Mnk1	Mnk1	5	6	8	9
MNK1 and MNK2 , which are activated in vivo by ERK1/2 and p38 MAPK , participate in transcriptional and translational regulation , inflammatory responses , proliferation and survival [ XREF_BIBR , XREF_BIBR ] .	MNK1 and MNK2, which are activated in vivo by ERK1/2 and p38 MAPK, participate in transcriptional and translational regulation, inflammatory responses, proliferation and survival [XREF_BIBR, XREF_BIBR].	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MNK1	MNK1	MNK1	10	11	0	1
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR TNFalpha downstream MAPK kinases such as p38 , ERK and MAP kinase activated protein kinase 1 ( MNK1 ) selectively increase IRES mediated translation of a subset of mRNAs .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR TNFalpha downstream MAPK kinases such as p38, ERK and MAP kinase activated protein kinase 1 (MNK1) selectively increase IRES mediated translation of a subset of mRNAs.	15	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	MNK1	MNK1	MNK1	17	18	26	27
In addition to its effects on ERK mediated Mnk1 activation and protein synthesis , beta-arrestin 2 has also been reported to facilitate ERK mediated phosphorylation of ribosomal S6 kinase ( p90RSK ) in VSMC [ XREF_BIBR ] .	In addition to its effects on ERK mediated Mnk1 activation and protein synthesis, beta-arrestin 2 has also been reported to facilitate ERK mediated phosphorylation of ribosomal S6 kinase (p90RSK) in VSMC [XREF_BIBR].	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK	ERK	ERK	Mnk1	Mnk1	Mnk1	6	7	8	9
In contrast , the EGFR inhibitor completely abolished the increase in PPARgamma phosphorylation induced by treating cells with TNF-alpha , a cytokine reported to promote MAPK activation and suppression of PPARgamma activity in pre-adipocytes XREF_BIBR .	In contrast, the EGFR inhibitor completely abolished the increase in PPARgamma phosphorylation induced by treating cells with TNF-alpha, a cytokine reported to promote MAPK activation and suppression of PPARgamma activity in pre-adipocytes XREF_BIBR.	25	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	25	26	30	31
This dual approach is expected to avoid ( a ) ERK cascade mediated downregulation of PPARgamma , ( b ) MEK driven nuclear export and cytoplasmic retention of PPARgamma and ( c ) nongenomic amplification loops of PPARgamma ligands towards the ERK cascade , but to promote ( d ) the growth arresting and proapoptotic genomic functions of PPARgamma and its ligands , and ( e ) the negative crosstalk of PPARgamma with promitotic and proinflammatory transcription factors in the nucleus .	This dual approach is expected to avoid (a) ERK cascade mediated downregulation of PPARgamma, (b) MEK driven nuclear export and cytoplasmic retention of PPARgamma and (c) nongenomic amplification loops of PPARgamma ligands towards the ERK cascade, but to promote (d) the growth arresting and proapoptotic genomic functions of PPARgamma and its ligands, and (e) the negative crosstalk of PPARgamma with promitotic and proinflammatory transcription factors in the nucleus.	10	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	10	11	15	16
Both signalling targets of activated TLR4 , NF-kappaB 30 and MAPK 38 can down-regulate PPARgamma , suggesting that under conditions of inhibited MD2-TLR4 signalling , PPARgamma down-regulation was likewise inhibited .	Both signalling targets of activated TLR4, NF-kappaB 30 and MAPK 38 can down-regulate PPARgamma, suggesting that under conditions of inhibited MD2-TLR4 signalling, PPARgamma down-regulation was likewise inhibited.	2	15	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	10	11	14	15
ERK and p-38 activation have been previously established as part of GPR54 signaling , On the other hand , inhibition of MAPK and ERK signaling pathway was reported to suppress adipogenesis and down regulation of PPARgamma .	ERK and p-38 activation have been previously established as part of GPR54 signaling, On the other hand, inhibition of MAPK and ERK signaling pathway was reported to suppress adipogenesis and down regulation of PPARgamma.	0	36	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	0	1	35	36
To evaluate the role of MAPK and ERK signaling in the leptin induced suppression of PPARgamma inhibitory effects on growth plate cell chondrogenic differentiation and chondrocyte hypertrophy , MAPK and ERK inhibitor PD98059 was presupplemented in the medium 30min before the treatment with leptin and/or ciglitazone for 5 days .	To evaluate the role of MAPK and ERK signaling in the leptin induced suppression of PPARgamma inhibitory effects on growth plate cell chondrogenic differentiation and chondrocyte hypertrophy, MAPK and ERK inhibitor PD98059 was presupplemented in the medium 30min before the treatment with leptin and/or ciglitazone for 5 days.	12	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	28	29	15	16
Other studies found that ERK activity is necessary for the expression of C/EBPalpha and PPARgamma in 3T3-L1 preadipocytes , XREF_BIBR and that PPARgamma is activated by ERK or interacts with ERK-kinase1/2 ( MEKs ) in cancer .	Other studies found that ERK activity is necessary for the expression of C/EBPalpha and PPARgamma in 3T3-L1 preadipocytes, XREF_BIBR and that PPARgamma is activated by ERK or interacts with ERK-kinase1/2 (MEKs) in cancer.	22	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	26	27	22	23
Inhibition of ERK MAP kinase by PD98059 abolished the early and rapid induction of PPARgamma , while the inhibition of JNK MAP kinase by SP600125 nullifies the late inhibitory effect on the PPARgamma expression in a dose dependent manner .	Inhibition of ERK MAP kinase by PD98059 abolished the early and rapid induction of PPARgamma, while the inhibition of JNK MAP kinase by SP600125 nullifies the late inhibitory effect on the PPARgamma expression in a dose dependent manner.	2	15	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	2	3	14	15
Binding of NADA to CB 1 receptor initiates also different intracellular pathways , like MAPK that presumably activates PPARgamma .	Binding of NADA to CB 1 receptor initiates also different intracellular pathways, like MAPK that presumably activates PPARgamma.	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	14	15	18	19
PD98 ,059 , a MAPK and ERK kinase inhibitor , reversed the stretch induced reduction of PPARgamma ( 2 ) at both mRNA and protein levels achieved during the induction period .	PD98,059, a MAPK and ERK kinase inhibitor, reversed the stretch induced reduction of PPARgamma (2) at both mRNA and protein levels achieved during the induction period.	0	26	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	4	5	16	17
Involvement of MAPK signaling in AGEs induced PPARgamma down-regulation .	Involvement of MAPK signaling in AGEs induced PPARgamma down-regulation.	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	2	3	7	8
The MEK1 and ERK signaling pathway is known to promote adipogenesis by enhancing PPARgamma and CEBPalpha gene expression XREF_BIBR , XREF_BIBR , a step later to CEBPbeta induction and a cascade which is inversely regulated by atRA XREF_BIBR .	The MEK1 and ERK signaling pathway is known to promote adipogenesis by enhancing PPARgamma and CEBPalpha gene expression XREF_BIBR, XREF_BIBR, a step later to CEBPbeta induction and a cascade which is inversely regulated by atRA XREF_BIBR.	3	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	3	4	13	14
Given that over-activation of ERK blocks late stage of adipogenesis by repressing PPARgamma activity XREF_BIBR , XREF_BIBR , this increase would be consistent with the idea that the repressive effect of Rasal2 deficiency on adipogenesis in these cells is executed through raising ERK activity .	Given that over-activation of ERK blocks late stage of adipogenesis by repressing PPARgamma activity XREF_BIBR, XREF_BIBR, this increase would be consistent with the idea that the repressive effect of Rasal2 deficiency on adipogenesis in these cells is executed through raising ERK activity.	2	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	4	5	12	13
Emodin increased PPARgamma protein and luciferase reporter activity , which were abolished by inhibitors of MAPK extracellular signaling regulated kinase ( ERK ) kinase ( MEK )/ERK and AMPK .	Emodin increased PPARgamma protein and luciferase reporter activity, which were abolished by inhibitors of MAPK extracellular signaling regulated kinase (ERK) kinase (MEK)/ERK and AMPK.	2	17	abolished	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	PPARgamma protein	PPARgamma protein	PPARgamma protein	15	16	2	4
Similar results were obtained from HEK293T cells , whereas SW480 cells were resistant , presumably due to strong RAS activity caused by mutated KRASG12V alleles that lead to cytosolic retention and inactivation of PPARgamma by MEK1 and ERK1/2 .	Similar results were obtained from HEK293T cells, whereas SW480 cells were resistant, presumably due to strong RAS activity caused by mutated KRASG12V alleles that lead to cytosolic retention and inactivation of PPARgamma by MEK1 and ERK1/2.	26	38	lead	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	PPARgamma	PPARgamma	PPARgamma	37	38	33	34
The IGF mediated MAPK activation , in turn , may modulate the genomic activity of PPAR-gamma by the inhibition of its antiproliferative and prodifferentiating functions , thereby contributing to the tumor promoting role of IGF pathway .	The IGF mediated MAPK activation, in turn, may modulate the genomic activity of PPAR-gamma by the inhibition of its antiproliferative and prodifferentiating functions, thereby contributing to the tumor promoting role of IGF pathway.	1	16	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	IGF mediated MAPK	mapk	PPAR-gamma	PPAR-gamma	ppar-gamma	3	4	15	16
However , it must be emphasized that our findings do not determine if ERK 1/2 is both necessary and sufficient to induce downregulation of PPARgamma .	However, it must be emphasized that our findings do not determine if ERK 1/2 is both necessary and sufficient to induce downregulation of PPARgamma.	13	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK 1/2	ERK 1/2	ERK 1/2	PPARgamma	PPARgamma	PPARgamma	13	15	24	25
In the present study , the underlying mechanisms of PI3K and MAPK pathway mediated PPARgamma , and PGC-1alpha co-regulator activation , as well as the effects of downstream proteins , COX-2 and FoxO4 , on cell apoptosis were investigated .	In the present study, the underlying mechanisms of PI3K and MAPK pathway mediated PPARgamma, and PGC-1alpha co-regulator activation, as well as the effects of downstream proteins, COX-2 and FoxO4, on cell apoptosis were investigated.	9	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	11	12	14	15
Interestingly , MAPK signaling can also modulate PPAR-gamma functions by regulating the expression of co-factors needed for PPAR-gamma transcriptional activation [ XREF_BIBR ] .	Interestingly, MAPK signaling can also modulate PPAR-gamma functions by regulating the expression of co-factors needed for PPAR-gamma transcriptional activation [XREF_BIBR].	2	8	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	PPAR-gamma	PPAR-gamma	PPAR-gamma	2	3	7	8
Our results also suggested that ERK activation and inactivation of PPAR-gamma are involved in GR down regulation because the co-transfection of PPAR-gamma and MEK1 led to PPAR-gamma phosphorylation on Serine 112 and enhanced GR degradation .	Our results also suggested that ERK activation and inactivation of PPAR-gamma are involved in GR down regulation because the co-transfection of PPAR-gamma and MEK1 led to PPAR-gamma phosphorylation on Serine 112 and enhanced GR degradation.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	PPAR-gamma	PPAR-gamma	PPAR-gamma	5	6	10	11
The activated ERK signaling also suppresses the inhibition of PPAR-gamma to MMP-13 , thereby resulting in cartilage degradation ( XREF_FIG ) .	The activated ERK signaling also suppresses the inhibition of PPAR-gamma to MMP-13, thereby resulting in cartilage degradation (XREF_FIG).	2	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PPAR-gamma	PPAR-gamma	PPAR-gamma	2	3	9	10
The role of p38 MAPK in PPARgamma transcriptional activation also further explains how NO/p38 MAPK signaling , independent of GPR40 , induces PPARgamma target genes .	The role of p38 MAPK in PPARgamma transcriptional activation also further explains how NO/p38 MAPK signaling, independent of GPR40, induces PPARgamma target genes.	14	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	14	15	22	23
Mechanisms of PPARgamma induced downstream cellular events and ERK1/2 mediated stimulation of PPARgamma by CDK5 were also investigated .	Mechanisms of PPARgamma induced downstream cellular events and ERK1/2 mediated stimulation of PPARgamma by CDK5 were also investigated.	8	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	PPARgamma	PPARgamma	PPARgamma	8	9	12	13
Fas in turn activated FADD which then triggers the same caspase signaling pathway as DD and OD without the involvement of RIP .	Fas in turn activated FADD which then triggers the same caspase signaling pathway as DD and OD without the involvement of RIP.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	0	1	4	5
Both TNFR-I and Fas mediated apoptotic pathways use FADD as a common conduit [ XREF_BIBR ] for the activation of apoptotic signaling .	Both TNFR-I and Fas mediated apoptotic pathways use FADD as a common conduit [XREF_BIBR] for the activation of apoptotic signaling.	1	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	3	4	8	9
Since Fadd -/- Ripk3 -/- mice developed lymphoproliferation resembling that caused by the Fas mutant lpr mice , one can argue that Fas triggers necroptosis of Fadd -/- T cells through RIPK3 .	Since Fadd -/- Ripk3 -/- mice developed lymphoproliferation resembling that caused by the Fas mutant lpr mice, one can argue that Fas triggers necroptosis of Fadd -/- T cells through RIPK3.	22	27	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	Fadd	Fadd	Fadd	22	23	26	27
These results support an essential role of calmodulin in mediating Fas induced FADD independent activation of Src-ERK signaling pathways , which promote survival signaling in pancreatic cancer cells .	These results support an essential role of calmodulin in mediating Fas induced FADD independent activation of Src-ERK signaling pathways, which promote survival signaling in pancreatic cancer cells.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	10	11	12	13
Fas activates IL-1beta and IL-18 in a caspase-8- and FADD dependent and Rip3 independent pathway .	Fas activates IL-1beta and IL-18 in a caspase-8- and FADD dependent and Rip3 independent pathway.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	0	1	9	10
CRPs in turn provide a platform for Fas oligomerization , which facilitates formation of the death induced signaling complex ( DISC ) , an event essential for the other 98 % of Fas induced FADD and Caspase 8 activation , and eventually apoptosis of these cells [ XREF_BIBR ] .	CRPs in turn provide a platform for Fas oligomerization, which facilitates formation of the death induced signaling complex (DISC), an event essential for the other 98% of Fas induced FADD and Caspase 8 activation, and eventually apoptosis of these cells [XREF_BIBR].	30	36	induced	Positive_early_activation	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	32	33	34	35
In the first , phosphorylated dimers of Hsp-27 interact with Daxx and block Fas mediated apoptosis , but with no effect on Fas induced FADD and caspase dependent apoptosis ( Charette et al , 2000 ) .	In the first, phosphorylated dimers of Hsp-27 interact with Daxx and block Fas mediated apoptosis, but with no effect on Fas induced FADD and caspase dependent apoptosis (Charette et al, 2000).	20	28	induced	Positive_early_activation	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	22	23	24	25
TRAIL-DR4/5 can induce apoptosis via Fas associated protein with death domain and death inducing signaling complex ( FADD and DISC )/caspase-8 signaling in several cell types , including neurons and oligodendroglia .	TRAIL-DR4/5 can induce apoptosis via Fas associated protein with death domain and death inducing signaling complex (FADD and DISC)/caspase-8 signaling in several cell types, including neurons and oligodendroglia.	3	21	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	5	6	17	18
Both types of IFNs induce and activate death receptors such as CD95 , which then activates FADD , subsequently activating caspase 8 .	Both types of IFNs induce and activate death receptors such as CD95, which then activates FADD, subsequently activating caspase 8.	8	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95	CD95	CD95	FADD	FADD	FADD	11	12	16	17
By contrast , Fas activation promoted the survival of the FADD knockdown MiaPaCa-2 and BxPC-3 cells in a concentration dependent manner .	By contrast, Fas activation promoted the survival of the FADD knockdown MiaPaCa-2 and BxPC-3 cells in a concentration dependent manner.	3	12	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	3	4	10	11
IFNs induce apoptosis by activating death receptors such as Fas ( CD95 ) , which then activates the adaptor FADD , leading to subsequent caspase-8 activation .	IFNs induce apoptosis by activating death receptors such as Fas (CD95), which then activates the adaptor FADD, leading to subsequent caspase-8 activation.	6	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	9	10	19	20
This study shows that hesperetin induces apoptosis in H522 cells via a pathway independentof p53 and Bax but triggers the death-receptor Fas initiated FADD / caspase-8-dependent apoptotic pathway .	This study shows that hesperetin induces apoptosis in H522 cells via a pathway independentof p53 and Bax but triggers the death-receptor Fas initiated FADD / caspase-8-dependent apoptotic pathway.	18	27	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	21	22	23	24
Furthermore , virus encoded Fas associated death domain like interleukin-1beta ( IL-1beta )-converting enzyme inhibitory proteins ( vFLIP ) inhibit the activation of caspase 8 by targeting a complex of FADD and caspase 8 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Furthermore, virus encoded Fas associated death domain like interleukin-1beta (IL-1beta)-converting enzyme inhibitory proteins (vFLIP) inhibit the activation of caspase 8 by targeting a complex of FADD and caspase 8 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	31	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fas	Fas	Fas	FADD	FADD	FADD	4	5	30	31
HSP27 expression had no effect on Fas induced FADD- and caspase dependent apoptosis .	HSP27 expression had no effect on Fas induced FADD- and caspase dependent apoptosis.	4	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD-	FADD-	FADD-	6	7	8	9
Overall , our results indicate that CD95 ( APO-1 ) induces the FADD- and caspase 8 dependent internalization of Na ( + ) , K ( + )-ATPase through intracellular GSH loss , and the subsequent generation of H ( 2 ) O ( 2 )-mediated serine phosphorylation of Na ( + ) , K ( + )-ATPase alpha1 subunit .	Overall, our results indicate that CD95 (APO-1) induces the FADD- and caspase 8 dependent internalization of Na (+), K (+)-ATPase through intracellular GSH loss, and the subsequent generation of H (2) O (2)-mediated serine phosphorylation of Na (+), K (+)-ATPase alpha1 subunit.	6	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95	CD95	CD95	FADD-	FADD-	FADD-	6	7	12	13
It is assumed that the engagement of Fas causes oligomerization of FADD , which leads to activation of caspase 8 .	It is assumed that the engagement of Fas causes oligomerization of FADD, which leads to activation of caspase 8.	5	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	7	8	11	12
Ligation of Fas by CTLs , NK or antibodies induces the FADD pathway that leads to caspase 8 dependent apoptosis within Fas+ cells .	Ligation of Fas by CTLs, NK or antibodies induces the FADD pathway that leads to caspase 8 dependent apoptosis within Fas+ cells.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	2	3	11	12
The extrinsic pathway works through the binding of specific ligands to cell surface death receptors , such as Fas and CD95 , TNF-R1 , or TRAIL , which in turn activate the death domain protein , FADD , and caspase-8 .	The extrinsic pathway works through the binding of specific ligands to cell surface death receptors, such as Fas and CD95, TNF-R1, or TRAIL, which in turn activate the death domain protein, FADD, and caspase-8.	20	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD95	CD95	CD95	FADD	FADD	FADD	20	21	36	37
In contrast , TLR3 deficiency markedly attenuated I/R induced increases in the levels of Fas by 27.2 % and prevented I/R increased FasL and FADD , respectively , compared with WT I/R mice .	In contrast, TLR3 deficiency markedly attenuated I/R induced increases in the levels of Fas by 27.2% and prevented I/R increased FasL and FADD, respectively, compared with WT I/R mice.	3	25	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fas	TLR3 deficiency markedly attenuated I/R induced increases in the levels of Fas	fas	FADD	FADD	fadd	14	15	24	25
The exact stoichiometry of adapters mediating caspase activation has , however , never been determined , and it is possible that multiple Fas trimers are required to allow the assembly of multiple FADD adapters bringing several FLICE proteins together and allowing reciprocal cleavage and subsequent activation of the caspase .	The exact stoichiometry of adapters mediating caspase activation has, however, never been determined, and it is possible that multiple Fas trimers are required to allow the assembly of multiple FADD adapters bringing several FLICE proteins together and allowing reciprocal cleavage and subsequent activation of the caspase.	22	33	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	FADD	FADD	FADD	22	23	32	33
ERK activation can stimulate activity of SPHK1 , thus causing a feed-forward autocrine loop by production of S1P ligand [ XREF_BIBR ] , thereby explaining the homeostatic ERK activity that is reduced by VPC01091 ( XREF_FIG ) .	ERK activation can stimulate activity of SPHK1, thus causing a feed-forward autocrine loop by production of S1P ligand [XREF_BIBR], thereby explaining the homeostatic ERK activity that is reduced by VPC01091 (XREF_FIG).	0	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	SPHK1	SPHK1	SPHK1	0	1	6	7
While this canonical pathway operates in the activation of ERK1/2 in response to other growth factors such as the fibroblast growth factor ( FGF ) and epidermal growth factor ( EGF ) , VEGF activation of this cascade seems to be fundamentally different involving the complex feedback mechanism initiated by calcium and ERK1/2 dependent activation of sphingosine kinase 1 ( SphK1 ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	While this canonical pathway operates in the activation of ERK1/2 in response to other growth factors such as the fibroblast growth factor (FGF) and epidermal growth factor (EGF), VEGF activation of this cascade seems to be fundamentally different involving the complex feedback mechanism initiated by calcium and ERK1/2 dependent activation of sphingosine kinase 1 (SphK1) [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	50	59	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	sphingosine kinase 1	sphingosine kinase 1	sphingosine kinase 1	52	53	56	59
It is also known that EGFR downstream signaling leads to the activation of Erk1/2 [ XREF_BIBR ] and that Erk1/2 activates SphK1 [ XREF_BIBR ] .	It is also known that EGFR downstream signaling leads to the activation of Erk1/2 [XREF_BIBR] and that Erk1/2 activates SphK1 [XREF_BIBR].	19	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	SphK1	SphK1	SphK1	19	20	21	22
It is thus possible that a positive feedback loop exists , whereby activated ERK1/2 stimulates SPHK1 , leading to increased intracellular S1P as well as S1P export .	It is thus possible that a positive feedback loop exists, whereby activated ERK1/2 stimulates SPHK1, leading to increased intracellular S1P as well as S1P export.	12	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	SPHK1	SPHK1	SPHK1	13	14	15	16
It was necessary to determine whether the OGD model of neuronal ischemia is cytotoxic to human N2a cells and to the molecular mechanisms underlying the OGD mediated activation of IRE1-alpha inducing Jun N-terminal kinase ( JNK1/2 ) and p38 MAP Kinase ( MAPK ) .	It was necessary to determine whether the OGD model of neuronal ischemia is cytotoxic to human N2a cells and to the molecular mechanisms underlying the OGD mediated activation of IRE1-alpha inducing Jun N-terminal kinase (JNK1/2) and p38 MAP Kinase (MAPK).	27	33	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRE1-alpha	IRE1-alpha	IRE1-alpha	Jun	Jun	Jun	29	30	31	32
Their work demonstrated that the transcription factor AP-1 , activated by IRE1 and ATF6 , is responsible for induction of miR-199-5p and thereby creates a negative feedback loop [ XREF_BIBR , XREF_BIBR ] .	Their work demonstrated that the transcription factor AP-1, activated by IRE1 and ATF6, is responsible for induction of miR-199-5p and thereby creates a negative feedback loop [XREF_BIBR, XREF_BIBR].	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IRE1	IRE1	IRE1	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	11	12	5	8
Furthermore , in addition to promoting the first step in XBP1 splicing , phosphorylated mammalian IRE1 is able to activate Jun N-terminal kinase ( JNK ) , by recruiting the scaffold protein TRAF2 .	Furthermore, in addition to promoting the first step in XBP1 splicing, phosphorylated mammalian IRE1 is able to activate Jun N-terminal kinase (JNK), by recruiting the scaffold protein TRAF2.	14	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRE1	IRE1	IRE1	Jun	Jun	Jun	15	16	20	21
In mammalian cells , IRE1 not only splices XBP1 mRNA but also activates Jun N-terminal kinase , a serine directed protein kinase , in response to ER stress in embryonic fibroblasts , and directly interacts with pro apoptotic factors , such as BAX and BAK , to contribute to apoptosis in ER stressed cells [ XREF_BIBR , XREF_BIBR ] .	In mammalian cells, IRE1 not only splices XBP1 mRNA but also activates Jun N-terminal kinase, a serine directed protein kinase, in response to ER stress in embryonic fibroblasts, and directly interacts with pro apoptotic factors, such as BAX and BAK, to contribute to apoptosis in ER stressed cells [XREF_BIBR, XREF_BIBR].	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRE1	IRE1	IRE1	Jun	Jun	Jun	4	5	13	14
In order to confirm that HIV-1 gp120 mediated activation of IRE1alpha led to activation of JNK and its transcription factor AP-1 , we determined the effect of IRE1alpha knockdown on phosphorylated JNK and cJUN ( XREF_FIG ) .	In order to confirm that HIV-1 gp120 mediated activation of IRE1alpha led to activation of JNK and its transcription factor AP-1, we determined the effect of IRE1alpha knockdown on phosphorylated JNK and cJUN (XREF_FIG).	6	21	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IRE1alpha	gp120 mediated activation of IRE1alpha	ire1alpha	transcription factor AP-1	transcription factor AP-1	transcription factor ap-1	10	11	18	21
IRE1alpha also activates Jun kinase ( JNK ) in a process involving phosphorylation of JNK by MKK4 , providing another stimulus to cell death .	IRE1alpha also activates Jun kinase (JNK) in a process involving phosphorylation of JNK by MKK4, providing another stimulus to cell death.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRE1alpha	IRE1alpha	IRE1alpha	Jun	Jun	Jun	0	1	3	4
In mammalian cells , IRE1 can trigger PCD by activating the Jun amino-terminal kinase ( JNK ) pathway XREF_BIBR .	In mammalian cells, IRE1 can trigger PCD by activating the Jun amino-terminal kinase (JNK) pathway XREF_BIBR.	4	13	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRE1	IRE1	IRE1	Jun	Jun	Jun	4	5	11	12
Because IRE1 triggers c-Jun signaling , we examined the possible involvement of c-Jun in up-regulation of MTHFR .	Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR.	1	4	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRE1	IRE1	IRE1	c-Jun	c-Jun	c-Jun	1	2	3	4
Among them , IRE1 mediated activation of Jun N-terminal kinase ( JNK ) contributes to cell death by phosphorylating and inactivating the anti-apoptotic regulator BCL-2 XREF_BIBR .	Among them, IRE1 mediated activation of Jun N-terminal kinase (JNK) contributes to cell death by phosphorylating and inactivating the anti-apoptotic regulator BCL-2 XREF_BIBR.	3	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	IRE1	IRE1	IRE1	Jun	Jun	Jun	3	4	7	8
To clarify whether erinacine A has an inhibitory effect on the MPP+ model of neuronal injury that is cytotoxic to N2a cells and the molecular mechanisms underlying the MPP+ -mediated activation of IRE1a inducing Jun N-terminal kinase ( JNK1/2 ) and p38 MAP Kinase ( MAPK ) , we induced N2a cells to MPP+ for 24h , performed MTT assays and examined the protein levels of the ER stress signaling pathway .	To clarify whether erinacine A has an inhibitory effect on the MPP+ model of neuronal injury that is cytotoxic to N2a cells and the molecular mechanisms underlying the MPP+ -mediated activation of IRE1a inducing Jun N-terminal kinase (JNK1/2) and p38 MAP Kinase (MAPK), we induced N2a cells to MPP+ for 24h, performed MTT assays and examined the protein levels of the ER stress signaling pathway.	30	36	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRE1a	IRE1a	IRE1a	Jun	Jun	Jun	32	33	34	35
In response to strong ER stress , IRE1 signaling also causes regulated IRE1 dependent mRNA decay ( RIDD ) and Jun N-terminal kinase ( JNK ) activation .	In response to strong ER stress, IRE1 signaling also causes regulated IRE1 dependent mRNA decay (RIDD) and Jun N-terminal kinase (JNK) activation.	7	22	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRE1	IRE1	IRE1	Jun	Jun	Jun	7	8	20	21
US28 cell-death induction is prevented by coexpression of C-FLIP , a protein that inhibits Fas associated death domain protein ( FADD )-mediated activation of caspase 10 and caspase 8 , and by coexpression of the HCMV antiapoptotic protein IE1 .	US28 cell-death induction is prevented by coexpression of C-FLIP, a protein that inhibits Fas associated death domain protein (FADD)-mediated activation of caspase 10 and caspase 8, and by coexpression of the HCMV antiapoptotic protein IE1.	20	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase 10	caspase 10	caspase 10	20	21	24	26
VISA also recruits the Fas associated death domain protein ( FADD ) , which activate caspase-10 and caspase-8 , driving NF-kappaB activation XREF_BIBR .	VISA also recruits the Fas associated death domain protein (FADD), which activate caspase-10 and caspase-8, driving NF-kappaB activation XREF_BIBR.	8	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-10	caspase-10	caspase-10	10	11	15	16
Collectively , these findings indicate that flunarizine triggers apoptosis in Jurkat cells via FADD independent activation of caspase-10 .	Collectively, these findings indicate that flunarizine triggers apoptosis in Jurkat cells via FADD independent activation of caspase-10.	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-10	caspase-10	caspase-10	13	14	17	18
These data indicate that AML1 functions are potentially regulated by ERK , which is activated by cytokine and growth factor stimuli .	These data indicate that AML1 functions are potentially regulated by ERK, which is activated by cytokine and growth factor stimuli.	4	14	potentially regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	AML1	AML1	AML1	10	11	4	5
Function study demonstrated that FAXDC2 promoted megakaryocytic differentiation by enhancing ERK signaling that subsequently upregulated RUNX1 .	Function study demonstrated that FAXDC2 promoted megakaryocytic differentiation by enhancing ERK signaling that subsequently upregulated RUNX1.	10	16	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	RUNX1	RUNX1	RUNX1	10	11	15	16
Therefore , our observations suggest that FAXDC2 enhances megakaryocytic differentiation by strengthening ERK signaling and expression of RUNX1 , a vital transcriptional factor of megakaryocytic differentiation .	Therefore, our observations suggest that FAXDC2 enhances megakaryocytic differentiation by strengthening ERK signaling and expression of RUNX1, a vital transcriptional factor of megakaryocytic differentiation.	12	22	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	RUNX1	RUNX1	RUNX1	12	13	17	18
Although differences between wild-type AML1 and phosphorylation site mutants in DNA binding affinity were not observed , we have shown that ERK dependent phosphorylation potentiates the transactivation ability of AML1 .	Although differences between wild-type AML1 and phosphorylation site mutants in DNA binding affinity were not observed, we have shown that ERK dependent phosphorylation potentiates the transactivation ability of AML1.	21	30	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK dependent phosphorylation	erk	AML1	AML1	aml1	21	22	29	30
PTEN loss enhances the expressions of EGR1 , c-JUN and EZH2 , which in turn suppresses AR transcription factor activity and output .	PTEN loss enhances the expressions of EGR1, c-JUN and EZH2, which in turn suppresses AR transcription factor activity and output.	0	19	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EZH2	PTEN loss enhances the expressions of EGR1, c-JUN and EZH2	ezh2	AR	AR	ar	10	11	16	17
Silencing of EZH2 selectively prevented biding of AR to co-occupied binding sites but not to other peaks .	Silencing of EZH2 selectively prevented biding of AR to co-occupied binding sites but not to other peaks.	0	8	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EZH2	EZH2	EZH2	AR	AR	AR	2	3	7	8
Therefore , our results establish CCN3 as an important regulator of prostate cancer and indicate a novel mechanism by which the epigenetic regulator EZH2 indirectly activates AR signaling and favoring CRPC progression .	Therefore, our results establish CCN3 as an important regulator of prostate cancer and indicate a novel mechanism by which the epigenetic regulator EZH2 indirectly activates AR signaling and favoring CRPC progression.	20	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EZH2	EZH2	EZH2	AR	AR	AR	23	24	26	27
Xu et al discovered that in the castration resistant prostate cancer cells , EZH2 could be a transcriptional coactivator of androgen receptor instead of a transcriptional repressor of PCR2 .	Xu et al discovered that in the castration resistant prostate cancer cells, EZH2 could be a transcriptional coactivator of androgen receptor instead of a transcriptional repressor of PCR2.	13	22	be a transcriptional coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	EZH2	EZH2	EZH2	androgen receptor	androgen receptor	androgen receptor	13	14	20	22
Taken together , our data reveal a novel function of the matricellular protein CCN3 in inhibiting AR signaling and thus CRPC progression through its cytoplasmic form and suggest a novel mechanism by which the epigenetic regulator EZH2 indirectly activates AR signaling in CRPC .	Taken together, our data reveal a novel function of the matricellular protein CCN3 in inhibiting AR signaling and thus CRPC progression through its cytoplasmic form and suggest a novel mechanism by which the epigenetic regulator EZH2 indirectly activates AR signaling in CRPC.	33	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EZH2	EZH2	EZH2	AR	AR	AR	36	37	39	40
EZH2 is also overexpressed in hormone-refractory metastatic prostate cancer , suggesting EZH2 promotes AR independent growth [ XREF_BIBR ] .	EZH2 is also overexpressed in hormone-refractory metastatic prostate cancer, suggesting EZH2 promotes AR independent growth [XREF_BIBR].	11	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EZH2	EZH2	EZH2	AR	AR	AR	11	12	13	14
93 This AR interaction and coactivator function of EZH2 is mediated by AKT dependent phosphorylation of EZH2 on serine 21 , which also impairs its ability to methylate H3K27 and presumably directs it to one or more alternative substrates .	93 This AR interaction and coactivator function of EZH2 is mediated by AKT dependent phosphorylation of EZH2 on serine 21, which also impairs its ability to methylate H3K27 and presumably directs it to one or more alternative substrates.	2	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EZH2	phosphorylation of EZH2 on serine	ezh2	AR	AR	ar	16	17	2	3
The size or number of spheres derived from Kras ( G12D ) + AR tumorigenic cells was similarly suppressed by the SAHA or DZNep treatment ( XREF_FIG ) , suggesting enhanced sphere formation capacity in Kras ( G12D ) + AR tumorigenic cells is likely mediated by EZH2 activity .	The size or number of spheres derived from Kras (G12D) + AR tumorigenic cells was similarly suppressed by the SAHA or DZNep treatment (XREF_FIG), suggesting enhanced sphere formation capacity in Kras (G12D) + AR tumorigenic cells is likely mediated by EZH2 activity.	1	48	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EZH2	EZH2	EZH2	AR	AR	AR	47	48	13	14
It has become very clear that TCR activation in caspase 8- or FADD deficient T cells promotes RIP1- and RIP3 dependent necroptosis XREF_BIBR , XREF_BIBR - XREF_BIBR .	It has become very clear that TCR activation in caspase 8- or FADD deficient T cells promotes RIP1- and RIP3 dependent necroptosis XREF_BIBR, XREF_BIBR - XREF_BIBR.	7	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	RIP1-	RIP1-	RIP1-	12	13	17	18
cFLIP deficient [ XREF_BIBR ] or RIP1 deficient mice [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] die during development but are fully rescued by the combined elimination of apoptotic ( Casp8 or FADD ) and necroptotic ( RIP3 or MLKL ) machinery .	cFLIP deficient [XREF_BIBR] or RIP1 deficient mice [XREF_BIBR, XREF_BIBR, XREF_BIBR] die during development but are fully rescued by the combined elimination of apoptotic (Casp8 or FADD) and necroptotic (RIP3 or MLKL) machinery.	6	33	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	RIP1	RIP1	RIP1	32	33	6	7
However , loss of FADD does not prevent neonatal lethality of RIP1 -/- mice .	However, loss of FADD does not prevent neonatal lethality of RIP1 -/- mice.	2	13	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD	loss of FADD	fadd	RIP1	RIP1	rip1	4	5	11	12
Similarly , FADD deficiency partially rescued RIP1 -/- B cell development ( XREF_SUPPLEMENTARY ) .	Similarly, FADD deficiency partially rescued RIP1 -/- B cell development (XREF_SUPPLEMENTARY).	2	9	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	RIP1	RIP1	RIP1	2	3	6	7
However , loss or inhibition of either FADD or CASP8 induces RIP1- and RIP3 dependent necroptosis , an alternative cell death pathway [ XREF_BIBR ] .	However, loss or inhibition of either FADD or CASP8 induces RIP1- and RIP3 dependent necroptosis, an alternative cell death pathway [XREF_BIBR].	2	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	loss or inhibition of either FADD	fadd	RIP1-	RIP1-	rip1-	7	8	11	12
However , HSP27 blocked Fas induced translocation of Daxx from the nucleus to the cytoplasm and Fas induced Daxx- and Ask1 dependent apoptosis .	However, HSP27 blocked Fas induced translocation of Daxx from the nucleus to the cytoplasm and Fas induced Daxx- and Ask1 dependent apoptosis.	16	22	induced	Positive_early_activation	Positive_activation	Positive_activation	Fas	Fas	Fas	Daxx-	Daxx-	Daxx-	16	17	18	19
Fas activation induced Daxx to interact with apoptosis signal regulating kinase 1 ( ASK1 ) .	Fas activation induced Daxx to interact with apoptosis signal regulating kinase 1 (ASK1).	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	Daxx	Daxx	Daxx	0	1	3	4
Fas activation induced Daxx to interact with ASK1 , which consequently relieved an inhibitory intramolecular interaction between the amino- and carboxyl-termini of ASK1 , activating its kinase activity .	Fas activation induced Daxx to interact with ASK1, which consequently relieved an inhibitory intramolecular interaction between the amino- and carboxyl-termini of ASK1, activating its kinase activity.	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	Daxx	Daxx	Daxx	0	1	3	4
We show that Fas triggered death of normal embryonic motoneurons requires transcriptional upregulation of neuronal NOS and involves Daxx , ASK1 , and p38 together with the classical FADD and caspase -8 cascade .	We show that Fas triggered death of normal embryonic motoneurons requires transcriptional upregulation of neuronal NOS and involves Daxx, ASK1, and p38 together with the classical FADD and caspase -8 cascade.	3	23	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	Daxx	Daxx	Daxx	3	4	18	19
However , some evidence also indicates that Fas activates Jnk independently of Daxx [ XREF_BIBR , XREF_BIBR ] .	However, some evidence also indicates that Fas activates Jnk independently of Daxx [XREF_BIBR, XREF_BIBR].	7	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	Daxx	Daxx	Daxx	7	8	12	13
Some reports suggest that the death domain of Fas can directly activate apoptosis signal regulating kinase 1 ( ASK1 ) facilitating the translocation of Daxx from nucleus to cytoplasm .	Some reports suggest that the death domain of Fas can directly activate apoptosis signal regulating kinase 1 (ASK1) facilitating the translocation of Daxx from nucleus to cytoplasm.	6	20	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	ASK1	ASK1	ASK1	8	9	18	19
We recently reported that Smad4 activity and stability are directly regulated by 2 major signaling pathways , RTK and MAPK and Wnt and GSK3 .	We recently reported that Smad4 activity and stability are directly regulated by 2 major signaling pathways, RTK and MAPK and Wnt and GSK3.	4	20	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Smad4	Smad4	Smad4	19	20	4	5
Smad4 activity is directly regulated by the Wnt and fibroblast growth factor ( FGF ) pathways through hierarchical phosphorylation by GSK3 and Erk .	Smad4 activity is directly regulated by the Wnt and fibroblast growth factor (FGF) pathways through hierarchical phosphorylation by GSK3 and Erk.	0	23	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Erk	Erk	Erk	Smad4	Smad4	Smad4	22	23	0	1
Several studies showed that p38 and ERK pathways might mediate Smad4 independent TGF-beta1 responses [ XREF_BIBR - XREF_BIBR ] .	Several studies showed that p38 and ERK pathways might mediate Smad4 independent TGF-beta1 responses [XREF_BIBR - XREF_BIBR].	4	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	Smad4	Smad4	Smad4	6	7	10	11
We demonstrated by fluorescent immunohistochemical staining of hBid -/- liver sections that Fas stimulation does not induce activation of either RIP-1 or RIP-3 , or does not lead to the in vivo formation RIP-1 and RIP-3 complex 12 hours post Jo-2 injection ( XREF_FIG ) , shown to be necessary for the initiation of programmed necrosis [ XREF_BIBR ] .	We demonstrated by fluorescent immunohistochemical staining of hBid -/- liver sections that Fas stimulation does not induce activation of either RIP-1 or RIP-3, or does not lead to the in vivo formation RIP-1 and RIP-3 complex 12 hours post Jo-2 injection (XREF_FIG), shown to be necessary for the initiation of programmed necrosis [XREF_BIBR].	12	37	lead	Positive_regulation_syntax_7_verb	Positive_activation	Positive_regulation	Fas	Fas	fas	RIP-1	RIP-1 and RIP-3 complex	rip-1	12	13	33	34
Furthermore , gemcitabine co-treatment strongly increased the amount of cells undergoing CD95 induced RIP1 regulated necrosis .	Furthermore, gemcitabine co-treatment strongly increased the amount of cells undergoing CD95 induced RIP1 regulated necrosis.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	CD95	CD95	CD95	RIP1	RIP1	RIP1	11	12	13	14
Consequently , loss of a functional FANCC results in decreased activation of STAT1 following IFN-gamma stimulation .	Consequently, loss of a functional FANCC results in decreased activation of STAT1 following IFN-gamma stimulation.	2	15	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	FANCC	loss of a functional FANCC	fancc	STAT1	STAT1	stat1	6	7	12	13
FANCM also promotes the retention of chicken TopBP1 in chromatin and the restart of stalled replication forks .	FANCM also promotes the retention of chicken TopBP1 in chromatin and the restart of stalled replication forks.	0	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FANCM	FANCM	FANCM	TopBP1	TopBP1	TopBP1	0	1	7	8
FASN dependent activation of Wnt1 occurs via its palmitoylation .	FASN dependent activation of Wnt1 occurs via its palmitoylation.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FASN	FASN	FASN	Wnt1	Wnt1	Wnt1	0	1	4	5
The addition of insulin increased the amount of Exo70 in the vicinity of the plasma membrane and stimulated the tethering and fusion of GLUT4 vesicles , but the rates of fusion and GLUT4 exposure were not affected by overexpression of Exo70 .	The addition of insulin increased the amount of Exo70 in the vicinity of the plasma membrane and stimulated the tethering and fusion of GLUT4 vesicles, but the rates of fusion and GLUT4 exposure were not affected by overexpression of Exo70.	3	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Exo70	insulin increased the amount of Exo70	exo70	GLUT4	GLUT4	glut4	8	9	23	24
In this study , we found that Pin1 dependent isomerization of Runx2 is the critical step for FGF2 induced Runx2 transactivation function .	In this study, we found that Pin1 dependent isomerization of Runx2 is the critical step for FGF2 induced Runx2 transactivation function.	15	21	induced	Positive_early_activation	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	17	18	19	20
p65 and miR -105 is essential for FGF2 mediated Runx2 and ADAMTS upregulation .	p65 and miR -105 is essential for FGF2 mediated Runx2 and ADAMTS upregulation.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	7	8	9	10
We have previously shown that Cx43 amplifies FGF2 dependent signaling to increase the activity of the transcription factor Runx2 .	We have previously shown that Cx43 amplifies FGF2 dependent signaling to increase the activity of the transcription factor Runx2.	7	19	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	7	8	18	19
Upregulated endogenous expression of BMP-2 , TGF-beta1 , and FGF-2 might stimulate the activation of Runx2 expression , and activated Runx2 could express the downstream ALP expression through the Smad pathway [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Upregulated endogenous expression of BMP-2, TGF-beta1, and FGF-2 might stimulate the activation of Runx2 expression, and activated Runx2 could express the downstream ALP expression through the Smad pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	17	stimulate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	FGF-2	expression of BMP-2, TGF-beta1, and FGF-2	fgf-2	Runx2	Runx2 expression	runx2	9	10	15	16
For example , the osteogenic transcription factor Runx2 can be upregulated by FGF2 , FGF4 , and FGF8 .	For example, the osteogenic transcription factor Runx2 can be upregulated by FGF2, FGF4, and FGF8.	3	17	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	12	13	7	8
In human prostate cancer DU145 cells , FSK ( 1 muM ) and FGF2 ( 10 ng/ml ) increased BSP and Runx2 mRNA and protein levels at 3 and 12h , respectively .	In human prostate cancer DU145 cells, FSK (1 muM) and FGF2 (10 ng/ml) increased BSP and Runx2 mRNA and protein levels at 3 and 12h, respectively.	7	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	13	14	21	22
Electrophoretic mobility shift assays also showed that FGF2 treatment increases the specific binding of Runx2 to the cognate response element in the osteocalcin gene promoter .	Electrophoretic mobility shift assays also showed that FGF2 treatment increases the specific binding of Runx2 to the cognate response element in the osteocalcin gene promoter.	7	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	7	8	14	15
In the present study , FGF2 ( 10 ng/mL ) was found to increase the levels of Runx2 and BSP mRNA at 3 and 12 h in human osteoblast like Saos2 cells .	In the present study, FGF2 (10 ng/mL) was found to increase the levels of Runx2 and BSP mRNA at 3 and 12 h in human osteoblast like Saos2 cells.	5	20	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	5	6	17	18
FGF-2 is also known to enhance Runx-2 and Smads nuclear localization in BMP-2 canonical signaling in osteoblasts , supporting the synergistic effect of FGF and BMP-2 .	FGF-2 is also known to enhance Runx-2 and Smads nuclear localization in BMP-2 canonical signaling in osteoblasts, supporting the synergistic effect of FGF and BMP-2.	0	8	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	Runx-2	Runx-2	Runx-2	0	1	6	7
In both of these studies , FGF2 treatment in vitro caused increased expression of the Runx2 gene [ XREF_BIBR , XREF_BIBR ] .	In both of these studies, FGF2 treatment in vitro caused increased expression of the Runx2 gene [XREF_BIBR, XREF_BIBR].	6	16	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	6	7	15	16
For example , proteoglycans support FGF2 signaling , and FGF2 signaling modulates the activity of Runx2 and osteoblast specific gene expression [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	For example, proteoglycans support FGF2 signaling, and FGF2 signaling modulates the activity of Runx2 and osteoblast specific gene expression [XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR].	9	21	modulates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	FGF2	FGF2	fgf2	Runx2	Runx2 and osteoblast specific gene expression	runx2	9	10	15	16
Both FGF2 and IL-1beta activate RUNX2 , which leads to transactivation of MMP-13 in chondrocytes .	Both FGF2 and IL-1beta activate RUNX2, which leads to transactivation of MMP-13 in chondrocytes.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	RUNX2	RUNX2	RUNX2	1	2	5	6
FGF2 was also able to promote Runx2 nuclear localization [ XREF_BIBR ] , a requirement for its function as a transcription factor .	FGF2 was also able to promote Runx2 nuclear localization [XREF_BIBR], a requirement for its function as a transcription factor.	0	8	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	0	1	6	7
This suggests that BMP-2 should increase the expression of Runx2 , and that the activation of Runx2 should be promoted by the FGF2 signaling pathway which activated ERK and Runx2 .	This suggests that BMP-2 should increase the expression of Runx2, and that the activation of Runx2 should be promoted by the FGF2 signaling pathway which activated ERK and Runx2.	22	30	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	22	23	29	30
In addition to activation by MAPK , FGF-2 also increases Runx2 activity through the PKCdelta pathway .	In addition to activation by MAPK, FGF-2 also increases Runx2 activity through the PKCdelta pathway.	7	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	Runx2	Runx2	Runx2	7	8	10	11
Inhibitors of MEK and ERK signaling blocked up-regulation of the MMP-13 promoter by RUNX2 and FGF2 , and also blocked the activation of RUNX2 by FGF2 .	Inhibitors of MEK and ERK signaling blocked up-regulation of the MMP-13 promoter by RUNX2 and FGF2, and also blocked the activation of RUNX2 by FGF2.	19	26	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	FGF2	FGF2	FGF2	RUNX2	RUNX2	RUNX2	25	26	23	24
First , the percentage of cells responding to FGF-2 stimulation of Runx2 activity is increased when Cx43 is overexpressed and reduced when Cx43 level or function is decreased [ XREF_BIBR , XREF_BIBR ] .	First, the percentage of cells responding to FGF-2 stimulation of Runx2 activity is increased when Cx43 is overexpressed and reduced when Cx43 level or function is decreased [XREF_BIBR, XREF_BIBR].	8	12	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	Runx2	Runx2	Runx2	8	9	11	12
BFGF elicits the effects of differentially splicing RUNX2 .	BFGF elicits the effects of differentially splicing RUNX2.	0	8	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BFGF	BFGF	BFGF	RUNX2	RUNX2	RUNX2	0	1	7	8
In particular , FGF-2 has been shown to upregulate RUNX2 , a key hypertrophic regulator , via PKCdelta activation , which , in turn , controls type X collagen , MMP13 and ADAMTS5 at the level of transcription in articular chondrocytes [ XREF_BIBR , XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	In particular, FGF-2 has been shown to upregulate RUNX2, a key hypertrophic regulator, via PKCdelta activation, which, in turn, controls type X collagen, MMP13 and ADAMTS5 at the level of transcription in articular chondrocytes [XREF_BIBR, XREF_BIBR; XREF_BIBR; XREF_BIBR].	3	18	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	RUNX2	RUNX2	RUNX2	3	4	9	10
FGF-2 expression is thought to activate Runx2 upregulation via the mitogen activated protein kinase ( MAPK ) pathway , but Runx2 upregulation can also be induced by BMP-2 or TGF-beta 1 stimulation via Smad and the MAPK intracellular signaling pathway XREF_BIBR , XREF_BIBR .	FGF-2 expression is thought to activate Runx2 upregulation via the mitogen activated protein kinase (MAPK) pathway, but Runx2 upregulation can also be induced by BMP-2 or TGF-beta 1 stimulation via Smad and the MAPK intracellular signaling pathway XREF_BIBR, XREF_BIBR.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2 expression	fgf-2	Runx2	Runx2	runx2	0	1	6	7
These results may be associated with the increase of Runx2 mRNA and protein expression triggered by FGF-2 and are similar to previously reported studies , which identified that the addition of FGF-2 to culture media suppressed the expression of Col1a1 mRNA at all time-points < 14 days .	These results may be associated with the increase of Runx2 mRNA and protein expression triggered by FGF-2 and are similar to previously reported studies, which identified that the addition of FGF-2 to culture media suppressed the expression of Col1a1 mRNA at all time-points < 14 days.	9	17	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	Runx2	Runx2	Runx2	16	17	9	10
In addition , experiments with Runx2-knockout cells showed that , although the PKC pathway largely regulates FGF2 stimulated Runx2 activity by up-regulating Runx2 expression , it also modifies Runx2 protein post-translationally and thereby increases its transcriptional activity .	In addition, experiments with Runx2-knockout cells showed that, although the PKC pathway largely regulates FGF2 stimulated Runx2 activity by up-regulating Runx2 expression, it also modifies Runx2 protein post-translationally and thereby increases its transcriptional activity.	15	24	stimulated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	FGF2	FGF2	fgf2	Runx2	Runx2 expression	runx2	16	17	22	23
In addition , FGF-2 induces the Runx2 activity through phosphorylation of distinct consensus sites of ERK and PKC pathways XREF_BIBR - XREF_BIBR .	In addition, FGF-2 induces the Runx2 activity through phosphorylation of distinct consensus sites of ERK and PKC pathways XREF_BIBR - XREF_BIBR.	3	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	Runx2	Runx2	Runx2	3	4	6	7
A Runx2 deletion mutant lacking the entire C-terminal PST domain ( proline/serine/threonine rich domain ) ( Delta258-528 ) loses its response to FGF-2 stimulation , indicating that FGF-2 activates Runx2 by phosphorylating certain residues in the C-terminal PST domain through the MAPK pathway .	A Runx2 deletion mutant lacking the entire C-terminal PST domain (proline/serine/threonine rich domain) (Delta258-528) loses its response to FGF-2 stimulation, indicating that FGF-2 activates Runx2 by phosphorylating certain residues in the C-terminal PST domain through the MAPK pathway.	27	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	Runx2	Runx2	Runx2	27	28	29	30
Consistent with our previous work [ XREF_BIBR ; XREF_BIBR ] and the work of others [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] , FGF2 stimulated Runx2 activity ( XREF_FIG ) .	Consistent with our previous work [XREF_BIBR; XREF_BIBR] and the work of others [XREF_BIBR; XREF_BIBR; XREF_BIBR], FGF2 stimulated Runx2 activity (XREF_FIG).	4	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	23	24	25	26
FGF-2 treatment increased Runx-2 protein and phospho-CREBs in cells transfected with either vector or Fgf2 coding sequence ( XREF_FIG ) .	FGF-2 treatment increased Runx-2 protein and phospho-CREBs in cells transfected with either vector or Fgf2 coding sequence (XREF_FIG).	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	Runx-2 protein	Runx-2 protein	Runx-2 protein	0	1	3	5
These results indicate that FGF-2 signaling may enhance osteoblast differentiation by suppressing TWIST1 and up regulating Runx2 in cultured GCT stromal cells .	These results indicate that FGF-2 signaling may enhance osteoblast differentiation by suppressing TWIST1 and up regulating Runx2 in cultured GCT stromal cells.	4	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	Runx2	Runx2	Runx2	4	5	16	17
Importantly , Western blotting studies demonstrated that specific knockdown of FGF-2 expression in COBs from Fgf2 +/+ mice blocked the increment in both Runx-2 and CREBs induced by PTH .	Importantly, Western blotting studies demonstrated that specific knockdown of FGF-2 expression in COBs from Fgf2 +/+ mice blocked the increment in both Runx-2 and CREBs induced by PTH.	10	25	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2 expression	fgf-2	Runx-2	Runx-2	runx-2	10	11	23	24
Knockdown of IP6K1 inhibited the FGF2 induced Runx2 activity both basally and in response to Cx43 overexpression more potently than knockdown of IP6K2 ( XREF_FIG ) .	Knockdown of IP6K1 inhibited the FGF2 induced Runx2 activity both basally and in response to Cx43 overexpression more potently than knockdown of IP6K2 (XREF_FIG).	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	5	6	7	8
The results of real-time polymerase chain reaction ( PCR ) and Western blotting suggested that FGF2 increased the pool of committed osteoblasts by up-regulating the Cbfa1 and Runx2 gene .	The results of real-time polymerase chain reaction (PCR) and Western blotting suggested that FGF2 increased the pool of committed osteoblasts by up-regulating the Cbfa1 and Runx2 gene.	15	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Cbfa1	Cbfa1	Cbfa1	15	16	25	26
FGF-2 signaling also results in the activation of AP-1 and RUNX2 , the latter of which may account for ADAMTS-5 induction [ XREF_BIBR ; XREF_BIBR ] ( XREF_FIG ) .	FGF-2 signaling also results in the activation of AP-1 and RUNX2, the latter of which may account for ADAMTS-5 induction [XREF_BIBR; XREF_BIBR] (XREF_FIG).	0	11	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	RUNX2	RUNX2	RUNX2	0	1	10	11
Therefore , we examined how expression of proteoglycan related genes in osteoprogenitors responds to FGF2 signaling in the presence or absence Runx2 .	Therefore, we examined how expression of proteoglycan related genes in osteoprogenitors responds to FGF2 signaling in the presence or absence Runx2.	14	22	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	14	15	21	22
Cell pretreatment with specific RSK inhibitor ( FMK ) prevented FGF2 mediated FGFR2 internalization suggesting that intracellular trafficking of this receptor is regulated by RSK .	Cell pretreatment with specific RSK inhibitor (FMK) prevented FGF2 mediated FGFR2 internalization suggesting that intracellular trafficking of this receptor is regulated by RSK.	9	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	10	11	12	13
In addition , RSK activity was found to exert a significant impact on FGF2 triggered FGFR2 internalization .	In addition, RSK activity was found to exert a significant impact on FGF2 triggered FGFR2 internalization.	11	16	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	13	14	15	16
It has been observed that stimulation with FGF2 promoted FGFR2 internalization .	It has been observed that stimulation with FGF2 promoted FGFR2 internalization.	5	10	promoted	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	7	8	9	10
FGF2 , an important component required to maintain pluripotency of hPSCs , activates FGFR2 and also stimulates MAPK signaling .	FGF2, an important component required to maintain pluripotency of hPSCs, activates FGFR2 and also stimulates MAPK signaling.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	0	1	13	14
To verify whether loss of ectodermal Fgfr2 was sufficient to block acute Shh downregulation ex vivo , Msx2-cre ; Fgfr2 cKO explants were treated with FGF2 ( XREF_FIG ) .	To verify whether loss of ectodermal Fgfr2 was sufficient to block acute Shh downregulation ex vivo, Msx2-cre; Fgfr2 cKO explants were treated with FGF2 (XREF_FIG).	19	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	Fgfr2	Fgfr2	Fgfr2	25	26	19	20
In the present study , we described formononetin inhibited FGF2 induced FGFR2 activation at relatively low concentrations in vitro assays .	In the present study, we described formononetin inhibited FGF2 induced FGFR2 activation at relatively low concentrations in vitro assays.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	9	10	11	12
Increased expression of SPP1 , ALP , and Runx2 mediated by the activation of ERK1/2 via FGF-2 and FGFR-2 signaling has been observed in GCTB stromal cells treated with FGF2 79 .	Increased expression of SPP1, ALP, and Runx2 mediated by the activation of ERK1/2 via FGF-2 and FGFR-2 signaling has been observed in GCTB stromal cells treated with FGF2 79.	16	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR-2	FGFR-2	FGFR-2	29	30	18	19
Immunoblot experiments showed that although the level of total FGFR2 protein was unaffected , the level of p-FGFR was significantly increased in HHSteCs treated with supplement solution or FGF2 ( 4 ng/ml ) compared with the untreated control ; the ratio of p-FGFR and FGFR2 was markedly increased by 5.2- and 4.4-fold in HHSteCs treated with supplement solution and FGF2 , respectively .	Immunoblot experiments showed that although the level of total FGFR2 protein was unaffected, the level of p-FGFR was significantly increased in HHSteCs treated with supplement solution or FGF2 (4 ng/ml) compared with the untreated control; the ratio of p-FGFR and FGFR2 was markedly increased by 5.2- and 4.4-fold in HHSteCs treated with supplement solution and FGF2, respectively.	40	60	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	59	60	44	45
When WT FGFR2 was activated by FGF2 , we found 79 DEGs , of which 48 were up-regulated and 31 were down-regulated ( XREF_SUPPLEMENTARY ) .	When WT FGFR2 was activated by FGF2, we found 79 DEGs, of which 48 were up-regulated and 31 were down-regulated (XREF_SUPPLEMENTARY).	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	6	7	2	3
Negr1 silencing induced a significant reduction in the total FGFR2 protein level independent of FGFb mediated FGFR2 internalization ( XREF_FIG E , F and XREF_SUPPLEMENTARY E ) .	Negr1 silencing induced a significant reduction in the total FGFR2 protein level independent of FGFb mediated FGFR2 internalization (XREF_FIG E, F and XREF_SUPPLEMENTARY E).	12	17	mediated	Positive_early_activation	Positive_activation	Negative_activation	FGFb	FGFb	FGFb	FGFR2	FGFR2	FGFR2	14	15	16	17
Here , an involvement of RSK in FGF2 triggered FGFR2 internalization was studied .	Here, an involvement of RSK in FGF2 triggered FGFR2 internalization was studied.	5	10	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	7	8	9	10
These data suggest that FGF2 and FGF10 preferentially activate FGFR1 and FGFR2 , respectively .	These data suggest that FGF2 and FGF10 preferentially activate FGFR1 and FGFR2, respectively.	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	4	5	11	12
Thus , our analysis revealed that the majority of the modifications in gene expression in WT and S252W fibroblasts following FGFR2 activation by FGF2 were different .	Thus, our analysis revealed that the majority of the modifications in gene expression in WT and S252W fibroblasts following FGFR2 activation by FGF2 were different.	20	24	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	23	24	20	21
This is because although FGF2 and FGF9 both activate FGFR2 in OLs , FGF9 is more selective for FGFR2 , based on data described by XREF_BIBR .	This is because although FGF2 and FGF9 both activate FGFR2 in OLs, FGF9 is more selective for FGFR2, based on data described by XREF_BIBR.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	4	5	9	10
These findings suggest that C1GALT1 modifies O-glycans on FGFR2 and regulates bFGF induced activation of FGFR2 in colon cancer cells .	These findings suggest that C1GALT1 modifies O-glycans on FGFR2 and regulates bFGF induced activation of FGFR2 in colon cancer cells.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	bFGF	bFGF	bFGF	FGFR2	FGFR2	FGFR2	11	12	15	16
A number of other stimuli that act through the ERK and MAPK pathway , including FGFR2 activation by FGF2 and mechanical loading of osteoblasts , also stimulate RUNX2 phosphorylation and transcriptional activity [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	A number of other stimuli that act through the ERK and MAPK pathway, including FGFR2 activation by FGF2 and mechanical loading of osteoblasts, also stimulate RUNX2 phosphorylation and transcriptional activity [XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR].	15	19	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	18	19	15	16
Since FGF-1 and FGF-3 can both activate one FGF receptor isoform ( FGFR2 IIIb ) that is not activated by FGF-2 , these results suggest that activation of FGFR2 IIIb is sufficient to induce fiber cell differentiation throughout the lens epithelium in vivo .	Since FGF-1 and FGF-3 can both activate one FGF receptor isoform (FGFR2 IIIb) that is not activated by FGF-2, these results suggest that activation of FGFR2 IIIb is sufficient to induce fiber cell differentiation throughout the lens epithelium in vivo.	12	21	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	FGFR2	FGFR2	FGFR2	20	21	12	13
We have found that stimulation with FGF2 promoted FGFR2 internalization ; however pretreatment with specific RSK inhibitor ( FMK ) effectively prevented this effect .	We have found that stimulation with FGF2 promoted FGFR2 internalization; however pretreatment with specific RSK inhibitor (FMK) effectively prevented this effect.	4	9	promoted	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	6	7	8	9
Additionally , expression of DEGs in FGFR2 +/C342Y fibroblasts treated with FGF2 did not correlate with the expression levels obtained in FGFR2 +/S252W fibroblasts under the same treatment .	Additionally, expression of DEGs in FGFR2 +/C342Y fibroblasts treated with FGF2 did not correlate with the expression levels obtained in FGFR2 +/S252W fibroblasts under the same treatment.	6	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	11	12	6	7
FGFR2 is targeted by bFGF and positively regulates osteogenic differentiation XREF_BIBR and as expected , FGFR2 expression declines with donor age .	FGFR2 is targeted by bFGF and positively regulates osteogenic differentiation XREF_BIBR and as expected, FGFR2 expression declines with donor age.	0	7	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	bFGF	bFGF	bFGF	FGFR2	FGFR2	FGFR2	4	5	0	1
Our studies of Fgfr1 expression in embryos and at P1 will be described elsewhere , but support the role of FGFR1 in telencephalic development .	Our studies of Fgfr1 expression in embryos and at P1 will be described elsewhere, but support the role of FGFR1 in telencephalic development.	3	23	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fgfr1	Fgfr1 expression	fgfr1	FGFR1	FGFR1	fgfr1	3	4	20	21
Expression of FGFR1 in a UC cell line that expresses relatively low levels of FGFRs induced EMT , indicating a context dependent effect of FGFR1 in urothelial tumor cells .	Expression of FGFR1 in a UC cell line that expresses relatively low levels of FGFRs induced EMT, indicating a context dependent effect of FGFR1 in urothelial tumor cells.	0	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR1	Expression of FGFR1	fgfr1	FGFR1	FGFR1	fgfr1	2	3	24	25
Importantly , FGFR1 expression is retained on residual dopaminergic neurons in the SNc from PD brain supporting FGFR1 as a potential target for therapeutic intervention .	Importantly, FGFR1 expression is retained on residual dopaminergic neurons in the SNc from PD brain supporting FGFR1 as a potential target for therapeutic intervention.	2	18	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR1	FGFR1 expression	fgfr1	FGFR1	FGFR1	fgfr1	2	3	17	18
It has been already shown that AHR activation induced by coal tar increases FLG expression contributing to the therapeutic effect of coal tar on the development of AD ; 21 however , whether OVOL1 is involved in the upregulation of FLG induced by AHR activation has not been examined .	It has been already shown that AHR activation induced by coal tar increases FLG expression contributing to the therapeutic effect of coal tar on the development of AD; 21 however, whether OVOL1 is involved in the upregulation of FLG induced by AHR activation has not been examined.	11	41	contributing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLG	tar increases FLG expression	flg	FLG	FLG	flg	13	14	40	41
Next , FGFR-1 levels were modulated in PE cells and their progeny using either the FGFR-1 or the antisense FGFR-1 viruses .	Next, FGFR-1 levels were modulated in PE cells and their progeny using either the FGFR-1 or the antisense FGFR-1 viruses.	2	20	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR-1	FGFR-1 levels	fgfr-1	FGFR-1	FGFR-1	fgfr-1	2	3	15	16
There were overexpression of aFGF and FGFR1 in the ovarian epithelial cancer in western blot , too .	There were overexpression of aFGF and FGFR1 in the ovarian epithelial cancer in western blot, too.	1	7	were overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	FGFR1	overexpression of aFGF and FGFR1	fgfr1	FGFR1	FGFR1	fgfr1	6	7	6	7
Accordingly , down-regulation of FLG expression in organotypic human keratinocyte cultures yields lower-than-normal levels of t-UCA ; while simultaneously enhancing UV-B sensitivity ; while conversely , caspase 14 over-expression accelerates the conversion of FLG into t-UCA , providing further photoprotection .	Accordingly, down-regulation of FLG expression in organotypic human keratinocyte cultures yields lower-than-normal levels of t-UCA; while simultaneously enhancing UV-B sensitivity; while conversely, caspase 14 over-expression accelerates the conversion of FLG into t-UCA, providing further photoprotection.	4	34	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLG	FLG expression	flg	FLG	FLG	flg	4	5	33	34
Combined expression of FGFR1 and FGFR2 enhanced the prognostic value of FGFR1 and FGFR2 in MPNST .	Combined expression of FGFR1 and FGFR2 enhanced the prognostic value of FGFR1 and FGFR2 in MPNST.	1	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR1	expression of FGFR1	fgfr1	FGFR1	FGFR1	fgfr1	3	4	11	12
FGFR1 ( SP/NLS ) causes FGFR1 to be constitutively nuclear .	FGFR1 (SP/NLS) causes FGFR1 to be constitutively nuclear.	0	6	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SP/NLS	SP/NLS	SP/NLS	FGFR1	FGFR1	FGFR1	2	3	5	6
Importantly , we showed that GATA3 directly increases miR-573 expression , and thus down-regulates FGFR1 expression , EMT and invasion of PCa cells in a miR-573-dependent manner , supporting the involvement of GATA3 , miR-573 and FGFR1 in controlling the EMT process during PCa metastasis .	Importantly, we showed that GATA3 directly increases miR-573 expression, and thus down-regulates FGFR1 expression, EMT and invasion of PCa cells in a miR-573-dependent manner, supporting the involvement of GATA3, miR-573 and FGFR1 in controlling the EMT process during PCa metastasis.	14	37	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR1	FGFR1 expression	fgfr1	FGFR1	FGFR1	fgfr1	14	15	36	37
Upon exposure to growth factors , the juxtamembrane tyrosine residue 463 of FGFR1 is phosphorylated , followed by the transient phosphorylation of Crk to mediate the co-complexing of FGFR1 and Crk [ XREF_BIBR ] .	Upon exposure to growth factors, the juxtamembrane tyrosine residue 463 of FGFR1 is phosphorylated, followed by the transient phosphorylation of Crk to mediate the co-complexing of FGFR1 and Crk [XREF_BIBR].	8	32	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR1	tyrosine residue 463 of FGFR1 is phosphorylated	fgfr1	FGFR1	FGFR1	fgfr1	12	13	28	29
Moreover , the upregulation of ERK1 and ERK2 phosphorylation in injured secondary cultures and in cells treated with bFGF was markedly reduced by BB94 , whereas TIMP-2 lacked a clear effect .	Moreover, the upregulation of ERK1 and ERK2 phosphorylation in injured secondary cultures and in cells treated with bFGF was markedly reduced by BB94, whereas TIMP-2 lacked a clear effect.	5	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	bFGF	bFGF	bFGF	ERK2	ERK2	ERK2	18	19	7	8
FGF2 activates ERK1 and ERK2 signaling in osteoblasts ; however , 25 microM MAPK-ERK kinase ( MEK ) inhibitor PD98059 ( inhibits by > 85 % the phosphorylation of ERK1 and ERK2 ) has no effect on MMP1 promoter activation by FGF2 .	FGF2 activates ERK1 and ERK2 signaling in osteoblasts; however, 25 microM MAPK-ERK kinase (MEK) inhibitor PD98059 (inhibits by> 85% the phosphorylation of ERK1 and ERK2) has no effect on MMP1 promoter activation by FGF2.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	ERK2	ERK2	ERK2	0	1	4	5
Furthermore , ERK2 was also activated by bFGF and PDGF-BB in the mouse osteoblastic cell line , MC3T3-E1 .	Furthermore, ERK2 was also activated by bFGF and PDGF-BB in the mouse osteoblastic cell line, MC3T3-E1.	2	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	bFGF	bFGF	bFGF	ERK2	ERK2	ERK2	7	8	2	3
Additionally , oligodendrocytes that have matured to the O1+ stage and beyond can use FGF-2 stimulated ERK2 activation for survival .	Additionally, oligodendrocytes that have matured to the O1+ stage and beyond can use FGF-2 stimulated ERK2 activation for survival.	13	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	ERK2	ERK2	ERK2	14	15	16	17
FGF2 activates the MAP kinases ERK1 and ERK2 , and also PI3K and AKT and c-Jun , and stimulates signaling cascades by activation of activin A. XREF_BIBR , XREF_BIBR Induction of alpha2beta1 , alpha3beta1 , alpha6beta1 , and alpha6beta4 integrin transcription requires the FGF2-FGFR signal pathway and is reinforced by the ALK4-activin A signaling pathway .	FGF2 activates the MAP kinases ERK1 and ERK2, and also PI3K and AKT and c-Jun, and stimulates signaling cascades by activation of activin A. XREF_BIBR, XREF_BIBR Induction of alpha2beta1, alpha3beta1, alpha6beta1, and alpha6beta4 integrin transcription requires the FGF2-FGFR signal pathway and is reinforced by the ALK4-activin A signaling pathway.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	ERK2	ERK2	ERK2	0	1	7	8
It was found that MAPK1 ,3 activation by FGF2 inhibits the release of Smac from mitochondria .	It was found that MAPK1,3 activation by FGF2 inhibits the release of Smac from mitochondria.	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	MAPK1	MAPK1	MAPK1	8	9	4	5
However , isoproterenol and 8-bromo-cAMP partially inhibited the bFGF induction of ERK-2 activity , but only isoproterenol inhibited the proliferation of both cell types .	However, isoproterenol and 8-bromo-cAMP partially inhibited the bFGF induction of ERK-2 activity, but only isoproterenol inhibited the proliferation of both cell types.	8	12	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	bFGF	bFGF	bFGF	ERK-2	ERK-2	ERK-2	8	9	11	12
bFGF , isoproterenol , and 8-bromo-cAMP alone increased ERK-2 activity in both cell types .	bFGF, isoproterenol, and 8-bromo-cAMP alone increased ERK-2 activity in both cell types.	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	bFGF	bFGF	bFGF	ERK-2	ERK-2	ERK-2	0	1	8	9
TNF-alpha and IL-1alpha activate Nf-kappabeta , whereas bFGF and PDGF activate the ERK-1 and ERK-2 MAPK pathway resulting in activation of AP-1 , another transcription factor of MMP-9 .	TNF-alpha and IL-1alpha activate Nf-kappabeta, whereas bFGF and PDGF activate the ERK-1 and ERK-2 MAPK pathway resulting in activation of AP-1, another transcription factor of MMP-9.	7	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	bFGF	bFGF	bFGF	ERK-2	ERK-2	ERK-2	7	8	14	15
The results demonstrated that both ERK1 and ERK2 were activated by FGF-2 and PDGF-BB .	The results demonstrated that both ERK1 and ERK2 were activated by FGF-2 and PDGF-BB.	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	ERK2	ERK2	ERK2	11	12	7	8
This study indicated that bFGF stimulated gastric epithelial RGM-1 cells proliferation via up-regulating FGFR1 and FGFR2 , activating ERK1 and ERK2 signal transduction pathway and COX-2 pathway .	This study indicated that bFGF stimulated gastric epithelial RGM-1 cells proliferation via up-regulating FGFR1 and FGFR2, activating ERK1 and ERK2 signal transduction pathway and COX-2 pathway.	4	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	bFGF	bFGF	bFGF	ERK2	ERK2	ERK2	4	5	20	21
Simultaneous activation and rapid nuclear translocation of MAP kinases ( ERK-1 and ERK-2 ) were observed in cells treated with NGF or bFGF .	Simultaneous activation and rapid nuclear translocation of MAP kinases (ERK-1 and ERK-2) were observed in cells treated with NGF or bFGF.	1	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	bFGF	bFGF	bFGF	ERK-2	ERK-2	ERK-2	22	23	12	13
ERK2 activation by PDGF was more sensitive to inhibition of tyrosine kinases , whereas ERK2 activation by FGF-2 was relatively more sensitive to inhibitors of protein kinase C.	ERK2 activation by PDGF was more sensitive to inhibition of tyrosine kinases, whereas ERK2 activation by FGF-2 was relatively more sensitive to inhibitors of protein kinase C.	14	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	ERK2	ERK2	ERK2	17	18	14	15
However , activation of ERK2 by FGF-2 was not affected by PGE2 whereas that of JNK1 by U46619 was inhibited , suggesting that inhibition of COX-2 expression by cAMP may be downstream of ERK2 .	However, activation of ERK2 by FGF-2 was not affected by PGE2 whereas that of JNK1 by U46619 was inhibited, suggesting that inhibition of COX-2 expression by cAMP may be downstream of ERK2.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	ERK2	ERK2	ERK2	6	7	4	5
XREF_BIBR , who found the wild-type FGFR3 activating STAT1 to the levels 4.8-fold or 20-fold lower than K650M .	XREF_BIBR, who found the wild-type FGFR3 activating STAT1 to the levels 4.8-fold or 20-fold lower than K650M.	3	9	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	6	7	8	9
Both PLCgamma and STAT1 were activated by FGFR3 signaling , but a dominant negative form of PLCgamma ( DN-PLCgamma ) remarkably reduced STAT1 phosphorylation .	Both PLCgamma and STAT1 were activated by FGFR3 signaling, but a dominant negative form of PLCgamma (DN-PLCgamma) remarkably reduced STAT1 phosphorylation.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	7	8	3	4
For instance , other interacting proteins that facilitate FGFR3 mediated STAT1 activation could exist in cells .	For instance, other interacting proteins that facilitate FGFR3 mediated STAT1 activation could exist in cells.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	8	9	10	11
STAT1 activation by FGFR3 : A major mechanism or just an unusual signaling feature restricted to K650 mutants ?	STAT1 activation by FGFR3 : A major mechanism or just an unusual signaling feature restricted to K650 mutants?	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	3	4	0	1
For example , whilst the STAT1 signaling pathway mediates the effects of FGFR3 in chondrocytes , STAT1 is not activated by FGFR3 signaling in NIH-3T3 , or multiple myeloma cell lines .	For example, whilst the STAT1 signaling pathway mediates the effects of FGFR3 in chondrocytes, STAT1 is not activated by FGFR3 signaling in NIH-3T3, or multiple myeloma cell lines.	16	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	21	22	16	17
Many studies report that other FGFR3 activating mutants associated with skeletal dysplasias or cancer do not cause STAT1 activation or only activate STAT1 several-fold less than K650M or K650E-FGFR3 .	Many studies report that other FGFR3 activating mutants associated with skeletal dysplasias or cancer do not cause STAT1 activation or only activate STAT1 several-fold less than K650M or K650E-FGFR3.	4	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	5	6	17	18
In the growth plate , FGFR3 activates STAT1 and the ERK1/2 and p38 branches of the MAPK pathway ( XREF_FIG ) .	In the growth plate, FGFR3 activates STAT1 and the ERK1/2 and p38 branches of the MAPK pathway (XREF_FIG).	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	5	6	7	8
Taken together , we found that wild-type FGFR3 as well as G380R , R248C and Y373C mutants may activate STAT1 depending on the cellular environment , although this activation is significantly lower when compared to K650M or K650E-FGFR3 ( XREF_FIG ) .	Taken together, we found that wild-type FGFR3 as well as G380R, R248C and Y373C mutants may activate STAT1 depending on the cellular environment, although this activation is significantly lower when compared to K650M or K650E-FGFR3 (XREF_FIG).	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	7	8	19	20
Here we reveal that phospholipase C gamma ( PLCgamma ) mediates FGFR3 induced STAT1 activation .	Here we reveal that phospholipase C gamma (PLCgamma) mediates FGFR3 induced STAT1 activation.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	11	12	13	14
To date , the activation of STAT1 by FGFR3 is believed by many to be the major mechanism of pathological FGFR3 medited inhibition of cartilage growth , regardless of the limited evidence experimentally confirming this hypothesis .	To date, the activation of STAT1 by FGFR3 is believed by many to be the major mechanism of pathological FGFR3 medited inhibition of cartilage growth, regardless of the limited evidence experimentally confirming this hypothesis.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	8	9	6	7
Since FGFR3 activation leads to chondrocyte growth arrest accompanied by induction of cell cycle inhibitors ( CKI ) [ XREF_BIBR , XREF_BIBR ] , and activation of STAT1 leads to CKI induction [ XREF_BIBR ] , it has been hypothesized that FGFR3 activates STAT1 to induce CKIs that in turn inhibit chondrocyte proliferation [ XREF_BIBR ] .	Since FGFR3 activation leads to chondrocyte growth arrest accompanied by induction of cell cycle inhibitors (CKI) [XREF_BIBR, XREF_BIBR], and activation of STAT1 leads to CKI induction [XREF_BIBR], it has been hypothesized that FGFR3 activates STAT1 to induce CKIs that in turn inhibit chondrocyte proliferation [XREF_BIBR].	41	44	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	41	42	43	44
At present , the FGFR3 mediated activation of STAT1 is believed to be a prominent mechanism of pathological FGFR3 signaling in cartilage [ for reviews see references 2-4 ] .	At present, the FGFR3 mediated activation of STAT1 is believed to be a prominent mechanism of pathological FGFR3 signaling in cartilage [for reviews see references 2-4].	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	4	5	8	9
PLCgamma mediated FGFR3 induced STAT1 activation and this signaling cascade involved in the induction of apoptosis in the chondrogenic cell line ATDC5 [ XREF_BIBR ] .	PLCgamma mediated FGFR3 induced STAT1 activation and this signaling cascade involved in the induction of apoptosis in the chondrogenic cell line ATDC5 [XREF_BIBR].	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	STAT1	STAT1	STAT1	2	3	4	5
Normally , mesenchymal ligands FGF7 and FGF10 activate the FGFR2 IIIb isoform , whereas epithelial FGFs -2 , -4 , -6 , -8 , and -9 activate the FGFR2 IIIc isoform [ XREF_BIBR - XREF_BIBR ] .	Normally, mesenchymal ligands FGF7 and FGF10 activate the FGFR2 IIIb isoform, whereas epithelial FGFs -2, -4, -6, -8, and -9 activate the FGFR2 IIIc isoform [XREF_BIBR - XREF_BIBR].	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	FGFR2	FGFR2	FGFR2	6	7	9	10
FGF7 and FGF10 , which only bind to FGFR2 , have also been shown to drive migration and/or invasion in a variety of tissue types and our lab has also shown that FGF10 stimulation of FGFR2 in the Ishikawa endometrial cancer cell line drives migration and invasion ( unpublished data ) .	FGF7 and FGF10, which only bind to FGFR2, have also been shown to drive migration and/or invasion in a variety of tissue types and our lab has also shown that FGF10 stimulation of FGFR2 in the Ishikawa endometrial cancer cell line drives migration and invasion (unpublished data).	32	36	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	FGFR2	FGFR2	FGFR2	32	33	35	36
This expression pattern matches the one described for the mouse lung XREF_BIBR and suggests that , also in the chick model , FGFR2 might be activated by FGF10 during the embryonic phase of development XREF_BIBR .	This expression pattern matches the one described for the mouse lung XREF_BIBR and suggests that, also in the chick model, FGFR2 might be activated by FGF10 during the embryonic phase of development XREF_BIBR.	22	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	FGFR2	FGFR2	FGFR2	27	28	22	23
FGF-10 is known to primarily activate FGFR-2 with little stimulatory action on FGFR-1 XREF_BIBR .	FGF-10 is known to primarily activate FGFR-2 with little stimulatory action on FGFR-1 XREF_BIBR.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-10	FGF-10	FGF-10	FGFR-2	FGFR-2	FGFR-2	0	1	6	7
Immunofluorescence and immunoelectron microscopy analysis showed that KGFR internalization triggered by either KGF or FGF10 occurs through clathrin coated pits .	Immunofluorescence and immunoelectron microscopy analysis showed that KGFR internalization triggered by either KGF or FGF10 occurs through clathrin coated pits.	7	15	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	KGFR	KGFR	KGFR	14	15	7	8
To selectively stain the plasma membrane receptors and exclusively follow them during endocytosis , HaCaT KGFR cells were incubated at 4degreesC with the anti-Bek polyclonal antibodies , directed against the extracellular portion of KGFR , and then treated with KGF or FGF10 for 5 , 10 and 30 minutes at 37degreesC , to induce receptor internalization .	To selectively stain the plasma membrane receptors and exclusively follow them during endocytosis, HaCaT KGFR cells were incubated at 4degreesC with the anti-Bek polyclonal antibodies, directed against the extracellular portion of KGFR, and then treated with KGF or FGF10 for 5, 10 and 30 minutes at 37degreesC, to induce receptor internalization.	31	42	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	KGFR	KGFR	KGFR	41	42	33	34
FGF10 produced by pancreatic stromal cells stimulates FGFR2 signaling in human pancreatic cancer cells resulting in increased migration and invasion .	FGF10 produced by pancreatic stromal cells stimulates FGFR2 signaling in human pancreatic cancer cells resulting in increased migration and invasion.	0	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	FGFR2	FGFR2	FGFR2	0	1	7	8
FGF7 and FGF10 activate only the b isoform of FGFR2 ( FGFR2b ) .	FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b).	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	FGFR2	FGFR2	FGFR2	2	3	9	10
Further analysis suggested that Fgf10 from the mesenchyme activates Fgfr2 in the lid ectoderm .	Further analysis suggested that Fgf10 from the mesenchyme activates Fgfr2 in the lid ectoderm.	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fgf10	Fgf10	Fgf10	Fgfr2	Fgfr2	Fgfr2	4	5	9	10
For example , epithelially expressed FGFR2b ( that is , FGFR2 IIIb isoform ) can be activated by FGF7 and FGF10 , ligands produced in mesenchymal tissue [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	For example, epithelially expressed FGFR2b (that is, FGFR2 IIIb isoform) can be activated by FGF7 and FGF10, ligands produced in mesenchymal tissue [XREF_BIBR, XREF_BIBR, XREF_BIBR].	10	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	FGFR2	FGFR2	FGFR2	20	21	10	11
As an example of ligand mediated trafficking , it has been shown that the keratinocyte growth factor receptor and fibroblast growth factor receptor 2b ( KGFR and FGFR2b ) can be activated by two different ligands , the keratinocyte growth factor ( KGF )/fibroblast growth factor ( FGF ) 7 and the FGF10 and KGF2 .	As an example of ligand mediated trafficking, it has been shown that the keratinocyte growth factor receptor and fibroblast growth factor receptor 2b (KGFR and FGFR2b) can be activated by two different ligands, the keratinocyte growth factor (KGF)/fibroblast growth factor (FGF) 7 and the FGF10 and KGF2.	14	54	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	keratinocyte growth factor receptor	keratinocyte growth factor receptor	keratinocyte growth factor receptor	52	53	14	18
Unfortunately , the amount of KGFR in non transfected pre-confluent cells is not sufficient enough to be followed by conventional immunofluorescence methods , as previously reported by our group XREF_BIBR ; therefore , HaCaT keratinocytes were transiently transfected with the human KGFR ( HaCaT KGFR ) and treated with KGF or FGF10 , as above .	Unfortunately, the amount of KGFR in non transfected pre-confluent cells is not sufficient enough to be followed by conventional immunofluorescence methods, as previously reported by our group XREF_BIBR; therefore, HaCaT keratinocytes were transiently transfected with the human KGFR (HaCaT KGFR) and treated with KGF or FGF10, as above.	37	52	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	KGFR	KGFR	KGFR	51	52	41	42
Because we have previously demonstrated that , once internalized by the ligands , KGFR follows two alternative endocytic routes , i.e. KGF targets the receptor to the degradative pathway , whereas FGF10 induces KGFR sorting to the recycling compartment XREF_BIBR , future work will be focused to characterize the recycling pathways responsible for KGFR polarization during cell motility .	Because we have previously demonstrated that, once internalized by the ligands, KGFR follows two alternative endocytic routes, i.e. KGF targets the receptor to the degradative pathway, whereas FGF10 induces KGFR sorting to the recycling compartment XREF_BIBR, future work will be focused to characterize the recycling pathways responsible for KGFR polarization during cell motility.	31	34	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	KGFR	KGFR	KGFR	31	32	33	34
Fgf10 is synthesized in UGM and stimulates mitogenesis by activating fibroblast growth factor receptor type 2 ( FGFR2 ) in UGE .	Fgf10 is synthesized in UGM and stimulates mitogenesis by activating fibroblast growth factor receptor type 2 (FGFR2) in UGE.	0	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fgf10	Fgf10	Fgf10	FGFR2	FGFR2	FGFR2	0	1	17	18
To this aim , we first characterized the intracellular dots in which cortactin was clusterized when HaCaT KGFR cells were treated with KGF and FGF10 .	To this aim, we first characterized the intracellular dots in which cortactin was clusterized when HaCaT KGFR cells were treated with KGF and FGF10.	17	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF10	FGF10	FGF10	KGFR	KGFR	KGFR	24	25	17	18
Earlier studies had shown deletion of FGFR-3 in mice resulted in spontaneous OA suggesting FGF-2 activation of FGFR-3 might be chondroprotective 38 while FGFR-1 was proposed to mediate catabolic effects of FGF-2 based on in vitro experiments .	Earlier studies had shown deletion of FGFR-3 in mice resulted in spontaneous OA suggesting FGF-2 activation of FGFR-3 might be chondroprotective 38 while FGFR-1 was proposed to mediate catabolic effects of FGF-2 based on in vitro experiments.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	FGFR-3	FGFR-3	FGFR-3	14	15	17	18
Furthermore , no other senescence markers were induced by the expression of the FGFR3 mutants with exception of CAVEOLIN 1 , which was upregulated to the levels similar to those induced by FGF2 mediated activation of endogenous FGFR3 ( XREF_FIG , XREF_FIG ) .	Furthermore, no other senescence markers were induced by the expression of the FGFR3 mutants with exception of CAVEOLIN 1, which was upregulated to the levels similar to those induced by FGF2 mediated activation of endogenous FGFR3 (XREF_FIG, XREF_FIG).	32	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	32	33	37	38
In addition , DRG neurons express FGFR-3 , which is activated by FGF-2 , promoting neuronal survival and neuritogenesis by PI3K and MAPK signaling pathways respectively , in vitro and in vivo [ XREF_BIBR , XREF_BIBR ] .	In addition, DRG neurons express FGFR-3, which is activated by FGF-2, promoting neuronal survival and neuritogenesis by PI3K and MAPK signaling pathways respectively, in vitro and in vivo [XREF_BIBR, XREF_BIBR].	6	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	FGFR-3	FGFR-3	FGFR-3	12	13	6	7
RCS chondrocytes respond to FGF2 mediated activation of endogenous FGFR3 via potent growth arrest in the G1-phase of the cell cycle ( XREF_FIG ) [ XREF_BIBR ] , that is dependent on signaling through the ERK MAP kinase pathway [ XREF_BIBR , XREF_BIBR ] .	RCS chondrocytes respond to FGF2 mediated activation of endogenous FGFR3 via potent growth arrest in the G1-phase of the cell cycle (XREF_FIG) [XREF_BIBR], that is dependent on signaling through the ERK MAP kinase pathway [XREF_BIBR, XREF_BIBR].	4	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	4	5	9	10
For example , FGF2 activation of FGFR1 or FGFR3 has been shown to promote resistance to EGFR inhibitors in lung cancer , B-RAF inhibitors in melanoma , BCR-ABL inhibitors in CML , and KIT inhibitors in gastrointestinal stromal tumors .	For example, FGF2 activation of FGFR1 or FGFR3 has been shown to promote resistance to EGFR inhibitors in lung cancer, B-RAF inhibitors in melanoma, BCR-ABL inhibitors in CML, and KIT inhibitors in gastrointestinal stromal tumors.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	3	4	8	9
The hypothesis that BoNT/A acts as an agonist for FGFR3 was further supported by demonstrating that treatment with rH C / A resulted in phosphorylation of FGFR3 , achieving similar levels of activation as cells treated with identical concentrations of FGF2 ( XREF_FIG ) .	The hypothesis that BoNT/A acts as an agonist for FGFR3 was further supported by demonstrating that treatment with rH C / A resulted in phosphorylation of FGFR3, achieving similar levels of activation as cells treated with identical concentrations of FGF2 (XREF_FIG).	24	42	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	40	41	26	27
In vivo , FGFR3 , which can be activated by both FGF1 and FGF2 , is expressed specifically by astrocytes and their precursors in postnatal spinal cord .	In vivo, FGFR3, which can be activated by both FGF1 and FGF2, is expressed specifically by astrocytes and their precursors in postnatal spinal cord.	1	14	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	13	14	3	4
FGF-2 highly upregulates FGFR3 in murine chondrocytes ( current study ) , whereas FGF-2 significantly downregulates FGFR3 in human articular chondrocytes ( 26 ) .	FGF-2 highly upregulates FGFR3 in murine chondrocytes (current study), whereas FGF-2 significantly downregulates FGFR3 in human articular chondrocytes (26).	13	20	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF-2	FGF-2	FGF-2	FGFR3	FGFR3	FGFR3	13	14	16	17
FGFR3 signaling induced by FGF2 and FGF18 has been coupled with chondrogenic and anabolic responses in chondrocytes , however , it has been shown to have paradoxical roles in mitogenicity in the growth plate , both promoting and inhibiting chondrocyte proliferation depending on the stage of cartilage development .	FGFR3 signaling induced by FGF2 and FGF18 has been coupled with chondrogenic and anabolic responses in chondrocytes, however, it has been shown to have paradoxical roles in mitogenicity in the growth plate, both promoting and inhibiting chondrocyte proliferation depending on the stage of cartilage development.	0	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	4	5	0	1
We conclude that FGF2 activation of FGFR3 inactivates GC-B by a reversible dephosphorylation mechanism and suggest that dephosphorylation is a universal inactivation mechanism commonly employed by natriuretic peptide stimulated guanylyl cyclase receptors .	We conclude that FGF2 activation of FGFR3 inactivates GC-B by a reversible dephosphorylation mechanism and suggest that dephosphorylation is a universal inactivation mechanism commonly employed by natriuretic peptide stimulated guanylyl cyclase receptors.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	3	4	6	7
Here , we demonstrate that FGF2 stimulation of FGFR3 causes a rapid , potent , and reversible inhibition of endogenous GC-B enzymatic activity in rat chondrosarcoma cells .	Here, we demonstrate that FGF2 stimulation of FGFR3 causes a rapid, potent, and reversible inhibition of endogenous GC-B enzymatic activity in rat chondrosarcoma cells.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	5	6	8	9
This is likely a result of FGF2 mediated activation of endogenous FGFR2/4 or FGFR3 , expressed in 293T ( data not shown ) or RCS cells XREF_BIBR .	This is likely a result of FGF2 mediated activation of endogenous FGFR2/4 or FGFR3, expressed in 293T (data not shown) or RCS cells XREF_BIBR.	6	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	6	7	13	14
These criteria together permit interpretations that the primary functions of FGFR1 and FGFR3 signaling by FGF-2 are distinctive in human adult articular chondrocytes .	These criteria together permit interpretations that the primary functions of FGFR1 and FGFR3 signaling by FGF-2 are distinctive in human adult articular chondrocytes.	10	16	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	FGFR3	FGFR3	FGFR3	15	16	12	13
FGF2 , FGF9 and 18 modulated the expression profile of FGFR1 and FGFR3 in hMSC during expansion and chondrogenesis .	FGF2, FGF9 and 18 modulated the expression profile of FGFR1 and FGFR3 in hMSC during expansion and chondrogenesis.	0	13	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	0	1	12	13
FGFR3 , in particular , is activated by FGF-2 via the ERK MAPK dependent signaling pathway in microglia .	FGFR3, in particular, is activated by FGF-2 via the ERK MAPK dependent signaling pathway in microglia.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	FGFR3	FGFR3	FGFR3	8	9	0	1
We next evaluated whether overexpression of activating FGFR3 mutants causes senescence similar to FGF2 mediated activation of endogenous FGFR3 .	We next evaluated whether overexpression of activating FGFR3 mutants causes senescence similar to FGF2 mediated activation of endogenous FGFR3.	13	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	13	14	18	19
In conclusion , in PC12 cells the NGF- and bFGF stimulated ERK1 appears to be involved in the induction of the threonine phosphorylation of the EGF receptor and the decrease in the number of high affinity EGF binding sites .	In conclusion, in PC12 cells the NGF- and bFGF stimulated ERK1 appears to be involved in the induction of the threonine phosphorylation of the EGF receptor and the decrease in the number of high affinity EGF binding sites.	7	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	bFGF	bFGF	bFGF	ERK1	ERK1	ERK1	9	10	11	12
In vitro studies have shown that growth factors including , Neuregulin1 , PDGF , IGF-1 , BDNF , NT3 and FGF-2 activate ERK1 and ERK2 in the oligodendrocyte-lineage cells and therefore can potentially stimulate myelination upstream of ERK1 and ERK2 in vivo .	In vitro studies have shown that growth factors including, Neuregulin1, PDGF, IGF-1, BDNF, NT3 and FGF-2 activate ERK1 and ERK2 in the oligodendrocyte-lineage cells and therefore can potentially stimulate myelination upstream of ERK1 and ERK2 in vivo.	7	24	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	ERK1	ERK1	ERK1	20	21	22	23
The selected-phage-derived peptide synthesized by solid phase method using a rapid and practical Fmoc strategy was found to specifically compete with bFGF for binding to its receptors , inhibit bFGF stimulated cell proliferation by inducing cell cycle arrest , and block bFGF induced activation of Erk1 and Erk2 kinase in B16-F10 melanoma cells .	The selected-phage-derived peptide synthesized by solid phase method using a rapid and practical Fmoc strategy was found to specifically compete with bFGF for binding to its receptors, inhibit bFGF stimulated cell proliferation by inducing cell cycle arrest, and block bFGF induced activation of Erk1 and Erk2 kinase in B16-F10 melanoma cells.	40	48	induced	Positive_early_activation	Positive_activation	Negative_activation	bFGF	bFGF	bFGF	Erk1	Erk1	Erk1	41	42	45	46
The novel finding in the present study is that ERK1 ,2 and Akt activation and subsequent EC proliferation in response to pravastatin is partially mediated by endogenous FGF-2 through the activation of the FGFR .	The novel finding in the present study is that ERK1,2 and Akt activation and subsequent EC proliferation in response to pravastatin is partially mediated by endogenous FGF-2 through the activation of the FGFR.	9	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	ERK1	ERK1	ERK1	27	28	9	10
Results have demonstrated that in addition to ERK2 , ERK1 is activated by FGF-2 and PDGF-BB in normal HOB and HBMS cells .	Results have demonstrated that in addition to ERK2, ERK1 is activated by FGF-2 and PDGF-BB in normal HOB and HBMS cells.	9	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	ERK1	ERK1	ERK1	13	14	9	10
ERK-1 and -2 are activated by FGF-2 released from endothelial cells in response to injury .	ERK-1 and -2 are activated by FGF-2 released from endothelial cells in response to injury.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	ERK-1	ERK-1	ERK-1	6	7	0	1
Subsequent research revealed that fibulin-5 promotes coacervation of tropoelastin and its deposition onto microfibrils XREF_BIBR ) by interacting with LTBP-4 , thereby leading to cross linking and elastic fiber assembly XREF_BIBR , XREF_BIBR ) .	Subsequent research revealed that fibulin-5 promotes coacervation of tropoelastin and its deposition onto microfibrils XREF_BIBR) by interacting with LTBP-4, thereby leading to cross linking and elastic fiber assembly XREF_BIBR, XREF_BIBR).	4	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-5	fibulin-5	fibulin-5	tropoelastin	tropoelastin	tropoelastin	4	5	8	9
The binding of fibulin-5 increases the coacervation and crosslinking of tropoelastin , facilitating elastic fiber formation .	The binding of fibulin-5 increases the coacervation and crosslinking of tropoelastin, facilitating elastic fiber formation.	1	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-5	fibulin-5	fibulin-5	tropoelastin	tropoelastin	tropoelastin	3	4	10	11
Second , fibulin-5 is required to mediate the appropriate integration of elastin into the microfibril bundle .	Second, fibulin-5 is required to mediate the appropriate integration of elastin into the microfibril bundle.	2	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-5	fibulin-5	fibulin-5	elastin	elastin	elastin	2	3	11	12
Fibulin-5 promotes coacervation of tropoelastin .	Fibulin-5 promotes coacervation of tropoelastin.	0	5	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fibulin-5	Fibulin-5	Fibulin-5	tropoelastin	tropoelastin	tropoelastin	0	1	4	5
Fibulin-5 preferentially binds tropoelastin , but not to polymerized elastin in vitro and it has been shown that recombinant fibulin-5 accelerates coacervation of tropoelastin in vitro .	Fibulin-5 preferentially binds tropoelastin, but not to polymerized elastin in vitro and it has been shown that recombinant fibulin-5 accelerates coacervation of tropoelastin in vitro.	18	24	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-5	fibulin-5	fibulin-5	tropoelastin	tropoelastin	tropoelastin	19	20	23	24
EC-SOD is also known to bind to tropoelastin , a process that is mediated by Fbln5 .	EC-SOD is also known to bind to tropoelastin, a process that is mediated by Fbln5.	5	16	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Fbln5	Fbln5	Fbln5	tropoelastin	tropoelastin	tropoelastin	15	16	7	8
Here , depletion of fibulin-5 caused the appearance of elastin rich thick fibrous structures , as seen by light microscopy , and of numerous small elastin globules accreted into large aggregates adjacent to microfibril bundles , as seen by electron microscopy .	Here, depletion of fibulin-5 caused the appearance of elastin rich thick fibrous structures, as seen by light microscopy, and of numerous small elastin globules accreted into large aggregates adjacent to microfibril bundles, as seen by electron microscopy.	2	16	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	fibulin-5	fibulin-5	fibulin-5	elastin	elastin	elastin	4	5	9	10
Fibulin-5 deposits on microfibrils , promotes aggregation of tropoelastin molecules through coacervation , and also interacts with LOXL1 , 2 , and 4 , which are enzymes that cross-link elastin .	Fibulin-5 deposits on microfibrils, promotes aggregation of tropoelastin molecules through coacervation, and also interacts with LOXL1, 2, and 4, which are enzymes that cross-link elastin.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fibulin-5	Fibulin-5	Fibulin-5	tropoelastin	tropoelastin	tropoelastin	0	1	8	9
In addition , fibulin-5 enhances tropoelastin coacervation .	In addition, fibulin-5 enhances tropoelastin coacervation.	3	6	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-5	fibulin-5	fibulin-5	tropoelastin	tropoelastin	tropoelastin	3	4	5	6
Data that support this model indicate that fibulin 5 potentially increases the coacervation of tropoelastin , enhancing elastic fiber formation .	Data that support this model indicate that fibulin 5 potentially increases the coacervation of tropoelastin, enhancing elastic fiber formation.	7	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin 5	fibulin 5	fibulin 5	tropoelastin	tropoelastin	tropoelastin	7	9	14	15
This competition may facilitate fibulin-5 targeting of tropoelastin onto microfibrils .	This competition may facilitate fibulin-5 targeting of tropoelastin onto microfibrils.	4	8	targeting	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	fibulin-5	fibulin-5	fibulin-5	tropoelastin	tropoelastin	tropoelastin	4	5	7	8
In contrast , as illustrated in XREF_FIG , the truncated form of fibulin-5 can not associate with microfibrils or integrins , and therefore is unable to promote the organization of the elastic fiber assembly , although the truncated form of fibulin-5 itself has the ability to bind tropoelastin and enhance coacervation of tropoelastin as well ( unpublished data ) .	In contrast, as illustrated in XREF_FIG, the truncated form of fibulin-5 can not associate with microfibrils or integrins, and therefore is unable to promote the organization of the elastic fiber assembly, although the truncated form of fibulin-5 itself has the ability to bind tropoelastin and enhance coacervation of tropoelastin as well (unpublished data).	38	57	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-5	fibulin-5	fibulin-5	tropoelastin	tropoelastin	tropoelastin	40	41	52	53
Missense mutations in fibulin 5 cause the elastin disorder cutis laxa and have been associated with age related macular degeneration , a leading cause of blindness .	Missense mutations in fibulin 5 cause the elastin disorder cutis laxa and have been associated with age related macular degeneration, a leading cause of blindness.	1	10	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin 5	fibulin 5	fibulin 5	elastin	elastin	elastin	3	5	7	8
The aforementioned data suggest that deposition of fibulin-5 onto microfibrils accelerates fibrillar tropoelastin deposition , but it was not clear if the tropoelastin molecules are cross linked to form mature functional elastic fibers .	The aforementioned data suggest that deposition of fibulin-5 onto microfibrils accelerates fibrillar tropoelastin deposition, but it was not clear if the tropoelastin molecules are cross linked to form mature functional elastic fibers.	5	13	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-5	fibulin-5	fibulin-5	tropoelastin	tropoelastin	tropoelastin	7	8	12	13
In the presence of recombinant fibulin-5 protein , tropoelastin started to coacervate at lower temperatures ( XREF_FIG ) , suggesting that fibulin-5 promotes coacervation of tropoelastin .	In the presence of recombinant fibulin-5 protein, tropoelastin started to coacervate at lower temperatures (XREF_FIG), suggesting that fibulin-5 promotes coacervation of tropoelastin.	21	26	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-5	fibulin-5	fibulin-5	tropoelastin	tropoelastin	tropoelastin	21	22	25	26
Others have shown that fibulin-5 accelerates the self aggregation process of elastin , called coacervation XREF_BIBR , and fibulin-5 limits maturation of the coacervated elastin XREF_BIBR .	Others have shown that fibulin-5 accelerates the self aggregation process of elastin, called coacervation XREF_BIBR, and fibulin-5 limits maturation of the coacervated elastin XREF_BIBR.	4	12	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibulin-5	fibulin-5	fibulin-5	elastin	elastin	elastin	4	5	11	12
Overexpression of Fbln5 increases deposition of elastic fibers and the level of the elastin specific cross-link , desmosine , in elastogenic cells .	Overexpression of Fbln5 increases deposition of elastic fibers and the level of the elastin specific cross-link, desmosine, in elastogenic cells.	0	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fbln5	Overexpression of Fbln5	fbln5	elastin	elastin	elastin	2	3	13	14
Untransfected U2OS cells , U2OS R1 cells highly expressing FGFR1 , and BJ cells naturally expressing FGFR1 were treated with FGF1 V -AuNPs or AuNPs and then irradiated with NIR light ( 808 nm ) .	Untransfected U2OS cells, U2OS R1 cells highly expressing FGFR1, and BJ cells naturally expressing FGFR1 were treated with FGF1 V -AuNPs or AuNPs and then irradiated with NIR light (808 nm).	8	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR1	FGFR1	FGFR1	20	21	9	10
A possible connection between the ERK2 and JNK1 MAP kinases transduction cascades was investigated in Xenopus oocytes expressing FGFR1 stimulated by FGF1 .	A possible connection between the ERK2 and JNK1 MAP kinases transduction cascades was investigated in Xenopus oocytes expressing FGFR1 stimulated by FGF1.	17	22	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR1	FGFR1	FGFR1	21	22	18	19
Although FGF stimulation promotes robust complex formation between activated WT FGFR1 and PLCgamma , ( XREF_FIG , top left two lanes ) , complex formation with PLCgamma could not be detected in FGF1 stimulated cells expressing the FGFR1 ( Y766F ) mutant or FGFR1 with mutations in amino acids of the C-lobe ( secondary interface ) that function as binding sites for the secondary binding sites on the N-SH2 domain ( XREF_FIG ) .	Although FGF stimulation promotes robust complex formation between activated WT FGFR1 and PLCgamma, (XREF_FIG, top left two lanes), complex formation with PLCgamma could not be detected in FGF1 stimulated cells expressing the FGFR1 (Y766F) mutant or FGFR1 with mutations in amino acids of the C-lobe (secondary interface) that function as binding sites for the secondary binding sites on the N-SH2 domain (XREF_FIG).	30	57	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR1	FGFR1	FGFR1	32	33	37	38
Acidic fibroblast growth factor ( aFGF ) stimulated tyrosine kinase activity of FLG in vitro and in living cells , suggesting that FLG encodes the membrane receptor for aFGF .	Acidic fibroblast growth factor (aFGF) stimulated tyrosine kinase activity of FLG in vitro and in living cells, suggesting that FLG encodes the membrane receptor for aFGF.	0	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Acidic fibroblast growth factor	Acidic fibroblast growth factor	Acidic fibroblast growth factor	FLG	FLG	FLG	0	4	12	13
WT FGF1 induces ternary complex formation ( integrin , FGF1 , and FGF receptor-1 ( FGFR1 ) , when cells are treated with FGF1 .	WT FGF1 induces ternary complex formation (integrin, FGF1, and FGF receptor-1 (FGFR1), when cells are treated with FGF1.	13	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR1	FGFR1	FGFR1	23	24	15	16
Interestingly , none of the studied antibodies blocked FGF1 dependent activation of FGFR1 , as detected by ERK1/2 and FGFR1 specific phosphorylation .	Interestingly, none of the studied antibodies blocked FGF1 dependent activation of FGFR1, as detected by ERK1/2 and FGFR1 specific phosphorylation.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR1	FGFR1	FGFR1	8	9	12	13
The effect of FGF-1 on encapsulated islets is unclear , but FGF-1 is known to activate fibroblast growth factor receptor-1 ( FGFR1 ) on beta-cells , which regulates function , survival , and proliferation .	The effect of FGF-1 on encapsulated islets is unclear, but FGF-1 is known to activate fibroblast growth factor receptor-1 (FGFR1) on beta-cells, which regulates function, survival, and proliferation.	11	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-1	FGF-1	FGF-1	fibroblast growth factor receptor-1	fibroblast growth factor receptor-1	fibroblast growth factor receptor-1	11	12	16	20
FGF1 and FGF17 , both of which can signal to FGFR1 and FGFR2 , also showed maximum expression at 14 DPF ( P < 0.001 ) .	FGF1 and FGF17, both of which can signal to FGFR1 and FGFR2, also showed maximum expression at 14 DPF (P < 0.001).	0	15	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR1	FGFR1	FGFR1	0	1	10	11
Moreover , FGF-1 or FGF-4 retroviral infection of the ventricular wall of embryonic quail caused an upregulation of FGFR1 and VEGFR-2 in epicardial and subepicardial cells adjacent to the FGF overexpressing sites .	Moreover, FGF-1 or FGF-4 retroviral infection of the ventricular wall of embryonic quail caused an upregulation of FGFR1 and VEGFR-2 in epicardial and subepicardial cells adjacent to the FGF overexpressing sites.	2	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-1	FGF-1	FGF-1	FGFR1	FGFR1	FGFR1	2	3	18	19
In previous studies , FGF1 was proved to stimulate FGFR2 by interaction and subsequently induce the downstream signaling cascade including RAS , MAPK and ERK signaling pathway in several cancers .	In previous studies, FGF1 was proved to stimulate FGFR2 by interaction and subsequently induce the downstream signaling cascade including RAS, MAPK and ERK signaling pathway in several cancers.	4	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR2	FGFR2	FGFR2	4	5	9	10
Cells were stimulated with FGF1 , which stimulates all FGFR isotypes , the FGFR2 selective ligand FGF7 , or the FGFR4 selective ligand FGF19 .	Cells were stimulated with FGF1, which stimulates all FGFR isotypes, the FGFR2 selective ligand FGF7, or the FGFR4 selective ligand FGF19.	2	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR2	FGFR2	FGFR2	4	5	13	14
FGFR2 was weakly stimulated by FGF1 ( and completely blocked by the FGFR specific tyrosine kinase inhibitor PD173074 ) suggesting its presence at the plasma membrane ( XREF_FIG ) .	FGFR2 was weakly stimulated by FGF1 (and completely blocked by the FGFR specific tyrosine kinase inhibitor PD173074) suggesting its presence at the plasma membrane (XREF_FIG).	0	6	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR2	FGFR2	FGFR2	5	6	0	1
In comparison FGFR2 dimerization was absent in the non stimulated state in MPI knockdown cells lines and was weakly restored by FGF1 stimulation ( XREF_FIG ) .	In comparison FGFR2 dimerization was absent in the non stimulated state in MPI knockdown cells lines and was weakly restored by FGF1 stimulation (XREF_FIG).	2	22	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR2	FGFR2	FGFR2	21	22	2	3
On the basis of the clinical data and statistical analysis of our experiments , we boldly hypothesized that FGF1 overexpression in gastric adenocarcinoma may cause ectopic activation of FGFR2 and subsequently result in unfavorable prognosis .	On the basis of the clinical data and statistical analysis of our experiments, we boldly hypothesized that FGF1 overexpression in gastric adenocarcinoma may cause ectopic activation of FGFR2 and subsequently result in unfavorable prognosis.	18	29	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1 overexpression	fgf1	FGFR2	FGFR2	fgfr2	18	19	28	29
However , because FGFR2 can still be stimulated by FGF1 plus heparin in the setting of MPI knockdown , we conclude that MPI knockdown does not completely eliminate function of the receptor , but impairs formation of stable FGFR dimers .	However, because FGFR2 can still be stimulated by FGF1 plus heparin in the setting of MPI knockdown, we conclude that MPI knockdown does not completely eliminate function of the receptor, but impairs formation of stable FGFR dimers.	3	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR2	FGFR2	FGFR2	9	10	3	4
Keratinocyte growth factor receptor ( KGFR ) , also known as fibroblast growth factor receptor ( FGFR ) 2 IIIb , is located in many types of epithelial cells and is activated by four known ligands ( FGF-1 , FGF-3 , FGF-7 ( also known as KGF ) and FGF-10 ) that are predominantly synthesized by mesenchymal cells .	Keratinocyte growth factor receptor (KGFR), also known as fibroblast growth factor receptor (FGFR) 2 IIIb, is located in many types of epithelial cells and is activated by four known ligands (FGF-1, FGF-3, FGF-7 (also known as KGF) and FGF-10) that are predominantly synthesized by mesenchymal cells.	0	49	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF-1	FGF-1	FGF-1	Keratinocyte growth factor receptor	Keratinocyte growth factor receptor	Keratinocyte growth factor receptor	37	38	0	4
Finally , we show that parental FaDu tumors engineered to overexpress FGF1 ligand exhibit complete resistance to EGFR and ERBB3 blockade in vivo ( XREF_SUPPLEMENTARY ) , indicating that ligand activated FGFR3 can also drive resistance ( although in this experiment we can not rule out contributions from FGFR2 or FGFR4 , which can be activated by FGF1 and which are expressed in FaDu cells ) .	Finally, we show that parental FaDu tumors engineered to overexpress FGF1 ligand exhibit complete resistance to EGFR and ERBB3 blockade in vivo (XREF_SUPPLEMENTARY), indicating that ligand activated FGFR3 can also drive resistance (although in this experiment we can not rule out contributions from FGFR2 or FGFR4, which can be activated by FGF1 and which are expressed in FaDu cells).	44	58	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR2	FGFR2	FGFR2	57	58	48	49
Furthermore , we suspected that ectopic FGF1 overexpression may stimulate FGFR2 continuously , and expected FGF1 to be a promising molecular drug target in gastric adenocarcinoma .	Furthermore, we suspected that ectopic FGF1 overexpression may stimulate FGFR2 continuously, and expected FGF1 to be a promising molecular drug target in gastric adenocarcinoma.	6	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1 overexpression	fgf1	FGFR2	FGFR2	fgfr2	6	7	10	11
While FGF1 activates FGFR2 , it appears that other factors may play a contributing role in terms of breast cancer risk and survival .	While FGF1 activates FGFR2, it appears that other factors may play a contributing role in terms of breast cancer risk and survival.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR2	FGFR2	FGFR2	1	2	3	4
Overexpression of the latter bek form in NIH3T3 cells has been used to demonstrate that the N-terminal Ig like domain and acidic region are not required for binding or activation of bek by aFGF or bFGF .	Overexpression of the latter bek form in NIH3T3 cells has been used to demonstrate that the N-terminal Ig like domain and acidic region are not required for binding or activation of bek by aFGF or bFGF.	25	35	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	aFGF	aFGF	aFGF	bek	bek	bek	33	34	31	32
This would be consistent with evidences showing that FGF-1 stimulates cytokine production in Jurkat T-cells via NF-kB activation [ XREF_BIBR ] , while FGFR2 activation by FGF-1 potentiates the secretion of TNF-alpha and IL-6 in LPS and INFgamma stimulated human astrocytes and microglia [ XREF_BIBR ] .	This would be consistent with evidences showing that FGF-1 stimulates cytokine production in Jurkat T-cells via NF-kB activation [XREF_BIBR], while FGFR2 activation by FGF-1 potentiates the secretion of TNF-alpha and IL-6 in LPS and INFgamma stimulated human astrocytes and microglia [XREF_BIBR].	23	27	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FGF-1	FGF-1	FGF-1	FGFR2	FGFR2	FGFR2	26	27	23	24
In contrast , murine FGFR-3 IIIc was preferentially activated by FGF-1 .	In contrast, murine FGFR-3 IIIc was preferentially activated by FGF-1.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGF-1	FGF-1	FGF-1	FGFR-3	FGFR-3	FGFR-3	10	11	4	5
This suggests that FGF1 and PMA may promote FGFR3 cleavage through distinct mechanisms .	This suggests that FGF1 and PMA may promote FGFR3 cleavage through distinct mechanisms.	3	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR3	FGFR3	FGFR3	3	4	8	9
XREF_FIG shows that Baf treatment blocked FGF1 induced cleavage of FGFR3 .	XREF_FIG shows that Baf treatment blocked FGF1 induced cleavage of FGFR3.	6	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR3	FGFR3	FGFR3	6	7	10	11
Stimulation of cells with FGF-1 activates FGFR3 , which further activates c-Src , and thus induces c-Src-dependent phosphorylation of the MUC1 CT on the YEKV motif [ XREF_BIBR ] .	Stimulation of cells with FGF-1 activates FGFR3, which further activates c-Src, and thus induces c-Src-dependent phosphorylation of the MUC1 CT on the YEKV motif [XREF_BIBR].	2	21	activates	Positive_regulation_token_1_verb	Positive_activation	Positive_regulation	FGF-1	FGF-1	fgf-1	FGFR3	FGFR3, which further activates c-Src, and thus induces c-Src-dependent phosphorylation of the MUC1	fgfr3	4	5	6	7
Because FGF1 and PMA appear to promote cleavage of FGFR3 through distinct mechanisms , we asked whether MMP inhibitors could block PMA induced cleavage .	Because FGF1 and PMA appear to promote cleavage of FGFR3 through distinct mechanisms, we asked whether MMP inhibitors could block PMA induced cleavage.	1	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR3	FGFR3	FGFR3	1	2	9	10
Our findings indicate that tyrosine phosphorylation of FGFR3 is necessary but not sufficient for FGF1 induced cleavage of FGFR3 .	Our findings indicate that tyrosine phosphorylation of FGFR3 is necessary but not sufficient for FGF1 induced cleavage of FGFR3.	14	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR3	FGFR3	FGFR3	14	15	18	19
We used FGF1 non stimulated and stimulated conditions based on previous reports that FGF1 not only stimulates WT FGFR3 but also enhances signalling by FGFR3-TACC3 fusion [ XREF_BIBR ] .	We used FGF1 non stimulated and stimulated conditions based on previous reports that FGF1 not only stimulates WT FGFR3 but also enhances signalling by FGFR3-TACC3 fusion [XREF_BIBR].	1	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR3	FGFR3	FGFR3	2	3	18	19
However , although rFGFR1 phosphorylates all of the Y --> F mutants , substitution of Y136 , Y243 or Y244 attenuates the FGFR1 dependent increase of PDHK1 kinase activity assessed by S293 phosphorylation levels of PDHA1 proteins , while double mutation of both Y243 and Y244 abolishes the enhanced activation of PDHK1 by FGFR1 ( XREF_FIG ) .	However, although rFGFR1 phosphorylates all of the Y --> F mutants, substitution of Y136, Y243 or Y244 attenuates the FGFR1 dependent increase of PDHK1 kinase activity assessed by S293 phosphorylation levels of PDHA1 proteins, while double mutation of both Y243 and Y244 abolishes the enhanced activation of PDHK1 by FGFR1 (XREF_FIG).	22	28	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGFR1	FGFR1	FGFR1	PDHK1	PDHK1	PDHK1	22	23	26	27
FGFR1 activates PDHK1 through direct phosphorylation at multiple tyrosine sites that promotes ATP and PDC binding to PDHK1 .	FGFR1 activates PDHK1 through direct phosphorylation at multiple tyrosine sites that promotes ATP and PDC binding to PDHK1.	0	3	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FGFR1	FGFR1	FGFR1	PDHK1	PDHK1	PDHK1	0	1	2	3
These findings suggest a dual role for FGFR1 in regulation of PDHK1 in cancer metabolism , which consists of a long-term mechanism by which FGFR1 may phosphorylate PKM2 to promote PDHK1 gene expression and a short-term mechanism by which FGFR1 activates PDHK1 through tyrosine phosphorylation at multiple sites .	These findings suggest a dual role for FGFR1 in regulation of PDHK1 in cancer metabolism, which consists of a long-term mechanism by which FGFR1 may phosphorylate PKM2 to promote PDHK1 gene expression and a short-term mechanism by which FGFR1 activates PDHK1 through tyrosine phosphorylation at multiple sites.	39	42	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR1	FGFR1	FGFR1	PDHK1	PDHK1	PDHK1	39	40	41	42
FGFR1 mediated the anti-glycolytic function of miR-361-5p by regulating the activity of PDHK1 and LDHA .	FGFR1 mediated the anti-glycolytic function of miR-361-5p by regulating the activity of PDHK1 and LDHA.	0	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR1	FGFR1	FGFR1	PDHK1	PDHK1	PDHK1	0	1	12	13
Thus , Rab11 dependent recycling of FGFR4 maintains proper levels of FGFR4 in cells and regulates FGF1 induced FGFR4 signalling .	Thus, Rab11 dependent recycling of FGFR4 maintains proper levels of FGFR4 in cells and regulates FGF1 induced FGFR4 signalling.	16	19	induced	Positive_early_activation	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR4	FGFR4	FGFR4	16	17	18	19
Moreover , both FGF1 and FGF19 also stimulate the activation of FGFR4 , a member of the FGFR family lacking the ' b ' isoforms .	Moreover, both FGF1 and FGF19 also stimulate the activation of FGFR4, a member of the FGFR family lacking the ' b ' isoforms.	2	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF1	FGF1	FGF1	FGFR4	FGFR4	FGFR4	3	4	11	12
Induction of FGFR-4 in malignant astrocytomas is consistent with previous reports demonstrating that expression of aFGF , which activates FGFR-4 , increases in astrocytomas .	Induction of FGFR-4 in malignant astrocytomas is consistent with previous reports demonstrating that expression of aFGF, which activates FGFR-4, increases in astrocytomas.	13	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	aFGF	expression of aFGF	afgf	FGFR-4	FGFR-4	fgfr-4	15	16	19	20
FGFR activation of YAP appears to be driven largely by FGF5 activation of FGFR2 , as siRNA silencing of this ligand or receptor , respectively , inhibited YAP nuclear localization .	FGFR activation of YAP appears to be driven largely by FGF5 activation of FGFR2, as siRNA silencing of this ligand or receptor, respectively, inhibited YAP nuclear localization.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FGF5	FGF5	FGF5	FGFR2	FGFR2	FGFR2	10	11	13	14
We show that FGF23 , but not FGF2 , can activate FGFR4 on cardiac myocytes and that FGFR4 blockade or deletion inhibits hypertrophic effects of FGF23 , but not of FGF2 .	We show that FGF23, but not FGF2, can activate FGFR4 on cardiac myocytes and that FGFR4 blockade or deletion inhibits hypertrophic effects of FGF23, but not of FGF2.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR4	FGFR4	FGFR4	7	8	11	12
Biological assays show that both HM ( 8 ) and HM ( 10 ) are significantly more potent than HM ( 6 ) in promoting FGF2 mediated FGFR4 signaling .	Biological assays show that both HM (8) and HM (10) are significantly more potent than HM (6) in promoting FGF2 mediated FGFR4 signaling.	24	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR4	FGFR4	FGFR4	25	26	27	28
In contrast , FGF2 and the pro hypertrophic angiotensin ( Ang ) II induced hypertrophic growth of NMVM independently of FGFR4 .	In contrast, FGF2 and the pro hypertrophic angiotensin (Ang) II induced hypertrophic growth of NMVM independently of FGFR4.	3	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	FGFR4	FGFR4	FGFR4	3	4	20	21
At E3.25 , when a subpopulation of ICM cells acquires a PrE fate , Fgf4 is expressed in the ICM and may thus signal both in an autocrine or in a paracrine fashion to Fgfr1 and Fgfr2 also expressed in ICM cells .	At E3.25, when a subpopulation of ICM cells acquires a PrE fate, Fgf4 is expressed in the ICM and may thus signal both in an autocrine or in a paracrine fashion to Fgfr1 and Fgfr2 also expressed in ICM cells.	14	37	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Fgf4	Fgf4 is expressed	fgf4	Fgfr2	Fgfr2	fgfr2	14	15	36	37
Although treatment with exogenous Fgf rescues PrE development in Fgf4 -/- embryos and induces conversion of all ICM cells into PrE cells in wild-type embryos , Fgf4 failed to restore PrE development in Fgfr1 -/-; Fgfr2 -/- embryos .	Although treatment with exogenous Fgf rescues PrE development in Fgf4 -/- embryos and induces conversion of all ICM cells into PrE cells in wild-type embryos, Fgf4 failed to restore PrE development in Fgfr1 -/-; Fgfr2 -/- embryos.	26	37	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fgf4	Fgf4	Fgf4	Fgfr2	Fgfr2	Fgfr2	26	27	35	36
Thus , while maturation of Nodal is under ExE control , Nodal signalling promotes ExE maintenance indirectly by sustaining Fgf4 expression in the EPI that , in turn , activates Fgfr2 signalling in the ExE .	Thus, while maturation of Nodal is under ExE control, Nodal signalling promotes ExE maintenance indirectly by sustaining Fgf4 expression in the EPI that, in turn, activates Fgfr2 signalling in the ExE.	19	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fgf4	Fgf4 expression	fgf4	Fgfr2	Fgfr2	fgfr2	19	20	30	31
To determine how fibrillin-1 enhances active TGFbeta and stimulates Smad2 signaling , we first investigated what PF10 interacts with in HDF cultures .	To determine how fibrillin-1 enhances active TGFbeta and stimulates Smad2 signaling, we first investigated what PF10 interacts with in HDF cultures.	3	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibrillin-1	fibrillin-1	fibrillin-1	Smad2	Smad2	Smad2	3	4	9	10
Our first step was to determine whether fibrillin-1 could stimulate the Smad2 pathway .	Our first step was to determine whether fibrillin-1 could stimulate the Smad2 pathway.	7	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibrillin-1	fibrillin-1	fibrillin-1	Smad2	Smad2	Smad2	7	8	11	12
We have discovered that a specific fibrillin-1 sequence encoded by exons 44-49 ( in recombinant fragments PF10 and PF11 ) enhances endogenous active TGFbeta1 and Smad2 signaling .	We have discovered that a specific fibrillin-1 sequence encoded by exons 44-49 (in recombinant fragments PF10 and PF11) enhances endogenous active TGFbeta1 and Smad2 signaling.	6	26	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	fibrillin-1	fibrillin-1	fibrillin-1	Smad2	Smad2	Smad2	6	7	25	26
Stimulation of Smad2 signaling by fibrillin-1 requires TGFbetaRI and II.	Stimulation of Smad2 signaling by fibrillin-1 requires TGFbetaRI and II.	2	6	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	fibrillin-1	fibrillin-1	fibrillin-1	Smad2	Smad2	Smad2	5	6	2	3
Our findings indicate that high expression of FGFR4 in connection with the Arg388 allele is associated with poor clinical outcome and support the significance of FGFR4 as a diagnostic marker and a target for therapeutic intervention in human HNSCC .	Our findings indicate that high expression of FGFR4 in connection with the Arg388 allele is associated with poor clinical outcome and support the significance of FGFR4 as a diagnostic marker and a target for therapeutic intervention in human HNSCC.	5	32	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR4	expression of FGFR4	fgfr4	FGFR4	FGFR4	fgfr4	7	8	25	26
Fbxo38 supports Klf7 in this role by acting as a transcriptional cofactor at the promoter of the cell cycle inhibitor p21 WAF1 and Cip1 [ XREF_BIBR ] .	Fbxo38 supports Klf7 in this role by acting as a transcriptional cofactor at the promoter of the cell cycle inhibitor p21 WAF1 and Cip1 [XREF_BIBR].	0	5	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fbxo38	Fbxo38	Fbxo38	Klf7	Klf7	Klf7	0	1	2	3
Furthermore , FGF-2 upon release by neurons activates c-jun N-terminal kinase 1 and 2 pathway which also contributes to neuronal survival .	Furthermore, FGF-2 upon release by neurons activates c-jun N-terminal kinase 1 and 2 pathway which also contributes to neuronal survival.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	c-jun N-terminal kinase 1	c-jun N-terminal kinase 1	c-jun N-terminal kinase 1	2	3	8	12
Several signalling pathways have been implicated in the reprogramming process , including BMP XREF_BIBR , G protein receptor , hypoxia mediated , JAK-STAT , NFkB , NOTCH , TGFbeta and FGF2 signalling XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR We recently demonstrated an important role for stress activated JNK1 and SAPK signalling in overcoming the reprogramming barriers encountered during the initiation stage of reprogramming including acceleration of cellular proliferation and progression of MET XREF_BIBR .	Several signalling pathways have been implicated in the reprogramming process, including BMP XREF_BIBR, G protein receptor, hypoxia mediated, JAK-STAT, NFkB, NOTCH, TGFbeta and FGF2 signalling XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR We recently demonstrated an important role for stress activated JNK1 and SAPK signalling in overcoming the reprogramming barriers encountered during the initiation stage of reprogramming including acceleration of cellular proliferation and progression of MET XREF_BIBR.	22	49	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FGF2	FGF2	FGF2	JNK1	JNK1	JNK1	30	31	46	47
FYN phosphorylation of FES has been reported to enhance FES activity by relieving autoinhibition 48 .	FYN phosphorylation of FES has been reported to enhance FES activity by relieving autoinhibition 48.	0	10	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FES	FYN phosphorylation of FES	fes	FES	FES	fes	3	4	9	10
Overactive FGFR3 and ERBB2 in bladder cancer presumably would activate Stat3 that is down-stream to these two receptor tyrosine kinases [ XREF_BIBR ] .	Overactive FGFR3 and ERBB2 in bladder cancer presumably would activate Stat3 that is down-stream to these two receptor tyrosine kinases [XREF_BIBR].	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR3	FGFR3	FGFR3	Stat3	Stat3	Stat3	1	2	10	11
Recombinant IL-10 ( rIL-10 ) increased the tyrosine phosphorylation of Stat3 , upregulated the levels of Fer , and increased the association of Fer with phosphorylated Stat3 ( pYStat3 ) .	Recombinant IL-10 (rIL-10) increased the tyrosine phosphorylation of Stat3, upregulated the levels of Fer, and increased the association of Fer with phosphorylated Stat3 (pYStat3).	1	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fer	IL-10 (rIL-10) increased the tyrosine phosphorylation of Stat3, upregulated the levels of Fer	fer	Fer	Fer	fer	16	17	23	24
Expression of phospho-fibroblast growth factor receptor 1 ( p-FGFR1 ) increased in HAECs rather than HUVECs when treated with recombinant FGF2 and FGF5 ( XREF_SUPPLEMENTARY ) .	Expression of phospho-fibroblast growth factor receptor 1 (p-FGFR1) increased in HAECs rather than HUVECs when treated with recombinant FGF2 and FGF5 (XREF_SUPPLEMENTARY).	0	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	FGF5	FGF5	FGF5	p-FGFR1	p-FGFR1	p-FGFR1	22	23	8	9
In contrast , in mesenchymal like KRAS mutant lung cancers , FGFR1 was dominantly expressed but suppressed by the negative regulator sprouty proteins ; MEK inhibition led to de-repression of SPRY4 and subsequent FGFR1 mediated re-activation of MEK and AKT .	In contrast, in mesenchymal like KRAS mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator sprouty proteins; MEK inhibition led to de-repression of SPRY4 and subsequent FGFR1 mediated re-activation of MEK and AKT.	26	39	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR1	FGFR1	FGFR1	MEK	MEK	MEK	33	34	37	38
Given the proximity of Fgf9 in mesenchyme surrounding the condensations and Fgf18 in nascent perichondrium , it is likely that FGF9 and FGF18 could signal locally to FGFR2 and FGFR3 .	Given the proximity of Fgf9 in mesenchyme surrounding the condensations and Fgf18 in nascent perichondrium, it is likely that FGF9 and FGF18 could signal locally to FGFR2 and FGFR3.	20	29	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	FGF18	FGF18	FGF18	FGFR2	FGFR2	FGFR2	22	23	27	28
Molecular studies confirm that FKBP52 is a component of AR complexes , and cellular studies in yeast and human cell models demonstrate that FKBP52 can enhance AR mediated transactivation .	Molecular studies confirm that FKBP52 is a component of AR complexes, and cellular studies in yeast and human cell models demonstrate that FKBP52 can enhance AR mediated transactivation.	23	28	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	23	24	26	27
An exception is that FKBP51 stimulates AR [ XREF_BIBR ] .	An exception is that FKBP51 stimulates AR [XREF_BIBR].	4	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP51	FKBP51	FKBP51	AR	AR	AR	4	5	6	7
The FKBP52 mutation F130Y abrogates PPIase activity without disrupting the conformation of the proline rich loop , and without inhibiting FKBP52 potentiation of AR activity alone [ XREF_BIBR ] .	The FKBP52 mutation F130Y abrogates PPIase activity without disrupting the conformation of the proline rich loop, and without inhibiting FKBP52 potentiation of AR activity alone [XREF_BIBR].	20	24	potentiation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	20	21	23	24
In addition , given that FKBP52 co-regulation with beta-catenin is independent of Hsp90 and specific for AR , we propose that FKBP52 potentiation of AR , GR and PR activity within the Hsp90 chaperone complex occurs at a receptor surface that is distinct from BF3 .	In addition, given that FKBP52 co-regulation with beta-catenin is independent of Hsp90 and specific for AR, we propose that FKBP52 potentiation of AR, GR and PR activity within the Hsp90 chaperone complex occurs at a receptor surface that is distinct from BF3.	21	29	potentiation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	21	22	24	25
Based on available evidence , the knockdown of FKBP52 is expected to significantly reduce AR signaling leading to a loss of proliferation in AR dependent prostate cancer cells , which could prevent the selection of clonal populations .	Based on available evidence, the knockdown of FKBP52 is expected to significantly reduce AR signaling leading to a loss of proliferation in AR dependent prostate cancer cells, which could prevent the selection of clonal populations.	6	15	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	8	9	14	15
Overexpression of FKBP51 in AD LNCaP cells increased AR transcriptional activity in the presence and absence of androgen , whereas siRNA knockdown of FKBP51 dramatically decreased AD gene transcription and proliferation .	Overexpression of FKBP51 in AD LNCaP cells increased AR transcriptional activity in the presence and absence of androgen, whereas siRNA knockdown of FKBP51 dramatically decreased AD gene transcription and proliferation.	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP51	Overexpression of FKBP51	fkbp51	AR	AR	ar	2	3	8	9
The AR inhibitor MJC13 blocks FKBP52 stimulated AR activity in yeast and cell culture but does not interact with FKBP52 and was unable to displace androgens from the AR pocket [ XREF_BIBR ] .	The AR inhibitor MJC13 blocks FKBP52 stimulated AR activity in yeast and cell culture but does not interact with FKBP52 and was unable to displace androgens from the AR pocket [XREF_BIBR].	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	5	6	7	8
Given that FKBP52 can potentiate AR activity through interaction with Hsp90 , and in the absence of beta-catenin in yeast , we aimed to determine if the pre-established domain and functional requirements for FKBP52 potentiation of AR activity alone directly mirror those of FKBP52 co-regulation with beta-catenin .	Given that FKBP52 can potentiate AR activity through interaction with Hsp90, and in the absence of beta-catenin in yeast, we aimed to determine if the pre-established domain and functional requirements for FKBP52 potentiation of AR activity alone directly mirror those of FKBP52 co-regulation with beta-catenin.	33	37	potentiation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	33	34	36	37
Collectively , these results demonstrate that with ID4 knockdown [ L (-) ID4 ] , Hsp27 dependent nuclear translocation and FKBP52 potentiated AR signaling further lead to increased tumorigenicity , both invitro and invivo .	Collectively, these results demonstrate that with ID4 knockdown [L (-) ID4], Hsp27 dependent nuclear translocation and FKBP52 potentiated AR signaling further lead to increased tumorigenicity, both invitro and invivo.	18	23	potentiated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	20	21	22	23
Our data also suggest that in the absence of ID4 , FKBP52 significantly potentiated AR signaling leading to increased proliferation and tumor growth .	Our data also suggest that in the absence of ID4, FKBP52 significantly potentiated AR signaling leading to increased proliferation and tumor growth.	11	15	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	11	12	14	15
Both groups found evidence for compromised AR activity in the knockout mice , and showed that FKBP52 potentiates AR signalling in response to androgen in prostate cell lines .	Both groups found evidence for compromised AR activity in the knockout mice, and showed that FKBP52 potentiates AR signalling in response to androgen in prostate cell lines.	16	19	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	16	17	18	19
Our data also suggest a role for FKBP52 and beta-catenin in promoting hormone independent AR activity given that FKBP52 synergized with beta-catenin to promote AR mediated expression of a reporter gene in the 52KO MEF cells in the absence of hormone addition ( Figs XREF_FIG , XREF_FIG ) , although this effect was not consistently significant between assays ( XREF_FIG ) .	Our data also suggest a role for FKBP52 and beta-catenin in promoting hormone independent AR activity given that FKBP52 synergized with beta-catenin to promote AR mediated expression of a reporter gene in the 52KO MEF cells in the absence of hormone addition (Figs XREF_FIG, XREF_FIG), although this effect was not consistently significant between assays (XREF_FIG).	18	25	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	18	19	24	25
Recent study shows that Hsp90 and its co-chaperone FKBP51 also promotes hormone independent nuclear localization of androgen receptor in prostate cancer cells and thereby plays a critical role in progression of prostate cancer .	Recent study shows that Hsp90 and its co-chaperone FKBP51 also promotes hormone independent nuclear localization of androgen receptor in prostate cancer cells and thereby plays a critical role in progression of prostate cancer.	4	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP51	FKBP51	FKBP51	androgen receptor	androgen receptor	androgen receptor	8	9	16	18
In cells , FKBP51 expression promotes superchaperone complex association with AR and increases the number of AR molecules that undergo androgen binding .	In cells, FKBP51 expression promotes superchaperone complex association with AR and increases the number of AR molecules that undergo androgen binding.	3	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP51	FKBP51 expression	fkbp51	AR	AR	ar	3	4	16	17
MJC13 completely inhibited both hormone independent and hormone dependent AR activity mediated by FKBP52 and beta-catenin at low micro molar concentrations ( XREF_FIG ) .	MJC13 completely inhibited both hormone independent and hormone dependent AR activity mediated by FKBP52 and beta-catenin at low micro molar concentrations (XREF_FIG).	9	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	13	14	9	10
Collectively , these results indicated that knockdown of ID4 enhances tumorigenicity of prostate cancer cells in theCRPC conditions , more importantly through FKBP52 mediated AR signaling .	Collectively, these results indicated that knockdown of ID4 enhances tumorigenicity of prostate cancer cells in theCRPC conditions, more importantly through FKBP52 mediated AR signaling.	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	22	23	24	25
Altered expression of androgen receptor signaling regulators in Ggamma-globin-Tag tumors , such as FKBP4 , NCOA4 , and calreticulin ( see expression profiles at http://caarraydb.nci.nih.gov/caarray/ ) might be linked to the acquisition of androgen independence and aggressiveness in this model .	Altered expression of androgen receptor signaling regulators in Ggamma-globin-Tag tumors, such as FKBP4, NCOA4, and calreticulin (see expression profiles at http://caarraydb.nci.nih.gov/caarray/) might be linked to the acquisition of androgen independence and aggressiveness in this model.	3	20	signaling regulators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	FKBP4	FKBP4	FKBP4	androgen receptor	androgen receptor	androgen receptor	13	14	3	5
A series of small molecules that can specifically inhibit FKBP52 mediated potentiation of AR signaling through the putative targeting of the AR BF3 surface were recently identified and characterized .	A series of small molecules that can specifically inhibit FKBP52 mediated potentiation of AR signaling through the putative targeting of the AR BF3 surface were recently identified and characterized.	8	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	9	10	13	14
Although peptidyl-prolyl cis-trans isomerase ( PPIase ) enzymatic activity is not required for FKBP52 potentiation of AR activity , the PPIase domain ( FK1 ) is essential .	Although peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity is not required for FKBP52 potentiation of AR activity, the PPIase domain (FK1) is essential.	13	17	potentiation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	13	14	16	17
Potentiation of AR by FKBP51 was not found in other studies and may be cell type dependent [ XREF_BIBR , XREF_BIBR ] .	Potentiation of AR by FKBP51 was not found in other studies and may be cell type dependent [XREF_BIBR, XREF_BIBR].	0	5	Potentiation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	FKBP51	FKBP51	FKBP51	AR	AR	AR	4	5	2	3
Together , our results demonstrate that ID4 selectively regulates AR activity through direct interaction with FKBP52 , and its loss , promotes CRPC through FKBP52 mediated AR signaling .	Together, our results demonstrate that ID4 selectively regulates AR activity through direct interaction with FKBP52, and its loss, promotes CRPC through FKBP52 mediated AR signaling.	22	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	24	25	26	27
The results also indicate that FKBP51 overexpression can cause the AR of AD LNCaP cells to mimic AR found in the AI C4-2 cells by increasing the constitutive and hormone induced activities of the AR .	The results also indicate that FKBP51 overexpression can cause the AR of AD LNCaP cells to mimic AR found in the AI C4-2 cells by increasing the constitutive and hormone induced activities of the AR.	5	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP51	FKBP51 overexpression	fkbp51	AR	AR	ar	5	6	10	11
Consistent with our previous observation , in the present study loss of ID4 enhanced invivo tumor growth in the castration resistant environment , more importantly through FKBP52 mediated AR signaling pathway .	Consistent with our previous observation, in the present study loss of ID4 enhanced invivo tumor growth in the castration resistant environment, more importantly through FKBP52 mediated AR signaling pathway.	24	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	26	27	28	29
FKBP51 has the overall effect of reducing receptor transcriptional activity , with the exception of androgen receptor , whose transcriptional activity is increased by FKBP51 [ XREF_BIBR ] .	FKBP51 has the overall effect of reducing receptor transcriptional activity, with the exception of androgen receptor, whose transcriptional activity is increased by FKBP51 [XREF_BIBR].	15	26	increased	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	FKBP51	FKBP51	FKBP51	androgen receptor	androgen receptor	androgen receptor	24	25	15	17
While the FKBP52 peptidyl-prolyl cis/trans isomerase ( PPIase ) catalytic activity is not required for FKBP52 potentiation of AR activity , the PPIase domain ( FK1 ) is essential .	While the FKBP52 peptidyl-prolyl cis/trans isomerase (PPIase) catalytic activity is not required for FKBP52 potentiation of AR activity, the PPIase domain (FK1) is essential.	15	19	potentiation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	15	16	18	19
Concomitant with the decreased serum PSA levels in the MJC13 treated xenografts , these results further confirmed that MJC13 effectively inhibited FKBP52 mediated AR signaling invivo .	Concomitant with the decreased serum PSA levels in the MJC13 treated xenografts, these results further confirmed that MJC13 effectively inhibited FKBP52 mediated AR signaling invivo.	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	21	22	23	24
Taken together these results confirm FKBP51 as an androgen induced gene , demonstrate a physical interaction between FKBP51 and AR and suggest that FKBP51 over expression increases AR transcriptional activity in prostate cancer .	Taken together these results confirm FKBP51 as an androgen induced gene, demonstrate a physical interaction between FKBP51 and AR and suggest that FKBP51 over expression increases AR transcriptional activity in prostate cancer.	23	28	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP51	FKBP51	FKBP51	AR	AR	AR	23	24	27	28
In androgen dependent tumor cell lines , FKBP51 hyperexpression increased androgen receptor transcriptional activity in the presence and absence of androgens ; whereas , knockdown of FKBP51 dramatically decreased androgen dependent gene transcription and proliferation .	In androgen dependent tumor cell lines, FKBP51 hyperexpression increased androgen receptor transcriptional activity in the presence and absence of androgens; whereas, knockdown of FKBP51 dramatically decreased androgen dependent gene transcription and proliferation.	7	12	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FKBP51	FKBP51 hyperexpression	fkbp51	androgen receptor	androgen receptor	androgen receptor	7	8	10	12
As discussed above , this could arise from compensation by FKBP51 , which also promotes AR activity .	As discussed above, this could arise from compensation by FKBP51, which also promotes AR activity.	6	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP51	FKBP51	FKBP51	AR	AR	AR	10	11	15	16
FLT3-ITD and FLT3 with an activating amino acid substitution in the tyrosine kinase domain , such as FLT3-D835Y , also constitutively activate the PI3K and Akt and MEK and Erk signaling pathways as well as STAT5 to stimulate proliferation and enhance survival of hematopoietic cells .	FLT3-ITD and FLT3 with an activating amino acid substitution in the tyrosine kinase domain, such as FLT3-D835Y, also constitutively activate the PI3K and Akt and MEK and Erk signaling pathways as well as STAT5 to stimulate proliferation and enhance survival of hematopoietic cells.	0	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	Akt	Akt	Akt	2	3	25	26
Mechanisms which contribute to increased mTOR activity in ALL may be the activation of PI3K and AKT by mutations of the tumor suppressor gene PTEN XREF_BIBR , and by abberant signals from TCL1 , BCR-ABL , growth factor receptors ( such as IGF-1R and c-kit ) , IL-7R , flt-3 XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR and oncogenic NOTCH1 , the latter one specifically in T-ALL .	Mechanisms which contribute to increased mTOR activity in ALL may be the activation of PI3K and AKT by mutations of the tumor suppressor gene PTEN XREF_BIBR, and by abberant signals from TCL1, BCR-ABL, growth factor receptors (such as IGF-1R and c-kit), IL-7R, flt-3 XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR and oncogenic NOTCH1, the latter one specifically in T-ALL.	12	50	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	flt-3	flt-3	flt-3	AKT	AKT	AKT	49	50	16	17
In addition , the overexpression of FLT3 has been reported to activate the AKT and MAPK pathways , but not the STAT5 pathway , which suggests that the overexpression of FLT3 has overlapping downstream pathways with FLT3-ITD .	In addition, the overexpression of FLT3 has been reported to activate the AKT and MAPK pathways, but not the STAT5 pathway, which suggests that the overexpression of FLT3 has overlapping downstream pathways with FLT3-ITD.	4	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	overexpression of FLT3	flt3	AKT	AKT	akt	6	7	13	14
For AML with FLT3-ITD , it has been reported that various FLT3 kinase inhibitors synergistically enhanced cytotoxic effects of the PI3K and Akt pathway inhibitors , including GDC-0941 and MK-2206 [ XREF_BIBR , XREF_BIBR ] .	For AML with FLT3-ITD, it has been reported that various FLT3 kinase inhibitors synergistically enhanced cytotoxic effects of the PI3K and Akt pathway inhibitors, including GDC-0941 and MK-2206 [XREF_BIBR, XREF_BIBR].	11	24	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	Akt	Akt	Akt	11	12	22	23
Wild-type FLT3 activates the PI3K and AKT , RAS and ERK and p38 pathways in response to FL stimulation while FLT3-ITD constitutively activates those pathways [ XREF_BIBR - XREF_BIBR ] .	Wild-type FLT3 activates the PI3K and AKT, RAS and ERK and p38 pathways in response to FL stimulation while FLT3-ITD constitutively activates those pathways [XREF_BIBR - XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	1	2	6	7
The STAT5 , PI-3 kinase and AKT and Ras and Map kinase pathways are activated by FLT3 and are important in cell survival and proliferation in cells that are dependent on FLT3 activity .	The STAT5, PI-3 kinase and AKT and Ras and Map kinase pathways are activated by FLT3 and are important in cell survival and proliferation in cells that are dependent on FLT3 activity.	1	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	16	17	6	7
While wild-type FLT3 activates AKT , ERK and p38 signaling , FLT3-ITD activates in addition to AKT , ERK and p38 signaling also STAT5 signaling .	While wild-type FLT3 activates AKT, ERK and p38 signaling, FLT3-ITD activates in addition to AKT, ERK and p38 signaling also STAT5 signaling.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	2	3	4	5
The PI3K and AKT pathway is constitutively activated by FLT3 ITD mutations [ XREF_BIBR , XREF_BIBR ] .	The PI3K and AKT pathway is constitutively activated by FLT3 ITD mutations [XREF_BIBR, XREF_BIBR].	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	9	10	3	4
As described in Introduction , wild-type FLT3 activation results in activation of the PI3K and AKT , ERK , and p38 pathways [ XREF_BIBR , XREF_BIBR ] .	As described in Introduction, wild-type FLT3 activation results in activation of the PI3K and AKT, ERK, and p38 pathways [XREF_BIBR, XREF_BIBR].	6	17	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	6	7	15	16
FLT3 stimulation promotes cell proliferation by activating phosphoinositol-3-kinase ( PI3K ) , Ras GTPase , protein kinase B ( Akt ) and mitogen activated protein kinase ( MAPK ) pathways 1 .	FLT3 stimulation promotes cell proliferation by activating phosphoinositol-3-kinase (PI3K), Ras GTPase, protein kinase B (Akt) and mitogen activated protein kinase (MAPK) pathways 1.	0	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	Akt	Akt	Akt	0	1	19	20
FLT3 ITD mutations are found in ~ 25 % of KN-AML and lead to constitutive activation of the downstream mitogen activated protein kinase ( MAPK ) , AKT , and signal transducer and activator of transcription ( STAT ) signaling pathways linked to FLT3 .	FLT3 ITD mutations are found in ~ 25% of KN-AML and lead to constitutive activation of the downstream mitogen activated protein kinase (MAPK), AKT, and signal transducer and activator of transcription (STAT) signaling pathways linked to FLT3.	0	28	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	0	1	27	28
When we combined lestaurtinib with the MEK inhibitor , U0126 , a modest suppression of the FLT3 and ITD A627E mutant cells resulted , which indicates that the AKT and/or STAT5 pathways activated by FLT3 and ITD are still providing some survival and proliferation advantages .	When we combined lestaurtinib with the MEK inhibitor, U0126, a modest suppression of the FLT3 and ITD A627E mutant cells resulted, which indicates that the AKT and/or STAT5 pathways activated by FLT3 and ITD are still providing some survival and proliferation advantages.	27	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	34	35	28	29
For example , internal tandem duplication mutations in the FLT3 gene , affecting approximately 25 % of patients with AML , lead to constitutive FLT3 signaling which activates Akt and confers a poor prognosis .	For example, internal tandem duplication mutations in the FLT3 gene, affecting approximately 25% of patients with AML, lead to constitutive FLT3 signaling which activates Akt and confers a poor prognosis.	24	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	Akt	Akt	Akt	24	25	28	29
Recently we demonstrated that BEX1 , a brain X linked family protein negatively regulates FLT3 signaling by modulating FLT3 induced AKT activation [ XREF_BIBR ] .	Recently we demonstrated that BEX1, a brain X linked family protein negatively regulates FLT3 signaling by modulating FLT3 induced AKT activation [XREF_BIBR].	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	18	19	20	21
Activation of wild-type FLT3 resulted in activation of the AKT , ERK and p38 signaling pathways .	Activation of wild-type FLT3 resulted in activation of the AKT, ERK and p38 signaling pathways.	0	15	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	3	4	9	10
In contrast to the FLT3 ITD mutants , ligand stimulated FLT3 wild-type receptors activate AKT and MAPK , but not STAT5 [ XREF_BIBR ] .	In contrast to the FLT3 ITD mutants, ligand stimulated FLT3 wild-type receptors activate AKT and MAPK, but not STAT5 [XREF_BIBR].	10	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	10	11	14	15
In this report , we observed that GADS associated with FLT3 through phosphotyrosine residues 955 and 969 , which are identical to the GRB2 binding sites in FLT3 , and enhances FLT3 induced AKT , ERK , p38 and STAT5 phosphorylation [ XREF_BIBR ] .	In this report, we observed that GADS associated with FLT3 through phosphotyrosine residues 955 and 969, which are identical to the GRB2 binding sites in FLT3, and enhances FLT3 induced AKT, ERK, p38 and STAT5 phosphorylation [XREF_BIBR].	30	42	induced	Positive_early_activation	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	AKT	AKT	AKT	31	32	33	34
Previous studies have shown that the Akt pathway suppresses protein degradation by inactivating FoxO , which induces Fbxo32 ( MAFbx ) [ XREF_BIBR , XREF_BIBR ] and Trim63 ( MuRF1 ) [ XREF_BIBR ] .	Previous studies have shown that the Akt pathway suppresses protein degradation by inactivating FoxO, which induces Fbxo32 (MAFbx) [XREF_BIBR, XREF_BIBR] and Trim63 (MuRF1) [XREF_BIBR].	8	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	Fbxo32	Fbxo32	Fbxo32	13	14	17	18
PI3K and Akt signaling regulates Atrogin-1 and MuRF-1 protein levels by inhibiting FoxO transcription factor mediated induction of atrogin-1 and MuRF-1 gene expression XREF_BIBR , XREF_BIBR , XREF_BIBR .	PI3K and Akt signaling regulates Atrogin-1 and MuRF-1 protein levels by inhibiting FoxO transcription factor mediated induction of atrogin-1 and MuRF-1 gene expression XREF_BIBR, XREF_BIBR, XREF_BIBR.	12	20	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	atrogin-1	atrogin-1	atrogin-1	12	13	18	19
In such conditions , FOXO is transited to the cell nucleus and stimulates the synthesis atrogin-1 and muscle atrophy f-box ( MAFbx ) and Muscle ring finger 1 protein ( MuRF1 ) .	In such conditions, FOXO is transited to the cell nucleus and stimulates the synthesis atrogin-1 and muscle atrophy f-box (MAFbx) and Muscle ring finger 1 protein (MuRF1).	4	26	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FOXO	FOXO	FOXO	atrogin-1	atrogin-1	atrogin-1	4	5	15	16
FoxO transcription factors , which are normally phosphorylated and inactivated by phosphatidylinositol 3-kinase ( PI3K )-Akt/PKB , translocate into the cell nucleus and induce the transcription of the skeletal muscle specific E3 ubiquitin ligases , muscle RING-finger protein-1 ( MuRF1 ) , and atrogin-1 and muscle atrophy F-box ( MAFbx ) [ XREF_BIBR ] , as well as autophagy related genes such as LC3 and Bnip3 [ XREF_BIBR ] .	FoxO transcription factors, which are normally phosphorylated and inactivated by phosphatidylinositol 3-kinase (PI3K)-Akt/PKB, translocate into the cell nucleus and induce the transcription of the skeletal muscle specific E3 ubiquitin ligases, muscle RING-finger protein-1 (MuRF1), and atrogin-1 and muscle atrophy F-box (MAFbx) [XREF_BIBR], as well as autophagy related genes such as LC3 and Bnip3 [XREF_BIBR].	0	47	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxO	FoxO transcription factors, which are normally phosphorylated	foxo	atrogin-1	atrogin-1	atrogin-1	0	1	43	44
One is mediated by class O type of forkhead transcription factors ( FoxO ) that upregulate MuRF-1 and MAFbx .	One is mediated by class O type of forkhead transcription factors (FoxO) that upregulate MuRF-1 and MAFbx.	10	19	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	MAFbx	MAFbx	MAFbx	12	13	18	19
Various signal proteins and transcription factors regulate muscle atrophy through the Forkhead box O ( FOXO ) factor , which stimulates atrogin-1 and Muscle RING-finger protein-1 ( MURF1 ) and thereby induces proteolysis through three proteolytic systems ( 1 .	Various signal proteins and transcription factors regulate muscle atrophy through the Forkhead box O (FOXO) factor, which stimulates atrogin-1 and Muscle RING-finger protein-1 (MURF1) and thereby induces proteolysis through three proteolytic systems (1.	13	25	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FOXO	FOXO	FOXO	atrogin-1	atrogin-1	atrogin-1	15	16	21	22
In another feed-forward mechanism , MAFbx , which is activated by FoxO , acts in turn as coactivator of FoxO [ XREF_BIBR ] .	In another feed-forward mechanism, MAFbx, which is activated by FoxO, acts in turn as coactivator of FoxO [XREF_BIBR].	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	MAFbx	MAFbx	MAFbx	11	12	5	6
Our data are consistent with a model whereby alcohol increases proteolysis via FOXO independent increase in atrogin-1 , which degrades eIF3f and therefore impairs formation of a functional preinitiation complex and protein synthesis .	Our data are consistent with a model whereby alcohol increases proteolysis via FOXO independent increase in atrogin-1, which degrades eIF3f and therefore impairs formation of a functional preinitiation complex and protein synthesis.	12	23	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FOXO	FOXO	FOXO	atrogin-1	atrogin-1	atrogin-1	12	13	16	17
FoxO induction of MAFbx and Atrogin has recently been shown to inhibit Cn activity ; thus , the inhibition of FoxO by CnAbeta1 might indirectly contribute to the increased Cn activity in CnAbeta1 expressing cells .	FoxO induction of MAFbx and Atrogin has recently been shown to inhibit Cn activity; thus, the inhibition of FoxO by CnAbeta1 might indirectly contribute to the increased Cn activity in CnAbeta1 expressing cells.	0	5	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	MAFbx	MAFbx	MAFbx	0	1	3	4
The FoxO target atrogin-1 ubiquitinates and degrades calcineurin , preventing Akt mediated hypertrophic signaling , and atrogin-1 also acts as a FoxO coactivator through noncanonical polyubiquitination to inhibit Akt mediated signaling .	The FoxO target atrogin-1 ubiquitinates and degrades calcineurin, preventing Akt mediated hypertrophic signaling, and atrogin-1 also acts as a FoxO coactivator through noncanonical polyubiquitination to inhibit Akt mediated signaling.	0	8	target	Positive_regulation_token_1_verb	Positive_activation	Positive_regulation	FoxO	FoxO	foxo	atrogin-1	atrogin-1 ubiquitinates and degrades calcineurin	atrogin-1	1	2	3	4
Additionally , the FOXO family of genes target Atrogin-1 and MuRF-1 , and partially control their function .	Additionally, the FOXO family of genes target Atrogin-1 and MuRF-1, and partially control their function.	3	10	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FOXO	FOXO	FOXO	Atrogin-1	Atrogin-1	Atrogin-1	3	4	8	9
In other studies , overexpression of PGC-1alpha prevented the induction of FoxO mediated atrogenes , MuRF-1 and Atrogin-1 and MAFbx , and the reduction in fiber size during atrophy [ XREF_BIBR , XREF_BIBR ] .	In other studies, overexpression of PGC-1alpha prevented the induction of FoxO mediated atrogenes, MuRF-1 and Atrogin-1 and MAFbx, and the reduction in fiber size during atrophy [XREF_BIBR, XREF_BIBR].	9	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	Atrogin-1	Atrogin-1	Atrogin-1	11	12	17	18
Down-stimulation of Akt activates the forkhead box protein O ( FoxO ) family which increases atrogin-1 and MuRF-1 , two potent inducers of protein degradation [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Down-stimulation of Akt activates the forkhead box protein O (FoxO) family which increases atrogin-1 and MuRF-1, two potent inducers of protein degradation [XREF_BIBR, XREF_BIBR - XREF_BIBR].	10	21	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	atrogin-1	atrogin-1	atrogin-1	10	11	15	16
FoxO dependent activation of atrogin-1 and muscle atrophy is inhibited by the peroxisome proliferator activated receptor gamma coactivator 1alpha ( PGC1alpha ) , a transcriptional coactivator .	FoxO dependent activation of atrogin-1 and muscle atrophy is inhibited by the peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC1alpha), a transcriptional coactivator.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	atrogin-1	atrogin-1	atrogin-1	0	1	4	5
In differentiated muscle , active FoxO proteins are localized in the nucleus and activate transcription of the muscle specific E3 ubiquitin ligases Atrogin-1 and MuRF-1 and many genes associated with autophagy , causing substantial atrophy .	In differentiated muscle, active FoxO proteins are localized in the nucleus and activate transcription of the muscle specific E3 ubiquitin ligases Atrogin-1 and MuRF-1 and many genes associated with autophagy, causing substantial atrophy.	5	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	Atrogin-1	Atrogin-1	Atrogin-1	5	6	22	23
Recently , it was shown that FLT3L and type I IFN act synergistically to promote pDC development from common lymphoid progenitors by inducing upregulation of FLT3 41 .	Recently, it was shown that FLT3L and type I IFN act synergistically to promote pDC development from common lymphoid progenitors by inducing upregulation of FLT3 41.	6	26	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3L	FLT3L	FLT3L	FLT3	FLT3	FLT3	6	7	25	26
XREF_BIBR , XREF_BIBR FLT3 is normally activated by binding FLT3 ligand ( FL ) , which prompts receptor dimerization and kinase activity with the subsequent activation of multiple downstream signaling pathways , including Ras and MAP kinase , AKT and STAT5 .	XREF_BIBR, XREF_BIBR FLT3 is normally activated by binding FLT3 ligand (FL), which prompts receptor dimerization and kinase activity with the subsequent activation of multiple downstream signaling pathways, including Ras and MAP kinase, AKT and STAT5.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FLT3 ligand	FLT3 ligand	FLT3 ligand	FLT3	FLT3	FLT3	9	11	3	4
Flt3L stimulates Flt3 and CD135 , a receptor tyrosine kinase expressed on early hematopoietic progenitors , leading to STAT3 signaling which also is essential for DC development .	Flt3L stimulates Flt3 and CD135, a receptor tyrosine kinase expressed on early hematopoietic progenitors, leading to STAT3 signaling which also is essential for DC development.	0	16	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Flt3L	Flt3L	Flt3L	Flt3	Flt3	Flt3	0	1	2	3
Antigens , such as PR-3 , RHAMM , Survivin , WT-1 and PRAME , were upregulated by constitutively active FLT3-ITD as well as FLT3-WT activated by FLT3 ligand ( FL ) .	Antigens, such as PR-3, RHAMM, Survivin, WT-1 and PRAME, were upregulated by constitutively active FLT3-ITD as well as FLT3-WT activated by FLT3 ligand (FL).	15	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FLT3 ligand	FLT3 ligand	FLT3 ligand	FLT3-WT	FLT3-WT	FLT3-WT	26	28	23	24
Low Flt3 expression did not result from receptor internalization as a consequence of culture in the presence of Flt3L , as Flt3L deprivation for 24 h did not result in Flt3 upregulation on the surface of Cas9-Hoxb8 cells ( data not shown ) .	Low Flt3 expression did not result from receptor internalization as a consequence of culture in the presence of Flt3L, as Flt3L deprivation for 24 h did not result in Flt3 upregulation on the surface of Cas9-Hoxb8 cells (data not shown).	21	32	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Flt3L	Flt3L	Flt3L	Flt3	Flt3	Flt3	21	22	30	31
These data confirm prior findings XREF_BIBR and suggest FLT3L independent signaling in FLT3 ITD AML .	These data confirm prior findings XREF_BIBR and suggest FLT3L independent signaling in FLT3 ITD AML.	8	14	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FLT3L	FLT3L	FLT3L	FLT3	FLT3	FLT3	8	9	12	13
Since FLT3 ligand promotes the dimerization and phosphorylation of FLT3 within 5-15min and subsequently activates several pathways involved in cell survival and proliferation , such as RAS/RAF/Erk , PI3K/Akt/mTOR , and JAK and STAT [ XREF_BIBR ] , it was supposed that FLT3L expressed by CAR-T cells might promote dimerization and activation of FLT3 in FLT3-WT cells , and activation of the signal transduction cascades in FLT3 wild-type leukemia cells may promote their survival and relieve damage .	Since FLT3 ligand promotes the dimerization and phosphorylation of FLT3 within 5-15min and subsequently activates several pathways involved in cell survival and proliferation, such as RAS/RAF/Erk, PI3K/Akt/mTOR, and JAK and STAT [XREF_BIBR], it was supposed that FLT3L expressed by CAR-T cells might promote dimerization and activation of FLT3 in FLT3-WT cells, and activation of the signal transduction cascades in FLT3 wild-type leukemia cells may promote their survival and relieve damage.	42	54	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3L	FLT3L expressed	flt3l	FLT3	FLT3	flt3	42	43	53	54
We report here that Flt-3L and Il-7 synergistically stimulated the expansion of primary Il-7R ( + ) Flt-3 ( + ) progenitor cells and a hematopoietic progenitor cell line ectopically expressing the receptors .	We report here that Flt-3L and Il-7 synergistically stimulated the expansion of primary Il-7R (+) Flt-3 (+) progenitor cells and a hematopoietic progenitor cell line ectopically expressing the receptors.	4	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Flt-3L	Flt-3L	Flt-3L	Flt-3	Flt-3	Flt-3	4	5	17	18
After unblinding clinical and mutational data , the results confirmed that in the verification sample set the FLT3L induced p-S6 responses were muted and more homogeneous in FLT3 ITD AML samples with high mutational load compared to FLT3 WT AML ( XREF_FIG ) .	After unblinding clinical and mutational data, the results confirmed that in the verification sample set the FLT3L induced p-S6 responses were muted and more homogeneous in FLT3 ITD AML samples with high mutational load compared to FLT3 WT AML (XREF_FIG).	16	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3L	FLT3L	FLT3L	FLT3	FLT3	FLT3	17	18	27	28
FLT3 ligand ( FLT3L ) stimulates primitive hematopoietic cells by binding to and activating the FLT3 receptor ( FLT3R ) .	FLT3 ligand (FLT3L) stimulates primitive hematopoietic cells by binding to and activating the FLT3 receptor (FLT3R).	1	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3L	FLT3L	FLT3L	FLT3	FLT3	FLT3	3	4	15	16
FLT3 signaling may also be activated in AML cells by autocrine stimulation by FLT3 ligand XREF_BIBR .	FLT3 signaling may also be activated in AML cells by autocrine stimulation by FLT3 ligand XREF_BIBR.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FLT3 ligand	FLT3 ligand	FLT3 ligand	FLT3	FLT3	FLT3	13	15	0	1
Furthermore , it was found that FLT3L CAR-T cells could activate the FLT3 and ERK signaling pathway of FLT3 + leukemia cells with wild-type FLT3 ; meanwhile , it had no inhibitory effects on the colony formation of CD34 + stem cells derived from normal human umbilical cord blood .	Furthermore, it was found that FLT3L CAR-T cells could activate the FLT3 and ERK signaling pathway of FLT3 + leukemia cells with wild-type FLT3; meanwhile, it had no inhibitory effects on the colony formation of CD34 + stem cells derived from normal human umbilical cord blood.	6	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3L	FLT3L	FLT3L	FLT3	FLT3	FLT3	6	7	12	13
The binding of FLT3 ligand ( FL ) causes the FLT3 protein to dimerize , initiating kinase activity which includes autophosphorylation and phosphorylation of substrate proteins .	The binding of FLT3 ligand (FL) causes the FLT3 protein to dimerize, initiating kinase activity which includes autophosphorylation and phosphorylation of substrate proteins.	3	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3 ligand	FLT3 ligand	FLT3 ligand	FLT3	FLT3	FLT3	3	5	10	11
Interestingly , normal FLT3 ligand mediated FLT3 signaling leads to only weak phosphorylation of STAT5 in BaF/3 cells .	Interestingly, normal FLT3 ligand mediated FLT3 signaling leads to only weak phosphorylation of STAT5 in BaF/3 cells.	3	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	FLT3 ligand	FLT3 ligand	FLT3 ligand	FLT3	FLT3	FLT3	3	5	6	7
Using purified bone marrow progenitors , we showed that GM-CSF dominantly inhibits Flt3L driven pDC development from the lin - Flt3 + bone marrow compartment in vitro ( XREF_FIG ) .	Using purified bone marrow progenitors, we showed that GM-CSF dominantly inhibits Flt3L driven pDC development from the lin - Flt3 + bone marrow compartment in vitro (XREF_FIG).	11	28	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Flt3L	Flt3L	Flt3L	Flt3	Flt3	Flt3	12	13	20	21
In vivo treatment of FLT3L CAR-T cells could significantly prolong the survival of FLT3 + mouse model .	In vivo treatment of FLT3L CAR-T cells could significantly prolong the survival of FLT3 + mouse model.	4	16	prolong	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3L	FLT3L	FLT3L	FLT3	FLT3	FLT3	4	5	13	14
We observed a strong association between FYN and wild-type FLT3 which was enhanced by FLT3 ligand ( FL ) stimulation .	We observed a strong association between FYN and wild-type FLT3 which was enhanced by FLT3 ligand (FL) stimulation.	4	17	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FLT3 ligand	FLT3 ligand	FLT3 ligand	FLT3	FLT3	FLT3	14	16	9	10
With the observations in BA/F3 cells and our recent findings which linked Akt activity to N-CoR loss ( Nin et al , submitted manuscript ) , we hypothesized that Flt3 activation by the Flt3 ligand might have potentiated the effects of N-CoR loss , thus amplifying the growth advantage in AML-M5 .	With the observations in BA/F3 cells and our recent findings which linked Akt activity to N-CoR loss (Nin et al, submitted manuscript), we hypothesized that Flt3 activation by the Flt3 ligand might have potentiated the effects of N-CoR loss, thus amplifying the growth advantage in AML-M5.	29	35	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Flt3 ligand	Flt3 ligand	Flt3 ligand	Flt3	Flt3	Flt3	33	35	29	30
ERK activity increases the expression of transcription factor c-Fos and also phosphorylates c-Fos , leading to its dimerization with c-Jun to form the transcription factor AP-1 .	ERK activity increases the expression of transcription factor c-Fos and also phosphorylates c-Fos, leading to its dimerization with c-Jun to form the transcription factor AP-1.	0	26	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Fos	ERK activity increases the expression of transcription factor c-Fos and also phosphorylates c-Fos	c-fos	transcription factor AP-1	transcription factor AP-1	transcription factor ap-1	12	13	23	26
Furthermore , since c-Fos can activate transcription factor AP-1 , a link between OxLDL , AP-1 , miRNA-29b , and cardiovascular disease had been suggested .	Furthermore, since c-Fos can activate transcription factor AP-1, a link between OxLDL, AP-1, miRNA-29b, and cardiovascular disease had been suggested.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Fos	c-Fos	c-Fos	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	3	4	6	9
Previously , we found IL-7 induced c-Fos , c-Jun expression , and phosphorylation , promoted c-Fos and c and Jun heterodimer formation , and enhanced the activity of c-Fos and c-Jun .	Previously, we found IL-7 induced c-Fos, c-Jun expression, and phosphorylation, promoted c-Fos and c and Jun heterodimer formation, and enhanced the activity of c-Fos and c-Jun.	4	31	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Fos	IL-7 induced c-Fos, c-Jun expression, and phosphorylation	c-fos	c-Jun	c-Jun	c-jun	6	7	30	31
Compared with HI controls ( c-Fos = 30.37 +/-7.39 from cortical samples , 58.61 +/-3.64 from hippocampal samples ; c-Jun = 52.48 +/-14.23 from cortical samples , 35.55 +/-4.73 from hippocampal samples ) , there was a significant down-regulation of c-Fos and c-Jun expressions from cortical and hippocampal samples in rats treated with DIZ before ( c-Fos = 11.10 +/-4.64 from cortical samples , 4.82 +/-3.38 from hippocampal samples ; c-Jun = 19.01 +/-5.29 from cortical samples , 35.55 +/-4.73 from hippocampal samples ) or post- ( c-Fos = 18.81 +/-7.93 from cortical samples , 11.33 +/-7.05 from hippocampal samples ; c-Jun = 24.64 +/-10.01 from cortical samples , 19.75 +/-3.47 from hippocampal samples ) HI insults .	Compared with HI controls (c-Fos = 30.37 +/-7.39 from cortical samples, 58.61 +/-3.64 from hippocampal samples; c-Jun = 52.48 +/-14.23 from cortical samples, 35.55 +/-4.73 from hippocampal samples), there was a significant down-regulation of c-Fos and c-Jun expressions from cortical and hippocampal samples in rats treated with DIZ before (c-Fos = 11.10 +/-4.64 from cortical samples, 4.82 +/-3.38 from hippocampal samples; c-Jun = 19.01 +/-5.29 from cortical samples, 35.55 +/-4.73 from hippocampal samples) or post- (c-Fos = 18.81 +/-7.93 from cortical samples, 11.33 +/-7.05 from hippocampal samples; c-Jun = 24.64 +/-10.01 from cortical samples, 19.75 +/-3.47 from hippocampal samples) HI insults.	42	116	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	c-Fos	c-Fos	c-Fos	c-Jun	c-Jun	c-Jun	56	57	42	43
For example , co-expression of c-fos with c-jun , leading to c-fos : c and jun dimer formation , enhances the transforming capacity of c-jun , whereas pairing c-jun with junB inhibits c-jun transforming capacity .	For example, co-expression of c-fos with c-jun, leading to c-fos : c and jun dimer formation, enhances the transforming capacity of c-jun, whereas pairing c-jun with junB inhibits c-jun transforming capacity.	3	25	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-fos	co-expression of c-fos	c-fos	c-jun	c-jun	c-jun	5	6	24	25
H. pylori strains that do not express CagA or that are mutated in cag genes encoded by the CagI pathogenicity island do not induce activator protein 1 , MAP kinase activity , or c-fos or c-jun activation .	H. pylori strains that do not express CagA or that are mutated in cag genes encoded by the CagI pathogenicity island do not induce activator protein 1, MAP kinase activity, or c-fos or c-jun activation.	23	36	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-fos	c-fos	c-fos	activator protein 1	activator protein 1	activator protein 1	33	34	24	27
For example , coexpression of c-fos with c-jun , leading to c-fos : c and jun dimer formation , enhances the transforming capacity of c-jun , whereas pairing c-jun with junB inhibits c-jun transforming capacity [ XREF_BIBR - XREF_BIBR ] .	For example, coexpression of c-fos with c-jun, leading to c-fos : c and jun dimer formation, enhances the transforming capacity of c-jun, whereas pairing c-jun with junB inhibits c-jun transforming capacity [XREF_BIBR - XREF_BIBR].	3	25	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-fos	coexpression of c-fos	c-fos	c-jun	c-jun	c-jun	5	6	24	25
Among the immediate-early response genes , expression of c-Jun and c-Fos is induced to form the transcription factor AP-1 that regulates transcription of genes implicated in cell proliferation or differentiation .	Among the immediate-early response genes, expression of c-Jun and c-Fos is induced to form the transcription factor AP-1 that regulates transcription of genes implicated in cell proliferation or differentiation.	6	22	induced	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	c-Fos	expression of c-Jun and c-Fos	c-fos	transcription factor AP-1	transcription factor AP-1 that regulates transcription	transcription factor ap-1	10	11	16	19
In particular , the RANKL-RANK interaction stimulates several transcription factors and MAP kinases , induces the expression of c-Fos family members , and promotes the nuclear translocation of both Jun proteins and NFATc1 [ XREF_BIBR ] .	In particular, the RANKL-RANK interaction stimulates several transcription factors and MAP kinases, induces the expression of c-Fos family members, and promotes the nuclear translocation of both Jun proteins and NFATc1 [XREF_BIBR].	4	30	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Fos	RANKL-RANK interaction stimulates several transcription factors and MAP kinases, induces the expression of c-Fos	c-fos	Jun	Jun	jun	18	19	29	30
We further analyzed the activity of c-fos , c-jun , c-myb and nm23 which are described to be involved in c-myc transcriptional activation , c-jun and c-fos were not constitutively activated and can be excluded as regulators .	We further analyzed the activity of c-fos, c-jun, c-myb and nm23 which are described to be involved in c-myc transcriptional activation, c-jun and c-fos were not constitutively activated and can be excluded as regulators.	4	31	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-fos	c-fos	c-fos	c-jun	c-jun	c-jun	26	27	8	9
Upon dephosphorylation , FoxO transcription factors namely FoxO1 and FoxO3 translocate to the nucleus and upregulate MurF1 and MAFbx and Atrogin -1 21 .	Upon dephosphorylation, FoxO transcription factors namely FoxO1 and FoxO3 translocate to the nucleus and upregulate MurF1 and MAFbx and Atrogin -1 21.	3	20	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	MurF1	MurF1	MurF1	3	4	16	17
MuRF1 is upregulated by NF-kappaB- 20 , PGC-1alpha- 21 and FoxO dependent 22 mechanisms .	MuRF1 is upregulated by NF-kappaB- 20, PGC-1alpha- 21 and FoxO dependent 22 mechanisms.	0	11	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	MuRF1	MuRF1	MuRF1	10	11	0	1
More recently , the calcineurin variant CnAbeta1 was suggested to block the nuclear localization of Foxo protein and the expression of several Foxo targeted genes ( MuRF1 , Gadd45a , Pmaip1 , and atrogin ) in C2C12 myoblasts [ XREF_BIBR ] .	More recently, the calcineurin variant CnAbeta1 was suggested to block the nuclear localization of Foxo protein and the expression of several Foxo targeted genes (MuRF1, Gadd45a, Pmaip1, and atrogin) in C2C12 myoblasts [XREF_BIBR].	4	33	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Foxo	calcineurin variant CnAbeta1 was suggested to block the nuclear localization of Foxo protein and the expression of several Foxo	foxo	MuRF1	MuRF1	murf1	22	23	26	27
The FoxO family is necessary to activate the MURF-1 and antrogin-1 enzymes [ XREF_BIBR ] that act on the degradation pathway of the ubiquitin proteasome .	The FoxO family is necessary to activate the MURF-1 and antrogin-1 enzymes [XREF_BIBR] that act on the degradation pathway of the ubiquitin proteasome.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	MURF-1	MURF-1	MURF-1	1	2	8	9
For example , MUFAs and PUFAs have been reported to prevent palmitate induced reductions in insulin sensitivity as well as conveying anti-inflammatory effects in skeletal muscle cells.55 , 62 , 63 Indeed , NF-kB dependent transcriptional regulation has been implicated in promoting disuse muscle atrophy in rat soleus muscle by increasing FoxO mediated activation of the MuRF1 promoter.64 Moreover , a recent study demonstrated that diminished anabolic signalling in skeletal muscle of aged mice coincided with the accumulation of intramuscular ceramide and DAG , as well as increased TNF-alpha mRNA abundance.65 Interestingly , feeding fish oil to weaning piglets , which resulted in the enrichment of EPA , DHA , and total omega-3 PUFA content within gastrocnemius muscle , coincided with a reduction in muscle TNF-alpha levels and reduced expression of Toll like receptor 4 ( TLR4 ) , a target receptor for saturated fatty acids which stimulates pro inflammatory signalling in response to its activation.66 Notably , TLR4 stimulation by its ligand lipopolysaccharide has been reported to induce muscle catabolism in C2C12 myotubes through activation of the ubiquitin-proteasome and autophagy-lysosome pathways.67 In addition , DHA treatment of human muscle cells co-cultured with macrophages has been shown to attenuate macrophage induced protein content of Fn14 , a positive modulator of MuRF-1 expression.68 , 69 Therefore , based on these findings , it is conceivable that the reported anti-inflammatory actions of unsaturated fatty acids in skeletal muscle cells may contribute , at least in part , to their ability to preserve muscle mass and/or function .	For example, MUFAs and PUFAs have been reported to prevent palmitate induced reductions in insulin sensitivity as well as conveying anti-inflammatory effects in skeletal muscle cells.55, 62, 63 Indeed, NF-kB dependent transcriptional regulation has been implicated in promoting disuse muscle atrophy in rat soleus muscle by increasing FoxO mediated activation of the MuRF1 promoter.64 Moreover, a recent study demonstrated that diminished anabolic signalling in skeletal muscle of aged mice coincided with the accumulation of intramuscular ceramide and DAG, as well as increased TNF-alpha mRNA abundance.65 Interestingly, feeding fish oil to weaning piglets, which resulted in the enrichment of EPA, DHA, and total omega-3 PUFA content within gastrocnemius muscle, coincided with a reduction in muscle TNF-alpha levels and reduced expression of Toll like receptor 4 (TLR4), a target receptor for saturated fatty acids which stimulates pro inflammatory signalling in response to its activation.66 Notably, TLR4 stimulation by its ligand lipopolysaccharide has been reported to induce muscle catabolism in C2C12 myotubes through activation of the ubiquitin-proteasome and autophagy-lysosome pathways.67 In addition, DHA treatment of human muscle cells co-cultured with macrophages has been shown to attenuate macrophage induced protein content of Fn14, a positive modulator of MuRF-1 expression.68, 69 Therefore, based on these findings, it is conceivable that the reported anti-inflammatory actions of unsaturated fatty acids in skeletal muscle cells may contribute, at least in part, to their ability to preserve muscle mass and/or function.	51	251	mediated	Positive_early_activation	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	MuRF1	MuRF1	MuRF1	51	52	56	57
Somewhat surprisingly although MAFbx appeared to have a role in muscle atrophy in previous studies XREF_BIBR , XREF_BIBR , in the present study , the mRNA and protein levels of MAFbx were unaffected by HMB ( data not shown ) , presumably because MAFbx is not directly regulated by glucocorticoid receptor , whereas MuRF1 is directly regulated by glucocorticoid receptor and FoxO XREF_BIBR .	Somewhat surprisingly although MAFbx appeared to have a role in muscle atrophy in previous studies XREF_BIBR, XREF_BIBR, in the present study, the mRNA and protein levels of MAFbx were unaffected by HMB (data not shown), presumably because MAFbx is not directly regulated by glucocorticoid receptor, whereas MuRF1 is directly regulated by glucocorticoid receptor and FoxO XREF_BIBR.	53	62	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FoxO	FoxO	FoxO	MuRF1	MuRF1	MuRF1	61	62	53	54
Aberrant overexpression of wild-type FLT3 in infant MLL-r and hyperdiploid ALL can cause constitutive FLT3 activation ; therefore , lestaurtinib was next investigated in cell lines and primary patient samples with these lesions .	Aberrant overexpression of wild-type FLT3 in infant MLL-r and hyperdiploid ALL can cause constitutive FLT3 activation; therefore, lestaurtinib was next investigated in cell lines and primary patient samples with these lesions.	1	15	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	overexpression of wild-type FLT3	flt3	FLT3	FLT3	flt3	4	5	14	15
The precise pattern of expression of FLT3 by HSC and HPC and the roles of FL in normal hematopoiesis are critical to a better understanding of AML subtypes , the process of disease progression , as well as for the development of therapeutic strategies to target FLT3 mutated AML .	The precise pattern of expression of FLT3 by HSC and HPC and the roles of FL in normal hematopoiesis are critical to a better understanding of AML subtypes, the process of disease progression, as well as for the development of therapeutic strategies to target FLT3 mutated AML.	4	47	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	expression of FLT3	flt3	FLT3	FLT3	flt3	6	7	46	47
Of note , altered FLT3 mRNA expression also seems to contribute to the TKI mediated increase in surface FLT3 that has been demonstrated in FLT3-TKI-resistant cells , XREF_BIBR , XREF_BIBR pointing toward a feedback response mechanism to compensate the lack of mature FLT3 receptor in the FLT3 mutated cellular setting .	Of note, altered FLT3 mRNA expression also seems to contribute to the TKI mediated increase in surface FLT3 that has been demonstrated in FLT3-TKI-resistant cells, XREF_BIBR, XREF_BIBR pointing toward a feedback response mechanism to compensate the lack of mature FLT3 receptor in the FLT3 mutated cellular setting.	4	19	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	FLT3 mRNA expression	flt3	FLT3	FLT3	flt3	4	5	18	19
Furthermore , Axl-Fc diminished FL induced FLT3 phosphorylation and impeded the physical interaction between Axl and FLT3 in CD34 + HPCs .	Furthermore, Axl-Fc diminished FL induced FLT3 phosphorylation and impeded the physical interaction between Axl and FLT3 in CD34 + HPCs.	2	20	impeded	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FLT3	Axl-Fc diminished FL induced FLT3 phosphorylation	flt3	FLT3	FLT3	flt3	6	7	16	17
FLT3 related pathways were activated in AML by ITD mutations or the overexpression of FLT3 .	FLT3 related pathways were activated in AML by ITD mutations or the overexpression of FLT3.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FLT3	overexpression of FLT3	flt3	FLT3	FLT3	flt3	14	15	0	1
The FLT3 signal resulted from expression on the leukemic blasts , and was not caused by increased FLT3 expression on normal CD34+ stem and progenitor cells in the leukemic samples .	The FLT3 signal resulted from expression on the leukemic blasts, and was not caused by increased FLT3 expression on normal CD34+ stem and progenitor cells in the leukemic samples.	1	19	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FLT3	FLT3 expression	flt3	FLT3	FLT3	flt3	17	18	1	2
Compared with litters from LPS treated animals , which exhibited a mean of ~ 40 % FGR ( XREF_FIG ) , treatment with Eta completely prevented LPS induced FGR , indicating that TNF may be a key cytokine in the pathogenesis of inflammation induced FGR ( XREF_FIG ) .	Compared with litters from LPS treated animals, which exhibited a mean of ~ 40% FGR (XREF_FIG), treatment with Eta completely prevented LPS induced FGR, indicating that TNF may be a key cytokine in the pathogenesis of inflammation induced FGR (XREF_FIG).	26	46	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGR	LPS induced FGR	fgr	FGR	FGR	fgr	28	29	44	45
FLT1 hypermethylation causing alterations of FLT1 function could serve as a useful biomarker for predicting changes in FLT1 status in RCCs .	FLT1 hypermethylation causing alterations of FLT1 function could serve as a useful biomarker for predicting changes in FLT1 status in RCCs.	0	6	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT1	FLT1 hypermethylation	flt1	FLT1	FLT1	flt1	0	1	5	6
Transfection of ETS-1 siRNA in HUVECs reduced both ETS-1 ( P < 0.01 ) and VEGFR1 transcription ( P < 0.05 ) , and induced measureable decrease of ETS-1 and VEGFR1 protein .	Transfection of ETS-1 siRNA in HUVECs reduced both ETS-1 (P < 0.01) and VEGFR1 transcription (P < 0.05), and induced measureable decrease of ETS-1 and VEGFR1 protein.	2	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFR1	ETS-1 siRNA in HUVECs reduced both ETS-1 (P < 0.01) and VEGFR1 transcription	vegfr1	VEGFR1	VEGFR1	vegfr1	15	16	30	31
First , forced miR-200 expression suppressed Flt1 levels in a metastasis-prone lung adenocarcinoma cell line and negatively regulated the Flt1 3 '-UTR in reporter assays .	First, forced miR-200 expression suppressed Flt1 levels in a metastasis-prone lung adenocarcinoma cell line and negatively regulated the Flt1 3 '-UTR in reporter assays.	3	21	negatively regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Flt1	miR-200 expression suppressed Flt1 levels	flt1	Flt1	Flt1	flt1	6	7	19	20
To further characterize small molecule 1 and its specificity , we used two model systems of breast cancer : BT474 breast cancer cells with high endogenous expression of VEGFR-3 that we previously used to assess the FAK-VEGFR-3 interaction XREF_BIBR , and MCF7 breast cancer cells with undetectable endogenous VEGFR-3 expression that were engineered to overexpress VEGFR-3 ( XREF_SUPPLEMENTARY ) .	To further characterize small molecule 1 and its specificity, we used two model systems of breast cancer : BT474 breast cancer cells with high endogenous expression of VEGFR-3 that we previously used to assess the FAK-VEGFR-3 interaction XREF_BIBR, and MCF7 breast cancer cells with undetectable endogenous VEGFR-3 expression that were engineered to overexpress VEGFR-3 (XREF_SUPPLEMENTARY).	48	56	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR-3	VEGFR-3 expression	vegfr-3	VEGFR-3	VEGFR-3	vegfr-3	48	49	55	56
VEGF-C or VEGF-D binding to VEGFR3 stimulates tyrosine kinase activation and phosphorylation of VEGFR3 cytoplasmic domain residues Tyr 830 , Tyr 833 , Tyr 853 , Tyr 1063 , Tyr 1068 , Tyr 1230 , Tyr 1231 , Tyr 1265 , Tyr 1333 , Tyr 1337 and Tyr 1363 ( XREF_FIG ) [ XREF_BIBR ] .	VEGF-C or VEGF-D binding to VEGFR3 stimulates tyrosine kinase activation and phosphorylation of VEGFR3 cytoplasmic domain residues Tyr 830, Tyr 833, Tyr 853, Tyr 1063, Tyr 1068, Tyr 1230, Tyr 1231, Tyr 1265, Tyr 1333, Tyr 1337 and Tyr 1363 (XREF_FIG) [XREF_BIBR].	9	19	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	VEGFR3	phosphorylation of VEGFR3 cytoplasmic domain residues Tyr 830	vegfr3	VEGFR3	VEGFR3	vegfr3	13	14	13	14
This study demonstrated that PS-A at the concentration of IC 50migration markedly reduces VEGFR-3 expression and inhibits the activation of VEGFR-3 signaling , indicating that PS-A may have the potential to prevent the progression of human malignancies .	This study demonstrated that PS-A at the concentration of IC 50migration markedly reduces VEGFR-3 expression and inhibits the activation of VEGFR-3 signaling, indicating that PS-A may have the potential to prevent the progression of human malignancies.	4	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFR-3	PS-A at the concentration of IC 50migration markedly reduces VEGFR-3 expression	vegfr-3	VEGFR-3	VEGFR-3	vegfr-3	13	14	20	21
Reciprocally , FHL2 is able to modulate AR signaling by altering the effect of Aryl hydrocarbon receptor ( AhR ) imposing AR activity .	Reciprocally, FHL2 is able to modulate AR signaling by altering the effect of Aryl hydrocarbon receptor (AhR) imposing AR activity.	2	8	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FHL2	FHL2	FHL2	AR	AR	AR	2	3	7	8
In an agonist- and AF-2-dependent manner FHL2 selectively increases the transcriptional activity of the AR , but not that of any other nuclear receptor .	In an agonist- and AF-2-dependent manner FHL2 selectively increases the transcriptional activity of the AR, but not that of any other nuclear receptor.	6	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FHL2	FHL2	FHL2	AR	AR	AR	6	7	14	15
In prostate cancer , FHL2 acts as a coactivator , shifts to the nucleus and subsequently activates FHL2- and androgen receptor dependent genes [ XREF_BIBR ] .	In prostate cancer, FHL2 acts as a coactivator, shifts to the nucleus and subsequently activates FHL2- and androgen receptor dependent genes [XREF_BIBR].	4	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FHL2	FHL2	FHL2	androgen receptor	androgen receptor	androgen receptor	4	5	19	21
FHL2 also increases transcriptional activity of androgen receptor ( AR ) XREF_BIBR , which is important in regulation of bone formation and resorption XREF_BIBR , XREF_BIBR .	FHL2 also increases transcriptional activity of androgen receptor (AR) XREF_BIBR, which is important in regulation of bone formation and resorption XREF_BIBR, XREF_BIBR.	0	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FHL2	FHL2	FHL2	androgen receptor	androgen receptor	androgen receptor	0	1	6	8
As a coactivator of AR , FHL2 in turn robustly stimulates the AR activity that is critical for prostate cancer progression XREF_BIBR , XREF_BIBR .	As a coactivator of AR, FHL2 in turn robustly stimulates the AR activity that is critical for prostate cancer progression XREF_BIBR, XREF_BIBR.	6	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FHL2	FHL2	FHL2	AR	AR	AR	6	7	12	13
PELP1 knockdown by small interfering RNA or PELP1 mutant , which lacks an activation domain , reduced FHL2 mediated AR transactivation .	PELP1 knockdown by small interfering RNA or PELP1 mutant, which lacks an activation domain, reduced FHL2 mediated AR transactivation.	16	20	mediated	Positive_early_activation	Positive_activation	Negative_activation	FHL2	FHL2	FHL2	AR	AR	AR	17	18	19	20
PELP1 interacted with AR and enhanced FHL2 mediated AR transactivation functions .	PELP1 interacted with AR and enhanced FHL2 mediated AR transactivation functions.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	FHL2	FHL2	FHL2	AR	AR	AR	6	7	8	9
FHL2 may have dual roles , acting both as an adaptor protein as well as a transcription coactivator and selectively increases the transcriptional activity of the androgen receptor .	FHL2 may have dual roles, acting both as an adaptor protein as well as a transcription coactivator and selectively increases the transcriptional activity of the androgen receptor.	0	28	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FHL2	FHL2	FHL2	androgen receptor	androgen receptor	androgen receptor	0	1	26	28
RNA-seq data suggest that FGFR4 is the most significant gene that was affected by HNK treatment and FGFR4 is known to mediate STAT3 signaling pathway .	RNA-seq data suggest that FGFR4 is the most significant gene that was affected by HNK treatment and FGFR4 is known to mediate STAT3 signaling pathway.	17	24	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR4	FGFR4	FGFR4	STAT3	STAT3	STAT3	17	18	22	23
Using Fgfr4 single nucleotide polymorphism knock-in mice and transgenic mouse models for breast and lung cancers , we validate the enhanced STAT3 signalling induced by the FGFR4 Arg388-variant in vivo .	Using Fgfr4 single nucleotide polymorphism knock-in mice and transgenic mouse models for breast and lung cancers, we validate the enhanced STAT3 signalling induced by the FGFR4 Arg388-variant in vivo.	21	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FGFR4	FGFR4	FGFR4	STAT3	STAT3	STAT3	26	27	21	22
Overexpression of this FGFR4 variant caused STAT3 overactivation .	Overexpression of this FGFR4 variant caused STAT3 overactivation.	0	7	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR4	Overexpression of this FGFR4	fgfr4	STAT3	STAT3	stat3	3	4	6	7
FGFR4 , along with FGFR1 and FGFR3 , has been shown to modulate the activity of STAT3 , and in pituitary tumours the polymorphic FGFR4 G388R variant mediates pituitary oncogenesis through activation of STAT3 , but not the MAPK pathway .	FGFR4, along with FGFR1 and FGFR3, has been shown to modulate the activity of STAT3, and in pituitary tumours the polymorphic FGFR4 G388R variant mediates pituitary oncogenesis through activation of STAT3, but not the MAPK pathway.	0	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR4	FGFR4	FGFR4	STAT3	STAT3	STAT3	0	1	16	17
Here , we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro oncogenic effects in NSCLC in vitro and in vivo .	Here, we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro oncogenic effects in NSCLC in vitro and in vivo.	6	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR4	FGFR4	FGFR4	STAT3	STAT3	STAT3	6	7	11	12
29 FGFR4 silencing downregulates the anti-apoptotic proteins c-FLIP and Bcl-2 and reduces STAT3 activity in colon cancer cells .	29 FGFR4 silencing downregulates the anti-apoptotic proteins c-FLIP and Bcl-2 and reduces STAT3 activity in colon cancer cells.	1	13	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR4	FGFR4	FGFR4	STAT3	STAT3	STAT3	1	2	12	13
This activation of Stat5a by Flt3 was also observed in COS-7 cells cotransfected with Flt3 receptor and Stat5 expression vectors .	This activation of Stat5a by Flt3 was also observed in COS-7 cells cotransfected with Flt3 receptor and Stat5 expression vectors.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Flt3	Flt3	Flt3	Stat5a	Stat5a	Stat5a	5	6	3	4
These results confirmed that Flt3 preferentially activated Stat5a .	These results confirmed that Flt3 preferentially activated Stat5a.	4	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Flt3	Flt3	Flt3	Stat5a	Stat5a	Stat5a	4	5	7	8
Our data show that FL stimulation of wild-type Flt3 preferentially activates Stat5a , and our in vivo data strongly suggest that Stat5a , but not Stat5b , plays a critical and potentially physiological role in mediating the synergistic effects of FL.	Our data show that FL stimulation of wild-type Flt3 preferentially activates Stat5a, and our in vivo data strongly suggest that Stat5a, but not Stat5b, plays a critical and potentially physiological role in mediating the synergistic effects of FL.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Flt3	Flt3	Flt3	Stat5a	Stat5a	Stat5a	8	9	11	12
In addition , Flt3 has been shown to activate Stat3 [ XREF_BIBR , XREF_BIBR ] and Stat5a [ XREF_BIBR ] signaling mediators .	In addition, Flt3 has been shown to activate Stat3 [XREF_BIBR, XREF_BIBR] and Stat5a [XREF_BIBR] signaling mediators.	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Flt3	Flt3	Flt3	Stat5a	Stat5a	Stat5a	3	4	16	17
We found that , unlike most RTKs , Flt3 potently activates only Stat5a without activation of any Jaks .	We found that, unlike most RTKs, Flt3 potently activates only Stat5a without activation of any Jaks.	8	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Flt3	Flt3	Flt3	Stat5a	Stat5a	Stat5a	8	9	12	13
Therefore , to examine the role played by Sdc4 in PCP signaling , we investigated whether FN stimulation of Sdc4 facilitates Fzd7 dependent Rac1 activation .	Therefore, to examine the role played by Sdc4 in PCP signaling, we investigated whether FN stimulation of Sdc4 facilitates Fzd7 dependent Rac1 activation.	16	20	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FN	FN	FN	Sdc4	Sdc4	Sdc4	16	17	19	20
We hypothesized that RhoG might also trigger integrin endocytosis upon engagement of syndecan-4 by fibronectin .	We hypothesized that RhoG might also trigger integrin endocytosis upon engagement of syndecan-4 by fibronectin.	6	15	trigger	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	fibronectin	fibronectin	fibronectin	syndecan-4	syndecan-4	syndecan-4	14	15	12	13
The effects of Sdc4 on RhoA activity after Sdc4 stimulation by fibronectin are summarized in XREF_FIG .	The effects of Sdc4 on RhoA activity after Sdc4 stimulation by fibronectin are summarized in XREF_FIG.	8	12	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	fibronectin	fibronectin	fibronectin	Sdc4	Sdc4	Sdc4	11	12	8	9
Fli-1 overexpression in these cells induces changes in the expression of key hematopoietic TFs such as SCL and TAL1 , GATA-1 , RUNX1 that may promote properties of self-renewal and favor the transition to a more immature erythroid phenotype .	Fli-1 overexpression in these cells induces changes in the expression of key hematopoietic TFs such as SCL and TAL1, GATA-1, RUNX1 that may promote properties of self-renewal and favor the transition to a more immature erythroid phenotype.	0	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fli-1	Fli-1 overexpression	fli-1	GATA-1	GATA-1	gata-1	0	1	20	21
Unexpectedly , FLI-1 enhances the stimulating activity of GATA-1 on a GATA-1-responsive promoter but represses that of EKLF on beta-globin and an EKLF responsive artificial promoters .	Unexpectedly, FLI-1 enhances the stimulating activity of GATA-1 on a GATA-1-responsive promoter but represses that of EKLF on beta-globin and an EKLF responsive artificial promoters.	2	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLI-1	FLI-1	FLI-1	GATA-1	GATA-1	GATA-1	2	3	8	9
Binding sites for Gata1 and Fli1 can be found in the enhancers of many megakaryocyte specific genes XREF_BIBR , and Fli1 enhances the activity of Gata1 at megakaryocytic promoters and represses the activity of erythroid factors at erythroid promoters XREF_BIBR .	Binding sites for Gata1 and Fli1 can be found in the enhancers of many megakaryocyte specific genes XREF_BIBR, and Fli1 enhances the activity of Gata1 at megakaryocytic promoters and represses the activity of erythroid factors at erythroid promoters XREF_BIBR.	20	30	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fli1	Fli1	Fli1	Gata1	Gata1	Gata1	20	21	25	26
In addition , a recent study has shown that FOXP2 sumoylation modulates transcriptional activity of FOXP2 in regulating target genes such as DISC1 , SRPX2 and MIR200C .	In addition, a recent study has shown that FOXP2 sumoylation modulates transcriptional activity of FOXP2 in regulating target genes such as DISC1, SRPX2 and MIR200C.	9	16	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FOXP2	FOXP2 sumoylation	foxp2	FOXP2	FOXP2	foxp2	9	10	15	16
Noticeably , the SUMOylation of the murine Foxp2 had been previously hypothesized to promote the dissociation of the Foxp2 dimer from its target promoter , leading to an overall reduction of Foxp2 transcription suppressive activity [ XREF_BIBR ] .	Noticeably, the SUMOylation of the murine Foxp2 had been previously hypothesized to promote the dissociation of the Foxp2 dimer from its target promoter, leading to an overall reduction of Foxp2 transcription suppressive activity [XREF_BIBR].	3	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Foxp2	SUMOylation of the murine Foxp2	foxp2	Foxp2	Foxp2	foxp2	7	8	18	19
Thus we have shown that FoxO3a dependent modulation of GILZ represents an entirely novel mechanism through which MIF can influence glucocorticoid sensitivity .	Thus we have shown that FoxO3a dependent modulation of GILZ represents an entirely novel mechanism through which MIF can influence glucocorticoid sensitivity.	5	10	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FoxO3a	FoxO3a	FoxO3a	GILZ	GILZ	GILZ	5	6	9	10
Active nuclear FOXO3A induces GILZ , which in turn negatively regulates its own expression by promoting the nuclear exclusion of FOXO3A XREF_BIBR XREF_BIBR .	Active nuclear FOXO3A induces GILZ, which in turn negatively regulates its own expression by promoting the nuclear exclusion of FOXO3A XREF_BIBR XREF_BIBR.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FOXO3A	FOXO3A	FOXO3A	GILZ	GILZ	GILZ	2	3	4	5
FoxH1 mediates a Grg4 and Smad2 dependent transcriptional switch in Nodal signaling during Xenopus mesoderm development .	FoxH1 mediates a Grg4 and Smad2 dependent transcriptional switch in Nodal signaling during Xenopus mesoderm development.	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxH1	FoxH1	FoxH1	Smad2	Smad2	Smad2	0	1	5	6
Shp2 is constitutively activated by internal tandem duplications of FLT3 , and the incidence of such mutation is increased Hox overexpressing AML [ XREF_BIBR , XREF_BIBR ] .	Shp2 is constitutively activated by internal tandem duplications of FLT3, and the incidence of such mutation is increased Hox overexpressing AML [XREF_BIBR, XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FLT3	FLT3	FLT3	Shp2	Shp2	Shp2	9	10	0	1
Also , both FN and LM supported activation of ERK1 and ERK2 in response to PDGF and bFGF .	Also, both FN and LM supported activation of ERK1 and ERK2 in response to PDGF and bFGF.	2	11	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FN	FN	FN	ERK1	ERK1	ERK1	3	4	9	10
It should also be noted that Fhit expression can enhance the effects of the p53 tumor suppressor [ XREF_BIBR ] by modulating p53 regulated genes [ XREF_BIBR ] .	It should also be noted that Fhit expression can enhance the effects of the p53 tumor suppressor [XREF_BIBR] by modulating p53 regulated genes [XREF_BIBR].	6	24	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fhit	Fhit expression	fhit	p53	p53	p53	6	7	22	23
Among Fyn mediated NR2B tyrosine phosphorylation sites , Y1472 has been studied the most extensively .	Among Fyn mediated NR2B tyrosine phosphorylation sites, Y1472 has been studied the most extensively.	0	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	NR2B	NR2B	NR2B	1	2	3	4
Fyn may lead to increased calpain activity by upregulating NR2B receptor activity via tyrosine phosphorylation .	Fyn may lead to increased calpain activity by upregulating NR2B receptor activity via tyrosine phosphorylation.	0	11	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	NR2B	NR2B	NR2B	0	1	9	10
Both the tyrosine kinase Fyn and the tyrosine phosphatase striatal enriched protein tyrosine phosphatase ( STEP ) are known to target the NMDA receptor subunit GluN2B on tyrosine 1472 , which is a critical residue that mediates NMDAR endocytosis .	Both the tyrosine kinase Fyn and the tyrosine phosphatase striatal enriched protein tyrosine phosphatase (STEP) are known to target the NMDA receptor subunit GluN2B on tyrosine 1472, which is a critical residue that mediates NMDAR endocytosis.	0	26	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	GluN2B	GluN2B	GluN2B	4	5	25	26
Although Fyn and calpain are active intracellularly , and SAP102 and NR2B associate intracellularly , the Fyn mediated increase of NR2B cleavage by calpain is limited to cell surface receptors .	Although Fyn and calpain are active intracellularly, and SAP102 and NR2B associate intracellularly, the Fyn mediated increase of NR2B cleavage by calpain is limited to cell surface receptors.	16	21	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	NR2B	NR2B	NR2B	16	17	20	21
Fyn selectively modulates the function of GluN2B containing NMDARs , by phosphorylation of the GluN2B on the Y1472 epitope [ XREF_BIBR , XREF_BIBR ] .	Fyn selectively modulates the function of GluN2B containing NMDARs, by phosphorylation of the GluN2B on the Y1472 epitope [XREF_BIBR, XREF_BIBR].	0	7	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	GluN2B	GluN2B	GluN2B	0	1	6	7
Further , Reelin binding to its receptors results in phosphorylation of NMDA receptor subunits NR2A and NR2B which is mediated by DAB1 and SRC and FYN activation .	Further, Reelin binding to its receptors results in phosphorylation of NMDA receptor subunits NR2A and NR2B which is mediated by DAB1 and SRC and FYN activation.	7	26	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FYN	FYN	FYN	NR2B	NR2B	NR2B	25	26	16	17
XREF_BIBR found that phosphorylation of Y1336 by Fyn promotes calpain cleavage of NR2B in an in vitro glutamate toxicity model .	XREF_BIBR found that phosphorylation of Y1336 by Fyn promotes calpain cleavage of NR2B in an in vitro glutamate toxicity model.	3	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	phosphorylation of Y1336 by Fyn	fyn	NR2B	NR2B	nr2b	7	8	12	13
It was observed that NR2B p-Tyr1472 was increased by the activation of Fyn after 150-muM NMDA exposure .	It was observed that NR2B p-Tyr1472 was increased by the activation of Fyn after 150-muM NMDA exposure.	4	13	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	NR2B	NR2B	NR2B	12	13	4	5
The tyrosine kinase , Fyn , targets the GluN2B subunit of the NMDA receptor , and XREF_BIBR demonstrated that Fyn-kinase activity was a critical component of determining whether ethanol could inhibit the function of NMDA receptors .	The tyrosine kinase, Fyn, targets the GluN2B subunit of the NMDA receptor, and XREF_BIBR demonstrated that Fyn-kinase activity was a critical component of determining whether ethanol could inhibit the function of NMDA receptors.	2	9	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	GluN2B	GluN2B	GluN2B	4	5	8	9
Our results suggested that Fyn mediated NR2B signaling plays a critical role in regulation of prediabetic neuropathy and that the increased expression and function of NR2B subunit containing NMDARs may contribute to the progression of neuropathy in type 2 diabetes .	Our results suggested that Fyn mediated NR2B signaling plays a critical role in regulation of prediabetic neuropathy and that the increased expression and function of NR2B subunit containing NMDARs may contribute to the progression of neuropathy in type 2 diabetes.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	NR2B	NR2B	NR2B	4	5	6	7
In HEK cells , mutation of Tyr 1336 eliminates the potentiating effect of Fyn on calpain mediated NR2B cleavage .	In HEK cells, mutation of Tyr 1336 eliminates the potentiating effect of Fyn on calpain mediated NR2B cleavage.	11	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	NR2B	NR2B	NR2B	13	14	17	18
Concurrently , Fyn activates Cdk5 to phosphorylate collapsin response-mediator protein , to reduce microtubule assembly [ XREF_BIBR ] .	Concurrently, Fyn activates Cdk5 to phosphorylate collapsin response-mediator protein, to reduce microtubule assembly [XREF_BIBR].	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	Cdk5	Cdk5	Cdk5	2	3	4	5
The exact pathways by which PDGF activates migration of OPCs is unknown ; however activation of Cdk5 by Fyn followed by phosphorylation of WAVE2 , activation of the ERK pathway , increase of intracellular Ca 2+ levels and modulation of components of the cytoskeleton may be involved [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	The exact pathways by which PDGF activates migration of OPCs is unknown; however activation of Cdk5 by Fyn followed by phosphorylation of WAVE2, activation of the ERK pathway, increase of intracellular Ca 2+ levels and modulation of components of the cytoskeleton may be involved [XREF_BIBR, XREF_BIBR - XREF_BIBR].	14	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	Cdk5	Cdk5	Cdk5	18	19	16	17
CDK5 activity can be modulated by c-Abl kinase and Fyn kinase .	CDK5 activity can be modulated by c-Abl kinase and Fyn kinase.	0	10	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	CDK5	CDK5	CDK5	9	10	0	1
XREF_BIBR , XREF_BIBR Another Src-tyrosine kinase , Fyn , regulates the phosphorylation of CRMP1 , and , through a Sema3A- and plexinA2 dependent mechanism , activates Cdk5 , leading to growth cone collapse ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR Another Src-tyrosine kinase, Fyn, regulates the phosphorylation of CRMP1, and, through a Sema3A- and plexinA2 dependent mechanism, activates Cdk5, leading to growth cone collapse (XREF_FIG).	2	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	Cdk5	Cdk5	Cdk5	7	8	26	27
Thus , although it will be of interest to examine the effects of toxicant exposure on other Fyn targets , it currently seems that Fyn mediated activation of c-Cbl is central to understanding the effects of toxicants on O-2A and OPCs .	Thus, although it will be of interest to examine the effects of toxicant exposure on other Fyn targets, it currently seems that Fyn mediated activation of c-Cbl is central to understanding the effects of toxicants on O-2A and OPCs.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	c-Cbl	c-Cbl	c-Cbl	24	25	28	29
It is tempting to speculate that Fyn activates c-Cbl and that ubiquitinylation of ZAP-70 causes its exclusion from lipid rafts , preventing movement into the immune synapse where ZAP-70 can bind to CD3zeta .	It is tempting to speculate that Fyn activates c-Cbl and that ubiquitinylation of ZAP-70 causes its exclusion from lipid rafts, preventing movement into the immune synapse where ZAP-70 can bind to CD3zeta.	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	c-Cbl	c-Cbl	c-Cbl	6	7	8	9
Such a possibility is particularly intriguing in light of multiple reports that c-Cbl can be activated by Fyn kinase , a Src family kinase that can be activated by oxidative stress [ XREF_BIBR - XREF_BIBR ] .	Such a possibility is particularly intriguing in light of multiple reports that c-Cbl can be activated by Fyn kinase, a Src family kinase that can be activated by oxidative stress [XREF_BIBR - XREF_BIBR].	12	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	c-Cbl	c-Cbl	c-Cbl	17	18	12	13
Such a defect may be occurring at the early signaling synapse , in line with a recognized alteration of TCR signaling components , such as enhanced Fyn kinase activity , differential activation of the Cbl pathway , impairment of membrane translocation of Son of sevenless ( mSOS ) Ras GDP releasing factor , and the exclusion of mSOS and Phospholipase C ( PLC )-gamma1 from the TCR , Grb2 , and Zap70 complex , resulting in hypoactivation [ XREF_BIBR ] .	Such a defect may be occurring at the early signaling synapse, in line with a recognized alteration of TCR signaling components, such as enhanced Fyn kinase activity, differential activation of the Cbl pathway, impairment of membrane translocation of Son of sevenless (mSOS) Ras GDP releasing factor, and the exclusion of mSOS and Phospholipase C (PLC)-gamma1 from the TCR, Grb2, and Zap70 complex, resulting in hypoactivation [XREF_BIBR].	26	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	Cbl	Cbl	Cbl	26	27	34	35
This possibility seemed especially attractive since c-Cbl does not target TrkC and is activated by Fyn , an enzyme previously shown to be activated by oxidative stress .	This possibility seemed especially attractive since c-Cbl does n't target TrkC and is activated by Fyn, an enzyme previously shown to be activated by oxidative stress.	6	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	c-Cbl	c-Cbl	c-Cbl	15	16	6	7
This first step activates a pathway wherein Fyn activates c-Cbl , a ubiquitin ligase that plays a critical role in modulating degradation of a specific subset of receptor tyrosine kinases ( RTKs ) .	This first step activates a pathway wherein Fyn activates c-Cbl, a ubiquitin ligase that plays a critical role in modulating degradation of a specific subset of receptor tyrosine kinases (RTKs).	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	c-Cbl	c-Cbl	c-Cbl	7	8	9	10
Conversely , phosphorylation of c-Cbl on Y731 by Fyn allows c-Cbl to act as an adapter protein for phosphoinositide-3 kinase ( PI-3 kinase ) , thereby enhancing TCR signaling [ XREF_BIBR , XREF_BIBR ] .	Conversely, phosphorylation of c-Cbl on Y731 by Fyn allows c-Cbl to act as an adapter protein for phosphoinositide-3 kinase (PI-3 kinase), thereby enhancing TCR signaling [XREF_BIBR, XREF_BIBR].	6	12	allows	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	c-Cbl	c-Cbl	c-Cbl	8	9	10	11
Phosphorylation of Fyn at serine 21 is reported to activate Fyn kinase XREF_BIBR .	Phosphorylation of Fyn at serine 21 is reported to activate Fyn kinase XREF_BIBR.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Phosphorylation of Fyn at serine 21	fyn	Fyn	Fyn	fyn	2	3	10	11
The coexpression of Fyn with TOM1L increased the level of the phosphorylated form of Fyn indicating that TOM1L has the ability to activate Fyn .	The coexpression of Fyn with TOM1L increased the level of the phosphorylated form of Fyn indicating that TOM1L has the ability to activate Fyn.	1	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	coexpression of Fyn	fyn	Fyn	Fyn	fyn	3	4	14	15
However , it remains unclear whether the loss of Fyn causes a constant or increasing negative effect on dendritic spine density in the Fyn knockout mice beyond 1 year of age .	However, it remains unclear whether the loss of Fyn causes a constant or increasing negative effect on dendritic spine density in the Fyn knockout mice beyond 1 year of age.	7	25	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Fyn	loss of Fyn	fyn	Fyn	Fyn	fyn	9	10	23	24
PTPalpha knockout ( KO ) mice have increased phosphorylation of Fyn at its inhibitory site ( Y 531 ) and decreased Fyn activity .	PTPalpha knockout (KO) mice have increased phosphorylation of Fyn at its inhibitory site (Y 531) and decreased Fyn activity.	0	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fyn	PTPalpha knockout (KO) mice have increased phosphorylation of Fyn	fyn	Fyn	Fyn	fyn	10	11	21	22
Importantly either pretreatment did not modulate Fyn phosphorylation on its own ( data not shown ) .	Importantly either pretreatment did not modulate Fyn phosphorylation on its own (data not shown).	5	8	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn phosphorylation	fyn	Fyn	Fyn	fyn	6	7	6	7
Interestingly , Fyn KO mice have normal levels of pY NR2A , while Fyn OE mice have increased pY NR2A .	Interestingly, Fyn KO mice have normal levels of pY NR2A, while Fyn OE mice have increased pY NR2A.	13	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	NR2A	NR2A	NR2A	13	14	19	20
For instance , S1480 phosphorylation by CKII decreases Y1472 phosphorylation by Fyn , which underlies the switch from NR2B to NR2A at synapses during development [ XREF_BIBR ] .	For instance, S1480 phosphorylation by CKII decreases Y1472 phosphorylation by Fyn, which underlies the switch from NR2B to NR2A at synapses during development [XREF_BIBR].	7	22	underlies	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	NR2A	NR2A	NR2A	11	12	20	21
To investigate which kinase or kinase family is involved in regulation of Furin induced Notch-1 cleavage , several kinase inhibitors were tested .	To investigate which kinase or kinase family is involved in regulation of Furin induced Notch-1 cleavage, several kinase inhibitors were tested.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	Furin	Furin	Furin	Notch-1	Notch-1	Notch-1	12	13	14	15
To determine whether the GGCT like activity of Botch is required for the regulation of S1 cleavage of Notch1 , Flag-Notch1-EGFP ( Flag-N1-GFP ) was treated with furin in the presence or absence of Botch or Botch E115A .	To determine whether the GGCT like activity of Botch is required for the regulation of S1 cleavage of Notch1, Flag-Notch1-EGFP (Flag-N1-GFP) was treated with furin in the presence or absence of Botch or Botch E115A.	20	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	furin	furin	furin	Flag-Notch1-EGFP	Flag-Notch1-EGFP	Flag-Notch1-EGFP	27	28	20	21
Furin inhibition by siRNA increased pro Notch1 and decreased mature Notch1 , indicating the inhibition of Notch1 processing .	Furin inhibition by siRNA increased pro Notch1 and decreased mature Notch1, indicating the inhibition of Notch1 processing.	0	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Furin	Furin	Furin	Notch1	Notch1	Notch1	0	1	10	11
Furin can degrade Notch1 and produce NICD fragments , which function as transcription factor .	Furin can degrade Notch1 and produce NICD fragments, which function as transcription factor.	0	7	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Furin	Furin	Furin	NICD	NICD	NICD	0	1	6	7
In contrast , we have recently demonstrated that PI3K inhibitors do not alter activation of Rlk by Fyn , suggesting that the requirements for activation of Rlk by Src family kinases are distinct from the other Tec kinases .	In contrast, we have recently demonstrated that PI3K inhibitors do not alter activation of Rlk by Fyn, suggesting that the requirements for activation of Rlk by Src family kinases are distinct from the other Tec kinases.	12	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	Rlk	Rlk	Rlk	17	18	15	16
Because Fyn is able to target both PI ( 3 ) K and ADAP , it is able to control cytotoxicity and cytokine production in NK cells .	Because Fyn is able to target both PI (3) K and ADAP, it is able to control cytotoxicity and cytokine production in NK cells.	1	14	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	ADAP	ADAP	ADAP	1	2	13	14
This suggests that Fzd7 locally activates Rac1 to facilitate directed migration .	This suggests that Fzd7 locally activates Rac1 to facilitate directed migration.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fzd7	Fzd7	Fzd7	Rac1	Rac1	Rac1	3	4	6	7
SLAM engagement amplified PKC-theta recruitment in wt but not SAP- or Fyn deficient cells , arguing that a SAP and Fyn mediated pathway enhances PKC-theta and NF-kappaB 1 activation and suggesting a role for this pathway in T ( H ) 2 regulation .	SLAM engagement amplified PKC-theta recruitment in wt but not SAP- or Fyn deficient cells, arguing that a SAP and Fyn mediated pathway enhances PKC-theta and NF-kappaB 1 activation and suggesting a role for this pathway in T (H) 2 regulation.	20	28	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	PKC-theta	PKC-theta	PKC-theta	20	21	24	25
Previous studies have demonstrated that SLAM regulates Th2 cytokine production by triggering PKC-theta and that the CBM complex is downstream of PKC-theta , which is stimulated by Fyn in NK cells .	Previous studies have demonstrated that SLAM regulates Th2 cytokine production by triggering PKC-theta and that the CBM complex is downstream of PKC-theta, which is stimulated by Fyn in NK cells.	19	30	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	PKC-theta	PKC-theta	PKC-theta	27	28	21	22
In NK cells , SAP couples activated 2B4 to the kinase Fyn , which in turn activates Vav1 , while blocking the inhibitory phosphatase SHIP-1 from binding to 2B4 .	In NK cells, SAP couples activated 2B4 to the kinase Fyn, which in turn activates Vav1, while blocking the inhibitory phosphatase SHIP-1 from binding to 2B4.	6	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	Vav1	Vav1	Vav1	11	12	17	18
Previously , we had found that the phosphorylation of FRS2 induces association of FRS2 and growth factor receptor binding protein 2 ( Grb2 ) .	Previously, we had found that the phosphorylation of FRS2 induces association of FRS2 and growth factor receptor binding protein 2 (Grb2).	7	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FRS2	phosphorylation of FRS2	frs2	Grb2	Grb2	grb2	9	10	22	23
Enhancing the tyrosine phosphorylation of FRS2 increased the recruitment of Grb2 .	Enhancing the tyrosine phosphorylation of FRS2 increased the recruitment of Grb2.	0	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FRS2	phosphorylation of FRS2	frs2	Grb2	Grb2	grb2	5	6	10	11
2 Increased Srcasm expression in vivo suppresses epidermal hyperproliferation induced by over-expression of Fyn , an SFK , in transgenic mice .	2 Increased Srcasm expression in vivo suppresses epidermal hyperproliferation induced by over-expression of Fyn, an SFK, in transgenic mice.	0	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fyn	over-expression of Fyn	fyn	Srcasm	Srcasm	srcasm	13	14	2	3
Fyn protein levels can also be down-regulated by the Src activating and signaling molecule Srcasm , but since Srcasm does not influence Fyn mRNA levels , it can not account for regulation of Fyn by active Ras we observed .	Fyn protein levels can also be down-regulated by the Src activating and signaling molecule Srcasm, but since Srcasm does not influence Fyn mRNA levels, it can not account for regulation of Fyn by active Ras we observed.	0	15	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fyn	Fyn protein levels	fyn	Srcasm	Srcasm	srcasm	0	1	14	15
Second , tyrosine phosphorylation of FRS2 downstream from FGFR1 might activate the tyrosine phosphatase Shp2 and reduce TrkB signaling .	Second, tyrosine phosphorylation of FRS2 downstream from FGFR1 might activate the tyrosine phosphatase Shp2 and reduce TrkB signaling.	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FRS2	tyrosine phosphorylation of FRS2	frs2	Shp2	Shp2	shp2	5	6	14	15
PSD-95 associates with the last four amino acids of the GluN2B subunit , which are in close proximity to the Tyr 1472 residues targeted by Fyn .	PSD-95 associates with the last four amino acids of the GluN2B subunit, which are in close proximity to the Tyr 1472 residues targeted by Fyn.	0	26	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fyn	Fyn	Fyn	PSD-95	PSD-95	PSD-95	25	26	0	1
Expression of Fz4 in HEK293 cells increases recruitment of Dvl2 to the cell surface in a ligand independent manner [ XREF_BIBR ] .	Expression of Fz4 in HEK293 cells increases recruitment of Dvl2 to the cell surface in a ligand independent manner [XREF_BIBR].	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fz4	Expression of Fz4	fz4	Dvl2	Dvl2	dvl2	2	3	9	10
FZD8 activate Wnt and beta-catenin signaling in the presence of LRP6 and Wnt-3a in cancer , though there are few reports about its role and mechanism .	FZD8 activate Wnt and beta-catenin signaling in the presence of LRP6 and Wnt-3a in cancer, though there are few reports about its role and mechanism.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FZD8	FZD8	FZD8	LRP6	LRP6	LRP6	0	1	10	11
Therefore , it may well be that exclusive inhibition of the AXL and Gas6 axis , as it has been discussed for gliomas and other cancer types [ XREF_BIBR ] , might not suffice to prevent AXL activation in GBMs .	Therefore, it may well be that exclusive inhibition of the AXL and Gas6 axis, as it has been discussed for gliomas and other cancer types [XREF_BIBR], might not suffice to prevent AXL activation in GBMs.	11	37	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	AXL	AXL	AXL	13	14	36	37
Gas6 activates the tyrosine kinase Tyro3 receptor in neurons and Axl receptor in oligodendroglia and vascular cells , resulting in cytoprotection .	Gas6 activates the tyrosine kinase Tyro3 receptor in neurons and Axl receptor in oligodendroglia and vascular cells, resulting in cytoprotection.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	10	11
We have recently shown that warfarin exerts its anti-cancer effects by inhibiting Gas6 mediated Axl activation in PDA tumor cells .	We have recently shown that warfarin exerts its anti-cancer effects by inhibiting Gas6 mediated Axl activation in PDA tumor cells.	12	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	12	13	14	15
Short term treatment of recombinant human GAS6 ( 500 ng/ml for one hour ) did not induce AXL in the OCI-AML3 cells ( Online Supplementary Figure S10B ) .	Short term treatment of recombinant human GAS6 (500 ng/ml for one hour) did not induce AXL in the OCI-AML3 cells (Online Supplementary Figure S10B).	2	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	6	7	17	18
Furthermore , Gas6 stimulation of Axl in Hca-F cells resulted primarily in the down-regulation of Cyr61 , a member of the CCN protein family involved in tumor progression .	Furthermore, Gas6 stimulation of Axl in Hca-F cells resulted primarily in the down-regulation of Cyr61, a member of the CCN protein family involved in tumor progression.	2	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	2	3	5	6
Gas6 induced Axl and c-Src localization into lipid raft and caveolin-1-enriched fractions .	Gas6 induced Axl and c-Src localization into lipid raft and caveolin-1-enriched fractions.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	2	3
cDNA microarray analysis of 12,687 genes then revealed that Gas6 stimulation of Axl in Mel 290 cells results primarily in the down-regulation of Cyr61 , a member of the CCN protein family involved in tumor progression .	cDNA microarray analysis of 12,687 genes then revealed that Gas6 stimulation of Axl in Mel 290 cells results primarily in the down-regulation of Cyr61, a member of the CCN protein family involved in tumor progression.	9	16	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	9	10	12	13
Interactions between TAM RTKs and ligands have been investigated by various labs and it is now generally accepted that Gas6 activates Axl , Tyro3 , and MerTK , and that Protein S activates MerTK and Tyro3 .	Interactions between TAM RTKs and ligands have been investigated by various labs and it is now generally accepted that Gas6 activates Axl, Tyro3, and MerTK, and that Protein S activates MerTK and Tyro3.	19	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	19	20	21	22
Early experiments demonstrated that chimeric EGFR and Axl receptors could induce proliferation through Ras/Raf1/MEK-1/ERK1/2 and Gas6 stimulation of endogenous Axl was mitogenic in fibroblasts .	Early experiments demonstrated that chimeric EGFR and Axl receptors could induce proliferation through Ras/Raf1/MEK-1/ERK1/2 and Gas6 stimulation of endogenous Axl was mitogenic in fibroblasts.	15	20	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	15	16	19	20
In vitro assays , the proliferation , migration and invasion of WT cells decreased with Axl knockdown and significantly increased with Axl activation by Gas6 ( P < 0.05 ) .	In vitro assays, the proliferation, migration and invasion of WT cells decreased with Axl knockdown and significantly increased with Axl activation by Gas6 (P < 0.05).	19	26	increased	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	24	25	21	22
Silencing Gas6 in LCAF hTERT reduced the Axl activation and H1299 cell migration induced by CM from LCAF hTERT .	Silencing Gas6 in LCAF hTERT reduced the Axl activation and H1299 cell migration induced by CM from LCAF hTERT.	0	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	1	2	7	8
Gas6 activation of Axl in VSMC stimulates migration and inhibits apoptosis XREF_BIBR , XREF_BIBR .	Gas6 activation of Axl in VSMC stimulates migration and inhibits apoptosis XREF_BIBR, XREF_BIBR.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	3	4
These data demonstrate that the Gas6 stimulation of ovarian cancer cells activates RTK Axl .	These data demonstrate that the Gas6 stimulation of ovarian cancer cells activates RTK Axl.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	5	6	13	14
In cancer , AXL signaling can be activated by GAS6 in an autocrine or paracrine manner .	In cancer, AXL signaling can be activated by GAS6 in an autocrine or paracrine manner.	3	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	9	10	3	4
Gas6 mediated Axl dimerisation is likely to occur in two steps , with a high-affinity 1:1 Gas6 and Axl complex forming first .	Gas6 mediated Axl dimerisation is likely to occur in two steps, with a high-affinity 1:1 Gas6 and Axl complex forming first.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	2	3
Although EGFR activation promotes ACK1 turnover , Axl activation by GAS6 does not ; interestingly , the reciprocal down-regulation of GAS6 stimulated Axl is blocked by removing ACK1 .	Although EGFR activation promotes ACK1 turnover, Axl activation by GAS6 does not; interestingly, the reciprocal down-regulation of GAS6 stimulated Axl is blocked by removing ACK1.	18	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	20	21	22	23
GAS6 , through binding to AXL , activates AXL to control cellular growth or maintenance .	GAS6, through binding to AXL, activates AXL to control cellular growth or maintenance.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	0	1	8	9
Tyrosine autophosphorylation of Mer was stimulated by both Protein S and GAS-6 , but Axl could only be activated by GAS-6 ( XREF_FIG ) .	Tyrosine autophosphorylation of Mer was stimulated by both Protein S and GAS-6, but Axl could only be activated by GAS-6 (XREF_FIG).	14	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GAS-6	GAS-6	GAS-6	Axl	Axl	Axl	20	21	14	15
Since both AXL and MET are activated by heparan sulfate proteoglycans tethered ligands , GAS6 and HGF respectively , and both display directional chemotaxis in GnRH neurons , we postulated that their pathways may interact in GnRH neuronal cells .	Since both AXL and MET are activated by heparan sulfate proteoglycans tethered ligands, GAS6 and HGF respectively, and both display directional chemotaxis in GnRH neurons, we postulated that their pathways may interact in GnRH neuronal cells.	1	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	14	15	2	3
40 Even though AXL can be activated by Gas6 , alternative ligand independent mechanisms , including the interaction with EGFR , which is frequently express in TNBC , have been demonstrated .	40 Even though AXL can be activated by Gas6, alternative ligand independent mechanisms, including the interaction with EGFR, which is frequently express in TNBC, have been demonstrated.	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	AXL	AXL	AXL	8	9	3	4
Six major clusters indicating gains of autocrine pathway activation in mesenchymal like NSCLC models were observed : IL11 and IL6 mediated gp130-JAK activation ; Gas6 mediated Axl and Tyro3 activation ; fibronectin mediated alpha5beta1-integrin activation ; TGFbeta- and BMP1- mediated receptor signaling ; and autocrine FGFR and PDGFR networks were acquired in an EMT dependent manner .	Six major clusters indicating gains of autocrine pathway activation in mesenchymal like NSCLC models were observed : IL11 and IL6 mediated gp130-JAK activation; Gas6 mediated Axl and Tyro3 activation; fibronectin mediated alpha5beta1-integrin activation; TGFbeta- and BMP1- mediated receptor signaling; and autocrine FGFR and PDGFR networks were acquired in an EMT dependent manner.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	24	25	26	27
GAS6 downregulates expression of its receptor , Axl , and hypoxia is sufficient to prevent GAS6 mediated downregulation of Axl .	GAS6 downregulates expression of its receptor, Axl, and hypoxia is sufficient to prevent GAS6 mediated downregulation of Axl.	14	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	15	16	19	20
Furthermore , it has been shown that the presence of GAS6 activates the recycling of Axl receptors in the cell membrane [ XREF_BIBR ] .	Furthermore, it has been shown that the presence of GAS6 activates the recycling of Axl receptors in the cell membrane [XREF_BIBR].	8	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	10	11	15	16
We next found that luteolin abrogated Axl phosphorylation in response to growth arrest-specific6 ( Gas6 ) , its ligand , implying the inhibitory effect of luteolin on Gas6 induced Axl activation .	We next found that luteolin abrogated Axl phosphorylation in response to growth arrest-specific6 (Gas6), its ligand, implying the inhibitory effect of luteolin on Gas6 induced Axl activation.	20	30	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	27	28	29	30
DN10764 inhibited the GAS6 induced AXL signaling pathway .	DN10764 inhibited the GAS6 induced AXL signaling pathway.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	3	4	5	6
52 At a mechanistic level , Gas6 induced activation of Axl suppresses TLR and type I interferon ( IFN ) receptor JAK-STAT signaling by upregulating the expression of SOCS1 and SOCS3 , thereby turning off the expression of inflammatory cytokines including TNF-alpha , IL-1beta , and IFN-alpha .	52 At a mechanistic level, Gas6 induced activation of Axl suppresses TLR and type I interferon (IFN) receptor JAK-STAT signaling by upregulating the expression of SOCS1 and SOCS3, thereby turning off the expression of inflammatory cytokines including TNF-alpha, IL-1beta, and IFN-alpha.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	6	7	10	11
This is best illustrated in the case of Gas6 activation of Axl , which is uniquely dependent on Gas6 for activation .	This is best illustrated in the case of Gas6 activation of Axl, which is uniquely dependent on Gas6 for activation.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	8	9	11	12
We then evaluated the effect of BGB324 on Gas6 stimulated activity of Axl and Tyro3 in the GBM cell lines .	We then evaluated the effect of BGB324 on Gas6 stimulated activity of Axl and Tyro3 in the GBM cell lines.	2	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	8	9	12	13
In order to determine whether GAS6 regulates the expression of its receptor , Axl , PC3 and DU145 cells were treated with GAS6 at different time points following overnight serum starvation .	In order to determine whether GAS6 regulates the expression of its receptor, Axl, PC3 and DU145 cells were treated with GAS6 at different time points following overnight serum starvation.	11	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	22	23	13	14
Gas6 induced Axl signaling in presence of Sunitinib is also diversified displaying onset of Axl dependent EGFR and METR activation and activation of classical MAPK pathways .	Gas6 induced Axl signaling in presence of Sunitinib is also diversified displaying onset of Axl dependent EGFR and METR activation and activation of classical MAPK pathways.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	2	3
Gas6 has previously been shown to activate both Axl and Rse and Tyro3 , two other receptor tyrosine kinases in the same family as Mer .	Gas6 has previously been shown to activate both Axl and Rse and Tyro3, two other receptor tyrosine kinases in the same family as Mer.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	8	9
More importantly , 13 was evaluated for its ability to block GAS6 mediated activation of AXL in pancreatic cancer cells .	More importantly, 13 was evaluated for its ability to block GAS6 mediated activation of AXL in pancreatic cancer cells.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	11	12	15	16
These data clearly show , for the first time , that the Gas6 stimulated Axl signaling pathway is dependent on the adhesion of ovarian cancer cells to the ECM through the integrin beta3 .	These data clearly show, for the first time, that the Gas6 stimulated Axl signaling pathway is dependent on the adhesion of ovarian cancer cells to the ECM through the integrin beta3.	11	16	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	12	13	14	15
We speculate that during cellular stress , resulting in Gas6 activation of Axl , PI3 kinase can bind either YXXM site , and inhibit the binding of Grb2 to Axl at the YVN site .	We speculate that during cellular stress, resulting in Gas6 activation of Axl, PI3 kinase can bind either YXXM site, and inhibit the binding of Grb2 to Axl at the YVN site.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	9	10	12	13
Colo699 cells were used for this experiment because they express high levels of Mer and do not express Axl ( XREF_FIG ) , thereby eliminating complications due to Axl activation by the shared ligand Gas6 ( XREF_FIG ) .	Colo699 cells were used for this experiment because they express high levels of Mer and do not express Axl (XREF_FIG), thereby eliminating complications due to Axl activation by the shared ligand Gas6 (XREF_FIG).	28	35	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	34	35	28	29
As the major ligand of Axl , Gas6 may activate Axl signaling pathway and initiate its downstream events .	As the major ligand of Axl, Gas6 may activate Axl signaling pathway and initiate its downstream events.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	7	8	10	11
While the mechanism of AXL overexpression is outside the scope of this study , we found that DDLPS and PLS cells are capable of producing and secreting GAS6 in an autocrine manner , and that exogenous administration of GAS6 enhances activation of AXL and downstream effectors in these cells .	While the mechanism of AXL overexpression is outside the scope of this study, we found that DDLPS and PLS cells are capable of producing and secreting GAS6 in an autocrine manner, and that exogenous administration of GAS6 enhances activation of AXL and downstream effectors in these cells.	36	43	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	38	39	42	43
A significant increase in the understanding of how Tyro3 RTKs contribute to the immunomodulatory effect of apoptotic cells came from the recent finding that activation of Axl by Gas6 or apoptotic cells induces Twist proteins 1 and 2 213 , which are basic helix-loop-helix transcriptional repressors that inhibit production of TNF-alpha and other NF-kappaB-dependent inflammatory cytokines 214 .	A significant increase in the understanding of how Tyro3 RTKs contribute to the immunomodulatory effect of apoptotic cells came from the recent finding that activation of Axl by Gas6 or apoptotic cells induces Twist proteins 1 and 2 213, which are basic helix-loop-helix transcriptional repressors that inhibit production of TNF-alpha and other NF-kappaB-dependent inflammatory cytokines 214.	24	31	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	28	29	26	27
These results are consistent with recent studies that show gamma carboxylation of Gas6 is required for Gas6 mediated Axl activation .	These results are consistent with recent studies that show gamma carboxylation of Gas6 is required for Gas6 mediated Axl activation.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	16	17	18	19
AXL is activated though autocrine and paracrine signaling by the GAS6 ligand , and this complex is degraded in the lysosome following endocytosis .	AXL is activated though autocrine and paracrine signaling by the GAS6 ligand, and this complex is degraded in the lysosome following endocytosis.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	10	11	0	1
Indeed , activation of AXL by GAS6 was demonstrated in various cancer models [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Indeed, activation of AXL by GAS6 was demonstrated in various cancer models [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	6	7	4	5
The importance of Gas6 in Arg auxotrophic response was further demonstrated using two Gas6 shRNA showing that knockdown of Gas6 abolished Axl activation ( XREF_FIG ) , whereas overexpression of Gas6 enhanced Axl activation ( XREF_FIG ) .	The importance of Gas6 in Arg auxotrophic response was further demonstrated using two Gas6 shRNA showing that knockdown of Gas6 abolished Axl activation (XREF_FIG), whereas overexpression of Gas6 enhanced Axl activation (XREF_FIG).	17	22	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	19	20	21	22
11 In addition , Axl activation stimulated by its ligand Gas6 induced expression of the pro survival family of proteins Bcl-2 and Bcl-xL and activated NF-kappaB , thus suppressing apoptosis .	11 In addition, Axl activation stimulated by its ligand Gas6 induced expression of the pro survival family of proteins Bcl-2 and Bcl-xL and activated NF-kappaB, thus suppressing apoptosis.	4	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	10	11	4	5
It is well established that Gas6 stimulates Axl and results in autophosphorylation of putative SH2 binding domains .	It is well established that Gas6 stimulates Axl and results in autophosphorylation of putative SH2 binding domains.	5	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	5	6	7	8
However , Gas6 -- a VKDP gamma carboxylated by GGCX -- activates AXL ( AXL receptor tyrosine kinase ; OMIM * 109135 ) , a receptor tyrosine kinase ( RTK ) that interacts with non muscle myosin IIB , an essential protein for normal development of the murine heart [ XREF_BIBR , XREF_BIBR ] .	However, Gas6 -- a VKDP gamma carboxylated by GGCX -- activates AXL (AXL receptor tyrosine kinase; OMIM * 109135), a receptor tyrosine kinase (RTK) that interacts with non muscle myosin IIB, an essential protein for normal development of the murine heart [XREF_BIBR, XREF_BIBR].	2	38	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Gas6	Gas6	gas6	AXL	AXL (AXL receptor tyrosine kinase; OMIM * 109135), a receptor tyrosine kinase (RTK) that interacts with non muscle myosin IIB	axl	2	3	12	13
Based on these findings , it is presumed that Gas6 derived from CAFs promotes migration of Axl expressing lung cancer cells during chemotherapy and is involved in poor clinical outcome .	Based on these findings, it is presumed that Gas6 derived from CAFs promotes migration of Axl expressing lung cancer cells during chemotherapy and is involved in poor clinical outcome.	9	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	9	10	16	17
HSCs were obtained from wild type and Axl -/- mice , treated with recombinant Gas6 protein ( rGas6 ) , Axl siRNAs or the Axl inhibitor BGB324 , and analyzed by western blot and real-time PCR .	HSCs were obtained from wild type and Axl -/- mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR.	5	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	14	15	7	8
Although we demonstrate that the SH2 domain of the effector molecule ARG binds to Gas6 stimulated Axl , IP of full-length proteins demonstrate that Axl only interacts with p85 and Grb2 .	Although we demonstrate that the SH2 domain of the effector molecule ARG binds to Gas6 stimulated Axl, IP of full-length proteins demonstrate that Axl only interacts with p85 and Grb2.	12	18	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	14	15	16	17
Gas6 activation of Axl in vivo .	Gas6 activation of Axl in vivo.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	3	4
Alternatively , GAS6 expressed by the tumor microenvironment was also shown to activate AXL in a paracrine manner [ XREF_BIBR , XREF_BIBR ] .	Alternatively, GAS6 expressed by the tumor microenvironment was also shown to activate AXL in a paracrine manner [XREF_BIBR, XREF_BIBR].	2	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6 expressed	gas6	AXL	AXL	axl	2	3	13	14
However , only Gas6 was able to drive Axl dependent phagocytosis .	However, only Gas6 was able to drive Axl dependent phagocytosis.	2	10	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	3	4	8	9
15 When AXL is activated by its ligand GAS6 , 25 it also contributes to key physiological processes such as cell survival , proliferation and migration 29 mainly through the MAPK and PI3K signaling pathways .	15 When AXL is activated by its ligand GAS6, 25 it also contributes to key physiological processes such as cell survival, proliferation and migration 29 mainly through the MAPK and PI3K signaling pathways.	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	8	9	2	3
As noted above , RPE cells do not express Axl , which , in addition , is only activated by Gas6 ( XREF_FIG ) .	As noted above, RPE cells do not express Axl, which, in addition, is only activated by Gas6 (XREF_FIG).	8	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	20	21	9	10
These results clearly demonstrated that DN10764 can inhibit GAS6 induced AXL signaling pathways .	These results clearly demonstrated that DN10764 can inhibit GAS6 induced AXL signaling pathways.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	8	9	10	11
As shown in Figure XREF_FIG C , Axl activation by Gas6 was most profoundly enhanced when cells were treated with 10microM calcium ionophore , indicating native ( intrinsic ) PS externalization could also induce TAM activation .	As shown in Figure XREF_FIG C, Axl activation by Gas6 was most profoundly enhanced when cells were treated with 10microM calcium ionophore, indicating native (intrinsic) PS externalization could also induce TAM activation.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	10	11	7	8
The role of GAS6 activation of Axl and MerTK has been shown to be down-regulatory of the inflammatory innate response for several of its cellular components , including dendritic cells , natural killer cells and macrophages [ XREF_BIBR ] .	The role of GAS6 activation of Axl and MerTK has been shown to be down-regulatory of the inflammatory innate response for several of its cellular components, including dendritic cells, natural killer cells and macrophages [XREF_BIBR].	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	3	4	6	7
Gas6 mediated Axl signaling , which is enhanced and diversified in the presence of Sunitinib possibly contributes to acquired chemoresistance , recurrence of aggressive disease and metastasis of CCRCC tumors .	Gas6 mediated Axl signaling, which is enhanced and diversified in the presence of Sunitinib possibly contributes to acquired chemoresistance, recurrence of aggressive disease and metastasis of CCRCC tumors.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	2	3
The plasma concentrations of Gas6 and Axl were significantly altered in SLE and BD patients , suggesting that the Axl receptor shedding is an active process affected by and influences Gas6 mediated Axl signaling in both diseases .	The plasma concentrations of Gas6 and Axl were significantly altered in SLE and BD patients, suggesting that the Axl receptor shedding is an active process affected by and influences Gas6 mediated Axl signaling in both diseases.	29	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	30	31	32	33
However , copious free exogenous Gas6 is able to activate Axl and Mer receptors , leading to the downward cascade which aids in phagocytosis and inhibits NF-kappaB and neutrophil migration .	However, copious free exogenous Gas6 is able to activate Axl and Mer receptors, leading to the downward cascade which aids in phagocytosis and inhibits NF-kappaB and neutrophil migration.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	5	6	10	11
In this regard , the addition of either PtdSer displaying enveloped viruses or PtdSer displaying apoptotic cells has been found to markedly shift the dose response curves for Pros1 activation of Mer and Gas6 activation of Axl and Mer to lower ligand concentrations .	In this regard, the addition of either PtdSer displaying enveloped viruses or PtdSer displaying apoptotic cells has been found to markedly shift the dose response curves for Pros1 activation of Mer and Gas6 activation of Axl and Mer to lower ligand concentrations.	33	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	33	34	36	37
Autocrine Gas6 stimulation of Axl and Tyro3 activity were established from array and RT-PCR RNA abundance measurements .	Autocrine Gas6 stimulation of Axl and Tyro3 activity were established from array and RT-PCR RNA abundance measurements.	1	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	1	2	4	5
Together these data suggest that Gas6 activates Axl , and that protein S exerts its cellular effects on SVZ cells by activating Tyro3 pathway and inhibiting Gas6 induced Axl activation .	Together these data suggest that Gas6 activates Axl, and that protein S exerts its cellular effects on SVZ cells by activating Tyro3 pathway and inhibiting Gas6 induced Axl activation.	13	29	induced	Positive_early_activation	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	26	27	28	29
This mitogenic activity of Gas6 strictly correlates with its ability to interact with NIH3T3 endogenous Axl receptor since it can be abolished by soluble Axl extracellular domain and activates both Axl intrinsic kinase activity and the downstream MAPK pathway .	This mitogenic activity of Gas6 strictly correlates with its ability to interact with NIH3T3 endogenous Axl receptor since it can be abolished by soluble Axl extracellular domain and activates both Axl intrinsic kinase activity and the downstream MAPK pathway.	2	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	4	5	30	31
Therefore , we investigated the effect of DN10764 on GAS6 stimulated AXL signaling pathways .	Therefore, we investigated the effect of DN10764 on GAS6 stimulated AXL signaling pathways.	7	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	9	10	11	12
We conclude that Gas6 induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low dose warfarin or other Axl targeting agents may improve outcome in patients with Axl expressing tumors .	We conclude that Gas6 induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low dose warfarin or other Axl targeting agents may improve outcome in patients with Axl expressing tumors.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	3	4	5	6
Gas6 additionally activates AXL , which could mean that AXL targeting is a more attractive approach to treat ES patients in the future than IGF-1R-targeting .	Gas6 additionally activates AXL, which could mean that AXL targeting is a more attractive approach to treat ES patients in the future than IGF-1R-targeting.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	AXL	AXL	AXL	0	1	3	4
Gas6 mediated Axl signaling influences endothelial activation , neointima formation and immune regulation .	Gas6 mediated Axl signaling influences endothelial activation, neointima formation and immune regulation.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	2	3
Activation of Axl by Gas6 treatment and silencing of Axl via Axl shRNA were used to examine the effect of Axl on OSCC cell line .	Activation of Axl by Gas6 treatment and silencing of Axl via Axl shRNA were used to examine the effect of Axl on OSCC cell line.	0	9	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	4	5	2	3
Here , we show that Axl stimulation by GAS6 results in inhibition of the ligand dependent activation of vascular endothelial growth factor ( VEGF ) receptor 2 and the consequent activation of an angiogenic program in vascular endothelial cells .	Here, we show that Axl stimulation by GAS6 results in inhibition of the ligand dependent activation of vascular endothelial growth factor (VEGF) receptor 2 and the consequent activation of an angiogenic program in vascular endothelial cells.	5	9	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	8	9	5	6
The vitamin K dependent Gas6 protein ( product of growth arrest specific gene 6 ) binds to , and activates the TAM receptor tyrosine kinases Tyro3 , Axl and Mer .	The vitamin K dependent Gas6 protein (product of growth arrest specific gene 6) binds to, and activates the TAM receptor tyrosine kinases Tyro3, Axl and Mer.	4	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	4	5	27	28
Axl ' s conserved YXXM motif ( s ) are necessary for Gas6 activated Axl to signal to Akt .	Axl 's conserved YXXM motif (s) are necessary for Gas6 activated Axl to signal to Akt.	10	16	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	12	13	14	15
Our data show that warfarin exerts its anti-cancer effects by inhibiting Gas6 mediated Axl activation on tumor cells .	Our data show that warfarin exerts its anti-cancer effects by inhibiting Gas6 mediated Axl activation on tumor cells.	11	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	11	12	13	14
Furthermore , full-length Gas6 can not activate Axl in the presence of EDTA , which disrupts the binding of the Gas6 Gla domain to PtdSer .	Furthermore, full-length Gas6 can not activate Axl in the presence of EDTA, which disrupts the binding of the Gas6 Gla domain to PtdSer.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	3	4	7	8
For instance , in the osteosarcoma cell lines MG63 and U2OS , Axl activation by recombinant human Gas6 can protect tumour cells from apoptosis caused by serum starvation [ XREF_BIBR ] , and knockdown of Axl inhibits osteosarcoma cell proliferation and induces apoptosis .	For instance, in the osteosarcoma cell lines MG63 and U2OS, Axl activation by recombinant human Gas6 can protect tumour cells from apoptosis caused by serum starvation [XREF_BIBR], and knockdown of Axl inhibits osteosarcoma cell proliferation and induces apoptosis.	12	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	17	18	12	13
These results indicate that the binding of full-length Gas6 alone , in the absence of simultaneous Ca 2+ -dependent binding of its Gla domain to PtdSer , is insufficient to trigger Axl activation .	These results indicate that the binding of full-length Gas6 alone, in the absence of simultaneous Ca 2+ -dependent binding of its Gla domain to PtdSer, is insufficient to trigger Axl activation.	5	32	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	8	9	31	32
Hypoxic conditions , mimicked using CoCl2 , prevented the Gas6 mediated downregulation of Axl and therefore can stabilize Gas6-Axl interactions [ XREF_BIBR ] .	Hypoxic conditions, mimicked using CoCl2, prevented the Gas6 mediated downregulation of Axl and therefore can stabilize Gas6-Axl interactions [XREF_BIBR].	8	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	9	10	13	14
Moreover , since Gas6 ligand only is functional and can stimulate Axl properly when correctly gamma carboxylated processed by Vitamin K XREF_BIBR , we examined whether Gas6 was present and gamma carboxylated in the matched ccRCC biopsies .	Moreover, since Gas6 ligand only is functional and can stimulate Axl properly when correctly gamma carboxylated processed by Vitamin K XREF_BIBR, we examined whether Gas6 was present and gamma carboxylated in the matched ccRCC biopsies.	3	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	3	4	11	12
Kirane A et al found that Gas6 induced Axl signaling is a critical for pancreatic cancer progression and its inhibition with warfarin may improve outcome of the patients XREF_BIBR .	Kirane A et al found that Gas6 induced Axl signaling is a critical for pancreatic cancer progression and its inhibition with warfarin may improve outcome of the patients XREF_BIBR.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	6	7	8	9
However , they were as competent as VSVg pseudotyped virions at potentiating Gas6 induced Axl activation ( XREF_SUPPLEMENTARY ) .	However, they were as competent as VSVg pseudotyped virions at potentiating Gas6 induced Axl activation (XREF_SUPPLEMENTARY).	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	12	13	14	15
Gas6 , a ligand of receptor tyrosine kinases Axl , Sky , and Mer , potentiates cell proliferation and prevents cell death .	Gas6, a ligand of receptor tyrosine kinases Axl, Sky, and Mer, potentiates cell proliferation and prevents cell death.	0	19	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	8	9
Gas6 mediated activation of Axl in ccRCC cells resulted in Axl phosphorylation , receptor down-regulation , decreased cell-viability and migratory capacity .	Gas6 mediated activation of Axl in ccRCC cells resulted in Axl phosphorylation, receptor down-regulation, decreased cell-viability and migratory capacity.	0	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	4	5
GAS6 stimulation of Axl plays a role in chemotaxis in these cells .	GAS6 stimulation of Axl plays a role in chemotaxis in these cells.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	0	1	3	4
Gas6 activation of Axl in VSMC has been shown to stimulate ERK1/2 and Akt which are required to promote migration and inhibit apoptosis , respectively XREF_BIBR , XREF_BIBR .	Gas6 activation of Axl in VSMC has been shown to stimulate ERK1/2 and Akt which are required to promote migration and inhibit apoptosis, respectively XREF_BIBR, XREF_BIBR.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	3	4
Furthermore , Gas6 is identified as a novel growth factor for thyroid carcinoma cells overexpressing Axl receptor tyrosine kinase .	Furthermore, Gas6 is identified as a novel growth factor for thyroid carcinoma cells overexpressing Axl receptor tyrosine kinase.	2	18	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	2	3	15	16
Axl is significantly activated by Gas6 but not by protein S ; however , the coaddition of Gas6 and protein S suppresses Axl activation ( XREF_FIG F- XREF_FIG H ) .	Axl is significantly activated by Gas6 but not by protein S; however, the coaddition of Gas6 and protein S suppresses Axl activation (XREF_FIG F- XREF_FIG H).	17	23	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	17	18	22	23
Notably , we find that the Gla domains of TAM ligands are dispensable for receptor binding but are critical for optimal receptor activation , and that for Gas6 activation of Axl , this requirement is absolute .	Notably, we find that the Gla domains of TAM ligands are dispensable for receptor binding but are critical for optimal receptor activation, and that for Gas6 activation of Axl, this requirement is absolute.	27	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	27	28	30	31
Activation of Axl by Gas6 can induce chemotaxis of dendritic cells ( DCs ) which can prevent them from undergoing apoptosis [ XREF_BIBR ] .	Activation of Axl by Gas6 can induce chemotaxis of dendritic cells (DCs) which can prevent them from undergoing apoptosis [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	4	5	2	3
In breast cancer cells , DN10764 inhibited cell proliferation and GAS6 mediated AXL signaling , consequently resulting in suppressed migration and invasion .	In breast cancer cells, DN10764 inhibited cell proliferation and GAS6 mediated AXL signaling, consequently resulting in suppressed migration and invasion.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	10	11	12	13
This raises the possibility that GAS6 independent activation of AXL , as previously described , may be driving therapeutic resistance and prognosis .	This raises the possibility that GAS6 independent activation of AXL, as previously described, may be driving therapeutic resistance and prognosis.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	5	6	9	10
To determine the effect of warfarin on Gas6 induced Axl signaling in PDA we evaluated phosphorylated Axl ( pAxl ) and downstream signaling via the PI3K-Akt signaling pathway .	To determine the effect of warfarin on Gas6 induced Axl signaling in PDA we evaluated phosphorylated Axl (pAxl) and downstream signaling via the PI3K-Akt signaling pathway.	1	10	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	7	8	9	10
In GnRH neuronal cell lines , Gas6 induced neuronal migration by activating Axl via p38 MAPK pathway .	In GnRH neuronal cell lines, Gas6 induced neuronal migration by activating Axl via p38 MAPK pathway.	6	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	6	7	12	13
Stimulation of microglial phagocytosis by both Gas6 and Pros1 demonstrates that it is mediated principally by Mer , since Axl is activated only by Gas6 XREF_BIBR , XREF_BIBR .	Stimulation of microglial phagocytosis by both Gas6 and Pros1 demonstrates that it is mediated principally by Mer, since Axl is activated only by Gas6 XREF_BIBR, XREF_BIBR.	19	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	24	25	19	20
In breast cancer cells , DN10764 was found to inhibit cell proliferation and GAS6 mediated AXL signaling pathways , resulting in the suppression of migration and invasion .	In breast cancer cells, DN10764 was found to inhibit cell proliferation and GAS6 mediated AXL signaling pathways, resulting in the suppression of migration and invasion.	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	13	14	15	16
Protein S and a structurally similar protein , Gas6 , have been found to stimulate members of the Axl and Sky family of receptor tyrosine kinases .	Protein S and a structurally similar protein, Gas6, have been found to stimulate members of the Axl and Sky family of receptor tyrosine kinases.	6	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	8	9	18	19
We found that the viral envelope of PtdSer also binds Gas6 , and Gas6 mediates binding of virus to Axl on target cells .	We found that the viral envelope of PtdSer also binds Gas6, and Gas6 mediates binding of virus to Axl on target cells.	13	22	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	13	14	19	20
While only Gas6 directly activates Axl , ProS1 activation of Tyro3 and MerTK can indirectly activate Axl through receptor heterodimerization .	While only Gas6 directly activates Axl, ProS1 activation of Tyro3 and MerTK can indirectly activate Axl through receptor heterodimerization.	1	6	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	2	3	5	6
It remains to be explored how Gas6 mediated Axl signaling affects B cells normally and in SLE .	It remains to be explored how Gas6 mediated Axl signaling affects B cells normally and in SLE.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	6	7	8	9
Axl activation by Gas6 , on the other hand , was not further enhanced in the presence of apoptotic cells and decreased by calcium stressed cells in some cases .	Axl activation by Gas6, on the other hand, was not further enhanced in the presence of apoptotic cells and decreased by calcium stressed cells in some cases.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	3	4	0	1
Growth arrest specific protein6 ( Gas6 ) induces the activation of Axl receptor tyrosine kinase ( Axl ) , which plays an important role in angiogenic processes , including proliferation , migration , invasion , tube formation and pericyte recruitment of endothelial cells .	Growth arrest specific protein6 (Gas6) induces the activation of Axl receptor tyrosine kinase (Axl), which plays an important role in angiogenic processes, including proliferation, migration, invasion, tube formation and pericyte recruitment of endothelial cells.	1	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	5	6	11	12
Since warfarin blocks vitamin K dependent gamma carboxylation of glutamic acids and the gamma-carboxyglutamic acid rich ( GLA ) domain of Gas6 is required to induce Axl tyrosine kinase activity , we hypothesized that the anti-tumor activity of warfarin could be due to inhibition of Gas6 mediated Axl activation on tumor cells .	Since warfarin blocks vitamin K dependent gamma carboxylation of glutamic acids and the gamma-carboxyglutamic acid rich (GLA) domain of Gas6 is required to induce Axl tyrosine kinase activity, we hypothesized that the anti-tumor activity of warfarin could be due to inhibition of Gas6 mediated Axl activation on tumor cells.	43	48	mediated	Positive_early_activation	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	45	46	47	48
Thus , the TAM receptors fall into two groups based on features of their ligand and PtdSer activation profiles : Tyro3 and Mer are activated by both Gas6 and Pros1 , whereas Axl is activated only by Gas6 ; and while Gla-less Gas6 is a substantially weaker ligand for Tyro3 and Mer , it is effectively dead as a ligand for Axl .	Thus, the TAM receptors fall into two groups based on features of their ligand and PtdSer activation profiles : Tyro3 and Mer are activated by both Gas6 and Pros1, whereas Axl is activated only by Gas6; and while Gla-less Gas6 is a substantially weaker ligand for Tyro3 and Mer, it is effectively dead as a ligand for Axl.	32	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	37	38	32	33
In a stressful situation Gas6 activation of Axl recruits PI3 kinase directly to Axl at the pYALM or pYVNM motifs , leading to cell survival .	In a stressful situation Gas6 activation of Axl recruits PI3 kinase directly to Axl at the pYALM or pYVNM motifs, leading to cell survival.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	4	5	7	8
First , Gas6 stimulated Axl in the kidney is necessary for renal mesangial cell proliferation , which contributes to nephritis [ XREF_BIBR - XREF_BIBR ] .	First, Gas6 stimulated Axl in the kidney is necessary for renal mesangial cell proliferation, which contributes to nephritis [XREF_BIBR - XREF_BIBR].	2	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	2	3	4	5
Gas6 activates Axl signalling in GBM cells .	Gas6 activates Axl signalling in GBM cells.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	2	3
The effect of antioxidants on the interaction of MHC-IIB with Axl mediated by Gas6 was studied by pre-treating VSMC for 30 min with N-acetylcysteine ( 1 mM ) , and ebselen ( 40 microM ) .	The effect of antioxidants on the interaction of MHC-IIB with Axl mediated by Gas6 was studied by pre-treating VSMC for 30 min with N-acetylcysteine (1 mM), and ebselen (40 microM).	8	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	13	14	10	11
Upon Gas6 dependent activation of Axl , endogenous Elmo2 becomes phosphorylated on Tyr 713 and enters into a physical complex with Axl in breast cancer cells .	Upon Gas6 dependent activation of Axl, endogenous Elmo2 becomes phosphorylated on Tyr 713 and enters into a physical complex with Axl in breast cancer cells.	1	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	1	2	5	6
Whereas Gas6 is able to activate all TAM receptors ( Axl > Tyro3 > > > Mer ) , Protein S is only capable of activating Tyro3 and Mer ( Tyro3 > Mer ) .	Whereas Gas6 is able to activate all TAM receptors (Axl> Tyro3>>> Mer), Protein S is only capable of activating Tyro3 and Mer (Tyro3> Mer).	1	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	1	2	10	11
Activation of AXL by GAS6 has been reported to directly induce a number of intracellular signaling pathways including PI3K , RAS , MAPK , SRC , and PLC ( for recent review , ) .	Activation of AXL by GAS6 has been reported to directly induce a number of intracellular signaling pathways including PI3K, RAS, MAPK, SRC, and PLC (for recent review,).	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	4	5	2	3
However , examination of GAS6 induced AXL signaling events clearly showed that DN10764 dose-dependently inhibits GAS6 induced activation of AXL and subsequent AKT and ERK signaling .	However, examination of GAS6 induced AXL signaling events clearly showed that DN10764 dose-dependently inhibits GAS6 induced activation of AXL and subsequent AKT and ERK signaling.	15	25	induced	Positive_early_activation	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	15	16	19	20
Gas6 induced signaling pathway effects on migration may therefore mediate the receptor tyrosine kinase family members , Axl , Mer , and Tyro3 , in HRMECs .	Gas6 induced signaling pathway effects on migration may therefore mediate the receptor tyrosine kinase family members, Axl, Mer, and Tyro3, in HRMECs.	0	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	17	18
APOPTOTIC BODIES ELICIT GAS6 MEDIATED MIGRATION OF AXL EXPRESSING TUMOR CELLS .	APOPTOTIC BODIES ELICIT GAS6 MEDIATED MIGRATION OF AXL EXPRESSING TUMOR CELLS.	3	10	MEDIATED	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	3	4	7	8
Tyro3 and Mer are activated by both ligands but only Gas6 activates Axl .	Tyro3 and Mer are activated by both ligands but only Gas6 activates Axl.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	10	11	12	13
Gas6 activates Axl , Tyro3 , and Mer receptor tyrosine kinases in a concentration dependent manner .	Gas6 activates Axl, Tyro3, and Mer receptor tyrosine kinases in a concentration dependent manner.	0	7	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	0	1	2	3
Further , Gas6 stimulation of Axl results in recruitment of active PI3 kinase which leads to downstream activation of Akt at threonine 308 .	Further, Gas6 stimulation of Axl results in recruitment of active PI3 kinase which leads to downstream activation of Akt at threonine 308.	2	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	2	3	5	6
Furthermore , p130Cas is necessary for maximum Gas6 stimulated Axl activation .	Furthermore, p130Cas is necessary for maximum Gas6 stimulated Axl activation.	6	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	7	8	9	10
Gas6 mediated AXL dimerization is likely to occur in two steps , with a high-affinity 1:1 Gas6 and AXL complex forming first , then lateral diffusion of such complexes leading to the formation of a dimeric signaling complex [ XREF_BIBR ] .	Gas6 mediated AXL dimerization is likely to occur in two steps, with a high-affinity 1:1 Gas6 and AXL complex forming first, then lateral diffusion of such complexes leading to the formation of a dimeric signaling complex [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	AXL	AXL	AXL	0	1	2	3
GAS6 mediated AXL activation promotes cell proliferation , migration , and invasion of DDLPS and PLS cells .	GAS6 mediated AXL activation promotes cell proliferation, migration, and invasion of DDLPS and PLS cells.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	0	1	2	3
GAS-6 activation of Mer and Axl was significantly enhanced by the inclusion of apoptotic cells ( XREF_FIG , lane 4 ) .	GAS-6 activation of Mer and Axl was significantly enhanced by the inclusion of apoptotic cells (XREF_FIG, lane 4).	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GAS-6	GAS-6	GAS-6	Axl	Axl	Axl	0	1	5	6
In this study , we demonstrate in vitro and in vivo that Gas6 stimulation of the Axl receptor recruits p85 and Grb2 to Axl via their respective SH2 domains , and alternatively , p85 can indirectly associate with Axl by binding to Grb2 .	In this study, we demonstrate in vitro and in vivo that Gas6 stimulation of the Axl receptor recruits p85 and Grb2 to Axl via their respective SH2 domains, and alternatively, p85 can indirectly associate with Axl by binding to Grb2.	12	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	12	13	16	17
Gas6 activation of AXL and TYRO3 increased neuronal migration ; whereas silencing of both AXL and TYRO3 reversed the response to Gas6 , but had no effect on basal migration .	Gas6 activation of AXL and TYRO3 increased neuronal migration; whereas silencing of both AXL and TYRO3 reversed the response to Gas6, but had no effect on basal migration.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	AXL	AXL	AXL	0	1	3	4
Gas6 is expressed in EOC cells and activates the TAM RTK Axl .	Gas6 is expressed in EOC cells and activates the TAM RTK Axl.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6 is expressed	gas6	Axl	Axl	axl	0	1	11	12
Investigation of Gas6 mediated Axl signaling in CCRCC and endothelial cells reveals a Sunitinib resistant Gas6-Axl signaling that is sustained and enhanced and specifically triggers downstream AKT and PRAS40 activation in an intensified manner .	Investigation of Gas6 mediated Axl signaling in CCRCC and endothelial cells reveals a Sunitinib resistant Gas6-Axl signaling that is sustained and enhanced and specifically triggers downstream AKT and PRAS40 activation in an intensified manner.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	2	3	4	5
In contrast , Axl is activated by only Gas6 under inflammatory conditions and acts as a receptor for immune suppression .	In contrast, Axl is activated by only Gas6 under inflammatory conditions and acts as a receptor for immune suppression.	3	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	8	9	3	4
This shift pattern was consistent between both cell lines , with HGF having more of an effect than IGF1 , whereas no effect was seen with activation of AXL by GAS6 in these cells .	This shift pattern was consistent between both cell lines, with HGF having more of an effect than IGF1, whereas no effect was seen with activation of AXL by GAS6 in these cells.	24	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	30	31	28	29
The TYRO3 , Axl , Mer ( TAM ) tyrosine receptor kinases activated by Gas 6 and PROS1 regulate inflammation by inhibiting Toll like receptors ( TLR ) / JAK-STAT activation and contribute to NIREG ' s functions .	The TYRO3, Axl, Mer (TAM) tyrosine receptor kinases activated by Gas 6 and PROS1 regulate inflammation by inhibiting Toll like receptors (TLR) / JAK-STAT activation and contribute to NIREG 's functions.	3	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas 6	Gas 6	Gas 6	Axl	Axl	Axl	14	16	3	4
Not unexpectedly , Gas6 stimulation of the Axl receptor was accompanied by increased phosphorylation of Akt and Erk1/2 ( as a measure of MAPK pathway activation ) in both cell lines .	Not unexpectedly, Gas6 stimulation of the Axl receptor was accompanied by increased phosphorylation of Akt and Erk1/2 (as a measure of MAPK pathway activation) in both cell lines.	3	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	3	4	7	8
For example , EGFR-TKI resistance could be caused by MET amplification [ XREF_BIBR ] , HGF triggered MET activation [ XREF_BIBR ] , Gas6 triggered AXL activation [ XREF_BIBR ] , and HER2 amplification [ XREF_BIBR ] in EGFR mutant lung cancer .	For example, EGFR-TKI resistance could be caused by MET amplification [XREF_BIBR], HGF triggered MET activation [XREF_BIBR], Gas6 triggered AXL activation [XREF_BIBR], and HER2 amplification [XREF_BIBR] in EGFR mutant lung cancer.	23	28	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	AXL	AXL	AXL	23	24	25	26
Axl , Mer , or Tyro3 shRNA transfected cells showed reduction of Axl , Mer , or Tyro3 mRNA levels , and Gas6 induced Axl , Mer , or Tyro3 mRNAs levels .	Axl, Mer, or Tyro3 shRNA transfected cells showed reduction of Axl, Mer, or Tyro3 mRNA levels, and Gas6 induced Axl, Mer, or Tyro3 mRNAs levels.	22	31	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	22	23	24	25
Previous reports revealed that cross talk between Gas6 and Axl and VEGFR2 and Axl stimulation by Gas6 resulted in inhibition of the ligand dependent activation of VEGFR2 and the consequent activation of an angiogenic program in vascular ECs [ XREF_BIBR ] .	Previous reports revealed that cross talk between Gas6 and Axl and VEGFR2 and Axl stimulation by Gas6 resulted in inhibition of the ligand dependent activation of VEGFR2 and the consequent activation of an angiogenic program in vascular ECs [XREF_BIBR].	11	17	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	16	17	13	14
A study has also demonstrated that Gas6 stimulated TAM ( Tyro3 , Axl , and Mer ) activation suppresses demyelination and significantly promotes remyelination in the spinal cord ( Gruber et al ., 2014 ) .	A study has also demonstrated that Gas6 stimulated TAM (Tyro3, Axl, and Mer) activation suppresses demyelination and significantly promotes remyelination in the spinal cord (Gruber et al., 2014).	6	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	6	7	12	13
Exogenous GAS6 stimulation increased AXL activation in all cell lines evaluated ; furthermore , Lipo-246 , PLS-1 , and LiSa2 cells displayed increased phosphatidylinositol-3-kinase ( PI3K ) pathway activity , as measured by AKT phosphorylation at S473 .	Exogenous GAS6 stimulation increased AXL activation in all cell lines evaluated; furthermore, Lipo-246, PLS-1, and LiSa2 cells displayed increased phosphatidylinositol-3-kinase (PI3K) pathway activity, as measured by AKT phosphorylation at S473.	1	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	1	2	4	5
24 However , here we did not observe any effect on EGFR phosphorylation by Gas6 induced Axl activation ( which we have previously shown in this cell line 15 ) .	24 However, here we did not observe any effect on EGFR phosphorylation by Gas6 induced Axl activation (which we have previously shown in this cell line 15).	7	23	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	14	15	16	17
Then exogenous GAS6 was added at 600ng/ml concentration for 15mins to stimulate AXL activation .	Then exogenous GAS6 was added at 600ng/ml concentration for 15mins to stimulate AXL activation.	1	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	2	3	12	13
Several different mechanisms can induce activation of AXL signaling pathways , including GAS6 driven ligand dependent AXL dimerization , ligand independent homodimerization between 2 AXL monomers , and heterometric dimerization between AXL and a non TAM receptor [ XREF_BIBR ] .	Several different mechanisms can induce activation of AXL signaling pathways, including GAS6 driven ligand dependent AXL dimerization, ligand independent homodimerization between 2 AXL monomers, and heterometric dimerization between AXL and a non TAM receptor [XREF_BIBR].	5	17	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	12	13	16	17
To assess whether beta3 integrin was involved in Gas6 stimulated Axl activation , NL3507 cells were allowed to adhere on FN coated dishes for 30 min in the presence of Ab able to inhibit integrin beta3/FN interaction .	To assess whether beta3 integrin was involved in Gas6 stimulated Axl activation, NL3507 cells were allowed to adhere on FN coated dishes for 30 min in the presence of Ab able to inhibit integrin beta3/FN interaction.	6	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	8	9	10	11
Indeed , low-dose warfarin treatment in mice decreases tumor growth and metastasis by blocking the Gas6 induced Axl receptor activation [ XREF_BIBR ] .	Indeed, low-dose warfarin treatment in mice decreases tumor growth and metastasis by blocking the Gas6 induced Axl receptor activation [XREF_BIBR].	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	15	16	17	18
In summary , whereas Mer , activated by Gas6 or Pros1 , is predominantly responsible for homeostatic phagocytosis in immunosuppressive environments , Axl , activated by Gas6 but not Pros1 , preferentially regulates phagocytosis and negative feedback pathways under inflammatory conditions .	In summary, whereas Mer, activated by Gas6 or Pros1, is predominantly responsible for homeostatic phagocytosis in immunosuppressive environments, Axl, activated by Gas6 but not Pros1, preferentially regulates phagocytosis and negative feedback pathways under inflammatory conditions.	22	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	26	27	22	23
XREF_BIBR Axl activation and signaling by Gas6 have been implicated in multiple cellular responses , including cell survival , proliferation and migration .	XREF_BIBR Axl activation and signaling by Gas6 have been implicated in multiple cellular responses, including cell survival, proliferation and migration.	1	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	6	7	1	2
78 More recently , Gas6 induced Axl stimulation led to STAT1 activation in mouse bone marrow dendritic cells , an effect dependent upon type I interferon ( IFN ) receptor expression .	78 More recently, Gas6 induced Axl stimulation led to STAT1 activation in mouse bone marrow dendritic cells, an effect dependent upon type I interferon (IFN) receptor expression.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	4	5	6	7
Using two GBM cell lines with a basal level of Axl activity , we observed that Gas6 activates Axl and Axl associated signalling in SNB-19 cells but also that Axl signalling appeared to be Gas6 independent in the UP007 cell line .	Using two GBM cell lines with a basal level of Axl activity, we observed that Gas6 activates Axl and Axl associated signalling in SNB-19 cells but also that Axl signalling appeared to be Gas6 independent in the UP007 cell line.	16	21	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	16	17	18	19
As shown in XREF_FIG , Akt and the cell survival pathway is activated by Gas6 stimulation of Axl in as little as 1 min .	As shown in XREF_FIG, Akt and the cell survival pathway is activated by Gas6 stimulation of Axl in as little as 1 min.	14	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	14	15	17	18
Human Gas6 is able to activate Axl and Sky .	Human Gas6 is able to activate Axl and Sky.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	1	2	6	7
By combining immunoblotting and immunofluorescence experiments performed on separated CA1 , CA3 or DG subregions , we established that a GDNF treatment either if rapid ( 30 min ) or prolonged ( 48 h ) induces a strong activation of the Ret and ERK signalling preferentially in the CA3 subfield .	By combining immunoblotting and immunofluorescence experiments performed on separated CA1, CA3 or DG subregions, we established that a GDNF treatment either if rapid (30 min) or prolonged (48 h) induces a strong activation of the Ret and ERK signalling preferentially in the CA3 subfield.	20	44	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	20	21	41	42
Since RET has been shown to be an ER dependent gene [ XREF_BIBR ] , the presence of E2 in the culture medium enhanced RET expression resulting in a stronger activation of GDNF induced RET downstream signaling .	Since RET has been shown to be an ER dependent gene [XREF_BIBR], the presence of E2 in the culture medium enhanced RET expression resulting in a stronger activation of GDNF induced RET downstream signaling.	30	36	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	32	33	34	35
Given the striking loss of GDNF mediated Ret activation , we hypothesized that loss of p75 may result in changes of cell surface localization of Ret .	Given the striking loss of GDNF mediated Ret activation, we hypothesized that loss of p75 may result in changes of cell surface localization of Ret.	3	8	mediated	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	5	6	7	8
During late embryonic and early postnatal periods , trkA expressing neurons differentiate into two subpopulations of nociceptive neurons ; trkA retaining peptidergic neurons , and non peptidergic neurons that repress trkA and instead activate Ret , a receptor for glial derived neurotrophic factor ( GDNF ; Figure XREF_FIG ) .	During late embryonic and early postnatal periods, trkA expressing neurons differentiate into two subpopulations of nociceptive neurons; trkA retaining peptidergic neurons, and non peptidergic neurons that repress trkA and instead activate Ret, a receptor for glial derived neurotrophic factor (GDNF; Figure XREF_FIG).	27	47	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	44	45	34	35
In principal , RET signaling may be activated by any of the four RET ligands ( GDNF , NRTN , ARTN , and PSPN ) .	In principal, RET signaling may be activated by any of the four RET ligands (GDNF, NRTN, ARTN, and PSPN).	3	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	16	17	3	4
Less well studied is the role of GDNF signaling in cancer , although it has been shown that GDNF can promote cell migration and chemotaxis and invasion of a RET +/GFRa1+ pancreatic cell line and that these activities are dependent on the activation of the MAPK and PI3K pathways ( Viet et al ., 2004 ) .	Less well studied is the role of GDNF signaling in cancer, although it has been shown that GDNF can promote cell migration and chemotaxis and invasion of a RET +/GFRa1+ pancreatic cell line and that these activities are dependent on the activation of the MAPK and PI3K pathways (Viet et al., 2004).	18	33	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	18	19	29	30
These results , taken together , indicate that GDNF may induce Ret activation and the consequent downstream signalling in a specific population of hippocampal CA3 cells in the pyramidal layer that are IB4 positive .	These results, taken together, indicate that GDNF may induce Ret activation and the consequent downstream signalling in a specific population of hippocampal CA3 cells in the pyramidal layer that are IB4 positive.	8	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	8	9	11	12
GDNF Induces the Association of Ret and F-Actin .	GDNF Induces the Association of Ret and F-Actin.	0	7	Induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	0	1	5	6
Collectively , this study shows that CA3 and CA1 hippocampal regions are highly responsive to GDNF induced Ret activation and neuroprotection , and suggest that , upon excitotoxicity , such neuroprotection involves a GDNF modulation of microglial cell activity .	Collectively, this study shows that CA3 and CA1 hippocampal regions are highly responsive to GDNF induced Ret activation and neuroprotection, and suggest that, upon excitotoxicity, such neuroprotection involves a GDNF modulation of microglial cell activity.	13	23	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	15	16	17	18
We examined the breast cancer cell lines for Ret mediated motility in response to GDNF , which activates Ret , as shown by an increase in its phospho-tyrosine content ( pY ) [ XREF_FIG A and ] .	We examined the breast cancer cell lines for Ret mediated motility in response to GDNF, which activates Ret, as shown by an increase in its phospho-tyrosine content (pY) [XREF_FIG A and].	9	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	14	15	18	19
These results suggest that cross-talk signaling through other receptors is not involved in the RET pathways activated by GDNF .	These results suggest that cross-talk signaling through other receptors is not involved in the RET pathways activated by GDNF.	14	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	18	19	14	15
Indeed , the Wnt pathway target Axin2 is reduced in epithelial cultures derived from Ret51 mice and upregulated when wild-type FEnS are treated with the Ret ligand GDNF : a treatment that also promotes their branching .	Indeed, the Wnt pathway target Axin2 is reduced in epithelial cultures derived from Ret51 mice and upregulated when wild-type FEnS are treated with the Ret ligand GDNF : a treatment that also promotes their branching.	14	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret51	Ret51	Ret51	27	28	14	15
To elucidate the molecular basis for signaling specificity of GDNF mediated RET signaling in kidney development , we characterized mice that exclusively express either the human RET9 or RET51 isoform , or express these isoforms with individual mutations in docking tyrosines for PTB and SH2-domain-containing adaptors Src ( Y981 ) , PLCgamma ( Y1015 ) , and Shc ( Y1062 ) .	To elucidate the molecular basis for signaling specificity of GDNF mediated RET signaling in kidney development, we characterized mice that exclusively express either the human RET9 or RET51 isoform, or express these isoforms with individual mutations in docking tyrosines for PTB and SH2-domain-containing adaptors Src (Y981), PLCgamma (Y1015), and Shc (Y1062).	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	9	10	11	12
These findings suggest that our model of GDNF mediated RET signaling as a mechanism for chemotaxis and PNI may be clinically relevant for patients with ACC .	These findings suggest that our model of GDNF mediated RET signaling as a mechanism for chemotaxis and PNI may be clinically relevant for patients with ACC.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	7	8	9	10
Our results demonstrate that GDNF mediated RET signaling is critical for the fate of undifferentiated spermatogonia and that abnormalities in this pathway may contribute to male infertility and testicular germ cell tumors .	Our results demonstrate that GDNF mediated RET signaling is critical for the fate of undifferentiated spermatogonia and that abnormalities in this pathway may contribute to male infertility and testicular germ cell tumors.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	4	5	6	7
Inflammatory response pathways were previously reported to be regulated by GDNF mediated RET activation .	Inflammatory response pathways were previously reported to be regulated by GDNF mediated RET activation.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	10	11	12	13
Sominone , a compound with low molecular weight , may be a GDNF independent stimulator of the RET pathway and/or a novel modulator of RET signalling .	Sominone, a compound with low molecular weight, may be a GDNF independent stimulator of the RET pathway and/or a novel modulator of RET signalling.	12	18	stimulator	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	12	13	17	18
The RET receptor is activated by glial cell line derived neurotrophic factor ( GDNF ) , which has been shown in breast cancer models to result in activation of signal transduction pathways including ERK1/2 and AKT , leading to increased proliferation and cell survival .	The RET receptor is activated by glial cell line derived neurotrophic factor (GDNF), which has been shown in breast cancer models to result in activation of signal transduction pathways including ERK1/2 and AKT, leading to increased proliferation and cell survival.	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	glial cell line derived neurotrophic factor	glial cell line derived neurotrophic factor	glial cell line derived neurotrophic factor	RET	RET	RET	6	12	1	2
To confirm that GDNF induced Ret translocation to lipid rafts , we examined the subcellular localization of Ret protein in MN9D cells by OptiPrep ( TM ) density gradient centrifugation .	To confirm that GDNF induced Ret translocation to lipid rafts, we examined the subcellular localization of Ret protein in MN9D cells by OptiPrep (TM) density gradient centrifugation.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	3	4	5	6
On the other hand , RET can be activated by GFRa1 and GDNF in trans using both heterologous cells and tissue explants .	On the other hand, RET can be activated by GFRa1 and GDNF in trans using both heterologous cells and tissue explants.	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	12	13	5	6
There is additional evidence that GDNF can activate SFKs in a Ret independent manner [ XREF_BIBR , XREF_BIBR ] in DRG from Ret deficient mice and two neuronal cell lines that lack Ret expression ( NIH3T3 and SHEP neurobalstoma ) , stably transfected with GFRalpha-1 .	There is additional evidence that GDNF can activate SFKs in a Ret independent manner [XREF_BIBR, XREF_BIBR] in DRG from Ret deficient mice and two neuronal cell lines that lack Ret expression (NIH3T3 and SHEP neurobalstoma), stably transfected with GFRalpha-1.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	5	6	11	12
Previous studies have also indicated that GDNF stimulates a Ret independent signaling pathway [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Previous studies have also indicated that GDNF stimulates a Ret independent signaling pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	6	7	9	10
In addition , GDNF crosstalk is weak with other GFRalpha receptors and can trigger Ret independent signaling through GFRalpha1 .	In addition, GDNF crosstalk is weak with other GFRalpha receptors and can trigger Ret independent signaling through GFRalpha1.	3	16	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	3	4	14	15
GDNF signals through the ret receptor tyrosine kinase ; GDNF activation of ret is mediated by GFRalpha1 [ XREF_BIBR ] .	GDNF signals through the ret receptor tyrosine kinase; GDNF activation of ret is mediated by GFRalpha1 [XREF_BIBR].	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	ret	ret	ret	9	10	12	13
Consequently , soluble GFRalpha1 was added for optimal GDNF induced RET signaling activation ( XREF_SUPPLEMENTARY ) as previously described [ XREF_BIBR ] .	Consequently, soluble GFRalpha1 was added for optimal GDNF induced RET signaling activation (XREF_SUPPLEMENTARY) as previously described [XREF_BIBR].	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	8	9	10	11
It is believed that Gdnf , produced in the metanephric mesenchyme , activates Ret signaling in the Wolffian duct to initiate the formation of the metanephros .	It is believed that Gdnf, produced in the metanephric mesenchyme, activates Ret signaling in the Wolffian duct to initiate the formation of the metanephros.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gdnf	Gdnf	Gdnf	Ret	Ret	Ret	4	5	13	14
GDNF and GFRalpha activation of RET results in transphosphorylation of tyrosine residues in its intracellular kinase domain that triggers multiple intracellular signaling pathways that in concert regulate cell proliferation , migration , differentiation , survival , neurite outgrowth , and synaptic plasticity XREF_BIBR .	GDNF and GFRalpha activation of RET results in transphosphorylation of tyrosine residues in its intracellular kinase domain that triggers multiple intracellular signaling pathways that in concert regulate cell proliferation, migration, differentiation, survival, neurite outgrowth, and synaptic plasticity XREF_BIBR.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	0	1	5	6
p75 augments GDNF mediated Ret activation by increasing cell surface localization of Ret .	p75 augments GDNF mediated Ret activation by increasing cell surface localization of Ret.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	2	3	4	5
For example , it has been shown that GDNF mediated Ret activation increases PI3K activity and the phosphorylation of Akt in Ret expressing MDCK cells .	For example, it has been shown that GDNF mediated Ret activation increases PI3K activity and the phosphorylation of Akt in Ret expressing MDCK cells.	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	8	9	10	11
Activation of RET by GDNF has been shown to require an accessory component , GDNFR-alpha ( RETL1 ) .	Activation of RET by GDNF has been shown to require an accessory component, GDNFR-alpha (RETL1).	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	4	5	2	3
As described above , the main signaling pathways activated via GDNF mediated Ret activation are the MAPK , PI3K and PLCgamma ( XREF_FIG ) .	As described above, the main signaling pathways activated via GDNF mediated Ret activation are the MAPK, PI3K and PLCgamma (XREF_FIG).	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	10	11	12	13
Ret activation by GDNF was also observed in cultured embryonic rat spinal cord motor neurons , a cell type that responds to GDNF in vivo .	Ret activation by GDNF was also observed in cultured embryonic rat spinal cord motor neurons, a cell type that responds to GDNF in vivo.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	3	4	0	1
RET receptor activation by GDNF therefore triggers cellular Ca 2+ responses by a molecular mechanism involving Tyr1015 , but not Tyr1062 .	RET receptor activation by GDNF therefore triggers cellular Ca 2+ responses by a molecular mechanism involving Tyr1015, but not Tyr1062.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	4	5	0	1
These results confirmed that cross-talk signaling pathways via other receptors are not significantly involved in GDNF activation of RET signaling pathways .	These results confirmed that cross-talk signaling pathways via other receptors are not significantly involved in GDNF activation of RET signaling pathways.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	15	16	18	19
In response to such localized stimulation by GDNF induced Ret signal transduction , WD cells compete for inclusion in the forming primary ureteric bud based on their Ret activity levels .	In response to such localized stimulation by GDNF induced Ret signal transduction, WD cells compete for inclusion in the forming primary ureteric bud based on their Ret activity levels.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	7	8	9	10
XREF_BIBR In addition , mice depleted of the GFRalpha1 gene , a primary co-receptor responsible for the GDNF mediated activation of the RET kinase , had a similar phenotype to GDNF-/- mice with moderate neuronal loss ( 33 % ) in the SMG PSG .	XREF_BIBR In addition, mice depleted of the GFRalpha1 gene, a primary co-receptor responsible for the GDNF mediated activation of the RET kinase, had a similar phenotype to GDNF-/- mice with moderate neuronal loss (33%) in the SMG PSG.	14	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	17	18	22	23
In addition , the mechanisms by which the two accessory proteins facilitate the activation of RET by GDNF are quite distinct .	In addition, the mechanisms by which the two accessory proteins facilitate the activation of RET by GDNF are quite distinct.	11	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	17	18	15	16
GDNF and NRTN treatments were able to partially rescue Ret + neurons from apoptosis ( XREF_FIG ; p < 0.001 for each ) , and this rescue affect was substantially diminished in p75-cKO ( p < 0.0001 for each ) .	GDNF and NRTN treatments were able to partially rescue Ret + neurons from apoptosis (XREF_FIG; p < 0.001 for each), and this rescue affect was substantially diminished in p75-cKO (p < 0.0001 for each).	0	11	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	0	1	9	10
Therefore , GDNF mediated RET kinase activation is associated with the pathogenesis of malignant melanoma .	Therefore, GDNF mediated RET kinase activation is associated with the pathogenesis of malignant melanoma.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	2	3	4	5
The activation of RET by GDNF is known for its role in the proliferation and viability of neuroblastoma XREF_BIBR , XREF_BIBR .	The activation of RET by GDNF is known for its role in the proliferation and viability of neuroblastoma XREF_BIBR, XREF_BIBR.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	5	6	3	4
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR GDNF can also activate RET via GFRalpha2 and NRTN via GFRalpha .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR GDNF can also activate RET via GFRalpha2 and NRTN via GFRalpha.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	7	8	11	12
Based on the role of RET in mouse SSC self-renewal we propose that the M918T mutation modifies the signal transduced from GDNF activated RET downstream through the SFK , PI3K and AKT and possibly RAS pathways leading to the production of mutation clusters .	Based on the role of RET in mouse SSC self-renewal we propose that the M918T mutation modifies the signal transduced from GDNF activated RET downstream through the SFK, PI3K and AKT and possibly RAS pathways leading to the production of mutation clusters.	19	36	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	21	22	23	24
Glial cell line derived neurotrophic factor ( GDNF ) activates the receptor tyrosine kinase RET by binding to the GDNF family receptor alpha1 ( GFRalpha1 ) and forming the GDNF ( 2 )-GFRalpha1 ( 2 )-RET ( 2 ) heterohexamer complex .	Glial cell line derived neurotrophic factor (GDNF) activates the receptor tyrosine kinase RET by binding to the GDNF family receptor alpha1 (GFRalpha1) and forming the GDNF (2)-GFRalpha1 (2)-RET (2) heterohexamer complex.	2	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	7	8	14	15
GDNF and GFRalpha1 have been shown to activate the transmembrane receptor RET and the neural cell adhesion molecule ( NCAM ) in neurons XREF_BIBR , XREF_BIBR .	GDNF and GFRalpha1 have been shown to activate the transmembrane receptor RET and the neural cell adhesion molecule (NCAM) in neurons XREF_BIBR, XREF_BIBR.	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	0	1	11	12
NTN and GDNF also caused sustained activation of Ret and the mitogen activated protein kinase pathway in SCG neurons .	NTN and GDNF also caused sustained activation of Ret and the mitogen activated protein kinase pathway in SCG neurons.	0	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	2	3	8	9
Ret51 immunoprecipitation of the supernatants from the streptavidin pull-downs confirmed that GDNF stimulation of axons activated Ret in a sustained fashion ( because of axonal proteasome inhibition ) regardless of whether the distal axons were biotinylated or not ( XREF_FIG ) .	Ret51 immunoprecipitation of the supernatants from the streptavidin pull-downs confirmed that GDNF stimulation of axons activated Ret in a sustained fashion (because of axonal proteasome inhibition) regardless of whether the distal axons were biotinylated or not (XREF_FIG).	11	39	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	11	12	16	17
Thus , Ret independent signaling by GDNF has an apparent role in the ureteric branching but may be less significant in the primary bud formation .	Thus, Ret independent signaling by GDNF has an apparent role in the ureteric branching but may be less significant in the primary bud formation.	2	7	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	6	7	2	3
These results suggest that p75 augments GDNF mediated Ret activation .	These results suggest that p75 augments GDNF mediated Ret activation.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	6	7	8	9
We here demonstrate that RET receptor activation by GDNF stimulates cytosolic Ca 2+ signaling through a PLCgamma phosphotyrosine binding site at Tyr1015 .	We here demonstrate that RET receptor activation by GDNF stimulates cytosolic Ca 2+ signaling through a PLCgamma phosphotyrosine binding site at Tyr1015.	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	8	9	4	5
Because Ret activation by GDNF and GFRalpha1 is required for ENS precursor survival , proliferation and migration , Ret deficiency causes intestinal aganglionosis ( Hirschsprung disease ) in mice and humans .	Because Ret activation by GDNF and GFRalpha1 is required for ENS precursor survival, proliferation and migration, Ret deficiency causes intestinal aganglionosis (Hirschsprung disease) in mice and humans.	1	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	4	5	1	2
Our recent study found that zebrafish GDNF and GFRalpha1 could activate human RET , revealing the structural and functional conservation of RET from an evolutionary perspective [ XREF_BIBR ] .	Our recent study found that zebrafish GDNF and GFRalpha1 could activate human RET, revealing the structural and functional conservation of RET from an evolutionary perspective [XREF_BIBR].	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	6	7	12	13
Furthermore , we demonstrate that p75 is required for GDNF mediated Ret activation , survival , and cell surface localization of Ret in DRG neurons .	Furthermore, we demonstrate that p75 is required for GDNF mediated Ret activation, survival, and cell surface localization of Ret in DRG neurons.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	9	10	11	12
Signaling pathway , genome-wide chromatin binding , and transcriptome analyses have demonstrated that SPIN1 has a direct impact on the expression of GDNF , which activates RET pathway XREF_BIBR .	Signaling pathway, genome-wide chromatin binding, and transcriptome analyses have demonstrated that SPIN1 has a direct impact on the expression of GDNF, which activates RET pathway XREF_BIBR.	20	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	expression of GDNF	gdnf	RET	RET	ret	22	23	26	27
RET activation by GDNF is also required for the secondary radial migration that gives rise to the submucosal plexus [ XREF_BIBR ] .	RET activation by GDNF is also required for the secondary radial migration that gives rise to the submucosal plexus [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	3	4	0	1
To exclude the possibility that cross-talk signaling pathways via other receptors are involved in GDNF activation of RET signaling pathways , we transfected small interfering RNA ( siRNA ) against RET in RETp cells ( ME1 ) , and GDNF induced cell proliferation was assessed .	To exclude the possibility that cross-talk signaling pathways via other receptors are involved in GDNF activation of RET signaling pathways, we transfected small interfering RNA (siRNA) against RET in RETp cells (ME1), and GDNF induced cell proliferation was assessed.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	14	15	17	18
On the basis of these results it is possible to conclude that in SH-SY5Y and LAN-5 cells , Ret is activated by a GDNF independent mechanism .	On the basis of these results it is possible to conclude that in SH-SY5Y and LAN-5 cells, Ret is activated by a GDNF independent mechanism.	18	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	23	24	18	19
Our results demonstrate a novel RET signaling pathway where GDNF stimulates cytosolic Ca 2+ signaling through the PLCgamma phosphotyrosine binding site Tyr1015 of RET .	Our results demonstrate a novel RET signaling pathway where GDNF stimulates cytosolic Ca 2+ signaling through the PLCgamma phosphotyrosine binding site Tyr1015 of RET.	9	24	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	9	10	23	24
Several positive feedback mechanisms , including the up-regulation of Ret by Gdnf signaling at branch tips , adding robustness to the receptor tyrosine kinase ( RTK ) regulated branching process .	Several positive feedback mechanisms, including the up-regulation of Ret by Gdnf signaling at branch tips, adding robustness to the receptor tyrosine kinase (RTK) regulated branching process.	7	12	up-regulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Gdnf	Gdnf	Gdnf	Ret	Ret	Ret	11	12	9	10
Moreover , GDNF can activate the RET tyrosine kinase domain .	Moreover, GDNF can activate the RET tyrosine kinase domain.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	2	3	6	7
Interestingly , we found that , while in the absence of the excitotoxicity insult , GDNF stimulates Ret dependent signalling mainly in the subpopulation of IB4 positive cells of the CA3 region ( see above ) , the pattern of GDNF dependent activation of Ret changes following NMDA treatment .	Interestingly, we found that, while in the absence of the excitotoxicity insult, GDNF stimulates Ret dependent signalling mainly in the subpopulation of IB4 positive cells of the CA3 region (see above), the pattern of GDNF dependent activation of Ret changes following NMDA treatment.	15	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	15	16	17	18
GDNF is secreted from mesenchymal cells adjacent to the UB XREF_BIBR and activates its receptor Ret locally at the UB tips .	GDNF is secreted from mesenchymal cells adjacent to the UB XREF_BIBR and activates its receptor Ret locally at the UB tips.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	0	1	15	16
The binding of GDNF triggers the activation of the multicomponent signaling GFRalpha-1 , Ret , and receptor complex which modulates the self-renewal of SSCs and the development of undifferentiated spermatogonial cells via multiple signaling pathways ( Scr signaling pathway / Ras signaling pathway ) XREF_BIBR , XREF_BIBR , XREF_BIBR .	The binding of GDNF triggers the activation of the multicomponent signaling GFRalpha-1, Ret, and receptor complex which modulates the self-renewal of SSCs and the development of undifferentiated spermatogonial cells via multiple signaling pathways (Scr signaling pathway / Ras signaling pathway) XREF_BIBR, XREF_BIBR, XREF_BIBR.	1	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	3	4	13	14
GDNF activates Met in both Ret dependent and -independent signaling .	GDNF activates Met in both Ret dependent and -independent signaling.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	0	1	5	6
The most effective inhibitor identified , NVP-AST487 , suppressed GDNF stimulated RET downstream signaling and 3D tumor spheroid growth .	The most effective inhibitor identified, NVP-AST487, suppressed GDNF stimulated RET downstream signaling and 3D tumor spheroid growth.	8	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	9	10	11	12
GDNF activates Ret at the tips of ureteric bud epithelia , where Ret is expressed in two major splice variants , Ret9 and Ret51 , which differ only in their COOH-terminal amino acids .	GDNF activates Ret at the tips of ureteric bud epithelia, where Ret is expressed in two major splice variants, Ret9 and Ret51, which differ only in their COOH-terminal amino acids.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	0	1	2	3
GDNF mediated RET signaling is critical for the self-renewal and proliferation of SSCs [ XREF_BIBR ] .	GDNF mediated RET signaling is critical for the self-renewal and proliferation of SSCs [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	0	1	2	3
In Transwell migration assays , GDNF induced RET activation resulted in a significant increase in BT474-AROM3 cell motility , which was blocked to a similar extent by both letrozole and NVP-AST487 treatment .	In Transwell migration assays, GDNF induced RET activation resulted in a significant increase in BT474-AROM3 cell motility, which was blocked to a similar extent by both letrozole and NVP-AST487 treatment.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	5	6	7	8
After Ret activation by GDNF , CD2AP dissociates .	After Ret activation by GDNF, CD2AP dissociates.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	4	5	1	2
Surprisingly , we also found that zebrafish GDNF as well as zebrafish GFRalpha1 robustly activated human RET signaling and promoted the survival of cultured mouse dopaminergic neurons with comparable efficiency to mammalian GDNF , unlike E. coli produced human proteins .	Surprisingly, we also found that zebrafish GDNF as well as zebrafish GFRalpha1 robustly activated human RET signaling and promoted the survival of cultured mouse dopaminergic neurons with comparable efficiency to mammalian GDNF, unlike E. coli produced human proteins.	6	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	7	8	16	17
Likewise , activation of RET by GDNF induces HH signaling , whereas knockdown of RET attenuates both basal and GDNF induced activities of HH signaling .	Likewise, activation of RET by GDNF induces HH signaling, whereas knockdown of RET attenuates both basal and GDNF induced activities of HH signaling.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	6	7	4	5
Transcriptional responses were lower in magnitude in TamR MCF-7 cells following both 1 and 24 hours of GDNF treatment , likely reflecting a dampened GDNF response in TamR lines due to higher basal levels of GDNF acting to stimulate the RET receptor in an autocrine fashion , as expected based on our previous work [ XREF_BIBR ] .	Transcriptional responses were lower in magnitude in TamR MCF-7 cells following both 1 and 24 hours of GDNF treatment, likely reflecting a dampened GDNF response in TamR lines due to higher basal levels of GDNF acting to stimulate the RET receptor in an autocrine fashion, as expected based on our previous work [XREF_BIBR].	33	41	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	levels of GDNF	gdnf	RET	RET	ret	35	36	40	41
Gdnf secreted by the MM activates a Gfra1 and Ret receptor-tyrosine kinase complex and triggers outgrowth of Ret positive cells from the nephric duct toward the Gdnf signal [ XREF_BIBR , XREF_BIBR ] .	Gdnf secreted by the MM activates a Gfra1 and Ret receptor-tyrosine kinase complex and triggers outgrowth of Ret positive cells from the nephric duct toward the Gdnf signal [XREF_BIBR, XREF_BIBR].	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gdnf	Gdnf	Gdnf	Ret	Ret	Ret	0	1	9	10
The glial-cell-line-derived neurotrophic factor ( GDNF ) ligand activates the Ret receptor through the assembly of a multiprotein complex , including the GDNF family receptor alpha1 ( GFRalpha1 ) molecule .	The glial-cell-line-derived neurotrophic factor (GDNF) ligand activates the Ret receptor through the assembly of a multiprotein complex, including the GDNF family receptor alpha1 (GFRalpha1) molecule.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	5	6	10	11
We found that regorafenib blocked GDNF induced RET signaling in NB cells .	We found that regorafenib blocked GDNF induced RET signaling in NB cells.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	5	6	7	8
To further confirm these findings we blocked GDNF dependent activation of Ret by two different inhibitors : 1 ) the D4 aptamer , that inhibits Ret activity by directly binding its extracellular domain XREF_BIBR , XREF_BIBR ; 2 ) a truncated Ret protein , the EC-Ret wt peptide , that competes for binding to GDNF , thus depleting the culture medium of the functional ligand XREF_BIBR , XREF_BIBR , XREF_BIBR .	To further confirm these findings we blocked GDNF dependent activation of Ret by two different inhibitors : 1) the D4 aptamer, that inhibits Ret activity by directly binding its extracellular domain XREF_BIBR, XREF_BIBR; 2) a truncated Ret protein, the EC-Ret wt peptide, that competes for binding to GDNF, thus depleting the culture medium of the functional ligand XREF_BIBR, XREF_BIBR, XREF_BIBR.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	7	8	11	12
In contrast to the role of ShcC in activating the PI3K and AKT signalling pathway XREF_BIBR , AKT phosphorylation was found to be suppressed in the GDNF treated SK-N-AS cells overexpressing ShcD and RET compared with the untreated cells .	In contrast to the role of ShcC in activating the PI3K and AKT signalling pathway XREF_BIBR, AKT phosphorylation was found to be suppressed in the GDNF treated SK-N-AS cells overexpressing ShcD and RET compared with the untreated cells.	23	34	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	26	27	33	34
Following the binding of RET , a receptor tyrosine kinase , to the GDNF coreceptor GDNF family receptor alpha-1 ( GFRA1 ) , GDNF activates the RET and GFRA1 receptor tyrosine kinase and thereby triggers a signaling cascade that includes the extracellular signal regulated kinase ( ERK ) , phosphoinositol 3-kinase ( PI3K ) , and phospholipase ( PLC ) zeta pathways [ XREF_BIBR ] .	Following the binding of RET, a receptor tyrosine kinase, to the GDNF coreceptor GDNF family receptor alpha-1 (GFRA1), GDNF activates the RET and GFRA1 receptor tyrosine kinase and thereby triggers a signaling cascade that includes the extracellular signal regulated kinase (ERK), phosphoinositol 3-kinase (PI3K), and phospholipase (PLC) zeta pathways [XREF_BIBR].	23	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	23	24	26	27
GDNF stimulation activates Ret and ERK signalling in rat organotypic hippocampal slices .	GDNF stimulation activates Ret and ERK signalling in rat organotypic hippocampal slices.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	0	1	3	4
Exogenous GDNF partially restores the renal phenotype of ret deficient mice .	Exogenous GDNF partially restores the renal phenotype of ret deficient mice.	0	10	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	ret	ret	ret	1	2	8	9
GDNF , along with GDNF family receptor alpha1 ( GFRalpha1 ) , activates the tyrosine kinase receptor RET ( expressed in the WD ) to promote the localized UB outgrowth .	GDNF, along with GDNF family receptor alpha1 (GFRalpha1), activates the tyrosine kinase receptor RET (expressed in the WD) to promote the localized UB outgrowth.	0	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	0	1	17	18
XREF_BIBR , XREF_BIBR , XREF_BIBR Thus , Ret might be activated by a GDNF independent mechanism to stimulate SNpc dopaminergic neuron survival .	XREF_BIBR, XREF_BIBR, XREF_BIBR Thus, Ret might be activated by a GDNF independent mechanism to stimulate SNpc dopaminergic neuron survival.	7	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	13	14	7	8
Thus , at least for sympathetic neurons , mutation of Dhcr7 does not appear to have any consequence on GDNF induced Ret signaling .	Thus, at least for sympathetic neurons, mutation of Dhcr7 does not appear to have any consequence on GDNF induced Ret signaling.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	19	20	21	22
It was demonstrated that the presence of heparin-sulfates is required for GDNF activation of RET tyrosine kinase activation in a MDCK cell line XREF_BIBR .	It was demonstrated that the presence of heparin-sulfates is required for GDNF activation of RET tyrosine kinase activation in a MDCK cell line XREF_BIBR.	11	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	11	12	14	15
The ligand , GDNF , stimulates RET activity through a co-receptor , GFR alpha-1 .	The ligand, GDNF, stimulates RET activity through a co-receptor, GFR alpha-1.	1	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	3	4	6	7
The purpose of our study was to further explore the signaling mechanisms of GDNF and to determine whether the actin cytoskeleton is involved in the GDNF induced Ret translocation into lipid rafts .	The purpose of our study was to further explore the signaling mechanisms of GDNF and to determine whether the actin cytoskeleton is involved in the GDNF induced Ret translocation into lipid rafts.	22	28	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	25	26	27	28
This report demonstrates that the glial cell line derived neurotrophic factor ( GDNF ) activates RET , as measured by tyrosine phosphorylation of the intracellular catalytic domain .	This report demonstrates that the glial cell line derived neurotrophic factor (GDNF) activates RET, as measured by tyrosine phosphorylation of the intracellular catalytic domain.	7	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	12	13	15	16
One such signal is the neurotrophic factor Gdnf , which is specifically expressed by the gut mesenchyme and activates the receptor tyrosine kinase Ret ( induced in pre-ENCCs as they approach the foregut ) to promote ENCC survival and proliferation [ XREF_BIBR , XREF_BIBR ] .	One such signal is the neurotrophic factor Gdnf, which is specifically expressed by the gut mesenchyme and activates the receptor tyrosine kinase Ret (induced in pre-ENCCs as they approach the foregut) to promote ENCC survival and proliferation [XREF_BIBR, XREF_BIBR].	2	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gdnf	Gdnf, which is specifically expressed	gdnf	Ret	Ret	ret	7	8	23	24
Indeed , if in LAN-5 and SH-SY5Y cells Ret is activated by a GDNF independent mechanism , using these molecules should have not to affect RA induced Ret phosphorylation and differentiation .	Indeed, if in LAN-5 and SH-SY5Y cells Ret is activated by a GDNF independent mechanism, using these molecules should have not to affect RA induced Ret phosphorylation and differentiation.	8	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	13	14	8	9
Endoneurial macrophages are shown to secrete high levels of GDNF , which activates RET and promotes perineural invasion of pancreatic cancer XREF_BIBR .	Endoneurial macrophages are shown to secrete high levels of GDNF, which activates RET and promotes perineural invasion of pancreatic cancer XREF_BIBR.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	levels of GDNF	gdnf	RET	RET	ret	9	10	13	14
Activation of Ret by GDNF induces cell proliferation in the UB tip cells [ XREF_BIBR , XREF_BIBR ] .	Activation of Ret by GDNF induces cell proliferation in the UB tip cells [XREF_BIBR, XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	4	5	2	3
In addition , GDNF stimulates Ret signaling in the UB tip cells to induce UB branching and nephron formation [ XREF_BIBR ] .	In addition, GDNF stimulates Ret signaling in the UB tip cells to induce UB branching and nephron formation [XREF_BIBR].	3	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	3	4	5	6
These results indicated that actin polymerization was integral to GDNF induced Ret translocation .	These results indicated that actin polymerization was integral to GDNF induced Ret translocation.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	9	10	11	12
Analysis of 155 patient samples revealed that levels of GDNF , activated RET ( RETph ) , and MAZ were elevated in all four types of liposarcoma .	Analysis of 155 patient samples revealed that levels of GDNF, activated RET (RETph), and MAZ were elevated in all four types of liposarcoma.	7	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	levels of GDNF	gdnf	RET	RET	ret	9	10	12	13
In breast cancer cells in two-dimensional and three-dimensional culture , GDNF mediated RET signaling is enhanced in a model of aromatase inhibitor resistance .	In breast cancer cells in two-dimensional and three-dimensional culture, GDNF mediated RET signaling is enhanced in a model of aromatase inhibitor resistance.	10	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	10	11	12	13
Activation of Ret by GDNF in the presence of its cognate coreceptor , GFRalpha1 , leads to autophosphorylation of tyrosine residues in the cytoplasmic domain of Ret and subsequent recruitment of signaling mediators such as PLCgamma and the adaptor proteins Grb2 , Shc , FRS-2 , and dok1-5 .	Activation of Ret by GDNF in the presence of its cognate coreceptor, GFRalpha1, leads to autophosphorylation of tyrosine residues in the cytoplasmic domain of Ret and subsequent recruitment of signaling mediators such as PLCgamma and the adaptor proteins Grb2, Shc, FRS-2, and dok1-5.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	4	5	2	3
However , whether the actin cytoskeleton is involved in GDNF induced Ret translocation into lipid rafts is unclear .	However, whether the actin cytoskeleton is involved in GDNF induced Ret translocation into lipid rafts is unclear.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	9	10	11	12
Since RET can be activated by GFLs and GFRas either in cis or in trans ( mainly by GDNF and GFRa1 ) in vitro , we asked if the expression patterns of Gfra1 , Gfra2 , Gdnf , and Nrtn in the developing SC and DRGs would provide insight into RET signaling in RA mechanoreceptors in vivo .	Since RET can be activated by GFLs and GFRas either in cis or in trans (mainly by GDNF and GFRa1) in vitro, we asked if the expression patterns of Gfra1, Gfra2, Gdnf, and Nrtn in the developing SC and DRGs would provide insight into RET signaling in RA mechanoreceptors in vivo.	1	20	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	18	19	1	2
GDNF activates Ret and ERK signalling in a specific population of IB4 positive cells in the CA3 subregion .	GDNF activates Ret and ERK signalling in a specific population of IB4 positive cells in the CA3 subregion.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	0	1	2	3
The Actin Cytoskeleton Is Involved in GDNF Induced Ret Translocation into Lipid Rafts .	The Actin Cytoskeleton Is Involved in GDNF Induced Ret Translocation into Lipid Rafts.	6	9	Induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	6	7	8	9
The cells were either untransfected or transiently co- transfected with GFP-ShcD and MYC-RET and then left untreated or treated with GDNF .	The cells were either untransfected or transiently co- transfected with GFP-ShcD and MYC-RET and then left untreated or treated with GDNF.	8	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	MYC-RET	MYC-RET	MYC-RET	20	21	12	13
In contrast to the GDNF induced Ret activation , the GFRalpha1 mediated Met activation promotes tubulogenesis but only weak chemokinetic motility of MDCK cells .	In contrast to the GDNF induced Ret activation, the GFRalpha1 mediated Met activation promotes tubulogenesis but only weak chemokinetic motility of MDCK cells.	1	7	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	4	5	6	7
To further confirm GDNF induced Ret translocation into lipid rafts , we used patching and immunofluorescence to visualize the colocalization of lipid rafts and Ret after GDNF treatment for 30 min .	To further confirm GDNF induced Ret translocation into lipid rafts, we used patching and immunofluorescence to visualize the colocalization of lipid rafts and Ret after GDNF treatment for 30 min.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	3	4	5	6
These results indicated that PLC dependent GDNF and RET signaling played a role in the migratory movement of neuronal progenitor cells overexpressing RET in the VZ .	These results indicated that PLC dependent GDNF and RET signaling played a role in the migratory movement of neuronal progenitor cells overexpressing RET in the VZ.	4	25	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	6	7	22	23
The GDNF stimulated tangential migration of GABAergic neurons was dependent of GFRalpha1 but not of RET XREF_BIBR .	The GDNF stimulated tangential migration of GABAergic neurons was dependent of GFRalpha1 but not of RET XREF_BIBR.	0	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	1	2	15	16
In accordance with these results , we observe increased levels of GDNF , activated RET , and MAZ in human liposarcoma compared to normal adipose tissue or lipoma .	In accordance with these results, we observe increased levels of GDNF, activated RET, and MAZ in human liposarcoma compared to normal adipose tissue or lipoma.	9	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	levels of GDNF	gdnf	RET	RET	ret	11	12	14	15
We analyzed the survival responses and downstream signaling elicited by GDNF on sympathetic neurons from different Ret knockin mice .	We analyzed the survival responses and downstream signaling elicited by GDNF on sympathetic neurons from different Ret knockin mice.	8	18	elicited	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	10	11	16	17
We found that SRF and AP-1 are the transcription factors responsible for transducing the immediate changes in response to GDNF induced RET activation , and that these factors act downstream of ERK signaling by releasing promoter proximal paused Pol II into productive elongation .	We found that SRF and AP-1 are the transcription factors responsible for transducing the immediate changes in response to GDNF induced RET activation, and that these factors act downstream of ERK signaling by releasing promoter proximal paused Pol II into productive elongation.	12	22	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	19	20	21	22
GDNF activates either RET or NCAM via GFR-alpha1 , NRTN via GFR-alpha2 , ARTN via GFR-alpha3 , and PSPN uses GFR-alpha4 .	GDNF activates either RET or NCAM via GFR-alpha1, NRTN via GFR-alpha2, ARTN via GFR-alpha3, and PSPN uses GFR-alpha4.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	0	1	3	4
Mammalian Ret is activated by GDNF to instruct epithelial morphogenesis in the uteric duct of the kidney XREF_BIBR and Ret activating mutations have been implicated in a variety of human cancers including epithelial cancers ( breast and lung ) and multiple endocrine neoplasia ( men2 ) XREF_BIBR - XREF_BIBR .	Mammalian Ret is activated by GDNF to instruct epithelial morphogenesis in the uteric duct of the kidney XREF_BIBR and Ret activating mutations have been implicated in a variety of human cancers including epithelial cancers (breast and lung) and multiple endocrine neoplasia (men2) XREF_BIBR - XREF_BIBR.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	5	6	1	2
Pull-down assays using the Dok-6 phosphotyrosine binding ( PTB ) domain and GDNF activated Ret indicate that Dok-6 binds to the phosphorylated Ret Tyr ( 1062 ) residue .	Pull-down assays using the Dok-6 phosphotyrosine binding (PTB) domain and GDNF activated Ret indicate that Dok-6 binds to the phosphorylated Ret Tyr (1062) residue.	10	15	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	12	13	14	15
The RET receptor tyrosine kinase is activated by GDNF and controls outgrowth and invasion of the ureteric bud epithelia in the developing kidney .	The RET receptor tyrosine kinase is activated by GDNF and controls outgrowth and invasion of the ureteric bud epithelia in the developing kidney.	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	8	9	1	2
Glial cell line derived neurotrophic factor ( GDNF ) binds to the GDNF family co-receptor alpha1 ( GFRalpha1 ) and activates RET receptor tyrosine kinase .	Glial cell line derived neurotrophic factor (GDNF) binds to the GDNF family co-receptor alpha1 (GFRalpha1) and activates RET receptor tyrosine kinase.	2	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	7	8	21	22
Recent data indicate that GDNF induced migration of Ret transfected MDCK cells is critically dependent on Ret and its downstream signaling via the PI3 kinase pathway .	Recent data indicate that GDNF induced migration of Ret transfected MDCK cells is critically dependent on Ret and its downstream signaling via the PI3 kinase pathway.	4	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	4	5	8	9
Endogenous GDNF produced by endocrine resistant cells is translated , secreted into the media , and activates RET signaling in nearby cells .	Endogenous GDNF produced by endocrine resistant cells is translated, secreted into the media, and activates RET signaling in nearby cells.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	1	2	17	18
Using co-immunoprecipitation we found that GDNF could induce interactions of Ret and actin cytoskeleton .	Using co-immunoprecipitation we found that GDNF could induce interactions of Ret and actin cytoskeleton.	5	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	5	6	10	11
GDNF failed to elevate cytosolic Ca 2+ in RET WT expressing cells that were pre-treated with U73122 ( XREF_TABLE and XREF_FIG ) .	GDNF failed to elevate cytosolic Ca 2+ in RET WT expressing cells that were pre-treated with U73122 (XREF_TABLE and XREF_FIG).	0	9	elevate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	0	1	8	9
The expression level of intrinsic Ret , Gdnf , and Gfralpha1 transcripts in malignant melanomas from RET-transgenic mice was significantly upregulated compared with those in benign melanocytic tumors , and GDNF treatment activated RET via phosphorylated Tyr 905 in human malignant melanoma cells XREF_BIBR .	The expression level of intrinsic Ret, Gdnf, and Gfralpha1 transcripts in malignant melanomas from RET-transgenic mice was significantly upregulated compared with those in benign melanocytic tumors, and GDNF treatment activated RET via phosphorylated Tyr 905 in human malignant melanoma cells XREF_BIBR.	30	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	30	31	33	34
Because Met is the only receptor to promote branching of wild-type MDCK cells , we tested whether GDNF activates Met in non Ret signaling .	Because Met is the only receptor to promote branching of wild-type MDCK cells, we tested whether GDNF activates Met in non Ret signaling.	17	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	17	18	22	23
Zebrafish GDNF and its co-receptor GFRalpha1 activate the human RET receptor and promote the survival of dopaminergic neurons in vitro .	Zebrafish GDNF and its co-receptor GFRalpha1 activate the human RET receptor and promote the survival of dopaminergic neurons in vitro.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	1	2	9	10
To confirm whether F-actin is involved in GDNF mediated Ret translocation to lipid rafts , we performed co-immunoprecipitation experiments .	To confirm whether F-actin is involved in GDNF mediated Ret translocation to lipid rafts, we performed co-immunoprecipitation experiments.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	7	8	9	10
The GDNF ligand activates the RET receptor through the assembly of a multiprotein complex , including the GDNF family receptor alpha1 ( GFRalpha1 ) molecule , which have important functions in the development and maintenance of sensory , enteric , sympathetic and parasympathetic neurons and a variety of non neural tissues XREF_BIBR .	The GDNF ligand activates the RET receptor through the assembly of a multiprotein complex, including the GDNF family receptor alpha1 (GFRalpha1) molecule, which have important functions in the development and maintenance of sensory, enteric, sympathetic and parasympathetic neurons and a variety of non neural tissues XREF_BIBR.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	1	2	5	6
LTin cells responded to all RET ligands in trans , requiring factors from other cells , whereas RET was activated in enteric neurons exclusively by GDNF in cis .	LTin cells responded to all RET ligands in trans, requiring factors from other cells, whereas RET was activated in enteric neurons exclusively by GDNF in cis.	17	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	25	26	17	18
Collectively , this study shows that CA3 and CA1 hippocampal regions are highly responsive to GDNF induced Ret receptor activation and neuroprotection , and suggest that , upon excitotoxicity , such neuroprotective action involves a GDNF modulation of microglial cell activity .	Collectively, this study shows that CA3 and CA1 hippocampal regions are highly responsive to GDNF induced Ret receptor activation and neuroprotection, and suggest that, upon excitotoxicity, such neuroprotective action involves a GDNF modulation of microglial cell activity.	13	24	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	15	16	17	18
In addition , activation of Ret tyrosine kinase activity , either via GDNF stimulation of full-length Ret or via epidermal growth factor stimulation of an epidermal growth factor receptor-Ret chimeric receptor , results in phosphatidylinositol 3-kinase activation and phosphatidylinositol 3-kinase-dependent formation of large lamellipodia .	In addition, activation of Ret tyrosine kinase activity, either via GDNF stimulation of full-length Ret or via epidermal growth factor stimulation of an epidermal growth factor receptor-Ret chimeric receptor, results in phosphatidylinositol 3-kinase activation and phosphatidylinositol 3-kinase-dependent formation of large lamellipodia.	12	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	12	13	16	17
Glial cell derived neurotrophic factor ( GDNF ) is secreted by Sertoli cells , and promotes germ stem cell proliferation by activating RET , a tyrosine kinase receptor .	Glial cell derived neurotrophic factor (GDNF) is secreted by Sertoli cells, and promotes germ stem cell proliferation by activating RET, a tyrosine kinase receptor.	1	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	6	7	22	23
Given that p75 is required for GDNF mediated Ret activation , we sought to determine whether loss of p75 impacted GFL mediated DRG neuron survival .	Given that p75 is required for GDNF mediated Ret activation, we sought to determine whether loss of p75 impacted GFL mediated DRG neuron survival.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	6	7	8	9
41 Given the key role of excitotoxicity in OGD induced downregulation of Ret51 and cell death , we investigated the effect of toxic stimulation with glutamate on GDNF induced Ret51 activation by transphosphorylation .	41 Given the key role of excitotoxicity in OGD induced downregulation of Ret51 and cell death, we investigated the effect of toxic stimulation with glutamate on GDNF induced Ret51 activation by transphosphorylation.	25	30	induced	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret51	Ret51	Ret51	27	28	29	30
Neurotrophic factors are extra-cellular environmental cues to neurons and include the glial derived neurotrophic factor ( GDNF ) family ligands ( GFL ) that activate the tyrosine kinase receptor RET in the nervous system , kidney and haematopoietic progenitors XREF_BIBR - XREF_BIBR .	Neurotrophic factors are extra-cellular environmental cues to neurons and include the glial derived neurotrophic factor (GDNF) family ligands (GFL) that activate the tyrosine kinase receptor RET in the nervous system, kidney and haematopoietic progenitors XREF_BIBR - XREF_BIBR.	14	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	16	17	29	30
Stimulation of Ret by GDNF and soluble GFRalpha-1 rescued mitochondrial fragmentation , demonstrating that endogenous mammalian Ret can rescue mitochondrial impairments ( XREF_FIG C and D ) .	Stimulation of Ret by GDNF and soluble GFRalpha-1 rescued mitochondrial fragmentation, demonstrating that endogenous mammalian Ret can rescue mitochondrial impairments (XREF_FIG C and D).	0	7	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	4	5	2	3
GDNF is an essential trophic factor for ENCDC during fetal development because GDNF activates the RET transmembrane tyrosine kinase via the co-receptor GFRalpha1 .	GDNF is an essential trophic factor for ENCDC during fetal development because GDNF activates the RET transmembrane tyrosine kinase via the co-receptor GFRalpha1.	12	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	12	13	15	16
GDNF can also signal RET independently through GFR1alpha .	GDNF can also signal RET independently through GFR1alpha.	0	5	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	0	1	4	5
Taken together , these data indicate that when Ret was activated by GDNF in distal axons , it was degraded in axons , thus preventing it from being retrogradely transported to the cell bodies .	Taken together, these data indicate that when Ret was activated by GDNF in distal axons, it was degraded in axons, thus preventing it from being retrogradely transported to the cell bodies.	8	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	12	13	8	9
Our interpretation of the D4 aptamer ' s mode of action relies upon three observations : ( 1 ) D4 binds with similar affinities to cells expressing RET in a monomeric or dimeric form ; ( 2 ) D4 inhibits dimerization dependent RET activation , as a consequence either of GDNF stimulation of RET wt or RET M918T or of constitutive dimerization of the RET C634Y mutant ; and ( 3 ) D4 does not inhibit a monomeric form of RET that is constitutively activated by a mutation in the intracellular kinase domain ( RET M918T ) .	Our interpretation of the D4 aptamer 's mode of action relies upon three observations : (1) D4 binds with similar affinities to cells expressing RET in a monomeric or dimeric form; (2) D4 inhibits dimerization dependent RET activation, as a consequence either of GDNF stimulation of RET wt or RET M918T or of constitutive dimerization of the RET C634Y mutant; and (3) D4 does not inhibit a monomeric form of RET that is constitutively activated by a mutation in the intracellular kinase domain (RET M918T).	50	57	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	50	51	53	54
Indeed , the D4 aptamer interferes with the GDNF mediated Ret dimerization and the EC-Ret wt molecule competes for binding to GDNF thus depleting the culture medium of the functional ligand XREF_BIBR , XREF_BIBR , XREF_BIBR .	Indeed, the D4 aptamer interferes with the GDNF mediated Ret dimerization and the EC-Ret wt molecule competes for binding to GDNF thus depleting the culture medium of the functional ligand XREF_BIBR, XREF_BIBR, XREF_BIBR.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	8	9	10	11
In ureteric tip explants , RA signaling is required for Gdnf mediated activation of Ret ( and most likely Ret dependent targets ) in the ureteric epithelium .	In ureteric tip explants, RA signaling is required for Gdnf mediated activation of Ret (and most likely Ret dependent targets) in the ureteric epithelium.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gdnf	Gdnf	Gdnf	Ret	Ret	Ret	10	11	14	15
GDNF signals through a receptor complex consisting of the receptor tyrosine kinase Ret and a glycosyl-phosphatidylinositol ( GPI )-linked receptor termed GDNFR-alpha .	GDNF signals through a receptor complex consisting of the receptor tyrosine kinase Ret and a glycosyl-phosphatidylinositol (GPI)-linked receptor termed GDNFR-alpha.	0	19	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	0	1	12	13
In neural cells , GDNF activates the Src family kinases in a RET independent manner .	In neural cells, GDNF activates the Src family kinases in a RET independent manner.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	4	5	12	13
Third , as was shown for artemin and GFRalpha3 [ XREF_BIBR ] , a high concentration of zGDNF may shift the equilibrium from the heterotrimeric GFRalpha1 2 : GDNF that activates RET to the heterodimer GFRalpha1 : GDNF .	Third, as was shown for artemin and GFRalpha3 [XREF_BIBR], a high concentration of zGDNF may shift the equilibrium from the heterotrimeric GFRalpha1 2 : GDNF that activates RET to the heterodimer GFRalpha1 : GDNF.	25	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	28	29	31	32
In this system , GDNF secretion in the metanephric mesenchyme activates the Ret receptor tyrosine kinase via its ligand binding GFRalpha1 co-receptor .	In this system, GDNF secretion in the metanephric mesenchyme activates the Ret receptor tyrosine kinase via its ligand binding GFRalpha1 co-receptor.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	4	5	12	13
We also found that Ret , a downstream target of GFRalpha1 , was functionally activated by GDNF in Ape1 and Ref-1-expressing cells .	We also found that Ret, a downstream target of GFRalpha1, was functionally activated by GDNF in Ape1 and Ref-1-expressing cells.	4	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	16	17	4	5
We observed that GLP-1 and exendin-4 induced neurite outgrowth in a manner similar to nerve growth factor ( NGF ) , which was reversed by coincubation with the selective GLP-1 receptor antagonist exendin ( 9-39 ) .	We observed that GLP-1 and exendin-4 induced neurite outgrowth in a manner similar to nerve growth factor (NGF), which was reversed by coincubation with the selective GLP-1 receptor antagonist exendin (9-39).	3	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	3	4	29	31
The administration of GLP-1 ( 9-36 ) after I/R injury increased vasodilatation and coronary flow in wild-type and Glp1r -/- mice .	The administration of GLP-1 (9-36) after I/R injury increased vasodilatation and coronary flow in wild-type and Glp1r -/- mice.	1	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	Glp1r	Glp1r	Glp1r	3	4	18	19
We have recently showed that GLP-1 stimulates GLP-1 receptor and adenylate cyclase and PKA signaling pathway in VSMC [ XREF_BIBR ] .	We have recently showed that GLP-1 stimulates GLP-1 receptor and adenylate cyclase and PKA signaling pathway in VSMC [XREF_BIBR].	5	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	5	6	7	9
Furthermore , GLP-1 ( 9-36 ) administration during reperfusion reduced ischemic damage after ischemia-reperfusion and increased cGMP release , vasodilatation , and coronary flow in wild-type and Glp1r (-/-) mice , with modest effects on glucose uptake .	Furthermore, GLP-1 (9-36) administration during reperfusion reduced ischemic damage after ischemia-reperfusion and increased cGMP release, vasodilatation, and coronary flow in wild-type and Glp1r (-/-) mice, with modest effects on glucose uptake.	2	29	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	Glp1r	Glp1r	Glp1r	2	3	27	28
For studies involving double KO ( Glp1r -/- : Glp2r -/-) mice or mice treated with native GLP-1 and GLP-2 peptides , weights of saline flushed intestines were used ( see supplementary information ) .	For studies involving double KO (Glp1r -/- : Glp2r -/-) mice or mice treated with native GLP-1 and GLP-2 peptides, weights of saline flushed intestines were used (see supplementary information).	6	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	GLP-2	GLP-2	GLP-2	Glp1r	Glp1r	Glp1r	19	20	6	7
However , many of its vasoprotective actions have also been described for the GLP-1 metabolite ( 9-37 ) , which does not activate the GLP-1 receptor , suggesting the presence of an additional , yet unknown , signaling pathway .	However, many of its vasoprotective actions have also been described for the GLP-1 metabolite (9-37), which does not activate the GLP-1 receptor, suggesting the presence of an additional, yet unknown, signaling pathway.	13	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	13	14	24	26
Increased levels of GLP-1 could , therefore , potentiate GLP-1R activity in the tongue , especially considering our previous findings that the enzyme that degrades GLP-1 in the peripheral circulation ( dipeptidyl peptidase-4 ) is not present in taste cells of mice .	Increased levels of GLP-1 could, therefore, potentiate GLP-1R activity in the tongue, especially considering our previous findings that the enzyme that degrades GLP-1 in the peripheral circulation (dipeptidyl peptidase-4) is not present in taste cells of mice.	1	10	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	levels of GLP-1	glp-1	GLP-1R	GLP-1R	glp-1r	3	4	9	10
These findings suggest that GLP-1 contributes significantly to the hyperinsulinemia and subsequent hypoglycemia , and strongly support the GLP-1 receptor as a potential target for treatment of PPH after gastric surgery .	These findings suggest that GLP-1 contributes significantly to the hyperinsulinemia and subsequent hypoglycemia, and strongly support the GLP-1 receptor as a potential target for treatment of PPH after gastric surgery.	4	20	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	4	5	18	20
Indeed , lowered plasma active GLP-1 levels observed in T2DM patients support the GLP-1 receptor agonism as an appropriate therapeutic strategy [ XREF_BIBR ] .	Indeed, lowered plasma active GLP-1 levels observed in T2DM patients support the GLP-1 receptor agonism as an appropriate therapeutic strategy [XREF_BIBR].	5	15	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1 levels	glp-1	GLP-1 receptor	GLP-1 receptor	glp-1 receptor	5	6	13	15
To determine whether GLP1 protected cardiomyocytes against palmitate induced apoptosis via GLP1R , cardiomyocytes cultured at palmitate for 24h were treated with GLP1 ( 25nM ) alone , or in combination with an increasing amount ( 25-400nM ) of exendin-( 9-39 ) , a specific and competitive antagonist of GLP1R .	To determine whether GLP1 protected cardiomyocytes against palmitate induced apoptosis via GLP1R, cardiomyocytes cultured at palmitate for 24h were treated with GLP1 (25nM) alone, or in combination with an increasing amount (25-400nM) of exendin-(9-39), a specific and competitive antagonist of GLP1R.	9	47	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	GLP1	GLP1	GLP1	GLP1R	GLP1R	GLP1R	22	23	11	12
BETP increased oxyntomodulin binding affinity for the GLP-1 receptor and enhanced oxyntomodulin mediated GLP-1 receptor signaling as measured by activation of the alpha subunit of heterotrimeric G protein and cAMP accumulation .	BETP increased oxyntomodulin binding affinity for the GLP-1 receptor and enhanced oxyntomodulin mediated GLP-1 receptor signaling as measured by activation of the alpha subunit of heterotrimeric G protein and cAMP accumulation.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	oxyntomodulin	oxyntomodulin	oxyntomodulin	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	11	12	13	15
XREF_BIBR - XREF_BIBR Within the periphery , GLP-1 activates GLP-1R on vagal afferent neurons in the small intestine , portal vein , liver and upper GI tract .	XREF_BIBR - XREF_BIBR Within the periphery, GLP-1 activates GLP-1R on vagal afferent neurons in the small intestine, portal vein, liver and upper GI tract.	7	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	7	8	9	10
OXM activates both the GLP-1 receptor ( GLP1R ) and the glucagon receptor ( GCGR ) .	OXM activates both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR).	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXM	OXM	OXM	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	0	1	4	6
Recent studies using BRET have shown that GLP-1 can induce heterodimerisation of GLP-1R and GIPR , whereas treatment with GIP reversed dimer formation .	Recent studies using BRET have shown that GLP-1 can induce heterodimerisation of GLP-1R and GIPR, whereas treatment with GIP reversed dimer formation.	7	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	7	8	12	13
GLP-1 activates the GLP-1 receptor ( GLP-1R ) , leading to stimulating insulin secretion , biosynthesis and sensitivity , improving the damage of beta-cell , reducing glucagon secretion , slowing gastric emptying as well as suppressing appetite [ XREF_BIBR ] .	GLP-1 activates the GLP-1 receptor (GLP-1R), leading to stimulating insulin secretion, biosynthesis and sensitivity, improving the damage of beta-cell, reducing glucagon secretion, slowing gastric emptying as well as suppressing appetite [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	0	1	3	5
An alternative explanation is that peripherally secreted GLP-1 activates GLP-1R located in the innervation of both the intestine and portal vein .	An alternative explanation is that peripherally secreted GLP-1 activates GLP-1R located in the innervation of both the intestine and portal vein.	6	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	7	8	9	10
The GLP-1 peptide activates its cognate Class B-type GLP-1 receptor to induce a c-Src-dependent EGFR transactivation process .	The GLP-1 peptide activates its cognate Class B-type GLP-1 receptor to induce a c-Src-dependent EGFR transactivation process.	1	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	1	2	8	10
Additionally , compounds 2 and B reduced , in a non competitive manner , GLP-1 induced GLP-1R coupling to Galpha q and internalisation ( XREF_FIG ) .	Additionally, compounds 2 and B reduced, in a non competitive manner, GLP-1 induced GLP-1R coupling to Galpha q and internalisation (XREF_FIG).	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	14	15	16	17
GLP-1 mimetics ( e.g ., Byetta ) and GLP-1 analogs ( e.g ., Victoza ) activate the beta cell GLP-1 receptor ( GLP-1R ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) .	GLP-1 mimetics (e.g., Byetta) and GLP-1 analogs (e.g., Victoza) activate the beta cell GLP-1 receptor (GLP-1R), and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus (T2DM).	0	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	0	1	19	21
Therefore , it is possible that they prevent GLP-1 induced GLP-1R internalisation by inhibiting GLP-1 bound hGLP-1R coupling to the Galpha q pathway required for intracellular Ca 2+ accumulation and thereby ERK phosphorylation [ XREF_BIBR ] .	Therefore, it is possible that they prevent GLP-1 induced GLP-1R internalisation by inhibiting GLP-1 bound hGLP-1R coupling to the Galpha q pathway required for intracellular Ca 2+ accumulation and thereby ERK phosphorylation [XREF_BIBR].	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	8	9	10	11
However , in experimental studies , some vasoprotective actions have also been described for the metabolite GLP-1 ( 9-36 ) , which does not activate the GLP-1 receptor , hence suggesting the presence of a dual , yet undefined , signaling pathway .	However, in experimental studies, some vasoprotective actions have also been described for the metabolite GLP-1 (9-36), which does not activate the GLP-1 receptor, hence suggesting the presence of a dual, yet undefined, signaling pathway.	12	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	16	17	26	28
Our observation , that both diuresis and natriuresis positively correlated with plasma GLP-1 levels , is consistent with the renal effects being mediated by GLP-1 activation of the GLP-1 receptor .	Our observation, that both diuresis and natriuresis positively correlated with plasma GLP-1 levels, is consistent with the renal effects being mediated by GLP-1 activation of the GLP-1 receptor.	24	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	24	25	28	30
GLP-1 is generally thought to signal as a hormone , directly activating beta-cell GLP1R to enhance glucose stimulated insulin secretion , i.e. the incretin effect .	GLP-1 is generally thought to signal as a hormone, directly activating beta-cell GLP1R to enhance glucose stimulated insulin secretion, i.e. the incretin effect.	0	14	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP1R	GLP1R	GLP1R	0	1	13	14
Therefore , a PET radioligand based on a GLP-1 agonist that targets the GLP-1R was sought as a potential non invasive imaging agent for BCM .	Therefore, a PET radioligand based on a GLP-1 agonist that targets the GLP-1R was sought as a potential non invasive imaging agent for BCM.	8	14	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	8	9	13	14
This truncated form of GLP-1 does not activate the GLP-1R and is inactive as an insulinotropic agent ( although there is some debate on this point ) [ XREF_BIBR ] .	This truncated form of GLP-1 does not activate the GLP-1R and is inactive as an insulinotropic agent (although there is some debate on this point) [XREF_BIBR].	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	4	5	9	10
To demonstrate the effectiveness of the direct functional assay system , we attempted to detect the GLP1R activation by native GLP1 , its analogue S 2 -GLP1 , and Ex4 secreted by yeast .	To demonstrate the effectiveness of the direct functional assay system, we attempted to detect the GLP1R activation by native GLP1, its analogue S 2 -GLP1, and Ex4 secreted by yeast.	16	21	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GLP1	GLP1	GLP1	GLP1R	GLP1R	GLP1R	20	21	16	17
Here , we report that a nonapeptide , GLP1 ( 28-36 ) amide , derived from the C-terminal domain of the insulinotropic GLP1 , exerts cytoprotective actions on INS-1 beta-cells and on dispersed human islet cells in vitro in conditions of glucolipotoxicity and increased oxidative stress independently of the GLP1 receptor .	Here, we report that a nonapeptide, GLP1 (28-36) amide, derived from the C-terminal domain of the insulinotropic GLP1, exerts cytoprotective actions on INS-1 beta-cells and on dispersed human islet cells in vitro in conditions of glucolipotoxicity and increased oxidative stress independently of the GLP1 receptor.	6	51	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP1	GLP1	GLP1	GLP1 receptor	GLP1 receptor	GLP1 receptor	8	9	49	51
It is still not completely clear if peripheral GLP-1 acts locally to alter gastrointestinal motility and appetite , or if GLP-1 can directly activate brain GLP-1R to modulate these functions and behaviors .	It is still not completely clear if peripheral GLP-1 acts locally to alter gastrointestinal motility and appetite, or if GLP-1 can directly activate brain GLP-1R to modulate these functions and behaviors.	20	26	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	20	21	25	26
Recent studies also presented here , however , diminish the relevance of the vagus nerve for the pharmacological intervention of obesity and diabetes with chronic GLP-1R agonist treatments , suggesting that endogenous intestinal GLP-1 and GLP-1R agonists may activate different GLP-1R populations .	Recent studies also presented here, however, diminish the relevance of the vagus nerve for the pharmacological intervention of obesity and diabetes with chronic GLP-1R agonist treatments, suggesting that endogenous intestinal GLP-1 and GLP-1R agonists may activate different GLP-1R populations.	31	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	33	34	40	41
In rodent models , GLP-1 activates the GLP-1 receptor to produce mild vasodilation , inotropic action , and ischemic preconditioning .	In rodent models, GLP-1 activates the GLP-1 receptor to produce mild vasodilation, inotropic action, and ischemic preconditioning.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	4	5	7	9
Inflammatory reactions might be reduced by GLP-1R agonists and DPP-4 inhibitors , due to macrophages shift into M2 type through T regulatory lymphocytes ( Tregs ) , whose function is increased by GLP-1 [ XREF_BIBR ] .	Inflammatory reactions might be reduced by GLP-1R agonists and DPP-4 inhibitors, due to macrophages shift into M2 type through T regulatory lymphocytes (Tregs), whose function is increased by GLP-1 [XREF_BIBR].	6	34	increased	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	32	33	6	7
XREF_BIBR - XREF_BIBR GLP-1R is activated by four endogenous GLP-1 peptides ( GLP-1 ( 1-37 ) , GLP-1 ( 7-37 ) , GLP ( 1-36 ) NH 2 , and GLP-1 ( 7-36 ) NH 2 ) and a fifth structurally analogous peptide oxyntomodulin .	XREF_BIBR - XREF_BIBR GLP-1R is activated by four endogenous GLP-1 peptides (GLP-1 (1-37), GLP-1 (7-37), GLP (1-36) NH 2, and GLP-1 (7-36) NH 2) and a fifth structurally analogous peptide oxyntomodulin.	2	44	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	oxyntomodulin	oxyntomodulin	oxyntomodulin	GLP-1R	GLP-1R	GLP-1R	43	44	3	4
GLP-1 activation of GLP-1R appears to act through the G alpha subunit to stimulate a metabolism- and Ca 2+ -independent pathway .	GLP-1 activation of GLP-1R appears to act through the G alpha subunit to stimulate a metabolism- and Ca 2+ -independent pathway.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	0	1	3	4
Because OXM activates the GLP1R with lower affinity than GLP-1 , we generated a peptide analog ( Q --> E , OXMQ3E ) that does not exhibit glucagon receptor agonist activity but retains the same affinity as OXM for GLP1R .	Because OXM activates the GLP1R with lower affinity than GLP-1, we generated a peptide analog (Q --> E, OXMQ3E) that does not exhibit glucagon receptor agonist activity but retains the same affinity as OXM for GLP1R.	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXM	OXM	OXM	GLP1R	GLP1R	GLP1R	1	2	4	5
Thus , young BBdp rats displayed decreased concentrations of bioactive GLP-1 in jejunum and ileum , reduced GLP-1R in islets , and lower second-phase insulin response to iv GLP-1 than controls .	Thus, young BBdp rats displayed decreased concentrations of bioactive GLP-1 in jejunum and ileum, reduced GLP-1R in islets, and lower second-phase insulin response to iv GLP-1 than controls.	7	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	10	11	17	18
GLP-1 and liraglutide activate the GLP-1R , thereby promoting pre-adipocyte proliferation and inhibition of apoptosis .	GLP-1 and liraglutide activate the GLP-1R, thereby promoting pre-adipocyte proliferation and inhibition of apoptosis.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	0	1	5	6
GLP-1 ( 9-36 ) may also activate GLP-1R and downstream Akt and PI3K and AMPKalpha mediators .	GLP-1 (9-36) may also activate GLP-1R and downstream Akt and PI3K and AMPKalpha mediators.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	0	1	7	8
In this study , antagonists Ex ( 9-39 ) [ XREF_BIBR , XREF_BIBR ] and JANT-4 [ XREF_BIBR ] inhibited GLP-1 induced GLP-1R internalisation and signalling but not compound 2 or compound B induced signalling , suggesting a second agonist binding site on the hGLP-1R that is distinct from the orthosteric binding site .	In this study, antagonists Ex (9-39) [XREF_BIBR, XREF_BIBR] and JANT-4 [XREF_BIBR] inhibited GLP-1 induced GLP-1R internalisation and signalling but not compound 2 or compound B induced signalling, suggesting a second agonist binding site on the hGLP-1R that is distinct from the orthosteric binding site.	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	20	21	22	23
XREF_BIBR We suggest that GLP-1 activates GLP-1R expressed by vagal efferent fibres innervating the ventricles , triggering pre-junctional release of acetylcholine , which protects ventricular cardiomyocytes via activation of M3 muscarinic receptors .	XREF_BIBR We suggest that GLP-1 activates GLP-1R expressed by vagal efferent fibres innervating the ventricles, triggering pre-junctional release of acetylcholine, which protects ventricular cardiomyocytes via activation of M3 muscarinic receptors.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	4	5	6	7
Nearly sustained insulinotropic action of GLP-1 in type 2 diabetic patients revealed its therapeutic potential and initiated the ongoing development of GLP-1R agonists as well as inhibitors of dipeptidyl peptidase-4 , which rapidly degrades incretin hormones in vivo .	Nearly sustained insulinotropic action of GLP-1 in type 2 diabetic patients revealed its therapeutic potential and initiated the ongoing development of GLP-1R agonists as well as inhibitors of dipeptidyl peptidase-4, which rapidly degrades incretin hormones in vivo.	3	22	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	5	6	21	22
Although GLP-1 was previously thought to increase muscle glucose uptake 25 , in hyperinsulinemic-euglycemic clamps GLP-1R null mice have a global increase in insulin sensitivity , driven by increased muscle glucose uptake , but at the same time reduced hepatic insulin sensitivity 26 .	Although GLP-1 was previously thought to increase muscle glucose uptake 25, in hyperinsulinemic-euglycemic clamps GLP-1R null mice have a global increase in insulin sensitivity, driven by increased muscle glucose uptake, but at the same time reduced hepatic insulin sensitivity 26.	1	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	1	2	15	16
GLP-2 mediates some of its actions via GLP-2R , a member of the glucagon and GLP-1R superfamily 18 .	GLP-2 mediates some of its actions via GLP-2R, a member of the glucagon and GLP-1R superfamily 18.	0	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-2	GLP-2	GLP-2	GLP-1R	GLP-1R	GLP-1R	0	1	15	16
Exendin is a GLP-1 ( glucagon like peptide-1 ) analogue that targets the GLP-1R .	Exendin is a GLP-1 (glucagon like peptide-1) analogue that targets the GLP-1R.	3	14	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	3	4	13	14
Although compound 2 can inhibit GLP-1 7-36 amide mediated internalization of the GLP-1R XREF_BIBR , this was not involved in this enhanced signaling as similar effects were seen in membrane preparations from HEK-GLP-1R cells ( XREF_FIG ) .	Although compound 2 can inhibit GLP-1 7-36 amide mediated internalization of the GLP-1R XREF_BIBR, this was not involved in this enhanced signaling as similar effects were seen in membrane preparations from HEK-GLP-1R cells (XREF_FIG).	5	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	5	6	12	13
In the intestine and pancreas , activation of GLP1R by GLP1 stimulates insulin release and slows gastric emptying .	In the intestine and pancreas, activation of GLP1R by GLP1 stimulates insulin release and slows gastric emptying.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GLP1	GLP1	GLP1	GLP1R	GLP1R	GLP1R	10	11	8	9
Both drugs have distinct pharmacodynamics : GLP-1 analoga directly stimulate the GLP-1 receptor , whereas DPP-IV inhibitors act by slowing the rapid degradation of GLP-1 ( 7-36 ) to GLP-1 ( 9-36 ) XREF_BIBR , XREF_BIBR .	Both drugs have distinct pharmacodynamics : GLP-1 analoga directly stimulate the GLP-1 receptor, whereas DPP-IV inhibitors act by slowing the rapid degradation of GLP-1 (7-36) to GLP-1 (9-36) XREF_BIBR, XREF_BIBR.	6	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	6	7	11	13
GLP-1 elevating agents and GLP-1 receptor agonists improve endothelial function in hypertension , suggesting that GLP-1 signaling could be a therapeutic target in hypertension related vascular events .	GLP-1 elevating agents and GLP-1 receptor agonists improve endothelial function in hypertension, suggesting that GLP-1 signaling could be a therapeutic target in hypertension related vascular events.	0	7	elevating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	0	1	4	6
As human GLP-1 is able to bind with high affinity and potently activate the platypus GLP-1R ( XREF_FIG and ( XREF_SUPPLEMENTARY ) , we conclude that the platypus receptor functions in a similar manner to hGLP-1R .	As human GLP-1 is able to bind with high affinity and potently activate the platypus GLP-1R (XREF_FIG and (XREF_SUPPLEMENTARY), we conclude that the platypus receptor functions in a similar manner to hGLP-1R.	1	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	2	3	15	16
Like the VTA GLP-1R , those in the NAc contribute to the intake suppressive responses by GLP-1 .	Like the VTA GLP-1R, those in the NAc contribute to the intake suppressive responses by GLP-1.	0	17	contribute	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	16	17	3	4
Indeed , it was possible that peripheral GLP-1 through a vagal afferent independent pathway crossed the BBB to directly activate the central GLP-1R of NTS .	Indeed, it was possible that peripheral GLP-1 through a vagal afferent independent pathway crossed the BBB to directly activate the central GLP-1R of NTS.	6	24	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	7	8	22	23
This perception is further supported by the observations that in GLP-1R -/- mice , both native GLP-1 and 9-36a produced increased coronary flow in isolated hearts and vasodilation of mesenteric arteries in both wild type and GLP-1R -/- mice .	This perception is further supported by the observations that in GLP-1R -/- mice, both native GLP-1 and 9-36a produced increased coronary flow in isolated hearts and vasodilation of mesenteric arteries in both wild type and GLP-1R -/- mice.	12	38	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	16	17	36	37
Similarly to OXM , GCG can activate the GLP-1R , but this requires concentrations well in excess of those used here where we infused GCG , OXM , and GLP-1 in the same molar range .	Similarly to OXM, GCG can activate the GLP-1R, but this requires concentrations well in excess of those used here where we infused GCG, OXM, and GLP-1 in the same molar range.	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GCG	GCG	GCG	GLP-1R	GLP-1R	GLP-1R	4	5	8	9
XREF_BIBR GLP-1 activates the GLP-1 receptor in the pancreatic islets , which leads to an increase in secretion of insulin and inhibition of glucagon .	XREF_BIBR GLP-1 activates the GLP-1 receptor in the pancreatic islets, which leads to an increase in secretion of insulin and inhibition of glucagon.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	1	2	4	6
OXM activates both , the GLP-1 receptor ( GLP1R ) and glucagon receptor ( GCGR ) in vitro , albeit with 10- to 100-fold reduced potency compared with the cognate ligands GLP-1 and glucagon , respectively .	OXM activates both, the GLP-1 receptor (GLP1R) and glucagon receptor (GCGR) in vitro, albeit with 10- to 100-fold reduced potency compared with the cognate ligands GLP-1 and glucagon, respectively.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXM	OXM	OXM	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	0	1	5	7
The GLP-1 , and mimetics like exendin-4 ( exenatide ) and liraglutide , activate GLP-1 receptor signaling pathways that converge with the insulin activated intracellular signaling pathway [ XREF_BIBR ] .	The GLP-1, and mimetics like exendin-4 (exenatide) and liraglutide, activate GLP-1 receptor signaling pathways that converge with the insulin activated intracellular signaling pathway [XREF_BIBR].	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	1	2	14	16
Collectively , these data implicate that caveolae and caveolins are essential for GLP-1 induced cardiac protection by mediating the GLP-1R .	Collectively, these data implicate that caveolae and caveolins are essential for GLP-1 induced cardiac protection by mediating the GLP-1R.	12	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	12	13	19	20
To identify these new classes , we developed novel and robust primary and secondary high-throughput screening ( HTS ) systems in which PAMs were identified to enhance the GLP-1R signaling induced by GLP-1 ( 9-36 ) amide .	To identify these new classes, we developed novel and robust primary and secondary high-throughput screening (HTS) systems in which PAMs were identified to enhance the GLP-1R signaling induced by GLP-1 (9-36) amide.	28	34	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	32	33	28	29
GLP-1 and EXE stimulate glucose dependent insulin secretion and decrease glucagon release after binding to the GLP-1 Receptor ( GLP-1R ) present on pancreatic endocrine beta- and alpha-cells [ XREF_BIBR , XREF_BIBR ] .	GLP-1 and EXE stimulate glucose dependent insulin secretion and decrease glucagon release after binding to the GLP-1 Receptor (GLP-1R) present on pancreatic endocrine beta- and alpha-cells [XREF_BIBR, XREF_BIBR].	0	18	stimulate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 Receptor	GLP-1 Receptor	GLP-1 Receptor	0	1	16	18
Moreover , the use of chronic CNS GLP-1r blockade assumes that CNS GLP-1r are activated solely by NTS GLP-1 and not by intestinal GLP-1 .	Moreover, the use of chronic CNS GLP-1r blockade assumes that CNS GLP-1r are activated solely by NTS GLP-1 and not by intestinal GLP-1.	11	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1r	GLP-1r	GLP-1r	23	24	12	13
This study illustrates pharmacology of differential activation of GLP-1R by GLP-1 and compounds 2 and B. Introduction .	This study illustrates pharmacology of differential activation of GLP-1R by GLP-1 and compounds 2 and B. Introduction.	2	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	10	11	8	9
Administration of glucagon increases BAT thermogenesis , at least partly via a central mechanism since icv injections of glucagon , glucagon like peptide-1 ( GLP-1 ) , or oxyntomodulin , a dual GLP-1 receptor and glucagon receptor agonist , increase BAT SNA and TBAT .	Administration of glucagon increases BAT thermogenesis, at least partly via a central mechanism since icv injections of glucagon, glucagon like peptide-1 (GLP-1), or oxyntomodulin, a dual GLP-1 receptor and glucagon receptor agonist, increase BAT SNA and TBAT.	0	34	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	2	3	32	34
Furthermore , we assessed here the effect of compounds 2 and B on GLP-1 mediated GLP-1R activation and internalisation .	Furthermore, we assessed here the effect of compounds 2 and B on GLP-1 mediated GLP-1R activation and internalisation.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	13	14	15	16
Thus , it can not be ruled out that the delivery of macronutrients to the more distal parts of the gut following RYGB may induce higher local release of GLP-1 and GLP-2 , which could further enhance GLP-1R and GLP-2R trophic signaling to promote hypertrophy of the alimentary and common limb .	Thus, it can not be ruled out that the delivery of macronutrients to the more distal parts of the gut following RYGB may induce higher local release of GLP-1 and GLP-2, which could further enhance GLP-1R and GLP-2R trophic signaling to promote hypertrophy of the alimentary and common limb.	27	41	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	29	30	37	38
However , it is highly unlikely that GLP-1 administration into either jugular or hepatic portal vein causes significant activation of central GLP-1 receptors .	However, it is highly unlikely that GLP-1 administration into either jugular or hepatic portal vein causes significant activation of central GLP-1 receptors.	7	23	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptors	GLP-1 receptors	GLP-1 receptors	7	8	21	23
Thus , we examined the changes in GLP-1R expression in both retinas of healthy and diabetic rats treated with or without GLP-1 .	Thus, we examined the changes in GLP-1R expression in both retinas of healthy and diabetic rats treated with or without GLP-1.	7	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	21	22	7	8
Oxyntomodulin activates both the human glucagon receptor and GLP-1 receptor with reduced efficacy compared to the native peptides XREF_BIBR , XREF_BIBR , XREF_BIBR .	Oxyntomodulin activates both the human glucagon receptor and GLP-1 receptor with reduced efficacy compared to the native peptides XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Oxyntomodulin	Oxyntomodulin	Oxyntomodulin	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	0	1	8	10
GLP1 ( 28-36 ) amide nonapeptide does not activate the GLP1 receptor in beta-cells .	GLP1 (28-36) amide nonapeptide does not activate the GLP1 receptor in beta-cells.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP1	GLP1	GLP1	GLP1 receptor	GLP1 receptor	GLP1 receptor	0	1	10	12
This result suggests that GLP-1 activates the GLP-1R which couples with the G protein and adenyl cyclase complex to enhance cAMP production .	This result suggests that GLP-1 activates the GLP-1R which couples with the G-protein and adenyl cyclase complex to enhance cAMP production.	4	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	4	5	7	8
Glucagon like peptide-1 ( GLP1 ) is a 30-amino acid peptide hormone activating the GLP1 receptor ( GLP1R ) , a class B G protein coupled receptor ( GPCR ) , and is considered to be effective for treating diabetes and other metabolic diseases .	Glucagon like peptide-1 (GLP1) is a 30-amino acid peptide hormone activating the GLP1 receptor (GLP1R), a class B G protein coupled receptor (GPCR), and is considered to be effective for treating diabetes and other metabolic diseases.	0	16	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP1	GLP1	GLP1	GLP1 receptor	GLP1 receptor	GLP1 receptor	4	5	14	16
Induction of ERK signaling was attributed to GLP-1 activation of the GLP-1R by co-incubation with exendin 9-39 , an antagonist of GLP-1R .	Induction of ERK signaling was attributed to GLP-1 activation of the GLP-1R by co-incubation with exendin 9-39, an antagonist of GLP-1R.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	7	8	11	12
Effect of compounds 2 and B on GLP-1 induced GLP-1R activation and internalisation .	Effect of compounds 2 and B on GLP-1 induced GLP-1R activation and internalisation.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	7	8	9	10
While PYY has no effect on insulin secretion , the effects of GLP-1 are sufficiently powerful to allow development of GLP-1 receptor agonists for the treatment of diabetes .	While PYY has no effect on insulin secretion, the effects of GLP-1 are sufficiently powerful to allow development of GLP-1 receptor agonists for the treatment of diabetes.	10	22	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	12	13	20	22
Abrahamsson et al also proposed that endogenous GLP-1 has a short window of activity , whereas exogenous GLP-1 analogs promote persistent GLP-1 receptor activation .	Abrahamsson et al also proposed that endogenous GLP-1 has a short window of activity, whereas exogenous GLP-1 analogs promote persistent GLP-1 receptor activation.	17	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	17	18	21	23
It was evident that wenyujinoside , 28-deglucosylchikusetsusaponin IV , or the control ( GLP-1 ) could induce conformational change of GLP-1 receptor differently ( XREF_FIG ) .	It was evident that wenyujinoside, 28-deglucosylchikusetsusaponin IV, or the control (GLP-1) could induce conformational change of GLP-1 receptor differently (XREF_FIG).	11	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	13	14	20	22
Because plasma GLP-1 levels were also significantly increased , we tested the hypothesis that this source of GLP-1 could activate CNS GLP-1R and regulate glucose levels .	Because plasma GLP-1 levels were also significantly increased, we tested the hypothesis that this source of GLP-1 could activate CNS GLP-1R and regulate glucose levels.	15	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	17	18	21	22
Thus , oxyntomodulin or simultaneous activation of GLP1R and GCGR should increase plasma concentrations of FGF-21 and adiponectin in humans ( XREF_FIG ) .	Thus, oxyntomodulin or simultaneous activation of GLP1R and GCGR should increase plasma concentrations of FGF-21 and adiponectin in humans (XREF_FIG).	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	oxyntomodulin	oxyntomodulin	oxyntomodulin	GLP1R	GLP1R	GLP1R	2	3	7	8
Unlike the glucose lowering effect of GLP-1 ( 7-37 ) , the glucose lowering effect of GLP-1 ( 1-37 ) could not be blocked by the GLP-1R antagonist exendin ( 9-39 ) , suggesting that GLP-1 ( 1-37 ) might activate the GLP-1R via a different mechanism .	Unlike the glucose lowering effect of GLP-1 (7-37), the glucose lowering effect of GLP-1 (1-37) could not be blocked by the GLP-1R antagonist exendin (9-39), suggesting that GLP-1 (1-37) might activate the GLP-1R via a different mechanism.	35	46	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	35	36	42	43
Whilst these studies demarcate the potential scope for effects of endogenous GLP-1 released from PPG neurons , the question remains , whether some of the effects observed are due to supraphysiological concentrations of GLP-1 producing a pattern of GLP-1 receptor activation that would not occur under physiological conditions .	Whilst these studies demarcate the potential scope for effects of endogenous GLP-1 released from PPG neurons, the question remains, whether some of the effects observed are due to supraphysiological concentrations of GLP-1 producing a pattern of GLP-1 receptor activation that would not occur under physiological conditions.	31	40	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	33	34	38	40
It is unclear if these differences are due to engagement of additional receptors and/or the reported difference on GLP1R signaling by OXM or simply a different brain penetration and affinity at the receptors .	It is unclear if these differences are due to engagement of additional receptors and/or the reported difference on GLP1R signaling by OXM or simply a different brain penetration and affinity at the receptors.	18	22	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	OXM	OXM	OXM	GLP1R	GLP1R	GLP1R	21	22	18	19
Although these studies have yielded promising results , with improved insulin sensitivity and lowered blood glucose levels , these treatments have also resulted in high levels of circulating GLP-1 , which may promote GLP-1 receptor desensitization over time .	Although these studies have yielded promising results, with improved insulin sensitivity and lowered blood glucose levels, these treatments have also resulted in high levels of circulating GLP-1, which may promote GLP-1 receptor desensitization over time.	27	35	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	28	29	33	35
XREF_BIBR Stimulation of the GLP-1 receptor ( GLP-1R ) by GLP-1 or exenatide increases cAMP production in beta-cells , XREF_BIBR , XREF_BIBR thereby activating protein kinase A ( PKA ) and the exchange proteins directly activated by cAMP ( Epac ) .	XREF_BIBR Stimulation of the GLP-1 receptor (GLP-1R) by GLP-1 or exenatide increases cAMP production in beta-cells, XREF_BIBR, XREF_BIBR thereby activating protein kinase A (PKA) and the exchange proteins directly activated by cAMP (Epac).	1	15	Stimulation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	10	11	4	6
Mechanisms by which sitagliptin causes a reduction in blood pressure are GLP-1 receptor mediated endothelial vasodilatation by nitric oxide stimulatory effect , the endothelium independent vasodilatory effect of GLP-1 and increased excretion of sodium in urine that is done by proximal tubule [ XREF_BIBR ] .	Mechanisms by which sitagliptin causes a reduction in blood pressure are GLP-1 receptor mediated endothelial vasodilatation by nitric oxide stimulatory effect, the endothelium independent vasodilatory effect of GLP-1 and increased excretion of sodium in urine that is done by proximal tubule [XREF_BIBR].	11	29	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	28	29	11	13
In T2D , the incretin effect is reduced 6 , but therapeutically , incretin activity can be provided by supraphysiological dosages of GLP-1 or related agents stimulating the GLP-1 receptor ( GLP-1R ) 7 .	In T2D, the incretin effect is reduced 6, but therapeutically, incretin activity can be provided by supraphysiological dosages of GLP-1 or related agents stimulating the GLP-1 receptor (GLP-1R) 7.	22	30	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	22	23	28	30
GLP-1 ( 7-36 ) is quickly degraded by circulating dipeptidyl peptidase 4 ( DPP-4 ) to yield GLP-1 ( 9-36 ) , which does not activate the GLP-1R , and is inactive as an insulinotropic agent .	GLP-1 (7-36) is quickly degraded by circulating dipeptidyl peptidase 4 (DPP-4) to yield GLP-1 (9-36), which does not activate the GLP-1R, and is inactive as an insulinotropic agent.	16	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	17	18	27	28
GLP-1 is neuroprotective and activates the GLP-1 receptor in the brain ( Gao et al ., 2011 ) .	GLP-1 is neuroprotective and activates the GLP-1 receptor in the brain (Gao et al., 2011).	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	0	1	6	8
A large body of preclinical data has demonstrated that the enhancement of GLP-1R signaling by either GLP-1 RAs or DPP4Is enhances beta-cell function , proliferation and regeneration and diminishes beta-cell apoptosis ; thereby , providing a net increase in functional beta-cell mass [ XREF_BIBR ] .	A large body of preclinical data has demonstrated that the enhancement of GLP-1R signaling by either GLP-1 RAs or DPP4Is enhances beta-cell function, proliferation and regeneration and diminishes beta-cell apoptosis; thereby, providing a net increase in functional beta-cell mass [XREF_BIBR].	12	17	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	16	17	12	13
Although oxyntomodulin and glucagon can also stimulate the GLP-1 receptor , a limited number of studies have suggested that GLP-1 can not bind to the GCGR .	Although oxyntomodulin and glucagon can also stimulate the GLP-1 receptor, a limited number of studies have suggested that GLP-1 can not bind to the GCGR.	1	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	3	4	8	10
Porcine growth hormone induces the nuclear localization of porcine growth hormone receptor in vivo .	Porcine growth hormone induces the nuclear localization of porcine growth hormone receptor in vivo.	1	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	growth hormone	growth hormone	growth hormone	growth hormone receptor	growth hormone receptor	growth hormone receptor	1	3	9	12
GH induces activation of the GH receptor ( GHR )-associated cytoplasmic tyrosine kinase , JAK2 , resulting in tyrosine phosphorylation of the GHR and activation of STAT ( signal transducer and activator of transcription ) , Ras-mitogen-activated protein kinase , and phosphoinositol 3-kinase signaling pathways , among others .	GH induces activation of the GH receptor (GHR)-associated cytoplasmic tyrosine kinase, JAK2, resulting in tyrosine phosphorylation of the GHR and activation of STAT (signal transducer and activator of transcription), Ras-mitogen-activated protein kinase, and phosphoinositol 3-kinase signaling pathways, among others.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GH receptor	GH receptor	GH receptor	0	1	5	7
However , until recently , whether GH could induce nuclear localization of GHR in vivo was unclear .	However, until recently, whether GH could induce nuclear localization of GHR in vivo was unclear.	6	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	6	7	12	13
However , the combination of E2 and GH up-regulated the cellular concentrations of GHBP and GHR 2- to 3-fold .	However, the combination of E2 and GH up-regulated the cellular concentrations of GHBP and GHR 2- to 3-fold.	3	15	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHBP	GHBP	GHBP	7	8	13	14
In signaling experiments , brief pretreatment of GH responsive human fibrosarcoma cells with anti-GHR ( ext-mAb ) dramatically inhibited GH induced Janus kinase 2 and signal transducer and activator of transcription 5 tyrosine phosphorylation and prevented GH induced GHR disulfide linkage ( a reflection of GH induced conformational changes ) .	In signaling experiments, brief pretreatment of GH responsive human fibrosarcoma cells with anti-GHR (ext-mAb) dramatically inhibited GH induced Janus kinase 2 and signal transducer and activator of transcription 5 tyrosine phosphorylation and prevented GH induced GHR disulfide linkage (a reflection of GH induced conformational changes).	36	40	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	36	37	38	39
XREF_BIBR In addition , IGF-I antibodies block GH induced oocyte maturation in rat follicles , XREF_BIBR and IGF-I administration improves follicular maturation in GHR knockout mice XREF_BIBR and the maturation of mouse oocytes nonsynergistically with GH .	XREF_BIBR In addition, IGF-I antibodies block GH induced oocyte maturation in rat follicles, XREF_BIBR and IGF-I administration improves follicular maturation in GHR knockout mice XREF_BIBR and the maturation of mouse oocytes nonsynergistically with GH.	7	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	7	8	23	24
Growth hormone ( GH ) could activate pathways involved in DNA repair process by binding to growth hormone receptor ( GHR ) , which is thought as one of the mechanisms of radioprotection .	Growth hormone (GH) could activate pathways involved in DNA repair process by binding to growth hormone receptor (GHR), which is thought as one of the mechanisms of radioprotection.	1	19	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	GH	GH	GH	growth hormone receptor	growth hormone receptor	growth hormone receptor	3	4	16	19
However , a JAK2 mutant lacking the kinase like and kinase domains did not mediate GH induced GHR down-regulation .	However, a JAK2 mutant lacking the kinase like and kinase domains did not mediate GH induced GHR down-regulation.	14	18	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	15	16	17	18
A continuous infusion of human GH in dwarf males raised plasma GHBP to 23.5 +/- 3.5 micrograms/l compared with 6.7 +/- 0.5 micrograms/l in sham infused animals , whereas suppression of GH by continuous infusion of a long acting somatostatin analogue in female dwarf rats had no effect on GHBP .	A continuous infusion of human GH in dwarf males raised plasma GHBP to 23.5 +/- 3.5 micrograms/l compared with 6.7 +/- 0.5 micrograms/l in sham infused animals, whereas suppression of GH by continuous infusion of a long acting somatostatin analogue in female dwarf rats had no effect on GHBP.	2	22	raised	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHBP	GHBP	GHBP	5	6	11	12
GH therapy induced an alkaline phosphatase increment of 59 +/- 49 IU/mL , an insulin like growth factor-I increment of 32.6 +/- 11.9 nmol/L , and a GH binding protein increment of 10.2 +/- 2.7 % .	GH therapy induced an alkaline phosphatase increment of 59 +/- 49 IU/mL, an insulin like growth factor-I increment of 32.6 +/- 11.9 nmol/L, and a GH binding protein increment of 10.2 +/- 2.7%.	0	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GH binding protein	GH binding protein	GH binding protein	0	1	27	30
Preliminary experiments confirmed the expression of the GH receptor ( GHR ) gene in primary cultures of neonatal rat cardiomyocytes ( PC ) , the specific binding of GH by HL-1 cardiomyocytes , and the GH induced activation of GHR and its classical downstream effectors in the latter .	Preliminary experiments confirmed the expression of the GH receptor (GHR) gene in primary cultures of neonatal rat cardiomyocytes (PC), the specific binding of GH by HL-1 cardiomyocytes, and the GH induced activation of GHR and its classical downstream effectors in the latter.	34	40	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	35	36	39	40
Furthermore , GHR and PRLR associate in a fashion augmented acutely by GH , even though GH primarily activates PRLR , rather than GHR , in these cells .	Furthermore, GHR and PRLR associate in a fashion augmented acutely by GH, even though GH primarily activates PRLR, rather than GHR, in these cells.	2	13	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	12	13	2	3
XREF_BIBR , who showed that phosphorylation of cytosolic tyrosine residues is important for GH induced GHR endocytosis .	XREF_BIBR, who showed that phosphorylation of cytosolic tyrosine residues is important for GH induced GHR endocytosis.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	13	14	15	16
The GH receptor induced by frequent or continuous administration of GH was mainly somatogenic , since an excess of unlabeled ovine PRL inhibited GH binding only to a minor extent .	The GH receptor induced by frequent or continuous administration of GH was mainly somatogenic, since an excess of unlabeled ovine PRL inhibited GH binding only to a minor extent.	1	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GH	GH	GH	GH receptor	GH receptor	GH receptor	10	11	1	3
In humans , GHR is activated by GH , whereas PRLR is activated by both GH and PRL .	In humans, GHR is activated by GH, whereas PRLR is activated by both GH and PRL.	3	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	7	8	3	4
Here , we used the GH responsive rat liver cell line CWSV-1 to investigate the role of CIS and the proteasome in GH induced GHR internalization .	Here, we used the GH responsive rat liver cell line CWSV-1 to investigate the role of CIS and the proteasome in GH induced GHR internalization.	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	22	23	24	25
Growth hormone is believed to activate the growth hormone receptor ( GHR ) by dimerizing two identical receptor subunits , leading to activation of JAK2 kinase associated with the cytoplasmic domain .	Growth hormone is believed to activate the growth hormone receptor (GHR) by dimerizing two identical receptor subunits, leading to activation of JAK2 kinase associated with the cytoplasmic domain.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Growth hormone	Growth hormone	Growth hormone	growth hormone receptor	growth hormone receptor	growth hormone receptor	0	2	7	10
Depletion of betaTrCP resulted in inhibition of GHR endocytosis for both constitutive and GH induced GHR endocytosis ( XREF_FIG ) .	Depletion of betaTrCP resulted in inhibition of GHR endocytosis for both constitutive and GH induced GHR endocytosis (XREF_FIG).	3	16	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	13	14	15	16
Growth hormone receptor activation is initiated by GH induced homodimerization of receptor molecules .	Growth hormone receptor activation is initiated by GH induced homodimerization of receptor molecules.	0	8	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GH	GH	GH	Growth hormone receptor	Growth hormone receptor	Growth hormone receptor	7	8	0	3
Collectively , our data suggest that determinants required for JAK2 to protect mature GHR from constitutive degradation differ from those that drive GH induced GHR down-regulation .	Collectively, our data suggest that determinants required for JAK2 to protect mature GHR from constitutive degradation differ from those that drive GH induced GHR down-regulation.	22	25	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	22	23	24	25
Clathrin depletion strongly inhibited GH induced GHR endocytosis , demonstrating that GH induced GHR endocytosis is clathrin dependent ( XREF_FIG ) .	Clathrin depletion strongly inhibited GH induced GHR endocytosis, demonstrating that GH induced GHR endocytosis is clathrin dependent (XREF_FIG).	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	4	5	6	7
In the absence of any exogenous hGH , no STAT5 activation was evident as murine GH ( poorly expressed in Ba/F3 cells ) and bovine GH ( small amounts present in the serum ) do not activate human GHR .	In the absence of any exogenous hGH, no STAT5 activation was evident as murine GH (poorly expressed in Ba/F3 cells) and bovine GH (small amounts present in the serum) do not activate human GHR.	24	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	25	26	38	39
A critical step in growth hormone ( GH ) signalling is the GH induced activation of the GH receptor ( GHR )-associated tyrosine kinase , JAK2 .	A critical step in growth hormone (GH) signalling is the GH induced activation of the GH receptor (GHR)-associated tyrosine kinase, JAK2.	4	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	growth hormone	growth hormone	growth hormone	GH receptor	GH receptor	GH receptor	4	6	17	19
Previously , we have shown that the ubiquitin conjugation system mediates GH induced GHR internalization .	Previously, we have shown that the ubiquitin conjugation system mediates GH induced GHR internalization.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	11	12	13	14
A GH induced GHR conformational change is generally accepted to be required for its activation , although the nature of this conformational change remains unclear .	A GH induced GHR conformational change is generally accepted to be required for its activation, although the nature of this conformational change remains unclear.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	1	2	3	4
GH enhanced IGF-I , IGF binding receptor-3 , and GH receptor but declined with daily and intermittent calcitriol .	GH enhanced IGF-I, IGF binding receptor-3, and GH receptor but declined with daily and intermittent calcitriol.	0	12	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GH receptor	GH receptor	GH receptor	0	1	9	11
Nandrolone up-regulated AR , ESR2 and PGR in K562 cells , and SRD5A1 , PPARA and JAK2 in Jurkat cells ; IGF-I up-regulated EPOR and PGR in HL60 cells , and SRD5A1 in Jurkat ; GH up-regulated SRD5A1 and GHR in K562 .	Nandrolone up-regulated AR, ESR2 and PGR in K562 cells, and SRD5A1, PPARA and JAK2 in Jurkat cells; IGF-I up-regulated EPOR and PGR in HL60 cells, and SRD5A1 in Jurkat; GH up-regulated SRD5A1 and GHR in K562.	35	40	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	35	36	39	40
Presumably , GH activation of GHR with protein : protein interaction with InsR not only can enhance InsR activation by insulin at membrane level , but also intensify the signal transduction via STAT 5 -, ERK 1/2 - and Akt dependent mechanisms .	Presumably, GH activation of GHR with protein : protein interaction with InsR not only can enhance InsR activation by insulin at membrane level, but also intensify the signal transduction via STAT 5 -, ERK 1/2 - and Akt dependent mechanisms.	2	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	2	3	5	6
In hepatocytes , GH activates GH receptor , which recruits JAK2 to activate Stat5 by phosphorylation .	In hepatocytes, GH activates GH receptor, which recruits JAK2 to activate Stat5 by phosphorylation.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GH receptor	GH receptor	GH receptor	3	4	5	7
The increased tyrosyl phosphorylation of GHR detected after incubation of cells with GH is consistent either with GH increasing tyrosine kinase activity associated with the GHR or with GH inducing a conformational change in GHR that renders it susceptible to tyrosyl phosphorylation .	The increased tyrosyl phosphorylation of GHR detected after incubation of cells with GH is consistent either with GH increasing tyrosine kinase activity associated with the GHR or with GH inducing a conformational change in GHR that renders it susceptible to tyrosyl phosphorylation.	14	35	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	28	29	34	35
A GH induced GHR conformational change has been generally accepted to be required for its activation , although the nature of this conformational change remains unclear .	A GH induced GHR conformational change has been generally accepted to be required for its activation, although the nature of this conformational change remains unclear.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	1	2	3	4
Subsequently , we asked whether GH induced GHR endocytosis depends on the same E3 ligase as constitutive GHR endocytosis .	Subsequently, we asked whether GH induced GHR endocytosis depends on the same E3 ligase as constitutive GHR endocytosis.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	5	6	7	8
Primate growth hormone can trigger non primate growth hormone receptor ( GHR ) , but primates GHR can not be activated by non primate GH .	Primate growth hormone can trigger non primate growth hormone receptor (GHR), but primates GHR can not be activated by non primate GH.	1	10	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	growth hormone	growth hormone	growth hormone	growth hormone receptor	growth hormone receptor	growth hormone receptor	1	3	7	10
In children with GH deficiencies , the lack of GH exposure may cause GHR on IH tissues to be more sensitive to GH stimulation .	In children with GH deficiencies, the lack of GH exposure may cause GHR on IH tissues to be more sensitive to GH stimulation.	9	16	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	9	10	13	14
For the second criterion we asked whether GH induced GHR endocytosis occurs via clathrin coated pits .	For the second criterion we asked whether GH induced GHR endocytosis occurs via clathrin coated pits.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	7	8	9	10
The binding of JAK2 by the homo-dimeric GHR , which , like all Type I cytokine receptor , lack intrinsic kinase activities , is crucial for activating the GH induced GHR signaling cascades .	The binding of JAK2 by the homo-dimeric GHR, which, like all Type I cytokine receptor, lack intrinsic kinase activities, is crucial for activating the GH induced GHR signaling cascades.	27	32	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	28	29	30	31
These data indicate that GH is able to increase GHR endocytosis and lower the GHR steady state level only in the presence of Jak2 .	These data indicate that GH is able to increase GHR endocytosis and lower the GHR steady state level only in the presence of Jak2.	4	17	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	4	5	14	15
We conclude that both GH induced GHR endocytosis and constitutive GHR endocytosis depend on betaTrCP binding via the UbE-motif rather than via the DSGxxS motif .	We conclude that both GH induced GHR endocytosis and constitutive GHR endocytosis depend on betaTrCP binding via the UbE-motif rather than via the DSGxxS motif.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	4	5	6	7
Specifically , autocrine or paracrine GH induced GH-R signalling may be linked to ciliated cell homeostasis of the porcine oviduct .	Specifically, autocrine or paracrine GH induced GH-R signalling may be linked to ciliated cell homeostasis of the porcine oviduct.	2	8	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GH-R	GH-R	GH-R	5	6	7	8
ICI 182-780 , a competitive inhibitor of E2 for the estrogen receptor ( ER ) , at different concentrations inhibited the E2 and GH induced stimulation of GHBP and GHR .	ICI 182-780, a competitive inhibitor of E2 for the estrogen receptor (ER), at different concentrations inhibited the E2 and GH induced stimulation of GHBP and GHR.	21	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	23	24	29	30
In diet restricted rats , GH administration increased GHR and IGF-I mRNA ; however , GHR reached basal levels observed in animals feeding with a high protein diet .	In diet restricted rats, GH administration increased GHR and IGF-I mRNA; however, GHR reached basal levels observed in animals feeding with a high protein diet.	5	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	5	6	8	9
During the placebo control period , serum IGF-I , LBM , and TBW increased ( P < 0.001 ) , whereas BF decreased ( P < 0.001 ) and serum GHBP was unchanged in the group treated with GH compared with the patients treated with placebo .	During the placebo control period, serum IGF-I, LBM, and TBW increased (P < 0.001), whereas BF decreased (P < 0.001) and serum GHBP was unchanged in the group treated with GH compared with the patients treated with placebo.	29	39	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	GH	GH	GH	GHBP	GHBP	GHBP	38	39	30	31
Herein we explored GHR and JAK2 determinants for both constitutive and GH induced GHR down-regulation , exploiting the previously characterized GHR- and JAK2 deficient gamma2A reconstitution system .	Herein we explored GHR and JAK2 determinants for both constitutive and GH induced GHR down-regulation, exploiting the previously characterized GHR- and JAK2 deficient gamma2A reconstitution system.	6	14	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	11	12	13	14
The transient nature of the dimerization or GH induced conformational change of predimerized GHRs kinetics was not a result of GHR internalization , as neither potassium- nor cholesterol-depletion treatments prolonged the FRET signal .	The transient nature of the dimerization or GH induced conformational change of predimerized GHRs kinetics was not a result of GHR internalization, as neither potassium- nor cholesterol-depletion treatments prolonged the FRET signal.	2	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	7	8	20	21
On the other hand , our data demonstrate that primary hepatocytes cultured on matrigel do provide a model to study some GH activated mechanisms ; those directly related to the activation of the GH receptor and its signaling molecules .	On the other hand, our data demonstrate that primary hepatocytes cultured on matrigel do provide a model to study some GH activated mechanisms; those directly related to the activation of the GH receptor and its signaling molecules.	20	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GH receptor	GH receptor	GH receptor	21	22	33	35
Although the absence of JAK2 precluded GH stimulated signaling , GH induced GHR disulfide linkage ( a proxy for the GH induced conformational changes in the GHR dimer ) proceeded independent of JAK2 expression , indicating that the earliest steps in GH induced GHR triggering are not prevented by the absence of JAK2 .	Although the absence of JAK2 precluded GH stimulated signaling, GH induced GHR disulfide linkage (a proxy for the GH induced conformational changes in the GHR dimer) proceeded independent of JAK2 expression, indicating that the earliest steps in GH induced GHR triggering are not prevented by the absence of JAK2.	39	44	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	41	42	43	44
Interaction of GH with its cell surface GH receptor ( GHR ) , by virtue of receptor dimerization , causes activation of the GHR associated cytoplasmic tyrosine kinase , JAK2 .	Interaction of GH with its cell surface GH receptor (GHR), by virtue of receptor dimerization, causes activation of the GHR associated cytoplasmic tyrosine kinase, JAK2.	0	24	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	2	3	23	24
GH activates GHR by dimerizing two identical receptor subunits , leading to Janus family of protein tyrosine kinases 2 kinase activation that in turn activates a number of intracellular pathways .	GH activates GHR by dimerizing two identical receptor subunits, leading to Janus family of protein tyrosine kinases 2 kinase activation that in turn activates a number of intracellular pathways.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	0	1	2	3
On the other hand , GH can induce desensitization of the GHR and this requires Jak2 kinase activity .	On the other hand, GH can induce desensitization of the GHR and this requires Jak2 kinase activity.	5	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	5	6	11	12
A Fab fragment of anti-GHR ( ext-mAb ) inhibited GH induced GHR disulfide linkage and signaling , as well as phorbol ester induced GHR proteolysis , in a fashion similar to the intact antibody .	A Fab fragment of anti-GHR (ext-mAb) inhibited GH induced GHR disulfide linkage and signaling, as well as phorbol ester induced GHR proteolysis, in a fashion similar to the intact antibody.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	9	10	11	12
We conclude GH induced GHR disulfide linkage is not required for GHR dimerization , and activation and GH enhanced GHR-JAK2 association depends more on GHR dimerization than on GHR and/or JAK2 tyrosine phosphorylation .	We conclude GH induced GHR disulfide linkage is not required for GHR dimerization, and activation and GH enhanced GHR-JAK2 association depends more on GHR dimerization than on GHR and/or JAK2 tyrosine phosphorylation.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	2	3	4	5
Since GH regulates cellular cytoskeleton with potential implications in GH signaling , we investigated the effects of actin cytoskeleton disruption on the kinetics of GH activated GHR and Janus kinase 2 ( JAK2 )/signal transducer and activator of transcription 5 ( STAT5 ) signaling pathway .	Since GH regulates cellular cytoskeleton with potential implications in GH signaling, we investigated the effects of actin cytoskeleton disruption on the kinetics of GH activated GHR and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signaling pathway.	22	29	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	24	25	26	27
Furthermore , an autocrine and paracrine mode of GH action was suggested by the demonstration that Ba/F3 cells produce GH , and that addition of GH antagonists ( B2036 and G120K ) promotes apoptosis of Ba/F3 GHR cells .	Furthermore, an autocrine and paracrine mode of GH action was suggested by the demonstration that Ba/F3 cells produce GH, and that addition of GH antagonists (B2036 and G120K) promotes apoptosis of Ba/F3 GHR cells.	25	37	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	25	26	36	37
Growth hormone ( GH ) induces cell differentiation and maturation by combining its receptor GHR with 191 amino acid monomeric peptides that are secreted from the eosinocyte anterior pituitary , initiating the anabolism inside the cells and promoting cell proliferation .	Growth hormone (GH) induces cell differentiation and maturation by combining its receptor GHR with 191 amino acid monomeric peptides that are secreted from the eosinocyte anterior pituitary, initiating the anabolism inside the cells and promoting cell proliferation.	1	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	3	4	14	15
By using the GH antagonist , G120K , and an antibody recognizing a dimerization sensitive GHR epitope , we demonstrated that GH induced GHR disulfide linkage reflects GH induced GHR dimerization .	By using the GH antagonist, G120K, and an antibody recognizing a dimerization sensitive GHR epitope, we demonstrated that GH induced GHR disulfide linkage reflects GH induced GHR dimerization.	27	30	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	27	28	29	30
Both GH induced GHR dimerization and JAK2 tyrosine kinase activation are critical in initiation of GH signaling .	Both GH induced GHR dimerization and JAK2 tyrosine kinase activation are critical in initiation of GH signaling.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	1	2	3	4
We now employ assays of cellular signaling and receptor conformational changes to examine whether GH molecules harboring two site 1 regions can trigger GHR activation .	We now employ assays of cellular signaling and receptor conformational changes to examine whether GH molecules harboring two site 1 regions can trigger GHR activation.	14	24	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	14	15	23	24
XREF_FIG confirmed that mutation of all tyrosines did not affect GH induced GHR endocytosis .	XREF_FIG confirmed that mutation of all tyrosines did not affect GH induced GHR endocytosis.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	10	11	12	13
As expected , GH and GH-GH , but not G120R , induced GHR disulfide linkage , as assessed by anti-GHR blotting of cell extracts resolved by SDS-PAGE under nonreducing conditions .	As expected, GH and GH-GH, but not G120R, induced GHR disulfide linkage, as assessed by anti-GHR blotting of cell extracts resolved by SDS-PAGE under nonreducing conditions.	3	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	3	4	12	13
In the human , GH can activate both the prolactin receptor ( PRLR ) and the growth hormone receptor ( GHR ) .	In the human, GH can activate both the prolactin receptor (PRLR) and the growth hormone receptor (GHR).	4	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	growth hormone receptor	growth hormone receptor	growth hormone receptor	4	5	16	19
Growth hormone ( GH ) initiates its cellular action by properly dimerizing GH receptor ( GHR ) .	Growth hormone (GH) initiates its cellular action by properly dimerizing GH receptor (GHR).	0	14	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Growth hormone	Growth hormone	Growth hormone	GH receptor	GH receptor	GH receptor	0	2	12	14
Quantification showed that GH stimulated GHR endocytosis is reduced from 50 % to about 20 % under conditions of either clathrin or betaTrCP depletion , indicating that both proteins are required for GH induced GHR endocytosis .	Quantification showed that GH stimulated GHR endocytosis is reduced from 50% to about 20% under conditions of either clathrin or betaTrCP depletion, indicating that both proteins are required for GH induced GHR endocytosis.	32	35	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	32	33	34	35
If that is the case , GH induced GHR endocytosis should ( i ) use the UbE motif and the SCF ( betaTrCP ) ligase , ( ii ) depend on clathrin and ( iii ) not depend on the phosphorylation status of the GHR .	If that is the case, GH induced GHR endocytosis should (i) use the UbE motif and the SCF (betaTrCP) ligase, (ii) depend on clathrin and (iii) not depend on the phosphorylation status of the GHR.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	6	7	8	9
Activation of GHR by GH overexpression in the mouse hypothalamus has a powerful orexigenic effect [ XREF_BIBR ] .	Activation of GHR by GH overexpression in the mouse hypothalamus has a powerful orexigenic effect [XREF_BIBR].	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GH	GH overexpression	gh	GHR	GHR	ghr	4	5	2	3
Interaction of GH with the cell-surface GH receptor ( GHR ) causes activation of the GHR associated tyrosine kinase , JAK2 , and consequent triggering of signaling cascades including the STAT , Ras/Raf/MEK1/MAP kinase , and insulin receptor substrate-1 ( IRS-1 )/PI3kinase pathways .	Interaction of GH with the cell-surface GH receptor (GHR) causes activation of the GHR associated tyrosine kinase, JAK2, and consequent triggering of signaling cascades including the STAT, Ras/Raf/MEK1/MAP kinase, and insulin receptor substrate-1 (IRS-1)/PI3kinase pathways.	0	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	2	3	15	16
This is consistent with a recently report that showed GH induced GHR down-regulation .	This is consistent with a recently report that showed GH induced GHR down-regulation.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	9	10	11	12
Like JAK2 induced protection from constitutive down-regulation , GH induced GHR down-regulation required the GHR Box 1 element and an intact JAK2 FERM domain .	Like JAK2 induced protection from constitutive down-regulation, GH induced GHR down-regulation required the GHR Box 1 element and an intact JAK2 FERM domain.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	8	9	10	11
In summary , we found that GH induced GHR endocytosis and constitutive GHR endocytosis share the same characteristics .	In summary, we found that GH induced GHR endocytosis and constitutive GHR endocytosis share the same characteristics.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	6	7	8	9
Measures that diminished GH dependent JAK2 and GHR tyrosine phosphorylation diminished neither GH induced GHR disulfide linkage nor GH enhanced GHR-JAK2 association .	Measures that diminished GH dependent JAK2 and GHR tyrosine phosphorylation diminished neither GH induced GHR disulfide linkage nor GH enhanced GHR-JAK2 association.	10	16	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	12	13	14	15
The GH activated GHR induces pro survival mechanisms downstream of the classical JAK-STAT pathway and finally initiates target gene transcription , which may result in increased stem cell cycling [ XREF_BIBR ] .	The GH activated GHR induces pro survival mechanisms downstream of the classical JAK-STAT pathway and finally initiates target gene transcription, which may result in increased stem cell cycling [XREF_BIBR].	0	20	activated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	GH	GH	gh	GHR	GHR induces pro survival mechanisms downstream of the classical JAK-STAT pathway and finally initiates target gene transcription	ghr	1	2	3	4
To ascertain that GH induced GHR endocytosis ( degradation ) in IM9 cells depends on the ubiquitin system as previously shown for GHR endocytosis in various tissue culture cells , we used the proteasomal inhibitor MG132 XREF_BIBR .	To ascertain that GH induced GHR endocytosis (degradation) in IM9 cells depends on the ubiquitin system as previously shown for GHR endocytosis in various tissue culture cells, we used the proteasomal inhibitor MG132 XREF_BIBR.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	3	4	5	6
In addition , it remains unclear whether pGH could induce nuclear localization of pGHR in vivo , although the phenomenon of GH induced GHR nuclear localization has been reported in vitro .	In addition, it remains unclear whether pGH could induce nuclear localization of pGHR in vivo, although the phenomenon of GH induced GHR nuclear localization has been reported in vitro.	19	25	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	21	22	23	24
It thus appears that GH activates the GHR within stromal fibroblasts and/or adipocytes , thereby inducing expression of IGF-I , which then acts on the IGF-IR in the epithelium .	It thus appears that GH activates the GHR within stromal fibroblasts and/or adipocytes, thereby inducing expression of IGF-I, which then acts on the IGF-IR in the epithelium.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	4	5	7	8
The observation that GH induces dimerization of the soluble GHBP and membrane GHR , and that dimerization of GHR appears to be critical for GH bioactivity suggests that the presentation of GH to target cells , in an unbound form or as a monomeric or dimeric complex with GHBP , may have significant implications for the ability of GH to activate specific postreceptor signaling pathways ( tyrosine kinase , protein kinase C , G protein pathways ) known to be utilized by GH for its diverse biological effects .	The observation that GH induces dimerization of the soluble GHBP and membrane GHR, and that dimerization of GHR appears to be critical for GH bioactivity suggests that the presentation of GH to target cells, in an unbound form or as a monomeric or dimeric complex with GHBP, may have significant implications for the ability of GH to activate specific postreceptor signaling pathways (tyrosine kinase, protein kinase C, G protein pathways) known to be utilized by GH for its diverse biological effects.	3	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	3	4	12	13
ICI 182-780 , a competitive inhibitor of E2 for the estrogen receptor ( ER ) , at different concentrations inhibited the E2- and GH induced stimulation of GHBP and GHR .	ICI 182-780, a competitive inhibitor of E2 for the estrogen receptor (ER), at different concentrations inhibited the E2- and GH induced stimulation of GHBP and GHR.	21	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHBP	GHBP	GHBP	23	24	27	28
Despite information about GHR-GHR association derived from elegant fluorescence resonance energy transfer and bioluminescence resonance energy transfer studies , an assessment of the dynamics of GH induced GHR conformational changes has been lacking .	Despite information about GHR-GHR association derived from elegant fluorescence resonance energy transfer and bioluminescence resonance energy transfer studies, an assessment of the dynamics of GH induced GHR conformational changes has been lacking.	23	29	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	25	26	27	28
As shown in XREF_FIG , GH and B-32 , but not the control antibody , activated GHR in porcine hepatocytes and CHO-GHR cells .	As shown in XREF_FIG, GH and B-32, but not the control antibody, activated GHR in porcine hepatocytes and CHO-GHR cells.	5	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	5	6	16	17
We evaluated the interrelationship between , and regulation of , the hepatic growth hormone receptor and serum GH binding protein ( GH BP ) in pigs treated with recombinant porcine growth hormone ( rpGH ) .	We evaluated the interrelationship between, and regulation of, the hepatic growth hormone receptor and serum GH binding protein (GH BP) in pigs treated with recombinant porcine growth hormone (rpGH).	17	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	growth hormone	growth hormone	growth hormone	GH binding protein	GH binding protein	GH binding protein	30	32	17	20
Exogenous GH stimulation of Ba/F3 GHR cells induced cyclins E and A and the cyclin dependent kinase inhibitor p21 ( waf1 and cip1 ) and repressed cyclin dependent kinase inhibitor p27 ( kip1 ) .	Exogenous GH stimulation of Ba/F3 GHR cells induced cyclins E and A and the cyclin dependent kinase inhibitor p21 (waf1 and cip1) and repressed cyclin dependent kinase inhibitor p27 (kip1).	1	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	1	2	5	6
GHBP is increased by GH replacement in GH deficient adults , but does not predict biochemical response to GH replacement .	GHBP is increased by GH replacement in GH deficient adults, but does not predict biochemical response to GH replacement.	0	14	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GH	GH	GH	GHBP	GHBP	GHBP	4	5	0	1
Upon GH treatment we observed that mutation of the UbE motif resulted in inhibition of GH induced GHR endocytosis ( XREF_FIG ) , indicating that the UbE motif is essential for GH induced GHR endocytosis .	Upon GH treatment we observed that mutation of the UbE motif resulted in inhibition of GH induced GHR endocytosis (XREF_FIG), indicating that the UbE motif is essential for GH induced GHR endocytosis.	13	18	induced	Positive_early_activation	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	15	16	17	18
Finally , using growth hormone receptor ( GHR ) gene disrupted mice , we showed that regulation by E ( 2 ) of IGF production was independent of GH induced GHR signaling in mouse fallopian tubes in vivo .	Finally, using growth hormone receptor (GHR) gene disrupted mice, we showed that regulation by E (2) of IGF production was independent of GH induced GHR signaling in mouse fallopian tubes in vivo.	24	31	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	28	29	30	31
The clinical relevance of measuring GHBP in adult GHD patients is limited to the first screening step to diagnose GHD , because long-term GH therapy tends to restore serum GHBP to pretreatment levels .	The clinical relevance of measuring GHBP in adult GHD patients is limited to the first screening step to diagnose GHD, because long-term GH therapy tends to restore serum GHBP to pretreatment levels.	23	30	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHBP	GHBP	GHBP	23	24	29	30
Ribonuclease protection assays revealed that injection of GH in a slow-release formula increased both hepatic GHR and IGF-I mRNAs 1 wk after the injection .	Ribonuclease protection assays revealed that injection of GH in a slow-release formula increased both hepatic GHR and IGF-I mRNAs 1 wk after the injection.	5	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	7	8	15	16
In muscle , GH treatment increased IGF-I mRNA ( 13.3 vs. 22.8 ; P < 0.05 ) but not GHR ( 8.3 vs. 9.5 ) or IGF-II ( 16.1 vs. 16.9 ) .	In muscle, GH treatment increased IGF-I mRNA (13.3 vs. 22.8; P < 0.05) but not GHR (8.3 vs. 9.5) or IGF-II (16.1 vs. 16.9).	3	26	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	3	4	19	20
Treatment with LH , but not GH , increased ( P < 0.05 ) concentrations of mRNA encoding GH-R to values observed in pituitary-intact ewes .	Treatment with LH, but not GH, increased (P < 0.05) concentrations of mRNA encoding GH-R to values observed in pituitary-intact ewes.	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GH-R	GH-R	GH-R	6	7	18	19
Previous studies have shown that growth hormone ( GH ) recruits the adapter protein SH2B1beta to the GH activated , GH receptor associated tyrosine kinase JAK2 , implicating SH2B1beta in GH dependent actin cytoskeleton remodeling , and suggesting that phosphorylation at serines 161 and 165 in SH2B1beta releases SH2B1beta from the plasma membrane .	Previous studies have shown that growth hormone (GH) recruits the adapter protein SH2B1beta to the GH activated, GH receptor associated tyrosine kinase JAK2, implicating SH2B1beta in GH dependent actin cytoskeleton remodeling, and suggesting that phosphorylation at serines 161 and 165 in SH2B1beta releases SH2B1beta from the plasma membrane.	10	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GH receptor	GH receptor	GH receptor	17	18	20	22
Rabbit GHR expressing human fibrosarcoma cells ( C14 ) were treated with GH , G120R , GH-GH , or G120R-G120R .	Rabbit GHR expressing human fibrosarcoma cells (C14) were treated with GH, G120R, GH-GH, or G120R-G120R.	0	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	12	13	1	2
Here , using human malignant melanoma cells , we examined the effects of GH excess or siRNA mediated GHR knock-down ( GHRKD ) on tumor proliferation , migration and invasion .	Here, using human malignant melanoma cells, we examined the effects of GH excess or siRNA mediated GHR knock-down (GHRKD) on tumor proliferation, migration and invasion.	13	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	13	14	18	19
By using both transient and stable expression systems , we determined that cysteine 241 ( an unpaired extracellular cysteine ) was critical for GH induced GHR disulfide linkage ; however , GH induced GHR dimerization , GHR-JAK2 interaction , and GHR , JAK2 , and STAT5 tyrosine phosphorylation still proceeded when this cysteine residue was mutated .	By using both transient and stable expression systems, we determined that cysteine 241 (an unpaired extracellular cysteine) was critical for GH induced GHR disulfide linkage; however, GH induced GHR dimerization, GHR-JAK2 interaction, and GHR, JAK2, and STAT5 tyrosine phosphorylation still proceeded when this cysteine residue was mutated.	23	27	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	23	24	25	26
Hepatic GH can interact with its receptor ( GHR ) on the surface of target cells and induces the association of GHR with Janus kinase ( JAK ) -2 to initiate tyrosine phosphorylation of GHR and JAK2 .	Hepatic GH can interact with its receptor (GHR) on the surface of target cells and induces the association of GHR with Janus kinase (JAK) -2 to initiate tyrosine phosphorylation of GHR and JAK2.	0	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	1	2	21	22
Overexpression of the Y119E mutant does not affect the GH induced GHR increased ubiquitination since it does not bind .	Overexpression of the Y119E mutant does n't affect the GH induced GHR increased ubiquitination since it does not bind.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	9	10	11	12
GH infusion further increased placental GH-R and IGF-IR , but abolished the increase in IGF-I mRNA levels .	GH infusion further increased placental GH-R and IGF-IR, but abolished the increase in IGF-I mRNA levels.	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GH-R	GH-R	GH-R	0	1	5	6
However , it is still unknown if GH induced GH-R signalling may support other functions within the oviduct .	However, it is still unknown if GH induced GH-R signalling may support other functions within the oviduct.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GH-R	GH-R	GH-R	7	8	9	10
Initially , the role of GH in both normal breast development and tumorigenesis was linked to that of prolactin , because human GH activates both GHR and prolactin receptor .	Initially, the role of GH in both normal breast development and tumorigenesis was linked to that of prolactin, because human GH activates both GHR and prolactin receptor.	21	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	22	23	25	26
HepG2 cells were transiently transfected with expression vectors containing Oatp1b2 or OATP1B3 promoter fragments , cDNAs for Stat5a , and the receptors for PRL ( PRLR ( L ) ) or GH ( GHR ) , and treated with PRL or GH .	HepG2 cells were transiently transfected with expression vectors containing Oatp1b2 or OATP1B3 promoter fragments, cDNAs for Stat5a, and the receptors for PRL (PRLR (L)) or GH (GHR), and treated with PRL or GH.	31	42	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	41	42	33	34
GH acts via its cell membrane receptor to initiate a cascade of signal transduction pathways downstream of the GHR .	GH acts via its cell membrane receptor to initiate a cascade of signal transduction pathways downstream of the GHR.	0	19	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	0	1	18	19
Collectively , our data indicate that the composition and/or length of the TMD affect some aspects of GHR function , but do not affect receptor predimerization or GH induced GHR activation .	Collectively, our data indicate that the composition and/or length of the TMD affect some aspects of GHR function, but do not affect receptor predimerization or GH induced GHR activation.	23	30	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	27	28	29	30
GH up-regulates GHBP in the absence of E2 , whereas E2 treatment does not raise GHBP in the absence of GH .	GH up-regulates GHBP in the absence of E2, whereas E2 treatment does not raise GHBP in the absence of GH.	0	5	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHBP	GHBP	GHBP	0	1	2	3
In liver , GH treatment increased GHR ( 6.0 vs. 9.7 ; P < 0.01 ) and IGF-I ( 5.2 vs. 49.0 ; P < 0.001 ) but not IGF-II ( 19.5 vs. 17.2 ) mRNA .	In liver, GH treatment increased GHR (6.0 vs. 9.7; P < 0.01) and IGF-I (5.2 vs. 49.0; P < 0.001) but not IGF-II (19.5 vs. 17.2) mRNA.	3	29	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	3	4	6	7
If IM9 cells contain sufficient amounts of Jak2 to accumulate endogenous GHRs at the cell surface , we expect that GH stimulation triggers GHR endocytosis by Jak2 phosphorylation on Y119 and detachment from the GHR .	If IM9 cells contain sufficient amounts of Jak2 to accumulate endogenous GHRs at the cell surface, we expect that GH stimulation triggers GHR endocytosis by Jak2 phosphorylation on Y119 and detachment from the GHR.	20	24	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	20	21	23	24
The signal transduction mechanism of GHR is normally a four-step process : ( 1 ) one GH molecule and two GHR molecules recognize each other ; ( 2 ) GH binds to two GHRs ; ( 3 ) GH induces GHR 2 dimerization forming a GH ( GHR ) 2 complex ; and ( 4 ) the GH ( GHR ) 2 complex triggers signaling , such as Janus kinase 2 , signal transducer and activator of transcription 5 ( JAK2 and STAT5 ) , and Src family kinases [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The signal transduction mechanism of GHR is normally a four-step process : (1) one GH molecule and two GHR molecules recognize each other; (2) GH binds to two GHRs; (3) GH induces GHR 2 dimerization forming a GH (GHR) 2 complex; and (4) the GH (GHR) 2 complex triggers signaling, such as Janus kinase 2, signal transducer and activator of transcription 5 (JAK2 and STAT5), and Src family kinases [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	38	42	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	38	39	40	41
Since human growth hormone gene can activate both the growth hormone receptor ( GHR ) and the prolactin ( PRL ) receptor ( PRLR ) , it is not clear which receptor system is responsible for the malignant transformation .	Since human growth hormone gene can activate both the growth hormone receptor (GHR) and the prolactin (PRL) receptor (PRLR), it is not clear which receptor system is responsible for the malignant transformation.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	growth hormone	growth hormone	growth hormone	growth hormone receptor	growth hormone receptor	growth hormone receptor	2	4	9	12
Additionally , GH induced further accumulation of GHR , Grb2 , and SHC proteins in the CM fraction .	Additionally, GH induced further accumulation of GHR, Grb2, and SHC proteins in the CM fraction.	2	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	2	3	7	8
Highly purified GH-receptor preparations from 3T3-F442A fibroblasts , whose differentiation into adipocytes is promoted by GH , have been shown to contain a tyrosine kinase capable of phosphorylating GH receptors .	Highly purified GH-receptor preparations from 3T3-F442A fibroblasts, whose differentiation into adipocytes is promoted by GH, have been shown to contain a tyrosine kinase capable of phosphorylating GH receptors.	2	16	promoted	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	GH	GH	GH	GH-receptor	GH-receptor	GH-receptor	15	16	2	3
Continuous long-term porcine somatotropin ( pST ) injections ( daily for 6 to 7 wk ) increased GHBP activity ( P less than.05 ) .	Continuous long-term porcine somatotropin (pST) injections (daily for 6 to 7 wk) increased GHBP activity (P less than.05).	3	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	somatotropin	somatotropin	somatotropin	GHBP	GHBP	GHBP	3	4	17	18
Knockdown of SIRT1 enhanced the acetylation and GH induced tyrosine phosphorylation of STAT5 , as well as the GH induced interaction of the GH receptor with STAT5 .	Knockdown of SIRT1 enhanced the acetylation and GH induced tyrosine phosphorylation of STAT5, as well as the GH induced interaction of the GH receptor with STAT5.	5	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	acetylation and GH induced tyrosine	gh	GH receptor	GH receptor	gh receptor	7	8	23	25
Growth hormone increased GH receptor mRNA , IGF-I mRNA and IGF-I protein secreted into the culture medium .	Growth hormone increased GH receptor mRNA, IGF-I mRNA and IGF-I protein secreted into the culture medium.	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Growth hormone	Growth hormone	Growth hormone	GH receptor	GH receptor	GH receptor	0	2	3	5
GHSR activation by ghrelin requires a unique acylation of the hormone that occurs during its synthesis , although unacyl-ghrelin , which has actions via an as-of-yet unknown receptor , also exists in circulation XREF_BIBR , XREF_BIBR , XREF_BIBR .	GHSR activation by ghrelin requires a unique acylation of the hormone that occurs during its synthesis, although unacyl-ghrelin, which has actions via an as-of-yet unknown receptor, also exists in circulation XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHSR	GHSR	GHSR	3	4	0	1
In contrast , haloperidol ( an antipsychotic agent ) failed to enhance this ghrelin mediated GHS-R activation , as demonstrated by both the CellKey ( TM ) and Ca ( 2+ ) imaging assays .	In contrast, haloperidol (an antipsychotic agent) failed to enhance this ghrelin mediated GHS-R activation, as demonstrated by both the CellKey (TM) and Ca (2+) imaging assays.	11	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	13	14	15	16
Des-acyl ghrelin does not activate ghrelin receptor , GHSR-1a , but several studies suggest that this form of ghrelin exhibits some GHSR-1a-independent biological activities , such as a prevention of skeletal muscle atrophy [ XREF_BIBR ] , protection of endothelial cells and cardiomyocytes in the heart [ XREF_BIBR ] , or influence on glucose metabolism [ XREF_BIBR ] .	Des-acyl ghrelin does not activate ghrelin receptor, GHSR-1a, but several studies suggest that this form of ghrelin exhibits some GHSR-1a-independent biological activities, such as a prevention of skeletal muscle atrophy [XREF_BIBR], protection of endothelial cells and cardiomyocytes in the heart [XREF_BIBR], or influence on glucose metabolism [XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	1	2	5	7
GHSR type 1a ( GHSR1a ) mRNA levels were also increased by ghrelin , and these ghrelin induced levels were suppressed by a GHSR1a antagonist .	GHSR type 1a (GHSR1a) mRNA levels were also increased by ghrelin, and these ghrelin induced levels were suppressed by a GHSR1a antagonist.	0	13	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHSR	GHSR	GHSR	12	13	0	1
Activation of GHS-R by ghrelin amplifies dopamine and D1R induced cAMP accumulation .	Activation of GHS-R by ghrelin amplifies dopamine and D1R induced cAMP accumulation.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	4	5	2	3
By activating GHS-R in the hypothalamus , ghrelin stimulates orexigenic neurons and promotes preferential ingestion of fat XREF_BIBR , XREF_BIBR , XREF_BIBR .	By activating GHS-R in the hypothalamus, ghrelin stimulates orexigenic neurons and promotes preferential ingestion of fat XREF_BIBR, XREF_BIBR, XREF_BIBR.	1	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	7	8	2	3
GHRL stimulates the production of GH through the activation of GHSR-1a in the hypothalamus and increases appetite and food intake independent of GHSR .	GHRL stimulates the production of GH through the activation of GHSR-1a in the hypothalamus and increases appetite and food intake independent of GHSR.	0	23	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GHRL	GHRL	GHRL	GHSR	GHSR	GHSR	0	1	22	23
Ghrelin has been shown to produce GHS-R internalization into vesicles in vitro via endosomal trafficking , where it gets recycled back to the membrane without being degraded .	Ghrelin has been shown to produce GHS-R internalization into vesicles in vitro via endosomal trafficking, where it gets recycled back to the membrane without being degraded.	0	7	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ghrelin	Ghrelin	Ghrelin	GHS-R	GHS-R	GHS-R	0	1	6	7
It was shown that both rat and synthetic chicken ghrelin peptides bound to and activated the GHS-R in vitro ( cell culture assay system ) with equal potency and stimulated GH release into plasma in vivo with similar dose response curves [ XREF_BIBR ] .	It was shown that both rat and synthetic chicken ghrelin peptides bound to and activated the GHS-R in vitro (cell culture assay system) with equal potency and stimulated GH release into plasma in vivo with similar dose response curves [XREF_BIBR].	9	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	9	10	16	17
Together , these results suggest that olanzapine , but not haloperidol , promotes appetite by enhancing ghrelin mediated GHS-R signaling .	Together, these results suggest that olanzapine, but not haloperidol, promotes appetite by enhancing ghrelin mediated GHS-R signaling.	16	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	16	17	18	19
An exposure of the ghrelin receptor to oleic acid has been reported to delay and inhibit ghrelin induced desensitization and internalization of the ghrelin receptor [ XREF_BIBR ] , suggesting naturally existing unsaturated fatty acids may regulate the ghrelin receptor activity .	An exposure of the ghrelin receptor to oleic acid has been reported to delay and inhibit ghrelin induced desensitization and internalization of the ghrelin receptor [XREF_BIBR], suggesting naturally existing unsaturated fatty acids may regulate the ghrelin receptor activity.	13	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	16	17	23	25
In vitro , RKT directly enhanced ghrelin induced GHS-R activation .	In vitro, RKT directly enhanced ghrelin induced GHS-R activation.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	6	7	8	9
Sustained high plasma ghrelin levels in GERD rats may cause systemic GHS-R depolarization .	Sustained high plasma ghrelin levels in GERD rats may cause systemic GHS-R depolarization.	3	12	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin levels	ghrelin	GHS-R	GHS-R	ghs-r	3	4	11	12
In addition , GHS-Rs have been described to have high constitutive activity and ablation of this ligand independent constitutive activity without affecting ghrelin mediated GHS-R signaling has significant consequences for stature and weight alone .	In addition, GHS-Rs have been described to have high constitutive activity and ablation of this ligand independent constitutive activity without affecting ghrelin mediated GHS-R signaling has significant consequences for stature and weight alone.	21	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	22	23	24	25
The canonical effector of GHSR is phospholipase C dependent XREF_BIBR , XREF_BIBR , but GHSR activation by ghrelin can elicit the activation of other pathways depending on the tissue context XREF_BIBR .	The canonical effector of GHSR is phospholipase C dependent XREF_BIBR, XREF_BIBR, but GHSR activation by ghrelin can elicit the activation of other pathways depending on the tissue context XREF_BIBR.	14	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHSR	GHSR	GHSR	17	18	14	15
Calorie intake was not statistically different between AgRP-Cre ; Ghsr f/f and Ghsr f/f mice treated with either saline or ghrelin ( XREF_FIG E ) , indicating that the difference in adiposity is independent of hyperphagia .	Calorie intake was not statistically different between AgRP-Cre; Ghsr f/f and Ghsr f/f mice treated with either saline or ghrelin (XREF_FIG E), indicating that the difference in adiposity is independent of hyperphagia.	9	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	Ghsr	Ghsr	Ghsr	20	21	9	10
Of appreciable note , hyperphagia observed under pathophysiological conditions , such as streptozotocin induced diabetes , is mediated by increased ghrelin release , which targets the ghrelin receptor on NPY and AgRP neurons XREF_BIBR .	Of appreciable note, hyperphagia observed under pathophysiological conditions, such as streptozotocin induced diabetes, is mediated by increased ghrelin release, which targets the ghrelin receptor on NPY and AgRP neurons XREF_BIBR.	20	28	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	20	21	26	28
However , only ghrelin activates GHS-R ; the effects of DAG and obestatin are mediated through other receptors [ XREF_BIBR ] .	However, only ghrelin activates GHS-R; the effects of DAG and obestatin are mediated through other receptors [XREF_BIBR].	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	3	4	5	6
In vitro , the activation of GHSR by ghrelin amplifies dopamine/D 1 -induced cAMP accumulation .	In vitro, the activation of GHSR by ghrelin amplifies dopamine/D 1 -induced cAMP accumulation.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHSR	GHSR	GHSR	8	9	6	7
Although counter to evidence that ghrelin stimulates rather than inhibits feeding behavior , the unlikely possibility remained that blocking endogenous ghrelin signaling with either a GHSR1a antagonist or ablation of ghsr might overcome the inhibitory effect of cabergoline on food-intake .	Although counter to evidence that ghrelin stimulates rather than inhibits feeding behavior, the unlikely possibility remained that blocking endogenous ghrelin signaling with either a GHSR1a antagonist or ablation of ghsr might overcome the inhibitory effect of cabergoline on food-intake.	20	31	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	ghsr	ghsr	ghsr	20	21	30	31
Ghrelin activates the growth hormone secretagogue receptor GHS-R .	Ghrelin activates the growth hormone secretagogue receptor GHS-R.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ghrelin	Ghrelin	Ghrelin	GHS-R	GHS-R	GHS-R	0	1	7	8
( 2 ) Ghrelin induced GHS-R activation resulted in activation of AMPK .	(2) Ghrelin induced GHS-R activation resulted in activation of AMPK.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	Ghrelin	Ghrelin	Ghrelin	GHS-R	GHS-R	GHS-R	3	4	5	6
Ghrelin activates the ghrelin receptor ( GHSR ) , a seven transmembrane G coupled protein linked to Gq and activation of these receptors on Arc NPY neurons increases intracellular Ca 2+ levels and activates CamKK [ XREF_BIBR ] .	Ghrelin activates the ghrelin receptor (GHSR), a seven transmembrane G coupled protein linked to Gq and activation of these receptors on Arc NPY neurons increases intracellular Ca 2+ levels and activates CamKK [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ghrelin	Ghrelin	Ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	0	1	3	5
Ghsr activation by ghrelin excites NPY neurons [ XREF_BIBR ] and initiates a signaling cascade that increases transcription of NPY and AgRP [ XREF_BIBR ] .	Ghsr activation by ghrelin excites NPY neurons [XREF_BIBR] and initiates a signaling cascade that increases transcription of NPY and AgRP [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	Ghsr	Ghsr	Ghsr	3	4	0	1
Cell based assays have demonstrated that ghrelin requires esterification with an acyl side chain on its Ser3 residue to activate GHSR at concentrations within the low-nanomolar range .	Cell based assays have demonstrated that ghrelin requires esterification with an acyl side chain on its Ser3 residue to activate GHSR at concentrations within the low-nanomolar range.	6	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHSR	GHSR	GHSR	6	7	20	21
An alternative , but not mutually exclusive , hypothesis is that the increase in plasma ghrelin levels observed after CR in our group of mice might have been insufficient to stimulate ghrelin receptor activation in the SNc .	An alternative, but not mutually exclusive, hypothesis is that the increase in plasma ghrelin levels observed after CR in our group of mice might have been insufficient to stimulate ghrelin receptor activation in the SNc.	15	33	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin levels	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	15	16	31	33
Obestatin ( up to 10 microM ) did not modulate recombinant ghrelin receptor function .	Obestatin (up to 10 microM) did not modulate recombinant ghrelin receptor function.	0	13	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Obestatin	Obestatin	Obestatin	ghrelin receptor	ghrelin receptor	ghrelin receptor	0	1	11	13
In slices from fasted rats , ghrelin activation of a postsynaptic ghrelin receptor , the growth hormone secretagogue receptor type 1a ( GHS-R1a ) , in VP neurons caused the dendritic release of VP , which stimulated astrocytes to release the gliotransmitter adenosine triphosphate ( ATP ) .	In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP).	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	6	7	11	13
We demonstrated that obestatin induced GSIS in INS-1 beta-cells is dependent on GHS-R expression ; obestatin induced GSIS is abolished in Ghsr -/- mice , and islets isolated from Ghsr -/- and beta-cell-specific Ghsr knockout mice .	We demonstrated that obestatin induced GSIS in INS-1 beta-cells is dependent on GHS-R expression; obestatin induced GSIS is abolished in Ghsr -/- mice, and islets isolated from Ghsr -/- and beta-cell-specific Ghsr knockout mice.	15	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	obestatin	obestatin	obestatin	Ghsr	Ghsr	Ghsr	15	16	21	22
[ XREF_BIBR XREF_BIBR ] However , complete characterization of these signaling pathways in relation to ghrelin activation of GHS-R 1a and GHS-R 1b pathways is needed .	[XREF_BIBR XREF_BIBR] However, complete characterization of these signaling pathways in relation to ghrelin activation of GHS-R 1a and GHS-R 1b pathways is needed.	15	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	15	16	18	19
Ghrelin and its synthetic peptide GHRP-6 accelerate gastric emptying perhaps by activating GHS-R of cholinergic excitatory pathways and nitrergic nervous pathways in the enteric nervous system .	Ghrelin and its synthetic peptide GHRP-6 accelerate gastric emptying perhaps by activating GHS-R of cholinergic excitatory pathways and nitrergic nervous pathways in the enteric nervous system.	0	20	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ghrelin	Ghrelin	Ghrelin	GHS-R	GHS-R	GHS-R	0	1	12	13
Several reports indicate that repeated or continuous activation of GHS-R by exogenous GHSs or ghrelin results in a diminished GH secretory response .	Several reports indicate that repeated or continuous activation of GHS-R by exogenous GHSs or ghrelin results in a diminished GH secretory response.	7	15	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	14	15	9	10
Here , we found that ghrelin increased GHS-R receptor up-regulation , and the enhancement of ghrelin induced glioma cell motility markedly inhibited by a GHS-R antagonist .	Here, we found that ghrelin increased GHS-R receptor up-regulation, and the enhancement of ghrelin induced glioma cell motility markedly inhibited by a GHS-R antagonist.	5	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	5	6	7	8
Since GHS-R is exclusively activated by ghrelin , only ghrelin signaling is blocked in Ghsr -/- mice , while obestatin signaling is intact .	Since GHS-R is exclusively activated by ghrelin, only ghrelin signaling is blocked in Ghsr -/- mice, while obestatin signaling is intact.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	6	7	1	2
Furthermore , ghrelin activation of GHSR potently excites NPY neurons and controls calcium homeostasis .	Furthermore, ghrelin activation of GHSR potently excites NPY neurons and controls calcium homeostasis.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHSR	GHSR	GHSR	2	3	5	6
It is possible that other ghrelin related peptides might contribute to the differential phenotypes of HFCS fed Ghrelin -/- and Ghsr -/- mice .	It is possible that other ghrelin related peptides might contribute to the differential phenotypes of HFCS fed Ghrelin -/- and Ghsr -/- mice.	5	22	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	Ghsr	Ghsr	Ghsr	5	6	20	21
Chronically high ghrelin levels , as seen in CR Ghrelin WT mice activates the ghrelin receptor , GHSR , to activate AMPK and send it to areas of high energy demand , i.e. the striatum where dopamine is released .	Chronically high ghrelin levels, as seen in CR Ghrelin WT mice activates the ghrelin receptor, GHSR, to activate AMPK and send it to areas of high energy demand, i.e. the striatum where dopamine is released.	2	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin levels	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	2	3	14	16
HFD : leptin decreased GHS-R and GPR7 , ghrelin increased GHS-R and GPR7 .	HFD : leptin decreased GHS-R and GPR7, ghrelin increased GHS-R and GPR7.	8	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	8	9	10	11
It is not yet clear whether this inhibitory activity on lipolysis is also shared by the major circulating isoform , des-acyl ghrelin , that does not activate the ghrelin receptor , namely the type 1a GH secretagogue-receptor ( GHS-R1a ) and lacks the endocrine effects of the acylated form .	It is not yet clear whether this inhibitory activity on lipolysis is also shared by the major circulating isoform, des-acyl ghrelin, that does not activate the ghrelin receptor, namely the type 1a GH secretagogue-receptor (GHS-R1a) and lacks the endocrine effects of the acylated form.	18	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	21	22	28	30
Ghrelin stimulates food intake and increases fat mass [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] partly by activating GHSR in the NPY and AgRP neurons within ARC [ XREF_BIBR , XREF_BIBR ] .	Ghrelin stimulates food intake and increases fat mass [XREF_BIBR, XREF_BIBR, XREF_BIBR] partly by activating GHSR in the NPY and AgRP neurons within ARC [XREF_BIBR, XREF_BIBR].	0	24	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ghrelin	Ghrelin	Ghrelin	GHSR	GHSR	GHSR	0	1	18	19
Des-acyl ghrelin , widely accepted to work independently of the ghrelin receptor , is increasingly being implicated in a number of biological functions .	Des-acyl ghrelin, widely accepted to work independently of the ghrelin receptor, is increasingly being implicated in a number of biological functions.	0	16	accepted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	1	2	10	12
Ghrelin and scheduled feeding both induced strong enrichment of Agrp ( 24- and 8.9-fold ) , Npy ( 22- and 7.8-fold ) , and Ghsr ( 6.1- and 6.9-fold ) , and we confirmed extensive colocalization between pS6 and AgRP and NPY neurons of the Arc under both conditions ( XREF_FIG ) .	Ghrelin and scheduled feeding both induced strong enrichment of Agrp (24- and 8.9-fold), Npy (22- and 7.8-fold), and Ghsr (6.1- and 6.9-fold), and we confirmed extensive colocalization between pS6 and AgRP and NPY neurons of the Arc under both conditions (XREF_FIG).	0	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ghrelin	Ghrelin	Ghrelin	Ghsr	Ghsr	Ghsr	0	1	24	25
While the signaling pathways downstream of GHS-R stimulation by ghrelin , confirmed above , are understood , the ion channels and Ca 2+ entry pathways that underlie increased neuronal activity are less well defined .	While the signaling pathways downstream of GHS-R stimulation by ghrelin, confirmed above, are understood, the ion channels and Ca 2+ entry pathways that underlie increased neuronal activity are less well defined.	6	10	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	9	10	6	7
GHSR is expressed abundantly in hippocampal neurons , and we recently demonstrated that pharmacological activation of GHSR by ghrelin in ventral and temporal subregions of the hippocampus ( vHP ) potently stimulates food intake by increasing both meal frequency and meal size .	GHSR is expressed abundantly in hippocampal neurons, and we recently demonstrated that pharmacological activation of GHSR by ghrelin in ventral and temporal subregions of the hippocampus (vHP) potently stimulates food intake by increasing both meal frequency and meal size.	14	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHSR	GHSR	GHSR	18	19	16	17
Combined together , in normal animals ghrelin may stimulate gastroduodenal motility by activating the GHS-R on vagal afferent nerve terminals and affect NPY neurons in the hypothalamus , and Y2 and/or Y4 receptors in the brain may mediate the action of ghrelin ( XREF_FIG , XREF_TABLE ) .	Combined together, in normal animals ghrelin may stimulate gastroduodenal motility by activating the GHS-R on vagal afferent nerve terminals and affect NPY neurons in the hypothalamus, and Y2 and/or Y4 receptors in the brain may mediate the action of ghrelin (XREF_FIG, XREF_TABLE).	6	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	6	7	14	15
The molecular mechanisms involved under ghrelin activation of GHSR receptor are not completely understood , but in hypothalamus , AMP dependent protein kinase ( AMPK ) has a key role in intracellular signal transduction [ XREF_BIBR - XREF_BIBR ] .	The molecular mechanisms involved under ghrelin activation of GHSR receptor are not completely understood, but in hypothalamus, AMP dependent protein kinase (AMPK) has a key role in intracellular signal transduction [XREF_BIBR - XREF_BIBR].	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHSR	GHSR	GHSR	5	6	8	9
These results indicate that ghrelin and des-acyl ghrelin induce proliferation of neuronal precursor cells that is both dependent and independent of GHS-R , suggesting that both ghrelin and des-acyl ghrelin are involved in neurogenesis of the fetal spinal cord .	These results indicate that ghrelin and des-acyl ghrelin induce proliferation of neuronal precursor cells that is both dependent and independent of GHS-R, suggesting that both ghrelin and des-acyl ghrelin are involved in neurogenesis of the fetal spinal cord.	4	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	4	5	21	22
Unlike ghrelin induced GHSR activity , the physiological role of GHSR constitutive activity and the mechanisms that underlie GHSR neuronal modulation remain elusive .	Unlike ghrelin induced GHSR activity, the physiological role of GHSR constitutive activity and the mechanisms that underlie GHSR neuronal modulation remain elusive.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHSR	GHSR	GHSR	1	2	3	4
Together these results suggest that des-acyl ghrelin does not bind to or activate the GHS-R in birds .	Together these results suggest that des-acyl ghrelin does not bind to or activate the GHS-R in birds.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	6	7	14	15
Since des-acyl ghrelin does not activate GHS-R , it initially was thought to be biologically inactive .	Since des-acyl ghrelin does not activate GHS-R, it initially was thought to be biologically inactive.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	2	3	6	7
To determine the implications of obestatin on insulin secretion in vivo , we further investigated obestatin induced GSIS in Ghsr -/- mice .	To determine the implications of obestatin on insulin secretion in vivo, we further investigated obestatin induced GSIS in Ghsr -/- mice.	15	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	obestatin	obestatin	obestatin	Ghsr	Ghsr	Ghsr	15	16	19	20
In this study , we investigated the effect of olanzapine on ghrelin mediated GHS-R signaling by using an electrical impedance based receptor biosensor assay system ( CellKey ( TM ) ) .	In this study, we investigated the effect of olanzapine on ghrelin mediated GHS-R signaling by using an electrical impedance based receptor biosensor assay system (CellKey (TM)).	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	11	12	13	14
This review highlights the latest mechanism by which ghrelin modulates body growth , appetite and energy metabolism by exploring pharmacological actions of the hormone and consequences of genetic or pharmacological blockade of the ghrelin and GHS-R ( Growth Hormone Secretagogue Receptor ) system on physiological responses in specific nutritional situations .	This review highlights the latest mechanism by which ghrelin modulates body growth, appetite and energy metabolism by exploring pharmacological actions of the hormone and consequences of genetic or pharmacological blockade of the ghrelin and GHS-R (Growth Hormone Secretagogue Receptor) system on physiological responses in specific nutritional situations.	8	42	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	8	9	35	36
Because the half-life of acylated ghrelin is short [ ~ 30m ] , we used MK-0677 ( also known as ibutamoren mesylate ) , a highly selective GHSR-1a agonist with a half-life of at least 5-6h , instead of exogenous acylated ghrelin in order to more closely model the prolonged stress induced increases in GHSR activation by endogenous ghrelin .	Because the half-life of acylated ghrelin is short [~ 30m], we used MK-0677 (also known as ibutamoren mesylate), a highly selective GHSR-1a agonist with a half-life of at least 5-6h, instead of exogenous acylated ghrelin in order to more closely model the prolonged stress induced increases in GHSR activation by endogenous ghrelin.	51	59	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHSR	GHSR	GHSR	58	59	54	55
Thus , GHS-R activation by ghrelin in NPY and AgRP neurons of the hypothalamus through these peripheral pathways stimulates appetite .	Thus, GHS-R activation by ghrelin in NPY and AgRP neurons of the hypothalamus through these peripheral pathways stimulates appetite.	2	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	5	6	2	3
MK-0677 is a ghrelin agonist that potently stimulates the GHS-R1a ghrelin receptor .	MK-0677 is a ghrelin agonist that potently stimulates the GHS-R1a ghrelin receptor.	3	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	3	4	10	12
A removal of ghrelin from culture media reversed the effect of ghrelin on spines , suggesting that maintenance of ghrelin induced increase in spine density may require continuous activation of the ghrelin receptor and downstream signaling mechanisms .	A removal of ghrelin from culture media reversed the effect of ghrelin on spines, suggesting that maintenance of ghrelin induced increase in spine density may require continuous activation of the ghrelin receptor and downstream signaling mechanisms.	17	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	19	20	31	33
L-168 ,049 inhibits the fixation of glucagon on GcgR and glucagon stimulated cAMP synthesis in CHO cells expressing human GcgR .	L-168,049 inhibits the fixation of glucagon on GcgR and glucagon stimulated cAMP synthesis in CHO cells expressing human GcgR.	4	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GcgR	GcgR	GcgR	6	7	19	20
Together , these studies suggest that glucagon receptor activation by OXM causes increased energy expenditure , however , other potential explanations for the results , such as increased diuresis or faecal excretion , have not been excluded .	Together, these studies suggest that glucagon receptor activation by OXM causes increased energy expenditure, however, other potential explanations for the results, such as increased diuresis or faecal excretion, have not been excluded.	6	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	OXM	OXM	OXM	glucagon receptor	glucagon receptor	glucagon receptor	10	11	6	8
However , the lack of effect of GRPP and GRPP-LP in the liver supports a lack of activation of the glucagon receptor .	However, the lack of effect of GRPP and GRPP-LP in the liver supports a lack of activation of the glucagon receptor.	5	22	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRPP	GRPP	GRPP	glucagon receptor	glucagon receptor	glucagon receptor	7	8	20	22
We show here unambiguously that neither OXM nor glucagon can modulate the I HR of Gcgr -/- mice .	We show here unambiguously that neither OXM nor glucagon can modulate the I HR of Gcgr -/- mice.	6	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	Gcgr	Gcgr	Gcgr	8	9	15	16
Activation of GCGR by glucagon leads to increased glucose production by the liver .	Activation of GCGR by glucagon leads to increased glucose production by the liver.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	4	5	2	3
These results indicated that glucagon directly stimulated colon cancer cell growth through binding to GCGR .	These results indicated that glucagon directly stimulated colon cancer cell growth through binding to GCGR.	4	15	stimulated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	4	5	14	15
Both glucagon and oxyntomodulin activated the glucagon receptor in a yeast strain containing either the GPA1 and Galphas or GPA1 and Galphai chimeras with similar potencies .	Both glucagon and oxyntomodulin activated the glucagon receptor in a yeast strain containing either the GPA1 and Galphas or GPA1 and Galphai chimeras with similar potencies.	1	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	oxyntomodulin	oxyntomodulin	oxyntomodulin	glucagon receptor	glucagon receptor	glucagon receptor	3	4	6	8
Complete disruption of glucagon signaling in GcgR -/- mice is associated with defects in endocrine cell differentiation and increased embryonic lethality .	Complete disruption of glucagon signaling in GcgR -/- mice is associated with defects in endocrine cell differentiation and increased embryonic lethality.	3	8	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GcgR	GcgR	GcgR	3	4	6	7
Initially , we used yeast strains expressing the GCGR and either the GPA1 and Galpha s or GPA1 and Galpha i chimera , and we determined that GLP-1 was able to weakly activate the GCGR , thereby acting as a partial agonist compared with glucagon ( XREF_FIG , B and C , and XREF_TABLE and XREF_TABLE ) .	Initially, we used yeast strains expressing the GCGR and either the GPA1 and Galpha s or GPA1 and Galpha i chimera, and we determined that GLP-1 was able to weakly activate the GCGR, thereby acting as a partial agonist compared with glucagon (XREF_FIG, B and C, and XREF_TABLE and XREF_TABLE).	27	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GCGR	GCGR	GCGR	27	28	34	35
Exogenous glucagon administration reduced plasma triglycerides in WT mice , inhibited TG synthesis and secretion , and stimulated FA beta oxidation in Gcgr +/+ hepatocytes .	Exogenous glucagon administration reduced plasma triglycerides in WT mice, inhibited TG synthesis and secretion, and stimulated FA beta oxidation in Gcgr +/+ hepatocytes.	1	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	Gcgr	Gcgr	Gcgr	1	2	22	23
A recent study reports that glucagon modulates its own secretion by binding to the glucagon receptor , which was detected by physiological assays and by PCR analysis on FACS isolated rat alpha cells .	A recent study reports that glucagon modulates its own secretion by binding to the glucagon receptor, which was detected by physiological assays and by PCR analysis on FACS isolated rat alpha cells.	5	16	modulates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	glucagon receptor	glucagon receptor	glucagon receptor	5	6	14	16
As summarized in XREF_FIG A , glucagon and OXM , the only members of the glucagon superfamily that activate GCGR , incorporate a neutral polar residue at position three ( glutamine , Q ) .	As summarized in XREF_FIG A, glucagon and OXM, the only members of the glucagon superfamily that activate GCGR, incorporate a neutral polar residue at position three (glutamine, Q).	6	21	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	OXM	OXM	OXM	GCGR	GCGR	GCGR	8	9	19	20
Furthermore , to identify the mechanisms promoting colon cancer cell growth by glucagon , the activation of downstream signals of GCGR was examined by western blotting using colon cancer cells treated with glucagon .	Furthermore, to identify the mechanisms promoting colon cancer cell growth by glucagon, the activation of downstream signals of GCGR was examined by western blotting using colon cancer cells treated with glucagon.	18	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	32	33	20	21
The glucagon receptor is activated by glucagon and is a member of the class B G protein coupled family of receptors , coupled to G alpha receptor [ XREF_BIBR ] .	The glucagon receptor is activated by glucagon and is a member of the class B G protein coupled family of receptors, coupled to G alpha receptor [XREF_BIBR].	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	glucagon receptor	glucagon receptor	glucagon receptor	6	7	1	3
A new study demonstrates that glucagon mediated activation of the glucagon receptor is bolstered by co-expression of RAMP2 .	A new study demonstrates that glucagon mediated activation of the glucagon receptor is bolstered by co-expression of RAMP2.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	glucagon receptor	glucagon receptor	glucagon receptor	5	6	10	12
OXM does activate the glucagon receptor , though less potently than native glucagon due to the octapeptide tail .	OXM does activate the glucagon receptor, though less potently than native glucagon due to the octapeptide tail.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXM	OXM	OXM	glucagon receptor	glucagon receptor	glucagon receptor	0	1	4	6
The GCGR can be activated by glucagon and regulates the release of glucose .	The GCGR can be activated by glucagon and regulates the release of glucose.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	6	7	1	2
Activation of GCGR by glucagon leads to increased glucose production in the liver , achieved by stimulating both glycogenolysis and gluconeogenesis .	Activation of GCGR by glucagon leads to increased glucose production in the liver, achieved by stimulating both glycogenolysis and gluconeogenesis.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	4	5	2	3
When the GCGR was stimulated by oxyntomodulin or analog G ( X ) , the E max ( efficacy ) was increased in the presence of RAMP2 .	When the GCGR was stimulated by oxyntomodulin or analog G (X), the E max (efficacy) was increased in the presence of RAMP2.	1	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	oxyntomodulin	oxyntomodulin	oxyntomodulin	GCGR	GCGR	GCGR	6	7	2	3
These data show that OXM functionally activates the GCGR ex-vivo and in vivo XREF_BIBR .	These data show that OXM functionally activates the GCGR ex-vivo and in vivo XREF_BIBR.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXM	OXM	OXM	GCGR	GCGR	GCGR	4	5	8	9
Recently , several publications expanded the initial findings on the mechanism of action of OXM and demonstrated that OXM has glycogenolytic properties in perfused mice liver showing that OXM can functionally activate the GCGR .	Recently, several publications expanded the initial findings on the mechanism of action of OXM and demonstrated that OXM has glycogenolytic properties in perfused mice liver showing that OXM can functionally activate the GCGR.	28	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXM	OXM	OXM	GCGR	GCGR	GCGR	28	29	33	34
Furthermore , to measure the internalization kinetics of the glucagon activated GCGR , we followed the glucagon induced localization change of the Cy3 labeled GCGR H372 mutant by confocal microscopy over a period of 60 min .	Furthermore, to measure the internalization kinetics of the glucagon activated GCGR, we followed the glucagon induced localization change of the Cy3 labeled GCGR H372 mutant by confocal microscopy over a period of 60 min.	6	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	9	10	11	12
To further understand the cellular mechanisms by which glucagon and related ligands activate the glucagon receptor ( GCGR ) , we investigated the interaction of the GCGR with receptor activity modifying protein ( RAMP ) 2 , a member of the family of receptor activity modifying proteins .	To further understand the cellular mechanisms by which glucagon and related ligands activate the glucagon receptor (GCGR), we investigated the interaction of the GCGR with receptor activity modifying protein (RAMP) 2, a member of the family of receptor activity modifying proteins.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	glucagon receptor	glucagon receptor	glucagon receptor	8	9	14	16
To study the GCGR interactome under liganded and unliganded states , CHO cells expressing GCGR were treated with or without glucagon , followed by AP-MS analyses ( XREF_FIG ) .	To study the GCGR interactome under liganded and unliganded states, CHO cells expressing GCGR were treated with or without glucagon, followed by AP-MS analyses (XREF_FIG).	13	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	20	21	14	15
We tested the ability of these mAb7 variants to inhibit glucagon activation of GCGR .	We tested the ability of these mAb7 variants to inhibit glucagon activation of GCGR.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	10	11	13	14
This is in contrast to the inhibitory impact of RAMP2 association on glucagon mediated GCGR responses in the GPA1 and Galpha i -expressing yeast .	This is in contrast to the inhibitory impact of RAMP2 association on glucagon mediated GCGR responses in the GPA1 and Galpha i -expressing yeast.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	12	13	14	15
Our findings show that OXM , but not OXMQ3E , activates the GCGR in vivo .	Our findings show that OXM, but not OXMQ3E, activates the GCGR in vivo.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXM	OXM	OXM	GCGR	GCGR	GCGR	4	5	12	13
We conclude that defective glucagon signaling causes PNETs in the Gcgr -/- mice , which may be used as a model of human PNETs .	We conclude that defective glucagon signaling causes PNETs in the Gcgr -/- mice, which may be used as a model of human PNETs.	4	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	Gcgr	Gcgr	Gcgr	4	5	10	11
Glucagon induces intracellular Ca ( 2+ ) ( [ Ca ( 2+ ) ] ( i ) ) elevation by stimulating glucagon receptor ( GCGR ) .	Glucagon induces intracellular Ca (2+) ([Ca (2+)] (i)) elevation by stimulating glucagon receptor (GCGR).	0	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Glucagon	Glucagon	Glucagon	glucagon receptor	glucagon receptor	glucagon receptor	0	1	21	23
The dramatic transcriptional alterations of these pathways may reflect an adaptive response to innate loss of glucagon signaling in the Gcgr -/- liver .	The dramatic transcriptional alterations of these pathways may reflect an adaptive response to innate loss of glucagon signaling in the Gcgr -/- liver.	16	22	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	Gcgr	Gcgr	Gcgr	16	17	20	21
In addition , pharmacological activation of GCGR by glucagon , a master regulator of fasting metabolism , decreases food intake in rodents and humans , suggesting a potential role for GCGR signaling in the pharmacology of OXM .	In addition, pharmacological activation of GCGR by glucagon, a master regulator of fasting metabolism, decreases food intake in rodents and humans, suggesting a potential role for GCGR signaling in the pharmacology of OXM.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	8	9	6	7
These pathways are also regulated through GCGR signaling mediated by glucagon [ XREF_BIBR - XREF_BIBR ] .	These pathways are also regulated through GCGR signaling mediated by glucagon [XREF_BIBR - XREF_BIBR].	6	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	10	11	6	7
GCGR is activated by the 29 amino acid hormonal peptide , glucagon ( XREF_SUPPLEMENTARY ) , and is a potential drug target for type 2 diabetes 2 .	GCGR is activated by the 29 amino acid hormonal peptide, glucagon (XREF_SUPPLEMENTARY), and is a potential drug target for type 2 diabetes 2.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	11	12	0	1
Injection of the glucagon agonist Lys17 ,18 , Glu21-glucagon induced a down-regulation of glucagon receptor mRNA content .	Injection of the glucagon agonist Lys17,18,Glu21-glucagon induced a down-regulation of glucagon receptor mRNA content.	3	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	glucagon receptor	glucagon receptor	glucagon receptor	3	4	13	15
Glucagon agonist induced the cAMP and PKA pathway in GCGR expressing cells .	Glucagon agonist induced the cAMP and PKA pathway in GCGR expressing cells.	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Glucagon	Glucagon	Glucagon	GCGR	GCGR	GCGR	0	1	9	10
Interestingly , glucagon mediated activation of the rat GCGr in vitro was reduced by the lower concentrations of the Glu 3 analogues tested , including Glu 3 of native OXM .	Interestingly, glucagon mediated activation of the rat GCGr in vitro was reduced by the lower concentrations of the Glu 3 analogues tested, including Glu 3 of native OXM.	2	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGr	GCGr	GCGr	2	3	8	9
A surprising finding is that both zebrafish glucagon peptides fail to activate mouse GCGR ( XREF_FIG ) .	A surprising finding is that both zebrafish glucagon peptides fail to activate mouse GCGR (XREF_FIG).	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	7	8	13	14
These data suggest that the lack of glucagon signalling leads to a lean phenotype , independent of the diet , by either a direct action of the Gcgr or by the increased GLP-1 levels in the central nervous system or the periphery .	These data suggest that the lack of glucagon signalling leads to a lean phenotype, independent of the diet, by either a direct action of the Gcgr or by the increased GLP-1 levels in the central nervous system or the periphery.	9	34	leads	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	GLP-1	GLP-1 levels	glp-1	Gcgr	Gcgr	gcgr	32	33	27	28
The glucagon receptor ( GCGR ) belongs to the secretin like ( class B ) family of G protein coupled receptors ( GPCRs ) and is activated by the peptide hormone glucagon .	The glucagon receptor (GCGR) belongs to the secretin like (class B) family of G protein coupled receptors (GPCRs) and is activated by the peptide hormone glucagon.	1	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	glucagon receptor	glucagon receptor	glucagon receptor	31	32	1	3
Consistent with previous studies on PTH1R XREF_BIBR , XREF_BIBR and GLP-1R XREF_BIBR , in this study we found that activation of GCGR by glucagon also induced the beta-catenin signaling pathway .	Consistent with previous studies on PTH1R XREF_BIBR, XREF_BIBR and GLP-1R XREF_BIBR, in this study we found that activation of GCGR by glucagon also induced the beta-catenin signaling pathway.	19	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	23	24	21	22
Previous reports also provide evidence that Gas6 induced Mer activation is responsible for the reduction of inflammatory cytokine expression in cells only expressing Mer but not Axl or Tyro3 .	Previous reports also provide evidence that Gas6 induced Mer activation is responsible for the reduction of inflammatory cytokine expression in cells only expressing Mer but not Axl or Tyro3.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer	Mer	Mer	6	7	8	9
We also observed a transient activation of p42 MAP kinase following activation of Mer by Gas6 .	We also observed a transient activation of p42 MAP kinase following activation of Mer by Gas6.	2	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer	Mer	Mer	15	16	13	14
The ubiquitous availability of Gas6 and apoptotic material could easily stimulate Mer if it is ectopically expressed on malignant cells .	The ubiquitous availability of Gas6 and apoptotic material could easily stimulate Mer if it is ectopically expressed on malignant cells.	4	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer	Mer	Mer	4	5	11	12
GAS6 overexpression activates MERTK via phosphorylation leading to a decreased p-ERK and p-p 38 and increased cell cycle inhibitors and dormancy associated transcription factors p27 , NR2F1 , SOX2 and NANOG [ XREF_BIBR ] .	GAS6 overexpression activates MERTK via phosphorylation leading to a decreased p-ERK and p-p 38 and increased cell cycle inhibitors and dormancy associated transcription factors p27, NR2F1, SOX2 and NANOG [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6 overexpression	gas6	MERTK	MERTK	mertk	0	1	3	4
XREF_BIBR , XREF_BIBR , XREF_BIBR There are two established ligands for the TAM RTKs , Protein S ( gene name Pros1 ) , which activates Tyro3 and Mer , and Gas6 , which activates all three TAMs , XREF_BIBR , XREF_BIBR although other ligands have been suggested .	XREF_BIBR, XREF_BIBR, XREF_BIBR There are two established ligands for the TAM RTKs, Protein S (gene name Pros1), which activates Tyro3 and Mer, and Gas6, which activates all three TAMs, XREF_BIBR, XREF_BIBR although other ligands have been suggested.	0	33	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer	Mer	Mer	30	31	27	28
We found that the activation of Mer receptor signaling by endogenous GAS6 regulates the establishment and/or the maintenance of PCa CSCs within the bone marrow microenvironment .	We found that the activation of Mer receptor signaling by endogenous GAS6 regulates the establishment and/or the maintenance of PCa CSCs within the bone marrow microenvironment.	6	12	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	Mer	Mer	Mer	11	12	6	7
MERTK can be activated by MFG-E8 , Gas6 or PROS1 [ XREF_BIBR , XREF_BIBR ] .	MERTK can be activated by MFG-E8, Gas6 or PROS1 [XREF_BIBR, XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	MERTK	MERTK	MERTK	7	8	0	1
Mer is one member of Axl receptor tyrosine kinase family , and its ligand Gas6 can stimulate activity of Mer receptor tyrosine kinase after binding it , and then activate the downstream signal transduction pathway , Mer participates in cell inflammation , apoptosis , tumorigenesis , thrombosis and hemostasis .	Mer is one member of Axl receptor tyrosine kinase family, and its ligand Gas6 can stimulate activity of Mer receptor tyrosine kinase after binding it, and then activate the downstream signal transduction pathway, Mer participates in cell inflammation, apoptosis, tumorigenesis, thrombosis and hemostasis.	12	29	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer	Mer	Mer	14	15	19	20
Furthermore , using homology models and biochemical verifications , we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface the between TAM Ig1 ectodomain and Gas6 Lg domain .	Furthermore, using homology models and biochemical verifications, we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface the between TAM Ig1 ectodomain and Gas6 Lg domain.	17	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mertk	Mertk	Mertk	17	18	21	22
We propose that the early defect in the Gas6 KO mice is secondary to the loss of Gas6 activation of Mer in the vagina .	We propose that the early defect in the Gas6 KO mice is secondary to the loss of Gas6 activation of Mer in the vagina.	17	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer	Mer	Mer	17	18	20	21
To better understand the mechanism by which MerTK activation provides an advantage in T-cell leukemia cells , we screened a human phospho-kinase array for changes in phosphorylation status of proteins in response to Gas6 mediated activation of MerTK .	To better understand the mechanism by which MerTK activation provides an advantage in T-cell leukemia cells, we screened a human phospho-kinase array for changes in phosphorylation status of proteins in response to Gas6 mediated activation of MerTK.	33	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	MerTK	MerTK	MerTK	33	34	37	38
While mice lacking functional MerTK have postnatal degeneration of photoreceptors and blindness , mice lacking Gas6 are normal , leading to the conclusion that Protein S and Gas6 ( or other MerTK ligands ) stimulate MerTK in RPE cells .	While mice lacking functional MerTK have postnatal degeneration of photoreceptors and blindness, mice lacking Gas6 are normal, leading to the conclusion that Protein S and Gas6 (or other MerTK ligands) stimulate MerTK in RPE cells.	25	38	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	MerTK	MerTK	MerTK	27	28	35	36
Furthermore , using homology models and biochemical verifications , we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain .	Furthermore, using homology models and biochemical verifications, we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain.	17	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mertk	Mertk	Mertk	17	18	21	22
Furthermore , GAS6 overexpression activated phosphorylation of MERTK in PCa cells , leading to an increase in the number of cancer stem cells ( CSCs ) among DTCs recovered from the bone marrow , suggesting that activation of Mer receptor signaling by endogenous GAS6 can contribute to the establishment of PCa CSCs ( CD133 +/CD44+ ) in the bone marrow [ XREF_BIBR ] .	Furthermore, GAS6 overexpression activated phosphorylation of MERTK in PCa cells, leading to an increase in the number of cancer stem cells (CSCs) among DTCs recovered from the bone marrow, suggesting that activation of Mer receptor signaling by endogenous GAS6 can contribute to the establishment of PCa CSCs (CD133 +/CD44+) in the bone marrow [XREF_BIBR].	38	44	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	Mer	Mer	Mer	43	44	38	39
10 MerTK is activated by the ligands Protein S and Gas6 , two structurally similar vitamin K dependent proteins .	10 MerTK is activated by the ligands Protein S and Gas6, two structurally similar vitamin K dependent proteins.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	MerTK	MerTK	MerTK	10	11	1	2
Graham and colleagues recently found that Gas6 induces an intracellular 150-KDa MerTK glycoform .	Graham and colleagues recently found that Gas6 induces an intracellular 150-KDa MerTK glycoform.	6	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	MerTK	MerTK	MerTK	6	7	11	12
21 Multiple signaling pathways are activated upon Gas6 stimulation of Mer receptor tyrosine kinase .	21 Multiple signaling pathways are activated upon Gas6 stimulation of Mer receptor tyrosine kinase.	7	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer	Mer	Mer	7	8	10	11
101 Mer-TK is activated by Gas6 or protein S and acts as a receptor for the maintenance of self-tolerance in resting macrophages .	101 Mer-TK is activated by Gas6 or protein S and acts as a receptor for the maintenance of self-tolerance in resting macrophages.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer-TK	Mer-TK	Mer-TK	5	6	1	2
Our results suggest that the activation of Mer receptor signaling by endogenous GAS6 contributes to the establishment and/or maintenance of PCa CSCs in the bone marrow microenvironment .	Our results suggest that the activation of Mer receptor signaling by endogenous GAS6 contributes to the establishment and/or maintenance of PCa CSCs in the bone marrow microenvironment.	7	13	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	Mer	Mer	Mer	12	13	7	8
The dose dependent nature of this behavior is consistent with a requirement for kinase activation , as 100 nM Gas6 is not sufficient to activate Mer in vitro .	The dose dependent nature of this behavior is consistent with a requirement for kinase activation, as 100 nM Gas6 is not sufficient to activate Mer in vitro.	17	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer	Mer	Mer	19	20	25	26
In addition , Gas6 treatment did not induce VEGF in Mertk -/- macrophages ( not shown ) .	In addition, Gas6 treatment did not induce VEGF in Mertk -/- macrophages (not shown).	3	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mertk	Mertk	Mertk	3	4	10	11
TYRO3 and MERTK can both be activated by binding of their endogenous ligands protein S and Gas6 , whereas AXL can only bind Gas6 [ XREF_BIBR ] .	TYRO3 and MERTK can both be activated by binding of their endogenous ligands protein S and Gas6, whereas AXL can only bind Gas6 [XREF_BIBR].	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	MERTK	MERTK	MERTK	16	17	2	3
Prolonged Gas6 exposure induces a smaller molecular weight form of Mer .	Prolonged Gas6 exposure induces a smaller molecular weight form of Mer.	1	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer	Mer	Mer	1	2	10	11
Some studies have suggested that the relevant MerTK ligand is ProS [ XREF_BIBR , XREF_BIBR ] , but GAS6 has also been shown to activate MerTK [ XREF_BIBR ] .	Some studies have suggested that the relevant MerTK ligand is ProS [XREF_BIBR, XREF_BIBR], but GAS6 has also been shown to activate MerTK [XREF_BIBR].	18	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	MerTK	MerTK	MerTK	18	19	25	26
It is interesting to note that individual TAM receptor family members use different molecules to bridge them to PtdSer externalised on apoptotic cells : MerTK and Tyro3 are activated by both Gas6 and Protein S , whereas the sole ligand for Axl is Gas6 [ XREF_BIBR , XREF_BIBR ] .	It is interesting to note that individual TAM receptor family members use different molecules to bridge them to PtdSer externalised on apoptotic cells : MerTK and Tyro3 are activated by both Gas6 and Protein S, whereas the sole ligand for Axl is Gas6 [XREF_BIBR, XREF_BIBR].	24	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	MerTK	MerTK	MerTK	31	32	24	25
Both Gas6 and Pros1 are ligands for the MerTK receptor and could therefore increase TAM signaling , via apoptotic cells or direct stimulation of the MerTK receptor on macrophages .	Both Gas6 and Pros1 are ligands for the MerTK receptor and could therefore increase TAM signaling, via apoptotic cells or direct stimulation of the MerTK receptor on macrophages.	0	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	MerTK	MerTK	MerTK	1	2	25	26
Also , although this study was focused on the nonmicroglial response to Gas6 , it is nevertheless possible , considering the phagocytosis mediating role of Mer , that Gas6 could also activate Mer in microglia in our culture model ; this requires further investigation .	Also, although this study was focused on the nonmicroglial response to Gas6, it is nevertheless possible, considering the phagocytosis mediating role of Mer, that Gas6 could also activate Mer in microglia in our culture model; this requires further investigation.	28	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Mer	Mer	Mer	28	29	32	33
Activation of Tyro3 by Gas6 protects PC12 cells from death induced by serum starvation and NGF deprivation XREF_BIBR , XREF_BIBR .	Activation of Tyro3 by Gas6 protects PC12 cells from death induced by serum starvation and NGF deprivation XREF_BIBR, XREF_BIBR.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	4	5	2	3
We generated soluble and monomeric versions of the human Tyro3 extracellular domain and human Gas6 for affinity measurements and correlated these values with the level of Gas6 required to induce Tyro3 signaling in cellular assays .	We generated soluble and monomeric versions of the human Tyro3 extracellular domain and human Gas6 for affinity measurements and correlated these values with the level of Gas6 required to induce Tyro3 signaling in cellular assays.	24	31	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	level of Gas6	gas6	Tyro3	Tyro3	tyro3	26	27	30	31
The present findings show that PS also activates the PI3K and Akt anti-apoptotic signaling from the Tyro3 receptor in neurons , suggesting both PS and Gas 6 activate neuronal Tyro3 .	The present findings show that PS also activates the PI3K and Akt anti-apoptotic signaling from the Tyro3 receptor in neurons, suggesting both PS and Gas 6 activate neuronal Tyro3.	23	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas 6	Gas 6	Gas 6	Tyro3	Tyro3	Tyro3	25	27	29	30
Cotreatment of cerebellar slices with Gas6 significantly attenuated demyelination as determined by MBP immunostaining , and Gas6 activated Tyro3 receptor through its phosphorylation .	Cotreatment of cerebellar slices with Gas6 significantly attenuated demyelination as determined by MBP immunostaining, and Gas6 activated Tyro3 receptor through its phosphorylation.	16	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	16	17	18	19
Thus , Gas6 stimulated a higher activation state of Tyro3 after 3h in the optic nerve , as observed by increased p-Tyro3 protein levels .	Thus, Gas6 stimulated a higher activation state of Tyro3 after 3h in the optic nerve, as observed by increased p-Tyro3 protein levels.	2	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	2	3	9	10
Recent data have showed that osteoblast derived growth-arrest specific 6 ( GAS6 ) ligands induced PCa cells that express a high GAS6 receptor Axl / Tyro3 ratio to a largely dormant phenotype , whereas PCa cells that express a low Axl / Tyro3 ratio to escape from dormancy ( XREF_FIG ) [ XREF_BIBR ] .	Recent data have showed that osteoblast derived growth-arrest specific 6 (GAS6) ligands induced PCa cells that express a high GAS6 receptor Axl / Tyro3 ratio to a largely dormant phenotype, whereas PCa cells that express a low Axl / Tyro3 ratio to escape from dormancy (XREF_FIG) [XREF_BIBR].	11	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAS6	GAS6	GAS6	Tyro3	Tyro3	Tyro3	11	12	25	26
This review summarizes recent developments in our understanding of the necessity of Gas6 stimulated Tyro3 activation for Schwann cell myelination and/or remyelination .	This review summarizes recent developments in our understanding of the necessity of Gas6 stimulated Tyro3 activation for Schwann cell myelination and/or remyelination.	10	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	12	13	14	15
Collectively , Gas6 induced Tyro3 activation directly promote phosphorylation of Fyn and the events play roles myelination , acting through Akt signaling in Schwann cells ( XREF_FIG ) .	Collectively, Gas6 induced Tyro3 activation directly promote phosphorylation of Fyn and the events play roles myelination, acting through Akt signaling in Schwann cells (XREF_FIG).	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	2	3	4	5
The Western blotting shows that compared with control , Gas6 stimulated a significant increase in p-Tyro3 protein levels in optic nerves , showing that Gas6 directly activates Tyro3 in the white matter ( XREF_FIG ) .	The Western blotting shows that compared with control, Gas6 stimulated a significant increase in p-Tyro3 protein levels in optic nerves, showing that Gas6 directly activates Tyro3 in the white matter (XREF_FIG).	24	31	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	24	25	27	28
Thus , Gas6 as a ligand for Sky specifically binds to and stimulates Sky receptor tyrosine kinase .	Thus, Gas6 as a ligand for Sky specifically binds to and stimulates Sky receptor tyrosine kinase.	2	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Sky	Sky	Sky	2	3	13	14
Tyro3 receptor is significantly activated by protein S but not by Gas6 and the combined addition of Gas6 and protein S does not alter the activation level of Tyro3 by protein S ( XREF_FIG F- XREF_FIG H ) .	Tyro3 receptor is significantly activated by protein S but not by Gas6 and the combined addition of Gas6 and protein S does not alter the activation level of Tyro3 by protein S (XREF_FIG F- XREF_FIG H).	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	11	12	0	1
In addition , Gas6 also could increase Dtk receptor ( XREF_FIG ) .	In addition, Gas6 also could increase Dtk receptor (XREF_FIG).	3	8	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Dtk	Dtk	Dtk	3	4	7	8
Consistent with this hypothesis , we found that the PtdSer binding protein Annexin A5 antagonized Gas6 activation of Tyro3 in Tyro3_TAM TKO MEFs ( XREF_FIG ) .	Consistent with this hypothesis, we found that the PtdSer binding protein Annexin A5 antagonized Gas6 activation of Tyro3 in Tyro3_TAM TKO MEFs (XREF_FIG).	15	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	15	16	18	19
The half-maximal concentration of Gas6 that stimulated Sky was about 1 nM .	The half-maximal concentration of Gas6 that stimulated Sky was about 1 nM.	2	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Sky	Sky	Sky	4	5	7	8
The Fzd receptors can respond to Wnt proteins to activate the canonical beta-catenin pathway which is important for both initiation and progression of cancers .	The Fzd receptors can respond to Wnt proteins to activate the canonical beta-catenin pathway which is important for both initiation and progression of cancers.	1	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fzd	Fzd	Fzd	beta-catenin	beta-catenin	beta-catenin	1	2	12	13
Furthermore , Fzd ligands , which are structurally unrelated to Wnts , such as the Norrie disease pseudoglioma protein ( Nrp , Norrin ) , have been described to activate beta-catenin transcriptional activity particularly in the vascular system and are discussed in detail in the following chapters [ XREF_BIBR ] .	Furthermore, Fzd ligands, which are structurally unrelated to Wnts, such as the Norrie disease pseudoglioma protein (Nrp, Norrin), have been described to activate beta-catenin transcriptional activity particularly in the vascular system and are discussed in detail in the following chapters [XREF_BIBR].	2	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fzd	Fzd	Fzd	beta-catenin	beta-catenin	beta-catenin	2	3	30	31
In the fruitfly Drosophila , Fz can activate two distinct developmental pathways : the Wnt and beta-catenin pathway and the Fz/planar cell polarity ( Fz/PCP ) pathway .	In the fruitfly Drosophila, Fz can activate two distinct developmental pathways : the Wnt and beta-catenin pathway and the Fz/planar cell polarity (Fz/PCP) pathway.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fz	Fz	Fz	beta-catenin	beta-catenin	beta-catenin	5	6	16	17
Based on the current studies , transmembrane receptor Frizzled ( Fz ) firstly received Wnt signals , then passed it to DSH to form a complex , activating beta-catenin with association of CEMIP flowed towards nucleus .	Based on the current studies, transmembrane receptor Frizzled (Fz) firstly received Wnt signals, then passed it to DSH to form a complex, activating beta-catenin with association of CEMIP flowed towards nucleus.	8	29	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fz	Fz	Fz	beta-catenin	beta-catenin	beta-catenin	10	11	28	29
We demonstrate that the cytoplasmic sequences of Fz2 and Fz preferentially activate the beta-catenin and planar polarity cascade , respectively .	We demonstrate that the cytoplasmic sequences of Fz2 and Fz preferentially activate the beta-catenin and planar polarity cascade, respectively.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fz	Fz	Fz	beta-catenin	beta-catenin	beta-catenin	9	10	13	14
Constitutively activated Frizzled ( Fz ) increases the stability of beta-catenin , inhibits apoptosis , inhibits adipogenesis , and induces osteoblastogenesis .	Constitutively activated Frizzled (Fz) increases the stability of beta-catenin, inhibits apoptosis, inhibits adipogenesis, and induces osteoblastogenesis.	2	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fz	Fz	Fz	beta-catenin	beta-catenin	beta-catenin	4	5	10	11
Both beta-Catenin dependent and independent Wnt pathways are activated by heteromeric receptor complexes of Frizzled family seven-pass transmembrane receptors and LRP5/6 or PTK7/Ryk/Ror2 co-receptors , respectively .	Both beta-Catenin dependent and independent Wnt pathways are activated by heteromeric receptor complexes of Frizzled family seven-pass transmembrane receptors and LRP5/6 or PTK7/Ryk/Ror2 co-receptors, respectively.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Frizzled	Frizzled	Frizzled	beta-Catenin	beta-Catenin	beta-Catenin	14	15	1	2
Many of FZD receptors , including FZD3 and FZD7 , are able to activate the canonical beta-catenin pathway , whereas data are not so obvious for FZD6 .	Many of FZD receptors, including FZD3 and FZD7, are able to activate the canonical beta-catenin pathway, whereas data are not so obvious for FZD6.	2	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FZD	FZD	FZD	beta-catenin	beta-catenin	beta-catenin	2	3	16	17
Instead , Wnt activation requires the binding of Wnt family proteins to their receptors of the Frizzled family ( Fz ) that subsequently promotes beta-catenin accumulation into the nucleus , which binds TCF4 , activating the transcription of several genes involved in cell cycle regulation and proliferation [ XREF_BIBR ] .	Instead, Wnt activation requires the binding of Wnt family proteins to their receptors of the Frizzled family (Fz) that subsequently promotes beta-catenin accumulation into the nucleus, which binds TCF4, activating the transcription of several genes involved in cell cycle regulation and proliferation [XREF_BIBR].	16	25	promotes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Frizzled	Frizzled	Frizzled	beta-catenin	beta-catenin	beta-catenin	16	17	24	25
Because forced clustering of Fz and LRP is sufficient to activate beta-catenin signaling independently of Wnts , ligand stimulation is thought to promote the assembly of higher order LRP5/6 coreceptor complexes that in turn drive signaling .	Because forced clustering of Fz and LRP is sufficient to activate beta-catenin signaling independently of Wnts, ligand stimulation is thought to promote the assembly of higher order LRP5/6 coreceptor complexes that in turn drive signaling.	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fz	Fz	Fz	beta-catenin	beta-catenin	beta-catenin	4	5	11	12
When activated by Wnt ligands , co-activation of the Frizzled and low-density lipoprotein receptor related proteins ( LRP ) receptors induces the inhibition of the destruction complex and the consequent stabilization of beta-catenin in the cytoplasm .	When activated by Wnt ligands, co-activation of the Frizzled and low-density lipoprotein receptor related proteins (LRP) receptors induces the inhibition of the destruction complex and the consequent stabilization of beta-catenin in the cytoplasm.	6	35	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Frizzled	Frizzled	Frizzled	beta-catenin	beta-catenin	beta-catenin	9	10	32	33
Clearly , future studies are required to characterize the regulation of WNT pathway gene expression by TGF-beta 1 in more detail , as we report that TGF-beta 1 induces WNT and FZD mRNA expression in human lung fibroblasts and activates beta-catenin signaling , which contributes to the fibroblast phenotype and function .	Clearly, future studies are required to characterize the regulation of WNT pathway gene expression by TGF-beta 1 in more detail, as we report that TGF-beta 1 induces WNT and FZD mRNA expression in human lung fibroblasts and activates beta-catenin signaling, which contributes to the fibroblast phenotype and function.	26	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FZD	TGF-beta 1 induces WNT and FZD mRNA expression	fzd	beta-catenin	beta-catenin	beta-catenin	31	32	40	41
Wnt activation of Frizzled and Dvl mediated inhibition of GSK3 allows beta-catenin to accumulate in the nucleus , interacting with members of the lymphoid enhancer factor ( LEF )/T-cell factor ( TCF ) class of architectural high mobility group ( HMG ) box transcription factors [ XREF_BIBR - XREF_BIBR ] .	Wnt activation of Frizzled and Dvl mediated inhibition of GSK3 allows beta-catenin to accumulate in the nucleus, interacting with members of the lymphoid enhancer factor (LEF)/T-cell factor (TCF) class of architectural high mobility group (HMG) box transcription factors [XREF_BIBR - XREF_BIBR].	1	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Frizzled	Frizzled	Frizzled	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
The Frizzled ( FZD ) receptor , activated by Wnt , produces beta catenin , which acts on TCF and LEF-1 to promote melanocyte differentiation .	The Frizzled (FZD) receptor, activated by Wnt, produces beta catenin, which acts on TCF and LEF-1 to promote melanocyte differentiation.	3	14	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FZD	FZD	FZD	beta catenin	beta catenin	beta catenin	3	4	12	14
WNT and Fzd activation of the beta-catenin pathway is further modulated by proteoglycans and/or arrow/LRP-5/LRP-6 as co-receptors XREF_BIBR and by antagonists such as Secreted Frizzled Related Proteins ( SFRPs ) XREF_BIBR .	WNT and Fzd activation of the beta-catenin pathway is further modulated by proteoglycans and/or arrow/LRP-5/LRP-6 as co-receptors XREF_BIBR and by antagonists such as Secreted Frizzled Related Proteins (SFRPs) XREF_BIBR.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Fzd	Fzd	Fzd	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
FZD activation of canonical beta-catenin signaling requires the adapter protein Dishevelled ( Dvl ) .	FZD activation of canonical beta-catenin signaling requires the adapter protein Dishevelled (Dvl).	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	FZD	FZD	FZD	beta-catenin	beta-catenin	beta-catenin	0	1	4	5
Wnt and FZD induced YAP and TAZ activation was independent of LRP5/6 co-receptors and beta-catenin .	Wnt and FZD induced YAP and TAZ activation was independent of LRP5/6 co-receptors and beta-catenin.	0	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FZD	FZD	FZD	beta-catenin	beta-catenin	beta-catenin	2	3	14	15
Wnt stimulated Fzd and LRP activation inhibits the otherwise constitutive degradation of cytosolic beta-catenin , permitting nuclear translocation , TCF/LEF binding and the activation of genes controlling cell proliferation , migration and morphogenesis .	Wnt stimulated Fzd and LRP activation inhibits the otherwise constitutive degradation of cytosolic beta-catenin, permitting nuclear translocation, TCF/LEF binding and the activation of genes controlling cell proliferation, migration and morphogenesis.	2	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Fzd	Fzd	Fzd	beta-catenin	beta-catenin	beta-catenin	2	3	13	14
Although it is widely accepted that the canonical Wnt and beta-catenin signaling axis is initiated by Wnt mediated Fz and LRP5/6 heterodimerization XREF_BIBR , XREF_BIBR , XREF_BIBR , key molecular details involved in canonical Wnt signaling propagation remain elusive , such as the details of how Dvl activates the dismantling of the destruction complex .	Although it is widely accepted that the canonical Wnt and beta-catenin signaling axis is initiated by Wnt mediated Fz and LRP5/6 heterodimerization XREF_BIBR, XREF_BIBR, XREF_BIBR, key molecular details involved in canonical Wnt signaling propagation remain elusive, such as the details of how Dvl activates the dismantling of the destruction complex.	10	22	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fz	Wnt mediated Fz	fz	beta-catenin	beta-catenin	beta-catenin	18	19	10	11
Also expression of FzD receptors ( Fzd7 and 8 ) is up-regulated ( although the co-receptor Lrp6 is down-regulated ) as well as the key players beta-catenin ( Ctnnb1 ) and Tcf7 , which are regulating the expression of down-stream target genes ( Wisp1 , Fosl1 , Myc ) .	Also expression of FzD receptors (Fzd7 and 8) is up-regulated (although the co-receptor Lrp6 is down-regulated) as well as the key players beta-catenin (Ctnnb1) and Tcf7, which are regulating the expression of down-stream target genes (Wisp1, Fosl1, Myc).	1	31	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FzD	expression of FzD	fzd	beta-catenin	beta-catenin	beta-catenin	3	4	26	27
In canonical Wnt signalling , Fzd receptors respond to Wnt proteins in the presence of co-receptor LRP5/6 to activate and propagate the canonical Wnt and beta-catenin pathway .	In canonical Wnt signalling, Fzd receptors respond to Wnt proteins in the presence of co-receptor LRP5/6 to activate and propagate the canonical Wnt and beta-catenin pathway.	5	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fzd	Fzd	Fzd	beta-catenin	beta-catenin	beta-catenin	5	6	25	26
Wnt and beta-catenin signaling induced by the Norrin and Frizzled -4 pathway has been shown to improve capillary repair following oxygen induced retinopathy ( OIR ) in the mouse , a model for retinopathy of prematurity .	Wnt and beta-catenin signaling induced by the Norrin and Frizzled -4 pathway has been shown to improve capillary repair following oxygen induced retinopathy (OIR) in the mouse, a model for retinopathy of prematurity.	0	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Frizzled	Frizzled	Frizzled	beta-catenin	beta-catenin	beta-catenin	9	10	2	3
Wnts activating the canonical pathway bind both Frizzled ( Fz ) and LRP receptors resulting in activation of the transcription factor beta-catenin .	Wnts activating the canonical pathway bind both Frizzled (Fz) and LRP receptors resulting in activation of the transcription factor beta-catenin.	6	22	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Fz	Fz	Fz	beta-catenin	beta-catenin	beta-catenin	9	10	21	22
However , while activation of beta-catenin by Frizzled has been demonstrated in macrophages , to date , no studies have investigated if EPO affects this pathway or if EPO has any effect on Wnt-1 .	However, while activation of beta-catenin by Frizzled has been demonstrated in macrophages, to date, no studies have investigated if EPO affects this pathway or if EPO has any effect on Wnt-1.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Frizzled	Frizzled	Frizzled	beta-catenin	beta-catenin	beta-catenin	7	8	5	6
Here , we identified epithelial Wnt7a and Wnt7b as possible ligands of Fzd mediated beta-catenin ( Ctnnb1 )-dependent ( canonical ) Wnt signaling in the adjacent undifferentiated periotic mesenchyme ( POM ) .	Here, we identified epithelial Wnt7a and Wnt7b as possible ligands of Fzd mediated beta-catenin (Ctnnb1)-dependent (canonical) Wnt signaling in the adjacent undifferentiated periotic mesenchyme (POM).	10	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Fzd	Fzd	Fzd	beta-catenin	beta-catenin	beta-catenin	12	13	14	15
As FZD receptors rescued Wnt and beta-catenin signaling , but FZD CRDs further enhanced the inhibitory effects of FZC18 , these findings indicate that the effects of FZC18 may not result from endoplasmic reticulum toxicity through clogging of the secretion pathway with cysteine rich proteins .	As FZD receptors rescued Wnt and beta-catenin signaling, but FZD CRDs further enhanced the inhibitory effects of FZC18, these findings indicate that the effects of FZC18 may not result from endoplasmic reticulum toxicity through clogging of the secretion pathway with cysteine rich proteins.	1	7	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FZD	FZD	FZD	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
Wnt signaling is initiated upon the binding of canonical Wnt ligands to their coreceptors Fz and LRP5/6 to stimulate the Wnt-beta-catenin signaling pathway by destroying the beta-catenin destruction complex ( XREF_FIG ) .	Wnt signaling is initiated upon the binding of canonical Wnt ligands to their coreceptors Fz and LRP5/6 to stimulate the Wnt-beta-catenin signaling pathway by destroying the beta-catenin destruction complex (XREF_FIG).	14	28	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fz	Fz	Fz	beta-catenin	beta-catenin	beta-catenin	14	15	26	27
Wnt activated FZD receptor and LRP5/6 co-receptor inhibit glycogen synthase kinase 3 beta ( GSK3beta ) , the central effector of the beta-catenin destruction complex , and thus signal the stabilization of beta-catenin , which in turn forms a transcriptional complex with T-cell factor and lymphoid enhancer factor ( TCF/LEF ) XREF_BIBR .	Wnt activated FZD receptor and LRP5/6 co-receptor inhibit glycogen synthase kinase 3 beta (GSK3beta), the central effector of the beta-catenin destruction complex, and thus signal the stabilization of beta-catenin, which in turn forms a transcriptional complex with T-cell factor and lymphoid enhancer factor (TCF/LEF) XREF_BIBR.	2	37	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FZD	FZD	FZD	beta-catenin	beta-catenin	beta-catenin	2	3	32	33
Csnk1e encodes the casein kinase 1in subunit , which may mediate canonical WNT and beta-catenin and noncanonical WNT Fzd / planar cell polarity signaling , while the related casein kinase 1delta subunit may phosphorylate VANGL2 downstream of noncanonical WNT signaling .	Csnk1e encodes the casein kinase 1in subunit, which may mediate canonical WNT and beta-catenin and noncanonical WNT Fzd / planar cell polarity signaling, while the related casein kinase 1delta subunit may phosphorylate VANGL2 downstream of noncanonical WNT signaling.	1	33	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fzd	Fzd	Fzd	beta-catenin	beta-catenin	beta-catenin	18	19	14	15
In Wnt stimulated fibroblasts , the FZD receptor inhibits GSK-3beta activity and blocks beta-catenin degradation .	In Wnt stimulated fibroblasts, the FZD receptor inhibits GSK-3beta activity and blocks beta-catenin degradation.	6	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FZD	FZD	FZD	beta-catenin	beta-catenin	beta-catenin	6	7	13	14
These findings are consistent with the hypothesis that the high level of endogenous galanin in injured primary afferents activates peripheral GalR2 , which leads to an increase in C-fibre mechanical activation thresholds and a marked reduction in evoked and ongoing nociceptive responses .	These findings are consistent with the hypothesis that the high level of endogenous galanin in injured primary afferents activates peripheral GalR2, which leads to an increase in C-fibre mechanical activation thresholds and a marked reduction in evoked and ongoing nociceptive responses.	10	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	galanin	level of endogenous galanin	galanin	GalR2	GalR2	galr2	13	14	20	21
We show that while Galanin induces the activation of the galanin receptor 2 ( Galr2 ) that leads to a robust stimulation toward Galphaq protein and beta-arrestin1/2 , an alternative ligand Spexin and its analog have biased agonism toward G protein signaling relative to Galanin .	We show that while Galanin induces the activation of the galanin receptor 2 (Galr2) that leads to a robust stimulation toward Galphaq protein and beta-arrestin1/2, an alternative ligand Spexin and its analog have biased agonism toward G protein signaling relative to Galanin.	4	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galanin	Galanin	Galanin	Galr2	Galr2	Galr2	4	5	14	15
Preincubation with M35 or M40 did not prevent galanin induced internalization of GALR1-EGFP or GALR2-EGFP .	Preincubation with M35 or M40 did not prevent galanin induced internalization of GALR1-EGFP or GALR2-EGFP.	7	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	galanin	galanin	galanin	GALR2-EGFP	GALR2-EGFP	GALR2-EGFP	8	9	14	15
Then the functional role of injury increased galanin activation of GalR2 was thought to process pro nociception [ XREF_BIBR , XREF_BIBR ] .	Then the functional role of injury increased galanin activation of GalR2 was thought to process pro nociception [XREF_BIBR, XREF_BIBR].	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	galanin	galanin	galanin	GalR2	GalR2	GalR2	7	8	10	11
GalR2 activation by high concentration galanin inhibits primary afferent nociceptor activity and thereby reduces nociceptive input to the spinal cord .	GalR2 activation by high concentration galanin inhibits primary afferent nociceptor activity and thereby reduces nociceptive input to the spinal cord.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	galanin	galanin	galanin	GalR2	GalR2	GalR2	5	6	0	1
Even without a change in expression , GAL induced GALR2 signaling may be amplified by concurrent downregulation of GALR1 .	Even without a change in expression, GAL induced GALR2 signaling may be amplified by concurrent downregulation of GALR1.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	GAL	GAL	GAL	GALR2	GALR2	GALR2	7	8	9	10
conclude that GalR2 , when activated by galanin ( or other agonists ) , inhibits the activity of primary nociceptive afferents , reducing nociceptive transmission into the spinal cord .	conclude that GalR2, when activated by galanin (or other agonists), inhibits the activity of primary nociceptive afferents, reducing nociceptive transmission into the spinal cord.	2	14	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	galanin	galanin	galanin	GalR2	GalR2	GalR2	7	8	2	3
Thus , both Galanin and Spexin stimulate Galr2 and are generally localized in brain regions with Galr2 expression XREF_BIBR , XREF_BIBR .	Thus, both Galanin and Spexin stimulate Galr2 and are generally localized in brain regions with Galr2 expression XREF_BIBR, XREF_BIBR.	2	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galanin	Galanin	Galanin	Galr2	Galr2	Galr2	3	4	7	8
Galanin stimulation at low temperature caused GALR2-EGFP aggregation and clustering on the surface but no translocation to cytoplasm .	Galanin stimulation at low temperature caused GALR2-EGFP aggregation and clustering on the surface but no translocation to cytoplasm.	0	7	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galanin	Galanin	Galanin	GALR2-EGFP	GALR2-EGFP	GALR2-EGFP	0	1	6	7
To determine whether Galr2 can adopt distinct conformations induced by different endogenous ligands , we monitored the Net DeltaBRET signal upon stimulation of Galr2 by Galanin , Spexin , or Fmoc-dA4-dQ14 using a panel of FlasH BRET conformational biosensors based on human beta-arrestin2 .	To determine whether Galr2 can adopt distinct conformations induced by different endogenous ligands, we monitored the Net DeltaBRET signal upon stimulation of Galr2 by Galanin, Spexin, or Fmoc-dA4-dQ14 using a panel of FlasH BRET conformational biosensors based on human beta-arrestin2.	15	30	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Galanin	Galanin	Galanin	Galr2	Galr2	Galr2	25	26	23	24
CYM2503 potentiated the galanin stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor , whereas it exhibited no detectable affinity for the ( 125 ) I galanin binding site of GalR2 receptor , an effect consistent with that of a positive allosteric modulator .	CYM2503 potentiated the galanin stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor, whereas it exhibited no detectable affinity for the (125) I galanin binding site of GalR2 receptor, an effect consistent with that of a positive allosteric modulator.	2	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	galanin	galanin	galanin	GalR2	GalR2	GalR2	3	4	12	13
To determine the role of GALR2 in cell proliferation , cells starved for 24 hours were treated with various concentrations of galanin , and counted with a Coulter counter .	To determine the role of GALR2 in cell proliferation, cells starved for 24 hours were treated with various concentrations of galanin, and counted with a Coulter counter.	3	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	galanin	galanin	galanin	GALR2	GALR2	GALR2	21	22	5	6
These data suggest a role for galanin in BMMSC migration , probably through activation of the GalR2 receptor .	These data suggest a role for galanin in BMMSC migration, probably through activation of the GalR2 receptor.	4	17	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	galanin	galanin	galanin	GalR2	GalR2	GalR2	6	7	16	17
Galanin activates three receptors , the galanin receptor 1 ( GalR1 ) , GalR2 and GalR3 .	Galanin activates three receptors, the galanin receptor 1 (GalR1), GalR2 and GalR3.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galanin	Galanin	Galanin	GalR2	GalR2	GalR2	0	1	13	14
Conversely , galanin appears to activate GalR2 pre-synaptically .	Conversely, galanin appears to activate GalR2 pre-synaptically.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	galanin	galanin	galanin	GalR2	GalR2	GalR2	2	3	6	7
These findings of an increase in C-fibre mechanical activation thresholds and spontaneous nociceptive responses are compatible with the observed reversal in allodynia in the Gal-OE mice , and support the hypothesis that the high levels of endogenous galanin in injured primary afferents activate a peripheral GalR2 mediated anti-nociceptive pathway .	These findings of an increase in C-fibre mechanical activation thresholds and spontaneous nociceptive responses are compatible with the observed reversal in allodynia in the Gal-OE mice, and support the hypothesis that the high levels of endogenous galanin in injured primary afferents activate a peripheral GalR2 mediated anti-nociceptive pathway.	34	46	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	galanin	levels of endogenous galanin	galanin	GalR2	GalR2	galr2	37	38	45	46
GAL induces three G-protein-coupled receptors , GALR1 , GALR2 and GALR3 .	GAL induces three G-protein-coupled receptors, GALR1, GALR2 and GALR3.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAL	GAL	GAL	GALR2	GALR2	GALR2	0	1	8	9
The endogenous and exogenous effects of galanin are mediated by three receptor subtypes , which are termed : GALR1 , GALR2 , and GALR3 .	The endogenous and exogenous effects of galanin are mediated by three receptor subtypes, which are termed : GALR1, GALR2, and GALR3.	4	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	galanin	galanin	galanin	GALR2	GALR2	GALR2	6	7	20	21
Our data reveal a novel mechanism by which GAL from nerves stimulates GALR2 on cancer cells to induce NFATC2 mediated transcription of cyclooxygenase-2 and GAL .	Our data reveal a novel mechanism by which GAL from nerves stimulates GALR2 on cancer cells to induce NFATC2 mediated transcription of cyclooxygenase-2 and GAL.	8	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GAL	GAL	GAL	GALR2	GALR2	GALR2	8	9	12	13
We found that Spexin and Galanin induce specific active conformations of Galr2 , which may lead to different internalization rates of the receptor as well as different signaling outputs .	We found that Spexin and Galanin induce specific active conformations of Galr2, which may lead to different internalization rates of the receptor as well as different signaling outputs.	3	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galanin	Galanin	Galanin	Galr2	Galr2	Galr2	5	6	11	12
Galanin induced decreases in nucleus accumbens and striatum EPSPs and morphine conditioned place preference require both GalR1 and GalR2 .	Galanin induced decreases in nucleus accumbens and striatum EPSPs and morphine conditioned place preference require both GalR1 and GalR2.	0	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galanin	Galanin	Galanin	GalR2	GalR2	GalR2	0	1	18	19
To verify that GALR2 promotes neuritogenesis , we disrupted GAL mediated GALR2 induction .	To verify that GALR2 promotes neuritogenesis, we disrupted GAL mediated GALR2 induction.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	GAL	GAL	GAL	GALR2	GALR2	GALR2	9	10	11	12
They showed that galanin 1 receptors ( GalR1 ) mediate cold allodynia and GalR2 mediates mechanical allodynia .	They showed that galanin 1 receptors (GalR1) mediate cold allodynia and GalR2 mediates mechanical allodynia.	3	14	mediate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	galanin	galanin	galanin	GalR2	GalR2	GalR2	3	4	13	14
Because BMP9 mediated ALK1 activation leads to SMAD1 ,5,8 phosphorylation and ERK activation ( XREF_FIG ) , we tested if activation of ERK and / or SMAD was required for BMP9-ALK1-mediated sprouting inhibition and induction of Notch target genes .	Because BMP9 mediated ALK1 activation leads to SMAD1,5,8 phosphorylation and ERK activation (XREF_FIG), we tested if activation of ERK and / or SMAD was required for BMP9-ALK1-mediated sprouting inhibition and induction of Notch target genes.	1	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	BMP9	BMP9	BMP9	ALK1	ALK1	ALK1	1	2	3	4
HMEC-1 cells were transfected with different pALK1 reporter constructs and treated with either TGF-beta1 or BMP9 using the time and dose previously established in endothelial cells [ XREF_BIBR ] .	HMEC-1 cells were transfected with different pALK1 reporter constructs and treated with either TGF-beta1 or BMP9 using the time and dose previously established in endothelial cells [XREF_BIBR].	6	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BMP9	BMP9	BMP9	pALK1	pALK1	pALK1	15	16	6	7
These data imply that in a cell-type with low expression of ActRIIB , BMP-9 might still signal due to its high affinity to ALK1 , then forming complexes with other type II receptors .	These data imply that in a cell-type with low expression of ActRIIB, BMP-9 might still signal due to its high affinity to ALK1, then forming complexes with other type II receptors.	13	24	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BMP-9	BMP-9	BMP-9	ALK1	ALK1	ALK1	13	14	23	24
BMP-4 is essential for angiogenesis and is antagonized by matrix Gla protein ( MGP ) and crossveinless 2 ( CV2 ) , both induced by the activin receptor like-kinase 1 ( ALK1 ) when stimulated by BMP-9 .	BMP-4 is essential for angiogenesis and is antagonized by matrix Gla protein (MGP) and crossveinless 2 (CV2), both induced by the activin receptor like-kinase 1 (ALK1) when stimulated by BMP-9.	23	37	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	BMP-9	BMP-9	BMP-9	ALK1	ALK1	ALK1	36	37	31	32
We also demonstrate that BMP-9 activates the TGF-beta and ALK1 pathway in brain microvessels as indicated by increased nuclear translocation of specific Smad proteins associated with signaling mediated by the ALK1 receptor ( i.e ., pSmad1/5/8 ) .	We also demonstrate that BMP-9 activates the TGF-beta and ALK1 pathway in brain microvessels as indicated by increased nuclear translocation of specific Smad proteins associated with signaling mediated by the ALK1 receptor (i.e., pSmad1/5/8).	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-9	BMP-9	BMP-9	ALK1	ALK1	ALK1	4	5	9	10
In contrast , no calcification was observed at 0.5 ng/ml BMP9 , a concentration that would exclusively activate ALK1 .	In contrast, no calcification was observed at 0.5 ng/ml BMP9, a concentration that would exclusively activate ALK1.	6	19	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	BMP9	BMP9	BMP9	ALK1	ALK1	ALK1	10	11	18	19
Interestingly , endoglin was shown to promote ALK1 dependent Smad1/5 signaling , consistent with our finding that reduced levels of endoglin shifts the balance towards the ALK5 induced Smad2/3 pathway and with previous studies demonstrating a requirement of endoglin for BMP9 induced ALK1 signaling [ XREF_BIBR ] .	Interestingly, endoglin was shown to promote ALK1 dependent Smad1/5 signaling, consistent with our finding that reduced levels of endoglin shifts the balance towards the ALK5 induced Smad2/3 pathway and with previous studies demonstrating a requirement of endoglin for BMP9 induced ALK1 signaling [XREF_BIBR].	38	43	induced	Positive_early_activation	Positive_activation	Positive_activation	BMP9	BMP9	BMP9	ALK1	ALK1	ALK1	40	41	42	43
Whereas other unknown factors may contribute to the non osteogenic , endothelial specific ALK1 mediated signaling by BMP9 , optimum concentrations of circulating BMP9 maybe an important factor essential for maintaining endothelial specificity .	Whereas other unknown factors may contribute to the non osteogenic, endothelial specific ALK1 mediated signaling by BMP9, optimum concentrations of circulating BMP9 maybe an important factor essential for maintaining endothelial specificity.	5	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BMP9	BMP9	BMP9	ALK1	ALK1	ALK1	17	18	13	14
Endogenously , BMP9 activates ALK1 with high affinity ( EC50 = 50pg/ml ) .	Endogenously, BMP9 activates ALK1 with high affinity (EC50 = 50pg/ml).	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP9	BMP9	BMP9	ALK1	ALK1	ALK1	2	3	4	5
LV mRNA levels of ligands associated with ALK-1 signaling including TGF-beta1 , BMP-7 and BMP-9 were similar among all groups ( XREF_FIG ) .	LV mRNA levels of ligands associated with ALK-1 signaling including TGF-beta1, BMP-7 and BMP-9 were similar among all groups (XREF_FIG).	7	15	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	BMP-9	BMP-9	BMP-9	ALK-1	ALK-1	ALK-1	14	15	7	8
Analysis of Jag1 and VEGFR1 expression in retinal vessels following intraocular BMP9 injections showed that both proteins were upregulated in the angiogenic front of BMP9 treated compared to control PBS injected eyes ( XREF_SUPPLEMENTARY ) , indicating that the gene expression changes observed in vitro following BMP9 activation of ALK1 signaling were also seen in vivo .	Analysis of Jag1 and VEGFR1 expression in retinal vessels following intraocular BMP9 injections showed that both proteins were upregulated in the angiogenic front of BMP9 treated compared to control PBS injected eyes (XREF_SUPPLEMENTARY), indicating that the gene expression changes observed in vitro following BMP9 activation of ALK1 signaling were also seen in vivo.	46	50	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BMP9	BMP9	BMP9	ALK1	ALK1	ALK1	46	47	49	50
Although the EC 50 of Bmp9 on mouse endothelium in vivo is not known , we expect that the Bmp9 levels are sufficient to fully activate Alk1 in retinal vessels .	Although the EC 50 of Bmp9 on mouse endothelium in vivo is not known, we expect that the Bmp9 levels are sufficient to fully activate Alk1 in retinal vessels.	19	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bmp9	Bmp9 levels	bmp9	Alk1	Alk1	alk1	19	20	26	27
BMP9 stimulated calcification at concentrations of 5ng/ml or greater , representing concentrations at which BMP9 can stimulate both ALK1 and ALK2 .	BMP9 stimulated calcification at concentrations of 5ng/ml or greater, representing concentrations at which BMP9 can stimulate both ALK1 and ALK2.	14	20	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP9	BMP9	BMP9	ALK1	ALK1	ALK1	14	15	18	19
Exactly how CCK promotes the stemness of prostate CSCs is still unclear , although the binding and activation of CCKBR by gastrin , a hormone peptide structurally related to CCK , was found to regulate the proliferation of normal and malignant colon stem cells through suppression of both BMP-2 and Id4 expression [ XREF_BIBR ] .	Exactly how CCK promotes the stemness of prostate CSCs is still unclear, although the binding and activation of CCKBR by gastrin, a hormone peptide structurally related to CCK, was found to regulate the proliferation of normal and malignant colon stem cells through suppression of both BMP-2 and Id4 expression [XREF_BIBR].	15	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCKBR	CCKBR	CCKBR	21	22	19	20
These results support the notion that gastrin promotes CCK2R dependent FAK catalytic activation and paxillin tyrosine phosphorylation in DLD-1 cells associated with increased FA formation and the acquisition of a motile cell phenotype .	These results support the notion that gastrin promotes CCK2R dependent FAK catalytic activation and paxillin tyrosine phosphorylation in DLD-1 cells associated with increased FA formation and the acquisition of a motile cell phenotype.	6	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCK2R	CCK2R	CCK2R	6	7	8	9
In addition , it is possible that gastrin peptides on the NP surface could activate the CCKBR , stimulating the proliferation of tumor cells .	In addition, it is possible that gastrin peptides on the NP surface could activate the CCKBR, stimulating the proliferation of tumor cells.	7	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCKBR	CCKBR	CCKBR	7	8	16	17
Growth of gastric cancer cell lines containing the gastrin and CCKB receptor was significantly enhanced by gastrin and glycine extended gastrin .	Growth of gastric cancer cell lines containing the gastrin and CCKB receptor was significantly enhanced by gastrin and glycine extended gastrin.	8	18	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCKB receptor	CCKB receptor	CCKB receptor	16	17	10	12
Expectedly , CCKBR mRNA expression was markedly elevated in AGS and MKN1 cells treated with gastrin ( P = 0.017 and P = 0.047 , respectively ) ( XREF_FIG ) .	Expectedly, CCKBR mRNA expression was markedly elevated in AGS and MKN1 cells treated with gastrin (P = 0.017 and P = 0.047, respectively) (XREF_FIG).	2	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCKBR	CCKBR	CCKBR	15	16	2	3
Molecular experiments indicated that trastuzumab and gastrin co-treatment synergistically enhanced the stability of CCKBR .	Molecular experiments indicated that trastuzumab and gastrin co-treatment synergistically enhanced the stability of CCKBR.	4	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCKBR	CCKBR	CCKBR	6	7	13	14
In the mouse , in situ hybridization indicates that gastrin directly stimulates the growth of the pit cell lineage by inducing the CCK-B receptor in pit cell precursors 24 .	In the mouse, in situ hybridization indicates that gastrin directly stimulates the growth of the pit cell lineage by inducing the CCK-B receptor in pit cell precursors 24.	9	24	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCK-B receptor	CCK-B receptor	CCK-B receptor	9	10	22	24
Moreover , gastrin can activate the CCKBR leading to proliferative signaling .	Moreover, gastrin can activate the CCKBR leading to proliferative signaling.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCKBR	CCKBR	CCKBR	2	3	6	7
In this sense , a model of metastatic medullary thyroid cancer has been successfully used to evaluate the diagnostic and therapeutic potential of radiolabeled gastrin directed to target CCKB receptor expressing tumors in vivo .	In this sense, a model of metastatic medullary thyroid cancer has been successfully used to evaluate the diagnostic and therapeutic potential of radiolabeled gastrin directed to target CCKB receptor expressing tumors in vivo.	23	30	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCKB receptor	CCKB receptor	CCKB receptor	24	25	28	30
These data suggest that gastrin stimulates CCK2R activation leading to increased miR-222 expression which in turn decreases p27 mRNA and protein expression via the PKC and PI3K signalling pathways .	These data suggest that gastrin stimulates CCK2R activation leading to increased miR-222 expression which in turn decreases p27 mRNA and protein expression via the PKC and PI3K signalling pathways.	4	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCK2R	CCK2R	CCK2R	4	5	6	7
Gastrin activation of the CCK-B receptor , can act in a pro proliferative manner through the activation of mitogen activated protein kinases ( MAPKs ) [ including the four sub-groups ERK1/2 , JNKs , ERK5 , and p38-MAPKs ] and cyclins .	Gastrin activation of the CCK-B receptor, can act in a pro proliferative manner through the activation of mitogen activated protein kinases (MAPKs) [including the four sub-groups ERK1/2, JNKs, ERK5, and p38-MAPKs] and cyclins.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Gastrin	Gastrin	Gastrin	CCK-B receptor	CCK-B receptor	CCK-B receptor	0	1	4	6
Gastrin mediates its effects on the proximal and distal stomach through binding to the CCK2R , a seven-transmembrane , G protein coupled receptor .	Gastrin mediates its effects on the proximal and distal stomach through binding to the CCK2R, a seven-transmembrane, G protein coupled receptor.	0	17	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Gastrin	Gastrin	Gastrin	CCK2R	CCK2R	CCK2R	0	1	14	15
The use of radiolabeled gastrin analogs targeting the cholecystokinin-2 receptor ( CCK2R ) is an attractive approach .	The use of radiolabeled gastrin analogs targeting the cholecystokinin-2 receptor (CCK2R) is an attractive approach.	4	10	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	cholecystokinin-2 receptor	cholecystokinin-2 receptor	cholecystokinin-2 receptor	4	5	8	10
Interestingly , expression of Dok-6 potentiated GDNF induced neurite outgrowth in GDNF family receptor alpha1 ( GFRalpha1 )-expressing Neuro2A cells that was dependent upon the C-terminal residues of Dok-6 .	Interestingly, expression of Dok-6 potentiated GDNF induced neurite outgrowth in GDNF family receptor alpha1 (GFRalpha1)-expressing Neuro2A cells that was dependent upon the C-terminal residues of Dok-6.	6	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	GFRalpha1	GFRalpha1	GFRalpha1	6	7	16	17
Since GDNF is neuroprotective , up-regulation of GFRalpha-1 and c-Ret could enhance the responsiveness to GDNF and reduce neuronal damage .	Since GDNF is neuroprotective, up-regulation of GFRalpha-1 and c-Ret could enhance the responsiveness to GDNF and reduce neuronal damage.	1	9	is neuroprotective, up-regulation	Positive_activation_copula_1	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	GFRalpha-1	GFRalpha-1	GFRalpha-1	1	2	7	8
Both FGF2 and GDNF induced morphologically distinct large GFRA1 + clusters invivo .	Both FGF2 and GDNF induced morphologically distinct large GFRA1 + clusters invivo.	1	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	GFRA1	GFRA1	GFRA1	3	4	8	9
Fusion of the amino terminus of the mature GDNF to the carboxyl terminus of the heavy chain of the targeting IgG places the GDNF in a dimeric configuration ( Boado and Pardridge , 2008 ) , which replicates the GDNF dimer that activates the GFRalpha1 .	Fusion of the amino terminus of the mature GDNF to the carboxyl terminus of the heavy chain of the targeting IgG places the GDNF in a dimeric configuration (Boado and Pardridge, 2008), which replicates the GDNF dimer that activates the GFRalpha1.	39	45	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	GFRalpha1	GFRalpha1	GFRalpha1	39	40	44	45
However , the invivo dynamics of the GDNF stimulated GFRalpha1 positive spermatogonia remains unclear .	However, the invivo dynamics of the GDNF stimulated GFRalpha1 positive spermatogonia remains unclear.	4	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	GFRalpha1	GFRalpha1	GFRalpha1	7	8	9	10
During MN pool specification , activation of Ret and Gfralpha1 signaling by Gdnf is required for Pea3 expression in a subset of LMC neurons .	During MN pool specification, activation of Ret and Gfralpha1 signaling by Gdnf is required for Pea3 expression in a subset of LMC neurons.	9	13	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Gdnf	Gdnf	Gdnf	Gfralpha1	Gfralpha1	Gfralpha1	12	13	9	10
Therefore , GDNF stimulation of GFRalpha-1 and NCAM may not be the only mechanism by which Fyn is activated , but the increases in NCAM homophilic binding can also contribute to Fyn phosphorylation .	Therefore, GDNF stimulation of GFRalpha-1 and NCAM may not be the only mechanism by which Fyn is activated, but the increases in NCAM homophilic binding can also contribute to Fyn phosphorylation.	2	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	GFRalpha-1	GFRalpha-1	GFRalpha-1	2	3	5	6
Because little is known regarding how GPI anchored GFRalpha1 and NCAM and soluble GFRalpha1 and NCAM signalling differ , we additionally explored how GDNF signalling in the presence ( in cis and trans ) and absence ( in cis ) of soluble GFRalpha1 might be altered by miR-511 transfection .	Because little is known regarding how GPI anchored GFRalpha1 and NCAM and soluble GFRalpha1 and NCAM signalling differ, we additionally explored how GDNF signalling in the presence (in cis and trans) and absence (in cis) of soluble GFRalpha1 might be altered by miR-511 transfection.	23	43	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	GFRalpha1	GFRalpha1	GFRalpha1	23	24	42	43
Stage specific ectopic expression of GDNF caused the accumulation of a GFRA1 + LIN28 - A single population , which has enhanced SSC activity compared with wild type , suggesting that GDNF normally limits self-renewal to specific stages .	Stage specific ectopic expression of GDNF caused the accumulation of a GFRA1 + LIN28 - A single population, which has enhanced SSC activity compared with wild type, suggesting that GDNF normally limits self-renewal to specific stages.	3	12	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	expression of GDNF	gdnf	GFRA1	GFRA1	gfra1	5	6	11	12
As GFRalpha-1 is activated by GDNF and GDNF related neurotrophic factors , the widespread distribution of GFRalpha-1 in neurons with different phenotypes indicates that the neuronal activity of these neurons is likely to be affected by GDNF and GDNF related neurotrophic factors .	As GFRalpha-1 is activated by GDNF and GDNF related neurotrophic factors, the widespread distribution of GFRalpha-1 in neurons with different phenotypes indicates that the neuronal activity of these neurons is likely to be affected by GDNF and GDNF related neurotrophic factors.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	GFRalpha-1	GFRalpha-1	GFRalpha-1	5	6	1	2
In rodents , gestational augmentation of beta-cell mass is controlled by the placental lactogens PLI and PLII XREF_BIBR and growth hormone which activates the rodent , but not human prolactin receptor XREF_BIBR .	In rodents, gestational augmentation of beta-cell mass is controlled by the placental lactogens PLI and PLII XREF_BIBR and growth hormone which activates the rodent, but not human prolactin receptor XREF_BIBR.	19	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	growth hormone	growth hormone	growth hormone	prolactin receptor	prolactin receptor	prolactin receptor	19	21	29	31
Because GH can also activate the prolactin receptor , we investigated if the effect on mammosphere formation was dependent on GHR .	Because GH can also activate the prolactin receptor, we investigated if the effect on mammosphere formation was dependent on GHR.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	prolactin receptor	prolactin receptor	prolactin receptor	1	2	6	8
Lactogens include prolactin , growth hormone and placental lactogen , all of which can activate the prolactin receptor .	Lactogens include prolactin, growth hormone and placental lactogen, all of which can activate the prolactin receptor.	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	growth hormone	growth hormone	growth hormone	prolactin receptor	prolactin receptor	prolactin receptor	4	6	16	18
When TCF1 is over expressed GATA3 expression increased further supporting the notion that TCF1 can regulate Gata3 .	When TCF1 is over expressed GATA3 expression increased further supporting the notion that TCF1 can regulate Gata3.	5	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GATA3	GATA3 expression	gata3	Gata3	Gata3	gata3	5	6	16	17
Since phosphorylation of GATA3 at Thr315 and Ser316 modulates the function of GATA3 , it is of particular interest to study the pathophysiological roles of GATA3 phosphorylation in HDR syndrome .	Since phosphorylation of GATA3 at Thr315 and Ser316 modulates the function of GATA3, it is of particular interest to study the pathophysiological roles of GATA3 phosphorylation in HDR syndrome.	1	13	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GATA3	phosphorylation of GATA3 at Thr315 and Ser316	gata3	GATA3	GATA3	gata3	3	4	12	13
Moreover , early studies by Murphy and colleagues demonstrated that ectopic expression of GATA3 via retroviral transduction led to the induction of GATA3 mRNA encoded by the endogenous gene .	Moreover, early studies by Murphy and colleagues demonstrated that ectopic expression of GATA3 via retroviral transduction led to the induction of GATA3 mRNA encoded by the endogenous gene.	11	23	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	GATA3	expression of GATA3	gata3	GATA3	GATA3	gata3	13	14	22	23
As is the case for FOXP3 and its interaction partners , one could imagine that a change in the relative levels of T-bet or GATA3 could shift the balance and allow GATA3 to bind to Th2 sites .	As is the case for FOXP3 and its interaction partners, one could imagine that a change in the relative levels of T-bet or GATA3 could shift the balance and allow GATA3 to bind to Th2 sites.	20	33	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GATA3	levels of T-bet or GATA3	gata3	GATA3	GATA3	gata3	24	25	31	32
In contrast , GATA3 expression was not significantly expressed in any of the hPSCs compared with somatic cells but was highly upregulated after 15 days of differentiation ( XREF_SUPPLEMENTARY ) , suggesting the crucial role of GATA3 in the development of immunogenicity in differentiated hPSCs .	In contrast, GATA3 expression was not significantly expressed in any of the hPSCs compared with somatic cells but was highly upregulated after 15 days of differentiation (XREF_SUPPLEMENTARY), suggesting the crucial role of GATA3 in the development of immunogenicity in differentiated hPSCs.	3	37	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GATA3	GATA3 expression	gata3	GATA3	GATA3	gata3	3	4	36	37
Thus , it is possible that loss of either Nkx2-5 or Gata3 disrupts ternary complexes of GATA3 , NKX2-5 , and SRF that are required for the expression of genes involved in the differentiation and/or maintenance of pyloric smooth muscle .	Thus, it is possible that loss of either Nkx2-5 or Gata3 disrupts ternary complexes of GATA3, NKX2-5, and SRF that are required for the expression of genes involved in the differentiation and/or maintenance of pyloric smooth muscle.	6	24	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Gata3	loss of either Nkx2-5 or Gata3	gata3	GATA3	GATA3	gata3	11	12	16	17
It should be determined in future experiments if phosphorylation of GATA3 by p38 directly regulates the binding of GATA3 to the promoters of Il5 and Il13 and the expression of IL-5 and IL-13 in NH cells .	It should be determined in future experiments if phosphorylation of GATA3 by p38 directly regulates the binding of GATA3 to the promoters of Il5 and Il13 and the expression of IL-5 and IL-13 in NH cells.	8	19	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GATA3	phosphorylation of GATA3	gata3	GATA3	GATA3	gata3	10	11	18	19
Ectopic expression of GATA-3 in developing Th1 cells , but not in Th1 clone HDK1 , induced endogenous GATA-3 , suggesting an autoregulatory mechanism for maintenance of GATA-3 expression in Th2 cells .	Ectopic expression of GATA-3 in developing Th1 cells, but not in Th1 clone HDK1, induced endogenous GATA-3, suggesting an autoregulatory mechanism for maintenance of GATA-3 expression in Th2 cells.	1	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GATA-3	expression of GATA-3	gata-3	GATA-3	GATA-3	gata-3	3	4	18	19
In the present work , we show the role of GATA3 phosphorylation at serine 308 for PR induced GATA3 protein turnover .	In the present work, we show the role of GATA3 phosphorylation at serine 308 for PR induced GATA3 protein turnover.	10	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GATA3	GATA3 phosphorylation at serine 308	gata3	GATA3	GATA3	gata3	10	11	18	19
GDNF activate NCAM and intracellular Fyn and FAK and promote the growth of nerve cells [ XREF_BIBR ] .	GDNF activate NCAM and intracellular Fyn and FAK and promote the growth of nerve cells [XREF_BIBR].	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	NCAM	NCAM	NCAM	0	1	2	3
GDNF Enhanced SC Production of NCAM but not L1 .	GDNF Enhanced SC Production of NCAM but not L1.	0	6	Enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	NCAM	NCAM	NCAM	0	1	5	6
We found that GDNF induces an increase in the partitioning of NCAM and heparan sulfate proteoglycan agrin into lipid rafts and that heparinase inhibits GDNF signaling in SCs .	We found that GDNF induces an increase in the partitioning of NCAM and heparan sulfate proteoglycan agrin into lipid rafts and that heparinase inhibits GDNF signaling in SCs.	3	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	NCAM	NCAM	NCAM	3	4	11	12
XREF_BIBR observed severely compromised neuritogenesis upon GDNF stimulation in NCAM KO neurons when compared to WT neurons .	XREF_BIBR observed severely compromised neuritogenesis upon GDNF stimulation in NCAM KO neurons when compared to WT neurons.	6	11	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	NCAM	NCAM	NCAM	6	7	9	10
We have also demonstrated that Gata2 augmented the functional role of Etv2 in the development of endothelial and hematopoietic lineages .	We have also demonstrated that Gata2 augmented the functional role of Etv2 in the development of endothelial and hematopoietic lineages.	5	12	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gata2	Gata2	Gata2	Etv2	Etv2	Etv2	5	6	11	12
These results establish that Gata2 could augment the function of Etv2 in the hematopoietic and endothelial lineages in the ES/EB system .	These results establish that Gata2 could augment the function of Etv2 in the hematopoietic and endothelial lineages in the ES/EB system.	4	11	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gata2	Gata2	Gata2	Etv2	Etv2	Etv2	4	5	10	11
Previous studies suggested that Gata2 and Scl are direct targets of ER71 .	Previous studies suggested that Gata2 and Scl are direct targets of ER71.	4	12	are direct targets	Positive_activation_copula_1	Positive_activation	Positive_activation	Gata2	Gata2	Gata2	ER71	ER71	ER71	4	5	11	12
Using the embryoid body differentiation system , we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation .	Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation.	10	18	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gata2	co-expression of Gata2	gata2	Etv2	Etv2	etv2	12	13	17	18
Transcriptional assays with the Spi1 promoter reporter demonstrated that Gata2 cooperates with Etv2 and augments the transcriptional activity of Etv2 .	Transcriptional assays with the Spi1 promoter reporter demonstrated that Gata2 cooperates with Etv2 and augments the transcriptional activity of Etv2.	9	20	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gata2	Gata2	Gata2	Etv2	Etv2	Etv2	9	10	19	20
Increased co-expression of GATA2 significantly augments ER71 in the production of endothelial and blood cells from differentiating murine ESC .	Increased co-expression of GATA2 significantly augments ER71 in the production of endothelial and blood cells from differentiating murine ESC.	1	9	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GATA2	co-expression of GATA2	gata2	ER71	ER71	er71	3	4	6	7
GMPS and MDH1 promote p53 function under conditions of stress .	GMPS and MDH1 promote p53 function under conditions of stress.	0	5	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GMPS	GMPS	GMPS	p53	p53	p53	0	1	4	5
However , depletion of the guanidine nucleotide pool causes a GMPS mediated p53 response .	However, depletion of the guanidine nucleotide pool causes a GMPS mediated p53 response.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	GMPS	GMPS	GMPS	p53	p53	p53	10	11	12	13
It has been reported that in response to GMP deprivation , GMPS promotes p53 stabilization by preventing p53 ubiquitination [ XREF_BIBR ] .	It has been reported that in response to GMP deprivation, GMPS promotes p53 stabilization by preventing p53 ubiquitination [XREF_BIBR].	11	19	promotes	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	GMPS	GMPS	gmps	p53	p53 ubiquitination	p53	11	12	17	18
One possible explanation is that guanosine 5 '-monophosphate synthase ( GMPS ) might sense the depletion of GMP and activate p53 .	One possible explanation is that guanosine 5 '-monophosphate synthase (GMPS) might sense the depletion of GMP and activate p53.	8	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GMPS	GMPS	GMPS	p53	p53	p53	10	11	20	21
GMPS retention in the cytoplasm is mediated by a ubiquitylation dependent mechanism , thus preventing p53 induction .	GMPS retention in the cytoplasm is mediated by a ubiquitylation dependent mechanism, thus preventing p53 induction.	0	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GMPS	GMPS	GMPS	p53	p53	p53	0	1	15	16
They showed that one such region , predicted cis-regulatory module 1 , is occupied by GATA-1 in erythroid cells , which is consistent with their data indicating transcriptional up-regulation of FOG-1 by GATA-1 .	They showed that one such region, predicted cis-regulatory module 1, is occupied by GATA-1 in erythroid cells, which is consistent with their data indicating transcriptional up-regulation of FOG-1 by GATA-1.	26	33	up-regulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GATA-1	GATA-1	GATA-1	FOG-1	FOG-1	FOG-1	32	33	30	31
Furthermore , FOG-1 is activated by GATA-1 and PU.1 is activated by XREF_BIBR .	Furthermore, FOG-1 is activated by GATA-1 and PU.1 is activated by XREF_BIBR.	2	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GATA-1	GATA-1	GATA-1	FOG-1	FOG-1	FOG-1	6	7	2	3
GATA-2 induces the expression of GATA-1 , which first activates its cofactor FOG-1 , and then downregulates GATA-2 cooperatively with FOG-1 .	GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GATA-1	GATA-2 induces the expression of GATA-1	gata-1	FOG-1	FOG-1	fog-1	5	6	12	13
This observation contrasts with the lack of increased neuron cell death in the DRG of conditional Runx1 knockout animals [ XREF_BIBR ] and , more importantly , with the observation that the total number of DRG neurons was increased , rather than decreased , when Runx1 was inactivated in transgenic Runx1 deficient animals selectively rescued by GATA-1 promoter driven Runx1 reactivation [ XREF_BIBR ] .	This observation contrasts with the lack of increased neuron cell death in the DRG of conditional Runx1 knockout animals [XREF_BIBR] and, more importantly, with the observation that the total number of DRG neurons was increased, rather than decreased, when Runx1 was inactivated in transgenic Runx1 deficient animals selectively rescued by GATA-1 promoter driven Runx1 reactivation [XREF_BIBR].	56	60	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GATA-1	GATA-1	GATA-1	Runx1	Runx1	Runx1	56	57	59	60
In particular , we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification , in particular phosphorylation by cyclin dependent kinases .	In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin dependent kinases.	12	20	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	GATA-1	GATA-1	GATA-1	RUNX1	RUNX1	RUNX1	12	13	14	15
Long-term GDNF overexpression led to increased GTP cyclohydrolase I ( GTPCH I ) activity and tetrahydrobiopterin ( BH4 ) levels .	Long-term GDNF overexpression led to increased GTP cyclohydrolase I (GTPCH I) activity and tetrahydrobiopterin (BH4) levels.	1	9	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF overexpression	gdnf	GTP cyclohydrolase I	GTP cyclohydrolase I	gtp cyclohydrolase i	1	2	6	9
GOLPH3 may activates AKT and mTOR signaling to promote the progression of human bladder cancer .	GOLPH3 may activates AKT and mTOR signaling to promote the progression of human bladder cancer.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	0	1	5	6
Also , it has been reported that GOLPH3 overexpression promotes cell proliferation and tumorigenesis by activating mTOR signaling , enhancing AKT activity , as well as decreasing FOXO1 transcriptional activity [ XREF_BIBR , XREF_BIBR ] .	Also, it has been reported that GOLPH3 overexpression promotes cell proliferation and tumorigenesis by activating mTOR signaling, enhancing AKT activity, as well as decreasing FOXO1 transcriptional activity [XREF_BIBR, XREF_BIBR].	7	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3 overexpression	golph3	mTOR	mTOR	mtor	7	8	16	17
Further studies plan on exploring the function of GOLPH3 and the mechanism for its up-regulation in ESCC tumor , and to clarify whether GOLPH3 modulates mTOR signalling and rapamycin sensitivity in ESCC .	Further studies plan on exploring the function of GOLPH3 and the mechanism for its up-regulation in ESCC tumor, and to clarify whether GOLPH3 modulates mTOR signalling and rapamycin sensitivity in ESCC.	23	26	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	23	24	25	26
Knockdown of GOLPH3 decreased the proliferation , migration and invasion of bladder cancer cells and the tumor growth in xenograft mice , which may be associated with GOLPH3 modulation of AKT and mTOR signaling .	Knockdown of GOLPH3 decreased the proliferation, migration and invasion of bladder cancer cells and the tumor growth in xenograft mice, which may be associated with GOLPH3 modulation of AKT and mTOR signaling.	27	33	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	27	28	32	33
Future work will be required to determine whether GOLPH3 modulates glycosyltransferase retention and/or receptor internalization in mammalian cells , and more importantly whether these processes provide a mechanism to regulate the mTOR signaling response mediated by GOLPH3 .	Future work will be required to determine whether GOLPH3 modulates glycosyltransferase retention and/or receptor internalization in mammalian cells, and more importantly whether these processes provide a mechanism to regulate the mTOR signaling response mediated by GOLPH3.	31	37	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	36	37	31	32
Then , we validated that GOLPH3 overexpression activates mTOR signaling ( XREF_FIG ) and confers autophagy resistance ( XREF_FIG ) using three autophagy markers ( namely , cathepsin B , BNIP3 and LC3 ) .	Then, we validated that GOLPH3 overexpression activates mTOR signaling (XREF_FIG) and confers autophagy resistance (XREF_FIG) using three autophagy markers (namely, cathepsin B, BNIP3 and LC3).	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3 overexpression	golph3	mTOR	mTOR	mtor	5	6	8	9
It has been elucidated that GOLPH3 can regulate cell size , enhance growth-factor-induced mTOR signaling in many human cancer cell lines like A549 and CRL-5889 , and alter the response to rapamycin which is a mTOR inhibitor in vivo [ XREF_BIBR ] .	It has been elucidated that GOLPH3 can regulate cell size, enhance growth-factor-induced mTOR signaling in many human cancer cell lines like A549 and CRL-5889, and alter the response to rapamycin which is a mTOR inhibitor in vivo [XREF_BIBR].	5	27	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	5	6	13	14
To test the hypothesis that GOLPH3 also activates AKT and mTOR signaling in bladder cancer , western blotting was performed to examine the protein level of AKT and mTOR signaling pathway components .	To test the hypothesis that GOLPH3 also activates AKT and mTOR signaling in bladder cancer, western blotting was performed to examine the protein level of AKT and mTOR signaling pathway components.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	5	6	10	11
It has been reported that GOLPH3 , as a potent oncogene , activates mTOR signaling by phosphorylating both mTORC1 and mTORC2 specific substrates .	It has been reported that GOLPH3, as a potent oncogene, activates mTOR signaling by phosphorylating both mTORC1 and mTORC2 specific substrates.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	5	6	13	14
Mechanistically , GOLPH3 regulates cell size , enhances growth-factor-induced mTOR signalling in human cancer cells , and alters the response to rapamycin in vivo [ XREF_BIBR ] .	Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR signalling in human cancer cells, and alters the response to rapamycin in vivo [XREF_BIBR].	2	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	2	3	9	10
Although the mechanistic basis for GOLPH3 activation of mTOR signaling remains unclear , several lines of evidence suggest that GOLPH3 plays a role in vesicular trafficking and glycosylation , which are associated with oncogenicity .	Although the mechanistic basis for GOLPH3 activation of mTOR signaling remains unclear, several lines of evidence suggest that GOLPH3 plays a role in vesicular trafficking and glycosylation, which are associated with oncogenicity.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	5	6	8	9
It has been reported that overexpression of GOLPH3 promotes cell transformation by enhancing the activity of the serine/threonine kinase mTOR in breast cancer [ XREF_BIBR , XREF_BIBR ] .	It has been reported that overexpression of GOLPH3 promotes cell transformation by enhancing the activity of the serine/threonine kinase mTOR in breast cancer [XREF_BIBR, XREF_BIBR].	5	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	overexpression of GOLPH3	golph3	mTOR	mTOR	mtor	7	8	19	20
GOLPH3 , which encodes a peripheral membrane protein of the Golgi stack and may have a regulatory role in Golgi trafficking , was recently shown to enhance growth-factor-induced mTOR signaling and consequently alter response to rapamycin , an mTOR inhibitor , in cancer cells [ XREF_BIBR ] .	GOLPH3, which encodes a peripheral membrane protein of the Golgi stack and may have a regulatory role in Golgi trafficking, was recently shown to enhance growth-factor-induced mTOR signaling and consequently alter response to rapamycin, an mTOR inhibitor, in cancer cells [XREF_BIBR].	0	32	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	0	1	28	29
GOLPH3 enhances growth-factor induced mTOR signaling and modulate the response to rapamycin [ XREF_BIBR ] .	GOLPH3 enhances growth-factor induced mTOR signaling and modulate the response to rapamycin [XREF_BIBR].	0	5	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	0	1	4	5
To test whether GOLPH3 could also promote the progression of HCC by activating mTOR signaling pathway , we examined the expression of key proteins involved in mTOR singling pathway including mTOR , AKT and S6K1 .	To test whether GOLPH3 could also promote the progression of HCC by activating mTOR signaling pathway, we examined the expression of key proteins involved in mTOR singling pathway including mTOR, AKT and S6K1.	3	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	3	4	13	14
Perhaps GOLPH3 could regulate Raptor to activate mTOR signaling cascade in HCC .	Perhaps GOLPH3 could regulate Raptor to activate mTOR signaling cascade in HCC.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	1	2	7	8
GOLPH3 activates the mTOR signaling in HCC both in vitro and invivo .	GOLPH3 activates the mTOR signaling in HCC both in vitro and invivo.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	0	1	3	4
GOLPH3 silencing inhibited AKT and m-TOR signaling , increased the cyclin dependent kinase ( CDK ) inhibitor p27 and decreased the CDK regulator cyclin D1 and matrix metallopeptidase 9 ( MMP9 ) .	GOLPH3 silencing inhibited AKT and m-TOR signaling, increased the cyclin dependent kinase (CDK) inhibitor p27 and decreased the CDK regulator cyclin D1 and matrix metallopeptidase 9 (MMP9).	0	6	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	m-TOR	m-TOR	m-TOR	0	1	5	6
GOLPH3 has been shown to activate mTOR signaling XREF_BIBR .	GOLPH3 has been shown to activate mTOR signaling XREF_BIBR.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	0	1	6	7
Golgi phosphoprotein 3 ( GOLPH3 ) promotes hepatocellular carcinoma progression by activating mTOR signaling pathway .	Golgi phosphoprotein 3 (GOLPH3) promotes hepatocellular carcinoma progression by activating mTOR signaling pathway.	0	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Golgi phosphoprotein 3	Golgi phosphoprotein 3	Golgi phosphoprotein 3	mTOR	mTOR	mTOR	0	3	12	13
In addition to follow-up studies examining GOLPH3 and retromer mediated mTOR signaling , it will also be important to assess the relevance of GOLPH3 ' s PtdIns ( 4 ) P binding activity in the context of cancer signaling , which may offer clues to whether GOLPH3 ' s oncogenic activity requires recruitment to the Golgi or stems from Golgi independent gain-of-function activities outside of the Golgi .	In addition to follow-up studies examining GOLPH3 and retromer mediated mTOR signaling, it will also be important to assess the relevance of GOLPH3 's PtdIns (4) P binding activity in the context of cancer signaling, which may offer clues to whether GOLPH3 's oncogenic activity requires recruitment to the Golgi or stems from Golgi independent gain-of-function activities outside of the Golgi.	6	11	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	6	7	10	11
However , whether GOLPH3 can promote HCC progression by activating mTOR signaling is still unknown .	However, whether GOLPH3 can promote HCC progression by activating mTOR signaling is still unknown.	3	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	3	4	10	11
Whether the mTOR pathway is targeted by GOLPH3 , with its inhibition reversing resistance to radiotherapy in rectal cancer needs to be addressed in future studies .	Whether the mTOR pathway is targeted by GOLPH3, with its inhibition reversing resistance to radiotherapy in rectal cancer needs to be addressed in future studies.	2	8	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	7	8	2	3
It was shown that Golph3 enlarges cell size , enhances growth-factor-induced mTOR signaling in human cancer cells , and increases the sensitivity to an mTOR inhibitor [ XREF_BIBR ] .	It was shown that Golph3 enlarges cell size, enhances growth-factor-induced mTOR signaling in human cancer cells, and increases the sensitivity to an mTOR inhibitor [XREF_BIBR].	4	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Golph3	Golph3	Golph3	mTOR	mTOR	mTOR	4	5	11	12
Indeed , GOLPH3 has been found to enhance mTOR signaling XREF_BIBR .	Indeed, GOLPH3 has been found to enhance mTOR signaling XREF_BIBR.	2	10	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	2	3	8	9
The current study suggests that GOLPH3 contributes to the tumorigenesis of HCC by activating mTOR signaling pathway .	The current study suggests that GOLPH3 contributes to the tumorigenesis of HCC by activating mTOR signaling pathway.	5	16	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	5	6	14	15
In addition , GOLPH3 may primarily activate the Akt and mTOR signaling pathway via the activated mTORC1 complex rather than the mTORC2 complex , resulting in p70S6 and 4E-BP1 phosphorylation , thereby affecting gastric cancer .	In addition, GOLPH3 may primarily activate the Akt and mTOR signaling pathway via the activated mTORC1 complex rather than the mTORC2 complex, resulting in p70S6 and 4E-BP1 phosphorylation, thereby affecting gastric cancer.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	3	4	10	11
GOLPH3 modulates mTOR signaling and rapamycin sensitivity in cancer .	GOLPH3 modulates mTOR signaling and rapamycin sensitivity in cancer.	0	3	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	0	1	2	3
These results indicate that GOLPH3 may activate AKT and mTOR signaling to promote the progression of human bladder cancer .	These results indicate that GOLPH3 may activate AKT and mTOR signaling to promote the progression of human bladder cancer.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	4	5	9	10
Collectively , these data provided strong biochemical evidence that GOLPH3 activates mTOR signaling through phosphorylation of both mTORC1- and mTORC2 specific substrates .	Collectively, these data provided strong biochemical evidence that GOLPH3 activates mTOR signaling through phosphorylation of both mTORC1- and mTORC2 specific substrates.	9	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	9	10	11	12
Furthermore , expression of GOLPH3 increased mTOR and AKT activity , whereby in melanocytes GOLPH3 overexpression in conjunction with mutant BRAF or NRAS resulted in increased anchorage independent and xenograft growth in vivo .	Furthermore, expression of GOLPH3 increased mTOR and AKT activity, whereby in melanocytes GOLPH3 overexpression in conjunction with mutant BRAF or NRAS resulted in increased anchorage independent and xenograft growth in vivo.	2	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	expression of GOLPH3	golph3	mTOR	mTOR	mtor	4	5	6	7
GOLPH3 activates mTOR signaling .	GOLPH3 activates mTOR signaling.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	0	1	2	3
In view of previous studies reporting that GOLPH3 modulated mTOR signaling 10 , 26 , our study may suggest new ideas for investigating the multiple functions of GOLPH3 .	In view of previous studies reporting that GOLPH3 modulated mTOR signaling 10, 26, our study may suggest new ideas for investigating the multiple functions of GOLPH3.	7	10	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	7	8	9	10
To test the hypothesis that GOLPH3 activates mTOR signaling , we first examined the biological consequences of GOLPH3 modulation .	To test the hypothesis that GOLPH3 activates mTOR signaling, we first examined the biological consequences of GOLPH3 modulation.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mTOR	mTOR	mTOR	5	6	7	8
Activated forms of Galphaq , Galpha12 and Galpha13 each elicit Rho activation by interacting with and stimulating subsets of Rho specific guanosine nucleotide exchange factors .	Activated forms of Galphaq, Galpha12 and Galpha13 each elicit Rho activation by interacting with and stimulating subsets of Rho specific guanosine nucleotide exchange factors.	3	11	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	Rho	Rho	Rho	7	8	10	11
Since Rho activation is a critical process in S1P induced Cl - current and RhoA can be activated by G alpha13 after receptor activation , it is most likely that activation of chloride currents occurred after S1P binding to the S1PR 3 receptor expressed in sensory neurons .	Since Rho activation is a critical process in S1P induced Cl - current and RhoA can be activated by G alpha13 after receptor activation, it is most likely that activation of chloride currents occurred after S1P binding to the S1PR 3 receptor expressed in sensory neurons.	12	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	G alpha13	G alpha13	G alpha13	RhoA	RhoA	RhoA	19	21	14	15
Moreover , the ability of CXCR4 to engage in G alpha13 -mediated cell signaling events that activate Rho pathways leading to cell adhesion has been previously demonstrated [ XREF_BIBR ] .	Moreover, the ability of CXCR4 to engage in G alpha13 -mediated cell signaling events that activate Rho pathways leading to cell adhesion has been previously demonstrated [XREF_BIBR].	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	G alpha13	G alpha13	G alpha13	Rho	Rho	Rho	9	11	17	18
However , initial GPCR and Galpha13 mediated activation of RhoA is transient [ XREF_BIBR ] .	However, initial GPCR and Galpha13 mediated activation of RhoA is transient [XREF_BIBR].	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	RhoA	RhoA	RhoA	5	6	9	10
p115RhoGEF S330A and S330D fail to induce Galpha13 mediated activation of RhoA in vitro .	p115RhoGEF S330A and S330D fail to induce Galpha13 mediated activation of RhoA in vitro.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	RhoA	RhoA	RhoA	7	8	11	12
The effect of decreased GNA13 may be to decrease stimulation of Rho , while decreasing the GAP would decrease inactivation of Rho with concomitant decreased cell spreading on the extracellular matrix .	The effect of decreased GNA13 may be to decrease stimulation of Rho, while decreasing the GAP would decrease inactivation of Rho with concomitant decreased cell spreading on the extracellular matrix.	1	12	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GNA13	GNA13	GNA13	Rho	Rho	Rho	4	5	11	12
Src is activated by GPCRs through its association with beta-arrestin , Gs and Gi , or GPCRs , whereas FAK activation by GPCRs is through Galpha12- and Galpha13 mediated Rho dependent tyrosine phosphorylation .	Src is activated by GPCRs through its association with beta-arrestin, Gs and Gi, or GPCRs, whereas FAK activation by GPCRs is through Galpha12- and Galpha13 mediated Rho dependent tyrosine phosphorylation.	16	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	Rho	Rho	Rho	27	28	29	30
Galpha13 is known to participate in CCK induced RhoA activation in pancreatic acini XREF_BIBR .	Galpha13 is known to participate in CCK induced RhoA activation in pancreatic acini XREF_BIBR.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	RhoA	RhoA	RhoA	0	1	8	9
Here we show that GPR55 is activated by lysophosphatidylinositol ( LPI ) and couples to Galpha13 , which in turn activates RhoA and RhoA kinase ( ROCK ) .	Here we show that GPR55 is activated by lysophosphatidylinositol (LPI) and couples to Galpha13, which in turn activates RhoA and RhoA kinase (ROCK).	6	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	RhoA	RhoA	RhoA	15	16	21	22
The activation of RhoA , a small GTPase involved in reorganizing actin cytoskeleton and a mediator of EGF induced invasion of pancreatic cancer cell lines is inhibited in MCF-7 cells by the relocation of Galpha13 to the plasma membrane by RGS16 preventing Galpha13 mediated activation of RhoA [ XREF_BIBR , XREF_BIBR ] .	The activation of RhoA, a small GTPase involved in reorganizing actin cytoskeleton and a mediator of EGF induced invasion of pancreatic cancer cell lines is inhibited in MCF-7 cells by the relocation of Galpha13 to the plasma membrane by RGS16 preventing Galpha13 mediated activation of RhoA [XREF_BIBR, XREF_BIBR].	42	50	mediated	Positive_early_activation	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	RhoA	RhoA	RhoA	42	43	46	47
In dendrites , miR-138 represses acyl protein thioesterase 1 ( APT1 ) , a depalmitoylation enzyme , and thus inhibits spine growth via increasing membrane localization of alpha 13 subunits of G proteins ( Galpha13 ) , which upregulates RhoA activity and presumably promotes actin depolymerization .	In dendrites, miR-138 represses acyl protein thioesterase 1 (APT1), a depalmitoylation enzyme, and thus inhibits spine growth via increasing membrane localization of alpha 13 subunits of G proteins (Galpha13), which upregulates RhoA activity and presumably promotes actin depolymerization.	32	40	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	RhoA	RhoA	RhoA	34	35	39	40
Signalling through G alpha13 activates RhoA and hence ROCK , whereas G alphaq signals through PLCbeta to activate PKC and increase intracellular calcium .	Signalling through G alpha13 activates RhoA and hence ROCK, whereas G alphaq signals through PLCbeta to activate PKC and increase intracellular calcium.	2	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	G alpha13	G alpha13	G alpha13	RhoA	RhoA	RhoA	2	4	5	6
RhoA is a clear candidate as a downstream effector for the Galpha13 thymocyte survival pathway since biochemical and cell biological evidence has been reported that Galpha13 specifically activates RhoA but not Rac or Cdc42 .	RhoA is a clear candidate as a downstream effector for the Galpha13 thymocyte survival pathway since biochemical and cell biological evidence has been reported that Galpha13 specifically activates RhoA but not Rac or Cdc42.	25	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	RhoA	RhoA	RhoA	25	26	28	29
One APT1 substrate is heterotrimeric G protein subunit alpha 13 ( G alpha13 ) ; when palmitoylated , G alpha13 activates Rho signaling , which reduces actin dynamics and restricts spine growth [ XREF_BIBR ] .	One APT1 substrate is heterotrimeric G protein subunit alpha 13 (G alpha13); when palmitoylated, G alpha13 activates Rho signaling, which reduces actin dynamics and restricts spine growth [XREF_BIBR].	18	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	G alpha13	G alpha13	G alpha13	Rho	Rho	Rho	18	20	21	22
The present study was undertaken to determine whether the GNA13 mediated RHOA signaling pathway may be involved in acrosome reaction in bovine caudal sperm , and whether AKAPs may be involved in its targeting and regulation .	The present study was undertaken to determine whether the GNA13 mediated RHOA signaling pathway may be involved in acrosome reaction in bovine caudal sperm, and whether AKAPs may be involved in its targeting and regulation.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	GNA13	GNA13	GNA13	RHOA	RHOA	RHOA	9	10	11	12
High level of miRNA-138 leads to a significant decrease in APT1 level and subsequently increases Galpha13 palmitoylation and membrane localization , which can activate the Rho dependent signaling cascade and thereby induce dendritic spine shrinkage with a concomitant reduction in synaptic transmission [ XREF_BIBR ] .	High level of miRNA-138 leads to a significant decrease in APT1 level and subsequently increases Galpha13 palmitoylation and membrane localization, which can activate the Rho dependent signaling cascade and thereby induce dendritic spine shrinkage with a concomitant reduction in synaptic transmission [XREF_BIBR].	15	28	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	Rho	Rho	Rho	15	16	25	26
We could show that in COS-7 cells , expression of GTPase deficient mutants of Galpha12 and Galpha13 triggered Rho activation as measured by increased Rho-GTP levels .	We could show that in COS-7 cells, expression of GTPase deficient mutants of Galpha12 and Galpha13 triggered Rho activation as measured by increased Rho-GTP levels.	12	19	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	Rho	Rho	Rho	16	17	18	19
Among the G-proteins , Galpha13 mediates the signaling of Rho ( RAS homology ) family members that regulate reorganization of the actin cytoskeleton XREF_BIBR - XREF_BIBR .	Among the G-proteins, Galpha13 mediates the signaling of Rho (RAS homology) family members that regulate reorganization of the actin cytoskeleton XREF_BIBR - XREF_BIBR.	4	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	Rho	Rho	Rho	4	5	9	10
The synergism between Galpha13 and GEF115 indicates that GEF115 mediates Galpha13 induced activation of Rho and SRF .	The synergism between Galpha13 and GEF115 indicates that GEF115 mediates Galpha13 induced activation of Rho and SRF.	10	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	Rho	Rho	Rho	10	11	14	15
Our results support the hypothesis that Galpha12 and Galpha13 activate Rho and suggest that Galpha12 and Galpha13 may mediate the tyrosine phosphorylation of p125 focal adhesion kinase , paxillin , and p130 Crk associated substrate .	Our results support the hypothesis that Galpha12 and Galpha13 activate Rho and suggest that Galpha12 and Galpha13 may mediate the tyrosine phosphorylation of p125 focal adhesion kinase, paxillin, and p130 Crk associated substrate.	6	11	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	Rho	Rho	Rho	8	9	10	11
Although GnRH induces EGR1 in both cell lines , the levels of the DNA binding protein are lower and disappear more quickly in alphaT3 than in LbetaT2 cells .	Although GnRH induces EGR1 in both cell lines, the levels of the DNA binding protein are lower and disappear more quickly in alphaT3 than in LbetaT2 cells.	1	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	EGR1	EGR1	EGR1	1	2	3	4
In contrast , GNRH pulses every 240 min only increased Egr1 PT ( 6-fold ; p < 0.05 ) after 24h of pulses , but increased Egr1 mRNA 4-fold between 4-24h of treatment ; and Egr1 mRNA levels were significantly greater at 24h in rats receiving GNRH pulses every 240min vs. 30min ( p < 0.05 ) .	In contrast, GNRH pulses every 240 min only increased Egr1 PT (6-fold; p < 0.05) after 24h of pulses, but increased Egr1 mRNA 4-fold between 4-24h of treatment; and Egr1 mRNA levels were significantly greater at 24h in rats receiving GNRH pulses every 240min vs. 30min (p < 0.05).	3	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GNRH	GNRH	GNRH	Egr1	Egr1	Egr1	3	4	10	11
GNRH increased both Egr1 PT and mRNA with maximal responses seen at 10 min ( 45-fold ) for PT and 45 min ( 150-fold ) for mRNA ( p < 0.05 vs. 0 time ) .	GNRH increased both Egr1 PT and mRNA with maximal responses seen at 10 min (45-fold) for PT and 45 min (150-fold) for mRNA (p < 0.05 vs. 0 time).	0	4	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GNRH	GNRH	GNRH	Egr1	Egr1	Egr1	0	1	3	4
Finally , this group reported that GnRH mediated activation of early growth response protein-1 ( EGR-1 ) also leads to activation of per1 expression .	Finally, this group reported that GnRH mediated activation of early growth response protein-1 (EGR-1) also leads to activation of per1 expression.	6	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	early growth response protein-1	early growth response protein-1	early growth response protein-1	6	7	10	14
Also , the CAMK2 blocker , KN62 partially suppresses GNRH induction of Egr1 promoter activity in aT3 cells [ XREF_BIBR ] .	Also, the CAMK2 blocker, KN62 partially suppresses GNRH induction of Egr1 promoter activity in aT3 cells [XREF_BIBR].	9	14	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GNRH	GNRH	GNRH	Egr1	Egr1	Egr1	9	10	12	13
Similarly , I ( Egr1 ; GnRH ) was greater in LbetaT2 cells , presumably because GnRH has a more sustained effect on ppERK and causes a more pronounced increase in Egr1 driven zsGREEN expression than in HeLa cells ( XREF_FIG and data not shown ) .	Similarly, I (Egr1; GnRH) was greater in LbetaT2 cells, presumably because GnRH has a more sustained effect on ppERK and causes a more pronounced increase in Egr1 driven zsGREEN expression than in HeLa cells (XREF_FIG and data not shown).	16	32	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	Egr1	Egr1	Egr1	16	17	31	32
We examined gene expression in LbetaT2 cells after E and/or GnRH treatment , and found that E suppressed expression of transcription factor Zfhx1a , and enhanced GnRH stimulation of Egr-1 mRNA and protein .	We examined gene expression in LbetaT2 cells after E and/or GnRH treatment, and found that E suppressed expression of transcription factor Zfhx1a, and enhanced GnRH stimulation of Egr-1 mRNA and protein.	26	30	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	Egr-1	Egr-1	Egr-1	26	27	29	30
Egr-1 , but not SF-1 , protein was induced by GnRH and accumulated with MG-132 .	Egr-1, but not SF-1, protein was induced by GnRH and accumulated with MG-132.	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	Egr-1	Egr-1	Egr-1	10	11	0	1
In rats , fast GNRH pulses ( every 30min ) induced Egr1 primary transcript ( PT ) and mRNA stably 2-fold ( p < 0.05 ) for 1-24h .	In rats, fast GNRH pulses (every 30min) induced Egr1 primary transcript (PT) and mRNA stably 2-fold (p < 0.05) for 1-24h.	4	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GNRH	GNRH	GNRH	Egr1	Egr1	Egr1	4	5	11	12
Several basal transcription factors including specific protein 1 , steroidogenic factor 1 ( SF1 ) and paired like homeodomain transcription factor ( PITX1 ) synergize with early growth response protein 1 ( EGR1 ) induced by GnRH signaling to up-regulate Lhb transcription .	Several basal transcription factors including specific protein 1, steroidogenic factor 1 (SF1) and paired like homeodomain transcription factor (PITX1) synergize with early growth response protein 1 (EGR1) induced by GnRH signaling to up-regulate Lhb transcription.	26	37	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	early growth response protein 1	early growth response protein 1	early growth response protein 1	36	37	26	31
We now show that GnRH is a potent stimulator of Egr-1 , but not Ptx1 or SF-1 , expression .	We now show that GnRH is a potent stimulator of Egr-1, but not Ptx1 or SF-1, expression.	4	11	is a potent stimulator	Positive_activation_copula_1	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	Egr-1	Egr-1	Egr-1	4	5	10	11
GnRH also caused a dose dependent increase in Egr-1 luc activity with pulsatile treatment ( 5-min pulses at hourly intervals for 8 h ) , and again the pEC 50 value ( 8.5 +/- 0.2 , XREF_FIG C ) was comparable with values for pulsatile GnRH effects on alphaGSU-, FSHbeta- and LHbeta-luc activity .	GnRH also caused a dose dependent increase in Egr-1 luc activity with pulsatile treatment (5-min pulses at hourly intervals for 8 h), and again the pEC 50 value (8.5 +/- 0.2, XREF_FIG C) was comparable with values for pulsatile GnRH effects on alphaGSU-, FSHbeta- and LHbeta-luc activity.	0	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	Egr-1	Egr-1	Egr-1	0	1	8	9
Although other Egr proteins are expressed in LbetaT2 cells and are capable of interacting with SF-1 , GnRH stimulation of Egr-1 was the most robust .	Although other Egr proteins are expressed in LbetaT2 cells and are capable of interacting with SF-1, GnRH stimulation of Egr-1 was the most robust.	17	21	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	Egr-1	Egr-1	Egr-1	17	18	20	21
Mutations that abolish protein binding to these SREs and Ets binding sites completely eliminated GnRH mediated transcriptional activation of the Egr-1 promoter .	Mutations that abolish protein binding to these SREs and Ets binding sites completely eliminated GnRH mediated transcriptional activation of the Egr-1 promoter.	13	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	Egr-1	Egr-1	Egr-1	14	15	20	21
Here , we determined that GnRH induces rapidly both Egr1 and c-Fos , but specifically decreases the rate of c-Fos degradation .	Here, we determined that GnRH induces rapidly both Egr1 and c-Fos, but specifically decreases the rate of c-Fos degradation.	5	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	Egr1	Egr1	Egr1	5	6	9	10
Similarly , Lawson et al [ XREF_BIBR ] reported that Egr1 mRNA increased rapidly and transiently in response to GNRH and was maximally stimulated by faster frequency GNRH pulses ( < 60min interpulse interval ) .	Similarly, Lawson et al [XREF_BIBR] reported that Egr1 mRNA increased rapidly and transiently in response to GNRH and was maximally stimulated by faster frequency GNRH pulses (< 60min interpulse interval).	10	28	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GNRH	GNRH	GNRH	Egr1	Egr1	Egr1	27	28	10	11
GNRH induction of EGR1 protein is pronounced and mRNA half-life is extended from 11 to 24 minutes in LbetaT2 cells compared to alphaT3-1 cells .	GNRH induction of EGR1 protein is pronounced and mRNA half-life is extended from 11 to 24 minutes in LbetaT2 cells compared to alphaT3-1 cells.	0	4	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GNRH	GNRH	GNRH	EGR1	EGR1	EGR1	0	1	3	4
The large changes in Egr1 gene expression reflected similar increases in EGR1 protein levels ; GNRH increased EGR1 protein 13 and 4.7-fold at 45 and 120min , respectively ( XREF_FIG ; p < 0.05 ) .	The large changes in Egr1 gene expression reflected similar increases in EGR1 protein levels; GNRH increased EGR1 protein 13 and 4.7-fold at 45 and 120min, respectively (XREF_FIG; p < 0.05).	15	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GNRH	GNRH	GNRH	EGR1	EGR1	EGR1	15	16	17	18
In cultured rat pituitary cells , GNRH pulses ( every 60min ) increased Egr1 ( PT = 2.5-3 fold ; mRNA = 1.5-2 fold ; p < 0.05 ) .	In cultured rat pituitary cells, GNRH pulses (every 60min) increased Egr1 (PT = 2.5-3 fold; mRNA = 1.5-2 fold; p < 0.05).	6	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GNRH	GNRH	GNRH	Egr1	Egr1	Egr1	6	7	13	14
Here we report that GNRH induction of Egr1 PT and mRNA in perifused rat pituitary cells are also MAPK8/9 , but not MAPK14 , dependent ; though in shorter duration ( 3h ) studies , SP was only partially effective in suppressing GNRH induced increases in Lhb and Egr1 PTs .	Here we report that GNRH induction of Egr1 PT and mRNA in perifused rat pituitary cells are also MAPK8/9, but not MAPK14, dependent; though in shorter duration (3h) studies, SP was only partially effective in suppressing GNRH induced increases in Lhb and Egr1 PTs.	4	8	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GNRH	GNRH	GNRH	Egr1	Egr1	Egr1	4	5	7	8
Furthermore , Egr-1 and Egr-2 have been firmly implicated as being essential in mediating the maximal GnRH stimulation of LHbeta gene expression ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] and are both induced by high GnRH pulse frequencies .	Furthermore, Egr-1 and Egr-2 have been firmly implicated as being essential in mediating the maximal GnRH stimulation of LHbeta gene expression (XREF_FIG) [XREF_BIBR, XREF_BIBR] and are both induced by high GnRH pulse frequencies.	2	38	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GnRH	GnRH	GnRH	Egr-1	Egr-1	Egr-1	36	37	2	3
Although much is known about the mechanism by which p115RhoGEF is activated by Galpha13 , little is known about other means that regulate p115RhoGEF activity .	Although much is known about the mechanism by which p115RhoGEF is activated by Galpha13, little is known about other means that regulate p115RhoGEF activity.	9	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	p115RhoGEF	p115RhoGEF	p115RhoGEF	13	14	9	10
Ectopic expression of p115-RhoGEF or Galpha13 , which activates p115-RhoGEF activity , leads to inhibition of HIV-1 replication .	Ectopic expression of p115-RhoGEF or Galpha13, which activates p115-RhoGEF activity, leads to inhibition of HIV-1 replication.	1	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galpha13	expression of p115-RhoGEF or Galpha13	galpha13	p115-RhoGEF	p115-RhoGEF	p115-rhogef	5	6	9	10
Furthermore , binding of activated Galpha13 to this RGS domain stimulated GEF activity of p115RhoGEF .	Furthermore, binding of activated Galpha13 to this RGS domain stimulated GEF activity of p115RhoGEF.	2	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	p115RhoGEF	p115RhoGEF	p115RhoGEF	5	6	14	15
Though the activation of p115RhoGEF by Galpha13 is well-known , little else is known about how p115RhoGEF itself is regulated .	Though the activation of p115RhoGEF by Galpha13 is well-known, little else is known about how p115RhoGEF itself is regulated.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Galpha13	Galpha13	Galpha13	p115RhoGEF	p115RhoGEF	p115RhoGEF	6	7	4	5
It has been reported that glypican-4 ( GPC4 ) overexpression in HeLaS3 cells promotes Wnt5a induced receptor mediated endocytosis and Rac1 activation and that Wnt5a induces the internalization of GPC4 with Fz2 , followed by the localization of the complex to clathrin positive vesicles XREF_BIBR .	It has been reported that glypican-4 (GPC4) overexpression in HeLaS3 cells promotes Wnt5a induced receptor mediated endocytosis and Rac1 activation and that Wnt5a induces the internalization of GPC4 with Fz2, followed by the localization of the complex to clathrin positive vesicles XREF_BIBR.	5	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glypican-4	glypican-4 (GPC4) overexpression	glypican-4	Wnt5a	Wnt5a	wnt5a	5	6	14	15
Expression of GPC4 enhanced the Wnt3a dependent beta-catenin pathway and the Wnt5a dependent beta-catenin-independent pathway , and knockdown of GPC4 suppressed both pathways .	Expression of GPC4 enhanced the Wnt3a dependent beta-catenin pathway and the Wnt5a dependent beta-catenin-independent pathway, and knockdown of GPC4 suppressed both pathways.	0	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPC4	Expression of GPC4	gpc4	Wnt5a	Wnt5a	wnt5a	2	3	11	12
The GNAQ induced activation of RhoA and Rac1 initiate the nuclear expression of growth promoting genes by inducing rapid cytoskeletal changes and the activation multiple MAPKs , including JNK and p38 .	The GNAQ induced activation of RhoA and Rac1 initiate the nuclear expression of growth promoting genes by inducing rapid cytoskeletal changes and the activation multiple MAPKs, including JNK and p38.	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	GNAQ	GNAQ	GNAQ	RhoA	RhoA	RhoA	1	2	5	6
All three Ras isoforms ( Hras , Kras , and Nras ) were activated by oncogenic GNAQ ( XREF_FIG ) .	All three Ras isoforms (Hras, Kras, and Nras) were activated by oncogenic GNAQ (XREF_FIG).	3	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GNAQ	GNAQ	GNAQ	Hras	Hras	Hras	16	17	5	6
At least in some cases , it appears that ERalpha and GPER1 may function together to activate EGFR , since a physical interaction between ERalpha , GPER1 and EGFR is reported in endometrial and tamoxifen resistant breast cancer cells [ XREF_BIBR ] .	At least in some cases, it appears that ERalpha and GPER1 may function together to activate EGFR, since a physical interaction between ERalpha, GPER1 and EGFR is reported in endometrial and tamoxifen resistant breast cancer cells [XREF_BIBR].	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER1	GPER1	GPER1	EGFR	EGFR	EGFR	11	12	17	18
Previous research showed that activation of GPER by G-1 in breast cancer cells triggers the activation of the EGFR signaling pathway .	Previous research showed that activation of GPER by G-1 in breast cancer cells triggers the activation of the EGFR signaling pathway.	4	20	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	6	7	18	19
Our results indicate that GPER activation of the epidermal growth factor receptor and ERK in response to estradiol treatment plays a critical role in the secretion of insulin from beta-cells .	Our results indicate that GPER activation of the epidermal growth factor receptor and ERK in response to estradiol treatment plays a critical role in the secretion of insulin from beta-cells.	4	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GPER	GPER	GPER	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	4	5	8	12
GPER also maintains meiotic arrest of zebrafish oocytes through estrogen- and BPA dependent GPER activation of epidermal growth factor receptor ( EGFR ) and mitogen activated protein kinase ( MAPK ) signaling .	GPER also maintains meiotic arrest of zebrafish oocytes through estrogen- and BPA dependent GPER activation of epidermal growth factor receptor (EGFR) and mitogen activated protein kinase (MAPK) signaling.	13	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GPER	GPER	GPER	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	13	14	16	20
Together , these results suggest that activation of GPER induces transactivation of EGFR in PCASMC which contributes to the vasoconstriction effect of GPER .	Together, these results suggest that activation of GPER induces transactivation of EGFR in PCASMC which contributes to the vasoconstriction effect of GPER.	6	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	8	9	12	13
These data demonstrate that activation of GPER induces transactivation of EGFR .	These data demonstrate that activation of GPER induces transactivation of EGFR.	4	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	6	7	10	11
In addition , since GM6001 treatment significantly inhibited G-1-enhancement of ET-1 constriction , it seems highly likely that MMP activity is a component of the transactivation of EGFR induced by GPER activation .	In addition, since GM6001 treatment significantly inhibited G-1-enhancement of ET-1 constriction, it seems highly likely that MMP activity is a component of the transactivation of EGFR induced by GPER activation.	25	31	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	30	31	27	28
The possible activation of EGFR by GPR30 involves activation of MMPs or ADAMs to cleave EGF precursor ligands to activate EGFR tyrosine kinase phosphorylation ; however , the exact role of these signaling intermediates in this particular model requires further investigation .	The possible activation of EGFR by GPR30 involves activation of MMPs or ADAMs to cleave EGF precursor ligands to activate EGFR tyrosine kinase phosphorylation; however, the exact role of these signaling intermediates in this particular model requires further investigation.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GPR30	GPR30	GPR30	EGFR	EGFR	EGFR	6	7	4	5
Two groups have shown independently that both ERalpha and GPER mediated EGFR transactivation .	Two groups have shown independently that both ERalpha and GPER mediated EGFR transactivation.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	9	10	11	12
ERalpha and ERbeta predominantly function through genomic signalling events , while GPER stimulates EGFR , ERK1/2 and PI3K through a non genomic rapid signalling mechanism , leading to widespread effects on neuroendocrine , immune and reproductive functions .	ERalpha and ERbeta predominantly function through genomic signalling events, while GPER stimulates EGFR, ERK1/2 and PI3K through a non genomic rapid signalling mechanism, leading to widespread effects on neuroendocrine, immune and reproductive functions.	11	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	11	12	13	14
Selective activation of GPER by G-1 can also activate EGFR , upregulate c-fos , cyclin D1 , cyclin E , and cyclin A , and promote cell proliferation .	Selective activation of GPER by G-1 can also activate EGFR, upregulate c-fos, cyclin D1, cyclin E, and cyclin A, and promote cell proliferation.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	3	4	9	10
We noted that GPR30 activation increased ligand dependent EGFR activity , leading to an Erk1/2 mediated transcriptional response , thus contributing to the development of tamoxifen resistance in breast cancer cells .	We noted that GPR30 activation increased ligand dependent EGFR activity, leading to an Erk1/2 mediated transcriptional response, thus contributing to the development of tamoxifen resistance in breast cancer cells.	3	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR30	GPR30	GPR30	EGFR	EGFR	EGFR	3	4	8	9
In ovarian cancer cells estrogens and G1 , the GPR30 agonist , were shown to activate the EGFR pathway , resulting in upregulation of c-Fos expression .	In ovarian cancer cells estrogens and G1, the GPR30 agonist, were shown to activate the EGFR pathway, resulting in upregulation of c-Fos expression.	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR30	GPR30	GPR30	EGFR	EGFR	EGFR	9	10	17	18
Moreover , it has been reported that GPR30 , can mediate estrogen dependent signaling and EGFR transactivation by estradiol XREF_BIBR , This is consistent with our results showing that 5 day treatment of alphaERKO mice with EGF induced GPR30 in the mammary glands .	Moreover, it has been reported that GPR30, can mediate estrogen dependent signaling and EGFR transactivation by estradiol XREF_BIBR, This is consistent with our results showing that 5 day treatment of alphaERKO mice with EGF induced GPR30 in the mammary glands.	7	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR30	GPR30	GPR30	EGFR	EGFR	EGFR	7	8	15	16
An interesting result was obtained in the case of spermatids , where ERalpha and GPER mediated activation of the EGFR and ERK signalling cascade , which led to promotion of apoptosis ; however , the same signalling cascade activated by ERbeta prevented the apoptosis [ XREF_BIBR ] .	An interesting result was obtained in the case of spermatids, where ERalpha and GPER mediated activation of the EGFR and ERK signalling cascade, which led to promotion of apoptosis; however, the same signalling cascade activated by ERbeta prevented the apoptosis [XREF_BIBR].	12	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	14	15	19	20
GPER1 activation can also result in EGFR activation by release of heparin bounded EGF , and it has been shown that EGFR signaling pathway can induce CREB phosphorylation at S133 .	GPER1 activation can also result in EGFR activation by release of heparin bounded EGF, and it has been shown that EGFR signaling pathway can induce CREB phosphorylation at S133.	0	8	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	GPER1	GPER1	GPER1	EGFR	EGFR	EGFR	0	1	6	7
Although it has been demonstrated that activation of GPER induces EGFR transactivation in breast cancer cells [ XREF_BIBR ] , there is not much information available in vascular smooth muscle .	Although it has been demonstrated that activation of GPER induces EGFR transactivation in breast cancer cells [XREF_BIBR], there is not much information available in vascular smooth muscle.	6	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	8	9	10	11
Previous studies suggested that GPR30 activation triggers the MMP dependent transactivation of EGFR , as well as the activation of ERK and AKT [ XREF_BIBR ] .	Previous studies suggested that GPR30 activation triggers the MMP dependent transactivation of EGFR, as well as the activation of ERK and AKT [XREF_BIBR].	4	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR30	GPR30	GPR30	EGFR	EGFR	EGFR	4	5	12	13
G-1 stimulation of heparin binding EGF ( HB-EGF ) release and tyrosine phosphorylation of EGFR have further confirmed the notion that activation of GPER indeed causes transactivation of EGFR and thus induces enhanced vasoactive contraction of coronary artery .	G-1 stimulation of heparin binding EGF (HB-EGF) release and tyrosine phosphorylation of EGFR have further confirmed the notion that activation of GPER indeed causes transactivation of EGFR and thus induces enhanced vasoactive contraction of coronary artery.	21	29	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	23	24	28	29
MIBE prevents the GPER mediated EGFR and ERK activation .	MIBE prevents the GPER mediated EGFR and ERK activation.	1	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	3	4	5	6
Inter-cell transfer of calcium and activation of P13K are known to be signal pathways and , as a result , it is known that GPER stimulates EGFR transcription XREF_BIBR and estrogen mediates the complex and prompt activation of cells in many aspects .	Inter-cell transfer of calcium and activation of P13K are known to be signal pathways and, as a result, it is known that GPER stimulates EGFR transcription XREF_BIBR and estrogen mediates the complex and prompt activation of cells in many aspects.	24	28	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	24	25	26	27
These data indicate that the activation of GPER induces transactivation of EGFR .	These data indicate that the activation of GPER induces transactivation of EGFR.	5	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	7	8	11	12
Dozens of studies have revealed the downstream signaling of GPR30 , which is coupled to stimulatory G ( Gs ) protein and acts to activate adenylate cyclase and epidermal growth factor receptor [ XREF_BIBR ] .	Dozens of studies have revealed the downstream signaling of GPR30, which is coupled to stimulatory G (Gs) protein and acts to activate adenylate cyclase and epidermal growth factor receptor [XREF_BIBR].	7	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR30	GPR30	GPR30	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	9	10	28	32
These data indicate that activation of GPER induces EGFR activity that is involved in the G-1 potentiation of vascular contraction .	These data indicate that activation of GPER induces EGFR activity that is involved in the G-1 potentiation of vascular contraction.	4	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	6	7	8	9
GPR30 activation also induced the activation of PI3-kinase and Akt dependent signaling and transactivation of the epidermal growth factor receptor via Src protein kinase [ XREF_BIBR - XREF_BIBR ] .	GPR30 activation also induced the activation of PI3-kinase and Akt-dependent signaling and transactivation of the epidermal growth factor receptor via Src protein kinase [XREF_BIBR - XREF_BIBR].	0	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR30	GPR30	GPR30	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	16	20
GPER activation increased ligand dependent EGFR activity , leading to an ERK1/2 mediated transcriptional response .	GPER activation increased ligand dependent EGFR activity, leading to an ERK1/2 mediated transcriptional response.	0	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	EGFR	EGFR	EGFR	0	1	5	6
In 2002 , the same group reported that GPER mediated the transactivation of the epidermal growth factor receptor ( EGFR ) to the MAPK signaling axis in response to E 2 .	In 2002, the same group reported that GPER mediated the transactivation of the epidermal growth factor receptor (EGFR) to the MAPK signaling axis in response to E 2.	8	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPER	GPER	GPER	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	8	9	14	18
Our studies and others have also demonstrated that GPR30 mediates the rapid response to E 2 in a variety of estrogen responsive cancer cells by activating the epidermal growth factor receptor ( EGFR )-mitogen-activated protein kinase ( MAPK ) transduction pathway .	Our studies and others have also demonstrated that GPR30 mediates the rapid response to E 2 in a variety of estrogen responsive cancer cells by activating the epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) transduction pathway.	8	35	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GPR30	GPR30	GPR30	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	8	9	27	31
DAPT and LiCl decrease NICD , Hes-1 and GSK-3beta but enhance p-GSK-3beta and p-AKT immunofluorescence in BV-2 cells .	DAPT and LiCl decrease NICD, Hes-1 and GSK-3beta but enhance p-GSK-3beta and p-AKT immunofluorescence in BV-2 cells.	6	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p-GSK-3beta	p-GSK-3beta	p-GSK-3beta	8	9	11	12
The results revealed that GAE treatment decreased the phosphorylation of GSK3beta , thus preventing the inactivation of GSK3beta .	The results revealed that GAE treatment decreased the phosphorylation of GSK3beta, thus preventing the inactivation of GSK3beta.	4	18	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GAE treatment decreased the phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	10	11	17	18
Phosphorylation of GSK-3beta at tyrosine ( Y ) 216 also regulates it activity and may activate GSK-3beta .	Phosphorylation of GSK-3beta at tyrosine (Y) 216 also regulates it activity and may activate GSK-3beta.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	Phosphorylation of GSK-3beta at tyrosine	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	16	17
In a recent report , decreased GSK3beta phosphorylation promoted GSK3beta activation and degradation of beta-catenin [ XREF_BIBR ] .	In a recent report, decreased GSK3beta phosphorylation promoted GSK3beta activation and degradation of beta-catenin [XREF_BIBR].	6	10	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta phosphorylation	gsk3beta	GSK3beta	GSK3beta	gsk3beta	6	7	9	10
More in depth analysis showed that TZD alone can significantly attenuate GSK3beta expression , which inhibited total GSK3beta via antagonizing its transcription .	More in depth analysis showed that TZD alone can significantly attenuate GSK3beta expression, which inhibited total GSK3beta via antagonizing its transcription.	6	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	TZD alone can significantly attenuate GSK3beta expression	gsk3beta	GSK3beta	GSK3beta	gsk3beta	11	12	17	18
Exposure of this domain leads to activation of protein phosphatase-1 ( PP1 ) which then dephosphorylates GSK3beta at the Ser 9 residue , enhancing GSK3beta activity .	Exposure of this domain leads to activation of protein phosphatase-1 (PP1) which then dephosphorylates GSK3beta at the Ser 9 residue, enhancing GSK3beta activity.	8	25	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	protein phosphatase-1 (PP1) which then dephosphorylates GSK3beta at the Ser 9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	16	17	24	25
We also observed an increase in phosphorylation of the inhibitory Ser 9 residue of GSK-3beta , which has been proposed to enhance beta-catenin signaling by promoting the accumulation of beta-catenin protein levels , in a manner analogous to Wnt mediated GSK-3beta inactivation .	We also observed an increase in phosphorylation of the inhibitory Ser 9 residue of GSK-3beta, which has been proposed to enhance beta-catenin signaling by promoting the accumulation of beta-catenin protein levels, in a manner analogous to Wnt mediated GSK-3beta inactivation.	6	41	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	phosphorylation of the inhibitory Ser 9 residue of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	14	15	40	41
GSK3beta is activated or inactivated by transfection of S9A-GSK3beta and DN-GSK3beta , respectively , in A549 cells .	GSK3beta is activated or inactivated by transfection of S9A-GSK3beta and DN-GSK3beta, respectively, in A549 cells.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DN-GSK3beta	DN-GSK3beta	DN-GSK3beta	GSK3beta	GSK3beta	GSK3beta	10	11	0	1
Recently , we found that phosphorylation of GSK-3beta at Ser9 by IPC and EPO treatment induced physical interaction of phospho-GSK-3beta with ANT , and this phospho-GSK-3beta-ANT interaction inhibited binding of ANT to cyclophilin D.	Recently, we found that phosphorylation of GSK-3beta at Ser9 by IPC and EPO treatment induced physical interaction of phospho-GSK-3beta with ANT, and this phospho-GSK-3beta-ANT interaction inhibited binding of ANT to cyclophilin D.	5	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	phosphorylation of GSK-3beta at Ser9	gsk-3beta	phospho-GSK-3beta	phospho-GSK-3beta	phospho-gsk-3beta	7	8	19	20
In vitro activity assays demonstrated that GSK-3beta phosphorylation mediated by PKCzeta enhanced GSK-3beta activity .	In vitro activity assays demonstrated that GSK-3beta phosphorylation mediated by PKCzeta enhanced GSK-3beta activity.	6	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	6	7	12	13
During the induction of LTD , GSK3beta is activated by protein phosphatase 1 via dephosphorylation of GSK3beta Ser9 [ XREF_BIBR ] .	During the induction of LTD, GSK3beta is activated by protein phosphatase 1 via dephosphorylation of GSK3beta Ser9 [XREF_BIBR].	6	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GSK3beta	phosphatase 1 via dephosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	16	17	6	7
This notion is consistent with previous observations that GSK3beta is more highly active in the nucleus than in cytoplasm [ XREF_BIBR ] , plus our own experiment results that demonstrate that enforced overexpression of constitutively active GSK3beta caused the nuclear accumulation of survivin as well as GSK3beta ; whereas transfection of dominant negative GSK3beta or treatment with the GSK3beta inhibitor LiCl did not increase nuclear survivin or GSK3beta , but in contrast , increased the cytoplasmic expression of these two proteins .	This notion is consistent with previous observations that GSK3beta is more highly active in the nucleus than in cytoplasm [XREF_BIBR], plus our own experiment results that demonstrate that enforced overexpression of constitutively active GSK3beta caused the nuclear accumulation of survivin as well as GSK3beta; whereas transfection of dominant negative GSK3beta or treatment with the GSK3beta inhibitor LiCl did not increase nuclear survivin or GSK3beta, but in contrast, increased the cytoplasmic expression of these two proteins.	32	47	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	overexpression of constitutively active GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	36	37	46	47
We found that the active phosphorylation of GSK-3beta at Tyr216 ( pY216-GSK-3beta ) increased and the inhibitory phosphorylation of GSK-3beta at Ser9 ( pS9-GSK-3beta ) decreased at 24 and 48 hours after infusion of TM , suggesting activation of GSK-3beta by TM .	We found that the active phosphorylation of GSK-3beta at Tyr216 (pY216-GSK-3beta) increased and the inhibitory phosphorylation of GSK-3beta at Ser9 (pS9-GSK-3beta) decreased at 24 and 48 hours after infusion of TM, suggesting activation of GSK-3beta by TM.	17	40	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	phosphorylation of GSK-3beta at Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	19	20	39	40
Moreover , reports demonstrated that glutamate decreased the expression of p-GSK-3beta , which would increase GSK-3beta activity during glutamate induced neurotoxicity 24 .	Moreover, reports demonstrated that glutamate decreased the expression of p-GSK-3beta, which would increase GSK-3beta activity during glutamate induced neurotoxicity 24.	8	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-GSK-3beta	expression of p-GSK-3beta	p-gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	10	11	15	16
GDNF , through activation of the PI3-kinase pathway enhanced the phosphorylation of GSK-3beta at its N-terminal serine 9 residue , and promoted the association of GSK-3beta with 14-3-3 .	GDNF, through activation of the PI3-kinase pathway enhanced the phosphorylation of GSK-3beta at its N-terminal serine 9 residue, and promoted the association of GSK-3beta with 14-3-3.	0	26	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GDNF, through activation of the PI3-kinase pathway enhanced the phosphorylation of GSK-3beta at its N-terminal serine 9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	12	13	25	26
Therefore , we investigated the effect of DIF-1 on GSK-3beta and found that DIF-1 dephosphorylated GSK-3beta on Ser9 and induced the nuclear translocation of GSK-3beta , suggesting that DIF-1 activated GSK-3beta .	Therefore, we investigated the effect of DIF-1 on GSK-3beta and found that DIF-1 dephosphorylated GSK-3beta on Ser9 and induced the nuclear translocation of GSK-3beta, suggesting that DIF-1 activated GSK-3beta.	13	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	DIF-1 dephosphorylated GSK-3beta on Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	15	16	24	25
It is known that Ser9 phosphorylation inhibits GSK-3beta activity and Tyr216 phosphorylation increases GSK-3beta activity XREF_BIBR - XREF_BIBR .	It is known that Ser9 phosphorylation inhibits GSK-3beta activity and Tyr216 phosphorylation increases GSK-3beta activity XREF_BIBR - XREF_BIBR.	7	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta activity and Tyr216 phosphorylation	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	7	8	13	14
Here we show that phosphorylation of GSK3beta at Ser 389 / Thr 390 is specifically induced in response to DNA double-strand breaks ( DSBs ) and targets nuclear GSK3beta .	Here we show that phosphorylation of GSK3beta at Ser 389 / Thr 390 is specifically induced in response to DNA double-strand breaks (DSBs) and targets nuclear GSK3beta.	4	29	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	phosphorylation of GSK3beta at Ser 389 / Thr 390	gsk3beta	GSK3beta	GSK3beta	gsk3beta	6	7	28	29
Instead , increased phosphorylation of glycogen synthase kinase-3 beta ( GSK-3beta ) ( Ser9 ) caused GSK-3beta activation .	Instead, increased phosphorylation of glycogen synthase kinase-3 beta (GSK-3beta) (Ser9) caused GSK-3beta activation.	3	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	phosphorylation of glycogen synthase kinase-3 beta (GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	10	11	16	17
We also show that the reduced levels of npS9 GSK3beta in HEK293 cells treated with protein phosphatase inhibitor causes a reduction in GSK3beta kinase activity by using the 12B2 npS9 GSK3beta antibody .	We also show that the reduced levels of npS9 GSK3beta in HEK293 cells treated with protein phosphatase inhibitor causes a reduction in GSK3beta kinase activity by using the 12B2 npS9 GSK3beta antibody.	6	24	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	levels of npS9 GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	9	10	22	23
FPN reduced the Akt phosphorylation on Ser473 , and in parallel with the inactivation of Akt , phosphorylation of GSK3beta on Ser9 which inactivates GSK3beta , decreased after treatment with FPN .	FPN reduced the Akt phosphorylation on Ser473, and in parallel with the inactivation of Akt, phosphorylation of GSK3beta on Ser9 which inactivates GSK3beta, decreased after treatment with FPN.	17	26	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta on Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	19	20	24	25
Results suggested that TMT inhibited GSK-3beta phosphorylation which activated GSK-3beta signaling .	Results suggested that TMT inhibited GSK-3beta phosphorylation which activated GSK-3beta signaling.	3	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	TMT inhibited GSK-3beta phosphorylation	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	5	6	9	10
Phosphorylation of GSK-3beta at serine 389 by p38 enhances inactivation of GSK-3beta and results in subsequent stabilization and accumulation of soluble beta-cat XREF_BIBR , XREF_BIBR .	Phosphorylation of GSK-3beta at serine 389 by p38 enhances inactivation of GSK-3beta and results in subsequent stabilization and accumulation of soluble beta-cat XREF_BIBR, XREF_BIBR.	0	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	Phosphorylation of GSK-3beta at serine 389	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	11	12
In this study , Abeta25-35 treatment is found to increase GSK-3beta activity and pretreatment with puerarin preventesAbeta induced activation of GSK-3beta based on Western blot analysis .	In this study, Abeta25-35 treatment is found to increase GSK-3beta activity and pretreatment with puerarin preventesAbeta induced activation of GSK-3beta based on Western blot analysis.	9	21	increase	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	GSK-3beta	puerarin preventesAbeta induced activation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	20	21	10	11
DEX actually decreased GSK-3beta activity ( an increase in pGSK-3beta and GSK-3beta ratio ) in wild-type HEK293 cells on D3 ( data not shown ) .	DEX actually decreased GSK-3beta activity (an increase in pGSK-3beta and GSK-3beta ratio) in wild-type HEK293 cells on D3 (data not shown).	3	12	increase	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	pGSK-3beta	pGSK-3beta	pGSK-3beta	3	4	9	10
Transgenic PKCbetaII mice exhibit decreased GSK3beta activity in the colonic epithelium in vivo , consistent with the finding that PKCbetaII can directly phosphorylate GSK3beta at Serine 9 , a phosphorylation event that inhibits GSK3beta activity .	Transgenic PKCbetaII mice exhibit decreased GSK3beta activity in the colonic epithelium in vivo, consistent with the finding that PKCbetaII can directly phosphorylate GSK3beta at Serine 9, a phosphorylation event that inhibits GSK3beta activity.	19	34	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	GSK3beta	PKCbetaII can directly phosphorylate GSK3beta at Serine 9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	23	24	33	34
However , phosphorylation of GSK 3beta at Serine 9 was significantly increased at 1day , 1week , and 6weeks on the ipsilateral side after primary blast exposure of the hippocampus , indicating a decrease in GSK 3beta activity .	However, phosphorylation of GSK 3beta at Serine 9 was significantly increased at 1day, 1week, and 6weeks on the ipsilateral side after primary blast exposure of the hippocampus, indicating a decrease in GSK 3beta activity.	2	37	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK 3beta	phosphorylation of GSK 3beta at Serine 9	gsk 3beta	GSK 3beta	GSK 3beta	gsk 3beta	4	6	35	37
This PPP2R5delta reduction increases the phosphorylation of GSK3beta at serine 9 , which inactivates GSK3beta , indicating that PPP2R5delta positively regulates GSK3beta activity in the brain .	This PPP2R5delta reduction increases the phosphorylation of GSK3beta at serine 9, which inactivates GSK3beta, indicating that PPP2R5delta positively regulates GSK3beta activity in the brain.	5	15	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta at serine 9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	7	8	14	15
Cell proliferation was greatly increased after GSK-3beta gene knockdown by siRNA , and significantly decreased after GSK-3beta upregulation by pGSK-3beta as compared with NC_siR and empty vector controls ( P < 0.05 , Fig .	Cell proliferation was greatly increased after GSK-3beta gene knockdown by siRNA, and significantly decreased after GSK-3beta upregulation by pGSK-3beta as compared with NC_siR and empty vector controls (P < 0.05, Fig.	16	20	upregulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	pGSK-3beta	pGSK-3beta	pGSK-3beta	GSK-3beta	GSK-3beta	GSK-3beta	19	20	16	17
Silencing of GSK3beta expression decreased GSK3beta mRNA by 60-70 % and GSK3beta protein level by 70-80 % , whereas a control siRNA had no effect ( XREF_FIG ) .	Silencing of GSK3beta expression decreased GSK3beta mRNA by 60-70% and GSK3beta protein level by 70-80%, whereas a control siRNA had no effect (XREF_FIG).	2	6	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta expression	gsk3beta	GSK3beta	GSK3beta	gsk3beta	2	3	5	6
Exogenous GRP induced scratching behavior is completely abolished in Grpr KO mice .	Exogenous GRP induced scratching behavior is completely abolished in Grpr KO mice.	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRP	GRP	GRP	Grpr	Grpr	Grpr	1	2	9	10
Finally , as noted above , recent studies defined a subset of presumptive excitatory interneurons that express GRP , a peptide implicated in the transmission of pruritoceptive ( itch ) messages from the periphery , and another population that expresses GRPR , which is targeted by GRP .	Finally, as noted above, recent studies defined a subset of presumptive excitatory interneurons that express GRP, a peptide implicated in the transmission of pruritoceptive (itch) messages from the periphery, and another population that expresses GRPR, which is targeted by GRP.	39	47	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	46	47	40	41
Activation of GRPR by GRP therefore increased spontaneous inhibitory activity in LA pyramidal neurons in agreement with earlier findings XREF_BIBR .	Activation of GRPR by GRP therefore increased spontaneous inhibitory activity in LA pyramidal neurons in agreement with earlier findings XREF_BIBR.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	4	5	2	3
In addition , we found that GRP promotes testosterone secretion , and increases GRPR mRNA and protein expression in cultured Leydig cells in vitro .	In addition, we found that GRP promotes testosterone secretion, and increases GRPR mRNA and protein expression in cultured Leydig cells in vitro.	6	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	6	7	13	14
Epidermal scores for GRPR were significantly decreased in Bleo +2 A11 mice compared to Bleo alone ( 0.5 +/-0.3 , 1.9 +/-0.3 , P < 0.005 ) , like prior studies of GRPR up-regulation by GRP .	Epidermal scores for GRPR were significantly decreased in Bleo +2 A11 mice compared to Bleo alone (0.5 +/-0.3, 1.9 +/-0.3, P < 0.005), like prior studies of GRPR up-regulation by GRP.	32	36	up-regulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	35	36	32	33
Of the 23 GRPR neurons treated with PTX , GRP induced calcium responses in 16/23 ( 70 % ) were completely inhibited by U-50 ,488 , 2/23 ( 9 % ) showed partial inhibition , whereas 5/23 ( 21 % ) were resistant to U-50 ,488 treatment .	Of the 23 GRPR neurons treated with PTX, GRP induced calcium responses in 16/23 (70%) were completely inhibited by U-50,488, 2/23 (9%) showed partial inhibition, whereas 5/23 (21%) were resistant to U-50,488 treatment.	3	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	9	10	3	4
GRP depletion after the contagious itch test supported the idea that GRP is released from GRPergic fibers to activate GRPR neurons .	GRP depletion after the contagious itch test supported the idea that GRP is released from GRPergic fibers to activate GRPR neurons.	11	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	11	12	19	20
These results suggested that GRP secreted by NE like cells increased PC3 invasion by activating GRPR in AR deficient cells .	These results suggested that GRP secreted by NE like cells increased PC3 invasion by activating GRPR in AR deficient cells.	4	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	4	5	15	16
GRPR activation by GRP or bombesin stimulates the growth of glioma cell lines .	GRPR activation by GRP or bombesin stimulates the growth of glioma cell lines.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	3	4	0	1
GRP acted in concert with IL-22 to enhance the expression its receptor GRPR ( XREF_FIG ) .	GRP acted in concert with IL-22 to enhance the expression its receptor GRPR (XREF_FIG).	0	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	0	1	12	13
Since NMB is expressed in both CGRP and IB4 fibers , it is conceivable that NMB and GRP afferents could simultaneously target both NMBR and GRPR neurons directly to trigger concurrent activation in response to a specific pruritogen 12 .	Since NMB is expressed in both CGRP and IB4 fibers, it is conceivable that NMB and GRP afferents could simultaneously target both NMBR and GRPR neurons directly to trigger concurrent activation in response to a specific pruritogen 12.	15	26	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	17	18	25	26
Furthermore , GRP not only strongly induced TSLP but also increased the expression IL-33 and GRPR synergistically with IL-22 .	Furthermore, GRP not only strongly induced TSLP but also increased the expression IL-33 and GRPR synergistically with IL-22.	2	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	2	3	15	16
They showed that morphine triggers internalization of both GRPR and MOR1D , while GRP specifically triggers GRPR internalization and morphine independent scratching [ XREF_BIBR ] .	They showed that morphine triggers internalization of both GRPR and MOR1D, while GRP specifically triggers GRPR internalization and morphine independent scratching [XREF_BIBR].	13	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	13	14	16	17
Such a unidirectional signaling may ensure that opioid encoded itch information is correctly relayed to the GRPR- signaling machinery , and avoids accidental engagement of MOR1D that may result in inappropriate signaling , such as a condition when GRPR is activated by GRP released from primary afferents .	Such a unidirectional signaling may ensure that opioid encoded itch information is correctly relayed to the GRPR- signaling machinery, and avoids accidental engagement of MOR1D that may result in inappropriate signaling, such as a condition when GRPR is activated by GRP released from primary afferents.	38	43	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	42	43	38	39
Modulation of GSK3beta can markedly increase p53 dependent activation of Bax , leading to cytochrome c release , loss of mitochondrial membrane potential and caspase-9 processing [ XREF_BIBR ] .	Modulation of GSK3beta can markedly increase p53 dependent activation of Bax, leading to cytochrome c release, loss of mitochondrial membrane potential and caspase-9 processing [XREF_BIBR].	0	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Bax	Bax	Bax	2	3	10	11
In cardiomyocytes , silencing of SMP30 expression attenuated Akt and GSK-3beta phosphorylation , and increased Bax to Bcl-2 ratio and cardiomyocyte apoptosis induced by hydrogen peroxide .	In cardiomyocytes, silencing of SMP30 expression attenuated Akt and GSK-3beta phosphorylation, and increased Bax to Bcl-2 ratio and cardiomyocyte apoptosis induced by hydrogen peroxide.	5	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	SMP30 expression attenuated Akt and GSK-3beta phosphorylation	gsk-3beta	Bax	Bax	bax	10	11	15	16
Pharmacologic modulation of GSK-3beta markedly impaired p53 dependent transactivation of targets including p21 and Puma but promoted p53 dependent conformational activation of Bax , resulting in cytochrome c release , loss of mitochondrial membrane potential , and caspase-9 processing .	Pharmacologic modulation of GSK-3beta markedly impaired p53 dependent transactivation of targets including p21 and Puma but promoted p53 dependent conformational activation of Bax, resulting in cytochrome c release, loss of mitochondrial membrane potential, and caspase-9 processing.	1	23	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Bax	Bax	Bax	3	4	22	23
In a similar manner , either mutation or deletion of the identified GSK-3beta phosphorylation motif prevented the localization of Bax to mitochondria in cerebellar granule neurons undergoing apoptosis .	In a similar manner, either mutation or deletion of the identified GSK-3beta phosphorylation motif prevented the localization of Bax to mitochondria in cerebellar granule neurons undergoing apoptosis.	12	20	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	Bax	Bax	bax	12	13	19	20
In ischemic AKI , GSK3beta was suggested to activate Bax via phosphorylation and the pharmacological inhibitor of GSK3beta , TDZD-8 , could block Bax activation to afford significant renoprotective effects .	In ischemic AKI, GSK3beta was suggested to activate Bax via phosphorylation and the pharmacological inhibitor of GSK3beta, TDZD-8, could block Bax activation to afford significant renoprotective effects.	15	24	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Bax	Bax	Bax	17	18	23	24
Finally , inhibition of GSK3beta blocked ROS production , Bax activation and the down regulation of ROS scavenging genes .	Finally, inhibition of GSK3beta blocked ROS production, Bax activation and the down regulation of ROS scavenging genes.	2	10	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Bax	Bax	Bax	4	5	9	10
GSK3beta further activated the Bax family and Caspase family of apoptosis mediating kinases .	GSK3beta further activated the Bax family and Caspase family of apoptosis mediating kinases.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Bax	Bax	Bax	0	1	4	5
In addition , GSK3beta promoted Bax activation by down-regulating Mcl-1 upon HF-LPLI treatment .	In addition, GSK3beta promoted Bax activation by down-regulating Mcl-1 upon HF-LPLI treatment.	3	6	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Bax	Bax	Bax	3	4	5	6
Previous studies have shown that upregulation of GSK-3beta activity can activate Bax , c-jun and the caspases family , in normal histiocytes and various tumor cells [ XREF_BIBR XREF_BIBR ] , resulting in cell apoptosis .	Previous studies have shown that upregulation of GSK-3beta activity can activate Bax, c-jun and the caspases family, in normal histiocytes and various tumor cells [XREF_BIBR XREF_BIBR], resulting in cell apoptosis.	7	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Bax	Bax	Bax	7	8	11	12
TDZD-8 also reduced renal injury in rats injured by I/R by inhibiting GSK-3beta induced Bax activation and apoptosis [ XREF_BIBR ] .	TDZD-8 also reduced renal injury in rats injured by I/R by inhibiting GSK-3beta induced Bax activation and apoptosis [XREF_BIBR].	11	15	induced	Positive_early_activation	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Bax	Bax	Bax	12	13	14	15
Modulation of GSK3beta expression can markedly increase p53 dependent activation of Bax , leading to cytochrome c release and initiation of the intrinsic apoptotic pathway .	Modulation of GSK3beta expression can markedly increase p53 dependent activation of Bax, leading to cytochrome c release and initiation of the intrinsic apoptotic pathway.	2	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta expression	gsk3beta	Bax	Bax	bax	2	3	11	12
Western blot exhibited that GSK3beta inhibitor 4-benzyl-2-methyl-1 , 2,4-thiadiazolidine-3 , 5-dione ( TDZD8 ) and EPO not only increased the phosphorylation of GSK3beta but also inhibited the mitochondrial translocation of Bax .	Western blot exhibited that GSK3beta inhibitor 4-benzyl-2-methyl-1, 2,4-thiadiazolidine-3, 5-dione (TDZD8) and EPO not only increased the phosphorylation of GSK3beta but also inhibited the mitochondrial translocation of Bax.	4	31	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta inhibitor 4-benzyl-2-methyl-1, 2,4-thiadiazolidine-3, 5-dione (TDZD8) and EPO not only increased the phosphorylation of GSK3beta	gsk3beta	Bax	Bax	bax	22	23	30	31
Taken together , GSK3beta mediated Bax activation induces apoptosis and tubular damage that contribute to acute ischemic kidney injury .	Taken together, GSK3beta mediated Bax activation induces apoptosis and tubular damage that contribute to acute ischemic kidney injury.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Bax	Bax	Bax	3	4	5	6
Furthermore , Sal could increase the phosphorylation level of Akt and GSK3beta , upregulate the ratio of Bcl-2 and Bax , and inhibit the activation of caspase-3 , caspase-6 , and caspase-9 .	Furthermore, Sal could increase the phosphorylation level of Akt and GSK3beta, upregulate the ratio of Bcl-2 and Bax, and inhibit the activation of caspase-3, caspase-6, and caspase-9.	2	20	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	Sal could increase the phosphorylation level of Akt and GSK3beta	gsk3beta	Bax	Bax	bax	11	12	19	20
Here we demonstrate that mammalian Smo ( mSmo ) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1alpha and GRK2 .	Here we demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1alpha and GRK2.	4	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GRK2	GRK2	GRK2	Smo	Smo	Smo	21	22	5	6
We considered the possibility that other previously unidentified Grk2 sites might be sufficient to mediate Smo activation ; based on the consensus Grk2 phosphorylation sites32 , we identified two further putative sites within the mSmo CTT ; mutagenesis of these additional sites in mSmoSA ( mSmo14SA ) did not affect the rescue efficiency ( Fig XREF_FIG C ) .	We considered the possibility that other previously unidentified Grk2 sites might be sufficient to mediate Smo activation; based on the consensus Grk2 phosphorylation sites32, we identified two further putative sites within the mSmo CTT; mutagenesis of these additional sites in mSmoSA (mSmo14SA) did not affect the rescue efficiency (Fig XREF_FIG C).	8	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Grk2	Grk2	Grk2	Smo	Smo	Smo	8	9	15	16
We found that the SA0-5 mutation abolished Shh , CK1alpha , or GRK2 induced Smo mobility shift ( XREF_FIG , lanes 5-12 ) .	We found that the SA0-5 mutation abolished Shh, CK1alpha, or GRK2 induced Smo mobility shift (XREF_FIG, lanes 5-12).	6	16	induced	Positive_early_activation	Positive_activation	Positive_activation	GRK2	GRK2	GRK2	Smo	Smo	Smo	12	13	14	15
Previous studies have suggested that Grk2 potentiates Smo activity by phosphorylating its C-terminal tail ( CTT ) .	Previous studies have suggested that Grk2 potentiates Smo activity by phosphorylating its C-terminal tail (CTT).	5	8	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Grk2	Grk2	Grk2	Smo	Smo	Smo	5	6	7	8
Two ( non mutually exclusive ) mechanisms have been proposed to explain the positive role of GRK2 in Hh signaling : ( 1 ) GRK2 promotes the ciliary localization of SMO and ( 2 ) GRK2 induces the clearance of GPR161 from the ciliary membrane , leading to a decrease in Galpha s and PKA activity .	Two (non mutually exclusive) mechanisms have been proposed to explain the positive role of GRK2 in Hh signaling : (1) GRK2 promotes the ciliary localization of SMO and (2) GRK2 induces the clearance of GPR161 from the ciliary membrane, leading to a decrease in Galpha s and PKA activity.	24	31	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRK2	GRK2	GRK2	SMO	SMO	SMO	24	25	30	31
Several analyses have led to the conclusion that the principal role of Grk2 in Hh signalling is to potentiate activity of Smo by phosphorylating its CTT 15 , 16 , 17 .	Several analyses have led to the conclusion that the principal role of Grk2 in Hh signalling is to potentiate activity of Smo by phosphorylating its CTT 15, 16, 17.	10	22	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Grk2	Grk2	Grk2	Smo	Smo	Smo	12	13	21	22
Additionally , new evidence suggests that GRK2 mediates signaling from the atypical GPCR Smoothened ( Smo ) , thereby playing an important role in the Hedgehog ( Hh ) signaling pathway during embryonic development [ XREF_BIBR - XREF_BIBR ] .	Additionally, new evidence suggests that GRK2 mediates signaling from the atypical GPCR Smoothened (Smo), thereby playing an important role in the Hedgehog (Hh) signaling pathway during embryonic development [XREF_BIBR - XREF_BIBR].	6	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRK2	GRK2	GRK2	Smo	Smo	Smo	6	7	15	16
GRK2 activity promoted association of Smo with beta-arrestin-2 .	GRK2 activity promoted association of Smo with beta-arrestin-2.	0	6	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRK2	GRK2	GRK2	Smo	Smo	Smo	0	1	5	6
In addition to PKA and CK1alpha and epsilon , Smo activity is also modulated by casein kinase 2 ( CK2 ) , atypical protein kinase C ( aPKC ) , and G protein coupled receptor kinase 2 ( Gprk2 ) [ XREF_BIBR - XREF_BIBR ] .	In addition to PKA and CK1alpha and epsilon, Smo activity is also modulated by casein kinase 2 (CK2), atypical protein kinase C (aPKC), and G protein coupled receptor kinase 2 (Gprk2) [XREF_BIBR - XREF_BIBR].	9	37	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	G protein coupled receptor kinase 2	G protein coupled receptor kinase 2	G protein coupled receptor kinase 2	Smo	Smo	Smo	31	37	9	10
The data presented here demonstrate that AMF and PGI can mediate drug delivery to gp78 and AMFR expressing tumor cells in vitro and in vivo .	The data presented here demonstrate that AMF and PGI can mediate drug delivery to gp78 and AMFR expressing tumor cells in vitro and in vivo.	6	17	mediate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	AMF	AMF	AMF	AMFR	AMFR	AMFR	6	7	16	17
AMF induces gp78 internalization to intracellular tubulovesicles including lysosome and transport to the leading edge .	AMF induces gp78 internalization to intracellular tubulovesicles including lysosome and transport to the leading edge.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AMF	AMF	AMF	gp78	gp78	gp78	0	1	2	3
Worth to mention , the activation of AMFR by AMF can stimulate a signaling cascade , dependent on protein kinase C , and upregulates the Rho like GTPase , RhoA and RhoC .	Worth to mention, the activation of AMFR by AMF can stimulate a signaling cascade, dependent on protein kinase C, and upregulates the Rho like GTPase, RhoA and RhoC.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	AMF	AMF	AMF	AMFR	AMFR	AMFR	9	10	7	8
AMF induces gp78 internalization to intracellular tubulovesicles and transport to the leading edge stimulating pseudopodial protrusion and cell motility .	AMF induces gp78 internalization to intracellular tubulovesicles and transport to the leading edge stimulating pseudopodial protrusion and cell motility.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AMF	AMF	AMF	gp78	gp78	gp78	0	1	2	3
Activation of AMFR by AMF has been demonstrated to alter cell adhesion , motility and angiogenesis .	Activation of AMFR by AMF has been demonstrated to alter cell adhesion, motility and angiogenesis.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	AMF	AMF	AMF	AMFR	AMFR	AMFR	4	5	2	3
These data indicated that GPI positively regulates its receptor gp78 and promotes G1/S phase transition via the activation of ERK and the upregulation of Cyclin D1 expression .	These data indicated that GPI positively regulates its receptor gp78 and promotes G1/S phase transition via the activation of ERK and the upregulation of Cyclin D1 expression.	4	11	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	GPI	GPI	GPI	gp78	gp78	gp78	4	5	9	10
The stimulation of AMFR by AMF can trigger a signaling cascade , dependent on protein kinase C , and promotes the activation and upregulation of Rho like GTPase , RhoA and RhoC .	The stimulation of AMFR by AMF can trigger a signaling cascade, dependent on protein kinase C, and promotes the activation and upregulation of Rho like GTPase, RhoA and RhoC.	1	6	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	AMF	AMF	AMF	AMFR	AMFR	AMFR	5	6	3	4
AMF stimulates AMFR in an autocrine manner and results in signalling cascades relying on PKC and activates Rho like GTPase , RhoA , and Rac1 , which enhance cell motility .	AMF stimulates AMFR in an autocrine manner and results in signalling cascades relying on PKC and activates Rho like GTPase, RhoA, and Rac1, which enhance cell motility.	0	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AMF	AMF	AMF	AMFR	AMFR	AMFR	0	1	2	3
The activation of autocrine motility factor receptor ( AMFR ) by autocrine motility factor ( AMF ) , a motility stimulating protein that is secreted by tumor cells , has been demonstrated to be important in proliferation , apoptosis and tumor migration .	The activation of autocrine motility factor receptor (AMFR) by autocrine motility factor (AMF), a motility stimulating protein that is secreted by tumor cells, has been demonstrated to be important in proliferation, apoptosis and tumor migration.	1	14	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	autocrine motility factor	autocrine motility factor	autocrine motility factor	autocrine motility factor receptor	autocrine motility factor receptor	autocrine motility factor receptor	11	14	3	7
As shown in Figure XREF_FIG a ( lanes 1 and 2 ) , treatment of Me501 cells with LiCl ( 20mM ) , a well established inhibitor of GSK3-beta , caused a marked decrease of cellular Axin-1 and a concomitant increase of beta-catenin .	As shown in Figure XREF_FIG a (lanes 1 and 2), treatment of Me501 cells with LiCl (20mM), a well established inhibitor of GSK3-beta, caused a marked decrease of cellular Axin-1 and a concomitant increase of beta-catenin.	26	37	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3-beta	GSK3-beta	GSK3-beta	Axin-1	Axin-1	Axin-1	28	29	36	37
We uncovered that Merlin upregulates the destruction complex associated protein Axin1 , initiated by GSK-3beta activation .	We uncovered that Merlin upregulates the destruction complex associated protein Axin1, initiated by GSK-3beta activation.	8	15	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Axin1	Axin1	Axin1	14	15	10	11
Furthermore , GSK3beta binding of axin directs axin to target beta-catenin and shields GSK3beta from the action of Akt [ XREF_BIBR ] .	Furthermore, GSK3beta binding of axin directs axin to target beta-catenin and shields GSK3beta from the action of Akt [XREF_BIBR].	2	8	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	axin	axin	axin	2	3	7	8
Moreover , GSK-3beta or CDK5 inhibition failed to downregulate ER stress efficiently , suggesting that ER stress functions upstream of GSK-3beta or CDK5 .	Moreover, GSK-3beta or CDK5 inhibition failed to downregulate ER stress efficiently, suggesting that ER stress functions upstream of GSK-3beta or CDK5.	2	10	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	ER	ER	ER	2	3	9	10
In addition , GSK-3beta or CDK5 inhibition failed to reduce ER stress , suggesting that ER stress occurs upstream of GSK-3beta or CDK5 .	In addition, GSK-3beta or CDK5 inhibition failed to reduce ER stress, suggesting that ER stress occurs upstream of GSK-3beta or CDK5.	3	11	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	ER	ER	ER	3	4	10	11
GSK3beta ( glycogen synthase 3beta ) enhances ERalpha activity in neuronal cells [ XREF_BIBR ] .	GSK3beta (glycogen synthase 3beta) enhances ERalpha activity in neuronal cells [XREF_BIBR].	0	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	ERalpha	ERalpha	ERalpha	0	1	7	8
Therefore , in this study , we investigated the effects of ginsenoside Rb1 on GSK3beta mediated ER stress in high glucose treated hippocampal neurons .	Therefore, in this study, we investigated the effects of ginsenoside Rb1 on GSK3beta mediated ER stress in high glucose treated hippocampal neurons.	14	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	ER	ER	ER	14	15	16	17
Indeed , our current studies demonstrate that GSK-3beta mediates ER stress induced lysosomal apoptosis in leukemia involving caspase-2-induced LMP and cathepsin B relocation , which result in caspase-8 and -3 activation [ XREF_BIBR ] .	Indeed, our current studies demonstrate that GSK-3beta mediates ER stress induced lysosomal apoptosis in leukemia involving caspase-2-induced LMP and cathepsin B relocation, which result in caspase-8 and -3 activation [XREF_BIBR].	7	10	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	ER	ER	ER	7	8	9	10
Moreover , Akt activation inhibits downstream substrates such as GSK3beta and Foxo1 , which directly regulate PPARgamma , C/EBPbeta , and C/EBPalpha [ XREF_BIBR , XREF_BIBR ] .	Moreover, Akt activation inhibits downstream substrates such as GSK3beta and Foxo1, which directly regulate PPARgamma, C/EBPbeta, and C/EBPalpha [XREF_BIBR, XREF_BIBR].	6	19	directly regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	C/EBPbeta	C/EBPbeta	C/EBPbeta	9	10	18	19
Moreover , Akt regulates adipogenesis via the phosphorylation and inactivation of substrates , such as GSK3beta , which directly regulates PPARgamma , C/EBPbeta , C/EBPalpha and beta-catenin XREF_BIBR , XREF_BIBR .	Moreover, Akt regulates adipogenesis via the phosphorylation and inactivation of substrates, such as GSK3beta, which directly regulates PPARgamma, C/EBPbeta, C/EBPalpha and beta-catenin XREF_BIBR, XREF_BIBR.	4	27	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	C/EBPbeta	C/EBPbeta	C/EBPbeta	15	16	22	23
Moreover , Akt regulates adipogenesis via the phosphorylation and inactivation of substrates such as Foxo1 and GSK3beta , which directly regulate PPARgamma , C/EBPbeta , C/EBPalpha , and GS [ XREF_BIBR , XREF_BIBR ] .	Moreover, Akt regulates adipogenesis via the phosphorylation and inactivation of substrates such as Foxo1 and GSK3beta, which directly regulate PPARgamma, C/EBPbeta, C/EBPalpha, and GS [XREF_BIBR, XREF_BIBR].	11	24	directly regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	C/EBPbeta	C/EBPbeta	C/EBPbeta	16	17	23	24
GSK3beta induced C/EBPbeta activates PPAR-gamma , that in turn activates the differentiating factor C/EBPalpha leading to the production of adiponectin and completion of adipocyte differentiation [ XREF_BIBR , XREF_BIBR ] .	GSK3beta induced C/EBPbeta activates PPAR-gamma, that in turn activates the differentiating factor C/EBPalpha leading to the production of adiponectin and completion of adipocyte differentiation [XREF_BIBR, XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	C/EBPbeta	C/EBPbeta	C/EBPbeta	0	1	2	3
In rod photoreceptors rhodopsin kinase ( RK ) mediates rapid desensitization of rod photoreceptors to light by catalyzing phosphorylation of the visual pigment rhodopsin .	In rod photoreceptors rhodopsin kinase (RK) mediates rapid desensitization of rod photoreceptors to light by catalyzing phosphorylation of the visual pigment rhodopsin.	4	24	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	RK	RK	RK	rhodopsin	rhodopsin	rhodopsin	6	7	23	24
Arr1 and Grk1 modulate the decay of photoactivated rhodopsin .	Arr1 and Grk1 modulate the decay of photoactivated rhodopsin.	0	9	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Grk1	Grk1	Grk1	rhodopsin	rhodopsin	rhodopsin	2	3	8	9
The interpretation given by the authors for this result is that the measurement of tau D occurs after RK mediated rhodopsin ( R * ) shutoff has been completed and thus only reflects the rate limiting step of RGS mediated effector shutdown .	The interpretation given by the authors for this result is that the measurement of tau D occurs after RK mediated rhodopsin (R *) shutoff has been completed and thus only reflects the rate limiting step of RGS mediated effector shutdown.	18	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	RK	RK	RK	rhodopsin	rhodopsin	rhodopsin	18	19	20	21
The role of RK in rods would thus be to accelerate inactivation of activated rhodopsin molecules that in concert with regeneration leads to the normal rate of recovery of sensitivity .	The role of RK in rods would thus be to accelerate inactivation of activated rhodopsin molecules that in concert with regeneration leads to the normal rate of recovery of sensitivity.	1	15	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RK	RK	RK	rhodopsin	rhodopsin	rhodopsin	3	4	14	15
Thus , the inhibition of rhodopsin kinase prevents this rhodopsin inactivation , and thus halts the cascade and allows time for rhodopsin to ' recover ' back into its ' cis ' optical isomer ' stand by ' form .	Thus, the inhibition of rhodopsin kinase prevents this rhodopsin inactivation, and thus halts the cascade and allows time for rhodopsin to ' recover ' back into its ' cis ' optical isomer ' stand by ' form.	5	10	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	rhodopsin kinase	rhodopsin kinase	rhodopsin kinase	rhodopsin	rhodopsin	rhodopsin	5	7	9	10
Fbxo4 is also activated by GSK3beta via phosphorylation , which is necessary for its dimerisation and E3 ligase activity 8 .	Fbxo4 is also activated by GSK3beta via phosphorylation, which is necessary for its dimerisation and E3 ligase activity 8.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Fbxo4	Fbxo4	Fbxo4	5	6	0	1
Therefore , FBXO4 is activated concurrent with the phosphorylation of Thr286 in cyclin D1 by GSK3beta [ XREF_BIBR ] .	Therefore, FBXO4 is activated concurrent with the phosphorylation of Thr286 in cyclin D1 by GSK3beta [XREF_BIBR].	2	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	FBXO4	FBXO4	FBXO4	15	16	2	3
GSK3beta and 14-3-3epsilon activate FBXO4 by stimulating FBXO4 dimerization , a requirement for targeting cyclin D1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	GSK3beta and 14-3-3epsilon activate FBXO4 by stimulating FBXO4 dimerization, a requirement for targeting cyclin D1 [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	FBXO4	FBXO4	FBXO4	0	1	4	5
Inhibition of GSK3beta activity through overexpression of RasV12 or GSK3beta knockdown resulted in an inhibition of S12 phosphorylation and decreased Fbx4 dimerization ( XREF_SUPPLEMENTARY ) .	Inhibition of GSK3beta activity through overexpression of RasV12 or GSK3beta knockdown resulted in an inhibition of S12 phosphorylation and decreased Fbx4 dimerization (XREF_SUPPLEMENTARY).	2	21	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Fbx4	Fbx4	Fbx4	2	3	20	21
We showed that specific inhibition of GSK-3beta by BIO dramatically downregulated C/EBPalpha , FABP4 and PPARgamma , known to act at different stages of adipocyte maturation [ XREF_BIBR ] .	We showed that specific inhibition of GSK-3beta by BIO dramatically downregulated C/EBPalpha, FABP4 and PPARgamma, known to act at different stages of adipocyte maturation [XREF_BIBR].	4	17	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	C/EBPalpha	C/EBPalpha	C/EBPalpha	6	7	11	12
The activated GSK-3beta not only repressed cell proliferation , but also activated C/EBPalpha , which maintained miR-122 levels and thereby enforced IGF-1R suppression .	The activated GSK-3beta not only repressed cell proliferation, but also activated C/EBPalpha, which maintained miR-122 levels and thereby enforced IGF-1R suppression.	0	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	C/EBPalpha	C/EBPalpha	C/EBPalpha	2	3	12	13
Selection of these pre-existing subclones resulted in FGFR inhibitor resistance because of the activation of AKT and extracellular signal regulated kinase by MET signaling that was mediated by GRB2 associated binding protein 1 ( GAB1 ) .	Selection of these pre-existing subclones resulted in FGFR inhibitor resistance because of the activation of AKT and extracellular signal regulated kinase by MET signaling that was mediated by GRB2 associated binding protein 1 (GAB1).	23	35	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	GRB2	GRB2	GRB2	GAB1	GAB1	GAB1	28	29	34	35
Signaling cascades that are activated by direct binding of their adaptors or effectors to EGFR include the mitogen activated protein kinase ( MAPK ) pathway ( mediated by the adaptors Grb2 and Shc ) , the phosphatidylinositol 3-kinase ( PI3K ) pathway acting through the kinase Akt and the transcription factor nuclear factor kappaB ( PI3K/Akt/NF-kappaB ; mediated by the adaptors Grb2 and Gab1 ) , and the phospholipase C-gamma ( PLC-gamma ) pathway ( mediated by direct recruitment of PLC-gamma to the receptor ) .	Signaling cascades that are activated by direct binding of their adaptors or effectors to EGFR include the mitogen activated protein kinase (MAPK) pathway (mediated by the adaptors Grb2 and Shc), the phosphatidylinositol 3-kinase (PI3K) pathway acting through the kinase Akt and the transcription factor nuclear factor kappaB (PI3K/Akt/NF-kappaB; mediated by the adaptors Grb2 and Gab1), and the phospholipase C-gamma (PLC-gamma) pathway (mediated by direct recruitment of PLC-gamma to the receptor).	53	64	mediated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Grb2	Grb2	Grb2	Gab1	Gab1	Gab1	61	62	63	64
In this case , a multi-level logical description would be most appropriate : active Grb2 ( i.e ., Grb2 bound to ErbB1 homo- or heterodimers ) activates Gab1 to level 1 , whereas Grb2 AND PIP3 activate Gab1 to level 2 .	In this case, a multi-level logical description would be most appropriate : active Grb2 (i.e., Grb2 bound to ErbB1 homo- or heterodimers) activates Gab1 to level 1, whereas Grb2 AND PIP3 activate Gab1 to level 2.	13	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Grb2	Grb2	Grb2	Gab1	Gab1	Gab1	14	15	27	28
Furthermore , the depletion of DDB1 decreased Hsp90 inhibitor induced GRK5 destabilization and UV irradiation induced GRK5 degradation .	Furthermore, the depletion of DDB1 decreased Hsp90 inhibitor induced GRK5 destabilization and UV irradiation induced GRK5 degradation.	5	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRK5	DDB1 decreased Hsp90 inhibitor induced GRK5	grk5	GRK5	GRK5	grk5	10	11	16	17
Furthermore , depletion of DDB1 inhibited Hsp90 inhibitor induced GRK5 destabilization and UV irradiation induced GRK5 degradation .	Furthermore, depletion of DDB1 inhibited Hsp90 inhibitor induced GRK5 destabilization and UV irradiation induced GRK5 degradation.	6	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GRK5	Hsp90 inhibitor induced GRK5	grk5	GRK5	GRK5	grk5	9	10	15	16
In support of our conclusion , previous reports have also shown that Grb2 mediates receptor degradation by recruiting c-Cbl .	In support of our conclusion, previous reports have also shown that Grb2 mediates receptor degradation by recruiting c-Cbl.	12	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Grb2	Grb2	Grb2	c-Cbl	c-Cbl	c-Cbl	12	13	18	19
LAT interaction with the c-Cbl proline rich domain can be mediated by Grb-2 , PLC-gamma , or NCK , and ZAP-70 interacts with the TKB domain of c-Cbl .	LAT interaction with the c-Cbl proline rich domain can be mediated by Grb-2, PLC-gamma, or NCK, and ZAP-70 interacts with the TKB domain of c-Cbl.	4	14	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Grb-2	Grb-2	Grb-2	c-Cbl	c-Cbl	c-Cbl	12	13	4	5
In addition to its signaling role , Grb2 is known to mediate the interaction of c-Cbl with activated receptor molecules .	In addition to its signaling role, Grb2 is known to mediate the interaction of c-Cbl with activated receptor molecules.	7	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Grb2	Grb2	Grb2	c-Cbl	c-Cbl	c-Cbl	7	8	15	16
Furthermore , the innate immune regulator STAT-5 and the kinase GSK3beta mediate the activation of Tip60 in HPV positive cells .	Furthermore, the innate immune regulator STAT-5 and the kinase GSK3beta mediate the activation of Tip60 in HPV positive cells.	6	19	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Tip60	Tip60	Tip60	10	11	15	16
In receptor tyrosine kinase ( RTK )/Ras pathway Grb2 adapter mediates the activation of Ras by bringing the guanine nucleotide exchange factor Sos1 to the plasma membrane adjacent to the membrane associated Ras .	In receptor tyrosine kinase (RTK)/Ras pathway Grb2 adapter mediates the activation of Ras by bringing the guanine nucleotide exchange factor Sos1 to the plasma membrane adjacent to the membrane associated Ras.	8	26	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Grb2	Grb2	Grb2	Sos1	Sos1	Sos1	8	9	22	23
Alternatively , Grb2 might dimerize Gab2 or cause a conformational change in Gab2 via the Grb2 SH3 binding site , which might allow the Gab2 PH domain to interact with the phagocytic cup in a PIP3 independent manner .	Alternatively, Grb2 might dimerize Gab2 or cause a conformational change in Gab2 via the Grb2 SH3 binding site, which might allow the Gab2 PH domain to interact with the phagocytic cup in a PIP3 independent manner.	2	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Grb2	Grb2	Grb2	Gab2	Gab2	Gab2	2	3	12	13
Binding of Grb2 SH2 domain to Tyr177 of Bcr-Abl activates Gab2 and Ras , resulting in constitutive activation of PI3K and Akt and Erk [ XREF_BIBR , XREF_BIBR ] .	Binding of Grb2 SH2 domain to Tyr177 of Bcr-Abl activates Gab2 and Ras, resulting in constitutive activation of PI3K and Akt and Erk [XREF_BIBR, XREF_BIBR].	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Grb2	Grb2	Grb2	Gab2	Gab2	Gab2	2	3	10	11
For example , GSK-3beta positively regulates E-cadherin by negatively controlling the stability of SNAIL and SLUG , as the repressors of E-cadherin [ XREF_BIBR ] .	For example, GSK-3beta positively regulates E-cadherin by negatively controlling the stability of SNAIL and SLUG, as the repressors of E-cadherin [XREF_BIBR].	3	7	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	E-cadherin	E-cadherin	E-cadherin	3	4	6	7
In a control experiment , we confirmed that ectopic expression of N-terminal Flag tagged Snail ( Flag-Snail ) induced E-cadherin suppression ( XREF_FIG ) and that expression of GSK3beta-HA inhibited the Snail mediated suppression of E-cadherin ( XREF_FIG ) .	In a control experiment, we confirmed that ectopic expression of N-terminal Flag tagged Snail (Flag-Snail) induced E-cadherin suppression (XREF_FIG) and that expression of GSK3beta-HA inhibited the Snail mediated suppression of E-cadherin (XREF_FIG).	26	37	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta-HA	expression of GSK3beta-HA	gsk3beta-ha	E-cadherin	E-cadherin	e-cadherin	28	29	35	36
Second , an increase in PYK2 -dependent phosphorylation of GSK3alpha and beta-Tyr 279/216 will activate GSK3alpha and beta , an event that may occur in response to TNF .	Second, an increase in PYK2 -dependent phosphorylation of GSK3alpha and beta-Tyr 279/216 will activate GSK3alpha and beta, an event that may occur in response to TNF.	5	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3alpha	PYK2 -dependent phosphorylation of GSK3alpha	gsk3alpha	GSK3alpha	GSK3alpha	gsk3alpha	9	10	15	16
In vitro , HLMFs produced HB-EGF and their conditioned media induced EGFR activation and promoted disruption of adherens junctions , migratory and invasive properties in CCA cells .	In vitro, HLMFs produced HB-EGF and their conditioned media induced EGFR activation and promoted disruption of adherens junctions, migratory and invasive properties in CCA cells.	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	5	6	11	12
This study not only associates Tgf-alpha and Hb-egf expression with wild-type Egfr oncogenicity but also ascribes the proangiogenic activity of Egfr in this tumor model to a novel mesenchymal Hb-egf and Egfr signaling axis , whereby endothelial and pericyte derived Hb-egf activates Egfr specifically in tumor associated perivascular cells , leading to increased pericyte coverage of the tumor endothelium and enhanced angiogenesis .	This study not only associates Tgf-alpha and Hb-egf expression with wild-type Egfr oncogenicity but also ascribes the proangiogenic activity of Egfr in this tumor model to a novel mesenchymal Hb-egf and Egfr signaling axis, whereby endothelial and pericyte derived Hb-egf activates Egfr specifically in tumor associated perivascular cells, leading to increased pericyte coverage of the tumor endothelium and enhanced angiogenesis.	24	60	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Hb-egf	Hb-egf	Hb-egf	Egfr	Egfr	Egfr	29	30	42	43
These data suggest that ERK1/2 , but not PI3K , p38 , or JNK , indeed act upstream to HB-EGF shedding and EGFR activation , which was further confirmed by the fact that HB-EGF treatment activated EGFR in the presence of the MEK inhibitor .	These data suggest that ERK1/2, but not PI3K, p38, or JNK, indeed act upstream to HB-EGF shedding and EGFR activation, which was further confirmed by the fact that HB-EGF treatment activated EGFR in the presence of the MEK inhibitor.	33	37	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	33	34	36	37
These findings suggest that HB-EGF activates the EGF receptor in human pancreatic cancer cells , but that it is not involved in enhancing the biological aggressiveness of this malignancy in vivo .	These findings suggest that HB-EGF activates the EGF receptor in human pancreatic cancer cells, but that it is not involved in enhancing the biological aggressiveness of this malignancy in vivo.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGF receptor	EGF receptor	EGF receptor	4	5	7	9
In the myocardial ECM , heparanase mediated release of HBEGF might be necessary to elicit transactivation of EGFR in cardiomyocytes .	In the myocardial ECM, heparanase mediated release of HBEGF might be necessary to elicit transactivation of EGFR in cardiomyocytes.	7	18	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	EGFR	EGFR	EGFR	9	10	17	18
It was concluded that HER4 is a newly described receptor for HB-EGF and that HB-EGF can activate two EGF receptor subtypes , HER1 and HER4 , but with different biological responses .	It was concluded that HER4 is a newly described receptor for HB-EGF and that HB-EGF can activate two EGF receptor subtypes, HER1 and HER4, but with different biological responses.	14	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	HER1	HER1	HER1	14	15	22	23
ADAM17 is also critical for EGFR signaling due to the proteolytic release of several ligands of EGFR in the vessels , such as HB-EGF .	ADAM17 is also critical for EGFR signaling due to the proteolytic release of several ligands of EGFR in the vessels, such as HB-EGF.	5	24	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	23	24	5	6
EGFRvIII induced expression of HB-EGF is biologically significant , and HB-EGF overexpression was shown to accelerate EGFRvIII induced tumorigenicity while HB-EGF silencing attenuated EGFRvIII mediated tumorigenicity in an orthotopic model .	EGFRvIII induced expression of HB-EGF is biologically significant, and HB-EGF overexpression was shown to accelerate EGFRvIII induced tumorigenicity while HB-EGF silencing attenuated EGFRvIII mediated tumorigenicity in an orthotopic model.	20	25	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFRvIII	EGFRvIII	EGFRvIII	20	21	23	24
S1P stimulated transactivation of EGFR requires matrix metalloproteinase activation , which induces proteolytic cleavage of transmembrane pro- heparin binding EGF like growth factor ( HB-EGF ) that subsequently activates EGFR [ XREF_BIBR ] .	S1P stimulated transactivation of EGFR requires matrix metalloproteinase activation, which induces proteolytic cleavage of transmembrane pro- heparin binding EGF like growth factor (HB-EGF) that subsequently activates EGFR [XREF_BIBR].	22	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	24	25	29	30
First , we show that the protein kinase activity of PI3K regulates Src activity , a known activator of MMPs [ XREF_BIBR ] , to promote cleavage of the EGFR ligand HB-EGF mediating EGFR transactivation [ XREF_BIBR , XREF_BIBR ] .	First, we show that the protein kinase activity of PI3K regulates Src activity, a known activator of MMPs [XREF_BIBR], to promote cleavage of the EGFR ligand HB-EGF mediating EGFR transactivation [XREF_BIBR, XREF_BIBR].	26	34	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	31	32	33	34
G protein coupled receptor ( GPCR ) agonists also stimulate pro-HB-EGF shedding , which mediates EGF-R transactivation by GPCR signaling XREF_BIBR , XREF_BIBR .	G protein coupled receptor (GPCR) agonists also stimulate pro-HB-EGF shedding, which mediates EGF-R transactivation by GPCR signaling XREF_BIBR, XREF_BIBR.	9	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pro-HB-EGF	pro-HB-EGF	pro-HB-EGF	EGF-R	EGF-R	EGF-R	10	11	15	16
Also , stable overexpression of HB-EGF in U87vIII cells or in GBM 9 neurosphere cells results in increased EGFRvIII activation ( XREF_SUPPLEMENTARY and XREF_FIG ) .	Also, stable overexpression of HB-EGF in U87vIII cells or in GBM 9 neurosphere cells results in increased EGFRvIII activation (XREF_SUPPLEMENTARY and XREF_FIG).	3	20	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	HB-EGF	overexpression of HB-EGF	hb-egf	EGFRvIII	EGFRvIII	egfrviii	5	6	18	19
A significant increase in HER1 expression in myometrial cells was observed when treated with HB-EGF at concentrations > 10 ng/ml , whereas a significant increase in HER1 expression in leiomyoma cells was noted only by the treatment with HB-EGF at concentrations > 100 ng/ml .	A significant increase in HER1 expression in myometrial cells was observed when treated with HB-EGF at concentrations> 10 ng/ml, whereas a significant increase in HER1 expression in leiomyoma cells was noted only by the treatment with HB-EGF at concentrations> 100 ng/ml.	4	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	HER1	HER1	HER1	14	15	4	5
XREF_BIBR , XREF_BIBR As HER2 works as heterodimers combined with other HER family members such as EGFR , GPER1 induced HB-EGF abundance might trigger EGFR and HER2 substrate progresses .	XREF_BIBR, XREF_BIBR As HER2 works as heterodimers combined with other HER family members such as EGFR, GPER1 induced HB-EGF abundance might trigger EGFR and HER2 substrate progresses.	18	27	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	GPER1 induced HB-EGF	hb-egf	EGFR	EGFR	egfr	20	21	24	25
We conclude that the inhibition of HB-EGF mediated EGFR activation is one of the alternative mechanisms for the antihypertrophic action of adiponectin .	We conclude that the inhibition of HB-EGF mediated EGFR activation is one of the alternative mechanisms for the antihypertrophic action of adiponectin.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	6	7	8	9
To verify whether HB-EGF stimulates HER1 mediated chemotaxis in cancer cells , we tested the inhibitory effect of tyrphostin AG1478 in HB-EGF-induced chemotaxis .	To verify whether HB-EGF stimulates HER1 mediated chemotaxis in cancer cells, we tested the inhibitory effect of tyrphostin AG1478 in HB-EGF-induced chemotaxis.	3	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	HER1	HER1	HER1	3	4	5	6
The strong activation of EGFR by HB-EGF ( XREF_FIG ) and our data showing that LPA induced ERK phosphorylation ( XREF_FIG ) depends on MP mediated release of HB-EGF further suggest an important role of HB-EGF during the early phases of wound healing .	The strong activation of EGFR by HB-EGF (XREF_FIG) and our data showing that LPA induced ERK phosphorylation (XREF_FIG) depends on MP mediated release of HB-EGF further suggest an important role of HB-EGF during the early phases of wound healing.	2	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	6	7	4	5
The authors convincingly demonstrated a crucial pathogenic role for HB-EGF activation of glomerular EGFR signaling in a mouse model of anti-GBM-induced RPGN ( XREF_FIG ) .	The authors convincingly demonstrated a crucial pathogenic role for HB-EGF activation of glomerular EGFR signaling in a mouse model of anti-GBM-induced RPGN (XREF_FIG).	9	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	9	10	13	14
We have found that the presence of these inhibitors blocked the effect of sPLA 2 -IIA on EGFR phosphorylation as well as on ectodomain shedding of HB-EGF , suggesting a possible role of ADAMs and HB-EGF in sPLA 2 -IIA induced EGFR transactivation .	We have found that the presence of these inhibitors blocked the effect of sPLA 2 -IIA on EGFR phosphorylation as well as on ectodomain shedding of HB-EGF, suggesting a possible role of ADAMs and HB-EGF in sPLA 2 -IIA induced EGFR transactivation.	35	42	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	35	36	41	42
However , both TGF-alpha and HB-EGF ( 16 and 4 nM ) robustly induced EGFR endocytosis in HaCaT cells ( XREF_FIG ) , implicating that they are unlikely to be responsible for the EGFR activation upon cholinergic stimulation , although their role in this process can not be completely excluded .	However, both TGF-alpha and HB-EGF (16 and 4 nM) robustly induced EGFR endocytosis in HaCaT cells (XREF_FIG), implicating that they are unlikely to be responsible for the EGFR activation upon cholinergic stimulation, although their role in this process can not be completely excluded.	3	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	5	6	14	15
Moreover , GPER-1 activation leads to activation and release of heparin bound growth factor ( HB-EGF ) , which in turn activates the epidermal growth factor receptor ( EGFR ) followed by phosphorylation of MAPK [ XREF_BIBR ] .	Moreover, GPER-1 activation leads to activation and release of heparin bound growth factor (HB-EGF), which in turn activates the epidermal growth factor receptor (EGFR) followed by phosphorylation of MAPK [XREF_BIBR].	13	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	15	16	23	27
XREF_BIBR It has also been reported that H pylori increases HB-EGF shedding through upregulation of MMPs to trigger constitutive EGFR signal activation , which initiates neoplastic transformation of gastric epithelial cells .	XREF_BIBR It has also been reported that H pylori increases HB-EGF shedding through upregulation of MMPs to trigger constitutive EGFR signal activation, which initiates neoplastic transformation of gastric epithelial cells.	9	21	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	10	11	19	20
Our results are consistent with a mechanism in which autocrine HBEGF expression results in sustained EGFR activation as well as concomitant increased invadopodium formation through increased phosphorylation of cortactin and enhanced invadopodium function and matrix degradation due increases in Src activation .	Our results are consistent with a mechanism in which autocrine HBEGF expression results in sustained EGFR activation as well as concomitant increased invadopodium formation through increased phosphorylation of cortactin and enhanced invadopodium function and matrix degradation due increases in Src activation.	10	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	HBEGF	HBEGF expression	hbegf	EGFR	EGFR	egfr	10	11	15	16
These results indicate that soluble HB-EGF secreted from the tip of the leading edge activates the EGFR and ERK pathway , and that synergy with TGFalpha is required for leading edge extension in epithelial sheet migration during eyelid closure .	These results indicate that soluble HB-EGF secreted from the tip of the leading edge activates the EGFR and ERK pathway, and that synergy with TGFalpha is required for leading edge extension in epithelial sheet migration during eyelid closure.	4	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	5	6	16	17
Thus expression of HBEGF leads to increased activation of the EGFR with no change in proliferation rate .	Thus expression of HBEGF leads to increased activation of the EGFR with no change in proliferation rate.	1	13	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	HBEGF	expression of HBEGF	hbegf	EGFR	EGFR	egfr	3	4	10	11
HB-EGF activation of EGFR in cultured podocytes led to dedifferentiation and conversion to a proliferative and migratory phenotype , consistent with what has been reported to occur in vivo in crescent formation 1 .	HB-EGF activation of EGFR in cultured podocytes led to dedifferentiation and conversion to a proliferative and migratory phenotype, consistent with what has been reported to occur in vivo in crescent formation 1.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	0	1	3	4
HB-EGF further activates EGFR and hence triggers the metastatic and invasive behaviors of cancers .	HB-EGF further activates EGFR and hence triggers the metastatic and invasive behaviors of cancers.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	0	1	3	4
The presence of EGFR activators in the ovarian tumor microenvironment predicts that dual targeting of EGFR and EGFR activators such as HB-EGF or GPCRs would lead to more complete inhibition of EGFR signaling compared with monoclonal antibodies or TKIs alone .	The presence of EGFR activators in the ovarian tumor microenvironment predicts that dual targeting of EGFR and EGFR activators such as HB-EGF or GPCRs would lead to more complete inhibition of EGFR signaling compared with monoclonal antibodies or TKIs alone.	15	23	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	21	22	15	16
Collectively , these findings indicate that ACh induced cell migration is mediated by MMP7 mediated release of HBEGF , an ERBB ligand that activates ERBB1 and downstream ERK and PI3K signaling .	Collectively, these findings indicate that ACh induced cell migration is mediated by MMP7 mediated release of HBEGF, an ERBB ligand that activates ERBB1 and downstream ERK and PI3K signaling.	15	30	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	ERBB1	ERBB1	ERBB1	17	18	24	25
The released HB-EGF could activate EGFR and MAPK and ERK cascade ( XREF_BIBR ; XREF_BIBR ; XREF_BIBR .	The released HB-EGF could activate EGFR and MAPK and ERK cascade (XREF_BIBR; XREF_BIBR; XREF_BIBR.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	2	3	5	6
The protease inhibitors did not affect the activation of EGFR by HB-EGF but those inhibitors that target HB-EGF did inhibit the responses appropriately [ XREF_FIG ] .	The protease inhibitors did not affect the activation of EGFR by HB-EGF but those inhibitors that target HB-EGF did inhibit the responses appropriately [XREF_FIG].	5	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	11	12	9	10
The classical genomic actions of testosterone have been well characterized ; however , our results indicate that TBA may also initiate a quicker , nongenomic response that involves activation of G protein coupled receptors ( GPCR ) resulting in activation of matrix metalloproteinases 2 and 9 ( MMP2 and MMP9 ) that release membrane bound heparin binding epidermal growth factor like growth factor ( hbEGF ) , which then binds to and activates the epidermal growth factor receptor ( EGFR ) and/or erbB2 .	The classical genomic actions of testosterone have been well characterized; however, our results indicate that TBA may also initiate a quicker, nongenomic response that involves activation of G protein coupled receptors (GPCR) resulting in activation of matrix metalloproteinases 2 and 9 (MMP2 and MMP9) that release membrane bound heparin binding epidermal growth factor like growth factor (hbEGF), which then binds to and activates the epidermal growth factor receptor (EGFR) and/or erbB2.	62	78	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hbEGF	hbEGF	hbEGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	64	65	74	78
We also found greater HB-EGF expression in Fak deficient livers compared to WT livers after PHx , and inhibition of HB-EGF abrogates the enhanced EGFR and accelerated liver regeneration induced by Fak deletion .	We also found greater HB-EGF expression in Fak deficient livers compared to WT livers after PHx, and inhibition of HB-EGF abrogates the enhanced EGFR and accelerated liver regeneration induced by Fak deletion.	18	25	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	20	21	24	25
Moreover , EGFR and ERK1/2 phosphorylation was strongly stimulated by adding HB-EGF to cultures treated with FGF7 and MM , whereas HB-EGF did not activate the EGFR or ERK1/2 in the presence of Cetuximab ( XREF_FIG , only ERK1/2 phosphorylation of primary human keratinocytes is shown in XREF_SUPPLEMENTARY ) .	Moreover, EGFR and ERK1/2 phosphorylation was strongly stimulated by adding HB-EGF to cultures treated with FGF7 and MM, whereas HB-EGF did not activate the EGFR or ERK1/2 in the presence of Cetuximab (XREF_FIG, only ERK1/2 phosphorylation of primary human keratinocytes is shown in XREF_SUPPLEMENTARY).	21	28	activate	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	21	22	26	27
These results strongly suggest that E2 may stimulate BSC proliferation by binding to GPER-1 resulting in MMP2/9 catalyzed release of cell membrane bound hbEGF and subsequent activation of epidermal growth factor receptor by binding of released hbEGF .	These results strongly suggest that E2 may stimulate BSC proliferation by binding to GPER-1 resulting in MMP2/9 catalyzed release of cell membrane bound hbEGF and subsequent activation of epidermal growth factor receptor by binding of released hbEGF.	23	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	hbEGF	hbEGF	hbEGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	23	24	28	32
And soluble HB-EGF activates EGFR .	And soluble HB-EGF activates EGFR.	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	2	3	4	5
Collectively , our findings provide the first evidence that HB-EGF stimulates EGFR and ERK signaling to promote AQP3 expression in trophoblastic cells , and AQP3 plays a vital role in HB-EGF-induced embryo implantation .	Collectively, our findings provide the first evidence that HB-EGF stimulates EGFR and ERK signaling to promote AQP3 expression in trophoblastic cells, and AQP3 plays a vital role in HB-EGF-induced embryo implantation.	9	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	9	10	11	12
Therefore , in the ovarian cancer cells , the Hippo and YAP signaling pathway may interact with the ERBB signaling pathway , especially the HBEGF- and neuregulin activated EGFR and ERBB3 signaling pathways , to drive the initiation and progression of ovarian cancer .	Therefore, in the ovarian cancer cells, the Hippo and YAP signaling pathway may interact with the ERBB signaling pathway, especially the HBEGF- and neuregulin activated EGFR and ERBB3 signaling pathways, to drive the initiation and progression of ovarian cancer.	23	32	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HBEGF-	HBEGF-	HBEGF-	EGFR	EGFR	EGFR	24	25	28	29
Therefore , we next investigated whether EGFR activation by HB-EGF was involved in triggering the nuclear export of CFP-PLZF in HT1080 and HB-EGF cells .	Therefore, we next investigated whether EGFR activation by HB-EGF was involved in triggering the nuclear export of CFP-PLZF in HT1080 and HB-EGF cells.	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	9	10	6	7
CXCL12 induced mononuclear phagocytes to release HB-EGF , which activated HER1 and triggered anti-apoptotic and proliferative signals in cancer cells .	CXCL12 induced mononuclear phagocytes to release HB-EGF, which activated HER1 and triggered anti-apoptotic and proliferative signals in cancer cells.	5	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	HER1	HER1	HER1	6	7	10	11
These observations led us to fully characterize this HB-EGF triggered , EGFR : GPNMB dependent signaling pathway in TNBC .	These observations led us to fully characterize this HB-EGF triggered, EGFR : GPNMB dependent signaling pathway in TNBC.	6	13	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	8	9	11	12
The contribution of HB-EGF was also shown by our demonstration that blockade of HB-EGF with CRM197 [ XREF_BIBR ] , which prevents ectodomain shedding of proHB-EGF , significantly inhibited EGFR activation as well as E. coli invasion of HBMEC .	The contribution of HB-EGF was also shown by our demonstration that blockade of HB-EGF with CRM197 [XREF_BIBR], which prevents ectodomain shedding of proHB-EGF, significantly inhibited EGFR activation as well as E. coli invasion of HBMEC.	11	30	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	13	14	29	30
The extracellular HSPGs can bind and regulate the activity of HB-EGF that is a potent EGFR ligand , and EGFR activation by HB-EGF plays a role in the hypertrophic signaling in cardiomyocytes XREF_BIBR , XREF_BIBR .	The extracellular HSPGs can bind and regulate the activity of HB-EGF that is a potent EGFR ligand, and EGFR activation by HB-EGF plays a role in the hypertrophic signaling in cardiomyocytes XREF_BIBR, XREF_BIBR.	19	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	22	23	19	20
It is well known that HB-EGF activates EGFR signaling and promotes G1-phase progression in the cell cycle by regulating the expression of cyclin D via the Ras-MAPK signaling cascade .	It is well known that HB-EGF activates EGFR signaling and promotes G1-phase progression in the cell cycle by regulating the expression of cyclin D via the Ras-MAPK signaling cascade.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	5	6	7	8
The latter could enzymatically cleave membrane bound HB-EGF , to produce soluble HB-EGF that constitutively activated EGFR via increased EGFR phosphorylation and its downstream ERK signaling .	The latter could enzymatically cleave membrane bound HB-EGF, to produce soluble HB-EGF that constitutively activated EGFR via increased EGFR phosphorylation and its downstream ERK signaling.	10	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	12	13	16	17
For example , MMP-7 shedding of HB-EGF stimulates EGF receptor signaling and the proliferation of squamous cell carcinoma cells .	For example, MMP-7 shedding of HB-EGF stimulates EGF receptor signaling and the proliferation of squamous cell carcinoma cells.	3	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGF receptor	EGF receptor	EGF receptor	6	7	8	10
ET in turn induces metalloproteinase mediated cleavage of pro HBEGF and ectoshedding of HBEGF , which activates the EGFR and stimulates hBNP promoter activity .	ET in turn induces metalloproteinase mediated cleavage of pro HBEGF and ectoshedding of HBEGF, which activates the EGFR and stimulates hBNP promoter activity.	6	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	EGFR	EGFR	EGFR	13	14	18	19
Active HBEGF then activates EGFR , leading to IL-8 induction .	Active HBEGF then activates EGFR, leading to IL-8 induction.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	EGFR	EGFR	EGFR	1	2	4	5
Further , we provide evidence of a novel mechanism linking SAH to K V current suppression involving HB-EGF mediated activation of EGFR .	Further, we provide evidence of a novel mechanism linking SAH to K V current suppression involving HB-EGF mediated activation of EGFR.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	17	18	21	22
HB-EGF mediated activation of EGFR is an important driver of MDA-MB-231 cell invasiveness , particularly for brain metastases [ XREF_BIBR ] .	HB-EGF mediated activation of EGFR is an important driver of MDA-MB-231 cell invasiveness, particularly for brain metastases [XREF_BIBR].	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	0	1	4	5
The results presented herein are consistent with a pathogenic pathway of RPGN in which HBEGF can be induced in the kidney to elicit EGFR activation primarily in podocytes , which in turn promotes glomerular lesions .	The results presented herein are consistent with a pathogenic pathway of RPGN in which HBEGF can be induced in the kidney to elicit EGFR activation primarily in podocytes, which in turn promotes glomerular lesions.	14	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	EGFR	EGFR	EGFR	14	15	23	24
These results demonstrate that HBEGF mediated HER1 signaling through PIK3 is an important component of EVT invasion .	These results demonstrate that HBEGF mediated HER1 signaling through PIK3 is an important component of EVT invasion.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	HER1	HER1	HER1	4	5	6	7
HB-EGF induces EGFRvIII activation .	HB-EGF induces EGFRvIII activation.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFRvIII	EGFRvIII	EGFRvIII	0	1	2	3
Inhibition of ADAM-10 and -12 , and of HB-EGF blocked EGFR activation in response to CTF .	Inhibition of ADAM-10 and -12, and of HB-EGF blocked EGFR activation in response to CTF.	0	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	8	9	10	11
Specifically , we have previously demonstrated that inactivation of Lgr4 induced an eye open at birth phenotype by reducing epithelial cell proliferation and migration through HB-EGF mediated EGFR activation [ XREF_BIBR , XREF_BIBR ] .	Specifically, we have previously demonstrated that inactivation of Lgr4 induced an eye open at birth phenotype by reducing epithelial cell proliferation and migration through HB-EGF mediated EGFR activation [XREF_BIBR, XREF_BIBR].	25	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	25	26	27	28
Because Hb-egf is a potent mitogen for smooth muscle cells and is able to trigger smooth muscle cell migration toward endothelial cells in vitro , XREF_BIBR , XREF_BIBR we pursued the hypothesis that Hb-egf activates Egfr signaling inside perivascular cells and stimulates pericyte coverage of the tumor vasculature in vivo .	Because Hb-egf is a potent mitogen for smooth muscle cells and is able to trigger smooth muscle cell migration toward endothelial cells in vitro, XREF_BIBR, XREF_BIBR we pursued the hypothesis that Hb-egf activates Egfr signaling inside perivascular cells and stimulates pericyte coverage of the tumor vasculature in vivo.	33	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hb-egf	Hb-egf	Hb-egf	Egfr	Egfr	Egfr	33	34	35	36
Transactivation engages the release of the heparin binding-EGF ( HB-EGF ) that stimulates EGFR on the same cells in an autocrine mode of action .	Transactivation engages the release of the heparin binding-EGF (HB-EGF) that stimulates EGFR on the same cells in an autocrine mode of action.	3	14	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	9	10	13	14
In contrast , the EGFR activation caused by HB-EGF was inhibited by trastuzumab .	In contrast, the EGFR activation caused by HB-EGF was inhibited by trastuzumab.	4	9	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	8	9	4	5
This is suggested by several observations : ( 1 ) HB-EGF is expressed in human peritoneal mesothelial cells and peritoneal macrophages ;[ XREF_BIBR ] ( 2 ) activation of EGFR by HB-EGF induces proliferation of cultured human peritoneal mesothelial cells ( HPMC ) and conversion into a more fibroblastoid phenotype ;[ XREF_BIBR ] and ( 3 ) exposure of HPMC to EGF promoted their conversion into a fibroblastoid phenotype , resulting in increased extracellular matrix protein synthesis .	This is suggested by several observations : (1) HB-EGF is expressed in human peritoneal mesothelial cells and peritoneal macrophages;[XREF_BIBR] (2) activation of EGFR by HB-EGF induces proliferation of cultured human peritoneal mesothelial cells (HPMC) and conversion into a more fibroblastoid phenotype;[XREF_BIBR] and (3) exposure of HPMC to EGF promoted their conversion into a fibroblastoid phenotype, resulting in increased extracellular matrix protein synthesis.	27	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	31	32	29	30
In fact , in glioma cell lines , the inducible expression of EGFRvIII can enhance HB-EGF expression and can activate EGFR dependent pathways via a positive feedback autocrine loop [ XREF_BIBR ] .	In fact, in glioma cell lines, the inducible expression of EGFRvIII can enhance HB-EGF expression and can activate EGFR dependent pathways via a positive feedback autocrine loop [XREF_BIBR].	10	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	expression of EGFRvIII can enhance HB-EGF expression	hb-egf	EGFR	EGFR	egfr	15	16	20	21
Consistent with this view is the observation that activation of EGFR by expression of HB-EGF in transgenic mice leads to development of serrated lesions that resemble human hyperplastic polyps .	Consistent with this view is the observation that activation of EGFR by expression of HB-EGF in transgenic mice leads to development of serrated lesions that resemble human hyperplastic polyps.	8	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HB-EGF	expression of HB-EGF	hb-egf	EGFR	EGFR	egfr	14	15	10	11
XREF_BIBR Previous studies have reported that H. pylori activated EGFR is mediated by stimulation of HB-EGF release from gastric epithelial cells , XREF_BIBR , XREF_BIBR since ADAM-17 can regulate HB-EGF cleavage and ligand binding , XREF_BIBR , XREF_BIBR we determined whether ADAM-17 is involved in H. pylori regulated EGFR transactivation and apoptosis .	XREF_BIBR Previous studies have reported that H. pylori activated EGFR is mediated by stimulation of HB-EGF release from gastric epithelial cells, XREF_BIBR, XREF_BIBR since ADAM-17 can regulate HB-EGF cleavage and ligand binding, XREF_BIBR, XREF_BIBR we determined whether ADAM-17 is involved in H. pylori regulated EGFR transactivation and apoptosis.	9	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	15	16	9	10
The cleaved substrate can bind to its receptor and then the activated receptor initiates downstream signaling events : ADAM-17 can cleave HB-EGF which , in turn , activates EGFR and initiates cell proliferation ( XREF_FIG ) .	The cleaved substrate can bind to its receptor and then the activated receptor initiates downstream signaling events : ADAM-17 can cleave HB-EGF which, in turn, activates EGFR and initiates cell proliferation (XREF_FIG).	20	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	21	22	28	29
Therefore , we examined whether HB-EGF shedding was involved in E2- or S1P induced EGFR transactivation .	Therefore, we examined whether HB-EGF shedding was involved in E2- or S1P induced EGFR transactivation.	5	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	5	6	14	15
In this cell , EGFR autocrine regulation by HB-EGF would be enhanced by the release of HB-EGF under the influence of NTS .	In this cell, EGFR autocrine regulation by HB-EGF would be enhanced by the release of HB-EGF under the influence of NTS.	4	17	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	16	17	4	5
For example , transactivation of EGFR by released HB-EGF through LPA receptor activation by LPA in Cos-7 cells induces the activation of major EGFR signaling pathways including ERK , PLC-gamma1 and PI3K-Akt pathways , which is similar to the direct activation of EGFR by HB-EGF [ XREF_BIBR ] .	For example, transactivation of EGFR by released HB-EGF through LPA receptor activation by LPA in Cos-7 cells induces the activation of major EGFR signaling pathways including ERK, PLC-gamma1 and PI3K-Akt pathways, which is similar to the direct activation of EGFR by HB-EGF [XREF_BIBR].	40	46	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	44	45	42	43
Recently , many investigators have reported that GPCRs such as GPR30 , enhance the MMPs mediated HB-EGF protein release , and initiate the EGFR signaling .	Recently, many investigators have reported that GPCRs such as GPR30, enhance the MMPs mediated HB-EGF protein release, and initiate the EGFR signaling.	14	24	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	MMPs mediated HB-EGF	hb-egf	EGFR	EGFR	egfr	16	17	23	24
ErbB1 and ErbB2 receptors were activated by HB-EGF .	ErbB1 and ErbB2 receptors were activated by HB-EGF.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	ErbB1	ErbB1	ErbB1	7	8	0	1
We have previously reported that ectodomain shedding of proHB-EGF evokes two independent signaling pathways : 1 ) EGFR signaling induced by soluble forms of HB-EGF and 2 ) signaling driven by a remnant peptide composed of the transmembrane and cytoplasmic fragment .	We have previously reported that ectodomain shedding of proHB-EGF evokes two independent signaling pathways : 1) EGFR signaling induced by soluble forms of HB-EGF and 2) signaling driven by a remnant peptide composed of the transmembrane and cytoplasmic fragment.	17	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	24	25	17	18
Here , we show that HB-EGF induced EGF receptor ( EGFR ) activation by Y1068 phosphorylation , Mapk and Erk pathway activation , and led to an increase in cell proliferation , more prominent in Bioactive3D than in 2D cultures .	Here, we show that HB-EGF induced EGF receptor (EGFR) activation by Y1068 phosphorylation, Mapk and Erk pathway activation, and led to an increase in cell proliferation, more prominent in Bioactive3D than in 2D cultures.	5	24	induced	Positive_early_activation	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGF receptor	EGF receptor	EGF receptor	5	6	7	9
These results strongly suggest that EGFR activation by HB-EGF is critical for disease development in HBUS mice , but they do not rule out that activation of other tyrosine kinase receptors may also be important for pathogenesis , because gefitinib may also block other tyrosine kinase receptors XREF_BIBR , XREF_BIBR .	These results strongly suggest that EGFR activation by HB-EGF is critical for disease development in HBUS mice, but they do not rule out that activation of other tyrosine kinase receptors may also be important for pathogenesis, because gefitinib may also block other tyrosine kinase receptors XREF_BIBR, XREF_BIBR.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	8	9	5	6
In addition , AKT phosphorylation in response to stimulation with HB-EGF was attenuated by transfection with GPC1 siRNA compared with NC siRNA in transfected TE8 cells , suggesting that GPC1 regulates EGFR activity and downstream AKT signalling induced by HB-EGF .	In addition, AKT phosphorylation in response to stimulation with HB-EGF was attenuated by transfection with GPC1 siRNA compared with NC siRNA in transfected TE8 cells, suggesting that GPC1 regulates EGFR activity and downstream AKT signalling induced by HB-EGF.	31	40	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	39	40	31	32
It is considered that Hb-EGF can activate EGFR and induce NSC proliferation via the EGFR signaling pathway .	It is considered that Hb-EGF can activate EGFR and induce NSC proliferation via the EGFR signaling pathway.	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hb-EGF	Hb-EGF	Hb-EGF	EGFR	EGFR	EGFR	4	5	7	8
Overall , these findings , together with c-Src-dependent EGFR transactivation , suggest that NAGLU deficient cardiomyoblasts develop a hypertrophic phenotype through a coordinated intracellular and extracellular EGFR activation induced by c-Src and HB-EGF , respectively .	Overall, these findings, together with c-Src-dependent EGFR transactivation, suggest that NAGLU deficient cardiomyoblasts develop a hypertrophic phenotype through a coordinated intracellular and extracellular EGFR activation induced by c-Src and HB-EGF, respectively.	16	33	induced	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	32	33	26	27
The metalloprotease domain of ADAM9 can cleave the heparin binding epidermal growth factor like growth factor ( HB-EGF ) precursor to yield soluble HB-EGF 29 , thereby activating epidermal growth factor receptor ( EGFR ) signal transduction to promote tumor growth and angiogenesis 30 .	The metalloprotease domain of ADAM9 can cleave the heparin binding epidermal growth factor like growth factor (HB-EGF) precursor to yield soluble HB-EGF 29, thereby activating epidermal growth factor receptor (EGFR) signal transduction to promote tumor growth and angiogenesis 30.	21	32	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	23	24	28	32
From these results , we concluded that Galphaq mediates UV induced COX-2 expression through activation of EGFR by HB-EGF , of which ectodomain shedding was stimulated through sequential activation of PLC , PKCdelta and MMP-2 in HaCaT cells .	From these results, we concluded that Galphaq mediates UV induced COX-2 expression through activation of EGFR by HB-EGF, of which ectodomain shedding was stimulated through sequential activation of PLC, PKCdelta and MMP-2 in HaCaT cells.	10	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	18	19	16	17
Because mononuclear phagocytes express both CXCL12 GPCRs and HB-EGF , we argued that the recruitment of mononuclear phagocytes to a site of metastasis such as liver through CXCL12 should induce a release of HB-EGF , which is expected to activate HER1 and favour tumour progression .	Because mononuclear phagocytes express both CXCL12 GPCRs and HB-EGF, we argued that the recruitment of mononuclear phagocytes to a site of metastasis such as liver through CXCL12 should induce a release of HB-EGF, which is expected to activate HER1 and favour tumour progression.	31	44	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	HER1	HER1	HER1	33	34	40	41
TGF-beta1-induced early Smad3 phosphorylation is independent of transient EGFR transactivation and ERK1/2 activation initiated by HB-EGF release , whereas Src mediated chronic EGFR transactivation and ERK1/2 activation participate in Smad3 activation in a relatively modest and delayed manner .	TGF-beta1-induced early Smad3 phosphorylation is independent of transient EGFR transactivation and ERK1/2 activation initiated by HB-EGF release, whereas Src mediated chronic EGFR transactivation and ERK1/2 activation participate in Smad3 activation in a relatively modest and delayed manner.	8	16	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	15	16	8	9
HB-EGF is released into the extracellular space and strongly activates EGF receptor .	HB-EGF is released into the extracellular space and strongly activates EGF receptor.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGF receptor	EGF receptor	EGF receptor	0	1	10	12
HBEGF expression increases EGFR activation but not proliferation .	HBEGF expression increases EGFR activation but not proliferation.	0	4	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HBEGF	HBEGF expression	hbegf	EGFR	EGFR	egfr	0	1	3	4
Lgr4 activates multiple signaling pathways , including G alphas / cAMP/PKA/CREB XREF_BIBR - XREF_BIBR , XREF_BIBR , HB-EGF mediated EGFR transactivation XREF_BIBR , XREF_BIBR , and potentiation of Wnt signaling through binding R-spondin XREF_BIBR , XREF_BIBR .	Lgr4 activates multiple signaling pathways, including G alphas / cAMP/PKA/CREB XREF_BIBR - XREF_BIBR, XREF_BIBR, HB-EGF mediated EGFR transactivation XREF_BIBR, XREF_BIBR, and potentiation of Wnt signaling through binding R-spondin XREF_BIBR, XREF_BIBR.	15	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	17	18	19	20
HB-EGF is shed and activates EGFR on HSC3 cells .	HB-EGF is shed and activates EGFR on HSC3 cells.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	0	1	5	6
There are two input nodes , the MET receptor , stimulated through HGF , as well as EGFR , stimulated by HBEGF .	There are two input nodes, the MET receptor, stimulated through HGF, as well as EGFR, stimulated by HBEGF.	1	22	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	EGFR	EGFR	EGFR	21	22	17	18
Mesenchymal Hb-egf mediates Egfr activation and functions in tumor associated pericytes .	Mesenchymal Hb-egf mediates Egfr activation and functions in tumor associated pericytes.	0	4	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hb-egf	Hb-egf	Hb-egf	Egfr	Egfr	Egfr	1	2	3	4
HBEGF has been shown to mediate the subsequent autocrine activation of EGFR ; ( iii ) The activation of cJUN and cFOS nodes leads to an initiation of the AP-1 system , which in turn stimulates the uPA and uPAR signalling pathway by activation of the uPAR , triggering the formation from plasminogen activator to plasmin .	HBEGF has been shown to mediate the subsequent autocrine activation of EGFR; (iii) The activation of cJUN and cFOS nodes leads to an initiation of the AP-1 system, which in turn stimulates the uPA and uPAR signalling pathway by activation of the uPAR, triggering the formation from plasminogen activator to plasmin.	0	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	EGFR	EGFR	EGFR	0	1	11	12
Hb-egf activates Egfr in pericytes and enhances pericytes coverage of the tumor endothelium .	Hb-egf activates Egfr in pericytes and enhances pericytes coverage of the tumor endothelium.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hb-egf	Hb-egf	Hb-egf	Egfr	Egfr	Egfr	0	1	2	3
XREF_BIBR , XREF_BIBR , XREF_BIBR We have observed that in astrocytes in vitro , HBEGF activates not only Egfr but also Axl , a member of the TAM family of RTKs .	XREF_BIBR, XREF_BIBR, XREF_BIBR We have observed that in astrocytes in vitro, HBEGF activates not only Egfr but also Axl, a member of the TAM family of RTKs.	14	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	Egfr	Egfr	Egfr	14	15	18	19
Hence , HB-EGF elevating EGFR signaling and antioxidants such as NAC reducing oxidative stress may have synergistic effects on epithelial cells and therefore may prevent or reverse epithelial defects , including compromised barrier function and delayed wound healing , in diabetic corneas .	Hence, HB-EGF elevating EGFR signaling and antioxidants such as NAC reducing oxidative stress may have synergistic effects on epithelial cells and therefore may prevent or reverse epithelial defects, including compromised barrier function and delayed wound healing, in diabetic corneas.	2	24	elevating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	2	3	4	5
Since ACh/M1 signaling transactivates EGFR by MMP mediated release of HBEGF in prostate epithelium , we predicted that 1 ) HBEGF would increase K5+ cell proliferation , and 2 ) an EGFR antagonist ( PD168393 referred to here as PD ) would inhibit CCh induced K5+ cell proliferation .	Since ACh/M1 signaling transactivates EGFR by MMP mediated release of HBEGF in prostate epithelium, we predicted that 1) HBEGF would increase K5+ cell proliferation, and 2) an EGFR antagonist (PD168393 referred to here as PD) would inhibit CCh induced K5+ cell proliferation.	20	32	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	EGFR	EGFR	EGFR	20	21	31	32
These findings were consistent with the idea that upregulation of HB-EGF mRNA by fulvestrant resulted in stimulation of EGFR family members and decreased response to fulvestrant .	These findings were consistent with the idea that upregulation of HB-EGF mRNA by fulvestrant resulted in stimulation of EGFR family members and decreased response to fulvestrant.	10	20	resulted in stimulation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	10	11	18	19
We show that increased EGFRwt or HB-EGF promotes EGFRvIII dimerization .	We show that increased EGFRwt or HB-EGF promotes EGFRvIII dimerization.	4	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFRvIII	EGFRvIII	EGFRvIII	6	7	8	9
While both proHB-EGF and soluble HB-EGF can stimulate the EGFR [ XREF_BIBR ] , only stimulation of kidney epithelial cells with the membrane anchored proHB-EGF protects cells from anoikis and increases cell survival [ XREF_BIBR ] .	While both proHB-EGF and soluble HB-EGF can stimulate the EGFR [XREF_BIBR], only stimulation of kidney epithelial cells with the membrane anchored proHB-EGF protects cells from anoikis and increases cell survival [XREF_BIBR].	2	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	5	6	9	10
Release of HB-EGF allows it to activate the EGFR signaling pathway , resulting in induction of Erk1/2 phosphorylation with consequent stimulation of cell growth [ XREF_BIBR ] .	Release of HB-EGF allows it to activate the EGFR signaling pathway, resulting in induction of Erk1/2 phosphorylation with consequent stimulation of cell growth [XREF_BIBR].	0	10	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	2	3	8	9
This suggests that the cleavage of HB-EGF and HB-EGF-mediated activation of EGFR in response to gonococci is a tightly controlled process .	This suggests that the cleavage of HB-EGF and HB-EGF-mediated activation of EGFR in response to gonococci is a tightly controlled process.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	6	7	11	12
HB-EGF stimulated EGFR , MEK1/2 , Erk1/2 , Akt , and PLCgamma ( XREF_FIG ) .	HB-EGF stimulated EGFR, MEK1/2, Erk1/2, Akt, and PLCgamma (XREF_FIG).	0	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	0	1	2	3
Hb-egf activates Egfr in pericytes of the tumor vasculature .	Hb-egf activates Egfr in pericytes of the tumor vasculature.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hb-egf	Hb-egf	Hb-egf	Egfr	Egfr	Egfr	0	1	2	3
Moreover , the ability of HB-EGF to largely rescue the decreased tube formation of ADAM17 deficient endothelial cells suggests that the underlying mechanism involves EGFR signaling stimulated by HB-EGF or related EGFR-ligands released by ADAM17 from endothelial cells .	Moreover, the ability of HB-EGF to largely rescue the decreased tube formation of ADAM17 deficient endothelial cells suggests that the underlying mechanism involves EGFR signaling stimulated by HB-EGF or related EGFR-ligands released by ADAM17 from endothelial cells.	24	31	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	28	29	24	25
This is in agreement with findings in other epithelial systems suggesting that activation of EGFR by HB-EGF is important for this process .	This is in agreement with findings in other epithelial systems suggesting that activation of EGFR by HB-EGF is important for this process.	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	16	17	14	15
In conclusion , the present study showed that macrophage infiltration predicted poor prognosis in MLS , and a possible underlying mechanism is that HB-EGF secretion by macrophages enhanced MLS cell motility and invasion by activating EGFR .	In conclusion, the present study showed that macrophage infiltration predicted poor prognosis in MLS, and a possible underlying mechanism is that HB-EGF secretion by macrophages enhanced MLS cell motility and invasion by activating EGFR.	23	36	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	23	24	35	36
In this model , there is a sequence of three transmembrane signaling events : G protein coupled receptor activation followed by matrix metalloproteinase ( MMP ) activation , and subsequent activation of EGFR by HB-EGF , or other latent ligands of EGFR .	In this model, there is a sequence of three transmembrane signaling events : G protein coupled receptor activation followed by matrix metalloproteinase (MMP) activation, and subsequent activation of EGFR by HB-EGF, or other latent ligands of EGFR.	19	35	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	34	35	32	33
We hypothesized that TBA activates GPCR , resulting in activation of MMP2/9 that releases hbEGF , which activates the EGFR and/or erbB2 .	We hypothesized that TBA activates GPCR, resulting in activation of MMP2/9 that releases hbEGF, which activates the EGFR and/or erbB2.	13	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hbEGF	hbEGF	hbEGF	EGFR	EGFR	EGFR	14	15	19	20
By binding and activating EGFR , HB-EGF in turn triggers EGFR downstream signaling pathways including MAPKs , which then induce a rapid and sustained induction of HB-EGF mRNA expression and secretion of HB-EGF .	By binding and activating EGFR, HB-EGF in turn triggers EGFR downstream signaling pathways including MAPKs, which then induce a rapid and sustained induction of HB-EGF mRNA expression and secretion of HB-EGF.	6	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	6	7	10	11
Release of HB-EGF can stimulate the EGFR signaling pathway , leading to induction of Erk1/2 phosphorylation [ XREF_BIBR ] .	Release of HB-EGF can stimulate the EGFR signaling pathway, leading to induction of Erk1/2 phosphorylation [XREF_BIBR].	0	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	2	3	6	7
Importantly , HTCs did not display increased EGFR signaling ( XREF_FIG ) , which can be activated by DTR shedding and impairs terminal chondrocyte differentiation and cartilage remodeling .	Importantly, HTCs did not display increased EGFR signaling (XREF_FIG), which can be activated by DTR shedding and impairs terminal chondrocyte differentiation and cartilage remodeling.	7	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DTR	DTR	DTR	EGFR	EGFR	EGFR	18	19	7	8
Our group has previously reported that LGR4 regulates the proliferation and migration of keratinocyte through HB-EGF mediated EGFR transactivation [ XREF_BIBR ] .	Our group has previously reported that LGR4 regulates the proliferation and migration of keratinocyte through HB-EGF mediated EGFR transactivation [XREF_BIBR].	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	15	16	17	18
We conclude that Gbetagamma mediates UVB induced human keratinocyte apoptosis by augmenting the ectodomain shedding of HB-EGF , which sequentially activates EGFR and p38 .	We conclude that Gbetagamma mediates UVB induced human keratinocyte apoptosis by augmenting the ectodomain shedding of HB-EGF, which sequentially activates EGFR and p38.	14	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	16	17	21	22
If stromal cells are treated with 8-Br-cAMP , which is known to artificially induce decidualization , the soluble form of HBEGF is upregulated , as are its receptors , HER1 and HER4 .	If stromal cells are treated with 8-Br-cAMP, which is known to artificially induce decidualization, the soluble form of HBEGF is upregulated, as are its receptors, HER1 and HER4.	18	30	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HBEGF	HBEGF	HBEGF	HER1	HER1	HER1	20	21	29	30
Even though serial initial events including GPCR activation , cleavage of pro-HB-EGF , and HB-EGF release have not been determined in the present study , HB-EGF may mediate transactivation of EGFR in H. pylori infected gastric epithelial cells .	Even though serial initial events including GPCR activation, cleavage of pro-HB-EGF, and HB-EGF release have not been determined in the present study, HB-EGF may mediate transactivation of EGFR in H. pylori infected gastric epithelial cells.	25	31	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	25	26	30	31
The possibility that the observed ERK phosphorylation is downstream of EGFR activation caused by HB-EGF release was ruled out , as knockdown of ADAM17 , leading to a complete block of shedding , had no effect on PMA induced ERK activation .	The possibility that the observed ERK phosphorylation is downstream of EGFR activation caused by HB-EGF release was ruled out, as knockdown of ADAM17, leading to a complete block of shedding, had no effect on PMA induced ERK activation.	10	15	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	14	15	10	11
Furthermore , increased HB-EGF levels lead to substantially increased dimerization of EGFRvIII compared to cells with silenced HB-EGF ( XREF_FIG ) .	Furthermore, increased HB-EGF levels lead to substantially increased dimerization of EGFRvIII compared to cells with silenced HB-EGF (XREF_FIG).	3	12	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF levels	hb-egf	EGFRvIII	EGFRvIII	egfrviii	3	4	11	12
It seemed likely that the function of LIV-1 was to stimulate the expression of MMP2 , MMP9 and HB-EGF proteins , which in turn activated EGFR and downstream ERK signaling , leading to EMT that facilitated local tumor growth and its distant metastases to bone and soft tissues ( XREF_FIG ) .	It seemed likely that the function of LIV-1 was to stimulate the expression of MMP2, MMP9 and HB-EGF proteins, which in turn activated EGFR and downstream ERK signaling, leading to EMT that facilitated local tumor growth and its distant metastases to bone and soft tissues (XREF_FIG).	7	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	LIV-1 was to stimulate the expression of MMP2, MMP9 and HB-EGF	hb-egf	EGFR	EGFR	egfr	18	19	25	26
Additionally , HB-EGF activates ErbB-4 ( HER4 ) and N-arginine dibasic convertase ( NRDc ) , the latter representing a specific receptor for HB-EGF only .	Additionally, HB-EGF activates ErbB-4 (HER4) and N-arginine dibasic convertase (NRDc), the latter representing a specific receptor for HB-EGF only.	2	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	ErbB-4	ErbB-4	ErbB-4	2	3	4	5
ErbB4 was activated by both HRG-beta1 and HB-EGF stimulation ; however , compared with HRG-beta1 , HB-EGF induced phosphorylation of the 80-kDa cytoplasmic cleavage fragment of the JM-a and CYT -2 isoform .	ErbB4 was activated by both HRG-beta1 and HB-EGF stimulation; however, compared with HRG-beta1, HB-EGF induced phosphorylation of the 80-kDa cytoplasmic cleavage fragment of the JM-a and CYT -2 isoform.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	ErbB4	ErbB4	ErbB4	7	8	0	1
In addition , HB-EGF activates ErbB-4 as well as the HB-EGF specific receptor nardilysin , leading to increased cell migration .	In addition, HB-EGF activates ErbB-4 as well as the HB-EGF specific receptor nardilysin, leading to increased cell migration.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	ErbB-4	ErbB-4	ErbB-4	3	4	5	6
The EGFR activation was the highest after stimulation with HB-EGF , and only HB-EGF could activate HER-4 with lesser degrees in 1Cc8 when compared to SCC1 , consistent with the lower expression of the receptors in 1Cc8 .	The EGFR activation was the highest after stimulation with HB-EGF, and only HB-EGF could activate HER-4 with lesser degrees in 1Cc8 when compared to SCC1, consistent with the lower expression of the receptors in 1Cc8.	12	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	HER-4	HER-4	HER-4	13	14	16	17
In fact , AG1478 in the micromolar range can also inhibit ErbB4 activation in tumoral cell lines30 or cardiac cells.12 , 23 Normal ErbB4 activation by HB-EGF is essential for the adult heart .	In fact, AG1478 in the micromolar range can also inhibit ErbB4 activation in tumoral cell lines30 or cardiac cells.12, 23 Normal ErbB4 activation by HB-EGF is essential for the adult heart.	23	27	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	ErbB4	ErbB4	ErbB4	26	27	23	24
Besides binding , HB-EGF activates HER4 .	Besides binding, HB-EGF activates HER4.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	HER4	HER4	HER4	3	4	5	6
In addition , HB-EGF activates ErbB-4 ( HER4 ) as well as the HB-EGF-specific non tyrosine kinase receptor N-arginine dibasic convertase ( NRDc ) [ XREF_BIBR , XREF_BIBR ] .	In addition, HB-EGF activates ErbB-4 (HER4) as well as the HB-EGF-specific non tyrosine kinase receptor N-arginine dibasic convertase (NRDc) [XREF_BIBR, XREF_BIBR].	3	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	ErbB-4	ErbB-4	ErbB-4	3	4	5	6
In addition , HB-EGF activates ErbB-4 ( HER4 ) as well as the HB-EGF-specific non tyrosine kinase receptor N-arginine dibasic convertase ( NRDc ) .	In addition, HB-EGF activates ErbB-4 (HER4) as well as the HB-EGF-specific non tyrosine kinase receptor N-arginine dibasic convertase (NRDc).	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	ErbB-4	ErbB-4	ErbB-4	3	4	5	6
In in vitro 3D collagen gel culture , HB-EGF induced tubulogenesis only in MDCK II cells expressing the ErbB4 JM-a and CYT -2 isoform , an ErbB4 isoform with the ability to translocate to the nucleus after ADAM dependent cleavage .	In in vitro 3D collagen gel culture, HB-EGF induced tubulogenesis only in MDCK II cells expressing the ErbB4 JM-a and CYT -2 isoform, an ErbB4 isoform with the ability to translocate to the nucleus after ADAM dependent cleavage.	8	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	ErbB4	ErbB4	ErbB4	8	9	26	27
This demonstrates that in hypoxic cardiomyocytes treated with the HER2 inhibitor trastuzumab HB-EGF activates HER2 and HER4 , and both receptors hereby become resistant to trastuzumab inhibition .	This demonstrates that in hypoxic cardiomyocytes treated with the HER2 inhibitor trastuzumab HB-EGF activates HER2 and HER4, and both receptors hereby become resistant to trastuzumab inhibition.	11	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	HER4	HER4	HER4	12	13	16	17
We report the effects of uroguanylin mediated activation of the GC-C and cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress induced visceral hypersensitivity .	We report the effects of uroguanylin mediated activation of the GC-C and cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress induced visceral hypersensitivity.	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GC-C	GC-C	GC-C	5	6	10	11
In both tissues , GC-C activation by UGN peaks at pH 5.0 and is markedly lower at pH 8.0 [ XREF_BIBR ] .	In both tissues, GC-C activation by UGN peaks at pH 5.0 and is markedly lower at pH 8.0 [XREF_BIBR].	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	UGN	UGN	UGN	GC-C	GC-C	GC-C	7	8	4	5
GC-A is stimulated by atrial and B-type natriuretic peptide ( ANP and BNP ) , whereas GC-B is activated by C-type natriuretic peptide ( CNP ) , and GC-C is initiated by guanylin and uroguanylin .	GC-A is stimulated by atrial and B-type natriuretic peptide (ANP and BNP), whereas GC-B is activated by C-type natriuretic peptide (CNP), and GC-C is initiated by guanylin and uroguanylin.	28	35	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GC-C	GC-C	GC-C	34	35	28	29
Gn and Ugn , however , are less potent activators of GC-C than is ST and their presence does not result in secretory diarrhea .	Gn and Ugn, however, are less potent activators of GC-C than is ST and their presence does not result in secretory diarrhea.	0	12	are less potent activators	Positive_activation_copula_1	Positive_activation	Positive_activation	Ugn	Ugn	Ugn	GC-C	GC-C	GC-C	2	3	11	12
Stool water content was identical in (-) and ( + ) mice , confirming that central expression of transgenic uroguanylin did not induce intestinal GUCY2C fluid secretion ( XREF_SUPPLEMENTARY ) .	Stool water content was identical in (-) and (+) mice, confirming that central expression of transgenic uroguanylin did not induce intestinal GUCY2C fluid secretion (XREF_SUPPLEMENTARY).	16	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uroguanylin	expression of transgenic uroguanylin	uroguanylin	GUCY2C	GUCY2C	gucy2c	19	20	24	25
Plecanatide is the first uroguanylin analog that stimulates GC-C receptors on gastrointestinal mucosa with pH sensitive receptor binding .	Plecanatide is the first uroguanylin analog that stimulates GC-C receptors on gastrointestinal mucosa with pH sensitive receptor binding.	4	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GC-C	GC-C	GC-C	4	5	8	9
The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin , inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways .	The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin, inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways.	11	17	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GUCY2C	GUCY2C	GUCY2C	13	14	16	17
Additionally , uroguanylin acts as an endocrine hormone , secreted into the systemic circulation postprandially to activate hypothalamic GUCY2C and induce satiety [ XREF_BIBR - XREF_BIBR ] .	Additionally, uroguanylin acts as an endocrine hormone, secreted into the systemic circulation postprandially to activate hypothalamic GUCY2C and induce satiety [XREF_BIBR - XREF_BIBR].	2	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GUCY2C	GUCY2C	GUCY2C	2	3	18	19
The persistent natriuresis of GC-C knockout mice treated with UGN [ XREF_BIBR ] , and the lack of GC-C mRNA in the CCD [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] suggest GC-C and cGMP independent signaling by UGN in this nephron segment .	The persistent natriuresis of GC-C knockout mice treated with UGN [XREF_BIBR], and the lack of GC-C mRNA in the CCD [XREF_BIBR, XREF_BIBR, XREF_BIBR] suggest GC-C and cGMP independent signaling by UGN in this nephron segment.	4	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	UGN	UGN	UGN	GC-C	GC-C	GC-C	9	10	4	5
GUCY2C is activated by two known endogenous peptide hormones , guanylin and uroguanylin , which also are produced in the intestinal epithelium and activate GUCY2C in a paracrine fashion .	GUCY2C is activated by two known endogenous peptide hormones, guanylin and uroguanylin, which also are produced in the intestinal epithelium and activate GUCY2C in a paracrine fashion.	8	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GUCY2C	GUCY2C	GUCY2C	12	13	24	25
Proximal tubular GC-C activation by UGN at low pH produces natriuresis and diuresis through inhibition of both basolateral Na + -K + -ATPase and luminal Na + / H + exchange and K + channels , whereas at high pH , UGN produces kaliuresis , at least in part , through cGMP independent , G-protein-dependent K + channel stimulation [ XREF_BIBR , XREF_BIBR ] .	Proximal tubular GC-C activation by UGN at low pH produces natriuresis and diuresis through inhibition of both basolateral Na + -K + -ATPase and luminal Na + / H + exchange and K + channels, whereas at high pH, UGN produces kaliuresis, at least in part, through cGMP independent, G-protein-dependent K + channel stimulation [XREF_BIBR, XREF_BIBR].	2	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	UGN	UGN	UGN	GC-C	GC-C	GC-C	5	6	2	3
GC-C can be activated by bacterial heat-stable enterotoxins , guanylin , and uroguanylin .	GC-C can be activated by bacterial heat-stable enterotoxins, guanylin, and uroguanylin.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GC-C	GC-C	GC-C	12	13	0	1
7 Continuous supraphysiological concentrations of uroguanylin ( ~ 10 -4 -10 -5 M ) , 44 in vast excess of the Kd of hormone-receptor binding ( ~ 10 -9 M ) , likely induced long-term desensitization of GUCY2C and its efferent regulation of feeding .	7 Continuous supraphysiological concentrations of uroguanylin (~ 10 -4 -10 -5 M), 44 in vast excess of the Kd of hormone-receptor binding (~ 10 -9 M), likely induced long-term desensitization of GUCY2C and its efferent regulation of feeding.	3	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GUCY2C	GUCY2C	GUCY2C	5	6	37	38
Uroguanylin produced in the colon of Gn -/- mice may activate GC-C at a minimal level and drive moderate resistance to DSS colitis .	Uroguanylin produced in the colon of Gn -/- mice may activate GC-C at a minimal level and drive moderate resistance to DSS colitis.	0	12	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Uroguanylin	Uroguanylin	Uroguanylin	GC-C	GC-C	GC-C	0	1	11	12
The high incidence of diarrhea observed in clinical evaluations with linaclotide [ XREF_BIBR ] may possibly be due to uncontrolled activation of GC-C receptors in the GI tract due to the lack of luminal pH-dependence of linaclotide in activation of GC-C receptors , compared with the pH-dependence of GC-C activation by its physiological activator uroguanylin [ XREF_BIBR ] .	The high incidence of diarrhea observed in clinical evaluations with linaclotide [XREF_BIBR] may possibly be due to uncontrolled activation of GC-C receptors in the GI tract due to the lack of luminal pH-dependence of linaclotide in activation of GC-C receptors, compared with the pH-dependence of GC-C activation by its physiological activator uroguanylin [XREF_BIBR].	48	56	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GC-C	GC-C	GC-C	54	55	48	49
87 GUCY2C is activated by the endogenous hormones guanylin ( GUCA2A ) and uroguanylin ( GUCA2B ) in a paracrine fashion in the intestine .	87 GUCY2C is activated by the endogenous hormones guanylin (GUCA2A) and uroguanylin (GUCA2B) in a paracrine fashion in the intestine.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GUCY2C	GUCY2C	GUCY2C	13	14	1	2
In response to oral salt load , GN and UGN are secreted into the intestinal lumen and into the circulation and activate the enterocyte luminal membrane receptor GC-C .	In response to oral salt load, GN and UGN are secreted into the intestinal lumen and into the circulation and activate the enterocyte luminal membrane receptor GC-C.	7	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UGN	UGN	UGN	GC-C	GC-C	GC-C	9	10	27	28
41 Supraphysiological concentrations of uroguanylin could induce novel GUCY2C independent effects , either through additional guanylyl cyclases expressed in the brain 45 or through receptors other than guanylyl cyclases .	41 Supraphysiological concentrations of uroguanylin could induce novel GUCY2C independent effects, either through additional guanylyl cyclases expressed in the brain 45 or through receptors other than guanylyl cyclases.	2	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GUCY2C	GUCY2C	GUCY2C	4	5	8	9
Previous reports indicated that T84 cells express GC-C which can be activated by the natural hormones guanylin and uroguanylin and the heat stable enterotoxin STa to increase production of cGMP ( Forte etal .	Previous reports indicated that T84 cells express GC-C which can be activated by the natural hormones guanylin and uroguanylin and the heat stable enterotoxin STa to increase production of cGMP (Forte etal.	6	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GC-C	GC-C	GC-C	18	19	7	8
GC-C can be activated by bacterial enterotoxins , guanylin , and uroguanylin .	GC-C can be activated by bacterial enterotoxins, guanylin, and uroguanylin.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GC-C	GC-C	GC-C	11	12	0	1
Uroguanylin , a member of the guanylin peptide family , is an endogenous activator of intestinal guanylate cyclase ( GC-C ) .	Uroguanylin, a member of the guanylin peptide family, is an endogenous activator of intestinal guanylate cyclase (GC-C).	0	18	is an endogenous activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Uroguanylin	Uroguanylin	Uroguanylin	intestinal guanylate cyclase	intestinal guanylate cyclase	intestinal guanylate cyclase	0	1	15	18
The reduced afferent drive effected by GC-C activators like uroguanylin is evident from our current study .	The reduced afferent drive effected by GC-C activators like uroguanylin is evident from our current study.	6	10	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GC-C	GC-C	GC-C	9	10	6	7
GC-C receptor activation by its endogenous paracrine hormones uroguanylin and guanylin , and the resulting intracellular production of its downstream effector cyclic GMP , occurs in a pH dependent manner and modulates key physiological functions .	GC-C receptor activation by its endogenous paracrine hormones uroguanylin and guanylin, and the resulting intracellular production of its downstream effector cyclic GMP, occurs in a pH dependent manner and modulates key physiological functions.	0	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GC-C	GC-C	GC-C	8	9	0	1
Linaclotide is a 14 amino-acid peptide minimally absorbed and that mimics the action of the endogenous guanylin and uroguanylin activating the GC-C receptor ; it is minimally absorbed and with a low bioavailability .	Linaclotide is a 14 amino-acid peptide minimally absorbed and that mimics the action of the endogenous guanylin and uroguanylin activating the GC-C receptor; it is minimally absorbed and with a low bioavailability.	12	22	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GC-C	GC-C	GC-C	18	19	21	22
GUCY2C is activated by the endogenous hormones guanylin and uroguanylin , which are also produced in the intestinal epithelium and activate GUCY2C in a paracrine fashion .	GUCY2C is activated by the endogenous hormones guanylin and uroguanylin, which are also produced in the intestinal epithelium and activate GUCY2C in a paracrine fashion.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	uroguanylin	uroguanylin	uroguanylin	GUCY2C	GUCY2C	GUCY2C	9	10	0	1
native and synthetic GCAP-II activate GC-C , the specific guanylate cyclase receptor , of cultured human colon carcinoma ( T84 ) cells .	native and synthetic GCAP-II activate GC-C, the specific guanylate cyclase receptor, of cultured human colon carcinoma (T84) cells.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GCAP-II	GCAP-II	GCAP-II	GC-C	GC-C	GC-C	3	4	5	6
Guanylin activates an intestinal guanylate cyclase ( GCC ) and stimulates electrolyte movement across the gut epithelium .	Guanylin activates an intestinal guanylate cyclase (GCC) and stimulates electrolyte movement across the gut epithelium.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Guanylin	Guanylin	Guanylin	intestinal guanylate cyclase	intestinal guanylate cyclase	intestinal guanylate cyclase	0	1	3	6
Based on these data , we propose that guanylin is an activator of intestinal guanylate cyclase and that it stimulates this enzyme through the same receptor binding region as the heat-stable enterotoxins .	Based on these data, we propose that guanylin is an activator of intestinal guanylate cyclase and that it stimulates this enzyme through the same receptor binding region as the heat-stable enterotoxins.	8	16	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	intestinal guanylate cyclase	intestinal guanylate cyclase	intestinal guanylate cyclase	8	9	13	16
Guanylin , a 15-amino acid peptide , activates intestinal guanylate cyclase C receptor , thereby regulating intestinal fluid and electrolyte transport through the second messenger , cyclic GMP .	Guanylin, a 15-amino acid peptide, activates intestinal guanylate cyclase C receptor, thereby regulating intestinal fluid and electrolyte transport through the second messenger, cyclic GMP.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Guanylin	Guanylin	Guanylin	intestinal guanylate cyclase	intestinal guanylate cyclase	intestinal guanylate cyclase	0	1	8	11
We establish that 1 ) uroguanylin is essentially restricted to small bowel ; 2 ) guanylin is very low in proximal small bowel , increasing to prominent levels in distal small bowel and throughout colon ; 3 ) GC-C messenger RNA and STa binding sites are uniformly expressed throughout the intestine ; and 4 ) GC-C-mediated cGMP synthesis peaks at the proximal and distal extremes of the intestine ( duodenum and colon ) , but is nearly absent in the middle ( ileum ) .	We establish that 1) uroguanylin is essentially restricted to small bowel; 2) guanylin is very low in proximal small bowel, increasing to prominent levels in distal small bowel and throughout colon; 3) GC-C messenger RNA and STa binding sites are uniformly expressed throughout the intestine; and 4) GC-C-mediated cGMP synthesis peaks at the proximal and distal extremes of the intestine (duodenum and colon), but is nearly absent in the middle (ileum).	8	58	increasing	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	GC-C	GC-C	GC-C	15	16	38	39
The polypeptide guanylin is an endogenous activator of small intestinal guanylate cyclase .	The polypeptide guanylin is an endogenous activator of small intestinal guanylate cyclase.	0	12	is an endogenous activator	Positive_activation_copula_1	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	intestinal guanylate cyclase	intestinal guanylate cyclase	intestinal guanylate cyclase	2	3	9	12
These results demonstrate that guanylin is an endogenous activator of STaR .	These results demonstrate that guanylin is an endogenous activator of STaR.	4	11	is an endogenous activator	Positive_activation_copula_1	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	STaR	STaR	STaR	4	5	10	11
The latter is more potent when GC-C activator guanylin , or its analog Escherichia coli heat-stable enterotoxin ( ST ) , is added to the mucosal rather than serosal side of intestinal monolayers .	The latter is more potent when GC-C activator guanylin, or its analog Escherichia coli heat-stable enterotoxin (ST), is added to the mucosal rather than serosal side of intestinal monolayers.	6	22	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	GC-C	GC-C	GC-C	8	9	6	7
Subsequently , the functional relevance of an alternative STa binding receptor was explored by examining STa-, uroguanylin-, and guanylin stimulated duodenal bicarbonate secretion ( DBS ) in GC-C KO mice in vitro and in vivo .	Subsequently, the functional relevance of an alternative STa binding receptor was explored by examining STa-, uroguanylin-, and guanylin stimulated duodenal bicarbonate secretion (DBS) in GC-C KO mice in vitro and in vivo.	18	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	GC-C	GC-C	GC-C	18	19	27	28
An emerging paradigm suggests that guanylin loss disrupting the GUCY2C paracrine signaling axis , and epithelial cell homeostasis , is a required step in colorectal cancer initiation .	An emerging paradigm suggests that guanylin loss disrupting the GUCY2C paracrine signaling axis, and epithelial cell homeostasis, is a required step in colorectal cancer initiation.	5	12	disrupting	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	GUCY2C	GUCY2C	GUCY2C	5	6	9	10
However , it did not affect membrane bound guanylate cyclase GC-C stimulated by guanylin or Escherichia coli heat-stable toxin STa .	However, it did not affect membrane bound guanylate cyclase GC-C stimulated by guanylin or Escherichia coli heat-stable toxin STa.	7	18	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	GC-C	GC-C	GC-C	13	14	10	11
Positive controls included guanylin which also activates GC-C , and NaNP , which activates the soluble form of guanylate cyclase , yielding much higher levels of [ cGMP ] i in T84 cells than linaclotide .	Positive controls included guanylin which also activates GC-C, and NaNP, which activates the soluble form of guanylate cyclase, yielding much higher levels of [cGMP] i in T84 cells than linaclotide.	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	GC-C	GC-C	GC-C	3	4	7	8
Conversely , studies performed with the pGC activators , particularly the GC-C activators guanylin , uroguanylin , and ST h , have been promising .	Conversely, studies performed with the pGC activators, particularly the GC-C activators guanylin, uroguanylin, and ST h, have been promising.	2	19	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	GC-C	GC-C	GC-C	13	14	11	12
Intestinal guanylate cyclase C is activated by guanylin , an endogenous peptide .	Intestinal guanylate cyclase C is activated by guanylin, an endogenous peptide.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	guanylin	guanylin	guanylin	Intestinal guanylate cyclase	Intestinal guanylate cyclase	Intestinal guanylate cyclase	7	8	0	3
GSK3beta increased the transcriptional activity of the p53 protein in vivo .	GSK3beta increased the transcriptional activity of the p53 protein in vivo.	0	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	0	1	7	8
GSK-3beta was found to promote p53 mRNA translation via phosphorylating RNPC1 .	GSK-3beta was found to promote p53 mRNA translation via phosphorylating RNPC1.	0	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	0	1	5	6
In IMR90 cells , Doxo treatment induced p53 upregulation , accompanied by complete downregulation of CDC7 , which was partially reversed by silencing of either miR-192/215 or GSK3beta and Fbxw7beta ( XREF_FIG ) .	In IMR90 cells, Doxo treatment induced p53 upregulation, accompanied by complete downregulation of CDC7, which was partially reversed by silencing of either miR-192/215 or GSK3beta and Fbxw7beta (XREF_FIG).	7	31	reversed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	27	28	7	8
Suppression of GSK-3beta by adding doxycycline prevented the redistribution of p53 induced by sorafenib .	Suppression of GSK-3beta by adding doxycycline prevented the redistribution of p53 induced by sorafenib.	0	11	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	2	3	10	11
This sequence of molecular events in GI mucosa was supported by the kinetics of accumulation of pro apoptotic markers , cleaved PARP1 and Bax , 24 and altered activity of GSK-3beta , which contributes to p53 and Bcl-2 family mediated pro apoptotic signaling .	This sequence of molecular events in GI mucosa was supported by the kinetics of accumulation of pro apoptotic markers, cleaved PARP1 and Bax, 24 and altered activity of GSK-3beta, which contributes to p53 and Bcl-2 family mediated pro apoptotic signaling.	28	36	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	30	31	35	36
Since GSK-3beta reduces let-7 production by lowering p53 , and p53 was reported to control the transcriptional levels of several let-7 family members XREF_BIBR , we asked if GSK-3beta might affect let-7 transcription .	Since GSK-3beta reduces let-7 production by lowering p53, and p53 was reported to control the transcriptional levels of several let-7 family members XREF_BIBR, we asked if GSK-3beta might affect let-7 transcription.	1	8	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	1	2	7	8
P53 induced the Wnt and beta-catenin pathway by direct miR-34a regulation of Axin2 and GSK-3beta [ XREF_BIBR ] .	P53 induced the Wnt and beta-catenin pathway by direct miR-34a regulation of Axin2 and GSK-3beta [XREF_BIBR].	0	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	P53	P53	P53	14	15	0	1
In fact , ER stress induces the cytoplasmic localization and enhances the destabilization of p53 due to phosphorylation at serine 315 and serine 376 , which is mediated by glycogen synthase kinase-3-beta ( GSK3-beta ) .	In fact, ER stress induces the cytoplasmic localization and enhances the destabilization of p53 due to phosphorylation at serine 315 and serine 376, which is mediated by glycogen synthase kinase-3-beta (GSK3-beta).	12	34	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	GSK3-beta	GSK3-beta	GSK3-beta	p53	p53	p53	33	34	14	15
Thus , these data suggest that the suppression of GSK3beta activation by P7C3 inhibits p53 activation and protects cells against MPP + toxicity .	Thus, these data suggest that the suppression of GSK3beta activation by P7C3 inhibits p53 activation and protects cells against MPP + toxicity.	9	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	9	10	14	15
GSK3beta activity was not required for p53 binding , but inhibition of GSK3beta stabilized the association , suggesting a transient interaction during which active GSK3beta promotes actions of p53 .	GSK3beta activity was not required for p53 binding, but inhibition of GSK3beta stabilized the association, suggesting a transient interaction during which active GSK3beta promotes actions of p53.	23	29	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	24	25	28	29
Collectively , these results support the notion that GSK-3beta represses let-7 production by reducing the abundance of p53 , a positive regulator of let-7 transcription .	Collectively, these results support the notion that GSK-3beta represses let-7 production by reducing the abundance of p53, a positive regulator of let-7 transcription.	8	21	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	8	9	17	18
For example , evidence shows that GSK-3beta modulates p53 activity and also affects c-Myc and NFkappaB activities which can further regulate many other important genes in cell cycle regulation and oncogenesis [ XREF_BIBR , XREF_BIBR ] .	For example, evidence shows that GSK-3beta modulates p53 activity and also affects c-Myc and NFkappaB activities which can further regulate many other important genes in cell cycle regulation and oncogenesis [XREF_BIBR, XREF_BIBR].	6	12	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	6	7	8	9
Note that GSK3beta also increases p53 activity providing an additional positive feedback in the cycle .	Note that GSK3beta also increases p53 activity providing an additional positive feedback in the cycle.	1	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	2	3	5	6
Despite elevated MAP kinase activity , cyclin D1 and cyclin E2 overexpression , and increased AKT activity that produced areas of highly proliferative papillomatous keratinocytes , increasing levels of GSK3beta inactivation induced a novel p53 and p21 WAF expression profile , which subsequently halted proliferation and accelerated differentiation to give the hallmark keratosis of keratoacanthomas .	Despite elevated MAP kinase activity, cyclin D1 and cyclin E2 overexpression, and increased AKT activity that produced areas of highly proliferative papillomatous keratinocytes, increasing levels of GSK3beta inactivation induced a novel p53 and p21 WAF expression profile, which subsequently halted proliferation and accelerated differentiation to give the hallmark keratosis of keratoacanthomas.	29	39	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	29	30	34	35
Other reports link GSK3 inhibition to increased cell survival upon induction of DNA damage by preventing its action on p53 ; active GSK3beta binds to and promotes the actions of p53 XREF_BIBR - XREF_BIBR .	Other reports link GSK3 inhibition to increased cell survival upon induction of DNA damage by preventing its action on p53; active GSK3beta binds to and promotes the actions of p53 XREF_BIBR - XREF_BIBR.	21	31	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	22	23	30	31
In addition , CDH17 knockdown increased P53 expression ; a possible mechanism would be that CDH17 knockdown leads to reduced GSK-3beta phosphorylation , which in turn activates p53 dependent apoptosis and antagonizes tumor growth XREF_BIBR .	In addition, CDH17 knockdown increased P53 expression; a possible mechanism would be that CDH17 knockdown leads to reduced GSK-3beta phosphorylation, which in turn activates p53 dependent apoptosis and antagonizes tumor growth XREF_BIBR.	20	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	p53	p53	p53	20	21	27	28
In human neuroblastoma and lung carcinoma cells , studies found that apoptotic stimuli stimulate increases in both nuclear and mitochondrial levels of GSK-3beta , which colocalize with p53 and contribute to p53 induced transcriptional and apoptosis signaling .	In human neuroblastoma and lung carcinoma cells, studies found that apoptotic stimuli stimulate increases in both nuclear and mitochondrial levels of GSK-3beta, which colocalize with p53 and contribute to p53 induced transcriptional and apoptosis signaling.	14	32	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	22	23	31	32
Also , GSK-3beta inactivation induces a p53 dependent apoptotic pathway resulting in a diminished colorectal cancer cell growth XREF_BIBR , XREF_BIBR .	Also, GSK-3beta inactivation induces a p53 dependent apoptotic pathway resulting in a diminished colorectal cancer cell growth XREF_BIBR, XREF_BIBR.	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	2	3	6	7
GSK3beta activation mediated p53 independent PUMA induction following idelalisib treatment .	GSK3beta activation mediated p53 independent PUMA induction following idelalisib treatment.	0	6	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	0	1	3	4
It has been reported that mitochondrial oxidative stress activates GSK3beta 27 and that an inhibition of GSK3beta attenuates p53 activity .	It has been reported that mitochondrial oxidative stress activates GSK3beta 27 and that an inhibition of GSK3beta attenuates p53 activity.	14	19	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	16	17	18	19
The present data indicates that transcriptional activation of p53 by GSK3beta requires both serines 33 and 37 , but it does not allow us to determine if phosphorylation of serine 33 is dependent on phosphorylation of serine 37 in vivo .	The present data indicates that transcriptional activation of p53 by GSK3beta requires both serines 33 and 37, but it does not allow us to determine if phosphorylation of serine 33 is dependent on phosphorylation of serine 37 in vivo.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	10	11	8	9
Recent studies have revealed that deregulation of GSK3beta promotes tumor cell survival , proliferation , invasion and resistance to chemo- and radiation therapy in humans by inhibiting p53 and RB tumor suppressors , inducing intracellular NF-kappaB signaling , Cyclin D1 over-expression and local chronic inflammation XREF_BIBR , XREF_BIBR .	Recent studies have revealed that deregulation of GSK3beta promotes tumor cell survival, proliferation, invasion and resistance to chemo- and radiation therapy in humans by inhibiting p53 and RB tumor suppressors, inducing intracellular NF-kappaB signaling, Cyclin D1 over-expression and local chronic inflammation XREF_BIBR, XREF_BIBR.	5	31	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	7	8	27	28
Thus , Fos synergism with Pten loss elicited a benign tumour context where GSK3beta induced p53 and p21 WAF expression continually switched AKT associated proliferation into differentiation , preventing further progression .	Thus, Fos synergism with Pten loss elicited a benign tumour context where GSK3beta induced p53 and p21 WAF expression continually switched AKT associated proliferation into differentiation, preventing further progression.	13	21	induced	Positive_early_activation	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	13	14	15	16
GSK-3beta inhibition blocks radiation induced accumulation of p53 by upregulating levels of MDM2 that subsequently result in decreased radiation dependent apoptosis [ XREF_BIBR ] .	GSK-3beta inhibition blocks radiation induced accumulation of p53 by upregulating levels of MDM2 that subsequently result in decreased radiation dependent apoptosis [XREF_BIBR].	0	8	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	0	1	7	8
XREF_BIBR , XREF_BIBR Most importantly , GSK3beta interacts with and promotes the transcriptional activity of p53 .	XREF_BIBR, XREF_BIBR Most importantly, GSK3beta interacts with and promotes the transcriptional activity of p53.	6	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	6	7	15	16
Based on these findings , we concluded that activation of OX1R by orexin-A might possess a therapeutic strategy for bone disease .	Based on these findings, we concluded that activation of OX1R by orexin-A might possess a therapeutic strategy for bone disease.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	orexin-A	orexin-A	orexin-A	OX1R	OX1R	OX1R	12	13	10	11
These results suggest that , by activating OX1R , orexin-A potentiates the IBa , L of rat GCs through a distinct Gq/PI-PLC/IP3/Ca ( 2+ )/PKC signaling pathway .	These results suggest that, by activating OX1R, orexin-A potentiates the IBa, L of rat GCs through a distinct Gq/PI-PLC/IP3/Ca (2+)/PKC signaling pathway.	6	11	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	orexin-A	orexin-A	orexin-A	OX1R	OX1R	OX1R	9	10	7	8
The SRE-luc activity of GHSR1a and OX1R cells treated with orexin A was increased ( p < 0.01 ) , compared with HEK293 OX1R cells .	The SRE-luc activity of GHSR1a and OX1R cells treated with orexin A was increased (p < 0.01), compared with HEK293 OX1R cells.	4	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	orexin	orexin	orexin	OX1R	OX1R	OX1R	10	11	6	7
Here , we focus on orexin-A ' s action at the OX1R for several reasons : ( 1 ) orexin-A treatment increases food intake , ( 2 ) the OX1R selective antagonist SB334867 reduces feeding without causing behaviors that indicate malaise or distress , and ( 3 ) activation of the OX1R by orexin-B has little effect on feeding .	Here, we focus on orexin-A 's action at the OX1R for several reasons : (1) orexin-A treatment increases food intake, (2) the OX1R selective antagonist SB334867 reduces feeding without causing behaviors that indicate malaise or distress, and (3) activation of the OX1R by orexin-B has little effect on feeding.	19	33	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	orexin-A	orexin-A	orexin-A	OX1R	OX1R	OX1R	19	20	29	30
To test whether orexin A induced increases in PICs were exclusively mediated by orexin receptor 1 ( OX1R ) , OX1R expressing PC12 ( PC12-OX1R ) cells were incubated with different dose of orexin A , and then , PICs mRNA and immunoreactivity were measured .	To test whether orexin A induced increases in PICs were exclusively mediated by orexin receptor 1 (OX1R), OX1R expressing PC12 (PC12-OX1R) cells were incubated with different dose of orexin A, and then, PICs mRNA and immunoreactivity were measured.	3	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	orexin	orexin	orexin	OX1R	OX1R	OX1R	3	4	17	18
Two other GPCRs , HCRTR1 activated by neuropeptide orexin and GRM5 activated by glutamate ( released due to the indirect action of HIFs 31 like HIF3A observed in the SM group ) , promote various pathways leading to PLD activation XREF_BIBR , XREF_BIBR .	Two other GPCRs, HCRTR1 activated by neuropeptide orexin and GRM5 activated by glutamate (released due to the indirect action of HIFs 31 like HIF3A observed in the SM group), promote various pathways leading to PLD activation XREF_BIBR, XREF_BIBR.	2	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	orexin	orexin	orexin	HCRTR1	HCRTR1	HCRTR1	8	9	4	5
We hypothesized that DR rats have greater : 1 ) basal SPA , 2 ) orexin A induced SPA , and 3 ) preproorexin , orexin 1 and 2 receptor ( OX1R and OX2R ) mRNA , compared with DIO rats .	We hypothesized that DR rats have greater : 1) basal SPA, 2) orexin A induced SPA, and 3) preproorexin, orexin 1 and 2 receptor (OX1R and OX2R) mRNA, compared with DIO rats.	15	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	orexin	orexin	orexin	OX1R	OX1R	OX1R	15	16	31	32
Furthermore , orexin A increased cellular TG content via ERK1/2 , JNK , and p38 MAPK as well as OX1R .	Furthermore, orexin A increased cellular TG content via ERK1/2, JNK, and p38 MAPK as well as OX1R.	2	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	orexin	orexin	orexin	OX1R	OX1R	OX1R	2	3	19	20
OX2R in mammals retained its ligand specificity for orexin A and B descended along the vertebrate lineage ; while OX1R is specifically activated by orexin A.	OX2R in mammals retained its ligand specificity for orexin A and B descended along the vertebrate lineage; while OX1R is specifically activated by orexin A.	19	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	orexin	orexin	orexin	OX1R	OX1R	OX1R	24	25	19	20
Orexin-A can activate both OX1R and OX2R , but no studies have reported their existence in astrocytes .	Orexin-A can activate both OX1R and OX2R, but no studies have reported their existence in astrocytes.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Orexin-A	Orexin-A	Orexin-A	OX1R	OX1R	OX1R	0	1	4	5
However , blocking endocytosis with a 2 hour incubation with 80 muM ' Dynasore ' , a cell-permeable inhibitor of dynamin GTPase activity , significantly reduced orexin A induced OX1R internalization ( XREF_FIG ) but did not affect the orexin A induced attenuation of KOR mediated reduction of cAMP production ( XREF_FIG ) , suggesting that OX1R internalization is not required for its ability to modulate the function of KOR .	However, blocking endocytosis with a 2 hour incubation with 80 muM ' Dynasore ', a cell-permeable inhibitor of dynamin GTPase activity, significantly reduced orexin A induced OX1R internalization (XREF_FIG) but did not affect the orexin A induced attenuation of KOR mediated reduction of cAMP production (XREF_FIG), suggesting that OX1R internalization is not required for its ability to modulate the function of KOR.	26	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	orexin	orexin	orexin	OX1R	OX1R	OX1R	26	27	29	30
Therefore , hypocretin-1 may produce antinociception in part by activating postsynaptic HcrtR1 receptors and stimulating synthesis of 2-AG through a PLC-DAGL enzymatic cascade , culminating in retrograde inhibition of GABA release in the PAG .	Therefore, hypocretin-1 may produce antinociception in part by activating postsynaptic HcrtR1 receptors and stimulating synthesis of 2-AG through a PLC-DAGL enzymatic cascade, culminating in retrograde inhibition of GABA release in the PAG.	2	12	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hypocretin-1	hypocretin-1	hypocretin-1	HcrtR1	HcrtR1	HcrtR1	2	3	11	12
A prior study demonstrated that GSK-3beta inhibition suppresses the binding of NF-kappaB p65 to the nuclear co-activator CBP [ XREF_BIBR ] .	A prior study demonstrated that GSK-3beta inhibition suppresses the binding of NF-kappaB p65 to the nuclear co-activator CBP [XREF_BIBR].	5	13	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	5	6	11	13
Although the early steps leading to NF-kappaB activation were unaffected by inactivation of GSK-3beta , our results show that GSK-3beta inhibition attenuates p65 dependent transcription , suggesting that GSK-3beta positively regulates NF-kappaB in LPS stimulated microglia through reduction of transactivation activity of p65 .	Although the early steps leading to NF-kappaB activation were unaffected by inactivation of GSK-3beta, our results show that GSK-3beta inhibition attenuates p65 dependent transcription, suggesting that GSK-3beta positively regulates NF-kappaB in LPS stimulated microglia through reduction of transactivation activity of p65.	19	24	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p65	p65	p65	19	20	22	23
Similar to the report that active GSK3beta can enhance NF-kappaB and p65 , phospho-p65 was elevated in IVCL mice compared with those from the sham group .	Similar to the report that active GSK3beta can enhance NF-kappaB and p65, phospho-p65 was elevated in IVCL mice compared with those from the sham group.	5	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p65	p65	p65	6	7	11	12
It has also been shown that GSK-3beta contributes to the maintenance of active chromatin at Bcl-2 and XIAP promoters , allowing p65 binding and transcriptional activation of Bcl-2 and XIAP in cancer cells .	It has also been shown that GSK-3beta contributes to the maintenance of active chromatin at Bcl-2 and XIAP promoters, allowing p65 binding and transcriptional activation of Bcl-2 and XIAP in cancer cells.	6	22	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p65	p65	p65	6	7	21	22
GSK3beta increases the binding of NF-kappaB p65 to the coactivator CREB binding protein ( CBP ) , leading to proinflammatory gene activation , which competes against the binding of CREB to CBP , the latter regulating IL-10 expression [ XREF_BIBR ] .	GSK3beta increases the binding of NF-kappaB p65 to the coactivator CREB binding protein (CBP), leading to proinflammatory gene activation, which competes against the binding of CREB to CBP, the latter regulating IL-10 expression [XREF_BIBR].	0	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	0	1	5	7
GSK-3beta inhibition reduced the increase in NF-kappaB p65 activity caused by interleukin ( IL ) 1 in human e mbryonic kidney cells in vitro .	GSK-3beta inhibition reduced the increase in NF-kappaB p65 activity caused by interleukin (IL) 1 in human e mbryonic kidney cells in vitro.	0	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	0	1	6	8
Although inhibition of GSK-3beta may inhibit p65 directly , this effect is likely due to increased beta-catenin binding to p65 , as shown previously .	Although inhibition of GSK-3beta may inhibit p65 directly, this effect is likely due to increased beta-catenin binding to p65, as shown previously.	1	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	p65	p65	p65	3	4	6	7
This investigation of the central mechanism by which GSK-3beta positively regulates the inflammatory response showed that GSK-3beta inactivation suppresses TNF-alpha production by inhibiting NF-kappaB p65 transactivation activity through deacetylation of p65 at Lys310 .	This investigation of the central mechanism by which GSK-3beta positively regulates the inflammatory response showed that GSK-3beta inactivation suppresses TNF-alpha production by inhibiting NF-kappaB p65 transactivation activity through deacetylation of p65 at Lys310.	16	26	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	16	17	23	25
We then investigated whether GSK3beta modulates protein synthesis in Tsc2 -/- MEFs .	We then investigated whether GSK3beta modulates protein synthesis in Tsc2 -/- MEFs.	4	11	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Tsc2	Tsc2	Tsc2	4	5	9	10
Downstream targets of GSK3beta are S6K and TSC2 which both can be activated by GSK3beta resulting in an active state in this attractor .	Downstream targets of GSK3beta are S6K and TSC2 which both can be activated by GSK3beta resulting in an active state in this attractor.	5	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	TSC2	TSC2	TSC2	14	15	7	8
It should be stressed that GSK-3beta , downstream substrate inactivated by AKT1 , activates TSC1 and TSC2 .	It should be stressed that GSK-3beta, downstream substrate inactivated by AKT1, activates TSC1 and TSC2.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	TSC2	TSC2	TSC2	5	6	16	17
GSK3beta is able to phosphorylate and thereby activate TSC2 .	GSK3beta is able to phosphorylate and thereby activate TSC2.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	TSC2	TSC2	TSC2	0	1	8	9
GSK-3beta activates TSC2 and consequently further suppresses mTOR , whereas Akt inhibits TSC2 thus decreasing TSC2 suppression of mTOR .	GSK-3beta activates TSC2 and consequently further suppresses mTOR, whereas Akt inhibits TSC2 thus decreasing TSC2 suppression of mTOR.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	TSC2	TSC2	TSC2	0	1	2	3
Since GSK3beta is a component in the Wnt signaling pathway , the GSK3beta directed phosphorylation links the pathway to mTORC1 regulation , whereby an activated Wnt signaling pathway , which inhibits GSK3beta activity [ XREF_BIBR ] , is able to enhance mTORC1 activity by repressing GSK3beta dependent activation of TSC2 [ XREF_BIBR , XREF_BIBR ] .	Since GSK3beta is a component in the Wnt signaling pathway, the GSK3beta directed phosphorylation links the pathway to mTORC1 regulation, whereby an activated Wnt signaling pathway, which inhibits GSK3beta activity [XREF_BIBR], is able to enhance mTORC1 activity by repressing GSK3beta dependent activation of TSC2 [XREF_BIBR, XREF_BIBR].	45	53	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	TSC2	TSC2	TSC2	45	46	49	50
Disruption of the orexin system ( loss of peptides or functional OX2R ) in humans and animal models causes the sleep disorder narcolepsy XREF_BIBR , XREF_BIBR , which is characterized by excessive daytime sleepiness and cataplexy .	Disruption of the orexin system (loss of peptides or functional OX2R) in humans and animal models causes the sleep disorder narcolepsy XREF_BIBR, XREF_BIBR, which is characterized by excessive daytime sleepiness and cataplexy.	3	12	loss	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	orexin	orexin	orexin	OX2R	OX2R	OX2R	3	4	11	12
Several reports suggested that histaminergic neurons in the TMN play an important role in the arousal promoting effect of orexin , supported by the facts that the effect of ICV orexin A administration is markedly attenuated by the histamine H1 receptor antagonist pyrilamine and is absent in H1 histamine receptor knockout mice and that the TMN expresses OX2R abundantly , the subtype whose absence causes narcoleptic phenotype in mice and dogs .	Several reports suggested that histaminergic neurons in the TMN play an important role in the arousal promoting effect of orexin, supported by the facts that the effect of ICV orexin A administration is markedly attenuated by the histamine H1 receptor antagonist pyrilamine and is absent in H1 histamine receptor knockout mice and that the TMN expresses OX2R abundantly, the subtype whose absence causes narcoleptic phenotype in mice and dogs.	17	58	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	orexin	orexin	orexin	OX2R	OX2R	OX2R	19	20	57	58
With OX2R targeted by both OX isoforms , OX-A and OX-B , while OX1R is primarily targeted by OX-A , our findings in the aPVT , that both OX-A and OX-B promote ethanol drinking and that an OX2R but not OX1R antagonist suppresses it , support the specific involvement of OX2R in the aPVT in stimulating ethanol drinking .	With OX2R targeted by both OX isoforms, OX-A and OX-B, while OX1R is primarily targeted by OX-A, our findings in the aPVT, that both OX-A and OX-B promote ethanol drinking and that an OX2R but not OX1R antagonist suppresses it, support the specific involvement of OX2R in the aPVT in stimulating ethanol drinking.	0	45	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	OX	OX	OX	OX2R	OX2R	OX2R	5	6	1	2
Willars et al demonstrated that orexin A ( 100 nM ) increased the labeling of OX2R with G s and G I subunits , however the same effect was not observed for G o and G q subunits .	Willars et al demonstrated that orexin A (100 nM) increased the labeling of OX2R with G s and G I subunits, however the same effect was not observed for G o and G q subunits.	5	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	orexin	orexin	orexin	OX2R	OX2R	OX2R	5	6	15	16
The activation of OX2R by orexin-A or -B opens nonselective cation channels to depolarize orexin neurons [ XREF_BIBR ] , and regulates the opening of K channels [ XREF_BIBR , XREF_BIBR ] , and promotes the release of presynaptic glutamate [ XREF_BIBR , XREF_BIBR ] , and gamma-aminobutyric acid ( GABA ) [ XREF_BIBR ] .	The activation of OX2R by orexin-A or -B opens nonselective cation channels to depolarize orexin neurons [XREF_BIBR], and regulates the opening of K channels [XREF_BIBR, XREF_BIBR], and promotes the release of presynaptic glutamate [XREF_BIBR, XREF_BIBR], and gamma-aminobutyric acid (GABA) [XREF_BIBR].	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	orexin-A	orexin-A	orexin-A	OX2R	OX2R	OX2R	5	6	3	4
Because ghrelin directly stimulates orexin neurons , it is highly likely that those OX2R positive DMH and LH neurons are stimulated by the orexin neurons that are activated by ghrelin ( XREF_FIG ) .	Because ghrelin directly stimulates orexin neurons, it is highly likely that those OX2R positive DMH and LH neurons are stimulated by the orexin neurons that are activated by ghrelin (XREF_FIG).	13	24	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	orexin	orexin	orexin	OX2R	OX2R	OX2R	23	24	13	14
From above observation we conclude that OX2R activation by orexin B induces ERK and CREB phosphorylation and orexin A played the same role as orexin B. Several isoforms of PKC may be involved in prolonged CREB phosphorylation .	From above observation we conclude that OX2R activation by orexin B induces ERK and CREB phosphorylation and orexin A played the same role as orexin B. Several isoforms of PKC may be involved in prolonged CREB phosphorylation.	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	orexin	orexin	orexin	OX2R	OX2R	OX2R	9	10	6	7
In contrast , it has been shown in cell line models that GSK3beta positively modulates Notch signalling by protecting the intracellular domain of Notch1 ( ICN1 ) from proteasome degradation [ XREF_BIBR ] .	In contrast, it has been shown in cell line models that GSK3beta positively modulates Notch signalling by protecting the intracellular domain of Notch1 (ICN1) from proteasome degradation [XREF_BIBR].	10	25	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	12	13	23	24
Taken together , these findings argue that GSK3beta down-regulates signaling by limiting the presence of Notch1 at the cell surface , possibly by promoting receptor endocytosis or inhibiting its recycling .	Taken together, these findings argue that GSK3beta down-regulates signaling by limiting the presence of Notch1 at the cell surface, possibly by promoting receptor endocytosis or inhibiting its recycling.	7	16	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	7	8	15	16
Collectively , these findings argue that GSK3beta inactivation stimulates Notch signaling capacity by enhancing Notch1 recycling via recycling routes that include the rab4a dependent trafficking pathway .	Collectively, these findings argue that GSK3beta inactivation stimulates Notch signaling capacity by enhancing Notch1 recycling via recycling routes that include the rab4a dependent trafficking pathway.	6	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	6	7	14	15
196 Conversely , GSK3beta has been shown to phosphorylate and positively regulate Notch1 in different models .	196 Conversely, GSK3beta has been shown to phosphorylate and positively regulate Notch1 in different models.	3	15	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	3	4	12	13
We reasoned that if GSK3beta promoted Notch1 internalization , acute inactivation of the kinase should lead to diminished antibody uptake .	We reasoned that if GSK3beta promoted Notch1 internalization, acute inactivation of the kinase should lead to diminished antibody uptake.	4	7	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	4	5	6	7
GSK3beta inactivation enhances Notch1 recycling rates .	GSK3beta inactivation enhances Notch1 recycling rates.	0	5	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	0	1	3	4
Human 53BP1 binding is known to be mediated , at least in part , through MDC1 and as MDC1 can not bind to H2AX without phosphorylated S139 and de-phosphorylated Y142 [ XREF_BIBR ] , this indicates that 53BP1 IRIF formation must not be solely dependent on H2AX mediated MDC1 localisation .	Human 53BP1 binding is known to be mediated, at least in part, through MDC1 and as MDC1 can not bind to H2AX without phosphorylated S139 and de-phosphorylated Y142 [XREF_BIBR], this indicates that 53BP1 IRIF formation must not be solely dependent on H2AX mediated MDC1 localisation.	44	49	mediated	Positive_early_activation	Positive_activation	Positive_activation	H2AX	H2AX	H2AX	MDC1	MDC1	MDC1	46	47	48	49
The MRE11/RAD50/NBS1 ( MRN ) complex recruits Ataxia and telangiectasia mutated protein ( ATM ) , which phosphorylates H2AX aiding recruitment of the mediator protein , MDC1 , and tethering of MRN and ATM at the DSB .	The MRE11/RAD50/NBS1 (MRN) complex recruits Ataxia and telangiectasia mutated protein (ATM), which phosphorylates H2AX aiding recruitment of the mediator protein, MDC1, and tethering of MRN and ATM at the DSB.	9	27	aiding	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	H2AX	telangiectasia mutated protein (ATM), which phosphorylates H2AX	h2ax	MDC1	MDC1	mdc1	18	19	26	27
The phosphorylation of histone H2AX ( giving rise to gammaH2AX ) at sites of DSBs allows binding of MDC1 , which acts as a scaffold for the formation of large protein complexes spreading appreciable distances from the site of the actual break [ XREF_BIBR ] .	The phosphorylation of histone H2AX (giving rise to gammaH2AX) at sites of DSBs allows binding of MDC1, which acts as a scaffold for the formation of large protein complexes spreading appreciable distances from the site of the actual break [XREF_BIBR].	1	21	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	histone H2AX	phosphorylation of histone H2AX	histone h2ax	MDC1	MDC1	mdc1	3	5	18	19
Once ATM is activated , it phosphorylates H2AX , enabling the recruitment of NFBD1 through the BRCT domain .	Once ATM is activated, it phosphorylates H2AX, enabling the recruitment of NFBD1 through the BRCT domain.	6	14	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	H2AX	phosphorylates H2AX	h2ax	NFBD1	NFBD1	nfbd1	7	8	13	14
An important function of H2AX phosphorylation at arrested forks appears to allow recruitment of the checkpoint mediator MDC1 .	An important function of H2AX phosphorylation at arrested forks appears to allow recruitment of the checkpoint mediator MDC1.	4	18	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	H2AX	H2AX phosphorylation	h2ax	MDC1	MDC1	mdc1	4	5	17	18
But Ridley reported a new form of WASP regulation in macrophages , where a receptor ( probably the CSF-1 receptor ) can turn on the Src kinase Hck , which can then phosphorylate and thus activate the Arp2/3 activator WASP .	But Ridley reported a new form of WASP regulation in macrophages, where a receptor (probably the CSF-1 receptor) can turn on the Src kinase Hck, which can then phosphorylate and thus activate the Arp2/3 activator WASP.	22	40	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Hck	Hck	Hck	WASP	WASP	WASP	27	28	39	40
Hck can also activate WASP through phosphorylation of Y291 , leading to Arp2/3 binding and actin filament assembly .	Hck can also activate WASP through phosphorylation of Y291, leading to Arp2/3 binding and actin filament assembly.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hck	Hck	Hck	WASP	WASP	WASP	0	1	4	5
In light of this , we therefore hypothesized that the PKCepsilon cardioprotective program is also activated in response to chronic hypoxic stress and mediated by downstream targets GSK3beta and HIF-1alpha to modulate myocardial metabolism and maintain mitochondrial homeostasis .	In light of this, we therefore hypothesized that the PKCepsilon cardioprotective program is also activated in response to chronic hypoxic stress and mediated by downstream targets GSK3beta and HIF-1alpha to modulate myocardial metabolism and maintain mitochondrial homeostasis.	10	29	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	PKCepsilon	PKCepsilon	PKCepsilon	27	28	10	11
Conversely , wild-type hearts exhibit lower PGC1alpha levels and decreased mitochondrial respiration , thus reinforcing our hypothesis that PKCepsilon cardioprotection is mediated at least in part by a p-GSK3beta and HIF-1alpha signaling cascade .	Conversely, wild-type hearts exhibit lower PGC1alpha levels and decreased mitochondrial respiration, thus reinforcing our hypothesis that PKCepsilon cardioprotection is mediated at least in part by a p-GSK3beta and HIF-1alpha signaling cascade.	18	32	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p-GSK3beta	p-GSK3beta	p-GSK3beta	PKCepsilon	PKCepsilon	PKCepsilon	28	29	18	19
Hck Mediates Induction of the AAM Endotype Independently of Stat3 .	Hck Mediates Induction of the AAM Endotype Independently of Stat3.	0	10	Mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hck	Hck	Hck	Stat3	Stat3	Stat3	0	1	9	10
From these collective observations , we surmise that Hck mediated Th2-cytokine and Stat6 independent AAM polarization occurs also largely independent of Stat3 .	From these collective observations, we surmise that Hck mediated Th2-cytokine and Stat6-independent AAM polarization occurs also largely independent of Stat3.	8	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hck	Hck	Hck	Stat3	Stat3	Stat3	8	9	21	22
Combination targeting of HDAC1 and aPKC robustly inhibited GLI1 , lowering drug doses needed in vitro , in vivo , and ex vivo in patient derived BCC explants .	Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient derived BCC explants.	1	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HDAC1	HDAC1	HDAC1	GLI1	GLI1	GLI1	3	4	8	9
We also demonstrate , for the first time , that PTP1B is bound to the c-Met receptor and that its tyrosine phosphorylation is down regulated when HGF increases the activity of c-Met and its downstream signals .	We also demonstrate, for the first time, that PTP1B is bound to the c-Met receptor and that its tyrosine phosphorylation is down regulated when HGF increases the activity of c-Met and its downstream signals.	26	35	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	26	27	31	32
Another important effect of HGF mediated activation of c-Met is the stimulation of downstream effectors through the RAS and mitogen activated protein kinase ( MAPK ) signaling pathway [ XREF_BIBR ] .	Another important effect of HGF mediated activation of c-Met is the stimulation of downstream effectors through the RAS and mitogen activated protein kinase (MAPK) signaling pathway [XREF_BIBR].	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	8	9
Logical network of HGF and H. pylori triggered c-Met signal transduction .	Logical network of HGF and H. pylori triggered c-Met signal transduction.	3	10	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	8	9
HGF upregulated c-Met and phosphorylated Met expression in MSCs and enhanced its liver protection effect .	HGF upregulated c-Met and phosphorylated Met expression in MSCs and enhanced its liver protection effect.	0	10	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	2	3
Both pMET Y1234/1235 and pMET Y1349 were activated by exogenous HGF and inhibited by XL184 even in the presence of HGF .	Both pMET Y1234/1235 and pMET Y1349 were activated by exogenous HGF and inhibited by XL184 even in the presence of HGF.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	pMET	pMET	pMET	10	11	4	5
Using neutralizing antibodies against VEGFR1 ( MF1 ) and VEGFR2 ( DC101 ) , we found that VEGF dependent suppression of HGF mediated P-MET and P-FAK in GBM cells was abrogated by addition of DC101 , but not MF1 ( XREF_FIG ) .	Using neutralizing antibodies against VEGFR1 (MF1) and VEGFR2 (DC101), we found that VEGF dependent suppression of HGF mediated P-MET and P-FAK in GBM cells was abrogated by addition of DC101, but not MF1 (XREF_FIG).	19	28	mediated	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	P-MET	P-MET	P-MET	21	22	23	24
While autocrine HGF activation of c-Met has been reported in other cancer types , HNSCC cells fail to secrete detectable levels of the ligand , indicating the TAF supplied HGF activates c-Met in a predominantly paracrine manner [ XREF_BIBR , XREF_BIBR ] .	While autocrine HGF activation of c-Met has been reported in other cancer types, HNSCC cells fail to secrete detectable levels of the ligand, indicating the TAF supplied HGF activates c-Met in a predominantly paracrine manner [XREF_BIBR, XREF_BIBR].	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	5	6
As shown in XREF_FIG c , p-Met , p-PI3K and p85 , p-Akt and GRP78 were increased by CAF matrix or recombinant HGF , whereas the levels of total Met , PI3K p85 and Akt did not change .	As shown in XREF_FIG c, p-Met, p-PI3K and p85, p-Akt and GRP78 were increased by CAF matrix or recombinant HGF, whereas the levels of total Met, PI3K p85 and Akt did not change.	6	23	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	p-Met	p-Met	p-Met	22	23	6	7
However , CAF derived HGF and subsequent activation of the HGF receptor c-Met have been shown to mediate resistance to targeted RAF inhibition .	However, CAF derived HGF and subsequent activation of the HGF receptor c-Met have been shown to mediate resistance to targeted RAF inhibition.	4	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	HGF receptor	HGF receptor	HGF receptor	4	5	10	12
Interestingly , HGF treatment induced also a stronger activation of its receptor c-Met , Akt and Erk in MDA-MB-231 cells stably overexpressing H19 compared to parental cells ( XREF_SUPPLEMENTARY ) .	Interestingly, HGF treatment induced also a stronger activation of its receptor c-Met, Akt and Erk in MDA-MB-231 cells stably overexpressing H19 compared to parental cells (XREF_SUPPLEMENTARY).	2	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	12	13
HGF induced activation of c-Met mediates cellular motility and invasion , and is important for cell proliferation , morphogenesis , angiogenesis , as well as protection from apoptosis .	HGF induced activation of c-Met mediates cellular motility and invasion, and is important for cell proliferation, morphogenesis, angiogenesis, as well as protection from apoptosis.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	4	5
Similarly , ectopic expression of SPSB1 in human MDA-MB-231 breast cancer cells also enhanced HGF induced c-MET activation ( XREF_SUPPLEMENTARY ) .	Similarly, ectopic expression of SPSB1 in human MDA-MB-231 breast cancer cells also enhanced HGF induced c-MET activation (XREF_SUPPLEMENTARY).	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	14	15	16	17
[ XREF_BIBR ] In mammary carcinoma cells , EGFR inhibition significantly blocked HGF activation of c-Met and EGFR and inhibition of these pathways mitigated HGF induced proliferation and motility .	[XREF_BIBR] In mammary carcinoma cells, EGFR inhibition significantly blocked HGF activation of c-Met and EGFR and inhibition of these pathways mitigated HGF induced proliferation and motility.	12	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	12	13	15	16
The blebbing response was dependent on autocrine HGF ( hepatocyte growth factor ) activation of c-Met and prevented by inhibition of RhoA , ROCK and p38 MAPK ( p38 mitogen activated protein kinase ) , but not ERK ( extracellular-signal-regulated kinase ) or PI3K ( phosphoinositide 3-kinase ) .	The blebbing response was dependent on autocrine HGF (hepatocyte growth factor) activation of c-Met and prevented by inhibition of RhoA, ROCK and p38 MAPK (p38 mitogen activated protein kinase), but not ERK (extracellular-signal-regulated kinase) or PI3K (phosphoinositide 3-kinase).	6	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	7	8	15	16
The effectiveness of this approach was exemplified with Nbs against hepatocyte growth factor ( HGF ) that activate c-Met , but fail to interfere with the EGFR signaling as this receptor is activated by multiple ligands .	The effectiveness of this approach was exemplified with Nbs against hepatocyte growth factor (HGF) that activate c-Met, but fail to interfere with the EGFR signaling as this receptor is activated by multiple ligands.	10	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-Met	c-Met	c-Met	10	13	18	19
88 HGF is produced by bone marrow stromal cells and leads to c-MET activation and its downstream consequences .	88 HGF is produced by bone marrow stromal cells and leads to c-MET activation and its downstream consequences.	0	13	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	1	2	12	13
In addition , c-MET activation by gene amplification and HGF can independently rescue not only PI3K and AKT but also ERK signaling in the presence of gefitinib and lead to drug resistance .	In addition, c-MET activation by gene amplification and HGF can independently rescue not only PI3K and AKT but also ERK signaling in the presence of gefitinib and lead to drug resistance.	3	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	9	10	3	4
EMT can induced by many growth factors , such as hepatocyte growth factor , which can activate c-Met signaling pathway XREF_BIBR .	EMT can induced by many growth factors, such as hepatocyte growth factor, which can activate c-Met signaling pathway XREF_BIBR.	10	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-Met	c-Met	c-Met	10	13	17	18
HGF stimulates the activation of PI3K , pp60 c-src , phospholipase C gamma , c-Met and Ras-ERK signaling pathways .	HGF stimulates the activation of PI3K, pp60 c-src, phospholipase C gamma, c-Met and Ras-ERK signaling pathways.	0	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	14	15
VEGF stimulated activation of VEGFR2 on GBM cells recruited the cytoplasmic phosphotyrosine phosphatase PTP1B toward HGF activated c-Met , leading to c-Met dephosphorylation and suppression of cell motility ( XREF_FIG ) .	VEGF stimulated activation of VEGFR2 on GBM cells recruited the cytoplasmic phosphotyrosine phosphatase PTP1B toward HGF activated c-Met, leading to c-Met dephosphorylation and suppression of cell motility (XREF_FIG).	13	18	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	15	16	17	18
PKG II prevents HGF induced c-Met activation by phosphorylating c-Met at Ser985 .	PKG II prevents HGF induced c-Met activation by phosphorylating c-Met at Ser985.	3	12	induced	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	HGF	HGF	hgf	c-Met	phosphorylating c-Met at Ser985	c-met	3	4	9	10
In these cells , CD82 reduces both integrin dependent and HGF induced activation of c-Met , although the levels of integrin are not altered .	In these cells, CD82 reduces both integrin dependent and HGF induced activation of c-Met, although the levels of integrin are not altered.	7	15	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	10	11	14	15
In the prostate cancer cell lines , DU145 and PC3 , KAI1 and CD82 reduced both integrin dependent and HGF induced activation of c-Met , subsequently inhibiting signaling to activate Src , resulting in reduced activation of p130Cas [ XREF_BIBR ] .	In the prostate cancer cell lines, DU145 and PC3, KAI1 and CD82 reduced both integrin dependent and HGF induced activation of c-Met, subsequently inhibiting signaling to activate Src, resulting in reduced activation of p130Cas [XREF_BIBR].	16	24	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	19	20	23	24
Activation of c-MET by HGF and its signaling pathways is pivotal for cellular morphogenesis , regeneration , proliferation , migration , angiogenesis and invasion [ XREF_BIBR ] .	Activation of c-MET by HGF and its signaling pathways is pivotal for cellular morphogenesis, regeneration, proliferation, migration, angiogenesis and invasion [XREF_BIBR].	0	8	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	4	5	2	3
In contrast to HGF activated c-Met , CagA replaces Gab1 and/or Grb2 and leads to PLCgamma1 activation [ XREF_BIBR ] .	In contrast to HGF activated c-Met, CagA replaces Gab1 and/or Grb2 and leads to PLCgamma1 activation [XREF_BIBR].	1	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	5	6
Hepatocyte growth factor stimulation of c-Met results in activation of key oncogenic signalling pathways that increase cell proliferation , survival , migration and invasion .	Hepatocyte growth factor stimulation of c-Met results in activation of key oncogenic signalling pathways that increase cell proliferation, survival, migration and invasion.	0	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Hepatocyte growth factor	Hepatocyte growth factor	Hepatocyte growth factor	c-Met	c-Met	c-Met	0	3	5	6
In HNSCC , matriptase , the protease required to cleave the pro HGF form , is also co-expressed with c-Met on the surface of HNSCC tumor epithelial cells enabling enhanced HGF mediated activation of c-Met and downstream signaling [ XREF_BIBR ] .	In HNSCC, matriptase, the protease required to cleave the pro HGF form, is also co-expressed with c-Met on the surface of HNSCC tumor epithelial cells enabling enhanced HGF mediated activation of c-Met and downstream signaling [XREF_BIBR].	30	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	30	31	34	35
This platform , which is similar to the phosphorylation assays described above except whole cell lysates are substituted for the purified kinase , revealed changes in the phosphorylation profiles of immortalized U373 cancer cells and gliablastoma tumors upon hepatocyte growth factor ( HGF )-mediated activation of the c-Met signaling pathway .	This platform, which is similar to the phosphorylation assays described above except whole cell lysates are substituted for the purified kinase, revealed changes in the phosphorylation profiles of immortalized U373 cancer cells and gliablastoma tumors upon hepatocyte growth factor (HGF)-mediated activation of the c-Met signaling pathway.	38	49	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-Met	c-Met	c-Met	38	41	47	48
Subsequently , we also found that small interfering RNA against c-Met induced A549 cell autophagy while promotion of c-Met by hepatocyte growth factor ( HGF ) suppressed A549 cell autophagy .	Subsequently, we also found that small interfering RNA against c-Met induced A549 cell autophagy while promotion of c-Met by hepatocyte growth factor (HGF) suppressed A549 cell autophagy.	16	23	promotion	Positive_activation_token_2_noun	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-Met	c-Met	c-Met	20	23	18	19
XREF_BIBR , XREF_BIBR , XREF_BIBR Interestingly , in malignant proliferation , HGF has been detected also in tumour epithelial cells along with its receptor , raising the possibility of c-met activation through an autocrine loop .	XREF_BIBR, XREF_BIBR, XREF_BIBR Interestingly, in malignant proliferation, HGF has been detected also in tumour epithelial cells along with its receptor, raising the possibility of c-met activation through an autocrine loop.	11	30	raising	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-met	c-met	c-met	11	12	29	30
HGF activated pMET in both PC9 and PC9GR cells .	HGF activated pMET in both PC9 and PC9GR cells.	0	3	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	pMET	pMET	pMET	0	1	2	3
Combined overexpression of HGF and c-MET have been observed in numerous sarcomas [ XREF_BIBR - XREF_BIBR ] , and HGF can activate c-MET in an autocrine manner in these tumors .	Combined overexpression of HGF and c-MET have been observed in numerous sarcomas [XREF_BIBR - XREF_BIBR], and HGF can activate c-MET in an autocrine manner in these tumors.	19	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	19	20	22	23
Influenza infection stimulated the secretion of IL-8 and GM-CSF by AECs plated on rat-tail collagen through EGFR activation likely by TGF-alpha released from AECs and through c-Met activated by HGF secreted from lung fibroblasts .	Influenza infection stimulated the secretion of IL-8 and GM-CSF by AECs plated on rat-tail collagen through EGFR activation likely by TGF-alpha released from AECs and through c-Met activated by HGF secreted from lung fibroblasts.	11	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	29	30	26	27
Pretreatment of OC abrogated HGF induced c-MET activation of MDA-MB-231 , MCF-7 and BT-474 cells [ XREF_BIBR ] .	Pretreatment of OC abrogated HGF induced c-MET activation of MDA-MB-231, MCF-7 and BT-474 cells [XREF_BIBR].	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	4	5	6	7
The concentration profile of different molecular factors changes over time in the wound healing process , and activation of c-Met by HGF might have an effect in later stages .	The concentration profile of different molecular factors changes over time in the wound healing process, and activation of c-Met by HGF might have an effect in later stages.	17	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	21	22	19	20
In conclusion , both mouse and human versions of c-Met-Fc effectively block HGF induced activation of c-Met and inhibit growth of tumor xenografts , providing further evidence that c-Met is an important target for oncology therapeutics .	In conclusion, both mouse and human versions of c-Met-Fc effectively block HGF induced activation of c-Met and inhibit growth of tumor xenografts, providing further evidence that c-Met is an important target for oncology therapeutics.	12	18	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	12	13	16	17
HGF stimulation triggers c-Met induction of several biological responses that collectively give rise to invasive growth during embryo development [ XREF_BIBR , XREF_BIBR ] .	HGF stimulation triggers c-Met induction of several biological responses that collectively give rise to invasive growth during embryo development [XREF_BIBR, XREF_BIBR].	0	4	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	3	4
We therefore continued our studies by focusing specifically on c-Met and by studying what effects c-Met activation by its ligand HGF may have on cell migration and invasion and which effector pathways are needed to mediate the c-Met responses .	We therefore continued our studies by focusing specifically on c-Met and by studying what effects c-Met activation by its ligand HGF may have on cell migration and invasion and which effector pathways are needed to mediate the c-Met responses.	15	21	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	20	21	15	16
c-Met is activated by autocrine expression of HGF in some of these tumor cell lines .	c-Met is activated by autocrine expression of HGF in some of these tumor cell lines.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	expression of HGF	hgf	c-Met	c-Met	c-met	7	8	0	1
Furthermore , c-MET is widely activated in CCS in an autocrine fashion by its ligand HGF , and CCS strongly depends on HGF and c-MET signaling [ XREF_BIBR , XREF_BIBR ] .	Furthermore, c-MET is widely activated in CCS in an autocrine fashion by its ligand HGF, and CCS strongly depends on HGF and c-MET signaling [XREF_BIBR, XREF_BIBR].	2	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	15	16	2	3
Although blocking HGF with a neutralizing antibody has also been successful as part of a dual inhibitor strategy XREF_BIBR , XREF_BIBR , a c-Met TKI has the advantage of additionally blocking HGF independent signaling of c-Met caused by lateral signaling from other tyrosine kinases .	Although blocking HGF with a neutralizing antibody has also been successful as part of a dual inhibitor strategy XREF_BIBR, XREF_BIBR, a c-Met TKI has the advantage of additionally blocking HGF independent signaling of c-Met caused by lateral signaling from other tyrosine kinases.	31	36	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	31	32	35	36
The secondary EGFR T790M mutation accounts for about half of acquired resistance mechanisms.1 As a bypass pathway , c-Met activation caused by c-Met gene amplification , mutation and/or its ligand hepatocyte growth factor ( HGF ) overexpression has been reported as another important mechanism in this process.2 In particular , HGF overexpression was observed in about 61 % of patients with acquired resistance.3 Therefore , targeting HGF and c-Met pathway is important for more effective targeted therapy in lung cancer .	The secondary EGFR T790M mutation accounts for about half of acquired resistance mechanisms.1 As a bypass pathway, c-Met activation caused by c-Met gene amplification, mutation and/or its ligand hepatocyte growth factor (HGF) overexpression has been reported as another important mechanism in this process.2 In particular, HGF overexpression was observed in about 61% of patients with acquired resistance.3 Therefore, targeting HGF and c-Met pathway is important for more effective targeted therapy in lung cancer.	50	69	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF overexpression	hgf	c-Met	c-Met	c-met	50	51	68	69
Proteomic analysis showed that stromal secretion of the growth factor hepatocyte growth factor ( HGF ) resulted in activation of the HGF receptor MET , reactivation of the MAPK and PI3K and AKT pathways , and immediate resistance to RAF inhibition .	Proteomic analysis showed that stromal secretion of the growth factor hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the MAPK and PI3K and AKT pathways, and immediate resistance to RAF inhibition.	12	23	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	HGF receptor	HGF receptor	HGF receptor	14	15	21	23
ABT-700 and parental mAb m224G11 blocked the HGF induced c-Met phosphorylation of A549 tumor cell line with an IC 50 of 1.0 nM .	ABT-700 and parental mAb m224G11 blocked the HGF induced c-Met phosphorylation of A549 tumor cell line with an IC 50 of 1.0 nM.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	7	8	9	10
Generally , activation of c-Met by HGF is controlled through release of ligand by a paracrine process in which mesenchymal cells and cells of the innate immune system secrete HGF , followed by ligand activation on the cell surface and internalization of the activated receptor .	Generally, activation of c-Met by HGF is controlled through release of ligand by a paracrine process in which mesenchymal cells and cells of the innate immune system secrete HGF, followed by ligand activation on the cell surface and internalization of the activated receptor.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	6	7	4	5
Instead , reconstitution of plexin-B1 expression in melanomas inhibits HGF dependent activation of c-Met and migration [ XREF_BIBR ] .	Instead, reconstitution of plexin-B1 expression in melanomas inhibits HGF dependent activation of c-Met and migration [XREF_BIBR].	9	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	9	10	13	14
Exposure of DU145 prostate tumor cells to hepatic growth factor ( HGF ) stimulates the activation of c-Met and downstream PI3-kinase and MAPK pathways , leading to increased scattering , motility , and invasion , which was prevented by the addition of 5 mumol/L of EGCG [ XREF_BIBR ] .	Exposure of DU145 prostate tumor cells to hepatic growth factor (HGF) stimulates the activation of c-Met and downstream PI3-kinase and MAPK pathways, leading to increased scattering, motility, and invasion, which was prevented by the addition of 5 mumol/L of EGCG [XREF_BIBR].	0	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	17	18
We found Foretinib decreased basal- and HGF induced c-MET activity at low concentrations .	We found Foretinib decreased basal- and HGF induced c-MET activity at low concentrations.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	6	7	8	9
PAK4 is a member of the PAK family of serine/threonine kinases , which act as effectors for several small GTPases , and has been specifically identified to function downstream of HGF mediated c-Met activation in a PI3K dependent manner .	PAK4 is a member of the PAK family of serine/threonine kinases, which act as effectors for several small GTPases, and has been specifically identified to function downstream of HGF mediated c-Met activation in a PI3K dependent manner.	28	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	30	31	32	33
Upon HGF binding , HGF induced c-Met activation , which was higher and was sustained in CAV1 clones compared to mocks over the 24-h time course of the experiments ( XREF_FIG , and XREF_SUPPLEMENTARY ) .	Upon HGF binding, HGF induced c-Met activation, which was higher and was sustained in CAV1 clones compared to mocks over the 24-h time course of the experiments (XREF_FIG, and XREF_SUPPLEMENTARY).	4	14	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	6	7
Finally , the c-Met inhibitor , XL880 , suppressed HGF induced c-Met activation as well as S1PR1 and ITGB4 transactivation .	Finally, the c-Met inhibitor, XL880, suppressed HGF induced c-Met activation as well as S1PR1 and ITGB4 transactivation.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	9	10	11	12
Humanized anti-HGF antibody attenuated HGF activated c-Met signaling pathway and enhanced apoptotic cell death induced by CPT-11 in colorectal cancer cells .	Humanized anti-HGF antibody attenuated HGF activated c-Met signaling pathway and enhanced apoptotic cell death induced by CPT-11 in colorectal cancer cells.	3	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	6	7
HGF induced activation of c-met also leads to activation of Ron by transphosphorylating tyrosine residues , showing cross talking between c-met and Ron and coordinated intracellular signaling networks [ XREF_BIBR ] .	HGF induced activation of c-met also leads to activation of Ron by transphosphorylating tyrosine residues, showing cross talking between c-met and Ron and coordinated intracellular signaling networks [XREF_BIBR].	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-met	c-met	c-met	0	1	4	5
Immunoprecipitation and Western blotting results showed that PKG II could bind with c-Met and phosphorylate its Ser985 , and thereby inhibited HGF induced activation of c-Met and MAPK and ERK and PI3K/Akt/mTOR mediated signal transduction .	Immunoprecipitation and Western blotting results showed that PKG II could bind with c-Met and phosphorylate its Ser985, and thereby inhibited HGF induced activation of c-Met and MAPK and ERK and PI3K/Akt/mTOR mediated signal transduction.	21	27	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	21	22	25	26
We show that MCJs are naturally more endocytic than other sites of the apical membrane , that endocytosis and Lm invasion of MCJs depends on functional dynamin , and that c-Met activation by soluble InlB or hepatocyte growth factor ( HGF ) increases MCJ endocytosis .	We show that MCJs are naturally more endocytic than other sites of the apical membrane, that endocytosis and Lm invasion of MCJs depends on functional dynamin, and that c-Met activation by soluble InlB or hepatocyte growth factor (HGF) increases MCJ endocytosis.	30	39	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-Met	c-Met	c-Met	36	39	30	31
c-Met activation by HGF treatment significantly induced cell proliferation in all tested cells .	c-Met activation by HGF treatment significantly induced cell proliferation in all tested cells.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	0	1
These specific phosphoepitope sites might not be involved in the SRC activation by HGF stimulated c-MET signalling .	These specific phosphoepitope sites might not be involved in the SRC activation by HGF stimulated c-MET signalling.	7	16	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	13	14	15	16
HGF increases 10- to 20-fold in the plasma within the first 3 hours after PHx and activates the HGF receptor cMet within 30-60 minutes.104 , 105 Similarly , plasma concentration of TNF-alpha , IL-6 , epidermal growth factor , and TGF-beta1 increase within 1-2 hours after PHx .	HGF increases 10- to 20-fold in the plasma within the first 3 hours after PHx and activates the HGF receptor cMet within 30-60 minutes.104, 105 Similarly, plasma concentration of TNF-alpha, IL-6, epidermal growth factor, and TGF-beta1 increase within 1-2 hours after PHx.	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	HGF receptor	HGF receptor	HGF receptor	0	1	18	20
This is perhaps not surprising , as an aberrant c-Met signalling , either caused by overexpression and mutation of c-Met or by coexpression of c-Met and HGF , has been found in a variety of other malignancies ( Maulik et al , 2002 ) .	This is perhaps not surprising, as an aberrant c-Met signalling, either caused by overexpression and mutation of c-Met or by coexpression of c-Met and HGF, has been found in a variety of other malignancies (Maulik et al, 2002).	9	27	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	coexpression of c-Met and HGF	hgf	c-Met	c-Met	c-met	26	27	9	10
Host-pathogen systems biology : logical modelling of hepatocyte growth factor and Helicobacter pylori induced c-Met signal transduction .	Host-pathogen systems biology : logical modelling of hepatocyte growth factor and Helicobacter pylori induced c-Met signal transduction.	7	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-Met	c-Met	c-Met	7	10	14	15
The hysteristic phenomenon on the mRNA expression of these two genes may indicate that c-Met , a receptor for HGF , would not be triggered simultaneously by the expression of HGF .	The hysteristic phenomenon on the mRNA expression of these two genes may indicate that c-Met, a receptor for HGF, would not be triggered simultaneously by the expression of HGF.	14	31	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	expression of HGF	hgf	c-Met	c-Met	c-met	30	31	14	15
c-Met is expressed by epithelial cells , endothelial cells , neurons , hepatocytes , and hematopoietic cells.14 c-Met is involved in epithelial-mesenchymal transition and plays a critical role in tissue modeling during embryogenesis ; postpartum c-Met has a limited role in tissue repair , particularly in the liver.15 HGF induces c-Met dimerization and activation , leading to stimulation of multiple downstream signaling pathways , including mitogen activated protein kinase , phosphoinositide 3-kinase , signal transducer and activator of transcription , and nuclear factor kappa-B.16 These pathways execute the cellular effects of c-Met activation , including increased proliferation , survival , mobilization , invasiveness , and epithelial-mesenchymal transition.17 c-Met Signaling in Liver Disease and HCC .	c-Met is expressed by epithelial cells, endothelial cells, neurons, hepatocytes, and hematopoietic cells.14 c-Met is involved in epithelial-mesenchymal transition and plays a critical role in tissue modeling during embryogenesis; postpartum c-Met has a limited role in tissue repair, particularly in the liver.15 HGF induces c-Met dimerization and activation, leading to stimulation of multiple downstream signaling pathways, including mitogen activated protein kinase, phosphoinositide 3-kinase, signal transducer and activator of transcription, and nuclear factor kappa-B.16 These pathways execute the cellular effects of c-Met activation, including increased proliferation, survival, mobilization, invasiveness, and epithelial-mesenchymal transition.17 c-Met Signaling in Liver Disease and HCC.	48	111	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	48	49	50	51
Finally , we determined the downstream signal transduction of HGF stimulation of c-Met with and without inhibition of c-Met ( with geldanamycin , an anisamycin antibiotic that inhibits c-Met in SCLC ) or PI3K ( with LY294002 ) .	Finally, we determined the downstream signal transduction of HGF stimulation of c-Met with and without inhibition of c-Met (with geldanamycin, an anisamycin antibiotic that inhibits c-Met in SCLC) or PI3K (with LY294002).	9	33	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	9	10	12	13
We demonstrated that primary CCS and tumor derived cell lines express c-Met that is activated in an autocrine fashion by HGF expression in some CCS cell lines .	We demonstrated that primary CCS and tumor derived cell lines express c-Met that is activated in an autocrine fashion by HGF expression in some CCS cell lines.	10	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF expression	hgf	c-Met	c-Met	c-met	20	21	11	12
Activation of c-Met by HGF in breast cancer cell lines leads to the interaction of c-Src and c-Met and subsequent activation of c-Src .	Activation of c-Met by HGF in breast cancer cell lines leads to the interaction of c-Src and c-Met and subsequent activation of c-Src.	0	9	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	2	3
Stimulation of c-Met by HGF leads to receptor dimerization , which induces phosphorylation at 1349 and 1356 salient tyrosine sites and its kinase domain .	Stimulation of c-Met by HGF leads to receptor dimerization, which induces phosphorylation at 1349 and 1356 salient tyrosine sites and its kinase domain.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	2	3
We demonstrate that Btk is a novel proximal component of HGF induced c-MET ( HGF receptor ) signaling .	We demonstrate that Btk is a novel proximal component of HGF induced c-MET (HGF receptor) signaling.	8	17	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	10	11	12	13
The model was built on the current understanding of the biochemical processes involved in HGF and H. pylori induced c-Met signal transduction and iteratively improved by validation with published experimental results .	The model was built on the current understanding of the biochemical processes involved in HGF and H. pylori induced c-Met signal transduction and iteratively improved by validation with published experimental results.	14	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	14	15	19	20
In contrast , siRNA silencing of MUC1 increased HGF induced c-Met activation and HGF induced cell motility and invasion .	In contrast, siRNA silencing of MUC1 increased HGF induced c-Met activation and HGF induced cell motility and invasion.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	10	11
However , such an approach would be highly impractical because of the failure in retaining c-MET phosphorylation in clinical samples.40 In fact , several studies have evaluated HGF and c-MET expression in SS clinical specimens probably due to the difficulty of detecting c-MET phosphorylation.24 , 25 , 26 , 27 On the basis of our results , we proposed that co-expression of HGF and c-MET should result in c-MET autocrine activation and be predictive of response to anti-HGF and c-MET therapies in SS .	However, such an approach would be highly impractical because of the failure in retaining c-MET phosphorylation in clinical samples.40 In fact, several studies have evaluated HGF and c-MET expression in SS clinical specimens probably due to the difficulty of detecting c-MET phosphorylation.24, 25, 26, 27 On the basis of our results, we proposed that co-expression of HGF and c-MET should result in c-MET autocrine activation and be predictive of response to anti-HGF and c-MET therapies in SS.	60	71	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	HGF	co-expression of HGF	hgf	c-MET	c-MET	c-met	62	63	68	69
The results demonstrate that PTP inhibition enhances HGF induced activation of c-Met and suggest that bpV ( phen ) acts by preventing the de-phosphorylation and inactivation of c- Met through inhibition of associated PTPs .	The results demonstrate that PTP inhibition enhances HGF induced activation of c-Met and suggest that bpV (phen) acts by preventing the de-phosphorylation and inactivation of c- Met through inhibition of associated PTPs.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	7	8	11	12
In addition , HGF induced c-MET activation has been shown to lead to drug resistance by selecting for pre-existing c-MET-amplified clones in NSCLC cell lines .	In addition, HGF induced c-MET activation has been shown to lead to drug resistance by selecting for pre-existing c-MET-amplified clones in NSCLC cell lines.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	3	4	5	6
Treatment of KHM-3S ( an EGFR mutated small cell lung cancer cell line ) with the ligand HGF activated pMET and pERK , inducing resistance to Erlotinib .	Treatment of KHM-3S (an EGFR mutated small cell lung cancer cell line) with the ligand HGF activated pMET and pERK, inducing resistance to Erlotinib.	0	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	pMET	pMET	pMET	17	18	19	20
HGF activates c-Met signaling pathways , altering the expression of many genes , including matrix metalloproteinases ( MMPs ) .	HGF activates c-Met signaling pathways, altering the expression of many genes, including matrix metalloproteinases (MMPs).	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	2	3
In vitro experiments showed that HGF supported survival in B-CLL cells supporting the possible function of HGF and c-met pathway in B-CLL .	In vitro experiments showed that HGF supported survival in B-CLL cells supporting the possible function of HGF and c-met pathway in B-CLL.	5	19	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-met	c-met	c-met	5	6	18	19
These results indicate that increased HGF expression from Tgfbr2 deficient fibroblasts enhance c-Met and Ron signaling in mammary carcinoma cells .	These results indicate that increased HGF expression from Tgfbr2 deficient fibroblasts enhance c-Met and Ron signaling in mammary carcinoma cells.	5	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF expression	hgf	c-Met	c-Met	c-met	5	6	12	13
As shown in XREF_FIG , LZ8 suppressed the HGF induced c-Met signaling [ XREF_BIBR ] , including p-c-Met , p-JNK , p-ERK , and p-paxilllin ( Ser 178 ) by 85 % to 90 % in HepG2 ( XREF_FIG ) .	As shown in XREF_FIG, LZ8 suppressed the HGF induced c-Met signaling [XREF_BIBR], including p-c-Met, p-JNK, p-ERK, and p-paxilllin (Ser 178) by 85% to 90% in HepG2 (XREF_FIG).	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	10	11
HGF binds with high affinity to , and induces the dimerization of , c-Met , its transmembrane tyrosine kinase receptor .	HGF binds with high affinity to, and induces the dimerization of, c-Met, its transmembrane tyrosine kinase receptor.	0	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	13	14
One limitation of the NSG mouse model in this regard is that mouse HGF does not activate the human c-MET ; thus , the authors are likely analyzing the effects of tumor derived HGF or ligand independent signaling .	One limitation of the NSG mouse model in this regard is that mouse HGF does not activate the human c-MET; thus, the authors are likely analyzing the effects of tumor derived HGF or ligand independent signaling.	12	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	13	14	19	20
HGF secreted by CAFs results in activation of the HGF receptor MET and downstream MAPK and PI3K and AKT signaling pathways , which are responsible for the immediate resistance of BRAF-mutant melanoma to BRAF inhibitors XREF_BIBR .	HGF secreted by CAFs results in activation of the HGF receptor MET and downstream MAPK and PI3K and AKT signaling pathways, which are responsible for the immediate resistance of BRAF-mutant melanoma to BRAF inhibitors XREF_BIBR.	0	11	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	HGF receptor	HGF receptor	HGF receptor	0	1	9	11
Ficlatuzumab is a humanized anti-HGF mAb that inhibits HGF induced c-MET activation .	Ficlatuzumab is a humanized anti-HGF mAb that inhibits HGF induced c-MET activation.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	8	9	10	11
In genetically engineered HGF-mouse models , continuous expression of HGF drives a c-MET autocrine loop that promotes cutaneous and metastatic melanoma [ XREF_BIBR - XREF_BIBR ] .	In genetically engineered HGF-mouse models, continuous expression of HGF drives a c-MET autocrine loop that promotes cutaneous and metastatic melanoma [XREF_BIBR - XREF_BIBR].	7	14	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	expression of HGF	hgf	c-MET	c-MET	c-met	9	10	12	13
For example , a HGF independent activation of c-Met by fibronectin was reported to promote the tumor invasion and metastasis [ XREF_BIBR ] .	For example, a HGF independent activation of c-Met by fibronectin was reported to promote the tumor invasion and metastasis [XREF_BIBR].	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	8	9
Short-term resveratrol exposure substantially decreased HGF induced c-Met signaling pathway activation , and long-term exposure to resveratrol markedly inhibited c-Met expression on the cell membrane .	Short-term resveratrol exposure substantially decreased HGF induced c-Met signaling pathway activation, and long-term exposure to resveratrol markedly inhibited c-Met expression on the cell membrane.	5	18	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	7	8
In these settings , both HGF induced activation of c-Met and HGF induced signaling to Erk were severely repressed as compared with the control siRNA treated cells .	In these settings, both HGF induced activation of c-Met and HGF induced signaling to Erk were severely repressed as compared with the control siRNA treated cells.	4	11	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	9	10
Phosphorylation of c-MET is also characterized using immunohistochemistry assay and western blotting assay ; as is expected , high levels of liver HGF promotes the activation of c-MET in metastases ( XREF_FIG ) .	Phosphorylation of c-MET is also characterized using immunohistochemistry assay and western blotting assay; as is expected, high levels of liver HGF promotes the activation of c-MET in metastases (XREF_FIG).	19	29	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	levels of liver HGF	hgf	c-MET	c-MET	c-met	22	23	27	28
DCC-2701 , a small molecule of c-MET inhibitor , effectively inhibits c-MET activation induced by HGF providing microenvironment .	DCC-2701, a small molecule of c-MET inhibitor, effectively inhibits c-MET activation induced by HGF providing microenvironment.	11	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	15	16	11	12
The small molecule bryostatin 1 activates PKC [ XREF_BIBR ] whereas HGF activates c-Met [ XREF_BIBR ] .	The small molecule bryostatin 1 activates PKC [XREF_BIBR] whereas HGF activates c-Met [XREF_BIBR].	11	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	13	14
The HGF dependent rate of c-Met internalization also was reduced markedly in beta1A-YYFF versus beta1A cells ( XREF_FIG ) , suggesting that beta1-integrin internalization is required for optimal HGF mediated c-Met internalization .	The HGF dependent rate of c-Met internalization also was reduced markedly in beta1A-YYFF versus beta1A cells (XREF_FIG), suggesting that beta1-integrin internalization is required for optimal HGF mediated c-Met internalization.	25	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	28	29	30	31
Our analyses indicated that EGFR inhibition significantly blocked HGF activation of c-Met and EGFR and that inhibition of these pathways mitigated HGF induced proliferation and motility .	Our analyses indicated that EGFR inhibition significantly blocked HGF activation of c-Met and EGFR and that inhibition of these pathways mitigated HGF induced proliferation and motility.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	11	12
In primary mammary carcinoma cells and human breast cancer cell lines , addition of HAI-1 and HAI-2 inhibited pro HGF mediated c-Met signaling and cell proliferation .	In primary mammary carcinoma cells and human breast cancer cell lines, addition of HAI-1 and HAI-2 inhibited pro HGF mediated c-Met signaling and cell proliferation.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	19	20	21	22
We previously reported that c-Met is activated by HGF in a paracrine manner in HNSCC as well .	We previously reported that c-Met is activated by HGF in a paracrine manner in HNSCC as well.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	4	5
The dual anaplastic lymphoma kinase ( ALK ) and c-Met receptor tyrosine kinase inhibitor CM-118 inhibited ALK signaling and HGF induced c-Met signaling , thus interrupting the c-Met-EGFR cross-talk .	The dual anaplastic lymphoma kinase (ALK) and c-Met receptor tyrosine kinase inhibitor CM-118 inhibited ALK signaling and HGF induced c-Met signaling, thus interrupting the c-Met-EGFR cross-talk.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	19	20	21	22
EGCG added up to 4 h after the addition of HGF still blocked cell scattering and reduced the HGF induced phosphorylation of c-Met , Akt , and Erk , suggesting that EGCG could act both by preventing activation of c-Met by HGF and by attenuating the activity of pathways already induced by HGF .	EGCG added up to 4 h after the addition of HGF still blocked cell scattering and reduced the HGF induced phosphorylation of c-Met, Akt, and Erk, suggesting that EGCG could act both by preventing activation of c-Met by HGF and by attenuating the activity of pathways already induced by HGF.	36	42	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	41	42	39	40
For the metPathway ( Signaling of Hepatocyte Growth Factor Receptor ) , the hepatocyte growth factor receptor , also called c-Met , is activated by hepatocyte growth factor ( HGF ) .	For the metPathway (Signaling of Hepatocyte Growth Factor Receptor), the hepatocyte growth factor receptor, also called c-Met, is activated by hepatocyte growth factor (HGF).	13	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor receptor	hepatocyte growth factor receptor	hepatocyte growth factor receptor	25	28	13	17
However , we found that 24h ARQ197 pretreatment was necessary to block acute , HGF induced c-Met signaling .	However, we found that 24h ARQ197 pretreatment was necessary to block acute, HGF induced c-Met signaling.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	14	15	16	17
The results revealed that the level of p-c-Met ( Tyr1234 ) was increased distinctly in cells infected with Ad-LacZ and treated with HGF , and decreased in cells infected with Ad-PKG II , treated with cGMP and HGF , demonstrating that the increase of PKG II activity efficiently blocked the HGF induced activation of c-Met .	The results revealed that the level of p-c-Met (Tyr1234) was increased distinctly in cells infected with Ad-LacZ and treated with HGF, and decreased in cells infected with Ad-PKG II, treated with cGMP and HGF, demonstrating that the increase of PKG II activity efficiently blocked the HGF induced activation of c-Met.	49	55	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	50	51	54	55
Both types of hepatomas were revealed to have higher adenoviral gene transduction efficiencies and more efficient expressions of the HGF transgene , which successfully activated the HGF receptor and c-Met in an autocrine fashion , than those of other types of cancer .	Both types of hepatomas were revealed to have higher adenoviral gene transduction efficiencies and more efficient expressions of the HGF transgene, which successfully activated the HGF receptor and c-Met in an autocrine fashion, than those of other types of cancer.	19	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	HGF receptor	HGF receptor	HGF receptor	19	20	26	28
Together , the above results indicated that HGF induced c-MET activation contributes to hBMSC osteogenic differentiation ( XREF_FIG A ) .	Together, the above results indicated that HGF induced c-MET activation contributes to hBMSC osteogenic differentiation (XREF_FIG A).	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	7	8	9	10
Specifically , HGF induced c-Met activation enhanced the capability of the individual cells to migrate in a JNK dependent manner .	Specifically, HGF induced c-Met activation enhanced the capability of the individual cells to migrate in a JNK dependent manner.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	4	5
27 Activation of c-Met by HGF results in signaling leading to tumor growth , metastasis , and angiogenesis .	27 Activation of c-Met by HGF results in signaling leading to tumor growth, metastasis, and angiogenesis.	1	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	3	4
It is a humanized monoclonal antibody that sequesters HGF , thereby preventing the stimulation of c-Met by HGF .	It is a humanized monoclonal antibody that sequesters HGF, thereby preventing the stimulation of c-Met by HGF.	11	18	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	17	18	15	16
HGF stimulation further enhanced this effect , whereas depletion of MAP4K4 prevented both temperature shift- and HGF induced c-Met internalization .	HGF stimulation further enhanced this effect, whereas depletion of MAP4K4 prevented both temperature shift- and HGF induced c-Met internalization.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	16	17	18	19
HGF induced activation of c-MET in DLBCL cells resulted in MEK dependent phosphorylation of the MAP kinases ERK1 and ERK2 , the linkages to the regulation of cell proliferation [ XREF_BIBR ] .	HGF induced activation of c-MET in DLBCL cells resulted in MEK dependent phosphorylation of the MAP kinases ERK1 and ERK2, the linkages to the regulation of cell proliferation [XREF_BIBR].	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	0	1	4	5
This is also demonstrated in HCE cells , in which SHP-2-gene silencing decreased the activation of c-Met induced by HGF in the presence of the PTP inhibitor .	This is also demonstrated in HCE cells, in which SHP-2-gene silencing decreased the activation of c-Met induced by HGF in the presence of the PTP inhibitor.	14	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	19	20	16	17
In physionormative settings , binding of HGF activates c-Met by phosphorylating two intracellular tyrosine residues , inducing catalytic activity [ XREF_BIBR ] .	In physionormative settings, binding of HGF activates c-Met by phosphorylating two intracellular tyrosine residues, inducing catalytic activity [XREF_BIBR].	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	6	7	8	9
HGF induced c-Met activation protects prostate cancer cells against cytotoxicity and apoptosis induced by DNA damaging agents ( e , g. adriamycin and ionizing radiation ) [ XREF_BIBR ] .	HGF induced c-Met activation protects prostate cancer cells against cytotoxicity and apoptosis induced by DNA damaging agents (e, g. adriamycin and ionizing radiation) [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	2	3
In addition to HGF induced c-Met activation , the c-Met pathway is also stimulated through HGF independent mechanisms such as c-Met transcriptional upregulation , genomic amplifications , mutations , and structural variations including gene fusions [ XREF_BIBR , XREF_BIBR ] .	In addition to HGF induced c-Met activation, the c-Met pathway is also stimulated through HGF independent mechanisms such as c-Met transcriptional upregulation, genomic amplifications, mutations, and structural variations including gene fusions [XREF_BIBR, XREF_BIBR].	0	13	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	5	6
Activation of c-MET by hepatocyte growth factor ( HGF ) leads to recruitment of a plethora of proteins including Gab-1 .	Activation of c-MET by hepatocyte growth factor (HGF) leads to recruitment of a plethora of proteins including Gab-1.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-MET	c-MET	c-MET	4	7	2	3
Based on extensive biochemical analyses and global proteomics analyses , we have shown that HGF activation of c-Met results in a plethora of effects , such as activation of signal transduction molecules , leading to various biological effects controlling cell proliferation and differentiation , cell survival and apoptosis , and cytoskeleton related functions .	Based on extensive biochemical analyses and global proteomics analyses, we have shown that HGF activation of c-Met results in a plethora of effects, such as activation of signal transduction molecules, leading to various biological effects controlling cell proliferation and differentiation, cell survival and apoptosis, and cytoskeleton related functions.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	14	15	17	18
HGF , produced by some cancer cells , stimulates c-Met , through activation of the autocrine signaling system .	HGF, produced by some cancer cells, stimulates c-Met, through activation of the autocrine signaling system.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	9	10
Heparin inhibited HGF activated c-Met and ERK1/2 activation in a dose dependent manner ( XREF_FIG ) .	Heparin inhibited HGF activated c-Met and ERK1/2 activation in a dose dependent manner (XREF_FIG).	1	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	4	5
Upon proteolytic cleavage by matriptase , pro HGF is converted to active HGF , which in turn initiates c-Met signaling and activates multiple downstream targets , including the P13 and AKT pathway , and the c-Met docking protein , Gab1 .	Upon proteolytic cleavage by matriptase, pro HGF is converted to active HGF, which in turn initiates c-Met signaling and activates multiple downstream targets, including the P13 and AKT pathway, and the c-Met docking protein, Gab1.	9	21	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	12	13	18	19
Exogenous HGF led to the activation of c-Met on 4 distinct sites ( XREF_FIG ) .	Exogenous HGF led to the activation of c-Met on 4 distinct sites (XREF_FIG).	0	8	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	1	2	7	8
Despite a slightly lower size of total MET protein corresponding to the expression of a shortened MET ( from exon 14 skipping and removal of 47 amino-acids [ L964-D1010 ] ) , we were unable to detect constitutive activation of MET phosphorylation in H596 cells in vitro ( XREF_FIG ) without the addition of the MET ligand HGF that can readily activate p-MET in H596 [ XREF_BIBR - XREF_BIBR ] .	Despite a slightly lower size of total MET protein corresponding to the expression of a shortened MET (from exon 14 skipping and removal of 47 amino-acids [L964-D1010]), we were unable to detect constitutive activation of MET phosphorylation in H596 cells in vitro (XREF_FIG) without the addition of the MET ligand HGF that can readily activate p-MET in H596 [XREF_BIBR - XREF_BIBR].	52	68	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	p-MET	p-MET	p-MET	57	58	62	63
Tivantinib and Crizotinib also inhibited HGF induced c-MET phosphorylation of MDA-MB-231 and HT29 in a dose dependent manner ( XREF_SUPPLEMENTARY ) .	Tivantinib and Crizotinib also inhibited HGF induced c-MET phosphorylation of MDA-MB-231 and HT29 in a dose dependent manner (XREF_SUPPLEMENTARY).	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	5	6	7	8
The ability of TNF-alpha to inhibit HGF induced c-met activity was impaired by sodium orthovanadate , suggesting that the inhibitory effect of TNF-alpha was mediated by a protein-tyrosine phosphatase .	The ability of TNF-alpha to inhibit HGF induced c-met activity was impaired by sodium orthovanadate, suggesting that the inhibitory effect of TNF-alpha was mediated by a protein-tyrosine phosphatase.	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-met	c-met	c-met	6	7	8	9
Myoblasts seem to utilize c-MET signaling for enhanced migration , regardless of an exogenous HGF source , and HGF stimulated myoblast motility requires c-MET .	Myoblasts seem to utilize c-MET signaling for enhanced migration, regardless of an exogenous HGF source, and HGF stimulated myoblast motility requires c-MET.	18	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	18	19	23	24
Hepatocyte growth factor stimulation results in activation of c-Met and downstream signal transduction pathways .	Hepatocyte growth factor stimulation results in activation of c-Met and downstream signal transduction pathways.	0	13	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Hepatocyte growth factor	Hepatocyte growth factor	Hepatocyte growth factor	c-Met	c-Met	c-Met	0	3	8	9
Furthermore , reduced ITGB4 expression attenuated HGF induced c-Met activation , c-Met and S1PR1 interaction , and effected decreases in S1P- and HGF induced EC barrier enhancement .	Furthermore, reduced ITGB4 expression attenuated HGF induced c-Met activation, c-Met and S1PR1 interaction, and effected decreases in S1P- and HGF induced EC barrier enhancement.	6	17	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	6	7	8	9
Western blot analysis revealed that HGF specifically activated c-Met signaling , which was not reduced in the presence of the EGFR inhibitor .	Western blot analysis revealed that HGF specifically activated c-Met signaling, which was not reduced in the presence of the EGFR inhibitor.	5	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	8	9
In A549 cells , we did observe that tivantinib incubation mitigated activation of c-MET by HGF ( XREF_SUPPLEMENTARY ) .	In A549 cells, we did observe that tivantinib incubation mitigated activation of c-MET by HGF (XREF_SUPPLEMENTARY).	10	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	15	16	13	14
For example , Ephedrae herba , an ingredient of Maoto , which is a traditional Kampo medicine capable of preventing progression of breast cancer and mouse osteosarcoma , can downregulate the c-Met signal by promoting HGF stimulated c-Met endocytosis and its degradation [ XREF_BIBR ] .	For example, Ephedrae herba, an ingredient of Maoto, which is a traditional Kampo medicine capable of preventing progression of breast cancer and mouse osteosarcoma, can downregulate the c-Met signal by promoting HGF stimulated c-Met endocytosis and its degradation [XREF_BIBR].	35	38	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	35	36	37	38
In conclusion , we have discovered an association of mutated NRAS with increased HGF dependent activation of c-Met and with enhanced sensitivity to c-Met inhibition .	In conclusion, we have discovered an association of mutated NRAS with increased HGF dependent activation of c-Met and with enhanced sensitivity to c-Met inhibition.	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	13	14	17	18
In contrast to HGF induced c-Met down-regulation , the effect of CCK was decreased by a lysosome inhibitor ( concanamycin ) but not the proteasome inhibitor lactacystin .	In contrast to HGF induced c-Met down-regulation, the effect of CCK was decreased by a lysosome inhibitor (concanamycin) but not the proteasome inhibitor lactacystin.	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	5	6
HGF secreted from fibroblasts activated the c-Met signaling cascade in 4T1 cells similar to recombinant murine HGF ( XREF_FIG ) .	HGF secreted from fibroblasts activated the c-Met signaling cascade in 4T1 cells similar to recombinant murine HGF (XREF_FIG).	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	6	7
Surprisingly , S3DN cells also showed suppressed HGF induced activation of c-met , and had nearly undetectable basal c-met activity , as revealed by a phospho specific c-met antibody .	Surprisingly, S3DN cells also showed suppressed HGF induced activation of c-met, and had nearly undetectable basal c-met activity, as revealed by a phospho specific c-met antibody.	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-met	c-met	c-met	7	8	11	12
Activation of the Erk and JNK signaling pathways were not affected by luteolin even after long preincubation when c-Met was no longer maximally activated by HGF .	Activation of the Erk and JNK signaling pathways were not affected by luteolin even after long preincubation when c-Met was no longer maximally activated by HGF.	18	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	25	26	18	19
The mechanism whereby HGF activation of c-MET leads to increased motility , migration , and invasion in cancer cells has not been well defined .	The mechanism whereby HGF activation of c-MET leads to increased motility, migration, and invasion in cancer cells has not been well defined.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	3	4	6	7
c-Met is activated by HGF through a paracrine mechanism to promote cellular morphogenesis enabling cells to acquire mesenchymal phenotypes in part through the epithelial-mesenchymal transition , contributing to metastasis .	c-Met is activated by HGF through a paracrine mechanism to promote cellular morphogenesis enabling cells to acquire mesenchymal phenotypes in part through the epithelial-mesenchymal transition, contributing to metastasis.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	0	1
HGF mediated c-Met activation generates a variety of cellular responses , including motility , invasion and branching morphogenesis .	HGF mediated c-Met activation generates a variety of cellular responses, including motility, invasion and branching morphogenesis.	0	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	2	3
Stimulation of c-met by HGF results in the activation of several downstream signal transduction pathways including PI3K and AKT , MAPK , and PKC [ XREF_BIBR ] .	Stimulation of c-met by HGF results in the activation of several downstream signal transduction pathways including PI3K and AKT, MAPK, and PKC [XREF_BIBR].	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-met	c-met	c-met	4	5	2	3
We show for the first time that HGF induced c-Met activation enhanced the speed of migration of the individual Medulloblastoma cells and show that the Ser/Thr kinase MAP4K4 is an essential mediator in this process .	We show for the first time that HGF induced c-Met activation enhanced the speed of migration of the individual Medulloblastoma cells and show that the Ser/Thr kinase MAP4K4 is an essential mediator in this process.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	7	8	9	10
Furthermore , in preclinical studies , HGF induced c-MET signaling resulted in resistance to gefitinib in NSCLC and lapatinib in breast cancer cell lines XREF_BIBR , XREF_BIBR .	Furthermore, in preclinical studies, HGF induced c-MET signaling resulted in resistance to gefitinib in NSCLC and lapatinib in breast cancer cell lines XREF_BIBR, XREF_BIBR.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	6	7	8	9
Activation of c-Met by HGF leads to a variety of cellular signals that mediate tumor growth , metastasis , and angiogenesis .	Activation of c-Met by HGF leads to a variety of cellular signals that mediate tumor growth, metastasis, and angiogenesis.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	2	3
Activated c-Met in normal cells - predominantly in stromal cells including MSC - plays a major role in organogenesis and wound healing whereas in tumor cells , HGF activated c-Met contributes to invasive and metastatic behavior [ XREF_BIBR , XREF_BIBR ] .	Activated c-Met in normal cells - predominantly in stromal cells including MSC - plays a major role in organogenesis and wound healing whereas in tumor cells, HGF activated c-Met contributes to invasive and metastatic behavior [XREF_BIBR, XREF_BIBR].	27	30	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	27	28	29	30
We observed that both HGF and c-MET were also overexpressed in Asra-EPS and VAESBJ cells , indicating that c-MET was aberrantly activated by autocrine HGF stimulation in EpS .	We observed that both HGF and c-MET were also overexpressed in Asra-EPS and VAESBJ cells, indicating that c-MET was aberrantly activated by autocrine HGF stimulation in EpS.	18	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	24	25	18	19
In addition to amplification , mutation , or transcriptional alteration of MET , c-Met may be activated by protein overexpression or paracrine and autocrine signaling of HGF [ XREF_BIBR - XREF_BIBR ] .	In addition to amplification, mutation, or transcriptional alteration of MET, c-Met may be activated by protein overexpression or paracrine and autocrine signaling of HGF [XREF_BIBR - XREF_BIBR].	13	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	26	27	13	14
Western blotting analysis also showed that CAF derived HGF or recombinant HGF activated c-Met and phosphoinositide 3-kinase ( PI3K )/Akt and glucose regulated protein 78 ( GRP78 ) signalling pathways in ovarian cancer cells , and these effects could be abrogated by anti-HGF and c-Met inhibitor INCB28060 .	Western blotting analysis also showed that CAF derived HGF or recombinant HGF activated c-Met and phosphoinositide 3-kinase (PI3K)/Akt and glucose regulated protein 78 (GRP78) signalling pathways in ovarian cancer cells, and these effects could be abrogated by anti-HGF and c-Met inhibitor INCB28060.	7	16	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	13	14
Surprisingly , responsiveness to METi did not correlate with p-MET which is usually induced by HGF .	Surprisingly, responsiveness to METi did not correlate with p-MET which is usually induced by HGF.	7	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	p-MET	p-MET	p-MET	15	16	9	10
It is noteworthy that c-MET on Tyr 1349 , the multisubstrate docking site , was highly induced by physiological HGF and the HGF induced phosphorylation was effectively inhibited by DCC-2701 .	It is noteworthy that c-MET on Tyr 1349, the multisubstrate docking site, was highly induced by physiological HGF and the HGF induced phosphorylation was effectively inhibited by DCC-2701.	4	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	19	20	4	5
HGF activates several downstream effectors of c-Met such as the mitogen activated protein kinases extracellular signal regulated kinase 1/extracellular signal regulated kinase 2 and phospholipase C-gamma , whereas signal transducer and activator of transcription 3 is constitutively activated in neuroblastoma cells expressing c-Met .	HGF activates several downstream effectors of c-Met such as the mitogen activated protein kinases extracellular signal regulated kinase 1/extracellular signal regulated kinase 2 and phospholipase C-gamma, whereas signal transducer and activator of transcription 3 is constitutively activated in neuroblastoma cells expressing c-Met.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	6	7
In these same cells , an increase in ROS production was also observed when c-Met was activated by HGF treatment [ XREF_BIBR ] .	In these same cells, an increase in ROS production was also observed when c-Met was activated by HGF treatment [XREF_BIBR].	14	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	18	19	14	15
Binding of HGF to c-Met activates the catalytic tyrosine kinase domain of c-Met and subsequently activates the MAPK and PI3K signal pathways , contributing to the expression of the pro angiogenic factors IL-8 and VEGF [ XREF_BIBR ] .	Binding of HGF to c-Met activates the catalytic tyrosine kinase domain of c-Met and subsequently activates the MAPK and PI3K signal pathways, contributing to the expression of the pro angiogenic factors IL-8 and VEGF [XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	12	13
MET proto-oncogene encodes the hepatocyte growth factor receptor ( HGFR or MET ) , which can be activated by its ligand hepatocyte growth factor ( HGF ) .	MET proto-oncogene encodes the hepatocyte growth factor receptor (HGFR or MET), which can be activated by its ligand hepatocyte growth factor (HGF).	4	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor receptor	hepatocyte growth factor receptor	hepatocyte growth factor receptor	21	24	4	8
However , it is likely that the requirement for RAS pathway activation for tumor development and progression in humans is achieved in the mouse through the activation of c-MET by HGF over-expression .	However, it is likely that the requirement for RAS pathway activation for tumor development and progression in humans is achieved in the mouse through the activation of c-MET by HGF over-expression.	26	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF over-expression	hgf	c-MET	c-MET	c-met	30	31	28	29
Taken together , our study shows that ROS contributes to HGF stimulated c-Met activation and that overexpressing the extracellular antioxidant enzyme , EcSOD suppresses this oncogenic cancer-fibroblast interaction .	Taken together, our study shows that ROS contributes to HGF stimulated c-Met activation and that overexpressing the extracellular antioxidant enzyme, EcSOD suppresses this oncogenic cancer-fibroblast interaction.	8	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	10	11	12	13
Both receptor and ligand are attractive therapeutic targets ; however , preclinical models are limited because murine HGF does not activate human c-Met .	Both receptor and ligand are attractive therapeutic targets; however, preclinical models are limited because murine HGF does not activate human c-Met.	16	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	17	18	22	23
The antagonistic interaction between VEGF and HGF and MET appeared specific , as neither EGF nor PDGF suppress P-MET or P-FAK induced by HGF ( XREF_SUPPLEMENTARY ) .	The antagonistic interaction between VEGF and HGF and MET appeared specific, as neither EGF nor PDGF suppress P-MET or P-FAK induced by HGF (XREF_SUPPLEMENTARY).	17	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	P-MET	P-MET	P-MET	23	24	18	19
Importantly , when HGF induced P-MET and P-FAK was tempered by VEGF in VEGFKO cells , N-cadherin was correspondingly suppressed ( XREF_FIG ) .	Importantly, when HGF induced P-MET and P-FAK was tempered by VEGF in VEGFKO cells, N-cadherin was correspondingly suppressed (XREF_FIG).	3	9	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	P-MET	P-MET	P-MET	3	4	5	6
Using specific inhibitors of phosphatidylinositol-3-kinase ( PI3K ) , protein kinase B ( Akt ) or focal adhesion kinase ( FAK ) , we demonstrated that in NS/P cells HGF activated c-Met induces PI3k-Akt signaling which then leads to FAK activation .	Using specific inhibitors of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) or focal adhesion kinase (FAK), we demonstrated that in NS/P cells HGF activated c-Met induces PI3k-Akt signaling which then leads to FAK activation.	29	32	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	29	30	31	32
ABT-700 activity differs from the recently reported anti-c-Met antibody LY2875358 [ XREF_BIBR ] in tumor cells where c-Met signaling can be driven by both receptor expression and HGF stimulation .	ABT-700 activity differs from the recently reported anti-c-Met antibody LY2875358 [XREF_BIBR] in tumor cells where c-Met signaling can be driven by both receptor expression and HGF stimulation.	17	28	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	27	28	17	18
Consistent with data from the previous experiment , activation of c-Met by HGF was prevented by knockdown of FASN in both KM20 and HT29 cell lines ( XREF_FIG ) .	Consistent with data from the previous experiment, activation of c-Met by HGF was prevented by knockdown of FASN in both KM20 and HT29 cell lines (XREF_FIG).	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	12	13	10	11
When Ser985 of c-Met was mutated to Aspartic acid for mimicking phosphorylation of this site , HGF induced activation of c-Met was prevented .	When Ser985 of c-Met was mutated to Aspartic acid for mimicking phosphorylation of this site, HGF induced activation of c-Met was prevented.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	16	17	20	21
c-MET crosstalk with EGFR has been demonstrated , 41 and indeed , EGFR inhibition has been shown to lead to abrogation of HGF induced c-MET activation , thus mitigating HGF induced migration .	c-MET crosstalk with EGFR has been demonstrated, 41 and indeed, EGFR inhibition has been shown to lead to abrogation of HGF induced c-MET activation, thus mitigating HGF induced migration.	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	22	23	24	25
Stromal cell secretion of hepatocyte growth factor ( HGF ) also activates the HGF receptor , c-Met ( cellular-mesenchymal to epithelial transition factor ) , and may contribute to PLX4032 resistance in melanoma .	Stromal cell secretion of hepatocyte growth factor (HGF) also activates the HGF receptor, c-Met (cellular-mesenchymal to epithelial transition factor), and may contribute to PLX4032 resistance in melanoma.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	HGF receptor	HGF receptor	HGF receptor	8	9	13	15
Abrogation of HGF induced c-Met and downstream signaling was seen in mesothelioma cells .	Abrogation of HGF induced c-Met and downstream signaling was seen in mesothelioma cells.	0	9	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	4	5
HGF induced elevation of p-beta-catenin and c-Myc levels observed in our study implies that beta-catenin participates in HGF mediated c-Met signaling in HCC cells .	HGF induced elevation of p-beta-catenin and c-Myc levels observed in our study implies that beta-catenin participates in HGF mediated c-Met signaling in HCC cells.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	17	18	19	20
After birth , c-Met activation by HGF is likely to be involved in epithelial-mesenchymal transition ( EMT ) , as well as hepatic , renal and epidermis regeneration [ XREF_BIBR , XREF_BIBR ] .	After birth, c-Met activation by HGF is likely to be involved in epithelial-mesenchymal transition (EMT), as well as hepatic, renal and epidermis regeneration [XREF_BIBR, XREF_BIBR].	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	6	7	3	4
Binding of HGF to c-Met activates the catalytic tyrosine kinase domain of c-Met and subsequently activates the MEK and PI3K signal pathways , contributing to the expression of the pro angiogenic factors IL-8 and VEGF XREF_BIBR .	Binding of HGF to c-Met activates the catalytic tyrosine kinase domain of c-Met and subsequently activates the MEK and PI3K signal pathways, contributing to the expression of the pro angiogenic factors IL-8 and VEGF XREF_BIBR.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	12	13
Based on the above findings , we hypothesized that short-term exogenous activation of c-MET by HGF might sensitize glioblastoma in vivo xenograft growth to inhibition by METi .	Based on the above findings, we hypothesized that short-term exogenous activation of c-MET by HGF might sensitize glioblastoma in vivo xenograft growth to inhibition by METi.	11	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	15	16	13	14
HGF induced activation of c-MET induced PI3K dependent phosphorylation of PKB and AKT and its substrates GSK3 and FOXO3a , contributing to its anti-apoptotic function [ XREF_BIBR ] .	HGF induced activation of c-MET induced PI3K dependent phosphorylation of PKB and AKT and its substrates GSK3 and FOXO3a, contributing to its anti-apoptotic function [XREF_BIBR].	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	0	1	4	5
In this study , we identified a pivotal endocytic motif in c-Met and tested it for selective modulation of HGF induced c-Met response .	In this study, we identified a pivotal endocytic motif in c-Met and tested it for selective modulation of HGF induced c-Met response.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	19	20	21	22
Elevated c-Met expression in tumor cells also leads to enhanced c-Met activity within the tumor tissue , since profound HGF expression within the tumor stroma activates c-Met on cancer cells in a paracrine manner .	Elevated c-Met expression in tumor cells also leads to enhanced c-Met activity within the tumor tissue, since profound HGF expression within the tumor stroma activates c-Met on cancer cells in a paracrine manner.	19	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF expression	hgf	c-Met	c-Met	c-met	19	20	26	27
Taken together , these studies suggest a key role for HGF independent and HGF dependent activation of c-MET as a molecular driver of CRC cell migration and invasion in vitro .	Taken together, these studies suggest a key role for HGF independent and HGF dependent activation of c-MET as a molecular driver of CRC cell migration and invasion in vitro.	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	13	14	17	18
In these cancers , c-Met may be aberrantly activated by mutation , autocrine or paracrine HGF stimulation or overexpression .	In these cancers, c-Met may be aberrantly activated by mutation, autocrine or paracrine HGF stimulation or overexpression.	4	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	15	16	4	5
Aberrant activation of HGF and c-MET signalling by mutation , autocrine or paracrine HGF stimulation , or overexpression has been implicated in the oncogenesis of large number of cancers [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Aberrant activation of HGF and c-MET signalling by mutation, autocrine or paracrine HGF stimulation, or overexpression has been implicated in the oncogenesis of large number of cancers [XREF_BIBR, XREF_BIBR - XREF_BIBR].	3	14	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	13	14	5	6
Treatment with 10 nM cabozantinib suppressed HGF activated pMET , pAKT , pERK and p-mTOR .	Treatment with 10 nM cabozantinib suppressed HGF activated pMET, pAKT, pERK and p-mTOR.	5	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	pMET	pMET	pMET	6	7	8	9
Of note , Khoury and coworkers [ XREF_BIBR ] recently demonstrated that HGF mediated c-met signalling in the presence of constitutively active HER2 leads to a downregulation of E-cad and promotes epithelial-mesenchymal transition in MDCK cells .	Of note, Khoury and coworkers [XREF_BIBR] recently demonstrated that HGF mediated c-met signalling in the presence of constitutively active HER2 leads to a downregulation of E-cad and promotes epithelial-mesenchymal transition in MDCK cells.	12	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-met	c-met	c-met	12	13	14	15
We previously elucidated that ligand activation of c-Met by HGF increases proliferation of HNSCC cells and a clinically relevant c-Met TKI , PF2341066 , inhibited HGF induced phosphorylation of both MAPK and AKT , and decreased wound healing in vitro .	We previously elucidated that ligand activation of c-Met by HGF increases proliferation of HNSCC cells and a clinically relevant c-Met TKI, PF2341066, inhibited HGF induced phosphorylation of both MAPK and AKT, and decreased wound healing in vitro.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	9	10	7	8
To determine whether HGF induced c-Met activation indeed caused increased cell motility , we determined the speed of single cells .	To determine whether HGF induced c-Met activation indeed caused increased cell motility, we determined the speed of single cells.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	5	6
c-Met activation by HGF was also shown to confer resistance to irreversible EGFR inhibitors .	c-Met activation by HGF was also shown to confer resistance to irreversible EGFR inhibitors.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	0	1
Our results showed that HES1 expression was up-regulated 8 days after HGF over-expression , whereas HGF induced c-Met activation was comparable to the control group at this time-point , suggesting that HGF and c-Met signalling could be negatively regulated by Notch3 and HES1 in VSMCs ; a finding consistent with a previous study showing negative feedback between HES1 and c-Met expression XREF_BIBR .	Our results showed that HES1 expression was up-regulated 8 days after HGF over-expression, whereas HGF induced c-Met activation was comparable to the control group at this time-point, suggesting that HGF and c-Met signalling could be negatively regulated by Notch3 and HES1 in VSMCs; a finding consistent with a previous study showing negative feedback between HES1 and c-Met expression XREF_BIBR.	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	15	16	17	18
XREF_BIBR - XREF_BIBR Murine hepatocyte growth factor ( HGF ) , the ligand for c-Met , does not activate human c-Met .	XREF_BIBR - XREF_BIBR Murine hepatocyte growth factor (HGF), the ligand for c-Met, does not activate human c-Met.	6	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	20	21
In addition to functioning as HGF activator , our data revealed novel function of MTP on HGF stimulated c-Met signaling activation .	In addition to functioning as HGF activator, our data revealed novel function of MTP on HGF stimulated c-Met signaling activation.	14	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	16	17	18	19
Sorafenib treatment and MMP inactivation inhibited HGF induced c-MET and MEK and ERK pathways .	Sorafenib treatment and MMP inactivation inhibited HGF induced c-MET and MEK and ERK pathways.	6	13	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	6	7	8	9
Through these intermediary pathways , HGF induced c-Met activation triggers a variety of cellular responses , including proliferation , survival , cytoskeleton rearrangements , cell-cell dissociation , and motility .	Through these intermediary pathways, HGF induced c-Met activation triggers a variety of cellular responses, including proliferation, survival, cytoskeleton rearrangements, cell-cell dissociation, and motility.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	7	8
Using in vitro and ex vivo models , we demonstrate that INC280 inhibits HGF induced c-MET , and reduces downstream signalling .	Using in vitro and ex vivo models, we demonstrate that INC280 inhibits HGF induced c-MET, and reduces downstream signalling.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	13	14	15	16
HGF induces dimerization and activation of the c-Met at the plasma membrane .	HGF induces dimerization and activation of the c-Met at the plasma membrane.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	7	8
These data indicated that HGF induces drug resistance by activating c-Met pathway in vivo .	These data indicated that HGF induces drug resistance by activating c-Met pathway in vivo.	4	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	10	11
In our recent study , we demonstrated that HGF induced c-Met endocytosis directs fluctuant JNK and paxillin signaling in a PKCepsilon- and GGA3 dependent manner , leading to HCC cell migration [ XREF_BIBR ] .	In our recent study, we demonstrated that HGF induced c-Met endocytosis directs fluctuant JNK and paxillin signaling in a PKCepsilon- and GGA3 dependent manner, leading to HCC cell migration [XREF_BIBR].	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	10	11
These findings provide in vitro evidence that sorafenib suppresses HGF induced EMT and cell migration and invasion , as well as HGF induced c-MET and MEK and ERK pathways .	These findings provide in vitro evidence that sorafenib suppresses HGF induced EMT and cell migration and invasion, as well as HGF induced c-MET and MEK and ERK pathways.	14	28	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	21	22	23	24
Chemically generated NK4 ( from recombinant human HGF/SF ) was found to be able to inhibit HGF induced activation ( tyrosine phosphorylation ) of the HGF/SF receptor cMET but was itself unable to activate cMET .	Chemically generated NK4 (from recombinant human HGF/SF) was found to be able to inhibit HGF induced activation (tyrosine phosphorylation) of the HGF/SF receptor cMET but was itself unable to activate cMET.	16	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	HGF/SF receptor	HGF/SF receptor	HGF/SF receptor	16	17	25	27
It is possible that the expression of HGF by these 5 cell lines does induce the motility of these c-met positive cells , which can also be homed to the liver via HGF secretion .	It is possible that the expression of HGF by these 5 cell lines does induce the motility of these c-met positive cells, which can also be homed to the liver via HGF secretion.	5	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	expression of HGF	hgf	c-met	c-met	c-met	7	8	19	20
To further investigate the mechanism of luteolin mediated decrease in HGF mediated c-Met activity , we performed Western blot analysis using whole cell lysates from DU145 cells treated with luteolin for various times .	To further investigate the mechanism of luteolin mediated decrease in HGF mediated c-Met activity, we performed Western blot analysis using whole cell lysates from DU145 cells treated with luteolin for various times.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	10	11	12	13
Together these studies prompted us to test whether Divalinal-AngIV ( divalinal ) could block HGF dependent activation of c-Met and the acquisition of MA dependence .	Together these studies prompted us to test whether Divalinal-AngIV (divalinal) could block HGF dependent activation of c-Met and the acquisition of MA dependence.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	14	15	18	19
c-Met activation by HGF altered the expression of 27-fold more genes in PTEN-null glioblastoma cells than in PTEN homozygous primary normal human astrocytes ( 523 vs 19 genes ) .	c-Met activation by HGF altered the expression of 27-fold more genes in PTEN-null glioblastoma cells than in PTEN homozygous primary normal human astrocytes (523 vs 19 genes).	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	0	1
Inversely , enhancement of the c-Met activation by exogenous HGF blocked endothelial and tubular apoptotic injuries and acute renal failure .	Inversely, enhancement of the c-Met activation by exogenous HGF blocked endothelial and tubular apoptotic injuries and acute renal failure.	5	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	9	10	5	6
Animals bearing pre-established tumor xenografts expressing activated c-Met were treated with either neutralizing anti- hepatocyte growth factor ( HGF ) monoclonal antibody L2G7 or with the c-Met kinase inhibitor PF2341066 ( Crizotinib ) .	Animals bearing pre-established tumor xenografts expressing activated c-Met were treated with either neutralizing anti- hepatocyte growth factor (HGF) monoclonal antibody L2G7 or with the c-Met kinase inhibitor PF2341066 (Crizotinib).	5	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-Met	c-Met	c-Met	14	17	7	8
MET gene encodes the receptor tyrosine kinase ( RTK ) MET or c-MET that is activated by the ligand HGF ( hepatocyte growth factor ) .	MET gene encodes the receptor tyrosine kinase (RTK) MET or c-MET that is activated by the ligand HGF (hepatocyte growth factor).	2	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	19	20	12	13
Despite an acute activation of Rac1 at the cell periphery , HGF induces c-Met trafficking to a perinulcear endosome for sustained activation of Rac1 , which triggers optimal membrane ruffling , cell migration , and invasion .	Despite an acute activation of Rac1 at the cell periphery, HGF induces c-Met trafficking to a perinulcear endosome for sustained activation of Rac1, which triggers optimal membrane ruffling, cell migration, and invasion.	11	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	13	14
During development and differentiation , HGF induced activation of c-Met initiates cell migration events .	During development and differentiation, HGF induced activation of c-Met initiates cell migration events.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	9	10
However , exogenous HGF failed to significantly reduce albuminuria in podo-met -/- mice , suggesting that podocyte specific c-met activation by HGF confers renal protection .	However, exogenous HGF failed to significantly reduce albuminuria in podo-met -/- mice, suggesting that podocyte specific c-met activation by HGF confers renal protection.	16	22	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-met	c-met	c-met	21	22	18	19
Stimulation of small lung cancer cells with HGF activates c-Met and increases phosphorylation of Y397 of FAK .	Stimulation of small lung cancer cells with HGF activates c-Met and increases phosphorylation of Y397 of FAK.	5	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	7	8	9	10
A possible explanation for this intriguing phenomenon is that short-term exogenous activation of c-MET by HGF triggers fast oncogene addiction that renders tumors dependent on c-MET .	A possible explanation for this intriguing phenomenon is that short-term exogenous activation of c-MET by HGF triggers fast oncogene addiction that renders tumors dependent on c-MET.	11	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	15	16	13	14
Hepatocyte growth factor mediated c-MET activation was also a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR activating mutations .	Hepatocyte growth factor mediated c-MET activation was also a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR activating mutations.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Hepatocyte growth factor	Hepatocyte growth factor	Hepatocyte growth factor	c-MET	c-MET	c-MET	0	3	4	5
The physical association between MET and VEGFR2 was observed independent of stimulation of either receptor with its cognate ligand , but P-MET co-precipitated only when cells were stimulated with HGF , and addition of VEGF suppressed HGF stimulated P-MET only when cells were transduced with WT-VEGR2 , not VEGFR2-Delta450C ( XREF_FIG ) .	The physical association between MET and VEGFR2 was observed independent of stimulation of either receptor with its cognate ligand, but P-MET co-precipitated only when cells were stimulated with HGF, and addition of VEGF suppressed HGF stimulated P-MET only when cells were transduced with WT-VEGR2, not VEGFR2-Delta450C (XREF_FIG).	35	39	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	P-MET	P-MET	P-MET	36	37	38	39
Our results now show that hepatocyte growth factor synthesized by myofibroblasts associated with prostate cancer cells induces activation of HGF-receptor and cMet and stimulates hyaluronan and CD44v9 signaling .	Our results now show that hepatocyte growth factor synthesized by myofibroblasts associated with prostate cancer cells induces activation of HGF-receptor and cMet and stimulates hyaluronan and CD44v9 signaling.	5	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	HGF-receptor	HGF-receptor	HGF-receptor	5	8	19	20
HGF mediated activation of c-MET promotes CRC cell migration and invasion .	HGF mediated activation of c-MET promotes CRC cell migration and invasion.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	0	1	4	5
Migration of lung endothelial cells requires HGF mediated activation of c-MET , which signals through the PI3K and Akt pathway and results in the accumulation of p47 phox / Rac1 in lamellipodia and localized production of H 2 O 2 to the leading edge of the cell .	Migration of lung endothelial cells requires HGF mediated activation of c-MET, which signals through the PI3K and Akt pathway and results in the accumulation of p47 phox / Rac1 in lamellipodia and localized production of H 2 O 2 to the leading edge of the cell.	6	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	6	7	10	11
PKG II blocks HGF induced c-Met activation in AGS and HGC-27 cells .	PKG II blocks HGF induced c-Met activation in AGS and HGC-27 cells.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	5	6
Based on fluorescence staining of c-Met , c-Met expression was prominent on the U87MG tumor cells but absent on the MDA-MB-231 cells and rh-HGF can target c-Met with high specificity ( XREF_FIG ) .	Based on fluorescence staining of c-Met, c-Met expression was prominent on the U87MG tumor cells but absent on the MDA-MB-231 cells and rh-HGF can target c-Met with high specificity (XREF_FIG).	23	27	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	rh-HGF	rh-HGF	rh-HGF	c-Met	c-Met	c-Met	23	24	26	27
In addition , HGF accelerates the emergence of c-MET amplification in gefitinib resistant lung cancer cells .	In addition, HGF accelerates the emergence of c-MET amplification in gefitinib resistant lung cancer cells.	3	9	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	3	4	8	9
Importantly , HGF induced c-MET activation promoted rapid downregulation of c-MET protein levels , while the MET transcript remained unaltered .	Importantly, HGF induced c-MET activation promoted rapid downregulation of c-MET protein levels, while the MET transcript remained unaltered.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	2	3	4	5
Analysis of mRNA expression of key informative genes showed that HGF induces downregulation of PI3K a component of the HGF and c-Met pathway that is involved in apoptosis protection .	Analysis of mRNA expression of key informative genes showed that HGF induces downregulation of PI3K a component of the HGF and c-Met pathway that is involved in apoptosis protection.	10	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	10	11	21	22
Moreover , stromal secretion of hepatocyte growth factor was recently demonstrated to activate the c-MET pathway and leads to resistance to EGFR-TKIs in breast cancers , an effect already well-known in non small cell lung cancer [ XREF_BIBR ] .	Moreover, stromal secretion of hepatocyte growth factor was recently demonstrated to activate the c-MET pathway and leads to resistance to EGFR-TKIs in breast cancers, an effect already well-known in non small cell lung cancer [XREF_BIBR].	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-MET	c-MET	c-MET	5	8	14	15
Next , we wished to determine whether Spsb1 could potentiate HGF induced c-Met signaling .	Next, we wished to determine whether Spsb1 could potentiate HGF induced c-Met signaling.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	10	11	12	13
CLN0003_SL1 , a 50-mer DNA aptamer that binds to the c-Met protein , was found to inhibit HGF induced c-Met activation .	CLN0003_SL1, a 50-mer DNA aptamer that binds to the c-Met protein, was found to inhibit HGF induced c-Met activation.	16	20	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	17	18	19	20
Exogenous HGF rescued c-MET pathway activity in the presence of TGF-beta .	Exogenous HGF rescued c-MET pathway activity in the presence of TGF-beta.	0	5	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	1	2	3	4
However , the simultaneous addition of Ngal and HGF leads to direct association of the two proteins , and results in a partial inhibition of HGF mediated activation of c-Met and the downstream MAPK and phosphatidylinositol 3-kinase signaling pathways .	However, the simultaneous addition of Ngal and HGF leads to direct association of the two proteins, and results in a partial inhibition of HGF mediated activation of c-Met and the downstream MAPK and phosphatidylinositol 3-kinase signaling pathways.	25	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	25	26	29	30
A similar association between gefitinib resistance and HGF induced c-MET activation has also been reported for lung adenocarcinomas containing activating EGFR mutations XREF_BIBR .	A similar association between gefitinib resistance and HGF induced c-MET activation has also been reported for lung adenocarcinomas containing activating EGFR mutations XREF_BIBR.	2	10	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	7	8	9	10
When A549 cells , which express c-MET but not phospho-c-MET ( XREF_SUPPLEMENTARY ) , were treated with HGF ligand , phospho-c-MET level was increased and downstream AKT and ERK signaling was also significantly activated .	When A549 cells, which express c-MET but not phospho-c-MET (XREF_SUPPLEMENTARY), were treated with HGF ligand, phospho-c-MET level was increased and downstream AKT and ERK signaling was also significantly activated.	5	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	17	18	6	7
Although beta1-integrin in a complex with tensin-4 and Met maintains the stability of Met , another clinically relevant oncogenic GFR , alpha6beta4-integrin is important for HGF mediated activation of c-Met to drive tumorigenesis and cancer cell invasion .	Although beta1-integrin in a complex with tensin-4 and Met maintains the stability of Met, another clinically relevant oncogenic GFR, alpha6beta4-integrin is important for HGF mediated activation of c-Met to drive tumorigenesis and cancer cell invasion.	25	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	25	26	29	30
IRCR201 also demonstrates low agonistic activity and disrupts c-Met signaling pathway activation induced by both HGF dependent and independent mechanisms in various cancer types , eliciting distinct molecular traits compared to other c-Met-targeting antibodies .	IRCR201 also demonstrates low agonistic activity and disrupts c-Met signaling pathway activation induced by both HGF dependent and independent mechanisms in various cancer types, eliciting distinct molecular traits compared to other c-Met-targeting antibodies.	8	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	15	16	8	9
Paracrine HGF induced activation of c-MET plays in important role in the pathogenesis of gastric cancers .	Paracrine HGF induced activation of c-MET plays in important role in the pathogenesis of gastric cancers.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	1	2	5	6
The addition of a secondary kinase inhibitor , crizotinib , blocked HGF induced pMET and pERK activation , restoring sensitivity to erlotinib .	The addition of a secondary kinase inhibitor, crizotinib, blocked HGF induced pMET and pERK activation, restoring sensitivity to erlotinib.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	pMET	pMET	pMET	11	12	13	14
According to Bogler ' s model , autocrined HGF activates c-MET signaling to enhance HGF expression in DeltaEGFR expressing GBM cells ( Garnett etal ., 2013 ) .	According to Bogler 's model, autocrined HGF activates c-MET signaling to enhance HGF expression in DeltaEGFR expressing GBM cells (Garnett etal., 2013).	7	11	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	8	9	10	11
The decrease in pMet appeared to coincide with the loss of total c-Met , suggesting that the perceived reduction in HGF mediated activation of c-Met is likely due to the reduction in total c-Met protein .	The decrease in pMet appeared to coincide with the loss of total c-Met, suggesting that the perceived reduction in HGF mediated activation of c-Met is likely due to the reduction in total c-Met protein.	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	20	21	24	25
c-Met activation by scatter factor and hepatocyte growth factor ( SF/HGF ) altered the expression of 27-fold more genes in PTEN-null U-373MG cells than in PTEN homozygous primary normal human astrocytes ( 523 vs 19 genes ) .	c-Met activation by scatter factor and hepatocyte growth factor (SF/HGF) altered the expression of 27-fold more genes in PTEN-null U-373MG cells than in PTEN homozygous primary normal human astrocytes (523 vs 19 genes).	0	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-Met	c-Met	c-Met	6	9	0	1
Among them , hepatocyte growth factor ( HGF ) ( also known as scattering factor ) activates the c-Met signaling pathway , thereby increasing the invasive and metastatic potentials of the cells and allowing the survival of cancer cells in the bloodstream in the absence of anchorage .	Among them, hepatocyte growth factor (HGF) (also known as scattering factor) activates the c-Met signaling pathway, thereby increasing the invasive and metastatic potentials of the cells and allowing the survival of cancer cells in the bloodstream in the absence of anchorage.	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	7	8	18	19
XREF_BIBR Ficlatuzumab ( AV-299 ; SCH 900105 , AVEO Pharmaceuticals , Cambridge , MA , USA ) is a humanized monoclonal antibody against HGF that inhibits the HGF induced c-Met signaling pathway by neutralizing HGF and c-Met binding .	XREF_BIBR Ficlatuzumab (AV-299; SCH 900105, AVEO Pharmaceuticals, Cambridge, MA, USA) is a humanized monoclonal antibody against HGF that inhibits the HGF induced c-Met signaling pathway by neutralizing HGF and c-Met binding.	26	31	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	27	28	29	30
When EGCG treatment was given after the addition of HGF , cell scattering was blocked and there was reduction in the HGF induced phosphorylation of c-Met , Akt , and ERK1/2 , signifying that EGCG could prevent activation of c-Met by HGF and decrease the activity of pathways induced by HGF [ XREF_BIBR ] .	When EGCG treatment was given after the addition of HGF, cell scattering was blocked and there was reduction in the HGF induced phosphorylation of c-Met, Akt, and ERK1/2, signifying that EGCG could prevent activation of c-Met by HGF and decrease the activity of pathways induced by HGF [XREF_BIBR].	36	42	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	41	42	39	40
Among these signaling molecules , Hepatocyte Growth Factor ( HGF ) is released by many cell types of the tumor microenvironment to target its receptor c-MET within the cells of the primary tumor .	Among these signaling molecules, Hepatocyte Growth Factor (HGF) is released by many cell types of the tumor microenvironment to target its receptor c-MET within the cells of the primary tumor.	5	26	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hepatocyte Growth Factor	Hepatocyte Growth Factor	Hepatocyte Growth Factor	c-MET	c-MET	c-MET	5	8	25	26
We demonstrate that c-Met activation by hepatocyte growth factor / scatter factor ( HGF ) leads to a survival cascade , while its blockade results in induction of mature B cell death .	We demonstrate that c-Met activation by hepatocyte growth factor / scatter factor (HGF) leads to a survival cascade, while its blockade results in induction of mature B cell death.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-Met	c-Met	c-Met	6	9	3	4
In tumor cells , c-Met activation mediated by HGF causes the triggering of a diverse series of signaling cascades resulting in cell growth , proliferation , invasion , and protection from apoptosis .	In tumor cells, c-Met activation mediated by HGF causes the triggering of a diverse series of signaling cascades resulting in cell growth, proliferation, invasion, and protection from apoptosis.	4	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	4	5
Moreover , (-)-oleocanthal treatment effects were found to be mediated via inhibition of HGF induced c-Met activation and its downstream mitogenic signaling pathways .	Moreover, (-)-oleocanthal treatment effects were found to be mediated via inhibition of HGF induced c-Met activation and its downstream mitogenic signaling pathways.	11	16	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	13	14	15	16
c-Met activation by HGF treatment also significantly induced cell cycle progression in all tested cells .	c-Met activation by HGF treatment also significantly induced cell cycle progression in all tested cells.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	0	1
Since a high basal level of phosphorylated c-Met is also observed in PC-3 cells , it was anticipated that an HGF and c-Met autocrine loop that induces constitutive c-Met activation exist in this cell line .	Since a high basal level of phosphorylated c-Met is also observed in PC-3 cells, it was anticipated that an HGF and c-Met autocrine loop that induces constitutive c-Met activation exist in this cell line.	19	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	20	21	28	29
Furthermore , we demonstrate that the recurrence promoting effects of Spsb1 are due to its ability to protect cells from apoptosis induced by chemotherapy as well as by HER2 and neu pathway inhibition , and that the pro survival effects of Spsb1 are attributable to its ability to potentiate HGF induced c-MET signaling .	Furthermore, we demonstrate that the recurrence promoting effects of Spsb1 are due to its ability to protect cells from apoptosis induced by chemotherapy as well as by HER2 and neu pathway inhibition, and that the pro survival effects of Spsb1 are attributable to its ability to potentiate HGF induced c-MET signaling.	48	52	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	49	50	51	52
Here , we report that HGF mediated c-Met stimulation triggers a mesenchymal-type collective cell invasion .	Here, we report that HGF mediated c-Met stimulation triggers a mesenchymal-type collective cell invasion.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	7	8
Even though HGF activates c-Met in INA-6 cells the effects of HGF on cell proliferation in this cell line are moderate .	Even though HGF activates c-Met in INA-6 cells the effects of HGF on cell proliferation in this cell line are moderate.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	4	5
The mechanisms of deregulation of the c-Met receptor are wide ranging and include overexpression and mutation of the receptor leading to constitutive kinase activation in the presence or absence of gene amplification as well as paracrine or autocrine activation of c-Met by HGF [ XREF_BIBR ] .	The mechanisms of deregulation of the c-Met receptor are wide ranging and include overexpression and mutation of the receptor leading to constitutive kinase activation in the presence or absence of gene amplification as well as paracrine or autocrine activation of c-Met by HGF [XREF_BIBR].	38	44	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	42	43	40	41
We additionally report the generation of another c-Met specific aptamer CLN64 with rRfY ( 2 '-ribo purine and 2 '-fluoro pyrimidine ) composition and its influence on HGF dependent activation of the c-Met pathway .	We additionally report the generation of another c-Met specific aptamer CLN64 with rRfY (2 '-ribo purine and 2 '-fluoro pyrimidine) composition and its influence on HGF dependent activation of the c-Met pathway.	27	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	27	28	32	33
In contrast to the bivalent DN30 , a one armed antibody ( OA-5D5 ) was developed by Genentech , thereby preventing HGF mediated activation of c-MET , and resulting in suppressed growth in multiple cancer models .	In contrast to the bivalent DN30, a one armed antibody (OA-5D5) was developed by Genentech, thereby preventing HGF mediated activation of c-MET, and resulting in suppressed growth in multiple cancer models.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	21	22	25	26
XREF_BIBR A recent report has shown that stromal cell secretion of HGF in the tumor microenvironment resulted in activation of HGF receptor Met , and of MAPK and phosphatidylinositol-3-OH kinase-Akt signaling pathways in human melanoma cells .	XREF_BIBR A recent report has shown that stromal cell secretion of HGF in the tumor microenvironment resulted in activation of HGF receptor Met, and of MAPK and phosphatidylinositol-3-OH kinase-Akt signaling pathways in human melanoma cells.	9	22	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	HGF receptor	HGF receptor	HGF receptor	11	12	20	22
Expression of the HGF receptor c-Met in these models was predominantly found in vascular endothelial cells and not in tumor cells , therefore suggesting a role for HGF stimulated c-Met signaling in endothelial cells to bypass anti-VEGF therapy .	Expression of the HGF receptor c-Met in these models was predominantly found in vascular endothelial cells and not in tumor cells, therefore suggesting a role for HGF stimulated c-Met signaling in endothelial cells to bypass anti-VEGF therapy.	25	30	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	27	28	29	30
It shows an association of mutated NRAS with increased HGF dependent activation of c-Met and with enhanced sensitivity to c-Met inhibition [ XREF_BIBR ] .	It shows an association of mutated NRAS with increased HGF dependent activation of c-Met and with enhanced sensitivity to c-Met inhibition [XREF_BIBR].	9	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	9	10	13	14
HGF induced c-Met activation drives an intricate cascade of molecular events , involving multiple downstream targets , such as the mitogen activated protein kinase ( MAPK ) and PI3K pathways .	HGF induced c-Met activation drives an intricate cascade of molecular events, involving multiple downstream targets, such as the mitogen activated protein kinase (MAPK) and PI3K pathways.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	2	3
Hepatocyte growth factor ( HGF ) binding to c-Met causes c-Met dimerization , which helps to initiate various cellular signaling cascades including AKT , ERK and MAPK , and JNK .	Hepatocyte growth factor (HGF) binding to c-Met causes c-Met dimerization, which helps to initiate various cellular signaling cascades including AKT, ERK and MAPK, and JNK.	0	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hepatocyte growth factor	Hepatocyte growth factor	Hepatocyte growth factor	c-Met	c-Met	c-Met	0	3	10	11
Stimulation of c-MET by HGF showed a clear increase of Bcl-xl and Mcl-1 suggesting that tivantinib might antagonize the effect of c-MET-dependent expression of these molecules in cells overexpressing this receptor regardless of the inhibitory effect of tivantinib on the kinase activity of c-MET .	Stimulation of c-MET by HGF showed a clear increase of Bcl-xl and Mcl-1 suggesting that tivantinib might antagonize the effect of c-MET-dependent expression of these molecules in cells overexpressing this receptor regardless of the inhibitory effect of tivantinib on the kinase activity of c-MET.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	4	5	2	3
Because COX-2 action is downstream of c-Met signaling induced by HGF as well as upstream of HGF independent lateral signaling to c-Met in NSCLC 9 , we examined whether the combination of inhibiting the c-Met pathway with crizotinib and the COX-2 pathway with celecoxib would have enhanced anti-proliferative effects in NSCLC .	Because COX-2 action is downstream of c-Met signaling induced by HGF as well as upstream of HGF independent lateral signaling to c-Met in NSCLC 9, we examined whether the combination of inhibiting the c-Met pathway with crizotinib and the COX-2 pathway with celecoxib would have enhanced anti-proliferative effects in NSCLC.	6	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	10	11	6	7
One effect of HGF mediated c-MET activation is increased angiogenesis and reduced fibrosis .	One effect of HGF mediated c-MET activation is increased angiogenesis and reduced fibrosis.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	3	4	5	6
We next demonstrated that myofibroblast derived conditioned medium can further potentiate migration and invasion of CRC cells through HGF dependent activation of c-MET in CRC cells .	We next demonstrated that myofibroblast derived conditioned medium can further potentiate migration and invasion of CRC cells through HGF dependent activation of c-MET in CRC cells.	18	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	18	19	22	23
Taken together , these results suggested that HGF could directly interact with SCs to activate c-met and subsequently increase migration and proliferation of SCs .	Taken together, these results suggested that HGF could directly interact with SCs to activate c-met and subsequently increase migration and proliferation of SCs.	7	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-met	c-met	c-met	7	8	15	16
HGF upregulated c-Met and phosphorylated Met expression in MSCs .	HGF upregulated c-Met and phosphorylated Met expression in MSCs.	0	4	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	2	3
Additionally , deguelin suppressed HGF induced activation of the c-Met signaling pathway .	Additionally, deguelin suppressed HGF induced activation of the c-Met signaling pathway.	4	11	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	9	10
HGF secreted by stromal cells in the tumor microenvironment can activate the HGF receptor MET , initiating MAPK and PI3K signaling to confer resistance to BRAF inhibition .	HGF secreted by stromal cells in the tumor microenvironment can activate the HGF receptor MET, initiating MAPK and PI3K signaling to confer resistance to BRAF inhibition.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	HGF receptor	HGF receptor	HGF receptor	0	1	12	14
If Egr1 is a target of the HGF and c-Met signaling pathway and heparin inhibits HGF induced migration and invasion via Egr1 , then heparin is likely to inhibit HGF induced c-Met activation and downstream signaling .	If Egr1 is a target of the HGF and c-Met signaling pathway and heparin inhibits HGF induced migration and invasion via Egr1, then heparin is likely to inhibit HGF induced c-Met activation and downstream signaling.	28	32	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	29	30	31	32
Our results also showed that silencing of MUC1 by siRNA upregulated HGF mediated c-Met signaling network .	Our results also showed that silencing of MUC1 by siRNA upregulated HGF mediated c-Met signaling network.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	13	14
In such cells , namely human hepatoma cells HepG2 , ICAM-1 can be coimmunoprecipitated with c-Met , and siRNAs against ICAM-1 abrogate HGF induced c-Met and Erk activation .	In such cells, namely human hepatoma cells HepG2, ICAM-1 can be coimmunoprecipitated with c-Met, and siRNAs against ICAM-1 abrogate HGF induced c-Met and Erk activation.	22	27	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	22	23	24	25
In conclusion , HGF could stimulate the growth of certain human hepatoma cells , probably through activation of c-Met and MAPKs .	In conclusion, HGF could stimulate the growth of certain human hepatoma cells, probably through activation of c-Met and MAPKs.	3	20	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	18	19
HGF activation of c-MET causes homodimerization and trans-phosphorylation at tyrosines ( Tyr ) 1234/1235 in the c-MET catalytic domain .	HGF activation of c-MET causes homodimerization and trans-phosphorylation at tyrosines (Tyr) 1234/1235 in the c-MET catalytic domain.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	0	1	3	4
XREF_BIBR , XREF_BIBR Because HGF activates c-Met through phosphorylation at the active residues Tyr 1234 and Tyr 1235 , we focused on PTP1B , which regulates this pathway and influences proliferation through phosphorylation of ERK1/2 .	XREF_BIBR, XREF_BIBR Because HGF activates c-Met through phosphorylation at the active residues Tyr 1234 and Tyr 1235, we focused on PTP1B, which regulates this pathway and influences proliferation through phosphorylation of ERK1/2.	3	7	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	6	7
This HGF mediated c-Met signaling activates multiple downstream targets , including the PI3 and AKT pathway , and the c-Met docking protein , Gab1 .	This HGF mediated c-Met signaling activates multiple downstream targets, including the PI3 and AKT pathway, and the c-Met docking protein, Gab1.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	1	2	3	4
SOMG-833 strongly suppressed c-MET-mediated signaling transduction regardless of mechanistic complexity implicated in c-MET activation , including MET gene amplification , MET gene fusion , and HGF stimulated c-MET activation .	SOMG-833 strongly suppressed c-MET-mediated signaling transduction regardless of mechanistic complexity implicated in c-MET activation, including MET gene amplification, MET gene fusion, and HGF stimulated c-MET activation.	25	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	25	26	27	28
c-Met and HGF are reported to be overexpressed in over 80 % of HNSCCs and increased c-Met copy numbers in 13 % of HNSCC tumor samples .	c-Met and HGF are reported to be overexpressed in over 80% of HNSCCs and increased c-Met copy numbers in 13% of HNSCC tumor samples.	0	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	16	17
Since c-Met activation by HGF induces similar downstream pathways as EGFR in HNSCC , c-Met may either act in consort with EGFR or act as a compensatory signaling pathway in the setting of EGFR blockade or vice versa .	Since c-Met activation by HGF induces similar downstream pathways as EGFR in HNSCC, c-Met may either act in consort with EGFR or act as a compensatory signaling pathway in the setting of EGFR blockade or vice versa.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	1	2
Antibodies that abrogate the activation of c-Met by HGF significantly inhibit xenograft growth of colon tumors .	Antibodies that abrogate the activation of c-Met by HGF significantly inhibit xenograft growth of colon tumors.	2	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	6	7
As observed above , there was a significant downregulation of HGF activated c-Met after treatment with MTE combined with erlotinib or gefitinib , while each drug alone had no obvious influence on phosphorylated Met expression .	As observed above, there was a significant downregulation of HGF activated c-Met after treatment with MTE combined with erlotinib or gefitinib, while each drug alone had no obvious influence on phosphorylated Met expression.	8	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	10	11	12	13
Hepatocyte growth factor induced c-MET activation leads to increased membrane ruffling , filopodia formation , and also motility and migration in SCLC ( Maulik et al , 2002a ) .	Hepatocyte growth factor induced c-MET activation leads to increased membrane ruffling, filopodia formation, and also motility and migration in SCLC (Maulik et al, 2002a).	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Hepatocyte growth factor	Hepatocyte growth factor	Hepatocyte growth factor	c-MET	c-MET	c-MET	0	3	4	5
In contrast , c-Met phosphorylation was only 1.8-fold in cells treated with Sema4D and HGF , a difference which was significant ( p < 0.05 ) .	In contrast, c-Met phosphorylation was only 1.8-fold in cells treated with Sema4D and HGF, a difference which was significant (p < 0.05).	3	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	14	15	3	4
We found that HGF induced activation of c-Met signaling increased the expression level of Egr1 , parallel to increased adhesion , motility and invasion of HCC cell lines .	We found that HGF induced activation of c-Met signaling increased the expression level of Egr1, parallel to increased adhesion, motility and invasion of HCC cell lines.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	7	8
The results of our study demonstrated that c-Met was activated by HGF stimulation in ESCC , as in other malignancies .	The results of our study demonstrated that c-Met was activated by HGF stimulation in ESCC, as in other malignancies.	7	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	7	8
We demonstrated that c-Met activation by its ligand HGF promotes single cell motility of MB cells and their invasion into Matrigel and 3D collagen gels .	We demonstrated that c-Met activation by its ligand HGF promotes single cell motility of MB cells and their invasion into Matrigel and 3D collagen gels.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	3	4
The molecular mechanisms of c-Met activation by HGF are still unclear .	The molecular mechanisms of c-Met activation by HGF are still unclear.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	7	8	4	5
Our data show that HGF stimulated the motility of UM cells , and induced the activation of both c-MET and PI3K and AKT , but not ERK1/2 .	Our data show that HGF stimulated the motility of UM cells, and induced the activation of both c-MET and PI3K and AKT, but not ERK1/2.	4	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	4	5	18	19
However , dysregulation of c-Met signaling caused by receptor mutation , c-Met or HGF overexpression , gene amplification , or transcriptional upregulation can result in various pathological outcomes , including cancer [ XREF_BIBR - XREF_BIBR ] .	However, dysregulation of c-Met signaling caused by receptor mutation, c-Met or HGF overexpression, gene amplification, or transcriptional upregulation can result in various pathological outcomes, including cancer [XREF_BIBR - XREF_BIBR].	4	15	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF overexpression	hgf	c-Met	c-Met	c-met	13	14	4	5
HGF mediated c-Met activation induces collective cancer cell invasion through beta1 integrin trafficking .	HGF mediated c-Met activation induces collective cancer cell invasion through beta1 integrin trafficking.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	2	3
Thus , an unidentified adaptor protein of c-Met may be a key determinant to recruit PIP5K1A to HGF stimulated c-Met .	Thus, an unidentified adaptor protein of c-Met may be a key determinant to recruit PIP5K1A to HGF stimulated c-Met.	14	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	17	18	19	20
MET ( the hepatocyte growth factor receptor , HGFR , also known as c-Met , AUTS9 ; RCCP2 ; DFNB97 , and as mesenchymal-epithelial transition factor ) is activated by its ligand HGF and exerts broad biological effects associated with malignancy including cell proliferation , cell scattering and migration , induction of cell polarity , and angiogenesis .	MET (the hepatocyte growth factor receptor, HGFR, also known as c-Met, AUTS9; RCCP2; DFNB97, and as mesenchymal-epithelial transition factor) is activated by its ligand HGF and exerts broad biological effects associated with malignancy including cell proliferation, cell scattering and migration, induction of cell polarity, and angiogenesis.	3	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	hepatocyte growth factor receptor	hepatocyte growth factor receptor	hepatocyte growth factor receptor	32	33	3	7
Moreover , our data showed stimulatory effect of CAV1 on c-Met signaling , as overexpression of CAV1 accelerated HGF induced c-Met , and silencing of CAV1 reduced activation of c-Met .	Moreover, our data showed stimulatory effect of CAV1 on c-Met signaling, as overexpression of CAV1 accelerated HGF induced c-Met, and silencing of CAV1 reduced activation of c-Met.	18	21	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	18	19	20	21
HGF was found to induce c-MET activation and ERK activation , together with increased COX2 protein expression ; these changes were followed by a subsequent increase in invasive activity .	HGF was found to induce c-MET activation and ERK activation, together with increased COX2 protein expression; these changes were followed by a subsequent increase in invasive activity.	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	0	1	5	6
Interestingly , other natural products such as (-)-oleocanthal , which is derived from olive oil , can inhibit HGF induced c-Met activation and its invasive properties in breast cancer XREF_BIBR .	Interestingly, other natural products such as (-)-oleocanthal, which is derived from olive oil, can inhibit HGF induced c-Met activation and its invasive properties in breast cancer XREF_BIBR.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	18	19	20	21
This result confirms that c-Met activation in this melanoma cell line is mediated exclusively by HGF and not by another secreted factor in the conditioned medium .	This result confirms that c-Met activation in this melanoma cell line is mediated exclusively by HGF and not by another secreted factor in the conditioned medium.	4	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	15	16	4	5
Conversely , knockdown of endogenous SPSB1 impaired HGF induced c-MET activation in human Hs578T breast cancer cells and in mouse HER2 and neu primary mammary tumor cells subjected to HER2 and neu down-regulation ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Conversely, knockdown of endogenous SPSB1 impaired HGF induced c-MET activation in human Hs578T breast cancer cells and in mouse HER2 and neu primary mammary tumor cells subjected to HER2 and neu down-regulation (XREF_FIG and XREF_SUPPLEMENTARY).	2	10	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	7	8	9	10
Furthermore , HGF has been shown to accelerate the emergence of c-MET amplification in gefitinib resistant lung cancer cells .	Furthermore, HGF has been shown to accelerate the emergence of c-MET amplification in gefitinib resistant lung cancer cells.	2	12	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	2	3	11	12
For example , IGF-1R is often activated by IGF-1 secreted by the liver , and c-Met is often activated by HGF secreted from stromal cells or activated in a ligand independent manner .	For example, IGF-1R is often activated by IGF-1 secreted by the liver, and c-Met is often activated by HGF secreted from stromal cells or activated in a ligand independent manner.	15	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	20	21	15	16
Taken together , these data suggest that ABT-700 is a differentiated anti-c-Met antibody with strong antagonistic effect on both HGF independent constitutive c-Met signaling and HGF dependent activation of c-Met .	Taken together, these data suggest that ABT-700 is a differentiated anti-c-Met antibody with strong antagonistic effect on both HGF independent constitutive c-Met signaling and HGF dependent activation of c-Met.	25	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	25	26	29	30
Finally , we investigated whether LZ8 could block HGF induced c-Met signaling in HepG2 .	Finally, we investigated whether LZ8 could block HGF induced c-Met signaling in HepG2.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	10	11
c-Met and RON can be activated by HGF and macrophage stimulating protein ( MSP ) , respectively .	c-Met and RON can be activated by HGF and macrophage stimulating protein (MSP), respectively.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	7	8	0	1
Since the HGF and c-Met signaling axis upregulates both MET gene expression and HIF-1 activity , amplification of HGF induced c-Met signaling by hypoxia indicates a positive feedback loop between HIF-1 and c-Met ; one that could drive oxygen deprived cancer cells toward a more metastatic state .	Since the HGF and c-Met signaling axis upregulates both MET gene expression and HIF-1 activity, amplification of HGF induced c-Met signaling by hypoxia indicates a positive feedback loop between HIF-1 and c-Met; one that could drive oxygen deprived cancer cells toward a more metastatic state.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	18	19	20	21
To induce the c-Met phosphorylation , the cells were treated with HGF or infected with the H. pylori cagA mutant strain before lysis .	To induce the c-Met phosphorylation, the cells were treated with HGF or infected with the H. pylori cagA mutant strain before lysis.	3	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	3	4
To further ensure that these microarray results accurately identified previously reported components of the HGF stimulated c-Met pathway , we performed immunoblot analyses to confirm the expected phosphorylation events of a subset of the known targets , namely pSer473 of AKT , pThr202 and pTyr204 of ERK1/2 , pThr218 and pTry220 of mitogen activated protein kinase 7 ( MAPK7 and ERK5 ) XREF_BIBR , and pSer380 of 90 kDa ribosomal S6 kinases ( p90RSK ) XREF_BIBR .	To further ensure that these microarray results accurately identified previously reported components of the HGF stimulated c-Met pathway, we performed immunoblot analyses to confirm the expected phosphorylation events of a subset of the known targets, namely pSer473 of AKT, pThr202 and pTyr204 of ERK1/2, pThr218 and pTry220 of mitogen activated protein kinase 7 (MAPK7 and ERK5) XREF_BIBR, and pSer380 of 90 kDa ribosomal S6 kinases (p90RSK) XREF_BIBR.	11	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	14	15	16	17
Consequently , there is a positive feedback in HGF mediated c-Met signalling , that has not been previously reported .	Consequently, there is a positive feedback in HGF mediated c-Met signalling, that has not been previously reported.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	8	9	10	11
To test whether HGF induced phenotypes could report c-Met activation , HGF was added in the presence of the c-Met function blocking Fab antibody , Genentech 5D5 Fab ( Genentech , South San Francisco , CA ) .	To test whether HGF induced phenotypes could report c-Met activation, HGF was added in the presence of the c-Met function blocking Fab antibody, Genentech 5D5 Fab (Genentech, South San Francisco, CA).	3	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	8	9
PHA665752 completely abrogated HGF mediated activation of c-Met in SH-EP cells as determined by p-Met ( Y1234/1235 ) levels ; PHA665752 also completely blocked HGF induced phosphorylation of both MAPK and PI3-K downstream signaling , using p-Erk 1/2 and p-Akt ( ser473 ) levels as surrogate markers , respectively .	PHA665752 completely abrogated HGF mediated activation of c-Met in SH-EP cells as determined by p-Met (Y1234/1235) levels; PHA665752 also completely blocked HGF induced phosphorylation of both MAPK and PI3-K downstream signaling, using p-Erk 1/2 and p-Akt (ser473) levels as surrogate markers, respectively.	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	7	8
Work from our lab demonstrated fibroblasts from normal human ovaries secrete high levels of hepatocyte growth factor , ( HGF ) which binds to and activate c-MET mediated signaling on EOC tumor cells .	Work from our lab demonstrated fibroblasts from normal human ovaries secrete high levels of hepatocyte growth factor, (HGF) which binds to and activate c-MET mediated signaling on EOC tumor cells.	12	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hepatocyte growth factor	levels of hepatocyte growth factor	hepatocyte growth factor	c-MET	c-MET	c-met	14	17	26	27
Heparin inhibits HGF induced activation of c-Met and ERK1/2 , MMP-2 and MMP-9 .	Heparin inhibits HGF induced activation of c-Met and ERK1/2, MMP-2 and MMP-9.	2	12	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	6	7
As neutralizing antibodies to HGF inhibited phosphorylation of c-Met , Ron , p42/44MAPK and Stat3 proteins , these data provide strong evidence that HGF derived from Tgfbr2 deficient fibroblasts enhance c-Met and Ron signaling in mammary carcinoma cells to promote cell scattering and invasion .	As neutralizing antibodies to HGF inhibited phosphorylation of c-Met, Ron, p42/44MAPK and Stat3 proteins, these data provide strong evidence that HGF derived from Tgfbr2 deficient fibroblasts enhance c-Met and Ron signaling in mammary carcinoma cells to promote cell scattering and invasion.	23	33	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	23	24	30	31
All melanocytic cells expressed the HGF receptor c-Met , and autocrine HGF caused constitutive activation of c-Met , MAPK and PI3K .	All melanocytic cells expressed the HGF receptor c-Met, and autocrine HGF caused constitutive activation of c-Met, MAPK and PI3K.	10	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	16	17
On the basis of our study and previous reports , it is likely that activation of c-Met signaling by HGF may trigger a series of parallel kinase cascades downstream .	On the basis of our study and previous reports, it is likely that activation of c-Met signaling by HGF may trigger a series of parallel kinase cascades downstream.	16	20	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	19	20	16	17
In order to test whether the greater effect of DCC-2701 within IHFNO-303 CM is due to the HGF induced activation of c-MET , similar experiment was conducted using standard media containing recombinant HGF ( 100 ng/mL ) in OVCAR5 and OVCAR10 cells that represent c-MET positive and negative cells , respectively .	In order to test whether the greater effect of DCC-2701 within IHFNO-303 CM is due to the HGF induced activation of c-MET, similar experiment was conducted using standard media containing recombinant HGF (100 ng/mL) in OVCAR5 and OVCAR10 cells that represent c-MET positive and negative cells, respectively.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	17	18	21	22
This would suggest that the transcriptional upregulation of c-Met by HGF could be a mechanism of delayed compensation to maintain the c-Met receptor level at cell surface , without compromising on the dynamics of HGF signalling .	This would suggest that the transcriptional upregulation of c-Met by HGF could be a mechanism of delayed compensation to maintain the c-Met receptor level at cell surface, without compromising on the dynamics of HGF signalling.	6	11	upregulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	10	11	8	9
[ XREF_BIBR - XREF_BIBR ] HGF stimulation of c-Met can lead to proliferation , increased survival , altered motility , enhanced invasion into extracellular matrix , and more rapid formation of tubules .	[XREF_BIBR - XREF_BIBR] HGF stimulation of c-Met can lead to proliferation, increased survival, altered motility, enhanced invasion into extracellular matrix, and more rapid formation of tubules.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	8	9
VEGFKO cells stimulated with VEGF 121 were still able to diminish HGF stimulated P-MET ( XREF_FIG ) , and NRP-1 did not co-precipitate with VEGFR2 and MET ( data not shown ) , indicating that the inhibitory effect of VEGF is independent of NRP-1 .	VEGFKO cells stimulated with VEGF 121 were still able to diminish HGF stimulated P-MET (XREF_FIG), and NRP-1 did not co-precipitate with VEGFR2 and MET (data not shown), indicating that the inhibitory effect of VEGF is independent of NRP-1.	10	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	P-MET	P-MET	P-MET	11	12	13	14
To further assess the effects of HGF induced c-Met activation on the MUC1 expression , we prepared whole cell lysates from Mahlavu and SNU-449 cells after 15 , 30 , and 60min of HGF treatment .	To further assess the effects of HGF induced c-Met activation on the MUC1 expression, we prepared whole cell lysates from Mahlavu and SNU-449 cells after 15, 30, and 60min of HGF treatment.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	6	7	8	9
In this HGF signaling pathway , we speculated that Arf6 , which constitutively interacts with c-Met , recruits PIP5K1A to c-Met , when it is activated by HGF stimulation .	In this HGF signaling pathway, we speculated that Arf6, which constitutively interacts with c-Met, recruits PIP5K1A to c-Met, when it is activated by HGF stimulation.	17	28	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	27	28	20	21
Looking at live cells , the team found that HGF stimulation caused c-Met and STAT3 to colocalize on endosomes at the periphery , where STAT3 became phosphorylated .	Looking at live cells, the team found that HGF stimulation caused c-Met and STAT3 to colocalize on endosomes at the periphery, where STAT3 became phosphorylated.	9	14	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	9	10	12	13
Through these intermediary pathways , HGF induced c-Met activation triggers a variety of cellular responses , including proliferation , survival , cytoskeletal rearrangements , cell-cell dissociation , and motility [ XREF_BIBR , XREF_BIBR ] .	Through these intermediary pathways, HGF induced c-Met activation triggers a variety of cellular responses, including proliferation, survival, cytoskeletal rearrangements, cell-cell dissociation, and motility [XREF_BIBR, XREF_BIBR].	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	7	8
HGF activation of c-Met induces cyclooxygenase-2 ( COX-2 ) , resulting in downstream stimulation by PGE2 of additional pathways .	HGF activation of c-Met induces cyclooxygenase-2 (COX-2), resulting in downstream stimulation by PGE2 of additional pathways.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	3	4
The impact of HGF mediated activation of c-Met on downstream signaling was evaluated using U87 glioma cells expressing a previously described bioluminescent Akt reporter ( BAR ) [ XREF_BIBR ] .	The impact of HGF mediated activation of c-Met on downstream signaling was evaluated using U87 glioma cells expressing a previously described bioluminescent Akt reporter (BAR) [XREF_BIBR].	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	7	8
Among them , HGF ( also known as scattering factor ) activates the c-Met signaling pathway , thereby , increasing the invasive and metastatic potentials of the cells and allowing the survival of cancer cells in the bloodstream in the absence of anchorage [ XREF_BIBR , XREF_BIBR ] .	Among them, HGF (also known as scattering factor) activates the c-Met signaling pathway, thereby, increasing the invasive and metastatic potentials of the cells and allowing the survival of cancer cells in the bloodstream in the absence of anchorage [XREF_BIBR, XREF_BIBR].	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	3	4	13	14
In MDA-MB-231 cells , berbamine decreases FBS induced c-Met phosphorylation [ XREF_BIBR ] , and green tea catechins inhibit HGF induced c-Met activation and signaling [ XREF_BIBR ] .	In MDA-MB-231 cells, berbamine decreases FBS induced c-Met phosphorylation [XREF_BIBR], and green tea catechins inhibit HGF induced c-Met activation and signaling [XREF_BIBR].	19	22	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	19	20	21	22
We note that chemotherapeutics can initiate the release of damage associated molecular pattern ( DAMP ) protein , such as HSP90 or HMGB1 that can activate TLR4 [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] and these agents have been implicated in the development of neuropathic states [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	We note that chemotherapeutics can initiate the release of damage associated molecular pattern (DAMP) protein, such as HSP90 or HMGB1 that can activate TLR4 [XREF_BIBR; XREF_BIBR; XREF_BIBR] and these agents have been implicated in the development of neuropathic states [XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR].	16	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	22	23	26	27
HMGB1 is able to form complexes with TLR ligands and activate receptor for advanced glycation end products as well as TLR2 and TLR4 .	HMGB1 is able to form complexes with TLR ligands and activate receptor for advanced glycation end products as well as TLR2 and TLR4.	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	22	23
In the present study , we investigated whether the immunonutrient , omega-3 PUFA , inhibited TBI induced microglial activation and the subsequent inflammatory response and also facilitated neuronal recovery through inhibition of both HMGB1 translocation and release , and HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway .	In the present study, we investigated whether the immunonutrient, omega-3 PUFA, inhibited TBI induced microglial activation and the subsequent inflammatory response and also facilitated neuronal recovery through inhibition of both HMGB1 translocation and release, and HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway.	39	48	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	39	40	44	45
As HMGB1 has been shown to activate the TLR4 and NF-kappaB signaling pathway which induces the release of various inflammatory factors [ XREF_BIBR ] , changes in TLR4 and NF-kappaB signaling pathway related factors ( NF-kappaB p65 , p-IkappaB , and TLR4 ) were measured after omega-3 PUFA supplementation using western blot analysis and immunofluorescence staining .	As HMGB1 has been shown to activate the TLR4 and NF-kappaB signaling pathway which induces the release of various inflammatory factors [XREF_BIBR], changes in TLR4 and NF-kappaB signaling pathway related factors (NF-kappaB p65, p-IkappaB, and TLR4) were measured after omega-3 PUFA supplementation using western blot analysis and immunofluorescence staining.	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	8	9
We tested if hippocampal HMGB1 levels were increased by inescapable foot shocks since HMGB1 stimulates TLR4 and HMGB1 was reported to be increased by inescapable tail shocks .	We tested if hippocampal HMGB1 levels were increased by inescapable foot shocks since HMGB1 stimulates TLR4 and HMGB1 was reported to be increased by inescapable tail shocks.	13	22	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	13	14	15	16
These studies support the hypothesis that HMGB1 activates TLR4 receptors inducing TNFalpha and IL-1beta mRNA .	These studies support the hypothesis that HMGB1 activates TLR4 receptors inducing TNFalpha and IL-1beta mRNA.	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	8	9
In a future study , we plan to address the specificity of HMGB1 activation of TLR4 by studying the effects of HMGB1 inhibition on DBD .	In a future study, we plan to address the specificity of HMGB1 activation of TLR4 by studying the effects of HMGB1 inhibition on DBD.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	12	13	15	16
Mechanistically , these findings have now been extended by showing that ( i ) Eritoran blocked HMGB1 mediated TLR4 dependent signaling in vitro , HMGB1 release into serum in vivo , and protected comparably to P5779 , a highly selective HMGB1 inhibitor ; and ( ii ) inhibited pulmonary lung edema equivalently to AT-1001 , an inhibitor of zonulin induced pulmonary edema 32 .	Mechanistically, these findings have now been extended by showing that (i) Eritoran blocked HMGB1 mediated TLR4 dependent signaling in vitro, HMGB1 release into serum in vivo, and protected comparably to P5779, a highly selective HMGB1 inhibitor; and (ii) inhibited pulmonary lung edema equivalently to AT-1001, an inhibitor of zonulin induced pulmonary edema 32.	15	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	16	17	18	19
Taken together , our study showed that the immunonutrient , omega-3 PUFA , inhibited HMGB1 translocation and extracellular release , thus affecting HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway .	Taken together, our study showed that the immunonutrient, omega-3 PUFA, inhibited HMGB1 translocation and extracellular release, thus affecting HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway.	22	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	22	23	27	28
Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation , secretion , and HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway to evaluate the effects of omega-3 PUFA supplementation and gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI .	Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway to evaluate the effects of omega-3 PUFA supplementation and gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI.	17	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	17	18	22	23
Similarly , it was reported that the level of TLR4 increased in the primary cultured neurons and astrocytes treated with HMGB1 .	Similarly, it was reported that the level of TLR4 increased in the primary cultured neurons and astrocytes treated with HMGB1.	7	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	20	21	9	10
Using this model , we have identified a critical role for TLR4 signaling on the pulmonary epithelium in the development of NEC associated lung disease , and have demonstrated a pathway by which TLR4 signaling on the intestinal epithelium leads to gut derived HMGB1 release , which activates TLR4 on the lung epithelium leading to neutrophil recruitment via the induction of CXCR5 .	Using this model, we have identified a critical role for TLR4 signaling on the pulmonary epithelium in the development of NEC associated lung disease, and have demonstrated a pathway by which TLR4 signaling on the intestinal epithelium leads to gut derived HMGB1 release, which activates TLR4 on the lung epithelium leading to neutrophil recruitment via the induction of CXCR5.	43	49	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	43	44	48	49
HMGB1 for example can activate not only RAGE but also TLR4 [ XREF_BIBR ] .	HMGB1 for example can activate not only RAGE but also TLR4 [XREF_BIBR].	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	10	11
Interestingly , HMGB1 , a cytokine like protein that can activate TLR4 receptors and potentiate cytokine responses , rises in blood about 16 h after infection and remains elevated for several days .	Interestingly, HMGB1, a cytokine like protein that can activate TLR4 receptors and potentiate cytokine responses, rises in blood about 16 h after infection and remains elevated for several days.	2	27	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	11	12
Conversely , a partial and reversible oxidation of HMGB1 ( C23-C45 disulfide bond ) is required to activate a TLR4 mediated production of cytokines from macrophages [ XREF_BIBR ] .	Conversely, a partial and reversible oxidation of HMGB1 (C23-C45 disulfide bond) is required to activate a TLR4 mediated production of cytokines from macrophages [XREF_BIBR].	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	19	20
HMGB1 also up-regulated RAGE , but not TLR-2 or TLR-4 , expression on monocytes , which was inhibited by antibodies ( Abs ) against ICAM-1 , B7.1 , B7.2 and CD40 .	HMGB1 also up-regulated RAGE, but not TLR-2 or TLR-4, expression on monocytes, which was inhibited by antibodies (Abs) against ICAM-1, B7.1, B7.2 and CD40.	0	10	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR-4	TLR-4	TLR-4	0	1	9	10
Of note , HMGB1 alone is able to activate TLR4 , whereas for the activation of TLR2 and 9 , HMGB1 has to form complexes with apoptotically released nucleosomes and ssDNA , respectively [ XREF_BIBR ] .	Of note, HMGB1 alone is able to activate TLR4, whereas for the activation of TLR2 and 9, HMGB1 has to form complexes with apoptotically released nucleosomes and ssDNA, respectively [XREF_BIBR].	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	3	4	9	10
Furthermore , increased hepatocyte expression and release of HMGB1 triggers TLR4 and MyD88 signaling and inflammation in response to FFA infusion or HFD [ XREF_BIBR ] .	Furthermore, increased hepatocyte expression and release of HMGB1 triggers TLR4 and MyD88 signaling and inflammation in response to FFA infusion or HFD [XREF_BIBR].	4	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	expression and release of HMGB1	hmgb1	TLR4	TLR4	tlr4	8	9	10	11
In conclusion , our findings suggest that PTEN and Foxo1 signaling is critical for triggering HMGB1 mediated innate TLR4 activation in ALI .	In conclusion, our findings suggest that PTEN and Foxo1 signaling is critical for triggering HMGB1 mediated innate TLR4 activation in ALI.	15	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	15	16	18	19
We hypothesize that the release of HMGB1 from damaged or necrotic cells may produce an early inflammatory response by activating the TLR4 system .	We hypothesize that the release of HMGB1 from damaged or necrotic cells may produce an early inflammatory response by activating the TLR4 system.	4	22	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	21	22
HMGB1 stimulates the RAGE , TLR2 , and TLR4 receptors on neighboring monocytes and macrophages and results in the induction of several inflammatory cytokines , including TNFalpha and IL-1beta .	HMGB1 stimulates the RAGE, TLR2, and TLR4 receptors on neighboring monocytes and macrophages and results in the induction of several inflammatory cytokines, including TNFalpha and IL-1beta.	0	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	8	9
Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase .	Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR-4	TLR-4	TLR-4	6	7	9	10
However , our study showed that the HMGB1 induced tissue damage and death were independent of TLR4 signaling .	However, our study showed that the HMGB1 induced tissue damage and death were independent of TLR4 signaling.	6	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	7	8	16	17
The activation of the IL-1R1 and TLR4 signaling pathways by their endogenous ligands IL-1beta and HMGB1 , respectively , is pivotal for the generation of neuroinflammatory responses during seizures or after epileptogenic injuries , and their pharmacological blockade or genetic inactivation results in powerful anticonvulsive effects .	The activation of the IL-1R1 and TLR4 signaling pathways by their endogenous ligands IL-1beta and HMGB1, respectively, is pivotal for the generation of neuroinflammatory responses during seizures or after epileptogenic injuries, and their pharmacological blockade or genetic inactivation results in powerful anticonvulsive effects.	1	16	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	15	16	6	7
TLR4 , for example , can be activated by bacterial LPS and cellular HMGB1 .	TLR4, for example, can be activated by bacterial LPS and cellular HMGB1.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	13	14	0	1
93 HMGB1 and lipopolysaccharide ( LPS ) complex can activate TLR4 ; XREF_BIBR , XREF_BIBR while HMGB1 and nucleosome preferentially engages TLR2 .	93 HMGB1 and lipopolysaccharide (LPS) complex can activate TLR4; XREF_BIBR, XREF_BIBR while HMGB1 and nucleosome preferentially engages TLR2.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	10	11
Finally , after intracerebral hemorrhage , HMGB-1 appears to stimulate TLR2 and TLR4 and provide a beneficial neurogenesis at later time points .	Finally, after intracerebral hemorrhage, HMGB-1 appears to stimulate TLR2 and TLR4 and provide a beneficial neurogenesis at later time points.	6	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB-1	HMGB-1	HMGB-1	TLR4	TLR4	TLR4	6	7	12	13
It has been hypothesized that HMGB1 may also activate TLR2 in addition to TLR4 .	It has been hypothesized that HMGB1 may also activate TLR2 in addition to TLR4.	5	14	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	5	6	13	14
TLR4 was one of the few receptors for HMGB1 that was up-regulated in the lungs of CS exposed mice , suggesting that TLR4 might be activated by HMGB1 .	TLR4 was one of the few receptors for HMGB1 that was up-regulated in the lungs of CS exposed mice, suggesting that TLR4 might be activated by HMGB1.	22	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	27	28	22	23
Hence , HMGB1 activates PTEN and Foxo1 signaling and mediates TLR4 driven inflammatory response .	Hence, HMGB1 activates PTEN and Foxo1 signaling and mediates TLR4 driven inflammatory response.	2	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	10	11
N-3 PUFA supplementation also inhibits microglial activation by inhibiting nuclear translocation and secretion of high-mobility group box 1 ( HMGB1 ) and HMGB1 mediated activation of TLR4 and NF-kappabeta signalling pathways in a model of traumatic brain injury [ XREF_BIBR ] .	N-3 PUFA supplementation also inhibits microglial activation by inhibiting nuclear translocation and secretion of high-mobility group box 1 (HMGB1) and HMGB1 mediated activation of TLR4 and NF-kappabeta signalling pathways in a model of traumatic brain injury [XREF_BIBR].	22	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	22	23	26	27
Therefore , the most likely scenario is that HMGB1 is released from necrotic parenchymal cells to activate TLR4 on dendritic cells which in turn release TNFalpha to promote tissue injury .	Therefore, the most likely scenario is that HMGB1 is released from necrotic parenchymal cells to activate TLR4 on dendritic cells which in turn release TNFalpha to promote tissue injury.	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	17	18
Thus , while HMGB1 is an activator of TLR4 , its release is also determined , in part , by TLR4 itself .	Thus, while HMGB1 is an activator of TLR4, its release is also determined, in part, by TLR4 itself.	3	9	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	3	4	8	9
Together , our results suggest that the initial release of HMGB1 triggers a TLR4 dependent inflammatory response that leads to tumour development .	Together, our results suggest that the initial release of HMGB1 triggers a TLR4 dependent inflammatory response that leads to tumour development.	8	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	10	11	13	14
TLR4 can be activated by HMGB1 , an endogenous danger signal protein released by immune cells or by neurons and glia in the CNS in response to cell damage or neuronal hyperexcitability .	TLR4 can be activated by HMGB1, an endogenous danger signal protein released by immune cells or by neurons and glia in the CNS in response to cell damage or neuronal hyperexcitability.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	5	6	0	1
HMGB1 in turn activated TLR4 and elevated the pro tumor factors IL-6 and miR-21 , together with other important factors like MMP9 and miR-155 , to induce carcinogenesis XREF_BIBR .	HMGB1 in turn activated TLR4 and elevated the pro tumor factors IL-6 and miR-21, together with other important factors like MMP9 and miR-155, to induce carcinogenesis XREF_BIBR.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	4	5
HMGB1 among other alarmins has been shown to activate TLR4 after its release from necrotic cells [ XREF_BIBR ] .	HMGB1 among other alarmins has been shown to activate TLR4 after its release from necrotic cells [XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	9	10
Therefore we infer that HMGB1 triggers TLR4 mediated signaling in the lungs of CS exposed mice .	Therefore we infer that HMGB1 triggers TLR4 mediated signaling in the lungs of CS exposed mice.	4	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	4	5	6	7
Extracellular HMGB1 can activate TLR2 , TLR4 and TLR9 in immune cells .	Extracellular HMGB1 can activate TLR2, TLR4 and TLR9 in immune cells.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	6	7
HMGB1 increases PTEN and Foxo1 activity and activates innate TLR4 in ALI .	HMGB1 increases PTEN and Foxo1 activity and activates innate TLR4 in ALI.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	9	10
Of these alarmins , HMGB1 is known to activate TLR2 and TLR4 and produce the full array of inflammatory responses , including NF-kappab activity and synthesis of inflammatory cytokines .	Of these alarmins, HMGB1 is known to activate TLR2 and TLR4 and produce the full array of inflammatory responses, including NF-kappab activity and synthesis of inflammatory cytokines.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	4	5	11	12
In this process , HMGB1 triggers three specific downstream receptors , RAGE , TLR-2 and TLR-4 , of which RAGE may be the most important .	In this process, HMGB1 triggers three specific downstream receptors, RAGE, TLR-2 and TLR-4, of which RAGE may be the most important.	4	24	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR-4	TLR-4	TLR-4	4	5	15	16
In this model , proximal tubule cells released HMGB1 after injury by ROS , and this HMGB1 stimulates TLR4 ( +/+ ) , but not TLR4 (-/-) , macrophages to produce IL-6 .	In this model, proximal tubule cells released HMGB1 after injury by ROS, and this HMGB1 stimulates TLR4 (+/+), but not TLR4 (-/-), macrophages to produce IL-6.	15	28	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	16	17	18	19
Furthermore , kaempferol significantly reduced HMGB1 level and suppressed TLR4 and MyD88 inflammatory pathway in both transcription level and translation level .	Furthermore, kaempferol significantly reduced HMGB1 level and suppressed TLR4 and MyD88 inflammatory pathway in both transcription level and translation level.	2	13	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	kaempferol significantly reduced HMGB1 level	hmgb1	TLR4	TLR4	tlr4	5	6	9	10
To determine if HMGB1 is the primary ligand activating RAGE or TLR4 following TBI , wildtype C57BL/6 mice were treated with a HMGB1 neutralizing antibody ( HMGB1 Ab ) or control antibody prior to TBI .	To determine if HMGB1 is the primary ligand activating RAGE or TLR4 following TBI, wildtype C57BL/6 mice were treated with a HMGB1 neutralizing antibody (HMGB1 Ab) or control antibody prior to TBI.	8	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	22	23	11	12
Dying tumor cells release HMGB1 that has been shown to activate TLR4 on DCs .	Dying tumor cells release HMGB1 that has been shown to activate TLR4 on DCs.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	4	5	11	12
Thus , it is possible that stress induced glucocorticoids increase HMGB1 , which then activates TLR4 and NLRP3 to increase cytokines and chemokines .	Thus, it is possible that stress induced glucocorticoids increase HMGB1, which then activates TLR4 and NLRP3 to increase cytokines and chemokines.	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	10	11	15	16
However , the effects of omega-3 PUFA on HMGB1 expression and HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway are not clear .	However, the effects of omega-3 PUFA on HMGB1 expression and HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway are not clear.	11	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	11	12	16	17
Combined HMGB1 and prooxidant treatment increases TLR4 signaling in RAW-Blue ( TM ) cells .	Combined HMGB1 and prooxidant treatment increases TLR4 signaling in RAW-Blue (TM) cells.	0	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	6	7
Chemotherapy induced cell death triggers the release of the high-mobility group box 1 protein ( HMGB1 ) , which stimulates TLR4 and elicits an immune response that is required for the success of the therapy .	Chemotherapy induced cell death triggers the release of the high-mobility group box 1 protein (HMGB1), which stimulates TLR4 and elicits an immune response that is required for the success of the therapy.	13	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	15	16	20	21
Endogenous TLR4 activators such as HMGB1 account for a significant part of TLR4 signaling in liver I/R .	Endogenous TLR4 activators such as HMGB1 account for a significant part of TLR4 signaling in liver I/R.	1	6	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	5	6	1	2
HMGB1 can also activate central immune signaling , as it can trigger TLR4 similar to LPS , via the MD2 and CD14 complex , and requires adaptor protein MyD88 to trigger downstream inflammatory actions .	HMGB1 can also activate central immune signaling, as it can trigger TLR4 similar to LPS, via the MD2 and CD14 complex, and requires adaptor protein MyD88 to trigger downstream inflammatory actions.	0	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	12	13
We have demonstrated that HMGB1 induced TLR4 activation leads to rapid TLR2 upregulation in lung endothelial cells , as well as other cell types , and that this contributes to a hyper-responsive state .	We have demonstrated that HMGB1 induced TLR4 activation leads to rapid TLR2 upregulation in lung endothelial cells, as well as other cell types, and that this contributes to a hyper-responsive state.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	4	5	6	7
However , HMGB1 increased P-gp TLR4 , and RAGE protein levels in bEnd.3 cells in a concentration related manner as detected using Western blotting ( P < 0.05 , XREF_FIG ) .	However, HMGB1 increased P-gp TLR4, and RAGE protein levels in bEnd.3 cells in a concentration related manner as detected using Western blotting (P < 0.05, XREF_FIG).	2	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	5	6
The HMGB1 containing supernatant stimulates only TLR ( +/+ ) macrophages to produce IL6 ( XREF_FIG ) .	The HMGB1 containing supernatant stimulates only TLR (+/+) macrophages to produce IL6 (XREF_FIG).	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	+/+	+/+	+/+	1	2	8	9
Indeed , HMGB1 induced MHC-class I expression and muscle fatigue through binding to TLR4 , but not RAGE .	Indeed, HMGB1 induced MHC-class I expression and muscle fatigue through binding to TLR4, but not RAGE.	2	17	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	13	14
Stimulation of TLR4 by HMGB1 initiates a cascade of inflammatory reactions similarly to the LPS stimulation .	Stimulation of TLR4 by HMGB1 initiates a cascade of inflammatory reactions similarly to the LPS stimulation.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	4	5	2	3
Although ethanol induced release of HMGB1 from neurons activates TLR4 receptors and NF-kappaB transcription increasing synthesis of proinflammatory cytokines in brain ( see XREF_FIG , XREF_FIG , and XREF_FIG ) , a second mechanism involves ethanol induced increases in blood proinflammatory cytokines that spread and amplify gene induction in brain ( see XREF_FIG ) .	Although ethanol induced release of HMGB1 from neurons activates TLR4 receptors and NF-kappaB transcription increasing synthesis of proinflammatory cytokines in brain (see XREF_FIG, XREF_FIG, and XREF_FIG), a second mechanism involves ethanol induced increases in blood proinflammatory cytokines that spread and amplify gene induction in brain (see XREF_FIG).	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	5	6	9	10
HMGB1 induced platelet activation depended TLR4 .	HMGB1 induced platelet activation depended TLR4.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	5	6
Inhibition of HMGB1 inhibited TLR4 and vice versa suggesting the existence of HMGB1-TLR4 axis in glioma cells .	Inhibition of HMGB1 inhibited TLR4 and vice versa suggesting the existence of HMGB1-TLR4 axis in glioma cells.	0	6	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	4	5
IL-1alpha and high mobility group box 1 ( HMGB1 ) , which activate IL-1R1 and TLR4 , respectively , were proposed to play a central role in the phenotype observed and the expression levels of both molecules were increased in IL-1R8-deficient mice .	IL-1alpha and high mobility group box 1 (HMGB1), which activate IL-1R1 and TLR4, respectively, were proposed to play a central role in the phenotype observed and the expression levels of both molecules were increased in IL-1R8-deficient mice.	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1alpha and high mobility group box 1	IL-1alpha and high mobility group box 1	IL-1alpha and high mobility group box 1	TLR4	TLR4	TLR4	0	7	15	16
HMGB1 Induces Cytokine and Chemokine Release Via TLR4 in Macrophages and SMCs .	HMGB1 Induces Cytokine and Chemokine Release Via TLR4 in Macrophages and SMCs.	0	8	Induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	7	8
TLR4 dependent activation of dendritic cells by an HMGB1 derived peptide adjuvant .	TLR4 dependent activation of dendritic cells by an HMGB1 derived peptide adjuvant.	0	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	0	1
HMGB1 for example activates both TLR2 and TLR4 and the transmembrane multi-ligand receptor of immunoglobulin superfamily [ XREF_BIBR , XREF_BIBR ] .	HMGB1 for example activates both TLR2 and TLR4 and the transmembrane multi-ligand receptor of immunoglobulin superfamily [XREF_BIBR, XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	7	8
HMGB1 can also activate TLR2 in addition to TLR4 and differential TLR activation appears to depend on the particular tumor model used [ XREF_BIBR ] .	HMGB1 can also activate TLR2 in addition to TLR4 and differential TLR activation appears to depend on the particular tumor model used [XREF_BIBR].	0	9	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	8	9
This result indicates that extracellular HMGB1 could initiate TLR4 signal pathway .	This result indicates that extracellular HMGB1 could initiate TLR4 signal pathway.	4	10	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	5	6	8	9
While reduced HMGB1 has chemoattractant properties for macrophage and microglia , disulfide HMGB1 induces proinflammatory cytokine release from immune cells by activating TLR4 and contributes to hyperexcitability and seizures in animal models by modulating Ca 2+ permeability of NR2B-NMDAR .	While reduced HMGB1 has chemoattractant properties for macrophage and microglia, disulfide HMGB1 induces proinflammatory cytokine release from immune cells by activating TLR4 and contributes to hyperexcitability and seizures in animal models by modulating Ca 2+ permeability of NR2B-NMDAR.	11	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	12	13	22	23
Since HMGB1 induced TLR4 signaling has been found to be dependent on both MD-2 and CD14 , Eritoran likely inhibits the interaction of HMGB1 with these two coreceptors as well .	Since HMGB1 induced TLR4 signaling has been found to be dependent on both MD-2 and CD14, Eritoran likely inhibits the interaction of HMGB1 with these two coreceptors as well.	1	4	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	3	4
Interestingly , autophagic cancer associated fibroblasts secrete HMGB1 activating TLR4 in luminal breast cancer cells , enhancing their stemness and tumorigenicity , correlating TLR4 activation with poor prognosis and increased relapse rate 42 .	Interestingly, autophagic cancer associated fibroblasts secrete HMGB1 activating TLR4 in luminal breast cancer cells, enhancing their stemness and tumorigenicity, correlating TLR4 activation with poor prognosis and increased relapse rate 42.	6	14	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	7	8	9	10
In vitro stimulation of neutrophils with recombinant HMGB1 caused TLR4 dependent activation of NAD ( P ) H oxidase as well as increased ROS production through both MyD88-IRAK4-p38 MAPK and MyD88-IRAK4-AKT signaling pathways [ XREF_BIBR ] .	In vitro stimulation of neutrophils with recombinant HMGB1 caused TLR4 dependent activation of NAD (P) H oxidase as well as increased ROS production through both MyD88-IRAK4-p38 MAPK and MyD88-IRAK4-AKT signaling pathways [XREF_BIBR].	4	11	caused	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	7	8	9	10
The results presented here are consistent with our previous findings that the blockage of TLR4 signaling by neutralizing HMGB1 was associated with modestly better graft function , and delayed rejection post ischemia-reperfusion injury in a cardiac transplantation model 20 .	The results presented here are consistent with our previous findings that the blockage of TLR4 signaling by neutralizing HMGB1 was associated with modestly better graft function, and delayed rejection post ischemia-reperfusion injury in a cardiac transplantation model 20.	14	19	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	18	19	14	15
Interestingly , high glucose was shown to induce HMGB1 mediated activation of TLR4 in vascular smooth muscle cells .	Interestingly, high glucose was shown to induce HMGB1 mediated activation of TLR4 in vascular smooth muscle cells.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	12	13
Moreover , HMGB1 induced a down-regulation of TLR4 and MD2 and upregulation of TLR2 , TLR9 and TLR adaptor molecule 1 ( Ticam1 ) ( XREF_FIG ) .	Moreover, HMGB1 induced a down-regulation of TLR4 and MD2 and upregulation of TLR2, TLR9 and TLR adaptor molecule 1 (Ticam1) (XREF_FIG).	2	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	7	8
Our present results supported the notion that positive feedback loops of neuroinflammation in brain may require HMGB1 activation of microglial TLR4 , resulting in a production of microglia released proinflammatory mediators such as TNF-alpha and IL-1beta , which further increase the release of HMGB1 from neurons and other cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Our present results supported the notion that positive feedback loops of neuroinflammation in brain may require HMGB1 activation of microglial TLR4, resulting in a production of microglia released proinflammatory mediators such as TNF-alpha and IL-1beta, which further increase the release of HMGB1 from neurons and other cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	16	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	16	17	20	21
Cumulatively , our mouse and cotton rat data with Eritoran , a TLR4 antagonist developed for the treatment of sepsis , showed that Eritoran treatment inhibited influenza virus induced , ( i ) oxidized phospholipid expression mediated cytokine storm in vivo and in vitro , ( ii ) HMGB1 mediated TLR4 dependent signaling in vitro , and ( iii ) HMGB1 release into serum in vivo , and improved influenza induced lethality , lung pathology , and clinical symptoms .	Cumulatively, our mouse and cotton rat data with Eritoran, a TLR4 antagonist developed for the treatment of sepsis, showed that Eritoran treatment inhibited influenza virus induced, (i) oxidized phospholipid expression mediated cytokine storm in vivo and in vitro, (ii) HMGB1 mediated TLR4 dependent signaling in vitro, and (iii) HMGB1 release into serum in vivo, and improved influenza induced lethality, lung pathology, and clinical symptoms.	36	61	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	48	49	50	51
HMGB1 activates inflammatory pathways by stimulating TLR4 in many types of tissue injury .	HMGB1 activates inflammatory pathways by stimulating TLR4 in many types of tissue injury.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	6	7
In steatosis hepatic , HMGB-1 , releasing from hepatocytes in response to FFAs , is promoting an increased TLR4 protein levels and release of hepatic pro inflammatory and pro fibrogenic cytokines .	In steatosis hepatic, HMGB-1, releasing from hepatocytes in response to FFAs, is promoting an increased TLR4 protein levels and release of hepatic pro inflammatory and pro fibrogenic cytokines.	4	22	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB-1	HMGB-1	HMGB-1	TLR4	TLR4	TLR4	4	5	18	19
Although HMGB1 has been suggested to activate TLRs , HMGB1 at this concentration was not able to induce significant increases of Ccl2 , Tnfalpha , Tlr2 and Tlr4 ( XREF_FIG B ) .	Although HMGB1 has been suggested to activate TLRs, HMGB1 at this concentration was not able to induce significant increases of Ccl2, Tnfalpha, Tlr2 and Tlr4 (XREF_FIG B).	9	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	Tlr4	Tlr4	Tlr4	9	10	27	28
TLR4 activation by HMGB1 appears to have a protumorigenic function during skin carcinogenesis , but TLR2 , TLR9 , and IL-18 ( unpublished data ) do not .	TLR4 activation by HMGB1 appears to have a protumorigenic function during skin carcinogenesis, but TLR2, TLR9, and IL-18 (unpublished data) do not.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	3	4	0	1
Thus far , HMGB-1 and hyaluronan are potential TLR4 activators in models of soft tissue injury ; however , a large number of endogenous TLR4 ligands exist , including surfactant , heat shock , heme , and other matrix proteins , and HMGB-1 .	Thus far, HMGB-1 and hyaluronan are potential TLR4 activators in models of soft tissue injury; however, a large number of endogenous TLR4 ligands exist, including surfactant, heat shock, heme, and other matrix proteins, and HMGB-1.	8	43	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	HMGB-1	HMGB-1	HMGB-1	TLR4	TLR4	TLR4	42	43	8	9
Conclusion HMGB1 was recruited in the intestinal tissues to activate TLR4 signaling pathway after severe burn , further activates the downstream signal transcripts and releases a series of inflammatory cytokines to induce inflammatory response , which is involved in Th1 and Th2 cell mediated immune function obstacle of rats .	Conclusion HMGB1 was recruited in the intestinal tissues to activate TLR4 signaling pathway after severe burn, further activates the downstream signal transcripts and releases a series of inflammatory cytokines to induce inflammatory response, which is involved in Th1 and Th2 cell mediated immune function obstacle of rats.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	10	11
Additionally , HMGB1 released during ICD may activate TLR4 .	Additionally, HMGB1 released during ICD may activate TLR4.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	8	9
XREF_BIBR , XREF_BIBR Furthermore , HMGB1 is reported to activate TLR4- and RAGE signaling pathways to induce caspase-1 activation with the subsequent production of multiple inflammatory mediators , which in turn promote cancer invasion and metastasis .	XREF_BIBR, XREF_BIBR Furthermore, HMGB1 is reported to activate TLR4- and RAGE signaling pathways to induce caspase-1 activation with the subsequent production of multiple inflammatory mediators, which in turn promote cancer invasion and metastasis.	5	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4-	TLR4-	TLR4-	5	6	10	11
In addition , as it is known that HMGB1 may activate TLR4 and RAGE receptors , creating a functional tripod that contributes to up-regulate pro inflammatory mediators , gene expression analysis of both receptors was also made in the same murine samples ; results showed a clear decrease in their mRNA levels after DPG treatment .	In addition, as it is known that HMGB1 may activate TLR4 and RAGE receptors, creating a functional tripod that contributes to up-regulate pro inflammatory mediators, gene expression analysis of both receptors was also made in the same murine samples; results showed a clear decrease in their mRNA levels after DPG treatment.	8	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	11	12
HMGB1 has been shown to activate TLR4 and contribute to inflammation caused by I/R injury .	HMGB1 has been shown to activate TLR4 and contribute to inflammation caused by I/R injury.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	6	7
To date , no studies have elucidated if omega-3 PUFA affects HMGB1 translocation and release , or the exact mechanisms involved in HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway in TBI induced microglial activation and the subsquent inflammatory response [ XREF_BIBR , XREF_BIBR ] .	To date, no studies have elucidated if omega-3 PUFA affects HMGB1 translocation and release, or the exact mechanisms involved in HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway in TBI induced microglial activation and the subsquent inflammatory response [XREF_BIBR, XREF_BIBR].	22	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	22	23	27	28
We examined whether prooxidants enhance HMGB1 induced TLR4 signaling through NF-kappaB activation .	We examined whether prooxidants enhance HMGB1 induced TLR4 signaling through NF-kappaB activation.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	5	6	7	8
In term of endogenous TLR ligands in cancer , HMGB1 can activate TLR2 and TLR4 , and versican acts as a TLR2 agonist .	In term of endogenous TLR ligands in cancer, HMGB1 can activate TLR2 and TLR4, and versican acts as a TLR2 agonist.	9	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	9	10	14	15
HMGB-1 may then target TLR4 on microglia to activate NF-kappaB and increase NLRP3 expression , thereby priming the NLRP3 inflammasome .	HMGB-1 may then target TLR4 on microglia to activate NF-kappaB and increase NLRP3 expression, thereby priming the NLRP3 inflammasome.	0	5	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB-1	HMGB-1	HMGB-1	TLR4	TLR4	TLR4	0	1	4	5
This study demonstrates that PTEN and Foxo1 signaling is critical for triggering HMGB1 mediated TLR4 activation in ALI .	This study demonstrates that PTEN and Foxo1 signaling is critical for triggering HMGB1 mediated TLR4 activation in ALI.	12	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	12	13	14	15
Plasma HMGB1 levels are elevated and related to viral load and MD2 and TLR4 in patients with HIV infection .	Plasma HMGB1 levels are elevated and related to viral load and MD2 and TLR4 in patients with HIV infection.	1	14	elevated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	HMGB1	HMGB1 levels	hmgb1	TLR4	TLR4	tlr4	1	2	13	14
First identified as a nuclear protein and transcription factor , HMGB1 is expressed ubiquitously and mediates inflammatory responses via its receptors , currently identified as RAGE ( receptor for advanced glycation end products ) as well as TLR2 and TLR4 .	First identified as a nuclear protein and transcription factor, HMGB1 is expressed ubiquitously and mediates inflammatory responses via its receptors, currently identified as RAGE (receptor for advanced glycation end products) as well as TLR2 and TLR4.	10	40	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1 is expressed	hmgb1	TLR4	TLR4	tlr4	10	11	39	40
We used pharmacological approaches to further clarify that TLR4 stimulation by HMGB1 or prooxidants would play a role in SEAP release through NF-kappaB activation ( XREF_FIG ) .	We used pharmacological approaches to further clarify that TLR4 stimulation by HMGB1 or prooxidants would play a role in SEAP release through NF-kappaB activation (XREF_FIG).	8	13	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	11	12	8	9
Islets release endogenous HMGB1 that stimulates TLR2 and TLR4 and prevents engraftment .	Islets release endogenous HMGB1 that stimulates TLR2 and TLR4 and prevents engraftment.	1	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	3	4	8	9
HMGB1 activates TLR4 through both the medullary differentiation factor ( MyD88 ) and non-MyD88-dependent pathways , triggering a signal cascade , either directly through the nuclear factor-kappaB ( NF-kappaB ) pathway or indirectly via the PI3K or MAPKs pathway .	HMGB1 activates TLR4 through both the medullary differentiation factor (MyD88) and non-MyD88-dependent pathways, triggering a signal cascade, either directly through the nuclear factor-kappaB (NF-kappaB) pathway or indirectly via the PI3K or MAPKs pathway.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	2	3
Several studies show that TLR4 activation by HMGB1 administration in vivo caused or worsened organ damage and that HMGB1 inhibition ameliorated survival or disease phenotype in animal models of stroke , ischemia-reperfusion , sepsis , and shock .	Several studies show that TLR4 activation by HMGB1 administration in vivo caused or worsened organ damage and that HMGB1 inhibition ameliorated survival or disease phenotype in animal models of stroke, ischemia-reperfusion, sepsis, and shock.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	7	8	4	5
The inhibitory effects of omega-3 PUFA supplementation on the inflammatory response and on TLR4 and NF-kappaB signaling pathway activation was reversed by LPS , suggesting HMGB1 mediated activation of the TLR4 and NF-kappaB pathway has an important role in TBI induced inflammatory responses .	The inhibitory effects of omega-3 PUFA supplementation on the inflammatory response and on TLR4 and NF-kappaB signaling pathway activation was reversed by LPS, suggesting HMGB1 mediated activation of the TLR4 and NF-kappaB pathway has an important role in TBI induced inflammatory responses.	25	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	25	26	30	31
Furthermore , omega-3 PUFA supplementation inhibited TBI induced microglial activation and the subsequent inflammatory response by regulating HMGB1 nuclear translocation and secretion and also HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway , leading to neuroprotective effects .	Furthermore, omega-3 PUFA supplementation inhibited TBI induced microglial activation and the subsequent inflammatory response by regulating HMGB1 nuclear translocation and secretion and also HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway, leading to neuroprotective effects.	24	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	24	25	29	30
In contrast , the small-molecule HMGB1 inhibitor P5779 binds outside the deep hydrophobic pocket of MD-2 and blocks HMGB1 induced TLR4 signaling , but not LPS induced signaling .	In contrast, the small-molecule HMGB1 inhibitor P5779 binds outside the deep hydrophobic pocket of MD-2 and blocks HMGB1 induced TLR4 signaling, but not LPS induced signaling.	18	21	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	18	19	20	21
To confirm that disulfide HMGB1 induced macrophage activation via TLR4 , peritoneal macrophages from WT , TLR4 -/-, MyD88 -/-, or Trif Lps2 mice were treated with recombinant disulfide HMGB1 for 8 hours .	To confirm that disulfide HMGB1 induced macrophage activation via TLR4, peritoneal macrophages from WT, TLR4 -/-, MyD88 -/-, or Trif Lps2 mice were treated with recombinant disulfide HMGB1 for 8 hours.	14	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	29	30	16	17
Our study supports the notion that TLR4 and MyD88 signaling in liver parenchymal cells plays a pivotal role during the early progression of HFD induced NAFLD , in which free HMGB1 served as a positive component mediating TLR4 activation .	Our study supports the notion that TLR4 and MyD88 signaling in liver parenchymal cells plays a pivotal role during the early progression of HFD induced NAFLD, in which free HMGB1 served as a positive component mediating TLR4 activation.	29	38	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	30	31	37	38
HMGB1 causes TLR4 dependent activation of NADPH oxidase as well as increased ROS production .	HMGB1 causes TLR4 dependent activation of NADPH oxidase as well as increased ROS production.	0	4	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	2	3
These findings demonstrate a novel pathway by which TLR4 activation by HMGB1 delays mucosal repair and suggest a novel potential therapeutic target in the amelioration of intestinal inflammatory diseases like NEC .	These findings demonstrate a novel pathway by which TLR4 activation by HMGB1 delays mucosal repair and suggest a novel potential therapeutic target in the amelioration of intestinal inflammatory diseases like NEC.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	11	12	8	9
Consistent with our findings , enhanced HMGB1 activated TLR4 and NF-kappaB , leading to increased macrophage sequestration along with expression of proinflammatory cytokines ( TNF-alpha and IL-12p40 ) and chemokines ( MCP-1 and CXCL-10 ) .	Consistent with our findings, enhanced HMGB1 activated TLR4 and NF-kappaB, leading to increased macrophage sequestration along with expression of proinflammatory cytokines (TNF-alpha and IL-12p40) and chemokines (MCP-1 and CXCL-10).	5	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	8	9
XREF_BIBR , XREF_BIBR In this case , HMGB1 enables the TLR4 dependent activation of dendritic cells and promotes antigen cross presentation to cytotoxic T cells .	XREF_BIBR, XREF_BIBR In this case, HMGB1 enables the TLR4 dependent activation of dendritic cells and promotes antigen cross presentation to cytotoxic T cells.	7	17	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	7	8	10	11
Studies have shown that the number of tumor infiltrating T cells was positive correlated with secretion of HMGB1 by cancer cells [ XREF_BIBR ] , specialists speculated that the underlying mechanism may be related to activation of TLR4 by HMGB1 in tumor microenvironment .	Studies have shown that the number of tumor infiltrating T cells was positive correlated with secretion of HMGB1 by cancer cells [XREF_BIBR], specialists speculated that the underlying mechanism may be related to activation of TLR4 by HMGB1 in tumor microenvironment.	33	42	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	39	40	37	38
In the present study , we show that type 1 diabetic patients have high circulating levels of HMGB1 , which could trigger TLR2 and TLR4 activation , leading to a proinflammatory state .	In the present study, we show that type 1 diabetic patients have high circulating levels of HMGB1, which could trigger TLR2 and TLR4 activation, leading to a proinflammatory state.	15	25	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	levels of HMGB1	hmgb1	TLR4	TLR4	tlr4	17	18	24	25
Moreover , a recent paper described that the activation of TLR4 by HMGB1 increased afferent evoked dentate gyrus excitability after concussive brain injury in mice [ XREF_BIBR ] , an event that increases the risk of developing epileptic seizures in animal models and in humans .	Moreover, a recent paper described that the activation of TLR4 by HMGB1 increased afferent evoked dentate gyrus excitability after concussive brain injury in mice [XREF_BIBR], an event that increases the risk of developing epileptic seizures in animal models and in humans.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	12	13	10	11
Liver I/R injury is exacerbated via activation of TLR4 by HMGB1 , a damage associated molecular pattern ( DAMP ) protein released from dying cells .	Liver I/R injury is exacerbated via activation of TLR4 by HMGB1, a damage associated molecular pattern (DAMP) protein released from dying cells.	4	13	activation	Positive_activation_syntax_6_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	10	11	8	9
One would expect that any TLR4 ( +/+ ) renal leukocyte would be stimulated by HMGB1 released by injured ischemic renal cells and would produce maladaptive IL6 , as discussed in the next paragraphs , and injure the kidney .	One would expect that any TLR4 (+/+) renal leukocyte would be stimulated by HMGB1 released by injured ischemic renal cells and would produce maladaptive IL6, as discussed in the next paragraphs, and injure the kidney.	4	16	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	15	16	5	6
It has previously been described that HMGB1 excerpts biological effects via triggering of the TLR4 receptor , but until recently there was lack of evidence to support the idea of a critical role of HMGB1 induced TLR4 activation in disease pathogenesis .	It has previously been described that HMGB1 excerpts biological effects via triggering of the TLR4 receptor, but until recently there was lack of evidence to support the idea of a critical role of HMGB1 induced TLR4 activation in disease pathogenesis.	6	37	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	36	37
These results demonstrate that PTEN and Foxo1 signaling is critical for triggering HMGB1 mediated innate TLR4 activation during ALI .	These results demonstrate that PTEN and Foxo1 signaling is critical for triggering HMGB1 mediated innate TLR4 activation during ALI.	12	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	12	13	15	16
Overall , HMGB1 activation of TLR2 and/or TLR4 could both initiate and sustain a pro inflammatory phenotype , ultimately explaining the increased expression of NF-kappaB dependent genes .	Overall, HMGB1 activation of TLR2 and/or TLR4 could both initiate and sustain a pro inflammatory phenotype, ultimately explaining the increased expression of NF-kappaB dependent genes.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	7	8
Furthermore , HMGB1 , complexed with DNA and pathogenic anti-DNA autoantibodies , activates its receptors , TLR2 , TLR4 and RAGE , and may thereby be involved in anti-DNA autoantibody induced kidney damage in lupus nephritis .	Furthermore, HMGB1, complexed with DNA and pathogenic anti-DNA autoantibodies, activates its receptors, TLR2, TLR4 and RAGE, and may thereby be involved in anti-DNA autoantibody induced kidney damage in lupus nephritis.	2	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	18	19
Moreover , there was also an additive effect in the TLR-4 and RAGE promotion by IL-1beta and HMGB1 .	Moreover, there was also an additive effect in the TLR-4 and RAGE promotion by IL-1beta and HMGB1.	10	18	promotion	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR-4	TLR-4	TLR-4	17	18	10	11
Furthermore , activation of TLR4 by HMGB1 has been reported to induce migration and invasion of A549 and H838 lung cancer cells by activating integrin alphavbeta3 and focal adhesion kinase through the TLR4 and NF-kappaB pathway .	Furthermore, activation of TLR4 by HMGB1 has been reported to induce migration and invasion of A549 and H838 lung cancer cells by activating integrin alphavbeta3 and focal adhesion kinase through the TLR4 and NF-kappaB pathway.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	4	5
In vitro , TLR4 expression was increased in VSMCs treated with HMGB1 .	In vitro, TLR4 expression was increased in VSMCs treated with HMGB1.	3	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	11	12	3	4
In conclusion , the present study showed that DEX exerted a protective effect on LPS induced ALI rats likely through the HMGB1 mediated TLR4 and NF-kappaB and PI3K/Akt/mTOR pathways .	In conclusion, the present study showed that DEX exerted a protective effect on LPS induced ALI rats likely through the HMGB1 mediated TLR4 and NF-kappaB and PI3K/Akt/mTOR pathways.	18	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	21	22	23	24
HMGB-1 released from damaged hepatocytes may activate TLR2 in addition to TLR4 as an endogenous ligand in NASH .	HMGB-1 released from damaged hepatocytes may activate TLR2 in addition to TLR4 as an endogenous ligand in NASH.	0	12	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	HMGB-1	HMGB-1	HMGB-1	TLR4	TLR4	TLR4	0	1	11	12
Moreover , TLR4 signaling triggered by HMGB1 is able to stimulate an inflammatory response leading to tumor development in a skin model of tumorigenesis 39 .	Moreover, TLR4 signaling triggered by HMGB1 is able to stimulate an inflammatory response leading to tumor development in a skin model of tumorigenesis 39.	2	7	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	2	3
HMGB1 released from hypoxic HCC cells could activate TLR-4 and RAGE signaling pathways , induce inflammation , and promote cancer invasion and metastasis [ XREF_BIBR ] .	HMGB1 released from hypoxic HCC cells could activate TLR-4 and RAGE signaling pathways, induce inflammation, and promote cancer invasion and metastasis [XREF_BIBR].	0	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR-4	TLR-4	TLR-4	0	1	8	9
In this regard , we gained insights into the molecular mechanisms underlying the ability of S. aureus to dampen the HMGB1 induced TLR4 signaling by the novel virulence factor PSMs .	In this regard, we gained insights into the molecular mechanisms underlying the ability of S. aureus to dampen the HMGB1 induced TLR4 signaling by the novel virulence factor PSMs.	19	23	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	20	21	22	23
We used a combination of fluorescent microscopy imaging , flow cytometer and TBARs [ XREF_BIBR ] to provide insight on the contributory factors that may regulate ROS and HMGB1 coupled activation of TLR4 in our cell model systems .	We used a combination of fluorescent microscopy imaging, flow cytometer and TBARs [XREF_BIBR] to provide insight on the contributory factors that may regulate ROS and HMGB1 coupled activation of TLR4 in our cell model systems.	26	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	28	29	32	33
As an endogenous ligand of TLR4 , HMGB1 activates TLR4 signaling in HSCs to enhance their inflammatory phenotype , indicating that TLR4 signaling need not rely solely on gut derived LPS for activation during liver injury .	As an endogenous ligand of TLR4, HMGB1 activates TLR4 signaling in HSCs to enhance their inflammatory phenotype, indicating that TLR4 signaling need not rely solely on gut derived LPS for activation during liver injury.	7	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	7	8	9	10
The activation of TLR4 signaling by HMGB1 has been verified in cell lines [ XREF_BIBR , XREF_BIBR ] .	The activation of TLR4 signaling by HMGB1 has been verified in cell lines [XREF_BIBR, XREF_BIBR].	3	7	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	3	4
In this model , proximal tubule cells release HMGB1 after injury by ROS and this HMGB1 stimulates TLR4 ( +/+ ) , but not TLR4 (-/-) , macrophages to produce IL6 ( XREF_FIG ) .	In this model, proximal tubule cells release HMGB1 after injury by ROS and this HMGB1 stimulates TLR4 (+/+), but not TLR4 (-/-), macrophages to produce IL6 (XREF_FIG).	10	18	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	15	16	17	18
Recently , another scenario was suggested : allergens induce oxidative stress and activate the inflammasome and HMGB1 mediated TLR4 , resulting in the synthesis of IL-18 [ XREF_BIBR ] .	Recently, another scenario was suggested : allergens induce oxidative stress and activate the inflammasome and HMGB1 mediated TLR4, resulting in the synthesis of IL-18 [XREF_BIBR].	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	16	17	18	19
Regardless of the cell type involved , TLR4 activation by HMGB1 appears to serve a proinflammatory role in the early stages of ischemia-reperfusion injury .	Regardless of the cell type involved, TLR4 activation by HMGB1 appears to serve a proinflammatory role in the early stages of ischemia-reperfusion injury.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	10	11	7	8
HMGB1 increases TLR4 signaling in HEK-Blue mTLR4 cells .	HMGB1 increases TLR4 signaling in HEK-Blue mTLR4 cells.	0	3	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	2	3
In addition , western blotting of lysates of the aorta and densitometric quantification showed that the siHMGB1 lentivirus s knocked down HMGB1 in the aorta , HMGB1 knockdown reversed the high Pi induced upregulation of TLR4 and downregulation of klotho in CKD mice .	In addition, western blotting of lysates of the aorta and densitometric quantification showed that the siHMGB1 lentivirus s knocked down HMGB1 in the aorta, HMGB1 knockdown reversed the high Pi induced upregulation of TLR4 and downregulation of klotho in CKD mice.	26	37	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	26	27	35	36
We have provided evidence that HMGB1 stimulates TLR4 signaling in I/R in the liver ; however , it is unknown whether TLR4 participates in hypoxia induced ROS production and HMGB1 release .	We have provided evidence that HMGB1 stimulates TLR4 signaling in I/R in the liver; however, it is unknown whether TLR4 participates in hypoxia induced ROS production and HMGB1 release.	5	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	5	6	7	8
Chemotherapy induced cell death triggers the release of the HMGB1 , which stimulates TLR4 and elicits an immune response that is required for the success of the therapy .	Chemotherapy induced cell death triggers the release of the HMGB1, which stimulates TLR4 and elicits an immune response that is required for the success of the therapy.	6	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	9	10	13	14
The specific HMGB1 isoform known to activate TLR4 signaling ( disulfide HMGB1 ) stimulates smooth muscle cell to migrate and produce monocyte chemotactic protein 1/CCL2 ) via TLR4 .	The specific HMGB1 isoform known to activate TLR4 signaling (disulfide HMGB1) stimulates smooth muscle cell to migrate and produce monocyte chemotactic protein 1/CCL2) via TLR4.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	7	8
omega-3 PUFA supplementation influences HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway in lesioned cortices .	omega-3 PUFA supplementation influences HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway in lesioned cortices.	4	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	4	5	9	10
The data confirmed that ROS and HMGB1 coupled stimulation of TLR4 through NF-kappaB activation could selectively occur in cells with multiple TLR expression .	The data confirmed that ROS and HMGB1 coupled stimulation of TLR4 through NF-kappaB activation could selectively occur in cells with multiple TLR expression.	4	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	10	11
HMGB1 induced myofibroblast differentiation and cell migration through RAGE but not TLR2 and TLR4 .	HMGB1 induced myofibroblast differentiation and cell migration through RAGE but not TLR2 and TLR4.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	13	14
CD14 has been shown to participate in disulfide HMGB1 induced TLR4 activation .	CD14 has been shown to participate in disulfide HMGB1 induced TLR4 activation.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	10	11
Accordingly , chemotherapeutic drugs or radiotherapy require TLR4 activating DAMPs to achieve therapeutic effects : HMGB1 is released following anthracycline treatment or radiotherapy resulting in HMGB1 mediated TLR4 activation on DC and tumor elimination by tumor specific T cells .	Accordingly, chemotherapeutic drugs or radiotherapy require TLR4 activating DAMPs to achieve therapeutic effects : HMGB1 is released following anthracycline treatment or radiotherapy resulting in HMGB1 mediated TLR4 activation on DC and tumor elimination by tumor specific T cells.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	25	26	27	28
Spinal HMGB1 induced TLR4 mediated long lasting pain hypersensitivity and glial activation in experimental arthritis [ XREF_BIBR ] .	Spinal HMGB1 induced TLR4 mediated long lasting pain hypersensitivity and glial activation in experimental arthritis [XREF_BIBR].	0	8	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	3	4
Recent studies indicate that ethanol in the gut releases HMGB1 which activates TLR4 causing the gut to leak endotoxin LPS like bacterial products that stimulate proinflammatory cytokine induction in the liver thereby increasing circulating blood cytokines .	Recent studies indicate that ethanol in the gut releases HMGB1 which activates TLR4 causing the gut to leak endotoxin LPS like bacterial products that stimulate proinflammatory cytokine induction in the liver thereby increasing circulating blood cytokines.	8	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	9	10	12	13
HMGB1 can activate TLR2 and TLR4 on the surface of tumor and immune cells and , as a result , induce tumor progression and metastasis [ XREF_BIBR ] .	HMGB1 can activate TLR2 and TLR4 on the surface of tumor and immune cells and, as a result, induce tumor progression and metastasis [XREF_BIBR].	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	5	6
This mechanism is important in real life because cancer patients who have a polymorphism that prevents HMGB1 activation of TLR4 obtain significantly less long-term benefit from chemotherapy .	This mechanism is important in real life because cancer patients who have a polymorphism that prevents HMGB1 activation of TLR4 obtain significantly less long-term benefit from chemotherapy.	16	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	16	17	19	20
On the other hand , RAGE could bind to other ligands like HMGB1 and S100P , which subsequently activated TLR-4 and PI3K-Akt pathways , and favored lung cancer progression [ XREF_BIBR , XREF_BIBR ] .	On the other hand, RAGE could bind to other ligands like HMGB1 and S100P, which subsequently activated TLR-4 and PI3K-Akt pathways, and favored lung cancer progression [XREF_BIBR, XREF_BIBR].	7	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR-4	TLR-4	TLR-4	12	13	19	20
Therefore , the most likely scenario is that HMGB1 is released from necrotic parenchymal cells to activate TLR4 on DC which in turn releases TNF-alpha to promote tissue injury .	Therefore, the most likely scenario is that HMGB1 is released from necrotic parenchymal cells to activate TLR4 on DC which in turn releases TNF-alpha to promote tissue injury.	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	17	18
Since HMGB1 may activate TLR4 and HA may stimulate TLR2 in addition to TLR4 , it is possible that induction of beta-arrestin 1 by HMGB1 may be TLR4 dependent whereas induction of beta-arrestin 2 may be through TLR2 .	Since HMGB1 may activate TLR4 and HA may stimulate TLR2 in addition to TLR4, it is possible that induction of beta-arrestin 1 by HMGB1 may be TLR4 dependent whereas induction of beta-arrestin 2 may be through TLR2.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	4	5
Additionally HMGB1 produced in mammalian cell cultures and therefore devoid of bacterial contaminants or endogenous danger signals does not activate TLR4 ( unpublished observation ) .	Additionally HMGB1 produced in mammalian cell cultures and therefore devoid of bacterial contaminants or endogenous danger signals does not activate TLR4 (unpublished observation).	1	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	20	21
It is interesting to speculate whether HMGB1 , released as a consequence of tissue necrosis or therapy , results in genotype dependent differential activation of TLR4 , which contributes to the observed differences in survival .	It is interesting to speculate whether HMGB1, released as a consequence of tissue necrosis or therapy, results in genotype dependent differential activation of TLR4, which contributes to the observed differences in survival.	6	28	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	25	26
In addition , endogenous ligands for TLRs were also identified , including HSP70 and HMGB1 , which have been shown to up-regulate TLR2 and TLR4 on tumor cell surfaces and induce tumor progression and metastasis XREF_BIBR , XREF_BIBR .	In addition, endogenous ligands for TLRs were also identified, including HSP70 and HMGB1, which have been shown to up-regulate TLR2 and TLR4 on tumor cell surfaces and induce tumor progression and metastasis XREF_BIBR, XREF_BIBR.	9	25	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	14	15	24	25
Our findings indicate HMGB1 release activates TLR4 inducing proinflammatory cytokines TNFalpha and IL-1beta .	Our findings indicate HMGB1 release activates TLR4 inducing proinflammatory cytokines TNFalpha and IL-1beta.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	3	4	6	7
Again rage -/- mice were not used in these model systems , leaving open the possibility that HMGB1 triggers TLR4 in combination with RAGE triggering .	Again rage -/- mice were not used in these model systems, leaving open the possibility that HMGB1 triggers TLR4 in combination with RAGE triggering.	17	21	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	17	18	19	20
Our data confirm that synergistic increase in TNFalpha and IL-6 release was due to prooxidant and HMGB1 coupled activation of TLR4 .	Our data confirm that synergistic increase in TNFalpha and IL-6 release was due to prooxidant and HMGB1 coupled activation of TLR4.	16	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	16	17	20	21
Following cerebral ischemia , the activation of TLR4 by HMGB-1 induces MMP-9 up-regulation in neurons and astrocytes and promotes detrimental effects by macrophages infiltrating the injured brain .	Following cerebral ischemia, the activation of TLR4 by HMGB-1 induces MMP-9 up-regulation in neurons and astrocytes and promotes detrimental effects by macrophages infiltrating the injured brain.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HMGB-1	HMGB-1	HMGB-1	TLR4	TLR4	TLR4	9	10	7	8
Upon TNF-alpha stimulation , TLR4 is activated by HMGB1 that is immediately released after the generation of reactive oxygen species , and plays a crucial role in the signal transduction .	Upon TNF-alpha stimulation, TLR4 is activated by HMGB1 that is immediately released after the generation of reactive oxygen species, and plays a crucial role in the signal transduction.	4	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	4	5
Conclusion : These results suggest that in hypoxic HCC cells , HMGB1 activates TLR4 and RAGE signaling pathways to induce caspase-1 activation with subsequent production of multiple inflammatory mediators which in turn promotes cancer invasion and metastasis .	Conclusion : These results suggest that in hypoxic HCC cells, HMGB1 activates TLR4 and RAGE signaling pathways to induce caspase-1 activation with subsequent production of multiple inflammatory mediators which in turn promotes cancer invasion and metastasis.	11	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	11	12	13	14
Dying cells produce danger signals , such as HMGB1 protein , which may activate TLR2 and TLR4 and/or the receptor for advanced glycation end products and induce apoptosis .	Dying cells produce danger signals, such as HMGB1 protein, which may activate TLR2 and TLR4 and/or the receptor for advanced glycation end products and induce apoptosis.	8	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	16	17
High motility group box 1 ( HMGB1 ) responds to pathogens , both exogenous and endogenous , to activate TLR4 , leading to phosphorylation of NF-kappaB and increased production of proinflammatory molecules in endothelial cells [ XREF_BIBR ] .	High motility group box 1 (HMGB1) responds to pathogens, both exogenous and endogenous, to activate TLR4, leading to phosphorylation of NF-kappaB and increased production of proinflammatory molecules in endothelial cells [XREF_BIBR].	3	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	19	20
50 In isolated hepatocytes , free fatty acids stimulate secretion of HMGB1 , which in turn activates hepatocyte TLR4 signalling in an autocrine manner , leading to hepatocyte NF-kappaB activation and cytokine expression .	50 In isolated hepatocytes, free fatty acids stimulate secretion of HMGB1, which in turn activates hepatocyte TLR4 signalling in an autocrine manner, leading to hepatocyte NF-kappaB activation and cytokine expression.	9	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	11	12	18	19
To gain further insight into a potential functional relevance of ROS and HMGB1 coupled activation of TLR4 , we used primary macrophages from TLR4-KO and TLR4-WT mice in the presence and absence of prooxidants and/or HMGB1 combination .	To gain further insight into a potential functional relevance of ROS and HMGB1 coupled activation of TLR4, we used primary macrophages from TLR4-KO and TLR4-WT mice in the presence and absence of prooxidants and/or HMGB1 combination.	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	12	13	16	17
Overall , our results indicated that omega-3 PUFA supplementation could inhibit HMGB1 mediated activation of the TLR4 and NF-kappaB pathway and attenuate the subsequent inflammatory response after TBI .	Overall, our results indicated that omega-3 PUFA supplementation could inhibit HMGB1 mediated activation of the TLR4 and NF-kappaB pathway and attenuate the subsequent inflammatory response after TBI.	11	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	11	12	16	17
Extracellular HMGB1 activates TLR4 and RAGE signal pathways , subsequently the downstream of caspase-1 , and then pro inflammatory cytokines IL-1beta and IL-18 are cleaved and released , which in turn promote HCC invasion and metastasis in hypoxia .	Extracellular HMGB1 activates TLR4 and RAGE signal pathways, subsequently the downstream of caspase-1, and then pro inflammatory cytokines IL-1beta and IL-18 are cleaved and released, which in turn promote HCC invasion and metastasis in hypoxia.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	3	4
Recent studies indicate that ethanol in the gut releases HMGB1 , which activates TLR4 receptors causing the gut to leak endotoxin LPS like bacterial products stimulating proinflammatory cytokine induction in the liver .	Recent studies indicate that ethanol in the gut releases HMGB1, which activates TLR4 receptors causing the gut to leak endotoxin LPS like bacterial products stimulating proinflammatory cytokine induction in the liver.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	9	10	13	14
Excess glucose triggered a trophoblast sterile inflammatory IL-8 and antimigratory response through HMGB1 activation of TLR4 .	Excess glucose triggered a trophoblast sterile inflammatory IL-8 and antimigratory response through HMGB1 activation of TLR4.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	12	13	15	16
By contrast , PSMalpha1-alpha3 significantly inhibited the HMGB1 induced TLR4 and NF-kappaB signaling pathway .	By contrast, PSMalpha1-alpha3 significantly inhibited the HMGB1 induced TLR4 and NF-kappaB signaling pathway.	6	13	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	7	8	9	10
Subsequently , levels of HMGB1 , a ubiquitously expressed , cytokine like protein that can activate TLR4 and potentiate cytokine responses , increase about 16 hours after infection and remain elevated for several days .	Subsequently, levels of HMGB1, a ubiquitously expressed, cytokine like protein that can activate TLR4 and potentiate cytokine responses, increase about 16 hours after infection and remain elevated for several days.	2	17	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	HMGB1	levels of HMGB1	hmgb1	TLR4	TLR4	tlr4	4	5	16	17
TLR4 is expressed on hepatocytes , Kupffer cells , HSCs , and sinusoidal endothelial cells.105 , 106 , 107 HMGB1 activation of TLR4 mainly occurs in myeloid cells ,108 , 109 , 110 although the binding site in these and other cells has yet to be identified .	TLR4 is expressed on hepatocytes, Kupffer cells, HSCs, and sinusoidal endothelial cells.105, 106, 107 HMGB1 activation of TLR4 mainly occurs in myeloid cells,108, 109, 110 although the binding site in these and other cells has yet to be identified.	19	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	19	20	22	23
We identified that Hmgb1 released from UV damaged keratinocytes initiates a TLR4 and Myd88 dependent myeloid driven inflammatory response that fosters metastatic spread of melanoma cells .	We identified that Hmgb1 released from UV damaged keratinocytes initiates a TLR4 and Myd88 dependent myeloid driven inflammatory response that fosters metastatic spread of melanoma cells.	3	16	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hmgb1	Hmgb1	Hmgb1	TLR4	TLR4	TLR4	3	4	11	12
HMGB1 enhances prooxidant mediated TLR4 signaling in HEK-Blue mTLR4 cells .	HMGB1 enhances prooxidant mediated TLR4 signaling in HEK-Blue mTLR4 cells.	0	5	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	4	5
For example , HMGB1 , a nuclear protein that is released during cell necrosis , has been shown to contribute to liver IRI by activating TLR4 .	For example, HMGB1, a nuclear protein that is released during cell necrosis, has been shown to contribute to liver IRI by activating TLR4.	3	26	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	3	4	25	26
The Tsung laboratory showed that in hypoxic HCC cells , HMGB1 activates TLR4- and RAGE signaling pathways to induce caspase-1 activation with the ensuing production of multiple inflammatory mediators , which in turn promote cancer invasion and metastasis167 ; yet , the authors did not discuss the potential effect of caspase-1 cleavage of HMGB1 .	The Tsung laboratory showed that in hypoxic HCC cells, HMGB1 activates TLR4- and RAGE signaling pathways to induce caspase-1 activation with the ensuing production of multiple inflammatory mediators, which in turn promote cancer invasion and metastasis167; yet, the authors did not discuss the potential effect of caspase-1 cleavage of HMGB1.	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4-	TLR4-	TLR4-	10	11	12	13
For TLR4 , it has been reported that HMGB1 released by autophagic cancer associated fibroblasts in the breast cancer microenvironment activated TLR4 on luminal breast cancer cells to facilitate the expansion of breast CSCs and the maintenance of their stemness .	For TLR4, it has been reported that HMGB1 released by autophagic cancer associated fibroblasts in the breast cancer microenvironment activated TLR4 on luminal breast cancer cells to facilitate the expansion of breast CSCs and the maintenance of their stemness.	8	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	21	22
It is indicated that decreased HDAC activity by ethanol releases neuronal HMGB1 , which activates TLR4 and leads to inflammatory cascades [ XREF_BIBR ] .	It is indicated that decreased HDAC activity by ethanol releases neuronal HMGB1, which activates TLR4 and leads to inflammatory cascades [XREF_BIBR].	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	11	12	15	16
We found that ASC deficiency inhibited Caspase-1 and IL-1beta signaling , leading to the protection against liver IR-damage , local enhancement of antiapoptotic functions , and downregulation of HMGB1 mediated TLR4 driven inflammation .	We found that ASC deficiency inhibited Caspase-1 and IL-1beta signaling, leading to the protection against liver IR-damage, local enhancement of antiapoptotic functions, and downregulation of HMGB1 mediated TLR4 driven inflammation.	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	28	29	30	31
Based upon these findings , we hypothesized that TLR4 can be activated by HMGB-1 , which subsequently triggers the release of inflammatory cytokines and results in ALI .	Based upon these findings, we hypothesized that TLR4 can be activated by HMGB-1, which subsequently triggers the release of inflammatory cytokines and results in ALI.	8	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB-1	HMGB-1	HMGB-1	TLR4	TLR4	TLR4	13	14	8	9
38 In contrast , binding of HMGB1 to CD24 and the further mobilization of Siglec-10 ( or mouse Siglec-G ) was shown to antagonize HMGB1 induced TLR4 activation in dendritic cells .	38 In contrast, binding of HMGB1 to CD24 and the further mobilization of Siglec-10 (or mouse Siglec-G) was shown to antagonize HMGB1 induced TLR4 activation in dendritic cells.	23	27	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	24	25	26	27
For instance , endogenous HMGB1 could trigger TLR2 , TLR4 and TLR9 activation whereas endogenous HSP60 and HSP70 only ligate TLR2 and TLR4 .	For instance, endogenous HMGB1 could trigger TLR2, TLR4 and TLR9 activation whereas endogenous HSP60 and HSP70 only ligate TLR2 and TLR4.	3	12	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	4	5	9	10
In human airway epithelial wound closure , HMGB1 has been shown to induce TLR4- and RAGE mediated wound closure , ECM protein and receptor expression , and intracellular signaling .	In human airway epithelial wound closure, HMGB1 has been shown to induce TLR4- and RAGE mediated wound closure, ECM protein and receptor expression, and intracellular signaling.	7	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4-	TLR4-	TLR4-	7	8	13	14
In addition , NEC is associated with increased TLR4 activator HMGB1 [ XREF_BIBR ] , co-receptor myeloid differentiation protein-2 ( MD-2 ) [ XREF_BIBR ] and co-receptor cluster of differentiation 14 [ XREF_BIBR ] .	In addition, NEC is associated with increased TLR4 activator HMGB1 [XREF_BIBR], co-receptor myeloid differentiation protein-2 (MD-2) [XREF_BIBR] and co-receptor cluster of differentiation 14 [XREF_BIBR].	5	27	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	10	11	8	9
Direct addition of either lipopolysaccharide ( LPS ) , a specific TLR4 agonist , or recombinant HMGB1 induced TLR4 dependent IL-6 release from C8-B4 microglia and primary human microglia , but not from EOC.20 cells , further indicating that neuronal HMGB1 may be essential to trigger microglial IL-6 release .	Direct addition of either lipopolysaccharide (LPS), a specific TLR4 agonist, or recombinant HMGB1 induced TLR4 dependent IL-6 release from C8-B4 microglia and primary human microglia, but not from EOC.20 cells, further indicating that neuronal HMGB1 may be essential to trigger microglial IL-6 release.	1	19	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	16	17	18	19
MD-2 is a critical accessory protein that is necessary for both LPS- and HMGB1 induced TLR4 signaling ( Nagai etal ., 2002 ; Yang etal ., 2015 ) .	MD-2 is a critical accessory protein that is necessary for both LPS- and HMGB1 induced TLR4 signaling (Nagai etal., 2002; Yang etal., 2015).	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	13	14	15	16
XREF_BIBR , XREF_BIBR - XREF_BIBR During ischemic AKI , injury to these cells should result in the release of HMGB1 , and this HMGB1 should stimulate TLR4 on the adjacent endothelium .	XREF_BIBR, XREF_BIBR - XREF_BIBR During ischemic AKI, injury to these cells should result in the release of HMGB1, and this HMGB1 should stimulate TLR4 on the adjacent endothelium.	22	27	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	23	24	26	27
The findings reported here support the notion that positive feedback loops of neuroimmune activation in brain may require HMGB1 activation of microglial TLR4 resulting in production of microglia released proinflammatory mediators such as TNFa and IL-1beta , which further augments release of HMGB1 from neurons and other cells ( XREF_FIG ) .	The findings reported here support the notion that positive feedback loops of neuroimmune activation in brain may require HMGB1 activation of microglial TLR4 resulting in production of microglia released proinflammatory mediators such as TNFa and IL-1beta, which further augments release of HMGB1 from neurons and other cells (XREF_FIG).	18	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	18	19	22	23
These two studies together suggested that extracellular HMGB1 led to islet beta cells damage via binding to TLR4 on beta cells .	These two studies together suggested that extracellular HMGB1 led to islet beta cells damage via binding to TLR4 on beta cells.	6	18	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	7	8	17	18
Our results suggest that the release of HMGB1 in the wounds initiates TLR4 dependent responses that contribute to neovascularization .	Our results suggest that the release of HMGB1 in the wounds initiates TLR4 dependent responses that contribute to neovascularization.	5	14	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	7	8	12	13
Therefore , the investigation of the roles of HMGB1 translocation and release , and HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway in TBI induced microglial activation and the subsequent inflammatory response , is paramount to further understand the mechanisms of TBI induced secondary brain damage .	Therefore, the investigation of the roles of HMGB1 translocation and release, and HMGB1 mediated activation of the TLR4 and NF-kappaB signaling pathway in TBI induced microglial activation and the subsequent inflammatory response, is paramount to further understand the mechanisms of TBI induced secondary brain damage.	14	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	14	15	19	20
Hence , HMGB1 , a ubiquitous nuclear protein which is actively released by stimulation of the innate immune system and passively released by ischemic tissues , may trigger TLR4 .	Hence, HMGB1, a ubiquitous nuclear protein which is actively released by stimulation of the innate immune system and passively released by ischemic tissues, may trigger TLR4.	2	29	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	28	29
HMGB1 induces phagocyte activation and cell migration through binding to membrane receptors , such as RAGE , Toll like receptor ( TLR ) 2 , and TLR4 , to activate downstream signaling pathways XREF_BIBR XREF_BIBR XREF_BIBR .	HMGB1 induces phagocyte activation and cell migration through binding to membrane receptors, such as RAGE, Toll like receptor (TLR) 2, and TLR4, to activate downstream signaling pathways XREF_BIBR XREF_BIBR XREF_BIBR.	0	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	26	27
These findings suggest that ethanol releases HMGB1 that stimulates TLR4 leading to induction of IL-1beta .	These findings suggest that ethanol releases HMGB1 that stimulates TLR4 leading to induction of IL-1beta.	2	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	6	7	9	10
In addition , in vitro stimulation of PMN with recombinant HMGB1 caused TLR4 dependent activation of NAD ( P ) H oxidase as well as increased ROS production through both MyD88-IRAK4-p38 MAPK and MyD88-IRAK4-Akt signaling pathways .	In addition, in vitro stimulation of PMN with recombinant HMGB1 caused TLR4 dependent activation of NAD (P) H oxidase as well as increased ROS production through both MyD88-IRAK4-p38 MAPK and MyD88-IRAK4-Akt signaling pathways.	7	14	caused	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	10	11	12	13
The effects of omega-3 PUFA supplementation on HMGB1 translocation and release and HMGB1 induced TLR4 and NF-kappaB activation have , to date , not been fully elucidated .	The effects of omega-3 PUFA supplementation on HMGB1 translocation and release and HMGB1 induced TLR4 and NF-kappaB activation have, to date, not been fully elucidated.	8	17	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	12	13	14	15
In this study , HMGB1 remained expressed in the nucleus of the peri-FCD brain tissue , suggesting that TLR4 may have been upregulated by the release of extracellular HMGB1 in chronic injury caused by repeated epileptic activities in FCD lesion .	In this study, HMGB1 remained expressed in the nucleus of the peri-FCD brain tissue, suggesting that TLR4 may have been upregulated by the release of extracellular HMGB1 in chronic injury caused by repeated epileptic activities in FCD lesion.	18	29	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	28	29	18	19
Furthermore , we find that HMGB1 increases adhesion molecule expression on wild-type , but not TLR4 (-/-) , endothelia in vitro .	Furthermore, we find that HMGB1 increases adhesion molecule expression on wild-type, but not TLR4 (-/-), endothelia in vitro.	5	18	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	5	6	15	16
A wide array of endogenous DAMPs may trigger TLR4 activation , including high-mobility group box-1 ( HMGB1 ) , amyloid-beta , fibronectin , and others [ XREF_BIBR ] .	A wide array of endogenous DAMPs may trigger TLR4 activation, including high-mobility group box-1 (HMGB1), amyloid-beta, fibronectin, and others [XREF_BIBR].	8	17	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	16	17	8	9
Activation of TLR4 by HMGB1 in neurons and astrocytes has been proposed as a critical event for decreasing seizure threshold and initiating brain inflammation [ XREF_BIBR ] .	Activation of TLR4 by HMGB1 in neurons and astrocytes has been proposed as a critical event for decreasing seizure threshold and initiating brain inflammation [XREF_BIBR].	0	8	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	4	5	2	3
Accordingly , we found that Oxa-Cyc makes dying tumor cells release HMGB1 , which activates TLR4 directly .	Accordingly, we found that Oxa-Cyc makes dying tumor cells release HMGB1, which activates TLR4 directly.	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	11	12	15	16
Because HMGB1 or extracellular histone activates TLR4 signaling 33 , this action may contribute to the induction of macrophages to M1 34 .	Because HMGB1 or extracellular histone activates TLR4 signaling 33, this action may contribute to the induction of macrophages to M1 34.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	6	7
This TLR4 mutation is associated with an increased frequency of metastasis and worsened survival in breast cancer patients , suggesting that clinical outcome is affected by HMGB1 activated TLR4 signaling .	This TLR4 mutation is associated with an increased frequency of metastasis and worsened survival in breast cancer patients, suggesting that clinical outcome is affected by HMGB1 activated TLR4 signaling.	24	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	26	27	28	29
Extracellular HMGB1 subsequently activates microglial TLR4 leading to production of proinflammatory cytokines TNFalpha and IL-1beta .	Extracellular HMGB1 subsequently activates microglial TLR4 leading to production of proinflammatory cytokines TNFalpha and IL-1beta.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	5	6
In addition , it has been reported that HMGB1 could also activate TLR4 and RAGE in astrocytes .	In addition, it has been reported that HMGB1 could also activate TLR4 and RAGE in astrocytes.	8	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	8	9	12	13
HMGB1 can induce apoptosis via NF-kappaB by activating TLR-4 .	HMGB1 can induce apoptosis via NF-kappaB by activating TLR-4.	0	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR-4	TLR-4	TLR-4	0	1	8	9
These data demonstrate that HMGB1 mediated activation of TLR4 promotes experimental PH and identify HMGB1 and/or TLR4 as potential therapeutic targets for the treatment of PH .	These data demonstrate that HMGB1 mediated activation of TLR4 promotes experimental PH and identify HMGB1 and/or TLR4 as potential therapeutic targets for the treatment of PH.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	4	5	8	9
Extracellular HMGB1 activates TLR4 dependent signal by directly binding to TLR4 and MD-2 .	Extracellular HMGB1 activates TLR4 dependent signal by directly binding to TLR4/MD-2.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	3	4
Since the concentrations of HMGB1 used did not show effects alone , we suspect that TLR4 or RAGE activation by HMGB1 is not responsible for our findings .	Since the concentrations of HMGB1 used did not show effects alone, we suspect that TLR4 or RAGE activation by HMGB1 is not responsible for our findings.	15	21	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	20	21	15	16
78 Ultraviolet irradiation of melanoma cells and the subsequent release of HMGB1 from damaged keratinocytes was also recently shown to induce a TLR4 dependent inflammatory environment that proved to be an important step toward perivascular invasion and metastasis in melanoma .	78 Ultraviolet irradiation of melanoma cells and the subsequent release of HMGB1 from damaged keratinocytes was also recently shown to induce a TLR4 dependent inflammatory environment that proved to be an important step toward perivascular invasion and metastasis in melanoma.	9	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	11	12	22	23
25 HMGB1 can also stimulate TLR4 in endothelial cells thus the attachment of monocytes and macrophages may not be augmented through CD200 signaling .	25 HMGB1 can also stimulate TLR4 in endothelial cells thus the attachment of monocytes and macrophages may not be augmented through CD200 signaling.	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	1	2	5	6
HMGB1 induces TLR4 mediated proinflammatory cytokine production .	HMGB1 induces TLR4 mediated proinflammatory cytokine production.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	2	3
Release of HMGB1 activates the cell surface TLR4 on KCs and leads to a subsequent release of cytotoxic mediators ( TNF-alpha , IL-6 and chemokine IP-10 ) , alongside an inappropriate activation of the pro apoptotic protein kinase JNK and stress responsive NF-kappaB , all of which are mediators of cell injury [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Release of HMGB1 activates the cell surface TLR4 on KCs and leads to a subsequent release of cytotoxic mediators (TNF-alpha, IL-6 and chemokine IP-10), alongside an inappropriate activation of the pro apoptotic protein kinase JNK and stress responsive NF-kappaB, all of which are mediators of cell injury [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	7	8
The data we have presented here support an essential role for additive and/or synergistic interactions of prooxidants- and HMGB1 mediated TLR4 stimulation that activates NF-kappaB .	The data we have presented here support an essential role for additive and/or synergistic interactions of prooxidants- and HMGB1 mediated TLR4 stimulation that activates NF-kappaB.	14	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	18	19	20	21
HMGB1 activates TLR4 by binding to the TLR4 coreceptors CD14 and MD-2 .	HMGB1 activates TLR4 by binding to the TLR4 coreceptors CD14 and MD-2.	0	3	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	2	3
HMGB1 activates TLR4 on KCs [ XREF_BIBR ] and hepatocytes [ XREF_BIBR ] .	HMGB1 activates TLR4 on KCs [XREF_BIBR] and hepatocytes [XREF_BIBR].	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	0	1	2	3
Besides AGEs , RAGE can also be activated by high-mobility group box 1 ( HMGB1 ) [ XREF_BIBR ] .	Besides AGEs, RAGE can also be activated by high-mobility group box 1 (HMGB1) [XREF_BIBR].	3	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	14	15	3	4
A potential underlying mechanism may be that HMGB1 activates RAGE , resulting in inflammation in epileptic brains .	A potential underlying mechanism may be that HMGB1 activates RAGE, resulting in inflammation in epileptic brains.	7	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	7	8	9	10
To determine the role of RAGE in mediating the priming effect of HMGB1 on MLVEC pyroptosis , MLVEC isolated from WT and RAGE -/- mice were sequentially treated with HMGB1 ( 0.5 mug/ml ) for 4h and then with LPS ( 1mug/ml ) for 24h .	To determine the role of RAGE in mediating the priming effect of HMGB1 on MLVEC pyroptosis, MLVEC isolated from WT and RAGE -/- mice were sequentially treated with HMGB1 (0.5 mug/ml) for 4h and then with LPS (1mug/ml) for 24h.	18	35	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	29	30	22	23
Secreted HMGB1 stimulates RAGE , TLR2 and TLR4 ( the three main HMGB1 receptors ) expressed on neighboring macrophages and induces the release of several inflammatory cytokines , including TNF-alpha and IL-1beta .	Secreted HMGB1 stimulates RAGE, TLR2 and TLR4 (the three main HMGB1 receptors) expressed on neighboring macrophages and induces the release of several inflammatory cytokines, including TNF-alpha and IL-1beta.	0	7	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	1	2	3	4
Extracellular HMGB1 induces autophagy by binding its receptor RAGE .	Extracellular HMGB1 induces autophagy by binding its receptor RAGE.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	1	2	8	9
In preeclampsia , there is evidence for activation of RAGE , and enhanced amounts of HMGB1 have also been demonstrated in the placenta and amniotic fluid , but not , so far , in maternal blood .	In preeclampsia, there is evidence for activation of RAGE, and enhanced amounts of HMGB1 have also been demonstrated in the placenta and amniotic fluid, but not, so far, in maternal blood.	4	16	is evidence for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	HMGB1	amounts of HMGB1	hmgb1	RAGE	RAGE	rage	15	16	9	10
Huh7 cells were cultured and either transfected with RAGE siRNA or treated with HMGB1 as described in Section 3.3 .	Huh7 cells were cultured and either transfected with RAGE siRNA or treated with HMGB1 as described in Section 3.3.	8	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	13	14	8	9
Moreover , HMGB1 located in the extracellular space can lead to the upregulation of RAGE in multiple cell types [ XREF_BIBR , XREF_BIBR ] .	Moreover, HMGB1 located in the extracellular space can lead to the upregulation of RAGE in multiple cell types [XREF_BIBR, XREF_BIBR].	2	15	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	2	3	14	15
HMGB1 directs RAGE mediated lung IR injury and activation of iNKT cells .	HMGB1 directs RAGE mediated lung IR injury and activation of iNKT cells.	0	8	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	2	3
HMGB1 could not only promote the occurrence of cerebral vasospasm , but also increase the gene and protein expression levels of RAGE in neurons and microglia around the hematoma , and the number of microglia was also significantly increased .	HMGB1 could not only promote the occurrence of cerebral vasospasm, but also increase the gene and protein expression levels of RAGE in neurons and microglia around the hematoma, and the number of microglia was also significantly increased.	0	25	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	21	22
Though initial reports suggested that extracellular HMGB1 released by necrotic and inflammatory cells functions as a late acting cytokine mediating endotoxin related lethality in mice and cytokine synthesis in monocytes , there has been greater recognition that the effect of HMGB1 activation of RAGE has acute effects on leukocyte chemotaxis and vascular barrier disruption .	Though initial reports suggested that extracellular HMGB1 released by necrotic and inflammatory cells functions as a late acting cytokine mediating endotoxin related lethality in mice and cytokine synthesis in monocytes, there has been greater recognition that the effect of HMGB1 activation of RAGE has acute effects on leukocyte chemotaxis and vascular barrier disruption.	40	44	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	40	41	43	44
The ICH rat model induced by collagenase indicates that HMGB1 promotes angiogenesis mainly by mediating RAGE .	The ICH rat model induced by collagenase indicates that HMGB1 promotes angiogenesis mainly by mediating RAGE.	9	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	9	10	15	16
In other words , RAGE would be activated by unmodified HMGB1 , but not by acetylated HMGB1 .	In other words, RAGE would be activated by unmodified HMGB1, but not by acetylated HMGB1.	4	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	10	11	4	5
RAGE activation by HMGB1 in iNKT cells triggered the IL-17 production [ XREF_BIBR ] .	RAGE activation by HMGB1 in iNKT cells triggered the IL-17 production [XREF_BIBR].	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	3	4	0	1
In this context , HMGB1 might be a preferential activator of RAGE , also promoting stimulation of other receptors when present in low concentrations ( or the other way around ) .	In this context, HMGB1 might be a preferential activator of RAGE, also promoting stimulation of other receptors when present in low concentrations (or the other way around).	4	12	be a preferential activator	Positive_activation_copula_1	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	11	12
In our laboratory , we recently demonstrated that intravitreal administration of HMGB1 to normal rats induced significant upregulation of ICAM-1 , HMGB1 , and RAGE and NF-kappaB activation in the retina ( Mohammad et al ., unpublished data ) .	In our laboratory, we recently demonstrated that intravitreal administration of HMGB1 to normal rats induced significant upregulation of ICAM-1, HMGB1, and RAGE and NF-kappaB activation in the retina (Mohammad et al., unpublished data).	9	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	11	12	24	25
When in a complex with CpG containing DNA , HMGB1 can also induce the synergistic interaction and activation of RAGE and TLR9 XREF_BIBR .	When in a complex with CpG containing DNA, HMGB1 can also induce the synergistic interaction and activation of RAGE and TLR9 XREF_BIBR.	9	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	9	10	19	20
Extracellular HMGB1 activates RAGE , which in turn can promote an immune response [ XREF_BIBR , XREF_BIBR ] .	Extracellular HMGB1 activates RAGE, which in turn can promote an immune response [XREF_BIBR, XREF_BIBR].	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	1	2	3	4
The direct binding of RAGE to Abeta , mainly to its aggregated forms , is considered important in mediating amyloid toxicity [ XREF_BIBR ] and RAGE activation by HMGB1 has recently been considered to have a crucial role in favoring neurodegeneration contributing to the development of amyotrophic lateral sclerosis [ XREF_BIBR ] .	The direct binding of RAGE to Abeta, mainly to its aggregated forms, is considered important in mediating amyloid toxicity [XREF_BIBR] and RAGE activation by HMGB1 has recently been considered to have a crucial role in favoring neurodegeneration contributing to the development of amyotrophic lateral sclerosis [XREF_BIBR].	25	29	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	28	29	25	26
In contrast , HMGB1 could be inhibited by PPARgamma agonists [ XREF_BIBR ] ; ( 2 ) HMGB1 activated RAGE and NF-kB [ XREF_BIBR , XREF_BIBR ] and/or TLR-4 and caspase-1 [ XREF_BIBR ] for HCC metastasis ; ( 3 ) HMGB1 also mediated the activation of metastasis by inducing IL6 and Stat3-miR -21 axis [ XREF_BIBR ] .	In contrast, HMGB1 could be inhibited by PPARgamma agonists [XREF_BIBR]; (2) HMGB1 activated RAGE and NF-kB [XREF_BIBR, XREF_BIBR] and/or TLR-4 and caspase-1 [XREF_BIBR] for HCC metastasis; (3) HMGB1 also mediated the activation of metastasis by inducing IL6 and Stat3-miR -21 axis [XREF_BIBR].	6	23	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	17	18	19	20
Extracellular HMGB1 in its reduced form promotes autophagy through binding to RAGE , which may contribute to lactate production and glutamine metabolism for tumor growth .	Extracellular HMGB1 in its reduced form promotes autophagy through binding to RAGE, which may contribute to lactate production and glutamine metabolism for tumor growth.	0	15	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	1	2	11	12
Extracellular HMGB1 promotes autophagy in a RAGE dependent manner [ XREF_BIBR ] .	Extracellular HMGB1 promotes autophagy in a RAGE dependent manner [XREF_BIBR].	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	1	2	6	7
Whether HMGB1 activation of neuronal RAGE and the resultant increase in neuronal excitability during or following nerve injury induced inflammation , represents a neuropathological consequence , is generally unknown .	Whether HMGB1 activation of neuronal RAGE and the resultant increase in neuronal excitability during or following nerve injury induced inflammation, represents a neuropathological consequence, is generally unknown.	1	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	1	2	5	6
For instance , HMGB1 , perhaps the best characterized alarmin found in the injury conditioned medium , is also known to activate RAGE ( another pattern recognition receptor ) and has been recently suspected to contribute to spinal cord injury inflammation XREF_BIBR .	For instance, HMGB1, perhaps the best characterized alarmin found in the injury conditioned medium, is also known to activate RAGE (another pattern recognition receptor) and has been recently suspected to contribute to spinal cord injury inflammation XREF_BIBR.	3	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	3	4	22	23
Finally , as a non nervous cell model , here we have utilized the erythroleukemia cell line described above on the basis of its known calcium dependent and RAGE independent activation of the differentiation program promoted by sub-nanomolar amounts of extracellular HMGB1 XREF_BIBR , XREF_BIBR .	Finally, as a non nervous cell model, here we have utilized the erythroleukemia cell line described above on the basis of its known calcium dependent and RAGE independent activation of the differentiation program promoted by sub-nanomolar amounts of extracellular HMGB1 XREF_BIBR, XREF_BIBR.	28	42	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	41	42	28	29
Based on these results , we think that the main mechanism responsible for inhibition of ethyl pyruvate on CVB3 induced AVMC may be due to that it suppressed HMGB1 mediated RAGE and NF-KappaB pathway .	Based on these results, we think that the main mechanism responsible for inhibition of ethyl pyruvate on CVB3 induced AVMC may be due to that it suppressed HMGB1 mediated RAGE and NF-KappaB pathway.	27	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	28	29	30	31
Furthermore , HMGB1 elicited the activation of the RAGE and extracellular signal related kinase ( ERK ) 1/2 signaling pathway , which correlated with barrier dysfunction in the 16HBE cells .	Furthermore, HMGB1 elicited the activation of the RAGE and extracellular signal related kinase (ERK) 1/2 signaling pathway, which correlated with barrier dysfunction in the 16HBE cells.	2	13	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	2	3	8	9
Activation of RAGE by HMGB1 is known to initiate a rapid and sustained inflammatory response culminating in the activation of mitogen activated protein kinases ( MAPkinases ) , nuclear factor kappaB ( NF-kB ) and RhoGTPases .	Activation of RAGE by HMGB1 is known to initiate a rapid and sustained inflammatory response culminating in the activation of mitogen activated protein kinases (MAPkinases), nuclear factor kappaB (NF-kB) and RhoGTPases.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	2	3
HMGB1 activates RAGE to induce EMT in PC3 cells .	HMGB1 activates RAGE to induce EMT in PC3 cells.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	2	3
It has been revealed that HMGB1 may activate the RAGE signaling pathway and induce the activation of NF-kappaB to promote cellular processes .	It has been revealed that HMGB1 may activate the RAGE signaling pathway and induce the activation of NF-kappaB to promote cellular processes.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	5	6	9	10
The NFkappaB transcription factor increases the expression of HMGB1 and its receptor RAGE , increasing pro inflammatory RAGE signaling by a feed-forward mechanism [ XREF_BIBR ] .	The NFkappaB transcription factor increases the expression of HMGB1 and its receptor RAGE, increasing pro inflammatory RAGE signaling by a feed-forward mechanism [XREF_BIBR].	1	18	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	NFkappaB transcription factor increases the expression of HMGB1	hmgb1	RAGE	RAGE	rage	8	9	17	18
Furthermore , IVIg significantly prevented HMGB1 induced increases of TLR and RAGE signalling cascade proteins such as NF-kappaB-p-p65 , p-JNK , p-p38 MAPK and p-c-Jun .	Furthermore, IVIg significantly prevented HMGB1 induced increases of TLR and RAGE signalling cascade proteins such as NF-kappaB-p-p65, p-JNK, p-p38 MAPK and p-c-Jun.	5	14	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	5	6	11	12
HMGB1 also induced elevated expression of RAGE protein .	HMGB1 also induced elevated expression of RAGE protein.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	6	7
For instance , extracellular HMGB1 activation of RAGE contributes to increased transcription of nuclear factor kappa-light-chain-enhancer of activated B cells ( NF-kappaB ) increasing expression of proinflammatory cytokines , oxidases , and other neuroimmune genes .	For instance, extracellular HMGB1 activation of RAGE contributes to increased transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) increasing expression of proinflammatory cytokines, oxidases, and other neuroimmune genes.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	7	8
MLVEC from WT , Nlrp3 -/-, and RAGE -/- mice were sequentially treated with HMGB1 ( 0.5 mug/ml ) for 4h and then with LPS ( 1mug/ml ) for 0-24h .	MLVEC from WT, Nlrp3 -/-, and RAGE -/- mice were sequentially treated with HMGB1 (0.5 mug/ml) for 4h and then with LPS (1mug/ml) for 0-24h.	0	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	14	15	7	8
HMGB1 induced RAGE can lead to the phosphorylation and degradation of IkappaB and NF-kappaB-mediated activation of gene expression , NF-kappaB signaling pathway also affect HMGB1 expression by cross-talk .	HMGB1 induced RAGE can lead to the phosphorylation and degradation of IkappaB and NF-kappaB-mediated activation of gene expression, NF-kappaB signaling pathway also affect HMGB1 expression by cross-talk.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	2	3
Furthermore , HMGB1 released during chemotherapy enhances the ability of remnant cancer cells to regrow and metastasize in a RAGE dependent way .	Furthermore, HMGB1 released during chemotherapy enhances the ability of remnant cancer cells to regrow and metastasize in a RAGE dependent way.	2	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	2	3	19	20
The rhabdomyosarcoma cell lines used here and C2C12 myoblasts express and release HMGB1 , which activates RAGE in an autocrine manner .	The rhabdomyosarcoma cell lines used here and C2C12 myoblasts express and release HMGB1, which activates RAGE in an autocrine manner.	9	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	12	13	16	17
HMGB1 mediated activation of RAGE leads to microglia recruitment in a model of stroke .	HMGB1 mediated activation of RAGE leads to microglia recruitment in a model of stroke.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	4	5
RAGE downstream phosphorylation cascades in INS1E cells treated with AGE or HMGB1 .	RAGE downstream phosphorylation cascades in INS1E cells treated with AGE or HMGB1.	0	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	11	12	0	1
It has been suggested that the release of heat shock proteins ( many of which are induced upon cell stress ) may stimulate innate cells ; the release of HMGB1 upon cell damage can stimulate TLRs and RAGE .	It has been suggested that the release of heat shock proteins (many of which are induced upon cell stress) may stimulate innate cells; the release of HMGB1 upon cell damage can stimulate TLRs and RAGE.	27	38	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	29	30	37	38
Alveolar macrophage produced HMGB1 modulates RAGE mediated activation of iNKT cells .	Alveolar macrophage produced HMGB1 modulates RAGE mediated activation of iNKT cells.	3	7	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	3	4	5	6
36 Consistent with these results , the HMGB1 induced kinase activity of ERK is significantly more pronounced in RAGE expressing cells .	36 Consistent with these results, the HMGB1 induced kinase activity of ERK is significantly more pronounced in RAGE expressing cells.	6	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	7	8	18	19
In fact , during liver I/R , HMGB1 activates RAGE , leading to JNK and c-Jun activation with subsequent ergosterol-1 up-regulation.103 In the context of APAP intoxication , HMGB1 acted through RAGE to trigger neutrophil recruitment during liver necrosis , which mediated subsequent liver damage.23 RAGE deficient neutrophils had 80 % reduction in migration toward necrotic liver tissue .	In fact, during liver I/R, HMGB1 activates RAGE, leading to JNK and c-Jun activation with subsequent ergosterol-1 up-regulation.103 In the context of APAP intoxication, HMGB1 acted through RAGE to trigger neutrophil recruitment during liver necrosis, which mediated subsequent liver damage.23 RAGE deficient neutrophils had 80% reduction in migration toward necrotic liver tissue.	7	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	7	8	9	10
We suggest that after skin injury , extracellular HMGB1 induces RAGE- and TLR2/4 mediated fibroblast activation .	We suggest that after skin injury, extracellular HMGB1 induces RAGE- and TLR2/4 mediated fibroblast activation.	7	13	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE-	RAGE-	RAGE-	8	9	10	11
Based on experimental data , HMGB1 activates RAGE signaling and induces NF-kappaB activation to promote cellular proliferation in hepatocellular carcinoma ( HCC ) cell lines [ XREF_BIBR ] .	Based on experimental data, HMGB1 activates RAGE signaling and induces NF-kappaB activation to promote cellular proliferation in hepatocellular carcinoma (HCC) cell lines [XREF_BIBR].	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	5	6	7	8
These results suggest that HMGB1 mediated RAGE activation in iNKT cells is critical for the initiation of lung IR injury .	These results suggest that HMGB1 mediated RAGE activation in iNKT cells is critical for the initiation of lung IR injury.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	6	7
Intravitreal administration of HMGB-1 to normal rats induced significant upregulation of intercellular adhesion molecule-1 ( ICAM-1 ) , soluble intercellular adhesion molecule-1 ( sICAM-1 ) , HMGB-1 , RAGE , ERK ( 1/2 ) , and NF-kappaB , and significantly increased retinal vascular permeability , whereas the expression of TLR2 and occludin was downregulated .	Intravitreal administration of HMGB-1 to normal rats induced significant upregulation of intercellular adhesion molecule-1 (ICAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), HMGB-1, RAGE, ERK (1/2), and NF-kappaB, and significantly increased retinal vascular permeability, whereas the expression of TLR2 and occludin was downregulated.	1	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB-1	HMGB-1	HMGB-1	RAGE	RAGE	RAGE	3	4	28	29
However HA also activates CD44 and HMGB1 additionally activates RAGE receptor .	However HA also activates CD44 and HMGB1 additionally activates RAGE receptor.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	6	7	9	10
Except that HMGB1 induces proinflammatory cytokines and chemokines , RAGE activation by HMGB1 results in increased invasiveness of SF from RA patients [ XREF_BIBR ] .	Except that HMGB1 induces proinflammatory cytokines and chemokines, RAGE activation by HMGB1 results in increased invasiveness of SF from RA patients [XREF_BIBR].	9	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	12	13	9	10
We next sought to identify the receptor through which HMGB1 signalled to trigger ASM remodelling in RAGE deficient mice .	We next sought to identify the receptor through which HMGB1 signalled to trigger ASM remodelling in RAGE deficient mice.	9	18	signalled	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	9	10	16	17
Moreover , HMGB1 dependent activation of RAGE leads to activation of the NF-kappaB pathway , as well as signal transduction through ERK and p38 , to promote cytokine production and cell survival .	Moreover, HMGB1 dependent activation of RAGE leads to activation of the NF-kappaB pathway, as well as signal transduction through ERK and p38, to promote cytokine production and cell survival.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	2	3	6	7
HMGB1 activates RAGE signaling pathways and induces NF-kB activation to promote cellular proliferation , invasion , and metastasis , in HCC cell lines [ XREF_BIBR ] .	HMGB1 activates RAGE signaling pathways and induces NF-kB activation to promote cellular proliferation, invasion, and metastasis, in HCC cell lines [XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	2	3
The activation of RAGE by HMGB1 can induce the generation of seizures and initiate an innate immune response leading to inflammatory reaction in astrocytes [ XREF_BIBR ] .	The activation of RAGE by HMGB1 can induce the generation of seizures and initiate an innate immune response leading to inflammatory reaction in astrocytes [XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	5	6	3	4
As epithelial cell responses are fundamental drivers of asthma , including abnormal repair-restitution linked to changes in extracellular matrix ( ECM ) synthesis , we tested the hypothesis that HMGB1 promotes bronchial epithelial cell wound repair via TLR4 and/or RAGE signaling that regulates ECM ( fibronectin and the gamma2-chain of laminin-5 ) and integrin protein abundance .	As epithelial cell responses are fundamental drivers of asthma, including abnormal repair-restitution linked to changes in extracellular matrix (ECM) synthesis, we tested the hypothesis that HMGB1 promotes bronchial epithelial cell wound repair via TLR4 and/or RAGE signaling that regulates ECM (fibronectin and the gamma2-chain of laminin-5) and integrin protein abundance.	29	40	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	29	30	39	40
Animal models suggest that HMGB1 induced RAGE activation may contribute to IRI via activation of nuclear factor KB ( NF-KB ) in epithelial cells and production of IL-17 by natural killer T cells .	Animal models suggest that HMGB1 induced RAGE activation may contribute to IRI via activation of nuclear factor KB (NF-KB) in epithelial cells and production of IL-17 by natural killer T cells.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	6	7
HMGB-1 induced RAGE activation has been associated with renal dysfunction in models of systemic lupus erythematosis .	HMGB-1 induced RAGE activation has been associated with renal dysfunction in models of systemic lupus erythematosis.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB-1	HMGB-1	HMGB-1	RAGE	RAGE	RAGE	0	1	2	3
By contrast , RAGE activation by HMGB1 in LD cultures results in activation of both p38 MAPK and ERK1/2 at early differentiation stages stimulating proliferation and activating the myogenic program similar to S100B .	By contrast, RAGE activation by HMGB1 in LD cultures results in activation of both p38 MAPK and ERK1/2 at early differentiation stages stimulating proliferation and activating the myogenic program similar to S100B.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	6	7	3	4
Given that RAGE expression is upregulated by HMGB1 , the reduction in RAGE intensity in vivo upon VEGF-A 165 b treatment ( XREF_FIG C ) suggests that this treatment could reduce HMGB1 activation of RAGE or modify the downstream signalling from HMGB1-RAGE activation that results in the feed-forward agonist induced upregulation of RAGE , resulting in reduced pain , rather than exerting direct effects on neuronal TRPV1 .	Given that RAGE expression is upregulated by HMGB1, the reduction in RAGE intensity in vivo upon VEGF-A 165 b treatment (XREF_FIG C) suggests that this treatment could reduce HMGB1 activation of RAGE or modify the downstream signalling from HMGB1-RAGE activation that results in the feed-forward agonist induced upregulation of RAGE, resulting in reduced pain, rather than exerting direct effects on neuronal TRPV1.	31	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	31	32	34	35
The cells were cultured and either transfected with RAGE siRNA or treated with HMGB1 as described in Section 3.3 .	The cells were cultured and either transfected with RAGE siRNA or treated with HMGB1 as described in Section 3.3.	8	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	13	14	8	9
Activation of RAGE by HMGB1 promotes chemotaxis and cytokine production through the upregulation NF-kappabeta pathways .	Activation of RAGE by HMGB1 promotes chemotaxis and cytokine production through the upregulation NF-kappabeta pathways.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	2	3
Taken together , our findings support a novel mechanism whereby reactive astrocytes release HMGB1 that upregulates RAGE receptors on brain endothelial cells , thus augmenting beta2-integrin-mediated EPC adhesion and transmigration .	Taken together, our findings support a novel mechanism whereby reactive astrocytes release HMGB1 that upregulates RAGE receptors on brain endothelial cells, thus augmenting beta2-integrin-mediated EPC adhesion and transmigration.	12	17	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	13	14	16	17
As previously reported [ XREF_BIBR ] , we observed an increase in RAGE expression in cells treated with HMGB1 , while in cells pretreated with EP , HMGB1 induced RAGE mRNA levels were significantly lower ( XREF_SUPPLEMENTARY ) .	As previously reported [XREF_BIBR], we observed an increase in RAGE expression in cells treated with HMGB1, while in cells pretreated with EP, HMGB1 induced RAGE mRNA levels were significantly lower (XREF_SUPPLEMENTARY).	12	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	18	19	12	13
HMGB1 mediated RAGE activation participates in various pathological conditions including cancer , sepsis , diabetes and Alzheimer ' s disease [ XREF_BIBR ] .	HMGB1 mediated RAGE activation participates in various pathological conditions including cancer, sepsis, diabetes and Alzheimer 's disease [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	2	3
Importantly , HMGB1 can activate not only RAGE but also other receptors , most notably Toll like receptors 2 and 4 [ XREF_BIBR ] , and anti-HMGB1 treatment caused an additional survival benefit in RAGE deficient mice injected with high-dose endotoxin , suggesting that HMGB1 acts only partially via RAGE during endotoxin shock [ XREF_BIBR ] .	Importantly, HMGB1 can activate not only RAGE but also other receptors, most notably Toll like receptors 2 and 4 [XREF_BIBR], and anti-HMGB1 treatment caused an additional survival benefit in RAGE deficient mice injected with high-dose endotoxin, suggesting that HMGB1 acts only partially via RAGE during endotoxin shock [XREF_BIBR].	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	2	3	7	8
To determine whether an overall decrease in oxidative stress might also prevent RAGE induced apoptosis , pericytes were treated with 0.5 mug/ml HMGB1 in the absence or presence of several known cell-penetrant antioxidants .	To determine whether an overall decrease in oxidative stress might also prevent RAGE induced apoptosis, pericytes were treated with 0.5 mug/ml HMGB1 in the absence or presence of several known cell-penetrant antioxidants.	12	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	22	23	12	13
Total RAGE mRNA expression in HMGB1 stimulated and unstimulated WT , IKKbeta -/-, and IKKalpha -/- MEFs indicate that RAGE induction by HMGB1 requires IKKbeta but is independent of IKKalpha ( XREF_FIG ) , whereas basal RAGE expression was not influenced by either IKK ( data not shown ) .	Total RAGE mRNA expression in HMGB1 stimulated and unstimulated WT, IKKbeta -/-, and IKKalpha -/- MEFs indicate that RAGE induction by HMGB1 requires IKKbeta but is independent of IKKalpha (XREF_FIG), whereas basal RAGE expression was not influenced by either IKK (data not shown).	19	23	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	22	23	19	20
RAGE activation by HMGB1 in HD myoblasts results in p38 MAPK dependent stimulation of differentiation and inhibition of proliferation via p38 MAPK dependent inhibition of ERK1/2 XREF_BIBR , XREF_BIBR .	RAGE activation by HMGB1 in HD myoblasts results in p38 MAPK dependent stimulation of differentiation and inhibition of proliferation via p38 MAPK dependent inhibition of ERK1/2 XREF_BIBR, XREF_BIBR.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	3	4	0	1
HMGB1 may signal TLRs and RAGE to activate nuclear factor-kappaB ( NF-kappaB ) , which induces the production of proinflammatory cytokines and the upregulation of leukocyte adhesion molecules , thereby promoting injury and inflammation .	HMGB1 may signal TLRs and RAGE to activate nuclear factor-kappaB (NF-kappaB), which induces the production of proinflammatory cytokines and the upregulation of leukocyte adhesion molecules, thereby promoting injury and inflammation.	0	6	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	5	6
Moreover , we also observed a similar degree of IKKbeta dependency for HMGB1 induction of RAGE mRNA by MPhis ( XREF_SUPPLEMENTARY ) .	Moreover, we also observed a similar degree of IKKbeta dependency for HMGB1 induction of RAGE mRNA by MPhis (XREF_SUPPLEMENTARY).	12	16	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	12	13	15	16
Huh7 cells were either transfected with RAGE siRNA or treated with HMGB1 .	Huh7 cells were either transfected with RAGE siRNA or treated with HMGB1.	6	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	11	12	6	7
Our results reinforce prior reports that HMGB1 may stimulate RAGE activation of NF-kappaB , so it is conceivable that pulmonary dysfunction following TBI include the production of pro inflammatory cytokines such as IL-6 , TGF-beta and IL-17a .	Our results reinforce prior reports that HMGB1 may stimulate RAGE activation of NF-kappaB, so it is conceivable that pulmonary dysfunction following TBI include the production of pro inflammatory cytokines such as IL-6, TGF-beta and IL-17a.	6	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	6	7	9	10
Thus , although HMGB1 mediated activation of RAGE promotes type-2 inflammation ( which is known to induce the hallmark pathologies of asthma ) , in the absence of RAGE HMGB1 can directly induce features of airway remodelling and thus contribute to airway hyperreactivity independently of type-2 inflammation .	Thus, although HMGB1 mediated activation of RAGE promotes type-2 inflammation (which is known to induce the hallmark pathologies of asthma), in the absence of RAGE HMGB1 can directly induce features of airway remodelling and thus contribute to airway hyperreactivity independently of type-2 inflammation.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	3	4	7	8
Thus , we propose that RAGE activated by HMGB1 functions as a sensor of necrotic cell death at the core of the ischemia and mediates the activation of brain macrophages , mainly immigrant macrophages .	Thus, we propose that RAGE activated by HMGB1 functions as a sensor of necrotic cell death at the core of the ischemia and mediates the activation of brain macrophages, mainly immigrant macrophages.	5	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	8	9	5	6
Mechanistically , CD24 was shown to regulate CD8 + T cell activation through HMGB1 mediated engagement of T cell RAGE .	Mechanistically, CD24 was shown to regulate CD8 + T cell activation through HMGB1 mediated engagement of T cell RAGE.	6	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	13	14	19	20
The authors hypothesize that HMGB1 is released by necrotic tumor cells and enhances cell resistance by activating RAGE , inducing autophagy , and inhibiting apoptosis [ XREF_BIBR ] .	The authors hypothesize that HMGB1 is released by necrotic tumor cells and enhances cell resistance by activating RAGE, inducing autophagy, and inhibiting apoptosis [XREF_BIBR].	4	18	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	17	18
HMGB1 can activate the RAGE receptor and TLRs to elicit proinflammatory responses including the release of TNF-alpha and IL-1beta .	HMGB1 can activate the RAGE receptor and TLRs to elicit proinflammatory responses including the release of TNF-alpha and IL-1beta.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	4	5
In turn , when HMGB1 binds to target RAGE and/or TLRs on brain microvascular ECs they are source of proinflammatory agents by releasing TNF and other cytokines [ XREF_BIBR ] .	In turn, when HMGB1 binds to target RAGE and/or TLRs on brain microvascular ECs they are source of proinflammatory agents by releasing TNF and other cytokines [XREF_BIBR].	4	9	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	8	9
To explore whether RAGE contributes to HCC cellular proliferation , Huh7 cells were either transfected with RAGE siRNA or treated with HMGB1 .	To explore whether RAGE contributes to HCC cellular proliferation, Huh7 cells were either transfected with RAGE siRNA or treated with HMGB1.	16	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	21	22	16	17
Several studies have shown RAGE activated by HMGB1 may play a dominant role in neutrophil recruitment and migration , and anti-RAGE antibodies suppress migratory activity and cytokine release in IECs .	Several studies have shown RAGE activated by HMGB1 may play a dominant role in neutrophil recruitment and migration, and anti-RAGE antibodies suppress migratory activity and cytokine release in IECs.	4	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	7	8	4	5
Extracellular HMGB1 triggers inflammation by binding the multiligand receptor RAGE ( the receptor for advanced glycation end products ) and Toll like receptors ( TLR 2 , TLR 4 , and TLR 9 ) with signalling converge on the AKT activating pathways [ XREF_BIBR ] .	Extracellular HMGB1 triggers inflammation by binding the multiligand receptor RAGE (the receptor for advanced glycation end products) and Toll like receptors (TLR 2, TLR 4, and TLR 9) with signalling converge on the AKT activating pathways [XREF_BIBR].	0	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	1	2	9	10
Although our real-time PCR experiments clearly show that IKKbeta is necessary for HMGB1 induction of RAGE mRNA ( XREF_FIG , XREF_SUPPLEMENTARY ) , RAGE protein expression essentially remained at the limit of detection in either HMGB1 prestimulated MEFs or macrophages .	Although our real-time PCR experiments clearly show that IKKbeta is necessary for HMGB1 induction of RAGE mRNA (XREF_FIG, XREF_SUPPLEMENTARY), RAGE protein expression essentially remained at the limit of detection in either HMGB1 prestimulated MEFs or macrophages.	12	16	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	12	13	15	16
XREF_BIBR Our data indicated that AGE or HMGB1 activated RAGE in pancreatic fibroblasts , and that subsequently secreted cytokines ( including others that we did not measure ) inhibited glucose stimulated insulin secretion from INS1E cells ( XREF_FIG ) .	XREF_BIBR Our data indicated that AGE or HMGB1 activated RAGE in pancreatic fibroblasts, and that subsequently secreted cytokines (including others that we did not measure) inhibited glucose stimulated insulin secretion from INS1E cells (XREF_FIG).	5	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	7	8	9	10
Collectively , these data demonstrate that HMGB1 activates RAGE signaling pathways and induces NF-kB activation to promote cellular proliferation , invasion , and metastasis , in HCC cell lines .	Collectively, these data demonstrate that HMGB1 activates RAGE signaling pathways and induces NF-kB activation to promote cellular proliferation, invasion, and metastasis, in HCC cell lines.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	6	7	8	9
36 How RAGE signaling is modulated by HMGB1 during stroke recovery is not fully understood .	36 How RAGE signaling is modulated by HMGB1 during stroke recovery is not fully understood.	2	8	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	7	8	2	3
Here we found that HMGB1 ( 200 ng/ml ) markedly increased cardiomyocyte death , which was fully abolished by sRAGE ( 14 ng/ml ) ( XREF_FIG ) , indicating that , under the present experimental conditions , HMGB1 triggers cardiac cell death by activating RAGE .	Here we found that HMGB1 (200 ng/ml) markedly increased cardiomyocyte death, which was fully abolished by sRAGE (14 ng/ml) (XREF_FIG), indicating that, under the present experimental conditions, HMGB1 triggers cardiac cell death by activating RAGE.	37	45	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	37	38	44	45
Binding of its ligand HMGB1 promotes RAGE shedding .	Binding of its ligand HMGB1 promotes RAGE shedding.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	6	7
It is tempting to speculate that HMGB1 induced activation of RAGE during the first 24 h in LD myoblasts results in an extent of p38 MAPK activation sufficient to activate the myogenic program but insufficient to inhibit ERK1/2 .	It is tempting to speculate that HMGB1 induced activation of RAGE during the first 24 h in LD myoblasts results in an extent of p38 MAPK activation sufficient to activate the myogenic program but insufficient to inhibit ERK1/2.	6	15	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	6	7	10	11
Moreover , HMGB1 induces RAGE and TLR4 mediated neuroinflammation and necrosis after injuries such as lesions in the spinal cord and brain .	Moreover, HMGB1 induces RAGE and TLR4 mediated neuroinflammation and necrosis after injuries such as lesions in the spinal cord and brain.	2	7	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	2	3	4	5
111 During atherosclerosis , RAGE increases HMGB1 expression and release , XREF_BIBR , XREF_BIBR and in vitro treatment of endothelial cells ( human umbilical vein endothelial cells ) with extracellular HMGB1 induces RAGE dependent ER stress .	111 During atherosclerosis, RAGE increases HMGB1 expression and release, XREF_BIBR, XREF_BIBR and in vitro treatment of endothelial cells (human umbilical vein endothelial cells) with extracellular HMGB1 induces RAGE dependent ER stress.	20	33	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	30	31	32	33
Apoptotic osteocytes release more HMGB1 , which in turn activates RAGE in osteoclast precursors to induce osteoclast differentiation .	Apoptotic osteocytes release more HMGB1, which in turn activates RAGE in osteoclast precursors to induce osteoclast differentiation.	2	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	10	11
RAGE activation via its multiple ligands , including HMGB1 , plays a key role in various diseases , including acute or chronic inflammatory conditions such as sepsis and diseases such as rheumatoid arthritis , diabetic nephropathy , and cancer [ XREF_BIBR - XREF_BIBR ] .	RAGE activation via its multiple ligands, including HMGB1, plays a key role in various diseases, including acute or chronic inflammatory conditions such as sepsis and diseases such as rheumatoid arthritis, diabetic nephropathy, and cancer [XREF_BIBR - XREF_BIBR].	0	9	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	8	9	0	1
Thus , in the context of diabetes , HMGB1 may potentially mediate inflammation by activating any or all of TLR2 , 4 or RAGE in DN .	Thus, in the context of diabetes, HMGB1 may potentially mediate inflammation by activating any or all of TLR2, 4 or RAGE in DN.	8	24	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	8	9	23	24
Moreover , in hypoxic HCC cells , HMGB1 activates the RAGE signaling pathway to induce caspase-1 activity with subsequent production of multiple inflammatory mediators , which , in turn , could enhance the invasion and metastasis of HCC [ XREF_BIBR ] .	Moreover, in hypoxic HCC cells, HMGB1 activates the RAGE signaling pathway to induce caspase-1 activity with subsequent production of multiple inflammatory mediators, which, in turn, could enhance the invasion and metastasis of HCC [XREF_BIBR].	7	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	7	8	10	11
These results suggest that HMGB1 mediated RAGE activation on iNKT cells is critical for initiation of lung ischemia-reperfusion injury and that a crosstalk between macrophages and iNKT cells via the HMGB1 and RAGE axis mediates IL-17 production by iNKT cells causing neutrophil infiltration and lung ischemia-reperfusion injury .	These results suggest that HMGB1 mediated RAGE activation on iNKT cells is critical for initiation of lung ischemia-reperfusion injury and that a crosstalk between macrophages and iNKT cells via the HMGB1 and RAGE axis mediates IL-17 production by iNKT cells causing neutrophil infiltration and lung ischemia-reperfusion injury.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	6	7
HMGB1 enhances CXCL12 induced migration exclusively via CXCR4 and in a RAGE- and TLR independent manner .	HMGB1 enhances CXCL12 induced migration exclusively via CXCR4 and in a RAGE- and TLR independent manner.	0	15	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE-	RAGE-	RAGE-	0	1	11	12
Moreover , RAGE activation by HMGB1 results in increased invasiveness of fibroblast like synoviocytes from rheumatoid arthritis patients [ XREF_BIBR ] .	Moreover, RAGE activation by HMGB1 results in increased invasiveness of fibroblast like synoviocytes from rheumatoid arthritis patients [XREF_BIBR].	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	5	6	2	3
Following its release , HMGB1 activates TLRs and RAGE , which facilitate proinflammatory responses in a cyclic fashion ( XREF_FIG ) .	Following its release, HMGB1 activates TLRs and RAGE, which facilitate proinflammatory responses in a cyclic fashion (XREF_FIG).	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	8	9
Therefore , we hypothesized that HMGB1 activated RAGE to facilitate NSCs migration .	Therefore, we hypothesized that HMGB1 activated RAGE to facilitate NSCs migration.	5	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	5	6	7	8
Thus , HMGB1 induced ability of RAGE to stimulate differentiation and inhibit proliferation in HD cultures , as opposed to the inability of S100B to stimulate RAGE in this condition , likely reflects the ability of S100B , but not HMGB1 to bind bFGF and FGFR1 .	Thus, HMGB1 induced ability of RAGE to stimulate differentiation and inhibit proliferation in HD cultures, as opposed to the inability of S100B to stimulate RAGE in this condition, likely reflects the ability of S100B, but not HMGB1 to bind bFGF and FGFR1.	2	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	2	3	6	7
Since HMGB1 is an essential part of the immune complexes in lupus and since the immune complexes lead to immune activation via a pathway involving RAGE , the elevation of HMGB1 and the simultaneous decline of sRAGE could favour HMGB1-RAGE signalling as an important pathogenic mechanism .	Since HMGB1 is an essential part of the immune complexes in lupus and since the immune complexes lead to immune activation via a pathway involving RAGE, the elevation of HMGB1 and the simultaneous decline of sRAGE could favour HMGB1-RAGE signalling as an important pathogenic mechanism.	1	26	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	1	2	25	26
The TLRs and RAGE and the NF-kappaB signalling were also additively promoted by IL-1beta and HMGB1 .	The TLRs and RAGE and the NF-kappaB signalling were also additively promoted by IL-1beta and HMGB1.	1	16	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	15	16	3	4
Furthermore , HMGB1 enhances IL-10 release and T ( reg ) suppressive capacity in a RAGE dependent manner .	Furthermore, HMGB1 enhances IL-10 release and T (reg) suppressive capacity in a RAGE dependent manner.	2	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	2	3	15	16
HMGB1 signals the demise of HM by binding with high affinity to RAGE ( Receptor for Advanced Glycation End products ) of neighboring cells , including macrophages and surviving HM .	HMGB1 signals the demise of HM by binding with high affinity to RAGE (Receptor for Advanced Glycation End products) of neighboring cells, including macrophages and surviving HM.	0	29	signals	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	12	13
In cultured NRVCs , stimulation with rHMGB1 did not reduce the cell viability measured by either MTT assay or CCK8 assay ( XREF_FIG ) , but increased cardiomyocyte hypertrophy significantly which was not antagonized by co-treatment with anti-RAGE neutralizing antibody ( XREF_FIG ) , indicating that HMGB1 induced cardiomyocyte hypertrophy is RAGE independent .	In cultured NRVCs, stimulation with rHMGB1 did n't reduce the cell viability measured by either MTT assay or CCK8 assay (XREF_FIG), but increased cardiomyocyte hypertrophy significantly which was not antagonized by co-treatment with anti-RAGE neutralizing antibody (XREF_FIG), indicating that HMGB1 induced cardiomyocyte hypertrophy is RAGE independent.	46	52	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	46	47	51	52
HMGB1 increases TRPV1-agonist-evoked Ca 2+ responses , which is a RAGE mediated effect that is blocked with VEGF-A 165 b. HMGB1 is a RAGE agonist that has been implicated in peripheral nociceptive signalling .	HMGB1 increases TRPV1-agonist-evoked Ca 2+ responses, which is a RAGE mediated effect that is blocked with VEGF-A 165 b. HMGB1 is a RAGE agonist that has been implicated in peripheral nociceptive signalling.	0	24	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	0	1	23	24
HIPK2 induces cell death by activating p53 dependent [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] and independent pathways ( including the JNK signaling pathway ) [ XREF_BIBR , XREF_BIBR ] , to promote tumor cell apoptosis .	HIPK2 induces cell death by activating p53 dependent [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] and independent pathways (including the JNK signaling pathway) [XREF_BIBR, XREF_BIBR], to promote tumor cell apoptosis.	0	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	6	7
Upon DNA damage , HIPK2 activated p53 was shown to repress Gal-3 XREF_BIBR .	Upon DNA damage, HIPK2 activated p53 was shown to repress Gal-3 XREF_BIBR.	4	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	4	5	6	7
We found that HG reduced HIPK2 protein levels , therefore impairing HIPK2 induced p53 apoptotic activity .	We found that HG reduced HIPK2 protein levels, therefore impairing HIPK2 induced p53 apoptotic activity.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	11	12	13	14
RITA induced HIPK2 stabilization and consequent phosphorylation of p53 on Ser46 ( XREF_SUPPLEMENTARY ) and caused p53 dependent cytotoxicity ( XREF_FIG , and XREF_SUPPLEMENTARY ) through both transcription dependent and -independent pathways ( XREF_FIG ) .	RITA induced HIPK2 stabilization and consequent phosphorylation of p53 on Ser46 (XREF_SUPPLEMENTARY) and caused p53 dependent cytotoxicity (XREF_FIG, and XREF_SUPPLEMENTARY) through both transcription dependent and -independent pathways (XREF_FIG).	0	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	RITA induced HIPK2 stabilization and consequent phosphorylation of p53 on Ser46	hipk2	p53	p53	p53	2	3	16	17
Thus , cutaneous HPV23 E6 prevents HIPK2 mediated p53 Ser 46 phosphorylation , which may favour survival of UV damaged keratinocytes and skin carcinogenesis by apoptosis evasion .	Thus, cutaneous HPV23 E6 prevents HIPK2 mediated p53 Ser 46 phosphorylation, which may favour survival of UV damaged keratinocytes and skin carcinogenesis by apoptosis evasion.	5	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	6	7	8	9
These results reveal a new apoptotic pathway induced by HIPK2 activated p53 and requiring repression of the antiapoptotic factor Gal-3 .	These results reveal a new apoptotic pathway induced by HIPK2 activated p53 and requiring repression of the antiapoptotic factor Gal-3.	7	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	9	10	11	12
This suggests that while HIPK2 can enhance p300 regulation of p53 , it is not required for its activity .	This suggests that while HIPK2 can enhance p300 regulation of p53, it is not required for its activity.	4	11	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	4	5	10	11
Thus , HIPK2 by phosphorylating p53 on serine 46 is believed to activate p53 to induce apoptosis in response to genotoxic stress .	Thus, HIPK2 by phosphorylating p53 on serine 46 is believed to activate p53 to induce apoptosis in response to genotoxic stress.	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	2	3	13	14
HIPK2 modulates wild-type p53 activity toward proapoptotic transcription and tumor suppression by the phosphorylation of serine 46 .	HIPK2 modulates wild-type p53 activity toward proapoptotic transcription and tumor suppression by the phosphorylation of serine 46.	0	4	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	3	4
The HIPK2 induced p53 ( p ) Ser46 in RKO cells , abolished by HIF-1alpha co-expression , was completely re-established by zinc treatment that , as expected , concomitantly rescued the HIF-1alpha-induced HIPK2 downregulation .	The HIPK2 induced p53 (p) Ser46 in RKO cells, abolished by HIF-1alpha co-expression, was completely re-established by zinc treatment that, as expected, concomitantly rescued the HIF-1alpha-induced HIPK2 downregulation.	0	29	induced	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	1	2	3	4
PARP1 overexpression suppressed the HIPK2 mediated p53 activation and cell death .	PARP1 overexpression suppressed the HIPK2 mediated p53 activation and cell death.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	4	5	6	7
These results suggest that SIM mediated HIPK2 targeting to PML-NBs is crucial for HIPK2 mediated p53 activation and induction of apoptosis .	These results suggest that SIM mediated HIPK2 targeting to PML-NBs is crucial for HIPK2 mediated p53 activation and induction of apoptosis.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	13	14	15	16
46 Mechanistically , it has been shown that HIPK2 induces tumor cell apoptosis by activating the p53 pathway .	46 Mechanistically, it has been shown that HIPK2 induces tumor cell apoptosis by activating the p53 pathway.	8	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	8	9	16	17
Increasing HIPK2 stability by promoting its acetylation might be potentially useful to increase the efficacy of chemotherapy targeting HIPK2 or p53 .	Increasing HIPK2 stability by promoting its acetylation might be potentially useful to increase the efficacy of chemotherapy targeting HIPK2 or p53.	1	21	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	1	2	20	21
Functionally , we demonstrate that HPV23 E6 inhibits HIPK2 mediated p53 Ser 46 phosphorylation through enforcing dissociation of the HIPK2 and p53 complex .	Functionally, we demonstrate that HPV23 E6 inhibits HIPK2 mediated p53 Ser 46 phosphorylation through enforcing dissociation of the HIPK2 and p53 complex.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	8	9	10	11
Conversely , overexpression of wild-type HIPK2 kinase , but not of the catalytic inactive mutant HIPK2 K221R , potentiated doxorubicin induced accumulation of p53 at mitochondria ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Conversely, overexpression of wild-type HIPK2 kinase, but not of the catalytic inactive mutant HIPK2 K221R, potentiated doxorubicin induced accumulation of p53 at mitochondria (XREF_FIG and XREF_SUPPLEMENTARY).	2	24	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	overexpression of wild-type HIPK2	hipk2	p53	p53	p53	5	6	23	24
Moreover , HIPK2 impairment during hypoxia induces de-repression of target genes such as HIF-1alpha , and inhibition of p53 activity XREF_BIBR .	Moreover, HIPK2 impairment during hypoxia induces de-repression of target genes such as HIF-1alpha, and inhibition of p53 activity XREF_BIBR.	2	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	2	3	18	19
These results demonstrate that HIPK2 mediates HIV induced activation of p53 , TGFbeta , and Wnt and Notch pathways in RTECs .	These results demonstrate that HIPK2 mediates HIV induced activation of p53, TGFbeta, and Wnt and Notch pathways in RTECs.	4	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	4	5	10	11
The proposed targets for miR-934 are also potent tumor suppressors : HOXA4 has been shown to inhibit cell motility and invasion in ovarian carcinoma [ XREF_BIBR ] ; MLL3 is involved in a p53 coactivator complex , with knockout resulting in epithelial tumor formation in mice [ XREF_BIBR ] ; and HIPK2 mediates apoptosis and activates p53 via phosphorylation at Ser46 [ XREF_BIBR ] .	The proposed targets for miR-934 are also potent tumor suppressors : HOXA4 has been shown to inhibit cell motility and invasion in ovarian carcinoma [XREF_BIBR]; MLL3 is involved in a p53 coactivator complex, with knockout resulting in epithelial tumor formation in mice [XREF_BIBR]; and HIPK2 mediates apoptosis and activates p53 via phosphorylation at Ser46 [XREF_BIBR].	51	58	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	51	52	56	57
The purpose of our investigation was to evaluate whether hypoxia could deregulate the HIPK2 induced p53 dependent apoptotic transcriptional activity in response to drug and therefore contribute to chemoresistance and whether zinc could counteract this HIPK2 and p53Ser46 inhibition .	The purpose of our investigation was to evaluate whether hypoxia could deregulate the HIPK2 induced p53 dependent apoptotic transcriptional activity in response to drug and therefore contribute to chemoresistance and whether zinc could counteract this HIPK2 and p53Ser46 inhibition.	12	26	induced	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	13	14	15	16
In a similar assay , which we have used to study HIPK2 mediated activation of p53 specific promoter elements , we looked for a role of HIPK2 in activation of NFkappaB mediated transcription .	In a similar assay, which we have used to study HIPK2 mediated activation of p53 specific promoter elements, we looked for a role of HIPK2 in activation of NFkappaB mediated transcription.	11	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	11	12	15	16
They showed for the first time that hypoxia induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug , underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment .	They showed for the first time that hypoxia induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug, underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment.	9	26	reactivated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	9	10	24	25
HIPK2 mediated p53 dependent apoptosis critically involves p53 Ser 46 phosphorylation , which in turn allows recruitment of the acetylase CREB binding protein to acetylate p53 at Lys 382 .	HIPK2 mediated p53 dependent apoptosis critically involves p53 Ser 46 phosphorylation, which in turn allows recruitment of the acetylase CREB binding protein to acetylate p53 at Lys 382.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	2	3
The p53 responsive enhancer element becomes activated by HIPK2 in cell lines with p53 but not in a cell line devoid of p53 .	The p53 responsive enhancer element becomes activated by HIPK2 in cell lines with p53 but not in a cell line devoid of p53.	6	14	activated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	8	9	13	14
Taken together , our results show the loss of the p53 activator HIPK2 in WDTC and the concomitant upregulation of the anti-apoptotic factor Gal-3 .	Taken together, our results show the loss of the p53 activator HIPK2 in WDTC and the concomitant upregulation of the anti-apoptotic factor Gal-3.	7	18	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	12	13	10	11
However , HIPK2 is not sufficient for phosphorylation of three crucial serine residues of p53 , suggesting that HIPK2 induced p53 activation does not involve phosphorylation of p53 .	However, HIPK2 is not sufficient for phosphorylation of three crucial serine residues of p53, suggesting that HIPK2 induced p53 activation does not involve phosphorylation of p53.	18	21	induced	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	18	19	20	21
We found that HIPK2 rescues p53 transcriptional activity overcoming MDM2 inhibition , and that restoration of this p53 function induces apoptosis .	We found that HIPK2 rescues p53 transcriptional activity overcoming MDM2 inhibition, and that restoration of this p53 function induces apoptosis.	3	7	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	3	4	5	6
Since HIPK2 activates p53 by phosphorylation XREF_BIBR , XREF_BIBR and HIPK2 is stabilized by p300 as we have shown in this study , p300 seems to ensure activation of p53 by directly modifying p53 and also stabilizing its upstream regulator HIPK2 under DNA damage conditions .	Since HIPK2 activates p53 by phosphorylation XREF_BIBR, XREF_BIBR and HIPK2 is stabilized by p300 as we have shown in this study, p300 seems to ensure activation of p53 by directly modifying p53 and also stabilizing its upstream regulator HIPK2 under DNA damage conditions.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	1	2	3	4
HIPK2 mediated p53 Ser 46 phosphorylation presumably takes place at promyelocytic leukemia ( PML ) nuclear bodies .	HIPK2 mediated p53 Ser 46 phosphorylation presumably takes place at promyelocytic leukemia (PML) nuclear bodies.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	2	3
Early induced p53 allows caspase mediated cleavage of HIPK2 following aspartic acids 916 and 977 .	Early induced p53 allows caspase mediated cleavage of HIPK2 following aspartic acids 916 and 977.	1	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	8	9	2	3
The Loss of the p53 Activator HIPK2 Is Responsible for Galectin-3 Overexpression in Well Differentiated Thyroid Carcinomas .	The Loss of the p53 Activator HIPK2 Is Responsible for Galectin-3 Overexpression in Well Differentiated Thyroid Carcinomas.	1	7	Activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	6	7	4	5
Therefore , agents such as HIPK2 that can increase active p53 in tumor cells by hinder the MDM2-p53 interaction might have therapeutic utility in sensitizing tumor cells to chemo- or radio-therapy .	Therefore, agents such as HIPK2 that can increase active p53 in tumor cells by hinder the MDM2-p53 interaction might have therapeutic utility in sensitizing tumor cells to chemo- or radio-therapy.	2	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	5	6	10	11
In addition , HIPK2 can promote p53 independent apoptosis through interaction with C-terminal binding protein ( CtBP ) and Deltap63alpha .	In addition, HIPK2 can promote p53 independent apoptosis through interaction with C-terminal binding protein (CtBP) and Deltap63alpha.	3	8	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	3	4	6	7
Furthermore , we evaluated whether HIPK2 induced p53 transcriptional activity inhibited by cobalt ( XREF_FIG ) could be restored by zinc .	Furthermore, we evaluated whether HIPK2 induced p53 transcriptional activity inhibited by cobalt (XREF_FIG) could be restored by zinc.	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	5	6	7	8
In response to genotoxic damage , HIPK2 stimulates p53 depended and -independent cell cycle arrest and apoptosis [ XREF_BIBR - XREF_BIBR ] and specific reduction of HIPK2 expression by anti-sense oligonucleotides or RNAi was shown to impair apoptosis and induce resistance to different anticancer treatments [ XREF_BIBR , XREF_BIBR ] .	In response to genotoxic damage, HIPK2 stimulates p53 depended and -independent cell cycle arrest and apoptosis [XREF_BIBR - XREF_BIBR] and specific reduction of HIPK2 expression by anti-sense oligonucleotides or RNAi was shown to impair apoptosis and induce resistance to different anticancer treatments [XREF_BIBR, XREF_BIBR].	6	39	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	6	7	8	9
To obtain insight into the mechanisms underlying the inhibition of HIPK2 mediated p53 Ser 46 phosphorylation by HPV23 E6 we analyzed whether HPV23 E6 has an influence on HIPK2 and p53 complex formation .	To obtain insight into the mechanisms underlying the inhibition of HIPK2 mediated p53 Ser 46 phosphorylation by HPV23 E6 we analyzed whether HPV23 E6 has an influence on HIPK2 and p53 complex formation.	8	13	mediated	Positive_early_activation	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	10	11	12	13
In addition , HIPK2 also activates the apoptotic response independent of p53 by regulating the JNK pathway and by targeting the anti-apoptotic transcriptional repressor CtBP for degradation .	In addition, HIPK2 also activates the apoptotic response independent of p53 by regulating the JNK pathway and by targeting the anti-apoptotic transcriptional repressor CtBP for degradation.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	3	4	11	12
To directly address the question whether HIPK2 might promote p53 localization to mitochondria , we knocked down HIPK2 expression by RNAi in HCT116 p53 +/+ cells and consequently observed a decrease of stress induced mitochondrial accumulation of p53 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	To directly address the question whether HIPK2 might promote p53 localization to mitochondria, we knocked down HIPK2 expression by RNAi in HCT116 p53 +/+ cells and consequently observed a decrease of stress induced mitochondrial accumulation of p53 (XREF_FIG and XREF_SUPPLEMENTARY).	6	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	6	7	9	10
Moreover , ZnCl 2 has been also shown to inhibit HIF-1 activity and restore the HIPK2 induced p53 apoptotic activity [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Moreover, ZnCl 2 has been also shown to inhibit HIF-1 activity and restore the HIPK2 induced p53 apoptotic activity [XREF_BIBR, XREF_BIBR, XREF_BIBR].	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	15	16	17	18
The direct effect of HIF-1alpha on HIPK2 induced p53 activation was then analysed under conditions of proteins overexpression .	The direct effect of HIF-1alpha on HIPK2 induced p53 activation was then analysed under conditions of proteins overexpression.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	6	7	8	9
HIPK2 activation by chemotherapeutic drugs , including ADR and cisplatin , results in p53 phosphorylation at Ser46 with specific induction of apoptosis [ XREF_BIBR , XREF_BIBR ] ; on the other hand , HIPK2 is unable to induce apoptosis in p53 mutant cells [ XREF_BIBR ] , although p53 independent apoptotic pathways activated by HIPK2 have been reported [ XREF_BIBR - XREF_BIBR ] .	HIPK2 activation by chemotherapeutic drugs, including ADR and cisplatin, results in p53 phosphorylation at Ser46 with specific induction of apoptosis [XREF_BIBR, XREF_BIBR]; on the other hand, HIPK2 is unable to induce apoptosis in p53 mutant cells [XREF_BIBR], although p53 independent apoptotic pathways activated by HIPK2 have been reported [XREF_BIBR - XREF_BIBR].	48	55	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	54	55	48	49
Emerging data also indicate that HIPK2 silencing by siRNA impairs p53 tumor suppressor function , induces chemoresistance , and increases in vivo tumor growth [ XREF_BIBR ] .	Emerging data also indicate that HIPK2 silencing by siRNA impairs p53 tumor suppressor function, induces chemoresistance, and increases in vivo tumor growth [XREF_BIBR].	5	13	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	5	6	10	11
HIPK2 has been shown to be Ser/Thr kinase which phosphorylates p53 at Ser 46 and enhance proapoptotic activity of p53 [ XREF_BIBR ] .	HIPK2 has been shown to be Ser/Thr kinase which phosphorylates p53 at Ser 46 and enhance proapoptotic activity of p53 [XREF_BIBR].	0	21	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2 has been shown to be Ser/Thr kinase which phosphorylates p53 at Ser 46	hipk2	p53	p53	p53	0	1	19	20
26 Consistently , we found that p53 is activated in kidneys of Tg26 mice , and knockout of HIPK2 abolished HIV induced activation of p53 in RTEC and kidney cortices .	26 Consistently, we found that p53 is activated in kidneys of Tg26 mice, and knockout of HIPK2 abolished HIV induced activation of p53 in RTEC and kidney cortices.	16	25	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	18	19	24	25
However , exposure of cells to physiological stress - such as hypoxia , oxidative stress , or UV damage - is known to stabilize HIPK2 , leading to the HIPK2 dependent activation of p53 and the cell death pathway .	However, exposure of cells to physiological stress - such as hypoxia, oxidative stress, or UV damage - is known to stabilize HIPK2, leading to the HIPK2 dependent activation of p53 and the cell death pathway.	29	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	29	30	33	34
Accumulating evidence has shown that broader genotoxic stress agents including ionizing radiation , DNA damaging chemotherapeutic agents and a cyclin dependent kinase 2 inhibitor roscovitine activate HIPK2 , which in turn activates p53 .	Accumulating evidence has shown that broader genotoxic stress agents including ionizing radiation, DNA damaging chemotherapeutic agents and a cyclin dependent kinase 2 inhibitor roscovitine activate HIPK2, which in turn activates p53.	25	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	26	27	32	33
After HIPK2 was first reported to induce p53 apoptotic activity through Ser46 phosphorylation , a number of studies uncovered additional molecular mechanisms for HIPK2 mediated p53 regulation and other downstream transcription factors that participate in cancer progression [ XREF_BIBR ] .	After HIPK2 was first reported to induce p53 apoptotic activity through Ser46 phosphorylation, a number of studies uncovered additional molecular mechanisms for HIPK2 mediated p53 regulation and other downstream transcription factors that participate in cancer progression [XREF_BIBR].	1	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	1	2	7	8
HIPK2 mediated activation of the p53 transcription factor by phosphorylation at Ser46 results in upregulation of p53AIP1 protein .	HIPK2 mediated activation of the p53 transcription factor by phosphorylation at Ser46 results in upregulation of p53AIP1 protein.	0	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	5	6
HIPK2 induces p53 dependent apoptosis through phosphorylating p53 at Ser46 and acetylating p53 at Lys382 [ XREF_BIBR , XREF_BIBR ] .	HIPK2 induces p53 dependent apoptosis through phosphorylating p53 at Ser46 and acetylating p53 at Lys382 [XREF_BIBR, XREF_BIBR].	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	2	3
HIPK2 activates p53 via several different mechanisms .	HIPK2 activates p53 via several different mechanisms.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	2	3
Interestingly , a loss of p53 activator HIPK2 ( homeodomain interacting protein kinase-2 ) , a critical molecule that is necessary for p53 phosphorylation on serine 46 , has been finally demonstrated in WDTC and was found responsible for p53 loss of function , galectin-3 overexpression and block of apoptosis [ XREF_BIBR ] .	Interestingly, a loss of p53 activator HIPK2 (homeodomain interacting protein kinase-2), a critical molecule that is necessary for p53 phosphorylation on serine 46, has been finally demonstrated in WDTC and was found responsible for p53 loss of function, galectin-3 overexpression and block of apoptosis [XREF_BIBR].	3	9	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	7	8	5	6
Moreover , we demonstrate that binding of E6 to HIPK2 inhibits HIPK2 mediated p53 Ser 46 phosphorylation by enforcing dissociation of the HIPK2 and p53 complex .	Moreover, we demonstrate that binding of E6 to HIPK2 inhibits HIPK2 mediated p53 Ser 46 phosphorylation by enforcing dissociation of the HIPK2 and p53 complex.	10	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	11	12	13	14
HIPK2 knockdown impairs p53 pro apoptotic gene transcription in response to drugs and predisposes to chemoresistance [ XREF_BIBR ] and increased tumor growth in vivo [ XREF_BIBR ] .	HIPK2 knockdown impairs p53 pro apoptotic gene transcription in response to drugs and predisposes to chemoresistance [XREF_BIBR] and increased tumor growth in vivo [XREF_BIBR].	0	7	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	3	4
To assess the impact of HIPK2 induced p53 posttranslational modifications on p53 specific activation of proapoptotic gene promoters the transcriptional activity of wtp53 compared to that of p53 mutants following HIPK2 overexpression was evaluated in a p53 and null cell line ( H1299 ) .	To assess the impact of HIPK2 induced p53 posttranslational modifications on p53 specific activation of proapoptotic gene promoters the transcriptional activity of wtp53 compared to that of p53 mutants following HIPK2 overexpression was evaluated in a p53 and null cell line (H1299).	3	9	induced	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	5	6	7	8
As mentioned before p53 can be inactivated by the HMGB1 sister protein HMGA1 by translocation of the p53 activator HIPK2 [ XREF_BIBR ] .	As mentioned before p53 can be inactivated by the HMGB1 sister protein HMGA1 by translocation of the p53 activator HIPK2 [XREF_BIBR].	14	20	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	19	20	17	18
To note that , although p53 Ser46 is not targeted exclusively by HIPK2 , other putative phosphorylating agents of this residue , notably DYRK2 XREF_BIBR and PKC XREF_BIBR , are nearly unaffected by the inhibitor under conditions where HIPK2 is > 70 % inhibited ( see XREF_SUPPLEMENTARY ) .	To note that, although p53 Ser46 is not targeted exclusively by HIPK2, other putative phosphorylating agents of this residue, notably DYRK2 XREF_BIBR and PKC XREF_BIBR, are nearly unaffected by the inhibitor under conditions where HIPK2 is> 70% inhibited (see XREF_SUPPLEMENTARY).	5	13	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	12	13	5	6
HIPK2 activates p53 apoptotic function in response to genotoxic stress .	HIPK2 activates p53 apoptotic function in response to genotoxic stress.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	2	3
Of note , ectopic HIPK2 can restore p53 and Ser46 apoptotic activity and overcome chemoresistance , as shown in an ovarian cancer model resistant to cisplatin XREF_BIBR .	Of note, ectopic HIPK2 can restore p53 and Ser46 apoptotic activity and overcome chemoresistance, as shown in an ovarian cancer model resistant to cisplatin XREF_BIBR.	3	13	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	4	5	7	8
Alternatively , HIPK2 could potentially up-regulate p53 dependent activation of Bax .	Alternatively, HIPK2 could potentially up-regulate p53 dependent activation of Bax.	2	8	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	2	3	6	7
A generated Axin , Tip60 , HIPK2 , and p53 complex in the presence of a lethal dose of genotoxic factors allows full activation of p53 , resulting in p53 dependent apoptosis [ XREF_BIBR ] .	A generated Axin, Tip60, HIPK2, and p53 complex in the presence of a lethal dose of genotoxic factors allows full activation of p53, resulting in p53 dependent apoptosis [XREF_BIBR].	2	26	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	6	7	25	26
The genes rai17 and hipk2 were up-regulated , both of which are activators of p53 .	The genes rai17 and hipk2 were up-regulated, both of which are activators of p53.	2	15	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hipk2	hipk2	hipk2	p53	p53	p53	4	5	14	15
HIPK2 also enhances expression levels of p53 protein .	HIPK2 also enhances expression levels of p53 protein.	0	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	6	7
This is a hint that the increase of p53 protein induced by wildtype HIPK2 could be responsible for the enhanced transcriptional activity mediated by p53 binding promoter elements .	This is a hint that the increase of p53 protein induced by wildtype HIPK2 could be responsible for the enhanced transcriptional activity mediated by p53 binding promoter elements.	8	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	13	14	8	9
XREF_BIBR Therefore , HIPK2 induces apoptosis in p53 null cells through CtBP degradation in response to apoptotic stimuli .	XREF_BIBR Therefore, HIPK2 induces apoptosis in p53 null cells through CtBP degradation in response to apoptotic stimuli.	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	3	4	7	8
In summary , these experiments reveal a novel function for Sp100 as a coactivator for HIPK2 mediated p53 activation .	In summary, these experiments reveal a novel function for Sp100 as a coactivator for HIPK2 mediated p53 activation.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	15	16	17	18
Functionally , the SIM dependent targeting of HIPK2 to PML NBs is crucial for HIPK2 mediated p53 activation and induction of apoptosis XREF_BIBR .	Functionally, the SIM dependent targeting of HIPK2 to PML NBs is crucial for HIPK2 mediated p53 activation and induction of apoptosis XREF_BIBR.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	14	15	16	17
HIPK2 modulates p53 activity towards pro apoptotic transcription .	HIPK2 modulates p53 activity towards pro apoptotic transcription.	0	3	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	2	3
Altogether , these data indicate that HG strongly impaired HIPK2 induced p53 apoptotic activity .	Altogether, these data indicate that HG strongly impaired HIPK2 induced p53 apoptotic activity.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	9	10	11	12
For example , genotoxic damage induces mammalian Hipk2 , and HIPK2 potentiates p53 pro apoptotic activity through direct phosphorylation [ XREF_BIBR ] .	For example, genotoxic damage induces mammalian Hipk2, and HIPK2 potentiates p53 pro apoptotic activity through direct phosphorylation [XREF_BIBR].	10	15	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	10	11	12	13
We show here for the first time that hypoxia induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug , underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment .	We show here for the first time that hypoxia induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug, underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment.	10	27	reactivated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	10	11	25	26
Together , these findings showed that knockout of HIPK2 abolished HIV induced activation of p53 , TGF-beta and Smad3 , and Wnt and Notch pathways in the kidney cortex of Tg26 mice .	Together, these findings showed that knockout of HIPK2 abolished HIV induced activation of p53, TGF-beta and Smad3, and Wnt and Notch pathways in the kidney cortex of Tg26 mice.	6	18	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	8	9	14	15
A defective HIPK2 activated P53 system has been implicated in the pathogenesis of idiopathic pulmonary fibrosis .	A defective HIPK2 activated P53 system has been implicated in the pathogenesis of idiopathic pulmonary fibrosis.	0	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	P53	P53	P53	2	3	4	5
In this regard , we found that HIPK2 cooperates with PCAF to induce selectively p53 transcriptional activity toward the p21Waf1 promoter while depletion of either HIPK2 or PCAF abolished this function .	In this regard, we found that HIPK2 cooperates with PCAF to induce selectively p53 transcriptional activity toward the p21Waf1 promoter while depletion of either HIPK2 or PCAF abolished this function.	7	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	7	8	14	15
HIPK2 phosphorylates and activates oncosuppressor p53 for apoptotic function in response to drugs XREF_BIBR , XREF_BIBR .	HIPK2 phosphorylates and activates oncosuppressor p53 for apoptotic function in response to drugs XREF_BIBR, XREF_BIBR.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	5	6
In addition , HIPK2 activates several pro apoptotic ( p53 ) , pro fibrotic ( TGF-beta ( transforming growth factor beta )-Smad3 and Wnt-Notch pathways ) , and pro inflammatory ( NF-kappaB ) pathways in RTEC .	In addition, HIPK2 activates several pro apoptotic (p53), pro fibrotic (TGF-beta (transforming growth factor beta)-Smad3 and Wnt-Notch pathways), and pro inflammatory (NF-kappaB) pathways in RTEC.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	3	4	9	10
Accordingly , the kinase function of HIPK2 mediates the increased expression of p53 target genes , which results in growth arrest and the enhancement of UV induced apoptosis .	Accordingly, the kinase function of HIPK2 mediates the increased expression of p53 target genes, which results in growth arrest and the enhancement of UV induced apoptosis.	4	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	6	7	12	13
HIPK2 and Pin1 cooperate to induce direct apoptotic activity of p53 at mitochondria .	HIPK2 and Pin1 cooperate to induce direct apoptotic activity of p53 at mitochondria.	0	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	10	11
Interestingly , although CAV DGV irreversibly accumulates in the membranes of the ER and on lipid droplets , deregulation of cholesterol fluxes modify signaling pathways at the cell surface , such as the H-Ras mediated activation of Raf-1 .	Interestingly, although CAV DGV irreversibly accumulates in the membranes of the ER and on lipid droplets, deregulation of cholesterol fluxes modify signaling pathways at the cell surface, such as the H-Ras mediated activation of Raf-1.	33	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	H-Ras	H-Ras	H-Ras	Raf-1	Raf-1	Raf-1	33	34	37	38
Tyrosine kinase oncogenes and receptors and p21ras can activate Raf-1 , and recent studies have suggested that Raf-1 functions upstream of MEK ( MAP and ERK kinase ) , which phosphorylates and activates ERK .	Tyrosine kinase oncogenes and receptors and p21ras can activate Raf-1, and recent studies have suggested that Raf-1 functions upstream of MEK (MAP and ERK kinase), which phosphorylates and activates ERK.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21ras	p21ras	p21ras	Raf-1	Raf-1	Raf-1	6	7	9	10
Taken together , these data suggest that JAK2 and p21ras cooperate to activate Raf-1 .	Taken together, these data suggest that JAK2 and p21ras cooperate to activate Raf-1.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21ras	p21ras	p21ras	Raf-1	Raf-1	Raf-1	9	10	13	14
Moreover , we demonstrated that HRAS enhanced gastric carcinoma aggressiveness by activating VEGFA/PI3K/AKT pathway and Raf-1 signaling .	Moreover, we demonstrated that HRAS enhanced gastric carcinoma aggressiveness by activating VEGFA/PI3K/AKT pathway and Raf-1 signaling.	5	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HRAS	HRAS	HRAS	Raf-1	Raf-1	Raf-1	5	6	15	16
Ha-Ras proteins carrying mutations N26G and V45E , which failed to bind to CRR , also failed to activate Raf-1 .	Ha-Ras proteins carrying mutations N26G and V45E, which failed to bind to CRR, also failed to activate Raf-1.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ha-Ras	Ha-Ras	Ha-Ras	Raf-1	Raf-1	Raf-1	0	1	19	20
Initially we made use of HCT116 colon cancer cells expressing in wild type cells mutant active K-RAS D13 or mutant forms of H-RAS V12 that specifically activated RAF-1 or PI3K ( XREF_FIG ) .	Initially we made use of HCT116 colon cancer cells expressing in wild type cells mutant active K-RAS D13 or mutant forms of H-RAS V12 that specifically activated RAF-1 or PI3K (XREF_FIG).	22	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	H-RAS	H-RAS	H-RAS	RAF-1	RAF-1	RAF-1	22	23	27	28
As PP2A has positive role in H-ras dependent activation of Raf-1 which consequently activates ERK pathway , ALA promises downregulation of ERK pathway through inactivation of PP2A .	As PP2A has positive role in H-ras dependent activation of Raf-1 which consequently activates ERK pathway, ALA promises downregulation of ERK pathway through inactivation of PP2A.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	H-ras	H-ras	H-ras	Raf-1	Raf-1	Raf-1	6	7	10	11
The protective effect of H-RAS V12 was lost in cells expressing a mutant H-RAS V12 protein that specifically activated RAF-1 but not a H-RAS V12 protein that specifically activated PI3K ( XREF_FIG ) .	The protective effect of H-RAS V12 was lost in cells expressing a mutant H-RAS V12 protein that specifically activated RAF-1 but not a H-RAS V12 protein that specifically activated PI3K (XREF_FIG).	13	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	H-RAS	H-RAS	H-RAS	RAF-1	RAF-1	RAF-1	13	14	19	20
For example , a yeast two-hybrid screen identified a series of compounds exemplified by MCP1 which inhibits mutant or wild type HRAS driven promoter and reporter constructs , HRAS driven RAF1 activation , and mutant HRAS or NRAS dependent phenotypes including anchorage independent growth and loss of cytoskeletal organization .	For example, a yeast two-hybrid screen identified a series of compounds exemplified by MCP1 which inhibits mutant or wild type HRAS driven promoter and reporter constructs, HRAS driven RAF1 activation, and mutant HRAS or NRAS dependent phenotypes including anchorage independent growth and loss of cytoskeletal organization.	17	31	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HRAS	HRAS	HRAS	RAF1	RAF1	RAF1	28	29	30	31
However , these molecules were markedly down-regulated on osteoblasts transfected with expression vector encoding fully activated H-Ras ( V12 ) , H-Ras ( V12 ) T35S , activating Raf-1 and mitogen activated protein kinase ( MAPK ) , or an active Raf-1 but not on cells having H-Ras ( V12 ) Y40C , a phosphoinositide 3-kinase ( PI3K )-binding mutant .	However, these molecules were markedly down-regulated on osteoblasts transfected with expression vector encoding fully activated H-Ras (V12), H-Ras (V12) T35S, activating Raf-1 and mitogen-activated protein kinase (MAPK), or an active Raf-1 but not on cells having H-Ras (V12) Y40C, a phosphoinositide 3-kinase (PI3K)-binding mutant.	13	41	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	H-Ras	H-Ras	H-Ras	Raf-1	Raf-1	Raf-1	16	17	28	29
To address this question , we developed a cell-free system in which the activated form of H-Ras can induce Raf-1 activation .	To address this question, we developed a cell-free system in which the activated form of H-Ras can induce Raf-1 activation.	14	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	H-Ras	H-Ras	H-Ras	Raf-1	Raf-1	Raf-1	16	17	19	20
Hhat mediated Shh palmitoylation can occur independently of autocleavage or cholesterol modification XREF_BIBR .	Hhat mediated Shh palmitoylation can occur independently of autocleavage or cholesterol modification XREF_BIBR.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	0	1	2	3
Loss of Hhat function disrupts Shh signaling .	Loss of Hhat function disrupts Shh signaling.	2	6	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	2	3	5	6
It was shown that HHATL interacts directly with Shh decreasing the efficiency of Shh palmitoylation [ XREF_BIBR ] , being proposed as a negative regulator of the HHAT driven N palmitoylation of Shh and of the Hh pathway .	It was shown that HHATL interacts directly with Shh decreasing the efficiency of Shh palmitoylation [XREF_BIBR], being proposed as a negative regulator of the HHAT driven N palmitoylation of Shh and of the Hh pathway.	24	33	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HHAT	HHAT	HHAT	Shh	Shh	Shh	27	28	32	33
These results are supported by a recent paper XREF_BIBR which showed that Hhat knockdown in NSCLC inhibited Shh palmitoylation as well as growth and survival of the tumor cells .	These results are supported by a recent paper XREF_BIBR which showed that Hhat knockdown in NSCLC inhibited Shh palmitoylation as well as growth and survival of the tumor cells.	12	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	12	13	17	18
A high-throughput screen of approximately 64K compounds designed to identify inhibitors of Hhat mediated SHh palmitoylation identified four structurally related thiophenes with IC 50 values ranging from 0.2-5 muM [ XREF_BIBR ] .	A high-throughput screen of approximately 64K compounds designed to identify inhibitors of Hhat mediated SHh palmitoylation identified four structurally related thiophenes with IC 50 values ranging from 0.2-5 muM [XREF_BIBR].	10	15	mediated	Positive_early_activation	Positive_activation	Negative_activation	Hhat	Hhat	Hhat	SHh	SHh	SHh	12	13	14	15
In this study , we describe the first example of a small-molecule that inhibits the activity of Hhat in vitro and blocks Hhat mediated Shh palmitoylation in cells .	In this study, we describe the first example of a small-molecule that inhibits the activity of Hhat in vitro and blocks Hhat mediated Shh palmitoylation in cells.	22	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	22	23	24	25
In an effort to discover a small-molecule inhibitor of Hhat , we conducted a high-throughput screen using a peptide based assay to monitor Hhat mediated Shh palmitoylation .	In an effort to discover a small-molecule inhibitor of Hhat, we conducted a high-throughput screen using a peptide based assay to monitor Hhat mediated Shh palmitoylation.	23	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	23	24	25	26
Knowledge of the topological organization of Hhat transmembrane helices would enhance our understanding of Hhat mediated Shh palmitoylation .	Knowledge of the topological organization of Hhat transmembrane helices would enhance our understanding of Hhat mediated Shh palmitoylation.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	14	15	16	17
Hhat encodes an acyltransferase and our results demonstrate that Hhat loss-of-function results in diminished palmitoylation of Shh .	Hhat encodes an acyltransferase and our results demonstrate that Hhat loss-of-function results in diminished palmitoylation of Shh.	9	17	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	9	10	16	17
To further validate the requirement for Hhat , we used RU-SKI 43 , a small molecule inhibitor of Hhat that specifically blocks Hhat mediated palmitoylation of Shh .	To further validate the requirement for Hhat, we used RU-SKI 43, a small molecule inhibitor of Hhat that specifically blocks Hhat mediated palmitoylation of Shh.	21	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	22	23	26	27
Hhat inhibition would prevent activation of all signaling downstream of Shh , including non canonical , Smo independent signaling pathways that operate within the tumor cells .	Hhat inhibition would prevent activation of all signaling downstream of Shh, including non canonical, Smo independent signaling pathways that operate within the tumor cells.	0	11	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	0	1	10	11
Hhat inhibition would block all downstream Shh signaling , including noncanonical , Smo independent pathways XREF_BIBR , XREF_BIBR .	Hhat inhibition would block all downstream Shh signaling, including noncanonical, Smo independent pathways XREF_BIBR, XREF_BIBR.	0	7	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	0	1	6	7
Subsequent probing with alpha-FLAG-HRP allowed determination of the level of Hhat catalyzed Shh ( 1-11 ) labeling through colorimetric readout using the TMB reaction ( XREF_FIG B ) .	Subsequent probing with alpha-FLAG-HRP allowed determination of the level of Hhat catalyzed Shh (1-11) labeling through colorimetric readout using the TMB reaction (XREF_FIG B).	8	16	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Hhat	level of Hhat	hhat	Shh	Shh	shh	10	11	12	13
Hhat mediated Shh palmitoylation is critical for Shh function during development .	Hhat mediated Shh palmitoylation is critical for Shh function during development.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	0	1	2	3
We therefore hypothesized that Hhat loss-of-function should disrupt the palmitoylation of Shh and perturb its signaling effects in Hhat Creface and Creface embryos .	We therefore hypothesized that Hhat loss-of-function should disrupt the palmitoylation of Shh and perturb its signaling effects in Hhat Creface and Creface embryos.	4	12	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	4	5	11	12
The disruption of Hhat diminishes palmitoylation of SHH which perturbs its secretion and long range activity [ XREF_BIBR , XREF_BIBR ] .	The disruption of Hhat diminishes palmitoylation of SHH which perturbs its secretion and long range activity [XREF_BIBR, XREF_BIBR].	1	8	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	SHH	SHH	SHH	3	4	7	8
Inhibition of Hhat is predicted to block Shh signaling in cells .	Inhibition of Hhat is predicted to block Shh signaling in cells.	0	8	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	2	3	7	8
Moreover , we found that Rap1B as well as Ki-Ras and Ha-Ras stimulate the B-Raf activity .	Moreover, we found that Rap1B as well as Ki-Ras and Ha-Ras stimulate the B-Raf activity.	5	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ha-Ras	Ha-Ras	Ha-Ras	B-Raf	B-Raf	B-Raf	11	12	14	15
Germline mutations in HRAS cause Costello syndrome , and mutations in KRAS , BRAF , and MAP2K1/2 ( MEK1/2 ) cause CFC syndrome .	Germline mutations in HRAS cause Costello syndrome, and mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) cause CFC syndrome.	1	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HRAS	HRAS	HRAS	BRAF	BRAF	BRAF	3	4	13	14
Mutagenesis studies of the free cysteines suggested that the HLA-G dimer more efficiently inhibits NK killing than the monomer and increases the efficiency of ILT2 signaling [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Mutagenesis studies of the free cysteines suggested that the HLA-G dimer more efficiently inhibits NK killing than the monomer and increases the efficiency of ILT2 signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	25	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HLA-G	HLA-G	HLA-G	ILT2	ILT2	ILT2	9	10	24	25
As a consequence , deficiency of soluble HLA-G might diminish the inhibitory effects of LIR-1 on CD8+ T cells in CMV positive RA patients .	As a consequence, deficiency of soluble HLA-G might diminish the inhibitory effects of LIR-1 on CD8+ T cells in CMV positive RA patients.	4	15	diminish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HLA-G	HLA-G	HLA-G	LIR-1	LIR-1	LIR-1	7	8	14	15
[ XREF_BIBR XREF_BIBR ] It has also been demonstrated that HLA-G may up-regulate ILT-2 , ILT-4 and killer-cell immunoglobulin like receptor-2DL4 on the membrane of antigen presenting cells , NK cells and CD4 + T-cells without preceding for antigenic co-stimulation .	[XREF_BIBR XREF_BIBR] It has also been demonstrated that HLA-G may up-regulate ILT-2, ILT-4 and killer-cell immunoglobulin like receptor-2DL4 on the membrane of antigen presenting cells, NK cells and CD4 + T-cells without preceding for antigenic co-stimulation.	10	18	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HLA-G	HLA-G	HLA-G	ILT-2	ILT-2	ILT-2	10	11	13	14
It has been determined that human monocyte derived DC that highly express ILT2 and ILT4 receptors , when treated with HLA-G and stimulated with allogeneic T cells , still maintain a stable tolerogenic like phenotype ( CD80 low , CD86 low , HLA-DR low ) with the potential to induce T cell anergy [ XREF_BIBR ] .	It has been determined that human monocyte derived DC that highly express ILT2 and ILT4 receptors, when treated with HLA-G and stimulated with allogeneic T cells, still maintain a stable tolerogenic like phenotype (CD80 low, CD86 low, HLA-DR low) with the potential to induce T cell anergy [XREF_BIBR].	12	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HLA-G	HLA-G	HLA-G	ILT2	ILT2	ILT2	20	21	12	13
Furthermore , target tumor cells ectopically overexpressing human HLA-G were unable to block specific cell killing by CAR engineered NK-92 ( Zhang et al ., unpublished data ) , although NK-92 cells express the immunoregulatory receptors KIR2DL4 and ILT-2 , which are activated by HLA-G .	Furthermore, target tumor cells ectopically overexpressing human HLA-G were unable to block specific cell killing by CAR engineered NK-92 (Zhang et al., unpublished data), although NK-92 cells express the immunoregulatory receptors KIR2DL4 and ILT-2, which are activated by HLA-G.	32	45	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HLA-G	HLA-G	HLA-G	ILT-2	ILT-2	ILT-2	44	45	38	39
Thus it is possible that expression of the FHC HLA-G in the invasive trophoblasts may serve to attenuate LIR-1 inhibition and allow for the appropriate cytokine production by dNK necessary for pregnancy to succeed .	Thus it is possible that expression of the FHC HLA-G in the invasive trophoblasts may serve to attenuate LIR-1 inhibition and allow for the appropriate cytokine production by dNK necessary for pregnancy to succeed.	5	19	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HLA-G	expression of the FHC HLA-G	hla-g	LIR-1	LIR-1	lir-1	9	10	18	19
The miR-548q-mediated downregulation of HLA-G caused an increase in the ILT2 + NK cell mediated cell lysis of the tumor cells , which was statistically significant in the E : T-ratios ( 1:1 and 5:1 ) when compared the respective mock transfectants .	The miR-548q-mediated downregulation of HLA-G caused an increase in the ILT2 + NK cell mediated cell lysis of the tumor cells, which was statistically significant in the E : T-ratios (1:1 and 5:1) when compared the respective mock transfectants.	2	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HLA-G	HLA-G	HLA-G	ILT2	ILT2	ILT2	4	5	10	11
Among transcription factors which we have analysed , activator protein 1 ( AP-1 ) but not SP-1 was modulated by H-ras .	Among transcription factors which we have analysed, activator protein 1 (AP-1) but not SP-1 was modulated by H-ras.	8	21	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	H-ras	H-ras	H-ras	activator protein 1	activator protein 1	activator protein 1	20	21	8	11
On the contrary , both R-Ras3 and H-Ras activated the Jun N-terminal kinase ( JNK ) to a similar extent .	On the contrary, both R-Ras3 and H-Ras activated the Jun N-terminal kinase (JNK) to a similar extent.	5	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	H-Ras	H-Ras	H-Ras	Jun	Jun	Jun	7	8	10	11
Thus , it is possible that a HLA-G associated haplotype could contribute to MS risk by influencing signaling via LILRB1 and ILT2 or the KIR2DL4 natural killer ( NK ) receptors XREF_BIBR .	Thus, it is possible that a HLA-G associated haplotype could contribute to MS risk by influencing signaling via LILRB1 and ILT2 or the KIR2DL4 natural killer (NK) receptors XREF_BIBR.	6	26	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HLA-G	HLA-G	HLA-G	KIR2DL4	KIR2DL4	KIR2DL4	7	8	24	25
A subset of NK cells , the decidual NK cells , undergo senescence upon activation of CD158d by HLA-G , which secreted by fetal trophoblasts during pregnancy 17 .	A subset of NK cells, the decidual NK cells, undergo senescence upon activation of CD158d by HLA-G, which secreted by fetal trophoblasts during pregnancy 17.	11	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HLA-G	HLA-G	HLA-G	CD158d	CD158d	CD158d	18	19	16	17
KIR2DL4 stimulation by HLA-G is considered to induce tolerance at the maternal-fetal barrier as well as IFN-gamma release of NK cells but not cytotoxicity .	KIR2DL4 stimulation by HLA-G is considered to induce tolerance at the maternal-fetal barrier as well as IFN-gamma release of NK cells but not cytotoxicity.	0	4	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HLA-G	HLA-G	HLA-G	KIR2DL4	KIR2DL4	KIR2DL4	3	4	0	1
Approximately one-third of the NUP98-HOXD13 mice that transform to AML spontaneously upregulate Meis1 ( 34 ) , or undergo spontaneous mutations of Ras pathway genes , therefore , we anticipated that some Hoxa9 mice might likewise up-regulate Meis1 or other , undefined complementary genes and transform to AML .	Approximately one-third of the NUP98-HOXD13 mice that transform to AML spontaneously upregulate Meis1 (34), or undergo spontaneous mutations of Ras pathway genes, therefore, we anticipated that some Hoxa9 mice might likewise up-regulate Meis1 or other, undefined complementary genes and transform to AML.	32	43	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hoxa9	Hoxa9	Hoxa9	Meis1	Meis1	Meis1	32	33	37	38
These data indicate that HOXA9 modulates Meis1 during normal murine hematopoiesis .	These data indicate that HOXA9 modulates Meis1 during normal murine hematopoiesis.	4	7	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HOXA9	HOXA9	HOXA9	Meis1	Meis1	Meis1	4	5	6	7
To explore the relevance of miR-155 in AML , we investigated the dependency of Hoxa9 and Meis1 induced leukemias on miR-155 expression by overexpressing Hoxa9 and Meis1 in BM cells of mice lacking miR-155 expression ( Hoxa9 and Meis1 155-/-) .	To explore the relevance of miR-155 in AML, we investigated the dependency of Hoxa9 and Meis1 induced leukemias on miR-155 expression by overexpressing Hoxa9 and Meis1 in BM cells of mice lacking miR-155 expression (Hoxa9 and Meis1 155-/-).	12	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hoxa9	Hoxa9	Hoxa9	Meis1	Meis1	Meis1	14	15	26	27
Faber et al showed that loss of Hoxa9 causes downregulation of the Meis1 mRNA , while overexpression of HOXA9 upregulates Meis1 [ XREF_BIBR ] .	Faber et al showed that loss of Hoxa9 causes downregulation of the Meis1 mRNA, while overexpression of HOXA9 upregulates Meis1 [XREF_BIBR].	5	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HOXA9	loss of Hoxa9	hoxa9	Meis1	Meis1	meis1	7	8	12	13
Moreover , when we expressed constitutively active RAS or RAB5 , along with p110alpha and p85 or p110beta and p85 in COS7 cells , and measured PIP 3 -levels ( XREF_FIG C ) or steady-state phospho-AKT ( XREF_FIG A available online ) as indicators of PI3K activity , HRAS and KRAS strongly enhanced p110alpha activity , whereas p110beta was not stimulated by either RAS proteins or RAB5 .	Moreover, when we expressed constitutively active RAS or RAB5, along with p110alpha and p85 or p110beta and p85 in COS7 cells, and measured PIP 3 -levels (XREF_FIG C) or steady-state phospho-AKT (XREF_FIG A available online) as indicators of PI3K activity, HRAS and KRAS strongly enhanced p110alpha activity, whereas p110beta was not stimulated by either RAS proteins or RAB5.	48	54	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HRAS	HRAS	HRAS	p110alpha	p110alpha	p110alpha	48	49	53	54
Hrs and Hgs is localized to early endosomes and synergizes with SARA to present Smad2 to the activated receptor complex .	Hrs and Hgs is localized to early endosomes and synergizes with SARA to present Smad2 to the activated receptor complex.	0	15	synergizes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hgs	Hgs	Hgs	Smad2	Smad2	Smad2	2	3	14	15
We also reported that HGS enhance the association of ACTR1 and SMAD2 for ACTIVIN signaling .	We also reported that HGS enhance the association of ACTR1 and SMAD2 for ACTIVIN signaling.	4	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGS	HGS	HGS	SMAD2	SMAD2	SMAD2	4	5	11	12
The entire family of Dyrk family kinases has been implicated in cell cycle regulation , with Dyrk1A and HIPK2 targeting cyclin D1 and p27 , respectively [ XREF_BIBR ] .	The entire family of Dyrk family kinases has been implicated in cell cycle regulation, with Dyrk1A and HIPK2 targeting cyclin D1 and p27, respectively [XREF_BIBR].	9	24	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p27	p27	p27	18	19	23	24
Either box A or box B of HMGB1 enhanced the HoxD9 mediated transactivation alone .	Either box A or box B of HMGB1 enhanced the HoxD9 mediated transactivation alone.	2	12	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	HoxD9	HoxD9	HoxD9	7	8	10	11
Together with our previous reports , we conclude that the activation of IGF-1R signaling in explanted VSMC triggers both PI3K and Akt and PI3K and ERK pathways , thereby contributing to down-regulation of stress-resistance and up-regulation of cell proliferation .	Together with our previous reports, we conclude that the activation of IGF-1R signaling in explanted VSMC triggers both PI3K and Akt and PI3K and ERK pathways, thereby contributing to down-regulation of stress-resistance and up-regulation of cell proliferation.	12	22	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	12	13	21	22
Although we did not explore these mechanisms in our model , the cross-talk between IGF-1R and other activators of Akt may have contributed to our findings .	Although we did not explore these mechanisms in our model, the cross-talk between IGF-1R and other activators of Akt may have contributed to our findings.	14	20	activators	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	14	15	19	20
Inhibition of IGF-IR signaling using the receptor antagonist NVP did not affect MAPK signaling but significantly depleted activation of IGF-IR and Akt to below basal levels in both cell lines ( XREF_FIG ) .	Inhibition of IGF-IR signaling using the receptor antagonist NVP did not affect MAPK signaling but significantly depleted activation of IGF-IR and Akt to below basal levels in both cell lines (XREF_FIG).	2	22	depleted	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	2	3	21	22
Thus , we concluded that in VHL deficient cells , IGF1R activates AKT through PI3K , and AKT stabilizes the Bak and Mcl-1 complex , thereby making these cells resistant to mitochondria dependent apoptosis .	Thus, we concluded that in VHL deficient cells, IGF1R activates AKT through PI3K, and AKT stabilizes the Bak and Mcl-1 complex, thereby making these cells resistant to mitochondria dependent apoptosis.	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	10	11	12	13
As such , concurrent inhibition of both EGFR and InsR and IGF1R is necessary to effectively attenuate AKT signaling and induce significant response in glioblastoma .	As such, concurrent inhibition of both EGFR and InsR and IGF1R is necessary to effectively attenuate AKT signaling and induce significant response in glioblastoma.	7	18	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	11	12	17	18
However , IGF-1R activation is known to stimulate MEK-Erk1/2 and PI3K-Akt signaling , which in turn regulate EMT transcription factors .	However, IGF-1R activation is known to stimulate MEK-Erk1/2 and PI3K-Akt signaling, which in turn regulate EMT transcription factors.	2	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	2	3	10	11
Researchers have found that IGF-1R can activate the shared PI3K and AKT signaling pathway .	Researchers have found that IGF-1R can activate the shared PI3K and AKT signaling pathway.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	4	5	11	12
IGF1R is part of the IGF signaling axis and mediates mitogenic and antiapoptotic signals involving the PI3K-Akt and MAPK-ERK pathways .	IGF1R is part of the IGF signaling axis and mediates mitogenic and antiapoptotic signals involving the PI3K-Akt and MAPK-ERK pathways.	0	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	16	17
IGF1R , EGFR and many other RTK share common response pathways ; they all activate both the Ras-ERK proliferation pathway and the PI3K-AKT pro survival pathway .	IGF1R, EGFR and many other RTK share common response pathways; they all activate both the Ras-ERK proliferation pathway and the PI3K-AKT pro survival pathway.	0	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	22	23
Combining IGF-1R inhibition with EGFR inhibition may reduce this AKT pathway activity .	Combining IGF-1R inhibition with EGFR inhibition may reduce this AKT pathway activity.	1	11	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	1	2	9	10
We further showed that blockade of the InsR and IGF1R pathway by OSI-906 significantly repressed AKT activity in all tested lines with the exception of GBM46 ( XREF_FIG , and XREF_SUPPLEMENTARY ) , underscoring the role of the InsR and IGF1R pathway in maintaining AKT activities in glioblastoma .	We further showed that blockade of the InsR and IGF1R pathway by OSI-906 significantly repressed AKT activity in all tested lines with the exception of GBM46 (XREF_FIG, and XREF_SUPPLEMENTARY), underscoring the role of the InsR and IGF1R pathway in maintaining AKT activities in glioblastoma.	7	16	repressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	9	10	15	16
Taken together , these data implicate ER modulated IGF-1R and InsR signaling in mTORC1 inhibitor induced feedback activation of PI3K and AKT .	Taken together, these data implicate ER modulated IGF-1R and InsR signaling in mTORC1 inhibitor induced feedback activation of PI3K and AKT.	8	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	8	9	21	22
It is known that IGF-1R activates AKT , which in turn can inhibit PTEN through inactivating the PTEN activator FoX3a via phosphorylation , resulting in inhibition of the PTEN downstream effector eIF2alpha , an ER stress marker , which is involved in modulating immune responses 24 .	It is known that IGF-1R activates AKT, which in turn can inhibit PTEN through inactivating the PTEN activator FoX3a via phosphorylation, resulting in inhibition of the PTEN downstream effector eIF2alpha, an ER stress marker, which is involved in modulating immune responses 24.	4	23	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	4	5	6	7
The addition of HuIFN-beta to RSa cultures reduced cell viability , down-regulated expression of IGF1R and IRS2 ( putative miR-431 target genes ) , and inhibited the PI3K-Akt and MAPK pathways .	The addition of HuIFN-beta to RSa cultures reduced cell viability, down-regulated expression of IGF1R and IRS2 (putative miR-431 target genes), and inhibited the PI3K-Akt and MAPK pathways.	3	30	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	HuIFN-beta to RSa cultures reduced cell viability, down-regulated expression of IGF1R	igf1r	PI3K-Akt	PI3K-Akt	pi3k-akt	14	15	27	28
Upon ligand binding , IGF1R activates multiple downstream signaling cascades , the two most prominent being PI3K and AKT and RAS/RAF/MEK/ERK .	Upon ligand binding, IGF1R activates multiple downstream signaling cascades, the two most prominent being PI3K and AKT and RAS/RAF/MEK/ERK.	4	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	4	5	18	19
It has been shown that IGF1R activation leads to both PI3 and AKT and RAS/RAF/ERK activation.8 However , we found that knockdown of IGF1R or ceritinib inhibits only the activation of AKT but not ERK in HCC cells .	It has been shown that IGF1R activation leads to both PI3 and AKT and RAS/RAF/ERK activation.8 However, we found that knockdown of IGF1R or ceritinib inhibits only the activation of AKT but not ERK in HCC cells.	21	32	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	23	24	31	32
We hypothesize that the concomitant activation of PI3K and Akt ( through insulin and IGF -1 and EGF receptors ) , PKD and ERK ( via agonist induced Gq signaling ) and mTORC1 ( synergistically through PI3K and Akt induced by insulin and IGF-1R and EGFR and GPCR stimulated ERK and p90RSK ) in PDAC cells potently stimulates DNA synthesis and proliferation of these cancer cells , and thus provide potential targets for chemotherapeutic intervention .	We hypothesize that the concomitant activation of PI3K and Akt (through insulin and IGF -1 and EGF receptors), PKD and ERK (via agonist induced Gq signaling) and mTORC1 (synergistically through PI3K and Akt induced by insulin and IGF-1R and EGFR and GPCR stimulated ERK and p90RSK) in PDAC cells potently stimulates DNA synthesis and proliferation of these cancer cells, and thus provide potential targets for chemotherapeutic intervention.	7	44	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	43	44	38	39
Thus , in VHL deficient cells , IGF1R activated AKT and stabilized the Bak and Mcl-1 complex , thereby conferring cell resistance to apoptosis .	Thus, in VHL deficient cells, IGF1R activated AKT and stabilized the Bak and Mcl-1 complex, thereby conferring cell resistance to apoptosis.	7	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	7	8	9	10
IGF-1R activation by tyrosine phosphorylation of beta subunit results in activation of PI3K and AKT and RAS and MAPK pathways [ XREF_BIBR , XREF_BIBR ] which in turn regulate cell survival and proliferation .	IGF-1R activation by tyrosine phosphorylation of beta subunit results in activation of PI3K and AKT and RAS and MAPK pathways [XREF_BIBR, XREF_BIBR] which in turn regulate cell survival and proliferation.	0	15	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	0	1	14	15
IGF1R signaling mediates feedback activation of AKT upon mTOR inhibition .	IGF1R signaling mediates feedback activation of AKT upon mTOR inhibition.	0	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	0	1	6	7
Since IGF-1R similar to other RTKs like EGFR or Erbb2 potently induces AKT signaling pathway [ XREF_BIBR ] , it might indicate its involvement in the induction of senescence .	Since IGF-1R similar to other RTKs like EGFR or Erbb2 potently induces AKT signaling pathway [XREF_BIBR], it might indicate its involvement in the induction of senescence.	1	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	1	2	12	13
We further examined the role of IR and IGF-IR on Wnt3a stimulated P-LRP6 , IR/IGF-IR , Akt , and S6K in PC-3 cells by using AG1204 ( an IR and IGF-IR inhibitor ) and PPP ( an IGF-IR-specific inhibitor ) .	We further examined the role of IR and IGF-IR on Wnt3a stimulated P-LRP6, IR/IGF-IR, Akt, and S6K in PC-3 cells by using AG1204 (an IR and IGF-IR inhibitor) and PPP (an IGF-IR-specific inhibitor).	4	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	8	9	16	17
Although in that network AKT cascades are only connected to EGF specific pathways , IGF-1R is also known to activate AKT XREF_BIBR .	Although in that network AKT cascades are only connected to EGF specific pathways, IGF-1R is also known to activate AKT XREF_BIBR.	14	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	14	15	20	21
Furthermore , our results demonstrated that siRNA mediated IGF1R knockdown activated Akt pathway and rescued H 2 O 2 -induced apoptosis .	Furthermore, our results demonstrated that siRNA mediated IGF1R knockdown activated Akt pathway and rescued H 2 O 2 -induced apoptosis.	6	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	siRNA mediated IGF1R	igf1r	Akt	Akt	akt	8	9	11	12
IGF-1R phosphorylation upon ligand binding led to activation of Akt pathway and downstream antiapoptotic effects .	IGF-1R phosphorylation upon ligand binding led to activation of Akt pathway and downstream antiapoptotic effects.	0	10	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R phosphorylation	igf-1r	Akt	Akt	akt	0	1	9	10
A decrease in IRS1 levels reduces IGF1R signaling and activation of the PI3K-AKT pathway .	A decrease in IRS1 levels reduces IGF1R signaling and activation of the PI3K-AKT pathway.	6	13	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-AKT	PI3K-AKT	PI3K-AKT	6	7	12	13
Combination of mTOR and IGF inhibitors has been shown to have a synergistic effect by inhibiting the AKT activation mediated by IGF-1R .	Combination of mTOR and IGF inhibitors has been shown to have a synergistic effect by inhibiting the AKT activation mediated by IGF-1R.	17	22	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	21	22	17	18
IGF1R activity induces AKT signalling .	IGF1R activity induces AKT signalling.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	0	1	3	4
XREF_BIBR , XREF_BIBR , XREF_BIBR It is postulated that somatostatin analog therapy attenuates intracellular signaling via the IGF-1R axis , XREF_BIBR and it has been shown that stimulation of IGF-1R causes crossactivation of the PI3K-Akt cascade .	XREF_BIBR, XREF_BIBR, XREF_BIBR It is postulated that somatostatin analog therapy attenuates intracellular signaling via the IGF-1R axis, XREF_BIBR and it has been shown that stimulation of IGF-1R causes crossactivation of the PI3K-Akt cascade.	27	35	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	29	30	34	35
Similar phenotypes have been observed in animals with targeted loss of the phosphoinositide dependent protein kinase ( pdpk1 ) , which is required for IR or IGF-1R dependent activation of Akt 80 .	Similar phenotypes have been observed in animals with targeted loss of the phosphoinositide dependent protein kinase (pdpk1), which is required for IR or IGF-1R dependent activation of Akt 80.	24	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	26	27	30	31
IGF-1R is autophosphorylated upon ligand binding and activates the PI3K-AKT pathway , strongly implicated in the development and growth of cancer cells , as well as resistance to chemotherapy [ XREF_BIBR , XREF_BIBR ] .	IGF-1R is autophosphorylated upon ligand binding and activates the PI3K-AKT pathway, strongly implicated in the development and growth of cancer cells, as well as resistance to chemotherapy [XREF_BIBR, XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R is autophosphorylated	igf-1r	PI3K-AKT	PI3K-AKT	pi3k-akt	0	1	9	10
Blockade of IGF1R signaling by ganitumab inhibited activation of PI 3 K Akt pathway , leading to cell growth inhibition .	Blockade of IGF1R signaling by ganitumab inhibited activation of PI 3 K Akt pathway, leading to cell growth inhibition.	2	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	2	3	12	13
Then this autophosphorylationy of IGF1R leads to the phosphorylation of its downstream signaling intermediates such as insulin receptor substrate ( IRS ) and Shc XREF_BIBR , and activates the AKT and ERK1/2 signaling XREF_BIBR .	Then this autophosphorylationy of IGF1R leads to the phosphorylation of its downstream signaling intermediates such as insulin receptor substrate (IRS) and Shc XREF_BIBR, and activates the AKT and ERK1/2 signaling XREF_BIBR.	2	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	autophosphorylationy of IGF1R	igf1r	AKT	AKT	akt	4	5	29	30
Transgenic K5-HER2 mice display epidermal hyperplasia and develop spontaneous skin tumors 22 , while overexpression of IGF-1R led to enhanced activation of IGF-1R , MAPK , PI3K and Akt signaling XREF_BIBR , XREF_BIBR and increased skin tumor burden XREF_BIBR , XREF_BIBR .	Transgenic K5-HER2 mice display epidermal hyperplasia and develop spontaneous skin tumors 22, while overexpression of IGF-1R led to enhanced activation of IGF-1R, MAPK, PI3K and Akt signaling XREF_BIBR, XREF_BIBR and increased skin tumor burden XREF_BIBR, XREF_BIBR.	14	30	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IGF-1R	overexpression of IGF-1R	igf-1r	Akt	Akt	akt	16	17	28	29
In this study , we identified that dual inhibition of EGFR and IGF-1R could block the PI3K and AKT signaling pathway .	In this study, we identified that dual inhibition of EGFR and IGF-1R could block the PI3K and AKT signaling pathway.	8	20	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	12	13	18	19
Although Akt and its activating kinase PDK1 are known to be activated downstream of IGF1R and phosphorylate Ser83 and Ser966 in ASK1 , respectively , we find no change in Akt activity levels in myeloma cells treated with SSTN IGF1R .	Although Akt and its activating kinase PDK1 are known to be activated downstream of IGF1R and phosphorylate Ser83 and Ser966 in ASK1, respectively, we find no change in Akt activity levels in myeloma cells treated with SSTN IGF1R.	30	40	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	39	40	30	31
A subsequent analyses of signal transduction pathways revealed that IGF-IR inhibition with PPP reduced activation of PI3K and Akt and MAPK and Erk signaling in Jurkat and Molt-3 cells ( XREF_FIG ) .	A subsequent analyses of signal transduction pathways revealed that IGF-IR inhibition with PPP reduced activation of PI3K and Akt and MAPK and Erk signaling in Jurkat and Molt-3 cells (XREF_FIG).	9	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	9	10	18	19
Upon IGF-1 binding , IGF-1R activates the PI3K and Akt cascade , which promotes G 1 to S cell cycle progression [ XREF_BIBR ] and elevates cell proliferation [ XREF_BIBR ] .	Upon IGF-1 binding, IGF-1R activates the PI3K and Akt cascade, which promotes G 1 to S cell cycle progression [XREF_BIBR] and elevates cell proliferation [XREF_BIBR].	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	4	5	9	10
Upon IGF-1 binding , IGF1R activates the PI3K and Akt cascade , which promotes G1 to S cell cycle progression and elevates cell proliferation XREF_BIBR , XREF_BIBR .	Upon IGF-1 binding, IGF1R activates the PI3K and Akt cascade, which promotes G1 to S cell cycle progression and elevates cell proliferation XREF_BIBR, XREF_BIBR.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	4	5	9	10
Cross-talk between IGF-2 / IGF-IR system and PI3K-Akt pathway was further demonstrated by findings wherein IGF-IR suppression inhibited Akt activation , and IGF-IR activation was inhibited following PI3K inhibition .	Cross-talk between IGF-2 / IGF-IR system and PI3K-Akt pathway was further demonstrated by findings wherein IGF-IR suppression inhibited Akt activation, and IGF-IR activation was inhibited following PI3K inhibition.	15	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	15	16	18	19
IGF1R , like EGFR and many other receptor tyrosine kinases ( RTKs ) , activates both the Ras-ERK proliferation pathway and the PI3K-AKT pro survival pathway .	IGF1R, like EGFR and many other receptor tyrosine kinases (RTKs), activates both the Ras-ERK proliferation pathway and the PI3K-AKT pro survival pathway.	0	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	22	23
In GR cells , activated IGF1R activates Akt and Erk which could lead to NF-kappaB activation .	In GR cells, activated IGF1R activates Akt and Erk which could lead to NF-kappaB activation.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	5	6	7	8
Formation of this complex prevents SHP-2 from dephosphorylating IGF-IR and results in sustained phosphorylation of IGF-IR and downstream activation of Akt kinase , and the inhibition of apoptosis through up-regulation of the anti-apoptotic factor Bcl [ XREF_BIBR ] .	Formation of this complex prevents SHP-2 from dephosphorylating IGF-IR and results in sustained phosphorylation of IGF-IR and downstream activation of Akt kinase, and the inhibition of apoptosis through up-regulation of the anti-apoptotic factor Bcl [XREF_BIBR].	13	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-IR	phosphorylation of IGF-IR	igf-ir	Akt	Akt	akt	15	16	20	21
IGF-1R activates the Ras and Erk- and PI3K and Akt associated signal transduction pathways .	IGF-1R activates the Ras and Erk- and PI3K and Akt associated signal transduction pathways.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	0	1	9	10
Based upon data indicating that inhibition of mTOR leads to IGF1R dependent activation of AKT , combinations of agents that inhibit these pathways also appear warranted .	Based upon data indicating that inhibition of mTOR leads to IGF1R dependent activation of AKT, combinations of agents that inhibit these pathways also appear warranted.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	10	11	14	15
Thus , induction of IGF1R by TECs in LCs stimulates Akt activation to enhance cell survival after doxorubicin treatment .	Thus, induction of IGF1R by TECs in LCs stimulates Akt activation to enhance cell survival after doxorubicin treatment.	2	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	4	5	10	11
These data are in agreement with published results and demonstrate that IGF-1R mediated Akt activity is not regulated by EGFR signaling , and that IGF-1R mediated Erk1/2 activity is ErbB dependent [ XREF_BIBR ] .	These data are in agreement with published results and demonstrate that IGF-1R mediated Akt activity is not regulated by EGFR signaling, and that IGF-1R mediated Erk1/2 activity is ErbB dependent [XREF_BIBR].	11	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	11	12	13	14
Interestingly , both inhibition of IGF-1R and ILK by treatment with PPP and CPD22 dramatically decreases feedback activation of AKT following MEK suppression .	Interestingly, both inhibition of IGF-1R and ILK by treatment with PPP and CPD22 dramatically decreases feedback activation of AKT following MEK suppression.	3	22	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	5	6	19	20
A key reason for this relates to the fact that the IGF-1R is a potent activator of Akt which consistent with the findings that inhibition of mTOR signaling by rapamycin frequently results in the loss of feedback inhibition of IGF-1R signaling , in turn , leading to Akt activation .	A key reason for this relates to the fact that the IGF-1R is a potent activator of Akt which consistent with the findings that inhibition of mTOR signaling by rapamycin frequently results in the loss of feedback inhibition of IGF-1R signaling, in turn, leading to Akt activation.	10	18	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	11	12	17	18
Both IGF-1R and PDGFR can activate PI3K and AKT signaling and modulate survival .	Both IGF-1R and PDGFR can activate PI3K and AKT signaling and modulate survival.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	1	2	8	9
IGF-I receptor , which belongs to receptor tyrosine kinase ( RTK ) family , activates the PI3K-AKT signaling cascade in response to IGFs , thereby promoting differentiation of skeletal muscle cells .	IGF-I receptor, which belongs to receptor tyrosine kinase (RTK) family, activates the PI3K-AKT signaling cascade in response to IGFs, thereby promoting differentiation of skeletal muscle cells.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I receptor	IGF-I receptor	IGF-I receptor	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	2	16	17
Immunoblots of tumor tissues confirmed that the phosphorylation of IGF-1R and downstream targets of Akt and Erk1/2 were remarkably decreased in SCID mice treated with blocking antibodies of alpha ( v ) beta3 or IGF-1R .	Immunoblots of tumor tissues confirmed that the phosphorylation of IGF-1R and downstream targets of Akt and Erk1/2 were remarkably decreased in SCID mice treated with blocking antibodies of alpha (v) beta3 or IGF-1R.	7	16	targets	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1R	phosphorylation of IGF-1R	igf-1r	Akt	Akt	akt	9	10	14	15
IGF-1R preferentially activates Akt in NSCs and ERK in differentiated neurons .	IGF-1R preferentially activates Akt in NSCs and ERK in differentiated neurons.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	0	1	3	4
Hyperglycemia Enhances the Proliferation of Non Tumorigenic and Malignant Mammary Epithelial Cells through Increased leptin and IGF1R Signaling and Activation of AKT and mTOR .	Hyperglycemia Enhances the Proliferation of Non Tumorigenic and Malignant Mammary Epithelial Cells through Increased leptin and IGF1R Signaling and Activation of AKT and mTOR.	16	23	Signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	16	17	21	22
This suggests that the Ob sera induced Akt and ERK1/2 activation described above may be at least partly mediated by IGF-1R signaling that is upregulated by a mechanism independent of bioavailable IGF-1 levels .	This suggests that the Ob sera induced Akt and ERK1/2 activation described above may be at least partly mediated by IGF-1R signaling that is upregulated by a mechanism independent of bioavailable IGF-1 levels.	7	21	mediated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	20	21	7	8
Additionally , simvastatin suppressed IGF-1R expression and IGF-1 induced ERK and Akt activation in bile duct cancer cells .	Additionally, simvastatin suppressed IGF-1R expression and IGF-1 induced ERK and Akt activation in bile duct cancer cells.	4	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R expression	igf-1r	Akt	Akt	akt	4	5	11	12
Other important observations from this study include enhanced IGF1R signaling and increased AKT and mTOR activation under hyperglycemia in both non tumorigenic and malignant breast epithelial cells .	Other important observations from this study include enhanced IGF1R signaling and increased AKT and mTOR activation under hyperglycemia in both non tumorigenic and malignant breast epithelial cells.	7	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	8	9	12	13
In this model , after cells are exposed to IGF-1 , IGF-1R is activated , which then activates the PI3K-Akt pathway .	In this model, after cells are exposed to IGF-1, IGF-1R is activated, which then activates the PI3K-Akt pathway.	11	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	11	12	19	20
Activation of IGF-1 and IGF-1R stimulates the PI-3K and Akt pathway and inhibits the GSK-3beta pathway , to exert their effect on the antioxidant defense of neuron-, metabolism of glucose- and synthesis of anti-apoptotic-associated proteins , which result in the protective effect and ultimately in neuronal survival .	Activation of IGF-1 and IGF-1R stimulates the PI-3K and Akt pathway and inhibits the GSK-3beta pathway, to exert their effect on the antioxidant defense of neuron-, metabolism of glucose- and synthesis of anti-apoptotic-associated proteins, which result in the protective effect and ultimately in neuronal survival.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	4	5	9	10
We propose that RMS pathogenesis involves increased IGF1R expression that enhances AKT and Bcl-x L -mediated cell survival , and the blockage of IGF1R results in inhibition of survival signal from Bcl-x L and cell death in the sensitive Bcl-2 negative cells .	We propose that RMS pathogenesis involves increased IGF1R expression that enhances AKT and Bcl-x L -mediated cell survival, and the blockage of IGF1R results in inhibition of survival signal from Bcl-x L and cell death in the sensitive Bcl-2 negative cells.	7	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R expression	igf1r	AKT	AKT	akt	7	8	11	12
As a matter of fact , several in vitro and in vivo studies demonstrated that over-expression of IGF-1R and aberrant activation of Akt are associated with increased radio-resistance and favor genetic instability after a radiation induced DNA damage , by promoting non homologous end joining ( NHEJ ) repair pathway over homologous recombination ( HR ) .	As a matter of fact, several in vitro and in vivo studies demonstrated that over-expression of IGF-1R and aberrant activation of Akt are associated with increased radio-resistance and favor genetic instability after a radiation induced DNA damage, by promoting non homologous end joining (NHEJ) repair pathway over homologous recombination (HR).	15	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1R	over-expression of IGF-1R	igf-1r	Akt	Akt	akt	17	18	22	23
IGF1R and IR are receptor tyrosine kinases ( RTKs ) and activate the PI3K and Akt and mitogen activated protein kinase ( MAPK ) signalling pathways XREF_BIBR .	IGF1R and IR are receptor tyrosine kinases (RTKs) and activate the PI3K and Akt and mitogen activated protein kinase (MAPK) signalling pathways XREF_BIBR.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	0	1	15	16
TTC549 cells expressed high levels of IGF-1R , which may be directly causing constitutive PI3K and Akt activation as evidenced by the reduction in Akt phosphorylation upon treatment with NVP-AEW541 .	TTC549 cells expressed high levels of IGF-1R, which may be directly causing constitutive PI3K and Akt activation as evidenced by the reduction in Akt phosphorylation upon treatment with NVP-AEW541.	4	17	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	levels of IGF-1R	igf-1r	Akt	Akt	akt	6	7	16	17
However , CP failed to induce the auto-phosphorylation of IGF-1R or activate PI3K and AKT ( XREF_FIG ) .	However, CP failed to induce the auto-phosphorylation of IGF-1R or activate PI3K and AKT (XREF_FIG).	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	CP failed to induce the auto-phosphorylation of IGF-1R	igf-1r	AKT	AKT	akt	9	10	14	15
IGF-1R signaling activates the PI3K and AKT survival pathway and is involved in resistance to EGFR and HER2 inhibitors .	IGF-1R signaling activates the PI3K and AKT survival pathway and is involved in resistance to EGFR and HER2 inhibitors.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	0	1	6	7
However , even though IGF1R inhibition limited the induction of P-AKT by vemurafenib , this combination was still less effective than vemurafenib and gefitinib ( XREF_SUPPLEMENTARY ) .	However, even though IGF1R inhibition limited the induction of P-AKT by vemurafenib, this combination was still less effective than vemurafenib and gefitinib (XREF_SUPPLEMENTARY).	4	11	limited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	P-AKT	P-AKT	P-AKT	4	5	10	11
Our results suggested that AKT was activated by IGF1R and responsible for VEGF expression .	Our results suggested that AKT was activated by IGF1R and responsible for VEGF expression.	4	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	8	9	4	5
In addition to activating the RAF-MEK-ERK pathway , IGF1R and other RTKs are known to activate PI3K-AKT signaling , which is known to be an important regulator of cell survival and proliferation [ XREF_BIBR , XREF_BIBR ] .	In addition to activating the RAF-MEK-ERK pathway, IGF1R and other RTKs are known to activate PI3K-AKT signaling, which is known to be an important regulator of cell survival and proliferation [XREF_BIBR, XREF_BIBR].	8	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-AKT	PI3K-AKT	PI3K-AKT	8	9	16	17
Pharmacological blockade of InsR and IGF-1R with OSI-906 inhibited PI3K and AKT and LTED cell growth .	Pharmacological blockade of InsR and IGF-1R with OSI-906 inhibited PI3K and AKT and LTED cell growth.	1	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	5	6	11	12
15 These data collectively showed that self-colony formation depends on both JAG2 expression and IGF1R and C-KIT activation of AKT pathway .	15 These data collectively showed that self-colony formation depends on both JAG2 expression and IGF1R and C-KIT activation of AKT pathway.	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	14	15	19	20
IGF1R JM analogue 16 inhibited IGF-1 induced activity of AKT in a dose dependent manner ( XREF_FIG ) and was significantly less effective in inhibiting insulin induced activation of AKT .	IGF1R JM analogue 16 inhibited IGF-1 induced activity of AKT in a dose dependent manner (XREF_FIG) and was significantly less effective in inhibiting insulin induced activation of AKT.	0	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	0	1	29	30
Inhibition of IGF1R and IRS2 , as well as components of mTORC2 complex , blocked the activation of AKT ( XREF_FIG ) , suggesting a causal link between the feedback activation of AKT following ridaforolimus exposure and IGF1R signaling .	Inhibition of IGF1R and IRS2, as well as components of mTORC2 complex, blocked the activation of AKT (XREF_FIG), suggesting a causal link between the feedback activation of AKT following ridaforolimus exposure and IGF1R signaling.	0	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	2	3	18	19
Indeed , inhibition of IGF-IR and InsR or PI3K abrogated AKT PH-GFP membrane localization and P-AKT following treatment with AZD5363 .	Indeed, inhibition of IGF-IR and InsR or PI3K abrogated AKT PH-GFP membrane localization and P-AKT following treatment with AZD5363.	2	13	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	AKT	AKT	AKT	4	5	10	11
IGF-1R was reported to be transactivated by GABA B receptor through G i/o protein , PLCbeta and focal adhesion kinase ( FAK ) , and then further induced MEK and ERK 1/2 and PI3K and Akt activation XREF_BIBR XREF_BIBR .	IGF-1R was reported to be transactivated by GABA B receptor through G i/o protein, PLCbeta and focal adhesion kinase (FAK), and then further induced MEK and ERK 1/2 and PI3K and Akt activation XREF_BIBR XREF_BIBR.	0	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	0	1	35	36
Intriguingly , the fusion is regulated through AKT dependent signaling induced by IGF1R overexpression and is downregulated upon IGF1R-inhibition ( % expression of control +/- SD = 27.2 +/- 1.3 , P < .001 ) .	Intriguingly, the fusion is regulated through AKT dependent signaling induced by IGF1R overexpression and is downregulated upon IGF1R-inhibition (% expression of control +/- SD = 27.2 +/- 1.3, P <.001).	7	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1R	IGF1R overexpression	igf1r	AKT	AKT	akt	12	13	7	8
The mechanistic basis for this effect seems to be an increased baseline activation of IGF1R mediated activation of AKT in cells that express oncogenic KRAS .	The mechanistic basis for this effect seems to be an increased baseline activation of IGF1R mediated activation of AKT in cells that express oncogenic KRAS.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	14	15	18	19
As IGF-IR blockade can acutely inhibit Akt activity in our cell lines , such a mechanism may explain the subsequent phosphorylation of erbB3 ; however , further studies are required to confirm this hypothesis .	As IGF-IR blockade can acutely inhibit Akt activity in our cell lines, such a mechanism may explain the subsequent phosphorylation of erbB3; however, further studies are required to confirm this hypothesis.	1	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	1	2	6	7
Blockade of IGF-1R signalling by specific inhibitors can decrease tumour growth in a xenograft mouse model by disrupting the association of IRS-1 with PI3K and downregulating PI3K and AKT signalling .	Blockade of IGF-1R signalling by specific inhibitors can decrease tumour growth in a xenograft mouse model by disrupting the association of IRS-1 with PI3K and downregulating PI3K and AKT signalling.	2	29	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	2	3	28	29
IGF-I promotes proliferation of neural cells by interacting with the IGF-IR which may activate the PI3K and Akt or the MAP kinase pathways .	IGF-I promotes proliferation of neural cells by interacting with the IGF-IR which may activate the PI3K and Akt or the MAP kinase pathways.	7	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	10	11	17	18
Upon activation by the mitogenic ligands IGF-1 and IGF-2 , the IGF-1R is phosphorylated , stimulating downstream intracellular pathways ( the PI3K and AKT and Ras/MEK/ERK pathways ) that lead totumor proliferation , survival , and metastasis .	Upon activation by the mitogenic ligands IGF-1 and IGF-2, the IGF-1R is phosphorylated, stimulating downstream intracellular pathways (the PI3K and AKT and Ras/MEK/ERK pathways) that lead totumor proliferation, survival, and metastasis.	6	26	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1 and IGF-2, the IGF-1R is phosphorylated	igf-1r	AKT	AKT	akt	11	12	23	24
IGF1R activation by ligand exposure in growth factor deprived cells induces Akt activation in the FET , CBS and GEO colon cancer cell lines .	IGF1R activation by ligand exposure in growth factor deprived cells induces Akt activation in the FET, CBS and GEO colon cancer cell lines.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	0	1	11	12
In sarcoma , IGF1R activation is known to activate the phosphatidylinositol-3-kinase/serine/threonine kinase Akt and Mammalian target of rapamycin ( PI3K/Akt/mTOR ) pathway which promotes cancer progression and metastasis [ XREF_BIBR ] .	In sarcoma, IGF1R activation is known to activate the phosphatidylinositol-3-kinase/serine/threonine kinase Akt and Mammalian target of rapamycin (PI3K/Akt/mTOR) pathway which promotes cancer progression and metastasis [XREF_BIBR].	3	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	3	4	12	13
Further investigation revealed that increased hepatic IGF1 and IGF1R expression and action induce AKT and mTOR activation in Lrp6 mut and mut mice .	Further investigation revealed that increased hepatic IGF1 and IGF1R expression and action induce AKT and mTOR activation in Lrp6 mut and mut mice.	8	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R expression	igf1r	AKT	AKT	akt	8	9	13	14
Blockade of IGF-I receptor function prevented rapamycin ' s activation of AKT .	Blockade of IGF-I receptor function prevented rapamycin 's activation of AKT.	2	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I receptor	IGF-I receptor	IGF-I receptor	AKT	AKT	AKT	2	4	11	12
Co-targeting ERBB2 and IGF1R reduces Erk and AKT activation , cell proliferation , in vitro invasion , and xenograft tumor growth to a greater extent than targeting either receptor individually .	Co-targeting ERBB2 and IGF1R reduces Erk and AKT activation, cell proliferation, in vitro invasion, and xenograft tumor growth to a greater extent than targeting either receptor individually.	1	8	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	3	4	7	8
Diet induced changes to circulating IGF-1 to modulate IGF-1R and EGFR activation and signaling downstream of AKT and mTOR [ XREF_BIBR ] .	Diet induced changes to circulating IGF-1 to modulate IGF-1R and EGFR activation and signaling downstream of AKT and mTOR [XREF_BIBR].	8	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	8	9	16	17
IGF1R inhibition blocked the induction of P-AKT completely ( > 90 % ) in WiDr cells and by ~ 50 % in HT-29 cells .	IGF1R inhibition blocked the induction of P-AKT completely (> 90%) in WiDr cells and by ~ 50% in HT-29 cells.	0	7	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	P-AKT	P-AKT	P-AKT	0	1	6	7
Preclinical studies indicate that IGF1R inhibition prevents the induction of PI3K and AKT by mTOR inhibitors , thus sensitizing tumor cells for growth inhibition and death and providing a strong rationale for the combination of IGF1R and mTOR inhibitors in the clinic .	Preclinical studies indicate that IGF1R inhibition prevents the induction of PI3K and AKT by mTOR inhibitors, thus sensitizing tumor cells for growth inhibition and death and providing a strong rationale for the combination of IGF1R and mTOR inhibitors in the clinic.	4	13	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	4	5	12	13
Our data also demonstrate that inhibition of EGFR signaling with AG1478 does not inhibit IGF-1R induced Akt activity but does block EGF induced Akt activity .	Our data also demonstrate that inhibition of EGFR signaling with AG1478 does not inhibit IGF-1R induced Akt activity but does block EGF induced Akt activity.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	14	15	16	17
Akt activation upon knockdown of FAS was suppressed by simultaneous knockdown of IGF-1R ( XREF_FIG ) .	Akt activation upon knockdown of FAS was suppressed by simultaneous knockdown of IGF-1R (XREF_FIG).	0	14	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	12	13	0	1
In contrast , in urothelial cancer derived cells decorin severely inhibits ligand dependent IGF-IR activation and downstream activation of the Akt and MAPK pathways .	In contrast, in urothelial cancer derived cells decorin severely inhibits ligand dependent IGF-IR activation and downstream activation of the Akt and MAPK pathways.	13	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	13	14	20	21
In fact , IGF-I is the most potent stimulator of collagen biosynthesis [ XREF_BIBR , XREF_BIBR ] and IGF-I receptor mediated Akt dependent signaling pathway induces collagen gene expression [ XREF_BIBR ] .	In fact, IGF-I is the most potent stimulator of collagen biosynthesis [XREF_BIBR, XREF_BIBR] and IGF-I receptor mediated Akt dependent signaling pathway induces collagen gene expression [XREF_BIBR].	18	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF-I receptor	IGF-I receptor	IGF-I receptor	Akt	Akt	Akt	18	20	21	22
We then tested if inhibition of either IGF-1R or ILK suppresses feedback activation of AKT following MEK suppression .	We then tested if inhibition of either IGF-1R or ILK suppresses feedback activation of AKT following MEK suppression.	4	17	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	7	8	14	15
In this regard , IGF-IR induces activation of Ras/raf/MAPK and PI3K and Akt signaling , which alter the expression of genes involved in cell proliferation and survival , thus contributing to breast carcinogenesis .	In this regard, IGF-IR induces activation of Ras/raf/MAPK and PI3K and Akt signaling, which alter the expression of genes involved in cell proliferation and survival, thus contributing to breast carcinogenesis.	4	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	4	5	12	13
IGF-1R blockade inhibited the Akt pathway more than the extracellular signal regulated kinase ( ERK ) pathway in the K-RAS-MT transfectants .	IGF-1R blockade inhibited the Akt pathway more than the extracellular signal regulated kinase (ERK) pathway in the K-RAS-MT transfectants.	0	5	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	0	1	4	5
To confirm IGF1R stimulated PI3K-Akt in these contexts , we pulsed serum starved leukemia cells with recombinant IGF-1 and measured phospho-Akt activation by flow cytometry .	To confirm IGF1R stimulated PI3K-Akt in these contexts, we pulsed serum starved leukemia cells with recombinant IGF-1 and measured phospho-Akt activation by flow cytometry.	1	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	2	3	4	5
Furthermore , persistent IGF-1R signaling induces PI3K and Akt activation in these resistant cells whereas treatment with an IGF1R inhibitor blocked Akt phosphorylation with no inhibition of ERK [ XREF_BIBR ] .	Furthermore, persistent IGF-1R signaling induces PI3K and Akt activation in these resistant cells whereas treatment with an IGF1R inhibitor blocked Akt phosphorylation with no inhibition of ERK [XREF_BIBR].	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	3	4	8	9
Activation of IGF-IR upregulates PI3K and AKT signaling and increases proliferation and survival .	Activation of IGF-IR upregulates PI3K and AKT signaling and increases proliferation and survival.	0	7	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	AKT	AKT	AKT	2	3	6	7
In preclinical studies , exogenous IGFs completely reversed the antiproliferative effects of rapamycin [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , while inhibition of IGF-1R , either by a small molecule inhibitor or an IGF-1R antibody such as Cixutumumab , abrogated the induction of AKT activity and enhanced the antiproliferative effect of rapamycin [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In preclinical studies, exogenous IGFs completely reversed the antiproliferative effects of rapamycin [XREF_BIBR, XREF_BIBR, XREF_BIBR], while inhibition of IGF-1R, either by a small molecule inhibitor or an IGF-1R antibody such as Cixutumumab, abrogated the induction of AKT activity and enhanced the antiproliferative effect of rapamycin [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	22	45	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	24	25	44	45
Moreover , IGF and IGF-1R can indirectly stimulate the PI3K and Akt pathway in an interactive osteogenic signaling network , which is necessary for both bone development and remodeling 16 .	Moreover, IGF and IGF-1R can indirectly stimulate the PI3K and Akt pathway in an interactive osteogenic signaling network, which is necessary for both bone development and remodeling 16.	2	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	4	5	11	12
In fact , knockdown of IGF-1R inhibited human CRC cells growth and downstream PI3K and Akt that , in turn , caused the activation of GSK3beta .	In fact, knockdown of IGF-1R inhibited human CRC cells growth and downstream PI3K and Akt that, in turn, caused the activation of GSK3beta.	3	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	5	6	15	16
IGF-1R mediated Akt activity thus appears to be an important regulator of IGF-1R induced-LIP expression and may also be important for EGF mediated LIP expression .	IGF-1R mediated Akt activity thus appears to be an important regulator of IGF-1R induced-LIP expression and may also be important for EGF mediated LIP expression.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	0	1	2	3
IGF and IGF-IR stimulates the PI3K-Akt pathway in a stereotypical way - sustained tonal induction .	IGF and IGF-IR stimulates the PI3K-Akt pathway in a stereotypical way - sustained tonal induction.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	PI3K-Akt	PI3K-Akt	PI3K-Akt	2	3	5	6
In one report , it was demonstrated that GRKs phosphorylate IGF-IR , which recruits beta-arrestin and subsequently modulates downstream ERK and AKT mediated signaling as well as IGF-IR degradation .	In one report, it was demonstrated that GRKs phosphorylate IGF-IR, which recruits beta-arrestin and subsequently modulates downstream ERK and AKT mediated signaling as well as IGF-IR degradation.	8	23	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	GRKs phosphorylate IGF-IR	igf-ir	AKT	AKT	akt	10	11	21	22
IGF-IR activates the PI3K and Akt and p42 and p44 MAPK pathways , which regulate the activation of transcription factors , such as AP-1 .	IGF-IR activates the PI3K and Akt and p42 and p44 MAPK pathways, which regulate the activation of transcription factors, such as AP-1.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	0	1	5	6
Combined inhibition of CDK4 and IGF1R was confirmed to cooperatively suppress the activation of AKT pathway and consequently suppress DDLS .	Combined inhibition of CDK4 and IGF1R was confirmed to cooperatively suppress the activation of AKT pathway and consequently suppress DDLS.	1	15	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	5	6	14	15
The IGF-1R phosphorylation activates PI3K and AKT signaling pathway leading to cell survival .	The IGF-1R phosphorylation activates PI3K and AKT signaling pathway leading to cell survival.	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R phosphorylation	igf-1r	AKT	AKT	akt	1	2	6	7
Inhibition of IGF1R activity by its tyrosine kinase inhibitor NVP-AEW541 or its siRNA led to cytotoxicity and apoptosis in GIST cell lines by blocking the AKT and mitogen activated protein kinase ( MAPK ) pathway signaling .	Inhibition of IGF1R activity by its tyrosine kinase inhibitor NVP-AEW541 or its siRNA led to cytotoxicity and apoptosis in GIST cell lines by blocking the AKT and mitogen activated protein kinase (MAPK) pathway signaling.	2	30	led	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	2	3	25	26
Since the klotho can inhibit the IGF-1/R signaling pathway in our previous study , and autophosphorylation of IGF-1R induces the activation of Akt by phosphorylation , we hypothesized that klotho could alleviate the resistance of lung cancer cells ( A549DDP and H460DDP cells ) to chemotherapeutics in which Akt plays an important role .	Since the klotho can inhibit the IGF-1/R signaling pathway in our previous study, and autophosphorylation of IGF-1R induces the activation of Akt by phosphorylation, we hypothesized that klotho could alleviate the resistance of lung cancer cells (A549DDP and H460DDP cells) to chemotherapeutics in which Akt plays an important role.	15	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	autophosphorylation of IGF-1R	igf-1r	Akt	Akt	akt	17	18	22	23
Furthermore , the fusion was shown to be regulated through AKT dependent signaling induced by IGF1R overexpression .	Furthermore, the fusion was shown to be regulated through AKT dependent signaling induced by IGF1R overexpression.	10	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1R	IGF1R overexpression	igf1r	AKT	AKT	akt	15	16	10	11
miR-375 can significantly inhibit LSCC cell proliferation , migration , and invasion and promote apoptosis to suppress tumor via IGF1R mediated AKT signaling pathway .	miR-375 can significantly inhibit LSCC cell proliferation, migration, and invasion and promote apoptosis to suppress tumor via IGF1R mediated AKT signaling pathway.	17	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	19	20	21	22
The phosphorylation of IGF-1 receptor ( IGF-1R ) , after IGF-1 binding , leads to activation of MAPK and PI3K and Akt signaling pathway [ XREF_BIBR ] .	The phosphorylation of IGF-1 receptor (IGF-1R), after IGF-1 binding, leads to activation of MAPK and PI3K and Akt signaling pathway [XREF_BIBR].	1	25	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IGF-1R	phosphorylation of IGF-1 receptor (IGF-1R	igf-1r	Akt	Akt	akt	6	7	21	22
Although these mechanisms were not explored in our model , the cross-talk between IGF-1R and other activators of Akt and ERK may have contributed to our findings .	Although these mechanisms were not explored in our model, the cross-talk between IGF-1R and other activators of Akt and ERK may have contributed to our findings.	13	20	activators	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	13	14	18	19
In addition , IGF-I receptor and estrogen receptor activation synergistically increase the activity of the kinase Akt , and coordinately regulate protection from neurotoxicity .	In addition, IGF-I receptor and estrogen receptor activation synergistically increase the activity of the kinase Akt, and coordinately regulate protection from neurotoxicity.	3	17	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I receptor	IGF-I receptor	IGF-I receptor	Akt	Akt	Akt	3	5	16	17
Our studies suggest that in the drug resistant cell lines , downregulation of IGFBP3 leads to activation of IGF1R signaling , which activates PI3K and AKT signaling resulting in resistance to either PF299804 or WZ4002 .	Our studies suggest that in the drug resistant cell lines, downregulation of IGFBP3 leads to activation of IGF1R signaling, which activates PI3K and AKT signaling resulting in resistance to either PF299804 or WZ4002.	18	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	18	19	25	26
Blockade of InsR and IGF-1R is required to inhibit PI3K and AKT and prevent emergence of hormone independent cells .	Blockade of InsR and IGF-1R is required to inhibit PI3K and AKT and prevent emergence of hormone independent cells.	0	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	4	5	11	12
Since EGFR , IGF-1R and CRAF have been known to be the key components of RTK-RAS-RAF-MEK-ERK ( MAPK ) and/or PI3K and AKT signaling pathways , we further determined if single or combined inhibition of EGFR , IGF-1R and CRAF could suppress the activation of MAPK and PI3K and AKT signaling in VemR melanoma cells .	Since EGFR, IGF-1R and CRAF have been known to be the key components of RTK-RAS-RAF-MEK-ERK (MAPK) and/or PI3K and AKT signaling pathways, we further determined if single or combined inhibition of EGFR, IGF-1R and CRAF could suppress the activation of MAPK and PI3K and AKT signaling in VemR melanoma cells.	33	50	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	37	38	49	50
This study further suggested that phosphorylation of Ob-R and IGF-IR subsequently activated downstream signaling molecules Akt , ERK , IRS-1 , and IRS-2 .	This study further suggested that phosphorylation of Ob-R and IGF-IR subsequently activated downstream signaling molecules Akt, ERK, IRS-1, and IRS-2.	5	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	phosphorylation of Ob-R and IGF-IR	igf-ir	Akt	Akt	akt	9	10	15	16
IGF1R activated both the Ras-ERK and PI3K-AKT pathways , but only the latter pathway interfered with mitochondria dependent apoptosis .	IGF1R activated both the Ras-ERK and PI3K-AKT pathways, but only the latter pathway interfered with mitochondria dependent apoptosis.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	6	7
Dual inhibition of EGFR and IGF-1R was done to reverse the drug resistance and test PI3K and AKT signaling pathway .	Dual inhibition of EGFR and IGF-1R was done to reverse the drug resistance and test PI3K and AKT signaling pathway.	1	19	reverse	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	5	6	17	18
Dual inhibition of EGFR and IGF-1R could block the PI3K and AKT signaling pathway .	Dual inhibition of EGFR and IGF-1R could block the PI3K and AKT signaling pathway.	1	13	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	5	6	11	12
In another preclinical GBM study , the EGFR TKI gefitinib was effective in attenuating downstream MAPK/MEK/ERK activity , but concurrent inhibition of EGFR and IGF-1R and INSR was required to suppress Akt and induce apoptosis [ XREF_BIBR ] .	In another preclinical GBM study, the EGFR TKI gefitinib was effective in attenuating downstream MAPK/MEK/ERK activity, but concurrent inhibition of EGFR and IGF-1R and INSR was required to suppress Akt and induce apoptosis [XREF_BIBR].	20	32	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	24	25	31	32
XREF_BIBR SRC activity is essential for the up-regulation of IGF-IR by CEACAM6 induced AKT activity .	XREF_BIBR SRC activity is essential for the up-regulation of IGF-IR by CEACAM6 induced AKT activity.	7	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	AKT	AKT	AKT	9	10	13	14
Upon activation by the mitogenic ligands IGF-I and IGF-II , the IGF-1R is activated to trigger intracellular signaling pathways ( Ras/MEK/ERK and PI3K and AKT pathways ) that result in tumor progression and metastasis XREF_BIBR .	Upon activation by the mitogenic ligands IGF-I and IGF-II, the IGF-1R is activated to trigger intracellular signaling pathways (Ras/MEK/ERK and PI3K and AKT pathways) that result in tumor progression and metastasis XREF_BIBR.	10	25	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	11	12	24	25
Inhibition of IGF-IR and InsR or PI3K abrogated AKT PH-GFP membrane localization and T308 P-AKT following treatment with AZD5363 .	Inhibition of IGF-IR and InsR or PI3K abrogated AKT PH-GFP membrane localization and T308 P-AKT following treatment with AZD5363.	0	11	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	AKT	AKT	AKT	2	3	8	9
Regarding specific pathways , insulin like growth factors ( IGFs ) are commonly upregulated in cancers and activate IGF1R , which subsequently activates the pro tumourigenic PI3K-Akt pathway .	Regarding specific pathways, insulin like growth factors (IGFs) are commonly upregulated in cancers and activate IGF1R, which subsequently activates the pro tumourigenic PI3K-Akt pathway.	17	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	18	19	26	27
miR-378a-3p overexpression suppressed IGF1R expression in rhabdomyosarcoma derived RH30 cells and decreased the phosphorylation level of AKT protein , which is known as a key signaling molecule in rhabdomyosarcoma .	miR-378a-3p overexpression suppressed IGF1R expression in rhabdomyosarcoma derived RH30 cells and decreased the phosphorylation level of AKT protein, which is known as a key signaling molecule in rhabdomyosarcoma.	0	17	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	miR-378a-3p overexpression suppressed IGF1R expression	igf1r	AKT	AKT	akt	3	4	16	17
Then we pre-treated PC9GR cells with Akt or Erk inhibitor to inhibit the activation of Akt or Erk and found that IGF1 induced p65 activation was blocked by either Akt or Erk inhibition , which further demonstrated that IGF1R activates Akt and Erk both of which could then activate p65 .	Then we pre-treated PC9GR cells with Akt or Erk inhibitor to inhibit the activation of Akt or Erk and found that IGF1 induced p65 activation was blocked by either Akt or Erk inhibition, which further demonstrated that IGF1R activates Akt and Erk both of which could then activate p65.	38	48	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	38	39	40	41
Inhibition of InsR and IGF-1R with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone independent cells and tumors in vivo , inhibited parental and LTED cell growth and PI3K and AKT signaling , and suppressed growth of established MCF-7 xenografts in ovariectomized mice , whereas treatment with the neutralizing IGF-1R monoclonal antibody MAB391 was ineffective .	Inhibition of InsR and IGF-1R with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone independent cells and tumors in vivo, inhibited parental and LTED cell growth and PI3K and AKT signaling, and suppressed growth of established MCF-7 xenografts in ovariectomized mice, whereas treatment with the neutralizing IGF-1R monoclonal antibody MAB391 was ineffective.	0	34	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	4	5	33	34
In tumor cells , EI-04 effectively inhibited EGFR and IGF-1R phosphorylation , and concurrently blocked downstream AKT and ERK activation , resulting in greater inhibition of tumor cell growth and cell cycle progression than the single mAbs .	In tumor cells, EI-04 effectively inhibited EGFR and IGF-1R phosphorylation, and concurrently blocked downstream AKT and ERK activation, resulting in greater inhibition of tumor cell growth and cell cycle progression than the single mAbs.	4	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	EI-04 effectively inhibited EGFR and IGF-1R phosphorylation	igf-1r	AKT	AKT	akt	9	10	16	17
In the study of cell lines , IGF-1R leads to EGFR-TKI resistance by regulating the metabolism , proliferation and apoptosis of tumor cells and continuously activating the PI3K-AKT signaling pathway .	In the study of cell lines, IGF-1R leads to EGFR-TKI resistance by regulating the metabolism, proliferation and apoptosis of tumor cells and continuously activating the PI3K-AKT signaling pathway.	7	29	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	PI3K-AKT	PI3K-AKT	PI3K-AKT	7	8	27	28
IGF1R activates the AKT signaling pathway [ XREF_BIBR ] .	IGF1R activates the AKT signaling pathway [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	0	1	3	4
Pretreatment with EGF-IGF-LDP-AE inhibited EGF-, IGF stimulated EGFR and IGF-1R phosphorylation , and blocked two main downstream signaling molecules AKT and ERK activation .	Pretreatment with EGF-IGF-LDP-AE inhibited EGF-, IGF stimulated EGFR and IGF-1R phosphorylation, and blocked two main downstream signaling molecules AKT and ERK activation.	4	22	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	EGF-, IGF stimulated EGFR and IGF-1R phosphorylation	igf-1r	AKT	AKT	akt	9	10	19	20
The PI3K and Akt pathway is activated by the IGF-I receptor via the adaptor molecules insulin receptor substrate ( IRS )-l and IRS-2 in bone cells XREF_BIBR , XREF_BIBR , and PI3K signaling has been found to have an essential role in IGF induced osteoblast differentiation XREF_BIBR .	The PI3K and Akt pathway is activated by the IGF-I receptor via the adaptor molecules insulin receptor substrate (IRS)-l and IRS-2 in bone cells XREF_BIBR, XREF_BIBR, and PI3K signaling has been found to have an essential role in IGF induced osteoblast differentiation XREF_BIBR.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-I receptor	IGF-I receptor	IGF-I receptor	Akt	Akt	Akt	9	11	3	4
We next tested whether disruption of the IGF-1R signaling will reduce Akt activation .	We next tested whether disruption of the IGF-1R signaling will reduce Akt activation.	7	12	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	7	8	11	12
Once activated by IGF-1 , IGF-1R triggers the downstream cascade reactions , the Ras-MAPK pathway and the PI3K-Akt pathway .	Once activated by IGF-1, IGF-1R triggers the downstream cascade reactions, the Ras-MAPK pathway and the PI3K-Akt pathway.	5	18	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	5	6	17	18
Similarly to the c-MET receptor , the IGF-1R also leads to activation of the AKT pathway without EGFR in NSCLC cells .	Similarly to the c-MET receptor, the IGF-1R also leads to activation of the AKT pathway without EGFR in NSCLC cells.	6	15	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	7	8	14	15
Thus , VHL deficient cells gain resistance to 2DG-ABT through the raised expression of IGF1R and subsequent activation of PI3K-AKT , and not by activating hypoxia inducible factors which they can not activate [ XREF_BIBR ] .	Thus, VHL deficient cells gain resistance to 2DG-ABT through the raised expression of IGF1R and subsequent activation of PI3K-AKT, and not by activating hypoxia inducible factors which they can not activate [XREF_BIBR].	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-AKT	PI3K-AKT	PI3K-AKT	14	15	19	20
XREF_BIBR - XREF_BIBR Activated IGF1R may initiate a signaling cascade axe , the PI3K and AKT signaling pathway .	XREF_BIBR - XREF_BIBR Activated IGF1R may initiate a signaling cascade axe, the PI3K and AKT signaling pathway.	4	17	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	4	5	15	16
Inhibition of ER , IGF-1R and InsR , or IRS-1/2 suppressed AKT activation induced by mTORC1 inhibition .	Inhibition of ER, IGF-1R and InsR, or IRS-1/2 suppressed AKT activation induced by mTORC1 inhibition.	0	12	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	4	5	11	12
Moreover , simultaneous knockdown of the IGF1R and the insulin receptor with shRNAs markedly reduced the activation of AKT and substantially impaired hepatocyte differentiation .	Moreover, simultaneous knockdown of the IGF1R and the insulin receptor with shRNAs markedly reduced the activation of AKT and substantially impaired hepatocyte differentiation.	3	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	6	7	18	19
We wondered whether erbB3 receptor and IGF-1R equally initiated activation of the PI-3K and Akt signaling and Src kinase , which might also influence the lapatinib sensitivity of trastuzumab resistant cells .	We wondered whether erbB3 receptor and IGF-1R equally initiated activation of the PI-3K and Akt signaling and Src kinase, which might also influence the lapatinib sensitivity of trastuzumab resistant cells.	4	15	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	6	7	14	15
Thus we speculated IGF-1R and AKT inhibition might increase p53 apoptotic function by inhibiting AKT and activating GSK3beta ( reducing the inhibitory phosphorylation of GSK3beta at serine 9 ) and thus promoting K120 acetylation of p53 .	Thus we speculated IGF-1R and AKT inhibition might increase p53 apoptotic function by inhibiting AKT and activating GSK3beta (reducing the inhibitory phosphorylation of GSK3beta at serine 9) and thus promoting K120 acetylation of p53.	3	15	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	3	4	14	15
3.3 Crk II knockdown downregulated IGF-IR levels and suppressed PI3K and Akt signaling pathway in CWR-22rv1 cells .	3.3 Crk II knockdown downregulated IGF-IR levels and suppressed PI3K and Akt signaling pathway in CWR-22rv1 cells.	1	13	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-IR	Crk II knockdown downregulated IGF-IR levels	igf-ir	Akt	Akt	akt	5	6	11	12
Upon IGF1 binding , IGF1R undergoes auto-phosphorylation , associates with intracellular adaptor proteins called IRSs ( insulin and IGF1 receptor substrates ) , and activates either the Akt or the Ras/MEK/ERK signaling pathways .	Upon IGF1 binding, IGF1R undergoes auto-phosphorylation, associates with intracellular adaptor proteins called IRSs (insulin and IGF1 receptor substrates), and activates either the Akt or the Ras/MEK/ERK signaling pathways.	4	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	4	5	27	28
Simultaneous inhibition of IGF-1R and InsR and HER receptors inhibited AKT and ERK activation .	Simultaneous inhibition of IGF-1R and InsR and HER receptors inhibited AKT and ERK activation.	1	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	3	4	10	11
In cell lines harboring T790M mutation , the PI3K-AKT and MAPK pathways were induced simultaneously by the activation IGF1R signaling responsible for afatinib [ XREF_BIBR ] and WZ4002 [ XREF_BIBR ] resistance .	In cell lines harboring T790M mutation, the PI3K-AKT and MAPK pathways were induced simultaneously by the activation IGF1R signaling responsible for afatinib [XREF_BIBR] and WZ4002 [XREF_BIBR] resistance.	8	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-AKT	PI3K-AKT	PI3K-AKT	18	19	8	9
Blockade of IGF1R signaling by ganitumab has been found to inhibit activation of the PI3 kinase and AKT pathway , leading to growth inhibition in preclinical tumor models of pancreatic adenocarcinoma .	Blockade of IGF1R signaling by ganitumab has been found to inhibit activation of the PI3 kinase and AKT pathway, leading to growth inhibition in preclinical tumor models of pancreatic adenocarcinoma.	2	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	2	3	17	18
The observed phenotype was independent of the Akt pathway since absence of IGF-1R caused inactivation of PI3K-Akt pathway .	The observed phenotype was independent of the Akt pathway since absence of IGF-1R caused inactivation of PI3K-Akt pathway.	10	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	12	13	16	17
Trop-2 could attenuate IGF-1R signalling mediated AKT and beta-catenin and ERK activation through a direct binding of IGF1 .	Trop-2 could attenuate IGF-1R signalling mediated AKT and beta-catenin and ERK activation through a direct binding of IGF1.	3	11	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	3	4	6	7
The IGF-IR activates multiple downstream effector molecules , some of the most well-known following IGF stimulation , are the ERKs and Akt .	The IGF-IR activates multiple downstream effector molecules, some of the most well-known following IGF stimulation, are the ERKs and Akt.	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	1	2	21	22
They further suggest that the IGF and IGF-1R pathway mediated feedback activation of AKT and that combining rapamycin and IGF-1R inhibitors enhanced antitumor effects XREF_BIBR , XREF_BIBR .	They further suggest that the IGF and IGF-1R pathway mediated feedback activation of AKT and that combining rapamycin and IGF-1R inhibitors enhanced antitumor effects XREF_BIBR, XREF_BIBR.	5	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	7	8	13	14
Our results demonstrate that the prolonged Akt signaling elicited by IRS-1-mediated surface retention of IGF-IR affects the FoxO targeting gene expression .	Our results demonstrate that the prolonged Akt signaling elicited by IRS-1-mediated surface retention of IGF-IR affects the FoxO targeting gene expression.	6	15	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	14	15	6	7
Previous reports suggest that the stimulation of IGF1R can lead to the activation of at least two signaling pathways involving mitogen activated protein kinase and AKT under conditions that often require the removal or reduction of other growth factors .	Previous reports suggest that the stimulation of IGF1R can lead to the activation of at least two signaling pathways involving mitogen activated protein kinase and AKT under conditions that often require the removal or reduction of other growth factors.	5	30	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	7	8	25	26
miR-122 suppresses IGF-1R expression and attenuates IGF-1R and Akt signaling , which sustains the activity of glycogen synthase kinase 3 beta and in turn represses cancer cell proliferation [ XREF_BIBR ] .	miR-122 suppresses IGF-1R expression and attenuates IGF-1R and Akt signaling, which sustains the activity of glycogen synthase kinase 3 beta and in turn represses cancer cell proliferation [XREF_BIBR].	0	9	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	miR-122 suppresses IGF-1R expression	igf-1r	Akt	Akt	akt	2	3	8	9
demonstrated that elimination of persistent IGF1R induced Akt activity was required to reestablish gefitinib sensitivity .	demonstrated that elimination of persistent IGF1R induced Akt activity was required to reestablish gefitinib sensitivity.	2	8	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	5	6	7	8
Gene expression analysis indicated increased expression levels of Igf1 and its receptor Igf1r that activated Akt signaling pathway ( XREF_TABLE ) .	Gene expression analysis indicated increased expression levels of Igf1 and its receptor Igf1r that activated Akt signaling pathway (XREF_TABLE).	3	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Igf1r	Igf1r	Igf1r	Akt	Akt	Akt	12	13	15	16
Pharmacological or genetic inhibition of IGF-1R inhibited only downstream PI3K and AKT signaling ; exogenous IGF-1 increased PI3K mediated signaling , but was not sufficient to induce resistance .	Pharmacological or genetic inhibition of IGF-1R inhibited only downstream PI3K and AKT signaling; exogenous IGF-1 increased PI3K mediated signaling, but was not sufficient to induce resistance.	3	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	5	6	11	12
Furthermore , inhibition of IGF-1R may abrograte some AKT activation in a TORC1 independent manner [ XREF_BIBR ] .	Furthermore, inhibition of IGF-1R may abrograte some AKT activation in a TORC1 independent manner [XREF_BIBR].	2	9	abrograte	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	4	5	8	9
Overexpression of IGF-1R or an increase in levels of IGF-1R and HER2 heterodimers can potently activate PI3K and AKT signaling and confer resistance to trastuzumab in laboratory studies .	Overexpression of IGF-1R or an increase in levels of IGF-1R and HER2 heterodimers can potently activate PI3K and AKT signaling and confer resistance to trastuzumab in laboratory studies.	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	Overexpression of IGF-1R	igf-1r	AKT	AKT	akt	2	3	18	19
To determine whether knockdown of IGF1R enhances the inhibitory efficacy of sorafenib on HCC cell growth by inhibiting AKT activity , we overexpressed constitutively active AKT in IGF1R knockdown cells .	To determine whether knockdown of IGF1R enhances the inhibitory efficacy of sorafenib on HCC cell growth by inhibiting AKT activity, we overexpressed constitutively active AKT in IGF1R knockdown cells.	3	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	5	6	18	19
Phosphorylation of IGF-1R can activate Akt by a cascade signaling pathway , eliciting a repertoire of cellular responses including proliferation , and the protection of cells from death [ XREF_BIBR ] .	Phosphorylation of IGF-1R can activate Akt by a cascade signaling pathway, eliciting a repertoire of cellular responses including proliferation, and the protection of cells from death [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	Phosphorylation of IGF-1R	igf-1r	Akt	Akt	akt	2	3	5	6
Because p-IGF1R induce PI3K-AKT pathway activation and MMP3 can directly induce epithelial-mesenchymal transition [ XREF_BIBR ] , a widely known mechanisms of chemotherapy-resistance , we hypothesize that GIST patients with positive immunophenotype ( either p-IGF-1R positive or MMP7 positive ) can contribute to IM resistance .	Because p-IGF1R induce PI3K-AKT pathway activation and MMP3 can directly induce epithelial-mesenchymal transition [XREF_BIBR], a widely known mechanisms of chemotherapy-resistance, we hypothesize that GIST patients with positive immunophenotype (either p-IGF-1R positive or MMP7 positive) can contribute to IM resistance.	1	5	induce	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p-IGF1R	p-IGF1R	p-IGF1R	PI3K-AKT	PI3K-AKT	PI3K-AKT	1	2	3	4
Activation of IGF1R triggers two main downstream pathways : the PI3K-Akt and the RAF and ERK cascade .	Activation of IGF1R triggers two main downstream pathways : the PI3K-Akt and the RAF and ERK cascade.	0	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	2	3	10	11
In the cell line studies , IGF1R siRNA and monoclonal antibody MK-0646 inhibited MPNST proliferation , invasion , and migration by blocking the AKT and PI3K pathways .	In the cell line studies, IGF1R siRNA and monoclonal antibody MK-0646 inhibited MPNST proliferation, invasion, and migration by blocking the AKT and PI3K pathways.	6	26	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	6	7	23	24
It has been revealed that down-regulation of IGF-1R stimulates the PI3K-Akt pathway , which is involved in cell autophagy .	It has been revealed that down-regulation of IGF-1R stimulates the PI3K-Akt pathway, which is involved in cell autophagy.	5	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	7	8	10	11
Erk and Akt Activation by the IGF1R .	Erk and Akt Activation by the IGF1R.	0	7	Activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	6	7	2	3
Furthermore , this response persisted up to 24 hours , indicating IGF1R inhibition can prevent Akt reactivation that was observed with buparlisib treatment alone ( XREF_FIG ) .	Furthermore, this response persisted up to 24 hours, indicating IGF1R inhibition can prevent Akt reactivation that was observed with buparlisib treatment alone (XREF_FIG).	11	16	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	11	12	15	16
Two such upstream pathways originate with IGF-1R , which will activate Akt and Ras when bound by its ligand [ XREF_BIBR ] .	Two such upstream pathways originate with IGF-1R, which will activate Akt and Ras when bound by its ligand [XREF_BIBR].	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	6	7	11	12
In addition , knockdown of IGF1R and its signaling pathway also blocked AKT activation , providing further evidence for the role of the IGF1R pathway in this setting .	In addition, knockdown of IGF1R and its signaling pathway also blocked AKT activation, providing further evidence for the role of the IGF1R pathway in this setting.	3	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	5	6	12	13
Both EGFR and IGF1R can both mediate down-stream MAPK and AKT signaling independently of one another or in concert , because of the existence of EGFR and IGF1R cross talk [ XREF_BIBR ] .	Both EGFR and IGF1R can both mediate down-stream MAPK and AKT signaling independently of one another or in concert, because of the existence of EGFR and IGF1R cross talk [XREF_BIBR].	1	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	3	4	10	11
Similarly , the inhibition of IGF-1R phosphorylation with linsitinib was sufficient to block the activation of AKT ( XREF_FIG ) , and residual cancer cells that were treated with the IGF-1R inhibitor showed an increased expression of active Caspase 3 .	Similarly, the inhibition of IGF-1R phosphorylation with linsitinib was sufficient to block the activation of AKT (XREF_FIG), and residual cancer cells that were treated with the IGF-1R inhibitor showed an increased expression of active Caspase 3.	5	18	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R phosphorylation	igf-1r	AKT	AKT	akt	5	6	16	17
They found TROP2 could attenuate IGF-1R signalling mediated AKT activation through a direct binding of IGF1 .	They found TROP2 could attenuate IGF-1R signalling mediated AKT activation through a direct binding of IGF1.	5	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	5	6	8	9
We demonstrated that PTEN loss increases and prolongs IGF-IR and HER3 tyr phosphorylation , p85-IRS-1 and p85-HER3 binding , and E2 induced , IGF-IR and IRS-1-dependent activation of PI3K and AKT ( XREF_FIG - XREF_FIG , Fig .	We demonstrated that PTEN loss increases and prolongs IGF-IR and HER3 tyr phosphorylation, p85-IRS-1 and p85-HER3 binding, and E2 induced, IGF-IR and IRS-1-dependent activation of PI3K and AKT (XREF_FIG - XREF_FIG, Fig.	23	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	AKT	AKT	AKT	23	24	30	31
This suggests that P-REX1 promotes IGF-1Rbeta and InsRbeta activation independently of PI3K and AKT activity .	This suggests that P-REX1 promotes IGF-1Rbeta and InsRbeta activation independently of PI3K and AKT activity.	5	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1Rbeta	IGF-1Rbeta	IGF-1Rbeta	AKT	AKT	AKT	5	6	13	14
XREF_BIBR , XREF_BIBR It has been reported that activation of IGF-1R stimulates PI3K and AKT pathway , regulating cell proliferation , migration , invasion .	XREF_BIBR, XREF_BIBR It has been reported that activation of IGF-1R stimulates PI3K and AKT pathway, regulating cell proliferation, migration, invasion.	8	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	10	11	14	15
Noting that the growth inhibitory ( nuclear ) function of p27 is required for EGFR-TKI efficacy , IGF1R activation causes resistance to EGFR-TKIs , the IGF1R is a potent activator of Akt , and Akt phosphorylates p27 at T157 with resultant cytoplasmic sequestration of p27 and cell cycle progression , we evaluated regulation of p27 by EGFR-TKIs in an OSCC cell line in the presence or absence of simultaneous IGF1R activation .	Noting that the growth inhibitory (nuclear) function of p27 is required for EGFR-TKI efficacy, IGF1R activation causes resistance to EGFR-TKIs, the IGF1R is a potent activator of Akt, and Akt phosphorylates p27 at T157 with resultant cytoplasmic sequestration of p27 and cell cycle progression, we evaluated regulation of p27 by EGFR-TKIs in an OSCC cell line in the presence or absence of simultaneous IGF1R activation.	24	32	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	25	26	31	32
To accomplish this , the IGF-1R is a potent activator of Akt which fits with the findings that inhibition of mTOR signaling by rapamycin frequently results in the loss of feedback inhibition of IGF-1R signaling , in turn , resulting in Akt activation [ XREF_BIBR ] .	To accomplish this, the IGF-1R is a potent activator of Akt which fits with the findings that inhibition of mTOR signaling by rapamycin frequently results in the loss of feedback inhibition of IGF-1R signaling, in turn, resulting in Akt activation [XREF_BIBR].	4	12	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	5	6	11	12
In the present study , blockage of IGF-1R by HMJ-30 reduced NF-kappaB activity and downregulated PI3K and AKT and Ras and MAPK pathway signaling , resulting in MET in U-2 OS cells .	In the present study, blockage of IGF-1R by HMJ-30 reduced NF-kappaB activity and downregulated PI3K and AKT and Ras and MAPK pathway signaling, resulting in MET in U-2 OS cells.	5	18	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	7	8	17	18
Ligand binding to IR and IGF-1R activates Akt signaling pathways .	Ligand binding to IR and IGF-1R activates Akt signaling pathways.	1	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	5	6	7	8
Therefore , activation of either FAK or IGF-1R induces the PI3K-Akt pathway and cell survival .	Therefore, activation of either FAK or IGF-1R induces the PI3K-Akt pathway and cell survival.	2	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	PI3K-Akt	PI3K-Akt	PI3K-Akt	7	8	10	11
Another potential benefit of mTOR is that its blockade of IGF1R may prevent the counterproductive rapamycin induced upregulation of Akt [ XREF_BIBR ] .	Another potential benefit of mTOR is that its blockade of IGF1R may prevent the counterproductive rapamycin induced upregulation of Akt [XREF_BIBR].	8	21	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	10	11	19	20
Many breast cancers harbor genetic alterations resulting in aberrant PI3K and Akt signaling or over-express heterologous receptor networks , such as IGF-IR , that potently activate PI3K and Akt .	Many breast cancers harbor genetic alterations resulting in aberrant PI3K and Akt signaling or over-express heterologous receptor networks, such as IGF-IR, that potently activate PI3K and Akt.	17	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	Akt	Akt	Akt	21	22	28	29
Celecoxib suppresses phosphorylation of IGF-1R , upregulates the expression of IGFBP-3 and downregulates the AKT signaling pathway .	Celecoxib suppresses phosphorylation of IGF-1R, upregulates the expression of IGFBP-3 and downregulates the AKT signaling pathway.	0	16	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	Celecoxib suppresses phosphorylation of IGF-1R	igf-1r	AKT	AKT	akt	4	5	14	15
The data shown here that inhibition of IGF-IR inhibits strain mediated activation of AKT correlates with our previous observations that IGF signaling is an essential component of the osteoblasts response to strain .	The data shown here that inhibition of IGF-IR inhibits strain mediated activation of AKT correlates with our previous observations that IGF signaling is an essential component of the osteoblasts response to strain.	5	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	AKT	AKT	AKT	7	8	13	14
Furthermore , IGF-1R signaling activates PI3K and Akt pathways which leads to mTOR activation [ XREF_BIBR , XREF_BIBR ] .	Furthermore, IGF-1R signaling activates PI3K and Akt pathways which leads to mTOR activation [XREF_BIBR, XREF_BIBR].	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	2	3	7	8
In several models , IGF-1R and IRS-1 mediate the majority of PI 3 kinase and Akt -1 induction .	In several models, IGF-1R and IRS-1 mediate the majority of PI 3 kinase and Akt -1 induction.	4	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	4	5	15	16
These results imply that in MCF-7 cells , IGF-IR mainly drives PI3K and AKT ( XREF_FIG - XREF_FIG ) , but EGFR/HER2/HER3 may also contribute to hormone independent growth and antiestrogen resistance ( XREF_FIG ) .	These results imply that in MCF-7 cells, IGF-IR mainly drives PI3K and AKT (XREF_FIG - XREF_FIG), but EGFR/HER2/HER3 may also contribute to hormone independent growth and antiestrogen resistance (XREF_FIG).	8	14	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	AKT	AKT	AKT	8	9	13	14
IGF-1R activation is known to enhance AKT signaling , which can stabilize certain mRNAs by blocking AU rich element binding proteins that recruit deadenylases to degrade mRNAs containing AREs .	IGF-1R activation is known to enhance AKT signaling, which can stabilize certain mRNAs by blocking AU rich element binding proteins that recruit deadenylases to degrade mRNAs containing AREs.	0	7	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	0	1	6	7
Inhibition of phospho-IGF-1R by enterolactone blocked IGF-1-induced activation of AKT and its downstream targets , such as phospho-p70S6K1 and phospho-GSK-3 beta .	Inhibition of phospho-IGF-1R by enterolactone blocked IGF-1-induced activation of AKT and its downstream targets, such as phospho-p70S6K1 and phospho-GSK-3 beta.	0	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	phospho-IGF-1R	phospho-IGF-1R	phospho-IGF-1R	AKT	AKT	AKT	2	3	9	10
Taken together , these results suggest that the miR-99 family plays an important role in dermal wound healing by concurrently targeting IGF1R , mTOR , and AKT1 ( as well as AKT2 , to a lesser extent ) , which in turn modulate the PI3K and AKT and mTOR signaling pathways .	Taken together, these results suggest that the miR-99 family plays an important role in dermal wound healing by concurrently targeting IGF1R, mTOR, and AKT1 (as well as AKT2, to a lesser extent), which in turn modulate the PI3K and AKT and mTOR signaling pathways.	20	47	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	21	22	46	47
IGF-1 binds the IGF1 receptor ( IGF1-R ) initiating AKT activation promoting protein synthesis and inhibiting protein degradation [ XREF_BIBR ] .	IGF-1 binds the IGF1 receptor (IGF1-R) initiating AKT activation promoting protein synthesis and inhibiting protein degradation [XREF_BIBR].	4	10	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1-R	IGF1-R	IGF1-R	AKT	AKT	AKT	6	7	9	10
One unique feature of the signal transduction in HER2+ breast cancer cell lines and CEACAM6 expression is the interaction of the HER2 pathway and TGF-beta signaling.17 Overexpression of CEACAM6 results in alteration and reorganization of the ECM and activation of the TME playing a key role in tumor invasion.54 CEACAM6 signaling increases SRC activity , leading to increased IGF-I secretion , with autocrine and paracrine stimulation of the IGF-1R activating the PI3K and AKT pathway .	One unique feature of the signal transduction in HER2+ breast cancer cell lines and CEACAM6 expression is the interaction of the HER2 pathway and TGF-beta signaling.17 Overexpression of CEACAM6 results in alteration and reorganization of the ECM and activation of the TME playing a key role in tumor invasion.54 CEACAM6 signaling increases SRC activity, leading to increased IGF-I secretion, with autocrine and paracrine stimulation of the IGF-1R activating the PI3K and AKT pathway.	65	74	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	68	69	73	74
Mdm2 is shown to trigger K63 linked ubiquitination of IGF-1R and promotes the internalization of IGF-1R to the early endosome ( XREF_TABLE ) .	Mdm2 is shown to trigger K63 linked ubiquitination of IGF-1R and promotes the internalization of IGF-1R to the early endosome (XREF_TABLE).	0	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	Mdm2 is shown to trigger K63 linked ubiquitination of IGF-1R	igf-1r	IGF-1R	IGF-1R	igf-1r	9	10	15	16
In contrast , pIGF-1R ( Tyr 1131 ) , pIGF-1R ( Tyr 1135/1136 , data not shown ) , and pAkt ( Ser 473 ) levels were obviously higher in HBEC cells expressing p53i and/or RAS v12 than in parental HBEC cells ( XREF_FIG , right ) , suggesting that loss of p53 expression and/or mutation of KRAS ( V12 ) led the HBE cells to produce IGFs and activate IGF-1R .	In contrast, pIGF-1R (Tyr 1131), pIGF-1R (Tyr 1135/1136, data not shown), and pAkt (Ser 473) levels were obviously higher in HBEC cells expressing p53i and/or RAS v12 than in parental HBEC cells (XREF_FIG, right), suggesting that loss of p53 expression and/or mutation of KRAS (V12) led the HBE cells to produce IGFs and activate IGF-1R.	3	71	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pIGF-1R	pIGF-1R	pIGF-1R	IGF-1R	IGF-1R	IGF-1R	3	4	70	71
Following loss of UBQLN1 in lung adenocarcinoma cells , there is accelerated loss of IGF1R .	Following loss of UBQLN1 in lung adenocarcinoma cells, there is accelerated loss of IGF1R.	10	15	is accelerated loss	Negative_activation_copula_1	Positive_activation	Negative_activation	IGF1R	loss of IGF1R	igf1r	IGF1R	IGF1R	igf1r	14	15	14	15
IGF-IR overexpression provided the primary tumor cells with a survival advantage in serum-free media and seemed to induce ligand independent activation of the IGF-IR because RM11A cells cultured in the presence of Dox were largely nonresponsive to exogenous IGFs .	IGF-IR overexpression provided the primary tumor cells with a survival advantage in serum-free media and seemed to induce ligand independent activation of the IGF-IR because RM11A cells cultured in the presence of Dox were largely nonresponsive to exogenous IGFs.	0	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR overexpression	igf-ir	IGF-IR	IGF-IR	igf-ir	0	1	23	24
As demonstrated in normal liver cells in physiological conditions , miR-122 has been suggested to suppress IGF1R expression , by binding to the untranslated region of the messenger , which codifies for IGF1R , thus blocking IGF1R translation .	As demonstrated in normal liver cells in physiological conditions, miR-122 has been suggested to suppress IGF1R expression, by binding to the untranslated region of the messenger, which codifies for IGF1R, thus blocking IGF1R translation.	10	37	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	miR-122 has been suggested to suppress IGF1R expression	igf1r	IGF1R	IGF1R	igf1r	16	17	36	37
Overexpression of beta-arrestin1 by plasmid transfection enhanced the CP induced IGF-1R degradation and down-regulation of beta-arrestin1 by siRNA transfection partially reversed the IGF-1R degradation ( XREF_FIG ) .	Overexpression of beta-arrestin1 by plasmid transfection enhanced the CP induced IGF-1R degradation and down-regulation of beta-arrestin1 by siRNA transfection partially reversed the IGF-1R degradation (XREF_FIG).	0	23	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	Overexpression of beta-arrestin1 by plasmid transfection enhanced the CP induced IGF-1R	igf-1r	IGF-1R	IGF-1R	igf-1r	10	11	22	23
We functionally tested whether cortical neuron specific loss of IGF1R would disrupt the CST development by generating Igf1r loxp and loxp ; Neurod6 Cre mutants .	We functionally tested whether cortical neuron specific loss of IGF1R would disrupt the CST development by generating Igf1r loxp and loxp; Neurod6 Cre mutants.	7	18	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	loss of IGF1R	igf1r	Igf1r	Igf1r	igf1r	9	10	17	18
At 1 ng/ml , TRAIL stimulates IGF1R mRNA expression greater than insulin like growth factor-1 and also activates the IGF1R promoter 7-fold .	At 1 ng/ml, TRAIL stimulates IGF1R mRNA expression greater than insulin like growth factor-1 and also activates the IGF1R promoter 7-fold.	4	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	TRAIL stimulates IGF1R mRNA expression	igf1r	IGF1R	IGF1R	igf1r	6	7	19	20
Moreover , a dynamic interplay between IGF and ERalpha in breast cancer cells has been demonstrated , where IGF-1R increase ERalpha phosphorylation and activity via mTOR and S6K1 and ERalpha mediates IGF-1R , IRS-1 and IGF ligand expression [ XREF_BIBR ] .	Moreover, a dynamic interplay between IGF and ERalpha in breast cancer cells has been demonstrated, where IGF-1R increase ERalpha phosphorylation and activity via mTOR and S6K1 and ERalpha mediates IGF-1R, IRS-1 and IGF ligand expression [XREF_BIBR].	18	38	increase	Positive_regulation_syntax_5_noun	Positive_activation	Positive_regulation	IGF-1R	IGF-1R	igf-1r	IGF-1R	ERalpha phosphorylation and activity via mTOR and S6K1 and ERalpha mediates IGF-1R, IRS-1 and IGF ligand expression	igf-1r	18	19	31	32
MiR-99a negatively regulates IGF1R protein levels and reduces IGF1R signaling .	MiR-99a negatively regulates IGF1R protein levels and reduces IGF1R signaling.	0	9	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	MiR-99a negatively regulates IGF1R protein levels	igf1r	IGF1R	IGF1R	igf1r	3	4	8	9
NRP2 represses IGF-1R expression and inhibits IGF-1R signaling .	NRP2 represses IGF-1R expression and inhibits IGF-1R signaling.	0	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	NRP2 represses IGF-1R expression	igf-1r	IGF-1R	IGF-1R	igf-1r	2	3	6	7
In the present study , rats from the different groups , including the control group , were STZ induced T2D animals that showed variable degrees of hyperglycemia ; however , the IR and IGF-1R however , the IR and IGF1R expression are significantly increased in the GLAR group respect the control group .	In the present study, rats from the different groups, including the control group, were STZ induced T2D animals that showed variable degrees of hyperglycemia; however, the IR and IGF-1R however, the IR and IGF1R expression are significantly increased in the GLAR group respect the control group.	31	44	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R expression	igf1r	IGF-1R	IGF-1R	igf-1r	39	40	33	34
In contrast , overexpression of IGF-IR allowed SHEP and IGF-IR transfectants to survive in media supplemented only by IGF-II .	In contrast, overexpression of IGF-IR allowed SHEP and IGF-IR transfectants to survive in media supplemented only by IGF-II.	3	10	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	overexpression of IGF-IR	igf-ir	IGF-IR	IGF-IR	igf-ir	5	6	9	10
In addition , estradiol induces the expression of IGF-1 and IGF-1R in the brain and activates the signaling cascade of IGF-1R via ERalpha .	In addition, estradiol induces the expression of IGF-1 and IGF-1R in the brain and activates the signaling cascade of IGF-1R via ERalpha.	3	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	estradiol induces the expression of IGF-1 and IGF-1R	igf-1r	IGF-1R	IGF-1R	igf-1r	10	11	20	21
To date , therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor ( IGF-IR ) .	To date, therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor (IGF-IR).	14	22	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	IGF-I receptor	IGF-I receptor	IGF-I receptor	21	22	18	20
It is concluded that there is overexpression of IGF-IR in marrow nucleated cells in MDS and AML cases .	It is concluded that there is overexpression of IGF-IR in marrow nucleated cells in MDS and AML cases.	5	12	is overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	IGF-IR	overexpression of IGF-IR	igf-ir	IGF-IR	IGF-IR	igf-ir	8	9	8	9
In support of this hypothesis , we report here that : ( 1 ) IRS-1 expression increases cell adhesion and decreases cell motility ; ( 2 ) over-expression of the IGF-IR , in the absence of IRS-1 , causes growth arrest and ( 3 ) a combination of IGF-IR and IRS-1 restores the transformed phenotype of LNCaP cells .	In support of this hypothesis, we report here that : (1) IRS-1 expression increases cell adhesion and decreases cell motility; (2) over-expression of the IGF-IR, in the absence of IRS-1, causes growth arrest and (3) a combination of IGF-IR and IRS-1 restores the transformed phenotype of LNCaP cells.	27	50	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	over-expression of the IGF-IR	igf-ir	IGF-IR	IGF-IR	igf-ir	30	31	48	49
The consequences of this mechanism are significant for several reasons , including our finding that Bmi-1 represses transcription of the IGF-1R and abrogates IGF-1R signaling .	The consequences of this mechanism are significant for several reasons, including our finding that Bmi-1 represses transcription of the IGF-1R and abrogates IGF-1R signaling.	15	24	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	Bmi-1 represses transcription of the IGF-1R	igf-1r	IGF-1R	IGF-1R	igf-1r	20	21	23	24
IGF1R and IR/IGF1R hybrids are activated by both IGF1 and -2 , which trigger autophosphorylation of IGF1R and subsequent downstream signal transduction .	IGF1R and IR/IGF1R hybrids are activated by both IGF1 and -2, which trigger autophosphorylation of IGF1R and subsequent downstream signal transduction.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1R	IGF1 and -2, which trigger autophosphorylation of IGF1R	igf1r	IGF1R	IGF1R	igf1r	16	17	0	1
This antibody , m708.5 , potently inhibited both IGF1- and IGF2 induced phosphorylation of IGF1R as well as IGF2 induced phosphorylation of the IR , and less potently growth of MCF-7 cancer cell expressing IGF1R .	This antibody, m708.5, potently inhibited both IGF1- and IGF2 induced phosphorylation of IGF1R as well as IGF2 induced phosphorylation of the IR, and less potently growth of MCF-7 cancer cell expressing IGF1R.	3	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	m708.5, potently inhibited both IGF1- and IGF2 induced phosphorylation of IGF1R	igf1r	IGF1R	IGF1R	igf1r	14	15	34	35
We were able to show here that ad-IGF-IR/950 induced the increased expression of IGF-IR on the cell surface and ad-IGF-IR/482 induced the secretion of the soluble fragment of IGF-IR .	We were able to show here that ad-IGF-IR/950 induced the increased expression of IGF-IR on the cell surface and ad-IGF-IR/482 induced the secretion of the soluble fragment of IGF-IR.	11	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	expression of IGF-IR	igf-ir	IGF-IR	IGF-IR	igf-ir	13	14	28	29
After this switch , independent from tyrosine phosphorylation of the IGF-IR , an entirely different mechanism is utilized to activate the mitogenic ( MAP ) pathways of the IGF-IR .	After this switch, independent from tyrosine phosphorylation of the IGF-IR, an entirely different mechanism is utilized to activate the mitogenic (MAP) pathways of the IGF-IR.	7	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	phosphorylation of the IGF-IR	igf-ir	IGF-IR	IGF-IR	igf-ir	10	11	28	29
As evident from Figure XREF_FIG , IGF1R inhibition significantly decreased invasion of both MDA-MB-231 and BT549 IGF1R-KD cells compared to EV control cells ( p < 0.001 ) .	As evident from Figure XREF_FIG, IGF1R inhibition significantly decreased invasion of both MDA-MB-231 and BT549 IGF1R-KD cells compared to EV control cells (p < 0.001).	6	17	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	IGF1R-KD	IGF1R-KD	IGF1R-KD	6	7	16	17
Despite lack of differential expression for total Igf1r , Igf1r phosphorylation was increased in the Pdgfralpha hi Igf1r hi populations as well as ( modestly ) in the Pdgfralpha lo Igf1r hi population .	Despite lack of differential expression for total Igf1r, Igf1r phosphorylation was increased in the Pdgfralpha hi Igf1r hi populations as well as (modestly) in the Pdgfralpha lo Igf1r hi population.	9	32	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Igf1r	Igf1r phosphorylation	igf1r	Igf1r	Igf1r	igf1r	9	10	17	18
However , it is unclear whether the ubiquitination of IGF-1R driven by these E3 ligases directly regulates the trafficking and signaling transduction of IGF-1R .	However, it is unclear whether the ubiquitination of IGF-1R driven by these E3 ligases directly regulates the trafficking and signaling transduction of IGF-1R.	7	24	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	ubiquitination of IGF-1R	igf-1r	IGF-1R	IGF-1R	igf-1r	9	10	23	24
Ligand activation of IGF-IR results in intrinsic tyrosine kinase phosphorylation and activates downstream adaptor protein IRS-1 and Shc , leading to activation of two main signaling pathways , IRS-1/PI3K/Akt and Ras/Raf/ERK pathways respectively [ XREF_BIBR - XREF_BIBR ] .	Ligand activation of IGF-IR results in intrinsic tyrosine kinase phosphorylation and activates downstream adaptor protein IRS-1 and Shc, leading to activation of two main signaling pathways, IRS-1/PI3K/Akt and Ras/Raf/ERK pathways respectively [XREF_BIBR - XREF_BIBR].	1	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	IRS-1	IRS-1	IRS-1	3	4	15	16
Moreover , the decrease of IGF1R impairs the sensitivity of IRS1 to the stimulation by IGF1 .	Moreover, the decrease of IGF1R impairs the sensitivity of IRS1 to the stimulation by IGF1.	3	11	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	IRS1	IRS1	IRS1	5	6	10	11
Similarly , mammalian target of rapamycin ( m-TOR ) inhibitors can activate PI3K-Akt pathway via loss of negative feedback on IRS-1 ( insulin receptor substrate -- 1 ) , an effect that can be suppressed by IGF-1R blockade [ XREF_BIBR - XREF_BIBR ] .	Similarly, mammalian target of rapamycin (m-TOR) inhibitors can activate PI3K-Akt pathway via loss of negative feedback on IRS-1 (insulin receptor substrate -- 1), an effect that can be suppressed by IGF-1R blockade [XREF_BIBR - XREF_BIBR].	11	37	suppressed	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	IRS-1	IRS-1	IRS-1	36	37	20	21
In cancer cells , IGF-1R activates IRS-1 by stimulating several intracellular signaling proteins such as PI3K and Akt kinase .	In cancer cells, IGF-1R activates IRS-1 by stimulating several intracellular signaling proteins such as PI3K and Akt kinase.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	IRS-1	IRS-1	IRS-1	4	5	6	7
Recently , we demonstrated that IGF-1R kinase inhibitor PQIP causes marked antitumor activity in these colon cancer cell lines by abrogating the IGF-1R mediated activation of IRS1 and Akt to inhibit survival signaling , and inducing apoptosis .	Recently, we demonstrated that IGF-1R kinase inhibitor PQIP causes marked antitumor activity in these colon cancer cell lines by abrogating the IGF-1R mediated activation of IRS1 and Akt to inhibit survival signaling, and inducing apoptosis.	22	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	IRS1	IRS1	IRS1	22	23	26	27
Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot .	Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot.	4	11	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	IRS1	IRS1	IRS1	4	5	10	11
IRS1 activated by IGF-IR recruits intracellular proteins containing SH2 domains , leading to activation of the PI3K-AKT , which is responsible for most of the metabolic actions of insulin , FOXO1 pathways [ XREF_BIBR ] .	IRS1 activated by IGF-IR recruits intracellular proteins containing SH2 domains, leading to activation of the PI3K-AKT, which is responsible for most of the metabolic actions of insulin, FOXO1 pathways [XREF_BIBR].	0	4	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	IRS1	IRS1	IRS1	3	4	0	1
Under normoglycemic conditions vascular smooth muscle and endothelial cells are cystostatic and stimulation of the IGF-I receptor activates the adaptor protein IRS-1 which leads to PI-3 kinase pathway activation .	Under normoglycemic conditions vascular smooth muscle and endothelial cells are cystostatic and stimulation of the IGF-I receptor activates the adaptor protein IRS-1 which leads to PI-3 kinase pathway activation.	15	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I receptor	IGF-I receptor	IGF-I receptor	IRS-1	IRS-1	IRS-1	15	17	21	22
Activation of IGF-IR results in intrinsic tyrosine kinase phosphorylation and activates downstream adaptor protein IRS-1 and Shc , leading to activation of IRS-1/PI3K/Akt [ XREF_BIBR ] .	Activation of IGF-IR results in intrinsic tyrosine kinase phosphorylation and activates downstream adaptor protein IRS-1 and Shc, leading to activation of IRS-1/PI3K/Akt [XREF_BIBR].	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	IRS-1	IRS-1	IRS-1	2	3	14	15
Inhibiting IGF1R in conjunction with mTORC1 inhibition should abrogate this feedback activation of IRS1 , potentially leading to more effective antitumor activity .	Inhibiting IGF1R in conjunction with mTORC1 inhibition should abrogate this feedback activation of IRS1, potentially leading to more effective antitumor activity.	0	14	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	IRS1	IRS1	IRS1	1	2	13	14
Inhibition of IGF-IR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to down-regulate PI3K and AKT signaling and to inhibit cell growth .	Inhibition of IGF-IR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to down-regulate PI3K and AKT signaling and to inhibit cell growth.	2	9	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	IRS-1	IRS-1	IRS-1	2	3	8	9
This compensatory mechanism promotes cell survival because inhibition of IGF-1R activity in either presence or absence of AICAR decreases P-IRS-1 ( Ser794 ) and P-Akt ( Thr308 ) levels and significantly increases apoptotic cell death .	This compensatory mechanism promotes cell survival because inhibition of IGF-1R activity in either presence or absence of AICAR decreases P-IRS-1 (Ser794) and P-Akt (Thr308) levels and significantly increases apoptotic cell death.	9	26	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	P-IRS-1	P-IRS-1	P-IRS-1	9	10	19	20
To investigate the roles of TGFbeta and IGF signaling pathways in miR-130a and miR-145 regulations of myeloid immune function , overexpression constructs of Tgfbr2 , Igf1r , and Irs1 without 3 '-UTR were utilized to prevent the mRNA degradation of TbetaRII , IGF1R and IRS1 in Gr-1 + CD11b + cells by miR-130a or miR-145 .	To investigate the roles of TGFbeta and IGF signaling pathways in miR-130a and miR-145 regulations of myeloid immune function, overexpression constructs of Tgfbr2, Igf1r, and Irs1 without 3 '-UTR were utilized to prevent the mRNA degradation of TbetaRII, IGF1R and IRS1 in Gr-1 + CD11b + cells by miR-130a or miR-145.	21	45	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Igf1r	Igf1r	Igf1r	IRS1	IRS1	IRS1	25	26	44	45
The inhibition of IGF-IR by siRNA and PPP downregulated pIRS-1 , pAKT , and pSTAT3 and induced caspase-3 cleavage in MCL .	The inhibition of IGF-IR by siRNA and PPP downregulated pIRS-1, pAKT, and pSTAT3 and induced caspase-3 cleavage in MCL.	1	14	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	pIRS-1	pIRS-1	pIRS-1	3	4	9	10
These cells lack IRS-1 and -2 expression , yet express functional IGF-IR , allowing us to investigate whether IGF-IR activation stimulates cell proliferation and motility in the absence of IRS-1 and -2 .	These cells lack IRS-1 and -2 expression, yet express functional IGF-IR, allowing us to investigate whether IGF-IR activation stimulates cell proliferation and motility in the absence of IRS-1 and -2.	18	31	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	IGF-IR	IGF-IR	IRS-1	IRS-1	IRS-1	18	19	29	30
IGF-1 and IGF-1R induces differentiation rather than proliferation when the cells do not express or underexpress insulin receptor substrate-1 ( IRS-1 ) , a docking protein for both IGF-1R and the insulin receptor that is known to send a mitogenic , anti-apoptotic and anti-differentiation signal XREF_BIBR XREF_BIBR .	IGF-1 and IGF-1R induces differentiation rather than proliferation when the cells do not express or underexpress insulin receptor substrate-1 (IRS-1), a docking protein for both IGF-1R and the insulin receptor that is known to send a mitogenic, anti-apoptotic and anti-differentiation signal XREF_BIBR XREF_BIBR.	0	19	induces	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IGF-1R	IGF-1R	igf-1r	insulin receptor substrate-1	express or underexpress insulin receptor substrate-1	insulin receptor substrate-1	2	3	16	19
This suggests that IFNbeta stimulates IFNAR on the endothelial cells and activates an intracellular pathway that preserves TJ proteins in the setting of OGD .	This suggests that IFNbeta stimulates IFNAR on the endothelial cells and activates an intracellular pathway that preserves TJ proteins in the setting of OGD.	3	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFNbeta	IFNbeta	IFNbeta	IFNAR	IFNAR	IFNAR	3	4	5	6
Secretion of IFN-beta activates the IFNAR complex in an autocrine manner .	Secretion of IFN-beta activates the IFNAR complex in an autocrine manner.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	IFNAR	IFNAR	IFNAR	2	3	5	6
Taken together , the HCC cells that express low IFNAR2 and are resistant to IFN-alpha were sensitive to the growth-inhibitory effect of IFN-beta , which might be mediated by stronger IFN signal transduction and distinct binding to IFNAR compared to IFN-alpha .	Taken together, the HCC cells that express low IFNAR2 and are resistant to IFN-alpha were sensitive to the growth-inhibitory effect of IFN-beta, which might be mediated by stronger IFN signal transduction and distinct binding to IFNAR compared to IFN-alpha.	20	40	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	IFNAR	IFNAR	IFNAR	22	23	37	38
Several studies have demonstrated that IFNbeta induces endocytosis and degradation of IFNAR1 to regulate the cell signaling [ XREF_BIBR - XREF_BIBR ] en just 30 minutes after IFNbeta stimulation , a down-regulation of IFNAR1 has been described in some cell lines , while IFNAR2 expression displayed a considerably slower basal turnover and the extent of its down-regulation diminished as IFNAR1 expression decreased in cells [ XREF_BIBR ] .	Several studies have demonstrated that IFNbeta induces endocytosis and degradation of IFNAR1 to regulate the cell signaling [XREF_BIBR - XREF_BIBR] en just 30 minutes after IFNbeta stimulation, a down-regulation of IFNAR1 has been described in some cell lines, while IFNAR2 expression displayed a considerably slower basal turnover and the extent of its down-regulation diminished as IFNAR1 expression decreased in cells [XREF_BIBR].	5	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFNbeta	IFNbeta	IFNbeta	IFNAR1	IFNAR1	IFNAR1	5	6	11	12
To activate Ifnar signaling , primary macrophages were treated with IFN-beta , and the levels of caspase-11 and NOS2 , Ifnar dependent transcripts , were measured .	To activate Ifnar signaling, primary macrophages were treated with IFN-beta, and the levels of caspase-11 and NOS2, Ifnar dependent transcripts, were measured.	2	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	Ifnar	Ifnar	Ifnar	10	11	2	3
We thus isolated LCVs from B6 wt and IFNAR-/- BMMs treated or not treated with IFNbeta and assessed recruitment of the ER marker Calnexin or the endolysosomal marker Lamp-1 .	We thus isolated LCVs from B6 wt and IFNAR-/- BMMs treated or not treated with IFNbeta and assessed recruitment of the ER marker Calnexin or the endolysosomal marker Lamp-1.	8	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFNbeta	IFNbeta	IFNbeta	IFNAR-/-	IFNAR-/-	IFNAR-/-	15	16	8	9
Although IFN-lambda transcripts were strongly up-regulated to similar levels in intestines of all mouse strains examined , IFN-beta transcripts were induced less efficiently with considerably weaker IFN-beta induction in Ifnar1 -/- Ifnlr1 -/- mice than in WT or Ifnlr1 -/- mice ( XREF_FIG ) , possibly due to the absence of a positive feedback loop in these animals .	Although IFN-lambda transcripts were strongly up-regulated to similar levels in intestines of all mouse strains examined, IFN-beta transcripts were induced less efficiently with considerably weaker IFN-beta induction in Ifnar1 -/- Ifnlr1 -/- mice than in WT or Ifnlr1 -/- mice (XREF_FIG), possibly due to the absence of a positive feedback loop in these animals.	26	31	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	Ifnar1	Ifnar1	Ifnar1	26	27	29	30
The IFN-beta-mediated induction of CTLA-4 and IFNAR was enriched in the FOXP3 + subset but was not exclusive to FOXP3 + Tregs because IFN-beta also induced a CTLA-4 + IFNAR + Tconv subset ( data not shown ) .	The IFN-beta-mediated induction of CTLA-4 and IFNAR was enriched in the FOXP3 + subset but was not exclusive to FOXP3 + Tregs because IFN-beta also induced a CTLA-4 + IFNAR + Tconv subset (data not shown).	23	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	IFNAR	IFNAR	IFNAR	23	24	29	30
Both IFNalpha and IFNbeta signal through a common receptor IFNAR that consists of IFNAR1 and IFNAR2 chains .	Both IFNalpha and IFNbeta signal through a common receptor IFNAR that consists of IFNAR1 and IFNAR2 chains.	1	16	signal	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IFNbeta	IFNbeta	IFNbeta	IFNAR1	IFNAR1	IFNAR1	3	4	13	14
The overall results show an increase in IFNAR1 level in MS patients treated with IFN-B .	The overall results show an increase in IFNAR1 level in MS patients treated with IFN-B.	7	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFN-B	IFN-B	IFN-B	IFNAR1	IFNAR1	IFNAR1	14	15	7	8
IFN-beta then activates IFNAR in an auto- and paracrine manner .	IFN-beta then activates IFNAR in an auto- and paracrine manner.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	IFNAR	IFNAR	IFNAR	0	1	3	4
While IFN-alpha production in IFN-beta 2/- mice could have been promoted by priming with natural type I IFN , produced pathogen independently , IFN-alpha production in IFN-beta and IFNAR double deficient mice indicated that IFNAR triggering was not a prerequisite for early IFN-alpha production .	While IFN-alpha production in IFN-beta 2/- mice could have been promoted by priming with natural type I IFN, produced pathogen independently, IFN-alpha production in IFN-beta and IFNAR double deficient mice indicated that IFNAR triggering was not a prerequisite for early IFN-alpha production.	4	29	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	IFNAR	IFNAR	IFNAR	4	5	28	29
For example , IFN-beta , but not IFN-alpha , induces the association of tyrosine phosphorylated receptor components ifnar1 and ifnar2 , and has activity in cells lacking the IFN receptor associated , Janus kinase tyk2 .	For example, IFN-beta, but not IFN-alpha, induces the association of tyrosine phosphorylated receptor components ifnar1 and ifnar2, and has activity in cells lacking the IFN receptor associated, Janus kinase tyk2.	3	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	ifnar1	ifnar1	ifnar1	3	4	17	18
RIG-I regulated IFN-beta secretions from infected cells could lead to the Trif activation observed here and the IFNAR1 and 2 receptor induction , which represent two plausible and distinct mechanisms to induce protease production .	RIG-I regulated IFN-beta secretions from infected cells could lead to the Trif activation observed here and the IFNAR1 and 2 receptor induction, which represent two plausible and distinct mechanisms to induce protease production.	2	21	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	IFNAR1	IFNAR1	IFNAR1	2	3	17	18
As expected , Oct-6 was not upregulated by IFNbeta in cells lacking the IFNalpha and beta receptor subunit Ifnar1 , excluding the possibility that effects are mediated by any other component that might be present in the IFNbeta preparation .	As expected, Oct-6 was not upregulated by IFNbeta in cells lacking the IFNalpha and beta receptor subunit Ifnar1, excluding the possibility that effects are mediated by any other component that might be present in the IFNbeta preparation.	6	19	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFNbeta	IFNbeta	IFNbeta	Ifnar1	Ifnar1	Ifnar1	8	9	18	19
In this pathway , IFN-beta stimulates the cell-surface receptor subunits IFNAR1 and IFNAR2 to activate associated JAK family members JAK1 and TYK2 .	In this pathway, IFN-beta stimulates the cell-surface receptor subunits IFNAR1 and IFNAR2 to activate associated JAK family members JAK1 and TYK2.	4	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	IFNAR1	IFNAR1	IFNAR1	4	5	10	11
Since chronic cell stimulation by interferon-beta induces IFNAR protein down-regulation , we suggest that the increase of IFNAR1 mRNA might serve as a mechanism for counterbalancing the loss of protein receptor , enhancing , at least in this sub-group of patients , cell responsiveness to interferon-beta .	Since chronic cell stimulation by interferon-beta induces IFNAR protein down-regulation, we suggest that the increase of IFNAR1 mRNA might serve as a mechanism for counterbalancing the loss of protein receptor, enhancing, at least in this sub-group of patients, cell responsiveness to interferon-beta.	3	9	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	interferon-beta	interferon-beta	interferon-beta	IFNAR	IFNAR	IFNAR	5	6	7	8
IFN-beta induced early during Chlamydia infection requires TLR3 signaling , but does not involve IFNAR .	IFN-beta induced early during Chlamydia infection requires TLR3 signaling, but does not involve IFNAR.	0	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	IFNAR	IFNAR	IFNAR	0	1	14	15
In brief , wild-type ( WT ) , scrambled shRNA-, or IFNGR1 shRNA transduced B16 and BL6 melanoma cells were treated with different doses of IFN-gamma ( 0-1000 U/mL ) for 48 h ( dose response studies ) .	In brief, wild-type (WT), scrambled shRNA-, or IFNGR1 shRNA transduced B16 and BL6 melanoma cells were treated with different doses of IFN-gamma (0-1000 U/mL) for 48 h (dose response studies).	9	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IFN-gamma	IFN-gamma	IFN-gamma	IFNGR1	IFNGR1	IFNGR1	25	26	11	12
We were thus interested in the possible association of activated JAK2 and JAK1 in the IFNgamma , IFNGR1 , and pSTAT1alpha complex formed in cells treated with IFNgamma at the cytoplasmic , nuclear , and specific gene level .	We were thus interested in the possible association of activated JAK2 and JAK1 in the IFNgamma, IFNGR1, and pSTAT1alpha complex formed in cells treated with IFNgamma at the cytoplasmic, nuclear, and specific gene level.	7	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFNgamma	IFNgamma	IFNgamma	IFNGR1	IFNGR1	IFNGR1	27	28	17	18
IFN-gamma receptor chain 1 ( IFNGR-1 ) tyrosine phosphorylation is markedly enhanced in cells treated with TNF-alpha and IFN-gamma without alteration in receptor levels .	IFN-gamma receptor chain 1 (IFNGR-1) tyrosine phosphorylation is markedly enhanced in cells treated with TNF-alpha and IFN-gamma without alteration in receptor levels.	0	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	IFNGR-1	IFNGR-1	IFNGR-1	18	19	5	6
Binding of IFN-gamma induces rearrangement of the intracellular domains of both IFN-gammaR1 and IFN-gammaR2 thereby allowing more space for downstream signaling components to bind .	Binding of IFN-gamma induces rearrangement of the intracellular domains of both IFN-gammaR1 and IFN-gammaR2 thereby allowing more space for downstream signaling components to bind.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	IFN-gammaR1	IFN-gammaR1	IFN-gammaR1	2	3	11	12
Cell surface binding of interferon-gamma ( IFNgamma ) induces dimerization of the two receptor subunits IFNGR1 and IFNGR2 which is followed by the auto-phosphorylation of non covalently receptor associated Janus kinases ( JAKs ) .	Cell surface binding of interferon-gamma (IFNgamma) induces dimerization of the two receptor subunits IFNGR1 and IFNGR2 which is followed by the auto-phosphorylation of non covalently receptor associated Janus kinases (JAKs).	2	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interferon-gamma	interferon-gamma	interferon-gamma	IFNGR1	IFNGR1	IFNGR1	4	5	15	16
The function of Th1 cells is presumably impaired due to disruption of IFN-gamma signaling in Ifngr -/- mice .	The function of Th1 cells is presumably impaired due to disruption of IFN-gamma signaling in Ifngr -/- mice.	12	17	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	Ifngr	Ifngr	Ifngr	12	13	15	16
Association of pJAK1 and pJAK2 with IFNGR1 in cells treated with IFNgamma .	Association of pJAK1 and pJAK2 with IFNGR1 in cells treated with IFNgamma.	0	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFNgamma	IFNgamma	IFNgamma	IFNGR1	IFNGR1	IFNGR1	11	12	6	7
IFNgamma treatment ( 48h ) induced normal [ XREF_BIBR ] decline of IFNGR1 by receptor internalization ( not shown ) in all tested cell lines .	IFNgamma treatment (48h) induced normal [XREF_BIBR] decline of IFNGR1 by receptor internalization (not shown) in all tested cell lines.	0	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFNgamma	IFNgamma	IFNgamma	IFNGR1	IFNGR1	IFNGR1	0	1	12	13
By ELISA , we did not observe any significant alteration of the total amounts of IFN-gammaR1 and -R2 in Jurkat cells treated with fg SKA IFN-gamma ( 10 fg/mL ) for 24 , 48 , 72 , and 96 h vs. their controls exposed to SKA Physiological Solution alone ( SKA PS , the same amount used for fg SKA IFN-gamma ) ( XREF_FIG a , b ) .	By ELISA, we did not observe any significant alteration of the total amounts of IFN-gammaR1 and -R2 in Jurkat cells treated with fg SKA IFN-gamma (10 fg/mL) for 24, 48, 72, and 96 h vs. their controls exposed to SKA Physiological Solution alone (SKA PS, the same amount used for fg SKA IFN-gamma) (XREF_FIG a, b).	13	51	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	IFN-gammaR1	IFN-gammaR1	IFN-gammaR1	25	26	15	16
As indicated earlier , JAK2 moves from the cytoplasmic domain of IFNGR2 to IFNGR1 in cells treated with IFNgamma via a previously unknown mechanism .	As indicated earlier, JAK2 moves from the cytoplasmic domain of IFNGR2 to IFNGR1 in cells treated with IFNgamma via a previously unknown mechanism.	11	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFNgamma	IFNgamma	IFNgamma	IFNGR1	IFNGR1	IFNGR1	18	19	13	14
IFN-gamma also signals through a heterodimeric receptor , consisting of IFNGR1 and IFNGR2 associated with Jak1 and Jak2 respectively .	IFN-gamma also signals through a heterodimeric receptor, consisting of IFNGR1 and IFNGR2 associated with Jak1 and Jak2 respectively.	0	13	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	IFNGR1	IFNGR1	IFNGR1	0	1	10	11
Notably , inhibiting GSK-3 decreased Con A induced IFN-gamma production in both wild-type and IFN-gamma receptor 1 deficient C57BL/6 mice .	Notably, inhibiting GSK-3 decreased Con A induced IFN-gamma production in both wild-type and IFN-gamma receptor 1 deficient C57BL/6 mice.	3	17	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IFN-gamma	GSK-3 decreased Con A induced IFN-gamma	ifn-gamma	IFN-gamma receptor 1	IFN-gamma receptor 1	ifn-gamma receptor 1	8	9	14	17
IFN-gamma signals through a heterodimeric transmembrane receptor that consists of the subunits IFNGR1 and IFNGR2 .	IFN-gamma signals through a heterodimeric transmembrane receptor that consists of the subunits IFNGR1 and IFNGR2.	0	14	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	IFNGR1	IFNGR1	IFNGR1	0	1	12	13
Cell surface binding of IFN-gamma induces dimerization of its receptor subunits ( IFNGR1 and IFNGR2 ) and subsequent activation of the receptor associated JAK kinases 1 and 2 .	Cell surface binding of IFN-gamma induces dimerization of its receptor subunits (IFNGR1 and IFNGR2) and subsequent activation of the receptor associated JAK kinases 1 and 2.	2	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	IFNGR1	IFNGR1	IFNGR1	4	5	12	13
Here , we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 ( PTEN ) transcription through downregulation of p53 .	Here, we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription through downregulation of p53.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Id-1	Id-1	Id-1	Akt	Akt	Akt	5	6	8	9
After finding that Id1 activated PI3K , Akt , and NFkappaB , we wished to demonstrate that PI3K and Akt is required for the Id1 mediated activation of NFkappaB .	After finding that Id1 activated PI3K, Akt, and NFkappaB, we wished to demonstrate that PI3K and Akt is required for the Id1 mediated activation of NFkappaB.	3	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Id1	Id1	Id1	Akt	Akt	Akt	3	4	7	8
Furthermore , BMP and Id1 can activate AKT via PTEN repression , however , this is unlikely to be the only mechanism responsible .	Furthermore, BMP and Id1 can activate AKT via PTEN repression, however, this is unlikely to be the only mechanism responsible.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Id1	Id1	Id1	AKT	AKT	AKT	4	5	7	8
In the present study , we observed that Id1 activated the PI3K and Akt signalling pathway in the regulation of EPC proliferation .	In the present study, we observed that Id1 activated the PI3K and Akt signalling pathway in the regulation of EPC proliferation.	8	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Id1	Id1	Id1	Akt	Akt	Akt	8	9	13	14
In one study on breast cancer cell , ID-1 was reported to activate the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 transcription through down-regulation of p53 23 , suggesting an ID-1-mediated change of p53 level .	In one study on breast cancer cell, ID-1 was reported to activate the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 transcription through down-regulation of p53 23, suggesting an ID-1-mediated change of p53 level.	8	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ID-1	ID-1	ID-1	Akt	Akt	Akt	8	9	14	15
It has been documented that Id1 activates Akt through the PI3K pathway .	It has been documented that Id1 activates Akt through the PI3K pathway.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Id1	Id1	Id1	Akt	Akt	Akt	5	6	7	8
As Id1 was known to promote Akt activation via phosphorylation in lung cancer and other caner types [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , we also examined whether treatment of paclitaxel and cisplatin affected the expression level of phosphorylated Akt .	As Id1 was known to promote Akt activation via phosphorylation in lung cancer and other caner types [XREF_BIBR, XREF_BIBR, XREF_BIBR], we also examined whether treatment of paclitaxel and cisplatin affected the expression level of phosphorylated Akt.	1	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Id1	Id1	Id1	Akt	Akt	Akt	1	2	6	7
For example , while little is presently known about the impact of pERK on MCF7 Id1 , in esophageal cancer Id1 promotes tumorigenesis in part by phospho activation of Akt , and this effect is reflected in Id1 overexpressing MCF7 cells where Id1 also activates the Akt pathway .	For example, while little is presently known about the impact of pERK on MCF7 Id1, in esophageal cancer Id1 promotes tumorigenesis in part by phospho activation of Akt, and this effect is reflected in Id1 overexpressing MCF7 cells where Id1 also activates the Akt pathway.	42	47	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Id1	Id1	Id1	Akt	Akt	Akt	42	43	46	47
Id1 activates the PI3K and Akt , PI3K/Akt/NFkappaB , and NFkappaB and survivin signalling pathways , and protects cancer cells from apoptosis in vitro [ XREF_BIBR - XREF_BIBR ] .	Id1 activates the PI3K and Akt, PI3K/Akt/NFkappaB, and NFkappaB and survivin signalling pathways, and protects cancer cells from apoptosis in vitro [XREF_BIBR - XREF_BIBR].	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Id1	Id1	Id1	Akt	Akt	Akt	0	1	5	6
The latter after interaction with receptors IFN-gamma receptor 1 induces consecutive activation of Janus kinase 1 , tyrosine kinase 2 , and STAT1/2 , then activation of IFN stimulated genes and suppression of SREBP2 transcriptional factor .	The latter after interaction with receptors IFN-gamma receptor 1 induces consecutive activation of Janus kinase 1, tyrosine kinase 2, and STAT1/2, then activation of IFN stimulated genes and suppression of SREBP2 transcriptional factor.	6	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-gamma receptor 1	IFN-gamma receptor 1	IFN-gamma receptor 1	Janus kinase 1	Janus kinase 1	Janus kinase 1	6	9	13	16
In this study , we identified that IFN-beta stimulates IL-10 production by activating the JAK1- and PI3K signaling pathways .	In this study, we identified that IFN-beta stimulates IL-10 production by activating the JAK1- and PI3K signaling pathways.	7	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	JAK1-	JAK1-	JAK1-	7	8	14	15
In the current study , we identified that IFN-beta stimulates IL-10 production by activating the JAK1- and PI3K signaling pathways .	In the current study, we identified that IFN-beta stimulates IL-10 production by activating the JAK1- and PI3K signaling pathways.	8	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	JAK1-	JAK1-	JAK1-	8	9	15	16
Similar to the effects of JAK1 inhibition on the levels of phosphorylated Akt , IFN-beta stimulation of JAK1 deficient MEFs or human DC treated with a JAK inhibitor did not induce any discernible increase in the levels of GSK3-beta ( S9 ) compared with nonstimulated control cells ( XREF_FIG ) .	Similar to the effects of JAK1 inhibition on the levels of phosphorylated Akt, IFN-beta stimulation of JAK1 deficient MEFs or human DC treated with a JAK inhibitor did not induce any discernible increase in the levels of GSK3-beta (S9) compared with nonstimulated control cells (XREF_FIG).	14	19	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	JAK1	JAK1	JAK1	14	15	17	18
IFN-alpha and IFN-beta stimulate the activity of JAK1 and TYK2 proteins , leading to STAT1 and STAT2 tyrosine phosphorylation , and ultimately induce IL-4 secretion and subsequent activation of B cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	IFN-alpha and IFN-beta stimulate the activity of JAK1 and TYK2 proteins, leading to STAT1 and STAT2 tyrosine phosphorylation, and ultimately induce IL-4 secretion and subsequent activation of B cells [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	JAK1	JAK1	JAK1	2	3	7	8
In the canonical type I IFN induced signaling pathway , IFN-beta activates Janus kinase 1 and tyrosine kinase 2 , which phosphorylate the cytoplasmic transcription factors signal transducer and activator of transcription 1 ( STAT1 ) and STAT2 XREF_BIBR , XREF_BIBR .	In the canonical type I IFN induced signaling pathway, IFN-beta activates Janus kinase 1 and tyrosine kinase 2, which phosphorylate the cytoplasmic transcription factors signal transducer and activator of transcription 1 (STAT1) and STAT2 XREF_BIBR, XREF_BIBR.	10	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	Janus kinase 1	Janus kinase 1	Janus kinase 1	10	11	12	15
For instance , only IFNbeta induced JAK1 activation in human myocardial fibroblasts , and this was associated with a 120-fold higher potency to trigger an anti-viral response ( vs IFNalpha ) ; also in human vascular endothelial cells , a 2-3 log difference was observed for IFNbeta vs IFNalpha in functional assays , and IFNbeta was 100-fold more potent than IFNalpha with respect to the inhibition of differentiation of human monocytes into osteoclasts .	For instance, only IFNbeta induced JAK1 activation in human myocardial fibroblasts, and this was associated with a 120-fold higher potency to trigger an anti-viral response (vs IFNalpha); also in human vascular endothelial cells, a 2-3 log difference was observed for IFNbeta vs IFNalpha in functional assays, and IFNbeta was 100-fold more potent than IFNalpha with respect to the inhibition of differentiation of human monocytes into osteoclasts.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IFNbeta	IFNbeta	IFNbeta	JAK1	JAK1	JAK1	4	5	6	7
IFNbeta is secreted by BMDMs following LPS stimulation and is also able to activate JAK1 and Tyk2 signaling .	IFNbeta is secreted by BMDMs following LPS stimulation and is also able to activate JAK1 and Tyk2 signaling.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFNbeta	IFNbeta	IFNbeta	JAK1	JAK1	JAK1	0	1	14	15
These placentas may be viewed as IGF resistant tissue where IGF1 signaling is blunted due to reduced expression of the IGF1R ; impairment of the IRS-2 and phosphatidyl inositol 3-kinase pathway ; and reduced p38 and c-Jun N-terminal kinase activation [ XREF_BIBR ] .	These placentas may be viewed as IGF resistant tissue where IGF1 signaling is blunted due to reduced expression of the IGF1R; impairment of the IRS-2 and phosphatidyl inositol 3-kinase pathway; and reduced p38 and c-Jun N-terminal kinase activation [XREF_BIBR].	17	30	impairment	Negative_activation_syntax_7_noun	Positive_activation	Positive_activation	IGF1R	expression of the IGF1R	igf1r	IRS-2	IRS-2	irs-2	20	21	25	26
Since AFB1 induces IGF-IR phosphorylation , up-regulates IRS2 , but down-regulates IRS1 , it is unclear how AFB1 may affect hepatoma cell proliferation .	Since AFB1 induces IGF-IR phosphorylation, up-regulates IRS2, but down-regulates IRS1, it is unclear how AFB1 may affect hepatoma cell proliferation.	1	8	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-IR	AFB1 induces IGF-IR phosphorylation	igf-ir	IRS2	IRS2	irs2	3	4	7	8
We further demonstrate that disruption of the IGF-1R decreases mammary epithelial cell expression of the signaling intermediates insulin receptor substrate ( IRS ) -1 and IRS-2 .	We further demonstrate that disruption of the IGF-1R decreases mammary epithelial cell expression of the signaling intermediates insulin receptor substrate (IRS) -1 and IRS-2.	4	26	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	IRS-2	IRS-2	IRS-2	7	8	25	26
Since IRS-1 is required for IGF-1R stimulation of cell proliferation and IRS-2 is involved in cancer motility and metastasis , 98 inhibition of their function or expression could be therapeutically exploited .	Since IRS-1 is required for IGF-1R stimulation of cell proliferation and IRS-2 is involved in cancer motility and metastasis, 98 inhibition of their function or expression could be therapeutically exploited.	5	12	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	IRS-2	IRS-2	IRS-2	5	6	11	12
Furthermore , by activating ERK1/2 , IGF-1R transcriptionally upregulated IRS-2 .	Furthermore, by activating ERK1/2, IGF-1R transcriptionally upregulated IRS-2.	6	10	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	IRS-2	IRS-2	IRS-2	6	7	9	10
This interaction phosphorylates IGF1R to further activate insulin receptor substrate 2 ( IRS2 ) and insulin receptor substrate 4 ( IRS4 ) .	This interaction phosphorylates IGF1R to further activate insulin receptor substrate 2 (IRS2) and insulin receptor substrate 4 (IRS4).	2	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	phosphorylates IGF1R	igf1r	IRS2	IRS2	irs2	3	4	12	13
Complementarily , IGF-1R preferentially activates IRS-2 [ XREF_BIBR ] as it was found that IRS-2 contains a KLRB domain that functions to block the tyrosine kinase domain in the cytoplasmic region of the IR , and that such does not happen in the IGF-1R .	Complementarily, IGF-1R preferentially activates IRS-2 [XREF_BIBR] as it was found that IRS-2 contains a KLRB domain that functions to block the tyrosine kinase domain in the cytoplasmic region of the IR, and that such does not happen in the IGF-1R.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	IRS-2	IRS-2	IRS-2	2	3	5	6
IFNgamma signaling of naive T cells causes a down regulation of IFNgammaR2 and an up regulation of IL-12Rbeta2 .	IFNgamma signaling of naive T cells causes a down regulation of IFNgammaR2 and an up regulation of IL-12Rbeta2.	0	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFNgamma	IFNgamma	IFNgamma	IFNgammaR2	IFNgammaR2	IFNgammaR2	0	1	11	12
The diagnosis of partial IFN-gammaR2 deficiency is clinically useful , as affected patients should be treated with IFN-gamma , [ corrected ] unlike patients with complete IFN-gammaR2 deficiency .	The diagnosis of partial IFN-gammaR2 deficiency is clinically useful, as affected patients should be treated with IFN-gamma, [corrected] unlike patients with complete IFN-gammaR2 deficiency.	4	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	IFN-gammaR2	IFN-gammaR2	IFN-gammaR2	17	18	4	5
Consistent with the role of Tyk2 in the regulation of tyrosyl phosphorylation of STAT3 , expression of constitutively active STAT3 ( S3C ) could restore the mitochondrial respiration and IFN-beta-stimulated apoptosis in Tyk2 -/- cells treated with IFN-beta .	Consistent with the role of Tyk2 in the regulation of tyrosyl phosphorylation of STAT3, expression of constitutively active STAT3 (S3C) could restore the mitochondrial respiration and IFN-beta-stimulated apoptosis in Tyk2 -/- cells treated with IFN-beta.	27	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	Tyk2	Tyk2	Tyk2	37	38	32	33
Prior exposure to cur-cumin also induced a moderate increase of IFNAR2 by IFN-beta ( XREF_FIG ) .	Prior exposure to cur-cumin also induced a moderate increase of IFNAR2 by IFN-beta (XREF_FIG).	5	14	increase	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IFN-beta	IFN-beta	IFN-beta	IFNAR2	IFNAR2	IFNAR2	12	13	10	11
In cardiomyocytes , insulin like growth factor-1 ( IGF-1 ) , the survival factor through which IGF-1 receptor ( IGF-1R ) activates the phosphatidylinositol-3 kinase and protein kinase B and the Ras-Raf-MEK-ERK ( Ras-Raf-mitogen-activated protein kinase-extracellular receptor kinase ) pathways , should be taken into consideration for preventing myocyte apoptosis .	In cardiomyocytes, insulin like growth factor-1 (IGF-1), the survival factor through which IGF-1 receptor (IGF-1R) activates the phosphatidylinositol-3 kinase and protein kinase B and the Ras-Raf-MEK-ERK (Ras-Raf-mitogen-activated protein kinase-extracellular receptor kinase) pathways, should be taken into consideration for preventing myocyte apoptosis.	17	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	protein kinase B	protein kinase B	protein kinase B	19	20	26	29
IGF1R phosphorylates its adapter protein , insulin receptor substrate 1 ( IRS1 ) , to indirectly activate AKT1 , a serine/threonine protein kinase involved in adipocyte metabolism .	IGF1R phosphorylates its adapter protein, insulin receptor substrate 1 (IRS1), to indirectly activate AKT1, a serine/threonine protein kinase involved in adipocyte metabolism.	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	AKT1	AKT1	AKT1	0	1	17	18
IGF1R mRNA silencing caused an 80 % reduction in Akt1 mRNA in mtDNA depleted cells and 10 % reduction in reverted cells , but no change in control cells ( XREF_FIG B ) .	IGF1R mRNA silencing caused an 80% reduction in Akt1 mRNA in mtDNA depleted cells and 10% reduction in reverted cells, but no change in control cells (XREF_FIG B).	0	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	Akt1	Akt1	Akt1	0	1	9	10
Briefly , IFN-gamma stimulated ( 50 U/mL , or dose response as indicated ) Nramp1 + or Nramp1 - macrophages were seeded at a density of 4 x 10 5 cells into 24-well tissue culture plates and cultured for 16 h. Activated macrophages were infected at a multiplicity of infection ( MOI ) of 1 and incubated at 37degreesC , 5 % CO 2 .	Briefly, IFN-gamma stimulated (50 U/mL, or dose response as indicated) Nramp1 + or Nramp1 - macrophages were seeded at a density of 4 x 10 5 cells into 24-well tissue culture plates and cultured for 16 h. Activated macrophages were infected at a multiplicity of infection (MOI) of 1 and incubated at 37degreesC, 5% CO 2.	2	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	Nramp1	Nramp1	Nramp1	2	3	14	15
IFN-gamma expression was significantly increased in both Salmonella infected and DSS treated ( to induce colitis ) SLC11A1 +/+ mice , compared to congenic SLC11A1 deficient mice .	IFN-gamma expression was significantly increased in both Salmonella infected and DSS treated (to induce colitis) SLC11A1 +/+ mice, compared to congenic SLC11A1 deficient mice.	0	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma expression	ifn-gamma	SLC11A1	SLC11A1	slc11a1	0	1	17	18
Levels of CIITA and RFX5 increase in the nucleus of cells treated with IFN-gamma .	Levels of CIITA and RFX5 increase in the nucleus of cells treated with IFN-gamma.	2	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	RFX5	RFX5	RFX5	13	14	4	5
Class II transactivator , when bound to GTP [ XREF_BIBR ] , enters the nucleus and activates transcription of its target genes via activation of the transcription factor DNA binding protein RFX5 ( RFX5 ) which itself was upregulated by IFN-gamma treatment , in PLB-985 cells , this study ( XREF_TABLE ) .	Class II transactivator, when bound to GTP [XREF_BIBR], enters the nucleus and activates transcription of its target genes via activation of the transcription factor DNA binding protein RFX5 (RFX5) which itself was upregulated by IFN-gamma treatment, in PLB-985 cells, this study (XREF_TABLE).	17	41	upregulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IFN-gamma	IFN-gamma	IFN-gamma	RFX5	RFX5	RFX5	40	41	33	34
In this report , we investigated whether and how ICK targets Raptor to regulate the activity of mTORC1 .	In this report, we investigated whether and how ICK targets Raptor to regulate the activity of mTORC1.	9	13	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ICK	ICK	ICK	Raptor	Raptor	Raptor	9	10	11	12
Both IGF-I and -II induced significant down-regulation of IGF-I receptor mRNA .	Both IGF-I and -II induced significant down-regulation of IGF-I receptor mRNA.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	1	2	8	10
In these lung cancer cells , TM4SF4 overexpression increased the expression of IGF1 , a ligand that activates IGF1R , which appears to be a key event in activation of the IGF1R pathway .	In these lung cancer cells, TM4SF4 overexpression increased the expression of IGF1, a ligand that activates IGF1R, which appears to be a key event in activation of the IGF1R pathway.	6	26	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IGF1	TM4SF4 overexpression increased the expression of IGF1	igf1	IGF1R	IGF1R	igf1r	12	13	18	19
IGF-R overexpression has been observed in several OS cell lines , and is reliant on activation of IGF-1R by IGF- 1 to stimulate OS cell growth and metastatic dormancy in in vivo and in vitro [ XREF_BIBR , XREF_BIBR ] .	IGF-R overexpression has been observed in several OS cell lines, and is reliant on activation of IGF-1R by IGF- 1 to stimulate OS cell growth and metastatic dormancy in in vivo and in vitro [XREF_BIBR, XREF_BIBR].	15	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF- 1	IGF- 1	IGF- 1	IGF-1R	IGF-1R	IGF-1R	19	21	17	18
The conventional consensus posited that leptin and IGF1 cross the blood-brain-barrier ( BBB ) and consequently elicit their effects by activating their respective receptors , Ob-Rb ( leptin receptor isoform b ) and IGF1R that are widely expressed in the brain .	The conventional consensus posited that leptin and IGF1 cross the blood-brain-barrier (BBB) and consequently elicit their effects by activating their respective receptors, Ob-Rb (leptin receptor isoform b) and IGF1R that are widely expressed in the brain.	5	38	elicit	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IGF1	IGF1	igf1	IGF1R	IGF1R that are widely expressed	igf1r	7	8	33	34
The eAd suppressed the signal transduction of IGF-1R mediated by exogenous IGF-I or IGF-II in breast cancer cell lines through neutralizing both IGF-I and IGF-II .	The eAd suppressed the signal transduction of IGF-1R mediated by exogenous IGF-I or IGF-II in breast cancer cell lines through neutralizing both IGF-I and IGF-II.	5	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-1R	IGF-1R	IGF-1R	11	12	7	8
In experiments conducted using cells homozygously transfected with the IGF-IR R431L mutation ; ( i ) IGF-I binding was not affected ; ( ii ) DNA synthesis induced by IGF-I was decreased ; ( iii ) IGF-IR internalization stimulated by IGF-I was decreased and ( iv ) IGF-I-stimulated tyrosine phosphorylation was reduced IGF-IR by low concentrations of IGF-I and on insulin receptor substrate ( IRS ) -1 and IRS-2 .	In experiments conducted using cells homozygously transfected with the IGF-IR R431L mutation; (i) IGF-I binding was not affected; (ii) DNA synthesis induced by IGF-I was decreased; (iii) IGF-IR internalization stimulated by IGF-I was decreased and (iv) IGF-I-stimulated tyrosine phosphorylation was reduced IGF-IR by low concentrations of IGF-I and on insulin receptor substrate (IRS) -1 and IRS-2.	36	41	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	40	41	36	37
These higher levels of IGF-1 and IGF-2 promote IGF-1R signalling and the consequently activated downstream pathways .	These higher levels of IGF-1 and IGF-2 promote IGF-1R signalling and the consequently activated downstream pathways.	2	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	levels of IGF-1	igf-1	IGF-1R	IGF-1R	igf-1r	4	5	8	9
It has been previously shown that IGFBP-3 up-regulates IGF-I expression and induces activation of the IGF-IR pathway in certain breast cancer cells 32 .	It has been previously shown that IGFBP-3 up-regulates IGF-I expression and induces activation of the IGF-IR pathway in certain breast cancer cells 32.	6	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGFBP-3 up-regulates IGF-I expression	igf-i	IGF-IR	IGF-IR	igf-ir	8	9	15	16
These results indicate that direct activation of IGF-1R by IGF-1 is associated with the cell aggregation induced by 2.5 nM CG , but not the spheroid formation by 40 nM CG .	These results indicate that direct activation of IGF-1R by IGF-1 is associated with the cell aggregation induced by 2.5 nM CG, but not the spheroid formation by 40 nM CG.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	9	10	7	8
We observed a decrease both in IGF-1 stimulated phosphorylation of GSK3bbeta ( XREF_FIG ) and in Igfbp5 transcript levels ( XREF_FIG ) , confirming a reduction of IGF-1 dependent signaling in Igf1r +/- mice as would be predicted for a biologically significant impairment of IGF-1R function .	We observed a decrease both in IGF-1 stimulated phosphorylation of GSK3bbeta (XREF_FIG) and in Igfbp5 transcript levels (XREF_FIG), confirming a reduction of IGF-1 dependent signaling in Igf1r +/- mice as would be predicted for a biologically significant impairment of IGF-1R function.	27	37	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	Igf1r	Igf1r	Igf1r	27	28	31	32
While the IR is activated by insulin , IGF-1R is activated by its ligands , IGF-1 and IGF-II .	While the IR is activated by insulin, IGF-1R is activated by its ligands, IGF-1 and IGF-II.	8	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	15	16	8	9
The IR and IGF1R are activated by insulin and IGF-1 respectively , however a third ligand , IGF-2 , binds both the IGF1R and a splice variant of the IR called IR-A XREF_BIBR .	The IR and IGF1R are activated by insulin and IGF-1 respectively, however a third ligand, IGF-2, binds both the IGF1R and a splice variant of the IR called IR-A XREF_BIBR.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	9	10	3	4
IGF-1R belongs to the large class of tyrosine kinase transmembrane receptors and is directly activated by IGF-1 as well as the related growth factor IGF-2 XREF_BIBR .	IGF-1R belongs to the large class of tyrosine kinase transmembrane receptors and is directly activated by IGF-1 as well as the related growth factor IGF-2 XREF_BIBR.	0	25	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	16	17	0	1
Intestinal smooth muscle cells express endogenous IGF-I , which activates the cognate IGF-I receptor and regulates muscle cell hyperplasia by concomitantly stimulating proliferation and inhibiting apoptosis .	Intestinal smooth muscle cells express endogenous IGF-I, which activates the cognate IGF-I receptor and regulates muscle cell hyperplasia by concomitantly stimulating proliferation and inhibiting apoptosis.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	6	7	12	14
It is well known that blood IGF-1 can cross the blood-brain barrier , activate the IGF-1 and IGF-1R signaling pathway , influence the hippocampal structure and improve cognition and neuroplasticity .	It is well known that blood IGF-1 can cross the blood-brain barrier, activate the IGF-1 and IGF-1R signaling pathway, influence the hippocampal structure and improve cognition and neuroplasticity.	5	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	6	7	17	18
Occupancy of alphaVbeta3 integrin by these ligands increases the intensity and duration of IGF-I stimulated IGF-I receptor activation and mediates excess smooth muscle growth in patients with stricturing Crohn ' s disease XREF_BIBR .	Occupancy of alphaVbeta3 integrin by these ligands increases the intensity and duration of IGF-I stimulated IGF-I receptor activation and mediates excess smooth muscle growth in patients with stricturing Crohn 's disease XREF_BIBR.	9	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	13	14	15	17
Gene expression profiling identified downregulation of IGFBP-3 and IGFBP-4 , binding proteins that attenuate IGF1 induced activation of IGF1R , as the mechanism whereby the IGF1R pathway becomes engaged in gefitinib resistant cells .	Gene expression profiling identified downregulation of IGFBP-3 and IGFBP-4, binding proteins that attenuate IGF1 induced activation of IGF1R, as the mechanism whereby the IGF1R pathway becomes engaged in gefitinib resistant cells.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	14	15	18	19
IGF-1 secretion into the extracellular environment results in activation of IGF-1R and PI3K signaling in glioma cells , supporting tumor growth and malignancy ( see model in XREF_FIG ) .	IGF-1 secretion into the extracellular environment results in activation of IGF-1R and PI3K signaling in glioma cells, supporting tumor growth and malignancy (see model in XREF_FIG).	0	13	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	10	11
However , addition of exogenous IGF1 in combination with hypoxia increased IGF1R activation , even in the face of decreased total IGF1R .	However, addition of exogenous IGF1 in combination with hypoxia increased IGF1R activation, even in the face of decreased total IGF1R.	2	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	5	6	11	12
IGF-1 might be a ligand of Trop2 , allowing it to activate downstream mediators ( PIP 2 and Ca 2+ ) and modulate IGF1R signaling .	IGF-1 might be a ligand of Trop2, allowing it to activate downstream mediators (PIP 2 and Ca 2+) and modulate IGF1R signaling.	0	24	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	0	1	23	24
Luteolin inhibited insulin like growth factor 1 ( IGF-1 ) induced activation of IGF-1R and AKT in prostate cancer PC-3 and DU145 cells .	Luteolin inhibited insulin like growth factor 1 (IGF-1) induced activation of IGF-1R and AKT in prostate cancer PC-3 and DU145 cells.	2	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	8	9	13	14
As the IGF-IR can be activated by IGF-I , IGF-II , and pro-IGF-II , we nominated the output of the bioassay as bioactive IGF .	As the IGF-IR can be activated by IGF-I, IGF-II, and pro-IGF-II, we nominated the output of the bioassay as bioactive IGF.	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	7	8	2	3
In the axis of PKA/PI3K/Akt , IGF-1 is required to initiate IGF-1R but it is not enough for activation of IRS .	In the axis of PKA/PI3K/Akt, IGF-1 is required to initiate IGF-1R but it is not enough for activation of IRS.	6	12	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	6	7	11	12
IGF-1 agonistically stimulates its cognate tyrosine kinase IGF-1 receptor ( IGF-1R ) as well as the structurally related insulin receptor .	IGF-1 agonistically stimulates its cognate tyrosine kinase IGF-1 receptor (IGF-1R) as well as the structurally related insulin receptor.	0	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	10	11
Ganitumab inhibited IGF1 induced activation of IGF1R in murine lungs and CT26 murine colon carcinoma cells and tumors .	Ganitumab inhibited IGF1 induced activation of IGF1R in murine lungs and CT26 murine colon carcinoma cells and tumors.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	2	3	6	7
To examine the potential crosstalk of reciprocal transactivation between IGF-1R and CXCR4 , CD49f + AP + GSCs were treated with IGF-1 with or without PPP supplementation .	To examine the potential crosstalk of reciprocal transactivation between IGF-1R and CXCR4, CD49f + AP + GSCs were treated with IGF-1 with or without PPP supplementation.	7	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	21	22	9	10
The IGF-I receptor ( IGF-IR ) signaling pathway mediated by IGF-I may be involved in enhanced canine sperm function .	The IGF-I receptor (IGF-IR) signaling pathway mediated by IGF-I may be involved in enhanced canine sperm function.	1	11	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	10	11	1	3
IGF-I induces association of beta 1 integrins and IGF-IR and increases adhesion of myeloma cells to fibronectin .	IGF-I induces association of beta 1 integrins and IGF-IR and increases adhesion of myeloma cells to fibronectin.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	0	1	8	9
With regard to IGF-1 mediated activation of IGF-1R , studies indicate that bioactive forms of IGFs are tightly controlled by the presence of their binding proteins-IGFBPs [ XREF_BIBR ] .	With regard to IGF-1 mediated activation of IGF-1R, studies indicate that bioactive forms of IGFs are tightly controlled by the presence of their binding proteins-IGFBPs [XREF_BIBR].	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	3	4	7	8
In vitro and in vivo studies demonstrated that both osteosarcoma and Ewing sarcoma cells are highly dependent on IGF-1R signaling , and activation of IGF-1R by IGF-1 stimulated osteosarcoma cell growth and metastatic behavior in vivo .	In vitro and in vivo studies demonstrated that both osteosarcoma and Ewing sarcoma cells are highly dependent on IGF-1R signaling, and activation of IGF-1R by IGF-1 stimulated osteosarcoma cell growth and metastatic behavior in vivo.	22	27	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	26	27	24	25
We have shown that although echistatin blocks IGF-1 activation of IGF-1R , neither skeletal unloading nor echistatin alters the recruitment of SHP-2 to IGF-1R .	We have shown that although echistatin blocks IGF-1 activation of IGF-1R, neither skeletal unloading nor echistatin alters the recruitment of SHP-2 to IGF-1R.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	7	8	10	11
Next , we examined IGF-1R activation in H2228 cells treated with IGF-1 or IGF-1 plus metformin .	Next, we examined IGF-1R activation in H2228 cells treated with IGF-1 or IGF-1 plus metformin.	4	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	13	14	4	5
On the other hand , our present study showed IGF-I and its receptor affected the association of IGF-IR with ERalpha , and ERalpha is involved in IGF-IR signaling pathway induced by IGF-I .	On the other hand, our present study showed IGF-I and its receptor affected the association of IGF-IR with ERalpha, and ERalpha is involved in IGF-IR signaling pathway induced by IGF-I.	26	32	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	31	32	26	27
Additional experimentation showed that the IGF-1R is activated by IGF-1 ( XREF_SUPPLEMENTARY ) .	Additional experimentation showed that the IGF-1R is activated by IGF-1 (XREF_SUPPLEMENTARY).	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	9	10	5	6
Our results suggest that IGF1R and hybrid IR/IGF1R are activated by physiological concentrations of IGF1 and 2 in HASMC and this propagates downstream signaling and biological effects , while insulin has no effect on its receptor or downstream signaling probably due to a preponderance of IGF1R and incorporation of IR into hybrid IR/IGF1R .	Our results suggest that IGF1R and hybrid IR/IGF1R are activated by physiological concentrations of IGF1 and 2 in HASMC and this propagates downstream signaling and biological effects, while insulin has no effect on its receptor or downstream signaling probably due to a preponderance of IGF1R and incorporation of IR into hybrid IR/IGF1R.	4	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	14	15	4	5
As shown in XREF_FIG , both IGF-1 and CP could induce IGF-1R down-regulation in a time dependent manner .	As shown in XREF_FIG, both IGF-1 and CP could induce IGF-1R down-regulation in a time dependent manner.	5	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	6	7	11	12
IGF-I fails to enhance the association of IGF-IR to ERalpha in this cell .	IGF-I fails to enhance the association of IGF-IR to ERalpha in this cell.	0	8	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	0	1	7	8
IGF-I did not activate the IGF-IR .	IGF-I did not activate the IGF-IR.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	0	1	5	6
Regarding chondrogenesis , IGF1 in combination with TGFbetas enhances in vitro chondrocytes proliferation and collagen II production , while for the adipogenic fate commitment , IGF1 activates IGF1R dependent AKT and PKB signaling , increasing Ppargamma expression and lipid accumulation .	Regarding chondrogenesis, IGF1 in combination with TGFbetas enhances in vitro chondrocytes proliferation and collagen II production, while for the adipogenic fate commitment, IGF1 activates IGF1R dependent AKT and PKB signaling, increasing Ppargamma expression and lipid accumulation.	25	28	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	25	26	27	28
As the IGF-1R signaling could be activated by IGF-1 , we explored the optimal activation dose and time of IGF-1 in DLBCL cell lines .	As the IGF-1R signaling could be activated by IGF-1, we explored the optimal activation dose and time of IGF-1 in DLBCL cell lines.	2	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	8	9	2	3
As shown in XREF_FIG , after cell starvation , IGF-1 could activate IGF-1R signaling pathway in a time dependent manner , with pAKT and pERK peaked after 10 min of stimulation .	As shown in XREF_FIG, after cell starvation, IGF-1 could activate IGF-1R signaling pathway in a time dependent manner, with pAKT and pERK peaked after 10 min of stimulation.	9	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	9	10	12	13
There are three natural ligands , IGF-I , IGF-2 and insulin , which are capable of binding and activating the IGF-IR .	There are three natural ligands, IGF-I, IGF-2 and insulin, which are capable of binding and activating the IGF-IR.	4	21	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	6	7	20	21
Although both IGF-1 and IGF-2 activate IGF-1R , the latter shares a similar tetrameric alpha2beta2 structure with insulin receptor ( IR ) .	Although both IGF-1 and IGF-2 activate IGF-1R, the latter shares a similar tetrameric alpha2beta2 structure with insulin receptor (IR).	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	2	3	6	7
IGF-1 induced activation of IGF-1R led to AKT ( Protein Kinase B ) phosphorylation that may phosphorylate BAD ( BCL2 Associated Death Promoter ) and its dissociation from BCL2 to prevent apoptosis .	IGF-1 induced activation of IGF-1R led to AKT (Protein Kinase B) phosphorylation that may phosphorylate BAD (BCL2 Associated Death Promoter) and its dissociation from BCL2 to prevent apoptosis.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	4	5
IGF-I promotes the survival of multiple cell types by activating the IGF-I receptor ( IGF-IR ) , which signals downstream to a serine/threonine kinase termed Akt .	IGF-I promotes the survival of multiple cell types by activating the IGF-I receptor (IGF-IR), which signals downstream to a serine/threonine kinase termed Akt.	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	0	1	11	13
Activation of INSR and IGF1R by insulin and IGF1 : time dependency studies .	Activation of INSR and IGF1R by insulin and IGF1 : time dependency studies.	0	9	Activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	8	9	4	5
In this study , we found prolonged ( > 9 h ) association of PI3K with IGF-IR induced by IGF-I stimulation .	In this study, we found prolonged (> 9 h) association of PI3K with IGF-IR induced by IGF-I stimulation.	5	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	19	20	16	17
Most of these effects are more likely mediated by interactions with its specific receptor IGF-IIR , although it can not be completely excluded that the decrease in lipid damage was also partially ( nearly 39 % of the effect ) mediated by the IGF-IR , as shown in the brain tissue of old rats treated with IGF-I XREF_BIBR , XREF_BIBR .	Most of these effects are more likely mediated by interactions with its specific receptor IGF-IIR, although it can not be completely excluded that the decrease in lipid damage was also partially (nearly 39% of the effect) mediated by the IGF-IR, as shown in the brain tissue of old rats treated with IGF-I XREF_BIBR, XREF_BIBR.	40	57	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	56	57	43	44
However , combined exposure of IGF-I and either EA or EB significantly increased IGF-IR activation compared to IGF-I alone .	However, combined exposure of IGF-I and either EA or EB significantly increased IGF-IR activation compared to IGF-I alone.	3	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	5	6	13	14
IGF-IR is a transmembrane tyrosine kinase receptor and is activated by IGF-I and IGF-II .	IGF-IR is a transmembrane tyrosine kinase receptor and is activated by IGF-I and IGF-II.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	11	12	0	1
Kaempferol inhibits IGF-I- and HRG-beta-induced activation of the IGF-IR and ErbB3 signaling pathways .	Kaempferol inhibits IGF-I- and HRG-beta-induced activation of the IGF-IR and ErbB3 signaling pathways.	2	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-I-	IGF-I-	IGF-I-	IGF-IR	IGF-IR	IGF-IR	2	3	8	9
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR More recently , it has been shown that IGF1 enriches CRC stem cells , and that targeting IGF1-R results in reduction of CRC stem cell phenotype in colon cancer .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR More recently, it has been shown that IGF1 enriches CRC stem cells, and that targeting IGF1-R results in reduction of CRC stem cell phenotype in colon cancer.	19	29	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1-R	IGF1-R	IGF1-R	19	20	28	29
Our results suggest that TM4SF4 overexpression in lung carcinoma cells results in resistance to radiotherapy via IGF1 induced IGF1R activation and blocking the activity of TM4SF4 using specific antibody can be a promising therapeutics against TM4SF4 overexpressing lung adenocarcinoma .	Our results suggest that TM4SF4 overexpression in lung carcinoma cells results in resistance to radiotherapy via IGF1 induced IGF1R activation and blocking the activity of TM4SF4 using specific antibody can be a promising therapeutics against TM4SF4 overexpressing lung adenocarcinoma.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	16	17	18	19
IGF-1 induces IGF-1R modification by small ubiquitin like modifier protein-1 ( SUMO-1 ) and its translocation to the nucleus [ XREF_BIBR ] .	IGF-1 induces IGF-1R modification by small ubiquitin like modifier protein-1 (SUMO-1) and its translocation to the nucleus [XREF_BIBR].	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	2	3
IGF-1 activates the IGF1R , which is a receptor tyrosine kinase present on many cell types in many tissues .	IGF-1 activates the IGF1R, which is a receptor tyrosine kinase present on many cell types in many tissues.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	0	1	3	4
IGF-1 promotes proliferation of nerve cells by binding to IGF-1R , which can activate two canonical pathways : PI3K and Akt or MAPK ( Mairet-Coello et al ., 2009 ; Yuan et al ., 2015 ) .	IGF-1 promotes proliferation of nerve cells by binding to IGF-1R, which can activate two canonical pathways : PI3K and Akt or MAPK (Mairet-Coello et al., 2009; Yuan et al., 2015).	0	13	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	9	10
However IGF-1R tyrosine kinase inhibitor did not prevent the GH induced STAT5 activation whereas it inhibited the IGF-1 induced IGF-1R signaling .	However IGF-1R tyrosine kinase inhibitor did not prevent the GH induced STAT5 activation whereas it inhibited the IGF-1 induced IGF-1R signaling.	16	20	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	17	18	19	20
The clinical trials to date have identified that IGF-1 and IGFBP3 serum levels increase in response to IGF-1R targeted therapy .	The clinical trials to date have identified that IGF-1 and IGFBP3 serum levels increase in response to IGF-1R targeted therapy.	8	18	increase	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IGF-1	IGF-1 and IGFBP3 serum levels	igf-1	IGF-1R	IGF-1R	igf-1r	8	9	17	18
IGF-1 stimulation increased MCF7 and IGF-1R proliferation by 60 % to 64 % ( P < 0.001 ) over the cotreatment of 4-OH-TAM or FUL ( 1 muM ) with E2 , whereas this IGF-1-promoted antiestrogen resistance was significantly abrogated by BMS-536924 , U0126 and BEZ235 equivalently to their inhibitory effects on relative kinase phosphorylation .	IGF-1 stimulation increased MCF7 and IGF-1R proliferation by 60% to 64% (P < 0.001) over the cotreatment of 4-OH-TAM or FUL (1 muM) with E2, whereas this IGF-1-promoted antiestrogen resistance was significantly abrogated by BMS-536924, U0126 and BEZ235 equivalently to their inhibitory effects on relative kinase phosphorylation.	0	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	5	6
In human aortic smooth muscle cells , both IGF-I and IGF-II activate IGF-IR and/or IR/IGF-IR at physiological concentrations [ XREF_BIBR ] .	In human aortic smooth muscle cells, both IGF-I and IGF-II activate IGF-IR and/or IR/IGF-IR at physiological concentrations [XREF_BIBR].	7	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	8	9	12	13
Studies using bone anabolic factors such as PTH which stimulate autocrine signaling by IGF-I through the IGF-I receptor have shown that IRS-1 expression is required for a normal bone anabolic response to PTH .	Studies using bone anabolic factors such as PTH which stimulate autocrine signaling by IGF-I through the IGF-I receptor have shown that IRS-1 expression is required for a normal bone anabolic response to PTH.	9	18	stimulate	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	13	14	16	18
It is known that IGF-I primarily stimulates IGF-IR whereas IGF-II is capable of activating both IGF-IR and IR-A .	It is known that IGF-I primarily stimulates IGF-IR whereas IGF-II is capable of activating both IGF-IR and IR-A.	4	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	4	5	7	8
After two hours of incubation , A12 almost completely blocked IGF-1 induced activation of IGF-1R in HCC tumor cells ( XREF_FIG ) .	After two hours of incubation, A12 almost completely blocked IGF-1 induced activation of IGF-1R in HCC tumor cells (XREF_FIG).	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	10	11	14	15
IGF1R , activated by IGF1 and IGF2 derived from endocrine , autocrine and paracrine sources , transduces signals to PI3K/AKT/mTOR and mitogen activated protein kinase ( MAPK ) signaling pathways , via insulin receptor substrate 1 ( IRS-1 ) , mediating the regulation of cell growth , proliferation , motility , invasion and metastasis , in a variety of human malignancies [ XREF_BIBR ] .	IGF1R, activated by IGF1 and IGF2 derived from endocrine, autocrine and paracrine sources, transduces signals to PI3K/AKT/mTOR and mitogen activated protein kinase (MAPK) signaling pathways, via insulin receptor substrate 1 (IRS-1), mediating the regulation of cell growth, proliferation, motility, invasion and metastasis, in a variety of human malignancies [XREF_BIBR].	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	4	5	0	1
According to our finding that IGF-1 exerts a tight feedback control on its cognate receptor , reduced IGF-1 levels may trigger peripheral IGF1R upregulation and vascular pathology .	According to our finding that IGF-1 exerts a tight feedback control on its cognate receptor, reduced IGF-1 levels may trigger peripheral IGF1R upregulation and vascular pathology.	17	23	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1 levels	igf-1	IGF1R	IGF1R	igf1r	17	18	22	23
Both GH and IGF-I stimulated the accumulation of IGF-I receptor mRNA in the most immature proliferative zone cells but did not alter the accumulation of IGF binding protein 4 mRNA in any fraction .	Both GH and IGF-I stimulated the accumulation of IGF-I receptor mRNA in the most immature proliferative zone cells but did not alter the accumulation of IGF binding protein 4 mRNA in any fraction.	1	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	3	4	8	10
With the exception of selected malignancies ( such as Ewing ' s sarcomas , in which the IGF1R is constitutively activated by autocrine production of IGF1 ) , the majority of primary tumors may exhibit only minimal-to-modest antitumor responses to IGF1R directed therapy ( at least when administered as monotherapy without other concomitant treatments ) .	With the exception of selected malignancies (such as Ewing 's sarcomas, in which the IGF1R is constitutively activated by autocrine production of IGF1), the majority of primary tumors may exhibit only minimal-to-modest antitumor responses to IGF1R directed therapy (at least when administered as monotherapy without other concomitant treatments).	16	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	25	26	17	18
IGF-I rapidly and transiently induces association of IGF-IR and beta1 integrin , with phosphorylation of IGF-IR , IRS-1 , and p85 ( PI3-K ) .	IGF-I rapidly and transiently induces association of IGF-IR and beta1 integrin, with phosphorylation of IGF-IR, IRS-1, and p85 (PI3-K).	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	0	1	7	8
IGF-1 activated IGF1R , IRS-1 , MAP kinase and Akt in the MCF-7 , MDA-MB-231 and HBL-100 cell lines .	IGF-1 activated IGF1R, IRS-1, MAP kinase and Akt in the MCF-7, MDA-MB-231 and HBL-100 cell lines.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	0	1	2	3
IGF-I fails to enhance the association of IGF-IR and ERalpha in MCF-7 SX13 cells .	IGF-I fails to enhance the association of IGF-IR and ERalpha in MCF-7 SX13 cells.	0	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	0	1	7	8
To examine if blocking IGF-1R inhibits SMC proliferation , quiescent SMCs were treated with IGF-1 ( 1 ng/ml ) in the presence or absence of PPP , the IGF-1R inhibitor .	To examine if blocking IGF-1R inhibits SMC proliferation, quiescent SMCs were treated with IGF-1 (1 ng/ml) in the presence or absence of PPP, the IGF-1R inhibitor.	3	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	14	15	4	5
Analysis of this model suggested , and experimental results confirmed , that IGFBPs were key regulators of IGF1 mediated IGF1R activation .	Analysis of this model suggested, and experimental results confirmed, that IGFBPs were key regulators of IGF1 mediated IGF1R activation.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	17	18	19	20
The expression levels of IGF-1 and p-IGF-1R were significantly increased in A549 cells treated with IGF-1 as compared to those treated with IGF-1+ AG1024 or untreated cells .	The expression levels of IGF-1 and p-IGF-1R were significantly increased in A549 cells treated with IGF-1 as compared to those treated with IGF-1+ AG1024 or untreated cells.	2	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	p-IGF-1R	p-IGF-1R	p-IGF-1R	15	16	6	7
Therefore we suggest that adipogenesis is initiated by IGF-1 activation of IGF-1Rbeta following its recruitment to the cilium associated with cilia elongation .	Therefore we suggest that adipogenesis is initiated by IGF-1 activation of IGF-1Rbeta following its recruitment to the cilium associated with cilia elongation.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1Rbeta	IGF-1Rbeta	IGF-1Rbeta	8	9	11	12
Activation of IGF-1R by IGF-1 and IGF-2 in GS-12 cells was blocked by IMC-A12 .	Activation of IGF-1R by IGF-1 and IGF-2 in GS-12 cells was blocked by IMC-A12.	0	9	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	4	5	2	3
IGF-I stimulation in SKBR3 and IGF-IR stable transfectants resulted in increased expression of a p27kip1 ubiquitin ligase , Skp2 [ XREF_BIBR ] .	IGF-I stimulation in SKBR3 and IGF-IR stable transfectants resulted in increased expression of a p27kip1 ubiquitin ligase, Skp2 [XREF_BIBR].	0	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	0	1	5	6
Activation of IGF1R by IGF-I resulted in the phosphorylation of both IRS-1 and IRS-2 in C4-12 cells .	Activation of IGF1R by IGF-I resulted in the phosphorylation of both IRS-1 and IRS-2 in C4-12 cells.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF1R	IGF1R	IGF1R	4	5	2	3
IGF-I activates IGF-I receptor ( IGF-IR ) tyrosine kinase , followed by phosphorylation of substrates such as insulin receptor substrates ( IRS ) leading to binding of signaling molecules containing SH2 domains , including phosphatidylinositol 3-kinase ( PI3K ) to IRS and activation of the downstream signaling pathways .	IGF-I activates IGF-I receptor (IGF-IR) tyrosine kinase, followed by phosphorylation of substrates such as insulin receptor substrates (IRS) leading to binding of signaling molecules containing SH2 domains, including phosphatidylinositol 3-kinase (PI3K) to IRS and activation of the downstream signaling pathways.	0	4	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	0	1	2	4
We found that IGF-1 activated the IGF-1R , insulin receptor substrate ( IRS )-1, phosphatidylinositol 3-kinase , and Akt in a time dependent manner in alphaT3 cells .	We found that IGF-1 activated the IGF-1R, insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase, and Akt in a time dependent manner in alphaT3 cells.	3	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	3	4	6	7
In intestinal smooth muscle , the intensity and duration of IGF-I stimulated IGF-IR activity is positively regulated by ligand occupancy of alphaVbeta3 integrin by the resultant temporally regulated translocation of SH2 domain containing tyrosine phosphatase-2 from alphaVbeta3 integrin to the IGF-I receptor .	In intestinal smooth muscle, the intensity and duration of IGF-I stimulated IGF-IR activity is positively regulated by ligand occupancy of alphaVbeta3 integrin by the resultant temporally regulated translocation of SH2 domain containing tyrosine phosphatase-2 from alphaVbeta3 integrin to the IGF-I receptor.	6	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	10	11	12	13
Full-length MGF directly stimulates the IGF-IR .	Full-length MGF directly stimulates the IGF-IR.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MGF	MGF	MGF	IGF-IR	IGF-IR	IGF-IR	1	2	5	6
The treatment of cells with dynasore blocked dynamin mediated clathrin dependent endocytosis , but did not affect the IGF-1 stimulated appearance of phospho-IGF-1R at the base of cilium ( XREF_SUPPLEMENTARY ) .	The treatment of cells with dynasore blocked dynamin mediated clathrin dependent endocytosis, but did not affect the IGF-1 stimulated appearance of phospho-IGF-1R at the base of cilium (XREF_SUPPLEMENTARY).	17	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	phospho-IGF-1R	phospho-IGF-1R	phospho-IGF-1R	18	19	22	23
The activation of IGF-IR by IGF-I results in its autophosphorylation at tyrosine residues [ XREF_BIBR , XREF_BIBR ] .	The activation of IGF-IR by IGF-I results in its autophosphorylation at tyrosine residues [XREF_BIBR, XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	5	6	3	4
It was evident that IGF-1R could be modulated by IGF-1 .	It was evident that IGF-1R could be modulated by IGF-1.	4	10	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	9	10	4	5
The IGF1 mediated activation of IGF1R has been demonstrated to contribute to tumor progression XREF_BIBR .	The IGF1 mediated activation of IGF1R has been demonstrated to contribute to tumor progression XREF_BIBR.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	1	2	5	6
Administration of IGF-I still elicited cell number increase in IGF-IR .	Administration of IGF-I still elicited cell number increase in IGF-IR.	0	10	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	2	3	9	10
In parallel , IGF-I activates IGF-I receptor , insulin receptor substrate-1 ( IRS-1 ) , phosphatidylinositol 3 ( PI-3 )-kinase , and FAK .	In parallel, IGF-I activates IGF-I receptor, insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3 (PI-3)-kinase, and FAK.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	3	4	5	7
Here , we report that IGF-1 promotes the modification of IGF-1R by small ubiquitin like modifier protein-1 ( SUMO-1 ) and its translocation to the nucleus .	Here, we report that IGF-1 promotes the modification of IGF-1R by small ubiquitin like modifier protein-1 (SUMO-1) and its translocation to the nucleus.	5	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	5	6	10	11
Since IGF-I and IGF-II activate IGF-1R through paracrine and autocrine loops [ XREF_BIBR ] , each of the cell lines was therefore treated with 50ng IGF-I .	Since IGF-I and IGF-II activate IGF-1R through paracrine and autocrine loops [XREF_BIBR], each of the cell lines was therefore treated with 50ng IGF-I.	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-1R	IGF-1R	IGF-1R	1	2	5	6
To specifically examine the effects of BMS-754807 on IGF-1 stimulation of IGF-1R , we determined the effect of increasing doses of the inhibitor on PARP cleavage .	To specifically examine the effects of BMS-754807 on IGF-1 stimulation of IGF-1R, we determined the effect of increasing doses of the inhibitor on PARP cleavage.	8	12	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	8	9	11	12
We also investigated whether Brg1 and IGF-1R accumulation at the SNAI2 promoter could be induced by IGF-1 .	We also investigated whether Brg1 and IGF-1R accumulation at the SNAI2 promoter could be induced by IGF-1.	4	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	16	17	6	7
Moreover , tyrosine phosphorylation of STAT3 , JAK1 , and JAK2 was increased upon IGF-I stimulation of endogenous IGF-IR in 293T cells transfected with the respective STAT or JAK expression vector .	Moreover, tyrosine phosphorylation of STAT3, JAK1, and JAK2 was increased upon IGF-I stimulation of endogenous IGF-IR in 293T cells transfected with the respective STAT or JAK expression vector.	14	19	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	14	15	18	19
To study the interaction between IGF-1R and intact IGF-1 or T-IGF1 , the activation of IGF-1R by IGF-1 was first investigated in different human lung cancer cell lines , including CL1-0 ( a well studied lung ADC cell line ) , NCI-H520 ( a lung SCC cell line ) , NCI-H460 and NCI-H661 cells ( two large-cell carcinoma cell lines ) .	To study the interaction between IGF-1R and intact IGF-1 or T-IGF1, the activation of IGF-1R by IGF-1 was first investigated in different human lung cancer cell lines, including CL1-0 (a well studied lung ADC cell line), NCI-H520 (a lung SCC cell line), NCI-H460 and NCI-H661 cells (two large-cell carcinoma cell lines).	13	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	17	18	15	16
An understanding of the IGF-I system in neurons , including the regulation of IGF-I availability and signaling mechanisms initiated by IGF-I activation of the IGF-I receptor ( IGF-IR ) , is an important starting point for discussing the therapeutic potential of IGF-I in ALS .	An understanding of the IGF-I system in neurons, including the regulation of IGF-I availability and signaling mechanisms initiated by IGF-I activation of the IGF-I receptor (IGF-IR), is an important starting point for discussing the therapeutic potential of IGF-I in ALS.	20	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	20	21	24	26
Moreover , over-expression of human IGF-I in prostate epithelial cells in a transgenic mouse model led to activation of the IGF-IR and spontaneous tumorigenesis in prostate epithelium , while suppression of IGF-IR inhibited prostate tumor cell growth and invasion in rats .	Moreover, over-expression of human IGF-I in prostate epithelial cells in a transgenic mouse model led to activation of the IGF-IR and spontaneous tumorigenesis in prostate epithelium, while suppression of IGF-IR inhibited prostate tumor cell growth and invasion in rats.	2	23	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	over-expression of human IGF-I	igf-i	IGF-IR	IGF-IR	igf-ir	5	6	20	21
Insulin and AspB10 led to IR phosphorylation , while IGF-I led to IGF-IR and hybrid receptor activation in vitro .	Insulin and AspB10 led to IR phosphorylation, while IGF-I led to IGF-IR and hybrid receptor activation in vitro.	9	16	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	9	10	12	13
XREF_BIBR examined the ability of IGF-1 to increase the number of differentiated neurons and found that IGF-1 activation of IGF1R promotes differentiation of postmitotic neuronal precursors in vitro .	XREF_BIBR examined the ability of IGF-1 to increase the number of differentiated neurons and found that IGF-1 activation of IGF1R promotes differentiation of postmitotic neuronal precursors in vitro.	16	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	16	17	19	20
IGF-1 activation of insulin receptor or IGF-1R can initiate Ras and ErK signaling .	IGF-1 activation of insulin receptor or IGF-1R can initiate Ras and ErK signaling.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	6	7
IGF1R activation by IGF1 can induce cell proliferation , cell survival , transformation , metastasis and angiogenesis as well as inhibit apoptosis in different cancer cell lines [ XREF_BIBR ] .	IGF1R activation by IGF1 can induce cell proliferation, cell survival, transformation, metastasis and angiogenesis as well as inhibit apoptosis in different cancer cell lines [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	3	4	0	1
In this context , a typical concentration of 10-100ng/mL of IGF-1 is sufficient to activate only the IGF-1R and not the IR .	In this context, a typical concentration of 10-100ng/mL of IGF-1 is sufficient to activate only the IGF-1R and not the IR.	8	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	10	11	17	18
We also demonstrated that IGF-I downregulated miR-143 and upregulated IGF-IR and IRSI , the well-known oncogenes in carcinogenesis .	We also demonstrated that IGF-I downregulated miR-143 and upregulated IGF-IR and IRSI, the well-known oncogenes in carcinogenesis.	4	15	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	4	5	9	10
The endogenous ligands of IR include insulin , IGF-1 , and IGF-2 , but IGF-1R is activated only by IGF-1 and IGF-2 [ XREF_BIBR ] .	The endogenous ligands of IR include insulin, IGF-1, and IGF-2, but IGF-1R is activated only by IGF-1 and IGF-2 [XREF_BIBR].	14	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	19	20	14	15
High levels of IGFBPs sequester large amounts of IGF1 , effectively reducing the level of IGF1 and actually enhance the impact of IGF1R blocking antibody relative to low IGFBP conditions .	High levels of IGFBPs sequester large amounts of IGF1, effectively reducing the level of IGF1 and actually enhance the impact of IGF1R blocking antibody relative to low IGFBP conditions.	1	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	levels of IGFBPs sequester large amounts of IGF1	igf1	IGF1R	IGF1R	igf1r	8	9	22	23
We extended this knowledge showing that IGF-1 can act as positive regulator of adipogenesis in primary human ASCs and simultaneously induces IGF-1R and DIRAS3 , indicating an interplay between IGF-1 and DIRAS3 in modulating adipogenesis .	We extended this knowledge showing that IGF-1 can act as positive regulator of adipogenesis in primary human ASCs and simultaneously induces IGF-1R and DIRAS3, indicating an interplay between IGF-1 and DIRAS3 in modulating adipogenesis.	6	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	6	7	21	22
Since IGF-1 activation of the IGF-1R can cross-talk and activate the ER-alpha signaling pathway ( Fagan and Yee , 2008 ) we propose that likewise , IGF-2 can activate the ER-alpha .	Since IGF-1 activation of the IGF-1R can cross-talk and activate the ER-alpha signaling pathway (Fagan and Yee, 2008) we propose that likewise, IGF-2 can activate the ER-alpha.	1	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	1	2	5	6
The IGF system is a key participant in ES development and progression , and the functions of this system are mainly sustained by the autocrine production of IGF1 , which induces constitutive IGF1R activation .	The IGF system is a key participant in ES development and progression, and the functions of this system are mainly sustained by the autocrine production of IGF1, which induces constitutive IGF1R activation.	25	33	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	27	28	32	33
Importantly , selinexor inhibited insulin like growth factor 1 ( IGF1 ) activation of IGF-1R and AKT pathway through upregulation of insulin like growth factor binding protein 5 ( IGFBP5 ) .	Importantly, selinexor inhibited insulin like growth factor 1 (IGF1) activation of IGF-1R and AKT pathway through upregulation of insulin like growth factor binding protein 5 (IGFBP5).	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF-1R	IGF-1R	IGF-1R	10	11	14	15
Under these conditions , ganitumab inhibited IGF-1- and IGF-2-induced activation of IGF1R at all ligand concentrations ( XREF_FIG ) .	Under these conditions, ganitumab inhibited IGF-1- and IGF-2-induced activation of IGF1R at all ligand concentrations (XREF_FIG).	6	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1-	IGF-1-	IGF-1-	IGF1R	IGF1R	IGF1R	6	7	11	12
The aim of this study was to assess whether IGF-IR and downstream signaling molecules content and activation induced by IGF-I have differences in placentas of different gestational ages and according to birth weight .	The aim of this study was to assess whether IGF-IR and downstream signaling molecules content and activation induced by IGF-I have differences in placentas of different gestational ages and according to birth weight.	9	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	19	20	9	10
Because human epidermal keratinocytes do not produce IGF-1 , the IGF-1R is primarily activated by IGF-1 produced and secreted by adjacent fibroblasts in the papillary dermis .	Because human epidermal keratinocytes do not produce IGF-1, the IGF-1R is primarily activated by IGF-1 produced and secreted by adjacent fibroblasts in the papillary dermis.	9	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	15	16	10	11
To further explore the involvement of p-IGF-1R and this pathway in the anti-migratory effect of luteolin , IGF-1 was used to upregulate p-IGF-1R .	To further explore the involvement of p-IGF-1R and this pathway in the anti-migratory effect of luteolin, IGF-1 was used to upregulate p-IGF-1R.	17	23	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	p-IGF-1R	p-IGF-1R	p-IGF-1R	17	18	22	23
Loss of IGF-I prevents formation of TEBs , and IGF-IR deficiency in MECs compromises embryonic mammary bud development and proliferation of the TEB cap cells .	Loss of IGF-I prevents formation of TEBs, and IGF-IR deficiency in MECs compromises embryonic mammary bud development and proliferation of the TEB cap cells.	0	10	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-I	Loss of IGF-I	igf-i	IGF-IR	IGF-IR	igf-ir	2	3	9	10
The IGF-1R is activated by IGF-I and IGF-II , resulting in phosphorylation of tyrosines in its kinase domain and the adaptor proteins insulin receptor substrate ( IRS ) family and Src homology and collagen domain proteins ( Shc ) , which then transduces signals via the AKT and MAPK pathways [ XREF_BIBR , XREF_BIBR ] .	The IGF-1R is activated by IGF-I and IGF-II, resulting in phosphorylation of tyrosines in its kinase domain and the adaptor proteins insulin receptor substrate (IRS) family and Src homology and collagen domain proteins (Shc), which then transduces signals via the AKT and MAPK pathways [XREF_BIBR, XREF_BIBR].	0	42	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-1R	IGF-1R	IGF-1R	5	6	1	2
Through co-immunoprecipitation and western blot assay , we confirmed that GRK2 can interact with insulin like growth factor 1 receptor ( IGF-1R ) and inhibits IGF1 induced activation of IGF1R signaling pathway .	Through co-immunoprecipitation and western blot assay, we confirmed that GRK2 can interact with insulin like growth factor 1 receptor (IGF-1R) and inhibits IGF1 induced activation of IGF1R signaling pathway.	25	31	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	25	26	29	30
This issue is complicated by the fact that IGF-1R is activated preferentially by IGF-1 and the IR-A by IGF-2 , and ligand induced internalization and trafficking of the receptors may be different in response to ligand stimulation .	This issue is complicated by the fact that IGF-1R is activated preferentially by IGF-1 and the IR-A by IGF-2, and ligand induced internalization and trafficking of the receptors may be different in response to ligand stimulation.	8	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	13	14	8	9
IGF-1 protected against serum deprivation insult and activated IGF-1R , AKT , ERK1/2 signaling in SH-SY5Y cells .	IGF-1 protected against serum deprivation insult and activated IGF-1R, AKT, ERK1/2 signaling in SH-SY5Y cells.	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	8	9
First , our data suggest that IGF1 more strongly activates IGF1R under hypoxic conditions .	First, our data suggest that IGF1 more strongly activates IGF1R under hypoxic conditions.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	6	7	10	11
In mammals , alveolar macrophages release IGF-1 when mice are exposed to house dust mites and IGF-1 activates IGF-1R on the surface of airway epithelial cells .	In mammals, alveolar macrophages release IGF-1 when mice are exposed to house dust mites and IGF-1 activates IGF-1R on the surface of airway epithelial cells.	16	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	16	17	18	19
The concept that INSR activation ( mainly by insulin ) leads primarily to metabolic activities while IGF1R activation ( mainly by IGF1 or IGF2 ) leads to proliferative events was the prevalent dogma for more than 45years .	The concept that INSR activation (mainly by insulin) leads primarily to metabolic activities while IGF1R activation (mainly by IGF1 or IGF2) leads to proliferative events was the prevalent dogma for more than 45years.	16	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	21	22	16	17
While we provide evidence that the Hybrid-R is phosphorylated at the plasma membrane , we have not yet established whether IGF-1 mediates nuclear trafficking of the IGF-1R or whether this receptor traffics to the nucleus independent of ligand .	While we provide evidence that the Hybrid-R is phosphorylated at the plasma membrane, we have not yet established whether IGF-1 mediates nuclear trafficking of the IGF-1R or whether this receptor traffics to the nucleus independent of ligand.	20	35	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	20	21	26	27
Although both IGF-1 and IGF-2 activate IGF-1R , the binding sites for IGF-1 and IGF-2 on the receptor are distinct .	Although both IGF-1 and IGF-2 activate IGF-1R, the binding sites for IGF-1 and IGF-2 on the receptor are distinct.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	2	3	6	7
EGFR was not phosphorylated in MCF10A cells or MCF 7 cells 16 hr after addition of IGF-1 To confirm that IGF-1 was indeed activating the IGF-1R signaling cascade , we analyzed p-IGF-1R and p-Akt expression at 20 min and 16 hr .	EGFR was not phosphorylated in MCF10A cells or MCF 7 cells 16 hr after addition of IGF-1 To confirm that IGF-1 was indeed activating the IGF-1R signaling cascade, we analyzed p-IGF-1R and p-Akt expression at 20 min and 16 hr.	20	27	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	20	21	25	26
In our hands , human MGF and Goldspink-MGF in the IGF-IR KIRA assay induced no stimulatory activity of the IGF-IR .	In our hands, human MGF and Goldspink-MGF in the IGF-IR KIRA assay induced no stimulatory activity of the IGF-IR.	4	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MGF	MGF	MGF	IGF-IR	IGF-IR	IGF-IR	5	6	19	20
Human IGF1 and IGF2 share 62 % sequence identity and have overlapping functions : both IGF1 and IGF2 can activate the IGF1R which can drive tumor cell proliferation .	Human IGF1 and IGF2 share 62% sequence identity and have overlapping functions : both IGF1 and IGF2 can activate the IGF1R which can drive tumor cell proliferation.	0	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	1	2	21	22
As expected , IGF1 stimulation led to an increase in MAP kinase activation in R-cells expressing wild-type IGF1R .	As expected, IGF1 stimulation led to an increase in MAP kinase activation in R-cells expressing wild-type IGF1R.	3	18	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	3	4	17	18
In conclusion , we have demonstrated IGF-I induced association of IGF-IR and ERalpha .	In conclusion, we have demonstrated IGF-I induced association of IGF-IR and ERalpha.	6	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	6	7	10	11
Furthermore , a blockade of IGF-1 reduced the activity of IGF-1R .	Furthermore, a blockade of IGF-1 reduced the activity of IGF-1R.	3	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	5	6	10	11
Moreover , IGF-I and/or IL-4 induced long-term cell growth of the IGF-IR transfectants .	Moreover, IGF-I and/or IL-4 induced long-term cell growth of the IGF-IR transfectants.	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	2	3	11	12
In LCC6-WT cells , both IGF-I and insulin treatment activated IGF1R as measured by total phosphotyrosine immunoblotting ( XREF_FIG , lane 2 ) .	In LCC6-WT cells, both IGF-I and insulin treatment activated IGF1R as measured by total phosphotyrosine immunoblotting (XREF_FIG, lane 2).	5	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF1R	IGF1R	IGF1R	5	6	10	11
In contrast , IGF-1 induces much higher levels of phosporylation of the IGF-1R than of the IR .	In contrast, IGF-1 induces much higher levels of phosporylation of the IGF-1R than of the IR.	3	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	3	4	12	13
A revised model has now been developed to explain how IGF-I or other activating ligands initiate IGF-IR internalization and subsequent degradation through lysosomal or proteasomal pathways .	A revised model has now been developed to explain how IGF-I or other activating ligands initiate IGF-IR internalization and subsequent degradation through lysosomal or proteasomal pathways.	10	17	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	10	11	16	17
IGF-1 induced IGF-1R activation can not only utilize beta-arrestin1 but also GRKs of GPCRs signaling machinery as regulators XREF_BIBR XREF_BIBR XREF_BIBR .	IGF-1 induced IGF-1R activation can not only utilize beta-arrestin1 but also GRKs of GPCRs signaling machinery as regulators XREF_BIBR XREF_BIBR XREF_BIBR.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	2	3
IGF-1R is primarily activated by its cognate ligands ( IGF-1 and IGF-2 ) with 1/2 to 1/15 the affinity for IGF-2 that it has for IGF-1 .	IGF-1R is primarily activated by its cognate ligands (IGF-1 and IGF-2) with 1/2 to 1/15 the affinity for IGF-2 that it has for IGF-1.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	9	10	0	1
Higher concentrations of IGF1 inducing downregulation of the IGF1R is a well-known negative feedback mechanism XREF_BIBR .	Higher concentrations of IGF1 inducing downregulation of the IGF1R is a well-known negative feedback mechanism XREF_BIBR.	1	9	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	3	4	8	9
In MCF-7 cells , estradiol ( E2 ) and IGF-I induced the rapid association of ER to IGF-IR , however , the interaction was abrogated in MCF-7 SX13 cells .	In MCF-7 cells, estradiol (E2) and IGF-I induced the rapid association of ER to IGF-IR, however, the interaction was abrogated in MCF-7 SX13 cells.	4	18	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	9	10	17	18
Exogenous IGF-1 administration in EGFR-TKIs-naive PC-9 and H460 cells also triggered IGF1R activation , and subsequently EMT .	Exogenous IGF-1 administration in EGFR-TKIs-naive PC-9 and H460 cells also triggered IGF1R activation, and subsequently EMT.	1	12	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	1	2	11	12
IGF-1R and P-Akt were faintly stained in untreated young cells under control conditions ( 0 h ) ; IGF-1R was greatly induced by IGF-1 treatment for 6 h and P-Akt became considerably abundant in the nuclei at 6 h ; however , both were diminished after 24 h treatment ( 24 h ) .	IGF-1R and P-Akt were faintly stained in untreated young cells under control conditions (0 h); IGF-1R was greatly induced by IGF-1 treatment for 6 h and P-Akt became considerably abundant in the nuclei at 6 h; however, both were diminished after 24 h treatment (24 h).	18	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	23	24	18	19
When C1 and IGFIR haploinsufficient fibroblasts ( c. 3348_3366dup , p.R877 * or IGF1R CNV ) were treated with IGF-I ( 100ng/ml , 24h ) , the emitted MFI were found to be reproducibly , and comparably , further reduced ( XREF_FIG and XREF_FIG ) .	When C1 and IGFIR haploinsufficient fibroblasts (c. 3348_3366dup, p.R877 * or IGF1R CNV) were treated with IGF-I (100ng/ml, 24h), the emitted MFI were found to be reproducibly, and comparably, further reduced (XREF_FIG and XREF_FIG).	1	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF1R	IGF1R	IGF1R	19	20	13	14
Here , IGF-1 directly promoted M2 macrophage polarization by activating the IGF1R signaling pathway , demonstrating for the first time that this pathway is important in macrophage polarization .	Here, IGF-1 directly promoted M2 macrophage polarization by activating the IGF1R signaling pathway, demonstrating for the first time that this pathway is important in macrophage polarization.	2	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	2	3	11	12
Given the tight binding between IGF-1 and IGFBPs ( K d = 0.06-0.22 nM ) , the sequestering of IGF-1 by IGFBPs effectively reduces the amount of IGF-1 available to activate IGF-1R .	Given the tight binding between IGF-1 and IGFBPs (K d = 0.06-0.22 nM), the sequestering of IGF-1 by IGFBPs effectively reduces the amount of IGF-1 available to activate IGF-1R.	25	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	amount of IGF-1	igf-1	IGF-1R	IGF-1R	igf-1r	27	28	31	32
IGF-1 is believed to activate IGF-1R , which recruits IRS-1 , activating Ras , and then C-Raf , and eventually the phosphorylation of ERK .	IGF-1 is believed to activate IGF-1R, which recruits IRS-1, activating Ras, and then C-Raf, and eventually the phosphorylation of ERK.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	5	6
However , PDGF increased synthesis of the IGF1R in a concentration- and time dependent manner , and prevented the IGF1 induced downregulation of the IGF1R XREF_BIBR .	However, PDGF increased synthesis of the IGF1R in a concentration- and time dependent manner, and prevented the IGF1 induced downregulation of the IGF1R XREF_BIBR.	18	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	19	20	24	25
Incubation of A549 cells with EGF resulted in significant increased phosphorylation levels of EGFR , IGF-1R and ERK , while IGF-1 treatment could activate the IGF-1R , AKT and ERK .	Incubation of A549 cells with EGF resulted in significant increased phosphorylation levels of EGFR, IGF-1R and ERK, while IGF-1 treatment could activate the IGF-1R, AKT and ERK.	20	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	20	21	25	26
Human IGF-1 and IGF-2 share 62 % sequence identity and have overlapping functions : both IGF-1 and IGF-2 can activate the IGF-1R which can drive tumor cell proliferation .	Human IGF-1 and IGF-2 share 62% sequence identity and have overlapping functions : both IGF-1 and IGF-2 can activate the IGF-1R which can drive tumor cell proliferation.	0	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	1	2	21	22
The IGF-1R is activated by the binding of the ligands IGF-1 and IGF-2 , which has a nearly 20-fold higher affinity for IGF-1 than for IGF-2 .	The IGF-1R is activated by the binding of the ligands IGF-1 and IGF-2, which has a nearly 20-fold higher affinity for IGF-1 than for IGF-2.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	10	11	1	2
Insulin , IGF-I and IGF-II caused down-regulation of IGF-IR ; the effect is concentration and time dependent .	Insulin, IGF-I and IGF-II caused down-regulation of IGF-IR; the effect is concentration and time dependent.	0	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	2	3	8	9
We found that WT IGF1 induced co-precipitation of IGF1R and integrin beta4 , but R36E and R37E was defective in this function .	We found that WT IGF1 induced co-precipitation of IGF1R and integrin beta4, but R36E and R37E was defective in this function.	3	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	4	5	8	9
High intraocular IGF-I , resulting from overexpression of IGF-I in the retina , increased IGF-I receptor content and signaling and led to accumulation of vascular endothelial growth factor .	High intraocular IGF-I, resulting from overexpression of IGF-I in the retina, increased IGF-I receptor content and signaling and led to accumulation of vascular endothelial growth factor.	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	2	3	14	16
Treatment of IGF-I for 20min stimulated the intrinsic tyrosine kinase activity of IGF1R , resulting in phosphorylation in both mesothelioma cells and control LP9 mesothelial cells ( XREF_FIG ) .	Treatment of IGF-I for 20min stimulated the intrinsic tyrosine kinase activity of IGF1R, resulting in phosphorylation in both mesothelioma cells and control LP9 mesothelial cells (XREF_FIG).	0	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF1R	IGF1R	IGF1R	2	3	12	13
Molecular studies demonstrated that in canine osteosarcoma IGF-IR is activated by IGF-1 mostly in a paracrine or endocrine ( rather than autocrine ) manner , leading to activation of AKT and MAPK signalling .	Molecular studies demonstrated that in canine osteosarcoma IGF-IR is activated by IGF-1 mostly in a paracrine or endocrine (rather than autocrine) manner, leading to activation of AKT and MAPK signalling.	7	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-IR	IGF-IR	IGF-IR	11	12	7	8
Collectively , these data indicate that i ) IGF1 activates IGF1R and INSR in both C4-2 and P69 cell lines ; ii ) INSR activation by IGF1 is not affected by A12 treatment ( in comparison with the complete inhibition of IGF1R ) ; and iii ) downstream signaling cascades are inhibited by A12 only to a limited extent .	Collectively, these data indicate that i) IGF1 activates IGF1R and INSR in both C4-2 and P69 cell lines; ii) INSR activation by IGF1 is not affected by A12 treatment (in comparison with the complete inhibition of IGF1R); and iii) downstream signaling cascades are inhibited by A12 only to a limited extent.	8	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	8	9	10	11
For example , IGFBP-4 inhibits IGF-I activation of IGF-1R when the binding protein and ligand complex is targeted for proteolysis .	For example, IGFBP-4 inhibits IGF-I activation of IGF-1R when the binding protein and ligand complex is targeted for proteolysis.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-1R	IGF-1R	IGF-1R	5	6	8	9
When the recycling was inhibited by primaquine , surface IGF-IR levels were reduced by IGF-I treatment within 1 hr , and phospho-IGF-IR levels followed this time dependent changes ( XREF_FIG ) , indicating that IGF-I indeed triggers IGF-IR endocytosis from cell surface and that the recycling contributes to the apparent surface maintenance of IGF-IR .	When the recycling was inhibited by primaquine, surface IGF-IR levels were reduced by IGF-I treatment within 1 hr, and phospho-IGF-IR levels followed this time dependent changes (XREF_FIG), indicating that IGF-I indeed triggers IGF-IR endocytosis from cell surface and that the recycling contributes to the apparent surface maintenance of IGF-IR.	34	38	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	34	35	37	38
In the brain , IGF1R is activated by two ligands ( IGF1 and IGF2 ) , and IGF1 has been shown to play a role in synaptic plasticity and acts as a potential treatment target for the cognitive dysfunction XREF_BIBR .	In the brain, IGF1R is activated by two ligands (IGF1 and IGF2), and IGF1 has been shown to play a role in synaptic plasticity and acts as a potential treatment target for the cognitive dysfunction XREF_BIBR.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	11	12	4	5
Consistent with these findings , the expression of IGF-1 in the alveolar epithelium resulted in increased spontaneous tumors , showing that IGF-1R activated by persistent IGF-1 expression can induce lung tumor development in mice .	Consistent with these findings, the expression of IGF-1 in the alveolar epithelium resulted in increased spontaneous tumors, showing that IGF-1R activated by persistent IGF-1 expression can induce lung tumor development in mice.	21	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1 expression	igf-1	IGF-1R	IGF-1R	igf-1r	25	26	21	22
Selective targeting of the IGF signaling network has proven to be extremely challenging due , in part , to the fact that insulin , IGF-1 and IGF-2 can all activate IGF-1-R and/or IGF-2R , as well as the insulin receptor ( XREF_FIG ) .	Selective targeting of the IGF signaling network has proven to be extremely challenging due, in part, to the fact that insulin, IGF-1 and IGF-2 can all activate IGF-1-R and/or IGF-2R, as well as the insulin receptor (XREF_FIG).	22	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1-R	IGF-1-R	IGF-1-R	24	25	30	31
No IGF-IR stimulatory activity was induced by human MGF and Goldspink-MGF , respectively .	No IGF-IR stimulatory activity was induced by human MGF and Goldspink-MGF, respectively.	1	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MGF	MGF	MGF	IGF-IR	IGF-IR	IGF-IR	8	9	1	2
We conclude that : 1 ) insulin at physiological concentrations selectively activates IR signaling in bAECs ; 2 ) bAECs express IGF-IR and insulin and IGF-I hybrid receptors in addition to IR ; 3 ) high concentrations of insulin ( > or = 1-5 nM ) activate IGF-IR and hybrid receptors as well as IR ; and 4 ) this crossover activation can confound interpretation of studies of insulin action in ECs when high insulin concentrations are used .	We conclude that : 1) insulin at physiological concentrations selectively activates IR signaling in bAECs; 2) bAECs express IGF-IR and insulin and IGF-I hybrid receptors in addition to IR; 3) high concentrations of insulin (> or = 1-5 nM) activate IGF-IR and hybrid receptors as well as IR; and 4) this crossover activation can confound interpretation of studies of insulin action in ECs when high insulin concentrations are used.	25	50	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	25	26	47	48
demonstrated that IGFBP2 recruits endothelial cells to metastatic breast cancer cells by modulating IGF1 mediated activation of IGF1R .	demonstrated that IGFBP2 recruits endothelial cells to metastatic breast cancer cells by modulating IGF1 mediated activation of IGF1R.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	13	14	17	18
The signal transduction of the IGF signaling pathway is initiated by the activation of IGF-1R by IGF-1 .	The signal transduction of the IGF signaling pathway is initiated by the activation of IGF-1R by IGF-1.	9	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	16	17	14	15
Thus , in the medium , either IGF1 or insulin activates IGF1R , and its signal is transduced to AKT .	Thus, in the medium, either IGF1 or insulin activates IGF1R, and its signal is transduced to AKT.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	7	8	11	12
IGF-I similarly induced IGF-IR activation in kaempferol treated cells , but to a lesser degree , indicating that kaempferol inhibited IGF-IR activation ( XREF_FIG ) .	IGF-I similarly induced IGF-IR activation in kaempferol treated cells, but to a lesser degree, indicating that kaempferol inhibited IGF-IR activation (XREF_FIG).	0	4	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	0	1	3	4
Activation of IGF-1R by IGF-1 or inhibition of IGF-1R by R1507 had minimal effect on ERK activation in either R1507 sensitive or resistant lines .	Activation of IGF-1R by IGF-1 or inhibition of IGF-1R by R1507 had minimal effect on ERK activation in either R1507 sensitive or resistant lines.	0	8	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	4	5	2	3
As demonstrated in XREF_FIG , metformin could significantly attenuate the IGF-1 induced activation of IGF-1R , AKT and ERK in a panel of NSCLC cell lines , which could at least partially explain the antitumor effects of metformin in XREF_FIG .	As demonstrated in XREF_FIG, metformin could significantly attenuate the IGF-1 induced activation of IGF-1R, AKT and ERK in a panel of NSCLC cell lines, which could at least partially explain the antitumor effects of metformin in XREF_FIG.	9	18	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	10	11	14	15
In addition , the mRNA expression of IGF-1R in morula-stage embryos treated with IGF-1 was determined .	In addition, the mRNA expression of IGF-1R in morula-stage embryos treated with IGF-1 was determined.	5	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	13	14	7	8
IGF-1-mediated activation of neurotropin receptors , and IGF-1R activation ( by IGF-1 or insulin ) involves signaling of downstream proteins .	IGF-1-mediated activation of neurotropin receptors, and IGF-1R activation (by IGF-1 or insulin) involves signaling of downstream proteins.	7	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	11	12	7	8
Addition of 25 ng/mL IGF-I to P6 cell media ( XREF_FIG , lane 2 ( positive control ) stimulated the phosphorylation of IGF-IRbeta ( Tyr1135 ) ( +2700 % ) compared to P6 cells incubated in media lacking IGF-I ( XREF_FIG , lane 1 , negative control ) , confirming that IGF-I stimulates IGF-1R activity in P6 cells .	Addition of 25 ng/mL IGF-I to P6 cell media (XREF_FIG, lane 2 (positive control) stimulated the phosphorylation of IGF-IRbeta (Tyr1135) (+2700%) compared to P6 cells incubated in media lacking IGF-I (XREF_FIG, lane 1, negative control), confirming that IGF-I stimulates IGF-1R activity in P6 cells.	51	54	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-1R	IGF-1R	IGF-1R	51	52	53	54
This IGF-1 expression may serve as a paracrine growth factor to activate the IGF-1R pathway and the downstream Ras/PI3K/Akt/mTOR pathway in pancreatic cells .	This IGF-1 expression may serve as a paracrine growth factor to activate the IGF-1R pathway and the downstream Ras/PI3K/Akt/mTOR pathway in pancreatic cells.	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1 expression	igf-1	IGF-1R	IGF-1R	igf-1r	1	2	13	14
Not unexpectedly , IGF1R is activated by IGF1 present in the serum , as it is blocked by IGF1R blocking antibody or serum starvation , and is activated in the absence of serum by exogenous IGF1 ( XREF_FIG ) .	Not unexpectedly, IGF1R is activated by IGF1 present in the serum, as it is blocked by IGF1R blocking antibody or serum starvation, and is activated in the absence of serum by exogenous IGF1 (XREF_FIG).	3	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	7	8	3	4
Our finding that full-length MGF directly stimulates the IGF-IR , challenges the current concept that the E-peptide of pro-IGF-I has to be cleaved off from the IGF-I molecule to become biologically active [ XREF_BIBR , XREF_BIBR ] .	Our finding that full-length MGF directly stimulates the IGF-IR, challenges the current concept that the E-peptide of pro-IGF-I has to be cleaved off from the IGF-I molecule to become biologically active [XREF_BIBR, XREF_BIBR].	3	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MGF	MGF	MGF	IGF-IR	IGF-IR	IGF-IR	4	5	8	9
Why the IGF-IR can not be activated even by pharmacological doses of IGF-1 in AD brain is so far unexplained .	Why the IGF-IR can not be activated even by pharmacological doses of IGF-1 in AD brain is so far unexplained.	1	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-IR	IGF-IR	IGF-IR	12	13	2	3
IGF-1 upregulates cell cycle progression primarily by activating the phosphatidylinositol 3-kinase ( PI3K )/Akt/mammalian target of rapamycin ( mTOR ) signal transduction pathway downstream of IGF-1R .	IGF-1 upregulates cell cycle progression primarily by activating the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signal transduction pathway downstream of IGF-1R.	0	26	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	25	26
Functionally , we found that endogenous IGF1R is internalized into an SNX1 decorated compartment in MCF-7 cells treated with IGF-1 ( XREF_FIG ) .	Functionally, we found that endogenous IGF1R is internalized into an SNX1 decorated compartment in MCF-7 cells treated with IGF-1 (XREF_FIG).	5	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	19	20	6	7
Western blot analysis showed that IGF1 induced activation of IGF-1R that was blocked by A12 corroborating the clonogenic cell survival data .	Western blot analysis showed that IGF1 induced activation of IGF-1R that was blocked by A12 corroborating the clonogenic cell survival data.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF-1R	IGF-1R	IGF-1R	5	6	9	10
IGF-1R is activated by its ligands IGF-1 and IGF-2 .	IGF-1R is activated by its ligands IGF-1 and IGF-2.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	6	7	0	1
IGF1R was activated by IGF-1 but not by insulin in each sarcoma model .	IGF1R was activated by IGF-1 but not by insulin in each sarcoma model.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	4	5	0	1
Thus , IGF-1 and IGF-2 promote hCSC division by activating IGF-1R , while IGF-2R has no influence on hCSC replication .	Thus, IGF-1 and IGF-2 promote hCSC division by activating IGF-1R, while IGF-2R has no influence on hCSC replication.	2	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	2	3	10	11
10 Although these opposite processes of cell growth may be cell context dependent , whether activation of IGF-1R by IGF-1 or IGF-2 regulates exclusively hCSC division or induces also the commitment of hCSCs to the myocyte lineage is presently unknown .	10 Although these opposite processes of cell growth may be cell context dependent, whether activation of IGF-1R by IGF-1 or IGF-2 regulates exclusively hCSC division or induces also the commitment of hCSCs to the myocyte lineage is presently unknown.	15	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	19	20	17	18
Additionally , the response of hCSCs to IGFs may be time dependent ; the early activation of IGF-1R by IGF-1 or IGF-2 and cell multiplication ( see XREF_FIG ) may be followed by hCSC differentiation .	Additionally, the response of hCSCs to IGFs may be time dependent; the early activation of IGF-1R by IGF-1 or IGF-2 and cell multiplication (see XREF_FIG) may be followed by hCSC differentiation.	15	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	19	20	17	18
The IR-A and IGF1R hybrid receptors are strongly activated by IGF-I and IGF-II and weakly activated by insulin .	The IR-A and IGF1R hybrid receptors are strongly activated by IGF-I and IGF-II and weakly activated by insulin.	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF1R	IGF1R	IGF1R	10	11	3	4
The BMOp cells from unloaded bone demonstrate a failure to activate the IGF-I receptor and downstream signaling cascades when treated with IGF-I .	The BMOp cells from unloaded bone demonstrate a failure to activate the IGF-I receptor and downstream signaling cascades when treated with IGF-I.	12	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	21	22	12	14
As a negative control , IGF-1 did not induce IGF-1R activation .	As a negative control, IGF-1 did not induce IGF-1R activation.	5	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	5	6	9	10
Furthermore , IGF-1 , ligand of IGF-1R , induced the up-regulation of IGF-1R and increased the proliferation of leukemia cell line .	Furthermore, IGF-1, ligand of IGF-1R, induced the up-regulation of IGF-1R and increased the proliferation of leukemia cell line.	2	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	2	3	12	13
IGFBP2 produced by metastatic cells has been reported to recruit endothelia by modulating IGF1 mediated activation of IGF1R on endothelial cells resulting in enhanced endothelial migration towards metastatic cells [ XREF_BIBR ] .	IGFBP2 produced by metastatic cells has been reported to recruit endothelia by modulating IGF1 mediated activation of IGF1R on endothelial cells resulting in enhanced endothelial migration towards metastatic cells [XREF_BIBR].	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	13	14	17	18
IGF-1R activation by IGF-1 and IGF-2 has been shown to stimulate the growth of a wide range of cancer cells .	IGF-1R activation by IGF-1 and IGF-2 has been shown to stimulate the growth of a wide range of cancer cells.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	3	4	0	1
Examination of Met 1 breast cancer cells , overexpressing PyVmT , demonstrated that insulin and IGF-I augment the interaction of IR and IGF-IR with PyVmT , by tyrosine phosphorylation of PyVmT .	Examination of Met 1 breast cancer cells, overexpressing PyVmT, demonstrated that insulin and IGF-I augment the interaction of IR and IGF-IR with PyVmT, by tyrosine phosphorylation of PyVmT.	13	24	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	15	16	22	23
The presence of IGF-I ( 100 ng ) alone in P6 cells stimulated IGF-1R ( 100 % ) ( Lane 2 ) .	The presence of IGF-I (100 ng) alone in P6 cells stimulated IGF-1R (100%) (Lane 2).	1	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-1R	IGF-1R	IGF-1R	3	4	13	14
Specifically , when tested in vitro at ratios that were detected in normal human tears , IGFBP3 was not able to inhibit activation of the receptor by IGF-1 ; however , IGFBP3 completely abrogated IGF-1 activation of the IGF-1R when tested at a ratio replicating that found in diabetic tears .	Specifically, when tested in vitro at ratios that were detected in normal human tears, IGFBP3 was not able to inhibit activation of the receptor by IGF-1; however, IGFBP3 completely abrogated IGF-1 activation of the IGF-1R when tested at a ratio replicating that found in diabetic tears.	34	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	34	35	38	39
We also found that both IGF1R and IR are activated by IGF-1 or exercise , implying that IGF1R- and IR mediated signals could contribute to hypertrophic responses of the heart to exercise training .	We also found that both IGF1R and IR are activated by IGF-1 or exercise, implying that IGF1R- and IR mediated signals could contribute to hypertrophic responses of the heart to exercise training.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	11	12	5	6
IGF1 mediated IGF1R activation attenuated the sensitivity to gefitinib and induced EMT in parental PC9 cells .	IGF1 mediated IGF1R activation attenuated the sensitivity to gefitinib and induced EMT in parental PC9 cells.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	0	1	2	3
Intraocular , but not systemic expression of IGF-1 increases IGF-1R content and signaling and led to accumulation of VEGF and increased retinal vessel paracellular permeability [ XREF_BIBR ] .	Intraocular, but not systemic expression of IGF-1 increases IGF-1R content and signaling and led to accumulation of VEGF and increased retinal vessel paracellular permeability [XREF_BIBR].	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	7	8	9	10
Importantly , phenformin significantly suppressed IGF1 induced IGF1R activation .	Importantly, phenformin significantly suppressed IGF1 induced IGF1R activation.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	5	6	7	8
Next , we determined whether IGF-1 signaling can be inhibited using inhibitors of IGF-1R , PI3K , and AKT .	Next, we determined whether IGF-1 signaling can be inhibited using inhibitors of IGF-1R, PI3K, and AKT.	5	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	5	6	13	14
Leptin and IGF1 then act in an autocrine and paracrine manner to enhance both leptin and IGF1R signaling in breast epithelial cells .	Leptin and IGF1 then act in an autocrine and paracrine manner to enhance both leptin and IGF1R signaling in breast epithelial cells.	0	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	2	3	16	17
Relatively high IGF-1R levels on TAO fibroblasts result in proliferation when treated with IGF-1 .	Relatively high IGF-1R levels on TAO fibroblasts result in proliferation when treated with IGF-1.	2	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	13	14	2	3
IGF-I and high concentrations of glargine and insulin activates the IGF-IR .	IGF-I and high concentrations of glargine and insulin activates the IGF-IR.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	0	1	10	11
These findings suggest that both IGF1R and IR can be activated by IGF-1 and may contribute to the development of exercise induced cardiac hypertrophy in a functionally redundant fashion .	These findings suggest that both IGF1R and IR can be activated by IGF-1 and may contribute to the development of exercise induced cardiac hypertrophy in a functionally redundant fashion.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	12	13	5	6
Due to structural and functional similarity , insulin and IGF-1 can activate both IR and IGF-1R , however they exhibit higher affinity to own receptors ( < 1 nM ) .	Due to structural and functional similarity, insulin and IGF-1 can activate both IR and IGF-1R, however they exhibit higher affinity to own receptors (< 1 nM).	7	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	9	10	15	16
3.3 IGF-1 stimulation of IGF-1R and its downstream signaling .	3.3 IGF-1 stimulation of IGF-1R and its downstream signaling.	1	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	1	2	4	5
Both IGF1 and insulin are capable of binding and activating the IGF1R .	Both IGF1 and insulin are capable of binding and activating the IGF1R.	0	12	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	1	2	11	12
Moreover , metformin suppressed the activation of IGF-1R stimulated by IGF-1 .	Moreover, metformin suppressed the activation of IGF-1R stimulated by IGF-1.	5	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	10	11	7	8
Significant evidence has implicated IGF1-R in the pathogenesis of GO XREF_BIBR , XREF_BIBR and IGF-1 induces hyaluronan synthesis in GO fibroblasts XREF_BIBR , as well as cytokine responses XREF_BIBR , XREF_BIBR .	Significant evidence has implicated IGF1-R in the pathogenesis of GO XREF_BIBR, XREF_BIBR and IGF-1 induces hyaluronan synthesis in GO fibroblasts XREF_BIBR, as well as cytokine responses XREF_BIBR, XREF_BIBR.	3	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1-R	IGF1-R	IGF1-R	14	15	4	5
Diet induced changes in circulating IGF-1 modulate IGF-1R and EGFR activation and downstream signaling to Akt and mTOR .	Diet induced changes in circulating IGF-1 modulate IGF-1R and EGFR activation and downstream signaling to Akt and mTOR.	4	10	modulate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	5	6	7	8
Therefore , IGF-1 can promote ovarian cancer stem cell proliferation by activating IGF-1R , and NVP can block this effect .	Therefore, IGF-1 can promote ovarian cancer stem cell proliferation by activating IGF-1R, and NVP can block this effect.	2	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	2	3	12	13
This may be relevant to MM cells in the bone marrow , where malignant cells stimulate the bone marrow stromal cells ( BMSCs ) to produce the cytokines IL-6 and IGF1 , which stimulates the IL6 and IGF1R receptors respectively , leading to activation of AKT ( and ERK ) signaling .	This may be relevant to MM cells in the bone marrow, where malignant cells stimulate the bone marrow stromal cells (BMSCs) to produce the cytokines IL-6 and IGF1, which stimulates the IL6 and IGF1R receptors respectively, leading to activation of AKT (and ERK) signaling.	25	38	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	30	31	37	38
In contrast , IGF1 induced a transient activation of IGF-1R and AKT , irrespective of trametinib treatment , with phosphorylation returning to basal levels at later ( > 8 hours ) time points ( XREF_SUPPLEMENTARY ) .	In contrast, IGF1 induced a transient activation of IGF-1R and AKT, irrespective of trametinib treatment, with phosphorylation returning to basal levels at later (> 8 hours) time points (XREF_SUPPLEMENTARY).	3	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF-1R	IGF-1R	IGF-1R	3	4	9	10
EGFR phosphorylation correlated directly with IGF-1 induced activation of the IGF-1R .	EGFR phosphorylation correlated directly with IGF-1 induced activation of the IGF-1R.	2	11	induced	Positive_early_activation	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	5	6	10	11
These results suggest that NBI-31772 produces behavioral effects by increasing levels of IGF-I that in turn activate the IGF-I receptor .	These results suggest that NBI-31772 produces behavioral effects by increasing levels of IGF-I that in turn activate the IGF-I receptor.	10	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	levels of IGF-I	igf-i	IGF-I receptor	IGF-I receptor	igf-i receptor	12	13	18	20
IGF-1 , IGF-2 , and high concentrations of insulin can activate the IGF-1R resulting in tyrosine kinase activity .	IGF-1, IGF-2, and high concentrations of insulin can activate the IGF-1R resulting in tyrosine kinase activity.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	0	1	12	13
Across cell lines , activation of IGF1R by IGF-1 occurred within a narrow range of concentrations ( EC 50 : 0.2 to 2.7 nM ) .	Across cell lines, activation of IGF1R by IGF-1 occurred within a narrow range of concentrations (EC 50 : 0.2 to 2.7 nM).	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	8	9	6	7
Thus , IGF-1 and exercise may activate both IGF1R and IR in the heart , and IGF1R- and IR mediated signals may play redundant roles in the development of cardiac hypertrophy in response to exercise training .	Thus, IGF-1 and exercise may activate both IGF1R and IR in the heart, and IGF1R- and IR mediated signals may play redundant roles in the development of cardiac hypertrophy in response to exercise training.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	2	3	8	9
Increased signaling from IGF1R activated by IGF1 activates the PI3K signaling pathway .	Increased signaling from IGF1R activated by IGF1 activates the PI3K signaling pathway.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	6	7	3	4
As outlined above , it is likely that both IGF-I and IGF-II stimulate the IGF-IR during early growth as has been shown for IGF ligand actions in fetal growth .	As outlined above, it is likely that both IGF-I and IGF-II stimulate the IGF-IR during early growth as has been shown for IGF ligand actions in fetal growth.	8	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	9	10	14	15
On the other hand , IGF1R activation ( primarily by IGF1 or IGF2 ) is mainly linked to growth and differentiation .	On the other hand, IGF1R activation (primarily by IGF1 or IGF2) is mainly linked to growth and differentiation.	5	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	10	11	5	6
While Aleksic et al [ XREF_BIBR ] showed that IGF1 stimulated IGF1R activation is indeed required for nuclear translocation , our present data indicates that nuclear IGF1R transport may occur in a ligand independent manner .	While Aleksic et al [XREF_BIBR] showed that IGF1 stimulated IGF1R activation is indeed required for nuclear translocation, our present data indicates that nuclear IGF1R transport may occur in a ligand independent manner.	9	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	9	10	11	12
In OV-90 cells , IGF-I and insulin activated IGF-IR at low concentrations but did not display concentration dependent activation .	In OV-90 cells, IGF-I and insulin activated IGF-IR at low concentrations but did not display concentration dependent activation.	4	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	4	5	8	9
We found that IGF-1 was only able to activate IGF1R and Akt in recipient cells when it was mixed with CM from TSC2 +/+ cells , but not with that from TSC2-/- cells ( XREF_FIG ) .	We found that IGF-1 was only able to activate IGF1R and Akt in recipient cells when it was mixed with CM from TSC2 +/+ cells, but not with that from TSC2-/- cells (XREF_FIG).	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	3	4	9	10
In cultured myoblasts , growth factor deprivation initiates the differentiation program owing to the induction of IGF-II and subsequent activation of the IGF-I receptor and a major downstream pathway mediated by PI3K and Akt .	In cultured myoblasts, growth factor deprivation initiates the differentiation program owing to the induction of IGF-II and subsequent activation of the IGF-I receptor and a major downstream pathway mediated by PI3K and Akt.	16	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-I receptor	IGF-I receptor	IGF-I receptor	16	17	22	24
Although tamoxifen resistant cells expressed reduced IGF1R protein levels compared with the wild-type MCF-7 cells , phosphorylated IGF1R protein levels were similar in the two cell lines under basal growth conditions , possibly as a consequence of increased IGF2 expression , which activated both IGF1R and EGFR .	Although tamoxifen resistant cells expressed reduced IGF1R protein levels compared with the wild-type MCF-7 cells, phosphorylated IGF1R protein levels were similar in the two cell lines under basal growth conditions, possibly as a consequence of increased IGF2 expression, which activated both IGF1R and EGFR.	38	46	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2 expression	igf2	IGF1R	IGF1R	igf1r	38	39	44	45
The model was calibrated and validated using an ovarian cancer cell line , OVCAR5 , and then analyzed to determine the relative impact of IGF2R and IGFBPs on IGF2 mediated IGF1R activation .	The model was calibrated and validated using an ovarian cancer cell line, OVCAR5, and then analyzed to determine the relative impact of IGF2R and IGFBPs on IGF2 mediated IGF1R activation.	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IGF1R	IGF1R	IGF1R	28	29	30	31
The increase in IGF2 transcription via beta-AR , signal transducer and activator of transcription 3 ( STAT3 ) , and nuclear factor-kappa B ( NF-kappaB ) was associated with NNK induced IGF-1R activation .	The increase in IGF2 transcription via beta-AR, signal transducer and activator of transcription 3 (STAT3), and nuclear factor-kappa B (NF-kappaB) was associated with NNK induced IGF-1R activation.	3	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2 transcription	igf2	IGF-1R	IGF-1R	igf-1r	3	4	31	32
Other known examples include MET activation in SNU-5 ( MET amplification ) XREF_BIBR and H2009 ( constitutive MET phosphorylation ) XREF_BIBR ; EGFR in HCC827 , HCC4006 ( EGFR exon19del mutant ) XREF_BIBR ; ERBB3 in MDAMB453 ( constitutive ERBB3 phosphorylation ) XREF_BIBR ; FGFR2 in KATOIII ( FGFR2 amplification ) XREF_BIBR ; IGF1R in Huh7 ( increased expression and secretion of IGF2 leads to constitutive IGF1R activation ) XREF_BIBR .	Other known examples include MET activation in SNU-5 (MET amplification) XREF_BIBR and H2009 (constitutive MET phosphorylation) XREF_BIBR; EGFR in HCC827, HCC4006 (EGFR exon19del mutant) XREF_BIBR; ERBB3 in MDAMB453 (constitutive ERBB3 phosphorylation) XREF_BIBR; FGFR2 in KATOIII (FGFR2 amplification) XREF_BIBR; IGF1R in Huh7 (increased expression and secretion of IGF2 leads to constitutive IGF1R activation) XREF_BIBR.	58	67	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IGF2	expression and secretion of IGF2	igf2	IGF1R	IGF1R	igf1r	62	63	66	67
In murine cancer models methylation changes in the differentially methylated region 2 of IGF2 have been associated with overexpression of IGF2 [ XREF_BIBR ] , which in turn might activate IGF1R signalling and increase cell growth .	In murine cancer models methylation changes in the differentially methylated region 2 of IGF2 have been associated with overexpression of IGF2 [XREF_BIBR], which in turn might activate IGF1R signalling and increase cell growth.	18	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	overexpression of IGF2	igf2	IGF1R	IGF1R	igf1r	20	21	30	31
Gene profiling identifies pancreatic CCR2+ myeloid cells as a prominent source of IGF2 , which contributes to IGF1R mediated islet proliferation .	Gene profiling identifies pancreatic CCR2+ myeloid cells as a prominent source of IGF2, which contributes to IGF1R mediated islet proliferation.	10	18	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IGF1R	IGF1R	IGF1R	12	13	17	18
IGF-II , produced by breast cancer epithelial and stromal cells , enhances tumor growth by activating the IGF-I receptor ( IGF-I-R ) via autocrine and paracrine mechanisms .	IGF-II, produced by breast cancer epithelial and stromal cells, enhances tumor growth by activating the IGF-I receptor (IGF-I-R) via autocrine and paracrine mechanisms.	0	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-I receptor	IGF-I receptor	IGF-I receptor	0	1	17	19
IGF-II Promotes NSP Self-Renewal Independent of IGF-1R .	IGF-II Promotes NSP Self-Renewal Independent of IGF-1R.	0	7	Promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-1R	IGF-1R	IGF-1R	0	1	6	7
Igf2 is both necessary and sufficient to promote progenitor proliferation in culture , and genetic perturbations of Igf2 or its receptor Igf1R lead to microcephaly in mice .	Igf2 is both necessary and sufficient to promote progenitor proliferation in culture, and genetic perturbations of Igf2 or its receptor Igf1R lead to microcephaly in mice.	0	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Igf2	Igf2	Igf2	Igf1R	Igf1R	Igf1R	0	1	21	22
However , IR could replace IGF-IR if efficiently activated by IGF-II .	However, IR could replace IGF-IR if efficiently activated by IGF-II.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-IR	IGF-IR	IGF-IR	10	11	5	6
Furthermore , the IGF-II and IGF1R signaling plays an important role in the CAF-CSC interaction , in that IGF-II activates IGF1R , followed by phosphorylation of Akt and expression of Nanog [ XREF_BIBR ] .	Furthermore, the IGF-II and IGF1R signaling plays an important role in the CAF-CSC interaction, in that IGF-II activates IGF1R, followed by phosphorylation of Akt and expression of Nanog [XREF_BIBR].	17	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF1R	IGF1R	IGF1R	18	19	20	21
IGF-1R activation is triggered by autocrine secretion of IGF-2 .	IGF-1R activation is triggered by autocrine secretion of IGF-2.	0	9	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IGF-1R	IGF-1R	IGF-1R	8	9	0	1
TGF-beta1 also diminished stimulation of IGF-II gene expression in myoblasts , decreased IGF-II secretion , and reduced IGF-I receptor activation .	TGF-beta1 also diminished stimulation of IGF-II gene expression in myoblasts, decreased IGF-II secretion, and reduced IGF-I receptor activation.	0	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-II	TGF-beta1 also diminished stimulation of IGF-II gene expression	igf-ii	IGF-I receptor	IGF-I receptor	igf-i receptor	5	6	17	19
IGF-2 activates both IGF1R and the mammalian INSR-A variant , effectively integrating signaling from both receptors XREF_BIBR .	IGF-2 activates both IGF1R and the mammalian INSR-A variant, effectively integrating signaling from both receptors XREF_BIBR.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IGF1R	IGF1R	IGF1R	0	1	3	4
These findings suggest that DNMT1 mediated aberrant methylation of the H19 and IGF2 ICR enables vorinostat induced IGF2 overexpression and IGF-1R activation .	These findings suggest that DNMT1 mediated aberrant methylation of the H19 and IGF2 ICR enables vorinostat induced IGF2 overexpression and IGF-1R activation.	7	21	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	methylation of the H19 and IGF2	igf2	IGF-1R	IGF-1R	igf-1r	12	13	20	21
Interestingly , the expression of IGF2R was inversely correlated with heart weight and a stronger inverse relationship existed when the analysis was restricted to the embryo culture groups only , suggesting that IGF2R plays the role of a clearance receptor for IGF2 , and thus decreased IGF2R signalling may be responsible for the increase in heart weight because less IGF2 is available to activate the IGF1R signalling pathway leading to cardiac growth [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Interestingly, the expression of IGF2R was inversely correlated with heart weight and a stronger inverse relationship existed when the analysis was restricted to the embryo culture groups only, suggesting that IGF2R plays the role of a clearance receptor for IGF2, and thus decreased IGF2R signalling may be responsible for the increase in heart weight because less IGF2 is available to activate the IGF1R signalling pathway leading to cardiac growth [XREF_BIBR, XREF_BIBR, XREF_BIBR].	58	67	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IGF1R	IGF1R	IGF1R	59	60	65	66
IGF1R is activated by IGF2 , which is secreted by cancer associated fibroblasts in a paracrine manner .	IGF1R is activated by IGF2, which is secreted by cancer associated fibroblasts in a paracrine manner.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IGF1R	IGF1R	IGF1R	4	5	0	1
It is hypothesized that by blocking the activation of AKT by IGF-II stimulation of IGF-1R , ACC tumors may be more sensitive to cytotoxic chemotherapy .	It is hypothesized that by blocking the activation of AKT by IGF-II stimulation of IGF-1R, ACC tumors may be more sensitive to cytotoxic chemotherapy.	11	15	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-1R	IGF-1R	IGF-1R	11	12	14	15
Because IGF2 targeting antibody inhibits ligand activation of both IGF1R and IR-A , IGF2 targeting treatment may offer better outcomes compared with IGF1R targeting or IGF1R and INSR targeting therapy .	Because IGF2 targeting antibody inhibits ligand activation of both IGF1R and IR-A, IGF2 targeting treatment may offer better outcomes compared with IGF1R targeting or IGF1R and INSR targeting therapy.	1	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF2	IGF2	IGF2	IGF1R	IGF1R	IGF1R	1	2	9	10
This assay also detects IGF-II and pro-IGF-II activation of the IGF-IR ( cross-reactivity 12 % and 2 % , respectively ) , but the cross-reactivity of proinsulin and insulin is negligible ( < 1 % ) .	This assay also detects IGF-II and pro-IGF-II activation of the IGF-IR (cross-reactivity 12% and 2%, respectively), but the cross-reactivity of proinsulin and insulin is negligible (< 1%).	4	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-IR	IGF-IR	IGF-IR	4	5	10	11
LOI leads to overexpression of IGF2 , activates IGF1R and AKT1 , and is a powerful driver of cell proliferation .	LOI leads to overexpression of IGF2, activates IGF1R and AKT1, and is a powerful driver of cell proliferation.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	LOI leads to overexpression of IGF2	igf2	IGF1R	IGF1R	igf1r	5	6	8	9
In this model , IGF-II activates IGF-IR in hyperproliferative , oncogene expressing beta cells and is uniformly expressed in invasive tumors .	In this model, IGF-II activates IGF-IR in hyperproliferative, oncogene expressing beta cells and is uniformly expressed in invasive tumors.	4	17	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-IR	IGF-IR	IGF-IR	4	5	6	7
If the hypothesis that IGF2 stimulates IGF1R mediated signaling downstream of MEK is correct , then ectopic expression of IGF2 in KRAS G12D - and BRAF V600E -expressing cells should rescue survival in the setting of MEK inhibition , but not PI3K inhibition .	If the hypothesis that IGF2 stimulates IGF1R mediated signaling downstream of MEK is correct, then ectopic expression of IGF2 in KRAS G12D - and BRAF V600E -expressing cells should rescue survival in the setting of MEK inhibition, but not PI3K inhibition.	4	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IGF1R	IGF1R	IGF1R	4	5	6	7
Phosphorylation of Igf1R and Akt increased dramatically when treated with exogenous Igf2 protein .	Phosphorylation of Igf1R and Akt increased dramatically when treated with exogenous Igf2 protein.	0	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Igf2	Igf2	Igf2	Igf1R	Igf1R	Igf1R	11	12	2	3
Given that IGF-II can activate both IGF-1R and IR-A , we hypothesized that IGF-II-mediated IR signaling may facilitate de novo resistance to IGF-1R antibodies .	Given that IGF-II can activate both IGF-1R and IR-A, we hypothesized that IGF-II-mediated IR signaling may facilitate de novo resistance to IGF-1R antibodies.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-1R	IGF-1R	IGF-1R	2	3	6	7
In contrast , IGF-I receptor down-regulation induced by IGF-II is mediated through IGF-I , but not IGF-II , receptors in muscle cells .	In contrast, IGF-I receptor down-regulation induced by IGF-II is mediated through IGF-I, but not IGF-II, receptors in muscle cells.	3	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-I receptor	IGF-I receptor	IGF-I receptor	8	9	3	5
This paper shows that IGF-2 is able to promote breast cancer cell survival by activating the IGF-1R and the IR-A which promotes the activation of cell survival pathways .	This paper shows that IGF-2 is able to promote breast cancer cell survival by activating the IGF-1R and the IR-A which promotes the activation of cell survival pathways.	4	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IGF-1R	IGF-1R	IGF-1R	4	5	16	17
Indeed , we showed that Igf2 expression is induced downstream of MEK , resulting in the autocrine activation of IGF1R and subsequent stimulation of the PI3K and AKT pathway .	Indeed, we showed that Igf2 expression is induced downstream of MEK, resulting in the autocrine activation of IGF1R and subsequent stimulation of the PI3K and AKT pathway.	5	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Igf2	Igf2 expression	igf2	IGF1R	IGF1R	igf1r	5	6	19	20
For example , when RM11A murine breast cancer cells that express high levels of exogenous IGF-IR were treated with IGF-I or IGF-II , the proliferative and survival potential of these cells was not enhanced , suggesting a ligand independent mechanism [ XREF_BIBR ] .	For example, when RM11A murine breast cancer cells that express high levels of exogenous IGF-IR were treated with IGF-I or IGF-II, the proliferative and survival potential of these cells was not enhanced, suggesting a ligand independent mechanism [XREF_BIBR].	12	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-IR	IGF-IR	IGF-IR	21	22	15	16
In contrast , the overexpression of MyoD ( a protein that plays a major role in regulating muscle differentiation ) in C3H 10T1/2 mouse embryonic fibroblast cells induces IGF-2 expression which in turn activates IGF-1R and its downstream target AKT [ XREF_BIBR ] .	In contrast, the overexpression of MyoD (a protein that plays a major role in regulating muscle differentiation) in C3H 10T1/2 mouse embryonic fibroblast cells induces IGF-2 expression which in turn activates IGF-1R and its downstream target AKT [XREF_BIBR].	28	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-2	IGF-2 expression	igf-2	IGF-1R	IGF-1R	igf-1r	28	29	34	35
The FnIII-1 domain antibodies were also mechanistically distinct ; characterized by high agonistic activity , potent receptor downregulation , inefficient inhibition of IGF1R activation by IGF-2 , and inefficient inhibition IGF1R and INSR hybrid activation by IGF-1 and IGF-2 .	The FnIII-1 domain antibodies were also mechanistically distinct; characterized by high agonistic activity, potent receptor downregulation, inefficient inhibition of IGF1R activation by IGF-2, and inefficient inhibition IGF1R and INSR hybrid activation by IGF-1 and IGF-2.	22	26	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IGF1R	IGF1R	IGF1R	25	26	22	23
Rotwein and colleagues have reported that in cultured muscle cells , secreted IGF-II stimulates the IGF-IR , PI3K , and Akt to induce the expression of the cyclin dependent kinase inhibitor p21 and Myogenin , and through this mechanism , maintains myoblast viability during early myogenesis .	Rotwein and colleagues have reported that in cultured muscle cells, secreted IGF-II stimulates the IGF-IR, PI3K, and Akt to induce the expression of the cyclin dependent kinase inhibitor p21 and Myogenin, and through this mechanism, maintains myoblast viability during early myogenesis.	12	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-IR	IGF-IR	IGF-IR	12	13	15	16
To confirm that m610 prevents signal transduction mediated by receptor interaction with IGF-2 in MDA PCa 2b cells , we firstly investigated whether IGF-2 activates IGF-1R and IR in the cells by immunoprecipitation-western blot analysis .	To confirm that m610 prevents signal transduction mediated by receptor interaction with IGF-2 in MDA PCa 2b cells, we firstly investigated whether IGF-2 activates IGF-1R and IR in the cells by immunoprecipitation-western blot analysis.	23	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IGF-1R	IGF-1R	IGF-1R	23	24	25	26
At low concentrations , IGF-I was more potent than IGF-II in inhibiting IGF-I receptor mRNA accumulation , suggesting that IGF-I receptor down-regulation induced by IGF-II is mediated principally through the IGF-I receptor in these cells .	At low concentrations, IGF-I was more potent than IGF-II in inhibiting IGF-I receptor mRNA accumulation, suggesting that IGF-I receptor down-regulation induced by IGF-II is mediated principally through the IGF-I receptor in these cells.	19	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-I receptor	IGF-I receptor	IGF-I receptor	24	25	19	21
In addition to IGF1R , IGF2 also activates the insulin receptor ( IR ) isoform A and therefore antibodies against IGF2 can inhibit cell proliferation mediated by the signaling through both IGF1R and IR triggered by IGF2 .	In addition to IGF1R, IGF2 also activates the insulin receptor (IR) isoform A and therefore antibodies against IGF2 can inhibit cell proliferation mediated by the signaling through both IGF1R and IR triggered by IGF2.	25	37	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IGF1R	IGF1R	IGF1R	36	37	31	32
Dissecting the effects of local IGF-1 levels in VSMC is impractical because their complex distribution modulated by several high affinity binding proteins , and IGF-1R signaling could also be activated by IGF-II and insulin ligands .	Dissecting the effects of local IGF-1 levels in VSMC is impractical because their complex distribution modulated by several high affinity binding proteins, and IGF-1R signaling could also be activated by IGF-II and insulin ligands.	24	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-1R	IGF-1R	IGF-1R	31	32	24	25
IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program .	IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program.	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IGF1R	IGF1R	IGF1R	0	1	4	5
In order to elucidate at which level RGZ interferes with the activated IGF-I axis both in basal conditions ( IGF-IR activated by endogenously produced IGF-II ) and following a further activation of the receptor by exogenous addition of IGF-I , we investigated the signaling pathways acting downstream of the receptor .	In order to elucidate at which level RGZ interferes with the activated IGF-I axis both in basal conditions (IGF-IR activated by endogenously produced IGF-II) and following a further activation of the receptor by exogenous addition of IGF-I, we investigated the signaling pathways acting downstream of the receptor.	17	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-IR	IGF-IR	IGF-IR	24	25	19	20
Recent studies showed that epicardium secretes IGF2 , which activates IGF1R and subsequently ERK in CMs to induce proliferation XREF_BIBR , XREF_BIBR .	Recent studies showed that epicardium secretes IGF2, which activates IGF1R and subsequently ERK in CMs to induce proliferation XREF_BIBR, XREF_BIBR.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IGF1R	IGF1R	IGF1R	6	7	10	11
IGF-II stimulates both mitogenesis and myogenesis through its binding and activation of the IGF-I receptor ( IGF-IR ) .	IGF-II stimulates both mitogenesis and myogenesis through its binding and activation of the IGF-I receptor (IGF-IR).	0	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-I receptor	IGF-I receptor	IGF-I receptor	0	1	13	15
Thus , IGF-II induces IGF-I receptor down-regulation in muscle cells through multiple mechanisms , including decreasing IGF-I receptor mRNA and stimulating IGF-I receptor protein degradation .	Thus, IGF-II induces IGF-I receptor down-regulation in muscle cells through multiple mechanisms, including decreasing IGF-I receptor mRNA and stimulating IGF-I receptor protein degradation.	2	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-I receptor	IGF-I receptor	IGF-I receptor	2	3	4	6
TRIF dependent signaling following TLR3 activation acts through recruitment of the IKKs TBK1 and IKKepsilon which activate IRF3 XREF_BIBR .	TRIF dependent signaling following TLR3 activation acts through recruitment of the IKKs TBK1 and IKKepsilon which activate IRF3 XREF_BIBR.	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	14	15	17	18
Upon engagement of RIG-I or MDA5 with MAVS , MAVS activates the IKK related kinase , TBK1 and IKKi , which activates IRF3 and IRF7 , resulting in the transcription of type I interferons .	Upon engagement of RIG-I or MDA5 with MAVS, MAVS activates the IKK related kinase, TBK1 and IKKi, which activates IRF3 and IRF7, resulting in the transcription of type I interferons.	14	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKi	IKKi	IKKi	IRF3	IRF3	IRF3	18	19	22	23
The RLR adaptor MAVS and the kinases TBK1 and IKKepsilon all promoted IRF3 activation in this assay when overexpressed ( XREF_FIG ) .	The RLR adaptor MAVS and the kinases TBK1 and IKKepsilon all promoted IRF3 activation in this assay when overexpressed (XREF_FIG).	7	13	promoted	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	9	10	12	13
IRF3 is normally activated by the kinases TBK1 and IKKepsilon .	IRF3 is normally activated by the kinases TBK1 and IKKepsilon.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	9	10	0	1
Upon infection , IRF-3 is activated through phosphorylation of Ser/Thr residues in its C-terminal domain by the kinases , IKK-i and/or TBK-1 .	Upon infection, IRF-3 is activated through phosphorylation of Ser/Thr residues in its C-terminal domain by the kinases, IKK-i and/or TBK-1.	3	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKK-i	IKK-i	IKK-i	IRF-3	IRF-3	IRF-3	19	20	3	4
The MDA-5 and MAVS complex then recruits both the IKKepsilon and TBK1 and IKK alpha/beta/gamma complexes , which subsequently activate interferon regulatory factor 3 ( IRF3 ) and NF-kappaB pathways [ XREF_BIBR - XREF_BIBR ] .	The MDA-5 and MAVS complex then recruits both the IKKepsilon and TBK1 and IKK alpha/beta/gamma complexes, which subsequently activate interferon regulatory factor 3 (IRF3) and NF-kappaB pathways [XREF_BIBR - XREF_BIBR].	6	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	interferon regulatory factor 3	interferon regulatory factor 3	interferon regulatory factor 3	9	10	20	24
W protein of NiV inhibits the host IFN response by sequestering STAT1 in the nucleus [ XREF_BIBR - XREF_BIBR ] and by blocking virus and TLR3 dependent ISG induction and TBK1 and IKKepsilon mediated IRF3 activation [ XREF_BIBR ] .	W protein of NiV inhibits the host IFN response by sequestering STAT1 in the nucleus [XREF_BIBR - XREF_BIBR] and by blocking virus and TLR3 dependent ISG induction and TBK1 and IKKepsilon mediated IRF3 activation [XREF_BIBR].	28	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	32	33	34	35
IPS-1 located on the mitochondrial membrane mediates the induction of proinflammatory cytokines via activation of the IKK kinase complex and NFkappaB , while it also mediates the induction of IFNs through the IKK related kinases TBK1 and IKKepsilon which activate IRF3 .	IPS-1 located on the mitochondrial membrane mediates the induction of proinflammatory cytokines via activation of the IKK kinase complex and NFkappaB, while it also mediates the induction of IFNs through the IKK related kinases TBK1 and IKKepsilon which activate IRF3.	25	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	37	38	40	41
TRIF enlists the non canonical IKKs , TBK1 and IKKepsilon , which activate IRF3 .	TRIF enlists the non canonical IKKs, TBK1 and IKKepsilon, which activate IRF3.	5	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	9	10	13	14
Consequently , the expression of M protein prevents the formation of TRAF3.TANK.TBK1 and IKKepsilon complex and thereby inhibits TBK1 and IKKepsilon dependent activation of IRF3 and IRF7 transcription factors .	Consequently, the expression of M protein prevents the formation of TRAF3.TANK.TBK1 and IKKepsilon complex and thereby inhibits TBK1 and IKKepsilon dependent activation of IRF3 and IRF7 transcription factors.	18	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	20	21	24	25
SARS M protein inhibits the activation of IRF3 mediated by both TBK1 and IKKepsilon .	SARS M protein inhibits the activation of IRF3 mediated by both TBK1 and IKKepsilon.	5	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	13	14	7	8
These data show that RIG-I and MDA5 sense DENV RNA replication and induce type I IFN responses via TBK1 and IKKepsilon mediated IRF3 signaling .	These data show that RIG-I and MDA5 sense DENV RNA replication and induce type I IFN responses via TBK1 and IKKepsilon mediated IRF3 signaling.	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	20	21	22	23
To confirm the actual contribution of TBK-1 and IRF-3 module to the TBEV induced RANTES expression , T98G cells were treated with BX795 , an inhibitor blocking TBK1- and IKKepsilon mediated activation of IRF-3 , followed by TBEV infection .	To confirm the actual contribution of TBK-1 and IRF-3 module to the TBEV induced RANTES expression, T98G cells were treated with BX795, an inhibitor blocking TBK1- and IKKepsilon mediated activation of IRF-3, followed by TBEV infection.	27	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF-3	IRF-3	IRF-3	29	30	33	34
Alternatively , some nuclear factors other than IRF3 , which are also required for activation of IFNbeta promoter activity , may not be activated by mutant IKKepsilon and dimerization of IKKepsilon is critically required for phosphorylation of the nuclear factors .	Alternatively, some nuclear factors other than IRF3, which are also required for activation of IFNbeta promoter activity, may not be activated by mutant IKKepsilon and dimerization of IKKepsilon is critically required for phosphorylation of the nuclear factors.	7	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	30	31	7	8
Finally , the ability of SARS-CoV M protein to actively interfere with the formation of the TRAF3.TANK.TBK1 and IKKepsilon complex , thereby inhibiting TBK1 and IKKepsilon dependent activation of IRF3 and IRF7 , is yet another mechanism by which SARS-CoV prevents the production of IFN-alpha and beta XREF_BIBR .	Finally, the ability of SARS-CoV M protein to actively interfere with the formation of the TRAF3.TANK.TBK1 and IKKepsilon complex, thereby inhibiting TBK1 and IKKepsilon dependent activation of IRF3 and IRF7, is yet another mechanism by which SARS-CoV prevents the production of IFN-alpha and beta XREF_BIBR.	23	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	25	26	29	30
Reintroduction of either TBK1 or IKK-i but not their KA mutants into TBK1 -/- MEFs could rescue activation of IRF3 and IFNbeta production , indicating that IKK-i may be functionally redundant with TBK1 during viral infections .	Reintroduction of either TBK1 or IKK-i but not their KA mutants into TBK1 -/- MEFs could rescue activation of IRF3 and IFNbeta production, indicating that IKK-i may be functionally redundant with TBK1 during viral infections.	0	22	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKK-i	IKK-i	IKK-i	IRF3	IRF3	IRF3	5	6	19	20
Thus , IKK-i is able to mediate IRF3 activation in response to SeV in the absence of TBK1 .	Thus, IKK-i is able to mediate IRF3 activation in response to SeV in the absence of TBK1.	2	8	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKK-i	IKK-i	IKK-i	IRF3	IRF3	IRF3	2	3	7	8
Expression of IKKepsilon , which activates IRF3 , also inhibited TGF-beta-induced transcription , and this inhibition was enhanced when wild-type IRF3 was co-expressed ( XREF_FIG ) .	Expression of IKKepsilon, which activates IRF3, also inhibited TGF-beta-induced transcription, and this inhibition was enhanced when wild-type IRF3 was co-expressed (XREF_FIG).	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	Expression of IKKepsilon	ikkepsilon	IRF3	IRF3	irf3	2	3	6	7
During viral infections , TLR3 binding to dsRNA of viruses in endosomes is linked to signaling pathways that activate cytoplasmic TBK1 and IKKepsilon , which ultimately activate IRF3 .	During viral infections, TLR3 binding to dsRNA of viruses in endosomes is linked to signaling pathways that activate cytoplasmic TBK1 and IKKepsilon, which ultimately activate IRF3.	18	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	22	23	27	28
BX795 , an inhibitor of TBK1 and IKKepsilon , inhibited the activation of IRF3 ( XREF_FIG , 4 th lane ) , and restored the inhibition of TGF-beta-induced transcription by TpIC ( XREF_FIG , lanes 3 , 4 ) .	BX795, an inhibitor of TBK1 and IKKepsilon, inhibited the activation of IRF3 (XREF_FIG, 4 th lane), and restored the inhibition of TGF-beta-induced transcription by TpIC (XREF_FIG, lanes 3, 4).	3	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	7	8	13	14
In the MyD88 independent signaling pathways , the non typical IKKs IKKi and IKKepsilon and TBK1 mediate the activation of IRF3 downstream of TRIF , 17 which is responsible for type-I IFN responses in non DCs .	In the MyD88 independent signaling pathways, the non typical IKKs IKKi and IKKepsilon and TBK1 mediate the activation of IRF3 downstream of TRIF, 17 which is responsible for type-I IFN responses in non DCs.	7	23	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKi	IKKi	IKKi	IRF3	IRF3	IRF3	11	12	20	21
Detailed analysis indicated the HBV polymerase protein can dampen the interaction between TBK1 and IKKepsilon and DDX3 [ XREF_BIBR ] , while DDX3 has been involved in TBK1 and IKKepsilon mediated IRF-3 activation [ XREF_BIBR , XREF_BIBR ] .	Detailed analysis indicated the HBV polymerase protein can dampen the interaction between TBK1 and IKKepsilon and DDX3 [XREF_BIBR], while DDX3 has been involved in TBK1 and IKKepsilon mediated IRF-3 activation [XREF_BIBR, XREF_BIBR].	25	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF-3	IRF-3	IRF-3	29	30	31	32
Both IKKepsilon and TBK1 are known to activate the transcription factors IRF3 and IRF7 to induce type I IFNs .	Both IKKepsilon and TBK1 are known to activate the transcription factors IRF3 and IRF7 to induce type I IFNs.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	1	2	11	12
Similarly , TBK and IKKi are required to activate IRF-3 XREF_BIBR .	Similarly, TBK and IKKi are required to activate IRF-3 XREF_BIBR.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKi	IKKi	IKKi	IRF-3	IRF-3	IRF-3	4	5	9	10
Besides TRIF , other upstream molecules have been identified as being responsible for IRF-3 activation , including TRAF3 , TANK , AKT , TBK1 , IKKepsilon , and IKKbeta [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Besides TRIF, other upstream molecules have been identified as being responsible for IRF-3 activation, including TRAF3, TANK, AKT, TBK1, IKKepsilon, and IKKbeta [XREF_BIBR, XREF_BIBR, XREF_BIBR].	13	26	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF-3	IRF-3	IRF-3	25	26	13	14
Phosphorylation of IKKepsilon leads to activation of IRF3 transcriptional activity and the induction of IFNbeta and various IFN stimulated genes ( ISGs ) .	Phosphorylation of IKKepsilon leads to activation of IRF3 transcriptional activity and the induction of IFNbeta and various IFN stimulated genes (ISGs).	0	9	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IKKepsilon	Phosphorylation of IKKepsilon	ikkepsilon	IRF3	IRF3	irf3	2	3	7	8
IRF3 is activated by TBK1 and IKKi in response to B-DNA transfection XREF_BIBR , suggesting that cytosolic DNA activates signaling pathways similar to RLH signaling .	IRF3 is activated by TBK1 and IKKi in response to B-DNA transfection XREF_BIBR, suggesting that cytosolic DNA activates signaling pathways similar to RLH signaling.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKi	IKKi	IKKi	IRF3	IRF3	IRF3	6	7	0	1
Activated RIG-I and MDA5 associate with the IPS-1 ( a.k.a. MAVS ) adapter to promote activation of the non classical IKK related kinases TBK-1 and IKKepsilon that activate IRF3 and NF-kappaB , which together with ATF2 and c-JUN induce production of IFNbeta that following interaction with its receptor ( IFNAR ) leads to activation of the JAK and STAT signaling pathway inducing the expression of hundreds of type I interferon ( IFN-I ) stimulated genes ( ISGs ) , to produce a cellular antiviral state .	Activated RIG-I and MDA5 associate with the IPS-1 (a.k.a. MAVS) adapter to promote activation of the non classical IKK related kinases TBK-1 and IKKepsilon that activate IRF3 and NF-kappaB, which together with ATF2 and c-JUN induce production of IFNbeta that following interaction with its receptor (IFNAR) leads to activation of the JAK and STAT signaling pathway inducing the expression of hundreds of type I interferon (IFN-I) stimulated genes (ISGs), to produce a cellular antiviral state.	22	80	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	25	26	28	29
IPS-1 , with the help of TRAF-3 , facilitates the activation of two kinases , TANK binding kinase-1 ( TBK1 ) and IKKi ( also known as IKKe ) , that go on to activate IRF-3 [ XREF_BIBR , XREF_BIBR ] .	IPS-1, with the help of TRAF-3, facilitates the activation of two kinases, TANK binding kinase-1 (TBK1) and IKKi (also known as IKKe), that go on to activate IRF-3 [XREF_BIBR, XREF_BIBR].	10	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKi	IKKi	IKKi	IRF-3	IRF-3	IRF-3	22	23	35	36
The kinases TBK-1 and IKK-epsilon activate IRF-3 and IRF-7 leading to their homo- and heterodimerization and subsequent nuclear import .	The kinases TBK-1 and IKK-epsilon activate IRF-3 and IRF-7 leading to their homo- and heterodimerization and subsequent nuclear import.	2	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKK-epsilon	IKK-epsilon	IKK-epsilon	IRF-3	IRF-3	IRF-3	4	5	6	7
The non canonical IKK family members TBK1 and IKBKE activate the interferon regulatory factor 3 ( IRF3 ) and IRF7 to form a functional homodimer or heterodimer .	The non canonical IKK family members TBK1 and IKBKE activate the interferon regulatory factor 3 (IRF3) and IRF7 to form a functional homodimer or heterodimer.	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKBKE	IKBKE	IKBKE	interferon regulatory factor 3	interferon regulatory factor 3	interferon regulatory factor 3	8	9	11	15
Our data suggest that expression of IKK-i can activate both NFkappaB and IRF3 , leading to the production of several cytokines including interferon beta .	Our data suggest that expression of IKK-i can activate both NFkappaB and IRF3, leading to the production of several cytokines including interferon beta.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKK-i	expression of IKK-i	ikk-i	IRF3	IRF3	irf3	6	7	12	13
TRIF and MAVS both activate the downstream kinases TANK binding kinase 1 ( TBK1 ) and IkappaB kinase ( IKK-epsilon ) , which in turn activates the transcription factors IRF3 and NF-kappaB to initiate type I IFN production XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	TRIF and MAVS both activate the downstream kinases TANK binding kinase 1 (TBK1) and IkappaB kinase (IKK-epsilon), which in turn activates the transcription factors IRF3 and NF-kappaB to initiate type I IFN production XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	17	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKK-epsilon	IKK-epsilon	IKK-epsilon	IRF3	IRF3	IRF3	19	20	29	30
All of these TLR independent pathways converge at the IKK related kinases , TBK1 and IKK-epsilon , which phosphorylate and activate IRF3 and IRF7 .	All of these TLR independent pathways converge at the IKK related kinases, TBK1 and IKK-epsilon, which phosphorylate and activate IRF3 and IRF7.	11	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKK-epsilon	IKK-epsilon	IKK-epsilon	IRF3	IRF3	IRF3	15	16	21	22
Recruitment of TRIF to the receptor initiates phosphorylation of IKKepsilon , which activates the transcription factors IRF3 and IRF7 , and generates anti-viral molecules such as IFN-beta .	Recruitment of TRIF to the receptor initiates phosphorylation of IKKepsilon, which activates the transcription factors IRF3 and IRF7, and generates anti-viral molecules such as IFN-beta.	2	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	TRIF to the receptor initiates phosphorylation of IKKepsilon	ikkepsilon	IRF3	IRF3	irf3	9	10	16	17
It has been shown that the noncanonical IKKs , IKKepsilon and TANK binding kinase-1 ( TBK1 ) , mediate activation of IRF3 through interaction with TRIF and TRAM , thereby inducing the IFNbeta promoter [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It has been shown that the noncanonical IKKs, IKKepsilon and TANK binding kinase-1 (TBK1), mediate activation of IRF3 through interaction with TRIF and TRAM, thereby inducing the IFNbeta promoter [XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	22	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	9	10	21	22
TLR3 recruits the adaptor molecule TRIF to induce type I IFN gene via interactions with TRAF3 , TBK1 , and IKKepsilon , which , in turn , activate the latent transcription factors IRF-3 and IRF-7 , whereas other TLRs associating with the adaptor protein MyD88 form a complex with TRAF6 , IRAK1 , and IRAK4 to activate kinases that regulate IRF-5 and IRF-7 .	TLR3 recruits the adaptor molecule TRIF to induce type I IFN gene via interactions with TRAF3, TBK1, and IKKepsilon, which, in turn, activate the latent transcription factors IRF-3 and IRF-7, whereas other TLRs associating with the adaptor protein MyD88 form a complex with TRAF6, IRAK1, and IRAK4 to activate kinases that regulate IRF-5 and IRF-7.	7	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF-3	IRF-3	IRF-3	20	21	32	33
IPS-1 activates two major signaling pathways : ( i ) activation of the IKK kinase complex and NF-kappaB leading to the induction of proinflammatory cytokines , and ( ii ) activation of IKK related kinases TBK1 and IKKepsilon , which activate IRF3 to induce expression of type I IFNs .	IPS-1 activates two major signaling pathways : (i) activation of the IKK kinase complex and NF-kappaB leading to the induction of proinflammatory cytokines, and (ii) activation of IKK related kinases TBK1 and IKKepsilon, which activate IRF3 to induce expression of type I IFNs.	34	42	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	37	38	41	42
MyD88 , TRIF , RIG-1 , and PKR each activate the production of type I IFN by utilizing the TANK binding kinase-1 ( TBK1 ) and/or the inducible IkappaB kinase ( IKK-i ) , which activate the transcription factors IRF3 and IRF7 , inducing the transcription of type I and type III IFN .	MyD88, TRIF, RIG-1, and PKR each activate the production of type I IFN by utilizing the TANK binding kinase-1 (TBK1) and/or the inducible IkappaB kinase (IKK-i), which activate the transcription factors IRF3 and IRF7, inducing the transcription of type I and type III IFN.	29	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKK-i	IKK-i	IKK-i	IRF3	IRF3	IRF3	31	32	39	40
A20 also required TAX1BP1 to target to TBK1 and IKKi and block TBK1 and IKKi dependent activation of IRF3 [ XREF_BIBR ] .	A20 also required TAX1BP1 to target to TBK1 and IKKi and block TBK1 and IKKi dependent activation of IRF3 [XREF_BIBR].	12	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IKKi	IKKi	IKKi	IRF3	IRF3	IRF3	14	15	18	19
[ XREF_BIBR , XREF_BIBR ] MVNP stimulates the activation of TBK1 and IKKepsilon , which in turn activate IRF3 , and thereby IRF3 target genes , such as interferon beta ( INFbeta ) .	[XREF_BIBR, XREF_BIBR] MVNP stimulates the activation of TBK1 and IKKepsilon, which in turn activate IRF3, and thereby IRF3 target genes, such as interferon beta (INFbeta).	8	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	12	13	18	19
This complex recruits TAK1 , a kinase that activates NF-kappaB , or TBK1 and IKKepsilon , kinases that activate IRF-3 and/or IRF-7 .	This complex recruits TAK1, a kinase that activates NF-kappaB, or TBK1 and IKKepsilon, kinases that activate IRF-3 and/or IRF-7.	3	21	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF-3	IRF-3	IRF-3	14	15	19	20
TRIF can also recruit a signaling complex involving the non canonical IKKs , TBK1 and IKKi , which induce IRF3 activation , mediated by TRAF3 [ XREF_BIBR ] .	TRIF can also recruit a signaling complex involving the non canonical IKKs, TBK1 and IKKi, which induce IRF3 activation, mediated by TRAF3 [XREF_BIBR].	6	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKi	IKKi	IKKi	IRF3	IRF3	IRF3	15	16	19	20
The TLR3 and TRIF complex recruits TRAF3 , TBK1 , and IKKepsilon , which activates IRF3 .	The TLR3 and TRIF complex recruits TRAF3, TBK1, and IKKepsilon, which activates IRF3.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	11	12	15	16
MAVS stimulates IKKE and TBK1 , which in turn activate IRF3 and IRF7 .	MAVS stimulates IKKE and TBK1, which in turn activate IRF3 and IRF7.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKE	IKKE	IKKE	IRF3	IRF3	IRF3	2	3	10	11
MAVS complexes with the adaptor protein TRAF3 , recruiting the scaffold protein TANK and the IkappaB kinases ( IKKs ) TANK binding kinase 1 ( TBK1 ) and IKKepsilon , which activate the transcription factor IRF3 .	MAVS complexes with the adaptor protein TRAF3, recruiting the scaffold protein TANK and the IkappaB kinases (IKKs) TANK binding kinase 1 (TBK1) and IKKepsilon, which activate the transcription factor IRF3.	8	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	28	29	35	36
TBK1 and IKKepsilon activation of IRF3 can also occur upon host recognition of viral DNA via the STING pathway .	TBK1 and IKKepsilon activation of IRF3 can also occur upon host recognition of viral DNA via the STING pathway.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	2	3	5	6
Signaling through the IPS-1 associated TRADD , FADD , and RIP1 complex results in the recruitment of TANK and NEMO to the IPS-1 signalosome to facilitate IRF3 and IRF7 activation by TBK1 or IKKi , IKKalpha-IKKbeta-dependent activation of NF-kappaB , and IFN production .	Signaling through the IPS-1 associated TRADD, FADD, and RIP1 complex results in the recruitment of TANK and NEMO to the IPS-1 signalosome to facilitate IRF3 and IRF7 activation by TBK1 or IKKi, IKKalpha-IKKbeta-dependent activation of NF-kappaB, and IFN production.	26	34	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IKKi	IKKi	IKKi	IRF3	IRF3	IRF3	33	34	26	27
Moreover , K7 binds to the cellular DEAD-box RNA helicase DDX3 XREF_BIBR , which forms part of a complex containing TBK1 and IKKepsilon , that activates IRF3 , thus inhibiting IRF3/7 phosphorylation and in consequence induction of the IFN-beta promoter and IFN-beta gene transcription XREF_BIBR .	Moreover, K7 binds to the cellular DEAD-box RNA helicase DDX3 XREF_BIBR, which forms part of a complex containing TBK1 and IKKepsilon, that activates IRF3, thus inhibiting IRF3/7 phosphorylation and in consequence induction of the IFN-beta promoter and IFN-beta gene transcription XREF_BIBR.	19	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	22	23	26	27
Through as yet unidentified mediators , MAVS propagates the signal to the TBK1 and IKKi kinases that finally activate IRF3 and NF-kappaB ( XREF_FIG ) .	Through as yet unidentified mediators, MAVS propagates the signal to the TBK1 and IKKi kinases that finally activate IRF3 and NF-kappaB (XREF_FIG).	12	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKi	IKKi	IKKi	IRF3	IRF3	IRF3	14	15	19	20
TBK1 and IKKepsilon have been reported to activate both IRF3 and IRF7 and NF-kappaB , and possibly both C/EBPbeta and C/EBPdelta .	TBK1 and IKKepsilon have been reported to activate both IRF3 and IRF7 and NF-kappaB, and possibly both C/EBPbeta and C/EBPdelta.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF3	IRF3	IRF3	2	3	9	10
In this model , IGF2 activated INSR was shown to compensate for IGF1R interruption to rescue embryonic growth XREF_BIBR .	In this model, IGF2 activated INSR was shown to compensate for IGF1R interruption to rescue embryonic growth XREF_BIBR.	4	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	INSR	INSR	INSR	4	5	6	7
The insulin receptor is known to exist as two splice variants , insulin receptor-A ( IR : A ) and insulin receptor-B ( IR : B ) [ XREF_BIBR ] , where IR : A is preferentially activated by IGF-II over insulin , and signals via the MAPK pathway to induce mitogenic signaling .	The insulin receptor is known to exist as two splice variants, insulin receptor-A (IR : A) and insulin receptor-B (IR : B) [XREF_BIBR], where IR : A is preferentially activated by IGF-II over insulin, and signals via the MAPK pathway to induce mitogenic signaling.	32	41	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IR	IR	IR	39	40	32	33
It is believed that IR activated by IGF-II contributes to resistance to anti-IGF-1R therapy XREF_BIBR .	It is believed that IR activated by IGF-II contributes to resistance to anti-IGF-1R therapy XREF_BIBR.	4	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IR	IR	IR	7	8	4	5
Importantly , it is becoming increasingly evident that IR activation by IGF-2 enhances the growth of Ewing sarcoma and breast cancer in addition to the IGF-1R activation : cotargeting IGF-1R and IR is likely to be more effective than targeting the IGF-1R alone .	Importantly, it is becoming increasingly evident that IR activation by IGF-2 enhances the growth of Ewing sarcoma and breast cancer in addition to the IGF-1R activation : cotargeting IGF-1R and IR is likely to be more effective than targeting the IGF-1R alone.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IR	IR	IR	11	12	8	9
Thus , both IGF-II precursor forms are present in human plasma but do not preferentially activate the IR .	Thus, both IGF-II precursor forms are present in human plasma but do not preferentially activate the IR.	3	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IR	IR	IR	3	4	17	18
IGF2 can activate the IGF1 receptor or insulin receptor or hybrids of these two receptors to contribute to prostate cancer progression to castration resistance .	IGF2 can activate the IGF1 receptor or insulin receptor or hybrids of these two receptors to contribute to prostate cancer progression to castration resistance.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	insulin receptor	insulin receptor	insulin receptor	0	1	7	9
Herein , we find that , in breast cancer the IR is activated by IGF-II .	Herein, we find that, in breast cancer the IR is activated by IGF-II.	9	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IR	IR	IR	14	15	10	11
Insulin treatment causes comparable activation of AKT and ERK1/2 in WT ( XREF_FIG ) but , in contrast , IGF2 treatment strongly activates INSR and ERK1/2 only in the INSR-A expressing HKO hepatocytes ( XREF_FIG ) .	Insulin treatment causes comparable activation of AKT and ERK1/2 in WT (XREF_FIG) but, in contrast, IGF2 treatment strongly activates INSR and ERK1/2 only in the INSR-A expressing HKO hepatocytes (XREF_FIG).	19	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	INSR	INSR	INSR	19	20	23	24
IGF-1 and IGF-2 share a 62 % sequence homology and have overlapping but distinct functions : both IGF-1 and IGF-2 activate the IGF-1 receptor ( IGF-1R ) , while IGF-2 also can activate the insulin receptor ( IR ) .	IGF-1 and IGF-2 share a 62% sequence homology and have overlapping but distinct functions : both IGF-1 and IGF-2 activate the IGF-1 receptor (IGF-1R), while IGF-2 also can activate the insulin receptor (IR).	29	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	insulin receptor	insulin receptor	insulin receptor	29	30	34	36
Anti-IGF-1R monoclonal antibodies ( mAbs ) do not inhibit IGF ligand 2 ( IGF-2 ) activation of the insulin receptor isoform-A ( INSR-A ) , which may limit their anti-proliferative activity .	Anti-IGF-1R monoclonal antibodies (mAbs) do not inhibit IGF ligand 2 (IGF-2) activation of the insulin receptor isoform-A (INSR-A), which may limit their anti-proliferative activity.	13	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	insulin receptor	insulin receptor	insulin receptor	13	14	18	20
Less appreciated is that IGF-II , but not IGF-I , activates a splice variant of the insulin receptor ( IR ) known as IR-A .	Less appreciated is that IGF-II, but not IGF-I, activates a splice variant of the insulin receptor (IR) known as IR-A.	4	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	insulin receptor	insulin receptor	insulin receptor	4	5	16	18
Taken together , these data support that IR-A overexpression drives endometrial carcinogenesis , and we additionally propose that increased IGF-2 secretion in cells overexpressing IR-A may further stimulate the IR pathway .	Taken together, these data support that IR-A overexpression drives endometrial carcinogenesis, and we additionally propose that increased IGF-2 secretion in cells overexpressing IR-A may further stimulate the IR pathway.	19	30	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IR	IR	IR	19	20	29	30
Although no response in patients with refractory WT was observed , this was a single-agent trial and drugs that only target IGF1R may be non efficacious as they fail to target the insulin receptor , another tyrosine kinase receptor that is activated by IGF1 and IGF2 in addition to insulin itself .	Although no response in patients with refractory WT was observed, this was a single-agent trial and drugs that only target IGF1R may be non efficacious as they fail to target the insulin receptor, another tyrosine kinase receptor that is activated by IGF1 and IGF2 in addition to insulin itself.	32	46	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	insulin receptor	insulin receptor	insulin receptor	45	46	32	34
NSPs grow in 4.4 microM insulin , but the number of NSPs obtained is greater in IGF-II-supplemented media ; therefore , IR stimulation is necessary for NSP growth ; however , NSC self-renewal is more effectively obtained when IGF-II rather than insulin activates the IR .	NSPs grow in 4.4 microM insulin, but the number of NSPs obtained is greater in IGF-II-supplemented media; therefore, IR stimulation is necessary for NSP growth; however, NSC self-renewal is more effectively obtained when IGF-II rather than insulin activates the IR.	38	45	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IR	IR	IR	38	39	44	45
Furthermore , IGF2 can drive IR signaling when IGF1R is selectively targeted , which might present another drawback for specific anti-IGF1R targeting .	Furthermore, IGF2 can drive IR signaling when IGF1R is selectively targeted, which might present another drawback for specific anti-IGF1R targeting.	2	6	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IR	IR	IR	2	3	5	6
Since IGF-II also activates the insulin receptor ( INSR ) , we propose that higher IGF-II levels among AA BC patients translates into higher INSR activation .	Since IGF-II also activates the insulin receptor (INSR), we propose that higher IGF-II levels among AA BC patients translates into higher INSR activation.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	insulin receptor	insulin receptor	insulin receptor	1	2	5	7
It is known that IGF-II causes activation of the IR [ XREF_BIBR ] ; but its expression is confined mainly to fetal development and thus circulates at extremely low levels postnatally in rodents [ XREF_BIBR ] .	It is known that IGF-II causes activation of the IR [XREF_BIBR]; but its expression is confined mainly to fetal development and thus circulates at extremely low levels postnatally in rodents [XREF_BIBR].	4	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IR	IR	IR	4	5	9	10
The C-domain of IGF2 is important for increased activation of IR-A compared to IR-B [ XREF_BIBR ] and the mechanism by which IGF1 and IGF2 activate IR and IGF1R is similar to insulin activation of IR by cross bridging the two receptor halves [ XREF_BIBR ] .	The C-domain of IGF2 is important for increased activation of IR-A compared to IR-B [XREF_BIBR] and the mechanism by which IGF1 and IGF2 activate IR and IGF1R is similar to insulin activation of IR by cross bridging the two receptor halves [XREF_BIBR].	22	30	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IR	IR	IR	24	25	26	27
IR is a known mitogenic driver for tumor cells , and IR activated by IGF-2 , can compensate for IGF-1R disruption in tumor cells .	IR is a known mitogenic driver for tumor cells, and IR activated by IGF-2, can compensate for IGF-1R disruption in tumor cells.	11	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IR	IR	IR	14	15	11	12
Our results from the immunohistological examinations ( XREF_FIG ) and Western blot analyses ( XREF_FIG ) suggest that IR activation by IGF-2 plays an important role in the prostate cancer cell growth in bone in addition to the IGF-1R activation .	Our results from the immunohistological examinations (XREF_FIG) and Western blot analyses (XREF_FIG) suggest that IR activation by IGF-2 plays an important role in the prostate cancer cell growth in bone in addition to the IGF-1R activation.	18	22	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IR	IR	IR	21	22	18	19
Moreover , IGF-II also activated the IR in breast cancer tissue specimens ; IGF-II was 10-100 % as potent as insulin .	Moreover, IGF-II also activated the IR in breast cancer tissue specimens; IGF-II was 10-100% as potent as insulin.	2	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IR	IR	IR	2	3	6	7
Conclusions : IGF-II promotes a fast IR internalization favoring mitogenic signaling whereas insulin activated IR would endures signaling from the membrane .	Conclusions : IGF-II promotes a fast IR internalization favoring mitogenic signaling whereas insulin activated IR would endures signaling from the membrane.	2	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IR	IR	IR	2	3	6	7
IGF2 can activate the IGF1 receptor ( IGF1R ) or insulin receptor ( INSR ) or hybrids of these two receptors .	IGF2 can activate the IGF1 receptor (IGF1R) or insulin receptor (INSR) or hybrids of these two receptors.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	insulin receptor	insulin receptor	insulin receptor	0	1	10	12
Overall , our data support the hypothesis that IR activation by IGF-2 may account for the failure of IGF-1R only targeting agents to suppress TNBC cell migration in vitro , suggesting that it may also be involved in the disappointing clinical activity exhibited by such agents .	Overall, our data support the hypothesis that IR activation by IGF-2 may account for the failure of IGF-1R only targeting agents to suppress TNBC cell migration in vitro, suggesting that it may also be involved in the disappointing clinical activity exhibited by such agents.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IR	IR	IR	11	12	8	9
In fact , the activation of INSR by IGF2 was first described in a mouse development model .	In fact, the activation of INSR by IGF2 was first described in a mouse development model.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	INSR	INSR	INSR	8	9	6	7
Since IGF-II activates the insulin receptor ( INSR ) , we propose that the INSR signaling is also activated in this system .	Since IGF-II activates the insulin receptor (INSR), we propose that the INSR signaling is also activated in this system.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	insulin receptor	insulin receptor	insulin receptor	1	2	4	6
In most of these tumors , cell growth is dependent on IR activation by insulin , suggesting a mitogenic role of this hormone [ XREF_BIBR ] , although IR , isoform A , may also be activated by IGF-II [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In most of these tumors, cell growth is dependent on IR activation by insulin, suggesting a mitogenic role of this hormone [XREF_BIBR], although IR, isoform A, may also be activated by IGF-II [XREF_BIBR, XREF_BIBR, XREF_BIBR].	28	44	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IR	IR	IR	38	39	28	29
Thus , these data show that IL-17A , rather than IL-22 , activates its receptor IL-17RA to directly induce REG3A in skin keratinocytes , whereas IL-22 cooperatively increases REG3A in combination with IL-17A .	Thus, these data show that IL-17A, rather than IL-22, activates its receptor IL-17RA to directly induce REG3A in skin keratinocytes, whereas IL-22 cooperatively increases REG3A in combination with IL-17A.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	6	7	15	16
IL-17A signals through a specific cell surface receptor complex which consists of IL-17RA and IL-17RC XREF_BIBR .	IL-17A signals through a specific cell surface receptor complex which consists of IL-17RA and IL-17RC XREF_BIBR.	0	15	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	0	1	12	13
IL-17A gene transfer , using minicircle DNA , induced the expansion of IL-17RA + CD11b + Gr1 low osteoclast precursors .	IL-17A gene transfer, using minicircle DNA, induced the expansion of IL-17RA + CD11b + Gr1 low osteoclast precursors.	0	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	0	1	12	13
IL-17A , mainly secreted by Th17 cells , can promote the proliferation of IL-17R + AML cells and inhibit the generation and differentiation of Th1 cells .	IL-17A, mainly secreted by Th17 cells, can promote the proliferation of IL-17R + AML cells and inhibit the generation and differentiation of Th1 cells.	0	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17R	IL-17R	IL-17R	0	1	13	14
IL-17A gene transfer induced the expansion of IL-17RA + CD11b + Gr1 low osteoclast precursors and a concomitant elevation of biomarkers indicative of bone resorption .	IL-17A gene transfer induced the expansion of IL-17RA + CD11b + Gr1 low osteoclast precursors and a concomitant elevation of biomarkers indicative of bone resorption.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	0	1	7	8
In contrast , deletion of hematopoietic IL-17A production or genetic deletion of IL-17RA protected from bile duct ligation induced liver injury [ XREF_BIBR ] and from carbon tetrachloride ( CCl4 ) induced liver damage something associated with decreased expression of pro inflammatory cytokines and decreased fibrosis [ XREF_BIBR , XREF_BIBR ] .	In contrast, deletion of hematopoietic IL-17A production or genetic deletion of IL-17RA protected from bile duct ligation induced liver injury [XREF_BIBR] and from carbon tetrachloride (CCl4) induced liver damage something associated with decreased expression of pro inflammatory cytokines and decreased fibrosis [XREF_BIBR, XREF_BIBR].	6	13	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	6	7	12	13
XREF_BIBR , XREF_BIBR IL-17A signaling is mediated through IL-17 receptor A ( IL-17RA ) and IL-17RC , XREF_BIBR , XREF_BIBR and keratinocytes upregulate IL-17RA upon skin injury .	XREF_BIBR, XREF_BIBR IL-17A signaling is mediated through IL-17 receptor A (IL-17RA) and IL-17RC, XREF_BIBR, XREF_BIBR and keratinocytes upregulate IL-17RA upon skin injury.	3	24	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	3	4	23	24
We conclude that IL-17A mediated suppression of IL-17F production and secretion requires IL-17RA and is relevant to maintain the normal set-point of blood neutrophil counts in vivo .	We conclude that IL-17A mediated suppression of IL-17F production and secretion requires IL-17RA and is relevant to maintain the normal set-point of blood neutrophil counts in vivo.	3	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	3	4	12	13
Mechanistically , IL-17 expressed by this lymphocyte subset activates IL-17R on epithelial and stromal cells , resulting in the production of IL-6 , IL-1 and other inflammatory cytokines that act in a positive feedback loop on the gammadelta T cells and differentiating T H 17 cells to amplify inflammation XREF_BIBR , XREF_BIBR .	Mechanistically, IL-17 expressed by this lymphocyte subset activates IL-17R on epithelial and stromal cells, resulting in the production of IL-6, IL-1 and other inflammatory cytokines that act in a positive feedback loop on the gammadelta T cells and differentiating T H 17 cells to amplify inflammation XREF_BIBR, XREF_BIBR.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17	IL-17 expressed	il-17	IL-17R	IL-17R	il-17r	2	3	9	10
IL-17A is secreted as a homodimer and activates its receptor IL-17RA , which leads to increased production of cytokines and chemokines , including TNF-alpha , IL-1beta , IL-8 , and IL-6 in target cells .	IL-17A is secreted as a homodimer and activates its receptor IL-17RA, which leads to increased production of cytokines and chemokines, including TNF-alpha, IL-1beta, IL-8, and IL-6 in target cells.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	0	1	10	11
IL-17A , a signature cytokine secreted by Th17 cells , induced the proliferation of IL-17 receptor ( IL-17R )-positive AML cells via IL-17R , in which activation of PI3K and Akt and Jak and Stat3 signaling pathway may play important roles .	IL-17A, a signature cytokine secreted by Th17 cells, induced the proliferation of IL-17 receptor (IL-17R)-positive AML cells via IL-17R, in which activation of PI3K and Akt and Jak and Stat3 signaling pathway may play important roles.	0	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17R	IL-17R	IL-17R	0	1	17	18
Tumor necrosis factor receptor associated factor 6 ( TRAF-6 ) plays an indispensable role in IL-17R signaling as IL-17 stimulation fails to activate IL-17R signaling in TRAF-6-deficient mouse embryonic fibroblasts XREF_BIBR , XREF_BIBR .	Tumor necrosis factor receptor associated factor 6 (TRAF-6) plays an indispensable role in IL-17R signaling as IL-17 stimulation fails to activate IL-17R signaling in TRAF-6-deficient mouse embryonic fibroblasts XREF_BIBR, XREF_BIBR.	18	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17	IL-17	IL-17	IL-17R	IL-17R	IL-17R	18	19	23	24
However , in WT and IL-17RA -/- co-cultures treated with both cytokines , IL-17A enhanced IL-13-dependent C3 and Il13ra2 expression in the WT cells but not the IL-17RA -/- cells .	However, in WT and IL-17RA -/- co-cultures treated with both cytokines, IL-17A enhanced IL-13-dependent C3 and Il13ra2 expression in the WT cells but not the IL-17RA -/- cells.	3	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	13	14	5	6
However , IL-17A failed to directly stimulate the production of collagen ( XREF_FIG ) or Cx3cl1 ( XREF_FIG ) in CFs , indicating that more complex mechanisms were involved in regulating fibrosis and the accumulation of Ly6C lo MO/MPhis in Il17ra -/- hearts during IL-17A-driven DCMi .	However, IL-17A failed to directly stimulate the production of collagen (XREF_FIG) or Cx3cl1 (XREF_FIG) in CFs, indicating that more complex mechanisms were involved in regulating fibrosis and the accumulation of Ly6C lo MO/MPhis in Il17ra -/- hearts during IL-17A-driven DCMi.	2	42	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	Il17ra	Il17ra	Il17ra	2	3	40	41
In TbetaRII knockout tumor cells , we determined basal and IL-17 stimulated secretion of CXCL1/5 and expression of IL-17R .	In TbetaRII knockout tumor cells, we determined basal and IL-17 stimulated secretion of CXCL1/5 and expression of IL-17R.	8	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17	IL-17	IL-17	IL-17R	IL-17R	IL-17R	10	11	18	19
IL-17 antiserum decreases and IL-17 increases IL-17RA .	IL-17 antiserum decreases and IL-17 increases IL-17RA.	2	7	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-17	IL-17	IL-17	IL-17RA	IL-17RA	IL-17RA	4	5	6	7
To determine whether IL-17A directly induced a downregulation of IL-17RA in a paracrine negative feedback loop , OPCs were stimulated in culture with IL-17A , and IL-17RA was quantified .	To determine whether IL-17A directly induced a downregulation of IL-17RA in a paracrine negative feedback loop, OPCs were stimulated in culture with IL-17A, and IL-17RA was quantified.	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	3	4	9	10
The upregulation of IL-17A and subsequent activation of IL-17RA does not only induce the production of an array of antimicrobial peptides and complement factors but also regulates the secretion of IgA into the intestinal lumen .	The upregulation of IL-17A and subsequent activation of IL-17RA does not only induce the production of an array of antimicrobial peptides and complement factors but also regulates the secretion of IgA into the intestinal lumen.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	3	4	8	9
By contrast , these issues were successfully addressed with cultured bone-marrow , as the liquid culture system allows us to exclude factors extrinsic to the bone-marrow and helps us gain insight of the primary consequences of IL-17A activation of IL-17RA in developing eosinophils .	By contrast, these issues were successfully addressed with cultured bone-marrow, as the liquid culture system allows us to exclude factors extrinsic to the bone-marrow and helps us gain insight of the primary consequences of IL-17A activation of IL-17RA in developing eosinophils.	36	42	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	36	37	39	40
- In the present study , we demonstrate that Th17 cell frequencies and IL-17 are elevated in PB and BM of AML patients ; IL-17A promotes the proliferation of U937 cells as well as IL-17 receptor ( IL-17R )-positive primary AML cells via IL-17R ; patients with high Th17 cell frequencies have poor prognosis whereas patients with high Th1 frequencies have prolonged survival .	- In the present study, we demonstrate that Th17 cell frequencies and IL-17 are elevated in PB and BM of AML patients; IL-17A promotes the proliferation of U937 cells as well as IL-17 receptor (IL-17R)-positive primary AML cells via IL-17R; patients with high Th17 cell frequencies have poor prognosis whereas patients with high Th1 frequencies have prolonged survival.	24	41	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17R	IL-17R	IL-17R	24	25	37	38
IL-17RA , which dimerizes with IL-17RC and RE , can be activated by IL-17A , C , F and IL-25 .	IL-17RA, which dimerizes with IL-17RC and RE, can be activated by IL-17A, C, F and IL-25.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	13	14	0	1
Thus , IL-17 promotes estrogen deficient osteoporosis in an IL-17RA and Act1 dependent manner .	Thus, IL-17 promotes estrogen deficient osteoporosis in an IL-17RA and Act1-dependent manner.	2	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17	IL-17	IL-17	IL-17RA	IL-17RA	IL-17RA	2	3	9	10
IL-17A and IL-17F then activate the IL-17R , which is present on keratinocytes , to produce proinflammatory cytokines , chemokines , and adhesion molecules that mediate neutrophil recruitment to a site of cutaneous S. aureus infection .	IL-17A and IL-17F then activate the IL-17R, which is present on keratinocytes, to produce proinflammatory cytokines, chemokines, and adhesion molecules that mediate neutrophil recruitment to a site of cutaneous S. aureus infection.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17R	IL-17R	IL-17R	0	1	6	7
We found that IL-17A only promotes the proliferation of U937 cells and IL-17R + primary AML cells , but not all AML cell lines as well as primary AML cells , consistent with a previous report .	We found that IL-17A only promotes the proliferation of U937 cells and IL-17R + primary AML cells, but not all AML cell lines as well as primary AML cells, consistent with a previous report.	3	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	IL-17R	IL-17R	IL-17R	3	4	12	13
Similarly , a coated , but not soluble IL-17A preparation markedly enhanced T H17 polarization of both wildtype and IL-17 receptor A deficient ( Il17ra -/-) splenocytes ( XREF_SUPPLEMENTARY ) .	Similarly, a coated, but not soluble IL-17A preparation markedly enhanced T H17 polarization of both wildtype and IL-17 receptor A deficient (Il17ra -/-) splenocytes (XREF_SUPPLEMENTARY).	8	25	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	Il17ra	Il17ra	Il17ra	8	9	24	25
In addition , IL-17 promotes the proliferation of HSCs , the upregulation of TGF-beta receptor , IL-17RA , and IL-17RC .	In addition, IL-17 promotes the proliferation of HSCs, the upregulation of TGF-beta receptor, IL-17RA, and IL-17RC.	3	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17	IL-17	IL-17	IL-17RA	IL-17RA	IL-17RA	3	4	16	17
IL-17 dosage-dependently increased IL-17RA .	IL-17 dosage-dependently increased IL-17RA.	0	4	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17	IL-17	IL-17	IL-17RA	IL-17RA	IL-17RA	0	1	3	4
Blockade of IL-17A diminishes atherosclerosis in Ad-IL-17RA : Fc treated Apoe -/- mice .	Blockade of IL-17A diminishes atherosclerosis in Ad-IL-17RA : Fc treated Apoe -/- mice.	0	7	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-17A	IL-17A	IL-17A	Ad-IL-17RA	Ad-IL-17RA	Ad-IL-17RA	2	3	6	7
Interestingly , sIL17R reduced Il17rc retinal transcripts ( XREF_SUPPLEMENTARY ) , which , together with the observation that IL17A induces IL17RA and IL17RC in vitro XREF_BIBR , suggests a positive feedback loop may amplify IL17 signals in susceptible tissues .	Interestingly, sIL17R reduced Il17rc retinal transcripts (XREF_SUPPLEMENTARY), which, together with the observation that IL17A induces IL17RA and IL17RC in vitro XREF_BIBR, suggests a positive feedback loop may amplify IL17 signals in susceptible tissues.	18	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL17A	IL17A	IL17A	IL17RA	IL17RA	IL17RA	18	19	20	21
But it remains possible that IL-11 secretion by the MC38-CC1-L cells might activate the GP130 and STAT3 signalling and reduce metastasis ; 41 this remains to be further evaluated .	But it remains possible that IL-11 secretion by the MC38-CC1-L cells might activate the GP130 and STAT3 signalling and reduce metastasis; 41 this remains to be further evaluated.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	GP130	GP130	GP130	5	6	14	15
These studies also demonstrated that IL-11 , rather than IL-6 , mediates the effects of gp130 activation on gastric tumorigenesis XREF_BIBR .	These studies also demonstrated that IL-11, rather than IL-6, mediates the effects of gp130 activation on gastric tumorigenesis XREF_BIBR.	5	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	5	6	15	16
We constructed super-cytokine Hyper- IL11 ( H11 ) by linking soluble IL-11 receptor alpha ( sIL-11Ralpha ) with IL-11 , which directly targets beta-receptor ( gp130 ) signal transducing subunit .	We constructed super-cytokine Hyper- IL11 (H11) by linking soluble IL-11 receptor alpha (sIL-11Ralpha) with IL-11, which directly targets beta-receptor (gp130) signal transducing subunit.	9	29	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	18	19	25	26
The inflammatory cytokines IL-6 and IL-11 induce gp130 homodimerization after binding to their specific alpha receptors , which leads to the activation of the Janus kinase and STAT signal transduction pathway .	The inflammatory cytokines IL-6 and IL-11 induce gp130 homodimerization after binding to their specific alpha receptors, which leads to the activation of the Janus kinase and STAT signal transduction pathway.	3	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	5	6	7	8
TGF-beta response in CAFs led to secretion of IL-11 , which in turn can induce GP130 and STAT3 signaling in neoplastic cells to support tumor initiation and accelerate metastasis .	TGF-beta response in CAFs led to secretion of IL-11, which in turn can induce GP130 and STAT3 signaling in neoplastic cells to support tumor initiation and accelerate metastasis.	6	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	GP130	GP130	GP130	8	9	15	16
IL-11 signaling through interacting with IL-11R induces dimerization of membrane bound gp130 and subsequent signal transduction .	IL-11 signaling through interacting with IL-11R induces dimerization of membrane bound gp130 and subsequent signal transduction.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	0	1	11	12
gp130 is IL-6 family receptor signaling subunit , and IL-6 family gp130 driver IL-11 drives hyperactivation of STAT3 contributing gastric phenotype .	gp130 is IL-6 family receptor signaling subunit, and IL-6 family gp130 driver IL-11 drives hyperactivation of STAT3 contributing gastric phenotype.	11	15	driver	Positive_activation_token_1_noun	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	13	14	11	12
These results support the selectivity of Bazedoxifene for inhibiting GP130 and STAT3 signaling mediated by IL-6 and IL-11 but not OSM and LIF .	These results support the selectivity of Bazedoxifene for inhibiting GP130 and STAT3 signaling mediated by IL-6 and IL-11 but not OSM and LIF.	9	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	GP130	GP130	GP130	17	18	9	10
Similarly , in mice with CAC , mutations in gp130 increase STAT3 activation by IL6 and IL11 , which protects against epithelial damage and inflammation from dextran sodium sulphate but accelerates tumorigenesis 69 .	Similarly, in mice with CAC, mutations in gp130 increase STAT3 activation by IL6 and IL11, which protects against epithelial damage and inflammation from dextran sodium sulphate but accelerates tumorigenesis 69.	9	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL11	IL11	IL11	gp130	gp130	gp130	16	17	9	10
Hyper-IL-11 ( H11 ) is a fusion protein comprising IL-11 and soluble IL-11 receptor directly targeting gp130 .	Hyper-IL-11 (H11) is a fusion protein comprising IL-11 and soluble IL-11 receptor directly targeting gp130.	9	17	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	9	10	16	17
IL-1RT1 -/- mice treated with IL-11 showed immune and gastric cell marker changes similar to those observed in gp130 757FF xIL-1RT1 -/- cardiac lesions , whereas wildtype mice treated with IL-11 did not .	IL-1RT1 -/- mice treated with IL-11 showed immune and gastric cell marker changes similar to those observed in gp130 757FF xIL-1RT1 -/- cardiac lesions, whereas wildtype mice treated with IL-11 did not.	18	31	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	30	31	18	19
IL-11 and STAT3 mediates the development of gp130 757FF xIL-1RT1 -/- cardiac lesions .	IL-11 and STAT3 mediates the development of gp130 757FF xIL-1RT1 -/- cardiac lesions.	0	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	0	1	7	8
IL-6 and IL-11 activate gp130 signalling and induce the association of tyrosine phosphorylated gp130 with the Src family kinases ( SFKs ) Src and Yes , thereby stimulating their tyrosine kinase activity 65 .	IL-6 and IL-11 activate gp130 signalling and induce the association of tyrosine phosphorylated gp130 with the Src family kinases (SFKs) Src and Yes, thereby stimulating their tyrosine kinase activity 65.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	2	3	4	5
In this study , we report the new role of Bazedoxifene as a GP130 inhibitor to inhibit GP130 and STAT3 signaling pathway mediated by IL-6 and IL-11 , induce apoptosis in pancreatic cancer cells , and suppress the tumor growth in human pancreatic cancer xenograft , suggesting that Bazedoxifene may serve as a novel therapeutic drug for pancreatic cancer by targeting GP130 and STAT3 signaling pathway .	In this study, we report the new role of Bazedoxifene as a GP130 inhibitor to inhibit GP130 and STAT3 signaling pathway mediated by IL-6 and IL-11, induce apoptosis in pancreatic cancer cells, and suppress the tumor growth in human pancreatic cancer xenograft, suggesting that Bazedoxifene may serve as a novel therapeutic drug for pancreatic cancer by targeting GP130 and STAT3 signaling pathway.	17	27	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	GP130	GP130	GP130	26	27	17	18
Introduction of one of these mutants , which harbors a deletion of Tyr 186 to Tyr 190 ( gp130DeltaYY ) , into Ba/F3-gp 130 cells led to cytokine independent phosphorylation of STAT3 and cellular proliferation , which was blocked by an anti-gp130 antibody which specifically neutralizes IL-11 signaling in wildtype gp130 [ XREF_BIBR ] .	Introduction of one of these mutants, which harbors a deletion of Tyr 186 to Tyr 190 (gp130DeltaYY), into Ba/F3-gp 130 cells led to cytokine independent phosphorylation of STAT3 and cellular proliferation, which was blocked by an anti-gp130 antibody which specifically neutralizes IL-11 signaling in wildtype gp130 [XREF_BIBR].	46	52	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	46	47	50	51
Based on our findings , we suggested Bazedoxifene is a potent inhibitor of GP130 and STAT3 signaling mediated by IL-6 and IL-11 .	Based on our findings, we suggested Bazedoxifene is a potent inhibitor of GP130 and STAT3 signaling mediated by IL-6 and IL-11.	13	22	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	GP130	GP130	GP130	21	22	13	14
As IL-11 administration may promote endogenous expression of gp130 ligands , thereby confounding its effects , we measured the mRNA expression of endogenous gastric IL-6 and IL-11 .	As IL-11 administration may promote endogenous expression of gp130 ligands, thereby confounding its effects, we measured the mRNA expression of endogenous gastric IL-6 and IL-11.	1	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	1	2	8	9
These results indicate Bazedoxifene is an inhibitor of GP130 and STAT3 signaling pathway mediated by IL-6 and IL-11 in pancreatic cancer cells .	These results indicate Bazedoxifene is an inhibitor of GP130 and STAT3 signaling pathway mediated by IL-6 and IL-11 in pancreatic cancer cells.	8	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	GP130	GP130	GP130	17	18	8	9
Thermal control of adhesion is maintained in IL-6-deficient mice through a gp130 dependent compensatory mechanism mediated by IL-6-related cytokines ( i.e ., oncostatin M [ OSM ] , leukemia inhibitory factor [ LIF ] , and IL-11 ) .	Thermal control of adhesion is maintained in IL-6-deficient mice through a gp130 dependent compensatory mechanism mediated by IL-6-related cytokines (i.e., oncostatin M [OSM], leukemia inhibitory factor [LIF], and IL-11).	11	37	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	36	37	11	12
The studies reported here indicate that IL-27p28 , independently of EBI3 , can block the ability of IL-6 to promote T H 17 responses , and can function as a natural antagonist of gp130 signaling mediated by IL-6 , IL-11 and IL-27 .	The studies reported here indicate that IL-27p28, independently of EBI3, can block the ability of IL-6 to promote T H 17 responses, and can function as a natural antagonist of gp130 signaling mediated by IL-6, IL-11 and IL-27.	33	40	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	39	40	33	34
Interestingly , a marked activation of IL-6 and IL-11 signaling in inflammatory hepatocellular adenomas was directly caused by gain-of-function mutations within the gp130-receptor chain , leading to ligand independent constitutively active gp130 receptors 5 .	Interestingly, a marked activation of IL-6 and IL-11 signaling in inflammatory hepatocellular adenomas was directly caused by gain-of-function mutations within the gp130-receptor chain, leading to ligand independent constitutively active gp130 receptors 5.	6	32	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	8	9	31	32
As the transmembrane and intracellular part of the alpha-receptors are not required for formation of the signaling complex [ XREF_BIBR , XREF_BIBR ] , IL-6 and IL-11 can also initiate dimerization of two gp130 molecules via their respective soluble alpha-receptor .	As the transmembrane and intracellular part of the alpha-receptors are not required for formation of the signaling complex [XREF_BIBR, XREF_BIBR], IL-6 and IL-11 can also initiate dimerization of two gp130 molecules via their respective soluble alpha-receptor.	19	34	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	26	27	33	34
Secretion of IL-11 by TGF-beta stimulated CAFs triggers GP-130 and STAT-3 signaling in cancer cells .	Secretion of IL-11 by TGF-beta stimulated CAFs triggers GP-130 and STAT-3 signaling in cancer cells.	0	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	GP-130	GP-130	GP-130	2	3	8	9
In addition , also IL-6 and IL-11 , which signal trough GP130 were inactive .	In addition, also IL-6 and IL-11, which signal trough GP130 were inactive.	4	13	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	GP130	GP130	GP130	6	7	11	12
The functional receptor complexes assembled in response to interleukin-6 and -11 ( IL-6 and IL-11 ) , leukemia inhibitory factor ( LIF ) , oncostatin M ( OSM ) , and ciliary neurotrophic factor ( CNTF ) , all involve the signal transducer gp130 : IL-6 and IL-11 induce homodimerization of gp130 , while the rest heterodimerize gp130 with other gp130 related beta subunits .	The functional receptor complexes assembled in response to interleukin-6 and -11 (IL-6 and IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), and ciliary neurotrophic factor (CNTF), all involve the signal transducer gp130 : IL-6 and IL-11 induce homodimerization of gp130, while the rest heterodimerize gp130 with other gp130 related beta subunits.	45	52	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	47	48	51	52
However , we have yet to confirm by immunological means that IL-11 is mediating gp130 activation .	However, we have yet to confirm by immunological means that IL-11 is mediating gp130 activation.	11	15	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	11	12	14	15
Taken together , our data support the concept that IL-6 and IL-11 activate gp130 by very similar molecular mechanisms .	Taken together, our data support the concept that IL-6 and IL-11 activate gp130 by very similar molecular mechanisms.	9	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	11	12	13	14
Secretion of IL11 by TGF-beta-stimulated cancer associated fibroblasts ( CAFs ) triggers GP130 and STAT3 signalling in tumour cells .	Secretion of IL11 by TGF-beta-stimulated cancer associated fibroblasts (CAFs) triggers GP130 and STAT3 signalling in tumour cells.	0	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL11	IL11	IL11	GP130	GP130	GP130	2	3	12	13
IRF3 and NF-kappaB then cooperate to activate interferon-beta expression , which initiates an antiviral response through IRF7 expression , IRF7 activation by TBK1 or IKKepsilon , and coordinate regulation of IRF7-and IRF3 responsive genes .	IRF3 and NF-kappaB then cooperate to activate interferon-beta expression, which initiates an antiviral response through IRF7 expression, IRF7 activation by TBK1 or IKKepsilon, and coordinate regulation of IRF7-and IRF3 responsive genes.	19	25	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF7	IRF7	IRF7	24	25	19	20
We next examined whether vIRF4 also inhibits IKKepsilon or TBK1 associated activation of IRF7 transcriptional activity , given that the expression of either IKKepsilon or TBK1 kinases lead to phosphorylation of IRF7 .	We next examined whether vIRF4 also inhibits IKKepsilon or TBK1 associated activation of IRF7 transcriptional activity, given that the expression of either IKKepsilon or TBK1 kinases lead to phosphorylation of IRF7.	7	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF7	IRF7	IRF7	7	8	13	14
Activated MAVS recruits key kinases , IkappaB kinase epsilon ( IKKepsilon ) and TANK binding kinase 1 ( TBK1 ) , that activate transcription factors , NFkappaB and interferon regulatory factor ( IRF ) -3 and IRF-7 .	Activated MAVS recruits key kinases, IkappaB kinase epsilon (IKKepsilon) and TANK binding kinase 1 (TBK1), that activate transcription factors, NFkappaB and interferon regulatory factor (IRF) -3 and IRF-7.	8	37	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IKKepsilon	IKKepsilon	IKKepsilon	IRF-7	IRF-7	IRF-7	10	11	36	37
The IKKbeta mediated p65 nuclear localization and epithelial-to-mesenchymal transition ( EMT ) modulated by the NKX2-1 and p53 axis is responsible for soft-agar growth , invasion , and xenograft tumour formation .	The IKKbeta mediated p65 nuclear localization and epithelial-to-mesenchymal transition (EMT) modulated by the NKX2-1 and p53 axis is responsible for soft-agar growth, invasion, and xenograft tumour formation.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	p65	p65	p65	1	2	3	4
The manner in which p65 is suppressed in macrophages by direct inhibition of IKKbeta is similar to that seen upon co-culture with neutrophils .	The manner in which p65 is suppressed in macrophages by direct inhibition of IKKbeta is similar to that seen upon co-culture with neutrophils.	4	14	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	p65	p65	p65	13	14	4	5
Thus , IKKbeta mediated RelA activation is primarily required for limiting NDV replication in MEFs .	Thus, IKKbeta mediated RelA activation is primarily required for limiting NDV replication in MEFs.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	RelA	RelA	RelA	2	3	4	5
We postulated that the difference in the RelA responses induced by long lasting IKK2 in the presence or absence of non canonical signal would decode into differential gene activities .	We postulated that the difference in the RelA responses induced by long lasting IKK2 in the presence or absence of non canonical signal would decode into differential gene activities.	7	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKK2	IKK2	IKK2	RelA	RelA	RelA	13	14	7	8
In summary , we provided evidence to demonstrate that NKX2-1 and p53 axis modulated IKKbeta mediated p65 nuclear localization plays a critical role in tumour progression of lung adenocarcinoma .	In summary, we provided evidence to demonstrate that NKX2-1 and p53 axis modulated IKKbeta mediated p65 nuclear localization plays a critical role in tumour progression of lung adenocarcinoma.	13	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	p65	p65	p65	14	15	16	17
BMS345541 , an inhibitor of IKKbeta and NFkappaBp65 , significantly inhibited the IL-13 and pIKKbeta induced upregulation of NFkappaBp65 in co-cultured ESF cells ( XREF_FIG ) .	BMS345541, an inhibitor of IKKbeta and NFkappaBp65, significantly inhibited the IL-13 and pIKKbeta-induced upregulation of NFkappaBp65 in co-cultured ESF cells (XREF_FIG).	3	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	NFkappaBp65	NFkappaBp65	NFkappaBp65	5	6	18	19
Results of recent studies indicate that activation of p65 by IKKbeta is independent of classical IkappaB degradation [ XREF_BIBR , XREF_BIBR ] .	Results of recent studies indicate that activation of p65 by IKKbeta is independent of classical IkappaB degradation [XREF_BIBR, XREF_BIBR].	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	p65	p65	p65	10	11	8	9
It has been reported that IKKbeta , another subunit of IKK complex , activates p65 activity through phosphorylation of IkappaBalpha .	It has been reported that IKKbeta, another subunit of IKK complex, activates p65 activity through phosphorylation of IkappaBalpha.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	p65	p65	p65	5	6	14	15
However , the current study revealed that upregulated neuronal A20 expression was likely the key mechanism by which early EA treatment inhibits IKKbeta phosphorylation and reduces the neuronal nuclear translocation of p65 to prevent NF-kB signaling induced inflammatory injury .	However, the current study revealed that upregulated neuronal A20 expression was likely the key mechanism by which early EA treatment inhibits IKKbeta phosphorylation and reduces the neuronal nuclear translocation of p65 to prevent NF-kB signaling induced inflammatory injury.	19	32	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKbeta	EA treatment inhibits IKKbeta phosphorylation	ikkbeta	p65	p65	p65	22	23	31	32
IKKbeta mediated p65 nuclear translocation is little reported via regulation of IKKbeta at transcriptional level .	IKKbeta mediated p65 nuclear translocation is little reported via regulation of IKKbeta at transcriptional level.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	p65	p65	p65	0	1	2	3
Here , we found overexpression of Best-3 inhibited TNFalpha induced IKKbeta and IkappaBalpha phosphorylation , blocked TNFalpha induced ubiquitination and subsequent degradation of IkappaBalpha , and suppressed the nuclear translocation of p65 and p50 .	Here, we found overexpression of Best-3 inhibited TNFalpha induced IKKbeta and IkappaBalpha phosphorylation, blocked TNFalpha induced ubiquitination and subsequent degradation of IkappaBalpha, and suppressed the nuclear translocation of p65 and p50.	4	33	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKbeta	overexpression of Best-3 inhibited TNFalpha induced IKKbeta and IkappaBalpha phosphorylation	ikkbeta	p65	p65	p65	10	11	31	32
In line with previous studies , our data demonstrated that TKL can strongly inhibit the phosphorylation of IKKbeta and IkappaBalpha , and subsequently reduce the nuclear translocation of NF-kappaB p65 ( p65 ) .	In line with previous studies, our data demonstrated that TKL can strongly inhibit the phosphorylation of IKKbeta and IkappaBalpha, and subsequently reduce the nuclear translocation of NF-kappaB p65 (p65).	10	30	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKbeta	TKL can strongly inhibit the phosphorylation of IKKbeta	ikkbeta	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	17	18	28	30
We therefore explored the possibility that soft-agar growth and invasiveness changed by the NKX2-1 and p53 axis could be predominately through modulating IKKbeta mediated p65 nuclear localization .	We therefore explored the possibility that soft-agar growth and invasiveness changed by the NKX2-1 and p53 axis could be predominately through modulating IKKbeta mediated p65 nuclear localization.	22	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	p65	p65	p65	22	23	24	25
Consistent with these results , we found that knockdown of USP18 enhanced NF-kappaB-luc activity induced by TNF-alpha , LPS , MyD88 , TRAF6 , TAK1-TAB1 , IKKbeta , but not p65 ( XREF_FIG ) .	Consistent with these results, we found that knockdown of USP18 enhanced NF-kappaB-luc activity induced by TNF-alpha, LPS, MyD88, TRAF6, TAK1-TAB1, IKKbeta, but not p65 (XREF_FIG).	11	32	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	p65	p65	p65	26	27	30	31
Moreover evidence has also been reported for an IKKbeta signaling dependent pathway driving phospho-NF-kappaB p65 ( Ser536 ) into the nucleus and other evidence for the signaling induced nuclear import of phospho-NF-kappaB p65 ( Ser536 ) by an IkappaBalpha independent pathway has also been documented .	Moreover evidence has also been reported for an IKKbeta signaling dependent pathway driving phospho-NF-kappaB p65 (Ser536) into the nucleus and other evidence for the signaling induced nuclear import of phospho-NF-kappaB p65 (Ser536) by an IkappaBalpha independent pathway has also been documented.	8	16	driving	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	p65	p65	p65	8	9	14	15
The IKKbeta mediated p65 nuclear localization is essential for promoting inflammatory associated cancer , such as lung adenocarcinoma , colon cancer , pancreatic adenocarcinoma , and ovarian cancer [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The IKKbeta mediated p65 nuclear localization is essential for promoting inflammatory associated cancer, such as lung adenocarcinoma, colon cancer, pancreatic adenocarcinoma, and ovarian cancer [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	p65	p65	p65	1	2	3	4
In contrast , superactivation of IKK2 in neonatal liver through Tet-Off hepatocyte specific transgenic expression of constitutively active IKK2 ( IKK2ca ) markedly activates p65 and induces proinflammatory genes , chronic inflammation , and liver fibrosis in adult mice [ XREF_BIBR ] .	In contrast, superactivation of IKK2 in neonatal liver through Tet-Off hepatocyte specific transgenic expression of constitutively active IKK2 (IKK2ca) markedly activates p65 and induces proinflammatory genes, chronic inflammation, and liver fibrosis in adult mice [XREF_BIBR].	3	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKK2	IKK2	IKK2	p65	p65	p65	5	6	24	25
Both IL-4 and IL-13 can activate IL-4Ralpha signaling .	Both IL-4 and IL-13 can activate IL-4Ralpha signaling.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	3	4	6	7
Unlike the type I IL4R , the type II IL4R can also bind and be activated by IL13 , although IL4 binds with higher affinity [ XREF_BIBR ] .	Unlike the type I IL4R, the type II IL4R can also bind and be activated by IL13, although IL4 binds with higher affinity [XREF_BIBR].	6	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL13	IL13	IL13	IL4R	IL4R	IL4R	17	18	9	10
In contrast , in the absence of IL13Ralpha2 expression , IL13 signaling through Type II IL4R is possibly increased and the IL13 induced apoptotic pathway is activated , although , it is not yet clear if this IL13 induced apoptotic pathway is downstream of Type II IL4R .	In contrast, in the absence of IL13Ralpha2 expression, IL13 signaling through Type II IL4R is possibly increased and the IL13 induced apoptotic pathway is activated, although, it is not yet clear if this IL13 induced apoptotic pathway is downstream of Type II IL4R.	36	47	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL13	IL13	IL13	IL4R	IL4R	IL4R	37	38	46	47
M2a macrophages are stimulated by IL-4 and IL-13 and exhibit IL-4 receptor alpha ( IL-4Ralpha ) signaling .	M2a macrophages are stimulated by IL-4 and IL-13 and exhibit IL-4 receptor alpha (IL-4Ralpha) signaling.	3	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	7	8	14	15
IL-4Ralpha paired with IL-13Ralpha1 can be activated by IL-13 or IL-4 .	IL-4Ralpha paired with IL-13Ralpha1 can be activated by IL-13 or IL-4.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	8	9	0	1
Briefly , both IL-4 and IL-13 cytokines can activate IL4R , which subsequently activates the Janus kinase and signal transducer and activator of transcription ( JAK and STAT ) signaling pathways leading to the synthesis of IgE 26 .	Briefly, both IL-4 and IL-13 cytokines can activate IL4R, which subsequently activates the Janus kinase and signal transducer and activator of transcription (JAK and STAT) signaling pathways leading to the synthesis of IgE 26.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL4R	IL4R	IL4R	5	6	9	10
When splenocytes were cultured with GMAg , these cells produced significantly high levels of IL-13 from day 4 PI ( P < 0.05 ) , suggesting that IL-13 might be triggering IL-4Ralpha in G. seoi infection ( XREF_FIG ) .	When splenocytes were cultured with GMAg, these cells produced significantly high levels of IL-13 from day 4 PI (P < 0.05), suggesting that IL-13 might be triggering IL-4Ralpha in G. seoi infection (XREF_FIG).	27	35	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	27	28	31	32
IL-4Ralpha dependent immunity to N. brasiliensis re-infection is driven by IL-13 signalling .	IL-4Ralpha dependent immunity to N. brasiliensis re-infection is driven by IL-13 signalling.	0	11	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	10	11	0	1
Redundant or compensatory expression of key molecules by multiple cell types could explain why allergic airway disease was recently and , to us , surprisingly , found to be unaffected in LysM-Cre IL-4Ra Flox mice in which macrophages can not be activated by IL-4 or IL-13 XREF_BIBR .	Redundant or compensatory expression of key molecules by multiple cell types could explain why allergic airway disease was recently and, to us, surprisingly, found to be unaffected in LysM-Cre IL-4Ra Flox mice in which macrophages can not be activated by IL-4 or IL-13 XREF_BIBR.	32	46	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ra	IL-4Ra	IL-4Ra	45	46	32	33
IL-4 and IL-13 share the same receptors : a type 1 receptor with the IL-4Ralpha subunit that can only be activated by IL-4 , and the type 2 receptor , a heterodimer consisting of IL-4Ralpha and IL-13Ralpha1 , that can be activated by both IL-4 and IL-13 .	IL-4 and IL-13 share the same receptors : a type 1 receptor with the IL-4Ralpha subunit that can only be activated by IL-4, and the type 2 receptor, a heterodimer consisting of IL-4Ralpha and IL-13Ralpha1, that can be activated by both IL-4 and IL-13.	32	47	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	46	47	34	35
The type 2 response is principally effected through the IL-4Ralpha and STAT6 pathways , driven by either or both IL-4 and IL-13 .	The type 2 response is principally effected through the IL-4Ralpha and STAT6 pathways, driven by either or both IL-4 and IL-13.	9	22	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	21	22	9	10
Activation of IL-4Ralpha by IL-13 or IL-4 induced signal transducer and activation of transcription-6 ( STAT6 ) , p42 / p44 ERK , p38 , and to a lesser extent , SAPK and JNK mitogen activated protein kinase phosphorylation .	Activation of IL-4Ralpha by IL-13 or IL-4 induced signal transducer and activation of transcription-6 (STAT6), p42 / p44 ERK, p38, and to a lesser extent, SAPK and JNK mitogen activated protein kinase phosphorylation.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	4	5	2	3
For example , in the absence of IL13Ralpha2 , will there be increased binding of the type II IL4R by IL13 that would have a different outcome to when that receptor is bound by IL4 ?	For example, in the absence of IL13Ralpha2, will there be increased binding of the type II IL4R by IL13 that would have a different outcome to when that receptor is bound by IL4?	12	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL13	IL13	IL13	IL4R	IL4R	IL4R	20	21	18	19
Notably , interleukin-13 ( IL13 ) can also activate the Type II IL4R .	Notably, interleukin-13 (IL13) can also activate the Type II IL4R.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-13	interleukin-13	interleukin-13	IL4R	IL4R	IL4R	2	3	12	13
Increased IL-13 also induced the upregulation of CD80 , IL-4Ralpha , and IL-13Ralpha2 .	Increased IL-13 also induced the upregulation of CD80, IL-4Ralpha, and IL-13Ralpha2.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	1	2	9	10
The downstream effector cytokine IL-13 can further trigger the activation and transdifferentiation of HSCs in an IL-4Ra- and STAT6 dependent manner to induce potent fibrogenic responses , suggesting a pathogenic capacity of ILC2s in the context of the tissue damage response [ XREF_BIBR ] .	The downstream effector cytokine IL-13 can further trigger the activation and transdifferentiation of HSCs in an IL-4Ra- and STAT6 dependent manner to induce potent fibrogenic responses, suggesting a pathogenic capacity of ILC2s in the context of the tissue damage response [XREF_BIBR].	0	20	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ra-	IL-4Ra-	IL-4Ra-	4	5	16	17
Kinetic expression studies of IL-4 and IL-13 activated bone marrow derived macrophages ( BMDM ) infected with HN878 , followed by gene set enrichment analysis , revealed that the MyD88 and IL-6 , IL-10 , G-CSF pathways are significantly enriched , but not the IL-4Ralpha driven pathway .	Kinetic expression studies of IL-4 and IL-13 activated bone marrow derived macrophages (BMDM) infected with HN878, followed by gene set enrichment analysis, revealed that the MyD88 and IL-6, IL-10, G-CSF pathways are significantly enriched, but not the IL-4Ralpha driven pathway.	2	45	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	6	7	44	45
As expected , IL-13 had no detectable effects in IL-4Ralpha -/- mice and induced BAL eosinophilia and goblet cell hyperplasia only in the IL-4Ralpha +/- mice .	As expected, IL-13 had no detectable effects in IL-4Ralpha -/- mice and induced BAL eosinophilia and goblet cell hyperplasia only in the IL-4Ralpha +/- mice.	3	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	3	4	23	24
The function of IL-13Ralpha2 as a decoy receptor that negatively regulates IL-13 activation of IL-13Ralpha1 and IL-4Ralpha has been demonstrated in several settings [ XREF_BIBR ] .	The function of IL-13Ralpha2 as a decoy receptor that negatively regulates IL-13 activation of IL-13Ralpha1 and IL-4Ralpha has been demonstrated in several settings [XREF_BIBR].	11	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	11	12	16	17
These cells remained CD14 positive and expressed high levels of IL-10 receptor ( IL-10R ) , suggesting that IL-10 mediates its effects by up-regulating the IL-10R .	These cells remained CD14 positive and expressed high levels of IL-10 receptor (IL-10R), suggesting that IL-10 mediates its effects by up-regulating the IL-10R.	18	26	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-10	IL-10	IL-10	IL-10R	IL-10R	IL-10R	18	19	25	26
In summary , EGF induces IL10 secretion , and IL10 activated IL10RA recruits p-Src to activate JAK1 and STAT3 , thus leading to the upregulation of EGFR expression .	In summary, EGF induces IL10 secretion, and IL10 activated IL10RA recruits p-Src to activate JAK1 and STAT3, thus leading to the upregulation of EGFR expression.	9	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL10	IL10	IL10	IL10RA	IL10RA	IL10RA	9	10	11	12
In turn , IL-10 secreted by Th1 and T cells stimulate IL-10R1 and IL-10R2 on Kupffer cells and macrophages , causing their prolonged activation .	In turn, IL-10 secreted by Th1 and T cells stimulate IL-10R1 and IL-10R2 on Kupffer cells and macrophages, causing their prolonged activation.	3	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-10	IL-10	IL-10	IL-10R1	IL-10R1	IL-10R1	3	4	11	12
This IL-10 insensitivity of aged astrocytes resulted in a failure to induce IL-10R1 and TGFbeta and resolve microglial activation .	This IL-10 insensitivity of aged astrocytes resulted in a failure to induce IL-10R1 and TGFbeta and resolve microglial activation.	1	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-10	IL-10	IL-10	IL-10R1	IL-10R1	IL-10R1	1	2	12	13
Based on our data and the result of previous studies , we suggest that IL10 activates IL10RA to recruit JAK1 and induce its autophosphorylation .	Based on our data and the result of previous studies, we suggest that IL10 activates IL10RA to recruit JAK1 and induce its autophosphorylation.	14	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL10	IL10	IL10	IL10RA	IL10RA	IL10RA	14	15	16	17
Control experiments where the cells were incubated with IL-10 plus secondary IgG antibody showed that the secondary antibodies did not block IL-10 activation of the IL-10R .	Control experiments where the cells were incubated with IL-10 plus secondary IgG antibody showed that the secondary antibodies did not block IL-10 activation of the IL-10R.	21	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-10	IL-10	IL-10	IL-10R	IL-10R	IL-10R	21	22	25	26
Therefore , we found that the mutation to alanine at Y496 not only abolished the interaction with p-STAT3 but also decreased the association with p-Src , indicating that IL10 activated IL10RA recruits p-Src through Y496 phosphorylation .	Therefore, we found that the mutation to alanine at Y496 not only abolished the interaction with p-STAT3 but also decreased the association with p-Src, indicating that IL10 activated IL10RA recruits p-Src through Y496 phosphorylation.	28	32	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL10	IL10	IL10	IL10RA	IL10RA	IL10RA	28	29	30	31
IL-10 may suppress differentiation of IFN-gamma secreting cells in the CLNs once the cells have proliferated and re-express their IL-10R .	IL-10 may suppress differentiation of IFN-gamma secreting cells in the CLNs once the cells have proliferated and re-express their IL-10R.	0	20	re-express	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-10	IL-10	IL-10	IL-10R	IL-10R	IL-10R	0	1	19	20
Human iPSdMs derived from an IL-10RA -/- mutant iPS did not respond to IL-10 stimulation ( XREF_FIG ) , consistent with the important role of IL-10RA in mediating IL-10 signalling .	Human iPSdMs derived from an IL-10RA -/- mutant iPS did not respond to IL-10 stimulation (XREF_FIG), consistent with the important role of IL-10RA in mediating IL-10 signalling.	13	26	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-10	IL-10	IL-10	IL-10RA	IL-10RA	IL-10RA	13	14	25	26
Furthermore , our data demonstrated that IL-10 induced a fetal-type HA enriched PCM in AFBs , regardless of the quantity differences of primary receptor IL-10R1 between FFBs and AFBs ( Supplemental Fig .	Furthermore, our data demonstrated that IL-10 induced a fetal-type HA enriched PCM in AFBs, regardless of the quantity differences of primary receptor IL-10R1 between FFBs and AFBs (Supplemental Fig.	6	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-10	IL-10	IL-10	IL-10R1	IL-10R1	IL-10R1	6	7	24	25
These structures will certainly provide insights into if NEMO induced IKK2 structure or how NEMO is poised to integrate other adapters to activate IKK .	These structures will certainly provide insights into if NEMO induced IKK2 structure or how NEMO is poised to integrate other adapters to activate IKK.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	NEMO	NEMO	NEMO	IKK2	IKK2	IKK2	8	9	10	11
IKKbeta catalytic activity is promoted by IKKgamma , a regulatory protein that promotes activity of the IKK complex .	IKKbeta catalytic activity is promoted by IKKgamma, a regulatory protein that promotes activity of the IKK complex.	0	10	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKgamma	IKKgamma	IKKgamma	IKKbeta	IKKbeta	IKKbeta	6	7	0	1
The oxRhoA-GTP bound to IKKgamma activated IKKbeta , leading to IkappaB phosphorylation and degradation , consequently NF-kappaB activation .	The oxRhoA-GTP bound to IKKgamma activated IKKbeta, leading to IkappaB phosphorylation and degradation, consequently NF-kappaB activation.	2	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IKKgamma	IKKgamma	IKKgamma	IKKbeta	IKKbeta	IKKbeta	4	5	6	7
The molecular mechanism by which NEMO induces activation of IKKalpha and IKKbeta remains largely unknown , although various models have been suggested .	The molecular mechanism by which NEMO induces activation of IKKalpha and IKKbeta remains largely unknown, although various models have been suggested.	5	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NEMO	NEMO	NEMO	IKKbeta	IKKbeta	IKKbeta	5	6	11	12
NEMO directs IKKbeta activity away from alternative substrates .	NEMO directs IKKbeta activity away from alternative substrates.	0	3	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NEMO	NEMO	NEMO	IKKbeta	IKKbeta	IKKbeta	0	1	2	3
To safeguard the BBB , TAK1 and NEMO trigger an IKK2- and p65 NF-kappaB-mediated pathway that ultimately up-regulates the tight junction protein occludin by limiting its proteasomal degradation .	To safeguard the BBB, TAK1 and NEMO trigger an IKK2- and p65 NF-kappaB-mediated pathway that ultimately up-regulates the tight junction protein occludin by limiting its proteasomal degradation.	5	17	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NEMO	NEMO	NEMO	IKK2-	IKK2-	IKK2-	7	8	10	11
Mutations in either IKKgamma or Tax that prevent formation of these higher order Tax.IKK complexes also interfere with the ability of Tax to induce IKKbeta catalytic function in vivo .	Mutations in either IKKgamma or Tax that prevent formation of these higher order Tax.IKK complexes also interfere with the ability of Tax to induce IKKbeta catalytic function in vivo.	0	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKgamma	IKKgamma	IKKgamma	IKKbeta	IKKbeta	IKKbeta	3	4	24	25
The sequential phosphorylation and ubiquitination of sumoylated nuclear NEMO results in the export of NEMO from the nucleus to the cytosol , where the latter activates IKKbeta and induces NF-kappaB .	The sequential phosphorylation and ubiquitination of sumoylated nuclear NEMO results in the export of NEMO from the nucleus to the cytosol, where the latter activates IKKbeta and induces NF-kappaB.	12	27	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	NEMO	export of NEMO from the nucleus to the cytosol	nemo	IKKbeta	IKKbeta	ikkbeta	14	15	26	27
The canonical pathway is mediated by the NEMO dependent activation of IKK2 leading to the phosphorylation and degradation of the classic inhibitors of kappaB ( IkappaB alpha , epsilon ) .	The canonical pathway is mediated by the NEMO dependent activation of IKK2 leading to the phosphorylation and degradation of the classic inhibitors of kappaB (IkappaB alpha, epsilon).	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NEMO	NEMO	NEMO	IKK2	IKK2	IKK2	7	8	11	12
This association leads to polyubiquitination of IKKgamma and phosphorylation of IKKbeta by TAK1 , activating IKKbeta .	This association leads to polyubiquitination of IKKgamma and phosphorylation of IKKbeta by TAK1, activating IKKbeta.	2	16	activating	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IKKgamma	leads to polyubiquitination of IKKgamma and phosphorylation of IKKbeta by TAK1	ikkgamma	IKKbeta	IKKbeta	ikkbeta	6	7	15	16
IGF-I , IGF-II , and insulin have all been shown to promote redistribution of the CI-MPR to the cell surface .	IGF-I, IGF-II, and insulin have all been shown to promote redistribution of the CI-MPR to the cell surface.	0	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	CI-MPR	CI-MPR	CI-MPR	2	3	15	16
As IGF-II targets the igf2r to lysosomal degradation , mutations in the genes encoding either the receptor ( Igf2r ) or its ligand ( Igf2 ) will affect the activity of the other , and result in a reduced endosomal trafficking of hydrolases necessary for reovirus disassembly [ XREF_BIBR ] .	As IGF-II targets the igf2r to lysosomal degradation, mutations in the genes encoding either the receptor (Igf2r) or its ligand (Igf2) will affect the activity of the other, and result in a reduced endosomal trafficking of hydrolases necessary for reovirus disassembly [XREF_BIBR].	1	5	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	igf2r	igf2r	igf2r	1	2	4	5
Leu27IGF2 , an analog of IGF2 that interacts selectively with the IGF2R , was used to specifically activate IGF2R signaling in this study .	Leu27IGF2, an analog of IGF2 that interacts selectively with the IGF2R, was used to specifically activate IGF2R signaling in this study.	3	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF2	IGF2	IGF2	IGF2R	IGF2R	IGF2R	5	6	18	19
The IGF-II stimulatory effect was shown to be sensitive to the phosphatidylinositol 3-kinase ( PI3K ) inhibitor , wortmannin , suggesting that CI-MPR redistribution is triggered by binding of IGF-II to the IGF-I receptor , a receptor known to activate PI3K .	The IGF-II stimulatory effect was shown to be sensitive to the phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, suggesting that CI-MPR redistribution is triggered by binding of IGF-II to the IGF-I receptor, a receptor known to activate PI3K.	22	30	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	CI-MPR	CI-MPR	CI-MPR	29	30	22	23
Thus , activation of IGF-2R by IGF-2 initiates apoptosis opposing the survival effects promoted by IGF-1 .	Thus, activation of IGF-2R by IGF-2 initiates apoptosis opposing the survival effects promoted by IGF-1.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IGF-2R	IGF-2R	IGF-2R	6	7	4	5
In hippocampal slices , IGF-II promotes IGF-II receptor dependent , persistent long-term potentiation after weak synaptic stimulation .	In hippocampal slices, IGF-II promotes IGF-II receptor dependent, persistent long-term potentiation after weak synaptic stimulation.	4	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-II receptor	IGF-II receptor	IGF-II receptor	4	5	6	8
Although IGF-II activating the IGF-II receptor signaling pathway has been found to stimulate cardiomyocyte hypertrophy , the role of IGF-II in cardiac cell apoptosis remains unclear .	Although IGF-II activating the IGF-II receptor signaling pathway has been found to stimulate cardiomyocyte hypertrophy, the role of IGF-II in cardiac cell apoptosis remains unclear.	1	12	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-II	IGF-II	IGF-II	IGF-II receptor	IGF-II receptor	IGF-II receptor	1	2	4	6
Leu27-IGF-2 , an IGF-2 analogue to activate specially the IGF-2R , was used to specifically stimulate IGF-2R .	Leu27-IGF-2, an IGF-2 analogue to activate specially the IGF-2R, was used to specifically stimulate IGF-2R.	3	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IGF-2R	IGF-2R	IGF-2R	3	4	16	17
IL-13 is known to mediate its effects by interaction with its cognate cell surface receptor [ comprising the IL-4 receptor alpha ( IL-4Ralpha ) chain and the IL-13 receptor alpha 1 ( IL-13Ralpha1 ) chain ] whereas IL-6 binds to a different receptor comprising a unique protein binding subunit ( IL-6R ) , which recruits two glycoprotein 130 ( GP130 ) monomers to mediate signal transduction .	IL-13 is known to mediate its effects by interaction with its cognate cell surface receptor [comprising the IL-4 receptor alpha (IL-4Ralpha) chain and the IL-13 receptor alpha 1 (IL-13Ralpha1) chain] whereas IL-6 binds to a different receptor comprising a unique protein binding subunit (IL-6R), which recruits two glycoprotein 130 (GP130) monomers to mediate signal transduction.	0	34	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-13Ralpha1	IL-13Ralpha1	IL-13Ralpha1	0	1	32	33
In light of the findings that in IL-13Ralpha1 -/- mice the GMPs remained uncommitted with a phenotype similar to the Lin - cKit + Sca1 + bone marrow stem cells , it is possible that IL-13 contributes both survival and differentiation functions to the IL-13Ralpha1 + ETP cells .	In light of the findings that in IL-13Ralpha1 -/- mice the GMPs remained uncommitted with a phenotype similar to the Lin - cKit + Sca1 + bone marrow stem cells, it is possible that IL-13 contributes both survival and differentiation functions to the IL-13Ralpha1 + ETP cells.	35	47	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-13Ralpha1	IL-13Ralpha1	IL-13Ralpha1	35	36	44	45
IL-13 stimulation of IL-13Ralpha1 was mediated via a blood leukocyte dependent and partially IL-4Ralpha-dependent pathway .	IL-13 stimulation of IL-13Ralpha1 was mediated via a blood leukocyte dependent and partially IL-4Ralpha-dependent pathway.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-13Ralpha1	IL-13Ralpha1	IL-13Ralpha1	0	1	3	4
Effect of corilagin on the IL-13Ralpha1 signaling pathway after IL-13 stimulation in IL-13Ralpha1 up-regulated and down-regulated ana-1 cells .	Effect of corilagin on the IL-13Ralpha1 signaling pathway after IL-13 stimulation in IL-13Ralpha1 up-regulated and down-regulated ana-1 cells.	9	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-13Ralpha1	IL-13Ralpha1	IL-13Ralpha1	9	10	12	13
In the absence of IL-4 , protection is almost completely abrogated by blockade of IL-13 using a soluble IL-13R fusion protein ( Bancroft , A.J ., manuscript in preparation ) .	In the absence of IL-4, protection is almost completely abrogated by blockade of IL-13 using a soluble IL-13R fusion protein (Bancroft, A.J., manuscript in preparation).	10	20	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-13R	IL-13R	IL-13R	14	15	18	19
Likewise , we show here that CD8+ T-cell supernatants from SSc patients induce STAT-6 activation in normal dermal fibroblasts in vitro as well as synthesis of ECM , both inhibited by a mAb to IL-13 , suggesting that IL-13 produced by CD8+ T cells in scleroderma skin may activate IL-13Ralpha1 signaling in local fibroblasts to promote dermal sclerosis .	Likewise, we show here that CD8+ T-cell supernatants from SSc patients induce STAT-6 activation in normal dermal fibroblasts in vitro as well as synthesis of ECM, both inhibited by a mAb to IL-13, suggesting that IL-13 produced by CD8+ T cells in scleroderma skin may activate IL-13Ralpha1 signaling in local fibroblasts to promote dermal sclerosis.	38	50	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13	IL-13	IL-13	IL-13Ralpha1	IL-13Ralpha1	IL-13Ralpha1	38	39	49	50
In this study , T cells that specifically demonstrated high levels of IL-15RA expression were treated with IL-15 prior to transfer into leukemia bearing mice .	In this study, T cells that specifically demonstrated high levels of IL-15RA expression were treated with IL-15 prior to transfer into leukemia bearing mice.	12	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-15	IL-15	IL-15	IL-15RA	IL-15RA	IL-15RA	17	18	12	13
The key distinctions between these two cytokines are ( a ) IL-15 exhibits an affinity for its private alpha receptor subunit that is 400-fold higher than that of IL-2 and ( b ) IL-15 primarily signals in trans , with monocytes or dendritic cells ( DCs ) presenting IL-15Ralpha to NK cells or T cells rather than the conventional cis activation mechanism favored by IL-2 .	The key distinctions between these two cytokines are (a) IL-15 exhibits an affinity for its private alpha receptor subunit that is 400-fold higher than that of IL-2 and (b) IL-15 primarily signals in trans, with monocytes or dendritic cells (DCs) presenting IL-15Ralpha to NK cells or T cells rather than the conventional cis activation mechanism favored by IL-2.	33	61	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-15	IL-15	IL-15	IL-15Ralpha	IL-15Ralpha	IL-15Ralpha	33	34	48	49
IL-15 induces signaling by both cis- and trans-presentation of IL-15 and IL-15Ralpha to CD122 and gammac .	IL-15 induces signaling by both cis- and trans-presentation of IL-15 and IL-15Ralpha to CD122 and gammac.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-15	IL-15	IL-15	IL-15Ralpha	IL-15Ralpha	IL-15Ralpha	0	1	11	12
The coordinated upregulation of surface IL-15 and IL-15Ralpha during EAE supported the possible requirement of IL-15Ralpha for IL-15 elaboration .	The coordinated upregulation of surface IL-15 and IL-15Ralpha during EAE supported the possible requirement of IL-15Ralpha for IL-15 elaboration.	2	16	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-15	IL-15	IL-15	IL-15Ralpha	IL-15Ralpha	IL-15Ralpha	5	6	15	16
By contrast , IL-15 induced only minimal CD8 + T cell proliferation in IL-15Ralpha -/ - mice ( XREF_FIG C ) .	By contrast, IL-15 induced only minimal CD8 + T cell proliferation in IL-15Ralpha -/ - mice (XREF_FIG C).	3	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-15	IL-15	IL-15	IL-15Ralpha	IL-15Ralpha	IL-15Ralpha	3	4	13	14
Despite shorter culture conditions of 16 hours , we observed that CD8+ T cells transfected with IL-15RA and treated with IL-15 demonstrate higher % viability in the presence of dexamethasone compared to similarly treated no RNA transfected cells ( XREF_FIG ) .	Despite shorter culture conditions of 16 hours, we observed that CD8+ T cells transfected with IL-15RA and treated with IL-15 demonstrate higher% viability in the presence of dexamethasone compared to similarly treated no RNA transfected cells (XREF_FIG).	14	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-15	IL-15	IL-15	IL-15RA	IL-15RA	IL-15RA	20	21	16	17
JAK3 is solely activated by type I cytokine receptors featuring a common gamma-chain ( gammac ) subunit that are activated by IL-2 , IL-4 , IL-7 , IL-9 , IL-15 , and IL-21 7 ; mutations in either the gamma-chain or JAK3 have been identified in humans as a cause of severe combined immunodeficiency disease ( SCID ) , which manifests as a depletion of T , B , and natural killer ( NK ) cells with no other defects XREF_BIBR , XREF_BIBR .	JAK3 is solely activated by type I cytokine receptors featuring a common gamma-chain (gammac) subunit that are activated by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 7; mutations in either the gamma-chain or JAK3 have been identified in humans as a cause of severe combined immunodeficiency disease (SCID), which manifests as a depletion of T, B, and natural killer (NK) cells with no other defects XREF_BIBR, XREF_BIBR.	14	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-15	IL-15	IL-15	gammac	gammac	gammac	29	30	14	15
Our results suggest the existence in both normal and leukemic CD34+ cells of a constitutive production of a bioactive IL-15 that does not lead to NK differentiation and further indicate that membrane bound IL-15 and constitutive activation of gammac are hallmarks of leukemic progenitors .	Our results suggest the existence in both normal and leukemic CD34+ cells of a constitutive production of a bioactive IL-15 that does not lead to NK differentiation and further indicate that membrane bound IL-15 and constitutive activation of gammac are hallmarks of leukemic progenitors.	33	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-15	IL-15	IL-15	gammac	gammac	gammac	33	34	38	39
Since IL-15 and IL-2 stimulate signaling via the same receptor subunits , IL-2 and IL-15b and common gamma chain ( gammac ) 26 , we wondered whether Tbkbp1 also played a role in regulating IL-2-stimulated signaling in NKT cells .	Since IL-15 and IL-2 stimulate signaling via the same receptor subunits, IL-2 and IL-15b and common gamma chain (gammac) 26, we wondered whether Tbkbp1 also played a role in regulating IL-2-stimulated signaling in NKT cells.	1	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-15	IL-15	IL-15	common gamma chain	common gamma chain	common gamma chain	1	2	16	19
Moreover , although MFI value of pSTAT-1 in IL-15 stimulated , gammac receptor neutralized PBMCs ( green line ) was reduced in comparison with IL-15 stimulated normal PBMCs ( P = 0.0027 , Figure XREF_FIG ) , it is still remarkably elevated in comparison of MFI value in gammac receptor neutralized PBMCs ( P < 0.0001 , Figure XREF_FIG ) .	Moreover, although MFI value of pSTAT-1 in IL-15 stimulated, gammac receptor neutralized PBMCs (green line) was reduced in comparison with IL-15 stimulated normal PBMCs (P = 0.0027, Figure XREF_FIG), it is still remarkably elevated in comparison of MFI value in gammac receptor neutralized PBMCs (P < 0.0001, Figure XREF_FIG).	6	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-15	IL-15	IL-15	gammac	gammac	gammac	8	9	11	12
IL-10 increased Il10rb only in rat .	IL-10 increased Il10rb only in rat.	0	3	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-10	IL-10	IL-10	Il10rb	Il10rb	Il10rb	0	1	2	3
THP-1 macrophages transfected with either unspecific control siRNA or IL10RB specific siRNA were cultivated in different media after transfection and treated with IL10 .	THP-1 macrophages transfected with either unspecific control siRNA or IL10RB specific siRNA were cultivated in different media after transfection and treated with IL10.	9	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL10	IL10	IL10	IL10RB	IL10RB	IL10RB	22	23	9	10
demonstrated that IGF-1 activates CnA and its downstream targets , the NFAT transcription factors , but the activation mechanism was not described .	demonstrated that IGF-1 activates CnA and its downstream targets, the NFAT transcription factors, but the activation mechanism was not described.	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	CnA	CnA	CnA	2	3	4	5
Significantly CnA is activated by IGF-1 and participates in recovery from muscle injury [ XREF_BIBR ] .	Significantly CnA is activated by IGF-1 and participates in recovery from muscle injury [XREF_BIBR].	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-1	IGF-1	IGF-1	CnA	CnA	CnA	5	6	1	2
The gammac subunit also activates JAK3 , whereas IL-13Ralpha1 activates two other kinases , tyrosine kinase 2 ( TYK2 ) and JAK2 .	The gammac subunit also activates JAK3, whereas IL-13Ralpha1 activates two other kinases, tyrosine kinase 2 (TYK2) and JAK2.	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13Ralpha1	IL-13Ralpha1	IL-13Ralpha1	TYK2	TYK2	TYK2	8	9	18	19
Indeed , gamma c activates the tyrosine kinase Janus kinase 3 ( JAK3 ) , whereas IL-13Ralpha1 activates Tyk2 and JAK2 .	Indeed, gamma c activates the tyrosine kinase Janus kinase 3 (JAK3), whereas IL-13Ralpha1 activates Tyk2 and JAK2.	16	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-13Ralpha1	IL-13Ralpha1	IL-13Ralpha1	Tyk2	Tyk2	Tyk2	16	17	18	19
Binding of IL-10 to its receptors , IL-10 R1 and IL10R2 , results in activation of Jak1 and Tyk2 , which subsequently activate STAT-1 , 3 and 5 [ XREF_BIBR ] .	Binding of IL-10 to its receptors, IL-10 R1 and IL10R2, results in activation of Jak1 and Tyk2, which subsequently activate STAT-1, 3 and 5 [XREF_BIBR].	0	19	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	IL10R2	IL10R2	IL10R2	Tyk2	Tyk2	Tyk2	10	11	18	19
In addition , in vitro studies in suture mesenchymal cells found that IHH positively regulated BMP2 and BMP4 transcript abundance , associated with upregulation of osteogenic markers .	In addition, in vitro studies in suture mesenchymal cells found that IHH positively regulated BMP2 and BMP4 transcript abundance, associated with upregulation of osteogenic markers.	12	19	positively regulated	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	IHH	IHH	IHH	BMP2	BMP2	BMP2	12	13	15	16
The microarray data did not reveal any changes in Indian hedgehog ( Ihh ) , but Ihh was observed to up-regulate BMP2 and PTHLH during the endochondral ossification XREF_BIBR , XREF_BIBR .	The microarray data did not reveal any changes in Indian hedgehog (Ihh), but Ihh was observed to up-regulate BMP2 and PTHLH during the endochondral ossification XREF_BIBR, XREF_BIBR.	16	23	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ihh	Ihh	Ihh	BMP2	BMP2	BMP2	16	17	21	22
The application of cDNA microarray analysis has revealed that lack of IL-11 signalling in IL11Ra -/- mice results in differences in mRNA expression compared to wild type during artificial decidualization .	The application of cDNA microarray analysis has revealed that lack of IL-11 signalling in IL11Ra -/- mice results in differences in mRNA expression compared to wild type during artificial decidualization.	11	16	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	IL11Ra	IL11Ra	IL11Ra	11	12	14	15
TBK1 and IKKepsilon inhibition accelerated cellular senescence by suppressing the p65 subunit of NF-kappaB and inducing p16 Ink4a .	TBK1 and IKKepsilon inhibition accelerated cellular senescence by suppressing the p65 subunit of NF-kappaB and inducing p16 Ink4a.	0	11	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKepsilon	IKKepsilon	IKKepsilon	p65	p65	p65	2	3	10	11
Mechanistic investigations indicated that IL15RA signaling activated JAK1 , STAT1 , STAT2 , AKT , PRAS40 , and ERK1/2 in the absence of IL2RB and IL2RG , whereas neither STAT5 nor JAK2 were activated .	Mechanistic investigations indicated that IL15RA signaling activated JAK1, STAT1, STAT2, AKT, PRAS40, and ERK1/2 in the absence of IL2RB and IL2RG, whereas neither STAT5 nor JAK2 were activated.	4	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL15RA	IL15RA	IL15RA	IL2RB	IL2RB	IL2RB	4	5	23	24
These findings suggested that the functional single nucleotide polymorphism ( SNP ) IL-12A rs2243115 GG genotype may increase the risk of RA in RF negative patients , and the IL-12B rs3212227 AC and AC+ CC genotypes are associated with RA risk in older patients , RF positive patients and ACPA negative patients .	These findings suggested that the functional single nucleotide polymorphism (SNP) IL-12A rs2243115 GG genotype may increase the risk of RA in RF negative patients, and the IL-12B rs3212227 AC and AC+CC genotypes are associated with RA risk in older patients, RF positive patients and ACPA negative patients.	12	31	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-12A	IL-12A	IL-12A	IL-12B	IL-12B	IL-12B	12	13	29	30
We found that the recombinant IL18 preparation did not increase CNV in Il18r1 -/- mice ( XREF_SUPPLEMENTARY ) , which also indicates that the MBL IL18 diluent and excipients are not pro angiogenic .	We found that the recombinant IL18 preparation did not increase CNV in Il18r1 -/- mice (XREF_SUPPLEMENTARY), which also indicates that the MBL IL18 diluent and excipients are not pro angiogenic.	5	21	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL18	IL18	IL18	Il18r1	Il18r1	Il18r1	5	6	12	13
The persistence of high level of CD4 + CD25 + Foxp3 + Treg in the serum of patients treated with IL-2 , was associated with poor clinical response [ XREF_BIBR , XREF_BIBR ] .	The persistence of high level of CD4 + CD25 + Foxp3 + Treg in the serum of patients treated with IL-2, was associated with poor clinical response [XREF_BIBR, XREF_BIBR].	1	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	20	21	8	9
Therefore , we concluded that IL-2 complexes induced CD4 + CD25 high cells with stable expression of Foxp3 .	Therefore, we concluded that IL-2 complexes induced CD4 + CD25 high cells with stable expression of Foxp3.	5	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	5	6	10	11
Normally , the Th17 and Th1 response dominate , and IL-2 induces naive CD4 + CD25 + Treg activated by MBP to express Ifngr and Il12rb2 .	Normally, the Th17 and Th1 response dominate, and IL-2 induces naive CD4 + CD25 + Treg activated by MBP to express Ifngr and Il12rb2.	10	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	10	11	15	16
Conversely , provision of IL-2 was able to induce CD25 up-regulation on a proportion of CD25 low FoxP3 + CD4 + T cells ( XREF_FIG ) .	Conversely, provision of IL-2 was able to induce CD25 up-regulation on a proportion of CD25 low FoxP3 + CD4 + T cells (XREF_FIG).	2	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	4	5	9	10
High concentrations of IL-2 may signal through lower affinity IL2Rbeta-gamma complexes and thereby may drive IL-2 dependent growth independent of CD25 .	High concentrations of IL-2 may signal through lower affinity IL2Rbeta-gamma complexes and thereby may drive IL-2 dependent growth independent of CD25.	1	21	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	20	21
Concomitant with this cell proliferative and metabolic response was expression of JAK-STAT signaling molecules induced by IL-2 in response to activation ( CD25 , JAK2 , CISH , BCL3 , STAT1 , STAT3 , TSLP , SOCS1-3 ) as well as upregulation of various cytokines ( IFNG , IFN1B , IL-2 , IL-4 , IL6ST , IL13 , IL21 , IL22 ) and cytokine receptors ( IFNLR1 , IL11RA , IL12RB2 , IL15RA , IL2RA , IL2RB , IL23R , IL3RA , IL6R , IL7R , IL9R ) .	Concomitant with this cell proliferative and metabolic response was expression of JAK-STAT signaling molecules induced by IL-2 in response to activation (CD25, JAK2, CISH, BCL3, STAT1, STAT3, TSLP, SOCS1-3) as well as upregulation of various cytokines (IFNG, IFN1B, IL-2, IL-4, IL6ST, IL13, IL21, IL22) and cytokine receptors (IFNLR1, IL11RA, IL12RB2, IL15RA, IL2RA, IL2RB, IL23R, IL3RA, IL6R, IL7R, IL9R).	14	36	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	16	17	22	23
The proliferation and interleukin-2 production of CD4 + CD25 - alphabetaTcells were inhibited in a cell-contact manner by Vdelta2 gammadeltaTcells .	The proliferation and interleukin-2 production of CD4 + CD25 - alphabetaTcells were inhibited in a cell-contact manner by Vdelta2 gammadeltaTcells.	1	9	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	interleukin-2	interleukin-2	interleukin-2	CD25	CD25	CD25	3	4	8	9
Interestingly , we also observed significant increases in the percentage of activated CD4 + ( i.e ., CD4 + CD25 + ) T cells in the course of this trial , again emphasizing the possibility that IL-2 caused activation and expansion of CD4 + T cells , including CD4 + CD25 high FOXP3 + Tregs .	Interestingly, we also observed significant increases in the percentage of activated CD4 + (i.e., CD4 + CD25 +) T cells in the course of this trial, again emphasizing the possibility that IL-2 caused activation and expansion of CD4 + T cells, including CD4 + CD25 high FOXP3 + Tregs.	36	52	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	36	37	50	51
Despite increases in CD25 expression , T lymphocytes from patients treated with IL-2 did not have increased expression of early ( CD69 ) or late ( CD95 ) activation markers or evidence of recent proliferation ( Ki67 ) .	Despite increases in CD25 expression, T lymphocytes from patients treated with IL-2 did not have increased expression of early (CD69) or late (CD95) activation markers or evidence of recent proliferation (Ki67).	3	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	12	13	3	4
In the tumor , IL-2 levels might be just sufficient to support CD25 high Tregs , which accumulate and consume the available IL-2 , depriving infiltrating Teffs of this essential cytokine .	In the tumor, IL-2 levels might be just sufficient to support CD25 high Tregs, which accumulate and consume the available IL-2, depriving infiltrating Teffs of this essential cytokine.	4	14	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2 levels	il-2	CD25	CD25	cd25	4	5	12	13
IL-2 promoted induction of IL-2Ra on the surface of cells from the SNP mice ( XREF_FIG ) .	IL-2 promoted induction of IL-2Ra on the surface of cells from the SNP mice (XREF_FIG).	0	5	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	IL-2Ra	IL-2Ra	IL-2Ra	0	1	4	5
CD28 co-stimulation also leads to the production of IL-2 , which can further direct the differentiation of CD4 + T cells into CD4 + CD25 + Tregs [ XREF_BIBR , XREF_BIBR ] .	CD28 co-stimulation also leads to the production of IL-2, which can further direct the differentiation of CD4 + T cells into CD4 + CD25 + Tregs [XREF_BIBR, XREF_BIBR].	6	28	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	8	9	24	25
Moreover , both low and high dose prophylactic IL-2 treatments resulted in a significant increase in CD25 expression and frequency of CD25 + cells only within the stable Foxp3 + T cell fraction suggesting that IL-2 preferentially favours the fitness of stable Foxp3 + -->+ T REG cells without preventing T REG cell reprogramming .	Moreover, both low and high dose prophylactic IL-2 treatments resulted in a significant increase in CD25 expression and frequency of CD25 + cells only within the stable Foxp3 + T cell fraction suggesting that IL-2 preferentially favours the fitness of stable Foxp3 + -->+ T REG cells without preventing T REG cell reprogramming.	8	22	increase	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	8	9	21	22
IL-2 treatments early after Mycobacterium tuberculosis infection of macaques induced simultaneous expansion of CD4 + CD25 + Foxp3 + Treg , CD8 + CD25 + Foxp3 + T cells , and CD4 + T effector and CD8 + T effector and Vgamma2Vdelta2 T effector populations producing anti-M .	IL-2 treatments early after Mycobacterium tuberculosis infection of macaques induced simultaneous expansion of CD4 + CD25 + Foxp3 + Treg, CD8 + CD25 + Foxp3 + T cells, and CD4 + T effector and CD8 + T effector and Vgamma2Vdelta2 T effector populations producing anti-M.	0	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	15	16
After binding to its receptor ( IL-2R ) , IL-2 triggers its production of as well as IL-2Ra .	After binding to its receptor (IL-2R), IL-2 triggers its production of as well as IL-2Ra.	9	18	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	IL-2Ra	IL-2Ra	IL-2Ra	9	10	17	18
While IL-2 and TGF-beta increased the percentage of CD4 + CD25 + FoxP3 + T cells , the addition of rapamycin markedly enhanced this effect .	While IL-2 and TGF-beta increased the percentage of CD4 + CD25 + FoxP3 + T cells, the addition of rapamycin markedly enhanced this effect.	1	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	10	11
Thus , ATG , but not alemtuzumab or the IL-2 receptor antagonists , induces expansion of CD4 + CD25 + Treg when cultured with human peripheral blood lymphocytes in vitro [ XREF_BIBR ] .	Thus, ATG, but not alemtuzumab or the IL-2 receptor antagonists, induces expansion of CD4 + CD25 + Treg when cultured with human peripheral blood lymphocytes in vitro [XREF_BIBR].	9	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	9	10	18	19
XREF_BIBR Among recent translational studies focusing on immunostimulatory cytokines in general , we found of particular interest the works of ( 1 ) Guermonprez and colleagues , who discovered a signaling pathway triggered by Plasmodium infection that regulates DC homeostasis and adaptive immune response upon the release of fms related tyrosine kinase 3 ligand ( FLT3L ) ; XREF_BIBR ( 2 ) Sim and coworkers , who demonstrated that CD4 + CD25 + FOXP3 + Tregs accumulating in melanoma patients treated with high-dose IL-2 express inducible T-cell co-stimulator ( ICOS ) and exhibit an activated phenotype , as indicated by elevated levels of CD39 , CD73 and transforming growth factor beta1 ( TGFbeta1 ) ; XREF_BIBR ( 3 ) Mortha and collaborators , who showed that GM-CSF is required for the establishment of Treg dependent oral tolerance by intestinal macrophages ; XREF_BIBR and ( 4 ) West et al ., who demonstrated that combining IL-2 with a mAb specific for CD274 mediates synergistic immunostimulatory effects .	XREF_BIBR Among recent translational studies focusing on immunostimulatory cytokines in general, we found of particular interest the works of (1) Guermonprez and colleagues, who discovered a signaling pathway triggered by Plasmodium infection that regulates DC homeostasis and adaptive immune response upon the release of fms related tyrosine kinase 3 ligand (FLT3L); XREF_BIBR (2) Sim and coworkers, who demonstrated that CD4 + CD25 + FOXP3 + Tregs accumulating in melanoma patients treated with high-dose IL-2 express inducible T-cell co-stimulator (ICOS) and exhibit an activated phenotype, as indicated by elevated levels of CD39, CD73 and transforming growth factor beta1 (TGFbeta1); XREF_BIBR (3) Mortha and collaborators, who showed that GM-CSF is required for the establishment of Treg dependent oral tolerance by intestinal macrophages; XREF_BIBR and (4) West et al., who demonstrated that combining IL-2 with a mAb specific for CD274 mediates synergistic immunostimulatory effects.	71	164	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	83	84	71	72
While IL-2 and TGF-beta increased the percentage of CD4 + CD25 + cells that expressed FOXP3 after 5 days of culture , the addition of atRA to TGF-beta markedly enhanced this effect ( XREF_FIG , A and B ) .	While IL-2 and TGF-beta increased the percentage of CD4 + CD25 + cells that expressed FOXP3 after 5 days of culture, the addition of atRA to TGF-beta markedly enhanced this effect (XREF_FIG, A and B).	1	15	increased	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-2	IL-2	il-2	CD25	CD25 + cells that expressed	cd25	1	2	10	11
Exogenous IL-2 considerably increased the frequencies and the absolute cell numbers of splenic CD25 + Foxp3 + CD4 + Treg cells both in wild-type and IkappaBalpha-SR Tg mice .	Exogenous IL-2 considerably increased the frequencies and the absolute cell numbers of splenic CD25 + Foxp3 + CD4 + Treg cells both in wild-type and IkappaBalpha-SR Tg mice.	0	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	13	14
We also assessed suppressive activities of CD4 + CD25 + cells induced by IL-2 and TGF-beta with or without anti-IFN-gamma and anti-IL-4 or control IgG .	We also assessed suppressive activities of CD4 + CD25 + cells induced by IL-2 and TGF-beta with or without anti-IFN-gamma and anti-IL-4 or control IgG.	2	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	13	14	8	9
These data suggest that neutralization of IFN-gamma and IL-4 not only increases the Foxp3 expression in CD4 + CD25 + cells induced by IL-2 and TGF-beta , but also enhances the suppressive activity of these cells .	These data suggest that neutralization of IFN-gamma and IL-4 not only increases the Foxp3 expression in CD4 + CD25 + cells induced by IL-2 and TGF-beta, but also enhances the suppressive activity of these cells.	11	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	23	24	18	19
IL-2 produced by CD4 + T cells can induce peripheral conversion of CD25 - T cells into CD25 + Foxp3 + inducible regulatory ( iT reg ) cells , leading one to predict that if the primary defect of Nod2 -/- T cells in this situation was in producing IL-2 , a more severe disease would ensue as a result of impaired iT reg cell generation .	IL-2 produced by CD4 + T cells can induce peripheral conversion of CD25 - T cells into CD25 + Foxp3 + inducible regulatory (iT reg) cells, leading one to predict that if the primary defect of Nod2 -/- T cells in this situation was in producing IL-2, a more severe disease would ensue as a result of impaired iT reg cell generation.	0	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	12	13
In contrast , whereas CD4 + CD25 - thymocytes differentiated into FOXP3 + cells by stimulating with anti-CD3 , anti-CD28 , IL-2 , and TGF-beta-like peripheral naive CD4 + T cells , stimulation of CD4 + CD25 - thymocytes with anti-CD3 and IL-2 or anti-CD3 , anti-CD28 , and IL-2 induced vigorous expansion but not the differentiation of CD4 + CD25 - cells into FOXP3 + cells ( XREF_FIG ) .	In contrast, whereas CD4 + CD25 - thymocytes differentiated into FOXP3 + cells by stimulating with anti-CD3, anti-CD28, IL-2, and TGF-beta-like peripheral naive CD4 + T cells, stimulation of CD4 + CD25 - thymocytes with anti-CD3 and IL-2 or anti-CD3, anti-CD28, and IL-2 induced vigorous expansion but not the differentiation of CD4 + CD25 - cells into FOXP3 + cells (XREF_FIG).	34	61	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	49	50	60	61
The assay was validated by measuring the IL-2 induced enrichment of the IL2RA enhancer XREF_BIBR element named Positive Regulatory Region ( PRR ) III ( XREF_FIG ) via STAT5 antibodies as compared to the control serum .	The assay was validated by measuring the IL-2 induced enrichment of the IL2RA enhancer XREF_BIBR element named Positive Regulatory Region (PRR) III (XREF_FIG) via STAT5 antibodies as compared to the control serum.	6	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	IL2RA	IL2RA	IL2RA	7	8	12	13
This was demonstrated when the self quenching efficiency of the conjugate was identical , when we switched the antibody from trastuzumab to daclizumab ( Dac ) , which is also a CDR grafted humanized monoclonal antibody ( IgG 1 subclass ) targeting CD25 ( IL-2 receptor alpha subunit ) .	This was demonstrated when the self quenching efficiency of the conjugate was identical, when we switched the antibody from trastuzumab to daclizumab (Dac), which is also a CDR grafted humanized monoclonal antibody (IgG 1 subclass) targeting CD25 (IL-2 receptor alpha subunit).	41	45	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	44	45	42	43
[ XREF_BIBR ] We hypothesized that IL-2 administration promoted the expansion of both CD4 + CD25 + Tregs and conventional effector T cells , which did not alter the overall immune balance ; whereas , the administration of IL-15 enhanced the expansion and function of CD8 + CD122 + but not CD4 + CD25 + Tregs .	[XREF_BIBR] We hypothesized that IL-2 administration promoted the expansion of both CD4 + CD25 + Tregs and conventional effector T cells, which did not alter the overall immune balance; whereas, the administration of IL-15 enhanced the expansion and function of CD8 + CD122 + but not CD4 + CD25 + Tregs.	6	17	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	6	7	15	16
Study of TCR- and TCR and CD28 induced downstream signals revealed that M. leprae antigens curtail phosphorylation of both Erk1/2 and p38MAPK , consequently altering terminal signalling events like reduced binding of NFAT on IL-2 promoter and transcription of IL-2 gene , diminished expression of activation markers ( CD25 and CD69 ) .	Study of TCR- and TCR and CD28 induced downstream signals revealed that M. leprae antigens curtail phosphorylation of both Erk1/2 and p38MAPK, consequently altering terminal signalling events like reduced binding of NFAT on IL-2 promoter and transcription of IL-2 gene, diminished expression of activation markers (CD25 and CD69).	39	50	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	39	40	48	49
In the MLNs , IL-2 and TGF-beta are required to induce production of CD4 + CD25 + Foxp3 + inducible Tregs from naive CD4 + CD25 - T cells .	In the MLNs, IL-2 and TGF-beta are required to induce production of CD4 + CD25 + Foxp3 + inducible Tregs from naive CD4 + CD25 - T cells.	4	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	4	5	15	16
IL-2 signaling induces both the differentiation and survival of effector T cells , and the inability to upregulate CD25 , and therefore respond to IL-2 , is associated with T cell anergy and tolerance .	IL-2 signaling induces both the differentiation and survival of effector T cells, and the inability to upregulate CD25, and therefore respond to IL-2, is associated with T cell anergy and tolerance.	0	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	18	19
High IL-2 concentrations but not high virus inputs lead to surface upregulation of CD25 and significant cellular proliferation in CD4 ( + ) CD25 (-) cells .	High IL-2 concentrations but not high virus inputs lead to surface upregulation of CD25 and significant cellular proliferation in CD4 (+) CD25 (-) cells.	1	17	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	13	14
This IL-2 production causes an inhibition of the CD4 + CD25 + FoxP3 + suppressive activity and an increase in the population of CD4 + CD25neg T cells .	This IL-2 production causes an inhibition of the CD4 + CD25 + FoxP3 + suppressive activity and an increase in the population of CD4 + CD25neg T cells.	1	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	10	11
Denileukin diftitox ( DD ) , a diphtheria toxin fragment IL-2 fusion protein , is thought to target and kill CD25 ( + ) cells .	Denileukin diftitox (DD), a diphtheria toxin fragment IL-2 fusion protein, is thought to target and kill CD25 (+) cells.	10	21	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	10	11	20	21
Most importantly , the addition of anti-CD28 or exogenous IL-2 not only markedly enhanced the responses of the CD4 + CD25 - cells , but almost completely abrogated the suppressive effects due to CD4 + CD25 + cells .	Most importantly, the addition of anti-CD28 or exogenous IL-2 not only markedly enhanced the responses of the CD4 + CD25 - cells, but almost completely abrogated the suppressive effects due to CD4 + CD25 + cells.	4	22	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	9	10	20	21
In our study , low-dose CTX demonstrated a limited capacity to modulate circulating Tregs ; however , low-dose IL-2 produced a remarkable boost of CD4 + CD25 hi Foxp3 + Tregs in PBMCs .	In our study, low-dose CTX demonstrated a limited capacity to modulate circulating Tregs; however, low-dose IL-2 produced a remarkable boost of CD4 + CD25 hi Foxp3 + Tregs in PBMCs.	17	30	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	18	19	26	27
TNF and IL-2 up-regulate both TNFR2 and CD25 on Tregs , resulting in a reciprocal amplification loop in the activation of Tregs .	TNF and IL-2 up-regulate both TNFR2 and CD25 on Tregs, resulting in a reciprocal amplification loop in the activation of Tregs.	0	8	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	7	8
First , in control experiments , we tested the ability of an IL-2 neutralizing antibody to inhibit recombinant IL-2 in vitro ; anti-IL-2 antibody was capable of limiting proliferation , and impairing IL-2 driven increases in cell size and CD25 upregulation ( XREF_FIG ) .	First, in control experiments, we tested the ability of an IL-2 neutralizing antibody to inhibit recombinant IL-2 in vitro; anti-IL-2 antibody was capable of limiting proliferation, and impairing IL-2 driven increases in cell size and CD25 upregulation (XREF_FIG).	32	40	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	32	33	39	40
Indeed , high-dose IL-2 has been shown to promote the accumulation of immunosuppressive CD4 + CD25 + FOXP3 + regulatory T cells ( Tregs ) in both cancer and HIV-1 patients , XREF_BIBR , XREF_BIBR - XREF_BIBR while GM-CSF has been involved in the establishment of Treg mediated oral tolerance by intestinal macrophages .	Indeed, high-dose IL-2 has been shown to promote the accumulation of immunosuppressive CD4 + CD25 + FOXP3 + regulatory T cells (Tregs) in both cancer and HIV-1 patients, XREF_BIBR, XREF_BIBR - XREF_BIBR while GM-CSF has been involved in the establishment of Treg mediated oral tolerance by intestinal macrophages.	2	47	promote	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	15	16
Furthermore , it is likely the lower expression of Bim in CD25 lo T reg that affords these cells a survival advantage over CD25 hi T reg , especially when IL-2 becomes limiting , and promotes increased CD25 lo T reg accrual .	Furthermore, it is likely the lower expression of Bim in CD25 lo T reg that affords these cells a survival advantage over CD25 hi T reg, especially when IL-2 becomes limiting, and promotes increased CD25 lo T reg accrual.	30	38	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	30	31	37	38
By flow cytometry , TNF and IL-2 co-incubation also increased the number of CD4 + CD25 hi FOXP3 cells in cultured human cells from blood ( XREF_FIG ) .	By flow cytometry, TNF and IL-2 co-incubation also increased the number of CD4 + CD25 hi FOXP3 cells in cultured human cells from blood (XREF_FIG).	4	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	6	7	15	16
In human T reg -cell biology , IL-2 is supposed to induce a peripheral expansion of CD4 + CD25 high FOXP3 + T reg cells as suggested by Wei et al ..	In human T reg -cell biology, IL-2 is supposed to induce a peripheral expansion of CD4 + CD25 high FOXP3 + T reg cells as suggested by Wei et al..	7	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	7	8	18	19
Furthermore , IL-2 could rescue both CD25 - and CD25 + cells to a limited extent in our system ( XREF_FIG B ) , but no lack of rescue was noted in cells from APS-II or control patients ( XREF_FIG ) .	Furthermore, IL-2 could rescue both CD25 - and CD25 + cells to a limited extent in our system (XREF_FIG B), but no lack of rescue was noted in cells from APS-II or control patients (XREF_FIG).	2	11	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	6	7
Apoptosis of CD4 + CD25 high T cells in response to Sirolimus requires activation of T Cell Receptor and is modulated by IL-2 .	Apoptosis of CD4 + CD25 high T cells in response to Sirolimus requires activation of T Cell Receptor and is modulated by IL-2.	0	23	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	22	23	4	5
Apoptosis of CD4 + CD25 high T Cells in Type 1 Diabetes May Be Partially Mediated by IL-2 Deprivation .	Apoptosis of CD4 + CD25 high T Cells in Type 1 Diabetes May Be Partially Mediated by IL-2 Deprivation.	0	18	Mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	17	18	4	5
Next , we sought to determine whether IL-2 signaling and resulting induction of pSTAT5 and CD25 are required for 2D2-Kv1.3 KO cells to ameliorate EAE .	Next, we sought to determine whether IL-2 signaling and resulting induction of pSTAT5 and CD25 are required for 2D2-Kv1.3 KO cells to ameliorate EAE.	7	16	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	7	8	15	16
We also demonstrated that naive CD4 + CD25 + FOXP3 + Treg activated by a specific antigen and the Type-2 cytokine IL-4 , but not the usual Treg cytokine IL-2 , are induced to express IL-5Ralpha and that IL-5 further activates these antigen specific Treg .	We also demonstrated that naive CD4 + CD25 + FOXP3 + Treg activated by a specific antigen and the Type-2 cytokine IL-4, but not the usual Treg cytokine IL-2, are induced to express IL-5Ralpha and that IL-5 further activates these antigen specific Treg.	5	30	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	29	30	7	8
A series of pilot experiments revealed that IL-2 enhanced the proliferation of CD25 + T cells only at high doses ( 100-1 ,000 U/ml ) .	A series of pilot experiments revealed that IL-2 enhanced the proliferation of CD25 + T cells only at high doses (100-1,000 U/ml).	7	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	7	8	12	13
However , only IL-2 up-regulated cell-surface expression of the p55 subunit of the IL-2R ( p55 IL-2R ) as measured by flow cytometry and RIA .	However, only IL-2 up-regulated cell-surface expression of the p55 subunit of the IL-2R (p55 IL-2R) as measured by flow cytometry and RIA.	2	10	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	p55	p55	p55	3	4	9	10
Activation of memory T cells associated with IL-2 production and membrane expression of CD25 molecule was resistant to dexamethasone .	Activation of memory T cells associated with IL-2 production and membrane expression of CD25 molecule was resistant to dexamethasone.	7	14	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	7	8	13	14
Although IL-2 stimulation of CD25 promoter activity has been shown without TCR signaling XREF_BIBR , it seems implausible that Tregs would gain suppressor function in the absence of TCR activation XREF_BIBR .	Although IL-2 stimulation of CD25 promoter activity has been shown without TCR signaling XREF_BIBR, it seems implausible that Tregs would gain suppressor function in the absence of TCR activation XREF_BIBR.	1	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	4	5
In the steady state , IL-2 is produced by activated CD4 + CD25 + Foxp3 - T cells and is thought to act in a paracrine fashion to link the size of the T reg cell compartment to the number of these activated T cells , thereby ensuring that autoimmunity and inflammatory diseases do not develop as a result of uncontrolled T cell activation .	In the steady state, IL-2 is produced by activated CD4 + CD25 + Foxp3 - T cells and is thought to act in a paracrine fashion to link the size of the T reg cell compartment to the number of these activated T cells, thereby ensuring that autoimmunity and inflammatory diseases do not develop as a result of uncontrolled T cell activation.	5	22	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	5	6	12	13
Recently we have developed monovalent and bivalent human IL-2 fusion toxins targeting human CD25 + cells using unique diphtheria toxin resistant yeast Pichia Pastoris expression system .	Recently we have developed monovalent and bivalent human IL-2 fusion toxins targeting human CD25 + cells using unique diphtheria toxin resistant yeast Pichia Pastoris expression system.	8	25	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	8	9	13	14
However , IL-2 induced more significant proliferation of CD25 + CD4 + , but not CD25 - CD4 + , T cells in the presence of DCs without OVA antigen , and this could be blocked by anti-IL-2R antibody completely ( XREF_FIG A , middle ) .	However, IL-2 induced more significant proliferation of CD25 + CD4 +, but not CD25 - CD4 +, T cells in the presence of DCs without OVA antigen, and this could be blocked by anti-IL-2R antibody completely (XREF_FIG A, middle).	2	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	8	9
We attempted to explain the molecular mechanisms underlying the IL-2 and IL-2R-independent induction of CD25 by AQ .	We attempted to explain the molecular mechanisms underlying the IL-2 and IL-2R-independent induction of CD25 by AQ.	9	15	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	9	10	14	15
These results suggested that at the early phase , Cis expression was independent of endogenous IL-2 production and expression of the high-affinity IL-2 receptor CD25 ( IL-2Ralpha ) .	These results suggested that at the early phase, Cis expression was independent of endogenous IL-2 production and expression of the high-affinity IL-2 receptor CD25 (IL-2Ralpha).	15	26	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	15	16	24	25
In addition , as IL-2 stimulated lung CD25 + ILC2 to produce IL-9 , this may have a positive feedback effect on ILCs , since lung ILCs cultured with IL-9 increased the production of type 2 cytokines XREF_BIBR and up-regulated the anti-apoptotic protein BCL-3 , thereby promoting ILC2 survival XREF_BIBR .	In addition, as IL-2 stimulated lung CD25 + ILC2 to produce IL-9, this may have a positive feedback effect on ILCs, since lung ILCs cultured with IL-9 increased the production of type 2 cytokines XREF_BIBR and up-regulated the anti-apoptotic protein BCL-3, thereby promoting ILC2 survival XREF_BIBR.	3	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	4	5	7	8
This suggests that IL-21 and IL-2 may control the balance between CD25 + and CD25 - Tfr , since IL-2 enhances the proliferation of naive and eTregs ( which are the precursors of Tfr ) and CD25 + Tfr in the follicle , while blocking full differentiation into germinal center-resident CD25 - Tfr .	This suggests that IL-21 and IL-2 may control the balance between CD25 + and CD25 - Tfr, since IL-2 enhances the proliferation of naive and eTregs (which are the precursors of Tfr) and CD25 + Tfr in the follicle, while blocking full differentiation into germinal center-resident CD25 - Tfr.	3	38	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	5	6	36	37
IL-2 treatment also induced expansion of CD8 + CD25 + Foxp3 + T cells ( XREF_FIG ) .	IL-2 treatment also induced expansion of CD8 + CD25 + Foxp3 + T cells (XREF_FIG).	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	8	9
In this study , we have demonstrated that DNA demethylation by 5-Aza can promote Treg cell induction by suboptimal TCR stimulation of human CD4 + CD25 - T cells through increasing IL-2 production in CD25 dim and CD25 - cells .	In this study, we have demonstrated that DNA demethylation by 5-Aza can promote Treg cell induction by suboptimal TCR stimulation of human CD4 + CD25 - T cells through increasing IL-2 production in CD25 dim and CD25 - cells.	31	35	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	31	32	34	35
CD25 - lymphocytes from infected mice were hyporesponsive to antigenic stimulation in vitro even in the absence of CD25 + T reg cells unless treated with high dose IL-2 .	CD25 - lymphocytes from infected mice were hyporesponsive to antigenic stimulation in vitro even in the absence of CD25 + T reg cells unless treated with high dose IL-2.	16	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	28	29	18	19
The CD25 molecule ( high affinity IL-2 receptor ) expressed on T reg cells is targeted by the antibody daclizumab ( Zenapax ) and by the IL-2 diphtheria toxin fusion protein denileukin diftitox ( Ontak ) .	The CD25 molecule (high affinity IL-2 receptor) expressed on T reg cells is targeted by the antibody daclizumab (Zenapax) and by the IL-2 diphtheria toxin fusion protein denileukin diftitox (Ontak).	1	32	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	26	27	1	2
Considering that PKC-theta-deficient mice exhibit impaired IL-2 production and up-regulation of CD25 , one likely mechanism underlying the impaired Th2 cell differentiation could be the reduced level of IL-2 .	Considering that PKC-theta-deficient mice exhibit impaired IL-2 production and up-regulation of CD25, one likely mechanism underlying the impaired Th2 cell differentiation could be the reduced level of IL-2.	6	12	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	6	7	11	12
One possible explanation is that IL-2 causes the expansion of regulatory CD4 + CD25 + T cells , which might limit subsequent CD4 T cell activation [ XREF_BIBR ] .	One possible explanation is that IL-2 causes the expansion of regulatory CD4 + CD25 + T cells, which might limit subsequent CD4 T cell activation [XREF_BIBR].	5	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	5	6	13	14
Our finding that the percentage and absolute numbers of CD4 + CD25 high cells in mice treated with IL-2 complexes are profoundly increased led us to evaluate Foxp3 expression in the expanded cells .	Our finding that the percentage and absolute numbers of CD4 + CD25 high cells in mice treated with IL-2 complexes are profoundly increased led us to evaluate Foxp3 expression in the expanded cells.	11	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	18	19	11	12
The data demonstrated that both monovalent and bivalent human IL-2 fusion toxins significantly prolonged the survival of the human CD25 + tumor bearing NSG mice in a dose dependent manner .	The data demonstrated that both monovalent and bivalent human IL-2 fusion toxins significantly prolonged the survival of the human CD25 + tumor bearing NSG mice in a dose dependent manner.	9	20	prolonged	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	9	10	19	20
The addition of IL-2 and/or IL-15 in the absence of a polyclonal or allogeneic T cell stimulus did not induce significant proliferation in the CD25 + or CD25 - T cell subset ( data not shown ) .	The addition of IL-2 and/or IL-15 in the absence of a polyclonal or allogeneic T cell stimulus did not induce significant proliferation in the CD25 + or CD25 - T cell subset (data not shown).	1	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	24	25
Addition of exogenous IL-2 partially restored the proliferation of CD25 + CD4 + Tr cells in response to anti-CD3 mAbs , and proliferation was further enhanced by soluble anti-CD28 mAbs ( XREF_FIG A ) .	Addition of exogenous IL-2 partially restored the proliferation of CD25 + CD4 + Tr cells in response to anti-CD3 mAbs, and proliferation was further enhanced by soluble anti-CD28 mAbs (XREF_FIG A).	0	10	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	9	10
Both IL-2 , combined with TGF-beta , have been suggested to enable the conversion of iTreg from CD4 + CD25 - Foxp3 - precursors in the periphery .	Both IL-2, combined with TGF-beta, have been suggested to enable the conversion of iTreg from CD4 + CD25 - Foxp3 - precursors in the periphery.	0	21	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	19	20
In contrast , IL-2 significantly increased the frequencies as well as total cell numbers of mature CD25 + Foxp3 + CD4SP thymic Treg cells in IkappaBalpha-SR Tg mice , whereas thymic Treg cells from wild-type control mice were only slightly affected ( XREF_FIG ) .	In contrast, IL-2 significantly increased the frequencies as well as total cell numbers of mature CD25 + Foxp3 + CD4SP thymic Treg cells in IkappaBalpha-SR Tg mice, whereas thymic Treg cells from wild-type control mice were only slightly affected (XREF_FIG).	3	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	16	17
After IL-2 induced down-regulation of the TAC antigen , the progenitor cell was unresponsive to IL-2 , even 72 hr after IL-2 withdrawal .	After IL-2 induced down-regulation of the TAC antigen, the progenitor cell was unresponsive to IL-2, even 72 hr after IL-2 withdrawal.	1	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	TAC antigen	TAC antigen	TAC antigen	1	2	6	8
In addition to endogenous Foxp3+ Tregs , substantial evidence exists that the combination of IL-2 and TGF-beta can induce naive CD4 + CD25 - cells to become FOXP3 + iTregs in both mice and humans .	In addition to endogenous Foxp3+ Tregs, substantial evidence exists that the combination of IL-2 and TGF-beta can induce naive CD4 + CD25 - cells to become FOXP3 + iTregs in both mice and humans.	12	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	14	15	22	23
Interestingly , IL-2 itself stimulated lung CD25 + ILCs , which have phenotypes similar to those of ILC2s , to produce type 2 cytokines and IL-9 in culture .	Interestingly, IL-2 itself stimulated lung CD25 + ILCs, which have phenotypes similar to those of ILC2s, to produce type 2 cytokines and IL-9 in culture.	2	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	6	7
Compared with the untreated control ( 0IU/ml ) group of PBMCs , IL-2 treatments at 25 , 50 and 100IU/ml significantly induced expansion of CD4 + CD25 + Foxp3 + Tregs , and ~ 70 % more Tregs were expanded by all three doses of IL-2 compared with untreated cells ( XREF_FIG ) .	Compared with the untreated control (0IU/ml) group of PBMCs, IL-2 treatments at 25, 50 and 100IU/ml significantly induced expansion of CD4 + CD25 + Foxp3 + Tregs, and ~ 70% more Tregs were expanded by all three doses of IL-2 compared with untreated cells (XREF_FIG).	12	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	12	13	26	27
During the initial activation phase this transient release of IL-2 by both CD4 and CD8 T cells , as well as exposure to antigen and other proinflammatory cytokines , including IL-12 , stimulates upregulation of CD25 , which enhances the affinity of the IL-2 receptor by 100-fold , thereby increasing the sensitivity of the responding T cells to this cytokine .	During the initial activation phase this transient release of IL-2 by both CD4 and CD8 T cells, as well as exposure to antigen and other proinflammatory cytokines, including IL-12, stimulates upregulation of CD25, which enhances the affinity of the IL-2 receptor by 100-fold, thereby increasing the sensitivity of the responding T cells to this cytokine.	7	38	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	9	10	35	36
Interleukin-2 targets its receptor CD25 on the malignant cells and diphtheria toxin inhibits intracellular protein synthesis and leads to cell death following its delivery into the cell .	Interleukin-2 targets its receptor CD25 on the malignant cells and diphtheria toxin inhibits intracellular protein synthesis and leads to cell death following its delivery into the cell.	0	5	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin-2	Interleukin-2	Interleukin-2	CD25	CD25	CD25	0	1	4	5
Virus infected or IFN-gamma treated cell culture supernatants containing sHLA-E were found to partially inhibit IL-2 mediated induction of CD25 molecules on NKL cells .	Virus infected or IFN-gamma treated cell culture supernatants containing sHLA-E were found to partially inhibit IL-2 mediated induction of CD25 molecules on NKL cells.	15	20	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	15	16	19	20
In the few residual , viable cells , CD25 , IFNgamma , and GZB were induced only by combined IL-2 and IL-12 , and the enhanced expression of these molecules dropped to background levels when the cytokine concentration was diluted to one-tenth ( Suppl .	In the few residual, viable cells, CD25, IFNgamma, and GZB were induced only by combined IL-2 and IL-12, and the enhanced expression of these molecules dropped to background levels when the cytokine concentration was diluted to one-tenth (Suppl.	6	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	19	20	8	9
IL-2 increased plasma blast generation and immunoglobulin secretion from normal but not CD25 deficient cells ; these results demonstrate that IL-21 sensitizes B cells to the stimulatory effects of IL-2 via STAT3 .	IL-2 increased plasma blast generation and immunoglobulin secretion from normal but not CD25 deficient cells; these results demonstrate that IL-21 sensitizes B cells to the stimulatory effects of IL-2 via STAT3.	0	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	12	13
Thus , IL-2 enhances antigen dependent and -independent proliferation of CD25 + CD4 + T cells in response to DCs .	Thus, IL-2 enhances antigen dependent and -independent proliferation of CD25 + CD4 + T cells in response to DCs.	2	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	10	11
Similarly , IL2 induced conversion of CD4 + CD25 + Foxp3 - thymic Treg progenitors into CD4 + Foxp3 + mature Tregs .	Similarly, IL2 induced conversion of CD4 + CD25 + Foxp3 - thymic Treg progenitors into CD4 + Foxp3 + mature Tregs.	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL2	IL2	IL2	CD25	CD25	CD25	2	3	8	9
Although IL-2 secreting Th cells upregulate CD25 , Long and Adler [ XREF_BIBR ] reported that they lack phosphorylated STAT5 , a key intermediate in the IL-2R signal transduction cascade .	Although IL-2 secreting Th cells upregulate CD25, Long and Adler [XREF_BIBR] reported that they lack phosphorylated STAT5, a key intermediate in the IL-2R signal transduction cascade.	1	7	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	6	7
Moreover , the results , in XREF_FIG , showed that transgenic TCTP inhibited apoptosis of CD4+ CD25 high Tregs induced by IL-2 withdrawal ( IL-2 , 0 ng/ml ) from 18.7 % in wild-type controls to 12.7 % in TCTP transgenic mice .	Moreover, the results, in XREF_FIG, showed that transgenic TCTP inhibited apoptosis of CD4+ CD25 high Tregs induced by IL-2 withdrawal (IL-2, 0 ng/ml) from 18.7% in wild-type controls to 12.7% in TCTP transgenic mice.	16	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	21	22	16	17
Again , IL-2 blockade did not fully suppress the response of CD25 + CD4 + T cells to DCs , so that additional growth factors are likely to be important after an initial cell contact dependent activation by DCs ( XREF_FIG ) .	Again, IL-2 blockade did not fully suppress the response of CD25 + CD4 + T cells to DCs, so that additional growth factors are likely to be important after an initial cell contact dependent activation by DCs (XREF_FIG).	2	12	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	11	12
IL-2 treatment significantly increased B helper T cell dependent IgG secretion ( XREF_FIG ) and CD25 + PD1 + Bcl6 low Tfh cells induced significantly higher IgG production by B cells than did CD25 - PD1 + Tfh cells ( XREF_FIG ) .	IL-2 treatment significantly increased B helper T cell dependent IgG secretion (XREF_FIG) and CD25 + PD1 + Bcl6 low Tfh cells induced significantly higher IgG production by B cells than did CD25 - PD1 + Tfh cells (XREF_FIG).	0	38	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	15	16
The addition of exogenous IL-2 only induced a minute response in the CD25 + CD4 + T cells themselves ( XREF_FIG A , top ; note the units on the y axis ) .	The addition of exogenous IL-2 only induced a minute response in the CD25 + CD4 + T cells themselves (XREF_FIG A, top; note the units on the y axis).	1	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	4	5	12	13
Based on cytokine producing CD4 + CD25 + CD134 + T cells as well as IFN-gamma , IL-2 , IL-13 and IL-21 secretion assessed by Luminex , the median immune score increased significantly from median -6 ( IQR -10 to -4 ) to 9 ( IQR 9 to 10 ) between baseline and the post-vaccination time point ( p = 0.008 ) .	Based on cytokine producing CD4 + CD25 + CD134 + T cells as well as IFN-gamma, IL-2, IL-13 and IL-21 secretion assessed by Luminex, the median immune score increased significantly from median -6 (IQR -10 to -4) to 9 (IQR 9 to 10) between baseline and the post-vaccination time point (p = 0.008).	3	22	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	17	18	6	7
IL-2 treatments during M. tuberculosis infection of macaques induced increases in CD4 + CD25 + Foxp3 + Treg in circulation and pulmonary compartment .	IL-2 treatments during M. tuberculosis infection of macaques induced increases in CD4 + CD25 + Foxp3 + Treg in circulation and pulmonary compartment.	0	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	13	14
Defective IL-2 Induction in KJ + CD25 + Cells .	Defective IL-2 Induction in KJ + CD25 + Cells.	1	8	Induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	6	7
They exhibit constitutive IL-2 promoter activation and expression of activation markers CD25 ( IL-2 receptor alpha ) and CD69 , suggesting that they are primed for a rapid response .	They exhibit constitutive IL-2 promoter activation and expression of activation markers CD25 (IL-2 receptor alpha) and CD69, suggesting that they are primed for a rapid response.	3	18	promoter activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	11	12
As shown in XREF_FIG , few Foxp3 and GFP + cells could be detected in the 6 day culture of CD4 + CD25 - Foxp3 and GFP - splenocytes , which were treated with or without exogenous IL-2 during conditioning .	As shown in XREF_FIG, few Foxp3 and GFP + cells could be detected in the 6 day culture of CD4 + CD25 - Foxp3 and GFP - splenocytes, which were treated with or without exogenous IL-2 during conditioning.	18	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	37	38	22	23
The precursors of the human CD4 + CD25 + T cells induced by IL-2 and TGF-beta appear to be the small number of CD25 + cells in the naive fraction .	The precursors of the human CD4 + CD25 + T cells induced by IL-2 and TGF-beta appear to be the small number of CD25 + cells in the naive fraction.	7	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	13	14	7	8
Moreover , CD28 ligation induces IL-2 production and upregulation of surface CD25 , the IL-2 receptor alpha chain , and proliferation .	Moreover, CD28 ligation induces IL-2 production and upregulation of surface CD25, the IL-2 receptor alpha chain, and proliferation.	5	20	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	5	6	11	12
However , IL-2 production and subsequent up-regulation of CD25 , early perforin independent cytolysis , and early down-regulation of Bcl-2 expression were detected only in T cells transferred in hosts expressing full agonist alloAg .	However, IL-2 production and subsequent up-regulation of CD25, early perforin independent cytolysis, and early down-regulation of Bcl-2 expression were detected only in T cells transferred in hosts expressing full agonist alloAg.	2	17	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	8	9
IL-2 signaling may be involved in the regulatory function and might underlie the differential capacities of AND versus CD25 + cells for in vitro regulation .	IL-2 signaling may be involved in the regulatory function and might underlie the differential capacities of AND versus CD25 + cells for in vitro regulation.	0	20	underlie	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	18	19
IL-4 does not interfere with the upregulation of CD25 by IL-2 .	IL-4 does not interfere with the upregulation of CD25 by IL-2.	3	11	upregulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	10	11	8	9
The CD25 induction by IL-2 seems to involve different mechanisms because in the absence of IL-2 , CsA alone was able to mediate CD25 expression on the few remaining CD56 dim NK cells .	The CD25 induction by IL-2 seems to involve different mechanisms because in the absence of IL-2, CsA alone was able to mediate CD25 expression on the few remaining CD56 dim NK cells.	1	5	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	4	5	1	2
Addition of IL-2 increased the cell yield by 5-fold , but also enhanced single positive CD25 + Foxp3 - T cells ( activation without conversion ) .	Addition of IL-2 increased the cell yield by 5-fold, but also enhanced single positive CD25 + Foxp3 - T cells (activation without conversion).	0	17	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	15	16
IL-2 increased global CD25 + CD127 low FoxP3 + Tregs ( p < 0.05 ) while it decreased HIV- but not CMV- specific CD39 + FoxP3 + CD25 + CD134 + Tregs ( p < 0.05 ) .	IL-2 increased global CD25 + CD127 low FoxP3 + Tregs (p < 0.05) while it decreased HIV- but not CMV- specific CD39 + FoxP3 + CD25 + CD134 + Tregs (p < 0.05).	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	3	4
When Foxp3 was identified as a specific hallmark for nTreg cells , studies immediately confirmed that the combination of IL-2 and TGF-beta was able to induce CD25 - Foxp3 - precursors to express Foxp3 , and with this expression came suppressive activity [ XREF_BIBR - XREF_BIBR ] .	When Foxp3 was identified as a specific hallmark for nTreg cells, studies immediately confirmed that the combination of IL-2 and TGF-beta was able to induce CD25 - Foxp3 - precursors to express Foxp3, and with this expression came suppressive activity [XREF_BIBR - XREF_BIBR].	17	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	19	20	26	27
Taken together , these experiments demonstrated that our design objectives had been achieved ; with IL-2 3X Fc treatment causing prominent expansion of CD25 - MP CD8 and NK cells but no expansion of CD25 + Tregs .	Taken together, these experiments demonstrated that our design objectives had been achieved; with IL-2 3X Fc treatment causing prominent expansion of CD25 - MP CD8 and NK cells but no expansion of CD25 + Tregs.	15	24	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	15	16	23	24
Thus , while IL-2 may enhance IL-33-driven Th2 cytokine production by Lin - CD25 + CD44 hi cells , IL-7 may be involved in Lin - CD25 + CD44 hi cell proliferation , activation or both .	Thus, while IL-2 may enhance IL-33-driven Th2 cytokine production by Lin - CD25 + CD44 hi cells, IL-7 may be involved in Lin - CD25 + CD44 hi cell proliferation, activation or both.	3	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	13	14
Thymocytes treated with concanavalin-A and interleukin-2 upregulated CD25 at 72 h of culture .	Thymocytes treated with concanavalin-A and interleukin-2 upregulated CD25 at 72 h of culture.	1	8	upregulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	interleukin-2	interleukin-2	interleukin-2	CD25	CD25	CD25	5	6	7	8
Notably , IL-2 and JES6-1 injections increased the proportion of CD127 + CD25 + ILCs in the aorta ( XREF_FIG ) .	Notably, IL-2 and JES6-1 injections increased the proportion of CD127 + CD25 + ILCs in the aorta (XREF_FIG).	2	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	12	13
We have recently shown that IL-2 treatment of bacillus Calmette-Guerin-infected macaques can induce expansion of CD4 + CD25 + Foxp3 + Treg in the blood .	We have recently shown that IL-2 treatment of bacillus Calmette-Guerin-infected macaques can induce expansion of CD4 + CD25 + Foxp3 + Treg in the blood.	5	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	5	6	17	18
For this purpose , freshly isolated CD4 + CD25 - responder cells from AChR primed mice treated with isotype control Ab were mixed at a ratio of 1 to 1 with CD4 + CD25 + T cells purified from AChR primed mice treated with either IL-2 complexes or isotype control Ab .	For this purpose, freshly isolated CD4 + CD25 - responder cells from AChR primed mice treated with isotype control Ab were mixed at a ratio of 1 to 1 with CD4 + CD25 + T cells purified from AChR primed mice treated with either IL-2 complexes or isotype control Ab.	33	46	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	45	46	33	34
Both IL-2 and IL-4 induced non-alloantigen-specific proliferation of naive and tolerant CD4 + CD25 + T cells .	Both IL-2 and IL-4 induced non-alloantigen-specific proliferation of naive and tolerant CD4 + CD25 + T cells.	0	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	13	14
The CD4 + CD25 + cells inhibit the induction of IL-2 production in the responder CD4 + CD25 - population , and suppression can be overcome by the addition of exogenous IL-2 or enhancement of endogenous IL-2 production .	The CD4 + CD25 + cells inhibit the induction of IL-2 production in the responder CD4 + CD25 - population, and suppression can be overcome by the addition of exogenous IL-2 or enhancement of endogenous IL-2 production.	10	18	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	10	11	17	18
Thus , IL2 can also activate CD4 + CD25 + Foxp3 + lymphocytes , which are capable of suppressing the T cell mediated anti-tumor activity .	Thus, IL2 can also activate CD4 + CD25 + Foxp3 + lymphocytes, which are capable of suppressing the T cell mediated anti-tumor activity.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL2	IL2	IL2	CD25	CD25	CD25	2	3	8	9
The ability of high dose IL-2 together with H. pylori antigen to activate these CD25 - T cells is indicative of anergy .	The ability of high dose IL-2 together with H. pylori antigen to activate these CD25 - T cells is indicative of anergy.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	5	6	14	15
In vitro expanded CD25 + CD4 + Tr cells failed to proliferate in response to anti-CD3 mAbs alone , and proliferation could only be completely restored by the addition of exogenous IL-2 ( XREF_FIG A ) .	In vitro expanded CD25 + CD4 + Tr cells failed to proliferate in response to anti-CD3 mAbs alone, and proliferation could only be completely restored by the addition of exogenous IL-2 (XREF_FIG A).	0	34	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	31	32	3	4
Because IL-2 signaling further upregulates CD25 , T reg can even increase their ability to capture IL-2 as compared to T conv which need to initiate CD25 expression post TCR mediated activation .	Because IL-2 signaling further upregulates CD25, T reg can even increase their ability to capture IL-2 as compared to T conv which need to initiate CD25 expression post TCR mediated activation.	1	6	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	5	6
IL-2 has been described to modulate in vitro human CD4+ CD25 hi+ T Reg and CD4+ CD25 - responder T cells death and growth arrest by differentially using the granzyme-perforin pathway depending on its concentration .	IL-2 has been described to modulate in vitro human CD4+ CD25 hi+ T Reg and CD4+ CD25 - responder T cells death and growth arrest by differentially using the granzyme-perforin pathway depending on its concentration.	0	24	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	10	11
IL-2 stimulates faster cycling rates in CD25 + T cells from NOD mice ( XREF_FIG ) , possibly because the relative IL-2 insufficiency in these mice in vivo XREF_BIBR .	IL-2 stimulates faster cycling rates in CD25 + T cells from NOD mice (XREF_FIG), possibly because the relative IL-2 insufficiency in these mice in vivo XREF_BIBR.	0	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	6	7
Once this split occurred , then work by others suggests a scenario in which IL-2 receptor signaling in the CD25 + cells activates STAT5 , which induces the IL-12 receptor and T-bet , and suppresses Bcl6 and CXCR5 by inducing Blimp-1 .	Once this split occurred, then work by others suggests a scenario in which IL-2 receptor signaling in the CD25 + cells activates STAT5, which induces the IL-12 receptor and T-bet, and suppresses Bcl6 and CXCR5 by inducing Blimp-1.	14	21	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	14	15	19	20
Interestingly , IL-2 seems to specifically stimulate the CD4 + CD25 + Treg cells in the pancreas rather diabetogenic effector T cells [ XREF_BIBR ] .	Interestingly, IL-2 seems to specifically stimulate the CD4 + CD25 + Treg cells in the pancreas rather diabetogenic effector T cells [XREF_BIBR].	2	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	10	11
IL-2 , used to expand T or NK cells in vitro and in vivo , also promotes the expansion of T regulatory cells ( Tregs ) which express the IL2 receptor alpha chain CD25 .	IL-2, used to expand T or NK cells in vitro and in vivo, also promotes the expansion of T regulatory cells (Tregs) which express the IL2 receptor alpha chain CD25.	0	34	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	33	34
The factors regulating expression of CD25 are fairly well described : TCR engagement or IL-2 itself induces CD25 during T cell priming .	The factors regulating expression of CD25 are fairly well described : TCR engagement or IL-2 itself induces CD25 during T cell priming.	9	18	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	14	15	17	18
We have demonstrated previously that IL2 and LPS treatment is required to activate CD4 + CD25 + Treg cells from FIV - cats [ XREF_BIBR , XREF_BIBR ] .	We have demonstrated previously that IL2 and LPS treatment is required to activate CD4 + CD25 + Treg cells from FIV - cats [XREF_BIBR, XREF_BIBR].	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL2	IL2	IL2	CD25	CD25	CD25	5	6	15	16
Reduced IL-2 production correlated with a smaller proportion of Foxp3 + CD4 + T cells in the pancreatic lymph nodes and reduced functional competence of CD4 + CD25 + regulatory T cells , suggesting a mechanism for the association of Idd3 with diabetes susceptibility .	Reduced IL-2 production correlated with a smaller proportion of Foxp3 + CD4 + T cells in the pancreatic lymph nodes and reduced functional competence of CD4 + CD25 + regulatory T cells, suggesting a mechanism for the association of Idd3 with diabetes susceptibility.	1	31	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	27	28
Interleukin 1 ( IL 1 ) or IL 2 did not induce Tac antigen .	Interleukin 1 (IL 1) or IL 2 did not induce Tac antigen.	0	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL 2	IL 2	IL 2	Tac antigen	Tac antigen	Tac antigen	7	9	12	14
Here , we review emerging , novel mechanisms involved in contact dependent , TR mediated suppression of IL-2 production in responder CD25- T lymphocytes and the potential involvement of inducible cAMP early repressor ( ICER ) in this suppression .	Here, we review emerging, novel mechanisms involved in contact dependent, TR mediated suppression of IL-2 production in responder CD25- T lymphocytes and the potential involvement of inducible cAMP early repressor (ICER) in this suppression.	17	23	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25-	CD25-	CD25-	17	18	21	22
The fold increase of CD25 MFI induced by 50,000 or 100,000 IU of IL-2 was 1.4 +/-0.2 or 1.8 +/-0.2 in CD4 + Tregs and 1.3 +/-0.4 or 1.8 +/-0.5 in CD8 + Tregs , respectively .	The fold increase of CD25 MFI induced by 50,000 or 100,000 IU of IL-2 was 1.4 +/-0.2 or 1.8 +/-0.2 in CD4 + Tregs and 1.3 +/-0.4 or 1.8 +/-0.5 in CD8 + Tregs, respectively.	4	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	13	14	4	5
Of note , IL-2 induced CD25 upregulation at 24 and 48 hours as expected ( XREF_FIG ) , and c-Myc protein expression strongly correlated with CD25 expression ( XREF_SUPPLEMENTARY ) .	Of note, IL-2 induced CD25 upregulation at 24 and 48 hours as expected (XREF_FIG), and c-Myc protein expression strongly correlated with CD25 expression (XREF_SUPPLEMENTARY).	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	5	6
The intermittent IL-2 treatments reproducibly induced major expansion of CD4 + CD25 + Foxp3 + T cells in the macaques ( XREF_FIG ) .	The intermittent IL-2 treatments reproducibly induced major expansion of CD4 + CD25 + Foxp3 + T cells in the macaques (XREF_FIG).	2	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	11	12
In this model , IL-2 would directly drive maturation of CD4 + Foxp3 - CD25 + thymocytes into mature CD4 + Foxp3 hi CD25 + Tregs , where Foxp3 and CD25 are direct targets of IL-2R-dependent STAT5 activation .	In this model, IL-2 would directly drive maturation of CD4 + Foxp3 - CD25 + thymocytes into mature CD4 + Foxp3 hi CD25 + Tregs, where Foxp3 and CD25 are direct targets of IL-2R-dependent STAT5 activation.	4	16	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	4	5	14	15
Moreover , recent studies have clearly demonstrated that in addition to activating T and NK cells , IL-2 also substantially expands and activates CD4 + CD25 + Tregs , a potential mediator of tumor induced immune suppression XREF_BIBR .	Moreover, recent studies have clearly demonstrated that in addition to activating T and NK cells, IL-2 also substantially expands and activates CD4 + CD25 + Tregs, a potential mediator of tumor induced immune suppression XREF_BIBR.	17	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	17	18	25	26
It was recently shown that administration of IL-2 complexed with a particular anti-IL-2 antibody ( clone JES6-1 ) to rag1 -/- mice selectively allows expansion of CD25 + ILC2s 11 .	It was recently shown that administration of IL-2 complexed with a particular anti-IL-2 antibody (clone JES6-1) to rag1 -/- mice selectively allows expansion of CD25 + ILC2s 11.	5	27	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	7	8	26	27
Dissection of gene elements critical for CD25 expression revealed that TCR and IL-2 activate different elements of the CD25 gene to enhance transcription .	Dissection of gene elements critical for CD25 expression revealed that TCR and IL-2 activate different elements of the CD25 gene to enhance transcription.	10	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	12	13	18	19
Conversion did not appear to be an artifact of co-culture as CD4 + CD25 + cells treated with IL2 alone were not capable of inducing iTreg function in Th target cells ( iTreg conversion control , not shown ) .	Conversion did not appear to be an artifact of co-culture as CD4 + CD25 + cells treated with IL2 alone were not capable of inducing iTreg function in Th target cells (iTreg conversion control, not shown).	12	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL2	IL2	IL2	CD25	CD25	CD25	18	19	13	14
Our results suggest that CD4 + CD25 + Foxp3 + Treg activated by antigen and IL-2 , like activated effector T cells , express il-12rbeta2 and respond to IL-12p70 .	Our results suggest that CD4 + CD25 + Foxp3 + Treg activated by antigen and IL-2, like activated effector T cells, express il-12rbeta2 and respond to IL-12p70.	5	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	15	16	6	7
In patients with chronic GvHD , Matsuoka and co-workers reported that daily administration of low-dose IL-2 induced selective expansion of functional CD4 + CD25 + CD127 - Tregs , improved chronic GvHD , restored CD4 + T cell homeostasis , and promoted the reestablishment of immune tolerance .	In patients with chronic GvHD, Matsuoka and co-workers reported that daily administration of low-dose IL-2 induced selective expansion of functional CD4 + CD25 + CD127 - Tregs, improved chronic GvHD, restored CD4 + T cell homeostasis, and promoted the reestablishment of immune tolerance.	12	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	15	16	23	24
Conversely , the lack of IL-2 receptor signaling in the early CD25 - cells may have been conducive to Bcl6 expression , which we found was essential for formation of early CXCR5 + effector cells and subsequent PD-1 - T CM precursor and PD-1 + T FH cell progeny .	Conversely, the lack of IL-2 receptor signaling in the early CD25 - cells may have been conducive to Bcl6 expression, which we found was essential for formation of early CXCR5 + effector cells and subsequent PD-1 - T CM precursor and PD-1 + T FH cell progeny.	5	12	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	5	6	11	12
These results demonstrate that low-dose IL-2 promotes the generation of CD4 + CD25 + Foxp3 + T regulatory cells through the STAT5 pathway , and provides additional evidence for supporting the role of IL2 and STAT5 in regulatory T cell development and function .	These results demonstrate that low-dose IL-2 promotes the generation of CD4 + CD25 + Foxp3 + T regulatory cells through the STAT5 pathway, and provides additional evidence for supporting the role of IL2 and STAT5 in regulatory T cell development and function.	4	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	5	6	12	13
Human purified CD4 ( + ) CD25 ( high ) T cell subsets stimulated via TCR and CD28 or by IL-2 survived and expanded up to 40-fold in the presence of 1 nM rapamycin , while CD4 ( + ) CD25 ( low ) or CD4 ( + ) CD25 (-) T cells did not .	Human purified CD4 (+) CD25 (high) T cell subsets stimulated via TCR and CD28 or by IL-2 survived and expanded up to 40-fold in the presence of 1 nM rapamycin, while CD4 (+) CD25 (low) or CD4 (+) CD25 (-) T cells did not.	1	21	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	20	21	6	7
A short-term IL-2 treatment regimen induced a marked expansion of CD4 + CD25 + Foxp3 + Treg cells and the subsequent suppression of the mycobacterium induced expansion of Vgamma2Vdelta2 T cells during BCG infection in macaques .	A short-term IL-2 treatment regimen induced a marked expansion of CD4 + CD25 + Foxp3 + Treg cells and the subsequent suppression of the mycobacterium induced expansion of Vgamma2Vdelta2 T cells during BCG infection in macaques.	2	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	12	13
Notably , intermittent IL-2 treatment regimen induced trafficking and accumulation of CD4 + CD25 + Foxp3 + Treg and CD8 + CD25 + Foxp3 + T cells in the pulmonary compartment as apparent increases in numbers of these cells were seen in the BAL fluid after each of the IL-2 treatments ( XREF_FIG ) .	Notably, intermittent IL-2 treatment regimen induced trafficking and accumulation of CD4 + CD25 + Foxp3 + Treg and CD8 + CD25 + Foxp3 + T cells in the pulmonary compartment as apparent increases in numbers of these cells were seen in the BAL fluid after each of the IL-2 treatments (XREF_FIG).	3	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	13	14
IL-2 administration increased significantly HIV specific CD4 + CD25 + CD134 + T-cell responses , which inversely correlated with viral load after TI ( r = -0.7 , p < 0.007 ) in the vaccine/IL -2 group .	IL-2 administration increased significantly HIV specific CD4 + CD25 + CD134 + T-cell responses, which inversely correlated with viral load after TI (r = -0.7, p < 0.007) in the vaccine/IL -2 group.	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	8	9
Most strikingly , addition of IL-2 to these cultures markedly upregulated CD25 as expected , but did not alter the high GFP threshold for proliferation , even with low peptide concentration or weak peptide affinity ( XREF_FIG ) .	Most strikingly, addition of IL-2 to these cultures markedly upregulated CD25 as expected, but did not alter the high GFP threshold for proliferation, even with low peptide concentration or weak peptide affinity (XREF_FIG).	3	12	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	5	6	11	12
Our data provide evidence for the hypothesis that adhesion receptor directed release of IL-2 may result in a locally high concentration of IL-2 that triggers high-affinity IL-2R signaling and up-regulates p55 IL-2R to enhance cytokine responsiveness .	Our data provide evidence for the hypothesis that adhesion receptor directed release of IL-2 may result in a locally high concentration of IL-2 that triggers high-affinity IL-2R signaling and up-regulates p55 IL-2R to enhance cytokine responsiveness.	20	31	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	p55	p55	p55	22	23	30	31
Once the stimulation by self-peptides reaches its limit , a negative feedback loop is formed in which the increase in CD4 + CD25 + T cells caused by excess IL-2 inhibits activated CD4+ T cells and this reduces IL-2 production which results in reduction in Treg cell number .	Once the stimulation by self-peptides reaches its limit, a negative feedback loop is formed in which the increase in CD4 + CD25 + T cells caused by excess IL-2 inhibits activated CD4+ T cells and this reduces IL-2 production which results in reduction in Treg cell number.	22	30	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	29	30	22	23
In contrast , exogenous IL-2 enhanced the proliferative response of CD4 + CD25 - responder cells only a little in response to very weak stimulation ( XREF_FIG ) , while CD4 + CD25 - responder cells were almost insensitive to exogenous IL-2 in their proliferative responsiveness in response to relatively strong stimulation ( XREF_FIG and Figs XREF_FIG & XREF_FIG ) , suggesting autocrine fashion in the supply of IL-2 .	In contrast, exogenous IL-2 enhanced the proliferative response of CD4 + CD25 - responder cells only a little in response to very weak stimulation (XREF_FIG), while CD4 + CD25 - responder cells were almost insensitive to exogenous IL-2 in their proliferative responsiveness in response to relatively strong stimulation (XREF_FIG and Figs XREF_FIG & XREF_FIG), suggesting autocrine fashion in the supply of IL-2.	3	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	4	5	12	13
For example , subcutaneous administration of low dose IL-2 ( 0.6 - 1.0 x 10 6 IU/m 2 / day ) has been found to increase the number of CD4 + CD25 + FOXP3 + T regulatory cells [ XREF_BIBR ] and may ameliorate GVHD in the setting of steroid-refractory chronic GVHD [ XREF_BIBR ] .	For example, subcutaneous administration of low dose IL-2 (0.6 - 1.0 x 10 6 IU/m 2 / day) has been found to increase the number of CD4 + CD25 + FOXP3 + T regulatory cells [XREF_BIBR] and may ameliorate GVHD in the setting of steroid-refractory chronic GVHD [XREF_BIBR].	4	37	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	8	9	31	32
Under such conditions , the CD25 + population suppresses both the proliferation and IL-2 production of the CD25 - cells in a dose dependent manner [ XREF_BIBR , XREF_BIBR ] .	Under such conditions, the CD25 + population suppresses both the proliferation and IL-2 production of the CD25 - cells in a dose dependent manner [XREF_BIBR, XREF_BIBR].	11	18	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	13	14	17	18
A putative explanation may be that IL-2 can potently induce Stat5 activation in CD4 + CD25 + Foxp3 - splenocytes as shown by flow cytometric analysis of phosphorylated Stat5 ( Stat5 pY694 ) ( XREF_FIG ) , while none of the remaining tested gammac cytokines were as effective as IL-2 in activating Stat5 in CD4 + CD25 + Foxp3 - splenocytes ( XREF_FIG ) .	A putative explanation may be that IL-2 can potently induce Stat5 activation in CD4 + CD25 + Foxp3 - splenocytes as shown by flow cytometric analysis of phosphorylated Stat5 (Stat5 pY694) (XREF_FIG), while none of the remaining tested gammac cytokines were as effective as IL-2 in activating Stat5 in CD4 + CD25 + Foxp3 - splenocytes (XREF_FIG).	6	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	6	7	15	16
The expansion of our T-cell clone was mediated by IL-2 which theoretically could have enhanced CD25 expression XREF_BIBR .	The expansion of our T-cell clone was mediated by IL-2 which theoretically could have enhanced CD25 expression XREF_BIBR.	7	17	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	9	10	15	16
In sarcoma patients treated with cyclophosphamide and adjuvant IL-2 ( at a dose of either 9 x 10 6 IU/M 2 / day CIVI 4 days and week x 3 wks starting on weeks 6 , 12 , 18 , or 3 x 10 6 IU/M 2 / dose SQ 3 times and week x 16 weeks starting at week 6 ) in combination with vaccine , IL-2 caused a preferential expansion of the CD4 + CD25 high Treg compartment .	In sarcoma patients treated with cyclophosphamide and adjuvant IL-2 (at a dose of either 9 x 10 6 IU/M 2 / day CIVI 4 days and week x 3 wks starting on weeks 6, 12, 18, or 3 x 10 6 IU/M 2 / dose SQ 3 times and week x 16 weeks starting at week 6) in combination with vaccine, IL-2 caused a preferential expansion of the CD4 + CD25 high Treg compartment.	67	79	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	67	68	76	77
Currently , many clinical ACT protocols use IL-2 for ex vivo expansion of anti-tumor T cells although IL-2 additionally expands and activates immunosuppressive CD4 + CD25 + FoxP3 + T Regs .	Currently, many clinical ACT protocols use IL-2 for ex vivo expansion of anti-tumor T cells although IL-2 additionally expands and activates immunosuppressive CD4 + CD25 + FoxP3 + T Regs.	17	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	17	18	25	26
Although IL-15 reportedly exerts functional effects on lymphocytes similar to those of IL-2 , only IL-2 was able to promote the MODE-K cell mediated upregulation of CD25 on cultured IELs .	Although IL-15 reportedly exerts functional effects on lymphocytes similar to those of IL-2, only IL-2 was able to promote the MODE-K cell mediated upregulation of CD25 on cultured IELs.	14	27	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	15	16	26	27
There was a significant increase in IL-2 producing CD8 + T cells from the RA patients with higher numbers of CD4 + CD25 high T cells ( RA3 group ) .	There was a significant increase in IL-2 producing CD8 + T cells from the RA patients with higher numbers of CD4 + CD25 high T cells (RA3 group).	4	25	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	6	7	22	23
CD25 , a subunit of the IL-2 receptor is up-regulated by IL-2 in conjunction with TCR stimulation , and at early stages of the response to lymphocytic choriomeningitis virus ( LCMV ) infection , CD25 expression promotes the development of terminally differentiated effector CD8 + T cells .	CD25, a subunit of the IL-2 receptor is up-regulated by IL-2 in conjunction with TCR stimulation, and at early stages of the response to lymphocytic choriomeningitis virus (LCMV) infection, CD25 expression promotes the development of terminally differentiated effector CD8 + T cells.	0	13	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	11	12	0	1
IL-2 increased plasmablast generation and immunoglobulin secretion from normal , but not CD25 deficient , naive B cells stimulated with CD40L and IL-21 .	IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25 deficient, naive B cells stimulated with CD40L/IL-21.	0	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	12	13
In addition , induction of p55 by IL-2 was abrogated in autologous PB NK cells .	In addition, induction of p55 by IL-2 was abrogated in autologous PB NK cells.	3	8	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	p55	p55	p55	7	8	5	6
The data demonstrated that both monovalent and bivalent human IL-2 fusion toxins significantly prolonged the survival of the human CD25 + tumor bearing NSG mice in a dose dependent manner compared to the vehicle only control .	The data demonstrated that both monovalent and bivalent human IL-2 fusion toxins significantly prolonged the survival of the human CD25 + tumor bearing NSG mice in a dose dependent manner compared to the vehicle only control.	9	20	prolonged	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	9	10	19	20
In the context of senescence , this regulation was a consequence of IL-1R signaling specifically activated by IL-1alpha but not IL-1beta .	In the context of senescence, this regulation was a consequence of IL-1R signaling specifically activated by IL-1alpha but not IL-1beta.	12	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	20	21	12	13
These include CXCL1/KC and probably CXCL2 , 5 , and 8 , which recruit neutrophils from limbal capillaries to the corneal stroma , and IL-1alpha and IL-1beta , which then feedback to activate the IL-1R1 and MyD88 pathway in macrophages and most likely also in resident corneal epithelial cells and stromal fibroblasts .	These include CXCL1/KC and probably CXCL2, 5, and 8, which recruit neutrophils from limbal capillaries to the corneal stroma, and IL-1alpha and IL-1beta, which then feedback to activate the IL-1R1 and MyD88 pathway in macrophages and most likely also in resident corneal epithelial cells and stromal fibroblasts.	5	37	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	26	27	34	35
A human experiment has shown that IL-1beta induces the secretion of IL-1ra , and that induction of IL-1beta precedes secretion of IL-1ra .	A human experiment has shown that IL-1beta induces the secretion of IL-1ra, and that induction of IL-1beta precedes secretion of IL-1ra.	6	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	6	7	11	12
IL-1RA , an anti-inflammatory cytokine , is induced by IL-1beta and blocks the pro inflammatory cytokine action of IL-1beta at IL-1 receptor I. IL-1RA can be easily measured compare with IL-1beta , and systemic levels of IL-1RA are elevated in obesity , insulin resistance and type 2 diabetes patients .	IL-1RA, an anti-inflammatory cytokine, is induced by IL-1beta and blocks the pro inflammatory cytokine action of IL-1beta at IL-1 receptor I. IL-1RA can be easily measured compare with IL-1beta, and systemic levels of IL-1RA are elevated in obesity, insulin resistance and type 2 diabetes patients.	0	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1RA	IL-1RA	IL-1RA	9	10	0	1
IL-1alpha and IL-1beta are also produced , which activate an IL-1R1 and MyD88 positive feedback loop in macrophages and IL-1R on other resident cells in the cornea .	IL-1alpha and IL-1beta are also produced, which activate an IL-1R1 and MyD88-positive feedback loop in macrophages and IL-1R on other resident cells in the cornea.	0	19	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	2	3	10	11
The induction of IL-1Ra by IL-1beta is an important counterregulatory mechanism and may at least partially account for the increased IL-1Ra levels found in the carriers of allele II [ XREF_BIBR , XREF_BIBR ] .	The induction of IL-1Ra by IL-1beta is an important counterregulatory mechanism and may at least partially account for the increased IL-1Ra levels found in the carriers of allele II [XREF_BIBR, XREF_BIBR].	1	6	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	5	6	3	4
Treating PHCs with MATN3 in the presence of IL-1beta significantly enhanced IL-1Ra protein concentration in culture medium compared to that of cells treated with IL-1beta alone .	Treating PHCs with MATN3 in the presence of IL-1beta significantly enhanced IL-1Ra protein concentration in culture medium compared to that of cells treated with IL-1beta alone.	11	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	24	25	11	12
Whereas IL-1beta treatment induced IL-17 producing MOG specific T cells in Il1r -/- mice , IKKi deficiency reduced the impact of IL-1 on MOG specific Th17 cells ( XREF_FIG ) .	Whereas IL-1beta treatment induced IL-17 producing MOG specific T cells in Il1r -/- mice, IKKi deficiency reduced the impact of IL-1 on MOG specific Th17 cells (XREF_FIG).	1	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	Il1r	Il1r	Il1r	1	2	11	12
IL-1 beta induced production of both IL-1Ra and IL-1 alpha at each time point and concentration tested .	IL-1 beta induced production of both IL-1Ra and IL-1 alpha at each time point and concentration tested.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1 beta	IL-1 beta	IL-1 beta	IL-1Ra	IL-1Ra	IL-1Ra	0	2	6	7
Liposaccharides ( LPS ) , as well as IL-1alpha and IL-1beta were found to stimulate IL-1alpha and IL-1ra , but not IL-1beta production , in Sertoli cells from immature mice .	Liposaccharides (LPS), as well as IL-1alpha and IL-1beta were found to stimulate IL-1alpha and IL-1ra, but not IL-1beta production, in Sertoli cells from immature mice.	0	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	10	11	17	18
In freshly isolated primary chondrocytes , A77 1726 used at 100 mumol/l also enhanced secretion of IL-1Ra induced by IL-1beta .	In freshly isolated primary chondrocytes, A77 1726 used at 100 mumol/l also enhanced secretion of IL-1Ra induced by IL-1beta.	14	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	19	20	16	17
AT derived IL-1beta acts in an autocrine or paracrine fashion to contribute to obese AT inflammation and dysfunction , and accordingly , ablation of IL-1beta signaling in IL-1R knockout mice attenuated the HFD induced AT and systemic IR [ XREF_BIBR ] .	AT derived IL-1beta acts in an autocrine or paracrine fashion to contribute to obese AT inflammation and dysfunction, and accordingly, ablation of IL-1beta signaling in IL-1R knockout mice attenuated the HFD induced AT and systemic IR [XREF_BIBR].	24	29	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	24	25	27	28
In terms of protein levels , E2 downregulated IL-1beta but upregulated IL-1ra and thereby decreased the IL-1beta and IL-1 ra ratio at 24h .	In terms of protein levels, E2 downregulated IL-1beta but upregulated IL-1ra and thereby decreased the IL-1beta and IL-1 ra ratio at 24h.	8	14	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	8	9	11	12
43 Interestingly , IL-1beta up-regulates NGF both in vitro and in vivo , XREF_BIBR , XREF_BIBR and application of IL-1Ra in a TBI rat model suppresses NGF mediated plasticity .	43 Interestingly, IL-1beta up-regulates NGF both in vitro and in vivo, XREF_BIBR, XREF_BIBR and application of IL-1Ra in a TBI rat model suppresses NGF mediated plasticity.	3	24	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	3	4	19	20
In subcultured de-differentiated chondrocytes , A77 1726 exhibited a marked dose dependent effect on IL-1beta induced IL-1Ra production , which was greatest at 100 mumol/l .	In subcultured de-differentiated chondrocytes, A77 1726 exhibited a marked dose dependent effect on IL-1beta induced IL-1Ra production, which was greatest at 100 mumol/l.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	14	15	16	17
Likewise , parallel cultures comparing IL-1R1 hi and IL-1R1 lo subpopulations of stage 3 iNK cells revealed that , whereas IL-15 alone maintained survival of both IL-1R1 hi and IL-1R1 lo subpopulations of stage 3 iNK cells in vitro , the addition of IL-1beta enhanced proliferation of the IL-1R1 hi , but not the IL-1R1 lo , subpopulation of stage 3 iNK cells ( XREF_FIG ) .	Likewise, parallel cultures comparing IL-1R1 hi and IL-1R1 lo subpopulations of stage 3 iNK cells revealed that, whereas IL-15 alone maintained survival of both IL-1R1 hi and IL-1R1 lo subpopulations of stage 3 iNK cells in vitro, the addition of IL-1beta enhanced proliferation of the IL-1R1 hi, but not the IL-1R1 lo, subpopulation of stage 3 iNK cells (XREF_FIG).	41	49	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	43	44	48	49
For example , previous study showed that the haplotype of IL1B , IL1RN , IL1R1 , and IL1R2 increased the risk of venous thrombosis [ XREF_BIBR ] , and IL1 and IL1Ra , CTLA-4 and Apo1 and Fas genes polymorphisms associate with IgA nephropathy [ XREF_BIBR ] .	For example, previous study showed that the haplotype of IL1B, IL1RN, IL1R1, and IL1R2 increased the risk of venous thrombosis [XREF_BIBR], and IL1 and IL1Ra, CTLA-4 and Apo1 and Fas genes polymorphisms associate with IgA nephropathy [XREF_BIBR].	8	32	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL1B	IL1B	IL1B	IL1Ra	IL1Ra	IL1Ra	10	11	31	32
We also show that P. aeruginosa activates NF-kappaB in macrophages through both the TIR containing adaptor protein ( TIRAP )/MyD88 dependent and the TRIF dependent pathways , and that IL-1alpha and IL-1beta activation of IL-1R1 is an important feedback pathway in the host response to P. aeruginosa .	We also show that P. aeruginosa activates NF-kappaB in macrophages through both the TIR containing adaptor protein (TIRAP)/MyD88 dependent and the TRIF dependent pathways, and that IL-1alpha and IL-1beta activation of IL-1R1 is an important feedback pathway in the host response to P. aeruginosa.	29	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	31	32	34	35
We next investigated whether the stimulatory effect of A77 1726 was restricted to IL-1Ra production induced by IL-1beta , or whether it could also be observed in the presence of other proinflammatory cytokines , such as TNF-alpha .	We next investigated whether the stimulatory effect of A77 1726 was restricted to IL-1Ra production induced by IL-1beta, or whether it could also be observed in the presence of other proinflammatory cytokines, such as TNF-alpha.	13	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	17	18	13	14
Activation of IL-1R1 by IL-1beta is also known to activate several signaling pathways that have been implicated in the antineurogenic effects of IL-1beta including JNK , GSK3beta and NF-kappaB .	Activation of IL-1R1 by IL-1beta is also known to activate several signaling pathways that have been implicated in the antineurogenic effects of IL-1beta including JNK, GSK3beta and NF-kappaB.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	4	5	2	3
The regulation of IL-1ra in somatotroph adenoma cells is different from human cultured monocytes , in which IL-1 beta significantly stimulated IL-1ra secretion into the culture supernatants , and no change of intracellular IL-1ra content was observed .	The regulation of IL-1ra in somatotroph adenoma cells is different from human cultured monocytes, in which IL-1 beta significantly stimulated IL-1ra secretion into the culture supernatants, and no change of intracellular IL-1ra content was observed.	17	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1 beta	IL-1 beta	IL-1 beta	IL-1ra	IL-1ra	IL-1ra	17	19	21	22
By contrast , IL-1R is activated by IL-1alpha and IL-1beta , which are produced by host cells 15 .	By contrast, IL-1R is activated by IL-1alpha and IL-1beta, which are produced by host cells 15.	3	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	9	10	3	4
We demonstrate that activation of IL1R1 by IL-1beta ( or IL-1alpha ) may carry an important activation signal for innate immune responses , with the example of antimicrobial peptide production .	We demonstrate that activation of IL1R1 by IL-1beta (or IL-1alpha) may carry an important activation signal for innate immune responses, with the example of antimicrobial peptide production.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL1R1	IL1R1	IL1R1	7	8	5	6
Compared with controls , asymptomatic patients had increased production of IL-1beta and IL-12 ( both P < 0.05 ) , unchanged production of TNF-alpha , IFN-gamma and IL-1ra and notably reduced production of IL-10 , IL-2 and sIL2-ralpha ( all P < 0.05 ) .	Compared with controls, asymptomatic patients had increased production of IL-1beta and IL-12 (both P < 0.05), unchanged production of TNF-alpha, IFN-gamma and IL-1ra and notably reduced production of IL-10, IL-2 and sIL2-ralpha (all P < 0.05).	8	28	production	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	10	11	27	28
The family contains IL-1alpha and IL-1beta , which both activate the same receptor , IL-1R , [ XREF_BIBR ] and IL-18 which activates the IL-18R [ XREF_BIBR ] , [ XREF_BIBR ] .	The family contains IL-1alpha and IL-1beta, which both activate the same receptor, IL-1R, [XREF_BIBR] and IL-18 which activates the IL-18R [XREF_BIBR], [XREF_BIBR].	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	5	6	14	15
19 Recent evidence suggests that IL-1beta induces human IL-1R1 + Th17 cells to upregulate IFN-gamma production , thereby giving rise to Th17 and Th1 cells with a potentially pathogenic profile .	19 Recent evidence suggests that IL-1beta induces human IL-1R1 + Th17 cells to upregulate IFN-gamma production, thereby giving rise to Th17 and Th1 cells with a potentially pathogenic profile.	5	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	5	6	8	9
Since IL-1Ra does not activate IL-1 receptor cell signaling cascades and IL-1Ra production can be induced by IL-1beta and/or IL-1alpha , it is plausible that the increased IL-1Ra in the ascites and the associated poor prognosis is due to secreted IL-1beta signaling [ XREF_BIBR ] .	Since IL-1Ra does not activate IL-1 receptor cell signaling cascades and IL-1Ra production can be induced by IL-1beta and/or IL-1alpha, it is plausible that the increased IL-1Ra in the ascites and the associated poor prognosis is due to secreted IL-1beta signaling [XREF_BIBR].	11	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	17	18	11	12
In addition , the Fas mediated IL-1beta production was required for Th17 and Th1 induction during bacterial infection : Th17 and Th1 induction was abolished in Fas -/- mice , whereas supplementation with recombinant IL-1beta restored Th17 and Th1 induction via IL-1 receptor 1 ( IL-1R1 ) , and rescued the mortality of Fas -/- mice infected with Listeria IL-1R1 , but not apoptosis associated speck like protein containing a caspase recruitment domain or Fas on T cells , was required for Th17 and Th1 induction , indicating that IL-1beta stimulates IL-1R1 on T cells for Th17 and Th1 induction .	In addition, the Fas mediated IL-1beta production was required for Th17 and Th1 induction during bacterial infection : Th17 and Th1 induction was abolished in Fas -/- mice, whereas supplementation with recombinant IL-1beta restored Th17 and Th1 induction via IL-1 receptor 1 (IL-1R1), and rescued the mortality of Fas -/- mice infected with Listeria IL-1R1, but not apoptosis associated speck like protein containing a caspase recruitment domain or Fas on T cells, was required for Th17 and Th1 induction, indicating that IL-1beta stimulates IL-1R1 on T cells for Th17 and Th1 induction.	89	99	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	89	90	91	92
Two distinct cytokines , IL-1alpha and IL-1beta , can stimulate the IL-1R .	Two distinct cytokines, IL-1alpha and IL-1beta, can stimulate the IL-1R.	2	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	6	7	11	12
The other speculation is that IL-33 induces IL-1alpha and IL-1beta ( data not shown ) , and then IL-1alpha and IL-1beta in turn activate IL-1R to induce iNOS in macrophages XREF_BIBR .	The other speculation is that IL-33 induces IL-1alpha and IL-1beta (data not shown), and then IL-1alpha and IL-1beta in turn activate IL-1R to induce iNOS in macrophages XREF_BIBR.	18	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	20	21	24	25
While IL-1R1 can be stimulated by either of two cytokines , IL-1alpha or IL-1beta , it has been shown that IL-1beta plays a pivotal role in disease pathogenesis because it not only directly stimulates IL-1R1-dependent inflammatory signaling , but is also needed for the secretion of IL-1alpha from cells .	While IL-1R1 can be stimulated by either of two cytokines, IL-1alpha or IL-1beta, it has been shown that IL-1beta plays a pivotal role in disease pathogenesis because it not only directly stimulates IL-1R1-dependent inflammatory signaling, but is also needed for the secretion of IL-1alpha from cells.	1	14	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	13	14	1	2
The results show that young IL-1beta ko and IL-1r1ko mice showed an impairment in spatial memory task learning in the WM , suggesting that brain IL-1beta activates IL-1r1 to facilitate hippocampal spatial learning and memory in young mice .	The results show that young IL-1beta ko and IL-1r1ko mice showed an impairment in spatial memory task learning in the WM, suggesting that brain IL-1beta activates IL-1r1 to facilitate hippocampal spatial learning and memory in young mice.	24	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1r1	IL-1r1	IL-1r1	25	26	27	28
In contrast , neutralizing antibodies against IL-1beta did not suppress inflammatory cytokine secretion , suggesting that IL-1beta secretion levels at senescence are not sufficient to produce a significant level of IL-1R signaling .	In contrast, neutralizing antibodies against IL-1beta did not suppress inflammatory cytokine secretion, suggesting that IL-1beta secretion levels at senescence are not sufficient to produce a significant level of IL-1R signaling.	16	31	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta secretion levels	il-1beta	IL-1R	IL-1R	il-1r	16	17	30	31
If IL-1Ra is stimulated by IL-1beta in a linear manner , only two stable steady states would have been found .	If IL-1Ra is stimulated by IL-1beta in a linear manner, only two stable steady states would have been found.	1	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	5	6	1	2
Suppression of Mtb replication was a specific action of IL-1beta , since neither Tim3-Ig nor IL-1beta were able to inhibit bacterial growth in infected Mphi lacking IL-1R ( XREF_FIG ) .	Suppression of Mtb replication was a specific action of IL-1beta, since neither Tim3-Ig nor IL-1beta were able to inhibit bacterial growth in infected Mphi lacking IL-1R (XREF_FIG).	13	28	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	15	16	26	27
Our previous studies showed that hCG down-regulates the IL1B induced increase in IL1R2 and IL1RN in human ESCs and further enhances the IL1B induced increase in IL1R1 , thereby amplifying in vitro the release of angiogenic activity XREF_BIBR .	Our previous studies showed that hCG down-regulates the IL1B induced increase in IL1R2 and IL1RN in human ESCs and further enhances the IL1B induced increase in IL1R1, thereby amplifying in vitro the release of angiogenic activity XREF_BIBR.	21	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL1B	IL1B	IL1B	IL1R1	IL1R1	IL1R1	22	23	26	27
Moreover , treatment of transformed alphaTC-1 cells with IL-1beta increased IL-1Ra immunoreactivity similar to that observed in transformed INS-1 beta-cells , although alphaTC-1 cells had much lower basal IL-1Ra immunoreactivity as compared to INS-1 beta-cells .	Moreover, treatment of transformed alphaTC-1 cells with IL-1beta increased IL-1Ra immunoreactivity similar to that observed in transformed INS-1 beta-cells, although alphaTC-1 cells had much lower basal IL-1Ra immunoreactivity as compared to INS-1 beta-cells.	6	11	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	8	9	10	11
This observation is consistent with reports that IL-1beta is a potential inducer of IL-1ra , and suggests a feedback mechanism of IL-1 activity .	This observation is consistent with reports that IL-1beta is a potential inducer of IL-1ra, and suggests a feedback mechanism of IL-1 activity.	7	16	is a potential inducer	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	7	8	13	14
A major branch of the innate immune system is regulated by the Toll like receptors ( TLRs ) , which are receptors for endogenous damage associated molecules released from injured cells as well as pathogen derived molecules , and interleukin-1 receptors ( IL-1R ) , which are activated by IL-1alpha , IL-1beta and IL-18 cytokines .	A major branch of the innate immune system is regulated by the Toll like receptors (TLRs), which are receptors for endogenous damage associated molecules released from injured cells as well as pathogen derived molecules, and interleukin-1 receptors (IL-1R), which are activated by IL-1alpha, IL-1beta and IL-18 cytokines.	40	54	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	51	52	42	43
IL-1 alpha or IL-1 beta at a dose of 10 ng/ml induced 3 to 6 ng/ml of IL-1ra , while TNF-alpha at a dose of 100 ng/ml stimulated only 1.4 ng/ml of IL-1ra .	IL-1 alpha or IL-1 beta at a dose of 10 ng/ml induced 3 to 6 ng/ml of IL-1ra, while TNF-alpha at a dose of 100 ng/ml stimulated only 1.4 ng/ml of IL-1ra.	3	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1 beta	IL-1 beta	IL-1 beta	IL-1ra	IL-1ra	IL-1ra	3	5	17	18
Given that mononuclear phagocytes can produce both the proinflammatory cytokines IL-1 alpha , IL-1 beta , and TNF-alpha as well as the suppressive cytokine IL-1ra , we proposed that IL-1 alpha , IL-1 beta , and TNF-alpha may induce IL-1ra from mononuclear phagocytes .	Given that mononuclear phagocytes can produce both the proinflammatory cytokines IL-1 alpha, IL-1 beta, and TNF-alpha as well as the suppressive cytokine IL-1ra, we proposed that IL-1 alpha, IL-1 beta, and TNF-alpha may induce IL-1ra from mononuclear phagocytes.	32	40	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1 beta	IL-1 beta	IL-1 beta	IL-1ra	IL-1ra	IL-1ra	32	34	39	40
Our findings indicate that : ( i ) IL-1beta directly affects the central nervous system and acts independently of infiltrating hematogenous cells ; ( ii ) IL-1beta induces microglial activation but is not neurotoxic per se ; ( iii ) IL-1beta enhances excitotoxic neuronal damage and microglial activation and ( iv ) IL-1ra , even when applied for only 4 h , reduces neuronal cell death and the number of microglial cells after excitotoxic damage .	Our findings indicate that : (i) IL-1beta directly affects the central nervous system and acts independently of infiltrating hematogenous cells; (ii) IL-1beta induces microglial activation but is not neurotoxic per se; (iii) IL-1beta enhances excitotoxic neuronal damage and microglial activation and (iv) IL-1ra, even when applied for only 4 h, reduces neuronal cell death and the number of microglial cells after excitotoxic damage.	40	53	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	40	41	52	53
In the CNS , activation of IL-1R1 by IL-1beta activates signaling pathways that modulate intracellular calcium [ XREF_BIBR ] , expression of neurotransmitter receptors [ XREF_BIBR ] , activation of cAMP response element binding ( CREB ) [ XREF_BIBR ] and brain derived neurotrophic factor ( BDNF ) expression [ XREF_BIBR ] .	In the CNS, activation of IL-1R1 by IL-1beta activates signaling pathways that modulate intracellular calcium [XREF_BIBR], expression of neurotransmitter receptors [XREF_BIBR], activation of cAMP response element binding (CREB) [XREF_BIBR] and brain derived neurotrophic factor (BDNF) expression [XREF_BIBR].	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	8	9	6	7
Our in vivo study showed that prevention of IL-1beta maturation in Casp-1 -/- and Nalp3 -/- mice or of IL-1beta signaling in Il1r -/- mice reduced circulating sTNFR1 concentrations after CLP .	Our in vivo study showed that prevention of IL-1beta maturation in Casp-1 -/- and Nalp3 -/- mice or of IL-1beta signaling in Il1r -/- mice reduced circulating sTNFR1 concentrations after CLP.	19	23	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	Il1r	Il1r	Il1r	19	20	22	23
Activation of IL-1R by IL-1beta in astrocytes , decreases glutamate reuptake and simultaneously stimulates the release of glutamate from astroglial cells via TNFalpha induction , mediated through activation of TNFalphaR [ XREF_BIBR ] .	Activation of IL-1R by IL-1beta in astrocytes, decreases glutamate reuptake and simultaneously stimulates the release of glutamate from astroglial cells via TNFalpha induction, mediated through activation of TNFalphaR [XREF_BIBR].	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	4	5	2	3
This notion is supported by our invitro studies , which showed that IL-1beta can induce IL-1Ra production in both transformed INS-1 beta-cells and alphaTC-1 cells ; albeit IL-1Ra immunoreactivity was much lower in alphaTC-1 cells and inducing IL-1Ra production in alphaTC-1 cells required a higher concentration of IL-1beta as compared to INS-1 beta-cells .	This notion is supported by our invitro studies, which showed that IL-1beta can induce IL-1Ra production in both transformed INS-1 beta-cells and alphaTC-1 cells; albeit IL-1Ra immunoreactivity was much lower in alphaTC-1 cells and inducing IL-1Ra production in alphaTC-1 cells required a higher concentration of IL-1beta as compared to INS-1 beta-cells.	12	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	12	13	15	16
As expected , IL-1 beta highly stimulated NO , IL-6 , IL-8 , IL-10 , IL-1ra , PGE ( 2 ) and stromelysin synthesis , but dramatically decreased PG production .	As expected, IL-1 beta highly stimulated NO, IL-6, IL-8, IL-10, IL-1ra, PGE (2) and stromelysin synthesis, but dramatically decreased PG production.	3	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1 beta	IL-1 beta	IL-1 beta	IL-1ra	IL-1ra	IL-1ra	3	5	15	16
As shown in XREF_TABLE , IL-6 and CXCL1 were detectable at very low levels in WT mice treated with saline or in IL-1R1 -/- mice treated with IL-1beta but these molecules were robustly expressed in WT mice treated with IL-1beta .	As shown in XREF_TABLE, IL-6 and CXCL1 were detectable at very low levels in WT mice treated with saline or in IL-1R1 -/- mice treated with IL-1beta but these molecules were robustly expressed in WT mice treated with IL-1beta.	17	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1 -/-	IL-1R1 -/-	IL-1R1 -/-	27	28	22	24
The pHEMA particles were then used in an in vitro setting with IL1Ra , and it was demonstrated that cells treated with IL1beta and exposed to IL1Ra nanoparticles maintained NF-kappaB expression levels similar to those of unstimulated controls , demonstrating protection [ XREF_BIBR ] .	The pHEMA particles were then used in an in vitro setting with IL1Ra, and it was demonstrated that cells treated with IL1beta and exposed to IL1Ra nanoparticles maintained NF-kappaB expression levels similar to those of unstimulated controls, demonstrating protection [XREF_BIBR].	10	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL1beta	IL1beta	IL1beta	IL1Ra	IL1Ra	IL1Ra	22	23	12	13
Furthermore , disruption of IL-1beta signaling by caspase-1 KO specifically within bone marrow derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1beta .	Furthermore, disruption of IL-1beta signaling by caspase-1 KO specifically within bone marrow derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1beta.	18	27	promoted	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	26	27	24	25
CFA induced inflammatory orofacial hyperalgesia produces an increase in IL-1beta activation of IL-1R in the ipsilateral Vi/Vc .	CFA induced inflammatory orofacial hyperalgesia produces an increase in IL-1beta activation of IL-1R in the ipsilateral Vi/Vc.	9	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	9	10	12	13
IL-1beta markedly stimulated the induction of IL-1R1 , which preceded the induction of iNOS .	IL-1beta markedly stimulated the induction of IL-1R1, which preceded the induction of iNOS.	0	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	0	1	6	7
During the response to seizures , the IL-1beta system induces IL-1Ra , which acts by limiting IL-1beta-mediated pro inflammatory actions .	During the response to seizures, the IL-1beta system induces IL-1Ra, which acts by limiting IL-1beta-mediated pro inflammatory actions.	7	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	7	8	10	11
We found that the IL1RA and IL-1beta balance in dM supernatants in both basal and TLR stimulated conditions always favored IL-1RA .	We found that the IL1RA and IL-1beta balance in dM supernatants in both basal and TLR stimulated conditions always favored IL-1RA.	4	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1RA	IL-1RA	IL-1RA	6	7	20	21
In response to seizures , the IL-1beta system induces IL-1Ra , which acts by limiting IL-1beta-mediated proinflammatory actions XREF_BIBR .	In response to seizures, the IL-1beta system induces IL-1Ra, which acts by limiting IL-1beta-mediated proinflammatory actions XREF_BIBR.	6	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	6	7	9	10
However , IL-1 alpha and IL-1 beta were better inducers of IL-1ra than was TNF-alpha .	However, IL-1 alpha and IL-1 beta were better inducers of IL-1ra than was TNF-alpha.	5	12	were better inducers	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-1 beta	IL-1 beta	IL-1 beta	IL-1ra	IL-1ra	IL-1ra	5	7	11	12
In chondrocytes , IFNbeta alone had no effect , but dose dependently enhanced the secretion of IL1Ra induced by IL1beta .	In chondrocytes, IFNbeta alone had no effect, but dose dependently enhanced the secretion of IL1Ra induced by IL1beta.	14	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL1beta	IL1beta	IL1beta	IL1Ra	IL1Ra	IL1Ra	19	20	16	17
In Q705K transduced cells , we have found the release of TNF to be a downstream event of IL-1R activation by IL-1beta , whereas the increased gene expression of TNF in these cells was not an IL-1R regulated event [ XREF_BIBR ] .	In Q705K transduced cells, we have found the release of TNF to be a downstream event of IL-1R activation by IL-1beta, whereas the increased gene expression of TNF in these cells was not an IL-1R regulated event [XREF_BIBR].	18	22	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	21	22	18	19
However , IL-1beta alone could not induce IL-17 production in Il1rn -/- gammadelta T cells , even though these cells expressed IL-1R , consistent with a report that IL-1beta alone does not induce IL-17 in peritoneum- and lung derived gammadelta T cells expressing high levels of IL-1R XREF_BIBR .	However, IL-1beta alone could not induce IL-17 production in Il1rn -/- gammadelta T cells, even though these cells expressed IL-1R, consistent with a report that IL-1beta alone does not induce IL-17 in peritoneum- and lung derived gammadelta T cells expressing high levels of IL-1R XREF_BIBR.	2	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	2	3	21	22
Also , the effective IL-1beta concentration required to induce IL-1Ra in alphaTC-1 cells was higher than that in INS-1 beta-cells .	Also, the effective IL-1beta concentration required to induce IL-1Ra in alphaTC-1 cells was higher than that in INS-1 beta-cells.	4	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	4	5	9	10
Our previous studies showed that hCG down-regulates the IL1B induced increase of IL1R2 and IL1RN in ESCs and amplifies the IL1B induced increase of IL1R1 XREF_BIBR .	Our previous studies showed that hCG down-regulates the IL1B induced increase of IL1R2 and IL1RN in ESCs and amplifies the IL1B induced increase of IL1R1 XREF_BIBR.	19	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL1B	IL1B	IL1B	IL1R1	IL1R1	IL1R1	20	21	24	25
We thus propose that the presence of IL-1alpha or IL-1beta is sufficient to trigger IL-1R pathway , an essential component in the development of innate response to acute M. tuberculosis infection , but may not be sufficient for full control of the infection .	We thus propose that the presence of IL-1alpha or IL-1beta is sufficient to trigger IL-1R pathway, an essential component in the development of innate response to acute M. tuberculosis infection, but may not be sufficient for full control of the infection.	5	15	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	9	10	14	15
Human gastric cancer cell lines ( MKN7 , MKN74 , and TMK-1 ) with and without pretreatment of IL-1 receptor antagonist ( IL-1ra ) were treated with IL-1beta or infected with H. pylori .	Human gastric cancer cell lines (MKN7, MKN74, and TMK-1) with and without pretreatment of IL-1 receptor antagonist (IL-1ra) were treated with IL-1beta or infected with H. pylori.	4	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	27	28	22	23
Although both IL-1alpha and IL-1beta can activate IL-1R and MyD88 signaling , their cellular source and post-translational processing are different [ XREF_BIBR ] .	Although both IL-1alpha and IL-1beta can activate IL-1R and MyD88 signaling, their cellular source and post-translational processing are different [XREF_BIBR].	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	4	5	7	8
7 LPS and IL-1beta stimulate different receptors with similar intracellular signaling machinery ( TLR4 and IL1R1 , respectively ) 40 therefore the simultaneous presence of these two molecules may additively increase the activity of their overlapping pathways .	7 LPS and IL-1beta stimulate different receptors with similar intracellular signaling machinery (TLR4 and IL1R1, respectively) 40 therefore the simultaneous presence of these two molecules may additively increase the activity of their overlapping pathways.	1	16	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL1R1	IL1R1	IL1R1	3	4	15	16
Primary sensory neurons particularly nociceptors in DRGs express IL-1 receptors ( IL-1R ) , and activation of IL-1R by IL-1beta can activate nociceptors rapidly to generate action potentials and elicit pain hypersensitivity via regulating sodium and potassium currents [ XREF_BIBR , XREF_BIBR ] .	Primary sensory neurons particularly nociceptors in DRGs express IL-1 receptors (IL-1R), and activation of IL-1R by IL-1beta can activate nociceptors rapidly to generate action potentials and elicit pain hypersensitivity via regulating sodium and potassium currents [XREF_BIBR, XREF_BIBR].	7	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	19	20	17	18
The elevated basal levels of IL-1ra in the aged may occur in reaction to the basal elevations of IL-1beta , as IL-1beta can initiate the release of IL-1ra along with several other molecules .	The elevated basal levels of IL-1ra in the aged may occur in reaction to the basal elevations of IL-1beta, as IL-1beta can initiate the release of IL-1ra along with several other molecules.	21	28	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	21	22	27	28
However , we found that while an IL-1R antagonist peptide ( IL-1RA ) completely prevents NF-kappaB activation in hepatocytes treated with IL-1beta , the peptide has no effect on palmitate dependent NF-kappaB activation ( XREF_FIG ) .	However, we found that while an IL-1R antagonist peptide (IL-1RA) completely prevents NF-kappaB activation in hepatocytes treated with IL-1beta, the peptide has no effect on palmitate dependent NF-kappaB activation (XREF_FIG).	9	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1RA	IL-1RA	IL-1RA	21	22	11	12
IL1R is activated by IL1beta , a known sleep regulatory molecule [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	IL1R is activated by IL1beta, a known sleep regulatory molecule [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL1beta	IL1beta	IL1beta	IL1R	IL1R	IL1R	4	5	0	1
Thus , mature IL-1beta likely acts predominantly in a paracrine or endocrine manner , activating IL-1R signaling in effector cells such as CD4+ T-cells .	Thus, mature IL-1beta likely acts predominantly in a paracrine or endocrine manner, activating IL-1R signaling in effector cells such as CD4+ T-cells.	2	16	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	3	4	15	16
The greater IL-1beta content in the hypothalamus compared with frontal cortex as early as 1 h after MDMA injection could trigger the release of IL-1ra in an attempt to limit the effects of the released IL-1beta .	The greater IL-1beta content in the hypothalamus compared with frontal cortex as early as 1 h after MDMA injection could trigger the release of IL-1ra in an attempt to limit the effects of the released IL-1beta.	2	25	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	2	3	24	25
Taken together , these data suggest that the inflammatory airway response to intranasal challenge with Ova initiated by CFA and Ova immunization requires signaling through the IL-1R1 by IL-1alpha but not by IL-1beta .	Taken together, these data suggest that the inflammatory airway response to intranasal challenge with Ova initiated by CFA and Ova immunization requires signaling through the IL-1R1 by IL-1alpha but not by IL-1beta.	23	33	signaling	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	32	33	26	27
Recently , we demonstrated that IL-1beta and PGF2 induce Il1r1 in cultured human myometrial smooth muscle cells ( Verstraeten etal .	Recently, we demonstrated that IL-1beta and PGF2 induce Il1r1 in cultured human myometrial smooth muscle cells (Verstraeten etal.	5	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	Il1r1	Il1r1	Il1r1	5	6	9	10
Orbital fibroblasts , unlike those from skin , fail to express high levels of IL-1 receptor antagonist ( IL-1ra ) when treated with IL-1beta , leading to loss of modulation of IL-1 action .	Orbital fibroblasts, unlike those from skin, fail to express high levels of IL-1 receptor antagonist (IL-1ra) when treated with IL-1beta, leading to loss of modulation of IL-1 action.	16	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	23	24	18	19
One can argue that since IL-1alpha or IL-1beta stimulates IL-1Ra production , a lower level of IL-1Ra reflects less functional IL-1 due to inhibition of IL-1 signaling .	One can argue that since IL-1alpha or IL-1beta stimulates IL-1Ra production, a lower level of IL-1Ra reflects less functional IL-1 due to inhibition of IL-1 signaling.	5	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	7	8	9	10
IL-1beta induces IL-1Ra production ; thus , upregulated IL-1Ra levels are considered to reflect higher IL-1beta activity [ XREF_BIBR ] and predispose to insulin resistance and type 2 diabetes [ XREF_BIBR ] .	IL-1beta induces IL-1Ra production; thus, upregulated IL-1Ra levels are considered to reflect higher IL-1beta activity [XREF_BIBR] and predispose to insulin resistance and type 2 diabetes [XREF_BIBR].	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	0	1	2	3
IL1B up-regulated both the signaling IL1R1 and the inhibitory IL1R2 , while adding hCG further increased IL1R1 and significantly downregulated IL1R2 .	IL1B up-regulated both the signaling IL1R1 and the inhibitory IL1R2, while adding hCG further increased IL1R1 and significantly downregulated IL1R2.	0	9	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL1B	IL1B	IL1B	IL1R1	IL1R1	IL1R1	0	1	5	6
IL-1R , which also functions through MyD88 , is activated by the pro inflammatory cytokines IL-1beta and IL-18 and contributes to retinal degeneration .	IL-1R, which also functions through MyD88, is activated by the pro inflammatory cytokines IL-1beta and IL-18 and contributes to retinal degeneration.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	15	16	0	1
This is mediated by IL-1beta activation of IL-1R and MyD88 signaling , which triggers NF-kappaB and other signaling molecules that induce proinflammatory mediators and chemokines to promote neutrophil trafficking from the circulation into the infected tissue XREF_BIBR .	This is mediated by IL-1beta activation of IL-1R and MyD88 signaling, which triggers NF-kappaB and other signaling molecules that induce proinflammatory mediators and chemokines to promote neutrophil trafficking from the circulation into the infected tissue XREF_BIBR.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	4	5	7	8
IL-1R is activated by its ligands IL-1alpha and IL-1beta [ XREF_BIBR ; XREF_BIBR ] .	IL-1R is activated by its ligands IL-1alpha and IL-1beta [XREF_BIBR; XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	8	9	0	1
Because IL-1beta has been shown to increase IL-1ra secretion , we next investigated if there were any correlations between O 3 -induced changes in IL-1beta and IL-1ra .	Because IL-1beta has been shown to increase IL-1ra secretion, we next investigated if there were any correlations between O 3 -induced changes in IL-1beta and IL-1ra.	1	8	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	1	2	7	8
This finding suggests that primary human alpha-cells , same as beta-cells , produce IL-1Ra and that elevated IL-1beta levels associated with islet culture and amyloid formation may promote IL-1Ra production in alpha-cells .	This finding suggests that primary human alpha-cells, same as beta-cells, produce IL-1Ra and that elevated IL-1beta levels associated with islet culture and amyloid formation may promote IL-1Ra production in alpha-cells.	17	29	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta levels	il-1beta	IL-1Ra	IL-1Ra	il-1ra	17	18	28	29
IL-1beta also activates IL-1R1 on nociceptor neurons to increase TRPV1 expression and , consequently , pain sensitivity to thermal stimuli [ XREF_BIBR ] .	IL-1beta also activates IL-1R1 on nociceptor neurons to increase TRPV1 expression and, consequently, pain sensitivity to thermal stimuli [XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	0	1	3	4
For constructs co-treated with IL-1beta and IL-1ra conditioned media , modulus was significantly greater than for constructs treated with IL-1beta alone and was not significantly different from untreated controls for all collection intervals .	For constructs co-treated with IL-1beta and IL-1ra conditioned media, modulus was significantly greater than for constructs treated with IL-1beta alone and was not significantly different from untreated controls for all collection intervals.	2	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	19	20	6	7
Elevation of IL-1beta induces a robust release of other pro inflammatory cytokines including IL-6 and IL-8 , as well as its competitive antagonist IL-1RA ( interleukin-1 receptor antagonist ) a potent anticonvulsant XREF_BIBR , XREF_BIBR .	Elevation of IL-1beta induces a robust release of other pro inflammatory cytokines including IL-6 and IL-8, as well as its competitive antagonist IL-1RA (interleukin-1 receptor antagonist) a potent anticonvulsant XREF_BIBR, XREF_BIBR.	0	34	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1RA	IL-1RA	IL-1RA	2	3	23	24
In both young and old rats , IL-1beta induced a significant up-regulation of cerebellar IL-1Ra , IL-1RI , and TGF-beta1 mRNAs ; hippocampal TGF-beta1 mRNA ; hypothalamic IL-1beta , IL-1Ra , TGF-beta1 , and gp 130 mRNAs ; and midbrain IL-1beta and TGF-beta1 mRNAs .	In both young and old rats, IL-1beta induced a significant up-regulation of cerebellar IL-1Ra, IL-1RI, and TGF-beta1 mRNAs; hippocampal TGF-beta1 mRNA; hypothalamic IL-1beta, IL-1Ra, TGF-beta1, and gp 130 mRNAs; and midbrain IL-1beta and TGF-beta1 mRNAs.	7	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	7	8	14	15
The simulated therapy slows down the loss of beta-cell mass ( XREF_FIG , red crosses ) because increased IL-1Ra drives IL-1beta into a less pathological regime .	The simulated therapy slows down the loss of beta-cell mass (XREF_FIG, red crosses) because increased IL-1Ra drives IL-1beta into a less pathological regime.	18	25	drives	Positive_activation_token_1_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	20	21	18	19
IL-1 beta was shown to induce a rapid and strong synthesis of IL-6 and IL-1ra in the pituitary but failed to regulate GH contents or release .	IL-1 beta was shown to induce a rapid and strong synthesis of IL-6 and IL-1ra in the pituitary but failed to regulate GH contents or release.	0	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1 beta	IL-1 beta	IL-1 beta	IL-1ra	IL-1ra	IL-1ra	0	2	14	15
As a central pro inflammatory mediator , IL-1beta leads to the activation of IL-1R1 and MyD88 signalling pathways , which induces the activation of transcription factor NF-kB .	As a central pro inflammatory mediator, IL-1beta leads to the activation of IL-1R1 and MyD88 signalling pathways, which induces the activation of transcription factor NF-kB.	7	17	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	7	8	13	14
The results show that chronic icy microinfusion of IL-1 beta induced significant anorexia , increased the cerebellar IL-1RI mRNA content , increased IL-1Ra and IL-1 beta mRNAs levels in the cerebellum > midbrain > cortex > hippocampus , and induced profiles of IL-1RI mRNA , IL-1Ra mRNA , and IL-1 beta mRNA that were highly intercorrelated .	The results show that chronic icy microinfusion of IL-1 beta induced significant anorexia, increased the cerebellar IL-1RI mRNA content, increased IL-1Ra and IL-1 beta mRNAs levels in the cerebellum> midbrain> cortex> hippocampus, and induced profiles of IL-1RI mRNA, IL-1Ra mRNA, and IL-1 beta mRNA that were highly intercorrelated.	8	28	increased	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-1 beta	IL-1 beta	il-1 beta	IL-1Ra	IL-1Ra and IL-1 beta mRNAs levels	il-1ra	8	10	22	23
Although ACS ( IRAP II ( TM ) ) increased IL-1Ra and IGF-1 in equine cartilage explants treated with IL-1beta , there was no significant difference in MMP-3 production and proteoglycan loss or synthesis between ACS and serum treated samples suggesting minimal beneficial effects of ACS on cartilage matrix metabolism .	Although ACS (IRAP II (TM)) increased IL-1Ra and IGF-1 in equine cartilage explants treated with IL-1beta, there was no significant difference in MMP-3 production and proteoglycan loss or synthesis between ACS and serum treated samples suggesting minimal beneficial effects of ACS on cartilage matrix metabolism.	9	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	19	20	10	11
IL-1beta ( the main secreted isoform ) is produced by microglia to act primarily on astrocytes , and we have reported previously that IL-1beta induces the production of secondary inflammatory mediators via binding to the IL-1 receptor type 1 ( IL-1R1 ) and downstream activation of the extracellular signal regulated kinase ( ERK1/2 ) in these cells .	IL-1beta (the main secreted isoform) is produced by microglia to act primarily on astrocytes, and we have reported previously that IL-1beta induces the production of secondary inflammatory mediators via binding to the IL-1 receptor type 1 (IL-1R1) and downstream activation of the extracellular signal regulated kinase (ERK1/2) in these cells.	23	44	induces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	23	24	40	41
LPS and both doses of IL-1beta increased IL-1ra ( F = 6.500 , df 7,29 , p < 0.05 ) .	LPS and both doses of IL-1beta increased IL-1ra (F = 6.500, df 7,29, p < 0.05).	3	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	5	6	7	8
IL-1beta also activates IL-1R to contribute to hyperalgesia and the establishment of peripheral and central sensitization [ XREF_BIBR , XREF_BIBR ] .	IL-1beta also activates IL-1R to contribute to hyperalgesia and the establishment of peripheral and central sensitization [XREF_BIBR, XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	0	1	3	4
In contrast to mononuclear phagocytes , IL-1 alpha , IL-1 beta , and TNF-alpha did not induce further IL-1ra production in alveolar macrophages .	In contrast to mononuclear phagocytes, IL-1 alpha, IL-1 beta, and TNF-alpha did not induce further IL-1ra production in alveolar macrophages.	9	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1 beta	IL-1 beta	IL-1 beta	IL-1ra	IL-1ra	IL-1ra	9	11	18	19
Furthermore , for IL-1 beta induced IL-1ra , immunoprecipitation of IL-1 beta with an anti-IL-1 beta antibody , but not a preimmune antibody , blocked the induction of IL-1ra .	Furthermore, for IL-1 beta induced IL-1ra, immunoprecipitation of IL-1 beta with an anti-IL-1 beta antibody, but not a preimmune antibody, blocked the induction of IL-1ra.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-1 beta	IL-1 beta	IL-1 beta	IL-1ra	IL-1ra	IL-1ra	3	5	6	7
IL-1RA production in hepatocytes is stimulated by IL-1beta and interferon , inflammation stimulates myeloid cells production of IL-1RA , and IL-1RA can arise from macrophages induced by IL-6 .	IL-1RA production in hepatocytes is stimulated by IL-1beta and interferon, inflammation stimulates myeloid cells production of IL-1RA, and IL-1RA can arise from macrophages induced by IL-6.	0	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1RA	IL-1RA	IL-1RA	7	8	0	1
Further studies examined how IL1R1 receptor activation by IL-1beta induced lymphangiogenesis .	Further studies examined how IL1R1 receptor activation by IL-1beta induced lymphangiogenesis.	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL1R1	IL1R1	IL1R1	8	9	4	5
Greater complexity is exhibited by the system , because the IL-1R signals exclusively through the adapter MyD88 , and thus signaling pathways activated by IL-1beta parallel those activated by the TLRs .	Greater complexity is exhibited by the system, because the IL-1R signals exclusively through the adapter MyD88, and thus signaling pathways activated by IL-1beta parallel those activated by the TLRs.	10	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	24	25	10	11
IL-1alpha was used to stimulate IL-1R signaling whereas a receptor antagonist , IL-1Ra , was used to inhibit a positive feedback loop .	IL-1alpha was used to stimulate IL-1R signaling whereas a receptor antagonist, IL-1Ra, was used to inhibit a positive feedback loop.	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1R	IL-1R	IL-1R	0	1	5	6
Our group has previously demonstrated overexpression of IL-1ra , which antagonizes the functions of IL-1alpha , beta , in DEN induced hepatic tumors 24 , and an increase in IL-1ra over IL-1alpha , beta contributes to tumor growth 35 , 36 .	Our group has previously demonstrated overexpression of IL-1ra, which antagonizes the functions of IL-1alpha, beta, in DEN induced hepatic tumors 24, and an increase in IL-1ra over IL-1alpha, beta contributes to tumor growth 35, 36.	12	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1ra	IL-1ra	IL-1ra	14	15	29	30
Of note , while it can not be excluded that the association of plasma apoB with hyperinsulinemia and IR may also be related to increased production of IL-1alpha , which promotes IL-1Ra secretion , IL-1alpha is rarely found in circulation and its role in T2D in humans is less clear .	Of note, while it can not be excluded that the association of plasma apoB with hyperinsulinemia and IR may also be related to increased production of IL-1alpha, which promotes IL-1Ra secretion, IL-1alpha is rarely found in circulation and its role in T2D in humans is less clear.	25	32	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1Ra	IL-1Ra	IL-1Ra	27	28	31	32
Because of the intermediate role of IRAK-1 in the activation of NF-kappaB after IL-1R stimulation by IL-1alpha ,, we examined the correlation between the immunohistochemical expression of IRAK-1 with that of IL-1 alpha ( an IL- 1R ligand ) and NF-kappaB using the 306 NSCLCs placed in TMAs .	Because of the intermediate role of IRAK-1 in the activation of NF-kappaB after IL-1R stimulation by IL-1alpha,, we examined the correlation between the immunohistochemical expression of IRAK-1 with that of IL-1 alpha (an IL- 1R ligand) and NF-kappaB using the 306 NSCLCs placed in TMAs.	13	17	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1R	IL-1R	IL-1R	16	17	13	14
74 Interestingly , IL-1R autocrine stimulation by IL-1alpha and downstream MyD88 activation were shown to be crucial for the establishment of the inflammation involved in RAS dependent carcinogenesis .	74 Interestingly, IL-1R autocrine stimulation by IL-1alpha and downstream MyD88 activation were shown to be crucial for the establishment of the inflammation involved in RAS dependent carcinogenesis.	3	11	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1R	IL-1R	IL-1R	7	8	3	4
Addition of recombinant IL1A ( rIL1A ) rescued both IL1R1 signalling and IL6 secretion in the rapamycin treated cells ( XREF_FIG ) .	Addition of recombinant IL1A (rIL1A) rescued both IL1R1 signalling and IL6 secretion in the rapamycin treated cells (XREF_FIG).	0	10	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL1A	IL1A	IL1A	IL1R1	IL1R1	IL1R1	3	4	9	10
In addition , IL-1alpha , which also activates IL-1R , could contribute to the inflammatory response in vivo .	In addition, IL-1alpha, which also activates IL-1R, could contribute to the inflammatory response in vivo.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1R	IL-1R	IL-1R	3	4	8	9
Addition of IL-1 alpha could stimulate IL-1R , IL-1 alpha , and IL-6 mRNA synthesis in the epithelial , stromal , and endothelial components of the cornea .	Addition of IL-1 alpha could stimulate IL-1R, IL-1 alpha, and IL-6 mRNA synthesis in the epithelial, stromal, and endothelial components of the cornea.	2	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1 alpha	IL-1 alpha	IL-1 alpha	IL-1R	IL-1R	IL-1R	2	4	6	7
Interference with IL-1alpha signaling or ablation of IL-1R1 inhibited hepatocellular carcinoma ( HCC ) development [ XREF_BIBR ] .	Interference with IL-1alpha signaling or ablation of IL-1R1 inhibited hepatocellular carcinoma (HCC) development [XREF_BIBR].	2	8	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1R1	IL-1R1	IL-1R1	2	3	7	8
In addition to promoting tumour progression , by controlling Treg recruitment via CCL22 signalling , however , IL-1A mediated IL-1R1 signalling has also been reported to have anti-tumour functions .	In addition to promoting tumour progression, by controlling Treg recruitment via CCL22 signalling, however, IL-1A mediated IL-1R1 signalling has also been reported to have anti-tumour functions.	17	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-1A	IL-1A	IL-1A	IL-1R1	IL-1R1	IL-1R1	17	18	19	20
IL-1alpha was increased 2.1-fold at 6 h by 200 cGy of gamma radiation ( data not shown ) , however , IL-1beta , IL-1RA , TNF-alpha , IL-6 , and IFN-gamma were not .	IL-1alpha was increased 2.1-fold at 6 h by 200 cGy of gamma radiation (data not shown), however, IL-1beta, IL-1RA, TNF-alpha, IL-6, and IFN-gamma were not.	0	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1RA	IL-1RA	IL-1RA	0	1	23	24
The secreted IL-1alpha may further stimulate the cells through MyD88 independent IL-1R pathway that initiates a late phase response [ XREF_BIBR , XREF_BIBR ] .	The secreted IL-1alpha may further stimulate the cells through MyD88 independent IL-1R pathway that initiates a late phase response [XREF_BIBR, XREF_BIBR].	0	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1R	IL-1R	IL-1R	2	3	11	12
In this context , in response to damage or noxious stimulus assault , the initial pro inflammatory IL-1R1 signaling can be mediated by IL-1alpha , while chronic inflammatory response even without any pathogen presence may then be sustained by both IL-1alpha and IL-1beta .	In this context, in response to damage or noxious stimulus assault, the initial pro inflammatory IL-1R1 signaling can be mediated by IL-1alpha, while chronic inflammatory response even without any pathogen presence may then be sustained by both IL-1alpha and IL-1beta.	17	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1R1	IL-1R1	IL-1R1	23	24	17	18
Because of the intermediate role of IRAK-1 in the activation of NF-kappaB after IL-1R stimulation by IL-1alpha , we examined the influence of the combined expression of these biomarkers on disease outcomes of patients with NSCLC .	Because of the intermediate role of IRAK-1 in the activation of NF-kappaB after IL-1R stimulation by IL-1alpha, we examined the influence of the combined expression of these biomarkers on disease outcomes of patients with NSCLC.	13	17	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1R	IL-1R	IL-1R	16	17	13	14
Both human and mouse IL-34 were also able to activate the feline CSF-1R in vitro ; again the mouse ligand was less active .	Both human and mouse IL-34 were also able to activate the feline CSF-1R in vitro; again the mouse ligand was less active.	1	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	CSF-1R	CSF-1R	CSF-1R	4	5	12	13
The CSF1R is activated by macrophage colony stimulating factor ( CSF1 ) and IL-34 [ XREF_BIBR ] , and is essential for differentiation , proliferation and survival of monocytes , macrophages and their progenitors [ XREF_BIBR ] .	The CSF1R is activated by macrophage colony stimulating factor (CSF1) and IL-34 [XREF_BIBR], and is essential for differentiation, proliferation and survival of monocytes, macrophages and their progenitors [XREF_BIBR].	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	CSF1R	CSF1R	CSF1R	13	14	1	2
CSF-1 or IL-34 activation of the CSF-1R on NPCs suppresses NPC self-renewal and stimulates neuronal survival and differentiation .	CSF-1 or IL-34 activation of the CSF-1R on NPCs suppresses NPC self-renewal and stimulates neuronal survival and differentiation.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	CSF-1R	CSF-1R	CSF-1R	2	3	6	7
CSF-1 or IL-34 stimulation of CSF1R promotes macrophage differentiation , activation and osteoclastogenesis , and pharmacological inhibition of CSF1R is beneficial in animal models of arthritis .	CSF-1 or IL-34 stimulation of CSF1R promotes macrophage differentiation, activation and osteoclastogenesis, and pharmacological inhibition of CSF1R is beneficial in animal models of arthritis.	2	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	CSF1R	CSF1R	CSF1R	2	3	5	6
IL-34 shares little aminoacid homology with CSF1 but can bind to and activate CSF1R , at least in vitro XREF_BIBR , XREF_BIBR .	IL-34 shares little aminoacid homology with CSF1 but can bind to and activate CSF1R, at least in vitro XREF_BIBR, XREF_BIBR.	0	19	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	CSF1R	CSF1R	CSF1R	0	1	13	14
The CSF-1 receptor ( CSF-1R ) is activated by the homodimeric growth factors colony stimulating factor-1 ( CSF-1 ) and interleukin-34 ( IL-34 ) .	The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34).	1	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-34	interleukin-34	interleukin-34	CSF-1 receptor	CSF-1 receptor	CSF-1 receptor	20	21	1	3
However , attempts to replicate the level of growth stimulation with either purified recombinant CSF-1 , or purified IL-34 , which also activates the CSF-1R XREF_BIBR , were only partially successful ( XREF_SUPPLEMENTARY -E ) .	However, attempts to replicate the level of growth stimulation with either purified recombinant CSF-1, or purified IL-34, which also activates the CSF-1R XREF_BIBR, were only partially successful (XREF_SUPPLEMENTARY -E).	17	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	CSF-1R	CSF-1R	CSF-1R	18	19	24	25
Interestingly , the interleukin-34 ( IL-34 ) cytokine , which is found across evolutionary distant species also binds to and activates CSF-1R in mammals resulting in the initiation of distinct biological activity and signal activation .	Interestingly, the interleukin-34 (IL-34) cytokine, which is found across evolutionary distant species also binds to and activates CSF-1R in mammals resulting in the initiation of distinct biological activity and signal activation.	3	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-34	interleukin-34	interleukin-34	CSF-1R	CSF-1R	CSF-1R	3	4	21	22
IL-34 induces a stringer activation of the signaling cascade downstream of Csf1r , but this activation lasts much shorter compared to Csf1 binding .	IL-34 induces a stringer activation of the signaling cascade downstream of Csf1r, but this activation lasts much shorter compared to Csf1 binding.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	Csf1r	Csf1r	Csf1r	0	1	11	12
IL-34 was shown to trigger CSF-1R signaling and macrophage survival , proliferation , and differentiation in vitro [ XREF_BIBR , XREF_BIBR ] .	IL-34 was shown to trigger CSF-1R signaling and macrophage survival, proliferation, and differentiation in vitro [XREF_BIBR, XREF_BIBR].	0	6	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	CSF-1R	CSF-1R	CSF-1R	0	1	5	6
Furthermore , IL-34 interaction with Syndecan modulates IL-34 activation of the CSF-1R .	Furthermore, IL-34 interaction with Syndecan modulates IL-34 activation of the CSF-1R.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	CSF-1R	CSF-1R	CSF-1R	7	8	11	12
Thus , IL-34 can activate CSF-1R and compensate for the lack of CSF-1 in these mice .	Thus, IL-34 can activate CSF-1R and compensate for the lack of CSF-1 in these mice.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	CSF-1R	CSF-1R	CSF-1R	2	3	5	6
Another ligand , interlukin-34 ( IL-34 ) , was recently reported to activate the CSF-1R receptor in a different manner .	Another ligand, interlukin-34 (IL-34), was recently reported to activate the CSF-1R receptor in a different manner.	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-34	IL-34	IL-34	CSF-1R	CSF-1R	CSF-1R	5	6	14	15
IL-1 induced a strong interaction among the IL-1R , activated IRAK-1 , MyD88 , and WT , but not mutant , IRAK-4 .	IL-1 induced a strong interaction among the IL-1R, activated IRAK-1, MyD88, and WT, but not mutant, IRAK-4.	1	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1R	IL-1R	IL-1R	MyD88	MyD88	MyD88	7	8	12	13
Considering the important role of MyD88in the TLR and IL-1R signalling pathway , the present study successfully constructed and developed a lentivirus mediated MyD88 gene interference vector using RNAi , which showed good infection and interference effects .	Considering the important role of MyD88in the TLR and IL-1R signalling pathway, the present study successfully constructed and developed a lentivirus mediated MyD88 gene interference vector using RNAi, which showed good infection and interference effects.	9	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1R	IL-1R	IL-1R	MyD88	MyD88	MyD88	9	10	23	24
IL-1R and most TLR superfamily members activate the signal transducer MyD88 ( Myeloid differentiation primary response gene 88 ) .	IL-1R and most TLR superfamily members activate the signal transducer MyD88 (Myeloid differentiation primary response gene 88).	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1R	IL-1R	IL-1R	MyD88	MyD88	MyD88	0	1	10	11
However , as in P. aeruginosa keratitis , S. marcescens corneal infection was dependent on TLR4/MD -2 and IL-1R1 activation of MyD88 [ XREF_BIBR ] .	However, as in P. aeruginosa keratitis, S. marcescens corneal infection was dependent on TLR4/MD -2 and IL-1R1 activation of MyD88 [XREF_BIBR].	18	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-1R1	IL-1R1	IL-1R1	MyD88	MyD88	MyD88	18	19	21	22
A recent study has used chimeric mice to show that CARD9 dependent protective responses to A. fumigatus lung infection are dependent on myeloid cells , whereas the required MyD88 adaptor molecule dependent response is mediated by IL-1R1 activation on pulmonary epithelial cells and not TLRs .	A recent study has used chimeric mice to show that CARD9 dependent protective responses to A. fumigatus lung infection are dependent on myeloid cells, whereas the required MyD88 adaptor molecule dependent response is mediated by IL-1R1 activation on pulmonary epithelial cells and not TLRs.	28	37	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-1R1	IL-1R1	IL-1R1	MyD88	MyD88	MyD88	36	37	28	29
Instead , IL-1R1 triggers MyD88 dependent promotion of lung fibrosis as shown by reduced fibrosis in IL-1R1-deficient mice that resembles the reduced fibrosis observed in MyD88 deficient mice ( see also the chapter on the role of the inflammasome in fibrosis by W. Mehal in this issue ) .	Instead, IL-1R1 triggers MyD88 dependent promotion of lung fibrosis as shown by reduced fibrosis in IL-1R1-deficient mice that resembles the reduced fibrosis observed in MyD88 deficient mice (see also the chapter on the role of the inflammasome in fibrosis by W. Mehal in this issue).	2	6	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1R1	IL-1R1	IL-1R1	MyD88	MyD88	MyD88	2	3	4	5
The above findings support the hypothesis that IL-1R1 rather than TLR or IL-18 signaling underlies the critical role of MyD88 in early host resistance to M. tuberculosis and for the first time assign to IL-1beta a major nonredundant function in acute control of this pathogen .	The above findings support the hypothesis that IL-1R1 rather than TLR or IL-18 signaling underlies the critical role of MyD88 in early host resistance to M. tuberculosis and for the first time assign to IL-1beta a major nonredundant function in acute control of this pathogen.	7	23	underlies	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1R1	IL-1R1	IL-1R1	MyD88	MyD88	MyD88	7	8	19	20
However , IL-1R1 does not mediate the MyD88 dependent cytokine response to GBS .	However, IL-1R1 does not mediate the MyD88 dependent cytokine response to GBS.	2	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1R1	IL-1R1	IL-1R1	MyD88	MyD88	MyD88	2	3	7	8
IL-1beta upregulates inflammatory responses via IL-1R activation of MyD88 , resulting in IL-6 production and neutrophil recruitment .	IL-1beta upregulates inflammatory responses via IL-1R activation of MyD88, resulting in IL-6 production and neutrophil recruitment.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-1R	IL-1R	IL-1R	MyD88	MyD88	MyD88	5	6	8	9
These results indicate that reduced MyD88 dependent TLR and IL-1R signaling in rd1 and MyD88 -/- leads to reduction in mRNA expression of specific chemokines associated with retinal degeneration .	These results indicate that reduced MyD88 dependent TLR and IL-1R signaling in rd1 and MyD88 -/- leads to reduction in mRNA expression of specific chemokines associated with retinal degeneration.	9	15	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-1R	IL-1R	IL-1R	MyD88	MyD88	MyD88	9	10	14	15
In this paper , in addition to confirming the major role of IL-1R1 signaling in MyD88 dependent host resistance to M. tuberculosis , we have now identified IL-1beta as a critical ligand in this pathway .	In this paper, in addition to confirming the major role of IL-1R1 signaling in MyD88 dependent host resistance to M. tuberculosis, we have now identified IL-1beta as a critical ligand in this pathway.	12	18	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-1R1	IL-1R1	IL-1R1	MyD88	MyD88	MyD88	12	13	15	16
TLR and IL-1R signaling activates the MyD88 dependent pathway with the formation of the myddosome , involving the helical assembly of the MyD88 , IRAK4 , IRAK2 , and IRAK1 complex [ XREF_BIBR ] .	TLR and IL-1R signaling activates the MyD88 dependent pathway with the formation of the myddosome, involving the helical assembly of the MyD88, IRAK4, IRAK2, and IRAK1 complex [XREF_BIBR].	0	31	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-1R	IL-1R	il-1r	MyD88	MyD88, IRAK4, IRAK2, and IRAK1 complex	myd88	2	3	22	23
Stimulation of the IL-1R also results in induction of the MyD88 dependent pathway and the secretion of IL-6 .	Stimulation of the IL-1R also results in induction of the MyD88 dependent pathway and the secretion of IL-6.	0	12	results in induction	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	IL-1R	IL-1R	IL-1R	MyD88	MyD88	MyD88	3	4	10	11
IL-21 , another cytokine evaluated in our study , is mainly produced by activated CD4 + T cells , follicular T-helper cells and natural killer T cells and targets a number of IL-21 receptor expressing cells , primarily B , T and NK cells but also macrophages and dendritic cells .	IL-21, another cytokine evaluated in our study, is mainly produced by activated CD4 + T cells, follicular T-helper cells and natural killer T cells and targets a number of IL-21 receptor expressing cells, primarily B, T and NK cells but also macrophages and dendritic cells.	0	35	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-21	IL-21	IL-21	IL-21 receptor	IL-21 receptor	IL-21 receptor	0	1	32	34
Interestingly , IL-21 treatment caused a rapid IL-21R down-modulation so that by 1 h , less than 40 % of the initial level remained on the cell surface and this amount persisted until at least 3 h ( XREF_FIG , and data not shown ) .	Interestingly, IL-21 treatment caused a rapid IL-21R down-modulation so that by 1 h, less than 40% of the initial level remained on the cell surface and this amount persisted until at least 3 h (XREF_FIG, and data not shown).	2	8	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-21	IL-21	IL-21	IL-21R	IL-21R	IL-21R	2	3	7	8
IL-21 signals through a heterodimer of a unique IL-21 receptor and the common gamma-chain cytokine receptor .	IL-21 signals through a heterodimer of a unique IL-21 receptor and the common gamma-chain cytokine receptor.	0	10	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-21	IL-21	IL-21	IL-21 receptor	IL-21 receptor	IL-21 receptor	0	1	8	10
Bcl6 overexpression led to increased expression of endogenous Bcl6 mRNA as well as IL-21R , IL-6R , and CXCR5 mRNA , similar to cells treated with IL-6 or IL-21 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Bcl6 overexpression led to increased expression of endogenous Bcl6 mRNA as well as IL-21R, IL-6R, and CXCR5 mRNA, similar to cells treated with IL-6 or IL-21 (XREF_FIG and XREF_SUPPLEMENTARY).	2	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-21	IL-21	IL-21	IL-21R	IL-21R	IL-21R	28	29	13	14
Furthermore , IL-21 induced IL-21 receptor ( IL-21R ) and IFN-gamma , perforin , but not granmyze B , expression in CD8+ cells from four selected SHIV infected RMs .	Furthermore, IL-21 induced IL-21 receptor (IL-21R) and IFN-gamma, perforin, but not granmyze B, expression in CD8+ cells from four selected SHIV infected RMs.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-21	IL-21	IL-21	IL-21 receptor	IL-21 receptor	IL-21 receptor	2	3	4	6
Here we investigate the role of IL-21 in human pDC activation and function and observe that IL-21 activates signal transducer and activator of transcription 3 in line with the finding that pDCs express the IL-21 receptor .	Here we investigate the role of IL-21 in human pDC activation and function and observe that IL-21 activates signal transducer and activator of transcription 3 in line with the finding that pDCs express the IL-21 receptor.	16	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-21	IL-21	IL-21	IL-21 receptor	IL-21 receptor	IL-21 receptor	16	17	34	36
After ~ 5 days , culture in the presence of IL-21 increased the proportion of IL-2 producing IL-21R +/- CD8 T cells but did not augment the responses of IL-21R-/- CD8 T cells ( XREF_FIG ) .	After ~ 5 days, culture in the presence of IL-21 increased the proportion of IL-2 producing IL-21R +/- CD8 T cells but did not augment the responses of IL-21R-/- CD8 T cells (XREF_FIG).	8	21	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-21	IL-21	IL-21	IL-21R	IL-21R	IL-21R	10	11	17	18
This explains the reduction , but not complete abolition , of IL-12-induced IL-21 production in STAT3- and IL21R deficient CD4 + T cells , with the low levels of IL-21 observed being induced by an IL-12/STAT4-dependent/STAT3-independent pathway .	This explains the reduction, but not complete abolition, of IL-12-induced IL-21 production in STAT3- and IL21R deficient CD4 + T cells, with the low levels of IL-21 observed being induced by an IL-12/STAT4-dependent/STAT3-independent pathway.	12	18	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-21	IL-21	IL-21	IL21R	IL21R	IL21R	12	13	17	18
Interleukin-21 signals via heterodimers of the IL-21 receptor ( IL-21R ) and the common cytokine receptor gamma-chain ( IL-2Rgammac ) .	Interleukin-21 signals via heterodimers of the IL-21 receptor (IL-21R) and the common cytokine receptor gamma-chain (IL-2Rgammac).	0	8	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Interleukin-21	Interleukin-21	Interleukin-21	IL-21 receptor	IL-21 receptor	IL-21 receptor	0	1	6	8
Further validations by intracellular Ki-67 staining conducted on WT- versus IL-21R -/- -derived BM treated with IL-21 ( 50ng/ml ) revealed a twofold increase in LSK expansion over basal levels ( Additional file 1 : Figure S1 ; Fig .	Further validations by intracellular Ki-67 staining conducted on WT- versus IL-21R -/- -derived BM treated with IL-21 (50ng/ml) revealed a twofold increase in LSK expansion over basal levels (Additional file 1 : Figure S1; Fig.	8	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-21	IL-21	IL-21	IL-21R	IL-21R	IL-21R	16	17	10	11
Exogenous IL-21 rescues the functional Tfh defect in STAT1 GOF mutant and IL21R- and IL10R deficient naive CD4 + T cells .	Exogenous IL-21 rescues the functional Tfh defect in STAT1 GOF mutant and IL21R- and IL10R deficient naive CD4 + T cells.	0	20	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-21	IL-21	IL-21	IL21R-	IL21R-	IL21R-	1	2	12	13
Also the IL-27p28 subunit ( IL-30 ) induces STAT3 mediated signals independently of the IL-27Ralpha through the IL-6R via a gp130 dimer .	Also the IL-27p28 subunit (IL-30) induces STAT3 mediated signals independently of the IL-27Ralpha through the IL-6R via a gp130 dimer.	3	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-30	IL-30	IL-30	IL-27Ralpha	IL-27Ralpha	IL-27Ralpha	5	6	14	15
To confirm this hypothesis , the effect of IL30 on IL12 mediated toxicity was tested in WSX1 -/- mice .	To confirm this hypothesis, the effect of IL30 on IL12 mediated toxicity was tested in WSX1 -/- mice.	6	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL30	IL30	IL30	WSX1	WSX1	WSX1	8	9	16	17
IL-27 signals via its heterodimeric receptor , which consists of the IL-6 receptor subunit gp130 and WSX-1 ( also known as TCCR ) .	IL-27 signals via its heterodimeric receptor, which consists of the IL-6 receptor subunit gp130 and WSX-1 (also known as TCCR).	0	17	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-27	IL-27	IL-27	WSX-1	WSX-1	WSX-1	0	1	16	17
Moreover , IL27 signaling in WSX1 positive tumor cells ( LLC-WSX1 ) reduces rather than promotes tumor growth ( XREF_FIG ) , consistent with other publications XREF_BIBR .	Moreover, IL27 signaling in WSX1 positive tumor cells (LLC-WSX1) reduces rather than promotes tumor growth (XREF_FIG), consistent with other publications XREF_BIBR.	2	8	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL27	IL27	IL27	WSX1	WSX1	WSX1	2	3	5	6
Rapamycin not only upregulated the expression of IL-27 in UECC but also increased the expression of IL-27Rs ( WSX-1 and gp130 ) on NK cells .	Rapamycin not only upregulated the expression of IL-27 in UECC but also increased the expression of IL-27Rs (WSX-1 and gp130) on NK cells.	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-27	Rapamycin not only upregulated the expression of IL-27	il-27	WSX-1	WSX-1	wsx-1	7	8	18	19
Produced by activated antigen presenting cells ( APCs ) such as dendritic cells and macrophages , IL-27 signals through a heterodimeric receptor ( IL-27R ) consisting of the WSX-1 and the gp130 subunits , which is expressed in a variety of cell types including T lymphocytes and myeloid cells .	Produced by activated antigen presenting cells (APCs) such as dendritic cells and macrophages, IL-27 signals through a heterodimeric receptor (IL-27R) consisting of the WSX-1 and the gp130 subunits, which is expressed in a variety of cell types including T lymphocytes and myeloid cells.	16	29	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-27	IL-27	IL-27	WSX-1	WSX-1	WSX-1	16	17	28	29
IL-27 signals via its heterodimeric receptor ( IL-27R ) , which consists of the receptor subunits gp130 and WSX-1 .	IL-27 signals via its heterodimeric receptor (IL-27R), which consists of the receptor subunits gp130 and WSX-1.	0	19	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-27	IL-27	IL-27	WSX-1	WSX-1	WSX-1	0	1	18	19
The IL-27-mediated effect was IL-27-specific since IL-27 stimulated Il27ra -/- Tregs did not display enhanced suppression ( XREF_FIG , open square ) .	The IL-27-mediated effect was IL-27-specific since IL-27 stimulated Il27ra -/- Tregs did not display enhanced suppression (XREF_FIG, open square).	6	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-27	IL-27	IL-27	Il27ra	Il27ra	Il27ra	6	7	8	9
Deficiency of either the IL27 subunit Epstein-Barr virus induced gene 3 ( EBI3 ) or the IL27 receptor WSX1 in the host animals had no effect on tumor growth inhibition induced by WSX1 expression in tumor cells .	Deficiency of either the IL27 subunit Epstein-Barr virus induced gene 3 (EBI3) or the IL27 receptor WSX1 in the host animals had no effect on tumor growth inhibition induced by WSX1 expression in tumor cells.	4	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL27	IL27	IL27	WSX1	WSX1	WSX1	4	5	18	19
IL-22 activates IL-22R on epithelial cells which leads to production of antimicrobial proteins RegIIIgamma and RegIIIbeta to eliminate the mucosal bacterial pathogen .	IL-22 activates IL-22R on epithelial cells which leads to production of antimicrobial proteins RegIIIgamma and RegIIIbeta to eliminate the mucosal bacterial pathogen.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22	IL-22	IL-22	IL-22R	IL-22R	IL-22R	0	1	2	3
XREF_BIBR Firstly , we analyzed the effect of IL-22 on MM cell growth : IL-22 treatment increased proliferation of IL-22RA1 + MM cells at levels comparable with IL-6 ( XREF_FIG ) .	XREF_BIBR Firstly, we analyzed the effect of IL-22 on MM cell growth : IL-22 treatment increased proliferation of IL-22RA1 + MM cells at levels comparable with IL-6 (XREF_FIG).	14	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22	IL-22	IL-22	IL-22RA1	IL-22RA1	IL-22RA1	14	15	19	20
IL22 activates IL22R and IL10R2 signaling and induces the release of antimicrobial peptides and matrix metalloproteinases from fibroblasts , endothelial cells , epithelial cells , osteoblasts , macrophages , and DC [ XREF_BIBR , XREF_BIBR ] .	IL22 activates IL22R and IL10R2 signaling and induces the release of antimicrobial peptides and matrix metalloproteinases from fibroblasts, endothelial cells, epithelial cells, osteoblasts, macrophages, and DC [XREF_BIBR, XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL22	IL22	IL22	IL22R	IL22R	IL22R	0	1	2	3
Since endogenous IL-22 was not detected in all studied GBM cells , we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells .	Since endogenous IL-22 was not detected in all studied GBM cells, we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells.	15	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-22	IL-22	IL-22	IL-22R	IL-22R	IL-22R	22	23	15	16
As mentioned before , IL-22RA1 is highly expressed in the liver and can activate STAT3 .	As mentioned before, IL-22RA1 is highly expressed in the liver and can activate STAT3.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22RA1	IL-22RA1 is highly expressed	il-22ra1	STAT3	STAT3	stat3	4	5	14	15
In contrast to the dominant induction of STAT3 by IL-22R signaling , IL-22 augmentation of IFN-lambda ISG expression in response to rotavirus infection is dependent upon STAT1 activation .	In contrast to the dominant induction of STAT3 by IL-22R signaling, IL-22 augmentation of IFN-lambda ISG expression in response to rotavirus infection is dependent upon STAT1 activation.	5	10	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-22R	IL-22R	IL-22R	STAT3	STAT3	STAT3	9	10	7	8
Deletion of the C-terminal part of IL-22R dramatically decreased its ability to activate STAT3 and to mediate IL-22 activity in cell lines , demonstrating that preassociation of STAT3 with this cytokine receptor , independent from the interaction between the Src homology 2 domain and phosphotyrosines , is required for its full activity .	Deletion of the C-terminal part of IL-22R dramatically decreased its ability to activate STAT3 and to mediate IL-22 activity in cell lines, demonstrating that preassociation of STAT3 with this cytokine receptor, independent from the interaction between the Src homology 2 domain and phosphotyrosines, is required for its full activity.	4	14	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22R	IL-22R	IL-22R	STAT3	STAT3	STAT3	6	7	13	14
In addition , IL-22R is expressed in liver stem and progenitor cells and in vitro stimulation of these cells with IL-22 results in STAT3 activation and cell proliferation XREF_BIBR .	In addition, IL-22R is expressed in liver stem and progenitor cells and in vitro stimulation of these cells with IL-22 results in STAT3 activation and cell proliferation XREF_BIBR.	3	25	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IL-22R	IL-22R	IL-22R	STAT3	STAT3	STAT3	3	4	23	24
It also remains to be determined if there is a continual level of HVEM-STAT3 activation , triggered by CD160 in IEL , for maintaining epithelial innate immunity , which is boosted by IL-22R mediated STAT3 activation after infection , or if the CD160-HVEM interaction is likewise induced .	It also remains to be determined if there is a continual level of HVEM-STAT3 activation, triggered by CD160 in IEL, for maintaining epithelial innate immunity, which is boosted by IL-22R mediated STAT3 activation after infection, or if the CD160-HVEM interaction is likewise induced.	30	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-22R	IL-22R	IL-22R	STAT3	STAT3	STAT3	32	33	34	35
IL-22R is highly expressed on non hematopoietic cells of the intestine , including stromal and epithelial cells , and activates STAT3 to promote the elaboration of antimicrobial peptides , including RegIIIbeta , RegIIIgamma , and mucins XREF_BIBR .	IL-22R is highly expressed on non hematopoietic cells of the intestine, including stromal and epithelial cells, and activates STAT3 to promote the elaboration of antimicrobial peptides, including RegIIIbeta, RegIIIgamma, and mucins XREF_BIBR.	0	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22R	IL-22R is highly expressed	il-22r	STAT3	STAT3	stat3	0	1	20	21
Collectively , these findings indicate that IL-22BP mediates epithelial autoregulation of IL-22 signaling to control cutaneous pathogenesis .	Collectively, these findings indicate that IL-22BP mediates epithelial autoregulation of IL-22 signaling to control cutaneous pathogenesis.	6	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	6	7	11	12
Downregulation of IL-22BP is most likely necessary to allow IL-22 to function in the case of infections or tissue damage .	Downregulation of IL-22BP is most likely necessary to allow IL-22 to function in the case of infections or tissue damage.	0	11	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	2	3	9	10
During dextran sulfate sodium induced colitis , a dysfunctional IL-18 and IL-22BP pathway in Aim2 -/- mice promotes excessive IL-22 production and elevated STAT3 activation .	During dextran sulfate sodium induced colitis, a dysfunctional IL-18 and IL-22BP pathway in Aim2 -/- mice promotes excessive IL-22 production and elevated STAT3 activation.	11	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	11	12	19	20
During cellular damage , IL-22BP is downregulated , allowing IL-22 to induce tissue repair .	During cellular damage, IL-22BP is downregulated, allowing IL-22 to induce tissue repair.	4	11	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	4	5	9	10
To further analyze the role of IL-22 during septic peritonitis , mice were treated with recombinant IL-22BP generated as Fcgamma2a fusion protein .	To further analyze the role of IL-22 during septic peritonitis, mice were treated with recombinant IL-22BP generated as Fcgamma2a fusion protein.	4	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	16	17	6	7
Given that IL-22BP deficiency causes an excessive activation of IL-22 signaling , Il22ra2 -/- mice might exhibit abnormalities in FAE properties .	Given that IL-22BP deficiency causes an excessive activation of IL-22 signaling, Il22ra2 -/- mice might exhibit abnormalities in FAE properties.	2	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	2	3	9	10
This results in the downregulation of IL-22BP , which would enable IL-22 to promote tissue repair .	This results in the downregulation of IL-22BP, which would enable IL-22 to promote tissue repair.	4	12	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	6	7	11	12
In addition , GM1 increased Arg 1 expression through CD206 and gammac mediated activation of Janus kinase 3 ( JAK3 ) and signal transducer and activator of transcription- 6 ( STAT-6 ) .	In addition, GM1 increased Arg 1 expression through CD206 and gammac mediated activation of Janus kinase 3 (JAK3) and signal transducer and activator of transcription- 6 (STAT-6).	9	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	gammac	gammac	gammac	Janus kinase 3	Janus kinase 3	Janus kinase 3	11	12	15	18
As a potent inhibitor of Jak3 , tofacitinib very effectively blocks signaling by common gammac cytokines : IL-2 , IL-4 , IL-7 , IL-9 , IL-15 and IL-21 1 .	As a potent inhibitor of Jak3, tofacitinib very effectively blocks signaling by common gammac cytokines : IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 1.	3	15	blocks	Negative_activation_syntax_3_verb	Positive_activation	Positive_activation	gammac	gammac	gammac	Jak3	Jak3	Jak3	14	15	5	6
Because gammac activates JAK3 to promote nuclear translocation of STAT transcription factors , many JAK3 inhibitors were developed and have been shown to prevent allograft rejection .	Because gammac activates JAK3 to promote nuclear translocation of STAT transcription factors, many JAK3 inhibitors were developed and have been shown to prevent allograft rejection.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gammac	gammac	gammac	JAK3	JAK3	JAK3	1	2	3	4
All of the gammac cytokines , activate the jak1 and jak3 kinases upon binding to their specific and the common gamma chains , respectively .	All of the gammac cytokines, activate the jak1 and jak3 kinases upon binding to their specific and the common gamma chains, respectively.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gammac	gammac	gammac	jak3	jak3	jak3	3	4	10	11
The stimulation of IL-1R cells with IL-1 induced the interaction of IRAK4 with IRAK1 and the conversion of IRAK1 into a variety of more slowly migrating species ( XREF_FIG ) .	The stimulation of IL-1R cells with IL-1 induced the interaction of IRAK4 with IRAK1 and the conversion of IRAK1 into a variety of more slowly migrating species (XREF_FIG).	3	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1R	IL-1R	IL-1R	IRAK1	IRAK1	IRAK1	3	4	18	19
Stimulation of IL-1R and TLR with IL-1beta results in activation of IRAK1 and subsequent recruitment of TRAF6 to IRAK1 complexes .	Stimulation of IL-1R and TLR with IL-1beta results in activation of IRAK1 and subsequent recruitment of TRAF6 to IRAK1 complexes.	0	12	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	IL-1R	IL-1R	IL-1R	IRAK1	IRAK1	IRAK1	2	3	11	12
However , when inflammatory cytokine secretion is high , ( left branch ) , high IL-1R signaling activates the downstream kinase IRAK1 , ultimately resulting in activation of NFkB .	However, when inflammatory cytokine secretion is high, (left branch), high IL-1R signaling activates the downstream kinase IRAK1, ultimately resulting in activation of NFkB.	15	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1R	IL-1R	IL-1R	IRAK1	IRAK1	IRAK1	15	16	21	22
Sumoylation of IL-1R mediates IL1-R associated kinase ( IRAK )-dependent downstream signal activation .	Sumoylation of IL-1R mediates IL1-R associated kinase (IRAK)-dependent downstream signal activation.	0	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1R	Sumoylation of IL-1R	il-1r	IRAK	IRAK	irak	2	3	8	9
Signaling through IL23R induces Janus kinase 2 ( JAK2 ) and tyrosine kinase 2 ( tyk2 ) phosphorylation , which activate STAT3 , leading to the upregulation of RORgammat , and subsequent increases in the inflammatory cytokines IL17 and IL22 .	Signaling through IL23R induces Janus kinase 2 (JAK2) and tyrosine kinase 2 (tyk2) phosphorylation, which activate STAT3, leading to the upregulation of RORgammat, and subsequent increases in the inflammatory cytokines IL17 and IL22.	0	7	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL23R	IL23R	IL23R	Janus kinase 2	Janus kinase 2	Janus kinase 2	2	3	4	7
As we know , IL-23 and IL-23R activated JAK2 and STAT3 to induce Th17 cell differentiation and this pathway contributed to the IBD pathogenesis [ XREF_BIBR - XREF_BIBR ] .	As we know, IL-23 and IL-23R activated JAK2 and STAT3 to induce Th17 cell differentiation and this pathway contributed to the IBD pathogenesis [XREF_BIBR - XREF_BIBR].	4	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-23R	IL-23R	IL-23R	JAK2	JAK2	JAK2	6	7	8	9
This cytokine signals through a heterodimeric receptor composed of IL-12Rbeta1 and IL-23R , which activates Jak2 and Tyk2 , STAT1/STAT3/STAT4/STAT5 .	This cytokine signals through a heterodimeric receptor composed of IL-12Rbeta1 and IL-23R, which activates Jak2 and Tyk2, STAT1/STAT3/STAT4/STAT5.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-23R	IL-23R	IL-23R	Jak2	Jak2	Jak2	11	12	15	16
CD is associated with JAK2 signaling pathway which is activated by IL-23 and IL-23R receptor [ XREF_BIBR ] .	CD is associated with JAK2 signaling pathway which is activated by IL-23 and IL-23R receptor [XREF_BIBR].	4	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-23R	IL-23R	IL-23R	JAK2	JAK2	JAK2	13	14	4	5
The cytokine IL-31 induces the formation of a heterodimer of GPL ( gp130 like receptor ) and OSMR .	The cytokine IL-31 induces the formation of a heterodimer of GPL (gp130 like receptor) and OSMR.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-31	IL-31	IL-31	GPL	GPL	GPL	2	3	10	11
Thus , IL-31 in both human AD and AD like mouse models derives from cutaneous T H 2 cells and may activate IL-31RA on sensory nerves .	Thus, IL-31 in both human AD and AD like mouse models derives from cutaneous T H 2 cells and may activate IL-31RA on sensory nerves.	2	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-31	IL-31	IL-31	IL-31RA	IL-31RA	IL-31RA	2	3	22	23
We report no difference in lymphocyte Th2-type cytokine production after Ag immunization between IL-31RA KO mice , mice treated with the IL-31 mAb , or control animals .	We report no difference in lymphocyte Th2-type cytokine production after Ag immunization between IL-31RA KO mice, mice treated with the IL-31 mAb, or control animals.	13	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-31	IL-31	IL-31	IL-31RA	IL-31RA	IL-31RA	21	22	13	14
We demonstrate that IL-31 induces itch by directly activating IL-31RA on TRPV1 + / TRPA1 + sensory nerves in the skin .	We demonstrate that IL-31 induces itch by directly activating IL-31RA on TRPV1 + / TRPA1 + sensory nerves in the skin.	3	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-31	IL-31	IL-31	IL-31RA	IL-31RA	IL-31RA	3	4	9	10
It has been showed that high concentrations of As +3 significantly inhibited gammac receptor signaling such as IL-2 and IL-6 .	It has been showed that high concentrations of As +3 significantly inhibited gammac receptor signaling such as IL-2 and IL-6.	12	19	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	gammac	gammac	gammac	17	18	12	13
Interleukin-2 ( IL-2 ) induces heterodimerization of the IL-2 receptor beta ( IL-2Rbeta ) and gammac chains of its receptor and activates the Janus family tyrosine kinases , Jak1 and Jak3 .	Interleukin-2 (IL-2) induces heterodimerization of the IL-2 receptor beta (IL-2Rbeta) and gammac chains of its receptor and activates the Janus family tyrosine kinases, Jak1 and Jak3.	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	gammac	gammac	gammac	2	3	15	16
In B cells , IL-21R signaling activates STAT3 to induce the expression of Bcl-6 , a master regulator of the GC response .	In B cells, IL-21R signaling activates STAT3 to induce the expression of Bcl-6, a master regulator of the GC response.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-21R	IL-21R	IL-21R	STAT3	STAT3	STAT3	4	5	7	8
Engagement of the IL-21 receptor activates STAT1 , STAT3 , STAT5a and STAT5b [ XREF_BIBR ] , and in human B cells clearly phosphorylates STAT3 the most sustained , while STAT5 is only weakly and transiently activated [ XREF_BIBR , XREF_BIBR ] .	Engagement of the IL-21 receptor activates STAT1, STAT3, STAT5a and STAT5b [XREF_BIBR], and in human B cells clearly phosphorylates STAT3 the most sustained, while STAT5 is only weakly and transiently activated [XREF_BIBR, XREF_BIBR].	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-21 receptor	IL-21 receptor	IL-21 receptor	STAT3	STAT3	STAT3	3	5	8	9
XREF_BIBR , XREF_BIBR IL-21R signaling induces the activation of Jak1 , Jak3 , STAT1 , STAT3 , STAT5 , PI3K , and mitogen activated protein kinase proteins .	XREF_BIBR, XREF_BIBR IL-21R signaling induces the activation of Jak1, Jak3, STAT1, STAT3, STAT5, PI3K, and mitogen activated protein kinase proteins.	3	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-21R	IL-21R	IL-21R	STAT3	STAT3	STAT3	3	4	15	16
In response to ligand stimulation , IL-2R , IL-15R , and IL-21R activate Jak1 and Jak3 .	In response to ligand stimulation, IL-2R, IL-15R, and IL-21R activate Jak1 and Jak3.	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-21R	IL-21R	IL-21R	Jak3	Jak3	Jak3	11	12	15	16
4 IL-22 signals via the IL-22 receptor that consists of IL-22 receptor A1 ( IL-22RA1 ) and IL-10R2 chains .	4 IL-22 signals via the IL-22 receptor that consists of IL-22 receptor A1 (IL-22RA1) and IL-10R2 chains.	1	18	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-22	IL-22	IL-22	IL-10R2	IL-10R2	IL-10R2	1	2	17	18
Similar to the action of several other cytokines on their receptors , IL-22 upregulated expression of its own receptor ( XREF_FIG ) , specifically the IL-22R1 subunit , but not the IL-10R2 chain shared with several other cytokines .	Similar to the action of several other cytokines on their receptors, IL-22 upregulated expression of its own receptor (XREF_FIG), specifically the IL-22R1 subunit, but not the IL-10R2 chain shared with several other cytokines.	0	32	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-22	IL-22	IL-22	IL-10R2	IL-10R2	IL-10R2	12	13	31	32
The IL-23R , which is composed of the IL-23Ralpha chain and IL-12Rbeta1 , also activates STAT3 and STAT4 [ XREF_BIBR ] .	The IL-23R, which is composed of the IL-23Ralpha chain and IL-12Rbeta1, also activates STAT3 and STAT4 [XREF_BIBR].	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-23R	IL-23R	IL-23R	STAT4	STAT4	STAT4	1	2	17	18
RORgammat does not appear to enhance its own expression , and although it does promote expression of IL-21 , which can act as an autocrine cytokine for STAT3 activation , it also promotes expression of the IL-23 receptor , which though also a STAT3 activator , activates STAT4 that in turn induces T-bet , which directly suppresses RORgammat expression .	RORgammat does not appear to enhance its own expression, and although it does promote expression of IL-21, which can act as an autocrine cytokine for STAT3 activation, it also promotes expression of the IL-23 receptor, which though also a STAT3 activator, activates STAT4 that in turn induces T-bet, which directly suppresses RORgammat expression.	33	51	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-23 receptor	expression of the IL-23 receptor	il-23 receptor	STAT4	STAT4	stat4	36	38	47	48
Of course , the IL23R induces the activation of STAT3 and STAT4 so if heterodimers are generated this might undermine this hypothesis give the pro inflammatory effects of IL-23 , but availability of excess free pSTAT3 induced by IL-23 might be responsible for activating effects of IL-23 .	Of course, the IL23R induces the activation of STAT3 and STAT4 so if heterodimers are generated this might undermine this hypothesis give the pro inflammatory effects of IL-23, but availability of excess free pSTAT3 induced by IL-23 might be responsible for activating effects of IL-23.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL23R	IL23R	IL23R	STAT4	STAT4	STAT4	4	5	11	12
Binding of IL-24 to either of its two possible heterodimeric receptors IL-20R1 and IL-20R2 and IL-22R and IL-20R2 activates STAT3 and/or STAT1 in target tissues such as lung , testis , ovary , keratinocytes and skin .	Binding of IL-24 to either of its two possible heterodimeric receptors IL-20R1 and IL-20R2 and IL-22R and IL-20R2 activates STAT3 and/or STAT1 in target tissues such as lung, testis, ovary, keratinocytes and skin.	10	20	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-20R2	IL-20R2	IL-20R2	STAT3	STAT3	STAT3	17	18	19	20
Much lower ( 0.1 fold TBP ) was the expression of IL-22R followed by even lower amounts of IL-20R1 suggesting that STAT3 activation of cultured keratinocytes is mediated by engagement of the type II receptor IL-22R and IL-20R2 .	Much lower (0.1 fold TBP) was the expression of IL-22R followed by even lower amounts of IL-20R1 suggesting that STAT3 activation of cultured keratinocytes is mediated by engagement of the type II receptor IL-22R and IL-20R2.	21	38	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-20R2	IL-20R2	IL-20R2	STAT3	STAT3	STAT3	37	38	21	22
Interaction of IL1beta with the extracellular domains of IL1RI and IL1RAcP causes juxtaposition of the intracellular Toll-IL-1 receptor domains of IL1RI and IL1RAcP and triggers intracellular signalling XREF_BIBR .	Interaction of IL1beta with the extracellular domains of IL1RI and IL1RAcP causes juxtaposition of the intracellular Toll-IL-1 receptor domains of IL1RI and IL1RAcP and triggers intracellular signalling XREF_BIBR.	0	23	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL1beta	IL1beta	IL1beta	IL1RAcP	IL1RAcP	IL1RAcP	2	3	22	23
IL-1beta increased IL-1beta , IL-1 receptor types I and II ( IL-1RI and IL-1RII ) , IL-1 receptor accessory protein soluble form ( IL-1R AcP II ) , IL-1 receptor antagonist ( IL-1Ra ) , TNF-alpha , and TGF-beta1 mRNAs in the hypothalamus from obese and lean rats .	IL-1beta increased IL-1beta, IL-1 receptor types I and II (IL-1RI and IL-1RII), IL-1 receptor accessory protein soluble form (IL-1R AcP II), IL-1 receptor antagonist (IL-1Ra), TNF-alpha, and TGF-beta1 mRNAs in the hypothalamus from obese and lean rats.	0	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1 receptor accessory protein	IL-1 receptor accessory protein	IL-1 receptor accessory protein	0	1	16	20
Stronger CD122 signaling mediated primarily by IL-2 is required to support T EM cells .	Stronger CD122 signaling mediated primarily by IL-2 is required to support T EM cells.	1	7	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD122	CD122	CD122	6	7	1	2
Interestingly , a subsequent clinical study demonstrated that IL-2 administration did not express significant levels of CD25 but did upregulate CD122 on NK cells .	Interestingly, a subsequent clinical study demonstrated that IL-2 administration did not express significant levels of CD25 but did upregulate CD122 on NK cells.	8	21	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-2	IL-2	IL-2	CD122	CD122	CD122	8	9	20	21
IL-19 activates the type I IL-20 receptor complex ( IL-20R1 and IL-20R2 ) , which is also activated by IL-20 and -24 .	IL-19 activates the type I IL-20 receptor complex (IL-20R1 and IL-20R2), which is also activated by IL-20 and -24.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-19	IL-19	IL-19	IL-20R1	IL-20R1	IL-20R1	0	1	9	10
Our findings indicate that IL-3r activation induces Jak2 activation via tyrosine phosphorylation and that this initial event is followed by tyrosine phosphorylation of PI 3-kinase and Akt serine phosphorylation as suggested by the inhibitory effect of AG-490 on the phosphorylation of both proteins .	Our findings indicate that IL-3r activation induces Jak2 activation via tyrosine phosphorylation and that this initial event is followed by tyrosine phosphorylation of PI 3-kinase and Akt serine phosphorylation as suggested by the inhibitory effect of AG-490 on the phosphorylation of both proteins.	4	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-3r	IL-3r	IL-3r	Jak2	Jak2	Jak2	4	5	7	8
In addition , DHT treatment augmented endogenous STAT3 mediated gene expression by IL-6 .	In addition, DHT treatment augmented endogenous STAT3 mediated gene expression by IL-6.	5	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	7	8
In the present study , we found that IL-6 stimulates cell growth and JAK and STAT3 pathway in PCa cells .	In the present study, we found that IL-6 stimulates cell growth and JAK and STAT3 pathway in PCa cells.	8	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	15	16
Since pSTAT3 is mostly activated by IL-6 stimulation , this indicates that the TLR1/2 agonist , through increase in the expression of IL-6 , plays an important role in immune response function of PBLs .	Since pSTAT3 is mostly activated by IL-6 stimulation, this indicates that the TLR1/2 agonist, through increase in the expression of IL-6, plays an important role in immune response function of PBLs.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	6	7	1	2
Immunocytochemical staining revealed that IL-6 enhanced immunoreactivities for the phosphorylated forms of both JAK2 and signal transducer and activator of transcription 3 ( STAT3 ) , as well as that for PMP22 .	Immunocytochemical staining revealed that IL-6 enhanced immunoreactivities for the phosphorylated forms of both JAK2 and signal transducer and activator of transcription 3 (STAT3), as well as that for PMP22.	4	24	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	23	24
In normal cells , activation of STAT3 by IL-6 is regulated by a negative feedback loop through the activity of suppressor of the cytokine signaling 3 ( SOCS3 ) whose expression can be induced by IL-6 signaling [ XREF_BIBR , XREF_BIBR ] .	In normal cells, activation of STAT3 by IL-6 is regulated by a negative feedback loop through the activity of suppressor of the cytokine signaling 3 (SOCS3) whose expression can be induced by IL-6 signaling [XREF_BIBR, XREF_BIBR].	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	6	7
STAT3 activation by IL-6 in Cal33 cells exhibited a bimodal distribution , with a > = 10 % apparently non responding subpopulation at all concentrations tested ( XREF_FIG ) .	STAT3 activation by IL-6 in Cal33 cells exhibited a bimodal distribution, with a> = 10% apparently non responding subpopulation at all concentrations tested (XREF_FIG).	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	0	1
Similarly , the overexpression of Atg16L1 ( Halo tagged ) in HepG2 cells decreased IL6 induced STAT3 activation .	Similarly, the overexpression of Atg16L1 (Halo tagged) in HepG2 cells decreased IL6 induced STAT3 activation.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	14	15	16	17
Because HIF1 is downstream of STAT3 , IL6 induced STAT3 might thus serve as a central hub for the coordination of gene expression patterns that are involved in inflammation ( HIF1 , Arg1 , Socs3 ) , remodeling ( Arg1 ) , metabolism ( HIF1 ) , proliferation and apoptosis ( Pim1 , Nfatc2 ) , and vascularization ( Vegfa ) .	Because HIF1 is downstream of STAT3, IL6 induced STAT3 might thus serve as a central hub for the coordination of gene expression patterns that are involved in inflammation (HIF1, Arg1, Socs3), remodeling (Arg1), metabolism (HIF1), proliferation and apoptosis (Pim1, Nfatc2), and vascularization (Vegfa).	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	7	8	9	10
Monocyte pSTAT3 fluorescence intensity , promoted by IL-6 , was lower in sepsis and AP patients with OD than in AP patients without OD ( P < 0.001 ) .	Monocyte pSTAT3 fluorescence intensity, promoted by IL-6, was lower in sepsis and AP patients with OD than in AP patients without OD (P < 0.001).	1	8	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	7	8	1	2
A previous report suggests that the Stat3 activity is stimulated by a soluble IL-6 receptor in HTLV-1-transformed T cells [ XREF_BIBR ] .	A previous report suggests that the Stat3 activity is stimulated by a soluble IL-6 receptor in HTLV-1-transformed T cells [XREF_BIBR].	6	14	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	13	14	6	7
Induction of Stat-3 by interleukin-6 has been linked to miR-21 in multiple myeloma cells , and miR-21 is considered an oncogenic miRNA exhibiting antiapoptotic activity in various carcinomas cell lines , suggesting that the inactivation of miR-21 could be therapeutically beneficial toward the treatment of PC .	Induction of Stat-3 by interleukin-6 has been linked to miR-21 in multiple myeloma cells, and miR-21 is considered an oncogenic miRNA exhibiting antiapoptotic activity in various carcinomas cell lines, suggesting that the inactivation of miR-21 could be therapeutically beneficial toward the treatment of PC.	0	5	Induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	Stat-3	Stat-3	Stat-3	4	5	2	3
Interestingly , STAT3 activation by IL-6 appeared biphasic , with peak phosphorylation at 1 and 24 h ( XREF_FIG ) .	Interestingly, STAT3 activation by IL-6 appeared biphasic, with peak phosphorylation at 1 and 24 h (XREF_FIG).	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	2	3
IL-6 commonly activates STAT3 in breast cancer models .	IL-6 commonly activates STAT3 in breast cancer models.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
Both these cytokines were however biologically active , as IL-17F induced IL-6 in stromal cell cultures and IL-21 activated STAT3 in human LPMCs ( not shown ) .	Both these cytokines were however biologically active, as IL-17F induced IL-6 in stromal cell cultures and IL-21 activated STAT3 in human LPMCs (not shown).	9	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-17F induced IL-6	il-6	STAT3	STAT3	stat3	11	12	19	20
In WT mice , IL-6 neutralization only slightly reduced pSTAT3 without affecting fibrin ( XREF_FIG ) indicating that IL-6 induced pSTAT3 is strongly regulated by CYLD , which limits STAT3 activity and STAT3 dependent fibrin production .	In WT mice, IL-6 neutralization only slightly reduced pSTAT3 without affecting fibrin (XREF_FIG) indicating that IL-6 induced pSTAT3 is strongly regulated by CYLD, which limits STAT3 activity and STAT3 dependent fibrin production.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	18	19	20	21
STAT3 and NF-kappaB could be activated by IL-6 to prevent apoptosis and promote proliferation of malignant tumor cells [ XREF_BIBR ] .	STAT3 and NF-kappaB could be activated by IL-6 to prevent apoptosis and promote proliferation of malignant tumor cells [XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	0	1
XREF_BIBR - XREF_BIBR In the absence of SOCS3 , IL-6 causes persistent STAT3 activation that correlates with an anti-inflammatory effect similar to the one induced by IL-10 .	XREF_BIBR - XREF_BIBR In the absence of SOCS3, IL-6 causes persistent STAT3 activation that correlates with an anti-inflammatory effect similar to the one induced by IL-10.	9	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	12	13
The increased IL-6 levels could activate STAT3 in surrounding cells , which would increase production of IL-6 and other cytokines by these cells .	The increased IL-6 levels could activate STAT3 in surrounding cells, which would increase production of IL-6 and other cytokines by these cells.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 levels	il-6	STAT3	STAT3	stat3	2	3	6	7
The present study demonstrates that SFN treatment inhibits constitutive and interleukin-6 ( IL6 )-inducible activation of STAT3 in human prostate cancer cells .	The present study demonstrates that SFN treatment inhibits constitutive and interleukin-6 (IL6)-inducible activation of STAT3 in human prostate cancer cells.	7	21	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	10	11	16	17
These data strongly suggested that , blockage of the IL-6 can inhibit STAT3 activated and repress tumor growth in vivo in select tumor cells .	These data strongly suggested that, blockage of the IL-6 can inhibit STAT3 activated and repress tumor growth in vivo in select tumor cells.	6	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	12	13
IL-6 is elevated in HER2 positive breast cancer where IL-6 activated STAT3 and induced an autocrine loop of IL-6 and STAT3 expression [ XREF_BIBR ] .	IL-6 is elevated in HER2 positive breast cancer where IL-6 activated STAT3 and induced an autocrine loop of IL-6 and STAT3 expression [XREF_BIBR].	9	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	20	21
STAT3 is also activated by IL-6 and its receptors , IL6R and gp130 ( latter encoded by IL6ST ) , have also been implicated in immune mediated disease .	STAT3 is also activated by IL-6 and its receptors, IL6R and gp130 (latter encoded by IL6ST), have also been implicated in immune mediated disease.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
Specific JAK and STAT pathways have been shown to be essential for the differentiation of distinct Th subsets : Th2 differentiation requires activation of the IL-2 and STAT5 and IL-4 and STAT6 signaling pathways , Th1 differentiation depends on IFN-gamma and STAT1 and IL-12 and STAT4 signaling while differentiation of Th17 cells primarily requires STAT3 and STAT4 activated by IL-6 or IL-23 .	Specific JAK and STAT pathways have been shown to be essential for the differentiation of distinct Th subsets : Th2 differentiation requires activation of the IL-2 and STAT5 and IL-4 and STAT6 signaling pathways, Th1 differentiation depends on IFN-gamma and STAT1 and IL-12 and STAT4 signaling while differentiation of Th17 cells primarily requires STAT3 and STAT4 activated by IL-6 or IL-23.	53	61	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	59	60	54	55
Preliminary data from our lab demonstrated that human recombinant IL-6 induces a moderate increase of STAT3 activation , while LIF induces a dramatic activation of STAT3 at early time point ( 15 to 30 min ) .	Preliminary data from our lab demonstrated that human recombinant IL-6 induces a moderate increase of STAT3 activation, while LIF induces a dramatic activation of STAT3 at early time point (15 to 30 min).	7	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	15	16
We found that lupeol also suppressed STAT3 activation induced by IL-6 , one of the many tumour cell growth factors that activate STAT3 .	We found that lupeol also suppressed STAT3 activation induced by IL-6, one of the many tumour cell growth factors that activate STAT3.	8	23	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	22	23
We wanted to see whether activation of STAT-3 by IL-6 or overexpression of STAT-3 by transient transfection increases beta-catenin and TCF -1 signaling .	We wanted to see whether activation of STAT-3 by IL-6 or overexpression of STAT-3 by transient transfection increases beta-catenin and TCF -1 signaling.	3	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	9	10	7	8
Particularly , STAT3 activated by IL-6 has a key role in preventing apoptosis and stimulating growth of multiple myeloma cells .	Particularly, STAT3 activated by IL-6 has a key role in preventing apoptosis and stimulating growth of multiple myeloma cells.	2	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	2	3
IL-6 , which as indicated above activates STAT3 , is also an important negative regulator of Foxp3 [ XREF_BIBR , XREF_BIBR ] .	IL-6, which as indicated above activates STAT3, is also an important negative regulator of Foxp3 [XREF_BIBR, XREF_BIBR].	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	7	8
IL-6 also activated STAT3 , probably by direct phosphorylation of STAT3 by JAK .	IL-6 also activated STAT3, probably by direct phosphorylation of STAT3 by JAK.	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
Hence , more research is needed to establish the effects of EGCG on STAT3 activation , whose overactivity in pathological conditions is mediated by IL-6 trans-signaling through the sIL-6R .	Hence, more research is needed to establish the effects of EGCG on STAT3 activation, whose overactivity in pathological conditions is mediated by IL-6 trans-signaling through the sIL-6R.	13	25	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	13	14
It has been reported recently that HSP27 is key to IL-6 dependent and IL-6 independent EMT in prostate cancer cells , by acting on IL-6 induced activation of STAT3 and Twist and Snail .	It has been reported recently that HSP27 is key to IL-6 dependent and IL-6 independent EMT in prostate cancer cells, by acting on IL-6 induced activation of STAT3 and Twist and Snail.	22	32	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	28	29
We propose that the increase in IL-6 stimulated by CKD and possibly other cytokines , activates p-Stat3 which triggers muscle wasting .	We propose that the increase in IL-6 stimulated by CKD and possibly other cytokines, activates p-Stat3 which triggers muscle wasting.	4	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-Stat3	p-Stat3	p-Stat3	6	7	16	17
Notably , exogenous interleukin-6 neither prevented the inhibition of JAK1 and STAT3 nor the death of MM cells induced by cAMP .	Notably, exogenous interleukin-6 neither prevented the inhibition of JAK1 and STAT3 nor the death of MM cells induced by cAMP.	2	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	3	4	11	12
As alcohol induced liver injury is unaffected by the absence of STAT3 from hepatocytes ( see above ) and IL-6 activates STAT3 in sinusoidal endothelial cells , we hypothesized that hepatoprotection by IL-6 in alcoholic liver injury is mediated via activation of STAT3 in endothelial cells .	As alcohol induced liver injury is unaffected by the absence of STAT3 from hepatocytes (see above) and IL-6 activates STAT3 in sinusoidal endothelial cells, we hypothesized that hepatoprotection by IL-6 in alcoholic liver injury is mediated via activation of STAT3 in endothelial cells.	19	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	21	22
In extra-thyroidal tissues , the HGF and c-met and IL-6 and IL-6 receptor ( IL-6R ) systems activate STAT3 , a member of the signal transducers and activators of transcription ( STATs ) family .	In extra-thyroidal tissues, the HGF and c-met and IL-6 and IL-6 receptor (IL-6R) systems activate STAT3, a member of the signal transducers and activators of transcription (STATs) family.	9	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	18	19
The pursuit of mechanisms involved revealed adenosine and IL-6 dependent activation of STAT-3 in airway epithelial cells .	The pursuit of mechanisms involved revealed adenosine and IL-6 dependent activation of STAT-3 in airway epithelial cells.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	8	9	12	13
The stroma infiltrating immune cells secrete IL-6 that activates STAT3 and triggers progression of PanINs to PDAC .	The stroma infiltrating immune cells secrete IL-6 that activates STAT3 and triggers progression of PanINs to PDAC.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	9	10
The effect of acute ethanol on STAT3 activation has not been reported for CNS tissue , but in other cell types ( i.e ., liver cells , monocytes ) acute ethanol reduces IL-6 activation of STAT3 .	The effect of acute ethanol on STAT3 activation has not been reported for CNS tissue, but in other cell types (i.e., liver cells, monocytes) acute ethanol reduces IL-6 activation of STAT3.	32	36	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	32	33	35	36
Recent investigations suggested a protective role of IL-6 mediated STAT3 signaling in intestinal epithelial cells .	Recent investigations suggested a protective role of IL-6 mediated STAT3 signaling in intestinal epithelial cells.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
Resistance training , for instance , increases satellite cell content and activation status , and stimulates satellite cell proliferation by IL-6 induced activation of STAT3 signaling [ XREF_BIBR , XREF_BIBR ] .	Resistance training, for instance, increases satellite cell content and activation status, and stimulates satellite cell proliferation by IL-6 induced activation of STAT3 signaling [XREF_BIBR, XREF_BIBR].	15	25	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	24	25
RORgammaT mRNA is induced by IL-6 and TGF-beta and is further upregulated by IL-6 and IL-23 activation of STAT3 [ XREF_BIBR ] .	RORgammaT mRNA is induced by IL-6 and TGF-beta and is further upregulated by IL-6 and IL-23 activation of STAT3 [XREF_BIBR].	13	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	18	19
Activation of STAT3 by IL-6 plays a crucial role in inflammation induced disease pathogenesis XREF_BIBR , XREF_BIBR , XREF_BIBR .	Activation of STAT3 by IL-6 plays a crucial role in inflammation induced disease pathogenesis XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	2	3
For example , STAT3 activation initiated by IL-6 in tumor associated endothelial cells , TAM , and MDSC induces their ability to express VEGF and bFGF in a feed-forward loop that positively regulates angiogenesis within tumor tissues [ XREF_BIBR ] .	For example, STAT3 activation initiated by IL-6 in tumor associated endothelial cells, TAM, and MDSC induces their ability to express VEGF and bFGF in a feed-forward loop that positively regulates angiogenesis within tumor tissues [XREF_BIBR].	3	9	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	3	4
IL-6 treatment ( 20 ng/ml ) of NCM460 cells induced STAT3 activation in 12 hours ( XREF_FIG ) .	IL-6 treatment (20 ng/ml) of NCM460 cells induced STAT3 activation in 12 hours (XREF_FIG).	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	10	11
Moreover , knockdown of TRiC in HEPG2 cells reduced their sensitivity to IL-6 induced STAT3 activation .	Moreover, knockdown of TRiC in HEPG2 cells reduced their sensitivity to IL-6 induced STAT3 activation.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	14	15
IL-6 activates its downstream target signal transducer and activator of transcription 3 ( STAT3 ) , which is constitutively active in several malignancies including those of the head and neck [ XREF_BIBR ] .	IL-6 activates its downstream target signal transducer and activator of transcription 3 (STAT3), which is constitutively active in several malignancies including those of the head and neck [XREF_BIBR].	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	13	14
In an earlier study , IL-6 induced p-STAT3 activation in DU-145 and LNCap cells , and Ginkgetin therapy resulted in 31.6 % reduction in the level of p-STAT3 .	In an earlier study, IL-6 induced p-STAT3 activation in DU-145 and LNCap cells, and Ginkgetin therapy resulted in 31.6% reduction in the level of p-STAT3.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	5	6	7	8
For instance , STAT1 is activated by IFNgamma , whilst STAT3 is activated by IL-6 and IL-10 signalling , and STAT5 is activated by GM-CSF or IL-2 XREF_BIBR .	For instance, STAT1 is activated by IFNgamma, whilst STAT3 is activated by IL-6 and IL-10 signalling, and STAT5 is activated by GM-CSF or IL-2 XREF_BIBR.	10	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	10	11
Since STAT3 is activated by either IL-6 or IL-21 , deficiency of one these cytokine may be sufficient to prevent STAT3 activation and , thereby , lead to hyper IgE production .	Since STAT3 is activated by either IL-6 or IL-21, deficiency of one these cytokine may be sufficient to prevent STAT3 activation and, thereby, lead to hyper IgE production.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	1	2
TKIs have also proved to induce expression of IL-6 , which activates the JAK1 and STAT3 signaling pathway through the IL-6 receptor ( IL-6R ) , leading to increased survival .	TKIs have also proved to induce expression of IL-6, which activates the JAK1 and STAT3 signaling pathway through the IL-6 receptor (IL-6R), leading to increased survival.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	expression of IL-6	il-6	STAT3	STAT3	stat3	8	9	15	16
Moreover , we examined whether enhanced IL-6 by TrkC actually activates the JAK2 and STAT3 pathway .	Moreover, we examined whether enhanced IL-6 by TrkC actually activates the JAK2 and STAT3 pathway.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	14	15
While other cytokines such as IL-11 and G-CSF are known to activate pulmonary STAT3 in response to insults our studies indicate a role for IL-6 activation of STAT3 in the setting of burn and ethanol exposure .	While other cytokines such as IL-11 and G-CSF are known to activate pulmonary STAT3 in response to insults our studies indicate a role for IL-6 activation of STAT3 in the setting of burn and ethanol exposure.	24	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	27	28
We showed that sanguinarine inhibited cell motility in DU145 cells expressing constitutively activated Stat3 and LN-s17 cells expressing activated Stat3 induced by IL-6 .	We showed that sanguinarine inhibited cell motility in DU145 cells expressing constitutively activated Stat3 and LN-s17 cells expressing activated Stat3 induced by IL-6.	17	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	22	23	19	20
No decrease in social interaction and no activation of STAT3 were developed in IL-6 deficient mice , suggesting that IL-6 activation of STAT3 is positively linked to LPS effect on social interaction .	No decrease in social interaction and no activation of STAT3 were developed in IL-6 deficient mice, suggesting that IL-6 activation of STAT3 is positively linked to LPS effect on social interaction.	19	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	22	23
Interleukin-6 ( IL-6 ) initiates STAT3 signaling in plasma membrane rafts with the subsequent transit of Tyr phosphorylated STAT3 ( PY-STAT3 ) through the cytoplasmic compartment to the nucleus in association with accessory proteins .	Interleukin-6 (IL-6) initiates STAT3 signaling in plasma membrane rafts with the subsequent transit of Tyr phosphorylated STAT3 (PY-STAT3) through the cytoplasmic compartment to the nucleus in association with accessory proteins.	0	6	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	5	6
IL-6 activates Stat1 and Stat3 .	IL-6 activates Stat1 and Stat3.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	4	5
31 To further investigate the role of classic and trans-signalling in epithelial wound healing in vitro , we assessed the effect of IL-6 and hIL-6 in an epithelial scratch assay in HT29 cells 32 using IL-6 and hIL-6 concentrations , which were able to induce STAT3 in a robust manner .	31 To further investigate the role of classic and trans-signalling in epithelial wound healing in vitro, we assessed the effect of IL-6 and hIL-6 in an epithelial scratch assay in HT29 cells 32 using IL-6 and hIL-6 concentrations, which were able to induce STAT3 in a robust manner.	35	46	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	35	36	45	46
Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma .	Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma.	3	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	5	6
Subsequently , IL-6 promotes an abnormal proliferation of the hepatocytes by triggering the signal transducer and activator of transcription 3 ( STAT-3 ) and ERK pathways , which in turn control target genes involved in both cell proliferation and survival , thus contributing to HCC progression .	Subsequently, IL-6 promotes an abnormal proliferation of the hepatocytes by triggering the signal transducer and activator of transcription 3 (STAT-3) and ERK pathways, which in turn control target genes involved in both cell proliferation and survival, thus contributing to HCC progression.	2	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	2	3	21	22
We propose that downregulation of HOXA10 in the decidual cells promotes the expression of LIF and IL-6 , which , in a paracrine manner , activates STAT3 in the trophoblast cells , leading to an increase in MMPs to facilitate invasion .	We propose that downregulation of HOXA10 in the decidual cells promotes the expression of LIF and IL-6, which, in a paracrine manner, activates STAT3 in the trophoblast cells, leading to an increase in MMPs to facilitate invasion.	5	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	HOXA10 in the decidual cells promotes the expression of LIF and IL-6	il-6	STAT3	STAT3	stat3	16	17	26	27
IL-6 activates STAT3 and is important in the acute phase response to injury .	IL-6 activates STAT3 and is important in the acute phase response to injury.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
The inhibition of JAK predictably blocked IL-6 induced activation of STAT3 , but failed to block the activation of MAPK erk1/2 , and unexpectedly enhanced MMP-9 expression .	The inhibition of JAK predictably blocked IL-6 induced activation of STAT3, but failed to block the activation of MAPK erk1/2, and unexpectedly enhanced MMP-9 expression.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	10	11
Despite that STAT3 activation by IL-6 has been considered detrimental in intestinal inflammation XREF_BIBR , our study showed that STAT3 activation by IL-22 seems beneficial , preventing overproduction of inflammatory chemokine-CCL20 .	Despite that STAT3 activation by IL-6 has been considered detrimental in intestinal inflammation XREF_BIBR, our study showed that STAT3 activation by IL-22 seems beneficial, preventing overproduction of inflammatory chemokine-CCL20.	2	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	2	3
IL-6 mediated activation of STAT-3 has been implicated in several diseases XREF_BIBR , XREF_BIBR , XREF_BIBR ; however , little is known about the ability of adenosine to activate this pathway in the context of chronic lung disease .	IL-6 mediated activation of STAT-3 has been implicated in several diseases XREF_BIBR, XREF_BIBR, XREF_BIBR; however, little is known about the ability of adenosine to activate this pathway in the context of chronic lung disease.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	0	1	4	5
Treatment of the PC14PE6 and AS2 cells with AG490 resulted in inhibition of the phosphorylated JAK2 and Stat3 induced by autocrine IL-6 ( XREF_FIG ) .	Treatment of the PC14PE6 and AS2 cells with AG490 resulted in inhibition of the phosphorylated JAK2 and Stat3 induced by autocrine IL-6 (XREF_FIG).	11	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	21	22	17	18
The effect of Nef induced IL-6 in immDCs was verified to find out whether IL-6 release in response to activation by Nef , is able to induce STAT3 .	The effect of Nef induced IL-6 in immDCs was verified to find out whether IL-6 release in response to activation by Nef, is able to induce STAT3.	14	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	27	28
STAT3 activation by IL-6 has been shown to result in the activation of JAK leading to induction of Th17 response .	STAT3 activation by IL-6 has been shown to result in the activation of JAK leading to induction of Th17 response.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	0	1
We have previously demonstrated that IL-6 is abundantly present in WF [ XREF_BIBR ] and it is known that IL-6 triggers many of the STAT3 related phenotypes [ XREF_BIBR , XREF_BIBR ] .	We have previously demonstrated that IL-6 is abundantly present in WF [XREF_BIBR] and it is known that IL-6 triggers many of the STAT3 related phenotypes [XREF_BIBR, XREF_BIBR].	19	26	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	24	25
These results reveal that endogenous IL-6 release from MSCs activated IL-6R and STAT3 but had no effect on the downstream factors Bax and Bcl-2 .	These results reveal that endogenous IL-6 release from MSCs activated IL-6R and STAT3 but had no effect on the downstream factors Bax and Bcl-2.	5	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	12	13
This has important potential consequences in modulating a tumor promoting microenvironment , as IL-6 activate the STAT3 transcription factor in epithelial , myeloid cells , and myofibroblasts , promoting CRC tumorigenesis .	This has important potential consequences in modulating a tumor promoting microenvironment, as IL-6 activate the STAT3 transcription factor in epithelial, myeloid cells, and myofibroblasts, promoting CRC tumorigenesis.	13	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	16	17
XREF_BIBR - XREF_BIBR The levels of IL-6 typically found in the serum of cancer patients is within the picogram range ( 100-500 pg/ml ) , at which there is very little evidence in vitro that IL-6 activates STAT-3 .	XREF_BIBR - XREF_BIBR The levels of IL-6 typically found in the serum of cancer patients is within the picogram range (100-500 pg/ml), at which there is very little evidence in vitro that IL-6 activates STAT-3.	35	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	35	36	37	38
OvMSCs secreted IL-6 activated STAT3 in SKOV3 cells .	OvMSCs secreted IL-6 activated STAT3 in SKOV3 cells.	1	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
One consequence of this lower production of IL-6 can be reduced IL-6 and STAT3 signaling , which is required for the differentiation of IL-17 producing CD4 positive T lymphocytes .	One consequence of this lower production of IL-6 can be reduced IL-6 and STAT3 signaling, which is required for the differentiation of IL-17 producing CD4 positive T lymphocytes.	5	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	13	14
The results suggested that IL6 induced p-STAT3 activation is associated with the upregulation of the EMT marker vimentin in both HCT116 and HT29 cells ( XREF_FIG ) .	The results suggested that IL6 induced p-STAT3 activation is associated with the upregulation of the EMT marker vimentin in both HCT116 and HT29 cells (XREF_FIG).	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	p-STAT3	p-STAT3	p-STAT3	4	5	6	7
In lung cancer cell lines , CCL2 and IL-6 synergistically induce EMT in a Twist and STAT3 dependent fashion ( Chen etal ., 2015b ) .	In lung cancer cell lines, CCL2 and IL-6 synergistically induce EMT in a Twist and STAT3 dependent fashion (Chen etal., 2015b).	6	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	16	17
Inflammatory cytokines IL-1 and IL-6 also modulate pro oncogenic transcription factor STAT3 , thereby increasing survival , proliferation , angiogenesis , invasion , and metastasis of cancer cells [ XREF_BIBR ] .	Inflammatory cytokines IL-1 and IL-6 also modulate pro oncogenic transcription factor STAT3, thereby increasing survival, proliferation, angiogenesis, invasion, and metastasis of cancer cells [XREF_BIBR].	2	12	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	11	12
Regarding murine CXCR5 , it is feasible that IL6 driven STAT3 ( and STAT1 ) binds at the CXCR5 promoter in conjunction with Maf and Batf and drives CXCR5 expression in an E protein dependent manner .	Regarding murine CXCR5, it is feasible that IL6 driven STAT3 (and STAT1) binds at the CXCR5 promoter in conjunction with Maf and Batf and drives CXCR5 expression in an E protein dependent manner.	8	15	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	8	9	10	11
IL-6 is a prominent activator of STAT3 which plays a central role in cardiac physiology and pathophysiology [ XREF_BIBR ] .	IL-6 is a prominent activator of STAT3 which plays a central role in cardiac physiology and pathophysiology [XREF_BIBR].	0	7	is a prominent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
In cardiac myocytes and thyrocytes , IL-6 activated STAT3 can increase Wnt5a .	In cardiac myocytes and thyrocytes, IL-6 activated STAT3 can increase Wnt5a.	6	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
Previous researches have shown that endogenous HA fragments induced IL-6 production via a CD44 independent mechanism in bone marrow cells 21 , and IL-6 activated Stat3 pathway in various cancers XREF_BIBR , XREF_BIBR , XREF_BIBR .	Previous researches have shown that endogenous HA fragments induced IL-6 production via a CD44 independent mechanism in bone marrow cells 21, and IL-6 activated Stat3 pathway in various cancers XREF_BIBR, XREF_BIBR, XREF_BIBR.	23	26	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	23	24	25	26
TNF-alpha upregulates IL-6 via the signal transduction factor NF-kB , and IL-6 activates STAT3 .	TNF-alpha upregulates IL-6 via the signal transduction factor NF-kB, and IL-6 activates STAT3.	11	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	13	14
To further elucidate and confirm that IL-6 activation of Stat3 was mediated by an IL-6-IL6R-IL6ST signaling complex via JAK kinases , we stably expressed a mutant IL6ST receptor and inhibited JAK1 expression in 3T3-HER2 Stat3-luciferase cells ( XREF_SUPPLEMENTARY ) .	To further elucidate and confirm that IL-6 activation of Stat3 was mediated by an IL-6-IL6R-IL6ST signaling complex via JAK kinases, we stably expressed a mutant IL6ST receptor and inhibited JAK1 expression in 3T3-HER2 Stat3-luciferase cells (XREF_SUPPLEMENTARY).	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	9	10
STAT3 was originally described as an acute-phase response factor ( APRF ) induced by IL-6 [ XREF_BIBR , XREF_BIBR ] , and many cytokines produced by innate and adaptive immune cells including IL-10 , IL-21 , IL-23 , and IL-27 have now been shown to induce STAT3 activation [ XREF_BIBR ] .	STAT3 was originally described as an acute-phase response factor (APRF) induced by IL-6 [XREF_BIBR, XREF_BIBR], and many cytokines produced by innate and adaptive immune cells including IL-10, IL-21, IL-23, and IL-27 have now been shown to induce STAT3 activation [XREF_BIBR].	6	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	acute-phase response factor	acute-phase response factor	acute-phase response factor	14	15	6	9
STAT3 , activated by IL-6 and IL-23 , has a critical role in Th17 development [ XREF_BIBR , XREF_BIBR ] .	STAT3, activated by IL-6 and IL-23, has a critical role in Th17 development [XREF_BIBR, XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
IL-6 can directly activate STAT-3 through the JAK and STAT pathway .	IL-6 can directly activate STAT-3 through the JAK and STAT pathway.	0	5	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	0	1	4	5
Importantly , the physical association of SOCS3 and MAP1S has been shown to be necessary for the functional attenuation of STAT3 activation induced by IL-6 in macrophages XREF_BIBR .	Importantly, the physical association of SOCS3 and MAP1S has been shown to be necessary for the functional attenuation of STAT3 activation induced by IL-6 in macrophages XREF_BIBR.	20	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	20	21
Interestingly , IL-6 is known to induce the differentiation of the STAT3 dependent Th17 lineage from naive T cells XREF_BIBR - XREF_BIBR and inhibit FOXP3 expression XREF_BIBR , XREF_BIBR .	Interestingly, IL-6 is known to induce the differentiation of the STAT3 dependent Th17 lineage from naive T cells XREF_BIBR - XREF_BIBR and inhibit FOXP3 expression XREF_BIBR, XREF_BIBR.	2	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	11	12
Interestingly , STAT3 is also activated by the cytokines IL-6 and IL-10 , which antagonize anti-microbial effector function and thereby enhance the growth of the intracellular pathogens T. gondii , Mycobacterium , and Leishmania .	Interestingly, STAT3 is also activated by the cytokines IL-6 and IL-10, which antagonize anti-microbial effector function and thereby enhance the growth of the intracellular pathogens T. gondii, Mycobacterium, and Leishmania.	2	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	2	3
In the present study , we further explored whether VDUP1 affected JNK or STAT-3 activation mediated by TNF-alpha or IL-6 .	In the present study, we further explored whether VDUP1 affected JNK or STAT-3 activation mediated by TNF-alpha or IL-6.	11	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	19	20	13	14
They affected cellular responses to various cytokines , including IFN-alpha and beta , IFN-gamma , and IL-27 , which predominantly activate STAT1 over STAT3 , and IL-6 and IL-21 , which predominantly activate STAT3 over STAT1 .	They affected cellular responses to various cytokines, including IFN-alpha and beta, IFN-gamma, and IL-27, which predominantly activate STAT1 over STAT3, and IL-6 and IL-21, which predominantly activate STAT3 over STAT1.	9	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	33	34
IFN-gamma and IL-6 could both activate STAT1 and STAT3 , but fewer STAT1 * and STAT3 * molecules were sequestered by STAT1/3 heterodimers , so its transcriptional activation function was repressed .	IFN-gamma and IL-6 could both activate STAT1 and STAT3, but fewer STAT1 * and STAT3 * molecules were sequestered by STAT1/3 heterodimers, so its transcriptional activation function was repressed.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
Additionally , IL-6 administration to cultured myotubes increased STAT3 activation and suppressed MFN-2 in a dose dependent manner [ XREF_BIBR ] .	Additionally, IL-6 administration to cultured myotubes increased STAT3 activation and suppressed MFN-2 in a dose dependent manner [XREF_BIBR].	2	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
We suggested that the IL6 produced by STAT3 activity could further stimulate STAT3 related pathways , resulting in an aggravating effect on inflammatory responses in diabetic nephropathy XREF_BIBR .	We suggested that the IL6 produced by STAT3 activity could further stimulate STAT3 related pathways, resulting in an aggravating effect on inflammatory responses in diabetic nephropathy XREF_BIBR.	3	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	4	5	12	13
Nguyen and colleagues demonstrated that when chronic inflammation is present , increased IL-6 expression leads to persistent activation of intestinal epithelial STAT3 , which regulates S1P production through SphK1 [ XREF_BIBR ] ( XREF_FIG ) .	Nguyen and colleagues demonstrated that when chronic inflammation is present, increased IL-6 expression leads to persistent activation of intestinal epithelial STAT3, which regulates S1P production through SphK1 [XREF_BIBR] (XREF_FIG).	12	24	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6 expression	il-6	STAT3	STAT3	stat3	12	13	21	22
In the lung , the concentration of IL-6 was increased , which aberrantly activated oncogenic Stat3 and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells .	In the lung, the concentration of IL-6 was increased, which aberrantly activated oncogenic Stat3 and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells.	5	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	7	8	15	16
On the other hand , IL-6 ( an inducer of vascular smooth muscle cells [ VSMC ] proliferation and release of leukocyte chemoattractants ) , has been shown to partially activate the JAK and STAT3 pathway [ XREF_BIBR ] .	On the other hand, IL-6 (an inducer of vascular smooth muscle cells [VSMC] proliferation and release of leukocyte chemoattractants), has been shown to partially activate the JAK and STAT3 pathway [XREF_BIBR].	5	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	34	35
Therefore , therapeutic targeting of PSCs and/or IL-6 may provide a novel approach for anti-fibrotic and anti-neoplastic therapy , which could suppress IL-6 induced STAT3 activation and contribute to reduced invasiveness and tumorigenicity of PDAC .	Therefore, therapeutic targeting of PSCs and/or IL-6 may provide a novel approach for anti-fibrotic and anti-neoplastic therapy, which could suppress IL-6 induced STAT3 activation and contribute to reduced invasiveness and tumorigenicity of PDAC.	21	25	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	24	25
Surprisingly , IL-6 still initiates significant STAT3 movement into the nucleus when trafficking along the endocytic pathway is inhibited by 15 degreesC temperature restriction and NH 4 Cl treatment .	Surprisingly, IL-6 still initiates significant STAT3 movement into the nucleus when trafficking along the endocytic pathway is inhibited by 15 degreesC temperature restriction and NH 4 Cl treatment.	2	7	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	6	7
It is believed that IL-6 induction of transient STAT3 activation is responsible for its pro inflammatory response , while IL-10 induces prolonged STAT3 activation and subsequently inhibits inflammatory responses in macrophages XREF_BIBR .	It is believed that IL-6 induction of transient STAT3 activation is responsible for its pro inflammatory response, while IL-10 induces prolonged STAT3 activation and subsequently inhibits inflammatory responses in macrophages XREF_BIBR.	4	9	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	8	9
We have previously demonstrated that the organ sparing effect of IL-6 administration in our T/HS model is mediated by Stat3 activation within parenchymal cells , i.e. hepatocytes , cardiomyocytes , and alveolar epithelial cells of the liver , hear , and lung , respectively .	We have previously demonstrated that the organ sparing effect of IL-6 administration in our T/HS model is mediated by Stat3 activation within parenchymal cells, i.e. hepatocytes, cardiomyocytes, and alveolar epithelial cells of the liver, hear, and lung, respectively.	10	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	10	11	19	20
IL-6 and epidermal growth factor upregulate STAT3 by phosphorylation .	IL-6 and epidermal growth factor upregulate STAT3 by phosphorylation.	0	7	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
Prostate cancer cells expressing autocrine IL-6 are resistant to enzalutamide and autocrine IL-6 leads to constitutive activation of Stat3 and its target genes .	Prostate cancer cells expressing autocrine IL-6 are resistant to enzalutamide and autocrine IL-6 leads to constitutive activation of Stat3 and its target genes.	11	22	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	12	13	18	19
This increase in IL-6 production could then further stimulate the Stat3 pathway resulting in a vicious cycle of escalating inflammation and inflammatory response in the diabetic milieu .	This increase in IL-6 production could then further stimulate the Stat3 pathway resulting in a vicious cycle of escalating inflammation and inflammatory response in the diabetic milieu.	3	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	10	11
IL-6 activates STAT3 and promotes compensatory proliferation in hepatocytes that escaped cell death , subsequently promoting tumor development .	IL-6 activates STAT3 and promotes compensatory proliferation in hepatocytes that escaped cell death, subsequently promoting tumor development.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Finally , tyrosine motifs in gp130 are also crucial for recruitment of the feedback inhibitor SOCS3 ( suppressor of cytokine signaling 3 ) , which modulate IL-6 signaling via Jak inactivation and inhibition of STAT3 and gp130 contact XREF_BIBR .	Finally, tyrosine motifs in gp130 are also crucial for recruitment of the feedback inhibitor SOCS3 (suppressor of cytokine signaling 3), which modulate IL-6 signaling via Jak inactivation and inhibition of STAT3 and gp130 contact XREF_BIBR.	26	38	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	34	35
4 LIF is a cytokine from the IL-6 family , which acts through the LIFR and gp130 receptor and activates STAT3 transcription factor at Tyr 705 that provides activation of pluripotency genes expression and downregulation of such differentiation markers as Gata3 , Gata4 , T/brachyury and Eomes .	4 LIF is a cytokine from the IL-6 family, which acts through the LIFR and gp130 receptor and activates STAT3 transcription factor at Tyr 705 that provides activation of pluripotency genes expression and downregulation of such differentiation markers as Gata3, Gata4, T/brachyury and Eomes.	7	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	20	21
Taken together these results indicate that the ability of flavone to induce SOCS3 expression and inhibit IL-6 promoted STAT3 activation occurs independently of elevations in intracellular cAMP in HUVECs .	Taken together these results indicate that the ability of flavone to induce SOCS3 expression and inhibit IL-6 promoted STAT3 activation occurs independently of elevations in intracellular cAMP in HUVECs.	16	19	promoted	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	18	19
IL-6 and to a lesser extent IL-21 activate STAT3 to interfere with IL-2 production .	IL-6 and to a lesser extent IL-21 activate STAT3 to interfere with IL-2 production.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	8	9
In addition , LIF and IL-6 mediated STAT3 dependent regulation of the Oct4-NANOG circuitry has been shown to be necessary to maintain the pluripotent inner cell mass , the source of embryonic stem cells [ XREF_BIBR ] .	In addition, LIF and IL-6 mediated STAT3 dependent regulation of the Oct4-NANOG circuitry has been shown to be necessary to maintain the pluripotent inner cell mass, the source of embryonic stem cells [XREF_BIBR].	3	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
Autocrine IL-6 constitutively activates Stat3 pathway and enhances androgen receptor transactivation in prostate cancer cells .	Autocrine IL-6 constitutively activates Stat3 pathway and enhances androgen receptor transactivation in prostate cancer cells.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	4	5
These data indicate that the constitutive Stat3 activation in the investigated AML blasts is caused by high IL-6 secretion levels , thus stimulating the Jak and Stat pathway in an autocrine manner , a paracrine manner , or both .	These data indicate that the constitutive Stat3 activation in the investigated AML blasts is caused by high IL-6 secretion levels, thus stimulating the Jak and Stat pathway in an autocrine manner, a paracrine manner, or both.	6	20	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6 secretion levels	il-6	Stat3	Stat3	stat3	17	18	6	7
The cytokines , such as IL-10 , IL-21 , IL-22 , IL-23 , and IL-6 , activate STAT3 and , in addition to IL-13 , are also regulated through STAT3 .	The cytokines, such as IL-10, IL-21, IL-22, IL-23, and IL-6, activate STAT3 and, in addition to IL-13, are also regulated through STAT3.	1	23	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	17	18
It is well known that IL-6 activates the signal transducers and activators of transcription ( stat ) 1 and stat3 heterodimer , stat3 homodimer , and Ras dependent mitogen activated protein kinase ( MAPK ) cascades in multiple cell systems .	It is well known that IL-6 activates the signal transducers and activators of transcription (stat) 1 and stat3 heterodimer, stat3 homodimer, and Ras dependent mitogen activated protein kinase (MAPK) cascades in multiple cell systems.	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	stat3	stat3	stat3	5	6	19	20
FN-beta1 integrin signal was also found to synergistically enhance STAT3 activation induced by EGF and IL-6 in breast or other cancer cells [ XREF_BIBR , XREF_BIBR ] .	FN-beta1 integrin signal was also found to synergistically enhance STAT3 activation induced by EGF and IL-6 in breast or other cancer cells [XREF_BIBR, XREF_BIBR].	9	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	9	10
Similar with the study showing that NOX4 dependent ROS generation contributes to hypoxia induced IL-6 production in renal cell carcinoma cells [ XREF_BIBR ] , in the present study , we found that NOX4 could enhance IL-6 expression and stimulate its downstream JAK and STAT3 signaling in NSCLC cells through stimulation of PI3K and Akt pathway .	Similar with the study showing that NOX4 dependent ROS generation contributes to hypoxia induced IL-6 production in renal cell carcinoma cells [XREF_BIBR], in the present study, we found that NOX4 could enhance IL-6 expression and stimulate its downstream JAK and STAT3 signaling in NSCLC cells through stimulation of PI3K and Akt pathway.	33	45	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	NOX4 could enhance IL-6 expression	il-6	STAT3	STAT3	stat3	36	37	44	45
XREF_BIBR Antrocin , a sesquiterpene lactone isolated from A. camphorata , a medicinal mushroom , considerably inhibited interleukin 6 induced activation of STAT3 , constitutive activation of STAT-3 , and its nuclear accumulation .	XREF_BIBR Antrocin, a sesquiterpene lactone isolated from A. camphorata, a medicinal mushroom, considerably inhibited interleukin 6 induced activation of STAT3, constitutive activation of STAT-3, and its nuclear accumulation.	17	23	induced	Positive_early_activation	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	STAT3	STAT3	STAT3	17	19	22	23
These results are consistent with the reports on the preferential activation of Stat3 by IL-6 and the increase in IL-6 gene expression in slow muscles during exercise [ XREF_BIBR - XREF_BIBR ] and suggest that elevated levels of IL-6 protein could contribute to the increase in p-Stat3 signaling in the soleus , while presumably other upstream factors promote increase p-Stat3 in the TA muscles of VDR -/- mice .	These results are consistent with the reports on the preferential activation of Stat3 by IL-6 and the increase in IL-6 gene expression in slow muscles during exercise [XREF_BIBR - XREF_BIBR] and suggest that elevated levels of IL-6 protein could contribute to the increase in p-Stat3 signaling in the soleus, while presumably other upstream factors promote increase p-Stat3 in the TA muscles of VDR -/- mice.	3	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	14	15	12	13
The combination of IL-6 and sIL-6R was used to promote optimal STAT-3 activation .	The combination of IL-6 and sIL-6R was used to promote optimal STAT-3 activation.	1	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	3	4	11	12
IL-6 type cytokines activate transcription factor signal transducer and activator of transcription 3 ( STAT3 ) , which has a key role in inflammation and the innate immune response .	IL-6 type cytokines activate transcription factor signal transducer and activator of transcription 3 (STAT3), which has a key role in inflammation and the innate immune response.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	14	15
However , IL-6 activation of the transcription factor STAT3 in pre-cancerous IECs not only enhances their survival but also promotes tumor proliferation .	However, IL-6 activation of the transcription factor STAT3 in pre-cancerous IECs not only enhances their survival but also promotes tumor proliferation.	2	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
These results suggested that STAT3 activated by IL-6 contributes to the migration of and invasion by MKN1 and MKN7 cells .	These results suggested that STAT3 activated by IL-6 contributes to the migration of and invasion by MKN1 and MKN7 cells.	4	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	4	5
Taken together , these data suggest that the activation of STAT3 driven by maternal IL-6 in response to MIA is responsible for the observed elevation in PLP-K expression .	Taken together, these data suggest that the activation of STAT3 driven by maternal IL-6 in response to MIA is responsible for the observed elevation in PLP-K expression.	8	16	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	10	11
XREF_BIBR In a mouse model with the mutant Kras gene , STAT3 signaling activated by IL-6 promotes pancreatic cancer cell metastasis and mediates pancreatic ductal adenocarcinoma development .	XREF_BIBR In a mouse model with the mutant Kras gene, STAT3 signaling activated by IL-6 promotes pancreatic cancer cell metastasis and mediates pancreatic ductal adenocarcinoma development.	11	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	11	12
IL-23 and IL-6 activate STAT3 signaling , now considered necessary and unique for T H 17 differentiation [ XREF_BIBR ] .	IL-23 and IL-6 activate STAT3 signaling, now considered necessary and unique for T H 17 differentiation [XREF_BIBR].	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
In addition , IL6 activated STAT3 can be negatively regulated by SOCS3 that inhibits JAK activation by binding to gp130 through its SH2 domain .	In addition, IL6 activated STAT3 can be negatively regulated by SOCS3 that inhibits JAK activation by binding to gp130 through its SH2 domain.	3	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	3	4	5	6
In serum deprived HepG2 cells , STAT3 is not activated and addition of IL-6 for 15 min caused the accumulation of P-STAT3 in the nucleus ( XREF_FIG ) .	In serum deprived HepG2 cells, STAT3 is not activated and addition of IL-6 for 15 min caused the accumulation of P-STAT3 in the nucleus (XREF_FIG).	11	22	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	P-STAT3	P-STAT3	P-STAT3	13	14	21	22
In addition , C. burnetii stimulated gene networks organized around the IL-6 and IL-13 pathways , which both modulate STAT3 .	In addition, C. burnetii stimulated gene networks organized around the IL-6 and IL-13 pathways, which both modulate STAT3.	11	20	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	19	20
Since in contrast to IL-10 , STAT3 activation by IL-6 is negatively regulated by the suppressor of cytokine signaling 3 ( SOCS3 ) , a member of the family of SH2 containing E3 ligases , this lack of effectiveness could be related to the observed SOCS3 up-regulation in obese adipose tissue ( XREF_FIG ) .	Since in contrast to IL-10, STAT3 activation by IL-6 is negatively regulated by the suppressor of cytokine signaling 3 (SOCS3), a member of the family of SH2 containing E3 ligases, this lack of effectiveness could be related to the observed SOCS3 up-regulation in obese adipose tissue (XREF_FIG).	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	6	7
Stat3 signaling in MDSCs may also be potentially modulated by IL-6 [ XREF_BIBR , XREF_BIBR ] .	Stat3 signaling in MDSCs may also be potentially modulated by IL-6 [XREF_BIBR, XREF_BIBR].	0	14	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	10	11	0	1
The interleukin-6 ( IL-6 ) receptor is well known to interact with STAT3 and mediates STAT3 dependent signaling events in a broad range of cell types .	The interleukin-6 (IL-6) receptor is well known to interact with STAT3 and mediates STAT3 dependent signaling events in a broad range of cell types.	1	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	1	2	15	16
In this work , the ectopic expression of IL-6 in MCF7 cells activated the JAK2 and STAT3 pathway and Twist , leading to the acquisition of mesenchymal markers and properties .	In this work, the ectopic expression of IL-6 in MCF7 cells activated the JAK2 and STAT3 pathway and Twist, leading to the acquisition of mesenchymal markers and properties.	6	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	expression of IL-6	il-6	STAT3	STAT3	stat3	8	9	16	17
Since both IL-21 and IL-6 activate Stat3 , TGF-beta1 combined with IL-21 exhibits similar effect to TGF-beta1 and IL-6 with respect to Th17 cell differentiation [ XREF_BIBR , XREF_BIBR ] .	Since both IL-21 and IL-6 activate Stat3, TGF-beta1 combined with IL-21 exhibits similar effect to TGF-beta1 and IL-6 with respect to Th17 cell differentiation [XREF_BIBR, XREF_BIBR].	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	6	7
Taken together , it is suggested that IL-6 trans-signaling initiated by Ang II could activate STAT3 in podocytes in a TRPC6 dependent manner which consequently affect the differentiation , cell cycle , and other physiopathologic processes of podocytes .	Taken together, it is suggested that IL-6 trans-signaling initiated by Ang II could activate STAT3 in podocytes in a TRPC6 dependent manner which consequently affect the differentiation, cell cycle, and other physiopathologic processes of podocytes.	7	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	15	16
We demonstrated that LY5 inhibited constitutive Interleukin-6 ( IL-6 )-induced STAT3 phosphorylation , STAT3 nuclear translocation , decreased STAT3 downstream targeted gene expression and induced apoptosis in liver and colon cancer cells .	We demonstrated that LY5 inhibited constitutive Interleukin-6 (IL-6)-induced STAT3 phosphorylation, STAT3 nuclear translocation, decreased STAT3 downstream targeted gene expression and induced apoptosis in liver and colon cancer cells.	6	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Interleukin-6	Interleukin-6 (IL-6)-induced STAT3 phosphorylation	interleukin-6	STAT3	STAT3	stat3	6	7	18	19
Binding of IL-6 to its receptor activates Stat3 .	Binding of IL-6 to its receptor activates Stat3.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	7	8
Stat3 was activated by IL-6 in Capan-2 cells ; protein expression of p-Stat3 was increased significantly in Capan-2 cells .	Stat3 was activated by IL-6 in Capan-2 cells; protein expression of p-Stat3 was increased significantly in Capan-2 cells.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	0	1
IL-6 is well known to activate STAT3 by phosphorylation at Y705 [ XREF_BIBR ] .	IL-6 is well known to activate STAT3 by phosphorylation at Y705 [XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
In gastric epithelial cells IL-11 , not IL-6 triggers STAT3 signalling and REG3gamma induction .	In gastric epithelial cells IL-11, not IL-6 triggers STAT3 signalling and REG3gamma induction.	6	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
The IL6 mediated activation of STAT3 conferred partial but marked protection against SFN induced apoptosis as evidenced by cytoplasmic histone associated DNA fragmentation and cleavage of poly-( ADP-ribose )-polymerase and procaspase-3 .	The IL6 mediated activation of STAT3 conferred partial but marked protection against SFN induced apoptosis as evidenced by cytoplasmic histone associated DNA fragmentation and cleavage of poly-(ADP-ribose)-polymerase and procaspase-3.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	5	6
The STAT3 pathway is activated by IL-6 , IL-23 or TGF-beta1 and promotes the expression of the transcription factor RORyt , which leads to the secretion of IL-17A , IL-17F , IL-6 , IL-22 and TNF-alpha and to the development of Th17 cells .	The STAT3 pathway is activated by IL-6, IL-23 or TGF-beta1 and promotes the expression of the transcription factor RORyt, which leads to the secretion of IL-17A, IL-17F, IL-6, IL-22 and TNF-alpha and to the development of Th17 cells.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	1	2
Cytokines of the interleukin-6 ( IL-6 ) family , including IL-6 , are potent activators of the JAK and STAT3 pathway and predominantly activate STAT3 via JAK1 and JAK2 .	Cytokines of the interleukin-6 (IL-6) family, including IL-6, are potent activators of the JAK and STAT3 pathway and predominantly activate STAT3 via JAK1 and JAK2.	5	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	24	25
Binding of IL-6 to its receptor activates MAPK- and JAK and STAT3 signaling pathways .	Binding of IL-6 to its receptor activates MAPK- and JAK and STAT3 signaling pathways.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	11	12
Then we detected protein level of LYN , IL-6R , STAT3 , P-STAT3 after treated with IL-6 ( 25 ng/ml ) for 48 hours .	Then we detected protein level of LYN, IL-6R, STAT3, P-STAT3 after treated with IL-6 (25 ng/ml) for 48 hours.	6	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	P-STAT3	P-STAT3	P-STAT3	16	17	12	13
As shown in Figure XREF_FIG and XREF_SUPPLEMENTARY , activation of STAT3 by IL6 , or overexpression of total or phosphorylated STAT3 significantly suppressed crizotinib induced autophagy in lung cancer cells .	As shown in Figure XREF_FIG and XREF_SUPPLEMENTARY, activation of STAT3 by IL6, or overexpression of total or phosphorylated STAT3 significantly suppressed crizotinib induced autophagy in lung cancer cells.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	12	13	10	11
Lymph node cells from mice treated with p28 and p40 blocked adoptive transfer of EAU to naive syngeneic mice by immunopathogenic T cells and suppressive effects of p28 and p40 derived in part from antagonizing STAT1 and STAT3 pathways induced by IL-27 and IL-6 .	Lymph node cells from mice treated with p28 and p40 blocked adoptive transfer of EAU to naive syngeneic mice by immunopathogenic T cells and suppressive effects of p28 and p40 derived in part from antagonizing STAT1 and STAT3 pathways induced by IL-27 and IL-6.	35	44	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	43	44	37	38
T H 17 cell differentiation is driven by TGF-beta and the proinflammatory cytokines IL-6 , IL-21 , and IL-23 , which induce the transcription factor RAR related orphan receptor gamma ( RORgamma ) and activate STAT3 [ XREF_BIBR ] .	T H 17 cell differentiation is driven by TGF-beta and the proinflammatory cytokines IL-6, IL-21, and IL-23, which induce the transcription factor RAR related orphan receptor gamma (RORgamma) and activate STAT3 [XREF_BIBR].	6	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	35	36
For example , STAT3 activation initiated by IL-6 in tumor associated endothelial cells , TAM , and MSCs induces their ability to express VEGF and bFGF in a feed-forward loop that positively regulates angiogenesis within tumor tissues [ XREF_BIBR ] .	For example, STAT3 activation initiated by IL-6 in tumor associated endothelial cells, TAM, and MSCs induces their ability to express VEGF and bFGF in a feed-forward loop that positively regulates angiogenesis within tumor tissues [XREF_BIBR].	3	9	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	3	4
IL-6 induced transcriptional activity of STAT3 only in LNCaP .	IL-6 induced transcriptional activity of STAT3 only in LNCaP.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Differentiation in mice appears to be directed by the presence of both TGF-beta and inflammatory cytokines , such as IL-6 or IL-21 that activate Stat3 signaling pathways in the T cells .	Differentiation in mice appears to be directed by the presence of both TGF-beta and inflammatory cytokines, such as IL-6 or IL-21 that activate Stat3 signaling pathways in the T cells.	9	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	19	20	24	25
IL-6 activated STAT3 via a CaMKII dependent manner .	IL-6 activated STAT3 via a CaMKII dependent manner.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Given that chronic inflammatory diseases are promoted by IL-6 and IL-6-related cytokine mediated STAT3 pathways , and that the expression of SOCS3 is able to inhibit STAT3 activation , it appears that SOCS3 holds the potential to regulate inflammatory diseases related to IL-6 activation .	Given that chronic inflammatory diseases are promoted by IL-6 and IL-6-related cytokine mediated STAT3 pathways, and that the expression of SOCS3 is able to inhibit STAT3 activation, it appears that SOCS3 holds the potential to regulate inflammatory diseases related to IL-6 activation.	8	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	13	14
It has been well established that one of the most important functions of IL-6 is to activate STAT3 .	It has been well established that one of the most important functions of IL-6 is to activate STAT3.	11	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	17	18
In murine models of cutaneous squamous cell carcinoma ( SCC ) , IL-17-mediated inflammation has been shown to promote tumor formation and progression through the induction of IL-6 , which in turn activates STAT3 .	In murine models of cutaneous squamous cell carcinoma (SCC), IL-17-mediated inflammation has been shown to promote tumor formation and progression through the induction of IL-6, which in turn activates STAT3.	25	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	27	28	33	34
In normal macrophages , SOCS3 expression is induced by IL6 mediated Stat3 and NF-kappaB signaling and serves as a negative regulator of this pathway .	In normal macrophages, SOCS3 expression is induced by IL6 mediated Stat3 and NF-kappaB signaling and serves as a negative regulator of this pathway.	7	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	9	10	11	12
Furthermore , we identified the IL-6 receptor ( IL-6R ) , which mediates IL-6-dependent STAT3 activation , as a direct miR-204 target .	Furthermore, we identified the IL-6 receptor (IL-6R), which mediates IL-6-dependent STAT3 activation, as a direct miR-204 target.	5	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	14	15
Our in vitro data showed that only IL-6 induced STAT3 activation in BMDMs , as opposed to OSM .	Our in vitro data showed that only IL-6 induced STAT3 activation in BMDMs, as opposed to OSM.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
Interleukin-6 promoted proliferation of MSCs and expression of P53 , MDM2 , and STAT3 in MSCs .	Interleukin-6 promoted proliferation of MSCs and expression of P53, MDM2, and STAT3 in MSCs.	0	14	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin-6	Interleukin-6	Interleukin-6	STAT3	STAT3	STAT3	0	1	13	14
Numerous human cancer cell lines , including HT-29 , do not constitutively express p-STAT3 in vitro , however , previous studies have demonstrated that IL-6 can stimulate STAT3 activation in HT-29 cells .	Numerous human cancer cell lines, including HT-29, do not constitutively express p-STAT3 in vitro, however, previous studies have demonstrated that IL-6 can stimulate STAT3 activation in HT-29 cells.	24	28	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	27	28
Strikingly , co-administration of IL-6 and sIL-6R significantly increased pSTAT3 staining in DRG neuron nuclei .	Strikingly, co-administration of IL-6 and sIL-6R significantly increased pSTAT3 staining in DRG neuron nuclei.	2	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	4	5	9	10
These data are consistent with earlier studies showing that RA enhances phosphorylation of Smad3 in response to TGF-beta treatment and that activation of STAT3 by IL-6 leads to desensitization of TGF-beta signaling .	These data are consistent with earlier studies showing that RA enhances phosphorylation of Smad3 in response to TGF-beta treatment and that activation of STAT3 by IL-6 leads to desensitization of TGF-beta signaling.	21	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	23	24
This might be due to a reciprocal nuclear regulation of NF-kappaB on Stat3 or an indirect effect of NF-kappaB target protein suppression including IL-6 or IL-10 , which are required to activate Stat3 signaling .	This might be due to a reciprocal nuclear regulation of NF-kappaB on Stat3 or an indirect effect of NF-kappaB target protein suppression including IL-6 or IL-10, which are required to activate Stat3 signaling.	3	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	23	24	32	33
Phosphorylation levels of ERK1/2 and STAT3 proteins induced by IL-6 were analyzed by western blotting .	Phosphorylation levels of ERK1/2 and STAT3 proteins induced by IL-6 were analyzed by western blotting.	3	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	5	6
Since IL-6 treatment induced EMT phenotype , STAT3 activation and Oct-4 activation , we next wished to determine which intracellular signaling pathways are activated upon IL-6 treatment .	Since IL-6 treatment induced EMT phenotype, STAT3 activation and Oct-4 activation, we next wished to determine which intracellular signaling pathways are activated upon IL-6 treatment.	1	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	7	8
Whereas direct LPS treatment did not lead to STAT activation in cultured epithelial or endothelial cells , IL-6 activated STAT3 in both of these cell types .	Whereas direct LPS treatment did not lead to STAT activation in cultured epithelial or endothelial cells, IL-6 activated STAT3 in both of these cell types.	17	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	19	20
Interestingly , Ubr1 expression is dependent on the STAT3 activity induced by the IL-6 and gp130 signaling pathway .	Interestingly, Ubr1 expression is dependent on the STAT3 activity induced by the IL-6 and gp130 signaling pathway.	8	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	8	9
Myc tagged STAT3 proteins were affinity purified from 293T transfectants treated with IL-6 .	Myc tagged STAT3 proteins were affinity purified from 293T transfectants treated with IL-6.	2	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	2	3
These studies suggest that there is constitutive STAT3 activation in normal tissue and that there is no evidence that elevated levels of IL-6 and sIL-6R lead to additional activation of STAT3 in the sinonasal tissue of CRSwNP patients .	These studies suggest that there is constitutive STAT3 activation in normal tissue and that there is no evidence that elevated levels of IL-6 and sIL-6R lead to additional activation of STAT3 in the sinonasal tissue of CRSwNP patients.	20	31	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	levels of IL-6	il-6	STAT3	STAT3	stat3	22	23	30	31
As IL-6 induced STAT3 activation was found to be down-regulated after quercetin exposure , a subsequent FACS analysis was done to measure IL-6 titer upon quercetin exposure .	As IL-6 induced STAT3 activation was found to be down-regulated after quercetin exposure, a subsequent FACS analysis was done to measure IL-6 titer upon quercetin exposure.	1	4	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	3	4
SOCS3 then , in turn , inhibits IL-6 signaling via binding to gp130 , resulting in IL-6 induction of transient STAT3 activation , while SOCS3 does not block IL-10 activation of STAT3 ; therefore , IL-10 induces prolonged STAT3 activation XREF_BIBR .	SOCS3 then, in turn, inhibits IL-6 signaling via binding to gp130, resulting in IL-6 induction of transient STAT3 activation, while SOCS3 does not block IL-10 activation of STAT3; therefore, IL-10 induces prolonged STAT3 activation XREF_BIBR.	16	21	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	20	21
Increase of the IL-6 concentration can potentially activates downstream Stat3 ( phosphorylation ) in AT II epithelial cells to induce bronchioalveolar adenocarcinoma .	Increase of the IL-6 concentration can potentially activates downstream Stat3 (phosphorylation) in AT II epithelial cells to induce bronchioalveolar adenocarcinoma.	3	17	potentially activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	9	10
This suggests that the exacerbated liver damage in IL-6 knockout mice after alcohol feeding may be due to STAT3 independent signaling of IL-6 in hepatocytes , IL-6 activation of STAT3 in nonparenchymal cells , or both .	This suggests that the exacerbated liver damage in IL-6 knockout mice after alcohol feeding may be due to STAT3 independent signaling of IL-6 in hepatocytes, IL-6 activation of STAT3 in nonparenchymal cells, or both.	26	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	29	30
Interferon-gamma is a potent activator of STAT-1 ; the interleukin-6 ( IL-6 ) family members including IL-6 , leukemia inhibitory factor ( LIF ) primarily activate STAT-3 ; STAT2 is almost uniquely tyrosine phosphorylated and activated in the presence of IFNalpha and beta ; STAT4 is predominantly activated in response to IL-12 and STAT6 is primarily activated by IL-4 and the highly related cytokine IL-13 .	Interferon-gamma is a potent activator of STAT-1; the interleukin-6 (IL-6) family members including IL-6, leukemia inhibitory factor (LIF) primarily activate STAT-3; STAT2 is almost uniquely tyrosine phosphorylated and activated in the presence of IFNalpha and beta; STAT4 is predominantly activated in response to IL-12 and STAT6 is primarily activated by IL-4 and the highly related cytokine IL-13.	9	27	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	11	12	26	27
Since TNFalpha typically activates NFkappaB and IL-6 typically activates STAT3 , we hypothesized that IL-6 and TNFalpha induction of TNFR2 would be mediated by activation of both of these transcription factors .	Since TNFalpha typically activates NFkappaB and IL-6 typically activates STAT3, we hypothesized that IL-6 and TNFalpha induction of TNFR2 would be mediated by activation of both of these transcription factors.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	9	10
Stimulation of IL-6 trans-signaling with an IL-6 and sIL-6R fusion protein activated STAT3 in renal tubular epithelium and prevented AKI .	Stimulation of IL-6 trans-signaling with an IL-6 and sIL-6R fusion protein activated STAT3 in renal tubular epithelium and prevented AKI.	2	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	12	13
Our data showed that STAT3 played an important role in the TBr induced cytotoxicity , although induction of STAT3 by IL-6 in TBr treated cells could only partially rescue the cells from cytotoxicity ( XREF_FIG ) .	Our data showed that STAT3 played an important role in the TBr induced cytotoxicity, although induction of STAT3 by IL-6 in TBr treated cells could only partially rescue the cells from cytotoxicity (XREF_FIG).	16	22	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	18	19
Extended ( both 48 and 72h ) treatment of H2009 with the STAT3 activator IL6 elevated the levels of LOX , which was completely abolished upon overexpression of RIP4 or RIP4KD ( XREF_FIG ) .	Extended (both 48 and 72h) treatment of H2009 with the STAT3 activator IL6 elevated the levels of LOX, which was completely abolished upon overexpression of RIP4 or RIP4KD (XREF_FIG).	9	15	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	14	15	12	13
[ XREF_BIBR ] Moreover , IL6 mediated STAT3 activation has recently been found to compromise the therapeutic effect of chemotherapy in MCL .	[XREF_BIBR] Moreover, IL6 mediated STAT3 activation has recently been found to compromise the therapeutic effect of chemotherapy in MCL.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	5	6	7	8
In other cell types , Jak1 has been demonstrated to be absolutely required for IL-6 mediated activation of STAT3 .	In other cell types, Jak1 has been demonstrated to be absolutely required for IL-6 mediated activation of STAT3.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	18	19
Moreover , in the liver , STAT3 is mainly activated by IL-6 and related cytokines and promotes anchorage independent growth [ XREF_BIBR - XREF_BIBR ] .	Moreover, in the liver, STAT3 is mainly activated by IL-6 and related cytokines and promotes anchorage independent growth [XREF_BIBR - XREF_BIBR].	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	6	7
These results indicate that IL-6 trans-signaling can activate pSTAT3 via sIL-6R to activate gp130 in DRG neurons .	These results indicate that IL-6 trans-signaling can activate pSTAT3 via sIL-6R to activate gp130 in DRG neurons.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	4	5	8	9
Similar to IL-22 , IL-6 also activates STAT3 in hepatocytes and protects against ethanol induced liver injury .	Similar to IL-22, IL-6 also activates STAT3 in hepatocytes and protects against ethanol induced liver injury.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	7	8
In GL261 glioma cells , TNF-alpha-induced NF-kappaB activation was observed at 1 h , and STAT3 activation at 6 h. STAT3 is typically activated within 5-15 min of stimulation by members of the IL-6 family of cytokines .	In GL261 glioma cells, TNF-alpha-induced NF-kappaB activation was observed at 1 h, and STAT3 activation at 6 h. STAT3 is typically activated within 5-15 min of stimulation by members of the IL-6 family of cytokines.	15	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	33	34	15	16
Furthermore , IL-6 signaling activates the Signal transducer and activator of transcription 3 ( STAT3 ) , and plays an anti-inflammatory role [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Furthermore, IL-6 signaling activates the Signal transducer and activator of transcription 3 (STAT3), and plays an anti-inflammatory role [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	14	15
The induction of ROR-gammat is dependent on STAT-3 , which is preferentially activated by IL-6 , IL-21 , and IL-23 .	The induction of ROR-gammat is dependent on STAT-3, which is preferentially activated by IL-6, IL-21, and IL-23.	5	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	14	15	7	8
Since both IL-17 and IL-6 induce STAT3 activity , we also examined the expression of the STAT3 target gene Socs3 .	Since both IL-17 and IL-6 induce STAT3 activity, we also examined the expression of the STAT3 target gene Socs3.	2	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
As shown in XREF_FIG , EGF or IL-6 stimulation increased activated STAT3 in the nucleus evidenced by increased binding of hSIE .	As shown in XREF_FIG, EGF or IL-6 stimulation increased activated STAT3 in the nucleus evidenced by increased binding of hSIE.	5	14	increased activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	11	12
IL-6 stimulation also induced similar strengths of STAT1 * and STAT3 * in SHP-2 and SOCS3 combined knockout conditions .	IL-6 stimulation also induced similar strengths of STAT1 * and STAT3 * in SHP-2 and SOCS3 combined knockout conditions.	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	10	11
In their studies , constitutive IL-6 expression activated STAT3 and consequentially promoted and maintained the EMT phenotype .	In their studies, constitutive IL-6 expression activated STAT3 and consequentially promoted and maintained the EMT phenotype.	5	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 expression	il-6	STAT3	STAT3	stat3	5	6	8	9
5 , 95 K-Ras activation causes pancreatic neoplastic epithelial ( PanIN ) cells to produce cytokines such as IL-6 and IL-11 , which activate STAT3 in an autocrine manner 96 and recruit immune ( particularly myeloid ) cells .	5, 95 K-Ras activation causes pancreatic neoplastic epithelial (PanIN) cells to produce cytokines such as IL-6 and IL-11, which activate STAT3 in an autocrine manner 96 and recruit immune (particularly myeloid) cells.	15	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	24	25
Because STAT3 is activated by interleukin-6 ( IL-6 ) family cytokines , which bind to their respective receptor and transduce signals through glycoprotein 130 ( gp130 ) , we investigated whether typical STAT3 stimuli produce similar effects on mitoSTAT3 .	Because STAT3 is activated by interleukin-6 (IL-6) family cytokines, which bind to their respective receptor and transduce signals through glycoprotein 130 (gp130), we investigated whether typical STAT3 stimuli produce similar effects on mitoSTAT3.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	5	6	1	2
STAT3 is also activated by IL-6 , IL-21 , and IL-23 and synergizes with RORgammat for the differentiation and maintenance of IL-17 .	STAT3 is also activated by IL-6, IL-21, and IL-23 and synergizes with RORgammat for the differentiation and maintenance of IL-17.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
In turn , IL-6 activated NF-kappaB and STAT3 transcription factors through the RTK signaling pathway .	In turn, IL-6 activated NF-kappaB and STAT3 transcription factors through the RTK signaling pathway.	3	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	7	8
The level of IL-6 was remarkably increased , implicating that the release of IL-6 that drives the STAT3 activation initiates the survival signaling transition .	The level of IL-6 was remarkably increased, implicating that the release of IL-6 that drives the STAT3 activation initiates the survival signaling transition.	11	18	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	17	18
Stat3 was originally identified as an acute-phase response factor , activated by IL-6 and other cytokines [ XREF_BIBR ] , but has been implicated in cellular transformation and carcinogenesis [ XREF_BIBR ] .	Stat3 was originally identified as an acute-phase response factor, activated by IL-6 and other cytokines [XREF_BIBR], but has been implicated in cellular transformation and carcinogenesis [XREF_BIBR].	6	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	acute-phase response factor	acute-phase response factor	acute-phase response factor	12	13	6	9
Collectively , these data demonstrated that IL-6 secreted by endothelial cells signals through IL-6R to activate STAT3 signaling , which functions as a critical regulator of the self-renewal and survival of head and neck cancer stem cells .	Collectively, these data demonstrated that IL-6 secreted by endothelial cells signals through IL-6R to activate STAT3 signaling, which functions as a critical regulator of the self-renewal and survival of head and neck cancer stem cells.	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	16	17
IL-6 is known to activate other signaling pathways in hepatocytes that are independent of STAT3 , including mitogen activated protein kinases , protein kinase C , and peroxisome proliferator activated receptor-delta .	IL-6 is known to activate other signaling pathways in hepatocytes that are independent of STAT3, including mitogen activated protein kinases, protein kinase C, and peroxisome proliferator activated receptor-delta.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	14	15
38 These studies suggest that epithelial Stat3 induced by IL-6 and/or IL-22 plays a critical role in CAC .	38 These studies suggest that epithelial Stat3 induced by IL-6 and/or IL-22 plays a critical role in CAC.	5	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	6	7
Thus , paracrine production of IL-6 can promote autocrine STAT3 signaling .	Thus, paracrine production of IL-6 can promote autocrine STAT3 signaling.	3	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	9	10
beta1 integrin adhesion enhances IL-6 mediated STAT3 signaling in Myeloma cells : Implications for Microenvironment Influence on Tumor Survival and Proliferation .	beta1 integrin adhesion enhances IL-6 mediated STAT3 signaling in Myeloma cells : Implications for Microenvironment Influence on Tumor Survival and Proliferation.	3	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
AGS cells were transiently transfected with IRF-1 and with EV and or c-myc-tagged STAT3 and then after 24 h cells treated with either IL-6 ( 50 ng/ml ) or co-cultured with H. pylori at MOI of 100:1 .	AGS cells were transiently transfected with IRF-1 and with EV and or c-myc-tagged STAT3 and then after 24 h cells treated with either IL-6 (50 ng/ml) or co-cultured with H. pylori at MOI of 100:1.	6	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	23	24	13	14
Our data indicate that AZD1480 blocks endogenous as well as IL-6 induced STAT3 activation .	Our data indicate that AZD1480 blocks endogenous as well as IL-6 induced STAT3 activation.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	12	13
Nguyen and Gao showed that PE inhibits IL-6 activation of STAT3 in hepatic cells by a p42/44 mitogen activated protein kinase dependent mechanism , although the authors did not address whether alpha l -AR activation alone might alter Stat3 activity .	Nguyen and Gao showed that PE inhibits IL-6 activation of STAT3 in hepatic cells by a p42/44 mitogen activated protein kinase dependent mechanism, although the authors did not address whether alpha l -AR activation alone might alter Stat3 activity.	7	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	10	11
IL-6 , upon receptor binding , activates STAT3 via the gp130/JAK/STAT pathway XREF_BIBR XREF_BIBR .	IL-6, upon receptor binding, activates STAT3 via the gp130/JAK/STAT pathway XREF_BIBR XREF_BIBR.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	7	8
For instance , in a study investigating the HPA axis response to chronic stress , STAT3 signaling cascade was activated by IL-6 stimuli in rat hypothalami .	For instance, in a study investigating the HPA axis response to chronic stress, STAT3 signaling cascade was activated by IL-6 stimuli in rat hypothalami.	15	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	15	16
XREF_BIBR In our highly metastatic cells , we found that increased IL-6 production in response to TNFalpha induced an autocrine gp130- and IL-6R-dependent activation of STAT3 , inhibiting caspase-3-mediated apoptosis .	XREF_BIBR In our highly metastatic cells, we found that increased IL-6 production in response to TNFalpha induced an autocrine gp130- and IL-6R-dependent activation of STAT3, inhibiting caspase-3-mediated apoptosis.	11	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	25	26
Interestingly , LGR4 overexpression is at least partially regulated via STAT-3 signaling , which in turn is mediated by IL-6 , another cytokine that is vastly present in the BM microenvironment of MM patients .	Interestingly, LGR4 overexpression is at least partially regulated via STAT-3 signaling, which in turn is mediated by IL-6, another cytokine that is vastly present in the BM microenvironment of MM patients.	10	22	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	19	20	10	11
Given that IL-6 can activate downstream STAT3 , a key oncogene constitutively activated in many cancer including HCCs and contributing to cancer cell proliferation and survival [ XREF_BIBR , XREF_BIBR ] [ XREF_BIBR , XREF_BIBR ] [ XREF_BIBR , XREF_BIBR ] , we examined hepatic STAT3 activation in both genotypes 10-month post DEN injection .	Given that IL-6 can activate downstream STAT3, a key oncogene constitutively activated in many cancer including HCCs and contributing to cancer cell proliferation and survival [XREF_BIBR, XREF_BIBR] [XREF_BIBR, XREF_BIBR] [XREF_BIBR, XREF_BIBR], we examined hepatic STAT3 activation in both genotypes 10-month post DEN injection.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	6	7
Although STAT3 is predominantly activated by IL-6 , other cytokines such as IL-10 also activate this transcription factor XREF_BIBR XREF_BIBR .	Although STAT3 is predominantly activated by IL-6, other cytokines such as IL-10 also activate this transcription factor XREF_BIBR XREF_BIBR.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	1	2
IL-6 induces both STAT3 and APE1 to bind the suppressor of cytokine signaling-3 and gamma-fibrionogen promoters in their native chromatin environment .	IL-6 induces both STAT3 and APE1 to bind the suppressor of cytokine signaling-3 and gamma-fibrionogen promoters in their native chromatin environment.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
IL6 signals promote STAT3 activation in GBM cells in vitro , and targeting either STAT3 or IL6 decreases GBM cell survival [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	IL6 signals promote STAT3 activation in GBM cells in vitro, and targeting either STAT3 or IL6 decreases GBM cell survival [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	4	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	3	4
To confirm the hypothesis that the amylin sensitizing effect on leptin signaling is caused by an amylin induced increase in IL-6 activation of JAK and STAT3 signaling , IgG or IL-6 antibodies were infused into the LV of rats for 5 days .	To confirm the hypothesis that the amylin sensitizing effect on leptin signaling is caused by an amylin induced increase in IL-6 activation of JAK and STAT3 signaling, IgG or IL-6 antibodies were infused into the LV of rats for 5 days.	20	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	25	26
IL-6 derived from breast cancer cells can activate STAT3 in MDSCs in 4T1 BALB/c mice , which stimulates the noncanonical NF-kappaB subunit p52 and causes RelB translocation into the nucleus , where they interact directly with the indoleamine 2,3-dioxygenase ( IDO ) promoter sequence to promote expression of IDO [ XREF_BIBR ] .	IL-6 derived from breast cancer cells can activate STAT3 in MDSCs in 4T1 BALB/c mice, which stimulates the noncanonical NF-kappaB subunit p52 and causes RelB translocation into the nucleus, where they interact directly with the indoleamine 2,3-dioxygenase (IDO) promoter sequence to promote expression of IDO [XREF_BIBR].	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	8	9
Treatment with IL-6 induced STAT3 activation more significantly in SP than non SP cells .	Treatment with IL-6 induced STAT3 activation more significantly in SP than non SP cells.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
We conclude that IL-6 activated independently the JAK2 and STAT3 and ERK1/2 pathways , but only JAK2 and STAT3 signaling mediated the NO associated decrease in contractility .	We conclude that IL-6 activated independently the JAK2 and STAT3 and ERK1/2 pathways, but only JAK2 and STAT3 signaling mediated the NO associated decrease in contractility.	3	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	9	10
IL-6 signaling through gp130 activates the protein-tyrosine kinase , Janus kinase 1 ( JAK1 ) , and transiently activates signal transducer and activator of transcription 3 ( STAT3 ) dimerization and phosphorylation , followed by STAT3 nuclear translocation and target gene transcription .	IL-6 signaling through gp130 activates the protein-tyrosine kinase, Janus kinase 1 (JAK1), and transiently activates signal transducer and activator of transcription 3 (STAT3) dimerization and phosphorylation, followed by STAT3 nuclear translocation and target gene transcription.	0	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	27	28
Our data demonstrated that IL-6 siRNA could not enhance inactivation of the JAK1 and STAT3 signaling pathway and apoptosis in H1975 cells treated with matrine ( XREF_FIG and XREF_FIG ) .	Our data demonstrated that IL-6 siRNA could not enhance inactivation of the JAK1 and STAT3 signaling pathway and apoptosis in H1975 cells treated with matrine (XREF_FIG and XREF_FIG).	4	16	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	14	15
Autocrine IL-6 induced Stat3 activation and paclitaxel resistance in AS2 cells .	Autocrine IL-6 induced Stat3 activation and paclitaxel resistance in AS2 cells.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	3	4
Besides induced activation of STAT3 by IL-6 type cytokines , STAT3 can be constitutively activated through permanently dimerized gp130 .	Besides induced activation of STAT3 by IL-6 type cytokines, STAT3 can be constitutively activated through permanently dimerized gp130.	2	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	4	5
Interleukin 6 ( IL6 ) potently activates JAK and STAT3 signaling through the cell surface type I cytokine receptor [ XREF_BIBR ] .	Interleukin 6 (IL6) potently activates JAK and STAT3 signaling through the cell surface type I cytokine receptor [XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	3	4	9	10
It is likely that elevated bile acids induce IL-6 , which in turn activates STAT3 .	It is likely that elevated bile acids induce IL-6, which in turn activates STAT3.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	14	15
Interleukin 17A ( IL-17A ) , a pro inflammatory cytokine secreted by CD4 + Th17 cells , triggers tumor cells to produce interleukin 6 ( IL-6 ) , which in turn activates STAT3 dependent survival and angiogenesis [ XREF_BIBR ] .	Interleukin 17A (IL-17A), a pro inflammatory cytokine secreted by CD4 + Th17 cells, triggers tumor cells to produce interleukin 6 (IL-6), which in turn activates STAT3 dependent survival and angiogenesis [XREF_BIBR].	21	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	STAT3	STAT3	STAT3	22	24	32	33
Moreover , IL-6 secretion induced by HER2 overexpression elicited JAK2 and STAT3 activation [ XREF_BIBR ] .	Moreover, IL-6 secretion induced by HER2 overexpression elicited JAK2 and STAT3 activation [XREF_BIBR].	2	12	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	11	12
IL-6 , IL-21 , and IL-27 all activate STAT3 but yet have very different effects on Th17 differentiation .	IL-6, IL-21, and IL-27 all activate STAT3 but yet have very different effects on Th17 differentiation.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	8	9
3 Interleukin-6 ( IL-6 ) is secreted by BMSCs into the microenvironment and activates the STAT3 pathway in MM cells to promote PIM transcription .	3 Interleukin-6 (IL-6) is secreted by BMSCs into the microenvironment and activates the STAT3 pathway in MM cells to promote PIM transcription.	1	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	15	16
They further showed that STAT3 is activated via autocrine signaling by IL-6 family ligands and genetic or pharmacologic inhibition of the gp130 and JAK2 signaling pathway disrupts activation of STAT3 [ XREF_BIBR ] .	They further showed that STAT3 is activated via autocrine signaling by IL-6 family ligands and genetic or pharmacologic inhibition of the gp130 and JAK2 signaling pathway disrupts activation of STAT3 [XREF_BIBR].	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	4	5
In parallel , STAT3 activation by IL-6 is responsible for Foxp3 downregulation in both differentiating and differentiated Tregs , accounting for the critical role of IL-6 in determining the balance between Th17 and iTreg induction .	In parallel, STAT3 activation by IL-6 is responsible for Foxp3 downregulation in both differentiating and differentiated Tregs, accounting for the critical role of IL-6 in determining the balance between Th17 and iTreg induction.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	3	4
Because IL-6-induced activation of STAT-3 was prolonged in gp130 F759 and F759 T cells , while IL-6 failed to activate STAT-3 in gp130 FXXQ and FXXQ T cells , it is most likely that STAT-3 has a suppressive effect on the anti-CD3-induced upregulation of FasL in activated T cells .	Because IL-6-induced activation of STAT-3 was prolonged in gp130 F759 and F759 T cells, while IL-6 failed to activate STAT-3 in gp130 FXXQ and FXXQ T cells, it is most likely that STAT-3 has a suppressive effect on the anti-CD3-induced upregulation of FasL in activated T cells.	16	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	16	17	20	21
Using in vitro and in vivo approaches , our results suggested that IL-6 mediates STAT3 activation in kidney fibrosis and that phosphorylated ( p ) STAT3 binds to Fgalpha , Fgbeta , and Fggamma promoters in the kidney to regulate their transcription .	Using in vitro and in vivo approaches, our results suggested that IL-6 mediates STAT3 activation in kidney fibrosis and that phosphorylated (p) STAT3 binds to Fgalpha, Fgbeta, and Fggamma promoters in the kidney to regulate their transcription.	12	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	14	15
IL6 is known to activate STAT3 through the Jak kinase 46 .	IL6 is known to activate STAT3 through the Jak kinase 46.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	5	6
On molecular analysis , significant expressions of COX-2 and IL-6 , activated NF-kappaB and STAT3 , increased apoptosis , and marked oxidative stresses were noted in H. pylori infected group relevant to tumorigenesis , but these were all significantly attenuated in cpKimchi group .	On molecular analysis, significant expressions of COX-2 and IL-6, activated NF-kappaB and STAT3, increased apoptosis, and marked oxidative stresses were noted in H. pylori infected group relevant to tumorigenesis, but these were all significantly attenuated in cpKimchi group.	5	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	expressions of COX-2 and IL-6	il-6	STAT3	STAT3	stat3	9	10	14	15
XREF_BIBR , XREF_BIBR IL-6 and other gp130 utilizing cytokines could induce STAT3 activation , promoting the induction of inflammatory cytokines .	XREF_BIBR, XREF_BIBR IL-6 and other gp130 utilizing cytokines could induce STAT3 activation, promoting the induction of inflammatory cytokines.	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	11	12
A potential candidate is IL-6 , since the activation of STAT3 by IL-6 and JAK signaling pathway is well established XREF_BIBR , XREF_BIBR .	A potential candidate is IL-6, since the activation of STAT3 by IL-6 and JAK signaling pathway is well established XREF_BIBR, XREF_BIBR.	8	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	10	11
In this study , we demonstrate that STAT3 , activated by IL-6 , regulates ABCA3 expression in vivo and in vitro .	In this study, we demonstrate that STAT3, activated by IL-6, regulates ABCA3 expression in vivo and in vitro.	7	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	7	8
For example , STAT3 can be activated in skeletal muscle by either IL-6 or IT XREF_BIBR , XREF_BIBR .	For example, STAT3 can be activated in skeletal muscle by either IL-6 or IT XREF_BIBR, XREF_BIBR.	3	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	3	4
Phosphorylation of STAT3 on Tyr705 is the major mechanism of STAT3 activation , which is mediated by JAK upon stimulation of the heterodimeric gp130 and cytokine specific receptor complex by the IL-6 family of cytokines , including IL-6 , leukemia inhibitory factor ( LIF ) , ciliary neurotrophic factor , oncostatin M , IL-11 , and cardiotrophin-1 .	Phosphorylation of STAT3 on Tyr705 is the major mechanism of STAT3 activation, which is mediated by JAK upon stimulation of the heterodimeric gp130 and cytokine specific receptor complex by the IL-6 family of cytokines, including IL-6, leukemia inhibitory factor (LIF), ciliary neurotrophic factor, oncostatin M, IL-11, and cardiotrophin-1.	10	32	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	31	32	10	11
IL-6 activates STAT3 [ XREF_BIBR ] and might therefore induce cell proliferation .	IL-6 activates STAT3 [XREF_BIBR] and might therefore induce cell proliferation.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
In response to IL-6 stimulation STAT3 becomes phosphorylated and translocates into the nucleus where it binds to enhancer sequences of target genes .	In response to IL-6 stimulation STAT3 becomes phosphorylated and translocates into the nucleus where it binds to enhancer sequences of target genes.	1	9	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
The present study builds on these observations and demonstrates that WA inhibits constitutive as well as interleukin-6 ( IL-6 )-inducible activation of signal transducer and activator of transcription 3 ( STAT3 ) , which is an oncogenic transcription factor activated in many human malignancies including breast cancer .	The present study builds on these observations and demonstrates that WA inhibits constitutive as well as interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies including breast cancer.	11	38	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	16	17	30	31
IL-6 is able to bind to IL-6R and gp130 and activate the Jak and Stat3 pathway .	IL-6 is able to bind to IL-6R and gp130 and activate the Jak and Stat3 pathway.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	14	15
XREF_BIBR IL6 , IL11 , and other cytokines that signal through the gp130 receptors activate STAT3 , and STAT3 is reported to be overactivated in gastric cancer and gastric cancer stem cells , indicating poor prognosis .	XREF_BIBR IL6, IL11, and other cytokines that signal through the gp130 receptors activate STAT3, and STAT3 is reported to be overactivated in gastric cancer and gastric cancer stem cells, indicating poor prognosis.	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	15	16
IL-6 activates AR in a STAT3 dependent manner and antibodies to IL-6 reverses castration-resistance .	IL-6 activates AR in a STAT3 dependent manner and antibodies to IL-6 reverses castration-resistance.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
IL-6 caused STAT3 kinase activation , resulting in anti-apoptotic Bcl-2 expression and inhibiting of apoptosis proteins such as Bcl-xl and Mcl-1 .	IL-6 caused STAT3 kinase activation, resulting in anti-apoptotic Bcl-2 expression and inhibiting of apoptosis proteins such as Bcl-xl and Mcl-1.	0	4	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
It is of note that this is the region in which regenerative hyperplasia is seen in patients with advanced SOS and , as such , it appears likely that this is driven by IL-6 mediated activation of STAT3 .	It is of note that this is the region in which regenerative hyperplasia is seen in patients with advanced SOS and, as such, it appears likely that this is driven by IL-6 mediated activation of STAT3.	33	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	33	34	37	38
CS-IVa-Be inhibited constitutive and IL6 induced STAT3 activation , repressed STAT3 DNA binding activity , STAT3 nuclear translocation , IL6 induced STAT3 luciferase reporter activity , IL6 induced STAT3 regulated antiapoptosis gene expression in MDA-MB-231 cells , and IL6 induced TF-1 cell proliferation .	CS-IVa-Be inhibited constitutive and IL6 induced STAT3 activation, repressed STAT3 DNA binding activity, STAT3 nuclear translocation, IL6 induced STAT3 luciferase reporter activity, IL6 induced STAT3 regulated antiapoptosis gene expression in MDA-MB-231 cells, and IL6 induced TF-1 cell proliferation.	26	29	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	26	27	28	29
After the expression vectors pRc and RSVgp130 and pRc and RSV were transfected into Jurkat cells , IL-6 could activate APRF , but could not do NF-IL6 .	After the expression vectors pRc and RSVgp130 and pRc and RSV were transfected into Jurkat cells, IL-6 could activate APRF, but could not do NF-IL6.	17	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	APRF	APRF	APRF	17	18	20	21
Activated SOCS3 is known to selectively suppress STAT-3 activation induced by IL-6 , granulocyte-colony stimulating factor ( GCSF ) , and leptin , XREF_BIBR , XREF_BIBR whereas deficiency of SOCS3 increases TGFbeta production and simultaneously enhances Th17 cell development .	Activated SOCS3 is known to selectively suppress STAT-3 activation induced by IL-6, granulocyte-colony stimulating factor (GCSF), and leptin, XREF_BIBR, XREF_BIBR whereas deficiency of SOCS3 increases TGFbeta production and simultaneously enhances Th17 cell development.	7	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	11	12	7	8
Interleukin 6 and interleukin 11 , known to activate STAT3 synergistically , stimulated the SP-B promoter activity with retinoic acid , which is at least partially mediated through interactions between STAT3 and retinoid nuclear receptor enhanceosome proteins in pulmonary epithelial cells .	Interleukin 6 and interleukin 11, known to activate STAT3 synergistically, stimulated the SP-B promoter activity with retinoic acid, which is at least partially mediated through interactions between STAT3 and retinoid nuclear receptor enhanceosome proteins in pulmonary epithelial cells.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin 6	Interleukin 6	Interleukin 6	STAT3	STAT3	STAT3	0	2	9	10
Since IL-6 can strongly activate the STAT3 signaling pathway , it is reasonable to expect STAT3 also plays a critical role in HCC development .	Since IL-6 can strongly activate the STAT3 signaling pathway, it is reasonable to expect STAT3 also plays a critical role in HCC development.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	6	7
STAT-3 promotes cell survival in response to selected growth factors and is activated by combined BCR cross linking and IL-6 ( IL-10 ) .	STAT-3 promotes cell survival in response to selected growth factors and is activated by combined BCR cross linking and IL-6 (IL-10).	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	19	20	0	1
3.4 IL-6 stimulation activates STAT3 but not Akt or ERK1/2 .	3.4 IL-6 stimulation activates STAT3 but not Akt or ERK1/2.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	4	5
HER2- IL-6 activation of Stat3 significantly enhances tumor growth in vivo .	HER2- IL-6 activation of Stat3 significantly enhances tumor growth in vivo.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	4	5
Our experiments showed that IL-6 treatment induced STAT3 and Chk2 activation and attenuated CREB and ATF -1 phosphorylation in MUC2 silenced HT-29 cancer cells .	Our experiments showed that IL-6 treatment induced STAT3 and Chk2 activation and attenuated CREB and ATF -1 phosphorylation in MUC2 silenced HT-29 cancer cells.	4	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	7	8
MSC produce high levels of IL-6 , which activates STAT3 transcription factors , resulting in a longer life span of the neutrophils , as indicated in XREF_FIG [ XREF_BIBR ] .	MSC produce high levels of IL-6, which activates STAT3 transcription factors, resulting in a longer life span of the neutrophils, as indicated in XREF_FIG [XREF_BIBR].	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	MSC produce high levels of IL-6	il-6	STAT3	STAT3	stat3	5	6	9	10
STAT3 is activated by IL-6 in the tumor microenvironment 39 .	STAT3 is activated by IL-6 in the tumor microenvironment 39.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
In contrast to what we observed with IL-10 stimulation , the activation of pSTAT3 by IL-6 was normal in IL-10R Impaired T R 1 cells ( XREF_FIG ) .	In contrast to what we observed with IL-10 stimulation, the activation of pSTAT3 by IL-6 was normal in IL-10R Impaired T R 1 cells (XREF_FIG).	5	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	15	16	13	14
Moreover , the IL6 mediated activation of STAT3 activation confers partial yet statistically significant protection against SFN induced apoptosis .	Moreover, the IL6 mediated activation of STAT3 activation confers partial yet statistically significant protection against SFN induced apoptosis.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	3	4	7	8
Inversely , an enhanced induction of p-STAT3 by IL-6 was also achieved in NCI-H1299 cells with stably overexpressed AKR1C1 .	Inversely, an enhanced induction of p-STAT3 by IL-6 was also achieved in NCI-H1299 cells with stably overexpressed AKR1C1.	4	9	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	8	9	6	7
Initial IL-6 stimulation activates Stat3 , resulting in the increased expression of Th17 cytokines , including IL-21 as well as Th17 transcription factors .	Initial IL-6 stimulation activates Stat3, resulting in the increased expression of Th17 cytokines, including IL-21 as well as Th17 transcription factors.	1	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	4	5
IL-6 activation of STAT3 has been implicated in prostate cancer progression [ XREF_BIBR , XREF_BIBR ] .	IL-6 activation of STAT3 has been implicated in prostate cancer progression [XREF_BIBR, XREF_BIBR].	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
As a case in point , both interleukin-10 ( IL-10 ) and IL-6 activate STAT3 ( Signal transducer and activator of transcription 3 ) transcription factor ; however , the former leads to anti-inflammatory response while the latter initiates inflammation ( XREF_FIG ) .	As a case in point, both interleukin-10 (IL-10) and IL-6 activate STAT3 (Signal transducer and activator of transcription 3) transcription factor; however, the former leads to anti-inflammatory response while the latter initiates inflammation (XREF_FIG).	4	27	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	14	15
IL-6 treatment activates the gp130 and STAT3 pathway in gastric cancer cells to up-regulate MUC4 , which can be detected at early stages of the gastric carcinogenetic process .	IL-6 treatment activates the gp130 and STAT3 pathway in gastric cancer cells to up-regulate MUC4, which can be detected at early stages of the gastric carcinogenetic process.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
We found that combined treatments of IL-6 and TNF-alpha activate STAT3 in a synergistic manner , and promoted STAT3 and NF-kappaB physically bind each other .	We found that combined treatments of IL-6 and TNF-alpha activate STAT3 in a synergistic manner, and promoted STAT3 and NF-kappaB physically bind each other.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	10	11
We studied the effect of avicin D on the localization of both constitutive and IL-6 induced Stat3 in U266 ( XREF_FIG ) and RPMI-8226 ( XREF_FIG ) cells .	We studied the effect of avicin D on the localization of both constitutive and IL-6 induced Stat3 in U266 (XREF_FIG) and RPMI-8226 (XREF_FIG) cells.	9	17	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	14	15	16	17
Earlier , we have shown that macrophage derived IL-6 induced STAT3 dependent protective fibrin production by hepatocytes in listeriosis .	Earlier, we have shown that macrophage derived IL-6 induced STAT3 dependent protective fibrin production by hepatocytes in listeriosis.	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
Notably , STAT3 activation in TIME cells was not mediated by IL6 .	Notably, STAT3 activation in TIME cells was not mediated by IL6.	2	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	11	12	2	3
The WASF1 and WASF2 genes are not activated by IL6 promotion of STAT3 signaling 26 and our unpublished observations do not show STAT3 binding sites in their promoter regions .	The WASF1 and WASF2 genes are not activated by IL6 promotion of STAT3 signaling 26 and our unpublished observations do not show STAT3 binding sites in their promoter regions.	9	13	promotion	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	9	10	12	13
These results indicated that SFN treatment inhibited constitutive and IL6 induced transcriptional activity of STAT3 in DU145 and LNCaP cells .	These results indicated that SFN treatment inhibited constitutive and IL6 induced transcriptional activity of STAT3 in DU145 and LNCaP cells.	7	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	9	10	14	15
This suggests that IL-6 may promote IL-22 production in a T cell STAT3 independent manner via activation of STAT3 in other cell types rather than T cells , as IL-22 can be produced by NK cells in addition to T cells .	This suggests that IL-6 may promote IL-22 production in a T cell STAT3 independent manner via activation of STAT3 in other cell types rather than T cells, as IL-22 can be produced by NK cells in addition to T cells.	3	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	12	13
IFN-gamma preferentially activates STAT1 through JAK1 and JAK2 and IL-6 activates STAT3 through JAK1 .	IFN-gamma preferentially activates STAT1 through JAK1 and JAK2 and IL-6 activates STAT3 through JAK1.	9	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
XREF_BIBR , XREF_BIBR STAT3 is mainly induced by IL-6 and IL-23 , both of which signal via TYK2 .	XREF_BIBR, XREF_BIBR STAT3 is mainly induced by IL-6 and IL-23, both of which signal via TYK2.	0	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	3	4
Activation of STAT3 by IL-6 has already been reported in NB and other cancer tumors , but by demonstrating that blocking IL-6 or its receptor is not sufficient to block STAT3 activation , the data indicate that other soluble factors than IL-6 present in the CM activate STAT3 and ERK1/2 .	Activation of STAT3 by IL-6 has already been reported in NB and other cancer tumors, but by demonstrating that blocking IL-6 or its receptor is not sufficient to block STAT3 activation, the data indicate that other soluble factors than IL-6 present in the CM activate STAT3 and ERK1/2.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	2	3
IL-6 has been shown to mediate the activation of STAT3 in adult Schwann cells and rat schwannoma cells .	IL-6 has been shown to mediate the activation of STAT3 in adult Schwann cells and rat schwannoma cells.	0	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	9	10
In this suggested model , neurosin-PAR2-mediated IL-6 secretion feeds forward to activate STAT3 signaling by activation of the IL-6 receptor .	In this suggested model, neurosin-PAR2-mediated IL-6 secretion feeds forward to activate STAT3 signaling by activation of the IL-6 receptor.	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	12	13
IL-6 signalling also drives the activation of STAT3 , which can bind ISRE cis-elements , another potential mechanism to activate the ERVK LTR .	IL-6 signalling also drives the activation of STAT3, which can bind ISRE cis-elements, another potential mechanism to activate the ERVK LTR.	0	11	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	7	8
Interestingly , IL-6 activates signal transducer and activator of transcription 3 ( STAT3 ) , a transcription factor released during the acute-phase response [ XREF_BIBR ] .	Interestingly, IL-6 activates signal transducer and activator of transcription 3 (STAT3), a transcription factor released during the acute-phase response [XREF_BIBR].	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	12	13
In summary , we have shown that STAT3 is activated in HS by IL-6 trans-signaling pathways that mediate ECM production and dermal fibroblast proliferation .	In summary, we have shown that STAT3 is activated in HS by IL-6 trans-signaling pathways that mediate ECM production and dermal fibroblast proliferation.	7	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	7	8
In this study , we show that IL-6 induces ERK1/2 activation in undifferentiated MSCs but not STAT3 , the downstream regulator of the gp130/IL -6 family signaling pathway .	In this study, we show that IL-6 induces ERK1/2 activation in undifferentiated MSCs but not STAT3, the downstream regulator of the gp130/IL -6 family signaling pathway.	7	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	16	17
Together , these results indicate that during E. coli pneumonia , select IL-6 family members activate alveolar epithelial STAT3 , which functions to promote neutrophil recruitment and to limit both infection and lung injury .	Together, these results indicate that during E. coli pneumonia, select IL-6 family members activate alveolar epithelial STAT3, which functions to promote neutrophil recruitment and to limit both infection and lung injury.	12	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	18	19
IL-6 has been reported to activate Janus kinase ( JAK ) and signal transducer and activator of transcription 3 ( STAT3 ) pathways 22 to promote a cellular microenvironment that may promote cancer growth .	IL-6 has been reported to activate Janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3) pathways 22 to promote a cellular microenvironment that may promote cancer growth.	0	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	20	21
In a previous study , the IL-6 receptor ( IL-6R ) was strongly expressed in SKOV3 cells and exogenous IL-6 stimulated STAT3 activation , increasing SKOV3 migration .	In a previous study, the IL-6 receptor (IL-6R) was strongly expressed in SKOV3 cells and exogenous IL-6 stimulated STAT3 activation, increasing SKOV3 migration.	18	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	21	22
STAT3 is Activated via Autocrine Signaling by IL-6 Family Ligands .	STAT3 is Activated via Autocrine Signaling by IL-6 Family Ligands.	0	9	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	0	1
Likewise , IL-6 , a major inflammatory cytokine , promoted tumorigenesis , and induced the expansion of cancer stem cells by activating the STAT3 signaling pathway XREF_BIBR , XREF_BIBR .	Likewise, IL-6, a major inflammatory cytokine, promoted tumorigenesis, and induced the expansion of cancer stem cells by activating the STAT3 signaling pathway XREF_BIBR, XREF_BIBR.	2	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	23	24
Indeed , we found that exposure of C2C12 myotubes to IL-6 stimulates p-Stat3 and sequentially increases the expression of C/EBPdelta .	Indeed, we found that exposure of C2C12 myotubes to IL-6 stimulates p-Stat3 and sequentially increases the expression of C/EBPdelta.	8	13	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-Stat3	p-Stat3	p-Stat3	10	11	12	13
In addition , we show that IL6 not only stimulates STAT3 function but is a direct STAT3 target gene , as STAT3 occupies its promoter and transcriptional induction is STAT3 dependent ( not shown , Additional file 1 : Figure S5 ) .	In addition, we show that IL6 not only stimulates STAT3 function but is a direct STAT3 target gene, as STAT3 occupies its promoter and transcriptional induction is STAT3 dependent (not shown, Additional file 1 : Figure S5).	6	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	6	7	10	11
Specifically , IL-6 secreted by IL-6-producing cancers activates STAT3 to stimulate cell proliferation in basal like breast cancer cells , but not in luminal breast cancer .	Specifically, IL-6 secreted by IL-6-producing cancers activates STAT3 to stimulate cell proliferation in basal like breast cancer cells, but not in luminal breast cancer.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
IL-6 and TNFalpha can induce STAT3 activation and induce Th 22 specification , a process that is dependent on the aryl hydrocarbon receptor [ XREF_BIBR ] .	IL-6 and TNFalpha can induce STAT3 activation and induce Th 22 specification, a process that is dependent on the aryl hydrocarbon receptor [XREF_BIBR].	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
IL-6 and IL-27 induce similar pSTAT3 profiles in S1KO T cells .	IL-6 and IL-27 induce similar pSTAT3 profiles in S1KO T cells.	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	0	1	5	6
Interestingly , PROS attenuated phosphorylation of STAT3 in A549 and H460 cells and also reduced the expression of IL6 activated p-ERK and p-STAT3 in STAT3 low level H1299 cells , demonstrating the potent role of STAT3 in PROS induced apoptosis .	Interestingly, PROS attenuated phosphorylation of STAT3 in A549 and H460 cells and also reduced the expression of IL6 activated p-ERK and p-STAT3 in STAT3 low level H1299 cells, demonstrating the potent role of STAT3 in PROS induced apoptosis.	16	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	expression of IL6	il6	p-STAT3	p-STAT3	p-stat3	18	19	22	23
On the other hand , IL-17 increases the level of IL-6 and IL-8 in NSCLC cell lines and activates the STAT3 signaling pathway , mediating tumor angiogenesis [ XREF_BIBR , XREF_BIBR ] .	On the other hand, IL-17 increases the level of IL-6 and IL-8 in NSCLC cell lines and activates the STAT3 signaling pathway, mediating tumor angiogenesis [XREF_BIBR, XREF_BIBR].	5	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-17 increases the level of IL-6	il-6	STAT3	STAT3	stat3	10	11	20	21
110 IL-6 activates STAT3 dependent pathway and the signal mediated by IL-6 and STAT3 is terminated by SOCS3 .	110 IL-6 activates STAT3 dependent pathway and the signal mediated by IL-6 and STAT3 is terminated by SOCS3.	0	5	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	3	4
Although G-CSF and IL-6 both induce activation of Stat3 , each activates a distinct isoform of Stat3 ; IL-6 activates Stat3alpha , whereas extracts of G-CSF-stimulated PMN contained only Stat3gamma , a short isoform of Stat3 derived from proteolytic cleavage of Stat3alpha ( 28 , and Tweardy , D.J ., unpublished data ) .	Although G-CSF and IL-6 both induce activation of Stat3, each activates a distinct isoform of Stat3; IL-6 activates Stat3alpha, whereas extracts of G-CSF-stimulated PMN contained only Stat3gamma, a short isoform of Stat3 derived from proteolytic cleavage of Stat3alpha (28, and Tweardy, D.J., unpublished data).	1	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	8	9
We defined a feed-forward loop , in which nuclear factor kappaB induction elicits Stat3 activation and pro differentiating interleukin-6 expression causes the further expansion of neuroendocrine communications .	We defined a feed-forward loop, in which nuclear factor kappaB induction elicits Stat3 activation and pro differentiating interleukin-6 expression causes the further expansion of neuroendocrine communications.	12	20	elicits	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6 expression	interleukin-6	Stat3	Stat3	stat3	18	19	13	14
Because IL-23 , IL-21 and IL-6 induce IL-17 production by activating Stat3 , it is not surprised that deletion of Stat3 in T cells abrogated Th17 cell differentiation .	Because IL-23, IL-21 and IL-6 induce IL-17 production by activating Stat3, it is not surprised that deletion of Stat3 in T cells abrogated Th17 cell differentiation.	1	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	5	6	11	12
XREF_BIBR As both IL-6 and IL-11 activate Stat3 , and in turn are regulated by Stat3 and/or NFkappaB , XREF_BIBR , XREF_BIBR it is likely that iron and colonic inflammation may regulate IL-11 in a similar manner to IL-6 .	XREF_BIBR As both IL-6 and IL-11 activate Stat3, and in turn are regulated by Stat3 and/or NFkappaB, XREF_BIBR, XREF_BIBR it is likely that iron and colonic inflammation may regulate IL-11 in a similar manner to IL-6.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	7	8
Also STAT3 signaling triggered by the proinflammatory cytokine IL-6 , which has been shown to antagonize Foxp3 and counteract Treg suppressive function , is capable of inducing DNMT1 expression and promotes the activity of this enzyme resulting in methylation of critical foxp3 loci and downregulation of the transcription factor .	Also STAT3 signaling triggered by the proinflammatory cytokine IL-6, which has been shown to antagonize Foxp3 and counteract Treg suppressive function, is capable of inducing DNMT1 expression and promotes the activity of this enzyme resulting in methylation of critical foxp3 loci and downregulation of the transcription factor.	1	9	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	1	2
To identify the signaling mechanism responsible for this up-regulation , we explored the involvement of the three main signals induced by IL-6 ; STAT3 , Akt and ERK 1/2 .	To identify the signaling mechanism responsible for this up-regulation, we explored the involvement of the three main signals induced by IL-6; STAT3, Akt and ERK 1/2.	18	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	23	24
Our observations on alpha5beta1 role in the activation of IL-6 mediated Stat3 signaling activation in glioma xenograft cells also corroborate previous reports on the role of alpha5beta1 integrin adhesion in elevating the IL-6-mediated STAT3 pathway in multiple myeloma cells .	Our observations on alpha5beta1 role in the activation of IL-6 mediated Stat3 signaling activation in glioma xenograft cells also corroborate previous reports on the role of alpha5beta1 integrin adhesion in elevating the IL-6-mediated STAT3 pathway in multiple myeloma cells.	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	11	12
The role of beta1 integrin in enhancing IL-6 mediated Stat3 signaling in multiple myeloma has been previously elucidated .	The role of beta1 integrin in enhancing IL-6 mediated Stat3 signaling in multiple myeloma has been previously elucidated.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	7	8	9	10
As seen in XREF_FIG B , IL-6 , but not insulin , markedly increased p-STAT3 .	As seen in XREF_FIG B, IL-6, but not insulin, markedly increased p-STAT3.	6	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	6	7	14	15
Given that IL-6 produced by non parenchymal cells activates the transcription factor STAT3 in the liver ,24 the decrease in IL-6 production in gankyrin deficient inflammatory cells may lead to reduced STAT3 activity in tumor cells through a paracrine mechanism .	Given that IL-6 produced by non parenchymal cells activates the transcription factor STAT3 in the liver,24 the decrease in IL-6 production in gankyrin deficient inflammatory cells may lead to reduced STAT3 activity in tumor cells through a paracrine mechanism.	2	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	12	13
HER2 mediated secretion of IL-6 triggered JAK1-Stat3 signaling in an autocrine manner , resulting in amplified IL-6 activation of Stat3 in HER2+ cells and significantly enhanced HER2 mediated transformation .	HER2 mediated secretion of IL-6 triggered JAK1-Stat3 signaling in an autocrine manner, resulting in amplified IL-6 activation of Stat3 in HER2+ cells and significantly enhanced HER2 mediated transformation.	16	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	16	17	19	20
IL-6 is a vascular inflammation indicator and activates JAK and STAT3 signalling to promote atherosclerosis development XREF_BIBR .	IL-6 is a vascular inflammation indicator and activates JAK and STAT3 signalling to promote atherosclerosis development XREF_BIBR.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	10	11
Our computational modeling are further supported by Bazedoxifene can inhibit P-STAT3 induced by IL-6 and IL-11 .	Our computational modeling are further supported by Bazedoxifene can inhibit P-STAT3 induced by IL-6 and IL-11.	9	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	P-STAT3	P-STAT3	P-STAT3	13	14	10	11
More recently , several studies have indicated that IL-6 triggers muscle atrophy by activating the STAT3 ( Signal transducer and activator of transcription 3 ) pathway ( Bonetto etal , 2011 , 2012 ; Sala & Sacco , 2016 ; Zimmers etal , 2016 ) .	More recently, several studies have indicated that IL-6 triggers muscle atrophy by activating the STAT3 (Signal transducer and activator of transcription 3) pathway (Bonetto etal, 2011, 2012; Sala & Sacco, 2016; Zimmers etal, 2016).	8	25	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	15	16
IFN-gamma is a potent activator of Stat1 , while IL-6 primarily activates Stat3 .	IFN-gamma is a potent activator of Stat1, while IL-6 primarily activates Stat3.	9	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	12	13
IL-6 promotes Stat3 activation and Socs3 is part of a negative-feedback loop to inhibit Stat3 activation .	IL-6 promotes Stat3 activation and Socs3 is part of a negative-feedback loop to inhibit Stat3 activation.	0	3	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	2	3
Indeed , STAT3 is activated not only by IL-6 but also by other cytokines and factors in the microenvironment , including IL-11 , IL-22 , HGF and EGF family members , at least during colitis stage and potentially during CAC and CRC tumorigenesis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Indeed, STAT3 is activated not only by IL-6 but also by other cytokines and factors in the microenvironment, including IL-11, IL-22, HGF and EGF family members, at least during colitis stage and potentially during CAC and CRC tumorigenesis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	2	3
It is known that IL-6 induces a transient STAT3 signal and that IL-10 induces a sustained STAT3 signal due to the STAT3 induced inhibitor SOCS3 ' s ability to bind to the IL-6R and not the IL-10R .	It is known that IL-6 induces a transient STAT3 signal and that IL-10 induces a sustained STAT3 signal due to the STAT3 induced inhibitor SOCS3 's ability to bind to the IL-6R and not the IL-10R.	4	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	8	9
We found that evodiamine suppressed both constitutive and interleukin-6 ( IL-6 )-induced activation of STAT3 tyrosine 705 ( Tyr ( 705 ) ) effectively .	We found that evodiamine suppressed both constitutive and interleukin-6 (IL-6)-induced activation of STAT3 tyrosine 705 (Tyr (705)) effectively.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	14	15
It is well known that IL-6 activates Stat3 to suppress gluconeogenesis .	It is well known that IL-6 activates Stat3 to suppress gluconeogenesis.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	5	6	7	8
For example , IL-6 activates STAT3 , which regulates a number of genes involved in proliferation , apoptosis , and angiogenesis [ XREF_BIBR ] .	For example, IL-6 activates STAT3, which regulates a number of genes involved in proliferation, apoptosis, and angiogenesis [XREF_BIBR].	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
Then , IL-6 in turn activated JAK2 and STAT3 signaling and subsequently up-regulated its downstream targets IL-8 , MMP2 , and VEGF .	Then, IL-6 in turn activated JAK2 and STAT3 signaling and subsequently up-regulated its downstream targets IL-8, MMP2, and VEGF.	2	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
Accumulating evidence suggests that IL-6 and other members of the IL-6 family that activate STAT3 , such as IL-11 , leukemia inhibitory factor , oncostatin M and ciliary neurotrophic factor , play an important role in the development and progression of cachexia and have increasingly been implicated in the molecular mechanisms of muscle atrophy .	Accumulating evidence suggests that IL-6 and other members of the IL-6 family that activate STAT3, such as IL-11, leukemia inhibitory factor, oncostatin M and ciliary neurotrophic factor, play an important role in the development and progression of cachexia and have increasingly been implicated in the molecular mechanisms of muscle atrophy.	10	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	14	15
IL-6 has been shown to activate STAT3 , whereas STAT3 activates in turn VEGF and tumor angiogenesis .	IL-6 has been shown to activate STAT3, whereas STAT3 activates in turn VEGF and tumor angiogenesis.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
This suggests that Stat3 dependent tumorigenesis is mediated by IL6 .	This suggests that Stat3 dependent tumorigenesis is mediated by IL6.	3	10	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	9	10	3	4
IL-6 induces the STAT3 signaling pathway in tumor cells .	IL-6 induces the STAT3 signaling pathway in tumor cells.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
STAT3 is induced by IL-6 and LIF during myeloid cell differentiation .	STAT3 is induced by IL-6 and LIF during myeloid cell differentiation.	0	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
The IL-6 signaling pathway activates the transcription factor signal transducer and activator of transcription 3 ( STAT3 ) , which has been reported to be involved in the regulation of CTSS activity 24 We first asked whether IL-6 exerts a direct effect on Ctss expression .	The IL-6 signaling pathway activates the transcription factor signal transducer and activator of transcription 3 (STAT3), which has been reported to be involved in the regulation of CTSS activity 24 We first asked whether IL-6 exerts a direct effect on Ctss expression.	1	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	16	17
Because IL-6 and IL-21 can activate STAT3 pathway , we examined whether activation of STAT3 is required for ETV5 mediated induction of Maf expression .	Because IL-6 and IL-21 can activate STAT3 pathway, we examined whether activation of STAT3 is required for ETV5 mediated induction of Maf expression.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	6	7
The activation of JAK and STAT3 signaling by IL-6 is tightly regulated by SOCS ( suppressor of cytokine signaling ) and PIAS ( protein inhibitor of activated STAT ) .	The activation of JAK and STAT3 signaling by IL-6 is tightly regulated by SOCS (suppressor of cytokine signaling) and PIAS (protein inhibitor of activated STAT).	3	9	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	5	6
Finally , as in LCL8664 cells , IL-6 was shown to activate the STAT3 pathway in UMCL01-101 even in the presence of TGF-beta1 .	Finally, as in LCL8664 cells, IL-6 was shown to activate the STAT3 pathway in UMCL01-101 even in the presence of TGF-beta1.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	13	14
Reduced NF-KB additionally may reduce IL-6 mRNA expression , which in turn could inhibit IL-6 protein expression and reduce STAT-3 activation and affect its target genes ( such as IL-6 and c-myc ) involved in cell proliferation .	Reduced NF-KB additionally may reduce IL-6 mRNA expression, which in turn could inhibit IL-6 protein expression and reduce STAT-3 activation and affect its target genes (such as IL-6 and c-myc) involved in cell proliferation.	1	20	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	NF-KB additionally may reduce IL-6 mRNA expression	il-6	STAT-3	STAT-3	stat-3	5	6	19	20
In Schwann cells , IL-6 , acting via gp130 , and NRG-1 , acting via ErbB2/3 , can both induce STAT3 activation on Ser727 and Tyr705 .	In Schwann cells, IL-6, acting via gp130, and NRG-1, acting via ErbB2/3, can both induce STAT3 activation on Ser727 and Tyr705.	4	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	20	21
STAT3 is activated by binding of Interleukin-6 ( IL-6 ) to the gp130 receptor , which leads to phosphorylation by Janus activated kinase 2 ( JAK2 ) [ XREF_BIBR ] .	STAT3 is activated by binding of Interleukin-6 (IL-6) to the gp130 receptor, which leads to phosphorylation by Janus activated kinase 2 (JAK2) [XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Interleukin-6	Interleukin-6	Interleukin-6	STAT3	STAT3	STAT3	6	7	0	1
In addition , IL-6-induced dimerization of IL-6 receptor activates STAT3 , which contributes to cancer progression in cancer inflammatory environment [ XREF_BIBR , XREF_BIBR ] .	In addition, IL-6-induced dimerization of IL-6 receptor activates STAT3, which contributes to cancer progression in cancer inflammatory environment [XREF_BIBR, XREF_BIBR].	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	9	10
The results from western blot showed that IL-6 can induce STAT3 activation which is consistent with the previous report .	The results from western blot showed that IL-6 can induce STAT3 activation which is consistent with the previous report.	7	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	10	11
We next investigated whether the induction of IL-17 and IL-6 in TPA treated skin mediated downstream Stat3 activation .	We next investigated whether the induction of IL-17 and IL-6 in TPA treated skin mediated downstream Stat3 activation.	5	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	16	17
Despite the lack of a significant difference in the expression levels of phosphorylated Akt between LNCaP/Co and LNCaP and IL-6 # 1 ( data not shown ) , exogenous IL-6 rapidly activated MAPK and STAT3 pathways in LNCaP/Co , but not in LNCaP and IL-6 # 1 ; that is , phosphorylated p44/42 MAPK and STAT3 , which were not induced in LNCaP and IL-6 # 1 , became detectable in LNCaP/Co 5 and 15min after treatment with IL-6 , respectively ( XREF_FIG ) .	Despite the lack of a significant difference in the expression levels of phosphorylated Akt between LNCaP/Co and LNCaP/IL-6# 1 (data not shown), exogenous IL-6 rapidly activated MAPK and STAT3 pathways in LNCaP/Co, but not in LNCaP/IL-6# 1; that is, phosphorylated p44/42 MAPK and STAT3, which were not induced in LNCaP/IL-6# 1, became detectable in LNCaP/Co 5 and 15min after treatment with IL-6, respectively (XREF_FIG).	28	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	29	30	34	35
IL-6 activation of JAK and STAT3 pathway was accompanied by transition from androgen sensitive to androgen-insensitive prostate cancer cell growth .	IL-6 activation of JAK and STAT3 pathway was accompanied by transition from androgen sensitive to androgen-insensitive prostate cancer cell growth.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Further examination of this panel of cytokines indicated exogenous IL-6 and OSM elicited strong pY705 and pS727 Stat3 in both NF and KF , with OSM being the stronger inducer XREF_BIBR .	Further examination of this panel of cytokines indicated exogenous IL-6 and OSM elicited strong pY705 and pS727 Stat3 in both NF and KF, with OSM being the stronger inducer XREF_BIBR.	8	18	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	17	18
Under conditions of Kupffer cell depletion , the phosphorylation of STAT3 was detected in the regenerating liver after hepatectomy , suggesting that IL-6 could be produced by LSECs ( instead of Kupffer cells ) at a sufficient level to activate STAT3 [ XREF_BIBR ] .	Under conditions of Kupffer cell depletion, the phosphorylation of STAT3 was detected in the regenerating liver after hepatectomy, suggesting that IL-6 could be produced by LSECs (instead of Kupffer cells) at a sufficient level to activate STAT3 [XREF_BIBR].	22	42	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	40	41
This was particularly so in the case of IL-6 induced STAT3 activation , that was markedly absent in the mTOR deficient T cells .	This was particularly so in the case of IL-6 induced STAT3 activation, that was markedly absent in the mTOR deficient T cells.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
IL-6 and sIL-6R induced the activation of the transcription factors , STAT3 , NF-kappaB p65 ( nucleus ) , and Bcl-2 .	IL-6 and sIL-6R induced the activation of the transcription factors, STAT3, NF-kappaB p65 (nucleus), and Bcl-2.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	11	12
Hyper activation of NFkappaB can increase the production of IL-6 , which can then act on IECs to activate STAT3 .	Hyper activation of NFkappaB can increase the production of IL-6, which can then act on IECs to activate STAT3.	7	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	19	20
XREF_BIBR By contrast , IL-6 , which is known to activate STAT3 in other contexts , does not play a role in control of STAT3 activity during this process .	XREF_BIBR By contrast, IL-6, which is known to activate STAT3 in other contexts, does not play a role in control of STAT3 activity during this process.	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	11	12
To verify that IL-6R was functional in NBT2 cells , we tested the activation of STAT3 in cells treated with exogenous IL-6 in the presence of sIL-6R , the mediator of IL-6 trans signaling .	To verify that IL-6R was functional in NBT2 cells, we tested the activation of STAT3 in cells treated with exogenous IL-6 in the presence of sIL-6R, the mediator of IL-6 trans signaling.	13	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	15	16
This protein reduction results from excessive protein degradation by the ubiquitin-proteasome system ( UPS ) , in which the protein selective E3-ligase , ubiquitin protein ligase E3 component n-recognin 1 ( Ubr1 ) [ XREF_BIBR ] , is upregulated by STAT3 activation downstream of inflammatory signals , such as interleukin-6 ( IL-6 ) .	This protein reduction results from excessive protein degradation by the ubiquitin-proteasome system (UPS), in which the protein selective E3-ligase, ubiquitin protein ligase E3 component n-recognin 1 (Ubr1) [XREF_BIBR], is upregulated by STAT3 activation downstream of inflammatory signals, such as interleukin-6 (IL-6).	40	52	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	51	52	40	41
For instance , IL-6 and its receptor were implicated in the progression of non small cell lung carcinoma ( NSCLC ) XREF_BIBR and were shown to induce enhanced STAT3 activity XREF_BIBR .	For instance, IL-6 and its receptor were implicated in the progression of non small cell lung carcinoma (NSCLC) XREF_BIBR and were shown to induce enhanced STAT3 activity XREF_BIBR.	3	29	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	28	29
Several recent studies have shown that the proinflammatory cytokine IL-6 directly acts on epithelial cells to induce the activation of signal transducer and activator of transcription 3 ( STAT3 ) and thereby induces the proliferation of epithelial cells in AOM+ DSS colitis .	Several recent studies have shown that the proinflammatory cytokine IL-6 directly acts on epithelial cells to induce the activation of signal transducer and activator of transcription 3 (STAT3) and thereby induces the proliferation of epithelial cells in AOM+DSS colitis.	6	32	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	28	29
Specifically , in the absence of androgens , IL-6 was shown to induce association of Stat3 and AR , followed by increased expression of AR regulated genes [ XREF_BIBR ] .	Specifically, in the absence of androgens, IL-6 was shown to induce association of Stat3 and AR, followed by increased expression of AR regulated genes [XREF_BIBR].	8	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	8	9	15	16
In our rodent model of T/HS we found increased Stat3 activation in the livers of rats subjected to T/HS and treated with IL-6 at the beginning of resuscitation .	In our rodent model of T/HS we found increased Stat3 activation in the livers of rats subjected to T/HS and treated with IL-6 at the beginning of resuscitation.	9	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	22	23	9	10
Paracrine IL-6 enhances autocrine IL-6 and pStat3 signaling and migration in MCF-10A-Ras cells .	Paracrine IL-6 enhances autocrine IL-6 and pStat3 signaling and migration in MCF-10A-Ras cells.	0	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pStat3	pStat3	pStat3	1	2	6	7
IL-6 can activate Stat3 through the gp130 subunit and mediate the diverse effects of Stat3 in development and diseases .	IL-6 can activate Stat3 through the gp130 subunit and mediate the diverse effects of Stat3 in development and diseases.	0	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	14	15
IL-6 in turn acts on the myeloma cells in paracrine manner to activate the STAT3 signaling cascade .	IL-6 in turn acts on the myeloma cells in paracrine manner to activate the STAT3 signaling cascade.	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	14	15
miR-1195 has been shown by in silico analysis to bind STAT3 [ XREF_BIBR ] , while miR-181a-5p has been shown with quantitative RT-PCR to be increased after activation of STAT3 by IL-6 [ XREF_BIBR ] .	miR-1195 has been shown by in silico analysis to bind STAT3 [XREF_BIBR], while miR-181a-5p has been shown with quantitative RT-PCR to be increased after activation of STAT3 by IL-6 [XREF_BIBR].	27	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	31	32	29	30
IL-6 activates STAT3 , resulting in the initiation of liver regeneration after PH [ XREF_BIBR ] .	IL-6 activates STAT3, resulting in the initiation of liver regeneration after PH [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Interestingly , IL-6 is known to activate STAT3 which in turn interacts with NF-kappaB to form ReLA survival complex that gives the radio resistant property to cancer cells 52 .	Interestingly, IL-6 is known to activate STAT3 which in turn interacts with NF-kappaB to form ReLA survival complex that gives the radio resistant property to cancer cells 52.	2	15	activate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	STAT3	STAT3 which in turn interacts with NF-kappaB	stat3	2	3	7	8
Addition of IL-6 induced STAT3 activation in Hep3B cells and led to protection against doxorubicin .	Addition of IL-6 induced STAT3 activation in Hep3B cells and led to protection against doxorubicin.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
Through IL-6 activation of STAT3 , MCP-1 is also expressed by VSMCs and may increase macrophage abundance in the aortic media to create an environment susceptible to dilation .	Through IL-6 activation of STAT3, MCP-1 is also expressed by VSMCs and may increase macrophage abundance in the aortic media to create an environment susceptible to dilation.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	4	5
XREF_BIBR , XREF_BIBR Besides , as a critical NF-kappaB-dependent pro tumorigenic cytokine produced by lamina propria myeloid cells , IL-6 activates STAT3 in both inflammatory cells and the epithelial cells from where the tumors arose .	XREF_BIBR, XREF_BIBR Besides, as a critical NF-kappaB-dependent pro tumorigenic cytokine produced by lamina propria myeloid cells, IL-6 activates STAT3 in both inflammatory cells and the epithelial cells from where the tumors arose.	19	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	21	22
These IL6ST mutations lead to ligand independent activation of the IL-6 receptor , which promotes STAT3 signaling and induces the acute-phase inflammatory response within hepatocytes .	These IL6ST mutations lead to ligand independent activation of the IL-6 receptor, which promotes STAT3 signaling and induces the acute-phase inflammatory response within hepatocytes.	10	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	15	16
IL-6 acts on hepatocytes via the IL-6 receptor , activating the signal transducer and activator of transcription 3 ( STAT3 ) and extracellular signal related kinase 1 and 2 ( ERK1/2 ) pathways XREF_BIBR XREF_BIBR .	IL-6 acts on hepatocytes via the IL-6 receptor, activating the signal transducer and activator of transcription 3 (STAT3) and extracellular signal related kinase 1 and 2 (ERK1/2) pathways XREF_BIBR XREF_BIBR.	0	20	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	19	20
The compound induces apoptosis in MDA-MB-231 cells by inhibiting IL-6 family induced STAT3 activity through the IL-6/JAK/STAT3 signaling pathway .	The compound induces apoptosis in MDA-MB-231 cells by inhibiting IL-6 family induced STAT3 activity through the IL-6/JAK/STAT3 signaling pathway.	9	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	12	13
We found that AKBA also suppressed STAT3 activation induced by IL-6 , one of many tumor cell growth factors that activate STAT3 .	We found that AKBA also suppressed STAT3 activation induced by IL-6, one of many tumor cell growth factors that activate STAT3.	6	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	6	7
Because IL-6 activates Signal transducer and activator of transcription 3 ( STAT3 ) for epithelial survival , the changes in STAT3 signaling and IL-6 production in the inflamed colonic tissue need to be further studied .	Because IL-6 activates Signal transducer and activator of transcription 3 (STAT3) for epithelial survival, the changes in STAT3 signaling and IL-6 production in the inflamed colonic tissue need to be further studied.	1	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	11	12
Mechanistically IL6 causes STAT-3 activation leading to proconvertase 1/3 -- the relevant GLP-1 processing enzyme -- and proglucagon expression [ XREF_BIBR ] .	Mechanistically IL6 causes STAT-3 activation leading to proconvertase 1/3 -- the relevant GLP-1 processing enzyme -- and proglucagon expression [XREF_BIBR].	1	4	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT-3	STAT-3	STAT-3	1	2	3	4
Recombinant IL-6 and MF-CM activated STAT3 and upregulated TGF-beta in cancer cells .	Recombinant IL-6 and MF-CM activated STAT3 and upregulated TGF-beta in cancer cells.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	5	6
In this manuscript we report that aberrant activation of PI3K and Akt pathway plays a critical role in the proliferation , self-renewal and tumorigenicity of NSCLC TICs by establishing an autocrine IL-6 and IL-6r signalling loop that activates STAT3 .	In this manuscript we report that aberrant activation of PI3K and Akt pathway plays a critical role in the proliferation, self-renewal and tumorigenicity of NSCLC TICs by establishing an autocrine IL-6 and IL-6r signalling loop that activates STAT3.	28	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	31	32	38	39
We show that IL-6 leads to transcriptional activation of signal transducer and activator of transcription 3 ( STAT3 ) in human SH-SY5Y neuroblastoma cells .	We show that IL-6 leads to transcriptional activation of signal transducer and activator of transcription 3 (STAT3) in human SH-SY5Y neuroblastoma cells.	3	18	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	17	18
Subsequently , many research teams have found that polarization of Th17 can be efficiently induced by transforming growth factor-beta1 ( TGF-beta1 ) and IL-6 , which activate Smad family proteins and STAT3 , respectively .	Subsequently, many research teams have found that polarization of Th17 can be efficiently induced by transforming growth factor-beta1 (TGF-beta1) and IL-6, which activate Smad family proteins and STAT3, respectively.	16	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	23	24	31	32
However , when STAT1 could only be activated by IFN-gamma and STAT3 could only be activated by IL-6 , combined stimulation still caused greater activation of STAT1 and STAT3 than separate stimulation .	However, when STAT1 could only be activated by IFN-gamma and STAT3 could only be activated by IL-6, combined stimulation still caused greater activation of STAT1 and STAT3 than separate stimulation.	11	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	11	12
IL-6 and leptin have been shown to activate STAT3 in hepatic stellate cells and promote their survival and proliferation , thereby contributing to liver fibrogenesis XREF_BIBR , XREF_BIBR .	IL-6 and leptin have been shown to activate STAT3 in hepatic stellate cells and promote their survival and proliferation, thereby contributing to liver fibrogenesis XREF_BIBR, XREF_BIBR.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	8	9
The related cytokines Il-6 , ciliary neurotrophic factor , as well as epidermal growth factor , do not activate Stat3 , although epidermal growth factor stimulates mitogen activated protein kinase .	The related cytokines Il-6, ciliary neurotrophic factor, as well as epidermal growth factor, do not activate Stat3, although epidermal growth factor stimulates mitogen activated protein kinase.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Il-6	Il-6	Il-6	Stat3	Stat3	Stat3	3	4	19	20
IL-6 stimulation of WT-STAT3 induced the luciferase reporter gene 15-to 20-fold ( XREF_FIG ) .	IL-6 stimulation of WT-STAT3 induced the luciferase reporter gene 15-to 20-fold (XREF_FIG).	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	WT-STAT3	WT-STAT3	WT-STAT3	0	1	3	4
To determine if IL-6 activation of Stat3 was also important for the anti-apoptotic effects of IL-6 in SBR50 , we examined the hearts of SBR50/IL -6 rats pre-treated with GQ-ODN vs. NS-ODN for nucleosome levels and TUNEL positive nuclei .	To determine if IL-6 activation of Stat3 was also important for the anti-apoptotic effects of IL-6 in SBR50, we examined the hearts of SBR50/IL -6 rats pre-treated with GQ-ODN vs. NS-ODN for nucleosome levels and TUNEL positive nuclei.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	6	7
IL-6 also activates STAT3 causing direct activation of miR-21 and miR-18b-1 , which respectively inhibit PTEN and CYLD ( tumor suppressor genes ) .	IL-6 also activates STAT3 causing direct activation of miR-21 and miR-18b-1, which respectively inhibit PTEN and CYLD (tumor suppressor genes).	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
In addition to IL-11 , IL-22 , HGF , and EGF family members , the proinflammatory cytokine IL-6 is a potent activator of STAT3 .	In addition to IL-11, IL-22, HGF, and EGF family members, the proinflammatory cytokine IL-6 is a potent activator of STAT3.	14	24	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	23	24
For example , Interleukin 6 activates STAT3 to induce the transcription of miR-21 and miR-181-b1 genes .	For example, Interleukin 6 activates STAT3 to induce the transcription of miR-21 and miR-181-b1 genes.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin 6	Interleukin 6	Interleukin 6	STAT3	STAT3	STAT3	3	5	6	7
IL-6 recognition by IL-6R was shown to induce pro inflammatory STAT3 activation both in vivo and in vitro , in various cell types , including HEK 293 cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	IL-6 recognition by IL-6R was shown to induce pro inflammatory STAT3 activation both in vivo and in vitro, in various cell types, including HEK 293 cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	10	11
We conclude that IL-6 promotes the EMT process , possibly by activating the JAK2 and STAT3 signaling pathway .	We conclude that IL-6 promotes the EMT process, possibly by activating the JAK2 and STAT3 signaling pathway.	3	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	15	16
These effects result from a point mutation in gp130 , leading to enhanced STAT3 activation by IL-6 .	These effects result from a point mutation in gp130, leading to enhanced STAT3 activation by IL-6.	13	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	13	14
As a member of signal transducers and activators of transcription ( STATs ) family , STAT3 mainly activated by IL-6 is a vital transcription factor providing hepatoprotection against Fas mediated apoptotic liver damage by two mechanisms : direct inactivation of caspases and reduction of reactive oxygen species [ XREF_BIBR ] .	As a member of signal transducers and activators of transcription (STATs) family, STAT3 mainly activated by IL-6 is a vital transcription factor providing hepatoprotection against Fas mediated apoptotic liver damage by two mechanisms : direct inactivation of caspases and reduction of reactive oxygen species [XREF_BIBR].	15	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	15	16
The reduction in beta-catenin protein was not prevented by proteasome inhibition , and IL6 induced STAT3 activation resulted in increased beta-catenin mRNA .	The reduction in beta-catenin protein was not prevented by proteasome inhibition, and IL6 induced STAT3 activation resulted in increased beta-catenin mRNA.	13	16	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	13	14	15	16
For example , IL-6 and TNF have been shown to activate STAT3 , IL-6 mediates its effects through the STAT3 pathway , and STAT3 competes with the transcription factor NF-kappaB .	For example, IL-6 and TNF have been shown to activate STAT3, IL-6 mediates its effects through the STAT3 pathway, and STAT3 competes with the transcription factor NF-kappaB.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	11	12
IL-6 activates STAT3 exclusively ; when IL-6 levels were raised 10 to 100 fold , STAT1 activation was noted as well [ XREF_BIBR , XREF_BIBR ] .	IL-6 activates STAT3 exclusively; when IL-6 levels were raised 10 to 100 fold, STAT1 activation was noted as well [XREF_BIBR, XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Stroma derived factors regulate tumor growth by acting in a paracrine manner to alter signaling pathways in tumor cells , such as activation of NF-kappaB by TNF and IL-1 , and activation of STAT3 by IL-6 .	Stroma derived factors regulate tumor growth by acting in a paracrine manner to alter signaling pathways in tumor cells, such as activation of NF-kappaB by TNF and IL-1, and activation of STAT3 by IL-6.	13	36	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	35	36	33	34
The neuroprotective growth factors CNTF , IL6 , OSM and LIF induce STAT3 activation and protect against light toxicity and mutation damage XREF_BIBR , XREF_BIBR , XREF_BIBR .	The neuroprotective growth factors CNTF, IL6, OSM and LIF induce STAT3 activation and protect against light toxicity and mutation damage XREF_BIBR, XREF_BIBR, XREF_BIBR.	4	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	6	7	12	13
With activated STAT3 , IL-6 emerges senescent at early passages in cervical cancer tissues infected with high-risk HPV and activates the STAT3 and cellular senescence [ XREF_BIBR ] .	With activated STAT3, IL-6 emerges senescent at early passages in cervical cancer tissues infected with high-risk HPV and activates the STAT3 and cellular senescence [XREF_BIBR].	4	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	21	22
Thus , T cells treated with IL-21+ IL-6 had a high pSTAT3 : pSTAT1 ratio similar to T cells treated with IL-6 alone and showed a similar degree of Th17 differentiation .	Thus, T cells treated with IL-21+ IL-6 had a high pSTAT3 : pSTAT1 ratio similar to T cells treated with IL-6 alone and showed a similar degree of Th17 differentiation.	8	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	21	22	11	12
To determine whether TGF-beta inhibition of IL-6-induced SOCS3 expression would result in enhanced STAT3 activation , STAT3 phosphorylation at both Tyr and Ser sites was measured at a series of time points from 15 min to 8 h. IL-6 stimulated STAT3 activation in naive CD4 + T cells by 15 min , which peaked at 1 h and then declined at 2 h. Treatment with TGF-beta did not affect IL-6-induced STAT3 activation at the earlier time point ( 15 min ) , but enhanced STAT-3 activation at 0.5 h and at each subsequent time point ( XREF_FIG ) .	To determine whether TGF-beta inhibition of IL-6-induced SOCS3 expression would result in enhanced STAT3 activation, STAT3 phosphorylation at both Tyr and Ser sites was measured at a series of time points from 15 min to 8 h. IL-6 stimulated STAT3 activation in naive CD4 + T cells by 15 min, which peaked at 1 h and then declined at 2 h. Treatment with TGF-beta did not affect IL-6-induced STAT3 activation at the earlier time point (15 min), but enhanced STAT-3 activation at 0.5 h and at each subsequent time point (XREF_FIG).	34	41	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	38	39	40	41
To establish whether STAT3 is activated by IL-6 in HNSCC lines , we transiently stimulated the UM-SCC-1 and UM-SCC-47 scrambled control and RhoC knockdown clones with IL-6 ( 50 etag/ml ) .	To establish whether STAT3 is activated by IL-6 in HNSCC lines, we transiently stimulated the UM-SCC-1 and UM-SCC-47 scrambled control and RhoC knockdown clones with IL-6 (50 etag/ml).	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	3	4
Next , we co-transfected LNCaP cells with a reporter vector containing the Gal4 binding site and an expression vector encoding a chimeric protein consisting of the N-terminal domain ( NTD ) of human AR ( AR-NTD ; amino acids 1-558 ) fused to the Gal4-DNA binding domain ( Gal4DBD ) , which can be activated by forskolin ( FSK ) or IL-6 in the absence of androgen and serum to stimulate PKA and STAT3 signaling , respectively .	Next, we co-transfected LNCaP cells with a reporter vector containing the Gal4 binding site and an expression vector encoding a chimeric protein consisting of the N-terminal domain (NTD) of human AR (AR-NTD; amino acids 1-558) fused to the Gal4-DNA binding domain (Gal4DBD), which can be activated by forskolin (FSK) or IL-6 in the absence of androgen and serum to stimulate PKA and STAT3 signaling, respectively.	54	74	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	61	62	73	74
CHX completely blocked the induction of phosphotyrosine 705 STAT3 s in nuclear extracts from B-2 cells treated with anti-Ig for 3 h , whereas CHX had no effect on phosphotyrosine 705 STAT3 stimulated by IL-6 .	CHX completely blocked the induction of phosphotyrosine 705 STAT3 s in nuclear extracts from B-2 cells treated with anti-Ig for 3 h, whereas CHX had no effect on phosphotyrosine 705 STAT3 stimulated by IL-6.	27	35	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	34	35	31	32
We documented that IL-6 secreted by IR cells activates the JAK2 and STAT3 pathway through IL-6 receptor in cancer cells , leading to the IGF-1Ec upregulation and PEc secretion , as well as to the IL-6 expression and secretion .	We documented that IL-6 secreted by IR cells activates the JAK2 and STAT3 pathway through IL-6 receptor in cancer cells, leading to the IGF-1Ec upregulation and PEc secretion, as well as to the IL-6 expression and secretion.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	12	13
In turn , IL-6 activates STAT3 , leading to transcriptional upregulation of downstream growth related genes .	In turn, IL-6 activates STAT3, leading to transcriptional upregulation of downstream growth related genes.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
SOCS3 Inhibits IL-6 Cytokine induced STAT3 Activation and Protective Effect on Neurons .	SOCS3 Inhibits IL-6 Cytokine induced STAT3 Activation and Protective Effect on Neurons.	2	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	5	6
Despite being considered a prototypic M2 myeloid cell marker of alternative activation , Arg1 can also be expressed by CAMPhi in a STAT3 dependent pathway activated by IL-10 , IL-6 or macrophage colony stimulating factor ( M-CSF ) [ XREF_BIBR ] .	Despite being considered a prototypic M2 myeloid cell marker of alternative activation, Arg1 can also be expressed by CAMPhi in a STAT3 dependent pathway activated by IL-10, IL-6 or macrophage colony stimulating factor (M-CSF) [XREF_BIBR].	22	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	29	30	22	23
By contrast , IL-6 is a potent activator of STAT3 , which contributes to its anti-inflammatory functions [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	By contrast, IL-6 is a potent activator of STAT3, which contributes to its anti-inflammatory functions [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	12	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	9	10
Although a similar mechanism is considered in cervical cancer , there is no report other than that of XREF_BIBR that revealed the activation of Stat3 mediated by IL-6 .	Although a similar mechanism is considered in cervical cancer, there is no report other than that of XREF_BIBR that revealed the activation of Stat3 mediated by IL-6.	22	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	27	28	24	25
IL-6 in turn activates JAK2 and STAT3 and subsequently stimulates IL-8 , MMP2 , and VEGF production .	IL-6 in turn activates JAK2 and STAT3 and subsequently stimulates IL-8, MMP2, and VEGF production.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
Taken together , these data indicate that IL-6 release by MSCs activates the IL-6 and STAT3 signaling pathway in neurons following OGD but has no effect on the suppression of apoptosis .	Taken together, these data indicate that IL-6 release by MSCs activates the IL-6 and STAT3 signaling pathway in neurons following OGD but has no effect on the suppression of apoptosis.	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	15	16
Cells from SOCS1 knockout mice showed that , at physiological levels , SOCS1 has no effect on the magnitude or duration of IL6 induced Stat3 activation but does have a significant inhibitory effect on the magnitude of IL6 induced Stat1 activation XREF_BIBR , so it is possible that SOCS1 is responsible for the pathway specific regulation of IL-6 signaling in early SLE .	Cells from SOCS1 knockout mice showed that, at physiological levels, SOCS1 has no effect on the magnitude or duration of IL6 induced Stat3 activation but does have a significant inhibitory effect on the magnitude of IL6 induced Stat1 activation XREF_BIBR, so it is possible that SOCS1 is responsible for the pathway specific regulation of IL-6 signaling in early SLE.	18	25	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	22	23	24	25
Most recently , and relevant to this study , was the discovery that Ahsp gene expression increased in K562 cells upon cytokine Il6 induced STAT3 activation [ XREF_BIBR ] .	Most recently, and relevant to this study, was the discovery that Ahsp gene expression increased in K562 cells upon cytokine Il6 induced STAT3 activation [XREF_BIBR].	16	25	induced	Positive_early_activation	Positive_activation	Positive_activation	Il6	Il6	Il6	STAT3	STAT3	STAT3	22	23	24	25
These results demonstrate that EGF and IL-6 increased activated STAT3 in the nuclei of prostate cancer cells and the inhibitors had the opposite effect .	These results demonstrate that EGF and IL-6 increased activated STAT3 in the nuclei of prostate cancer cells and the inhibitors had the opposite effect.	4	12	increased activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	9	10
IL-6 induces STAT3 activation , and persistently activated STAT3 promotes the proliferation and metastasis of many cancers [ XREF_BIBR ] .	IL-6 induces STAT3 activation, and persistently activated STAT3 promotes the proliferation and metastasis of many cancers [XREF_BIBR].	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
The results revaled that STAT3 protein was significantly activated and phosphorylated by IL-6 , accompanied by the increased levels of alpha-SMA protein ( XREF_FIG ) .	The results revaled that STAT3 protein was significantly activated and phosphorylated by IL-6, accompanied by the increased levels of alpha-SMA protein (XREF_FIG).	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	4	5
Importantly , STAT3 is prominently activated at sites of chronic inflammation by IL-6 and initiates a positive that is highly predisposing condition for cancer [ XREF_BIBR ] .	Importantly, STAT3 is prominently activated at sites of chronic inflammation by IL-6 and initiates a positive that is highly predisposing condition for cancer [XREF_BIBR].	2	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	2	3
Thus , the withdrawal of IL-6 mediated STAT3 signaling may be necessary for differentiation to occur .	Thus, the withdrawal of IL-6 mediated STAT3 signaling may be necessary for differentiation to occur.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
Therefore , this ruled out the possibility that the increased level of c-myc protein might be the consequence of transcriptional changes of c-MYC mRNA expression due to STAT3 activation by IL-6 .	Therefore, this ruled out the possibility that the increased level of c-myc protein might be the consequence of transcriptional changes of c-MYC mRNA expression due to STAT3 activation by IL-6.	27	31	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	30	31	27	28
IL-6 induces ROR1 promoter activity in MM1 cells by activating Stat3 .	IL-6 induces ROR1 promoter activity in MM1 cells by activating Stat3.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	10	11
IL-6 treatment increased the activity of STAT3 , which could be blocked by luteolin .	IL-6 treatment increased the activity of STAT3, which could be blocked by luteolin.	0	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
XREF_BIBR In these cells , activation of STAT3 by IL-6 treatment suppresses apoptosis as assessed by TUNEL staining , and knockdown of either STAT3 or Oct-1 by RNA interference enhances apoptosis .	XREF_BIBR In these cells, activation of STAT3 by IL-6 treatment suppresses apoptosis as assessed by TUNEL staining, and knockdown of either STAT3 or Oct-1 by RNA interference enhances apoptosis.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	7	8
Ueda ' s group found that , in LNCaP cells , IL-6 activates the whole JAK and STAT3 system with consequent STAT3 phosphorylation at both sites of regulation ( Tyr 705 and Ser 727 , respectively ) .	Ueda 's group found that, in LNCaP cells, IL-6 activates the whole JAK and STAT3 system with consequent STAT3 phosphorylation at both sites of regulation (Tyr 705 and Ser 727, respectively).	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	17	18
IL-6 treatment also induced STAT3 activation in HSCs ( XREF_SUPPLEMENTARY ) ; however , the roles of STAT3 in liver fibrogenesis remain controversial .	IL-6 treatment also induced STAT3 activation in HSCs (XREF_SUPPLEMENTARY); however, the roles of STAT3 in liver fibrogenesis remain controversial.	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Because IL-6 family cytokines activate ERK and MAPK and PI3K and Akt pathways as well as JAK and STAT3 pathway through its receptor gp130 , these pathways may lead to compensation of proliferation in STAT3 deficient hepatocytes .	Because IL-6 family cytokines activate ERK and MAPK and PI3K and Akt pathways as well as JAK and STAT3 pathway through its receptor gp130, these pathways may lead to compensation of proliferation in STAT3 deficient hepatocytes.	1	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	18	19
Here we show that the proinflammatory cytokine interleukin-6 ( IL-6 ) has prosurvival effects and chronically activates the Jak2 and STAT3 signalling pathway in a model of benign prostatic hyperplasia ( BPH-1 ) .	Here we show that the proinflammatory cytokine interleukin-6 (IL-6) has prosurvival effects and chronically activates the Jak2 and STAT3 signalling pathway in a model of benign prostatic hyperplasia (BPH-1).	7	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	20	21
However , injections of IL-6 restored STAT3 activity through recovery of IL-6R association against ischemic reperfusion ( XREF_FIG ) .	However, injections of IL-6 restored STAT3 activity through recovery of IL-6R association against ischemic reperfusion (XREF_FIG).	2	7	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
In contrast to STAT-1 , STAT-3 , which is activated by the IL-6 cytokine family , has cardioprotective effects in cardiac myocytes exposed to I/R .	In contrast to STAT-1, STAT-3, which is activated by the IL-6 cytokine family, has cardioprotective effects in cardiac myocytes exposed to I/R.	5	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	12	13	5	6
In contrast , IL-6 reportedly activates STAT3 and failed to support in vitro HSC self-renewal in our previous study .	In contrast, IL-6 reportedly activates STAT3 and failed to support in vitro HSC self-renewal in our previous study.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	6	7
In this context it is of interest that IL-6 together with IL-21 and IL-23 promote sustained STAT3 activation , which favors the Th17 developmental program of CD4+ lymphocytes [ XREF_BIBR ] .	In this context it is of interest that IL-6 together with IL-21 and IL-23 promote sustained STAT3 activation, which favors the Th17 developmental program of CD4+ lymphocytes [XREF_BIBR].	8	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	16	17
IFN-gamma and IL-6 activate STAT-1 and STAT-3 transcription factors respectively , which interact with their cis-elements on MUC1 promoter to upregulate its expression in tumor cells .	IFN-gamma and IL-6 activate STAT-1 and STAT-3 transcription factors respectively, which interact with their cis-elements on MUC1 promoter to upregulate its expression in tumor cells.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	2	3	6	7
We now show that IL-6-induced AR mediated gene activation requires the activation of STAT3 by IL-6 in LNCaP prostate cancer cells .	We now show that IL-6-induced AR mediated gene activation requires the activation of STAT3 by IL-6 in LNCaP prostate cancer cells.	9	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	13	14
Similarly , inhibition of NF-kappaB by the super-repressor of IkappaB ( S32/36A ) abrogated the IL-6 paracrine activation of STAT3 in HNSCC cells .	Similarly, inhibition of NF-kappaB by the super-repressor of IkappaB (S32/36A) abrogated the IL-6 paracrine activation of STAT3 in HNSCC cells.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	19	20
We were able to show that SH2D4A and SORBS3 represent two tumor suppressor genes that cooperate to inhibit IL-6 mediated STAT3 ( Signal Transducer and Activator of Transcription 3 ) signaling in hepatocarcinogenesis .	We were able to show that SH2D4A and SORBS3 represent two tumor suppressor genes that cooperate to inhibit IL-6 mediated STAT3 (Signal Transducer and Activator of Transcription 3) signaling in hepatocarcinogenesis.	17	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	20	21
In this report , we demonstrate that IL-6 treatment induces STAT3 activation ( pSTAT3 ) , pSTAT3 binds to the human C/EBPdelta gene promoter and induces its expression .	In this report, we demonstrate that IL-6 treatment induces STAT3 activation (pSTAT3), pSTAT3 binds to the human C/EBPdelta gene promoter and induces its expression.	7	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	10	11
IL-6 induces the activation of signal transducer and activator of transcription 3 ( STAT3 ) transcription factor .	IL-6 induces the activation of signal transducer and activator of transcription 3 (STAT3) transcription factor.	0	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	13	14
We next considered IL-6 activation of STAT1 and STAT3 byEMSA .	We next considered IL-6 activation of STAT1 and STAT3 byEMSA.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	8	9
IL-27 and the related cytokine family member , IL-6 , signal through the common receptor signalling chain , gp130 , to activate STAT3 XREF_BIBR .	IL-27 and the related cytokine family member, IL-6, signal through the common receptor signalling chain, gp130, to activate STAT3 XREF_BIBR.	6	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	22	23
XREF_BIBR , XREF_BIBR IL-6 produced by myeloid cells infiltrating the pre-cancerous tissue activates STAT3 in IECs , thus triggering survival and proliferation of pre-malignant cells and supporting a persistent inflammatory microenvironment that later will also sustain STAT3 dependent tumor growth .	XREF_BIBR, XREF_BIBR IL-6 produced by myeloid cells infiltrating the pre-cancerous tissue activates STAT3 in IECs, thus triggering survival and proliferation of pre-malignant cells and supporting a persistent inflammatory microenvironment that later will also sustain STAT3 dependent tumor growth.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	13	14
However , even though we induced Stat3 activation by IL-6 treatment in non Stat3 activated AsPC-1 cells , the LTP-1-induced mitotic arrest wo not be affected ( XREF_FIG ) , which indicated the parallel of LTP-1-induced mitotic arrest and LTP-1-inhibited Stat3 phosphorylation .	However, even though we induced Stat3 activation by IL-6 treatment in non Stat3 activated AsPC-1 cells, the LTP-1-induced mitotic arrest wo n't be affected (XREF_FIG), which indicated the parallel of LTP-1-induced mitotic arrest and LTP-1-inhibited Stat3 phosphorylation.	5	14	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	13	14
In conclusion , the present study provides experimental evidence to indicate that cancer chemopreventive agent SFN causes suppression of constitutive as well as IL6 induced activation of STAT3 in human prostate cancer cells irrespective of their androgen-responsiveness .	In conclusion, the present study provides experimental evidence to indicate that cancer chemopreventive agent SFN causes suppression of constitutive as well as IL6 induced activation of STAT3 in human prostate cancer cells irrespective of their androgen-responsiveness.	16	32	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	23	24	27	28
We first chose to knock in the Y705F STAT3 mutant allele into the human colon cancer cell line HCT116 , because we had shown that STAT3 can be activated by interleukin-6 ( IL-6 ) in HCT116 cells and because HCT116 had been widely used for successful gene targeting by homologous recombination .	We first chose to knock in the Y705F STAT3 mutant allele into the human colon cancer cell line HCT116, because we had shown that STAT3 can be activated by interleukin-6 (IL-6) in HCT116 cells and because HCT116 had been widely used for successful gene targeting by homologous recombination.	25	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	30	31	25	26
In support of this concept , MM cells cultured on fibronectin coated surface had more robust IL6 induced STAT3 activation than those cultured in cell suspension [ XREF_BIBR ] .	In support of this concept, MM cells cultured on fibronectin coated surface had more robust IL6 induced STAT3 activation than those cultured in cell suspension [XREF_BIBR].	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	16	17	18	19
IL-6 cytokines preferentially activate STAT-3 , leading to dimerization , nuclear translocation , and binding to Interferon-Gamma [ IFN-gamma ] Activated Site like DNA elements .	IL-6 cytokines preferentially activate STAT-3, leading to dimerization, nuclear translocation, and binding to Interferon-Gamma [IFN-gamma] Activated Site like DNA elements.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	0	1	4	5
The present study shows that , induced by CSE , IL-6 , a pro inflammatory cytokine , leads to activation of STAT3 , a transcription activator .	The present study shows that, induced by CSE, IL-6, a pro inflammatory cytokine, leads to activation of STAT3, a transcription activator.	10	25	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	21	22
Furthermore , curcumin markedly decreased serum TNF-alpha and IL-6 levels and downregulated renal protein levels of JAK2 and STAT3 pathway components .	Furthermore, curcumin markedly decreased serum TNF-alpha and IL-6 levels and downregulated renal protein levels of JAK2 and STAT3 pathway components.	2	20	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	curcumin markedly decreased serum TNF-alpha and IL-6 levels	il-6	STAT3	STAT3	stat3	8	9	18	19
IL-6 , IL-10 , and IL-27 can all activate STAT3 ( IL-6-STAT3 axis ) and thereby can suppress macrophage immunocompetence .	IL-6, IL-10, and IL-27 can all activate STAT3 (IL-6-STAT3 axis) and thereby can suppress macrophage immunocompetence.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	9	10
This was shown to be independent of gp130 expression and to be due to differential IL-6 signaling in these two fibroblast populations : in normal lung fibroblasts , IL-6 induced sustained STAT3 signaling leading to increased expression of the Cyclin Dependent Kinase Inhibitor ( CDKI ) p19 INK4D ; however , in IPF lung fibroblasts , IL-6 induced sustained SHP-2 and ERK MAPK signaling leading to the decreased expression of the CDKI p27 Kip1 , increased Cyclin D 1 activation , and enhanced proliferation .	This was shown to be independent of gp130 expression and to be due to differential IL-6 signaling in these two fibroblast populations : in normal lung fibroblasts, IL-6 induced sustained STAT3 signaling leading to increased expression of the Cyclin Dependent Kinase Inhibitor (CDKI) p19 INK4D; however, in IPF lung fibroblasts, IL-6 induced sustained SHP-2 and ERK MAPK signaling leading to the decreased expression of the CDKI p27 Kip1, increased Cyclin D 1 activation, and enhanced proliferation.	28	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	28	29	31	32
Paradoxically , the pro inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10 both activate STAT3 , yet generate nearly opposing cellular responses .	Paradoxically, the pro inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10 both activate STAT3, yet generate nearly opposing cellular responses.	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	14	15
Furthermore , at this low concentration of OSM ( 2.78 ng/ml ) , OSM alone did not induce a STAT3 response , suggesting there may be some cooperativity between IL-6 and OSM activation of STAT3 .	Furthermore, at this low concentration of OSM (2.78 ng/ml), OSM alone did not induce a STAT3 response, suggesting there may be some cooperativity between IL-6 and OSM activation of STAT3.	29	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	29	30	34	35
IL-6 Activates STAT3 in Glioma Cells .	IL-6 Activates STAT3 in Glioma Cells.	0	5	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
This suggests that IL-6 protection from ethanol induced hepatocyte apoptosis is independent of STAT3 signaling in hepatocytes in this model of mild alcoholic liver injury .	This suggests that IL-6 protection from ethanol induced hepatocyte apoptosis is independent of STAT3 signaling in hepatocytes in this model of mild alcoholic liver injury.	3	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	13	14
We have previously shown that Tkip inhibits IL-6 activation of STAT3 , which involves JAK2 , and that SOCS1-KIR has a similar effect .	We have previously shown that Tkip inhibits IL-6 activation of STAT3, which involves JAK2, and that SOCS1-KIR has a similar effect.	7	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	10	11
Other members of the IL-6 family , which utilize the gp130 receptor also activate STAT3 .	Other members of the IL-6 family, which utilize the gp130 receptor also activate STAT3.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	14	15
In contrast , it has been demonstrated that IL-6 activates STAT3 to regulate the expression of target genes , and activation of STAT3 upregulates IL-6 in a number of cancer cells 47 , forming a positive feedback loop .	In contrast, it has been demonstrated that IL-6 activates STAT3 to regulate the expression of target genes, and activation of STAT3 upregulates IL-6 in a number of cancer cells 47, forming a positive feedback loop.	8	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
IL-6 induces STAT-3 in neighboring hepatocytes and promotes proliferation and HCC development [ XREF_BIBR ] .	IL-6 induces STAT-3 in neighboring hepatocytes and promotes proliferation and HCC development [XREF_BIBR].	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	0	1	2	3
Moreover , NF-kappaB can induce expression of a variety of molecules , including interleukin-6 ( IL-6 ) , that activate STAT3 [ XREF_BIBR ] ; some genes may be induced by both NF-kappaB and STAT3 ; and STAT3 can enhance and prolong NF-kappaB mediated transcription [ XREF_BIBR ] .	Moreover, NF-kappaB can induce expression of a variety of molecules, including interleukin-6 (IL-6), that activate STAT3 [XREF_BIBR]; some genes may be induced by both NF-kappaB and STAT3; and STAT3 can enhance and prolong NF-kappaB mediated transcription [XREF_BIBR].	5	22	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	13	14	20	21
While , IL-1beta synergizes with IL-23 and IL-6 to regulate Th17 cell differentiation , in which IL-23 and IL-6 can enhance the amplitude and duration of phospho-STAT3 activity , while IL-1beta can alter the ratio of STAT3 and STAT5 [ XREF_BIBR ] , and to maintain cytokine expression in Th17 response [ XREF_BIBR ] .	While, IL-1beta synergizes with IL-23 and IL-6 to regulate Th17 cell differentiation, in which IL-23 and IL-6 can enhance the amplitude and duration of phospho-STAT3 activity, while IL-1beta can alter the ratio of STAT3 and STAT5 [XREF_BIBR], and to maintain cytokine expression in Th17 response [XREF_BIBR].	16	27	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	phospho-STAT3	phospho-STAT3	phospho-STAT3	18	19	26	27
The IL-6 receptor potently activates signal transducer and activator of transcription factors 3 ( STAT3 ) , and AMP kinase ( AMPK ) .	The IL-6 receptor potently activates signal transducer and activator of transcription factors 3 (STAT3), and AMP kinase (AMPK).	1	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	14	15
IL-6 has been reported to induce transient activation of STAT3 , 31 and our data indicate a tight association of STAT3 signaling with IFN-gamma but not TNFalpha production in IL-15 DCs ( XREF_FIG ) .	IL-6 has been reported to induce transient activation of STAT3, 31 and our data indicate a tight association of STAT3 signaling with IFN-gamma but not TNFalpha production in IL-15 DCs (XREF_FIG).	0	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	9	10
We hypothesised that therapy induced stromal IL6 secretion would stimulate STAT3 in neighbouring cancer cells .	We hypothesised that therapy induced stromal IL6 secretion would stimulate STAT3 in neighbouring cancer cells.	6	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	6	7	10	11
The increase in STAT3 reporter activity that was driven by IL-6 was potentiated by CDK1 ( XREF_FIG ) .	The increase in STAT3 reporter activity that was driven by IL-6 was potentiated by CDK1 (XREF_FIG).	3	11	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	3	4
The phosphatation of STAT3 induced by HB-EGF but not by IL-6 was blocked by PD153035 .	The phosphatation of STAT3 induced by HB-EGF but not by IL-6 was blocked by PD153035.	1	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	3	4
Although all cytokine pathways involved in Th17 cell differentiation result in the upregulation of RORgammat expression , IL-6 , IL-21 , and IL-23 signalling pathways additionally activate STAT3 , which directly binds the IL-17 and IL-21 promoters [ XREF_BIBR , XREF_BIBR ] .	Although all cytokine pathways involved in Th17 cell differentiation result in the upregulation of RORgammat expression, IL-6, IL-21, and IL-23 signalling pathways additionally activate STAT3, which directly binds the IL-17 and IL-21 promoters [XREF_BIBR, XREF_BIBR].	17	34	activate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	STAT3	STAT3, which directly binds the IL-17	stat3	17	18	27	28
Activation of STAT3 , as assessed by pSTAT3 immunoblots , was evident in lysates of OSM stimulated cells in dose dependent fashion , whereas IL-6 , LIF , IL-31 , or TNF did not elevate pSTAT3 .	Activation of STAT3, as assessed by pSTAT3 immunoblots, was evident in lysates of OSM stimulated cells in dose dependent fashion, whereas IL-6, LIF, IL-31, or TNF did not elevate pSTAT3.	24	36	elevate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	24	25	35	36
The induction of the APR requires elaboration of early response cytokines including IL-1 , which primarily activates NF-kappaB , and IL-6 , which predominantly activates STAT3 XREF_BIBR , XREF_BIBR , XREF_BIBR .	The induction of the APR requires elaboration of early response cytokines including IL-1, which primarily activates NF-kappaB, and IL-6, which predominantly activates STAT3 XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	25	26
G-CSF and IL-6 are potent activators of STAT3 in hematopoietic progenitor cells and neutrophils .	G-CSF and IL-6 are potent activators of STAT3 in hematopoietic progenitor cells and neutrophils.	0	13	are potent activators	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	7	8
As binding of IL-6 to the respective receptor mediates activation of the JAK2 and STAT3 cascade a positive feedback loop between the Notch pathway and STAT3 seemed likely .	As binding of IL-6 to the respective receptor mediates activation of the JAK2 and STAT3 cascade a positive feedback loop between the Notch pathway and STAT3 seemed likely.	1	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	14	15
IL-6 is a potent activator of STAT3 , and thus it is tempting to speculate that as with IFNgamma and STAT1 during T H 1 cell responses , IL-6 simultaneously promotes T H 17 cell differentiation while acting on T Reg cells via STAT3 to maximize their ability to modulate T H 17 responses .	IL-6 is a potent activator of STAT3, and thus it is tempting to speculate that as with IFNgamma and STAT1 during T H 1 cell responses, IL-6 simultaneously promotes T H 17 cell differentiation while acting on T Reg cells via STAT3 to maximize their ability to modulate T H 17 responses.	0	7	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
IL-6 activated the JAK and STAT3 signal pathway manifested by increased pSTAT3 immunoreactivity in pyramidal cells of the sensorimotor cortex ( XREF_FIG ) compared with that of saline group ( XREF_FIG ) .	IL-6 activated the JAK and STAT3 signal pathway manifested by increased pSTAT3 immunoreactivity in pyramidal cells of the sensorimotor cortex (XREF_FIG) compared with that of saline group (XREF_FIG).	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
We speculate such immune cells directly or indirectly trigger a local response , comprising inflammatory cytokines including IL-6 and downstream activation of the gp130 and STAT3 pathway to mediate nerve retraction and damage .	We speculate such immune cells directly or indirectly trigger a local response, comprising inflammatory cytokines including IL-6 and downstream activation of the gp130 and STAT3 pathway to mediate nerve retraction and damage.	17	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	25	26
For example , Leptin and IL-6 can increase Stat3 signaling and chronic Stat3 expression induces obesity in mouse models XREF_BIBR , XREF_BIBR .	For example, Leptin and IL-6 can increase Stat3 signaling and chronic Stat3 expression induces obesity in mouse models XREF_BIBR, XREF_BIBR.	3	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	5	6	8	9
IL-6 mediated STAT3 activation plays a central role in IEC regeneration and proliferation .	IL-6 mediated STAT3 activation plays a central role in IEC regeneration and proliferation.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Furthermore , liver injury leads to increased IL-6 levels , which can activate STAT3 , and STAT3 activation is a well-known mechanism responsible for liver carcinogenesis .	Furthermore, liver injury leads to increased IL-6 levels, which can activate STAT3, and STAT3 activation is a well-known mechanism responsible for liver carcinogenesis.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 levels	il-6	STAT3	STAT3	stat3	7	8	13	14
Since IL6 activates STAT3 , which then can activate IL6 , it is unlikely that STAT3 is initiating IL6 transcription .	Since IL6 activates STAT3, which then can activate IL6, it is unlikely that STAT3 is initiating IL6 transcription.	1	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	3	4
Celastrol also inhibited both the constitutive and IL6 induced activation of STAT3 , which induced apoptosis as indicated by an increase in the accumulation of cells in the sub-G1 phase , an increase in the expression of pro apoptotic proteins and activation of caspase-3 .	Celastrol also inhibited both the constitutive and IL6 induced activation of STAT3, which induced apoptosis as indicated by an increase in the accumulation of cells in the sub-G1 phase, an increase in the expression of pro apoptotic proteins and activation of caspase-3.	5	14	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	7	8	11	12
ErbB2 mediated IL-6 expression in human tumor cells causes Stat3 activation and facilitates oncogenic growth .	ErbB2 mediated IL-6 expression in human tumor cells causes Stat3 activation and facilitates oncogenic growth.	0	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	ErbB2 mediated IL-6 expression	il-6	Stat3	Stat3	stat3	2	3	9	10
DIM not only eliminated constitutive activation of STAT3 , but also blocked IL-6 mediated activation of STAT3 .	DIM not only eliminated constitutive activation of STAT3, but also blocked IL-6 mediated activation of STAT3.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	16	17
These pSTAT3 results are in agreement with previous animal and cell culture studies in which interleukin-6 promoted liver inflammation by activating hepatic STAT3 [ XREF_BIBR ] .	These pSTAT3 results are in agreement with previous animal and cell culture studies in which interleukin-6 promoted liver inflammation by activating hepatic STAT3 [XREF_BIBR].	15	24	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	15	16	22	23
This feedback loop is maintained by IL-6 mediated STAT3 activation which in turn activates NF-kappaB effecting Lin28 and let7 ( XREF_FIG ) .	This feedback loop is maintained by IL-6 mediated STAT3 activation which in turn activates NF-kappaB effecting Lin28 and let7 (XREF_FIG).	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
We examined whether L61H46 could suppress the nuclear translocation of STAT3 induced by IL-6 .	We examined whether L61H46 could suppress the nuclear translocation of STAT3 induced by IL-6.	8	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	10	11
Furthermore , BxCM , IL-6 , or G-CSF led to the activation of signal transducer and activator of transcription 3 ( STAT3 ) in CD14+ monocytes to different degrees .	Furthermore, BxCM, IL-6, or G-CSF led to the activation of signal transducer and activator of transcription 3 (STAT3) in CD14+ monocytes to different degrees.	2	22	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	21	22
Interestingly , peretinoin suppressed the expression of IL6 induced p-STAT3 and restored the expression of LC3B-II .	Interestingly, peretinoin suppressed the expression of IL6 induced p-STAT3 and restored the expression of LC3B-II.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	p-STAT3	p-STAT3	p-STAT3	7	8	9	10
Among STATs which mainly activated through phosphorylation by JAK1 , JAK2 and TYK2 , STAT1 and STAT4 are involved in Th1 differentiation while STAT3 is activated by IL-6 and IL-23 and mainly involved in Th17 differentiation XREF_BIBR , XREF_BIBR .	Among STATs which mainly activated through phosphorylation by JAK1, JAK2 and TYK2, STAT1 and STAT4 are involved in Th1 differentiation while STAT3 is activated by IL-6 and IL-23 and mainly involved in Th17 differentiation XREF_BIBR, XREF_BIBR.	23	32	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	27	28	23	24
Activated STAT3 was able to transform cells in vitro and was required for cell transformation of a number of oncogenes and activation of STAT3 by interleukin-6 or expression of activated c-Src induced Twist expression at the protein and mRNA levels [ XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Activated STAT3 was able to transform cells in vitro and was required for cell transformation of a number of oncogenes and activation of STAT3 by interleukin-6 or expression of activated c-Src induced Twist expression at the protein and mRNA levels [XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	11	30	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	25	26	23	24
Herein , we show that IL-6 robustly activates signal transducer and activator of transcription 3 ( STAT3 ) , a transcription factor that is involved in autophagy .	Herein, we show that IL-6 robustly activates signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in autophagy.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	16	17
Exposure of IL-6 and TGF-beta induces Stat3 and down-regulates Gfi , both events being relevant for the induction of CD39 and CD73 by Th17 cells .	Exposure of IL-6 and TGF-beta induces Stat3 and down-regulates Gfi, both events being relevant for the induction of CD39 and CD73 by Th17 cells.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	6	7
Signal transduction studies demonstrated that IL-6 activated not only two major signaling pathways , SHP2/MEK/ERK and JAK and STAT3 , but also the SHP2/PI3K/Akt2 signaling pathway .	Signal transduction studies demonstrated that IL-6 activated not only two major signaling pathways, SHP2/MEK/ERK and JAK and STAT3, but also the SHP2/PI3K/Akt2 signaling pathway.	5	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	18	19
STAT3 plays an important role in initiating IL-17 gene transcription , and STAT3 dependent signals ( such as IL-6 receptor signaling ) play an important role in the development of IL-17 producing CD4+ T cells .	STAT3 plays an important role in initiating IL-17 gene transcription, and STAT3 dependent signals (such as IL-6 receptor signaling) play an important role in the development of IL-17 producing CD4+ T cells.	12	20	signals	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	12	13
As IL-6 is a major activator of STAT3 in inflammation , and overproduction of IL-6 has been found in many type of colitis , IL-6 may play an important role in the development of colitis .	As IL-6 is a major activator of STAT3 in inflammation, and overproduction of IL-6 has been found in many type of colitis, IL-6 may play an important role in the development of colitis.	1	9	is a major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	7	8
Paradoxically , the pro inflammatory IL-6 and the anti-inflammatory IL-10 , generating nearly opposing cellular responses , both activate STAT3 after binding to their receptors .	Paradoxically, the pro inflammatory IL-6 and the anti-inflammatory IL-10, generating nearly opposing cellular responses, both activate STAT3 after binding to their receptors.	2	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	19	20
When cells were serum starved and subsequently treated with IL-6 and S3I-201 for 16 hours , IL-6 induction of phospho-STAT3 and PTTG were dose-dependently attenuated ( XREF_FIG ) .	When cells were serum starved and subsequently treated with IL-6 and S3I-201 for 16 hours, IL-6 induction of phospho-STAT3 and PTTG were dose-dependently attenuated (XREF_FIG).	16	21	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	phospho-STAT3	phospho-STAT3	phospho-STAT3	16	17	19	20
Both IL-6 and BMSC culture supernatants markedly upregulated p-STAT3 , which was blocked by LBH589 ( XREF_FIG ) .	Both IL-6 and BMSC culture supernatants markedly upregulated p-STAT3, which was blocked by LBH589 (XREF_FIG).	1	12	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	1	2	8	9
Both IL-6 and BMX can activate transcription factor STAT3 , which drives GSC proliferation and maintenance XREF_BIBR , XREF_BIBR .	Both IL-6 and BMX can activate transcription factor STAT3, which drives GSC proliferation and maintenance XREF_BIBR, XREF_BIBR.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	8	9
IL-23 , IL-17 and IL-6 induce and activate the transcription factors , STAT3 and RORc .	IL-23, IL-17 and IL-6 induce and activate the transcription factors, STAT3 and RORc.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	12	13
2 ) CUDR increased the Stat3 promoter luciferase activity in hepatocyte like cells treated with IL6 .	2) CUDR increased the Stat3 promoter luciferase activity in hepatocyte like cells treated with IL6.	5	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	15	16	5	6
Ectopic expression of IL6 significantly activated p-JAK2 and p-STAT3 and increased BxPC3 cell proliferation ( XREF_FIG ) .	Ectopic expression of IL6 significantly activated p-JAK2 and p-STAT3 and increased BxPC3 cell proliferation (XREF_FIG).	1	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	expression of IL6	il6	p-STAT3	p-STAT3	p-stat3	3	4	8	9
The combination of IL-6 and TGFbeta preferentially activates Stat3 , which upregulates RORgammat , a critical transcription factor for Th17 cells [ XREF_BIBR ] .	The combination of IL-6 and TGFbeta preferentially activates Stat3, which upregulates RORgammat, a critical transcription factor for Th17 cells [XREF_BIBR].	1	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	8	9
MEDI5117 inhibited IL6 mediated activation of STAT3 , suppressing the growth of several tumor types driven by IL6 autocrine signaling .	MEDI5117 inhibited IL6 mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	2	3	6	7
In this case , autocrine IL-6 secretion was shown to activate the JAK1 and STAT3 pathway ( increased pSTAT3 signal in afatinib treated H1975 or PC9-GR cells ) , and inhibition of IL-6 or JAK1 restored afatinib sensitivity in vitro .	In this case, autocrine IL-6 secretion was shown to activate the JAK1 and STAT3 pathway (increased pSTAT3 signal in afatinib treated H1975 or PC9-GR cells), and inhibition of IL-6 or JAK1 restored afatinib sensitivity in vitro.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	14	15
In addition , Jo etal observed that STAT3 was activated by high-glucose stimulation and IL-6 administration , whereas this effect was attenuated by anti-IL-6 neutralizing antibodies .	In addition, Jo etal observed that STAT3 was activated by high-glucose stimulation and IL-6 administration, whereas this effect was attenuated by anti-IL-6 neutralizing antibodies.	7	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	7	8
The IL-6 receptor complex promotes activation of the signal transducer and activator of transcription 3 ( Stat3 ) through the Jak kinase [ XREF_BIBR ] .	The IL-6 receptor complex promotes activation of the signal transducer and activator of transcription 3 (Stat3) through the Jak kinase [XREF_BIBR].	1	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	16	17
Ligation of several cytokine ( most notably IL6 ) receptors and growth factor receptors can activate STAT3 ; activation typically involves phosphorylation of a tyrosine residue ( Y705 ) .	Ligation of several cytokine (most notably IL6) receptors and growth factor receptors can activate STAT3; activation typically involves phosphorylation of a tyrosine residue (Y705).	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	7	8	16	17
While IL-6 treatment resulted in maximal activation of STAT3 at relatively small doses ( 1 ng/ml ) , this level of STAT3 phosphorylation was not seen at even 50 times the dose of IL-21 ( 50 ng/ml ) ( XREF_FIG ) .	While IL-6 treatment resulted in maximal activation of STAT3 at relatively small doses (1 ng/ml), this level of STAT3 phosphorylation was not seen at even 50 times the dose of IL-21 (50 ng/ml) (XREF_FIG).	1	9	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	8	9
Blocking IL-6 suppresses STAT-3 activation in the pancreas and consequently attenuates the severity of severe acute pancreatitis by promotion of pancreatic acinar cell apoptosis .	Blocking IL-6 suppresses STAT-3 activation in the pancreas and consequently attenuates the severity of severe acute pancreatitis by promotion of pancreatic acinar cell apoptosis.	0	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	1	2	3	4
Because IL-6 , which is known to activate STAT3 in CLL cells XREF_BIBR , upregulated miR-155 levels , and STAT3-siRNA downregulated the expression miR-155 , we concluded that STAT3 activates miR-155 .	Because IL-6, which is known to activate STAT3 in CLL cells XREF_BIBR, upregulated miR-155 levels, and STAT3-siRNA downregulated the expression miR-155, we concluded that STAT3 activates miR-155.	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	8	9
The level of STAT3 ( Y705 ) phosphorylation declined after the cells were treated with IL-6 for 4h .	The level of STAT3 (Y705) phosphorylation declined after the cells were treated with IL-6 for 4h.	1	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	3	4
Such reduction of the IL-6 level can limit STAT3 activation in the macrophages , leading to the interruption of the inflammatory amplification loop .	Such reduction of the IL-6 level can limit STAT3 activation in the macrophages, leading to the interruption of the inflammatory amplification loop.	4	9	limit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 level	il-6	STAT3	STAT3	stat3	4	5	8	9
As a control , IL-6 treatment of these B cell populations produced an increase in pSTAT3 that was equally shared by the CD25 + and CD25 - B1a populations .	As a control, IL-6 treatment of these B cell populations produced an increase in pSTAT3 that was equally shared by the CD25 + and CD25 - B1a populations.	4	28	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	4	5	15	16
In A549 cells , IL-6 ( 10 ng/ml ) up-regulated pSTAT3 whereas 6-OAP suppressed this up-regulation at both protein and mRNA levels .	In A549 cells, IL-6 (10 ng/ml) up-regulated pSTAT3 whereas 6-OAP suppressed this up-regulation at both protein and mRNA levels.	4	11	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	4	5	10	11
A computational model of IL-6 and IL-10 signaling predicted that IL-6 stimulation results in transient activation of STAT3 , with a rapid decline in phosphorylation and nuclear localization .	A computational model of IL-6 and IL-10 signaling predicted that IL-6 stimulation results in transient activation of STAT3, with a rapid decline in phosphorylation and nuclear localization.	10	18	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	17	18
SMAR1 expression was observed to be inversely correlated with IL-6 mediated pSTAT3 , and not with SMAD signaling , at the protein ( XREF_FIG ) as well as at the transcription levels ( XREF_FIG ) .	SMAR1 expression was observed to be inversely correlated with IL-6 mediated pSTAT3, and not with SMAD signaling, at the protein (XREF_FIG) as well as at the transcription levels (XREF_FIG).	7	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	9	10	11	12
Furthermore , we show that hippuristanol perturbs the activation of the STAT3 pathway and expression of STAT3 gene targets such as IL-6 .	Furthermore, we show that hippuristanol perturbs the activation of the STAT3 pathway and expression of STAT3 gene targets such as IL-6.	16	22	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	16	17
Among these , the activation of STAT3 by IL-6 and IL-23 is crucial in Th17 lineage differentiation .	Among these, the activation of STAT3 by IL-6 and IL-23 is crucial in Th17 lineage differentiation.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	6	7
And given that a previous report demonstrated that mouse IL-6 lacks activities on human cells , it is suggested that STAT3 activation by IL-6 secreted from the tumour cells , not from the stromal cells , is involved in the promotion of tumour growth in this model .	And given that a previous report demonstrated that mouse IL-6 lacks activities on human cells, it is suggested that STAT3 activation by IL-6 secreted from the tumour cells, not from the stromal cells, is involved in the promotion of tumour growth in this model.	20	24	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	23	24	20	21
In our immortalized NPE cell models , overexpression of IL-6R was found to be primarily responsible for the enhanced response to IL6 activation of STAT3 signaling ( XREF_FIG ) .	In our immortalized NPE cell models, overexpression of IL-6R was found to be primarily responsible for the enhanced response to IL6 activation of STAT3 signaling (XREF_FIG).	21	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	21	22	24	25
On the other hand , in immune cells , NF-kappaB and STAT3 are instrumental for the production of pro inflammatory cytokines , which mediate NF-kappaB and STAT3 activation in cancer cells , including IL-1 , TNF , IL-6 and IL-23 .	On the other hand, in immune cells, NF-kappaB and STAT3 are instrumental for the production of pro inflammatory cytokines, which mediate NF-kappaB and STAT3 activation in cancer cells, including IL-1, TNF, IL-6 and IL-23.	24	38	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	37	38	26	27
We found that AKBA inhibited both constitutive and IL-6 induced STAT3 activation in MM cells and that it involved the inhibition of activation of JAK2 and c-Src and the induction of SHP-1 .	We found that AKBA inhibited both constitutive and IL-6 induced STAT3 activation in MM cells and that it involved the inhibition of activation of JAK2 and c-Src and the induction of SHP-1.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
Intravitreal injection of IL-6 activates STAT3 and transforms RGCs into a regenerative state .	Intravitreal injection of IL-6 activates STAT3 and transforms RGCs into a regenerative state.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
In differentiated cells , inhibition of Hsp90 by GA suppresses the IL-6 induced activation of Stat3 , suggesting potential involvement of Hsp90 in IL-6 signaling pathway 49 .	In differentiated cells, inhibition of Hsp90 by GA suppresses the IL-6 induced activation of Stat3, suggesting potential involvement of Hsp90 in IL-6 signaling pathway 49.	10	16	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	11	12	15	16
Similarly , the STAT3 inhibitor ( STAT3i ) S3I-201 also abolished iron- and IL6 activated p-STAT3 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Similarly, the STAT3 inhibitor (STAT3i) S3I-201 also abolished iron- and IL6 activated p-STAT3 (XREF_FIG and XREF_SUPPLEMENTARY).	11	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	p-STAT3	p-STAT3	p-STAT3	13	14	15	16
To address this question , BxPC-3 cells were treated with IL-6 , which specifically activates STAT-3 by phosphorylation at Tyr 705 , and determined HIF-1alpha and VEGF expression .	To address this question, BxPC-3 cells were treated with IL-6, which specifically activates STAT-3 by phosphorylation at Tyr 705, and determined HIF-1alpha and VEGF expression.	8	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	10	11	15	16
IL-6 activates both the STAT3 and SHP2/Gab/MAPK signaling pathways via the gp130 signal transducer .	IL-6 activates both the STAT3 and SHP2/Gab/MAPK signaling pathways via the gp130 signal transducer.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Interestingly , while IL-6 stimulation of IL-6R activates STAT3 in multiple hematopoietic cell types , STAT1 is strongly activated by IL-6 selectively in CD4 T cells ( XREF_FIG ) .	Interestingly, while IL-6 stimulation of IL-6R activates STAT3 in multiple hematopoietic cell types, STAT1 is strongly activated by IL-6 selectively in CD4 T cells (XREF_FIG).	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	8	9
IL-6 Activated STAT3 and TNF-alpha Activated STAT1 , STAT3 , and STAT1 Heterodimerize upon IL-6 and TNF-alpha Cotreatments .	IL-6 Activated STAT3 and TNF-alpha Activated STAT1, STAT3, and STAT1 Heterodimerize upon IL-6 and TNF-alpha Cotreatments.	0	5	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Collectively , these data demonstrate that overexpression of IL-6 activates Stat3 and AR signaling pathways in prostate cancer cells .	Collectively, these data demonstrate that overexpression of IL-6 activates Stat3 and AR signaling pathways in prostate cancer cells.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	overexpression of IL-6	il-6	Stat3	Stat3	stat3	8	9	10	11
IL-6 activation of Stat3 in tumor cells results in increases in antiapoptotic , proproliferation , and proangiogenic genes , as well as suppression of certain proinflammatory genes .	IL-6 activation of Stat3 in tumor cells results in increases in antiapoptotic, proproliferation, and proangiogenic genes, as well as suppression of certain proinflammatory genes.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	3	4
The induction of RORgammat is dependent on STAT3 , which is preferentially activated by IL-6 , IL-21 and IL-23 , and plays a key role in the regulation of IL-17 production by T H 17 cells [ XREF_BIBR ] .	The induction of RORgammat is dependent on STAT3, which is preferentially activated by IL-6, IL-21 and IL-23, and plays a key role in the regulation of IL-17 production by T H 17 cells [XREF_BIBR].	5	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	7	8
In a pilot experiment performed with EBV immortalized , IgA1 producing cell lines derived from PBMC from an IgAN patient and a HC , we tested whether the canonical STAT3 pathway was activated by IL-6 .	In a pilot experiment performed with EBV immortalized, IgA1 producing cell lines derived from PBMC from an IgAN patient and a HC, we tested whether the canonical STAT3 pathway was activated by IL-6.	29	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	34	35	29	30
In this study , we found that STAT3 was synergistically activated by IL-6 and TNF-alpha .	In this study, we found that STAT3 was synergistically activated by IL-6 and TNF-alpha.	7	14	synergistically activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	7	8
Hepcidin is an acute phase antibacterial protein , induced by IL-6 , through JAK and Stat3 pathway , released from the liver and excreted from the urine .	Hepcidin is an acute phase antibacterial protein, induced by IL-6, through JAK and Stat3 pathway, released from the liver and excreted from the urine.	8	16	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	10	11	15	16
The inflammatory response induces hepcidin expression via the IL6 dependent activation of JAK and STAT3 signaling .	The inflammatory response induces hepcidin expression via the IL6 dependent activation of JAK and STAT3 signaling.	8	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	8	9	14	15
Since the cytokine interleukin-6 ( IL-6 ) promotes tumor cell proliferation by activating STAT3 signaling , we sought to examine whether resveratrol can attenuate IL-6-induced STAT3 transcriptional activity in LNCaP-FGC cells .	Since the cytokine interleukin-6 (IL-6) promotes tumor cell proliferation by activating STAT3 signaling, we sought to examine whether resveratrol can attenuate IL-6-induced STAT3 transcriptional activity in LNCaP-FGC cells.	3	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	13	14
IL6 and STAT3 signalling dysregulation , caused by IL6 deficiency , resulted in skewing of the immune modulatory properties of MSCs to favour a pro inflammatory profile .	IL6 and STAT3 signalling dysregulation, caused by IL6 deficiency, resulted in skewing of the immune modulatory properties of MSCs to favour a pro inflammatory profile.	0	9	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	8	9	2	3
Taken together , these data strongly suggest that BLCAP inhibits IL-6 induced STAT3 activation .	Taken together, these data strongly suggest that BLCAP inhibits IL-6 induced STAT3 activation.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	12	13
The present study highlighted that quercetin could modulate IL-6 induced STAT3 activation by decreasing cellular titer of IL-6 in A549 cells .	The present study highlighted that quercetin could modulate IL-6 induced STAT3 activation by decreasing cellular titer of IL-6 in A549 cells.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
As IL-6 is known to activate STAT3 in the TME , we evaluated STAT3 activation ( assessed by phosphorylation of STAT3 ) in co-cultures of NBT2 cells and macrophages .	As IL-6 is known to activate STAT3 in the TME, we evaluated STAT3 activation (assessed by phosphorylation of STAT3) in co-cultures of NBT2 cells and macrophages.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	6	7
XREF_BIBR , XREF_BIBR In the absence of SOCS3 in macrophages , mice were protected from LPS induced endotoxemia , and this was likely due to the enhanced anti-inflammatory effects of STAT3 induced by IL-10 , IL-6 , IL-11 , and LIF in these cells .	XREF_BIBR, XREF_BIBR In the absence of SOCS3 in macrophages, mice were protected from LPS induced endotoxemia, and this was likely due to the enhanced anti-inflammatory effects of STAT3 induced by IL-10, IL-6, IL-11, and LIF in these cells.	28	36	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	35	36	30	31
Acute in vitro treatment with ethanol blocks IL-6 activation of STAT3 in freshly isolated hepatocytes .	Acute in vitro treatment with ethanol blocks IL-6 activation of STAT3 in freshly isolated hepatocytes.	7	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	10	11
The increased STAT3 signaling is mediated by elevated expression of fibronection ( FN ) , EGF , and IL-6 in an autocrine manner , which convergently leads to trastuzumab resistance via upregulating the expression of MUC1 and MUC4 , two downstream targets of STAT3 capable of inducing trastuzumab resistance via maintaining HER2 activation and masking of trastuzumab binding to HER2 respectively .	The increased STAT3 signaling is mediated by elevated expression of fibronection (FN), EGF, and IL-6 in an autocrine manner, which convergently leads to trastuzumab resistance via upregulating the expression of MUC1 and MUC4, two downstream targets of STAT3 capable of inducing trastuzumab resistance via maintaining HER2 activation and masking of trastuzumab binding to HER2 respectively.	2	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	expression of fibronection (FN), EGF, and IL-6	il-6	STAT3	STAT3	stat3	18	19	2	3
It has been reported that the IL-6 cytokine family is able to induce Stat3 activation through the gp130 receptor by using an ' unconventional ' signaling route that involves ERK1/2 phosphorylation [ XREF_BIBR ] .	It has been reported that the IL-6 cytokine family is able to induce Stat3 activation through the gp130 receptor by using an ' unconventional ' signaling route that involves ERK1/2 phosphorylation [XREF_BIBR].	6	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	13	14
Western blot analysis at 16 h ( XREF_FIG , lanes 1 and 2 ) showed a robust phospho-STAT3 signal , confirming that two doses of IL6 and sIL6R produce sustained STAT3 activation .	Western blot analysis at 16 h (XREF_FIG, lanes 1 and 2) showed a robust phospho-STAT3 signal, confirming that two doses of IL6 and sIL6R produce sustained STAT3 activation.	23	31	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	25	26	30	31
Taken together , these observations confirm that CaMKII is upstream of STAT3 and plays important role in the activation of STAT3 by IL-6 .	Taken together, these observations confirm that CaMKII is upstream of STAT3 and plays important role in the activation of STAT3 by IL-6.	13	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	20	21
This IL-6 induced STAT3 signalling is evidenced by the up-regulation of the downstream genes regulated by p-STAT3 .	This IL-6 induced STAT3 signalling is evidenced by the up-regulation of the downstream genes regulated by p-STAT3.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	3	4
STAT3 activators IL-6 and CCL2 chemokine have been shown to play a role in modulating EMT in PCa .	STAT3 activators IL-6 and CCL2 chemokine have been shown to play a role in modulating EMT in PCa.	0	10	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	0	1
IL-6 secreted by MDSCs then activates Stat3 pathway in cancer cells , resulting in promoting cancer cell proliferation .	IL-6 secreted by MDSCs then activates Stat3 pathway in cancer cells, resulting in promoting cancer cell proliferation.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	6	7
Our receptor tyrosine kinase array screen revealed that IL-6 induced STAT3 ( Tyr 705 ) and TNF-alpha induced STAT1 ( Tyr 701 ) activations .	Our receptor tyrosine kinase array screen revealed that IL-6 induced STAT3 (Tyr 705) and TNF-alpha induced STAT1 (Tyr 701) activations.	8	17	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
Furthermore , IL-6 mediated activation of STAT3 in tumor cells results in increases in anti-apoptotic , pro proliferation , and pro angiogenic genes [ XREF_BIBR ] .	Furthermore, IL-6 mediated activation of STAT3 in tumor cells results in increases in anti-apoptotic, pro proliferation, and pro angiogenic genes [XREF_BIBR].	2	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	6	7
MM.1 S cells , which lack constitutively active STAT3 , were treated with different concentrations of IL-6 and then examined for p-STAT3 .	MM.1 S cells, which lack constitutively active STAT3, were treated with different concentrations of IL-6 and then examined for p-STAT3.	5	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	8	9
Since TGF-beta signaling , unlike IL6 , IL21 , and IL23 , does not activate STAT3 , its role appears to involve in the enhancement of STAT3 activation .	Since TGF-beta signaling, unlike IL6, IL21, and IL23, does not activate STAT3, its role appears to involve in the enhancement of STAT3 activation.	5	16	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	5	6	15	16
CBP therapy enhanced STAT3 activation while IL-6 blockade eliminated STAT3 activation in both CBP treated LoVo cells and vehicle control .	CBP therapy enhanced STAT3 activation while IL-6 blockade eliminated STAT3 activation in both CBP treated LoVo cells and vehicle control.	6	10	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	9	10
Additionally , the activation of STAT3 induced by IL-6 was also suppressed by SFN treatment .	Additionally, the activation of STAT3 induced by IL-6 was also suppressed by SFN treatment.	3	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	5	6
These inhibitors may block transcription of the SIE-bla reporter gene by preventing STAT3 phosphorylation , as IL-6 requires MEK or Src activity to activate STAT3 in some cell types XREF_BIBR , XREF_BIBR .	These inhibitors may block transcription of the SIE-bla reporter gene by preventing STAT3 phosphorylation, as IL-6 requires MEK or Src activity to activate STAT3 in some cell types XREF_BIBR, XREF_BIBR.	16	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	24	25
[ XREF_BIBR ] Its close homologue STAP-2 was shown to mediate the IL-6 induced STAT3 activation .	[XREF_BIBR] Its close homologue STAP-2 was shown to mediate the IL-6 induced STAT3 activation.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	14	15
Furthermore , STAT3 activation by IL-6 is required for activation and maturation of dendritic cells ( DCs ) , which are involved in self-antigen tolerance and antigen presentation [ XREF_BIBR ] .	Furthermore, STAT3 activation by IL-6 is required for activation and maturation of dendritic cells (DCs), which are involved in self-antigen tolerance and antigen presentation [XREF_BIBR].	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	2	3
U266 cells transiently transfected with Ly6E Stat3-luciferase construct were treated with avicin D. Constitutive , and IL-6 induced Stat3 activity was assessed by measuring the luciferase activity .	U266 cells transiently transfected with Ly6E Stat3-luciferase construct were treated with avicin D. Constitutive, and IL-6 induced Stat3 activity was assessed by measuring the luciferase activity.	16	19	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	16	17	18	19
However , phospho-STAT3 induced by IL-6 was unaffected after hypoxia treatment .	However, phospho-STAT3 induced by IL-6 was unaffected after hypoxia treatment.	2	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	phospho-STAT3	phospho-STAT3	phospho-STAT3	5	6	2	3
To examine the mechanisms regulating the production of IL-6 , we tested if STAT3 not only was activated by IL-6 but also participated in a feed-forward loop promoting IL-6 production in primary glia as was recently identified in B lymphocytes [ XREF_BIBR ] .	To examine the mechanisms regulating the production of IL-6, we tested if STAT3 not only was activated by IL-6 but also participated in a feed-forward loop promoting IL-6 production in primary glia as was recently identified in B lymphocytes [XREF_BIBR].	13	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	13	14
SOCS3 can bind to the Y759 residue on the adaptor molecule gp130 and thus preventing constitutive IL-6 signaling and activation of STAT3 in a steadily state [ XREF_BIBR , XREF_BIBR ] .	SOCS3 can bind to the Y759 residue on the adaptor molecule gp130 and thus preventing constitutive IL-6 signaling and activation of STAT3 in a steadily state [XREF_BIBR, XREF_BIBR].	16	22	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	21	22
BLCAP inhibits IL-6 induced STAT3 activation .	BLCAP inhibits IL-6 induced STAT3 activation.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
We have previously shown that IL-6 also activates STAT3 in sinusoidal endothelial cells .	We have previously shown that IL-6 also activates STAT3 in sinusoidal endothelial cells.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	8	9
Furthermore , using a specific STAT3 responsive luciferase reporter we showed that DAB2IP could significantly suppress both baseline and induction of STAT3 transactivation elicited by interleukin-6 ( IL-6 ) treatment in C4-2 cells , meanwhile LAPC-4 KD cells showed a significantly increased baseline of STAT3 transcription activity ( XREF_FIG ) .	Furthermore, using a specific STAT3 responsive luciferase reporter we showed that DAB2IP could significantly suppress both baseline and induction of STAT3 transactivation elicited by interleukin-6 (IL-6) treatment in C4-2 cells, meanwhile LAPC-4 KD cells showed a significantly increased baseline of STAT3 transcription activity (XREF_FIG).	21	29	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	25	26	21	22
Only recently it was shown that STAT3 is activated by IL-6 and modulates collagen production in aHSC and myofibroblasts [ XREF_BIBR , XREF_BIBR ] , and mice deficient of STAT3 in HSCs are less susceptible to liver fibrosis , implying that IL-17A , leptin , IL-6 , and HGH signaling in HSCs may promote the development of liver fibrosis by activation of STAT3 in HSCs .	Only recently it was shown that STAT3 is activated by IL-6 and modulates collagen production in aHSC and myofibroblasts [XREF_BIBR, XREF_BIBR], and mice deficient of STAT3 in HSCs are less susceptible to liver fibrosis, implying that IL-17A, leptin, IL-6, and HGH signaling in HSCs may promote the development of liver fibrosis by activation of STAT3 in HSCs.	6	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	6	7
IL-6 activates STAT3 via gp130 and IL-6 receptor complex .	IL-6 activates STAT3 via gp130 and IL-6 receptor complex.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
In this report , we have demonstrated that cellular adhesion to FN potentiated IL-6 stimulated STAT3 activity in the RPMI 8226 cell line .	In this report, we have demonstrated that cellular adhesion to FN potentiated IL-6 stimulated STAT3 activity in the RPMI 8226 cell line.	12	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	15	16
Cytokines secreted by the activated tumor stroma modulate tumor growth and enhance invasiveness of tumor cells by activation of oncogenic signaling pathways in tumor cells , including activation of NF-kappaB by TNFalpha and IL-1beta , and activation of STAT3 by IL-6 [ XREF_BIBR ] .	Cytokines secreted by the activated tumor stroma modulate tumor growth and enhance invasiveness of tumor cells by activation of oncogenic signaling pathways in tumor cells, including activation of NF-kappaB by TNFalpha and IL-1beta, and activation of STAT3 by IL-6 [XREF_BIBR].	36	42	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	40	41	38	39
We also found that IL-6 secreted by tumor associated fibroblasts could upregulate STAT3 activation in NPC cells in culture .	We also found that IL-6 secreted by tumor associated fibroblasts could upregulate STAT3 activation in NPC cells in culture.	4	13	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	12	13
13 The activation of STAT3 by IL-6 in sinusoidal endothelial cells may also contribute to the hepatoprotective function of IL-6 .	13 The activation of STAT3 by IL-6 in sinusoidal endothelial cells may also contribute to the hepatoprotective function of IL-6.	2	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	4	5
Obesity can increase IL-6 and TNF-alpha production , which causes hepatic inflammation and activates STAT3 to promote hepatocellular carcinoma [ XREF_BIBR ] .	Obesity can increase IL-6 and TNF-alpha production, which causes hepatic inflammation and activates STAT3 to promote hepatocellular carcinoma [XREF_BIBR].	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	14	15
This is probably because long term activation of STAT3 by IL-6 enhances the transcription and expression of STAT3 .	This is probably because long term activation of STAT3 by IL-6 enhances the transcription and expression of STAT3.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	8	9
Because TNF-alpha and IL-6 can activate NFkappaB and Stat3 , respectively , which are transcription factors that play an important role in hepatocyte proliferation [ XREF_BIBR ] , we investigated NFkappaB and Stat3 activation by EMSA using nuclear lysates prepared from LN treated livers and NFkappaB and Stat3 specific oligonucleotide probes .	Because TNF-alpha and IL-6 can activate NFkappaB and Stat3, respectively, which are transcription factors that play an important role in hepatocyte proliferation [XREF_BIBR], we investigated NFkappaB and Stat3 activation by EMSA using nuclear lysates prepared from LN treated livers and NFkappaB and Stat3 specific oligonucleotide probes.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	8	9
The STAT3 pathway can be activated either by IL-10 and IL-6 cytokines or by growth factors such as VEGF , TGF-beta , G-CSF , PDGF , EGF and MAPkinases [ XREF_BIBR , XREF_BIBR ] .	The STAT3 pathway can be activated either by IL-10 and IL-6 cytokines or by growth factors such as VEGF, TGF-beta, G-CSF, PDGF, EGF and MAPkinases [XREF_BIBR, XREF_BIBR].	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	1	2
Although LPS activated NF-kappaB may or may not be responsible for the direct regulation of TNF-alpha promoter activation , IL-6 production in response to LPS treatment can activate STAT3 , there by activating AGG-element promoters including TNF-alpha .	Although LPS activated NF-kappaB may or may not be responsible for the direct regulation of TNF-alpha promoter activation, IL-6 production in response to LPS treatment can activate STAT3, there by activating AGG-element promoters including TNF-alpha.	19	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	28	29
STAT3 is activated by the cytokine IL-6 as well as other growth factors , including epidermal growth factor receptor ( EGFR ) , fibroblast growth factor receptor ( FGFR ) , and platelet derived growth factor receptor ( PDGFR ) through tyrosine phosphorylation [ XREF_BIBR ] .	STAT3 is activated by the cytokine IL-6 as well as other growth factors, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), and platelet derived growth factor receptor (PDGFR) through tyrosine phosphorylation [XREF_BIBR].	0	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	0	1
Indeed , we found that IL-6 activated STAT3 , which was translocated to the nucleus and induced MMP-2 expression in LF fibroblasts .	Indeed, we found that IL-6 activated STAT3, which was translocated to the nucleus and induced MMP-2 expression in LF fibroblasts.	5	15	activated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	STAT3	STAT3, which was translocated to the nucleus	stat3	5	6	7	8
All IL-6 family cytokines , including OSM , activate JAK and STAT3 signaling downstream of the common gp130 IL-6 receptor subunit .	All IL-6 family cytokines, including OSM, activate JAK and STAT3 signaling downstream of the common gp130 IL-6 receptor subunit.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	11	12
As STAT3 signal was always activated by IL-6 and JAK2 signaling pathway , the expression of IL-6 mRNA and protein in MGC803 cells , AGS cells and CAFs were examined .	As STAT3 signal was always activated by IL-6 and JAK2 signaling pathway, the expression of IL-6 mRNA and protein in MGC803 cells, AGS cells and CAFs were examined.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	1	2
IL-6 signaling activates STAT3 by phosphorylating at tyrosine 705 .	IL-6 signaling activates STAT3 by phosphorylating at tyrosine 705.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
STAT3 can be activated by cytokines ( IL-6 , IFN-alpha ) , growth factors ( EGF , IGF-1 and PDGF , etc ) and non receptor tyrosine kinases ( Src and all the JAK family proteins ) [ XREF_BIBR ] .	STAT3 can be activated by cytokines (IL-6, IFN-alpha), growth factors (EGF, IGF-1 and PDGF, etc) and non receptor tyrosine kinases (Src and all the JAK family proteins) [XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	0	1
Finally , adenosine differentially regulates IL-10 and IL-6 induced STAT3 activation in M2c macrophages .	Finally, adenosine differentially regulates IL-10 and IL-6 induced STAT3 activation in M2c macrophages.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
The STAT3 and ERK1/2 pathways are similarly activated by IL-6 in both cells either expressing or not expressing CD45 .	The STAT3 and ERK1/2 pathways are similarly activated by IL-6 in both cells either expressing or not expressing CD45.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	1	2
IL-6 acts via its receptor ( CD126 ) to activate signal transduction pathways ( JAK and STAT3 and PI3K and Akt ) , inducing proliferation and preventing apoptosis , and thereby contributing to drug resistance [ XREF_BIBR , XREF_BIBR ] .	IL-6 acts via its receptor (CD126) to activate signal transduction pathways (JAK and STAT3 and PI3K and Akt), inducing proliferation and preventing apoptosis, and thereby contributing to drug resistance [XREF_BIBR, XREF_BIBR].	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	16	17
XREF_BIBR In an extension of this study , Lesina et al XREF_BIBR identified the myeloid origin cells as a source of pro inflammatory cytokine IL-6 that activates STAT3 in the pancreas and nourishes the formation and progression of PanIN lesions .	XREF_BIBR In an extension of this study, Lesina et al XREF_BIBR identified the myeloid origin cells as a source of pro inflammatory cytokine IL-6 that activates STAT3 in the pancreas and nourishes the formation and progression of PanIN lesions.	19	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	27	28
STAT3 is initially activated by IL-6 , subsequently by autocrine IL-21 , and the differentiation is finally determined by its master transcription factor RORgammat [ XREF_BIBR , XREF_BIBR ] .	STAT3 is initially activated by IL-6, subsequently by autocrine IL-21, and the differentiation is finally determined by its master transcription factor RORgammat [XREF_BIBR, XREF_BIBR].	0	6	initially activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
IL6 activates STAT3 , which directly interacts with the NF-kappaB family member RELA , contributing to constitutive NF-kappaB activation [ XREF_BIBR ] , and COX2 and PGE2 also activates STAT3 , leading to NF-kappaB activation [ XREF_BIBR ] .	IL6 activates STAT3, which directly interacts with the NF-kappaB family member RELA, contributing to constitutive NF-kappaB activation [XREF_BIBR], and COX2 and PGE2 also activates STAT3, leading to NF-kappaB activation [XREF_BIBR].	0	14	activates	Positive_regulation_token_1_verb	Positive_activation	Positive_regulation	IL6	IL6	il6	STAT3	STAT3, which directly interacts with the NF-kappaB family member RELA	stat3	0	1	2	3
IL-6 is known to activate both the STAT3 and MAPK signal transduction pathways .	IL-6 is known to activate both the STAT3 and MAPK signal transduction pathways.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	7	8
Cell derived IL-6 activates STAT3 via JAK in gastric cancer cells without MET activation .	Cell derived IL-6 activates STAT3 via JAK in gastric cancer cells without MET activation.	1	6	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
Not surprisingly , IL-6 triggers P38 MAPK and STAT3 signaling in the wild-type B16 cells ( XREF_SUPPLEMENTARY ) .	Not surprisingly, IL-6 triggers P38 MAPK and STAT3 signaling in the wild-type B16 cells (XREF_SUPPLEMENTARY).	3	9	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	8	9
Corroborating these findings , a qualitative assessment of STAT3 phosphorylation ( indicative of activation ) by immunoblotting revealed a time dependent activation of STAT3 by IL-6 , IL-10 and IL-11 that mirrored the respective cytokines ' ability to up-regulate Arg1 and Ym1 protein expression .	Corroborating these findings, a qualitative assessment of STAT3 phosphorylation (indicative of activation) by immunoblotting revealed a time dependent activation of STAT3 by IL-6, IL-10 and IL-11 that mirrored the respective cytokines ' ability to up-regulate Arg1 and Ym1 protein expression.	17	31	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	23	24
Meanwhile , we observed the pSTAT3 induction in Vgamma4 - gammadelta 27- cells when treated with IL-6 , but not in Vgamma4 + gammadelta 27- cells .	Meanwhile, we observed the pSTAT3 induction in Vgamma4 - gammadelta 27- cells when treated with IL-6, but not in Vgamma4 + gammadelta 27- cells.	5	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	16	17	5	6
IL-6 activated the transcription factors STAT3 and C/EBP up to 2.6-fold and 2.2-fold , respectively .	IL-6 activated the transcription factors STAT3 and C/EBP up to 2.6-fold and 2.2-fold, respectively.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
These results suggest that irradiation induced IL-6 secretion , which activated STAT3 , and finally could inhibit IL-12 production in DCs .	These results suggest that irradiation induced IL-6 secretion, which activated STAT3, and finally could inhibit IL-12 production in DCs.	6	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	11	12
STAT3 signaling in MDSC can be modulated by IL-6 [ XREF_BIBR , XREF_BIBR ] , which has been shown to enhance CSCs and EMT in cancer .	STAT3 signaling in MDSC can be modulated by IL-6 [XREF_BIBR, XREF_BIBR], which has been shown to enhance CSCs and EMT in cancer.	0	10	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	0	1
Interestingly , only CDK1 could potentiate the activation of STAT3 by IL6 ( XREF_SUPPLEMENTARY ) .	Interestingly, only CDK1 could potentiate the activation of STAT3 by IL6 (XREF_SUPPLEMENTARY).	5	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	11	12	9	10
Activation of STAT3 target gene in HSF by IL-6 trans-signaling pathway .	Activation of STAT3 target gene in HSF by IL-6 trans-signaling pathway.	0	10	Activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	2	3
Interleukin-6 ( IL-6 ) , a major inflammatory cytokine , is a potent activator of STAT3 .	Interleukin-6 (IL-6), a major inflammatory cytokine, is a potent activator of STAT3.	0	16	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Interleukin-6	Interleukin-6	Interleukin-6	STAT3	STAT3	STAT3	0	1	15	16
However , neither phosphorylation in JAK2 nor STAT3 was able to be detected in the cells treated with WP1066 or WP1066+ IL-6 , indicating that the signaling pathway of JAK2-STAT3 was inhibited .	However, neither phosphorylation in JAK2 nor STAT3 was able to be detected in the cells treated with WP1066 or WP1066+ IL-6, indicating that the signaling pathway of JAK2-STAT3 was inhibited.	3	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	7	8
To assess if CDK1 is essential for iron and IL6 induced STAT3 activity , siRNA or CDK1/2 inhibitor ( CDKi ) Dinaciclib was used to inhibit CDK1 expression or function .	To assess if CDK1 is essential for iron and IL6 induced STAT3 activity, siRNA or CDK1/2 inhibitor (CDKi) Dinaciclib was used to inhibit CDK1 expression or function.	5	12	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	9	10	11	12
Although Stat3 signaling can be induced by other cytokines , such as G-CSF [ XREF_BIBR ] and leptin [ XREF_BIBR ] , current data suggests that Stat3 in hepatocytes is almost exclusively activated by IL-6 .	Although Stat3 signaling can be induced by other cytokines, such as G-CSF [XREF_BIBR] and leptin [XREF_BIBR], current data suggests that Stat3 in hepatocytes is almost exclusively activated by IL-6.	26	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	34	35	26	27
IL-6 , a proinflammatory cytokine responsible for differentiating Th0 cells into pathogenic Th17 cells , activates STAT3 transcription factor .	IL-6, a proinflammatory cytokine responsible for differentiating Th0 cells into pathogenic Th17 cells, activates STAT3 transcription factor.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	16	17
The ability of Bazedoxifene to generate stronger inhibition of cell viability when combined with gemcitabine or paclitaxel and is likely due to its ability to inhibit one of the pathway or more than one pathways combined : ( I ) autocrine IL-6 induction of P-STAT3 ; ( II ) autocrine IL-6 and non GP130 pathway ( s ) induction of P-ERK in BXPC-3 and Capan-1 cells and induction of P-AKT in BXPC-3 cells ; ( III ) other pathway ( s ) in addition to STAT3 , ERK , and AKT .	The ability of Bazedoxifene to generate stronger inhibition of cell viability when combined with gemcitabine or paclitaxel and is likely due to its ability to inhibit one of the pathway or more than one pathways combined : (I) autocrine IL-6 induction of P-STAT3; (II) autocrine IL-6 and non GP130 pathway (s) induction of P-ERK in BXPC-3 and Capan-1 cells and induction of P-AKT in BXPC-3 cells; (III) other pathway (s) in addition to STAT3, ERK, and AKT.	41	45	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	P-STAT3	P-STAT3	P-STAT3	41	42	44	45
Among these candidate cytokines , IL-6 , which activates Stat3 through the gp130 and Jak pathway , is notable for its pleitrophic tumor promoting activities , including anti-apoptotic , pro invasive , and immune-stimulatory effects attributable to the activation of Stat3 target genes [ XREF_BIBR , XREF_BIBR ] .	Among these candidate cytokines, IL-6, which activates Stat3 through the gp130 and Jak pathway, is notable for its pleitrophic tumor promoting activities, including anti-apoptotic, pro invasive, and immune-stimulatory effects attributable to the activation of Stat3 target genes [XREF_BIBR, XREF_BIBR].	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	5	6	9	10
Activation of STAT3 by IL-6 and IL-23 drives the production of IL-17 by CD4 + T cells .	Activation of STAT3 by IL-6 and IL-23 drives the production of IL-17 by CD4 + T cells.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	2	3
Since TGF-beta induces apoptosis in several cell types [ XREF_BIBR - XREF_BIBR ] while the activation of STAT3 by IL-6 exerts a survival influence on target cells [ XREF_BIBR , XREF_BIBR ] , the possibility was next considered that IL-6 signaling might rescue TGF-beta1-mediated inhibition through an anti-apoptotic effect .	Since TGF-beta induces apoptosis in several cell types [XREF_BIBR - XREF_BIBR] while the activation of STAT3 by IL-6 exerts a survival influence on target cells [XREF_BIBR, XREF_BIBR], the possibility was next considered that IL-6 signaling might rescue TGF-beta1-mediated inhibition through an anti-apoptotic effect.	15	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	17	18
Stat1 activation attenuates IL-6 induced Stat3 activity in U-266-1970 cells .	Stat1 activation attenuates IL-6 induced Stat3 activity in U-266-1970 cells.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	5	6
A CD4 T cell gene signature for early rheumatoid arthritis implicates interleukin 6 mediated STAT3 signalling , particularly in anti-citrullinated peptide antibody negative disease .	A CD4 T cell gene signature for early rheumatoid arthritis implicates interleukin 6 mediated STAT3 signalling, particularly in anti-citrullinated peptide antibody negative disease.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	STAT3	STAT3	STAT3	11	13	14	15
Interestingly , activation of STAT3 by IL-6 , examined in these same experiments , was only modest as compared to that by IL-22 .	Interestingly, activation of STAT3 by IL-6, examined in these same experiments, was only modest as compared to that by IL-22.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	4	5
The inflammatory cytokines IFNgamma , IL-6 and TNFalpha are upstream activators of STAT1 , STAT3 and NFkappaB , respectively .	The inflammatory cytokines IFNgamma, IL-6 and TNFalpha are upstream activators of STAT1, STAT3 and NFkappaB, respectively.	3	15	are upstream activators	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	14	15
Here we aimed to explore the effect of acute alcohol on induction of SOCS1 and SOCS3 and regulation of STAT3 and STAT1 pathways induced by IL-6 or IFNs in human monocytes .	Here we aimed to explore the effect of acute alcohol on induction of SOCS1 and SOCS3 and regulation of STAT3 and STAT1 pathways induced by IL-6 or IFNs in human monocytes.	19	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	19	20
Because IL-6 is a key activator of STAT3 and is important in inflammation mediated cancer progression , we explored the possibility that IL-6-IL-6 receptor signaling activates STAT3 in tumor associated B cells .	Because IL-6 is a key activator of STAT3 and is important in inflammation mediated cancer progression, we explored the possibility that IL-6-IL-6 receptor signaling activates STAT3 in tumor associated B cells.	1	10	is a key activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	7	8
Cytokines of the IL-6 family activate STAT3 in vitro [ XREF_BIBR ] .	Cytokines of the IL-6 family activate STAT3 in vitro [XREF_BIBR].	3	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	6	7
These findings suggest that IL-6 may promote tumor development by activating STAT3 .	These findings suggest that IL-6 may promote tumor development by activating STAT3.	4	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	11	12
SOCS3 is an anti-inflammatory protein that limits IL-6 induction of STAT3 , as well as TNFalpha induction of NFkappaB .	SOCS3 is an anti-inflammatory protein that limits IL-6 induction of STAT3, as well as TNFalpha induction of NFkappaB.	7	11	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	10	11
By treating cancer cells with exogenous IL-6 , we confirmed that IL-6 promotes cell invasion by stimulating the STAT3 and Bcl-X L pathway .	By treating cancer cells with exogenous IL-6, we confirmed that IL-6 promotes cell invasion by stimulating the STAT3 and Bcl-X L pathway.	11	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	18	19
The IL-6 and MIP-2 produced enhance and prolong the activity of STAT3 leading to excessive neutrophil recruitment into the inflamed region , which induces PLAG to reduce the overactivated STAT3 to the normal level .	The IL-6 and MIP-2 produced enhance and prolong the activity of STAT3 leading to excessive neutrophil recruitment into the inflamed region, which induces PLAG to reduce the overactivated STAT3 to the normal level.	0	12	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	11	12
Both EGF and IL-6 immediately activated STAT3 , but the GSCs with FoxM1 knockdown were less responsive to EGF or IL-6 treatment than were the normal control cells ( XREF_FIG ) .	Both EGF and IL-6 immediately activated STAT3, but the GSCs with FoxM1 knockdown were less responsive to EGF or IL-6 treatment than were the normal control cells (XREF_FIG).	1	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	6	7
Interestingly , IL-6 was able to strongly activate STAT3 in tumor organoids , in contrast to studies using acinar cells isolated from Kras G12D mice that concluded that IL-6 trans-signaling is necessary to mediate robust STAT3 activation in pancreatic tumor cells .	Interestingly, IL-6 was able to strongly activate STAT3 in tumor organoids, in contrast to studies using acinar cells isolated from Kras G12D mice that concluded that IL-6 trans-signaling is necessary to mediate robust STAT3 activation in pancreatic tumor cells.	28	36	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	28	29	35	36
Recent studies indicate that SOCS3 plays a key role in regulating the divergent action of IL-10 and IL-6 , by specifically blocking STAT3 activation induced by IL-6 but not that induced by IL-10 [ XREF_BIBR , XREF_BIBR ] .	Recent studies indicate that SOCS3 plays a key role in regulating the divergent action of IL-10 and IL-6, by specifically blocking STAT3 activation induced by IL-6 but not that induced by IL-10 [XREF_BIBR, XREF_BIBR].	22	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	22	23
Some of this protective effect may depend on IL-6 , which activates the anti-apoptotic transcription factor STAT3 .	Some of this protective effect may depend on IL-6, which activates the anti-apoptotic transcription factor STAT3.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	16	17
We chose this dose of IL-6 based on previous data from our laboratory XREF_BIBR and others XREF_BIBR , which demonstrated that similar concentrations of IL-6 activated AMPK and STAT3 ( Signal Transducer and Activator of Transcription 3 ) and induced SOCS3 ( Suppressor of Cytokine Signaling 3 ) mRNA in cultured adipocytes and adipose tissue .	We chose this dose of IL-6 based on previous data from our laboratory XREF_BIBR and others XREF_BIBR, which demonstrated that similar concentrations of IL-6 activated AMPK and STAT3 (Signal Transducer and Activator of Transcription 3) and induced SOCS3 (Suppressor of Cytokine Signaling 3) mRNA in cultured adipocytes and adipose tissue.	22	33	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	28	29
74 Although STAT-3 is activated by IL-6 , the transcription factor , hypoxia inducible factor-1alpha ( HIF-1alpha ) , can be also activated via IL-6 .	74 Although STAT-3 is activated by IL-6, the transcription factor, hypoxia inducible factor-1alpha (HIF-1alpha), can be also activated via IL-6.	2	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	6	7	2	3
This IL-6 concentration activates STAT3 in human dendritic cells .	This IL-6 concentration activates STAT3 in human dendritic cells.	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	4	5
Furthermore , exogenous administration of IL-6 potentiated NF Kappa B transcriptional activity , pSTAT3 ( Tyr705 ) and JAK inflammatory signaling as well as cell proliferation in CARF- or DOX treated MDA-MB-231 cells .	Furthermore, exogenous administration of IL-6 potentiated NF Kappa B transcriptional activity, pSTAT3 (Tyr705) and JAK inflammatory signaling as well as cell proliferation in CARF- or DOX treated MDA-MB-231 cells.	3	15	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	5	6	13	14
Injections of interleukin-6 ( IL-6 ) before and after middle cerebral artery occlusion in mice restored activity of STAT3 and additionally restored the transcriptional activity of the Mn-SOD promoter through recovery of the recruitment of STAT3 to the Mn-SOD promoter ; a resulting reduction in infarct volume was observed [ XREF_BIBR ] .	Injections of interleukin-6 (IL-6) before and after middle cerebral artery occlusion in mice restored activity of STAT3 and additionally restored the transcriptional activity of the Mn-SOD promoter through recovery of the recruitment of STAT3 to the Mn-SOD promoter; a resulting reduction in infarct volume was observed [XREF_BIBR].	0	19	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	2	3	18	19
It is well known that IL-6 together with the signal transducer gp130 activates STAT3 .	It is well known that IL-6 together with the signal transducer gp130 activates STAT3.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	13	14
In primary breast cancer , interleukin-6 ( IL-6 ) induced activation of its downstream effectors , JAK2 and STAT3 , and this signaling played a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth , invasion , and metastasis [ XREF_BIBR ] .	In primary breast cancer, interleukin-6 (IL-6) induced activation of its downstream effectors, JAK2 and STAT3, and this signaling played a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis [XREF_BIBR].	5	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	18	19
IL-6 and Oncostatin M ( OSM ) induce STAT3 activation ( phosphorylation ) and phosphorylated STAT3 ( pSTAT3 ) activates C/EBPdelta transcription in growth arrested cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	IL-6 and Oncostatin M (OSM) induce STAT3 activation (phosphorylation) and phosphorylated STAT3 (pSTAT3) activates C/EBPdelta transcription in growth arrested cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	22	induce	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	STAT3	STAT3 (pSTAT3) activates C/EBPdelta transcription	stat3	0	1	15	16
XREF_BIBR - XREF_BIBR Of note , IL-6 , IL-21 , and IL-23 all activate the transcription factor Stat3 .	XREF_BIBR - XREF_BIBR Of note, IL-6, IL-21, and IL-23 all activate the transcription factor Stat3.	2	18	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	17	18
We examined the time-course of STAT3 phosphorylation in RBECs treated with OSM , IL-6 , and LIF .	We examined the time-course of STAT3 phosphorylation in RBECs treated with OSM, IL-6, and LIF.	5	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	5	6
In this suggested model ( XREF_FIG ) , activation of PAR1 elicits IL-6 secretion that in turn activates STAT3 by conventional IL-6 receptor signaling .	In this suggested model (XREF_FIG), activation of PAR1 elicits IL-6 secretion that in turn activates STAT3 by conventional IL-6 receptor signaling.	12	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	18	19
35 STAT1 and STAT3 pathways are mediated by interleukin-6 , a cytokine that regulates the proliferation of myeloma cells ( IL-6 ) .	35 STAT1 and STAT3 pathways are mediated by interleukin-6, a cytokine that regulates the proliferation of myeloma cells (IL-6).	3	11	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	8	9	3	4
IL-6 induced the accumulation of P-STAT3 in the nucleus , whereas the pre-treatment with XZH-5 blocked this process ( XREF_FIG ) .	IL-6 induced the accumulation of P-STAT3 in the nucleus, whereas the pre-treatment with XZH-5 blocked this process (XREF_FIG).	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	P-STAT3	P-STAT3	P-STAT3	0	1	5	6
We found that cancer derived interleukin-6 ( IL-6 ) induces the immunosuppressive ability of MDSCs by activating the STAT3 and IDO signaling pathway , but the detailed molecular events are unclear .	We found that cancer derived interleukin-6 (IL-6) induces the immunosuppressive ability of MDSCs by activating the STAT3 and IDO signaling pathway, but the detailed molecular events are unclear.	3	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	18	19
We have found that Stat3 activated by autocrine IL-6 mediates the generation of malignant effusion via upregulation of VEGF in lung adenocarcinoma [ XREF_BIBR ] .	We have found that Stat3 activated by autocrine IL-6 mediates the generation of malignant effusion via upregulation of VEGF in lung adenocarcinoma [XREF_BIBR].	4	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	8	9	4	5
The CRH induced IL-6 promoted phosphorylation of janus kinase 2 ( JAK2 ) and signal transducers and activators of transcription 3 ( STAT3 ) .	The CRH induced IL-6 promoted phosphorylation of janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3).	1	23	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	CRH induced IL-6	il-6	STAT3	STAT3	stat3	3	4	22	23
Blocking IL-6 would inhibit STAT3 mediated IL-6 signaling , which maintains the CSC phenotype , and downregulate STAT3 target gene induction such as Bcl-xL , Survivin , and c-Myc .	Blocking IL-6 would inhibit STAT3 mediated IL-6 signaling, which maintains the CSC phenotype, and downregulate STAT3 target gene induction such as Bcl-xL, Survivin, and c-Myc.	0	7	inhibit	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	STAT3	STAT3 mediated IL-6	stat3	1	2	4	5
XREF_BIBR , XREF_BIBR For instance , IL-6 , a proinflammatory cytokine that utilizes gp130 , promotes the activation of STAT3 .	XREF_BIBR, XREF_BIBR For instance, IL-6, a proinflammatory cytokine that utilizes gp130, promotes the activation of STAT3.	6	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	19	20
IL-6 is thought to primarily activate STAT3 , and STAT3 is the primary input to the genetic network governing Th17 differentiation .	IL-6 is thought to primarily activate STAT3, and STAT3 is the primary input to the genetic network governing Th17 differentiation.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
Ingenuity pathway analysis ( IPA ) of the drug signatures from the LINCS database further revealed that glycoside Hst could significantly down-regulate JAK2 and STAT3 signaling ( P = 6.24 x10 -30 ) and IL-6 induced STAT3 signaling ( P = 6.81 x10 -16 ) , which is similar to the pathways of withaferin-A and STAT3-inhibitor VI ( XREF_SUPPLEMENTARY ) , indicating that Hst is a potential STAT3 inhibitor .	Ingenuity pathway analysis (IPA) of the drug signatures from the LINCS database further revealed that glycoside Hst could significantly down-regulate JAK2 and STAT3 signaling (P = 6.24 x10 -30) and IL-6 induced STAT3 signaling (P = 6.81 x10 -16), which is similar to the pathways of withaferin-A and STAT3-inhibitor VI (XREF_SUPPLEMENTARY), indicating that Hst is a potential STAT3 inhibitor.	21	37	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	34	35	36	37
Since IL-6 induces STAT3 dependent fibrin synthesis by hepatocytes XREF_BIBR , we studied the CYLD dependent regulation of IL-6-induced fibrin production in cultivated WT and Cyld -/- hepatocytes .	Since IL-6 induces STAT3 dependent fibrin synthesis by hepatocytes XREF_BIBR, we studied the CYLD dependent regulation of IL-6-induced fibrin production in cultivated WT and Cyld -/- hepatocytes.	1	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	3	4
While TNF-alpha was relatively ineffective , IL-6 activated myocardial cell STAT3 by about 8-fold , indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis .	While TNF-alpha was relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold, indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis.	6	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	10	11
To clarify this we tested whether IL-6 activates the Stat3 transcription factor , to drive a program of antimicrobial peptide gene expression in infected urothelium during UTI .	To clarify this we tested whether IL-6 activates the Stat3 transcription factor, to drive a program of antimicrobial peptide gene expression in infected urothelium during UTI.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	9	10
The data from the four investigated melanoma cell lines clearly showed that IL-6 only induced a pronounced activation of the transcription factor STAT3 , whereas neither Akt nor ERK1/2 were activated .	The data from the four investigated melanoma cell lines clearly showed that IL-6 only induced a pronounced activation of the transcription factor STAT3, whereas neither Akt nor ERK1/2 were activated.	12	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	22	23
Resolution of increased reactive oxygen species requires increased expression of genes responsible for dismutation of increased ROS which is partially achieved by IL-6 mediated activation of signal transducers and activators of transcription 3 ( STAT3 ) .	Resolution of increased reactive oxygen species requires increased expression of genes responsible for dismutation of increased ROS which is partially achieved by IL-6 mediated activation of signal transducers and activators of transcription 3 (STAT3).	22	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	34	35
Interleukin-6 ( IL-6 ) , a member of the glycoprotein 130 family of cytokines , can induce activation of STAT3 signaling pathways to affect downstream signaling and cellular events .	Interleukin-6 (IL-6), a member of the glycoprotein 130 family of cytokines, can induce activation of STAT3 signaling pathways to affect downstream signaling and cellular events.	0	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	19	20
Interestingly , IL-6 induced STAT3 activation and Erbin expression simultaneously .	Interestingly, IL-6 induced STAT3 activation and Erbin expression simultaneously.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
IL-6 also activates STAT3 in non tumor cells .	IL-6 also activates STAT3 in non tumor cells.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
SOCS proteins are inducible inhibitors that negatively regulate STAT3 and STAT1 signaling pathways induced by cytokines , IL-6 or IFNs .	SOCS proteins are inducible inhibitors that negatively regulate STAT3 and STAT1 signaling pathways induced by cytokines, IL-6 or IFNs.	8	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	8	9
IL-6 has been confirmed , in various cells , to activate STAT3 signaling and promote EMT , invasion , and metastasis .	IL-6 has been confirmed, in various cells, to activate STAT3 signaling and promote EMT, invasion, and metastasis.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	11	12
For instance , the STAT3 --> STAT3 interaction which corresponds to the stimulation of STAT3 by IL6 seems to be at a rather low level and can be removed .	For instance, the STAT3 --> STAT3 interaction which corresponds to the stimulation of STAT3 by IL6 seems to be at a rather low level and can be removed.	9	17	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	16	17	14	15
IL-6 strongly activated STAT3 pathway in HeLa , and slightly activated Akt or ERK ( Additional file XREF_SUPPLEMENTARY : Figure S2A ) .	IL-6 strongly activated STAT3 pathway in HeLa, and slightly activated Akt or ERK (Additional file XREF_SUPPLEMENTARY : Figure S2A).	0	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
IL-6 mediated activation of Stat3 is a major signaling pathway in the process of breast cancer metastasis .	IL-6 mediated activation of Stat3 is a major signaling pathway in the process of breast cancer metastasis.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	4	5
IL-11 , an IL-6 family cytokine , was supposed to activate STAT3 .	IL-11, an IL-6 family cytokine, was supposed to activate STAT3.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	11	12
IL-6 secreted by cancer cells activates STAT3 , and induces downstream events , including cancer cell proliferation and apoptosis inhibition .	IL-6 secreted by cancer cells activates STAT3, and induces downstream events, including cancer cell proliferation and apoptosis inhibition.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
Only TCM containing IL6 induced pStat3 in LECs and IL6-dep-TCM ( TCM immunodepleted of IL6 ) failed to induce phosphorylation of Stat3 in LECs ( XREF_FIG , and XREF_SUPPLEMENTARY ) .	Only TCM containing IL6 induced pStat3 in LECs and IL6-dep-TCM (TCM immunodepleted of IL6) failed to induce phosphorylation of Stat3 in LECs (XREF_FIG, and XREF_SUPPLEMENTARY).	2	22	induced	Positive_regulation_token_1_verb	Positive_activation	Positive_regulation	IL6	IL6	il6	pStat3	pStat3 in LECs and IL6-dep-TCM (TCM immunodepleted of IL6) failed to induce phosphorylation of Stat3	pstat3	3	4	5	6
NF-kappaB activation is a well-known player that promotes the production of IL-6 , which stimulates STAT3 activation .	NF-kappaB activation is a well-known player that promotes the production of IL-6, which stimulates STAT3 activation.	9	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	15	16
Importantly , IL-6 induced activation of STAT3 signal transduction coincides with augmented CSC marker expression .	Importantly, IL-6 induced activation of STAT3 signal transduction coincides with augmented CSC marker expression.	2	8	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	6	7
Interleukin-6 can activate STAT-3 signalling in regulator T cells and help tumour cells to escape immune surveillance .	Interleukin-6 can activate STAT-3 signalling in regulator T cells and help tumour cells to escape immune surveillance.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin-6	Interleukin-6	Interleukin-6	STAT-3	STAT-3	STAT-3	0	1	3	4
Interestingly , recent studies have demonstrated that IL-6 is a potent activator of STAT3 , providing a direct link between this pro inflammatory cytokine IL-6 and STAT3 XREF_BIBR , XREF_BIBR .	Interestingly, recent studies have demonstrated that IL-6 is a potent activator of STAT3, providing a direct link between this pro inflammatory cytokine IL-6 and STAT3 XREF_BIBR, XREF_BIBR.	7	14	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	13	14
These data suggest that during pneumonia caused by gram negative or gram positive bacteria , the expression of APPs in the liver depends on STAT3 activation by IL-6 and on RelA activation by early response cytokines .	These data suggest that during pneumonia caused by gram negative or gram positive bacteria, the expression of APPs in the liver depends on STAT3 activation by IL-6 and on RelA activation by early response cytokines.	24	28	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	27	28	24	25
Binding of IL-6 * sIL-6Ralpha to gp130 activates the transcription factor STAT3 via the IL-6 trans-signaling pathway , a pathway known to be crucial in the pathogenesis of inflammatory diseases .	Binding of IL-6 * sIL-6Ralpha to gp130 activates the transcription factor STAT3 via the IL-6 trans-signaling pathway, a pathway known to be crucial in the pathogenesis of inflammatory diseases.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	11	12
This observation is similar to reports that IL-6 mediated activation of STAT3 is enhanced in the absence of SOCS3 , and suggests that the mechanism utilized by SOCS3 to limit IL-6-activated STAT3 also affects STAT3 phosphorylation by T. gondii .	This observation is similar to reports that IL-6 mediated activation of STAT3 is enhanced in the absence of SOCS3, and suggests that the mechanism utilized by SOCS3 to limit IL-6-activated STAT3 also affects STAT3 phosphorylation by T. gondii.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	11	12
However , Arg1 can be expressed by M1 cells in a STAT3 dependent pathway triggered by IL-10 , IL-6 and G-CSF XREF_BIBR , XREF_BIBR .	However, Arg1 can be expressed by M1 cells in a STAT3 dependent pathway triggered by IL-10, IL-6 and G-CSF XREF_BIBR, XREF_BIBR.	11	21	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	11	12
IL-6 activates STAT3 most potently , but there is also evidence of IL-6-induced NFkappaB activation through PI3K and Akt XREF_BIBR - XREF_BIBR .	IL-6 activates STAT3 most potently, but there is also evidence of IL-6-induced NFkappaB activation through PI3K and Akt XREF_BIBR - XREF_BIBR.	0	4	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
For example , STAT3 can be activated by both IL-6 and IL-10 , yet their biological activities are diametrically opposed and counterregulatory with IL-6 contributing to inflammation and IL-10 blocking inflammation .	For example, STAT3 can be activated by both IL-6 and IL-10, yet their biological activities are diametrically opposed and counterregulatory with IL-6 contributing to inflammation and IL-10 blocking inflammation.	3	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	3	4
MEKs and ERKs inhibited IL-6 activation of Stat3 harboring a mutation at serine 727 , the major site for serine phosphorylation , similar to inhibition of wild-type Stat3 , and inhibited Janus kinases Jak1 and Jak2 upstream of Stat3 in the Jak-STAT-signaling pathway .	MEKs and ERKs inhibited IL-6 activation of Stat3 harboring a mutation at serine 727, the major site for serine phosphorylation, similar to inhibition of wild-type Stat3, and inhibited Janus kinases Jak1 and Jak2 upstream of Stat3 in the Jak-STAT-signaling pathway.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	7	8
EGCG dose-dependently inhibited Stat3 activation induced by IL-6 , but did not change the total Stat3 expression .	EGCG dose-dependently inhibited Stat3 activation induced by IL-6, but did not change the total Stat3 expression.	3	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	7	8	3	4
In addition , IL-6 induced activation of Stat3 in LNCaP and DU145 cells , but not in CWR22Rv1 cells .	In addition, IL-6 induced activation of Stat3 in LNCaP and DU145 cells, but not in CWR22Rv1 cells.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	7	8
Activation of STAT3 by IL-6 initiates proinflammatory response , while IL-10-mediated activation of STAT3 promotes anti-inflammatory response .	Activation of STAT3 by IL-6 initiates proinflammatory response, while IL-10-mediated activation of STAT3 promotes anti-inflammatory response.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	2	3
It is interesting that IL-6 activate only STAT3 in skeletal muscle , while myostatin activate SMAD2/3 and STAT3 .	It is interesting that IL-6 activate only STAT3 in skeletal muscle, while myostatin activate SMAD2/3 and STAT3.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	7	8
XREF_BIBR , XREF_BIBR Recently , the activation of STAT3 by IL-6 was found to promote cell proliferation and differentiation and the synthesis of collagens in cardiac fibroblasts ( CFs ) .	XREF_BIBR, XREF_BIBR Recently, the activation of STAT3 by IL-6 was found to promote cell proliferation and differentiation and the synthesis of collagens in cardiac fibroblasts (CFs).	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	8	9
Some evidence suggests that AngII in combination with IL-6 increases STAT3 signaling in proximal tubular cells and that IL-6 increases ENaC expression in cultured collecting duct cells XREF_BIBR , XREF_BIBR .	Some evidence suggests that AngII in combination with IL-6 increases STAT3 signaling in proximal tubular cells and that IL-6 increases ENaC expression in cultured collecting duct cells XREF_BIBR, XREF_BIBR.	6	11	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
IL-6 increased STAT3 transcactivity obviously and miR-149 * mimics suppressed STAT3 activity induced by IL-6 .	IL-6 increased STAT3 transcactivity obviously and miR-149 * mimics suppressed STAT3 activity induced by IL-6.	0	3	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Most studies have focused on gene regulation at the transcriptional level , for example , some have shown that the STAT3 gene itself is activated by IL-6 signals , and an IL-6 response element ( IL-6RE ) exists within the STAT3 gene promoter , containing both a low affinity STAT3 binding element and a cAMP responsive element ( CRE ) , thus activates the STAT3 gene in cooperation with an unidentified CRE binding protein XREF_BIBR .	Most studies have focused on gene regulation at the transcriptional level, for example, some have shown that the STAT3 gene itself is activated by IL-6 signals, and an IL-6 response element (IL-6RE) exists within the STAT3 gene promoter, containing both a low affinity STAT3 binding element and a cAMP responsive element (CRE), thus activates the STAT3 gene in cooperation with an unidentified CRE binding protein XREF_BIBR.	20	27	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	20	21
Then , IL-6 activated STAT3 and induced the proliferation of surviving hepatocytes .	Then, IL-6 activated STAT3 and induced the proliferation of surviving hepatocytes.	2	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
The inhibitory effect of TBr on the activation of STAT3 was further supported when TBr was even able to suppress the activation of STAT3 induced by externally applied IL-6 .	The inhibitory effect of TBr on the activation of STAT3 was further supported when TBr was even able to suppress the activation of STAT3 induced by externally applied IL-6.	21	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	28	29	23	24
Several IL-6-related angiogenic pathways have been reported , including IL-6 and HIF signalling in ovarian cancer and Stat3 and VEGF signalling in breast cancer .	Several IL-6-related angiogenic pathways have been reported, including IL-6 and HIF signalling in ovarian cancer and Stat3 and VEGF signalling in breast cancer.	9	18	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	17	18
For example , prolactin activates STAT5 to control proliferation , differentiation and survival XREF_BIBR , while STAT3 is activated by IL-6 and LIF to control cell death during involution XREF_BIBR .	For example, prolactin activates STAT5 to control proliferation, differentiation and survival XREF_BIBR, while STAT3 is activated by IL-6 and LIF to control cell death during involution XREF_BIBR.	16	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	16	17
In PC14PE6 and AS2 cells , a Stat3 positive human ADCLC cell line , autocrine IL-6 activated Stat3 via JAKs , not via Src kinase .	In PC14PE6 and AS2 cells, a Stat3 positive human ADCLC cell line, autocrine IL-6 activated Stat3 via JAKs, not via Src kinase.	14	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	15	16	17	18
The fact that TQ can abrogate IL-6 induced STAT3 activation has already been reported by our group previously [ XREF_BIBR ] .	The fact that TQ can abrogate IL-6 induced STAT3 activation has already been reported by our group previously [XREF_BIBR].	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
We therefore hypothesize that IL-6 activation of STAT3 may also help protect against ethanol induced endothelial damage .	We therefore hypothesize that IL-6 activation of STAT3 may also help protect against ethanol induced endothelial damage.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	7	8
Due to the high level of IL-6 that is found in the serum of burn injured mice in our study , and the fact that neutralization of G-CSF did not fully suppress STAT3 activation in bone marrow myeloid and myeloid progenitor cells , we speculate that IL-6 may contribute to the hematopoietic changes and resistance to infection in our model through direct activation of myeloid STAT3 and possibly hepatic STAT3 .	Due to the high level of IL-6 that is found in the serum of burn injured mice in our study, and the fact that neutralization of G-CSF did not fully suppress STAT3 activation in bone marrow myeloid and myeloid progenitor cells, we speculate that IL-6 may contribute to the hematopoietic changes and resistance to infection in our model through direct activation of myeloid STAT3 and possibly hepatic STAT3.	46	70	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	46	47	69	70
Hence , the infection induced expression of SOCS3 at 3 hpi is correlated with that of IL-24 , but not IL-6 , which is also known to activate the JAK and STAT3 pathway .	Hence, the infection induced expression of SOCS3 at 3 hpi is correlated with that of IL-24, but not IL-6, which is also known to activate the JAK and STAT3 pathway.	12	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	31	32
In contrast , exogenous soluble IL-6 induced p-Stat3 in wild-type , but not by Il6ra DeltaT T cells ( XREF_FIG ) .	In contrast, exogenous soluble IL-6 induced p-Stat3 in wild-type, but not by Il6ra DeltaT T cells (XREF_FIG).	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-Stat3	p-Stat3	p-Stat3	5	6	7	8
Previously , we have shown that autocrine IL-6 signaling induces a persistent activation of Stat3 .	Previously, we have shown that autocrine IL-6 signaling induces a persistent activation of Stat3.	7	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	7	8	14	15
Next , we tested the possibility whether SFN treatment affected IL6 induced activation of STAT3 .	Next, we tested the possibility whether SFN treatment affected IL6 induced activation of STAT3.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	10	11	14	15
As shown previously , the NF-kappaB-dependent tumor growth factor released by IECs could be IL-6 , which plays an important role in proliferation [ XREF_BIBR ] and can activates STAT3 .	As shown previously, the NF-kappaB-dependent tumor growth factor released by IECs could be IL-6, which plays an important role in proliferation [XREF_BIBR] and can activates STAT3.	1	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	29	30
Finally , we examined whether CP690 ,550 affects IL-6 receptor ( IL-6R ) pathway , which activates STAT3 through gp130 .	Finally, we examined whether CP690,550 affects IL-6 receptor (IL-6R) pathway, which activates STAT3 through gp130.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	17	18
The normalized data also correctly shows that IL-6 stimulates pSTAT3 induction .	The normalized data also correctly shows that IL-6 stimulates pSTAT3 induction.	7	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	7	8	9	10
In our previous work , we showed that IL-6 promotes a nuclear complex of STAT3 and CDK9 , a major component of active P and TEFb complex in derepression and activation of RNA Pol II on IL-6 inducible genes [ XREF_BIBR ] .	In our previous work, we showed that IL-6 promotes a nuclear complex of STAT3 and CDK9, a major component of active P and TEFb complex in derepression and activation of RNA Pol II on IL-6 inducible genes [XREF_BIBR].	8	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	14	15
Moreover , IL-6 treatment induced activation of STAT3 in HSG cells in vitro , further supporting that IL-6 can directly act on salivary gland epithelial cells .	Moreover, IL-6 treatment induced activation of STAT3 in HSG cells in vitro, further supporting that IL-6 can directly act on salivary gland epithelial cells.	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	7	8
Moreover , STAT3 activation by IL-6 , IL-21 , IL-22 , and IL-23 is maintained , suggesting that STAT3 activation by IL-26 is also intact .	Moreover, STAT3 activation by IL-6, IL-21, IL-22, and IL-23 is maintained, suggesting that STAT3 activation by IL-26 is also intact.	2	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	2	3
Of note , the transcription factor STAT3 is also activated by IL-6 and IL-21 and , together with the other Th17 characterizing transcription factor RORgamma , STAT3 is responsible for IL-17A and IL-17F expression 22 .	Of note, the transcription factor STAT3 is also activated by IL-6 and IL-21 and, together with the other Th17 characterizing transcription factor RORgamma, STAT3 is responsible for IL-17A and IL-17F expression 22.	3	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	6	7
TGF-beta no longer enhanced STAT-3 activation induced by IL-6 in TGF-betaRII DN CD4 + T cells ( XREF_FIG ) .	TGF-beta no longer enhanced STAT-3 activation induced by IL-6 in TGF-betaRII DN CD4 + T cells (XREF_FIG).	4	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	8	9	4	5
Thus far , our hypotheses and data are premised on the idea that TNF-alpha activated NF-kappaB is primarily responsible for IL-6 induction early ( within 1 h ) , and that IL-6 activated STAT3 is primarily responsible for STAT3 target gene expression later ( 2 h ) .	Thus far, our hypotheses and data are premised on the idea that TNF-alpha activated NF-kappaB is primarily responsible for IL-6 induction early (within 1 h), and that IL-6 activated STAT3 is primarily responsible for STAT3 target gene expression later (2 h).	31	36	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	31	32	33	34
20 Moreover , both IL-6 and IL-11 are strongly upregulated in gastric cancer biopsies , and it has been shown that IL-6 may increase STAT3 and ERK1/2 activation in H pylori dependent gastritis .	20 Moreover, both IL-6 and IL-11 are strongly upregulated in gastric cancer biopsies, and it has been shown that IL-6 may increase STAT3 and ERK1/2 activation in H pylori dependent gastritis.	21	27	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	24	25
The ability to stimulate parental MCF10A cells in a paracrine manner suggests that IL-6 may also activate STAT3 in an autocrine manner .	The ability to stimulate parental MCF10A cells in a paracrine manner suggests that IL-6 may also activate STAT3 in an autocrine manner.	13	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	17	18
IL-6 is pro inflammatory , promotes steatohepatitis and activates signal transducer and activator of transcription 3 ( STAT3 ) in hepatocytes , and all three mechanisms may be related to cancer induction .	IL-6 is pro inflammatory, promotes steatohepatitis and activates signal transducer and activator of transcription 3 (STAT3) in hepatocytes, and all three mechanisms may be related to cancer induction.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	17	18
These results indicate PSC secreted IL-6 activates STAT3 signaling in PDAC cells .	These results indicate PSC secreted IL-6 activates STAT3 signaling in PDAC cells.	4	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
XREF_BIBR This rapid termination of IL-6 signaling appears to be mediated by SOCS3 , which is encoded by a STAT3 target gene upregulated by both IL-6 and IL-10 that can inhibit signaling through the IL-6 receptor , but not the IL-10 receptor .	XREF_BIBR This rapid termination of IL-6 signaling appears to be mediated by SOCS3, which is encoded by a STAT3 target gene upregulated by both IL-6 and IL-10 that can inhibit signaling through the IL-6 receptor, but not the IL-10 receptor.	19	27	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	19	20
Studies in liver specific stat3-null mice demonstrate a significant contribution of the IL-6 induced STAT3 pathway to immediate-early gene expression 35 .	Studies in liver specific stat3-null mice demonstrate a significant contribution of the IL-6 induced STAT3 pathway to immediate-early gene expression 35.	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	14	15
These results indicated that STAT3 activation by IL-6 is involved in clinical cancer .	These results indicated that STAT3 activation by IL-6 is involved in clinical cancer.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	4	5
Therefore , STAT3 and Akt activation by these IL-6 family cytokines expressed by MOS-J and POS -1 cells were studied .	Therefore, STAT3 and Akt activation by these IL-6 family cytokines expressed by MOS-J and POS -1 cells were studied.	2	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	2	3
Furthermore , it is also suggested that Mao , which activates STAT3 induced by IL-6 , may be a useful therapeutic tool for fulminant hepatic failure .	Furthermore, it is also suggested that Mao, which activates STAT3 induced by IL-6, may be a useful therapeutic tool for fulminant hepatic failure.	10	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	11	12
IL-17 , in turn , induces IL-6 , which activates STAT3 , resulting in upregulation of genes that promote survival , such as bcl-x , in a variety of human cancer cell lines [ XREF_BIBR ] .	IL-17, in turn, induces IL-6, which activates STAT3, resulting in upregulation of genes that promote survival, such as bcl-x, in a variety of human cancer cell lines [XREF_BIBR].	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	10	11
IL-6 was known to play critical roles in Th17 cell differentiation XREF_BIBR , and STAT3 , which is activated by IL-6 , is a key transcription factors for this differentiation XREF_BIBR .	IL-6 was known to play critical roles in Th17 cell differentiation XREF_BIBR, and STAT3, which is activated by IL-6, is a key transcription factors for this differentiation XREF_BIBR.	14	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	14	15
STAT3 activation by IL-6 and IL-10 in primary T cell populations .	STAT3 activation by IL-6 and IL-10 in primary T cell populations.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	0	1
One model for NFkappaB-STAT3-mediated immunosuppression suggests that NFkappaB induced IL-6 expression activates STAT3 in tumor cells and modulates the production of inhibitory cytokines and chemokines resulting in decreased T cell infiltration and activation .	One model for NFkappaB-STAT3-mediated immunosuppression suggests that NFkappaB induced IL-6 expression activates STAT3 in tumor cells and modulates the production of inhibitory cytokines and chemokines resulting in decreased T cell infiltration and activation.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	NFkappaB induced IL-6 expression	il-6	STAT3	STAT3	stat3	9	10	12	13
IL-6 induces STAT3 activation which mediates its most biological functions , whereas IL-2 signals through STAT5 phosphorylation .	IL-6 induces STAT3 activation which mediates its most biological functions, whereas IL-2 signals through STAT5 phosphorylation.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
In addition , IL-6 , IL-10 , and VEGF activate STAT3 in tumor infiltrating immune cells , providing a feed forward mechanism for STAT3 activation in the tumor microenvironment .	In addition, IL-6, IL-10, and VEGF activate STAT3 in tumor infiltrating immune cells, providing a feed forward mechanism for STAT3 activation in the tumor microenvironment.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	10	11
However , TNF-alpha , IL-17 , IL-1beta stimulated the proliferation of RA-FLS and induced IL-6 gene expression as well as inducing activation of Stat3 and ERK 1/2 .	However, TNF-alpha, IL-17, IL-1beta stimulated the proliferation of RA-FLS and induced IL-6 gene expression as well as inducing activation of Stat3 and ERK 1/2.	2	26	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	TNF-alpha, IL-17, IL-1beta stimulated the proliferation of RA-FLS and induced IL-6 gene expression	il-6	Stat3	Stat3	stat3	14	15	23	24
This suggests that either IL-6 does not induce Stat3 in vivo or its absence is compensated for by other cytokines , such as leukemia-inhibitory factor ( LIF ) .	This suggests that either IL-6 does not induce Stat3 in vivo or its absence is compensated for by other cytokines, such as leukemia-inhibitory factor (LIF).	4	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	8	9
Enforced SOCS1 or SOCS3 expression in hepatocytes inhibits STAT3 activation and hepatocyte proliferation induced by IL-6 , hepatocyte growth factor ( HGF ) , and epidermal growth factor ( EGF ) , which results in the suppression of liver regeneration [ XREF_BIBR , XREF_BIBR ] .	Enforced SOCS1 or SOCS3 expression in hepatocytes inhibits STAT3 activation and hepatocyte proliferation induced by IL-6, hepatocyte growth factor (HGF), and epidermal growth factor (EGF), which results in the suppression of liver regeneration [XREF_BIBR, XREF_BIBR].	8	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	8	9
Interleukin 6 , one of the inflammatory cytokines found during retinal inflammation , activated STAT3 and decreased rhodopsin protein in adult retinal explants .	Interleukin 6, one of the inflammatory cytokines found during retinal inflammation, activated STAT3 and decreased rhodopsin protein in adult retinal explants.	0	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin 6	Interleukin 6	Interleukin 6	STAT3	STAT3	STAT3	0	2	14	15
Oncostatin M ( OSM ) , another IL-6 family member , is elevated in GBM tumors , and activates STAT-3 .	Oncostatin M (OSM), another IL-6 family member, is elevated in GBM tumors, and activates STAT-3.	7	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	7	8	19	20
XREF_BIBR XREF_BIBR Previous studies have shown increased pSTAT3 and phosphoSTAT1 ( pSTAT1 ) expression in Ps lesional skin XREF_BIBR and shown that IFNgamma , IL-6 and IL-22 can induce pSTAT1 or pSTAT3 in keratinocytes ; XREF_BIBR however , no study to date has examined their expression or regulation in PsA synovium or fibroblasts .	XREF_BIBR XREF_BIBR Previous studies have shown increased pSTAT3 and phosphoSTAT1 (pSTAT1) expression in Ps lesional skin XREF_BIBR and shown that IFNgamma, IL-6 and IL-22 can induce pSTAT1 or pSTAT3 in keratinocytes; XREF_BIBR however, no study to date has examined their expression or regulation in PsA synovium or fibroblasts.	22	32	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	24	25	31	32
Since blocking Stat3 function in tumor cells is also known to activate adaptive immunity XREF_BIBR , XREF_BIBR it may be that IL-6 induced Stat3 is in part responsible for no/low activation of NK cells in the co-cultures of NK cells and either HEp2 cells or UCLA-1 or HOK-16B tumors .	Since blocking Stat3 function in tumor cells is also known to activate adaptive immunity XREF_BIBR, XREF_BIBR it may be that IL-6 induced Stat3 is in part responsible for no/low activation of NK cells in the co-cultures of NK cells and either HEp2 cells or UCLA-1 or HOK-16B tumors.	21	27	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	21	22	23	24
IL-6 activated the Jak2 and STAT3 and PI3K and Akt pathways in MCL , and the inhibition of these pathways completely or partially abrogated IL-6-mediated protection of MCL cells .	IL-6 activated the Jak2 and STAT3 and PI3K and Akt pathways in MCL, and the inhibition of these pathways completely or partially abrogated IL-6-mediated protection of MCL cells.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Moreover , the enhanced STAT3 activation by IL-6 in NP460-EBV cells could be neutralized by anti-IL-6R antibody treatment ( XREF_FIG ) .	Moreover, the enhanced STAT3 activation by IL-6 in NP460-EBV cells could be neutralized by anti-IL-6R antibody treatment (XREF_FIG).	4	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	4	5
The MO4 cell line , which lacks constitutive expression of P-STAT3 , was treated with IL-6 , in order to induce P-STAT3 expression and the K1735-C4 cell line , characerized by constitutive expression of P-STAT3 , was treated with different doses of AZD1480 for 48 hours .	The MO4 cell line, which lacks constitutive expression of P-STAT3, was treated with IL-6, in order to induce P-STAT3 expression and the K1735-C4 cell line, characerized by constitutive expression of P-STAT3, was treated with different doses of AZD1480 for 48 hours.	8	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	P-STAT3	P-STAT3	P-STAT3	15	16	10	11
As shown in XREF_FIG , IL-6 can activate STAT3 by phosphorylation in a dose dependent manner , and we choose 5ng/mL IL-6 for subsequent experiment .	As shown in XREF_FIG, IL-6 can activate STAT3 by phosphorylation in a dose dependent manner, and we choose 5ng/mL IL-6 for subsequent experiment.	5	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	8	9
These CLL cells were treated with chlorambucil or fludarabine with or without anti-CD126 antibody tocilizumab for 24 hours and IL6 mediated STAT3 transcriptional activity and cell-cycle alteration were evaluated .	These CLL cells were treated with chlorambucil or fludarabine with or without anti-CD126 antibody tocilizumab for 24 hours and IL6 mediated STAT3 transcriptional activity and cell-cycle alteration were evaluated.	19	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	19	20	21	22
This enhanced activation of STAT3 by IL-6 treatment in NP460hTert-EBV cells was further confirmed by EMSA ( XREF_FIG ) .	This enhanced activation of STAT3 by IL-6 treatment in NP460hTert-EBV cells was further confirmed by EMSA (XREF_FIG).	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	4	5
IL-6 activates STAT3 which induces miR-21 .	IL-6 activates STAT3 which induces miR-21.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Since PA6 cells are known to express Interleukin 6 XREF_BIBR , it is possible that secretion of IL-6 by PA6 cells stimulates Stat3 signalling to favour self-renewal of ES cells in the presence of BMP4 .	Since PA6 cells are known to express Interleukin 6 XREF_BIBR, it is possible that secretion of IL-6 by PA6 cells stimulates Stat3 signalling to favour self-renewal of ES cells in the presence of BMP4.	15	23	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	17	18	22	23
IL-10 and IL-6 are both known to activate Stat3 yet only IL-10 exhibits anti-inflammatory properties .	IL-10 and IL-6 are both known to activate Stat3 yet only IL-10 exhibits anti-inflammatory properties.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	8	9
IL23 and IL6 activate the STAT3 transcription factor which in turn leads to differentiation of CD4+ helper T cells into Th17 cells that function in driving autoimmune inflammation by producing pro inflammatory cytokines , such as IL-17A , IL-17F and IL-22 [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	IL23 and IL6 activate the STAT3 transcription factor which in turn leads to differentiation of CD4+ helper T cells into Th17 cells that function in driving autoimmune inflammation by producing pro inflammatory cytokines, such as IL-17A, IL-17F and IL-22 [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	2	3	5	6
The induction of RORc is dependent on STAT3 , preferentially activated by IL-6 , IL-21 , and IL-23 in the presence of low amounts of TGF-beta [ XREF_BIBR , XREF_BIBR ] .	The induction of RORc is dependent on STAT3, preferentially activated by IL-6, IL-21, and IL-23 in the presence of low amounts of TGF-beta [XREF_BIBR, XREF_BIBR].	5	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	7	8
XREF_BIBR A study by Ahmed etal XREF_BIBR showed that targeting of IL-6 and STAT3 signaling by a novel antibody against gp130 significantly inhibited STAT3 activation leading to prompt disappearance of cysteine proteases of serpin B3/B4 mRNAs and markedly enhancing tumor cell apoptosis .	XREF_BIBR A study by Ahmed etal XREF_BIBR showed that targeting of IL-6 and STAT3 signaling by a novel antibody against gp130 significantly inhibited STAT3 activation leading to prompt disappearance of cysteine proteases of serpin B3/B4 mRNAs and markedly enhancing tumor cell apoptosis.	11	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	23	24
This suggests that autocrine effects of IL-6 and G-CSF may activate the JAK2 and STAT3 pathway in response to paclitaxel-treatment in HEY cells .	This suggests that autocrine effects of IL-6 and G-CSF may activate the JAK2 and STAT3 pathway in response to paclitaxel-treatment in HEY cells.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	14	15
XREF_BIBR XREF_BIBR IL-6 activates signal transducer and activator of transcription 3 ( STAT3 ) and has an important function in the inflammatory response .	XREF_BIBR XREF_BIBR IL-6 activates signal transducer and activator of transcription 3 (STAT3) and has an important function in the inflammatory response.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	12	13
Additionally , EMSA also showed significant reversal of IL-6-induced Stat3-DNA binding activity in pM+ pIL-6 treatment suggesting that the loss of MMP-2 activity inhibited the IL-6 mediated Stat3 activation ( XREF_FIG ) .	Additionally, EMSA also showed significant reversal of IL-6-induced Stat3-DNA binding activity in pM+ pIL-6 treatment suggesting that the loss of MMP-2 activity inhibited the IL-6 mediated Stat3 activation (XREF_FIG).	24	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	25	26	27	28
Analysis of activation of STAT3 showed that only OSM , and not LIF , IL-31 , IL-11 , nor IL-6 stimulation , resulted in elevated pSTAT3 signal , with or without added LPS , in either the adventitial fibroblast or the aortic smooth muscle cell cultures ( XREF_FIG ) .	Analysis of activation of STAT3 showed that only OSM, and not LIF, IL-31, IL-11, nor IL-6 stimulation, resulted in elevated pSTAT3 signal, with or without added LPS, in either the adventitial fibroblast or the aortic smooth muscle cell cultures (XREF_FIG).	19	27	signal	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	19	20	25	26
Indeed , STAT3 activation by G-CSF , IL-6 , and IL-1beta signalling was recently demonstrated in DRG neurons [ XREF_BIBR , XREF_BIBR ] .	Indeed, STAT3 activation by G-CSF, IL-6, and IL-1beta signalling was recently demonstrated in DRG neurons [XREF_BIBR, XREF_BIBR].	2	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	2	3
Maintenance of IL-17 production requires continued expression of Rorc provided through STAT3 activating signals such as IL-6 , IL-23 and IL-21 and inhibition of expression of T-bet and GATA3 .	Maintenance of IL-17 production requires continued expression of Rorc provided through STAT3 activating signals such as IL-6, IL-23 and IL-21 and inhibition of expression of T-bet and GATA3.	11	20	signals	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	11	12
IL-6 and TGFbeta1 activate the STAT3 and SMAD2/3 pathways in NK cells and suppress IL-2 induction of cytotoxicity , granzymes A and B release , perforin expression , and IFNgamma secretion .	IL-6 and TGFbeta1 activate the STAT3 and SMAD2/3 pathways in NK cells and suppress IL-2 induction of cytotoxicity, granzymes A and B release, perforin expression, and IFNgamma secretion.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Consistent with previous studies , GFP tagged STAT3 preformed dimers in the absence of IL-6 and upon IL-6 stimulation STAT3 dimerization significantly increased ( XREF_FIG ) .	Consistent with previous studies, GFP tagged STAT3 preformed dimers in the absence of IL-6 and upon IL-6 stimulation STAT3 dimerization significantly increased (XREF_FIG).	17	20	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	19	20
For instance , IL-1alpha released by dying hepatocytes in a liver challenged with the pro carcinogen diethyl nitrosamine ( DEN ) triggers IL-6 production , which activates STAT3 and promotes liver regeneration and tumor growth .	For instance, IL-1alpha released by dying hepatocytes in a liver challenged with the pro carcinogen diethyl nitrosamine (DEN) triggers IL-6 production, which activates STAT3 and promotes liver regeneration and tumor growth.	22	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	27	28
STAT3 is activated by IL-6 , IL-21 , and IL-23 , cytokines that are involved in Th17 cell differentiation , amplification , and maintenance .	STAT3 is activated by IL-6, IL-21, and IL-23, cytokines that are involved in Th17 cell differentiation, amplification, and maintenance.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
It has been reported that IL-6 can activate signaling pathways of Stat3 , Erk , MAPK , and Akt [ XREF_BIBR ] [ XREF_BIBR ] [ XREF_BIBR ] .	It has been reported that IL-6 can activate signaling pathways of Stat3, Erk, MAPK, and Akt [XREF_BIBR] [XREF_BIBR] [XREF_BIBR].	5	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	5	6	11	12
If reduced IL-6 signaling is responsible for the poor response of aged CD4 T cells , we reasoned the * DC should act in vitro to restore IL-6 induction of pSTAT3 and that using * DC made from BM of Il6 -/- mice should prevent the advantage conferred by the TLR agonist activation of the APC .	If reduced IL-6 signaling is responsible for the poor response of aged CD4 T cells, we reasoned the * DC should act in vitro to restore IL-6 induction of pSTAT3 and that using * DC made from BM of Il6 -/- mice should prevent the advantage conferred by the TLR agonist activation of the APC.	27	31	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	27	28	30	31
Indeed , STAT3 activation by IL-6 from MSCs has been reported to promote the proliferation and metastasis of osteosarcoma .	Indeed, STAT3 activation by IL-6 from MSCs has been reported to promote the proliferation and metastasis of osteosarcoma.	2	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	2	3
Understanding how IL-6 and other soluble factors may lead to STAT3 activation via the tumor microenvironment will provide new therapeutic regimens for breast carcinomas and other cancers with elevated p-STAT3 levels .	Understanding how IL-6 and other soluble factors may lead to STAT3 activation via the tumor microenvironment will provide new therapeutic regimens for breast carcinomas and other cancers with elevated p-STAT3 levels.	2	11	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	10	11
STAT3 is constitutively activated in both tumor and immune cells by IL-6 .	STAT3 is constitutively activated in both tumor and immune cells by IL-6.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	0	1
We also found that IL-6 promotes the activation of not only the downstream molecule STAT3 but also the Nrf2-antioxidant pathway , leading to a significant decrease in oxidative stress by upregulating Mn-SOD .	We also found that IL-6 promotes the activation of not only the downstream molecule STAT3 but also the Nrf2-antioxidant pathway, leading to a significant decrease in oxidative stress by upregulating Mn-SOD.	4	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	14	15
It was recently reported that capsaicin inhibited interleukin-6 ( IL-6 )-induced activation of signal transducer and activator of transcription 3 ( STAT3 ) , an anti-apoptotic transcription factor .	It was recently reported that capsaicin inhibited interleukin-6 (IL-6)-induced activation of signal transducer and activator of transcription 3 (STAT3), an anti-apoptotic transcription factor.	9	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	21	22
In summary , results of the present study firstly demonstrate the direct regulatory constraint of IL6 induced STAT3 signaling on SERT expression , function and depression like behavior in the mouse ( XREF_FIG ) .	In summary, results of the present study firstly demonstrate the direct regulatory constraint of IL6 induced STAT3 signaling on SERT expression, function and depression like behavior in the mouse (XREF_FIG).	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	15	16	17	18
To examine whether IL-6 and EGF could activate STAT3 signaling in podocytes we exposed cultured murine podocytes to IL-6 and EGF and then performed western blotting to determine STAT3 phosphorylation , which is a marker of activation of STAT3 signaling .	To examine whether IL-6 and EGF could activate STAT3 signaling in podocytes we exposed cultured murine podocytes to IL-6 and EGF and then performed western blotting to determine STAT3 phosphorylation, which is a marker of activation of STAT3 signaling.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	8	9
Hence , there is additional complexity to the inflammatory feedback loop that involves STAT3 transcriptionally upregulating NF-kappaB and IL6 , both of which activate STAT3 .	Hence, there is additional complexity to the inflammatory feedback loop that involves STAT3 transcriptionally upregulating NF-kappaB and IL6, both of which activate STAT3.	15	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	18	19	24	25
During liver injury , IL-6 activates STAT3 in liver parenchymal and non parenchymal cells [ XREF_BIBR , XREF_BIBR ] .	During liver injury, IL-6 activates STAT3 in liver parenchymal and non parenchymal cells [XREF_BIBR, XREF_BIBR].	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
HCC development is often preceded by liver injury and inflammation and , consequently , the production of pro tumorigenic cytokines , in particular IL-6 , which induces STAT3 activation in hepatocytes .	HCC development is often preceded by liver injury and inflammation and, consequently, the production of pro tumorigenic cytokines, in particular IL-6, which induces STAT3 activation in hepatocytes.	4	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	23	24	27	28
IL-6 mainly activates STAT3 , and to a minor extent STAT1 .	IL-6 mainly activates STAT3, and to a minor extent STAT1.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
IL-6 treatment also increased pSTAT3 in the pancreatic epithelial non neoplastic cell line , HPDE ( XREF_FIG ) .	IL-6 treatment also increased pSTAT3 in the pancreatic epithelial non neoplastic cell line, HPDE (XREF_FIG).	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	0	1	4	5
IL-6 and IL-1beta can activate STAT3 and NF-kappaB , possibly resulting in an increase of anti-apoptotic proteins in PC cells .	IL-6 and IL-1beta can activate STAT3 and NF-kappaB, possibly resulting in an increase of anti-apoptotic proteins in PC cells.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Benzyl isothiocyanate , an extract from cruciferous vegetables , blocks STAT3 activation induced by IL-6 in MDA-MB-453 breast cancer cells and PANC-1 pancreatic cancer cells [ XREF_BIBR ] .	Benzyl isothiocyanate, an extract from cruciferous vegetables, blocks STAT3 activation induced by IL-6 in MDA-MB-453 breast cancer cells and PANC-1 pancreatic cancer cells [XREF_BIBR].	10	26	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	10	11
We next examined the contribution of IL-6 to the activation of STAT-3 in this model by monitoring P-STAT-3 in the lungs of mice treated with IL-6 neutralizing antibodies or following genetic removal of IL-6 .	We next examined the contribution of IL-6 to the activation of STAT-3 in this model by monitoring P-STAT-3 in the lungs of mice treated with IL-6 neutralizing antibodies or following genetic removal of IL-6.	16	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	P-STAT-3	P-STAT-3	P-STAT-3	25	26	17	18
STAT3 activation by IL-6 causes the disruption of skeletal muscle proteostasis through both anabolic and catabolic signaling [ XREF_BIBR ] .	STAT3 activation by IL-6 causes the disruption of skeletal muscle proteostasis through both anabolic and catabolic signaling [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	0	1
We hypothesize that PSC secreted IL-6 activates STAT3 signaling to promote PanIN progression to PDAC .	We hypothesize that PSC secreted IL-6 activates STAT3 signaling to promote PanIN progression to PDAC.	4	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
We hypothesized that alveolar epithelial STAT3 is activated by IL-6 family cytokines and is required for effective responses during gram negative bacterial pneumonia .	We hypothesized that alveolar epithelial STAT3 is activated by IL-6 family cytokines and is required for effective responses during gram negative bacterial pneumonia.	3	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	5	6
Once miR-204 is down-regulated , the Src activator SHP2 is directly up-regulated and IL-6 and PDGF production increased , reinforcing STAT3 activation via Src and allowing NFAT activation .	Once miR-204 is down-regulated, the Src activator SHP2 is directly up-regulated and IL-6 and PDGF production increased, reinforcing STAT3 activation via Src and allowing NFAT activation.	13	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	20	21
IL-6 and TNF-alpha cotreatments activated STAT3 synergistically and upregulated Oct-4 .	IL-6 and TNF-alpha cotreatments activated STAT3 synergistically and upregulated Oct-4.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
These data suggest that both desialylated platelets and IL-6 lead to STAT3 mediated hepatic TPO mRNA expression downstream of the AMR-JAK2 and IL6 receptor ( IL-6R )-JAK1 signaling cascades , respectively .	These data suggest that both desialylated platelets and IL-6 lead to STAT3 mediated hepatic TPO mRNA expression downstream of the AMR-JAK2 and IL6 receptor (IL-6R)-JAK1 signaling cascades, respectively.	6	12	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	11	12
XREF_BIBR , XREF_BIBR , XREF_BIBR IL-6 , which is a NFkappaB target gene , can activate STAT3 , a regulator of S1PR1 expression .	XREF_BIBR, XREF_BIBR, XREF_BIBR IL-6, which is a NFkappaB target gene, can activate STAT3, a regulator of S1PR1 expression.	2	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	16	17
However , no appreciable effect on IL-6 induced pSTAT3 was observed following with pre-treatment with the C3R metabolite ( XREF_FIG ) .	However, no appreciable effect on IL-6 induced pSTAT3 was observed following with pre-treatment with the C3R metabolite (XREF_FIG).	4	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	6	7	8	9
The contribution of STAT3 activation by IL-6 produced by BM-MSC to EMDR has been previously shown by us .	The contribution of STAT3 activation by IL-6 produced by BM-MSC to EMDR has been previously shown by us.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	3	4
XREF_SUPPLEMENTARY , XREF_SUPPLEMENTARY In summary , in pancreatic epithelial cells , activation of oncogenic Kras promotes production of inflammatory mediators , including IL-6 , IL-11 , TNFalpha , and IL-1alpha , which activate STAT3 and/or NF-kappaB in an autocrine or paracrine manner to promote cell survival and proliferation , and maintain an inflammatory tumor microenvironment .	XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY In summary, in pancreatic epithelial cells, activation of oncogenic Kras promotes production of inflammatory mediators, including IL-6, IL-11, TNFalpha, and IL-1alpha, which activate STAT3 and/or NF-kappaB in an autocrine or paracrine manner to promote cell survival and proliferation, and maintain an inflammatory tumor microenvironment.	22	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	33	34
MDA EV and MDA RKIP were transfected with the STAT3 reporter and treated with IL-6 as previously described in XREF_FIG .	MDA EV and MDA RKIP were transfected with the STAT3 reporter and treated with IL-6 as previously described in XREF_FIG.	9	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	9	10
As interleukin-6 acts intracellularly through STAT-3 , it might be that elevated extracellular level of IL-6 induces STAT-3 dependent pathway in ASCs and by previously mentioned interaction with Smads can enhance VEGF secretion .	As interleukin-6 acts intracellularly through STAT-3, it might be that elevated extracellular level of IL-6 induces STAT-3 dependent pathway in ASCs and by previously mentioned interaction with Smads can enhance VEGF secretion.	13	19	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	level of IL-6	il-6	STAT-3	STAT-3	stat-3	15	16	17	18
NF-kB consequently induced by IKK triggered sustained IL-6 expression that constitutively activates STAT3 in Rrm2b deficient cells .	NF-kB consequently induced by IKK triggered sustained IL-6 expression that constitutively activates STAT3 in Rrm2b deficient cells.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	NF-kB consequently induced by IKK triggered sustained IL-6 expression	il-6	STAT3	STAT3	stat3	7	8	12	13
We have shown recently that IL-6 and leukemia inhibitory factor rapidly activate a latent cytoplasmic transcription factor , acute-phase response factor ( APRF ) , by tyrosine phosphorylation , which then binds to IL-6 response elements of various IL-6 target genes .	We have shown recently that IL-6 and leukemia inhibitory factor rapidly activate a latent cytoplasmic transcription factor, acute-phase response factor (APRF), by tyrosine phosphorylation, which then binds to IL-6 response elements of various IL-6 target genes.	5	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	acute-phase response factor	acute-phase response factor	acute-phase response factor	5	6	18	21
IL-6 alone activated pSTAT3 to the 0.38 folds of total STAT3 , but IL-6 and TNF-alpha cotreatments elevated the pSTAT3 level to 0.97 folds of STAT3 in DLD1 cell line ( XREF_FIG ) .	IL-6 alone activated pSTAT3 to the 0.38 folds of total STAT3, but IL-6 and TNF-alpha cotreatments elevated the pSTAT3 level to 0.97 folds of STAT3 in DLD1 cell line (XREF_FIG).	13	29	elevated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	25	26
This study demonstrates that activation of STAT3 induced by interleukin-6 is promoted mainly by proliferative vessels in ruptured rotator cuff tendon .	This study demonstrates that activation of STAT3 induced by interleukin-6 is promoted mainly by proliferative vessels in ruptured rotator cuff tendon.	4	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	9	10	6	7
Our study revealed that IL-6 induces the activation of the Stat3 signaling and promotes the downmodulation of the p90RSK and eEF2 and mTOR and p70S6K axes , while it does not affect the activation of AKT .	Our study revealed that IL-6 induces the activation of the Stat3 signaling and promotes the downmodulation of the p90RSK and eEF2 and mTOR and p70S6K axes, while it does not affect the activation of AKT.	4	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	10	11
IL-6 signaling activates STAT3 , which subsequently drives Th17 differentiation [ XREF_BIBR ] .	IL-6 signaling activates STAT3, which subsequently drives Th17 differentiation [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
This effect was consistent when JAK2 and STAT3 signaling was activated by interleukin-6 ( IL-6 ) , and ameliorated when cells were treated with prevanadate , a protein tyrosin phosphatase inhibitor .	This effect was consistent when JAK2 and STAT3 signaling was activated by interleukin-6 (IL-6), and ameliorated when cells were treated with prevanadate, a protein tyrosin phosphatase inhibitor.	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	12	13	7	8
TGFbeta , IL-6 , and IL-21 drive the activation of STAT3 , which can subsequently activate RORgammat .	TGFbeta, IL-6, and IL-21 drive the activation of STAT3, which can subsequently activate RORgammat.	0	15	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	10	11
IL-6 produced by macrophages , T cells and fibroblasts of the tumor supporting stroma leads to activation of STAT3 and tumor progression .	IL-6 produced by macrophages, T cells and fibroblasts of the tumor supporting stroma leads to activation of STAT3 and tumor progression.	0	21	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	18	19
IL-6 Activates ERK1/2 , but not STAT3 in MSCs .	IL-6 Activates ERK1/2, but not STAT3 in MSCs.	0	8	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
A prominent exception is the STAT3 pathway , triggered by IL-6 as well as by other cytokines , where the main effect on IECs is inhibition of apoptosis , which in turn enhances cell survival rates even without involving the Wnt and beta-catenin pathway .	A prominent exception is the STAT3 pathway, triggered by IL-6 as well as by other cytokines, where the main effect on IECs is inhibition of apoptosis, which in turn enhances cell survival rates even without involving the Wnt and beta-catenin pathway.	5	11	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	5	6
pSTAT3 is increased in the placenta 3 hours post-poly ( I : C ) injection , with a maternal IL-6 dependent activation of pSTAT3 in the SP layer .	pSTAT3 is increased in the placenta 3 hours post-poly (I : C) injection, with a maternal IL-6 dependent activation of pSTAT3 in the SP layer.	19	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	19	20	23	24
As expected , we were able to observe suppression of IL-6 dependent activation of STAT3 reporter by J6/JFH1-WT and loss of this suppression by J6/JFH1-79A82A .	As expected, we were able to observe suppression of IL-6 dependent activation of STAT3 reporter by J6/JFH1-WT and loss of this suppression by J6/JFH1-79A82A.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	14	15
The results showed that IL6 , which promoted p-STAT3 activity , increased the levels of G6PD transcription in ACHN and 786-O stable cells by about 1.5 ~ 2 folds relative to the BSA controls .	The results showed that IL6, which promoted p-STAT3 activity, increased the levels of G6PD transcription in ACHN and 786-O stable cells by about 1.5 ~ 2 folds relative to the BSA controls.	4	11	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	p-STAT3	p-STAT3	p-STAT3	4	5	8	9
Ectopic expression of IRE1alpha and XBP1s in melanocytes and melanoma cells increased IL-6 levels and then activated intracellular STAT3 signaling , which was diminished by the addition of IL-6 antibodies .	Ectopic expression of IRE1alpha and XBP1s in melanocytes and melanoma cells increased IL-6 levels and then activated intracellular STAT3 signaling, which was diminished by the addition of IL-6 antibodies.	18	29	diminished	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	28	29	18	19
26 In co-cultures of limbal epithelial cells and limbal stromal cells , IL6 secretion was found to activate STAT3 signaling in the epithelial cell population , and this signaling pathway was proposed as an active component in the niche function of stromal cells .	26 In co-cultures of limbal epithelial cells and limbal stromal cells, IL6 secretion was found to activate STAT3 signaling in the epithelial cell population, and this signaling pathway was proposed as an active component in the niche function of stromal cells.	12	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	12	13	18	19
In concanavalin A ( Con A )-induced T cell hepatitis model , IFN-gamma activation of STAT1 is mainly responsible for SOCS1 induction , whereas IL-6 activation of STAT3 contributes to SOCS3 induction [ XREF_BIBR ] .	In concanavalin A (Con A)-induced T cell hepatitis model, IFN-gamma activation of STAT1 is mainly responsible for SOCS1 induction, whereas IL-6 activation of STAT3 contributes to SOCS3 induction [XREF_BIBR].	24	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	27	28
Growth receptors and their ligands , such as HER2 , EGFR , or EGF , activate NFkappaB , and the pro inflammatory cytokine IL-6 activates both NFkappaB and STAT3 XREF_BIBR .	Growth receptors and their ligands, such as HER2, EGFR, or EGF, activate NFkappaB, and the pro inflammatory cytokine IL-6 activates both NFkappaB and STAT3 XREF_BIBR.	19	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	23	24	28	29
STAT3 , activated by IL-6 , IL-21 , and IL-23 , is essential for T helper ( Th ) 17 cell development because it provides signal transduction that induces transcription of RORgammat , which in turn is crucial for the induction of Th17 cells .	STAT3, activated by IL-6, IL-21, and IL-23, is essential for T helper (Th) 17 cell development because it provides signal transduction that induces transcription of RORgammat, which in turn is crucial for the induction of Th17 cells.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
To determine if decreased pSTAT3 formation due to DOCK8 deficiency or DOCK8 N1986Y mutation reflected enhanced dephosphorylation of STAT3 , we analyzed pY705-STAT3 formation in DOCK8 deficient T cells treated with IL-6 in the absence of presence of the phosphotyrosine phosphatase inhibitor sodium orthovanadate ( Na 3 VO 4 ) .	To determine if decreased pSTAT3 formation due to DOCK8 deficiency or DOCK8 N1986Y mutation reflected enhanced dephosphorylation of STAT3, we analyzed pY705-STAT3 formation in DOCK8 deficient T cells treated with IL-6 in the absence of presence of the phosphotyrosine phosphatase inhibitor sodium orthovanadate (Na 3 VO 4).	16	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	31	32	18	19
We observed that the simultaneous expression of RANTES and IL-6 in MCF-7 cells induced a strong activation of STAT3 that might stimulate the anchorage independent growth , whereas in MDA-MB-231 RANTES+ IL 6 cells , in which STAT3 was constitutively activated , no effects on cell proliferation were observed .	We observed that the simultaneous expression of RANTES and IL-6 in MCF-7 cells induced a strong activation of STAT3 that might stimulate the anchorage independent growth, whereas in MDA-MB-231 RANTES+IL 6 cells, in which STAT3 was constitutively activated, no effects on cell proliferation were observed.	5	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	expression of RANTES and IL-6	il-6	STAT3	STAT3	stat3	9	10	18	19
It is known that STAT3 and C/EBP are activated by IL-6 and that IL-6 signalling is also affected by IL-10 , even though the exact mechanism is unclear .	It is known that STAT3 and C/EBP are activated by IL-6 and that IL-6 signalling is also affected by IL-10, even though the exact mechanism is unclear.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	4	5
These findings suggested that IL-6 may promote tumor development by activating STAT3 and subsequently activating downstream STAT3 target genes , including the anti-apoptotic gene encoding Bcl-XL and the cell cycle promoting genes encoding cyclin-D1 and c-Myc .	These findings suggested that IL-6 may promote tumor development by activating STAT3 and subsequently activating downstream STAT3 target genes, including the anti-apoptotic gene encoding Bcl-XL and the cell cycle promoting genes encoding cyclin-D1 and c-Myc.	4	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	11	12
In conclusion , Stat5a/b and Stat3 in CWR22Pc cells are activated by Prl and IL-6 , respectively .	In conclusion, Stat5a/b and Stat3 in CWR22Pc cells are activated by Prl and IL-6, respectively.	3	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	14	15	5	6
IL-6 , IL-21 , and IL-23 activate STAT3 , thus inducing the expression of ROR-gammat .	IL-6, IL-21, and IL-23 activate STAT3, thus inducing the expression of ROR-gammat.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	7	8
STAT3 , a crucial and well-known mediator of malignant progression in CRC XREF_BIBR , XREF_BIBR , is predominantly activated by IL-6 5 and IL-11 7 .	STAT3, a crucial and well-known mediator of malignant progression in CRC XREF_BIBR, XREF_BIBR, is predominantly activated by IL-6 5 and IL-11 7.	0	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	0	1
It has been reported that IL-6 induces the activation of NF-kappaB and STAT3 in the development of inflammatory arthritis [ XREF_BIBR ] .	It has been reported that IL-6 induces the activation of NF-kappaB and STAT3 in the development of inflammatory arthritis [XREF_BIBR].	5	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	12	13
The upregulation of IL-6 leads to hyperactivated STAT3 , AKT and MEK signaling in PAX5 - MCL cells .	The upregulation of IL-6 leads to hyperactivated STAT3, AKT and MEK signaling in PAX5 - MCL cells.	1	12	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	7	8
This is well exemplified in IL-6/JAK/STAT3 pathway mediated cancer inflammation in colorectal cancer : under the transcriptional drive of NF-kappaB , IL-6 is produced by bone marrow derived myeloid cells and then activates STAT3 in epithelial cells from which tumor arises .	This is well exemplified in IL-6/JAK/STAT3 pathway mediated cancer inflammation in colorectal cancer : under the transcriptional drive of NF-kappaB, IL-6 is produced by bone marrow derived myeloid cells and then activates STAT3 in epithelial cells from which tumor arises.	21	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	33	34
One prediction that can be made from such a network is that in SOCS3-/- mice , where IL-6 induces a sustained STAT3 signal , that IL-6 would act as an anti-inflammatory cytokine , which has indeed been observed experimentally in the literature .	One prediction that can be made from such a network is that in SOCS3-/- mice, where IL-6 induces a sustained STAT3 signal, that IL-6 would act as an anti-inflammatory cytokine, which has indeed been observed experimentally in the literature.	17	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	21	22
A potential mechanism is via a STAT2 dependent increase in the gene expression and secretion of pro inflammatory mediators like IL-6 , which then activate the oncogenic STAT3 signaling pathway .	A potential mechanism is via a STAT2 dependent increase in the gene expression and secretion of pro inflammatory mediators like IL-6, which then activate the oncogenic STAT3 signaling pathway.	8	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	27	28
Whereas induction of STAT3 dependent SOCS3 mRNA by IL-6 or IL-10 was inhibited by AICAR in the presence of ABT-702 , IL-4-induced expression of the typical STAT6 dependent target gene CCL18 was unaltered .	Whereas induction of STAT3 dependent SOCS3 mRNA by IL-6 or IL-10 was inhibited by AICAR in the presence of ABT-702, IL-4-induced expression of the typical STAT6 dependent target gene CCL18 was unaltered.	1	10	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	3	4
In the stomach mucosa , STAT3 is activated in response to stimuli by the IL-6 family of cytokines such as IL-6 and IL-11 , resulting in induction of Janus kinase ( JAK )/STAT3 signaling via the gp130 subunit of the IL-6 receptor .	In the stomach mucosa, STAT3 is activated in response to stimuli by the IL-6 family of cytokines such as IL-6 and IL-11, resulting in induction of Janus kinase (JAK)/STAT3 signaling via the gp130 subunit of the IL-6 receptor.	5	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	5	6
Subsequent studies have shown that IL-6 mediates its effects by activating the transcription factor STAT3 .	Subsequent studies have shown that IL-6 mediates its effects by activating the transcription factor STAT3.	5	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	14	15
STAT3 and NF-kappaB , however , are activated in response to different cytokines : whereas IL-6 is a major activator of STAT3 , TNF is a potent activator of NF-kappaB .	STAT3 and NF-kappaB, however, are activated in response to different cytokines : whereas IL-6 is a major activator of STAT3, TNF is a potent activator of NF-kappaB.	15	22	is a major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	21	22
Early IL-6 production , preferential activation of the STAT3 pathway , and potent neutralizing antibody responses all depended on viral recognition via TLR2 .	Early IL-6 production, preferential activation of the STAT3 pathway, and potent neutralizing antibody responses all depended on viral recognition via TLR2.	1	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	8	9
Stimulation of naive T cells in the presence of TGFbeta and IL-6 is sufficient to form IL-17-producing T cells XREF_BIBR , and IL-6 activates Stat3 , which is essential for formation of Th17 cells XREF_BIBR .	Stimulation of naive T cells in the presence of TGFbeta and IL-6 is sufficient to form IL-17-producing T cells XREF_BIBR, and IL-6 activates Stat3, which is essential for formation of Th17 cells XREF_BIBR.	22	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	22	23	24	25
XREF_BIBR IL-6 can activate the STAT3 pathway to promote progression of pancreatic intraepithelial neoplasia and development of PC .	XREF_BIBR IL-6 can activate the STAT3 pathway to promote progression of pancreatic intraepithelial neoplasia and development of PC.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	5	6
STAT3 activated by IL-6 contributes to migration of and invasion by gastric cancer cell lines .	STAT3 activated by IL-6 contributes to migration of and invasion by gastric cancer cell lines.	0	4	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	0	1
IL-6 family cytokines including IL-6 and IL-11 also activate STAT3 and , to a lesser extent , STAT1 , as well as MAPK and phosphatidylinositol 3-kinase ( PI3K ) cascades through the gp130 receptor to bring about its pleiotropic actions including anti-inflammatory effects , as recently reviewed elsewhere .	IL-6 family cytokines including IL-6 and IL-11 also activate STAT3 and, to a lesser extent, STAT1, as well as MAPK and phosphatidylinositol 3-kinase (PI3K) cascades through the gp130 receptor to bring about its pleiotropic actions including anti-inflammatory effects, as recently reviewed elsewhere.	0	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	9	10
IL-6 ( an activator of STAT3 ) can stimulate the episialin promoter , and binding of STAT3 to the STAT element in the episialin promoter is observed in bandshift assays [ XREF_BIBR ] .	IL-6 (an activator of STAT3) can stimulate the episialin promoter, and binding of STAT3 to the STAT element in the episialin promoter is observed in bandshift assays [XREF_BIBR].	0	8	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
As a result , IFN-gamma and IL-6 stimulation caused similar strong activation of STAT1 , STAT3 , SOCS1 and SOCS3 .	As a result, IFN-gamma and IL-6 stimulation caused similar strong activation of STAT1, STAT3, SOCS1 and SOCS3.	4	16	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	15	16
This chronic inflammation results in an elevated constitutive activity of NF-kappaB and a release of cytokines such as IL-6 , which by itself activates STAT3 .	This chronic inflammation results in an elevated constitutive activity of NF-kappaB and a release of cytokines such as IL-6, which by itself activates STAT3.	15	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	24	25
To further explore existing evidence that some proinflammatory cytokines ( e.g ., TNFalpha and IL1beta ) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR can modulate SERT activity , we tested the hypothesis that IL6 dependent activation of the STAT3 canonical inflammatory signaling XREF_BIBR exerts direct regulatory control over SERT expression , function and depression like behavior .	To further explore existing evidence that some proinflammatory cytokines (e.g., TNFalpha and IL1beta) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR can modulate SERT activity, we tested the hypothesis that IL6 dependent activation of the STAT3 canonical inflammatory signaling XREF_BIBR exerts direct regulatory control over SERT expression, function and depression like behavior.	30	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	30	31	35	36
IL-6 promotes tumor growth in a Stat-3 dependent pathway .	IL-6 promotes tumor growth in a Stat-3 dependent pathway.	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat-3	Stat-3	Stat-3	0	1	6	7
IL-6 , IL-21 and IL-23 , cytokines that activate STAT3 , are all necessary for the development of acute GvHD .	IL-6, IL-21 and IL-23, cytokines that activate STAT3, are all necessary for the development of acute GvHD.	0	13	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	9	10
For example , IL-6 activates STAT3 , but IL-10 inhibits the activation of STAT3 .	For example, IL-6 activates STAT3, but IL-10 inhibits the activation of STAT3.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
We further found that IL-6 blockade inhibits epithelial STAT3 activation and subsequent tumor cell proliferation in our K-ras mutant mouse which is in agreement with recently published data .	We further found that IL-6 blockade inhibits epithelial STAT3 activation and subsequent tumor cell proliferation in our K-ras mutant mouse which is in agreement with recently published data.	4	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	8	9
SOCS3 selectively blocks signaling by IL-6 , specifically prevents activation of STAT3 by IL-6 but not IL-10 XREF_BIBR , thereby preventing its ability to inhibit lipopolysaccharide ( LPS )-induced anti-inflammatory signaling .	SOCS3 selectively blocks signaling by IL-6, specifically prevents activation of STAT3 by IL-6 but not IL-10 XREF_BIBR, thereby preventing its ability to inhibit lipopolysaccharide (LPS)-induced anti-inflammatory signaling.	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	11	12
For example , activation of STAT3 by IL-6 and sIL-6R produced by MSC and TAM induces the expression of several pro survival proteins like survivin , MCL-1 and Bcl-XL that cause resistance to chemotherapeutic agents [ XREF_BIBR ] .	For example, activation of STAT3 by IL-6 and sIL-6R produced by MSC and TAM induces the expression of several pro survival proteins like survivin, MCL-1 and Bcl-XL that cause resistance to chemotherapeutic agents [XREF_BIBR].	3	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	5	6
In inflammatory cells , IL-6 mediated Stat3 signaling selectively induces a pro carcinogenic tumorigenic microenvironment .	In inflammatory cells, IL-6 mediated Stat3 signaling selectively induces a pro carcinogenic tumorigenic microenvironment.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	6	7
IL-6 signaling triggers binding of STAT3 to the ROR gammat locus , resulting in a positive feedback loop that drives T cells toward the T H 17 lineage 17 .	IL-6 signaling triggers binding of STAT3 to the ROR gammat locus, resulting in a positive feedback loop that drives T cells toward the T H 17 lineage 17.	0	6	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
SOCS3 limits the intensity and duration of IL-6 mediated STAT3 signaling in plasma cells .	SOCS3 limits the intensity and duration of IL-6 mediated STAT3 signaling in plasma cells.	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
Recent research suggests that PAR-1 promotes astrocytic expression of IL-6 , which in turn triggers STAT3 signaling cascade , causing enhanced migration of reactive astrocytes and astrogliosis after spinal cord injury [ XREF_BIBR ] .	Recent research suggests that PAR-1 promotes astrocytic expression of IL-6, which in turn triggers STAT3 signaling cascade, causing enhanced migration of reactive astrocytes and astrogliosis after spinal cord injury [XREF_BIBR].	4	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	PAR-1 promotes astrocytic expression of IL-6	il-6	STAT3	STAT3	stat3	9	10	15	16
IL-6 leads to the activation of Stat3 , which then dimerizes and binds to its cognate sites located in the regulatory regions of genes .	IL-6 leads to the activation of Stat3, which then dimerizes and binds to its cognate sites located in the regulatory regions of genes.	0	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	6	7
After binding with its receptor , IL-6 triggers activation of MEK and MAPK , JAK and STAT3 , and PI3K and Akt signaling pathways [ XREF_BIBR ] .	After binding with its receptor, IL-6 triggers activation of MEK and MAPK, JAK and STAT3, and PI3K and Akt signaling pathways [XREF_BIBR].	6	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	16	17
Here , we report that gp130 knock-in mice gp130 ( F759 and F759 ) , in which IL-6 family cytokine mediated Stat3 activation is enhanced , showed an osteosclerotic phenotype .	Here, we report that gp130 knock-in mice gp130 (F759 and F759), in which IL-6 family cytokine mediated Stat3 activation is enhanced, showed an osteosclerotic phenotype.	17	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	17	18	21	22
All isolates were evaluated for their inhibitory effects on IL6 induced STAT3 promoter activation in stably transfected Hep3B cells .	All isolates were evaluated for their inhibitory effects on IL6 induced STAT3 promoter activation in stably transfected Hep3B cells.	3	13	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	9	10	11	12
Activation of STAT3 by the IL-6 Cytokine Family in IBD .	Activation of STAT3 by the IL-6 Cytokine Family in IBD.	0	7	Activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	2	3
STAT3 mediated by IL-6 is another major cause to cardiac hypertrophy XREF_BIBR .	STAT3 mediated by IL-6 is another major cause to cardiac hypertrophy XREF_BIBR.	0	7	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	0	1
Exogenous IL-6 leads to the production and secretion of IL-6 and PEc from prostate cancer cells and tumors , by activating IL-6R and JAK2 and STAT3 pathway .	Exogenous IL-6 leads to the production and secretion of IL-6 and PEc from prostate cancer cells and tumors, by activating IL-6R and JAK2 and STAT3 pathway.	0	26	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	25	26
In particular , adiponectin transiently increases macrophage derived plasma IL-6 levels , which , in turn , activate hepatic STAT3 to induce hepatic IRS-2 expression and enhance insulin sensitivity in the liver XREF_BIBR .	In particular, adiponectin transiently increases macrophage derived plasma IL-6 levels, which, in turn, activate hepatic STAT3 to induce hepatic IRS-2 expression and enhance insulin sensitivity in the liver XREF_BIBR.	9	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 levels	il-6	STAT3	STAT3	stat3	9	10	19	20
demonstrated the role of beta1 integrin in IL-6 mediated Stat3 survival signaling in multiple myeloma cells .	demonstrated the role of beta1 integrin in IL-6 mediated Stat3 survival signaling in multiple myeloma cells.	0	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	7	8	9	10
Similar potency was also observed against IL-6 and IFN-alpha driven STAT1 phosphorylation in T cells , whereas IL-6 activation of STAT3 was less sensitive .	Similar potency was also observed against IL-6 and IFN-alpha driven STAT1 phosphorylation in T cells, whereas IL-6 activation of STAT3 was less sensitive.	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	20	21
Finally , it has been suggested that PACAP protects neurons from death after ischaemia through induction of IL-6 and consequent activation of the STAT3 and ERK ( extracellular-signal-regulated kinase ) signalling pathways .	Finally, it has been suggested that PACAP protects neurons from death after ischaemia through induction of IL-6 and consequent activation of the STAT3 and ERK (extracellular-signal-regulated kinase) signalling pathways.	17	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	23	24
Western blot analyses showed that IL-6 activated not only the downstream molecule STAT3 but also Nrf2 in the irradiated cells ( XREF_FIG ) .	Western blot analyses showed that IL-6 activated not only the downstream molecule STAT3 but also Nrf2 in the irradiated cells (XREF_FIG).	5	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	12	13
STAT3 increases production of IL-6 , which can further stimulate and prolong STAT3 activation in breast cancer epithelial cells in an autocrine as well as a paracrine fashion , as shown here in this manuscript .	STAT3 increases production of IL-6, which can further stimulate and prolong STAT3 activation in breast cancer epithelial cells in an autocrine as well as a paracrine fashion, as shown here in this manuscript.	2	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	12	13
IL-6 can enhance neuropathic pain in the dorsal horn by activating STAT3 signaling in glial cells after peripheral nerve injury .	IL-6 can enhance neuropathic pain in the dorsal horn by activating STAT3 signaling in glial cells after peripheral nerve injury.	0	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	11	12
To further confirm the hypothesis that the amylin sensitizing effect on leptin signaling is caused by an amylin induced increase in IL-6 activation of JAK and STAT3 signaling , WT and IL-6 KO mice were infused with either amylin or vehicle by minipumps for 2 weeks .	To further confirm the hypothesis that the amylin sensitizing effect on leptin signaling is caused by an amylin induced increase in IL-6 activation of JAK and STAT3 signaling, WT and IL-6 KO mice were infused with either amylin or vehicle by minipumps for 2 weeks.	21	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	26	27
Specifically , we demonstrate that ( a ) IL-6 signals through its trans-signaling pathway involving sIL-6R to activate STAT3 signaling , ( b ) IL-6 induces ROS generation , and coincides with hMSH3 ' s shift from the nucleus to the cytosol , ( c ) IL-6 elicits a dose dependent shift of hMSH3 , ( d ) inhibition of the IL-6 signaling pathway blocks the hMSH3 shift , and constitutively activated STAT3 induces hMSH3 shift without IL-6 treatment , and ( e ) IL-6 treatment increases endogenous tetranucleotide mutation frequency that defines EMAST .	Specifically, we demonstrate that (a) IL-6 signals through its trans-signaling pathway involving sIL-6R to activate STAT3 signaling, (b) IL-6 induces ROS generation, and coincides with hMSH3 's shift from the nucleus to the cytosol, (c) IL-6 elicits a dose dependent shift of hMSH3, (d) inhibition of the IL-6 signaling pathway blocks the hMSH3 shift, and constitutively activated STAT3 induces hMSH3 shift without IL-6 treatment, and (e) IL-6 treatment increases endogenous tetranucleotide mutation frequency that defines EMAST.	8	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	18	19
Thus , IL-6 induced an early and robust activation of Stat3 in antigen specific 2D2 T cells only when provided by DCs .	Thus, IL-6 induced an early and robust activation of Stat3 in antigen specific 2D2 T cells only when provided by DCs.	2	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	10	11
An IL-6 loop was found , where IL-6 activates the AKT , STAT3 and NF-kappaB pathways while suppressing PTEN expression [ XREF_BIBR ] .	An IL-6 loop was found, where IL-6 activates the AKT, STAT3 and NF-kappaB pathways while suppressing PTEN expression [XREF_BIBR].	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	12	13
In addition , many other IL-6 family cytokines activate STAT3 in hepatocytes and likely play roles similar to those of IL-6 in protecting against hepatocellular damage and promoting liver regeneration .	In addition, many other IL-6 family cytokines activate STAT3 in hepatocytes and likely play roles similar to those of IL-6 in protecting against hepatocellular damage and promoting liver regeneration.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	9	10
Accordingly , the activation of STAT3 by IL-6 in breast cancers also promotes the selection and expansion of CD44 high / CD24 low cells that possess stem like properties , XREF_BIBR , XREF_BIBR which is a hallmark of post-EMT carcinoma cells characterized by their enhanced tumorigenicity , pluripotency , and chemoresistance .	Accordingly, the activation of STAT3 by IL-6 in breast cancers also promotes the selection and expansion of CD44 high / CD24 low cells that possess stem like properties, XREF_BIBR, XREF_BIBR which is a hallmark of post-EMT carcinoma cells characterized by their enhanced tumorigenicity, pluripotency, and chemoresistance.	3	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	5	6
They showed that IL-6 mediated activation of Stat3 in human breast epithelial cell line increased miR-21 and miR-181b expression and maintained the transformed state by preventing their differentiation .	They showed that IL-6 mediated activation of Stat3 in human breast epithelial cell line increased miR-21 and miR-181b expression and maintained the transformed state by preventing their differentiation.	3	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	7	8
The levels of IL-6 in NBL patient serum and bone marrow have been reported to be elevated [ XREF_BIBR , XREF_BIBR ] , and the combination of IL-6 plus soluble IL-6R from monocytes has been shown to activate STAT3 and mediate drug resistance in NBL cells [ XREF_BIBR ] .	The levels of IL-6 in NBL patient serum and bone marrow have been reported to be elevated [XREF_BIBR, XREF_BIBR], and the combination of IL-6 plus soluble IL-6R from monocytes has been shown to activate STAT3 and mediate drug resistance in NBL cells [XREF_BIBR].	25	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	27	28	38	39
SOCS3 is an essential factor to block IL-6- and G-CSF-mediated activation of STAT3 signaling .	SOCS3 is an essential factor to block IL-6- and G-CSF-mediated activation of STAT3 signaling.	7	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6-	IL-6-	IL-6-	STAT3	STAT3	STAT3	7	8	12	13
In conclusion , hepatocytes are the major cell type responsible for LCN2 production after bacterial infection or PHx , and this response is dependent on IL-6 activation of the STAT3 signaling pathway .	In conclusion, hepatocytes are the major cell type responsible for LCN2 production after bacterial infection or PHx, and this response is dependent on IL-6 activation of the STAT3 signaling pathway.	25	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	29	30
IL-6 activates signal transducer and activator of transcription 3 ( STAT3 ) as part of an acute-phase response of infection .	IL-6 activates signal transducer and activator of transcription 3 (STAT3) as part of an acute-phase response of infection.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	10	11
No clear effect was seen with JAK2 or JAK3 silencing , suggesting that IL6 stimulates STAT3 mainly through JAK1 in HEK293 cells .	No clear effect was seen with JAK2 or JAK3 silencing, suggesting that IL6 stimulates STAT3 mainly through JAK1 in HEK293 cells.	13	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	13	14	15	16
IL-6 is down stream of the NF-kappaB pathway and among other things has been shown to induce Jak2 and Stat3 pathway .	IL-6 is down stream of the NF-kappaB pathway and among other things has been shown to induce Jak2 and Stat3 pathway.	0	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	19	20
XREF_BIBR It is well accepted that STAT3 serves as a downstream target of IL6 , which induces STAT3 activation through tyrosine 705 phosphorylation and cytoplasmic-to-nuclear shuttling , recognition of STAT3 specific DNA motifs , and transcriptional activation of target genes that are implicated throughout tumor development and involved in proliferation , survival , invasion and angiogenesis .	XREF_BIBR It is well accepted that STAT3 serves as a downstream target of IL6, which induces STAT3 activation through tyrosine 705 phosphorylation and cytoplasmic-to-nuclear shuttling, recognition of STAT3 specific DNA motifs, and transcriptional activation of target genes that are implicated throughout tumor development and involved in proliferation, survival, invasion and angiogenesis.	11	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	13	14	17	18
The p-STAT3 was induced by BMSC-CM treatment or by recombinant IL-6 treatment .	The p-STAT3 was induced by BMSC-CM treatment or by recombinant IL-6 treatment.	0	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	10	11	1	2
Because IL-6 induces STAT3 activation , we treated with IL-6 ( 10 ng/ml ) for various intervals ( 0 , 5 , 10 , 15 , 30 , and 60 min ) to select the optimal time point .	Because IL-6 induces STAT3 activation, we treated with IL-6 (10 ng/ml) for various intervals (0, 5, 10, 15, 30, and 60 min) to select the optimal time point.	3	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	3	4
We next detected that once STAT3 was activated by IL-6 , the phosphorylated STAT3 ( p-STAT3 ) would translocate into the nucleus of BXPC-3 cancer cells .	We next detected that once STAT3 was activated by IL-6, the phosphorylated STAT3 (p-STAT3) would translocate into the nucleus of BXPC-3 cancer cells.	5	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	5	6
In addition , STAT3 activation is required for the transcription of IL-17F , IL-21 , IL-22 , and IL-23R in T H 17 cells ; conversely , IL-6 or IL-21 induces STAT3 activation in T H 17 cells .	In addition, STAT3 activation is required for the transcription of IL-17F, IL-21, IL-22, and IL-23R in T H 17 cells; conversely, IL-6 or IL-21 induces STAT3 activation in T H 17 cells.	27	32	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	27	28	31	32
Previously , IL-6 has been shown to activate STAT3 in colon cancer through phosphorylation on the tyrosine 705 residue [ XREF_BIBR , XREF_BIBR ] .	Previously, IL-6 has been shown to activate STAT3 in colon cancer through phosphorylation on the tyrosine 705 residue [XREF_BIBR, XREF_BIBR].	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
In addition , because almost no other nuclei other than SCs were positive for p-STAT3 and the nuclear fraction western blots detected virtually no p-STAT3 as they were not sensitive enough to detect such a small percentage of cells expressing p-STAT3protein , it would appear that the IL-6 induced STAT3 signalling cascade occurred almost exclusively in SCs .	In addition, because almost no other nuclei other than SCs were positive for p-STAT3 and the nuclear fraction western blots detected virtually no p-STAT3 as they were not sensitive enough to detect such a small percentage of cells expressing p-STAT3protein, it would appear that the IL-6 induced STAT3 signalling cascade occurred almost exclusively in SCs.	46	51	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	47	48	49	50
Importantly NF-kappaB and Stat3 mediated signaling converge on the EMT process where IL6 mediated Stat3 activation promotes EMT through transcriptional induction of the E-cadherin repressor snail [ XREF_BIBR ] , while activation of NF-kappaB promotes posttranslational stabilization of the Snail protein [ XREF_BIBR ] .	Importantly NF-kappaB and Stat3 mediated signaling converge on the EMT process where IL6 mediated Stat3 activation promotes EMT through transcriptional induction of the E-cadherin repressor snail [XREF_BIBR], while activation of NF-kappaB promotes posttranslational stabilization of the Snail protein [XREF_BIBR].	12	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	12	13	14	15
We therefore determined whether IL-6 mediated IL-17-driven Stat3 activation in a tumor setting .	We therefore determined whether IL-6 mediated IL-17-driven Stat3 activation in a tumor setting.	4	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	7	8
More studies are needed to clarify the role of EGCG in suppression of STAT3 activity mediated by IL-6 trans-signaling .	More studies are needed to clarify the role of EGCG in suppression of STAT3 activity mediated by IL-6 trans-signaling.	13	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	13	14
XREF_BIBR In addition , Dominguez et al reported that intrathecal administration of IL-6 to naive rats rapidly activated microglial JAK and STAT3 and induced downstream changes that closely resemble controlled cortical impact ( CCI )-evoked alterations .	XREF_BIBR In addition, Dominguez et al reported that intrathecal administration of IL-6 to naive rats rapidly activated microglial JAK and STAT3 and induced downstream changes that closely resemble controlled cortical impact (CCI)-evoked alterations.	10	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	21	22
XREF_BIBR Moreover , JAK and STAT3 signaling is constitutively activated by IL-6 and frequently observed in various human cancers , including pancreatic cancer .	XREF_BIBR Moreover, JAK and STAT3 signaling is constitutively activated by IL-6 and frequently observed in various human cancers, including pancreatic cancer.	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	5	6
Thus , it is possible that the IL-6 and STAT3 induced miR-92a may further amplify IL-6 and Stat3 signaling through targeting SOCS5 , forming a positive feed-forward loop that drives CRC stem like properties and carcinogenesis .	Thus, it is possible that the IL-6 and STAT3 induced miR-92a may further amplify IL-6 and Stat3 signaling through targeting SOCS5, forming a positive feed-forward loop that drives CRC stem like properties and carcinogenesis.	6	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	7	8	17	18
Here , targeting IL-6 in B20 treated E0771 breast tumors in obese mice decreased STAT3 signaling , tumor cell proliferation , tumor growth , and metastasis and increased survival .	Here, targeting IL-6 in B20 treated E0771 breast tumors in obese mice decreased STAT3 signaling, tumor cell proliferation, tumor growth, and metastasis and increased survival.	2	27	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	14	15
Activation of STAT1 negatively regulates STAT3 activated by IL-6 , IL-17 , IL-21 , and IL-23 , as well as STAT6 activated by IL-4 .	Activation of STAT1 negatively regulates STAT3 activated by IL-6, IL-17, IL-21, and IL-23, as well as STAT6 activated by IL-4.	4	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	5	6
The data thus demonstrated that the protective effect of IL-6 on drug induced apoptosis in neuroblastoma was STAT3 activation dependent .	The data thus demonstrated that the protective effect of IL-6 on drug induced apoptosis in neuroblastoma was STAT3 activation dependent.	7	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	17	18
And IL-6 induced a significant increase of p-STAT3 in HNSCC cells earlier than the p-p70S6K increase .	And IL-6 induced a significant increase of p-STAT3 in HNSCC cells earlier than the p-p70S6K increase.	1	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	1	2	7	8
XREF_FIG shows that IL-6 activated JAK2 and STAT3 , and NVP-AUP922 inhibited the IL-6-activated JAK2-STAT3 signal transduction pathway in a dose dependent manner .	XREF_FIG shows that IL-6 activated JAK2 and STAT3, and NVP-AUP922 inhibited the IL-6-activated JAK2-STAT3 signal transduction pathway in a dose dependent manner.	3	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	7	8
Fibrosis was associated with increased expression of IL-6 and extensive activation of Stat3 .	Fibrosis was associated with increased expression of IL-6 and extensive activation of Stat3.	7	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	7	8	12	13
Previous studies found that IL-6 induced STAT3 binding to this same STAT3 site in the miR-21 promoter .	Previous studies found that IL-6 induced STAT3 binding to this same STAT3 site in the miR-21 promoter.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
All of IL-6 , IL-21 , and IL-23 activate the transcription factor Stat3 in T cells ; accordingly , Th17 differentiation is abrogated in Stat3 deficient T cells .	All of IL-6, IL-21, and IL-23 activate the transcription factor Stat3 in T cells; accordingly, Th17 differentiation is abrogated in Stat3 deficient T cells.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	12	13
There are seven known STATs ( STAT 1 , 2 , 3 , 4 , 5a , 5b , and 6 ) , of which STAT3 is mostly notably activated by the interleukin-6 ( IL-6 ) family of cytokine and thereby exerting inflammatory responses XREF_BIBR .	There are seven known STATs (STAT 1, 2, 3, 4, 5a, 5b, and 6), of which STAT3 is mostly notably activated by the interleukin-6 (IL-6) family of cytokine and thereby exerting inflammatory responses XREF_BIBR.	25	41	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	32	33	25	26
Thus , like in LCL8664 cells , IL-6 activation of the STAT3 pathway may account for the partial rescue of TGF-beta1-mediated growth inhibition .	Thus, like in LCL8664 cells, IL-6 activation of the STAT3 pathway may account for the partial rescue of TGF-beta1-mediated growth inhibition.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	11	12
The STAT3 activation by IL-6 is well documented to support growth , survival and metastasis of human cancer cells XREF_BIBR , XREF_BIBR .	The STAT3 activation by IL-6 is well documented to support growth, survival and metastasis of human cancer cells XREF_BIBR, XREF_BIBR.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	1	2
As IL6 activates STAT3 signaling in macrophages , which in turn can activate C/EBPbeta , we next examined whether paracrine , fibroblast derived IL6 could be responsible for the macrophage activation .	As IL6 activates STAT3 signaling in macrophages, which in turn can activate C/EBPbeta, we next examined whether paracrine, fibroblast derived IL6 could be responsible for the macrophage activation.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	3	4
STAT3 , as a classic downstream effector of IL-6 , can be transcriptionally upregulated by IL-6 [ XREF_BIBR ] .	STAT3, as a classic downstream effector of IL-6, can be transcriptionally upregulated by IL-6 [XREF_BIBR].	0	17	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	0	1
Initially , IL-6 activates STAT3 , then the combined effect of IL-6 and TGF-beta signaling leads to the expression of retinoid related orphan receptor ( ROR-gammat and ROR-alpha ) transcription factor resulting in the initiation of Th17 differentiation .	Initially, IL-6 activates STAT3, then the combined effect of IL-6 and TGF-beta signaling leads to the expression of retinoid related orphan receptor (ROR-gammat and ROR-alpha) transcription factor resulting in the initiation of Th17 differentiation.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
In particular , the cytokines IL-6 , IL-27 and IL-21 have key roles at different stages of Tfh development and mediate STAT-3 dependent production of the transcriptional factor B-cell lymphoma 6 ( Bcl-6 ) [ XREF_BIBR ] [ XREF_BIBR , XREF_BIBR ] .	In particular, the cytokines IL-6, IL-27 and IL-21 have key roles at different stages of Tfh development and mediate STAT-3 dependent production of the transcriptional factor B-cell lymphoma 6 (Bcl-6) [XREF_BIBR] [XREF_BIBR, XREF_BIBR].	3	23	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	5	6	21	22
We observed that IL-6 induced a high accumulation of pSTAT3 in WT SMMC-7721 cells but not in KO-3 and KO-4 cells ( XREF_FIG C ) .	We observed that IL-6 induced a high accumulation of pSTAT3 in WT SMMC-7721 cells but not in KO-3 and KO-4 cells (XREF_FIG C).	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	3	4	9	10
This is consistent with potency of AZD1480 for JAK1 in enzymatic assays , and prior data indicating that JAK1 has a major role in IL-6 mediated activation of STAT3 .	This is consistent with potency of AZD1480 for JAK1 in enzymatic assays, and prior data indicating that JAK1 has a major role in IL-6 mediated activation of STAT3.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	28	29
The protein levels of glycoprotein 130 receptor ( GP130 ) , the IL-6 receptor that activates the STAT3 pathway , were slightly decreased in livers of SHP Tg mice only ( XREF_FIG ) .	The protein levels of glycoprotein 130 receptor (GP130), the IL-6 receptor that activates the STAT3 pathway, were slightly decreased in livers of SHP Tg mice only (XREF_FIG).	12	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	17	18
Janus kinases ( JAKs ) phosphorylate and activate Stat3 in response to cytokines and Stat3 activation by IL-6 in FOCUS or SNU449 ( by ~ 2 to 4-fold ; XREF_SUPPLEMENTARY ) was blocked by ruxolitinib , a JAK1/2 inhibitor , or tofacitinib , a pan-JAK inhibitor ; EC 50 < 1 nM ; XREF_SUPPLEMENTARY ) .	Janus kinases (JAKs) phosphorylate and activate Stat3 in response to cytokines and Stat3 activation by IL-6 in FOCUS or SNU449 (by ~ 2 to 4-fold; XREF_SUPPLEMENTARY) was blocked by ruxolitinib, a JAK1/2 inhibitor, or tofacitinib, a pan-JAK inhibitor; EC 50 < 1 nM; XREF_SUPPLEMENTARY).	7	32	activate	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	17	18	14	15
The IL-6 family of cytokines , including OSM , preferentially activates STAT-3 , leading to dimerization , nuclear translocation , and binding to interferon-gamma-activated site like DNA elements XREF_BIBR .	The IL-6 family of cytokines, including OSM, preferentially activates STAT-3, leading to dimerization, nuclear translocation, and binding to interferon-gamma-activated site like DNA elements XREF_BIBR.	1	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	1	2	11	12
Subsequent studies demonstrated that IL6 mediated activation of STAT3 opposes STAT5 driven differentiation of TH9 cells ; however , this effect was mediated by inhibition of STAT5 activation through diminished IL2 production and not via induction of BCL6 46 .	Subsequent studies demonstrated that IL6 mediated activation of STAT3 opposes STAT5 driven differentiation of TH9 cells; however, this effect was mediated by inhibition of STAT5 activation through diminished IL2 production and not via induction of BCL6 46.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	4	5	8	9
This STAT3 mediated expression of SERPINB3/B4 , together with the notion that SERPINB3/B4 can induce the expression of IL-6 [ XREF_BIBR , XREF_BIBR ] , which activates STAT3 , indicate a feed-forward loop involving SERPINB3/B4 , IL-6 , and STAT3 that may play an important role in IL-6 signaling during tumor initiation and differentiation .	This STAT3 mediated expression of SERPINB3/B4, together with the notion that SERPINB3/B4 can induce the expression of IL-6 [XREF_BIBR, XREF_BIBR], which activates STAT3, indicate a feed-forward loop involving SERPINB3/B4, IL-6, and STAT3 that may play an important role in IL-6 signaling during tumor initiation and differentiation.	1	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	STAT3 mediated expression of SERPINB3/B4, together with the notion that SERPINB3/B4 can induce the expression of IL-6	il-6	STAT3	STAT3	stat3	18	19	27	28
In addition , the authors demonstrated that the paracrine release of IL-6 triggered the activation of STAT3 , leading to the suppression of hepatic glucose production .	In addition, the authors demonstrated that the paracrine release of IL-6 triggered the activation of STAT3, leading to the suppression of hepatic glucose production.	9	17	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	16	17
IL-6 dependent phosphorylation at S727 was not increased in STAT3 Y640F when compared to IL-6 activated STAT3 wt 31 .	IL-6 dependent phosphorylation at S727 was not increased in STAT3 Y640F when compared to IL-6 activated STAT3 wt 31.	12	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	16	17
STAT3 has been shown to cooperate with other inflammatory related transcription factors , such as NFATc1 , in pancreatic development , and STAT3 activation by IL-6 transignaling promotes progression of PanIN and development of PC .	STAT3 has been shown to cooperate with other inflammatory related transcription factors, such as NFATc1, in pancreatic development, and STAT3 activation by IL-6 transignaling promotes progression of PanIN and development of PC.	22	26	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	22	23
We found that the expression of phosphor-STAT3 , phosphor-ERK1/2 and phosphor-p38 was increased when treated with IL-6 , while only the phosphorylation of STAT3 was inhibited by irisin treatment .	We found that the expression of phosphor-STAT3, phosphor-ERK1/2 and phosphor-p38 was increased when treated with IL-6, while only the phosphorylation of STAT3 was inhibited by irisin treatment.	4	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	phosphor-STAT3	phosphor-STAT3	phosphor-STAT3	16	17	6	7
IL-10 and IL-6 engage receptors and then activate STAT3 and both induce the activation of SOCS3 which may differently modulate STAT3 activation induced by IL-10 and IL-6 XREF_BIBR .	IL-10 and IL-6 engage receptors and then activate STAT3 and both induce the activation of SOCS3 which may differently modulate STAT3 activation induced by IL-10 and IL-6 XREF_BIBR.	20	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	20	21
Our findings demonstrate that inhibition of IL-6 can suppress Stat3 activation and the full expansion of AAA , indicating that IL-6 is a major cytokine in the tissue activation of Stat3 .	Our findings demonstrate that inhibition of IL-6 can suppress Stat3 activation and the full expansion of AAA, indicating that IL-6 is a major cytokine in the tissue activation of Stat3.	4	10	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	9	10
IL-6 and IL-21 induce the activation of signal transducer and activator of transcription 3 ( STAT3 ) and promote the differentiation of mouse Tfh cells .	IL-6 and IL-21 induce the activation of signal transducer and activator of transcription 3 (STAT3) and promote the differentiation of mouse Tfh cells.	0	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	15	16
IL-6 from infiltrating macrophages in the pancreata of PDAC transgenic mice activated transcription factor STAT3 in pancreatic tumor cells , promoting tumor development [ XREF_BIBR ] .	IL-6 from infiltrating macrophages in the pancreata of PDAC transgenic mice activated transcription factor STAT3 in pancreatic tumor cells, promoting tumor development [XREF_BIBR].	0	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	14	15
Western blot and immunoprecipitation assays indicated that binding with YAP prolonged interleukin 6 induced STAT3 nuclear accumulation by blocking chromosomal maintenance 1 mediated STAT3 nuclear export without affecting its phosphorylation .	Western blot and immunoprecipitation assays indicated that binding with YAP prolonged interleukin 6 induced STAT3 nuclear accumulation by blocking chromosomal maintenance 1 mediated STAT3 nuclear export without affecting its phosphorylation.	7	16	induced	Positive_early_activation	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	STAT3	STAT3	STAT3	11	13	14	15
Nuclear accumulation of epidermal growth factor receptor ( EGFR ) and activation of STAT3 by IL-6 play a key role in iNOS expression and resultant DNA damage , leading to EBV related nasopharyngeal carcinoma [ XREF_BIBR , XREF_BIBR ] .	Nuclear accumulation of epidermal growth factor receptor (EGFR) and activation of STAT3 by IL-6 play a key role in iNOS expression and resultant DNA damage, leading to EBV related nasopharyngeal carcinoma [XREF_BIBR, XREF_BIBR].	11	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	13	14
XREF_BIBR STAT3 can be activated by the IL-6 cytokine and leptin as well as other growth factors , including epidermal growth factor receptor and platelet derived growth factor receptor through tyrosine phosphorylation .	XREF_BIBR STAT3 can be activated by the IL-6 cytokine and leptin as well as other growth factors, including epidermal growth factor receptor and platelet derived growth factor receptor through tyrosine phosphorylation.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	1	2
STAT3 activation by cytokines , such as interleukin-6 ( IL-6 ) , is mediated through the Janus family kinases ( JAK ) or Src [ XREF_BIBR ] .	STAT3 activation by cytokines, such as interleukin-6 (IL-6), is mediated through the Janus family kinases (JAK) or Src [XREF_BIBR].	0	9	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	7	8	0	1
Thus , IL-6 promotes the accumulation of Stat3 in mitochondria during CD4 cell activation .	Thus, IL-6 promotes the accumulation of Stat3 in mitochondria during CD4 cell activation.	2	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	7	8
Correction : Prevention of Hypovolemic Circulatory Collapse by IL-6 Activated Stat3 .	Correction : Prevention of Hypovolemic Circulatory Collapse by IL-6 Activated Stat3.	6	11	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	8	9	10	11
From these results it can be expected that also in rheumatoid arthritis patients IL-6 mediated STAT3 activation will play a key role in the disease XREF_BIBR .	From these results it can be expected that also in rheumatoid arthritis patients IL-6 mediated STAT3 activation will play a key role in the disease XREF_BIBR.	13	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	15	16
Mechanistic analyses show that autocrine secretion of IL-6 induced by loss of HIC1 activated STAT3 through IL-6 and JAK pathway and was associated with NSCLC progression .	Mechanistic analyses show that autocrine secretion of IL-6 induced by loss of HIC1 activated STAT3 through IL-6 and JAK pathway and was associated with NSCLC progression.	5	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	14	15
This led us to hypothesize that secretion of IL-6 from the surrounding microenvironment or neighboring cells would not be able to raise the activation of STAT3 after treatment with quercetin at the preferred dose .	This led us to hypothesize that secretion of IL-6 from the surrounding microenvironment or neighboring cells would not be able to raise the activation of STAT3 after treatment with quercetin at the preferred dose.	6	26	raise	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	25	26
Binding of IL-6 to its receptor initiates cellular events including activation of STAT3 upstream kinases , which then phosphorylate and activate STAT3 [ XREF_BIBR ] .	Binding of IL-6 to its receptor initiates cellular events including activation of STAT3 upstream kinases, which then phosphorylate and activate STAT3 [XREF_BIBR].	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	21	22
On the other hand , IL-6 leads to the activation of STAT3 .	On the other hand, IL-6 leads to the activation of STAT3.	5	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	11	12
The consequences of adenosine and IL-6 driven STAT-3 activation in airway epithelial cells are currently under investigation ; however , our findings identify this cell type as an important target of this pathway during chronic stages of disease where adenosine is elevated .	The consequences of adenosine and IL-6 driven STAT-3 activation in airway epithelial cells are currently under investigation; however, our findings identify this cell type as an important target of this pathway during chronic stages of disease where adenosine is elevated.	1	8	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	5	6	7	8
The p-STAT3 translocates into the nucleus , where p-STAT3 trans-activates IL-6 transcription ; the resulting IL-6 secretion subsequently may promote further constitutive STAT3 activation .	The p-STAT3 translocates into the nucleus, where p-STAT3 trans-activates IL-6 transcription; the resulting IL-6 secretion subsequently may promote further constitutive STAT3 activation.	15	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	22	23
IL-6 acts through several classic protein kinase cascades such as MAPK and phosphatidylinositoltriphosphate kinase ( PI-3 kinase ) , but can also directly activate the signal transducers and activators of transcription ( STAT ) factors STAT1 and STAT3 , due to the capability of acting by Janus kinases ( JAK ) .	IL-6 acts through several classic protein kinase cascades such as MAPK and phosphatidylinositoltriphosphate kinase (PI-3 kinase), but can also directly activate the signal transducers and activators of transcription (STAT) factors STAT1 and STAT3, due to the capability of acting by Janus kinases (JAK).	0	38	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	37	38
IL-6 , IL-21 , and IL-23 share the ability to activate Stat3 , which was shown to be critical for Th17 cell differentiation in mouse and man .	IL-6, IL-21, and IL-23 share the ability to activate Stat3, which was shown to be critical for Th17 cell differentiation in mouse and man.	0	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	11	12
P-STAT3 expression was induced in IL-6 treated cells , whereas IL-6 did not activate STAT3 in LLL12 pre-treated cells ( XREF_FIG ) .	P-STAT3 expression was induced in IL-6 treated cells, whereas IL-6 did not activate STAT3 in LLL12 pre-treated cells (XREF_FIG).	10	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	14	15
IL6 was reported to stimulate STAT3 activity which promotes tumor growth and survival of NSCLC via JAK and STAT3 signalling [ XREF_BIBR ] .	IL6 was reported to stimulate STAT3 activity which promotes tumor growth and survival of NSCLC via JAK and STAT3 signalling [XREF_BIBR].	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	5	6
The Kupffer cells then secrete the pro inflammatory cytokine IL-6 , which targets the hepatocytes and activates the canonical IL-6-signaling pathway involving gp130 mediated dimerization of STAT3 and the downstream activation of IL-6 target genes .	The Kupffer cells then secrete the pro inflammatory cytokine IL-6, which targets the hepatocytes and activates the canonical IL-6-signaling pathway involving gp130 mediated dimerization of STAT3 and the downstream activation of IL-6 target genes.	5	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	26	27
STIP1 knock-down markedly inhibited the IL6 stimulated STAT3 transcriptional activity , whereas only a partial block was observed for STAT5 .	STIP1 knock-down markedly inhibited the IL6 stimulated STAT3 transcriptional activity, whereas only a partial block was observed for STAT5.	4	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	5	6	7	8
This was the first study to prove that CAFs in HCC recruit DCs and convert them to regulatory DCs through IL-6 mediated STAT3 activation .	This was the first study to prove that CAFs in HCC recruit DCs and convert them to regulatory DCs through IL-6 mediated STAT3 activation.	14	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	22	23
Our signaling experiments showed that IL-6 activates 3 distinct signaling pathways : JAK and STAT3 , MAPK , and PI3K and Akt ( XREF_FIG ) .	Our signaling experiments showed that IL-6 activates 3 distinct signaling pathways : JAK and STAT3, MAPK, and PI3K and Akt (XREF_FIG).	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	14	15
Moreover , the effect of IL-6 , a cytokine that stimulates STAT3 activation , on the AR activity remains elusive .	Moreover, the effect of IL-6, a cytokine that stimulates STAT3 activation, on the AR activity remains elusive.	3	12	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	11	12
We tested this by a series of molecular studies using purified ACs cultured with or without the STAT3 activator IL-6 .	We tested this by a series of molecular studies using purified ACs cultured with or without the STAT3 activator IL-6.	12	20	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	17	18
Because STAT3 activation is triggered by IL-6 , which was used for in vitro MDSC expansion , we next investigated the role of estrogen signaling on IL6R .	Because STAT3 activation is triggered by IL-6, which was used for in vitro MDSC expansion, we next investigated the role of estrogen signaling on IL6R.	1	10	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	1	2
Notably , both IL-6 and IL-10 induce STAT3 activation in macrophages , but exert opposing functions .	Notably, both IL-6 and IL-10 induce STAT3 activation in macrophages, but exert opposing functions.	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	7	8
These data suggest that nuclear accumulation of EGFR and STAT3 activation by IL-6 play the key role in iNOS expression and resultant DNA damage , leading to EBV mediated NPC .	These data suggest that nuclear accumulation of EGFR and STAT3 activation by IL-6 play the key role in iNOS expression and resultant DNA damage, leading to EBV mediated NPC.	7	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	9	10
Mechanistic studies suggest that IL-6 promotes lung cancer cell proliferation and migration through activation of the transcription factor Signal Transducer and Activator of Transcription 3 ( STAT3 ) .	Mechanistic studies suggest that IL-6 promotes lung cancer cell proliferation and migration through activation of the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3).	4	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	26	27
However since we also observed inhibition of growth stimulation by AG490 , which inhibited both ERK 1/2 and STAT-3 , we can not rule out the possibility that STAT-3 provides an alternate pathway In B cells and renal cell carcinoma , IL-6 stimulates proliferation in a STAT-3 dependent manner .	However since we also observed inhibition of growth stimulation by AG490, which inhibited both ERK 1/2 and STAT-3, we can not rule out the possibility that STAT-3 provides an alternate pathway In B cells and renal cell carcinoma, IL-6 stimulates proliferation in a STAT-3 dependent manner.	41	48	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	41	42	46	47
Further analysis showed that ME3738 induces IL-6 serum levels and activates STAT3 DNA binding and target gene transcription .	Further analysis showed that ME3738 induces IL-6 serum levels and activates STAT3 DNA binding and target gene transcription.	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	ME3738 induces IL-6 serum levels	il-6	STAT3	STAT3	stat3	6	7	11	12
Immunoblot analysis revealed a 2.1 fold increase in the levels of p-STAT3 in astrocytes treated with IL-6 and ~ 70 % reduction in astrocytes treated with Stattic compared to vehicle treated cells .	Immunoblot analysis revealed a 2.1 fold increase in the levels of p-STAT3 in astrocytes treated with IL-6 and ~ 70% reduction in astrocytes treated with Stattic compared to vehicle treated cells.	9	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	16	17	11	12
In turn , the NF-kappaB transcription factor induces IL6 expression and thus activates STAT3 transcription factor , which binds directly on the MIR214 gene promoter area , re-enforcing its up-regulation .	In turn, the NF-kappaB transcription factor induces IL6 expression and thus activates STAT3 transcription factor, which binds directly on the MIR214 gene promoter area, re-enforcing its up-regulation.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	NF-kappaB transcription factor induces IL6 expression	il6	STAT3	STAT3	stat3	8	9	13	14
Since IL-6 can activate Stat3 that has been shown to contribute to EGFR associated cancer cell growth .	Since IL-6 can activate Stat3 that has been shown to contribute to EGFR associated cancer cell growth.	1	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	4	5
More interestingly , Interleukin-6 ( IL-6 ) increased the invasion ability and activation of JAK2 and STAT3 of MGC-803 and BGC-823 cells .	More interestingly, Interleukin-6 (IL-6) increased the invasion ability and activation of JAK2 and STAT3 of MGC-803 and BGC-823 cells.	3	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	16	17
The activation of STAT3 by Nef induced IL-6 gets suppressed on activation of IL-10 through gp120 .	The activation of STAT3 by Nef induced IL-6 gets suppressed on activation of IL-10 through gp120.	1	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	Nef induced IL-6	il-6	STAT3	STAT3	stat3	7	8	3	4
Both therapeutic interventions , androgen depletion and inhibition of IL-6 triggered STAT3 signaling , exert anti-tumor activity as monotherapy .	Both therapeutic interventions, androgen depletion and inhibition of IL-6 triggered STAT3 signaling, exert anti-tumor activity as monotherapy.	5	12	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
We then demonstrated that the upregulation of some of these survival proteins was STAT3 dependent by showing that stattic inhibited the nuclear expression of survivin in CHLA-255 cells treated with IL-6 and IL-6 + sIL-6R ( XREF_FIG ) and by documenting a marked decrease in survivin expression and an absence of Bcl-xL expression upon STAT3 KD in cells treated with IL-6 and IL-6 plus sIL-6R ( XREF_FIG ) .	We then demonstrated that the upregulation of some of these survival proteins was STAT3 dependent by showing that stattic inhibited the nuclear expression of survivin in CHLA-255 cells treated with IL-6 and IL-6 + sIL-6R (XREF_FIG) and by documenting a marked decrease in survivin expression and an absence of Bcl-xL expression upon STAT3 KD in cells treated with IL-6 and IL-6 plus sIL-6R (XREF_FIG).	54	63	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	62	63	54	55
In the liver , STAT3 is mainly activated by IL-6 and its related cytokines leptin , and IL-22 .	In the liver, STAT3 is mainly activated by IL-6 and its related cytokines leptin, and IL-22.	4	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	4	5
Moreover , the extract prevented both STAT3 activation , which induces inflammation related rhodopsin decrease , and the increase in interleukin-6 expression , which activates STAT3 .	Moreover, the extract prevented both STAT3 activation, which induces inflammation related rhodopsin decrease, and the increase in interleukin-6 expression, which activates STAT3.	6	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	STAT3 activation, which induces inflammation related rhodopsin decrease, and the increase in interleukin-6 expression	interleukin-6	STAT3	STAT3	stat3	20	21	25	26
IL-6 has also been shown to produce anti-apoptotic effects via gp130 and the activation of the JAK and STAT3 pathway XREF_BIBR .	IL-6 has also been shown to produce anti-apoptotic effects via gp130 and the activation of the JAK and STAT3 pathway XREF_BIBR.	0	20	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	18	19
We show that S1P and S1PR1 signaling induces persistent Stat3 activation , which is in sharp contrast to the transient nature of Stat3 activation induced by IL-6 .	We show that S1P and S1PR1 signaling induces persistent Stat3 activation, which is in sharp contrast to the transient nature of Stat3 activation induced by IL-6.	22	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	26	27	22	23
Because IL-6 was elevated in both WT-HFD and alphaHZ-HFD and is known to activate STAT3 , we studied the effects of IL-6 treatment on p85alpha , p55alpha , and p50alpha expression in differentiated 3T3-L1 adipocytes .	Because IL-6 was elevated in both WT-HFD and alphaHZ-HFD and is known to activate STAT3, we studied the effects of IL-6 treatment on p85alpha, p55alpha, and p50alpha expression in differentiated 3T3-L1 adipocytes.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	14	15
ChIP assays further revealed that pSTAT3 was recruited to the promoter region of the Lcn2 gene upon activation of STAT3 by IL-6 ( XREF_FIG ) .	ChIP assays further revealed that pSTAT3 was recruited to the promoter region of the Lcn2 gene upon activation of STAT3 by IL-6 (XREF_FIG).	7	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	19	20
In our recent report , we have shown that IL-6 induces a substantial activation of STAT-3 in murine myeloid cells , indicating that gp130 , the shared receptor subunit for IL-6 and IL-27 receptors , is expressed on these cells .	In our recent report, we have shown that IL-6 induces a substantial activation of STAT-3 in murine myeloid cells, indicating that gp130, the shared receptor subunit for IL-6 and IL-27 receptors, is expressed on these cells.	9	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	9	10	15	16
The data presented in this manuscript demonstrate that IL-6 is a paracrine activator of STAT3 in ERalpha- breast cell lines as well .	The data presented in this manuscript demonstrate that IL-6 is a paracrine activator of STAT3 in ERalpha- breast cell lines as well.	8	19	is a paracrine activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	14	15
In the same way , IL-6 stimulation of STAT-3 is required for SC proliferation following SKM overload .	In the same way, IL-6 stimulation of STAT-3 is required for SC proliferation following SKM overload.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	5	6	8	9
IL-6 is a potent activator of STAT3 .	IL-6 is a potent activator of STAT3.	0	7	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
In contrast , pSTAT3 induced by IL-6 is greatest prior to this time ( XREF_FIG , XREF_FIG ) .	In contrast, pSTAT3 induced by IL-6 is greatest prior to this time (XREF_FIG, XREF_FIG).	3	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	6	7	3	4
AZD1480 inhibited constitutive and IL-6 induced STAT-3 activation and subsequent nuclear translocation .	AZD1480 inhibited constitutive and IL-6 induced STAT-3 activation and subsequent nuclear translocation.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	4	5	6	7
The induction of STAT3 by IL-6 in Cal33 cells exhibited a high level of cell-to-cell variation even at the optimal exposure time of 15 minutes and a dose that produced maximal activation ( > = 50 ng/ml IL-6 ) .	The induction of STAT3 by IL-6 in Cal33 cells exhibited a high level of cell-to-cell variation even at the optimal exposure time of 15 minutes and a dose that produced maximal activation (> = 50 ng/ml IL-6).	1	8	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	3	4
LPS and IL-6 have already been shown to activate brain STAT3 signalling pathways .	LPS and IL-6 have already been shown to activate brain STAT3 signalling pathways.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	10	11
Increased IL-6 expression in Ncoa5 +/- mouse liver resulted in activation of STAT3 and SOCS3 , which negatively modulate insulin signaling .	Increased IL-6 expression in Ncoa5 +/- mouse liver resulted in activation of STAT3 and SOCS3, which negatively modulate insulin signaling.	1	14	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	IL-6	IL-6 expression	il-6	STAT3	STAT3	stat3	1	2	12	13
IL-6 activates STAT3 in liver and staining of liver sections with a phospho-STAT3 ( Tyr705 ) antibody confirmed that Ad-Del infection activated STAT3 in hepatocytes ( XREF_FIG ) .	IL-6 activates STAT3 in liver and staining of liver sections with a phospho-STAT3 (Tyr705) antibody confirmed that Ad-Del infection activated STAT3 in hepatocytes (XREF_FIG).	0	17	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Notably , treatment with both Ret kinase inhibitors ( NVP-AST487 or NVP-BBT594 ) significantly lowered IL6 induced Stat3 activation ( XREF_FIG B , C ) .	Notably, treatment with both Ret kinase inhibitors (NVP-AST487 or NVP-BBT594) significantly lowered IL6 induced Stat3 activation (XREF_FIG B, C).	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	15	16	17	18
IL-6 also induces insulin resistance in liver by activating STAT3 and stimulating the transcription of its target gene suppressors of cytokine signaling 3 ( SOCS3 ) [ XREF_BIBR ] .	IL-6 also induces insulin resistance in liver by activating STAT3 and stimulating the transcription of its target gene suppressors of cytokine signaling 3 (SOCS3) [XREF_BIBR].	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	9	10
XREF_BIBR , XREF_BIBR , XREF_BIBR IL-6 activates multiple cell survival and proliferation signaling pathways in myeloma cells , including the Janus kinase and signal transducer and activator of transcription 3 ( JAK and STAT3 ) pathway , XREF_BIBR , XREF_BIBR the mitogen activated protein kinase kinase and extracellular signal related kinase ( MEK and ERK ) pathway , and the phosphoinositide 3-kinase ( PI3-K )/Akt pathway .	XREF_BIBR, XREF_BIBR, XREF_BIBR IL-6 activates multiple cell survival and proliferation signaling pathways in myeloma cells, including the Janus kinase and signal transducer and activator of transcription 3 (JAK and STAT3) pathway, XREF_BIBR, XREF_BIBR the mitogen activated protein kinase kinase and extracellular signal related kinase (MEK and ERK) pathway, and the phosphoinositide 3-kinase (PI3-K)/Akt pathway.	0	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	33	34
STAT3 signaling is primarily activated by the binding of extracellular interleukins ( Interleukin-6 and leukemia inhibitory factor ) and growth factors ( basic fibroblast growth factor and platelet derived growth factor ) , secreted during inflammation and exercise , to regulate metabolic responses and stimulate muscle repair [ XREF_BIBR ] .	STAT3 signaling is primarily activated by the binding of extracellular interleukins (Interleukin-6 and leukemia inhibitory factor) and growth factors (basic fibroblast growth factor and platelet derived growth factor), secreted during inflammation and exercise, to regulate metabolic responses and stimulate muscle repair [XREF_BIBR].	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Interleukin-6	Interleukin-6	Interleukin-6	STAT3	STAT3	STAT3	12	13	0	1
Moderate levels of TNF-alpha or IL-6 have been shown to initiate the activation of STAT3 , a key protein in cardioprotective signaling pathway , whose activation is Brg1 dependent [ XREF_BIBR , XREF_BIBR ] .	Moderate levels of TNF-alpha or IL-6 have been shown to initiate the activation of STAT3, a key protein in cardioprotective signaling pathway, whose activation is Brg1 dependent [XREF_BIBR, XREF_BIBR].	1	18	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	levels of TNF-alpha or IL-6	il-6	STAT3	STAT3	stat3	5	6	14	15
Having established a means to experimentally induce STAT3 activation , we addressed a possible causal link between STAT3 activity and expression of MMP-1 in lung carcinoma cells , and mmp-1 gene transcription was assayed by real-time PCR upon activation of STAT3 by IL-6 in the three lung cancer cell lines BEN , KNS62 , and A549 .	Having established a means to experimentally induce STAT3 activation, we addressed a possible causal link between STAT3 activity and expression of MMP-1 in lung carcinoma cells, and mmp-1 gene transcription was assayed by real-time PCR upon activation of STAT3 by IL-6 in the three lung cancer cell lines BEN, KNS62, and A549.	33	55	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	42	43	40	41
These studies suggest STAT3 activation by IL-6 and GP130 signaling pathway play an important role in human pancreatic cancer development and progression .	These studies suggest STAT3 activation by IL-6 and GP130 signaling pathway play an important role in human pancreatic cancer development and progression.	3	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	3	4
We showed that IL-6 induces two major signal transduction pathways : STAT3 and SHP2/Gab/MAPK signaling , which involve the gp130 YxxQ and Y759 motives , respectively .	We showed that IL-6 induces two major signal transduction pathways : STAT3 and SHP2/Gab/MAPK signaling, which involve the gp130 YxxQ and Y759 motives, respectively.	3	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	11	12
A great deal of research has described the role of SOCS3 , which specifically prevents activation of STAT3 by IL-6 [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	A great deal of research has described the role of SOCS3, which specifically prevents activation of STAT3 by IL-6 [XREF_BIBR, XREF_BIBR - XREF_BIBR].	15	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	17	18
IL-6 induced p-STAT3 in a dose dependent manner for a period of 4 days after a single dose treatment in LNCaP-C3 cells , which was dependent on IL-6R as anti-IL-6R antibodies could abolish the induction completely .	IL-6 induced p-STAT3 in a dose dependent manner for a period of 4 days after a single dose treatment in LNCaP-C3 cells, which was dependent on IL-6R as anti-IL-6R antibodies could abolish the induction completely.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	0	1	2	3
In the present study , it was found that IL-6 was able to induce STAT3 activation , but the activation could be blocked by Stattic in a dose dependent manner in PC3M-1E8 cells .	In the present study, it was found that IL-6 was able to induce STAT3 activation, but the activation could be blocked by Stattic in a dose dependent manner in PC3M-1E8 cells.	9	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	14	15
This may also explain why classical STAT3 activators , such as IL-6 , do not appear to play a role in IL-17 induction in human Treg cells in this or other studies [ XREF_BIBR , XREF_BIBR ] .	This may also explain why classical STAT3 activators, such as IL-6, do not appear to play a role in IL-17 induction in human Treg cells in this or other studies [XREF_BIBR, XREF_BIBR].	6	12	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	6	7
This concentration of IL-6 was sufficient to stimulate STAT3 activation in C666-1 cells .	This concentration of IL-6 was sufficient to stimulate STAT3 activation in C666-1 cells.	1	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	8	9
The study provides further insights in to the co-operativity between MMP-2 and alpha5beta1 integrin by indirect physical interaction in the maintenance of constitutive IL-6 mediated Stat3 DNA binding activity and expression of subsequent downstream effector genes suggesting MMP-2 suppression as a potential therapeutic approach in glioma treatment .	The study provides further insights in to the co-operativity between MMP-2 and alpha5beta1 integrin by indirect physical interaction in the maintenance of constitutive IL-6 mediated Stat3 DNA binding activity and expression of subsequent downstream effector genes suggesting MMP-2 suppression as a potential therapeutic approach in glioma treatment.	20	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	23	24	25	26
IL-6 also stimulated Stat3 to increase the expression of CCAAT and enhancer binding protein delta ( C/EBPdelta ) .	IL-6 also stimulated Stat3 to increase the expression of CCAAT and enhancer binding protein delta (C/EBPdelta).	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	3	4
Stat3 is predominantly activated by the MM growth and survival factor IL-6 .	Stat3 is predominantly activated by the MM growth and survival factor IL-6.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	11	12	0	1
Thus , IL6 depends on Fak as well as Ret to activate Stat3 , results that could underpin IL6 ' s requirement for Ret to stimulate migration .	Thus, IL6 depends on Fak as well as Ret to activate Stat3, results that could underpin IL6 's requirement for Ret to stimulate migration.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	2	3	12	13
This positive feedback loop was found in both tumor cells and tumor associated stromal cells , and the IL-6 produced by these two types of cells mediates the crosstalk between them , and enables a persistent activation of STAT3 in both cell types .	This positive feedback loop was found in both tumor cells and tumor associated stromal cells, and the IL-6 produced by these two types of cells mediates the crosstalk between them, and enables a persistent activation of STAT3 in both cell types.	17	39	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	38	39
IL-6 activates transcriptional factor STAT3 and upregulates several growth promoting genes , such as myc and cyclin D1 [ XREF_BIBR ] .	IL-6 activates transcriptional factor STAT3 and upregulates several growth promoting genes, such as myc and cyclin D1 [XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
125 These studies also emphasize the link between NF-kappaB and other procarcinogenic pathways , such as Stat3 , mediated by the NF-kappaB target gene IL6 .	125 These studies also emphasize the link between NF-kappaB and other procarcinogenic pathways, such as Stat3, mediated by the NF-kappaB target gene IL6.	6	25	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	24	25	16	17
Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells .	Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells.	3	8	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
IL-6 signaling mediated via IL-6 receptors activates STAT3 , mitogen activated protein kinase , and phosphatidylinositol 3-kinase pathways .	IL-6 signaling mediated via IL-6 receptors activates STAT3, mitogen activated protein kinase, and phosphatidylinositol 3-kinase pathways.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	7	8
We found multiple MMP genes were significantly affected by inhibition of IL-6 secretion , thus demonstrating that HER2 mediated IL-6 secretion elicits autocrine activation of Stat3 , perturbing cellular gene expression .	We found multiple MMP genes were significantly affected by inhibition of IL-6 secretion, thus demonstrating that HER2 mediated IL-6 secretion elicits autocrine activation of Stat3, perturbing cellular gene expression.	17	26	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	HER2 mediated IL-6	il-6	Stat3	Stat3	stat3	19	20	25	26
In the asymmetrical model ( XREF_FIG ) , IL-6 activates STAT3 , which favors production of RORgammat over Foxp3 .	In the asymmetrical model (XREF_FIG), IL-6 activates STAT3, which favors production of RORgammat over Foxp3.	8	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
Although IL6 is an upstream activator of STAT3 , it remains to be determined whether the regulation of STAT3 by UVB required IL6 .	Although IL6 is an upstream activator of STAT3, it remains to be determined whether the regulation of STAT3 by UVB required IL6.	1	8	is an upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	7	8
Although H. pylori CagA mediated STAT3 activation requires IL-6 and the gp130 receptor , autocrine activation of STAT3 by IL-6 and IL-11 is not involved in H. pylori CagA mediated STAT3 activation [ XREF_BIBR ] .	Although H. pylori CagA mediated STAT3 activation requires IL-6 and the gp130 receptor, autocrine activation of STAT3 by IL-6 and IL-11 is not involved in H. pylori CagA mediated STAT3 activation [XREF_BIBR].	15	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	17	18
Adenosine and IL-6 Mediate STAT-3 Activation in Airway Epithelial Cells .	Adenosine and IL-6 Mediate STAT-3 Activation in Airway Epithelial Cells.	0	5	Mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	2	3	4	5
In fact , even though it has been reported that IL-6 activates STAT3 18 and that activated STAT3 binds to the TP53 gene promoter repressing the transcription of TP53 mRNA , 19 we found that no significant change occurred in the transcription level of TP53 mRNA in the NCM460 , HepG2 , SW1990 and LS174T cell lines ( XREF_FIG ) .	In fact, even though it has been reported that IL-6 activates STAT3 18 and that activated STAT3 binds to the TP53 gene promoter repressing the transcription of TP53 mRNA, 19 we found that no significant change occurred in the transcription level of TP53 mRNA in the NCM460, HepG2, SW1990 and LS174T cell lines (XREF_FIG).	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	12	13
IL-6 trans-signaling-dependent activation of STAT3 can drive cancer progression through the transcription of target genes including the cell cycle regulator cyclin D1 , the proto-oncogene c-myc , transcriptional regulators such as JunB , cFos , C/EBPbeta and C/EBPdelta , and metabolic regulators such as mTORC1 .	IL-6 trans-signaling-dependent activation of STAT3 can drive cancer progression through the transcription of target genes including the cell cycle regulator cyclin D1, the proto-oncogene c-myc, transcriptional regulators such as JunB, cFos, C/EBPbeta and C/EBPdelta, and metabolic regulators such as mTORC1.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
IL-6 activates STAT3 and stimulates Pim-1 kinase in pancreatic cell line models .	IL-6 activates STAT3 and stimulates Pim-1 kinase in pancreatic cell line models.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
IL-6 also increases the expression of antiapoptotic gene products , including Bcl-2 , Bcl-xL , Mcl-1 , survivin , and XIAP , and contributes chemoresistance and constitutive activation of STAT-3 that are resistant to chemotherapeutic agents .	IL-6 also increases the expression of antiapoptotic gene products, including Bcl-2, Bcl-xL, Mcl-1, survivin, and XIAP, and contributes chemoresistance and constitutive activation of STAT-3 that are resistant to chemotherapeutic agents.	0	30	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	0	1	29	30
IL-6 is a physiological activator of C/EBPbeta and STAT3 that was found by us to upregulate RTVP-1 expression in a STAT3 dependent manner .	IL-6 is a physiological activator of C/EBPbeta and STAT3 that was found by us to upregulate RTVP-1 expression in a STAT3 dependent manner.	0	18	is a physiological activator	Positive_regulation_copula_1	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	STAT3	STAT3 that was found by us to upregulate RTVP-1 expression	stat3	0	1	8	9
IL-6 did not activate ERK1/2 , AKT or NF-kappaB pathways in either LNCaP-C3 or LNCaP-S17 cell line , suggesting that IL-6 specifically activates the STAT3 pathway to induce NED .	IL-6 did not activate ERK1/2, AKT or NF-kappaB pathways in either LNCaP-C3 or LNCaP-S17 cell line, suggesting that IL-6 specifically activates the STAT3 pathway to induce NED.	20	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	24	25
Taken together , these findings reveal that while IL-6 is sufficient to efficiently activate STAT3 at most sites , IL-1beta is required for maximal STAT3 binding in 20 % of sites , while reducing it at others .	Taken together, these findings reveal that while IL-6 is sufficient to efficiently activate STAT3 at most sites, IL-1beta is required for maximal STAT3 binding in 20% of sites, while reducing it at others.	8	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	14	15
SOCS3 has recently been shown to specifically inhibit STAT3 activation induced by IL-6 but not by IL-10 , thereby regulating the divergent action of IL-6 and IL-10 [ XREF_BIBR , XREF_BIBR ] .	SOCS3 has recently been shown to specifically inhibit STAT3 activation induced by IL-6 but not by IL-10, thereby regulating the divergent action of IL-6 and IL-10 [XREF_BIBR, XREF_BIBR].	8	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	8	9
STAT3 is activated by stimulation of IL-6 which is an important autocrine and paracrine growth factor for prostate cancers and M-110 was shown to interfere with IL-6 induced activation of STAT3 .	STAT3 is activated by stimulation of IL-6 which is an important autocrine and paracrine growth factor for prostate cancers and M-110 was shown to interfere with IL-6 induced activation of STAT3.	24	31	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	30	31
In the liver , central insulin action augments IL-6 expression in Kupffer cells and activates STAT3 transcription factors in hepatocytes .	In the liver, central insulin action augments IL-6 expression in Kupffer cells and activates STAT3 transcription factors in hepatocytes.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	insulin action augments IL-6 expression	il-6	STAT3	STAT3	stat3	8	9	15	16
In most of these cases , IL-6 signaling mainly activates the transcription factor STAT3 , which exerts several pro survival , proliferative , migration and inflammatory functions .	In most of these cases, IL-6 signaling mainly activates the transcription factor STAT3, which exerts several pro survival, proliferative, migration and inflammatory functions.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	13	14
In contrast to EBV , KSHV encodes a homolog of the cellular IL6 ( i.e ., vIL6 ) which has been found to activate STAT3 via the common gp130 subunit of IL6 receptor in endothelial cells and PEL cell lines ; vIL6-gp130 signaling also originated in the endoplasmic reticulum .	In contrast to EBV, KSHV encodes a homolog of the cellular IL6 (i.e., vIL6) which has been found to activate STAT3 via the common gp130 subunit of IL6 receptor in endothelial cells and PEL cell lines; vIL6-gp130 signaling also originated in the endoplasmic reticulum.	8	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	12	13	24	25
This means that the IL-6 and STAT3 pathway in the co-cultures was activated by the IL-6 produced and secreted into the conditioned media , suggesting a positive autocrine feedback loop in such a co-culture environment which may function to augment IL-6 signals to neighboring BMSCs .	This means that the IL-6 and STAT3 pathway in the co-cultures was activated by the IL-6 produced and secreted into the conditioned media, suggesting a positive autocrine feedback loop in such a co-culture environment which may function to augment IL-6 signals to neighboring BMSCs.	4	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	6	7
We found that knock-down of STAT3 was associated with a fall in beta-catenin mRNA levels and that an increase in beta-catenin mRNA levels was observed following stimulation of cells with IL-6 ( a known activator of STAT3 ) .	We found that knock-down of STAT3 was associated with a fall in beta-catenin mRNA levels and that an increase in beta-catenin mRNA levels was observed following stimulation of cells with IL-6 (a known activator of STAT3).	26	37	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	30	31	36	37
Therefore , we hypothesize that autocrine IL-6 activation of Stat3 in ADCLC may be involved in the formation of malignant pleural effusion by upregulating VEGF .	Therefore, we hypothesize that autocrine IL-6 activation of Stat3 in ADCLC may be involved in the formation of malignant pleural effusion by upregulating VEGF.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	9	10
Binding of IL-6 to its receptor results in activation of STAT3 in immune cells and consequently in the suppression of immune mediators that activate the immune response [ XREF_BIBR ] .	Binding of IL-6 to its receptor results in activation of STAT3 in immune cells and consequently in the suppression of immune mediators that activate the immune response [XREF_BIBR].	0	18	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	10	11
IL-6 , IL-21 , or IL-23 can activate STAT3 , which is required for T H 17 cell differentiation and maintenance .	IL-6, IL-21, or IL-23 can activate STAT3, which is required for T H 17 cell differentiation and maintenance.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	8	9
In addition , the expression levels of STAT3 activator IL-6 are increased in patients with metastatic PCa compared with patients with nonmalignant diseases [ XREF_BIBR ] .	In addition, the expression levels of STAT3 activator IL-6 are increased in patients with metastatic PCa compared with patients with nonmalignant diseases [XREF_BIBR].	5	10	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	7	8
Following gp130 dimerization , IL-6 activates multiple signaling pathways ( Ras dependent MAPk cascade , STAT1 and STAT3 heterodimer pathway , and STAT3 homodimer pathway ) .	Following gp130 dimerization, IL-6 activates multiple signaling pathways (Ras dependent MAPk cascade, STAT1 and STAT3 heterodimer pathway, and STAT3 homodimer pathway).	4	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	22	23
For example , DATS treatment caused activation of c-Jun N-terminal kinase and inhibition of constitutive as well as interleukin-6 inducible activation of signal transducer and activator of transcription 3 ( STAT3 ) in human prostate cancer cells .	For example, DATS treatment caused activation of c-Jun N-terminal kinase and inhibition of constitutive as well as interleukin-6 inducible activation of signal transducer and activator of transcription 3 (STAT3) in human prostate cancer cells.	18	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	18	19	30	31
On the other hand , shRNA knockdown of IL-6 only prevented STAT3 activation but had no effect on NF-kappaB activation by miR-K12-1 .	On the other hand, shRNA knockdown of IL-6 only prevented STAT3 activation but had no effect on NF-kappaB activation by miR-K12-1.	6	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	11	12
At the first glance , it is puzzling that IL-6 and IL-27 , which both activate Stat3 pathways , have antagonistic properties .	At the first glance, it is puzzling that IL-6 and IL-27, which both activate Stat3 pathways, have antagonistic properties.	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	16	17
Since IL-6 levels drive STAT3 activation in HNSCC [ XREF_BIBR ] , perturbation of p-STAT3 may be due to SphK1 mediated changes in extracellular IL-6 concentrations .	Since IL-6 levels drive STAT3 activation in HNSCC [XREF_BIBR], perturbation of p-STAT3 may be due to SphK1 mediated changes in extracellular IL-6 concentrations.	1	5	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 levels	il-6	STAT3	STAT3	stat3	1	2	4	5
Once activated in malignant or immune cells , STAT3 can induce the expression of a subset of genes whose products are important for further STAT3 activation , including IL-6 , IL-22 , EGF , IL-23 and IL-10 as well as STAT3 dependent induction of cell surface growth factor and cytokine receptors ( EGFR , c-Met , IL-23R ) or cytoplasmic proto-oncogenes such as K-Ras , Src and c-Abl , whose products are capable of inducing STAT3 phosphorylation .	Once activated in malignant or immune cells, STAT3 can induce the expression of a subset of genes whose products are important for further STAT3 activation, including IL-6, IL-22, EGF, IL-23 and IL-10 as well as STAT3 dependent induction of cell surface growth factor and cytokine receptors (EGFR, c-Met, IL-23R) or cytoplasmic proto-oncogenes such as K-Ras, Src and c-Abl, whose products are capable of inducing STAT3 phosphorylation.	24	42	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	28	29	24	25
IL-6 induces STAT3 activation by phosphorylation of JAK2 at the tyrosine 1007 and 1008 .	IL-6 induces STAT3 activation by phosphorylation of JAK2 at the tyrosine 1007 and 1008.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
IL-6 signals through the Janus activated kinases 2 ( JAK2 ) and signal transducer and activator of transcription 3 ( STAT3 ) pathway .	IL-6 signals through the Janus activated kinases 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) pathway.	0	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	20	21
Of note , the IL-6 dependent activation of STAT3 by PDX was not associated with further suppression of Ppargc1 in insulin sensitive saline infused mice ( XREF_SUPPLEMENTARY ) .	Of note, the IL-6 dependent activation of STAT3 by PDX was not associated with further suppression of Ppargc1 in insulin sensitive saline infused mice (XREF_SUPPLEMENTARY).	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	8	9
IL-6 stimulated STAT3 activation to promoted a pro proliferative and anti-apoptotic program , which inhibited cDDP induced cytotoxicity by downregulating miR-204 and subsequently upregulating the expression of anti-apoptotic proteins .	IL-6 stimulated STAT3 activation to promoted a pro proliferative and anti-apoptotic program, which inhibited cDDP induced cytotoxicity by downregulating miR-204 and subsequently upregulating the expression of anti-apoptotic proteins.	0	3	stimulated	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
This study reveals that IL-6 receptor gp130 is contained in breast cancer cell derived exosomes and stimulates STAT3 signaling in bone marrow derived macrophages ( BMDMs ) .	This study reveals that IL-6 receptor gp130 is contained in breast cancer cell derived exosomes and stimulates STAT3 signaling in bone marrow derived macrophages (BMDMs).	4	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	17	18
The IL-6 in hepatocytes induces STAT3 activation and plays important roles in hepatoprotection and liver regeneration .	The IL-6 in hepatocytes induces STAT3 activation and plays important roles in hepatoprotection and liver regeneration.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	5	6
SOCS3 then targets GP130 , a receptor for IL6 , but not IL10R , and this difference in receptor targeting by SOCS3 results in shorter IL6 driven STAT3 activity , while IL10 driven STAT3 activation is prolonged XREF_BIBR .	SOCS3 then targets GP130, a receptor for IL6, but not IL10R, and this difference in receptor targeting by SOCS3 results in shorter IL6 driven STAT3 activity, while IL10 driven STAT3 activation is prolonged XREF_BIBR.	22	28	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	25	26	27	28
In myeloma , activation of STAT3 by IL-6 is primarily mediated by beta1 integrin dependent adhesion of myeloma cells to bone marrow stromal cells .	In myeloma, activation of STAT3 by IL-6 is primarily mediated by beta1 integrin dependent adhesion of myeloma cells to bone marrow stromal cells.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	5	6
STAT3 activation is induced by several cytokines , most notably IL-6 [ XREF_BIBR ] .	STAT3 activation is induced by several cytokines, most notably IL-6 [XREF_BIBR].	0	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	0	1
IL-6 binds to the IL-6 receptor complex , activates JAK and STAT3 signaling and then phosphorylated-STAT3 ( p-STAT3 ) translocates into the nucleus to promote the transcription of its target genes [ XREF_BIBR ] .	IL-6 binds to the IL-6 receptor complex, activates JAK and STAT3 signaling and then phosphorylated-STAT3 (p-STAT3) translocates into the nucleus to promote the transcription of its target genes [XREF_BIBR].	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	11	12
Combination of IL-6 with acetaldehyde , or with MAA did not additively or synergistically activate NF-kappaB , p38MAPK , or STAT3 in LX2 cells ( XREF_SUPPLEMENTARY ) .	Combination of IL-6 with acetaldehyde, or with MAA did not additively or synergistically activate NF-kappaB, p38MAPK, or STAT3 in LX2 cells (XREF_SUPPLEMENTARY).	0	21	synergistically activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	20	21
To reveal the molecular basis underlying the differences in IL-6-induced NED between LNCaP-C3 and LNCaP-S17 cell lines , we first examined activation of STAT3 by IL-6 because it has been well established that IL-6 activates JAK-STAT3 and/or PI3K-Etk-STAT3 pathways to induce NED in LNCaP cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	To reveal the molecular basis underlying the differences in IL-6-induced NED between LNCaP-C3 and LNCaP-S17 cell lines, we first examined activation of STAT3 by IL-6 because it has been well established that IL-6 activates JAK-STAT3 and/or PI3K-Etk-STAT3 pathways to induce NED in LNCaP cells [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	20	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	23	24
In addition , whereas functional IL-10 receptors lack on hepatocytes XREF_BIBR , IL-6 and IL-22 are pivotal mediators of the STAT3 driven acute phase response XREF_BIBR .	In addition, whereas functional IL-10 receptors lack on hepatocytes XREF_BIBR, IL-6 and IL-22 are pivotal mediators of the STAT3 driven acute phase response XREF_BIBR.	12	21	are pivotal mediators	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	20	21
Prostate specific IL-6 can autonomously induce prostate oncogenesis by expanding local inflammation , activating the STAT3 pathway and increasing paracrine insulin like growth factor ( IGF ) signaling to reprogram gene expression XREF_BIBR .	Prostate specific IL-6 can autonomously induce prostate oncogenesis by expanding local inflammation, activating the STAT3 pathway and increasing paracrine insulin like growth factor (IGF) signaling to reprogram gene expression XREF_BIBR.	0	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	15	16
However , other reports have shown that in myogenic cells the autocrine production of IL-6 can also induce Stat3 activation but promotes the myogenic differentiation [ XREF_BIBR , XREF_BIBR ] .	However, other reports have shown that in myogenic cells the autocrine production of IL-6 can also induce Stat3 activation but promotes the myogenic differentiation [XREF_BIBR, XREF_BIBR].	12	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	14	15	18	19
We tested cytokines that were reported to regulate the expression of the Reg family genes , regardless of whether they activate them , and found that IL-22 and IL-6 up-regulated REG Ialpha via MZF1 , RTEF1 and TEAD4 , and STAT3 and that IL-22 up-regulated REG Ibeta via HLTF and FOXN2 in human colon cells .	We tested cytokines that were reported to regulate the expression of the Reg family genes, regardless of whether they activate them, and found that IL-22 and IL-6 up-regulated REG Ialpha via MZF1, RTEF1 and TEAD4, and STAT3 and that IL-22 up-regulated REG Ibeta via HLTF and FOXN2 in human colon cells.	26	41	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	28	29	40	41
Our study also indicated that STAT3 activation by IL-6 from MSCs increases proliferation of cholangiocarcinoma .	Our study also indicated that STAT3 activation by IL-6 from MSCs increases proliferation of cholangiocarcinoma.	5	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	5	6
These findings indicate that JAK2 and STAT3 signaling pathway activated by IL-6 facilitates the development of hypersensitivity .	These findings indicate that JAK2 and STAT3 signaling pathway activated by IL-6 facilitates the development of hypersensitivity.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	6	7
IL-6 activates signal transducer and activator of transcription 3 ( STAT3 ) in hepatocytes and sinusoidal endothelial cells , while IL-10 activates STAT3 in Kupffer cells and macrophages , subsequently protecting against ALD .	IL-6 activates signal transducer and activator of transcription 3 (STAT3) in hepatocytes and sinusoidal endothelial cells, while IL-10 activates STAT3 in Kupffer cells and macrophages, subsequently protecting against ALD.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	10	11
These results thus suggested that cell derived IL-6 induces STAT3 activation through JAK in a subset of gastric cancer cells without MET activation .	These results thus suggested that cell derived IL-6 induces STAT3 activation through JAK in a subset of gastric cancer cells without MET activation.	6	10	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
Accordingly , in the present report , we could not detect constitutive tyrosine phosphorylation of STAT3 in all SCLC cell lines studied but IL-6 induced STAT3 activation only in the NCI-H446 cell line .	Accordingly, in the present report, we could not detect constitutive tyrosine phosphorylation of STAT3 in all SCLC cell lines studied but IL-6 induced STAT3 activation only in the NCI-H446 cell line.	23	26	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	23	24	25	26
In order to determine whether the IL-6 induced Stat3 anti-apoptosis pathway is linked with miRNA-21 , we first determined the effects of recombinant mouse IL-6 on Stat3 expression , mouse embryo viability , and the mRNA levels of apoptosis related genes and miRNA-21 during mouse embryo development in vitro .	In order to determine whether the IL-6 induced Stat3 anti-apoptosis pathway is linked with miRNA-21, we first determined the effects of recombinant mouse IL-6 on Stat3 expression, mouse embryo viability, and the mRNA levels of apoptosis related genes and miRNA-21 during mouse embryo development in vitro.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	8	9
35 Interestingly , simultaneous inhibition of IL-17A , TNF-alpha , IL-22 and IL-6 almost completely blocked STAT3 and NF-kB activation and the increased CRC cell growth induced by TIL derived supernatants .	35 Interestingly, simultaneous inhibition of IL-17A, TNF-alpha, IL-22 and IL-6 almost completely blocked STAT3 and NF-kB activation and the increased CRC cell growth induced by TIL derived supernatants.	4	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	16	17
Activation of STAT5 by IL-2 resulted in more binding of STAT5 and less binding of STAT3 at these sites , whereas activation of STAT3 by IL-6 induced the opposite ; the combination of the two STATs resulted in dynamic regulation of the IL-17 gene locus by the opposing effects of IL-2 ( STAT5 ) and IL-6 ( STAT3 ) [ XREF_BIBR ] .	Activation of STAT5 by IL-2 resulted in more binding of STAT5 and less binding of STAT3 at these sites, whereas activation of STAT3 by IL-6 induced the opposite; the combination of the two STATs resulted in dynamic regulation of the IL-17 gene locus by the opposing effects of IL-2 (STAT5) and IL-6 (STAT3) [XREF_BIBR].	21	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	23	24
IL-6 induced Stat3 and extracellular signal regulated kinase ( ERK ) 1/2 signalling but not p38 , c-Jun N-terminal kinase or Akt .	IL-6 induced Stat3 and extracellular signal regulated kinase (ERK) 1/2 signalling but not p38, c-Jun N-terminal kinase or Akt.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	2	3
The IL-6 cytokine activates STAT3 and STAT1 .	The IL-6 cytokine activates STAT3 and STAT1.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	4	5
IL-22 and IL-6 activated STAT3 in both cells lines , whereas activation of NF-kB was seen in cells stimulated with IL-17A or TNF-alpha .	IL-22 and IL-6 activated STAT3 in both cells lines, whereas activation of NF-kB was seen in cells stimulated with IL-17A or TNF-alpha.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
These data suggest that while IL-6 preferentially activates STAT3 , it can activate STAT1 as well , and the intracellular ratio between these two STATs will determine the nature of IL-6 response .	These data suggest that while IL-6 preferentially activates STAT3, it can activate STAT1 as well, and the intracellular ratio between these two STATs will determine the nature of IL-6 response.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	8	9
The efficacy of quercetin was found to be very large in inhibiting IL-6 induced STAT3 activation , especially in those cells that had been post treated with IL-6 .	The efficacy of quercetin was found to be very large in inhibiting IL-6 induced STAT3 activation, especially in those cells that had been post treated with IL-6.	14	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	27	28	14	15
We further show that constitutive IL-6 expression in the prostate , resembling chronic inflammation , activates STAT3 , reprograms prostate gene transcription to pro tumorigenic , activates the autocrine IL-6 and paracrine IGF signaling axis , and amplifies inflammation in the prostate and peri-prostatic adipose tissue .	We further show that constitutive IL-6 expression in the prostate, resembling chronic inflammation, activates STAT3, reprograms prostate gene transcription to pro tumorigenic, activates the autocrine IL-6 and paracrine IGF signaling axis, and amplifies inflammation in the prostate and peri-prostatic adipose tissue.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 expression	il-6	STAT3	STAT3	stat3	5	6	16	17
IL-6 activates STAT1 and STAT5 in addition to STAT3 .	IL-6 activates STAT1 and STAT5 in addition to STAT3.	0	9	activates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	8	9
One possibility is that mutant N-Ras induces an autocrine IL-6 feedback loop that activates Stat3 downstream of IL-6R .	One possibility is that mutant N-Ras induces an autocrine IL-6 feedback loop that activates Stat3 downstream of IL-6R.	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	14	15
In the presence of IL-6 , which activates STAT3 and suppresses the function and expression of Foxp3 , the relative level and activity of RORgammat is increased , favoring Th17 cell differentiation .	In the presence of IL-6, which activates STAT3 and suppresses the function and expression of Foxp3, the relative level and activity of RORgammat is increased, favoring Th17 cell differentiation.	2	10	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	8	9
The pleiotropic cytokine interleukin-6 ( IL-6 ) is a major activator of Stat3 ; IL-6 stimulates the formation of tyrosine phosphorylated Stat3 ( p-Stat3 ) in cancer cells [ XREF_BIBR , XREF_BIBR ] .	The pleiotropic cytokine interleukin-6 (IL-6) is a major activator of Stat3; IL-6 stimulates the formation of tyrosine phosphorylated Stat3 (p-Stat3) in cancer cells [XREF_BIBR, XREF_BIBR].	0	13	is a major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	Stat3	Stat3	Stat3	3	4	12	13
IL-6 transgene universally activates STAT3 pathway and reprograms gene expression in the prostate tissue .	IL-6 transgene universally activates STAT3 pathway and reprograms gene expression in the prostate tissue.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
These findings elucidate a mechanism dependent on the induction of an autocrine IL-6 activation loop through which Rac1 mediates STAT3 activation establishing a link between oncogenic GTPase activity and Janus kinase and STAT signaling .	These findings elucidate a mechanism dependent on the induction of an autocrine IL-6 activation loop through which Rac1 mediates STAT3 activation establishing a link between oncogenic GTPase activity and Janus kinase and STAT signaling.	12	20	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	19	20
XREF_BIBR The activation of STAT3 by IL-6 commences upon its binding to the IL-6 receptor ( IL-6R ) , which belongs to the class I family of cytokine receptors that form heterotetrameric complexes with the common signaling receptor , gp130 .	XREF_BIBR The activation of STAT3 by IL-6 commences upon its binding to the IL-6 receptor (IL-6R), which belongs to the class I family of cytokine receptors that form heterotetrameric complexes with the common signaling receptor, gp130.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	4	5
Our group demonstrated that IL-6 , a TLR signaling product , can activate STAT3 with resulting overexpression of Wnt5a in human papillary thyroid carcinoma , melanoma and pancreatic cancer [ XREF_BIBR , XREF_BIBR ] .	Our group demonstrated that IL-6, a TLR signaling product, can activate STAT3 with resulting overexpression of Wnt5a in human papillary thyroid carcinoma, melanoma and pancreatic cancer [XREF_BIBR, XREF_BIBR].	4	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	13	14
STAT3 activation induced by IL-6 is required for fascin expression and cell migration and invasion in MKN45 cells .	STAT3 activation induced by IL-6 is required for fascin expression and cell migration and invasion in MKN45 cells.	0	5	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
We found that incubation with IL-6 enhanced the co-immunoprecipitation of STAT3 with anti-STAT3 antibodies , suggesting that IL-6 enhances the binding of STAT3 to the miR-155 promoter ( XREF_FIG ) .	We found that incubation with IL-6 enhanced the co-immunoprecipitation of STAT3 with anti-STAT3 antibodies, suggesting that IL-6 enhances the binding of STAT3 to the miR-155 promoter (XREF_FIG).	17	23	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	22	23
Using a lentivirus system to deliver control or mutant Htt N terminal proteins to all cells of the brain , the Janus kinase ( JAK )/STAT3 pathway was found to play a prominent role in astrocyte activation in mice and monkeys [ XREF_BIBR ] JAK and STAT3 signaling is commonly triggered by IL-6 , a cytokine produced in HD brains by microglia [ XREF_BIBR ] .	Using a lentivirus system to deliver control or mutant Htt N terminal proteins to all cells of the brain, the Janus kinase (JAK)/STAT3 pathway was found to play a prominent role in astrocyte activation in mice and monkeys [XREF_BIBR] JAK and STAT3 signaling is commonly triggered by IL-6, a cytokine produced in HD brains by microglia [XREF_BIBR].	46	55	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	52	53	46	47
We hypothesized that one consequence of IL-6 induced STAT3 activation in pancreatic cell lines may be expression of Pim-1 kinase .	We hypothesized that one consequence of IL-6 induced STAT3 activation in pancreatic cell lines may be expression of Pim-1 kinase.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
Interestingly , suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6 .	Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6.	9	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	11	12
TGR5 overexpression with ligand treatment significantly suppressed STAT3 activity induced by IL-6 .	TGR5 overexpression with ligand treatment significantly suppressed STAT3 activity induced by IL-6.	7	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	7	8
In this regard , IL6 activates the STAT3 signaling pathway through the gp130 and IL6R complex on hepatocytes , and this process promotes liver regeneration , the acute-phase response , and hepatoprotection against Fas and toxic damage in liver XREF_BIBR .	In this regard, IL6 activates the STAT3 signaling pathway through the gp130 and IL6R complex on hepatocytes, and this process promotes liver regeneration, the acute-phase response, and hepatoprotection against Fas and toxic damage in liver XREF_BIBR.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	4	5	7	8
It can also down-regulate p-STAT3 induced by IL-6 [ XREF_BIBR ] .	It can also down-regulate p-STAT3 induced by IL-6 [XREF_BIBR].	3	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	7	8	4	5
We confirmed that STAT3 activation by IL-6 was capable of inducing ERBB2IP expression in primary human T cells .	We confirmed that STAT3 activation by IL-6 was capable of inducing ERBB2IP expression in primary human T cells.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	3	4
IL-6 then enhances both initiation and progression of CAC and stimulates Stat3 activation , which is necessary for intestinal mucosal regeneration after injury and for the development of CAC .	IL-6 then enhances both initiation and progression of CAC and stimulates Stat3 activation, which is necessary for intestinal mucosal regeneration after injury and for the development of CAC.	0	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	11	12
They also showed that STAT3 activation was caused by interleukin-6 ( IL-6 ) in an autocrine manner .	They also showed that STAT3 activation was caused by interleukin-6 (IL-6) in an autocrine manner.	4	16	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	9	10	4	5
Together , data in XREF_FIG and XREF_FIG indicate that one of the primary consequences of NF-kappaB activation in PI3K transformed cells is increased expression of IL-6 , which can then activate STAT3 in both normal epithelial cells and immune cells in a paracrine manner .	Together, data in XREF_FIG and XREF_FIG indicate that one of the primary consequences of NF-kappaB activation in PI3K transformed cells is increased expression of IL-6, which can then activate STAT3 in both normal epithelial cells and immune cells in a paracrine manner.	23	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	expression of IL-6	il-6	STAT3	STAT3	stat3	25	26	31	32
Indeed several cross amplifying signals have been described to associate a ) NOS2 expression to NF-kappaB activation and IL-6 synthesis ; b ) NF-kappaB activation to EBV LMP1 oncogene expression ; c ) LMP1 signaling to IL-6 induction and Stat-3 activation ; d ) IL-6 mediated perpetuation of Stat-3 activity to LMP1 expression and e ) IL-6 signaling to NF-kappaB mediated NOS2 induction [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Indeed several cross amplifying signals have been described to associate a) NOS2 expression to NF-kappaB activation and IL-6 synthesis; b) NF-kappaB activation to EBV LMP1 oncogene expression; c) LMP1 signaling to IL-6 induction and Stat-3 activation; d) IL-6 mediated perpetuation of Stat-3 activity to LMP1 expression and e) IL-6 signaling to NF-kappaB mediated NOS2 induction [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	7	49	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat-3	Stat-3	Stat-3	44	45	48	49
Exposure of DU145 and LNCaP cells to SFN resulted in suppression of ( a ) IL6 induced transcriptional activity of STAT3 as judged by luciferase reporter assay , and ( b ) nuclear translocation of pSTAT3 as revealed by immunofluorescence microscopy .	Exposure of DU145 and LNCaP cells to SFN resulted in suppression of (a) IL6 induced transcriptional activity of STAT3 as judged by luciferase reporter assay, and (b) nuclear translocation of pSTAT3 as revealed by immunofluorescence microscopy.	15	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	15	16	20	21
It is known that interleukin 6 ( IL-6 ) potently induces STAT3 activation in GSC and regulates their self-renewal capacity through IL-Ralpha binding ( Penuelas etal ., 2009 ; Wang etal ., 2009 ) .	It is known that interleukin 6 (IL-6) potently induces STAT3 activation in GSC and regulates their self-renewal capacity through IL-Ralpha binding (Penuelas etal., 2009; Wang etal., 2009).	4	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	STAT3	STAT3	STAT3	4	6	11	12
Moreover , iron is also essential in the activation of STAT3 by IL6 in cell lines and tumors .	Moreover, iron is also essential in the activation of STAT3 by IL6 in cell lines and tumors.	5	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	12	13	10	11
Thus , IL-6 activates the STAT3 pathway even in the presence of TGF-beta1 .	Thus, IL-6 activates the STAT3 pathway even in the presence of TGF-beta1.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	5	6
In addition , it was demonstrated that IL-6 can activate the JAK and STAT3 signaling pathways and is actively involved in tumor proliferation and prognosis .	In addition, it was demonstrated that IL-6 can activate the JAK and STAT3 signaling pathways and is actively involved in tumor proliferation and prognosis.	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	13	14
Interestingly , blockade of IL-6 using anti-IL-6 antibody suppresses STAT-3 activation in the pancreatic acinar cells and consequently diminishes the severity of acute pancreatitis by induction of pancreatic acinar cell apoptosis [ XREF_BIBR ] .	Interestingly, blockade of IL-6 using anti-IL-6 antibody suppresses STAT-3 activation in the pancreatic acinar cells and consequently diminishes the severity of acute pancreatitis by induction of pancreatic acinar cell apoptosis [XREF_BIBR].	2	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	4	5	9	10
Collectively these data support a role of IL-6 in expanding the prostate cancer stem like phenotype and suggest that ESE3 and EHF controls both basal and IL-6 induced STAT3 response .	Collectively these data support a role of IL-6 in expanding the prostate cancer stem like phenotype and suggest that ESE3 and EHF controls both basal and IL-6 induced STAT3 response.	22	29	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	28	29
The simultaneous presence of a CB 1 R agonist and IL-6 at subthreshold concentrations synergizes to activate CREB and STAT3 [ XREF_BIBR ] .	The simultaneous presence of a CB 1 R agonist and IL-6 at subthreshold concentrations synergizes to activate CREB and STAT3 [XREF_BIBR].	2	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	19	20
IL-6 activation of the JAK and STAT3 pathway induces tumor cells survival by up-regulation and activation of anti-apoptotic proteins Mcl-1 and Bcl-X L and c-Myc .	IL-6 activation of the JAK and STAT3 pathway induces tumor cells survival by up-regulation and activation of anti-apoptotic proteins Mcl-1 and Bcl-X L and c-Myc.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
STAT3 inducible , RA associated expression signature is activated by IL-6 in primary CD4 T cells of healthy donors in vitro .	STAT3 inducible, RA associated expression signature is activated by IL-6 in primary CD4 T cells of healthy donors in vitro.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	0	1
Immunofluorescence staining demonstrated that peretinoin suppressed the IL6 induced nuclear accumulation of p-STAT3 in MPH .	Immunofluorescence staining demonstrated that peretinoin suppressed the IL6 induced nuclear accumulation of p-STAT3 in MPH.	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	p-STAT3	p-STAT3	p-STAT3	7	8	12	13
Honokiol suppresses STAT3 activity induced by IL-6 , one of the many growth factors that activate STAT3 .	Honokiol suppresses STAT3 activity induced by IL-6, one of the many growth factors that activate STAT3.	2	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	2	3
IL-6 signals through its trans-signaling pathway , activating STAT3 to drive hMSH3 out of the nucleus .	IL-6 signals through its trans-signaling pathway, activating STAT3 to drive hMSH3 out of the nucleus.	0	9	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	8	9
Accordingly , IL-6 mediated constitutive activation of the STAT3 pathway , an essential event for uncontrolled cellular proliferation and transformation .	Accordingly, IL-6 mediated constitutive activation of the STAT3 pathway, an essential event for uncontrolled cellular proliferation and transformation.	2	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
At the same time , the increased IL-6 induced by LPS could stimulate the downstream factor STAT3 .	At the same time, the increased IL-6 induced by LPS could stimulate the downstream factor STAT3.	5	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	16	17
XREF_BIBR , XREF_BIBR IL-6 treatment of HepG2 cells activates the IL-6Ralpha and gp130 receptor resulting in the phosphorylation and activation of STAT3 and transcription of STAT3 dependent genes , two of which , p21waf1 and gamma-fibrinogen ( FBG ) , were the subject of independent studies on how STAT3 interacts with transcriptional regulators to initiate gene transcription .	XREF_BIBR, XREF_BIBR IL-6 treatment of HepG2 cells activates the IL-6Ralpha and gp130 receptor resulting in the phosphorylation and activation of STAT3 and transcription of STAT3 dependent genes, two of which, p21waf1 and gamma-fibrinogen (FBG), were the subject of independent studies on how STAT3 interacts with transcriptional regulators to initiate gene transcription.	3	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	25	26
Porcine IL-1beta and TNF-alpha significantly activated NF-kappaB and P38 , and STAT3 was activated by porcine IL-6 in HUVECs .	Porcine IL-1beta and TNF-alpha significantly activated NF-kappaB and P38, and STAT3 was activated by porcine IL-6 in HUVECs.	11	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	11	12
In breast cancer xenografts , IL-6 activates STAT3 by binding to its receptor ( gp130 ) and directly stimulates breast CSC self-renewal [ XREF_BIBR ] .	In breast cancer xenografts, IL-6 activates STAT3 by binding to its receptor (gp130) and directly stimulates breast CSC self-renewal [XREF_BIBR].	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
Given our observations here , it might be speculated that increased NF-kappaB activation as a consequence of pathological ER stress in the Xbp1 deficient epithelium might be an inciting event that leads to excessive production of IL-6 , which activates Stat3 , which may further transactivate Stat3 , Il6 , and Il11 .	Given our observations here, it might be speculated that increased NF-kappaB activation as a consequence of pathological ER stress in the Xbp1 deficient epithelium might be an inciting event that leads to excessive production of IL-6, which activates Stat3, which may further transactivate Stat3, Il6, and Il11.	34	45	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	36	37	40	41
The STAT3 activator IL-6 is particularly important for the development of functionally defective DCs .	The STAT3 activator IL-6 is particularly important for the development of functionally defective DCs.	0	6	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	1	2
IL-6 is known to activate STAT3 signalling in colonic epithelial cells and subsequently induced epithelial proliferation .	IL-6 is known to activate STAT3 signalling in colonic epithelial cells and subsequently induced epithelial proliferation.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Interestingly , IL-6 mediated activation of STAT3 and AR is also associated with inhibition of cell growth and differentiation of LNCaP cells to a neuroendocrine phenotype [ XREF_BIBR ] .	Interestingly, IL-6 mediated activation of STAT3 and AR is also associated with inhibition of cell growth and differentiation of LNCaP cells to a neuroendocrine phenotype [XREF_BIBR].	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	6	7
Interestingly , IL-6 failed to increase MMP in Stat3 deficient CD4 cells during activation ( XREF_FIG ) , indicating that effect of IL-6 on MMP in CD4 cells is dependent on Stat3 .	Interestingly, IL-6 failed to increase MMP in Stat3 deficient CD4 cells during activation (XREF_FIG), indicating that effect of IL-6 on MMP in CD4 cells is dependent on Stat3.	2	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	8	9
Moreover , IL-6 triggers STAT3 activation , making the Erlotinib treated cells more resistant to the treatment .	Moreover, IL-6 triggers STAT3 activation, making the Erlotinib treated cells more resistant to the treatment.	2	5	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
However , some cytosolic phosphorylated form of STAT3 activated by the IL-6 and gp130 signal has been found in the endosomal fraction as well , which then translocates into the nucleus and activates transcription .	However, some cytosolic phosphorylated form of STAT3 activated by the IL-6 and gp130 signal has been found in the endosomal fraction as well, which then translocates into the nucleus and activates transcription.	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	7	8
IL-6 , which is involved in melanoma survival , can activate STAT3 through JAK [ XREF_BIBR ] .	IL-6, which is involved in melanoma survival, can activate STAT3 through JAK [XREF_BIBR].	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	11	12
IL-6 knocked-out effectively attenuated the sorafenib induced down-regulation of p-STAT3 expression in 48 hr , which may be the effect of sorafenib on p-STAT3 depending on the basic expression of p-STAT3 associated IL-6 , that is , the time dependent up-regulation of p-STAT3 by IL-6 knocking-out .	IL-6 knocked-out effectively attenuated the sorafenib induced down-regulation of p-STAT3 expression in 48 hr, which may be the effect of sorafenib on p-STAT3 depending on the basic expression of p-STAT3 associated IL-6, that is, the time dependent up-regulation of p-STAT3 by IL-6 knocking-out.	40	45	up-regulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	44	45	42	43
We have demonstrated that MM cell adhesion to FN augments IL-6 induced STAT3 signaling .	We have demonstrated that MM cell adhesion to FN augments IL-6 induced STAT3 signaling.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	12	13
It also demonstrates a protective role of IL6 induced Stat3 activation against arsenite induced apoptosis .	It also demonstrates a protective role of IL6 induced Stat3 activation against arsenite induced apoptosis.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	7	8	9	10
3 Tregs are implicated in ameliorating GvHD , 1 while IL-6 activates JAK2 and STAT3 in T cells and fuels GvHD .	3 Tregs are implicated in ameliorating GvHD, 1 while IL-6 activates JAK2 and STAT3 in T cells and fuels GvHD.	10	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	14	15
STAT3 , which is most commonly activated by IL-6 , serves as a crucial regulator of inflammation and carcinogenesis .	STAT3, which is most commonly activated by IL-6, serves as a crucial regulator of inflammation and carcinogenesis.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	0	1
CSCs have been demonstrated to secret IL-6 , which could activate STAT3 signaling and induce the formation of a subpopulation of PCSCs from non stem PCa cells within the tumor XREF_BIBR , XREF_BIBR .	CSCs have been demonstrated to secret IL-6, which could activate STAT3 signaling and induce the formation of a subpopulation of PCSCs from non stem PCa cells within the tumor XREF_BIBR, XREF_BIBR.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	11	12
In fact , many breast cancer cell lines produce IL-6 , which activates STAT3 in an autocrine fashion by signaling through the IL-6 receptor and Jak kinases [ XREF_BIBR , XREF_BIBR ] .	In fact, many breast cancer cell lines produce IL-6, which activates STAT3 in an autocrine fashion by signaling through the IL-6 receptor and Jak kinases [XREF_BIBR, XREF_BIBR].	8	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	13	14
The results showed that IL-6 , a key trigger of STAT3 signaling , markedly activated STAT3 , but it was suppressed by SC09 in a time dependent manner .	The results showed that IL-6, a key trigger of STAT3 signaling, markedly activated STAT3, but it was suppressed by SC09 in a time dependent manner.	4	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	15	16
Collectively , these results suggest that MAPK activation through TLR2 ligation with DenV particles is achieved in infected DCs to produce IL-6 , which in turn activates STAT3 in both infected and uninfected bystander DCs in autocrine and paracrine manners , respectively .	Collectively, these results suggest that MAPK activation through TLR2 ligation with DenV particles is achieved in infected DCs to produce IL-6, which in turn activates STAT3 in both infected and uninfected bystander DCs in autocrine and paracrine manners, respectively.	20	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	27	28
STAT1 and STAT3 are important mediators within the JAK-STAT signaling pathway and are activated by interferon gamma and IL-6 ligands , respectively .	STAT1 and STAT3 are important mediators within the JAK-STAT signaling pathway and are activated by interferon gamma and IL-6 ligands, respectively.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	2	3
XREF_BIBR This might explain why LIF induced STAT3 signaling is in general sustained ( although at a reduced level from the initial increase ) , while IL-6 activation of STAT3 is brief ( personal observation ) .	XREF_BIBR This might explain why LIF induced STAT3 signaling is in general sustained (although at a reduced level from the initial increase), while IL-6 activation of STAT3 is brief (personal observation).	26	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	29	30
In contrast , IL-6 , also increased in RA , induces STAT3 preferentially in naive CD4 T cells suggesting a more restricted expression of the IL-6R ( data not shown ) .	In contrast, IL-6, also increased in RA, induces STAT3 preferentially in naive CD4 T cells suggesting a more restricted expression of the IL-6R (data not shown).	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	11	12
However , the pathogenic effects of IL6 induced STAT3 activation appears to be cell type specific and could vary depending on the degree and type of inflammatory infiltrate [ XREF_BIBR ] .	However, the pathogenic effects of IL6 induced STAT3 activation appears to be cell type specific and could vary depending on the degree and type of inflammatory infiltrate [XREF_BIBR].	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	6	7	8	9
IL-6 and ROSaccumulation is expected to induce the activation of the oncogenic transcription factor STAT3 .	IL-6 and ROSaccumulation is expected to induce the activation of the oncogenic transcription factor STAT3.	0	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	14	15
In contrast , NGF and EGF , in the presence or absence of IL-6 , cause mobility shifts of Stat3 that are consistent with serine phosphorylations .	In contrast, NGF and EGF, in the presence or absence of IL-6, cause mobility shifts of Stat3 that are consistent with serine phosphorylations.	9	20	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	13	14	19	20
Amongst the different STATs , the one most important for cancer is STAT3 , whose activity is stimulated by IL-6 , IL-11 and other members of their cytokine family , as well as different growth factors .	Amongst the different STATs, the one most important for cancer is STAT3, whose activity is stimulated by IL-6, IL-11 and other members of their cytokine family, as well as different growth factors.	3	35	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	12	13
Interestingly , STAT3 directly regulates the expression of NFKB1 , which encodes a subunit of NF-kappaB , and IL6 , a cytokine that stimulates STAT3 activity .	Interestingly, STAT3 directly regulates the expression of NFKB1, which encodes a subunit of NF-kappaB, and IL6, a cytokine that stimulates STAT3 activity.	4	25	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	18	19	24	25
We demonstrated that enforced expression of IL-6 in the prostate activated STAT3 pathway in the epithelium and stroma , induced an IL-6 autocrine and insulin like growth factor ( IGF ) paracrine loop , reprogrammed prostate oncogenic gene expression , and amplified pro tumorigenic inflammation in the prostate tissue microenvironment and peri-prostatic adipose tissue .	We demonstrated that enforced expression of IL-6 in the prostate activated STAT3 pathway in the epithelium and stroma, induced an IL-6 autocrine and insulin like growth factor (IGF) paracrine loop, reprogrammed prostate oncogenic gene expression, and amplified pro tumorigenic inflammation in the prostate tissue microenvironment and peri-prostatic adipose tissue.	4	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	expression of IL-6	il-6	STAT3	STAT3	stat3	6	7	11	12
Previous studies have shown that IL-6 induces JAK2 activation and STAT3 activation via Tyr705 phosphorylation .	Previous studies have shown that IL-6 induces JAK2 activation and STAT3 activation via Tyr705 phosphorylation.	5	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	10	11
The Stat3 gene itself is activated by IL-6 signals .	The Stat3 gene itself is activated by IL-6 signals.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	7	8	1	2
Conversely , IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM .	Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM.	2	6	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	5	6
We show by mutational analysis and supershift data that the IL-6 induced complex indeed contains the transcription factor APRF and Stat3 that is both necessary and sufficient for activation .	We show by mutational analysis and supershift data that the IL-6 induced complex indeed contains the transcription factor APRF and Stat3 that is both necessary and sufficient for activation.	9	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	10	11	20	21
IL-6 treatment also increased pYB-1 S102 levels as well as activated STAT3 in a similar fashion to epidermal growth factor ( EGF ) treatment .	IL-6 treatment also increased pYB-1 S102 levels as well as activated STAT3 in a similar fashion to epidermal growth factor (EGF) treatment.	0	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	11	12
Vaccinia induced rapid TLR2 dependent responses leading to IL-6 production , which then initiated STAT3 signaling in dendritic cells and T cells .	Vaccinia induced rapid TLR2 dependent responses leading to IL-6 production, which then initiated STAT3 signaling in dendritic cells and T cells.	8	15	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	14	15
Since IL-6 induction is known to trigger STAT3 activation in MM cells , we treated MM1.RL cells with WFA at various time points , followed by IL-6 treatment for 1 hour .	Since IL-6 induction is known to trigger STAT3 activation in MM cells, we treated MM1.RL cells with WFA at various time points, followed by IL-6 treatment for 1 hour.	1	8	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	7	8
Notably , as the major inflammation mediator , IL-6 is a dominant activator of STAT3 to promote cancer progression [ XREF_BIBR - XREF_BIBR ] .	Notably, as the major inflammation mediator, IL-6 is a dominant activator of STAT3 to promote cancer progression [XREF_BIBR - XREF_BIBR].	8	15	is a dominant activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	14	15
Correspondingly , HCCR expression increased when IL-6 was used to stimulate the activity of STAT3 .	Correspondingly, HCCR expression increased when IL-6 was used to stimulate the activity of STAT3.	6	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	14	15
IL-6 , which did not activate STAT3 and ERK1/2 , failed to induce the differentiation of cardiac stem cells into the endothelial cells .	IL-6, which did not activate STAT3 and ERK1/2, failed to induce the differentiation of cardiac stem cells into the endothelial cells.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
XREF_BIBR , XREF_BIBR IL-6 has been used to activate the JAK2 and STAT3 signaling pathway in vitro .	XREF_BIBR, XREF_BIBR IL-6 has been used to activate the JAK2 and STAT3 signaling pathway in vitro.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	12	13
IL-6 activates Stat3 , which has previously been demonstrated to activate the transcription of several anti-apoptotic genes and to contribute to apoptosis resistance in cancer cells .	IL-6 activates Stat3, which has previously been demonstrated to activate the transcription of several anti-apoptotic genes and to contribute to apoptosis resistance in cancer cells.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	2	3
IL-6 signaling has been implicated in various cancers , as the IL-6 receptor complex is linked to JAK activity targeting STAT3 .	IL-6 signaling has been implicated in various cancers, as the IL-6 receptor complex is linked to JAK activity targeting STAT3.	11	21	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	20	21
Importantly , IL-6 is an important inducer of STAT3 that supports the survival of cells under an inflammatory environment [ XREF_BIBR ] .	Importantly, IL-6 is an important inducer of STAT3 that supports the survival of cells under an inflammatory environment [XREF_BIBR].	2	9	is an important inducer	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
Thus , in the absence of mTOR , IL-6 fails to activate STAT3 and consequently the genetic programs that promote Th17 lineage commitment fail to be upregulated .	Thus, in the absence of mTOR, IL-6 fails to activate STAT3 and consequently the genetic programs that promote Th17 lineage commitment fail to be upregulated.	8	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	12	13
These effects are mediated by GA-hMSC-secreted interleukin-6 , which activates STAT3 in GSCs .	These effects are mediated by GA-hMSC-secreted interleukin-6, which activates STAT3 in GSCs.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	6	7	10	11
IL-6 induces STAT-3 activation which mediates resistance against apoptosis ; IL-6 also induces NF-kappaB activation to enhance the expression of adhesion molecule in IBD [ XREF_BIBR ] .	IL-6 induces STAT-3 activation which mediates resistance against apoptosis; IL-6 also induces NF-kappaB activation to enhance the expression of adhesion molecule in IBD [XREF_BIBR].	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	0	1	2	3
IL-6 combined with TGF-beta can persistently activate STAT3 signaling to initiate the differentiation of Th17 cells by inducing the transcription of RORgammat [ XREF_BIBR , XREF_BIBR ] .	IL-6 combined with TGF-beta can persistently activate STAT3 signaling to initiate the differentiation of Th17 cells by inducing the transcription of RORgammat [XREF_BIBR, XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	7	8
We observed that IL-1alpha and TGF-alpha treatments markedly increased the levels of most phospho-proteins whereas IL-6 and TNF-alpha treatments increased the levels of only a few phospho-proteins ( STAT3 for IL-6 and IkappaB-alpha , JNK , and c-Jun for TNF-alpha ) ( XREF_FIG ) ; the capability of modeling based normalization to discern truly significant activations can be appreciated by comparison to XREF_FIG B.	We observed that IL-1alpha and TGF-alpha treatments markedly increased the levels of most phospho-proteins whereas IL-6 and TNF-alpha treatments increased the levels of only a few phospho-proteins (STAT3 for IL-6 and IkappaB-alpha, JNK, and c-Jun for TNF-alpha) (XREF_FIG); the capability of modeling based normalization to discern truly significant activations can be appreciated by comparison to XREF_FIG B.	15	37	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	28	29
However , under some sublethal strikes , a loss of normal feedback modulation on STAT3 from SOCS3 can result in overactivation of STAT3 , thereby favoring IL-6 driven STAT3 [ XREF_BIBR , XREF_BIBR ] .	However, under some sublethal strikes, a loss of normal feedback modulation on STAT3 from SOCS3 can result in overactivation of STAT3, thereby favoring IL-6 driven STAT3 [XREF_BIBR, XREF_BIBR].	25	32	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	28	29
Inhibition of IL-6 in CCC cells suppressed Stat3 signaling and rendered cells sensitive to cytotoxic agents .	Inhibition of IL-6 in CCC cells suppressed Stat3 signaling and rendered cells sensitive to cytotoxic agents.	0	8	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	7	8
IL-6 can activate STAT3 to up-regulate the expression of miR-17/92 .	IL-6 can activate STAT3 to up-regulate the expression of miR-17/92.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
Increased susceptibility of IL-6 -/- mice to ethanol induced liver injury and apoptosis is independent of STAT3 in hepatocytes .	Increased susceptibility of IL-6 -/- mice to ethanol induced liver injury and apoptosis is independent of STAT3 in hepatocytes.	3	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	16	17
This suggests that IL-6 paracrine activation of STAT3 contributes to the process of breast tumorigenesis .	This suggests that IL-6 paracrine activation of STAT3 contributes to the process of breast tumorigenesis.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	7	8
IL-6 and TNF-alpha can activate STAT3 oncogenic signaling in obesity dependent carcinogenesis , as seen in HCC [ XREF_BIBR ] .	IL-6 and TNF-alpha can activate STAT3 oncogenic signaling in obesity dependent carcinogenesis, as seen in HCC [XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
IL-6 Inhibition Reduces STAT3 Activation and Enhances the Antitumor Effect of Carboplatin .	IL-6 Inhibition Reduces STAT3 Activation and Enhances the Antitumor Effect of Carboplatin.	0	4	Reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
Because IL-6 activates STAT3 , the activation of STAT3 by Hs738 CM was inhibited by the addition of IL-6-neutralizing antibody showing the functional involvement of IL-6 in Hs738 CM ( XREF_FIG ) .	Because IL-6 activates STAT3, the activation of STAT3 by Hs738 CM was inhibited by the addition of IL-6-neutralizing antibody showing the functional involvement of IL-6 in Hs738 CM (XREF_FIG).	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	3	4
IL-6 secreted from PSCs activates STAT3 signaling in PDAC cells .	IL-6 secreted from PSCs activates STAT3 signaling in PDAC cells.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
In adulthood , these mice showed deficits in social interaction , suggesting that not only does IL-6 activate the JAK2 and STAT3 pathway , but that it is also involved in the abnormal behavioral pathologies observed in MIA offspring and potentially autism and related disorders .	In adulthood, these mice showed deficits in social interaction, suggesting that not only does IL-6 activate the JAK2 and STAT3 pathway, but that it is also involved in the abnormal behavioral pathologies observed in MIA offspring and potentially autism and related disorders.	16	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	21	22
CHI3L1 and IL-6 , but not IL-22 , synergistically activates STAT3 .	CHI3L1 and IL-6, but not IL-22, synergistically activates STAT3.	0	11	synergistically activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	10	11
Consistent with Stat3 activation by IL-6 , the reduction in hepatic glucose production was associated with reduced expression of G6pc , and increased expression of Socs3 ( XREF_FIG ) .	Consistent with Stat3 activation by IL-6, the reduction in hepatic glucose production was associated with reduced expression of G6pc, and increased expression of Socs3 (XREF_FIG).	2	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	5	6	2	3
IL6 can activate both STAT3 at lower concentration and STAT5 higher concentration in isolation or parallel and therefore suppression of any of component may lead into accumulation of IL6 .	IL6 can activate both STAT3 at lower concentration and STAT5 higher concentration in isolation or parallel and therefore suppression of any of component may lead into accumulation of IL6.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	4	5
Indeed , STAT3 mediated IL-21 induction by IL-6 in naive T cells triggers a positive loop involving STAT3 , enhancing IL-21 production , induction of IL-23 receptor , and finally , IL-17 expression [ XREF_BIBR ] .	Indeed, STAT3 mediated IL-21 induction by IL-6 in naive T cells triggers a positive loop involving STAT3, enhancing IL-21 production, induction of IL-23 receptor, and finally, IL-17 expression [XREF_BIBR].	2	11	induction	Positive_regulation_syntax_2_noun	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	STAT3	STAT3 mediated IL-21	stat3	7	8	2	3
As a response to cellular stress , IL6 activation of the transcription factor STAT3 drives angiogenesis by inducing expression of VEGF and fibroblast growth factor by tumour cells , and thereby supports vascularization required for tumour growth and metastasis 43 , 44 .	As a response to cellular stress, IL6 activation of the transcription factor STAT3 drives angiogenesis by inducing expression of VEGF and fibroblast growth factor by tumour cells, and thereby supports vascularization required for tumour growth and metastasis 43, 44.	7	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	7	8	13	14
These findings challenge the current paradigm of IL4 and IL13-STAT 6 mediated alternative macrophage activation as the sole driver of vascular remodeling in PH and uncover a crosstalk between adventitial fibroblasts and macrophages in which paracrine IL6 activated STAT3 , HIF1 , and C/EBPbeta signaling is critical for macrophage activation and polarization .	These findings challenge the current paradigm of IL4 and IL13-STAT 6 mediated alternative macrophage activation as the sole driver of vascular remodeling in PH and uncover a crosstalk between adventitial fibroblasts and macrophages in which paracrine IL6 activated STAT3, HIF1, and C/EBPbeta signaling is critical for macrophage activation and polarization.	35	43	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	36	37	38	39
The finding that IL-6 mediates STAT3 activation specifically in the spongiotrophoblasts inhabiting the fetal compartment of MIA placentas suggests that IL-6 may affect offspring development by altering expression of critical placental hormones and growth factors .	The finding that IL-6 mediates STAT3 activation specifically in the spongiotrophoblasts inhabiting the fetal compartment of MIA placentas suggests that IL-6 may affect offspring development by altering expression of critical placental hormones and growth factors.	3	6	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
One important finding is that although IL6 transsignaling strongly increased STAT3 activation , it did not appreciably change the amount of STAT3 bound to the COL1A2 enhancer or the mRNA level of COL1A2 .	One important finding is that although IL6 transsignaling strongly increased STAT3 activation, it did not appreciably change the amount of STAT3 bound to the COL1A2 enhancer or the mRNA level of COL1A2.	6	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	6	7	10	11
In XREF_FIG , STAT3 hypoxic BRGs are depicted , note that IL6 is a target of STAT3 and that it is upregulated upon 2h hypoxia , OGD and 6h OGD but not after 6h hypoxia .	In XREF_FIG, STAT3 hypoxic BRGs are depicted, note that IL6 is a target of STAT3 and that it is upregulated upon 2h hypoxia, OGD and 6h OGD but not after 6h hypoxia.	11	17	is a target	Positive_activation_copula_1	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	11	12	16	17
Consistent with the known roles of IL6 and JAK-STAT signalling in the acute-phase response XREF_BIBR , XREF_BIBR , STAT3 mRNA and protein were significantly elevated in IHCA ( XREF_FIG ) .	Consistent with the known roles of IL6 and JAK-STAT signalling in the acute-phase response XREF_BIBR, XREF_BIBR, STAT3 mRNA and protein were significantly elevated in IHCA (XREF_FIG).	6	19	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	6	7	18	19
By contrast , IL-6 stimulation induced rapid increases in STAT1 * and STAT3 * , the maximum concentrations of which reached 900 nM and 500 nM , respectively , which was about three times higher than that in normal conditions .	By contrast, IL-6 stimulation induced rapid increases in STAT1 * and STAT3 *, the maximum concentrations of which reached 900 nM and 500 nM, respectively, which was about three times higher than that in normal conditions.	3	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	12	13
In addition , STAT1 inhibits STAT3 ( see below ) , which is activated by IL-6 , IL-23 , and IL-21 and is important for Th17 differentiation ; it is possible that STAT1 suppresses Th17 differentiation by targeting STAT3 ( XREF_FIG ) .	In addition, STAT1 inhibits STAT3 (see below), which is activated by IL-6, IL-23, and IL-21 and is important for Th17 differentiation; it is possible that STAT1 suppresses Th17 differentiation by targeting STAT3 (XREF_FIG).	4	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	5	6
In the present study , we show for the first time that interleukin-6 ( IL ) , in the presence of its soluble receptor ( sIL-6R ) , induces activation of JAK1 , JAK2 , and STAT1 and STAT3 proteins in bovine articular chondrocytes .	In the present study, we show for the first time that interleukin-6 (IL), in the presence of its soluble receptor (sIL-6R), induces activation of JAK1, JAK2, and STAT1 and STAT3 proteins in bovine articular chondrocytes.	12	39	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	12	13	38	39
Atg16L1 overexpression repressed the palmitate induced activation of NF-kappaB and IL6 induced activation of STAT3 .	Atg16L1 overexpression repressed the palmitate induced activation of NF-kappaB and IL6 induced activation of STAT3.	6	15	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	10	11	14	15
Our results also suggest that while activating mutations of EGFR may enhance IL-6 production and autocrine stimulation of STAT3 activity , additional cellular factors are important in modulating this pathway and the response of cells to IL6 .	Our results also suggest that while activating mutations of EGFR may enhance IL-6 production and autocrine stimulation of STAT3 activity, additional cellular factors are important in modulating this pathway and the response of cells to IL6.	12	19	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	18	19
To delineate the role of STAT3 in DIM mediated HIF-1alpha down regulation , cells were treated with IL-6 , which activates STAT3 phosphorylation , leading to the induction of HIF-1alpha .	To delineate the role of STAT3 in DIM mediated HIF-1alpha down regulation, cells were treated with IL-6, which activates STAT3 phosphorylation, leading to the induction of HIF-1alpha.	3	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	5	6
Finally , IL6 also elicits the synthesis of STAT3 , which is a crucial activator for cell transformation .	Finally, IL6 also elicits the synthesis of STAT3, which is a crucial activator for cell transformation.	2	14	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	2	3	8	9
Another important regulator of the inflammatory response is IL-6 , which activates STAT-1 and STAT-3 during tumor progression .	Another important regulator of the inflammatory response is IL-6, which activates STAT-1 and STAT-3 during tumor progression.	2	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	8	9	14	15
The molecular underpinnings for this inhibition remain to be elucidated , but given the short timeframe in which BITC is able to inhibit IL-6 mediated pSTAT3 , BITC might be expected to somehow interfere with proper assembly or functioning of the IL-6 receptor complex , or perhaps disrupt the subsequent interaction of an IL-6-dependent kinase with STAT3 .	The molecular underpinnings for this inhibition remain to be elucidated, but given the short timeframe in which BITC is able to inhibit IL-6 mediated pSTAT3, BITC might be expected to somehow interfere with proper assembly or functioning of the IL-6 receptor complex, or perhaps disrupt the subsequent interaction of an IL-6-dependent kinase with STAT3.	22	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	23	24	25	26
The autocrine signal loop of IL-6 secreted by cancer cells induces STAT3 activation .	The autocrine signal loop of IL-6 secreted by cancer cells induces STAT3 activation.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	11	12
Moreover , the IL6 target STAT3 was activated in MCF-10a-T cells ( XREF_FIG ) , and inhibiting IL6 or silencing STAT3 repressed colony formation of MCF-10a-T cells in soft agar ( XREF_FIG ) .	Moreover, the IL6 target STAT3 was activated in MCF-10a-T cells (XREF_FIG), and inhibiting IL6 or silencing STAT3 repressed colony formation of MCF-10a-T cells in soft agar (XREF_FIG).	2	7	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	3	4	5	6
By performing STAT3 chromatin immunoprecipitations ( ChIPs ) and quantitative PCR ( qPCR ) , we found IL-6 induced STAT3 binding to the Ube2n promoter in proximity to the conserved STATx site ( XREF_FIG ) .	By performing STAT3 chromatin immunoprecipitations (ChIPs) and quantitative PCR (qPCR), we found IL-6 induced STAT3 binding to the Ube2n promoter in proximity to the conserved STATx site (XREF_FIG).	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	19	20
Signal transducer and activator of transcription-3 ( STAT-3 ) , a member of STAT family closely linked with tumorigenesis is activated by epidermal growth factor ( EGF ) and interleukin-6 ( IL-6 ) receptors and various growth factors thus leading to tumor growth .	Signal transducer and activator of transcription-3 (STAT-3), a member of STAT family closely linked with tumorigenesis is activated by epidermal growth factor (EGF) and interleukin-6 (IL-6) receptors and various growth factors thus leading to tumor growth.	0	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	Signal transducer and activator of transcription-3	Signal transducer and activator of transcription-3	Signal transducer and activator of transcription-3	29	30	0	6
In the luciferase assay , ATBF1 was found to have no influence on STAT3 signaling induced by IL-6 stimulation , but it did synergistically enhance PIAS3 inhibition of activated STAT3 .	In the luciferase assay, ATBF1 was found to have no influence on STAT3 signaling induced by IL-6 stimulation, but it did synergistically enhance PIAS3 inhibition of activated STAT3.	13	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	13	14
A previous study has demonstrated that IL-6-deficient mice have increased numbers of mature DC , indicating that IL-6 plays a major role in blocking DC maturation invivo.17 In this study , STAT3 activation by IL-6 was involved in the suppression of TLR4 ligand and lipopolysaccharide ( LPS )-induced DC maturation and activation .	A previous study has demonstrated that IL-6-deficient mice have increased numbers of mature DC, indicating that IL-6 plays a major role in blocking DC maturation invivo.17 In this study, STAT3 activation by IL-6 was involved in the suppression of TLR4 ligand and lipopolysaccharide (LPS)-induced DC maturation and activation.	31	35	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	34	35	31	32
Thus , our studies suggest that while each cytokine , GH and IL-6 , may activate various members of the Jak-Stat pathway in overexpression studies , specific activation of Stat3 by IL-6 and of Jak2 and Stat5 by GH can be observed in HEK293 cells and that in this system the synergistic effect of dexamethasone appears specific for Stat5 .	Thus, our studies suggest that while each cytokine, GH and IL-6, may activate various members of the Jak-Stat pathway in overexpression studies, specific activation of Stat3 by IL-6 and of Jak2 and Stat5 by GH can be observed in HEK293 cells and that in this system the synergistic effect of dexamethasone appears specific for Stat5.	27	36	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	31	32	29	30
Because both IL-6 and IL-22 activate STAT3 signaling upon binding of their respective cognate receptors , we next examined whether their increased production in Trp53 -/- mice led to enhanced STAT3 activation .	Because both IL-6 and IL-22 activate STAT3 signaling upon binding of their respective cognate receptors, we next examined whether their increased production in Trp53 -/- mice led to enhanced STAT3 activation.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	6	7
Inhibition of IL6 signaling by JAK2 inhibitor treatment was required to suppress p-STAT3 in the presence of exogenous IL6 ( XREF_FIG ) .	Inhibition of IL6 signaling by JAK2 inhibitor treatment was required to suppress p-STAT3 in the presence of exogenous IL6 (XREF_FIG).	2	13	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	p-STAT3	p-STAT3	p-STAT3	2	3	12	13
In conclusion , we reported in this study that EBV infection in NPE cells enhanced their responsiveness to STAT3 activation by IL-6 .	In conclusion, we reported in this study that EBV infection in NPE cells enhanced their responsiveness to STAT3 activation by IL-6.	14	22	enhanced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	18	19
Thus , it is possible that constitutively activated NF-kappaB induces the production of IL-6 , which in turn activates STAT3 ( Kaptein et al , 1996 ; Chatterjee et al , 2002 ) and MM cell proliferation .	Thus, it is possible that constitutively activated NF-kappaB induces the production of IL-6, which in turn activates STAT3 (Kaptein et al, 1996; Chatterjee et al, 2002) and MM cell proliferation.	11	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	19	20
Several studies have identified STAT3 as an oncogenic transcription factor activated by inflammatory responses and IL6 is known to directly activate STAT3 .	Several studies have identified STAT3 as an oncogenic transcription factor activated by inflammatory responses and IL6 is known to directly activate STAT3.	15	22	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	15	16	21	22
In addition , IL-6 enhanced the activation of signal transducer and activator of transcription 3 ( STAT3 ) and led to hepatocyte proliferation after I/R injury 81 .	In addition, IL-6 enhanced the activation of signal transducer and activator of transcription 3 (STAT3) and led to hepatocyte proliferation after I/R injury 81.	3	19	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	16	17
An additional deletion of IL-6 or hepatic STAT3 diminishes STAT3 activation but increases STAT1 activation in HFD fed IL-10 -/- mice .	An additional deletion of IL-6 or hepatic STAT3 diminishes STAT3 activation but increases STAT1 activation in HFD fed IL-10 -/- mice.	4	10	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	9	10
The production of the IL-6 receptor and ligand complex activates both Janus kinase ( JAK ) and the signal transducer and activator of transcription 3 ( STAT3 ) pathways , which are key regulators of cell proliferation and apoptosis .	The production of the IL-6 receptor and ligand complex activates both Janus kinase (JAK) and the signal transducer and activator of transcription 3 (STAT3) pathways, which are key regulators of cell proliferation and apoptosis.	4	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	26	27
While IL-6 only weakly activated STAT3 , Hyper-IL-6 led to a strong phosphorylation even at low concentrations .	While IL-6 only weakly activated STAT3, Hyper-IL-6 led to a strong phosphorylation even at low concentrations.	1	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	5	6
Treatment of serum starved fibroblasts for 45 minutes with IL-6 activated STAT3 , as expected in the fibroblast cell line MRC-5 ( XREF_FIG ) .	Treatment of serum starved fibroblasts for 45 minutes with IL-6 activated STAT3, as expected in the fibroblast cell line MRC-5 (XREF_FIG).	7	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
Our results demonstrate that CCL2 and IL6 , which are present in the SSMC , also promote an activation of STAT3 and that STAT3 silencing prevents the acquisition of the mesenchymal , stemness and melanoma initiating phenotypes .	Our results demonstrate that CCL2 and IL6, which are present in the SSMC, also promote an activation of STAT3 and that STAT3 silencing prevents the acquisition of the mesenchymal, stemness and melanoma initiating phenotypes.	4	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	6	7	20	21
TNF-alpha and IL-6 are released from Kupffer cells and activate NF-kappaB and STAT3 to lead transcription of target genes for liver regeneration .	TNF-alpha and IL-6 are released from Kupffer cells and activate NF-kappaB and STAT3 to lead transcription of target genes for liver regeneration.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	12	13
STAT3 promotes cell survival in response to selected growth factors , and is activated by combined BCR crosslinking and IL-6 ( IL-10 ) .	STAT3 promotes cell survival in response to selected growth factors, and is activated by combined BCR crosslinking and IL-6 (IL-10).	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	0	1
These results indicate that Stat3 activation by IL-6 and IL-10 plays an important role in cell-to-cell interaction between tumor cells and macrophages in the ascites of AdEOC .	These results indicate that Stat3 activation by IL-6 and IL-10 plays an important role in cell-to-cell interaction between tumor cells and macrophages in the ascites of AdEOC.	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	7	8	4	5
IFN-gamma and IL-6 stimulation caused similar strong activation of STAT1 , STAT3 , SOCS1 and SOCS3 , which did not agree with previous experimental observations .	IFN-gamma and IL-6 stimulation caused similar strong activation of STAT1, STAT3, SOCS1 and SOCS3, which did not agree with previous experimental observations.	0	12	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	11	12
IL-6 induced STAT3 signaling and thereby increased retinal endothelial permeability and vascular leakage .	IL-6 induced STAT3 signaling and thereby increased retinal endothelial permeability and vascular leakage.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Although IL-6 also activates STAT3 and cooperates with IL-21 to promote the differentiation of CD4 Tfh cells , the loss of IL-6 , IL-21 , or both does not impair the development of anti-viral CD8 T responses following influenza infection , further illustrating the context dependent requirements for IL-21 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Although IL-6 also activates STAT3 and cooperates with IL-21 to promote the differentiation of CD4 Tfh cells, the loss of IL-6, IL-21, or both does not impair the development of anti-viral CD8 T responses following influenza infection, further illustrating the context dependent requirements for IL-21 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	4	5
XREF_BIBR , XREF_BIBR A recent study found that the IL6 co-receptor GP130 , up-regulated by YAP1 and TAZ in our study , also activates YAP1 independently of STAT3 .	XREF_BIBR, XREF_BIBR A recent study found that the IL6 co-receptor GP130, up-regulated by YAP1 and TAZ in our study, also activates YAP1 independently of STAT3.	9	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	9	10	27	28
By interacting with their respective receptors , TNF-alpha triggered IkappaB ( inhibitor of kappaB ) ubiquitination and activated NFkappaB complex [ XREF_BIBR ] , while IL-6 activated STAT3 [ XREF_BIBR ] and IKK ( IkappaB kinase ) , leading to the up-regulation of miR-21-5p [ XREF_BIBR ] .	By interacting with their respective receptors, TNF-alpha triggered IkappaB (inhibitor of kappaB) ubiquitination and activated NFkappaB complex [XREF_BIBR], while IL-6 activated STAT3 [XREF_BIBR] and IKK (IkappaB kinase), leading to the up-regulation of miR-21-5p [XREF_BIBR].	25	29	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	27	28
These results suggest that cancer secreted IL-6 induces STAT3 activation in other cells .	These results suggest that cancer secreted IL-6 induces STAT3 activation in other cells.	5	9	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
Moreover , these authors hypothesized that the elevation of IL-6 levels caused continuous activation of the gp130 and STAT3 pathway , leading to HF .	Moreover, these authors hypothesized that the elevation of IL-6 levels caused continuous activation of the gp130 and STAT3 pathway, leading to HF.	9	19	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 levels	il-6	STAT3	STAT3	stat3	9	10	18	19
Another example is ABC DLBCL , in which STAT3 is activated by IL-6 and IL-10 .	Another example is ABC DLBCL, in which STAT3 is activated by IL-6 and IL-10.	8	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	8	9
Activated Stat3 promotes the expression of numerous immunosuppressive factors , such as VEGF , interleukin-10 ( IL-10 ) , IL-6 , and IL-23 .	Activated Stat3 promotes the expression of numerous immunosuppressive factors, such as VEGF, interleukin-10 (IL-10), IL-6, and IL-23.	0	22	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	19	20	1	2
Expression of pSTAT3 ( Y705 ) was elevated in the cells treated with IL-6 for 4h and peaked in cells treated with 50ng/ml IL-6 .	Expression of pSTAT3 (Y705) was elevated in the cells treated with IL-6 for 4h and peaked in cells treated with 50ng/ml IL-6.	0	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	13	14	2	3
Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration .	Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration.	1	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	9	10
IL-6 and OSM stimulation induces binding of STAT3 to the IL-6 and OSM response element , while binding of the AP-1 protein was constitutive .	IL-6 and OSM stimulation induces binding of STAT3 to the IL-6 and OSM response element, while binding of the AP-1 protein was constitutive.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	7	8
A number of NF-kappaB encoded inflammatory factors , such as IL-6 , are activators of STAT3 , in turn creating a positive feedback loop , leads to dysregulated action of immune modulating pathways [ XREF_BIBR ] .	A number of NF-kappaB encoded inflammatory factors, such as IL-6, are activators of STAT3, in turn creating a positive feedback loop, leads to dysregulated action of immune modulating pathways [XREF_BIBR].	6	18	activators	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	15	16
These cells respond by expressing inflammation associated cytokines , one of which ( IL-6 ) , activates Stat3 and is believed to promote cell proliferation and regeneration .	These cells respond by expressing inflammation associated cytokines, one of which (IL-6), activates Stat3 and is believed to promote cell proliferation and regeneration.	9	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	13	14	17	18
For example , activation of signal transducer and activator of transcription 1 ( STAT1 ) by IFN-gamma induces hepatocyte apoptosis and cell cycle arrest , XREF_BIBR , XREF_BIBR , XREF_BIBR while activation of STAT3 by IL-6 and IL-22 induces anti-apoptotic and anti-oxidative stress proteins and consequently promotes hepatocyte survival and proliferation .	For example, activation of signal transducer and activator of transcription 1 (STAT1) by IFN-gamma induces hepatocyte apoptosis and cell cycle arrest, XREF_BIBR, XREF_BIBR, XREF_BIBR while activation of STAT3 by IL-6 and IL-22 induces anti-apoptotic and anti-oxidative stress proteins and consequently promotes hepatocyte survival and proliferation.	31	37	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	35	36	33	34
STAT3 can be activated by growth factor receptors including EGFR and platelet derived growth factor receptors ( PDGFR ) , as well as interleukin-6 receptor ( IL-6R and gp130 ) , Janus family kinases ( JAK ) , Abl family kinases , and Src family kinases [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	STAT3 can be activated by growth factor receptors including EGFR and platelet derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R and gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	23	24	0	1
Our data suggest that IL-6 and TNF-alpha cotreatments activate STAT3 .	Our data suggest that IL-6 and TNF-alpha cotreatments activate STAT3.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	9	10
These findings elucidate a mechanism dependent on the induction of an autocrine IL-6 activation loop through which Rac1 and the Rho family mediate STAT3 activation establishing a link between GTPase activity and Janus kinase and STAT signaling .	These findings elucidate a mechanism dependent on the induction of an autocrine IL-6 activation loop through which Rac1 and the Rho family mediate STAT3 activation establishing a link between GTPase activity and Janus kinase and STAT signaling.	12	24	mediate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	23	24
Functionally active Tfh cells are identified in blood circulation during RA remission [ XREF_BIBR , XREF_BIBR ] Notably , RA patients are early recognized by IL-6 dependent activation of STAT3 [ XREF_BIBR - XREF_BIBR ] , the major driving mechanism of Tfh development .	Functionally active Tfh cells are identified in blood circulation during RA remission [XREF_BIBR, XREF_BIBR] Notably, RA patients are early recognized by IL-6 dependent activation of STAT3 [XREF_BIBR - XREF_BIBR], the major driving mechanism of Tfh development.	25	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	29	30
IL-6 treatment stimulated lung Stat3 activation and prevented AEC apoptosis .	IL-6 treatment stimulated lung Stat3 activation and prevented AEC apoptosis.	0	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	4	5
IL-6 mediated activation of STAT3 transcription factor by its phosphorylation is critically involved in inflammation .	IL-6 mediated activation of STAT3 transcription factor by its phosphorylation is critically involved in inflammation.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
For example , the critical role of STAT3 induced by IL-6 and other inflammatory cytokines has been widely reported for the maintenance of CSCs [ XREF_BIBR ] .	For example, the critical role of STAT3 induced by IL-6 and other inflammatory cytokines has been widely reported for the maintenance of CSCs [XREF_BIBR].	5	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	7	8
To our knowledge , these results from in vivo as well as in vitro experiments provide the first evidence that CaMKII is necessary for the activation of STAT3 by IL-6 .	To our knowledge, these results from in vivo as well as in vitro experiments provide the first evidence that CaMKII is necessary for the activation of STAT3 by IL-6.	22	30	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	29	30	27	28
The IKKbeta inhibitor MLN120B also enhanced IL-6 induced STAT3 activation in dih cells and a human liver cancer cell line ( XREF_SUPPLEMENTARY ) .	The IKKbeta inhibitor MLN120B also enhanced IL-6 induced STAT3 activation in dih cells and a human liver cancer cell line (XREF_SUPPLEMENTARY).	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
In contrast to STAT1 , treatment with LPS alone increased the tyrosine phosphorylation of STAT3 , but this occurred only after 3-4 h , suggesting that it occurred at the later times in response to a cytokine produced in response to LPS , likely IL-6 , which is well-known to strongly activate STAT3 [ XREF_BIBR ] .	In contrast to STAT1, treatment with LPS alone increased the tyrosine phosphorylation of STAT3, but this occurred only after 3-4 h, suggesting that it occurred at the later times in response to a cytokine produced in response to LPS, likely IL-6, which is well-known to strongly activate STAT3 [XREF_BIBR].	41	54	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	44	45	52	53
For example , IL-6 treatment of cells induces the SUMO deconjugating enzyme SENP1 , which in turns removes PML SUMO moieties , thereby releasing STAT3 from PML NBs and de-repressing PML dependent STAT3 transcriptional activity .	For example, IL-6 treatment of cells induces the SUMO deconjugating enzyme SENP1, which in turns removes PML SUMO moieties, thereby releasing STAT3 from PML NBs and de-repressing PML dependent STAT3 transcriptional activity.	3	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	24	25
However , the increase of p-STAT3 induced by IL-6 was inhibited after treatment with quercetin ( XREF_FIG ) .	However, the increase of p-STAT3 induced by IL-6 was inhibited after treatment with quercetin (XREF_FIG).	3	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	8	9	5	6
Genetic ablation of IL-6 or its pharmacological inhibition decreases tumor cell proliferation and reduces CAC tumor multiplicity and growth [ XREF_BIBR , XREF_BIBR ] , mimicking more severe phenotype of epithelial cell specific deletion of STAT3 [ XREF_BIBR , XREF_BIBR ] .	Genetic ablation of IL-6 or its pharmacological inhibition decreases tumor cell proliferation and reduces CAC tumor multiplicity and growth [XREF_BIBR, XREF_BIBR], mimicking more severe phenotype of epithelial cell specific deletion of STAT3 [XREF_BIBR, XREF_BIBR].	1	39	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	35	36
IL-6 induces the procarcinogenic Stat3 pathway and transcriptionally activates proliferative , antiapoptotic and proangiogenic genes involved in cancer growth XREF_BIBR .	IL-6 induces the procarcinogenic Stat3 pathway and transcriptionally activates proliferative, antiapoptotic and proangiogenic genes involved in cancer growth XREF_BIBR.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	4	5
Therefore , we speculated that the dead cells could induce inflammation and higher levels of IL-6 , which in turn activated STAT3 in the survived cells that then give rise to tumors .	Therefore, we speculated that the dead cells could induce inflammation and higher levels of IL-6, which in turn activated STAT3 in the survived cells that then give rise to tumors.	9	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	21	22
The results suggest that IL-6 is able to activate expression CD44v6 and STAT3 .	The results suggest that IL-6 is able to activate expression CD44v6 and STAT3.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	12	13
Therefore , IL-6 and mIL-6R form complexes to activate the downstream STAT3 signaling pathway , which subsequently promotes osteogenic differentiation in BM-MSCs in an autocrine and paracrine manner .	Therefore, IL-6 and mIL-6R form complexes to activate the downstream STAT3 signaling pathway, which subsequently promotes osteogenic differentiation in BM-MSCs in an autocrine and paracrine manner.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	11	12
Although IKK activity is not constitutive , it is likely that periodic activation of IKK is required for NF-kappaB activity by facilitating its nuclear entry , while IL-6 production , which activates Stat3 , is necessary to maintain oncogenic progression in such models , and in certain human cancers .	Although IKK activity is not constitutive, it is likely that periodic activation of IKK is required for NF-kappaB activity by facilitating its nuclear entry, while IL-6 production, which activates Stat3, is necessary to maintain oncogenic progression in such models, and in certain human cancers.	27	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	27	28	32	33
Moreover , PTP1B specifically inhibits JAK2 activity , while IL-6 family cytokines activate STAT3 though both JAK1 and JAK2 ( 14 ) .	Moreover, PTP1B specifically inhibits JAK2 activity, while IL-6 family cytokines activate STAT3 though both JAK1 and JAK2 (14).	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	13	14
In chemically induced models of colitis , for instance , IL-6 promotes Stat3 dependent induction of proliferative , antiapoptotic , and cytoprotective gene programs , including proliferating cellular nuclear antigen , Bcl-x L , and heat shock protein ( Hsp ) -72 ( XREF_FIG ) .	In chemically induced models of colitis, for instance, IL-6 promotes Stat3 dependent induction of proliferative, antiapoptotic, and cytoprotective gene programs, including proliferating cellular nuclear antigen, Bcl-x L, and heat shock protein (Hsp) -72 (XREF_FIG).	10	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	10	11	12	13
Although IL-6 production by non parenchymal cells , such as Kupffer cells may play a role , these findings suggested that IL-6 produced in hepatocytes promoted the activation of the IL-6 and STAT3 signaling pathway and also exerted hepatoprotective effects in an autocrine manner .	Although IL-6 production by non parenchymal cells, such as Kupffer cells may play a role, these findings suggested that IL-6 produced in hepatocytes promoted the activation of the IL-6 and STAT3 signaling pathway and also exerted hepatoprotective effects in an autocrine manner.	21	37	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	32	33
Recently , in teleost , it was reported that recombinant trout IL-6 could activate the STAT3 pathway in trout macrophages [ XREF_BIBR ] .	Recently, in teleost, it was reported that recombinant trout IL-6 could activate the STAT3 pathway in trout macrophages [XREF_BIBR].	9	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	15	16
Further , IL-6 mediated Stat3 signaling through the sIL-6R .	Further, IL-6 mediated Stat3 signaling through the sIL-6R.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	4	5
Therefore , the ability of Bazedoxifene to inhibit cell viability and migration is likely due to its ability to inhibit one of the pathways or more than one pathways combined : ( I ) autocrine IL-6 induction of P-STAT3 ; ( II ) autocrine IL-6 and non GP130 pathway ( s ) induction of P-ERK and P-AKT ; ( III ) other pathway ( s ) in addition to STAT3 , ERK , and AKT .	Therefore, the ability of Bazedoxifene to inhibit cell viability and migration is likely due to its ability to inhibit one of the pathways or more than one pathways combined : (I) autocrine IL-6 induction of P-STAT3; (II) autocrine IL-6 and non GP130 pathway (s) induction of P-ERK and P-AKT; (III) other pathway (s) in addition to STAT3, ERK, and AKT.	35	39	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	P-STAT3	P-STAT3	P-STAT3	35	36	38	39
We incubated MM1 cells with IL-6 and , using Western immunoblotting , established that IL-6 induced upregulation of both pSTAT3 and GM-CSFRalpha in a dose- and time dependent manner ( XREF_FIG ) .	We incubated MM1 cells with IL-6 and, using Western immunoblotting, established that IL-6 induced upregulation of both pSTAT3 and GM-CSFRalpha in a dose- and time dependent manner (XREF_FIG).	14	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	14	15	19	20
STAT3 can be activated by IL-6 , a cytokine that binds to its receptor and phosphorylates at Tyr 705 .	STAT3 can be activated by IL-6, a cytokine that binds to its receptor and phosphorylates at Tyr 705.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
IL-6 and IL-21 induce STAT3 activation that in turn regulates the transcription factors RORgammat and RORalpha in the presence of TGF-beta , and thus Th17 cell differentiation .	IL-6 and IL-21 induce STAT3 activation that in turn regulates the transcription factors RORgammat and RORalpha in the presence of TGF-beta, and thus Th17 cell differentiation.	0	5	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
In other tissues devoid of high levels of RA , STAT3 activation by IL-6 efficiently represses FoxP3 transcription .	In other tissues devoid of high levels of RA, STAT3 activation by IL-6 efficiently represses FoxP3 transcription.	10	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	10	11
As described above , the JAK and STAT3 cascade activation is induced by both pro- ( IL-6 ) and anti-nociceptive ( IL-10 ) factors .	As described above, the JAK and STAT3 cascade activation is induced by both pro- (IL-6) and anti-nociceptive (IL-10) factors.	7	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	7	8
IL-6 was shown to activate the STAT3 pathway in LCL8664 cells even in the presence of TGF-beta1 , the downstream effects of which may include the activation of both proliferation associated and anti-apoptotic proteins that could counteract the growth-inhibitory effects of TGF-beta1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	IL-6 was shown to activate the STAT3 pathway in LCL8664 cells even in the presence of TGF-beta1, the downstream effects of which may include the activation of both proliferation associated and anti-apoptotic proteins that could counteract the growth-inhibitory effects of TGF-beta1 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
The cytokines IL-6 and IL-21 , which activate STAT3 , play significant roles in the development of human Th17 T cells 29 , as discussed above .	The cytokines IL-6 and IL-21, which activate STAT3, play significant roles in the development of human Th17 T cells 29, as discussed above.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
We also found in MC3T3 cells that IL-6 induced STAT3 activation was significantly higher in later culture stages , i.e. when IL-6 receptor expression was high .	We also found in MC3T3 cells that IL-6 induced STAT3 activation was significantly higher in later culture stages, i.e. when IL-6 receptor expression was high.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
IL-6 also activates the STAT3 transcription factor that , along with RORgammat , stimulates the differentiation of naive TCD4+ cells into the Th17 sub-category .	IL-6 also activates the STAT3 transcription factor that, along with RORgammat, stimulates the differentiation of naive TCD4+ cells into the Th17 sub-category.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Certain groups recently showed that STAT3 signaling in aged satellite cells was constitutively activated by long-term interleukin-6 stimulation , which led to a loss of regenerative capacity XREF_BIBR , XREF_BIBR .	Certain groups recently showed that STAT3 signaling in aged satellite cells was constitutively activated by long-term interleukin-6 stimulation, which led to a loss of regenerative capacity XREF_BIBR, XREF_BIBR.	5	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	16	17	5	6
In conclusion , our results suggested that the IL-17 mediated tumor promoting role involved a direct effect on tumor cells through IL-6 induction by activating the AKT pathway ; IL-6 in turn activated JAK2 and STAT3 and up-regulated proinvasive factors IL-8 , MMP2 , and VEGF both in vitro and in vivo .	In conclusion, our results suggested that the IL-17 mediated tumor promoting role involved a direct effect on tumor cells through IL-6 induction by activating the AKT pathway; IL-6 in turn activated JAK2 and STAT3 and up-regulated proinvasive factors IL-8, MMP2, and VEGF both in vitro and in vivo.	29	37	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	29	30	35	36
SOCS3 protein is expressed by IL-6 stimulation in a STAT3 dependent manner and inhibits STAT3 activation .	SOCS3 protein is expressed by IL-6 stimulation in a STAT3 dependent manner and inhibits STAT3 activation.	5	11	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	9	10
For example , STAT3 activated by IL-6 directly represses the miR-34a gene , which was shown to be necessary for invasion and metastasis of human colorectal cancer cells and was related to nodal and distant metastasis in patients .	For example, STAT3 activated by IL-6 directly represses the miR-34a gene, which was shown to be necessary for invasion and metastasis of human colorectal cancer cells and was related to nodal and distant metastasis in patients.	3	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	3	4
The basis for this phenotype is complex , but it appears that the enhanced ability of IL-11 , rather than IL-6 , to activate STAT3 and STAT1 in absence of SOCS3 promotes inflammation and cancer .	The basis for this phenotype is complex, but it appears that the enhanced ability of IL-11, rather than IL-6, to activate STAT3 and STAT1 in absence of SOCS3 promotes inflammation and cancer.	14	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	24	25
It is known that during acute phase reaction IL-6 activates STAT3 in hepatoma cells and IL-1 downregulates this response .	It is known that during acute phase reaction IL-6 activates STAT3 in hepatoma cells and IL-1 downregulates this response.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
Another potential mechanism by which PGE 2 enhances M2 dependent genes in a STAT3 dependent manner is through the production of Il6 , which is known to induce STAT3 activation [ XREF_BIBR - XREF_BIBR ] and M2 generation [ XREF_BIBR ] .	Another potential mechanism by which PGE 2 enhances M2 dependent genes in a STAT3 dependent manner is through the production of Il6, which is known to induce STAT3 activation [XREF_BIBR - XREF_BIBR] and M2 generation [XREF_BIBR].	19	29	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Il6	Il6	Il6	STAT3	STAT3	STAT3	21	22	28	29
Additionally , the inhibitor demonstrated reduced potency against IL-6 activation of STAT3 and significantly reduced inhibition of JAK2 mediated GM-CSF signaling .	Additionally, the inhibitor demonstrated reduced potency against IL-6 activation of STAT3 and significantly reduced inhibition of JAK2 mediated GM-CSF signaling.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	11	12
In an experimental model of Src oncogene dependent cancer transformation , induction of inflammation was critical for oncogenesis and Src induced inflammation was mediated by NF-kappaB leading to increased IL-6 production , which then in turn increased Stat3 activation .	In an experimental model of Src oncogene dependent cancer transformation, induction of inflammation was critical for oncogenesis and Src induced inflammation was mediated by NF-kappaB leading to increased IL-6 production, which then in turn increased Stat3 activation.	29	38	increased	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	29	30	37	38
Two families of cytokines are shown to play key roles in astrocytic differentiation of NSCs : IL-6 family cytokines that activate Stat3 and BMPs that activate Smad1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Two families of cytokines are shown to play key roles in astrocytic differentiation of NSCs : IL-6 family cytokines that activate Stat3 and BMPs that activate Smad1 [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	16	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	16	17	21	22
We observed that STAT3 activation induced by IL-6 was faint within one hour ( XREF_FIG ) .	We observed that STAT3 activation induced by IL-6 was faint within one hour (XREF_FIG).	3	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	3	4
Since TRIM27 deficiency also inhibited STAT3 activation by OSM , which is another IL-6 family member , it is possible that the retromer is a common platform for STAT3 activation induced by the IL-6 family members which share the common co-receptor gp130 .	Since TRIM27 deficiency also inhibited STAT3 activation by OSM, which is another IL-6 family member, it is possible that the retromer is a common platform for STAT3 activation induced by the IL-6 family members which share the common co-receptor gp130.	28	35	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	33	34	28	29
Their development depends on signals mediated by IL-6 ( and downstream activation of STAT3 ) and TGF-beta , IL-21 , and IL-23 and by induction of the lineage specifying transcription factor , retinoic acid related orphan nuclear receptor ( RORgammaT ) [ XREF_BIBR ] .	Their development depends on signals mediated by IL-6 (and downstream activation of STAT3) and TGF-beta, IL-21, and IL-23 and by induction of the lineage specifying transcription factor, retinoic acid related orphan nuclear receptor (RORgammaT) [XREF_BIBR].	5	21	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	13	14
In addition , STAT family members show cross regulation , and STAT1 and STAT3 are both activated by IL-6 in which the signaling specificity of IL-6 is modulated by activation of STAT3 such that removal of STAT3 results in prolonged STAT1 activation by IL-6 .	In addition, STAT family members show cross regulation, and STAT1 and STAT3 are both activated by IL-6 in which the signaling specificity of IL-6 is modulated by activation of STAT3 such that removal of STAT3 results in prolonged STAT1 activation by IL-6.	11	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	13	14
Interleukin-6 ( IL-6 )-type cytokines activate transcription factors Stat1 and Stat3 ( signal transducers and activators of transcription ) .	Interleukin-6 (IL-6)-type cytokines activate transcription factors Stat1 and Stat3 (signal transducers and activators of transcription).	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin-6	Interleukin-6	Interleukin-6	Stat3	Stat3	Stat3	0	1	10	11
Our results showed that in wild type astrocytes activation of STAT3 by IL-6 resulted in significant induction of Cryba1 transcript , an increase that was reduced in the presence of Stattic ( XREF_FIG ) .	Our results showed that in wild type astrocytes activation of STAT3 by IL-6 resulted in significant induction of Cryba1 transcript, an increase that was reduced in the presence of Stattic (XREF_FIG).	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	10	11
Additionally , in the pathogenesis of human gastric cancer , the increased tumor hepcidin expression was tightly associated with the upregulation of the JAK and STAT3 signaling pathway , which may be mediated by IL-6 .	Additionally, in the pathogenesis of human gastric cancer, the increased tumor hepcidin expression was tightly associated with the upregulation of the JAK and STAT3 signaling pathway, which may be mediated by IL-6.	25	35	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	34	35	25	26
Classic IL-6 signaling through the mIL-6R activates STAT3 leading to intestinal epithelial cell proliferation and inhibition of epithelial cell apoptosis thus playing a therapeutic role leading to regeneration of intestinal epithelial cells after damage from stressors [ XREF_BIBR ] .	Classic IL-6 signaling through the mIL-6R activates STAT3 leading to intestinal epithelial cell proliferation and inhibition of epithelial cell apoptosis thus playing a therapeutic role leading to regeneration of intestinal epithelial cells after damage from stressors [XREF_BIBR].	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	7	8
The main cause of STAT3 activation is elevated production of the pro inflammatory cytokines IL-6 , which leads to direct STAT3 activation , and TNF which stimulates the expression of IL-6 [ XREF_BIBR ] .	The main cause of STAT3 activation is elevated production of the pro inflammatory cytokines IL-6, which leads to direct STAT3 activation, and TNF which stimulates the expression of IL-6 [XREF_BIBR].	8	21	direct	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	20	21
To reveal the significance of Stat3 in lung development , fetal lung tissue explants were treated with Stat3 activator ( IL-6 ) or inhibitor ( cucurbitacin I ) .	To reveal the significance of Stat3 in lung development, fetal lung tissue explants were treated with Stat3 activator (IL-6) or inhibitor (cucurbitacin I).	3	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	20	21	5	6
Under static conditions , treatment with AngII did not augment expression of either cytokine ( XREF_FIG ) , and interestingly , AngII failed to amplify IL-6 or MCP-1 mRNA abundance induced by tension alone ( XREF_FIG , respectively ) , but pretreatment with WP1066 did significantly inhibit IL-6 transcription ( XREF_FIG ) , supporting STAT3 as an operative transcription factor in this response .	Under static conditions, treatment with AngII did not augment expression of either cytokine (XREF_FIG), and interestingly, AngII failed to amplify IL-6 or MCP-1 mRNA abundance induced by tension alone (XREF_FIG, respectively), but pretreatment with WP1066 did significantly inhibit IL-6 transcription (XREF_FIG), supporting STAT3 as an operative transcription factor in this response.	47	55	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 transcription	il-6	STAT3	STAT3	stat3	47	48	54	55
IL6 induced activation of STAT3 conferred protection against SFN induced apoptosis .	IL6 induced activation of STAT3 conferred protection against SFN induced apoptosis.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	4	5
This study aims to investigate the role of tumor derived IL6 and subsequent activation of the STAT3 pathway in PDAC cachexia .	This study aims to investigate the role of tumor derived IL6 and subsequent activation of the STAT3 pathway in PDAC cachexia.	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	10	11	16	17
As shown in XREF_FIG , IL-6 ( 10ng/mL ) and TPA ( 100nM ) treatment for 1h resulted in STAT3 activation while the pretreatment of cells with 25nM PSD-A for 4h effectively abrogated the IL-6- and TPA induced STAT3 activation .	As shown in XREF_FIG, IL-6 (10ng/mL) and TPA (100nM) treatment for 1h resulted in STAT3 activation while the pretreatment of cells with 25nM PSD-A for 4h effectively abrogated the IL-6- and TPA induced STAT3 activation.	5	21	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	19	20
Enforced expression of SOCS-3 also reduced IL-6 induction of phospho-STAT-3 and Mcl-1 .	Enforced expression of SOCS-3 also reduced IL-6 induction of phospho-STAT-3 and Mcl-1.	6	11	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	phospho-STAT-3	phospho-STAT-3	phospho-STAT-3	6	7	9	10
IL-6 from the stroma then induced Stat3 activation in the tumor cells .	IL-6 from the stroma then induced Stat3 activation in the tumor cells.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	6	7
IL-6 induces STAT3 ( signal transducer and activator of transcription 3 ) , which is needed for Rorc transcription .	IL-6 induces STAT3 (signal transducer and activator of transcription 3), which is needed for Rorc transcription.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
IL-6 and sIL-6R activate STAT3 in neuroblastoma cells .	IL-6 and sIL-6R activate STAT3 in neuroblastoma cells.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Interleukin-6 might dominantly activate STAT3 in endothelial cells , which might have a central role in endothelial cell proliferation and angiogenesis of CSDH outer membranes .	Interleukin-6 might dominantly activate STAT3 in endothelial cells, which might have a central role in endothelial cell proliferation and angiogenesis of CSDH outer membranes.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin-6	Interleukin-6	Interleukin-6	STAT3	STAT3	STAT3	0	1	4	5
NF-kappaB-dependent IL-10 and IL-6 secretion can activate STAT3 signaling in an autocrine manner .	NF-kappaB-dependent IL-10 and IL-6 secretion can activate STAT3 signaling in an autocrine manner.	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	7	8
A recent study found that cis-elements on the Foxp3 locus were partially re-methylated during Treg cell division and suggested that Stat6 and Stat3 , which are activated by IL-4 and IL-6 , respectively , may destabilize Foxp3 expression by recruiting Dnmt1 to the Foxp3 locus .	A recent study found that cis-elements on the Foxp3 locus were partially re-methylated during Treg cell division and suggested that Stat6 and Stat3, which are activated by IL-4 and IL-6, respectively, may destabilize Foxp3 expression by recruiting Dnmt1 to the Foxp3 locus.	20	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	30	31	22	23
Similarly , STAT3 , being activated by IL-6 and IL-21 promotes Th17 differentiation .	Similarly, STAT3, being activated by IL-6 and IL-21 promotes Th17 differentiation.	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	2	3
In line with that , MEDICA suppressed the IL-6- and HGF activated phospho-STAT3 ( Tyr705 ) in CRC HT29 or PTC BcPAP cells , and the constitutively-active STAT3 in A375 melanoma cells .	In line with that, MEDICA suppressed the IL-6- and HGF activated phospho-STAT3 (Tyr705) in CRC HT29 or PTC BcPAP cells, and the constitutively-active STAT3 in A375 melanoma cells.	7	31	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6-	IL-6-	IL-6-	STAT3	STAT3	STAT3	8	9	27	28
The JAK2 and STAT3 pathway is most commonly activated by the IL-6 receptor .	The JAK2 and STAT3 pathway is most commonly activated by the IL-6 receptor.	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	3	4
In CWR22Rv1 cells , IL-6 activated only Stat3 but not ERK1/2 or Akt ( XREF_SUPPLEMENTARY ) .	In CWR22Rv1 cells, IL-6 activated only Stat3 but not ERK1/2 or Akt (XREF_SUPPLEMENTARY).	4	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	7	8
On the other hand , IL-6 activates STAT3 .	On the other hand, IL-6 activates STAT3.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
IL-6 induced the accumulation of P-STAT3 in the nucleus , whereas the pretreatment with LLL12 blocked this process ( XREF_FIG ) .	IL-6 induced the accumulation of P-STAT3 in the nucleus, whereas the pretreatment with LLL12 blocked this process (XREF_FIG).	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	P-STAT3	P-STAT3	P-STAT3	0	1	5	6
Our results showed that IL-6 activation of the JAK2 and STAT3 signaling pathway was suppressed by IL-32alpha , which was consistent with its effects on the expression of genes associated with metastasis and invasion .	Our results showed that IL-6 activation of the JAK2 and STAT3 signaling pathway was suppressed by IL-32alpha, which was consistent with its effects on the expression of genes associated with metastasis and invasion.	4	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	10	11
IL-6 activates STAT3 which induces miR-21 and this interaction leads to the repression of PCAT29 .	IL-6 activates STAT3 which induces miR-21 and this interaction leads to the repression of PCAT29.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Conversely , sIL-6R and IL-6 triggered STAT3 and to a much lesser extent STAT1 tyrosine phosphorylation in NCI-N592 , NCI-H69 and NCI-H446 cells .	Conversely, sIL-6R and IL-6 triggered STAT3 and to a much lesser extent STAT1 tyrosine phosphorylation in NCI-N592, NCI-H69 and NCI-H446 cells.	2	7	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
COX2 also enhances cell growth and angiogenesis , ROS modify protein function , IL6 activates STAT3 further enhancing cell growth and stimulating growth factor production including the Reg protein XREF_BIBR , XREF_BIBR , XREF_BIBR .	COX2 also enhances cell growth and angiogenesis, ROS modify protein function, IL6 activates STAT3 further enhancing cell growth and stimulating growth factor production including the Reg protein XREF_BIBR, XREF_BIBR, XREF_BIBR.	13	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	13	14	15	16
We determined that crocin inhibited STAT3 activation induced by IL-6 in hepatocellular carcinoma Hep3B and HepG2 cells .	We determined that crocin inhibited STAT3 activation induced by IL-6 in hepatocellular carcinoma Hep3B and HepG2 cells.	5	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	5	6
Indeed , inhibition of JAK2 expression by shRNA reduced IL-6 induced STAT3 activation in both Ikkbeta f/f and Ikkbeta Delta dih cells ( XREF_SUPPLEMENTARY ) .	Indeed, inhibition of JAK2 expression by shRNA reduced IL-6 induced STAT3 activation in both Ikkbeta f/f and Ikkbeta Delta dih cells (XREF_SUPPLEMENTARY).	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
Consequently , TGF-beta treatment induced pSTAT3 in HuH-7 cells , although the effect was much weaker than induction of pSTAT3 by IL-6 ( XREF_SUPPLEMENTARY ) , linking the SMAD7 effects on STAT3 signaling to TGF-beta .	Consequently, TGF-beta treatment induced pSTAT3 in HuH-7 cells, although the effect was much weaker than induction of pSTAT3 by IL-6 (XREF_SUPPLEMENTARY), linking the SMAD7 effects on STAT3 signaling to TGF-beta.	14	23	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	21	22	19	20
IL-6 activates STAT3 signaling [ XREF_BIBR , XREF_BIBR ] .	IL-6 activates STAT3 signaling [XREF_BIBR, XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Accordingly , acute STAT3 activation by IL-6 treatment could efficiently up-regulate RHOU mRNA in the non transformed mammary epithelial cell line MCF10A .	Accordingly, acute STAT3 activation by IL-6 treatment could efficiently up-regulate RHOU mRNA in the non transformed mammary epithelial cell line MCF10A.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	3	4
IL6 through its receptor activates STAT3 which regulates expression of Oct3/4 , a major reprogramming factor known to induce expression of various stem cell associated genes and suppression of lineage commitment genes XREF_BIBR .	IL6 through its receptor activates STAT3 which regulates expression of Oct3/4, a major reprogramming factor known to induce expression of various stem cell associated genes and suppression of lineage commitment genes XREF_BIBR.	0	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	5	6
Interestingly , TAMs collaborated with MPCs by being a source of the agonistic soluble IL-6 receptor enhancing STAT3 activation .	Interestingly, TAMs collaborated with MPCs by being a source of the agonistic soluble IL-6 receptor enhancing STAT3 activation.	14	18	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	17	18
This pattern of activation suggests the possibility that acute IL-6 stimulation of STAT3 may lead to secretion of a second factor that then reactivates STAT3 signaling .	This pattern of activation suggests the possibility that acute IL-6 stimulation of STAT3 may lead to secretion of a second factor that then reactivates STAT3 signaling.	9	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	12	13
To further support this molecular path for MDSC accumulation , we found that Stat3 and C/EBP binding at miR-21 or miR-181b promoter was induced by IL-6 , using a luciferase reporter gene transfection into naive Gr1 + CD11b + cells .	To further support this molecular path for MDSC accumulation, we found that Stat3 and C/EBP binding at miR-21 or miR-181b promoter was induced by IL-6, using a luciferase reporter gene transfection into naive Gr1 + CD11b + cells.	13	26	induced	Positive_regulation_syntax_2_verb	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	Stat3	Stat3 and C/EBP binding	stat3	25	26	13	14
STAT3 activation , driven by IL-6 and IL-23 , is required for terminal Th17 differentiation and IL-22 production .	STAT3 activation, driven by IL-6 and IL-23, is required for terminal Th17 differentiation and IL-22 production.	0	7	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
IL-6 and TNF-alpha Cotreatments Activated STAT3 Synergistically Whereas Withaferin A Abolished the Activation .	IL-6 and TNF-alpha Cotreatments Activated STAT3 Synergistically Whereas Withaferin A Abolished the Activation.	0	6	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Colon cancer cells stimulate macrophages to produce IL-6 , which activates STAT3 in tumor cells 30 .	Colon cancer cells stimulate macrophages to produce IL-6, which activates STAT3 in tumor cells 30.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	11	12
For example , IL-6 trans-signaling-dependent activation of STAT3 and SOCS3 promotes pancreatic cancer in murine models .	For example, IL-6 trans-signaling-dependent activation of STAT3 and SOCS3 promotes pancreatic cancer in murine models.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	7	8
STAT3 may be activated by IL-6 to induce the production of IL-17 in IL-17-producing helper T cells .	STAT3 may be activated by IL-6 to induce the production of IL-17 in IL-17-producing helper T cells.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
STAT3 mRNA levels were significantly increased when the cells were treated with IL-6 , whereas when AG490 ( 50 muM ) was added to the cell cultures , IL-6-induced increase of STAT3 mRNA levels was abolished .	STAT3 mRNA levels were significantly increased when the cells were treated with IL-6, whereas when AG490 (50 muM) was added to the cell cultures, IL-6-induced increase of STAT3 mRNA levels was abolished.	0	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	0	1
These data suggested that enhanced IL6 secretion may activate STAT3 signaling , and circumvent the effect of MEK inhibition .	These data suggested that enhanced IL6 secretion may activate STAT3 signaling, and circumvent the effect of MEK inhibition.	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	5	6	9	10
Overproduction of IL-6 in vivo triggers constitutive STAT3 activation .	Overproduction of IL-6 in vivo triggers constitutive STAT3 activation.	0	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	7	8
This is consistent with studies in glioblastoma showing that inhibition of IL-6 or its receptor , IL-6Ralpha , diminishes STAT3 activation and , in turn , the number of glioblastoma stem cells [ XREF_BIBR ] .	This is consistent with studies in glioblastoma showing that inhibition of IL-6 or its receptor, IL-6Ralpha, diminishes STAT3 activation and, in turn, the number of glioblastoma stem cells [XREF_BIBR].	9	20	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	19	20
IL-6 leads to activation of STAT3 and/or Ras-mitogen-activated protein kinase ( MAPK ) signaling XREF_BIBR , while TNFalpha induces the activation of NF-kappaB XREF_BIBR .	IL-6 leads to activation of STAT3 and/or Ras-mitogen-activated protein kinase (MAPK) signaling XREF_BIBR, while TNFalpha induces the activation of NF-kappaB XREF_BIBR.	0	6	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Consistent with reports that utilized other cell types , IFN-gamma and IFN-lambda2 primarily activated STAT-1 phosphorylation in the MMHD3 cells , while IL-6 and IL-22 predominately induced STAT-3 activation ( XREF_FIG ) .	Consistent with reports that utilized other cell types, IFN-gamma and IFN-lambda2 primarily activated STAT-1 phosphorylation in the MMHD3 cells, while IL-6 and IL-22 predominately induced STAT-3 activation (XREF_FIG).	22	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	22	23	27	28
IL6 levels in MMP-9 -/- mice were sufficient to induce invasive growth and STAT3 activation in PDAC cells via IL6 receptor ( IL6R ) .	IL6 levels in MMP-9 -/- mice were sufficient to induce invasive growth and STAT3 activation in PDAC cells via IL6 receptor (IL6R).	0	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6 levels	il6	STAT3	STAT3	stat3	0	1	13	14
Stat3 induction of proliferative , antimicrobial , and cytoprotective genes by cytokines , such as IL-6 , IL-11 , and IL-22 , is important for maintenance of intestinal homeostasis .	Stat3 induction of proliferative, antimicrobial, and cytoprotective genes by cytokines, such as IL-6, IL-11, and IL-22, is important for maintenance of intestinal homeostasis.	0	20	induction	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	15	16	0	1
IL-6 activates Stat3 , which is essential for formation of Th17 cells and IL-6 and TGF-beta together are required to induce RORgammat , a lineage specific transcriptional factor of Th17 cells .	IL-6 activates Stat3, which is essential for formation of Th17 cells and IL-6 and TGF-beta together are required to induce RORgammat, a lineage specific transcriptional factor of Th17 cells.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	2	3
In addition , STAT3 transcriptional activation by IL-6 was crucial for the Cr ( VI )-induced miR-21 elevation .	In addition, STAT3 transcriptional activation by IL-6 was crucial for the Cr (VI)-induced miR-21 elevation.	3	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	3	4
IL-6 can trigger the activation of STAT3 and has been found to be associated with acquisition of resistance of gastric cancer cells to trastuzumab [ XREF_BIBR ] .	IL-6 can trigger the activation of STAT3 and has been found to be associated with acquisition of resistance of gastric cancer cells to trastuzumab [XREF_BIBR].	0	13	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
Indirect reduction of STAT3 by IL-6 targeting has been shown to decrease survival in GBM stem-cells [ XREF_BIBR ] .	Indirect reduction of STAT3 by IL-6 targeting has been shown to decrease survival in GBM stem-cells [XREF_BIBR].	1	6	reduction	Negative_activation_token_2_noun	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	3	4
Our results indicate that LLL12 blocks constitutive STAT3 and IL-6 induced STAT3 signaling and may be a potential therapeutic agent for MM .	Our results indicate that LLL12 blocks constitutive STAT3 and IL-6 induced STAT3 signaling and may be a potential therapeutic agent for MM.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
IL-6 may induce STAT3 signalling by binding to epithelial cells .	IL-6 may induce STAT3 signalling by binding to epithelial cells.	0	4	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
In Kupffer cells , IL-6 induces transient STAT3 activation and contributes to the pro inflammatory response .	In Kupffer cells, IL-6 induces transient STAT3 activation and contributes to the pro inflammatory response.	4	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	7	8
Similarly , we observed ~ 2.6-fold increase in Stat3 enrichment at miR-23a promoter in Hepa cells treated with IL-6 compared to untreated cells .	Similarly, we observed ~ 2.6-fold increase in Stat3 enrichment at miR-23a promoter in Hepa cells treated with IL-6 compared to untreated cells.	8	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	18	19	8	9
For example , the binding of the proinflammatory cytokine IL-6 to a complex of the IL-6 receptor alpha ( IL-6Ralpha , also known as CD126 ) and IL-6Rbeta ( CD130 ; signal transducing receptor gp130 ) activates the transcription activator STAT3 , resulting in differentiation of naive CD4 + T cells into Th17 cells by inducing the lineage specific transcription factor RORgammat XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	For example, the binding of the proinflammatory cytokine IL-6 to a complex of the IL-6 receptor alpha (IL-6Ralpha, also known as CD126) and IL-6Rbeta (CD130; signal transducing receptor gp130) activates the transcription activator STAT3, resulting in differentiation of naive CD4 + T cells into Th17 cells by inducing the lineage specific transcription factor RORgammat XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	4	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	40	41
IL-6 can stimulate STAT3 activation in epithelial intestinal cells 33 .	IL-6 can stimulate STAT3 activation in epithelial intestinal cells 33.	0	4	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
Furthermore , IL-6 , which is downstream of NF-kappaB and primarily produced by bone marrow derived myeloid cells , activates STAT3 in both inflammatory cells and the epithelial cells from which the tumours arose .	Furthermore, IL-6, which is downstream of NF-kappaB and primarily produced by bone marrow derived myeloid cells, activates STAT3 in both inflammatory cells and the epithelial cells from which the tumours arose.	2	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	20	21
The present study demonstrates that SFN , a promising cancer chemopreventive agent , inhibits both constitutive and IL6 induced activation of STAT3 in human prostate cancer cells regardless of their androgen-responsiveness .	The present study demonstrates that SFN, a promising cancer chemopreventive agent, inhibits both constitutive and IL6 induced activation of STAT3 in human prostate cancer cells regardless of their androgen-responsiveness.	15	26	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	17	18	21	22
These findings are in accordance with previous studies demonstrating that IL-6 treatment can activate p-STAT3 , decrease E-cadherin expression , and increase vimentin expression in other cancer cell lines , such as lung cancer cell lines 33 and breast cancer cell lines .	These findings are in accordance with previous studies demonstrating that IL-6 treatment can activate p-STAT3, decrease E-cadherin expression, and increase vimentin expression in other cancer cell lines, such as lung cancer cell lines 33 and breast cancer cell lines.	10	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	10	11	14	15
Whereas , IL-6 trans-signaling through sIL-6R activates STAT3 leading to inhibition of T-cell apoptosis resulting in persistently high levels of activated T-cells which continue to produce factors like cytokines that contribute to amplifying and sustaining the ongoing mucosal inflammation [ XREF_BIBR ] .	Whereas, IL-6 trans-signaling through sIL-6R activates STAT3 leading to inhibition of T-cell apoptosis resulting in persistently high levels of activated T-cells which continue to produce factors like cytokines that contribute to amplifying and sustaining the ongoing mucosal inflammation [XREF_BIBR].	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	7	8
In metastatic breast cancer cells , IL6 induced STAT3 cooperates with TNF induced NF-kappaB to activate fascin expression [ XREF_BIBR ] .	In metastatic breast cancer cells, IL6 induced STAT3 cooperates with TNF induced NF-kappaB to activate fascin expression [XREF_BIBR].	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	6	7	8	9
By contrast , STAT3 activation by IL-6 in CNE1 cells resulted in up-regulation of miR-21 ( XREF_FIG ) .	By contrast, STAT3 activation by IL-6 in CNE1 cells resulted in up-regulation of miR-21 (XREF_FIG).	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	3	4
By activating STAT3 , IL-6 promotes the growth of metastatic tumors in the brain by upregulating basic fibroblast growth factor , MMP-2 , and VEGF , which contribute to invasion and angiogenesis .	By activating STAT3, IL-6 promotes the growth of metastatic tumors in the brain by upregulating basic fibroblast growth factor, MMP-2, and VEGF, which contribute to invasion and angiogenesis.	1	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	2	3
Moreover , Y705F inhibits the action of endogenous Stat3 in cotransfected cells , reducing IL-6 induction of a Stat3 responsive reporter construct .	Moreover, Y705F inhibits the action of endogenous Stat3 in cotransfected cells, reducing IL-6 induction of a Stat3 responsive reporter construct.	14	21	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	14	15	18	19
Stat3 is activated by a wide range of cytokine and growth factors , such IL-6 and EGF [ XREF_BIBR , XREF_BIBR ] .	Stat3 is activated by a wide range of cytokine and growth factors, such IL-6 and EGF [XREF_BIBR, XREF_BIBR].	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	14	15	0	1
Furthermore , it was demonstrated that STAT3 activation by IL-6 led to prolonged survival of pathogenic T-cells in the lamina propria [ XREF_BIBR ] .	Furthermore, it was demonstrated that STAT3 activation by IL-6 led to prolonged survival of pathogenic T-cells in the lamina propria [XREF_BIBR].	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	6	7
STAT3 activation by IL-6 in INA-6 cells is a physiological way of activating the transcription factor .	STAT3 activation by IL-6 in INA-6 cells is a physiological way of activating the transcription factor.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	0	1
This is consistent with the paradigm that IL-6 itself plays an important and non redundant role in pressure overload induced activation of STAT3 .	This is consistent with the paradigm that IL-6 itself plays an important and non redundant role in pressure overload induced activation of STAT3.	7	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	22	23
Tumor derived IL-6 drives STAT3 nuclear translocation in immature myeloid cells , thus promoting proliferation and inhibiting apoptosis of MDSCs .	Tumor derived IL-6 drives STAT3 nuclear translocation in immature myeloid cells, thus promoting proliferation and inhibiting apoptosis of MDSCs.	2	6	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
Our results suggest that IL-6 and TNF-alpha activate STAT3 and STAT1 on the receptor tyrosine kinase levels , then form the triplet complex with NF-kappaB , subsequently induce cell invasiveness through the converged STAT3 , STAT1 , and NF-kappaB regulations on the target genes in colorectal cancer cells .	Our results suggest that IL-6 and TNF-alpha activate STAT3 and STAT1 on the receptor tyrosine kinase levels, then form the triplet complex with NF-kappaB, subsequently induce cell invasiveness through the converged STAT3, STAT1, and NF-kappaB regulations on the target genes in colorectal cancer cells.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	8	9
A concentration of 40ng/ml IL-6 was able to activate STAT3 and the presence of BCS did not affect STAT3 phosphorylation state in control cells or IL-6 treated cells .	A concentration of 40ng/ml IL-6 was able to activate STAT3 and the presence of BCS did not affect STAT3 phosphorylation state in control cells or IL-6 treated cells.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	9	10
XREF_BIBR , XREF_BIBR Elevated secretion of IL-6 in inflamed peripheral tissues activates STAT3 pathways resulting in the induction of ROR-gammat expression and activation of epigenetic changes that effect heritable competence for sustained expression of hallmark cytokines of the Th17 lineage ( IL-17A , IL-17F and IL-22 ) .	XREF_BIBR, XREF_BIBR Elevated secretion of IL-6 in inflamed peripheral tissues activates STAT3 pathways resulting in the induction of ROR-gammat expression and activation of epigenetic changes that effect heritable competence for sustained expression of hallmark cytokines of the Th17 lineage (IL-17A, IL-17F and IL-22).	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	12	13
The current studies suggest a model whereby STAT3 dependent tumorigenesis is mediated by IL-6 signals from the tumor microenvironment , and indeed , STAT3 activation in human tumors is often observed at the invasive front of tumors adjacent to inflammatory cells ( XREF_FIG ) .	The current studies suggest a model whereby STAT3 dependent tumorigenesis is mediated by IL-6 signals from the tumor microenvironment, and indeed, STAT3 activation in human tumors is often observed at the invasive front of tumors adjacent to inflammatory cells (XREF_FIG).	7	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	7	8
Nonetheless , NF-kappaB , Stat3 , and these three cytokines are interconnected : IL6 activates Stat3 , TNF-alpha and IL-17 activate NF-kappaB , while NF-kappaB and Stat3 control the production of all three cytokines with the exception of TNF-alpha , which is not transactivated by Stat3 .	Nonetheless, NF-kappaB, Stat3, and these three cytokines are interconnected : IL6 activates Stat3, TNF-alpha and IL-17 activate NF-kappaB, while NF-kappaB and Stat3 control the production of all three cytokines with the exception of TNF-alpha, which is not transactivated by Stat3.	13	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	13	14	15	16
As expected , EGF and IL-6 increased STAT3 reporter activity and enhanced the nuclear localization of phosphorylated STAT3 ( pSTAT3 ) ; whereas Cucurbitacin I and AG490 decreased STAT3 reporter activity dose and time-dependently and reduced the localization of pSTAT3 in the nuclei of prostate cancer cells .	As expected, EGF and IL-6 increased STAT3 reporter activity and enhanced the nuclear localization of phosphorylated STAT3 (pSTAT3); whereas Cucurbitacin I and AG490 decreased STAT3 reporter activity dose and time-dependently and reduced the localization of pSTAT3 in the nuclei of prostate cancer cells.	3	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
In these conditions , EGF ( XREF_SUPPLEMENTARY ) and IL-6 ( XREF_SUPPLEMENTARY ) still restored cancer cell proliferation in a STAT3 dependent manner .	In these conditions, EGF (XREF_SUPPLEMENTARY) and IL-6 (XREF_SUPPLEMENTARY) still restored cancer cell proliferation in a STAT3 dependent manner.	4	22	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	20	21
Confirming our prior findings , 4 the frequency of IL-6 activated pSTAT3 + CD4 + T cells at day +30 were significantly increased among those who developed grade II-IV acute GvHD .	Confirming our prior findings, 4 the frequency of IL-6 activated pSTAT3 + CD4 + T cells at day +30 were significantly increased among those who developed grade II-IV acute GvHD.	7	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	9	10	11	12
PPARgamma regulates DNA binding and transactivation of STAT3 , 25 and IL-6 induced STAT3 activation is associated with pro survival responses in glioma cells .	PPARgamma regulates DNA binding and transactivation of STAT3, 25 and IL-6 induced STAT3 activation is associated with pro survival responses in glioma cells.	3	14	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	13	14
As STAT3 is activated by IL-6 , we serum starved HCT116 cells and subsequently treated with IL-6 for 16 hours .	As STAT3 is activated by IL-6, we serum starved HCT116 cells and subsequently treated with IL-6 for 16 hours.	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	1	2
IL-6 and other cytokines such as IL-21 and IL-23 that induce and maintain T H 17 activate STAT3 , a critical transcription factor for T H 17 differentiation and the pathogenesis of autoimmune diseases including RA XREF_BIBR .	IL-6 and other cytokines such as IL-21 and IL-23 that induce and maintain T H 17 activate STAT3, a critical transcription factor for T H 17 differentiation and the pathogenesis of autoimmune diseases including RA XREF_BIBR.	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	17	18
JAK and STAT3 pathway activation , which may be stimulated by the carcinogenetic inflammatory cytokine IL-6 through gp130 , can lead to cell proliferation and antagonize cellular apoptosis [ XREF_BIBR ] .	JAK and STAT3 pathway activation, which may be stimulated by the carcinogenetic inflammatory cytokine IL-6 through gp130, can lead to cell proliferation and antagonize cellular apoptosis [XREF_BIBR].	0	16	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	2	3
The latter often involves the autocrine activation of the gp130 cytokine receptor in HNSCC cells by tumor released cytokines , such as IL-6 , which activates STAT3 independently from the activation status of EGFR .	The latter often involves the autocrine activation of the gp130 cytokine receptor in HNSCC cells by tumor released cytokines, such as IL-6, which activates STAT3 independently from the activation status of EGFR.	18	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	26	27
And STAT3 nuclear accumulation could be stimulated by IL-6 treatment ( XREF_FIG ) .	And STAT3 nuclear accumulation could be stimulated by IL-6 treatment (XREF_FIG).	1	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	1	2
Higher IL-6 expression in turn promoted STAT3 activation in the EGFR independent manner .	Higher IL-6 expression in turn promoted STAT3 activation in the EGFR independent manner.	1	7	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 expression	il-6	STAT3	STAT3	stat3	1	2	6	7
Blockade of IL-6 partially reduced p-STAT3 Y705 , but not p-NF-kB and p65 Ser536 , in DLD-1 and HT-29 cells cultured with TIL derived supernatants .	Blockade of IL-6 partially reduced p-STAT3 Y705, but not p-NF-kB and p65 Ser536, in DLD-1 and HT-29 cells cultured with TIL derived supernatants.	0	6	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	2	3	5	6
Non IL6 family of cytokines thus activate STAT3 either directly or indirectly .	Non IL6 family of cytokines thus activate STAT3 either directly or indirectly.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	7	8
Both IL-6 and IL-22 can induce the Stat3 signaling pathway in epithelial cells upon binding to their receptors .	Both IL-6 and IL-22 can induce the Stat3 signaling pathway in epithelial cells upon binding to their receptors.	0	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	7	8
Interestingly , this enhanced IL-6 and STAT3 response was mediated by overexpression of IL-6 receptor ( IL-6R ) .	Interestingly, this enhanced IL-6 and STAT3 response was mediated by overexpression of IL-6 receptor (IL-6R).	6	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	overexpression of IL-6	il-6	STAT3	STAT3	stat3	13	14	6	7
2 With this model , we previously demonstrated that IL-6 and FN-adhesion collaborated via post-translational alterations of the IL-6 receptor signaling complex to enhance signal transducer and activator of transcription 3 ( STAT3 ) activity and a more malignant phenotype .	2 With this model, we previously demonstrated that IL-6 and FN-adhesion collaborated via post-translational alterations of the IL-6 receptor signaling complex to enhance signal transducer and activator of transcription 3 (STAT3) activity and a more malignant phenotype.	9	33	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	32	33
Furthermore , IL-6 activates the transcription factor NF-kappaB and the STAT3 signal transduction pathway , which in turn regulate the expression of genes controlling cell proliferation and apoptosis in oral cancer .	Furthermore, IL-6 activates the transcription factor NF-kappaB and the STAT3 signal transduction pathway, which in turn regulate the expression of genes controlling cell proliferation and apoptosis in oral cancer.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	10	11
40 In addition , in T-lymphocytes , STAT3 inhibits the proliferative response to IL-2 , 54 whereas IL6 mediated activation of STAT3 inhibits hepatocyte proliferation 55 and growth of carcinoma and myeloid leukemia cells .	40 In addition, in T-lymphocytes, STAT3 inhibits the proliferative response to IL-2, 54 whereas IL6 mediated activation of STAT3 inhibits hepatocyte proliferation 55 and growth of carcinoma and myeloid leukemia cells.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	17	18	21	22
IL-6 activation of Stat3 in tumor cells results in increases in antiapoptotic , pro proliferative , and pro angiogenic genes , as well as suppression of certain proinflammatory genes [ XREF_BIBR ] .	IL-6 activation of Stat3 in tumor cells results in increases in antiapoptotic, pro proliferative, and pro angiogenic genes, as well as suppression of certain proinflammatory genes [XREF_BIBR].	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	3	4
To further strengthen the role of STAT3 in anoikis resistance , IL-6 was used to activate STAT3 .	To further strengthen the role of STAT3 in anoikis resistance, IL-6 was used to activate STAT3.	11	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	16	17
XREF_BIBR STAT3 is predominantly activated by IL-6 and IL-11 cytokines in CRCs .	XREF_BIBR STAT3 is predominantly activated by IL-6 and IL-11 cytokines in CRCs.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	1	2
Specifically , STAT3 induced by IL-6 promotes both B cell proliferation and differentiation into plasma cells .	Specifically, STAT3 induced by IL-6 promotes both B cell proliferation and differentiation into plasma cells.	2	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	2	3
IL-6 mediated STAT3 activation is important for downregulation of IL-2Ralpha to limit Th1 differentiation in an acute viral infection .	IL-6 mediated STAT3 activation is important for downregulation of IL-2Ralpha to limit Th1 differentiation in an acute viral infection.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Having observed significantly enhanced Stat3 phosphorylation in whole tumors in vivo , we next wanted to determine if IL-6 could mediate autocrine activation of Stat3 specifically within 3T3-HER2 tumor cells in vivo .	Having observed significantly enhanced Stat3 phosphorylation in whole tumors in vivo, we next wanted to determine if IL-6 could mediate autocrine activation of Stat3 specifically within 3T3-HER2 tumor cells in vivo.	18	25	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	18	19	24	25
IL-6 can activate STAT3 signaling in cells via two mechanisms .	IL-6 can activate STAT3 signaling in cells via two mechanisms.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
A recent study indicated that Il-6 and Tnfalpha synergistically activate Stat3 and NF-kB to promote colorectal cancer cell growth .	A recent study indicated that Il-6 and Tnfalpha synergistically activate Stat3 and NF-kB to promote colorectal cancer cell growth.	5	12	synergistically activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Il-6	Il-6	Il-6	Stat3	Stat3	Stat3	5	6	10	11
Another case in point is the divergence in the STAT3 activation profiles induced by IL-6 and IL-10 .	Another case in point is the divergence in the STAT3 activation profiles induced by IL-6 and IL-10.	9	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	9	10
In addition , STAT3 transcriptional activation by IL-6 was crucial for the arsenic induced miR-21 increase .	In addition, STAT3 transcriptional activation by IL-6 was crucial for the arsenic induced miR-21 increase.	3	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	3	4
IL-6 activated JAK2 and STAT3 pathways in LNCaP-C3 cells but not in LNCaP-S17 cells .	IL-6 activated JAK2 and STAT3 pathways in LNCaP-C3 cells but not in LNCaP-S17 cells.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Activation of STAT3 by IL-6 and subsequent changes in target gene expression are suppressed by 17beta-estradiol in MCF-7 cells , an effect attributed to the direct interaction between ER and STAT3 that prevents the DNA binding activity of STAT3 [ XREF_BIBR ] .	Activation of STAT3 by IL-6 and subsequent changes in target gene expression are suppressed by 17beta-estradiol in MCF-7 cells, an effect attributed to the direct interaction between ER and STAT3 that prevents the DNA binding activity of STAT3 [XREF_BIBR].	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	2	3
Given that VEGF is an important cytokine secreted by MM cells and BMSCs , that VEGF secretion can stimulate IL-6 secretion , and that IL-6 can activate the JAK2 and STAT3 , PI3K and AKT and ERK1/2 signal pathways to trigger MM cell proliferation and survival XREF_BIBR - XREF_BIBR , XREF_BIBR , the effect of DCZ3301 on VEGF and IL-6 secretion was explored .	Given that VEGF is an important cytokine secreted by MM cells and BMSCs, that VEGF secretion can stimulate IL-6 secretion, and that IL-6 can activate the JAK2 and STAT3, PI3K and AKT and ERK1/2 signal pathways to trigger MM cell proliferation and survival XREF_BIBR - XREF_BIBR, XREF_BIBR, the effect of DCZ3301 on VEGF and IL-6 secretion was explored.	24	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	30	31
Here we show that IL-6 activates at least two distinct STAT3 serine kinase pathways and that an H7 sensitive pathway is dominant over a PD98059 sensitive one in HepG2 cells stimulated with a low concentration of IL-6 .	Here we show that IL-6 activates at least two distinct STAT3 serine kinase pathways and that an H7 sensitive pathway is dominant over a PD98059 sensitive one in HepG2 cells stimulated with a low concentration of IL-6.	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	10	11
Notably , COX-2 has been characterized as an immediate early gene that can be induced by signals associated with infection and inflammation , including the pro inflammatory cytokines IL-1beta and IL-6 , which activate NF-kappaB and STAT3 respectively .	Notably, COX-2 has been characterized as an immediate early gene that can be induced by signals associated with infection and inflammation, including the pro inflammatory cytokines IL-1beta and IL-6, which activate NF-kappaB and STAT3 respectively.	17	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	30	31	36	37
After 30-minute treatment , cells stained positive for pSTAT3 were slightly but not significantly increased in DRG neurons treated with IL-6 alone ( XREF_FIG ) , consistent with our finding of very low expression of IL-6R in DRG neurons ( XREF_SUPPLEMENTARY ) .	After 30-minute treatment, cells stained positive for pSTAT3 were slightly but not significantly increased in DRG neurons treated with IL-6 alone (XREF_FIG), consistent with our finding of very low expression of IL-6R in DRG neurons (XREF_SUPPLEMENTARY).	8	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	20	21	8	9
Both STAT3 and NF-kappaB are involved in gene regulation of inflammation and activated by IL-6 and TNF-alpha .	Both STAT3 and NF-kappaB are involved in gene regulation of inflammation and activated by IL-6 and TNF-alpha.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	1	2
The authors show that IL-6 activates STAT3 in CD5 + B cells in an IL-6 receptor independent manner .	The authors show that IL-6 activates STAT3 in CD5 + B cells in an IL-6 receptor independent manner.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
Next , we investigated JAK1 subcellular distribution in ABC DLBCL cells in which JAK1 and STAT3 are activated by autocrine production of IL-6 and IL-10 .	Next, we investigated JAK1 subcellular distribution in ABC DLBCL cells in which JAK1 and STAT3 are activated by autocrine production of IL-6 and IL-10.	13	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	15	16
Because IL-6 directly activates signal transducer and activator of transcription 3 ( STAT3 ) , the effect of Oligonol on STAT3 signaling was tested by examining the mRNA levels of STAT3 and suppressor of cytokine signaling 3 ( SOCS3 ) .	Because IL-6 directly activates signal transducer and activator of transcription 3 (STAT3), the effect of Oligonol on STAT3 signaling was tested by examining the mRNA levels of STAT3 and suppressor of cytokine signaling 3 (SOCS3).	1	13	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	12	13
For instance , the plasma level of IL-6 is significantly elevated in patients with IBD , and the increased IL-6 activates STAT3 and JAKl signaling , promoting cell proliferation , evolution , and tumorigenic progression [ XREF_BIBR ] ; inhibition of JAKl signaling or IL-6 deficiency by targeted disruption diminishes CRC incidence and progression [ XREF_BIBR , XREF_BIBR ] .	For instance, the plasma level of IL-6 is significantly elevated in patients with IBD, and the increased IL-6 activates STAT3 and JAKl signaling, promoting cell proliferation, evolution, and tumorigenic progression [XREF_BIBR]; inhibition of JAKl signaling or IL-6 deficiency by targeted disruption diminishes CRC incidence and progression [XREF_BIBR, XREF_BIBR].	17	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	21	22
IL-6 and PKCepsilon are reported to be upstream and activate Stat-3 [ XREF_BIBR ] , whereas Akt has been shown to induce NF-kappaB [ XREF_BIBR ] .	IL-6 and PKCepsilon are reported to be upstream and activate Stat-3 [XREF_BIBR], whereas Akt has been shown to induce NF-kappaB [XREF_BIBR].	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat-3	Stat-3	Stat-3	0	1	10	11
Our data indicate that TNF-alpha elicits STAT1 pathway and IL-6 activates STAT3 pathway in terms of receptor tyrosine kinase levels .	Our data indicate that TNF-alpha elicits STAT1 pathway and IL-6 activates STAT3 pathway in terms of receptor tyrosine kinase levels.	7	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
In others , STAT3 is activated by autocrine production of IL-6 44 or through acquired activating mutations XREF_BIBR , XREF_BIBR .	In others, STAT3 is activated by autocrine production of IL-6 44 or through acquired activating mutations XREF_BIBR, XREF_BIBR.	3	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	3	4
The pro inflammatory cytokines IL-6 and G-CSF activate STAT3 through phosphorylation via their respective cognate surface receptors .	The pro inflammatory cytokines IL-6 and G-CSF activate STAT3 through phosphorylation via their respective cognate surface receptors.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	8	9
XREF_BIBR Thus , conditional KO of Stat3 in non lymphoid cells confirmed that the elevated production of IL-7 and expansion of CD4 + cells was dependent on the activation of Stat3 by IL-6 family cytokines .	XREF_BIBR Thus, conditional KO of Stat3 in non lymphoid cells confirmed that the elevated production of IL-7 and expansion of CD4 + cells was dependent on the activation of Stat3 by IL-6 family cytokines.	28	34	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	32	33	30	31
Early on during tumorigenesis , IL-6 is produced primarily by the stromal cells and activates the JAK and STAT3 pathway in neighboring tissue .	Early on during tumorigenesis, IL-6 is produced primarily by the stromal cells and activates the JAK and STAT3 pathway in neighboring tissue.	5	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	18	19
IL-6 is well known to activate STAT3 by phosphorylation at Tyr 705 .	IL-6 is well known to activate STAT3 by phosphorylation at Tyr 705.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
Moreover , DMC suppressed LPS induced IL-6 production , thereby blocking subsequent Stat3 activation .	Moreover, DMC suppressed LPS induced IL-6 production, thereby blocking subsequent Stat3 activation.	2	13	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	DMC suppressed LPS induced IL-6	il-6	Stat3	Stat3	stat3	6	7	12	13
Our observations that STAT3 expression was up-regulated after LPS and IL-6 treatment are consistent with previous studies showing that long-term treatment with IL-6 increases STAT3 protein expression XREF_BIBR .	Our observations that STAT3 expression was up-regulated after LPS and IL-6 treatment are consistent with previous studies showing that long-term treatment with IL-6 increases STAT3 protein expression XREF_BIBR.	20	27	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	24	25
Exposure to quercetin resulted in the reduction of GP130 , JAK1 and STAT3 activation by IL-6 , as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by IL-6 .	Exposure to quercetin resulted in the reduction of GP130, JAK1 and STAT3 activation by IL-6, as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by IL-6.	8	16	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	12	13
However , TNF-alpha-induced SOCS3 expression was significantly reduced by the presence of gp130 specific antibodies ( XREF_FIG ) , indicating that TNF-alpha-induced SOCS3 expression is at least partially mediated by gp130 , further suggesting that IL-6 activated STAT3 signals through gp130 and is responsible for the majority of SOCS3 expression .	However, TNF-alpha-induced SOCS3 expression was significantly reduced by the presence of gp130 specific antibodies (XREF_FIG), indicating that TNF-alpha-induced SOCS3 expression is at least partially mediated by gp130, further suggesting that IL-6 activated STAT3 signals through gp130 and is responsible for the majority of SOCS3 expression.	35	43	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	35	36	37	38
While it is well established that IL-6 activates STAT3 in macrophages , we have previously shown that IL-6 also stimulates phosphorylation of STAT1 , a key transcription factor for several antiviral interferon stimulated genes ( ISGs ) .	While it is well established that IL-6 activates STAT3 in macrophages, we have previously shown that IL-6 also stimulates phosphorylation of STAT1, a key transcription factor for several antiviral interferon stimulated genes (ISGs).	6	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
Collectively , these data provide genetic evidence that gp130 dependent STAT3 hyperactivation during hematopoiesis has pathological consequences affecting multiple organs , and therefore identify the threshold of STAT3 signaling elicited by IL-6 family cytokines as a critical determinant for hematopoietic homeostasis .	Collectively, these data provide genetic evidence that gp130 dependent STAT3 hyperactivation during hematopoiesis has pathological consequences affecting multiple organs, and therefore identify the threshold of STAT3 signaling elicited by IL-6 family cytokines as a critical determinant for hematopoietic homeostasis.	27	33	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	31	32	27	28
Moreover , LMP1 expression upregulates IL-6 production XREF_BIBR , XREF_BIBR , which activates STAT3 signaling to establish a positive feedback loop of STAT3/LMP1/IL-6/STAT3 activatioin to amplify STAT3 signaling in EBV infected NPC cells XREF_BIBR .	Moreover, LMP1 expression upregulates IL-6 production XREF_BIBR, XREF_BIBR, which activates STAT3 signaling to establish a positive feedback loop of STAT3/LMP1/IL-6/STAT3 activatioin to amplify STAT3 signaling in EBV infected NPC cells XREF_BIBR.	5	14	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	13	14
Altogether , these data indicate that APRF belongs to a growing family of Stat related proteins and that IFN-gamma and IL-6 use similar signaling pathways to activate IFN-gamma activation factor and APRF , respectively .	Altogether, these data indicate that APRF belongs to a growing family of Stat related proteins and that IFN-gamma and IL-6 use similar signaling pathways to activate IFN-gamma activation factor and APRF, respectively.	18	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	APRF	APRF	APRF	20	21	31	32
IL6 can activate both STAT1 and STAT3 , although this appears to be tissue and context specific [ XREF_BIBR ] .	IL6 can activate both STAT1 and STAT3, although this appears to be tissue and context specific [XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	6	7
Conversely , expression of constitutively active IKKbeta ( IKKbeta EE ) in Ikkbeta Delta dih cells inhibited IL-6 induced STAT3 activation ( XREF_SUPPLEMENTARY ) .	Conversely, expression of constitutively active IKKbeta (IKKbeta EE) in Ikkbeta Delta dih cells inhibited IL-6 induced STAT3 activation (XREF_SUPPLEMENTARY).	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	19	20
Although IL-21-induced STAT3 activation is involved in the development of Th17 cells via the induction of RORgammat , IL-6 alone might induce sufficient levels of STAT3 activation .	Although IL-21-induced STAT3 activation is involved in the development of Th17 cells via the induction of RORgammat, IL-6 alone might induce sufficient levels of STAT3 activation.	18	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	25	26
We demonstrate that IL-6 induction of STAT3 signaling occurred exclusively in the nuclei of SCs in response to MLC .	We demonstrate that IL-6 induction of STAT3 signaling occurred exclusively in the nuclei of SCs in response to MLC.	3	7	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	6	7
Accordingly , transient Stat3 activation by IL6 in wild-type macrophages promotes an inflammatory response , while sustained Stat3 activation by IL6 of gp130 Y757F mutant macrophages suppresses the inflammatory gene response through the induction of transcriptional repressors [ XREF_BIBR , XREF_BIBR ] .	Accordingly, transient Stat3 activation by IL6 in wild-type macrophages promotes an inflammatory response, while sustained Stat3 activation by IL6 of gp130 Y757F mutant macrophages suppresses the inflammatory gene response through the induction of transcriptional repressors [XREF_BIBR, XREF_BIBR].	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	6	7	3	4
The concentration of IL-6 used for this screen , 50 ng/mL , was selected to produce a maximal activation of STAT3 without an excess of IL-6 .	The concentration of IL-6 used for this screen, 50 ng/mL, was selected to produce a maximal activation of STAT3 without an excess of IL-6.	1	21	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	20	21
As IL6 is a potent activator of STAT3 , 40 recombinant mouse IL6 ( rIL6 ) was injected in the tail of D7 PDL pancreas , in order to evaluate the effect of increased STAT3 activation on beta-cell proliferation .	As IL6 is a potent activator of STAT3, 40 recombinant mouse IL6 (rIL6) was injected in the tail of D7 PDL pancreas, in order to evaluate the effect of increased STAT3 activation on beta-cell proliferation.	1	8	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	7	8
To examine whether IL-6 activates STAT3 in SAIDS-NHL as it does in other target cells [ XREF_BIBR ] , LCL8664 cells were treated with IL-6 , TGF-beta1 or a combination of the two cytokines for time periods ranging from 0 to 60 minutes .	To examine whether IL-6 activates STAT3 in SAIDS-NHL as it does in other target cells [XREF_BIBR], LCL8664 cells were treated with IL-6, TGF-beta1 or a combination of the two cytokines for time periods ranging from 0 to 60 minutes.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
STAT3 is activated by IL-6 and related cytokines , and is required for the stimulation of liver regeneration after partial hepatectomy , toxic damage or inflammation induced injury 101 because it induces genes with products that maintain cell survival and promote proliferation 102 .	STAT3 is activated by IL-6 and related cytokines, and is required for the stimulation of liver regeneration after partial hepatectomy, toxic damage or inflammation induced injury 101 because it induces genes with products that maintain cell survival and promote proliferation 102.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
Continuous addition of IL-6 to these cells induces transient activation of STAT3 , SHP-2 phosphorylation , and does not alter bcl-X ( L ) and c-myc expression .	Continuous addition of IL-6 to these cells induces transient activation of STAT3, SHP-2 phosphorylation, and does not alter bcl-X (L) and c-myc expression.	1	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	11	12
On the other hand , with a feedback mechanism , IL-6 increases the STAT3 signaling inhibitor protein SOCS3 , which induces the proteasomal degradation of IDO1 [ XREF_BIBR ] .	On the other hand, with a feedback mechanism, IL-6 increases the STAT3 signaling inhibitor protein SOCS3, which induces the proteasomal degradation of IDO1 [XREF_BIBR].	10	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	13	14
Specifically , and consistent with the effects of HF of Stat3 activation in naive CD4 T cells treated with TGFbeta plus IL-6 , HF treatment reduced the levels of sustained phosho-Stat3 in cells treated with IL-6 or IL-27 alone ( e.g ., 12-24 hours after adding ligand ) , without affecting Stat3 phosphorylation within the first 2 hours of adding ligand ( XREF_FIG ) .	Specifically, and consistent with the effects of HF of Stat3 activation in naive CD4 T cells treated with TGFbeta plus IL-6, HF treatment reduced the levels of sustained phosho-Stat3 in cells treated with IL-6 or IL-27 alone (e.g., 12-24 hours after adding ligand), without affecting Stat3 phosphorylation within the first 2 hours of adding ligand (XREF_FIG).	10	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	21	22	10	11
Finally , we determined the role of HIF1 signaling in IL6 mediated STAT3 regulated gene expression .	Finally, we determined the role of HIF1 signaling in IL6 mediated STAT3 regulated gene expression.	3	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	10	11	12	13
In conclusion , we demonstrated that HG stimulated podocytes produced and secreted IL6 , which activated the JAK2 and STAT3 pathway via autocrine or paracrine mechanisms and participated in the process of cellular hypertrophy invitro .	In conclusion, we demonstrated that HG stimulated podocytes produced and secreted IL6, which activated the JAK2 and STAT3 pathway via autocrine or paracrine mechanisms and participated in the process of cellular hypertrophy invitro.	9	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	12	13	19	20
We also examined pSTAT5 at day 5 of culture in control or STAT3 deficient Th9 cells treated with or without IL-6 or IL-21 to determine if the decrease in pSTAT5 induced by these cytokines was STAT3 dependent .	We also examined pSTAT5 at day 5 of culture in control or STAT3 deficient Th9 cells treated with or without IL-6 or IL-21 to determine if the decrease in pSTAT5 induced by these cytokines was STAT3 dependent.	10	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	12	13
We hypothesize that flagellin and IL-6 activate STAT3 through disparate signaling pathways .	We hypothesize that flagellin and IL-6 activate STAT3 through disparate signaling pathways.	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines .	IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
This is a question relevant to many biological systems and the fact that IL-6 and IL-27 both prominently activate STAT1 and STAT3 but have profoundly different effects on Th17 and Treg cells provides a system to dissect how apparently similar signals provide distinct functions .	This is a question relevant to many biological systems and the fact that IL-6 and IL-27 both prominently activate STAT1 and STAT3 but have profoundly different effects on Th17 and Treg cells provides a system to dissect how apparently similar signals provide distinct functions.	13	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	21	22
Indeed , IL-27 is a weak inducer of STAT3 and a much better inducer of STAT1 , whereas sIL-6R and IL-6 is a strong inducer of STAT3 .	Indeed, IL-27 is a weak inducer of STAT3 and a much better inducer of STAT1, whereas sIL-6R and IL-6 is a strong inducer of STAT3.	18	27	is a strong inducer	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	26	27
Conversely , low levels of miR-204 in cSCC would favour STAT3 pathway activation , which is also mediated by IL6 [ XREF_BIBR ] .	Conversely, low levels of miR-204 in cSCC would favour STAT3 pathway activation, which is also mediated by IL6 [XREF_BIBR].	10	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	19	20	10	11
Two distinct PPAR-gamma ligands suppress IL-6 activated STAT3 through various types of crosstalk including direct or mediated by the corepressor SMRT ( silencing mediator of retinoid and thyroid hormone receptor ) .	Two distinct PPAR-gamma ligands suppress IL-6 activated STAT3 through various types of crosstalk including direct or mediated by the corepressor SMRT (silencing mediator of retinoid and thyroid hormone receptor).	5	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
Finally , treatment with IL-6 induces STAT3 activation in hepatic lymphocytes and hepatic T cells , and blocking such activation abolishes the inhibitory effect of IL-6 on hepatic lymphocytes to restore liver injury .	Finally, treatment with IL-6 induces STAT3 activation in hepatic lymphocytes and hepatic T cells, and blocking such activation abolishes the inhibitory effect of IL-6 on hepatic lymphocytes to restore liver injury.	2	7	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
Most remarkably , LMP1 , through NFkappaB activation and IL6 expression activated STAT3 in NPC and HeLa cells .	Most remarkably, LMP1, through NFkappaB activation and IL6 expression activated STAT3 in NPC and HeLa cells.	9	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL6	IL6 expression	il6	STAT3	STAT3	stat3	9	10	12	13
These suppressive effects seemed to be ascribed to antagonizing the activation of STAT1 and STAT3 pathways induced by IL-27 and IL-6 , both of which signal through the gp130 receptor .	These suppressive effects seemed to be ascribed to antagonizing the activation of STAT1 and STAT3 pathways induced by IL-27 and IL-6, both of which signal through the gp130 receptor.	12	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	14	15
Previously , we have demonstrated that IL-6 can activate STAT3 in sinusoidal endothelial cells and such activation likely contributes to the hepatoprotective effect of IL-6 in fatty liver transplantation .	Previously, we have demonstrated that IL-6 can activate STAT3 in sinusoidal endothelial cells and such activation likely contributes to the hepatoprotective effect of IL-6 in fatty liver transplantation.	6	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	9	10
Cytokines secreted by the activated tumor stroma modulate tumor growth and regulate their survival and invasiveness through activation of oncogenic signaling pathways in tumor cells , examples being activation of NF-kappaB by TNFalpha and IL-1beta , and activation of STAT3 by IL-6 XREF_BIBR , XREF_BIBR .	Cytokines secreted by the activated tumor stroma modulate tumor growth and regulate their survival and invasiveness through activation of oncogenic signaling pathways in tumor cells, examples being activation of NF-kappaB by TNFalpha and IL-1beta, and activation of STAT3 by IL-6 XREF_BIBR, XREF_BIBR.	37	42	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	41	42	39	40
IL-6 is known to activate STAT3 and thereby activates proliferative and antiapoptotic pathways [ XREF_BIBR ] .	IL-6 is known to activate STAT3 and thereby activates proliferative and antiapoptotic pathways [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Moreover , the stimulation of IL-6 indeed enhanced only STAT3 in CC .	Moreover, the stimulation of IL-6 indeed enhanced only STAT3 in CC.	3	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	9	10
As reported previously , STAT3 can be activated by the cytockine IL-6 via JAK2 signaling [ XREF_BIBR , XREF_BIBR ] .	As reported previously, STAT3 can be activated by the cytockine IL-6 via JAK2 signaling [XREF_BIBR, XREF_BIBR].	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	4	5
For example , IL1beta induces the activation of MyD88 [ XREF_BIBR ] , and IFNgamma , IL-4 , and IL-6 activate STAT1 , STAT6 , and STAT3 , respectively , in hCMEC/D3 cells [ XREF_BIBR ] .	For example, IL1beta induces the activation of MyD88 [XREF_BIBR], and IFNgamma, IL-4, and IL-6 activate STAT1, STAT6, and STAT3, respectively, in hCMEC/D3 cells [XREF_BIBR].	8	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	26	27
Collectively , these studies suggest that TLR4 activation by a high dose of LPS in precursor cells induces GM-CSF and IL-6 production causing STAT5 and STAT3 activation respectively , which can support the development and function of MDSCs .	Collectively, these studies suggest that TLR4 activation by a high dose of LPS in precursor cells induces GM-CSF and IL-6 production causing STAT5 and STAT3 activation respectively, which can support the development and function of MDSCs.	18	26	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	25	26
Given that STAT3 is activated by inflammatory cytokine IL-6 , which could be induced after NF-kappaB activation via Lin28B and Let-7 [ XREF_BIBR ] , a positive feedback loop was established linking inflammation to tumorigenesis .	Given that STAT3 is activated by inflammatory cytokine IL-6, which could be induced after NF-kappaB activation via Lin28B and Let-7 [XREF_BIBR], a positive feedback loop was established linking inflammation to tumorigenesis.	2	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	2	3
However , since the level of Stat3 activation induced by PE is approximately half of that induced by IL-6 ( XREF_FIG ) , it is not surprising that combinational utilization of PE and IL-6 may cause less Stat3 activation than treatment with IL-6 alone , as described by Nguyen and Gao in their study .	However, since the level of Stat3 activation induced by PE is approximately half of that induced by IL-6 (XREF_FIG), it is not surprising that combinational utilization of PE and IL-6 may cause less Stat3 activation than treatment with IL-6 alone, as described by Nguyen and Gao in their study.	29	38	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	33	34	37	38
In human IBD and murine IBD models the transcription factor STAT3 is activated in epithelial cells by interleukin 22 , IL-6 and IL-10 and contributes substantially to wound healing and epithelial regeneration .	In human IBD and murine IBD models the transcription factor STAT3 is activated in epithelial cells by interleukin 22, IL-6 and IL-10 and contributes substantially to wound healing and epithelial regeneration.	7	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	10	11
Moreover , ChIP assay revealed that STAT3 was recruited to the promoter region of the Lcn2 gene upon activation of STAT3 by IL-6 ( XREF_FIG ) .	Moreover, ChIP assay revealed that STAT3 was recruited to the promoter region of the Lcn2 gene upon activation of STAT3 by IL-6 (XREF_FIG).	8	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	20	21
XREF_BIBR , XREF_BIBR Our results suggest that in IL-6 mediated STAT3 nuclear translocation , tyrosine phosphorylation is essential for its binding to myoferlin and subsequent translocation to nucleus .	XREF_BIBR, XREF_BIBR Our results suggest that in IL-6 mediated STAT3 nuclear translocation, tyrosine phosphorylation is essential for its binding to myoferlin and subsequent translocation to nucleus.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
IL-6 activates STAT3 and directly stimulates proliferation and migration of the benign noninvasive HaCaT-ras A-5 cells in vitro .	IL-6 activates STAT3 and directly stimulates proliferation and migration of the benign noninvasive HaCaT-ras A-5 cells in vitro.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
In this study , EPN tumor cells were shown to release IL6 , which activated myeloid cell STAT3 in a paracrine fashion .	In this study, EPN tumor cells were shown to release IL6, which activated myeloid cell STAT3 in a paracrine fashion.	10	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	11	12	17	18
IL-6 induced STAT3 activity is gaining attention in the role it plays in tumor initiating cells , cells that do not express the membrane bound IL-6 receptor and would therefore depend on IL-6 trans-signaling through the sIL-6R .	IL-6 induced STAT3 activity is gaining attention in the role it plays in tumor initiating cells, cells that do n't express the membrane bound IL-6 receptor and would therefore depend on IL-6 trans-signaling through the sIL-6R.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
IL-6 induces transient activation of STAT3 whereas IL-10 elicits a more sustained STAT3 response and this difference in activation kinetics was shown to be sufficient to account for the distinct biological outcomes of these two cytokines .	IL-6 induces transient activation of STAT3 whereas IL-10 elicits a more sustained STAT3 response and this difference in activation kinetics was shown to be sufficient to account for the distinct biological outcomes of these two cytokines.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
This study aimed to test whether overexpression of IL-6 and constitutive activation of Stat3 in prostate cancer cells increase resistance to enzalutamide .	This study aimed to test whether overexpression of IL-6 and constitutive activation of Stat3 in prostate cancer cells increase resistance to enzalutamide.	6	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	overexpression of IL-6	il-6	Stat3	Stat3	stat3	8	9	13	14
In addition to propagation of steatohepatitis , IL-6 leads to STAT3 activation in hepatocytes and STAT3 can stimulate the proliferation and progression of initiated hepatocytes ( He et al ., submitted ) and thus could be a molecular mediator of tumor promotion .	In addition to propagation of steatohepatitis, IL-6 leads to STAT3 activation in hepatocytes and STAT3 can stimulate the proliferation and progression of initiated hepatocytes (He et al., submitted) and thus could be a molecular mediator of tumor promotion.	7	11	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	10	11
Based on the facts that sustained NICD1 signals stimulate Il6 expression and that IL-6 can activate STAT3 in chondrogenic cells , we predicted that STAT3 signaling would be elevated in NICD1 GOF chondrocytes .	Based on the facts that sustained NICD1 signals stimulate Il6 expression and that IL-6 can activate STAT3 in chondrogenic cells, we predicted that STAT3 signaling would be elevated in NICD1 GOF chondrocytes.	13	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	16	17
XREF_BIBR In breast cancer , IL-6 activates the STAT3 pathway and its target genes , such as TGF-beta1 and HIF-1alpha , to increase the proportion of CD44 +/CD24- cancer stem like cells during chemotherapy induced apoptosis .	XREF_BIBR In breast cancer, IL-6 activates the STAT3 pathway and its target genes, such as TGF-beta1 and HIF-1alpha, to increase the proportion of CD44 +/CD24- cancer stem like cells during chemotherapy induced apoptosis.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	8	9
Only IL-6 and OSM stimulated strong pY705 Stat3 and cell proliferation in both normal and keloid fibroblasts .	Only IL-6 and OSM stimulated strong pY705 Stat3 and cell proliferation in both normal and keloid fibroblasts.	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	7	8
This could be due to one of several major possibilities : First , this could reflect that IL-6 is required at much lower concentrations to activate p-STAT3 in MCF-10A cells , and therefore , we were probably unable to completely block all of the IL-6 from the MDA-MB-231 cells ' conditioned media using neutralizing IL-6 antibody .	This could be due to one of several major possibilities : First, this could reflect that IL-6 is required at much lower concentrations to activate p-STAT3 in MCF-10A cells, and therefore, we were probably unable to completely block all of the IL-6 from the MDA-MB-231 cells ' conditioned media using neutralizing IL-6 antibody.	17	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	17	18	26	27
IL-17A , IL-22 , TNF-alpha and IL-6 activate STAT3 and NF-kB and contribute to the TIL derived culture supernatant mediated CRC cell proliferation .	IL-17A, IL-22, TNF-alpha and IL-6 activate STAT3 and NF-kB and contribute to the TIL derived culture supernatant mediated CRC cell proliferation.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
INA-6 cells are strictly dependent on exogenous IL-6 , which activates STAT3 in these cells .	INA-6 cells are strictly dependent on exogenous IL-6, which activates STAT3 in these cells.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	11	12
In contrast , IL6 was required to induce luciferase activity in WT STAT3 containing cells ( XREF_SUPPLEMENTARY ) .	In contrast, IL6 was required to induce luciferase activity in WT STAT3 containing cells (XREF_SUPPLEMENTARY).	3	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	3	4	12	13
IL-6 stimulated reactive oxygen species , arginase 1 and p-STAT3 in MDSCs .	IL-6 stimulated reactive oxygen species, arginase 1 and p-STAT3 in MDSCs.	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	0	1	9	10
Using in vitro cell cultures , we demonstrated that IL-6 stimulated STAT3 and extracellular regulated kinase ( ERK ) activity in both HCC cells and isolated hepatocytes .	Using in vitro cell cultures, we demonstrated that IL-6 stimulated STAT3 and extracellular regulated kinase (ERK) activity in both HCC cells and isolated hepatocytes.	9	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
Importantly , injection of recombinant IL-6 alone was sufficient to induce the pSTAT3 pathway in vivo ( data not shown ) , and a single dose of IL-6 rescued antiviral immunity in TLR2 -/- mice as measured by viral gene expression 7 days after infection ( XREF_FIG ) .	Importantly, injection of recombinant IL-6 alone was sufficient to induce the pSTAT3 pathway in vivo (data not shown), and a single dose of IL-6 rescued antiviral immunity in TLR2 -/- mice as measured by viral gene expression 7 days after infection (XREF_FIG).	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	5	6	12	13
To understand how STAT3 may become activated by HBV infection , we first measured the concentration of IL-6 -- a well-known cytokine inducer of STAT3 signaling -- in HBV infected PHH cultures prepared from 3 different donors .	To understand how STAT3 may become activated by HBV infection, we first measured the concentration of IL-6 -- a well-known cytokine inducer of STAT3 signaling -- in HBV infected PHH cultures prepared from 3 different donors.	15	32	inducer	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	24	25
Whether IL-6 signaling in the tumor microenvironment is autocrine mediated from carcinoma cells or paracrine mediated from stromal cells , such as fibroblasts , activated immune cells or endothelial cells , we have previously shown that sustained IL-6 signaling constitutively activates STAT3 in human breast cancer cells .	Whether IL-6 signaling in the tumor microenvironment is autocrine mediated from carcinoma cells or paracrine mediated from stromal cells, such as fibroblasts, activated immune cells or endothelial cells, we have previously shown that sustained IL-6 signaling constitutively activates STAT3 in human breast cancer cells.	37	46	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	37	38	41	42
Examples include IL-6 , IL-21 , and IL-27 , the latter of which activates STAT1 and STAT3 strongly and with comparable potency in many cell types .	Examples include IL-6, IL-21, and IL-27, the latter of which activates STAT1 and STAT3 strongly and with comparable potency in many cell types.	2	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	16	17
SFN has been shown to inhibit the interleukin-6 ( IL-6 )-inducible activation of STAT3 , which is an oncogenic transcription factor activated in many human malignancies , including prostate cancer [ XREF_BIBR ] .	SFN has been shown to inhibit the interleukin-6 (IL-6)-inducible activation of STAT3, which is an oncogenic transcription factor activated in many human malignancies, including prostate cancer [XREF_BIBR].	9	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	13	14
The results confirmed that IL-6 can stimulate Stat3 activation in Il6ra -/- CD5 + B cells , but not in Il6ra -/- CD5 - B cells ( XREF_FIG ) .	The results confirmed that IL-6 can stimulate Stat3 activation in Il6ra -/- CD5 + B cells, but not in Il6ra -/- CD5 - B cells (XREF_FIG).	4	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	7	8
In addition to its role in the positive feedback loop , IL6 activates STAT3 , a transcription factor that is critical for transformation .	In addition to its role in the positive feedback loop, IL6 activates STAT3, a transcription factor that is critical for transformation.	11	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	11	12	13	14
IL-6 , which is a proinflammatory cytokine that preferentially activates STAT3 , has been well recognized for its role in initiating and amplifying inflammatory processes .	IL-6, which is a proinflammatory cytokine that preferentially activates STAT3, has been well recognized for its role in initiating and amplifying inflammatory processes.	0	15	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	10	11
More recently , IL-6 transsignaling dependent activation of STAT3 and Socs3 was found to be required for promoting PanIN progression and pancreatic ductal adenocarcinoma ( PDAC ) .	More recently, IL-6 transsignaling dependent activation of STAT3 and Socs3 was found to be required for promoting PanIN progression and pancreatic ductal adenocarcinoma (PDAC).	3	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	8	9
JAK2 and STAT3 signaling is activated by IL-6 secreted from ASCs in ovarian cancer cells .	JAK2 and STAT3 signaling is activated by IL-6 secreted from ASCs in ovarian cancer cells.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	2	3
These observations collectively raise the critical question of how Stat3 remains persistently activated in cancer , especially in tumor cells in which Stat3 activation is mainly driven by IL-6 and in tumor stromal non transformed cells such as myeloid cells , where IL-6-induced Stat3 activation plays a critical role for tumor initiation and progression .	These observations collectively raise the critical question of how Stat3 remains persistently activated in cancer, especially in tumor cells in which Stat3 activation is mainly driven by IL-6 and in tumor stromal non transformed cells such as myeloid cells, where IL-6-induced Stat3 activation plays a critical role for tumor initiation and progression.	22	29	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	28	29	22	23
Importantly , while IL-6 stimulation increased pSTAT3 in WT mice by ~ 6-fold , in mKO mice there was no induction of pSTAT3 ( XREF_FIG D ) .	Importantly, while IL-6 stimulation increased pSTAT3 in WT mice by ~ 6-fold, in mKO mice there was no induction of pSTAT3 (XREF_FIG D).	3	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	3	4	6	7
Stat1 and Stat3 activated by NF-kappaB-dependent interleukin-6 ( IL-6 ) expression or by interferon-gamma ( IFN-gamma ) have been implicated in inflammation [ XREF_BIBR , XREF_BIBR ] .	Stat1 and Stat3 activated by NF-kappaB-dependent interleukin-6 (IL-6) expression or by interferon-gamma (IFN-gamma) have been implicated in inflammation [XREF_BIBR, XREF_BIBR].	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6 (IL-6) expression	interleukin-6	Stat3	Stat3	stat3	6	7	2	3
Treatment with a single preoperative dose of IL-6 restored STAT3 binding and hepatocyte proliferation and prevented liver damage in IL-6-deficient mice XREF_BIBR .	Treatment with a single preoperative dose of IL-6 restored STAT3 binding and hepatocyte proliferation and prevented liver damage in IL-6-deficient mice XREF_BIBR.	5	10	restored	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
In this study , we found that exogenous IL-6 treatment could stimulate STAT3 activity in NSCLC cells via activation of JAK ( but not JAK2 ) .	In this study, we found that exogenous IL-6 treatment could stimulate STAT3 activity in NSCLC cells via activation of JAK (but not JAK2).	8	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	12	13
Thus , the physiological activation of STAT3 by IL-6 is sensitive to high concentrations of JAK2 inhibitors whereas gp130 mutants appear to signal to STAT3 in a JAK2 independent fashion .	Thus, the physiological activation of STAT3 by IL-6 is sensitive to high concentrations of JAK2 inhibitors whereas gp130 mutants appear to signal to STAT3 in a JAK2 independent fashion.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	6	7
The differentiation of Th17 cells is initiated by TGF-beta , IL-6 , and IL-21 , which activate STAT3 and induce the expression of transcription factors , including retinoic acid related orphan receptor ( RORgamma t ) .	The differentiation of Th17 cells is initiated by TGF-beta, IL-6, and IL-21, which activate STAT3 and induce the expression of transcription factors, including retinoic acid related orphan receptor (RORgamma t).	6	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	17	18
found that intrathecal administration of IL-6 rapidly activated JAK and STAT3 signaling pathway in the spinal dorsal horn and elevated mechanical allodynia in rats .	found that intrathecal administration of IL-6 rapidly activated JAK and STAT3 signaling pathway in the spinal dorsal horn and elevated mechanical allodynia in rats.	3	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	10	11
Importantly , we found STAT3 activation by IL-6 was required for the suppression of LPS induced DC maturation .	Importantly, we found STAT3 activation by IL-6 was required for the suppression of LPS induced DC maturation.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	4	5
As shown in XREF_FIG , STAT3 , ERK1/2 and p38 phosphorylation was upregulated while being treated with IL-6 ( 100 ng/ml ) .	As shown in XREF_FIG, STAT3, ERK1/2 and p38 phosphorylation was upregulated while being treated with IL-6 (100 ng/ml).	5	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	5	6
In this study , we observed IL-6 induced a much more robust STAT3 activation in EBV infected NPE cells than uninfected cells ( XREF_FIG ) .	In this study, we observed IL-6 induced a much more robust STAT3 activation in EBV infected NPE cells than uninfected cells (XREF_FIG).	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	12	13
Our data revealed that inhibition of IL-6 attenuated STAT3 activation associated with increased E-cadherin and decreased VEGF and MMP-9 expressions .	Our data revealed that inhibition of IL-6 attenuated STAT3 activation associated with increased E-cadherin and decreased VEGF and MMP-9 expressions.	4	9	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
As shown in Figure XREF_FIG c-d , inhibition of IL-6 increased cell death and DNA damage and attenuated STAT3 activation after irradiation .	As shown in Figure XREF_FIG c-d, inhibition of IL-6 increased cell death and DNA damage and attenuated STAT3 activation after irradiation.	7	19	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	18	19
XREF_BIBR Muscle STAT3 activation by IL-6 is a common feature of cancer associated muscle wasting .	XREF_BIBR Muscle STAT3 activation by IL-6 is a common feature of cancer associated muscle wasting.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	2	3
Beyond IL-6 activating STAT3 through IL-6R and JAKs , the CMT treated patients showed upregulation of plasma levels of VEGF , which activates STAT3 through VEGFR1/2 tyrosine kinase domains [ XREF_BIBR - XREF_BIBR ] .	Beyond IL-6 activating STAT3 through IL-6R and JAKs, the CMT treated patients showed upregulation of plasma levels of VEGF, which activates STAT3 through VEGFR1/2 tyrosine kinase domains [XREF_BIBR - XREF_BIBR].	0	13	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	3	4
Unexpected , When we examined whether up-regulation of STAT3 by IL-6 could contribute to an increase in beta-Catenin-mediated transcriptional activity , we got negative results ( XREF_FIG ) .	Unexpected, When we examined whether up-regulation of STAT3 by IL-6 could contribute to an increase in beta-Catenin-mediated transcriptional activity, we got negative results (XREF_FIG).	6	11	up-regulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	8	9
Significantly , stable over expression of RKIP attenuates , while ablation of RKIP enhances , IL-6 mediated STAT3 activation ( XREF_FIG ) .	Significantly, stable over expression of RKIP attenuates, while ablation of RKIP enhances, IL-6 mediated STAT3 activation (XREF_FIG).	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	17	18
The induction of pSTAT3 by IL-6 was lost in EMT-hSAECs under all inhibitor conditions ( XREF_FIG ) , suggesting a general defect in the IL-6 signaling pathways following EMT .	The induction of pSTAT3 by IL-6 was lost in EMT-hSAECs under all inhibitor conditions (XREF_FIG), suggesting a general defect in the IL-6 signaling pathways following EMT.	1	6	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	5	6	3	4
As reported in other cell types , IL-6 and the anti-inflammatory cytokine IL-10 induce the activation of the STAT3 signaling pathway , which is implicated in cell proliferation and survival [ XREF_BIBR ] .	As reported in other cell types, IL-6 and the anti-inflammatory cytokine IL-10 induce the activation of the STAT3 signaling pathway, which is implicated in cell proliferation and survival [XREF_BIBR].	7	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	18	19
Studies indicate that elevated interleukin-6 ( IL-6 ) levels engage IL6Ralpha-gp130 receptor complexes to activate signal transducer and activator of transcription 3 ( STAT3 ) that is hyperactivated in many cancers including head and neck squamous cell carcinoma ( HNSCC ) .	Studies indicate that elevated interleukin-6 (IL-6) levels engage IL6Ralpha-gp130 receptor complexes to activate signal transducer and activator of transcription 3 (STAT3) that is hyperactivated in many cancers including head and neck squamous cell carcinoma (HNSCC).	3	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6 (IL-6) levels	interleukin-6	STAT3	STAT3	stat3	4	5	23	24
However , IL-6 stimulation induced the formation of STAT3 dimer as a megacomplex form whose molecular weight was more than 1MDa at the cytoplasm and a very slow diffusion complex in the nucleus .	However, IL-6 stimulation induced the formation of STAT3 dimer as a megacomplex form whose molecular weight was more than 1MDa at the cytoplasm and a very slow diffusion complex in the nucleus.	2	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
Consistently , LPS and IL-6 together enhanced both the wild-type and R382Q mutated STAT3 AGG-element dependent transcription activity .	Consistently, LPS and IL-6 together enhanced both the wild-type and R382Q mutated STAT3 AGG-element dependent transcription activity.	2	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	13	14
For example NF-kappaB promotes an inflammatory response through secretion of TNFalpha , IL1beta , and IL6 , of which IL6 triggers STAT3 activation .	For example NF-kappaB promotes an inflammatory response through secretion of TNFalpha, IL1beta, and IL6, of which IL6 triggers STAT3 activation.	8	22	triggers	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	15	16	21	22
STAT3 can be activated by IL-6 and IL-23 , and regulates the expression of RORgammaT , as STAT3 deficiency impairs RORgammaT expression and leads to elevated expressions of T-bet and Foxp3 [ XREF_BIBR ] .	STAT3 can be activated by IL-6 and IL-23, and regulates the expression of RORgammaT, as STAT3 deficiency impairs RORgammaT expression and leads to elevated expressions of T-bet and Foxp3 [XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
Previous studies have suggested that STAT3 is primarily activated in autocrine fashion by the interleukin-6 ( IL-6 ) family of cytokines in NSCLC XREF_BIBR , XREF_BIBR .	Previous studies have suggested that STAT3 is primarily activated in autocrine fashion by the interleukin-6 (IL-6) family of cytokines in NSCLC XREF_BIBR, XREF_BIBR.	5	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	14	15	5	6
IL-1 , IL-6 , and IL-8 are known to activate Stat3 and NF-kappaB pathways in tumor and stromal cells .	IL-1, IL-6, and IL-8 are known to activate Stat3 and NF-kappaB pathways in tumor and stromal cells.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	10	11
Therefore , in undifferentiated MSCs , IL-6 treatment activates ERK1/2 rather than STAT3 .	Therefore, in undifferentiated MSCs, IL-6 treatment activates ERK1/2 rather than STAT3.	6	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	12	13
However , IL-6 treatment failed to induce a significant activation of STAT3 in DIM treated cells .	However, IL-6 treatment failed to induce a significant activation of STAT3 in DIM treated cells.	2	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	11	12
PN-2921 was approximately three orders of magnitude less potent in inhibiting IL-6- induced pSTAT3 elicited by IL-6 orthologs from rodents as compared to that elicited by the human ortholog ( XREF_TABLE ) .	PN-2921 was approximately three orders of magnitude less potent in inhibiting IL-6- induced pSTAT3 elicited by IL-6 orthologs from rodents as compared to that elicited by the human ortholog (XREF_TABLE).	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6-	IL-6-	IL-6-	pSTAT3	pSTAT3	pSTAT3	11	12	13	14
IL-6 triggers many of the STAT3 related phenotypes .	IL-6 triggers many of the STAT3 related phenotypes.	0	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
IL-6 , produced following hepatectomy by Kupffer cells and hepatocytes , is the central trigger of LR via phosphorylation and activation of STAT3 .	IL-6, produced following hepatectomy by Kupffer cells and hepatocytes, is the central trigger of LR via phosphorylation and activation of STAT3.	0	23	is the central trigger	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	22	23
Gene expression profiling revealed that the E9 and E11 cell lines had substantially decreased abundance of the receptors for IL-6 , VEGF , and G-CSF ( XREF_TABLE ) , factors that activate STAT3 and impair the differentiation of myeloid cells to DCs .	Gene expression profiling revealed that the E9 and E11 cell lines had substantially decreased abundance of the receptors for IL-6, VEGF, and G-CSF (XREF_TABLE), factors that activate STAT3 and impair the differentiation of myeloid cells to DCs.	13	33	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	32	33
In the liver , STAT3 , mainly activated by IL-6 , has been shown to play key roles in acute phase response , protection against liver injury and promotion of liver regeneration [ XREF_BIBR ] .	In the liver, STAT3, mainly activated by IL-6, has been shown to play key roles in acute phase response, protection against liver injury and promotion of liver regeneration [XREF_BIBR].	4	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	4	5
IL-6 treatment of CAL27 cells induced a time dependent co-migration of myoferlin and STAT3 to nucleus ( XREF_FIG ) .	IL-6 treatment of CAL27 cells induced a time dependent co-migration of myoferlin and STAT3 to nucleus (XREF_FIG).	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	13	14
STAT3 activation by IL6 also has an alternate metabolic role and translocates to mitochondria to promote PDH activity and pyruvate metabolism that can support electron transport and oxidative phosphorylation [ XREF_BIBR , XREF_BIBR ] .	STAT3 activation by IL6 also has an alternate metabolic role and translocates to mitochondria to promote PDH activity and pyruvate metabolism that can support electron transport and oxidative phosphorylation [XREF_BIBR, XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	3	4	0	1
Concerning pulmonary inflammation , it was observed that IL-6 directly activates STAT3 [ XREF_BIBR ] , while in pulmonary emphysema , IL-6 drives the activation of STAT3 in a different manner [ XREF_BIBR ] .	Concerning pulmonary inflammation, it was observed that IL-6 directly activates STAT3 [XREF_BIBR], while in pulmonary emphysema, IL-6 drives the activation of STAT3 in a different manner [XREF_BIBR].	21	27	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	26	27
IL-6 induced in MCF-7 cells a strong and persistent activation of STAT3 and ERK1/2 and a slight activation of AKT at 30 ' .	IL-6 induced in MCF-7 cells a strong and persistent activation of STAT3 and ERK1/2 and a slight activation of AKT at 30 '.	0	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	11	12
Yet another study found that KSHV encoded IL6 ( vIL6 ) and mouse IL6 were both required for development of plasmacytosis and MCD like pathology in a transgenic mouse model ; IL6 is a potent activator of STAT3 .	Yet another study found that KSHV encoded IL6 (vIL6) and mouse IL6 were both required for development of plasmacytosis and MCD like pathology in a transgenic mouse model; IL6 is a potent activator of STAT3.	31	38	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	31	32	37	38
These results indicate that IL-6 is the dominant activator of STAT-3 in the lungs of Ada -/- mice .	These results indicate that IL-6 is the dominant activator of STAT-3 in the lungs of Ada -/- mice.	4	13	is the dominant activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	4	5	10	11
XREF_BIBR , XREF_BIBR These include the TNF induced NF-kappaB and the IL-6 induced STAT3 signaling pathways , discussed separately in detail below .	XREF_BIBR, XREF_BIBR These include the TNF induced NF-kappaB and the IL-6 induced STAT3 signaling pathways, discussed separately in detail below.	7	15	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	13	14
It has been reported that IL-6 and IL-10 induced by activation of NF-kappaB pathway indirectly activates STAT3 through either autocrine or paracrine mechanisms .	It has been reported that IL-6 and IL-10 induced by activation of NF-kappaB pathway indirectly activates STAT3 through either autocrine or paracrine mechanisms.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	16	17
Growing evidence suggests that JAK2 and STAT3 signaling can be activated by IL-6 and this activation is required for tumor initiation and progression [ XREF_BIBR , XREF_BIBR ] .	Growing evidence suggests that JAK2 and STAT3 signaling can be activated by IL-6 and this activation is required for tumor initiation and progression [XREF_BIBR, XREF_BIBR].	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	6	7
Our previous study demonstrated that in breast cancers , IL-6 stimulates STAT3 dependent , nuclear factor-kappaB-mediated indoleamine 2,3-dioxygenase ( IDO ) upregulation in MDSCs ; this triggers immunosuppressive effects of MDSCs in vitro and vivo .	Our previous study demonstrated that in breast cancers, IL-6 stimulates STAT3 dependent, nuclear factor-kappaB-mediated indoleamine 2,3-dioxygenase (IDO) upregulation in MDSCs; this triggers immunosuppressive effects of MDSCs in vitro and vivo.	9	21	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
IL-6 cytokine treatment induces STAT3 activation in primary neurons and SH-SY5Y cells , which also promotes SOCS3 expression as a transcriptional target gene .	IL-6 cytokine treatment induces STAT3 activation in primary neurons and SH-SY5Y cells, which also promotes SOCS3 expression as a transcriptional target gene.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Conversely , STAT3 activation by IL-6 treatment in CNE1 cells resulted in the up-regulation of miR-21 , suggesting that STAT3 and miR-21 are required for cellular transformation .	Conversely, STAT3 activation by IL-6 treatment in CNE1 cells resulted in the up-regulation of miR-21, suggesting that STAT3 and miR-21 are required for cellular transformation.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	2	3
Our results support these reports and revealed that IL-6 , as a central soluble factor that was positively regulated by ZEB1 , constantly activated STAT3 in HCC1954-Luc cells and exhibited cell proliferating potency both in cell culture and invivo .	Our results support these reports and revealed that IL-6, as a central soluble factor that was positively regulated by ZEB1, constantly activated STAT3 in HCC1954-Luc cells and exhibited cell proliferating potency both in cell culture and invivo.	8	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	24	25
In conjunction with transforming growth factor beta-1 , IL-6 , IL-21 and IL-23 , which activate STAT3 , the expression of RORgammat leads to the differentiation of Th17 cells in mice .	In conjunction with transforming growth factor beta-1, IL-6, IL-21 and IL-23, which activate STAT3, the expression of RORgammat leads to the differentiation of Th17 cells in mice.	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	16	17
Western blot analysis revealed that IL-6 induced the expression of phosphorylated STAT3 at the protein level , but had no noticeable effect on the phosphorylation of other protein kinase pathways , such as Ras/Raf/MEK/MAPK , PI3K and AKT pathways , suggesting that IL-6 , selectively triggers the JAK and STAT3 pathway in medulloblastoma cells ( XREF_FIG ) .	Western blot analysis revealed that IL-6 induced the expression of phosphorylated STAT3 at the protein level, but had no noticeable effect on the phosphorylation of other protein kinase pathways, such as Ras/Raf/MEK/MAPK, PI3K and AKT pathways, suggesting that IL-6, selectively triggers the JAK and STAT3 pathway in medulloblastoma cells (XREF_FIG).	42	50	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	42	43	49	50
STAT3 is activated by many growth factors and cytokines , most notably by the IL-6 cytokine family .	STAT3 is activated by many growth factors and cytokines, most notably by the IL-6 cytokine family.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	0	1
IL-27 , a member of the IL-6 and IL-12 family cytokines , activates STAT1 and STAT3 , promotes early helper T ( Th ) 1 differentiation and generation of IL-10-producing type 1 regulatory T ( Tr1 ) cells , and suppresses the production of inflammatory cytokines and inhibits Th2 differentiation .	IL-27, a member of the IL-6 and IL-12 family cytokines, activates STAT1 and STAT3, promotes early helper T (Th) 1 differentiation and generation of IL-10-producing type 1 regulatory T (Tr1) cells, and suppresses the production of inflammatory cytokines and inhibits Th2 differentiation.	3	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	15	16
Upon binding of its receptor , IL-6 activates STAT3 , which in turn can interfere with GR activities [ XREF_BIBR ] .	Upon binding of its receptor, IL-6 activates STAT3, which in turn can interfere with GR activities [XREF_BIBR].	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
Thus , SH2D4A directly binds to STAT3 protein in the cytoplasm leading to cytoplasmic retention and inhibition of IL-6 stimulation driven dimerization of STAT3 .	Thus, SH2D4A directly binds to STAT3 protein in the cytoplasm leading to cytoplasmic retention and inhibition of IL-6 stimulation driven dimerization of STAT3.	18	24	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	23	24
In a hepatocellular carcinoma ( HCC ) model , it was shown that TAM secrete IL-6 activating STAT3 in HCC cells and promoting expansion of cancer stem cells .	In a hepatocellular carcinoma (HCC) model, it was shown that TAM secrete IL-6 activating STAT3 in HCC cells and promoting expansion of cancer stem cells.	14	20	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	17	18
However , as shown in XREF_FIG , although IL-6 stimulated the activation of STAT3 in H7402 cells , the expression of MCM7 was not significantly changed .	However, as shown in XREF_FIG, although IL-6 stimulated the activation of STAT3 in H7402 cells, the expression of MCM7 was not significantly changed.	8	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	13	14
Indeed , IL-6 treatment of breast cancer cells ( MDA-MB-231 ) induced co-migration of myoferlin and STAT3 to nucleus ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Indeed, IL-6 treatment of breast cancer cells (MDA-MB-231) induced co-migration of myoferlin and STAT3 to nucleus (XREF_FIG and XREF_SUPPLEMENTARY).	2	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	16	17
Consistent with this possibility , previous studies have shown that stimulation of breast cancer cell lines with exogenous IL-6 induces STAT3 activation and down-regulation of E-cadherin to induce epithelial to mesenchymal transition [ XREF_BIBR ] .	Consistent with this possibility, previous studies have shown that stimulation of breast cancer cell lines with exogenous IL-6 induces STAT3 activation and down-regulation of E-cadherin to induce epithelial to mesenchymal transition [XREF_BIBR].	15	21	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	20	21
IL-6 promotes proliferation and survival of hepatocytes by activating STAT-3 signaling .	IL-6 promotes proliferation and survival of hepatocytes by activating STAT-3 signaling.	0	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	0	1	9	10
Moreover , IL-6 enhanced the activation of the JAK2 and STAT3 signalling pathway and therefore attenuated the germacrone induced apoptosis .	Moreover, IL-6 enhanced the activation of the JAK2 and STAT3 signalling pathway and therefore attenuated the germacrone induced apoptosis.	2	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	10	11
In a colitis associated cancer model induced by administration of azoxymethane and DSS , STAT3 activation by IL-6 is essential for epithelial cell survival during colitis and proliferation of tumour initiating cells .	In a colitis associated cancer model induced by administration of azoxymethane and DSS, STAT3 activation by IL-6 is essential for epithelial cell survival during colitis and proliferation of tumour initiating cells.	14	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	14	15
Stat3 , a transcription factor , gets activated by the IL-6 and induces the synthesis of CCL5 and VEGF among other factors from LEC .	Stat3, a transcription factor, gets activated by the IL-6 and induces the synthesis of CCL5 and VEGF among other factors from LEC.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	10	11	0	1
Quercetin was found to be able to down-regulate IL-6 mediated STAT3 activation ( p-STAT3 ) after 18 - 24 hours of A549 cells exposure to it , as revealed from the western blot and the FACS data .	Quercetin was found to be able to down-regulate IL-6 mediated STAT3 activation (p-STAT3) after 18 - 24 hours of A549 cells exposure to it, as revealed from the western blot and the FACS data.	7	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
To evaluate this , we examined the effect of two terpenes on the activation of STAT3 induced by IL-6 in human acute monocyticleukemia THP-1 cells .	To evaluate this, we examined the effect of two terpenes on the activation of STAT3 induced by IL-6 in human acute monocyticleukemia THP-1 cells.	13	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	15	16
Therefore , the study was designed to establish the efficacy of quercetin , if any , in modulating the IL-6 mediated STAT3 activation .	Therefore, the study was designed to establish the efficacy of quercetin, if any, in modulating the IL-6 mediated STAT3 activation.	18	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	21	22
This is significant because while not all tumors overexpress activated STAT3 , IL-6 secreted in the microenvironment may be able to activate STAT3 and LLL12 can block that activation and inhibit the pro tumorigenic effects of STAT3 .	This is significant because while not all tumors overexpress activated STAT3, IL-6 secreted in the microenvironment may be able to activate STAT3 and LLL12 can block that activation and inhibit the pro tumorigenic effects of STAT3.	12	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	22	23
Previously , we have shown that in colon carcinoma cell lines STAT3 activation can be induced by IL-6 stimulation XREF_BIBR .	Previously, we have shown that in colon carcinoma cell lines STAT3 activation can be induced by IL-6 stimulation XREF_BIBR.	11	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	11	12
Our observations demonstrate that generation of adenosine by CD73 contributes to SON expression in ePS cells through the autocrine activation of STAT3 by IL6 ( XREF_FIG ) .	Our observations demonstrate that generation of adenosine by CD73 contributes to SON expression in ePS cells through the autocrine activation of STAT3 by IL6 (XREF_FIG).	19	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	23	24	21	22
This suggests that IL-6 enhances the JAK and STAT3 signaling pathway to promote EC proliferation and angiogenesis in CSDH outer membranes [ XREF_BIBR ] .	This suggests that IL-6 enhances the JAK and STAT3 signaling pathway to promote EC proliferation and angiogenesis in CSDH outer membranes [XREF_BIBR].	3	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	8	9
Blocking IL-6 led to reduced STAT3 signaling .	Blocking IL-6 led to reduced STAT3 signaling.	0	6	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	5	6
Moreover , sulforaphane markedly suppressed the expression of IL-6 and alpha-SMA and inhibited Stat3 and Smad3 signaling pathways in keloid fibroblast KF112 cells .	Moreover, sulforaphane markedly suppressed the expression of IL-6 and alpha-SMA and inhibited Stat3 and Smad3 signaling pathways in keloid fibroblast KF112 cells.	2	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	sulforaphane markedly suppressed the expression of IL-6	il-6	Stat3	Stat3	stat3	8	9	13	14
IL-6 , which contains seven charged acid amino residues but no basic amino acid doublets in its C-terminus ( XREF_TABLE ) , did not induce pSTAT3 in T47D cells following incubation with collagens type I and XI .	IL-6, which contains seven charged acid amino residues but no basic amino acid doublets in its C-terminus (XREF_TABLE), did not induce pSTAT3 in T47D cells following incubation with collagens type I and XI.	0	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	0	1	25	26
The recent observation that IL-6 stimulation of the gp130 results in constitutive activation of Stat3 independently of EGFR in head and neck SCC cells is also of particular importance ( Sriuranpong et al , 2003 ) .	The recent observation that IL-6 stimulation of the gp130 results in constitutive activation of Stat3 independently of EGFR in head and neck SCC cells is also of particular importance (Sriuranpong et al, 2003).	4	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	14	15
Enrichment of interleukin-6 ( IL6 ) and STAT3 pathway genes were found to distinguish Group A EPN from Group B EPN and other brain tumors , implicating an IL6 activation of STAT3 mechanism .	Enrichment of interleukin-6 (IL6) and STAT3 pathway genes were found to distinguish Group A EPN from Group B EPN and other brain tumors, implicating an IL6 activation of STAT3 mechanism.	28	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	28	29	31	32
IL-6 and IL-6 receptor gene induction occurs as a result of activated STAT proteins and IL-6 mediates the long-term activation of STAT3 through an autocrine loop .	IL-6 and IL-6 receptor gene induction occurs as a result of activated STAT proteins and IL-6 mediates the long-term activation of STAT3 through an autocrine loop.	9	22	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	21	22
Because T cells express CD5 , we also confirmed that IL-6 stimulated Stat3 activation in T cells derived from Il6ra -/- mice ( XREF_FIG ) .	Because T cells express CD5, we also confirmed that IL-6 stimulated Stat3 activation in T cells derived from Il6ra -/- mice (XREF_FIG).	10	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	10	11	12	13
Conversely , in the absence of GM-CSF , combinations of SCF , Flt3L , IL-6 and/or G-CSF all promoted STAT3 activated MDSC which were highly susceptible to inhibition by sunitinib .	Conversely, in the absence of GM-CSF, combinations of SCF, Flt3L, IL-6 and/or G-CSF all promoted STAT3 activated MDSC which were highly susceptible to inhibition by sunitinib.	8	21	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	19	20
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR We found that IL-6 induced STAT3 activation and Erbin expression simultaneously .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR We found that IL-6 induced STAT3 activation and Erbin expression simultaneously.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	12	13
It was previously shown that in vitro Stat3 activation by IL-6 is abolished in primary human macrophages concurrently treated with LPS , independent of gene transcription .	It was previously shown that in vitro Stat3 activation by IL-6 is abolished in primary human macrophages concurrently treated with LPS, independent of gene transcription.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	10	11	7	8
Among the genes with decreased expression was that which encodes IL-6 , which can activate STAT3 in an autocrine manner .	Among the genes with decreased expression was that which encodes IL-6, which can activate STAT3 in an autocrine manner.	9	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	15	16
These findings indicate that autocrine activation of STAT3 by IL-6 was not involved in H. pylori mediated STAT3 phosphorylation .	These findings indicate that autocrine activation of STAT3 by IL-6 was not involved in H. pylori mediated STAT3 phosphorylation.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	7	8
However , it is worthwhile to point that IL-6 is well known to activate STAT3 and TSLP is also able to induce STAT3 activation .	However, it is worthwhile to point that IL-6 is well known to activate STAT3 and TSLP is also able to induce STAT3 activation.	8	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	14	15
To examine continued differentiation into long lived CD138 + PC , we supplemented anti-IgM and anti-CD 40/IL-21/IL-2 stimulated cultures on day 6 with IL-6 , IFN-alpha , and IL-21 , which further promotes robust STAT3 activation .	To examine continued differentiation into long lived CD138 + PC, we supplemented anti-IgM and anti-CD 40/IL-21/IL-2 stimulated cultures on day 6 with IL-6, IFN-alpha, and IL-21, which further promotes robust STAT3 activation.	23	35	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	23	24	34	35
IL-6 has been reported to activate STAT3 and was associated with tumorigenesis .	IL-6 has been reported to activate STAT3 and was associated with tumorigenesis.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
Taken together , these data indicate that PE inhibits IL-6 activation of STAT3 in hepatic cells by a p42/44 mitogen activated protein kinase dependent mechanism , and tyrosine phosphatases are involved .	Taken together, these data indicate that PE inhibits IL-6 activation of STAT3 in hepatic cells by a p42/44 mitogen activated protein kinase dependent mechanism, and tyrosine phosphatases are involved.	9	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	12	13
It should be remembered , however , that such statistical correlations are based on protein expression rather than functional assays looking at activation of STAT3 by IL-6 and IL-10 .	It should be remembered, however, that such statistical correlations are based on protein expression rather than functional assays looking at activation of STAT3 by IL-6 and IL-10.	20	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	24	25
STAT3 is an important anti-apoptotic pathway in myeloma and is activated by interleukin 6 , which is induced by NF-kappaB .	STAT3 is an important anti-apoptotic pathway in myeloma and is activated by interleukin 6, which is induced by NF-kappaB.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	STAT3	STAT3	STAT3	12	14	0	1
IL6 mediated STAT3 activation induces the gene transcription of BCL2 , BCL-XL , cFOS , and TIMP , all of which regulate cell survival and proliferation .	IL6 mediated STAT3 activation induces the gene transcription of BCL2, BCL-XL, cFOS, and TIMP, all of which regulate cell survival and proliferation.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	2	3
Human CD34 + cells express gp130 however the soluble IL-6 receptor is required to sensitize progenitors to the effects of IL-6 [ XREF_BIBR ] and mediates Stat3 activation [ XREF_BIBR ] to stimulate cell expansion during erythropoiesis [ XREF_BIBR , XREF_BIBR ] .	Human CD34 + cells express gp130 however the soluble IL-6 receptor is required to sensitize progenitors to the effects of IL-6 [XREF_BIBR] and mediates Stat3 activation [XREF_BIBR] to stimulate cell expansion during erythropoiesis [XREF_BIBR, XREF_BIBR].	9	29	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	26	27
TNFalpha activates p38-MAPK , whereas TNFalpha and IL-6 activate STAT3 .	TNFalpha activates p38-MAPK, whereas TNFalpha and IL-6 activate STAT3.	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
SOCS3 is a relatively specific inhibitor of gp130 and SOCS3 has been shown to negatively regulate Th17 development by the suppression of STAT3 activated by IL-6 or IL-23 [ XREF_BIBR ] .	SOCS3 is a relatively specific inhibitor of gp130 and SOCS3 has been shown to negatively regulate Th17 development by the suppression of STAT3 activated by IL-6 or IL-23 [XREF_BIBR].	20	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	22	23
IL-6 activation of APRF in HepG2 cells can be observed within minutes .	IL-6 activation of APRF in HepG2 cells can be observed within minutes.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	APRF	APRF	APRF	0	1	3	4
We found that the level of IL-6 was extremely high after trastuzumab treatment for six weeks when the STAT3 signaling became predominant survival signaling pathway in the resistant gastric cancer cells , implicating that the release of IL-6 that drives the STAT3 activation in response to trastuzumab initiates the survival signaling transition , which contributes to resistance to trastuzumab via a feedback mechanism .	We found that the level of IL-6 was extremely high after trastuzumab treatment for six weeks when the STAT3 signaling became predominant survival signaling pathway in the resistant gastric cancer cells, implicating that the release of IL-6 that drives the STAT3 activation in response to trastuzumab initiates the survival signaling transition, which contributes to resistance to trastuzumab via a feedback mechanism.	35	42	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	37	38	41	42
PSC secreted IL-6 activated STAT3 signaling in noninvasive , precursor PanIN cells as well as PDAC cells , resulting in enhanced cell invasion and colony formation in both cell types .	PSC secreted IL-6 activated STAT3 signaling in noninvasive, precursor PanIN cells as well as PDAC cells, resulting in enhanced cell invasion and colony formation in both cell types.	1	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
Also , in cell lines of malignant fibrous histiocytoma , a high secretion of IL-6 and constitutive activation of STAT3 were reported , reflecting an increase of tumor cell proliferation [ XREF_BIBR ] .	Also, in cell lines of malignant fibrous histiocytoma, a high secretion of IL-6 and constitutive activation of STAT3 were reported, reflecting an increase of tumor cell proliferation [XREF_BIBR].	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	19	20
STAT3 can be activated by IL6 , interferons , epidermal growth factor or leptin , through the activity of members of the receptor associated Janus kinase ( JAK ) family , which comprises JAK1 , JAK2 , JAK3 , or TYK2 [ XREF_BIBR - XREF_BIBR ] .	STAT3 can be activated by IL6, interferons, epidermal growth factor or leptin, through the activity of members of the receptor associated Janus kinase (JAK) family, which comprises JAK1, JAK2, JAK3, or TYK2 [XREF_BIBR - XREF_BIBR].	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	5	6	0	1
These interactions involve inflammatory cytokines including IL-1 , IL-6 and IL-8 , which in turn activate Stat3 and NF-kappaB pathways in both tumor and stromal cells .	These interactions involve inflammatory cytokines including IL-1, IL-6 and IL-8, which in turn activate Stat3 and NF-kappaB pathways in both tumor and stromal cells.	4	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	8	9	16	17
However , in cross-comparisons of DNA-shift competence and Western-blottable Tyr phosphorylated STAT1 and STAT3 species in cytoplasmic and nuclear extracts prepared from Hep3B cells treated with IFN-gamma or IL-6 or both in the presence or absence of vanadate we observed up to a 30-fold reduced DNA shift competence compared to Western blotting data especially in cells treated with vanadate [ 16 and unpublished data ] .	However, in cross-comparisons of DNA-shift competence and Western-blottable Tyr phosphorylated STAT1 and STAT3 species in cytoplasmic and nuclear extracts prepared from Hep3B cells treated with IFN-gamma or IL-6 or both in the presence or absence of vanadate we observed up to a 30-fold reduced DNA shift competence compared to Western blotting data especially in cells treated with vanadate [16 and unpublished data].	11	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	28	29	13	14
IL-6 was shown to activate STAT3 , even in the presence of TGF-beta1 , and thereby to activate proliferative and anti-apoptotic pathways .	IL-6 was shown to activate STAT3, even in the presence of TGF-beta1, and thereby to activate proliferative and anti-apoptotic pathways.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
In addition , both SAMe and MTA can lower IL-6 expression and inhibit IL-6 and STAT3 signaling in a colitis associated colon cancer model and in human colon cancer cells [ XREF_BIBR ] .	In addition, both SAMe and MTA can lower IL-6 expression and inhibit IL-6 and STAT3 signaling in a colitis associated colon cancer model and in human colon cancer cells [XREF_BIBR].	4	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	SAMe and MTA can lower IL-6 expression	il-6	STAT3	STAT3	stat3	9	10	15	16
The importance of B cell subsets in cancer immunity was made apparent in a recent study demonstrating that IL-6 dependent activation of STAT3 , which had long been associated with chronic inflammation in the tumor microenvironment [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , was confined to the subpopulation of CD5+ , but not CD5- B cells [ XREF_BIBR ] .	The importance of B cell subsets in cancer immunity was made apparent in a recent study demonstrating that IL-6 dependent activation of STAT3, which had long been associated with chronic inflammation in the tumor microenvironment [XREF_BIBR, XREF_BIBR, XREF_BIBR], was confined to the subpopulation of CD5+, but not CD5- B cells [XREF_BIBR].	18	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	22	23
For instance , no STAT3 signaling by IL-6 cytokine receptors is found in the prostate PC3 cells because these cells have lost the genes for STAT3 and STAT5 [ XREF_BIBR ] .	For instance, no STAT3 signaling by IL-6 cytokine receptors is found in the prostate PC3 cells because these cells have lost the genes for STAT3 and STAT5 [XREF_BIBR].	4	9	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	4	5
Our prostate specific IL-6 transgenic mice presented several intriguingly features in the prostate : ( 1 ) activation of STAT3 in the stroma ; ( 2 ) enriched infiltration of inflammatory cell types in the prostate ; and ( 3 ) enriched infiltration of inflammatory cells in the peri-prostatic adipose tissue .	Our prostate specific IL-6 transgenic mice presented several intriguingly features in the prostate : (1) activation of STAT3 in the stroma; (2) enriched infiltration of inflammatory cell types in the prostate; and (3) enriched infiltration of inflammatory cells in the peri-prostatic adipose tissue.	0	28	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	19	20
We found that IL-6 family cytokines , acting via Gp130 coupled receptors , stimulate Jak and Stat3 signaling in retinal ganglion cells after optic nerve injury .	We found that IL-6 family cytokines, acting via Gp130 coupled receptors, stimulate Jak and Stat3 signaling in retinal ganglion cells after optic nerve injury.	3	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	16	17
MRC-5 cells are largely unresponsive to IL6 and we did not assess IL6 mediated STAT3 induction .	MRC-5 cells are largely unresponsive to IL6 and we did not assess IL6 mediated STAT3 induction.	11	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	12	13	14	15
In contrast , short-term ethanol consumption enhanced the regenerative induction of Stat3 but inhibited IL-6 induced Stat3 activation .	In contrast, short-term ethanol consumption enhanced the regenerative induction of Stat3 but inhibited IL-6 induced Stat3 activation.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	14	15	16	17
IL-6 can stimulate STAT3 [ XREF_BIBR ] .	IL-6 can stimulate STAT3 [XREF_BIBR].	0	5	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
Although STAT3 signaling is beneficial to axonal growth through activating transcription of unidentified genes in DRG neurons [ XREF_BIBR ] , STAT3 is differentially activated by IL-6 cytokines in DRG sensory neurons by CNTF and LIF but not IL-6 [ XREF_BIBR ] .	Although STAT3 signaling is beneficial to axonal growth through activating transcription of unidentified genes in DRG neurons [XREF_BIBR], STAT3 is differentially activated by IL-6 cytokines in DRG sensory neurons by CNTF and LIF but not IL-6 [XREF_BIBR].	21	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	21	22
The p38 signaling pathway has been demonstrated to be involved in IL-6 induced STAT3 transcriptional activation .	The p38 signaling pathway has been demonstrated to be involved in IL-6 induced STAT3 transcriptional activation.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	13	14
Thus , we provide a comprehensive mechanism that contributes to the chemoresistance of EOC : IL-6 activates IL-6R and STAT3 to regulate the expression of miR-204 , which controls IL-6R expression .	Thus, we provide a comprehensive mechanism that contributes to the chemoresistance of EOC : IL-6 activates IL-6R and STAT3 to regulate the expression of miR-204, which controls IL-6R expression.	15	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	19	20
For example , IL-6 and IL-10 are both the activator of STAT3 .	For example, IL-6 and IL-10 are both the activator of STAT3.	3	12	are both the activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	11	12
As seen in XREF_SUPPLEMENTARY , an increase in STAT3 phosphorylation was seen in T cells treated with IL-6 from both wild type and knockout mice indicating that p70 S6K1 was not required for IL-6-mediated STAT3 phosphorylation .	As seen in XREF_SUPPLEMENTARY, an increase in STAT3 phosphorylation was seen in T cells treated with IL-6 from both wild type and knockout mice indicating that p70 S6K1 was not required for IL-6-mediated STAT3 phosphorylation.	8	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	8	9
Consistently , IL-21 is inducible in T cells by IL-6 , another cytokine that activates Stat3 .	Consistently, IL-21 is inducible in T cells by IL-6, another cytokine that activates Stat3.	4	16	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	9	10	15	16
IL-6 trans-signalling in turns induces STAT3 activation , which mediates anti-apoptotic signals and increased resistance to death of lamina propria T cells .	IL-6 trans-signalling in turns induces STAT3 activation, which mediates anti-apoptotic signals and increased resistance to death of lamina propria T cells.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
IL-6 induced STAT3 activation via Janus Kinases ( JAK ) has been implicated in HCC XREF_BIBR , XREF_BIBR .	IL-6 induced STAT3 activation via Janus Kinases (JAK) has been implicated in HCC XREF_BIBR, XREF_BIBR.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
IL-6 , whose production is stimulated by hypoxia and elevated in glioblastoma cells , stimulates the activation of the transcription factor STAT3 .	IL-6, whose production is stimulated by hypoxia and elevated in glioblastoma cells, stimulates the activation of the transcription factor STAT3.	0	22	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	21	22
Furthermore , in a study , it was shown that the activation of STAT3 by IL-6 increases gene expression of many survival proteins , such as Bcl-2 , Bcl-X , Mcl-1 , survivin , and X linked inhibitor of apoptosis protein .	Furthermore, in a study, it was shown that the activation of STAT3 by IL-6 increases gene expression of many survival proteins, such as Bcl-2, Bcl-X, Mcl-1, survivin, and X linked inhibitor of apoptosis protein.	11	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	13	14
One candidate gene , upregulated by IL-6 and IL-10-mediated activation of STAT3 , is SOCS3 which under normal circumstances can bind to the gp130 subunit of the IL-6 receptor complex and limit IL-6 signaling .	One candidate gene, upregulated by IL-6 and IL-10-mediated activation of STAT3, is SOCS3 which under normal circumstances can bind to the gp130 subunit of the IL-6 receptor complex and limit IL-6 signaling.	6	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	11	12
Similarly , activation of IL-6 can up-regulate STAT3 ( signal transducer and activator of transcription 3 ) , ultimately inducing excessive proliferation and apoptosis resistance in PASMCs 9 .	Similarly, activation of IL-6 can up-regulate STAT3 (signal transducer and activator of transcription 3), ultimately inducing excessive proliferation and apoptosis resistance in PASMCs 9.	2	19	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	7	8
Luciferase reporter assay showed that IL-6 increased STAT3 luciferase activity upto 5 folds of the control , whereas the addition of Physapubescin B declined the luciferase activity by 50-60 percent compared to IL-6 treatment alone .	Luciferase reporter assay showed that IL-6 increased STAT3 luciferase activity upto 5 folds of the control, whereas the addition of Physapubescin B declined the luciferase activity by 50-60 percent compared to IL-6 treatment alone.	5	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
Collectively , these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia , and therefore support the clinical evaluation of the IL-6 trans-signalling and STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia .	Collectively, these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling and STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.	15	36	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	35	36
Indeed , it has recently been reported that inhibition of STAT3 dependent signaling , which is activated by both LIF and IL-6 , can rescue age associated proliferative defects in mouse satellite cells 20 and promote satellite cell expansion 21 .	Indeed, it has recently been reported that inhibition of STAT3 dependent signaling, which is activated by both LIF and IL-6, can rescue age associated proliferative defects in mouse satellite cells 20 and promote satellite cell expansion 21.	10	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	10	11
171 Although IL-6 mRNA and protein levels were induced in ethanol fed hepatocyte RXRalpha-KO mice , elevated IL-6 did not result in STAT3 activation .	171 Although IL-6 mRNA and protein levels were induced in ethanol fed hepatocyte RXRalpha-KO mice, elevated IL-6 did not result in STAT3 activation.	16	24	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	22	23
IL-6 Cytokines Induce STAT3 Activation in Primary Neurons and SH-SY5Y Cells .	IL-6 Cytokines Induce STAT3 Activation in Primary Neurons and SH-SY5Y Cells.	0	4	Induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
IL-6 activates intracellular signaling of signal transducer and activator of transcription 3 ( STAT3 ) in epithelial and immune cells .	IL-6 activates intracellular signaling of signal transducer and activator of transcription 3 (STAT3) in epithelial and immune cells.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	13	14
Although IL-6 totally failed to induce IL-21 production in Stat3 -/- CD4 cells ( XREF_FIG ) , it was able to trigger the production of IL-21 in mut-Stat3 CD4 cells ( XREF_FIG ) .	Although IL-6 totally failed to induce IL-21 production in Stat3 -/- CD4 cells (XREF_FIG), it was able to trigger the production of IL-21 in mut-Stat3 CD4 cells (XREF_FIG).	1	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	9	10
Another study by O'Reilly et al also showed that STAT3 activation by IL-6 in dermal fibroblasts leads to TGFbeta activation through an indirect mechanism mediated by Gremlin-1 [ XREF_BIBR ] .	Another study by O'Reilly et al also showed that STAT3 activation by IL-6 in dermal fibroblasts leads to TGFbeta activation through an indirect mechanism mediated by Gremlin-1 [XREF_BIBR].	9	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	9	10
Further investigation demonstrated that IL-6 driven by XBP1s was secreted outside of cells and activated signal transducer and activator of transcription 3 ( STAT3 ) signaling in an autocrine and paracrine manner , to regulate the proliferation of Hep3B cells .	Further investigation demonstrated that IL-6 driven by XBP1s was secreted outside of cells and activated signal transducer and activator of transcription 3 (STAT3) signaling in an autocrine and paracrine manner, to regulate the proliferation of Hep3B cells.	4	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	23	24
To study the relationship between IL-6 and TIMP3 , we used western blotting to detect the levels of TIMP3 and p-STAT3 in Saos2 and Saos2-lung cells treated with 20 ng/mL of IL-6 for 24 h. Upon stimulation by IL-6 , the level of TIMP3 was downregulated , accompanied by the activation of p-STAT3 .	To study the relationship between IL-6 and TIMP3, we used western blotting to detect the levels of TIMP3 and p-STAT3 in Saos2 and Saos2-lung cells treated with 20 ng/mL of IL-6 for 24 h. Upon stimulation by IL-6, the level of TIMP3 was downregulated, accompanied by the activation of p-STAT3.	16	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	31	32	20	21
Importantly , we demonstrate that IL-6 and FN adhesion collaborate to activate STAT3 , but not ERK1/2 or Akt .	Importantly, we demonstrate that IL-6 and FN adhesion collaborate to activate STAT3, but not ERK1/2 or Akt.	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	12	13
Prevention of Hypovolemic Circulatory Collapse by IL-6 Activated Stat3 .	Prevention of Hypovolemic Circulatory Collapse by IL-6 Activated Stat3.	4	9	Activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	8	9
STAT3 can also be activated by numerous cytokines and especially IL-6 .	STAT3 can also be activated by numerous cytokines and especially IL-6.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	0	1
Both IL6 and OSM have been shown to activate STAT3 , AKT , and MAPK in several cell types , while our in vivo studies suggest strong activation of STAT3 with a mild increase in ERK1/2 .	Both IL6 and OSM have been shown to activate STAT3, AKT, and MAPK in several cell types, while our in vivo studies suggest strong activation of STAT3 with a mild increase in ERK1/2.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	9	10
After binding to its receptor ( IL-6R ) and recruiting signal transducer , GP130 ( also known as CD130 or IL-6ST ) , IL-6 can activate Janus Kinase ( JAK )/signal transducer and activator of transcription 3 ( STAT3 ) , Akt and mitogen activated protein kinase ( MAPK ) pathways to promote proliferation , survival and drug resistance of the MM cells XREF_BIBR .	After binding to its receptor (IL-6R) and recruiting signal transducer, GP130 (also known as CD130 or IL-6ST), IL-6 can activate Janus Kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), Akt and mitogen activated protein kinase (MAPK) pathways to promote proliferation, survival and drug resistance of the MM cells XREF_BIBR.	23	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	23	24	38	39
XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR IL-17-triggered release of IL-6 will consequently activate the STAT3 pathway , which will further activate the nuclear factor ( NF )-kappaB pathway .	XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR IL-17-triggered release of IL-6 will consequently activate the STAT3 pathway, which will further activate the nuclear factor (NF)-kappaB pathway.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	15	16
In further support of this , IL-6 induced STAT3 activation and cyclin D1 expression , and promoted growth of lung tumor cells in vitro ( XREF_SUPPLEMENTARY ) .	In further support of this, IL-6 induced STAT3 activation and cyclin D1 expression, and promoted growth of lung tumor cells in vitro (XREF_SUPPLEMENTARY).	6	16	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
Western blot analysis showed that IL-6 activated STAT3 signaling in MHCC-97L cells with high level of phosphorylated STAT3 ( Y705 ) , phosphorylated STAT3 ( S727 ) and c-Myc expression .	Western blot analysis showed that IL-6 activated STAT3 signaling in MHCC-97L cells with high level of phosphorylated STAT3 (Y705), phosphorylated STAT3 (S727) and c-Myc expression.	5	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
The CHI3L1 secreted by macrophages then activates NF-kB on the IECs , as well as macrophages to produce IL-6 , which activates STAT3 signaling pathway on the IECs to promote cell survival and proliferation .	The CHI3L1 secreted by macrophages then activates NF-kB on the IECs, as well as macrophages to produce IL-6, which activates STAT3 signaling pathway on the IECs to promote cell survival and proliferation.	17	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	22	23
In addition , in vitro treatment with IL-6 induces STAT3 activation in isolated sinusoidal endothelial cells , and ex vivo treatment of isolated rat livers with IL-6 induces STAT3 activation and protects against sinusoidal endothelial cell apoptosis after liver transplantation .	In addition, in vitro treatment with IL-6 induces STAT3 activation in isolated sinusoidal endothelial cells, and ex vivo treatment of isolated rat livers with IL-6 induces STAT3 activation and protects against sinusoidal endothelial cell apoptosis after liver transplantation.	24	29	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	28	29
STAT3 can be activated by IL-6 dependent or independent mechanisms such as a non canonical Frizzled 2 pathway [ XREF_BIBR ] or TGF-beta and LIF [ XREF_BIBR ] .	STAT3 can be activated by IL-6 dependent or independent mechanisms such as a non canonical Frizzled 2 pathway [XREF_BIBR] or TGF-beta and LIF [XREF_BIBR].	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
For example leptin modulates IEC production of IL-6 , which in turn activates STAT3 in naive T-helper cells that subsequently leads to differentiation into Th-17 cells XREF_BIBR , XREF_BIBR - XREF_BIBR .	For example leptin modulates IEC production of IL-6, which in turn activates STAT3 in naive T-helper cells that subsequently leads to differentiation into Th-17 cells XREF_BIBR, XREF_BIBR - XREF_BIBR.	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	13	14
In the liver , IL-6 , which is mainly produced by local macrophages , i.e. Kupffer cells , induces STAT3 activation in hepatocytes and protects by inducing neutrophilia XREF_BIBR .	In the liver, IL-6, which is mainly produced by local macrophages, i.e. Kupffer cells, induces STAT3 activation in hepatocytes and protects by inducing neutrophilia XREF_BIBR.	4	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	19	20
IL-6 injections also increased phospho-STAT3 activity ( XREF_FIG ) .	IL-6 injections also increased phospho-STAT3 activity (XREF_FIG).	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	phospho-STAT3	phospho-STAT3	phospho-STAT3	0	1	4	5
We further performed immunofluorescence of pSTAT3 in hepatocytes treated with or without IL6 ( 100ng/ml ) .	We further performed immunofluorescence of pSTAT3 in hepatocytes treated with or without IL6 (100ng/ml).	3	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL6	IL6	IL6	pSTAT3	pSTAT3	pSTAT3	12	13	5	6
One study using B16 melanoma cell lines has showed that IL-17A promoted tumor growth via angiogenesis and induced IL-6 production , which in turn activated oncogenic STAT3 , upregulating prosurvival and proangiogenic genes .	One study using B16 melanoma cell lines has showed that IL-17A promoted tumor growth via angiogenesis and induced IL-6 production, which in turn activated oncogenic STAT3, upregulating prosurvival and proangiogenic genes.	18	32	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	26	27
Activation of STAT3 signaling by IL6 family cytokines is required for CRC formation in AOM and DSS dependent mouse models and protects from colitis .	Activation of STAT3 signaling by IL6 family cytokines is required for CRC formation in AOM and DSS dependent mouse models and protects from colitis.	2	7	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	5	6	2	3
Abrogation of IL-6 induced STAT3 signaling network by YM155 may cause growth inhibition of MM cells even in presence of stromal cells .	Abrogation of IL-6 induced STAT3 signaling network by YM155 may cause growth inhibition of MM cells even in presence of stromal cells.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
Also , E3330 treatment significantly inhibited the STAT3 activity induced by IL-6 stimulation of PDAC cells ( XREF_FIG ; p < 0.05 ) , which was abrogated at higher E3330 doses .	Also, E3330 treatment significantly inhibited the STAT3 activity induced by IL-6 stimulation of PDAC cells (XREF_FIG; p < 0.05), which was abrogated at higher E3330 doses.	7	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	7	8
Moreover , we reveal that IL-6 activates the STAT3 and ERK pathways .	Moreover, we reveal that IL-6 activates the STAT3 and ERK pathways.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	8	9
STAT3 is mainly activated by IL-6 ( interleukin 6 ) and IL-22 in hepatocytes .	STAT3 is mainly activated by IL-6 (interleukin 6) and IL-22 in hepatocytes.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
Downstream IL-6 signaling JAK1 , STAT3 , and SOCS3 were consistently upregulated in the same bladder tumors with low IL-6 levels suggesting IL-6 independent activation of the JAK1 and STAT3 pathway .	Downstream IL-6 signaling JAK1, STAT3, and SOCS3 were consistently upregulated in the same bladder tumors with low IL-6 levels suggesting IL-6 independent activation of the JAK1 and STAT3 pathway.	22	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	29	30
IL-6 ( 10 ng/ml ) treatment induced STAT3 activation .	IL-6 (10 ng/ml) treatment induced STAT3 activation.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	7	8
The addition of exogenous IL-6 increased the proportion of pSTAT3 positive CD4+ T cells in a dose dependent manner in each group .	The addition of exogenous IL-6 increased the proportion of pSTAT3 positive CD4+ T cells in a dose dependent manner in each group.	1	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	4	5	9	10
These results indicated that HIC-1 attenuated cell invasion , even in the presence of IL-6 , which activates the STAT3 pathway .	These results indicated that HIC-1 attenuated cell invasion, even in the presence of IL-6, which activates the STAT3 pathway.	12	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	19	20
In vivo study also suggested IL-6 blockage inhibited STAT3 activation and therefore repressed H1650 xenografts cell growth XREF_BIBR .	In vivo study also suggested IL-6 blockage inhibited STAT3 activation and therefore repressed H1650 xenografts cell growth XREF_BIBR.	5	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	8	9
Th17 was defined based on RORgammat and STAT3 signaling mediated by IL-6 or IL-21 , all of which require the presence of TGF-betae [ XREF_BIBR - XREF_BIBR ] .	Th17 was defined based on RORgammat and STAT3 signaling mediated by IL-6 or IL-21, all of which require the presence of TGF-betae [XREF_BIBR - XREF_BIBR].	5	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	7	8
The Cyt induced STAT3 activation may be due to the production of IL-6 in response to the Cyt , as IL-6 activates STAT3 in synovial fibroblasts [ XREF_BIBR ] .	The Cyt induced STAT3 activation may be due to the production of IL-6 in response to the Cyt, as IL-6 activates STAT3 in synovial fibroblasts [XREF_BIBR].	20	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	22	23
In this study we demonstrate that IL-6 mediated activation of STAT3 occurs in conjunction with the phosphorylation of RKIP in vitro .	In this study we demonstrate that IL-6 mediated activation of STAT3 occurs in conjunction with the phosphorylation of RKIP in vitro.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	10	11
Thus , for the anti-atherosclerotic treatment with Statinibs to be most effective a treatment strategy should be considered during the stages were the M1 phenotype is dominant over the M2 phenotype , which correlates with low IL-10 levels and during which activation of STAT3 by IL-6 shifts to pro inflammatory responses .	Thus, for the anti-atherosclerotic treatment with Statinibs to be most effective a treatment strategy should be considered during the stages were the M1 phenotype is dominant over the M2 phenotype, which correlates with low IL-10 levels and during which activation of STAT3 by IL-6 shifts to pro inflammatory responses.	41	46	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	45	46	43	44
Next , we tested if anti-inflammatory steroidal lactone withaferin A can deactivate pSTAT3 induced by IL-6 and TNF-alpha cotreatments .	Next, we tested if anti-inflammatory steroidal lactone withaferin A can deactivate pSTAT3 induced by IL-6 and TNF-alpha cotreatments.	11	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	15	16	12	13
EGCG dose-dependently inhibited pStat3 induced by IL-6 ( P < 0.05 ) , but not tStat3 ( P > 0.05 ) .	EGCG dose-dependently inhibited pStat3 induced by IL-6 (P < 0.05), but not tStat3 (P> 0.05).	2	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pStat3	pStat3	pStat3	6	7	3	4
IL-6 , IL-21 , and IL-23 all preferentially activate Stat3 ( XREF_FIG ) .	IL-6, IL-21, and IL-23 all preferentially activate Stat3 (XREF_FIG).	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	9	10
As shown in XREF_FIG , both Stat3 and ERK1/2 , but not AKT or Stat5a/b , were activated by IL-6 stimulation in the absence of serum in the culture medium in DU145 cells .	As shown in XREF_FIG, both Stat3 and ERK1/2, but not AKT or Stat5a/b, were activated by IL-6 stimulation in the absence of serum in the culture medium in DU145 cells.	5	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	19	20	6	7
In tumor cells , however , STAT3 activators such as IL-6 , IL-10 and IL-11 are commonly overexpressed by cancer cells as well as by stromal cells in the solid tumor microenvironment .	In tumor cells, however, STAT3 activators such as IL-6, IL-10 and IL-11 are commonly overexpressed by cancer cells as well as by stromal cells in the solid tumor microenvironment.	6	14	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	6	7
IL-6 induces STAT3 activation , leading to cell proliferation and malignancy [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	IL-6 induces STAT3 activation, leading to cell proliferation and malignancy [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
When cells are insulted by abnormal physiological conditions , STAT3 can be constitutively activated by IL-6 signaling due to functional silencing of the SOCS3 gene through epigenetic hypermethylation [ XREF_BIBR , XREF_BIBR ] .	When cells are insulted by abnormal physiological conditions, STAT3 can be constitutively activated by IL-6 signaling due to functional silencing of the SOCS3 gene through epigenetic hypermethylation [XREF_BIBR, XREF_BIBR].	9	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	9	10
Treatment of PBMCs with FLLL32 also eliminated basal and IL-6 induced pSTAT3 .	Treatment of PBMCs with FLLL32 also eliminated basal and IL-6 induced pSTAT3.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	9	10	11	12
Conversely , while IL-6 stimulation of Stat1 and Stat3 is normal in Socs1 deficient cells , Stat1 activation by IFNgamma is prolonged .	Conversely, while IL-6 stimulation of Stat1 and Stat3 is normal in Socs1 deficient cells, Stat1 activation by IFNgamma is prolonged.	3	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	8	9
In individual experiments , IL-6 or siRNA-insensitive MMP-2 overexpression by pM-FL-A141G counteracted and restored the pM inhibited Stat3 DNA binding activity suggesting IL-6 and Stat3 signaling suppression in pM treated 4910 and 5310 cells .	In individual experiments, IL-6 or siRNA-insensitive MMP-2 overexpression by pM-FL-A141G counteracted and restored the pM inhibited Stat3 DNA binding activity suggesting IL-6 and Stat3 signaling suppression in pM treated 4910 and 5310 cells.	4	26	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 or siRNA-insensitive MMP-2 overexpression	il-6	Stat3	Stat3	stat3	4	5	24	25
SOCS3 is known to inhibit STAT3 , which is normally activated by IL-6 , insulin or prolactin XREF_BIBR - XREF_BIBR .	SOCS3 is known to inhibit STAT3, which is normally activated by IL-6, insulin or prolactin XREF_BIBR - XREF_BIBR.	4	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	5	6
Hepcidin is transcriptionally regulated by iron , through the bone morphogenetic protein-son of mothers against decapentaplegic ( BMP-SMAD ) pathway and by inflammation , through IL6 mediated STAT3 signaling .	Hepcidin is transcriptionally regulated by iron, through the bone morphogenetic protein-son of mothers against decapentaplegic (BMP-SMAD) pathway and by inflammation, through IL6 mediated STAT3 signaling.	3	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	25	26	27	28
STAT3 can be activated by IL-6-family cytokines in the classic IL-6 and JAK pathway [ XREF_BIBR , XREF_BIBR ] and by the growth factors EGF , FGF , and platelet derived growth factor ( PDGF ) in target cells expressing receptor tyrosine kinases [ XREF_BIBR ] .	STAT3 can be activated by IL-6-family cytokines in the classic IL-6 and JAK pathway [XREF_BIBR, XREF_BIBR] and by the growth factors EGF, FGF, and platelet derived growth factor (PDGF) in target cells expressing receptor tyrosine kinases [XREF_BIBR].	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	0	1
The model we propose is that STAT2 up-regulates IL-6 production , which in turn activates the STAT3 oncogenic pathway to drive tumor promotion .	The model we propose is that STAT2 up-regulates IL-6 production, which in turn activates the STAT3 oncogenic pathway to drive tumor promotion.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	16	17
To further confirm that IL-6 induced Stat3 activation contributes to TF expression in other lung adenocarcinoma cells , CL 1-0 and CL 1-5 cells were treated with IL-6 at various time points .	To further confirm that IL-6 induced Stat3 activation contributes to TF expression in other lung adenocarcinoma cells, CL 1-0 and CL 1-5 cells were treated with IL-6 at various time points.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	6	7
We further demonstrate that transgenic expression of IL-6 in the prostate activates oncogenic pathways , induces autocrine IL-6 secretion and steadily-state of STAT3 activation in the prostate tissue , upregulates paracrine insulin like growth factor ( IGF ) signaling axis , reprograms prostate oncogenic gene expression , and more intriguingly , amplifies inflammation in the prostate and peri-prostatic adipose tissue .	We further demonstrate that transgenic expression of IL-6 in the prostate activates oncogenic pathways, induces autocrine IL-6 secretion and steadily-state of STAT3 activation in the prostate tissue, upregulates paracrine insulin like growth factor (IGF) signaling axis, reprograms prostate oncogenic gene expression, and more intriguingly, amplifies inflammation in the prostate and peri-prostatic adipose tissue.	5	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	expression of IL-6	il-6	STAT3	STAT3	stat3	7	8	22	23
IL-6 is known to induce Stat3 activation .	IL-6 is known to induce Stat3 activation.	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	5	6
IL6 mainly activates STAT3 , however under certain conditions , STAT1 can also be activated by IL6 , [ XREF_BIBR - XREF_BIBR ] .	IL6 mainly activates STAT3, however under certain conditions, STAT1 can also be activated by IL6, [XREF_BIBR - XREF_BIBR].	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	3	4
These results demonstrate that AG490 strongly suppresses Stat3 activity and that IL-6 promotes Stat3 activity in pancreatic cancer cell lines .	These results demonstrate that AG490 strongly suppresses Stat3 activity and that IL-6 promotes Stat3 activity in pancreatic cancer cell lines.	11	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	11	12	13	14
IL-6 activated STAT3 was associated with the AGG-elements of these promoters , as revealed by STAT3-ChIP PCR analysis .	IL-6 activated STAT3 was associated with the AGG-elements of these promoters, as revealed by STAT3-ChIP PCR analysis.	0	4	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
While IL-10 induces STAT3 activation and subsequently inhibits LPS induced inflammatory responses in macrophages and Kupffer cells XREF_BIBR - XREF_BIBR , IL-6 also activates STAT3 but potentiates proinflammatory responses in peritoneal macrophages XREF_BIBR .	While IL-10 induces STAT3 activation and subsequently inhibits LPS induced inflammatory responses in macrophages and Kupffer cells XREF_BIBR - XREF_BIBR, IL-6 also activates STAT3 but potentiates proinflammatory responses in peritoneal macrophages XREF_BIBR.	21	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	24	25
Hence , IL-6 is generally known to activate JAK and STAT3 pathway regardless of binding to soluble or membrane bound IL-6R .	Hence, IL-6 is generally known to activate JAK and STAT3 pathway regardless of binding to soluble or membrane bound IL-6R.	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	10	11
It is well established that IL-6 activates distinct downstream signaling pathways : JAK and STAT3 and Ras and MAPK pathways .	It is well established that IL-6 activates distinct downstream signaling pathways : JAK and STAT3 and Ras and MAPK pathways.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	14	15
Both compounds inhibited IL-6 induced STAT3 activation with IC50s of 0.066 microM and 10 microM , respectively ( XREF_FIG and XREF_SUPPLEMENTARY , XREF_SUPPLEMENTARY ) .	Both compounds inhibited IL-6 induced STAT3 activation with IC50s of 0.066 microM and 10 microM, respectively (XREF_FIG and XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY).	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
Two peaks of p21 expression at early time after PH might be due to IL-6 dependent activation of STAT3 .	Two peaks of p21 expression at early time after PH might be due to IL-6 dependent activation of STAT3.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	18	19
Given the high level of IL6 gene expression we hypothesized that IL6 may be driving activation of STAT3 in Group A EPN .	Given the high level of IL6 gene expression we hypothesized that IL6 may be driving activation of STAT3 in Group A EPN.	11	21	be driving activation	Positive_activation_copula_1	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	11	12	17	18
This important finding defines a novel mechanism of PSC secreted IL-6 mediated activation of STAT3 signaling , as a critical regulator of tumor initiation and progression of PDAC .	This important finding defines a novel mechanism of PSC secreted IL-6 mediated activation of STAT3 signaling, as a critical regulator of tumor initiation and progression of PDAC.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	14	15
We have identified that interleukin-6 ( IL-6 ) , but not ciliary neurotrophic factor , leukemia inhibitory factor , or ligands for receptor tyrosine kinases , activates STAT3 in SCs .	We have identified that interleukin-6 (IL-6), but not ciliary neurotrophic factor, leukemia inhibitory factor, or ligands for receptor tyrosine kinases, activates STAT3 in SCs.	4	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	27	28
Moreover , IL-6 , bone marrow X linked nonreceptor tyrosine kinase , and EZH2 activate STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs , confirming the importance of STAT3 signaling in GSCs .	Moreover, IL-6, bone marrow X linked nonreceptor tyrosine kinase, and EZH2 activate STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs, confirming the importance of STAT3 signaling in GSCs.	2	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	15	16
We show that interleukin 6 , leukemia inhibitory factor and interferon gamma treatment induce the nuclear STAT3 and STAT1 proteins to bind to the sis inducible element of c-fos in both C6 glioma cells and primary cortical astrocytes .	We show that interleukin 6, leukemia inhibitory factor and interferon gamma treatment induce the nuclear STAT3 and STAT1 proteins to bind to the sis inducible element of c-fos in both C6 glioma cells and primary cortical astrocytes.	3	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	STAT3	STAT3	STAT3	3	5	16	17
In contrast , addition of the STAT3 activator IL6 to the culture at a papilloma associated concentration , 10ng/ml , markedly activated pSTAT3 Y705 and pSTAT3 S727 in both transgenic and wild type keratinocytes .	In contrast, addition of the STAT3 activator IL6 to the culture at a papilloma associated concentration, 10ng/ml, markedly activated pSTAT3 Y705 and pSTAT3 S727 in both transgenic and wild type keratinocytes.	3	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	pSTAT3	pSTAT3	pSTAT3	8	9	22	23
Whereas the transcription factor Stat6 is involved in IL-4 signaling , Stat3 is activated by IL-6 signaling .	Whereas the transcription factor Stat6 is involved in IL-4 signaling, Stat3 is activated by IL-6 signaling.	11	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	15	16	11	12
It has been demonstrated that STAT3 is activated by the cytokine interleukin-6 ( IL-6 ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It has been demonstrated that STAT3 is activated by the cytokine interleukin-6 (IL-6) [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	11	12	5	6
The present study has demonstrated that AG490 and S3I-201 markedly suppress STAT3 activity and that IL-6 promotes STAT3 activity in LNCaP cell lines .	The present study has demonstrated that AG490 and S3I-201 markedly suppress STAT3 activity and that IL-6 promotes STAT3 activity in LNCaP cell lines.	15	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	17	18
XREF_BIBR Furthermore , serum levels of IL-6 are significantly higher in hepatitis B patients than in healthy blood donors XREF_BIBR suggesting sustained IL-6 signaling and activation of STAT3 in HBV infection .	XREF_BIBR Furthermore, serum levels of IL-6 are significantly higher in hepatitis B patients than in healthy blood donors XREF_BIBR suggesting sustained IL-6 signaling and activation of STAT3 in HBV infection.	22	30	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	27	28
Consistent with the increase of IL-6 after CBP treatment , CBP enhanced the activation of STAT3 as evidenced by increased p-STAT3 level , while IL-6 blockade suppressed STAT3 activation ( XREF_FIG ) .	Consistent with the increase of IL-6 after CBP treatment, CBP enhanced the activation of STAT3 as evidenced by increased p-STAT3 level, while IL-6 blockade suppressed STAT3 activation (XREF_FIG).	24	28	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	27	28
Antiapoptotic proteins , such as Bcl-xL and Mcl-1 , were shown to be up-regulated in multiple myeloma cells in which constitutive Stat3 activity was induced by IL-6 [ XREF_BIBR , XREF_BIBR ] .	Antiapoptotic proteins, such as Bcl-xL and Mcl-1, were shown to be up-regulated in multiple myeloma cells in which constitutive Stat3 activity was induced by IL-6 [XREF_BIBR, XREF_BIBR].	21	30	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	26	27	21	22
Mice were then injected with a recombinant adenovirus that constitutively expressed STAT3 and found significant elevation of fibrinogen levels , indicating that IL-6 activation of STAT3 is a potent stimulator of the acute phase response that leads to significant cachexia .	Mice were then injected with a recombinant adenovirus that constitutively expressed STAT3 and found significant elevation of fibrinogen levels, indicating that IL-6 activation of STAT3 is a potent stimulator of the acute phase response that leads to significant cachexia.	22	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	25	26
IL-6 blockade significantly inhibited lung cancer promotion , tumor cell intrinsic STAT3 activation , tumor cell proliferation , and angiogenesis markers .	IL-6 blockade significantly inhibited lung cancer promotion, tumor cell intrinsic STAT3 activation, tumor cell proliferation, and angiogenesis markers.	0	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	11	12
Interestingly , the IL-6 receptor ( IL-6R ) , which mediates IL-6-dependent STAT3 activation , is identified as a direct miR-34a target .	Interestingly, the IL-6 receptor (IL-6R), which mediates IL-6-dependent STAT3 activation, is identified as a direct miR-34a target.	3	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	12	13
It has been shown that IL-6 treatment activates STAT3 and protects against cell death in liver sinusoidal endothelial cells XREF_BIBR , XREF_BIBR .	It has been shown that IL-6 treatment activates STAT3 and protects against cell death in liver sinusoidal endothelial cells XREF_BIBR, XREF_BIBR.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	8	9
Notably , the mutant hepatocytes displayed robustly decreased p-STAT3 ( Y705 ) with significantly increased cytoplasmic ac-STAT3 ; additionally , IL6 stimulation failed to upregulate p-STAT3 ( Y705 ) in the HDAC3 deficient cells .	Notably, the mutant hepatocytes displayed robustly decreased p-STAT3 (Y705) with significantly increased cytoplasmic ac-STAT3; additionally, IL6 stimulation failed to upregulate p-STAT3 (Y705) in the HDAC3 deficient cells.	20	33	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	p-STAT3	p-STAT3	p-STAT3	20	21	25	26
IL-6 , IL-6R and dimerization of glycoprotein-130 ( gp130 ) form a complex that activates the Janus kinase ( JAK ) and signal transducers and activators of transcription ( STAT ) pathway , and ultimately , the STAT3 pathway is activated by IL-6 to induce Ig production [ XREF_BIBR , XREF_BIBR ] .	IL-6, IL-6R and dimerization of glycoprotein-130 (gp130) form a complex that activates the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathway, and ultimately, the STAT3 pathway is activated by IL-6 to induce Ig production [XREF_BIBR, XREF_BIBR].	37	43	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	42	43	37	38
Interleukin 6 is released by irradiated macrophages and activates Janus-kinase 2 ( JAK2 )-signal transducer and activator of transcription 3 ( STAT3 ) .	Interleukin 6 is released by irradiated macrophages and activates Janus-kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3).	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin 6	Interleukin 6	Interleukin 6	STAT3	STAT3	STAT3	0	2	21	22
Our data strongly support the hypothesis that the enhancement of VMH leptin signaling by amylin is attributable to its direct action on VMH microglia to produce IL-6 , which then acts on its IL-6R and gp130 receptor complex to activate pSTAT3 , which is also downstream of Lepr-b signaling .	Our data strongly support the hypothesis that the enhancement of VMH leptin signaling by amylin is attributable to its direct action on VMH microglia to produce IL-6, which then acts on its IL-6R and gp130 receptor complex to activate pSTAT3, which is also downstream of Lepr-b signaling.	25	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	26	27	40	41
Such responses have been explained in dendritic cells by temporal activation of STAT3 by IL-6 vs prolonged effect of IL-10 via suppressor of cytokine signalling-3 ( SOCS3 ) activation [ XREF_BIBR ] .	Such responses have been explained in dendritic cells by temporal activation of STAT3 by IL-6 vs prolonged effect of IL-10 via suppressor of cytokine signalling-3 (SOCS3) activation [XREF_BIBR].	4	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	12	13
This suggests that the activation of STAT3 by IL-6 signaling may not act through the same upstream kinases in different pancreatic cancer cell lines .	This suggests that the activation of STAT3 by IL-6 signaling may not act through the same upstream kinases in different pancreatic cancer cell lines.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	6	7
IL-11 as well as IL-6 activates STAT3 , which is closely related to growth , differentiation and metastasis of cancer cells in the tumour microenvironment .	IL-11 as well as IL-6 activates STAT3, which is closely related to growth, differentiation and metastasis of cancer cells in the tumour microenvironment.	1	11	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
These data suggest that IL-11 but not IL-6 induced STAT3 activation promotes the development of cardiac lesions , a pathological outcome which is more frequent with ablated IL-1 signaling .	These data suggest that IL-11 but not IL-6 induced STAT3 activation promotes the development of cardiac lesions, a pathological outcome which is more frequent with ablated IL-1 signaling.	4	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
Considering that IL-6 mediated STAT3 activation drives Th17 cell development [ XREF_BIBR ] we tested components of this pathway in blood plasma and peripheral blood mononuclear cells .	Considering that IL-6 mediated STAT3 activation drives Th17 cell development [XREF_BIBR] we tested components of this pathway in blood plasma and peripheral blood mononuclear cells.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
Proteolytic degradation of SOCS3 protein in turn is controlled by constitutive activation of the IL6 mediated Stat3 and NF-kappaB pathway supporting a reciprocal relationship between Stat3 and NF-kappaB signaling and SOCS3 expression .	Proteolytic degradation of SOCS3 protein in turn is controlled by constitutive activation of the IL6 mediated Stat3 and NF-kappaB pathway supporting a reciprocal relationship between Stat3 and NF-kappaB signaling and SOCS3 expression.	11	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	14	15	16	17
Simultaneously , IL-6 activates STAT3 in the immune cells , particularly CD4 + T cells , to further mediate pro inflammatory response to attack and clear the invading pathogen .	Simultaneously, IL-6 activates STAT3 in the immune cells, particularly CD4 + T cells, to further mediate pro inflammatory response to attack and clear the invading pathogen.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
STAT3 activation induced by IL-6 via JAK has been implicated in colitis associated colon cancer [ XREF_BIBR ] .	STAT3 activation induced by IL-6 via JAK has been implicated in colitis associated colon cancer [XREF_BIBR].	0	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
STAT3 activation elicited by IL-6 , IL-23 , and IL-21 is indispensable for differentiation of activated T cells into Th17 effector cells .	STAT3 activation elicited by IL-6, IL-23, and IL-21 is indispensable for differentiation of activated T cells into Th17 effector cells.	0	9	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
STAT3 , activated by both IL-6 and IL-23 , plays a critical role in THi development .	STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
IL-6 rapidly induced STAT3 activation in MM.1 S cells in a time dependent manner , with maximum activation occurring at 10 min ( XREF_FIG ) .	IL-6 rapidly induced STAT3 activation in MM.1 S cells in a time dependent manner, with maximum activation occurring at 10 min (XREF_FIG).	0	4	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
EBV-infection of immortalized NPE cells enhanced their responses to STAT3 activation induced by IL-6 .	EBV-infection of immortalized NPE cells enhanced their responses to STAT3 activation induced by IL-6.	9	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	9	10
Importance of IL6 induced STAT3 in Th2 cell differentiation has also been reported XREF_BIBR .	Importance of IL6 induced STAT3 in Th2 cell differentiation has also been reported XREF_BIBR.	0	12	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	2	3	4	5
IL-6 signaling through IL-6R and gp130 induces robust activation of STAT3 signaling .	IL-6 signaling through IL-6R and gp130 induces robust activation of STAT3 signaling.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	10	11
The first demonstration of a miRNA-BMPR2 axis in PAH pathogenesis showed that IL-6 mediated activation of STAT3 resulted in inducing the expression of the miR-17-92 cluster in PAECs XREF_BIBR .	The first demonstration of a miRNA-BMPR2 axis in PAH pathogenesis showed that IL-6 mediated activation of STAT3 resulted in inducing the expression of the miR-17-92 cluster in PAECs XREF_BIBR.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	16	17
Besides activation of both Stat1 and Stat3 by IL-6 , it also was shown to negatively regulate SOCS3 expression , and recently the mechanism which interlaces the cytokine signaling with DNA methylation and leads to inhibition of IL-6 mediated silencing of SOCS3 expression was identified where IL-6 induced DNMT1 activity and promoted hypermethylation of SOCS3 leading to the inhibition of SOCS3 expression [ XREF_BIBR ] .	Besides activation of both Stat1 and Stat3 by IL-6, it also was shown to negatively regulate SOCS3 expression, and recently the mechanism which interlaces the cytokine signaling with DNA methylation and leads to inhibition of IL-6 mediated silencing of SOCS3 expression was identified where IL-6 induced DNMT1 activity and promoted hypermethylation of SOCS3 leading to the inhibition of SOCS3 expression [XREF_BIBR].	1	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	8	9	6	7
Similarly , cells pretreated with indicated concentrations ( 0 , 10 , 20 , 40 microM ) of SFN for 8 h followed by exposure to IL-6 ( 50 ng/mL ) for 15 min , the data showed that SFN also exhibited dose-dependently down-regulation STAT3 activation induced by IL-6 ( XREF_FIG G , H ) .	Similarly, cells pretreated with indicated concentrations (0, 10, 20, 40 microM) of SFN for 8 h followed by exposure to IL-6 (50 ng/mL) for 15 min, the data showed that SFN also exhibited dose-dependently down-regulation STAT3 activation induced by IL-6 (XREF_FIG G, H).	44	51	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	48	49	44	45
For instance , IL-6 secreted by CAFs can activate the JAK2 and STAT3 pathway in gastric cancer cells , thus boosting their migration and the ability to undergo EMT [ XREF_BIBR ] .	For instance, IL-6 secreted by CAFs can activate the JAK2 and STAT3 pathway in gastric cancer cells, thus boosting their migration and the ability to undergo EMT [XREF_BIBR].	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	12	13
A crucial initiating step in Th17 polarization is the activation of STAT3 by IL-6 , which is blocked by inhibition or knock-down of GSK3 in astrocytes .	A crucial initiating step in Th17 polarization is the activation of STAT3 by IL-6, which is blocked by inhibition or knock-down of GSK3 in astrocytes.	9	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	11	12
Here we found that autocrine IL-6 in LNCaP cells activates Stat3 pathway and enhances resistance to enzalutamide , while downregulation of Stat3 in LNCaP-s17 cells dramatically resensitized LNCaP-s17 cells to enzalutamide .	Here we found that autocrine IL-6 in LNCaP cells activates Stat3 pathway and enhances resistance to enzalutamide, while downregulation of Stat3 in LNCaP-s17 cells dramatically resensitized LNCaP-s17 cells to enzalutamide.	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	5	6	10	11
Cigarette smoke extract ( CSE ) exposure to human bronchial epithelial ( HBE ) cells induced IL-6 ( Interleukin 6 ) , a pro inflammatory cytokine that activates STAT3 ( Signal transducer and activator of transcription 3 ) , a transcription activator .	Cigarette smoke extract (CSE) exposure to human bronchial epithelial (HBE) cells induced IL-6 (Interleukin 6), a pro inflammatory cytokine that activates STAT3 (Signal transducer and activator of transcription 3), a transcription activator.	16	29	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Interleukin 6	Interleukin 6	Interleukin 6	STAT3	STAT3	STAT3	18	20	28	29
Second , DHA effectively inhibited activation of STAT3 induced by hypoxia and IL-6 in HNSCC cells .	Second, DHA effectively inhibited activation of STAT3 induced by hypoxia and IL-6 in HNSCC cells.	5	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	7	8
This study demonstrates for the first time that PSCs actively secrete IL-6 , which in turn activates STAT3 signaling in PanIN cells , and promotes the invasive and tumorigenic capacity of these pancreatic precursor lesions as well as already established PDAC cells .	This study demonstrates for the first time that PSCs actively secrete IL-6, which in turn activates STAT3 signaling in PanIN cells, and promotes the invasive and tumorigenic capacity of these pancreatic precursor lesions as well as already established PDAC cells.	10	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	17	18
We also detected the STAT3 phosphorylation in A549 and HCC827 cells treated with 50 ng/mL of IL-6 for 1 week .	We also detected the STAT3 phosphorylation in A549 and HCC827 cells treated with 50 ng/mL of IL-6 for 1 week.	4	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	4	5
Nevertheless , the reduction of IL-6 expression after STAT-1 decoy ODN treatment will cause a decreased activation of STAT-3 in synovial fibroblasts , where it promotes cell survival and proliferation [ XREF_BIBR ] .	Nevertheless, the reduction of IL-6 expression after STAT-1 decoy ODN treatment will cause a decreased activation of STAT-3 in synovial fibroblasts, where it promotes cell survival and proliferation [XREF_BIBR].	5	19	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 expression	il-6	STAT-3	STAT-3	stat-3	5	6	18	19
As STAT3 , but neither Akt nor ERK1/2 , was activated by IL-6 ( XREF_FIG ) , we subsequently repeated the recombinant IL-6 stimulations of HTB63 and A375 cells in the presence of a STAT3-inhibitor to examine whether the IL-6 induced WNT5A expression was regulated through STAT3 .	As STAT3, but neither Akt nor ERK1/2, was activated by IL-6 (XREF_FIG), we subsequently repeated the recombinant IL-6 stimulations of HTB63 and A375 cells in the presence of a STAT3-inhibitor to examine whether the IL-6 induced WNT5A expression was regulated through STAT3.	1	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	1	2
IL-6 plus sIL-6R induced STAT3 activation in RA-FLS .	IL-6 plus sIL-6R induced STAT3 activation in RA-FLS.	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Interestingly , IL-6 , IL-21 and IL-23 all activate Stat3 , which is critical for the effects of these cytokines on T H 17 cell differentiation ( Zhou et al ., 2007 ;.	Interestingly, IL-6, IL-21 and IL-23 all activate Stat3, which is critical for the effects of these cytokines on T H 17 cell differentiation (Zhou et al., 2007;.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	9	10
Of these , only STAT3 was activated by IL-6 in the melanoma cell lines tested .	Of these, only STAT3 was activated by IL-6 in the melanoma cell lines tested.	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	4	5
These cytokines , especially IL-6 , activate p-STAT3 and provide a strong association with arsenite induced carcinogenesis .	These cytokines, especially IL-6, activate p-STAT3 and provide a strong association with arsenite induced carcinogenesis.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	4	5	7	8
Interleukin-6 knockout completely prevented the hypertension and JAK2 and STAT3 activation without causing significant attenuation of the renal vasoconstrictor response .	Interleukin-6 knockout completely prevented the hypertension and JAK2 and STAT3 activation without causing significant attenuation of the renal vasoconstrictor response.	0	10	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin-6	Interleukin-6	Interleukin-6	STAT3	STAT3	STAT3	0	1	9	10
Furthermore , we found that IL-6 activates p-STAT3 which leads to increased chemoresistance in PDAC cells .	Furthermore, we found that IL-6 activates p-STAT3 which leads to increased chemoresistance in PDAC cells.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	5	6	7	8
We thus determined STAT1 and STAT3 signaling in WT BMDMs , in response to either IL6 or PH-Fib CM , and found that STAT1 was weakly phosphorylated and as expected STAT3 was strongly phosphorylated , demonstrating that the IL6 receptor can initiate both STAT3 and STAT1 signaling ( XREF_SUPPLEMENTARY ) .	We thus determined STAT1 and STAT3 signaling in WT BMDMs, in response to either IL6 or PH-Fib CM, and found that STAT1 was weakly phosphorylated and as expected STAT3 was strongly phosphorylated, demonstrating that the IL6 receptor can initiate both STAT3 and STAT1 signaling (XREF_SUPPLEMENTARY).	38	46	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	38	39	43	44
IL-6 signals through activation of Stat3 .	IL-6 signals through activation of Stat3.	0	6	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	5	6
IL-6 Initiates STAT3 and Erk1/2 Signaling and Crosstalk .	IL-6 Initiates STAT3 and Erk1/2 Signaling and Crosstalk.	0	5	Initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
The interleukin 6 ( IL-6 ) family cytokines Il6 and Lif , as well as the downstream mediator of cytokine action Stat3 also rise over this time .	The interleukin 6 (IL-6) family cytokines Il6 and Lif, as well as the downstream mediator of cytokine action Stat3 also rise over this time.	1	22	mediator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	Stat3	Stat3	Stat3	1	3	21	22
Thus , in PC12-E2 cells , Stat3 homodimers are preferentially activated by IL-6 , indicating a role for Stat3 in the regulation of cellular differentiation .	Thus, in PC12-E2 cells, Stat3 homodimers are preferentially activated by IL-6, indicating a role for Stat3 in the regulation of cellular differentiation.	6	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	12	13	6	7
However , in our cohort of established T1D , we did not observe an effect of the rs228145 C allele on mbIL-6R expression or IL-6 induced pSTAT3 ( XREF_FIG ) .	However, in our cohort of established T1D, we did not observe an effect of the rs228145 C allele on mbIL-6R expression or IL-6 induced pSTAT3 (XREF_FIG).	12	28	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	24	25	26	27
Because the activation of STAT3 by interleukin-6 also leads to DeltaNp63 up-regulation and the blockade of DeltaNp63 or STAT3 expression by siRNA leads to repression of the cell growth , the identified regulatory pathway is presumably of cell physiological significance .	Because the activation of STAT3 by interleukin-6 also leads to DeltaNp63 up-regulation and the blockade of DeltaNp63 or STAT3 expression by siRNA leads to repression of the cell growth, the identified regulatory pathway is presumably of cell physiological significance.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	6	7	4	5
There is evidence that SOCS1 inhibits constitutive and IL-6 induced activation of STAT3 in non CNS cells .	There is evidence that SOCS1 inhibits constitutive and IL-6 induced activation of STAT3 in non CNS cells.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	12	13
Third , several major STAT3 activators , including the v-Src kinase and the IL-6 cytokine , have been shown to promote tumor initiation and progression .	Third, several major STAT3 activators, including the v-Src kinase and the IL-6 cytokine, have been shown to promote tumor initiation and progression.	4	14	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	4	5
We tested this in SW620 by directly knocking down Stat3 and exposing cells to interleukin-6 ( an activator of Stat3 ) .	We tested this in SW620 by directly knocking down Stat3 and exposing cells to interleukin-6 (an activator of Stat3).	11	20	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	Stat3	Stat3	Stat3	14	15	19	20
As an important member of the STAT family , STAT3 can be activated by IL-6 and IL-23 after combining with IL-1b , TGF- b , and RoRct .	As an important member of the STAT family, STAT3 can be activated by IL-6 and IL-23 after combining with IL-1b, TGF- b, and RoRct.	9	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	9	10
Notably , STAT3 transcriptional activation by IL-6 is crucial for the Cr ( VI )-induced miR-21 elevation .	Notably, STAT3 transcriptional activation by IL-6 is crucial for the Cr (VI)-induced miR-21 elevation.	2	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	2	3
Elevated Stat3 activity in tumor stromal immune cells further promotes expression of cytokines and growth factors , including but not limited to IL-10 , IL-6 and VEGF , which in turn further activate Stat3 in tumor cells .	Elevated Stat3 activity in tumor stromal immune cells further promotes expression of cytokines and growth factors, including but not limited to IL-10, IL-6 and VEGF, which in turn further activate Stat3 in tumor cells.	20	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	24	25	33	34
Reciprocally , mTORC1 contributes to STAT4 and STAT3 activation mediated by IL-12 and IL-6 , respectively , while IL-4 mediated STAT6 activation requires mTORC2 activation [ XREF_BIBR ] .	Reciprocally, mTORC1 contributes to STAT4 and STAT3 activation mediated by IL-12 and IL-6, respectively, while IL-4 mediated STAT6 activation requires mTORC2 activation [XREF_BIBR].	5	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	7	8
Inducers of the STAT transcription factors include inflammatory cytokines , such as interleukin-6 ( IL-6 ) ( primarily an activator of STAT3 ) or interferon gamma ( IFNgamma ) ( primarily an activator of STAT1 ) [ XREF_BIBR , XREF_BIBR ] .	Inducers of the STAT transcription factors include inflammatory cytokines, such as interleukin-6 (IL-6) (primarily an activator of STAT3) or interferon gamma (IFNgamma) (primarily an activator of STAT1) [XREF_BIBR, XREF_BIBR].	8	22	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	12	13	21	22
MKN1 and MKN7 cells , both of which are negative for MET activation , produced interleukin-6 ( IL-6 ) that activated STAT3 through the Janus kinase pathway .	MKN1 and MKN7 cells, both of which are negative for MET activation, produced interleukin-6 (IL-6) that activated STAT3 through the Janus kinase pathway.	15	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	21	22
Further , we show that IL-17 did not exert its dominant pro tumoral role through its control on production of the NF-kB-dependent mediator , IL-6 , since the deletion of IL-6 or epithelial IL-6R did not impair CEC Stat3 activation and only non significantly decreased colon tumor numbers upon ETBF colonization .	Further, we show that IL-17 did not exert its dominant pro tumoral role through its control on production of the NF-kB-dependent mediator, IL-6, since the deletion of IL-6 or epithelial IL-6R did not impair CEC Stat3 activation and only non significantly decreased colon tumor numbers upon ETBF colonization.	30	39	impair	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	30	31	38	39
Therefore , although gp130 is used by both IL-6 and IL-27 to activate Stat3 , divergent downstream effects may occur because of an altered gp130 signaling pathway or potentially altered balance of kinase usage .	Therefore, although gp130 is used by both IL-6 and IL-27 to activate Stat3, divergent downstream effects may occur because of an altered gp130 signaling pathway or potentially altered balance of kinase usage.	5	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	8	9	13	14
As expected , IL-6 also significantly increased pStat3 and Stat3 ( 2.81 +/-0.56 versus 1.00 +/-0.24 ; P = 0.01 ) , but the effect peaked after 30 minutes of treatment .	As expected, IL-6 also significantly increased pStat3 and Stat3 (2.81 +/-0.56 versus 1.00 +/-0.24; P = 0.01), but the effect peaked after 30 minutes of treatment.	3	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pStat3	pStat3	pStat3	3	4	7	8
H1299 cells , which lack constitutively active STAT3 and ERK , were treated with IL-6 for different times and then examined for phosphorylated STAT3 and ERK .	H1299 cells, which lack constitutively active STAT3 and ERK, were treated with IL-6 for different times and then examined for phosphorylated STAT3 and ERK.	4	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	7	8
In a co-culture model with microglia and endothelial cells under a high glucose condition , the microglia derived IL-6 induced STAT3 activation in the retinal endothelial cells , leading to increasing endothelial permeability .	In a co-culture model with microglia and endothelial cells under a high glucose condition, the microglia derived IL-6 induced STAT3 activation in the retinal endothelial cells, leading to increasing endothelial permeability.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	20	21
IL6 mediated activation of STAT3 is implicated as a critical therapeutic target for cancer therapy .	IL6 mediated activation of STAT3 is implicated as a critical therapeutic target for cancer therapy.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	4	5
Proinflammatory cytokines , such as IL-6 and IL-21 , which activate STAT3 , overcome Foxp3 mediated inhibition of the transcriptional activity of RORgammat , increase the abundance of IL-23R , and thus push T cell differentiation toward a T H 17 like fate .	Proinflammatory cytokines, such as IL-6 and IL-21, which activate STAT3, overcome Foxp3 mediated inhibition of the transcriptional activity of RORgammat, increase the abundance of IL-23R, and thus push T cell differentiation toward a T H 17 like fate.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	11	12
However , IL-6 also activates STAT3 in many types of human cancer .	However, IL-6 also activates STAT3 in many types of human cancer.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	5	6
Such a reduced IL-6 level downregulates STAT3 activation in macrophages , leading to the impairment of the running inflammatory amplification loop ( XREF_FIG ) .	Such a reduced IL-6 level downregulates STAT3 activation in macrophages, leading to the impairment of the running inflammatory amplification loop (XREF_FIG).	3	7	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 level	il-6	STAT3	STAT3	stat3	3	4	6	7
In particular , IL-6 trans-signaling driven STAT3 activity is important for T cell recruitment during successful resolution of any inflammatory response and transition from innate to acquired immunity .	In particular, IL-6 trans-signaling driven STAT3 activity is important for T cell recruitment during successful resolution of any inflammatory response and transition from innate to acquired immunity.	3	7	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	6	7
As reported earlier ( Ueda et al , 2002a ; Jia et al , 2004 ) , exogenous IL-6 induced rapid activation of MAPK and STAT3 pathways in LNCaP/Co cells , which are unable to secrete endogenous IL-6 .	As reported earlier (Ueda et al, 2002a; Jia et al, 2004), exogenous IL-6 induced rapid activation of MAPK and STAT3 pathways in LNCaP/Co cells, which are unable to secrete endogenous IL-6.	17	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	25	26
IL-6 activates STAT3 signaling and then has cascading consequences for activating Snail-Smad3 and TGF-beta1 and vimentin as well as migration and invasion in liver cancer cells .	IL-6 activates STAT3 signaling and then has cascading consequences for activating Snail-Smad3 and TGF-beta1 and vimentin as well as migration and invasion in liver cancer cells.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
IL-6 also activates STAT3 and supports Ig secretion by human PCs via their heightened expression of the IL-6R .	IL-6 also activates STAT3 and supports Ig secretion by human PCs via their heightened expression of the IL-6R.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
Several studies have reported enhanced hepatic STAT3 activation due to IL-6 action , so we first analyzed the phosphorylation status of the IL-6 mediator STAT3 and then the expression of IL-6-regulated genes .	Several studies have reported enhanced hepatic STAT3 activation due to IL-6 action, so we first analyzed the phosphorylation status of the IL-6 mediator STAT3 and then the expression of IL-6-regulated genes.	19	25	mediator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	24	25
All the above mentioned cytokines are STAT3-target genes ; moreover , IL-6 , IL-4 and IL-13 activate the JAK1 and STAT3 axis with a feed-forward mechanism [ XREF_BIBR - XREF_BIBR ] .	All the above mentioned cytokines are STAT3-target genes; moreover, IL-6, IL-4 and IL-13 activate the JAK1 and STAT3 axis with a feed-forward mechanism [XREF_BIBR - XREF_BIBR].	11	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	20	21
To explore whether up-regulation of pY705 STAT3 could enhance cell migration , Mock-7721 was treated with IL-6 , an activator of pY705 STAT3 XREF_BIBR .	To explore whether up-regulation of pY705 STAT3 could enhance cell migration, Mock-7721 was treated with IL-6, an activator of pY705 STAT3 XREF_BIBR.	3	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	6	7
In HNSCC , activation of STAT3 by IL-6 and EGFR has been proven to be a key molecular event [ XREF_BIBR , XREF_BIBR ] .	In HNSCC, activation of STAT3 by IL-6 and EGFR has been proven to be a key molecular event [XREF_BIBR, XREF_BIBR].	3	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	5	6
IL6 signals promote STAT3 activation in GBM cells in vitro , and targeting either STAT3 or IL6 decreases GBM cell survival [ XREF_BIBR ] .	IL6 signals promote STAT3 activation in GBM cells in vitro, and targeting either STAT3 or IL6 decreases GBM cell survival [XREF_BIBR].	0	4	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	3	4
IL6 activation of the STAT3 transcription factor is necessary for neoplastic cellular transformation , and IL6 activates NF-kappaB , thereby completing a positive feedback loop .	IL6 activation of the STAT3 transcription factor is necessary for neoplastic cellular transformation, and IL6 activates NF-kappaB, thereby completing a positive feedback loop.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	4	5
Direct contact between platelets and LSECs triggered the secretion of S1P from the platelets , which induced the secretion of IL-6 from the LSECs ; thereafter , the increase of IL-6 caused the activation of the STAT3 pathway in hepatocytes , Akt and ERK1/2 activation and the promotion of hepatocyte proliferation [ XREF_BIBR ] .	Direct contact between platelets and LSECs triggered the secretion of S1P from the platelets, which induced the secretion of IL-6 from the LSECs; thereafter, the increase of IL-6 caused the activation of the STAT3 pathway in hepatocytes, Akt and ERK1/2 activation and the promotion of hepatocyte proliferation [XREF_BIBR].	28	37	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	30	31	36	37
IL-6 Induced STAT3 Signalling Is Associated with the Proliferation of Human Muscle Satellite Cells Following Acute Muscle Damage .	IL-6 Induced STAT3 Signalling Is Associated with the Proliferation of Human Muscle Satellite Cells Following Acute Muscle Damage.	0	5	Induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
STAT3 activation by IL6 treatment resulted in up-regulation of both miR-24 and miR-629 levels , while pharmacological inhibition of STAT3 ( JSI-124 ) strongly reduced miR-24 and miR-629 expression levels ( XREF_FIG ) .	STAT3 activation by IL6 treatment resulted in up-regulation of both miR-24 and miR-629 levels, while pharmacological inhibition of STAT3 (JSI-124) strongly reduced miR-24 and miR-629 expression levels (XREF_FIG).	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	3	4	0	1
Furthermore , IL-6 induces the activation of STAT3 , which is dysregulated in colon cancer .	Furthermore, IL-6 induces the activation of STAT3, which is dysregulated in colon cancer.	2	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	7	8
An alternative possibility is that PAR2 activates STAT3 indirectly by way of its ability to promote secretion of the canonical STAT3 activator IL-6 .	An alternative possibility is that PAR2 activates STAT3 indirectly by way of its ability to promote secretion of the canonical STAT3 activator IL-6.	16	23	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	20	21
IL-6 , one of the predominant cytokines , activates STAT3 in hepatocytes and plays a significant role in liver protection and reconstruction , yet it can prompt the pro inflammatory reaction in Kupffer cells via transient STAT3 activation .	IL-6, one of the predominant cytokines, activates STAT3 in hepatocytes and plays a significant role in liver protection and reconstruction, yet it can prompt the pro inflammatory reaction in Kupffer cells via transient STAT3 activation.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	9	10
For example , IL-6 acting via its receptor has been shown to activate STAT3 in LNCaP cells .	For example, IL-6 acting via its receptor has been shown to activate STAT3 in LNCaP cells.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	13	14
STAT3 was differentially activated by IL-6 in IgA1 secreting cells from patients with IgA nephropathy compared with those from healthy control subjects .	STAT3 was differentially activated by IL-6 in IgA1 secreting cells from patients with IgA nephropathy compared with those from healthy control subjects.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
In exploring the molecular mechanisms with human aortic endothelial cells ( HAECs ) , we found that recombinant IL-6 activated the STAT3 pathway , leading to the upregulation and overproduction of ICAM-1 and VCAM-1 .	In exploring the molecular mechanisms with human aortic endothelial cells (HAECs), we found that recombinant IL-6 activated the STAT3 pathway, leading to the upregulation and overproduction of ICAM-1 and VCAM-1.	17	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	21	22
Raloxifene is a suitable agent for targeting liver cancer and possibly certain type of cancer cells with constitutively activated STAT3 induced by IL-6 , due to its ability to inhibit IL-6 and GP130 binding as well as their potent growth suppressive activity both in vitro and in vivo .	Raloxifene is a suitable agent for targeting liver cancer and possibly certain type of cancer cells with constitutively activated STAT3 induced by IL-6, due to its ability to inhibit IL-6 and GP130 binding as well as their potent growth suppressive activity both in vitro and in vivo.	6	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	19	20
IL-6 activates STAT3 ( Signal transducer and activator of transcription 3 ) , a recently characterized regulator of myogenic lineage progression in MuSCs .	IL-6 activates STAT3 (Signal transducer and activator of transcription 3), a recently characterized regulator of myogenic lineage progression in MuSCs.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
When overexpressed in vivo , both OSM and IL-6 led to increased STAT3 activation , as examined on whole lung tissues .	When overexpressed in vivo, both OSM and IL-6 led to increased STAT3 activation, as examined on whole lung tissues.	6	13	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	12	13
During the acute-phase response , IL-6 release induced STAT3 protein and hepcidin mRNA , whereas mRNA levels of proteins in the iron sensing pathway ( HFE , hemojuvelin , and transferrin receptor 2 ) decreased .	During the acute-phase response, IL-6 release induced STAT3 protein and hepcidin mRNA, whereas mRNA levels of proteins in the iron sensing pathway (HFE, hemojuvelin, and transferrin receptor 2) decreased.	5	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	8	9
IL-6 signals via the IL-6R and gp130 complex and triggers downstream effectors STAT3 and Ras [ XREF_BIBR , XREF_BIBR ] .	IL-6 signals via the IL-6R and gp130 complex and triggers downstream effectors STAT3 and Ras [XREF_BIBR, XREF_BIBR].	0	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	12	13
For example , IL-6 , IL-21 , and IL-23 each can activate STAT3 protein , and this activation is essential for the expression of transcription factor RORgammat and thus Th17 cell induction .	For example, IL-6, IL-21, and IL-23 each can activate STAT3 protein, and this activation is essential for the expression of transcription factor RORgammat and thus Th17 cell induction.	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	12	13
We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro apoptotic genes .	We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro apoptotic genes.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	5	6	7	8
Both LIF and IL-6 signal through signal transducer and activator of transcription 3 ( STAT-3 ) .	Both LIF and IL-6 signal through signal transducer and activator of transcription 3 (STAT-3).	1	15	signal	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	3	4	14	15
Overexpression of STAT3C or induction of endogenous STAT3 activation by IL-6 evidently inhibited anoikis of cervical cancer cells , whereas inhibition of STAT3 activation by WP1066 greatly promoted anoikis , particularly in the cells with Erbin deficiency , indicating that the development of anoikis resistance is at least partially dependent upon STAT3 activation .	Overexpression of STAT3C or induction of endogenous STAT3 activation by IL-6 evidently inhibited anoikis of cervical cancer cells, whereas inhibition of STAT3 activation by WP1066 greatly promoted anoikis, particularly in the cells with Erbin deficiency, indicating that the development of anoikis resistance is at least partially dependent upon STAT3 activation.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	7	8
IL-6 induced STAT3 activation , however , is unlikely to be the only tumor promoting mechanism stimulated by obesity .	IL-6 induced STAT3 activation, however, is unlikely to be the only tumor promoting mechanism stimulated by obesity.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
IL6 mediated activation of the STAT3 transcription factor is necessary for transformation , and IL6 activates NF-kappaB , thereby completing a positive feedback loop .	IL6 mediated activation of the STAT3 transcription factor is necessary for transformation, and IL6 activates NF-kappaB, thereby completing a positive feedback loop.	0	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	5	6
In HNSCC several suppressive mechanisms have been identified that include : Deficiencies or alterations of tumor human leukocyte antigen ( HLA ) class I molecules expression along with overexpression of antigens causing T-cell tolerance Increases in immunosuppressive cytokines such Il-10 , IL-6 , and TGF-beta Aberrant activation of the transcription factors Signal Transducers and Activators of Transcription 3 ( STAT3 ) and NF-kB , which are notably linked to IL-6 and TGF-beta signaling respectively .	In HNSCC several suppressive mechanisms have been identified that include : Deficiencies or alterations of tumor human leukocyte antigen (HLA) class I molecules expression along with overexpression of antigens causing T-cell tolerance Increases in immunosuppressive cytokines such Il-10, IL-6, and TGF-beta Aberrant activation of the transcription factors Signal Transducers and Activators of Transcription 3 (STAT3) and NF-kB, which are notably linked to IL-6 and TGF-beta signaling respectively.	31	60	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	41	42	59	60
Functional studies showed that both genes synergize to inhibit IL-6 mediated STAT3 signaling .	Functional studies showed that both genes synergize to inhibit IL-6 mediated STAT3 signaling.	8	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
In U373 MG astrocytes , viral protein US28 of the Titan strain induces IL-6 production , which in turn activates STAT3 in an auto- and paracrine fashion [ XREF_BIBR ] .	In U373 MG astrocytes, viral protein US28 of the Titan strain induces IL-6 production, which in turn activates STAT3 in an auto- and paracrine fashion [XREF_BIBR].	13	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	20	21
Dysregulation of IL-6 Induced STAT3 and SOCS3 in Myocytes of People with type 2 Diabetes .	Dysregulation of IL-6 Induced STAT3 and SOCS3 in Myocytes of People with type 2 Diabetes.	0	6	Induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
Given these results , our previous results with STAT3 activation by IL-6 , the known cooperation with JAK1 and IL-6 receptors , and recent studies suggesting IL-6 driven STAT3 in lung cancer , we further investigated IL-6 as an upstream regulator of JAK1 and STAT3 in lung cancer cells .	Given these results, our previous results with STAT3 activation by IL-6, the known cooperation with JAK1 and IL-6 receptors, and recent studies suggesting IL-6 driven STAT3 in lung cancer, we further investigated IL-6 as an upstream regulator of JAK1 and STAT3 in lung cancer cells.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	8	9
We therefore performed Western blotting using an antibody specific for phosphorylated STAT3 ( Tyr705 ) and found that cells treated with IL-22 with or without H. pylori infection showed significantly strong and prolonged phosphorylation of STAT3 , while cells treated with IL-6 showed rather weak and transient STAT3 phosphorylation ( XREF_FIG ) .	We therefore performed Western blotting using an antibody specific for phosphorylated STAT3 (Tyr705) and found that cells treated with IL-22 with or without H. pylori infection showed significantly strong and prolonged phosphorylation of STAT3, while cells treated with IL-6 showed rather weak and transient STAT3 phosphorylation (XREF_FIG).	33	42	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	41	42	35	36
STAT3 can be activated by IL-6 , IL-10 and IL-21 , of which both IL-6 and IL-10 were elevated in serum samples of our SLE cohort ( data not shown ) .	STAT3 can be activated by IL-6, IL-10 and IL-21, of which both IL-6 and IL-10 were elevated in serum samples of our SLE cohort (data not shown).	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
Therefore , our data proved that hCAFs are capable of converting normal DCs into IDO producing cells through STAT3 activation mediated by IL-6 .	Therefore, our data proved that hCAFs are capable of converting normal DCs into IDO producing cells through STAT3 activation mediated by IL-6.	18	23	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	18	19
Studies showed that , during colitis associated colonic tumorigenesis , IL-6 in the intestinal lamina propria enhances STAT3 dependent proliferation of tumor initiating cells and protection of premalignant intestinal epithelial cells from apoptosis [ XREF_BIBR , XREF_BIBR ] .	Studies showed that, during colitis associated colonic tumorigenesis, IL-6 in the intestinal lamina propria enhances STAT3 dependent proliferation of tumor initiating cells and protection of premalignant intestinal epithelial cells from apoptosis [XREF_BIBR, XREF_BIBR].	10	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	17	18
Previous studies have demonstrated that STAT3 signalling has a critical role in the tumour formation of prostate cancer and IL-6 treatment results in the activation of STAT3 in prostate cancer cells .	Previous studies have demonstrated that STAT3 signalling has a critical role in the tumour formation of prostate cancer and IL-6 treatment results in the activation of STAT3 in prostate cancer cells.	19	30	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	26	27
It is well established that IL-6 activates STAT3 through IL-6Ralpha and gp130 [ XREF_BIBR ] .	It is well established that IL-6 activates STAT3 through IL-6Ralpha and gp130 [XREF_BIBR].	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
IL-6 activates GP130 and STAT3 signaling pathway through STAT3 nuclear translocation to bind DNA .	IL-6 activates GP130 and STAT3 signaling pathway through STAT3 nuclear translocation to bind DNA.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Although the molecular mechanisms of Tfh development are not fully understand , the engagement of TCR with high-affinity ligand and ICOS signaling were shown to be involved in the development of Tfh cells , in addition to STAT3 activating signals such as IL-6 and IL-21 [ XREF_BIBR , XREF_BIBR ] .	Although the molecular mechanisms of Tfh development are not fully understand, the engagement of TCR with high-affinity ligand and ICOS signaling were shown to be involved in the development of Tfh cells, in addition to STAT3 activating signals such as IL-6 and IL-21 [XREF_BIBR, XREF_BIBR].	37	46	signals	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	42	43	37	38
These data suggest that IL-6 activates STAT3 in DU145 and LNCaP cells but not in the normal RWPE-1 cell line ( XREF_FIG ) .	These data suggest that IL-6 activates STAT3 in DU145 and LNCaP cells but not in the normal RWPE-1 cell line (XREF_FIG).	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
Additionally , differences in phosphorylation residues can cause cells to mount alternative responses to autophagy ; in pancreatic cancer , secreted IL-6 induces p-STAT3 at Ser727 , which was an important residue for its mitochondrial localization , whereas in this study , STAT3 activation was marked by its phosphorylation at Tyr705 .	Additionally, differences in phosphorylation residues can cause cells to mount alternative responses to autophagy; in pancreatic cancer, secreted IL-6 induces p-STAT3 at Ser727, which was an important residue for its mitochondrial localization, whereas in this study, STAT3 activation was marked by its phosphorylation at Tyr705.	20	24	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	21	22	23	24
Collectively , these findings indicate that the nuclear accumulation of EGFR and activation of STAT3 by IL-6 play a key role in iNOS expression and resultant DNA damage , leading to EBV related NPC .	Collectively, these findings indicate that the nuclear accumulation of EGFR and activation of STAT3 by IL-6 play a key role in iNOS expression and resultant DNA damage, leading to EBV related NPC.	10	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	14	15
This is consistent with our hypothesis that pSTAT3 induction by IL-6 would be more likely to occur if SOCS-1 is methylated than if it is unmethylated .	This is consistent with our hypothesis that pSTAT3 induction by IL-6 would be more likely to occur if SOCS-1 is methylated than if it is unmethylated.	7	11	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	10	11	7	8
Relevant to cancers , IL-6 activates STAT3 signaling pathways and high levels of IL-6 is associated with poor prognosis in a variety of cancers such as prostate cancer , bladder cancer , ovarian cancer , colorectal cancer and GC [ XREF_BIBR , XREF_BIBR ] .	Relevant to cancers, IL-6 activates STAT3 signaling pathways and high levels of IL-6 is associated with poor prognosis in a variety of cancers such as prostate cancer, bladder cancer, ovarian cancer, colorectal cancer and GC [XREF_BIBR, XREF_BIBR].	2	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
Unlike lymphocytes , the IL-6 induced STAT3 phosphorylation of the patients ' monocytes was depressed [ XREF_BIBR ] .	Unlike lymphocytes, the IL-6 induced STAT3 phosphorylation of the patients ' monocytes was depressed [XREF_BIBR].	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
XREF_BIBR - XREF_BIBR IL-6 activates STAT3 and induces retinoic acid receptor related orphan receptor gamma-t ( RORgammat ) and RORalpha , cooperates with TGF-beta to guide differentiation of Th17 cells .	XREF_BIBR - XREF_BIBR IL-6 activates STAT3 and induces retinoic acid receptor related orphan receptor gamma-t (RORgammat) and RORalpha, cooperates with TGF-beta to guide differentiation of Th17 cells.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
The significance of the inhibitory action of IL-6 has been documented in reports that in the absence of SOCS3 , IL-6 induces a sustained STAT3 signal similar to that of IL-10 and becomes a potent inhibitor of macrophage production of TNF-alpha and IL-12 .	The significance of the inhibitory action of IL-6 has been documented in reports that in the absence of SOCS3, IL-6 induces a sustained STAT3 signal similar to that of IL-10 and becomes a potent inhibitor of macrophage production of TNF-alpha and IL-12.	20	32	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	24	25
Indispensably , STAT3 transcriptional activation by IL-6 is crucial for the arsenic induced miR-21 increase .	Indispensably, STAT3 transcriptional activation by IL-6 is crucial for the arsenic induced miR-21 increase.	2	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	2	3
This may be because the IL-10 receptor activates STAT3 in a SOCS3 ( suppressor of cytokine signaling 3 )-independent manner , while IL-6 receptor activation of STAT3 requires SOCS3 modulation [ XREF_BIBR ] .	This may be because the IL-10 receptor activates STAT3 in a SOCS3 (suppressor of cytokine signaling 3)-independent manner, while IL-6 receptor activation of STAT3 requires SOCS3 modulation [XREF_BIBR].	22	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	26	27
Upon IL-6 stimulation , HEK-Blue ( TM ) IL-6 cells trigger the activation of STAT3 and the subsequent secretion of SEAP , which can be monitored using the colorimetric reactive QUANTI-Blue ( TM ) ( Invivogen , San Diego , CA , USA ) .	Upon IL-6 stimulation, HEK-Blue (TM) IL-6 cells trigger the activation of STAT3 and the subsequent secretion of SEAP, which can be monitored using the colorimetric reactive QUANTI-Blue (TM) (Invivogen, San Diego, CA, USA).	8	15	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	14	15
In summary , our findings reveal a systemic mechanism of resistance via the activation of STAT3 by IL-6 from MSCs , with the subsequent up-regulation of MRP and MDR-1 expression .	In summary, our findings reveal a systemic mechanism of resistance via the activation of STAT3 by IL-6 from MSCs, with the subsequent up-regulation of MRP and MDR-1 expression.	5	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	15	16
The production of IL-6 by MSCs could interact with its cognate receptor in BCCs to activate STAT3 [ XREF_BIBR ] .	The production of IL-6 by MSCs could interact with its cognate receptor in BCCs to activate STAT3 [XREF_BIBR].	1	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	16	17
To evaluate the contributions of Stat3 and ERK1/2 signaling to IL-6-induced PC cell migration , DU145 cells were infected with lentiviruses expressing Stat3 shRNA and/or ERK1/2 shRNA and treated with IL-6 ( 5 nM ) for 72 h , after which the cells were tested for migratory potential in Boyden chamber assays for 16 h. IL-6 significantly increased migration of DU145 cells ( p = 0.0017 ) ( XREF_FIG ) .	To evaluate the contributions of Stat3 and ERK1/2 signaling to IL-6-induced PC cell migration, DU145 cells were infected with lentiviruses expressing Stat3 shRNA and/or ERK1/2 shRNA and treated with IL-6 (5 nM) for 72 h, after which the cells were tested for migratory potential in Boyden chamber assays for 16 h. IL-6 significantly increased migration of DU145 cells (p = 0.0017) (XREF_FIG).	22	36	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	30	31	22	23
It has been shown that IL-6 directly activates the signal transducer and activator of transcription 3 ( STAT3 ) , which in turn modulate CRP gene transcription .	It has been shown that IL-6 directly activates the signal transducer and activator of transcription 3 (STAT3), which in turn modulate CRP gene transcription.	5	27	directly activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	STAT3	STAT3), which in turn modulate CRP gene transcription	stat3	5	6	17	18
Consistently , in LPS treated BMDMs IL-10 and IL-6 caused a comparable Stat3 activation after 30 min of cytokine treatment whereas after 2 h Stat3 remained active only in cells stimulated with IL-10 but not IL-6 ( XREF_SUPPLEMENTARY ) .	Consistently, in LPS treated BMDMs IL-10 and IL-6 caused a comparable Stat3 activation after 30 min of cytokine treatment whereas after 2 h Stat3 remained active only in cells stimulated with IL-10 but not IL-6 (XREF_SUPPLEMENTARY).	6	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	8	9	12	13
SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10 .	SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10.	2	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	5	6
Therefore , it is reasonable that these two structurally distinct PPARgamma agonists suppress IL-6 activated STAT3 through diverse molecular mechanisms .	Therefore, it is reasonable that these two structurally distinct PPARgamma agonists suppress IL-6 activated STAT3 through diverse molecular mechanisms.	13	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	15	16
IL-6 had been shown activating the STAT3 and RORgammat signaling pathway , which can induce Th17 cells secreting IL-6 , IL-17 and other cytokines .	IL-6 had been shown activating the STAT3 and RORgammat signaling pathway, which can induce Th17 cells secreting IL-6, IL-17 and other cytokines.	0	14	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
Breast cancer cells expressed IL-6 receptor ( XREF_SUPPLEMENTARY ) and IL-6 activated STAT3 ( XREF_SUPPLEMENTARY ) .	Breast cancer cells expressed IL-6 receptor (XREF_SUPPLEMENTARY) and IL-6 activated STAT3 (XREF_SUPPLEMENTARY).	4	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	12	13
In addition , we have also recently reported that STAT3 activation induced by IL-6 is inhibited by endogenously generated nitric oxide ( NO ) from inducible NO synthase ( iNOS ) or exogenously supplemented GSNO via S nitrosylation of Cysteine 259 residue of STAT3 molecule , documenting that STAT3 S nitrosylation is a physiological regulation XREF_BIBR .	In addition, we have also recently reported that STAT3 activation induced by IL-6 is inhibited by endogenously generated nitric oxide (NO) from inducible NO synthase (iNOS) or exogenously supplemented GSNO via S nitrosylation of Cysteine 259 residue of STAT3 molecule, documenting that STAT3 S nitrosylation is a physiological regulation XREF_BIBR.	9	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	9	10
It is known that STAT-3 , activated by IL-6 in hypatocytes , promotes HCC cell growth in vitro and in vivo [ XREF_BIBR ] .	It is known that STAT-3, activated by IL-6 in hypatocytes, promotes HCC cell growth in vitro and in vivo [XREF_BIBR].	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	8	9	4	5
For instance , the paracrine sources of IL-6 from cancer associated fibroblasts , adipocytes , or myeloid cells on the edge of the tumors and the autocrine production of IL-6 can both activate the STAT3 .	For instance, the paracrine sources of IL-6 from cancer associated fibroblasts, adipocytes, or myeloid cells on the edge of the tumors and the autocrine production of IL-6 can both activate the STAT3.	5	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	34	35
IL-6 , which is a downstream gene of TNF-alpha and NF-kappaB , activates signal transducer and STAT-3 pathways XREF_BIBR , XREF_BIBR , XREF_BIBR .	IL-6, which is a downstream gene of TNF-alpha and NF-kappaB, activates signal transducer and STAT-3 pathways XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	0	1	16	17
Caco2-BBE cells , which are responsive to IL-6 , show decreased basal and IL-6- induced STAT3 activation , and decreased Bcl-xL and Bcl-2 protein expression when PHB is overexpressed ( XREF_FIG ) .	Caco2-BBE cells, which are responsive to IL-6, show decreased basal and IL-6- induced STAT3 activation, and decreased Bcl-xL and Bcl-2 protein expression when PHB is overexpressed (XREF_FIG).	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6-	IL-6-	IL-6-	STAT3	STAT3	STAT3	13	14	15	16
This interaction , which does not seem to involve a classical phosphotyrosine SH2 mediated binding , however , significantly enhances the interaction of Stat3 and the IL-6 receptor subunit glycoprotein ( gp ) 130 , which is the initial step for Stat3 activation by IL-6 .	This interaction, which does not seem to involve a classical phosphotyrosine SH2 mediated binding, however, significantly enhances the interaction of Stat3 and the IL-6 receptor subunit glycoprotein (gp) 130, which is the initial step for Stat3 activation by IL-6.	41	45	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	44	45	41	42
The transcription factor STAT3 is activated by cytokines of the IL-6 family .	The transcription factor STAT3 is activated by cytokines of the IL-6 family.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	3	4
IL-6 activates STAT-3 , a transcription factor that is required for expression of RORgammaT , a key transcription factor required for IL-17A production .	IL-6 activates STAT-3, a transcription factor that is required for expression of RORgammaT, a key transcription factor required for IL-17A production.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	0	1	2	3
STAT3 , known as the acute-phase response element , was first described in hepatocytes and can be activated by the interleukin-6 ( IL-6 ) cytokine family , type I interferon and epidermal growth factor ( EGF ) .	STAT3, known as the acute-phase response element, was first described in hepatocytes and can be activated by the interleukin-6 (IL-6) cytokine family, type I interferon and epidermal growth factor (EGF).	0	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	20	21	0	1
In addition to relative expression of miR-21 in STAT3 transfected groups treated with IL-6 were 0.54 +/- 0.08 and 0.51 +/- 0.13 in DU145 and LNCaP cells , respectively .	In addition to relative expression of miR-21 in STAT3 transfected groups treated with IL-6 were 0.54 +/- 0.08 and 0.51 +/- 0.13 in DU145 and LNCaP cells, respectively.	6	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	8	9
DFO also decreased IL6 induced p-STAT3 , whereas iron supplementation or DMT1 overexpression activated p-STAT3 , in a JAK dependent manner ( XREF_FIG ) .	DFO also decreased IL6 induced p-STAT3, whereas iron supplementation or DMT1 overexpression activated p-STAT3, in a JAK dependent manner (XREF_FIG).	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	p-STAT3	p-STAT3	p-STAT3	3	4	5	6
Particularly , the STAT3 pathway can be strongly activated by LMP1 via JAK3 kinase or an increase of IL6 secretion .	Particularly, the STAT3 pathway can be strongly activated by LMP1 via JAK3 kinase or an increase of IL6 secretion.	3	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	18	19	3	4
Therefore , it is tempting to hypothesize that the synergistic STAT3 activation by IL-6 and CHI3L1 in IECs , demonstrated in our current study , also serves to enhance immune regulation under the harsh inflammatory environment .	Therefore, it is tempting to hypothesize that the synergistic STAT3 activation by IL-6 and CHI3L1 in IECs, demonstrated in our current study, also serves to enhance immune regulation under the harsh inflammatory environment.	10	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	10	11
Our data indicate that Salmonella AvrA upregulates IL-6 , which in turn activates STAT3 and enhances proliferation .	Our data indicate that Salmonella AvrA upregulates IL-6, which in turn activates STAT3 and enhances proliferation.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	13	14
Increased expression of either IL6 or OSM in the context of PTEN loss resulted in increased activation of STAT3 over PTEN loss alone , indicating a potential molecular mechanism .	Increased expression of either IL6 or OSM in the context of PTEN loss resulted in increased activation of STAT3 over PTEN loss alone, indicating a potential molecular mechanism.	1	21	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IL6	expression of either IL6	il6	STAT3	STAT3	stat3	4	5	18	19
IL-6 activation of STAT3 via JAK was first demonstrated with in vitro studies on U266 cell lines , a human autocrine IL-6 dependent MM cell line .	IL-6 activation of STAT3 via JAK was first demonstrated with in vitro studies on U266 cell lines, a human autocrine IL-6 dependent MM cell line.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
In sinusoidal endothelial cells or hepatic stellate cells , IL-6 induces STAT3 activation and subsequently promotes cell survival XREF_BIBR .	In sinusoidal endothelial cells or hepatic stellate cells, IL-6 induces STAT3 activation and subsequently promotes cell survival XREF_BIBR.	9	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
In addition , it has been reported that IL-6 autocrine activates STAT3 in an EGFR independent manner and contribute to HNSCC cells proliferation XREF_BIBR , however , we found that IL-6 level was not changed in EGF treated cells .	In addition, it has been reported that IL-6 autocrine activates STAT3 in an EGFR independent manner and contribute to HNSCC cells proliferation XREF_BIBR, however, we found that IL-6 level was not changed in EGF treated cells.	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	11	12
Recent studies have also shown that sustained STAT3 activation is mediated by IL-6 in ovarian carcinoma , cholangiocarcinoma , colon cancer and lung adenocarcinoma XREF_BIBR - XREF_BIBR .	Recent studies have also shown that sustained STAT3 activation is mediated by IL-6 in ovarian carcinoma, cholangiocarcinoma, colon cancer and lung adenocarcinoma XREF_BIBR - XREF_BIBR.	7	26	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	7	8
GW501516 prevents the increase in SOCS3 protein levels and STAT3 activity induced by IL-6 in vivo .	GW501516 prevents the increase in SOCS3 protein levels and STAT3 activity induced by IL-6 in vivo.	9	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	9	10
We found that IL-6 , but not CNTF or LIF , activated STAT3 in Schwann cells .	We found that IL-6, but not CNTF or LIF, activated STAT3 in Schwann cells.	3	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	12	13
Treatment with the JAK1/2 inhibitor ruxolitinib XREF_BIBR blocked IL6 mediated STAT3 activation in vitro ( XREF_SUPPLEMENTARY ) and decreased pSTAT3 levels in primary tumours and in bone metastases ( XREF_FIG ) .	Treatment with the JAK1/2 inhibitor ruxolitinib XREF_BIBR blocked IL6 mediated STAT3 activation in vitro (XREF_SUPPLEMENTARY) and decreased pSTAT3 levels in primary tumours and in bone metastases (XREF_FIG).	7	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	8	9	10	11
IL-6 stimulated STAT3 activation and membrane localization of the IL-6 Signaling Complex are increased in Immortalized B-cell lines from IBD patients carrying the STAT3 risk allele .	IL-6 stimulated STAT3 activation and membrane localization of the IL-6 Signaling Complex are increased in Immortalized B-cell lines from IBD patients carrying the STAT3 risk allele.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
XREF_BIBR Moreover , mice overexpressing both IL-6 and its cognate receptor , which promoted sustained STAT3 activation , also show ventricular hypertrophy .	XREF_BIBR Moreover, mice overexpressing both IL-6 and its cognate receptor, which promoted sustained STAT3 activation, also show ventricular hypertrophy.	4	16	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	15	16
In addition , IL-6 activation rapidly induces Stat3 repressor SOCS3 [ XREF_BIBR ] .	In addition, IL-6 activation rapidly induces Stat3 repressor SOCS3 [XREF_BIBR].	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	7	8
Moreover , we demonstrated that injection of IL-6 into virgin and lactating mice activates Stat3 in mammary epithelium .	Moreover, we demonstrated that injection of IL-6 into virgin and lactating mice activates Stat3 in mammary epithelium.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	7	8	14	15
To study whether the IL-6 induced STAT3 activation protected Cyld -/- mice from lethal listeriosis by increased fibrin production , in vivo IL-6 , STAT3 and fibrin neutralization experiments were performed .	To study whether the IL-6 induced STAT3 activation protected Cyld -/- mice from lethal listeriosis by increased fibrin production, in vivo IL-6, STAT3 and fibrin neutralization experiments were performed.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
STAT3 activation is induced not only by IL-6 but also by IL-21 and IL-23 .	STAT3 activation is induced not only by IL-6 but also by IL-21 and IL-23.	0	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	0	1
Moreover , DC maturation is inhibited by the downregulation of the STAT3 pathway mediated by secretion of IL-6 by tumour cells .	Moreover, DC maturation is inhibited by the downregulation of the STAT3 pathway mediated by secretion of IL-6 by tumour cells.	11	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	11	12
XREF_FIG , TPA ( 100nM ) and IL-6 ( 10 ng/mL ) treatment for 1h significantly induced STAT3 activation while pretreatment of cells with 45muM ALT for 4h effectively inhibited TPA- and IL-6-induced activation of STAT3 in A549 cells .	XREF_FIG, TPA (100nM) and IL-6 (10 ng/mL) treatment for 1h significantly induced STAT3 activation while pretreatment of cells with 45muM ALT for 4h effectively inhibited TPA- and IL-6-induced activation of STAT3 in A549 cells.	4	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	17	18
In M1 acute myeloid leukemia cells , the pleiotropic cytokines IL-6 and LIF , which activate STAT3 , promote growth arrest and terminal differentiation of leukemic cells [ XREF_BIBR ] .	In M1 acute myeloid leukemia cells, the pleiotropic cytokines IL-6 and LIF, which activate STAT3, promote growth arrest and terminal differentiation of leukemic cells [XREF_BIBR].	7	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	16	17
However , association of the IL-6 receptor with the EGFR can activate STAT3 in presence of the inhibition of SOCS3 to JAK1 and JAK2 XREF_BIBR .	However, association of the IL-6 receptor with the EGFR can activate STAT3 in presence of the inhibition of SOCS3 to JAK1 and JAK2 XREF_BIBR.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	12	13
XREF_BIBR - XREF_BIBR These studies revealed that IL-6 triggered a STAT3 signalling cascade in hepatocytes that induced expression of anti-apoptotic and antioxidant genes , thereby promoting hepatocyte survival .	XREF_BIBR - XREF_BIBR These studies revealed that IL-6 triggered a STAT3 signalling cascade in hepatocytes that induced expression of anti-apoptotic and antioxidant genes, thereby promoting hepatocyte survival.	7	12	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	10	11
Our results suggested that the IL-17-mediated tumor promoting role involves a direct effect on tumor through IL-6 induction , which in turn activates Stat3 in both tumor as well as nontransformed cells constituting the tumor microenvironment .	Our results suggested that the IL-17-mediated tumor promoting role involves a direct effect on tumor through IL-6 induction, which in turn activates Stat3 in both tumor as well as nontransformed cells constituting the tumor microenvironment.	16	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	16	17	23	24
nucleatum triggers TLR signaling , resulting in IL-6 production that activates STAT3 which in turn induces important effectors driving oral cavity SCC growth and invasiveness ( i.e ., cyclin D1 , MMP9 , heparanase ) .	nucleatum triggers TLR signaling, resulting in IL-6 production that activates STAT3 which in turn induces important effectors driving oral cavity SCC growth and invasiveness (i.e., cyclin D1, MMP9, heparanase).	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	11	12
Whereas IL-22 and hIL-6 induced a strong expression of STAT3 target genes , IL-6 did not induce any STAT3 driven gene expression ( XREF_FIG ) .	Whereas IL-22 and hIL-6 induced a strong expression of STAT3 target genes, IL-6 did not induce any STAT3 driven gene expression (XREF_FIG).	13	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	18	19
As a result , we observed that IL-6 stimulated STAT3 transcriptional activity in a concentration dependent manner .	As a result, we observed that IL-6 stimulated STAT3 transcriptional activity in a concentration dependent manner.	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
In this case , it is likely that GFAP upregulation would be mediated solely by the JAK and STAT3 cascade potentially initiated by BM-MSC-secreted CNTF and IL6 .	In this case, it is likely that GFAP upregulation would be mediated solely by the JAK and STAT3 cascade potentially initiated by BM-MSC-secreted CNTF and IL6.	16	27	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	26	27	18	19
IL-6 trans-signaling induces STAT3 activity in hippocampus of aged mice .	IL-6 trans-signaling induces STAT3 activity in hippocampus of aged mice.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
The reason why STAT3 activation by IL-10 or IL-6 inhibits or promotes , respectively , the macrophage inflammatory response remains unclear .	The reason why STAT3 activation by IL-10 or IL-6 inhibits or promotes, respectively, the macrophage inflammatory response remains unclear.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	3	4
Cytokine expression profiles induced by TLR agonists and results from subsequent functional assays indicated that interleukin-6 ( IL-6 ) together with soluble IL-6 receptor ( sIL-6R ) enhanced osteogenic differentiation of ASCs by activating STAT3 .	Cytokine expression profiles induced by TLR agonists and results from subsequent functional assays indicated that interleukin-6 (IL-6) together with soluble IL-6 receptor (sIL-6R) enhanced osteogenic differentiation of ASCs by activating STAT3.	15	35	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	15	16	34	35
However , IL-6 was found to enhance Stat3 activity leading to cell growth and treatment with Jak2 inhibitor suppressed Stat3 phosphorylation but not FAK phosphorylation thus cell migration was not affected .	However, IL-6 was found to enhance Stat3 activity leading to cell growth and treatment with Jak2 inhibitor suppressed Stat3 phosphorylation but not FAK phosphorylation thus cell migration was not affected.	2	8	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	7	8
In keeping with this finding , we also demonstrated that the IL-6 inducer STAT3 is constitutively activated in adipocytes from CRC individuals .	In keeping with this finding, we also demonstrated that the IL-6 inducer STAT3 is constitutively activated in adipocytes from CRC individuals.	10	16	inducer	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	13	14
In murine Th17cells differentiated with IL-6 and TGF-beta in vitro , IL-6 was found to activate Stat3 , while TGF-beta suppressed the transcription factor Gfi-1 .	In murine Th17cells differentiated with IL-6 and TGF-beta in vitro, IL-6 was found to activate Stat3, while TGF-beta suppressed the transcription factor Gfi-1.	11	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	11	12	16	17
UA also inhibited the activation of STAT3 induced by interleukin-6 in DLD-1 colon cancer cells .	UA also inhibited the activation of STAT3 induced by interleukin-6 in DLD-1 colon cancer cells.	4	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	9	10	6	7
IL-6 activates STAT3 , whereas IL-10 inhibits the activation of STAT3 during tumor growth inhibition .	IL-6 activates STAT3, whereas IL-10 inhibits the activation of STAT3 during tumor growth inhibition.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Multiple myeloma cells , which lack constitutively active STAT3 , were treated with IL-6 for different times and then examined for phosphorylated STAT3 .	Multiple myeloma cells, which lack constitutively active STAT3, were treated with IL-6 for different times and then examined for phosphorylated STAT3.	5	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	8	9
In conclusion , prednisone , ibuprofen and betamethasone may prevent OA by suppressing the expression of IL-6 and IL-8 , subsequently inactivating NF-kappaB and STAT3 pathways , and ultimately , leading to decreased levels of collagen I , MMP-1 , and MMP-13 .	In conclusion, prednisone, ibuprofen and betamethasone may prevent OA by suppressing the expression of IL-6 and IL-8, subsequently inactivating NF-kappaB and STAT3 pathways, and ultimately, leading to decreased levels of collagen I, MMP-1, and MMP-13.	3	25	inactivating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	prednisone, ibuprofen and betamethasone may prevent OA by suppressing the expression of IL-6	il-6	STAT3	STAT3	stat3	16	17	24	25
STAT3 activation is induced by IL-6 , IL-21 , and IL-23 , and activated STAT3 directly binds to the STAT binding sites on the IL-17 gene promoter , increases IL-17 gene transcription , and then affects the expression of IL-17 by increasing the expression of RORgammat and RORalpha [ XREF_BIBR , XREF_BIBR ] .	STAT3 activation is induced by IL-6, IL-21, and IL-23, and activated STAT3 directly binds to the STAT binding sites on the IL-17 gene promoter, increases IL-17 gene transcription, and then affects the expression of IL-17 by increasing the expression of RORgammat and RORalpha [XREF_BIBR, XREF_BIBR].	0	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
Moreover , IL-6 driven STAT3 signaling induced the formation of a cancer stem like population from non stem PCa cells [ XREF_BIBR , XREF_BIBR ] , which could be inhibited by treatment with the small molecule STAT3 inhibitor , Stattic [ XREF_BIBR ] .	Moreover, IL-6 driven STAT3 signaling induced the formation of a cancer stem like population from non stem PCa cells [XREF_BIBR, XREF_BIBR], which could be inhibited by treatment with the small molecule STAT3 inhibitor, Stattic [XREF_BIBR].	2	6	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
XREF_FIG , sIL-6R and IL-6 is a stronger inducer of STAT3 than of STAT1 phosphorylation and , conversely , IL-27 mediates stronger STAT1 and weaker STAT3 phosphorylation , in NCI-H69 cells .	XREF_FIG, sIL-6R and IL-6 is a stronger inducer of STAT3 than of STAT1 phosphorylation and, conversely, IL-27 mediates stronger STAT1 and weaker STAT3 phosphorylation, in NCI-H69 cells.	0	11	is a stronger inducer	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	10	11
However , IL-6 also induces STAT3 dependent upregulation of IL-23 receptor .	However, IL-6 also induces STAT3 dependent upregulation of IL-23 receptor.	2	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	5	6
Moreover , the data from xenograft tumors demonstrated that inhibition of IL-6 attenuated angiogenesis and decreased p-STAT3 activation after irradiation .	Moreover, the data from xenograft tumors demonstrated that inhibition of IL-6 attenuated angiogenesis and decreased p-STAT3 activation after irradiation.	9	17	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	11	12	16	17
The activation of STAT3 by IL-6 has been proved to promote CSCs growth and proliferation [ XREF_BIBR ] .	The activation of STAT3 by IL-6 has been proved to promote CSCs growth and proliferation [XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	3	4
Th17 cells are characterized by high expression of the transcription factors retinoid orphan receptor ( ROR ) alpha and RORgammaT driven by IL-6 and TGF-beta signaling through STAT3 and SMAD pathways , respectively .	Th17 cells are characterized by high expression of the transcription factors retinoid orphan receptor (ROR) alpha and RORgammaT driven by IL-6 and TGF-beta signaling through STAT3 and SMAD pathways, respectively.	20	30	driven	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	27	28
Together , these data led us to hypothesize that IL6 may activate STAT3 in GSCs to contribute to GBM progression .	Together, these data led us to hypothesize that IL6 may activate STAT3 in GSCs to contribute to GBM progression.	8	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	9	10	12	13
1 Stat3 can be activated by the entire family of interleukin-6 ( IL-6 )-type cytokines , IL-10 , IL-22 , IL-17 , and IL-23 epidermal growth factor , leukemia inhibitory factor , basic fibroblast growth factor , oncostatin M , and the ciliary neurotrophic factor family of cytokines .	1 Stat3 can be activated by the entire family of interleukin-6 (IL-6)-type cytokines, IL-10, IL-22, IL-17, and IL-23 epidermal growth factor, leukemia inhibitory factor, basic fibroblast growth factor, oncostatin M, and the ciliary neurotrophic factor family of cytokines.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	Stat3	Stat3	Stat3	10	11	1	2
IL-6 initiates Th17 differentiation by activating STAT3 .	IL-6 initiates Th17 differentiation by activating STAT3.	0	7	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
In contrast , IL-6 induced Stat3 activation ( XREF_SUPPLEMENTARY ) but did not affect DUOX2 or VEGF-A mRNA expression ( XREF_SUPPLEMENTARY ) .	In contrast, IL-6 induced Stat3 activation (XREF_SUPPLEMENTARY) but did not affect DUOX2 or VEGF-A mRNA expression (XREF_SUPPLEMENTARY).	3	13	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	5	6
IL-6 signals through the Janus activated kinase and signal transducers and activators of transcription 3 ( JAK and STAT3 ) , mitogen activated protein kinase and extracellular-signal regulated kinase1/2 ( MAPK/ERK1/2 ) , and phosphatidylinositol 3-kinase/Akt ( PI3K and Akt ) pathways , all of which are implicated in cancer and metastasis [ XREF_BIBR ] .	IL-6 signals through the Janus activated kinase and signal transducers and activators of transcription 3 (JAK and STAT3), mitogen activated protein kinase and extracellular-signal regulated kinase1/2 (MAPK/ERK1/2), and phosphatidylinositol 3-kinase/Akt (PI3K and Akt) pathways, all of which are implicated in cancer and metastasis [XREF_BIBR].	0	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	18	19
In macrophages , inhibited GM-CSF activation of STAT5 , and IL-6 activation of STAT3 , while not influencing IL-4 activation of STAT6 .	In macrophages, inhibited GM-CSF activation of STAT5, and IL-6 activation of STAT3, while not influencing IL-4 activation of STAT6.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	13	14
The inhibitory effect of PE on IL-6 activation of STAT3 was also abolished by the tyrosine phosphatase inhibitor sodium vanadate , indicating involvement of protein tyrosine phosphatases .	The inhibitory effect of PE on IL-6 activation of STAT3 was also abolished by the tyrosine phosphatase inhibitor sodium vanadate, indicating involvement of protein tyrosine phosphatases.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	9	10
Activated STAT3 ( P-STAT3 ) is known to mediate uncontrolled cell growth in many types of human cancers ; and IL-6 , a pro inflammatory cytokine produced as a result of active TLR signaling , is known to activate STAT3 [ reviewed in ] .	Activated STAT3 (P-STAT3) is known to mediate uncontrolled cell growth in many types of human cancers; and IL-6, a pro inflammatory cytokine produced as a result of active TLR signaling, is known to activate STAT3 [reviewed in].	20	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	39	40
Our findings provide important insights to the mechanisms of STAT3 activation induced by the IL-6 family and identify TRIM27 as a potential therapeutic target for treatment of cancer .	Our findings provide important insights to the mechanisms of STAT3 activation induced by the IL-6 family and identify TRIM27 as a potential therapeutic target for treatment of cancer.	9	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	9	10
As shown in XREF_FIG , IL6 induced Stat3 responsive luciferase reporter activity in LNCaP cells , which was reduced by niclosamide treatment .	As shown in XREF_FIG, IL6 induced Stat3 responsive luciferase reporter activity in LNCaP cells, which was reduced by niclosamide treatment.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	5	6	7	8
Similarly , IL-6 promotes angiogenesis by activating the STAT3 pathway in cervical cancer [ XREF_BIBR ] .	Similarly, IL-6 promotes angiogenesis by activating the STAT3 pathway in cervical cancer [XREF_BIBR].	2	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	8	9
This was associated with increased level of IL-6 in BALF , which activated STAT3 in alveolar type II epithelial cells and increased expression of its downstream genes in the lung .	This was associated with increased level of IL-6 in BALF, which activated STAT3 in alveolar type II epithelial cells and increased expression of its downstream genes in the lung.	5	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	level of IL-6	il-6	STAT3	STAT3	stat3	7	8	13	14
Given that CuIIb markedly suppressed IL-6 production and that the Jak and STAT3 pathway is activated by IL-6 XREF_BIBR , we tested whether STAT3 phosphorylation is affected by CuIIb treatment .	Given that CuIIb markedly suppressed IL-6 production and that the Jak and STAT3 pathway is activated by IL-6 XREF_BIBR, we tested whether STAT3 phosphorylation is affected by CuIIb treatment.	10	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	12	13
IL6 induced STAT3 activation interfered with IL-12 synthesis through suppression of C-Rel phosphorylation in irradiated-DCs .	IL6 induced STAT3 activation interfered with IL-12 synthesis through suppression of C-Rel phosphorylation in irradiated-DCs.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	2	3
STAT3 signaling in MDSCs can be modulated by IL-6 , which has been shown to enhance CSCs and EMT in cancer [ XREF_BIBR , XREF_BIBR ] .	STAT3 signaling in MDSCs can be modulated by IL-6, which has been shown to enhance CSCs and EMT in cancer [XREF_BIBR, XREF_BIBR].	0	15	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	0	1
XREF_BIBR STAT3 is stimulated by cytokines , particularly interleukin-6 ( IL-6 ) .	XREF_BIBR STAT3 is stimulated by cytokines, particularly interleukin-6 (IL-6).	0	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	8	9	1	2
The mechanism in this process was that T cell secreted lymphotoxin could stimulate IL-6 production and signal transducer and activator of transcription 3 ( STAT3 ) activation in the liver [ XREF_BIBR ] .	The mechanism in this process was that T cell secreted lymphotoxin could stimulate IL-6 production and signal transducer and activator of transcription 3 (STAT3) activation in the liver [XREF_BIBR].	13	25	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	24	25
Human recombinant IL-6 activated STAT3 and human IL-4 activated STAT6 .	Human recombinant IL-6 activated STAT3 and human IL-4 activated STAT6.	0	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
Interestingly , although IL-6 , IL-10 , and IL-22 all stimulate STAT3 , only IL-22 seems to have solely anti-inflammatory effects protecting against acute and chronic liver damage .	Interestingly, although IL-6, IL-10, and IL-22 all stimulate STAT3, only IL-22 seems to have solely anti-inflammatory effects protecting against acute and chronic liver damage.	3	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	11	12
One possibility is suggested by the findings that injection of IL-6 into rodents activates Stat3 and stimulates muscle proteolysis .	One possibility is suggested by the findings that injection of IL-6 into rodents activates Stat3 and stimulates muscle proteolysis.	8	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	10	11	14	15
In the DNA pull down assay , IL-6 activated STAT3 proteins prepared from HepG2 nuclear fractions were precipitated by AGG-oligonucleotide beads as well as SIE-oligonucleotide beads as the positive control .	In the DNA pull down assay, IL-6 activated STAT3 proteins prepared from HepG2 nuclear fractions were precipitated by AGG-oligonucleotide beads as well as SIE-oligonucleotide beads as the positive control.	7	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
XREF_FIG showed that IL-6 could stimulate STAT3 activity after 24-hour treatment , which was reversed by either IL-6 neutralizing antibody siltuximab ( 20 mug/mL ) or JAKs inhibitor P6 ( 2.5 muM ) .	XREF_FIG showed that IL-6 could stimulate STAT3 activity after 24-hour treatment, which was reversed by either IL-6 neutralizing antibody siltuximab (20 mug/mL) or JAKs inhibitor P6 (2.5 muM).	3	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	6	7
Following gp130 dimerization , IL-6 activates multiple signaling pathways ( Ras dependent MAP Kinase cascade , STAT1 and STAT3 heterodimer pathway , and STAT3 homodimer pathway ) [ XREF_BIBR - XREF_BIBR ] .	Following gp130 dimerization, IL-6 activates multiple signaling pathways (Ras dependent MAP Kinase cascade, STAT1 and STAT3 heterodimer pathway, and STAT3 homodimer pathway) [XREF_BIBR - XREF_BIBR].	4	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	23	24
IL-6 is a strong inducer of STAT3 and by inference STAT3 was implicated in left ventricular hypertrophy and dysfunction in this study .	IL-6 is a strong inducer of STAT3 and by inference STAT3 was implicated in left ventricular hypertrophy and dysfunction in this study.	0	7	is a strong inducer	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
For example , miR-146b increase with age and repress the senescence associated proinflammatory cytokines IL-6 and IL-8 Activator of transcription 3 ( STAT3 ) and interleukin-6 ( IL-6 )-mediated signal transducer could be mechanisms by which chronic inflammation contributes to breast cancer such as a common oncogenic event .	For example, miR-146b increase with age and repress the senescence associated proinflammatory cytokines IL-6 and IL-8 Activator of transcription 3 (STAT3) and interleukin-6 (IL-6)-mediated signal transducer could be mechanisms by which chronic inflammation contributes to breast cancer such as a common oncogenic event.	14	23	Activator	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	22	23
However , IL-6 is known to activate STAT3 , which has a crucial role in radiation induced inflammatory responses .	However, IL-6 is known to activate STAT3, which has a crucial role in radiation induced inflammatory responses.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	7	8
Reports suggested that IL-6 elicits STAT3 activation and which in turn facilitates the survival of cells [ XREF_BIBR ] .	Reports suggested that IL-6 elicits STAT3 activation and which in turn facilitates the survival of cells [XREF_BIBR].	3	6	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
In addition to suppressing constitutive activity of STAT3 in MM cell lines and primary tumor samples , our data show that LLL12 prevents STAT3 activation induced through cytokine stimulation , including IFN-alpha and IL-6 .	In addition to suppressing constitutive activity of STAT3 in MM cell lines and primary tumor samples, our data show that LLL12 prevents STAT3 activation induced through cytokine stimulation, including IFN-alpha and IL-6.	23	34	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	33	34	23	24
IL-17 then promotes tumor growth through IL-6 induction , which in turn activates Stat3 in tumors .	IL-17 then promotes tumor growth through IL-6 induction, which in turn activates Stat3 in tumors.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	13	14
Unlike Stat3 +/+ CD4 cells , IL-6 failed to increase cytosolic Ca 2+ in Stat3 -/- CD4 cells ( XREF_FIG ) .	Unlike Stat3 +/+ CD4 cells, IL-6 failed to increase cytosolic Ca 2+ in Stat3 -/- CD4 cells (XREF_FIG).	6	17	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	14	15
These findings suggest that IL-6 secreted by CAFs promotes stem cell like properties in HCC cells by enhancing STAT3 and Notch signaling .	These findings suggest that IL-6 secreted by CAFs promotes stem cell like properties in HCC cells by enhancing STAT3 and Notch signaling.	4	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	18	19
Stat3 activation by IL-6 and IL-10 was also inhibited by LPS , as was observed after in vivo challenge with bacteria .	Stat3 activation by IL-6 and IL-10 was also inhibited by LPS, as was observed after in vivo challenge with bacteria.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	0	1
These findings suggest that the protective effect of STAT3 on beta-cell DNA integrity may not only depend on IL6 induced activation of STAT3 .	These findings suggest that the protective effect of STAT3 on beta-cell DNA integrity may not only depend on IL6 induced activation of STAT3.	16	23	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	18	19	22	23
IL-6 promotes STAT3 , which induces retinoic orphan receptor ( ROR ) transcription factors , RORalpha and RORgammaT , leading to production of Th 17 cytokines IL-17 , IL-17F , and IL-22 [ XREF_BIBR , XREF_BIBR ] .	IL-6 promotes STAT3, which induces retinoic orphan receptor (ROR) transcription factors, RORalpha and RORgammaT, leading to production of Th 17 cytokines IL-17, IL-17F, and IL-22 [XREF_BIBR, XREF_BIBR].	0	5	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Autocrine IL-6 signaling in PCa cells induces the constitutive activation of STAT3 , enhancing recruitment of the AR to the PSA promoter and rendering these cells resistant to the new generation anti-androgen Enzalutamide , which can be reversed by treatment with a STAT3 inhibitor [ XREF_BIBR ] .	Autocrine IL-6 signaling in PCa cells induces the constitutive activation of STAT3, enhancing recruitment of the AR to the PSA promoter and rendering these cells resistant to the new generation anti-androgen Enzalutamide, which can be reversed by treatment with a STAT3 inhibitor [XREF_BIBR].	1	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	11	12
Briefly , IL-6 induced STAT3 activation through the IL6R-gp130-JAK pathway XREF_BIBR , while IFNgamma and IFNalpha induced it by activating Type II- and Type I- interferon receptor-JAK pathway respectively XREF_BIBR .	Briefly, IL-6 induced STAT3 activation through the IL6R-gp130-JAK pathway XREF_BIBR, while IFNgamma and IFNalpha induced it by activating Type II- and Type I- interferon receptor-JAK pathway respectively XREF_BIBR.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
In addition , several other IL-6 family cytokines and IL-22 , which activate STAT3 in hepatocytes , are also reported to promote liver regeneration XREF_BIBR , XREF_BIBR , XREF_BIBR , while the anti-inflammatory cytokine IL-10 , which activates STAT3 in immune cells , has been shown to inhibit liver regeneration via suppression of the proinflammatory response during liver regeneration XREF_BIBR .	In addition, several other IL-6 family cytokines and IL-22, which activate STAT3 in hepatocytes, are also reported to promote liver regeneration XREF_BIBR, XREF_BIBR, XREF_BIBR, while the anti-inflammatory cytokine IL-10, which activates STAT3 in immune cells, has been shown to inhibit liver regeneration via suppression of the proinflammatory response during liver regeneration XREF_BIBR.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	13	14
In cultured cervical cancer cells , however , efficient STAT3 activation can only be elicited by IL-6 in the presence of soluble gp80 ( sgp80 ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In cultured cervical cancer cells, however, efficient STAT3 activation can only be elicited by IL-6 in the presence of soluble gp80 (sgp80) [XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	17	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	9	10
In conclusion the results presented here suggest that , among the multiple pathways that are activated in NSCLC , aberrant PI3K and Akt signalling contributes to promote and/or maintain NSCLC TICs by eliciting an autocrine IL-6 and IL-6r loop that activates the transcription factor STAT3 .	In conclusion the results presented here suggest that, among the multiple pathways that are activated in NSCLC, aberrant PI3K and Akt signalling contributes to promote and/or maintain NSCLC TICs by eliciting an autocrine IL-6 and IL-6r loop that activates the transcription factor STAT3.	32	45	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	35	36	44	45
In the above described experiments , IL-6 activated STAT1 and STAT3 and induced three main phenomena in LNCaP-JAK1 cells : antiviral state , cytostasis , and oncolysis upon non productive EHDV-TAU infection .	In the above described experiments, IL-6 activated STAT1 and STAT3 and induced three main phenomena in LNCaP-JAK1 cells : antiviral state, cytostasis, and oncolysis upon non productive EHDV-TAU infection.	6	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	10	11
In comparison to BSA controls , IL-6 activated the JAK and STAT3 pathway as indicated by increased pSTAT3 staining in RGCs and cells of the inner nuclear layer within the first 6h after injection ( XREF_FIG ) .	In comparison to BSA controls, IL-6 activated the JAK and STAT3 pathway as indicated by increased pSTAT3 staining in RGCs and cells of the inner nuclear layer within the first 6h after injection (XREF_FIG).	6	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	11	12
Activation of STAT3 by IL-6 is associated with inhibition of apoptosis , increased cell cycle gene expression , and activation of androgen receptor genes .	Activation of STAT3 by IL-6 is associated with inhibition of apoptosis, increased cell cycle gene expression, and activation of androgen receptor genes.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	2	3
A chromatin immunoprecipitation assay showed that IL-6 induced binding of phospho-Stat3 to a putative Stat3 site in the apelin promoter ; mutation of this site abrogated the LPS induced elevation in apelin promoter activity .	A chromatin immunoprecipitation assay showed that IL-6 induced binding of phospho-Stat3 to a putative Stat3 site in the apelin promoter; mutation of this site abrogated the LPS induced elevation in apelin promoter activity.	6	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	phospho-Stat3	phospho-Stat3	phospho-Stat3	6	7	10	11
However , high STAT3 activation was observed when C3H10T1/2 cells were treated with recombinant mouse Il-6 ( data not shown ) .	However, high STAT3 activation was observed when C3H10T1/2 cells were treated with recombinant mouse Il-6 (data not shown).	3	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Il-6	Il-6	Il-6	STAT3	STAT3	STAT3	15	16	3	4
Although it is generally accepted that both IL-6 and IL-23 activate STAT3 to in turn induce upregulation of Th17 hallmark transcription factor ROR-gammat , how AhR regulates IL-22 remains unclear .	Although it is generally accepted that both IL-6 and IL-23 activate STAT3 to in turn induce upregulation of Th17 hallmark transcription factor ROR-gammat, how AhR regulates IL-22 remains unclear.	6	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	11	12
Recombinant IL-6 was used to induce Stat3 activation ( XREF_FIG top left corner ) , and treatment of miR-185 overexpressed cells with IL-6 resulted in much more insulin secretion ( XREF_FIG ) , cell growth and viability ( XREF_FIG ) , and even less apoptosis ( XREF_FIG ) .	Recombinant IL-6 was used to induce Stat3 activation (XREF_FIG top left corner), and treatment of miR-185 overexpressed cells with IL-6 resulted in much more insulin secretion (XREF_FIG), cell growth and viability (XREF_FIG), and even less apoptosis (XREF_FIG).	0	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	6	7
In EC9706 cells , IL-6 , EGF , LIF and INF-gammaall activated STAT3 in a dose dependent manner , although the level of total STAT3 was not increased during the 30-minutes treatment .	In EC9706 cells, IL-6, EGF, LIF and INF-gammaall activated STAT3 in a dose dependent manner, although the level of total STAT3 was not increased during the 30-minutes treatment.	4	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	12	13
U266 is an immortal human B lymphocyte cell line that expresses high levels of the anti-apoptotic proteins through autocrine IL-6 induced STAT3 activation [ XREF_BIBR ] and constitutive NF-kappaB activation [ XREF_BIBR ] .	U266 is an immortal human B lymphocyte cell line that expresses high levels of the anti-apoptotic proteins through autocrine IL-6 induced STAT3 activation [XREF_BIBR] and constitutive NF-kappaB activation [XREF_BIBR].	16	22	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	21	22
Previous reports demonstrated that STAT3 activation induced by IL-6 is per se sufficient to induce muscle fiber wasting in vitro as well as in vivo and that STAT3 inhibition would abolish skeletal muscle wasting downstream of IL-6 in cancer cachexia models [ XREF_BIBR , XREF_BIBR ] .	Previous reports demonstrated that STAT3 activation induced by IL-6 is per se sufficient to induce muscle fiber wasting in vitro as well as in vivo and that STAT3 inhibition would abolish skeletal muscle wasting downstream of IL-6 in cancer cachexia models [XREF_BIBR, XREF_BIBR].	4	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	4	5
IL-6 predominantly activated JAK and STAT3 , MAPK , and PI3K and Akt signaling pathways .	IL-6 predominantly activated JAK and STAT3, MAPK, and PI3K and Akt signaling pathways.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Also , as IL-6 and STAT3 signaling has been shown to promote the differentiation of naive T cells into B cell helper T cells [ XREF_BIBR ] , the activation of STAT3 by IL-6 in CD4 + T cells may expand cellular activation to B cells to enhance the development of RA [ XREF_BIBR ] .	Also, as IL-6 and STAT3 signaling has been shown to promote the differentiation of naive T cells into B cell helper T cells [XREF_BIBR], the activation of STAT3 by IL-6 in CD4 + T cells may expand cellular activation to B cells to enhance the development of RA [XREF_BIBR].	29	38	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	33	34	31	32
We confirmed that STAT3 activation by IL-6 regulates MSCs induced chemoresistance .	We confirmed that STAT3 activation by IL-6 regulates MSCs induced chemoresistance.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	3	4
We then tested whether over-expression of GRIM-19 also can suppress IL-6 activated STAT3 signaling , HeLa cells were cultured in normal glucose and exposed to IL-6 stimulation .	We then tested whether over-expression of GRIM-19 also can suppress IL-6 activated STAT3 signaling, HeLa cells were cultured in normal glucose and exposed to IL-6 stimulation.	9	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	12	13
IL-6 and other cytokines exert their effects via the transmembrane receptor gp130 to activate Jak and STAT signaling , notably Jak2 and STAT3 .	IL-6 and other cytokines exert their effects via the transmembrane receptor gp130 to activate Jak and STAT signaling, notably Jak2 and STAT3.	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	22	23
On the other hand , STAT3 , which is mainly activated by IL-6 and its related cytokine , has key roles in acute phase responses that include protecting against liver injury and promoting liver regeneration [ XREF_BIBR - XREF_BIBR ] .	On the other hand, STAT3, which is mainly activated by IL-6 and its related cytokine, has key roles in acute phase responses that include protecting against liver injury and promoting liver regeneration [XREF_BIBR - XREF_BIBR].	5	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	5	6
From these results , we infer that arsenic induced IL-6 mediates STAT3 activation , which is crucial for miR-21 upregulation during lung carcinogenesis .	From these results, we infer that arsenic induced IL-6 mediates STAT3 activation, which is crucial for miR-21 upregulation during lung carcinogenesis.	7	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	arsenic induced IL-6	il-6	STAT3	STAT3	stat3	9	10	11	12
One may speculate that the hyper-production of IL-6 seemingly coming from the inflammatory cells present in GALT is STAT2 dependent and that a strong IL-6 activated STAT3 signaling is what drives progression of the tumors into later stages of carcinogenesis .	One may speculate that the hyper-production of IL-6 seemingly coming from the inflammatory cells present in GALT is STAT2 dependent and that a strong IL-6 activated STAT3 signaling is what drives progression of the tumors into later stages of carcinogenesis.	22	27	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	26	27
Additionally , we have shown that exogenous recombinant IL-6 , which has been previously shown to activate BSFs [ XREF_BIBR ] , up-regulates HuR and its downstream target DNMTl in a STAT3 dependent manner , and that this increase in DNMT1 level is required for the IL-6-dependent activation of BSFs .	Additionally, we have shown that exogenous recombinant IL-6, which has been previously shown to activate BSFs [XREF_BIBR], up-regulates HuR and its downstream target DNMTl in a STAT3 dependent manner, and that this increase in DNMT1 level is required for the IL-6-dependent activation of BSFs.	6	33	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	31	32
IL-17 induces IL-6 production , which in turn activates Stat3 and promotes cancer cells survival [ XREF_BIBR ] .	IL-17 induces IL-6 production, which in turn activates Stat3 and promotes cancer cells survival [XREF_BIBR].	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	9	10
IL-6 and IL-23 both activate STAT3 , and along with IL-1 and TGF-beta , these cytokines drive IL-17 production .	IL-6 and IL-23 both activate STAT3, and along with IL-1 and TGF-beta, these cytokines drive IL-17 production.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
STAT3 is activated by interleukin 6 ( IL6 , NP_000591 ) a pro inflammatory cytokine that is involved in early innate immune reactivity , as indicated by the high fever , acute phase response with increased levels of CRP ( NP_000558 ) , complement factors and fibrinogen , in the blood as well as the myriad of cellular markers altered in acute KD XREF_BIBR .	STAT3 is activated by interleukin 6 (IL6, NP_000591) a pro inflammatory cytokine that is involved in early innate immune reactivity, as indicated by the high fever, acute phase response with increased levels of CRP (NP_000558), complement factors and fibrinogen, in the blood as well as the myriad of cellular markers altered in acute KD XREF_BIBR.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	7	8	0	1
Cell based experiments suggest that the IL6 stimulated STAT3 to SOCS3 cascade causes hepatic insulin resistance by inhibiting insulin receptor signalling and increasing IRS1 degradation [ XREF_BIBR ] .	Cell based experiments suggest that the IL6 stimulated STAT3 to SOCS3 cascade causes hepatic insulin resistance by inhibiting insulin receptor signalling and increasing IRS1 degradation [XREF_BIBR].	5	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	6	7	8	9
MUC16c promoted Foxp3 expression and tumor associated Treg enrichment in tumor tissues through tumor secreted IL-6 activation of the JAK2 and STAT3 pathway .	MUC16c promoted Foxp3 expression and tumor associated Treg enrichment in tumor tissues through tumor secreted IL-6 activation of the JAK2 and STAT3 pathway.	15	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	21	22
The IL6 mediated activation of STAT3 is regulated by JAKs through cytoplasmic domain of gp130 of the IL6 receptor .	The IL6 mediated activation of STAT3 is regulated by JAKs through cytoplasmic domain of gp130 of the IL6 receptor.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	5	6
Raloxifene inhibited STAT3 activation induced by IL-6 , which induced Raoxifene at 15 mg/kg dose could reach an effective concentration in vivo .	Raloxifene inhibited STAT3 activation induced by IL-6, which induced Raoxifene at 15 mg/kg dose could reach an effective concentration in vivo.	2	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	2	3
PD180970 did not affect MAPK activation by PDGF or the JAK dependent activation of Stat3 by interleukin-6 .	PD180970 did not affect MAPK activation by PDGF or the JAK dependent activation of Stat3 by interleukin-6.	3	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	Stat3	Stat3	Stat3	16	17	14	15
This fact is well supported by the earlier reports that IL-1beta and IL-6 activates the NF-kappaB and Stat3 .	This fact is well supported by the earlier reports that IL-1beta and IL-6 activates the NF-kappaB and Stat3.	10	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	12	13	17	18
Thus , peretinoin induced autophagy and suppressed the IL6 induced activation of p-STAT3 .	Thus, peretinoin induced autophagy and suppressed the IL6 induced activation of p-STAT3.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	p-STAT3	p-STAT3	p-STAT3	8	9	12	13
The strongest pathway activity difference in the Myd88 knockout was in the activation of STAT3 , which is consistent with the role of MyD88 in IL-6 mediated STAT3 activity .	The strongest pathway activity difference in the Myd88 knockout was in the activation of STAT3, which is consistent with the role of MyD88 in IL-6 mediated STAT3 activity.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	27	28
Interestingly , that study showed that paracrine IL-6 activates STAT3 , HIF-1alpha , and C/EBPbeta in macrophages and that these transcription factors are necessary for macrophage activation and polarization .	Interestingly, that study showed that paracrine IL-6 activates STAT3, HIF-1alpha, and C/EBPbeta in macrophages and that these transcription factors are necessary for macrophage activation and polarization.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
16 Our FKBP12EC KO mice represent a novel system to study these interactions in vivo as they demonstrate SMAD2/3 activation , endothelial cell activation , increased IL-6 and IL-21 levels , decreased splenic SOCS3 gene expression , increased splenic STAT3 activity , and decreased splenic STAT5 activity , without changes in the anti-inflammatory cytokine TGF-beta .	16 Our FKBP12EC KO mice represent a novel system to study these interactions in vivo as they demonstrate SMAD2/3 activation, endothelial cell activation, increased IL-6 and IL-21 levels, decreased splenic SOCS3 gene expression, increased splenic STAT3 activity, and decreased splenic STAT5 activity, without changes in the anti-inflammatory cytokine TGF-beta.	18	40	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	SMAD2/3 activation, endothelial cell activation, increased IL-6 and IL-21 levels	il-6	STAT3	STAT3	stat3	26	27	39	40
The addition of IL-6 to the control medium activated JAK2 and STAT3 in the SKOV3 cells as did the ASC-CM , and JAK2 and STAT3 activation was attenuated by the anti-IL-6 neutralizing antibody ( XREF_FIG ) .	The addition of IL-6 to the control medium activated JAK2 and STAT3 in the SKOV3 cells as did the ASC-CM, and JAK2 and STAT3 activation was attenuated by the anti-IL-6 neutralizing antibody (XREF_FIG).	1	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	11	12
Overall , these results provide new insight into the role of quercetin as a blocker of the STAT3 activation pathway stimulated by IL-6 , with a potential role in the prevention and treatment of glioblastoma .	Overall, these results provide new insight into the role of quercetin as a blocker of the STAT3 activation pathway stimulated by IL-6, with a potential role in the prevention and treatment of glioblastoma.	17	23	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	17	18
Furthermore , our experiments using a neutralizing antibody or recombinant protein demonstrated the implication of autocrine IL-6 signalling in STAT3 activation in human gastric cancer cells .	Furthermore, our experiments using a neutralizing antibody or recombinant protein demonstrated the implication of autocrine IL-6 signalling in STAT3 activation in human gastric cancer cells.	16	20	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	19	20
IL-6 stimulation activates STAT3 .	IL-6 stimulation activates STAT3.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
Although gastric tumourigenesis in gp130 Y757F mice occurred independently of IL6 [ XREF_BIBR ] , we found that MyD88-deficiency reduced their tumour burden ( Jarnicki A , Puoczki T , Ernst M : A mouse model for innate immune cell mediated gastric tumorigenesis , submitted ) , consistent with our observation that excessive Stat3 activation increases Tlr4 expression and susceptibility of these mice to lipopolysaccharide induced septic shock ( Jenkins B , Jarnicki A , Thiem S , Ernst M : Systemic alteration of IL6 mediated Stat3 signaling increases susceptibility to endotoxemia in mice , submitted ) .	Although gastric tumourigenesis in gp130 Y757F mice occurred independently of IL6 [XREF_BIBR], we found that MyD88-deficiency reduced their tumour burden (Jarnicki A, Puoczki T, Ernst M : A mouse model for innate immune cell mediated gastric tumorigenesis, submitted), consistent with our observation that excessive Stat3 activation increases Tlr4 expression and susceptibility of these mice to lipopolysaccharide induced septic shock (Jenkins B, Jarnicki A, Thiem S, Ernst M : Systemic alteration of IL6 mediated Stat3 signaling increases susceptibility to endotoxemia in mice, submitted).	82	87	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	84	85	86	87
Pin1 enhances IL-6 mediated STAT3 signaling in various cancer cell lines .	Pin1 enhances IL-6 mediated STAT3 signaling in various cancer cell lines.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
Conversely , STAT3 activation by IL6 treatment in MCF-10A cells ( i.e. lacking the ER-Src construct ) results in up-regulation of these microRNAs ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Conversely, STAT3 activation by IL6 treatment in MCF-10A cells (i.e. lacking the ER-Src construct) results in up-regulation of these microRNAs (XREF_FIG, XREF_SUPPLEMENTARY).	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	5	6	2	3
Although STAT5b-RARalpha had no effect on ligand induced STAT5b activation , it enhanced interleukin 6 induced STAT3 dependent reporter activity , an effect shared by other APL fusion proteins including promyelocytic leukemia-RARalpha and promyelocytic leukemia zinc finger ( PLZF )-RARalpha .	Although STAT5b-RARalpha had no effect on ligand induced STAT5b activation, it enhanced interleukin 6 induced STAT3 dependent reporter activity, an effect shared by other APL fusion proteins including promyelocytic leukemia-RARalpha and promyelocytic leukemia zinc finger (PLZF)-RARalpha.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	STAT3	STAT3	STAT3	13	15	16	17
On the other hand , IL-6 , that is able to trigger the cell ' s STAT3 signaling pathway , appears to be associated to old-age anemia and is over-expressed in the aged mouse brain in response to LPS .	On the other hand, IL-6, that is able to trigger the cell 's STAT3 signaling pathway, appears to be associated to old-age anemia and is over-expressed in the aged mouse brain in response to LPS.	5	29	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	16	17
IL-6 is also known to induce Stat3 activation .	IL-6 is also known to induce Stat3 activation.	0	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	6	7
Adiponectin is well known to induce IL-6 synthesis in monocytes and macrophages and upregulation of IL-6 in adipose tissue resident macrophages has been shown to activate hepatic signal transducer and activator of transcription 3 ( STAT3 ) .	Adiponectin is well known to induce IL-6 synthesis in monocytes and macrophages and upregulation of IL-6 in adipose tissue resident macrophages has been shown to activate hepatic signal transducer and activator of transcription 3 (STAT3).	13	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	35	36
Response rates to HCV specific treatment are higher in HCV and HIV positive patients carrying the IL-6 HP genotype , which might be because of IL-6 mediated STAT3 activation .	Response rates to HCV specific treatment are higher in HCV and HIV positive patients carrying the IL-6 HP genotype, which might be because of IL-6 mediated STAT3 activation.	22	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	25	26	27	28
The trimeric interaction of IL-6 with soluble IL-6R and the common gp130 subunit is known to activate STAT3 and promote tumor growth [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The trimeric interaction of IL-6 with soluble IL-6R and the common gp130 subunit is known to activate STAT3 and promote tumor growth [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	17	18
We assume that IL-6 induces a moderately transient pSTAT3 signal that can roughly be approximated by a k deg , T value of 0.1 min -1 in WT macrophages .	We assume that IL-6 induces a moderately transient pSTAT3 signal that can roughly be approximated by a k deg, T value of 0.1 min -1 in WT macrophages.	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	3	4	8	9
IL-22 and IL-6 activated STAT3 in DLD-1 and HT-29 cells , whereas activation of NF-kB was seen in cells stimulated with IL-17A or TNF-alpha .	IL-22 and IL-6 activated STAT3 in DLD-1 and HT-29 cells, whereas activation of NF-kB was seen in cells stimulated with IL-17A or TNF-alpha.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
In particular , the aberrant production of IL-6 and CCL2 in mammary cancer activates STAT3 in CAFs , which finally sustains tumor associated inflammation and is required for breast cancer cell migration [ XREF_BIBR ] .	In particular, the aberrant production of IL-6 and CCL2 in mammary cancer activates STAT3 in CAFs, which finally sustains tumor associated inflammation and is required for breast cancer cell migration [XREF_BIBR].	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	14	15
Interestingly , IL-6 is a potent activator of Stat3 in a variety of cell types , and intracerebroventricular injection of IL-6 induced nuclear translocation of Stat3 in neurons of both the SON and PVN .	Interestingly, IL-6 is a potent activator of Stat3 in a variety of cell types, and intracerebroventricular injection of IL-6 induced nuclear translocation of Stat3 in neurons of both the SON and PVN.	2	14	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	8	9
IL-6 can activate the signal transducer and the activator of transcription 3 ( STAT3 ) , which is a signal transduction molecule that converges to many oncogenic signaling pathways , and controls the M2 polarization of macrophages as well .	IL-6 can activate the signal transducer and the activator of transcription 3 (STAT3), which is a signal transduction molecule that converges to many oncogenic signaling pathways, and controls the M2 polarization of macrophages as well.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	13	14
Intriguingly , while IL-6 also potently activates STAT3 , it does not share the inhibitory effects of IL-10 and G-CSF .	Intriguingly, while IL-6 also potently activates STAT3, it does not share the inhibitory effects of IL-10 and G-CSF.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	7	8
Multiple studies reported that IL-6 can promote caner cancer cells growth mainly by regulating STAT3 activity .	Multiple studies reported that IL-6 can promote caner cancer cells growth mainly by regulating STAT3 activity.	4	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	14	15
Specific to GBM , Jonathan et al ., showed that quercetin treatment significantly decreased the IL-6 mediated STAT3 activation in U87 and T98G cell lines in a concentration dependent manner [ XREF_BIBR ] .	Specific to GBM, Jonathan et al., showed that quercetin treatment significantly decreased the IL-6 mediated STAT3 activation in U87 and T98G cell lines in a concentration dependent manner [XREF_BIBR].	14	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	17	18
STAT3 is activated by the IL-6 cytokine and is regarded as a major factor mediating IL-6 function .	STAT3 is activated by the IL-6 cytokine and is regarded as a major factor mediating IL-6 function.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	0	1
22 Further growth of the premalingnant cells could be supported by the proinflammatory and prosurvival signaling pathways NF-kappaB and STAT3 , which are activated by TNF alpha and IL-6 , respectively .	22 Further growth of the premalingnant cells could be supported by the proinflammatory and prosurvival signaling pathways NF-kappaB and STAT3, which are activated by TNF alpha and IL-6, respectively.	9	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	28	29	19	20
In CECS , Stat3 activation by IL-6 , IL-10 / IL-22 and IL-23 has been shown to facilitate oncogenesis .	In CECS, Stat3 activation by IL-6, IL-10 / IL-22 and IL-23 has been shown to facilitate oncogenesis.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	3	4
Subsequently , IL-6R stimulation by IL-6 activates STAT3 , a key transcription factor that promotes naive CD4 + T cell differentiation into Th17cells .	Subsequently, IL-6R stimulation by IL-6 activates STAT3, a key transcription factor that promotes naive CD4 + T cell differentiation into Th17cells.	3	12	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
IL-6 can activate the JAK and STAT3 , MAPK , PI3K and ErbB2 pathways , all of which have been implicated in hormonal progression of CaP ( XREF_SUPPLEMENTARY shows schematic representation of these pathways ) .	IL-6 can activate the JAK and STAT3, MAPK, PI3K and ErbB2 pathways, all of which have been implicated in hormonal progression of CaP (XREF_SUPPLEMENTARY shows schematic representation of these pathways).	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	6	7
Interleukin ( IL )-27, one of the most recently discovered IL-6 family cytokines , activates both the signal transducer and activator of transcription ( STAT ) 1 and STAT3 , and plays multiple roles in pro- and anti-inflammatory immune responses .	Interleukin (IL)-27, one of the most recently discovered IL-6 family cytokines, activates both the signal transducer and activator of transcription (STAT) 1 and STAT3, and plays multiple roles in pro- and anti-inflammatory immune responses.	0	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	28	29
Taken together , our results support an essential role for IL6 mediated Stat3 activation in GSC growth and survival .	Taken together, our results support an essential role for IL6 mediated Stat3 activation in GSC growth and survival.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	10	11	12	13
Recent study showed that M2 TAMs derived prostaglandin E2 ( PGE2 ) could endow colon cancer cells with stem like qualities ; this effect was abolished by celecoxib , the COX-2-selective inhibitor , which blocks PGE2 production.36 Similarly , other cytokines such as EGF , TGF-beta1 and IL-6 released by TMAs also promote transforming of non CSCs into CSCs.37 , 38 , 39 MDSCs played an important role in stemness phenotypic plasticity of non CSCs through activation of notch signalling , EMT and up-regulation of stemness genes , such as , Nanog , Oct4 and Sox2 ,40 , 41 previous study showed that MDSCs released IL-6 activated stat3 and notch signalling pathway in breast cancer cells and endow these cells with stem like properties.42 In addition , CSCs could also dictate the characters of their surrounding stromal cells by secreting a variety of factors to promote tumour progression .	Recent study showed that M2 TAMs derived prostaglandin E2 (PGE2) could endow colon cancer cells with stem like qualities; this effect was abolished by celecoxib, the COX-2-selective inhibitor, which blocks PGE2 production.36 Similarly, other cytokines such as EGF, TGF-beta1 and IL-6 released by TMAs also promote transforming of non CSCs into CSCs.37, 38, 39 MDSCs played an important role in stemness phenotypic plasticity of non CSCs through activation of notch signalling, EMT and up-regulation of stemness genes, such as, Nanog, Oct4 and Sox2,40, 41 previous study showed that MDSCs released IL-6 activated stat3 and notch signalling pathway in breast cancer cells and endow these cells with stem like properties.42 In addition, CSCs could also dictate the characters of their surrounding stromal cells by secreting a variety of factors to promote tumour progression.	105	147	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	stat3	stat3	stat3	105	106	107	108
The inflammatory cytokine IL-6 , which is known to activate STAT3 , was added to the culture medium of cells that had been transfected with shRNA against Cav-1 .	The inflammatory cytokine IL-6, which is known to activate STAT3, was added to the culture medium of cells that had been transfected with shRNA against Cav-1.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	10	11
We now show that loss of PAR3 triggers increased production of interleukin-6 , which induces STAT3 signaling in an autocrine manner .	We now show that loss of PAR3 triggers increased production of interleukin-6, which induces STAT3 signaling in an autocrine manner.	9	16	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	11	12	15	16
Consistent with these , we show here that IL-6 activates Akt , Stat3 and NF-kB pathways while suppressing PTEN .	Consistent with these, we show here that IL-6 activates Akt, Stat3 and NF-kB pathways while suppressing PTEN.	8	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	8	9	12	13
The STAT3 mRNA levels are increased when the cells are treated with IL-6 [ XREF_BIBR ] ( XREF_TABLE ) .	The STAT3 mRNA levels are increased when the cells are treated with IL-6 [XREF_BIBR] (XREF_TABLE).	1	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	1	2
These data indicate that in pancreatic cancer cells , IL-6 upregulated DNMT1 by activating the IL-6 and STAT3 signaling pathway .	These data indicate that in pancreatic cancer cells, IL-6 upregulated DNMT1 by activating the IL-6 and STAT3 signaling pathway.	9	19	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	17	18
In summary , although both EphB1 and IL-6 activate STAT3 pathways , the transcriptional profile suggests that EphB1 shifts STAT3 mediated processes from a deleterious proinflammatory spectrum towards a more beneficial inflammatory transcriptional profile .	In summary, although both EphB1 and IL-6 activate STAT3 pathways, the transcriptional profile suggests that EphB1 shifts STAT3 mediated processes from a deleterious proinflammatory spectrum towards a more beneficial inflammatory transcriptional profile.	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
MM.1 S cells , which lack constitutively active STAT3 , were treated with IL-6 at different concentrations and then examined for phosphorylated STAT3 .	MM.1 S cells, which lack constitutively active STAT3, were treated with IL-6 at different concentrations and then examined for phosphorylated STAT3.	5	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	8	9
Interestingly , IL-6 can specifically direct STAT3 to inhibit G6pc transcription by blocking RNA polymerase II recruitment and decreasing histone H4 acetylation at the G6pc promoter 22 , a phenomenon not occurring on the Pck1 promoter .	Interestingly, IL-6 can specifically direct STAT3 to inhibit G6pc transcription by blocking RNA polymerase II recruitment and decreasing histone H4 acetylation at the G6pc promoter 22, a phenomenon not occurring on the Pck1 promoter.	2	7	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	6	7
Most notable among these activators is IL-6 which , through a gp130 mediated receptor , activates STAT3 , a critical signal transducer and activator of transcription associated with malignant transformation and tumorigenesis .	Most notable among these activators is IL-6 which, through a gp130 mediated receptor, activates STAT3, a critical signal transducer and activator of transcription associated with malignant transformation and tumorigenesis.	0	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	16	17
XREF_BIBR Further well characterized cytokine-STAT pathways include the activation of STAT3 by IL-6 and IL-10 , the activation of STAT4 by IL-12 and the activation of STAT5 by cytokines that signal through the common gamma chain , including IL-2 , IL-4 , IL-7 , IL-9 , IL-15 and IL-21 .	XREF_BIBR Further well characterized cytokine-STAT pathways include the activation of STAT3 by IL-6 and IL-10, the activation of STAT4 by IL-12 and the activation of STAT5 by cytokines that signal through the common gamma chain, including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.	8	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	10	11
In their model , IL-6 activates STAT3 , thereby increasing the miR-17-92 cluster expression and down-regulating BMPR2 .	In their model, IL-6 activates STAT3, thereby increasing the miR-17-92 cluster expression and down-regulating BMPR2.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
The effect of driving Th17-cell differentiation by BAFF may attribute to the fact that BAFF increased IL-6 receptor expression on CD4 + T cells , and enhanced IL6-IL-6R and p-STAT3 signaling pathway , and promoted the dendritic cell maturation and function [ XREF_BIBR , XREF_BIBR ] .	The effect of driving Th17-cell differentiation by BAFF may attribute to the fact that BAFF increased IL-6 receptor expression on CD4 + T cells, and enhanced IL6-IL-6R and p-STAT3 signaling pathway, and promoted the dendritic cell maturation and function [XREF_BIBR, XREF_BIBR].	14	31	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	BAFF increased IL-6 receptor expression	il-6	p-STAT3	p-STAT3	p-stat3	16	17	29	30
XREF_BIBR It has been shown that IL-6 strongly activates STAT3 and induces the expression of IFN responsive genes in SOCS3 deficient macrophages , indicating that IL-6 might mimic the actions of IFNs .	XREF_BIBR It has been shown that IL-6 strongly activates STAT3 and induces the expression of IFN responsive genes in SOCS3 deficient macrophages, indicating that IL-6 might mimic the actions of IFNs.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	9	10
Taken together , our studies indicate that RKIP overexpression inhibits and RKIP ablation significantly enhances IL-6 mediated STAT3 activation and that RKIP can inhibit STAT3 mediated tumor growth .	Taken together, our studies indicate that RKIP overexpression inhibits and RKIP ablation significantly enhances IL-6 mediated STAT3 activation and that RKIP can inhibit STAT3 mediated tumor growth.	14	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	17	18
The results suggest that IL-6 induces hyperactivation of STAT3 in circulating immune cells in active RA , and this subsequently desensitizes the IL-6 response in T cells .	The results suggest that IL-6 induces hyperactivation of STAT3 in circulating immune cells in active RA, and this subsequently desensitizes the IL-6 response in T cells.	4	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	8	9
In this study , we verified that wild type BLCAP inhibited IL-6 induced STAT3 activation , while the two edited forms of BLCAP ( CCLQ-FLAG and CCLR-FLAG ) partly or almost failed to inhibit STAT3 phosphorylation .	In this study, we verified that wild type BLCAP inhibited IL-6 induced STAT3 activation, while the two edited forms of BLCAP (CCLQ-FLAG and CCLR-FLAG) partly or almost failed to inhibit STAT3 phosphorylation.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	13	14
IL-6 activation of STAT3 is crucial for maintenance of the tumor progenitor cells phenotype .	IL-6 activation of STAT3 is crucial for maintenance of the tumor progenitor cells phenotype.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
There is evidence that interleukin-6 ( IL-6 ) and interferon-gamma ( IFN-gamma ) induce oval cell proliferation by activating signal transducer and activator of transcription 3 ( STAT3 ) in vitro [ XREF_BIBR ] .	There is evidence that interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) induce oval cell proliferation by activating signal transducer and activator of transcription 3 (STAT3) in vitro [XREF_BIBR].	4	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	4	5	27	28
Furthermore , this concentration of IL-6 was insufficient to activate STAT3 signaling ( XREF_SUPPLEMENTARY ) .	Furthermore, this concentration of IL-6 was insufficient to activate STAT3 signaling (XREF_SUPPLEMENTARY).	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	10	11
XREF_BIBR - XREF_BIBR STAT3 activation by IL-6 , IL-21 , and IL-23 results in the induction of genes encoding transcription factors , including Rorc , Maf , Irf4 , and Batf , which are essential for T H 17 cell differentiation .	XREF_BIBR - XREF_BIBR STAT3 activation by IL-6, IL-21, and IL-23 results in the induction of genes encoding transcription factors, including Rorc, Maf, Irf4, and Batf, which are essential for T H 17 cell differentiation.	3	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	3	4
IL-6 has synergistic effects with other proinflammatory cytokines and induces STAT3 signaling .	IL-6 has synergistic effects with other proinflammatory cytokines and induces STAT3 signaling.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	10	11
We next evaluated the optimal dose of avicin D required for dephosphorylation of both constitutive and IL-6 induced Stat3 in U266 cells .	We next evaluated the optimal dose of avicin D required for dephosphorylation of both constitutive and IL-6 induced Stat3 in U266 cells.	11	19	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	16	17	18	19
Since JAK and STAT genes were up-regulated in MCF10A-SNAI1 and IL6 activates STAT3 , we investigated , whether a long-term incubation of IL1beta might increase STAT3 activation through up-regulation of IL6 .	Since JAK and STAT genes were up-regulated in MCF10A-SNAI1 and IL6 activates STAT3, we investigated, whether a long-term incubation of IL1beta might increase STAT3 activation through up-regulation of IL6.	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	10	11	12	13
Its activity in pancreatic fibroblasts leads to the expression of IL-6 , an inflammatory cytokine that activates Stat3 in pancreatic cancer cells .	Its activity in pancreatic fibroblasts leads to the expression of IL-6, an inflammatory cytokine that activates Stat3 in pancreatic cancer cells.	8	21	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	expression of IL-6	il-6	Stat3	Stat3	stat3	10	11	17	18
IL-6 induces miR-223 down-regulation and promoted the augment and activation of STAT3 , which in turn facilitates the production of IL-6 and IL-1beta , thus forming a positive regulatory loop for the production of pro inflammatory cytokines ( XREF_FIG ) .	IL-6 induces miR-223 down-regulation and promoted the augment and activation of STAT3, which in turn facilitates the production of IL-6 and IL-1beta, thus forming a positive regulatory loop for the production of pro inflammatory cytokines (XREF_FIG).	0	16	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	11	12
IL-6 treatment strongly activated the JAK and Stat3 signaling pathway in TDSCs .	IL-6 treatment strongly activated the JAK and Stat3 signaling pathway in TDSCs.	0	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	0	1	7	8
Increased inflammatory cytokines , especially IL-6 , have been shown to activate STAT3 .	Increased inflammatory cytokines, especially IL-6, have been shown to activate STAT3.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	12	13
Our data suggest that miR-146b centrally mediates a negative feedback circuit connecting STAT3 activation to decreased NF-kappaB activity and IL-6 production , thereby inhibiting further STAT3 activity ( XREF_FIG ) .	Our data suggest that miR-146b centrally mediates a negative feedback circuit connecting STAT3 activation to decreased NF-kappaB activity and IL-6 production, thereby inhibiting further STAT3 activity (XREF_FIG).	19	26	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	25	26
Jak1 activity was also assessed as it is involved in IL-6 stimulated Stat3 activity .	Jak1 activity was also assessed as it is involved in IL-6 stimulated Stat3 activity.	8	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	10	11	12	13
For example , IL-6 signaling also activates the STAT3 pathway but is incapable of activating the anti-inflammatory response .	For example, IL-6 signaling also activates the STAT3 pathway but is incapable of activating the anti-inflammatory response.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	8	9
HER2 induced secretion of IL-6 can act in an autocrine fashion to elicit Stat3 mediated gene expression and signaling .	HER2 induced secretion of IL-6 can act in an autocrine fashion to elicit Stat3 mediated gene expression and signaling.	2	14	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	4	5	13	14
In CAC , altered epithelial and neoplastic cells and recruited immune cells continue to produce S1P and pro inflammatory cytokines such as IL-6 that activate oncogenic Stat3 to sustain tumor associated inflammation and to fuel tumor initiation , promotion , and progression .	In CAC, altered epithelial and neoplastic cells and recruited immune cells continue to produce S1P and pro inflammatory cytokines such as IL-6 that activate oncogenic Stat3 to sustain tumor associated inflammation and to fuel tumor initiation, promotion, and progression.	19	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	22	23	26	27
Inhibition of CXCL3 and IL6 has been shown in cancer cell lines to reduce Stat3 activation .	Inhibition of CXCL3 and IL6 has been shown in cancer cell lines to reduce Stat3 activation.	0	15	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	4	5	14	15
In spinal microglia , IL-6 is associated with inflammatory cytokine signaling to induce STAT3 , and also has the ability to trigger reactive astrogliosis [ XREF_BIBR , XREF_BIBR ] .	In spinal microglia, IL-6 is associated with inflammatory cytokine signaling to induce STAT3, and also has the ability to trigger reactive astrogliosis [XREF_BIBR, XREF_BIBR].	4	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	13	14
We recently showed that IL-6 efficiently activated both signal transducer and activator of transcription 3 ( STAT3 ) and extracellular signal regulated kinase 1/2 ( ERK1/2 ) in CD45- myeloma cell lines , although CD45- cells failed to proliferate in response to IL-6 .	We recently showed that IL-6 efficiently activated both signal transducer and activator of transcription 3 (STAT3) and extracellular signal regulated kinase 1/2 (ERK1/2) in CD45- myeloma cell lines, although CD45- cells failed to proliferate in response to IL-6.	4	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	16	17
For example , in the Cal33 assay used here , not all of the cells responded to IL-6 activation of STAT3 , whereas all cells responded to OSM ( XREF_FIG ) .	For example, in the Cal33 assay used here, not all of the cells responded to IL-6 activation of STAT3, whereas all cells responded to OSM (XREF_FIG).	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	20	21
XREF_BIBR , XREF_BIBR Induction of RORgammat is dependent on STAT3 signaling , which is preferentially activated by IL-6 .	XREF_BIBR, XREF_BIBR Induction of RORgammat is dependent on STAT3 signaling, which is preferentially activated by IL-6.	9	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	9	10
However , as we shall see , IL-6 and other cytokines that activate STAT3 have a particularly important role in malignant transformation of epithelial cells .	However, as we shall see, IL-6 and other cytokines that activate STAT3 have a particularly important role in malignant transformation of epithelial cells.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	13	14
There is no cross-talk between IL-6 and IFN-gamma ( STAT3 and STAT1 ) channels meaning that IL-6 can activate only STAT3 and IFN-gamma - only STAT1 ( XREF_FIG , XREF_FIG XREF_SUPPLEMENTARY - XREF_SUPPLEMENTARY ) .	There is no cross-talk between IL-6 and IFN-gamma (STAT3 and STAT1) channels meaning that IL-6 can activate only STAT3 and IFN-gamma - only STAT1 (XREF_FIG, XREF_FIG XREF_SUPPLEMENTARY - XREF_SUPPLEMENTARY).	16	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	20	21
Common to both miR-24 and miR-629 was the presence of a Stat3 binding site in their promoter and their direct regulation by Stat3 as demonstrated by ChIP assays and Stat3 dependent induction of their expression by IL-6 .	Common to both miR-24 and miR-629 was the presence of a Stat3 binding site in their promoter and their direct regulation by Stat3 as demonstrated by ChIP assays and Stat3 dependent induction of their expression by IL-6.	29	37	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	36	37	29	30
Although IL-21 , IL-6 , and IL-10 all activate STAT3 , their physiological actions differ , presumably as a result of when and where the cytokines are produced and their receptors are expressed .	Although IL-21, IL-6, and IL-10 all activate STAT3, their physiological actions differ, presumably as a result of when and where the cytokines are produced and their receptors are expressed.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	9	10
Indeed , IL-6 induced sustained phoshorylation of STAT1 and STAT3 in LysM-cre Socs3 fl/fl macrophages as compared to Socs3 fl/fl macrophages , yet demonstrated similar kinetics of activation of the MAP kinase ERK suggesting that only STAT signaling is altered in these macrophages ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Indeed, IL-6 induced sustained phoshorylation of STAT1 and STAT3 in LysM-cre Socs3 fl/fl macrophages as compared to Socs3 fl/fl macrophages, yet demonstrated similar kinetics of activation of the MAP kinase ERK suggesting that only STAT signaling is altered in these macrophages (XREF_FIG, XREF_SUPPLEMENTARY).	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	9	10
Blocking IL-6 suppresses STAT3 activation in the pancreas and consequently attenuated the severity of pancreatitis by promoting pancreatic acinar cell apoptosis .	Blocking IL-6 suppresses STAT3 activation in the pancreas and consequently attenuated the severity of pancreatitis by promoting pancreatic acinar cell apoptosis.	0	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	3	4
Similarly , glioma associated human MSC increased proliferation and self-renewal of GSC in vitro and increased their in vivo tumorigenicity by secreting interleukin-6 , which activates STAT3 in GSC [ XREF_BIBR ] .	Similarly, glioma associated human MSC increased proliferation and self-renewal of GSC in vitro and increased their in vivo tumorigenicity by secreting interleukin-6, which activates STAT3 in GSC [XREF_BIBR].	15	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	22	23	26	27
In this model , IL-1alpha-induced IL-6 activates STAT3 and promotes liver regeneration and tumor outgrowth .	In this model, IL-1alpha-induced IL-6 activates STAT3 and promotes liver regeneration and tumor outgrowth.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
Along these lines , NFkappaB activation is a major player in promoting the production of IL-6 , which stimulates STAT3 activation and completes a STAT3 --> NFkappaB --> IL-6 feed-forward signaling loop in developing carcinomas .	Along these lines, NFkappaB activation is a major player in promoting the production of IL-6, which stimulates STAT3 activation and completes a STAT3 --> NFkappaB --> IL-6 feed-forward signaling loop in developing carcinomas.	13	22	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	19	20
Neither interleukin-6 ( IL-6 ) nor IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation .	Neither interleukin-6 (IL-6) nor IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	13	14
Therefore , we determined whether IL-6 mediated IL-17-driven STAT3 activation in our study .	Therefore, we determined whether IL-6 mediated IL-17-driven STAT3 activation in our study.	5	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	8	9
Given that IL-6 can activate STAT3 as well as other pathways such as YAP1 , we hypothesized that YAP1 signaling might limit EGFR TKI response in EGFR-mutant cells .	Given that IL-6 can activate STAT3 as well as other pathways such as YAP1, we hypothesized that YAP1 signaling might limit EGFR TKI response in EGFR-mutant cells.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	5	6
The data suggests that PRX-1 has a role in preserving IL-6 induced STAT3 activation in normal cells .	The data suggests that PRX-1 has a role in preserving IL-6 induced STAT3 activation in normal cells.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	12	13
This may be because the peak levels of IL-6 were much higher than those of IL-22 , and IL-6 may induce much stronger STAT3 activation in hepatocytes after K. pneumoniae infection .	This may be because the peak levels of IL-6 were much higher than those of IL-22, and IL-6 may induce much stronger STAT3 activation in hepatocytes after K. pneumoniae infection.	18	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	23	24
Thus , c-Fos in photoreceptors promoted retinal neovascularization via the neuronal STAT3 and VEGF pathway induced by IL-6 and TNF/TNFAIP3/SOCS3 signals ( XREF_FIG ) .	Thus, c-Fos in photoreceptors promoted retinal neovascularization via the neuronal STAT3 and VEGF pathway induced by IL-6 and TNF/TNFAIP3/SOCS3 signals (XREF_FIG).	7	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	11	12
Mechanistically , HR (-)/HER2 ( + ) cells secrete high levels of the interleukin-6 ( IL-6 ) cytokine , inducing the activation of STAT3 , which in turn promotes a second autocrine stimulus to increase S100A8/9 complex ( calprotectin ) production and secretion .	Mechanistically, HR (-)/HER2 (+) cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion.	13	24	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	13	14	23	24
We previously demonstrated that AS2 cells produced autocrine IL-6 and the secreted IL-6 induced Stat3 activation and subsequently promoted tumor progression [ XREF_BIBR ] .	We previously demonstrated that AS2 cells produced autocrine IL-6 and the secreted IL-6 induced Stat3 activation and subsequently promoted tumor progression [XREF_BIBR].	8	15	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	12	13	14	15
IL-6 induces directly STAT3 signaling of cancer cells to upregulate several genes , such as c-myc , bcl-2 and Mcl-1 , resulting in induction of tumorigenesis [ XREF_BIBR ] .	IL-6 induces directly STAT3 signaling of cancer cells to upregulate several genes, such as c-myc, bcl-2 and Mcl-1, resulting in induction of tumorigenesis [XREF_BIBR].	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
Although IL-6 is a major activator of Stat3 , no studies have previous address the regulation of Stat3 in mitochondria by this cytokines .	Although IL-6 is a major activator of Stat3, no studies have previous address the regulation of Stat3 in mitochondria by this cytokines.	1	8	is a major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	7	8
It has been demonstrated in C2C12 myoblasts that IL-6 induces the activation of the Stat3 signalling and promotes the down regulation of the p90RSK and eEF2 and mTOR and p70S6K , resulting in inhibition of the myogenic program .	It has been demonstrated in C2C12 myoblasts that IL-6 induces the activation of the Stat3 signalling and promotes the down regulation of the p90RSK and eEF2 and mTOR and p70S6K, resulting in inhibition of the myogenic program.	8	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	8	9	14	15
IL-6 then activates STAT3 in the surviving hepatocytes that subsequently give rise to the tumors .	IL-6 then activates STAT3 in the surviving hepatocytes that subsequently give rise to the tumors.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	3	4
In this case , IL-6 activates STAT3 to induce Cyclin D1 in lung cancer cells , therefore promoting cancer proliferation ( XREF_FIG and XREF_SUPPLEMENTARY ) .	In this case, IL-6 activates STAT3 to induce Cyclin D1 in lung cancer cells, therefore promoting cancer proliferation (XREF_FIG and XREF_SUPPLEMENTARY).	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
Since IL-6 and IL-22 both activate STAT3 , and that this activation is impaired in the absence of CHI3L1 , the role of these two cytokines in STAT3 activation , relative to CHI3L1 , was next dissected .	Since IL-6 and IL-22 both activate STAT3, and that this activation is impaired in the absence of CHI3L1, the role of these two cytokines in STAT3 activation, relative to CHI3L1, was next dissected.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	6	7
Furthermore , IL-6 was found to stimulate STAT3 dependent NF-kappaB-mediated IDO upregulation in MDSCs .	Furthermore, IL-6 was found to stimulate STAT3 dependent NF-kappaB-mediated IDO upregulation in MDSCs.	2	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	7	8
Co-stimulation of CHI3L1 and IL-6 , but not IL-22 , synergistically activates STAT3 signaling pathway in IECs in an NF-kappaB and MAPK dependent manner .	Co-stimulation of CHI3L1 and IL-6, but not IL-22, synergistically activates STAT3 signaling pathway in IECs in an NF-kappaB and MAPK dependent manner.	0	14	synergistically activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	12	13
IL6 induced STAT3 activation was observed in mice with HgCl 2 -induced AKI .	IL6 induced STAT3 activation was observed in mice with HgCl 2 -induced AKI.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	2	3
These results indicate that IL-6 can enhance PMP22 production in Schwann cells via a JAK2 dependent pathway by probably activating STAT3 and thus may contribute to myelination .	These results indicate that IL-6 can enhance PMP22 production in Schwann cells via a JAK2 dependent pathway by probably activating STAT3 and thus may contribute to myelination.	4	21	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	20	21
The IL6 mediated increase in STAT3 associated luciferase activity was completely abolished in the presence of SFN ( XREF_FIG ) .	The IL6 mediated increase in STAT3 associated luciferase activity was completely abolished in the presence of SFN (XREF_FIG).	1	6	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	5	6
IL-6 activated YAP and STAT3 in human CRC cells and mouse primary hepatocytes ( XREF_FIG ) .	IL-6 activated YAP and STAT3 in human CRC cells and mouse primary hepatocytes (XREF_FIG).	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Increased IL-6 expression in the stromal compartment induces activation of STAT3 in the neighboring cancer cells , an essential molecular event for the progression of premalignant lesions in PDAC ( XREF_FIG ) .	Increased IL-6 expression in the stromal compartment induces activation of STAT3 in the neighboring cancer cells, an essential molecular event for the progression of premalignant lesions in PDAC (XREF_FIG).	1	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 expression	il-6	STAT3	STAT3	stat3	1	2	10	11
We show that IL6 secreted by the tumor cells activates Stat3 pathways in LECs , resulting in lymphatic expression of CCL5 and VEGF .	We show that IL6 secreted by the tumor cells activates Stat3 pathways in LECs, resulting in lymphatic expression of CCL5 and VEGF.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	3	4	10	11
In the IL-6-dependent human myeloma cell line U266 , IL-6 signals through Janus kinases to the activate STAT3 , which in turn up-regulates anti-apoptotic factors , and promotes the survival of tumor cells XREF_BIBR .	In the IL-6-dependent human myeloma cell line U266, IL-6 signals through Janus kinases to the activate STAT3, which in turn up-regulates anti-apoptotic factors, and promotes the survival of tumor cells XREF_BIBR.	9	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	17	18
STAT3 activation triggered by IL-6 and other inflammatory cytokines ( IL-21 , etc. ) , antagonizes Treg stability .	STAT3 activation triggered by IL-6 and other inflammatory cytokines (IL-21, etc.), antagonizes Treg stability.	0	8	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
IL-6 in turn can induce STAT3 activation in vitro and in vivo and halts DC differentiation [ XREF_BIBR , XREF_BIBR ] .	IL-6 in turn can induce STAT3 activation in vitro and in vivo and halts DC differentiation [XREF_BIBR, XREF_BIBR].	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	5	6
Th17-type cytokines , IL-6 and TNF-alpha synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth .	Th17-type cytokines, IL-6 and TNF-alpha synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth.	1	10	synergistically activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	8	9
We found that silencing GRN reduced IL-6 induced STAT3 transcriptional activity in these cells , suggesting that GRN is necessary for maximal STAT3 function in this cell system as well ( XREF_SUPPLEMENTARY ) .	We found that silencing GRN reduced IL-6 induced STAT3 transcriptional activity in these cells, suggesting that GRN is necessary for maximal STAT3 function in this cell system as well (XREF_SUPPLEMENTARY).	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
We have shown that astrocyte differentiation is largely dependent on IL-6 family cytokine mediated STAT3 activation and that there exists a STAT3 binding element in the promoter region of the gene for the astrocyte marker glial fibrillary acidic protein .	We have shown that astrocyte differentiation is largely dependent on IL-6 family cytokine mediated STAT3 activation and that there exists a STAT3 binding element in the promoter region of the gene for the astrocyte marker glial fibrillary acidic protein.	10	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	14	15
Unlike transient activation of STAT3 by IL-6 , S1P 1 signaling was shown to persistently activate this pathway through its influence on tumor cells and the tumor microenvironment ( see XREF_FIG ) .	Unlike transient activation of STAT3 by IL-6, S1P 1 signaling was shown to persistently activate this pathway through its influence on tumor cells and the tumor microenvironment (see XREF_FIG).	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	4	5
In endotoxin treated rats , there was significant inhibition of interleukin-6 activation of janus kinase-1 , gp 130 , the interleukin-6 receptor , STAT1 , and STAT3 .	In endotoxin treated rats, there was significant inhibition of interleukin-6 activation of janus kinase-1, gp 130, the interleukin-6 receptor, STAT1, and STAT3.	10	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	10	11	26	27
Interleukin-6 preferentially activates STAT3 with phosphorylation of Y705 via the JAK signaling pathway .	Interleukin-6 preferentially activates STAT3 with phosphorylation of Y705 via the JAK signaling pathway.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Interleukin-6	Interleukin-6	Interleukin-6	STAT3	STAT3	STAT3	0	1	3	4
[ XREF_BIBR ] In addition , IL-6 protein is known to activate STAT3 signaling pathway which plays an essential role in the pathogenesis and prevention of apoptosis [ XREF_BIBR ] as was observed in our study .	[XREF_BIBR] In addition, IL-6 protein is known to activate STAT3 signaling pathway which plays an essential role in the pathogenesis and prevention of apoptosis [XREF_BIBR] as was observed in our study.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	12	13
The interleukin-6 ( IL6 ) family of cytokines signals through the common receptor subunit gp130 , and subsequently activates Stat3 , MAPK , and PI3K .	The interleukin-6 (IL6) family of cytokines signals through the common receptor subunit gp130, and subsequently activates Stat3, MAPK, and PI3K.	3	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	3	4	19	20
However , other members of the IL-6 family are also able to activate STAT3 , including IL-10 [ XREF_BIBR ] , IL-11 [ XREF_BIBR ] , Ciliary Neurotrophic Factor ( CNTF ) [ XREF_BIBR ] , Leukemia Inhibitory Factor ( LIF ) [ XREF_BIBR ] and Oncostatin [ XREF_BIBR ] .	However, other members of the IL-6 family are also able to activate STAT3, including IL-10 [XREF_BIBR], IL-11 [XREF_BIBR], Ciliary Neurotrophic Factor (CNTF) [XREF_BIBR], Leukemia Inhibitory Factor (LIF) [XREF_BIBR] and Oncostatin [XREF_BIBR].	6	46	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	13	14
In the liver , STAT3 is mainly activated by IL-6 and related cytokines [ XREF_BIBR , XREF_BIBR ] .	In the liver, STAT3 is mainly activated by IL-6 and related cytokines [XREF_BIBR, XREF_BIBR].	4	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	4	5
Although there may be a partial Th1 and Th2 polarization of the immune response in CD versus UC , recent studies suggest that other cytokines like TNF-alpha , IL-1beta , and IL-17A which primarily activate NF-kappaB , IL-6 and Il-10 which primarily activate STAT3 have overlapping roles in UC and CD , blurring the Th1 and Th2 paradigm .	Although there may be a partial Th1 and Th2 polarization of the immune response in CD versus UC, recent studies suggest that other cytokines like TNF-alpha, IL-1beta, and IL-17A which primarily activate NF-kappaB, IL-6 and Il-10 which primarily activate STAT3 have overlapping roles in UC and CD, blurring the Th1 and Th2 paradigm.	34	44	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	37	38	43	44
STAT3 was activated by IL-6 in myeloma and prostate cancer cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , hepatocyte growth factor ( HGF ) and its receptor ( c-MET ) in leiomyosarcoma and breast cancer cells [ XREF_BIBR , XREF_BIBR ] , and Src in breast cancer and melanoma cells [ XREF_BIBR , XREF_BIBR ] .	STAT3 was activated by IL-6 in myeloma and prostate cancer cells [XREF_BIBR, XREF_BIBR, XREF_BIBR], hepatocyte growth factor (HGF) and its receptor (c-MET) in leiomyosarcoma and breast cancer cells [XREF_BIBR, XREF_BIBR], and Src in breast cancer and melanoma cells [XREF_BIBR, XREF_BIBR].	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	0	1
Both IL-6 and IL-11 are induced in response to NF-kappaB activation in immune cells of the tumor microenvironment can lead to STAT3 activation in both malignant and immune cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Both IL-6 and IL-11 are induced in response to NF-kappaB activation in immune cells of the tumor microenvironment can lead to STAT3 activation in both malignant and immune cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	22	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	21	22
IL-6 and IL-12 induce the signal transducer and activator of transcription ( STAT ) activity STAT3 and STAT4 , respectively , via the JAK family of proteins .	IL-6 and IL-12 induce the signal transducer and activator of transcription (STAT) activity STAT3 and STAT4, respectively, via the JAK family of proteins.	0	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	15	16
The activation of STAT3 by IL-6 in circulating CD4+ T cells raises intriguing questions as to the pathway ' s role in RA induction .	The activation of STAT3 by IL-6 in circulating CD4+ T cells raises intriguing questions as to the pathway 's role in RA induction.	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	3	4
After LN treatment , the mRNA levels of TNF-alpha , IL-6 , and Cox2 , which are expressed in activated Kupffer cells [ XREF_BIBR , XREF_BIBR ] , were increased , and NFkappaB and Stat3 , which are transcription factors that can be activated , respectively , by TNF-alpha and IL-6 to play important roles in hepatocyte proliferation [ XREF_BIBR ] , were activated .	After LN treatment, the mRNA levels of TNF-alpha, IL-6, and Cox2, which are expressed in activated Kupffer cells [XREF_BIBR, XREF_BIBR], were increased, and NFkappaB and Stat3, which are transcription factors that can be activated, respectively, by TNF-alpha and IL-6 to play important roles in hepatocyte proliferation [XREF_BIBR], were activated.	32	63	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	50	51	34	35
To investigate whether Ac2-26-induced SOCS3 expression negatively regulates gp130 cytokines signalling , we first analysed the effect of Ac2-26 on IL-6 induced STAT3 activation .	To investigate whether Ac2-26-induced SOCS3 expression negatively regulates gp130 cytokines signalling, we first analysed the effect of Ac2-26 on IL-6 induced STAT3 activation.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	22	23
IL-6 , and related cytokines , such as IL-11 , that are induced upon NF-kappaB activation , are potent activators of STAT3 and thereby link these two factors into a criticalNF-kappaB-IL-6-IL-11-STAT3oncogenic module that is active in most GI cancers .	IL-6, and related cytokines, such as IL-11, that are induced upon NF-kappaB activation, are potent activators of STAT3 and thereby link these two factors into a criticalNF-kappaB-IL-6-IL-11-STAT3oncogenic module that is active in most GI cancers.	0	24	are potent activators	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	21	22
Endothelial cells secrete IL-6 in response to inflammatory stimuli [ XREF_BIBR ] , and IL-6 activates its downstream target signal transducer and activator of transcription 3 ( STAT3 ) , which is activated in head and neck cancer [ XREF_BIBR ] .	Endothelial cells secrete IL-6 in response to inflammatory stimuli [XREF_BIBR], and IL-6 activates its downstream target signal transducer and activator of transcription 3 (STAT3), which is activated in head and neck cancer [XREF_BIBR].	14	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	27	28
As determined by immunofluorescence and immunoblotting analysis , IL-6 inhibition significantly attenuated the activation of STAT3 in vitro .	As determined by immunofluorescence and immunoblotting analysis, IL-6 inhibition significantly attenuated the activation of STAT3 in vitro.	8	16	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	15	16
As mentioned previously , in both ischemia and reperfusion and surgical manipulation models of intestinal dysfunction of the gut , up-regulation of IL-6 in the muscularis and mucosal layers induced STAT-3 activation .	As mentioned previously, in both ischemia and reperfusion and surgical manipulation models of intestinal dysfunction of the gut, up-regulation of IL-6 in the muscularis and mucosal layers induced STAT-3 activation.	20	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	22	23	30	31
While STAT3 mediated expansion of Th17 cells may initiate the acute uveitis , aberrant activation of STAT3 by IL-6 during the inflammatory process may promote development of chronic uveitis by inhibiting expansion of CD8 + regulatory T cells and thereby impeding recovery from the acute disease .	While STAT3 mediated expansion of Th17 cells may initiate the acute uveitis, aberrant activation of STAT3 by IL-6 during the inflammatory process may promote development of chronic uveitis by inhibiting expansion of CD8 + regulatory T cells and thereby impeding recovery from the acute disease.	14	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	16	17
IL-6 activates STAT3 by binding specifically to its cognate receptor on the cell membrane , i.e. IL-6R .	IL-6 activates STAT3 by binding specifically to its cognate receptor on the cell membrane, i.e. IL-6R.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	2	3
Stat3 in the liver is mainly activated by IL-6 and its related cytokines , IL-22 , IL-10 , EGF , HGF , and hepatitis B and C viral proteins .	Stat3 in the liver is mainly activated by IL-6 and its related cytokines, IL-22, IL-10, EGF, HGF, and hepatitis B and C viral proteins.	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	8	9	0	1
Because IL-6 activates STAT3 XREF_BIBR , we performed ChIP of CLL cells incubated without or with 30 ng/ml rhIL-6 to determine which putative miR-155 promoter binds STAT3 .	Because IL-6 activates STAT3 XREF_BIBR, we performed ChIP of CLL cells incubated without or with 30 ng/ml rhIL-6 to determine which putative miR-155 promoter binds STAT3.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	3	4
Without SOCS3 , however , IL-6 stimulation induced increases in STAT1 * and STAT3 * , the maximum concentrations of which reached 700 nM and 300 nM , respectively , which were about double those in normal conditions .	Without SOCS3, however, IL-6 stimulation induced increases in STAT1 * and STAT3 *, the maximum concentrations of which reached 700 nM and 300 nM, respectively, which were about double those in normal conditions.	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	13	14
Because IL-6 is known to activate STAT3 XREF_BIBR , we hypothesised that IL-6 and STAT3 signalling acted as an autocrine or paracrine loop to promote cell invasion .	Because IL-6 is known to activate STAT3 XREF_BIBR, we hypothesised that IL-6 and STAT3 signalling acted as an autocrine or paracrine loop to promote cell invasion.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	6	7
In cell culture , Hst was shown to inhibit IL-6 induced STAT3 reporter activity at 20-100muM .	In cell culture, Hst was shown to inhibit IL-6 induced STAT3 reporter activity at 20-100muM.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
Furthermore , although IFNgamma induces only activation of signal transducer and activator of transcription ( STAT ) 1 , IL-6 activates mainly STAT3 .	Furthermore, although IFNgamma induces only activation of signal transducer and activator of transcription (STAT) 1, IL-6 activates mainly STAT3.	19	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	22	23
Both IL-6 and IL-10 primarily activate Stat3 in macrophages , but with different biological outcomes ; IL-6 is primarily pro inflammatory whereas IL-10 is generally characterized as anti-inflammatory .	Both IL-6 and IL-10 primarily activate Stat3 in macrophages, but with different biological outcomes; IL-6 is primarily pro inflammatory whereas IL-10 is generally characterized as anti-inflammatory.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	6	7
Finally , our data also underscore a mechanistic role for IL-6 mediated pSTAT3 signaling in driving Skint transcription during a youthful wound response , and reveal an overall reduction in this circuitry in aged mice .	Finally, our data also underscore a mechanistic role for IL-6 mediated pSTAT3 signaling in driving Skint transcription during a youthful wound response, and reveal an overall reduction in this circuitry in aged mice.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	10	11	12	13
Intrathecal delivery of IL-6 activates JAK and STAT3 signal pathway in pyramidal cells of the sensorimotor cortex after spinal cord injury .	Intrathecal delivery of IL-6 activates JAK and STAT3 signal pathway in pyramidal cells of the sensorimotor cortex after spinal cord injury.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	7	8
These cells were treated with the novel JAK2 and STAT3 phosphorylation inhibitor WP1193 and/or the JAK and STAT3 activator IL-6 under normoxic and hypoxic conditions [ XREF_BIBR ] .	These cells were treated with the novel JAK2 and STAT3 phosphorylation inhibitor WP1193 and/or the JAK and STAT3 activator IL-6 under normoxic and hypoxic conditions [XREF_BIBR].	3	20	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	17	18
Th17 cells , which have been implicated in autoimmune diseases , require STAT3 signaling activated by IL-6 or IL-23 for their development .	Th17 cells, which have been implicated in autoimmune diseases, require STAT3 signaling activated by IL-6 or IL-23 for their development.	12	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	16	17	12	13
With a classic injury response , elevated IL-6 , combined with inflammation and multiple cell injury signals , activates STAT3 for multiple signaling events including both cell death and cell survival .	With a classic injury response, elevated IL-6, combined with inflammation and multiple cell injury signals, activates STAT3 for multiple signaling events including both cell death and cell survival.	6	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	19	20
However , IL-6 mediated STAT3 signaling also plays a protective role in IBD [ XREF_BIBR ] .	However, IL-6 mediated STAT3 signaling also plays a protective role in IBD [XREF_BIBR].	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	4	5
Our previous study demonstrated that STAT3 activation by IL-6 in colonic epithelial cells exacerbates experimental ulcerative colitis .	Our previous study demonstrated that STAT3 activation by IL-6 in colonic epithelial cells exacerbates experimental ulcerative colitis.	5	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	5	6
To investigate whether , arsenic induces an IL-6 mediated STAT3 binding to the miR-21 promoter , we analyzed IL-6 levels and STAT3 activation by ELISA , and STAT3 binding to the miR-21 promoter by ChIP assay .	To investigate whether, arsenic induces an IL-6 mediated STAT3 binding to the miR-21 promoter, we analyzed IL-6 levels and STAT3 activation by ELISA, and STAT3 binding to the miR-21 promoter by ChIP assay.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
XREF_BIBR Yeh et al XREF_BIBR revealed that STAT3 activation induced by IL-6 contributed to lung adenocarcinoma development .	XREF_BIBR Yeh et al XREF_BIBR revealed that STAT3 activation induced by IL-6 contributed to lung adenocarcinoma development.	7	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	7	8
This finding contrasts observations made in epithelial cancer cells , where IL-6 signalling induces pSTAT3 activation and contributes to epithelial cancer proliferation .	This finding contrasts observations made in epithelial cancer cells, where IL-6 signalling induces pSTAT3 activation and contributes to epithelial cancer proliferation.	11	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	11	12	14	15
The induction of Stat3 by IL-6 in myeloma cells has been shown to protect these cells from apoptotic stimuli emanating from the Fas ( CD95 and Apo-1 ) receptor or chemotherapeutic agents [ XREF_BIBR ] .	The induction of Stat3 by IL-6 in myeloma cells has been shown to protect these cells from apoptotic stimuli emanating from the Fas (CD95/Apo-1) receptor or chemotherapeutic agents [XREF_BIBR].	1	8	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	5	6	3	4
As IL10 activation of STAT3 leads to an anti-inflammatory response , but IL6 activation of STAT3 does not [ XREF_BIBR ] , it is possible that ligand activation of PPARbeta and delta interferes with the anti-inflammatory response associated with IL10 by interfering with STAT3 .	As IL10 activation of STAT3 leads to an anti-inflammatory response, but IL6 activation of STAT3 does not [XREF_BIBR], it is possible that ligand activation of PPARbeta and delta interferes with the anti-inflammatory response associated with IL10 by interfering with STAT3.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	12	13	15	16
Depletion of STAT3 by siRNA inhibited migration and invasion of these cells , suggesting that STAT3 activated by IL-6 contributes to regulation of cell motility .	Depletion of STAT3 by siRNA inhibited migration and invasion of these cells, suggesting that STAT3 activated by IL-6 contributes to regulation of cell motility.	15	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	15	16
LIF enhances the maintenance of stem cells [ XREF_BIBR ] , which may directly impact lung tissue regeneration and repair [ XREF_BIBR ] , similar to IL-6 activation of STAT3 [ XREF_BIBR ] .	LIF enhances the maintenance of stem cells [XREF_BIBR], which may directly impact lung tissue regeneration and repair [XREF_BIBR], similar to IL-6 activation of STAT3 [XREF_BIBR].	26	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	29	30
Regarding the mechanism underlying the repression of Foxp3 in developing T reg cells , IL-6- or IL-23-mediated activation of STAT3 has been shown to play a central role .	Regarding the mechanism underlying the repression of Foxp3 in developing T reg cells, IL-6- or IL-23-mediated activation of STAT3 has been shown to play a central role.	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6-	IL-6-	IL-6-	STAT3	STAT3	STAT3	14	15	19	20
Gp130 and IL-6 blockade inhibits Stat3 activation in breast cancer derived cell lines .	Gp130 and IL-6 blockade inhibits Stat3 activation in breast cancer derived cell lines.	0	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	2	3	5	6
Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 pathway , here we evaluate whether gp130 dependent STAT3 activation modulates atherosclerosis .	Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 pathway, here we evaluate whether gp130 dependent STAT3 activation modulates atherosclerosis.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	11	12
Because IL-6 and IL-11 can activate STAT3 , increased pSTAT3 observed in Naip1-6 Delta and Delta tumors might be related to the observed up-regulation of those cytokines .	Because IL-6 and IL-11 can activate STAT3, increased pSTAT3 observed in Naip1-6 Delta and Delta tumors might be related to the observed up-regulation of those cytokines.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	6	7
More significantly , we found that high concentrations of IL-6 were not able to activate Stat3 in HER2 inhibited cells , suggesting that HER2 plays a prominent role in the IL-6 mediated activation of Stat3 .	More significantly, we found that high concentrations of IL-6 were not able to activate Stat3 in HER2 inhibited cells, suggesting that HER2 plays a prominent role in the IL-6 mediated activation of Stat3.	30	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	30	31	34	35
There is now a growing evidence that acute exercise related IL-6 response act as an anti-inflammatory cytokine since IL-6 can exert inhibitory effects on TNF-alpha and IL-1 production XREF_BIBR and stimulate the production of both anti-inflammatory cytokines IL-1ra and IL-10 XREF_BIBR STAT3 is activated in SCs in a transient manner as only pSTAT3 was detectable in SCs ( Pax7 + ) after 2 hours of resistance exercise ( XREF_FIG ) .	There is now a growing evidence that acute exercise related IL-6 response act as an anti-inflammatory cytokine since IL-6 can exert inhibitory effects on TNF-alpha and IL-1 production XREF_BIBR and stimulate the production of both anti-inflammatory cytokines IL-1ra and IL-10 XREF_BIBR STAT3 is activated in SCs in a transient manner as only pSTAT3 was detectable in SCs (Pax7 +) after 2 hours of resistance exercise (XREF_FIG).	10	42	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	41	42
IL6 stimulated an autocrine IGFI and IGFIR expression STAT3 dependently , which stimulated stemness related properties in both the cell lines and the xenografted mouse tumors .	IL6 stimulated an autocrine IGFI and IGFIR expression STAT3 dependently, which stimulated stemness related properties in both the cell lines and the xenografted mouse tumors.	0	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	8	9
143 IL-6 treatment increases Stat3 production , which together with Sox2 stimulates formation of mouse foregut SCC .	143 IL-6 treatment increases Stat3 production, which together with Sox2 stimulates formation of mouse foregut SCC.	1	5	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	4	5
Ischemia leads to a JAK2 and STAT3 activation mediated by IL-6 .	Ischemia leads to a JAK2 and STAT3 activation mediated by IL-6.	4	11	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	6	7
In naive rats , intrathecal administration of a proalgesic cytokine IL-6 rapidly activated microglial JAK and STAT3 and induced downstream changes closely resembling CCI evoked alterations .	In naive rats, intrathecal administration of a proalgesic cytokine IL-6 rapidly activated microglial JAK and STAT3 and induced downstream changes closely resembling CCI evoked alterations.	5	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	16	17
To study if IL-6 could induce STAT3 activation in PC3M-1E8 cells and be inhibited by Stattic , PC3M-1E8 cells were cultured in serum-free medium overnight and then treated with 25 ng/mL IL-6 and Stattic at indicated concentration for 24 hours .	To study if IL-6 could induce STAT3 activation in PC3M-1E8 cells and be inhibited by Stattic, PC3M-1E8 cells were cultured in serum-free medium overnight and then treated with 25 ng/mL IL-6 and Stattic at indicated concentration for 24 hours.	3	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	6	7
56 The Th17 differentiation program involves IL6 activation of STAT3 , which is enhanced by SOCS1 , and induces the lineage specific transcription factor RORC .	56 The Th17 differentiation program involves IL6 activation of STAT3, which is enhanced by SOCS1, and induces the lineage specific transcription factor RORC.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	6	7	9	10
In our studies , we found that the concentration of IL-6 detected in the peripheral blood was below the threshold needed to stimulate STAT3 and SOCS3 activation .	In our studies, we found that the concentration of IL-6 detected in the peripheral blood was below the threshold needed to stimulate STAT3 and SOCS3 activation.	8	26	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	23	24
IL-6 in turn activated STAT3 by an autocrine loop .	IL-6 in turn activated STAT3 by an autocrine loop.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Constitutively active Stat3 is a part of the positive autocrine IL-6 loop and Stat3 activation in human tumors is often observed at the invasive front of tumors adjacent to inflammatory cells , which suggests that Stat3 dependent tumorigenesis is mediated by IL-6 .	Constitutively active Stat3 is a part of the positive autocrine IL-6 loop and Stat3 activation in human tumors is often observed at the invasive front of tumors adjacent to inflammatory cells, which suggests that Stat3 dependent tumorigenesis is mediated by IL-6.	35	42	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	41	42	35	36
These data suggest that IL-6 induced STAT3 activation is vital in the upregulation of lncTCF7 .	These data suggest that IL-6 induced STAT3 activation is vital in the upregulation of lncTCF7.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
Insulin can inhibit IL-6 induced gene expression XREF_BIBR , the dominant stimulator of hemopexin and other acute phase gene expression , via inhibiting IL-6 stimulation of STAT3 activation XREF_BIBR , XREF_BIBR .	Insulin can inhibit IL-6 induced gene expression XREF_BIBR, the dominant stimulator of hemopexin and other acute phase gene expression, via inhibiting IL-6 stimulation of STAT3 activation XREF_BIBR, XREF_BIBR.	23	28	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	23	24	26	27
The activation of STAT3 by IL-6 and IL-23 is a key event in Th17 lineage specification .	The activation of STAT3 by IL-6 and IL-23 is a key event in Th17 lineage specification.	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	3	4
Elevated expression of cytokines and cytokine receptors was also detected , including tumor necrosis factor superfamily members 12 and 21 , colony stimulating factor 1 receptor , FMS like tyrosine kinase 1 , chemokine ( C-X-C motif ) ligand 9 , the STAT3 activating cytokine osteopontin , IL-6 receptor ( IL-6R ) signal transducing subunit ( gp130 ) , and oncostatin M ( OSM ) receptor , which also activates STAT3 ( XREF_FIG ) .	Elevated expression of cytokines and cytokine receptors was also detected, including tumor necrosis factor superfamily members 12 and 21, colony stimulating factor 1 receptor, FMS like tyrosine kinase 1, chemokine (C-X-C motif) ligand 9, the STAT3 activating cytokine osteopontin, IL-6 receptor (IL-6R) signal transducing subunit (gp130), and oncostatin M (OSM) receptor, which also activates STAT3 (XREF_FIG).	47	72	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	47	48	70	71
Furthermore , IL-6 , even at low doses , induced long-term activation ( up to 24 hrs ) of STAT3 whereas IL-10 and IL-21 did not and this correlated with the capacity to suppress Th9 differentiation .	Furthermore, IL-6, even at low doses, induced long-term activation (up to 24 hrs) of STAT3 whereas IL-10 and IL-21 did not and this correlated with the capacity to suppress Th9 differentiation.	2	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	19	20
In contrast , TGFbeta and IL-6 trigger the coordinated activation of Smad3 and STAT3 to induce the transcription factor RORgammat necessary for Th17 differentiation .	In contrast, TGFbeta and IL-6 trigger the coordinated activation of Smad3 and STAT3 to induce the transcription factor RORgammat necessary for Th17 differentiation.	3	14	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	13	14
Collectively , in the presence of EBV infection ( both EBV infected NPE and EBV infected NPC cells ) , IL-6 induces hyperactivation of STAT3 .	Collectively, in the presence of EBV infection (both EBV infected NPE and EBV infected NPC cells), IL-6 induces hyperactivation of STAT3.	20	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	20	21	24	25
This is surprising because in other settings , STAT3 activation by IL-6 or IL-21 in TGF-beta-exposed T cells induces downregulation of Foxp3 and upregulation of the transcription factor RORgammat leading to induction of IL-17-producing Th17 cells [ XREF_BIBR ] .	This is surprising because in other settings, STAT3 activation by IL-6 or IL-21 in TGF-beta-exposed T cells induces downregulation of Foxp3 and upregulation of the transcription factor RORgammat leading to induction of IL-17-producing Th17 cells [XREF_BIBR].	8	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	8	9
A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6 , but not activation induced by leukemia inhibitory factor .	A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor.	8	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	10	11
STAT3 induced by IL-6 mediates pro inflammatory effects while STAT3 activated by IL-10 and IL-22 has anti-inflammatory properties .	STAT3 induced by IL-6 mediates pro inflammatory effects while STAT3 activated by IL-10 and IL-22 has anti-inflammatory properties.	0	4	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	0	1
We recently showed a feed forward loop as a result of the IL6 activation of the JAK2 and STAT3 where STAT3 acts as a promoter of WASF3 transcription and JAK2 activates WASF3 .	We recently showed a feed forward loop as a result of the IL6 activation of the JAK2 and STAT3 where STAT3 acts as a promoter of WASF3 transcription and JAK2 activates WASF3.	12	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	12	13	18	19
We found that IL-6 induced p-STAT3 at a dosage as low as 1 ng/ml , but the induction was maximal at a dosage of 50 ng/ml ( XREF_FIG ) .	We found that IL-6 induced p-STAT3 at a dosage as low as 1 ng/ml, but the induction was maximal at a dosage of 50 ng/ml (XREF_FIG).	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	3	4	5	6
Recovery after liver injury is mediated by the NF-kB ( Nuclear Factor Kappa-light-chain-enhancer of activated B cells ) and STAT3 ( Signal Transducer and Activator of Transcription 3 ) signaling pathways , both of which are activated by IL-6 [ XREF_BIBR ] .	Recovery after liver injury is mediated by the NF-kB (Nuclear Factor Kappa-light-chain-enhancer of activated B cells) and STAT3 (Signal Transducer and Activator of Transcription 3) signaling pathways, both of which are activated by IL-6 [XREF_BIBR].	5	40	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	38	39	19	20
Stat3 is typically activated by the IL-6 family cytokines and growth factors as well as by the Th2 cytokine IL-10 XREF_BIBR , XREF_BIBR , but whether it can be activated by IL-1 is not known .	Stat3 is typically activated by the IL-6 family cytokines and growth factors as well as by the Th2 cytokine IL-10 XREF_BIBR, XREF_BIBR, but whether it can be activated by IL-1 is not known.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	0	1
Previous studies have shown that sustained IL-6 expression can constitutively activate STAT3 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , which transactivates Twist gene expression and promotes carcinoma cell migration and invasion , as well as resistance to drug and radiation therapy [ XREF_BIBR ] .	Previous studies have shown that sustained IL-6 expression can constitutively activate STAT3 [XREF_BIBR, XREF_BIBR, XREF_BIBR], which transactivates Twist gene expression and promotes carcinoma cell migration and invasion, as well as resistance to drug and radiation therapy [XREF_BIBR].	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 expression	il-6	STAT3	STAT3	stat3	6	7	11	12
In DU145 cells , IL-6 is autonomously expressed and activates the IL-6 and STAT3 signaling pathway by an autocrine mechanism [ XREF_BIBR ] .	In DU145 cells, IL-6 is autonomously expressed and activates the IL-6 and STAT3 signaling pathway by an autocrine mechanism [XREF_BIBR].	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 is autonomously expressed	il-6	STAT3	STAT3	stat3	4	5	13	14
In addition to inducing STAT3 activation in lung epithelial cells , IL-6 activates STAT3 in other cells in lungs , particularly macrophages , to express IL-10 , which serves as a paracrine stimulus to further enhance lung epithelial STAT3 activation for lung homeostasis under oncogenic stress ( XREF_FIG and XREF_SUPPLEMENTARY ) .	In addition to inducing STAT3 activation in lung epithelial cells, IL-6 activates STAT3 in other cells in lungs, particularly macrophages, to express IL-10, which serves as a paracrine stimulus to further enhance lung epithelial STAT3 activation for lung homeostasis under oncogenic stress (XREF_FIG and XREF_SUPPLEMENTARY).	11	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	13	14
Consistent with immunoblotting data ( XREF_FIG ) , the IL6 stimulated STAT3 dependent luciferase activity in LNCaP cells was completely abolished by a 24 h exposure to 20 and 40 micromol/L SFN ( XREF_FIG ) .	Consistent with immunoblotting data (XREF_FIG), the IL6 stimulated STAT3 dependent luciferase activity in LNCaP cells was completely abolished by a 24 h exposure to 20 and 40 micromol/L SFN (XREF_FIG).	3	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	9	10	11	12
IL-6 stimulation of MCF-10A cells enhanced association of STAT3 and MUC1-C with the cyclin D1 promoter STAT binding region ( SBR ; -1045 to -839 ) , a response that was attenuated by GO-201 but not CP-1 ( XREF_SUPPLEMENTARY ) .	IL-6 stimulation of MCF-10A cells enhanced association of STAT3 and MUC1-C with the cyclin D1 promoter STAT binding region (SBR; -1045 to -839), a response that was attenuated by GO-201 but not CP-1 (XREF_SUPPLEMENTARY).	0	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	8	9
Also , IL-6 induced activation of STAT3 triggered miR-21 expression in Tca8113 and DDP and Tca8113 cells ( XREF_FIG ) .	Also, IL-6 induced activation of STAT3 triggered miR-21 expression in Tca8113 and DDP and Tca8113 cells (XREF_FIG).	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	6	7
In this study , we found that long-term treatment of lapatinib in HER2 positive breast cancer cells led to increased IL6 expression , subsequent activation of downstream STAT3 signaling , and the maintenance of stemness , all of which contributed to acquired lapatinib resistance .	In this study, we found that long-term treatment of lapatinib in HER2 positive breast cancer cells led to increased IL6 expression, subsequent activation of downstream STAT3 signaling, and the maintenance of stemness, all of which contributed to acquired lapatinib resistance.	20	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	20	21	27	28
Apart from IECs , STAT3 activation by IL-6 , IL-10 , and other cytokines ( mentioned above ) in myeloid cells also has important implications for IBD .	Apart from IECs, STAT3 activation by IL-6, IL-10, and other cytokines (mentioned above) in myeloid cells also has important implications for IBD.	4	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	4	5
In empty vector transfected cells , IL-6 induced a rapid accumulation of STAT3 within 20 min of stimulation , concomitant with the nuclear appearance of phospho-Tyr 705 STAT3 .	In empty vector transfected cells, IL-6 induced a rapid accumulation of STAT3 within 20 min of stimulation, concomitant with the nuclear appearance of phospho-Tyr 705 STAT3.	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	12	13
Analysis of Stat3 phosphorylation by Western blot showed a clear activation of Stat3 by IL-6 in CD8 + T cells ( XREF_FIG ) .	Analysis of Stat3 phosphorylation by Western blot showed a clear activation of Stat3 by IL-6 in CD8 + T cells (XREF_FIG).	7	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	14	15	12	13
Importantly , we find that IL-6 can activate STAT3 and the autophagy enzyme GABARAPL1 in human islets .	Importantly, we find that IL-6 can activate STAT3 and the autophagy enzyme GABARAPL1 in human islets.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	8	9
Also , IL-6 activates the STAT3 signaling pathway to increase the number of MDSCs [ XREF_BIBR ] .	Also, IL-6 activates the STAT3 signaling pathway to increase the number of MDSCs [XREF_BIBR].	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	5	6
That is , while IL-6 activation of STAT3 is required for repression of Foxp3 , RORgammat is not .	That is, while IL-6 activation of STAT3 is required for repression of Foxp3, RORgammat is not.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	7	8
This IL-6 mediated STAT-3 activation plays a crucial role in tumorigenesis [ XREF_BIBR ] .	This IL-6 mediated STAT-3 activation plays a crucial role in tumorigenesis [XREF_BIBR].	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	1	2	3	4
IL-6 deficiency abrogated satellite cell proliferation and myonuclear accretion in the preexisting myofiber by impairing STAT3 activation and expression of its target gene cyclin D1 .	IL-6 deficiency abrogated satellite cell proliferation and myonuclear accretion in the preexisting myofiber by impairing STAT3 activation and expression of its target gene cyclin D1.	0	16	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	15	16
Adm mRNA levels according to quantitative real-time polymerase chain reaction after activation of STAT3 by interleukin-6 ( IL-6 ) in Ishikawa cells ; immunohistochemistry for ADM in eutopic endometrial biopsies from women with endometriosis compared with healthy donors ; and MR-proADM levels measured by commercial immunoassay in plasma from healthy women and women with endometriosis who subsequently underwent surgical resection of ectopic lesions .	Adm mRNA levels according to quantitative real-time polymerase chain reaction after activation of STAT3 by interleukin-6 (IL-6) in Ishikawa cells; immunohistochemistry for ADM in eutopic endometrial biopsies from women with endometriosis compared with healthy donors; and MR-proADM levels measured by commercial immunoassay in plasma from healthy women and women with endometriosis who subsequently underwent surgical resection of ectopic lesions.	2	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	interleukin-6	interleukin-6	interleukin-6	STAT3	STAT3	STAT3	15	16	13	14
Upon binding to its cognate receptor on hepatocytes , IL-6 activates STAT3 signaling pathways , leading to gene expression that facilitates hepatocyte proliferation .	Upon binding to its cognate receptor on hepatocytes, IL-6 activates STAT3 signaling pathways, leading to gene expression that facilitates hepatocyte proliferation.	9	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	11	12
STAT3 signaling is commonly activated by IL-6 family cytokines , including IL-6 , Oncostatin M ( OSM ) and Leukemia Inhibitory Factor ( LIF ) [ XREF_BIBR ] .	STAT3 signaling is commonly activated by IL-6 family cytokines, including IL-6, Oncostatin M (OSM) and Leukemia Inhibitory Factor (LIF) [XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	0	1
The incomplete attenuation of Pim1 and Nfatc2 expression in macrophages in response to CM from siRNA-IL6-treated PH-Fibs raises the possibility that intracellular signaling pathways through src contribute to IL6 induced STAT3 signaling in macrophages and that enhanced proliferation and apoptosis resistance in the vessel wall , are also controlled by fibroblast derived IL6 in any IL6 responsive cell , including fibroblasts , macrophages , endothelial cells and smooth muscle cells .	The incomplete attenuation of Pim1 and Nfatc2 expression in macrophages in response to CM from siRNA-IL6-treated PH-Fibs raises the possibility that intracellular signaling pathways through src contribute to IL6 induced STAT3 signaling in macrophages and that enhanced proliferation and apoptosis resistance in the vessel wall, are also controlled by fibroblast derived IL6 in any IL6 responsive cell, including fibroblasts, macrophages, endothelial cells and smooth muscle cells.	26	31	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	28	29	30	31
IL-6 , IL-21 , and IL-23 all can activate STAT3 , and such activation of STAT3 is crucial for their effects on Th17 cell differentiation .	IL-6, IL-21, and IL-23 all can activate STAT3, and such activation of STAT3 is crucial for their effects on Th17 cell differentiation.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	9	10
The IL-6 secreted by MDSCs may directly activate a Stat3 pathway in cancer cells and promote tumor growth .	The IL-6 secreted by MDSCs may directly activate a Stat3 pathway in cancer cells and promote tumor growth.	0	15	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	1	2	9	10
More specifically , miR-30c-2-5p and miR-1-5p are immunosuppression regulators [ XREF_BIBR ] , whereas let-7a-1-5p regulates inflammation associated cytokine IL-6 ( interleukin-6 ) that induces STAT3 ( signal transducers and activators of transcription 3 ) signaling [ XREF_BIBR ] .	More specifically, miR-30c-2-5p and miR-1-5p are immunosuppression regulators [XREF_BIBR], whereas let-7a-1-5p regulates inflammation associated cytokine IL-6 (interleukin-6) that induces STAT3 (signal transducers and activators of transcription 3) signaling [XREF_BIBR].	17	37	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	25	26
Furthermore , IL-6 secreted from PSCs stimulates STAT3 signaling in both the mouse pancreatic precursor , noninvasive PanIN cells as well as in primary human PDAC cell lines .	Furthermore, IL-6 secreted from PSCs stimulates STAT3 signaling in both the mouse pancreatic precursor, noninvasive PanIN cells as well as in primary human PDAC cell lines.	2	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	7	8
However , CNTF and LIF , but not IL-6 , activated STAT3 in dorsal root ganglion neurons .	However, CNTF and LIF, but not IL-6, activated STAT3 in dorsal root ganglion neurons.	2	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	11	12
While the cytokines IL-6 and LIF activated STAT3 gene regulation in both SIE- and AGG-element-dependent manners , LPS failed to activate STAT3 gene regulation in an SIE dependent manner .	While the cytokines IL-6 and LIF activated STAT3 gene regulation in both SIE- and AGG-element-dependent manners, LPS failed to activate STAT3 gene regulation in an SIE dependent manner.	1	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	7	8
IL-6 trans-signaling-dependent activation of STAT3 can drive cancer progression through the transcription of target genes including the cell cycle regulator cyclin D1 , the proto-oncogene c-myc , transcriptional regulators such as JunB , cFos and C/EBPbeta and C/EBPdelta , and metabolic regulators such as mTORC1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	IL-6 trans-signaling-dependent activation of STAT3 can drive cancer progression through the transcription of target genes including the cell cycle regulator cyclin D1, the proto-oncogene c-myc, transcriptional regulators such as JunB, cFos and C/EBPbeta and C/EBPdelta, and metabolic regulators such as mTORC1 [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	4	5
Chronic ethanol exposure also abolishes endotoxin induced STAT3 activation in the liver and inhibits IL-6 activation of STAT3 in hepatocytes and sinusoidal endothelial cells .	Chronic ethanol exposure also abolishes endotoxin induced STAT3 activation in the liver and inhibits IL-6 activation of STAT3 in hepatocytes and sinusoidal endothelial cells.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	14	15	17	18
This suggests that not only does IL-6 drive STAT3 activation as previously documented [ XREF_BIBR ] , but S1P 1 knockdown also exerts control over STAT3 activation and affects downstream signaling to dampen IL-6 production and release .	This suggests that not only does IL-6 drive STAT3 activation as previously documented [XREF_BIBR], but S1P 1 knockdown also exerts control over STAT3 activation and affects downstream signaling to dampen IL-6 production and release.	6	9	drive	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	8	9
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR STAT3 is typically activated by the interleukin 6 ( IL-6 ) family of cytokines or growth factors that can be constitutively and excessively secreted by epithelial tumor cells , stromal cells or immune cells .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR STAT3 is typically activated by the interleukin 6 (IL-6) family of cytokines or growth factors that can be constitutively and excessively secreted by epithelial tumor cells, stromal cells or immune cells.	10	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	STAT3	STAT3	STAT3	19	21	13	14
Among these candidate cytokines , IL-6 , which activates Stat3 through the glycoprotein 130/Janus kinase ( gp130 and Jak ) pathway , is notable for its pleiotropic tumor promoting activities , including anti-apoptotic , pro invasive , and immune-stimulatory effects attributable to the activation of Stat3 target genes [ XREF_BIBR , XREF_BIBR ] .	Among these candidate cytokines, IL-6, which activates Stat3 through the glycoprotein 130/Janus kinase (gp130 and Jak) pathway, is notable for its pleiotropic tumor promoting activities, including anti-apoptotic, pro invasive, and immune-stimulatory effects attributable to the activation of Stat3 target genes [XREF_BIBR, XREF_BIBR].	5	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	5	6	9	10
Further , other signaling systems that require Stat3 activation such as the IL-6 receptor is similar in IfitmDel splenocytes to that of WT-responses ( data not shown ) .	Further, other signaling systems that require Stat3 activation such as the IL-6 receptor is similar in IfitmDel splenocytes to that of WT-responses (data not shown).	7	13	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	12	13	7	8
In the previous section , we showed that IFN-gamma and IL-6 could activate both STAT1 and STAT3 , which may explain the higher activation of STAT1 and STAT3 after combined stimulation .	In the previous section, we showed that IFN-gamma and IL-6 could activate both STAT1 and STAT3, which may explain the higher activation of STAT1 and STAT3 after combined stimulation.	8	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	16	17
CP690 ,550 almost completely inhibited STAT3 activation induced by IL-6 plus sIL-6R in RA-FLS .	CP690,550 almost completely inhibited STAT3 activation induced by IL-6 plus sIL-6R in RA-FLS.	5	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	5	6
Statistical analysis supported that pSTAT3 profiles induced by IL-6 and IL-27 in WT cells were significantly different ( P = 0.0139 ) , whereas pSTAT3 profiles induced by IL-6 and IL-27 in S1KO cells were not significantly different ( P = 0.0812 ) .	Statistical analysis supported that pSTAT3 profiles induced by IL-6 and IL-27 in WT cells were significantly different (P = 0.0139), whereas pSTAT3 profiles induced by IL-6 and IL-27 in S1KO cells were not significantly different (P = 0.0812).	4	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	8	9	4	5
In addition , endotoxin has been shown to stimulate the production of IL-6 by sinusoidal endothelial cells and Kupffer cells , and IL-6 can activate STAT3 in sinusoidal endothelial cells .	In addition, endotoxin has been shown to stimulate the production of IL-6 by sinusoidal endothelial cells and Kupffer cells, and IL-6 can activate STAT3 in sinusoidal endothelial cells.	22	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	22	23	25	26
Whereas STAT3 activation in T H 17 cells is especially enhanced by IL-6 , IL-21 and IL-23 , the STAT3 activation in T reg cells is especially enhanced by IL-10 [ XREF_BIBR ] .	Whereas STAT3 activation in T H 17 cells is especially enhanced by IL-6, IL-21 and IL-23, the STAT3 activation in T reg cells is especially enhanced by IL-10 [XREF_BIBR].	1	16	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	1	2
We reported previously that stimulation of glycoprotein 130 ( gp130 ) by a combination of human IL-6 and soluble IL-6 receptor ( sIL-6R ) could support proliferation , differentiation , and terminal maturation of erythroid cells in the absence of erythropoietin ( EPO ) from human CD34 ( + ) cells in culture with stem cell factor ( SCF ) .	We reported previously that stimulation of glycoprotein 130 (gp130) by a combination of human IL-6 and soluble IL-6 receptor (sIL-6R) could support proliferation, differentiation, and terminal maturation of erythroid cells in the absence of erythropoietin (EPO) from human CD34 (+) cells in culture with stem cell factor (SCF).	4	22	stimulation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	16	17	9	10
The complex of IL-6 and soluble IL-6R ( sIL-6R ) triggers dimerization of gp130 and induces responses on cells that do not express membrane bound IL-6R .	The complex of IL-6 and soluble IL-6R (sIL-6R) triggers dimerization of gp130 and induces responses on cells that do not express membrane bound IL-6R.	3	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	3	4	13	14
IL-6 family cytokines binding to their receptors trigger the dimerization of GP130 .	IL-6 family cytokines binding to their receptors trigger the dimerization of GP130.	0	12	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	GP130	GP130	GP130	0	1	11	12
Moreover , c-kit receptor signalling together with gp130 signalling by IL-6 have previously been shown to be involved in the maintenance of immortalised HSC like cell lines after transduction of HSCs with a constitutively active Notch1 receptor , or a constitutively active beta-catenin that activates the canonical Wnt signalling pathway XREF_BIBR , XREF_BIBR , although the specificity or efficiency of these events are unknown .	Moreover, c-kit receptor signalling together with gp130 signalling by IL-6 have previously been shown to be involved in the maintenance of immortalised HSC like cell lines after transduction of HSCs with a constitutively active Notch1 receptor, or a constitutively active beta-catenin that activates the canonical Wnt signalling pathway XREF_BIBR, XREF_BIBR, although the specificity or efficiency of these events are unknown.	7	11	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	10	11	7	8
Supporting the in vivo findings in both Ada -/-, SCD and CFA injected mice , we further demonstrated that IL-6 trans-signaling via sIL-6R activates gp130 , resulting in the translocalization of pSTAT3 to nucleus , and the induction of TRPV1 gene expression in isolated DRG neuronal cells from WT mice .	Supporting the in vivo findings in both Ada -/-, SCD and CFA injected mice, we further demonstrated that IL-6 trans-signaling via sIL-6R activates gp130, resulting in the translocalization of pSTAT3 to nucleus, and the induction of TRPV1 gene expression in isolated DRG neuronal cells from WT mice.	19	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	19	20	24	25
The IL-6 receptor ( IL-6R ) is expressed in HAEC , and Stat3 is phosphorylated in response to IL-6 stimulation of the IL-6R .	The IL-6 receptor (IL-6R) is expressed in HAEC, and Stat3 is phosphorylated in response to IL-6 stimulation of the IL-6R.	18	23	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	18	19	22	23
Abrogation of IL-6 mediated gp130 responses has been shown to prevent the generation of adaptive immune responses to Toxoplasma gondii infection , suggesting that signals via gp130 are important for protective memory responses .	Abrogation of IL-6 mediated gp130 responses has been shown to prevent the generation of adaptive immune responses to Toxoplasma gondii infection, suggesting that signals via gp130 are important for protective memory responses.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	4	5
Gp130 expressing cells - even in the absence of IL-6R - can be stimulated by the complex of IL-6 and sIL-6R XREF_BIBR and this process has been called trans-signaling XREF_BIBR .	Gp130 expressing cells - even in the absence of IL-6R - can be stimulated by the complex of IL-6 and sIL-6R XREF_BIBR and this process has been called trans-signaling XREF_BIBR.	0	21	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Gp130	Gp130	Gp130	18	19	0	1
Binding of IL-6 produced during virus infection to sIL-6 receptor would activate lymphocytes and enterocytes via membrane bound gp130 .	Binding of IL-6 produced during virus infection to sIL-6 receptor would activate lymphocytes and enterocytes via membrane bound gp130.	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	18	19
IL-6 exerts its effect on target cells by binding to the IL-6 specific membrane receptor ( IL-6R ) , which activates the transducer glycoprotein 130 ( gp130 ) , the second subunit of the IL-6R complex .	IL-6 exerts its effect on target cells by binding to the IL-6 specific membrane receptor (IL-6R), which activates the transducer glycoprotein 130 (gp130), the second subunit of the IL-6R complex.	11	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	11	12	26	27
RA was shown to inhibit IL-6R and IL-23R upregulation induced by TGF-beta and IL-6 , respectively .	RA was shown to inhibit IL-6R and IL-23R upregulation induced by TGF-beta and IL-6, respectively.	5	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	13	14	5	6
STAT3 is activated in lung adenocarcinomas through a mutant EGFR regulating the expression of the IL-6 cytokine , which , in turn , activates the gp130 and JAK pathway .	STAT3 is activated in lung adenocarcinomas through a mutant EGFR regulating the expression of the IL-6 cytokine, which, in turn, activates the gp130 and JAK pathway.	12	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	expression of the IL-6	il-6	gp130	gp130	gp130	15	16	25	26
Tocilizumab inhibited the proliferation of BaF and IL-6R induced by IL-6 , but did not inhibit the proliferation of BaF and IL-11R , BaF and OSMR , BaF and LIFR and BaF and CNTFR cells induced by their corresponding cytokines .	Tocilizumab inhibited the proliferation of BaF and IL-6R induced by IL-6, but did not inhibit the proliferation of BaF and IL-11R, BaF and OSMR, BaF and LIFR and BaF and CNTFR cells induced by their corresponding cytokines.	3	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	10	11	7	8
IL-6 mediated gp130 signaling has been linked to defects in hematopoietic differentiation ability of bone marrow precursors [ XREF_BIBR ] .	IL-6 mediated gp130 signaling has been linked to defects in hematopoietic differentiation ability of bone marrow precursors [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	0	1	2	3
It has been reported that Nav1.8-expressing C-fibres contain gp130 and respond to a fusion protein comprising IL-6 and the soluble type IL-6 receptor , which is known to stimulate gp130 without membrane bound type IL-6 receptors 38 .	It has been reported that Nav1.8-expressing C-fibres contain gp130 and respond to a fusion protein comprising IL-6 and the soluble type IL-6 receptor, which is known to stimulate gp130 without membrane bound type IL-6 receptors 38.	15	30	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	16	17	29	30
IL-6 mediates the susceptibility of gp130 hypermorphs to Toxoplasma gondii .	IL-6 mediates the susceptibility of gp130 hypermorphs to Toxoplasma gondii.	0	6	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	0	1	5	6
Binding of IL6 to its receptor activates the gp130 subunits , causing phosphorylation of JAK and subsequent phosphorylation of STATs .	Binding of IL6 to its receptor activates the gp130 subunits, causing phosphorylation of JAK and subsequent phosphorylation of STATs.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	gp130	gp130	gp130	2	3	8	9
In isolated adult cardiomyocytes , gp130 stimulation by IL-6 has been reported to decrease myocyte contractility during acute exposure .	In isolated adult cardiomyocytes, gp130 stimulation by IL-6 has been reported to decrease myocyte contractility during acute exposure.	5	9	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	8	9	5	6
Due to the fact that mouse IL-6 , secreted by mouse macrophages and natural killer cells , is not able to activate the human IL-6R we examined the IL-6 expression in human prostate cancer cells after co-incubation with mouse IIR cells .	Due to the fact that mouse IL-6, secreted by mouse macrophages and natural killer cells, is not able to activate the human IL-6R we examined the IL-6 expression in human prostate cancer cells after co-incubation with mouse IIR cells.	5	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	6	7	24	25
We sorted CD34 ( + ) IL-6R+ or CD34 ( + ) IL-6R- cells and studied the effect on hematopoietic colony formation of signaling through gp130 activated by IL-6 or a combination of IL-6 and recombinant soluble human IL-6R ( sIL-6R ) in the presence or absence of stem cell factor ( SCF ) and/or IL-3 .	We sorted CD34 (+) IL-6R+ or CD34 (+) IL-6R- cells and studied the effect on hematopoietic colony formation of signaling through gp130 activated by IL-6 or a combination of IL-6 and recombinant soluble human IL-6R (sIL-6R) in the presence or absence of stem cell factor (SCF) and/or IL-3.	23	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	28	29	25	26
By blocking the IL-6r binding site , IL-6 can not activate gp130 , which effectively eliminates most IL-6 signaling throughout the body .	By blocking the IL-6r binding site, IL-6 can not activate gp130, which effectively eliminates most IL-6 signaling throughout the body.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	7	8	11	12
In trans-signaling , cells expressing only gp130 and lack membrane bound IL-6R can be activated by IL-6 and soluble IL-6R ( sIL-6R ) complex .	In trans-signaling, cells expressing only gp130 and lack membrane bound IL-6R can be activated by IL-6 and soluble IL-6R (sIL-6R) complex.	11	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	16	17	11	12
IL6 induced activation of associated JAK2 precedes post-translational modification of gp130 followed by its internalization [ XREF_BIBR ] that is dependent on a di-leucine endocytic motif [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	IL6 induced activation of associated JAK2 precedes post-translational modification of gp130 followed by its internalization [XREF_BIBR] that is dependent on a di-leucine endocytic motif [XREF_BIBR; XREF_BIBR; XREF_BIBR].	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	gp130	gp130	gp130	0	1	10	11
It was soon established that the expression of IL-6R is restricted to some tissues , while that of gp130 is ubiquitous , and that IL-6 may upregulate gp130 expression XREF_BIBR .	It was soon established that the expression of IL-6R is restricted to some tissues, while that of gp130 is ubiquitous, and that IL-6 may upregulate gp130 expression XREF_BIBR.	24	29	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	24	25	27	28
It is likely that gp130 mediated signaling by IL-6 family members also plays a role in more immediate responses to glaucomatous stressors , namely elevated IOP .	It is likely that gp130 mediated signaling by IL-6 family members also plays a role in more immediate responses to glaucomatous stressors, namely elevated IOP.	4	10	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	8	9	4	5
When evaluating other IL6 family members which can also activate gp130 , we found that leukemia inhibitory factor ( LIF ; XREF_SUPPLEMENTARY ) but not ciliary neurotrophic factor ( CNTF ; XREF_SUPPLEMENTARY ) expression was associated with poor patient survival , although there was no consistent elevation of LIF or its receptor in GSCs ( XREF_SUPPLEMENTARY ) .	When evaluating other IL6 family members which can also activate gp130, we found that leukemia inhibitory factor (LIF; XREF_SUPPLEMENTARY) but not ciliary neurotrophic factor (CNTF; XREF_SUPPLEMENTARY) expression was associated with poor patient survival, although there was no consistent elevation of LIF or its receptor in GSCs (XREF_SUPPLEMENTARY).	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	gp130	gp130	gp130	3	4	10	11
While c-kit is activated by SCF ; gp130 , in cells which do not express sufficient amounts of IL-6R , can be activated by the complex of soluble IL-6R ( sIL-6R ) and IL-6 .	While c-kit is activated by SCF; gp130, in cells which do not express sufficient amounts of IL-6R, can be activated by the complex of soluble IL-6R (sIL-6R) and IL-6.	7	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	33	34	7	8
IL-6 activates gp130 mediated cis- or trans-signaling via membrane bound or soluble form of IL-6R ( sIL-6R ) [ XREF_BIBR ] .	IL-6 activates gp130 mediated cis- or trans-signaling via membrane bound or soluble form of IL-6R (sIL-6R) [XREF_BIBR].	0	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	0	1	2	3
We then tested whether IL-6 could also stimulate the proliferation of IL-6R positive neuroblastoma cells in vivo .	We then tested whether IL-6 could also stimulate the proliferation of IL-6R positive neuroblastoma cells in vivo.	4	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	4	5	11	12
By contrast , ectodomain cleavage of the IL-6 receptor ( IL-6R ) produces soluble IL-6R ( sIL-6R ) , which , in complex with IL-6 , has agonistic properties .	By contrast, ectodomain cleavage of the IL-6 receptor (IL-6R) produces soluble IL-6R (sIL-6R), which, in complex with IL-6, has agonistic properties.	7	26	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	7	8	14	15
Even in the absence of IL-6R , gp130 expressing cells can be activated by the complex of IL-6 and soluble IL-6R and this process has been called trans-signaling [ XREF_BIBR ] .	Even in the absence of IL-6R, gp130 expressing cells can be activated by the complex of IL-6 and soluble IL-6R and this process has been called trans-signaling [XREF_BIBR].	7	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	17	18	7	8
While IL-6 induces gp130 dimerization , CNTF , after the initial interaction with the specific , non signalling receptor subunit , CNTFR , induces the formation of gp130 and LIF-receptor heterodimers .	While IL-6 induces gp130 dimerization, CNTF, after the initial interaction with the specific, non signalling receptor subunit, CNTFR, induces the formation of gp130 and LIF-receptor heterodimers.	1	4	induces	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	1	2	3	4
Binding of IL-6 to its receptor activates the gp80 and gp130 signaling pathway , leading to activation of the downstream ERK1/2 and signal transducer and activator of transcription 3 ( STAT3 ) cascades .	Binding of IL-6 to its receptor activates the gp80 and gp130 signaling pathway, leading to activation of the downstream ERK1/2 and signal transducer and activator of transcription 3 (STAT3) cascades.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	10	11
Binding of IL-6 to its receptor activates the signal transducing receptor glycoprotein 130 ( gp130 ) , inducing homodimerization and activation of Janus kinases ( JAKs ) that in turn activate signal transducers and activators of transcription ( AKT1 , NF-kappaB , STAT3 ) [ XREF_BIBR - XREF_BIBR ] .	Binding of IL-6 to its receptor activates the signal transducing receptor glycoprotein 130 (gp130), inducing homodimerization and activation of Janus kinases (JAKs) that in turn activate signal transducers and activators of transcription (AKT1, NF-kappaB, STAT3) [XREF_BIBR - XREF_BIBR].	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	14	15
IL-6 in conjunction with TGFbeta was found to upregulate the IL-6R , perhaps perpetuating the effects of the cytokine .	IL-6 in conjunction with TGFbeta was found to upregulate the IL-6R, perhaps perpetuating the effects of the cytokine.	0	11	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	0	1	10	11
Also , enhancement of IL-6R by IL-6 recovered the pathway of STAT3 mediated Mn-SOD expression , and protected neuronal cells against ischemic reperfusion ( XREF_FIG , XREF_FIG , and XREF_FIG ) .	Also, enhancement of IL-6R by IL-6 recovered the pathway of STAT3 mediated Mn-SOD expression, and protected neuronal cells against ischemic reperfusion (XREF_FIG, XREF_FIG, and XREF_FIG).	2	7	enhancement	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	6	7	4	5
IL-6 induces homodimerization of gp130 and activates the Jak and STAT pathway of signal transduction .	IL-6 induces homodimerization of gp130 and activates the Jak and STAT pathway of signal transduction.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	0	1	4	5
Alternatively , IL-6 in a complex with soluble IL-6Ralpha ( sIL-6Ralpha ) can activate gp130 in cells ( trans-signaling ) .	Alternatively, IL-6 in a complex with soluble IL-6Ralpha (sIL-6Ralpha) can activate gp130 in cells (trans-signaling).	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	14	15
In addition , the administration of IL-6 can activate receptor gp80 and gp130 signaling pathways including downstream ERK-1/2 and signal transducer and activator of transcription-3 ( STAT3 ) phosphorylation in EPCs .	In addition, the administration of IL-6 can activate receptor gp80 and gp130 signaling pathways including downstream ERK-1/2 and signal transducer and activator of transcription-3 (STAT3) phosphorylation in EPCs.	4	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	6	7	12	13
Classically , IL-6 activates gp130 by binding a non signaling cognate IL-6 receptor , which then leads to the initiation of JAK and STAT signaling , a pathway that is often constitutively switched on in several inflammatory processes .	Classically, IL-6 activates gp130 by binding a non signaling cognate IL-6 receptor, which then leads to the initiation of JAK and STAT signaling, a pathway that is often constitutively switched on in several inflammatory processes.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	4	5
As expected , IL-6 stimulation of gp130 DeltaSTAT and DeltaSTAT cells , transiently transfected with a c-fos-luciferase reporter construct , yielded higher luciferase activity than IL-6 stimulation of wt cells ( XREF_FIG C ) .	As expected, IL-6 stimulation of gp130 DeltaSTAT and DeltaSTAT cells, transiently transfected with a c-fos-luciferase reporter construct, yielded higher luciferase activity than IL-6 stimulation of wt cells (XREF_FIG C).	3	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	3	4	6	7
All IL-6-type cytokines recruit membrane glycoprotein 130 ( gp130 ) to their receptor complexes , which signal to activate JAKs and to recruit STAT proteins due to IL-6 inducing gp130 homodimerization [ XREF_BIBR , XREF_BIBR ] .	All IL-6-type cytokines recruit membrane glycoprotein 130 (gp130) to their receptor complexes, which signal to activate JAKs and to recruit STAT proteins due to IL-6 inducing gp130 homodimerization [XREF_BIBR, XREF_BIBR].	25	30	inducing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	27	28	29	30
The data suggest that gp130 activation by IL-6 and LIF requires different regions of gp130 , that the Ig like module of gp130 may be required for IL-6-induced gp130 dimerization , and that the stoichiometry of the high affinity IL-6 receptor-complex differs from those of the receptor-complexes for LIF and OSM .	The data suggest that gp130 activation by IL-6 and LIF requires different regions of gp130, that the Ig like module of gp130 may be required for IL-6-induced gp130 dimerization, and that the stoichiometry of the high affinity IL-6 receptor-complex differs from those of the receptor-complexes for LIF and OSM.	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	7	8	4	5
The soluble IL-6 receptor ( sIL-6R ) can increase IL-6-induced signalling by forming a complex with IL-6 and membrane bound gp130 ( the receptor beta chain which transduces signals ) .	The soluble IL-6 receptor (sIL-6R) can increase IL-6-induced signalling by forming a complex with IL-6 and membrane bound gp130 (the receptor beta chain which transduces signals).	2	25	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	20	21
XREF_BIBR IL-6 activates a receptor complex , namely , the IL-6R and the signal transducing receptor subunit gp130 .	XREF_BIBR IL-6 activates a receptor complex, namely, the IL-6R and the signal transducing receptor subunit gp130.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	1	2	17	18
Cells that do not express IL-6R can not respond to IL-6 but can be stimulated by IL-6 bound to a soluble form of the IL-6R ( sIL-6R ) .	Cells that do not express IL-6R can not respond to IL-6 but can be stimulated by IL-6 bound to a soluble form of the IL-6R (sIL-6R).	5	17	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	16	17	5	6
Cells that do not produce the membrane bound IL-6R ( mIL-6R ) can be stimulated by IL-6 via a soluble form of the IL-6R ( sIL-6R ) .	Cells that do not produce the membrane bound IL-6R (mIL-6R) can be stimulated by IL-6 via a soluble form of the IL-6R (sIL-6R).	8	20	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	16	17	8	9
Like CNTF , LIF and IL-6 activate the gp130 receptor , which is involved in stimulating NSC renewal in the adult SVZ .	Like CNTF, LIF and IL-6 activate the gp130 receptor, which is involved in stimulating NSC renewal in the adult SVZ.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	5	6	8	9
Alternatively , IL-6 can activate cells lacking the membrane associated IL-6R when IL-6 binds the naturally occurring sIL-6R in a process called IL-6 trans-signalling , whereby IL-6 and sIL-6R complexes activate the gp130 signalling receptor on the cell surface .	Alternatively, IL-6 can activate cells lacking the membrane associated IL-6R when IL-6 binds the naturally occurring sIL-6R in a process called IL-6 trans-signalling, whereby IL-6 and sIL-6R complexes activate the gp130 signalling receptor on the cell surface.	22	34	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	22	23	32	33
IL-6 mediates its biological activity through the binding to a receptor complex ( IL-6Ralpha ) and triggers the dimerization of the signal transducing protein gp130 , resulting in the activation of the Jak and STAT signal transduction pathway , where STAT3 is the most important in transmitting cytokine signals from the membrane to the nucleus [ XREF_BIBR ] .	IL-6 mediates its biological activity through the binding to a receptor complex (IL-6Ralpha) and triggers the dimerization of the signal transducing protein gp130, resulting in the activation of the Jak and STAT signal transduction pathway, where STAT3 is the most important in transmitting cytokine signals from the membrane to the nucleus [XREF_BIBR].	0	25	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	0	1	24	25
Members of IL-6 family cytokines , such as leukemia inhibitory factor ( LIF ) and ciliary neurotrophic factor ( CNTF ) , activate the common signal transducing receptor gp130 .	Members of IL-6 family cytokines, such as leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF), activate the common signal transducing receptor gp130.	2	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	28	29
The IL-6 and soluble IL-6R complex activates gp130 , which is expressed on most cells , including neurons .	The IL-6 and soluble IL-6R complex activates gp130, which is expressed on most cells, including neurons.	0	17	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	gp130	gp130, which is expressed	gp130	1	2	7	8
Previous findings indicated that GP130 signaling , induced by IL-6 ligands , may switch-off the responsiveness to IL-27 , through the induction of the suppressor of cytokine signaling , SOCS3 , in human hepatocellular carcinoma cells [ XREF_BIBR ] .	Previous findings indicated that GP130 signaling, induced by IL-6 ligands, may switch-off the responsiveness to IL-27, through the induction of the suppressor of cytokine signaling, SOCS3, in human hepatocellular carcinoma cells [XREF_BIBR].	4	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	GP130	GP130	GP130	9	10	4	5
77 RA was shown to inhibit IL-6R and IL-23R upregulation induced by TGF-beta and IL-6 , respectively .	77 RA was shown to inhibit IL-6R and IL-23R upregulation induced by TGF-beta and IL-6, respectively.	6	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	14	15	6	7
Interaction of IL-6 and IL-6 receptor induces homodimerization of gp130 which interacts and activates an intracytoplasmic tyrosine kinase , JAK-1 kinase .	Interaction of IL-6 and IL-6 receptor induces homodimerization of gp130 which interacts and activates an intracytoplasmic tyrosine kinase, JAK-1 kinase.	2	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	9	10
IL-6 and TNF also promote regeneration of the injured intestinal mucosa XREF_BIBR , XREF_BIBR - XREF_BIBR , acting directly on epithelial cells by engaging IL-6 receptor ( IL-6R ) : gp130 heterotetramers and TNF receptor 1 ( TNFR1 ) , respectively .	IL-6 and TNF also promote regeneration of the injured intestinal mucosa XREF_BIBR, XREF_BIBR - XREF_BIBR, acting directly on epithelial cells by engaging IL-6 receptor (IL-6R) : gp130 heterotetramers and TNF receptor 1 (TNFR1), respectively.	0	31	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	0	1	30	31
Kaposi ' s sarcoma associated herpesvirus encodes a functional homolog of human interleukin-6 ( IL-6 ) that activates human gp130 .	Kaposi 's sarcoma associated herpesvirus encodes a functional homolog of human interleukin-6 (IL-6) that activates human gp130.	9	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	14	15	19	20
In this study we show that in addition to Jak family tyrosine kinase , the stimulation of gp130 by IL-6 plus soluble IL-6 receptor alpha induced the activation of Btk and Tec tyrosine kinases , whereas IL-3 and granulocyte colony stimulating factor activated Tec but not Btk in a pro B cell line .	In this study we show that in addition to Jak family tyrosine kinase, the stimulation of gp130 by IL-6 plus soluble IL-6 receptor alpha induced the activation of Btk and Tec tyrosine kinases, whereas IL-3 and granulocyte colony stimulating factor activated Tec but not Btk in a pro B cell line.	15	24	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	19	20	17	18
Up-regulation of IL-6 mRNA in adipose tissue and augmented IL-6 serum levels found in hfd fed WT mice were blunted in KAP Tg littermates , indicating that KAP beneficial effects preventing hepatic steatosis and IR might be related with its capacity to impair IL-6 production and inactivation of the IL6 and gp130 axis in hfd fed mice .	Up-regulation of IL-6 mRNA in adipose tissue and augmented IL-6 serum levels found in hfd fed WT mice were blunted in KAP Tg littermates, indicating that KAP beneficial effects preventing hepatic steatosis and IR might be related with its capacity to impair IL-6 production and inactivation of the IL6 and gp130 axis in hfd fed mice.	43	52	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	43	44	51	52
Biochemical analysis of IL-6 signals in gp130 F759 and F759 mutant T cells confirmed sustained and prolonged tyrosine phosphorylation of JAK-1 and STAT-3 and the absence of IL-6 induced SOCS-3 induction .	Biochemical analysis of IL-6 signals in gp130 F759 and F759 mutant T cells confirmed sustained and prolonged tyrosine phosphorylation of JAK-1 and STAT-3 and the absence of IL-6 induced SOCS-3 induction.	3	7	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	3	4	6	7
IL6 specifically signals through a complex of the IL6R ( also known as IL6R-alpha ) [ XREF_BIBR ] and the IL6 family common receptor gp130 [ XREF_BIBR , XREF_BIBR ] .	IL6 specifically signals through a complex of the IL6R (also known as IL6R-alpha) [XREF_BIBR] and the IL6 family common receptor gp130 [XREF_BIBR, XREF_BIBR].	0	26	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	gp130	gp130	gp130	0	1	24	25
Upon IL-6 binding , the IL-6 receptor ( IL-6R ) , which is essential for regenerative and anti-bacterial effects of IL-6 59 , activates the gp130 homodimer , leading to initiation of JAK and STAT signaling .	Upon IL-6 binding, the IL-6 receptor (IL-6R), which is essential for regenerative and anti-bacterial effects of IL-6 59, activates the gp130 homodimer, leading to initiation of JAK and STAT signaling.	5	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	5	6	25	26
Cytokines of the interleukin 6 ( IL-6 ) family , which activates the signal transducer gp130 , are major survival and growth factors for human multiple myeloma ( MM ) cells .	Cytokines of the interleukin 6 (IL-6) family, which activates the signal transducer gp130, are major survival and growth factors for human multiple myeloma (MM) cells.	3	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	gp130	gp130	gp130	3	5	15	16
Additional genetic approaches demonstrated that the TLR4 and Mal pathway contributed to LPS hypersensitivity and increased IL-6 production in gp130 ( F/F ) mice .	Additional genetic approaches demonstrated that the TLR4 and Mal pathway contributed to LPS hypersensitivity and increased IL-6 production in gp130 (F/F) mice.	16	21	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	16	17	19	20
In turn , tumor cell derived IL-6 induced gp130 and IL-6R-dependent activation of STAT3 , leading to reduced caspase-3 activation and apoptosis .	In turn, tumor cell derived IL-6 induced gp130 and IL-6R-dependent activation of STAT3, leading to reduced caspase-3 activation and apoptosis.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	6	7	8	9
XREF_BIBR , XREF_BIBR The sIL-6R in complex with IL-6 enables IL-6R lacking cells to respond to IL-6 mediated signaling .	XREF_BIBR, XREF_BIBR The sIL-6R in complex with IL-6 enables IL-6R lacking cells to respond to IL-6 mediated signaling.	6	11	enables	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	8	9	10	11
Both gp130 and IL-6R mRNA in liver were up-regulated in vivo by IL-6 .	Both gp130 and IL-6R mRNA in liver were up-regulated in vivo by IL-6.	1	13	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	12	13	1	2
IL6 induced gp130 and STAT3 signaling has been associated with chemokine production and trafficking of neutrophils , but not neutrophil apoptosis during acute inflammation .	IL6 induced gp130 and STAT3 signaling has been associated with chemokine production and trafficking of neutrophils, but not neutrophil apoptosis during acute inflammation.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	gp130	gp130	gp130	0	1	2	3
p28 exerts anti-inflammatory effects by acting as antagonist of gp-130 mediated signaling initiated by IL-6 or IL-27 [ XREF_BIBR ] .	p28 exerts anti-inflammatory effects by acting as antagonist of gp-130 mediated signaling initiated by IL-6 or IL-27 [XREF_BIBR].	9	18	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp-130	gp-130	gp-130	14	15	9	10
Serum levels of IL-6 are also correlated with clinical indices of disease activity in RA [ XREF_BIBR ] , and high levels of IL-6 may trigger a positive-feedback loop of gp130 signaling .	Serum levels of IL-6 are also correlated with clinical indices of disease activity in RA [XREF_BIBR], and high levels of IL-6 may trigger a positive-feedback loop of gp130 signaling.	21	31	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	levels of IL-6	il-6	gp130	gp130	gp130	23	24	30	31
This was confirmed by examining the abundance of transcriptionally active , tyrosine phosphorylated form of Stat3 ( pStat3 ) in lung fibroblasts obtained from gp130 757F , gp130 wt and gp130 DeltaStat mice treated with IL-6 for 0-180 min ( Supporting Information XREF_SUPPLEMENTARY ) .	This was confirmed by examining the abundance of transcriptionally active, tyrosine phosphorylated form of Stat3 (pStat3) in lung fibroblasts obtained from gp130 757F, gp130 wt and gp130 DeltaStat mice treated with IL-6 for 0-180 min (Supporting Information XREF_SUPPLEMENTARY).	24	37	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	35	36	24	25
IL-6 can bind to the soluble form of the IL-6 receptor , and can trigger gp130 signaling on target cells lacking the IL-6 receptor but expressing gp130 .	IL-6 can bind to the soluble form of the IL-6 receptor, and can trigger gp130 signaling on target cells lacking the IL-6 receptor but expressing gp130.	0	16	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	0	1	15	16
We then found that IL-6 receptor ( gp-80 ) was expressed in the EPCs , and that administration of IL-6 could activate receptor gp80 and gp130 signaling pathways including downstream extracellular signal regulated kinase 1/2 and STAT3 phosphorylation in EPCs .	We then found that IL-6 receptor (gp-80) was expressed in the EPCs, and that administration of IL-6 could activate receptor gp80 and gp130 signaling pathways including downstream extracellular signal regulated kinase 1/2 and STAT3 phosphorylation in EPCs.	17	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	19	20	25	26
Typically , gp130 activation by IL-6 promotes proinflammatory responses ; however , in macrophage specific SOCS3 knockout mice , IL-6 conversely attenuates the inflammatory responses .	Typically, gp130 activation by IL-6 promotes proinflammatory responses; however, in macrophage specific SOCS3 knockout mice, IL-6 conversely attenuates the inflammatory responses.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	5	6	2	3
Interaction of IL-6 with IL-6R triggers the association of gp130 and IL-6R , and the signal can be transduced through gp130 .	Interaction of IL-6 with IL-6R triggers the association of gp130 and IL-6R, and the signal can be transduced through gp130.	0	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	2	3	11	12
sIL-6R binds to IL-6 with comparable affinity as the mbIL-6R ; consequently , the complex of IL-6 and sIL-6R can activate gp130 , a membrane protein is ubiquitously expressed .	sIL-6R binds to IL-6 with comparable affinity as the mbIL-6R; consequently, the complex of IL-6 and sIL-6R can activate gp130, a membrane protein is ubiquitously expressed.	14	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	16	17	21	22
The identified drugs represent a new class of lead compounds with piperidine , benzothiophene , and indole scaffolds to inhibit IL-6 induced homodimerization of GP130 .	The identified drugs represent a new class of lead compounds with piperidine, benzothiophene, and indole scaffolds to inhibit IL-6 induced homodimerization of GP130.	19	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	GP130	GP130	GP130	20	21	24	25
sIL-6R and IL-6 is similar to hyper-IL-6 , an IL-6 and IL-6Ralpha extracellular domain chimera , which mimics natural , soluble IL-6 and IL-6Ralpha complexes and can directly activate the GP130 receptor in cells lacking IL-6Ralpha [ XREF_BIBR ] .	sIL-6R and IL-6 is similar to hyper-IL-6, an IL-6 and IL-6Ralpha extracellular domain chimera, which mimics natural, soluble IL-6 and IL-6Ralpha complexes and can directly activate the GP130 receptor in cells lacking IL-6Ralpha [XREF_BIBR].	6	31	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	GP130	GP130	GP130	9	10	30	31
In addition , KSHV encodes several virokines , including a viral IL-6 ( vIL-6 ) that can potently activate gp130 signaling XREF_BIBR and other viral homologs to angiogenic chemokines ( vMIP-I and III or vCCL-I-III ) .	In addition, KSHV encodes several virokines, including a viral IL-6 (vIL-6) that can potently activate gp130 signaling XREF_BIBR and other viral homologs to angiogenic chemokines (vMIP-I and III or vCCL-I-III).	6	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	11	12	19	20
Binding of IL-6 with its receptor initiates homodimerization of gp130 and then triggers signaling cascades through JAK-STAT , Ras-MAPK and PI3K-Akt pathways .	Binding of IL-6 with its receptor initiates homodimerization of gp130 and then triggers signaling cascades through JAK-STAT, Ras-MAPK and PI3K-Akt pathways.	0	10	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	9	10
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Upon biding to either mIL-6R or sIL-6R , IL-6 induces the homodimerization of the IL-6R and gp130 chains , resulting in the formation of a hexamer ( comprising two IL-6 , two IL-6R , and two gp130 proteins ) , XREF_BIBR which in turn triggers the downstream signaling cascade .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Upon biding to either mIL-6R or sIL-6R, IL-6 induces the homodimerization of the IL-6R and gp130 chains, resulting in the formation of a hexamer (comprising two IL-6, two IL-6R, and two gp130 proteins), XREF_BIBR which in turn triggers the downstream signaling cascade.	15	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	15	16	23	24
During inflammation increased IL-6 and sIL-6 levels cause activation of vascular endothelial gp130 leading to redistribution of VE-cadherin with disruption of adherence junctions between endothelial cells and subsequent capillary leakage [ XREF_BIBR ] .	During inflammation increased IL-6 and sIL-6 levels cause activation of vascular endothelial gp130 leading to redistribution of VE-cadherin with disruption of adherence junctions between endothelial cells and subsequent capillary leakage [XREF_BIBR].	3	13	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6 and sIL-6 levels	il-6	gp130	gp130	gp130	3	4	12	13
Collectively , these observations are consistent with the notion that elevated levels of recombinant SOCS-1 Flag protein were required to terminate IL-6 signaling in gp130 DeltaSTAT and DeltaSTAT mutant cells to compensate for impaired induction of endogenous SOCS-1 and SOCS-3 expression .	Collectively, these observations are consistent with the notion that elevated levels of recombinant SOCS-1 Flag protein were required to terminate IL-6 signaling in gp130 DeltaSTAT and DeltaSTAT mutant cells to compensate for impaired induction of endogenous SOCS-1 and SOCS-3 expression.	21	25	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	21	22	24	25
Here we investigated whether IL-6 modulates gp130 and related neuroinflammatory , cell survival and regulatory signaling in both healthy and glaucomatous retina .	Here we investigated whether IL-6 modulates gp130 and related neuroinflammatory, cell survival and regulatory signaling in both healthy and glaucomatous retina.	4	15	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	4	5	6	7
IL6R , STAT3 , and SOCS3 are essential for LPS induced IL-6 production in stromal cells but only IL6R is required in epithelial cells .	IL6R, STAT3, and SOCS3 are essential for LPS induced IL-6 production in stromal cells but only IL6R is required in epithelial cells.	11	19	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL6R	IL6R	IL6R	11	12	18	19
Another point is that the effects of IL-6 on target cells are mediated by plasma membrane receptor complexes containing the IL-6 receptor ( which is devoid of transducing activity ) and the common signal transducing receptor chain glycoprotein ( gp-130 ) .	Another point is that the effects of IL-6 on target cells are mediated by plasma membrane receptor complexes containing the IL-6 receptor (which is devoid of transducing activity) and the common signal transducing receptor chain glycoprotein (gp-130).	5	40	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp-130	gp-130	gp-130	7	8	39	40
In contrast , IL-6 primarily targets IL-6R + leukocytes and TCs and only indirectly affects IL-6R - ECs .	In contrast, IL-6 primarily targets IL-6R + leukocytes and TCs and only indirectly affects IL-6R - ECs.	3	14	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	3	4	6	7
Nevertheless , the effect of Ras and Raf activation on STAT3 was consistent in these two tumor types in that , in both MTC and PTC , Ras and Raf activates STAT3 via the IL-6 family cytokine mediated gp130 and JAK pathway and STAT3 operates in the context of tumor suppression .	Nevertheless, the effect of Ras and Raf activation on STAT3 was consistent in these two tumor types in that, in both MTC and PTC, Ras and Raf activates STAT3 via the IL-6 family cytokine mediated gp130 and JAK pathway and STAT3 operates in the context of tumor suppression.	34	41	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	34	35	38	39
SOCS3 regulates cytokine pathway activity stimulated by the IL-6 family , which signals through the IL-6R - gp130 to activate the STAT3 transcription factor .	SOCS3 regulates cytokine pathway activity stimulated by the IL-6 family, which signals through the IL-6R - gp130 to activate the STAT3 transcription factor.	8	18	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	8	9	17	18
We found that gp130 F/F Il-6 -/- as well as gp130 F/F Stat3 +/- mutant mice displayed lower levels of M. tuberculosis bacteria in lungs and diminished severity of pulmonary pathology when compared to gp130 F/F mice , indicating that the increased susceptibility of gp130 F/F mice is in part mediated by IL-6 and STAT3 activation ( XREF_FIG ) .	We found that gp130 F/F Il-6 -/- as well as gp130 F/F Stat3 +/- mutant mice displayed lower levels of M. tuberculosis bacteria in lungs and diminished severity of pulmonary pathology when compared to gp130 F/F mice, indicating that the increased susceptibility of gp130 F/F mice is in part mediated by IL-6 and STAT3 activation (XREF_FIG).	3	55	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	52	53	3	4
Although IL-6 by itself increased IL-6R activation 2.3-fold in Dami cells , co-incubation with 1.0 ng/ml and 10.0 ng/ml LPS increased TLR4 and IL-6R activation 4.5 and 4.9-fold , respectively ( XREF_FIG ) .	Although IL-6 by itself increased IL-6R activation 2.3-fold in Dami cells, co-incubation with 1.0 ng/ml and 10.0 ng/ml LPS increased TLR4 and IL-6R activation 4.5 and 4.9-fold, respectively (XREF_FIG).	1	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	1	2	5	6
Additional in vitro experiments found that IL-6 stimulation of neurons induced gp130 dependent TGF-beta1 , TGF-beta2 , and IL-27 production .	Additional in vitro experiments found that IL-6 stimulation of neurons induced gp130 dependent TGF-beta1, TGF-beta2, and IL-27 production.	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	6	7	11	12
IL-6 stimulates gp130 on stromal or osteoblastic cells , subsequently resulting in downstream signal transducer and activator transcription 3 mediated expression of RANKL and stimulation of osteoclast formation .	IL-6 stimulates gp130 on stromal or osteoblastic cells, subsequently resulting in downstream signal transducer and activator transcription 3 mediated expression of RANKL and stimulation of osteoclast formation.	0	3	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	0	1	2	3
IL-6 can induce gp130 dependent signalling via two modes , either classically by binding to the cognate gp80 IL-6R or via trans-signalling which utilises the sIL-6R XREF_BIBR .	IL-6 can induce gp130 dependent signalling via two modes, either classically by binding to the cognate gp80 IL-6R or via trans-signalling which utilises the sIL-6R XREF_BIBR.	0	5	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	0	1	3	4
Binding of IL-6 on IL-6R triggers dimerisation of gp130 , which results in activation of JAK1 and tyrosine phosphorylation of gp130 .	Binding of IL-6 on IL-6R triggers dimerisation of gp130, which results in activation of JAK1 and tyrosine phosphorylation of gp130.	0	21	triggers	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	gp130	gp130, which results in activation of JAK1 and tyrosine phosphorylation of gp130	gp130	2	3	8	9
Since LCN 2 , CXLC2 , TIMP-1 , HAMP and IL-24 protein expression is also induced to be released in the supernatant of hepatocytes upon IL-6 stimulation in a gp130 dependent manner , as confirmed by ELISA technique ( XREF_FIG ) .	Since LCN 2, CXLC2, TIMP-1, HAMP and IL-24 protein expression is also induced to be released in the supernatant of hepatocytes upon IL-6 stimulation in a gp130 dependent manner, as confirmed by ELISA technique (XREF_FIG).	25	31	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	25	26	29	30
Together , these data suggest that IL-6 signaling impacts specific components of stress induced neuroinflammatory , cell health and gp130 regulatory signaling that alters not only the nature , but also the magnitude , of these stress responses .	Together, these data suggest that IL-6 signaling impacts specific components of stress induced neuroinflammatory, cell health and gp130 regulatory signaling that alters not only the nature, but also the magnitude, of these stress responses.	6	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	6	7	19	20
We observed that IL-6 and IL-10 stimulation , and their combination , increased gp130 production at different time points .	We observed that IL-6 and IL-10 stimulation, and their combination, increased gp130 production at different time points.	3	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	3	4	13	14
The biological activity of IL-6 is mediated via a hexameric signaling complex , consisting of two molecules each of IL-6 , IL-6R and glycoprotein 130 .	The biological activity of IL-6 is mediated via a hexameric signaling complex, consisting of two molecules each of IL-6, IL-6R and glycoprotein 130.	2	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	4	5	21	22
Thus , the aptamer AIR-3 seemed not to interfere with the IL-6 mediated formation of the active signaling IL-6R complex .	Thus, the aptamer AIR-3 seemed not to interfere with the IL-6 mediated formation of the active signaling IL-6R complex.	10	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	11	12	18	19
The IL6 mediated activation of IL6R , a receptor located on the leukocytes and hepatocytes membrane , stimulates the proinflammatory cascade including hepatic production of acute phase reactants C-reactive protein and fibrinogen .	The IL6 mediated activation of IL6R, a receptor located on the leukocytes and hepatocytes membrane, stimulates the proinflammatory cascade including hepatic production of acute phase reactants C-reactive protein and fibrinogen.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	IL6R	IL6R	IL6R	1	2	5	6
Mechanistically , IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-alpha and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors .	Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-alpha and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors.	2	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	2	3	17	18
Our previous study showed that sSMCs release IL-1beta and IL-6 to activate IRAK and IL-6R and hence NF-kappaB in adjacent ECs 2 .	Our previous study showed that sSMCs release IL-1beta and IL-6 to activate IRAK and IL-6R and hence NF-kappaB in adjacent ECs 2.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	9	10	14	15
Since IL-6 , produced by myeloid and potentially other cells , is proposed as a key protumoral mediator activating Stat3 in its target cells , we tested whether IL-6 production in the TME as well as epithelial IL-6R contributes to epithelial Stat3 activation and tumor development upon ETBF colonization of Apc Min mice .	Since IL-6, produced by myeloid and potentially other cells, is proposed as a key protumoral mediator activating Stat3 in its target cells, we tested whether IL-6 production in the TME as well as epithelial IL-6R contributes to epithelial Stat3 activation and tumor development upon ETBF colonization of Apc Min mice.	28	38	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	28	29	37	38
However , IL-6 injections prevented disruption of IL-6R against reperfusion after tFCI , consequently restoring activity of STAT3 through recovery of the binding of STAT3 to gp130 .	However, IL-6 injections prevented disruption of IL-6R against reperfusion after tFCI, consequently restoring activity of STAT3 through recovery of the binding of STAT3 to gp130.	2	8	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	2	3	7	8
Imbalanced IL-6 family cytokine signalling in the gp130 ( 757FF ) mouse model of gastric cancer arising from hyperactivation of oncogenic STAT3 after altered SHP-2 : ERK1/2 signalling produces dysplastic antral tumours preceded by gastritis and metaplasia .	Imbalanced IL-6 family cytokine signalling in the gp130 (757FF) mouse model of gastric cancer arising from hyperactivation of oncogenic STAT3 after altered SHP-2 : ERK1/2 signalling produces dysplastic antral tumours preceded by gastritis and metaplasia.	1	12	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	1	2	7	8
Binding of IL-6 triggers an association of the IL-6R with the transducer protein , gp130 [ XREF_BIBR ] , initiating an intracellular cascade of phosphorylation of several signal proteins including Janus kinases , STAT factors [ XREF_BIBR ] as well as the MAPKs [ XREF_BIBR ; XREF_BIBR ] .	Binding of IL-6 triggers an association of the IL-6R with the transducer protein, gp130 [XREF_BIBR], initiating an intracellular cascade of phosphorylation of several signal proteins including Janus kinases, STAT factors [XREF_BIBR] as well as the MAPKs [XREF_BIBR; XREF_BIBR].	0	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	2	3	8	9
IL-6 produced by BMSC stimulates the proliferation of IL-6R positive but not IL-6R negative neuroblastoma cells .	IL-6 produced by BMSC stimulates the proliferation of IL-6R positive but not IL-6R negative neuroblastoma cells.	0	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	0	1	8	9
During trans-signalling , IL-6 binds to soluble forms of IL-6Ralpha ( sIL-6Ralpha ) , allowing activation of gp130 in cells that do not normally express IL-6Ralpha such as VECs XREF_BIBR ( XREF_FIG ) .	During trans-signalling, IL-6 binds to soluble forms of IL-6Ralpha (sIL-6Ralpha), allowing activation of gp130 in cells that do not normally express IL-6Ralpha such as VECs XREF_BIBR (XREF_FIG).	3	18	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	3	4	17	18
Binding of IL-6 to its receptor , IL-6R , promotes homodimerization of gp-130 , thereby activating Janus kinase ( JAK )/signal transducer and activator of transcription ( STAT ) and the MAPK pathway .	Binding of IL-6 to its receptor, IL-6R, promotes homodimerization of gp-130, thereby activating Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and the MAPK pathway.	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp-130	gp-130	gp-130	2	3	12	13
The IL-6 complex activation of gp130 also leads to activation of the MAPK signaling cascade .	The IL-6 complex activation of gp130 also leads to activation of the MAPK signaling cascade.	1	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	1	2	5	6
XREF_BIBR IL-6 form complexes with its soluble receptor , sIL-6R , which trigger gp130 dimerisation and signaling .	XREF_BIBR IL-6 form complexes with its soluble receptor, sIL-6R, which trigger gp130 dimerisation and signaling.	1	14	trigger	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	1	2	13	14
The findings suggest that IL-6R activation by IL-6 stimulates osteoclastic bone resorption either by reversing the inhibitory effect of high extracellular Ca ( 2+ ) in stromal containing systems or itself stimulating bone resorption along with Ca ( 2+ ) by micro-isolated osteoclasts .	The findings suggest that IL-6R activation by IL-6 stimulates osteoclastic bone resorption either by reversing the inhibitory effect of high extracellular Ca (2+) in stromal containing systems or itself stimulating bone resorption along with Ca (2+) by micro-isolated osteoclasts.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	7	8	4	5
Interleukin-6 ( IL-6 ) and soluble IL-6 receptor ( sIL-6R ) activation of gp130 represents an alternative pathway for osteoclast development in inflammatory conditions .	Interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) activation of gp130 represents an alternative pathway for osteoclast development in inflammatory conditions.	6	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	6	7	13	14
The interaction of Tbeta4 with ILK activates Akt , which promotes cell migration and survival .	The interaction of Tbeta4 with ILK activates Akt, which promotes cell migration and survival.	3	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	5	6	7	8
Activated ILK activates AKT [ XREF_BIBR ] .	Activated ILK activates AKT [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	AKT	AKT	AKT	1	2	3	4
Three primary integrin signaling molecules , FAK ( focal adhesion kinase ) , Shc and ILK ( integrin linked kinase ) , have been linked to cell survival and may activate the PI3K and Akt pathway XREF_BIBR - XREF_BIBR .	Three primary integrin signaling molecules, FAK (focal adhesion kinase), Shc and ILK (integrin linked kinase), have been linked to cell survival and may activate the PI3K and Akt pathway XREF_BIBR - XREF_BIBR.	2	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	15	16	34	35
ILK is also recruited to beta integrin cytoplasmic domain and promotes Akt activity .	ILK is also recruited to beta integrin cytoplasmic domain and promotes Akt activity.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	0	1	11	12
Our results corroborate the recent animal model observations that have shown that ILK mediated Akt and PKB activation is a key pathway for mediating cardiac dysfunction especially during heart failure and repair XREF_BIBR , XREF_BIBR , XREF_BIBR .	Our results corroborate the recent animal model observations that have shown that ILK mediated Akt and PKB activation is a key pathway for mediating cardiac dysfunction especially during heart failure and repair XREF_BIBR, XREF_BIBR, XREF_BIBR.	12	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	12	13	14	15
As indicated above , inhibition of ILK by 267 was expected to cause a decrease in P-AKT at serine 473 .	As indicated above, inhibition of ILK by 267 was expected to cause a decrease in P-AKT at serine 473.	4	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	P-AKT	P-AKT	P-AKT	6	7	16	17
Thus , the HIF-1alpha-ILK regulatory loop , along with this mTOR-HIF-1alpha positive feedback loop , can combine to drive mTOR mediated HIF-1alpha expression in cells , such as PC-3 and MCF-7 , in which ILK mediates Akt activation .	Thus, the HIF-1alpha-ILK regulatory loop, along with this mTOR-HIF-1alpha positive feedback loop, can combine to drive mTOR mediated HIF-1alpha expression in cells, such as PC-3 and MCF-7, in which ILK mediates Akt activation.	34	37	mediates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	34	35	36	37
We report that integrin signaling prevents apoptosis of embryonic hippocampal neurons by a mechanism involving integrin linked kinase ( ILK ) that activates Akt kinase .	We report that integrin signaling prevents apoptosis of embryonic hippocampal neurons by a mechanism involving integrin linked kinase (ILK) that activates Akt kinase.	17	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	19	20	23	24
The interaction between ILK and PARVA , and the ILK mediated Akt phosphorylation of Ser473 , were abolished by mutating ILK [ XREF_BIBR , XREF_BIBR ] .	The interaction between ILK and PARVA, and the ILK mediated Akt phosphorylation of Ser473, were abolished by mutating ILK [XREF_BIBR, XREF_BIBR].	8	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	9	10	11	12
As a result the KP-392 and KP-SD-1 and KP-SD-2 compounds were identified and shown to inhibit ILK mediated AKT activation and the EMT phenotype when tested using in vitro model cells .	As a result the KP-392 and KP-SD-1 and KP-SD-2 compounds were identified and shown to inhibit ILK mediated AKT activation and the EMT phenotype when tested using in vitro model cells.	15	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	ILK	ILK	ILK	AKT	AKT	AKT	16	17	18	19
The latter observations suggests that some cell lines have redundant pathways involved in the regulation of the PI3K and AKT pathway whereas other cell lines may exhibit a preference for ILK mediated activation of AKT .	The latter observations suggests that some cell lines have redundant pathways involved in the regulation of the PI3K and AKT pathway whereas other cell lines may exhibit a preference for ILK mediated activation of AKT.	30	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	ILK	ILK	ILK	AKT	AKT	AKT	30	31	34	35
The activation of Akt by ILK has been shown to be necessary for cardiomyocyte contractility , and phosphorylation at S473 of Akt was abolished in ilk -/- hearts .	The activation of Akt by ILK has been shown to be necessary for cardiomyocyte contractility, and phosphorylation at S473 of Akt was abolished in ilk -/- hearts.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	5	6	3	4
Once activated , FAK dissociates to ILK , which activates AKT and induces p21 degradation .	Once activated, FAK dissociates to ILK, which activates AKT and induces p21 degradation.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	AKT	AKT	AKT	6	7	10	11
In addition to PKD , another PI3K regulated kinase , Integrin Linked Kinase ( ILK ) has been shown to increase AKT activity via S473 phosphorylation .	In addition to PKD, another PI3K regulated kinase, Integrin Linked Kinase (ILK) has been shown to increase AKT activity via S473 phosphorylation.	12	22	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	AKT	AKT	AKT	14	15	21	22
It has been shown that ILK can mediate activation of AKT and thereby play key role in tumor progression and metastasis interacting with cytoplasmic domain of integrin beta1 [ XREF_BIBR - XREF_BIBR ] .	It has been shown that ILK can mediate activation of AKT and thereby play key role in tumor progression and metastasis interacting with cytoplasmic domain of integrin beta1 [XREF_BIBR - XREF_BIBR].	5	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	AKT	AKT	AKT	5	6	10	11
This result suggests that the FAK and Akt signaling pathway was markedly inactivated by ILK silencing in OC cells .	This result suggests that the FAK and Akt signaling pathway was markedly inactivated by ILK silencing in OC cells.	7	15	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	14	15	7	8
Since both PDK1 and ILK [ both of which activate AKT by phosphorylation of AKT at serine 473 ] have been established as the target genes for PPARdelta in mouse keratinocytes , we also examined expressions of these proteins .	Since both PDK1 and ILK [both of which activate AKT by phosphorylation of AKT at serine 473] have been established as the target genes for PPARdelta in mouse keratinocytes, we also examined expressions of these proteins.	2	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	AKT	AKT	AKT	4	5	10	11
These data from functional molecular imaging demonstrated that beta-parvin plays a regulatory role in the ILK mediated Akt ( also called protein kinase B ) signaling cascades , suggesting that beta-parvin might be a crucial modulator of cell survival .	These data from functional molecular imaging demonstrated that beta-parvin plays a regulatory role in the ILK mediated Akt (also called protein kinase B) signaling cascades, suggesting that beta-parvin might be a crucial modulator of cell survival.	12	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	15	16	17	18
In the present study , it was observed that ILK silencing down-regulated the activity of the FAK and Akt signaling pathway .	In the present study, it was observed that ILK silencing down-regulated the activity of the FAK and Akt signaling pathway.	9	20	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	9	10	18	19
Similarly , overexpression of the zinc finger transcription factor Klf5 in epithelial cells result in enhanced cellular migration through a direct interaction with integrin liked kinases ( ILK ) , which activates Akt .	Similarly, overexpression of the zinc finger transcription factor Klf5 in epithelial cells result in enhanced cellular migration through a direct interaction with integrin liked kinases (ILK), which activates Akt.	25	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	27	28	32	33
Aberrant ILK is involved in tumorigenesis , and it is speculated that ILK canonically stimulates AKT to promote NF-kappaB-mediated oncogenic processes , such as anti-apoptosis [ XREF_BIBR ] and survival [ XREF_BIBR ] .	Aberrant ILK is involved in tumorigenesis, and it is speculated that ILK canonically stimulates AKT to promote NF-kappaB-mediated oncogenic processes, such as anti-apoptosis [XREF_BIBR] and survival [XREF_BIBR].	12	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	AKT	AKT	AKT	12	13	15	16
Silencing the expression of ILK decreased the phosphorylation rate of Akt in the EECs , leading to upregulation of epithelial markers of EECs .	Silencing the expression of ILK decreased the phosphorylation rate of Akt in the EECs, leading to upregulation of epithelial markers of EECs.	2	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	expression of ILK	ilk	Akt	Akt	akt	4	5	10	11
These results revealed a critical role of PINCH in cell attachment , survival and hypertrophic growth of cardiomyocytes , in part at least via ILK activation of the Akt signaling pathway .	These results revealed a critical role of PINCH in cell attachment, survival and hypertrophic growth of cardiomyocytes, in part at least via ILK activation of the Akt signaling pathway.	24	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	24	25	28	29
Activated by binding of the phosphoinositide phospholipid product of PI3K , PIP 3 , to the PH like domain of ILK , ILK activates AKT and enhances cardiomyocyte survival ( XREF_FIG ) .	Activated by binding of the phosphoinositide phospholipid product of PI3K, PIP 3, to the PH like domain of ILK, ILK activates AKT and enhances cardiomyocyte survival (XREF_FIG).	22	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	AKT	AKT	AKT	22	23	24	25
Since ILK overexpression can promote activation of Akt XREF_BIBR , which in turn can inhibit cardiomyocyte apoptosis and improve cardiac contractility XREF_BIBR , we postulate that ILK exerts these beneficial effects through increasing the phosphorylation and hence activation of Akt .	Since ILK overexpression can promote activation of Akt XREF_BIBR, which in turn can inhibit cardiomyocyte apoptosis and improve cardiac contractility XREF_BIBR, we postulate that ILK exerts these beneficial effects through increasing the phosphorylation and hence activation of Akt.	1	8	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK overexpression	ilk	Akt	Akt	akt	1	2	7	8
XREF_BIBR Adhesion triggers integrin clustering and recruitment of adaptor molecules to focal adhesion complexes that are composed of a variety of protein kinases and adaptor molecules , including integrin linked kinase ( ILK ) , phosphatidylinositolphosphate-3 , 4 , 5 triphosphate , parvins , and paxillin ; ILK activates Akt .	XREF_BIBR Adhesion triggers integrin clustering and recruitment of adaptor molecules to focal adhesion complexes that are composed of a variety of protein kinases and adaptor molecules, including integrin linked kinase (ILK), phosphatidylinositolphosphate-3, 4, 5 triphosphate, parvins, and paxillin; ILK activates Akt.	47	50	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	47	48	49	50
Additionally , integrin linked kinase ( ILK ) has been described to activate Akt [ XREF_BIBR ] .	Additionally, integrin linked kinase (ILK) has been described to activate Akt [XREF_BIBR].	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	6	7	13	14
ILK and PDK1 can activate Akt by phasphation at different amino acid site , ser 473 and ser 308 , respectively , which all take part in Akt activation which consequently then inhibits GSK3beta at ser 9 .	ILK and PDK1 can activate Akt by phasphation at different amino acid site, ser 473 and ser 308, respectively, which all take part in Akt activation which consequently then inhibits GSK3beta at ser 9.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	0	1	5	6
This led to the notion that ILK directly activates Akt in vitro and in vivo .	This led to the notion that ILK directly activates Akt in vitro and in vivo.	6	12	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	6	7	9	10
The results indicated that ILK in both bladder cell lines could activate Akt throughout the increase of its phosphorylation as knockdown of ILK expression using ILK siRNA , resulted in unanimous reduction of Akt activation with slight difference in its total expression .	The results indicated that ILK in both bladder cell lines could activate Akt throughout the increase of its phosphorylation as knockdown of ILK expression using ILK siRNA, resulted in unanimous reduction of Akt activation with slight difference in its total expression.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	4	5	12	13
We investigated the role of endogenous cellular ILKAP in antagonizing ILK signaling of two key targets , PKB and GSK3beta .	We investigated the role of endogenous cellular ILKAP in antagonizing ILK signaling of two key targets, PKB and GSK3beta.	10	18	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ILK	ILK	ILK	PKB	PKB	PKB	10	11	17	18
The data shows that knockdown of ILK attenuates the response of these cells to LPS induced ser473 Akt activation .	The data shows that knockdown of ILK attenuates the response of these cells to LPS induced ser473 Akt activation.	4	18	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	6	7	17	18
In hepatocellular carcinoma , ILK activated Akt through phosphorylating Akt at Ser473 , resulting in EMT of liver epithelial cells and radioresistance and chemoresistance of hepatocellular carcinoma cells [ XREF_BIBR ] .	In hepatocellular carcinoma, ILK activated Akt through phosphorylating Akt at Ser473, resulting in EMT of liver epithelial cells and radioresistance and chemoresistance of hepatocellular carcinoma cells [XREF_BIBR].	4	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	4	5	6	7
We obtained two lines of evidence that Akt is targeted by ILK for phosphorylation in PC-3 cells .	We obtained two lines of evidence that Akt is targeted by ILK for phosphorylation in PC-3 cells.	7	12	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	11	12	7	8
In addition , integrin linked kinase ( ILK ) is required to activate feedback activation of PI3K-AKT pathway following MEK suppression in glioblastoma cells [ XREF_BIBR ] .	In addition, integrin linked kinase (ILK) is required to activate feedback activation of PI3K-AKT pathway following MEK suppression in glioblastoma cells [XREF_BIBR].	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	PI3K-AKT	PI3K-AKT	PI3K-AKT	7	8	16	17
We then examined the ability of the ED 50 dose of 2DG to block IL4 induced growth in 4T1 and MDA-MB-231 sh-control and IL4Ralpha knockdown cells by again quantifying changes in cell number .	We then examined the ability of the ED 50 dose of 2DG to block IL4 induced growth in 4T1 and MDA-MB-231 sh-control and IL4Ralpha knockdown cells by again quantifying changes in cell number.	13	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL4	IL4	IL4	IL4Ralpha	IL4Ralpha	IL4Ralpha	14	15	23	24
In contrast , the differences between signaling by IL-4 and IL-13 stem from the fact that while IL-4 is able to activate both the IL-4Ralpha and common gamma chain and IL-4Ralpha and IL-13Ralpha dimers , IL-13 can only activate the latter complex .	In contrast, the differences between signaling by IL-4 and IL-13 stem from the fact that while IL-4 is able to activate both the IL-4Ralpha and common gamma chain and IL-4Ralpha and IL-13Ralpha dimers, IL-13 can only activate the latter complex.	17	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	17	18	24	25
In addition , another IL-4 receptor signal transducer , Akt , was also activated in ARMS cells by IL-4 treatment ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	In addition, another IL-4 receptor signal transducer, Akt, was also activated in ARMS cells by IL-4 treatment (XREF_FIG; XREF_SUPPLEMENTARY).	4	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4 receptor	IL-4 receptor	IL-4 receptor	18	19	4	6
Both IL-4 and IL-2 induced upregulation of IL-4R on activated normal T cells but not on ATL cells .	Both IL-4 and IL-2 induced upregulation of IL-4R on activated normal T cells but not on ATL cells.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4R	IL-4R	IL-4R	1	2	7	8
Th2-type immune responses depend on the activation of the IL-4Ralpha and STAT6 pathway , which is elicited by IL-4 through its receptor IL-4R and involves phosphorylation of STAT6 and up-regulation of GATA-3 that transcribes Th2-type cytokines .	Th2-type immune responses depend on the activation of the IL-4Ralpha and STAT6 pathway, which is elicited by IL-4 through its receptor IL-4R and involves phosphorylation of STAT6 and up-regulation of GATA-3 that transcribes Th2-type cytokines.	9	19	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	18	19	9	10
Here , we found that IL-4 treatment increased IL-4Ralpha , STAT6 and PPARgamma , i.e. molecules that are expected to prolong alternative activation .	Here, we found that IL-4 treatment increased IL-4Ralpha, STAT6 and PPARgamma, i.e. molecules that are expected to prolong alternative activation.	5	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	5	6	8	9
Consistent with GRB2 recruitment and activation , IL-4 stimulation of Il4ra R576 but not WT splenocytes increased the phosphorylation of MAPKs , including the c-Raf , MKK3/6 , ERK1/2 and p38 MAPK ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Consistent with GRB2 recruitment and activation, IL-4 stimulation of Il4ra R576 but not WT splenocytes increased the phosphorylation of MAPKs, including the c-Raf, MKK3/6, ERK1/2 and p38 MAPK (XREF_FIG and XREF_SUPPLEMENTARY).	7	11	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	Il4ra	Il4ra	Il4ra	7	8	10	11
PBNCs formed by ligation of the IL-4 receptor targeting peptide , AP1 , to both sites ( 48AP1-PBNCs ) tethered IL-4R , expressing tumor cells with greater affinity than did PBNCs with AP1 ligated to a single site ( 24AP1-PBNCs ) .	PBNCs formed by ligation of the IL-4 receptor targeting peptide, AP1, to both sites (48AP1-PBNCs) tethered IL-4R, expressing tumor cells with greater affinity than did PBNCs with AP1 ligated to a single site (24AP1-PBNCs).	6	21	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4R	IL-4R	IL-4R	6	7	20	21
Another study conducted with young male mice suggests that IL-4 is preferentially produced and secreted by neurons after ischemic stroke and leads to an increase of IL-4R on microglia , providing more evidence for IL-4 as an endogenous defense mechanism to stroke .	Another study conducted with young male mice suggests that IL-4 is preferentially produced and secreted by neurons after ischemic stroke and leads to an increase of IL-4R on microglia, providing more evidence for IL-4 as an endogenous defense mechanism to stroke.	9	27	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4R	IL-4R	IL-4R	9	10	26	27
In wild-type cells IL-4Ralpha upregulation was elicited by as little as 15 pg/ml of IL-4 , while Stat6 -/- cells lost surface IL-4Ralpha at concentrations exceeding 500 pg/ml ( XREF_FIG ) .	In wild-type cells IL-4Ralpha upregulation was elicited by as little as 15 pg/ml of IL-4, while Stat6 -/- cells lost surface IL-4Ralpha at concentrations exceeding 500 pg/ml (XREF_FIG).	3	15	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	14	15	3	4
This result is consistent with our previous report , where IL-4Ralpha upregulation is induced by IL-4 in naive T cells 14 .	This result is consistent with our previous report, where IL-4Ralpha upregulation is induced by IL-4 in naive T cells 14.	10	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	15	16	10	11
Similarly , activation of T cells led to low-level expression of IL-4R , with IL-4 itself up-regulating IL-4R , especially in CD4 cells .	Similarly, activation of T cells led to low-level expression of IL-4R, with IL-4 itself up-regulating IL-4R, especially in CD4 cells.	6	18	up-regulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4R	IL-4R	IL-4R	14	15	17	18
To confirm that IL-4 was activating the IL-4Ralpha during the stimulation of huASMC , we examined the phosphorylation of downstream STAT-6 by western blot .	To confirm that IL-4 was activating the IL-4Ralpha during the stimulation of huASMC, we examined the phosphorylation of downstream STAT-6 by western blot.	3	8	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	3	4	7	8
While IL-4 production independently of IL-4Ralpha signaling has been observed in a number of immunological models previously XREF_BIBR , XREF_BIBR - XREF_BIBR this is the first time a sex associated influence on this ability has been identified .	While IL-4 production independently of IL-4Ralpha signaling has been observed in a number of immunological models previously XREF_BIBR, XREF_BIBR - XREF_BIBR this is the first time a sex associated influence on this ability has been identified.	1	6	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	1	2	5	6
Triggering of IL-4R by IL-4 induces activation of JAKs and Stat6 signaling and is essential for initiation of both Th2 and Th9 cell differentiation .	Triggering of IL-4R by IL-4 induces activation of JAKs and Stat6 signaling and is essential for initiation of both Th2 and Th9 cell differentiation.	0	5	Triggering	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4R	IL-4R	IL-4R	4	5	2	3
Because IL-4 is a potent upregulator of IL-4R , we considered the possibility that incremented levels of circulating IL-4 in RA accounted for the high surface expression of IL-4R .	Because IL-4 is a potent upregulator of IL-4R, we considered the possibility that incremented levels of circulating IL-4 in RA accounted for the high surface expression of IL-4R.	1	8	is a potent upregulator	Positive_activation_copula_1	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4R	IL-4R	IL-4R	1	2	7	8
Structure-function analyses have revealed that a tyrosine residue [ Tyr 497 , part of the insulin and IL-4R motif ( I4R ) ] on the transmembrane domain of IL-4Ralpha is necessary for the docking of IRS-2 to IL-4Ralpha after IL-4Ralpha has been activated by IL-4 .	Structure-function analyses have revealed that a tyrosine residue [Tyr 497, part of the insulin and IL-4R motif (I4R)] on the transmembrane domain of IL-4Ralpha is necessary for the docking of IRS-2 to IL-4Ralpha after IL-4Ralpha has been activated by IL-4.	39	45	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	44	45	39	40
Furthermore , in our study the IL4R gene was induced similarly by IL-4 in CLL and NBC , suggesting that the differential response arises downstream of IL4R .	Furthermore, in our study the IL4R gene was induced similarly by IL-4 in CLL and NBC, suggesting that the differential response arises downstream of IL4R.	6	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL4R	IL4R	IL4R	12	13	6	7
Defective IL-4-induced signaling in gammac -/- BMDMs was not caused by an inability of IL-4 to bind IL-4Ralpha because IL-4 blocked the capacity of anti-IL-4Ralpha to bind to IL-4Ralpha equally in WT and gammac -/- BMDMs .	Defective IL-4-induced signaling in gammac -/- BMDMs was not caused by an inability of IL-4 to bind IL-4Ralpha because IL-4 blocked the capacity of anti-IL-4Ralpha to bind to IL-4Ralpha equally in WT and gammac -/- BMDMs.	9	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	14	15	17	18
15 A recent study has found that in response to sublethal ischemia , IL-4 can be produced and secreted by neurons , resulting in the upregulation of IL4R on microglia and consequently propose this as an endogenous defense mechanism in the brain .	15 A recent study has found that in response to sublethal ischemia, IL-4 can be produced and secreted by neurons, resulting in the upregulation of IL4R on microglia and consequently propose this as an endogenous defense mechanism in the brain.	13	28	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL4R	IL4R	IL4R	13	14	27	28
IL-4 also signals through STAT6 and its receptor shares the IL-4Ralpha protein with the IL-13 receptor .	IL-4 also signals through STAT6 and its receptor shares the IL-4Ralpha protein with the IL-13 receptor.	0	12	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha protein	IL-4Ralpha protein	IL-4Ralpha protein	0	1	10	12
We have shown that , during helminth infection , IL-4 stimulation alone drives IL-4Ralpha upregulation on the bulk population of CD4 + T cells in the lymph node and Ag encounter causes its profound downregulation on highly activated Th cells .	We have shown that, during helminth infection, IL-4 stimulation alone drives IL-4Ralpha upregulation on the bulk population of CD4 + T cells in the lymph node and Ag encounter causes its profound downregulation on highly activated Th cells.	9	14	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	9	10	13	14
Because LysMCre mediated deletion of the floxed IL-4Ralpha gene is relatively inefficient XREF_BIBR we predicted that chronic IL-4 exposure was causing an outgrowth of IL-4Ralpha sufficient macrophages , such that by day 60 post infection all macrophages were wildtype .	Because LysMCre mediated deletion of the floxed IL-4Ralpha gene is relatively inefficient XREF_BIBR we predicted that chronic IL-4 exposure was causing an outgrowth of IL-4Ralpha sufficient macrophages, such that by day 60 post infection all macrophages were wildtype.	17	26	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	17	18	24	25
Whereas signaling of IL-12Rbeta 1 beta 2 complex by IL-12 induces STAT4 dependent IFN-gamma secretion with consequent Th1 differentiation 12 , signaling of IL-4Ralpha by IL-4 induces STAT6 dependent IL-4 secretion with consequent Th2 differentiation 13 .	Whereas signaling of IL-12Rbeta 1 beta 2 complex by IL-12 induces STAT4 dependent IFN-gamma secretion with consequent Th1 differentiation 12, signaling of IL-4Ralpha by IL-4 induces STAT6 dependent IL-4 secretion with consequent Th2 differentiation 13.	21	26	signaling	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	25	26	23	24
If Th1 cells can be specifically induced in neonates after primary exposure with an antigen XREF_BIBR , these cells express an IL-4Ralpha and IL-13Ralpha1 heteroreceptor that once triggered by IL-4 induces apoptosis of Th1 cells when triggered upon restimulation with the same antigen , thus leading to the development of a Th2 immune response XREF_BIBR .	If Th1 cells can be specifically induced in neonates after primary exposure with an antigen XREF_BIBR, these cells express an IL-4Ralpha and IL-13Ralpha1 heteroreceptor that once triggered by IL-4 induces apoptosis of Th1 cells when triggered upon restimulation with the same antigen, thus leading to the development of a Th2 immune response XREF_BIBR.	21	30	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	29	30	21	22
BMMs expressing IL-4Ralpha Y709 treated with IL-4 led to significantly higher expression of AAM genes ( Arginase1 , Chi3l3 ) and also Ccl11 in contrast to IL-13 .	BMMs expressing IL-4Ralpha Y709 treated with IL-4 led to significantly higher expression of AAM genes (Arginase1, Chi3l3) and also Ccl11 in contrast to IL-13.	2	7	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	6	7	2	3
In mouse only , TGFbeta1 increased Il4 and Il10 and both cytokines increased Il4r and Il13ra1 .	In mouse only, TGFbeta1 increased Il4 and Il10 and both cytokines increased Il4r and Il13ra1.	6	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Il4	Il4	Il4	Il4r	Il4r	Il4r	6	7	13	14
This was associated with IL-4 production independently of IL-4Ralpha signaling in male but not female CD4 + T cell specific ( Lck cre IL-4Ralpha -/lox ) IL-4Ralpha -/- BALB/c mice .	This was associated with IL-4 production independently of IL-4Ralpha signaling in male but not female CD4 + T cell specific (Lck cre IL-4Ralpha -/lox) IL-4Ralpha -/- BALB/c mice.	4	9	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	4	5	8	9
In contrast , IL-4Ralpha paired with the common gamma chain is only activated by IL-4 [ XREF_BIBR ] .	In contrast, IL-4Ralpha paired with the common gamma chain is only activated by IL-4 [XREF_BIBR].	3	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	14	15	3	4
IL-4Ralpha upregulation was restricted to the reactive lymph node , occurred within 4 d of infection , and was driven by an IL-4- and STAT6 dependent mechanism .	IL-4Ralpha upregulation was restricted to the reactive lymph node, occurred within 4 d of infection, and was driven by an IL-4- and STAT6 dependent mechanism.	0	26	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-4-	IL-4-	IL-4-	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	22	23	0	1
Bone marrow derived macrophages from wild-type or Il4ra -/- mice were treated with recombinant murine IL-4 , IL-13 or IFN-gamma ( 20 ng/mL ) for 30 min at 37degreesC .	Bone marrow derived macrophages from wild-type or Il4ra -/- mice were treated with recombinant murine IL-4, IL-13 or IFN-gamma (20 ng/mL) for 30 min at 37degreesC.	5	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	Il4ra	Il4ra	Il4ra	15	16	7	8
Levels of oval cell migration and proliferation were compared in CDE treated mouse strains that depict models of gp130 mediated hyperactive ERK-1/2 signaling ( gp130 ( deltaSTAT ) ) , hyperactive STAT-3 signaling ( gp130 ( Y757F ) and Socs-3 (-/deltaAlb ) ) or active ERK-1/2 as well as active STAT-3 signaling ( wild-type ) .	Levels of oval cell migration and proliferation were compared in CDE treated mouse strains that depict models of gp130 mediated hyperactive ERK-1/2 signaling (gp130 (deltaSTAT)), hyperactive STAT-3 signaling (gp130 (Y757F) and Socs-3 (-/deltaAlb)) or active ERK-1/2 as well as active STAT-3 signaling (wild-type).	16	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	ERK-1/2	ERK-1/2	ERK-1/2	18	19	21	22
Subsequent phosphorylation of tyrosine residues , by constitutively associated JAKs , on the cytoplasmic tail of gp130 enables activation of the JAK and STAT , MAPK and ERK , and PI3K and AKT pathways .	Subsequent phosphorylation of tyrosine residues, by constitutively associated JAKs, on the cytoplasmic tail of gp130 enables activation of the JAK and STAT, MAPK and ERK, and PI3K and AKT pathways.	1	27	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	phosphorylation of tyrosine residues, by constitutively associated JAKs, on the cytoplasmic tail of gp130	gp130	MAPK	MAPK	mapk	16	17	25	26
To determine the effect of hyperactive STAT3 signaling and IL-6 on lung fibrosis , an elegant study was performed using transgenic mice containing a mutation in the common IL-6 family receptor subunit , gp130 , leading to polarized and dysregulated STAT1/3 ( gp130 757F ) , or Erk1/2 ( gp130 DeltaStat ) signaling upon receptor activation .	To determine the effect of hyperactive STAT3 signaling and IL-6 on lung fibrosis, an elegant study was performed using transgenic mice containing a mutation in the common IL-6 family receptor subunit, gp130, leading to polarized and dysregulated STAT1/3 (gp130 757F), or Erk1/2 (gp130 DeltaStat) signaling upon receptor activation.	31	50	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	Erk1/2	Erk1/2	Erk1/2	33	34	47	48
It suggests that gp130 activate MAPK p42/44 and gp190 indirectly regulate its expression and function .	It suggests that gp130 activate MAPK p42/44 and gp190 indirectly regulate its expression and function.	3	6	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	3	4	5	6
It suggests that the oligomerization of the cytoplasmic regions of gp130 be potential to normally initiate MAPK p42/44 for the signal of HL-60 proliferation .	It suggests that the oligomerization of the cytoplasmic regions of gp130 be potential to normally initiate MAPK p42/44 for the signal of HL-60 proliferation.	8	17	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	10	11	16	17
These results demonstrate that IL-6/R and IL-17 increase activation of NF-kappaB and MAPK signaling pathways and transcriptional events occurring at the IL-6 promoter .	These results demonstrate that IL-6/R and IL-17 increase activation of NF-kappaB and MAPK signaling pathways and transcriptional events occurring at the IL-6 promoter.	4	13	increase activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-6/R	IL-6/R	IL-6/R	MAPK	MAPK	MAPK	4	5	12	13
Cytokines can induce MEK and ERK signals via the receptors , such as gp130 and CXCR1/2 XREF_BIBR , XREF_BIBR .	Cytokines can induce MEK and ERK signals via the receptors, such as gp130 and CXCR1/2 XREF_BIBR, XREF_BIBR.	3	16	signals	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	gp130	gp130	gp130	ERK	ERK	ERK	13	14	5	6
Under these conditions , the unglycosylated form of gp130 failed to activate STAT3 and ERK1/2 in response to the stimulation with LIF , IL-11 or IL-6 plus sIL-6R .	Under these conditions, the unglycosylated form of gp130 failed to activate STAT3 and ERK1/2 in response to the stimulation with LIF, IL-11 or IL-6 plus sIL-6R.	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	ERK1/2	ERK1/2	ERK1/2	8	9	14	15
In addition to the JAK and STAT pathway , gp130 cytokines can also activate the MAPK cascade ( ERKs 1 and 2 ) .	In addition to the JAK and STAT pathway, gp130 cytokines can also activate the MAPK cascade (ERKs 1 and 2).	9	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	9	10	15	16
IL-6 stimulates a target cell by a membrane bound receptor which can associate with gp130 , a signaling receptor protein which , through a cascade , activates the MAPK pathway [ XREF_BIBR ] .	IL-6 stimulates a target cell by a membrane bound receptor which can associate with gp130, a signaling receptor protein which, through a cascade, activates the MAPK pathway [XREF_BIBR].	12	29	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	14	15	28	29
As expected , endogenous gp130 can activate SHP2 and Erk only upon stimulation .	As expected, endogenous gp130 can activate SHP2 and Erk only upon stimulation.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	Erk	Erk	Erk	4	5	9	10
CagA Determines gp130 Activated Shp2 and ERK and JAK and STAT Signal Transduction .	CagA Determines gp130 Activated Shp2 and ERK and JAK and STAT Signal Transduction.	1	7	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	ERK	ERK	ERK	2	3	6	7
The second arm requires phosphorylation of the more proximal Y757 residue in gp130 , which induces ERK and PI3-kinase and Akt signaling .	The second arm requires phosphorylation of the more proximal Y757 residue in gp130, which induces ERK and PI3-kinase and Akt signaling.	4	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	phosphorylation of the more proximal Y757 residue in gp130	gp130	ERK	ERK	erk	12	13	16	17
When Ptpn11 ( also called Shp-2 ) , another hit from our screen , was prevented from interacting with a mutated gp130 receptor that failed to activate ERKs , this led to self-renewal .	When Ptpn11 (also called Shp-2), another hit from our screen, was prevented from interacting with a mutated gp130 receptor that failed to activate ERKs, this led to self-renewal.	21	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	ERKs	ERKs	ERKs	21	22	27	28
For example , a RAS and MAPK signaling pathway may also be activated by stimulation of gp130 [ XREF_BIBR , XREF_BIBR ] .	For example, a RAS and MAPK signaling pathway may also be activated by stimulation of gp130 [XREF_BIBR, XREF_BIBR].	6	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	16	17	6	7
Expression of receptors lacking this region or of chimeric gp130 ( Y118F ) point mutants inhibited MAPK activity by approximately 55 % , suggesting that Tyr 118 , but not box 3 , was required during activation of MAPK by gp130 .	Expression of receptors lacking this region or of chimeric gp130 (Y118F) point mutants inhibited MAPK activity by approximately 55%, suggesting that Tyr 118, but not box 3, was required during activation of MAPK by gp130.	34	41	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	40	41	38	39
Propagation of many of these signals ( IL-6 , LIF , and CNTF ) requires a combination of various ligand binding units and a common signal transducing unit gp130 , through which they activate the JAK and STAT , Ras and MAPK , extracellular regulated-signal kinase ( ERK ) , PI3K , and other pathways .	Propagation of many of these signals (IL-6, LIF, and CNTF) requires a combination of various ligand binding units and a common signal transducing unit gp130, through which they activate the JAK and STAT, Ras and MAPK, extracellular regulated-signal kinase (ERK), PI3K, and other pathways.	26	42	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	28	29	41	42
Our results demonstrate that gp130 and LIFR stimulate MAPK activity through box 3 independent mechanisms involving : ( i ) effects at Tyr 118 and Tyr 115 , respectively , for maximal stimulation of MAPK activity and ( ii ) a Jak and Tyk dependent pathway that , together with Tyr 118- or Tyr-115-generated signals , converges at the level of Ras during activation of MAPK by cytokine .	Our results demonstrate that gp130 and LIFR stimulate MAPK activity through box 3 independent mechanisms involving : (i) effects at Tyr 118 and Tyr 115, respectively, for maximal stimulation of MAPK activity and (ii) a Jak and Tyk dependent pathway that, together with Tyr 118- or Tyr-115-generated signals, converges at the level of Ras during activation of MAPK by cytokine.	4	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	4	5	8	9
IL-6 is synthesized and secreted in an active form , which binds first to its receptor ( IL-6R ) and then to the signaling gp130 molecule triggering STAT and ERK pathways .	IL-6 is synthesized and secreted in an active form, which binds first to its receptor (IL-6R) and then to the signaling gp130 molecule triggering STAT and ERK pathways.	24	30	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	ERK	ERK	ERK	24	25	29	30
Surprisingly , gp130 without any functional Box3 stimulates prolonged activation of MAPK , leading to an extended period of up-regulation of egr-1 and to an extracellularly regulated kinase mediated reduction in the IL-6-stimulated production of thiostatin .	Surprisingly, gp130 without any functional Box3 stimulates prolonged activation of MAPK, leading to an extended period of up-regulation of egr-1 and to an extracellularly regulated kinase mediated reduction in the IL-6-stimulated production of thiostatin.	2	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	2	3	11	12
IL-6 binds to its membrane receptor , which triggers signaling through gp130 , a common transducer that activates Jak and Stat3 and Ras and MAPK pathways in T cells .	IL-6 binds to its membrane receptor, which triggers signaling through gp130, a common transducer that activates Jak and Stat3 and Ras and MAPK pathways in T cells.	8	25	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	11	12	24	25
IL-7 induced IL-7R downregulation has the beneficial effect of increasing the number of CD8 T cells that can be supported by limiting amounts of in vivo IL-7 13 .	IL-7 induced IL-7R downregulation has the beneficial effect of increasing the number of CD8 T cells that can be supported by limiting amounts of in vivo IL-7 13.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7R	IL-7R	IL-7R	0	1	2	3
The IL-7 signaling pathway induces the internalization and degradation of the surface IL-7Ralpha .	The IL-7 signaling pathway induces the internalization and degradation of the surface IL-7Ralpha.	1	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	1	2	12	13
It has been shown that the level of IL-7 in Rag2KO mice is sufficient to cause IL-7Ralpha downregulation in adoptively transferred naive T cells 4 .	It has been shown that the level of IL-7 in Rag2KO mice is sufficient to cause IL-7Ralpha downregulation in adoptively transferred naive T cells 4.	6	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	level of IL-7	il-7	IL-7Ralpha	IL-7Ralpha	il-7ralpha	8	9	16	17
Blockade of IL-7 in KO mice down-regulates Bcl-2 and IL-7Ralpha up-regulation of BrdU + CD8 + T cells .	Blockade of IL-7 in KO mice down-regulates Bcl-2 and IL-7Ralpha up-regulation of BrdU + CD8 + T cells.	0	10	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	2	3	9	10
Nevertheless , IL-7 overabundance promotes IL-7R signaling in a considerable proportion of IEC ( XREF_SUPPLEMENTARY ) correlating with elevated levels of IEC proliferation and survival ( XREF_FIG ) .	Nevertheless, IL-7 overabundance promotes IL-7R signaling in a considerable proportion of IEC (XREF_SUPPLEMENTARY) correlating with elevated levels of IEC proliferation and survival (XREF_FIG).	2	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7R	IL-7R	IL-7R	2	3	5	6
IL-7 supports the proliferation and effector function of IL-7Ralpha .	IL-7 supports the proliferation and effector function of IL-7Ralpha.	0	9	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	0	1	8	9
It is well established that IL-7 promotes the transcriptional down-regulation of IL7RA , leading to decreased IL-7Ralpha surface expression .	It is well established that IL-7 promotes the transcriptional down-regulation of IL7RA, leading to decreased IL-7Ralpha surface expression.	5	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL7RA	IL7RA	IL7RA	5	6	11	12
We found that IL-7 , in sharp contrast to IL-2 , supports the proliferation and antitumor activity of IL-7Ralpha .	We found that IL-7, in sharp contrast to IL-2, supports the proliferation and antitumor activity of IL-7Ralpha.	3	19	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	3	4	18	19
To investigate the role of IL-7Ralpha signals induced by TSLP and IL-7 in early stages of human B cell production , we developed a human-only co-culture model that supports the production of human pro B cells and provides selective IL-7 or TSLP stimulation .	To investigate the role of IL-7Ralpha signals induced by TSLP and IL-7 in early stages of human B cell production, we developed a human-only co-culture model that supports the production of human pro B cells and provides selective IL-7 or TSLP stimulation.	5	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	11	12	5	6
This early inhibition was not due to an effect on IL-7R expression , as TCR stimulation had no impact on the rapid downregulation of IL-7R induced by IL-7 signalling in CD4 + ( XREF_SUPPLEMENTARY ) and in CD8 + T cells ( XREF_FIG ) .	This early inhibition was not due to an effect on IL-7R expression, as TCR stimulation had no impact on the rapid downregulation of IL-7R induced by IL-7 signalling in CD4 + (XREF_SUPPLEMENTARY) and in CD8 + T cells (XREF_FIG).	22	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7R	IL-7R	IL-7R	27	28	24	25
To elucidate the relationship between IL-7R expression and signaling , OT-1 and F5 cells were treated with varying IL-7 doses and their pStat5 and IL-7Ralpha surface expression dynamics were measured over 6h ( XREF_SUPPLEMENTARY ) .	To elucidate the relationship between IL-7R expression and signaling, OT-1 and F5 cells were treated with varying IL-7 doses and their pStat5 and IL-7Ralpha surface expression dynamics were measured over 6h (XREF_SUPPLEMENTARY).	5	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7R	IL-7R	IL-7R	18	19	5	6
Next , to confirm whether IL-7 directly induced TRAP + cells of IL-7Ralpha + monocytes , we isolated CD14 + monocytes expressing IL-7Ralpha from SFMCs of RA patients and cultured them with IL-7 .	Next, to confirm whether IL-7 directly induced TRAP + cells of IL-7Ralpha + monocytes, we isolated CD14 + monocytes expressing IL-7Ralpha from SFMCs of RA patients and cultured them with IL-7.	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	5	6	12	13
IL-7 can also improve the survival of IL-7-Ralpha + central memory populations and promote the production of IL-7Ralpha + long living memory stem T cells ( TSCM ) , which can self-renew and demonstrates the plasticity to differentiate into effectors [ XREF_BIBR ] .	IL-7 can also improve the survival of IL-7-Ralpha + central memory populations and promote the production of IL-7Ralpha + long living memory stem T cells (TSCM), which can self-renew and demonstrates the plasticity to differentiate into effectors [XREF_BIBR].	0	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	0	1	17	18
IL-7Ralpha signals induced by TSLP or IL-7 increase the in vivo production of human B cell precursors .	IL-7Ralpha signals induced by TSLP or IL-7 increase the in vivo production of human B cell precursors.	0	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	6	7	0	1
IL-7 supports the in vivo antitumor activity of IL-7Ralpha .	IL-7 supports the in vivo antitumor activity of IL-7Ralpha.	0	9	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	0	1	8	9
We show that higher doses of IL-7 induce proliferation ( XREF_FIG ) and cause down-regulation of IL-7R ( XREF_FIG b ) .	We show that higher doses of IL-7 induce proliferation (XREF_FIG) and cause down-regulation of IL-7R (XREF_FIG b).	4	19	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7R	IL-7R	IL-7R	6	7	16	17
In particular , we found unaltered expression of the IL7R , consistent with previous studies implicating reduced availability of IL7 and cytoplasmic signaling of the IL7R in the reduction of pro B cell numbers in aging [ XREF_BIBR , XREF_BIBR ] .	In particular, we found unaltered expression of the IL7R, consistent with previous studies implicating reduced availability of IL7 and cytoplasmic signaling of the IL7R in the reduction of pro B cell numbers in aging [XREF_BIBR, XREF_BIBR].	19	28	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL7	IL7	IL7	IL7R	IL7R	IL7R	19	20	25	26
Induction of IL-7R signalling by IL-7 results in the activation of a number of pathways leading to diverse biological outcomes .	Induction of IL-7R signalling by IL-7 results in the activation of a number of pathways leading to diverse biological outcomes.	2	6	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7R	IL-7R	IL-7R	5	6	2	3
Overall , our findings indicate that IL-7 triggers rapid IL-7Ralpha endocytosis , which is required for IL-7-mediated signaling and subsequent receptor degradation .	Overall, our findings indicate that IL-7 triggers rapid IL-7Ralpha endocytosis, which is required for IL-7-mediated signaling and subsequent receptor degradation.	6	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	6	7	9	10
This could mean that RRMS patients have a decrease signaling initiated by IL-7 , or the other IL7R ligand TSLP , and contributes to the development of RRMS .	This could mean that RRMS patients have a decrease signaling initiated by IL-7, or the other IL7R ligand TSLP, and contributes to the development of RRMS.	10	19	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL7R	IL7R	IL7R	12	13	17	18
Having demonstrated that IL-7 supports the proliferation and function of IL-7Ralpha .	Having demonstrated that IL-7 supports the proliferation and function of IL-7Ralpha.	3	11	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	3	4	10	11
Thus , IL-7R signaling elicited by IL-7 and TSLP in ILCs and stromal cells , respectively , are critical for regulating inflammatory responses in the gut .	Thus, IL-7R signaling elicited by IL-7 and TSLP in ILCs and stromal cells, respectively, are critical for regulating inflammatory responses in the gut.	2	8	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7R	IL-7R	IL-7R	6	7	2	3
Similarly , IL-7R internalization triggered by IL-7 stimulation may explain the reduced CD127 expression characterizing circulating HIV specific CTLs during hyperacute infection in patients .	Similarly, IL-7R internalization triggered by IL-7 stimulation may explain the reduced CD127 expression characterizing circulating HIV specific CTLs during hyperacute infection in patients.	2	7	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	IL-7R	IL-7R	IL-7R	6	7	2	3
This suggests that IL-6 can modulate IL-6Ralpha in our model .	This suggests that IL-6 can modulate IL-6Ralpha in our model.	3	7	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6Ralpha	IL-6Ralpha	IL-6Ralpha	3	4	6	7
This is consistent with impaired hepatocyte proliferation following PH in mice either chronically exposed to high IL-6 levels ( like A20 KO ) , or overexpressing the soluble IL-6-receptor gp80 and concomitantly treated with IL-6 .	This is consistent with impaired hepatocyte proliferation following PH in mice either chronically exposed to high IL-6 levels (like A20 KO), or overexpressing the soluble IL-6-receptor gp80 and concomitantly treated with IL-6.	25	35	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	gp80	gp80	gp80	34	35	29	30
However , the addition of 1 mug/mL of IL-6Ra resulted in increased BM ECFC colonies compared with BM treated with 1 mug/mL of IL-6 and no IL-6Ra ( mean +/-SE : 7 +/-0.2 vs. 5.8 +/-1.49 , P = 0.003 ) ( XREF_FIG ) .	However, the addition of 1 mug/mL of IL-6Ra resulted in increased BM ECFC colonies compared with BM treated with 1 mug/mL of IL-6 and no IL-6Ra (mean +/-SE : 7 +/-0.2 vs. 5.8 +/-1.49, P = 0.003) (XREF_FIG).	6	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6Ra	IL-6Ra	IL-6Ra	23	24	8	9
SC144 , a recently identified inhibitor of gp130 , was described to induce this phosphorylation of gp130 Ser782 and thus inhibit gp130 signal transduction [ XREF_BIBR ] .	SC144, a recently identified inhibitor of gp130, was described to induce this phosphorylation of gp130 Ser782 and thus inhibit gp130 signal transduction [XREF_BIBR].	5	18	induce	Positive_regulation_syntax_1_verb	Positive_activation	Negative_regulation	gp130	gp130	gp130	gp130	phosphorylation of gp130 Ser782	gp130	7	8	16	17
Hyper-IL-6 is a fusion protein of IL-6 and the soluble IL-6R , which mimics IL-6 trans-signaling and activates a gp130 homodimer [ XREF_BIBR ] .	Hyper-IL-6 is a fusion protein of IL-6 and the soluble IL-6R, which mimics IL-6 trans-signaling and activates a gp130 homodimer [XREF_BIBR].	4	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6R	IL-6R	IL-6R	gp130	gp130	gp130	10	11	19	20
Soluble form of the IL-6R ( sIL-6R ) occurs in various body fluids and might induce gp130 dimerization and signaling when complexed with IL-6 .	Soluble form of the IL-6R (sIL-6R) occurs in various body fluids and might induce gp130 dimerization and signaling when complexed with IL-6.	1	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6R	IL-6R	IL-6R	gp130	gp130	gp130	4	5	16	17
RAR suppresses Th17 differentiation through retinoic acid mediated inhibition of Il23r , Il6r and Irf4 expression and Smad2/3 phosphorylation via the TGFbeta receptor pathway XREF_BIBR .	RAR suppresses Th17 differentiation through retinoic acid mediated inhibition of Il23r, Il6r and Irf4 expression and Smad2/3 phosphorylation via the TGFbeta receptor pathway XREF_BIBR.	7	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Il6r	Il6r and Irf4 expression and Smad2/3 phosphorylation	il6r	Il6r	Il6r	il6r	12	13	12	13
The expressions of membrane bound IL-6R ( mIL-6R ) , sIL-6R and gp130 are enhanced in kidney cortex of diabetic mice accompanying with activated STAT3 by tyrosine 705 residue phosphorylation , while not serine 727 .	The expressions of membrane bound IL-6R (mIL-6R), sIL-6R and gp130 are enhanced in kidney cortex of diabetic mice accompanying with activated STAT3 by tyrosine 705 residue phosphorylation, while not serine 727.	4	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	IL-6R	IL-6R	IL-6R	12	13	5	6
Phosphorylation of gp130 on Ser 782 accelerated the internalization of membrane bound gp130 XREF_BIBR .	Phosphorylation of gp130 on Ser 782 accelerated the internalization of membrane bound gp130 XREF_BIBR.	0	13	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	Phosphorylation of gp130 on Ser 782	gp130	gp130	gp130	gp130	2	3	12	13
Classical activation consists of the IL-6 binding to the membrane bound IL-6R , while trans-signaling is the ability of a soluble IL-6R ( sIL-6R ) to bind IL-6 in the extracellular compartment to form an IL-6 and sIL-6R complex and in turn , activate gp130 .	Classical activation consists of the IL-6 binding to the membrane bound IL-6R, while trans-signaling is the ability of a soluble IL-6R (sIL-6R) to bind IL-6 in the extracellular compartment to form an IL-6 and sIL-6R complex and in turn, activate gp130.	11	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6R	IL-6R	IL-6R	gp130	gp130	gp130	11	12	44	45
Consistent with an even broader role for IL-2 in T H differentiation via regulation of cytokine receptors , IL-2 down-regulated Il6ra and Il6st and inhibition of T H 17 differentiation by IL-2 could be partially rescued by forced expression of Il6st , although our data also indicate that IL-2 can act via an Il6st independent mechanism as well .	Consistent with an even broader role for IL-2 in T H differentiation via regulation of cytokine receptors, IL-2 down-regulated Il6ra and Il6st and inhibition of T H 17 differentiation by IL-2 could be partially rescued by forced expression of Il6st, although our data also indicate that IL-2 can act via an Il6st independent mechanism as well.	19	41	rescued	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Il6st	expression of Il6st	il6st	Il6st	Il6st	il6st	40	41	22	23
After binding of IL-6 to membrane IL-6R or soluble IL-6R , the complex and GP130 protein synergistically stimulate Janus kinase 2 .	After binding of IL-6 to membrane IL-6R or soluble IL-6R, the complex and GP130 protein synergistically stimulate Janus kinase 2.	12	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GP130	GP130	GP130	Janus kinase 2	Janus kinase 2	Janus kinase 2	14	15	18	21
Using both pharmacological inhibitors and small interfering RNA knockdown , we show that the gp130 receptor mediated activation of both the JAK2 and STAT3 and PI3K and Akt cell signaling pathways is necessary for KSHV induced lymphatic reprogramming of endothelial cells .	Using both pharmacological inhibitors and small interfering RNA knockdown, we show that the gp130 receptor mediated activation of both the JAK2 and STAT3 and PI3K and Akt cell signaling pathways is necessary for KSHV induced lymphatic reprogramming of endothelial cells.	14	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK2	JAK2	JAK2	14	15	21	22
It has been suggested that diabetes related oxidative stress may induce vascular IL-6 expression and activate IL-6R and gp130 , which in turn activates the JAK2 and STAT3 signaling cascade [ XREF_BIBR ] .	It has been suggested that diabetes related oxidative stress may induce vascular IL-6 expression and activate IL-6R and gp130, which in turn activates the JAK2 and STAT3 signaling cascade [XREF_BIBR].	15	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK2	JAK2	JAK2	18	19	25	26
An earlier study XREF_BIBR in a murine transverse aortic constriction PO model demonstrates that STAT3 undergoes biphasic acute ( 3 h ) and hypertrophic responses ( 48 h ) via the gp130 mediated JAK2 signaling where the activated STAT3 plays an autoregulatory negative feedback role by promoting the expression of a JAK2 inhibitor protein , SOCS3 ( suppressor of cytokine signaling-3 ) .	An earlier study XREF_BIBR in a murine transverse aortic constriction PO model demonstrates that STAT3 undergoes biphasic acute (3 h) and hypertrophic responses (48 h) via the gp130 mediated JAK2 signaling where the activated STAT3 plays an autoregulatory negative feedback role by promoting the expression of a JAK2 inhibitor protein, SOCS3 (suppressor of cytokine signaling-3).	24	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK2	JAK2	JAK2	31	32	33	34
The IL-6 receptor ( gp130 ) , on binding to IL-6 , activates JAK1 , JAK2 and TYK2 .	The IL-6 receptor (gp130), on binding to IL-6, activates JAK1, JAK2 and TYK2.	2	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK2	JAK2	JAK2	4	5	15	16
This process is dependent on gp130 mediated activation of JAK2 and STAT3 signaling , which is known to underlie the induction of POMC mRNA expression by leptin , suggesting that LIF may activate hypothalamic POMC neurons in a similar manner [ XREF_BIBR , XREF_BIBR ] .	This process is dependent on gp130 mediated activation of JAK2 and STAT3 signaling, which is known to underlie the induction of POMC mRNA expression by leptin, suggesting that LIF may activate hypothalamic POMC neurons in a similar manner [XREF_BIBR, XREF_BIBR].	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK2	JAK2	JAK2	5	6	9	10
In addition , oncostatin M has been shown to induce EMT in tubular epithelial cells through GP130 mediated activation of JAK2 and STAT3 pathway ( Nightingale et al , 2004 ) , indicating that this pathway may be critical for cytokine and growth factor mediated responses regulating EMT biology in fibrogenesis and cancer .	In addition, oncostatin M has been shown to induce EMT in tubular epithelial cells through GP130 mediated activation of JAK2 and STAT3 pathway (Nightingale et al, 2004), indicating that this pathway may be critical for cytokine and growth factor mediated responses regulating EMT biology in fibrogenesis and cancer.	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	GP130	GP130	GP130	JAK2	JAK2	JAK2	16	17	20	21
gp130 dimerizing stimulus upregulates kinase activity of JAK2 as revealed by immunocomplex kinase assay .	gp130 dimerizing stimulus upregulates kinase activity of JAK2 as revealed by immunocomplex kinase assay.	0	8	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK2	JAK2	JAK2	0	1	7	8
Binding of IL-6 to its receptor induces phosphorylation of gp130 , which subsequently activates Ras/MEK/MAPK , JAK2 and STAT3 , and PI3K and Akt signaling cascades .	Binding of IL-6 to its receptor induces phosphorylation of gp130, which subsequently activates Ras/MEK/MAPK, JAK2 and STAT3, and PI3K and Akt signaling cascades.	2	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	IL-6 to its receptor induces phosphorylation of gp130	gp130	JAK2	JAK2	jak2	9	10	16	17
Dimerization of GP130 receptors induces the activation of janus kinases ( JAK1 and JAK2 ) , then subsequently activates signal transducer and activator of transcription 3 ( STAT3 ) and STAT1 [ XREF_BIBR ] .	Dimerization of GP130 receptors induces the activation of janus kinases (JAK1 and JAK2), then subsequently activates signal transducer and activator of transcription 3 (STAT3) and STAT1 [XREF_BIBR].	2	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GP130	GP130	GP130	JAK2	JAK2	JAK2	2	3	13	14
Binding of IL-6 to its receptor , IL-6R , activates the JAK kinase family ( JAK1 , JAK2 , and TYK2 ) .	Binding of IL-6 to its receptor, IL-6R, activates the JAK kinase family (JAK1, JAK2, and TYK2).	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6R	IL-6R	IL-6R	JAK2	JAK2	JAK2	7	8	17	18
IL-6 in prostate gland epithelial cells interacts with its receptor to form an IL-6R gp130 protein hexameric complex , causing downstream activation of the JAK2 and STAT pathway .	IL-6 in prostate gland epithelial cells interacts with its receptor to form an IL-6R gp130 protein hexameric complex, causing downstream activation of the JAK2 and STAT pathway.	14	27	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK2	JAK2	JAK2	14	15	24	25
Taken together , our results suggest that the gp130 mediated activation of JAK2 and STAT3 signaling pathway may play a key role in the induction of astrogliosis .	Taken together, our results suggest that the gp130 mediated activation of JAK2 and STAT3 signaling pathway may play a key role in the induction of astrogliosis.	8	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK2	JAK2	JAK2	8	9	12	13
Receptor binding stimulates gp130 mediated activation of the Janus kinase 2 ( JAK2 )/signal transducer and activator of transcription 3 ( STAT3 ) pathway [ XREF_BIBR ] , the same pathway activated by the binding of leptin to its receptor [ XREF_BIBR ] .	Receptor binding stimulates gp130 mediated activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway [XREF_BIBR], the same pathway activated by the binding of leptin to its receptor [XREF_BIBR].	3	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	gp130	gp130	gp130	Janus kinase 2	Janus kinase 2	Janus kinase 2	3	4	8	11
IL-6 controls differentiation of Th17 cells via binding IL-6 to the IL-6 receptor ' s alpha chain and to gp130 , both of which mainly activate JAK1 and STAT3 .	IL-6 controls differentiation of Th17 cells via binding IL-6 to the IL-6 receptor 's alpha chain and to gp130, both of which mainly activate JAK1 and STAT3.	2	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK1	JAK1	JAK1	19	20	26	27
Binding of one of these cytokines to its receptor and gp130 activates JAK-1 , JAK-2 , and TYK-2 , which phosphorylate tyrosine residues in the cytoplasmic domain of gp130 .	Binding of one of these cytokines to its receptor and gp130 activates JAK-1, JAK-2, and TYK-2, which phosphorylate tyrosine residues in the cytoplasmic domain of gp130.	5	14	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK-1	JAK-1	JAK-1	10	11	12	13
JAK1 is activated by gp130 cytokines , type I interferon , interferon-gamma , and betac cytokines ; its deficiency causes neurological defects and severe combined immunodeficiency .	JAK1 is activated by gp130 cytokines, type I interferon, interferon-gamma, and betac cytokines; its deficiency causes neurological defects and severe combined immunodeficiency.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	gp130	gp130	gp130	JAK1	JAK1	JAK1	4	5	0	1
The soluble form of gp80 ( sIL-6R ) is able to activate gp130 when complexed to the IL-6 molecule .	The soluble form of gp80 (sIL-6R) is able to activate gp130 when complexed to the IL-6 molecule.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp80	gp80	gp80	gp130	gp130	gp130	4	5	12	13
Soluble forms of gp80 also trigger membrane gp130 signaling when complexed with IL-6 , while soluble forms of gp130 inhibit the same process .	Soluble forms of gp80 also trigger membrane gp130 signaling when complexed with IL-6, while soluble forms of gp130 inhibit the same process.	1	8	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gp80	gp80	gp80	gp130	gp130	gp130	3	4	7	8
We show that ligand induced homodimerization of chimeric surface receptors consisting of the extracellular and transmembrane domains of the erythropoietin receptor and of the intracellular domain of IL-4Ralpha induces Janus kinase 1 ( Jak1 ) activation , STAT6 activation , and Cepsilon germline transcripts in human B cell line BJAB .	We show that ligand induced homodimerization of chimeric surface receptors consisting of the extracellular and transmembrane domains of the erythropoietin receptor and of the intracellular domain of IL-4Ralpha induces Janus kinase 1 (Jak1) activation, STAT6 activation, and Cepsilon germline transcripts in human B cell line BJAB.	25	32	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	Janus kinase 1	Janus kinase 1	Janus kinase 1	27	28	29	32
It is known that IL4Ralpha , gammac , and IL13Ralpha1 activate JAK1 , JAK3 , and tyrosine kinase ( Tyk2 ) , respectively [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	It is known that IL4Ralpha, gammac, and IL13Ralpha1 activate JAK1, JAK3, and tyrosine kinase (Tyk2), respectively [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] (XREF_FIG).	4	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL4Ralpha	IL4Ralpha	IL4Ralpha	JAK1	JAK1	JAK1	4	5	11	12
Shp2 was associated with IL-4Ralpha and inhibited JAK1 and STAT6 signaling through its phosphatase activity ; loss of Shp2 promoted the association of JAK1 with IL-4Ralpha , which enhanced IL-4-mediated JAK1 and STAT6 activation that resulted in M2 skewing .	Shp2 was associated with IL-4Ralpha and inhibited JAK1 and STAT6 signaling through its phosphatase activity; loss of Shp2 promoted the association of JAK1 with IL-4Ralpha, which enhanced IL-4-mediated JAK1 and STAT6 activation that resulted in M2 skewing.	19	35	enhanced	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	JAK1	JAK1	JAK1	25	26	30	31
INCENP and AIRK2 colocalized exactly in human cells , and INCENP was required to target AIRK2 correctly to centromeres and the central spindle .	INCENP and AIRK2 colocalized exactly in human cells, and INCENP was required to target AIRK2 correctly to centromeres and the central spindle.	10	16	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	INCENP	INCENP	INCENP	AIRK2	AIRK2	AIRK2	10	11	15	16
In addition , AURKB phosphorylation of INCENP allosterically activates AURKB .	In addition, AURKB phosphorylation of INCENP allosterically activates AURKB.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	INCENP	AURKB phosphorylation of INCENP	incenp	AURKB	AURKB	aurkb	6	7	9	10
Higher concentrations of IL-4 were required to activate STAT6 in gammac -/- macrophages compared to wild-type macrophages .	Higher concentrations of IL-4 were required to activate STAT6 in gammac -/- macrophages compared to wild-type macrophages.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	gammac	gammac	gammac	3	4	10	11
In contrast , IL-4 pre-treatment clearly did not enhance chemotaxis of gammaC -/- bmEos in response to eotaxin-1 .	In contrast, IL-4 pre-treatment clearly did not enhance chemotaxis of gammaC -/- bmEos in response to eotaxin-1.	3	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	gammaC	gammaC	gammaC	3	4	11	12
Surprisingly , human PBMC derived dendritic cells ( DCs ) exposed to super-IL-4 , which preferentially recruits the gammaC , failed to mature , compared to DCs treated with native IL-4 .	Surprisingly, human PBMC derived dendritic cells (DCs) exposed to super-IL-4, which preferentially recruits the gammaC, failed to mature, compared to DCs treated with native IL-4.	16	31	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	gammaC	gammaC	gammaC	30	31	18	19
IL-4 did not induce the production of arginase I or Ym1 in gammaC -/- BMMs , but IL-13 induced the production of both proteins , albeit at low abundance .	IL-4 did not induce the production of arginase I or Ym1 in gammaC -/- BMMs, but IL-13 induced the production of both proteins, albeit at low abundance.	0	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4	IL-4	IL-4	gammaC	gammaC	gammaC	0	1	12	13
The results of this study suggested that IL-5 produced by the type-2 inflammatory response to parasite infection promoted induction of autoantigen specific CD25 + Il5ra + T regulatory cells that reduced the severity of autoimmunity .	The results of this study suggested that IL-5 produced by the type-2 inflammatory response to parasite infection promoted induction of autoantigen specific CD25 + Il5ra + T regulatory cells that reduced the severity of autoimmunity.	7	25	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-5	IL-5	IL-5	Il5ra	Il5ra	Il5ra	7	8	24	25
We now provide evidence to indicate that IL-5 can upregulate IL-5Ralpha on bone marrow CD34+ progenitors in vitro , as we have demonstrated in vivo in atopic asthmatics .	We now provide evidence to indicate that IL-5 can upregulate IL-5Ralpha on bone marrow CD34+ progenitors in vitro, as we have demonstrated in vivo in atopic asthmatics.	7	11	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-5	IL-5	IL-5	IL-5Ralpha	IL-5Ralpha	IL-5Ralpha	7	8	10	11
We propose that one of the beneficial effects of parasites may be the high IL-5 level produced by a chronic Th2 response , promotes IL-5Ralpha expressing antigen specific Ts2 cells to control autoimmunity and allograft rejection .	We propose that one of the beneficial effects of parasites may be the high IL-5 level produced by a chronic Th2 response, promotes IL-5Ralpha expressing antigen specific Ts2 cells to control autoimmunity and allograft rejection.	14	29	promotes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IL-5	IL-5 level	il-5	IL-5Ralpha	IL-5Ralpha	il-5ralpha	14	15	24	25
Further study displayed that IL-5 can not stimulate discernible IL-5RA activation when only IL-5RA was introduced into the CD34+ cells .	Further study displayed that IL-5 can not stimulate discernible IL-5RA activation when only IL-5RA was introduced into the CD34+ cells.	4	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-5	IL-5	IL-5	IL-5RA	IL-5RA	IL-5RA	4	5	9	10
XREF_BIBR IL-5 signaling also promotes alternative splicing of the IL-5Ralpha gene to generate transmembrane forms of IL-5Ralpha .	XREF_BIBR IL-5 signaling also promotes alternative splicing of the IL-5Ralpha gene to generate transmembrane forms of IL-5Ralpha.	1	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-5	IL-5	IL-5	IL-5Ralpha	IL-5Ralpha	IL-5Ralpha	1	2	16	17
Herein , we show that IL-7 induces epitope masking of gammac protein in rapid and energy independent manner .	Herein, we show that IL-7 induces epitope masking of gammac protein in rapid and energy independent manner.	5	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	gammac	gammac	gammac	5	6	10	11
IL-7 Induces an Epitope Masking of gammac Protein in IL-7 Receptor Signaling Complex .	IL-7 Induces an Epitope Masking of gammac Protein in IL-7 Receptor Signaling Complex.	0	7	Induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7	IL-7	IL-7	gammac	gammac	gammac	0	1	6	7
The IL-4 receptor ( IL-4R ) signals the activation of the Janus kinase 3 ( JAK3 )-STAT6 pathway through its common gamma chain [ XREF_BIBR ] , which leads to the development of immature DCs .	The IL-4 receptor (IL-4R) signals the activation of the Janus kinase 3 (JAK3)-STAT6 pathway through its common gamma chain [XREF_BIBR], which leads to the development of immature DCs.	2	17	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4R	IL-4R	IL-4R	Janus kinase 3	Janus kinase 3	Janus kinase 3	4	5	11	14
Akt1 is subsequently activated by PDK1 and ILK [ XREF_BIBR , XREF_BIBR ] .	Akt1 is subsequently activated by PDK1 and ILK [XREF_BIBR, XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt1	Akt1	Akt1	7	8	0	1
ILK activates protein kinase B and inhibits the glycogen synthase kinase 3 ( GSK-3 ) activity in a phosphatidylinositol-3-kinase ( PI 3-kinase )-dependent manner .	ILK activates protein kinase B and inhibits the glycogen synthase kinase 3 (GSK-3) activity in a phosphatidylinositol-3-kinase (PI 3-kinase)-dependent manner.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	protein kinase B	protein kinase B	protein kinase B	0	1	2	5
Upon IL-7 binding , the IL-7R heterodimer activates Jak1 and Jak3 , leading to the activation of Stat5 proteins XREF_BIBR , XREF_BIBR .	Upon IL-7 binding, the IL-7R heterodimer activates Jak1 and Jak3, leading to the activation of Stat5 proteins XREF_BIBR, XREF_BIBR.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7R	IL-7R	IL-7R	Jak1	Jak1	Jak1	5	6	8	9
Engagement of IL-7R by IL-7 activates Janus kinase-signal transducers and activators of transcription ( JAK-STAT ) ( mainly JAK1 , JAK3 and STAT5 ) , phosphatidylinositol 3-kinase ( PI3K ) and Src family kinases signaling pathways [ XREF_BIBR , XREF_BIBR ] .	Engagement of IL-7R by IL-7 activates Janus kinase-signal transducers and activators of transcription (JAK-STAT) (mainly JAK1, JAK3 and STAT5), phosphatidylinositol 3-kinase (PI3K) and Src family kinases signaling pathways [XREF_BIBR, XREF_BIBR].	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-7R	IL-7R	IL-7R	JAK1	JAK1	JAK1	2	3	18	19
A greater increase in IL-3R expression was measured when M-NFS-60 cells were treated with both SVPII and IL-3 , and this enhanced expression was observed under both normal M-CSF and low ( 25 % ) M-CSF concentrations .	A greater increase in IL-3R expression was measured when M-NFS-60 cells were treated with both SVPII and IL-3, and this enhanced expression was observed under both normal M-CSF and low (25%) M-CSF concentrations.	4	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	IL-3	IL-3	IL-3	IL-3R	IL-3R	IL-3R	17	18	4	5
Conversely , over the same time period , IL-3 increased IL-3RA while GM-CSF has no effect on its own alpha-chain receptor ( CSF2RA , also called GM-CSFR ) ( XREF_FIG ) .	Conversely, over the same time period, IL-3 increased IL-3RA while GM-CSF has no effect on its own alpha-chain receptor (CSF2RA, also called GM-CSFR) (XREF_FIG).	8	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-3	IL-3	IL-3	IL-3RA	IL-3RA	IL-3RA	8	9	10	11
Rescue of ILK -/- fibroblasts by expression of wild-type ILK restored these responses to cyclic strain .	Rescue of ILK -/- fibroblasts by expression of wild-type ILK restored these responses to cyclic strain.	0	10	Rescue	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	ILK	expression of wild-type ILK	ilk	ILK	ILK	ilk	9	10	2	3
Overexpression of ILK in epithelial cells leads to enhanced anchorage independent cell growth , cell cycle progression , and constitutive up-regulation of cyclin D1 and cyclin A , suggesting ILK to be a proto-oncogene .	Overexpression of ILK in epithelial cells leads to enhanced anchorage independent cell growth, cell cycle progression, and constitutive up-regulation of cyclin D1 and cyclin A, suggesting ILK to be a proto-oncogene.	0	33	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	Overexpression of ILK	ilk	ILK	ILK	ilk	2	3	29	30
IL-9 stimulated suppressive function of Tregs in vitro , which provided a mechanistic explanation for more severe EAE , as the lack of IL-9 signaling in IL-9R -/- mice could have resulted in weaker suppressive Treg function , allowing for more robust encephalitogenic responses and consequently exaggerated EAE .	IL-9 stimulated suppressive function of Tregs in vitro, which provided a mechanistic explanation for more severe EAE, as the lack of IL-9 signaling in IL-9R -/- mice could have resulted in weaker suppressive Treg function, allowing for more robust encephalitogenic responses and consequently exaggerated EAE.	23	28	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IL-9	IL-9	IL-9	IL-9R	IL-9R	IL-9R	23	24	26	27
Using hemopoietic cell transfer experiments with recipients that overexpressed IL-9 but were deficient in the IL-9 receptor ( IL-9R ) , we could demonstrate that the effect of IL-9 on lung epithelial cells is indirect and could be fully restored by transfer of hemopoietic cells expressing IL-9R .	Using hemopoietic cell transfer experiments with recipients that overexpressed IL-9 but were deficient in the IL-9 receptor (IL-9R), we could demonstrate that the effect of IL-9 on lung epithelial cells is indirect and could be fully restored by transfer of hemopoietic cells expressing IL-9R.	26	47	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-9	IL-9	IL-9	IL-9R	IL-9R	IL-9R	28	29	46	47
Up-regulation of Nfil3 by IL-3 in BM derived mast cells was used as a positive control .	Up-regulation of Nfil3 by IL-3 in BM derived mast cells was used as a positive control.	0	6	Up-regulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-3	IL-3	IL-3	Nfil3	Nfil3	Nfil3	4	5	2	3
E4bp4 , a member of the basic region and leucine zipper transcription factor superfamily , is up-regulated by the interleukin-3 ( IL-3 ) signaling pathway and plays an important role in the anti-apoptotic response of IL-3 .	E4bp4, a member of the basic region and leucine zipper transcription factor superfamily, is up-regulated by the interleukin-3 (IL-3) signaling pathway and plays an important role in the anti-apoptotic response of IL-3.	0	26	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	interleukin-3	interleukin-3	interleukin-3	E4bp4	E4bp4	E4bp4	19	20	0	1
Similarly , IL-4R signaling has been shown to activate IRS-2 , but when we used mice bearing a point mutation in the IL-4R at the IRS-2 binding site , thus preventing recruitment and activation of IRS-2 by IL-4 without impacting STAT6 activation , recombinant IL-4 continued to inhibit IL-17 expression , demonstrating that IRS-2 activation is not required for suppression of IL-17 ( XREF_SUPPLEMENTARY ) .	Similarly, IL-4R signaling has been shown to activate IRS-2, but when we used mice bearing a point mutation in the IL-4R at the IRS-2 binding site, thus preventing recruitment and activation of IRS-2 by IL-4 without impacting STAT6 activation, recombinant IL-4 continued to inhibit IL-17 expression, demonstrating that IRS-2 activation is not required for suppression of IL-17 (XREF_SUPPLEMENTARY).	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-4R	IL-4R	IL-4R	IRS-2	IRS-2	IRS-2	2	3	9	10
We therefore hypothesized that PP2A inhibition would enhance insulin stimulated Akt activity and decrease glucose production .	We therefore hypothesized that PP2A inhibition would enhance insulin stimulated Akt activity and decrease glucose production.	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Insulin and IGF-1 receptors activate Akt to a similar extent , whereas GSK-3 inactivation in response to IGF-1 is considerably lower in both -/- and WT cells , compared to the effect of insulin in WT cells .	Insulin and IGF-1 receptors activate Akt to a similar extent, whereas GSK-3 inactivation in response to IGF-1 is considerably lower in both -/- and WT cells, compared to the effect of insulin in WT cells.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
Students will be fascinated to learn that the same kinase ( Akt ) that is activated by insulin to enhance cellular glucose uptake is also activated in most cancers .	Students will be fascinated to learn that the same kinase (Akt) that is activated by insulin to enhance cellular glucose uptake is also activated in most cancers.	9	18	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	11	12
Therefore , we investigated whether exposing L6 myotubes to SR141716 would abrogate the effects of CB1 activation on insulin stimulated PKB and ERK1/2 activation .	Therefore, we investigated whether exposing L6 myotubes to SR141716 would abrogate the effects of CB1 activation on insulin stimulated PKB and ERK1/2 activation.	11	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	18	19	20	21
These observations led us to formulate a model in which FGF modulates Akt activation through a mechanism distinct from insulin stimulated Akt activation and sensitive to CAPE activity ( XREF_FIG ) .	These observations led us to formulate a model in which FGF modulates Akt activation through a mechanism distinct from insulin stimulated Akt activation and sensitive to CAPE activity (XREF_FIG).	19	27	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
The activation of insulin and insulin like growth factor signaling stimulates two major kinase cascades : the PI3K and AKT pathway and MAPK and ERK pathways 5 .	The activation of insulin and insulin like growth factor signaling stimulates two major kinase cascades : the PI3K and AKT pathway and MAPK and ERK pathways 5.	1	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	19	20
Consistent with the hepatic and peripheral insulin sensitizing effects of rFGF1 , insulin stimulated AKT signaling was enhanced in both the liver and muscle of chronic rFGF1 treated DIO mice ( XREF_FIG ) .	Consistent with the hepatic and peripheral insulin sensitizing effects of rFGF1, insulin stimulated AKT signaling was enhanced in both the liver and muscle of chronic rFGF1 treated DIO mice (XREF_FIG).	12	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	14	15
In parallel , the activation of PI3K/Akt/mTOR is reported to cause insulin receptor substrate 1 ( IRS1 ) inhibition , disabling normal activation of PI3K and Akt by insulin , IGF-1 and other growth factors .	In parallel, the activation of PI3K/Akt/mTOR is reported to cause insulin receptor substrate 1 (IRS1) inhibition, disabling normal activation of PI3K and Akt by insulin, IGF-1 and other growth factors.	22	30	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	26	27
Here , we show that acute deletion of hepatic Phd3 , also known as Egln3 , improves insulin sensitivity and ameliorates diabetes by specifically stabilizing Hif-2alpha , which then increases Irs2 transcription and insulin stimulated Akt activation .	Here, we show that acute deletion of hepatic Phd3, also known as Egln3, improves insulin sensitivity and ameliorates diabetes by specifically stabilizing Hif-2alpha, which then increases Irs2 transcription and insulin stimulated Akt activation.	31	36	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	33	34	35	36
Thus , Gab1 acts to attenuate , through promotion of the Erk pathway , insulin elicited signals flowing through IRS and Akt proteins , which represents a novel balancing mechanism for control of insulin signal strength in the liver .	Thus, Gab1 acts to attenuate, through promotion of the Erk pathway, insulin elicited signals flowing through IRS and Akt proteins, which represents a novel balancing mechanism for control of insulin signal strength in the liver.	14	22	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	21	22
In contrast , Akti only modestly inhibited insulin induced PKB and mTOR ( mammalian target of rapamycin ) signalling , with little or no effect on glucose uptake and protein synthesis .	In contrast, Akti only modestly inhibited insulin induced PKB and mTOR (mammalian target of rapamycin) signalling, with little or no effect on glucose uptake and protein synthesis.	7	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	7	8	9	10
As a control , we found that there was no effect on the activation of Akt by insulin in cells expressing the mTOR AAA mutant ( XREF_FIG ) , indicating that mTOR polyubiquitination selectively affects mTORC1 , but not mTORC2 , activity .	As a control, we found that there was no effect on the activation of Akt by insulin in cells expressing the mTOR AAA mutant (XREF_FIG), indicating that mTOR polyubiquitination selectively affects mTORC1, but not mTORC2, activity.	8	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	15	16
In conclusion , as in the slow-twitch soleus muscle , adrenaline potentiates insulin stimulated PKB activation in the fast-twitch glycolytic epitrochlearis muscle without increasing IRS-1-associated PI 3-kinase activity .	In conclusion, as in the slow-twitch soleus muscle, adrenaline potentiates insulin stimulated PKB activation in the fast-twitch glycolytic epitrochlearis muscle without increasing IRS-1-associated PI 3-kinase activity.	11	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	12	13	14	15
Using HepG2 hepatoma cells , one study showed that p110beta inhibition by TGX-221 decreased insulin stimulated Akt activation [ XREF_BIBR ] , while a second study suggested that p110alpha is required but is not sufficient to mediate insulin signaling ; the combinational inhibition of p110alpha and p110beta or p110alpha and p110delta , but not inhibition of p110alpha alone , attenuated insulin signaling [ XREF_BIBR ] .	Using HepG2 hepatoma cells, one study showed that p110beta inhibition by TGX-221 decreased insulin stimulated Akt activation [XREF_BIBR], while a second study suggested that p110alpha is required but is not sufficient to mediate insulin signaling; the combinational inhibition of p110alpha and p110beta or p110alpha and p110delta, but not inhibition of p110alpha alone, attenuated insulin signaling [XREF_BIBR].	13	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
In the skeletal muscle of young SMLPL -/- mice , insulin signaling at the level of Akt was increased , suggesting that LPL derived lipids influence both basal and insulin stimulated Akt activation .	In the skeletal muscle of young SMLPL -/- mice, insulin signaling at the level of Akt was increased, suggesting that LPL derived lipids influence both basal and insulin stimulated Akt activation.	27	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	31	32
PGE ( 2 ) might contribute to hepatic insulin resistance via an EP3-receptor-dependent ERK1/2 activation resulting in a serine phosphorylation of insulin receptor substrate , thereby preventing an insulin dependent activation of Akt and glycogen synthesis .	PGE (2) might contribute to hepatic insulin resistance via an EP3-receptor-dependent ERK1/2 activation resulting in a serine phosphorylation of insulin receptor substrate, thereby preventing an insulin dependent activation of Akt and glycogen synthesis.	28	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	32	33
To confirm PTEN knockout in our mice , a dose response curve for insulin stimulated PKB Thr 308 phosphorylation was performed .	To confirm PTEN knockout in our mice, a dose response curve for insulin stimulated PKB Thr 308 phosphorylation was performed.	11	16	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	13	14	15	16
These phenotypes result from attenuation of Akt signaling driven by mTORC1 dependent insulin resistance .	These phenotypes result from attenuation of Akt signaling driven by mTORC1 dependent insulin resistance.	6	13	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	6	7
Briefly , upon insulin binding to its receptor , early steps in the insulin signaling cascade ( i.e ., insulin receptor [ IR ] , insulin receptor substrate 1 [ IRS-1 ] , and phosphoinositide 3-kinase [ PI3K ] ) are activated , resulting in the activation of PKB ( XREF_FIG ) .	Briefly, upon insulin binding to its receptor, early steps in the insulin signaling cascade (i.e., insulin receptor [IR], insulin receptor substrate 1 [IRS-1], and phosphoinositide 3-kinase [PI3K]) are activated, resulting in the activation of PKB (XREF_FIG).	13	50	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	13	14	48	49
That insulin mediated induction of AKT signaling plays a crucial role in neural differentiation of hESCs and hiPSCs , was confirmed in by removing insulin from the medium and using an Akt inhibitor ( VIII ) during the first 5 days of the protocol 18 .	That insulin mediated induction of AKT signaling plays a crucial role in neural differentiation of hESCs and hiPSCs, was confirmed in by removing insulin from the medium and using an Akt inhibitor (VIII) during the first 5 days of the protocol 18.	0	7	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	1	2	5	6
In particular , insulin and IGF -1 strongly activates AKT and PKB to promote BAD phosphorylation and its association with 14-3-3 , which releases Bcl-2 to inhibit apoptosis [ XREF_BIBR ] .	In particular, insulin and IGF -1 strongly activates AKT and PKB to promote BAD phosphorylation and its association with 14-3-3, which releases Bcl-2 to inhibit apoptosis [XREF_BIBR].	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	11	12
There was no significant difference in basal or insulin stimulated Akt activity between EtOH exposed rats and controls .	There was no significant difference in basal or insulin stimulated Akt activity between EtOH exposed rats and controls.	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
We also tested the effect of the compounds on downstream signaling ; using a phospho specific antibody that recognizes the phosphorylation of Thr308 in AKT , we observed that chelerythrine enhanced insulin induced activation of AKT .	We also tested the effect of the compounds on downstream signaling; using a phospho specific antibody that recognizes the phosphorylation of Thr308 in AKT, we observed that chelerythrine enhanced insulin induced activation of AKT.	31	36	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	31	32	35	36
However , knockdown of BMAL1 in isolated hepatocytes decreases insulin stimulated AKT activation ( which would promote , not attenuate , gluconeogenesis ) .	However, knockdown of BMAL1 in isolated hepatocytes decreases insulin stimulated AKT activation (which would promote, not attenuate, gluconeogenesis).	8	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	11	12
Akt is activated by insulin and various growth and survival factors .	Akt is activated by insulin and various growth and survival factors.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
Treatment of mouse hepatocytes with p85alpha antisense oligonucleotide caused a reduction of p85alpha and an increase in p50alpha and p55alpha isoforms and enhanced insulin stimulated PKB activation .	Treatment of mouse hepatocytes with p85alpha antisense oligonucleotide caused a reduction of p85alpha and an increase in p50alpha and p55alpha isoforms and enhanced insulin stimulated PKB activation.	22	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	23	24	25	26
Rictor deficiency prevents mTORC2 assembly and this causes a dramatic reduction of insulin mediated Akt S 473 phosphorylation in macrophages .	Rictor deficiency prevents mTORC2 assembly and this causes a dramatic reduction of insulin mediated Akt S 473 phosphorylation in macrophages.	10	15	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	14	15
Further study revealed that miR-291b-3p suppressed insulin stimulated AKT and GSK signaling and increased the expression of gluconeogenic genes in hepatocytes .	Further study revealed that miR-291b-3p suppressed insulin stimulated AKT and GSK signaling and increased the expression of gluconeogenic genes in hepatocytes.	5	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	8	9
Our results indicate that cardiac contractile dysfunction caused by a defect in insulin stimulated Akt and GLUT4 may be a major reason for the high mortality rate in I/R injured diabetic rats .	Our results indicate that cardiac contractile dysfunction caused by a defect in insulin stimulated Akt and GLUT4 may be a major reason for the high mortality rate in I/R injured diabetic rats.	10	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	14	15
Hepatocytes and liver tissue demonstrated normal insulin stimulation of Akt ( Supplemental FigureS4 ) .	Hepatocytes and liver tissue demonstrated normal insulin stimulation of Akt (Supplemental FigureS4).	6	12	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	9	10
We previously identified the insulin response element binding protein-1 ( IRE-BP1 ) as an effector of insulin induced Akt signaling in the liver , and showed that the 50-kDa carboxyl fragment confers the transcriptional activity of this factor .	We previously identified the insulin response element binding protein-1 (IRE-BP1) as an effector of insulin induced Akt signaling in the liver, and showed that the 50-kDa carboxyl fragment confers the transcriptional activity of this factor.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
The main signaling pathway controlling mTORC1 is the PI3 kinase and Akt pathway activated by the binding of growth factors or insulin to their cell surface receptors .	The main signaling pathway controlling mTORC1 is the PI3 kinase and Akt pathway activated by the binding of growth factors or insulin to their cell surface receptors.	11	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	11	12
Insulin induced Akt activation elicits Akt ' s phosphorylation of the transcription factor forkhead box protein 1 ( FoxO1 ) to suppress the expression of orexigenic neuropeptides .	Insulin induced Akt activation elicits Akt 's phosphorylation of the transcription factor forkhead box protein 1 (FoxO1) to suppress the expression of orexigenic neuropeptides.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
In addition , the PI3K and AKT activation by insulin is associated with translocation of glucose transporter type 4 ( GLUT4 ) [ XREF_BIBR ] .	In addition, the PI3K and AKT activation by insulin is associated with translocation of glucose transporter type 4 (GLUT4) [XREF_BIBR].	4	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	6	7
Tpm3.1 does not affect insulin stimulated Akt signaling .	Tpm3.1 does not affect insulin stimulated Akt signaling.	3	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Treatment of vascular endothelial cells with FFA impairs insulin stimulated activation of PI3K , PDK1 , Akt and eNOS [ XREF_BIBR - XREF_BIBR ] .	Treatment of vascular endothelial cells with FFA impairs insulin stimulated activation of PI3K, PDK1, Akt and eNOS [XREF_BIBR - XREF_BIBR].	7	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	16	17
Insulin potently activated Akt ( also called protein kinase B ) in AT/RT cells , as compared with other growth factors , such as epidermal growth factor .	Insulin potently activated Akt (also called protein kinase B) in AT/RT cells, as compared with other growth factors, such as epidermal growth factor.	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
Insulin resistance and glucose intolerance were associated with reduced protein expression of IRS-1 and IRS-2 as well as reduced insulin induced activation of phosphatidylinositol 3-kinase and Akt .	Insulin resistance and glucose intolerance were associated with reduced protein expression of IRS-1 and IRS-2 as well as reduced insulin induced activation of phosphatidylinositol 3-kinase and Akt.	0	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	26	27
Consistent with a progressive deterioration of insulin sensitivity upon prolonged HFD feeding in IL-6Ralpha T-KO mice , the insulin stimulated activation of tissue Akt , as detected by pS473 Akt , became comparable between IL-6Ralpha T-KO and control mice ( XREF_FIG ) .	Consistent with a progressive deterioration of insulin sensitivity upon prolonged HFD feeding in IL-6Ralpha T-KO mice, the insulin stimulated activation of tissue Akt, as detected by pS473 Akt, became comparable between IL-6Ralpha T-KO and control mice (XREF_FIG).	17	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	23	24
Variant TRIB3 , a protein known to regulate insulin dependent signaling to Akt , is associated with early-onset myocardial infarction ( MI ) in patients with Type 2 diabetes [ XREF_BIBR ] .	Variant TRIB3, a protein known to regulate insulin dependent signaling to Akt, is associated with early-onset myocardial infarction (MI) in patients with Type 2 diabetes [XREF_BIBR].	8	13	signaling	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	12	13
Insulin induced Akt activation signal was then analyzed by Western blotting .	Insulin induced Akt activation signal was then analyzed by Western blotting.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
As in murine cells , rapamycin treatment of human adipocytes inhibited S6K1 , blunted Ser636/639 phosphorylation of IRS-1 , leading to increased Akt activation and glucose uptake by insulin .	As in murine cells, rapamycin treatment of human adipocytes inhibited S6K1, blunted Ser636/639 phosphorylation of IRS-1, leading to increased Akt activation and glucose uptake by insulin.	22	29	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	22	23
T H 1 treatment also caused significant reductions in insulin stimulated P-Akt ( XREF_SUPPLEMENTARY ) , suggesting insulin resistance , in C2C12 myocytes .	T H 1 treatment also caused significant reductions in insulin stimulated P-Akt (XREF_SUPPLEMENTARY), suggesting insulin resistance, in C2C12 myocytes.	5	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	P-Akt	P-Akt	P-Akt	9	10	11	12
Insulin also activates phosphatidylinositol-4 ,5-bisphosphate 3-kinase ( PI3K ) - protein kinase B ( Akt ) signaling , which has been shown to be protective against both aminoglycoside and cisplatin ototoxicity , potentially through activation of pro survival MAPK signaling and/or inactivation or downregulation of pro apoptotic proteins .	Insulin also activates phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) - protein kinase B (Akt) signaling, which has been shown to be protective against both aminoglycoside and cisplatin ototoxicity, potentially through activation of pro survival MAPK signaling and/or inactivation or downregulation of pro apoptotic proteins.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	14	15
Insulin induced Akt activation is dose and time dependent in the PNS .	Insulin induced Akt activation is dose and time dependent in the PNS.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
These results indicate that PHLDB1 is a novel modulator of Akt protein kinase activation by insulin .	These results indicate that PHLDB1 is a novel modulator of Akt protein kinase activation by insulin.	10	16	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	10	11
In particular , we previously reported that IPMK is an essential protein for activation of the Akt and mTOR pathway as a genetic deletion of IPMK abolished either insulin or nutrients mediated Akt and mTOR signaling .	In particular, we previously reported that IPMK is an essential protein for activation of the Akt and mTOR pathway as a genetic deletion of IPMK abolished either insulin or nutrients mediated Akt and mTOR signaling.	26	35	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	32	33
From the PCA results , we identified the ratio of pAktS473 to Akt fluorescence after cells had been treated with insulin as the index that distinguished most between HWT and HDb cells .	From the PCA results, we identified the ratio of pAktS473 to Akt fluorescence after cells had been treated with insulin as the index that distinguished most between HWT and HDb cells.	12	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	12	13
Insulin stimulated pS473akt and PKB in the presence of either 5 or 50n insulin increased following chronic Dex treatment , without changing the total akt and PKB protein levels ( XREF_FIG ) .	Insulin stimulated pS473akt and PKB in the presence of either 5 or 50n insulin increased following chronic Dex treatment, without changing the total akt and PKB protein levels (XREF_FIG).	0	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	4	5
GLUT-4 is a glucose transporter whose translocation to the plasma membrane is regulated by insulin stimulated Akt signaling .	GLUT-4 is a glucose transporter whose translocation to the plasma membrane is regulated by insulin stimulated Akt signaling.	12	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
Tunicamycin significantly impaired insulin stimulated IRS1 Tyr 612 and Akt Thr 308 phosphorylation by 67 % and 27 % , respectively ( XREF_FIG ) .	Tunicamycin significantly impaired insulin stimulated IRS1 Tyr 612 and Akt Thr 308 phosphorylation by 67% and 27%, respectively (XREF_FIG).	0	22	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	9	10
Insulin and trophic factor induction of neuroprotective Akt activity is elevated by DHA via increases in phosphatidylserine regulated membrane docking and Akt activation [ XREF_BIBR ] .	Insulin and trophic factor induction of neuroprotective Akt activity is elevated by DHA via increases in phosphatidylserine regulated membrane docking and Akt activation [XREF_BIBR].	0	8	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	7	8
To assess the effect of HCV infection on insulin sensitivity , we examined the phosphorylation status of Akt and GSK3beta induced by insulin stimulation .	To assess the effect of HCV infection on insulin sensitivity, we examined the phosphorylation status of Akt and GSK3beta induced by insulin stimulation.	15	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	17	18
We have recently shown that liver specific ablation of p110beta had little effect on insulin stimulation of Akt and PKB and showed only very mildly impaired insulin sensitivity and glucose tolerance .	We have recently shown that liver specific ablation of p110beta had little effect on insulin stimulation of Akt and PKB and showed only very mildly impaired insulin sensitivity and glucose tolerance.	14	20	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	14	15	19	20
We further showed that insulin , but not amino acids , increases PKB activation and decreased TSC2 activation .	We further showed that insulin, but not amino acids, increases PKB activation and decreased TSC2 activation.	4	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	12	13
117 Akt is predominantly cytosolic and is activated through phosphorylation by insulin , insulin like growth factor-1 , and also erythropoietin .	117 Akt is predominantly cytosolic and is activated through phosphorylation by insulin, insulin like growth factor-1, and also erythropoietin.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	1	2
In addition , recombinant IL-6 and exercise restored insulin induced Akt and leptin induced and STAT-3 phosphorylation in the hypothalamus of obese animals ( XREF_SUPPLEMENTARY ) .	In addition, recombinant IL-6 and exercise restored insulin induced Akt and leptin induced and STAT-3 phosphorylation in the hypothalamus of obese animals (XREF_SUPPLEMENTARY).	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Treatment with high insulin downregulates insulin binding capacity and , when combined with high glucose , it produces a marked depletion of IRS-1 and -2 content together with an impaired sensitivity to insulin stimulation of PKB activity .	Treatment with high insulin downregulates insulin binding capacity and, when combined with high glucose, it produces a marked depletion of IRS-1 and -2 content together with an impaired sensitivity to insulin stimulation of PKB activity.	32	36	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	32	33	35	36
The expression patterns of miR-27a varied with hyperglycemia in the Gyoto-Kakizaki rat [ XREF_BIBR ] , and miRNA-143 overexpression inhibited insulin stimulated AKT activation and resulted in impaired glucose metabolism [ XREF_BIBR ] .	The expression patterns of miR-27a varied with hyperglycemia in the Gyoto-Kakizaki rat [XREF_BIBR], and miRNA-143 overexpression inhibited insulin stimulated AKT activation and resulted in impaired glucose metabolism [XREF_BIBR].	19	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	22	23
Although insulin acutely activated Akt in the absence of IR-B to translate into a proliferative signal , it may need a more sustained signal .	Although insulin acutely activated Akt in the absence of IR-B to translate into a proliferative signal, it may need a more sustained signal.	1	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	4	5
Insulin and IGF1 activated Akt to phosphorylate GSK3B at serine 9 , thus inhibiting GSK3B activity .	Insulin and IGF1 activated Akt to phosphorylate GSK3B at serine 9, thus inhibiting GSK3B activity.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
These observations suggest that SGK1 regulates GLUT1 and may contribute to or account for the PI3 kinase dependent but PKB independent stimulation of GLUT1 by insulin .	These observations suggest that SGK1 regulates GLUT1 and may contribute to or account for the PI3 kinase dependent but PKB independent stimulation of GLUT1 by insulin.	19	26	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	25	26	19	20
Cultured 3T3-L1 adipocytes silenced for Ecscr , and ex vivo adipocytes from Ecscr -/- mice , showed reduced basal and insulin stimulated AKT activation and excess lipid release .	Cultured 3T3-L1 adipocytes silenced for Ecscr, and ex vivo adipocytes from Ecscr -/- mice, showed reduced basal and insulin stimulated AKT activation and excess lipid release.	20	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	22	23
Expression of DNSHP-1 increased insulin induced Akt serine threonine kinase phosphorylation and augmented glucose uptake and glycogen synthesis .	Expression of DNSHP-1 increased insulin induced Akt serine threonine kinase phosphorylation and augmented glucose uptake and glycogen synthesis.	4	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
When a saponin rich fraction of the pressed cake was extracted with 100 % methanol ( B2 extract ) , a more potent stimulatory effect on insulin induced Akt activation was uncovered and modulation of ERK1/2 was lost .	When a saponin rich fraction of the pressed cake was extracted with 100% methanol (B2 extract), a more potent stimulatory effect on insulin induced Akt activation was uncovered and modulation of ERK1/2 was lost.	24	29	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	28	29
Note that insulin activation of both aPKC and Akt normally leads to increases in their association with scaffold protein , WD40 and ProF ; however , in livers of DIO mice , excess accumulation of aPKC diminishes Akt association with WD40 and ProF .	Note that insulin activation of both aPKC and Akt normally leads to increases in their association with scaffold protein, WD40 and ProF; however, in livers of DIO mice, excess accumulation of aPKC diminishes Akt association with WD40 and ProF.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	8	9
In contrast , the pituitary and ovary exhibited elevated basal levels of pAKT and were not resistant to insulin activation of AKT in the DIO mice ( XREF_FIG ) .	In contrast, the pituitary and ovary exhibited elevated basal levels of pAKT and were not resistant to insulin activation of AKT in the DIO mice (XREF_FIG).	18	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	18	19	21	22
Insulin stimulation further induces the dissociation of IRS proteins and Akt from the APPL1-IR complex , facilitating the binding of IRS1/2 to the activated IR near the plasma membrane .	Insulin stimulation further induces the dissociation of IRS proteins and Akt from the APPL1-IR complex, facilitating the binding of IRS1/2 to the activated IR near the plasma membrane.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	10	11
In summary , we report evidence indicating that the acute infusion of insulin activated the PI3K-Akt pathway and reduced IKK/IkappaB/NF-kappaB indicate an important molecular mechanism to the anti-inflammatory effect of the hormone in liver , muscle and adipose tissue of septic animals .	In summary, we report evidence indicating that the acute infusion of insulin activated the PI3K-Akt pathway and reduced IKK/IkappaB/NF-kappaB indicate an important molecular mechanism to the anti-inflammatory effect of the hormone in liver, muscle and adipose tissue of septic animals.	10	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	12	13	15	16
Insulin activated the PI3K and AKT pathway , but not the mitogen activated protein kinase pathway in the DE cells , and inhibition of the PI3K and AKT pathways by inhibitors markedly inhibited hepatocyte differentiation .	Insulin activated the PI3K and AKT pathway, but not the mitogen activated protein kinase pathway in the DE cells, and inhibition of the PI3K and AKT pathways by inhibitors markedly inhibited hepatocyte differentiation.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	5	6
Insulin can activate the PI3K-Akt pathway and counteract oxidative stress , likely by increasing NO release [ XREF_BIBR - XREF_BIBR ] .	Insulin can activate the PI3K-Akt pathway and counteract oxidative stress, likely by increasing NO release [XREF_BIBR - XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	4	5
In contrast , phosphatidylinositol 3-kinase ( PI 3-kinase ) and protein kinase B ( PKB ) activation by insulin and HGF is strong and sustained , whereas it is weak and transient with EGF and absent in the presence of TSH or PMA .	In contrast, phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (PKB) activation by insulin and HGF is strong and sustained, whereas it is weak and transient with EGF and absent in the presence of TSH or PMA.	14	20	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	18	19	14	15
Akt is activated by insulin and insulin like growth factor 1 ( IGF-1 ) , and the forced transgenic or pharmacologic induction of Akt in vivo or in vitro is sufficient to cause dramatic muscle hypertrophy and inhibit atrophy [ XREF_BIBR - XREF_BIBR ] .	Akt is activated by insulin and insulin like growth factor 1 (IGF-1), and the forced transgenic or pharmacologic induction of Akt in vivo or in vitro is sufficient to cause dramatic muscle hypertrophy and inhibit atrophy [XREF_BIBR - XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
One major signaling component in the myogenic program is Akt , which is activated by insulin and IGF stimulation , and its activity is critical for both myoblast proliferation and differentiation .	One major signaling component in the myogenic program is Akt, which is activated by insulin and IGF stimulation, and its activity is critical for both myoblast proliferation and differentiation.	3	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	9	10
Following trauma alone there was no significant change in insulin stimulated P-Akt ( S473 ) .	Following trauma alone there was no significant change in insulin stimulated P-Akt (S473).	7	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	P-Akt	P-Akt	P-Akt	9	10	11	12
Moreover , pretreatment of the L6 cells with wortmannin ( 100nM ) for 20 min significantly reduced gAdp ( 100nM ) induced and insulin ( 100nM ) induced Akt activation by ~ 80 and ~ 70 % , respectively .	Moreover, pretreatment of the L6 cells with wortmannin (100nM) for 20 min significantly reduced gAdp (100nM) induced and insulin (100nM) induced Akt activation by ~ 80 and ~ 70%, respectively.	23	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	28	29
An important finding of our study is that IGF1 and insulin effectively increase and maintain Akt and PKB in its phosphorylated state and concomitantly protect the cells from undergoing apoptosis .	An important finding of our study is that IGF1 and insulin effectively increase and maintain Akt and PKB in its phosphorylated state and concomitantly protect the cells from undergoing apoptosis.	8	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	10	11	17	18
The addition of insulin induced rapid activations of p70S6K and Akt , and the cells were rescued from macroautophagy .	The addition of insulin induced rapid activations of p70S6K and Akt, and the cells were rescued from macroautophagy.	1	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	10	11
Accordingly , the amino acid deprivation increased and the amino acid excess decreased insulin stimulated activation of Akt and 2-DOG uptake .	Accordingly, the amino acid deprivation increased and the amino acid excess decreased insulin stimulated activation of Akt and 2-DOG uptake.	12	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	17	18
It is well known that insulin can activate both PI3K and Akt pathway , which is responsible for glucose uptake , and MAPK pathway , which is crucial for insulin resistance formation .	It is well known that insulin can activate both PI3K and Akt pathway, which is responsible for glucose uptake, and MAPK pathway, which is crucial for insulin resistance formation.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	11	12
In fact , the saturated fatty acids palmitate ( PA ) and stearate ( SA ) , but not their monounsaturated counterparts oleate ( OA ) and palmitoleate ( POA ) , blocks insulin activation of Akt and PKB with concomitant accumulation of ceramide and diacylglycerol ( DAG ) in C2C12 myotubes [ XREF_BIBR ] .	In fact, the saturated fatty acids palmitate (PA) and stearate (SA), but not their monounsaturated counterparts oleate (OA) and palmitoleate (POA), blocks insulin activation of Akt and PKB with concomitant accumulation of ceramide and diacylglycerol (DAG) in C2C12 myotubes [XREF_BIBR].	33	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	33	34	36	37
Together , these observations suggest that , depending on cellular CEM abundance , fatty acid overload can inhibit insulin induced PKB signalling through at least one of two distinct mechanisms .	Together, these observations suggest that, depending on cellular CEM abundance, fatty acid overload can inhibit insulin induced PKB signalling through at least one of two distinct mechanisms.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	18	19	20	21
Previous reports have shown that Ang II is able to modulate insulin stimulated Akt activity and have suggested that this involves increased production of ROS XREF_BIBR , XREF_BIBR , XREF_BIBR .	Previous reports have shown that Ang II is able to modulate insulin stimulated Akt activity and have suggested that this involves increased production of ROS XREF_BIBR, XREF_BIBR, XREF_BIBR.	10	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Consequently , whereas ZAG treatment reduced the levels of phosphorylated AKT , pretreatment with propranolol restored insulin induced activation of AKT in human adipose cells ( XREF_FIG ) .	Consequently, whereas ZAG treatment reduced the levels of phosphorylated AKT, pretreatment with propranolol restored insulin induced activation of AKT in human adipose cells (XREF_FIG).	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	20	21
The presence of testosterone significantly reduced insulin induced AKT activation .	The presence of testosterone significantly reduced insulin induced AKT activation.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	8	9
An approximate physiological concentration of insulin in human plasma ( 60 pM ) did not activate PI3K and AKT in MCF-7 cells ( XREF_SUPPLEMENTARY ) .	An approximate physiological concentration of insulin in human plasma (60 pM) did not activate PI3K and AKT in MCF-7 cells (XREF_SUPPLEMENTARY).	3	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	18	19
Moreover , insulin induced activation of AKT was significantly up-regulated in muscle from the p85beta (-/-) mice .	Moreover, insulin induced activation of AKT was significantly up-regulated in muscle from the p85beta (-/-) mice.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	6	7
Insulin stimulation also leads to a differential Akt activation , implying altered Akt signaling capacity as a result of the K8/K18 loss .	Insulin stimulation also leads to a differential Akt activation, implying altered Akt signaling capacity as a result of the K8/K18 loss.	0	14	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	12	13
Herein we demonstrate that exposing muscle cells to particular saturated free fatty acids ( FFAs ) , but not mono-unsaturated FFAs , inhibits insulin stimulation of Akt and protein kinase B , a serine/threonine kinase that is a central mediator of insulin stimulated anabolic metabolism .	Herein we demonstrate that exposing muscle cells to particular saturated free fatty acids (FFAs), but not mono-unsaturated FFAs, inhibits insulin stimulation of Akt and protein kinase B, a serine/threonine kinase that is a central mediator of insulin stimulated anabolic metabolism.	23	28	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	26	27
This correlated with a progressive increase in hepatic steatosis ( XREF_FIG C-F ) and resistance to insulin induced AKT activation ( XREF_FIG G ) in the knockout animals .	This correlated with a progressive increase in hepatic steatosis (XREF_FIG C-F) and resistance to insulin induced AKT activation (XREF_FIG G) in the knockout animals.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	18	19
It was also revealed that insulin induced AKT activation , GLUT4 translocation to cell membrane and glucose uptake were significantly inhibited in chronic ROS treated 3T3-L1 adipocytes .	It was also revealed that insulin induced AKT activation, GLUT4 translocation to cell membrane and glucose uptake were significantly inhibited in chronic ROS treated 3T3-L1 adipocytes.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
These mutants did not inhibit insulin induced activation of Akt .	These mutants did not inhibit insulin induced activation of Akt.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	9	10
Taken together , the disruptions in obesity that occur in many of the pathways of adipocyte metabolism downstream of insulin activated Akt ( XREF_FIG ) mirror the situation in liver .	Taken together, the disruptions in obesity that occur in many of the pathways of adipocyte metabolism downstream of insulin activated Akt (XREF_FIG) mirror the situation in liver.	16	23	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
Several studies have demonstrated that the PI3K and AKT and RAS/MEK/ERK pathways are extensively stimulated by insulin in PDAC cells .	Several studies have demonstrated that the PI3K and AKT and RAS/MEK/ERK pathways are extensively stimulated by insulin in PDAC cells.	8	19	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	8	9
Further , there was reduced insulin induced Akt activation and increased tumor necrosis factor-alpha levels in vascular smooth muscle cells from Ren2 and Sprague-Dawley rats treated with angiotensin II , abnormalities that were abrogated by angiotensin type 1 receptor blockade with valsartan or antioxidant N-acetylcysteine .	Further, there was reduced insulin induced Akt activation and increased tumor necrosis factor-alpha levels in vascular smooth muscle cells from Ren2 and Sprague-Dawley rats treated with angiotensin II, abnormalities that were abrogated by angiotensin type 1 receptor blockade with valsartan or antioxidant N-acetylcysteine.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
As alluded to above , in rodent models of T2DM , whereas insulin activation of IRS-1 and PI3K and Akt is impaired in muscle and liver , and , whereas insulin activation of aPKC is impaired in muscle , insulin activation of hepatic IRS2 and PI3K and aPKC is conserved or heightened by hyperinsulinemia [ XREF_BIBR , XREF_BIBR ] .	As alluded to above, in rodent models of T2DM, whereas insulin activation of IRS-1 and PI3K and Akt is impaired in muscle and liver, and, whereas insulin activation of aPKC is impaired in muscle, insulin activation of hepatic IRS2 and PI3K and aPKC is conserved or heightened by hyperinsulinemia [XREF_BIBR, XREF_BIBR].	12	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	19	20
Both insulin and contractions activate Akt in skeletal muscle .	Both insulin and contractions activate Akt in skeletal muscle.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	5	6
Together , these data suggest that insulin activates the protein kinase Akt to directly phosphorylate the RGC , which produces a conformational change in the complex that decreases its access to RalA , resulting in increased activity of the G protein .	Together, these data suggest that insulin activates the protein kinase Akt to directly phosphorylate the RGC, which produces a conformational change in the complex that decreases its access to RalA, resulting in increased activity of the G protein.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	11	12
Instead , our observations support the notion that SR141716 acts to potentiate insulin stimulated PKB activity and because this enhancement in PKB activation is not observed in cells where CB1 expression has been silenced ( XREF_FIG ) , it implicates a role for the CB1 receptor in this sensitization .	Instead, our observations support the notion that SR141716 acts to potentiate insulin stimulated PKB activity and because this enhancement in PKB activation is not observed in cells where CB1 expression has been silenced (XREF_FIG), it implicates a role for the CB1 receptor in this sensitization.	11	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	12	13	14	15
Ceramide treatment blunted Akt activity but not PI 3-kinase activity , and insulin and EGF were unable to activate Akt .	Ceramide treatment blunted Akt activity but not PI 3-kinase activity, and insulin and EGF were unable to activate Akt.	12	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	19	20
MGO prevented the insulin dependent activation of the IRS1 and protein kinase Akt and endothelial nitric oxide synthase ( eNOS ) pathway , thereby blunting nitric oxide ( NO ) production , while extracellular signal regulated kinase ( ERK1/2 ) activation and endothelin-1 ( ET-1 ) release were increased by MGO in MAECs .	MGO prevented the insulin dependent activation of the IRS1 and protein kinase Akt and endothelial nitric oxide synthase (eNOS) pathway, thereby blunting nitric oxide (NO) production, while extracellular signal regulated kinase (ERK1/2) activation and endothelin-1 (ET-1) release were increased by MGO in MAECs.	3	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	12	13
In addition , Akt activation by serum and insulin is also inhibited by W-7 .	In addition, Akt activation by serum and insulin is also inhibited by W-7.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	3	4
Thus , insulin signaling in liver bifurcates in insulin resistant states , and this bifurcation at least partly explains how insulin activation of aPKC is conserved or excessive at the same time that insulin activation of hepatic Akt is impaired in diabetic liver [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Thus, insulin signaling in liver bifurcates in insulin resistant states, and this bifurcation at least partly explains how insulin activation of aPKC is conserved or excessive at the same time that insulin activation of hepatic Akt is impaired in diabetic liver [XREF_BIBR, XREF_BIBR, XREF_BIBR].	33	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	33	34	37	38
Interestingly , in non skeletal muscle cell lines that have normal insulin regulated Akt activation , SIRT2 , but not SIRT1 , bound strongly to Akt and appeared to negatively regulate insulin stimulated Akt activation .	Interestingly, in non skeletal muscle cell lines that have normal insulin regulated Akt activation, SIRT2, but not SIRT1, bound strongly to Akt and appeared to negatively regulate insulin stimulated Akt activation.	30	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	33	34
Mechanistically , we found that the preventive role of HT on Abeta ( 25-35 ) - induced cytotoxicity in astrocytes is moderated by an increased HT induced activation of Akt , which is mediated by the insulin signaling pathway .	Mechanistically, we found that the preventive role of HT on Abeta (25-35) - induced cytotoxicity in astrocytes is moderated by an increased HT induced activation of Akt, which is mediated by the insulin signaling pathway.	27	38	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	36	37	29	30
In liver , insulin increased the activation of IR , IRS-1 , PI 3-kinase , PKB and S6 , but had no effect on protein synthesis .	In liver, insulin increased the activation of IR, IRS-1, PI 3-kinase, PKB and S6, but had no effect on protein synthesis.	3	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	15	16
We found that insulin induced hepatic P-Akt was completely lost in animals at all three ages studied ( 3-, 6-, and 10-weeks old ) 90 min following trauma and hemorrhage ( TH90 ' ; XREF_FIG ) .	We found that insulin induced hepatic P-Akt was completely lost in animals at all three ages studied (3-, 6-, and 10-weeks old) 90 min following trauma and hemorrhage (TH90 '; XREF_FIG).	3	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	P-Akt	P-Akt	P-Akt	3	4	6	7
shRNA was used to downregulate the IR in both cell lines , and cells with reduced IR activity had decreased insulin stimulated Akt activation , with normal IGF-IR function .	shRNA was used to downregulate the IR in both cell lines, and cells with reduced IR activity had decreased insulin stimulated Akt activation, with normal IGF-IR function.	19	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
Insulin related activation of endothelial Akt and NO production led to reduction of sympathetic nerve activity , activation of ATP dependent K+ channels and release of vasodilator adenosine , resulting in vasodilation [ XREF_BIBR , XREF_BIBR ] , thereby increasing blood flow and cell survival [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Insulin related activation of endothelial Akt and NO production led to reduction of sympathetic nerve activity, activation of ATP dependent K+ channels and release of vasodilator adenosine, resulting in vasodilation [XREF_BIBR, XREF_BIBR], thereby increasing blood flow and cell survival [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
Interestingly , the co-treatment of insulin and curcumin produced a mutual synergistic activation of both AMPK and ACC and PI3-kinase and Akt pathways .	Interestingly, the co-treatment of insulin and curcumin produced a mutual synergistic activation of both AMPK and ACC and PI3-kinase and Akt pathways.	3	22	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	21	22
We next set out to uncover the underlying mechanism of thistemporarily enhanced insulin induced Akt signaling , using primary mouse hepatocytes as a cell based model .	We next set out to uncover the underlying mechanism of thistemporarily enhanced insulin induced Akt signaling, using primary mouse hepatocytes as a cell based model.	8	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	14	15
In Drosophila S2 cells F-actin rich lamellapodia are also being formed in response to insulin induced Akt signaling XREF_BIBR .	In Drosophila S2 cells F-actin rich lamellapodia are also being formed in response to insulin induced Akt signaling XREF_BIBR.	10	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
It would be premature to suggest this fully defines the outcome of miR-143 expression levels , since it was up-regulated in the liver of T2DM obese mouse models , where it also impaired glucose metabolism , but through induction of insulin resistance via miR-143-ORP8-dependent inhibition of insulin stimulated AKT activation [ XREF_BIBR ] .	It would be premature to suggest this fully defines the outcome of miR-143 expression levels, since it was up-regulated in the liver of T2DM obese mouse models, where it also impaired glucose metabolism, but through induction of insulin resistance via miR-143-ORP8-dependent inhibition of insulin stimulated AKT activation [XREF_BIBR].	44	49	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	46	47	48	49
The increase of iNOS expression paralleled the increase of insulin resistance , as evidenced by decreased tyrosine phosphorylation of IR and IRS-1 , IRS-1 expression , insulin stimulated activation of phosphatidylinositol 3-kinase and Akt and PKB , and insulin stimulated glucose uptake in mouse skeletal muscle .	The increase of iNOS expression paralleled the increase of insulin resistance, as evidenced by decreased tyrosine phosphorylation of IR and IRS-1, IRS-1 expression, insulin stimulated activation of phosphatidylinositol 3-kinase and Akt and PKB, and insulin stimulated glucose uptake in mouse skeletal muscle.	26	35	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	33	34
In agreement with enhanced phosphorylation of IR , IRS-1 , and IRS-2 , and their association with p85 PI3K , insulin stimulated Akt activation , as revealed by phosphorylation on residues S473 and T308 , was increased in Ptpn6 H-KO livers compared with that of Ptpn6 f/f counterparts .	In agreement with enhanced phosphorylation of IR, IRS-1, and IRS-2, and their association with p85 PI3K, insulin stimulated Akt activation, as revealed by phosphorylation on residues S473 and T308, was increased in Ptpn6 H-KO livers compared with that of Ptpn6 f/f counterparts.	20	23	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
This beneficial effect of p110alpha inactivation derives in part from a suppressed down-regulation of insulin receptor substrate ( IRS ) protein levels induced by age related hyperinsulinemia , and correlates with enhanced insulin induced Akt signalling in aged p110alpha deficient mice .	This beneficial effect of p110alpha inactivation derives in part from a suppressed down-regulation of insulin receptor substrate (IRS) protein levels induced by age related hyperinsulinemia, and correlates with enhanced insulin induced Akt signalling in aged p110alpha deficient mice.	29	35	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	32	33	34	35
The results showed that Akt phosphorylation was increased in SK-Hep-1 cells treated with insulin in a time- and concentration dependent manner , which was inhibited by saturated fatty acids , but not by unsaturated fatty acids .	The results showed that Akt phosphorylation was increased in SK-Hep-1 cells treated with insulin in a time- and concentration dependent manner, which was inhibited by saturated fatty acids, but not by unsaturated fatty acids.	4	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	4	5
We documented the HFCS induced alteration in the insulin signal transduction pathway , as shown by the impaired phosphorylation of IRS-1 protein as well as of the downstream key insulin signaling molecules , Akt , and GSK-3beta , an Akt substrate [ XREF_BIBR ] .	We documented the HFCS induced alteration in the insulin signal transduction pathway, as shown by the impaired phosphorylation of IRS-1 protein as well as of the downstream key insulin signaling molecules, Akt, and GSK-3beta, an Akt substrate [XREF_BIBR].	4	34	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	33	34
This notion was supported by a mouse study which showed that for PIK3R1 +/- mouse ( one allele loss of PIK3R1 ) , despite the decrease in p85alpha protein level , PI3-kinase activation was normal , and insulin stimulated Akt activity was in fact increased .	This notion was supported by a mouse study which showed that for PIK3R1 +/- mouse (one allele loss of PIK3R1), despite the decrease in p85alpha protein level, PI3-kinase activation was normal, and insulin stimulated Akt activity was in fact increased.	37	40	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	37	38	39	40
Although it has been reported that mTOR may contribute to Akt ( Ser 473 ) phosphorylation , XREF_BIBR inhibiting mTOR with rapamycin did not significantly impact Akt or AS160 phosphorylation in cells treated with either insulin or BFA .	Although it has been reported that mTOR may contribute to Akt (Ser 473) phosphorylation, XREF_BIBR inhibiting mTOR with rapamycin did not significantly impact Akt or AS160 phosphorylation in cells treated with either insulin or BFA.	22	37	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	35	36	26	27
The activation of protein kinase B ( PKB , also known as c-Akt ) is stimulated by insulin or growth factors and results from its phosphorylation at Thr308 and Ser473 .	The activation of protein kinase B (PKB, also known as c-Akt) is stimulated by insulin or growth factors and results from its phosphorylation at Thr308 and Ser473.	1	20	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	17	18	7	8
Tribbles is a Drosophila protein that slows cell cycle progression , and its mammalian homolog , TRB3 interferes with insulin induced activation of AKT .	Tribbles is a Drosophila protein that slows cell cycle progression, and its mammalian homolog, TRB3 interferes with insulin induced activation of AKT.	19	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	19	20	23	24
To substantiate the biochemical data , we carried out immunohistochemistry to examine the insulin induced activation of Akt in retinal sections prepared from eye cups that were stimulated with insulin in organ cultures .	To substantiate the biochemical data, we carried out immunohistochemistry to examine the insulin induced activation of Akt in retinal sections prepared from eye cups that were stimulated with insulin in organ cultures.	12	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	17	18
Insulin induced AKT activation involves increase in the level of plasma membrane phosphoinositide PIP3 through the activity of PI3K XREF_BIBR .	Insulin induced AKT activation involves increase in the level of plasma membrane phosphoinositide PIP3 through the activity of PI3K XREF_BIBR.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	2	3
In addition TWEAK activated PI3K and Akt in osteoblastic cells [ XREF_BIBR ] but inhibited insulin induced Akt activation in hepatocytes [ XREF_BIBR ] .	In addition TWEAK activated PI3K and Akt in osteoblastic cells [XREF_BIBR] but inhibited insulin induced Akt activation in hepatocytes [XREF_BIBR].	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
PDK1 ( a phosphatidylinositol trisphosphate dependent kinase ) and Akt and protein kinase B ( PKB ) activation by insulin showed no difference in B2 , F4 , and in control L6hIR cells .	PDK1 (a phosphatidylinositol trisphosphate dependent kinase) and Akt and protein kinase B (PKB) activation by insulin showed no difference in B2, F4, and in control L6hIR cells.	9	20	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	9	10
Muscle cells from diabetic patients displayed defective insulin action and a drastic reduction of insulin stimulated activity of all Akt isoforms .	Muscle cells from diabetic patients displayed defective insulin action and a drastic reduction of insulin stimulated activity of all Akt isoforms.	12	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	19	20
Acute signaling responses to glucose and insulin were similar ; however , late signaling events triggered by glucose and insulin differed markedly , with S6 and ERK robustly activated by glucose but not by insulin and AKT activated by insulin but not by glucose ( XREF_FIG ) .	Acute signaling responses to glucose and insulin were similar; however, late signaling events triggered by glucose and insulin differed markedly, with S6 and ERK robustly activated by glucose but not by insulin and AKT activated by insulin but not by glucose (XREF_FIG).	20	40	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	39	40	36	37
This approach revealed that antecedent pulsatile ( vs. constant ) insulin delivery resulted in increased Gck mRNA and AKT activation in response to an identical increment in insulin delivery ( XREF_FIG ) .	This approach revealed that antecedent pulsatile (vs. constant) insulin delivery resulted in increased Gck mRNA and AKT activation in response to an identical increment in insulin delivery (XREF_FIG).	10	20	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	18	19
Activated Akt mediates the metabolic actions of insulin such as augmenting glucose transport and promoting mTORC1 signaling to drive protein synthesis and cell growth .	Activated Akt mediates the metabolic actions of insulin such as augmenting glucose transport and promoting mTORC1 signaling to drive protein synthesis and cell growth.	0	14	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	1	2
In line with this model , medium supplementation , but not acute stimulation of the human hepatoma cell line HepG2 with high doses ( 30 mum ) of EETs , has been shown to increase insulin mediated activation of Akt , the central protein kinase in insulin signaling .	In line with this model, medium supplementation, but not acute stimulation of the human hepatoma cell line HepG2 with high doses (30 mum) of EETs, has been shown to increase insulin mediated activation of Akt, the central protein kinase in insulin signaling.	35	44	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	35	36	39	40
This analysis demonstrated that L Delta1 ,2 mice were partially protected against the HFD induced suppression of insulin stimulated AKT activation in liver , adipose tissue , and skeletal muscle that was detected in L WT mice ( XREF_FIG ) .	This analysis demonstrated that L Delta1,2 mice were partially protected against the HFD induced suppression of insulin stimulated AKT activation in liver, adipose tissue, and skeletal muscle that was detected in L WT mice (XREF_FIG).	15	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	17	18	19	20
Cmpd 28 treatment increased insulin induced Akt activation and decreased the levels of Trb3 , nuclear FoxO1 , and mRNAs of three FoxO1-target genes : G6pc , Pck1 , and Igfbp1 ( XREF_FIG ) .	Cmpd 28 treatment increased insulin induced Akt activation and decreased the levels of Trb3, nuclear FoxO1, and mRNAs of three FoxO1-target genes : G6pc, Pck1, and Igfbp1 (XREF_FIG).	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Under comparable conditions , insulin effectively stimulated Akt activity in cells expressing mCherry-Akt2 as assessed using the Akt reporter BKAR [ XREF_BIBR ] ; this activity was reversed with the Akt active site inhibitor GDC-0068 ( XREF_FIG ) .	Under comparable conditions, insulin effectively stimulated Akt activity in cells expressing mCherry-Akt2 as assessed using the Akt reporter BKAR [XREF_BIBR]; this activity was reversed with the Akt active site inhibitor GDC-0068 (XREF_FIG).	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	7	8
The presence of insulin also stimulated the activity of PKB , p70s6K , p42 and p44 MAPKs and p90RSK1 .	The presence of insulin also stimulated the activity of PKB, p70s6K, p42 and p44 MAPKs and p90RSK1.	1	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	9	10
The C. elegans insulin signalling pathway activates two Akt family members , AKT-1 and AKT-2 , as well as a serum and glucocorticoid inducible kinase , SGK-1 downstream of the phosphoinositide dependent kinase , PDK-1 .	The C. elegans insulin signalling pathway activates two Akt family members, AKT-1 and AKT-2, as well as a serum and glucocorticoid inducible kinase, SGK-1 downstream of the phosphoinositide dependent kinase, PDK-1.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	8	9
It can also control negatively insulin stimulated glucose transport , mainly through the redistribution of IRS-1 , while the subsequent degradation of IRS-1 downregulates insulin stimulated activation of Akt [ XREF_BIBR ] .	It can also control negatively insulin stimulated glucose transport, mainly through the redistribution of IRS-1, while the subsequent degradation of IRS-1 downregulates insulin stimulated activation of Akt [XREF_BIBR].	23	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	24	25	28	29
At ZT15 , the activation of Akt stimulated by insulin ( 100 nmol/L ) was significantly reduced in the mPer2 Brdm1 mice at 5 and 20 min .	At ZT15, the activation of Akt stimulated by insulin (100 nmol/L) was significantly reduced in the mPer2 Brdm1 mice at 5 and 20 min.	4	12	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	6	7
Then , we examined whether insulin induced Akt signaling in CVSMCs .	Then, we examined whether insulin induced Akt signaling in CVSMCs.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
In fact , NO causes FFA induced decreased insulin secretion in prediabetic rat islets ; iNOS is involved in the development of muscle insulin resistance in diet induced obesity by affecting PI 3-kinase and Akt in mice and the iNOS mRNA was 20 times higher in diabetic rats .	In fact, NO causes FFA induced decreased insulin secretion in prediabetic rat islets; iNOS is involved in the development of muscle insulin resistance in diet induced obesity by affecting PI 3-kinase and Akt in mice and the iNOS mRNA was 20 times higher in diabetic rats.	23	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	34	35
While BI-D1870 partially inhibited insulin stimulated PKB activation in these cells , this only partially inhibited AS160 phosphorylation and did not block GLUT4 trafficking , suggesting that p90RSK might regulate glucose transport after GLUT4 translocation .	While BI-D1870 partially inhibited insulin stimulated PKB activation in these cells, this only partially inhibited AS160 phosphorylation and did not block GLUT4 trafficking, suggesting that p90RSK might regulate glucose transport after GLUT4 translocation.	3	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	6	7
A second mTOR containing protein complex , mTORC2 , lies upstream of Akt and contributes to Akt activation by insulin and growth factors by phosphorylating S473 in its hydrophobic regulatory motif XREF_BIBR .	A second mTOR containing protein complex, mTORC2, lies upstream of Akt and contributes to Akt activation by insulin and growth factors by phosphorylating S473 in its hydrophobic regulatory motif XREF_BIBR.	14	22	contributes	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	16	17
In some studies , IR was associated with low activation of Akt by insulin , XREF_BIBR , XREF_BIBR whereas in other studies rapamycin promoted IR despite normal activation of the Akt axis .	In some studies, IR was associated with low activation of Akt by insulin, XREF_BIBR, XREF_BIBR whereas in other studies rapamycin promoted IR despite normal activation of the Akt axis.	9	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	11	12
Insulin activates the PI3K and Akt signalling pathway in melanoma cell lines .	Insulin activates the PI3K and Akt signalling pathway in melanoma cell lines.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
One likely contributor is the JNK pathway , which is activated during HCC development and inhibits insulin activated AKT .	One likely contributor is the JNK pathway, which is activated during HCC development and inhibits insulin activated AKT.	15	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	18	19
We previously reported that an upregulation of GRK2 and a decrease in beta-arrestin 2 inhibit insulin induced stimulation of Akt and eNOS signaling and that GRK2 overactivation may result from an increase in PKC activity in aortas from diabetic mice with hyperinsulinemia .	We previously reported that an upregulation of GRK2 and a decrease in beta-arrestin 2 inhibit insulin induced stimulation of Akt and eNOS signaling and that GRK2 overactivation may result from an increase in PKC activity in aortas from diabetic mice with hyperinsulinemia.	15	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	19	20
Furthermore , reduced systemic insulin signaling and down-regulation of the downstream insulin signaling component Akt and PI3K promotes hematopoietic and skin stem cell differentiation .	Furthermore, reduced systemic insulin signaling and down-regulation of the downstream insulin signaling component Akt and PI3K promotes hematopoietic and skin stem cell differentiation.	4	16	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	14	15
Strikingly , no significant changes in insulin stimulated AKT activation were detected in adipose tissue from 1 week fed HFD mice ( XREF_FIG D-E ) .	Strikingly, no significant changes in insulin stimulated AKT activation were detected in adipose tissue from 1 week fed HFD mice (XREF_FIG D-E).	4	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	8	9
Insulin dependent activation of Akt was blocked by 4 h treatment with manumycin ( P < 0.01 ) , a kinetic too rapid to be explained by Ras inhibition .	Insulin dependent activation of Akt was blocked by 4 h treatment with manumycin (P < 0.01), a kinetic too rapid to be explained by Ras inhibition.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
In a previous study we showed that insulin activation of Akt was unaffected when tension development was inhibited .	In a previous study we showed that insulin activation of Akt was unaffected when tension development was inhibited.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	10	11
These findings suggested that Cucumaria-PC exhibited significant anti-hyperglycemic activities through up-regulating PI3K and PKB signal pathway mediated by insulin .	These findings suggested that Cucumaria-PC exhibited significant anti-hyperglycemic activities through up-regulating PI3K and PKB signal pathway mediated by insulin.	11	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	18	19	13	14
Feeding a HFD suppressed insulin stimulated AKT activation in liver , adipose tissue , and muscle of Phi WT mice but not Phi KO mice ( XREF_FIG ) .	Feeding a HFD suppressed insulin stimulated AKT activation in liver, adipose tissue, and muscle of Phi WT mice but not Phi KO mice (XREF_FIG).	3	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	6	7
However , insulin induced activation of Akt was increased by rapamycin .	However, insulin induced activation of Akt was increased by rapamycin.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
We next examined insulin induced P-Akt in skeletal muscle following trauma and hemorrhage at different ages and consistent with our previous findings in adult animals , in 10-week old rats , insulin induced P-Akt ( S473 ) was severely diminished in triceps following trauma and hemorrhage ( TH90 ' ) compared with trauma alone ( T90 ' ; XREF_FIG ) .	We next examined insulin induced P-Akt in skeletal muscle following trauma and hemorrhage at different ages and consistent with our previous findings in adult animals, in 10-week old rats, insulin induced P-Akt (S473) was severely diminished in triceps following trauma and hemorrhage (TH90 ') compared with trauma alone (T90 '; XREF_FIG).	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	P-Akt	P-Akt	P-Akt	3	4	5	6
PKB was activated by insulin stimulation within 5min and reached a peak by 15-30min .	PKB was activated by insulin stimulation within 5min and reached a peak by 15-30min.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	0	1
The inactivation of GSK-3beta and activation of PKB by insulin were associated with their phosphorylation and this was also reversed by wortmannin .	The inactivation of GSK-3beta and activation of PKB by insulin were associated with their phosphorylation and this was also reversed by wortmannin.	3	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	9	10	7	8
For example , APPL1 KO in MEFs was found to reduce Akt activation induced by Hepatocyte Growth Factor , but not by EGF , insulin , or serum .	For example, APPL1 KO in MEFs was found to reduce Akt activation induced by Hepatocyte Growth Factor, but not by EGF, insulin, or serum.	11	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	24	25	11	12
Using dominant negative mutants of Akt or PKClambda ( downstream effectors of phosphoinositide 3-kinase ) , insulin stimulated Akt activity was found to be important in the regulation of adiponectin secretion by insulin in 3T3-L1 adipocytes .	Using dominant negative mutants of Akt or PKClambda (downstream effectors of phosphoinositide 3-kinase), insulin stimulated Akt activity was found to be important in the regulation of adiponectin secretion by insulin in 3T3-L1 adipocytes.	16	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
This insulin activated PI3K-Akt pathway may be linked to anorexia , as the administration of PI3K inhibitors has been shown to hinder the effect of insulin on lowering food intake .	This insulin activated PI3K-Akt pathway may be linked to anorexia, as the administration of PI3K inhibitors has been shown to hinder the effect of insulin on lowering food intake.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	1	2	3	4
However , this increase was severely blunted in the elderly subjects ( young : 0.55 +/-0.04 ; elderly : 0.18 +/-0.02 , P = 0.0002 ) and was associated with an ~ 40 % ( P = 0.004 ) reduction in insulin activation of Akt .	However, this increase was severely blunted in the elderly subjects (young : 0.55 +/-0.04; elderly : 0.18 +/-0.02, P = 0.0002) and was associated with an ~ 40% (P = 0.004) reduction in insulin activation of Akt.	41	45	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	41	42	44	45
Insulin mediated Akt activation in the myocardium triggers a variety of processes , like glucose uptake , modification of calcium signalling and anti-apoptotic effects [ XREF_BIBR ] .	Insulin mediated Akt activation in the myocardium triggers a variety of processes, like glucose uptake, modification of calcium signalling and anti-apoptotic effects [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
We found that SB203580 blocked insulin induced Akt activation .	We found that SB203580 blocked insulin induced Akt activation.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Thus , the goal of this study was to determine whether altered insulin activation of the PI3K and Akt and MAPK signalling pathways could contribute to the development of insulin resistance and type 2 diabetes in LBW humans .	Thus, the goal of this study was to determine whether altered insulin activation of the PI3K and Akt and MAPK signalling pathways could contribute to the development of insulin resistance and type 2 diabetes in LBW humans.	12	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	18	19
Oxidative stress associated with high cholesterol intake impairs insulin signaling , increases serine phosphorylation of IRS1 , and suppresses insulin stimulated PI3K and AKT activities , leading to increased stress activated c-Jun N-terminal kinase ( JNK ) activity that underlies cognitive impairments in mice [ XREF_BIBR ] .	Oxidative stress associated with high cholesterol intake impairs insulin signaling, increases serine phosphorylation of IRS1, and suppresses insulin stimulated PI3K and AKT activities, leading to increased stress activated c-Jun N-terminal kinase (JNK) activity that underlies cognitive impairments in mice [XREF_BIBR].	18	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	19	20	23	24
It was also reported that insulin mediated activation of Akt can negatively regulate AMPK activity [ XREF_BIBR ] .	It was also reported that insulin mediated activation of Akt can negatively regulate AMPK activity [XREF_BIBR].	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	9	10
Furthermore , we found that Nox4 gene silencing had a much greater inhibitory effect on insulin induced AKT activation than ERK1/2 activation ( XREF_FIG ) .	Furthermore, we found that Nox4 gene silencing had a much greater inhibitory effect on insulin induced AKT activation than ERK1/2 activation (XREF_FIG).	8	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	15	16	17	18
In addition , while HFD produced a blunted insulin response in WT mice , the hsf1 -/- mice exhibited normal insulin stimulated AKT signaling in liver and muscle ( XREF_SUPPLEMENTARY ) .	In addition, while HFD produced a blunted insulin response in WT mice, the hsf1 -/- mice exhibited normal insulin stimulated AKT signaling in liver and muscle (XREF_SUPPLEMENTARY).	18	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	22	23
PitIRKO DIO mice did not exhibit significantly increased phospho-Akt in response to insulin suggesting that the other cell types in the pituitary either do not express insulin receptor or that insulin signaling in other cell types does not activate Akt .	PitIRKO DIO mice did not exhibit significantly increased phospho-Akt in response to insulin suggesting that the other cell types in the pituitary either do not express insulin receptor or that insulin signaling in other cell types does not activate Akt.	30	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	30	31	39	40
The enhancement of insulin stimulated Akt activation in adipose tissue might contribute to the ability of C21 to enhance glucose uptake in this tissue ( Ohshima etal .	The enhancement of insulin stimulated Akt activation in adipose tissue might contribute to the ability of C21 to enhance glucose uptake in this tissue (Ohshima etal.	1	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
Serine residues phosphorylated by GSK3 are typically primed by phosphorylation at a nearby site ( SXXXS motif ) , and mutation of both S332 and S336 of IRS1 ( hS337 , hS341 ) to alanine enhances both basal and insulin stimulated tyrosine phosphorylation of IRS1 , as well as insulin stimulated AKT activation in cultured cells [ XREF_BIBR ] .	Serine residues phosphorylated by GSK3 are typically primed by phosphorylation at a nearby site (SXXXS motif), and mutation of both S332 and S336 of IRS1 (hS337, hS341) to alanine enhances both basal and insulin stimulated tyrosine phosphorylation of IRS1, as well as insulin stimulated AKT activation in cultured cells [XREF_BIBR].	40	52	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	49	50	51	52
At the organismal level , PI3K-C2beta inactivation induced an increase in insulin stimulated Akt signaling specifically in insulin target tissues ( liver , muscle , and adipose tissue ) but not in the spleen where PI3K-C2beta is expressed highly .	At the organismal level, PI3K-C2beta inactivation induced an increase in insulin stimulated Akt signaling specifically in insulin target tissues (liver, muscle, and adipose tissue) but not in the spleen where PI3K-C2beta is expressed highly.	7	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
From the results , we can propose that GRK2 acts by competing for beta-arrestin 2 upon insulin induced Akt and eNOS activation in the control or diabetic aorta .	From the results, we can propose that GRK2 acts by competing for beta-arrestin 2 upon insulin induced Akt and eNOS activation in the control or diabetic aorta.	13	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
We found that activation of insulin signaling triggers a strong induction of the AKT and mTOR cascade that is paralleled by increased synthesis of fatty acids , cholesterol , and triglycerides , induction of glycolysis , and decrease of fatty acid oxidation and gluconeogenesis in rat preneoplastic and neoplastic liver lesions , when compared with the healthy liver .	We found that activation of insulin signaling triggers a strong induction of the AKT and mTOR cascade that is paralleled by increased synthesis of fatty acids, cholesterol, and triglycerides, induction of glycolysis, and decrease of fatty acid oxidation and gluconeogenesis in rat preneoplastic and neoplastic liver lesions, when compared with the healthy liver.	5	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	13	14
Insulin stimulated Glut4 translocation requires PI3K activation and subsequent Akt activation .	Insulin stimulated Glut4 translocation requires PI3K activation and subsequent Akt activation.	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	9	10
In summary , our results indicate that NEP accelerates adipogenesis through enhancement of insulin mediated PI3K-Akt activation and imply a high therapeutic value of NEP in treating obesity and obesity related disorders .	In summary, our results indicate that NEP accelerates adipogenesis through enhancement of insulin mediated PI3K-Akt activation and imply a high therapeutic value of NEP in treating obesity and obesity related disorders.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	13	14	15	16
This observation is consistent with current biological understanding of the role of insulin in the apoptosis signaling network , where insulin augments AKT ( protein kinase B ) activity .	This observation is consistent with current biological understanding of the role of insulin in the apoptosis signaling network, where insulin augments AKT (protein kinase B) activity.	20	28	augments	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	22	23
In lean SHR adipocytes , Akt activation by 100 nM insulin peaked at 3 min at 25-fold , whereas SHROB adipocytes showed only 4-fold activation .	In lean SHR adipocytes, Akt activation by 100 nM insulin peaked at 3 min at 25-fold, whereas SHROB adipocytes showed only 4-fold activation.	5	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	5	6
Indeed , by activating Akt signaling cascade insulin mediates both mitochondrial fusion and FoxO1 nuclear exclusion .	Indeed, by activating Akt signaling cascade insulin mediates both mitochondrial fusion and FoxO1 nuclear exclusion.	4	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	4	5
In contrast to epithelial cells , laminin-511 does not stimulate Akt phosphorylation in muscle cells ; yet , Akt can be stimulated by EGF and insulin ( XREF_FIG ) .	In contrast to epithelial cells, laminin-511 does not stimulate Akt phosphorylation in muscle cells; yet, Akt can be stimulated by EGF and insulin (XREF_FIG).	18	26	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	18	19
Although there are discrepant reports regarding whether or not ATM plays a role in insulin stimulated activation of Akt , we gave the benefit of the doubt to the original report by Viniegra et al using Cos and 293T cells and a separate study using L6 myoblasts , both of which demonstrated a role of ATM in insulin action .	Although there are discrepant reports regarding whether or not ATM plays a role in insulin stimulated activation of Akt, we gave the benefit of the doubt to the original report by Viniegra et al using Cos and 293T cells and a separate study using L6 myoblasts, both of which demonstrated a role of ATM in insulin action.	12	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	18	19
INSULIN R by recruiting different substrate adaptors such as the IRS family of proteins can activate the PI3K and AKT pathway , promoting cell survival and proliferation .	INSULIN R by recruiting different substrate adaptors such as the IRS family of proteins can activate the PI3K and AKT pathway, promoting cell survival and proliferation.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	INSULIN	INSULIN	INSULIN	AKT	AKT	AKT	0	1	19	20
Insulin appears to activate the Akt kinase pathway within Leydig cells , which likely mediates the role of this hormone in steroidogenesis [ XREF_BIBR ] .	Insulin appears to activate the Akt kinase pathway within Leydig cells, which likely mediates the role of this hormone in steroidogenesis [XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
Analysis of our data suggested that PKC activation and oxidative stress may selectively inhibit insulin induced Akt and eNOS activation , causing endothelial dysfunction and inflammation .	Analysis of our data suggested that PKC activation and oxidative stress may selectively inhibit insulin induced Akt and eNOS activation, causing endothelial dysfunction and inflammation.	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
Ang II was reported to inhibit insulin stimulated Akt activation and decrease insulin stimulated GLUT4 abundance on cell membrane in L6 myotubes.24 In isolated mammalian skeletal muscle , exposure of Ang II for 2 h impaired the phosphorylation of Akt in insulin signaling and directly decreased insulin stimulated glucose uptake ,26 which was in alignment with our results .	Ang II was reported to inhibit insulin stimulated Akt activation and decrease insulin stimulated GLUT4 abundance on cell membrane in L6 myotubes.24 In isolated mammalian skeletal muscle, exposure of Ang II for 2 h impaired the phosphorylation of Akt in insulin signaling and directly decreased insulin stimulated glucose uptake,26 which was in alignment with our results.	5	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
IGF1 and insulin activated Akt and PKB in Saos-2 and B10 cells and concomitantly protected against apoptosis ( EC 50 for inhibition of apoptosis , 0.04 nmol/l for IGF1 , 1nmol/l for insulin ) .	IGF1 and insulin activated Akt and PKB in Saos-2 and B10 cells and concomitantly protected against apoptosis (EC 50 for inhibition of apoptosis, 0.04 nmol/l for IGF1, 1nmol/l for insulin).	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
PI3K is activated by insulin , which subsequently stimulates AKT , PDK1 , and PKCzeta , in succession .	PI3K is activated by insulin, which subsequently stimulates AKT, PDK1, and PKCzeta, in succession.	2	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	9	10
GK rats have been reported to have reduced insulin induced insulin receptor phosphorylation and reduced insulin induced Akt activity .	GK rats have been reported to have reduced insulin induced insulin receptor phosphorylation and reduced insulin induced Akt activity.	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
ONOO - inhibits insulin stimulated Akt activity through tyrosine nitration .	ONOO - inhibits insulin stimulated Akt activity through tyrosine nitration.	2	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
Therefore , unlike skeletal muscle cells in which physiological doses of insulin activate Akt and suppress FOXO3 , in keratinocytes insulin may not suppress FOXO3 .	Therefore, unlike skeletal muscle cells in which physiological doses of insulin activate Akt and suppress FOXO3, in keratinocytes insulin may not suppress FOXO3.	9	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
chronic exposure to high glucose or insulin downregulates acute insulin stimulated Akt activation , acting synergistically distal to PI 3-kinase .	chronic exposure to high glucose or insulin downregulates acute insulin stimulated Akt activation, acting synergistically distal to PI 3-kinase.	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
BEZ235 , indeed , completely blocked insulin stimulated Akt activity ( XREF_SUPPLEMENTARY ) .	BEZ235, indeed, completely blocked insulin stimulated Akt activity (XREF_SUPPLEMENTARY).	5	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Although insulin enhanced Akt activity , phosphorylation of mTOR and its downstream targets ( p70S6K and 4EBP1 ) required the addition of glucose .	Although insulin enhanced Akt activity, phosphorylation of mTOR and its downstream targets (p70S6K and 4EBP1) required the addition of glucose.	1	4	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
To this end , we studied the effect of a PI3K inhibitor LY294002 on insulin induced Akt protein translocation .	To this end, we studied the effect of a PI3K inhibitor LY294002 on insulin induced Akt protein translocation.	12	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
In general , during feeding FOXOs are largely inhibited by the insulin stimulated Akt whereas during fasting FOXOs are less phosphorylated and actively promote gluconeogenesis and lipolysis and inhibit glycolysis and lipogenesis XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	In general, during feeding FOXOs are largely inhibited by the insulin stimulated Akt whereas during fasting FOXOs are less phosphorylated and actively promote gluconeogenesis and lipolysis and inhibit glycolysis and lipogenesis XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	8	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Insulin increases the association of AKT with GLUT4 containing vesicles .	Insulin increases the association of AKT with GLUT4 containing vesicles.	0	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	5	6
In InsR and IGF1R negative GBM46 , insulin and IGF1 did not stimulate AKT or alter the ability of gefitinib to repress AKT ( XREF_SUPPLEMENTARY ) .	In InsR and IGF1R negative GBM46, insulin and IGF1 did not stimulate AKT or alter the ability of gefitinib to repress AKT (XREF_SUPPLEMENTARY).	7	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	13	14
The activation of insulin and IGF receptors triggers signalling cascades of the PI3K-AKT and MAPK and ERK pathways that promote mitogenesis and antagonize apoptosis in tumour development .	The activation of insulin and IGF receptors triggers signalling cascades of the PI3K-AKT and MAPK and ERK pathways that promote mitogenesis and antagonize apoptosis in tumour development.	3	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	12	13
Since IR is characterized by a marked reduction in insulin stimulated PI3 K mediated activation of Akt in liver and skeletal muscle , we hypothesized that ovariectomized rats ( OVX ) would exhibit reductions in the expression of proteins in PI3 K signaling pathway , including PI3 K and Akt .	Since IR is characterized by a marked reduction in insulin stimulated PI3 K mediated activation of Akt in liver and skeletal muscle, we hypothesized that ovariectomized rats (OVX) would exhibit reductions in the expression of proteins in PI3 K signaling pathway, including PI3 K and Akt.	7	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	16	17
Because high glucose induces Akt activation , we asked whether insulin , which also activates the PI3K-Akt pathway and controls glucose homeostasis , regulates the cell surface abundance of TGF-beta receptors .	Because high glucose induces Akt activation, we asked whether insulin, which also activates the PI3K-Akt pathway and controls glucose homeostasis, regulates the cell surface abundance of TGF-beta receptors.	10	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	10	11	16	17
TGF-beta signaling was stimulated by treatment of the cells with TGF-beta1 , while PI3K and AKT and ERK were activated by insulin administration ( XREF_FIG ) .	TGF-beta signaling was stimulated by treatment of the cells with TGF-beta1, while PI3K and AKT and ERK were activated by insulin administration (XREF_FIG).	13	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	21	22	15	16
Akt stands at the crossroads of growth factor and metabolic signaling and is strongly activated by insulin .	Akt stands at the crossroads of growth factor and metabolic signaling and is strongly activated by insulin.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	0	1
These results indicate that Sestrin2 is required for maintenance of insulin induced AKT activation and its sequelae during obesity .	These results indicate that Sestrin2 is required for maintenance of insulin induced AKT activation and its sequelae during obesity.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	12	13
In these cells , 100nM insulin did not efficiently stimulate Akt , however , incubation with 3 or 10muM THCV ( in palmitic acid pretreated cells ) and 1 or 3 muM THCV ( in insulin pretreated cells ) increased the sensitivity of HHL-5 cells to insulin in terms of Akt activation ( XREF_FIG ) .	In these cells, 100nM insulin did not efficiently stimulate Akt, however, incubation with 3 or 10muM THCV (in palmitic acid pretreated cells) and 1 or 3 muM THCV (in insulin pretreated cells) increased the sensitivity of HHL-5 cells to insulin in terms of Akt activation (XREF_FIG).	4	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	10	11
This process was found to be independent of the insulin signaling pathway ( as measured by insulin induced AKT activation ) or altered expression of GLUT1 and GLUT4 , proposing a defect in GLUT4 trafficking .	This process was found to be independent of the insulin signaling pathway (as measured by insulin induced AKT activation) or altered expression of GLUT1 and GLUT4, proposing a defect in GLUT4 trafficking.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	18	19
Insulin stimulated IRS-1 and Akt Thr 308 phosphorylation were reduced by 44 and 52 % , respectively , in TgKO muscle ( XREF_FIG B ) .	Insulin stimulated IRS-1 and Akt Thr 308 phosphorylation were reduced by 44 and 52%, respectively, in TgKO muscle (XREF_FIG B).	0	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
This way of GSK3 inactivation is known as the canonical pathway and is different from the PI3K and Akt dependent pathway triggered by insulin and related growth factors .	This way of GSK3 inactivation is known as the canonical pathway and is different from the PI3K and Akt dependent pathway triggered by insulin and related growth factors.	18	27	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	18	19
Akt is activated by insulin and insulin like growth factor ( IGF ) signaling ( IIS ) .	Akt is activated by insulin and insulin like growth factor (IGF) signaling (IIS).	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
Surprisingly the findings obtained with these separate domains reveal that ceramide blocks insulin stimulation of Akt and PKB by two independent mechanisms .	Surprisingly the findings obtained with these separate domains reveal that ceramide blocks insulin stimulation of Akt and PKB by two independent mechanisms.	12	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	12	13	17	18
We further investigated the activation of Akt in the presence or absence of the PTP-1B antisense ( XREF_FIG ) and consistent with the tyrosine phosphorylation of IRS-1 , the inhibitory effect of Ang II on the insulin induced Akt activation also was significantly inhibited by the PTP-1B antisense ( XREF_FIG ) ( * p < 0.05 vs. Ang II+ insulin , Ang II+ insulin+ PTP-1B sense ) .	We further investigated the activation of Akt in the presence or absence of the PTP-1B antisense (XREF_FIG) and consistent with the tyrosine phosphorylation of IRS-1, the inhibitory effect of Ang II on the insulin induced Akt activation also was significantly inhibited by the PTP-1B antisense (XREF_FIG) (* p < 0.05 vs. Ang II+ insulin, Ang II+ insulin+ PTP-1B sense).	33	39	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	36	37	38	39
How could these absences of Thr308 phosphorylation be reconciled with the essential role of PDK1 catalysed phosphorylation of Thr308 for activation of PKB by insulin and IGF1 [ XREF_BIBR ] ?	How could these absences of Thr308 phosphorylation be reconciled with the essential role of PDK1 catalysed phosphorylation of Thr308 for activation of PKB by insulin and IGF1 [XREF_BIBR]?	20	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	24	25	22	23
Insulin induced activation of Akt .	Insulin induced activation of Akt.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
However , effects of combined thiazolidinedione-metformin treatment on aPKC or PKB activation by sub-maximal and maximal insulin are unknown .	However, effects of combined thiazolidinedione-metformin treatment on aPKC or PKB activation by sub-maximal and maximal insulin are unknown.	8	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	16	17	10	11
No difference was observed between the stable cell line and un transfected cells , demonstrating effective insulin signalling and activation of Akt within the lentivirally transduced cell line .	No difference was observed between the stable cell line and un transfected cells, demonstrating effective insulin signalling and activation of Akt within the lentivirally transduced cell line.	16	22	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	21	22
Akt plays a critical role in controlling the balance between survival and apoptosis XREF_BIBR - XREF_BIBR and is activated by insulin and various growth and survival factors involving phosphatidylinositol 3-kinase ( PI3-kinase ) XREF_BIBR , XREF_BIBR .	Akt plays a critical role in controlling the balance between survival and apoptosis XREF_BIBR - XREF_BIBR and is activated by insulin and various growth and survival factors involving phosphatidylinositol 3-kinase (PI3-kinase) XREF_BIBR, XREF_BIBR.	0	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	0	1
INSR can be activated by the insulin ligand to trigger the PI3K and AKT signaling pathway and enhance tumor growth , migration and angiogenesis .	INSR can be activated by the insulin ligand to trigger the PI3K and AKT signaling pathway and enhance tumor growth, migration and angiogenesis.	6	15	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	13	14
PRIP1 interacts with Akt directly and is required for insulin induced association of Akt with GABA A Rs .	PRIP1 interacts with Akt directly and is required for insulin induced association of Akt with GABA A Rs.	9	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	13	14
Protein analysis of resistance arteries revealed that insulin mediated activation of Akt was preserved in obese rats , whereas expression of eNOS was markedly decreased .	Protein analysis of resistance arteries revealed that insulin mediated activation of Akt was preserved in obese rats, whereas expression of eNOS was markedly decreased.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	11	12
Moreover , Trib3 is also shown to be involved in insulin mediated Akt and PKB activation in the liver by mechanisms apparently unrelated to C/EBP , suggesting that Trib family members possibly function in a C/EBP independent fashion .	Moreover, Trib3 is also shown to be involved in insulin mediated Akt and PKB activation in the liver by mechanisms apparently unrelated to C/EBP, suggesting that Trib family members possibly function in a C/EBP independent fashion.	8	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
Expression of HA-GLUT4 in 3T3-L1 adipocytes does not alter insulin dependent activation of the Akt signaling pathway or the -fold response to insulin for glucose uptake ( supplemental Fig .	Expression of HA-GLUT4 in 3T3-L1 adipocytes does not alter insulin dependent activation of the Akt signaling pathway or the -fold response to insulin for glucose uptake (supplemental Fig.	9	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	14	15
Insulin activated PRAS40 and Akt , while ZnSO 4 activated PRAS40 , ERK1/2 , Akt and GSK-3beta in this system ( XREF_FIG ) .	Insulin activated PRAS40 and Akt, while ZnSO 4 activated PRAS40, ERK1/2, Akt and GSK-3beta in this system (XREF_FIG).	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
Activated JNK can either directly inhibit insulin induced AKT activation or promotes translocation of FoxO1 to the nucleus of pancreatic beta-cells .	Activated JNK can either directly inhibit insulin induced AKT activation or promotes translocation of FoxO1 to the nucleus of pancreatic beta-cells.	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	8	9
ORP8 and leptin suppress insulin sensitivity by preventing the insulin mediated activation of AKT and PI3K , respectively 125 .	ORP8 and leptin suppress insulin sensitivity by preventing the insulin mediated activation of AKT and PI3K, respectively 125.	9	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	13	14
In sebocytes , insulin signaling activated the phosphatidylinositide 3-kinase-Akt ( PI3K and Akt ) and mammalian target of rapamycin ( mTOR ) pathways , which , in turn , induced high protein and lipid synthesis , increased cell growth and proliferation as well as inflammation .	In sebocytes, insulin signaling activated the phosphatidylinositide 3-kinase-Akt (PI3K and Akt) and mammalian target of rapamycin (mTOR) pathways, which, in turn, induced high protein and lipid synthesis, increased cell growth and proliferation as well as inflammation.	3	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	12	13
We have previously shown that administration of insulin immediately following an ischemic insult activates the PI3K-Akt cell survival pathway , inhibits Bax translocation to the mitochondria , promotes favourable Bcl-2 family protein interactions on the mitochondria , inhibits Cytc release , and importantly , protects hippocampal structure and function XREF_BIBR , XREF_BIBR .	We have previously shown that administration of insulin immediately following an ischemic insult activates the PI3K-Akt cell survival pathway, inhibits Bax translocation to the mitochondria, promotes favourable Bcl-2 family protein interactions on the mitochondria, inhibits Cytc release, and importantly, protects hippocampal structure and function XREF_BIBR, XREF_BIBR.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	7	8	15	16
IGF1 and insulin induced a prompt , strong and sustained activation of Akt and PKB while ERK1/2 was activated only transiently , and only by IGF1 and not by insulin .	IGF1 and insulin induced a prompt, strong and sustained activation of Akt and PKB while ERK1/2 was activated only transiently, and only by IGF1 and not by insulin.	0	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	2	3	14	15
However , p110beta is dispensable for Akt activation induced by insulin , since p110alpha is the major PIP2 kinase in this signalling pathway [ XREF_BIBR ] .	However, p110beta is dispensable for Akt activation induced by insulin, since p110alpha is the major PIP2 kinase in this signalling pathway [XREF_BIBR].	6	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	6	7
Western blot analysis showed that suppression of insulin stimulated AKT activation as a result of HFD was substantially prevented in eWAT from Mkk6 -/- mice with liver and skeletal muscle also partially protected .	Western blot analysis showed that suppression of insulin stimulated AKT activation as a result of HFD was substantially prevented in eWAT from Mkk6 -/- mice with liver and skeletal muscle also partially protected.	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	9	10
The present study provides evidence that TF disrupts the insulin mediated activation of Akt specifically through a reduction in IRS-1 levels ( XREF_FIG ) .	The present study provides evidence that TF disrupts the insulin mediated activation of Akt specifically through a reduction in IRS-1 levels (XREF_FIG).	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	13	14
Insulin induces PKB activity , promoting phosphorylation of Ser 21 of GSK-3alpha and Ser 9 of GSK-3beta , thereby reducing total GSK-3 activity by between 20 and 80 % , dependent on cell type .	Insulin induces PKB activity, promoting phosphorylation of Ser 21 of GSK-3alpha and Ser 9 of GSK-3beta, thereby reducing total GSK-3 activity by between 20 and 80%, dependent on cell type.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	2	3
Although PI3K enzymatic activity is diminished in L-Pik3r1KO livers because of a reduced level of regulatory and catalytic subunits of PI3K , insulin stimulated Akt activity is actually increased .	Although PI3K enzymatic activity is diminished in L-Pik3r1KO livers because of a reduced level of regulatory and catalytic subunits of PI3K, insulin stimulated Akt activity is actually increased.	22	25	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	24	25
Its up-regulating effects on PI3K and PKB signal pathway mediated by insulin were noted .	Its up-regulating effects on PI3K and PKB signal pathway mediated by insulin were noted.	4	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	11	12	6	7
In this regard , the signaling cascade differs from the classic activation of PI3K-Akt by Insulin .	In this regard, the signaling cascade differs from the classic activation of PI3K-Akt by Insulin.	7	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	15	16	13	14
In addition , ezetimibe recovered insulin induced Akt activation , and reduced gluconeogenic genesin the liver of ZOF rats and cultured steatotic hepatocytes [ XREF_BIBR ] .	In addition, ezetimibe recovered insulin induced Akt activation, and reduced gluconeogenic genesin the liver of ZOF rats and cultured steatotic hepatocytes [XREF_BIBR].	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Addition of GAM to Muller cell culture repressed insulin induced activation of the Akt and mTORC1 signaling pathway .	Addition of GAM to Muller cell culture repressed insulin induced activation of the Akt and mTORC1 signaling pathway.	8	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	13	14
Both insulin and IGF-1 can activate the PI3K and Akt branch of the mosquito IIS pathway [ XREF_BIBR ] .	Both insulin and IGF-1 can activate the PI3K and Akt branch of the mosquito IIS pathway [XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	9	10
Indeed , both insulin and high glucose induce Akt activation , and increased cell surface TGF-beta receptor abundance and autocrine TGF-beta signaling .	Indeed, both insulin and high glucose induce Akt activation, and increased cell surface TGF-beta receptor abundance and autocrine TGF-beta signaling.	2	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	8	9
These results are consistent with data from a study conducted in subjects with type 2 diabetes that found insulin stimulated Akt and PKB did not change after 2 days of CR XREF_BIBR .	These results are consistent with data from a study conducted in subjects with type 2 diabetes that found insulin stimulated Akt and PKB did not change after 2 days of CR XREF_BIBR.	18	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	18	19	22	23
Abnormal insulin signaling in the human fetoplacental endothelium results in a lower NO bioavailability and Akt activation , thus reducing fetoplacental vascular reactivity in vitro .	Abnormal insulin signaling in the human fetoplacental endothelium results in a lower NO bioavailability and Akt activation, thus reducing fetoplacental vascular reactivity in vitro.	1	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	15	16
Collectively , these results establish a critical role for c-Src in JNK activation by FA and inhibition of insulin mediated AKT activation .	Collectively, these results establish a critical role for c-Src in JNK activation by FA and inhibition of insulin mediated AKT activation.	14	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	18	19	20	21
Vascular endothelial growth factor-A ( VEGF-A ) , fibroblast growth factor ( FGF-2 ) , angiopoietin-1 ( Ang-1 ) , and insulin , which all activate the PI3K and Akt pathway , inhibited the release of sEng from endothelial cells .	Vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor (FGF-2), angiopoietin-1 (Ang-1), and insulin, which all activate the PI3K and Akt pathway, inhibited the release of sEng from endothelial cells.	3	30	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	29	30
GH infusion did not change Akt protein expression , and insulin caused an approximately 13-fold increase in Akt activity ( 1,309 +/- 327 and 1,287 +/- 173 % ) after both GH and saline infusion .	GH infusion did not change Akt protein expression, and insulin caused an approximately 13-fold increase in Akt activity (1,309 +/- 327 and 1,287 +/- 173%) after both GH and saline infusion.	10	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	17	18
We found that AKT was equivalently responsive to insulin in both wild-type and TBK1 -/- MEFs , indicating that insulin induced AKT activation is TBK1 independent ( XREF_FIG ) .	We found that AKT was equivalently responsive to insulin in both wild-type and TBK1 -/- MEFs, indicating that insulin induced AKT activation is TBK1 independent (XREF_FIG).	19	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	19	20	21	22
Insulin induced P-AKT in skeletal muscle and adipose tissue was unchanged following acute psychological stress .	Insulin induced P-AKT in skeletal muscle and adipose tissue was unchanged following acute psychological stress.	0	10	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	P-AKT	P-AKT	P-AKT	0	1	2	3
Second , in cortical neurons culture , insulin activated Akt and downstream effectors within 15 min of treatment and lasted for 2 h. [ XREF_BIBR ] Twenty-four hours insulin stimulation mediated blunting of Akt and its downstream effectors .	Second, in cortical neurons culture, insulin activated Akt and downstream effectors within 15 min of treatment and lasted for 2 h. [XREF_BIBR] Twenty-four hours insulin stimulation mediated blunting of Akt and its downstream effectors.	7	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
We conclude that altered insulin activation of the PI3K and Akt but not the MAPK pathway precedes and may contribute to development of whole-body insulin resistance and type 2 diabetes in men with LBW .	We conclude that altered insulin activation of the PI3K and Akt but not the MAPK pathway precedes and may contribute to development of whole-body insulin resistance and type 2 diabetes in men with LBW.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	10	11
Since insulin activates eNOS through IRS1 and Akt pathway , we then investigated whether FABP4 have any effects on insulin stimulated IRS1 and Akt activation , which was monitored by phosphorylation at Tyr 989 and Ser 473 sites , respectively .	Since insulin activates eNOS through IRS1 and Akt pathway, we then investigated whether FABP4 have any effects on insulin stimulated IRS1 and Akt activation, which was monitored by phosphorylation at Tyr 989 and Ser 473 sites, respectively.	17	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	23	24
In recent years , focus within the field of hepatic insulin action has been predominantly on the effects mediated by Akt , the assumption being that a principal effect of insulin is to activate Akt .	In recent years, focus within the field of hepatic insulin action has been predominantly on the effects mediated by Akt, the assumption being that a principal effect of insulin is to activate Akt.	28	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	30	31	34	35
Compromised insulin stimulated Akt activation in mPer2 Brdm1 .	Compromised insulin stimulated Akt activation in mPer2 Brdm1.	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
Our previous studies revealed that treatment with troglitazone , a member of the TZD family , increases insulin stimulated IRS-1-associated PI3K activity and Akt activity in skeletal muscle of type 2 diabetic patients [ XREF_BIBR ] .	Our previous studies revealed that treatment with troglitazone, a member of the TZD family, increases insulin stimulated IRS-1-associated PI3K activity and Akt activity in skeletal muscle of type 2 diabetic patients [XREF_BIBR].	16	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	23	24
Indeed , insulin induces the activation of both the PI3K and AKT and the MEK and ERK signaling pathways , which are also activated by IGF-1 .	Indeed, insulin induces the activation of both the PI3K and AKT and the MEK and ERK signaling pathways, which are also activated by IGF-1.	2	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	11	12
As previously observed for whole-body insulin sensitivity ( insulin tolerance test ) , rosiglitazone treatment and iNOS deficiency both independently corrected defective insulin induced Akt and PKB activation in muscle , but their combination did not further increase insulin action in that tissue ( XREF_FIG ) .	As previously observed for whole-body insulin sensitivity (insulin tolerance test), rosiglitazone treatment and iNOS deficiency both independently corrected defective insulin induced Akt and PKB activation in muscle, but their combination did not further increase insulin action in that tissue (XREF_FIG).	21	27	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	24	25
There was a non significant trend ( P = 0.056 ) for increased phosphorylation of AKT Thr308 phosphorylation in the cytosolic fraction of muscle treated with 100muU/mL insulin ( XREF_FIG ) , but not in the membrane fraction .	There was a non significant trend (P = 0.056) for increased phosphorylation of AKT Thr308 phosphorylation in the cytosolic fraction of muscle treated with 100muU/mL insulin (XREF_FIG), but not in the membrane fraction.	15	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	27	28	15	16
Second , isoorientin restored insulin stimulated glucose uptake in dexamethasone induced insulin resistant 3T3-L1 adipocytes by reactivating Akt and AMPK .	Second, isoorientin restored insulin stimulated glucose uptake in dexamethasone induced insulin resistant 3T3-L1 adipocytes by reactivating Akt and AMPK.	4	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	17	18
We found that insulin and IGF-1 enhanced the proliferation of intestinal crypts ( including stem cells and other crypt cells ) isolated from obese humans , and PI3K and Akt , and not ERK signaling was involved in insulin or IGF-1-induced proliferation .	We found that insulin and IGF-1 enhanced the proliferation of intestinal crypts (including stem cells and other crypt cells) isolated from obese humans, and PI3K and Akt, and not ERK signaling was involved in insulin or IGF-1-induced proliferation.	3	30	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	29	30
Insulin stimulation of both PI 3-kinase activity and Akt serine ( 473 ) phosphorylation and modulation of GLUT4 content were studied in liver , muscle , and adipose tissue ( AT ) .	Insulin stimulation of both PI 3-kinase activity and Akt serine (473) phosphorylation and modulation of GLUT4 content were studied in liver, muscle, and adipose tissue (AT).	0	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	8	9
Insulin signaling , via downstream Akt activation , is important for maintenance of mitochondrial function in neurons [ XREF_BIBR , XREF_BIBR ] and insulin stimulated Akt activation is blunted in DRG neurons from STZ-diabetic mice [ XREF_BIBR ] .	Insulin signaling, via downstream Akt activation, is important for maintenance of mitochondrial function in neurons [XREF_BIBR, XREF_BIBR] and insulin stimulated Akt activation is blunted in DRG neurons from STZ-diabetic mice [XREF_BIBR].	16	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	25	26
IGF-I and insulin dependent induction of the PI3K and Akt pathway leads to feedback inhibition of signaling due to mTOR and S6K mediated phosphorylation and degradation of IRS-1 .	IGF-I and insulin dependent induction of the PI3K and Akt pathway leads to feedback inhibition of signaling due to mTOR and S6K mediated phosphorylation and degradation of IRS-1.	2	10	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	9	10
To study insulin dependent activation of Akt , wildtype and PINK1 -/- MEF were treated with insulin for various times and the levels of pSer473-Akt relative to total Akt were analyzed by Western blot .	To study insulin dependent activation of Akt, wildtype and PINK1 -/- MEF were treated with insulin for various times and the levels of pSer473-Akt relative to total Akt were analyzed by Western blot.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
When the study group was separated by BMI , no significant differences in basal or insulin stimulated levels of pAkt and total Akt ratio or pTBC1D4 and total TBC1D4 ratio were observed ( XREF_FIG , respectively ) .	When the study group was separated by BMI, no significant differences in basal or insulin stimulated levels of pAkt and total Akt ratio or pTBC1D4 and total TBC1D4 ratio were observed (XREF_FIG, respectively).	11	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	22	23
In contrast , hypomorphic PDK1 mice are viable and fertile , and insulin injection induces the normal activation of PKB , S6K and RSK .	In contrast, hypomorphic PDK1 mice are viable and fertile, and insulin injection induces the normal activation of PKB, S6K and RSK.	12	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	12	13	19	20
Since wortmannin and LY-294002 inhibit at the level of PI3K to modulate Akt activity , we could not directly evaluate the involvement of PI3K in Ang II induced Akt Thr 308 inhibition because both compounds also inhibit insulin induced Akt Thr 308 ( XREF_FIG ) and GSK-3alpha and beta ( data not shown ) phosphorylation [ XREF_BIBR ] .	Since wortmannin and LY-294002 inhibit at the level of PI3K to modulate Akt activity, we could not directly evaluate the involvement of PI3K in Ang II induced Akt Thr 308 inhibition because both compounds also inhibit insulin induced Akt Thr 308 (XREF_FIG) and GSK-3alpha and beta (data not shown) phosphorylation [XREF_BIBR].	37	40	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	37	38	39	40
These results are in keeping with the functional measures of insulin sensitivity described above as well as our previous report that NButGT does not prevent insulin stimulated activation of Akt in 3T3-L1 adipocytes .	These results are in keeping with the functional measures of insulin sensitivity described above as well as our previous report that NButGT does not prevent insulin stimulated activation of Akt in 3T3-L1 adipocytes.	24	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	29	30
These and other studies suggest that KDs induce a metabolic shift in malignant brain tissue towards a pro apoptotic , anti-angiogenic , anti-invasive and anti-inflammatory state accompanied by a marked reduction in tumor growth in vivo [ XREF_BIBR ] via mechanisms that include : ( 1 ) Reduction in blood glucose and insulin growth factor-1 levels [ XREF_BIBR ] ; ( 2 ) Attenuated insulin activated Akt and mTOR and Ras and mitogen activated protein kinase ( MAPK ) signaling pathways [ XREF_BIBR , XREF_BIBR ] ; ( 3 ) Induction of genes involved in oxidative stress protection and elimination of ROS through histone deactylase inhibition and altered expression of genes related to angiogenesis , vascular remodeling , invasion potential and the hypoxic response [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] ; ( 4 ) Enhanced cytotoxic T cell anti-tumor immunity [ XREF_BIBR ] ; and ( 5 ) Reduced inflammation via ketone body inhibition of the NLRP3 inflammasome and a reduction in other circulating inflammatory markers [ XREF_BIBR , XREF_BIBR ] .	These and other studies suggest that KDs induce a metabolic shift in malignant brain tissue towards a pro apoptotic, anti-angiogenic, anti-invasive and anti-inflammatory state accompanied by a marked reduction in tumor growth in vivo [XREF_BIBR] via mechanisms that include : (1) Reduction in blood glucose and insulin growth factor-1 levels [XREF_BIBR]; (2) Attenuated insulin activated Akt and mTOR and Ras and mitogen activated protein kinase (MAPK) signaling pathways [XREF_BIBR, XREF_BIBR]; (3) Induction of genes involved in oxidative stress protection and elimination of ROS through histone deactylase inhibition and altered expression of genes related to angiogenesis, vascular remodeling, invasion potential and the hypoxic response [XREF_BIBR, XREF_BIBR, XREF_BIBR]; (4) Enhanced cytotoxic T cell anti-tumor immunity [XREF_BIBR]; and (5) Reduced inflammation via ketone body inhibition of the NLRP3 inflammasome and a reduction in other circulating inflammatory markers [XREF_BIBR, XREF_BIBR].	64	170	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	64	65	66	67
Both inhibitors blocked the effect of Ang II on insulin induced activation of Akt .	Both inhibitors blocked the effect of Ang II on insulin induced activation of Akt.	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	13	14
In type 2 diabetes , impaired insulin induced Akt and endothelial nitric oxide synthase ( eNOS ) signaling may decrease the vascular relaxation response .	In type 2 diabetes, impaired insulin induced Akt and endothelial nitric oxide synthase (eNOS) signaling may decrease the vascular relaxation response.	5	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
It is well documented that tyrosine phosphorylation of IRS-1 is required for insulin stimulated PI3K and Akt .	It is well documented that tyrosine phosphorylation of IRS-1 is required for insulin stimulated PI3K and Akt.	10	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	16	17
Insulin activation of Akt was reduced by 49 +/- 4 % in the p110-alpha -/- livers as compared with p110-alpha +/+ controls , whereas the activation of Akt was similar in the p110-beta -/- and control livers ( XREF_FIG ) .	Insulin activation of Akt was reduced by 49 +/- 4% in the p110-alpha -/- livers as compared with p110-alpha +/+ controls, whereas the activation of Akt was similar in the p110-beta -/- and control livers (XREF_FIG).	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
Insulin can activate both the PI3K-Akt and the MEK1/2-Erk MAPK pathways .	Insulin can activate both the PI3K-Akt and the MEK1/2-Erk MAPK pathways.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	5	6
Our results showed that bovine insulin activated endomitotic DNA synthesis in silk gland cells and the PI3K and Akt and TOR/S6K/4E-BP pathways , but not the ERK pathway , were involved in this process .	Our results showed that bovine insulin activated endomitotic DNA synthesis in silk gland cells and the PI3K and Akt and TOR/S6K/4E-BP pathways, but not the ERK pathway, were involved in this process.	4	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	18	19
One possible mechanism is that insulin activates Akt and SGK1 and activated Akt and SGK1 modifies the function of WNK4 , since WNK4 has several Akt and SGK1 phosphorylation motifs , and phosphorylation at one of these sites has been reported to alter WNK4 kinase activity XREF_BIBR , XREF_BIBR .	One possible mechanism is that insulin activates Akt and SGK1 and activated Akt and SGK1 modifies the function of WNK4, since WNK4 has several Akt and SGK1 phosphorylation motifs, and phosphorylation at one of these sites has been reported to alter WNK4 kinase activity XREF_BIBR, XREF_BIBR.	5	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Taken together , these findings demonstrate for the first time that persistent activation of Akt signaling by insulin is detrimental to cardioprotection by IPC , which may explain in part the failure to precondition the diabetic heart .	Taken together, these findings demonstrate for the first time that persistent activation of Akt signaling by insulin is detrimental to cardioprotection by IPC, which may explain in part the failure to precondition the diabetic heart.	14	18	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	14	15
Total Akt was significantly higher in insulin stimulated C2Cer treated relative to unstimulated cultures , and the mean percentage increases in insulin stimulated total Akt were significantly higher in both C2Cer and C6Cer treated relative to vehicle treated cells ( XREF_FIG ) .	Total Akt was significantly higher in insulin stimulated C2Cer treated relative to unstimulated cultures, and the mean percentage increases in insulin stimulated total Akt were significantly higher in both C2Cer and C6Cer treated relative to vehicle treated cells (XREF_FIG).	19	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	24	25
The insulin activated Akt pathway is also known to play a critical role in adipogenesis [ XREF_BIBR XREF_BIBR ] .	The insulin activated Akt pathway is also known to play a critical role in adipogenesis [XREF_BIBR XREF_BIBR].	0	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
On the other hand , leucine blunted insulin stimulated 3-MG transport and reduced insulin stimulated Akt Thr ( 473 ) phosphorylation .	On the other hand, leucine blunted insulin stimulated 3-MG transport and reduced insulin stimulated Akt Thr (473) phosphorylation.	12	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
Insulin stimulated Akt activation is significantly decreased in advanced age in the rat skeletal muscle [ XREF_BIBR ] , as a result of TNF-alpha-induced insulin resistance [ XREF_BIBR ] .	Insulin stimulated Akt activation is significantly decreased in advanced age in the rat skeletal muscle [XREF_BIBR], as a result of TNF-alpha-induced insulin resistance [XREF_BIBR].	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Burn injury further led to diminished activation of signaling molecules acting downstream of IRS-1 that mediate the metabolic response to insulin , such as PI3K and AKT , while insulin administration directly into the portal vein of non burned animals caused robust activation of the PI3K and AKT signaling pathway .	Burn injury further led to diminished activation of signaling molecules acting downstream of IRS-1 that mediate the metabolic response to insulin, such as PI3K and AKT, while insulin administration directly into the portal vein of non burned animals caused robust activation of the PI3K and AKT signaling pathway.	29	49	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	29	30	47	48
Furthermore , the addition of insulin in vitro prevented the decrease in Akt and Foxo signaling induced by nutritional stress .	Furthermore, the addition of insulin in vitro prevented the decrease in Akt and Foxo signaling induced by nutritional stress.	3	15	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	12	13
However , cells treated with insulin+ T exhibited blunted phosphorylation of Akt compared with cells treated with insulin alone , indicating insulin resistance of the cells induced by T ( P < 0.05 ) .	However, cells treated with insulin+ T exhibited blunted phosphorylation of Akt compared with cells treated with insulin alone, indicating insulin resistance of the cells induced by T (P < 0.05).	9	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	11	12
In another words , it may be determined by the relative levels of insulin that could efficiently activate PI3K and Akt pathway .	In another words, it may be determined by the relative levels of insulin that could efficiently activate PI3K and Akt pathway.	11	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	Akt	Akt	akt	13	14	20	21
Likewise , we have studied the insulin stimulated AKT and FOXO1 signalling , which could be involved in regulating proliferation and/or apoptosis in beta-cells downstream of PTP1B XREF_BIBR , XREF_BIBR .	Likewise, we have studied the insulin stimulated AKT and FOXO1 signalling, which could be involved in regulating proliferation and/or apoptosis in beta-cells downstream of PTP1B XREF_BIBR, XREF_BIBR.	4	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	8	9
In tenocytes , glucocorticoid induced reduction of collagen synthesis was rescued by insulin treatment , which activated both ERK and Akt signals XREF_BIBR .	In tenocytes, glucocorticoid induced reduction of collagen synthesis was rescued by insulin treatment, which activated both ERK and Akt signals XREF_BIBR.	12	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	20	21
Both MAPK and PI3K-Akt pathways could be activated by insulin and lead to gene regulation of transduction pathway proteins .	Both MAPK and PI3K-Akt pathways could be activated by insulin and lead to gene regulation of transduction pathway proteins.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	9	10	3	4
Importantly , given that AKT is at the focal point of several signaling pathways , the question that arises is whether PPTR-1 is a broad regulator of AKT activity , or does it specifically play a role in insulin dependent activation of AKT ?	Importantly, given that AKT is at the focal point of several signaling pathways, the question that arises is whether PPTR-1 is a broad regulator of AKT activity, or does it specifically play a role in insulin dependent activation of AKT?	38	43	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	38	39	42	43
However , it is also known that the insulin mediated Akt signaling pathway is not a major pathway for the induction of glucose uptake by adipocytes , according to a previous report .	However, it is also known that the insulin mediated Akt signaling pathway is not a major pathway for the induction of glucose uptake by adipocytes, according to a previous report.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
In sum , insulin activation of Akt caused neither mTORC2 recruitment to FAs , nor cytoskeletal restructuring .	In sum, insulin activation of Akt caused neither mTORC2 recruitment to FAs, nor cytoskeletal restructuring.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	6	7
Our results indicate that SHIP2 plays a negative regulatory role via the 5 '-phosphatase activity in insulin signalling , and that PI ( 3,4,5 ) P3 rather than PI ( 3,4 ) P2 is important for in vivo regulation of insulin induced Akt activation leading to glycogen synthesis in L6 myotubes .	Our results indicate that SHIP2 plays a negative regulatory role via the 5 '-phosphatase activity in insulin signalling, and that PI (3,4,5) P3 rather than PI (3,4) P2 is important for in vivo regulation of insulin induced Akt activation leading to glycogen synthesis in L6 myotubes.	38	43	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	40	41	42	43
Insulin activates the mitogenic MAPK and ERK protein kinases and the metabolic PI3k-Akt pathways .	Insulin activates the mitogenic MAPK and ERK protein kinases and the metabolic PI3k-Akt pathways.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PI3k-Akt	PI3k-Akt	PI3k-Akt	0	1	12	13
We also show that cAMP inhibits insulin and amino acid stimulated mTORC1 activation independently of Rheb , Rag GTPases , TSC2 , PKB , MAPK and AMPK , indicating that cAMP may act independently of known regulatory inputs into mTOR .	We also show that cAMP inhibits insulin and amino acid stimulated mTORC1 activation independently of Rheb, Rag GTPases, TSC2, PKB, MAPK and AMPK, indicating that cAMP may act independently of known regulatory inputs into mTOR.	6	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	6	7	22	23
Down-stream of IRS1 , activation of Akt by insulin requires hierarchical phosphorylation on two residues , Thr308 and Ser473 XREF_BIBR .	Down-stream of IRS1, activation of Akt by insulin requires hierarchical phosphorylation on two residues, Thr308 and Ser473 XREF_BIBR.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	6	7
The activation of PI3K and Akt signaling by insulin and growth factors regulates muscular mass by reducing FoxO3a activity and , hence , by blocking the expression of MAFbx and MuRF1 XREF_BIBR .	The activation of PI3K and Akt signaling by insulin and growth factors regulates muscular mass by reducing FoxO3a activity and, hence, by blocking the expression of MAFbx and MuRF1 XREF_BIBR.	3	11	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	5	6
Further , BAF60c knockdown attenuated insulin stimulated AKT activation and glycolytic flux in transduced myotubes ( XREF_SUPPLEMENTARY ) .	Further, BAF60c knockdown attenuated insulin stimulated AKT activation and glycolytic flux in transduced myotubes (XREF_SUPPLEMENTARY).	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
To investigate whether varying concentrations of insulin would stimulate Akt and mTORC1 signaling , increasing concentrations of insulin were incubated with C2C12 myotubes for 30 , 60 , and 120 min .	To investigate whether varying concentrations of insulin would stimulate Akt and mTORC1 signaling, increasing concentrations of insulin were incubated with C2C12 myotubes for 30, 60, and 120 min.	4	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	9	10
Leptin and insulin induce the JAK-STAT3 and PI3K-Akt pathways , respectively , in hypothalamic neurons .	Leptin and insulin induce the JAK-STAT3 and PI3K-Akt pathways, respectively, in hypothalamic neurons.	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	2	3	7	8
High glucose levels combined with high insulin has been shown to result in impaired sensitivity to insulin stimulation of Akt activity .	High glucose levels combined with high insulin has been shown to result in impaired sensitivity to insulin stimulation of Akt activity.	16	20	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	19	20
Though we did not study changes in cardiac glucose metabolism or activation of insulin/PI3k/Akt signaling in these animals , it has previously been shown that 9-cis RA , which induces activation of RXR signaling , increased insulin stimulated glucose transport and activation of Akt in cardiomyocytes , indicating that the anti-apoptotic effect of ATRA and LGD1069 on diabetic heart , may be through activation of PI3KAkt signaling .	Though we did n't study changes in cardiac glucose metabolism or activation of insulin/PI3k/Akt signaling in these animals, it has previously been shown that 9-cis RA, which induces activation of RXR signaling, increased insulin stimulated glucose transport and activation of Akt in cardiomyocytes, indicating that the anti-apoptotic effect of ATRA and LGD1069 on diabetic heart, may be through activation of PI3KAkt signaling.	35	44	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	36	37	43	44
In fact , no difference was observed in the insulin stimulated AKT response for any of the given diets ( XREF_FIG ) .	In fact, no difference was observed in the insulin stimulated AKT response for any of the given diets (XREF_FIG).	6	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	11	12
In this study , we examined the effect of insulin induced Akt activation on albumin endocytosis in proximal tubule epithelial cells .	In this study, we examined the effect of insulin induced Akt activation on albumin endocytosis in proximal tubule epithelial cells.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
The PI3K inhibitor LY294002 was found to inhibit the insulin induced activation of Akt but the same inhibitor failed to inhibit the sorbitol induced activation of Akt .	The PI3K inhibitor LY294002 was found to inhibit the insulin induced activation of Akt but the same inhibitor failed to inhibit the sorbitol induced activation of Akt.	8	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	13	14
In this regard , our studies have also demonstrated that insulin stimulated Akt activity in skeletal muscle of these obese rats is very mildly reduced while PI3K activity is markedly reduced , as compared to lean rats [ XREF_BIBR ] .	In this regard, our studies have also demonstrated that insulin stimulated Akt activity in skeletal muscle of these obese rats is very mildly reduced while PI3K activity is markedly reduced, as compared to lean rats [XREF_BIBR].	10	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
PI3K and Akt pathway is one of the signaling cascades activated by insulin and plays a major role in hepatic glucose homeostasis XREF_BIBR , XREF_BIBR , and Akt knockout mice show insulin resistance that later developed to a phenotype of type 2 diabetes XREF_BIBR .	PI3K and Akt pathway is one of the signaling cascades activated by insulin and plays a major role in hepatic glucose homeostasis XREF_BIBR, XREF_BIBR, and Akt knockout mice show insulin resistance that later developed to a phenotype of type 2 diabetes XREF_BIBR.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	2	3
Although not usually described as part of the insulin-PI3K-GSK3 pathway , IDE upregulation requires insulin mediated AKT activation .	Although not usually described as part of the insulin-PI3K-GSK3 pathway, IDE upregulation requires insulin mediated AKT activation.	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	14	15	16	17
To determine if strain differences were apparent within the insulin signaling pathway , insulin stimulated Akt signaling was assessed in skeletal muscle and livers of 6J and 6N mice fed an LFD or HFD for 1 week .	To determine if strain differences were apparent within the insulin signaling pathway, insulin stimulated Akt signaling was assessed in skeletal muscle and livers of 6J and 6N mice fed an LFD or HFD for 1 week.	13	16	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
In the present study , our results demonstrated insulin played an therapic role in LPS induced ALI and the mechanism of ENaC mediated AFC by which insulin activated PI3K and Akt signaling pathway in vitro and in vivo .	In the present study, our results demonstrated insulin played an therapic role in LPS induced ALI and the mechanism of ENaC mediated AFC by which insulin activated PI3K and Akt signaling pathway in vitro and in vivo.	26	32	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	30	31
Although there was little difference in insulin stimulated pAkt and Akt protein ratios , H2A -/- adipocytes demonstrated less repression of the adipogenic and insulin sensitizing transcription factors Pparg , Irs1 and Pik3r3 , which binds Irs1 during insulin stimulation ( XREF_SUPPLEMENTARY ) .	Although there was little difference in insulin stimulated pAkt and Akt protein ratios, H2A -/- adipocytes demonstrated less repression of the adipogenic and insulin sensitizing transcription factors Pparg, Irs1 and Pik3r3, which binds Irs1 during insulin stimulation (XREF_SUPPLEMENTARY).	4	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	10	11
The studies include analysis of torpor responsive changes in cell signaling pathways ( insulin signaling Akt and PI3K pathway , MAPKs , AMPK , and GSK3 ) XREF_BIBR , mRNA expression changes for selected genes that were previously linked with the hibernation phenotype in ground squirrels XREF_BIBR , controls on transcription ( histone modification ) and translation ( mTOR and ribosomal proteins ) XREF_BIBR , carbohydrate fuel regulation at the pyruvate dehydrogenase locus XREF_BIBR , and cytoprotective mechanisms ( antioxidant defenses and heat shock proteins ) XREF_BIBR .	The studies include analysis of torpor responsive changes in cell signaling pathways (insulin signaling Akt and PI3K pathway, MAPKs, AMPK, and GSK3) XREF_BIBR, mRNA expression changes for selected genes that were previously linked with the hibernation phenotype in ground squirrels XREF_BIBR, controls on transcription (histone modification) and translation (mTOR and ribosomal proteins) XREF_BIBR, carbohydrate fuel regulation at the pyruvate dehydrogenase locus XREF_BIBR, and cytoprotective mechanisms (antioxidant defenses and heat shock proteins) XREF_BIBR.	3	25	signaling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
Higher concentrations of troglitazone ( > or = 1 microM ) inhibited both insulin stimulated PKB activity and expression of FAS .	Higher concentrations of troglitazone (> or = 1 microM) inhibited both insulin stimulated PKB activity and expression of FAS.	11	16	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	13	14	15	16
Src homology 2 containing inositol 5-phosphatase 2 ( SHIP2 ) has been identified as 5 '-inositol phosphatase that hydrolyzes PI ( 3,4,5 ) P ( 3 ) to PI ( 3,4 ) P ( 2 ) , which negatively regulates insulin induced Akt signaling in skeletal muscle .	Src homology 2 containing inositol 5-phosphatase 2 (SHIP2) has been identified as 5 '-inositol phosphatase that hydrolyzes PI (3,4,5) P (3) to PI (3,4) P (2), which negatively regulates insulin induced Akt signaling in skeletal muscle.	39	43	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	40	41	42	43
Later , as hepatic Akt activation by insulin is impaired , continued increases in hepatic aPKC , along with a modicum of basal Akt , or continued increases in resting Akt activity or other factors that activate mTOR/S6 kinase may be sufficient to maintain increases in hepatic lipogenesis .	Later, as hepatic Akt activation by insulin is impaired, continued increases in hepatic aPKC, along with a modicum of basal Akt, or continued increases in resting Akt activity or other factors that activate mTOR/S6 kinase may be sufficient to maintain increases in hepatic lipogenesis.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	4	5
Although insulin signaling activates the AKT pathway XREF_BIBR , AKT phosphorylation after insulin injection was comparable in adipose tissues from WT and Psmb8 -/- mice ( XREF_SUPPLEMENTARY ) , suggesting that the pathways downstream from AKT are altered in Psmb8 deficient cells .	Although insulin signaling activates the AKT pathway XREF_BIBR, AKT phosphorylation after insulin injection was comparable in adipose tissues from WT and Psmb8 -/- mice (XREF_SUPPLEMENTARY), suggesting that the pathways downstream from AKT are altered in Psmb8 deficient cells.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	1	2	5	6
Interestingly , we found that insulin treatment resulted in increased cytoplasmic Skp2 and nuclear p27 levels in the liver cells , suggesting that insulin mediated Akt activation may induce hepatocyte polyploidy by promoting the cytoplasmic retention of Skp2 ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Interestingly, we found that insulin treatment resulted in increased cytoplasmic Skp2 and nuclear p27 levels in the liver cells, suggesting that insulin mediated Akt activation may induce hepatocyte polyploidy by promoting the cytoplasmic retention of Skp2 (XREF_FIG, XREF_SUPPLEMENTARY).	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	25	26
These results indicate that calmodulin is necessary for insulin induced Akt activation in endothelial cell .	These results indicate that calmodulin is necessary for insulin induced Akt activation in endothelial cell.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Insulin and other growth factors that activate PI3K and Akt have been implicated as potent survival factors in mammalian cell culture [ XREF_BIBR , XREF_BIBR ] .	Insulin and other growth factors that activate PI3K and Akt have been implicated as potent survival factors in mammalian cell culture [XREF_BIBR, XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	9	10
In contrast , insulin , acting through its signaling pathway , activates Akt , which in turn activates phosphodiesterase 3-B , thereby accelerating the degradation of cAMP .	In contrast, insulin, acting through its signaling pathway, activates Akt, which in turn activates phosphodiesterase 3-B, thereby accelerating the degradation of cAMP.	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	12	13
In the present study we found that the observed potentiation by XMetS on insulin induced Erk activation was less that the potentiation of insulin stimulated Akt activation by XMetS .	In the present study we found that the observed potentiation by XMetS on insulin induced Erk activation was less that the potentiation of insulin stimulated Akt activation by XMetS.	21	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	25	26
Results Insulin or rhEGF stimulation led to Akt activation in CNE-1 cells .	Results Insulin or rhEGF stimulation led to Akt activation in CNE-1 cells.	0	8	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	1	2	7	8
In all three groups of rats , insulin significantly increased ERK2 , RSK2 , Akt , and p70S6k activities .	In all three groups of rats, insulin significantly increased ERK2, RSK2, Akt, and p70S6k activities.	7	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	14	15
Overexpression of dominant negative mutants of PKClambda inhibit insulin stimulated glucose uptake by ~ 60 % , and these mutants do not inhibit insulin induced activation of Akt [ XREF_BIBR ] .	Overexpression of dominant negative mutants of PKClambda inhibit insulin stimulated glucose uptake by ~ 60%, and these mutants do not inhibit insulin induced activation of Akt [XREF_BIBR].	23	29	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	27	28
EETs Enhance Insulin Induced Akt Activation in Primary Hepatocytes without Affecting IR or IRS-1 Phosphorylation .	EETs Enhance Insulin Induced Akt Activation in Primary Hepatocytes without Affecting IR or IRS-1 Phosphorylation.	1	5	Induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	2	3	4	5
Insulin activates PI3K and Akt signalling pathway which is known to up-regulate SUR2A XREF_BIBR .	Insulin activates PI3K and Akt signalling pathway which is known to up-regulate SUR2A XREF_BIBR.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
Next , we confirmed that insulin dependent stimulation of AKT is affected by GPS2 deletion invivo by monitoring AKT activation in adipose tissue under fasted and insulin stimulated conditions .	Next, we confirmed that insulin dependent stimulation of AKT is affected by GPS2 deletion invivo by monitoring AKT activation in adipose tissue under fasted and insulin stimulated conditions.	5	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	9	10
Intranasal insulin treatment restored the levels of AKT pT308 in the hippocampus of ICV-STZ rats ( XREF_FIG ) .	Intranasal insulin treatment restored the levels of AKT pT308 in the hippocampus of ICV-STZ rats (XREF_FIG).	1	8	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	1	2	7	8
In the cytosol , the elevated p70S6K activation in betaIRKO cells could potentially serine phosphorylate IRS1 and further dampen insulin stimulation of Akt in betaIRKO cells XREF_BIBR ( XREF_FIG ) , and potentiate IGF-I mediated pathways in the mutant cells .	In the cytosol, the elevated p70S6K activation in betaIRKO cells could potentially serine phosphorylate IRS1 and further dampen insulin stimulation of Akt in betaIRKO cells XREF_BIBR (XREF_FIG), and potentiate IGF-I mediated pathways in the mutant cells.	19	26	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	22	23
APPL1 enhances insulin stimulated activation of Akt and suppression of gluconeogenesis in hepatocytes and eNOS activation and NO production in enthelial cells via by blocking the association of Akt , a major signaling intermediate in the insulin signaling pathway , with its endogenous inhibitor tribble 3 ( TRB3 ) through a direct competition .	APPL1 enhances insulin stimulated activation of Akt and suppression of gluconeogenesis in hepatocytes and eNOS activation and NO production in enthelial cells via by blocking the association of Akt, a major signaling intermediate in the insulin signaling pathway, with its endogenous inhibitor tribble 3 (TRB3) through a direct competition.	1	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
Concomitantly , EPO partially rescued insulin stimulated AKT activation , reduced markers of oxidative stress , and restored heat-shock protein 72 expression in soleus muscles from HFD fed rats .	Concomitantly, EPO partially rescued insulin stimulated AKT activation, reduced markers of oxidative stress, and restored heat-shock protein 72 expression in soleus muscles from HFD fed rats.	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
The binding of growth factor or insulin to cell surface receptors activates PI3K , which converts the plasma membrane lipid PIP2 to PIP3 , subsequently recruits PDK1 and Akt to the plasma .	The binding of growth factor or insulin to cell surface receptors activates PI3K, which converts the plasma membrane lipid PIP2 to PIP3, subsequently recruits PDK1 and Akt to the plasma.	1	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	28	29
These results indicated that activation of Akt by insulin remains the same in lean and fatty hepatocytes .	These results indicated that activation of Akt by insulin remains the same in lean and fatty hepatocytes.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	6	7
Here we report that ubiquitin like protein 4A ( Ubl4A ) plays a crucial role in insulin induced Akt plasma membrane translocation .	Here we report that ubiquitin like protein 4A (Ubl4A) plays a crucial role in insulin induced Akt plasma membrane translocation.	14	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
ET-1 via ETAR pathway suppressed insulin induced AKT activation , whereas remained insulin induced ERK activation .	ET-1 via ETAR pathway suppressed insulin induced AKT activation, whereas remained insulin induced ERK activation.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
During reperfusion of the ischemic heart , insulin activates the AKT and AMPK pathways and inhibits the deleterious effects of angiotensin-I perfusion on SOD expression and cardiac function .	During reperfusion of the ischemic heart, insulin activates the AKT and AMPK pathways and inhibits the deleterious effects of angiotensin-I perfusion on SOD expression and cardiac function.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	10	11
Incubation of L6 myotubes with palmitate ( for 16 h ) increases intramyocellular ceramide and reduces insulin stimulated PKB activation and glucose uptake .	Incubation of L6 myotubes with palmitate (for 16 h) increases intramyocellular ceramide and reduces insulin stimulated PKB activation and glucose uptake.	15	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	16	17	18	19
Interestingly , it has been shown that insulin induced stimulation of PKB and Akt protects cardiomyocytes against oxidative stress [ XREF_BIBR ] , that some of the Akt phosphorylated in response to insulin translocates to mitochondria [ XREF_BIBR ] , and that phosphorylation by PKB and Akt inhibits NHE1 [ XREF_BIBR ] .	Interestingly, it has been shown that insulin induced stimulation of PKB and Akt protects cardiomyocytes against oxidative stress [XREF_BIBR], that some of the Akt phosphorylated in response to insulin translocates to mitochondria [XREF_BIBR], and that phosphorylation by PKB and Akt inhibits NHE1 [XREF_BIBR].	24	33	in response to	Positive_regulation_in_response_to	Positive_activation	Positive_regulation	insulin	insulin	insulin	Akt	Akt phosphorylated	akt	32	33	27	28
Consistent with these observations we found a ~ 30 % increase in hepatic DAG content and a ~ 25 % reduction in insulin stimulated Akt activity .	Consistent with these observations we found a ~ 30% increase in hepatic DAG content and a ~ 25% reduction in insulin stimulated Akt activity.	0	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	24	25
Nonetheless , in the sheep model , postnatal treatment with flutamide failed to restore normal insulin activation ( phosphorylation ) of AKT in the muscle and liver of prenatal testosterone treated females , indicating that insulin resistance in metabolic tissues is not overcome ( Lu & Padmanabhan , unpublished observations ) .	Nonetheless, in the sheep model, postnatal treatment with flutamide failed to restore normal insulin activation (phosphorylation) of AKT in the muscle and liver of prenatal testosterone treated females, indicating that insulin resistance in metabolic tissues is not overcome (Lu & Padmanabhan, unpublished observations).	15	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	15	16	21	22
Both insulin induced Akt activation and anti-apoptotic effect could be abrogated by wortmannin , a phosphatidylinositol ( PI ) 3-kinase inhibitor .	Both insulin induced Akt activation and anti-apoptotic effect could be abrogated by wortmannin, a phosphatidylinositol (PI) 3-kinase inhibitor.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
Insulin signaling through phosphatidylinositol 3-kinase ( PI 3-kinase ) activates the protein kinase Akt through phosphorylation of its threonine 308 and serine 473 residues by the PDK1 protein kinase and the Rictor-mammalian target of rapamycin complex ( mTORC2 ) , respectively .	Insulin signaling through phosphatidylinositol 3-kinase (PI 3-kinase) activates the protein kinase Akt through phosphorylation of its threonine 308 and serine 473 residues by the PDK1 protein kinase and the Rictor-mammalian target of rapamycin complex (mTORC2), respectively.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	13	14
Consistently , insulin mediated activation of Akt in a different cellular context ( U2OS cells ) is counteracted by TBP-1 overexpression ( XREF_FIG ) .	Consistently, insulin mediated activation of Akt in a different cellular context (U2OS cells) is counteracted by TBP-1 overexpression (XREF_FIG).	2	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
Insulin did not activate PKB and S6K , nor did it stimulate 6-phosphofructo-2-kinase and production of fructose 2,6-bisphosphate , in the hearts of mPDK1 (-/-) mice , consistent with PDK1 mediating these processes .	Insulin did not activate PKB and S6K, nor did it stimulate 6-phosphofructo-2-kinase and production of fructose 2,6-bisphosphate, in the hearts of mPDK1 (-/-) mice, consistent with PDK1 mediating these processes.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	4	5
Similar results were obtained in HepG2 cells , where insulin induced AKT activity led to phosphorylation of MLK3 at Ser 674 .	Similar results were obtained in HepG2 cells, where insulin induced AKT activity led to phosphorylation of MLK3 at Ser 674.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	11	12
XREF_FIG A , insulin activates Akt significantly , whereas oleuropein does not increase the phosphorylation of Akt despite results showing 10microM oleuropein to have an effect equivalent to that of 100nM insulin in inducing glucose uptake .	XREF_FIG A, insulin activates Akt significantly, whereas oleuropein does not increase the phosphorylation of Akt despite results showing 10microM oleuropein to have an effect equivalent to that of 100nM insulin in inducing glucose uptake.	1	6	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
This was evidenced by a full restoration of insulin mediated Akt activation ( XREF_FIG ) and glycogen synthesis ( XREF_FIG ) to GFP control levels in myotubes coexpressing ATGL and HSL compared with ATGL alone .	This was evidenced by a full restoration of insulin mediated Akt activation (XREF_FIG) and glycogen synthesis (XREF_FIG) to GFP control levels in myotubes coexpressing ATGL and HSL compared with ATGL alone.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
In the presence of OA and palmitate , PP2A remained in the eNOS complex ( XREF_FIG ) , but the insulin stimulated association of Akt and eNOS was restored ( XREF_FIG ) .	In the presence of OA and palmitate, PP2A remained in the eNOS complex (XREF_FIG), but the insulin stimulated association of Akt and eNOS was restored (XREF_FIG).	19	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	24	25
The potential role of the epsilon isozyme of protein kinase C ( PKC ) in the activation of Akt induced by insulin has now been examined .	The potential role of the epsilon isozyme of protein kinase C (PKC) in the activation of Akt induced by insulin has now been examined.	16	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	18	19
Based on the knowledge that Wnt and beta-catenin signaling is activated in HCC , we focused on Wnt and beta-catenin signaling and demonstrated that Irs1 expression was induced by Wnt3a stimulation in the primary hepatocytes , associated with insulin stimulated Akt activation .	Based on the knowledge that Wnt and beta-catenin signaling is activated in HCC, we focused on Wnt and beta-catenin signaling and demonstrated that Irs1 expression was induced by Wnt3a stimulation in the primary hepatocytes, associated with insulin stimulated Akt activation.	36	41	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	38	39	40	41
Furthermore , we reported that the upregulation of GRK2 and a decrease in beta-arrestin 2 inhibit the insulin induced stimulation of Akt and eNOS signaling , and that GRK2 overactivation may result from an increase in PKC activity in preparations of aortas from diabetic mice with hyperinsulinemia .	Furthermore, we reported that the upregulation of GRK2 and a decrease in beta-arrestin 2 inhibit the insulin induced stimulation of Akt and eNOS signaling, and that GRK2 overactivation may result from an increase in PKC activity in preparations of aortas from diabetic mice with hyperinsulinemia.	16	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	21	22
An over-expression of SHIP2 in adipocyte 3T3-L1 cells inhibits insulin signaling , and expression of the catalytic mutant SHIP2 enhances the activity of Akt induced by insulin and thus generates glucose uptake and glycogen synthesis [ XREF_BIBR ] .	An over-expression of SHIP2 in adipocyte 3T3-L1 cells inhibits insulin signaling, and expression of the catalytic mutant SHIP2 enhances the activity of Akt induced by insulin and thus generates glucose uptake and glycogen synthesis [XREF_BIBR].	21	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	23	24
These results support the notion that GSK3alpha has an inhibitory role in IL-1-, but not insulin induced AKT activation .	These results support the notion that GSK3alpha has an inhibitory role in IL-1-, but not insulin induced AKT activation.	14	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	15	16	17	18
During insulin stimulation Akt Ser 473 and mTOR Ser 2448 phosphorylation was increased on both examination days .	During insulin stimulation Akt Ser 473 and mTOR Ser 2448 phosphorylation was increased on both examination days.	0	12	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
Fucosterol downregulated insulin triggered PI3K and Akt , and ERK pathways .	Fucosterol downregulated insulin triggered PI3K and Akt, and ERK pathways.	2	7	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
These results indicate that , similar to the insulin mediated Akt activation in normal endothelial cells , the increased insulin sensitivity in ATP2B1 silenced HUVECs is calcium dependent .	These results indicate that, similar to the insulin mediated Akt activation in normal endothelial cells, the increased insulin sensitivity in ATP2B1 silenced HUVECs is calcium dependent.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Consistently , insulin induced Akt activation led to phosphorylation of WT-, but not T181A- nor T181E-XLF , and subsequently resulted in XLF dissociation from the LIG4 and XRCC4 complex ( XREF_FIG ) .	Consistently, insulin induced Akt activation led to phosphorylation of WT-, but not T181A- nor T181E-XLF, and subsequently resulted in XLF dissociation from the LIG4 and XRCC4 complex (XREF_FIG).	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
Our data further showed that gefitinib modestly reduced AKT signaling in EGFR-mutant glioblastoma and that addition of insulin or IGF1 activated AKT and abolished the ability of gefitinib to repress AKT signaling .	Our data further showed that gefitinib modestly reduced AKT signaling in EGFR-mutant glioblastoma and that addition of insulin or IGF1 activated AKT and abolished the ability of gefitinib to repress AKT signaling.	15	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	17	18	21	22
The observation that 13dmC did not inhibit insulin stimulation of MAPK and PKB is consistent with the AChR target for these toxins .	The observation that 13dmC did not inhibit insulin stimulation of MAPK and PKB is consistent with the AChR target for these toxins.	7	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	7	8	12	13
The aim of this study was to determine whether insulin activation of the PI3K and Akt and MAPK signalling pathways is altered in skeletal muscle of young adult men with LBW .	The aim of this study was to determine whether insulin activation of the PI3K and Akt and MAPK signalling pathways is altered in skeletal muscle of young adult men with LBW.	9	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	15	16
Surprisingly , hepatic Akt phosphorylation increased significantly which implies that insulin induced Akt response was enhanced because of reduced inhibition of Ang II.	Surprisingly, hepatic Akt phosphorylation increased significantly which implies that insulin induced Akt response was enhanced because of reduced inhibition of Ang II.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
The drug recovered insulin induced Akt activation and reduced gluconeogenic genes .	The drug recovered insulin induced Akt activation and reduced gluconeogenic genes.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
The consequence of this is decreased activity of the threonine serine kinase Akt , which is a key switch in the cell that controls paths leading to either protein production or breakdown , because Akt is activated by insulin and insulin like growth factor-1 .	The consequence of this is decreased activity of the threonine serine kinase Akt, which is a key switch in the cell that controls paths leading to either protein production or breakdown, because Akt is activated by insulin and insulin like growth factor-1.	34	40	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	38	39	34	35
Moreover , insulin treatment alleviated hyperglycemia ( XREF_FIG ) , markedly activated Akt and AMPK and showed a significant increase in GLUT4 translocation and subsequent glucose uptake in ischemia reperfused STZ hearts with or without IPC .	Moreover, insulin treatment alleviated hyperglycemia (XREF_FIG), markedly activated Akt and AMPK and showed a significant increase in GLUT4 translocation and subsequent glucose uptake in ischemia reperfused STZ hearts with or without IPC.	2	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	12	13
[ Also note , in STZ-diabetic rats , insulin activation of PKB and IRS-1 and PI3K are markedly impaired , but , in contrast , activation of aPKC and IRS-2 and PI3K are fully conserved ; unpublished observations ; MP Sajan , ML Standaert , RV Farese ] .	[Also note, in STZ-diabetic rats, insulin activation of PKB and IRS-1 and PI3K are markedly impaired, but, in contrast, activation of aPKC and IRS-2 and PI3K are fully conserved; unpublished observations; MP Sajan, ML Standaert, RV Farese].	8	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	11	12
Taken together , these data supported the notion that PHLPP-1 up-regulation restrains activation of Akt induced by insulin and suppresses myocytes survival .	Taken together, these data supported the notion that PHLPP-1 up-regulation restrains activation of Akt induced by insulin and suppresses myocytes survival.	12	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	14	15
At the molecular level , insulin and leptin both phosphorylate and activate Akt , which in turn activates the mammalian target of rapamycin ( mTOR ) complex 1 ( mTORC1 ) , a key pathway that links growth factors , hormones , and energy balance with cell proliferation .	At the molecular level, insulin and leptin both phosphorylate and activate Akt, which in turn activates the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a key pathway that links growth factors, hormones, and energy balance with cell proliferation.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	12	13
Insulin activated all Akt isoforms in lean muscles , whereas only Akt-1 was activated in obese muscles .	Insulin activated all Akt isoforms in lean muscles, whereas only Akt-1 was activated in obese muscles.	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
The increased insulin and IGF -1 resulted in activation of downstream Akt and mTOR cellular survival pathway .	The increased insulin and IGF -1 resulted in activation of downstream Akt and mTOR cellular survival pathway.	0	16	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	11	12
We demonstrate that PKC activation with either a phorbol ester or exogenous application of diacylglycerides impairs insulin induced Akt activation , whereas PKC inhibition augments insulin induced Akt activation .	We demonstrate that PKC activation with either a phorbol ester or exogenous application of diacylglycerides impairs insulin induced Akt activation, whereas PKC inhibition augments insulin induced Akt activation.	24	28	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
Increased insulin and IGF-I signaling activates the phosphoinositide-3 kinase and Akt pathway , thereby reducing the nuclear content of the transcription factor FoxO1 , the key nutrigenomic regulator of acne target genes .	Increased insulin and IGF-I signaling activates the phosphoinositide-3 kinase and Akt pathway, thereby reducing the nuclear content of the transcription factor FoxO1, the key nutrigenomic regulator of acne target genes.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	10	11
Further , overexpression of miR-143 in obese mice models inhibited insulin stimulated AKT activation , and impaired glucose metabolism .	Further, overexpression of miR-143 in obese mice models inhibited insulin stimulated AKT activation, and impaired glucose metabolism.	9	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	12	13
Hypertensive patients with high plasma insulin or metabolic syndrome have a greater occurrence of LVH , which could be due to insulin activation of the serine threonine kinase Akt and its downstream targets in the heart , resulting in cellular hypertrophy .	Hypertensive patients with high plasma insulin or metabolic syndrome have a greater occurrence of LVH, which could be due to insulin activation of the serine threonine kinase Akt and its downstream targets in the heart, resulting in cellular hypertrophy.	21	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	28	29
Myriocin treatment and CerS6 deletion restored insulin induced Akt signaling previously disrupted by ceramide [ XREF_BIBR , XREF_BIBR ] .	Myriocin treatment and CerS6 deletion restored insulin induced Akt signaling previously disrupted by ceramide [XREF_BIBR, XREF_BIBR].	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Insulin also promotes PI3K and AKT signaling pathway in zebrafish oocytes .	Insulin also promotes PI3K and AKT signaling pathway in zebrafish oocytes.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	5	6
CONLCUSIONS : PDK1 is likely to be one of the protein kinases that mediate the activation of PKB by insulin and growth factors .	CONLCUSIONS : PDK1 is likely to be one of the protein kinases that mediate the activation of PKB by insulin and growth factors.	15	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	19	20	17	18
In turn , circulating lipoprotein ceramide can mediate inflammatory cytokine release from adipose tissue macrophages , and inhibits insulin stimulated PKB activation in skeletal muscle ( Boon etal .	In turn, circulating lipoprotein ceramide can mediate inflammatory cytokine release from adipose tissue macrophages, and inhibits insulin stimulated PKB activation in skeletal muscle (Boon etal.	17	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	18	19	20	21
The aim of this study was to correlate insulin stimulation of glucose uptake and PKB activation with that induced by vanadate in adult ventricular myocytes from lean and obese Zucker fa/fa rats .	The aim of this study was to correlate insulin stimulation of glucose uptake and PKB activation with that induced by vanadate in adult ventricular myocytes from lean and obese Zucker fa/fa rats.	8	15	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	14	15
Furthermore , a significant increase in PKM2 protein expression and Akt phosphorylation was identified in MCF-7 cells treated with 100 ng/ml insulin .	Furthermore, a significant increase in PKM2 protein expression and Akt phosphorylation was identified in MCF-7 cells treated with 100 ng/ml insulin.	10	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	10	11
Furthermore , Akt activation by insulin is not associated with increased AMPKalpha1 Ser487 phosphorylation in HUVECs .	Furthermore, Akt activation by insulin is not associated with increased AMPKalpha1 Ser487 phosphorylation in HUVECs.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	2	3
In a separate set of animals , lean and obese mice were treated orally with the iNOS inhibitor aminoguanidine ( 20mg/kg/day , three weeks ) , after which the iNOS expression and the phosphorylation of insulin induced AKT , IRS-1 and IRbeta were analyzed .	In a separate set of animals, lean and obese mice were treated orally with the iNOS inhibitor aminoguanidine (20mg/kg/day, three weeks), after which the iNOS expression and the phosphorylation of insulin induced AKT, IRS-1 and IRbeta were analyzed.	33	43	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	35	36	37	38
In muscle , loss of p50alpha and p55alpha results in reduced levels of insulin stimulated insulin receptor substrate 1 ( IRS-1 ) and phosphotyrosine associated PI 3-kinase but enhanced levels of IRS-2-associated PI 3-kinase and Akt activation , whereas in adipocytes levels of both insulin stimulated PI 3-kinase and Akt are unchanged .	In muscle, loss of p50alpha and p55alpha results in reduced levels of insulin stimulated insulin receptor substrate 1 (IRS-1) and phosphotyrosine associated PI 3-kinase but enhanced levels of IRS-2-associated PI 3-kinase and Akt activation, whereas in adipocytes levels of both insulin stimulated PI 3-kinase and Akt are unchanged.	41	50	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of both insulin	insulin	Akt	Akt	akt	44	45	49	50
We also generated wild-type and double TAPP1 R211L and R211L TAPP2 R218L and R218L knock-in embryonic fibroblasts and found that insulin triggered enhanced production of PtdIns ( 3,4,5 ) P 3 and Akt activity in the double knock-in fibroblasts .	We also generated wild-type and double TAPP1 R211L and R211L TAPP2 R218L and R218L knock-in embryonic fibroblasts and found that insulin triggered enhanced production of PtdIns (3,4,5) P 3 and Akt activity in the double knock-in fibroblasts.	20	33	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	32	33
Activation of IRS-1 promotes the insulin stimulated activation of Akt via PI3K .	Activation of IRS-1 promotes the insulin stimulated activation of Akt via PI3K.	4	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	9	10
Within the 4h following FCS withdrawal IGF1 and insulin effectively activated Akt and PKB and prevented apoptosis , also when added with a 2-h delay .	Within the 4h following FCS withdrawal IGF1 and insulin effectively activated Akt and PKB and prevented apoptosis, also when added with a 2-h delay.	6	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	13	14
Insulin also activates Akt in the central nervous system ( CNS ) , where insulin action is critical for neuroendocrine and homeostatic responses involved in energy balance , hepatic glucose production , hypoglycemic counter regulation , peripheral fat metabolism , and reproduction XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Insulin also activates Akt in the central nervous system (CNS), where insulin action is critical for neuroendocrine and homeostatic responses involved in energy balance, hepatic glucose production, hypoglycemic counter regulation, peripheral fat metabolism, and reproduction XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
Insulin stimulated Akt threonine 308 phosphorylation decreased 45 % ( P < 0.005 ) between 6weeks and 6months of age , and a further 46 % ( P < 0.05 ) between 6 and 12months , in HFO .	Insulin stimulated Akt threonine 308 phosphorylation decreased 45% (P < 0.005) between 6weeks and 6months of age, and a further 46% (P < 0.05) between 6 and 12months, in HFO.	0	3	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Insulin induction of mTORC2 and resultant phospho-473 Akt further contrasts with mTORC2 and Akt signaling via mechanical force in that it does not require mTORC2 association with vinculin .	Insulin induction of mTORC2 and resultant phospho-473 Akt further contrasts with mTORC2 and Akt signaling via mechanical force in that it does not require mTORC2 association with vinculin.	0	8	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	7	8
For example , TBC1D1 has recently been identified ( as an AKT substrate ) in the insulin stimulated AKT cascade that facilitates GLUT4 translocation [ XREF_BIBR ] and regulates glucose uptake [ XREF_BIBR ] .	For example, TBC1D1 has recently been identified (as an AKT substrate) in the insulin stimulated AKT cascade that facilitates GLUT4 translocation [XREF_BIBR] and regulates glucose uptake [XREF_BIBR].	15	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	18	19
Administration of insulin in reperfusion enhances AKT mediated cardioprotection and leads to cross-talk between AKT and JNK pathways .	Administration of insulin in reperfusion enhances AKT mediated cardioprotection and leads to cross-talk between AKT and JNK pathways.	0	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	6	7
Conversely , the superoxide dismutase-mimetic antioxidant MnTBAP had no effect on cellular thiols in response to NFV , but protected against HO-1 induction and against the impairment in insulin stimulated Akt and protein kinase B activation and PARP cleavage .	Conversely, the superoxide dismutase-mimetic antioxidant MnTBAP had no effect on cellular thiols in response to NFV, but protected against HO-1 induction and against the impairment in insulin stimulated Akt and protein kinase B activation and PARP cleavage.	26	38	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	30	31
Consequently , hepatic lipogenic enzyme expression diminished , insulin activation of both Akt and aPKC in muscle improved , and problems of glucose intolerance , hyperlipidemia , hepatosteatosis , and weight gain were obviated .	Consequently, hepatic lipogenic enzyme expression diminished, insulin activation of both Akt and aPKC in muscle improved, and problems of glucose intolerance, hyperlipidemia, hepatosteatosis, and weight gain were obviated.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	12	13
These results indicate that insulin and RSV synergistically prevented cardiac dysfunction in diabetes and this may be in parallel with activation of the insulin mediated Akt and GLUT4 signaling pathway .	These results indicate that insulin and RSV synergistically prevented cardiac dysfunction in diabetes and this may be in parallel with activation of the insulin mediated Akt and GLUT4 signaling pathway.	20	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	25	26
The principal findings of this study are that 1 ) PVAT uncovers insulin induced vasodilation in muscle resistance arteries by secreting adiponectin and activating AMPKalpha2 in the vessel wall , 2 ) in obese db/db mice , PVAT dramatically increases in muscle and loses its ability to induce insulin mediated vasodilation , 3 ) this impaired interaction of PVAT with muscle resistance arteries is caused by a decrease in adiponectin release by PVAT and impairment of insulin stimulated Akt activation , and 4 ) the blunted insulin induced vasodilation with db/db PVAT can be restored by inhibition of JNK .	The principal findings of this study are that 1) PVAT uncovers insulin induced vasodilation in muscle resistance arteries by secreting adiponectin and activating AMPKalpha2 in the vessel wall, 2) in obese db/db mice, PVAT dramatically increases in muscle and loses its ability to induce insulin mediated vasodilation, 3) this impaired interaction of PVAT with muscle resistance arteries is caused by a decrease in adiponectin release by PVAT and impairment of insulin stimulated Akt activation, and 4) the blunted insulin induced vasodilation with db/db PVAT can be restored by inhibition of JNK.	76	98	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	76	77	78	79
At the late time point when proliferation was increased , glucose activated MTOR and ERK but not AKT , and insulin activated AKT but not MTOR or ERK .	At the late time point when proliferation was increased, glucose activated MTOR and ERK but not AKT, and insulin activated AKT but not MTOR or ERK.	20	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	22	23
Instead , growth factor induced or insulin induced activation of Akt promotes inactivating phosphorylation of GSK3alpha and GSK3beta at S21 and Ser9 , respectively , thereby abrogating their action as kinases [ XREF_BIBR ] .	Instead, growth factor induced or insulin induced activation of Akt promotes inactivating phosphorylation of GSK3alpha and GSK3beta at S21 and Ser9, respectively, thereby abrogating their action as kinases [XREF_BIBR].	3	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	10	11
It must also be noted that despite mediating the enhancement of insulin stimulated PKB activity , exposure of L6 myotubes to SR141716 alone does not induce activation of this kinase , contrary to previously published data .	It must also be noted that despite mediating the enhancement of insulin stimulated PKB activity, exposure of L6 myotubes to SR141716 alone does not induce activation of this kinase, contrary to previously published data.	9	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	11	12	13	14
Accordingly , Akt was activated by insulin and blocked when GDC-G326 was co-administered at reperfusion following a protocol of IRI .	Accordingly, Akt was activated by insulin and blocked when GDC-G326 was co-administered at reperfusion following a protocol of IRI.	2	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	2	3
PHLPP-1 protein level significantly affects insulin activated Akt .	PHLPP-1 protein level significantly affects insulin activated Akt.	4	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Insulin and IGF-I signaling activate Akt , leading to phosphorylation of TSC-2 , releasing its inhibitory influence on mTOR [ XREF_BIBR ] .	Insulin and IGF-I signaling activate Akt, leading to phosphorylation of TSC-2, releasing its inhibitory influence on mTOR [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
The main aim of this study was to provide further insight into the regulatory mechanisms governing the insulin signaling pathway by investigating the role of non proteolytic ubiquitination in insulin mediated activation of AKT .	The main aim of this study was to provide further insight into the regulatory mechanisms governing the insulin signaling pathway by investigating the role of non proteolytic ubiquitination in insulin mediated activation of AKT.	29	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	29	30	33	34
XREF_BIBR Similarly , mutp53 mediated block of DAB2IP functions promotes insulin induced activation of the PI3K-Akt pathway , enhancing cell proliferation and invasion in hormone independent breast and prostate cancers ( XREF_FIG ) .	XREF_BIBR Similarly, mutp53 mediated block of DAB2IP functions promotes insulin induced activation of the PI3K-Akt pathway, enhancing cell proliferation and invasion in hormone independent breast and prostate cancers (XREF_FIG).	10	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	10	11	15	16
Insulin stimulates NO release by activating PI3 and Akt signaling XREF_BIBR .	Insulin stimulates NO release by activating PI3 and Akt signaling XREF_BIBR.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	8	9
Consequently , decreased insulin stimulated Akt kinase activity has been recognized as an important component underlying insulin resistance .	Consequently, decreased insulin stimulated Akt kinase activity has been recognized as an important component underlying insulin resistance.	3	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
Interestingly , PDGF and insulin comparably stimulated both Akt isoforms , as well as numerous other signaling molecules , in undifferentiated 3T3-L1 preadipocytes .	Interestingly, PDGF and insulin comparably stimulated both Akt isoforms, as well as numerous other signaling molecules, in undifferentiated 3T3-L1 preadipocytes.	2	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	8	9
Thus , we examined whether MH and BL153 affected in vivo insulin targeting of Akt , which is required for insulin stimulated glucose uptake , and HK II , a glycolysis regulator .	Thus, we examined whether MH and BL153 affected in vivo insulin targeting of Akt, which is required for insulin stimulated glucose uptake, and HK II, a glycolysis regulator.	11	18	targeting	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	14	15
In the present study , we present evidence that insulin stimulates Akt and ERK and regulates inhibin-betaE in osteoblast like UMR-106 cells .	In the present study, we present evidence that insulin stimulates Akt and ERK and regulates inhibin-betaE in osteoblast like UMR-106 cells.	9	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
These data indicate that PKCepsilon is involved in insulin stimulated Akt activation , although it did not affect mTOR phosphorylation at the S2481 and S2448 sites .	These data indicate that PKCepsilon is involved in insulin stimulated Akt activation, although it did not affect mTOR phosphorylation at the S2481 and S2448 sites.	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
In healthy humans , insulin increases NOS activity by stimulating phosphotidylinositol-3 kinase and Akt kinase .	In healthy humans, insulin increases NOS activity by stimulating phosphotidylinositol-3 kinase and Akt kinase.	4	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	13	14
In control MAEC , P Thr308 AKT was robustly induced by FGF2 , FCS , and insulin .	In control MAEC, P Thr308 AKT was robustly induced by FGF2, FCS, and insulin.	4	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	6	7
In the two HF groups , insulin produced no additional activation of Akt ; in the LF group it produced a 2.5-fold activation of Akt ( XREF_FIG ) .	In the two HF groups, insulin produced no additional activation of Akt; in the LF group it produced a 2.5-fold activation of Akt (XREF_FIG).	6	13	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	12	13
NOS expression , insulin dependent triggering of PI3K and Akt pathway , resulting in eNOS phosphorylation and activation , as well as stimulation of ( MAPK )/ERK pathway , that leads to production of the vasoconstrictor factor endothelin ( ET ) -1 XREF_BIBR , XREF_BIBR , were evaluated in the cardiac tissue in the same groups .	NOS expression, insulin dependent triggering of PI3K and Akt pathway, resulting in eNOS phosphorylation and activation, as well as stimulation of (MAPK)/ERK pathway, that leads to production of the vasoconstrictor factor endothelin (ET) -1 XREF_BIBR, XREF_BIBR, were evaluated in the cardiac tissue in the same groups.	3	10	triggering	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	9	10
Akt activator insulin , which stimulates cell proliferation , was used as positive control to confirm the activity and specificity of LY .	Akt activator insulin, which stimulates cell proliferation, was used as positive control to confirm the activity and specificity of LY.	0	15	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	0	1
In the human protein array , we observed that insulin activated ERK1/2 , Akt and PRAS40 when compared to the control .	In the human protein array, we observed that insulin activated ERK1/2, Akt and PRAS40 when compared to the control.	9	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	13	14
Insulin signaling activates the Akt and PI3K and the Grb2/Ras/MEK/ERK kinase cascades XREF_BIBR , XREF_BIBR .	Insulin signaling activates the Akt and PI3K and the Grb2/Ras/MEK/ERK kinase cascades XREF_BIBR, XREF_BIBR.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
Evidence has been presented that MTP is a direct transcriptional target of another forkhead transcription factor FoxA2 , and with PGC1beta may regulate apoB and VLDL section in hepatocytes in a similar fashion as FoxO1 , as FoxA2 is also a target of insulin activated Akt leading to phosphorylation and nuclear exclusion [ XREF_BIBR ] .	Evidence has been presented that MTP is a direct transcriptional target of another forkhead transcription factor FoxA2, and with PGC1beta may regulate apoB and VLDL section in hepatocytes in a similar fashion as FoxO1, as FoxA2 is also a target of insulin activated Akt leading to phosphorylation and nuclear exclusion [XREF_BIBR].	41	46	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	43	44	45	46
Moreover , PALD mediated down regulation of IR was likely not simply an artifact of overexpression since PALD depletion by siRNA enhanced IR abundance and Y1162 and Y1163 phosphorylation levels with a corresponding augmentation in insulin induced AKT activation ( i.e ., T308 phosphorylation , XREF_FIG ) .	Moreover, PALD mediated down regulation of IR was likely not simply an artifact of overexpression since PALD depletion by siRNA enhanced IR abundance and Y1162 and Y1163 phosphorylation levels with a corresponding augmentation in insulin induced AKT activation (i.e., T308 phosphorylation, XREF_FIG).	33	38	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	35	36	37	38
Normal activation of PI3K and Akt by IGF-1 and insulin in Psen1-/- fibroblasts .	Normal activation of PI3K and Akt by IGF-1 and insulin in Psen1-/- fibroblasts.	1	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	5	6
As described above , both insulin and IGF stimulate the AKT and mTOR pathway to induce proliferation in the endometrium .	As described above, both insulin and IGF stimulate the AKT and mTOR pathway to induce proliferation in the endometrium.	4	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	10	11
Insulin and Insulin like growth factor-1 can activate the phosphoinositide-3-kinase / Akt and FoxO1 pathway in T cells in vitro .	Insulin and Insulin like growth factor-1 can activate the phosphoinositide-3-kinase / Akt and FoxO1 pathway in T cells in vitro.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	11	12
Consequently , IRS-1 ( Delta386-434 ) mediated insulin signaling ( activation of Akt and glycogen synthesis ) better than IRS-1 ( WT ) .	Consequently, IRS-1 (Delta386-434) mediated insulin signaling (activation of Akt and glycogen synthesis) better than IRS-1 (WT).	7	15	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	12	13
Since it has been reported that macrophage mediated inflammation suppresses insulin actions in adipocytes , factors secreted by Wnt5a treated macrophages were tested for their ability to inhibit insulin induced Akt activation in cultured adipocytes .	Since it has been reported that macrophage mediated inflammation suppresses insulin actions in adipocytes, factors secreted by Wnt5a treated macrophages were tested for their ability to inhibit insulin induced Akt activation in cultured adipocytes.	27	31	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	30	31
Following activation of the insulin receptor ( InsR ) , a receptor tyrosine kinase ( RTK ) , insulin induces PI3K-Akt and Erk MAPK pathway signaling , with Akt activation driving the translocation of the glucose transporter Glut4 from cytoplasmic vesicles to the cell surface to facilitate glucose import .	Following activation of the insulin receptor (InsR), a receptor tyrosine kinase (RTK), insulin induces PI3K-Akt and Erk MAPK pathway signaling, with Akt activation driving the translocation of the glucose transporter Glut4 from cytoplasmic vesicles to the cell surface to facilitate glucose import.	18	25	induces	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	18	19	20	21
Cardiomyocyte specific overexpression of constitutively activated mechanistic target of rapamycin ( mTOR ) , an important target and modulator of the insulin stimulated AKT pathway , did not elicit a significant increase in adult heart weight , even though mTOR is essential for cardiac development and growth during embryogenesis .	Cardiomyocyte specific overexpression of constitutively activated mechanistic target of rapamycin (mTOR), an important target and modulator of the insulin stimulated AKT pathway, did not elicit a significant increase in adult heart weight, even though mTOR is essential for cardiac development and growth during embryogenesis.	18	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	21	22	23	24
Autocrine insulin , in turn , activates phosphoinositol-3-kinase and Akt signalling .	Autocrine insulin, in turn, activates phosphoinositol-3-kinase and Akt signalling.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	9	10
In control TSC2 +/+ mouse embryo fibroblasts ( MEFs ) or TSC2 -/- MEFs in which wild-type TSC2 has been reintroduced , PKB is activated by insulin , IGF-1 , and EGF ( XREF_FIG A ) .	In control TSC2 +/+ mouse embryo fibroblasts (MEFs) or TSC2 -/- MEFs in which wild-type TSC2 has been reintroduced, PKB is activated by insulin, IGF-1, and EGF (XREF_FIG A).	22	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	26	27	22	23
Moreover , the changes in levels of F-2 ,6-P ( 2 ) and Akt phosphorylation revealed a pattern similar to that of streptozotocin mice treated with insulin , indicating that increasing hepatic content of F-2 ,6-P ( 2 ) mimics the action of insulin .	Moreover, the changes in levels of F-2,6-P (2) and Akt phosphorylation revealed a pattern similar to that of streptozotocin mice treated with insulin, indicating that increasing hepatic content of F-2,6-P (2) mimics the action of insulin.	13	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	13	14
One such mechanism is activation of Akt by insulin permitted by inhibition of PTEN and/or tribbles-3 .	One such mechanism is activation of Akt by insulin permitted by inhibition of PTEN and/or tribbles-3.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	6	7
There is evidence to suggest that APPL1 may function downstream of insulin in myoblasts [ XREF_BIBR , XREF_BIBR ] , indicating that cell-cell contact and insulin and IGF may cooperate to activate Akt .	There is evidence to suggest that APPL1 may function downstream of insulin in myoblasts [XREF_BIBR, XREF_BIBR], indicating that cell-cell contact and insulin and IGF may cooperate to activate Akt.	23	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	32	33
Exposure of cells to PC-TP inhibitors resulted in dose dependent , but insulin independent activation of Akt , p70-S6K and GSK3beta , which are key effectors of insulin signaling .	Exposure of cells to PC-TP inhibitors resulted in dose dependent, but insulin independent activation of Akt, p70-S6K and GSK3beta, which are key effectors of insulin signaling.	12	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	16	17
Grb10 was originally identified by us and others as a negative regulator of insulin stimulated PI3K and Akt signaling .	Grb10 was originally identified by us and others as a negative regulator of insulin stimulated PI3K and Akt signaling.	11	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	17	18
Furthermore , the upregulation of PPARgamma mediated PIK3R1 expression enhanced the insulin stimulated AKT activation in 3T3-L1 cells .	Furthermore, the upregulation of PPARgamma mediated PIK3R1 expression enhanced the insulin stimulated AKT activation in 3T3-L1 cells.	9	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	13	14
It has been shown that the tribbles homolog TRB3 ( also known as SKIP3 , NIPK and SINK ) , inhibits IGF-1 as well as insulin activation of Akt and PKB in the liver .	It has been shown that the tribbles homolog TRB3 (also known as SKIP3, NIPK and SINK), inhibits IGF-1 as well as insulin activation of Akt and PKB in the liver.	25	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	28	29
Insulin activates the PI3K-Akt and Raf-MEK-ERK signalling pathways in podocytes 8 , and by dephosphorylating the 3 '-position of the inositol ring of PI ( 3,4,5 ) P 3 , PTEN acts as a negative regulator of the PI3K-Akt pathway downstream of insulin .	Insulin activates the PI3K-Akt and Raf-MEK-ERK signalling pathways in podocytes 8, and by dephosphorylating the 3 '-position of the inositol ring of PI (3,4,5) P 3, PTEN acts as a negative regulator of the PI3K-Akt pathway downstream of insulin.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	3	4
We demonstrated that bacterial supernatants derived from gram negative species increasingly stimulate insulin secretion in beta-cells and TLR4 may promote inflammation by activating the PI3K and AKT signaling pathway to induce pro inflammatory molecules .	We demonstrated that bacterial supernatants derived from gram negative species increasingly stimulate insulin secretion in beta-cells and TLR4 may promote inflammation by activating the PI3K and AKT signaling pathway to induce pro inflammatory molecules.	12	28	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	26	27
We have characterized the effects of PKC activation on multiple steps of the insulin signaling cascade from the receptor to Akt phosphorylation in endothelial cells , and have identified a novel phosphorylation site on p85 subunit of PI3K ( threonine 86 ) , which is partially responsive to PKC activation and blunts insulin activation of Akt and eNOS in endothelial cells 16 .	We have characterized the effects of PKC activation on multiple steps of the insulin signaling cascade from the receptor to Akt phosphorylation in endothelial cells, and have identified a novel phosphorylation site on p85 subunit of PI3K (threonine 86), which is partially responsive to PKC activation and blunts insulin activation of Akt and eNOS in endothelial cells 16.	52	57	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	52	53	55	56
HKC-8 cells were transfected with a plasmid encoding double dominant Akt ( Akt-T308A and S473A ) and treated with insulin ( 100nM ) and albumin ( 100nm ) .	HKC-8 cells were transfected with a plasmid encoding double dominant Akt (Akt-T308A and S473A) and treated with insulin (100nM) and albumin (100nm).	7	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	10	11
These data suggest insulin acts on beta-cells in an endocrine manner in the normal situation ; and that in beta-cells lacking insulin receptors , insulin and glucose minimally activate the Akt pathway , while ERK phosphorylation and FoxO1 nuclear export occur independently of insulin signaling .	These data suggest insulin acts on beta-cells in an endocrine manner in the normal situation; and that in beta-cells lacking insulin receptors, insulin and glucose minimally activate the Akt pathway, while ERK phosphorylation and FoxO1 nuclear export occur independently of insulin signaling.	24	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	24	25	30	31
AKT signaling , which is predominantly triggered by insulin or insulin like growth factor , is also implicated in the development of cardiomyopathy .	AKT signaling, which is predominantly triggered by insulin or insulin like growth factor, is also implicated in the development of cardiomyopathy.	0	10	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	0	1
Insulin stimulated Akt activity was also significantly greater in the diabetic animals , but there was no change in protein expression .	Insulin stimulated Akt activity was also significantly greater in the diabetic animals, but there was no change in protein expression.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
We then analyzed the effects of a HFD on the phosphorylation of key insulin signaling molecules , Akt , and its downstream signaling molecules GSK3beta and FOXO3 .	We then analyzed the effects of a HFD on the phosphorylation of key insulin signaling molecules, Akt, and its downstream signaling molecules GSK3beta and FOXO3.	10	18	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	phosphorylation of key insulin	insulin	Akt	Akt	akt	13	14	17	18
Using Western analysis , we found that angiotensin II ( 100 nmol/L ; 18 hours ) caused a 61 +/-5% degradation of IRS-1 and abolished insulin induced activation of Akt .	Using Western analysis, we found that angiotensin II (100 nmol/L; 18 hours) caused a 61 +/-5% degradation of IRS-1 and abolished insulin induced activation of Akt.	25	30	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	29	30
PI3K and AKT pathway signaling to the phosphorylation of N-Methyl-d-Aspartate receptors ( NMDA receptors , NRs , NR1 and NR2B ) and downstream activation of the CaMKIV and CREB pathway and final production of neurotrophic factors were triggered by insulin , but impaired in the MHE rats .	PI3K and AKT pathway signaling to the phosphorylation of N-Methyl-d-Aspartate receptors (NMDA receptors, NRs, NR1 and NR2B) and downstream activation of the CaMKIV and CREB pathway and final production of neurotrophic factors were triggered by insulin, but impaired in the MHE rats.	0	40	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	39	40	2	3
Activation of PKB by insulin was inhibited by pretreatment of the hepatocytes with C2 ceramide .	Activation of PKB by insulin was inhibited by pretreatment of the hepatocytes with C2 ceramide.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	2	3
Further evidence showed that intrapancreatic insulin and IGF -1 in combination with the activation of K-Ras , a known oncogene for the development of PC , can stimulate PI3K and Akt signaling pathway , which contributes to the development and conferring aggressiveness of PC .	Further evidence showed that intrapancreatic insulin and IGF -1 in combination with the activation of K-Ras, a known oncogene for the development of PC, can stimulate PI3K and Akt signaling pathway, which contributes to the development and conferring aggressiveness of PC.	4	32	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	30	31
In cells lacking TBK1 , insulin activates AKT normally , but AKT activation by exocyst dependent mechanisms is impaired .	In cells lacking TBK1, insulin activates AKT normally, but AKT activation by exocyst dependent mechanisms is impaired.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
Indeed , Akt is rapidly stimulated by insulin and mediates many insulin signals , including glucose uptake .	Indeed, Akt is rapidly stimulated by insulin and mediates many insulin signals, including glucose uptake.	2	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	2	3
Further downstream , Dex treatment for 24h increased insulin stimulated pS473akt and PKB , with no alteration in total akt and PKB levels in the presence of either 5 or 50n insulin ( XREF_FIG ) .	Further downstream, Dex treatment for 24h increased insulin stimulated pS473akt and PKB, with no alteration in total akt and PKB levels in the presence of either 5 or 50n insulin (XREF_FIG).	7	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	12	13
Selective Role of PI3K-C2beta in Insulin Stimulated Akt Activation in Metabolic Tissues .	Selective Role of PI3K-C2beta in Insulin Stimulated Akt Activation in Metabolic Tissues.	5	8	Stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	5	6	7	8
The increased phosphorylation level of the receptor IGF-1R observed upon fibroblast treatment with insulin or the four different mixtures indicates that both insulin and steviol glycosides are able to activate the PI3K and Akt pathways .	The increased phosphorylation level of the receptor IGF-1R observed upon fibroblast treatment with insulin or the four different mixtures indicates that both insulin and steviol glycosides are able to activate the PI3K and Akt pathways.	21	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	33	34
siRNA mediated Gbeta1 knockdown markedly and specifically potentiates insulin dependent activation of kinase Akt , likely reflecting the removal of the inhibitory effect of Gbetagamma on PI3-Kalpha activity .	siRNA mediated Gbeta1 knockdown markedly and specifically potentiates insulin dependent activation of kinase Akt, likely reflecting the removal of the inhibitory effect of Gbetagamma on PI3-Kalpha activity.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	13	14
For example , insulin stimulation activates the PI3K and AKT pathway leading to phosphorylation of TSC2 on at least five regulatory sites thereby inhibiting its function [ XREF_BIBR , XREF_BIBR ] .	For example, insulin stimulation activates the PI3K and AKT pathway leading to phosphorylation of TSC2 on at least five regulatory sites thereby inhibiting its function [XREF_BIBR, XREF_BIBR].	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	9	10
Subsequent in vitro studies utilizing the saturated fatty acid palmitate determined that the central mechanism employed by skeletal muscle derived ceramide to block insulin action is through the inhibition of insulin stimulated Akt and PKB activation [ XREF_BIBR ] .	Subsequent in vitro studies utilizing the saturated fatty acid palmitate determined that the central mechanism employed by skeletal muscle derived ceramide to block insulin action is through the inhibition of insulin stimulated Akt and PKB activation [XREF_BIBR].	28	35	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	30	31	32	33
Expression of miR-143 and miR-145 is upregulated in the liver of mouse models of obesity , and the iperexpression of miR-143 impairs insulin stimulated AKT activation and glucose homeostasis .	Expression of miR-143 and miR-145 is upregulated in the liver of mouse models of obesity, and the iperexpression of miR-143 impairs insulin stimulated AKT activation and glucose homeostasis.	21	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	22	23	24	25
In cultured hepatocytes , PANDER overexpression induced lipid deposition , increased FOXO1 expression , and suppressed insulin stimulated Akt activation and FOXO1 inactivation .	In cultured hepatocytes, PANDER overexpression induced lipid deposition, increased FOXO1 expression, and suppressed insulin stimulated Akt activation and FOXO1 inactivation.	15	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
Binding of insulin to its receptor activates phosphatidylinositol 3-kinase ( PI3K ) and Akt .	Binding of insulin to its receptor activates phosphatidylinositol 3-kinase (PI3K) and Akt.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	13	14
NButGT treatment , and the associated increases in O-GlcNAc levels , did not impair insulin stimulated activation of Akt , IRS1 , or FoxO1 in the liver while Akt activation was also not impaired in muscle or fat tissues ( XREF_FIG ) .	NButGT treatment, and the associated increases in O-GlcNAc levels, did not impair insulin stimulated activation of Akt, IRS1, or FoxO1 in the liver while Akt activation was also not impaired in muscle or fat tissues (XREF_FIG).	13	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	18	19
The phosphatidylinositol-3 kinase inhibitor wortmannin attenuated insulin stimulated Akt activation and NO production .	The phosphatidylinositol-3 kinase inhibitor wortmannin attenuated insulin stimulated Akt activation and NO production.	5	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
However , this impairment was partial because treatment of the MEFs with insulin restored Akt activation and prevented apoptosis .	However, this impairment was partial because treatment of the MEFs with insulin restored Akt activation and prevented apoptosis.	10	15	restored	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	14	15
162 Although the mechanism is not fully elucidated , it has been shown that ceramide blocks insulin mediated activation of Akt and PKB XREF_BIBR - XREF_BIBR via direct inhibition of Akt and PKB phosphorylation or by stimulating protein phosphatase 2A that dephosphorylates Akt and PKB .	162 Although the mechanism is not fully elucidated, it has been shown that ceramide blocks insulin mediated activation of Akt and PKB XREF_BIBR - XREF_BIBR via direct inhibition of Akt and PKB phosphorylation or by stimulating protein phosphatase 2A that dephosphorylates Akt and PKB.	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	20	21
In the IGF-1 receptor expressing cells , the binding of insulin and/or IGF-1 activates the phosphoinositide-3 '-OH kinase and Akt kinase cascade for survival [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In the IGF-1 receptor expressing cells, the binding of insulin and/or IGF-1 activates the phosphoinositide-3 '-OH kinase and Akt kinase cascade for survival [XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	19	20
The stimulation of NOS activity is a downstream effect of Akt activation by insulin ; therefore , insulin resistance may be the cause of the reduced nitric oxide production in type 2 diabetes .	The stimulation of NOS activity is a downstream effect of Akt activation by insulin; therefore, insulin resistance may be the cause of the reduced nitric oxide production in type 2 diabetes.	10	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	10	11
Moreover , pharmacological inhibition of mitochondrial Ca 2+ uptake reduces insulin dependent activation of the canonical Akt pathway .	Moreover, pharmacological inhibition of mitochondrial Ca 2+ uptake reduces insulin dependent activation of the canonical Akt pathway.	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	16	17
In the HUCs , Western blot shows that wortmannin pretreatment blocked insulin induced AKT activation and downstream RNase 7 production ( XREF_FIG ) .	In the HUCs, Western blot shows that wortmannin pretreatment blocked insulin induced AKT activation and downstream RNase 7 production (XREF_FIG).	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	13	14
To address this , we monitored insulin induced activation of AKT .	To address this, we monitored insulin induced activation of AKT.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	10	11
Also , a decrease was found in insulin induced Akt serine phosphorylation in liver , muscle , and adipose tissue of septic animals when compared with sham rats , and diacerhein was able to increase Akt phosphorylation .	Also, a decrease was found in insulin induced Akt serine phosphorylation in liver, muscle, and adipose tissue of septic animals when compared with sham rats, and diacerhein was able to increase Akt phosphorylation.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
Our study uncovers a similar APPL1 based mechanism for IR trafficking , correlating with enhanced insulin stimulated Akt activation .	Our study uncovers a similar APPL1 based mechanism for IR trafficking, correlating with enhanced insulin stimulated Akt activation.	12	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
Knocking down INPP4B or PTEN in HMEC cells had little effect on basal Akt activation ( as judged by phosphorylation at Thr 308 or Ser 473 ) but had a significant effect on the magnitude and duration of insulin stimulated Akt activation ( XREF_FIG ) .	Knocking down INPP4B or PTEN in HMEC cells had little effect on basal Akt activation (as judged by phosphorylation at Thr 308 or Ser 473) but had a significant effect on the magnitude and duration of insulin stimulated Akt activation (XREF_FIG).	34	41	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	38	39	40	41
The insulin resistance in the PDK1 K465E and K465E animals is thought to result from partial inhibition of insulin induced activation of Akt isoforms .	The insulin resistance in the PDK1 K465E and K465E animals is thought to result from partial inhibition of insulin induced activation of Akt isoforms.	1	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	22	23
Our study showed that insulin increased activation of the PI3K and Akt pathway , and that inhibition of the pathway reversed insulin mediated protection against DTIC in both wild-type BRAF B16 cells and BRAF V600E Mel-RMu cells .	Our study showed that insulin increased activation of the PI3K and Akt pathway, and that inhibition of the pathway reversed insulin mediated protection against DTIC in both wild-type BRAF B16 cells and BRAF V600E Mel-RMu cells.	4	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	11	12
Our findings regarding a role for ATM in insulin action in C2C12 ( mouse ) cells mirror the previously reported of a requirement for ATM for full activation of Akt by insulin in Cos7 cells but do not agree with a report that insulin stimulated Akt phosphorylation is normal in NIH 3T3-L1 adipocytes treated with siRNAs against ATM or with our data from L6 myotubes and mouse soleus .	Our findings regarding a role for ATM in insulin action in C2C12 (mouse) cells mirror the previously reported of a requirement for ATM for full activation of Akt by insulin in Cos7 cells but do not agree with a report that insulin stimulated Akt phosphorylation is normal in NIH 3T3-L1 adipocytes treated with siRNAs against ATM or with our data from L6 myotubes and mouse soleus.	16	34	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	29	30
Insulin and insulin like growth factors activate the PI3K and AKT pathway to stimulate glucose uptake .	Insulin and insulin like growth factors activate the PI3K and AKT pathway to stimulate glucose uptake.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	10	11
Insulin secreted from beta-cells in response to glucose activates Akt and PKB , a known inducer of cell growth and survival through the IRS-PI3K pathway .	Insulin secreted from beta-cells in response to glucose activates Akt and PKB, a known inducer of cell growth and survival through the IRS-PI3K pathway.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	9	10
Insulin and IGF1 can activate PI3K and Akt to phosphorylate GSK3B at serine 9 and inhibit GSK3B activity , and consequently increase C/EBPbeta function to enhance IL-17-induced gene expression .	Insulin and IGF1 can activate PI3K and Akt to phosphorylate GSK3B at serine 9 and inhibit GSK3B activity, and consequently increase C/EBPbeta function to enhance IL-17-induced gene expression.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	7	8
These findings suggest that the reduction in glutathione produced by MR in HepG2 cells limits the capacity of the cells to reactivate oxidized PTEN , resulting in amplification of insulin activation of Akt by increasing PIP3 .	These findings suggest that the reduction in glutathione produced by MR in HepG2 cells limits the capacity of the cells to reactivate oxidized PTEN, resulting in amplification of insulin activation of Akt by increasing PIP3.	29	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	32	33
Together these data indicate that mTORC2 but not mTORC1 mediate the insulin stimulated Akt activation and that blocking mTORC1 with rapamycin under these conditions could lead to enhanced activation of Akt via mTORC2 .	Together these data indicate that mTORC2 but not mTORC1 mediate the insulin stimulated Akt activation and that blocking mTORC1 with rapamycin under these conditions could lead to enhanced activation of Akt via mTORC2.	9	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Despite this increase in oxidative stress , and contrary to what would be predicted , Gpx1 -/- mice maintained greater insulin sensitivity than their high fat fed controls both in measures of insulin tolerance tests and in insulin induced phosporylation of Akt in muscle .	Despite this increase in oxidative stress, and contrary to what would be predicted, Gpx1 -/- mice maintained greater insulin sensitivity than their high fat fed controls both in measures of insulin tolerance tests and in insulin induced phosporylation of Akt in muscle.	20	42	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	41	42
They demonstrated that fibrates upregulate TRB3 expression ( a protein that interferes with insulin induced activation of AKT ) , in mitogen activated lymphocytes of both wild type and knockout mice , suggesting that upregulation of this protein occurs in a PPAR-alpha-independent manner .	They demonstrated that fibrates upregulate TRB3 expression (a protein that interferes with insulin induced activation of AKT), in mitogen activated lymphocytes of both wild type and knockout mice, suggesting that upregulation of this protein occurs in a PPAR-alpha-independent manner.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	13	14	17	18
Although insulin induced AKT activation is known to phosphorylate and inactivate GSK3alpha and GSK3beta , we found GSK3alpha , but not GSK3beta formed a constitutive complex to phosphorylate and suppress AKT activation , showing that a reverse action from GSK to AKT can take place .	Although insulin induced AKT activation is known to phosphorylate and inactivate GSK3alpha and GSK3beta, we found GSK3alpha, but not GSK3beta formed a constitutive complex to phosphorylate and suppress AKT activation, showing that a reverse action from GSK to AKT can take place.	1	14	induced	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	insulin	insulin	insulin	AKT	AKT activation is known to phosphorylate and inactivate GSK3alpha and GSK3beta	akt	1	2	3	4
Both insulin and activated p21 Ras induce a physical association of AKT and PKCdelta , which is PI 3 K dependent , and both stimuli induce the physical association of PDK1 and PKCdelta , which requires a catalytically-active PKCdelta .	Both insulin and activated p21 Ras induce a physical association of AKT and PKCdelta, which is PI 3 K dependent, and both stimuli induce the physical association of PDK1 and PKCdelta, which requires a catalytically-active PKCdelta.	0	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	1	2	11	12
A recent review pointed out the importance of ubiquitin ligases in the protein degradation process and how Akt activation stimulated by insulin was able to modulate it [ XREF_BIBR ] .	A recent review pointed out the importance of ubiquitin ligases in the protein degradation process and how Akt activation stimulated by insulin was able to modulate it [XREF_BIBR].	17	22	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	17	18
The expression levels of insulin signaling molecules IRS-1 , Akt , eNOS , ERK1 and ERK2 , PKC-alpha , NFkappaB-p65 subunit and IkappaB-alpha in rat aortic endothelium were determined by immunohistochemistry and Western blot .	The expression levels of insulin signaling molecules IRS-1, Akt, eNOS, ERK1 and ERK2, PKC-alpha, NFkappaB-p65 subunit and IkappaB-alpha in rat aortic endothelium were determined by immunohistochemistry and Western blot.	2	15	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	Akt	Akt	akt	4	5	9	10
We next attempted to determine the expression of glycogen synthase kinase-3 ( GSK3 ) , which is a critical downstream target of the insulin stimulated PI3K and Akt signaling pathway XREF_BIBR in the rat uterus .	We next attempted to determine the expression of glycogen synthase kinase-3 (GSK3), which is a critical downstream target of the insulin stimulated PI3K and Akt signaling pathway XREF_BIBR in the rat uterus.	20	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	27	28
Although the mechanism is not completely clear , ceramide prevents insulin mediated activation of Akt and PKB XREF_BIBR - XREF_BIBR .	Although the mechanism is not completely clear, ceramide prevents insulin mediated activation of Akt and PKB XREF_BIBR - XREF_BIBR.	10	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	14	15
Insulin ( 10nM ) was used to stimulate insulin signaling ( insulin receptor substrate ( IRS-1 ) and Akt ) for 3min .	Insulin (10nM) was used to stimulate insulin signaling (insulin receptor substrate (IRS-1) and Akt) for 3min.	0	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	18	19
Immunoblots revealed that insulin upregulated activation of Akt and inhibited ERK activation through the PI3K pathway .	Immunoblots revealed that insulin upregulated activation of Akt and inhibited ERK activation through the PI3K pathway.	3	9	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
Where these pathways are functioning normally , glucose homeostasis requires the insulin mediated activation of PI3K-AKT and downregulation of PP2A [ XREF_BIBR ] .	Where these pathways are functioning normally, glucose homeostasis requires the insulin mediated activation of PI3K-AKT and downregulation of PP2A [XREF_BIBR].	11	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	11	12	15	16
In a previous study , we have reported that melanocortin receptor subtype 4 ( MC4R ) activation synergistically increases insulin stimulated AKT signaling and glucose uptake in neuronal cells [ XREF_BIBR ] .	In a previous study, we have reported that melanocortin receptor subtype 4 (MC4R) activation synergistically increases insulin stimulated AKT signaling and glucose uptake in neuronal cells [XREF_BIBR].	18	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	19	20	21	22
In skeletal muscle , the binding of IGF-1 or insulin to its cognitive receptor activates 2 major signaling pathways : the Ras-Raf-MEK-ERK pathway and the PI3K and AKT pathway .	In skeletal muscle, the binding of IGF-1 or insulin to its cognitive receptor activates 2 major signaling pathways : the Ras-Raf-MEK-ERK pathway and the PI3K and AKT pathway.	5	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	27	28
Insulin activated AKT signaling in Tregs , leading to inhibition of both IL-10 production and the ability of Tregs to suppress the production of TNF-alpha by macrophages in a contact independent manner .	Insulin activated AKT signaling in Tregs, leading to inhibition of both IL-10 production and the ability of Tregs to suppress the production of TNF-alpha by macrophages in a contact independent manner.	0	3	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	2	3
Insulin , but not hyperosmolarity , clearly increased the activities of PI3K and Akt .	Insulin, but not hyperosmolarity, clearly increased the activities of PI3K and Akt.	0	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	13	14
Furthermore , insulin induced activation of Akt and concurrently decreased gluconeogenic gene expression of g6pase1 and m-pepck correlate with increased FoxO1 phosphorylation in trout primary hepatocytes , arguing for an evolutionary conserved mechanism XREF_BIBR .	Furthermore, insulin induced activation of Akt and concurrently decreased gluconeogenic gene expression of g6pase1 and m-pepck correlate with increased FoxO1 phosphorylation in trout primary hepatocytes, arguing for an evolutionary conserved mechanism XREF_BIBR.	2	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
In conclusion , insulin activates PI3-K and Akt signaling pathway and promotes lactate production in ovarian GCs , but high androgen exerted no obvious influence on insulin signaling pathway and metabolic effect in GCs , suggesting that metabolic actions of insulin in ovarian GCs were unaffected by hyperandrogenism directly .	In conclusion, insulin activates PI3-K and Akt signaling pathway and promotes lactate production in ovarian GCs, but high androgen exerted no obvious influence on insulin signaling pathway and metabolic effect in GCs, suggesting that metabolic actions of insulin in ovarian GCs were unaffected by hyperandrogenism directly.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
Accordingly , mTORC2 was not recruited to FAs during insulin stimulation of Akt : insulin failed to induce association of vinculin with rictor , mTOR or Akt ( XREF_FIG ) .	Accordingly, mTORC2 was not recruited to FAs during insulin stimulation of Akt : insulin failed to induce association of vinculin with rictor, mTOR or Akt (XREF_FIG).	9	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	12	13
A major converging point in insulin signal transduction seems to underlie this imbalance ; namely , increased phosphorylation of serine of the critical insulin signalling factor IRS-1 leads to impaired PI3K engagement and stimulation of AKT XREF_BIBR - XREF_BIBR .	A major converging point in insulin signal transduction seems to underlie this imbalance; namely, increased phosphorylation of serine of the critical insulin signalling factor IRS-1 leads to impaired PI3K engagement and stimulation of AKT XREF_BIBR - XREF_BIBR.	17	36	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	insulin	phosphorylation of serine of the critical insulin	insulin	AKT	AKT	akt	23	24	35	36
Thus , despite the decrease in p85alpha , PI 3-kinase activation is normal , insulin stimulated Akt activity is increased , and glucose tolerance and insulin sensitivity are improved .	Thus, despite the decrease in p85alpha, PI 3-kinase activation is normal, insulin stimulated Akt activity is increased, and glucose tolerance and insulin sensitivity are improved.	14	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
The expression levels of the insulin signaling molecules pIRS-1 and IRS-1 , pIRS-2 and IRS-2 , Akt , PI3K , and pAkt and Akt were measured by western blot in livers from both the OF and NF groups .	The expression levels of the insulin signaling molecules pIRS-1 and IRS-1, pIRS-2 and IRS-2, Akt, PI3K, and pAkt and Akt were measured by western blot in livers from both the OF and NF groups.	2	21	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of the insulin	insulin	Akt	Akt	akt	5	6	16	17
These data support a model in which osmotic shock induced insulin resistance of downstream biological responses results from an inhibition of insulin stimulated PKB activation .	These data support a model in which osmotic shock induced insulin resistance of downstream biological responses results from an inhibition of insulin stimulated PKB activation.	19	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	PKB	PKB	PKB	21	22	23	24
Our study showed that insulin treatment activated Akt and ERK1/2 , while reducing phosphorylation of p38 MAPK 1 d after MI .	Our study showed that insulin treatment activated Akt and ERK1/2, while reducing phosphorylation of p38 MAPK 1 d after MI.	4	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	7	8
Dysregulation of insulin stimulated Akt activation in the liver of female Gnmt-/- mice .	Dysregulation of insulin stimulated Akt activation in the liver of female Gnmt-/- mice.	0	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
In addition , ORF4 mutant viruses with a reduced capacity to activate Akt showed the same phenotype , and activation of Akt by insulin was able to release this phenotype to a significant extent , thus providing further evidence for a role of Akt activation in promoting infection .	In addition, ORF4 mutant viruses with a reduced capacity to activate Akt showed the same phenotype, and activation of Akt by insulin was able to release this phenotype to a significant extent, thus providing further evidence for a role of Akt activation in promoting infection.	19	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	21	22
Our data demonstrate that only 5-10 % of maximal insulin induced PKB is required to fully repress PEPCK and G6Pase expression .	Our data demonstrate that only 5-10% of maximal insulin induced PKB is required to fully repress PEPCK and G6Pase expression.	6	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	9	10	11	12
In the vascular field , insulin mediated Akt activation in endothelial cells leads to enhanced nitric oxide ( NO ) production via both stimulation of L-arginine uptake and phosphorylation of endothelial NO synthase on Ser 1177 ( activated eNOS ) .	In the vascular field, insulin mediated Akt activation in endothelial cells leads to enhanced nitric oxide (NO) production via both stimulation of L-arginine uptake and phosphorylation of endothelial NO synthase on Ser 1177 (activated eNOS).	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Central to this dogma is that insulin activates the PI3K-AKT pathway , leading to Glut4 translocation and glucose uptake .	Central to this dogma is that insulin activates the PI3K-AKT pathway, leading to Glut4 translocation and glucose uptake.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	6	7	9	10
C-peptide did not affect insulin induced Akt or extracellular signal regulated kinase signalling ( 15min ) , but array data and gene silencing implicated sterol regulatory element binding transcription factor 1 ( SREBF1 ) .	C-peptide did not affect insulin induced Akt or extracellular signal regulated kinase signalling (15min), but array data and gene silencing implicated sterol regulatory element binding transcription factor 1 (SREBF1).	3	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Inactivation of the GAP domain of AS160 upon phosphorylation by insulin stimulated Akt renders its cognate Rab protein to the GTP bound form , which then initiates GLUT4 translocation .	Inactivation of the GAP domain of AS160 upon phosphorylation by insulin stimulated Akt renders its cognate Rab protein to the GTP bound form, which then initiates GLUT4 translocation.	8	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
Insulin activated PI3-K regulates the activation of atypical protein kinase C ( aPKC ) , as well as Akt which is responsible for the activation of Akt substrate160 kD ( AS160 ) .	Insulin activated PI3-K regulates the activation of atypical protein kinase C (aPKC), as well as Akt which is responsible for the activation of Akt substrate160 kD (AS160).	0	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	18	19
Studies of young rats have consistently found greater TBC1D4 phosphorylation with little or no change in insulin stimulated Akt activation post-exercise , whereas in old rats , insulin stimulated Akt activation was consistently altered , but TBC1D4 phosphorylation was not always increased .	Studies of young rats have consistently found greater TBC1D4 phosphorylation with little or no change in insulin stimulated Akt activation post-exercise, whereas in old rats, insulin stimulated Akt activation was consistently altered, but TBC1D4 phosphorylation was not always increased.	27	30	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	27	28	29	30
This newly identified IR-beta 2 AR complex herein reported may provide a molecular basis to understand and reconcile recent studies showing that betaAR activation impairs insulin induced Akt activation , GLUT4 translocation , and glucose uptake in cardiomyocytes , adipocytes , and skeletal muscle cells .	This newly identified IR-beta 2 AR complex herein reported may provide a molecular basis to understand and reconcile recent studies showing that betaAR activation impairs insulin induced Akt activation, GLUT4 translocation, and glucose uptake in cardiomyocytes, adipocytes, and skeletal muscle cells.	24	28	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
Pre-treatment with Torin 1 also abrogated the mobility shift of total AKT caused by insulin .	Pre-treatment with Torin 1 also abrogated the mobility shift of total AKT caused by insulin.	8	15	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	14	15	11	12
Instead , Elmo2 is required to promote the insulin induced membrane association of Akt .	Instead, Elmo2 is required to promote the insulin induced membrane association of Akt.	7	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	13	14
The ability of scopoletin to activate insulin mediated Akt and PKB was greater than that of rosiglitazone , a thiazolidinedione , and scopoletin was less adipogenic than rosiglitazone , as shown by the extent of lipid accumulation in differentiated adipocytes .	The ability of scopoletin to activate insulin mediated Akt and PKB was greater than that of rosiglitazone, a thiazolidinedione, and scopoletin was less adipogenic than rosiglitazone, as shown by the extent of lipid accumulation in differentiated adipocytes.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Insulin initially stimulates the PI3K and Akt signalling pathway .	Insulin initially stimulates the PI3K and Akt signalling pathway.	0	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	6	7
To determine whether insulin mediated induction of AKT signaling plays a crucial role in neural differentiation of hESCs and hiPSCs we tested the effect of either removing insulin from our medium or using an Akt inhibitor ( VIII ) during the first 5 days of the protocol 18 .	To determine whether insulin mediated induction of AKT signaling plays a crucial role in neural differentiation of hESCs and hiPSCs we tested the effect of either removing insulin from our medium or using an Akt inhibitor (VIII) during the first 5 days of the protocol 18.	3	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	7	8
Insulin stimulates production of NO in vascular endothelium via activation of phosphatidylinositol ( PI ) 3-kinase , Akt , and endothelial NO synthase .	Insulin stimulates production of NO in vascular endothelium via activation of phosphatidylinositol (PI) 3-kinase, Akt, and endothelial NO synthase.	0	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	17	18
Insulin can activate the Akt and mTOR pathway , therefore we further investigated the effect of insulin on the autophagy formation induced by PICT-1 overexpression .	Insulin can activate the Akt and mTOR pathway, therefore we further investigated the effect of insulin on the autophagy formation induced by PICT-1 overexpression.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
Possessing little sensitive PI3K and Akt for receptor activation , cells after overstimulation , although live , hardly respond to PI3K and Akt activators including GH , thyroxine and insulin .	Possessing little sensitive PI3K and Akt for receptor activation, cells after overstimulation, although live, hardly respond to PI3K and Akt activators including GH, thyroxine and insulin.	20	30	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	22	23
Also , IH altered insulin mediated activation of AKT but not ERK resulting in increased endothelin-1 transcription .	Also, IH altered insulin mediated activation of AKT but not ERK resulting in increased endothelin-1 transcription.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	8	9
Interestingly , intranasal insulin delivery in type 1 diabetic mice prevents cognitive decline , cerebral atrophy and the decrease of the PI3-K and Akt signaling pathway .	Interestingly, intranasal insulin delivery in type 1 diabetic mice prevents cognitive decline, cerebral atrophy and the decrease of the PI3-K and Akt signaling pathway.	3	25	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	23	24
Insulin treatment also induced AKT , MDM4 phosphorylation , as well as accumulation of MDM2 and cytosolic p53 , which was largely prevented by LY294002 .	Insulin treatment also induced AKT, MDM4 phosphorylation, as well as accumulation of MDM2 and cytosolic p53, which was largely prevented by LY294002.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	4	5
Therefore , our data suggest that APOE4 carriage leads to an increased insulin induced activation of cerebral Akt pathway , associated with higher AD like tau neuropathology .	Therefore, our data suggest that APOE4 carriage leads to an increased insulin induced activation of cerebral Akt pathway, associated with higher AD like tau neuropathology.	12	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	17	18
In DeltaIGF-1R osteoblasts , insulin signaling was markedly increased as evidenced by increased phosphorylation of insulin receptor substrate 1/2 and enhanced ERK and Akt activation .	In DeltaIGF-1R osteoblasts, insulin signaling was markedly increased as evidenced by increased phosphorylation of insulin receptor substrate 1/2 and enhanced ERK and Akt activation.	4	24	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	23	24
Recent experiments provide direct evidence that obesity induces overexpression of miR-143 , which acts to inhibit insulin stimulated AKT activation leading to impairment of glucose metabolism [ XREF_BIBR ] .	Recent experiments provide direct evidence that obesity induces overexpression of miR-143, which acts to inhibit insulin stimulated AKT activation leading to impairment of glucose metabolism [XREF_BIBR].	15	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	18	19
Maximal insulin stimulated Akt ( protein kinase B ) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia ( Krook et al ., Diabetes 46:2100-2114, 1997 ) .	Maximal insulin stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997).	0	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
These results demonstrate that DNJ can increase hepatic insulin sensitivity via strengthening of the insulin stimulated PKB and GSK-3beta signal pathway and by modulating glucose metabolic enzymes in db/db mice .	These results demonstrate that DNJ can increase hepatic insulin sensitivity via strengthening of the insulin stimulated PKB and GSK-3beta signal pathway and by modulating glucose metabolic enzymes in db/db mice.	11	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	14	15	16	17
For example , ectopic overexpression of INPP4B in leukemic cells has been reported to reduce Akt phosphorylation without affecting cell proliferation , XREF_BIBR and INPP4B depletion in human mammary epithelial cells using shRNA has been shown to increase insulin stimulated Akt activation and promote cell proliferation .	For example, ectopic overexpression of INPP4B in leukemic cells has been reported to reduce Akt phosphorylation without affecting cell proliferation, XREF_BIBR and INPP4B depletion in human mammary epithelial cells using shRNA has been shown to increase insulin stimulated Akt activation and promote cell proliferation.	37	41	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	38	39	40	41
Studies have found that TSA enhances IRS acetylation in human breast adenocarcinoma cell line MCF-7 , thus facilitating the activation of Akt by insulin .	Studies have found that TSA enhances IRS acetylation in human breast adenocarcinoma cell line MCF-7, thus facilitating the activation of Akt by insulin.	17	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	21	22
In skeletal muscles , however , adrenaline potentiates insulin stimulated PKB activation without having effect in the absence of insulin .	In skeletal muscles, however, adrenaline potentiates insulin stimulated PKB activation without having effect in the absence of insulin.	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	10	11
Insulin induced Akt signaling and skeletal muscle glucose disposal .	Insulin induced Akt signaling and skeletal muscle glucose disposal.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
3.6 GnRH blunts insulin and IGF1 activation of AKT .	3.6 GnRH blunts insulin and IGF1 activation of AKT.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	8	9
GLUT4 , which is glucose transport protein that is highly expressed in adipose tissues , shifts from its intracellular location to the cell membrane via insulin stimulated AKT signaling .	GLUT4, which is glucose transport protein that is highly expressed in adipose tissues, shifts from its intracellular location to the cell membrane via insulin stimulated AKT signaling.	23	28	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	25	26	27	28
NO/SNO inhibits insulin stimulated Akt activity , and mutation of C224 within Akt abolishes both Akt S nitrosylation and its inhibition by low-mass SNOs [ XREF_BIBR ] .	NO/SNO inhibits insulin stimulated Akt activity, and mutation of C224 within Akt abolishes both Akt S nitrosylation and its inhibition by low-mass SNOs [XREF_BIBR].	1	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
We hypothesized that insulin , which activates Akt signaling in hepatocytes , as well as signaling through p38 and MAPK p42 and p44 , would regulate iNOS expression during inflammation .	We hypothesized that insulin, which activates Akt signaling in hepatocytes, as well as signaling through p38 and MAPK p42 and p44, would regulate iNOS expression during inflammation.	3	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
Insulin effectively activated phosphatidylinositol 3 kinase and AKT to a similar extent in both c-Cbl-null and WT mice ( XREF_FIG , male animals panels B , C ; female animals panels D , E ) .	Insulin effectively activated phosphatidylinositol 3 kinase and AKT to a similar extent in both c-Cbl-null and WT mice (XREF_FIG, male animals panels B, C; female animals panels D, E).	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	7	8
Both insulin and vanadate activation of PKB was prevented by wortmannin and LY 294002 .	Both insulin and vanadate activation of PKB was prevented by wortmannin and LY 294002.	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	1	2	6	7
Insulin mediated activation of AKT is unaffected by DNA-PK inhibitor treatment , suggesting that this effect is restricted to DNA damage mediated activation of AKT and that , clinically , DNA-PK inhibition might prevent platinum induced AKT activation without interfering with normal glucose homeostasis , an unwanted toxicity of direct AKT inhibitors .	Insulin mediated activation of AKT is unaffected by DNA-PK inhibitor treatment, suggesting that this effect is restricted to DNA damage mediated activation of AKT and that, clinically, DNA-PK inhibition might prevent platinum induced AKT activation without interfering with normal glucose homeostasis, an unwanted toxicity of direct AKT inhibitors.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	4	5
Insulin receptor-IGF-1R hybrids , the insulin receptor , IGF-1R and IGF-2R phosphorylate insulin receptor substrates , which can then activate MAPKs and ultimately activate the PI3K- AKT oncogenic pathway .	Insulin receptor-IGF-1R hybrids, the insulin receptor, IGF-1R and IGF-2R phosphorylate insulin receptor substrates, which can then activate MAPKs and ultimately activate the PI3K- AKT oncogenic pathway.	0	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	Insulin receptor-IGF-1R hybrids, the insulin receptor, IGF-1R and IGF-2R phosphorylate insulin	insulin	AKT	AKT	akt	0	1	26	27
To test for enhanced signaling efficacy as a component of enhanced insulin sensitivity , acute insulin dependent activation of Akt was measured in liver , BAT , and skeletal muscle of mice after 8 weeks of the respective diets .	To test for enhanced signaling efficacy as a component of enhanced insulin sensitivity, acute insulin dependent activation of Akt was measured in liver, BAT, and skeletal muscle of mice after 8 weeks of the respective diets.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	19	20
Insulin stimulation causes a robust activation of Akt in insulin sensitive tissues like muscle and adipose , as well as in neurons of both the peripheral and central nervous systems .	Insulin stimulation causes a robust activation of Akt in insulin sensitive tissues like muscle and adipose, as well as in neurons of both the peripheral and central nervous systems.	0	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	7	8
However , Go-6976 treatment did not restore insulin stimulated Akt activation , suggesting that the target of Go-6976 action is either downstream of , or occurs parallel to , Akt activation .	However, Go-6976 treatment did not restore insulin stimulated Akt activation, suggesting that the target of Go-6976 action is either downstream of, or occurs parallel to, Akt activation.	6	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
As insulin activates PI3K and Akt and regulates intracellular ATP by regulating metabolism of carbohydrates and fats XREF_BIBR , it is quite possible that this hormone could regulate SUR2A and , consequently , cardiac resistance to stress .	As insulin activates PI3K and Akt and regulates intracellular ATP by regulating metabolism of carbohydrates and fats XREF_BIBR, it is quite possible that this hormone could regulate SUR2A and, consequently, cardiac resistance to stress.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	5	6
Finally , liver mTORC2 is essential for insulin induced AKT signalling regulation and its deletion or inactivation leads to dysregulated hepatic gluconeogenesis and glycogenolysis .	Finally, liver mTORC2 is essential for insulin induced AKT signalling regulation and its deletion or inactivation leads to dysregulated hepatic gluconeogenesis and glycogenolysis.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	9	10
In skeletal myotubes , palmitate alters insulin activation of ERK 1/2 and Akt [ XREF_BIBR ] .	In skeletal myotubes, palmitate alters insulin activation of ERK 1/2 and Akt [XREF_BIBR].	6	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	12	13
Upregulation of PTEN by chronic ethanol feeding leads to suppression of the insulin stimulated PI3K and AKT prosurvival pathway [ XREF_BIBR ] .	Upregulation of PTEN by chronic ethanol feeding leads to suppression of the insulin stimulated PI3K and AKT prosurvival pathway [XREF_BIBR].	9	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	16	17
Since insulin and KRAS are known to activate the PI3K and AKT pathway , we analyzed the effect of PI3K inhibition on S145 phosphorylation .	Since insulin and KRAS are known to activate the PI3K and AKT pathway, we analyzed the effect of PI3K inhibition on S145 phosphorylation.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	1	2	11	12
Specifically , overexpression of miR-143 , but not miR-145 , impairs insulin stimulated Akt activation and glucose homeostasis .	Specifically, overexpression of miR-143, but not miR-145, impairs insulin stimulated Akt activation and glucose homeostasis.	10	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Insulin growth factor-I induced activation of Akt followed by Bad phosphorylation after 15 minutes of incubation .	Insulin growth factor-I induced activation of Akt followed by Bad phosphorylation after 15 minutes of incubation.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	6	7
Consistent with these earlier reports , we observed that physiological concentrations of IGF1 , IGF2 or insulin activated the MAP kinase and Akt pathways ( XREF_FIG ) .	Consistent with these earlier reports, we observed that physiological concentrations of IGF1, IGF2 or insulin activated the MAP kinase and Akt pathways (XREF_FIG).	10	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	22	23
The mTORC1 complex phosphorylates its downstream effecter p70S6k , which could induce the degradation of insulin receptor substrate and further increase the insulin driven Akt activity .	The mTORC1 complex phosphorylates its downstream effecter p70S6k, which could induce the degradation of insulin receptor substrate and further increase the insulin driven Akt activity.	11	25	driven	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	24	25
Intraocular injection of insulin restores insulin receptor activity and Akt signaling prosurvival pathway in diabetic rat retinas [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Intraocular injection of insulin restores insulin receptor activity and Akt signaling prosurvival pathway in diabetic rat retinas [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	12	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	9	10
To study the function of the PDK1 ( 3-phosphoinositide-dependent protein kinase-1 ) signalling pathway in mediating insulin ' s actions in the liver , we employed CRE recombinase and loxP technology to generate L ( liver )-PDK1-/- mice , which lack expression of PDK1 in hepatocytes and in which insulin failed to induce activation of PKB in liver .	To study the function of the PDK1 (3-phosphoinositide-dependent protein kinase-1) signalling pathway in mediating insulin 's actions in the liver, we employed CRE recombinase and loxP technology to generate L (liver)-PDK1-/- mice, which lack expression of PDK1 in hepatocytes and in which insulin failed to induce activation of PKB in liver.	49	56	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	49	50	55	56
To assess the impact of pro survival factors on sEng release in a model system , isolated endothelial cells were incubated with VEGF-A , FGF-2 , Ang-1 , and insulin , which all activate the PI3K and Akt signalling .	To assess the impact of pro survival factors on sEng release in a model system, isolated endothelial cells were incubated with VEGF-A, FGF-2, Ang-1, and insulin, which all activate the PI3K and Akt signalling.	20	38	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	37	38
Insulin stimulated Akt activity was unaltered in both diet-groups at 3 h post exercise .	Insulin stimulated Akt activity was unaltered in both diet-groups at 3 h post exercise.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
The Akt and PKB pathway is stimulated by insulin and performs several vital functions relative to growth , survival and cellular metabolism .	The Akt and PKB pathway is stimulated by insulin and performs several vital functions relative to growth, survival and cellular metabolism.	1	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	3	4
Notably , the ability of stearate to increase IRS-1 phosphorylation at Ser 1101 ( XREF_FIG B ) , and to reduce insulin stimulated Akt ( XREF_FIG C ) and GSK-3alpha and beta phosphorylation ( XREF_FIG D ) was no longer observed when cells were pre-treated with TAK-242 .	Notably, the ability of stearate to increase IRS-1 phosphorylation at Ser 1101 (XREF_FIG B), and to reduce insulin stimulated Akt (XREF_FIG C) and GSK-3alpha and beta phosphorylation (XREF_FIG D) was no longer observed when cells were pre-treated with TAK-242.	20	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	23	24
XREF_BIBR , XREF_BIBR IGF1 and insulin activate the AKT pathway , whereas CD45 decreases this signaling by dephosphorylating both IGF1R and INSR .	XREF_BIBR, XREF_BIBR IGF1 and insulin activate the AKT pathway, whereas CD45 decreases this signaling by dephosphorylating both IGF1R and INSR.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	8	9
Vil-Cre mice also had smaller intestines compared with those of IE-irKO and IRfl/fl mice and greater insulin mediated activation of jejunal IR and AKT .	Vil-Cre mice also had smaller intestines compared with those of IE-irKO and IRfl/fl mice and greater insulin mediated activation of jejunal IR and AKT.	5	24	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	23	24
These data demonstrate that insulin induced down-regulation of NET requires Akt activity .	These data demonstrate that insulin induced down-regulation of NET requires Akt activity.	4	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	10	11
These results suggest that the alpha 1A -adrenergic receptor regulates GSK-3beta through two signaling pathways : one inhibits insulin induced GSK-3beta phosphorylation by blocking insulin activation of Akt , while another stimulates Ser 9 phosphorylation of GSK-3beta , probably via PKC .	These results suggest that the alpha 1A -adrenergic receptor regulates GSK-3beta through two signaling pathways : one inhibits insulin induced GSK-3beta phosphorylation by blocking insulin activation of Akt, while another stimulates Ser 9 phosphorylation of GSK-3beta, probably via PKC.	24	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	24	25	27	28
Putting these findings together , regulation of ACLY by Akt and acetylation presents an elegant model of matching insulin stimulated Akt activation and glucose uptake to generation of cytosolic acetyl CoA and subsequent acetylation of cytosolic proteins .	Putting these findings together, regulation of ACLY by Akt and acetylation presents an elegant model of matching insulin stimulated Akt activation and glucose uptake to generation of cytosolic acetyl CoA and subsequent acetylation of cytosolic proteins.	15	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	20	21
Therefore , the ability of CB1R antagonism to counteract low-grade inflammation and/or increase levels of adiponectin may , at least in part , contribute to its insulin sensitizing action in aged epididymal fat , as demonstrated by the 1.5-fold ( P < 0.05 ) augmentation in insulin induced PKB 308 phosphorylation .	Therefore, the ability of CB1R antagonism to counteract low-grade inflammation and/or increase levels of adiponectin may, at least in part, contribute to its insulin sensitizing action in aged epididymal fat, as demonstrated by the 1.5-fold (P < 0.05) augmentation in insulin induced PKB 308 phosphorylation.	35	49	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	46	47	48	49
No reduction of the phosphorylation of the downstream effectors of insulin signaling Akt and AS160 was however observed .	No reduction of the phosphorylation of the downstream effectors of insulin signaling Akt and AS160 was however observed.	8	14	signaling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
To find out the mechanism through which insulin induced AKT signaling is downregulated in Sesn2 -/- mouse liver , we analyzed activities of signaling components that act upstream of AKT .	To find out the mechanism through which insulin induced AKT signaling is downregulated in Sesn2 -/- mouse liver, we analyzed activities of signaling components that act upstream of AKT.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	9	10
Importantly , both wild-type TSC2 and the phosphorylation site mutants were equally efficient at restoring insulin stimulated Akt signaling to these cells .	Importantly, both wild-type TSC2 and the phosphorylation site mutants were equally efficient at restoring insulin stimulated Akt signaling to these cells.	15	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
In contrast , activation of Akt by insulin , an important survival pathway in cardiomyocytes , was not significantly reduced by dasatinib in either CFb or cardiomyocytes ( XREF_FIG ) .	In contrast, activation of Akt by insulin, an important survival pathway in cardiomyocytes, was not significantly reduced by dasatinib in either CFb or cardiomyocytes (XREF_FIG).	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	5	6
IGF1 and insulin both activated Akt and PKB strongly within minutes ; sustained activation of Akt and PKB was observed in response to both IGF1 and insulin while ERK1/2 activation was rather transient , and only observed in response to IGF1 .	IGF1 and insulin both activated Akt and PKB strongly within minutes; sustained activation of Akt and PKB was observed in response to both IGF1 and insulin while ERK1/2 activation was rather transient, and only observed in response to IGF1.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	2	3	7	8
Exogenous insulin activated the P13K and Akt pathway and inhibited Nedd4-2 in vivo and in vitro .	Exogenous insulin activated the P13K and Akt pathway and inhibited Nedd4-2 in vivo and in vitro.	0	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	6	7
In contrast , in vitro studies showed that treatment with recombinant Wnt5a protein does not affect insulin stimulated Akt activation in cultured 3T3-L1 adipocytes , thus suggesting that an indirect mechanism contributes to the effects of Wnt5a ablation on WAT insulin signaling in vivo .	In contrast, in vitro studies showed that treatment with recombinant Wnt5a protein does not affect insulin stimulated Akt activation in cultured 3T3-L1 adipocytes, thus suggesting that an indirect mechanism contributes to the effects of Wnt5a ablation on WAT insulin signaling in vivo.	15	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
Furthermore , the selective activation of Akt by insulin and IGF -1 suggests the existence of distinct regulatory activities of PI3 '-kinase in growth factor versus interferon signaling .	Furthermore, the selective activation of Akt by insulin and IGF -1 suggests the existence of distinct regulatory activities of PI3 '-kinase in growth factor versus interferon signaling.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	6	7
Our studies reveal a dissociation between insulin mediated Akt activation and glucose utilization following circadian disruption , potentially due to depression of I-1 .	Our studies reveal a dissociation between insulin mediated Akt activation and glucose utilization following circadian disruption, potentially due to depression of I-1.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
PKB activity is stimulated by insulin .	PKB activity is stimulated by insulin.	0	6	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	5	6	0	1
We found that insulin treatment , which activates PI3K-AKT , did not cause IM resistance in K562 cells ( XREF_SUPPLEMENTARY ) .	We found that insulin treatment, which activates PI3K-AKT, did not cause IM resistance in K562 cells (XREF_SUPPLEMENTARY).	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	8	9
Our results show that AMPK enhances activation of Akt by insulin , whereas it causes attenuation of mTOR and S6K1 signaling , both of which are beneficial to insulin action .	Our results show that AMPK enhances activation of Akt by insulin, whereas it causes attenuation of mTOR and S6K1 signaling, both of which are beneficial to insulin action.	5	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	8	9
These data demonstrate that deletion of Trib3 has minimal effect on insulin induced Akt activation in hepatic tissue , and , as such , they question any nonredundant role for Trb3 in the maintenance of glucose and energy homeostasis in mice .	These data demonstrate that deletion of Trib3 has minimal effect on insulin induced Akt activation in hepatic tissue, and, as such, they question any nonredundant role for Trb3 in the maintenance of glucose and energy homeostasis in mice.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Insulin is known to activate ( phosphorylate ) AKT through the PI3-K pathway , and insulin transport across the blood brain barrier is not saturated at plasma insulin levels observed in this experiment .	Insulin is known to activate (phosphorylate) AKT through the PI3-K pathway, and insulin transport across the blood brain barrier is not saturated at plasma insulin levels observed in this experiment.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	8	9
As expected , no pAKT was detected during serum starvation , and EGF or insulin induced AKT activity ( XREF_FIG ) .	As expected, no pAKT was detected during serum starvation, and EGF or insulin induced AKT activity (XREF_FIG).	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	14	15	16	17
In addition , insulin activated Akt is known to inhibit glycogen synthase kinases ( GSKs ) , and inhibition of GSK-3 activity has been shown to inhibit cisplatin ototoxicity in auditory cells .	In addition, insulin activated Akt is known to inhibit glycogen synthase kinases (GSKs), and inhibition of GSK-3 activity has been shown to inhibit cisplatin ototoxicity in auditory cells.	3	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
Insulin stimulation of AC16 cells resulted in a strong activation of Akt that was inhibited by overnight incubation with PA indicating that PA incubation and the associated increase in intracellular lipids blocks insulin induced phosphorylation of Akt .	Insulin stimulation of AC16 cells resulted in a strong activation of Akt that was inhibited by overnight incubation with PA indicating that PA incubation and the associated increase in intracellular lipids blocks insulin induced phosphorylation of Akt.	0	12	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	11	12
In adipocytes , one of the key biological output of insulin activation of Akt is the translocation of Glut4 to the plasma membrane , resulting in enhanced glucose uptake .	In adipocytes, one of the key biological output of insulin activation of Akt is the translocation of Glut4 to the plasma membrane, resulting in enhanced glucose uptake.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	13	14
Although we focused our experiments on hepatocytes , it is likely that the adipose tissue and muscle are also functionally involved in the global metabolic improvement seen in PI3K-C2beta KI mice , as we also observed clearly enhanced insulin induced Akt activation in these tissues .	Although we focused our experiments on hepatocytes, it is likely that the adipose tissue and muscle are also functionally involved in the global metabolic improvement seen in PI3K-C2beta KI mice, as we also observed clearly enhanced insulin induced Akt activation in these tissues.	37	41	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	38	39	40	41
Transgenic expression of APPL1 is sufficient to reverse both obesity- and ageing induced imbalances between insulin induced Akt dependent NO production and ERK1/2 dependent ET-1 release .	Transgenic expression of APPL1 is sufficient to reverse both obesity- and ageing induced imbalances between insulin induced Akt dependent NO production and ERK1/2 dependent ET-1 release.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
The negative effect of p17 on mTORC2 assembly and Akt phosphorylation at S473 is reversed in cells treated with insulin or overexpression of CDK2 .	The negative effect of p17 on mTORC2 assembly and Akt phosphorylation at S473 is reversed in cells treated with insulin or overexpression of CDK2.	9	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	9	10
The vascular Akt and eNOS signaling , which is activated by insulin and GLP-18 , 28 and inhibited by JNK ,11 , 17 was assessed by Western blotting in aortic lysates .	The vascular Akt and eNOS signaling, which is activated by insulin and GLP-18, 28 and inhibited by JNK,11, 17 was assessed by Western blotting in aortic lysates.	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	2	3
Insulin stimulated Akt and PKB kinase activity , as judged by immune complex kinase assay and phosphorylation status of the endogenous substrate of Akt and PKB , glycogen synthase kinase-3beta ( GSK-3beta ) , was significantly impaired in burned rats .	Insulin stimulated Akt and PKB kinase activity, as judged by immune complex kinase assay and phosphorylation status of the endogenous substrate of Akt and PKB, glycogen synthase kinase-3beta (GSK-3beta), was significantly impaired in burned rats.	0	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
In this report , we show that phenylmethimazole ( C10 ) blocks basal IL6 and leptin production as well as basal Socs-3 expression in fully differentiated 3T3L1 cells ( 3T3L1 adipocytes ) without affecting insulin stimulated AKT signaling .	In this report, we show that phenylmethimazole (C10) blocks basal IL6 and leptin production as well as basal Socs-3 expression in fully differentiated 3T3L1 cells (3T3L1 adipocytes) without affecting insulin stimulated AKT signaling.	34	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	34	35	36	37
Recently , AS160 ( Akt substrate of 160kDa ) has been identified as a downstream target of insulin stimulated Akt activity [ XREF_BIBR ] .	Recently, AS160 (Akt substrate of 160kDa) has been identified as a downstream target of insulin stimulated Akt activity [XREF_BIBR].	15	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	19	20
Overexpression of wt-PDK1 enhanced insulin induced activation of PKB as well as insulin induced phosphorylation of glycogen synthase kinase ( GSK ) 3alpha/beta , a direct downstream target of PKB , although insulin induced glycogen synthesis was not significantly enhanced by wt-PDK1 expression .	Overexpression of wt-PDK1 enhanced insulin induced activation of PKB as well as insulin induced phosphorylation of glycogen synthase kinase (GSK) 3alpha/beta, a direct downstream target of PKB, although insulin induced glycogen synthesis was not significantly enhanced by wt-PDK1 expression.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	8	9
Insulin stimulated Akt activation can also promote mTORC1 activity via direct phosphorylation and inhibition of TSC2 ,.	Insulin stimulated Akt activation can also promote mTORC1 activity via direct phosphorylation and inhibition of TSC2,.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Adipose tissue explants from WT-NC mice somewhat attenuated insulin stimulated Akt though not GSK3 phosphorylation in primary hepatocytes from IL-1RI ( i.e ., isolated from IL-1R1KO mice , XREF_FIG ) .	Adipose tissue explants from WT-NC mice somewhat attenuated insulin stimulated Akt though not GSK3 phosphorylation in primary hepatocytes from IL-1RI (i.e., isolated from IL-1R1KO mice, XREF_FIG).	7	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
In this study , we specifically looked at the ability of PKC to inhibit Akt activation induced by insulin in cultured rat aortic vascular smooth muscle cells ( VSMCs ) .	In this study, we specifically looked at the ability of PKC to inhibit Akt activation induced by insulin in cultured rat aortic vascular smooth muscle cells (VSMCs).	14	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	14	15
The absence of SIRT6 , consequently , enhances insulin signaling and activation of AKT , leading to hypoglycemia .	The absence of SIRT6, consequently, enhances insulin signaling and activation of AKT, leading to hypoglycemia.	8	14	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	13	14
However , we observed a nearly twofold increase in net insulin stimulated Ser473 Akt activation ( P < 0.01 ) upon insulin stimulation ( XREF_FIG ) in the red muscle of the SMLPL -/- mice .	However, we observed a nearly twofold increase in net insulin stimulated Ser473 Akt activation (P < 0.01) upon insulin stimulation (XREF_FIG) in the red muscle of the SMLPL -/- mice.	3	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	13	14
Our results show that Ang II , upon transactivation of the EGFR , inhibits insulin induced Akt activation through phosphorylation of IRS-1 at Ser 636 / Ser 639 and its subsequent proteasomal degradation by a mechanism that depends on the PI3K/ERK1/2/mTOR/S6K -1 signaling pathway .	Our results show that Ang II, upon transactivation of the EGFR, inhibits insulin induced Akt activation through phosphorylation of IRS-1 at Ser 636 / Ser 639 and its subsequent proteasomal degradation by a mechanism that depends on the PI3K/ERK1/2/mTOR/S6K -1 signaling pathway.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
Both TNF and IL-1beta significantly enhanced the phosphorylation of insulin receptor substrate-1 ( IRS1 ) at serine 307 ( XREF_FIG ) , a modification that has been shown to inhibit insulin induced PI3K-Akt activation , resulting in insulin resistance 35 .	Both TNF and IL-1beta significantly enhanced the phosphorylation of insulin receptor substrate-1 (IRS1) at serine 307 (XREF_FIG), a modification that has been shown to inhibit insulin induced PI3K-Akt activation, resulting in insulin resistance 35.	29	33	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	30	31	32	33
GnRH also stimulated c-Jun N-terminal kinase ( JNK ) and ERK activation , whereas insulin alone stimulated Akt .	GnRH also stimulated c-Jun N-terminal kinase (JNK) and ERK activation, whereas insulin alone stimulated Akt.	14	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	17	18
Furthermore , basal protein kinase B levels and insulin stimulated Akt , ERK and PI3-K have been shown to be defective in diabetic animals [ XREF_BIBR , XREF_BIBR ] .	Furthermore, basal protein kinase B levels and insulin stimulated Akt, ERK and PI3-K have been shown to be defective in diabetic animals [XREF_BIBR, XREF_BIBR].	6	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
There was a significant interaction between paternal group , age , and insulin condition ( P < 0.05 ) ; with post hoc analysis indicating that at 6weeks of age , insulin stimulated Akt threonine 308 phosphorylation was 70 % higher ( P < 0.05 ) in the HFO compared to the CFO .	There was a significant interaction between paternal group, age, and insulin condition (P < 0.05); with post hoc analysis indicating that at 6weeks of age, insulin stimulated Akt threonine 308 phosphorylation was 70% higher (P < 0.05) in the HFO compared to the CFO.	31	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	33	34
However , 10 mug/ml of insulin activated PI3K and AKT .	However, 10 mug/ml of insulin activated PI3K and AKT.	3	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	9	10
We first investigated the effect of C8 on insulin induced activation of Akt , the major player in the transmission of insulin metabolic effects 4 .	We first investigated the effect of C8 on insulin induced activation of Akt, the major player in the transmission of insulin metabolic effects 4.	2	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	12	13
Incubation of L6E9 myotubes with palmitate caused accumulation of triglycerides , diacylgycerol , and ceramide , produced an activation of PKCtheta and PKCzeta , and blocked insulin stimulated glucose metabolism , reducing insulin stimulated PKB activity by 60 % .	Incubation of L6E9 myotubes with palmitate caused accumulation of triglycerides, diacylgycerol, and ceramide, produced an activation of PKCtheta and PKCzeta, and blocked insulin stimulated glucose metabolism, reducing insulin stimulated PKB activity by 60%.	31	35	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	PKB	PKB	PKB	32	33	34	35
Overexpressing rat PKCtheta either unilaterally or bilaterally into the CeA inhibited insulin stimulation of Akt signaling and blocked the anorectic response to insulin injected into the amygdala .	Overexpressing rat PKCtheta either unilaterally or bilaterally into the CeA inhibited insulin stimulation of Akt signaling and blocked the anorectic response to insulin injected into the amygdala.	11	15	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	14	15
A similar fate befell adaptor protein APPL1 : originally shown to prevent the interaction of Trb3 with Akt and increase HGP inhibition by insulin , its knockout had no effect on glucose tolerance and insulin sensitivity .	A similar fate befell adaptor protein APPL1 : originally shown to prevent the interaction of Trb3 with Akt and increase HGP inhibition by insulin, its knockout had no effect on glucose tolerance and insulin sensitivity.	11	24	prevent	Negative_activation_syntax_3_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	17	18
To determine whether the serine/threonine kinase Akt ( also known as protein kinase B ) is activated in vivo by insulin administration in humans , and whether impaired activation of Akt could play a role in insulin resistance , we measured the activity and phosphorylation of Akt isoforms in skeletal muscle from 3 groups of subjects : lean , obese nondiabetic , and obese type 2 diabetic .	To determine whether the serine/threonine kinase Akt (also known as protein kinase B) is activated in vivo by insulin administration in humans, and whether impaired activation of Akt could play a role in insulin resistance, we measured the activity and phosphorylation of Akt isoforms in skeletal muscle from 3 groups of subjects : lean, obese nondiabetic, and obese type 2 diabetic.	3	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	6	7
XREF_BIBR In the absence of ER stress in Pompe disease fibroblasts , the inactivated Akt signaling cascade drives the cells to autophagy , which can be reversed with insulin , which activates Akt signaling .	XREF_BIBR In the absence of ER stress in Pompe disease fibroblasts, the inactivated Akt signaling cascade drives the cells to autophagy, which can be reversed with insulin, which activates Akt signaling.	26	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	32	33
This observation is consistent with a previous study that showed treatment with either recombinant WNT3A protein or overexpression of WNT3A protein in myoblasts enhanced insulin stimulated AKT activation at Ser473 XREF_BIBR .	This observation is consistent with a previous study that showed treatment with either recombinant WNT3A protein or overexpression of WNT3A protein in myoblasts enhanced insulin stimulated AKT activation at Ser473 XREF_BIBR.	23	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	24	25	26	27
The regulation mTOR activity by growth factors is mediated by the PI3K and Akt signaling pathway [ XREF_BIBR ] , activated by not just IGF-I , but also insulin and PDGF .	The regulation mTOR activity by growth factors is mediated by the PI3K and Akt signaling pathway [XREF_BIBR], activated by not just IGF-I, but also insulin and PDGF.	13	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	13	14
Insulin induced activation of Akt and eNOS and NO release were also significantly reduced ( XREF_FIG ) .	Insulin induced activation of Akt and eNOS and NO release were also significantly reduced (XREF_FIG).	0	13	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
In addition , Gab1 negatively regulates the hepatic insulin induced activation of AKT via the ERK1/2 mediated phosphorylation of IRS-1 on Ser612 [ XREF_BIBR ] .	In addition, Gab1 negatively regulates the hepatic insulin induced activation of AKT via the ERK1/2 mediated phosphorylation of IRS-1 on Ser612 [XREF_BIBR].	6	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	12	13
For example , insulin signaling activates PKB ( Protein kinase B/Akt ) to suppress GSK3 activity .	For example, insulin signaling activates PKB (Protein kinase B/Akt) to suppress GSK3 activity.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	6	7
Overexpression of the insulin signaling molecules IRS2 and Akt in the hypothalamus enhances the glucose lowering effect of insulin in streptozotocin induced diabetic rats .	Overexpression of the insulin signaling molecules IRS2 and Akt in the hypothalamus enhances the glucose lowering effect of insulin in streptozotocin induced diabetic rats.	0	9	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	Overexpression of the insulin	insulin	Akt	Akt	akt	3	4	8	9
Downregulation of S6K simultaneously with activation of Akt-Thr308 and -Ser473 suggests that glucose starvation mimics insulin stimulation upstream but not downstream of Akt .	Downregulation of S6K simultaneously with activation of Akt-Thr308 and -Ser473 suggests that glucose starvation mimics insulin stimulation upstream but not downstream of Akt.	15	23	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	22	23
The findings suggest insulin activates pI3K dependent Akt and SFK signaling pathways that are separate .	The findings suggest insulin activates pI3K dependent Akt and SFK signaling pathways that are separate.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
Akt is activated by insulin and IGF1 through their receptor activated phosphatidylinositol 3-kinase ( PI3K ) .	Akt is activated by insulin and IGF1 through their receptor activated phosphatidylinositol 3-kinase (PI3K).	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
( 2 ) The defect of insulin stimulated Akt and GLUT4 signaling parallels with ventricular contractile dysfunctions , bradycardia , and hypotension in STZ-diabetic rats .	(2) The defect of insulin stimulated Akt and GLUT4 signaling parallels with ventricular contractile dysfunctions, bradycardia, and hypotension in STZ-diabetic rats.	4	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Thus , mTORC2 regulates hepatic glucose and lipid metabolism via insulin induced Akt signaling to control whole-body metabolic homeostasis .	Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin induced Akt signaling to control whole-body metabolic homeostasis.	5	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
Mib treatment inhibited insulin stimulated AKT activity as evidenced by reduced phosphorylation of GSK-3beta and PRAS40 ( XREF_SUPPLEMENTARY ) , direct substrates of AKT .	Mib treatment inhibited insulin stimulated AKT activity as evidenced by reduced phosphorylation of GSK-3beta and PRAS40 (XREF_SUPPLEMENTARY), direct substrates of AKT.	2	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	5	6
In these and other higher eukaryotes , AKT is activated by insulin and the insulin like growth factor ( IGF-1 ) .	In these and other higher eukaryotes, AKT is activated by insulin and the insulin like growth factor (IGF-1).	7	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	7	8
Activation of AKT by insulin via the insulin receptor in the HepaRG spheroids containing stellate cells prior to chip loading demonstrated the physiologically relevant responsiveness of the liver spheroids .	Activation of AKT by insulin via the insulin receptor in the HepaRG spheroids containing stellate cells prior to chip loading demonstrated the physiologically relevant responsiveness of the liver spheroids.	0	8	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	2	3
To dissect the relative contribution of Baf60c- and insulin mediated AKT activation in glucose metabolism , we performed fasting and refeeding studies in WT and Tg mice following streptozotocin ( STZ ) treatments .	To dissect the relative contribution of Baf60c- and insulin mediated AKT activation in glucose metabolism, we performed fasting and refeeding studies in WT and Tg mice following streptozotocin (STZ) treatments.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	10	11
Insulin signaling increases AKT activity to further reduce FOXO1 activation .	Insulin signaling increases AKT activity to further reduce FOXO1 activation.	0	4	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	3	4
In normoxic conditions , insulin causes Akt to phosphorylate TSC2 .	In normoxic conditions, insulin causes Akt to phosphorylate TSC2.	4	7	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Hepatic insulin resistance in the high-fat fed rats was documented by a higher rate of hepatic glucose production in the high-fat fed rats ( 7.0 +/-1.6 mg/( kg-min ) compared to the low-fat fed rats ( 3.2 +/-1.1 mg/( kg-min ) , P < 0.04 unpaired ( 1 tailed ) t-test ] , which was associated with a 25 % reduction in insulin stimulated Akt and PKB activity ( 0.14 +/-0.01 AU/mug protein versus 0.11 +/-0.01 AU/mug protein , P < 0.01 ) .	Hepatic insulin resistance in the high-fat fed rats was documented by a higher rate of hepatic glucose production in the high-fat fed rats (7.0 +/-1.6 mg/(kg-min) compared to the low-fat fed rats (3.2 +/-1.1 mg/(kg-min), P < 0.04 unpaired (1 tailed) t-test], which was associated with a 25% reduction in insulin stimulated Akt and PKB activity (0.14 +/-0.01 AU/mug protein versus 0.11 +/-0.01 AU/mug protein, P < 0.01).	60	67	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	62	63	66	67
Insulin stimulated AKT activity was determined by immunoprecipitating tissue lysates with a polyclonal AKT antibody ( Upstate Biotechnology ) that recognized both AKT1 and AKT2 , coupled with protein G-Sepharose beads ( Amersham Pharmacia Biotechnology , Piscataway , NJ ) as previously described .	Insulin stimulated AKT activity was determined by immunoprecipitating tissue lysates with a polyclonal AKT antibody (Upstate Biotechnology) that recognized both AKT1 and AKT2, coupled with protein G-Sepharose beads (Amersham Pharmacia Biotechnology, Piscataway, NJ) as previously described.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	2	3
XREF_BIBR , XREF_BIBR It has been well established that under physiological conditions , insulin activates the PI3K-AKT pathway .	XREF_BIBR, XREF_BIBR It has been well established that under physiological conditions, insulin activates the PI3K-AKT pathway.	13	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	13	14	16	17
Thus , the present study demonstrates that : ( i ) in cardiomyocytes from lean and obese Zucker rats , both insulin and vanadate stimulate glucose uptake and PKB activation through a PI 3-kinase sensitive pathway .	Thus, the present study demonstrates that : (i) in cardiomyocytes from lean and obese Zucker rats, both insulin and vanadate stimulate glucose uptake and PKB activation through a PI 3-kinase sensitive pathway.	18	29	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	21	22	28	29
UA inhibited insulin induced Akt and eNOS axis .	UA inhibited insulin induced Akt and eNOS axis.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
After the 12- but not the 48-h fast , insulin stimulated AKT Ser ( 473 ) phosphorylation was greater in lean than obese subjects .	After the 12- but not the 48-h fast, insulin stimulated AKT Ser (473) phosphorylation was greater in lean than obese subjects.	9	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	11	12
Insulin activated both the PI3K-Akt and the MEK-ERK pathways .	Insulin activated both the PI3K-Akt and the MEK-ERK pathways.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	4	5
In summary , the current study may show that insulin activates the PI3K and Akt pathway in eyes with normal vision and eyes treated with positive and negative lenses but stimulates eye growth through the MEK and ERK pathway in eyes with normal vision and eyes treated with positive lenses .	In summary, the current study may show that insulin activates the PI3K and Akt pathway in eyes with normal vision and eyes treated with positive and negative lenses but stimulates eye growth through the MEK and ERK pathway in eyes with normal vision and eyes treated with positive lenses.	9	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	14	15
We also performed biochemical studies to investigate insulin stimulated AKT activation in Phi WT and Phi KO mice ( XREF_FIG ) .	We also performed biochemical studies to investigate insulin stimulated AKT activation in Phi WT and Phi KO mice (XREF_FIG).	6	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	9	10
Insulin increases lipogenic enzyme expression by activating Akt and aPKC which activate SREBP-1c ; this pathway is hyperactivated in insulin resistant states .	Insulin increases lipogenic enzyme expression by activating Akt and aPKC which activate SREBP-1c; this pathway is hyperactivated in insulin resistant states.	0	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	7	8
We observed a selective inhibition of insulin -induced activation of IRS-1 and Akt pathway while enhanced activation of MAPK , which is consistent with other studies shown in various insulin resistant state .	We observed a selective inhibition of insulin -induced activation of IRS-1 and Akt pathway while enhanced activation of MAPK, which is consistent with other studies shown in various insulin resistant state.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	12	13
Although the primary mechanism by which ceramides induce hepatic insulin resistance is not completely understood , exposure of cultured hepatocytes to short chain ceramides blunts insulin mediated activation of Akt , as well as glucokinase , an important enzyme that regulates insulin mediated glucose uptake and subsequent conversion to glycogen [ XREF_BIBR ] .	Although the primary mechanism by which ceramides induce hepatic insulin resistance is not completely understood, exposure of cultured hepatocytes to short chain ceramides blunts insulin mediated activation of Akt, as well as glucokinase, an important enzyme that regulates insulin mediated glucose uptake and subsequent conversion to glycogen [XREF_BIBR].	25	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	29	30
Moreover , KO mice exhibited an increase in insulin stimulated Akt signaling in the liver , further demonstrating that Mpzl3 can regulate insulin sensitivity in this tissue .	Moreover, KO mice exhibited an increase in insulin stimulated Akt signaling in the liver, further demonstrating that Mpzl3 can regulate insulin sensitivity in this tissue.	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Treatment with insulin which activates Akt signaling restored phosphorylation of both Akt and p70S6 kinase and suppressed autophagy in patient fibroblasts .	Treatment with insulin which activates Akt signaling restored phosphorylation of both Akt and p70S6 kinase and suppressed autophagy in patient fibroblasts.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	5	6
On the other side , despite the resistance in insulin induced Akt activity , the excessive basal cardiac insulin signaling is detrimental , and can exacerbate systolic dysfunction induced by pressure overload in mice [ XREF_BIBR ] .	On the other side, despite the resistance in insulin induced Akt activity, the excessive basal cardiac insulin signaling is detrimental, and can exacerbate systolic dysfunction induced by pressure overload in mice [XREF_BIBR].	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
Whether insulin activation of PI3K and Akt is involved in this regard is not currently known .	Whether insulin activation of PI3K and Akt is involved in this regard is not currently known.	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	6	7
Further investigations are needed to delineate the sequential events associated with the elevation of the hepatic lipogenesis upon insulin stimulation and activation of AKT and aPKC isoforms .	Further investigations are needed to delineate the sequential events associated with the elevation of the hepatic lipogenesis upon insulin stimulation and activation of AKT and aPKC isoforms.	18	26	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	18	19	23	24
The signaling mechanism is starting by phosphorylation of the insulin and insulin like growth factor-1 receptors , followed by activation of phosphatidylinositide 3-kinase ( PI3K ) , which in turn activates AKT .	The signaling mechanism is starting by phosphorylation of the insulin and insulin like growth factor-1 receptors, followed by activation of phosphatidylinositide 3-kinase (PI3K), which in turn activates AKT.	6	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	phosphorylation of the insulin and insulin like	insulin	AKT	AKT	akt	9	10	31	32
In summary , we specifically demonstrate that a low concentration of insulin effectively activates Akt and mTORC1 signaling .	In summary, we specifically demonstrate that a low concentration of insulin effectively activates Akt and mTORC1 signaling.	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	14	15
GC proliferation depends on glycolysis and insulin mediated AKT and mTOR signaling pathway ; therefore , addition of culture medium containing insulin and glucose may potentially promote GC proliferation and hence improve oocyte development .	GC proliferation depends on glycolysis and insulin mediated AKT and mTOR signaling pathway; therefore, addition of culture medium containing insulin and glucose may potentially promote GC proliferation and hence improve oocyte development.	2	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	8	9
High levels of insulin , which continue to activate PKB under ER stress , albeit to a lesser degree , can partially overcome anabolic resistance .	High levels of insulin, which continue to activate PKB under ER stress, albeit to a lesser degree, can partially overcome anabolic resistance.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	PKB	PKB	pkb	3	4	9	10
These features include insulin stimulated generation of an unusual monophosphorylated form of AKT at Thr308 ( pT308-AKT ) with only weak phosphorylation at Ser473 , impaired insulin stimulated pathways for lowering plasma levels of lipids and glucose , but continued lipogenic pathways and robust extracellular signal regulated kinase activation .	These features include insulin stimulated generation of an unusual monophosphorylated form of AKT at Thr308 (pT308-AKT) with only weak phosphorylation at Ser473, impaired insulin stimulated pathways for lowering plasma levels of lipids and glucose, but continued lipogenic pathways and robust extracellular signal regulated kinase activation.	3	39	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	12	13
Finally , liver mTORC2 is essential for insulin induced AKT signaling regulation and its deletion or inactivation leads to dysregulated hepatic gluconeogenesis and glycogenolysis .	Finally, liver mTORC2 is essential for insulin induced AKT signaling regulation and its deletion or inactivation leads to dysregulated hepatic gluconeogenesis and glycogenolysis.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	9	10
Insulin signalling activates the Akt and PI3K and Grb2/Ras/MEK/ERK kinase cascades .	Insulin signalling activates the Akt and PI3K and Grb2/Ras/MEK/ERK kinase cascades.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
On feeding , increased insulin signaling activates Akt in the cell , which in turn phosphorylates and inactivates GSK-3 , thus resulting in the activation of glycogen synthase .	On feeding, increased insulin signaling activates Akt in the cell, which in turn phosphorylates and inactivates GSK-3, thus resulting in the activation of glycogen synthase.	4	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	7	8
Activation of PKC plays a fundamental role in mediating the pathological effects associated with a hyperglycemia diabetic state , XREF_BIBR - XREF_BIBR whereas insulin and Ang II activates ERK1/2 , PI3K and Akt , and eNOS signaling cascades in the myocardium .	Activation of PKC plays a fundamental role in mediating the pathological effects associated with a hyperglycemia diabetic state, XREF_BIBR - XREF_BIBR whereas insulin and Ang II activates ERK1/2, PI3K and Akt, and eNOS signaling cascades in the myocardium.	23	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	32	33
We found that insulin activated Akt and induced subsequent migration in THP-1 .	We found that insulin activated Akt and induced subsequent migration in THP-1.	3	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
While activated AKT has many functions , one major event of insulin stimulation directly downstream of AKT is the phosphorylation and inhibition of glycogen synthase kinase-3 ( GSK-3 ) [ XREF_BIBR ] .	While activated AKT has many functions, one major event of insulin stimulation directly downstream of AKT is the phosphorylation and inhibition of glycogen synthase kinase-3 (GSK-3) [XREF_BIBR].	11	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	16	17
As reported in this model , Akt activation by insulin is inhibited , resulting in a relative state of insulin resistance ( XREF_SUPPLEMENTARY , bottom , 20 nM insulin ) .	As reported in this model, Akt activation by insulin is inhibited, resulting in a relative state of insulin resistance (XREF_SUPPLEMENTARY, bottom, 20 nM insulin).	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	6	7
Researchers illustrated that under basal conditions PRAS40 binds to mTOR to inactivate it , and that mTOR inactivation is relieved when insulin stimulation activates AKT to phosphorylate PRAS40 , thereby initiating release from mTOR .	Researchers illustrated that under basal conditions PRAS40 binds to mTOR to inactivate it, and that mTOR inactivation is relieved when insulin stimulation activates AKT to phosphorylate PRAS40, thereby initiating release from mTOR.	21	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	21	22	24	25
The study involved the Ras-ERK and the IRS-PKB pathways , mediating the mitogenic and metabolic effects of insulin , respectively , and found no significant difference in the expression , basal activity , or insulin activation of IRS-1 and PKB between PCOS subjects and controls [ XREF_BIBR ] .	The study involved the Ras-ERK and the IRS-PKB pathways, mediating the mitogenic and metabolic effects of insulin, respectively, and found no significant difference in the expression, basal activity, or insulin activation of IRS-1 and PKB between PCOS subjects and controls [XREF_BIBR].	34	40	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	34	35	39	40
The multifunctional AKT signaling pathway , which is activated by insulin , growth factors , and cytokines , is implicated in a diverse range of cellular functions including cell metabolism , survival , proliferation , and migration .	The multifunctional AKT signaling pathway, which is activated by insulin, growth factors, and cytokines, is implicated in a diverse range of cellular functions including cell metabolism, survival, proliferation, and migration.	2	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	2	3
Although palmitate induced activation of NF-kappaB was repressed by AMPK activation and by cellular overexpression of a mutated IkappaBalpha ( S32A and S36A ) super-repressor , this did not ameliorate the loss in insulin stimulated PKB activation or glucose transport .	Although palmitate induced activation of NF-kappaB was repressed by AMPK activation and by cellular overexpression of a mutated IkappaBalpha (S32A and S36A) super-repressor, this did not ameliorate the loss in insulin stimulated PKB activation or glucose transport.	29	36	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	33	34	35	36
PI3K and Akt signaling is also activated by insulin in the prothoracic glands of the silkworm [ XREF_BIBR ] and the ovaries of Aedes aegypti [ XREF_BIBR ] .	PI3K and Akt signaling is also activated by insulin in the prothoracic glands of the silkworm [XREF_BIBR] and the ovaries of Aedes aegypti [XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	2	3
Reactive oxygen species ( ROS ) generated by high glucose impaired , insulin stimulated activation of Akt and eNOS .	Reactive oxygen species (ROS) generated by high glucose impaired, insulin stimulated activation of Akt and eNOS.	12	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	16	17
Insulin and IGFs activate PI3K , and its PIP 3 product recruits and activates Akt to phosphorylate WNK1 at threonine 58 .	Insulin and IGFs activate PI3K, and its PIP 3 product recruits and activates Akt to phosphorylate WNK1 at threonine 58.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	14	15
Last , but not least , at the downstream signaling level , PI3K-C2beta inactivation in hepatocytes led to an increased insulin stimulated Akt activation without affecting MAPK signaling .	Last, but not least, at the downstream signaling level, PI3K-C2beta inactivation in hepatocytes led to an increased insulin stimulated Akt activation without affecting MAPK signaling.	16	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
In contrast , insulin activation of PI3K and Akt was reduced by 35-40 % in the db/db hearts as compared with wild-type ( XREF_FIG ) .	In contrast, insulin activation of PI3K and Akt was reduced by 35-40% in the db/db hearts as compared with wild-type (XREF_FIG).	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	8	9
The production of insulin in skeletal muscle increased the phosphorylated AKT and total AKT ratio in muscle fibers , indicating that insulin activated its signaling in an autocrine and paracrine manner .	The production of insulin in skeletal muscle increased the phosphorylated AKT and total AKT ratio in muscle fibers, indicating that insulin activated its signaling in an autocrine and paracrine manner.	1	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	10	11
Thus , we next investigated a biophysical mechanism by which insulin signaling could be disrupted and found that disruption of lipid microdomains via cholesterol depletion blocks insulin induced Akt activation and reduces insulin receptor tyrosine phosphorylation .	Thus, we next investigated a biophysical mechanism by which insulin signaling could be disrupted and found that disruption of lipid microdomains via cholesterol depletion blocks insulin induced Akt activation and reduces insulin receptor tyrosine phosphorylation.	25	29	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	28	29
Finally , in both cases , activation of AKT by insulin , or by activated p21 Ras , requires PKCdelta activity .	Finally, in both cases, activation of AKT by insulin, or by activated p21 Ras, requires PKCdelta activity.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	8	9
Treatment of WT and C2beta D1212A and D1212A hepatocytes with GDC-0941 , a class I PI3K selective inhibitor , blocked insulin stimulated Akt activation ( XREF_FIG B ) .	Treatment of WT and C2beta D1212A and D1212A hepatocytes with GDC-0941, a class I PI3K selective inhibitor, blocked insulin stimulated Akt activation (XREF_FIG B).	19	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
Upon insulin activation of PI3K and AKT signaling the interaction between CITED2 and GCN5 is attenuated , allowing for PGC-1alpha acetylation , while glucagon promotes CITED2 protein expression , releasing PGC-1alpha from the negative control of GCN-5 .	Upon insulin activation of PI3K and AKT signaling the interaction between CITED2 and GCN5 is attenuated, allowing for PGC-1alpha acetylation, while glucagon promotes CITED2 protein expression, releasing PGC-1alpha from the negative control of GCN-5.	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	1	2	6	7
In experiments presented here , it appeared that insulin produced a stronger Akt activation in the sciatic nerve compared to the DRG , whereas IGF-1 produced a stronger Akt activation in the DRG compared to the sciatic nerve .	In experiments presented here, it appeared that insulin produced a stronger Akt activation in the sciatic nerve compared to the DRG, whereas IGF-1 produced a stronger Akt activation in the DRG compared to the sciatic nerve.	8	13	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	12	13
The absence of RNase L siRNA effect on insulin response in Myo-siRNaseL could be explained by the fact that , at these concentrations of palmitate , inhibition of insulin response is yet maximal ( compare insulin stimulated P-Akt and Akt expression rate in cells transfected with Control and RNase L siRNA in XREF_FIG ) .	The absence of RNase L siRNA effect on insulin response in Myo-siRNaseL could be explained by the fact that, at these concentrations of palmitate, inhibition of insulin response is yet maximal (compare insulin stimulated P-Akt and Akt expression rate in cells transfected with Control and RNase L siRNA in XREF_FIG).	34	41	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	P-Akt	P-Akt	P-Akt	35	36	37	38
Consistent with this observation , 1muM PUGNAc did not perturb insulin stimulated activation of Akt ( XREF_FIG F ) .	Consistent with this observation, 1muM PUGNAc did not perturb insulin stimulated activation of Akt (XREF_FIG F).	9	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	14	15
In our study , KD of Tmod3 in adipocytes has no influence on proximal insulin signalling , as insulin stimulated Akt activation remains intact .	In our study, KD of Tmod3 in adipocytes has no influence on proximal insulin signalling, as insulin stimulated Akt activation remains intact.	18	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	20	21
Our data suggest that the decreases in both function and expression of renal Oat3 in diabetes are associated with an impairment of renal insulin induced Akt and PKB activation through PI3K/PKCzeta/Akt/PKB signaling pathway .	Our data suggest that the decreases in both function and expression of renal Oat3 in diabetes are associated with an impairment of renal insulin induced Akt and PKB activation through PI3K/PKCzeta/Akt/PKB signaling pathway.	20	28	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	25	26
In order to obtain Akt activation , we treated with insulin U2OS cells that were previously either treated with a MDM2 specific siRNA or , as control , with a luciferase siRNA ( XREF_FIG ) .	In order to obtain Akt activation, we treated with insulin U2OS cells that were previously either treated with a MDM2 specific siRNA or, as control, with a luciferase siRNA (XREF_FIG).	4	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	4	5
HeLa cells exhibited intact insulin signalling , as indicated by robust insulin stimulation of AKT Ser 473 phosphorylation ( XREF_SUPPLEMENTARY ) .	HeLa cells exhibited intact insulin signalling, as indicated by robust insulin stimulation of AKT Ser 473 phosphorylation (XREF_SUPPLEMENTARY).	11	15	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	14	15
Short-term Insulin mediated Akt activation may also activate pro survival signaling pathways related to Akt inhibition of apoptotic signaling 75 .	Short-term Insulin mediated Akt activation may also activate pro survival signaling pathways related to Akt inhibition of apoptotic signaling 75.	0	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	1	2	3	4
Reduced binding of insulin at the insulin like receptor inhibits the serine threonine kinase AKT , blocking phosphorylation of dFoxO .	Reduced binding of insulin at the insulin like receptor inhibits the serine threonine kinase AKT, blocking phosphorylation of dFoxO.	1	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	14	15
Importantly , expression of WT-SHIP2 inhibited insulin induced activation of Akt and protein kinase C lambda , whereas these activations were increased by expression of Delta IP-SHIP2 in vivo .	Importantly, expression of WT-SHIP2 inhibited insulin induced activation of Akt and protein kinase C lambda, whereas these activations were increased by expression of Delta IP-SHIP2 in vivo.	6	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	10	11
Both baseline and insulin mediated Akt activation was augmented in CBK and CCM hearts ( relative to littermate controls ) .	Both baseline and insulin mediated Akt activation was augmented in CBK and CCM hearts (relative to littermate controls).	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
p85 beta-/- cells , however , exhibit significantly increased insulin induced Akt activation , leading to increased anti-apoptosis .	p85 beta-/- cells, however, exhibit significantly increased insulin induced Akt activation, leading to increased anti-apoptosis.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
XREF_BIBR Thus , selective insulin resistance , caused by PKC activation , enhances insulin ' s pro atherosclerotic mechanisms via ERK1/2 signaling or inhibits its anti-atherosclerotic mechanisms by inhibiting the PI3K and Akt pathway .	XREF_BIBR Thus, selective insulin resistance, caused by PKC activation, enhances insulin 's pro atherosclerotic mechanisms via ERK1/2 signaling or inhibits its anti-atherosclerotic mechanisms by inhibiting the PI3K and Akt pathway.	4	33	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	32	33
The new information provided by the study is that cell-line-dependent differences in the role of ATM in insulin signaling provide support for specific experimental models in which to study the role of ATM in insulin stimulated activation of Akt ( C2C12 and RD cells ) and to examine Akt independent effects of ATM ( L6 cells and mouse skeletal muscle ) in mediation of insulin ' s effects .	The new information provided by the study is that cell-line-dependent differences in the role of ATM in insulin signaling provide support for specific experimental models in which to study the role of ATM in insulin stimulated activation of Akt (C2C12 and RD cells) and to examine Akt independent effects of ATM (L6 cells and mouse skeletal muscle) in mediation of insulin 's effects.	32	43	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	34	35	38	39
Moreover , AKT signaling was activated via autocrine signaling by insulin and the insulin receptor in INI-1-deficient AT/RTs [ XREF_BIBR ] .	Moreover, AKT signaling was activated via autocrine signaling by insulin and the insulin receptor in INI-1-deficient AT/RTs [XREF_BIBR].	2	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	2	3
Although treatment with insulin significantly re-established insulin stimulated Akt and GLUT4 signaling and improved ventricular contractile function in basal ( non-I/R ) condition , insulin had a slight reverse effect in I/R injured diabetic rat heart .	Although treatment with insulin significantly re-established insulin stimulated Akt and GLUT4 signaling and improved ventricular contractile function in basal (non-I/R) condition, insulin had a slight reverse effect in I/R injured diabetic rat heart.	5	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
In addition , dietary insulin activated Akt and protein kinase B and extracellular signal regulated kinase ( ERK ) in the mosquito midgut , suggesting that , as observed in Caenorhabditis elegans , the midgut may act as a ' signaling center ' for mosquito aging .	In addition, dietary insulin activated Akt and protein kinase B and extracellular signal regulated kinase (ERK) in the mosquito midgut, suggesting that, as observed in Caenorhabditis elegans, the midgut may act as a ' signaling center ' for mosquito aging.	3	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Results from many studies have indicated that lipid rafts are critical for proper insulin activation of both the PI3K and Akt signaling pathway and the MAPK pathway .	Results from many studies have indicated that lipid rafts are critical for proper insulin activation of both the PI3K and Akt signaling pathway and the MAPK pathway.	13	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	20	21
Importantly , Rab 2 , Rab 10 and Rab 14 are the AQP2 vesicle associated Rab proteins and are also reported as target substrates of AS160 in insulin stimulated Akt singaling XREF_BIBR .	Importantly, Rab 2, Rab 10 and Rab 14 are the AQP2 vesicle associated Rab proteins and are also reported as target substrates of AS160 in insulin stimulated Akt singaling XREF_BIBR.	20	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	27	28	29	30
Neither RIP140- nor PKCepsilon silencing affected the basal or insulin activated Akt or ERK1/2 activation profiles , but both manipulations enhanced pAS160 levels ( XREF_FIG ) .	Neither RIP140- nor PKCepsilon silencing affected the basal or insulin activated Akt or ERK1/2 activation profiles, but both manipulations enhanced pAS160 levels (XREF_FIG).	7	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
The two major insulin receptor substrates , IRS1 and IRS2 , activate PI3K and Akt pathway [ XREF_BIBR ] , and the PI3K/Akt/mTOR pathway inhibits autophagy when it is activated [ XREF_BIBR ] .	The two major insulin receptor substrates, IRS1 and IRS2, activate PI3K and Akt pathway [XREF_BIBR], and the PI3K/Akt/mTOR pathway inhibits autophagy when it is activated [XREF_BIBR].	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	14	15
IGF1 and insulin both activated Akt and PKB strongly within minutes in A549 cells as they did in Saos-2 and B10 cells ; sustained activation of Akt and PKB was observed in response to both IGF1 and insulin .	IGF1 and insulin both activated Akt and PKB strongly within minutes in A549 cells as they did in Saos-2 and B10 cells; sustained activation of Akt and PKB was observed in response to both IGF1 and insulin.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	5	6
The demonstration that insulin activation of Akt in endothelial cells enhanced nitric oxide production clarified an important aspect of insulin action to cause vascular relaxation and enhance blood flow which had been demonstrated by multiple clinical studies in the early 1990s .	The demonstration that insulin activation of Akt in endothelial cells enhanced nitric oxide production clarified an important aspect of insulin action to cause vascular relaxation and enhance blood flow which had been demonstrated by multiple clinical studies in the early 1990s.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	6	7
Insulin , for example , induces the sequential activation of PI3K and AKT .	Insulin, for example, induces the sequential activation of PI3K and AKT.	0	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	12	13
Also insulin mediated activation of the PKB and Akt-pathway was 40-50 % lower in hearts from both HF- and FISH-diet fed rats , compared to LF-diet fed hearts ( P < 0.05 ) .	Also insulin mediated activation of the PKB and Akt-pathway was 40-50% lower in hearts from both HF- and FISH-diet fed rats, compared to LF-diet fed hearts (P < 0.05).	1	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	1	2	6	7
In adipocytes , Adrbeta1 and Adrbeta3 stimulation reduces insulin signaling by uncoupling IRS1 phosphorylation [ XREF_BIBR , XREF_BIBR ] and Adrbeta1 suppresses insulin activation of Akt in cardiac muscle [ XREF_BIBR ] .	In adipocytes, Adrbeta1 and Adrbeta3 stimulation reduces insulin signaling by uncoupling IRS1 phosphorylation [XREF_BIBR, XREF_BIBR] and Adrbeta1 suppresses insulin activation of Akt in cardiac muscle [XREF_BIBR].	22	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	25	26
In contrast , PI3Kgamma KO mice showed marked reduction in phosphorylation of GSK-3 despite significant insulin induced activation of Akt ( XREF_FIG , left and right panels ) .	In contrast, PI3Kgamma KO mice showed marked reduction in phosphorylation of GSK-3 despite significant insulin induced activation of Akt (XREF_FIG, left and right panels).	6	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	19	20
In contrast to previous finding that insulin induced activation of Akt requires presence of Sesn2 demonstrated by using the Sesn2 knock out mouse model [ XREF_BIBR ] , our data suggested insulin treatment was still able to stimulate the enhanced phoshorylation of Akt-S473 in A549 cells with Sesn2 knocked down by shRNAs .	In contrast to previous finding that insulin induced activation of Akt requires presence of Sesn2 demonstrated by using the Sesn2 knock out mouse model [XREF_BIBR], our data suggested insulin treatment was still able to stimulate the enhanced phoshorylation of Akt-S473 in A549 cells with Sesn2 knocked down by shRNAs.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	10	11
Importantly , Grote and colleagues [ XREF_BIBR ] assessed insulin stimulated Akt activation was while insulin stimulation was not performed in the current study .	Importantly, Grote and colleagues [XREF_BIBR] assessed insulin stimulated Akt activation was while insulin stimulation was not performed in the current study.	8	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
Further , leucine alone can improve insulin activation of PKB in db/db mice .	Further, leucine alone can improve insulin activation of PKB in db/db mice.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	6	7	9	10
In the presence of 2-5A , insulin stimulated P-Akt and Akt expression rate and glucose uptake level were significantly increased in OB-IR group , by 119 % ( XREF_FIG ; * P = 0.013 ) and 38 % ( XREF_FIG ; * * P = 0.006 ) , respectively , whereas it had no effect in OB-IS .	In the presence of 2-5A, insulin stimulated P-Akt and Akt expression rate and glucose uptake level were significantly increased in OB-IR group, by 119% (XREF_FIG; * P = 0.013) and 38% (XREF_FIG; ** P = 0.006), respectively, whereas it had no effect in OB-IS.	6	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	P-Akt	P-Akt	P-Akt	6	7	8	9
G Protein Coupled Receptor Kinase 2 , With beta-Arrestin 2 , Impairs Insulin Induced Akt and Endothelial Nitric Oxide Synthase Signaling in ob/ob Mouse Aorta .	G Protein Coupled Receptor Kinase 2, With beta-Arrestin 2, Impairs Insulin Induced Akt and Endothelial Nitric Oxide Synthase Signaling in ob/ob Mouse Aorta.	11	18	Induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	12	13	14	15
Thus by activating PI3K and Akt and PKB signaling , insulin will induce mTOR activation and autophagy inhibition .	Thus by activating PI3K and Akt and PKB signaling, insulin will induce mTOR activation and autophagy inhibition.	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	5	6
Vinculin was knocked down in mdMSC using siRNA ; shown in XREF_FIG , insulin stimulated Akt activation was unaffected when vinculin was deficient .	Vinculin was knocked down in mdMSC using siRNA; shown in XREF_FIG, insulin stimulated Akt activation was unaffected when vinculin was deficient.	13	16	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
In conclusion , adrenaline potentiates insulin stimulated activation of PKB and p70 ( S6K ) via cAMP and Epac in skeletal muscle .	In conclusion, adrenaline potentiates insulin stimulated activation of PKB and p70 (S6K) via cAMP and Epac in skeletal muscle.	4	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	5	6	9	10
Here , we show that in EDL muscle from GK rats , maximal insulin stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment .	Here, we show that in EDL muscle from GK rats, maximal insulin stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment.	12	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
Dexamethasone is a synthetic glucocorticoid receptor ( GR ) agonist that promotes GR dependent gene transcription , IBMX is a cyclic nucleotide phosphodiesterase inhibitor that promotes accumulation of cAMP , insulin stimulates the PI3K and AKT pathway to modulate glucose and lipid metabolism , and rosiglitazone is a high-affinity PPARG agonist that promotes gene transactivation .	Dexamethasone is a synthetic glucocorticoid receptor (GR) agonist that promotes GR dependent gene transcription, IBMX is a cyclic nucleotide phosphodiesterase inhibitor that promotes accumulation of cAMP, insulin stimulates the PI3K and AKT pathway to modulate glucose and lipid metabolism, and rosiglitazone is a high-affinity PPARG agonist that promotes gene transactivation.	30	36	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	30	31	35	36
PEDF effects may modulate vascular tone and blood pressure by JNK activation and reduced insulin dependent activation of IRS-1 and Akt [ XREF_BIBR , XREF_BIBR ] .	PEDF effects may modulate vascular tone and blood pressure by JNK activation and reduced insulin dependent activation of IRS-1 and Akt [XREF_BIBR, XREF_BIBR].	14	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	20	21
However , Akt kinase activity was significantly stimulated by insulin and not contraction .	However, Akt kinase activity was significantly stimulated by insulin and not contraction.	2	12	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	2	3
In the fed state , insulin signaling activates insulin receptor , PI3K , and then subsequently activates Akt .	In the fed state, insulin signaling activates insulin receptor, PI3K, and then subsequently activates Akt.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	17	18
Akt was activated by insulin alone in the C57BL/6 strain and but not in db/db mice .	Akt was activated by insulin alone in the C57BL/6 strain and but not in db/db mice.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
A similar Akt activation by insulin detemir and human insulin was found in non malignant MCF-10A cells [ XREF_BIBR , XREF_BIBR ] and in non malignant fibroblasts expressing insulin receptor A isoform [ XREF_BIBR ] .	A similar Akt activation by insulin detemir and human insulin was found in non malignant MCF-10A cells [XREF_BIBR, XREF_BIBR] and in non malignant fibroblasts expressing insulin receptor A isoform [XREF_BIBR].	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	2	3
Although insulin treatment activated Akt in PI3Kgamma knockout mice , phosphorylation of GSK-3 was decreased compared to control mice .	Although insulin treatment activated Akt in PI3Kgamma knockout mice, phosphorylation of GSK-3 was decreased compared to control mice.	1	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	4	5
We show that insulin activates IRS-1 , Akt and PKB , and is only a mild activator of the ERK signaling cascade .	We show that insulin activates IRS-1, Akt and PKB, and is only a mild activator of the ERK signaling cascade.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
Western Blot results showed that 100nM , 200nM or 500nM anisomycin could effectively activate JNK signaling ( XREF_SUPPLEMENTARY ) , and 50nM , 100nM , 200nM or 500nM insulin could effectively activate Akt signaling ( XREF_SUPPLEMENTARY ) .	Western Blot results showed that 100nM, 200nM or 500nM anisomycin could effectively activate JNK signaling (XREF_SUPPLEMENTARY), and 50nM, 100nM, 200nM or 500nM insulin could effectively activate Akt signaling (XREF_SUPPLEMENTARY).	21	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	32	33
In both muscles , the increase of insulin elicited IRS-1 , Akt and ERK1/2 activation was observed along with an elevation in the IRS-1 expression level in MG53 -/- mice , compared with MG53 +/+ mice ( XREF_FIG ) .	In both muscles, the increase of insulin elicited IRS-1, Akt and ERK1/2 activation was observed along with an elevation in the IRS-1 expression level in MG53 -/- mice, compared with MG53 +/+ mice (XREF_FIG).	5	14	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	11	12
We observed that there was no difference in the basal Akt activity between wild-type TAPP1 +/+ TAPP2 +/+ and TAPP1 R211L and R211L TAPP2 R218L and R218L double knock-in mice , whereas insulin stimulated Akt activation was significantly enhanced in tissues derived from insulin injected TAPP1 R211L and R211L TAPP2 R218L and R218L double knock-in compared with wild-type TAPP1 +/+ TAPP2 +/+ animals ( XREF_FIG ) .	We observed that there was no difference in the basal Akt activity between wild-type TAPP1 +/+ TAPP2 +/+ and TAPP1 R211L and R211L TAPP2 R218L and R218L double knock-in mice, whereas insulin stimulated Akt activation was significantly enhanced in tissues derived from insulin injected TAPP1 R211L and R211L TAPP2 R218L and R218L double knock-in compared with wild-type TAPP1 +/+ TAPP2 +/+ animals (XREF_FIG).	32	44	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	32	33	34	35
Alternatively , binding of FA to muscle Toll like receptor 4 ( TLR4 ) can give rise to ceramides , which impair insulin stimulated AKT activation .	Alternatively, binding of FA to muscle Toll like receptor 4 (TLR4) can give rise to ceramides, which impair insulin stimulated AKT activation.	22	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	22	23	24	25
However , this reduction in the insulin ligand of the insulin signaling pathway led to a reduction in brain IRS-2 and diminished activation of Akt ( pAkt ) with increased activation of pGSK-3beta Ser9 .	However, this reduction in the insulin ligand of the insulin signaling pathway led to a reduction in brain IRS-2 and diminished activation of Akt (pAkt) with increased activation of pGSK-3beta Ser9.	6	26	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	24	25
These results suggest that VPA protects against low K ( + )-induced apoptosis by acting on the PI3K and PKB pathway ; however , VPA does not affect the increase of PKB activity caused by insulin in these cells .	These results suggest that VPA protects against low K (+)-induced apoptosis by acting on the PI3K and PKB pathway; however, VPA does not affect the increase of PKB activity caused by insulin in these cells.	31	38	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	35	36	31	32
Insulin activated the protein kinase Akt in cultured endothelial cells and increased the phosphorylation of eNOS on Ser ( 1177 ) but failed to increase endothelial cyclic GMP levels or to elicit the relaxation of endothelium-intact porcine coronary arteries .	Insulin activated the protein kinase Akt in cultured endothelial cells and increased the phosphorylation of eNOS on Ser (1177) but failed to increase endothelial cyclic GMP levels or to elicit the relaxation of endothelium-intact porcine coronary arteries.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
In contrast , XREF_BIBR demonstrated that up-regulation of GRK2 and a decrease in beta-arrestin2 inhibited insulin induced stimulation of Akt and eNOS signaling and that GRK2 overactivation may be induced by an increase in PKC activity in aortas from diabetic mice with hyperinsulinemia .	In contrast, XREF_BIBR demonstrated that up-regulation of GRK2 and a decrease in beta-arrestin2 inhibited insulin induced stimulation of Akt and eNOS signaling and that GRK2 overactivation may be induced by an increase in PKC activity in aortas from diabetic mice with hyperinsulinemia.	15	22	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	19	20
The cytosolic fractions , which contained insulin stimulated Akt , were mixed with the un stimulated mitochondria in the presence of ATP , NADH , and creatine phosphate and incubated at 25 degreesC for the indicated time periods .	The cytosolic fractions, which contained insulin stimulated Akt, were mixed with the un stimulated mitochondria in the presence of ATP, NADH, and creatine phosphate and incubated at 25 degreesC for the indicated time periods.	5	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Thus , insulin was able to directly activate PI3 kinase and AKT in the myocardium despite the absence of functional endothelial insulin receptors in the ESMIRO mice .	Thus, insulin was able to directly activate PI3 kinase and AKT in the myocardium despite the absence of functional endothelial insulin receptors in the ESMIRO mice.	2	12	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	11	12
The phosphorylation levels of insulin stimulated IRS-1 Ser 307 , Akt Ser 473 , and AS160 Thr 642 and the activity of p38 MAPK and SAPK and JNK in ANGII infused rats , when given access to running wheels , were normalized to the levels of the saline infusion group .	The phosphorylation levels of insulin stimulated IRS-1 Ser 307, Akt Ser 473, and AS160 Thr 642 and the activity of p38 MAPK and SAPK and JNK in ANGII infused rats, when given access to running wheels, were normalized to the levels of the saline infusion group.	2	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	Akt	Akt	akt	4	5	10	11
Germane to divergent activation of aPKC and PKB in diabetic liver , in IRS-1 knockout mice , insulin activation of aPKC and PKB is impaired in muscle , whereas , in liver , PKB activation is impaired , but aPKC activation is intact .	Germane to divergent activation of aPKC and PKB in diabetic liver, in IRS-1 knockout mice, insulin activation of aPKC and PKB is impaired in muscle, whereas, in liver, PKB activation is impaired, but aPKC activation is intact.	17	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	17	18	22	23
Insulin stimulation ( 1 nmol/l ) of IR kinase and PI 3-kinase were maximal within 5 min ( approximately 8- and 5-fold over basal , respectively ) , and insulin activation of PKB was maximal within 15 min ( approximately 3.5-fold over basal ) .	Insulin stimulation (1 nmol/l) of IR kinase and PI 3-kinase were maximal within 5 min (approximately 8- and 5-fold over basal, respectively), and insulin activation of PKB was maximal within 15 min (approximately 3.5-fold over basal).	29	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	29	30	32	33
All cholesterol depleted neuron derived cells , independent of the method of reduction , exhibited decreased phosphorylation and activation of IRS-1 and AKT following stimulation by insulin , insulin like growth factor-1 , or the neurotrophins ( NGF and BDNF ) .	All cholesterol depleted neuron derived cells, independent of the method of reduction, exhibited decreased phosphorylation and activation of IRS-1 and AKT following stimulation by insulin, insulin like growth factor-1, or the neurotrophins (NGF and BDNF).	22	27	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	26	27	22	23
Also , WD DJB rats displayed reduced fasting glycemia and insulinemia , and increased insulin induced Akt activation in the gastrocnemius .	Also, WD DJB rats displayed reduced fasting glycemia and insulinemia, and increased insulin induced Akt activation in the gastrocnemius.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
Growth factors or insulin activates class-I-phosphatidylinosital-3 kinase ( PI3K ) and AKT , which leads to mTOR activation through the tuberous sclerosis complex protein ( TSC )-Rheb signaling cascade 142 .	Growth factors or insulin activates class-I-phosphatidylinosital-3 kinase (PI3K) and AKT, which leads to mTOR activation through the tuberous sclerosis complex protein (TSC)-Rheb signaling cascade 142.	1	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	11	12
In muscle , insulin did not clearly activate Akt in HF-Con-AS animals , whereas insulin induced Akt phosphorylation was sustained in SHIP2-AS-treated rats .	In muscle, insulin did not clearly activate Akt in HF-Con-AS animals, whereas insulin induced Akt phosphorylation was sustained in SHIP2-AS-treated rats.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	8	9
The serine/threonine kinase Akt is activated by insulin and insulin like growth factors as a downstream target of PI3-Kinase XREF_BIBR , XREF_BIBR .	The serine/threonine kinase Akt is activated by insulin and insulin like growth factors as a downstream target of PI3-Kinase XREF_BIBR, XREF_BIBR.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	3	4
Insulin treatment rapidly activated Akt which was inhibited by Akt inhibitor in cardiomyocytes .	Insulin treatment rapidly activated Akt which was inhibited by Akt inhibitor in cardiomyocytes.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
But while overexpression of PKD in cardiomyocytes prevents lipid loading , AMPK overexpression promotes retention of insulin stimulated Akt signaling .	But while overexpression of PKD in cardiomyocytes prevents lipid loading, AMPK overexpression promotes retention of insulin stimulated Akt signaling.	14	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
Pharmacological inhibition of PP2A restored insulin induced Akt activation in palmitate treated cells XREF_BIBR .	Pharmacological inhibition of PP2A restored insulin induced Akt activation in palmitate treated cells XREF_BIBR.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
SEA also inhibits insulin induced activation of PKB and PKB downstream signaling which was associated with reduced basal and insulin induced glucose uptake , reduced lipogenesis as well as reduced ability of insulin to inhibit lipolysis .	SEA also inhibits insulin induced activation of PKB and PKB downstream signaling which was associated with reduced basal and insulin induced glucose uptake, reduced lipogenesis as well as reduced ability of insulin to inhibit lipolysis.	3	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	7	8
Accordingly , the upregulation of Ptpa , B56beta and B55alpha is particularly interesting as Ptpa has been shown to be required for PP2A activation XREF_BIBR , XREF_BIBR while B56beta XREF_BIBR and B55alpha XREF_BIBR have both been shown to target PP2A to Akt , thus potentially explaining why insulin activation of Akt is blunted while the effect of insulin upon lipogenesis is maintained .	Accordingly, the upregulation of Ptpa, B56beta and B55alpha is particularly interesting as Ptpa has been shown to be required for PP2A activation XREF_BIBR, XREF_BIBR while B56beta XREF_BIBR and B55alpha XREF_BIBR have both been shown to target PP2A to Akt, thus potentially explaining why insulin activation of Akt is blunted while the effect of insulin upon lipogenesis is maintained.	47	51	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	47	48	50	51
These results demonstrated that in vivo administration of insulin activated Akt through the PI3-kinase-dependent mechanism and reduced postischemic myocardial apoptotic death .	These results demonstrated that in vivo administration of insulin activated Akt through the PI3-kinase-dependent mechanism and reduced postischemic myocardial apoptotic death.	6	14	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Because insulin activated the Akt pathway more strongly than did EGF , we examined whether this pathway was involved in stimulating the increase in p57 abundance .	Because insulin activated the Akt pathway more strongly than did EGF, we examined whether this pathway was involved in stimulating the increase in p57 abundance.	1	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	4	5
There were no differences in basal IRS-1 p and Akt 1 p as well as insulin stimulated IRS-1 p , Akt 1 p and Akt 2 p between LFD and BM groups except basal Akt 2 p content was significantly higher in BM than in LFD mice .	There were no differences in basal IRS-1 p and Akt 1 p as well as insulin stimulated IRS-1 p, Akt 1 p and Akt 2 p between LFD and BM groups except basal Akt 2 p content was significantly higher in BM than in LFD mice.	1	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	20	21
Y-27632 upregulated insulin stimulated IRS-1 and Akt activation in pre-adipocytes 19 .	Y-27632 upregulated insulin stimulated IRS-1 and Akt activation in pre-adipocytes 19.	1	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
These findings suggest that insulin stimulated PI3K and Akt pathways oppose atherothrombotic factors in endothelium by multiple mechanisms including production of beneficial molecules such as NO and inhibition of pathogenenic molecules including PAI-1 , ICAM-1 , VCAM-1 , and E-selectin .	These findings suggest that insulin stimulated PI3K and Akt pathways oppose atherothrombotic factors in endothelium by multiple mechanisms including production of beneficial molecules such as NO and inhibition of pathogenenic molecules including PAI-1, ICAM-1, VCAM-1, and E-selectin.	4	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	8	9
( ii ) In obese Zucker rats , neither insulin nor vanadate could induce glucose uptake or activation of PKB to the same extent as in lean controls .	(ii) In obese Zucker rats, neither insulin nor vanadate could induce glucose uptake or activation of PKB to the same extent as in lean controls.	8	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	9	10	19	20
The effect of XMetS on insulin mediated Akt and Erk activation in cells expressing the hINSR .	The effect of XMetS on insulin mediated Akt and Erk activation in cells expressing the hINSR.	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Compared with 10-week-old mice , control mice at 15 months of age exhibited a 68 % reduction in insulin stimulated AKT serine 473 phosphorylation , which was prevented in M-PKCdeltaKO mice ( XREF_FIG ) .	Compared with 10-week-old mice, control mice at 15 months of age exhibited a 68% reduction in insulin stimulated AKT serine 473 phosphorylation, which was prevented in M-PKCdeltaKO mice (XREF_FIG).	16	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	18	19	20	21
There was no difference in insulin stimulated Akt and PKB activation at 10w compared to 25w in either controls or L-DKO mice ( XREF_FIG ) .	There was no difference in insulin stimulated Akt and PKB activation at 10w compared to 25w in either controls or L-DKO mice (XREF_FIG).	3	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Signalling-wise , Akt Ser474 was only increased by insulin and eEF2 Thr57 phosphorylation was only increased by contraction ( XREF_FIG A+ B ) .	Signalling-wise, Akt Ser474 was only increased by insulin and eEF2 Thr57 phosphorylation was only increased by contraction (XREF_FIG A+B).	2	9	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	2	3
When PI3K-PKB and Akt is stimulated by insulin it acts antagonistically to Ras and Raf-ERK pathway and when PI3K-PKB and Akt is blocked an increase in ERK1/2 phosphorylation occurs [ XREF_BIBR ] .	When PI3K-PKB and Akt is stimulated by insulin it acts antagonistically to Ras and Raf-ERK pathway and when PI3K-PKB and Akt is blocked an increase in ERK1/2 phosphorylation occurs [XREF_BIBR].	1	8	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	3	4
In contrast , loss of TC10alpha had no effect on the stimulation of Akt by insulin .	In contrast, loss of TC10alpha had no effect on the stimulation of Akt by insulin.	6	16	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	13	14
Moreover , compared with the control , significantly smaller eight-day differentiated adipocytes were observed , and these cells exhibited decreased IL-6 mRNA and increased GLUT4 mRNA levels ; these results also indicated the potential of vaspin to promote the insulin mediated AKT signaling pathway during the early phase of differentiation .	Moreover, compared with the control, significantly smaller eight-day differentiated adipocytes were observed, and these cells exhibited decreased IL-6 mRNA and increased GLUT4 mRNA levels; these results also indicated the potential of vaspin to promote the insulin mediated AKT signaling pathway during the early phase of differentiation.	37	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	39	40	41	42
Here , we propose that an increase in insulin secretion mediated by GPR40 can activate Akt and PKB to positively impact beta-cell survival .	Here, we propose that an increase in insulin secretion mediated by GPR40 can activate Akt and PKB to positively impact beta-cell survival.	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	17	18
However , it is important to note that gain of insulin stimulated Akt signaling in endothelial cells may not model any common human condition .	However, it is important to note that gain of insulin stimulated Akt signaling in endothelial cells may not model any common human condition.	8	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
The binding of insulin ( INS ) to insulin receptors could lead to tyrosine phosphorylation of insulin receptor substrates ( IRSs ) , which will in turn activate PI3K and AKT to trigger downstream actions to promote glucose uptake and storage XREF_BIBR XREF_BIBR ( XREF_FIG ) .	The binding of insulin (INS) to insulin receptors could lead to tyrosine phosphorylation of insulin receptor substrates (IRSs), which will in turn activate PI3K and AKT to trigger downstream actions to promote glucose uptake and storage XREF_BIBR XREF_BIBR (XREF_FIG).	1	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	binding of insulin (INS) to insulin receptors could lead to tyrosine	insulin	AKT	AKT	akt	3	4	30	31
The purpose of the present study was to determine in human skeletal muscle whether a single exercise bout and 7 days of consecutive endurance ( cycling ) training 1 ) increased insulin stimulated Akt pSer ( 473 ) and 2 ) altered the abundance of the protein tyrosine phosphatases ( PTPases ) , PTP1B and SHP2 .	The purpose of the present study was to determine in human skeletal muscle whether a single exercise bout and 7 days of consecutive endurance (cycling) training 1) increased insulin stimulated Akt pSer (473) and 2) altered the abundance of the protein tyrosine phosphatases (PTPases), PTP1B and SHP2.	30	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	33	34
How addition of glucose leads to Akt-TOR signaling has not been well characterized , and it has been proposed that changes in intracellular calcium or indirect activation of Akt by insulin or glucagon like peptide GLP-1 may be involved .	How addition of glucose leads to Akt-TOR signaling has not been well characterized, and it has been proposed that changes in intracellular calcium or indirect activation of Akt by insulin or glucagon like peptide GLP-1 may be involved.	26	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	30	31	28	29
These FOXOs are also negatively regulated by insulin and IGF -1 signaling [ XREF_BIBR ] : Activation of insulin and IGF -1 signaling increases activity of a serine threonine kinase Akt , which in turn phosphorylates FOXOs .	These FOXOs are also negatively regulated by insulin and IGF -1 signaling [XREF_BIBR] : Activation of insulin and IGF -1 signaling increases activity of a serine threonine kinase Akt, which in turn phosphorylates FOXOs.	18	31	increases activity	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	30	31
The insulin stimulated ratio of pAktthr308 and total Akt decreased after step reduction , with a post hoc analysis revealing the most pronounced effect after 4 h of insulin infusion .	The insulin stimulated ratio of pAktthr308 and total Akt decreased after step reduction, with a post hoc analysis revealing the most pronounced effect after 4 h of insulin infusion.	0	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	8	9
Insulin induced AKT activation is blunted in SERT mutant liver and muscle .	Insulin induced AKT activation is blunted in SERT mutant liver and muscle.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	2	3
Furthermore , miR-29 was highly expressed in muscle , fat and liver of type 2 diabetes rats and overexpression of miR-29 attenuated insulin induced Akt activation and glucose import XREF_BIBR .	Furthermore, miR-29 was highly expressed in muscle, fat and liver of type 2 diabetes rats and overexpression of miR-29 attenuated insulin induced Akt activation and glucose import XREF_BIBR.	22	25	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	24	25
Immunofluorescence analysis also revealed that transient H 2 O 2 treatment enhanced the activation of insulin induced AKT in 3T3-L1 adipocytes ( XREF_FIG ) .	Immunofluorescence analysis also revealed that transient H 2 O 2 treatment enhanced the activation of insulin induced AKT in 3T3-L1 adipocytes (XREF_FIG).	13	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	15	16	17	18
This demonstrates that wortmannin inhibits insulin activation of Akt in MCF-7 cells .	This demonstrates that wortmannin inhibits insulin activation of Akt in MCF-7 cells.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	8	9
JNK phosphorylates insulin receptor substrates ( IRS ) 1 and 2 at serine ( Ser ) or threonine ( Thr ) residues and thereby attenuate their insulin induced tyrosine ( Tyr ) phosphorylation , resulting in down-regulation of insulin signaling and diminished AKT activation XREF_BIBR .	JNK phosphorylates insulin receptor substrates (IRS) 1 and 2 at serine (Ser) or threonine (Thr) residues and thereby attenuate their insulin induced tyrosine (Tyr) phosphorylation, resulting in down-regulation of insulin signaling and diminished AKT activation XREF_BIBR.	0	44	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	JNK phosphorylates insulin	insulin	AKT	AKT	akt	2	3	42	43
Activation of Akt by insulin is a multistep process that for full activation requires hierarchical phosphorylation of two residues , the Thr 308 in the activation loop within the kinase domain , and the Ser 473 in the C-terminal of the kinase domain [ XREF_BIBR ] .	Activation of Akt by insulin is a multistep process that for full activation requires hierarchical phosphorylation of two residues, the Thr 308 in the activation loop within the kinase domain, and the Ser 473 in the C-terminal of the kinase domain [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	2	3
To assess the impact of PTH on insulin signaling , insulin induced activation of AKT , a downstream target of insulin signaling , was determined .	To assess the impact of PTH on insulin signaling, insulin induced activation of AKT, a downstream target of insulin signaling, was determined.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	14	15
The results indicated that , in isolated rat epitrochlearis muscle , 1 ) elevated phosphorylation of AS160 ( measured using anti-phospho-Akt substrate , PAS-AS160 , and phosphospecific anti-Thr ( 642 )-AS160 , pThr ( 642 )-AS160 ) consistently tracked with elevated insulin stimulated GT ; 2 ) PAS-TBC1D1 was not different from sedentary values at 3 or 27 h postexercise , when insulin sensitivity was increased ; 3 ) insulin stimulated Akt activity was not increased postexercise in muscles with increased insulin sensitivity ; 4 ) PAS-TBC1D1 was increased immediately postexercise , when insulin independent GT was elevated , and reversed at 3 and 27 h postexercise , when insulin independent GT was also reversed ; and 5 ) there was no significant effect of exercise or insulin on total abundance of AS160 , TBC1D1 , Akt , or GLUT4 protein with any of the protocols .	The results indicated that, in isolated rat epitrochlearis muscle, 1) elevated phosphorylation of AS160 (measured using anti-phospho-Akt substrate, PAS-AS160, and phosphospecific anti-Thr (642)-AS160, pThr (642)-AS160) consistently tracked with elevated insulin stimulated GT; 2) PAS-TBC1D1 was not different from sedentary values at 3 or 27 h postexercise, when insulin sensitivity was increased; 3) insulin stimulated Akt activity was not increased postexercise in muscles with increased insulin sensitivity; 4) PAS-TBC1D1 was increased immediately postexercise, when insulin independent GT was elevated, and reversed at 3 and 27 h postexercise, when insulin independent GT was also reversed; and 5) there was no significant effect of exercise or insulin on total abundance of AS160, TBC1D1, Akt, or GLUT4 protein with any of the protocols.	69	145	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	69	70	71	72
Interestingly , glycogen storage within pre-Sertoli cells appears to be dependent on the activation of the PI3K-AKT pathway , which is known to be activated by both insulin and IGFs XREF_BIBR .	Interestingly, glycogen storage within pre-Sertoli cells appears to be dependent on the activation of the PI3K-AKT pathway, which is known to be activated by both insulin and IGFs XREF_BIBR.	16	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	27	28	16	17
Western blot analysis indicates insulin produced similar activation of Akt Ser ( 473 ) and rpS6 Ser ( 240/244 ) in the ventral hypothalamus of control and dexamethasone treated rats .	Western blot analysis indicates insulin produced similar activation of Akt Ser (473) and rpS6 Ser (240/244) in the ventral hypothalamus of control and dexamethasone treated rats.	4	10	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	9	10
The cellular mechanism for enhanced insulin stimulated glucose uptake by skeletal muscle remains to be fully elucidated , but it has been demonstrated to occur concomitant with greater insulin induced activation of Akt [ XREF_BIBR , XREF_BIBR ] .	The cellular mechanism for enhanced insulin stimulated glucose uptake by skeletal muscle remains to be fully elucidated, but it has been demonstrated to occur concomitant with greater insulin induced activation of Akt [XREF_BIBR, XREF_BIBR].	25	33	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	32	33
This condition is different from insulin resistance in diabetes for which Akt activation by insulin is impaired due to other mechanisms 64 .	This condition is different from insulin resistance in diabetes for which Akt activation by insulin is impaired due to other mechanisms 64.	11	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	11	12
AMPK reactivation also strongly suppressed chronic mTORC1-S6K activation and hepatosteatosis in livers of obese Sesn2 -/- mice while it promoted insulin induced AKT activation .	AMPK reactivation also strongly suppressed chronic mTORC1-S6K activation and hepatosteatosis in livers of obese Sesn2 -/- mice while it promoted insulin induced AKT activation.	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	22	23
On the other hand , Hresko et al have shown that ATM plays no role in insulin stimulated activation of Akt in cultured adipocytes .	On the other hand, Hresko et al have shown that ATM plays no role in insulin stimulated activation of Akt in cultured adipocytes.	14	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	20	21
While TNF-alpha has been shown to impair the vasodilator effects of insulin in skeletal muscle resistance arteries through impairments of insulin activation of AKT in rats XREF_BIBR and impair insulin signaling and insulin stimulated glucose uptake in muscle XREF_BIBR , this work was done either ex vivo or in cultured cells .	While TNF-alpha has been shown to impair the vasodilator effects of insulin in skeletal muscle resistance arteries through impairments of insulin activation of AKT in rats XREF_BIBR and impair insulin signaling and insulin stimulated glucose uptake in muscle XREF_BIBR, this work was done either ex vivo or in cultured cells.	20	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	23	24
Insulin stimulated protein kinase B ( Akt ) activity , whereas AMPA pretreatment did not alter the insulin stimulated Akt activity .	Insulin stimulated protein kinase B (Akt) activity, whereas AMPA pretreatment did not alter the insulin stimulated Akt activity.	15	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	19	20
41 However , knocking down CREM in human HCC cell lines has no significant effect on insulin induced Akt activation ( XREF_SUPPLEMENTARY ) .	41 However, knocking down CREM in human HCC cell lines has no significant effect on insulin induced Akt activation (XREF_SUPPLEMENTARY).	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
A mutant Akt ( Akt-AA ) in which the phosphorylation sites targeted by growth factors are replaced by alanine was shown to inhibit insulin induced activation of both Akt and glycogen synthase in L6 myotubes .	A mutant Akt (Akt-AA) in which the phosphorylation sites targeted by growth factors are replaced by alanine was shown to inhibit insulin induced activation of both Akt and glycogen synthase in L6 myotubes.	23	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	28	29
We found that a single acute insulin injection increased Akt pSer473 in APOE4 compared to APOE3 mice ( +113 % versus +78.5 % ) , indicating that APOE4 carriage potentiates activation of insulin upstream signaling pathway in the brain .	We found that a single acute insulin injection increased Akt pSer473 in APOE4 compared to APOE3 mice (+113% versus +78.5%), indicating that APOE4 carriage potentiates activation of insulin upstream signaling pathway in the brain.	6	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	9	10
Insulin activates the PI3K and AKT pathway in both adult primary sensory neurons in culture and ex vivo rat sciatic nerve ( Jolivalt , unpublished ) and promotes neurite outgrowth and sprouting of IENF .	Insulin activates the PI3K and AKT pathway in both adult primary sensory neurons in culture and ex vivo rat sciatic nerve (Jolivalt, unpublished) and promotes neurite outgrowth and sprouting of IENF.	0	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	5	6
It is well known that PI3K and Akt pathway is activated by insulin ( Ins ) and suppressed by protein kinase C. Insulin receptor ( InR ) signaling is diminished and PKC activity is upregulated in type I and type II diabetes and these may lead to enhanced FBXO transcription and impaired BK channel function ( XREF_FIG ) .	It is well known that PI3K and Akt pathway is activated by insulin (Ins) and suppressed by protein kinase C. Insulin receptor (InR) signaling is diminished and PKC activity is upregulated in type I and type II diabetes and these may lead to enhanced FBXO transcription and impaired BK channel function (XREF_FIG).	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	7	8
Akt ( aka protein kinase B ) is activated by insulin and IGF-1 and has two known major downstream branches relevant to muscle protein synthesis : the mTOR pathway , which is activated by Akt , and the GSK3beta pathway , which is inhibited by Akt .	Akt (aka protein kinase B) is activated by insulin and IGF-1 and has two known major downstream branches relevant to muscle protein synthesis : the mTOR pathway, which is activated by Akt, and the GSK3beta pathway, which is inhibited by Akt.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	0	1
Leptin binding to all four forms of the short leptin receptor ( Ob-Ra , Ob-Rc , Ob-Rd and Ob-Rf ) , elicits activation of Janus Kinase ( JAK ) 2 and subsequent phosphorylation of insulin receptor substrates ( IRS ) , initiating activation of the PI3-K and Akt pathway 3 .	Leptin binding to all four forms of the short leptin receptor (Ob-Ra, Ob-Rc, Ob-Rd and Ob-Rf), elicits activation of Janus Kinase (JAK) 2 and subsequent phosphorylation of insulin receptor substrates (IRS), initiating activation of the PI3-K and Akt pathway 3.	0	48	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	Leptin binding to all four forms of the short leptin receptor (Ob-Ra, Ob-Rc, Ob-Rd and Ob-Rf), elicits activation of Janus Kinase (JAK) 2 and subsequent phosphorylation of insulin	insulin	Akt	Akt	akt	34	35	47	48
Our results showed that Alms1 GT/GT mice have aberrant insulin signaling either downstream or independent of AKT signaling , before the increase of body weight and circulating insulin levels .	Our results showed that Alms1 GT/GT mice have aberrant insulin signaling either downstream or independent of AKT signaling, before the increase of body weight and circulating insulin levels.	9	17	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	16	17
Interestingly , the crucial role of IL-7 on T-lymphocyte homeostasis ( in mice and human ) -- known for a long time -- was demonstrated to depend upon these metabolic pathways since IL-7 , alike insulin , promotes T cell survival and size in a PI3-K and Akt and mTOR dependent manner .	Interestingly, the crucial role of IL-7 on T-lymphocyte homeostasis (in mice and human) -- known for a long time -- was demonstrated to depend upon these metabolic pathways since IL-7, alike insulin, promotes T cell survival and size in a PI3-K and Akt and mTOR dependent manner.	32	48	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	35	36	47	48
The protective effect of SphK1 was linked to its enhancement of insulin stimulated kinases Akt and GSK3beta .	The protective effect of SphK1 was linked to its enhancement of insulin stimulated kinases Akt and GSK3beta.	9	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	14	15
Furthermore , APPL1 potentiates insulin induced Akt activation in its several metabolic targets , including adipocytes , muscle cells , and hepatocytes .	Furthermore, APPL1 potentiates insulin induced Akt activation in its several metabolic targets, including adipocytes, muscle cells, and hepatocytes.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
However , when ATP and insulin were added in combination , ATP dramatically reduced the insulin stimulated Akt activation ( 2-fold above basal ) .	However, when ATP and insulin were added in combination, ATP dramatically reduced the insulin stimulated Akt activation (2-fold above basal).	13	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
Next , we investigated the activation of Akt by insulin .	Next, we investigated the activation of Akt by insulin.	3	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	7	8
Activation of PKB by insulin is linked to its translocation from the cytosol to the plasma membrane .	Activation of PKB by insulin is linked to its translocation from the cytosol to the plasma membrane.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	2	3
Quercetin has been shown to stimulate glycogenolysis XREF_BIBR and to inhibit glucose uptake , insulin signaling and activation of Akt , a downstream effector of PI3K XREF_BIBR , XREF_BIBR .	Quercetin has been shown to stimulate glycogenolysis XREF_BIBR and to inhibit glucose uptake, insulin signaling and activation of Akt, a downstream effector of PI3K XREF_BIBR, XREF_BIBR.	14	20	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	19	20
Hypothalamic insulin significantly increases both pAkt and Akt and pSTAT3 and STAT3 in the liver XREF_BIBR and thus , may be involved in vagus nerve stimuli projected to the liver XREF_BIBR .	Hypothalamic insulin significantly increases both pAkt and Akt and pSTAT3 and STAT3 in the liver XREF_BIBR and thus, may be involved in vagus nerve stimuli projected to the liver XREF_BIBR.	0	21	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	7	8
In hepatocytes , insulin activation of Akt enhances both the synthesis and processing of the predominant SREBP isoform , SREBP1c [ XREF_BIBR , XREF_BIBR ] .	In hepatocytes, insulin activation of Akt enhances both the synthesis and processing of the predominant SREBP isoform, SREBP1c [XREF_BIBR, XREF_BIBR].	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	6	7
Endogenous Akt activity was also stimulated by insulin in cells expressing mCherry vector with BKAR and inhibited by treatment with GDC-0068 .	Endogenous Akt activity was also stimulated by insulin in cells expressing mCherry vector with BKAR and inhibited by treatment with GDC-0068.	1	8	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	1	2
The inhibitory effects of XMetD on insulin mediated Akt activation with cells expressing the mINSR were similar to cells expressing the hINSR .	The inhibitory effects of XMetD on insulin mediated Akt activation with cells expressing the mINSR were similar to cells expressing the hINSR.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
These data indicate that extracellular ATP and statins via the P2X7 receptor modulate insulin induced Akt signaling in epithelial cells .	These data indicate that extracellular ATP and statins via the P2X7 receptor modulate insulin induced Akt signaling in epithelial cells.	13	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
The absence of association between the levels of insulin stimulated P-Akt and Akt fold induction in SAT and GIR was not surprising as during hyperinsulinemic-euglycemic clamp , the large majority of perfused glucose ( 85 % ) is used by skeletal muscle [ XREF_BIBR ] .	The absence of association between the levels of insulin stimulated P-Akt and Akt fold induction in SAT and GIR was not surprising as during hyperinsulinemic-euglycemic clamp, the large majority of perfused glucose (85%) is used by skeletal muscle [XREF_BIBR].	6	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	P-Akt	P-Akt	p-akt	8	9	10	11
Exposure of cells to arsenite for 24h rendered cells less responsive toward stimulation of Akt by insulin .	Exposure of cells to arsenite for 24h rendered cells less responsive toward stimulation of Akt by insulin.	12	17	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	14	15
Pathologic hypertrophy is believed to result from events that involve biomechanical deformation signals , activation of G-protein-coupled receptors and their intracellular signaling pathways , and activation of the PI3K-Akt pathway initiated by insulin and other growth signals [ XREF_BIBR ] .	Pathologic hypertrophy is believed to result from events that involve biomechanical deformation signals, activation of G-protein-coupled receptors and their intracellular signaling pathways, and activation of the PI3K-Akt pathway initiated by insulin and other growth signals [XREF_BIBR].	28	38	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	32	33	28	29
To investigate the mechanism by which PKC impairs insulin stimulated Akt activity , we assessed various upstream mediators of Akt signaling .	To investigate the mechanism by which PKC impairs insulin stimulated Akt activity, we assessed various upstream mediators of Akt signaling.	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
We found that increased IPMK expression enhanced insulin mediated activation of Akt ( XREF_FIG ) .	We found that increased IPMK expression enhanced insulin mediated activation of Akt (XREF_FIG).	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	11	12
We further showed that insulin , but not amino acids , increases PKB activation and decreases TSC2 activation in neonatal muscle .	We further showed that insulin, but not amino acids, increases PKB activation and decreases TSC2 activation in neonatal muscle.	4	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	12	13
In addition , insulin stimulates the PI3-K and PKB pathway , initiating glucose uptake through upregulation of GLUT3 transporters .	In addition, insulin stimulates the PI3-K and PKB pathway, initiating glucose uptake through upregulation of GLUT3 transporters.	3	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	8	9
20 % ) as compared with unsynchronized cells , insulin stimulation still robustly activates AKT in G1/S arrested cells , and results in cleavage of ER localized SREBP to its nuclear localized form to levels equivalent to those of cells allowed to progress to G2/M ( XREF_FIG a ) .	20%) as compared with unsynchronized cells, insulin stimulation still robustly activates AKT in G1/S arrested cells, and results in cleavage of ER localized SREBP to its nuclear localized form to levels equivalent to those of cells allowed to progress to G2/M (XREF_FIG a).	9	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	14	15
XREF_BIBR This divergence in insulin signaling downstream of PI3K for glucose versus lipid metabolism has also been observed in liver , whereby insulin stimulates the PI3K-Akt axis to regulate gluconeogenesis and the PI3K-aPKC ( atypical protein kinase C ) lambda and zeta to regulate lipogenesis .	XREF_BIBR This divergence in insulin signaling downstream of PI3K for glucose versus lipid metabolism has also been observed in liver, whereby insulin stimulates the PI3K-Akt axis to regulate gluconeogenesis and the PI3K-aPKC (atypical protein kinase C) lambda and zeta to regulate lipogenesis.	22	26	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	22	23	25	26
IGF and insulin signaling produces the activation of the intracellular networks PI3K and AKT and RAS and MAPK .	IGF and insulin signaling produces the activation of the intracellular networks PI3K and AKT and RAS and MAPK.	0	14	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	13	14
This demonstrated that insulin stimulated PtdIns ( 3,4,5 ) P 3 synthesis and Akt activation were significantly reduced in classic insulin stimulated tissues , namely skeletal muscle and liver in the Iqgap1-null compared with WT mice ( XREF_FIG ) .	This demonstrated that insulin stimulated PtdIns (3,4,5) P 3 synthesis and Akt activation were significantly reduced in classic insulin stimulated tissues, namely skeletal muscle and liver in the Iqgap1-null compared with WT mice (XREF_FIG).	3	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	13	14
In J774.2 macrophage cells , insulin mediated activation of AKT was inhibited to a similar extent by inhibitors of p110alpha , p110beta or p110delta [ XREF_BIBR ] .	In J774.2 macrophage cells, insulin mediated activation of AKT was inhibited to a similar extent by inhibitors of p110alpha, p110beta or p110delta [XREF_BIBR].	5	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	9	10
Insulin like growth factor-I ( IGF-I ) and insulin dependent induction of the PI3K and Akt pathway leads to feedback inhibition of signaling due to mTOR and S6K mediated phosphorylation and degradation of IRS-1 .	Insulin like growth factor-I (IGF-I) and insulin dependent induction of the PI3K and Akt pathway leads to feedback inhibition of signaling due to mTOR and S6K mediated phosphorylation and degradation of IRS-1.	8	16	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	15	16
Because insulin is an essential component of the growth media of NMuMGs and insulin is known to stimulate Akt activity , exposure to insulin was included as a background control .	Because insulin is an essential component of the growth media of NMuMGs and insulin is known to stimulate Akt activity, exposure to insulin was included as a background control.	9	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	18	19
Two independent groups have also reported a lipid metabolism defect in mice with hepatic Rictor deletion , but they do not agree mechanistically [ XREF_BIBR , XREF_BIBR ] ; one group reports that some AKT effectors are less stimulated [ XREF_BIBR ] , while the other reports normal insulin stimulated AKT signaling [ XREF_BIBR ] .	Two independent groups have also reported a lipid metabolism defect in mice with hepatic Rictor deletion, but they do not agree mechanistically [XREF_BIBR, XREF_BIBR]; one group reports that some AKT effectors are less stimulated [XREF_BIBR], while the other reports normal insulin stimulated AKT signaling [XREF_BIBR].	46	51	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	48	49	50	51
Akt was activated by insulin or IGF-1 , but not IFNalpha , in the IFNalpha sensitive U-266 myeloma cell line .	Akt was activated by insulin or IGF-1, but not IFNalpha, in the IFNalpha sensitive U-266 myeloma cell line.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
Further , Ang II was observed to specifically inhibit activation of insulin induced Akt in hepatocytes [ XREF_BIBR ] .	Further, Ang II was observed to specifically inhibit activation of insulin induced Akt in hepatocytes [XREF_BIBR].	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Similar non synergistic or non additive effect of gAdp on insulin induced Akt activation was also observed in mouse C2C12 myocytes and rat vascular smooth muscle PAC cells .	Similar non synergistic or non additive effect of gAdp on insulin induced Akt activation was also observed in mouse C2C12 myocytes and rat vascular smooth muscle PAC cells.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
The present study examines the consequences of altered T-cad expression on VSMC for constitutive and insulin induced Akt and mTOR axis signaling and contractile competence .	The present study examines the consequences of altered T-cad expression on VSMC for constitutive and insulin induced Akt and mTOR axis signaling and contractile competence.	15	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
However , in contrast to the complete loss of insulin activation of the PKB and ERK pathways , there was an additive induction of tau phosphorylation following insulin in the anaesthetised animals .	However, in contrast to the complete loss of insulin activation of the PKB and ERK pathways, there was an additive induction of tau phosphorylation following insulin in the anaesthetised animals.	9	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	9	10	13	14
HFD fed rats and mice typically exhibit impairments in insulin stimulated hepatic Akt activity XREF_BIBR XREF_BIBR , which leads to a decrease in hepatic glycogen synthesis due to decreased activation of glycogen synthase-3beta ( GSK3beta ) XREF_BIBR .	HFD fed rats and mice typically exhibit impairments in insulin stimulated hepatic Akt activity XREF_BIBR XREF_BIBR, which leads to a decrease in hepatic glycogen synthesis due to decreased activation of glycogen synthase-3beta (GSK3beta) XREF_BIBR.	7	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	12	13
At the molecular level , long-term Sirolimus administration attenuated glucose uptake and metabolism in skeletal muscle by preventing full insulin induced Akt activation and altering the expression and translocation of glucose transporters to the plasma membrane .	At the molecular level, long-term Sirolimus administration attenuated glucose uptake and metabolism in skeletal muscle by preventing full insulin induced Akt activation and altering the expression and translocation of glucose transporters to the plasma membrane.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
However , with wortmannin treatment in PTEN silenced conditions a small increase in insulin induced Akt and GSK3beta phosphorylation was still observed ( XREF_FIG , panels B and D , respectively ; lane 4 vs. lane 3 ) .	However, with wortmannin treatment in PTEN silenced conditions a small increase in insulin induced Akt and GSK3beta phosphorylation was still observed (XREF_FIG, panels B and D, respectively; lane 4 vs. lane 3).	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
Moreover , IL6 treatment reduced insulin stimulated AKT activation in the liver of HFD fed F KO mice ( XREF_FIG ) .	Moreover, IL6 treatment reduced insulin stimulated AKT activation in the liver of HFD fed F KO mice (XREF_FIG).	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
We then evaluated whether OB-plasma might impair insulin stimulated Akt and eNOS activation by phosphorylation .	We then evaluated whether OB-plasma might impair insulin stimulated Akt and eNOS activation by phosphorylation.	6	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
In contrast , insulin alone produced a small activation of Akt and glycogen synthase kinase-3 in MIRKO mice , and prior exercise markedly enhanced this insulin effect .	In contrast, insulin alone produced a small activation of Akt and glycogen synthase kinase-3 in MIRKO mice, and prior exercise markedly enhanced this insulin effect.	3	14	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	10	11
BDM also blocked the action of HGA on insulin stimulated PKB and GSK3 alpha .	BDM also blocked the action of HGA on insulin stimulated PKB and GSK3 alpha.	2	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	10	11
The anti-adipogenic actions of FoxO1 appear to be under the control of insulin signaling as cells lacking either insulin receptor , or insulin receptor substrate or the insulin target AKT , have increased FoxO1 activity and impaired differentiation .	The anti-adipogenic actions of FoxO1 appear to be under the control of insulin signaling as cells lacking either insulin receptor, or insulin receptor substrate or the insulin target AKT, have increased FoxO1 activity and impaired differentiation.	15	30	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	27	28	29	30
Indeed , we have observed that insulin induced PI3K-AKT activation does not affect beta-catenin protein stability in HIRc-B cells ( XREF_FIG E ) , while myrAKT1 expression slightly prolongs beta-catenin protein t ( 1/2 ) in alphaT3-1 cells ( unpublished data ) .	Indeed, we have observed that insulin induced PI3K-AKT activation does not affect beta-catenin protein stability in HIRc-B cells (XREF_FIG E), while myrAKT1 expression slightly prolongs beta-catenin protein t (1/2) in alphaT3-1 cells (unpublished data).	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	6	7	8	9
Addition of GLP-1 significantly increased insulin mediated Akt , but not eNOS or ERK1/2 , phosphorylation in muscle ( XREF_FIG ) .	Addition of GLP-1 significantly increased insulin mediated Akt, but not eNOS or ERK1/2, phosphorylation in muscle (XREF_FIG).	4	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Moreover , even on HFD , ShcP mice resisted fatty-diet-induced insulin resistance in liver and muscles , whereas ShcL mice were more susceptible and lost insulin induced Akt activation in liver faster than controls ( data not shown ) .	Moreover, even on HFD, ShcP mice resisted fatty-diet-induced insulin resistance in liver and muscles, whereas ShcL mice were more susceptible and lost insulin induced Akt activation in liver faster than controls (data not shown).	25	28	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
These results are attributed to enhanced insulin stimulated Akt and p70S6K activation in the liver and skeletal glucose when compared to normal mice .	These results are attributed to enhanced insulin stimulated Akt and p70S6K activation in the liver and skeletal glucose when compared to normal mice.	3	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Based on the different localization patterns of mTORC2 and PLD1 , the lysosomal deficiency of PA probably does not regulate insulin stimulated Akt via mTORC2 .	Based on the different localization patterns of mTORC2 and PLD1, the lysosomal deficiency of PA probably does not regulate insulin stimulated Akt via mTORC2.	19	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
Regular insulin and other insulin analogs tested activated mainly the IR and the PI3K and Akt pathway .	Regular insulin and other insulin analogs tested activated mainly the IR and the PI3K and Akt pathway.	0	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	15	16
Pile of concrete evidence imply metformin as an Insulin sensitizer may enhance Akt and mTOR activity however the significance of Akt and mTOR recruitment has not yet been revealed in metformin induced neuroprotection against oxidative stress .	Pile of concrete evidence imply metformin as an Insulin sensitizer may enhance Akt and mTOR activity however the significance of Akt and mTOR recruitment has not yet been revealed in metformin induced neuroprotection against oxidative stress.	8	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	8	9	12	13
These results suggest that insulin stimulated Akt activation is mediated through PI3K .	These results suggest that insulin stimulated Akt activation is mediated through PI3K.	4	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
In SQAT , insulin administration significantly increased p-Ser AKT in lean Zuckers , LF and SARA fatty Zuckers , but not in the LARD and non SARA groups ( p < 0.05 ) .	In SQAT, insulin administration significantly increased p-Ser AKT in lean Zuckers, LF and SARA fatty Zuckers, but not in the LARD and non SARA groups (p < 0.05).	3	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	8	9
Our results suggest that PI3-kinase and Akt activation by insulin or EGF is beneficial for islet beta cell protection .	Our results suggest that PI3-kinase and Akt activation by insulin or EGF is beneficial for islet beta cell protection.	4	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	6	7
By contrast , insulin induced Akt activity was not affected by preincubation with anti-obestatin Ab .	By contrast, insulin induced Akt activity was not affected by preincubation with anti-obestatin Ab.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
Interacting with Ser/Thr protein kinases Akt , TRB3 impairs Akt activation induced by growth factors and insulin .	Interacting with Ser/Thr protein kinases Akt, TRB3 impairs Akt activation induced by growth factors and insulin.	9	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	9	10
We also confirmed that insulin signaling was intact in cells that expressed the Grp1 mutants , as adding insulin resulted in the activation of Akt ( XREF_FIG ) .	We also confirmed that insulin signaling was intact in cells that expressed the Grp1 mutants, as adding insulin resulted in the activation of Akt (XREF_FIG).	18	25	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	24	25
275 , 4803-4809 ) , but instead inhibits insulin induced Akt activation and GSK-3beta phosphorylation .	275, 4803-4809), but instead inhibits insulin induced Akt activation and GSK-3beta phosphorylation.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
The precise cellular mechanism for this healthful outcome is unknown , but it is accompanied by enhanced insulin stimulated activation of Akt .	The precise cellular mechanism for this healthful outcome is unknown, but it is accompanied by enhanced insulin stimulated activation of Akt.	14	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	21	22
Moreover , small interfering RNA mediated IRS-2 knockdown also inhibited insulin stimulated Akt activation and glucose uptake without affecting GLUT4 translocation and plasma membrane fusion .	Moreover, small interfering RNA mediated IRS-2 knockdown also inhibited insulin stimulated Akt activation and glucose uptake without affecting GLUT4 translocation and plasma membrane fusion.	9	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
Our study suggests that insulin stimulates the PI3K and Akt pathway under all visual conditions .	Our study suggests that insulin stimulates the PI3K and Akt pathway under all visual conditions.	4	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	9	10
The cytokines IL-3 , IL-4 , stem cell factor ( SCF ) , GM-CSF , and insulin all induced the rapid and transient activation of PKB in responsive cell lines .	The cytokines IL-3, IL-4, stem cell factor (SCF), GM-CSF, and insulin all induced the rapid and transient activation of PKB in responsive cell lines.	2	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	16	17	25	26
In summary , whereas ER stress only partially prevents insulin stimulation of PKB and mTORC1 , the lack of activation of PKB by amino acids results in a complete block of leucine stimulated activation of targets downstream of mTORC1 likely through hypophosphorylation of the mTORC1 kinase inhibitor PRAS40 .	In summary, whereas ER stress only partially prevents insulin stimulation of PKB and mTORC1, the lack of activation of PKB by amino acids results in a complete block of leucine stimulated activation of targets downstream of mTORC1 likely through hypophosphorylation of the mTORC1 kinase inhibitor PRAS40.	9	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	9	10	12	13
In non malignant MCF-10A cells , Akt activation by insulin glargine was stronger [ XREF_BIBR , XREF_BIBR ] , and in fibroblasts expressing insulin receptor B isoform it was weaker than that by human insulin [ XREF_BIBR ] .	In non malignant MCF-10A cells, Akt activation by insulin glargine was stronger [XREF_BIBR, XREF_BIBR], and in fibroblasts expressing insulin receptor B isoform it was weaker than that by human insulin [XREF_BIBR].	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	6	7
Interestingly , although both PtdIns-( 3,4,5 ) P3 and PtdIns ( 3,4 ) P2 have been implicated in the regulation of Akt activity in vitro , overexpression of SHIP2 inhibited insulin induced Akt activation , presumably by its 5 '-inositol phosphatase activity .	Interestingly, although both PtdIns-(3,4,5) P3 and PtdIns (3,4) P2 have been implicated in the regulation of Akt activity in vitro, overexpression of SHIP2 inhibited insulin induced Akt activation, presumably by its 5 '-inositol phosphatase activity.	30	33	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	30	31	32	33
Other studies show that topical insulin injections accelerate the healing of diabetic foot ulcers by stimulating the AKT and ERK pathways .	Other studies show that topical insulin injections accelerate the healing of diabetic foot ulcers by stimulating the AKT and ERK pathways.	5	20	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	17	18
As shown in XREF_FIG and XREF_FIG , growth factors such as insulin increase Akt activity , which in turns promotes mTORC1 activation by directly phosphorylating the tuberous sclerosis complex 1/2 ( TSC1/2 ) and PRAS40 .	As shown in XREF_FIG and XREF_FIG, growth factors such as insulin increase Akt activity, which in turns promotes mTORC1 activation by directly phosphorylating the tuberous sclerosis complex 1/2 (TSC1/2) and PRAS40.	11	14	increase	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Insulin sequentially activates the insulin receptor , PI3K , and Akt [ XREF_BIBR ] through phosphorylation at threonine 308 and serine 473 [ XREF_BIBR ] .	Insulin sequentially activates the insulin receptor, PI3K, and Akt [XREF_BIBR] through phosphorylation at threonine 308 and serine 473 [XREF_BIBR].	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	10	11
Drug treatment also increased insulin induced Akt activation in skeletal muscle ( XREF_FIG ) , which is consistent with an improvement in systemic glucose metabolism , whereas examination of islet morphology and function did not reveal significant effects after 2 weeks of treatment ( XREF_FIG ) .	Drug treatment also increased insulin induced Akt activation in skeletal muscle (XREF_FIG), which is consistent with an improvement in systemic glucose metabolism, whereas examination of islet morphology and function did not reveal significant effects after 2 weeks of treatment (XREF_FIG).	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
A previous study showed that insulin signal activates the PI3K and Akt pathway to promote the hepatocyte tetraploidization process .	A previous study showed that insulin signal activates the PI3K and Akt pathway to promote the hepatocyte tetraploidization process.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	11	12
In the liver , the PI3K and AKT pathway is primarily activated by insulin and IGF1 .	In the liver, the PI3K and AKT pathway is primarily activated by insulin and IGF1.	5	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	13	14	7	8
Some isoforms of PKC appear to have downregulatory effects on insulin signaling , such as PKC-beta , which suppresses the insulin induced activation of Akt and eNOS via direct phosphorylation of IRS1 .	Some isoforms of PKC appear to have downregulatory effects on insulin signaling, such as PKC-beta, which suppresses the insulin induced activation of Akt and eNOS via direct phosphorylation of IRS1.	19	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	24	25
Consequently , the cardioprotection of insulin induced Akt activation was impaired in aged hearts , resulting in more susceptible to MI/R injury .	Consequently, the cardioprotection of insulin induced Akt activation was impaired in aged hearts, resulting in more susceptible to MI/R injury.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Insulin mediated AKT activation occurs rapidly via cell surface receptor signalling [ 64 ] and served as a positive control for our Western blots on NRVMs .	Insulin mediated AKT activation occurs rapidly via cell surface receptor signalling [64] and served as a positive control for our Western blots on NRVMs.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	2	3
These studies revealed the following : ( i ) while insulin mediated Akt activation was not significantly affected by dasatinib , ( ii ) PDGF stimulated Akt activation to a greater extent in CFb and was substantially reduced by dasatinib , ( iii ) PDGF also stimulated Erk1/2 activation to a greater extent in CFb and that was blocked by dasatinib treatment .	These studies revealed the following : (i) while insulin mediated Akt activation was not significantly affected by dasatinib, (ii) PDGF stimulated Akt activation to a greater extent in CFb and was substantially reduced by dasatinib, (iii) PDGF also stimulated Erk1/2 activation to a greater extent in CFb and that was blocked by dasatinib treatment.	10	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
In agreement with previous reports showing that chronic ET-1 could decrease glucose uptake in adipocytes by dampening insulin stimulated Akt signaling , we also detected a reduction in glucose uptake following ET-1 treatment in all three groups ( XREF_FIG ) .	In agreement with previous reports showing that chronic ET-1 could decrease glucose uptake in adipocytes by dampening insulin stimulated Akt signaling, we also detected a reduction in glucose uptake following ET-1 treatment in all three groups (XREF_FIG).	17	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	19	20
We found activation of PKB in T cells treated with IL-2 and insulin , and neutrophils cultured with N-formyl-Met-Leu-Phe ( fMLP ) , insulin or granulocyte-macrophage colony stimulating factor .	We found activation of PKB in T cells treated with IL-2 and insulin, and neutrophils cultured with N-formyl-Met-Leu-Phe (fMLP), insulin or granulocyte-macrophage colony stimulating factor.	2	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	12	13	4	5
The EC 50 for insulin stimulated Akt activation in the absence of XMetD was 0.97 nM ( 95 % CI : 0.72 to 1.30 nM ) and increased to 103 nM ( 95 % CI : 88 to 119 nM ) in the presence of 333 nM XMetD .	The EC 50 for insulin stimulated Akt activation in the absence of XMetD was 0.97 nM (95% CI : 0.72 to 1.30 nM) and increased to 103 nM (95% CI : 88 to 119 nM) in the presence of 333 nM XMetD.	1	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Indeed in the liver , AICAR also restored AMPK activity and suppressed mTORC1-S6K activity ( XREF_FIG ) , and restored insulin induced AKT activation ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Indeed in the liver, AICAR also restored AMPK activity and suppressed mTORC1-S6K activity (XREF_FIG), and restored insulin induced AKT activation (XREF_FIG and XREF_SUPPLEMENTARY).	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	22	23
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR It is thought that increased accumulation of ceramide in these domains has a deleterious effect on insulin signaling either via activation of protein phosphatase ( PP2A ) that blocks insulin mediated activation of Akt or by disruption of lipid raft associated signaling complexes , both of which are crucial for insulin stimulated glucose uptake .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR It is thought that increased accumulation of ceramide in these domains has a deleterious effect on insulin signaling either via activation of protein phosphatase (PP2A) that blocks insulin mediated activation of Akt or by disruption of lipid raft associated signaling complexes, both of which are crucial for insulin stimulated glucose uptake.	36	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	36	37	40	41
Induced transgenic overexpression of miR-143 , but not miR-145 , impairs insulin stimulated AKT activation and glucose homeostasis .	Induced transgenic overexpression of miR-143, but not miR-145, impairs insulin stimulated AKT activation and glucose homeostasis.	10	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	13	14
Insulin activates its own gene and initiates the PI3K and Akt pathway , leading to anti-apoptosis and beta cells survival .	Insulin activates its own gene and initiates the PI3K and Akt pathway, leading to anti-apoptosis and beta cells survival.	0	11	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	10	11
We compared the insulin activation of PI3K-Akt ( glucose uptake ) and ERK-MAPK ( pro inflammation ) signaling pathways , intracellular and mitochondrial oxidative stress ( DCF and MitoSOX Red ) , and their responses to the antioxidant N-acetylcysteine ( NAC ) .	We compared the insulin activation of PI3K-Akt (glucose uptake) and ERK-MAPK (pro inflammation) signaling pathways, intracellular and mitochondrial oxidative stress (DCF and MitoSOX Red), and their responses to the antioxidant N-acetylcysteine (NAC).	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	3	4	6	7
The HyO DJB group displayed better glucose tolerance , associated with a normal hepatic insulin activation of Akt .	The HyO DJB group displayed better glucose tolerance, associated with a normal hepatic insulin activation of Akt.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	17	18
To determine whether insulin induced activation of Akt is regulated through PI3K activation , we incubated retinas in organ culture in the presence and absence of PI3K inhibitor LY294002 for 30 min followed by treatment with or without insulin .	To determine whether insulin induced activation of Akt is regulated through PI3K activation, we incubated retinas in organ culture in the presence and absence of PI3K inhibitor LY294002 for 30 min followed by treatment with or without insulin.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
Moreover , recent studies have indicated that insulin stimulated PI3K and Akt signaling regulates glucose metabolism in the brain , plays important roles in neural development and neuronal activities and affects learning and memory .	Moreover, recent studies have indicated that insulin stimulated PI3K and Akt signaling regulates glucose metabolism in the brain, plays important roles in neural development and neuronal activities and affects learning and memory.	7	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	11	12
In vitro studies indicate that exposure to saturated fatty acids increases DAG and ceramide in myotubes , and inhibits insulin stimulated glycogen synthesis and activation of Akt and protein Kinase B ( obligate intermediate in pathway of anabolic metabolism ) [ XREF_BIBR , XREF_BIBR ] .	In vitro studies indicate that exposure to saturated fatty acids increases DAG and ceramide in myotubes, and inhibits insulin stimulated glycogen synthesis and activation of Akt and protein Kinase B (obligate intermediate in pathway of anabolic metabolism) [XREF_BIBR, XREF_BIBR].	18	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	26	27
Insulin induced Akt activation is necessary and sufficient to promote Na ( + )/K ( + )-ATPase translocation to the plasma membrane .	Insulin induced Akt activation is necessary and sufficient to promote Na (+)/K (+)-ATPase translocation to the plasma membrane.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
In muscle and adipose tissue , insulin mediated Akt activation stimulates the translocation of glucose transporters to the membrane to allow glucose uptake .	In muscle and adipose tissue, insulin mediated Akt activation stimulates the translocation of glucose transporters to the membrane to allow glucose uptake.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
FFAs also attenuate the insulin activation of Akt through upregulation of PTEN [ XREF_BIBR ] ; or through induction of ceramide , which , in turn , activates PP2A and thereby decreases Akt activation [ XREF_BIBR ] ; or by enhancing the mTOR and S6K to IRS1 negative feedback signaling [ XREF_BIBR ] .	FFAs also attenuate the insulin activation of Akt through upregulation of PTEN [XREF_BIBR]; or through induction of ceramide, which, in turn, activates PP2A and thereby decreases Akt activation [XREF_BIBR]; or by enhancing the mTOR and S6K to IRS1 negative feedback signaling [XREF_BIBR].	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	7	8
Moreover , insulin stimulated P-Akt and Akt fold induction in skeletal muscle was negatively correlated with HOMA IR ( R = -0.433 , P = 0.019 ; XREF_FIG ) and positively correlated to GIR ( R = 0.409 , P = 0.018 ; XREF_FIG ) , and we also found associations with IkappaBalpha protein expression ( R = 0.525 , P = 0.004 ) and systemic fetuin-A levels ( R = -0.436 , P = 0.018 ) .	Moreover, insulin stimulated P-Akt and Akt fold induction in skeletal muscle was negatively correlated with HOMA IR (R = -0.433, P = 0.019; XREF_FIG) and positively correlated to GIR (R = 0.409, P = 0.018; XREF_FIG), and we also found associations with IkappaBalpha protein expression (R = 0.525, P = 0.004) and systemic fetuin-A levels (R = -0.436, P = 0.018).	2	31	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	P-Akt	P-Akt	P-Akt	2	3	4	5
Akt activation by insulin lispro was weaker than that by human insulin in fibroblasts expressing insulin receptor B isoform [ XREF_BIBR ] .	Akt activation by insulin lispro was weaker than that by human insulin in fibroblasts expressing insulin receptor B isoform [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	0	1
Consistent with mTORC1 and S6K1 mediated feedback mechanisms contributing to hepatic insulin resistance , adenoviral delivery of a proposed dominant negative Raptor mutant ( which lacks approximately 400 amino acids at its C-terminus and blocks the phosphorylation of S6K1 but not 4EBP1 when overexpressed in the liver ) enhances insulin stimulated PI3K-Akt signaling and improves glucose tolerance [ XREF_BIBR ] .	Consistent with mTORC1 and S6K1 mediated feedback mechanisms contributing to hepatic insulin resistance, adenoviral delivery of a proposed dominant negative Raptor mutant (which lacks approximately 400 amino acids at its C-terminus and blocks the phosphorylation of S6K1 but not 4EBP1 when overexpressed in the liver) enhances insulin stimulated PI3K-Akt signaling and improves glucose tolerance [XREF_BIBR].	48	52	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	49	50	51	52
Insulin activates downstream Akt kinase activity , which is achieved by the phosphorylation of the Thr308 residue and Ser473 residue .	Insulin activates downstream Akt kinase activity, which is achieved by the phosphorylation of the Thr308 residue and Ser473 residue.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
Our previous report documented that oxidative stress inhibited insulin stimulated Akt and endothelial nitric oxide synthase ( eNOS ) activation in obesity associated insulin resistance [ XREF_BIBR ] .	Our previous report documented that oxidative stress inhibited insulin stimulated Akt and endothelial nitric oxide synthase (eNOS) activation in obesity associated insulin resistance [XREF_BIBR].	8	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
We present evidence that this improvement of glucose homeostasis is associated with an activation of Akt and ERK1/2 under basal conditions in the liver and with an enhancement of insulin induced Akt activation in adipose tissue .	We present evidence that this improvement of glucose homeostasis is associated with an activation of Akt and ERK1/2 under basal conditions in the liver and with an enhancement of insulin induced Akt activation in adipose tissue.	27	32	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	31	32
Induction of the endogenous PI3K-Akt pathway in CHO cells ( by the insulin pathway ) , in T-cells ( via TCR activation ) or in neurons ( via TrKB activation ) potentiates Notch dependent responses .	Induction of the endogenous PI3K-Akt pathway in CHO cells (by the insulin pathway), in T-cells (via TCR activation) or in neurons (via TrKB activation) potentiates Notch dependent responses.	0	13	Induction	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	12	13	4	5
The half-life for activation of AKT by insulin is 1 min and , therefore , lies within the time frame of the observed effects .	The half-life for activation of AKT by insulin is 1 min and, therefore, lies within the time frame of the observed effects.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	5	6
In mammalian cells , insulin and insulin like growth factor signaling activate AKT and PKB kinase to negatively regulate the nuclear localization of DAF-16 homologs ( reviewed in ) .	In mammalian cells, insulin and insulin like growth factor signaling activate AKT and PKB kinase to negatively regulate the nuclear localization of DAF-16 homologs (reviewed in).	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	12	13
Intravenous injection of caffeine at a physiological dose ( 5 mg/kg ) in rats inhibited the phosphorylation of insulin stimulated IRS-1 Tyr ( 612 ) and Akt Ser ( 473 ) in epitrochlearis muscle .	Intravenous injection of caffeine at a physiological dose (5 mg/kg) in rats inhibited the phosphorylation of insulin stimulated IRS-1 Tyr (612) and Akt Ser (473) in epitrochlearis muscle.	3	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	caffeine at a physiological dose (5 mg/kg) in rats inhibited the phosphorylation of insulin	insulin	Akt	Akt	akt	18	19	26	27
Whereas we showed augmented Akt activation by rapamycin in cardiomyocytes , these studies raised several important questions whether : ( i ) the agonist stimulated Akt activation and its further augmentation by rapamycin requires mTORC2 , ( ii ) the previously reported negative regulation on mTORC2 via IRS-1 and/or Rictor phosphorylation is lost during rapamycin treatment , leading to enhanced mTORC2 activation , and ( iii ) the insulin stimulated Akt activation in cardiomyocytes and its augmentation by rapamycin requires PKCepsilon , functioning downstream of mTORC2 .	Whereas we showed augmented Akt activation by rapamycin in cardiomyocytes, these studies raised several important questions whether : (i) the agonist stimulated Akt activation and its further augmentation by rapamycin requires mTORC2, (ii) the previously reported negative regulation on mTORC2 via IRS-1 and/or Rictor phosphorylation is lost during rapamycin treatment, leading to enhanced mTORC2 activation, and (iii) the insulin stimulated Akt activation in cardiomyocytes and its augmentation by rapamycin requires PKCepsilon, functioning downstream of mTORC2.	67	79	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	68	69	70	71
Insulin stimulated phosphorylation of hepatic Akt and FoxO1 was disrupted in both LIRKO and LIRFKO mice ( XREF_FIG ) , demonstrating that insulin is not able to activate Akt signalling pathway in the absence of the hepatic IR ( XREF_FIG ) .	Insulin stimulated phosphorylation of hepatic Akt and FoxO1 was disrupted in both LIRKO and LIRFKO mice (XREF_FIG), demonstrating that insulin is not able to activate Akt signalling pathway in the absence of the hepatic IR (XREF_FIG).	22	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	28	29
Akt activation by insulin has been linked to suppression of FOXO ( forkhead box O ) and caspase-3 activity and also to a decrease in ubiquitin ligases expression [ XREF_BIBR ] .	Akt activation by insulin has been linked to suppression of FOXO (forkhead box O) and caspase-3 activity and also to a decrease in ubiquitin ligases expression [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	0	1
Functionally , mTORC2 serves as one of the two upstream kinases involved in the insulin dependent activation of the serine/threonine kinase PKB ( aka Akt ) .	Functionally, mTORC2 serves as one of the two upstream kinases involved in the insulin dependent activation of the serine/threonine kinase PKB (aka Akt).	14	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	14	15	21	22
Interestingly , STAT3 knockdown in control treated L6 myotubes XREF_BIBR , but not in cultured human muscle myotubes XREF_BIBR , also improved insulin mediated Akt activation and glycogen synthesis .	Interestingly, STAT3 knockdown in control treated L6 myotubes XREF_BIBR, but not in cultured human muscle myotubes XREF_BIBR, also improved insulin mediated Akt activation and glycogen synthesis.	21	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	24	25
However , only insulin activates Akt and PKB , and metformin activates AMPK [ XREF_BIBR ] .	However, only insulin activates Akt and PKB, and metformin activates AMPK [XREF_BIBR].	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	7	8
PP2A has previously been shown to be activated by palmitate XREF_BIBR and to inhibit insulin stimulated Akt activity , phosphorylation at Ser473 and glycogen synthesis in C2C12 myotubes XREF_BIBR .	PP2A has previously been shown to be activated by palmitate XREF_BIBR and to inhibit insulin stimulated Akt activity, phosphorylation at Ser473 and glycogen synthesis in C2C12 myotubes XREF_BIBR.	13	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
Both thrombin and insulin activate PKB and induce glucose uptake albeit with different kinetics .	Both thrombin and insulin activate PKB and induce glucose uptake albeit with different kinetics.	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	5	6
It would therefore appear that distinct mechanisms exist for the stimulation of PKB by insulin and isoproterenol in rat fat cells .	It would therefore appear that distinct mechanisms exist for the stimulation of PKB by insulin and isoproterenol in rat fat cells.	7	20	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	14	15	12	13
In 3T3-L1 adipocytes , interference with the IR-IRS-1 interaction did not cause inhibition of insulin stimulated AKT activation or glucose transport .	In 3T3-L1 adipocytes, interference with the IR-IRS-1 interaction did not cause inhibition of insulin stimulated AKT activation or glucose transport.	12	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	14	15	16	17
Consistent with this , mice with muscle selective deletion of JNK1 are protected from diet induced insulin resistance and show increased Akt activation and glucose metabolism in skeletal muscle [ XREF_BIBR ] .	Consistent with this, mice with muscle selective deletion of JNK1 are protected from diet induced insulin resistance and show increased Akt activation and glucose metabolism in skeletal muscle [XREF_BIBR].	16	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	21	22
Wortmannin and LY294002 , inhibitors of PI 3-kinase , reduced insulin dependent activation of PKB , whereas rapamycin , an inhibitor of p70 S6 kinase , had no effect .	Wortmannin and LY294002, inhibitors of PI 3-kinase, reduced insulin dependent activation of PKB, whereas rapamycin, an inhibitor of p70 S6 kinase, had no effect.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	10	11	14	15
PI3K and Akt signaling is stimulated by insulin .	PI3K and Akt signaling is stimulated by insulin.	0	8	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	2	3
The PI3K and Akt signaling , which is activated by insulin or IGF-1 , negatively regulates GSK3beta through increasing or decreasing phosphorylation at Ser 9 .	The PI3K and Akt signaling, which is activated by insulin or IGF-1, negatively regulates GSK3beta through increasing or decreasing phosphorylation at Ser 9.	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	3	4
Similarly , chronic insulin treatment of isolated DRG neurons ( mimicking hyperinsulinemia ) reduced insulin stimulated Akt activation [ XREF_BIBR ] .	Similarly, chronic insulin treatment of isolated DRG neurons (mimicking hyperinsulinemia) reduced insulin stimulated Akt activation [XREF_BIBR].	13	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
Under control conditions , insulin stimulated Akt and Erk activation and fatty acid uptake in WAT were not significantly affected by the ovarian cycle .	Under control conditions, insulin stimulated Akt and Erk activation and fatty acid uptake in WAT were not significantly affected by the ovarian cycle.	4	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
These results in HepG2 cells suggest that calpains play a role in the hepatic regulation of insulin stimulated glycogen synthesis independent of the PI3-kinase and Akt signaling pathway .	These results in HepG2 cells suggest that calpains play a role in the hepatic regulation of insulin stimulated glycogen synthesis independent of the PI3-kinase and Akt signaling pathway.	14	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	25	26
Furthermore , increased intracellular Ca 2+ is responsible for insulin induced Akt activation , which results in leptin secretion in adipocytes XREF_BIBR .	Furthermore, increased intracellular Ca 2+ is responsible for insulin induced Akt activation, which results in leptin secretion in adipocytes XREF_BIBR.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
The transcriptional regulators which respond to the insulin activation of PKB ( and perhaps of accessory signaling cascades ) and stimulate transcription at the liver GCK promoter remain elusive .	The transcriptional regulators which respond to the insulin activation of PKB (and perhaps of accessory signaling cascades) and stimulate transcription at the liver GCK promoter remain elusive.	7	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	7	8	10	11
The inhibition of insulin mediated Akt activity by S1P is completely abolished in the presence of PKCdelta siRNA indicating that this isozyme is selectively potent at causing dephosphorylation of Akt and modifying keratinocyte proliferation .	The inhibition of insulin mediated Akt activity by S1P is completely abolished in the presence of PKCdelta siRNA indicating that this isozyme is selectively potent at causing dephosphorylation of Akt and modifying keratinocyte proliferation.	1	6	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
However , a much less than maximal activation of Akt by insulin is needed to obtain a maximal stimulation of adipocyte glucose transport XREF_BIBR , XREF_BIBR .	However, a much less than maximal activation of Akt by insulin is needed to obtain a maximal stimulation of adipocyte glucose transport XREF_BIBR, XREF_BIBR.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	9	10
XREF_BIBR , XREF_BIBR Insulin is known to activate the PI3K and Akt pathway and thus increases carcinogenesis .	XREF_BIBR, XREF_BIBR Insulin is known to activate the PI3K and Akt pathway and thus increases carcinogenesis.	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	3	4	11	12
XREF_BIBR These results highlight the importance of insulin and IGF induction of the AKT pathway to stimulate beta cell proliferation through the inhibition of p27 Kip1 and FoxO1 .	XREF_BIBR These results highlight the importance of insulin and IGF induction of the AKT pathway to stimulate beta cell proliferation through the inhibition of p27 Kip1 and FoxO1.	7	14	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	13	14
Insulin and IGF -1 activates PI3-kinase and Akt pathway .	Insulin and IGF -1 activates PI3-kinase and Akt pathway.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	7	8
This NOS3 phosphorylation site can be regulated by Akt [ XREF_BIBR ] , which is activated by insulin [ XREF_BIBR ] .	This NOS3 phosphorylation site can be regulated by Akt [XREF_BIBR], which is activated by insulin [XREF_BIBR].	8	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	8	9
To account for this , insulin stimulated pAkt Thr308 / Akt was determined as the increase above basal pAkt Thr308 / Akt ( i.e. delta pAkt Thr308 / Akt ) .	To account for this, insulin stimulated pAkt Thr308 / Akt was determined as the increase above basal pAkt Thr308 / Akt (i.e. delta pAkt Thr308 / Akt).	5	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	21	22
While insulin administration causes a robust stimulation of AKT in a gonadotrope cell line , whether AKT signaling plays a role in luteinizing hormone secretion remains to be determined .	While insulin administration causes a robust stimulation of AKT in a gonadotrope cell line, whether AKT signaling plays a role in luteinizing hormone secretion remains to be determined.	1	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	1	2	8	9
Atypical PKCs and PKB are rapidly activated by insulin in adipocytes , liver , skeletal muscles , and other cell types by a mechanism requiring PI3K and its downstream effector , 3-phosphoinositide-dependent protein kinase-1 ( PDK-1 ) , which , in conjunction with PIP3 , phosphorylates critical threonine residues in the activation loops of atypical PKCs and PKB .	Atypical PKCs and PKB are rapidly activated by insulin in adipocytes, liver, skeletal muscles, and other cell types by a mechanism requiring PI3K and its downstream effector, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), which, in conjunction with PIP3, phosphorylates critical threonine residues in the activation loops of atypical PKCs and PKB.	1	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	3	4
Acute cardiac beta-AR activation potentiates insulin induced Akt mediated glucose uptake via PKA , while chronic beta-AR stimulation leads to insulin resistance ( characterized by sustained Akt activation and reduced Glucose transporter type 4 -GLUT4 - membrane levels ) and ultimately impaired glucose uptake .	Acute cardiac beta-AR activation potentiates insulin induced Akt mediated glucose uptake via PKA, while chronic beta-AR stimulation leads to insulin resistance (characterized by sustained Akt activation and reduced Glucose transporter type 4 -GLUT4 - membrane levels) and ultimately impaired glucose uptake.	4	43	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
For example , mTORC2 promotes cell survival via AKT [ XREF_BIBR , XREF_BIBR ] and also regulates hepatic glucose and lipid metabolism via insulin induced AKT signaling [ XREF_BIBR ] .	For example, mTORC2 promotes cell survival via AKT [XREF_BIBR, XREF_BIBR] and also regulates hepatic glucose and lipid metabolism via insulin induced AKT signaling [XREF_BIBR].	18	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	23	24	25	26
Insulin and IGF1 activate Akt and PKB and ERK1/2 in Saos-2 and B10 cells : time and dose dependence .	Insulin and IGF1 activate Akt and PKB and ERK1/2 in Saos-2 and B10 cells : time and dose dependence.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	6	7
62 Overexpression of PKC-beta2 and concomitant ApoE knockout ( KO ) in mice fed a high-fat diet resulted in a significant impairment in insulin stimulated Akt and eNOS activation , with augmented leukocyte-endothelial binding and increased ET-1 production .	62 Overexpression of PKC-beta2 and concomitant ApoE knockout (KO) in mice fed a high-fat diet resulted in a significant impairment in insulin stimulated Akt and eNOS activation, with augmented leukocyte-endothelial binding and increased ET-1 production.	21	28	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	25	26
Development of IR on chronic insulin treatment is accompanied by a decrease in insulin stimulation of Akt , p70S6K and GSK3beta , but does not affect MAPK mediated signaling pathways , a result mimicking that seen in muscle and adipocytes [ XREF_BIBR , XREF_BIBR ] .	Development of IR on chronic insulin treatment is accompanied by a decrease in insulin stimulation of Akt, p70S6K and GSK3beta, but does not affect MAPK mediated signaling pathways, a result mimicking that seen in muscle and adipocytes [XREF_BIBR, XREF_BIBR].	13	20	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	16	17
Both increased and unchanged insulin stimulated activation of Akt was observed in cultured myotubes with SIRT1 overexpression [ XREF_BIBR , XREF_BIBR ] .	Both increased and unchanged insulin stimulated activation of Akt was observed in cultured myotubes with SIRT1 overexpression [XREF_BIBR, XREF_BIBR].	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	8	9
Activation of signaling cascades of phosphatidylinositol 3-kinase ( PI-3K )/protein kinase B ( Akt ) is due to insulin or IGF-I effects ( the main regulators of GSK-3beta activity ) , which causes Akt activation and protein kinase B ( PKB ) directly through GSK-3beta phosphorylation .	Activation of signaling cascades of phosphatidylinositol 3-kinase (PI-3K)/protein kinase B (Akt) is due to insulin or IGF-I effects (the main regulators of GSK-3beta activity), which causes Akt activation and protein kinase B (PKB) directly through GSK-3beta phosphorylation.	18	34	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	33	34
In this study , the real-time DCF method revealed the reversibility and sustainability of insulin stimulation of Akt .	In this study, the real-time DCF method revealed the reversibility and sustainability of insulin stimulation of Akt.	14	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	17	18
Prominent signaling pathways including class-I A kinases are the insulin and insulin like growth factor signaling pathways mediating activation of Akt and protein kinase B and other downstream mediators which are important for the regulation of glucose metabolism and cell proliferation .	Prominent signaling pathways including class-I A kinases are the insulin and insulin like growth factor signaling pathways mediating activation of Akt and protein kinase B and other downstream mediators which are important for the regulation of glucose metabolism and cell proliferation.	2	24	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	20	21
We show that MTMR7 inhibited insulin mediated activation of AKT and ERK1/2 signaling and reduced proliferation of human CRC cells .	We show that MTMR7 inhibited insulin mediated activation of AKT and ERK1/2 signaling and reduced proliferation of human CRC cells.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	9	10
Importantly , we demonstrate that hepatic beta 2 -AR regulates insulin induced AKT activation via Grb2 mediated SRC recruitment through a G i -independent mechanism .	Importantly, we demonstrate that hepatic beta 2 -AR regulates insulin induced AKT activation via Grb2 mediated SRC recruitment through a G i -independent mechanism.	10	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	12	13
Surprisingly , insulin induced AKT activation was not affected by genetic obesity under conditions where DNL was markedly attenuated ( XREF_FIG C ) .	Surprisingly, insulin induced AKT activation was not affected by genetic obesity under conditions where DNL was markedly attenuated (XREF_FIG C).	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	4	5
No effect was observed in SAPK pathways ( p38MAPK and JNK ) , but E1a was able to affect the Akt activation mediated by insulin .	No effect was observed in SAPK pathways (p38MAPK and JNK), but E1a was able to affect the Akt activation mediated by insulin.	20	25	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	24	25	20	21
Mechanistically , H 2 O 2 treatment may enhance insulin stimulated AKT activation through the oxidation and inactivation of PTEN compared with single insulin treatment , resulting in increased GLUT4 translocation and glucose uptake .	Mechanistically, H 2 O 2 treatment may enhance insulin stimulated AKT activation through the oxidation and inactivation of PTEN compared with single insulin treatment, resulting in increased GLUT4 translocation and glucose uptake.	8	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	11	12
By interacting with TRB3 , an endogenous Akt inhibitor , APPL1 has been shown to enhance insulin stimulated Akt activity .	By interacting with TRB3, an endogenous Akt inhibitor, APPL1 has been shown to enhance insulin stimulated Akt activity.	15	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
Insulin did not induce additional AKT activation in OV-90 cells , and ganitumab was not agonistic when used in the absence of growth factors .	Insulin did not induce additional AKT activation in OV-90 cells, and ganitumab was not agonistic when used in the absence of growth factors.	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	5	6
As shown in XREF_FIG , insulin alone significantly increased phosphoryaltion of serine 473 of Akt maximally at 10 min ( % phosphorylation : 124.82 +/-15.9 at 10 min vs. 21 +/-8.8 in control group , * p < 0.05 ) and this effect was attenuated by pre-incubation with Ang II ( * p < 0.05 vs. insulin alone ) .	As shown in XREF_FIG, insulin alone significantly increased phosphoryaltion of serine 473 of Akt maximally at 10 min (% phosphorylation : 124.82 +/-15.9 at 10 min vs. 21 +/-8.8 in control group, * p < 0.05) and this effect was attenuated by pre-incubation with Ang II (* p < 0.05 vs. insulin alone).	5	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	14	15
It was surprising that p110-beta -/- mice on normal chow were hyperglycemic with increased expression of hepatic PEPCK and G6PC , since insulin activation of Akt appeared normal in these animals .	It was surprising that p110-beta -/- mice on normal chow were hyperglycemic with increased expression of hepatic PEPCK and G6PC, since insulin activation of Akt appeared normal in these animals.	22	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	25	26
In addition , mechanistically , this activation was different from that of growth factors since it did not require phosphorylation of the S473 residue , which is essential for full PKB activation induced by insulin .	In addition, mechanistically, this activation was different from that of growth factors since it did not require phosphorylation of the S473 residue, which is essential for full PKB activation induced by insulin.	30	35	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	34	35	30	31
Deacetylation of these proteins would then trigger their translocation to the cytoplasm where they would prevent insulin induced Akt activation and glut4 translocation to the membrane .	Deacetylation of these proteins would then trigger their translocation to the cytoplasm where they would prevent insulin induced Akt activation and glut4 translocation to the membrane.	15	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
In addition , beta-adrenergic receptor stimulation inhibits insulin induced activation of Akt [ XREF_BIBR - XREF_BIBR ] and suppresses its protective effect in cardiac myocytes [ XREF_BIBR ] .	In addition, beta-adrenergic receptor stimulation inhibits insulin induced activation of Akt [XREF_BIBR - XREF_BIBR] and suppresses its protective effect in cardiac myocytes [XREF_BIBR].	7	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	11	12
Insulin and IGF1 dependent signaling activates protein kinase B and serum and glucocorticoid inducible kinase ( PKB and SGK ) , which together phosphorylate and inactivate glycogen synthase kinase GSK3 .	Insulin and IGF1 dependent signaling activates protein kinase B and serum and glucocorticoid inducible kinase (PKB and SGK), which together phosphorylate and inactivate glycogen synthase kinase GSK3.	0	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	16	17
These findings demonstrate that APPL1 couples insulin stimulated Akt activation to GSIS by promoting the expression of the core exocytotic machinery involved in exocytosis and also suggest that reduced APPL1 expression in pancreatic islets may serve as a pathological link that couples insulin resistance to beta-cell dysfunction in type 2 diabetes .	These findings demonstrate that APPL1 couples insulin stimulated Akt activation to GSIS by promoting the expression of the core exocytotic machinery involved in exocytosis and also suggest that reduced APPL1 expression in pancreatic islets may serve as a pathological link that couples insulin resistance to beta-cell dysfunction in type 2 diabetes.	4	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
For example , insulin activates PI3K and Akt pathway , inhibits apoptosis of HSCs , and promotes expansion of HSCs .	For example, insulin activates PI3K and Akt pathway, inhibits apoptosis of HSCs, and promotes expansion of HSCs.	3	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
Also shown in XREF_FIG ( right panel ) , in the presence of blebbistatin , insulin fully activated Akt followed by GSK3beta phosphorylation .	Also shown in XREF_FIG (right panel), in the presence of blebbistatin, insulin fully activated Akt followed by GSK3beta phosphorylation.	15	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	18	19
Insulin could not activate PKB , as measured by the Ser473 phosphorylated form of the enzyme , in the obese Zucker rats to the same extent as in lean controls .	Insulin could not activate PKB, as measured by the Ser473 phosphorylated form of the enzyme, in the obese Zucker rats to the same extent as in lean controls.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	4	5
In pharmacological analyses , p110alpha inhibitors blocked insulin mediated activation of AKT in myotubes and adipocytes [ XREF_BIBR ] .	In pharmacological analyses, p110alpha inhibitors blocked insulin mediated activation of AKT in myotubes and adipocytes [XREF_BIBR].	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	11	12
The insulin and leptin activation of both AKT and ERK signalling pathways are prevented by downregulation of Sam68 expression in MDA-MB-231 and BT-474 ( XREF_SUPPLEMENTARY ) .	The insulin and leptin activation of both AKT and ERK signalling pathways are prevented by downregulation of Sam68 expression in MDA-MB-231 and BT-474 (XREF_SUPPLEMENTARY).	1	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	1	2	7	8
Interestingly , insulin also activated Akt activity by phosphorylation , whereas pre-treatment of HepIII failed to interfere Akt activation by insulin .	Interestingly, insulin also activated Akt activity by phosphorylation, whereas pre-treatment of HepIII failed to interfere Akt activation by insulin.	2	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	5	6
25 It is interesting that insulin stimulated AKT activation is inhibited by siRNA mediated FSP27 silencing .	25 It is interesting that insulin stimulated AKT activation is inhibited by siRNA mediated FSP27 silencing.	5	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
Focusing on the intra-omic Akt pathway , the EC 50 and T 1/2 values for the phosphorylation of Akt place this kinase in the same category as Class 3 IRGs ( XREF_TABLE ) , indicating that Akt activity is enhanced by induced insulin stimulation .	Focusing on the intra-omic Akt pathway, the EC 50 and T 1/2 values for the phosphorylation of Akt place this kinase in the same category as Class 3 IRGs (XREF_TABLE), indicating that Akt activity is enhanced by induced insulin stimulation.	36	43	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	42	43	36	37
We therefore examined the effects of burn injury on insulin stimulated Akt and PKB activation in skeletal muscle .	We therefore examined the effects of burn injury on insulin stimulated Akt and PKB activation in skeletal muscle.	6	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
We treated cells with insulin , a growth factor that activates the PI3K and Akt pathway , to monitor Akt phosphorylation in response to HAS2 depletion .	We treated cells with insulin, a growth factor that activates the PI3K and Akt pathway, to monitor Akt phosphorylation in response to HAS2 depletion.	1	15	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	14	15
Furthermore , insulin activation of Akt and p70 ( s6kinase ) , kinases downstream of PI3K , was unaffected by PDGF pretreatment .	Furthermore, insulin activation of Akt and p70 (s6kinase), kinases downstream of PI3K, was unaffected by PDGF pretreatment.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	5	6
Activation of this receptor leads to calcium mobilization and PROKR1 , a paralog with unusually high sequence similarity to this receptor , has been associated with insulin mediated Akt signalling and myocardial fibrosis , diastolic dysfunction and impaired capillary formation [ XREF_BIBR , XREF_BIBR ] .	Activation of this receptor leads to calcium mobilization and PROKR1, a paralog with unusually high sequence similarity to this receptor, has been associated with insulin mediated Akt signalling and myocardial fibrosis, diastolic dysfunction and impaired capillary formation [XREF_BIBR, XREF_BIBR].	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	28	29
This included a significant repression of insulin stimulated glucose uptake and the inhibition of insulin stimulated Akt signaling , most likely mediated through PI3-K regulation .	This included a significant repression of insulin stimulated glucose uptake and the inhibition of insulin stimulated Akt signaling, most likely mediated through PI3-K regulation.	12	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
TSH inhibits insulin stimulated Akt signaling in a cPKC dependent fashion , whereas insulin blocks TSH stimulated cPKC activity and lipolysis .	TSH inhibits insulin stimulated Akt signaling in a cPKC dependent fashion, whereas insulin blocks TSH stimulated cPKC activity and lipolysis.	1	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
We found that insulin increased Akt , but not AMPK , phosphorylation ( XREF_FIG ) .	We found that insulin increased Akt, but not AMPK, phosphorylation (XREF_FIG).	3	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
A serine/threonine kinase Akt , a constitutively active mutant of which was previously shown to stimulate glucose uptake , is activated by insulin , GH , and hyperosmolarity to approximately 4-fold , approximately 2.1-fold , and approximately 2.3-fold over basal level , respectively .	A serine/threonine kinase Akt, a constitutively active mutant of which was previously shown to stimulate glucose uptake, is activated by insulin, GH, and hyperosmolarity to approximately 4-fold, approximately 2.1-fold, and approximately 2.3-fold over basal level, respectively.	0	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	3	4
In wild-type MEFs ( Tsc2 +/+ ) , insulin significantly activated ERK , Akt and mTORC1 , and neither Akt nor mTORC1 was suppressed by inhibition of ERK .	In wild-type MEFs (Tsc2 +/+), insulin significantly activated ERK, Akt and mTORC1, and neither Akt nor mTORC1 was suppressed by inhibition of ERK.	8	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	13	14
The PI3K-AKT pathway is activated by the binding of growth factors or insulin to receptor tyrosine kinases ( RTKs ) .	The PI3K-AKT pathway is activated by the binding of growth factors or insulin to receptor tyrosine kinases (RTKs).	1	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	12	13	1	2
Activation of Akt induced by insulin was intact and more pronounced in flip -/- mice .	Activation of Akt induced by insulin was intact and more pronounced in flip -/- mice.	0	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	2	3
AS160 becomes phosphorylated on multiple Akt phosphomotifs as the result of insulin stimulated activation of Akt .	AS160 becomes phosphorylated on multiple Akt phosphomotifs as the result of insulin stimulated activation of Akt.	9	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	15	16
The influence of XMetS on insulin mediated Akt and Erk activation in CHO-hINSR cells expressing the B isoform of the INSR was studied .	The influence of XMetS on insulin mediated Akt and Erk activation in CHO-hINSR cells expressing the B isoform of the INSR was studied.	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Therefore , augmentation of insulin stimulated Akt activation by rapamycin was accompanied with the loss of phosphorylation of IRS-1 and Rictor on their negative regulatory sites , which might result in enhanced activation of mTORC2 and Akt .	Therefore, augmentation of insulin stimulated Akt activation by rapamycin was accompanied with the loss of phosphorylation of IRS-1 and Rictor on their negative regulatory sites, which might result in enhanced activation of mTORC2 and Akt.	2	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Insulin activates Akt , which subsequently phosphorylates the TSC complex , resulting in the dissociation of the TSC complex from Rheb , followed by Rheb GTP loading and mTORC1 activation .	Insulin activates Akt, which subsequently phosphorylates the TSC complex, resulting in the dissociation of the TSC complex from Rheb, followed by Rheb GTP loading and mTORC1 activation.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Analysis of insulin stimulated Akt activation in these cells showed a significant decrease in Akt phosphorylation , and this drop was observed more at the 400 MOI .	Analysis of insulin stimulated Akt activation in these cells showed a significant decrease in Akt phosphorylation, and this drop was observed more at the 400 MOI.	0	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
The IP 6 K1 knockout cells display markedly augmented IGF-1 and insulin stimulated Akt signaling , with enhanced phosphorylation of Akt downstream effectors such as GSK3beta , tuberin , p70S6 kinase1 , and S6 itself .	The IP 6 K1 knockout cells display markedly augmented IGF-1 and insulin stimulated Akt signaling, with enhanced phosphorylation of Akt downstream effectors such as GSK3beta, tuberin, p70S6 kinase1, and S6 itself.	6	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
In mammals , the insulin mediated activation of AKT is central to proper glucose disposal and other metabolic adaptations after feeding through differential actions in metabolic tissues .	In mammals, the insulin mediated activation of AKT is central to proper glucose disposal and other metabolic adaptations after feeding through differential actions in metabolic tissues.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	8	9
Basal and insulin stimulated Akt activation and tissue glucose uptake rates were also determined .	Basal and insulin stimulated Akt activation and tissue glucose uptake rates were also determined.	0	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
Interestingly , PGC-1alpha did not inhibit insulin mediated Akt activation ( XREF_SUPPLEMENTARY ) , indicating that PGC-1alpha specifically suppresses only certain pathways .	Interestingly, PGC-1alpha did not inhibit insulin mediated Akt activation (XREF_SUPPLEMENTARY), indicating that PGC-1alpha specifically suppresses only certain pathways.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Since insulin signaling through IRbeta or IGF1R activate PI3K and Akt signaling pathway , we determined levels of phosphorylated Akt , total Akt , phosphorylated Gsk3beta , total Gsk3beta , phosphorylated eIF2B , total eIF2B , phosphorylated S6 , and total S6 in anterior tibial skeletal muscle of sham and burn rats .	Since insulin signaling through IRbeta or IGF1R activate PI3K and Akt signaling pathway, we determined levels of phosphorylated Akt, total Akt, phosphorylated Gsk3beta, total Gsk3beta, phosphorylated eIF2B, total eIF2B, phosphorylated S6, and total S6 in anterior tibial skeletal muscle of sham and burn rats.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	10	11
Consistent with this , germ-line knockin of a KD allele of p110beta or acute liver specific ablation of p110beta has little effect on the ability of insulin to activate Akt and PKB in hepatocytes and only mildly impaired their insulin sensitivity and glucose homeostasis , consistent with a prior pharmacologic study showing that p110beta plays little role in insulin stimulated Akt and PKB activation .	Consistent with this, germ-line knockin of a KD allele of p110beta or acute liver specific ablation of p110beta has little effect on the ability of insulin to activate Akt and PKB in hepatocytes and only mildly impaired their insulin sensitivity and glucose homeostasis, consistent with a prior pharmacologic study showing that p110beta plays little role in insulin stimulated Akt and PKB activation.	54	63	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	58	59	60	61
The endothelial insulin response is parallel to that in traditional insulin responsive tissues , acting through a PI3 kinase pathway to activate the serine protease Akt and Protein Kinase B , which in turn activates endothelial nitric oxide synthase ( eNOS , also known as NOS3 ) .	The endothelial insulin response is parallel to that in traditional insulin responsive tissues, acting through a PI3 kinase pathway to activate the serine protease Akt and Protein Kinase B, which in turn activates endothelial nitric oxide synthase (eNOS, also known as NOS3).	10	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	25	26
These results suggest that RBM20 is the downstream substrate of PI3K and Akt signalling pathway activated by insulin .	These results suggest that RBM20 is the downstream substrate of PI3K and Akt signalling pathway activated by insulin.	10	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	12	13
We next investigated whether the PI3K and AKT pathway was activated by insulin in A-MEC , A-MEC-pc , and A-MEC-LAP cells .	We next investigated whether the PI3K and AKT pathway was activated by insulin in A-MEC, A-MEC-pc, and A-MEC-LAP cells.	5	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	7	8
Insulin acutely increased p-Ser AKT in lean and non SARA Zuckers ( p < 0.05 ) , although the response was significantly blunted in the non SARA group .	Insulin acutely increased p-Ser AKT in lean and non SARA Zuckers (p < 0.05), although the response was significantly blunted in the non SARA group.	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	4	5
However , the insulin signaling molecules insulin receptor substrate-1 ( IRS-1 ) and Akt were not affected by capsaicin .	However, the insulin signaling molecules insulin receptor substrate-1 (IRS-1) and Akt were not affected by capsaicin.	2	16	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	13	14
Neutralizing IL-1beta with anti-IL-1beta antibody effectively preserved insulin mediated Akt activation , indicating ER stress associated NLRP3 inflammasome activation was responsible for the impairment of insulin signaling .	Neutralizing IL-1beta with anti-IL-1beta antibody effectively preserved insulin mediated Akt activation, indicating ER stress associated NLRP3 inflammasome activation was responsible for the impairment of insulin signaling.	1	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
Akt is also activated by insulin and IGF-1 .	Akt is also activated by insulin and IGF-1.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	0	1
Insulin , insulin like growth factor , and other growth factors induce activation of PI3 kinase and Akt , which phosphorylate three Foxo amino acids XREF_BIBR .	Insulin, insulin like growth factor, and other growth factors induce activation of PI3 kinase and Akt, which phosphorylate three Foxo amino acids XREF_BIBR.	0	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	17	18
It is first striking that long-term high-fat feeding did not raise DAG and ceramides in skeletal muscle of wild-type and skeletal muscle specific ATGL knockout ( SMAKO ) mice , and that only subtle changes in skeletal muscle insulin mediated activation of Akt were observed .	It is first striking that long-term high-fat feeding did not raise DAG and ceramides in skeletal muscle of wild-type and skeletal muscle specific ATGL knockout (SMAKO) mice, and that only subtle changes in skeletal muscle insulin mediated activation of Akt were observed.	38	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	38	39	42	43
Although insulin activation of PI3K and Akt were both attenuated in the liver of our p110-alpha -/- mice fed normal chow , these effects did not lead to hyperglycemia .	Although insulin activation of PI3K and Akt were both attenuated in the liver of our p110-alpha -/- mice fed normal chow, these effects did not lead to hyperglycemia.	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	6	7
Trbl blocks insulin signaling upstream but not downstream of Akt .	Trbl blocks insulin signaling upstream but not downstream of Akt.	2	10	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	9	10
Potentiation of insulin induced Akt and eNOS signaling by APPL1 .	Potentiation of insulin induced Akt and eNOS signaling by APPL1.	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
To determine whether different Akt isoforms XREF_BIBR were activated by insulin and TGFbeta , we immunoprecipitated lysates with the three Akt isoforms , Akt1 , Akt2 and Akt3 and probed them with alpha-p-Akt ( pSer473 ) antibody ( XREF_FIG ) .	To determine whether different Akt isoforms XREF_BIBR were activated by insulin and TGFbeta, we immunoprecipitated lysates with the three Akt isoforms, Akt1, Akt2 and Akt3 and probed them with alpha-p-Akt (pSer473) antibody (XREF_FIG).	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	4	5
In this model , insulin ( or IGF1 ) activates IRS-1 and the Akt pathway to enhance nutrient accumulation .	In this model, insulin (or IGF1) activates IRS-1 and the Akt pathway to enhance nutrient accumulation.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	13	14
To investigate the potential interactions between the angiotensin II ( Ang II ) and insulin signaling systems , regulation of IRS-1 phosphorylation and insulin induced Akt activation by Ang II were examined in clone 9 ( C9 ) hepatocytes .	To investigate the potential interactions between the angiotensin II (Ang II) and insulin signaling systems, regulation of IRS-1 phosphorylation and insulin induced Akt activation by Ang II were examined in clone 9 (C9) hepatocytes.	18	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	25	26
Finally , LXA 4 also appeared to have a direct impact on adipocytes as it rescued TNF-alpha-induced desensitization to insulin stimulated Akt activation , which also correlated with increased GLUT-4 translocation .	Finally, LXA 4 also appeared to have a direct impact on adipocytes as it rescued TNF-alpha-induced desensitization to insulin stimulated Akt activation, which also correlated with increased GLUT-4 translocation.	17	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
These results are attributed to enhanced insulin stimulated Akt and p70S6K activation in the liver .	These results are attributed to enhanced insulin stimulated Akt and p70S6K activation in the liver.	3	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Phosphorylation of this site by active nPKCdelta are important for the insulin induced Akt stimulation .	Phosphorylation of this site by active nPKCdelta are important for the insulin induced Akt stimulation.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
These results indicate that insulin promoted NF-kappaB activation through phosphorylation of FOXO1 by upregulating PI3K and Akt signaling .	These results indicate that insulin promoted NF-kappaB activation through phosphorylation of FOXO1 by upregulating PI3K and Akt signaling.	4	17	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	16	17
Noteworthy , since brain IR does not desensitize , IDE may also constitute a negative feedback loop to control insulin action [ XREF_BIBR , XREF_BIBR ] , that is , PI3K and Akt activation by insulin may upregulate IDE , which may stop subsequent signaling and promote Abeta clearance in hippocampal neurons [ XREF_BIBR ] .	Noteworthy, since brain IR does not desensitize, IDE may also constitute a negative feedback loop to control insulin action [XREF_BIBR, XREF_BIBR], that is, PI3K and Akt activation by insulin may upregulate IDE, which may stop subsequent signaling and promote Abeta clearance in hippocampal neurons [XREF_BIBR].	30	36	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	35	36	32	33
Furthermore , previous studies have shown that increased intracellular Ca 2+ concentrations are responsible for insulin induced Akt activation XREF_BIBR .	Furthermore, previous studies have shown that increased intracellular Ca 2+ concentrations are responsible for insulin induced Akt activation XREF_BIBR.	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
These data suggest that c-Abl may not be a likely intermediary component for insulin induced Akt signaling events in RGC-5 cells .	These data suggest that c-Abl may not be a likely intermediary component for insulin induced Akt signaling events in RGC-5 cells.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
While , p110alpha at the PM did colocalize with E4-ORF1 there was no significant colocalization of E4-ORF1 and insulin receptor , consistent with the proposal that E4-ORF1 does not recapitulate spatial cues of insulin activation of PI3K-Akt ( XREF_FIG ) .	While, p110alpha at the PM did colocalize with E4-ORF1 there was no significant colocalization of E4-ORF1 and insulin receptor, consistent with the proposal that E4-ORF1 does not recapitulate spatial cues of insulin activation of PI3K-Akt (XREF_FIG).	33	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	33	34	36	37
Expectedly , insulin stimulated AKT ( S473 ) and to lesser extent AKT ( T308 ) phosphorylation was significantly higher in the liver of hsf1 -/- mice compared to WT controls ( XREF_FIG ) .	Expectedly, insulin stimulated AKT (S473) and to lesser extent AKT (T308) phosphorylation was significantly higher in the liver of hsf1 -/- mice compared to WT controls (XREF_FIG).	2	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	4	5
Our result showed that the expression level of pAkt Serine 473 and pGSK3beta were increased in NT control clone upon insulin stimulation , indicating that insulin could successfully activate Akt and GSK3beta in BEL7402 .	Our result showed that the expression level of pAkt Serine 473 and pGSK3beta were increased in NT control clone upon insulin stimulation, indicating that insulin could successfully activate Akt and GSK3beta in BEL7402.	25	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	29	30
The eNOS dimer and monomer ratio , NO bioavailability , basal and insulin stimulated PKB and eNOS phosphorylation responses were higher in aortae of Lcn2-KO mice .	The eNOS dimer and monomer ratio, NO bioavailability, basal and insulin stimulated PKB and eNOS phosphorylation responses were higher in aortae of Lcn2-KO mice.	2	18	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	12	13	14	15
Nonetheless , there is evidence for dissociation between insulin stimulated PI3K activation and insulin stimulated PKB activity in insulin resistant adipocytes and skeletal muscle ( Kim etal .	Nonetheless, there is evidence for dissociation between insulin stimulated PI3K activation and insulin stimulated PKB activity in insulin resistant adipocytes and skeletal muscle (Kim etal.	9	16	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	13	14	15	16
Moreover , insulin stimulated P-Akt and Akt and glucose uptake levels , which were significantly different between OB-IS and OB-IR groups , were no more significantly different between non transfected OB-IS and 2-5A-transfected OB-IR myotubes , indicating that RNase L activation by exogenous 2-5A restored insulin response in OB-IR myotubes ( XREF_FIG ) .	Moreover, insulin stimulated P-Akt and Akt and glucose uptake levels, which were significantly different between OB-IS and OB-IR groups, were no more significantly different between non transfected OB-IS and 2-5A-transfected OB-IR myotubes, indicating that RNase L activation by exogenous 2-5A restored insulin response in OB-IR myotubes (XREF_FIG).	2	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	P-Akt	P-Akt	P-Akt	2	3	4	5
Thus , PKCzeta is involved in insulin induced PKB activation via PI3K/PKCzeta/PKB signaling pathway .	Thus, PKCzeta is involved in insulin induced PKB activation via PI3K/PKCzeta/PKB signaling pathway.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	6	7	8	9
3.3 Insulin and GnRH differentially activate AKT and ERK .	3.3 Insulin and GnRH differentially activate AKT and ERK.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	1	2	6	7
Insulin strongly activates PKB , whereas adrenaline is not considered a major physiological regulator of PKB in heart .	Insulin strongly activates PKB, whereas adrenaline is not considered a major physiological regulator of PKB in heart.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	3	4
Kinase-dead ( KD ) PKB and KD 3-phosphoinositide-dependent kinase-1 ( PDK-1 ) cotransfectants acted as dominant negatives because both prevented the insulin induced activation of PKB as well as the inactivation of glycogen-synthase kinase-3 , an established substrate of PKB .	Kinase-dead (KD) PKB and KD 3-phosphoinositide-dependent kinase-1 (PDK-1) cotransfectants acted as dominant negatives because both prevented the insulin induced activation of PKB as well as the inactivation of glycogen-synthase kinase-3, an established substrate of PKB.	20	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	21	22	25	26
Importantly , in SYF -/- cells , PA treatment failed to inhibit insulin induced AKT activation , but reconstitution with c-Src restored PA induced inhibition of AKT Ser473 phosphorylation to the same magnitude seen in 3T3 fibroblasts ( XREF_FIG ) .	Importantly, in SYF -/- cells, PA treatment failed to inhibit insulin induced AKT activation, but reconstitution with c-Src restored PA induced inhibition of AKT Ser473 phosphorylation to the same magnitude seen in 3T3 fibroblasts (XREF_FIG).	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	14	15
In addition , ezetimibe recovered insulin induced Akt activation and reduced gluconeogenic genes in the liver of ZOF rats and cultured steatotic hepatocytes .	In addition, ezetimibe recovered insulin induced Akt activation and reduced gluconeogenic genes in the liver of ZOF rats and cultured steatotic hepatocytes.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
GLUT4 is an insulin sensitive glucose transporter that is translocated to the cell membrane when insulin activates PI3K and Akt signaling XREF_BIBR , XREF_BIBR .	GLUT4 is an insulin sensitive glucose transporter that is translocated to the cell membrane when insulin activates PI3K and Akt signaling XREF_BIBR, XREF_BIBR.	15	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	19	20
This suggests that insulin resistance is associated with alterations in the ability of skeletal muscle to activate Akt signaling following increased contractile loading ( XREF_FIG ) .	This suggests that insulin resistance is associated with alterations in the ability of skeletal muscle to activate Akt signaling following increased contractile loading (XREF_FIG).	3	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	17	18
In addition , insulin stimulated activation of Akt ( also known as protein kinase B ) ( 10-fold over basal ) , whereas ATP had little effect .	In addition, insulin stimulated activation of Akt (also known as protein kinase B) (10-fold over basal), whereas ATP had little effect.	3	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
Furthermore , insulin stimulated activation of Akt , but not mitogen activated protein kinase , was diminished .	Furthermore, insulin stimulated activation of Akt, but not mitogen activated protein kinase, was diminished.	2	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
In canonical insulin mediated Akt activation , stimulation of the insulin receptor , an RTK , ultimately leads to the generation of phosphatidylinositol ( 3,4,5 ) trisphosphate ( PIP 3 ) .	In canonical insulin mediated Akt activation, stimulation of the insulin receptor, an RTK, ultimately leads to the generation of phosphatidylinositol (3,4,5) trisphosphate (PIP 3).	0	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
This caused a reduction in insulin receptor expression and prevented the insulin mediated AKT activation and the suppression of ghrelin secretion with no impact on NE stimulated ghrelin secretion .	This caused a reduction in insulin receptor expression and prevented the insulin mediated AKT activation and the suppression of ghrelin secretion with no impact on NE stimulated ghrelin secretion.	10	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	13	14
In contrast , we found that cellular cholesterol enrichment can enhance basal AKT and mTOR signaling , and that CYP7A1 overexpression could strongly attenuate both basal and insulin activation of AKT and mTOR .	In contrast, we found that cellular cholesterol enrichment can enhance basal AKT and mTOR signaling, and that CYP7A1 overexpression could strongly attenuate both basal and insulin activation of AKT and mTOR.	25	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	27	28	30	31
Recently , it was found that mTORC1 also phosphorylates and activates growth factor receptor bound protein 10 ( Grb10 ) , which acts as an inhibitor of the insulin activated PI3K-AKT signaling pathway .	Recently, it was found that mTORC1 also phosphorylates and activates growth factor receptor bound protein 10 (Grb10), which acts as an inhibitor of the insulin activated PI3K-AKT signaling pathway.	28	32	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	28	29	30	31
PrRP and insulin rapidly and transiently stimulated the activation of Akt , and the PI3K inhibitor wortmannin blocked the PrRP- or insulin induced activation of Akt .	PrRP and insulin rapidly and transiently stimulated the activation of Akt, and the PI3K inhibitor wortmannin blocked the PrRP- or insulin induced activation of Akt.	19	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	25	26
Indeed , acute rCT-1 administration activates AKT in this tissue and enhances insulin induced AKT activation .	Indeed, acute rCT-1 administration activates AKT in this tissue and enhances insulin induced AKT activation.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	14	15
JNK activation may be suppressed by prolonged active Akt or basal active Akt , rather than peaked activation of Akt induced by insulin stimulation .	JNK activation may be suppressed by prolonged active Akt or basal active Akt, rather than peaked activation of Akt induced by insulin stimulation.	17	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	19	20
The reported mechanism of insulin sensitization in Vps15 liver KO mice is a reduced endocytosis and degradation of the insulin receptor , resulting in enhanced insulin mediated Akt signaling 48 .	The reported mechanism of insulin sensitization in Vps15 liver KO mice is a reduced endocytosis and degradation of the insulin receptor, resulting in enhanced insulin mediated Akt signaling 48.	22	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
Activation of insulin and IGF receptors stimulates the PI3K and AKT pathway which has been hypothesized to stabilize ERK dependent pathways downstream of MAPK XREF_BIBR .	Activation of insulin and IGF receptors stimulates the PI3K and AKT pathway which has been hypothesized to stabilize ERK dependent pathways downstream of MAPK XREF_BIBR.	2	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	10	11
Because insulin is able to activate Akt and inactivate AMP activated protein kinase ( AMPK ) in the heart , we hypothesized that Akt can regulate the activity of AMPK .	Because insulin is able to activate Akt and inactivate AMP activated protein kinase (AMPK) in the heart, we hypothesized that Akt can regulate the activity of AMPK.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	6	7
However , insulin failed to activate the Akt --> FoxO cascade in Irs2 (-/-) MEFs because Irs1 expression was reduced in these cells , and p110alpha-PI 3-kinase was inefficiently activated during recruitment by Irs1 .	However, insulin failed to activate the Akt --> FoxO cascade in Irs2 (-/-) MEFs because Irs1 expression was reduced in these cells, and p110alpha-PI 3-kinase was inefficiently activated during recruitment by Irs1.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	7	8
Since Akt does not directly phosphorylate AMPK , changes in Akt activity induced by insulin can regulate AMPK through changes in cellular AMP and ATP ratio .	Since Akt does not directly phosphorylate AMPK, changes in Akt activity induced by insulin can regulate AMPK through changes in cellular AMP and ATP ratio.	10	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	10	11
This latter pathway involves the function of the Cbl adaptor protein CAP ( Cbl associated protein ) as expression of a dominant interfering CAP blocks insulin stimulated GLUT4 translocation without significant effect on insulin activation of PI3 kinase signaling and Akt activation .	This latter pathway involves the function of the Cbl adaptor protein CAP (Cbl associated protein) as expression of a dominant interfering CAP blocks insulin stimulated GLUT4 translocation without significant effect on insulin activation of PI3 kinase signaling and Akt activation.	33	41	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	33	34	40	41
As a result , insulin activation of PI3K-Akt , which mediates neuronal survival , motility , energy metabolism , and plasticity , is impaired .	As a result, insulin activation of PI3K-Akt, which mediates neuronal survival, motility, energy metabolism, and plasticity, is impaired.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	4	5	7	8
Akt was activated by insulin and IGF-I during apoptosis .	Akt was activated by insulin and IGF-I during apoptosis.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
Thus BtB6 mice demonstrate the dissociation of insulin stimulated PI3K activity and Akt and PKB activation and represent a useful model to investigate the causes of insulin resistance in humans .	Thus BtB6 mice demonstrate the dissociation of insulin stimulated PI3K activity and Akt and PKB activation and represent a useful model to investigate the causes of insulin resistance in humans.	5	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	12	13
Testosterone had negatively affected insulin induced AKT activation , but there was significant difference in P-AKT ( Ser 473 ) levels of I (-) T (-) and I ( + ) T ( + ) samples , possibly because prolonged insulin treatment was not given to induce insulin resistance .	Testosterone had negatively affected insulin induced AKT activation, but there was significant difference in P-AKT (Ser 473) levels of I (-) T (-) and I (+) T (+) samples, possibly because prolonged insulin treatment was not given to induce insulin resistance.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	6	7
Importantly , KD-PKCzeta inhibits insulin resistance mediated mammalian target of rapamycin ( mTOR ) activation and cyclin-D2 upregulation independent of Akt activation .	Importantly, KD-PKCzeta inhibits insulin resistance mediated mammalian target of rapamycin (mTOR) activation and cyclin-D2 upregulation independent of Akt activation.	4	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	20	21
Collectively , these results strongly suggest that ZAG negatively affects insulin sensitivity on glucose uptake by reducing insulin induced AKT activation , in part , through PP2A activation .	Collectively, these results strongly suggest that ZAG negatively affects insulin sensitivity on glucose uptake by reducing insulin induced AKT activation, in part, through PP2A activation.	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	17	18	19	20
Consistent with our previous studies , there was a better correlation between Akt phosphorylation and substrate phosphorylation at the PM , with the ED 50 for insulin stimulated pSer-473 Akt at the PM being somewhat lower than that observed in the whole cell lysate ( XREF_FIG , A and B ) .	Consistent with our previous studies, there was a better correlation between Akt phosphorylation and substrate phosphorylation at the PM, with the ED 50 for insulin stimulated pSer-473 Akt at the PM being somewhat lower than that observed in the whole cell lysate (XREF_FIG, A and B).	23	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	29	30
To further assess a direct suppressive effect of CAMK2gamma on AKT , we generated a tetracycline inducible cell system to evaluate the effects of CAMK2gamma overexpression on insulin induced AKT activation .	To further assess a direct suppressive effect of CAMK2gamma on AKT, we generated a tetracycline inducible cell system to evaluate the effects of CAMK2gamma overexpression on insulin induced AKT activation.	20	30	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	27	28	29	30
Akt is also activated by the insulin and IGF-PI 3K signaling pathway and is involved in cell survival , proliferation , glucose metabolism and cell migration via many other factors , including mTOR , FoxOs , p21 and GSK3beta .	Akt is also activated by the insulin and IGF-PI 3K signaling pathway and is involved in cell survival, proliferation, glucose metabolism and cell migration via many other factors, including mTOR, FoxOs, p21 and GSK3beta.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	0	1
In the control group , aCSF was administrated to the mice hypothalamus and the insulin challenge activated the downstream signal molecule Akt ( phosphorylated Akt Serine 473 ) ( XREF_FIG , F ) without increasing IRS-1 serine302 activation ( XREF_FIG -E ) and Akt serine473 phosphorylation .	In the control group, aCSF was administrated to the mice hypothalamus and the insulin challenge activated the downstream signal molecule Akt (phosphorylated Akt Serine 473) (XREF_FIG, F) without increasing IRS-1 serine302 activation (XREF_FIG -E) and Akt serine473 phosphorylation.	14	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	21	22
Insulin stimulated Akt activity also increased after troglitazone treatment ( from 32 +/- 8 to 107 +/- 32 % stimulation , P < 0.05 ) but was unchanged after metformin therapy .	Insulin stimulated Akt activity also increased after troglitazone treatment (from 32 +/- 8 to 107 +/- 32% stimulation, P < 0.05) but was unchanged after metformin therapy.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Insulin stimulated Akt translocation was altered in diabetic myocardium .	Insulin stimulated Akt translocation was altered in diabetic myocardium.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
The insulin induced Akt activation also impacts renal tubular transport through several signaling pathways and thus regulates sodium reabsorption .	The insulin induced Akt activation also impacts renal tubular transport through several signaling pathways and thus regulates sodium reabsorption.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
Most studies also report that insulin stimulated PKB activity is unchanged after exercise , but some recent studies revealed that prior contractile activity induces higher insulin stimulated PKB threonine 308 phosphorylation compared to rested muscles , whereas insulin stimulated PKB phosphorylation at serine 473 was unchanged by exercise .	Most studies also report that insulin stimulated PKB activity is unchanged after exercise, but some recent studies revealed that prior contractile activity induces higher insulin stimulated PKB threonine 308 phosphorylation compared to rested muscles, whereas insulin stimulated PKB phosphorylation at serine 473 was unchanged by exercise.	5	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	5	6	7	8
Insulin stimulation of Akt and protein kinase B was also potentiated .	Insulin stimulation of Akt and protein kinase B was also potentiated.	0	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
In contrast , overexpression of a constitutively active form of Akt driven by the rat insulin promoter induced beta-cell mass XREF_BIBR , XREF_BIBR .	In contrast, overexpression of a constitutively active form of Akt driven by the rat insulin promoter induced beta-cell mass XREF_BIBR, XREF_BIBR.	8	16	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	10	11
Insulin stimulated Akt activation requires the presence of the two PI3K products phosphatidylinositol-3 ,4,5-trisphosphate ( PtdIns ( 3,4,5 ) P 3 ) and phosphatidylinositol-3 ,4-bisphosphate ( PtdIns ( 3,4 ) P 2 ) , membrane lipids that constitute docking sites for PH domain mediated protein anchoring required for Akt activating phosphorylation events XREF_BIBR .	Insulin stimulated Akt activation requires the presence of the two PI3K products phosphatidylinositol-3,4,5-trisphosphate (PtdIns (3,4,5) P 3) and phosphatidylinositol-3,4-bisphosphate (PtdIns (3,4) P 2), membrane lipids that constitute docking sites for PH domain mediated protein anchoring required for Akt activating phosphorylation events XREF_BIBR.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Hyperglycemia and insulin both modulate Akt activity in diabetic renal tissue XREF_BIBR , XREF_BIBR , XREF_BIBR .	Hyperglycemia and insulin both modulate Akt activity in diabetic renal tissue XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	6	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	5	6
While p-PAK Thr423 was prevented , the Rac1 Inhibitor II did not affect insulin signaling of Akt or PAS ( at 150-160 kDa ) ( XREF_FIG ) .	While p-PAK Thr423 was prevented, the Rac1 Inhibitor II did not affect insulin signaling of Akt or PAS (at 150-160 kDa) (XREF_FIG).	13	25	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	16	17
The main role of hepatic TRB3 on Akt activity is to bind to Akt and then inhibit its phosphorylation at Thr 308 and Ser 473 motifs , which are the critical motifs for Akt activation induced by growth factors and insulin [ XREF_BIBR ] .	The main role of hepatic TRB3 on Akt activity is to bind to Akt and then inhibit its phosphorylation at Thr 308 and Ser 473 motifs, which are the critical motifs for Akt activation induced by growth factors and insulin [XREF_BIBR].	33	42	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	40	41	33	34
Metformin in the presence of insulin activated Akt and this was dependent on phosphoinositide-3 kinase , as was translocation of Glut-4 to the membrane .	Metformin in the presence of insulin activated Akt and this was dependent on phosphoinositide-3 kinase, as was translocation of Glut-4 to the membrane.	3	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Insulin induced activations of Akt , mTOR , and S6K were decreased in the PDK1 knockout hearts .	Insulin induced activations of Akt, mTOR, and S6K were decreased in the PDK1 knockout hearts.	0	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
We find that in the presence of EGF , where ATP and NADH are low but proliferative rate is high , cells display increased bioenergetic instability and sensitivity to inhibition of oxidative respiration , which can be reversed by insulin mediated activation of Akt .	We find that in the presence of EGF, where ATP and NADH are low but proliferative rate is high, cells display increased bioenergetic instability and sensitivity to inhibition of oxidative respiration, which can be reversed by insulin mediated activation of Akt.	39	44	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	39	40	43	44
In diabetic males ( vs male controls and/or diabetic females ) : ( a ) systemic blood pressure was elevated , ( b ) the clonidine- and insulin induced Akt dependent aortic relaxations were impaired , but the ACh induced Akt independent and SNP induced endothelium independent aortic relaxations were not , ( c ) Akt and eNOS expression levels were lower , ( d ) both Akt phosphorylation at Ser ( 473 ) and eNOS phosphorylation at Ser ( 1177 ) in the aorta were lower under clonidine- or insulin stimulation , but not under ACh stimulation .	In diabetic males (vs male controls and/or diabetic females) : (a) systemic blood pressure was elevated, (b) the clonidine- and insulin induced Akt dependent aortic relaxations were impaired, but the ACh induced Akt independent and SNP induced endothelium independent aortic relaxations were not, (c) Akt and eNOS expression levels were lower, (d) both Akt phosphorylation at Ser (473) and eNOS phosphorylation at Ser (1177) in the aorta were lower under clonidine- or insulin stimulation, but not under ACh stimulation.	25	34	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	27	28	29	30
Insulin signaling induces Akt to phosphorylate FoxO1 on residues Thr 24 , Ser 256 , and Ser 319 , which results in FoxO1 cytoplasmic localization [ XREF_BIBR ] .	Insulin signaling induces Akt to phosphorylate FoxO1 on residues Thr 24, Ser 256, and Ser 319, which results in FoxO1 cytoplasmic localization [XREF_BIBR].	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
Insulin stimulation is known to increase the activity of Akt in vivo .	Insulin stimulation is known to increase the activity of Akt in vivo.	0	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	9	10
We have previously shown that the insulin resistance that develops in this model is associated with a marked inhibition of insulin stimulated Akt activation XREF_BIBR , XREF_BIBR and this was again observed in these experiments ( XREF_FIG ) .	We have previously shown that the insulin resistance that develops in this model is associated with a marked inhibition of insulin stimulated Akt activation XREF_BIBR, XREF_BIBR and this was again observed in these experiments (XREF_FIG).	18	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
PI3K and Akt activator insulin ( I9278 , Sigma ) was used at a concentration of 0.5 muL/mL to confirm functionality and specificity of LY in our experiments ( n = 10 ) .	PI3K and Akt activator insulin (I9278, Sigma) was used at a concentration of 0.5 muL/mL to confirm functionality and specificity of LY in our experiments (n = 10).	0	19	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	2	3
These results suggest that in the aorta in diabetic mice with hyperinsulinemia an upregulation of GRK2 and a decrease in beta-arrestin2 inhibit insulin induced stimulation of the Akt and eNOS pathway and that GRK2 overactivation may result from an increase in PKC activity .	These results suggest that in the aorta in diabetic mice with hyperinsulinemia an upregulation of GRK2 and a decrease in beta-arrestin2 inhibit insulin induced stimulation of the Akt and eNOS pathway and that GRK2 overactivation may result from an increase in PKC activity.	22	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	27	28
Studies of insulin mediated activation of Akt in the heart in rodent models of generalized insulin resistance have yielded variable and potentially divergent results , which might be explicable by differences in the models used and differences in experimental conditions , such as dietary lipid composition .	Studies of insulin mediated activation of Akt in the heart in rodent models of generalized insulin resistance have yielded variable and potentially divergent results, which might be explicable by differences in the models used and differences in experimental conditions, such as dietary lipid composition.	2	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
Leptin repletion to caloric restricted ob/ob mice restored insulin mediated activation of Akt in the heart .	Leptin repletion to caloric restricted ob/ob mice restored insulin mediated activation of Akt in the heart.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	12	13
Insulin activation of Akt was normal in beta -/- hearts , in agreement with recent studies demonstrating that p110beta is not a major effector of insulin signaling in other tissues XREF_BIBR , XREF_BIBR , XREF_BIBR .	Insulin activation of Akt was normal in beta -/- hearts, in agreement with recent studies demonstrating that p110beta is not a major effector of insulin signaling in other tissues XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
The MAPK and PI3K-Akt pathways can also be stimulated by activated EGF family receptors , insulin receptors , and IGF1Rs .	The MAPK and PI3K-Akt pathways can also be stimulated by activated EGF family receptors, insulin receptors, and IGF1Rs.	1	16	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	15	16	3	4
One of the mechanisms involved is the insulin pathway , which activates the PI3K and Akt pathway , acting as a metabolic sensor that responds to insulin stimulation and incorporates GLUT4 into the plasma membrane .	One of the mechanisms involved is the insulin pathway, which activates the PI3K and Akt pathway, acting as a metabolic sensor that responds to insulin stimulation and incorporates GLUT4 into the plasma membrane.	7	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	15	16
PI3K and Akt activation by insulin might contribute to the development of insulin resistance .	PI3K and Akt activation by insulin might contribute to the development of insulin resistance.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	2	3
Human insulin and analogs activated AKT and mTOR signaling and stimulated ALL cell proliferation ( as measured by flow cytometric methods ) , but metformin and rosiglitazone blocked AKT and mTOR signaling and inhibited proliferation .	Human insulin and analogs activated AKT and mTOR signaling and stimulated ALL cell proliferation (as measured by flow cytometric methods), but metformin and rosiglitazone blocked AKT and mTOR signaling and inhibited proliferation.	0	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	1	2	5	6
On the other hand , IR and PKB-Akt activation by insulin , which is patent in the immature cells , becomes highly increased after adipocyte maturation ( XREF_FIG ) .	On the other hand, IR and PKB-Akt activation by insulin, which is patent in the immature cells, becomes highly increased after adipocyte maturation (XREF_FIG).	5	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB-Akt	PKB-Akt	PKB-Akt	10	11	7	8
However , administration of insulin or IGF1 induced potent AKT activation that was resistant to gefitinib ( XREF_FIG ) , suggesting that the InsR and IGF1R pathway is the dominating RTK regulator for AKT .	However, administration of insulin or IGF1 induced potent AKT activation that was resistant to gefitinib (XREF_FIG), suggesting that the InsR and IGF1R pathway is the dominating RTK regulator for AKT.	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	9	10
Our results indicate that PMA treatments have little impact on basal and insulin stimulated glucose uptake and insulin induced Akt activation .	Our results indicate that PMA treatments have little impact on basal and insulin stimulated glucose uptake and insulin induced Akt activation.	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	19	20
These mice were viable , exhibited enhanced insulin sensitivity , and enhanced insulin dependent activation of AKT in skeletal muscle .	These mice were viable, exhibited enhanced insulin sensitivity, and enhanced insulin dependent activation of AKT in skeletal muscle.	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	16	17
However , inhibiting this pathway with the PI3-K inhibitor LY-294002 or depriving the cells of serum ( which normally promotes cell survival through cytokine and insulin mediated activation of Akt ) allowed L-744 ,832 to induce significant apoptosis in these cells .	However, inhibiting this pathway with the PI3-K inhibitor LY-294002 or depriving the cells of serum (which normally promotes cell survival through cytokine and insulin mediated activation of Akt) allowed L-744,832 to induce significant apoptosis in these cells.	23	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	29	30
High glucose and high insulin augmented activation of Akt , Erk , and p70S6 kinase .	High glucose and high insulin augmented activation of Akt, Erk, and p70S6 kinase.	1	10	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	8	9
Thus , these data show that both PI3-kinase and PKB activation by insulin are markedly reduced in Type 2 diabetes .	Thus, these data show that both PI3-kinase and PKB activation by insulin are markedly reduced in Type 2 diabetes.	9	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	12	13	9	10
At the molecular level , enhanced GRK2 abundance impairs insulin mediated AKT stimulation and glucose uptake by interacting with IRS1 in adipocytes and myocytes , by directly phosphorylating IRS1 at Ser 307 in cardiomyocytes , or by mediating insulin resistance induced by endothelin-1 by inhibiting both Galphaq/11 and IRS1 pathways in 3T3-L1 adipocytes .	At the molecular level, enhanced GRK2 abundance impairs insulin mediated AKT stimulation and glucose uptake by interacting with IRS1 in adipocytes and myocytes, by directly phosphorylating IRS1 at Ser 307 in cardiomyocytes, or by mediating insulin resistance induced by endothelin-1 by inhibiting both Galphaq/11 and IRS1 pathways in 3T3-L1 adipocytes.	8	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	11	12
Complementary to our findings in P19 cells ( Experiment 1 ) , it was reported that active Akt can promote the differentiation of neuronal precursor cells into GABAergic neuron like cells XREF_BIBR and that phosphorylation of GABA A R via insulin induced Akt signalling can lead to an increase in the number of GABA receptors on the plasma membrane XREF_BIBR , thereby increasing inhibitory fast synaptic transmission in neurons .	Complementary to our findings in P19 cells (Experiment 1), it was reported that active Akt can promote the differentiation of neuronal precursor cells into GABAergic neuron like cells XREF_BIBR and that phosphorylation of GABA A R via insulin induced Akt signalling can lead to an increase in the number of GABA receptors on the plasma membrane XREF_BIBR, thereby increasing inhibitory fast synaptic transmission in neurons.	38	43	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	40	41	42	43
Enhanced insulin stimulated Akt activation did not occur in betaKO-HFD mice .	Enhanced insulin stimulated Akt activation did not occur in betaKO-HFD mice.	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
In liver , insulin activated Akt similarly in both groups .	In liver, insulin activated Akt similarly in both groups.	3	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
Acute pretreatment ( up to 30 min ) using the mixed CB1 and CB2 agonist WIN55 ,212 -2 ( 100 nmol/l ) has no effect on insulin stimulated ERK1/2 or PKB activation ( XREF_FIG A ) .	Acute pretreatment (up to 30 min) using the mixed CB1 and CB2 agonist WIN55,212-2 (100 nmol/l) has no effect on insulin stimulated ERK1/2 or PKB activation (XREF_FIG A).	24	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	26	27	30	31
We also show that exposure of HUVECs to high-glucose conditions inhibits the insulin mediated activation of Akt and eNOS signalling and the subsequent NO generation in a dose dependent manner ( p < 0.05 ) .	We also show that exposure of HUVECs to high-glucose conditions inhibits the insulin mediated activation of Akt and eNOS signalling and the subsequent NO generation in a dose dependent manner (p < 0.05).	12	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	16	17
The palmitate induced decrease in basal and insulin stimulated Akt activation is consistent with previous research from our lab that demonstrated a ~ 30 % decrease in phospho-Akt Ser473 / total Akt after treatment of myotubes with 0.75 mM palmitate for 16 hours followed by 10 minutes of serum stimulation [ XREF_BIBR ] .	The palmitate induced decrease in basal and insulin stimulated Akt activation is consistent with previous research from our lab that demonstrated a ~ 30% decrease in phospho-Akt Ser473 / total Akt after treatment of myotubes with 0.75 mM palmitate for 16 hours followed by 10 minutes of serum stimulation [XREF_BIBR].	3	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
In the liver , bile salts and insulin both activate the AKT and ERK1/2 signaling pathways which yields a stronger signal than either alone .	In the liver, bile salts and insulin both activate the AKT and ERK1/2 signaling pathways which yields a stronger signal than either alone.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	11	12
Recent work in rodents shows that hepatic insulin resistance develops within a week of high-fat diet ( HFD ) feeding , coincident with reduced insulin stimulated glucose uptake into adipose tissue , but without losing insulin stimulated AKT signalling in fat , and before any detectable decrease in muscle glucose uptake , elevation of lipolysis or inflammation XREF_BIBR .	Recent work in rodents shows that hepatic insulin resistance develops within a week of high-fat diet (HFD) feeding, coincident with reduced insulin stimulated glucose uptake into adipose tissue, but without losing insulin stimulated AKT signalling in fat, and before any detectable decrease in muscle glucose uptake, elevation of lipolysis or inflammation XREF_BIBR.	35	38	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	35	36	37	38
IRS-1 phosphorylation reduced phosphatidylinositol 3-kinase activity ( PI3K ) and abolished insulin induced activation of Akt [ XREF_BIBR ] .	IRS-1 phosphorylation reduced phosphatidylinositol 3-kinase activity (PI3K) and abolished insulin induced activation of Akt [XREF_BIBR].	11	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	15	16
In R234Q PTEN transfectants , PKB activity could not be induced by insulin treatment , in contrast to parental cells or cells transfected with wt PTEN .	In R234Q PTEN transfectants, PKB activity could not be induced by insulin treatment, in contrast to parental cells or cells transfected with wt PTEN.	5	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	12	13	5	6
These data lead us to propose the hypothesis that full activation of PI3K is not necessary to maximally activate Akt , and that other pathways that are independent of PI3K are also involved in activation of Akt by insulin , at least in insulin resistant states .	These data lead us to propose the hypothesis that full activation of PI3K is not necessary to maximally activate Akt, and that other pathways that are independent of PI3K are also involved in activation of Akt by insulin, at least in insulin resistant states.	32	41	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	38	39	36	37
We therefore assessed the effects of lithium on basal and insulin stimulated glucose transport , glycogen synthesis , insulin signalling ( insulin receptor ( IR ) , Akt , and GSK-3 ) , and p38 MAPK in soleus muscle from female obese Zucker rats .	We therefore assessed the effects of lithium on basal and insulin stimulated glucose transport, glycogen synthesis, insulin signalling (insulin receptor (IR), Akt, and GSK-3), and p38 MAPK in soleus muscle from female obese Zucker rats.	10	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	27	28
A mutant Akt ( Akt-AA ) in which the phosphorylation sites ( Thr308 and Ser473 ) targeted by growth factors are replaced by alanine has now been shown to lack protein kinase activity and , when overexpressed in CHO cells or 3T3-L1 adipocytes with the use of an adenovirus vector , to inhibit insulin induced activation of endogenous Akt .	A mutant Akt (Akt-AA) in which the phosphorylation sites (Thr308 and Ser473) targeted by growth factors are replaced by alanine has now been shown to lack protein kinase activity and, when overexpressed in CHO cells or 3T3-L1 adipocytes with the use of an adenovirus vector, to inhibit insulin induced activation of endogenous Akt.	53	59	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	53	54	58	59
Insulin stimulation , which activates AKT , increases the concentration of PI ( 3,5 ) P 2 by inhibiting the phosphatase activity of SAC3 .	Insulin stimulation, which activates AKT, increases the concentration of PI (3,5) P 2 by inhibiting the phosphatase activity of SAC3.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	5	6
The results show that Akt dependent signaling , induced by cytokines or insulin , alters the IKK subunit dependent control of mTOR .	The results show that Akt dependent signaling, induced by cytokines or insulin, alters the IKK subunit dependent control of mTOR.	4	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	4	5
Insulin induced activation of Akt isoforms .	Insulin induced activation of Akt isoforms.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
The data shown in XREF_FIG and XREF_FIG suggest that imatinib may cause selective inhibition of PDGF induced PI 3-kinase downstream signaling events , including Akt , GSK-3beta , and p70S6kinase phosphorylation without affecting insulin induced Akt signaling .	The data shown in XREF_FIG and XREF_FIG suggest that imatinib may cause selective inhibition of PDGF induced PI 3-kinase downstream signaling events, including Akt, GSK-3beta, and p70S6kinase phosphorylation without affecting insulin induced Akt signaling.	32	36	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	33	34	35	36
Accumulating data also show that decreases in insulin induced Akt activation is found in various models of insulin resistance .	Accumulating data also show that decreases in insulin induced Akt activation is found in various models of insulin resistance.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
These studies suggested that CAV-1 KD did not affect insulin mediated activation of PKB , which is important in activation of PDE3B and the antilipolytic action of insulin .	These studies suggested that CAV-1 KD did not affect insulin mediated activation of PKB, which is important in activation of PDE3B and the antilipolytic action of insulin.	9	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	9	10	13	14
However , mTORC1 activity , monitored by its target S6K , was similar between Con and Sesn2 -/- mice ( XREF_SUPPLEMENTARY ) , and insulin induced AKT activation in liver ( XREF_SUPPLEMENTARY ) and in adipose tissue ( XREF_SUPPLEMENTARY ) was also comparable between lean Con and Sesn2 -/- mice .	However, mTORC1 activity, monitored by its target S6K, was similar between Con and Sesn2 -/- mice (XREF_SUPPLEMENTARY), and insulin induced AKT activation in liver (XREF_SUPPLEMENTARY) and in adipose tissue (XREF_SUPPLEMENTARY) was also comparable between lean Con and Sesn2 -/- mice.	12	27	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	24	25	26	27
The results presented here demonstrate that betaAR stimulation antagonizes the protective effect of the AKT pathway that is mediated by both insulin and HPC , through inhibiting their induction of Hif-1alpha and Sirt1 , which are key elements in a cell ' s adaptation to hypoxia ( XREF_FIG ) .	The results presented here demonstrate that betaAR stimulation antagonizes the protective effect of the AKT pathway that is mediated by both insulin and HPC, through inhibiting their induction of Hif-1alpha and Sirt1, which are key elements in a cell 's adaptation to hypoxia (XREF_FIG).	14	23	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	21	22	14	15
The mixed CB1 and CB2-receptor agonist WIN55 ,212 -2 downregulates insulin stimulated ERK1/2 activity but not PKB activation in skeletal L6 myotubes .	The mixed CB1 and CB2-receptor agonist WIN55,212-2 downregulates insulin stimulated ERK1/2 activity but not PKB activation in skeletal L6 myotubes.	9	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	10	11	16	17
Components in the proximal insulin pathway are similar between CON and IUGR fetal livers and , even in IUGR fetuses , insulin robustly activates nuclear AKT .	Components in the proximal insulin pathway are similar between CON and IUGR fetal livers and, even in IUGR fetuses, insulin robustly activates nuclear AKT.	21	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	21	22	25	26
Interestingly , we found a significant negative correlation between the BW of HFD fed mice and the response to insulin injection ( activation of AKT signalling ) in the liver ( R = -0.916 , P = 0.029 ) , whereas this effect was not as obvious in PGs ( R = -0.630 , P = 0.254 ) which might suggest the existence of a tissue dependent association between BW and insulin resistance under HFD conditions .	Interestingly, we found a significant negative correlation between the BW of HFD fed mice and the response to insulin injection (activation of AKT signalling) in the liver (R = -0.916, P = 0.029), whereas this effect was not as obvious in PGs (R = -0.630, P = 0.254) which might suggest the existence of a tissue dependent association between BW and insulin resistance under HFD conditions.	19	25	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	19	20	24	25
The role of insulin in resveratrol ' s effects on proliferation , and whether IGF1 , rather than insulin can activate Akt in keratinocytes are topics for future investigation .	The role of insulin in resveratrol 's effects on proliferation, and whether IGF1, rather than insulin can activate Akt in keratinocytes are topics for future investigation.	14	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	21	22
FOXO1 is controlled by competing pathways in the cell , namely activation by ROS [ XREF_BIBR - XREF_BIBR ] , and inhibition via the insulin activated PI3K and AKT pathway [ XREF_BIBR ] .	FOXO1 is controlled by competing pathways in the cell, namely activation by ROS [XREF_BIBR - XREF_BIBR], and inhibition via the insulin activated PI3K and AKT pathway [XREF_BIBR].	21	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	24	25	28	29
In both the AIF and TXNIP knockout mice protection against diet induced glucose intolerance was associated with heightened insulin mediated activation of Akt .	In both the AIF and TXNIP knockout mice protection against diet induced glucose intolerance was associated with heightened insulin mediated activation of Akt.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	22	23
Insulin stimulation of Akt ( Thr 308 and Ser 473 ) was PI-3-kinase-dependent , and phosphorylation of p70S6 kinase ( Thr389 ) was PI-3-kinase and mTOR dependent .	Insulin stimulation of Akt (Thr 308 and Ser 473) was PI-3-kinase-dependent, and phosphorylation of p70S6 kinase (Thr389) was PI-3-kinase and mTOR dependent.	0	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
Insulin induced the accumulation of SSH1L and active Akt ( a downstream effector of PI3K ) , together with a PI3K product phosphatidylinositol 3,4,5-trisphosphate , onto membrane protrusions .	Insulin induced the accumulation of SSH1L and active Akt (a downstream effector of PI3K), together with a PI3K product phosphatidylinositol 3,4,5-trisphosphate, onto membrane protrusions.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	8	9
We demonstrated that both insulin and steviol glycosides are able to increase glucose entry into the cells by activating the PI3K and Akt -- but not the AMPK -- pathway , thus inducing Glut4 translocation to the plasma membrane .	We demonstrated that both insulin and steviol glycosides are able to increase glucose entry into the cells by activating the PI3K and Akt -- but not the AMPK -- pathway, thus inducing Glut4 translocation to the plasma membrane.	3	29	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	22	23
Akt activation by insulin lispro was similar to that by human insulin in non malignant MCF-10 A cells [ XREF_BIBR , XREF_BIBR ] , and in fibroblasts expressing insulin receptor A isoform [ XREF_BIBR ] .	Akt activation by insulin lispro was similar to that by human insulin in non malignant MCF-10 A cells [XREF_BIBR, XREF_BIBR], and in fibroblasts expressing insulin receptor A isoform [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	0	1
Interestingly , the pseudophosphorylated NEP-NT GFP Ser6Asp variant had no inhibitory effect on insulin dependent activation of Akt ( XREF_FIG ) .	Interestingly, the pseudophosphorylated NEP-NT GFP Ser6Asp variant had no inhibitory effect on insulin dependent activation of Akt (XREF_FIG).	13	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	17	18
Insulin also activated Akt that lies downstream of PI 3-kinase .	Insulin also activated Akt that lies downstream of PI 3-kinase.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
Contraction and insulin use distinct signaling molecules , and insulin stimulated Akt is an important mediator of glucose transport and glycogen synthesis in skeletal muscle .	Contraction and insulin use distinct signaling molecules, and insulin stimulated Akt is an important mediator of glucose transport and glycogen synthesis in skeletal muscle.	9	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
In our current study , ATP2B1 gene silencing led to increased insulin induced Akt activation in endothelial cells that were cultured in vitro .	In our current study, ATP2B1 gene silencing led to increased insulin induced Akt activation in endothelial cells that were cultured in vitro.	8	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
In studies of animal models of insulin resistance , i.e. ob/ob mice and Gato-Kakazaki rats , focusing on hepatic Akt and aPKCs , insulin activation of Akt but not aPKCs was impaired XREF_BIBR , XREF_BIBR .	In studies of animal models of insulin resistance, i.e. ob/ob mice and Gato-Kakazaki rats, focusing on hepatic Akt and aPKCs, insulin activation of Akt but not aPKCs was impaired XREF_BIBR, XREF_BIBR.	23	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	26	27
Our laboratory and others have previously shown that aberrant signaling through the Akt pathway which is stimulated by insulin and other neuropeptides , disrupts central DA neurotransmission XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Our laboratory and others have previously shown that aberrant signaling through the Akt pathway which is stimulated by insulin and other neuropeptides, disrupts central DA neurotransmission XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	12	21	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	12	13
For example , Akt is responsible for cardioprotection mediated by leukemia inhibitory factor ( LIF ) or cardiotrophin-1 ( CT-1 ) , and Akt activation by insulin or S1P decreases I/R damage within hours in the isolated perfused heart or in vivo .	For example, Akt is responsible for cardioprotection mediated by leukemia inhibitory factor (LIF) or cardiotrophin-1 (CT-1), and Akt activation by insulin or S1P decreases I/R damage within hours in the isolated perfused heart or in vivo.	23	28	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	23	24
These findings suggest that insulin stimulated PI3K and Akt pathways oppose atherothrombotic factors in endothelium by multiple mechanisms including production of beneficial molecules such as NO and inhibition of pathogenic molecules including PAI-1 , ICAM-1 , VCAM-1 , and E-selectin .	These findings suggest that insulin stimulated PI3K and Akt pathways oppose atherothrombotic factors in endothelium by multiple mechanisms including production of beneficial molecules such as NO and inhibition of pathogenic molecules including PAI-1, ICAM-1, VCAM-1, and E-selectin.	4	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	8	9
XREF_BIBR Recent work from Chakraborty et al XREF_BIBR suggests a separate and seemingly novel feedback mechanism in the regulation of insulin signaling , whereby specific inositol pyrophosphates can also have an inhibitory effect on insulin stimulation of Akt and PKB by competing with PIP3 at the pleckstrin homology domain .	XREF_BIBR Recent work from Chakraborty et al XREF_BIBR suggests a separate and seemingly novel feedback mechanism in the regulation of insulin signaling, whereby specific inositol pyrophosphates can also have an inhibitory effect on insulin stimulation of Akt and PKB by competing with PIP3 at the pleckstrin homology domain.	34	40	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	34	35	39	40
Indeed , insulin stimulation of Akt results in pAMPK S485/491 , leading to a reduction in AMPK activity [ XREF_BIBR ] ( XREF_FIG ) .	Indeed, insulin stimulation of Akt results in pAMPK S485/491, leading to a reduction in AMPK activity [XREF_BIBR] (XREF_FIG).	2	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	5	6
In L6 myotubes , palmitate treatment , which is used to mimic the high fatty acid levels common to obesity and T2D , increases STAT3 activation and reduces insulin stimulated Akt activation and glycogen synthesis XREF_BIBR .	In L6 myotubes, palmitate treatment, which is used to mimic the high fatty acid levels common to obesity and T2D, increases STAT3 activation and reduces insulin stimulated Akt activation and glycogen synthesis XREF_BIBR.	27	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	30	31
XREF_BIBR We found a mild increase in GSK3beta phosphorylation indicating inactivation of GSK3beta at CT14 ( XREF_FIG ) , consistent with insulin activation of Akt kinase when the mouse begins to feed .	XREF_BIBR We found a mild increase in GSK3beta phosphorylation indicating inactivation of GSK3beta at CT14 (XREF_FIG), consistent with insulin activation of Akt kinase when the mouse begins to feed.	21	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	24	25
Although the tyrosine phosphorylation of insulin receptor substrate-1 was slightly reduced , correlating with a 25 % decrease in insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity , insulin stimulated Akt kinase activation was unaffected .	Although the tyrosine phosphorylation of insulin receptor substrate-1 was slightly reduced, correlating with a 25% decrease in insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity, insulin stimulated Akt kinase activation was unaffected.	26	30	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	28	29
Work has indicated that insulin treatment in whole retinal samples in vivo or in retinal explants will increase Akt activity , primarily through IRS-2 actions [ XREF_BIBR , XREF_BIBR ] .	Work has indicated that insulin treatment in whole retinal samples in vivo or in retinal explants will increase Akt activity, primarily through IRS-2 actions [XREF_BIBR, XREF_BIBR].	4	19	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	18	19
GLUT4 exocytosis is dependent on the inhibition of PARsylation by TNKS through insulin induced Akt signaling [ XREF_BIBR ] .	GLUT4 exocytosis is dependent on the inhibition of PARsylation by TNKS through insulin induced Akt signaling [XREF_BIBR].	3	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	14	15
A prominent insulin action is to promote glucose uptake into the muscle and fat cells by initiating PI3K and Akt signalling cascade to trigger the movement of a specialized pool of insulin responsive glucose transporter , GLUT4 , from intracellular compartments to the cell surface .	A prominent insulin action is to promote glucose uptake into the muscle and fat cells by initiating PI3K and Akt signalling cascade to trigger the movement of a specialized pool of insulin responsive glucose transporter, GLUT4, from intracellular compartments to the cell surface.	2	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	19	20
The present results show that Soy treatment in comparison with Cas consumption induces lower angiotensin release and increased insulin stimulated Akt activation in adipocytes .	The present results show that Soy treatment in comparison with Cas consumption induces lower angiotensin release and increased insulin stimulated Akt activation in adipocytes.	17	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	20	21
In addition , Akt was significantly stimulated by insulin in cardiomyocyte cell culture .	In addition, Akt was significantly stimulated by insulin in cardiomyocyte cell culture.	3	12	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	3	4
Given the well described role of Bmi1 in repressing transcription of target genes , we sought to determine whether the expression of the insulin signaling proteins upstream of Akt was altered in Bmi1 +/- livers .	Given the well described role of Bmi1 in repressing transcription of target genes, we sought to determine whether the expression of the insulin signaling proteins upstream of Akt was altered in Bmi1 +/- livers.	20	29	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	expression of the insulin	insulin	Akt	Akt	akt	23	24	28	29
Therefore , it was a surprise that mice lacking the various p85 regulatory subunits actually showed improved insulin signaling and enhanced insulin stimulated Akt activation .	Therefore, it was a surprise that mice lacking the various p85 regulatory subunits actually showed improved insulin signaling and enhanced insulin stimulated Akt activation.	20	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	23	24
The primary function of insulin induced Akt activation is to counteract FOXO1 and thus reduce glucose production during the fed state .	The primary function of insulin induced Akt activation is to counteract FOXO1 and thus reduce glucose production during the fed state.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
The results show that insulin stimulated Akt activity in the Akt1 +/+ cells , as demonstrated by the transformation of the red to green emission of LS456 ( XREF_FIG ) .	The results show that insulin stimulated Akt activity in the Akt1 +/+ cells, as demonstrated by the transformation of the red to green emission of LS456 (XREF_FIG).	4	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
These results demonstrate that burn injury impairs insulin stimulated Akt and PKB activation in skeletal muscle and suggest that attenuated Akt and PKB activation may be involved in deranged metabolism and muscle wasting observed after burn injury .	These results demonstrate that burn injury impairs insulin stimulated Akt and PKB activation in skeletal muscle and suggest that attenuated Akt and PKB activation may be involved in deranged metabolism and muscle wasting observed after burn injury.	6	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
In vitro kinase assay showed insulin activated Akt can directly phosphorylate nNOS ( S1416 ) .	In vitro kinase assay showed insulin activated Akt can directly phosphorylate nNOS (S1416).	4	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
However , based on the observation that neither FGF nor insulin activated AKT , they concluded that the Ras/PI3K/AKT pathway was not sensitive to Cu depletion and that Ras was not likely affected by loss of CTR1 .	However, based on the observation that neither FGF nor insulin activated AKT, they concluded that the Ras/PI3K/AKT pathway was not sensitive to Cu depletion and that Ras was not likely affected by loss of CTR1.	8	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	12	13
As shown in XREF_FIG E , insulin mediated Akt and eNOS activation were not observed in HAECs-elder but were detected in HAECs-middle , despite the expression levels of IR and IRS showing no significant difference between these HAECs ( XREF_FIG , F and G ) .	As shown in XREF_FIG E, insulin mediated Akt and eNOS activation were not observed in HAECs-elder but were detected in HAECs-middle, despite the expression levels of IR and IRS showing no significant difference between these HAECs (XREF_FIG, F and G).	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
A disruption of mTORC2 impairs insulin induced activation of AKT , a mTORC2 substrate , causing a reduced insulin stimulated glucose uptake in both adipose tissue and muscles of rictor knockout mice .	A disruption of mTORC2 impairs insulin induced activation of AKT, a mTORC2 substrate, causing a reduced insulin stimulated glucose uptake in both adipose tissue and muscles of rictor knockout mice.	5	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	9	10
While we found that overexpression of APPL1 greatly enhanced insulin stimulated Akt activation in mouse embryonic fibroblasts ( MEFs ) lacking IRS1 ( XREF_FIG ) or IRS2 ( XREF_FIG ) , overexpression of APPL1 had no effect on insulin stimulated Akt phosphorylation in 32D/IR cells ( XREF_FIG ) , which lack both endogenous IRS1 and IRS2 , indicating that the effect of APPL1 on insulin signaling depends upon IRS proteins .	While we found that overexpression of APPL1 greatly enhanced insulin stimulated Akt activation in mouse embryonic fibroblasts (MEFs) lacking IRS1 (XREF_FIG) or IRS2 (XREF_FIG), overexpression of APPL1 had no effect on insulin stimulated Akt phosphorylation in 32D/IR cells (XREF_FIG), which lack both endogenous IRS1 and IRS2, indicating that the effect of APPL1 on insulin signaling depends upon IRS proteins.	8	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
Because hyperinsulinemia and IR are the crucial pathogenic signals for the development of NASH [ XREF_BIBR ] , in this study , we also found that insulin stimulation in vitro could lead to AKT , p-MDM2 , MDM4 activation and impaired autophagy .	Because hyperinsulinemia and IR are the crucial pathogenic signals for the development of NASH [XREF_BIBR], in this study, we also found that insulin stimulation in vitro could lead to AKT, p-MDM2, MDM4 activation and impaired autophagy.	26	41	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	26	27	33	34
In support of this neuronal action , ALC has also been shown to block insulin stimulated Akt activation in cerebellar neurons , as well as inhibit brain derived neurotrophic factor induced Akt phosphorylation in the cerebral cortex .	In support of this neuronal action, ALC has also been shown to block insulin stimulated Akt activation in cerebellar neurons, as well as inhibit brain derived neurotrophic factor induced Akt phosphorylation in the cerebral cortex.	13	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
AZD5363 ( a pan-Akt inhibitor ) can inhibit Akt , thus increasing GSK3 activity , whereas insulin can activate Akt to inhibit GSK3 activity [ XREF_BIBR ] .	AZD5363 (a pan-Akt inhibitor) can inhibit Akt, thus increasing GSK3 activity, whereas insulin can activate Akt to inhibit GSK3 activity [XREF_BIBR].	16	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	19	20
In addition to GSK3beta inhibition , insulin mediated Akt activation leads to Foxo1 phosphorylation and blocks the expression of a number of genes involved in gluconeogenesis such as PEPCK and G6Pase [ XREF_BIBR , XREF_BIBR ] .	In addition to GSK3beta inhibition, insulin mediated Akt activation leads to Foxo1 phosphorylation and blocks the expression of a number of genes involved in gluconeogenesis such as PEPCK and G6Pase [XREF_BIBR, XREF_BIBR].	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
It has been reported Sin1 isoforms defined three distinct mTORC2 , mSin1.5-containing mTORC2 could not respond to insulin induced AKT HM-site phoshorylation .	It has been reported Sin1 isoforms defined three distinct mTORC2, mSin1.5-containing mTORC2 could not respond to insulin induced AKT HM-site phoshorylation.	15	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	17	18	19	20
To examine the role of Akt in glucosamine induced insulin resistance , we investigated time course for insulin stimulation of Akt activity and glucose transport during recovery from glucosamine induced insulin resistance .	To examine the role of Akt in glucosamine induced insulin resistance, we investigated time course for insulin stimulation of Akt activity and glucose transport during recovery from glucosamine induced insulin resistance.	17	21	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	20	21
Increasing concentrations of insulin failed to activate Akt in DKO cells , indicating the complete absence of insulin and IGF-1 signaling ( XREF_SUPPLEMENTARY ) .	Increasing concentrations of insulin failed to activate Akt in DKO cells, indicating the complete absence of insulin and IGF-1 signaling (XREF_SUPPLEMENTARY).	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
In our cohort , muscle IR was highly associated with systemic IR , as shown by the correlations between the levels of insulin stimulated P-Akt and Akt fold induction in skeletal muscle and the systemic insulin sensitivity related indexes HOMA IR and GIR .	In our cohort, muscle IR was highly associated with systemic IR, as shown by the correlations between the levels of insulin stimulated P-Akt and Akt fold induction in skeletal muscle and the systemic insulin sensitivity related indexes HOMA IR and GIR.	20	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	P-Akt	P-Akt	p-akt	22	23	24	25
To investigate whether increased insulin induced activation of Akt in the TAPP1 R211L and R211L TAPP2 R218L and R218L double knock-in mice enhanced insulin sensitivity in the most physiological context , we performed a hyperinsulinaemic-euglycaemic clamp , a method that is considered the gold standard for assessing insulin actions on whole body glucose homeostasis in vivo [ XREF_BIBR ] , on TAPP1 R211L and R211L TAPP2 R218L and R218L double knock-in mice and wild-type TAPP1 +/+ TAPP2 +/+ control mice .	To investigate whether increased insulin induced activation of Akt in the TAPP1 R211L and R211L TAPP2 R218L and R218L double knock-in mice enhanced insulin sensitivity in the most physiological context, we performed a hyperinsulinaemic-euglycaemic clamp, a method that is considered the gold standard for assessing insulin actions on whole body glucose homeostasis in vivo [XREF_BIBR], on TAPP1 R211L and R211L TAPP2 R218L and R218L double knock-in mice and wild-type TAPP1 +/+ TAPP2 +/+ control mice.	3	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	8	9
We demonstrate that Ecscr deletion enhances the insulin mediated Akt and endothelial nitric oxide synthase activation in endothelial cells , which increases insulin delivery into the skeletal muscle .	We demonstrate that Ecscr deletion enhances the insulin mediated Akt and endothelial nitric oxide synthase activation in endothelial cells, which increases insulin delivery into the skeletal muscle.	5	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
Components in the proximal insulin pathway are similar between CON and IUGR fetal livers ; even in IUGR fetuses , insulin robustly activates nuclear AKT protein .	Components in the proximal insulin pathway are similar between CON and IUGR fetal livers; even in IUGR fetuses, insulin robustly activates nuclear AKT protein.	20	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	24	25
Interestingly , a previous study has shown that chronic GH treatment of differentiated 3T3-L1 adipocytes reduces insulin stimulated 2-deoxyglucose ( DOG ) uptake and activation of AKT , leading to insulin resistance [ XREF_BIBR ] .	Interestingly, a previous study has shown that chronic GH treatment of differentiated 3T3-L1 adipocytes reduces insulin stimulated 2-deoxyglucose (DOG) uptake and activation of AKT, leading to insulin resistance [XREF_BIBR].	15	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	26	27
For example , insulin and IGF-I treatment promotes increases Akt signaling , which promotes mTORC1 complex assembly and MPS but also inhibits MPB via reduced proteolytic gene expression under control of the FOXO transcription factors [ XREF_BIBR , XREF_BIBR ] .	For example, insulin and IGF-I treatment promotes increases Akt signaling, which promotes mTORC1 complex assembly and MPS but also inhibits MPB via reduced proteolytic gene expression under control of the FOXO transcription factors [XREF_BIBR, XREF_BIBR].	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	9	10
Treatment of high-fat fed mice with vildagliptin , a dipeptidyl peptidase-4 inhibitor ( anti-diabetic drug ) , also restored insulin induced neuronal IR , IRS1 , and Akt activation and long-term depression , improved brain mitochondrial dysfunction , and enhanced cognitive function measured by the Morris water maze test XREF_BIBR .	Treatment of high-fat fed mice with vildagliptin, a dipeptidyl peptidase-4 inhibitor (anti-diabetic drug), also restored insulin induced neuronal IR, IRS1, and Akt activation and long-term depression, improved brain mitochondrial dysfunction, and enhanced cognitive function measured by the Morris water maze test XREF_BIBR.	19	39	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	27	28
Assessment of p21 Cip staining in pancreases from caAkt Tg and control mice demonstrated that insulin positive cells overexpressing Akt exhibit a predominantly cytoplasmic localisation of p21 Cip compared with a more diffuse staining observed in wild-type islet cells ( XREF_FIG ) .	Assessment of p21 Cip staining in pancreases from caAkt Tg and control mice demonstrated that insulin positive cells overexpressing Akt exhibit a predominantly cytoplasmic localisation of p21 Cip compared with a more diffuse staining observed in wild-type islet cells (XREF_FIG).	15	20	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	19	20
Although insulin stimulated Akt activity in muscle is not greater after acute exercise , Akt ' s phosphorylation of its protein substrate , known as Akt substrate of 160 kDa ( also called AS160 or TBC1D4 ) , is elevated in muscle postexercise .	Although insulin stimulated Akt activity in muscle is not greater after acute exercise, Akt 's phosphorylation of its protein substrate, known as Akt substrate of 160 kDa (also called AS160 or TBC1D4), is elevated in muscle postexercise.	1	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
We have previously shown that overexpression of TRB3 in C2C12 cells decreases insulin stimulated Akt activity via direct binding to Akt 6 .	We have previously shown that overexpression of TRB3 in C2C12 cells decreases insulin stimulated Akt activity via direct binding to Akt 6.	11	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	14	15
These data indicate that serine 83 in p85alpha PI3K is important for insulin induction of AKT and Erk1/2 activation .	These data indicate that serine 83 in p85alpha PI3K is important for insulin induction of AKT and Erk1/2 activation.	12	18	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	15	16
In addition , salidroside enhanced insulin mediated Akt activation and glucose uptake , and such enhancement can be specifically inhibited by compound C.	In addition, salidroside enhanced insulin mediated Akt activation and glucose uptake, and such enhancement can be specifically inhibited by compound C.	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
C21 treated mice showed an increase in both basal Akt and ERK1/2 phosphorylation levels in the liver , and increased insulin stimulated Akt activation in adipose tissue .	C21 treated mice showed an increase in both basal Akt and ERK1/2 phosphorylation levels in the liver, and increased insulin stimulated Akt activation in adipose tissue.	19	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
The unaltered levels of the Akt phosphorylation site T642 in AS160 in Vps34 D761A/+ myotubes suggest that Vps34 regulates GLUT4 translocation and glucose uptake in muscle cells via a pathway that does not involve the canonical insulin driven Akt and AS160 pathway but instead acts through AMPK substrates such as TBC1D1 .	The unaltered levels of the Akt phosphorylation site T642 in AS160 in Vps34 D761A/+ myotubes suggest that Vps34 regulates GLUT4 translocation and glucose uptake in muscle cells via a pathway that does not involve the canonical insulin driven Akt and AS160 pathway but instead acts through AMPK substrates such as TBC1D1.	33	41	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	36	37	38	39
Insulin activation of Akt isoforms is normal in muscle of obese non diabetic and diabetic subjects despite a marked decrease in IRS-1- and IRS-2-associated phosphoinositide 3-kinase ( PI3K ) activities ( ~ 50 % and 40 % respectively ) and in insulin stimulated glucose disposal ( ~ 60 % ) in obese diabetic subjects [ XREF_BIBR ] .	Insulin activation of Akt isoforms is normal in muscle of obese non diabetic and diabetic subjects despite a marked decrease in IRS-1- and IRS-2-associated phosphoinositide 3-kinase (PI3K) activities (~ 50% and 40% respectively) and in insulin stimulated glucose disposal (~ 60%) in obese diabetic subjects [XREF_BIBR].	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
Subsequently , we examined the effect of this dose of rapamycin along with a higher dose of rapamycin on insulin stimulated Akt and mTOR signaling in C2C12 myotubes .	Subsequently, we examined the effect of this dose of rapamycin along with a higher dose of rapamycin on insulin stimulated Akt and mTOR signaling in C2C12 myotubes.	3	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
Tribbles homolog 3 ( TRIB3 ) is a 45kDa pseudokinase , involved in the impairment of insulin signaling by affecting insulin induced Akt activation in several insulin target tissues [ XREF_BIBR ] .	Tribbles homolog 3 (TRIB3) is a 45kDa pseudokinase, involved in the impairment of insulin signaling by affecting insulin induced Akt activation in several insulin target tissues [XREF_BIBR].	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
Furthermore , tonic Akt activation by chronic insulin stimulation due to compensatory hyperinsulinemia may have deleterious effects .	Furthermore, tonic Akt activation by chronic insulin stimulation due to compensatory hyperinsulinemia may have deleterious effects.	3	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	3	4
In addition , long-term effect of high-glucose concentration on human media artery smooth muscle cells down-regulates of basal RAC-alpha serine/threonine protein kinase ( Akt ) phosphorylation , while acute stimulation of cells in high glucose with insulin activated Akt 37 .	In addition, long-term effect of high-glucose concentration on human media artery smooth muscle cells down-regulates of basal RAC-alpha serine/threonine protein kinase (Akt) phosphorylation, while acute stimulation of cells in high glucose with insulin activated Akt 37.	34	39	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	36	37	38	39
Previous studies demonstrated DHEA enhanced insulin stimulated PKCzeta and lambda activation in muscle and AKT activation in the liver of rats .	Previous studies demonstrated DHEA enhanced insulin stimulated PKCzeta and lambda activation in muscle and AKT activation in the liver of rats.	4	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	14	15
Conversely , the injection of recombinant IL-10 in the hypothalamus of obese animals at rest markedly reduced IKKbeta , PERK , and IRS-1 Ser307 phosphorylation and increased insulin induced Akt and leptin induced STAT-3 phosphorylation in the hypothalamic tissue of obese rats ( XREF_FIG ) .	Conversely, the injection of recombinant IL-10 in the hypothalamus of obese animals at rest markedly reduced IKKbeta, PERK, and IRS-1 Ser307 phosphorylation and increased insulin induced Akt and leptin induced STAT-3 phosphorylation in the hypothalamic tissue of obese rats (XREF_FIG).	27	32	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	27	28	29	30
Basal AKT phosphorylation in livers of tumor bearing mice was higher , whereas insulin stimulated AKT activation was comparable to control mice ( XREF_FIG ) .	Basal AKT phosphorylation in livers of tumor bearing mice was higher, whereas insulin stimulated AKT activation was comparable to control mice (XREF_FIG).	13	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	13	14	15	16
In addition , the insulin stimulated AKT activation was not significantly different between control and mutant hepatocytes ( XREF_SUPPLEMENTARY ) , indicating that the insulin signalling pathway was not impaired by the loss of Zbtb20 .	In addition, the insulin stimulated AKT activation was not significantly different between control and mutant hepatocytes (XREF_SUPPLEMENTARY), indicating that the insulin signalling pathway was not impaired by the loss of Zbtb20.	3	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	6	7
Here , we have provided evidence that C2-ceramide inhibits GLUT4 sorting into the Stx6 positive perinuclear sub-compartment and that this occurs even when insulin stimulation of Akt is allowed to recover .	Here, we have provided evidence that C2-ceramide inhibits GLUT4 sorting into the Stx6 positive perinuclear sub-compartment and that this occurs even when insulin stimulation of Akt is allowed to recover.	23	27	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	26	27
We hypothesize that this is the reason why activation of Akt by insulin did not completely reverse the phenotype of the ORF4 mutant .	We hypothesize that this is the reason why activation of Akt by insulin did not completely reverse the phenotype of the ORF4 mutant.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	10	11
To test if continuous exposure to insulin can favour tumour growth , we studied insulin and IGF1 dependent activation of ERK1/2 and Akt and PKB by Western blotting , inhibition of apoptosis by ELISA , and induction of proliferation by [ 3 H ]-thymidine incorporation in Saos-2 and B10 osteosarcoma cells .	To test if continuous exposure to insulin can favour tumour growth, we studied insulin and IGF1 dependent activation of ERK1/2 and Akt and PKB by Western blotting, inhibition of apoptosis by ELISA, and induction of proliferation by [3 H]-thymidine incorporation in Saos-2 and B10 osteosarcoma cells.	14	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	22	23
The defective IR signaling as indicated by the blunted insulin induced Akt activation further corroborates the insulin resistance phenotype .	The defective IR signaling as indicated by the blunted insulin induced Akt activation further corroborates the insulin resistance phenotype.	5	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
In addition , under normal growth conditions , stimulation of the insulin signaling pathway promotes Akt ( protein kinase B ) activation by phosphoinositide dependent kinase-1 ( PDK1 ) and the rapamycin-insensitive companion of TOR ( RICTOR )-containing TOR complex 2 ( TORC2 ) .	In addition, under normal growth conditions, stimulation of the insulin signaling pathway promotes Akt (protein kinase B) activation by phosphoinositide dependent kinase-1 (PDK1) and the rapamycin-insensitive companion of TOR (RICTOR)-containing TOR complex 2 (TORC2).	11	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	15	16
Akt activation by insulin glulisine was similar to that by human insulin in non malignant rat cardiomyocytes [ XREF_BIBR ] , and in fibroblasts expressing insulin receptor A isoform [ XREF_BIBR ] .	Akt activation by insulin glulisine was similar to that by human insulin in non malignant rat cardiomyocytes [XREF_BIBR], and in fibroblasts expressing insulin receptor A isoform [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	0	1
Insulin activates the PI3K and Akt pathway , critical for neuronal survival and growth , synaptic plasticity and development , and learning [ XREF_BIBR , XREF_BIBR ] .	Insulin activates the PI3K and Akt pathway, critical for neuronal survival and growth, synaptic plasticity and development, and learning [XREF_BIBR, XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
Insulin and a battery of growth factors may activate PKB or serum- and glucocorticoid regulated protein kinase ( SGK ) , resulting in the stimulation of FOXO phosphorylation and nuclear exclusion [ XREF_BIBR ] .	Insulin and a battery of growth factors may activate PKB or serum- and glucocorticoid regulated protein kinase (SGK), resulting in the stimulation of FOXO phosphorylation and nuclear exclusion [XREF_BIBR].	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	9	10
Moreover , insulin stimulated P-Akt and Akt fold induction in SAT did not correlate with the systemic insulin sensitivity related indexes HOMA IR ( R = 0.108 , P = 0.580 ; XREF_FIG ) and GIR ( R = -0.281 , P = 0.162 ; XREF_FIG ) .	Moreover, insulin stimulated P-Akt and Akt fold induction in SAT did not correlate with the systemic insulin sensitivity related indexes HOMA IR (R = 0.108, P = 0.580; XREF_FIG) and GIR (R = -0.281, P = 0.162; XREF_FIG).	2	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	P-Akt	P-Akt	P-Akt	2	3	4	5
Thus , in iLIRKO mice , there was a graded impairment of insulin stimulated Akt and ERKs signaling in brain , skeletal muscle , or interscapular brown adipose tissue , the degree of which correlated with the severity of IR deletion in the liver ( XREF_FIG ) .	Thus, in iLIRKO mice, there was a graded impairment of insulin stimulated Akt and ERKs signaling in brain, skeletal muscle, or interscapular brown adipose tissue, the degree of which correlated with the severity of IR deletion in the liver (XREF_FIG).	10	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	14	15
We previously showed that SRA promotes adipogenesis and stimulates insulin stimulated glucose uptake and Akt activation in adipocytes XREF_BIBR .	We previously showed that SRA promotes adipogenesis and stimulates insulin stimulated glucose uptake and Akt activation in adipocytes XREF_BIBR.	8	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	14	15
Euglycemic , hyperinsulinemic clamp and 1-[ ( 14 ) C ]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal , insulin stimulated glucose uptake , and the ratio of phospho- to total Akt ( P < 0.01 vs. control ) in striated muscle .	Euglycemic, hyperinsulinemic clamp and 1-[(14) C]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal, insulin stimulated glucose uptake, and the ratio of phospho- to total Akt (P < 0.01 vs. control) in striated muscle.	22	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	34	35
Phosphorylation of IRS-1 on Y612 and Y896 , sites required for insulin mediated Akt and ERK activation , showed reduced phosphorylation , suggesting an effect of Gpc4 deletion on insulin signaling .	Phosphorylation of IRS-1 on Y612 and Y896, sites required for insulin mediated Akt and ERK activation, showed reduced phosphorylation, suggesting an effect of Gpc4 deletion on insulin signaling.	9	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
The results indicated that LY294002 failed to inhibit the sorbitol induced activation of Akt , but LY294002 inhibited the insulin induced activation of Akt ( XREF_FIG ) , suggesting that Akt activation in hyperosomotic stress can also occur without PI3K activation .	The results indicated that LY294002 failed to inhibit the sorbitol induced activation of Akt, but LY294002 inhibited the insulin induced activation of Akt (XREF_FIG), suggesting that Akt activation in hyperosomotic stress can also occur without PI3K activation.	18	25	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	23	24
In the no-adipocyte control group , pretreatment with IBMX amplified insulin mediated activation of Akt by 66 % compared with the no IBMX condition .	In the no-adipocyte control group, pretreatment with IBMX amplified insulin mediated activation of Akt by 66% compared with the no IBMX condition.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	14	15
During the same period , protein kinase B ( PKB and Akt ) was discovered by a number of research groups and it was shown that within just one-minute following cell stimulation , insulin could trigger the activation of Akt in a PI3K dependent manner .	During the same period, protein kinase B (PKB and Akt) was discovered by a number of research groups and it was shown that within just one-minute following cell stimulation, insulin could trigger the activation of Akt in a PI3K dependent manner.	33	40	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	33	34	39	40
( 2 ) PI3K and Akt , which is induced by insulin or IGF-1 , plays a major role in the regulation of autophagy , protein synthesis and actin cytoskeleton via the Mammalian target of rapamycin ( mTOR ) signal activation to directly or indirectly promote neuronal survival .	(2) PI3K and Akt, which is induced by insulin or IGF-1, plays a major role in the regulation of autophagy, protein synthesis and actin cytoskeleton via the Mammalian target of rapamycin (mTOR) signal activation to directly or indirectly promote neuronal survival.	3	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	5	6
Two supposed mechanisms of resistance to mTOR inhibitors are Akt and PI3K activation , by means of mTORC2 and insulin growth factor ( IGF ) - IGF receptor signaling , respectively .	Two supposed mechanisms of resistance to mTOR inhibitors are Akt and PI3K activation, by means of mTORC2 and insulin growth factor (IGF) - IGF receptor signaling, respectively.	9	21	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	9	10
We confirmed that insulin robustly stimulated PKB to the same extent in exvivo muscles from both genotypes , whereas AS160-Thr649 phosphorylation was only potently stimulated by insulin in muscles from the wild-type mice , but not from knockin mice ( data not shown ) .	We confirmed that insulin robustly stimulated PKB to the same extent in exvivo muscles from both genotypes, whereas AS160-Thr649 phosphorylation was only potently stimulated by insulin in muscles from the wild-type mice, but not from knockin mice (data not shown).	3	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	6	7
There was almost a complete loss of insulin induced IRS-1-associated PI3K activity and marked reduction in insulin activation of Akt and aPKC in the liver of chronic p110-alpha knockout mice .	There was almost a complete loss of insulin induced IRS-1-associated PI3K activity and marked reduction in insulin activation of Akt and aPKC in the liver of chronic p110-alpha knockout mice.	16	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	19	20
Taken together , these results demonstrate that miR-291b-3p contributed to hyperglycemia and hepatic insulin resistance through suppressing insulin stimulated AKT and GSK signaling activation and increasing expression of gluconeogenic genes in hepatocytes .	Taken together, these results demonstrate that miR-291b-3p contributed to hyperglycemia and hepatic insulin resistance through suppressing insulin stimulated AKT and GSK signaling activation and increasing expression of gluconeogenic genes in hepatocytes.	16	23	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	17	18	19	20
Insulin promotes Akt dependent prosurvival signaling and reduces experimental ischemia reperfusion injury , but its clinical impact has been limited .	Insulin promotes Akt dependent prosurvival signaling and reduces experimental ischemia reperfusion injury, but its clinical impact has been limited.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
DPI completely inhibited the activation of phosphatidylinositol ( PI ) 3 '-kinase activity by insulin and reduced the insulin induced activation of the serine kinase Akt by up to 49 % ; these activities were restored when H ( 2 ) O ( 2 ) was added back to cells that had been pretreated with DPI .	DPI completely inhibited the activation of phosphatidylinositol (PI) 3 '-kinase activity by insulin and reduced the insulin induced activation of the serine kinase Akt by up to 49%; these activities were restored when H (2) O (2) was added back to cells that had been pretreated with DPI.	17	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	25	26
Insulin induced Akt activation results in AS160 phosphorylation and a rapid increase of Glut4 at the cell surface , thus conferring increased glucose uptake .	Insulin induced Akt activation results in AS160 phosphorylation and a rapid increase of Glut4 at the cell surface, thus conferring increased glucose uptake.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Blood pressure , mesenteric arteriolar vasorelaxation , superoxide anion ( O 2 - ) generation , NAD ( P ) H oxidase activity , and insulin stimulated Akt and endothelial nitric oxide synthase ( eNOS ) activation and nitric oxide ( NO ) production were determined .	Blood pressure, mesenteric arteriolar vasorelaxation, superoxide anion (O 2 -) generation, NAD (P) H oxidase activity, and insulin stimulated Akt and endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production were determined.	1	45	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
The activation of PKB by insulin appears to involve a novel PtdIns ( 3,4,5 ) P3 dependent protein kinase , which we have named PDK1 .	The activation of PKB by insulin appears to involve a novel PtdIns (3,4,5) P3 dependent protein kinase, which we have named PDK1.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	5	6	3	4
The downstream components of insulin induced Akt survival signaling after transient global brain ischemia remain to be identified .	The downstream components of insulin induced Akt survival signaling after transient global brain ischemia remain to be identified.	2	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Also in hepatocytes , insulin stimulated Akt signaling was enhanced and prolonged upon PI3K-C2beta inactivation ( XREF_FIG B ) , with no impact on MAPK signaling ( XREF_FIG B ) .	Also in hepatocytes, insulin stimulated Akt signaling was enhanced and prolonged upon PI3K-C2beta inactivation (XREF_FIG B), with no impact on MAPK signaling (XREF_FIG B).	4	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Insulin is known to activate PI3K and Akt signalling pathway and it was logically to expect that insulin would up-regulate SUR2A as this is what PI3K and Akt activation does XREF_BIBR .	Insulin is known to activate PI3K and Akt signalling pathway and it was logically to expect that insulin would up-regulate SUR2A as this is what PI3K and Akt activation does XREF_BIBR.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	7	8
APPL1 potentiates insulin stimulated Akt activation by competing with the Akt inhibitor Tribble-3 and suppressing ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1 ( RAF proto-oncogene serine/threonine protein kinase ) in HUVEC [ XREF_BIBR ] .	APPL1 potentiates insulin stimulated Akt activation by competing with the Akt inhibitor Tribble-3 and suppressing ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1 (RAF proto-oncogene serine/threonine protein kinase) in HUVEC [XREF_BIBR].	1	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
Adipocytes treated with a combination of both butyrate and insulin showed highest phospho-AKT abundance ( P < 0.05 ) and tendency ( P = 0.1 ) for higher phospho-AKT and AKT ratio , compared to cells treated with either butyrate or insulin alone .	Adipocytes treated with a combination of both butyrate and insulin showed highest phospho-AKT abundance (P < 0.05) and tendency (P = 0.1) for higher phospho-AKT and AKT ratio, compared to cells treated with either butyrate or insulin alone.	30	42	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	41	42	30	31
26 The inhibitor of S6K reproduced effects of rapamycin on insulin induced Akt activation , albeit it did not completely prevent insulin inducible activation of S6K .	26 The inhibitor of S6K reproduced effects of rapamycin on insulin induced Akt activation, albeit it did not completely prevent insulin inducible activation of S6K.	5	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
Overall these findings demonstrate that insulin stimulated Akt activity was impaired in TR-MUL cells exposed to GAM .	Overall these findings demonstrate that insulin stimulated Akt activity was impaired in TR-MUL cells exposed to GAM.	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Insulin induced Akt signaling drives TGF-beta receptor translocation to the cell surface .	Insulin induced Akt signaling drives TGF-beta receptor translocation to the cell surface.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Taken together , these results demonstrate that both insulin stimulated Akt signaling and PKC induced inhibition of Akt signaling depend on cholesterol enriched membrane microdomains , thus suggesting a putative biophysical mechanism underlying insulin resistance in diabetic retinopathy .	Taken together, these results demonstrate that both insulin stimulated Akt signaling and PKC induced inhibition of Akt signaling depend on cholesterol enriched membrane microdomains, thus suggesting a putative biophysical mechanism underlying insulin resistance in diabetic retinopathy.	8	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Thus , in contracting skeletal muscle , insulin stimulates glucose uptake and activates PKB , but not p70 ( S6K ) , by a PI 3-kinase-dependent mechanism that is independent of changes in IRS-1- and IRS-2-associated PI 3-kinase activity .	Thus, in contracting skeletal muscle, insulin stimulates glucose uptake and activates PKB, but not p70 (S6K), by a PI 3-kinase-dependent mechanism that is independent of changes in IRS-1- and IRS-2-associated PI 3-kinase activity.	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	7	8	13	14
Placement of serum starved HEK293 cells into serum and glucose-free medium rapidly activates AMPK phosphorylation of IRS1 on mS789 and hS794 , and mutation of this residue blocks the impairment of insulin stimulated AKT activation caused by glucose deprivation [ XREF_BIBR ] .	Placement of serum starved HEK293 cells into serum and glucose-free medium rapidly activates AMPK phosphorylation of IRS1 on mS789 and hS794, and mutation of this residue blocks the impairment of insulin stimulated AKT activation caused by glucose deprivation [XREF_BIBR].	29	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	31	32	33	34
Another polyphenol , caffeic acid phenethyl ester ( CAPE ) was shown to enhance insulin mediated Akt activation and to activate glucose uptake via the AMPK pathway in L6 muscle cells , suggesting that CAPE could directly activates both pathways XREF_BIBR .	Another polyphenol, caffeic acid phenethyl ester (CAPE) was shown to enhance insulin mediated Akt activation and to activate glucose uptake via the AMPK pathway in L6 muscle cells, suggesting that CAPE could directly activates both pathways XREF_BIBR.	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
PI3K-C2beta Inactivation Leads to Enhanced Insulin Stimulated Akt Signaling Selectively in Metabolic Tissues .	PI3K-C2beta Inactivation Leads to Enhanced Insulin Stimulated Akt Signaling Selectively in Metabolic Tissues.	5	8	Stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	5	6	7	8
The delicate process of starvation induced autophagy XREF_BIBR is inversely regulated by mTOR which is activated by PI3K-Akt induced by insulin or other growth factor XREF_BIBR , XREF_BIBR .	The delicate process of starvation induced autophagy XREF_BIBR is inversely regulated by mTOR which is activated by PI3K-Akt induced by insulin or other growth factor XREF_BIBR, XREF_BIBR.	15	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	20	21	17	18
In addition , insulin treatment produced 2.7-fold increase ( P < 0.01 ) of myocardial Akt activity and 28 % increase of myocardial NO production ( P < 0.05 ) , while p38 MAPK activity changed insignificantly as compared with that of vehicle ( P > 0.05 ) .	In addition, insulin treatment produced 2.7-fold increase (P < 0.01) of myocardial Akt activity and 28% increase of myocardial NO production (P < 0.05), while p38 MAPK activity changed insignificantly as compared with that of vehicle (P> 0.05).	3	16	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	15	16
In spite of the decrease in basal PKB phosphorylation , insulin ( 10-50 nM ) could still activate both PKB and S6K1 .	In spite of the decrease in basal PKB phosphorylation, insulin (10-50 nM) could still activate both PKB and S6K1.	10	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	10	11	19	20
However , insulin stimulated Akt activation was unaffected .	However, insulin stimulated Akt activation was unaffected.	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
AKT is activated by the events downstream of insulin and its activation is essential for insulin mediated glucose transport .	AKT is activated by the events downstream of insulin and its activation is essential for insulin mediated glucose transport.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	0	1
Consistent with the insulin resistance inherent in the HFD group , insulin did not induce a significant activation of Akt in this group .	Consistent with the insulin resistance inherent in the HFD group, insulin did not induce a significant activation of Akt in this group.	11	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	19	20
Additionally , TBF treatment significantly reduced phosphorylation of insulin receptor substrate 1 ( IRS-1 ) at serine 307 and increased insulin stimulated Akt and eNOS activation in the SHRs .	Additionally, TBF treatment significantly reduced phosphorylation of insulin receptor substrate 1 (IRS-1) at serine 307 and increased insulin stimulated Akt and eNOS activation in the SHRs.	19	25	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
Akt is activated by insulin , IGF-1 and various growth and survival factors , through PI 3-kinase and PDK1 , 2 ( XREF_FIG ) .	Akt is activated by insulin, IGF-1 and various growth and survival factors, through PI 3-kinase and PDK1, 2 (XREF_FIG).	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
In fact , insulin failed to significantly increase Akt activation over baseline in the DRG of ob/ob mice .	In fact, insulin failed to significantly increase Akt activation over baseline in the DRG of ob/ob mice.	3	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	8	9
Insulin can also activate the PI3K and Akt signaling pathway by its own receptor .	Insulin can also activate the PI3K and Akt signaling pathway by its own receptor.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	7	8
XREF_BIBR Our results showing that insulin activates the PI3K and Akt pathway leading to drug resistance reinforce the importance of extracellular stimuli of the pathway in protection of melanoma cells against treatment .	XREF_BIBR Our results showing that insulin activates the PI3K and Akt pathway leading to drug resistance reinforce the importance of extracellular stimuli of the pathway in protection of melanoma cells against treatment.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	10	11
Exposure of cardiomyocytes to 100 nm insulin activated PI3K-AKT signalling ( 15 min ) and induced a 1.9 +/- 0.3-fold increase in BNP gene expression ( 6 h ) .	Exposure of cardiomyocytes to 100 nm insulin activated PI3K-AKT signalling (15 min) and induced a 1.9 +/- 0.3-fold increase in BNP gene expression (6 h).	2	9	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	6	7	8	9
Interestingly , striated muscle specific PTEN null mice have been reported to have a ~ 50 % increase in heart mass XREF_BIBR and are protected from high fat diet induced insulin resistance and diabetes XREF_BIBR even though at baseline they showed a slight reduction in insulin stimulated PKB Thr 308 phosphorylation XREF_BIBR .	Interestingly, striated muscle specific PTEN null mice have been reported to have a ~ 50% increase in heart mass XREF_BIBR and are protected from high fat diet induced insulin resistance and diabetes XREF_BIBR even though at baseline they showed a slight reduction in insulin stimulated PKB Thr 308 phosphorylation XREF_BIBR.	40	48	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	45	46	47	48
In addition , C2-ceramide inhibited insulin stimulated AKT pathway by activating PP2A phosphatase , but not PI3-kinase or PKC-zeta activities .	In addition, C2-ceramide inhibited insulin stimulated AKT pathway by activating PP2A phosphatase, but not PI3-kinase or PKC-zeta activities.	4	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
The phosphorylation of NCoR1 by insulin induced Akt and PKB activation was , however , robustly induced with very fast kinetics ( i.e. 1 min in vitro and 10 min in vivo after insulin treatment ) , indicating that NCoR1 phosphorylation directly alters protein functions of NCoR1 most likely already before LXRalpha activation is initiated by ligand binding .	The phosphorylation of NCoR1 by insulin induced Akt and PKB activation was, however, robustly induced with very fast kinetics (i.e. 1 min in vitro and 10 min in vivo after insulin treatment), indicating that NCoR1 phosphorylation directly alters protein functions of NCoR1 most likely already before LXRalpha activation is initiated by ligand binding.	3	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Hepatic insulin resistance , characterized by a defect in insulin induced PI3K-Akt signal transduction , rapidly develops within 90 minutes following T-HS XREF_BIBR , but may have been alleviated within 48 hours post-T-HS in the present study .	Hepatic insulin resistance, characterized by a defect in insulin induced PI3K-Akt signal transduction, rapidly develops within 90 minutes following T-HS XREF_BIBR, but may have been alleviated within 48 hours post-T-HS in the present study.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	9	10	11	12
Interestingly , insulin stimulated Akt and eNOS signaling was increased only by normalizing the glucose concentration in human umbilical vein endothelial cells ( HUVECs ) with GRK2 overexpression , suggesting of an important role of hepatic GRK2 .	Interestingly, insulin stimulated Akt and eNOS signaling was increased only by normalizing the glucose concentration in human umbilical vein endothelial cells (HUVECs) with GRK2 overexpression, suggesting of an important role of hepatic GRK2.	2	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
The insulin induced Akt activity promotes cardiac hypertrophy [ XREF_BIBR , XREF_BIBR ] .	The insulin induced Akt activity promotes cardiac hypertrophy [XREF_BIBR, XREF_BIBR].	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
It has been suggested that elevated insulin activated PI3K and Akt pathway which stimulated NADPH oxidase depended superoxide production through the phosphorylation and translocation of its p47phos component from the cytosol to the membrane .	It has been suggested that elevated insulin activated PI3K and Akt pathway which stimulated NADPH oxidase depended superoxide production through the phosphorylation and translocation of its p47phos component from the cytosol to the membrane.	5	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	10	11
Downstream mediators of insulin induced Akt activation in muscle , liver , and adipose tissue were investigated in the PNS , including GSK3beta inhibition ( glycogen synthesis ) , activation of mTor ( protein synthesis ) , and activation of AS160 ( glucose uptake ) .	Downstream mediators of insulin induced Akt activation in muscle, liver, and adipose tissue were investigated in the PNS, including GSK3beta inhibition (glycogen synthesis), activation of mTor (protein synthesis), and activation of AS160 (glucose uptake).	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
Downstream insulin activation of Akt on the residue Ser473 was also impaired ( change insulin minus baseline -31 % , P < 0.05 ) during ATGL overexpression .	Downstream insulin activation of Akt on the residue Ser473 was also impaired (change insulin minus baseline -31%, P < 0.05) during ATGL overexpression.	1	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	4	5
Furthermore , an interfering mutant of PKB , which blocks insulin induced PKB activation and GSK-3beta inactivation , has no effect on S6K1 activation .	Furthermore, an interfering mutant of PKB, which blocks insulin induced PKB activation and GSK-3beta inactivation, has no effect on S6K1 activation.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	10	11	12	13
Glucose tolerance tests confirmed that the quercetin fed obese mice were more glucose tolerant , and activation of the insulin signaling molecules Akt in liver , muscle , and adipose tissue was stimulated .	Glucose tolerance tests confirmed that the quercetin fed obese mice were more glucose tolerant, and activation of the insulin signaling molecules Akt in liver, muscle, and adipose tissue was stimulated.	16	30	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	22	23
Insulin is a potent activator of PKB .	Insulin is a potent activator of PKB.	0	7	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	6	7
We further performed a Western blot analysis to measure the expression of several proteins that are involved in the insulin mediated PI3K-Akt signaling pathway in the uterus after metformin treatment ( XREF_FIG ) .	We further performed a Western blot analysis to measure the expression of several proteins that are involved in the insulin mediated PI3K-Akt signaling pathway in the uterus after metformin treatment (XREF_FIG).	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	19	20	21	22
The PI-3-kinase inhibitor wortmannin , could abolish glucose uptake as well as PKB activation elicited by both insulin and isoproterenol .	The PI-3-kinase inhibitor wortmannin, could abolish glucose uptake as well as PKB activation elicited by both insulin and isoproterenol.	12	19	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	17	18	12	13
A weaker Akt activation by insulin detemir compared to human insulin was found in non malignant cells , and in non malignant fibroblasts expressing insulin receptor B isoform [ XREF_BIBR ] .	A weaker Akt activation by insulin detemir compared to human insulin was found in non malignant cells, and in non malignant fibroblasts expressing insulin receptor B isoform [XREF_BIBR].	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	2	3
Thus , we assessed insulin ' s ability to stimulate phosphorylation of AKT , as a measure for insulin stimulated AKT activation in vivo .	Thus, we assessed insulin 's ability to stimulate phosphorylation of AKT, as a measure for insulin stimulated AKT activation in vivo.	16	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	18	19	20	21
Thus , insulin activation of Akt isoforms is normal in muscle of obese nondiabetic and obese diabetic subjects , despite decreases of approximately 50 % and 39 % in IRS-1- and IRS-2-associated PI 3-kinase activity , respectively , in obese diabetic subjects .	Thus, insulin activation of Akt isoforms is normal in muscle of obese nondiabetic and obese diabetic subjects, despite decreases of approximately 50% and 39% in IRS-1- and IRS-2-associated PI 3-kinase activity, respectively, in obese diabetic subjects.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	5	6
The adaptor protein APPL1 potentiates insulin stimulated Akt activation and downstream actions .	The adaptor protein APPL1 potentiates insulin stimulated Akt activation and downstream actions.	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Similar to the glucose uptake pattern , insulin stimulated Akt ( P < 0.05 ) and AS160 ( P < 0.06 ) phosphorylation were higher in soleus muscles from HCR compared with LCR ( XREF_FIG and XREF_FIG ) .	Similar to the glucose uptake pattern, insulin stimulated Akt (P < 0.05) and AS160 (P < 0.06) phosphorylation were higher in soleus muscles from HCR compared with LCR (XREF_FIG and XREF_FIG).	5	16	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
In vivo insulin signalling in skeletal muscle of patients harbouring the Arg1174Gln mutation is surprisingly intact , with modest impairments in insulin stimulated activity of Akt and glycogen synthase explaining the moderate degree of insulin resistance .	In vivo insulin signalling in skeletal muscle of patients harbouring the Arg1174Gln mutation is surprisingly intact, with modest impairments in insulin stimulated activity of Akt and glycogen synthase explaining the moderate degree of insulin resistance.	19	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	25	26
Insulin induced PI3K-Akt , SPAK and JNK , and p38 signal activation was detected by western blot analysis ( XREF_FIG B-D ) .	Insulin induced PI3K-Akt, SPAK and JNK, and p38 signal activation was detected by western blot analysis (XREF_FIG B-D).	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	2	3
We already knew from our studies ( XREF_FIG ) that insulin stimulated the PI3K and Akt pathway in chicks without lenses , as well as in chicks with positive lenses , and with negative lenses .	We already knew from our studies (XREF_FIG) that insulin stimulated the PI3K and Akt pathway in chicks without lenses, as well as in chicks with positive lenses, and with negative lenses.	10	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	15	16
Adipocytes from female mice have increased insulin stimulation of Akt and extracellular signal related kinase .	Adipocytes from female mice have increased insulin stimulation of Akt and extracellular signal related kinase.	6	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	9	10
Interestingly , pretreatment with SR141716 ( 100 nmol/l ) for 24 h significantly enhances both insulin stimulated PKB and ERK activity ( XREF_FIG ) , with an approximately twofold and threefold greater stimulation observed , respectively .	Interestingly, pretreatment with SR141716 (100 nmol/l) for 24 h significantly enhances both insulin stimulated PKB and ERK activity (XREF_FIG), with an approximately twofold and threefold greater stimulation observed, respectively.	13	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	15	16	17	18
Insulin administration also increased the p-AKT and total AKT ratio in liver extracts but , in this case , there was no difference in the ratio between VDR L/L and VDR L/L -Tie-2Cre + mice .	Insulin administration also increased the p-AKT and total AKT ratio in liver extracts but, in this case, there was no difference in the ratio between VDR L/L and VDR L/L -Tie-2Cre + mice.	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	8	9
This result can be explained by the fact that simultaneously to a stimulation of AMPK phosphorylation , CA decreases insulin stimulated Akt activation .	This result can be explained by the fact that simultaneously to a stimulation of AMPK phosphorylation, CA decreases insulin stimulated Akt activation.	18	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
Sepsis induced insulin resistance can also occur by induction of iNOS activity , probably by impairing insulin stimulated phosphatidylinositol 3-kinase ( PI 3-kinase ) and PKB activation , resulting in a decline in insulin stimulated-glucose uptake .	Sepsis induced insulin resistance can also occur by induction of iNOS activity, probably by impairing insulin stimulated phosphatidylinositol 3-kinase (PI 3-kinase) and PKB activation, resulting in a decline in insulin stimulated-glucose uptake.	16	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	16	17	25	26
Insulin Stimulated Akt Activation Is Blunted in DRG Neurons from Diabetic Mice .	Insulin Stimulated Akt Activation Is Blunted in DRG Neurons from Diabetic Mice.	0	3	Stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Intriguingly , CLA isomers sensitized insulin-Akt-responsive glucose uptake and prevented high insulin induced Akt desensitisation .	Intriguingly, CLA isomers sensitized insulin-Akt-responsive glucose uptake and prevented high insulin induced Akt desensitisation.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Akt induced by insulin signaling is also critical to the regulation of gluconeogenesis and glycolysis in the liver .	Akt induced by insulin signaling is also critical to the regulation of gluconeogenesis and glycolysis in the liver.	0	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	0	1
We used our previous computational model for the activation of AKT by insulin and slightly modified the parameters to fit the experimental data obtained in this study ( XREF_SUPPLEMENTARY , see Materials and methods ) .	We used our previous computational model for the activation of AKT by insulin and slightly modified the parameters to fit the experimental data obtained in this study (XREF_SUPPLEMENTARY, see Materials and methods).	1	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	10	11
The inactivation of GAPs such as the As160 through the insulin stimulated PI3K and Akt cascade results in the accumulation of RabGTP ' s and ultimately GLUT4 translocation .	The inactivation of GAPs such as the As160 through the insulin stimulated PI3K and Akt cascade results in the accumulation of RabGTP 's and ultimately GLUT4 translocation.	7	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	14	15
In addition , the insulin mediated activation of AKT , a measure of PI 3-kinase activity , was completely abolished in the presence of AICAR .	In addition, the insulin mediated activation of AKT, a measure of PI 3-kinase activity, was completely abolished in the presence of AICAR.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	8	9
A recent study has evidenced that host insulin activates E. multilocularis PI3K and AKT signaling pathways and stimulates germinative cell proliferation and larval development [ XREF_BIBR ] .	A recent study has evidenced that host insulin activates E. multilocularis PI3K and AKT signaling pathways and stimulates germinative cell proliferation and larval development [XREF_BIBR].	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	13	14
Extending these findings , in primary cultures of human skeletal muscle , cortisone ( 250 nmol/l , 24 h ) decreased insulin stimulated pThr 308 Akt and PKB without altering total Akt and PKB protein expression .	Extending these findings, in primary cultures of human skeletal muscle, cortisone (250 nmol/l, 24 h) decreased insulin stimulated pThr 308 Akt and PKB without altering total Akt and PKB protein expression.	20	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	25	26
Addition of NF-kappaB inhibitor BAY11 improved insulin stimulated AKT phosphorylation in the presence of TNF-alpha to 97 % of the insulin stimulated AKT ( XREF_FIG ) .	Addition of NF-kappaB inhibitor BAY11 improved insulin stimulated AKT phosphorylation in the presence of TNF-alpha to 97% of the insulin stimulated AKT (XREF_FIG).	17	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	22	23
Elevated Elvol6 may lead to accumulation of stearate ( 18:0 ) , a pro inflammatory saturated fatty acid [ XREF_BIBR ] and blocked insulin stimulated activation of AKT , thus impairing insulin signaling [ XREF_BIBR ] .	Elevated Elvol6 may lead to accumulation of stearate (18:0), a pro inflammatory saturated fatty acid [XREF_BIBR] and blocked insulin stimulated activation of AKT, thus impairing insulin signaling [XREF_BIBR].	22	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	23	24	27	28
Akt is activated by insulin or IGF1 signaling and is known to promote physiological CM hypertrophy [ XREF_BIBR - XREF_BIBR ] , suggesting that dynamic culture improves delivery of serum derived nutrients and growth factors to cells in engineered tissues .	Akt is activated by insulin or IGF1 signaling and is known to promote physiological CM hypertrophy [XREF_BIBR - XREF_BIBR], suggesting that dynamic culture improves delivery of serum derived nutrients and growth factors to cells in engineered tissues.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
Both the experimental data and simulations showed that the activation of the Ras and ERK and PI3K and AKT pathways by persistent EGF or insulin stimulation was transient ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Both the experimental data and simulations showed that the activation of the Ras and ERK and PI3K and AKT pathways by persistent EGF or insulin stimulation was transient (XREF_FIG and XREF_SUPPLEMENTARY).	9	25	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	24	25	18	19
Calphostin C treatment greatly enhanced insulin stimulated Akt activation in ATGL overexpressing myotubes ( +163 % , P < 0.01 compared with GFP with calphostin C ) ( XREF_FIG ) .	Calphostin C treatment greatly enhanced insulin stimulated Akt activation in ATGL overexpressing myotubes (+163%, P < 0.01 compared with GFP with calphostin C) (XREF_FIG).	4	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
The most consistent CR-effect on insulin signaling in skeletal muscle is greater insulin mediated activation of Akt , and we recently reported this CR-effect in epitrochlearis and soleus muscles from 24 month-old rats .	The most consistent CR-effect on insulin signaling in skeletal muscle is greater insulin mediated activation of Akt, and we recently reported this CR-effect in epitrochlearis and soleus muscles from 24 month-old rats.	11	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	16	17
APPL1 exerts opposite effects on insulin induced Akt and eNOS and ERK1/2 MAPK signaling cascades in cultured human endothelial cells .	APPL1 exerts opposite effects on insulin induced Akt and eNOS and ERK1/2 MAPK signaling cascades in cultured human endothelial cells.	3	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
It has been well known that hyperglycemia and insulin could modulate Akt activity in diabetic renal tissue [ XREF_BIBR - XREF_BIBR ] .	It has been well known that hyperglycemia and insulin could modulate Akt activity in diabetic renal tissue [XREF_BIBR - XREF_BIBR].	6	12	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	11	12
Insulin is able to stimulate mTORC complex , Akt kinase , JAK and STAT pathway , and many others .	Insulin is able to stimulate mTORC complex, Akt kinase, JAK and STAT pathway, and many others.	0	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	8	9
Hyperglycemia and insulin have been shown to modulate Akt activity in diabetic renal tissue XREF_BIBR , XREF_BIBR , XREF_BIBR .	Hyperglycemia and insulin have been shown to modulate Akt activity in diabetic renal tissue XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	9	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	8	9
Blood pressure , mesenteric arteriolar vasorelaxation , G protein coupled receptor kinase-2 ( GRK2 ) expression and activity , and insulin stimulated Akt and endothelial nitric oxide synthase ( eNOS ) activation were determined .	Blood pressure, mesenteric arteriolar vasorelaxation, G protein coupled receptor kinase-2 (GRK2) expression and activity, and insulin stimulated Akt and endothelial nitric oxide synthase (eNOS) activation were determined.	9	33	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	expression and activity, and insulin	insulin	Akt	Akt	akt	20	21	22	23
The PI3K and Akt signaling is activated by insulin [ XREF_BIBR ] .	The PI3K and Akt signaling is activated by insulin [XREF_BIBR].	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	3	4
In response to a postprandial like dose of 1nM insulin , a 1.7-fold increase in pAKT and AKT ( P < 0.05 ) was observed , while 100nM of insulin elicited an 8-fold increase in pAKT and AKT ( P < 0.0001 ; Fig .	In response to a postprandial like dose of 1nM insulin, a 1.7-fold increase in pAKT and AKT (P < 0.05) was observed, while 100nM of insulin elicited an 8-fold increase in pAKT and AKT (P < 0.0001; Fig.	27	43	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	29	30	37	38
Thus , AKT action is fairly low , for example , as matched to insulin induced AKT activity , the Ral and JNK signaling pathway acts in a conflicting manner .	Thus, AKT action is fairly low, for example, as matched to insulin induced AKT activity, the Ral and JNK signaling pathway acts in a conflicting manner.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	14	15	16	17
Expression of active mTOR paralleled Akt activity in D-0 (-51% , p < 0.01 vs. C ) , but not in D-4 and D-12 that demonstrated increases in active mTOR ( +55 % , +80 % resp ., p < 0.05 ) as compared to C. Moreover , insulin activated renal Akt ( +82 % , p < 0.01 ) , but not mTOR in C4 .	Expression of active mTOR paralleled Akt activity in D-0 (-51%, p < 0.01 vs. C), but not in D-4 and D-12 that demonstrated increases in active mTOR (+55%, +80% resp., p < 0.05) as compared to C. Moreover, insulin activated renal Akt (+82%, p < 0.01), but not mTOR in C4.	48	54	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	48	49	51	52
Fatty acid exposure decreased values for IRS-1 serine 312 phosphorylation as well as insulin stimulation of IRS-1 and Akt in cells from lean controls to values approximating those in myotubes from severely obese subjects ( XREF_FIG ) .	Fatty acid exposure decreased values for IRS-1 serine 312 phosphorylation as well as insulin stimulation of IRS-1 and Akt in cells from lean controls to values approximating those in myotubes from severely obese subjects (XREF_FIG).	13	19	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	18	19
Although Stz also failed to inhibit bFGF induced ERK activation and insulin induced Akt activation ( data not shown ) , both activation of caspase-3 and an increase of caspase-3 activity were detected ( XREF_FIG ) .	Although Stz also failed to inhibit bFGF induced ERK activation and insulin induced Akt activation (data not shown), both activation of caspase-3 and an increase of caspase-3 activity were detected (XREF_FIG).	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Insulin treatment caused sustained Akt activity , whereas EGF or PDGF-AA promoted transient signaling ; PDGF-BB produced sustained responses at higher concentrations , but short-term effects at low doses , actions that were independent of the PDGF-alpha receptor .	Insulin treatment caused sustained Akt activity, whereas EGF or PDGF-AA promoted transient signaling; PDGF-BB produced sustained responses at higher concentrations, but short-term effects at low doses, actions that were independent of the PDGF-alpha receptor.	0	5	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
Although hypothalamic activation of PKB by insulin has been reported previously [ XREF_BIBR ] , these are the first reports that leptin increases PKB activity and that both hormones increase the phosphorylation of GSK3 in the ARC .	Although hypothalamic activation of PKB by insulin has been reported previously [XREF_BIBR], these are the first reports that leptin increases PKB activity and that both hormones increase the phosphorylation of GSK3 in the ARC.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	6	7	4	5
Finally , through in vivo experiments , we found that chronic resistance training ( RT ) increased APPL1 expression and activated insulin induced Akt signaling in skeletal muscles of rats with T2D .	Finally, through in vivo experiments, we found that chronic resistance training (RT) increased APPL1 expression and activated insulin induced Akt signaling in skeletal muscles of rats with T2D.	18	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	23	24
The data demonstrated that lipoprotein lipase derived lipids modulated insulin signaling pathways , particularly basal and insulin stimulated Akt activation .	The data demonstrated that lipoprotein lipase derived lipids modulated insulin signaling pathways, particularly basal and insulin stimulated Akt activation.	9	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	18	19
Furthermore , insulin induced Akt activation in the skeletal muscle , liver and adipose tissue was blunted in the calorie restricted Bbs4 -/- mice relative to controls ( XREF_FIG ) .	Furthermore, insulin induced Akt activation in the skeletal muscle, liver and adipose tissue was blunted in the calorie restricted Bbs4 -/- mice relative to controls (XREF_FIG).	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
Our data indicate that insulin activation of Akt in myocytes is mediated mainly by p110alpha .	Our data indicate that insulin activation of Akt in myocytes is mediated mainly by p110alpha.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	7	8
We found that while insulin primarily activated Akt , FGF primarily activated Erk ( XREF_FIG ) .	We found that while insulin primarily activated Akt, FGF primarily activated Erk (XREF_FIG).	4	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	7	8
miR-214-Dependent Increase of PHLPP2 Levels Mediates the Impairment of Insulin Stimulated Akt Activation in Mouse Aortic Endothelial Cells Exposed to Methylglyoxal .	miR-214-Dependent Increase of PHLPP2 Levels Mediates the Impairment of Insulin Stimulated Akt Activation in Mouse Aortic Endothelial Cells Exposed to Methylglyoxal.	9	12	Stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	9	10	11	12
XREF_BIBR FoxO1 contains multiple phosphorylation sites including threonine 32 , serine 256 and serine 319 that become phosphorylated in response to insulin stimulated Akt .	XREF_BIBR FoxO1 contains multiple phosphorylation sites including threonine 32, serine 256 and serine 319 that become phosphorylated in response to insulin stimulated Akt.	17	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	23	24
Activation of the PI3K and Akt signaling pathway induced by insulin not only inhibits cardiomyocyte apoptosis but also substantially preserves and even improves regional and overall cardiac function .	Activation of the PI3K and Akt signaling pathway induced by insulin not only inhibits cardiomyocyte apoptosis but also substantially preserves and even improves regional and overall cardiac function.	5	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	5	6
Moreover , insulin is well known to activate the Akt and GSK-3beta signaling pathway and thus inhibits the activity of GSK-3beta XREF_BIBR , XREF_BIBR .	Moreover, insulin is well known to activate the Akt and GSK-3beta signaling pathway and thus inhibits the activity of GSK-3beta XREF_BIBR, XREF_BIBR.	2	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	9	10
These results support the conclusion that IRS-1 is important for insulin dependent activation of Akt signaling within the lactating mammary gland , but that loss of this protein has only modest impact on normal milk synthesis , since related signaling proteins such as IRS-2 may act in compensatory fashion .	These results support the conclusion that IRS-1 is important for insulin dependent activation of Akt signaling within the lactating mammary gland, but that loss of this protein has only modest impact on normal milk synthesis, since related signaling proteins such as IRS-2 may act in compensatory fashion.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	14	15
PQIP inhibited IGF-I and insulin induced Akt signaling .	PQIP inhibited IGF-I and insulin induced Akt signaling.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Interestingly , our current results indicate that C21 increases insulin stimulated activation of Akt and simultaneously inhibits insulin stimulated ERK1/2 activation in adipose tissue .	Interestingly, our current results indicate that C21 increases insulin stimulated activation of Akt and simultaneously inhibits insulin stimulated ERK1/2 activation in adipose tissue.	7	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	13	14
These results are similar to those reported in other cells with a few other GPCRs , such as the slow inhibition of Akt activation by norepinephrine activating adrenergic receptors in rat adrenal PC12 cells [ XREF_BIBR ] , the inhibition of insulin stimulated Akt activity by angiotensin in vascular smooth muscle cells [ XREF_BIBR ] or ability of dopamine D2/D3 receptor activation to cause inhibition of Akt phosphorylation in striatal tissue [ XREF_BIBR ] .	These results are similar to those reported in other cells with a few other GPCRs, such as the slow inhibition of Akt activation by norepinephrine activating adrenergic receptors in rat adrenal PC12 cells [XREF_BIBR], the inhibition of insulin stimulated Akt activity by angiotensin in vascular smooth muscle cells [XREF_BIBR] or ability of dopamine D2/D3 receptor activation to cause inhibition of Akt phosphorylation in striatal tissue [XREF_BIBR].	39	44	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	41	42	43	44
Insulin activation of Akt is essential for the regulation of cellular glucose uptake .	Insulin activation of Akt is essential for the regulation of cellular glucose uptake.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
To gain insight into the mechanism by which systemic glucose tolerance is improved in chow and HF diet fed macroH2A1.2 Tg mice , we characterized insulin induced AKT signaling in the skeletal muscle , liver and adipose tissues under insulin stimulated conditions ( 0.75Ukg-1 body weight , injected 15min before killing ) ( Additional file 3 : Figure S2 ) .	To gain insight into the mechanism by which systemic glucose tolerance is improved in chow and HF diet fed macroH2A1.2 Tg mice, we characterized insulin induced AKT signaling in the skeletal muscle, liver and adipose tissues under insulin stimulated conditions (0.75Ukg-1 body weight, injected 15min before killing) (Additional file 3 : Figure S2).	25	28	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	25	26	27	28
Both enhance insulin stimulated Akt activation but APS seems to cause greater activation .	Both enhance insulin stimulated Akt activation but APS seems to cause greater activation.	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
This phosphorylation was the reason why insulin failed to activate AKT in TSC2 deficient cells XREF_BIBR .	This phosphorylation was the reason why insulin failed to activate AKT in TSC2 deficient cells XREF_BIBR.	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	10	11
[ XREF_BIBR ] In the present study , we demonstrated that the MTs siRNA pretreatment activated Akt proteins induced by insulin treatment in 3T3-L1 preadipocytes ( XREF_FIG ) , and 3T3-L1 adipocytes with lipid droplets increased by MTs siRNA were suppressed by the PI3K inhibitor LY294002 ( XREF_FIG ) .	[XREF_BIBR] In the present study, we demonstrated that the MTs siRNA pretreatment activated Akt proteins induced by insulin treatment in 3T3-L1 preadipocytes (XREF_FIG), and 3T3-L1 adipocytes with lipid droplets increased by MTs siRNA were suppressed by the PI3K inhibitor LY294002 (XREF_FIG).	16	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	16	17
Insulin activates the PI3-K and Akt signalling , which stimulates glucose transport in adipose and muscle cells ( Grinspoon , 2001 ) .	Insulin activates the PI3-K and Akt signalling, which stimulates glucose transport in adipose and muscle cells (Grinspoon, 2001).	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
At first thought , this finding seems paradoxical because insulin simultaneously stimulates both PI3K and Akt and MEK and ERK signaling acutely .	At first thought, this finding seems paradoxical because insulin simultaneously stimulates both PI3K and Akt and MEK and ERK signaling acutely.	9	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	15	16
Second , at the ligand level , PI3K-C2beta inactivation increased insulin induced Akt signaling in hepatocytes , without altering EGF- or IGF mediated Akt signaling .	Second, at the ligand level, PI3K-C2beta inactivation increased insulin induced Akt signaling in hepatocytes, without altering EGF- or IGF mediated Akt signaling.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
To determine effects of iron overload on insulin response , we monitored insulin stimulated phospho activation of PKB .	To determine effects of iron overload on insulin response, we monitored insulin stimulated phospho activation of PKB.	11	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	12	13	17	18
Both platelet derived growth factor ( PDGF ) and insulin induced activation of Akt in BAECs , but only insulin caused HSP90-Akt-eNOS association and eNOS phosphorylation .	Both platelet derived growth factor (PDGF) and insulin induced activation of Akt in BAECs, but only insulin caused HSP90-Akt-eNOS association and eNOS phosphorylation.	2	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	13	14
However , we did not find any correlation between HOMA IR and insulin stimulated fold induction of P-Akt and Akt in SAT .	However, we did not find any correlation between HOMA IR and insulin stimulated fold induction of P-Akt and Akt in SAT.	12	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	P-Akt	P-Akt	P-Akt	12	13	17	18
Hyperinsulinemia was present , however , and the ability of insulin to increase myocardial glucose uptake and the translocation of GLUT4 was impaired , despite normal insulin mediated activation of Akt and protein kinase B ( PKB ) [ XREF_BIBR ] .	Hyperinsulinemia was present, however, and the ability of insulin to increase myocardial glucose uptake and the translocation of GLUT4 was impaired, despite normal insulin mediated activation of Akt and protein kinase B (PKB) [XREF_BIBR].	26	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	30	31
For example , the insulin signaling pathway that regulate individual development begin with the binding of insulin to insulin receptors , and thus trigger a series of intracellular signal transduction , ultimately playing a role after reaching the organ ; the PI3K-Akt signaling pathway is activated by many kinds of cellular stimuli or toxic insults activate the PI3k-Akt signaling pathway which is a regulator for fundamental cellular function including transcription , translation , proliferation , growth and survival .	For example, the insulin signaling pathway that regulate individual development begin with the binding of insulin to insulin receptors, and thus trigger a series of intracellular signal transduction, ultimately playing a role after reaching the organ; the PI3K-Akt signaling pathway is activated by many kinds of cellular stimuli or toxic insults activate the PI3k-Akt signaling pathway which is a regulator for fundamental cellular function including transcription, translation, proliferation, growth and survival.	4	59	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3k-Akt	PI3k-Akt	PI3k-Akt	4	5	57	58
In the current study , the most important question was whether GRK2 negatively controlled the insulin induced Akt and eNOS pathway in aortas from diabetic mice with hyperinsulinemia .	In the current study, the most important question was whether GRK2 negatively controlled the insulin induced Akt and eNOS pathway in aortas from diabetic mice with hyperinsulinemia.	14	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
As shown in XREF_FIG C , resveratrol treatment downregulated PTP1B in IRS2 -/- hepatocytes and , therefore , insulin induced Akt and Foxo1 phosphorylation were restored .	As shown in XREF_FIG C, resveratrol treatment downregulated PTP1B in IRS2 -/- hepatocytes and, therefore, insulin induced Akt and Foxo1 phosphorylation were restored.	18	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	20	21
Because fatty acids modulate insulin stimulated Akt signaling cascades in smooth muscle cells , we hypothesized that fatty acids would differentially regulate endothelial Akt signaling , eNOS phosphorylation , and NO production .	Because fatty acids modulate insulin stimulated Akt signaling cascades in smooth muscle cells, we hypothesized that fatty acids would differentially regulate endothelial Akt signaling, eNOS phosphorylation, and NO production.	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
In summary , both in vivo and in vitro evidence from the current study support a key role of APPL1 in modulating the vascular actions of insulin by controlling the balance between insulin induced Akt dependent NO production and ERK1/2 MAPK dependent ET-1 expression in endothelial cells ( XREF_FIG ) .	In summary, both in vivo and in vitro evidence from the current study support a key role of APPL1 in modulating the vascular actions of insulin by controlling the balance between insulin induced Akt dependent NO production and ERK1/2 MAPK dependent ET-1 expression in endothelial cells (XREF_FIG).	30	35	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	32	33	34	35
Insulin has been shown to activate the PI3K and Akt pathway leading to phosphorylation and activation of endothelial nitric oxide synthase ( eNOS ) and NO production [ XREF_BIBR , XREF_BIBR ] .	Insulin has been shown to activate the PI3K and Akt pathway leading to phosphorylation and activation of endothelial nitric oxide synthase (eNOS) and NO production [XREF_BIBR, XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	9	10
After 1 day of adrenaline infusion , glycogen content was reduced in both muscles ; insulin stimulated PKB ser ( 473 ) phosphorylation was increased in both muscles only at the highest insulin concentration .	After 1 day of adrenaline infusion, glycogen content was reduced in both muscles; insulin stimulated PKB ser (473) phosphorylation was increased in both muscles only at the highest insulin concentration.	15	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	15	16	17	18
After HFD feeding , insulin stimulated activation ( phosphorylation ) of Akt and GSK-3alpha in was significantly reduced in muscle to SD fed mice ( XREF_SUPPLEMENTARY ) .	After HFD feeding, insulin stimulated activation (phosphorylation) of Akt and GSK-3alpha in was significantly reduced in muscle to SD fed mice (XREF_SUPPLEMENTARY).	4	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	11	12
Nevertheless , fructose supplemented rats display an abnormal GTT and an impairment of insulin signaling in the three major insulin responsive tissues : in vWAT and liver , where fructose inhibits insulin induced Akt phosphorylation , and in skeletal muscle , where Akt is correctly activated by insulin but GLUT4 expression in the plasma membrane is reduced .	Nevertheless, fructose supplemented rats display an abnormal GTT and an impairment of insulin signaling in the three major insulin responsive tissues : in vWAT and liver, where fructose inhibits insulin induced Akt phosphorylation, and in skeletal muscle, where Akt is correctly activated by insulin but GLUT4 expression in the plasma membrane is reduced.	42	48	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	47	48	42	43
Insulin activates two main signaling pathways in its target tissues : the PI3K and Akt and the RAS-MAPK pathways .	Insulin activates two main signaling pathways in its target tissues : the PI3K and Akt and the RAS-MAPK pathways.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	14	15
The activation of Akt by insulin leads to downstream activation of the mammalian target of rapamycin ( mTOR ) and therefore we examined mTOR phosphorylation as an indicator of Akt activation .	The activation of Akt by insulin leads to downstream activation of the mammalian target of rapamycin (mTOR) and therefore we examined mTOR phosphorylation as an indicator of Akt activation.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	3	4
The high concentration of insulin in N2 has been shown to activate Akt mediated survival pathways through the IGF-1 receptor , which is known to promote OL survival and proliferation .	The high concentration of insulin in N2 has been shown to activate Akt mediated survival pathways through the IGF-1 receptor, which is known to promote OL survival and proliferation.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	12	13
In malignant cells , Akt activation by insulin detemir was weaker than that by human insulin .	In malignant cells, Akt activation by insulin detemir was weaker than that by human insulin.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	4	5
However , high fructose treatment diminishes insulin induced activation of Akt , S6 ( a downstream target of mTOR ) , and ERK in VSMCs ( present study ) .	However, high fructose treatment diminishes insulin induced activation of Akt, S6 (a downstream target of mTOR), and ERK in VSMCs (present study).	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	10	11
Insulin stimulated Akt and phosphatase and tensin homologue deleted on chromosome 10 ( PTEN ) activities in the liver were similar in p85alpha deficient and wild-type mice .	Insulin stimulated Akt and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activities in the liver were similar in p85alpha deficient and wild-type mice.	0	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
A new study shows that , without AKT-FoxO1 signaling , insulin still contributes to postprandial responses , revealing an AKT independent pathway for insulin action that might be exploited to treat metabolic disease ( pages 388-395 ) .	A new study shows that, without AKT-FoxO1 signaling, insulin still contributes to postprandial responses, revealing an AKT independent pathway for insulin action that might be exploited to treat metabolic disease (pages 388-395).	10	21	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	19	20
In addition to the transcriptional regulation of enzyme availability , insulin mediated activation of AKT impinges upon DNL through AMPK inhibition , resulting in dephosphorylation and activation of the Acetyl-CoA carboxylase ( ACC ) XREF_BIBR .	In addition to the transcriptional regulation of enzyme availability, insulin mediated activation of AKT impinges upon DNL through AMPK inhibition, resulting in dephosphorylation and activation of the Acetyl-CoA carboxylase (ACC) XREF_BIBR.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	14	15
In order to verify whether insulin induced AKT activation affects beta-catenin mRNA stabilization , we used insulin receptor overexpressing HIRc-B rat cells , which display strong responses to insulin [ XREF_BIBR , XREF_BIBR ] .	In order to verify whether insulin induced AKT activation affects beta-catenin mRNA stabilization, we used insulin receptor overexpressing HIRc-B rat cells, which display strong responses to insulin [XREF_BIBR, XREF_BIBR].	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
Consistent with these observations , analysis of insulin stimulated AKT phosphorylation in skeletal muscle and liver of control and JNK SM-C mice revealed that JNK overactivation in skeletal muscle did neither affect insulin stimulated AKT activation in muscle nor in liver ( XREF_FIG ) .	Consistent with these observations, analysis of insulin stimulated AKT phosphorylation in skeletal muscle and liver of control and JNK SM-C mice revealed that JNK overactivation in skeletal muscle did neither affect insulin stimulated AKT activation in muscle nor in liver (XREF_FIG).	31	35	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	32	33	34	35
The P-Akt and Akt and P-AS160 and AS160 ratios were increased by insulin during the clamp in muscle from both WT and SIRT3 KO HF fed mice , with no difference between genotypes ( XREF_FIG ) .	The P-Akt and Akt and P-AS160 and AS160 ratios were increased by insulin during the clamp in muscle from both WT and SIRT3 KO HF fed mice, with no difference between genotypes (XREF_FIG).	1	13	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	3	4
Similarly , pretreatment with ionomycin led to the inhibition of insulin stimulated membrane localization of endogenous Akt in CHO-IR cells ( XREF_SUPPLEMENTARY ) , suggesting that intracellular Ca 2+ overload prevents membrane translocation of Akt , potentially by inhibiting PH domain interactions with PI ( 3,4 ) P 2 or PI ( 3,4,5 ) P 3 .	Similarly, pretreatment with ionomycin led to the inhibition of insulin stimulated membrane localization of endogenous Akt in CHO-IR cells (XREF_SUPPLEMENTARY), suggesting that intracellular Ca 2+ overload prevents membrane translocation of Akt, potentially by inhibiting PH domain interactions with PI (3,4) P 2 or PI (3,4,5) P 3.	8	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	16	17
First , we demonstrated that the insulin activated Akt in HepG2 cells , measured as Akt phosphorylation , in a dose dependent manner ( XREF_FIG , left panel ) .	First, we demonstrated that the insulin activated Akt in HepG2 cells, measured as Akt phosphorylation, in a dose dependent manner (XREF_FIG, left panel).	5	26	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
These parallel defects in insulin stimulated Akt kinase activity and glucose transport in diabetic skeletal muscle suggest that reduced Akt kinase activity may play a role in the development of insulin resistance in NIDDM .	These parallel defects in insulin stimulated Akt kinase activity and glucose transport in diabetic skeletal muscle suggest that reduced Akt kinase activity may play a role in the development of insulin resistance in NIDDM.	2	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
The PI3K and Akt pathway is activated by insulin and growth factors to promote cell growth , differentiation and survival [ XREF_BIBR ] .	The PI3K and Akt pathway is activated by insulin and growth factors to promote cell growth, differentiation and survival [XREF_BIBR].	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	3	4
IGF-II and insulin each induced a significant increase in Akt activation that was unaffected when IR-B was silenced .	IGF-II and insulin each induced a significant increase in Akt activation that was unaffected when IR-B was silenced.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	9	10
PDK1 is likely to mediate the activation of PKB by insulin or growth factors .	PDK1 is likely to mediate the activation of PKB by insulin or growth factors.	6	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	10	11	8	9
Aripiprazole and clozapine ( but not olanzapine ) inhibited insulin stimulated AKT , suggesting impaired hypothalamic insulin action by some , but not all , APs .	Aripiprazole and clozapine (but not olanzapine) inhibited insulin stimulated AKT, suggesting impaired hypothalamic insulin action by some, but not all, APs.	8	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	11	12
Pretreatment of insulin , a potent stimulator of AKT kinase , partially reversed the inhibition of AKT kinase by sphingosine and counteracted the apoptotic action of this sphingolipid .	Pretreatment of insulin, a potent stimulator of AKT kinase, partially reversed the inhibition of AKT kinase by sphingosine and counteracted the apoptotic action of this sphingolipid.	0	17	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	16	17
Cardiac specific knockout of PDK1 abolishes the activation of AKT by insulin and results in heart failure through reduced cardiomyocyte volume and increased apoptosis .	Cardiac specific knockout of PDK1 abolishes the activation of AKT by insulin and results in heart failure through reduced cardiomyocyte volume and increased apoptosis.	5	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	9	10
In cells given 10uM cantharidin we observed a 40-50 % downregulation of total FoxO1 protein level ( XREF_SUPPLEMENTARY ) similar to what is observed in hepatocytes under conditions of intense insulin stimulated Akt signaling [ XREF_BIBR , XREF_BIBR ] .	In cells given 10uM cantharidin we observed a 40-50% downregulation of total FoxO1 protein level (XREF_SUPPLEMENTARY) similar to what is observed in hepatocytes under conditions of intense insulin stimulated Akt signaling [XREF_BIBR, XREF_BIBR].	27	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	30	31	32	33
In addition , insulin activated the downstream signaling pathways ( PI3K and AKT and Ras-Raf-MEK and ERK ) in C4-2 cells .	In addition, insulin activated the downstream signaling pathways (PI3K and AKT and Ras-Raf-MEK and ERK) in C4-2 cells.	3	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	12	13
Indeed , XREF_BIBR show that deletion of p110beta does not affect the ability of insulin to activate Akt in the liver , which supports the results of prior pharmacologic studies showing that p110beta does not play a significant role in insulin stimulated Akt activation .	Indeed, XREF_BIBR show that deletion of p110beta does not affect the ability of insulin to activate Akt in the liver, which supports the results of prior pharmacologic studies showing that p110beta does not play a significant role in insulin stimulated Akt activation.	35	43	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	40	41	42	43
Ataxia telangiectasia mutated ( ATM ) reportedly plays a role in insulin stimulated activation of Akt in some cell types but not others .	Ataxia telangiectasia mutated (ATM) reportedly plays a role in insulin stimulated activation of Akt in some cell types but not others.	9	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	15	16
Furthermore , insulin stimulated PKB Ser ( 473 ) and Thr ( 308 ) and GSK-3beta Ser ( 9 ) phosphorylation were blocked by caffeine and theophylline .	Furthermore, insulin stimulated PKB Ser (473) and Thr (308) and GSK-3beta Ser (9) phosphorylation were blocked by caffeine and theophylline.	2	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	2	3	4	5
Interestingly , insulin injection of wild-type mice , which activates PKB ( protein kinase B ) and inhibits GSK3 to a greater degree than feeding ( 50 % versus 25 % ) , does not repress these genes .	Interestingly, insulin injection of wild-type mice, which activates PKB (protein kinase B) and inhibits GSK3 to a greater degree than feeding (50% versus 25%), does not repress these genes.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	2	3	10	11
Insulin activates the Akt signaling pathway directly through its receptor and indirectly through the production of IGF-1 and its receptor .	Insulin activates the Akt signaling pathway directly through its receptor and indirectly through the production of IGF-1 and its receptor.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
Compromised insulin stimulated PI3K-AKT signaling in liver of Sesn2 -/- mice .	Compromised insulin stimulated PI3K-AKT signaling in liver of Sesn2 -/- mice.	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	1	2	3	4
To examine whether Sestrins , which control AMPK and mTORC1 activity , also modulate insulin induced AKT activation , we examined AKT phosphorylation in livers of Con and Sesn2 -/- mice kept on HFD before and after insulin administration .	To examine whether Sestrins, which control AMPK and mTORC1 activity, also modulate insulin induced AKT activation, we examined AKT phosphorylation in livers of Con and Sesn2 -/- mice kept on HFD before and after insulin administration.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	14	15	16	17
IGF-II more potently activated p70S6K and persistent ERK1/2 phosphorylation , whereas insulin via IR-A resulted in longer Akt activation [ XREF_BIBR ] .	IGF-II more potently activated p70S6K and persistent ERK1/2 phosphorylation, whereas insulin via IR-A resulted in longer Akt activation [XREF_BIBR].	11	19	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	17	18
The phosphorylation and activity of Akt , a major downstream effector of PI 3-kinase , as well as Akt dependent phosphorylation of glycogen synthase kinase-3 and p70S6 kinase were not affected by the lack of IRS-2 ; however , there was a decrease in insulin stimulation of Akt associated with the plasma membrane .	The phosphorylation and activity of Akt, a major downstream effector of PI 3-kinase, as well as Akt dependent phosphorylation of glycogen synthase kinase-3 and p70S6 kinase were not affected by the lack of IRS-2; however, there was a decrease in insulin stimulation of Akt associated with the plasma membrane.	44	48	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	44	45	47	48
Insulin not only promotes vascular relaxation by activating PI3K and Akt and stimulating eNOS activity in vascular cells , but also stimulates vasoconstrictor action by inducing secretion of endothelin-1 ( ET-1 ) , largely via ERK1/2 MAPK activation XREF_BIBR , XREF_BIBR .	Insulin not only promotes vascular relaxation by activating PI3K and Akt and stimulating eNOS activity in vascular cells, but also stimulates vasoconstrictor action by inducing secretion of endothelin-1 (ET-1), largely via ERK1/2 MAPK activation XREF_BIBR, XREF_BIBR.	0	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	10	11
Finally , insulin stimulated phosphorylation of Akt was blunted in fast twitch muscle of mice deficient in ATM XREF_BIBR , and ATM was reportedly required for full activation of Akt by insulin in cultured muscle cells XREF_BIBR .	Finally, insulin stimulated phosphorylation of Akt was blunted in fast twitch muscle of mice deficient in ATM XREF_BIBR, and ATM was reportedly required for full activation of Akt by insulin in cultured muscle cells XREF_BIBR.	24	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	29	30
In the meantime , PI3K and Akt pathway was activated by insulin and suppressed by above agents that caused IR .	In the meantime, PI3K and Akt pathway was activated by insulin and suppressed by above agents that caused IR.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	6	7
However , the authors identified that insulin activated Akt activity was downregulated by miR-29 .	However, the authors identified that insulin activated Akt activity was downregulated by miR-29.	6	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
The pan-PI3K inhibitor LY294002 has been shown to block insulin induced PI3K-Akt and PI3K-S6K activation differently , which are upstream and downstream events of mTOR I.	The pan-PI3K inhibitor LY294002 has been shown to block insulin induced PI3K-Akt and PI3K-S6K activation differently, which are upstream and downstream events of mTOR I.	8	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	9	10	11	12
Akt-AA almost completely inhibited insulin induced activation of both endogenous and recombinant Akt in HL1C cells .	Akt-AA almost completely inhibited insulin induced activation of both endogenous and recombinant Akt in HL1C cells.	4	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	12	13
The increased basal activity of p70S6K in PTP-1B-/- adipose correlated with decreases in IR substrate-1 protein levels and insulin stimulated Akt and protein kinase B activity , explaining the decrease in insulin sensitivity even as insulin receptor phosphorylation was unaffected .	The increased basal activity of p70S6K in PTP-1B-/- adipose correlated with decreases in IR substrate-1 protein levels and insulin stimulated Akt and protein kinase B activity, explaining the decrease in insulin sensitivity even as insulin receptor phosphorylation was unaffected.	18	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	20	21
SREBP1 is also regulated by multiple positive and negative phosphorylation events in response to other metabolic cues , including , for example , insulin , which activates AKT , thus suppressing GSK-3 and promoting stabilization of the nuclear form .	SREBP1 is also regulated by multiple positive and negative phosphorylation events in response to other metabolic cues, including, for example, insulin, which activates AKT, thus suppressing GSK-3 and promoting stabilization of the nuclear form.	18	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	23	24	27	28
Insulin and IGF-1-mediated activation of Akt leads to GSK-3beta inactivation , which triggers multiple cascades , including synthesis of proteins involved in neuronal glucose metabolism and antiapoptotic mechanisms [ XREF_BIBR , XREF_BIBR ] .	Insulin and IGF-1-mediated activation of Akt leads to GSK-3beta inactivation, which triggers multiple cascades, including synthesis of proteins involved in neuronal glucose metabolism and antiapoptotic mechanisms [XREF_BIBR, XREF_BIBR].	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
PKC-alpha , but not PKC-beta , is expressed in vascular smooth muscle cells , and overexpression of PKC-alpha , but not PKC-beta or PKC-delta , inhibited insulin induced Akt activation .	PKC-alpha, but not PKC-beta, is expressed in vascular smooth muscle cells, and overexpression of PKC-alpha, but not PKC-beta or PKC-delta, inhibited insulin induced Akt activation.	26	29	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	28	29
The strong correlation that we observed between muscle levels of insulin stimulated P-Akt and Akt fold induction and HOMA IR was in agreement with previous studies showing that HOMA IR not only reflects hepatic insulin sensitivity but also peripheral and whole-body insulin sensitivity [ XREF_BIBR , XREF_BIBR ] .	The strong correlation that we observed between muscle levels of insulin stimulated P-Akt and Akt fold induction and HOMA IR was in agreement with previous studies showing that HOMA IR not only reflects hepatic insulin sensitivity but also peripheral and whole-body insulin sensitivity [XREF_BIBR, XREF_BIBR].	8	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	P-Akt	P-Akt	p-akt	10	11	12	13
Notably , mice heterozygous for both p110alpha and p110beta exhibit glucose intolerance despite intact insulin stimulated AKT activity , suggesting that factors in addition to Akt are required for insulin signaling in the liver .	Notably, mice heterozygous for both p110alpha and p110beta exhibit glucose intolerance despite intact insulin stimulated AKT activity, suggesting that factors in addition to Akt are required for insulin signaling in the liver.	9	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	14	15	16	17
In the heart , insulin stimulated Akt phosphorylation of Ser 485 and Ser 491 has been associated with decreased phosphorylation of the Thr 172 site and blunted AMPK activation during ischemia [ XREF_BIBR ] .	In the heart, insulin stimulated Akt phosphorylation of Ser 485 and Ser 491 has been associated with decreased phosphorylation of the Thr 172 site and blunted AMPK activation during ischemia [XREF_BIBR].	4	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Taken together , high protein infant formula feeding overstimulates insulin and IGF-1 production , which both stimulate the downstream kinase AKT [ XREF_BIBR ] that finally activates mTORC1 [ XREF_BIBR - XREF_BIBR ] .	Taken together, high protein infant formula feeding overstimulates insulin and IGF-1 production, which both stimulate the downstream kinase AKT [XREF_BIBR] that finally activates mTORC1 [XREF_BIBR - XREF_BIBR].	9	22	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	20	21
AKT , also known as protein kinase B ( PKB ) , is activated by insulin via the PI3K signaling pathway .	AKT, also known as protein kinase B (PKB), is activated by insulin via the PI3K signaling pathway.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	15	16	0	1
Insulin stimulated mice further demonstrated AKT activation and insulin hypersensitivity in both livers and muscles after PFOA exposure .	Insulin stimulated mice further demonstrated AKT activation and insulin hypersensitivity in both livers and muscles after PFOA exposure.	0	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	5	6
In the liver , insulin activation of Akt plays an important role as the central regulator of glucose metabolism : Akt activates glycogen synthesis and glycolysis and suppresses gluconeogenesis .	In the liver, insulin activation of Akt plays an important role as the central regulator of glucose metabolism : Akt activates glycogen synthesis and glycolysis and suppresses gluconeogenesis.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	7	8
C21 treated mice also showed increased insulin mediated Akt activation in adipose tissue .	C21 treated mice also showed increased insulin mediated Akt activation in adipose tissue.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Insulin induced Akt Ser473 phosphorylation ( p-Akt ) by 9.4 +/- 0.9-fold ( XREF_FIG ) and eNOS Ser1176 ( mouse site , equivalents of human Ser1177 and bovine Ser1179 ) phosphorylation ( p-eNOS ) by 4.3 +/- 0.8-fold ( XREF_FIG ) in ApoE -/- mice .	Insulin induced Akt Ser473 phosphorylation (p-Akt) by 9.4 +/- 0.9-fold (XREF_FIG) and eNOS Ser1176 (mouse site, equivalents of human Ser1177 and bovine Ser1179) phosphorylation (p-eNOS) by 4.3 +/- 0.8-fold (XREF_FIG) in ApoE -/- mice.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Taken together , these studies demonstrate that the growth factors , insulin and IGF1 , activate AKT through their respective receptor signaling within the pituitary and that FOXO1 is a potential downstream effector of growth factor signaling in gonadotropes and other pituitary cell types such as thyrotropes and a subset of somatotropes .	Taken together, these studies demonstrate that the growth factors, insulin and IGF1, activate AKT through their respective receptor signaling within the pituitary and that FOXO1 is a potential downstream effector of growth factor signaling in gonadotropes and other pituitary cell types such as thyrotropes and a subset of somatotropes.	9	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	16	17
miR-143 has also been shown to associate with insulin stimulated AKT activation and glucose homeostasis in the liver through regulating its target oxysterol-binding-protein-related protein ( ORP ) 8 [ XREF_BIBR ] .	miR-143 has also been shown to associate with insulin stimulated AKT activation and glucose homeostasis in the liver through regulating its target oxysterol-binding-protein-related protein (ORP) 8 [XREF_BIBR].	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	10	11
Notably , both leptin and insulin activate PI3K and Akt signaling , as do several receptor tyrosine kinase ( RTKs ) that have been implicated in tail regeneration XREF_BIBR , XREF_BIBR , XREF_BIBR .	Notably, both leptin and insulin activate PI3K and Akt signaling, as do several receptor tyrosine kinase (RTKs) that have been implicated in tail regeneration XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	9	10
Somewhat surprisingly , no major differences in glucose or insulin tolerance were observed following ablation of BMAL1 in skeletal muscle , nor were differences in insulin mediated AKT activation .	Somewhat surprisingly, no major differences in glucose or insulin tolerance were observed following ablation of BMAL1 in skeletal muscle, nor were differences in insulin mediated AKT activation.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	25	26	27	28
In a previous study of non muscle cell lines ( CHO/IR and 3T3-L1 cells ) , ursolic acid enhanced insulin mediated Akt activation .	In a previous study of non muscle cell lines (CHO/IR and 3T3-L1 cells), ursolic acid enhanced insulin mediated Akt activation.	18	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
We have therefore proposed that in the normal , insulin sensitive state , insulin action on the endothelium is mainly mediating anti-atherogenic effects by activating the PI3K and Akt pathway .	We have therefore proposed that in the normal, insulin sensitive state, insulin action on the endothelium is mainly mediating anti-atherogenic effects by activating the PI3K and Akt pathway.	13	29	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	28	29
Protein expression of other key insulin signaling molecules ( IRS-1 , the p85 subunit of PI 3-kinase , and Akt ) was unaltered after either treatment .	Protein expression of other key insulin signaling molecules (IRS-1, the p85 subunit of PI 3-kinase, and Akt) was unaltered after either treatment.	1	20	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	expression of other key insulin	insulin	Akt	Akt	akt	5	6	19	20
miRNAs , such as miR-143-3p and miR-221-3p have been reported to be related to obesity and diabetes , as miRNA-143 inhibits insulin stimulated AKT activation and impairs glucose metabolism .	miRNAs, such as miR-143-3p and miR-221-3p have been reported to be related to obesity and diabetes, as miRNA-143 inhibits insulin stimulated AKT activation and impairs glucose metabolism.	20	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	21	22	23	24
However , in cardiac myocytes , palmitate did not change insulin activation of Akt ( XREF_FIG ) or ERK ( data not shown ) .	However, in cardiac myocytes, palmitate did not change insulin activation of Akt (XREF_FIG) or ERK (data not shown).	10	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	13	14
IGF1 and insulin activated PKB ( Akt and PKB ) rapidly and consistently maintained its phosphorylation .	IGF1 and insulin activated PKB (Akt and PKB) rapidly and consistently maintained its phosphorylation.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
Previous studies demonstrated that Rab proteins are associated with Akt signaling : ( 1 ) Both Rab 5 and Akt signaling are required to regulate insulin receptor mediated endocytosis XREF_BIBR , XREF_BIBR ; ( 2 ) Rab 10 is involved Na + , K + -ATPase translocation to the PM by insulin stimulated Akt activation XREF_BIBR ; ( 3 ) Rab 11 mediated Akt signaling promotes glucose uptake via GLUT1 trafficking XREF_BIBR ; ( 4 ) Rab 4 was identified as a specific Akt2 substrate in the modulating of GLUT4 vesicle trafficking XREF_BIBR ; ( 5 ) Rab 10 also mediated the regulatory signaling of GLUT4 trafficking dependent on the Akt pathway XREF_BIBR - XREF_BIBR ; and ( 6 ) Rab 11 activation by Akt phosphorylation induced internalization and recycling of the insulin like growth factor type-1 receptor and GLUT4 trafficking XREF_BIBR - XREF_BIBR .	Previous studies demonstrated that Rab proteins are associated with Akt signaling : (1) Both Rab 5 and Akt signaling are required to regulate insulin receptor mediated endocytosis XREF_BIBR, XREF_BIBR; (2) Rab 10 is involved Na +, K + -ATPase translocation to the PM by insulin stimulated Akt activation XREF_BIBR; (3) Rab 11 mediated Akt signaling promotes glucose uptake via GLUT1 trafficking XREF_BIBR; (4) Rab 4 was identified as a specific Akt2 substrate in the modulating of GLUT4 vesicle trafficking XREF_BIBR; (5) Rab 10 also mediated the regulatory signaling of GLUT4 trafficking dependent on the Akt pathway XREF_BIBR - XREF_BIBR; and (6) Rab 11 activation by Akt phosphorylation induced internalization and recycling of the insulin like growth factor type-1 receptor and GLUT4 trafficking XREF_BIBR - XREF_BIBR.	51	143	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	51	52	53	54
Insulin activated Akt in adipocytes , but no Akt activation was induced by any investigated DAG .	Insulin activated Akt in adipocytes, but no Akt activation was induced by any investigated DAG.	0	3	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Although IL-1beta treatment alone did not affect the phosphorylation or total expression of these proteins , IL-1beta inhibited insulin stimulated activation of PI3K and p85 , Akt and 4EBP1 , thus indicating an impairment of insulin signaling in the metabolic pathway .	Although IL-1beta treatment alone did not affect the phosphorylation or total expression of these proteins, IL-1beta inhibited insulin stimulated activation of PI3K and p85, Akt and 4EBP1, thus indicating an impairment of insulin signaling in the metabolic pathway.	17	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	26	27
As SGK1 , 3 and PKB are activated by insulin and IGF1 , the described mechanisms presumably participate in the hormonal stimulation of cellular amino acid uptake .	As SGK1, 3 and PKB are activated by insulin and IGF1, the described mechanisms presumably participate in the hormonal stimulation of cellular amino acid uptake.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	9	10	5	6
Insulin Induced PI3K-AKT Activation Stabilizes beta-Catenin mRNA and Increases Both mRNA and Protein Steady-State Levels .	Insulin Induced PI3K-AKT Activation Stabilizes beta-Catenin mRNA and Increases Both mRNA and Protein Steady-State Levels.	0	4	Induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	2	3
To study the underlying signaling pathway ( s ) that mediate ( s ) this increase , we tested the effect of insulin , which activates PI3K-Akt signaling , similarly to high glucose .	To study the underlying signaling pathway (s) that mediate (s) this increase, we tested the effect of insulin, which activates PI3K-Akt signaling, similarly to high glucose.	20	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	22	23	26	27
Studies of isolated Appl1 (-/-) murine embryonic fibroblasts ( MEFs ) showed that Akt activation by epidermal growth factor , insulin , or fetal bovine serum was similar to that observed in wild-type MEFs , although Akt activation by HGF was diminished in Appl1 (-/-) MEFs .	Studies of isolated Appl1 (-/-) murine embryonic fibroblasts (MEFs) showed that Akt activation by epidermal growth factor, insulin, or fetal bovine serum was similar to that observed in wild-type MEFs, although Akt activation by HGF was diminished in Appl1 (-/-) MEFs.	13	21	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	13	14
Infusion of insulin detemir into the head , but not into the portal or peripheral circulation , significantly increased both pAkt and Akt and pSTAT3 and STAT3 in the liver , compared with glargine infusion .	Infusion of insulin detemir into the head, but not into the portal or peripheral circulation, significantly increased both pAkt and Akt and pSTAT3 and STAT3 in the liver, compared with glargine infusion.	2	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	22	23
MiR-26b modulates insulin stimulated AKT activation via inhibition of its target gene , PTEN , and significantly increases insulin sensitivity via the PTEN/PI3K/AKT pathway .	MiR-26b modulates insulin stimulated AKT activation via inhibition of its target gene, PTEN, and significantly increases insulin sensitivity via the PTEN/PI3K/AKT pathway.	1	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	4	5
Berggreen et al reported that , in adipocytes , insulin stimulated Akt might regulate ACC by direct phosphorylation of AMPK , resulting in AMPK inhibition [ XREF_BIBR ] .	Berggreen et al reported that, in adipocytes, insulin stimulated Akt might regulate ACC by direct phosphorylation of AMPK, resulting in AMPK inhibition [XREF_BIBR].	9	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
Although a higher AKT activation by insulin than by EGF may contribute to additional Raf inhibition , our data suggest that this inhibition is insignificant in HEK293 cells ( XREF_SUPPLEMENTARY ) .	Although a higher AKT activation by insulin than by EGF may contribute to additional Raf inhibition, our data suggest that this inhibition is insignificant in HEK293 cells (XREF_SUPPLEMENTARY).	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	3	4
In hepatocytes , APPL1 potentiates insulin induced Akt activation by competing with the intracellular pseudokinase TRB3 for binding to Akt .	In hepatocytes, APPL1 potentiates insulin induced Akt activation by competing with the intracellular pseudokinase TRB3 for binding to Akt.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
TamR cells did not respond to IGF-I , but Akt was activated by IGF-II and insulin .	TamR cells did not respond to IGF-I, but Akt was activated by IGF-II and insulin.	9	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	9	10
In this study , we investigated the possibility that PKCdelta may be involved in insulin induced activation of PKB .	In this study, we investigated the possibility that PKCdelta may be involved in insulin induced activation of PKB.	12	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	14	15	18	19
Studies have shown that insulin and IGF -1 signaling activates the MAPK and Akt pathways , thereby regulating cellular proliferation and survival of cancer cells .	Studies have shown that insulin and IGF -1 signaling activates the MAPK and Akt pathways, thereby regulating cellular proliferation and survival of cancer cells.	4	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	13	14
The significance of exercise induced alterations in cytosolic SHP2 and insulin stimulated Akt pSer ( 473 ) on the improvement in insulin sensitivity requires further elucidation .	The significance of exercise induced alterations in cytosolic SHP2 and insulin stimulated Akt pSer (473) on the improvement in insulin sensitivity requires further elucidation.	5	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
Insulin activates other cellular signaling pathways in addition to PI3 kinase and Akt .	Insulin activates other cellular signaling pathways in addition to PI3 kinase and Akt.	0	13	activates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	12	13
One of the important targets of insulin stimulated Akt is FoxO1 XREF_BIBR XREF_BIBR .	One of the important targets of insulin stimulated Akt is FoxO1 XREF_BIBR XREF_BIBR.	4	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Sub-mitochondrial localization of the insulin stimulated Akt .	Sub-mitochondrial localization of the insulin stimulated Akt.	1	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
In turn , PKB , whose activity is stimulated by insulin , contributes to the activation of mTORC1 by phosphorylation and inactivation of tuberous sclerosis 2 ( TSC2 ) , a negative regulator of mTORC1 [ reviewed ] .	In turn, PKB, whose activity is stimulated by insulin, contributes to the activation of mTORC1 by phosphorylation and inactivation of tuberous sclerosis 2 (TSC2), a negative regulator of mTORC1 [reviewed].	3	12	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	10	11	3	4
The intracellular cascade of insulin activates AKT , a positive input for mTORC1 , and also a negative regulator of the FoxO transcription factors .	The intracellular cascade of insulin activates AKT, a positive input for mTORC1, and also a negative regulator of the FoxO transcription factors.	2	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	6	7
A closer look into the raw data shows that insulin barely induces IRbeta and AKT in primary cells .	A closer look into the raw data shows that insulin barely induces IRbeta and AKT in primary cells.	9	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	14	15
Activation of Akt by insulin in adipocytes is reduced in type 2 diabetes , and experimental reduction of Akt2 leads to decreased insulin sensitivity and reduced glucose disposal , both of which are features of PCOS .	Activation of Akt by insulin in adipocytes is reduced in type 2 diabetes, and experimental reduction of Akt2 leads to decreased insulin sensitivity and reduced glucose disposal, both of which are features of PCOS.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	2	3
The results from the Akt phosphorylation study ( XREF_FIG ) showed that H4IIE cells treated with 1 nM insulin exhibited a rapid onset and strong phospho-Akt signal at 5-min , 1-h and 4-h time points .	The results from the Akt phosphorylation study (XREF_FIG) showed that H4IIE cells treated with 1 nM insulin exhibited a rapid onset and strong phospho-Akt signal at 5-min, 1-h and 4-h time points.	4	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	4	5
Insulin induced P-AKT in the hippocampus , hypothalamus and amygdala was unchanged following acute psychological stress .	Insulin induced P-AKT in the hippocampus, hypothalamus and amygdala was unchanged following acute psychological stress.	0	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	P-AKT	P-AKT	P-AKT	0	1	2	3
As expected , insulin treatment could increase AKT kinase activity ( XREF_FIG ) .	As expected, insulin treatment could increase AKT kinase activity (XREF_FIG).	3	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	7	8
XREF_BIBR Insulin activates the Akt pathway in murine regulatory T cells ( Treg cells ) .	XREF_BIBR Insulin activates the Akt pathway in murine regulatory T cells (Treg cells).	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	1	2	4	5
Given that thyrotropin and insulin stimulate Akt activation in thyroid cells , we set out to determine the effects of Akt on thyroid cell proliferation , survival , and differentiation .	Given that thyrotropin and insulin stimulate Akt activation in thyroid cells, we set out to determine the effects of Akt on thyroid cell proliferation, survival, and differentiation.	2	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Additionally , activation of Akt by insulin administration was significantly reduced in the gWAT SM , and liver by HFD ; however , this activation was restored in HGF-Tg mice .	Additionally, activation of Akt by insulin administration was significantly reduced in the gWAT SM, and liver by HFD; however, this activation was restored in HGF-Tg mice.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	4	5
IGF-1 , and similarly insulin , activates the PI3K and Akt pathway , which promotes protein synthesis through mTOR and its downstream effectors , mTORC1/2 complexes , not to mention that mTOR activation in the skeletal muscle results in autophagy inhibition [ XREF_BIBR ] , thus determining at the same time both protein synthesis activation and inhibition of protein degradation .	IGF-1, and similarly insulin, activates the PI3K and Akt pathway, which promotes protein synthesis through mTOR and its downstream effectors, mTORC1/2 complexes, not to mention that mTOR activation in the skeletal muscle results in autophagy inhibition [XREF_BIBR], thus determining at the same time both protein synthesis activation and inhibition of protein degradation.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	10	11
To investigate the effect of MAG in insulin stimulated vascular Akt and eNOS signaling , we examined the expression of Akt , eNOS , and phosphorylated Akt and eNOS levels in vascular tissues from SHRs by immunoblotting .	To investigate the effect of MAG in insulin stimulated vascular Akt and eNOS signaling, we examined the expression of Akt, eNOS, and phosphorylated Akt and eNOS levels in vascular tissues from SHRs by immunoblotting.	1	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	10	11
Furthermore , insulin ( a mimic of the fed state ) activates AKT resulting in phosphorylation of NCoR on Ser1460 , which enhances its interaction with PPARalpha over LXRalpha , and results in repression of PPARalpha , decreased FFA oxidation and enhanced hepatic lipogenesis 96 ( XREF_FIG ) .	Furthermore, insulin (a mimic of the fed state) activates AKT resulting in phosphorylation of NCoR on Ser1460, which enhances its interaction with PPARalpha over LXRalpha, and results in repression of PPARalpha, decreased FFA oxidation and enhanced hepatic lipogenesis 96 (XREF_FIG).	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	12	13
Moreover , analysis of the levels and subcellular distribution of insulin receptor substrates 1 and 2 , the p85alpha subunit of phosphatidylinositol 3 '-kinase , and protein kinase B ( PKB )/cAKT in skeletal muscle did not identify any differences between the two strains ; the insulin dependent activation of PKB and cAKT was not different between the two strains .	Moreover, analysis of the levels and subcellular distribution of insulin receptor substrates 1 and 2, the p85alpha subunit of phosphatidylinositol 3 '-kinase, and protein kinase B (PKB)/cAKT in skeletal muscle did not identify any differences between the two strains; the insulin dependent activation of PKB and cAKT was not different between the two strains.	46	52	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	46	47	50	51
Insulin promotes hADSCs differentiations by activating PI3-kinase and Akt signaling pathways , which subsequently stimulate the expression of adipocyte specific genes , such as FAS , leptin and adiponectin [ XREF_BIBR ] .	Insulin promotes hADSCs differentiations by activating PI3-kinase and Akt signaling pathways, which subsequently stimulate the expression of adipocyte specific genes, such as FAS, leptin and adiponectin [XREF_BIBR].	0	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	8	9
The findings indicate that ( i ) the potency of insulin and IGF-1 receptors in stimulating glycogen synthesis correlates with their ability to inactivate GSK-3 , ( ii ) the extent of GSK-3 inactivation does not correlate with the extent of Akt activation mediated by insulin or IGF-1 receptors , indicating that the effect of insulin on GSK-3 requires additional kinases , and ( iii ) the pathways required for insulin stimulation of glycogen synthesis in mouse hepatocytes are PI 3-kinase-dependent and rapamycin sensitive .	The findings indicate that (i) the potency of insulin and IGF-1 receptors in stimulating glycogen synthesis correlates with their ability to inactivate GSK-3, (ii) the extent of GSK-3 inactivation does not correlate with the extent of Akt activation mediated by insulin or IGF-1 receptors, indicating that the effect of insulin on GSK-3 requires additional kinases, and (iii) the pathways required for insulin stimulation of glycogen synthesis in mouse hepatocytes are PI 3-kinase-dependent and rapamycin sensitive.	41	48	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	45	46	41	42
In order to quantitate the positive allosteric modulatory effects of XMetS on insulin stimulated Akt activation by the INSR , a Schild analysis was conducted XREF_BIBR , XREF_BIBR , XREF_BIBR .	In order to quantitate the positive allosteric modulatory effects of XMetS on insulin stimulated Akt activation by the INSR, a Schild analysis was conducted XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	14	15
AKT is activated by both insulin and IGF-1 in their signaling pathways .	AKT is activated by both insulin and IGF-1 in their signaling pathways.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	0	1
Incubation of myotubes with palmitate or tunicamycin inhibited insulin stimulated protein kinase B ( PKB ) / v-akt murine thymoma viral oncogene homologue 1 ( Akt ) .	Incubation of myotubes with palmitate or tunicamycin inhibited insulin stimulated protein kinase B (PKB) / v-akt murine thymoma viral oncogene homologue 1 (Akt).	7	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	25	26
Insulin induced AKT activation is intact in TBK1 -/- MEFs , however TLR4 , TLR3 , EGFR and glucose induced AKT activation is impaired .	Insulin induced AKT activation is intact in TBK1 -/- MEFs, however TLR4, TLR3, EGFR and glucose induced AKT activation is impaired.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	2	3
Interestingly , overexpression of either PTB or SAIN protein did not affect insulin induced AKT activation or insulin stimulated 2-deoxyglucose transport , even though both of these bioeffects are inhibited by wortmannin .	Interestingly, overexpression of either PTB or SAIN protein did not affect insulin induced AKT activation or insulin stimulated 2-deoxyglucose transport, even though both of these bioeffects are inhibited by wortmannin.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	14	15
As expected , insulin activated PKB ( 1.89 +/-0.34 vs. 0.74 +/-0.08 mU/mg prot in control heart , p < 0.05 ) .	As expected, insulin activated PKB (1.89 +/-0.34 vs. 0.74 +/-0.08 mU/mg prot in control heart, p < 0.05).	3	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	5	6
For example insulin mediated Akt activation has been described to phosphorylate the Cavalpha1 subunit , prevent its degradation and consequently increase I Ca , L [ XREF_BIBR , XREF_BIBR ] .	For example insulin mediated Akt activation has been described to phosphorylate the Cavalpha1 subunit, prevent its degradation and consequently increase I Ca, L [XREF_BIBR, XREF_BIBR].	0	14	mediated	Positive_regulation_token_1_verb	Positive_activation	Positive_regulation	insulin	insulin	insulin	Akt	Akt activation has been described to phosphorylate the Cavalpha1 subunit	akt	2	3	4	5
Insulin stimulated activations of IRS-1 , AKT and GSK3beta were significantly reduced in fibroblasts of LRP6 R611C mutation carriers compared to non carriers ( XREF_FIG ) .	Insulin stimulated activations of IRS-1, AKT and GSK3beta were significantly reduced in fibroblasts of LRP6 R611C mutation carriers compared to non carriers (XREF_FIG).	0	7	activations	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	6	7
A particularly destructive aspect of oxidative stress is the production of reactive oxygen species ( ROS ) which have been demonstrated to cause insulin resistance under different settings , impair glucose uptake in insulin sensitive tissues , and inhibit insulin stimulated Akt signaling .	A particularly destructive aspect of oxidative stress is the production of reactive oxygen species (ROS) which have been demonstrated to cause insulin resistance under different settings, impair glucose uptake in insulin sensitive tissues, and inhibit insulin stimulated Akt signaling.	39	42	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	39	40	41	42
Insulin activation of Akt was markedly inhibited in alpha -/- as compared to alpha +/+ hearts , but no significant difference was seen between beta -/- and beta +/+ hearts ( XREF_FIG ) .	Insulin activation of Akt was markedly inhibited in alpha -/- as compared to alpha +/+ hearts, but no significant difference was seen between beta -/- and beta +/+ hearts (XREF_FIG).	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
In wild-type mice on an HFD , insulin failed to significantly increase activation of IR , IRS-1 , and Akt .	In wild-type mice on an HFD, insulin failed to significantly increase activation of IR, IRS-1, and Akt.	7	20	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	19	20
In adipocytes , Hresko and Mueckler observed a 25 % increase in insulin activated Akt Ser 473 , despite the presence of an ILK siRNA [ XREF_BIBR ] .	In adipocytes, Hresko and Mueckler observed a 25% increase in insulin activated Akt Ser 473, despite the presence of an ILK siRNA [XREF_BIBR].	6	15	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	14	15
Insulin stimulated glucose uptake involves PI3-kinase and PKB , and the aim of the present study was to test the hypothesis that caffeine and theophylline inhibit insulin stimulated glucose uptake in skeletal muscles .	Insulin stimulated glucose uptake involves PI3-kinase and PKB, and the aim of the present study was to test the hypothesis that caffeine and theophylline inhibit insulin stimulated glucose uptake in skeletal muscles.	0	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	7	8
Second , biochemical analyses revealed constitutively elevated JNK activity and diminished insulin induced AKT activation in the liver of SERT deficient mice .	Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin induced AKT activation in the liver of SERT deficient mice.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	13	14
Takahashi and colleagues showed that hypertrophic stimuli that induce Akt activation ( such as IGF-1 or insulin and dexamethasone ) will elicit myocyte production of VEGFA .	Takahashi and colleagues showed that hypertrophic stimuli that induce Akt activation (such as IGF-1 or insulin and dexamethasone) will elicit myocyte production of VEGFA.	9	18	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	9	10
PKB was also activated by insulin , in a dose- and time dependent manner .	PKB was also activated by insulin, in a dose- and time dependent manner.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	5	6	0	1
These effects were associated with a partial reversion of hepatic steatosis , reduction in liver and skeletal muscle content of phosphorylated JNK , and an improvement in muscle insulin stimulated glucose uptake and Akt signaling .	These effects were associated with a partial reversion of hepatic steatosis, reduction in liver and skeletal muscle content of phosphorylated JNK, and an improvement in muscle insulin stimulated glucose uptake and Akt signaling.	25	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	33	34
Addition of leucine to the HFD almost completely rescued the insulin stimulation of IR , IRS-1 and AKT , returning them to levels similar to those in the CD mice ( XREF_FIG ) .	Addition of leucine to the HFD almost completely rescued the insulin stimulation of IR, IRS-1 and AKT, returning them to levels similar to those in the CD mice (XREF_FIG).	10	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	17	18
The insulin regulated activation of PI3K and Akt is important to regulate glucose disposal and other metabolic adaptations [ XREF_BIBR ] .	The insulin regulated activation of PI3K and Akt is important to regulate glucose disposal and other metabolic adaptations [XREF_BIBR].	1	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	7	8
In this regard , insulin induced Akt activation may mediate AMPKalpha Ser485/491 phosphorylation to inhibit AMPK activity [ XREF_BIBR ] .	In this regard, insulin induced Akt activation may mediate AMPKalpha Ser485/491 phosphorylation to inhibit AMPK activity [XREF_BIBR].	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
This probably explains why other factors , such as insulin and EGF , that stimulate Akt through the PI3K pathway , but do not activate Dvl , fail to cause an increase in cytosolic beta-catenin .	This probably explains why other factors, such as insulin and EGF, that stimulate Akt through the PI3K pathway, but do not activate Dvl, fail to cause an increase in cytosolic beta-catenin.	5	24	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	15	16
Insulin causes Akt activation through insulin receptor substrate 1 ( IRS1 ) phosphorylation , which activates phosphoinositide-3 kinase ( PI3K ) .	Insulin causes Akt activation through insulin receptor substrate 1 (IRS1) phosphorylation, which activates phosphoinositide-3 kinase (PI3K).	0	3	causes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Taken together , these data demonstrate that the insulin sensitization observed in Vps34 D761A/+ mice is independent of insulin mediated Akt and mTORC1 signaling .	Taken together, these data demonstrate that the insulin sensitization observed in Vps34 D761A/+ mice is independent of insulin mediated Akt and mTORC1 signaling.	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	20	21
Lrictor ( KO ) mice had defects in insulin stimulated Akt Ser 473 and Thr 308 phosphorylation , leading to decreased phosphorylation of Akt substrates FoxO , GSK-3beta , PRAS40 , AS160 , and Tsc2 .	Lrictor (KO) mice had defects in insulin stimulated Akt Ser 473 and Thr 308 phosphorylation, leading to decreased phosphorylation of Akt substrates FoxO, GSK-3beta, PRAS40, AS160, and Tsc2.	6	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Insulin activates AKT and protein kinase B through a well defined mechanism mediated by the IRS1 and PI3K pathway .	Insulin activates AKT and protein kinase B through a well defined mechanism mediated by the IRS1 and PI3K pathway.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	2	3
Because insulin has been shown to stimulate the protein kinase Akt , we investigated whether activation of Akt contributes to the apoptosis-suppressive effect of insulin and characterized the downstream signaling pathway .	Because insulin has been shown to stimulate the protein kinase Akt, we investigated whether activation of Akt contributes to the apoptosis-suppressive effect of insulin and characterized the downstream signaling pathway.	1	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	10	11
After one hour , insulin stimulated-glucose transport was significantly increased and continued to increase up to 6-24 h. Insulin stimulation of Akt , however , did not increase after 1-3 h and began to slightly increase after 6 h. Next , we investigated effects of osmotic shock and vanadate on glucose transport in glucosamine treated cells and found that glucosamine completely inhibited their actions in these cells .	After one hour, insulin stimulated-glucose transport was significantly increased and continued to increase up to 6-24 h. Insulin stimulation of Akt, however, did not increase after 1-3 h and began to slightly increase after 6 h. Next, we investigated effects of osmotic shock and vanadate on glucose transport in glucosamine treated cells and found that glucosamine completely inhibited their actions in these cells.	18	22	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	18	19	21	22
Since the MTs siRNA enhanced the insulin stimulated activation of Akt in the 3T3-L1 cells , we next evaluated the phosphorylated Akt in the adipose tissue of five-day-old WT and MTKO mice .	Since the MTs siRNA enhanced the insulin stimulated activation of Akt in the 3T3-L1 cells, we next evaluated the phosphorylated Akt in the adipose tissue of five-day-old WT and MTKO mice.	5	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	10	11
Using our pancreatic-substrate clamp technique , we clearly showed that insulin , but not amino acids and leucine , induce PKB activation .	Using our pancreatic-substrate clamp technique, we clearly showed that insulin, but not amino acids and leucine, induce PKB activation.	10	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	10	11	20	21
Moreover , in the cinnamon group , tyrosine phosphorylation of AKT was higher in the basal state compared with vehicle treated mice , and insulin stimulated P-AKT implicated an enhancement of 32 % compared to levels of vehicle treated mice ( 138.7 +/-12.6 vs. 105.4 +/-13.7 arb .	Moreover, in the cinnamon group, tyrosine phosphorylation of AKT was higher in the basal state compared with vehicle treated mice, and insulin stimulated P-AKT implicated an enhancement of 32% compared to levels of vehicle treated mice (138.7 +/-12.6 vs. 105.4 +/-13.7 arb.	24	27	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	P-AKT	P-AKT	P-AKT	24	25	26	27
In agreement , knockdown of INPP4b was found to phenocopy hallmarks of PTEN-suppression , such as increased AKT signaling triggered by insulin and showed an increased p53 dependent cellular senescence response upon co-suppression with PTEN .	In agreement, knockdown of INPP4b was found to phenocopy hallmarks of PTEN-suppression, such as increased AKT signaling triggered by insulin and showed an increased p53 dependent cellular senescence response upon co-suppression with PTEN.	17	22	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	21	22	17	18
Third , activated JNK1 would concurrently also promote the phosphorylation and subsequent proteasomal degradation of 14-3-3 scaffold proteins that mediate the nuclear export of FOXO-proteins into the cytosol in response to insulin mediated Akt activation XREF_BIBR XREF_BIBR .	Third, activated JNK1 would concurrently also promote the phosphorylation and subsequent proteasomal degradation of 14-3-3 scaffold proteins that mediate the nuclear export of FOXO-proteins into the cytosol in response to insulin mediated Akt activation XREF_BIBR XREF_BIBR.	7	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	33	34
It has been reported that miR-33a/b contributes to the regulation of fatty acid metabolism and insulin signaling , and miR-503 inhibits adipogenesis through classical insulin signal of PI3K and AKT by targeting bone morphogenetic protein receptor 1a .	It has been reported that miR-33a/b contributes to the regulation of fatty acid metabolism and insulin signaling, and miR-503 inhibits adipogenesis through classical insulin signal of PI3K and AKT by targeting bone morphogenetic protein receptor 1a.	24	30	signal	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	24	25	29	30
As shown in Figure XREF_FIG , Akt activation by insulin produced markedly lower levels of LC3-II conversion in the TCO treated cells than in the controls , suggesting that TCO induced autophagy in colorectal cancer cells by inhibition of the Akt and mTOR pathway .	As shown in Figure XREF_FIG, Akt activation by insulin produced markedly lower levels of LC3-II conversion in the TCO treated cells than in the controls, suggesting that TCO induced autophagy in colorectal cancer cells by inhibition of the Akt and mTOR pathway.	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	6	7
Moreover , neomycin reversed the inhibitory effect of wortmannin but not LY294002 on insulin stimulation of Akt kinase activity .	Moreover, neomycin reversed the inhibitory effect of wortmannin but not LY294002 on insulin stimulation of Akt kinase activity.	13	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	16	17
In contrast to the effects observed with the CB1 agonists , applying SR141716 alone potentiated both insulin stimulated PKB and ERK1/2 activity .	In contrast to the effects observed with the CB1 agonists, applying SR141716 alone potentiated both insulin stimulated PKB and ERK1/2 activity.	14	21	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	16	17	18	19
As shown in XREF_FIG , insulin caused gradual increase of pERK with increasing dose up to 1,000 ng/ml , whereas AKT was fully activated by even a low concentration of insulin ( 10ng/ml ) .	As shown in XREF_FIG, insulin caused gradual increase of pERK with increasing dose up to 1,000 ng/ml, whereas AKT was fully activated by even a low concentration of insulin (10ng/ml).	20	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	30	31	20	21
The resulting insulin and IGF -1 signaling ( IIS ) activates the phosphatidylinositol 3-kinase ( PI3K ) and Akt kinase that mediate the suppression of transcription factors of the Forkhead box O ( FoxO ) , which are supposed to prevent uncontrolled inflammatory response , indicating a link between Western diet and development of civilization diseases like cancers and T2DM .	The resulting insulin and IGF -1 signaling (IIS) activates the phosphatidylinositol 3-kinase (PI3K) and Akt kinase that mediate the suppression of transcription factors of the Forkhead box O (FoxO), which are supposed to prevent uncontrolled inflammatory response, indicating a link between Western diet and development of civilization diseases like cancers and T2DM.	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	18	19
On the other hand , insulin treatment for 24 hours resulted in maximal AKT activation at the 20 nM dose , without further stimulation by 200 nM insulin .	On the other hand, insulin treatment for 24 hours resulted in maximal AKT activation at the 20 nM dose, without further stimulation by 200 nM insulin.	5	15	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	13	14
On the other hand , PCB77 blocked insulin activated Akt signaling pathway , which was restored by pretreatment with TNFalpha neutralization antibody .	On the other hand, PCB77 blocked insulin activated Akt signaling pathway, which was restored by pretreatment with TNFalpha neutralization antibody.	6	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
Remarkably , PI3K-C2beta inactivation did not lead to an increase in insulin induced Akt signaling in the spleen ( XREF_FIG A ) , despite high expression of PI3K-C2beta in this tissue compared to metabolic tissues ( XREF_FIG A ) .	Remarkably, PI3K-C2beta inactivation did not lead to an increase in insulin induced Akt signaling in the spleen (XREF_FIG A), despite high expression of PI3K-C2beta in this tissue compared to metabolic tissues (XREF_FIG A).	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
In an attempt to clarify the role Akt plays in modulating insulin sensitivity after significant weight-loss through bariatric surgery , we carried out a detailed examination of the correlation between insulin stimulated glucose disposal and Akt signalling in eight morbidly obese insulin resistant volunteers before and after a Roux-en-Y gastric bypass ( RYGB ) .	In an attempt to clarify the role Akt plays in modulating insulin sensitivity after significant weight-loss through bariatric surgery, we carried out a detailed examination of the correlation between insulin stimulated glucose disposal and Akt signalling in eight morbidly obese insulin resistant volunteers before and after a Roux-en-Y gastric bypass (RYGB).	28	36	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	30	31	35	36
PTH treatment ( 10 nM ) significantly reduced insulin stimulated AKT activity ( 12 % ) in differentiated adipocytes compared to vehicle ( XREF_FIG ) .	PTH treatment (10 nM) significantly reduced insulin stimulated AKT activity (12%) in differentiated adipocytes compared to vehicle (XREF_FIG).	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	10	11
To directly examine potential roles for C/EBPbeta and HDAC4 , and C/EBPbeta target PDK4 in control of insulin stimulated AKT activation and glucose uptake , we analyzed AKT phosphorylation and glucose uptake in insulin stimulated hepa1-6 cells transfected with short interfering RNAs ( siRNAs ) directed to mouse C/EBPbeta ( siC and EBPbeta ) , HDAC4 ( siHDAC4 ) and PDK4 ( siPDK4 ) , respectively .	To directly examine potential roles for C/EBPbeta and HDAC4, and C/EBPbeta target PDK4 in control of insulin stimulated AKT activation and glucose uptake, we analyzed AKT phosphorylation and glucose uptake in insulin stimulated hepa1-6 cells transfected with short interfering RNAs (siRNAs) directed to mouse C/EBPbeta (siC and EBPbeta), HDAC4 (siHDAC4) and PDK4 (siPDK4), respectively.	15	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	17	18	19	20
Thapsigargin treated HL-1 cells were resistant to insulin stimulated Akt activation .	Thapsigargin treated HL-1 cells were resistant to insulin stimulated Akt activation.	5	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
However , insulin stimulation could partially or even totally reverse the physiologic blockade of PKB , indicating that the effect of TRB3 is reversible .	However, insulin stimulation could partially or even totally reverse the physiologic blockade of PKB, indicating that the effect of TRB3 is reversible.	2	15	reverse	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	2	3	14	15
One pathway inhibits insulin induced GSK-3beta phosphorylation by blocking insulin activation of Akt .	One pathway inhibits insulin induced GSK-3beta phosphorylation by blocking insulin activation of Akt.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	12	13
XREF_BIBR - XREF_BIBR Insulin induced activation of Akt , in addition to TSC1 and TSC2 inhibition , also leads to the direct phosphorylation of PRAS40 , which is thus unbound from mTORC1 and increases mTORC1 activity .	XREF_BIBR - XREF_BIBR Insulin induced activation of Akt, in addition to TSC1 and TSC2 inhibition, also leads to the direct phosphorylation of PRAS40, which is thus unbound from mTORC1 and increases mTORC1 activity.	2	33	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	3	4	7	8
These changes were associated with a 50 % increase in IRS-1 Ser312 and IRS-1 Ser636 phosphorylation and an approximately 60 % reduction in insulin stimulated Akt activation in the IR offspring .	These changes were associated with a 50% increase in IRS-1 Ser312 and IRS-1 Ser636 phosphorylation and an approximately 60% reduction in insulin stimulated Akt activation in the IR offspring.	3	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	25	26
These findings paralleled the in vivo data and show that insulin dependent activation of Akt and PI-3K were compromised in liver but not muscle after 8 weeks on the HF diet .	These findings paralleled the in vivo data and show that insulin dependent activation of Akt and PI-3K were compromised in liver but not muscle after 8 weeks on the HF diet.	10	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	14	15
And PCB77 was observed to alter insulin activated Akt signaling by TNFalpha secretion for the first time .	And PCB77 was observed to alter insulin activated Akt signaling by TNFalpha secretion for the first time.	5	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
AKT is normally activated by insulin through phosphorylation of the Thr 308 and Ser 473 sites respectively [ XREF_BIBR ] ; then AS160 ( AKT substrate of 160 kDa ) is phosphorylated and inhibited .	AKT is normally activated by insulin through phosphorylation of the Thr 308 and Ser 473 sites respectively [XREF_BIBR]; then AS160 (AKT substrate of 160 kDa) is phosphorylated and inhibited.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	0	1
In HepG2 cells , while insulin mediated Akt activation was inhibited by PA in a dose dependent manner , PEPCK and G-6-Pase expressions were increased greatly by PA after 8 hr treatment and lasted to 24 hr .	In HepG2 cells, while insulin mediated Akt activation was inhibited by PA in a dose dependent manner, PEPCK and G-6-Pase expressions were increased greatly by PA after 8 hr treatment and lasted to 24 hr.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Despite higher basal Akt in the HF group , insulin produced comparable additional activation of Akt among the groups ( XREF_FIG ) .	Despite higher basal Akt in the HF group, insulin produced comparable additional activation of Akt among the groups (XREF_FIG).	9	16	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	15	16
Considerable evidence now supports the following pathway in adipocytes : insulin activates the protein kinase Akt ; Akt phosphorylates the Rab GTPase activating protein TBC1D4 ; phosphorylation of TBC1D4 suppresses its GTPase activating activity toward its target Rabs , which include Rab10 ; as a consequence Rab10 , which is a component of the GLUT4 vesicles , converts from the GDP to the GTP form ; then the elevated Rab10-GTP in the GLUT4 vesicles in some way initiates their exocytosis [ XREF_BIBR - XREF_BIBR ] .	Considerable evidence now supports the following pathway in adipocytes : insulin activates the protein kinase Akt; Akt phosphorylates the Rab GTPase activating protein TBC1D4; phosphorylation of TBC1D4 suppresses its GTPase activating activity toward its target Rabs, which include Rab10; as a consequence Rab10, which is a component of the GLUT4 vesicles, converts from the GDP to the GTP form; then the elevated Rab10-GTP in the GLUT4 vesicles in some way initiates their exocytosis [XREF_BIBR - XREF_BIBR].	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	15	16
Insulin is now thought to activate PKC and Akt , as well as AS160 , which is a downstream signaling molecule of Akt .	Insulin is now thought to activate PKC and Akt, as well as AS160, which is a downstream signaling molecule of Akt.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	8	9
Furthermore , isolated hepatocytes from this strain displayed protection from palmitate induced attenuation of insulin stimulated Akt activation .	Furthermore, isolated hepatocytes from this strain displayed protection from palmitate induced attenuation of insulin stimulated Akt activation.	12	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
Moreover , reduced insulin induced activation of Akt is a hallmark of insulin resistance [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Moreover, reduced insulin induced activation of Akt is a hallmark of insulin resistance [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
In conclusion , improved glucose tolerance in diabetic GK rats by phlorizin treatment fully restored insulin stimulated activity of Akt kinase and glucose transport .	In conclusion, improved glucose tolerance in diabetic GK rats by phlorizin treatment fully restored insulin stimulated activity of Akt kinase and glucose transport.	14	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	19	20
Insulin activates Akt to inhibit the activity of GSK-3alpha or GSK-3beta isoforms by phosphorylating their NH 2 -terminal serine residues , terminating their inhibition of glycogen synthase .	Insulin activates Akt to inhibit the activity of GSK-3alpha or GSK-3beta isoforms by phosphorylating their NH 2 -terminal serine residues, terminating their inhibition of glycogen synthase.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Insulin stimulated AKT ( protein kinase B ) activation ( phosphorylation ) contributes to glucose and energy homeostasis .	Insulin stimulated AKT (protein kinase B) activation (phosphorylation) contributes to glucose and energy homeostasis.	0	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	2	3
As expected , AKT kinase activity was induced when cells were treated with insulin and inhibited by PI3K inhibitor wortmannin .	As expected, AKT kinase activity was induced when cells were treated with insulin and inhibited by PI3K inhibitor wortmannin.	3	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	13	14	3	4
On the other hand , angiotensin ( 1-7 ) counteracts the inhibitory effect of angiotensin II , being able to restore the insulin induced Akt and eNOS activation and the NO production .	On the other hand, angiotensin (1-7) counteracts the inhibitory effect of angiotensin II, being able to restore the insulin induced Akt and eNOS activation and the NO production.	21	27	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	24	25
Our findings suggest a direct relationship between GRK2 and vascular endothelial cells , and reveal that a rapid improvement in glucose concentrations directly leads to enhanced insulin stimulated Akt and eNOS signalling and NO production in HUVECs .	Our findings suggest a direct relationship between GRK2 and vascular endothelial cells, and reveal that a rapid improvement in glucose concentrations directly leads to enhanced insulin stimulated Akt and eNOS signalling and NO production in HUVECs.	23	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	28	29
In skeletal muscle , insulin increased the activation of IR , IRS-1 , PI 3-kinase , PKB and S6 and stimulated protein synthesis .	In skeletal muscle, insulin increased the activation of IR, IRS-1, PI 3-kinase, PKB and S6 and stimulated protein synthesis.	4	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	16	17
Stimulation of insulin signaling was mediated through induction of insulin receptor ( IR ) , IR substrate protein 1 ( IRS1 ) , IRS2 , and the p85 regulatory subunit of phosphoinositide-3-3-kinase , which led to enhanced insulin mediated activation of Akt .	Stimulation of insulin signaling was mediated through induction of insulin receptor (IR), IR substrate protein 1 (IRS1), IRS2, and the p85 regulatory subunit of phosphoinositide-3-3-kinase, which led to enhanced insulin mediated activation of Akt.	37	42	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	37	38	41	42
By intracerebroventricular injections , insulin was demonstrated to activate protein kinase B ( PKB or Akt ) via the phosphatidylinositol 3-kinase ( PI3-K ) pathway in the rat hippocampus .	By intracerebroventricular injections, insulin was demonstrated to activate protein kinase B (PKB or Akt) via the phosphatidylinositol 3-kinase (PI3-K) pathway in the rat hippocampus.	4	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	15	16
Sustained insulin activation of Akt is negatively regulated by the PP2A phosphatase ( Ugi etal .	Sustained insulin activation of Akt is negatively regulated by the PP2A phosphatase (Ugi etal.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	4	5
Furthermore , in skeletal muscles from insulin resistant models , including PTP-1B transgenic mice [ XREF_BIBR ] , leukocyte antigen related phosphatase ( LAR ) transgenic mice [ XREF_BIBR ] , and glucosamine infused rats [ XREF_BIBR ] , insulin induced Akt activation is normal but insulin stimulated glucose uptake is impaired .	Furthermore, in skeletal muscles from insulin resistant models, including PTP-1B transgenic mice [XREF_BIBR], leukocyte antigen related phosphatase (LAR) transgenic mice [XREF_BIBR], and glucosamine infused rats [XREF_BIBR], insulin induced Akt activation is normal but insulin stimulated glucose uptake is impaired.	39	42	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	39	40	41	42
GDC0941 also prevented Akt activation , as shown by immunoblotting for Akt phosphorylation on Ser 473 ( XREF_FIG ) , consistent with the dependence of insulin induced activation of Akt on PI3K activation .	GDC0941 also prevented Akt activation, as shown by immunoblotting for Akt phosphorylation on Ser 473 (XREF_FIG), consistent with the dependence of insulin induced activation of Akt on PI3K activation.	23	30	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	29	30
Additionally , C1-Ten overexpression in HEK293 cells led to inhibition of the AMPK pathway and insulin induced Akt activation .	Additionally, C1-Ten overexpression in HEK293 cells led to inhibition of the AMPK pathway and insulin induced Akt activation.	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
In vitro experiments in insulinoma cell lines and isolated islets demonstrate that Akt activation by glucose , insulin , IGF-1 and GLP-1 is a major component for the anti-apoptotic effects of these molecules [ XREF_BIBR - XREF_BIBR ] .	In vitro experiments in insulinoma cell lines and isolated islets demonstrate that Akt activation by glucose, insulin, IGF-1 and GLP-1 is a major component for the anti-apoptotic effects of these molecules [XREF_BIBR - XREF_BIBR].	12	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	12	13
AKT and PKC activities induced by insulin are increased in liver and muscle , respectively XREF_BIBR .	AKT and PKC activities induced by insulin are increased in liver and muscle, respectively XREF_BIBR.	0	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	0	1
To provide further evidence that the mTOR pathway is causally linked to ZD6474 induced autophagy , we analysed the autophagic response to ZD6474 in the presence or absence of insulin , a compound that strongly induces the Akt and mTOR cascade .	To provide further evidence that the mTOR pathway is causally linked to ZD6474 induced autophagy, we analysed the autophagic response to ZD6474 in the presence or absence of insulin, a compound that strongly induces the Akt and mTOR cascade.	25	40	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	37	38
Against the above background , we investigated whether and how in aortas from ob/ob mice ( a model of type 2 diabetes with hyperinsulinemia ) : 1 ) GRK2 and beta-arrestin 2 might regulate insulin induced Akt and eNOS signaling , and 2 ) GRK2 upregulation might hinder the establishment of a normal relationship between beta-arrestin 2 and Akt under insulin stimulation .	Against the above background, we investigated whether and how in aortas from ob/ob mice (a model of type 2 diabetes with hyperinsulinemia) : 1) GRK2 and beta-arrestin 2 might regulate insulin induced Akt and eNOS signaling, and 2) GRK2 upregulation might hinder the establishment of a normal relationship between beta-arrestin 2 and Akt under insulin stimulation.	33	39	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	34	35	36	37
Our observation that neurotoxicity is a consequence of 4-fold upregulated miR-126 is consistent with findings in hepatocytes , in which Rotenone induced dysfunctional mitochondria caused insulin resistance that was associated with a 3- to 4-fold increase of miR-126 , a 75 % decrease of IRS-1 , an insulin induced reduction of Glycogen , and downregulation of the pAKT and AKT , and pGSK-3beta and GSK3-3beta ratios [ XREF_BIBR ] .	Our observation that neurotoxicity is a consequence of 4-fold upregulated miR-126 is consistent with findings in hepatocytes, in which Rotenone induced dysfunctional mitochondria caused insulin resistance that was associated with a 3- to 4-fold increase of miR-126, a 75% decrease of IRS-1, an insulin induced reduction of Glycogen, and downregulation of the pAKT and AKT, and pGSK-3beta and GSK3-3beta ratios [XREF_BIBR].	46	60	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	47	48	59	60
As expected , insulin significantly increased the pAkt and total Akt ratio in myotubes from both groups before and after exercise ( XREF_FIG ) , whereas there were no significant effect of insulin on pTBC1D4 and total TBC1D4 ratio ( XREF_FIG ) .	As expected, insulin significantly increased the pAkt and total Akt ratio in myotubes from both groups before and after exercise (XREF_FIG), whereas there were no significant effect of insulin on pTBC1D4 and total TBC1D4 ratio (XREF_FIG).	3	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	10	11
In muscle microvessels , insulin can induce vasoconstriction through ERK1/2 dependent endothelin-1 ( ET-1 ) production and vasodilatation through insulin receptor substrate1/2 ( IRS1/2 ) - and Akt dependent nitric oxide ( NO ) production .	In muscle microvessels, insulin can induce vasoconstriction through ERK1/2 dependent endothelin-1 (ET-1) production and vasodilatation through insulin receptor substrate1/2 (IRS1/2) - and Akt dependent nitric oxide (NO) production.	4	34	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	27	28
Furthermore , CAPE enhanced both insulin mediated Akt activation and glucose uptake .	Furthermore, CAPE enhanced both insulin mediated Akt activation and glucose uptake.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Our results demonstrate that PTH treatment of differentiated adipocytes decreased insulin stimulated AKT activity at 24 h ( XREF_FIG ) .	Our results demonstrate that PTH treatment of differentiated adipocytes decreased insulin stimulated AKT activity at 24 h (XREF_FIG).	9	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	12	13
In summary , our findings indicate that Ang II impairs insulin induced Akt Thr 308 phosphorylation by increasing IRS-1 Ser 636 / Ser 639 phosphorylation and IRS-1 protein degradation , by a mechanism dependent on EGF transactivation that leads to PI3K/ERK1/2/mTOR/S6K -1 activation ( XREF_FIG ) .	In summary, our findings indicate that Ang II impairs insulin induced Akt Thr 308 phosphorylation by increasing IRS-1 Ser 636 / Ser 639 phosphorylation and IRS-1 protein degradation, by a mechanism dependent on EGF transactivation that leads to PI3K/ERK1/2/mTOR/S6K -1 activation (XREF_FIG).	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
Palmitate induced production and secretion of S1P from hepatocytes led to not only abrogation of insulin induced Akt activation , but also reduced glucokinase expression and consequent glycogen synthesis [ XREF_BIBR ] .	Palmitate induced production and secretion of S1P from hepatocytes led to not only abrogation of insulin induced Akt activation, but also reduced glucokinase expression and consequent glycogen synthesis [XREF_BIBR].	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	17	18
Insulin receptor downstream signalling has been studied extensively in attempts to identify the molecular alterations underlying the defective insulin stimulated Akt activation in T2D , and an increasingly complex signalling network is appearing XREF_BIBR .	Insulin receptor downstream signalling has been studied extensively in attempts to identify the molecular alterations underlying the defective insulin stimulated Akt activation in T2D, and an increasingly complex signalling network is appearing XREF_BIBR.	15	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	20	21
This would provide a molecular link by which insulin mediated activation of Akt leads to TORC1 activation , and hence tissue growth .	This would provide a molecular link by which insulin mediated activation of Akt leads to TORC1 activation, and hence tissue growth.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	12	13
37 Palmitate treatment similarly impaired insulin signaling in Myo-siControl and Myo-siRNaseL , as shown by a relative fold expression of insulin stimulated P-Akt and Akt rate inferior to 1 ( 0.75 +/-0.07 and 0.81 +/-0.10 , respectively ) , while it was significantly maintained and even increased in Myo-siRLI ( 1.41 +/-0.30 ) ( XREF_FIG ; * P = 0.032 ) .	37 Palmitate treatment similarly impaired insulin signaling in Myo-siControl and Myo-siRNaseL, as shown by a relative fold expression of insulin stimulated P-Akt and Akt rate inferior to 1 (0.75 +/-0.07 and 0.81 +/-0.10, respectively), while it was significantly maintained and even increased in Myo-siRLI (1.41 +/-0.30) (XREF_FIG; * P = 0.032).	18	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	expression of insulin	insulin	P-Akt	P-Akt	p-akt	20	21	22	23
We observed that AICAR , a cell permeable metabolic precursor of the AMPK activator ZMP , enhanced insulin stimulated Akt activation .	We observed that AICAR, a cell permeable metabolic precursor of the AMPK activator ZMP, enhanced insulin stimulated Akt activation.	16	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	19	20
Similar to this result , PA also decreased insulin dependent activation of AKT , glycogen synthase kinase 3 ( GSK-3 ; Fig .	Similar to this result, PA also decreased insulin dependent activation of AKT, glycogen synthase kinase 3 (GSK-3; Fig.	8	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	12	13
Thus , in cardiac myocytes , palmitate inhibits NRG-1beta stimulated phosphorylation of Akt , with preservation of both NRG-1beta activation of ERK , and insulin stimulation of Akt .	Thus, in cardiac myocytes, palmitate inhibits NRG-1beta stimulated phosphorylation of Akt, with preservation of both NRG-1beta activation of ERK, and insulin stimulation of Akt.	24	28	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	24	25	27	28
However , insulin induced activation of the Akt pathway also played a role in promoting ML-1 cell proliferation .	However, insulin induced activation of the Akt pathway also played a role in promoting ML-1 cell proliferation.	2	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	7	8
XREF_BIBR Additionally , although loss of Akt , which is downstream from the insulin receptor , led to a decrease in cell size , cells lacking both Akt and dTSC1 were similar in size to those lacking dTSC1 alone , confirming that dTSC2 : dTSC1 lies downstream of and antagonizes insulin mediated Akt signaling .	XREF_BIBR Additionally, although loss of Akt, which is downstream from the insulin receptor, led to a decrease in cell size, cells lacking both Akt and dTSC1 were similar in size to those lacking dTSC1 alone, confirming that dTSC2 : dTSC1 lies downstream of and antagonizes insulin mediated Akt signaling.	49	53	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	50	51	52	53
Polydatin markedly increased serum insulin levels in diabetic rats , and obviously activated the Akt signaling pathway in diabetic rat livers and insulin resistant HepG2 cells .	Polydatin markedly increased serum insulin levels in diabetic rats, and obviously activated the Akt signaling pathway in diabetic rat livers and insulin resistant HepG2 cells.	0	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	Polydatin markedly increased serum insulin levels	insulin	Akt	Akt	akt	4	5	14	15
Thus , a possible molecular mechanism of increased neuronal survival with insulin supplementation may be through insulin induced Akt activation , which in turn shuts down apoptosis through inhibition of both BAD and caspase 9 .	Thus, a possible molecular mechanism of increased neuronal survival with insulin supplementation may be through insulin induced Akt activation, which in turn shuts down apoptosis through inhibition of both BAD and caspase 9.	0	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
To better understand the intracellular signaling mechanism that causes the association of insulin resistance and hyperlipidemia with cardiovascular diseases , we specifically looked at the ability of lysophosphatidylcholine ( lysoPC ) to inhibit the Akt activation induced by insulin in cultured rat aortic vascular smooth muscle cells .	To better understand the intracellular signaling mechanism that causes the association of insulin resistance and hyperlipidemia with cardiovascular diseases, we specifically looked at the ability of lysophosphatidylcholine (lysoPC) to inhibit the Akt activation induced by insulin in cultured rat aortic vascular smooth muscle cells.	34	39	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	38	39	34	35
Insulin can activate the PI3K and Akt pathway , which triggers cellular glucose uptake in peripheral insulin sensitive tissues and in some regions of the brain .	Insulin can activate the PI3K and Akt pathway, which triggers cellular glucose uptake in peripheral insulin sensitive tissues and in some regions of the brain.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	6	7
Nevertheless , in both T and D males , there were no defects in glucose tolerance , insulin sensitivity or insulin mediated activation of AKT in soleus muscle , liver , or retroperitoneal fat .	Nevertheless, in both T and D males, there were no defects in glucose tolerance, insulin sensitivity or insulin mediated activation of AKT in soleus muscle, liver, or retroperitoneal fat.	12	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	24	25
Insulin stimulated Akt pSer ( 473 ) was approximately 50 % higher ( P < 0.05 ) 24 h following the acute bout of exercise , with this effect remaining after 7 days of training ( P < 0.05 ) .	Insulin stimulated Akt pSer (473) was approximately 50% higher (P < 0.05) 24 h following the acute bout of exercise, with this effect remaining after 7 days of training (P < 0.05).	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
While induction of ER stress has been shown to reduce insulin stimulated AKT activation and decrease IRS tyrosine phosphorylation 21 , to date , there has been no evidence establishing a direct link between the PI 3-kinase pathway and ER stress .	While induction of ER stress has been shown to reduce insulin stimulated AKT activation and decrease IRS tyrosine phosphorylation 21, to date, there has been no evidence establishing a direct link between the PI 3-kinase pathway and ER stress.	9	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	12	13
Early work in cultured myocytes and adipocytes suggested that ceramides impair insulin activation of AKT through two mechanisms : increased protein phosphatase-2A activity and impaired AKT translocation resulting from activation of atypical protein kinase C-zeta [ XREF_BIBR - XREF_BIBR ] .	Early work in cultured myocytes and adipocytes suggested that ceramides impair insulin activation of AKT through two mechanisms : increased protein phosphatase-2A activity and impaired AKT translocation resulting from activation of atypical protein kinase C-zeta [XREF_BIBR - XREF_BIBR].	11	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	14	15
Given the ability of TRB3 overexpression to antagonize insulin stimulated cardiac Akt signaling , we evaluated cardiac metabolism in transgenic mice .	Given the ability of TRB3 overexpression to antagonize insulin stimulated cardiac Akt signaling, we evaluated cardiac metabolism in transgenic mice.	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	11	12
It is possible that obese children have increased insulin signaling and that insulin mediated activation of Akt in the heart contributes to hypertrophy [ XREF_BIBR ] .	It is possible that obese children have increased insulin signaling and that insulin mediated activation of Akt in the heart contributes to hypertrophy [XREF_BIBR].	12	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	16	17
In primary rat hepatocytes , palmitate incubation resulted in a significant inhibition of insulin mediated Akt activation and a significant increase in PP2A expression and activity .	In primary rat hepatocytes, palmitate incubation resulted in a significant inhibition of insulin mediated Akt activation and a significant increase in PP2A expression and activity.	11	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
When cells are exposed to insulin or other stimulators of the PI3K and Akt pathway , FoxO1 is phosphorylated at least at three Akt consensus sites , Thr 24 , Ser 256 , Ser 319 .	When cells are exposed to insulin or other stimulators of the PI3K and Akt pathway, FoxO1 is phosphorylated at least at three Akt consensus sites, Thr 24, Ser 256, Ser 319.	5	14	stimulators	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	13	14
Insulin in turn activates a PI3K and AKT signaling cascade that acts mainly by downregulating FoxO1 activity to adapt to alterations in metabolic demands and to maintain nutrient homeostasis in the pancreas and the other peripheral tissues .	Insulin in turn activates a PI3K and AKT signaling cascade that acts mainly by downregulating FoxO1 activity to adapt to alterations in metabolic demands and to maintain nutrient homeostasis in the pancreas and the other peripheral tissues.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	7	8
An important attribute in diabetes and obesity is the presence of high levels of growth factors including insulin in blood which can activate the PI3K and Akt signalling pathway .	An important attribute in diabetes and obesity is the presence of high levels of growth factors including insulin in blood which can activate the PI3K and Akt signalling pathway.	15	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	26	27
We showed earlier that Akt activity is low in Ins2 Akita hearts as compared with nondiabetic hearts , and insulin injection strongly activated cardiac Akt in this diabetic mouse model .	We showed earlier that Akt activity is low in Ins2 Akita hearts as compared with nondiabetic hearts, and insulin injection strongly activated cardiac Akt in this diabetic mouse model.	19	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	24	25
Adapter protein containing PH domain , PTB domain , and leucine zipper motif 1 ( APPL1 ) has been reported as a positive regulator of insulin stimulated Akt activation .	Adapter protein containing PH domain, PTB domain, and leucine zipper motif 1 (APPL1) has been reported as a positive regulator of insulin stimulated Akt activation.	23	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
Taken together , these data indicate that PI3K-C2beta inactivation does not alter IR levels at the plasma membrane but affects IR trafficking , correlating with a temporary amplification of insulin stimulated class I PI3K and Akt signaling .	Taken together, these data indicate that PI3K-C2beta inactivation does not alter IR levels at the plasma membrane but affects IR trafficking, correlating with a temporary amplification of insulin stimulated class I PI3K and Akt signaling.	27	36	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	35	36
Our findings suggest that insulin activates PKC-zeta , and Akt and PKB downstream of PI3K , and that these pathways contribute to the insulin induced increase of L-dopa uptake into PTCs .	Our findings suggest that insulin activates PKC-zeta, and Akt and PKB downstream of PI3K, and that these pathways contribute to the insulin induced increase of L-dopa uptake into PTCs.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	11	12
Thus , under normal conditions , insulin promotes both the PI3K and Akt and MAPK pathways , supporting cell growth and survival .	Thus, under normal conditions, insulin promotes both the PI3K and Akt and MAPK pathways, supporting cell growth and survival.	6	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	12	13
Insulin resistance was induced by 24 h pretreatment with 10 (-7) m insulin , causing a marked reduction in activation of Akt and ERK1/2 .	Insulin resistance was induced by 24 h pretreatment with 10 (-7) m insulin, causing a marked reduction in activation of Akt and ERK1/2.	0	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	21	22
The interaction of PDK-1 with Grb14 facilitates Akt function : disruption of the interaction by overexpression of a construct of Grb14 mutated in the PDK-1 binding motif significantly decreases insulin dependent activation of Akt .	The interaction of PDK-1 with Grb14 facilitates Akt function : disruption of the interaction by overexpression of a construct of Grb14 mutated in the PDK-1 binding motif significantly decreases insulin dependent activation of Akt.	29	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	33	34
Akt activation by insulin glulisine was weaker than that by human insulin in MCF-10A cells [ XREF_BIBR ] , in mouse muscle tissue [ XREF_BIBR ] , in mouse liver tissue [ XREF_BIBR ] , and in fibroblasts expressing insulin receptor B isoform [ XREF_BIBR ] .	Akt activation by insulin glulisine was weaker than that by human insulin in MCF-10A cells [XREF_BIBR], in mouse muscle tissue [XREF_BIBR], in mouse liver tissue [XREF_BIBR], and in fibroblasts expressing insulin receptor B isoform [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	0	1
In both ob/ob and ob/ob-Gpat 1 -/- mice , insulin resistance was accompanied by elevated hepatic protein kinase C-epsilon activation and blunted insulin stimulated Akt activation .	In both ob/ob and ob/ob-Gpat 1 -/- mice, insulin resistance was accompanied by elevated hepatic protein kinase C-epsilon activation and blunted insulin stimulated Akt activation.	21	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	24	25
Increased levels of insulin and mitogens would lead to PI3K-Akt pathway activation and stimulation of translation ; they are opposed by AMPK , p53 and PTEN .	Increased levels of insulin and mitogens would lead to PI3K-Akt pathway activation and stimulation of translation; they are opposed by AMPK, p53 and PTEN.	1	11	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	PI3K-Akt	PI3K-Akt	pi3k-akt	3	4	9	10
Our studies with dominant negative PKCepsilon adenovirus ( XREF_FIG ) clearly indicate that the insulin stimulated Akt activation requires PKCepsilon .	Our studies with dominant negative PKCepsilon adenovirus (XREF_FIG) clearly indicate that the insulin stimulated Akt activation requires PKCepsilon.	13	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
The Akt and mTOR signalling pathway is activated by insulin .	The Akt and mTOR signalling pathway is activated by insulin.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	1	2
First , for most of the monitored responses ( e.g ., food intake , BW , EE , WAT remodeling , WAT thermogenic and lipogenic genes , liver FGF21 , glucose tolerance , fasting insulin , and hepatic Akt activation by insulin ) , leucine restriction faithfully reproduced the established effects of methionine restriction on these variables ( 16-17 , 22 , 26-27 , 30 , 35-36 ) .	First, for most of the monitored responses (e.g., food intake, BW, EE, WAT remodeling, WAT thermogenic and lipogenic genes, liver FGF21, glucose tolerance, fasting insulin, and hepatic Akt activation by insulin), leucine restriction faithfully reproduced the established effects of methionine restriction on these variables (16-17, 22, 26-27, 30, 35-36).	38	42	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	41	42	38	39
Interestingly , the PI3K and Akt pathway was also a highly likely candidate pathway to be targeted by either group of miRNAs The PI3K and Akt pathway is directly regulated by insulin signaling and has been shown to be dysregulated in skeletal muscle of people with T2DM ; we therefore chose to examine which genes within this pathway would be targeted by the differentially expressed miRNAs .	Interestingly, the PI3K and Akt pathway was also a highly likely candidate pathway to be targeted by either group of miRNAs The PI3K and Akt pathway is directly regulated by insulin signaling and has been shown to be dysregulated in skeletal muscle of people with T2DM; we therefore chose to examine which genes within this pathway would be targeted by the differentially expressed miRNAs.	23	32	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	25	26
Defects in insulin mediated activation of AKT can lead to insulin resistance and promote Type-2 diabetes .	Defects in insulin mediated activation of AKT can lead to insulin resistance and promote Type-2 diabetes.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	6	7
13 Insulin activates Akt and increases eNOS activity through the PI3K-Akt-eNOS pathway , XREF_BIBR , XREF_BIBR which activates eNOS through phosphorylation of serine 1177 35 and increased NO production .	13 Insulin activates Akt and increases eNOS activity through the PI3K-Akt-eNOS pathway, XREF_BIBR, XREF_BIBR which activates eNOS through phosphorylation of serine 1177 35 and increased NO production.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	1	2	3	4
Activation of PKB by insulin in alpha-cells is also observed in our lab ( data not shown ) .	Activation of PKB by insulin in alpha-cells is also observed in our lab (data not shown).	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	2	3
Insulin is well known to activate the Akt signaling cascade with various effects .	Insulin is well known to activate the Akt signaling cascade with various effects.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	7	8
The activation of Akt induced by clonidine or insulin can directly phosphorylate eNOS at Ser1177 and activate the enzyme , leading to NO production XREF_BIBR , XREF_BIBR .	The activation of Akt induced by clonidine or insulin can directly phosphorylate eNOS at Ser1177 and activate the enzyme, leading to NO production XREF_BIBR, XREF_BIBR.	1	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	3	4
MTMR7 inhibits insulin mediated AKT and ERK1/2 signaling in human CRC cells .	MTMR7 inhibits insulin mediated AKT and ERK1/2 signaling in human CRC cells.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	4	5
Activation of AKT by insulin signalling has also been linked to beta-cell survival XREF_BIBR , XREF_BIBR and to the degradation by the proteasome of the pro apoptotic protein p53 XREF_BIBR .	Activation of AKT by insulin signalling has also been linked to beta-cell survival XREF_BIBR, XREF_BIBR and to the degradation by the proteasome of the pro apoptotic protein p53 XREF_BIBR.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	2	3
The results demonstrate that two activated PKBalpha mutants , whose basal activity is equivalent to that of insulin induced wild-type PKB , inhibit GSK-3beta to the same extent as a highly active , constitutively membrane targeted wild-type PKB allele .	The results demonstrate that two activated PKBalpha mutants, whose basal activity is equivalent to that of insulin induced wild-type PKB, inhibit GSK-3beta to the same extent as a highly active, constitutively membrane targeted wild-type PKB allele.	15	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	17	18	20	21
Caffeine and theophylline block insulin stimulated glucose uptake independently of Ca ( 2+ ) release , and the likely mechanism is via blockade of insulin stimulated PI3-kinase and PKB activation .	Caffeine and theophylline block insulin stimulated glucose uptake independently of Ca (2+) release, and the likely mechanism is via blockade of insulin stimulated PI3-kinase and PKB activation.	22	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	PKB	PKB	PKB	24	25	28	29
We find that Akt , which could be activated by host insulin and L-arginine , was active in the tegument layer of both schistosomules and adult worms .	We find that Akt, which could be activated by host insulin and L-arginine, was active in the tegument layer of both schistosomules and adult worms.	3	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	3	4
The insulin induced activation of Akt and mTORC2 by IPMK appears mechanistically distinct from amino acid-mTORC1 signaling , as it involves IPMK ' s catalytic activity ( XREF_SUPPLEMENTARY ) .	The insulin induced activation of Akt and mTORC2 by IPMK appears mechanistically distinct from amino acid-mTORC1 signaling, as it involves IPMK 's catalytic activity (XREF_SUPPLEMENTARY).	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	5	6
As shown in XREF_FIG , phosphorylation of AKT and FOXO1 was clearly induced in cells treated with insulin for a relatively short periods ( 0-4h ) .	As shown in XREF_FIG, phosphorylation of AKT and FOXO1 was clearly induced in cells treated with insulin for a relatively short periods (0-4h).	5	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	17	18	7	8
In contrast , insulin stimulated robust activation of Akt as assessed using the Akt activity reporter , BKAR .	In contrast, insulin stimulated robust activation of Akt as assessed using the Akt activity reporter, BKAR.	3	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	8	9
For example , TNFalpha has been shown to block insulin action inducing serine/threonine phosphorylation of IRS1 [ XREF_BIBR , XREF_BIBR ] , and studies in HepG2 cells and primary mouse hepatocytes have shown that exposure to IL6 is associated with reduced IRS1 phosphorylation , and reduced insulin dependent activation of AKT [ XREF_BIBR ] .	For example, TNFalpha has been shown to block insulin action inducing serine/threonine phosphorylation of IRS1 [XREF_BIBR, XREF_BIBR], and studies in HepG2 cells and primary mouse hepatocytes have shown that exposure to IL6 is associated with reduced IRS1 phosphorylation, and reduced insulin dependent activation of AKT [XREF_BIBR].	46	52	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	46	47	50	51
XREF_FIG shows that regardless of glucose availability , Akt activation by insulin was inhibited by C2 ceramide .	XREF_FIG shows that regardless of glucose availability, Akt activation by insulin was inhibited by C2 ceramide.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	8	9
The PI3K inhibitor wortmannin abolished the insulin mediated activation of Akt and the reduction of chemokine and interleukin-6 levels .	The PI3K inhibitor wortmannin abolished the insulin mediated activation of Akt and the reduction of chemokine and interleukin-6 levels.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	10	11
Insulin induced Akt and eNOS activation was determined in primary cultured endothelial cells from ApoE -/- and Tg ( Prkcb ) ApoE -/- mice .	Insulin induced Akt and eNOS activation was determined in primary cultured endothelial cells from ApoE -/- and Tg (Prkcb) ApoE -/- mice.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
In summary , we have demonstrated that DJB does not increase glucose tolerance , insulin induced Akt signaling in liver or muscle , or skeletal muscle glucose disposal in GK rats .	In summary, we have demonstrated that DJB does not increase glucose tolerance, insulin induced Akt signaling in liver or muscle, or skeletal muscle glucose disposal in GK rats.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
Insulin and IGF-1 stimulate the mTOR pathway by activating the insulin receptor substrate-1 and the phosphatidylinositol-3-kinase and Akt signaling pathway .	Insulin and IGF-1 stimulate the mTOR pathway by activating the insulin receptor substrate-1 and the phosphatidylinositol-3-kinase and Akt signaling pathway.	0	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	17	18
Previous studies have demonstrated that AMPK can be inhibited by protein kinase B ( PKB ) ; however , PKB was activated by dobutamine and the elevated insulin that accompanied hyperglycemia , but there was no effect on AMPK activity .	Previous studies have demonstrated that AMPK can be inhibited by protein kinase B (PKB); however, PKB was activated by dobutamine and the elevated insulin that accompanied hyperglycemia, but there was no effect on AMPK activity.	19	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	27	28	19	20
As expected , we found that PST inhibited insulin stimulated PKB activity , since it depends on PI3-kinase activity .	As expected, we found that PST inhibited insulin stimulated PKB activity, since it depends on PI3-kinase activity.	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	10	11
The effects of C-peptide were not a result of inhibition of insulin mediated Akt and ERK signalling , but were related to reduced insulin induced SREBF1 expression .	The effects of C-peptide were not a result of inhibition of insulin mediated Akt and ERK signalling, but were related to reduced insulin induced SREBF1 expression.	9	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
These effects depend of protein kinase A ( PKA ) activated by glucagon and epinephrine , they are opposite to those of PKB stimulated by insulin signals .	These effects depend of protein kinase A (PKA) activated by glucagon and epinephrine, they are opposite to those of PKB stimulated by insulin signals.	20	26	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	25	26	22	23
C-Jun N-terminal kinases activation can either directly inhibit insulin induced Akt activation or promote the nuclear translocation of FoxO1 in beta-cells32 .	C-Jun N-terminal kinases activation can either directly inhibit insulin induced Akt activation or promote the nuclear translocation of FoxO1 in beta-cells32.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Here , we focused on the role of insulin induced Akt activation on ENaC .	Here, we focused on the role of insulin induced Akt activation on ENaC.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Insulin mediated AKT activation induces Ser 9 phosphorylation of GSK3 , leading to the suppression of its kinase activity 71 .	Insulin mediated AKT activation induces Ser 9 phosphorylation of GSK3, leading to the suppression of its kinase activity 71.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	2	3
The present study demonstrates an important role for insulin mediated Akt activation in the prevention of endothelial cell apoptosis , which may importantly contribute to cell homeostasis and the integrity of the endothelium .	The present study demonstrates an important role for insulin mediated Akt activation in the prevention of endothelial cell apoptosis, which may importantly contribute to cell homeostasis and the integrity of the endothelium.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Insulin and rosuvastatin have also been shown to activate the PI3K and Akt pathway , a pathway that is well known to be involved in cell survival and proliferation [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Insulin and rosuvastatin have also been shown to activate the PI3K and Akt pathway, a pathway that is well known to be involved in cell survival and proliferation [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	12	13
Akt is activated by insulin , various growth factors , and survival factors , and functions in a wortmannin sensitive pathway involving PI-3 kinase ( Franke et al , 1997 ) .	Akt is activated by insulin, various growth factors, and survival factors, and functions in a wortmannin sensitive pathway involving PI-3 kinase (Franke et al, 1997).	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
Frojdo and colleagues demonstrated in primary muscle and L6 myotubes that SIRT1 overexpression enhances , while SIRT1 knockdown impairs insulin stimulated activation of Akt [ XREF_BIBR ] .	Frojdo and colleagues demonstrated in primary muscle and L6 myotubes that SIRT1 overexpression enhances, while SIRT1 knockdown impairs insulin stimulated activation of Akt [XREF_BIBR].	18	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	23	24
The Akt upstream signaling such as insulin and IGF-1 integrates environmental stimuli to regulate life span through Foxo transcription factors ( phosphorylation in response to insulin and IGF-1-mediated Akt activation to expel Foxo from nucleus ) .	The Akt upstream signaling such as insulin and IGF-1 integrates environmental stimuli to regulate life span through Foxo transcription factors (phosphorylation in response to insulin and IGF-1-mediated Akt activation to expel Foxo from nucleus).	1	8	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	1	2
This is because LIRKO mice have unrestrained and unregulated HGP because FOXO1 is constitutively active in the absence of insulin stimulated Akt activation .	This is because LIRKO mice have unrestrained and unregulated HGP because FOXO1 is constitutively active in the absence of insulin stimulated Akt activation.	17	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
Second , a subset of responses to leucine restriction ( e.g ., liver triglycerides , liver lipogenic genes , insulin dependent activation of Akt in WAT , BAT and muscle ) did not reproduce the effects of methionine restriction on these variables .	Second, a subset of responses to leucine restriction (e.g., liver triglycerides, liver lipogenic genes, insulin dependent activation of Akt in WAT, BAT and muscle) did not reproduce the effects of methionine restriction on these variables.	19	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	23	24
Insulin stimulation activates PKB and increases the association of PKCalpha with PKB .	Insulin stimulation activates PKB and increases the association of PKCalpha with PKB.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	3	4
An ex vivo insulin stimulation study confirmed the insulin downstream signaling molecule Akt ( p-AktS473 ) was not activated by insulin in mouse hypothalamic tissue infused with Met CCL5 and , instead , the serine 302 phosphorylation increased .	An ex vivo insulin stimulation study confirmed the insulin downstream signaling molecule Akt (p-AktS473) was not activated by insulin in mouse hypothalamic tissue infused with Met CCL5 and, instead, the serine 302 phosphorylation increased.	9	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	12	13
Because greater insulin mediated Akt activation in muscle is a reliable CR-effect , it would be valuable to identify the specific Akt substrate ( s ) linking CR-effects on Akt to elevated glucose uptake .	Because greater insulin mediated Akt activation in muscle is a reliable CR-effect, it would be valuable to identify the specific Akt substrate (s) linking CR-effects on Akt to elevated glucose uptake.	1	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
It is generally accepted that insulin induced activation of PKB is strictly dependent on the activity of PI 3-kinase .	It is generally accepted that insulin induced activation of PKB is strictly dependent on the activity of PI 3-kinase.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	5	6	9	10
Given that Sestrin2 can function as a redox regulator , it may potentiate insulin induced AKT activation by preventing ROS accumulation .	Given that Sestrin2 can function as a redox regulator, it may potentiate insulin induced AKT activation by preventing ROS accumulation.	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	13	14	15	16
Although insulin stimulated pAkt and Akt did not progressively decrease among surgery groups following 13 weeks of HFD , there was a suppressed pAkt and Akt response in the non insulin stimulated ( saline injected ) 13 week HFD mice .	Although insulin stimulated pAkt and Akt did not progressively decrease among surgery groups following 13 weeks of HFD, there was a suppressed pAkt and Akt response in the non insulin stimulated (saline injected) 13 week HFD mice.	1	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	5	6
In addition , blocking ceramide synthesis has restored insulin mediated Akt activation in previously insulin resistant myotubes .	In addition, blocking ceramide synthesis has restored insulin mediated Akt activation in previously insulin resistant myotubes.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
In conclusion , OLGly , a lipoamino acid , was able to promote 3T3-L1 adipogenesis through the activation of CB1 receptor and the enhancement of insulin mediated Akt signaling pathway .	In conclusion, OLGly, a lipoamino acid, was able to promote 3T3-L1 adipogenesis through the activation of CB1 receptor and the enhancement of insulin mediated Akt signaling pathway.	23	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
Here , we reported that insulin induced activation of Akt and ERK1/2 in CVSMCs .	Here, we reported that insulin induced activation of Akt and ERK1/2 in CVSMCs.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	9	10
Finally , insulin induced muscle Akt Ser 473 phosphorylation was not different in HFF MCK-Cre ; Ptpn2 lox and lox versus Ptpn2 lox and lox mice ( XREF_FIG ) .	Finally, insulin induced muscle Akt Ser 473 phosphorylation was not different in HFF MCK-Cre; Ptpn2 lox and lox versus Ptpn2 lox and lox mice (XREF_FIG).	2	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	5	6
On the other hand , addition of insulin did not decrease the JNK activity , showing that insulin induced Akt activation may rather increase JNK activity .	On the other hand, addition of insulin did not decrease the JNK activity, showing that insulin induced Akt activation may rather increase JNK activity.	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	19	20
In the present study , we report that HDF induced IMLC accumulation , slow oxidative fiber enrichment , and insulin sensitivity reduction ( i.e ., reduced insulin stimulated AKT activation ) were actually associated with important alterations in the network of factors controlling mitochondrial morphogenesis machinery and metabolic functions , when compared with standard diet conditions .	In the present study, we report that HDF induced IMLC accumulation, slow oxidative fiber enrichment, and insulin sensitivity reduction (i.e., reduced insulin stimulated AKT activation) were actually associated with important alterations in the network of factors controlling mitochondrial morphogenesis machinery and metabolic functions, when compared with standard diet conditions.	25	29	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	26	27	28	29
It was revealed that inhibition of PI3K by LY294002 did not lead to decreased PKM2 mRNA expression , and activation of Akt by insulin did not result in increased PKM2 mRNA expression .	It was revealed that inhibition of PI3K by LY294002 did not lead to decreased PKM2 mRNA expression, and activation of Akt by insulin did not result in increased PKM2 mRNA expression.	19	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	21	22
When we identified mTORC2 as the long-sought kinase for Akt and PKB , I received a kind congratulatory note from Dario R. Alessi and Philip Cohen , which was very meaningful to me because they pioneered the study of how insulin activates Akt and PKB and identified the serine 473 phosphorylation site on Akt and PKB that mTORC2 turns out to phosphorylate .	When we identified mTORC2 as the long-sought kinase for Akt and PKB, I received a kind congratulatory note from Dario R. Alessi and Philip Cohen, which was very meaningful to me because they pioneered the study of how insulin activates Akt and PKB and identified the serine 473 phosphorylation site on Akt and PKB that mTORC2 turns out to phosphorylate.	40	46	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	40	41	44	45
Elevated FFA have been reported to reduce insulin stimulated IRS1 tyrosine phosphorylation , possibly via activation of PKCtheta , which would be expected to reduce insulin stimulated Akt activation [ XREF_BIBR ] .	Elevated FFA have been reported to reduce insulin stimulated IRS1 tyrosine phosphorylation, possibly via activation of PKCtheta, which would be expected to reduce insulin stimulated Akt activation [XREF_BIBR].	24	28	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
Insulin stimulated AKT activation ( i.e ., phosphorylation ) and 2-deoxy-D-[ 3 H ]-glucose ( 2DOG ) uptake were measured .	Insulin stimulated AKT activation (i.e., phosphorylation) and 2-deoxy-D-[3 H]-glucose (2DOG) uptake were measured.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	2	3
The Akt and mTOR dependent pathway was activated by insulin and leucine and further enhanced by 1,25 ( OH ) 2D3 .	The Akt and mTOR dependent pathway was activated by insulin and leucine and further enhanced by 1,25 (OH) 2D3.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	1	2
Insulin stimulation induces the dissociation of IRS proteins and Akt from the APPL1-IR complex , facilitating the binding of IRS1/2 to the activated IR near the plasma membrane [ XREF_BIBR ] .	Insulin stimulation induces the dissociation of IRS proteins and Akt from the APPL1-IR complex, facilitating the binding of IRS1/2 to the activated IR near the plasma membrane [XREF_BIBR].	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	9	10
The mTORC2 plays a key role in insulin activation of Akt by phosphorylating Ser 473 which primes Akt for Thr 308 phosphorylation by PDK1 [ XREF_BIBR ] .	The mTORC2 plays a key role in insulin activation of Akt by phosphorylating Ser 473 which primes Akt for Thr 308 phosphorylation by PDK1 [XREF_BIBR].	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	10	11
Our research is focused on the inhibitory effects of ethanol on insulin and insulin like growth factor ( IGF ) signaling because ( 1 ) insulin , IGF-1 , and IGF-II receptors are abundantly expressed in the developing CNS ; ( 2 ) signaling through these receptors mediates diverse neuronal functions , including survival and motility ; and ( 3 ) neurotoxic effects of ethanol target insulin- and IGF stimulated Erk MAPK and PI3 kinase -- Akt signaling .	Our research is focused on the inhibitory effects of ethanol on insulin and insulin like growth factor (IGF) signaling because (1) insulin, IGF-1, and IGF-II receptors are abundantly expressed in the developing CNS; (2) signaling through these receptors mediates diverse neuronal functions, including survival and motility; and (3) neurotoxic effects of ethanol target insulin- and IGF stimulated Erk MAPK and PI3 kinase -- Akt signaling.	66	77	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin-	insulin-	insulin-	Akt	Akt	Akt	66	67	76	77
AAH mediates neuronal motility , and is stimulated by insulin and IGF activation of PI3-kinase and Akt , or inhibition of GSK3beta .	AAH mediates neuronal motility, and is stimulated by insulin and IGF activation of PI3-kinase and Akt, or inhibition of GSK3beta.	9	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	16	17
419 , 101-109 ) , long-chain saturated FFAs inhibited insulin stimulation of Akt and protein kinase B , a central regulator of glucose uptake and anabolic metabolism .	419, 101-109), long-chain saturated FFAs inhibited insulin stimulation of Akt and protein kinase B, a central regulator of glucose uptake and anabolic metabolism.	9	15	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	12	13
Studies carried out in several cultured cells clearly report that the TRIB3 Q84R missense polymorphism , is a gain-of-function amino acid substitution , with the Arg ( 84 ) variant being a stronger inhibitor of insulin mediated AKT activation as compared with the more frequent Gln ( 84 ) variant .	Studies carried out in several cultured cells clearly report that the TRIB3 Q84R missense polymorphism, is a gain-of-function amino acid substitution, with the Arg (84) variant being a stronger inhibitor of insulin mediated AKT activation as compared with the more frequent Gln (84) variant.	33	38	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	35	36	37	38
Effect of ROS and RNS modulators on insulin stimulated Akt activity in cellulo .	Effect of ROS and RNS modulators on insulin stimulated Akt activity in cellulo.	5	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
Altogether , our results provide evidence that CA inhibits the insulin dependent stimulation of the Akt and mTOR pathway .	Altogether, our results provide evidence that CA inhibits the insulin dependent stimulation of the Akt and mTOR pathway.	10	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	15	16
Furthermore , testosterone treatment modulated the insulin dependent signal transduction pathways inducing a rapid and persistent activation of AKT , ERK and mTOR , and a transient inhibition of GSK3beta .	Furthermore, testosterone treatment modulated the insulin dependent signal transduction pathways inducing a rapid and persistent activation of AKT, ERK and mTOR, and a transient inhibition of GSK3beta.	6	19	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	18	19
The positive effects of ANG-( 1-7 ) on insulin stimulated glucose transport activity and Akt Ser ( 473 ) phosphorylation in soleus muscle were completely prevented in presence of 1000 nM A779 .	The positive effects of ANG-(1-7) on insulin stimulated glucose transport activity and Akt Ser (473) phosphorylation in soleus muscle were completely prevented in presence of 1000 nM A779.	1	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	14	15
Loss of Ubl4A results in the impairment of insulin induced Akt translocation to the plasma membrane and activation .	Loss of Ubl4A results in the impairment of insulin induced Akt translocation to the plasma membrane and activation.	6	11	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Activation of Akt by insulin is transmitted via phosphatidylinositol-3-OH kinase ( PI-3K ) and enhances glucose uptake .	Activation of Akt by insulin is transmitted via phosphatidylinositol-3-OH kinase (PI-3K) and enhances glucose uptake.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	2	3
Furthermore , it has demonstrated that ATM is necessary for full activation of Akt in response to insulin in Cos cells , and a role of ATM in insulin stimulated activation of Akt in cultured L6 myoblasts has been described .	Furthermore, it has demonstrated that ATM is necessary for full activation of Akt in response to insulin in Cos cells, and a role of ATM in insulin stimulated activation of Akt in cultured L6 myoblasts has been described.	26	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	28	29	32	33
Maximal insulin activates more Akt than required for maximal glucose transport stimulation .	Maximal insulin activates more Akt than required for maximal glucose transport stimulation.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	4	5
The insulin induced activation of Akt was even more pronounced in animals wearing positive lenses and negative lenses .	The insulin induced activation of Akt was even more pronounced in animals wearing positive lenses and negative lenses.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	5	6
Expressed in vitro , the Ile326 and the Met326 variant acted equally as a dominant negative and prevented ( 60-70 % inhibition ) insulin mediated activation of PKB by inhibiting the phosphorylation of PKB at Thr308 .	Expressed in vitro, the Ile326 and the Met326 variant acted equally as a dominant negative and prevented (60-70% inhibition) insulin mediated activation of PKB by inhibiting the phosphorylation of PKB at Thr308.	17	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	23	24	27	28
Indeed , miR-26b modulates the insulin stimulated AKT activation via the inhibition of its target gene PTEN , promoting the GLUT4 translocation to the plasma membrane and insulin induced glucose uptake in human mature adipocytes .	Indeed, miR-26b modulates the insulin stimulated AKT activation via the inhibition of its target gene PTEN, promoting the GLUT4 translocation to the plasma membrane and insulin induced glucose uptake in human mature adipocytes.	3	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
showed intact insulin activation of Akt in the liver , increased gluconeogenesis and hepatic PEPCK mRNA levels , hyperinsulinemia , hyperleptinemia , glucose intolerance , and reduced insulin sensitivity .	showed intact insulin activation of Akt in the liver, increased gluconeogenesis and hepatic PEPCK mRNA levels, hyperinsulinemia, hyperleptinemia, glucose intolerance, and reduced insulin sensitivity.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	5	6
Myostain has been shown to inhibit Akt , which is activated by two major protein-synthesis-promoting hormones , insulin and insulin like growth factor-1 ( IGF-1 ) .	Myostain has been shown to inhibit Akt, which is activated by two major protein-synthesis-promoting hormones, insulin and insulin like growth factor-1 (IGF-1).	5	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	6	7
In contrast , treatment with the DNA-PKcs inhibitor NU7026 reduced S473 phosphorylation of Akt upon irradiation or doxorubicin treatment , whereas DNA-PKcs inhibition did not affect Akt S473 phosphorylation in human umbilical vein endothelial cells treated with insulin [ XREF_BIBR ] .	In contrast, treatment with the DNA-PKcs inhibitor NU7026 reduced S473 phosphorylation of Akt upon irradiation or doxorubicin treatment, whereas DNA-PKcs inhibition did not affect Akt S473 phosphorylation in human umbilical vein endothelial cells treated with insulin [XREF_BIBR].	26	39	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	37	38	26	27
Live cell imaging reveals that global aPKC activity is constitutive and insulin unresponsive , in marked contrast to the insulin dependent activation of Akt monitored by an Akt specific reporter .	Live cell imaging reveals that global aPKC activity is constitutive and insulin unresponsive, in marked contrast to the insulin dependent activation of Akt monitored by an Akt specific reporter.	19	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	23	24
Moreover , we show that the enhanced PP2A expression is sufficient to inhibit insulin induced FoxO1 phosphorylation via blockade of insulin mediated Akt activation or/and through direct association and dephosphorylation of pS-FoxO1 .	Moreover, we show that the enhanced PP2A expression is sufficient to inhibit insulin induced FoxO1 phosphorylation via blockade of insulin mediated Akt activation or/and through direct association and dephosphorylation of pS-FoxO1.	18	24	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
In addition to Cdk1 activation , insulin activating through insulin receptors induces activation of MEK and ERK and Akt signaling pathway in cells expressing PJA1 mutant , suggesting a negative regulation of these pathways by PJA1 as well .	In addition to Cdk1 activation, insulin activating through insulin receptors induces activation of MEK and ERK and Akt signaling pathway in cells expressing PJA1 mutant, suggesting a negative regulation of these pathways by PJA1 as well.	6	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	18	19
Curiously , Akt kinase , a key pro survival molecule and a well established inhibitor of apoptotic cell death , has also recently been linked to necroptosis in L929 cells XREF_BIBR , where insulin dependent activation of Akt was suggested to promote necroptosis by suppressing autophagy .	Curiously, Akt kinase, a key pro survival molecule and a well established inhibitor of apoptotic cell death, has also recently been linked to necroptosis in L929 cells XREF_BIBR, where insulin dependent activation of Akt was suggested to promote necroptosis by suppressing autophagy.	33	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	33	34	37	38
In contrast , F KO mice exhibited HFD induced inhibition of insulin stimulated AKT activation in muscle ( XREF_SUPPLEMENTARY ) , but not in adipose tissue or liver ( XREF_FIG & XREF_FIG ) .	In contrast, F KO mice exhibited HFD induced inhibition of insulin stimulated AKT activation in muscle (XREF_SUPPLEMENTARY), but not in adipose tissue or liver (XREF_FIG & XREF_FIG).	9	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	13	14
sDPP-4 impairs insulin mediated activation of Akt in the human adipocyte , skeletal muscle , and smooth muscle cells in vitro [ XREF_BIBR ] .	sDPP-4 impairs insulin mediated activation of Akt in the human adipocyte, skeletal muscle, and smooth muscle cells in vitro [XREF_BIBR].	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
Presently , we examined insulin activation of aPKC and PKB in vastus lateralis muscle , adipocytes , and liver in wild-type and IRS-1 knockout mice , and observed striking tissue specific differences .	Presently, we examined insulin activation of aPKC and PKB in vastus lateralis muscle, adipocytes, and liver in wild-type and IRS-1 knockout mice, and observed striking tissue specific differences.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	4	5	9	10
Insulin activation induces stimulation of Akt and PKB and serum- and glucocorticoid inducible kinase isoforms , further resulting in the inhibition of glycogen synthase kinase ( GSK )-3.	Insulin activation induces stimulation of Akt and PKB and serum- and glucocorticoid inducible kinase isoforms, further resulting in the inhibition of glycogen synthase kinase (GSK)-3.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB	PKB	PKB	0	1	7	8
Akt activation by insulin glargine was similar to that by human insulin in non malignant primary human muscle cells [ XREF_BIBR ] , 3T3-L1 adipocytes [ XREF_BIBR ] , L6 myocytes [ XREF_BIBR ] , primary hepatocytes [ XREF_BIBR ] , primary vascular smooth muscle cells [ XREF_BIBR ] , and in fibroblasts expressing insulin receptor A isoform [ XREF_BIBR ] .	Akt activation by insulin glargine was similar to that by human insulin in non malignant primary human muscle cells [XREF_BIBR], 3T3-L1 adipocytes [XREF_BIBR], L6 myocytes [XREF_BIBR], primary hepatocytes [XREF_BIBR], primary vascular smooth muscle cells [XREF_BIBR], and in fibroblasts expressing insulin receptor A isoform [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	0	1
However , chronic ROS exposure attenuates the insulin stimulated AKT signaling pathway and causes insulin resistance in 3T3-L1 adipocytes .	However, chronic ROS exposure attenuates the insulin stimulated AKT signaling pathway and causes insulin resistance in 3T3-L1 adipocytes.	5	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	9	10
Our in vitro data confirm that insulin stimulates the expected canonical Akt signaling pathway in Mvt1 cells and also enhances Mvt1 proliferation .	Our in vitro data confirm that insulin stimulates the expected canonical Akt signaling pathway in Mvt1 cells and also enhances Mvt1 proliferation.	6	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	11	12
Insulin stimulation of Akt in alpha1beta2gamma2 expressing HEK293 cells led to an enhancement in surface receptors and an increase in the amplitude of GABA A R mediated mIPSCs .	Insulin stimulation of Akt in alpha1beta2gamma2 expressing HEK293 cells led to an enhancement in surface receptors and an increase in the amplitude of GABA A R mediated mIPSCs.	0	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
However , neither insulin stimulated Akt and TBC1D4 signaling and glucose transport exvivo , nor cell signaling invivo were altered by the diets .	However, neither insulin stimulated Akt and TBC1D4 signaling and glucose transport exvivo, nor cell signaling invivo were altered by the diets.	2	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
Moreover , APPL1 is required for the insulin mediated Akt activation in C2C12 cells .	Moreover, APPL1 is required for the insulin mediated Akt activation in C2C12 cells.	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	9	10
Overexpression of this mutated IRS1 by adenovirus ( ADIRS1mt ) in neonatal rat ventricular cardiomyocytes ( NRVMs ) removes the ADGRK2 inhibitory effects on insulin mediated activation of Akt ( XREF_FIG ) and GLUT4 translocation to the membrane ( XREF_SUPPLEMENTARY ) .	Overexpression of this mutated IRS1 by adenovirus (ADIRS1mt) in neonatal rat ventricular cardiomyocytes (NRVMs) removes the ADGRK2 inhibitory effects on insulin mediated activation of Akt (XREF_FIG) and GLUT4 translocation to the membrane (XREF_SUPPLEMENTARY).	24	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	24	25	28	29
In the present study , we observed that ATP2B1 gene silencing resulted in higher intracellular Ca 2+ and simultaneously led to enhanced insulin induced AKT activity .	In the present study, we observed that ATP2B1 gene silencing resulted in higher intracellular Ca 2+ and simultaneously led to enhanced insulin induced AKT activity.	19	25	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	22	23	24	25
In addition , insulin dependent activation of Akt , important in mediating insulin ' s downstream metabolic actions , is markedly inhibited by IL-6 treatment .	In addition, insulin dependent activation of Akt, important in mediating insulin 's downstream metabolic actions, is markedly inhibited by IL-6 treatment.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
The insulin signal acts through the insulin receptor to activate Akt to phosphorylate the FOXO transcription factor , thus barring FOXO from the nucleus .	The insulin signal acts through the insulin receptor to activate Akt to phosphorylate the FOXO transcription factor, thus barring FOXO from the nucleus.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	10	11
To demonstrate that Resv effectively improves insulin sensitivity in WAT , we studied the effects of this compound in 3T3-L1 adipocytes and found that the serum from rhesus monkeys fed with HFS + Resv diet normalized insulin induced Akt activation , increased the number of cells expressing GLUT4 and the quantity of this glucose transporter at the plasma membrane in response to an acute insulin challenge .	To demonstrate that Resv effectively improves insulin sensitivity in WAT, we studied the effects of this compound in 3T3-L1 adipocytes and found that the serum from rhesus monkeys fed with HFS + Resv diet normalized insulin induced Akt activation, increased the number of cells expressing GLUT4 and the quantity of this glucose transporter at the plasma membrane in response to an acute insulin challenge.	36	39	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	36	37	38	39
Consistent with the elevated PI3K and Akt signaling in Gpx1-/- myotubes , knockdown of Gpx1 ( ~ 50 % ) by RNA interference in C2C12 muscle cells also resulted in increased insulin induced Akt Ser 473 phosphorylation and this was suppressed by ebselen ( XREF_FIG ) .	Consistent with the elevated PI3K and Akt signaling in Gpx1-/- myotubes, knockdown of Gpx1 (~ 50%) by RNA interference in C2C12 muscle cells also resulted in increased insulin induced Akt Ser 473 phosphorylation and this was suppressed by ebselen (XREF_FIG).	30	34	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	33	34
Insulin activates the PI3K and PKB-AKT and Ras and MAPK-ERK pathways 33 .	Insulin activates the PI3K and PKB-AKT and Ras and MAPK-ERK pathways 33.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKB-AKT	PKB-AKT	PKB-AKT	0	1	5	6
It was first shown that carrageenan consumption -- in doses equivalent to those in foodstuff -- leads to glucose intolerance via increased IRS-1 serine phosphorylation and interference with insulin triggered PI3K-Akt pathway .	It was first shown that carrageenan consumption -- in doses equivalent to those in foodstuff -- leads to glucose intolerance via increased IRS-1 serine phosphorylation and interference with insulin triggered PI3K-Akt pathway.	26	31	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	28	29	30	31
We next assessed the role of Nox4 in insulin stimulated ERK1/2 and AKT activation .	We next assessed the role of Nox4 in insulin stimulated ERK1/2 and AKT activation.	2	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	12	13
Vehicle treated pre-conditioned media resulted in a significant and robust ( 802 +/-132% ) phosphorylation of Akt at serine 473 , a common marker of insulin stimulated Akt activity , and this was not affected by lipid loading with acLDL , or co-treatment with HDL ( XREF_FIG ) .	Vehicle treated pre-conditioned media resulted in a significant and robust (802 +/-132%) phosphorylation of Akt at serine 473, a common marker of insulin stimulated Akt activity, and this was not affected by lipid loading with acLDL, or co-treatment with HDL (XREF_FIG).	23	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
However , only the rise in insulin after a meal , and not amino acids , activates PKB and the signaling components that are upstream of PKB , that is , the insulin receptor , IRS-1 and PI 3-kinase .	However, only the rise in insulin after a meal, and not amino acids, activates PKB and the signaling components that are upstream of PKB, that is, the insulin receptor, IRS-1 and PI 3-kinase.	4	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	6	7	17	18
Effects of UA on Insulin Stimulated Activation of Akt and Endothelial Nitric Oxide Synthase ( eNOS ) Signaling .	Effects of UA on Insulin Stimulated Activation of Akt and Endothelial Nitric Oxide Synthase (eNOS) Signaling.	4	9	Stimulated Activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	4	5	8	9
Insulin activated ERK1/2 and Akt signaling pathway in CVSMCs .	Insulin activated ERK1/2 and Akt signaling pathway in CVSMCs.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
Increased AKT signaling by insulin was also evident in primary L-hsf1 -/- and hsf1 -/- hepatocytes ( unpublished data ) .	Increased AKT signaling by insulin was also evident in primary L-hsf1 -/- and hsf1 -/- hepatocytes (unpublished data).	1	5	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	4	5	1	2
A triple mutant of PKB failed to interfere with insulin activation of PKB in hepatocytes even at high overexpression levels achieved after adenovirus transduction .	A triple mutant of PKB failed to interfere with insulin activation of PKB in hepatocytes even at high overexpression levels achieved after adenovirus transduction.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	9	10	12	13
Since phosphorylation of AKT at Thr308 is an indicator for its activation , the results show an induction of AKT by insulin treatment in FDLE cells .	Since phosphorylation of AKT at Thr308 is an indicator for its activation, the results show an induction of AKT by insulin treatment in FDLE cells.	17	22	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	21	22	19	20
Interestingly , the effects of BDNF on translation were stronger than that of insulin likely because BDNF activates both Akt and MAPK , whereas insulin activates only Akt in neurons .	Interestingly, the effects of BDNF on translation were stronger than that of insulin likely because BDNF activates both Akt and MAPK, whereas insulin activates only Akt in neurons.	24	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	24	25	27	28
Overexpression of miR-181a-5p and miR-23a-3p in adipocytes upregulated insulin stimulated AKT activation and reduced TNFalpha induced IR , regulating PTEN and S6K expression .	Overexpression of miR-181a-5p and miR-23a-3p in adipocytes upregulated insulin stimulated AKT activation and reduced TNFalpha induced IR, regulating PTEN and S6K expression.	7	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	10	11
On the other hand , aPKC inhibition provoked increases in FoxO1 phosphorylation even in the absence of concurrent insulin stimulation of Akt , and the underlying mechanism is presently uncertain .	On the other hand, aPKC inhibition provoked increases in FoxO1 phosphorylation even in the absence of concurrent insulin stimulation of Akt, and the underlying mechanism is presently uncertain.	18	22	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	21	22
In prior studies we have reported that MC4R activation synergistically increases insulin stimulated AKT signaling and glucose uptake in hypothalamic cells [ XREF_BIBR ] .	In prior studies we have reported that MC4R activation synergistically increases insulin stimulated AKT signaling and glucose uptake in hypothalamic cells [XREF_BIBR].	10	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	11	12	13	14
The decrease in electrophoretic mobility and activation of PKB induced by insulin was reversed both in vitro by treatment of the enzyme with alkaline phosphatase and in the intact adipocyte upon removal of insulin or addition of the phosphatidylinositol 3-kinase ( PI 3-kinase ) inhibitor wortmannin .	The decrease in electrophoretic mobility and activation of PKB induced by insulin was reversed both in vitro by treatment of the enzyme with alkaline phosphatase and in the intact adipocyte upon removal of insulin or addition of the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin.	4	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	11	12	8	9
Akt is activated by insulin or various growth factors to function in a PI3K sensitive pathway .	Akt is activated by insulin or various growth factors to function in a PI3K sensitive pathway.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	0	1
Another miRNA highly elevated in the skeletal muscle of diabetic GK rats is miR-29 that has been implicated in inhibition of insulin action by inhibition of insulin stimulated Akt ( protein kinase B ) activation .	Another miRNA highly elevated in the skeletal muscle of diabetic GK rats is miR-29 that has been implicated in inhibition of insulin action by inhibition of insulin stimulated Akt (protein kinase B) activation.	24	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	26	27	28	29
Although chronic alcohol consumption can antagonize insulin stimulated AKT and AS160 phosphorylation in skeletal muscle of rats [ XREF_BIBR ] , other studies show phosphorylation of the insulin receptor , IRS-1 , PI3K and AKT was not impaired ( and may be increased ) in muscle from alcohol fed mice [ XREF_BIBR , XREF_BIBR ] , suggesting a defect in signal transduction downstream of AKT .	Although chronic alcohol consumption can antagonize insulin stimulated AKT and AS160 phosphorylation in skeletal muscle of rats [XREF_BIBR], other studies show phosphorylation of the insulin receptor, IRS-1, PI3K and AKT was not impaired (and may be increased) in muscle from alcohol fed mice [XREF_BIBR, XREF_BIBR], suggesting a defect in signal transduction downstream of AKT.	5	12	stimulated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	insulin	insulin	insulin	AKT	AKT and AS160 phosphorylation	akt	6	7	8	9
XREF_BIBR The TAU5 motif is most important for androgen independent activation of the AR , XREF_BIBR is controlled by insulin and IGF-1-mediated activation of AKT , and is thus connected to the nutrient status .	XREF_BIBR The TAU5 motif is most important for androgen independent activation of the AR, XREF_BIBR is controlled by insulin and IGF-1-mediated activation of AKT, and is thus connected to the nutrient status.	19	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	19	20	24	25
To directly test if Akt is activated by insulin in LbetaT2 cells , we preformed both time and dose response studies .	To directly test if Akt is activated by insulin in LbetaT2 cells, we preformed both time and dose response studies.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	4	5
Insulin ultimately triggers PI3K and Akt pathway , which contributes to IKK and NF-kappaB activation .	Insulin ultimately triggers PI3K and Akt pathway, which contributes to IKK and NF-kappaB activation.	0	6	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
As shown in XREF_FIG , incubation with glucose oxidase , which catalyzed the conversion of glucose to glucuronic acid and H 2 O 2 , did not change basic AKT phosphorylation levels ; however , the phosphorylation levels of insulin induced AKT in chronic ROS treated adipocytes were significantly decreased .	As shown in XREF_FIG, incubation with glucose oxidase, which catalyzed the conversion of glucose to glucuronic acid and H 2 O 2, did not change basic AKT phosphorylation levels; however, the phosphorylation levels of insulin induced AKT in chronic ROS treated adipocytes were significantly decreased.	37	44	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	39	40	41	42
Insulin induced stimulation of Akt directly increases endothelial nitric oxide ( NO ) production via endothelial nitric oxide synthase ( eNOS ) [ XREF_BIBR , XREF_BIBR ] .	Insulin induced stimulation of Akt directly increases endothelial nitric oxide (NO) production via endothelial nitric oxide synthase (eNOS) [XREF_BIBR, XREF_BIBR].	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
Insulin activation of Akt in adipocytes .	Insulin activation of Akt in adipocytes.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
As positive control for Akt phosphorylation , cardiomyocytes were treated with 100nM insulin .	As positive control for Akt phosphorylation, cardiomyocytes were treated with 100nM insulin.	4	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	4	5
Regarding its interaction with degradation , experiments by Kitamura et al XREF_BIBR on FOXO1 in betaTC3 cells ( pancreatic cells , in which Akt is permanently activated by endogenous insulin ) show that acetylation exerts a strong protective effect against degradation .	Regarding its interaction with degradation, experiments by Kitamura et al XREF_BIBR on FOXO1 in betaTC3 cells (pancreatic cells, in which Akt is permanently activated by endogenous insulin) show that acetylation exerts a strong protective effect against degradation.	23	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	23	24
XREF_BIBR There is an association between increased oxidative stress and GDM as excessive oxidative stress decreases the phosphorylation of insulin stimulated Akt , glycogen synthase kinase 3 ( GSK-3 ) and forkhead box O ( FOXO ) 1alpha and alters the phosphorylation of MAPKs , including p38 , extracelluar signal regulated protein kinase and JNK , all of which have been reported to contribute to insulin resistance .	XREF_BIBR There is an association between increased oxidative stress and GDM as excessive oxidative stress decreases the phosphorylation of insulin stimulated Akt, glycogen synthase kinase 3 (GSK-3) and forkhead box O (FOXO) 1alpha and alters the phosphorylation of MAPKs, including p38, extracelluar signal regulated protein kinase and JNK, all of which have been reported to contribute to insulin resistance.	17	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	phosphorylation of insulin	insulin	Akt	Akt	akt	19	20	21	22
Insulin mediated Akt activation leads to phosphorylation and inhibition of GSK3beta , activating glycogen synthase and increasing hepatic glycogen deposition [ XREF_BIBR ] .	Insulin mediated Akt activation leads to phosphorylation and inhibition of GSK3beta, activating glycogen synthase and increasing hepatic glycogen deposition [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
This result agrees with our previous findings demonstrating ZNT7 KO or knockdown can negatively impact the insulin mediated AKT activation in muscle and fat tissues leading to down-regulation of glucose uptake into myotubes and adipocytes 30 , 31 .	This result agrees with our previous findings demonstrating ZNT7 KO or knockdown can negatively impact the insulin mediated AKT activation in muscle and fat tissues leading to down-regulation of glucose uptake into myotubes and adipocytes 30, 31.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	18	19
TF cytoplasmic tail dependent signaling induced by ligand FVIIa binding blunts both basal and insulin mediated Akt activation and alters the expression of Akt target genes known to regulate weight gain .	TF cytoplasmic tail dependent signaling induced by ligand FVIIa binding blunts both basal and insulin mediated Akt activation and alters the expression of Akt target genes known to regulate weight gain.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
It is concluded that PKB , which is activated to a greater extent by insulin than EGF , and peak 2 , which is activated by insulin and counteracted by EGF , are possible candidates in mediating the stimulation of glycogen synthesis by insulin .	It is concluded that PKB, which is activated to a greater extent by insulin than EGF, and peak 2, which is activated by insulin and counteracted by EGF, are possible candidates in mediating the stimulation of glycogen synthesis by insulin.	4	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	14	15	4	5
Both butyrate and insulin significantly increased phospho-AKT abundance and phospho-AKT and AKT ratio ( P < 0.01 ) .	Both butyrate and insulin significantly increased phospho-AKT abundance and phospho-AKT and AKT ratio (P < 0.01).	1	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	11	12
Insulin or forskolin dose-dependently respectively activated PI3K and AKT or PKA and CREB signaling in neurons within 15 min ( XREF_SUPPLEMENTARY ) .	Insulin or forskolin dose-dependently respectively activated PI3K and AKT or PKA and CREB signaling in neurons within 15 min (XREF_SUPPLEMENTARY).	0	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	8	9
In a rat model of diet induced glucose intolerance , chronic EPO treatment improved fasting glucose levels and glucose tolerance , and partially rescued insulin stimulated AKT activation and reduced markers of oxidative stress XREF_BIBR .	In a rat model of diet induced glucose intolerance, chronic EPO treatment improved fasting glucose levels and glucose tolerance, and partially rescued insulin stimulated AKT activation and reduced markers of oxidative stress XREF_BIBR.	23	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	24	25	26	27
While BEZ-235 abolished the increase in activation of Akt induced by insulin in both B16 and Mel-RMu cells ( XREF_FIG ) , it also diminished insulin mediated protection against cytotoxicity induced by DTIC ( XREF_FIG ) .	While BEZ-235 abolished the increase in activation of Akt induced by insulin in both B16 and Mel-RMu cells (XREF_FIG), it also diminished insulin mediated protection against cytotoxicity induced by DTIC (XREF_FIG).	6	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	8	9
However , it remains unknown whether altering glucose tolerance and insulin resistance regulates insulin mediated Akt signaling related GRK2 in T2DM models .	However, it remains unknown whether altering glucose tolerance and insulin resistance regulates insulin mediated Akt signaling related GRK2 in T2DM models.	12	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
AKT can also be activated by insulin growth factor 1 ( IGF-1 ) XREF_BIBR , XREF_BIBR , XREF_BIBR .	AKT can also be activated by insulin growth factor 1 (IGF-1) XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	0	1
Insulin activated the phosphoinositide 3 ( PI3 ) kinase and Akt pathway and reduced apoptosis and necrosis by suppressing ROS increase and preserving DeltaPsi ( m ) .	Insulin activated the phosphoinositide 3 (PI3) kinase and Akt pathway and reduced apoptosis and necrosis by suppressing ROS increase and preserving DeltaPsi (m).	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	10	11
It is interesting to note that installment of BRD7 levels in the liver of obese and diabetic mice , while increasing the insulin stimulated Akt activation ( IRS1 --> PI3K --> Akt axis ) , it does not increase the sensitivity of IR --> IRS1 axis .	It is interesting to note that installment of BRD7 levels in the liver of obese and diabetic mice, while increasing the insulin stimulated Akt activation (IRS1 --> PI3K --> Akt axis), it does not increase the sensitivity of IR --> IRS1 axis.	20	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	24	25
Insulin stimulated Akt Thr 308 ( XREF_FIG ) andGSK-3alpha and beta ( datanot shown ) phosphorylation was not affected , indicating that Ang II/AT 1 R mediated EGF receptor transactivation is necessary for the inhibitory effect of Ang II on insulin induced Akt Thr 308 and GSK-3alpha and beta phosphorylation .	Insulin stimulated Akt Thr 308 (XREF_FIG) andGSK-3alpha and beta (datanot shown) phosphorylation was not affected, indicating that Ang II/AT 1 R mediated EGF receptor transactivation is necessary for the inhibitory effect of Ang II on insulin induced Akt Thr 308 and GSK-3alpha and beta phosphorylation.	38	43	induced	Positive_early_activation	Positive_activation	Negative_activation	Insulin	insulin	insulin	Akt	Akt	Akt	40	41	42	43
However , insulin , but not contraction , increased p70 ( S6K ) and Akt activities in the muscle .	However, insulin, but not contraction, increased p70 (S6K) and Akt activities in the muscle.	2	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	14	15
Finally , we demonstrate that in cultured brown adipocytes myostatin can inhibit insulin induced AKT activation .	Finally, we demonstrate that in cultured brown adipocytes myostatin can inhibit insulin induced AKT activation.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	14	15
Additionally , KN-62 affected neither insulin stimulated phosphoinositide 3-kinase nor Akt activity , suggesting that the effects of KN-62 are not due to non specific effects of this inhibitor on these regions of the insulin signalling cascade .	Additionally, KN-62 affected neither insulin stimulated phosphoinositide 3-kinase nor Akt activity, suggesting that the effects of KN-62 are not due to non specific effects of this inhibitor on these regions of the insulin signalling cascade.	3	11	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	10	11
Both insulin , previously shown to activate Akt , and TGFbeta induced Akt activation in NMuMG cells , albeit with different kinetics ( XREF_FIG , top and middle panels ) ; however , insulin mediated Akt activation did not result in hnRNP E1 phosphorylation ( XREF_FIG , bottom panel ) .	Both insulin, previously shown to activate Akt, and TGFbeta induced Akt activation in NMuMG cells, albeit with different kinetics (XREF_FIG, top and middle panels); however, insulin mediated Akt activation did not result in hnRNP E1 phosphorylation (XREF_FIG, bottom panel).	33	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	33	34	35	36
Resveratrol effectively inhibits insulin induced Akt and MAPK ( mitogen activated protein kinase ) activation mainly through disruption of the interactions between insulin receptor substrates and its downstream binding proteins including p85 regulatory subunit of phosphoinositide 3-kinase and Grb2 ( growth factor receptor bound protein 2 ) .	Resveratrol effectively inhibits insulin induced Akt and MAPK (mitogen activated protein kinase) activation mainly through disruption of the interactions between insulin receptor substrates and its downstream binding proteins including p85 regulatory subunit of phosphoinositide 3-kinase and Grb2 (growth factor receptor bound protein 2).	2	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
Canonical IS posits that , upon activation of AKT by insulin , glycogen synthase kinase 3 ( GSK3 ) is serine phosphorylated to reduce its activity .	Canonical IS posits that, upon activation of AKT by insulin, glycogen synthase kinase 3 (GSK3) is serine phosphorylated to reduce its activity.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	8	9
In 3T3-L1 cells , all 4 isoforms enhance insulin stimulated glucose and amino acid transport , glycogen synthesis , lipogenesis , Akt activity , and p70 S6 kinase activity .	In 3T3-L1 cells, all 4 isoforms enhance insulin stimulated glucose and amino acid transport, glycogen synthesis, lipogenesis, Akt activity, and p70 S6 kinase activity.	8	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	21	22
Importantly , when controlling for biological sex , percent body fat in HFO remained strongly correlated with insulin stimulated Akt serine 473 ( r = -0.55 , P < 0.05 ) and threonine 308 ( r = -0.70 , P < 0.005 ) , as well as , insulin stimulated AS160 threonine 642 phosphorylation ( r = -0.75 , P < 0.001 ) and serine 318 ( r = -0.67 , P < 0.005 ) .	Importantly, when controlling for biological sex, percent body fat in HFO remained strongly correlated with insulin stimulated Akt serine 473 (r = -0.55, P < 0.05) and threonine 308 (r = -0.70, P < 0.005), as well as, insulin stimulated AS160 threonine 642 phosphorylation (r = -0.75, P < 0.001) and serine 318 (r = -0.67, P < 0.005).	15	46	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	19	20
An inhibitor of PKB , Akt inhibitor ( Akti )-1/2 , was recently reported ; however , the specificity and efficacy against insulin induced PKB was not reported .	An inhibitor of PKB, Akt inhibitor (Akti)-1/2, was recently reported; however, the specificity and efficacy against insulin induced PKB was not reported.	18	27	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	22	23	24	25
Insulin induced Akt activation and the phosphorylation of forkhead transcription factor ( FKHR and Foxo1 ) , a negative regulator of PPARgamma transcription , were up-regulated by SH2-B overexpression , but reduced in SH2-B-deficient MEFs .	Insulin induced Akt activation and the phosphorylation of forkhead transcription factor (FKHR and Foxo1), a negative regulator of PPARgamma transcription, were up-regulated by SH2-B overexpression, but reduced in SH2-B-deficient MEFs.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
Several previous studies reported insulin induced Akt activation in mice requires intact mouse Sesn2 [ XREF_BIBR ] , but we still observed significant activation of Akt upon insulin stimulation in Sesn2 silencing cells .	Several previous studies reported insulin induced Akt activation in mice requires intact mouse Sesn2 [XREF_BIBR], but we still observed significant activation of Akt upon insulin stimulation in Sesn2 silencing cells.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Insulin or insulin like growth factor-1 IGF-I receptor signaling pathway activates phosphoinositide 3-kinase ( PI3-kinase ) and its downstream target Akt [ XREF_BIBR - XREF_BIBR ] .	Insulin or insulin like growth factor-1 IGF-I receptor signaling pathway activates phosphoinositide 3-kinase (PI3-kinase) and its downstream target Akt [XREF_BIBR - XREF_BIBR].	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	20	21
To enable delivery of the lipid at a rate that is compatible with clamp studies , we used fatty acid : palmitoleate instead of TG : palmitoleate and confirmed that palmitoleate enhanced muscle and liver insulin signaling in this setting by examining insulin stimulated activation of insulin receptor and AKT ( XREF_SUPPLEMENTARY ) .	To enable delivery of the lipid at a rate that is compatible with clamp studies, we used fatty acid : palmitoleate instead of TG : palmitoleate and confirmed that palmitoleate enhanced muscle and liver insulin signaling in this setting by examining insulin stimulated activation of insulin receptor and AKT (XREF_SUPPLEMENTARY).	42	50	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	42	43	49	50
Evaluation of protein levels and insulin induced tyrosine ( insulin receptor , insulin receptor substrates ( IRS ) -1 and -2 , ERK ( extracellular signal related kinase ) ) or serine ( Akt ; protein kinase B ) phosphorylation of proteins of the insulin signalling cascade revealed a tissue specific pattern of regulation of the molecular events triggered by insulin such that in white adipose tissue and skeletal muscle an impaired molecular response to insulin was detected , while in brown adipose tissue an enhanced response to insulin was evident .	Evaluation of protein levels and insulin induced tyrosine (insulin receptor, insulin receptor substrates (IRS) -1 and -2, ERK (extracellular signal related kinase)) or serine (Akt; protein kinase B) phosphorylation of proteins of the insulin signalling cascade revealed a tissue specific pattern of regulation of the molecular events triggered by insulin such that in white adipose tissue and skeletal muscle an impaired molecular response to insulin was detected, while in brown adipose tissue an enhanced response to insulin was evident.	0	37	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	33	34
Treatment with troglitazone increases insulin stimulated IRS-1-associated PI3K and Akt activity in skeletal muscle biopsies from T2D patients , and enhanced Akt phosphorylation in skeletal muscle from glucose-tolerant , insulin resistant , first-degree relatives of T2D patients [ XREF_BIBR ] .	Treatment with troglitazone increases insulin stimulated IRS-1-associated PI3K and Akt activity in skeletal muscle biopsies from T2D patients, and enhanced Akt phosphorylation in skeletal muscle from glucose-tolerant, insulin resistant, first-degree relatives of T2D patients [XREF_BIBR].	3	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	9	10
Interestingly , in vitro study data showed TRIB3 genetic variation ( c. 251 A > G , Gln84Arg , rs2295490 ) does not affect its protein level , but impacts on insulin stimulated Akt ( Thr308 , Ser473 ) and eNOS ( Ser1177 ) phosphorylation , which results in 2 to 3 times of decreased eNOS activity and nitric oxide production .	Interestingly, in vitro study data showed TRIB3 genetic variation (c. 251 A> G, Gln84Arg, rs2295490) does not affect its protein level, but impacts on insulin stimulated Akt (Thr308, Ser473) and eNOS (Ser1177) phosphorylation, which results in 2 to 3 times of decreased eNOS activity and nitric oxide production.	29	44	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	33	34
Given the potential bi-phasic changes in insulin signaling that occur in the evolution of heart failure or systemic insulin resistance namely an activation of Akt , followed later by loss of insulin mediated Akt signaling , pathways by which Akt activation may promote heart failure versus mechanisms linking impaired insulin signaling with heart failure will be discussed separately .	Given the potential bi-phasic changes in insulin signaling that occur in the evolution of heart failure or systemic insulin resistance namely an activation of Akt, followed later by loss of insulin mediated Akt signaling, pathways by which Akt activation may promote heart failure versus mechanisms linking impaired insulin signaling with heart failure will be discussed separately.	29	34	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	33	34
Encouraged by the above findings , we then explored the potential of using the DCF contrast technique to image insulin mediated activation of Akt in living cells .	Encouraged by the above findings, we then explored the potential of using the DCF contrast technique to image insulin mediated activation of Akt in living cells.	12	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	23	24
We show here that insulin activation of PI3K and Akt is blunted in the db/db heart .	We show here that insulin activation of PI3K and Akt is blunted in the db/db heart.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	9	10
Herein , we found that CD36 knockdown in C2C12 myotubes accelerated insulin stimulated Akt activation , but the activated signaling was sustained for a much shorter period of time as compared with WT cells , leading to exacerbated insulin induced insulin resistance .	Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared with WT cells, leading to exacerbated insulin induced insulin resistance.	10	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
The time course of the insulin stimulated increase in Akt was closely matched by GSK-3alpha Ser ( 21 ) phosphorylation and a 40-60 % decrease in GSK-3alpha and GSK-3beta activity .	The time course of the insulin stimulated increase in Akt was closely matched by GSK-3alpha Ser (21) phosphorylation and a 40-60% decrease in GSK-3alpha and GSK-3beta activity.	2	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	9	10
These results suggest that PrRP and insulin activate a PI3K-Akt cascade that is necessary to elicit rPRL promoter activity via a CREB dependent mechanism .	These results suggest that PrRP and insulin activate a PI3K-Akt cascade that is necessary to elicit rPRL promoter activity via a CREB dependent mechanism.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	6	7	9	10
This study was aimed to explore the effect of insulin on Abeta induced cell death and ERK and Akt signaling alteration in isolated hippocampal cell culture .	This study was aimed to explore the effect of insulin on Abeta induced cell death and ERK and Akt signaling alteration in isolated hippocampal cell culture.	7	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	18	19
Under these circumstances , insulin stimulated Akt was not affected .	Under these circumstances, insulin stimulated Akt was not affected.	4	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Of note , in human pre-adipocytes exogenous human lactoferrin ( hLf ) administration led to increase adipocyte differentiation , enhancing PPARgamma gene expression levels and insulin action , increasing insulin induced pSer473 Akt and decreasing glucose concentration in the media [ XREF_BIBR ] .	Of note, in human pre-adipocytes exogenous human lactoferrin (hLf) administration led to increase adipocyte differentiation, enhancing PPARgamma gene expression levels and insulin action, increasing insulin induced pSer473 Akt and decreasing glucose concentration in the media [XREF_BIBR].	28	36	induced	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	32	33
Ribosomal protein S3 is a substrate for another kinase , Akt , which can be activated by insulin and pro survival factors .	Ribosomal protein S3 is a substrate for another kinase, Akt, which can be activated by insulin and pro survival factors.	8	21	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	10	11
Both basal and insulin stimulated activation of Akt ( as assessed by phosphorylation of Akt on S473 and T308 ) and its downstream targets such as GSK3alpha and beta ( on S21 and S29 ) , AS160 ( on T642 ) , and PRAS40 ( on T246 ) ) and mTORC1 ( assessed by phosphorylation of S6K ( on T389 ) and S6 ( on S240 and 244 ) ) , were unaffected in Vps34 D761A/+ myotubes and hepatocytes , as well as in muscle , liver and white adipose tissue ( WAT ) in vivo .	Both basal and insulin stimulated activation of Akt (as assessed by phosphorylation of Akt on S473 and T308) and its downstream targets such as GSK3alpha and beta (on S21 and S29), AS160 (on T642), and PRAS40 (on T246)) and mTORC1 (assessed by phosphorylation of S6K (on T389) and S6 (on S240 and 244)), were unaffected in Vps34 D761A/+ myotubes and hepatocytes, as well as in muscle, liver and white adipose tissue (WAT) in vivo.	1	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
In this cellular model , insulin actions such as insulin stimulated glucose uptake and AKT activation in the insulin signaling pathway are decreased 11 .	In this cellular model, insulin actions such as insulin stimulated glucose uptake and AKT activation in the insulin signaling pathway are decreased 11.	6	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	9	10	14	15
A recent study in mice also revealed that the generalized insulin resistance and hyperinsulinemia that develops in the context of pressure overload cardiac hypertrophy drives excessive myocardial insulin signaling to Akt that contributes to accelerated LV remodeling and the transition to heart failure 23 .	A recent study in mice also revealed that the generalized insulin resistance and hyperinsulinemia that develops in the context of pressure overload cardiac hypertrophy drives excessive myocardial insulin signaling to Akt that contributes to accelerated LV remodeling and the transition to heart failure 23.	10	32	signaling	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	30	31
Our findings demonstrate that insulin acts in an autocrine manner to activate Akt and mediate the survival of isolated human islets .	Our findings demonstrate that insulin acts in an autocrine manner to activate Akt and mediate the survival of isolated human islets.	4	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	12	13
In summary , we have demonstrated that RET and PTC3 expression enhances basal and insulin stimulated DNA synthesis through PI3 kinase , cooperatively activates Akt with insulin via PI3 kinase , and preferentially activates the Akt rather than MAP kinase pathway in FRTL-5 cells .	In summary, we have demonstrated that RET and PTC3 expression enhances basal and insulin stimulated DNA synthesis through PI3 kinase, cooperatively activates Akt with insulin via PI3 kinase, and preferentially activates the Akt rather than MAP kinase pathway in FRTL-5 cells.	14	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	24	25
[ XREF_BIBR ] Metabolism in the fed state is largely controlled by insulin activation of Akt , one of the major upstream regulators of mTORC1 ( XREF_FIG ) .	[XREF_BIBR] Metabolism in the fed state is largely controlled by insulin activation of Akt, one of the major upstream regulators of mTORC1 (XREF_FIG).	12	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	15	16
Therefore , AS160 plays an important role in the regulation of insulin induced GLUT4 translocation .	Therefore, AS160 plays an important role in the regulation of insulin induced GLUT4 translocation.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
PIP3 , the phosphorylated form of PIP2 , recruits PH domain containing proteins and regulates insulin stimulated GLUT4 trafficking in peripheral tissues .	PIP3, the phosphorylated form of PIP2, recruits PH domain containing proteins and regulates insulin stimulated GLUT4 trafficking in peripheral tissues.	14	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
While wild type Sec5 had little effect on insulin stimulated Glut4 fusion with the plasma membrane , expression of Sec5 S 89 D markedly decreased Glut4 membrane fusion , consistent with the notion that RalA interaction is a prerequisite for exocyst function .	While wild type Sec5 had little effect on insulin stimulated Glut4 fusion with the plasma membrane, expression of Sec5 S 89 D markedly decreased Glut4 membrane fusion, consistent with the notion that RalA interaction is a prerequisite for exocyst function.	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	8	9	10	11
In plasma membranes of lean animals insulin was found to increase the GLUT4 abundance to 294 +/- 43 % of control with a significantly ( P = 0.009 ) reduced effect in the obese group ( 139 +/- 10 % of control ) .	In plasma membranes of lean animals insulin was found to increase the GLUT4 abundance to 294 +/- 43% of control with a significantly (P = 0.009) reduced effect in the obese group (139 +/- 10% of control).	6	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	12	13
In myotubes cultured in G5 , insulin induced GLUT4 translocation to the plasma membrane within 30 minutes ( XREF_FIG ) .	In myotubes cultured in G5, insulin induced GLUT4 translocation to the plasma membrane within 30 minutes (XREF_FIG).	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
These data demonstrate that insulin modulates the subcellular distribution of both GLUT4 and Rab4 in rats skeletal muscle , suggesting that Rab4 may play a role in the insulin stimulated movement of GLUT4 containing vesicles .	These data demonstrate that insulin modulates the subcellular distribution of both GLUT4 and Rab4 in rats skeletal muscle, suggesting that Rab4 may play a role in the insulin stimulated movement of GLUT4 containing vesicles.	4	13	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	11	12
Our data suggest that in 3T3-L1 adipocytes NPY inhibits insulin stimulated glucose uptake in a GLUT4 dependent manner .	Our data suggest that in 3T3-L1 adipocytes NPY inhibits insulin stimulated glucose uptake in a GLUT4 dependent manner.	8	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	15	16
We also demonstrated that insulin accelerated GLUT4 trafficking velocity , which supports previous reports showing that several motor proteins operate during GLUT4 translocation .	We also demonstrated that insulin accelerated GLUT4 trafficking velocity, which supports previous reports showing that several motor proteins operate during GLUT4 translocation.	4	8	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
For example , depolymerization of filamentous actin ( F-actin ) by the actin monomer sequestering agent , Latrunculin B exhibits a time- and concentration dependent decline in glucose transport into muscle cells , implicating the requirement of an intact F-actin network for insulin induced GLUT4 translocation and glucose uptake .	For example, depolymerization of filamentous actin (F-actin) by the actin monomer sequestering agent, Latrunculin B exhibits a time- and concentration dependent decline in glucose transport into muscle cells, implicating the requirement of an intact F-actin network for insulin induced GLUT4 translocation and glucose uptake.	40	45	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	42	43	44	45
LXR activation increases expression of the insulin stimulated glucose transporter GLUT4 and promotes glucose uptake in WAT and BAT XREF_BIBR - XREF_BIBR .	LXR activation increases expression of the insulin stimulated glucose transporter GLUT4 and promotes glucose uptake in WAT and BAT XREF_BIBR - XREF_BIBR.	0	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	LXR activation increases expression of the insulin	insulin	GLUT4	GLUT4	glut4	6	7	10	11
A Rac1 specific GEF termed P-Rex1 enhanced insulin induced GLUT4 translocation and membrane ruffle formation downstream of PI3K in adipocytes .	A Rac1 specific GEF termed P-Rex1 enhanced insulin induced GLUT4 translocation and membrane ruffle formation downstream of PI3K in adipocytes.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
The data presented support the hypothesis that Y521 phosphorylation of Munc18c by the insulin receptor tyrosine kinase abrogates binding to monomeric Sx4 and VAMP2 , suggesting that this event may play a role in insulin stimulated SNARE mediated delivery of GLUT4 to the PM .	The data presented support the hypothesis that Y521 phosphorylation of Munc18c by the insulin receptor tyrosine kinase abrogates binding to monomeric Sx4 and VAMP2, suggesting that this event may play a role in insulin stimulated SNARE mediated delivery of GLUT4 to the PM.	30	41	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	34	35	40	41
To examine whether the insulin stimulated increase in surface GLUT4 may result from a contribution of Myo1c to GLUT4 endocytosis , we quantified the effect of Myo1c knockdown on GLUT4 internalization .	To examine whether the insulin stimulated increase in surface GLUT4 may result from a contribution of Myo1c to GLUT4 endocytosis, we quantified the effect of Myo1c knockdown on GLUT4 internalization.	3	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	9	10
While long-term insulin stimulation caused GLUT4 down-regulation by 40-50 % , which was inhibited with lysosomal inhibitors and was associated with a selective reduction in GLUT4 in GSV , overexpression of Ubc9 antagonized these long-term effects of insulin .	While long-term insulin stimulation caused GLUT4 down-regulation by 40-50%, which was inhibited with lysosomal inhibitors and was associated with a selective reduction in GLUT4 in GSV, overexpression of Ubc9 antagonized these long-term effects of insulin.	2	6	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	5	6
Treatment of adipocytes with a Tpm3.1 inhibitor abrogates insulin stimulated GLUT4 accumulation at the PM and glucose uptake .	Treatment of adipocytes with a Tpm3.1 inhibitor abrogates insulin stimulated GLUT4 accumulation at the PM and glucose uptake.	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Microinjection of these constructs and the AB had no effect on insulin induced GLUT4 translocation or DNA synthesis .	Microinjection of these constructs and the AB had no effect on insulin induced GLUT4 translocation or DNA synthesis.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Thus , how insulin promotes the later steps of glut4 recycling is predicted to involve a more balanced distribution of stimulation through ARF6 , RalA , and Rab10 .	Thus, how insulin promotes the later steps of glut4 recycling is predicted to involve a more balanced distribution of stimulation through ARF6, RalA, and Rab10.	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	glut4	glut4	glut4	3	4	9	10
Experimentation with our simulation platform highlighted this component as a key regulator in the insulin mediated GLUT4 translocation pathway .	Experimentation with our simulation platform highlighted this component as a key regulator in the insulin mediated GLUT4 translocation pathway.	5	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
FFAs impair insulin signaling and transport of Glut-4 to the cell surface by inhibiting insulin receptor substrate associated PI3K via its p85a subunit , or more simply by FFA oxidation leading to decreased uptake of glucose .	FFAs impair insulin signaling and transport of Glut-4 to the cell surface by inhibiting insulin receptor substrate associated PI3K via its p85a subunit, or more simply by FFA oxidation leading to decreased uptake of glucose.	2	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut-4	Glut-4	Glut-4	2	3	7	8
Insulin Stimulated GLUT4 Redistribution to the Cell Surface Is Reduced in Adipocytes From Adipose Rab10 KO Mice .	Insulin Stimulated GLUT4 Redistribution to the Cell Surface Is Reduced in Adipocytes From Adipose Rab10 KO Mice.	0	3	Stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Insulin also modulates GLUT4 recycling from endosomes during insulin exposure [ XREF_BIBR ] .	Insulin also modulates GLUT4 recycling from endosomes during insulin exposure [XREF_BIBR].	0	4	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	3	4
Insulin increases intracellular glucose concentration by transferring GLUT4 to the plasma membrane localization where it exerts its function via vesicles that require acylated lipid .	Insulin increases intracellular glucose concentration by transferring GLUT4 to the plasma membrane localization where it exerts its function via vesicles that require acylated lipid.	0	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	7	8
In the current study , we showed that vitamin D deficiency via stably silencing 1alpha ( OH ) ase also caused insulin resistance in L02 hepatocytes , showing impaired insulin signaling and downregulation of GLUT4 .	In the current study, we showed that vitamin D deficiency via stably silencing 1alpha (OH) ase also caused insulin resistance in L02 hepatocytes, showing impaired insulin signaling and downregulation of GLUT4.	29	35	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	29	30	34	35
Introduction of Sec5 bearing mutations of the phosphorylation site to either alanine or aspartate disrupts insulin stimulated Glut4 exocytosis , as well as other trafficking processes in polarized epithelial cells and during development of zebrafish embryos .	Introduction of Sec5 bearing mutations of the phosphorylation site to either alanine or aspartate disrupts insulin stimulated Glut4 exocytosis, as well as other trafficking processes in polarized epithelial cells and during development of zebrafish embryos.	14	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	15	16	17	18
Insulin stimulation of the adipocytes increases the amount of Glut-4 protein in the caveolin rich membrane fractions , whereas Cav-1 depletion reduces the quantity of Glut-4 protein in the 3T3-L1 cells , enhancing its degradation and eventually affecting the insulin response XREF_BIBR .	Insulin stimulation of the adipocytes increases the amount of Glut-4 protein in the caveolin rich membrane fractions, whereas Cav-1 depletion reduces the quantity of Glut-4 protein in the 3T3-L1 cells, enhancing its degradation and eventually affecting the insulin response XREF_BIBR.	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut-4	Glut-4	Glut-4	0	1	9	10
In contrast , knockdown of CDP138 did not inhibit insulin stimulated GLUT4 accumulation at the periphery ( XREF_FIG ) .	In contrast, knockdown of CDP138 did not inhibit insulin stimulated GLUT4 accumulation at the periphery (XREF_FIG).	8	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Insulin stimulation increased GLUT4 in the cell surface of CHO-K1 cells to promote glucose uptake , however exogenous expression of the mutant tomosyn attenuated the increase by insulin .	Insulin stimulation increased GLUT4 in the cell surface of CHO-K1 cells to promote glucose uptake, however exogenous expression of the mutant tomosyn attenuated the increase by insulin.	0	4	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	3	4
New signaling and cytoskeletal mechanisms of insulin stimulated GLUT4 exocytosis are of emerging interest , particularly those at or just beneath the plasma membrane .	New signaling and cytoskeletal mechanisms of insulin stimulated GLUT4 exocytosis are of emerging interest, particularly those at or just beneath the plasma membrane.	1	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Other studies suggest that Munc18c is required for the insulin induced fusion of GLUT4 vesicles with the plasma membrane XREF_BIBR .	Other studies suggest that Munc18c is required for the insulin induced fusion of GLUT4 vesicles with the plasma membrane XREF_BIBR.	8	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	13	14
Several Rab proteins including Rab8a , Rab10 , and Rab14 have been shown to be involved in insulin mediated GLUT4 translocation in adipocytes .	Several Rab proteins including Rab8a, Rab10, and Rab14 have been shown to be involved in insulin mediated GLUT4 translocation in adipocytes.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
If the small stores are visible clouds of GSVs , this will increase the capacity for insulin mediated GLUT4 docking and fusion at the PM .	If the small stores are visible clouds of GSVs, this will increase the capacity for insulin mediated GLUT4 docking and fusion at the PM.	12	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
Honokiol dose-dependently increased the insulin induced GLUT4 translocation from cytoplasm to cell membrane .	Honokiol dose-dependently increased the insulin induced GLUT4 translocation from cytoplasm to cell membrane.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Nevertheless , as our findings thus far on 3T3-L1 cells suggested the possibility that insulin stimulated Glut4 recycling is an example of extensive physiological usage of ACAP1 , we sought to further define the mechanistic relationship between ACAP1 and the clathrin triskelion in these cells , using Glut4 recycling as the context .	Nevertheless, as our findings thus far on 3T3-L1 cells suggested the possibility that insulin stimulated Glut4 recycling is an example of extensive physiological usage of ACAP1, we sought to further define the mechanistic relationship between ACAP1 and the clathrin triskelion in these cells, using Glut4 recycling as the context.	14	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	14	15	16	17
In contrast , the trained group exhibited significantly greater insulin stimulated ( 2 mU/ml ) glucose transport activity in epitrochlearis muscles than the sedentary group ( 0.53 +/- 0.03 vs. 0.18 +/- 0.03 mumol.g-1 x 10 min-1 for trained and sedentary , respectively ) , which was paralleled by a significant enhancement of insulin stimulated cell surface GLUT-4 ( 5.33 +/- 0.20 vs. 1.57 +/- 0.14 disintegrations.min-1 .	In contrast, the trained group exhibited significantly greater insulin stimulated (2 mU/ml) glucose transport activity in epitrochlearis muscles than the sedentary group (0.53 +/- 0.03 vs. 0.18 +/- 0.03 mumol.g-1 x 10 min-1 for trained and sedentary, respectively), which was paralleled by a significant enhancement of insulin stimulated cell surface GLUT-4 (5.33 +/- 0.20 vs. 1.57 +/- 0.14 disintegrations.min-1.	51	66	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	53	54	57	58
These data reveal that insulin signaling targets the engagement or initiates the movement of GLUT4 containing membranes on microtubules via conventional kinesin through a PI3-kinase-independent mechanism .	These data reveal that insulin signaling targets the engagement or initiates the movement of GLUT4 containing membranes on microtubules via conventional kinesin through a PI3-kinase-independent mechanism.	4	15	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	14	15
KD of Tmod3 inhibits insulin stimulated GLUT4 PM insertion and glucose uptake .	KD of Tmod3 inhibits insulin stimulated GLUT4 PM insertion and glucose uptake.	3	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
However , no insulin was included in the incubation mixture for the experiments described in the current report , supporting that insulin independent modulation of GLUT3 and GLUT4 may also occur with neutrophil activation .	However, no insulin was included in the incubation mixture for the experiments described in the current report, supporting that insulin independent modulation of GLUT3 and GLUT4 may also occur with neutrophil activation.	21	28	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	27	28
Here we review the roles of Rab and Rho proteins , particularly Rab substrates of AS160 and Rac1 , in insulin stimulated GLUT4 traffic .	Here we review the roles of Rab and Rho proteins, particularly Rab substrates of AS160 and Rac1, in insulin stimulated GLUT4 traffic.	2	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Glucose first needs to enter the muscle cells via insulin mediated GLUT4 dependent transmembrane transport and then be converted to acetyl-CoA via the pyruvate dehydrogenase ( PDH ) complex .	Glucose first needs to enter the muscle cells via insulin mediated GLUT4 dependent transmembrane transport and then be converted to acetyl-CoA via the pyruvate dehydrogenase (PDH) complex.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
This , in turn , causes inhibition of the insulin mediated PKCzeta activity , and decreased insulin induced GLUT4 translocation to the plasma membrane XREF_BIBR - XREF_BIBR .	This, in turn, causes inhibition of the insulin mediated PKCzeta activity, and decreased insulin induced GLUT4 translocation to the plasma membrane XREF_BIBR - XREF_BIBR.	16	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
High MK-2206 doses ( > 10 3 IC50 for Akt1 and Akt2 inhibition ) partially inhibited insulin induced GLUT4 translocation in Akt1 W80A and Akt2 W80A cells , despite the fact that under those conditions the phosphorylation of Akt mutant kinases was largely preserved ( XREF_FIG ) , suggesting potential Akt independent effects of the inhibitor at those high doses .	High MK-2206 doses (> 10 3 IC50 for Akt1 and Akt2 inhibition) partially inhibited insulin induced GLUT4 translocation in Akt1 W80A and Akt2 W80A cells, despite the fact that under those conditions the phosphorylation of Akt mutant kinases was largely preserved (XREF_FIG), suggesting potential Akt independent effects of the inhibitor at those high doses.	16	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
In adipocytes , insulin can stimulate both adiponectin and GLUT4 vesicles trafficking but they are two different secretory vesicles [ XREF_BIBR ] .	In adipocytes, insulin can stimulate both adiponectin and GLUT4 vesicles trafficking but they are two different secretory vesicles [XREF_BIBR].	3	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	9	10
Intravital imaging indicates that insulin stimulated GLUT4 trafficking differs between t-tubules and sarcolemma .	Intravital imaging indicates that insulin stimulated GLUT4 trafficking differs between t-tubules and sarcolemma.	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Insulin stimulates upregulation of Glut-4 in muscle ( heart and striated ) and adipose tissues causing a shift of FDG distribution into peripheral muscle , soft tissues and fat , with lower tumor target-to-background uptake ratios .	Insulin stimulates upregulation of Glut-4 in muscle (heart and striated) and adipose tissues causing a shift of FDG distribution into peripheral muscle, soft tissues and fat, with lower tumor target-to-background uptake ratios.	0	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut-4	Glut-4	Glut-4	0	1	4	5
In conclusion , a defect in IRS-1 phosphorylation and PI3-k activation in hypertrophied hearts restricts insulin mediated GLUT-4 translocation and ischemia , a known stimulus of GLUT-4 translocation , does not compensate for this defect .	In conclusion, a defect in IRS-1 phosphorylation and PI3-k activation in hypertrophied hearts restricts insulin mediated GLUT-4 translocation and ischemia, a known stimulus of GLUT-4 translocation, does not compensate for this defect.	14	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	15	16	17	18
This is in contrast to what we have previously reported for insulin mediated GLUT4-EGFP translocation .	This is in contrast to what we have previously reported for insulin mediated GLUT4-EGFP translocation.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4-EGFP	GLUT4-EGFP	GLUT4-EGFP	11	12	13	14
The simultaneous and combined activation of Akt and PKC-lambda and zeta is necessary for insulin induced GLUT4 translocation in both heart [ XREF_BIBR ] and skeletal muscle [ XREF_BIBR ] , and likely also essential for insulin induced CD36 translocation .	The simultaneous and combined activation of Akt and PKC-lambda and zeta is necessary for insulin induced GLUT4 translocation in both heart [XREF_BIBR] and skeletal muscle [XREF_BIBR], and likely also essential for insulin induced CD36 translocation.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
These observations establish CDP138 as a novel molecular link between insulin stimulated Akt2 signaling and GLUT4 insertion into the PM .	These observations establish CDP138 as a novel molecular link between insulin stimulated Akt2 signaling and GLUT4 insertion into the PM.	8	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	15	16
Hence , it has been suggested that insulin stimulates movement of GLUT4 vesicles from the cell interior toward the PM along microtubule tracks .	Hence, it has been suggested that insulin stimulates movement of GLUT4 vesicles from the cell interior toward the PM along microtubule tracks.	7	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	11	12
Consistent with this idea , it is becoming increasingly apparent that lipid raft microdomains play a central importance in insulin action , including insulin stimulated GLUT4 translocation .	Consistent with this idea, it is becoming increasingly apparent that lipid raft microdomains play a central importance in insulin action, including insulin stimulated GLUT4 translocation.	3	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
Third , second-phase GSIS and insulin stimulated GLUT4 vesicle translocation involve relatively long-distance granule mobilization events , compared with the short-range docked primed transition event or the docking of granules already present in the plasma membrane localized readily releasable pool to support first-phase insulin release or rapid neurotransmitter release .	Third, second-phase GSIS and insulin stimulated GLUT4 vesicle translocation involve relatively long-distance granule mobilization events, compared with the short-range docked primed transition event or the docking of granules already present in the plasma membrane localized readily releasable pool to support first-phase insulin release or rapid neurotransmitter release.	0	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
AS160 ( Akt substrate of 160 kDa ) mediates insulin stimulated GLUT4 ( glucose transporter 4 ) translocation , but is widely expressed in insulin-insensitive tissues lacking GLUT4 .	AS160 (Akt substrate of 160 kDa) mediates insulin stimulated GLUT4 (glucose transporter 4) translocation, but is widely expressed in insulin-insensitive tissues lacking GLUT4.	8	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Furthermore , both GLUT4 overexpression levels and animal age are associated with increased basal and insulin stimulated glucose transport activities and cell surface GLUT4 .	Furthermore, both GLUT4 overexpression levels and animal age are associated with increased basal and insulin stimulated glucose transport activities and cell surface GLUT4.	15	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	23	24
Small interfering RNA mediated ACTN4 knockdown abolished the gain in surface exposed GLUT4 elicited by insulin but not by platelet derived growth factor , membrane depolarization , or mitochondrial uncoupling .	Small interfering RNA mediated ACTN4 knockdown abolished the gain in surface exposed GLUT4 elicited by insulin but not by platelet derived growth factor, membrane depolarization, or mitochondrial uncoupling.	6	16	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	12	13
The dose related reduction in UV by insulin obtained in the present study is in agreement with a previous report , XREF_BIBR where the stimulation of GLUT4 by insulin has been shown to enhance sodium and water retention in the renal tubules .	The dose related reduction in UV by insulin obtained in the present study is in agreement with a previous report, XREF_BIBR where the stimulation of GLUT4 by insulin has been shown to enhance sodium and water retention in the renal tubules.	24	29	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	28	29	26	27
After a meal , insulin stimulates GLUT4 storage vesicles to fuse with the cell surface membrane , allowing rapid uptake of glucose into the cell through GLUT4 and thus returning the blood glucose level to normal .	After a meal, insulin stimulates GLUT4 storage vesicles to fuse with the cell surface membrane, allowing rapid uptake of glucose into the cell through GLUT4 and thus returning the blood glucose level to normal.	4	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Contrary to this finding , in 3T3-L1 cells , insulin stimulates long-range movements of GLUT4 vesicles toward the PM , rather than inhibiting trafficking .	Contrary to this finding, in 3T3-L1 cells, insulin stimulates long-range movements of GLUT4 vesicles toward the PM, rather than inhibiting trafficking.	9	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	14	15
Basal Akt phosphorylation at Ser 473 residue , a key step in insulin stimulated glucose transport activity , and GLUT4 protein content were not different between the two groups ( XREF_FIG ) .	Basal Akt phosphorylation at Ser 473 residue, a key step in insulin stimulated glucose transport activity, and GLUT4 protein content were not different between the two groups (XREF_FIG).	10	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	19	20
Insulin enhances GLUT4 exocytosis without diminishing its endocytosis .	Insulin enhances GLUT4 exocytosis without diminishing its endocytosis.	0	3	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
The PLD1 activation plays a rate limiting step in the process of insulin stimulated fusion of Glut4 containing storage vesicles into the plasma membrane and increase of [ 3 H ] glucose uptake by adipocytes [ XREF_BIBR ] .	The PLD1 activation plays a rate limiting step in the process of insulin stimulated fusion of Glut4 containing storage vesicles into the plasma membrane and increase of [3 H] glucose uptake by adipocytes [XREF_BIBR].	10	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	12	13	16	17
We conclude that carbohydrate feeding that results in muscle glycogen supercompensation prevents the increase in maximally insulin stimulated glucose transport associated with an exercise training induced increase in muscle GLUT-4 .	We conclude that carbohydrate feeding that results in muscle glycogen supercompensation prevents the increase in maximally insulin stimulated glucose transport associated with an exercise training induced increase in muscle GLUT-4.	12	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	16	17	29	30
However , the effect of the Y521A mutant on insulin stimulated GLUT4 trafficking remains unclear , since over-expression of both wild-type or mutant forms of Munc18c both inhibited GLUT4 translocation [ XREF_BIBR ] .	However, the effect of the Y521A mutant on insulin stimulated GLUT4 trafficking remains unclear, since over-expression of both wild-type or mutant forms of Munc18c both inhibited GLUT4 translocation [XREF_BIBR].	7	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
These data show that ET-1-induced PIP2 and actin disruption impairs GLUT4 trafficking elicited by insulin and hyperosmolarity .	These data show that ET-1-induced PIP2 and actin disruption impairs GLUT4 trafficking elicited by insulin and hyperosmolarity.	10	16	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	10	11
Earlier research demonstrated a decline in insulin stimulated GLUT4 localized in the cell surface membranes of whole epitrochlearis muscles from HFD compared to LFD rats 37 .	Earlier research demonstrated a decline in insulin stimulated GLUT4 localized in the cell surface membranes of whole epitrochlearis muscles from HFD compared to LFD rats 37.	4	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Linear regression analysis showed that whereas a relatively low and nonsignificant correlation existed between GLUT-4 protein content and 2-DG uptake stimulated by insulin alone , significant correlations existed between GLUT-4 protein content and 2-DG uptake stimulated either by contractions alone ( r = 0.950 ) or by insulin and contractions in combination ( r = 0.992 ) .	Linear regression analysis showed that whereas a relatively low and nonsignificant correlation existed between GLUT-4 protein content and 2-DG uptake stimulated by insulin alone, significant correlations existed between GLUT-4 protein content and 2-DG uptake stimulated either by contractions alone (r = 0.950) or by insulin and contractions in combination (r = 0.992).	29	49	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	47	48	29	30
Other investigators found that in rat adipocytes , wortmannin blocks insulin stimulated GLUT4 trafficking at a step apparently distal to segregation from late endosomal and TGN markers , suggesting that GLUT4 does not recycle through these compartments ( Malide and Cushman 1997 ) .	Other investigators found that in rat adipocytes, wortmannin blocks insulin stimulated GLUT4 trafficking at a step apparently distal to segregation from late endosomal and TGN markers, suggesting that GLUT4 does not recycle through these compartments (Malide and Cushman 1997).	9	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Insulin resistance is driven by the stress response to critical illness initiating an overwhelming activation of pro inflammatory mediators ( tumour necrosis factor-alpha , interleukin-6 ) and counter-regulatory hormone excess ( glucagon , cortisol , catecholamines ) which lead to excessive hepatic gluconeogenesis and down-regulation of insulin mediated GLUT-4 glucose transporters [ XREF_BIBR ] .	Insulin resistance is driven by the stress response to critical illness initiating an overwhelming activation of pro inflammatory mediators (tumour necrosis factor-alpha, interleukin-6) and counter-regulatory hormone excess (glucagon, cortisol, catecholamines) which lead to excessive hepatic gluconeogenesis and down-regulation of insulin mediated GLUT-4 glucose transporters [XREF_BIBR].	44	50	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	46	47	48	49
However , when the ineffective dose 0.1 mg x kg (-1) FGF-21 was used in combination with insulin ( 4 u ) significantly increased the transcription levels of both GLUT1 and GLUT4 , the transcription level of GLUT1 was similar to that treated with 5 time concentration of FGF-21 alone ; the transcription level of GLUT4 is higher than that treated with insulin ( 4 u ) alone .	However, when the ineffective dose 0.1 mg x kg (-1) FGF-21 was used in combination with insulin (4 u) significantly increased the transcription levels of both GLUT1 and GLUT4, the transcription level of GLUT1 was similar to that treated with 5 time concentration of FGF-21 alone; the transcription level of GLUT4 is higher than that treated with insulin (4 u) alone.	53	67	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	62	63	55	56
E4-ORF1 significantly increased insulin stimulated ( 0.1 nM ) insertion of Glut4 into the PM , demonstrating E4-ORF1 promotes insulin stimulated fusion of Glut4 containing vesicle to the PM ( XREF_FIG ) .	E4-ORF1 significantly increased insulin stimulated (0.1 nM) insertion of Glut4 into the PM, demonstrating E4-ORF1 promotes insulin stimulated fusion of Glut4 containing vesicle to the PM (XREF_FIG).	3	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	3	4	11	12
Taken together , these results indicate that cytoplasmic RIP140 negatively regulates basal and insulin stimulated GLUT4 trafficking to the cell surface in these adipocytes .	Taken together, these results indicate that cytoplasmic RIP140 negatively regulates basal and insulin stimulated GLUT4 trafficking to the cell surface in these adipocytes.	13	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Insulin stimulates exocytosis of GLUT4 from an intracellular store to the cell surface of fat and muscle cells .	Insulin stimulates exocytosis of GLUT4 from an intracellular store to the cell surface of fat and muscle cells.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	4	5
The importance of PI3-K activation in insulin stimulated GLUT4 redistribution has been firmly established [ XREF_BIBR ] .	The importance of PI3-K activation in insulin stimulated GLUT4 redistribution has been firmly established [XREF_BIBR].	4	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
A previous study using adipocytes transiently knocked down for IRAP showed an impairment of the insulin mediated GLUT4 translocation .	A previous study using adipocytes transiently knocked down for IRAP showed an impairment of the insulin mediated GLUT4 translocation.	12	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
After insulin stimulation , we did not observe an increase in GLUT4 content in the PM fraction , but a 2.4 fold increase in the LD fraction , suggesting alterations in GLUT4 distribution and in insulin mediated GLUT4 trafficking .	After insulin stimulation, we did not observe an increase in GLUT4 content in the PM fraction, but a 2.4 fold increase in the LD fraction, suggesting alterations in GLUT4 distribution and in insulin mediated GLUT4 trafficking.	28	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	35	36	37	38
As a whole , our results suggest that Rab5 is not involved in insulin stimulated Glut4 exocytosis .	As a whole, our results suggest that Rab5 is not involved in insulin stimulated Glut4 exocytosis.	11	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	13	14	15	16
These results demonstrate the participation of endogenous MyoVa in insulin mediated GLUT4 exocytic movement .	These results demonstrate the participation of endogenous MyoVa in insulin mediated GLUT4 exocytic movement.	2	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
A. indica leaf extract may play a significant role in the management of type-2 diabetes mellitus by improving the expression of insulin signaling molecules and GLUT4 protein to enhance and oxidation in the skeletal muscle .	A. indica leaf extract may play a significant role in the management of type-2 diabetes mellitus by improving the expression of insulin signaling molecules and GLUT4 protein to enhance and oxidation in the skeletal muscle.	19	30	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	expression of insulin	insulin	GLUT4	GLUT4	glut4	21	22	25	26
Another interesting observation made in this study is the essential role of [ Ca 2+ ] i in insulin stimulated GLUT4 vesicle fusion .	Another interesting observation made in this study is the essential role of [Ca 2+] i in insulin stimulated GLUT4 vesicle fusion.	16	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
The direct pathway requires transport of glucose into cells , by one or more of several GLUTs ( glucose transporters ) [ XREF_BIBR ] : GLUT1 is widely distributed and provides basal glucose transport ; GLUT4 is up-regulated by insulin and is important in insulin sensitive tissues such as skeletal muscle and adipose tissue ; and GLUT2 is prominent in liver and the beta-cells of the pancreas and admits glucose based on a positive glucose gradient between the blood and the tissue .	The direct pathway requires transport of glucose into cells, by one or more of several GLUTs (glucose transporters) [XREF_BIBR] : GLUT1 is widely distributed and provides basal glucose transport; GLUT4 is up-regulated by insulin and is important in insulin sensitive tissues such as skeletal muscle and adipose tissue; and GLUT2 is prominent in liver and the beta-cells of the pancreas and admits glucose based on a positive glucose gradient between the blood and the tissue.	35	42	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	39	40	35	36
In conclusion , the finding that plasma membrane GLUT4 in the diabetic treated group is significantly higher than that of the diabetic group at 5 min but not at 15 min post-insulin injection indicates that vanadium treatment enhances insulin mediated GLUT4 translocation in cardiac tissue by enhancing its early response .	In conclusion, the finding that plasma membrane GLUT4 in the diabetic treated group is significantly higher than that of the diabetic group at 5 min but not at 15 min post-insulin injection indicates that vanadium treatment enhances insulin mediated GLUT4 translocation in cardiac tissue by enhancing its early response.	37	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	38	39	40	41
We now report that these peptides inhibit by 80-100 % the internalization of glucose transporters ( GLUT4 ) and insulin like growth factor II ( IGF-II ) receptors in insulin stimulated cells and correspondingly double insulin stimulated glucose transport activity and the number of GLUT4 and IGF-II receptors on the cell surface .	We now report that these peptides inhibit by 80-100% the internalization of glucose transporters (GLUT4) and insulin like growth factor II (IGF-II) receptors in insulin stimulated cells and correspondingly double insulin stimulated glucose transport activity and the number of GLUT4 and IGF-II receptors on the cell surface.	29	47	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	29	30	44	45
Arp2/3- and Cofilin coordinated Actin Dynamics Is Required for Insulin mediated GLUT4 Translocation to the Surface of Muscle Cells .	Arp2/3- and Cofilin coordinated Actin Dynamics Is Required for Insulin mediated GLUT4 Translocation to the Surface of Muscle Cells.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
The insulin activated PI3K ( phosphoinositide 3-kinase )/PKB ( protein kinase B , also known as Akt ) signalling axis plays a key role in mediating insulin stimulated GLUT4 trafficking .	The insulin activated PI3K (phosphoinositide 3-kinase)/PKB (protein kinase B, also known as Akt) signalling axis plays a key role in mediating insulin stimulated GLUT4 trafficking.	0	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	28	29
In the basal state , GLUT4 is retained within specific intracellular compartments and insulin rapidly increases the movement of GLUT4 from its intracellular compartment to the plasma membrane ( PM ) , where it captures the extracellular glucose for internalization .	In the basal state, GLUT4 is retained within specific intracellular compartments and insulin rapidly increases the movement of GLUT4 from its intracellular compartment to the plasma membrane (PM), where it captures the extracellular glucose for internalization.	13	23	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	19	20
Here we report that optimal insulin mediated GLUT4 translocation is dependent upon both microtubule and actin based cytoskeletal structures in cultured adipocytes .	Here we report that optimal insulin mediated GLUT4 translocation is dependent upon both microtubule and actin based cytoskeletal structures in cultured adipocytes.	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
Rab10 knockdown resulted in an attenuation of insulin induced GLUT4 redistribution to the plasma membrane and a concomitant 2-fold decrease in GLUT4 exocytosis rate .	Rab10 knockdown resulted in an attenuation of insulin induced GLUT4 redistribution to the plasma membrane and a concomitant 2-fold decrease in GLUT4 exocytosis rate.	5	10	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Pue could markedly improve the insulin resistance of 3T3-L1 lipocyte , which is realized possibly by way of inactivating CAP path , promoting Glut-4 transposition to cell membrane to increase the transportation of glucose .	Pue could markedly improve the insulin resistance of 3T3-L1 lipocyte, which is realized possibly by way of inactivating CAP path, promoting Glut-4 transposition to cell membrane to increase the transportation of glucose.	5	24	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut-4	Glut-4	Glut-4	5	6	23	24
Although multiple Rab isoforms are required for GLUT4 intracellular traffic , Rab10 is the Rab-isoform that is required for insulin mediated GLUT4 exocytosis [ XREF_BIBR , XREF_BIBR ] .	Although multiple Rab isoforms are required for GLUT4 intracellular traffic, Rab10 is the Rab-isoform that is required for insulin mediated GLUT4 exocytosis [XREF_BIBR, XREF_BIBR].	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
Our findings suggest that insulin activates both PKC-zeta and PKC-lambda in plasma membranes , microsomes , and GLUT4 vesicles by a mechanism requiring increases in PIP ( 3 ) , PDK-1-dependent phosphorylation of activation loop sites in PKC-zeta and lambda , and subsequent autophosphorylation and/or transphosphorylation .	Our findings suggest that insulin activates both PKC-zeta and PKC-lambda in plasma membranes, microsomes, and GLUT4 vesicles by a mechanism requiring increases in PIP (3), PDK-1-dependent phosphorylation of activation loop sites in PKC-zeta and lambda, and subsequent autophosphorylation and/or transphosphorylation.	4	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	17	18
Our studies reveal that the simultaneous disruption of VAMPs 2 , 3 and 8 completely inhibited insulin stimulated GLUT4 insertion into the plasma membrane , due to a block in vesicle docking at the plasma membrane .	Our studies reveal that the simultaneous disruption of VAMPs 2, 3 and 8 completely inhibited insulin stimulated GLUT4 insertion into the plasma membrane, due to a block in vesicle docking at the plasma membrane.	15	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
Natural compounds with insulin mimetic activity are being considered as potential therapeutic agents for the treatment/or management of type 2 DM , such as berberine enhanced insulin mediated GLUT4 translocation and glucose transport through the activation of AKT and AMPK pathways [ XREF_BIBR ] .	Natural compounds with insulin mimetic activity are being considered as potential therapeutic agents for the treatment/or management of type 2 DM, such as berberine enhanced insulin mediated GLUT4 translocation and glucose transport through the activation of AKT and AMPK pathways [XREF_BIBR].	25	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	28	29
Experiments directed more specifically at determining effects of Rab3 knockdown on GLUT4 translocation revealed that the insulin stimulated increase in cell-surface GLUT4 was inhibited by over 80 % .	Experiments directed more specifically at determining effects of Rab3 knockdown on GLUT4 translocation revealed that the insulin stimulated increase in cell-surface GLUT4 was inhibited by over 80%.	15	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	21	22
Expression of SHIP after nuclear microinjection in 3T3-L1 adipocytes inhibited insulin induced GLUT4 translocation by 100 +/- 21 % ( mean +/- the standard error ) at submaximal ( 3 ng/ml ) and 64 +/- 5 % at maximal ( 10 ng/ml ) insulin concentrations ( P < 0.05 and P < 0.001 , respectively ) .	Expression of SHIP after nuclear microinjection in 3T3-L1 adipocytes inhibited insulin induced GLUT4 translocation by 100 +/- 21% (mean +/- the standard error) at submaximal (3 ng/ml) and 64 +/- 5% at maximal (10 ng/ml) insulin concentrations (P < 0.05 and P < 0.001, respectively).	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
BBR enhanced acute insulin mediated GLUT4 translocation and glucose transport in insulin resistant myotubes through activation of AMPK and PI3K pathway [ XREF_BIBR ] .	BBR enhanced acute insulin mediated GLUT4 translocation and glucose transport in insulin resistant myotubes through activation of AMPK and PI3K pathway [XREF_BIBR].	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Although we observed minor differences in the shape of the insulin stimulated time response curves of our model compared to that of Sedaghat ' s model ( XREF_FIG ) , we believe that our model better suits the physiological system than the original , in terms of the insulin stimulated GLUT4 translocation response .	Although we observed minor differences in the shape of the insulin stimulated time response curves of our model compared to that of Sedaghat 's model (XREF_FIG), we believe that our model better suits the physiological system than the original, in terms of the insulin stimulated GLUT4 translocation response.	45	52	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	48	49	50	51
Therefore , Rut is determined to be a dual-functional inducer enhancing the insulin induced GLUT4 translocation at short term and GLUT4 expression at long term .	Therefore, Rut is determined to be a dual-functional inducer enhancing the insulin induced GLUT4 translocation at short term and GLUT4 expression at long term.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
We show that , insulin stimulated GLUT4 translocation can operate as a bistable switch , which ensures that GLUT4 settles between two discrete , but mutually exclusive stable steady states .	We show that, insulin stimulated GLUT4 translocation can operate as a bistable switch, which ensures that GLUT4 settles between two discrete, but mutually exclusive stable steady states.	4	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
The increased basal [ Ca2+ ] i can negatively modulate the insulin mediated stimulation of GLUT4 dependent glucose transport despite the possibility that Ca2+ i might not participate as a component in the insulin-receptor-regulated signaling pathway .	The increased basal [Ca2+] i can negatively modulate the insulin mediated stimulation of GLUT4 dependent glucose transport despite the possibility that Ca2+ i might not participate as a component in the insulin-receptor-regulated signaling pathway.	11	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	15	16
In both glucose- and glucosamine induced insulin resistant cell culture models , a reduction in the acute insulin stimulated GLUT4 translocation was detected accompanied by a significant alteration in membrane redistribution of Munc18-c , a negative regulator of t- and v-SNAREs .	In both glucose- and glucosamine induced insulin resistant cell culture models, a reduction in the acute insulin stimulated GLUT4 translocation was detected accompanied by a significant alteration in membrane redistribution of Munc18-c, a negative regulator of t- and v-SNAREs.	13	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Careful examination reveals that even our obIS group showed earliest signs of insulin resistance relative to nonobese controls with elevations in HOMA-IR , insulin and nonsignifcant increases in GLUT4 and HSD11B1 mRNA ( XREF_TABLE ) .	Careful examination reveals that even our obIS group showed earliest signs of insulin resistance relative to nonobese controls with elevations in HOMA-IR, insulin and nonsignifcant increases in GLUT4 and HSD11B1 mRNA (XREF_TABLE).	21	31	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	28	29
Our approach using QD to very sparsely label GLUT4 molecules reduces the highly complex regulation of GLUT4 , by individually examining elements of GLUT4 movements in greater detail , thereby offering a novel solution to understanding functional steps of insulin mediated GLUT4 trafficking .	Our approach using QD to very sparsely label GLUT4 molecules reduces the highly complex regulation of GLUT4, by individually examining elements of GLUT4 movements in greater detail, thereby offering a novel solution to understanding functional steps of insulin mediated GLUT4 trafficking.	37	42	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	39	40	41	42
Coinfusion of Glmn did not alter enrichment of the sarcolemmal markers 5 '-nucleotidase , Na +/K+ ATP ase , and phospholemman in either 25 , 30 , or 35 % f. Thus Glmn completely blocked movement of Glut 4 induced by insulin .	Coinfusion of Glmn did not alter enrichment of the sarcolemmal markers 5 '-nucleotidase, Na +/K+ATP ase, and phospholemman in either 25, 30, or 35% f. Thus Glmn completely blocked movement of Glut 4 induced by insulin.	35	42	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut 4	Glut 4	Glut 4	41	42	37	39
Elucidation of the intracellular location of these 2 GLUT4 vesicle pools in cardiac myocytes , their role in GLUT4 trafficking , and their relation to insulin induced GLUT4 translocation needs to be addressed .	Elucidation of the intracellular location of these 2 GLUT4 vesicle pools in cardiac myocytes, their role in GLUT4 trafficking, and their relation to insulin induced GLUT4 translocation needs to be addressed.	23	28	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	27	28
More recently , it has been reported that AMP activated protein kinase ( AMPK ) enhances insulin stimulated GLUT4 regulation via lowering membrane cholesterol levels [ XREF_BIBR ] .	More recently, it has been reported that AMP activated protein kinase (AMPK) enhances insulin stimulated GLUT4 regulation via lowering membrane cholesterol levels [XREF_BIBR].	15	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
Upon insulin stimulation GLUT4 vesicles translocate to , and fuse with , the plasma membrane .	Upon insulin stimulation GLUT4 vesicles translocate to, and fuse with, the plasma membrane.	1	4	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	3	4
Primary adipose tissue explants and 3T3-L1 adipocytes were pretreated for 30 min with GW9508 or DHA , followed by measurement of basal and insulin stimulated GLUT4 translocation ( XREF_FIG ) and 2-deoxyglucose ( 2-DOG ) transport ( XREF_FIG ) .	Primary adipose tissue explants and 3T3-L1 adipocytes were pretreated for 30 min with GW9508 or DHA, followed by measurement of basal and insulin stimulated GLUT4 translocation (XREF_FIG) and 2-deoxyglucose (2-DOG) transport (XREF_FIG).	19	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
Akt activation was required by T3 to enhance insulin induced GLUT4 translocation and glucose uptake in adipocytes .	Akt activation was required by T3 to enhance insulin induced GLUT4 translocation and glucose uptake in adipocytes.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
As a result , Ang II inhibited insulin induced GLUT-4 translocation from cytoplasm to the plasma membrane in RASMC .	As a result, Ang II inhibited insulin induced GLUT-4 translocation from cytoplasm to the plasma membrane in RASMC.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	7	8	9	10
Accordingly , fast twitch skeletal muscle fibres of TDP-43 transgenic mice show defective insulin induced GLUT4 translocation and glucose uptake 77 .	Accordingly, fast twitch skeletal muscle fibres of TDP-43 transgenic mice show defective insulin induced GLUT4 translocation and glucose uptake 77.	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
In our study , the phosphorylation of Tmod3 at S71 decreased actin monomer binding and potentiated the insulin stimulated GLUT4 exocytosis .	In our study, the phosphorylation of Tmod3 at S71 decreased actin monomer binding and potentiated the insulin stimulated GLUT4 exocytosis.	15	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Given that the binding of MyoVa-CT to Rab8A correlated with the ability of MyoVa-CT to interfere with GLUT4myc translocation to the cell surface , these findings implicate MyoVa as an effector of Rab8A required for insulin stimulated GLUT4 traffic .	Given that the binding of MyoVa-CT to Rab8A correlated with the ability of MyoVa-CT to interfere with GLUT4myc translocation to the cell surface, these findings implicate MyoVa as an effector of Rab8A required for insulin stimulated GLUT4 traffic.	33	38	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	35	36	37	38
Insulin increased cell surface localization of GLUT4 in 3T3L1-GLUT4myc adipocytes , and a similar effect was obtained with 1,2-dioleoyl-sn-glycerol ( DO-DAG ) , 1-oleoyl-2-acetyl-sn-glycerol ( OA-DAG ) , or 1,2-dipalmitoyl-sn-glycerol ( DP-DAG ) .	Insulin increased cell surface localization of GLUT4 in 3T3L1-GLUT4myc adipocytes, and a similar effect was obtained with 1,2-dioleoyl-sn-glycerol (DO-DAG), 1-oleoyl-2-acetyl-sn-glycerol (OA-DAG), or 1,2-dipalmitoyl-sn-glycerol (DP-DAG).	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Insulin , but not PI ( 3,4,5 ) P ( 3 ) , increased photolabeling of GLUT4 and immunolabeling with C-terminus antibody by 2.47-fold and 2.04-fold over basal , respectively .	Insulin, but not PI (3,4,5) P (3), increased photolabeling of GLUT4 and immunolabeling with C-terminus antibody by 2.47-fold and 2.04-fold over basal, respectively.	0	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	16	17
Insulin induced subcellular shift of GLUT4 to the cell surface in CHOIR-GLUT4-WT cells but had little effect in CHOIR-GLUT4-K44E cells .	Insulin induced subcellular shift of GLUT4 to the cell surface in CHOIR-GLUT4-WT cells but had little effect in CHOIR-GLUT4-K44E cells.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	5	6
Insulin induced reorganization of the subplasma membrane actin filaments may allow exocytic GLUT4 vesicles to fuse with the plasma membrane during stimulation by insulin .	Insulin induced reorganization of the subplasma membrane actin filaments may allow exocytic GLUT4 vesicles to fuse with the plasma membrane during stimulation by insulin.	0	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	12	13
Previously we reported that the phosphorylation of Synip on serine 99 is required for Synip dissociation from Syntaxin4 and insulin stimulated Glut4 translocation in cultured 3T3-L1 adipocytes .	Previously we reported that the phosphorylation of Synip on serine 99 is required for Synip dissociation from Syntaxin4 and insulin stimulated Glut4 translocation in cultured 3T3-L1 adipocytes.	15	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	19	20	21	22
Combined with evidence showing skeletal muscle PAK1 KO to exhibit attenuated insulin stimulated GLUT4 translocation [ XREF_BIBR ] , these data suggest that PAK1 but not PAK2 signaling is required for insulin stimulated GLUT4 vesicle exocytosis in L6 myoblasts , revealing a selective importance for PAK1 in this process .	Combined with evidence showing skeletal muscle PAK1 KO to exhibit attenuated insulin stimulated GLUT4 translocation [XREF_BIBR], these data suggest that PAK1 but not PAK2 signaling is required for insulin stimulated GLUT4 vesicle exocytosis in L6 myoblasts, revealing a selective importance for PAK1 in this process.	29	35	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	31	32	33	34
AKT2 activation is an essential step for insulin induced GLUT4 translocation in skeletal muscle , promoting glucose uptake [ XREF_BIBR - XREF_BIBR ] .	AKT2 activation is an essential step for insulin induced GLUT4 translocation in skeletal muscle, promoting glucose uptake [XREF_BIBR - XREF_BIBR].	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
The GLUT4 is responsible for glucose incorporation into muscle and adipocytes , and GLUT4 mediated glucose uptake is an important step in the control of glucose metabolism and is stimulated by insulin [ XREF_BIBR ] .	The GLUT4 is responsible for glucose incorporation into muscle and adipocytes, and GLUT4 mediated glucose uptake is an important step in the control of glucose metabolism and is stimulated by insulin [XREF_BIBR].	13	33	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	31	32	13	14
Cells transfected with Akt2 siRNA showed a significant reduction in insulin stimulated GLUT4 distribution to the periphery , consistent with the concept that Akt2 plays a role in GLUT4 trafficking .	Cells transfected with Akt2 siRNA showed a significant reduction in insulin stimulated GLUT4 distribution to the periphery, consistent with the concept that Akt2 plays a role in GLUT4 trafficking.	5	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Upon maximum insulin stimulation the steady state Glut4 PM levels increase by approximately ten-fold , predominantly due to insulin stimulation of Glut4 exocytosis .	Upon maximum insulin stimulation the steady state Glut4 PM levels increase by approximately ten-fold, predominantly due to insulin stimulation of Glut4 exocytosis.	18	22	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	18	19	21	22
Insulin administration caused a depletion of GLUT4 and IRAP but no changes in transferrin receptors , which suggests that this pool is heterogeneous .	Insulin administration caused a depletion of GLUT4 and IRAP but no changes in transferrin receptors, which suggests that this pool is heterogeneous.	0	8	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Insulin increases GLUT4 and GLUT3 total expression levels in all leukocytes .	Insulin increases GLUT4 and GLUT3 total expression levels in all leukocytes.	0	4	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Here , we generated a genetic knockin mouse model to study the specific roles that phospho-Thr649 and its resulting binding of 14-3-3 to AS160 play in insulin mediated GLUT4 trafficking and glucose homeostasis .	Here, we generated a genetic knockin mouse model to study the specific roles that phospho-Thr649 and its resulting binding of 14-3-3 to AS160 play in insulin mediated GLUT4 trafficking and glucose homeostasis.	19	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	28	29
SPATIAL-TEMPORAL KINETICS OF INSULIN MEDIATED GLUT4 TRAFFICKING .	SPATIAL-TEMPORAL KINETICS OF INSULIN MEDIATED GLUT4 TRAFFICKING.	1	6	MEDIATED	Positive_early_activation	Positive_activation	Positive_activation	INSULIN	INSULIN	INSULIN	GLUT4	GLUT4	GLUT4	3	4	5	6
In adipocytes , insulin stimulated GLUT4 uptake involves another Rho member -- Rhoq ; it does not require PI3K but is dependent upon formation of a Rhoq activating complex downstream of insulin stimulated insulin receptor XREF_BIBR , XREF_BIBR .	In adipocytes, insulin stimulated GLUT4 uptake involves another Rho member -- Rhoq; it does not require PI3K but is dependent upon formation of a Rhoq activating complex downstream of insulin stimulated insulin receptor XREF_BIBR, XREF_BIBR.	3	6	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
An intact microtubule network is specifically required for insulin mediated GLUT4 translocation since nocodazole treatment did not affect insulin mediated GLUT1 translocation or adipsin secretion .	An intact microtubule network is specifically required for insulin mediated GLUT4 translocation since nocodazole treatment did not affect insulin mediated GLUT1 translocation or adipsin secretion.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Nevertheless , the observation that the block in insulin stimulated GLUT4 trafficking observed with TBC1D13 overexpression could be overcome by co-expressing constitutively active Rab35 but not Rab10 and that other vesicular trafficking pathways were unaffected under these conditions , strongly supports the argument that this effect is quite specific .	Nevertheless, the observation that the block in insulin stimulated GLUT4 trafficking observed with TBC1D13 overexpression could be overcome by co-expressing constitutively active Rab35 but not Rab10 and that other vesicular trafficking pathways were unaffected under these conditions, strongly supports the argument that this effect is quite specific.	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
These include Xenopus oocyte maturation , proliferation and survival of fibroblasts , differentiation of PC12 and leukemic cells , activation of mitogen activated protein kinase ( MAPK ) and gene expression , and insulin induced glut4 translocation .	These include Xenopus oocyte maturation, proliferation and survival of fibroblasts, differentiation of PC12 and leukemic cells, activation of mitogen activated protein kinase (MAPK) and gene expression, and insulin induced glut4 translocation.	33	36	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	glut4	glut4	glut4	33	34	35	36
In the process of insulin stimulated GLUT4 vesicle exocytosis , Munc18c has been proposed to control SNARE complex formation by inactivating syntaxin 4 in a self associated conformation .	In the process of insulin stimulated GLUT4 vesicle exocytosis, Munc18c has been proposed to control SNARE complex formation by inactivating syntaxin 4 in a self associated conformation.	2	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Moreover , the p85 and p110 PI 3 '-kinase is required for the insulin stimulation of Glut-4 recycling to the plasma membrane and overexpression of p110alpha increases Glut 4 recycling in several systems .	Moreover, the p85 and p110 PI 3 '-kinase is required for the insulin stimulation of Glut-4 recycling to the plasma membrane and overexpression of p110alpha increases Glut 4 recycling in several systems.	13	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut-4	Glut-4	Glut-4	13	14	16	17
Additionally , glucose transporter ( GLUT4 ) is a rate limiting factor for glucose uptake in skeletal muscle , and Akt ( protein kinase B ) is a central mediator of insulin induced GLUT4 translocation from cytosol to membrane [ XREF_BIBR ] .	Additionally, glucose transporter (GLUT4) is a rate limiting factor for glucose uptake in skeletal muscle, and Akt (protein kinase B) is a central mediator of insulin induced GLUT4 translocation from cytosol to membrane [XREF_BIBR].	29	34	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	31	32	33	34
The presence of these lipid signals in mammalian adipose cells was shown to be important for insulin induced GLUT4 translocation to the membrane and sugar uptake XREF_BIBR , XREF_BIBR .	The presence of these lipid signals in mammalian adipose cells was shown to be important for insulin induced GLUT4 translocation to the membrane and sugar uptake XREF_BIBR, XREF_BIBR.	16	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
Insulin regulates exocyst assembly via activation of TC10 5 , and induces its recognition of the Glut4 vesicle via stimulation of RalA 7 .	Insulin regulates exocyst assembly via activation of TC10 5, and induces its recognition of the Glut4 vesicle via stimulation of RalA 7.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut4	Glut4	Glut4	0	1	16	17
Both PI3K dependent and PI3K independent pathways operate in the insulin induced GLUT4 translocation XREF_BIBR , XREF_BIBR .	Both PI3K dependent and PI3K independent pathways operate in the insulin induced GLUT4 translocation XREF_BIBR, XREF_BIBR.	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Time course analyses of insulin mediated GLUT4 translocation in Akt1 W80A and Akt2 W80A expressing cells showed that Akt1 and Akt2 drug resistant mutants promote and sustain GLUT4 translocation to the plasma membrane for up to 2h indistinguishably ( XREF_FIG G ) .	Time course analyses of insulin mediated GLUT4 translocation in Akt1 W80A and Akt2 W80A expressing cells showed that Akt1 and Akt2 drug resistant mutants promote and sustain GLUT4 translocation to the plasma membrane for up to 2h indistinguishably (XREF_FIG G).	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Angiotensin II Inhibits Insulin Stimulated GLUT4 Translocation and Akt Activation through Tyrosine Nitration Dependent Mechanisms .	Angiotensin II Inhibits Insulin Stimulated GLUT4 Translocation and Akt Activation through Tyrosine Nitration Dependent Mechanisms.	3	6	Stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
WT Rab4 and Rab4 Q67L microinjection had no effect on either basal or insulin induced GLUT4 translocation .	WT Rab4 and Rab4 Q67L microinjection had no effect on either basal or insulin induced GLUT4 translocation.	8	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Since the AKT proteins have been shown to regulate insulin stimulated GLUT4 trafficking , we next determined the level of GLUT4 protein in skeletal muscle whole cell homogenates .	Since the AKT proteins have been shown to regulate insulin stimulated GLUT4 trafficking, we next determined the level of GLUT4 protein in skeletal muscle whole cell homogenates.	8	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
RalA , which is present in GLUT4 vesicles in adipocytes , also interacts with the exocyst complex and its activation is required for insulin stimulated GLUT4 trafficking .	RalA, which is present in GLUT4 vesicles in adipocytes, also interacts with the exocyst complex and its activation is required for insulin stimulated GLUT4 trafficking.	21	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
Otherwise , an increased JNK expression caused by GAE treatments blocked an insulin induced GLUT4 translocation in adipocytes culture .	Otherwise, an increased JNK expression caused by GAE treatments blocked an insulin induced GLUT4 translocation in adipocytes culture.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Insulin ( 10mug/mL ) as the positive control upregulated GLUT4 gene and downregulated AKT , HSL , PI3KA , and Srebp1 genes compared to the untreated cells in the present study .	Insulin (10mug/mL) as the positive control upregulated GLUT4 gene and downregulated AKT, HSL, PI3KA, and Srebp1 genes compared to the untreated cells in the present study.	0	12	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	9	10
PI3kinase is known to participate in insulin mediated GLUT4 translocation .	PI3kinase is known to participate in insulin mediated GLUT4 translocation.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Insulin delocalizes its exchanger Gapex-5 to the plasma membrane and inhibits Rab31 activity , thus potentiating insulin induced GLUT4 translocation XREF_BIBR .	Insulin delocalizes its exchanger Gapex-5 to the plasma membrane and inhibits Rab31 activity, thus potentiating insulin induced GLUT4 translocation XREF_BIBR.	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
In these systems , insulin stimulates the remodeling of the cortical actin cytoskeleton 1 , 2 , 43 , 44 , 47 and inhibition of this remodeling with actin destabilizing ( Cytochalasin D or Latrunculin A/B ) 1 , 2 , 3 , 4 , 17 , 43 , 44 , 45 , 46 or -stabilizing drugs ( Jasplakinolide ) 1 , 3 abrogates insulin dependent GLUT4 vesicle fusion with the PM and glucose uptake .	In these systems, insulin stimulates the remodeling of the cortical actin cytoskeleton 1, 2, 43, 44, 47 and inhibition of this remodeling with actin destabilizing (Cytochalasin D or Latrunculin A/B) 1, 2, 3, 4, 17, 43, 44, 45, 46 or -stabilizing drugs (Jasplakinolide) 1, 3 abrogates insulin dependent GLUT4 vesicle fusion with the PM and glucose uptake.	4	68	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	66	67
Oleic acid ( 120 , 300mumol/L ) and linoleic acid ( 300mumol/L ) , but not palmitic acid , significantly decreased insulin mediated GLUT4 translocation .	Oleic acid (120, 300mumol/L) and linoleic acid (300mumol/L), but not palmitic acid, significantly decreased insulin mediated GLUT4 translocation.	20	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
It is suggested that NAALADase may function as a regulator required for the insulin stimulated GLUT4 vesicle movement and/or its exocytosis , thus may regulate insulin induced GLUT4 recruitment in rat adipocytes .	It is suggested that NAALADase may function as a regulator required for the insulin stimulated GLUT4 vesicle movement and/or its exocytosis, thus may regulate insulin induced GLUT4 recruitment in rat adipocytes.	24	28	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	27	28
Exercise training , however , did not alter insulin stimulated glucose transport activity or cell surface GLUT-4 in soleus muscles .	Exercise training, however, did not alter insulin stimulated glucose transport activity or cell surface GLUT-4 in soleus muscles.	7	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	8	9	16	17
In fructose chow fed animals receiving 2-week rosiglitazone ( 4mgkg -1 per day ) treatment , insulin stimulated GLUT 4 protein expression in the membrane fraction of soleus muscles was increased to achieve the level as in the standard chow fed group , but the GLUT 4 protein level in the cytosolic fraction of same sample was at 60 % of the level of their vehicle treated counterparts ( XREF_FIG ) .	In fructose chow fed animals receiving 2-week rosiglitazone (4mgkg -1 per day) treatment, insulin stimulated GLUT 4 protein expression in the membrane fraction of soleus muscles was increased to achieve the level as in the standard chow fed group, but the GLUT 4 protein level in the cytosolic fraction of same sample was at 60% of the level of their vehicle treated counterparts (XREF_FIG).	16	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	16	17	18	20
LIMA1 has been shown previously to interact with actin through cross linking and stabilization of the filaments , supporting the development of stress fibers [ XREF_BIBR ] which have been indicated in the insulin stimulated transport of GLUT4 [ XREF_BIBR ] .	LIMA1 has been shown previously to interact with actin through cross linking and stabilization of the filaments, supporting the development of stress fibers [XREF_BIBR] which have been indicated in the insulin stimulated transport of GLUT4 [XREF_BIBR].	30	39	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	33	34	37	38
Treatment with isoprenaline and adenosine deaminase also resulted in similar decreases in insulin stimulated cell-surface GLUT4 as assessed by both bis-mannose photolabelling of the substrate binding site and biotinylation of the extracellular carbohydrate moiety when evaluated under similar experimental conditions .	Treatment with isoprenaline and adenosine deaminase also resulted in similar decreases in insulin stimulated cell-surface GLUT4 as assessed by both bis-mannose photolabelling of the substrate binding site and biotinylation of the extracellular carbohydrate moiety when evaluated under similar experimental conditions.	7	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	15	16
We sought to simulate the insulin mediated GLUT4 translocation pathway with three novel characteristics : ( 1 ) the pathway is the most complete representation of the required components to date , especially those beyond As160 ; ( 2 ) the simulation platform incorporates stochastic variations among individual cells and realistically mimics local molecule availability in the signaling pathway , and ( 3 ) the response of hundreds of cells can be simulated in near real-time .	We sought to simulate the insulin mediated GLUT4 translocation pathway with three novel characteristics : (1) the pathway is the most complete representation of the required components to date, especially those beyond As160; (2) the simulation platform incorporates stochastic variations among individual cells and realistically mimics local molecule availability in the signaling pathway, and (3) the response of hundreds of cells can be simulated in near real-time.	3	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
In vitro studies showed that transient siRNA mediated down-regulation of Akt2 inhibits insulin induced GLUT4 translocation to the plasma membrane of 3T3-L1 adipocytes XREF_BIBR - XREF_BIBR , suggesting that impaired glucose transport in Akt2-null adipocytes is at least in part explained by defective regulation of GLUT4 trafficking in those cells .	In vitro studies showed that transient siRNA mediated down-regulation of Akt2 inhibits insulin induced GLUT4 translocation to the plasma membrane of 3T3-L1 adipocytes XREF_BIBR - XREF_BIBR, suggesting that impaired glucose transport in Akt2-null adipocytes is at least in part explained by defective regulation of GLUT4 trafficking in those cells.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Although the current data do not directly support the possibility of different pools of GLUT4 in muscle , they do demonstrate that the spatial temporal kinetics of contraction- and insulin stimulated GLUT4 translocation differ substantially .	Although the current data do not directly support the possibility of different pools of GLUT4 in muscle, they do demonstrate that the spatial temporal kinetics of contraction- and insulin stimulated GLUT4 translocation differ substantially.	25	32	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	29	30	31	32
To address the physiological role of BMP mediated upregulation of PPARgamma and GLUT4 , insulin stimulated glucose uptake , as one of the major functions of adipocytes , was analyzed .	To address the physiological role of BMP mediated upregulation of PPARgamma and GLUT4, insulin stimulated glucose uptake, as one of the major functions of adipocytes, was analyzed.	8	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	12	13
However , some years ago , it has been shown that the protein kinase B ( Akt ) substrate AS160 , which is phosphorylated by Akt upon insulin stimulation , plays a key role in insulin induced GLUT-4 translocation .	However, some years ago, it has been shown that the protein kinase B (Akt) substrate AS160, which is phosphorylated by Akt upon insulin stimulation, plays a key role in insulin induced GLUT-4 translocation.	33	38	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	35	36	37	38
In muscle and fat cells , insulin stimulates the delivery of GLUT4 from an intracellular location to the cell surface , where it facilitates glucose uptake thereby controlling the plasma glucose levels [ XREF_BIBR ] .	In muscle and fat cells, insulin stimulates the delivery of GLUT4 from an intracellular location to the cell surface, where it facilitates glucose uptake thereby controlling the plasma glucose levels [XREF_BIBR].	6	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	11	12
Beyond the ability to accurately simulate steady state or insulin activation , a third approach to evaluate the simulation was a comparison of predicted and observed insulin mediated GLUT4 translocation generated under disrupted conditions .	Beyond the ability to accurately simulate steady state or insulin activation, a third approach to evaluate the simulation was a comparison of predicted and observed insulin mediated GLUT4 translocation generated under disrupted conditions.	23	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	28	29
In an earlier study 9 analyzing whole epitrochlearis muscles using the same dietary protocols and the same insulin concentration as the current study , we found that the insulin stimulated muscles from LFD rats exceeded HFD values for phosphorylation of Akt substrate of 160kDa ( AS160 , also known as TBC1D4 ) on Thr 642 and Ser 588 , two sites that are crucial for regulating insulin stimulated GLUT4 translocation and glucose transport XREF_BIBR , XREF_BIBR .	In an earlier study 9 analyzing whole epitrochlearis muscles using the same dietary protocols and the same insulin concentration as the current study, we found that the insulin stimulated muscles from LFD rats exceeded HFD values for phosphorylation of Akt substrate of 160kDa (AS160, also known as TBC1D4) on Thr 642 and Ser 588, two sites that are crucial for regulating insulin stimulated GLUT4 translocation and glucose transport XREF_BIBR, XREF_BIBR.	65	69	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	66	67	68	69
Surprisingly insulin stimulated GLUT4 translocation was normal in L6 cells , despite a similar glucose uptake defect as observed in mature striated muscle .	Surprisingly insulin stimulated GLUT4 translocation was normal in L6 cells, despite a similar glucose uptake defect as observed in mature striated muscle.	1	4	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	3	4
Similar to its well characterized actions in muscle and fat , insulin mediated GLUT4 translocation has been demonstrated in neuronal cell lines , hippocampus , and hypothalamus .	Similar to its well characterized actions in muscle and fat, insulin mediated GLUT4 translocation has been demonstrated in neuronal cell lines, hippocampus, and hypothalamus.	11	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Moreover , the insulin stimulated fusion of GLUT4 vesicles with the plasma membrane can occur independently of Akt activity , although based on inhibition by wortmannin , it is dependent on phosphatidylinositol 3 ' kinase activity .	Moreover, the insulin stimulated fusion of GLUT4 vesicles with the plasma membrane can occur independently of Akt activity, although based on inhibition by wortmannin, it is dependent on phosphatidylinositol 3 ' kinase activity.	2	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	7	8
One of the early events in the development of Type 2 diabetes appears to be an inhibition of insulin mediated GLUT4 redistribution to the cell surface in tissues that express GLUT4 .	One of the early events in the development of Type 2 diabetes appears to be an inhibition of insulin mediated GLUT4 redistribution to the cell surface in tissues that express GLUT4.	16	21	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
Although it is possible that TBC1D1 is a target of CrPic , AS160 is the primary GLUT4 containing vesicle Rab-GAP implicated in insulin stimulated GLUT4 translocation and has also been shown to be phosphorylated by AMPK [ XREF_BIBR ] .	Although it is possible that TBC1D1 is a target of CrPic, AS160 is the primary GLUT4 containing vesicle Rab-GAP implicated in insulin stimulated GLUT4 translocation and has also been shown to be phosphorylated by AMPK [XREF_BIBR].	20	30	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	24	25
Insulin treatment of the streptozotocin-diabetic rats or refeeding the fasted animals causes a rapid recovery of the GLUT-4 mRNA to levels significantly above those observed in untreated control animals .	Insulin treatment of the streptozotocin-diabetic rats or refeeding the fasted animals causes a rapid recovery of the GLUT-4 mRNA to levels significantly above those observed in untreated control animals.	0	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT-4	GLUT-4	GLUT-4	0	1	17	18
Thus , conflicting data have been reported as to whether insulin stimulates GLUT4 exocytosis via a regulated secretory compartment , or if GLUT4 recycling occurs independently of insulin stimulated protein secretion .	Thus, conflicting data have been reported as to whether insulin stimulates GLUT4 exocytosis via a regulated secretory compartment, or if GLUT4 recycling occurs independently of insulin stimulated protein secretion.	10	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
However , others have reported a positive role for Munc18c in the insulin stimulated delivery of GLUT4 to the plasma membrane of adipocytes XREF_BIBR , XREF_BIBR .	However, others have reported a positive role for Munc18c in the insulin stimulated delivery of GLUT4 to the plasma membrane of adipocytes XREF_BIBR, XREF_BIBR.	4	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	16	17
In addition , our results suggest that insulin may also stimulate the formation of Glut4 vesicles and accelerate Glut4 recycling to the plasma membrane .	In addition, our results suggest that insulin may also stimulate the formation of Glut4 vesicles and accelerate Glut4 recycling to the plasma membrane.	7	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	7	8	14	15
We hypothesized that the dissociated DGKzeta activates PIP5K1alpha , and PIP5K1alpha activity plays important roles in insulin induced GLUT4 translocation .	We hypothesized that the dissociated DGKzeta activates PIP5K1alpha, and PIP5K1alpha activity plays important roles in insulin induced GLUT4 translocation.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
In normal conditions , insulin stimulates Glut4 activity in skeletal muscle via IRS tyrosine phosphorylation and downstream PI3K activation ( XREF_FIG ) .	In normal conditions, insulin stimulates Glut4 activity in skeletal muscle via IRS tyrosine phosphorylation and downstream PI3K activation (XREF_FIG).	4	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	4	5	6	7
In summary , insulin induced Glut4 translocation can be reconstituted in vitro to a limited extent by using isolated membranes .	In summary, insulin induced Glut4 translocation can be reconstituted in vitro to a limited extent by using isolated membranes.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	3	4	5	6
However , data using toxin specific cleavage of VAMP2 have been more controversial , with some studies reporting significant inhibition of insulin stimulated Glut4 translocation and others not .	However, data using toxin specific cleavage of VAMP2 have been more controversial, with some studies reporting significant inhibition of insulin stimulated Glut4 translocation and others not.	19	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	21	22	23	24
Although we see a trend toward a decrease in the insulin mediated GLUT4 translocation in our stable IRAP-KD adipocytes , the primary effect is observed in the basal state ( XREF_FIG E ) .	Although we see a trend toward a decrease in the insulin mediated GLUT4 translocation in our stable IRAP-KD adipocytes, the primary effect is observed in the basal state (XREF_FIG E).	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
These results suggested that insulin might activate GLUT4 via a p38 MAPK dependent pathway .	These results suggested that insulin might activate GLUT4 via a p38 MAPK dependent pathway.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	7	8
The second advantage for bone from a reduction in insulin action is a shift in glucose disposal away from insulin mediated glut4 pathways , such as muscle , toward glut1 and glut3 , which are the principal transporters of glucose in the osteoblast XREF_BIBR .	The second advantage for bone from a reduction in insulin action is a shift in glucose disposal away from insulin mediated glut4 pathways, such as muscle, toward glut1 and glut3, which are the principal transporters of glucose in the osteoblast XREF_BIBR.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	glut4	glut4	glut4	19	20	21	22
Incubation of adipocytes from either group with 7 nM insulin did not recruit GLUT5 to the plasma membrane , in spite of a 54 % insulin stimulated increase in GLUT4 in nonobese subjects .	Incubation of adipocytes from either group with 7 nM insulin did not recruit GLUT5 to the plasma membrane, in spite of a 54% insulin stimulated increase in GLUT4 in nonobese subjects.	25	32	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	29	30
While other chemical chaperones ( glycerol and 4-phenyl butyric acid ) also acutely enhanced insulin induced GLUT4 translocation , these effects were not mediated via changes in GLUT4 endocytosis .	While other chemical chaperones (glycerol and 4-phenyl butyric acid) also acutely enhanced insulin induced GLUT4 translocation, these effects were not mediated via changes in GLUT4 endocytosis.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Insulin stimulated myc-GLUT4-GFP translocation was quantified as the ratio of cell surface myc signal ( detected with TIRFM ) to the total GFP signal in the widefield image ( Epi-GFP ) .	Insulin stimulated myc-GLUT4-GFP translocation was quantified as the ratio of cell surface myc signal (detected with TIRFM) to the total GFP signal in the widefield image (Epi-GFP).	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	myc-GLUT4-GFP	myc-GLUT4-GFP	myc-GLUT4-GFP	0	1	2	3
In addition , it has recently been demonstrated that insulin induced GLUT4 exocytosis is accompanied by capping of Tpm3.1-containing actin filaments by Akt2 dependent phosphorylation of tropomodulin 3 which promotes actin filament stability 52 .	In addition, it has recently been demonstrated that insulin induced GLUT4 exocytosis is accompanied by capping of Tpm3.1-containing actin filaments by Akt2 dependent phosphorylation of tropomodulin 3 which promotes actin filament stability 52.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Briefly , glucose is taken up into the adipocyte through insulin mediated GLUT4 , converted to pyruvate , and transported into the mitochondria where it is converted to malonyl CoA .	Briefly, glucose is taken up into the adipocyte through insulin mediated GLUT4, converted to pyruvate, and transported into the mitochondria where it is converted to malonyl CoA.	4	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Therefore , insulin stimulation of GLUT4 is critical for regulating neuronal metabolism and energy production which are needed for memory and cognition .	Therefore, insulin stimulation of GLUT4 is critical for regulating neuronal metabolism and energy production which are needed for memory and cognition.	2	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	5	6
Using independent optogenetic control over PI3K and Akt signaling , the authors showed that Akt activation only partially recapitulates the PI3K- and insulin induced GLUT4 response , implicating Akt independent processes mediated through PI3K .	Using independent optogenetic control over PI3K and Akt signaling, the authors showed that Akt activation only partially recapitulates the PI3K- and insulin induced GLUT4 response, implicating Akt independent processes mediated through PI3K.	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	24	25
As mentioned above , insulin stimulates the relocation of GLUT4 from perinuclear stores to the plasma membrane and significantly stimulates glucose uptake into cells .	As mentioned above, insulin stimulates the relocation of GLUT4 from perinuclear stores to the plasma membrane and significantly stimulates glucose uptake into cells.	4	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	9	10
Indeed , a number of factors that are related to the enhanced muscle insulin sensitivity , such as insulin mediated GLUT4 translocation , increased sensitivity of GS to insulin , muscle glycogen content , and adenosine monophosphate activated protein kinase ( AMPK ) activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Indeed, a number of factors that are related to the enhanced muscle insulin sensitivity, such as insulin mediated GLUT4 translocation, increased sensitivity of GS to insulin, muscle glycogen content, and adenosine monophosphate activated protein kinase (AMPK) activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	14	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
Insulin stimulated GLUT4 translocation was measured with the GLUT4-EGFP reporter using TIRFM .	Insulin stimulated GLUT4 translocation was measured with the GLUT4-EGFP reporter using TIRFM.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
As the amount of adipose tissue is very important in severe obesity , Munc18c from adipose tissue could play a relevant role in the regulation of insulin stimulated exocytosis of GLUT4 containing vesicles .	As the amount of adipose tissue is very important in severe obesity, Munc18c from adipose tissue could play a relevant role in the regulation of insulin stimulated exocytosis of GLUT4 containing vesicles.	24	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	30	31
In STZ induced T1DM rats , GLUT4 mRNA and protein expression as well as glucose uptake in the heart were decreased , and restored by insulin administration , whereas GLUT1 mRNA expression was not significantly altered [ XREF_BIBR , XREF_BIBR ] .	In STZ induced T1DM rats, GLUT4 mRNA and protein expression as well as glucose uptake in the heart were decreased, and restored by insulin administration, whereas GLUT1 mRNA expression was not significantly altered [XREF_BIBR, XREF_BIBR].	6	26	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	6	7
As well , both maximal insulin stimulated glucose disposal ( Max GIR ) and GLUT4 protein content tended to remain increased at the 1-week post exercise measurement .	As well, both maximal insulin stimulated glucose disposal (Max GIR) and GLUT4 protein content tended to remain increased at the 1-week post exercise measurement.	3	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	14	15
While originally created to investigate the kinase responsible for insulin mediated GLUT 4 glucose transporter translocation , CK59 also offered an attractive option to those studying CaMKII and calcium channels , due to its potency ( IC 50 < 10 muM ) and cell permeability .	While originally created to investigate the kinase responsible for insulin mediated GLUT 4 glucose transporter translocation, CK59 also offered an attractive option to those studying CaMKII and calcium channels, due to its potency (IC 50 < 10 muM) and cell permeability.	7	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	9	10	11	13
Therefore , the notion that PI-3 kinase activation is necessary for insulin triggered GLUT4 exocytosis is supported , and it is through inhibition of this activity that wortmannin and LY294002 block insulin stimulated GLUT4 trafficking .	Therefore, the notion that PI-3 kinase activation is necessary for insulin triggered GLUT4 exocytosis is supported, and it is through inhibition of this activity that wortmannin and LY294002 block insulin stimulated GLUT4 trafficking.	9	14	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
In line with its role as a t-SNARE , SNAP23 along with these other SNAREs , has been shown to mediate insulin mediated GLUT4 docking and fusion with the plasma membrane ( Foster etal .	In line with its role as a t-SNARE, SNAP23 along with these other SNAREs, has been shown to mediate insulin mediated GLUT4 docking and fusion with the plasma membrane (Foster etal.	20	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
Caffeine also suppressed insulin induced GLUT4 translocation in the differentiated cells .	Caffeine also suppressed insulin induced GLUT4 translocation in the differentiated cells.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Although caffeine did not alter insulin induced activation of PI3K and protein kinase C-zeta ( PKCzeta ) , an isoform of atypical PKC , which is reported to have an important role in insulin induced GLUT4 translocation , we found that insulin induced phosphorylation and activation of Akt were blocked by pre-treatment with caffeine .	Although caffeine did not alter insulin induced activation of PI3K and protein kinase C-zeta (PKCzeta), an isoform of atypical PKC, which is reported to have an important role in insulin induced GLUT4 translocation, we found that insulin induced phosphorylation and activation of Akt were blocked by pre-treatment with caffeine.	31	36	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	33	34	35	36
In 3T3-L1 adipocytes transfected with scrambled siRNA , 100nM insulin enhanced the GLUT4 signal in the TIRF zone by about 2.5-fold .	In 3T3-L1 adipocytes transfected with scrambled siRNA, 100nM insulin enhanced the GLUT4 signal in the TIRF zone by about 2.5-fold.	8	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	12	13
Chia seeds normalized insulin stimulated GLUT-4 transporter , the abundance of IRS-1 and pAMPK , changed the profile of fatty acid phospholipids , reduced left-ventricle collagen deposition and normalized hypertension and dyslipidemia .	Chia seeds normalized insulin stimulated GLUT-4 transporter, the abundance of IRS-1 and pAMPK, changed the profile of fatty acid phospholipids, reduced left-ventricle collagen deposition and normalized hypertension and dyslipidemia.	2	6	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	3	4	5	6
Insulin stimulates TUG endoproteolytic cleavage to mobilize intracellular GLUT4 storage vesicles to the plasma membrane , an action that allows glucose to enter the cells by facilitative transport .	Insulin stimulates TUG endoproteolytic cleavage to mobilize intracellular GLUT4 storage vesicles to the plasma membrane, an action that allows glucose to enter the cells by facilitative transport.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	8	9
It has been suggested that insulin causes attachment of PI 3-kinases to the intracellular GLUT4 containing vesicles in rat adipose cells .	It has been suggested that insulin causes attachment of PI 3-kinases to the intracellular GLUT4 containing vesicles in rat adipose cells.	5	15	causes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	14	15
We hypothesized that MICAL-L2 is required for insulin induced GLUT4 translocation in muscle cells .	We hypothesized that MICAL-L2 is required for insulin induced GLUT4 translocation in muscle cells.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Muscle specific transgenic expression of GLUT4 improves insulin action in diabetic mice , which may be attributable to enhanced basal accumulation of GLUT4 at the cell surface as well as to a partial correction of the defect in insulin mediated GLUT4 translocation .	Muscle specific transgenic expression of GLUT4 improves insulin action in diabetic mice, which may be attributable to enhanced basal accumulation of GLUT4 at the cell surface as well as to a partial correction of the defect in insulin mediated GLUT4 translocation.	36	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	38	39	40	41
Greater than 70 % of siMunc18c treated cells coexpressing Flag-Munc18c-WT showed a restoration of insulin stimulated GLUT4-GFP cell surface distribution compared with cells expressing vector alone ( XREF_FIG , No Flag , images 1 and 2 , and graph ) .	Greater than 70% of siMunc18c treated cells coexpressing Flag-Munc18c-WT showed a restoration of insulin stimulated GLUT4-GFP cell surface distribution compared with cells expressing vector alone (XREF_FIG, No Flag, images 1 and 2, and graph).	12	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4-GFP	GLUT4-GFP	GLUT4-GFP	14	15	16	17
This perturbation led to no further exogenous insulin induced GLUT4 translocation , thereby disabling the insulin responsiveness of the skeletal muscle but retaining it in WAT .	This perturbation led to no further exogenous insulin induced GLUT4 translocation, thereby disabling the insulin responsiveness of the skeletal muscle but retaining it in WAT.	2	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Although the actual function of annexins in adipose cells remains to be determined , our data indicate that insulin stimulated GLUT4 trafficking does not rely on a change in subcellular location of any of the five annexins detected so far in these cells .	Although the actual function of annexins in adipose cells remains to be determined, our data indicate that insulin stimulated GLUT4 trafficking does not rely on a change in subcellular location of any of the five annexins detected so far in these cells.	18	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
Therefore , regardless of their differential substrate requirements for IR mediated phosphorylation in vitro , both Tyr521 and Tyr219 phosphorylation sites of Munc18c were required to confer its positive function in the process of insulin stimulated GLUT4 vesicle exocytosis in 3T3-L1 adipocytes .	Therefore, regardless of their differential substrate requirements for IR mediated phosphorylation in vitro, both Tyr521 and Tyr219 phosphorylation sites of Munc18c were required to confer its positive function in the process of insulin stimulated GLUT4 vesicle exocytosis in 3T3-L1 adipocytes.	32	38	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	34	35	36	37
In addition , DBK was able to potentiate insulin induced GLUT4 translocation to the plasma membrane in 3T3-L1 adipocytes ( XREF_FIG ) and insulin induced glucose uptake by isolated adipocytes ( XREF_FIG ) .	In addition, DBK was able to potentiate insulin induced GLUT4 translocation to the plasma membrane in 3T3-L1 adipocytes (XREF_FIG) and insulin induced glucose uptake by isolated adipocytes (XREF_FIG).	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
These impairments of intracellular insulin signaling could block GLUT-4 activation , reducing the uptake of glucose by cells .	These impairments of intracellular insulin signaling could block GLUT-4 activation, reducing the uptake of glucose by cells.	4	9	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	4	5	8	9
Insulin stimulated a 170 % increase in GLUT4 at the cell surface in myoblasts treated with vehicle alone ( DMSO ) , and IPA3 treatment abrogated this effect of insulin ( XREF_FIG ) .	Insulin stimulated a 170% increase in GLUT4 at the cell surface in myoblasts treated with vehicle alone (DMSO), and IPA3 treatment abrogated this effect of insulin (XREF_FIG).	0	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	7	8
The insulin stimulated GLUT4 vesicle docking at the plasma membrane requires an interaction between VAMP-2 ( vesicle associated membrane protein-2 ) on the GLUT4 vesicle and syntaxin-4 in the plasma membrane .	The insulin stimulated GLUT4 vesicle docking at the plasma membrane requires an interaction between VAMP-2 (vesicle associated membrane protein-2) on the GLUT4 vesicle and syntaxin-4 in the plasma membrane.	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	3	4
Insulin stimulated GLUT4 translocation is mainly mediated through a PI3K dependent pathway .	Insulin stimulated GLUT4 translocation is mainly mediated through a PI3K dependent pathway.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Time course of insulin mediated GLUT4 signaling events in the hippocampus .	Time course of insulin mediated GLUT4 signaling events in the hippocampus.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Insulin stimulation increases the fusion frequency of exocytic GLUT4 vesicles by approximately 4-fold , increasing GLUT4 content in the plasma membrane .	Insulin stimulation increases the fusion frequency of exocytic GLUT4 vesicles by approximately 4-fold, increasing GLUT4 content in the plasma membrane.	0	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	8	9
A short-chain ceramide analogue , C2-ceramide , precluded insulin induced GLUT4 mRNA accumulation and GLUT4-chloramphenicol acetyltransferase ( CAT ) full promoter activation .	A short-chain ceramide analogue, C2-ceramide, precluded insulin induced GLUT4 mRNA accumulation and GLUT4-chloramphenicol acetyltransferase (CAT) full promoter activation.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
As shown in XREF_FIG , insulin promoted a 3-fold increase in cell surface GLUT4-myc in irrelevant siRNA myotubes that was significantly reduced by Ang II.	As shown in XREF_FIG, insulin promoted a 3-fold increase in cell surface GLUT4-myc in irrelevant siRNA myotubes that was significantly reduced by Ang II.	5	17	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4-myc	GLUT4-myc	GLUT4-myc	5	6	13	14
Glucosamine , a metabolite of glucose via the hexosamine biosynthetic pathway , potently induces insulin resistance in skeletal muscle by impairing insulin induced GLUT4 translocation to the plasma membrane .	Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway, potently induces insulin resistance in skeletal muscle by impairing insulin induced GLUT4 translocation to the plasma membrane.	21	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
Insulin stimulated GLUT-4 appears to be the predominant glucose transporter in the adipocyte despite the constitutive presence of GLUT-1 transporters on the adipocyte membrane .	Insulin stimulated GLUT-4 appears to be the predominant glucose transporter in the adipocyte despite the constitutive presence of GLUT-1 transporters on the adipocyte membrane.	0	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT-4	GLUT-4	GLUT-4	0	1	2	3
Remarkably , no insulin stimulated increase in GLUT4 accumulation was observed in Doc2b -/- mice .	Remarkably, no insulin stimulated increase in GLUT4 accumulation was observed in Doc2b -/- mice.	2	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	7	8
Although subcellular fractionation studies demonstrate that insulin increases GLUT4 density in sarcolemma and transverse tubules , fractionation can not discern GLUT4 vesicle-membrane association from insertion and exofacial exposure .	Although subcellular fractionation studies demonstrate that insulin increases GLUT4 density in sarcolemma and transverse tubules, fractionation can not discern GLUT4 vesicle-membrane association from insertion and exofacial exposure.	6	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Curcumin , as an inhibitor of the phosphoinositide 5-kinase PIKfyve , was also reported to inhibit insulin induced GLUT4 translocation and glucose transport into 3T3-L1 adipocytes [ XREF_BIBR ] .	Curcumin, as an inhibitor of the phosphoinositide 5-kinase PIKfyve, was also reported to inhibit insulin induced GLUT4 translocation and glucose transport into 3T3-L1 adipocytes [XREF_BIBR].	15	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
XREF_BIBR This protein was indeed required for insulin stimulated GLUT4 translocation to the plasma membrane , particularly the fusion step , in adipocytes .	XREF_BIBR This protein was indeed required for insulin stimulated GLUT4 translocation to the plasma membrane, particularly the fusion step, in adipocytes.	5	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Taken together , these data show that insulin signaling accelerates the transition from docking of GLUT4 containing vesicles to their fusion with the plasma membrane and promotes GLUT4 accumulation in clathrin based endocytic structures on the plasma membrane .	Taken together, these data show that insulin signaling accelerates the transition from docking of GLUT4 containing vesicles to their fusion with the plasma membrane and promotes GLUT4 accumulation in clathrin based endocytic structures on the plasma membrane.	7	28	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	27	28
The small guanosine 5 '-triphosphate ( GTP ) ase Rab4 has been suggested to play a role in insulin induced GLUT4 translocation .	The small guanosine 5 '-triphosphate (GTP) ase Rab4 has been suggested to play a role in insulin induced GLUT4 translocation.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
Moreover , overstimulation of beta 2 ARs inhibited insulin induced GLUT4 translocation in beta 2 AR overexpressing HEK-293 cells and rat cardiomyocytes .	Moreover, overstimulation of beta 2 ARs inhibited insulin induced GLUT4 translocation in beta 2 AR overexpressing HEK-293 cells and rat cardiomyocytes.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
At the cellular level , insulin action , initiated by the binding to its cell surface receptor , involves a series of signaling cascades that can be schematically summarized as follows : receptor autophosphorylation and activation of receptor tyrosine kinase ; tyrosine phosphorylation of insulin receptor substrates ( IRSs ) 1 and 2 ; activation of phosphatidylinositol 3-kinase ( PI3K ) ; activation of Akt and its downstream mediator , AS160 , which stimulates the translocation of insulin mediated GLUT4 from intracellular vesicles to the plasma membrane .	At the cellular level, insulin action, initiated by the binding to its cell surface receptor, involves a series of signaling cascades that can be schematically summarized as follows : receptor autophosphorylation and activation of receptor tyrosine kinase; tyrosine phosphorylation of insulin receptor substrates (IRSs) 1 and 2; activation of phosphatidylinositol 3-kinase (PI3K); activation of Akt and its downstream mediator, AS160, which stimulates the translocation of insulin mediated GLUT4 from intracellular vesicles to the plasma membrane.	75	80	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	77	78	79	80
The intracellular pathways that lead to contraction- and insulin stimulated GLUT4 translocation seem to be different , allowing the attainment of a maximal effect when acting together .	The intracellular pathways that lead to contraction- and insulin stimulated GLUT4 translocation seem to be different, allowing the attainment of a maximal effect when acting together.	4	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Insulin induces an increase of GLUT4 in the plasma membrane by both increasing GLUT4 exocytosis and decreasing its endocytosis .	Insulin induces an increase of GLUT4 in the plasma membrane by both increasing GLUT4 exocytosis and decreasing its endocytosis.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	5	6
In contrast , microinjection of an antibody directed against the highly conserved region of Rab3 proteins had no effect on insulin induced GLUT4 .	In contrast, microinjection of an antibody directed against the highly conserved region of Rab3 proteins had no effect on insulin induced GLUT4.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Although insulin acutely stimulates glucose uptake by promotion of GLUT4 translocation from intracellular compartments to the plasma membrane in adipocytes and muscles , long term insulin stimulation causes GLUT4 depletion that is particularly prominent in the insulin responsive GLUT4 storage compartment .	Although insulin acutely stimulates glucose uptake by promotion of GLUT4 translocation from intracellular compartments to the plasma membrane in adipocytes and muscles, long term insulin stimulation causes GLUT4 depletion that is particularly prominent in the insulin responsive GLUT4 storage compartment.	25	29	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	28	29
When introduced into 3T3-L1 adipocytes , curcumin markedly inhibited insulin induced GLUT4 translocation and glucose transport .	When introduced into 3T3-L1 adipocytes, curcumin markedly inhibited insulin induced GLUT4 translocation and glucose transport.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Insulin depletion induces the down-regulation of GLUT4 in the heart .	Insulin depletion induces the down-regulation of GLUT4 in the heart.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
However , pretreatment of cells with latrunculin A ( 1 uM , t = 30 min ) before insulin stimulation severely inhibited exocytosis of GSV , which was observed by disappearance of Irap-pHluorin flashes as well as by disappearance of insulin stimulated increase in PM GLUT4 .	However, pretreatment of cells with latrunculin A (1 uM, t = 30 min) before insulin stimulation severely inhibited exocytosis of GSV, which was observed by disappearance of Irap-pHluorin flashes as well as by disappearance of insulin stimulated increase in PM GLUT4.	38	46	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	40	41	45	46
Insulin induced GLUT4 translocation requires PI3K mediated signal involving upstream insulin receptor , IRS , downstream Akt , and protein kinase C ( PKC ) target enzymes , which induces phosphorylation of rab-GTPase-activating protein , AS160 , leading to glucose uptake .	Insulin induced GLUT4 translocation requires PI3K mediated signal involving upstream insulin receptor, IRS, downstream Akt, and protein kinase C (PKC) target enzymes, which induces phosphorylation of rab-GTPase-activating protein, AS160, leading to glucose uptake.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
However , in cultured rat adipocytes , insulin increases GLUT1 but fails to increase GLUT4 , suggesting that additional factors are involved in vivo .	However, in cultured rat adipocytes, insulin increases GLUT1 but fails to increase GLUT4, suggesting that additional factors are involved in vivo.	7	15	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	14	15
In 3T3-L1 adipocytes , knockdown of TBC1D1 did not alter basal or insulin stimulated GLUT4 in surface membranes .	In 3T3-L1 adipocytes, knockdown of TBC1D1 did not alter basal or insulin stimulated GLUT4 in surface membranes.	10	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
While insulin increased cell surface GLUT4 by enhancing exocytosis and inter-endosomal transit , hyperosmolarity did so through retention .	While insulin increased cell surface GLUT4 by enhancing exocytosis and inter-endosomal transit, hyperosmolarity did so through retention.	1	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	5	6
In this study , both the insulin induced GLUT4 carrier translocation and GLUT4 dependent insulin stimulated glucose transport have been reconstituted in the Xenopus oocyte .	In this study, both the insulin induced GLUT4 carrier translocation and GLUT4 dependent insulin stimulated glucose transport have been reconstituted in the Xenopus oocyte.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Whereas in the presence of insulin , insulin receptor tyrosine kinase phosphorylates Munc18c on Tyr219 and Tyr521 sites , which release Munc18c from syntaxin4 , thus promotes the SNARE complex formation , and increases insulin stimulated GLUT4 vesicle exocytosis [ XREF_BIBR , XREF_BIBR ] .	Whereas in the presence of insulin, insulin receptor tyrosine kinase phosphorylates Munc18c on Tyr219 and Tyr521 sites, which release Munc18c from syntaxin4, thus promotes the SNARE complex formation, and increases insulin stimulated GLUT4 vesicle exocytosis [XREF_BIBR, XREF_BIBR].	33	38	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	34	35	36	37
Further experiments were consistent with phosphorylation of AS160 by PKB and Akt mediating insulin stimulated trafficking of GLUT4 to the plasma membrane .	Further experiments were consistent with phosphorylation of AS160 by PKB and Akt mediating insulin stimulated trafficking of GLUT4 to the plasma membrane.	3	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	17	18
Our findings that the Munc18c-Y219F and -Y521F mutants lacked the ability to dissociate from syntaxin 4 in response to the insulin stimulus , which is coordinate with the inability to restore GLUT4-GFP vesicle exocytosis in siMunc18c expressing cells , suggested that the ability to release syntaxin 4 was functionally important .	Our findings that the Munc18c-Y219F and -Y521F mutants lacked the ability to dissociate from syntaxin 4 in response to the insulin stimulus, which is coordinate with the inability to restore GLUT4-GFP vesicle exocytosis in siMunc18c expressing cells, suggested that the ability to release syntaxin 4 was functionally important.	20	33	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4-GFP	GLUT4-GFP	GLUT4-GFP	20	21	31	32
Furthermore , following insulin stimulation in isolated mouse muscles that endogenously expressed HA-GLUT4-GFP , the majority of insulin stimulated GLUT4 vesicle fusion events emanated from pretethered vesicles , while the small pool of mobile GLUT4 vesicles was not affected by insulin .	Furthermore, following insulin stimulation in isolated mouse muscles that endogenously expressed HA-GLUT4-GFP, the majority of insulin stimulated GLUT4 vesicle fusion events emanated from pretethered vesicles, while the small pool of mobile GLUT4 vesicles was not affected by insulin.	15	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels ( P = 0.053 ) and significantly reduced insulin stimulated GLUT4 cell membrane translocation ( P < 0.05 ) .	Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels (P = 0.053) and significantly reduced insulin stimulated GLUT4 cell membrane translocation (P < 0.05).	19	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Introduction into permeabilized 3T3L1 adipocytes of fructose 1,6-bisphosphate or the metabolic inhibitor 2-deoxyglucose , two agents that disrupt the interaction between aldolase and actin , inhibited insulin stimulated GLUT4 exocytosis without affecting GLUT4 endocytosis .	Introduction into permeabilized 3T3L1 adipocytes of fructose 1,6-bisphosphate or the metabolic inhibitor 2-deoxyglucose, two agents that disrupt the interaction between aldolase and actin, inhibited insulin stimulated GLUT4 exocytosis without affecting GLUT4 endocytosis.	25	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	28	29
Characterization of glucose uptake and GLUT4 trafficking in adipose and muscle tissues showed that only adipocyte basal glucose uptake was increased , whereas insulin stimulated glucose uptake and GLUT4 trafficking were impaired in both adipocytes and soleus muscle .	Characterization of glucose uptake and GLUT4 trafficking in adipose and muscle tissues showed that only adipocyte basal glucose uptake was increased, whereas insulin stimulated glucose uptake and GLUT4 trafficking were impaired in both adipocytes and soleus muscle.	23	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	28	29
Overexpression of an Exo70 mutant blocked insulin stimulated glucose uptake , but not the trafficking of Glut4 to the plasma membrane .	Overexpression of an Exo70 mutant blocked insulin stimulated glucose uptake, but not the trafficking of Glut4 to the plasma membrane.	5	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	6	7	16	17
Rosiglitasone , an insulin sensitizer , might up-regulate GLUT4 and CAP along with the peroxisome proliferators activated receptor gamma ( PPAR-gamma ) , which not only increases the GLUT4 , but also activates the CAP depended signaling pathway ; improves the translocating of GLUT4 to the cell membrane ; and increases the ability of glucose-uptake of cells .	Rosiglitasone, an insulin sensitizer, might up-regulate GLUT4 and CAP along with the peroxisome proliferators activated receptor gamma (PPAR-gamma), which not only increases the GLUT4, but also activates the CAP depended signaling pathway; improves the translocating of GLUT4 to the cell membrane; and increases the ability of glucose-uptake of cells.	3	10	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	8	9
Finally , analyses of the insulin signaling pathway demonstrated that the downstream signaling molecules involved in insulin induced GLUT4 translocation are not activated by FBS .	Finally, analyses of the insulin signaling pathway demonstrated that the downstream signaling molecules involved in insulin induced GLUT4 translocation are not activated by FBS.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
The principal role of the hormone insulin is to mediate the redistribution of the GLUT-4 isoform from an intracellular vesicle pool into plasma membranes of insulin responsive tissues , thus regulating the uptake of glucose .	The principal role of the hormone insulin is to mediate the redistribution of the GLUT-4 isoform from an intracellular vesicle pool into plasma membranes of insulin responsive tissues, thus regulating the uptake of glucose.	2	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	6	7	14	15
Such data argue that long-term insulin treatment results in the mis targeting of GLUT4 such that it no longer accesses the GSV compartment .	Such data argue that long-term insulin treatment results in the mis targeting of GLUT4 such that it no longer accesses the GSV compartment.	5	14	targeting	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	13	14
Cross-sectional analysis of skeletal muscle demonstrated both filamin and SHIP-2 localized to the sarcolemma , the site of insulin stimulated GLUT4 translocation ( XREF_FIG , I-L ) .	Cross-sectional analysis of skeletal muscle demonstrated both filamin and SHIP-2 localized to the sarcolemma, the site of insulin stimulated GLUT4 translocation (XREF_FIG, I-L).	16	21	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
In this model , insulin increases GLUT4 in the plasma membrane by releasing it from the static storage compartment .	In this model, insulin increases GLUT4 in the plasma membrane by releasing it from the static storage compartment.	4	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Our analysis revealed that insulin modulates the GLUT4 trafficking at multiple steps in the rat adipocyte , not only reducing the endocytotic rate constant 3-4-fold and increasing the exocytotic rate 8-24-fold but also increasing the two rate coefficients coupling the three intracellular compartments 2-6-fold each .	Our analysis revealed that insulin modulates the GLUT4 trafficking at multiple steps in the rat adipocyte, not only reducing the endocytotic rate constant 3-4-fold and increasing the exocytotic rate 8-24-fold but also increasing the two rate coefficients coupling the three intracellular compartments 2-6-fold each.	4	8	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	7	8
In contrast , expression of K44A and dynamin resulted in the cell-surface accumulation of GLUT4 under basal conditions and an inhibition of GLUT4 endocytosis without affecting insulin stimulated GLUT4 exocytosis .	In contrast, expression of K44A and dynamin resulted in the cell-surface accumulation of GLUT4 under basal conditions and an inhibition of GLUT4 endocytosis without affecting insulin stimulated GLUT4 exocytosis.	26	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	28	29
However , in contrast to the results for L6 cells with AS160 knockdown ( which did not alter the insulin stimulated net increase in cell-surface GLUT4 ) , silencing TBC1D1 in L6 cells resulted in greater insulin induced GLUT4 translocation versus control cells .	However, in contrast to the results for L6 cells with AS160 knockdown (which did not alter the insulin stimulated net increase in cell-surface GLUT4), silencing TBC1D1 in L6 cells resulted in greater insulin induced GLUT4 translocation versus control cells.	35	39	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	36	37	38	39
Both signaling arms are required to elicit proper insulin mediated GLUT4 translocation as perturbation of either one significantly reduces the GLUT4 response to insulin in muscle cells .	Both signaling arms are required to elicit proper insulin mediated GLUT4 translocation as perturbation of either one significantly reduces the GLUT4 response to insulin in muscle cells.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Akt regulates glucose uptake by phosphorylating TBC1D4 ( previously named AS160 ) , a Rab GTPase activating protein that regulates insulin stimulated GLUT4 trafficking .	Akt regulates glucose uptake by phosphorylating TBC1D4 (previously named AS160), a Rab GTPase activating protein that regulates insulin stimulated GLUT4 trafficking.	19	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
XREF_BIBR The same work also showed that insulin stimulated glucose uptake and cell surface GLUT-4 content were reduced in this mutated knockin model .	XREF_BIBR The same work also showed that insulin stimulated glucose uptake and cell surface GLUT-4 content were reduced in this mutated knockin model.	7	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	7	8	14	15
Exogenous insulin treatment of diabetic rats increased GLUT 4 content in soleus , cardiac muscle , and gastrocnemius , but had no effect in either vastus lateralis or rectus abdominis .	Exogenous insulin treatment of diabetic rats increased GLUT 4 content in soleus, cardiac muscle, and gastrocnemius, but had no effect in either vastus lateralis or rectus abdominis.	1	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	1	2	7	9
Tyrphostin AG1024 reduced insulin induced GLUT4 translocation for more than 50 % while it left serum action unaffected .	Tyrphostin AG1024 reduced insulin induced GLUT4 translocation for more than 50% while it left serum action unaffected.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Microinjection of an anti-KIF3 antibody into 3T3-L1 adipocytes decreased insulin induced GLUT4 exocytosis by 65 % but had no effect on endocytosis .	Microinjection of an anti-KIF3 antibody into 3T3-L1 adipocytes decreased insulin induced GLUT4 exocytosis by 65% but had no effect on endocytosis.	9	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Insulin stimulated Glut4 translocation promoted by endogenous Akt ( cells not treated with MK2206 ) was unaffected in adipocytes expressing either T309A or S474A mutants compared to control adipocytes ( XREF_FIG ) .	Insulin stimulated Glut4 translocation promoted by endogenous Akt (cells not treated with MK2206) was unaffected in adipocytes expressing either T309A or S474A mutants compared to control adipocytes (XREF_FIG).	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut4	Glut4	Glut4	0	1	2	3
We show that the expression of Rab4 DeltaCT in freshly isolated adipocytes inhibits insulin induced GLUT4 translocation , but only when this protein is in its GTP bound active form .	We show that the expression of Rab4 DeltaCT in freshly isolated adipocytes inhibits insulin induced GLUT4 translocation, but only when this protein is in its GTP bound active form.	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
The levels of insulin signaling molecules IRS-1 and GLUT-4 were assessed in ILP treated L6 myotubes by immunoblot analysis of cytoplasmic and plasma membrane fractions respectively .	The levels of insulin signaling molecules IRS-1 and GLUT-4 were assessed in ILP treated L6 myotubes by immunoblot analysis of cytoplasmic and plasma membrane fractions respectively.	1	9	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	GLUT-4	GLUT-4	glut-4	3	4	8	9
In summary , it is essential to show through experiments that , the stimulus response curve for insulin stimulated GLUT4 translocation exhibits hysteresis , - a distinctive splitting in stimulus response curve .	In summary, it is essential to show through experiments that, the stimulus response curve for insulin stimulated GLUT4 translocation exhibits hysteresis, - a distinctive splitting in stimulus response curve.	15	27	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Insulin is proposed to stimulate fusion of intracellular GLUT4 containing-vesicles with the plasma membrane in cardiac and skeletal myocytes while it does not affect the rate of endocytosis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Insulin is proposed to stimulate fusion of intracellular GLUT4 containing-vesicles with the plasma membrane in cardiac and skeletal myocytes while it does not affect the rate of endocytosis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	8	9
However , insulin stimulated GLUT4 translocation in GFP-HA-CaMKII cells was significantly higher , compared with either GFP-HA or GFP-HA-CaMKII K42M cells .	However, insulin stimulated GLUT4 translocation in GFP-HA-CaMKII cells was significantly higher, compared with either GFP-HA or GFP-HA-CaMKII K42M cells.	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Insulin stimulated GLUT4 translocation requires dynamic changes in the actin cytoskeleton or called actin remodeling .	Insulin stimulated GLUT4 translocation requires dynamic changes in the actin cytoskeleton or called actin remodeling.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Furthermore , Insulin stimulated GLUT4 translocation and glucose uptake are associated with NF- KB activation [ XREF_BIBR ] which , a susceptible gene for OSAS [ XREF_BIBR ] and nuclear receptor , plays a central role in inflammatory response and orchestrates over-expression of a range of factors including cytokines ( TNF-a , IL-6 and IL-8 ) and adhesion molecules ( intercellular adhesion molecule-1 ) [ XREF_BIBR , XREF_BIBR ] .	Furthermore, Insulin stimulated GLUT4 translocation and glucose uptake are associated with NF- KB activation [XREF_BIBR] which, a susceptible gene for OSAS [XREF_BIBR] and nuclear receptor, plays a central role in inflammatory response and orchestrates over-expression of a range of factors including cytokines (TNF-a, IL-6 and IL-8) and adhesion molecules (intercellular adhesion molecule-1) [XREF_BIBR, XREF_BIBR].	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
This concept is supported by previous findings that show insulin stimulates GLUT4 activity in a quantal manner rather than a dose dependent increase in exocytosis and/or decrease in endocytosis rates .	This concept is supported by previous findings that show insulin stimulates GLUT4 activity in a quantal manner rather than a dose dependent increase in exocytosis and/or decrease in endocytosis rates.	9	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Although , E4-ORF1 does not fully recapitulate insulin ' s effects on Glut4 , it enhances insulin stimulated insertion of Glut4 containing vesicles to the plasma membrane independent of Rab10 , a key regulator of Glut4 trafficking .	Although, E4-ORF1 does not fully recapitulate insulin 's effects on Glut4, it enhances insulin stimulated insertion of Glut4 containing vesicles to the plasma membrane independent of Rab10, a key regulator of Glut4 trafficking.	15	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	16	17	20	21
Thus , insulin mediated GLUT4 translocation is facilitated by Rab proteins , specifically Rab4 , Rab5 , and Rab11 .	Thus, insulin mediated GLUT4 translocation is facilitated by Rab proteins, specifically Rab4, Rab5, and Rab11.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
XREF_FIG summarizes our model for the insulin stimulation of GLUT4 exocytosis .	XREF_FIG summarizes our model for the insulin stimulation of GLUT4 exocytosis.	6	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	9	10
Similar data were obtained in adipocytes , where expression of the Akt phosho site mutant ( 4P ) inhibited insulin stimulated GLUT4 trafficking ~ 80 % .	Similar data were obtained in adipocytes, where expression of the Akt phosho site mutant (4P) inhibited insulin stimulated GLUT4 trafficking ~ 80%.	18	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
Thus , beta 2 AR is considered as the betaAR subtype that interferes with insulin mediated GLUT4 translocation in the heart .	Thus, beta 2 AR is considered as the betaAR subtype that interferes with insulin mediated GLUT4 translocation in the heart.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Our findings indicate that , although cellubrevin and VAMP are resident proteins in adipocyte GLUT4 containing vesicles , they are not required for the acute insulin induced delivery of GLUT4 to the plasma membrane .	Our findings indicate that, although cellubrevin and VAMP are resident proteins in adipocyte GLUT4 containing vesicles, they are not required for the acute insulin induced delivery of GLUT4 to the plasma membrane.	23	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	29	30
IRSs also leads to translocation of insulin mediated GLUT-4 from intracellular vesicles to the plasma membrane , facilitating glucose entry .	IRSs also leads to translocation of insulin mediated GLUT-4 from intracellular vesicles to the plasma membrane, facilitating glucose entry.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	6	7	8	9
It has been suggested that metformin augments Rab4 expression in an AMPK dependent manner , and that the former modulates insulin mediated GLUT-4 translocation to the plasma membrane [ XREF_BIBR ] .	It has been suggested that metformin augments Rab4 expression in an AMPK dependent manner, and that the former modulates insulin mediated GLUT-4 translocation to the plasma membrane [XREF_BIBR].	19	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	20	21	22	23
In the regulatory mode shift of Tbc1d1 , since only temporal Ser 237 phosphorylation with AICAR pretreatment was sufficient for subsequent insulin induced GLUT4 liberation along with Thr 596 ( but not Ser 237 ) phosphorylation , it is tempting to speculate that the PTB1 domain is responsible for the functionally crucial status of Tbc1d1 without relying on the phosphorylation status of Ser 237 upon executing the regulatory mode shift of Tbc1d1 that might be achieved by associating with unspecified PTB binding partner ( s ) .	In the regulatory mode shift of Tbc1d1, since only temporal Ser 237 phosphorylation with AICAR pretreatment was sufficient for subsequent insulin induced GLUT4 liberation along with Thr 596 (but not Ser 237) phosphorylation, it is tempting to speculate that the PTB1 domain is responsible for the functionally crucial status of Tbc1d1 without relying on the phosphorylation status of Ser 237 upon executing the regulatory mode shift of Tbc1d1 that might be achieved by associating with unspecified PTB binding partner (s).	18	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
Whether Munc18c fulfils a similar role in insulin induced GLUT4 translocation in the heart is not known .	Whether Munc18c fulfils a similar role in insulin induced GLUT4 translocation in the heart is not known.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Insulin accelerates GLUT4 and IRAP transport to the cell surface and simultaneously reduces GLUT4 internalization having as a global effect a rapid increase of GLUT4 in the plasma membrane of insulin stimulated adipocytes .	Insulin accelerates GLUT4 and IRAP transport to the cell surface and simultaneously reduces GLUT4 internalization having as a global effect a rapid increase of GLUT4 in the plasma membrane of insulin stimulated adipocytes.	0	12	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
In this model , insulin increases GLUT4 in the plasma membrane by modulating GLUT4 exocytosis and endocytosis .	In this model, insulin increases GLUT4 in the plasma membrane by modulating GLUT4 exocytosis and endocytosis.	4	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
In these rats , insulin induced the mobilization of GLUT4 from the internal pool , but the incorporation of the transporter protein into the plasma membrane is diminished .	In these rats, insulin induced the mobilization of GLUT4 from the internal pool, but the incorporation of the transporter protein into the plasma membrane is diminished.	4	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	9	10
Insulin stimulates glucose transport in muscle and adipose tissue by promoting the appearance of GLUT4 , the main glucose transporter isoform in these tissues , on the cell surface .	Insulin stimulates glucose transport in muscle and adipose tissue by promoting the appearance of GLUT4, the main glucose transporter isoform in these tissues, on the cell surface.	0	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	14	15
Subsequent investigation of Rut acting targets indicates that as a specific protein tyrosine phosphatase 1B ( PTP1B ) inhibitor Rut induces basal GLUT4 translocation to some extent and largely enhances insulin induced GLUT4 translocation through PI3 kinase-AKT and PKB pathway , while as an agonist of retinoid X receptor alpha ( RXRalpha ) , Rut potently increases GLUT4 expression .	Subsequent investigation of Rut acting targets indicates that as a specific protein tyrosine phosphatase 1B (PTP1B) inhibitor Rut induces basal GLUT4 translocation to some extent and largely enhances insulin induced GLUT4 translocation through PI3 kinase-AKT and PKB pathway, while as an agonist of retinoid X receptor alpha (RXRalpha), Rut potently increases GLUT4 expression.	29	33	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	30	31	32	33
One possible explanation for the discrepancy between GLUT4 levels determined by membrane fractionation and photolabelling assay is that insulin also stimulates a final plasma membrane-fusion step in GLUT4 trafficking .	One possible explanation for the discrepancy between GLUT4 levels determined by membrane fractionation and photolabelling assay is that insulin also stimulates a final plasma membrane-fusion step in GLUT4 trafficking.	18	28	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	27	28
The observation that cellubrevin does not colocalise with intracellular GLUT4 in skeletal muscle from two different species , rat and human , would strongly suggest that it is unlikely to participate in the insulin induced delivery of GLUT4 to the cell surface in skeletal muscle .	The observation that cellubrevin does not colocalise with intracellular GLUT4 in skeletal muscle from two different species, rat and human, would strongly suggest that it is unlikely to participate in the insulin induced delivery of GLUT4 to the cell surface in skeletal muscle.	32	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	33	34	37	38
The actin cytoskeleton plays an important role in insulin stimulated GLUT4 transport XREF_BIBR .	The actin cytoskeleton plays an important role in insulin stimulated GLUT4 transport XREF_BIBR.	6	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
For example in adipocytes , the Exo70 subunit has been shown to be recruited to the plasma membrane in a TC10 dependent fashion and to regulate the insulin stimulated exocytosis of Glut4 [ XREF_BIBR , XREF_BIBR ] .	For example in adipocytes, the Exo70 subunit has been shown to be recruited to the plasma membrane in a TC10 dependent fashion and to regulate the insulin stimulated exocytosis of Glut4 [XREF_BIBR, XREF_BIBR].	25	35	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	27	28	31	32
The molecular cascade leading to insulin mediated GLUT4 translocation has been partially defined : activation of the insulin pathway is initiated by insulin binding to the extracellular domain of the insulin receptor ( IR ) causing autophosphorylation of the intracellular domains .	The molecular cascade leading to insulin mediated GLUT4 translocation has been partially defined : activation of the insulin pathway is initiated by insulin binding to the extracellular domain of the insulin receptor (IR) causing autophosphorylation of the intracellular domains.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
Moreover , since Rab10 vesicles did not fuse with other vesicles prior to PM fusion , the direct trafficking model for insulin stimulated GLUT4 redistribution to the cell surface was supported .	Moreover, since Rab10 vesicles did not fuse with other vesicles prior to PM fusion, the direct trafficking model for insulin stimulated GLUT4 redistribution to the cell surface was supported.	19	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
Indeed , IL-1beta treatment of adipocytes , disturbs insulin signaling via downregulation of insulin receptor substrate-1 expression , leading to a marked reduction of insulin mediated GLUT-4 translocation [ XREF_BIBR , XREF_BIBR ] .	Indeed, IL-1beta treatment of adipocytes, disturbs insulin signaling via downregulation of insulin receptor substrate-1 expression, leading to a marked reduction of insulin mediated GLUT-4 translocation [XREF_BIBR, XREF_BIBR].	22	27	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	24	25	26	27
It is therefore a suitable system for studying various parameters affecting the mechanisms underlying insulin induced GLUT4 translocation in human skeletal muscle .	It is therefore a suitable system for studying various parameters affecting the mechanisms underlying insulin induced GLUT4 translocation in human skeletal muscle.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Insulin increased uptake in GLUT4 cells by as much as 6-fold ; whereas , the fold increase over basal uptake produced by insulin in GLUT1 cells was comparable to that ( 2-fold ) observed in the control myocytes .	Insulin increased uptake in GLUT4 cells by as much as 6-fold; whereas, the fold increase over basal uptake produced by insulin in GLUT1 cells was comparable to that (2-fold) observed in the control myocytes.	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	4	5
Insulin induced GLUT4 translocation and exposure of the transporter to the extracellular environment was not altered by pretreatment with SB203580 , as evidenced by a lack of effect of the inhibitor on the amount of GLUT4 present in the plasma membrane , as assessed by subcellular fractionation , the amount of GLUT4 that is able to undergo biotinylation on intact adipocytes and the level of extracellular exposure of an ectopically expressed GLUT-green fluorescence protein construct with a hemagglutinin tag in its first extracellular loop .	Insulin induced GLUT4 translocation and exposure of the transporter to the extracellular environment was not altered by pretreatment with SB203580, as evidenced by a lack of effect of the inhibitor on the amount of GLUT4 present in the plasma membrane, as assessed by subcellular fractionation, the amount of GLUT4 that is able to undergo biotinylation on intact adipocytes and the level of extracellular exposure of an ectopically expressed GLUT-green fluorescence protein construct with a hemagglutinin tag in its first extracellular loop.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
In unstimulated fat and muscle cells , the majority of GLUT4 exists in intracellular compartments , while the insulin signal stimulates the exocytosis of GLUT4 to the cell surface .	In unstimulated fat and muscle cells, the majority of GLUT4 exists in intracellular compartments, while the insulin signal stimulates the exocytosis of GLUT4 to the cell surface.	18	25	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	24	25
Insulin stimulated Glut4 and Vamp3 localization was visualized as previously described XREF_BIBR .	Insulin stimulated Glut4 and Vamp3 localization was visualized as previously described XREF_BIBR.	0	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut4	Glut4	Glut4	0	1	2	3
Stimulation of betaARs with epinephrine or norepinephrine reduced the amount of plasma membrane GLUT4 by inhibiting insulin induced GLUT4 translocation in adipocytes .	Stimulation of betaARs with epinephrine or norepinephrine reduced the amount of plasma membrane GLUT4 by inhibiting insulin induced GLUT4 translocation in adipocytes.	16	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
Initially , using quantitative microscopy to assess chimeric Glut4 recycling as previously described , we found that siRNA against ACAP1 substantially inhibited the insulin induced redistribution of internal Glut4 to the cell surface ( XREF_FIG ) .	Initially, using quantitative microscopy to assess chimeric Glut4 recycling as previously described, we found that siRNA against ACAP1 substantially inhibited the insulin induced redistribution of internal Glut4 to the cell surface (XREF_FIG).	22	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	23	24	28	29
The E 499 A/E 501 A mutations in the TELEY trafficking motif ( EE-GLUT4 ) shift the distribution of GLUT4 from GSVs to the endosome , resulting in a modest increase in surface GLUT4 in the basal state but a blunting of insulin stimulated GLUT4 translocation due to a depleted GSV pool .	The E 499 A/E 501 A mutations in the TELEY trafficking motif (EE-GLUT4) shift the distribution of GLUT4 from GSVs to the endosome, resulting in a modest increase in surface GLUT4 in the basal state but a blunting of insulin stimulated GLUT4 translocation due to a depleted GSV pool.	40	45	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	42	43	44	45
This analysis demonstrated that while serum- and insulin induced GLUT4 translocation were similarly affected by most of these inhibitors , there were three important differences .	This analysis demonstrated that while serum- and insulin induced GLUT4 translocation were similarly affected by most of these inhibitors, there were three important differences.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
In wild-type mice , GLUT4 content in plasma membrane ( PM ) fraction was increased 51 +/-15% by insulin injection , at the expense of the LDM pool of GLUT4 , which showed 23 +/-4% reduction upon insulin treatment .	In wild-type mice, GLUT4 content in plasma membrane (PM) fraction was increased 51 +/-15% by insulin injection, at the expense of the LDM pool of GLUT4, which showed 23 +/-4% reduction upon insulin treatment.	4	19	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	4	5
On the other hand , Munc18-3 , which has been intensively analyzed for the regulation of insulin mediated GLUT4 ( glucose transporter ) localization in adipocytes , seems to be involved in corticogenesis [ XREF_BIBR ] .	On the other hand, Munc18-3, which has been intensively analyzed for the regulation of insulin mediated GLUT4 (glucose transporter) localization in adipocytes, seems to be involved in corticogenesis [XREF_BIBR].	14	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
These results show that adenosine potentiates insulin- and contraction stimulated glucose transport in skeletal muscle by enhancing the increase in GLUT4 at the cell surface and raise the possibility that decreased adenosine production or action could play a causative role in insulin resistance .	These results show that adenosine potentiates insulin- and contraction stimulated glucose transport in skeletal muscle by enhancing the increase in GLUT4 at the cell surface and raise the possibility that decreased adenosine production or action could play a causative role in insulin resistance.	6	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin-	insulin-	insulin-	GLUT4	GLUT4	GLUT4	6	7	20	21
Only the VAMP2 regulated GLUT4 pool is stimulated by insulin , whereas VAMP3 may mediate GLUT4 recycling .	Only the VAMP2 regulated GLUT4 pool is stimulated by insulin, whereas VAMP3 may mediate GLUT4 recycling.	4	10	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	4	5
AS160 regulates insulin stimulated Glut4 trafficking , wherein its phosphorylation at Thr642 is necessary for Glut4 translocation [ XREF_BIBR ] .	AS160 regulates insulin stimulated Glut4 trafficking, wherein its phosphorylation at Thr642 is necessary for Glut4 translocation [XREF_BIBR].	1	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	2	3	4	5
In the latter case , the peptide dimerized with the full-length AS160 and consequently disrupted its interaction with 14-3-3 protein [ XREF_BIBR ] , which plays an important role in insulin stimulated GLUT4 trafficking [ XREF_BIBR ] .	In the latter case, the peptide dimerized with the full-length AS160 and consequently disrupted its interaction with 14-3-3 protein [XREF_BIBR], which plays an important role in insulin stimulated GLUT4 trafficking [XREF_BIBR].	28	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	30	31	32	33
In studies with syntaxin 4 heterozygous-knockout ( KO ) mice , syntaxin 4 has been shown to be a major molecule responsible for the regulation of insulin stimulated GLUT4 redistribution and glucose transport in skeletal muscle .	In studies with syntaxin 4 heterozygous-knockout (KO) mice, syntaxin 4 has been shown to be a major molecule responsible for the regulation of insulin stimulated GLUT4 redistribution and glucose transport in skeletal muscle.	24	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	28	29
Although CDP138 knockdown reduces insulin stimulated accumulation of myc-GLUT4-GFP on the cell surface before initiation of endocytosis , it does not significantly affect myc-GLUT4 endocytosis ( XREF_SUPPLEMENTARY ) , suggesting that CDP138 is specifically involved in the regulation of GLUT4 exocytosis .	Although CDP138 knockdown reduces insulin stimulated accumulation of myc-GLUT4-GFP on the cell surface before initiation of endocytosis, it does not significantly affect myc-GLUT4 endocytosis (XREF_SUPPLEMENTARY), suggesting that CDP138 is specifically involved in the regulation of GLUT4 exocytosis.	3	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	myc-GLUT4-GFP	myc-GLUT4-GFP	myc-GLUT4-GFP	4	5	8	9
Coexpression of P-Rex1 with an exofacially tagged form of the transporter in 3T3-L1 adipocytes showed that P-Rex1 promotes the insulin stimulated plasma membrane localization of Glut4 .	Coexpression of P-Rex1 with an exofacially tagged form of the transporter in 3T3-L1 adipocytes showed that P-Rex1 promotes the insulin stimulated plasma membrane localization of Glut4.	17	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	19	20	25	26
Consistently , insulin dramatically stimulated GLUT4 partitioning into the PM of 4-day cells .	Consistently, insulin dramatically stimulated GLUT4 partitioning into the PM of 4-day cells.	2	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	5	6
Immunoblot blot analysis revealed that 15 minute stimulation with insulin increased GLUT4 association to the plasma membrane in hippocampal slice preparations , an effect that was blocked by LY294002 ( XREF_FIG ) .	Immunoblot blot analysis revealed that 15 minute stimulation with insulin increased GLUT4 association to the plasma membrane in hippocampal slice preparations, an effect that was blocked by LY294002 (XREF_FIG).	7	12	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
In the present study , GLUT4 protein synthesis was stimulated by IGFs and insulin in a different manner throughout the cell culture .	In the present study, GLUT4 protein synthesis was stimulated by IGFs and insulin in a different manner throughout the cell culture.	5	14	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	5	6
Insulin resistance promotes downregulation of GLUT4 at the plasma membrane level and upregulation of miR-223 .	Insulin resistance promotes downregulation of GLUT4 at the plasma membrane level and upregulation of miR-223.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	5	6
This is predicted based upon our data showing the functional need for Tyr219 of Munc18c in insulin stimulated GLUT4-GFP vesicle exocytosis but that IR phosphorylation of the Munc18c mutant Y219F in vitro was unimpaired .	This is predicted based upon our data showing the functional need for Tyr219 of Munc18c in insulin stimulated GLUT4-GFP vesicle exocytosis but that IR phosphorylation of the Munc18c mutant Y219F in vitro was unimpaired.	7	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4-GFP	GLUT4-GFP	GLUT4-GFP	16	17	18	19
Whichever mechanism is at play in the case of Arl15 , it shows some degree of cargo specificity , as adipsin secretion via the Golgi 24 and insulin stimulated Glut4 translocation appear to not have been affected by its knockdown .	Whichever mechanism is at play in the case of Arl15, it shows some degree of cargo specificity, as adipsin secretion via the Golgi 24 and insulin stimulated Glut4 translocation appear to not have been affected by its knockdown.	21	30	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	27	28	29	30
Moreover , EHD1 is shown to interact through its EH domain with the protein EHBP1 , which is also required for insulin stimulated GLUT4 movements and hexose transport .	Moreover, EHD1 is shown to interact through its EH domain with the protein EHBP1, which is also required for insulin stimulated GLUT4 movements and hexose transport.	19	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
This latter is in agreement with previous reports where CytoD blocked the insulin mediated GLUT4 translocation in L6-myocytes 32 .	This latter is in agreement with previous reports where CytoD blocked the insulin mediated GLUT4 translocation in L6-myocytes 32.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Cell-surface GLUT4 was not further enhanced by insulin stimulation in either group .	Cell-surface GLUT4 was not further enhanced by insulin stimulation in either group.	0	8	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	1	2
Likewise , it is thought that phosphorylation of the GAP AS160 and TBC1D4 by Akt inhibits its activity toward Rab target proteins involved in insulin stimulated GLUT4 exocytosis .	Likewise, it is thought that phosphorylation of the GAP AS160 and TBC1D4 by Akt inhibits its activity toward Rab target proteins involved in insulin stimulated GLUT4 exocytosis.	22	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	24	25	26	27
Shorter intermittent hypoxic exposures as pathophysiology of OSAS might preferentially activate inflammatory pathways and over-expression of such inflammatory factors as TNF-alpha , IL-6 and IL-8 [ XREF_BIBR ] , which influences normal insulin signaling of adipocytes and GLUT4 , bringing about reduction of glucose assimilation triggering metabolic dysregulation [ XREF_BIBR ] .	Shorter intermittent hypoxic exposures as pathophysiology of OSAS might preferentially activate inflammatory pathways and over-expression of such inflammatory factors as TNF-alpha, IL-6 and IL-8 [XREF_BIBR], which influences normal insulin signaling of adipocytes and GLUT4, bringing about reduction of glucose assimilation triggering metabolic dysregulation [XREF_BIBR].	32	38	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	32	33	37	38
This is consistent with evidence AMPK improves insulin stimulated GLUT4 control by lowering membrane cholesterol [ XREF_BIBR ] .	This is consistent with evidence AMPK improves insulin stimulated GLUT4 control by lowering membrane cholesterol [XREF_BIBR].	6	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
By contrast , insulin stimulation of GLUT4 exocytosis is slowed by isoproterenol or acidification pre-treatments .	By contrast, insulin stimulation of GLUT4 exocytosis is slowed by isoproterenol or acidification pre-treatments.	3	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	6	7
Both insulin and BFA triggered redistribution of GLUT4 to cell surface ( XREF_FIG , marked with arrowheads ) .	Both insulin and BFA triggered redistribution of GLUT4 to cell surface (XREF_FIG, marked with arrowheads).	0	8	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	7	8
In the present study , which employs various imaging techniques on isolated skeletal myofibres , we show that one of the initial triggers of insulin induced GLUT4 translocation is heterotypic endomembrane fusion arising from very small static GLUT4 containing vesicles with a subset of transferrin receptor containing endosomes .	In the present study, which employs various imaging techniques on isolated skeletal myofibres, we show that one of the initial triggers of insulin induced GLUT4 translocation is heterotypic endomembrane fusion arising from very small static GLUT4 containing vesicles with a subset of transferrin receptor containing endosomes.	22	27	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	24	25	26	27
PDK1 is a critical kinase required for insulin induced GLUT4 translocation and glucose uptake [ XREF_BIBR - XREF_BIBR ] .	PDK1 is a critical kinase required for insulin induced GLUT4 translocation and glucose uptake [XREF_BIBR - XREF_BIBR].	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Insulin stimulation induces redistribution of GLUT4 from a perinuclear storage vesicular compartment to the cell surface , where glucose uptake takes place .	Insulin stimulation induces redistribution of GLUT4 from a perinuclear storage vesicular compartment to the cell surface, where glucose uptake takes place.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	5	6
This is in contrast to previous studies , which reported a decrease in surface GLUT4 stimulated by 170 nM insulin in RalA knockdown cells .	This is in contrast to previous studies, which reported a decrease in surface GLUT4 stimulated by 170 nM insulin in RalA knockdown cells.	11	23	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	14	15
Remarkably , the induction of Srebp-1c , Fasn , Glut4 and Chrebp-beta by insulin was enhanced in LOKO mice , providing further evidence of improved adipose tissue insulin sensitivity ( XREF_FIG ) .	Remarkably, the induction of Srebp-1c, Fasn, Glut4 and Chrebp-beta by insulin was enhanced in LOKO mice, providing further evidence of improved adipose tissue insulin sensitivity (XREF_FIG).	3	14	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	13	14	9	10
There are three existing Akt isoforms ( Akt1-3 ) in mammalian cells , and knockout and knockdown studies have identified Akt2 as the relevant isoform required for insulin stimulated GLUT4 trafficking and glucose uptake [ XREF_BIBR - XREF_BIBR ] .	There are three existing Akt isoforms (Akt1-3) in mammalian cells, and knockout and knockdown studies have identified Akt2 as the relevant isoform required for insulin stimulated GLUT4 trafficking and glucose uptake [XREF_BIBR - XREF_BIBR].	25	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	27	28	29	30
We have previously demonstrated that insulin stimulated plasma membrane GLUT4 protein concentration is reduced by high-fat feeding and increased in the high-fat fed-exercise trained animals .	We have previously demonstrated that insulin stimulated plasma membrane GLUT4 protein concentration is reduced by high-fat feeding and increased in the high-fat fed-exercise trained animals.	5	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	9	10
Genistein impaired glucose tolerance and attenuated insulin sensitivity in normal mice by inhibiting the insulin induced phosphorylation of insulin receptor substrate-1 ( IRS1 ) at tyrosine residues , leading to inhibition of insulin mediated GLUT4 translocation in adipocytes .	Genistein impaired glucose tolerance and attenuated insulin sensitivity in normal mice by inhibiting the insulin induced phosphorylation of insulin receptor substrate-1 (IRS1) at tyrosine residues, leading to inhibition of insulin mediated GLUT4 translocation in adipocytes.	30	35	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	32	33	34	35
Phosphorylation of this protein , identified as a GTPase activating domain for Rab , is found to be responsible for membrane trafficking of GLUT4 induced by the insulin and PI3K signaling .	Phosphorylation of this protein, identified as a GTPase activating domain for Rab, is found to be responsible for membrane trafficking of GLUT4 induced by the insulin and PI3K signaling.	21	30	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	27	28	23	24
Interestingly , the insulin stimulated increase of GLUT4 fusion was transient , and after a pronounced peak at 2-3 min , the fusion frequency declined to a level only slightly above the basal .	Interestingly, the insulin stimulated increase of GLUT4 fusion was transient, and after a pronounced peak at 2-3 min, the fusion frequency declined to a level only slightly above the basal.	2	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	7	8
Microtubules have also been proposed to regulate phosphatidylinositol 3-kinase activity during phagocytosis in macrophages XREF_BIBR , a process that shares with insulin induced GLUT4 trafficking a requirement for Akt membrane recruitment and activation .	Microtubules have also been proposed to regulate phosphatidylinositol 3-kinase activity during phagocytosis in macrophages XREF_BIBR, a process that shares with insulin induced GLUT4 trafficking a requirement for Akt membrane recruitment and activation.	19	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
These results led us to assess the roles of PIP5K1alpha in insulin induced GLUT4 translocation to the PM .	These results led us to assess the roles of PIP5K1alpha in insulin induced GLUT4 translocation to the PM.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Treatments with Akt inhibitor X abolished the promoting effect of T3 on insulin induced GLUT4 translocation as confirmed by both assays ( XREF_FIG ) .	Treatments with Akt inhibitor X abolished the promoting effect of T3 on insulin induced GLUT4 translocation as confirmed by both assays (XREF_FIG).	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
For example the amount of the myosin heavy chain MYH10 was increased ( 1.57 ) while MYH9 was unchanged ( -1.08 ) and MYO1C , which mediates insulin directed GLUT4 vesicle tethering was reduced ( -3.69 ) XREF_BIBR .	For example the amount of the myosin heavy chain MYH10 was increased (1.57) while MYH9 was unchanged (-1.08) and MYO1C, which mediates insulin directed GLUT4 vesicle tethering was reduced (-3.69) XREF_BIBR.	26	31	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	27	28	29	30
As indicated , Rut greatly enhances the insulin induced GLUT4 translocation at 8th hour ( Supplemental XREF_SUPPLEMENTARY and d ) and exhibits no obvious increment on GLUT4 protein level ( Supplemental XREF_SUPPLEMENTARY ) .	As indicated, Rut greatly enhances the insulin induced GLUT4 translocation at 8th hour (Supplemental XREF_SUPPLEMENTARY and d) and exhibits no obvious increment on GLUT4 protein level (Supplemental XREF_SUPPLEMENTARY).	6	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Insulin stimulated GLUT4 partitioning to the PM is mediated primarily by PI3K activated Akt which phosphorylates AS160 , a Rab-GTPase-activating protein ( Rab-GAP ) .	Insulin stimulated GLUT4 partitioning to the PM is mediated primarily by PI3K activated Akt which phosphorylates AS160, a Rab-GTPase-activating protein (Rab-GAP).	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
These results indicate that PIs , in particular lopinavir , inhibit insulin induced GLUT4 recruitment to the plasma membrane .	These results indicate that PIs, in particular lopinavir, inhibit insulin induced GLUT4 recruitment to the plasma membrane.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Interestingly , insulin enhanced cell-surface GLUT4 approximately 2-fold in isolated EDL and approximately 6-fold in perfused EDL of both transgenic and non transgenic mice .	Interestingly, insulin enhanced cell-surface GLUT4 approximately 2-fold in isolated EDL and approximately 6-fold in perfused EDL of both transgenic and non transgenic mice.	2	6	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	5	6
Quercetin inhibited insulin mediated GLUT4 translocation by inhibiting AS160 phosphorylation .	Quercetin inhibited insulin mediated GLUT4 translocation by inhibiting AS160 phosphorylation.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
However , the magnitude of the insulin stimulated increase in cell-surface GLUT4 photolabeling was nearly identical ( approximately 3-fold ) in wild-type and GLUT1 overexpressing muscles .	However, the magnitude of the insulin stimulated increase in cell-surface GLUT4 photolabeling was nearly identical (approximately 3-fold) in wild-type and GLUT1 overexpressing muscles.	3	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	11	12
These results suggest that the muscle insulin resistance of the obese Zucker rat is due to 1 ) a reduced plasma membrane GLUT-4 protein concentration , which results in part from an impairment in the insulin stimulated GLUT-4 protein translocation process , and 2 ) a defect in the insulin stimulated activation of this protein .	These results suggest that the muscle insulin resistance of the obese Zucker rat is due to 1) a reduced plasma membrane GLUT-4 protein concentration, which results in part from an impairment in the insulin stimulated GLUT-4 protein translocation process, and 2) a defect in the insulin stimulated activation of this protein.	6	24	resistance	Negative_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	6	7	22	23
Surprisingly , when insulin induces a burst of GLUT4 exocytosis , it does not merely accelerate this basal exocytosis , but rather stimulates ~ 60-fold another mode of exocytosis that disperses GLUT4 into PM .	Surprisingly, when insulin induces a burst of GLUT4 exocytosis, it does not merely accelerate this basal exocytosis, but rather stimulates ~ 60-fold another mode of exocytosis that disperses GLUT4 into PM.	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	8	9
Heightened peripheral insulin sensitivity correlated with elevated insulin stimulated GLUT4 vesicle accumulation in cell surface membranes of Doc2b Tg mouse skeletal muscle .	Heightened peripheral insulin sensitivity correlated with elevated insulin stimulated GLUT4 vesicle accumulation in cell surface membranes of Doc2b Tg mouse skeletal muscle.	4	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
EHD2 regulates insulin mediated GLUT4 trafficking to the cell surface .	EHD2 regulates insulin mediated GLUT4 trafficking to the cell surface.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Strikingly , insulin stimulated Akt activity , but not phosphatidylinositol 3 kinase activity , was blocked at 19 C. Consistent with a multistep process in GLUT4 trafficking , insulin stimulated GLUT4 translocation could be primed by treating cells with insulin at 19 C , whereas this was not the case for Akt activation .	Strikingly, insulin stimulated Akt activity, but not phosphatidylinositol 3 kinase activity, was blocked at 19 C. Consistent with a multistep process in GLUT4 trafficking, insulin stimulated GLUT4 translocation could be primed by treating cells with insulin at 19 C, whereas this was not the case for Akt activation.	28	31	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	28	29	30	31
In addition , these results suggest that in the presence of insulin GLUT 4 recycles from the cell surface , probably via the coated pit-endosome pathway that has been characterized for cell surface receptors , and also that insulin causes the redistribution of GLUT 4 by stimulating exocytosis from GLUT 4 containing tubulo-vesicular structures , rather than by slowing endocytosis of GLUT 4 .	In addition, these results suggest that in the presence of insulin GLUT 4 recycles from the cell surface, probably via the coated pit-endosome pathway that has been characterized for cell surface receptors, and also that insulin causes the redistribution of GLUT 4 by stimulating exocytosis from GLUT 4 containing tubulo-vesicular structures, rather than by slowing endocytosis of GLUT 4.	38	45	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	38	39	43	45
To identify potential regulators of insulin stimulated GLUT4 trafficking in adipocytes , we performed proteomic profiling of GSVs .	To identify potential regulators of insulin stimulated GLUT4 trafficking in adipocytes, we performed proteomic profiling of GSVs.	3	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
These results indicated that both DGKzeta and PIP5K1alpha positively regulate the insulin induced GLUT4 translocation .	These results indicated that both DGKzeta and PIP5K1alpha positively regulate the insulin induced GLUT4 translocation.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
An enhancement of insulin induced GLUT4 translocation was not observed in 3T3-L1 preadipocytes and L6 myotubes , indicating cell specificity .	An enhancement of insulin induced GLUT4 translocation was not observed in 3T3-L1 preadipocytes and L6 myotubes, indicating cell specificity.	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Addition of GTP gamma S was able to overcome this ATP dependence of insulin- stimulated GLUT4 movement .	Addition of GTP gamma S was able to overcome this ATP dependence of insulin- stimulated GLUT4 movement.	11	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin-	insulin-	insulin-	GLUT4	GLUT4	GLUT4	13	14	15	16
We have previously shown that insulin stimulates the movement of GLUT-4 from the T-V elements and TGR to the cell surface in other insulin sensitive cells .	We have previously shown that insulin stimulates the movement of GLUT-4 from the T-V elements and TGR to the cell surface in other insulin sensitive cells.	5	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	5	6	10	11
These results suggested a requirement for Munc18c in the insulin stimulated GLUT4 vesicle fusion and glucose uptake of 3T3-L1 adipocytes and corroborated prior analyses performed with the skeletal muscle of Munc18c +/- knockout mice .	These results suggested a requirement for Munc18c in the insulin stimulated GLUT4 vesicle fusion and glucose uptake of 3T3-L1 adipocytes and corroborated prior analyses performed with the skeletal muscle of Munc18c +/- knockout mice.	2	21	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
We investigated whether bavachin could stimulate insulin mediated GLUT4 translocation via Akt phosphorylation .	We investigated whether bavachin could stimulate insulin mediated GLUT4 translocation via Akt phosphorylation.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Although insulin stimulation of GLUT4 trafficking velocity apparently contributes to the acceleration of insulin responsive GLUT4 translocation , insulin responsive and wortmannin sensitive GLUT4 liberation from the putative GLUT4 storage compartments could be more important as the primary impact of insulin signals because this event is prerequisite to enhanced GLUT4 delivery to the plasma membrane .	Although insulin stimulation of GLUT4 trafficking velocity apparently contributes to the acceleration of insulin responsive GLUT4 translocation, insulin responsive and wortmannin sensitive GLUT4 liberation from the putative GLUT4 storage compartments could be more important as the primary impact of insulin signals because this event is prerequisite to enhanced GLUT4 delivery to the plasma membrane.	1	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	4	5
Rat 3Y1 cells lacking AS160 did not show insulin induced GLUT4 translocation .	Rat 3Y1 cells lacking AS160 did not show insulin induced GLUT4 translocation.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
It has previously been shown to play a central role in the pathogenesis of metabolic syndrome XREF_BIBR and to be involved in insulin stimulated Glut4 trafficking XREF_BIBR .	It has previously been shown to play a central role in the pathogenesis of metabolic syndrome XREF_BIBR and to be involved in insulin stimulated Glut4 trafficking XREF_BIBR.	20	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	22	23	24	25
To explore whether AICAR also affects insulin stimulated glucose transport and GLUT4 cell surface content , Wistar rats were subcutaneously injected with AICAR for 5 days in succession ( 1 mg/g body wt ) .	To explore whether AICAR also affects insulin stimulated glucose transport and GLUT4 cell surface content, Wistar rats were subcutaneously injected with AICAR for 5 days in succession (1 mg/g body wt).	5	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	11	12
Insulin releases an intracellular brake and promotes fusion pore expansion to translocate GLUT4 vesicles , and switches vesicle trafficking between distinct exocytic circuits .	Insulin releases an intracellular brake and promotes fusion pore expansion to translocate GLUT4 vesicles, and switches vesicle trafficking between distinct exocytic circuits.	0	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	12	13
In 3T3-L1 cells , expression of this truncated mutant leads to elevation of basal and reduction of insulin stimulated GLUT4 traffic .	In 3T3-L1 cells, expression of this truncated mutant leads to elevation of basal and reduction of insulin stimulated GLUT4 traffic.	15	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
In contrast , insulin resistance induced a more clustered distribution of GLUT4 and increased the mean number of molecules per cluster .	In contrast, insulin resistance induced a more clustered distribution of GLUT4 and increased the mean number of molecules per cluster.	3	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	11	12
Recently , Rab GTPase activating protein AS160 , a substrate of Akt , was shown to be involved in insulin modulation of GLUT4 trafficking in skeletal muscle and adipose tissue .	Recently, Rab GTPase activating protein AS160, a substrate of Akt, was shown to be involved in insulin modulation of GLUT4 trafficking in skeletal muscle and adipose tissue.	19	23	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	22	23
With the use of the same methodology , antibody , and achieving the same degree of plasma membrane purification and recovery , we found , however , that intraperitoneal administration of insulin to 7-wk-old rats within 30 min increased the content of GLUT-4 protein more than twofold ( P < 0.01 ) in the plasma membrane from red gastrocnemius and soleus muscle .	With the use of the same methodology, antibody, and achieving the same degree of plasma membrane purification and recovery, we found, however, that intraperitoneal administration of insulin to 7-wk-old rats within 30 min increased the content of GLUT-4 protein more than twofold (P < 0.01) in the plasma membrane from red gastrocnemius and soleus muscle.	29	43	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	31	32	42	43
This revealed the modulation of N glycosylation on specific proteins in IR , including those previously associated with insulin stimulated GLUT4 trafficking to the plasma membrane .	This revealed the modulation of N glycosylation on specific proteins in IR, including those previously associated with insulin stimulated GLUT4 trafficking to the plasma membrane.	16	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
Insulin derived signals promote not only GLUT4 mobilization toward the PM but also its traffic between endosomal compartments and internalization from the PM .	Insulin derived signals promote not only GLUT4 mobilization toward the PM but also its traffic between endosomal compartments and internalization from the PM.	0	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Current efforts in our laboratory are underway to examine whether insulin and IGFs stimulate the protein synthesis of GLUT4 in gilthead sea bream muscle cells .	Current efforts in our laboratory are underway to examine whether insulin and IGFs stimulate the protein synthesis of GLUT4 in gilthead sea bream muscle cells.	10	24	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	18	19
This finding is in line with a previous report that demonstrates increased sensitivity to insulin stimulated GLUT4 externalization in adipocytes of Munc18c knockout mice [ XREF_BIBR ] .	This finding is in line with a previous report that demonstrates increased sensitivity to insulin stimulated GLUT4 externalization in adipocytes of Munc18c knockout mice [XREF_BIBR].	12	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Insulin stimulated GLUT4 translocation is central to glucose homeostasis .	Insulin stimulated GLUT4 translocation is central to glucose homeostasis.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Although insulin increased glucose uptake in CHO cells and 3T3-L1 fibroblasts as well as in the cells expressing rat GLUT4 , an increment due to insulin above basal values was small , at most 2-fold , and no significant differences were observed in insulin stimulated glucose uptake between transfected and parental cells .	Although insulin increased glucose uptake in CHO cells and 3T3-L1 fibroblasts as well as in the cells expressing rat GLUT4, an increment due to insulin above basal values was small, at most 2-fold, and no significant differences were observed in insulin stimulated glucose uptake between transfected and parental cells.	1	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	19	20
Indeed , it was previously reported that ROS disrupted insulin induced cellular redistribution of insulin receptor substrate-1 ( IRS-1 ) and phosphatidylinositol 3-kinase ( PI 3-K ) , and thus impaired insulin induced GLUT4 translocation in 3T3-L1 adipocyte [ XREF_BIBR , XREF_BIBR ] .	Indeed, it was previously reported that ROS disrupted insulin induced cellular redistribution of insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI 3-K), and thus impaired insulin induced GLUT4 translocation in 3T3-L1 adipocyte [XREF_BIBR, XREF_BIBR].	30	34	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	31	32	33	34
The permeabilized adipocytes ( left panels ) showed that both insulin and FBS increased the appearance of HA-GLUT4 near or at the plasma membrane , while the non permeabilized cells ( right panels ) clearly demonstrated an increase in the amounts of GLUT4 at the cell surface upon stimulation with insulin or FBS .	The permeabilized adipocytes (left panels) showed that both insulin and FBS increased the appearance of HA-GLUT4 near or at the plasma membrane, while the non permeabilized cells (right panels) clearly demonstrated an increase in the amounts of GLUT4 at the cell surface upon stimulation with insulin or FBS.	9	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	HA-GLUT4	HA-GLUT4	HA-GLUT4	10	11	17	18
VAMP2 is key to the regulation of insulin induced GLUT4 translocation and glucose uptake via forming the SNARE complex , which is one of the important steps in regulation of GLUT4 translocation .	VAMP2 is key to the regulation of insulin induced GLUT4 translocation and glucose uptake via forming the SNARE complex, which is one of the important steps in regulation of GLUT4 translocation.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Insulin induced GLUT4 translocation requires at least two signals , one mediated through phosphatidylinositol 3-kinase ( PI3K ) and another via Galphaq/11 in 3T3L1 adipocytes .	Insulin induced GLUT4 translocation requires at least two signals, one mediated through phosphatidylinositol 3-kinase (PI3K) and another via Galphaq/11 in 3T3L1 adipocytes.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
As insulin stimulated GLUT 4 content in plasma membranes was not diminished by combined hyperglycemia and hyperinsulinemia , these results indicate functional GLUT 4 translocation in this model and suggest suppression of GLUT 4 transporter activity .	As insulin stimulated GLUT 4 content in plasma membranes was not diminished by combined hyperglycemia and hyperinsulinemia, these results indicate functional GLUT 4 translocation in this model and suggest suppression of GLUT 4 transporter activity.	1	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	1	2	3	5
Meanwhile , the insulin signaling was markedly increased as shown by increased phosphorylation of Akt and enhanced GLUT4 activation .	Meanwhile, the insulin signaling was markedly increased as shown by increased phosphorylation of Akt and enhanced GLUT4 activation.	3	18	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	17	18
XREF_BIBR , XREF_BIBR These data suggest that Akt2 might be involved in insulin induced GLUT4 translocation and glucose uptake .	XREF_BIBR, XREF_BIBR These data suggest that Akt2 might be involved in insulin induced GLUT4 translocation and glucose uptake.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Here we have further examined the effects of R ( s ) G ( s ) and R ( i ) G ( i ) ligands ( in which R ( s ) and R ( i ) are G ( s ) - and G ( i )-coupled receptors respectively ) on insulin stimulated cell-surface GLUT4 and the kinetics of GLUT4 trafficking in these same cells .	Here we have further examined the effects of R (s) G (s) and R (i) G (i) ligands (in which R (s) and R (i) are G (s) - and G (i)-coupled receptors respectively) on insulin stimulated cell-surface GLUT4 and the kinetics of GLUT4 trafficking in these same cells.	4	59	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	53	54	56	57
Insulin induced an approximately two-fold increase of GLUT 4 in a plasma membrane and transverse tubule enriched fraction and a decrease in the low density enriched membrane fraction in all three groups of rats .	Insulin induced an approximately two-fold increase of GLUT 4 in a plasma membrane and transverse tubule enriched fraction and a decrease in the low density enriched membrane fraction in all three groups of rats.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT 4	GLUT 4	GLUT 4	0	1	7	9
Insulin stimulation induces the redistribution of GLUT4 to the plasma membrane .	Insulin stimulation induces the redistribution of GLUT4 to the plasma membrane.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Although the insulin induced GLUT4 translocation in adipocytes was not affected by the Cd treatment , the 3-O-methy-D-glucose flux in insulin stimulated adipocytes of Cd treated rat was drastically reduced .	Although the insulin induced GLUT4 translocation in adipocytes was not affected by the Cd treatment, the 3-O-methy-D-glucose flux in insulin stimulated adipocytes of Cd treated rat was drastically reduced.	1	5	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
It remains to be demonstrated if ATP10A is directly involved in insulin stimulated mobilization of GLUT4 containing vesicles to the plasma membrane , or whether ATP10A exerts its effects on glucose metabolism via regulation of insulin receptor induced signalling .	It remains to be demonstrated if ATP10A is directly involved in insulin stimulated mobilization of GLUT4 containing vesicles to the plasma membrane, or whether ATP10A exerts its effects on glucose metabolism via regulation of insulin receptor induced signalling.	9	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	15	16
C2-ceramide , a short-chain ceramide analog , mimicked TNF-alpha to induce insulin resistance , decrease GLUT4 gene expression , and completely preclude insulin stimulated glucose uptake and insulin induced GLUT4 translocation to plasma membrane .	C2-ceramide, a short-chain ceramide analog, mimicked TNF-alpha to induce insulin resistance, decrease GLUT4 gene expression, and completely preclude insulin stimulated glucose uptake and insulin induced GLUT4 translocation to plasma membrane.	23	30	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	27	28	29	30
From all stimulus induced transporter translocation processes , insulin induced GLUT4 translocation is the most intensively studied [ XREF_BIBR ] .	From all stimulus induced transporter translocation processes, insulin induced GLUT4 translocation is the most intensively studied [XREF_BIBR].	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Regardless of the precise mechanism , it is attractive to consider the possibility that p97 may facilitate the insulin stimulated disassembly of a TUG and GLUT4 complex to release GLUT4 .	Regardless of the precise mechanism, it is attractive to consider the possibility that p97 may facilitate the insulin stimulated disassembly of a TUG and GLUT4 complex to release GLUT4.	16	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	29	30
Microinjection of Rab4 N121I and Rab4 antibodies had no effect on basal GLUT4 staining , but inhibited insulin induced GLUT4 translocation by 50 % compared with that in control IgG injected cells .	Microinjection of Rab4 N121I and Rab4 antibodies had no effect on basal GLUT4 staining, but inhibited insulin induced GLUT4 translocation by 50% compared with that in control IgG injected cells.	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
These observations , together with the fact that wortmannin , as found in adipocytes , inhibits insulin stimulated glucose transport in oocytes , suggest that the heterologous expression of GLUT4 in oocytes is a useful experimental model by which to study the cell biology of insulin induced GLUT4 translocation .	These observations, together with the fact that wortmannin, as found in adipocytes, inhibits insulin stimulated glucose transport in oocytes, suggest that the heterologous expression of GLUT4 in oocytes is a useful experimental model by which to study the cell biology of insulin induced GLUT4 translocation.	43	48	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	45	46	47	48
Insulin , a major regulator of glucose metabolism increases glucose transport by stimulating insertion of Glut-4 from intracellular compartment to the cell surface [ XREF_BIBR ] and further transition of Glut-4 to the plasma membrane fraction enriched by the caveolae [ XREF_BIBR ] .	Insulin, a major regulator of glucose metabolism increases glucose transport by stimulating insertion of Glut-4 from intracellular compartment to the cell surface [XREF_BIBR] and further transition of Glut-4 to the plasma membrane fraction enriched by the caveolae [XREF_BIBR].	0	18	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut-4	Glut-4	Glut-4	0	1	15	16
These studies , together with our recent observations underscore the role of insulin mediated Akt2 plasma membrane accumulation in GLUT4 regulation and suggest ClipR-59 as a putative regulator of Akt isoform functional specificity in insulin regulated glucose uptake .	These studies, together with our recent observations underscore the role of insulin mediated Akt2 plasma membrane accumulation in GLUT4 regulation and suggest ClipR-59 as a putative regulator of Akt isoform functional specificity in insulin regulated glucose uptake.	10	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	19	20
As shown in Figure XREF_FIG , both insulin stimulated Glut4 mRNA and protein expression were significantly increased in skeletal muscle of NCD mice as compared with that of HFD mice ( p < 0.05 ) .	As shown in Figure XREF_FIG, both insulin stimulated Glut4 mRNA and protein expression were significantly increased in skeletal muscle of NCD mice as compared with that of HFD mice (p < 0.05).	6	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	7	8	9	10
Pak1 is a Ser/Thr kinase that is involved in cytoskeleton remodelling , cell survival , cell cycle progression , and transcriptional regulation via the MAPK cascade.10 This protein is expressed in skeletal muscle and has been implicated in the regulation of myogenin and AChR expression following denervation of mature fibers.55 , 56 Moreover , in skeletal muscle , Pak1 has been associated with the regulation of glucose uptake through insulin induced Glut4 translocation56 , 57 , 58 and in contraction modulation by phosphorylating Myosin Light Chain Kinase.59 , 60 In addition , we have recently shown that Pak1 is down-regulated in atrophying gastrocnemius of Yoshida hepatoma bearing rats and others have reported it to be up-regulated in soleus muscles following Axokine administration.7 , 8 , 61 All this evidence points to a central role of Pak1 in processes related to muscle physiology .	Pak1 is a Ser/Thr kinase that is involved in cytoskeleton remodelling, cell survival, cell cycle progression, and transcriptional regulation via the MAPK cascade.10 This protein is expressed in skeletal muscle and has been implicated in the regulation of myogenin and AChR expression following denervation of mature fibers.55, 56 Moreover, in skeletal muscle, Pak1 has been associated with the regulation of glucose uptake through insulin induced Glut4 translocation56, 57, 58 and in contraction modulation by phosphorylating Myosin Light Chain Kinase.59, 60 In addition, we have recently shown that Pak1 is down-regulated in atrophying gastrocnemius of Yoshida hepatoma bearing rats and others have reported it to be up-regulated in soleus muscles following Axokine administration.7, 8, 61 All this evidence points to a central role of Pak1 in processes related to muscle physiology.	69	141	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	69	70	71	72
Insulin stimulated GLUT4-GFP neurite movement in WT hypothalamic neurons ( XREF_SUPPLEMENTARY ) , whereas little GLUT4-GFP movement was seen upon insulin stimulation in CCR5 -/- hypothalamic neurons ( XREF_SUPPLEMENTARY ) .	Insulin stimulated GLUT4-GFP neurite movement in WT hypothalamic neurons (XREF_SUPPLEMENTARY), whereas little GLUT4-GFP movement was seen upon insulin stimulation in CCR5 -/- hypothalamic neurons (XREF_SUPPLEMENTARY).	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4-GFP	GLUT4-GFP	GLUT4-GFP	0	1	2	3
In contrast to the specific C2-ceramide-induced attenuation of insulin stimulated GLUT4 translocation , overexpression of glutamine : fructose-6-phosphate amidotransferase , the rate limiting enzyme in the synthesis of UDP-N-acetylglucosamine , and/or pretreatment of cells with glucosamine , a precursor of UDP-N-acetylglucosamine , inhibited both insulin- and hyperosmolarity stimulated GLUT4 translocation .	In contrast to the specific C2-ceramide-induced attenuation of insulin stimulated GLUT4 translocation, overexpression of glutamine : fructose-6-phosphate amidotransferase, the rate limiting enzyme in the synthesis of UDP-N-acetylglucosamine, and/or pretreatment of cells with glucosamine, a precursor of UDP-N-acetylglucosamine, inhibited both insulin- and hyperosmolarity stimulated GLUT4 translocation.	6	31	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Insulin stimulated GLUT4 translocation was not affected , but OEA promoted Ser/Thr phosphorylation of GLUT4 , which may impair transport activity .	Insulin stimulated GLUT4 translocation was not affected, but OEA promoted Ser/Thr phosphorylation of GLUT4, which may impair transport activity.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Insulin stimulated glucose uptake and GLUT4 protein abundance at 2 h postexercise .	Insulin stimulated glucose uptake and GLUT4 protein abundance at 2 h postexercise.	0	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	5	6
Insulin stimulated glucose disposal in skeletal muscle accounts for 80 % of glucose uptake postprandial , localizing GLUT4 to the sarcolemma .	Insulin stimulated glucose disposal in skeletal muscle accounts for 80% of glucose uptake postprandial, localizing GLUT4 to the sarcolemma.	0	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	17	18
We studied the effects of microinjection of wild-type Rab4 glutathione S-transferase fusion protein ( WT Rab4 ) , a GTP binding defective mutant ( Rab4 N121I ) , a guanosine triphosphatase defective mutant ( Rab4 Q67L ) , and a Rab4 antibody on insulin induced GLUT4 translocation in 3T3-L1 adipocytes .	We studied the effects of microinjection of wild-type Rab4 glutathione S-transferase fusion protein (WT Rab4), a GTP binding defective mutant (Rab4 N121I), a guanosine triphosphatase defective mutant (Rab4 Q67L), and a Rab4 antibody on insulin induced GLUT4 translocation in 3T3-L1 adipocytes.	41	46	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	43	44	45	46
Because fluorescence is not lost but redistributes in times substantially faster than 70 s , these data further confirm that insulin stimulated tethering of GLUT4 vesicles in clusters is followed by fusion of the vesicles with the PM .	Because fluorescence is not lost but redistributes in times substantially faster than 70 s, these data further confirm that insulin stimulated tethering of GLUT4 vesicles in clusters is followed by fusion of the vesicles with the PM.	20	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	24	25
Insulin stimulated GLUT4 translocation seems to be regulated mainly via activation of phosphatidylinositol 3-kinase ( PI3-kinase ) and the AKT pathway [ XREF_BIBR ] .	Insulin stimulated GLUT4 translocation seems to be regulated mainly via activation of phosphatidylinositol 3-kinase (PI3-kinase) and the AKT pathway [XREF_BIBR].	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
As shown in XREF_FIG G we observed no changes in basal or insulin stimulated GLUT4 membrane fusion after 15min .	As shown in XREF_FIG G we observed no changes in basal or insulin stimulated GLUT4 membrane fusion after 15min.	8	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
In conclusion , wortmannin blocked insulin stimulated translocation of GLUT4 to the plasma membrane , suggesting that insulin induced GLUT4 translocation events observed in this study were supported by endogenous DInR and PI3K signaling pathways .	In conclusion, wortmannin blocked insulin stimulated translocation of GLUT4 to the plasma membrane, suggesting that insulin induced GLUT4 translocation events observed in this study were supported by endogenous DInR and PI3K signaling pathways.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
To address whether TDP-43 effects insulin mediated Glut4 translocation in other tissues , we isolated adipocytes from the gonadal fat pad of 6-8 week old transgenic and non transgenic mice and performed a Glut4 translocation assay .	To address whether TDP-43 effects insulin mediated Glut4 translocation in other tissues, we isolated adipocytes from the gonadal fat pad of 6-8 week old transgenic and non transgenic mice and performed a Glut4 translocation assay.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	5	6	7	8
In addition to AKT-AS160-regulated GSV accumulation at the PM , insulin also stimulates the redistribution of GLUT4 from the perinuclear storage compartment to the endosome and a modest increase in translocation of endosomal TR positive vesicles to the PM .	In addition to AKT-AS160-regulated GSV accumulation at the PM, insulin also stimulates the redistribution of GLUT4 from the perinuclear storage compartment to the endosome and a modest increase in translocation of endosomal TR positive vesicles to the PM.	10	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	16	17
In investigation of the short or long-term effects of Rut in 3T3-L1 adipocytes , we have detected the insulin induced GLUT4 translocation and glucose uptake in a time dependent manner .	In investigation of the short or long-term effects of Rut in 3T3-L1 adipocytes, we have detected the insulin induced GLUT4 translocation and glucose uptake in a time dependent manner.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
Although insulin administration rapidly increased ( p < 0.05 ) plasma membrane GLUT4 content in both red and white gastrocnemius muscles , the TBC1D1 ablation did not alter this response nor did it affect whole-body insulin tolerance , suggesting that TBC1D1 is not required for insulin induced GLUT4 trafficking events .	Although insulin administration rapidly increased (p < 0.05) plasma membrane GLUT4 content in both red and white gastrocnemius muscles, the TBC1D1 ablation did not alter this response nor did it affect whole-body insulin tolerance, suggesting that TBC1D1 is not required for insulin induced GLUT4 trafficking events.	43	49	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	45	46	47	48
The inhibitory effects of hrCRP on insulin signalling and insulin stimulated GLUT4 translocation were reversed by treatment with JNK inhibitor I and the mitogen activated protein kinase inhibitor , PD98059 .	The inhibitory effects of hrCRP on insulin signalling and insulin stimulated GLUT4 translocation were reversed by treatment with JNK inhibitor I and the mitogen activated protein kinase inhibitor, PD98059.	4	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Activated Akt phosphorylates its 160 kDa substrate ( AS160 ) , which stimulates the translocation of insulin mediated Glut4 from intracellular vesicles to the plasma membrane [ XREF_BIBR ] .	Activated Akt phosphorylates its 160 kDa substrate (AS160), which stimulates the translocation of insulin mediated Glut4 from intracellular vesicles to the plasma membrane [XREF_BIBR].	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	16	17	18	19
An AS160 mutant , in which four of the phosphorylation sites are replaced with alanine , but the Rab-GAP catalytic domain is intact , was insensitive to Akt2 dependent negative regulation , and remarkably inhibited insulin induced GLUT4 translocation in both skeletal muscle and adipocytes [ XREF_BIBR , XREF_BIBR ] .	An AS160 mutant, in which four of the phosphorylation sites are replaced with alanine, but the Rab-GAP catalytic domain is intact, was insensitive to Akt2 dependent negative regulation, and remarkably inhibited insulin induced GLUT4 translocation in both skeletal muscle and adipocytes [XREF_BIBR, XREF_BIBR].	34	38	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	35	36	37	38
In animal models , high fat-diet rats have defective insulin induced GLUT-4 translocation in skeletal muscle which has been associated with decreased Akt activity .	In animal models, high fat-diet rats have defective insulin induced GLUT-4 translocation in skeletal muscle which has been associated with decreased Akt activity.	7	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	9	10	11	12
More importantly , VAMP2 may be necessary for T3 to promote insulin induced GLUT4 translocation and glucose uptake because RNAi knockdown of VAMP2 abrogated the promoting effects of T3 on these processes .	More importantly, VAMP2 may be necessary for T3 to promote insulin induced GLUT4 translocation and glucose uptake because RNAi knockdown of VAMP2 abrogated the promoting effects of T3 on these processes.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
In rat adipocytes , insulin induced GLUT4 recruitment to the plasma membrane ( PM ) is associated with characteristic changes in the GLUT4 contents of three distinct endosomal fractions , T , H , and L.	In rat adipocytes, insulin induced GLUT4 recruitment to the plasma membrane (PM) is associated with characteristic changes in the GLUT4 contents of three distinct endosomal fractions, T, H, and L.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Instead , changes experienced by insulin stimulated GLUT4 make it susceptible to inhibition by SB203580 .	Instead, changes experienced by insulin stimulated GLUT4 make it susceptible to inhibition by SB203580.	3	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
In cultured 3T3-L1 adipocytes , sequestration is less complete , and maximal insulin stimulation typically produces a 4- to 8- fold increase in GLUT4 at the cell surface .	In cultured 3T3-L1 adipocytes, sequestration is less complete, and maximal insulin stimulation typically produces a 4- to 8- fold increase in GLUT4 at the cell surface.	12	24	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	23	24
A comparable defect in insulin mediated GLUT4 translocation to the cell surface ( ~ 50 % reduction ) was observed at this later stage of differentiation in lipid-droplet containing SVF adipocytes ( XREF_FIG ) , confirming that Rab10 deletion causes a partial inhibition of insulin stimulated GLUT4 translocation to the plasma membrane of adipocytes .	A comparable defect in insulin mediated GLUT4 translocation to the cell surface (~ 50% reduction) was observed at this later stage of differentiation in lipid-droplet containing SVF adipocytes (XREF_FIG), confirming that Rab10 deletion causes a partial inhibition of insulin stimulated GLUT4 translocation to the plasma membrane of adipocytes.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Clq may provide a useful tool to elucidate the signalling or fusion steps involved in insulin induced GLUT4 translocation .	Clq may provide a useful tool to elucidate the signalling or fusion steps involved in insulin induced GLUT4 translocation.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
Preincubation of adipocytes with cAMP antagonist , RpcAMP ( 10 (-4) M ) , and calcium channel blocker , nitrendipine ( 30 microM ) , improved the ability of insulin to dephosphorylate GLUT-4 and restored insulin stimulated GLUT-4 intrinsic activity .	Preincubation of adipocytes with cAMP antagonist, RpcAMP (10 (-4) M), and calcium channel blocker, nitrendipine (30 microM), improved the ability of insulin to dephosphorylate GLUT-4 and restored insulin stimulated GLUT-4 intrinsic activity.	34	39	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	35	36	37	38
We suggest that the stimulation of transport by insulin and PMA occurs via different mechanisms , which is manifested by the ability of insulin to induce a much greater increase in the plasma-membrane content of GLUT 4 compared with the phorbol ester .	We suggest that the stimulation of transport by insulin and PMA occurs via different mechanisms, which is manifested by the ability of insulin to induce a much greater increase in the plasma-membrane content of GLUT 4 compared with the phorbol ester.	21	37	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	23	24	35	37
In adipocytes , both Rab10 and Rab8A mediate insulin stimulated GLUT4 trafficking under the regulation of the same GTPase activating protein ( GAP ) AS160 .	In adipocytes, both Rab10 and Rab8A mediate insulin stimulated GLUT4 trafficking under the regulation of the same GTPase activating protein (GAP) AS160.	8	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
These findings strongly suggest that EHD2 interacts with GLUT4 in rat adipocytes and may play a key role in insulin induced GLUT4 recruitment to the plasma membrane .	These findings strongly suggest that EHD2 interacts with GLUT4 in rat adipocytes and may play a key role in insulin induced GLUT4 recruitment to the plasma membrane.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
From these findings , we expected the abnormal expression of mRNA to be related to the insulin and IGF signals of IGF1R , INSR , IRS1-2 , SLC2A2 , and SLC2A4 in SGA neonates , which were evaluated in this study .	From these findings, we expected the abnormal expression of mRNA to be related to the insulin and IGF signals of IGF1R, INSR, IRS1-2, SLC2A2, and SLC2A4 in SGA neonates, which were evaluated in this study.	16	31	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	SLC2A4	SLC2A4	SLC2A4	16	17	30	31
Both Exo70 [ XREF_BIBR , XREF_BIBR ] and Sec3 [ XREF_BIBR ] interact with PtdIns ( 4,5 ) P 2 , but the relevance of these interactions to insulin stimulated GLUT4 trafficking has not yet been examined .	Both Exo70 [XREF_BIBR, XREF_BIBR] and Sec3 [XREF_BIBR] interact with PtdIns (4,5) P 2, but the relevance of these interactions to insulin stimulated GLUT4 trafficking has not yet been examined.	26	31	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	28	29	30	31
To rule out the unlikely possibility that the insulin dependent increase in the mobile GLUT4 is solely due to the increase in rapidly vibrating molecules within a confined region , we next used mean-square displacement ( MSD ) curves .	To rule out the unlikely possibility that the insulin dependent increase in the mobile GLUT4 is solely due to the increase in rapidly vibrating molecules within a confined region, we next used mean-square displacement (MSD) curves.	8	15	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	14	15
Palmitate , but not palmitoleate , had mild effects on Akt phosphorylation but significantly inhibited insulin stimulated GLUT4 translocation and increased expression of pro inflammatory cytokines Il6 and Ccl2 Ceramides , hexosylceramides , and sphingosine-1-phosphate significantly heightened by palmitate correlated negatively with insulin sensitivity and positively with pro inflammatory indices .	Palmitate, but not palmitoleate, had mild effects on Akt phosphorylation but significantly inhibited insulin stimulated GLUT4 translocation and increased expression of pro inflammatory cytokines Il6 and Ccl2 Ceramides, hexosylceramides, and sphingosine-1-phosphate significantly heightened by palmitate correlated negatively with insulin sensitivity and positively with pro inflammatory indices.	14	49	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
Insulin increased T tubule membrane GLUT-4 content ( 2.8 +/- 0.4 golds and microm , P < 0.05 ) but had less effect on sarcolemmal GLUT-4 ( 1.72 +/- 0.53 golds and microm ) .	Insulin increased T tubule membrane GLUT-4 content (2.8 +/- 0.4 golds and microm, P < 0.05) but had less effect on sarcolemmal GLUT-4 (1.72 +/- 0.53 golds and microm).	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT-4	GLUT-4	GLUT-4	0	1	5	6
We also confirmed that siRNA against RalA and Rab10 were effective , as targeting either small GTPase in control cells inhibited glut4 recycling induced by insulin ( XREF_SUPPLEMENTARY ) .	We also confirmed that siRNA against RalA and Rab10 were effective, as targeting either small GTPase in control cells inhibited glut4 recycling induced by insulin (XREF_SUPPLEMENTARY).	21	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	glut4	glut4	glut4	25	26	21	22
Insulin increases glucose uptake by increasing the rate of exocytosis of the facilitative glucose transporter isoform 4 ( Glut4 ) relative to its endocytosis .	Insulin increases glucose uptake by increasing the rate of exocytosis of the facilitative glucose transporter isoform 4 (Glut4) relative to its endocytosis.	0	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut4	Glut4	Glut4	0	1	18	19
SEC16A is a RAB10 effector required for insulin stimulated GLUT4 trafficking in adipocytes .	SEC16A is a RAB10 effector required for insulin stimulated GLUT4 trafficking in adipocytes.	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Moreover , the insulin ( 100nM )-induced increase in the GLUT4 localization on the cell surface was also prevented by BX912 ( 100nM ) ( XREF_FIG B ) or knocking-down PDK1 ( XREF_FIG D ) .	Moreover, the insulin (100nM)-induced increase in the GLUT4 localization on the cell surface was also prevented by BX912 (100nM) (XREF_FIG B) or knocking-down PDK1 (XREF_FIG D).	3	11	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	10	11
Thus , the main SNARE proteins involved in insulin stimulated Glut4 exocytosis ( syntaxin 4 and VAMP2 ) are expressed in approximately equimolar amounts in adipocytes , whereas by contrast the endosomal v-SNARE cellubrevin is present at approximately 10-fold higher levels and the t-SNARE SNAP-23 is also present in an approximately 3-fold molar excess .	Thus, the main SNARE proteins involved in insulin stimulated Glut4 exocytosis (syntaxin 4 and VAMP2) are expressed in approximately equimolar amounts in adipocytes, whereas by contrast the endosomal v-SNARE cellubrevin is present at approximately 10-fold higher levels and the t-SNARE SNAP-23 is also present in an approximately 3-fold molar excess.	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	8	9	10	11
Furthermore , the results demonstrate that muscle overexpressing GLUT1 has normal insulin induced GLUT4 translocation and the ability to augment glucose-transport activity above the elevated basal rates .	Furthermore, the results demonstrate that muscle overexpressing GLUT1 has normal insulin induced GLUT4 translocation and the ability to augment glucose-transport activity above the elevated basal rates.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Translocation of GLUT4 induced by insulin or other stimuli from intracellular storage vesicles to the plasma membrane results in an immediate 10- to 20-fold increase in glucose uptake .	Translocation of GLUT4 induced by insulin or other stimuli from intracellular storage vesicles to the plasma membrane results in an immediate 10- to 20-fold increase in glucose uptake.	0	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	2	3
We investigated the role of Munc18c total and Tyr 218/219 and Tyr 521 phosphorylation in Munc18c interactions and the insulin stimulated SNARE mediated delivery of GLUT4 to the plasma membrane .	We investigated the role of Munc18c total and Tyr 218/219 and Tyr 521 phosphorylation in Munc18c interactions and the insulin stimulated SNARE mediated delivery of GLUT4 to the plasma membrane.	1	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	25	26
Collectively , all of the present findings concerning GLUT4 expression and translocation both in vitro and in vivo , demonstrated that SMR may contribute to enhancing the basal expression of GLUT4 in cells and partial correction of the defect in insulin mediated GLUT4 translocation , thereby mitigating IR in KK-Ay mice .	Collectively, all of the present findings concerning GLUT4 expression and translocation both in vitro and in vivo, demonstrated that SMR may contribute to enhancing the basal expression of GLUT4 in cells and partial correction of the defect in insulin mediated GLUT4 translocation, thereby mitigating IR in KK-Ay mice.	38	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	40	41	42	43
Considering that GLUT1 transporters also contribute to glucose uptake in cultured adipocytes , and the fact that siRNA can not completely abolish gene expression , these data suggest that the RGC regulates insulin stimulated GLUT4 trafficking in adipocytes .	Considering that GLUT1 transporters also contribute to glucose uptake in cultured adipocytes, and the fact that siRNA can not completely abolish gene expression, these data suggest that the RGC regulates insulin stimulated GLUT4 trafficking in adipocytes.	31	35	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	32	33	34	35
To further confirm these findings , we stimulated the diabetic atria with and without insulin ( at physiological concentration ) , and our results demonstrated that insulin stimulation rescued cell surface GLUT4 and 8 protein expression in the diabetic atria , suggesting that the down-regulation of both insulin sensitive GLUTs was mostly attributed to the lack of insulin production ( following beta cell destruction ) rather than an existing defect in the insulin signaling pathway in the atria of type 1 diabetic animals .	To further confirm these findings, we stimulated the diabetic atria with and without insulin (at physiological concentration), and our results demonstrated that insulin stimulation rescued cell surface GLUT4 and 8 protein expression in the diabetic atria, suggesting that the down-regulation of both insulin sensitive GLUTs was mostly attributed to the lack of insulin production (following beta cell destruction) rather than an existing defect in the insulin signaling pathway in the atria of type 1 diabetic animals.	26	35	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	31	32
Evidence suggests that an increased uptake of fatty acids both increases the lipid droplet pool and diverts SNAP23 from the plasma membrane away from the process of insulin stimulated GLUT4 translocation and glucose uptake , which could represent a novel mechanism to explain the association of lipid accumulation with insulin resistance XREF_BIBR .	Evidence suggests that an increased uptake of fatty acids both increases the lipid droplet pool and diverts SNAP23 from the plasma membrane away from the process of insulin stimulated GLUT4 translocation and glucose uptake, which could represent a novel mechanism to explain the association of lipid accumulation with insulin resistance XREF_BIBR.	25	30	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	27	28	29	30
In 3T3-L1 adipocytes , Galpha q is required for insulin induced GLUT4 translocation and the stimulation of 2-deoxy-d-glucose uptake .	In 3T3-L1 adipocytes, Galpha q is required for insulin induced GLUT4 translocation and the stimulation of 2-deoxy-d-glucose uptake.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
DENND1C can act as a GEF for Rab35 [ XREF_BIBR , XREF_BIBR ] , and Rab35 has been shown to play a role in insulin stimulated GLUT4 trafficking in adipocytes [ XREF_BIBR ] ; taken with our data this suggests that future investigation of DENND1C may be warranted to explore a potential role in glucose transport and homeostasis .	DENND1C can act as a GEF for Rab35 [XREF_BIBR, XREF_BIBR], and Rab35 has been shown to play a role in insulin stimulated GLUT4 trafficking in adipocytes [XREF_BIBR]; taken with our data this suggests that future investigation of DENND1C may be warranted to explore a potential role in glucose transport and homeostasis.	20	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	24	25	26	27
GLUT4 translocation in equines is insulin dependent , as has been described in rodents and farm animals , but insulin stimulated GLUT4 activation in ponies is lower than reported for pigs and cows under the same experimental conditions .	GLUT4 translocation in equines is insulin dependent, as has been described in rodents and farm animals, but insulin stimulated GLUT4 activation in ponies is lower than reported for pigs and cows under the same experimental conditions.	19	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
Isoproterenol pre-treatment reverses the alkalinizing effects of insulin and leads to attenuation of insulin stimulated glucose transport activity and exposure of GLUT4 to photolabeling reagents at the cell surface .	Isoproterenol pre-treatment reverses the alkalinizing effects of insulin and leads to attenuation of insulin stimulated glucose transport activity and exposure of GLUT4 to photolabeling reagents at the cell surface.	11	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	21	22
Antibodies against insulin stimulated GLUT4 were generated as previously described , and antibodies against GLUT1 were from Millipore ( 07-1401 ) .	Antibodies against insulin stimulated GLUT4 were generated as previously described, and antibodies against GLUT1 were from Millipore (07-1401).	0	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
In addition , a large body of evidence has identify Rab10 as an essential component in basolateral recycling in Madin-Darby canine kidney ( MDCK ) cells and in insulin stimulated GLUT4 recycling in adipocytes .	In addition, a large body of evidence has identify Rab10 as an essential component in basolateral recycling in Madin-Darby canine kidney (MDCK) cells and in insulin stimulated GLUT4 recycling in adipocytes.	14	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	28	29	30	31
Insulin stimulated Glut-4 translocation is regulated through a complex pathway .	Insulin stimulated Glut-4 translocation is regulated through a complex pathway.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut-4	Glut-4	Glut-4	0	1	2	3
Therefore , the insulin mediated GLUT4 translocation and glucose uptake can be completely inhibited by blocking a single step in the signaling pathway by wortmannin induced PI3-K inhibition .	Therefore, the insulin mediated GLUT4 translocation and glucose uptake can be completely inhibited by blocking a single step in the signaling pathway by wortmannin induced PI3-K inhibition.	2	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
We next examined the effect of IPA3 on insulin stimulated GLUT4 vesicle exocytosis and glucose uptake .	We next examined the effect of IPA3 on insulin stimulated GLUT4 vesicle exocytosis and glucose uptake.	2	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Insulin stimulation dissociated the DGKzeta and PIP5K1alpha from IRS-1 , leading to enhancement of insulin induced GLUT4 translocation through PIP5K activity ( XREF_FIG ) .	Insulin stimulation dissociated the DGKzeta and PIP5K1alpha from IRS-1, leading to enhancement of insulin induced GLUT4 translocation through PIP5K activity (XREF_FIG).	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
We propose that while noninsulin dependent GLUT1 and GLUT3 transport is adequate for resting needs , the surge in energy use during sustained cognitive activity requires the additional induction of insulin signaled GLUT4 transport .	We propose that while noninsulin dependent GLUT1 and GLUT3 transport is adequate for resting needs, the surge in energy use during sustained cognitive activity requires the additional induction of insulin signaled GLUT4 transport.	28	33	signaled	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	30	31	32	33
Insulin stimulation of the GLUT4 exocytosis rate constant is sufficient to account for most of the observed increase in glucose transport activity in rat and human muscle .	Insulin stimulation of the GLUT4 exocytosis rate constant is sufficient to account for most of the observed increase in glucose transport activity in rat and human muscle.	0	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	4	5
The effects of ANGII on skeletal muscle glucose uptake is related to 1 ) alterations in skeletal muscle blood flow , as well as 2 ) non hemodynamic effects of ANGII on insulin signaling and insulin stimulated glut-4 glucose uptake [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	The effects of ANGII on skeletal muscle glucose uptake is related to 1) alterations in skeletal muscle blood flow, as well as 2) non hemodynamic effects of ANGII on insulin signaling and insulin stimulated glut-4 glucose uptake [XREF_BIBR, XREF_BIBR - XREF_BIBR].	30	39	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	glut-4	glut-4	glut-4	35	36	37	38
It is well established that insulin induced remodeling of actin filaments into a cortical mesh is required for insulin stimulated GLUT4 exocytosis .	It is well established that insulin induced remodeling of actin filaments into a cortical mesh is required for insulin stimulated GLUT4 exocytosis.	16	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
A study reported in this issue of the JCI using mice lacking Munc18c , one of the vesicle trafficking proteins involved in GLUT4 translocation , has provided new insights into the signaling and trafficking intersection that controls insulin stimulated GLUT4 movement .	A study reported in this issue of the JCI using mice lacking Munc18c, one of the vesicle trafficking proteins involved in GLUT4 translocation, has provided new insights into the signaling and trafficking intersection that controls insulin stimulated GLUT4 movement.	36	40	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	37	38	39	40
We first confirmed that siRNA against Vamp2 in control adipocytes inhibited insulin stimulated glut4 recycling ( XREF_SUPPLEMENTARY ) , while siRNA against Vamp3 did not affect this recycling ( XREF_SUPPLEMENTARY ) .	We first confirmed that siRNA against Vamp2 in control adipocytes inhibited insulin stimulated glut4 recycling (XREF_SUPPLEMENTARY), while siRNA against Vamp3 did not affect this recycling (XREF_SUPPLEMENTARY).	10	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	glut4	glut4	glut4	11	12	13	14
Overexpression of dominant negative mutant of Exo70 blocks insulin stimulated GLUT4 vesicle fusion with the plasma membrane but not the redistribution of vesicles to the periphery of cells [ XREF_BIBR ] .	Overexpression of dominant negative mutant of Exo70 blocks insulin stimulated GLUT4 vesicle fusion with the plasma membrane but not the redistribution of vesicles to the periphery of cells [XREF_BIBR].	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
This HBP induced cholesterolgenic transcriptional response increases cholesterol in the plasma membrane ( PM ) , while reducing cortical filamentous actin ( F-actin ) that is essential for insulin stimulated GLUT4 mediated glucose transport ( Tsakiridis etal .	This HBP induced cholesterolgenic transcriptional response increases cholesterol in the plasma membrane (PM), while reducing cortical filamentous actin (F-actin) that is essential for insulin stimulated GLUT4 mediated glucose transport (Tsakiridis etal.	26	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	28	29	30	31
Findings in L6 myotubes concurred with those in HeLa cells , in that GIV was essential for insulin triggered GLUT4 exocytosis because GIV depleted myotubes ( ~ 80 % depletion ; XREF_FIG ) impaired exocytosis of GLUT4 by 70 % ; XREF_FIG ; XREF_SUPPLEMENTARY ) .	Findings in L6 myotubes concurred with those in HeLa cells, in that GIV was essential for insulin triggered GLUT4 exocytosis because GIV depleted myotubes (~ 80% depletion; XREF_FIG) impaired exocytosis of GLUT4 by 70%; XREF_FIG; XREF_SUPPLEMENTARY).	15	20	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Second , expression of constitutively active Akt in adipocytes increases glucose uptake , and conversely , a dominant negative form of Akt inhibits insulin induced GLUT4 translocation .	Second, expression of constitutively active Akt in adipocytes increases glucose uptake, and conversely, a dominant negative form of Akt inhibits insulin induced GLUT4 translocation.	22	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
Some groups reported that microtubule disrupting agents inhibited insulin induced GLUT4 translocation in 3T3-adipocytes [ XREF_BIBR , XREF_BIBR ] , while others did not find any effect on this process [ XREF_BIBR ] .	Some groups reported that microtubule disrupting agents inhibited insulin induced GLUT4 translocation in 3T3-adipocytes [XREF_BIBR, XREF_BIBR], while others did not find any effect on this process [XREF_BIBR].	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Despite extensive study , where insulin acts to modulate GLUT4 trafficking is controversial .	Despite extensive study, where insulin acts to modulate GLUT4 trafficking is controversial.	5	10	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	9	10
This calls for a revised model whereby insulin stimulated IR orchestrates the activation of syntaxin 4 for subsequent incoming insulin stimulated GLUT4 vesicles in parallel to its signaling to trigger the mobilization of those vesicles .	This calls for a revised model whereby insulin stimulated IR orchestrates the activation of syntaxin 4 for subsequent incoming insulin stimulated GLUT4 vesicles in parallel to its signaling to trigger the mobilization of those vesicles.	14	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
Compared with cells treated with insulin alone , adenosine in the presence of insulin increased the accessibility of GLUT4 to the extracellular photolabel by approximately 25 % , consistent with its enhancement of insulin stimulated glucose transport activity ; the plasma membrane concentration of GLUT4 as assessed by Western blotting was unchanged .	Compared with cells treated with insulin alone, adenosine in the presence of insulin increased the accessibility of GLUT4 to the extracellular photolabel by approximately 25%, consistent with its enhancement of insulin stimulated glucose transport activity; the plasma membrane concentration of GLUT4 as assessed by Western blotting was unchanged.	11	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	18	19
Notably , in Myo1c depleted cells , insulin stimulation increased the proportion of highly mobile GLUT4 vesicles ( from 21 % in control siNR treated cells to 40 % in Myo1c depleted cells ) and decreased the percentage of immobile GLUT4 vesicles ( from 31 to 7 % ; XREF_TABLE ) .	Notably, in Myo1c depleted cells, insulin stimulation increased the proportion of highly mobile GLUT4 vesicles (from 21% in control siNR treated cells to 40% in Myo1c depleted cells) and decreased the percentage of immobile GLUT4 vesicles (from 31 to 7%; XREF_TABLE).	7	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	15	16
Knockout of RABIF severely impaired insulin stimulated GLUT4 exocytosis in adipocytes .	Knockout of RABIF severely impaired insulin stimulated GLUT4 exocytosis in adipocytes.	2	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
To assess the role of Akt isoforms in insulin regulated GLUT4 trafficking we performed MK-2206 dose response analyses of insulin mediated GLUT4 translocation in our cell lines .	To assess the role of Akt isoforms in insulin regulated GLUT4 trafficking we performed MK-2206 dose response analyses of insulin mediated GLUT4 translocation in our cell lines.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
PKB and its substrate AS160 play an important role in insulin induced GLUT4 translocation and glucose transport .	PKB and its substrate AS160 play an important role in insulin induced GLUT4 translocation and glucose transport.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
The exocyst has been demonstrated to play a pivotal role in insulin stimulated GLUT4 trafficking , presumed by facilitating the tethering and docking of GLUT4 vesicles to the plasma membrane [ XREF_BIBR , XREF_BIBR ] .	The exocyst has been demonstrated to play a pivotal role in insulin stimulated GLUT4 trafficking, presumed by facilitating the tethering and docking of GLUT4 vesicles to the plasma membrane [XREF_BIBR, XREF_BIBR].	6	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Under basal conditions , GLUT4 displayed a perinuclear distribution , whereas insulin stimulation caused a redistribution of GLUT4 to the cell periphery ( XREF_FIG ) .	Under basal conditions, GLUT4 displayed a perinuclear distribution, whereas insulin stimulation caused a redistribution of GLUT4 to the cell periphery (XREF_FIG).	11	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	17	18
As it is well established that phosphorylation mediated inhibition of the RabGAP AS160 ( pThreonine642 ) is required for insulin stimulated GLUT4 vesicle docking and fusion with the PM XREF_BIBR , XREF_BIBR , and that this phosphorylation event is AKT2 specific and AKT1 independent 32 we next examined insulin stimulated pAS160 and AS160 .	As it is well established that phosphorylation mediated inhibition of the RabGAP AS160 (pThreonine642) is required for insulin stimulated GLUT4 vesicle docking and fusion with the PM XREF_BIBR, XREF_BIBR, and that this phosphorylation event is AKT2 specific and AKT1 independent 32 we next examined insulin stimulated pAS160 and AS160.	17	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
It is not clear if myricetin induced beta-endorphin secretion in fructose fed rats is mediated by pituitary gland dependent or -independent pathways ; however , it was strongly demonstrated that the myricetin mediated action converged at a point between the downstream targets of the peripheral MOR and the IRS-PI3-kinase signaling pathway , subsequently affecting insulin induced GLUT 4 translocation ( XREF_FIG ) .	It is not clear if myricetin induced beta-endorphin secretion in fructose fed rats is mediated by pituitary gland dependent or -independent pathways; however, it was strongly demonstrated that the myricetin mediated action converged at a point between the downstream targets of the peripheral MOR and the IRS-PI3-kinase signaling pathway, subsequently affecting insulin induced GLUT 4 translocation (XREF_FIG).	53	58	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	54	55	56	58
Furthermore , the location , expression , and insulin stimulated GLUT4 translocation are very different in cultured cells compared with mature muscle and may not require the same trafficking steps .	Furthermore, the location, expression, and insulin stimulated GLUT4 translocation are very different in cultured cells compared with mature muscle and may not require the same trafficking steps.	3	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
We propose a working model in which SWELL1 is activated by increases in adipocyte volume during adipocyte hypertrophy , and potentiates insulin-PI3K-AKT2 signaling via C-terminal LRRD interactions with GRB2-Cav1-IRS1-IR to support insulin mediated GLUT4 PM translocation , glucose import and lipogenesis .	We propose a working model in which SWELL1 is activated by increases in adipocyte volume during adipocyte hypertrophy, and potentiates insulin-PI3K-AKT2 signaling via C-terminal LRRD interactions with GRB2-Cav1-IRS1-IR to support insulin mediated GLUT4 PM translocation, glucose import and lipogenesis.	30	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	31	32	33	34
Osmotic shock and insulin stimulate GLUT4 translocation and glucose transport via mechanisms that are for the most part distinct yet convergent .	Osmotic shock and insulin stimulate GLUT4 translocation and glucose transport via mechanisms that are for the most part distinct yet convergent.	1	6	stimulate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Syntaxin 4 is the t-SNARE critical for insulin stimulated glucose transporter 4 ( GLUT4 )-plasma membrane fusion in adipocytes .	Syntaxin 4 is the t-SNARE critical for insulin stimulated glucose transporter 4 (GLUT4)-plasma membrane fusion in adipocytes.	5	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	13	14
Insulin considerably stimulates the rate of GLUT4 exocytosis with relatively little effect on the rate of internalization .	Insulin considerably stimulates the rate of GLUT4 exocytosis with relatively little effect on the rate of internalization.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Insulin stimulates the traffic of GLUT4 containing vesicles to the cell surface and induces their fusion to the plasma membrane XREF_BIBR .	Insulin stimulates the traffic of GLUT4 containing vesicles to the cell surface and induces their fusion to the plasma membrane XREF_BIBR.	0	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	5	6
The inhibition of the transcriptional activity of the fish and mammalian GLUT4 promoters by insulin is difficult to reconcile with the known stimulatory effects of insulin on GLUT4 mRNA levels in skeletal muscle in fish and mammalian species .	The inhibition of the transcriptional activity of the fish and mammalian GLUT4 promoters by insulin is difficult to reconcile with the known stimulatory effects of insulin on GLUT4 mRNA levels in skeletal muscle in fish and mammalian species.	11	15	promoters	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	11	12
A catalytically inactive mutant of SHIP had no effect on insulin induced GLUT4 translocation .	A catalytically inactive mutant of SHIP had no effect on insulin induced GLUT4 translocation.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Akt and Insulin Induced GLUT4 Translocation .	Akt and Insulin Induced GLUT4 Translocation.	0	5	Induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Future research will focus on how such regulatory mechanisms operate on Munc18c to control the insulin stimulated delivery of GLUT4 to the plasma membrane of adipocytes .	Future research will focus on how such regulatory mechanisms operate on Munc18c to control the insulin stimulated delivery of GLUT4 to the plasma membrane of adipocytes.	13	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	19	20
In addition , we have shown that physiological levels of insulin induce a 1.6-2.0 fold increase in GLUT4 content in skeletal muscle plasma membranes from control subjects , whereas no significant increase was noted in NIDDM skeletal muscle .	In addition, we have shown that physiological levels of insulin induce a 1.6-2.0 fold increase in GLUT4 content in skeletal muscle plasma membranes from control subjects, whereas no significant increase was noted in NIDDM skeletal muscle.	8	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	GLUT4	GLUT4	glut4	10	11	17	18
GSVs in adipocytes are formed by insulin stimulated budding of GLUT4 clusters that are associated with endosomal and trans-Golgi network ( TGN ) membranes .	GSVs in adipocytes are formed by insulin stimulated budding of GLUT4 clusters that are associated with endosomal and trans-Golgi network (TGN) membranes.	4	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	10	11
Acute exercise increases glucose homeostasis through the activation of AMPK -- the energy sensor of the cell -- leading to the translocation of GLUT4 to the cell membrane , an alternative to insulin induced GLUT4 translocation [ XREF_BIBR ] .	Acute exercise increases glucose homeostasis through the activation of AMPK -- the energy sensor of the cell -- leading to the translocation of GLUT4 to the cell membrane, an alternative to insulin induced GLUT4 translocation [XREF_BIBR].	30	35	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	32	33	34	35
In the present study , we show in 3T3-L1 adipocytes that Tbc1d1 is only 1/20 as abundant as AS160 , that knockdown of Tbc1d1 has no effect on insulin stimulated GLUT4 translocation , and that overexpressed Tbc1d1 also inhibits GLUT4 translocation elicited by activated Akt expression .	In the present study, we show in 3T3-L1 adipocytes that Tbc1d1 is only 1/20 as abundant as AS160, that knockdown of Tbc1d1 has no effect on insulin stimulated GLUT4 translocation, and that overexpressed Tbc1d1 also inhibits GLUT4 translocation elicited by activated Akt expression.	26	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	28	29	30	31
Ang II also impaired insulin stimulated GLUT4 transport in GLUT4-myc L6 myotubes , which was restored by ALCAR ( XREF_FIG ) .	Ang II also impaired insulin stimulated GLUT4 transport in GLUT4-myc L6 myotubes, which was restored by ALCAR (XREF_FIG).	3	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
The results suggest that exercise might limit insulin induced GLUT-4 recruitment and that following exercise , insulin may alter the intrinsic activity of plasma membrane glucose transporters .	The results suggest that exercise might limit insulin induced GLUT-4 recruitment and that following exercise, insulin may alter the intrinsic activity of plasma membrane glucose transporters.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	7	8	9	10
Insulin induced GLUT4 translocation to the cell surface was prevented by the phosphoinositide 3 kinase ( PI3K ) inhibitor wortmannin , the 3-phosphoinositide-dependent protein kinase 1 ( PDK1 ) inhibitor BX912 or the Akt1/2 inhibitor MK2206 , and by knocking-down PI3K , PDK1 or Akt1/2 .	Insulin induced GLUT4 translocation to the cell surface was prevented by the phosphoinositide 3 kinase (PI3K) inhibitor wortmannin, the 3-phosphoinositide-dependent protein kinase 1 (PDK1) inhibitor BX912 or the Akt1/2 inhibitor MK2206, and by knocking-down PI3K, PDK1 or Akt1/2.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
AKT phosphorylates a series of residues on AS160 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , of which Ser318 , Ser588 , Thr642 , and Ser751 phosphorylation are required for insulin induced GLUT4 translocation to the plasma membrane [ XREF_BIBR ] .	AKT phosphorylates a series of residues on AS160 [XREF_BIBR, XREF_BIBR, XREF_BIBR], of which Ser318, Ser588, Thr642, and Ser751 phosphorylation are required for insulin induced GLUT4 translocation to the plasma membrane [XREF_BIBR].	28	33	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	30	31	32	33
Munc18c may however only be involved in insulin stimulated GLUT4 trafficking , since GLUT4 trafficking in insulin resistant muscle is impaired while in the same muscles contraction stimulated GLUT4 trafficking remains normal [ XREF_BIBR - XREF_BIBR ] .	Munc18c may however only be involved in insulin stimulated GLUT4 trafficking, since GLUT4 trafficking in insulin resistant muscle is impaired while in the same muscles contraction stimulated GLUT4 trafficking remains normal [XREF_BIBR - XREF_BIBR].	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
The nutrient burden creates a positive mitochondrial membrane potential , which increases mtH 2 O 2 emissions , and chronic exposure to reactive oxygen species has been shown to inhibit insulin mediated GLUT4 translocation .	The nutrient burden creates a positive mitochondrial membrane potential, which increases mtH 2 O 2 emissions, and chronic exposure to reactive oxygen species has been shown to inhibit insulin mediated GLUT4 translocation.	29	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	30	31	32	33
The results from this study indicate that over-expression of TDP-43 can lead to significant weight gain , increased fat deposition , adipocyte hypertrophy , and abnormal insulin mediated Glut4 translocation in skeletal muscle .	The results from this study indicate that over-expression of TDP-43 can lead to significant weight gain, increased fat deposition, adipocyte hypertrophy, and abnormal insulin mediated Glut4 translocation in skeletal muscle.	11	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	26	27	28	29
Using this new procedure , we found that acute in vivo insulin administration ( 30 min ) increased GLUT-4 protein content in the plasma membrane and a T tubule fraction ( by approximately 80 % ) , whereas a smaller elevation ( 35 % ) was observed in another fraction enriched with T tubules .	Using this new procedure, we found that acute in vivo insulin administration (30 min) increased GLUT-4 protein content in the plasma membrane and a T tubule fraction (by approximately 80%), whereas a smaller elevation (35%) was observed in another fraction enriched with T tubules.	11	20	increased	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	11	12	18	19
These findings demonstrate that Munc18c inhibits insulin stimulated externalization of GLUT4 in a wortmannin sensitive manner , and they suggest that disruption of the interaction between syntaxin4 and Munc18c in adipocytes might result in enhancement of insulin stimulated GLUT4 externalization .	These findings demonstrate that Munc18c inhibits insulin stimulated externalization of GLUT4 in a wortmannin sensitive manner, and they suggest that disruption of the interaction between syntaxin4 and Munc18c in adipocytes might result in enhancement of insulin stimulated GLUT4 externalization.	5	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	10	11
Our results together with the finding that CK2 mediates the GLUT4 depletion induced in 3T3-L1 adipocytes by long-term insulin stimulation 40 demonstrate that CK2 is involved in GLUT4 regulation at different levels .	Our results together with the finding that CK2 mediates the GLUT4 depletion induced in 3T3-L1 adipocytes by long-term insulin stimulation 40 demonstrate that CK2 is involved in GLUT4 regulation at different levels.	10	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	10	11
In contrast , expression of other Rho GTPases , such as Cdc42 or Rho , did not affect insulin stimulated P-Rex1-mediated GLUT4 trafficking .	In contrast, expression of other Rho GTPases, such as Cdc42 or Rho, did not affect insulin stimulated P-Rex1-mediated GLUT4 trafficking.	17	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	21	22
VAMP2 was indispensable for T3 to promote insulin induced GLUT4 translocation and glucose uptake in adipocytes .	VAMP2 was indispensable for T3 to promote insulin induced GLUT4 translocation and glucose uptake in adipocytes.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Western blotting with an anti-COOH-terminal GLUT4 protein polyclonal antibody revealed that acute insulin injection in vivo ( 30 min ) increased the content of GLUT4 ( by 90 % ) in isolated PMs and markedly enhanced ( by 180 % ) GLUT4 content in purified TTs .	Western blotting with an anti-COOH-terminal GLUT4 protein polyclonal antibody revealed that acute insulin injection in vivo (30 min) increased the content of GLUT4 (by 90%) in isolated PMs and markedly enhanced (by 180%) GLUT4 content in purified TTs.	12	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	24	25
Although we have found that the activating mutants of Grp1 in the basal ( no insulin ) condition can bypass key small GTPases that regulate the later steps of glut4 recycling ( RalA and Rab10 ) to induce the surface expression of glut4 , we also note that these small GTPases have been shown previously to be required for glut4 recycling stimulated by insulin .	Although we have found that the activating mutants of Grp1 in the basal (no insulin) condition can bypass key small GTPases that regulate the later steps of glut4 recycling (RalA and Rab10) to induce the surface expression of glut4, we also note that these small GTPases have been shown previously to be required for glut4 recycling stimulated by insulin.	59	64	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	glut4	glut4	glut4	63	64	59	60
Insulin stimulates tethering of mobile GLUT4 vesicles to the PM .	Insulin stimulates tethering of mobile GLUT4 vesicles to the PM.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	5	6
Furthermore , skeletal muscle fractionation studies demonstrated a requirement for Doc2b in insulin stimulated GLUT4 accumulation to mediate glucose uptake ; SM-SNARE interactions in muscle fractions were found to be altered by Doc2b deletion .	Furthermore, skeletal muscle fractionation studies demonstrated a requirement for Doc2b in insulin stimulated GLUT4 accumulation to mediate glucose uptake; SM-SNARE interactions in muscle fractions were found to be altered by Doc2b deletion.	6	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Tpms have been identified to play an important role in a range of cellular processes with changes in protein expression , including the regulation of cell transformation 6 , 7 , ERK mediated proliferation 8 , insulin stimulated GLUT4 transport 9 , and anoikis 10 .	Tpms have been identified to play an important role in a range of cellular processes with changes in protein expression, including the regulation of cell transformation 6, 7, ERK mediated proliferation 8, insulin stimulated GLUT4 transport 9, and anoikis 10.	36	39	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	36	37	38	39
Both Akt and aPKC-lambda and zeta have been linked to insulin stimulated GLUT4 translocation and glucose uptake ( XREF_FIG ) [ XREF_BIBR ] .	Both Akt and aPKC-lambda and zeta have been linked to insulin stimulated GLUT4 translocation and glucose uptake (XREF_FIG) [XREF_BIBR].	8	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
In an attempt to identify proteins present in these structures , GLUT4 enriched vesicles prepared from rat adipocytes treated with or without insulin were prepared by sucrose velocity gradient centrifugation and immunoadsorbed with anti-GLUT4 antibody .	In an attempt to identify proteins present in these structures, GLUT4 enriched vesicles prepared from rat adipocytes treated with or without insulin were prepared by sucrose velocity gradient centrifugation and immunoadsorbed with anti-GLUT4 antibody.	11	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	11	12
We report here that Ang II impairs insulin mediated GLUT4 translocation ( XREF_FIG ) and inhibits the phosphorylation of Akt ( XREF_FIG ) which acts as a common upstream activator of most of insulin ' s metabolic actions including glucose uptake .	We report here that Ang II impairs insulin mediated GLUT4 translocation (XREF_FIG) and inhibits the phosphorylation of Akt (XREF_FIG) which acts as a common upstream activator of most of insulin 's metabolic actions including glucose uptake.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Insulin is known to induce LPL synthesis in adipocytes and stimulate LPL , ACC and Glut4 proteins .	Insulin is known to induce LPL synthesis in adipocytes and stimulate LPL, ACC and Glut4 proteins.	0	16	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut4	Glut4	Glut4	0	1	15	16
As proposed in the model presented in Figure XREF_FIG , incorporation of GLUT4 into the membrane is reduced in P1f overexpressing mdx myofibers ( consistent with their defective glucose uptake ) , whereas under normal conditions ( wild-type ) , or in situations where no plectin is encountered at the membrane ( cKO , dKO ; and where glucose uptake is normal ) , insulin stimulated GLUT4 transport towards the membrane can take place along MTs in an undisturbed way .	As proposed in the model presented in Figure XREF_FIG, incorporation of GLUT4 into the membrane is reduced in P1f overexpressing mdx myofibers (consistent with their defective glucose uptake), whereas under normal conditions (wild-type), or in situations where no plectin is encountered at the membrane (cKO, dKO; and where glucose uptake is normal), insulin stimulated GLUT4 transport towards the membrane can take place along MTs in an undisturbed way.	64	67	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	64	65	66	67
The central facilitator in insulin induced glucose transport is GLUT-4 , which is responsible for transporting ~ 80 % of the total glucose content from the bloodstream into skeletal muscle XREF_BIBR XREF_BIBR .	The central facilitator in insulin induced glucose transport is GLUT-4, which is responsible for transporting ~ 80% of the total glucose content from the bloodstream into skeletal muscle XREF_BIBR XREF_BIBR.	2	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	4	5	9	10
Importantly , our data support a model whereby insulin stimulated phosphorylation of one or both of these tyrosine residues is required for normal insulin stimulated GLUT4 exocytosis .	Importantly, our data support a model whereby insulin stimulated phosphorylation of one or both of these tyrosine residues is required for normal insulin stimulated GLUT4 exocytosis.	20	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
Spatiotemporal Regulators for Insulin Stimulated GLUT4 Vesicle Exocytosis .	Spatiotemporal Regulators for Insulin Stimulated GLUT4 Vesicle Exocytosis.	3	7	Stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Some mechanisms by which glycemic control is improved with exercise training include improved contraction mediated glucose uptake by muscle through metabolic demands and increased muscle blood flow , increased GLUT-4 protein content , and increased insulin mediated GLUT-4 intramyocellular translocation .	Some mechanisms by which glycemic control is improved with exercise training include improved contraction mediated glucose uptake by muscle through metabolic demands and increased muscle blood flow, increased GLUT-4 protein content, and increased insulin mediated GLUT-4 intramyocellular translocation.	34	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	35	36	37	38
For example , expression of kinase-dead ATM prevents the insulin stimulated increase of cell surface GLUT4 in L6 myoblasts XREF_BIBR .	For example, expression of kinase-dead ATM prevents the insulin stimulated increase of cell surface GLUT4 in L6 myoblasts XREF_BIBR.	7	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	15	16
RhoQ has been most extensively studied for its central role in insulin stimulated GLUT4 transport in adipocytes .	RhoQ has been most extensively studied for its central role in insulin stimulated GLUT4 transport in adipocytes.	5	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
In the healthy heart , nutrients increase plasma insulin levels triggering myocardial insulin signaling and the presence of both GLUT4 and CD36 at the myocyte sarcolemma , supporting metabolic flexibility .	In the healthy heart, nutrients increase plasma insulin levels triggering myocardial insulin signaling and the presence of both GLUT4 and CD36 at the myocyte sarcolemma, supporting metabolic flexibility.	8	21	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	GLUT4	GLUT4	glut4	8	9	19	20
In adipocytes TNFalpha inhibits insulin induced GLUT4 membrane translocation through IKKbeta mediated inhibitory phosphorylation of IRS1 at S312 .	In adipocytes TNFalpha inhibits insulin induced GLUT4 membrane translocation through IKKbeta mediated inhibitory phosphorylation of IRS1 at S312.	4	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Temporal Regulators of Insulin Stimulated GLUT4 Translocation .	Temporal Regulators of Insulin Stimulated GLUT4 Translocation.	3	6	Stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Plasma membrane GLUT4 protein concentration was greater in the rats treated with insulin compared with no insulin in the perfusate .	Plasma membrane GLUT4 protein concentration was greater in the rats treated with insulin compared with no insulin in the perfusate.	2	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	2	3
Here , we use acute pharmacological Akt inhibition to show that Akt is required for insulin stimulated exocytosis of GLUT4 to the plasma membrane .	Here, we use acute pharmacological Akt inhibition to show that Akt is required for insulin stimulated exocytosis of GLUT4 to the plasma membrane.	13	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	19	20
We have constructed similar mutants of CDP138 as described above but with mCherry fused at their C-terminus , and compared their effect on insulin stimulated GLUT4 trafficking and GSV - PM fusion , as detected with TIRFM in live adipocytes using GLUT4-EGFP and IRAP-pHluorin as the molecular probes , respectively .	We have constructed similar mutants of CDP138 as described above but with mCherry fused at their C-terminus, and compared their effect on insulin stimulated GLUT4 trafficking and GSV - PM fusion, as detected with TIRFM in live adipocytes using GLUT4-EGFP and IRAP-pHluorin as the molecular probes, respectively.	2	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
In this study , we have identified TBC1D13 as a Rab35 GAP and we provide a potential role for these proteins in insulin stimulated GLUT4 trafficking in adipocytes .	In this study, we have identified TBC1D13 as a Rab35 GAP and we provide a potential role for these proteins in insulin stimulated GLUT4 trafficking in adipocytes.	14	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	24	25
In summary , our results show that annexin II is a newly described thiazolidinedione response gene involved in insulin induced GLUT4 translocation in 3T3-L1 adipocytes .	In summary, our results show that annexin II is a newly described thiazolidinedione response gene involved in insulin induced GLUT4 translocation in 3T3-L1 adipocytes.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
The insulin stimulated increase in cell-surface GLUT4 , assessed using the 2-N-4-( 1-azi-2 ,2,2-trifluoroethyl ) benzoyl-1 ,3-bis-[ 2-( 3 ) H ] ( D-mannose-4-yloxy )-2-propylamine exofacial photolabeling technique , was reduced by approximately 70 % in the presence of 20 micromol/l indinavir .	The insulin stimulated increase in cell-surface GLUT4, assessed using the 2-N-4-(1-azi-2,2,2-trifluoroethyl) benzoyl-1,3-bis-[2-(3) H] (D-mannose-4-yloxy)-2-propylamine exofacial photolabeling technique, was reduced by approximately 70% in the presence of 20 micromol/l indinavir.	0	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	6	7
Recently , it has also been shown that a longer peptide ( amino acids 1-532 ) of AS160 could inhibit insulin stimulated GLUT4 vesicle fusion with the plasma membrane invitro [ XREF_BIBR ] .	Recently, it has also been shown that a longer peptide (amino acids 1-532) of AS160 could inhibit insulin stimulated GLUT4 vesicle fusion with the plasma membrane invitro [XREF_BIBR].	19	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Insulin ( 2 units ) and electrical stimulation increased the GLUT4 content in membrane fractions 1 and 2 , whereas they decreased it in LiBr treated membrane ( XREF_FIG C and E , G and I , K and M ) for the wild-type mice , with no change in the sk-NSPl1 content in either fraction ( XREF_FIG O-Q ) .	Insulin (2 units) and electrical stimulation increased the GLUT4 content in membrane fractions 1 and 2, whereas they decreased it in LiBr treated membrane (XREF_FIG C and E, G and I, K and M) for the wild-type mice, with no change in the sk-NSPl1 content in either fraction (XREF_FIG O-Q).	0	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	10	11
Incubation of adipocytes with polymyxin B prevented the insulin induced appearance of Glut 4 in the plasma membranes , but did not prevent their decrease from the low-density microsomal fraction .	Incubation of adipocytes with polymyxin B prevented the insulin induced appearance of Glut 4 in the plasma membranes, but did not prevent their decrease from the low-density microsomal fraction.	7	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut 4	Glut 4	Glut 4	8	9	12	14
On the other hand , total and phosphorylated Cbl was reduced during insulin resistance , suggesting that activation of Cbl and CAP is essential for insulin mediated GLUT4 translocation , in addition to activation of PI3K .	On the other hand, total and phosphorylated Cbl was reduced during insulin resistance, suggesting that activation of Cbl and CAP is essential for insulin mediated GLUT4 translocation, in addition to activation of PI3K.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	27	28
On the other hand , investigations have shown that GLUT4 translocation in skeletal muscle and heart is stimulated by bradykinin [ XREF_BIBR ] , which enhances insulin induced phosphorylation of insulin receptors and insulin stimulated association of IRS-1 and phosphatidylinositol-3-kinase in skeletal muscle of aged rats [ XREF_BIBR ] , all of which are essential for insulin mediated GLUT4 translocation and glucose transport .	On the other hand, investigations have shown that GLUT4 translocation in skeletal muscle and heart is stimulated by bradykinin [XREF_BIBR], which enhances insulin induced phosphorylation of insulin receptors and insulin stimulated association of IRS-1 and phosphatidylinositol-3-kinase in skeletal muscle of aged rats [XREF_BIBR], all of which are essential for insulin mediated GLUT4 translocation and glucose transport.	54	59	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	56	57	58	59
Interestingly , each of the proteins with a known role in GLUT4 trafficking also participates in similar vesicle traffic systems in other tissues XREF_BIBR , XREF_BIBR , XREF_BIBR ; currently no adipose tissue specific protein link exists between the specific insulin mediated function of GLUT4 and the ubiquitous trafficking machinery it exploits XREF_BIBR .	Interestingly, each of the proteins with a known role in GLUT4 trafficking also participates in similar vesicle traffic systems in other tissues XREF_BIBR, XREF_BIBR, XREF_BIBR; currently no adipose tissue specific protein link exists between the specific insulin mediated function of GLUT4 and the ubiquitous trafficking machinery it exploits XREF_BIBR.	36	45	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	40	41	44	45
As we know , insulin can cause a time dependent increase in GLUT4-EGFP fluorescence in the evanescent field .	As we know, insulin can cause a time dependent increase in GLUT4-EGFP fluorescence in the evanescent field.	4	13	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4-EGFP	GLUT4-EGFP	GLUT4-EGFP	4	5	12	13
In adipocytes a mode of GLUT4 exocytosis has been proposed to occur whereby in the basal state GLUT4 is retained in clusters in PM regions , while insulin stimulation increased the prevalence of these clusters but also elicited dispersal of GLUT4 molecules into the PM .	In adipocytes a mode of GLUT4 exocytosis has been proposed to occur whereby in the basal state GLUT4 is retained in clusters in PM regions, while insulin stimulation increased the prevalence of these clusters but also elicited dispersal of GLUT4 molecules into the PM.	27	41	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	27	28	40	41
Insulin increases GLUT4 at the muscle cell surface , and this process requires actin remodeling .	Insulin increases GLUT4 at the muscle cell surface, and this process requires actin remodeling.	0	3	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Interestingly , APPL1 interacts with Akt2 in unstimulated adipocytes , and down-regulation of APPL1 in adipocytes impairs insulin induced GLUT4 translocation and glucose transport , indicating that APPL1 might facilitate Akt2 signaling to GLUT4 XREF_BIBR .	Interestingly, APPL1 interacts with Akt2 in unstimulated adipocytes, and down-regulation of APPL1 in adipocytes impairs insulin induced GLUT4 translocation and glucose transport, indicating that APPL1 might facilitate Akt2 signaling to GLUT4 XREF_BIBR.	16	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
In summary , our results show that expression of SHIP inhibits insulin induced GLUT4 translocation , growth factor induced membrane ruffling , and DNA synthesis , indicating that PtdIns 3,4,5-P3 is the key phospholipid product mediating these biological actions .	In summary, our results show that expression of SHIP inhibits insulin induced GLUT4 translocation, growth factor induced membrane ruffling, and DNA synthesis, indicating that PtdIns 3,4,5-P3 is the key phospholipid product mediating these biological actions.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Insulin stimulates glucose uptake by recruiting glucose transporter 4 ( GLUT4 ) from an intracellular compartment to the cell surface ; this phenomenon is defective in type 2 diabetes .	Insulin stimulates glucose uptake by recruiting glucose transporter 4 (GLUT4) from an intracellular compartment to the cell surface; this phenomenon is defective in type 2 diabetes.	0	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	10	11
14-3-3 proteins can potentially interact with phosphorylated AS160 , and we have therefore examined whether quenching of 14-3-3 interaction can influence insulin stimulated GLUT4 vesicle fusion with the plasma membrane target .	14-3-3 proteins can potentially interact with phosphorylated AS160, and we have therefore examined whether quenching of 14-3-3 interaction can influence insulin stimulated GLUT4 vesicle fusion with the plasma membrane target.	20	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
Experiments in adipocyte and muscle cell culture systems have provided clear evidence for a role of the actin cytoskeleton in insulin stimulated GLUT4 trafficking and glucose uptake 1 , 2 , 3 , 4 , 17 , 43 , 44 , 45 , 46 , 47 , 48 .	Experiments in adipocyte and muscle cell culture systems have provided clear evidence for a role of the actin cytoskeleton in insulin stimulated GLUT4 trafficking and glucose uptake 1, 2, 3, 4, 17, 43, 44, 45, 46, 47, 48.	9	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Insulin increases the recycling of GLUT4 , resulting in a net translocation to the surface .	Insulin increases the recycling of GLUT4, resulting in a net translocation to the surface.	0	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	5	6
Insulin induces the redistribution of GLUT4 from intracellular compartments to the plasma membrane , by stimulating a large increase in exocytosis and a smaller inhibition of endocytosis .	Insulin induces the redistribution of GLUT4 from intracellular compartments to the plasma membrane, by stimulating a large increase in exocytosis and a smaller inhibition of endocytosis.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	5	6
We provided the first evidence to document the spatial-temporal kinetics of insulin induced GLUT4 trafficking steps in mature muscle : the GLUT4 vesicle recruitment and depletion , -membrane appearance , -recycling , and re-internalization .	We provided the first evidence to document the spatial-temporal kinetics of insulin induced GLUT4 trafficking steps in mature muscle : the GLUT4 vesicle recruitment and depletion, -membrane appearance, -recycling, and re-internalization.	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Insulin stimulated GLUT4 trafficking .	Insulin stimulated GLUT4 trafficking.	0	3	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
SEC16A and RAB10 function in insulin stimulated mobilization of GLUT4 from this compartment , consistent with the RAB10-SEC16A module promoting the formation of GSVs that ferry GLUT4 to the PM .	SEC16A and RAB10 function in insulin stimulated mobilization of GLUT4 from this compartment, consistent with the RAB10-SEC16A module promoting the formation of GSVs that ferry GLUT4 to the PM.	3	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	9	10
Thus , the time resolution used to study insulin stimulated GLUT4-EGFP trafficking has primarily been imaging every 15 sec although higher resolution ( sampling every 1-2 sec ) has been used without adding additional information .	Thus, the time resolution used to study insulin stimulated GLUT4-EGFP trafficking has primarily been imaging every 15 sec although higher resolution (sampling every 1-2 sec) has been used without adding additional information.	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4-EGFP	GLUT4-EGFP	GLUT4-EGFP	8	9	10	11
Activation of PI3K leads to the activation of the Akt serine/threonine protein kinase , a crucial regulator of insulin stimulated Glut4 trafficking .	Activation of PI3K leads to the activation of the Akt serine/threonine protein kinase, a crucial regulator of insulin stimulated Glut4 trafficking.	16	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	18	19	20	21
Stimulation of GLUT4 by insulin results in its translocation to the plasma membrane , activation of several kinases , and finally in a large glucose influx into cells .	Stimulation of GLUT4 by insulin results in its translocation to the plasma membrane, activation of several kinases, and finally in a large glucose influx into cells.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	2	3
Together , these studies strongly suggest the lipid rafts play an important role in the process of insulin stimulated GLUT4 vesicle exocytosis at the plasma membrane .	Together, these studies strongly suggest the lipid rafts play an important role in the process of insulin stimulated GLUT4 vesicle exocytosis at the plasma membrane.	15	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
These studies demonstrate that Rab10 is an essential component of the machinery responsible for insulin stimulation of GLUT4 trafficking to the plasma membrane of primary adipocytes .	These studies demonstrate that Rab10 is an essential component of the machinery responsible for insulin stimulation of GLUT4 trafficking to the plasma membrane of primary adipocytes.	14	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	17	18
What is not known is whether MyoIIA interacts with F-actin to regulate insulin induced GLUT4 fusion at the plasma membrane .	What is not known is whether MyoIIA interacts with F-actin to regulate insulin induced GLUT4 fusion at the plasma membrane.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Here we show that , when myc tagged GLUT4 was retrovirally expressed in 3T3-C2 cells , insulin stimulated GLUT4 translocation did occur on day 2 after the induction .	Here we show that, when myc tagged GLUT4 was retrovirally expressed in 3T3-C2 cells, insulin stimulated GLUT4 translocation did occur on day 2 after the induction.	16	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
In contrast , down-regulation of a different motor protein also implicated in insulin stimulated GLUT4 translocation , MyoIIA , caused a significant decrease in the percentage of cells with insulin induced cytosolic dispersion of GLUT4myc-GFP ( basal 14 +/- 10 % , insulin 36 +/- 11 % , p < 0.05 ; XREF_FIG ) .	In contrast, down-regulation of a different motor protein also implicated in insulin stimulated GLUT4 translocation, MyoIIA, caused a significant decrease in the percentage of cells with insulin induced cytosolic dispersion of GLUT4myc-GFP (basal 14 +/- 10%, insulin 36 +/- 11%, p < 0.05; XREF_FIG).	10	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Furthermore , RAB10 has been indicated as a critical transport molecule in insulin stimulated GLUT4 mediated recycling of adipocytes and basolateral recycling of MDCK cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Furthermore, RAB10 has been indicated as a critical transport molecule in insulin stimulated GLUT4 mediated recycling of adipocytes and basolateral recycling of MDCK cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	10	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Insulin stimulation led to a clear shift in the GLUT4-myc7-PE signal , but no BMP effect on control ( basal ) or insulin stimulated GLUT4 translocation was measured .	Insulin stimulation led to a clear shift in the GLUT4-myc7-PE signal, but no BMP effect on control (basal) or insulin stimulated GLUT4 translocation was measured.	15	25	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	24	25
Intriguingly , we found that , although insulin alone failed to release static GLUT4 as noted earlier ( XREF_FIG ) , insulin did trigger GLUT4 liberation when Tbc1d1 expressing cells had been treated previously with AICAR ( XREF_FIG ) .	Intriguingly, we found that, although insulin alone failed to release static GLUT4 as noted earlier (XREF_FIG), insulin did trigger GLUT4 liberation when Tbc1d1 expressing cells had been treated previously with AICAR (XREF_FIG).	21	25	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	24	25
We measured , daily ( on days 1-7 ) and/or weekly ( for 6 weeks ) , the diet induced changes in circulating substrates , insulin , sarcolemmal substrate transporters and transport , selected enzymes , intramyocellular lipids , mitochondrial fatty acid oxidation and basal and insulin stimulated sarcolemmal GLUT4 and glucose transport .	We measured, daily (on days 1-7) and/or weekly (for 6 weeks), the diet induced changes in circulating substrates, insulin, sarcolemmal substrate transporters and transport, selected enzymes, intramyocellular lipids, mitochondrial fatty acid oxidation and basal and insulin stimulated sarcolemmal GLUT4 and glucose transport.	46	52	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	46	47	49	50
Together these results establish Tmod3 as a novel Akt2 effector that mediates insulin induced cortical actin remodelling and subsequent GLUT4 membrane insertion .	Together these results establish Tmod3 as a novel Akt2 effector that mediates insulin induced cortical actin remodelling and subsequent GLUT4 membrane insertion.	11	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	19	20
Insulin primarily enhances the rate of GLUT4 exocytosis towards and fusion with the PM , a process termed GLUT4 translocation that results in a gain in PM GLUT4 [ XREF_BIBR ] .	Insulin primarily enhances the rate of GLUT4 exocytosis towards and fusion with the PM, a process termed GLUT4 translocation that results in a gain in PM GLUT4 [XREF_BIBR].	0	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Interestingly , knockdown of alpha-actinin-4 but not alpha-actinin-1 impaired insulin induced GLUT4 translocation [ XREF_BIBR ] .	Interestingly, knockdown of alpha-actinin-4 but not alpha-actinin-1 impaired insulin induced GLUT4 translocation [XREF_BIBR].	2	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Adipocytes derived from MEFs from Munc18c knockout mice show enhanced GLUT4 translocation , suggesting that Munc18c inhibits insulin stimulated externalization of GLUT4 .	Adipocytes derived from MEFs from Munc18c knockout mice show enhanced GLUT4 translocation, suggesting that Munc18c inhibits insulin stimulated externalization of GLUT4.	16	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	21	22
In control cells , insulin induced significant GLUT4 presence at the cell surface , while silencing of Tmod3 reduced the GLUT4 presence ( XREF_FIG ) .	In control cells, insulin induced significant GLUT4 presence at the cell surface, while silencing of Tmod3 reduced the GLUT4 presence (XREF_FIG).	4	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	7	8
Therefore , we hypothesize that the primary driver of increased SUV in GRMD skeletal muscle was due to insulin stimulated GLUT-4 uptake of [ 18 F ] DG .	Therefore, we hypothesize that the primary driver of increased SUV in GRMD skeletal muscle was due to insulin stimulated GLUT-4 uptake of [18 F] DG.	16	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	18	19	20	21
Tropomodulin3 is a novel Akt2 effector regulating insulin stimulated GLUT4 exocytosis through cortical actin remodelling .	Tropomodulin3 is a novel Akt2 effector regulating insulin stimulated GLUT4 exocytosis through cortical actin remodelling.	6	10	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
The reduction in glycogen concentration was associated with decreased expressions of the insulin stimulated GS and GLUT4 in hepatic and skeletal muscle tissues , respectively ( XREF_FIG ) .	The reduction in glycogen concentration was associated with decreased expressions of the insulin stimulated GS and GLUT4 in hepatic and skeletal muscle tissues, respectively (XREF_FIG).	9	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	expressions of the insulin	insulin	GLUT4	GLUT4	glut4	12	13	16	17
Under ND , insulin induced GLUT4 translocation was the same in both control and p38alpha Fab-KO mice .	Under ND, insulin induced GLUT4 translocation was the same in both control and p38alpha Fab-KO mice.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
High levels of Glut4 increase insulin responsiveness .	High levels of Glut4 increase insulin responsiveness.	3	6	increase	Positive_activation_token_1_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	5	6	3	4
Unlike the islet beta cell , which expresses and utilizes multiple Munc18-syntaxin complexes for multiple phases of insulin release , 3T3-L1 adipocytes use only the Munc18c-syntaxin 4 pair for the monophasic process of insulin stimulated GLUT4 vesicle exocytosis .	Unlike the islet beta cell, which expresses and utilizes multiple Munc18-syntaxin complexes for multiple phases of insulin release, 3T3-L1 adipocytes use only the Munc18c-syntaxin 4 pair for the monophasic process of insulin stimulated GLUT4 vesicle exocytosis.	31	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	33	34	35	36
At 5 min after treatment of adipocytes with insulin , a significant decrease was observed in associations of cellugyrin with both GLUT4 and VAMP2 , with concomitant increases between sortilin and GLUT4 or VAMP2 ( XREF_FIG ) , consistent with the notion that acute insulin treatment stimulates GLUT4 traffic from cellugyrin- to sortilin positive vesicles .	At 5 min after treatment of adipocytes with insulin, a significant decrease was observed in associations of cellugyrin with both GLUT4 and VAMP2, with concomitant increases between sortilin and GLUT4 or VAMP2 (XREF_FIG), consistent with the notion that acute insulin treatment stimulates GLUT4 traffic from cellugyrin- to sortilin positive vesicles.	44	48	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	44	45	47	48
Pre-incubation of 3T3-L1 adipocytes with 10muM BFA for 20min partially inhibited insulin stimulated GLUT4 translocation ( XREF_FIG A ) .	Pre-incubation of 3T3-L1 adipocytes with 10muM BFA for 20min partially inhibited insulin stimulated GLUT4 translocation (XREF_FIG A).	10	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
The adipose tissue from MG treated rats showed significantly reduced insulin stimulated glucose uptake , reduced plasma membrane GLUT4 protein , unchanged IR and IRS-1 protein , and reduced phosphorylation of IRS-1 and PI3K activity .	The adipose tissue from MG treated rats showed significantly reduced insulin stimulated glucose uptake, reduced plasma membrane GLUT4 protein, unchanged IR and IRS-1 protein, and reduced phosphorylation of IRS-1 and PI3K activity.	7	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	18	19
This effect is mediated by reversal of severe impairment of insulin induced GLUT4 translocation to the cell surface .	This effect is mediated by reversal of severe impairment of insulin induced GLUT4 translocation to the cell surface.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Over the past few years , and increasing number of laboratories have produced compelling data to demonstrate a role for both the actin and microtubule networks in the regulation of insulin mediated GLUT4 redistribution to the cell surface .	Over the past few years, and increasing number of laboratories have produced compelling data to demonstrate a role for both the actin and microtubule networks in the regulation of insulin mediated GLUT4 redistribution to the cell surface.	28	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	30	31	32	33
GLUT4 cycles to and from the plasma membrane and its exocytic rate is accelerated by insulin and muscle contraction to achieve a new steady state with more GLUT4 proteins at the muscle cell surface .	GLUT4 cycles to and from the plasma membrane and its exocytic rate is accelerated by insulin and muscle contraction to achieve a new steady state with more GLUT4 proteins at the muscle cell surface.	0	18	accelerated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	0	1
As expected , insulin elevated surface GLUT4 content and glucose uptake .	As expected, insulin elevated surface GLUT4 content and glucose uptake.	3	7	elevated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	6	7
As shown in XREF_FIG , PIP5K1alpha knockdown significantly suppressed insulin induced GLUT4 translocation to PM .	As shown in XREF_FIG, PIP5K1alpha knockdown significantly suppressed insulin induced GLUT4 translocation to PM.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Moreover , reduced insulin induced GLUT4 translocation [ XREF_BIBR ] and/or total content was also showed before [ XREF_BIBR ] .	Moreover, reduced insulin induced GLUT4 translocation [XREF_BIBR] and/or total content was also showed before [XREF_BIBR].	3	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
In this context , Tankyrase acts as a positive regulator of insulin mediated GLUT4 translocation from cytosolic vesicles to the cell surface to mediate glucose uptake [ XREF_BIBR ] .	In this context, Tankyrase acts as a positive regulator of insulin mediated GLUT4 translocation from cytosolic vesicles to the cell surface to mediate glucose uptake [XREF_BIBR].	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Treatment of cells with 10 microM nocodazole for 20 min , which results in large-scale depolymerization of the microtubule cytoskeleton ( data not shown ) , reduced the insulin stimulated increase in HA-GLUT4-eGFP intensity from 1.8-fold in the absence of nocodazole to 1.6-fold at 10 microM nocodazole ( XREF_FIG , XREF_TABLE ) .	Treatment of cells with 10 microM nocodazole for 20 min, which results in large-scale depolymerization of the microtubule cytoskeleton (data not shown), reduced the insulin stimulated increase in HA-GLUT4-eGFP intensity from 1.8-fold in the absence of nocodazole to 1.6-fold at 10 microM nocodazole (XREF_FIG, XREF_TABLE).	26	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	HA-GLUT4-eGFP	HA-GLUT4-eGFP	HA-GLUT4-eGFP	28	29	32	33
It was reported that TNKS1 enhanced insulin stimulated exocytosis of GLUT4 24 .	It was reported that TNKS1 enhanced insulin stimulated exocytosis of GLUT4 24.	5	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	10	11
Indeed , the previous work has shown that the exocytic sites of insulin stimulated GLUT4 vesicle exocytosis are spatially clustered on the plasma membrane , which are disrupted and become randomized after Sec8 knockdown [ XREF_BIBR ] .	Indeed, the previous work has shown that the exocytic sites of insulin stimulated GLUT4 vesicle exocytosis are spatially clustered on the plasma membrane, which are disrupted and become randomized after Sec8 knockdown [XREF_BIBR].	10	16	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Our findings indicate that naringenin inhibits the activity of phosphoinositide 3-kinase ( PI3K ) , a key regulator of insulin induced GLUT4 translocation , as shown by impaired phosphorylation of the downstream signaling molecule Akt .	Our findings indicate that naringenin inhibits the activity of phosphoinositide 3-kinase (PI3K), a key regulator of insulin induced GLUT4 translocation, as shown by impaired phosphorylation of the downstream signaling molecule Akt.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
Insulin alone increased PM Glut4 by 3-fold concomitant with a 56 % decrease in LDM .	Insulin alone increased PM Glut4 by 3-fold concomitant with a 56% decrease in LDM.	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut4	Glut4	Glut4	0	1	4	5
Insulin stimulates dissociation of GLUT4 from TUG , both in 3T3-L1 adipocytes and in muscle [ XREF_BIBR , XREF_BIBR ] .	Insulin stimulates dissociation of GLUT4 from TUG, both in 3T3-L1 adipocytes and in muscle [XREF_BIBR, XREF_BIBR].	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	4	5
This result indicates that , at least for 2.5 hours , the insulin mediated traffic of GLUT4 storage vesicles was unaffected by AGEs , reinforcing the important role of Slc2a4 and GLUT4 repressed expression .	This result indicates that, at least for 2.5 hours, the insulin mediated traffic of GLUT4 storage vesicles was unaffected by AGEs, reinforcing the important role of Slc2a4 and GLUT4 repressed expression.	11	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Slc2a4	Slc2a4	Slc2a4	12	13	29	30
These data are consistent with the hypothesis that DOC2b regulates insulin stimulated GLUT4 vesicle fusion .	These data are consistent with the hypothesis that DOC2b regulates insulin stimulated GLUT4 vesicle fusion.	9	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Preincubation of L6 myotubes with Ang II ( 10 nM ) for 30 min prior to stimulation completely abolished insulin mediated GLUT4 translocation , which decreased below control levels ( P < 0.05 ) .	Preincubation of L6 myotubes with Ang II (10 nM) for 30 min prior to stimulation completely abolished insulin mediated GLUT4 translocation, which decreased below control levels (P < 0.05).	18	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
In addition , we demonstrated that FXR does not interfere with insulin induced GLUT4 translocation to plasma membrane .	In addition, we demonstrated that FXR does not interfere with insulin induced GLUT4 translocation to plasma membrane.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Several studies showed that oxidative stress impairs insulin induced GLUT4 translocation .	Several studies showed that oxidative stress impairs insulin induced GLUT4 translocation.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
These observations indicate that PI 3-kinase is necessary for insulin induced GLUT4 translocation and glucose transport in adipocytes .	These observations indicate that PI 3-kinase is necessary for insulin induced GLUT4 translocation and glucose transport in adipocytes.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Insulin stimulates the halting , tethering , and fusion of mobile GLUT4 vesicles in rat adipose cells .	Insulin stimulates the halting, tethering, and fusion of mobile GLUT4 vesicles in rat adipose cells.	0	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	11	12
Knockdown of VAMP2 using siRNA abrogated the effects of T3 on insulin induced GLUT4 translocation and glucose uptake , suggesting that VAMP2 is an important mediator of these processes .	Knockdown of VAMP2 using siRNA abrogated the effects of T3 on insulin induced GLUT4 translocation and glucose uptake, suggesting that VAMP2 is an important mediator of these processes.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Insulin and Contraction induced GLUT4 Traffic in Muscle : Insights from a Novel Imaging Approach .	Insulin and Contraction induced GLUT4 Traffic in Muscle : Insights from a Novel Imaging Approach.	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	4	5
Interestingly , insulin has been reported to not only increase the frequency of fusion events , but also to stimulate the docking and tethering of GLUT4 vesicles to the plasma membrane , resulting in an accumulation of GLUT4 vesicles in and around the cell surface .	Interestingly, insulin has been reported to not only increase the frequency of fusion events, but also to stimulate the docking and tethering of GLUT4 vesicles to the plasma membrane, resulting in an accumulation of GLUT4 vesicles in and around the cell surface.	2	26	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	25	26
Insulin increases the cell surface abundance of GLUT3 and GLUT4 in resting monocytes and Blymphocytes ; in contrast , T-lymphocytes and PMLs are unresponsive to insulin .	Insulin increases the cell surface abundance of GLUT3 and GLUT4 in resting monocytes and Blymphocytes; in contrast, T-lymphocytes and PMLs are unresponsive to insulin.	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	9	10
Mutation of this sequence reduced the insulin induced exposure of GLUT4 at the cell surface of 3T3-L1 adipocytes by affecting fusion of the GLUT4 containing vesicles with the plasma membrane .	Mutation of this sequence reduced the insulin induced exposure of GLUT4 at the cell surface of 3T3-L1 adipocytes by affecting fusion of the GLUT4 containing vesicles with the plasma membrane.	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	10	11
AS160 Phosphotyrosine binding Domain Constructs Inhibit Insulin stimulated GLUT4 Vesicle Fusion with the Plasma Membrane * .	AS160 Phosphotyrosine binding Domain Constructs Inhibit Insulin stimulated GLUT4 Vesicle Fusion with the Plasma Membrane *.	6	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
An absolute requirement for an insulin stimulated increase in GLUT4 mobilization along microtubules has been challenged by experiments showing that expression of constitutively active Akt , a serine/threonine protein kinase , is sufficient even in the absence of an intact microtubule cytoskeleton to redistribute GLUT4 in response to insulin XREF_BIBR .	An absolute requirement for an insulin stimulated increase in GLUT4 mobilization along microtubules has been challenged by experiments showing that expression of constitutively active Akt, a serine/threonine protein kinase, is sufficient even in the absence of an intact microtubule cytoskeleton to redistribute GLUT4 in response to insulin XREF_BIBR.	2	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	9	10
On the other hand , in NSPl1-deficent skeletal muscle , although insulin also increased GLUT4 near the sarcolemma ( XREF_FIG C vs. E ) , distribution of GLUT4 was almost unchanged by electrical stimulation ( XREF_FIG C vs. G ) .	On the other hand, in NSPl1-deficent skeletal muscle, although insulin also increased GLUT4 near the sarcolemma (XREF_FIG C vs. E), distribution of GLUT4 was almost unchanged by electrical stimulation (XREF_FIG C vs. G).	11	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	14	15
In adipocytes , insulin triggers the redistribution of Glut4 from intracellular compartments to the plasma membrane .	In adipocytes, insulin triggers the redistribution of Glut4 from intracellular compartments to the plasma membrane.	3	9	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	3	4	8	9
Munc18c phosphorylation at Tyr219 and Tyr521 is required for insulin stimulated GLUT4 vesicle docking and fusion .	Munc18c phosphorylation at Tyr219 and Tyr521 is required for insulin stimulated GLUT4 vesicle docking and fusion.	7	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
The addition of insulin also induced the appearance of GLUT4 at the plasma membrane and tethering ( one such vesicle fusion event is shown in XREF_FIG , white circles in panels 1-7 ) , followed by fusion with the membrane , indicated by decreased fluorescence ( XREF_FIG , white circles in panels , 8-10 ) .	The addition of insulin also induced the appearance of GLUT4 at the plasma membrane and tethering (one such vesicle fusion event is shown in XREF_FIG, white circles in panels 1-7), followed by fusion with the membrane, indicated by decreased fluorescence (XREF_FIG, white circles in panels, 8-10).	1	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	9	10
Our analysis revealed that insulin modulates GLUT4 trafficking at multiple steps , including not only the endocytotic and exocytotic rates , but also the two rate coefficients coupling the three intracellular compartments .	Our analysis revealed that insulin modulates GLUT4 trafficking at multiple steps, including not only the endocytotic and exocytotic rates, but also the two rate coefficients coupling the three intracellular compartments.	4	7	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Together , these data indicate that insulin stimulation increases the population of GLUT4 being released from the immobilized state .	Together, these data indicate that insulin stimulation increases the population of GLUT4 being released from the immobilized state.	6	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	12	13
We conclude that in adipocytes , rosiglitazone increases cell surface GLUT4 levels by increasing its endosomal recycling and restores insulin induced GLUT4 translocation in insulin resistance .	We conclude that in adipocytes, rosiglitazone increases cell surface GLUT4 levels by increasing its endosomal recycling and restores insulin induced GLUT4 translocation in insulin resistance.	18	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
Insulin infusion lead to reduction in expression of GLUT4 ( p < 0.001 ) ( XREF_FIG ) in controls , while significant increase occurred in LBW men ( p < 0.05 ) .	Insulin infusion lead to reduction in expression of GLUT4 (p < 0.001) (XREF_FIG) in controls, while significant increase occurred in LBW men (p < 0.05).	0	15	lead	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	8	9
Insulin stimulates the surface accumulation of GLUT4 with a half time of 2-5 minutes , which reaches a plateau after 12 minutes [ XREF_BIBR ] .	Insulin stimulates the surface accumulation of GLUT4 with a half time of 2-5 minutes, which reaches a plateau after 12 minutes [XREF_BIBR].	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Insulin stimulation induces the release of GLUT4 via exocytosis , and cellular GLUT4 content becomes exposed at the cell surface XREF_BIBR , XREF_BIBR , XREF_BIBR .	Insulin stimulation induces the release of GLUT4 via exocytosis, and cellular GLUT4 content becomes exposed at the cell surface XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
In addition , GLUT4 translocation was also suppressed in cells overexpressing GKAP42-N ( the IRS-1 binding region of GKAP42 ) , which competed with GKAP42 for IRS-1 , indicating that GKAP42 binding to IRS-1 is required for insulin induced GLUT4 translocation .	In addition, GLUT4 translocation was also suppressed in cells overexpressing GKAP42-N (the IRS-1 binding region of GKAP42), which competed with GKAP42 for IRS-1, indicating that GKAP42 binding to IRS-1 is required for insulin induced GLUT4 translocation.	37	40	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	37	38	39	40
Furthermore , it has been shown that insulin stimulated GLUT4 storage vesicle exocytosis is regulated by exocyst complex function and involves the Ser/Thr kinase AKT .	Furthermore, it has been shown that insulin stimulated GLUT4 storage vesicle exocytosis is regulated by exocyst complex function and involves the Ser/Thr kinase AKT.	7	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Cardiomyocytes contain multiple types of SNARE proteins [ XREF_BIBR ] , which include the vSNARE vesicle associated membrane protein-2 ( VAMP2 ) , the tSNAREs soluble NSF-attachment protein-23 ( SNAP23 ) , and syntaxin4 , which each were found to be involved in insulin induced GLUT4 translocation in adipocytes and skeletal muscle [ XREF_BIBR ] .	Cardiomyocytes contain multiple types of SNARE proteins [XREF_BIBR], which include the vSNARE vesicle associated membrane protein-2 (VAMP2), the tSNAREs soluble NSF-attachment protein-23 (SNAP23), and syntaxin4, which each were found to be involved in insulin induced GLUT4 translocation in adipocytes and skeletal muscle [XREF_BIBR].	41	46	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	43	44	45	46
Consistent with these findings , we found that in neuronal cell culture , insulin increases glucose utilization in a GluT4 dependent manner .	Consistent with these findings, we found that in neuronal cell culture, insulin increases glucose utilization in a GluT4 dependent manner.	13	21	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GluT4	GluT4	GluT4	13	14	19	20
In support of this model , XREF_BIBR showed that VAMP2 , 3 , or 8 could each separately restore insulin stimulated GLUT4 translocation in cells devoid of endogenous VAMP2 , 3 , or 8 .	In support of this model, XREF_BIBR showed that VAMP2, 3, or 8 could each separately restore insulin stimulated GLUT4 translocation in cells devoid of endogenous VAMP2, 3, or 8.	18	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
Using the above mentioned novel capabilities , we revealed that insulin stimulation significantly increases numbers of GLUT4 containing vesicles approaching the plasma membrane that display different dwelling characteristics even at the very early time point of their visiting events ( XREF_FIG ) .	Using the above mentioned novel capabilities, we revealed that insulin stimulation significantly increases numbers of GLUT4 containing vesicles approaching the plasma membrane that display different dwelling characteristics even at the very early time point of their visiting events (XREF_FIG).	10	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	16	17
38 Consequently , the regulation of neuronal metabolism and the generation of energy needed for cognition and memory are linked to insulin stimulation of GLUT4 .	38 Consequently, the regulation of neuronal metabolism and the generation of energy needed for cognition and memory are linked to insulin stimulation of GLUT4.	21	25	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	24	25
Here , we tested the response to insulin mediated GLUT4 uptake of glucose .	Here, we tested the response to insulin mediated GLUT4 uptake of glucose.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Namely , the PI3K -- Akt and PKB insulin signaling pathway mediates insulin induced GLUT4 translocation as well as insulin induced CD36 translocation in cardiomyocytes .	Namely, the PI3K -- Akt and PKB insulin signaling pathway mediates insulin induced GLUT4 translocation as well as insulin induced CD36 translocation in cardiomyocytes.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Subcellular fractionation and immunoblotting analysis of GLUT4 distribution indicated that both contraction and insulin induced an identical increase ( 8-9-fold ) of GLUT4 in the plasma membrane with a concomitant decrease ( one third ) in the microsomal fraction .	Subcellular fractionation and immunoblotting analysis of GLUT4 distribution indicated that both contraction and insulin induced an identical increase (8-9-fold) of GLUT4 in the plasma membrane with a concomitant decrease (one third) in the microsomal fraction.	11	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	22	23
These results demonstrate that E4-ORF1 enhances insulin stimulated Glut4 trafficking to the PM without affecting general endocytic trafficking .	These results demonstrate that E4-ORF1 enhances insulin stimulated Glut4 trafficking to the PM without affecting general endocytic trafficking.	5	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	6	7	8	9
Together , these data demonstrate that insulin stimulation of GLUT4 translocation requires at least two independent signal transduction pathways , one mediated through the phosphatidylinositol 3-kinase and another through the trimeric GTP binding proteins G ( q ) and/or G ( 11 ) .	Together, these data demonstrate that insulin stimulation of GLUT4 translocation requires at least two independent signal transduction pathways, one mediated through the phosphatidylinositol 3-kinase and another through the trimeric GTP binding proteins G (q) and/or G (11).	6	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	9	10
Although it is well established that the proximal signalling mechanisms that lead to exercise- and insulin stimulated GLUT4 translocation are distinct , there is now extensive evidence that there is a convergence of exercise and insulin signalling at TBC1D1 ( tre-2 and USP6 , BUB2 , cdc16 domain family member 1 ) and AS160 ( Akt substrate of 160kDa ; also known as TBC1D4 ) .	Although it is well established that the proximal signalling mechanisms that lead to exercise- and insulin stimulated GLUT4 translocation are distinct, there is now extensive evidence that there is a convergence of exercise and insulin signalling at TBC1D1 (tre-2 and USP6, BUB2, cdc16 domain family member 1) and AS160 (Akt substrate of 160kDa; also known as TBC1D4).	11	18	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
One argument indicates that ceramides blunt insulin signaling by impairing activation of Akt and PKB , a central mediator of insulin mediated GLUT4 translocation and other anabolic effects .	One argument indicates that ceramides blunt insulin signaling by impairing activation of Akt and PKB, a central mediator of insulin mediated GLUT4 translocation and other anabolic effects.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Because insulin induced GLUT4 translocation is an important event , we next examined the effects of knockdown of DGKzeta on insulin dependent GLUT4 translocation and signaling activation in 3T3-L1 adipocytes .	Because insulin induced GLUT4 translocation is an important event, we next examined the effects of knockdown of DGKzeta on insulin dependent GLUT4 translocation and signaling activation in 3T3-L1 adipocytes.	1	4	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	3	4
In addition , some studies report a dramatic decrease in insulin stimulated GLUT4 redistribution to the cell surface following microtubule disruption XREF_BIBR , XREF_BIBR .	In addition, some studies report a dramatic decrease in insulin stimulated GLUT4 redistribution to the cell surface following microtubule disruption XREF_BIBR, XREF_BIBR.	8	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Transient H 2 O 2 increases insulin induced GLUT4 translocation and glucose uptake in 3T3-L1 adipocytes .	Transient H 2 O 2 increases insulin induced GLUT4 translocation and glucose uptake in 3T3-L1 adipocytes.	0	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Treatment of insulin stimulated 3T3-L1 adipocytes with the PI 3-kinase inhibitor LY294002 causes the accumulation of GLUT4 containing vesicles just beneath the cell surface .	Treatment of insulin stimulated 3T3-L1 adipocytes with the PI 3-kinase inhibitor LY294002 causes the accumulation of GLUT4 containing vesicles just beneath the cell surface.	0	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	16	17
In the present study , we examined the possible interaction between Rab4 and syntaxin 4 , both having been implicated in insulin induced GLUT4 translocation .	In the present study, we examined the possible interaction between Rab4 and syntaxin 4, both having been implicated in insulin induced GLUT4 translocation.	19	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
In skeletal muscle , cross-sectional analyses show the colocalization of filamin A with phosphoinositidylinositol 3,4,5 trisphosphate ( PtdIns [ 3,4,5 ] P 3 ) 5-phosphatase ( SHIP-2 ) in the membrane ruffles , and these are considered to be the sites of insulin induced GLUT4 translocation .	In skeletal muscle, cross-sectional analyses show the colocalization of filamin A with phosphoinositidylinositol 3,4,5 trisphosphate (PtdIns [3,4,5] P 3) 5-phosphatase (SHIP-2) in the membrane ruffles, and these are considered to be the sites of insulin induced GLUT4 translocation.	40	45	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	42	43	44	45
Transfection of skeletal myotubes with dominant negative mutant PKCdelta did not alter basal glucose uptake but blocked insulin induced GLUT4 translocation and glucose transport .	Transfection of skeletal myotubes with dominant negative mutant PKCdelta did not alter basal glucose uptake but blocked insulin induced GLUT4 translocation and glucose transport.	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
We now report in cultured cells , made insulin resistant HIV by PI treatment , that TLK19781 both increased the content of insulin stimulated GLUT4 at the plasma membrane , and enhanced insulin stimulated glucose transport .	We now report in cultured cells, made insulin resistant HIV by PI treatment, that TLK19781 both increased the content of insulin stimulated GLUT4 at the plasma membrane, and enhanced insulin stimulated glucose transport.	20	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	24	25
Conversely , isoprenaline , in the absence of adenosine , promoted a time dependent ( t1/2 approximately 2 min ) decrease in the accessibility of insulin stimulated cell surface GLUT4 of > 50 % , which directly correlated with the observed inhibition of transport activity ; the plasma membrane concentration of GLUT4 decreased by 0-15 % .	Conversely, isoprenaline, in the absence of adenosine, promoted a time dependent (t1/2 approximately 2 min) decrease in the accessibility of insulin stimulated cell surface GLUT4 of> 50%, which directly correlated with the observed inhibition of transport activity; the plasma membrane concentration of GLUT4 decreased by 0-15%.	23	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	29	30
These effects of insulin are synergetic with the increased delivery of monomers by exocytosis and altogether function to prolong GLUT4 retention in the PM and maximize efficiency of glucose transport .	These effects of insulin are synergetic with the increased delivery of monomers by exocytosis and altogether function to prolong GLUT4 retention in the PM and maximize efficiency of glucose transport.	1	20	prolong	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	19	20
Pyruvate oxidation went up ( XREF_FIG ) and so did insulin stimulated pAkt and GLUT4 ( XREF_FIG ) .	Pyruvate oxidation went up (XREF_FIG) and so did insulin stimulated pAkt and GLUT4 (XREF_FIG).	9	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	14	15
The activity of PKCzeta is required for insulin mediated GLUT4 translocation , although insulin does not further increase its activity in the heart .	The activity of PKCzeta is required for insulin mediated GLUT4 translocation, although insulin does not further increase its activity in the heart.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Insulin has been shown to increase GLUT4 detection in the TIRF zone as a result of its translocation from intracellular locations distant from the plasma membrane , i.e. outside the region of TIRF illumination .	Insulin has been shown to increase GLUT4 detection in the TIRF zone as a result of its translocation from intracellular locations distant from the plasma membrane, i.e. outside the region of TIRF illumination.	0	7	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Association of PKCbetaII and GLUT4 with membrane F-actin was enhanced by insulin , as was that of cytosolic and membrane MARCKS .	Association of PKCbetaII and GLUT4 with membrane F-actin was enhanced by insulin, as was that of cytosolic and membrane MARCKS.	0	12	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	4	5
Thus , unveiling the molecular mechanisms regulating insulin stimulated GLUT4 trafficking will significantly contribute to our understanding of whole body glucose homeostasis as well as the cell biology of protein trafficking , membrane dynamics , and organelle biogenesis .	Thus, unveiling the molecular mechanisms regulating insulin stimulated GLUT4 trafficking will significantly contribute to our understanding of whole body glucose homeostasis as well as the cell biology of protein trafficking, membrane dynamics, and organelle biogenesis.	6	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Activation of insulin receptors triggers a large increase of GLUT4 vesicle trafficking and exocytosis as compared to basal conditions .	Activation of insulin receptors triggers a large increase of GLUT4 vesicle trafficking and exocytosis as compared to basal conditions.	2	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	9	10
Nocodazole disruption of microtubules delayed the half-time for insulin stimulated accumulation of GLUT4 at the cell surface from a t 1/2 = 6.3 min in the absence of nocodazole to t 1/2 = 9.8 min at 10 microM nocodazole ( XREF_TABLE ) and introduced a time-lag in the intensity increase ( XREF_FIG inset , XREF_TABLE ) .	Nocodazole disruption of microtubules delayed the half-time for insulin stimulated accumulation of GLUT4 at the cell surface from a t 1/2 = 6.3 min in the absence of nocodazole to t 1/2 = 9.8 min at 10 microM nocodazole (XREF_TABLE) and introduced a time-lag in the intensity increase (XREF_FIG inset, XREF_TABLE).	6	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	12	13
Overexpression of human PLD1 facilitates the insulin stimulated Glut4 trafficking and glucose uptake .	Overexpression of human PLD1 facilitates the insulin stimulated Glut4 trafficking and glucose uptake.	4	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	6	7	8	9
The 14-3-3 binding phospho-Thr642 on AS160 is among the four sites mutated in the 4P mutant that can inhibit insulin induced GLUT4 translocation when overexpressed in muscle and fat cells .	The 14-3-3 binding phospho-Thr642 on AS160 is among the four sites mutated in the 4P mutant that can inhibit insulin induced GLUT4 translocation when overexpressed in muscle and fat cells.	18	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
As shown in XREF_FIG , DGKzeta overexpression significantly enhanced the insulin induced GLUT4 translocation in 3T3-L1 adipocytes .	As shown in XREF_FIG, DGKzeta overexpression significantly enhanced the insulin induced GLUT4 translocation in 3T3-L1 adipocytes.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Insulin stimulates glucose uptake into the target tissues of fat and muscle by recruiting or translocating Glut4 glucose transport proteins to their functional location at the cell surface .	Insulin stimulates glucose uptake into the target tissues of fat and muscle by recruiting or translocating Glut4 glucose transport proteins to their functional location at the cell surface.	0	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut4	Glut4	Glut4	0	1	16	17
Insulin ' s restraint of AS160 , but perhaps not TBC1D1 ( based on data from cultured cells ) , plays a major role in insulin mediated GLUT4 translocation .	Insulin 's restraint of AS160, but perhaps not TBC1D1 (based on data from cultured cells), plays a major role in insulin mediated GLUT4 translocation.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	27	28
Munc18c is solely utilized by adipocytes to regulate insulin stimulated GLUT4 vesicle exocytosis [ XREF_BIBR ] .	Munc18c is solely utilized by adipocytes to regulate insulin stimulated GLUT4 vesicle exocytosis [XREF_BIBR].	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
In contrast , insulin caused rapid , complete depletion of GLUT4 from pool 1 and reduced the GLUT1 content of pool 2 by approximately 50 % , whereas , surprisingly , no net decrease in GLUT4 occurred in this pool .	In contrast, insulin caused rapid, complete depletion of GLUT4 from pool 1 and reduced the GLUT1 content of pool 2 by approximately 50%, whereas, surprisingly, no net decrease in GLUT4 occurred in this pool.	3	15	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	10	11
For example , XBP1s activates the phosphorylation of AKT , a key player in insulin induced GLUT4 translocation in adipocytes XREF_BIBR , XREF_BIBR .	For example, XBP1s activates the phosphorylation of AKT, a key player in insulin induced GLUT4 translocation in adipocytes XREF_BIBR, XREF_BIBR.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Growing evidence supports the involvement of Rac1 in insulin induced GLUT4 vesicle translocation to the cell surface , both in cultured L6 muscle cells and mature primary skeletal muscle [ XREF_BIBR - XREF_BIBR ] .	Growing evidence supports the involvement of Rac1 in insulin induced GLUT4 vesicle translocation to the cell surface, both in cultured L6 muscle cells and mature primary skeletal muscle [XREF_BIBR - XREF_BIBR].	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Down-regulation of Rac1 or FLJ00068 by RNA interference , on the other hand , abrogated insulin induced GLUT4 translocation .	Down-regulation of Rac1 or FLJ00068 by RNA interference, on the other hand, abrogated insulin induced GLUT4 translocation.	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
These findings indicate that the ' classical ' IR-IR substrate-PI-3 ' kinase pathway , that is essential for insulin induced GLUT4 translocation , is not activated by arsenite .	These findings indicate that the ' classical ' IR-IR substrate-PI-3 ' kinase pathway, that is essential for insulin induced GLUT4 translocation, is not activated by arsenite.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
The insulin ( 100nM )-induced increase in the GLUT4 localization on the cell surface was significantly suppressed by knocking-down Akt1/2 ( XREF_FIG C ) .	The insulin (100nM)-induced increase in the GLUT4 localization on the cell surface was significantly suppressed by knocking-down Akt1/2 (XREF_FIG C).	1	9	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	8	9
These results support a model whereby AS160 , Rab8A , and myosin Vb are required for insulin induced GLUT4 translocation in muscle cells , potentially as part of a linear signaling cascade .	These results support a model whereby AS160, Rab8A, and myosin Vb are required for insulin induced GLUT4 translocation in muscle cells, potentially as part of a linear signaling cascade.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
Studies examining the role of actin cytoskeleton in this process in L6 myotubes and adipocytes have shown that disruption of actin cytoskeleton inhibits insulin mediated Glut-4 translocation [ XREF_BIBR , XREF_BIBR ] .	Studies examining the role of actin cytoskeleton in this process in L6 myotubes and adipocytes have shown that disruption of actin cytoskeleton inhibits insulin mediated Glut-4 translocation [XREF_BIBR, XREF_BIBR].	22	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut-4	Glut-4	Glut-4	23	24	25	26
However , knockdown of CDP138 did not significantly affect insulin stimulated GLUT4-EGFP accumulation in the TIRF zone in live adipocytes ( XREF_FIG ) .	However, knockdown of CDP138 did not significantly affect insulin stimulated GLUT4-EGFP accumulation in the TIRF zone in live adipocytes (XREF_FIG).	8	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4-EGFP	GLUT4-EGFP	GLUT4-EGFP	9	10	11	12
A number of small GTPases , including Ras , Rho , and Rab family members , have been implicated in insulin stimulated GLUT4 trafficking .	A number of small GTPases, including Ras, Rho, and Rab family members, have been implicated in insulin stimulated GLUT4 trafficking.	18	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Insulin stimulates glucose transport in these cell types by mediating the partial redistribution of GLUT4 from this intracellular compartment to the plasma membrane .	Insulin stimulates glucose transport in these cell types by mediating the partial redistribution of GLUT4 from this intracellular compartment to the plasma membrane.	0	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	14	15
Numerous studies suggest that the phosphoinositide 3-kinase ( PI 3-kinase )/protein kinase B ( PKB , also known as Akt ) signaling cascade downstream of the insulin receptor plays a central role in controlling insulin induced GLUT4 translocation .	Numerous studies suggest that the phosphoinositide 3-kinase (PI 3-kinase)/protein kinase B (PKB, also known as Akt) signaling cascade downstream of the insulin receptor plays a central role in controlling insulin induced GLUT4 translocation.	31	37	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	34	35	36	37
We conclude that the insulin stimulated movement of GLUT4 to the cell surface in adipocytes may require ATP early in the insulin signaling pathway and a GTP binding protein ( s ) at a later step ( s ) .	We conclude that the insulin stimulated movement of GLUT4 to the cell surface in adipocytes may require ATP early in the insulin signaling pathway and a GTP binding protein (s) at a later step (s).	3	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	8	9
Insulin stimulated Glut4 translocation and glucose transport are abolished by wortmannin , a specific inhibitor of phosphatidylinositol 3 '-kinase ( PI3K ) .	Insulin stimulated Glut4 translocation and glucose transport are abolished by wortmannin, a specific inhibitor of phosphatidylinositol 3 '-kinase (PI3K).	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut4	Glut4	Glut4	0	1	2	3
Interestingly , we found that incubation of IRW for 2 h but not IQW or LKP ameliorated Ang II induced decrease in insulin stimulated glucose uptake and GLUT4 abundance on cell membrane .	Interestingly, we found that incubation of IRW for 2 h but not IQW or LKP ameliorated Ang II induced decrease in insulin stimulated glucose uptake and GLUT4 abundance on cell membrane.	19	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	27	28
Employing subcellular membrane fractionation methods it has been shown that insulin induces a 2-fold increase in Glut 4 protein content in the plasma membrane of skeletal muscle from rats .	Employing subcellular membrane fractionation methods it has been shown that insulin induces a 2-fold increase in Glut 4 protein content in the plasma membrane of skeletal muscle from rats.	10	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut 4	Glut 4	Glut 4	10	11	16	18
The studies presented here are the first to characterize a MyoIIA-F-actin localization at the site of insulin induced GLUT4 fusion at the plasma membrane in adipocytes .	The studies presented here are the first to characterize a MyoIIA-F-actin localization at the site of insulin induced GLUT4 fusion at the plasma membrane in adipocytes.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
A short-chain ceramide analog , C2-ceramide , completely precluded insulin stimulated glucose uptake and insulin induced GLUT4 translocation to plasma membrane , as determined by Western blot or immunofluorescent localization of GLUT4 .	A short-chain ceramide analog, C2-ceramide, completely precluded insulin stimulated glucose uptake and insulin induced GLUT4 translocation to plasma membrane, as determined by Western blot or immunofluorescent localization of GLUT4.	10	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Together , these findings demonstrate that TUG is required to retain GLUT4 intracellularly in 3T3-L1 adipocytes in the absence of insulin and further implicate the insulin stimulated dissociation of TUG and GLUT4 as an important action by which insulin stimulates glucose uptake .	Together, these findings demonstrate that TUG is required to retain GLUT4 intracellularly in 3T3-L1 adipocytes in the absence of insulin and further implicate the insulin stimulated dissociation of TUG and GLUT4 as an important action by which insulin stimulates glucose uptake.	23	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	31	32
In this study , we investigated the role of Rab4 , a small GTPase binding protein , and the motor protein KIF3 ( kinesin II in mice ) in insulin induced GLUT4 exocytosis in 3T3-L1 adipocytes .	In this study, we investigated the role of Rab4, a small GTPase binding protein, and the motor protein KIF3 (kinesin II in mice) in insulin induced GLUT4 exocytosis in 3T3-L1 adipocytes.	21	32	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	29	30	31	32
Here , we show that the AS160 RabGAP , a substrate of Akt , is required for insulin stimulation of GLUT4 exocytosis .	Here, we show that the AS160 RabGAP, a substrate of Akt, is required for insulin stimulation of GLUT4 exocytosis.	17	21	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	20	21
This hypothesis was strengthened by the fact that Rab4 deltaCT , a Rab4 mutant lacking the geranylgeranylation sites , inhibited insulin induced recruitement of Glut4-myc to the cell surface , even when moderately overexpressed .	This hypothesis was strengthened by the fact that Rab4 deltaCT, a Rab4 mutant lacking the geranylgeranylation sites, inhibited insulin induced recruitement of Glut4-myc to the cell surface, even when moderately overexpressed.	20	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4-myc	Glut4-myc	Glut4-myc	20	21	24	25
The aim of the present study was to examine the subcellular distribution of a member of this family , Rab 3D , in rat adipose cells , given the hypothesis that this protein might be involved in insulin stimulated GLUT4 exocytosis .	The aim of the present study was to examine the subcellular distribution of a member of this family, Rab 3D, in rat adipose cells, given the hypothesis that this protein might be involved in insulin stimulated GLUT4 exocytosis.	35	40	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	37	38	39	40
This impairment of the insulin stimulated increase in cell surface GLUT4 was reversed by pretreatment with Re .	This impairment of the insulin stimulated increase in cell surface GLUT4 was reversed by pretreatment with Re.	1	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	10	11
Insulin stimulates glucose transport by delivering GLUT4 from a specialized storage compartment to the plasma membrane .	Insulin stimulates glucose transport by delivering GLUT4 from a specialized storage compartment to the plasma membrane.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Taken together , these data strongly suggest that the interaction between APS and Enigma is involved in insulin induced Glut 4 translocation by regulating cortical actin remodeling and raise the possibility that modification of APS and Enigma ratio could participate in the alteration of insulin induced glucose uptake in adipose tissue .	Taken together, these data strongly suggest that the interaction between APS and Enigma is involved in insulin induced Glut 4 translocation by regulating cortical actin remodeling and raise the possibility that modification of APS and Enigma ratio could participate in the alteration of insulin induced glucose uptake in adipose tissue.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut 4	Glut 4	Glut 4	17	18	19	21
In animals , these proteins lend combinatorial specificity to SNARE interactions for vesicle targeting and secretory membrane traffic , for example as dedicated to neurotransmitter release and insulin induced GLUT4 traffic XREF_BIBR , XREF_BIBR .	In animals, these proteins lend combinatorial specificity to SNARE interactions for vesicle targeting and secretory membrane traffic, for example as dedicated to neurotransmitter release and insulin induced GLUT4 traffic XREF_BIBR, XREF_BIBR.	22	31	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	27	28	29	30
XREF_BIBR , XREF_BIBR Without probes to discriminate GSVs from endosomal compartments , therefore , addressing whether insulin stimulated GLUT4 redistribution to the PM occurs by a direct or indirect route is unfeasible .	XREF_BIBR, XREF_BIBR Without probes to discriminate GSVs from endosomal compartments, therefore, addressing whether insulin stimulated GLUT4 redistribution to the PM occurs by a direct or indirect route is unfeasible.	16	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
However , our results here show that TDP-43 over-expression inhibits the insulin mediated mobilization of Glut4 in skeletal muscle but not in white adipocytes suggesting differential regulation of Glut4 trafficking .	However, our results here show that TDP-43 over-expression inhibits the insulin mediated mobilization of Glut4 in skeletal muscle but not in white adipocytes suggesting differential regulation of Glut4 trafficking.	9	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	11	12	15	16
To test this hypothesis , we examined the insulin induced GLUT4 translocation by modulating SL levels using various inhibitors of de novo SL synthesis .	To test this hypothesis, we examined the insulin induced GLUT4 translocation by modulating SL levels using various inhibitors of de novo SL synthesis.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Based on the above observations , we propose a simple model whereby insulin regulates SNARE regulator DOC2b , and basal level of [ Ca 2+ ] i may act in a constitutive manner to promote DOC2b-syntaxin-4 interaction involved in insulin stimulated GLUT4 vesicle fusion .	Based on the above observations, we propose a simple model whereby insulin regulates SNARE regulator DOC2b, and basal level of [Ca 2+] i may act in a constitutive manner to promote DOC2b-syntaxin-4 interaction involved in insulin stimulated GLUT4 vesicle fusion.	37	43	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	39	40	41	42
This result has been confirmed in 3T3-L1 adipocytes , a frequently used model for insulin mediated GLUT4 redistribution [ XREF_BIBR ] .	This result has been confirmed in 3T3-L1 adipocytes, a frequently used model for insulin mediated GLUT4 redistribution [XREF_BIBR].	4	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
B-in the gastrocnemius muscle : normalization of the enhanced lipid storage and the altered glucose oxidation , improving glucose phosphorylation ; decreasing protein mass level of nPKCtheta in the membrane fraction ; reversion of the impaired insulin stimulated glucose transporter Glut-4 , and glucose-6-phosphate and glycogen concentrations .	B-in the gastrocnemius muscle : normalization of the enhanced lipid storage and the altered glucose oxidation, improving glucose phosphorylation; decreasing protein mass level of nPKCtheta in the membrane fraction; reversion of the impaired insulin stimulated glucose transporter Glut-4, and glucose-6-phosphate and glycogen concentrations.	19	41	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	phosphorylation; decreasing protein mass level of nPKCtheta in the membrane fraction; reversion of the impaired insulin	insulin	Glut-4	Glut-4	glut-4	36	37	40	41
For example , syntaxin 4 and SNAP23 are thought to be the Q-SNAREs required for insulin stimulated GLUT4 plasma membrane fusion , and syntaxin 6 and 16 are thought to be required for intracellular sorting .	For example, syntaxin 4 and SNAP23 are thought to be the Q-SNAREs required for insulin stimulated GLUT4 plasma membrane fusion, and syntaxin 6 and 16 are thought to be required for intracellular sorting.	13	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
Subsequently , PDK1 phosphorylates PKB and Akt and the two atypical protein kinase C ( aPKC ) isoforms , PKClambda , and PKCzeta , which contribute in parallel to insulin induced GLUT4 translocation .	Subsequently, PDK1 phosphorylates PKB and Akt and the two atypical protein kinase C (aPKC) isoforms, PKClambda, and PKCzeta, which contribute in parallel to insulin induced GLUT4 translocation.	25	32	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	29	30	31	32
Levels of insulin stimulated cell surface GLUT4 above basal in type 2 diabetic patients were only approximately 10 % of those observed in healthy subjects .	Levels of insulin stimulated cell surface GLUT4 above basal in type 2 diabetic patients were only approximately 10% of those observed in healthy subjects.	0	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	Levels of insulin	insulin	GLUT4	GLUT4	glut4	2	3	6	7
Activation of Akt kinases downstream of PI 3-kinase plays an essential role in insulin stimulated GLUT4 exocytosis , and expression of an activated version of the kinase can promote glucose uptake in adipocytes , although to an extent less than that seen with insulin .	Activation of Akt kinases downstream of PI 3-kinase plays an essential role in insulin stimulated GLUT4 exocytosis, and expression of an activated version of the kinase can promote glucose uptake in adipocytes, although to an extent less than that seen with insulin.	11	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Glucose uptake into adipocyte and muscle cells involves insulin hormone stimulated transfer of GLUT4 ( glucose transporter 4 ) to the plasma membrane .	Glucose uptake into adipocyte and muscle cells involves insulin hormone stimulated transfer of GLUT4 (glucose transporter 4) to the plasma membrane.	8	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	13	14
Tropomodulin3 is a novel Akt2 effector regulating insulin stimulated GLUT4 exocytosis through cortical actin remodeling .	Tropomodulin3 is a novel Akt2 effector regulating insulin stimulated GLUT4 exocytosis through cortical actin remodeling.	6	10	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
To determine whether GLUT4 exocytosis is dependent on intact microtubule network , we measured insulin mediated GLUT4 exocytosis in 3T3-L1 adipocytes in which the microtubule network was depolymerized by pretreatment with nocodazole .	To determine whether GLUT4 exocytosis is dependent on intact microtubule network, we measured insulin mediated GLUT4 exocytosis in 3T3-L1 adipocytes in which the microtubule network was depolymerized by pretreatment with nocodazole.	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
The insulin stimulated trafficking of GLUT4 to the plasma membrane in muscle and fat tissue constitutes a central process in blood glucose homeostasis .	The insulin stimulated trafficking of GLUT4 to the plasma membrane in muscle and fat tissue constitutes a central process in blood glucose homeostasis.	0	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	5	6
It is well established that reorganization of filamentous actin beneath the plasma membrane plays a role in insulin induced GLUT4 translocation [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	It is well established that reorganization of filamentous actin beneath the plasma membrane plays a role in insulin induced GLUT4 translocation [XREF_BIBR, XREF_BIBR - XREF_BIBR].	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
New studies have shed important light on the distal mechanisms involved in insulin mediated Glut 4 translocation .	New studies have shed important light on the distal mechanisms involved in insulin mediated Glut 4 translocation.	10	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut 4	Glut 4	Glut 4	12	13	14	16
Here we report that the natural product ( + )-Rutamarin ( Rut ) functions as an efficient dual inducer on both insulin induced GLUT4 translocation and expression .	Here we report that the natural product (+)-Rutamarin (Rut) functions as an efficient dual inducer on both insulin induced GLUT4 translocation and expression.	18	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
To further study the role of VAMP2 in mediating the potentiating effect of T3 on insulin induced GLUT4 translocation and glucose uptake , we transfected adipocytes with siRNA against VAMP2 gene .	To further study the role of VAMP2 in mediating the potentiating effect of T3 on insulin induced GLUT4 translocation and glucose uptake, we transfected adipocytes with siRNA against VAMP2 gene.	8	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
In control muscle ( SHAM ) , insulin increased levels of surface-detectable GLUT-4 ( i.e ., translocated GLUT-4 ) 1.8-fold ( P < 0.05 ) , whereas DEN surface GLUT-4 was not increased by insulin ( P > 0.05 ) .	In control muscle (SHAM), insulin increased levels of surface-detectable GLUT-4 (i.e., translocated GLUT-4) 1.8-fold (P < 0.05), whereas DEN surface GLUT-4 was not increased by insulin (P> 0.05).	27	36	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	34	35	29	30
Furthermore , in fetal sheep , both glucose and insulin are able to upregulate muscle GLUT4 protein expression XREF_BIBR and , therefore , the dexamethasone induced increments in plasma glucose and insulin are likely to contribute to the increase in muscle GLUT4 seen in the present study .	Furthermore, in fetal sheep, both glucose and insulin are able to upregulate muscle GLUT4 protein expression XREF_BIBR and, therefore, the dexamethasone induced increments in plasma glucose and insulin are likely to contribute to the increase in muscle GLUT4 seen in the present study.	7	18	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	15	16
BK has been shown to improve insulin stimulation of GLUT4 ( glucose transporter 4 ) [ XREF_BIBR ] via a BK B2R induced NO pathway [ XREF_BIBR ] .	BK has been shown to improve insulin stimulation of GLUT4 (glucose transporter 4) [XREF_BIBR] via a BK B2R induced NO pathway [XREF_BIBR].	6	12	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	9	10
In the fed state glucose enters the adipocyte through insulin stimulated GLUT4 translocation and is rapidly phosphorylated to form G6P .	In the fed state glucose enters the adipocyte through insulin stimulated GLUT4 translocation and is rapidly phosphorylated to form G6P.	5	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Surprisingly , insulin increased plasma membrane GLUT4 content to comparable levels in control and diabetic rat skeletal muscle .	Surprisingly, insulin increased plasma membrane GLUT4 content to comparable levels in control and diabetic rat skeletal muscle.	2	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	6	7
Most important for postprandial whole body glucose disposal are muscle cells that take up glucose via GLUT 4 , which is upregulated by insulin [ XREF_BIBR ] .	Most important for postprandial whole body glucose disposal are muscle cells that take up glucose via GLUT 4, which is upregulated by insulin [XREF_BIBR].	14	25	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	23	24	16	18
The perinuclear-to-cytosolic dispersion of GLUT4 induced by insulin was preserved in Myo1c knockdown cells .	The perinuclear-to-cytosolic dispersion of GLUT4 induced by insulin was preserved in Myo1c knockdown cells.	2	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	4	5
There was no significant difference in the magnitude of insulin stimulated GLUT4 trafficking from intracellular membranes to the plasma membrane between strains .	There was no significant difference in the magnitude of insulin stimulated GLUT4 trafficking from intracellular membranes to the plasma membrane between strains.	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Termination of insulin signaling causes GLUT4 to be internalized and re-sequestered into IRVs .	Termination of insulin signaling causes GLUT4 to be internalized and re-sequestered into IRVs.	2	6	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	5	6
Insulin increased GLUT4 in PM from 13 to 42 % .	Insulin increased GLUT4 in PM from 13 to 42%.	0	3	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Moreover , Doc2b knockout mice exhibit peripheral insulin resistance and impaired insulin stimulated GLUT4 accumulation at skeletal muscle cell surfaces [ XREF_BIBR ] .	Moreover, Doc2b knockout mice exhibit peripheral insulin resistance and impaired insulin stimulated GLUT4 accumulation at skeletal muscle cell surfaces [XREF_BIBR].	7	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	13	14
GLUT4accumulates in tubulo-vesicular structures at a perinuclear pole only partly overlapping with the transferrin receptor , giantin , and furin ( respective markers of the recycling vesicles , Golgi complex , and trans-Golgi network ) , and insulin causes dispersion of perinuclear GLUT4 toward the cell periphery .	GLUT4accumulates in tubulo-vesicular structures at a perinuclear pole only partly overlapping with the transferrin receptor, giantin, and furin (respective markers of the recycling vesicles, Golgi complex, and trans-Golgi network), and insulin causes dispersion of perinuclear GLUT4 toward the cell periphery.	10	46	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	37	38	42	43
Collectively , these findings suggest that chronic aerobic exercise enhances components of both the classical and novel insulin signalling cascades in normal rodent skeletal muscle , which may contribute to an increased insulin stimulated plasma membrane GLUT4 protein concentration .	Collectively, these findings suggest that chronic aerobic exercise enhances components of both the classical and novel insulin signalling cascades in normal rodent skeletal muscle, which may contribute to an increased insulin stimulated plasma membrane GLUT4 protein concentration.	28	38	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	32	33	36	37
If insulin promotes tethering of GLUT4 vesicles to the PM , then to complete the insulin response docked vesicles must fuse to release GLUT4 to the PM .	If insulin promotes tethering of GLUT4 vesicles to the PM, then to complete the insulin response docked vesicles must fuse to release GLUT4 to the PM.	1	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	5	6
In conjunction with the earlier studies indicating that insulin elevates Rab10-GTP in GLUT4 vesicles and implicating the exocyst complex in GLUT4 translocation , these findings support the proposal that this interaction acts as a link between insulin signaling and GLUT4 vesicle exocytosis .	In conjunction with the earlier studies indicating that insulin elevates Rab10-GTP in GLUT4 vesicles and implicating the exocyst complex in GLUT4 translocation, these findings support the proposal that this interaction acts as a link between insulin signaling and GLUT4 vesicle exocytosis.	8	13	elevates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	12	13
Interestingly , both insulin mediated signaling and the appearance of GLUT4 in the plasma membrane involve microdomains .	Interestingly, both insulin mediated signaling and the appearance of GLUT4 in the plasma membrane involve microdomains.	2	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	10	11
Regardless of the detailed binding interactions however , all studies unequivocally agree that Doc2b is both required and limiting for insulin stimulated GLUT4 vesicle exocytosis , via a facilitative role in SNARE assembly .	Regardless of the detailed binding interactions however, all studies unequivocally agree that Doc2b is both required and limiting for insulin stimulated GLUT4 vesicle exocytosis, via a facilitative role in SNARE assembly.	18	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
While this is also true in skeletal muscle , because many muscles are often at rest , insulin mediated GLUT4 translocation represents a quantitatively more important mechanism regulating skeletal muscle glucose uptake than is the case in the heart .	While this is also true in skeletal muscle, because many muscles are often at rest, insulin mediated GLUT4 translocation represents a quantitatively more important mechanism regulating skeletal muscle glucose uptake than is the case in the heart.	17	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
XREF_FIG , membrane Glut4 but not cytoplasm Glut4 was significantly increased by insulin treatment in Ad-PTB infected cells .	XREF_FIG, membrane Glut4 but not cytoplasm Glut4 was significantly increased by insulin treatment in Ad-PTB infected cells.	0	13	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	12	13	7	8
Many studies have shown that key regulatory molecules involved in insulin stimulated GLUT4 trafficking are up-regulated upon differentiation of 3T3-L1 fibroblasts into adipocytes ; these include GLUT4 , VAMP2 , Syntaxin16 , and insulin responsive aminopeptidase .	Many studies have shown that key regulatory molecules involved in insulin stimulated GLUT4 trafficking are up-regulated upon differentiation of 3T3-L1 fibroblasts into adipocytes; these include GLUT4, VAMP2, Syntaxin16, and insulin responsive aminopeptidase.	8	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
In contrast , insulin did not increase surface-accessible GLUT4 in ethanol fed rats .	In contrast, insulin did not increase surface-accessible GLUT4 in ethanol fed rats.	3	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	8	9
In particular , insulin driven exocytosis of GLUT4 is much stronger than that of GLUT1 ( exocytosis rate constant of GLUT4 , k gsc4 , glut4_ins , is four times that of GLUT1 , k gsc1 , glut1_ins , as shown in XREF_SUPPLEMENTARY ) .	In particular, insulin driven exocytosis of GLUT4 is much stronger than that of GLUT1 (exocytosis rate constant of GLUT4, k gsc4, glut4_ins, is four times that of GLUT1, k gsc1, glut1_ins, as shown in XREF_SUPPLEMENTARY).	3	10	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	7	8
In truncated form , TUG acts in a dominant negative manner to inhibit insulin stimulated GLUT4 redistribution in Chinese hamster ovary cells and 3T3-L1 adipocytes .	In truncated form, TUG acts in a dominant negative manner to inhibit insulin stimulated GLUT4 redistribution in Chinese hamster ovary cells and 3T3-L1 adipocytes.	12	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
The AS160-4P mutant has been found to inhibit insulin induced GLUT4 translocation in 3T3-L1 adipocytes as well as L6 muscle cells .	The AS160-4P mutant has been found to inhibit insulin induced GLUT4 translocation in 3T3-L1 adipocytes as well as L6 muscle cells.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Together , these results demonstrate that metformin induces Rab4 expression via AMPK-AS160-PKC-zeta and modulates insulin mediated GLUT4 translocation .	Together, these results demonstrate that metformin induces Rab4 expression via AMPK-AS160-PKC-zeta and modulates insulin mediated GLUT4 translocation.	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Administrations of MgSO 4 or insulin in Type 2 diabetes mellitus animals increase GLUT4 gene and protein expression .	Administrations of MgSO 4 or insulin in Type 2 diabetes mellitus animals increase GLUT4 gene and protein expression.	0	14	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	13	14
Adipocytes of streptozotocin ( STZ ) induced diabetic rats demonstrated reduction in insulin stimulated glucose transport function and cellular Glut-4 content [ XREF_BIBR ] and evidences show that the change in the glucose transporter content is more specific for Glut-4 [ XREF_BIBR ] .	Adipocytes of streptozotocin (STZ) induced diabetic rats demonstrated reduction in insulin stimulated glucose transport function and cellular Glut-4 content [XREF_BIBR] and evidences show that the change in the glucose transporter content is more specific for Glut-4 [XREF_BIBR].	9	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut-4	Glut-4	Glut-4	12	13	19	20
In support of the concept that CLASP2 plays a role in the trafficking of GLUT4 at the cell periphery , CLASP2 knockdown by siRNA in L6 myotubes interfered with insulin stimulated GLUT4 localization to the plasma membrane .	In support of the concept that CLASP2 plays a role in the trafficking of GLUT4 at the cell periphery, CLASP2 knockdown by siRNA in L6 myotubes interfered with insulin stimulated GLUT4 localization to the plasma membrane.	27	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	29	30	31	32
Accordingly , expression of constitutive active PI3K and Akt in cardiomyocytes compromises the insulin induced GLUT4 dependent glucose uptake [ XREF_BIBR ] .	Accordingly, expression of constitutive active PI3K and Akt in cardiomyocytes compromises the insulin induced GLUT4 dependent glucose uptake [XREF_BIBR].	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Moreover , the beneficial effect of these AMPK activating agents on enhancing the insulin stimulated increase in membrane GLUT4 was eliminated by replenishing the reduced membrane cholesterol back to levels observed in control cells .	Moreover, the beneficial effect of these AMPK activating agents on enhancing the insulin stimulated increase in membrane GLUT4 was eliminated by replenishing the reduced membrane cholesterol back to levels observed in control cells.	11	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	18	19
Depletion of Arp2/3 Reduces Insulin mediated GLUT4 Gain on the Cell Surface .	Depletion of Arp2/3 Reduces Insulin mediated GLUT4 Gain on the Cell Surface.	3	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Akt is present in three isoforms with Akt1 contributing largely to growth , and Akt2 contributing to insulin mediated GLUT4 redistribution [ XREF_BIBR ] .	Akt is present in three isoforms with Akt1 contributing largely to growth, and Akt2 contributing to insulin mediated GLUT4 redistribution [XREF_BIBR].	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Despite the obesity , HFD fed Syn4 Tg mice retained the normal 2-fold increase in insulin stimulated GLUT4 accumulation in skeletal muscle t-tubules and sarcolemma reported for similarly aged chow fed control mice ( dashed line ) ; by contrast , HFD fed Con mice failed to respond to insulin ( XREF_FIG ) .	Despite the obesity, HFD fed Syn4 Tg mice retained the normal 2-fold increase in insulin stimulated GLUT4 accumulation in skeletal muscle t-tubules and sarcolemma reported for similarly aged chow fed control mice (dashed line); by contrast, HFD fed Con mice failed to respond to insulin (XREF_FIG).	13	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
In summary , several new essential features of insulin stimulated GLUT4 regulation have been revealed .	In summary, several new essential features of insulin stimulated GLUT4 regulation have been revealed.	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
However , in contrast to VAMP5 knockdown , insulin and oligomycin further increased the sarcolemmal abundance of GLUT4 in VAMP7 depleted cells .	However, in contrast to VAMP5 knockdown, insulin and oligomycin further increased the sarcolemmal abundance of GLUT4 in VAMP7 depleted cells.	8	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	17	18
The activation of p38 MAPK is thought to be involved in the insulin induced enhancement of intrinsic GLUT4 activity .	The activation of p38 MAPK is thought to be involved in the insulin induced enhancement of intrinsic GLUT4 activity.	12	18	enhancement	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	17	18
This is consistent with known transporter regulatory effect of nPKCdelta , which include stimulation of Na + -H + exchanger in glial cells , alpha1-adrenergic activation of Na + -K + -2 Cl - cotransport in tracheal epithelial cells , insulin mediated GLUT4 translocation in myocytes and adipocytes and serotonin mediated inhibition of Cl - / OH - exchange in Caco-2 cells .	This is consistent with known transporter regulatory effect of nPKCdelta, which include stimulation of Na + -H + exchanger in glial cells, alpha1-adrenergic activation of Na + -K + -2 Cl - cotransport in tracheal epithelial cells, insulin mediated GLUT4 translocation in myocytes and adipocytes and serotonin mediated inhibition of Cl - / OH - exchange in Caco-2 cells.	40	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	40	41	42	43
ClipR-59 preferentially binds to Akt2 , and down-regulation of ClipR-59 impairs insulin induced GLUT4 translocation and Akt mediated phosphorylation of AS160 .	ClipR-59 preferentially binds to Akt2, and down-regulation of ClipR-59 impairs insulin induced GLUT4 translocation and Akt mediated phosphorylation of AS160.	11	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
XREF_BIBR , XREF_BIBR These effects were exerted by inhibiting the activity of phosphoinositide 3-kinase ( PI3K ) , a key regulator of insulin induced GLUT4 translocation to the cellular membrane , and the mitogen activated protein kinases ( MAPK ) pathway , which regulates cellular functions including proliferation .	XREF_BIBR, XREF_BIBR These effects were exerted by inhibiting the activity of phosphoinositide 3-kinase (PI3K), a key regulator of insulin induced GLUT4 translocation to the cellular membrane, and the mitogen activated protein kinases (MAPK) pathway, which regulates cellular functions including proliferation.	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	24	25
Overexpression of the Rab10 QL had no significant effect on insulin stimulated GLUT4 translocation when expressed alone ( data not shown ) nor did it reverse the TBC1D13 WT block in GLUT4 translocation ( XREF_FIG ) .	Overexpression of the Rab10 QL had no significant effect on insulin stimulated GLUT4 translocation when expressed alone (data not shown) nor did it reverse the TBC1D13 WT block in GLUT4 translocation (XREF_FIG).	8	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Insulin treatment was associated with decreased PCK1 , mitochondrial PEPCK , glucose-6-phosphatase , propionyl-CoA-carboxylase alpha , carnitine-palmitoyl-transferase 1A , ACADVL , and insulin receptor mRNA , but increased IGF1 and SLC2A4 mRNA ap and pp and GHR1A mRNA pp .	Insulin treatment was associated with decreased PCK1, mitochondrial PEPCK, glucose-6-phosphatase, propionyl-CoA-carboxylase alpha, carnitine-palmitoyl-transferase 1A, ACADVL, and insulin receptor mRNA, but increased IGF1 and SLC2A4 mRNA ap and pp and GHR1A mRNA pp.	0	32	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	SLC2A4	SLC2A4	SLC2A4	0	1	30	31
Insulin and contraction mediated GLUT4 trafficking to the sarcolemma and the t-tubules in fully differentiated skeletal muscle have different spatial and temporal kinetics .	Insulin and contraction mediated GLUT4 trafficking to the sarcolemma and the t-tubules in fully differentiated skeletal muscle have different spatial and temporal kinetics.	0	5	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	4	5
Interestingly , the enhancement of Rut on the insulin induced GLUT4 translocation is even stronger than those of compound-2 ( C-2 ) , a known PTP1B selective inhibitor XREF_BIBR , and pervanadate , the reported general tyrosine phosphatase inhibitor XREF_BIBR ( XREF_FIG ) .	Interestingly, the enhancement of Rut on the insulin induced GLUT4 translocation is even stronger than those of compound-2 (C-2), a known PTP1B selective inhibitor XREF_BIBR, and pervanadate, the reported general tyrosine phosphatase inhibitor XREF_BIBR (XREF_FIG).	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
3T3-L1 adipocytes overexpressing AS160-4A show normal basal retention but lack insulin stimulated GLUT4 translocation .	3T3-L1 adipocytes overexpressing AS160-4A show normal basal retention but lack insulin stimulated GLUT4 translocation.	9	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
We do not dispute the data presented by XREF_BIBR showing that in the absence of VAMPs 2 , 3 , and 8 , any of these VAMPs alone can reconstitute insulin stimulated GLUT4 delivery to the cell surface .	We do not dispute the data presented by XREF_BIBR showing that in the absence of VAMPs 2, 3, and 8, any of these VAMPs alone can reconstitute insulin stimulated GLUT4 delivery to the cell surface.	29	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	30	31	32	33
Thus , insulin stimulates tighter and quicker attachment of mobile GLUT4 vesicles to the PM of adipose cells .	Thus, insulin stimulates tighter and quicker attachment of mobile GLUT4 vesicles to the PM of adipose cells.	2	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	10	11
Therefore , wortmannin also disrupts insulin stimulated GLUT4 traffic in the recycling endosomal pathway , at a step distal to the sorting of recycling proteins from late endosomal and TGN markers ; wortmannin does not appear to affect internalization from the plasma membrane , and delivery from early to late endosomes or from late endosomes to the TGN .	Therefore, wortmannin also disrupts insulin stimulated GLUT4 traffic in the recycling endosomal pathway, at a step distal to the sorting of recycling proteins from late endosomal and TGN markers; wortmannin does not appear to affect internalization from the plasma membrane, and delivery from early to late endosomes or from late endosomes to the TGN.	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
Rab31 , a Rab5 family member , participates in insulin induced GLUT4 translocation to the plasma membrane .	Rab31, a Rab5 family member, participates in insulin induced GLUT4 translocation to the plasma membrane.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
As such , a prevailing concept is that the interaction of vesicular Myo1c with F-actin regulates GLUT4 vesicle tethering to the actin cytoskeleton and subsequent insulin induced GLUT4 vesicle fusion to the PM .	As such, a prevailing concept is that the interaction of vesicular Myo1c with F-actin regulates GLUT4 vesicle tethering to the actin cytoskeleton and subsequent insulin induced GLUT4 vesicle fusion to the PM.	24	29	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	27	28
Re-expressing the wild type , or CP , but not CN , RIP140 reduced both basal and insulin stimulated GLUT4 partitioning to the PM .	Re-expressing the wild type, or CP, but not CN, RIP140 reduced both basal and insulin stimulated GLUT4 partitioning to the PM.	15	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
While it is clear that microtubules are involved in GLUT4 vesicle motility , whether microtubule based GLUT4 vesicle movement is required for the insulin induced GLUT4 redistribution to the plasma membrane is not known .	While it is clear that microtubules are involved in GLUT4 vesicle motility, whether microtubule based GLUT4 vesicle movement is required for the insulin induced GLUT4 redistribution to the plasma membrane is not known.	20	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
The latter suggests a deficient insulin induced trafficking of GLUT4 vesicles in isolated HTZ muscle fibers .	The latter suggests a deficient insulin induced trafficking of GLUT4 vesicles in isolated HTZ muscle fibers.	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	9	10
Knockdown of VAMP2 affected insulin induced GLUT4 translocation and glucose uptake , suggesting that VAMP2 is an important mediator of these processes 40 .	Knockdown of VAMP2 affected insulin induced GLUT4 translocation and glucose uptake, suggesting that VAMP2 is an important mediator of these processes 40.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Under this setting , insulin stimulated actin remodeling was restored , and the deleterious effect of Arp3 down-regulation on insulin mediated GLUT4 translocation was alleviated .	Under this setting, insulin stimulated actin remodeling was restored, and the deleterious effect of Arp3 down-regulation on insulin mediated GLUT4 translocation was alleviated.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
Given that excess HBP flux blunts the insulin stimulated GLUT4 action , Parker and colleagues also examined the status of insulin stimulated glycogen synthesis in 3T3-L1 adipocytes .	Given that excess HBP flux blunts the insulin stimulated GLUT4 action, Parker and colleagues also examined the status of insulin stimulated glycogen synthesis in 3T3-L1 adipocytes.	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
The mechanism for insulin induced GLUT4 translocation involves the binding of phosphorylated AS160 to 14-3-3 , which promotes the movement of GLUT4 storage vesicles to fuse with the plasma membrane XREF_BIBR .	The mechanism for insulin induced GLUT4 translocation involves the binding of phosphorylated AS160 to 14-3-3, which promotes the movement of GLUT4 storage vesicles to fuse with the plasma membrane XREF_BIBR.	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Indeed , while these studies provide provocative data to support the hypothesis that insulin stimulates GLUT4 trafficking in the CNS , it is important to note that diabetes phenotypes and glucose administration are associated with changes in plasma glucose and plasma insulin levels .	Indeed, while these studies provide provocative data to support the hypothesis that insulin stimulates GLUT4 trafficking in the CNS, it is important to note that diabetes phenotypes and glucose administration are associated with changes in plasma glucose and plasma insulin levels.	13	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Performing this glut4 recycling assay , we found that the addition of SecinH3 inhibited insulin stimulated glut4 recycling in adipocytes ( XREF_FIG ) .	Performing this glut4 recycling assay, we found that the addition of SecinH3 inhibited insulin stimulated glut4 recycling in adipocytes (XREF_FIG).	13	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	glut4	glut4	glut4	14	15	16	17
Our data do not support an obligatory requirement for long range microtubule based movement of GLUT4 vesicles for insulin mediated GLUT4 redistribution to the cell surface .	Our data do not support an obligatory requirement for long range microtubule based movement of GLUT4 vesicles for insulin mediated GLUT4 redistribution to the cell surface.	12	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
Consistent with that data , Rab11-FIP5 and Rip11 was shown to regulate insulin stimulated GLUT4 transport to plasma membrane in adipocytes .	Consistent with that data, Rab11-FIP5 and Rip11 was shown to regulate insulin stimulated GLUT4 transport to plasma membrane in adipocytes.	11	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
In conclusion , ( i ) STEAP4 regulates the function of IRS-1 , PI3K , and Akt and decreases insulin induced GLUT4 translocation and glucose uptake ; ( ii ) ROS related mitochondrial dysfunction may be related to a reduced IRS-1 correlation with the PI3K signaling pathway , leading to insulin resistance .	In conclusion, (i) STEAP4 regulates the function of IRS-1, PI3K, and Akt and decreases insulin induced GLUT4 translocation and glucose uptake; (ii) ROS related mitochondrial dysfunction may be related to a reduced IRS-1 correlation with the PI3K signaling pathway, leading to insulin resistance.	18	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
The main effect of insulin is to increase the rate of Glut 4 trafficking from its specific storage compartment to the plasma membrane .	The main effect of insulin is to increase the rate of Glut 4 trafficking from its specific storage compartment to the plasma membrane.	2	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut 4	Glut 4	Glut 4	4	5	11	13
Insulin augments the number of GLUT 4 receptors in adipose and skeletal muscle cells and the glucose uptake by myocytes [ XREF_BIBR ] .	Insulin augments the number of GLUT 4 receptors in adipose and skeletal muscle cells and the glucose uptake by myocytes [XREF_BIBR].	0	7	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT 4	GLUT 4	GLUT 4	0	1	5	7
Surface exposed GLUT4 induced by the insulin signalling is responsible for lowering postprandial hyperglycaemia to normal glucose levels XREF_BIBR XREF_BIBR XREF_BIBR .	Surface exposed GLUT4 induced by the insulin signalling is responsible for lowering postprandial hyperglycaemia to normal glucose levels XREF_BIBR XREF_BIBR XREF_BIBR.	0	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	2	3
siRNA mediated Rab13 knockdown blocked the insulin induced increase of GLUT4 at the muscle cell surface that was rescued by a Rab13 ortholog but not by Rab8A .	siRNA mediated Rab13 knockdown blocked the insulin induced increase of GLUT4 at the muscle cell surface that was rescued by a Rab13 ortholog but not by Rab8A.	5	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	10	11
However , they blocked both the GLUT4 internalization and the down-regulation of glucose transport triggered by insulin removal in 3T3-L1 adipocytes .	However, they blocked both the GLUT4 internalization and the down-regulation of glucose transport triggered by insulin removal in 3T3-L1 adipocytes.	6	17	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	6	7
Here we report that Axin , TNKS and KIF3A form a ternary complex that is required for insulin stimulated GLUT4 redistribution to the cell surface to increase glucose uptake .	Here we report that Axin, TNKS and KIF3A form a ternary complex that is required for insulin stimulated GLUT4 redistribution to the cell surface to increase glucose uptake.	15	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Glut4 functions to move glucose across the plasma membrane of cells , is found in skeletal muscle , and is induced by insulin or exercise [ XREF_BIBR ] .	Glut4 functions to move glucose across the plasma membrane of cells, is found in skeletal muscle, and is induced by insulin or exercise [XREF_BIBR].	0	26	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	22	23	0	1
On the other hand , shRNA mediated reduction of sortilin in intact C2C12 myotubes inhibited insulin induced GLUT4 recycling without dampening Akt phosphorylation .	On the other hand, shRNA mediated reduction of sortilin in intact C2C12 myotubes inhibited insulin induced GLUT4 recycling without dampening Akt phosphorylation.	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
Moreover , overexpression of PKCdelta in primary muscle cells has been shown to increase GLUT4 translocation and glucose uptake in the basal state , and pharmacological inhibition of PKCdelta caused downregulation of insulin induced GLUT4 translocation and glucose uptake .	Moreover, overexpression of PKCdelta in primary muscle cells has been shown to increase GLUT4 translocation and glucose uptake in the basal state, and pharmacological inhibition of PKCdelta caused downregulation of insulin induced GLUT4 translocation and glucose uptake.	30	35	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	32	33	34	35
A substantial amount of work has been performed to dissect insulin mediated GLUT4 translocation in adipocytes , which turns out to be similar in the heart .	A substantial amount of work has been performed to dissect insulin mediated GLUT4 translocation in adipocytes, which turns out to be similar in the heart.	9	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
The EHBP1 gene is required for insulin stimulated GLUT4 movements [ XREF_BIBR ] .	The EHBP1 gene is required for insulin stimulated GLUT4 movements [XREF_BIBR].	4	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
The effects of quercetin on insulin mediated GLUT4 translocation in 3T3-L1 cells under basal and insulin resistant conditions were investigated .	The effects of quercetin on insulin mediated GLUT4 translocation in 3T3-L1 cells under basal and insulin resistant conditions were investigated.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
Insulin stimulates glucose uptake into adipocytes and muscle tissues by recruiting GLUT4 molecules from intracellular sites to the plasma membrane ( PM ) .	Insulin stimulates glucose uptake into adipocytes and muscle tissues by recruiting GLUT4 molecules from intracellular sites to the plasma membrane (PM).	0	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	11	12
One of the proteins involved in the insulin mediated Glut4 trafficking is the phosphatidylinositol 32-kinase ( PI 3K )-dependent Ser473 kinase Akt .	One of the proteins involved in the insulin mediated Glut4 trafficking is the phosphatidylinositol 32-kinase (PI 3K)-dependent Ser473 kinase Akt.	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	7	8	9	10
The knockdown of DGKzeta or PIP5K1alpha reduced insulin induced GLUT4 translocation to the PM .	The knockdown of DGKzeta or PIP5K1alpha reduced insulin induced GLUT4 translocation to the PM.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Furthermore , these data support a model in which insulin stimulates GLUT4 exocytosis by releasing an inhibitor of GLUT4 movement to the cell surface , and it is this clamp on basal exocytosis that is missing in adipocytes lacking C/EBPalpha .	Furthermore, these data support a model in which insulin stimulates GLUT4 exocytosis by releasing an inhibitor of GLUT4 movement to the cell surface, and it is this clamp on basal exocytosis that is missing in adipocytes lacking C/EBPalpha.	9	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
These results point to a direct role of Rab4 in insulin induced GLUT4 translocation , and that this effect is dependent on nucleotide binding to the protein .	These results point to a direct role of Rab4 in insulin induced GLUT4 translocation, and that this effect is dependent on nucleotide binding to the protein.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Unlike TBC1D4 , the influence of TBC1D1 on specific steps of insulin stimulated GLUT4 trafficking has not been reported .	Unlike TBC1D4, the influence of TBC1D1 on specific steps of insulin stimulated GLUT4 trafficking has not been reported.	9	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Insulin mediated GLUT4 translocation is also dependent on the microtubule network XREF_BIBR , XREF_BIBR , which motor proteins such as kinesins can use as a track 12 for GSV trafficking .	Insulin mediated GLUT4 translocation is also dependent on the microtubule network XREF_BIBR, XREF_BIBR, which motor proteins such as kinesins can use as a track 12 for GSV trafficking.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Hence , there are arsenite sensitive proteins that contribute to insulin induced GLUT4 translocation without affecting CD36 dynamics .	Hence, there are arsenite sensitive proteins that contribute to insulin induced GLUT4 translocation without affecting CD36 dynamics.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
It is well established that proteins of the VAMP- ( synaptobrevin ) and syntaxin-families play a fundamental role in the insulin stimulated fusion of Glut4 containing vesicles with the plasma membrane .	It is well established that proteins of the VAMP- (synaptobrevin) and syntaxin-families play a fundamental role in the insulin stimulated fusion of Glut4 containing vesicles with the plasma membrane.	17	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	20	21	24	25
Knockdown of AS160 using siRNA confirms an inhibitory role for this protein in insulin mediated GLUT4 redistribution [ XREF_BIBR ] .	Knockdown of AS160 using siRNA confirms an inhibitory role for this protein in insulin mediated GLUT4 redistribution [XREF_BIBR].	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
We then examined the effects of DGKzeta overexpression on the insulin induced GLUT4 translocation .	We then examined the effects of DGKzeta overexpression on the insulin induced GLUT4 translocation.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
AS160 was first implicated as a regulator of insulin stimulated GLUT4 traffic by Lienhard and co-workers , who discovered that AS160 ( which has a mass of 160 kDa ) is a downstream substrate of the kinase Akt .	AS160 was first implicated as a regulator of insulin stimulated GLUT4 traffic by Lienhard and co-workers, who discovered that AS160 (which has a mass of 160 kDa) is a downstream substrate of the kinase Akt.	6	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Similarly , knockdown of phosphatidylinositol 4-phosphate 5-kinase 1alpha ( PIP5K1alpha ) , which had been reported to interact with DGKzeta , also inhibited insulin induced GLUT4 translocation .	Similarly, knockdown of phosphatidylinositol 4-phosphate 5-kinase 1alpha (PIP5K1alpha), which had been reported to interact with DGKzeta, also inhibited insulin induced GLUT4 translocation.	23	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
In addition , there was no effect of insulin or GTP gamma S on GLUT4 movement to the PM in noninsulin sensitive streptolysin-O-permeabilized 3T3-L1 fibroblasts overexpressing GLUT4 .	In addition, there was no effect of insulin or GTP gamma S on GLUT4 movement to the PM in noninsulin sensitive streptolysin-O-permeabilized 3T3-L1 fibroblasts overexpressing GLUT4.	8	27	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	26	27
In WT mice , insulin increased glucose transport ( +133 % ) and PM GLUT4 ( +60 % ) ( XREF_FIG ) , whereas in Munc18c -/+ mice , insulin stimulated glucose transport and GLUT4 appearance at the PM were impaired ( XREF_FIG ) .	In WT mice, insulin increased glucose transport (+133%) and PM GLUT4 (+60%) (XREF_FIG), whereas in Munc18c -/+ mice, insulin stimulated glucose transport and GLUT4 appearance at the PM were impaired (XREF_FIG).	4	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	14	15
Evidence to suggest the underlying mechanisms for how the HER2 oncogene caused both increased basal and insulin induced plasma membrane localization of GLUT4 , and the insulin independent growth phenotype came from our investigation of the transcriptome regulated by the HER2 oncogene .	Evidence to suggest the underlying mechanisms for how the HER2 oncogene caused both increased basal and insulin induced plasma membrane localization of GLUT4, and the insulin independent growth phenotype came from our investigation of the transcriptome regulated by the HER2 oncogene.	2	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	22	23
3T3-L1 adipocytes use solely the Munc18c-syntaxin4 pair to regulate insulin stimulated GLUT4 vesicle exocytosis [ XREF_BIBR , XREF_BIBR ] .	3T3-L1 adipocytes use solely the Munc18c-syntaxin4 pair to regulate insulin stimulated GLUT4 vesicle exocytosis [XREF_BIBR, XREF_BIBR].	8	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
The binding of insulin to the receptor in the musculature and in adipose tissue stimulates the transport of GluT 4 from the interior of the cells to the outer membrane .	The binding of insulin to the receptor in the musculature and in adipose tissue stimulates the transport of GluT 4 from the interior of the cells to the outer membrane.	1	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GluT 4	GluT 4	GluT 4	3	4	18	20
Surprisingly , isolated EDL muscles from diabetic db/db mice did not exhibit alterations in either basal or insulin stimulated glucose transport activity or cell surface GLUT4 compared to nondiabetic db/+ mice .	Surprisingly, isolated EDL muscles from diabetic db/db mice did not exhibit alterations in either basal or insulin stimulated glucose transport activity or cell surface GLUT4 compared to nondiabetic db/+ mice.	12	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	25	26
Insulin increases glucose transport by stimulating the trafficking of intracellular GLUT4 to the cell surface , a process known as GLUT4 translocation .	Insulin increases glucose transport by stimulating the trafficking of intracellular GLUT4 to the cell surface, a process known as GLUT4 translocation.	0	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	10	11
In this report , we have shown that DOC2b mediates insulin stimulated GLUT4 membrane fusion in adipocytes , while having no effect on the GLUT4 vesicle translocation step .	In this report, we have shown that DOC2b mediates insulin stimulated GLUT4 membrane fusion in adipocytes, while having no effect on the GLUT4 vesicle translocation step.	9	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Regarding actions beneath the PM , insulin promotes GLUT4 insertion by increasing the rate of vesicle fusion possibly by regulating cortical actin filament organization at exocytotic sites XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Regarding actions beneath the PM, insulin promotes GLUT4 insertion by increasing the rate of vesicle fusion possibly by regulating cortical actin filament organization at exocytotic sites XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	6	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
In accordance with these findings , serum does not appear to activate the same repertoire of downstream signaling molecules that are implicated in insulin induced GLUT4 translocation .	In accordance with these findings, serum does not appear to activate the same repertoire of downstream signaling molecules that are implicated in insulin induced GLUT4 translocation.	21	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
This observation suggested that insulin may increase GLUT4 activity via p38alpha and/or p38beta .	This observation suggested that insulin may increase GLUT4 activity via p38alpha and/or p38beta.	4	8	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	7	8
For example , it was reported that naringenin ( 1 ) , a flavanone mainly present in grapefruit which was shown to selectively bind to estrogen receptor beta , [ XREF_BIBR ] also inhibits insulin stimulated glucose uptake in breast cancer cells , by disrupting the insulin induced GLUT4 translocation from intracellular compartments to the plasma membrane .	For example, it was reported that naringenin (1), a flavanone mainly present in grapefruit which was shown to selectively bind to estrogen receptor beta, [XREF_BIBR] also inhibits insulin stimulated glucose uptake in breast cancer cells, by disrupting the insulin induced GLUT4 translocation from intracellular compartments to the plasma membrane.	45	49	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	46	47	48	49
Role of Akt2 Targets in Insulin Stimulated GLUT4 Translocation .	Role of Akt2 Targets in Insulin Stimulated GLUT4 Translocation.	5	8	Stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
Similar effects of PI3K inhibitors have been observed for insulin dependent up-regulation of the GLUT4 subtype of glucose transporter .	Similar effects of PI3K inhibitors have been observed for insulin dependent up-regulation of the GLUT4 subtype of glucose transporter.	9	15	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	14	15
In contrast , expression of Synip DeltaWW inhibited insulin stimulated Glut4 PM fusion by 40 % and surprisingly reduced the basal PM fused Glut4 by 70 % .	In contrast, expression of Synip DeltaWW inhibited insulin stimulated Glut4 PM fusion by 40% and surprisingly reduced the basal PM fused Glut4 by 70%.	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	8	9	10	11
The 3T3-L1 adipocytes have been a model system to study insulin stimulated Glut4 recycling , and Glut4 has been shown to reside in an internal endosomal compartment at the basal condition , when no insulin stimulation is applied .	The 3T3-L1 adipocytes have been a model system to study insulin stimulated Glut4 recycling, and Glut4 has been shown to reside in an internal endosomal compartment at the basal condition, when no insulin stimulation is applied.	9	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	10	11	12	13
Insulin also activates multiple signaling pathways to facilitate GLUT4 trafficking and insulin stimulated glucose uptake .	Insulin also activates multiple signaling pathways to facilitate GLUT4 trafficking and insulin stimulated glucose uptake.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	8	9
SiRNA knockdown of FLJ00068 markedly inhibited Myr-p110alpha- or Myr-Akt2-induced as well as insulin induced GLUT4 translocation , suggesting a crucial role for FLJ00068 downstream of Akt2 ( XREF_FIG ) .	SiRNA knockdown of FLJ00068 markedly inhibited Myr-p110alpha- or Myr-Akt2-induced as well as insulin induced GLUT4 translocation, suggesting a crucial role for FLJ00068 downstream of Akt2 (XREF_FIG).	6	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Conversely , Stx4 transgenic mice exhibit enhanced glucose uptake and insulin induced GLUT4 translocation to the cell membrane of the skeletal muscle [ XREF_BIBR ] .	Conversely, Stx4 transgenic mice exhibit enhanced glucose uptake and insulin induced GLUT4 translocation to the cell membrane of the skeletal muscle [XREF_BIBR].	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Remarkably , Doc2b Tg PM fractions exhibited a ~ 2.2-fold increase in insulin stimulated GLUT4 vesicle accumulation at the PM ( XREF_FIG ) .	Remarkably, Doc2b Tg PM fractions exhibited a ~ 2.2-fold increase in insulin stimulated GLUT4 vesicle accumulation at the PM (XREF_FIG).	10	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
We now show that ACAP1 is part of a novel clathrin coat complex that mediates the stimulation dependent recycling of integrin and insulin stimulated recycling of Glut4 .	We now show that ACAP1 is part of a novel clathrin coat complex that mediates the stimulation dependent recycling of integrin and insulin stimulated recycling of Glut4.	18	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	22	23	26	27
This explanation is supported by our finding that overexpression of AS160 and T642A , a dominant interfering mutant version of AS160 functioning as a Rab-GTPase-activating protein regulated and phosphorylated by the PI 3-kinase-dependent Akt activation , abolished insulin induced GLUT4 liberation ( XREF_FIG B and Supplemental Figure S3C ) , although its underlying mechanisms involving AS160 remain to be further clarified .	This explanation is supported by our finding that overexpression of AS160 and T642A, a dominant interfering mutant version of AS160 functioning as a Rab-GTPase-activating protein regulated and phosphorylated by the PI 3-kinase-dependent Akt activation, abolished insulin induced GLUT4 liberation (XREF_FIG B and Supplemental Figure S3C), although its underlying mechanisms involving AS160 remain to be further clarified.	37	40	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	37	38	39	40
Galphaq/11 antibody and RGS2 inhibited insulin induced GLUT4 translocation by 60 or 75 % , respectively , indicating that activated Galphaq is important for insulin induced glucose transport .	Galphaq/11 antibody and RGS2 inhibited insulin induced GLUT4 translocation by 60 or 75%, respectively, indicating that activated Galphaq is important for insulin induced glucose transport.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
It has been shown that agents that disturb actin polymerization , e.g ., latrunculin B or cytochalasin D , inhibit insulin induced GLUT4 translocation in adipocytes , skeletal muscle cells and cardiomyocytes [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It has been shown that agents that disturb actin polymerization, e.g., latrunculin B or cytochalasin D, inhibit insulin induced GLUT4 translocation in adipocytes, skeletal muscle cells and cardiomyocytes [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	19	23	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Previous results support a model in which TUG proteins trap these GLUT4 storage vesicles at the Golgi matrix , and in which insulin triggers endoproteolytic cleavage of TUG to translocate GLUT4 .	Previous results support a model in which TUG proteins trap these GLUT4 storage vesicles at the Golgi matrix, and in which insulin triggers endoproteolytic cleavage of TUG to translocate GLUT4.	22	31	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	30	31
Insulin and AICAR increased glucose transport and cell-surface GLUT4 content to a similar extent in control subjects .	Insulin and AICAR increased glucose transport and cell-surface GLUT4 content to a similar extent in control subjects.	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	8	9
To determine the functional relevance of Myo1c to insulin induced GLUT4 traffic in muscle cells , we used targeted small interfering RNA ( siRNA )-mediated Myo1c gene silencing .	To determine the functional relevance of Myo1c to insulin induced GLUT4 traffic in muscle cells, we used targeted small interfering RNA (siRNA)-mediated Myo1c gene silencing.	1	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Doc2b is critical to insulin triggered GLUT4 exocytosis , but its molecular mechanism of action has been unclear .	Doc2b is critical to insulin triggered GLUT4 exocytosis, but its molecular mechanism of action has been unclear.	2	7	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
These observations are consistent with previous studies that insulin targets GLUT4 vesicles to specific places of the PM of 3T3-L1 adipocytes .	These observations are consistent with previous studies that insulin targets GLUT4 vesicles to specific places of the PM of 3T3-L1 adipocytes.	8	11	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
As type I fibers are characterized by high capillary density , lipid storage capacity , insulin binding , insulin stimulated glucose uptake , high GLUT4 content , and high oxidative enzyme activities , a reduction in type I fibers may contribute to prolonged recovery from peak exercise and early fatigue in obese patients and those with T2DM .	As type I fibers are characterized by high capillary density, lipid storage capacity, insulin binding, insulin stimulated glucose uptake, high GLUT4 content, and high oxidative enzyme activities, a reduction in type I fibers may contribute to prolonged recovery from peak exercise and early fatigue in obese patients and those with T2DM.	18	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	24	25
Insulin triggers transport of blood glucose into adipocytes and muscle cells by stimulating a redistribution of GLUT4 from intracellular compartments to the PM .	Insulin triggers transport of blood glucose into adipocytes and muscle cells by stimulating a redistribution of GLUT4 from intracellular compartments to the PM.	0	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	16	17
This signaling cascade is similar to that previously described for insulin induced GLUT4 translocation .	This signaling cascade is similar to that previously described for insulin induced GLUT4 translocation.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Insulin signaling promotes the transport of GLUT4 vesicles to the cell surface and simultaneously limits endocytosis of GLUT4 [ XREF_BIBR ] .	Insulin signaling promotes the transport of GLUT4 vesicles to the cell surface and simultaneously limits endocytosis of GLUT4 [XREF_BIBR].	0	19	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	17	18
AngII inhibits insulin mediated GLUT4 translocation in this skeletal muscle model through a transient activation of ERK1/2 inhibiting insulin receptor substrate 1/2 ( IRS-1/2 ) and through a direct inhibitory nitration of Akt .	AngII inhibits insulin mediated GLUT4 translocation in this skeletal muscle model through a transient activation of ERK1/2 inhibiting insulin receptor substrate 1/2 (IRS-1/2) and through a direct inhibitory nitration of Akt.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Whereas the greater increase in AMPK activity seen in insulin resistant cells may not signal directly to GLUT4 , per se , it may rather suppress excess cholesterol biosynthesis that then positively impacts GLUT4 regulation by insulin .	Whereas the greater increase in AMPK activity seen in insulin resistant cells may not signal directly to GLUT4, per se, it may rather suppress excess cholesterol biosynthesis that then positively impacts GLUT4 regulation by insulin.	7	18	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	17	18
A key observation in this set of experiments was that pretreatment with wortmannin , a PI 3-kinase inhibitor , abolished insulin induced GLUT4 liberation , whereas once the cells were stimulated with insulin , posttreatment with wortmannin did not promptly restore the accelerated behavior to a quiescent state ( XREF_FIG B and Supplemental Figure S3 ) .	A key observation in this set of experiments was that pretreatment with wortmannin, a PI 3-kinase inhibitor, abolished insulin induced GLUT4 liberation, whereas once the cells were stimulated with insulin, posttreatment with wortmannin did not promptly restore the accelerated behavior to a quiescent state (XREF_FIG B and Supplemental Figure S3).	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Consistent with previous reports , expression of dominant negative Rab4 ( N121I ) decreased insulin induced GLUT4 translocation by 45 % .	Consistent with previous reports, expression of dominant negative Rab4 (N121I) decreased insulin induced GLUT4 translocation by 45%.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Rab and Rho especially seem to be involved in intracellular insulin action and affect insulin mediated GLUT4 translocation [ XREF_BIBR ] .	Rab and Rho especially seem to be involved in intracellular insulin action and affect insulin mediated GLUT4 translocation [XREF_BIBR].	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Both exercise and insulin cause GLUT4 to translocate from intracellular storage vesicles to the plasma membrane allowing the entry of glucose into the cell that can then be used as substrate during exercise or during recovery from exercise to replenish glycogen stores XREF_BIBR .	Both exercise and insulin cause GLUT4 to translocate from intracellular storage vesicles to the plasma membrane allowing the entry of glucose into the cell that can then be used as substrate during exercise or during recovery from exercise to replenish glycogen stores XREF_BIBR.	1	6	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
In Tmod3 depleted cells , re-expression of phosphorylation mimetic mutant S71D potentiates and phosphorylation defective mutant S71A mutant impairs the insulin stimulated GLUT4 exocytosis and glucose uptake .	In Tmod3 depleted cells, re-expression of phosphorylation mimetic mutant S71D potentiates and phosphorylation defective mutant S71A mutant impairs the insulin stimulated GLUT4 exocytosis and glucose uptake.	18	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Insulin stimulates GLUT4 exocytosis and partially inhibits its endocytosis , resulting in GLUT4 redistribution to the cell surface .	Insulin stimulates GLUT4 exocytosis and partially inhibits its endocytosis, resulting in GLUT4 redistribution to the cell surface.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
The association of 14-3-3gamma with insulin activated GLUT4 vesicles was significantly inhibited by the expression of the PTB domain construct ( XREF_FIG B ) .	The association of 14-3-3gamma with insulin activated GLUT4 vesicles was significantly inhibited by the expression of the PTB domain construct (XREF_FIG B).	3	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
To examine whether insulin responsive acceleration of intracellular GLUT4 dynamics contributes to making the plasma membrane more accessible , we next used our QD based approach with total internal reflection fluorescence ( TIRF ) microscopy ( XREF_FIG , A-C ) .	To examine whether insulin responsive acceleration of intracellular GLUT4 dynamics contributes to making the plasma membrane more accessible, we next used our QD based approach with total internal reflection fluorescence (TIRF) microscopy (XREF_FIG, A-C).	3	9	acceleration	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	8	9
IPA3 fully ablated insulin stimulated GLUT4 translocation to the PM , corroborating the observation of ablated insulin stimulated GLUT4 accumulation in the PM of skeletal muscle from PAK1 -/- knockout mice .	IPA3 fully ablated insulin stimulated GLUT4 translocation to the PM, corroborating the observation of ablated insulin stimulated GLUT4 accumulation in the PM of skeletal muscle from PAK1 -/- knockout mice.	13	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
Rac1 is already known to be important for insulin induced GLUT4 translocation ; this series of experiments introduces and establishes its importance in exercise induced skeletal muscle glucose uptake .	Rac1 is already known to be important for insulin induced GLUT4 translocation; this series of experiments introduces and establishes its importance in exercise induced skeletal muscle glucose uptake.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Insulin mediated GLUT4 trafficking is dependent on the local arrival of the hormone and the subsequent unilateral downstream pathway leading to GLUT4 trafficking .	Insulin mediated GLUT4 trafficking is dependent on the local arrival of the hormone and the subsequent unilateral downstream pathway leading to GLUT4 trafficking.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Insulin causes GLUT4 to translocate to the cell surface in fat and muscle , but Lisinski and coworkers found that insulin does not result in movement of GLUT6 to the cell surface .	Insulin causes GLUT4 to translocate to the cell surface in fat and muscle, but Lisinski and coworkers found that insulin does not result in movement of GLUT6 to the cell surface.	0	3	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
In addition , Mstn inhibited Glut4 mRNA and protein expression , and reduced insulin induced Glut4 membrane translocation and glucose uptake .	In addition, Mstn inhibited Glut4 mRNA and protein expression, and reduced insulin induced Glut4 membrane translocation and glucose uptake.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	13	14	15	16
Quantitative analysis shows that insulin increases GLUT4 labeling on the plasma membrane approximately sevenfold , contractions ninefold , and the two stimuli combined 14-fold , demonstrating a roughly additive effect of the two stimuli .	Quantitative analysis shows that insulin increases GLUT4 labeling on the plasma membrane approximately sevenfold, contractions ninefold, and the two stimuli combined 14-fold, demonstrating a roughly additive effect of the two stimuli.	4	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Significantly , an antibody against p62/CE introduced into rat adipocytes completely abolished the insulin induced GLUT4 recruitment to the plasma membrane in host cells without affecting the basal GLUT4 distribution .	Significantly, an antibody against p62/CE introduced into rat adipocytes completely abolished the insulin induced GLUT4 recruitment to the plasma membrane in host cells without affecting the basal GLUT4 distribution.	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Previous work has identified Rac1 as a downstream mediator of insulin stimulated glucose transport in cultured skeletal muscle , where in vitro siRNA silencing leads to abrogated actin remodeling and prevents insulin induced GLUT4 translocation .	Previous work has identified Rac1 as a downstream mediator of insulin stimulated glucose transport in cultured skeletal muscle, where in vitro siRNA silencing leads to abrogated actin remodeling and prevents insulin induced GLUT4 translocation.	30	34	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	31	32	33	34
Insulin stimulation increases the number of GLUT4 in the plasma membrane , but muscle contraction also stimulates translocation of GLUT4 to the plasma membrane independent of insulin .	Insulin stimulation increases the number of GLUT4 in the plasma membrane, but muscle contraction also stimulates translocation of GLUT4 to the plasma membrane independent of insulin.	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Expression of E4-ORF1 increased the rate of insulin stimulated Glut4 exocytosis ( XREF_FIG ) .	Expression of E4-ORF1 increased the rate of insulin stimulated Glut4 exocytosis (XREF_FIG).	5	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	7	8	9	10
In conclusion , our present study identifies TUSC5 as a novel regulator of prolonged insulin stimulated GLUT4 trafficking , thereby regulating glucose uptake in adipocytes .	In conclusion, our present study identifies TUSC5 as a novel regulator of prolonged insulin stimulated GLUT4 trafficking, thereby regulating glucose uptake in adipocytes.	11	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
An insulin mediated increase of GLUT4 concentration on the cell-surface enhances glucose-uptake to prevent an extracellular hyperglycemic milieu and to deliver glucose for metabolic purposes .	An insulin mediated increase of GLUT4 concentration on the cell-surface enhances glucose-uptake to prevent an extracellular hyperglycemic milieu and to deliver glucose for metabolic purposes.	1	6	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	5	6
Here we examined the effect of knockdown of AS160 , TBC1D1 , and Rabs 8A , 8B , 10 , and 14 ( in vitro substrates of AS160 and TBC1D1 Rab-GAP activities ) on insulin induced GLUT4 translocation in L6 muscle cells .	Here we examined the effect of knockdown of AS160, TBC1D1, and Rabs 8A, 8B, 10, and 14 (in vitro substrates of AS160 and TBC1D1 Rab-GAP activities) on insulin induced GLUT4 translocation in L6 muscle cells.	16	37	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	34	35	36	37
By contrast , insulin triggers a major GLUT4 redistribution from intracellular storage sites to the plasma membrane , accounting for large insulin stimulated increases in glucose uptake .	By contrast, insulin triggers a major GLUT4 redistribution from intracellular storage sites to the plasma membrane, accounting for large insulin stimulated increases in glucose uptake.	3	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	7	8
Intriguingly , this did not suppress the insulin mimetic stimulation of GLUT4 translocation by AICAR and DNP ; whereas siAMPK knockdown did , suggesting that increased AMPK activity affects basal and insulin stimulated GLUT4 regulation by divergent mechanisms .	Intriguingly, this did not suppress the insulin mimetic stimulation of GLUT4 translocation by AICAR and DNP; whereas siAMPK knockdown did, suggesting that increased AMPK activity affects basal and insulin stimulated GLUT4 regulation by divergent mechanisms.	29	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	31	32	33	34
Pioglitazone restores insulin induced Glut 4 translocation in normal tissues , without directly effecting cancer cells which rely on more efficient , but less regulated mechanisms for glucose uptake .	Pioglitazone restores insulin induced Glut 4 translocation in normal tissues, without directly effecting cancer cells which rely on more efficient, but less regulated mechanisms for glucose uptake.	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut 4	Glut 4	Glut 4	2	3	4	6
However , the increased basal intracellular GLUT4 in the diabetic treated group did not result in more insulin mediated GLUT4 translocation at 15 min after insulin injection .	However, the increased basal intracellular GLUT4 in the diabetic treated group did not result in more insulin mediated GLUT4 translocation at 15 min after insulin injection.	14	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
In mature adipocytes , glucose uptake is carried out by GLUT4 which is driven by insulin signaling transduction that is activated by sequential posphorylation of insulin signaling proteins , including IR , IRS1 , PI3K and Akt2 .	In mature adipocytes, glucose uptake is carried out by GLUT4 which is driven by insulin signaling transduction that is activated by sequential posphorylation of insulin signaling proteins, including IR, IRS1, PI3K and Akt2.	7	17	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	10	11
Collectively , our studies demonstrate that insulin stimulates myosin IIA activity and promotes the embedding of GLUT4 into the plasma membrane and the activation of GLUT4 .	Collectively, our studies demonstrate that insulin stimulates myosin IIA activity and promotes the embedding of GLUT4 into the plasma membrane and the activation of GLUT4.	6	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	16	17
These results suggest that conventional kinesin is dispensable for insulin induced GLUT4 translocation in cultured myoblasts and may thus reveal a cell-type specific role of the microtubules based cytoskeleton in glucose transport in response to insulin .	These results suggest that conventional kinesin is dispensable for insulin induced GLUT4 translocation in cultured myoblasts and may thus reveal a cell-type specific role of the microtubules based cytoskeleton in glucose transport in response to insulin.	9	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
These results suggest that the initial event caused by overnutrition may be oxidative stress , which produces insulin resistance , at least in part , via carbonylation and oxidation induced inactivation of GLUT4 .	These results suggest that the initial event caused by overnutrition may be oxidative stress, which produces insulin resistance, at least in part, via carbonylation and oxidation induced inactivation of GLUT4.	17	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	32	33
Interestingly , we identified several phosphorylation sites in a subset of proteins , which have previously been shown to be overexpressed in relation to type 2 diabetes or related traits or involved in insulin mediated GLUT4 translocation .	Interestingly, we identified several phosphorylation sites in a subset of proteins, which have previously been shown to be overexpressed in relation to type 2 diabetes or related traits or involved in insulin mediated GLUT4 translocation.	31	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	33	34	35	36
Similarly insulin stimulated GLUT4 translocation for glucose transport exibits bistable switch like response to the insulin input .	Similarly insulin stimulated GLUT4 translocation for glucose transport exibits bistable switch like response to the insulin input.	1	4	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	3	4
Examination of the time and temperature dependence of insulin stimulated GLUT4 and IRAP containing vesicle trafficking demonstrated an approximate 7-fold increase in the half-time for plasma membrane translocation at 23 degrees C ( t ( ( 1 )/( 2 ) ) = approximately 30 min ) compared with 37 degrees C ( t ( ( 1 )/( 2 ) ) = approximately 4 min ) without a significant change in the extent of either GLUT4 or IRAP translocation .	Examination of the time and temperature dependence of insulin stimulated GLUT4 and IRAP containing vesicle trafficking demonstrated an approximate 7-fold increase in the half-time for plasma membrane translocation at 23 degrees C (t ((1)/(2)) = approximately 30 min) compared with 37 degrees C (t ((1)/(2)) = approximately 4 min) without a significant change in the extent of either GLUT4 or IRAP translocation.	6	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Therefore , the enhancement of the insulin induced GLUT4 translocation by Rut has revealed its potent activity in insulin-sensitivity improvement .	Therefore, the enhancement of the insulin induced GLUT4 translocation by Rut has revealed its potent activity in insulin-sensitivity improvement.	3	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Insulin augments GLUT4 dissociation from clusters into PM and decreases the rate of endocytic uptake thus shifting PM GLUT4 towards dispersed monomers .	Insulin augments GLUT4 dissociation from clusters into PM and decreases the rate of endocytic uptake thus shifting PM GLUT4 towards dispersed monomers.	0	9	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
This finding marked a breakthrough in understanding how the insulin signal coordinately triggered mobilization of intracellular GLUT4 vesicles , while simultaneously preparing SNARE proteins at the PM for vesicle docking and fusion .	This finding marked a breakthrough in understanding how the insulin signal coordinately triggered mobilization of intracellular GLUT4 vesicles, while simultaneously preparing SNARE proteins at the PM for vesicle docking and fusion.	9	17	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	16	17
Although both adiponectin release and GLUT4 trafficking can be stimulated by insulin , the two proteins are localized in two different types of vesicles [ XREF_BIBR ] .	Although both adiponectin release and GLUT4 trafficking can be stimulated by insulin, the two proteins are localized in two different types of vesicles [XREF_BIBR].	5	12	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	5	6
Insulin stimulation induces a rapid subcellular redistribution of GLUT4 from the intracellular pool to the plasma membrane .	Insulin stimulation induces a rapid subcellular redistribution of GLUT4 from the intracellular pool to the plasma membrane.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	8	9
In conclusion , 5 days of AICAR administration induces a pronounced fiber type specific increase in insulin stimulated glucose uptake and GLUT4 cell surface content in rat skeletal muscle with the greatest effect observed on white fast-twitch glycolytic muscles ( EPI ) .	In conclusion, 5 days of AICAR administration induces a pronounced fiber type specific increase in insulin stimulated glucose uptake and GLUT4 cell surface content in rat skeletal muscle with the greatest effect observed on white fast-twitch glycolytic muscles (EPI).	8	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	21	22
For instance , new approaches to perturb insulin signaling in a rapid and specific manner , our group has recently applied an optogenetic system to control the activation of PI3K and Akt both spatially and temporally and dissect the role of individual of them in insulin stimulated GLUT4 vesicle exocytosis [ XREF_BIBR ] .	For instance, new approaches to perturb insulin signaling in a rapid and specific manner, our group has recently applied an optogenetic system to control the activation of PI3K and Akt both spatially and temporally and dissect the role of individual of them in insulin stimulated GLUT4 vesicle exocytosis [XREF_BIBR].	37	49	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	45	46	47	48
RhoQ has been most extensively studied for its central role in insulin stimulated GLUT4 transport in adipocytes [ XREF_BIBR ] .	RhoQ has been most extensively studied for its central role in insulin stimulated GLUT4 transport in adipocytes [XREF_BIBR].	5	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Taken together , these data demonstrate that insulin can induce GLUT4 vesicle actin comet tails that are necessary for the efficient translocation of GLUT4 from intracellular storage sites to the plasma membrane .	Taken together, these data demonstrate that insulin can induce GLUT4 vesicle actin comet tails that are necessary for the efficient translocation of GLUT4 from intracellular storage sites to the plasma membrane.	7	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	10	11
Taken together , our data show that Ang II inhibits insulin mediated GLUT4 translocation in this skeletal muscle model through at least two pathways : first through the transient activation of ERK1/2 which inhibit IRS-1/2 and second through a direct inhibitory nitration of Akt .	Taken together, our data show that Ang II inhibits insulin mediated GLUT4 translocation in this skeletal muscle model through at least two pathways : first through the transient activation of ERK1/2 which inhibit IRS-1/2 and second through a direct inhibitory nitration of Akt.	9	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
XREF_BIBR The results clearly demonstrated that insulin induced GLUT4 translocation to the sarcolemma was largely suppressed in gastrocnemius muscle of muscle specific rac1 knockout mice .	XREF_BIBR The results clearly demonstrated that insulin induced GLUT4 translocation to the sarcolemma was largely suppressed in gastrocnemius muscle of muscle specific rac1 knockout mice.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
In non equilibrium fractions , insulin led to small GLUT4 decrements in the 25 and 28 % sucrose fractions and increased GLUT4 in the 32 % sucrose fraction by 2.8-fold over basal in insulin sensitive but only by 1.5-fold in both insulin resistant and diabetic subgroups .	In non equilibrium fractions, insulin led to small GLUT4 decrements in the 25 and 28% sucrose fractions and increased GLUT4 in the 32% sucrose fraction by 2.8-fold over basal in insulin sensitive but only by 1.5-fold in both insulin resistant and diabetic subgroups.	5	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	21	22
Finally , although the function of TBC1D1 is unknown , the protein is structurally similar to a known regulator of insulin mediated Glut4 translocation .	Finally, although the function of TBC1D1 is unknown, the protein is structurally similar to a known regulator of insulin mediated Glut4 translocation.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	20	21	22	23
We infer that insulin levels increase in the OB during satiety to stimulate translocation of GLUT4 storage vesicles to the plasma membrane thereby increasing glucose uptake .	We infer that insulin levels increase in the OB during satiety to stimulate translocation of GLUT4 storage vesicles to the plasma membrane thereby increasing glucose uptake.	3	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	GLUT4	GLUT4	glut4	3	4	15	16
In skeletal muscle , insulin reversibly stimulates local depletion of GLUT4 storage vesicles at sarcolemma and t-tubules rather than inducing movement of intact storage vesicles .	In skeletal muscle, insulin reversibly stimulates local depletion of GLUT4 storage vesicles at sarcolemma and t-tubules rather than inducing movement of intact storage vesicles.	4	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	10	11
The increase in ADP ribose observed in the present study is likely indicative of exercise mediated enhancement of GLUT4 translocation and improved glucose uptake as opposed to insulin mediated GLUT4 translocation XREF_BIBR .	The increase in ADP ribose observed in the present study is likely indicative of exercise mediated enhancement of GLUT4 translocation and improved glucose uptake as opposed to insulin mediated GLUT4 translocation XREF_BIBR.	25	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	27	28	29	30
Defect of insulin induced GLUT4 translocation and actin remodeling may cause insulin resistance .	Defect of insulin induced GLUT4 translocation and actin remodeling may cause insulin resistance.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Moreover , inhibition of the ceramide biosynthesis with fumonisin B , which inhibits ceramide synthase , completely restored insulin induced GLUT4 mRNA and protein accumulation as well as GLUT4-CAT transactivation in the presence of TNF-alpha .	Moreover, inhibition of the ceramide biosynthesis with fumonisin B, which inhibits ceramide synthase, completely restored insulin induced GLUT4 mRNA and protein accumulation as well as GLUT4-CAT transactivation in the presence of TNF-alpha.	18	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
Importantly , Akt2 appears to regulate AS160 ( namely , Akt substrate protein of 160kDa ) , which is the most distal signaling protein that has been implicated in insulin mediated GLUT4 translocation and as such has emerged as a key regulator of GLUT trafficking .	Importantly, Akt2 appears to regulate AS160 (namely, Akt substrate protein of 160kDa), which is the most distal signaling protein that has been implicated in insulin mediated GLUT4 translocation and as such has emerged as a key regulator of GLUT trafficking.	27	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	29	30	31	32
Nonprocessive nonmuscle myosin II , which is known to form homodimers via the alpha-helical coiled-coil region , regulates insulin stimulated glucose uptake and fusion of GLUT4 vesicles to the plasma membrane .	Nonprocessive nonmuscle myosin II, which is known to form homodimers via the alpha-helical coiled-coil region, regulates insulin stimulated glucose uptake and fusion of GLUT4 vesicles to the plasma membrane.	17	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	25	26
In skeletal myotubes , which are similar to cardiac myocytes in the regulation of glucose metabolism , insulin stimulated GLUT4 translocation and glucose uptake is not affected by JAK2 silencing , whereas the proliferative effects of insulin are blunted .	In skeletal myotubes, which are similar to cardiac myocytes in the regulation of glucose metabolism, insulin stimulated GLUT4 translocation and glucose uptake is not affected by JAK2 silencing, whereas the proliferative effects of insulin are blunted.	17	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
We previously showed that in skeletal muscle , insulin stimulates proteolytic processing of the GLUT4 retention protein , TUG , to promote GLUT4 translocation and glucose uptake .	We previously showed that in skeletal muscle, insulin stimulates proteolytic processing of the GLUT4 retention protein, TUG, to promote GLUT4 translocation and glucose uptake.	8	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	14	15
To delineate the functional requirement for Munc18c phosphorylation at these putative sites in insulin stimulated GLUT4 vesicle exocytosis , the endogenous Munc18c protein level was reduced via coelectroporation of 3T3-L1 adipocytes with small hairpin RNA ( shRNA ) plasmid , coordinate with the coexpression of Flag tagged Munc18c-WT , -Y219F , or -Y521F mutants ( with Flag tagged proteins made resistant to RNAi ) .	To delineate the functional requirement for Munc18c phosphorylation at these putative sites in insulin stimulated GLUT4 vesicle exocytosis, the endogenous Munc18c protein level was reduced via coelectroporation of 3T3-L1 adipocytes with small hairpin RNA (shRNA) plasmid, coordinate with the coexpression of Flag tagged Munc18c-WT, -Y219F, or -Y521F mutants (with Flag tagged proteins made resistant to RNAi).	11	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Insulin induced GLUT4 translocation from intracellular storage vesicles onto cell surface involves multiple stages including soluble N-ethylmaleimide-sensitive factor attachment protein receptor ( SNARE )-mediated docking and fusion steps .	Insulin induced GLUT4 translocation from intracellular storage vesicles onto cell surface involves multiple stages including soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated docking and fusion steps.	0	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Akt substrate of 160 kDa ( AS160 ) is known to be a wortmannin sensitive downstream regulator of insulin signaling , and its T642 residue has been shown to function as a critical Akt dependent phosphorylation site responsible for exerting insulin induced GLUT4 translocation .	Akt substrate of 160 kDa (AS160) is known to be a wortmannin sensitive downstream regulator of insulin signaling, and its T642 residue has been shown to function as a critical Akt dependent phosphorylation site responsible for exerting insulin induced GLUT4 translocation.	39	43	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	40	41	42	43
Similarly , insulin increases GLUT4 labeling on the T tubule membrane approximately 15-fold , contractions 20-fold , and the two stimuli combined 30-fold , again a roughly additive effect .	Similarly, insulin increases GLUT4 labeling on the T tubule membrane approximately 15-fold, contractions 20-fold, and the two stimuli combined 30-fold, again a roughly additive effect.	2	5	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Acute insulin treatment caused the depletion of GLUT4 in both pools and of GLUT1 and SCAMP 39 in pool 2 .	Acute insulin treatment caused the depletion of GLUT4 in both pools and of GLUT1 and SCAMP 39 in pool 2.	1	8	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	7	8
Taken together , these data demonstrate that insulin stimulated GLUT4 externalization and glucose uptake is significantly impaired in skeletal muscle tissue of Doc2b -/- mice .	Taken together, these data demonstrate that insulin stimulated GLUT4 externalization and glucose uptake is significantly impaired in skeletal muscle tissue of Doc2b -/- mice.	7	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Insulin causes immobilization of GLUT4 positive vesicles underneath the plasma membrane , and this immobilization is dependent on the presence of Myo1c and its actin binding activity .	Insulin causes immobilization of GLUT4 positive vesicles underneath the plasma membrane, and this immobilization is dependent on the presence of Myo1c and its actin binding activity.	0	6	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	4	5
Effect of Aging and Physical Activity on Insulin stimulated GLUT4 Localization .	Effect of Aging and Physical Activity on Insulin stimulated GLUT4 Localization.	5	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Identification of Three Distinct Functional Sites of Insulin mediated GLUT4 Trafficking in Adipocytes Using Quantitative Single Molecule Imaging .	Identification of Three Distinct Functional Sites of Insulin mediated GLUT4 Trafficking in Adipocytes Using Quantitative Single Molecule Imaging.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Together , these findings provide evidence that the traditional understanding of insulin induced GLUT4 translocation as process consisting of 1 ) a large degree of GLUT4 vesicle movement towards the membranes ; 2 ) GLUT4 vesicle docking at the membranes ; and 3 ) GLUT4 vesicle fusion into the membranes may not accurately reflect GLUT4 trafficking in mature muscle .	Together, these findings provide evidence that the traditional understanding of insulin induced GLUT4 translocation as process consisting of 1) a large degree of GLUT4 vesicle movement towards the membranes; 2) GLUT4 vesicle docking at the membranes; and 3) GLUT4 vesicle fusion into the membranes may not accurately reflect GLUT4 trafficking in mature muscle.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Rosiglitazone ameliorated insulin resistance by TNF-alpha in brown adipocytes , restoring completely insulin stimulated glucose uptake and insulin induced GLUT4 translocation to plasma membrane in parallel to the insulin signalling cascade IRS-2/PI 3-kinase/Akt .	Rosiglitazone ameliorated insulin resistance by TNF-alpha in brown adipocytes, restoring completely insulin stimulated glucose uptake and insulin induced GLUT4 translocation to plasma membrane in parallel to the insulin signalling cascade IRS-2/PI 3-kinase/Akt.	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Several of the kinases involved in insulin induced GLUT4 translocation have been tested on their additional involvement in insulin induced CD36 translocation .	Several of the kinases involved in insulin induced GLUT4 translocation have been tested on their additional involvement in insulin induced CD36 translocation.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Insulin treatment greatly increases the rate of GLUT4 exocytosis and reduces the rate of endocytosis changing the equilibrium localization .	Insulin treatment greatly increases the rate of GLUT4 exocytosis and reduces the rate of endocytosis changing the equilibrium localization.	0	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	7	8
Insulin stimulates glucose transport in skeletal muscle , heart , and adipose tissue by promoting the appearance of GLUT4 , the major glucose transporter isoform present in these tissues , on the cell surface .	Insulin stimulates glucose transport in skeletal muscle, heart, and adipose tissue by promoting the appearance of GLUT4, the major glucose transporter isoform present in these tissues, on the cell surface.	0	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	18	19
For the insulin responsive glucose transporter GLUT4 ( glucose transporter number 4 ) , details are presented on how to quantitatively measure insulin induced GLUT4 translocation toward the plasma membrane ( transition state ) and to analyze cell surface recycling of GLUT4 in basal and insulin stimulated cells ( steady state ) .	For the insulin responsive glucose transporter GLUT4 (glucose transporter number 4), details are presented on how to quantitatively measure insulin induced GLUT4 translocation toward the plasma membrane (transition state) and to analyze cell surface recycling of GLUT4 in basal and insulin stimulated cells (steady state).	21	25	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	24	25
Notably however , although we had found that the association of ACAP1 with integrin beta1 was stimulation dependent , insulin stimulation did not enhance the association of Glut4 with either ACAP1 or CHC ( XREF_FIG ) .	Notably however, although we had found that the association of ACAP1 with integrin beta1 was stimulation dependent, insulin stimulation did not enhance the association of Glut4 with either ACAP1 or CHC (XREF_FIG).	19	28	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	19	20	27	28
The precise role of this PtdIns ( 3 ) P pool is currently unclear , but reductions in this pool are co-incident with reductions in insulin stimulated GLUT4 trafficking and glucose transport [ XREF_BIBR - XREF_BIBR ] .	The precise role of this PtdIns (3) P pool is currently unclear, but reductions in this pool are co-incident with reductions in insulin stimulated GLUT4 trafficking and glucose transport [XREF_BIBR - XREF_BIBR].	23	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	27	28
To determine the mechanism for enhancement of glucose transport with PAHSAs we analyzed the effects on insulin induced Glut4 translocation to the plasma membrane in adipocytes .	To determine the mechanism for enhancement of glucose transport with PAHSAs we analyzed the effects on insulin induced Glut4 translocation to the plasma membrane in adipocytes.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	16	17	18	19
These observations were intriguing and prompted us to probe the potential role for CaMKII in insulin stimulated GLUT4 traffic in muscle cells .	These observations were intriguing and prompted us to probe the potential role for CaMKII in insulin stimulated GLUT4 traffic in muscle cells.	8	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
Insulin induced GLUT4 translocation was reported to occur through a pathway involving IRS1/PI3K/PDK2/Akt2 S473 / AS160 in human skeletal muscle XREF_BIBR , and our results show that insulin stimulated a similar pathway in insulin sensitive myotubes ( XREF_FIG ) .	Insulin induced GLUT4 translocation was reported to occur through a pathway involving IRS1/PI3K/PDK2/Akt2 S473 / AS160 in human skeletal muscle XREF_BIBR, and our results show that insulin stimulated a similar pathway in insulin sensitive myotubes (XREF_FIG).	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
The augmentation in cell surface GLUT4 levels was maintained in adipocytes that were rendered insulin resistant in vitro by a 24h insulin treatment and moreover in these cells rosiglitazone also fully restored insulin induced GLUT4 translocation .	The augmentation in cell surface GLUT4 levels was maintained in adipocytes that were rendered insulin resistant in vitro by a 24h insulin treatment and moreover in these cells rosiglitazone also fully restored insulin induced GLUT4 translocation.	32	35	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	32	33	34	35
Glucose transporter 4 ( GLUT4 ) is expressed in skeletal and cardiac muscle and adipocytes and plays a major role in insulin stimulated glucose uptake ; insulin stimulation triggers a series of signal transduction to translocate intracellular GLUT4 containing vesicles to the plasma membrane , where GLUT4 is engaged in glucose uptake into cells .	Glucose transporter 4 (GLUT4) is expressed in skeletal and cardiac muscle and adipocytes and plays a major role in insulin stimulated glucose uptake; insulin stimulation triggers a series of signal transduction to translocate intracellular GLUT4 containing vesicles to the plasma membrane, where GLUT4 is engaged in glucose uptake into cells.	26	38	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	37	38
Collectively , these data implicate enhanced insulin stimulated GLUT4 vesicle accumulation ( docking and fusion ) at the PM as an underlying cause for the enhanced peripheral insulin sensitivity of the Doc2b Tg mice .	Collectively, these data implicate enhanced insulin stimulated GLUT4 vesicle accumulation (docking and fusion) at the PM as an underlying cause for the enhanced peripheral insulin sensitivity of the Doc2b Tg mice.	4	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
In line with these findings , adipocytes from Munc18c knockout ( KO ) mice exhibit increased sensitivity to insulin stimulated GLUT4 externalization and suggest that Munc18c-syntaxin4 interaction should be disrupted for docking and fusion to proceed [ XREF_BIBR ] .	In line with these findings, adipocytes from Munc18c knockout (KO) mice exhibit increased sensitivity to insulin stimulated GLUT4 externalization and suggest that Munc18c-syntaxin4 interaction should be disrupted for docking and fusion to proceed [XREF_BIBR].	16	21	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
Quercetin demonstrated divergent effects on insulin mediated GLUT4 translocation in adipocytes under basal and insulin resistant conditions , which were related to its regulation of AMPK activity .	Quercetin demonstrated divergent effects on insulin mediated GLUT4 translocation in adipocytes under basal and insulin resistant conditions, which were related to its regulation of AMPK activity.	1	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
Therefore , an integrated mode for active actin cycling is proposed that enables insulin mediated GLUT4 translocation and insertion into the muscle cell membrane .	Therefore, an integrated mode for active actin cycling is proposed that enables insulin mediated GLUT4 translocation and insertion into the muscle cell membrane.	12	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Subcellular fractionation and semiquantitative immunoblotting analysis revealed that BFA inhibits insulin induced redistribution of GLUT4 from microsomes to the plasma membranes , with a dose dependence similar to that for glucose transport inhibition .	Subcellular fractionation and semiquantitative immunoblotting analysis revealed that BFA inhibits insulin induced redistribution of GLUT4 from microsomes to the plasma membranes, with a dose dependence similar to that for glucose transport inhibition.	9	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	14	15
In transgenic muscle , the insulin stimulated shifts in GLUT4 distribution were inhibited by over 70 % .	In transgenic muscle, the insulin stimulated shifts in GLUT4 distribution were inhibited by over 70%.	4	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	9	10
As such , this circumstance has also contributed to the current view that insulin promotes glut4 recycling by targeting mainly its later steps .	As such, this circumstance has also contributed to the current view that insulin promotes glut4 recycling by targeting mainly its later steps.	13	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	glut4	glut4	glut4	13	14	15	16
These small vesicles , termed GLUT4 storage vesicles ( GSVs ) are believed to be the principle donors responsible for insulin stimulated GLUT4 delivery to the plasma membrane .	These small vesicles, termed GLUT4 storage vesicles (GSVs) are believed to be the principle donors responsible for insulin stimulated GLUT4 delivery to the plasma membrane.	18	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
The relative levels of plasma membrane localized GLUT4 in MCF10A and MCF10HER2 cells treated with and without insulin shown in XREF_FIG correlated with the relative amounts of glucose uptake shown in XREF_FIG .	The relative levels of plasma membrane localized GLUT4 in MCF10A and MCF10HER2 cells treated with and without insulin shown in XREF_FIG correlated with the relative amounts of glucose uptake shown in XREF_FIG.	2	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	7	8
The improved insulin sensitivity is the result of greater insulin mediated GLUT4 translocation , but the cellular events responsible for this are poorly understood .	The improved insulin sensitivity is the result of greater insulin mediated GLUT4 translocation, but the cellular events responsible for this are poorly understood.	6	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
The change in expression of the insulin stimulated glucose transporter GLUT4 could affect glucose uptake in the myocardial cells .	The change in expression of the insulin stimulated glucose transporter GLUT4 could affect glucose uptake in the myocardial cells.	3	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	expression of the insulin	insulin	GLUT4	GLUT4	glut4	6	7	10	11
As already explained , higher GLUT4 in PM regions may confer an insulin-sensitivity advantage and could provide the link between greater GLUT4 protein content and greater insulin mediated GLUT4 translocation and improved insulin sensitivity post-training .	As already explained, higher GLUT4 in PM regions may confer an insulin-sensitivity advantage and could provide the link between greater GLUT4 protein content and greater insulin mediated GLUT4 translocation and improved insulin sensitivity post-training.	16	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	28	29
On surface of membrane , insulin increases number of glucose carriers GLUT4 .	On surface of membrane, insulin increases number of glucose carriers GLUT4.	5	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	11	12
These data indicated that Akt activation was required by T3 to enhance insulin induced GLUT4 translocation .	These data indicated that Akt activation was required by T3 to enhance insulin induced GLUT4 translocation.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Moreover , it has been shown that insulin , via PI3K , induces the activation and intracellular redistribution in adipocytes of another member of the Rab family , Rab4 , which is involved in GLUT-4 vesicle trafficking XREF_BIBR .	Moreover, it has been shown that insulin, via PI3K, induces the activation and intracellular redistribution in adipocytes of another member of the Rab family, Rab4, which is involved in GLUT-4 vesicle trafficking XREF_BIBR.	7	37	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	7	8	34	35
Insulin is known to stimulate insulin receptor ( IR )-mediated signaling cascades that ultimately result in the recruitment of GLUT4 to the cell surface by dramatically accelerating GLUT4 insertion into the PM by exocytosis and inhibiting GLUT4 endocytosis , thereby increasing glucose flux into the cells .	Insulin is known to stimulate insulin receptor (IR)-mediated signaling cascades that ultimately result in the recruitment of GLUT4 to the cell surface by dramatically accelerating GLUT4 insertion into the PM by exocytosis and inhibiting GLUT4 endocytosis, thereby increasing glucose flux into the cells.	0	28	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	27	28
GLUT12 gene was identified in MCF-7 breast cancer cells by homology with the insulin stimulated GLUT4 gene , although its protein sequence displays more similarity with GLUT10 .	GLUT12 gene was identified in MCF-7 breast cancer cells by homology with the insulin stimulated GLUT4 gene, although its protein sequence displays more similarity with GLUT10.	3	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
The effect of vanadium on insulin induced GLUT4 translocation was studied at 5 min as the early insulin response and at 15 min after insulin injection as the maximal insulin response .	The effect of vanadium on insulin induced GLUT4 translocation was studied at 5 min as the early insulin response and at 15 min after insulin injection as the maximal insulin response.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
On the other hand , cells expressing phosphomimetic S71D showed further enhancement of insulin induced GLUT4 exocytosis ( XREF_FIG ) .	On the other hand, cells expressing phosphomimetic S71D showed further enhancement of insulin induced GLUT4 exocytosis (XREF_FIG).	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Therefore , treatment with GL extracts enhanced insulin mediated GLUT4 translocation on the plasma membrane of muscle cells , leading to the improvement of insulin sensitivity .	Therefore, treatment with GL extracts enhanced insulin mediated GLUT4 translocation on the plasma membrane of muscle cells, leading to the improvement of insulin sensitivity.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
In these cells insulin stimulated GLUT4 translocation is impaired , but can be corrected with exogenous PIP 2 addition to the PM that mediates a restoration of F-actin structure [ XREF_BIBR , XREF_BIBR ] .	In these cells insulin stimulated GLUT4 translocation is impaired, but can be corrected with exogenous PIP 2 addition to the PM that mediates a restoration of F-actin structure [XREF_BIBR, XREF_BIBR].	0	6	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
This hypothesis is in agreement with in vitro studies showing that incubation of L6E9 cells with NRG1 for 48h increased insulin mediated GLUT4 translocation to the plasma membrane and glucose uptake [ XREF_BIBR ] .	This hypothesis is in agreement with in vitro studies showing that incubation of L6E9 cells with NRG1 for 48h increased insulin mediated GLUT4 translocation to the plasma membrane and glucose uptake [XREF_BIBR].	19	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Insulin increases glucose transport in muscle by translocating GLUT 4 glucose transporting protein from intracellular stores to sarcolemma [ XREF_BIBR ] .	Insulin increases glucose transport in muscle by translocating GLUT 4 glucose transporting protein from intracellular stores to sarcolemma [XREF_BIBR].	0	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT 4	GLUT 4	GLUT 4	0	1	8	10
We find : 1 ) clusters are generated by fusion with retention of GLUT4 in nascent domains ; 2 ) GLUT4 is internalized at these domains after subsequent recruitment of clathrin , and 3 ) insulin induces a burst of GLUT4 exocytosis that mostly bypasses these domains and disperses GLUT4 directly into PM .	We find : 1) clusters are generated by fusion with retention of GLUT4 in nascent domains; 2) GLUT4 is internalized at these domains after subsequent recruitment of clathrin, and 3) insulin induces a burst of GLUT4 exocytosis that mostly bypasses these domains and disperses GLUT4 directly into PM.	35	41	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	35	36	40	41
These data suggest that Mstn inhibits Glut4 expression and insulin induced Glut4 integration into cytoplasmic membranes and glucose uptake and that these changes are mediated by direct insulin desensitizing effect and indirect suppression of AMPK activation .	These data suggest that Mstn inhibits Glut4 expression and insulin induced Glut4 integration into cytoplasmic membranes and glucose uptake and that these changes are mediated by direct insulin desensitizing effect and indirect suppression of AMPK activation.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	9	10	11	12
GPR120 activation appears to explain the effects on insulin induced Glut4 translocation and glucose uptake in adipocytes ( XREF_FIG ) , and may explain the effects on GLP-1 secretion and inhibition of inflammatory responses in immune cells .	GPR120 activation appears to explain the effects on insulin induced Glut4 translocation and glucose uptake in adipocytes (XREF_FIG), and may explain the effects on GLP-1 secretion and inhibition of inflammatory responses in immune cells.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	8	9	10	11
Together , these data indicate that insulin increases GLUT4 number in the mobile phase in a PI 3-kinase/AS160-dependent manner .	Together, these data indicate that insulin increases GLUT4 number in the mobile phase in a PI 3-kinase/AS160-dependent manner.	6	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
A Novel Method for Simulating Insulin Mediated GLUT4 Translocation .	A Novel Method for Simulating Insulin Mediated GLUT4 Translocation.	4	8	Mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
Recent work from our laboratory supports the concept that insulin also stimulates the intrinsic activity of GLUT4 through a signaling pathway that includes p38 MAPK .	Recent work from our laboratory supports the concept that insulin also stimulates the intrinsic activity of GLUT4 through a signaling pathway that includes p38 MAPK.	9	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	16	17
1,25 ( OH ) ( 2 ) D ( 3 ) treatment along with insulin enhanced GLUT4 translocation and glucose utilization compared with either insulin or 1,25 ( OH ) ( 2 ) D ( 3 ) alone in HG treated adipocytes .	1,25 (OH) (2) D (3) treatment along with insulin enhanced GLUT4 translocation and glucose utilization compared with either insulin or 1,25 (OH) (2) D (3) alone in HG treated adipocytes.	12	17	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
SNAP23 is required for insulin induced GLUT4 translocation to the plasma membrane and that it mediates the formation of a complex between syntaxin4 and VAMP2 [ XREF_BIBR ] .	SNAP23 is required for insulin induced GLUT4 translocation to the plasma membrane and that it mediates the formation of a complex between syntaxin4 and VAMP2 [XREF_BIBR].	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
In TUSC5 knockdown cells , insulin stimulated HA-GLUT4 translocation was significantly blunted at both 0.5 and 100 nm insulin .	In TUSC5 knockdown cells, insulin stimulated HA-GLUT4 translocation was significantly blunted at both 0.5 and 100 nm insulin.	5	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	HA-GLUT4	HA-GLUT4	HA-GLUT4	5	6	7	8
As previously shown , insulin stimulated a dramatic increase in plasma membrane bound GLUT4 compared to unstimulated adipocytes ( XREF_FIG ) .	As previously shown, insulin stimulated a dramatic increase in plasma membrane bound GLUT4 compared to unstimulated adipocytes (XREF_FIG).	4	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	13	14
Cells expressing Mutation1 or Mutation2 lacked an insulin mediated GLUT4 redistribution ( P = NS for comparison between basal state and insulin time points ) , a finding significantly different from PMVECs with No Mutation ( P < 0.05 at all time points for Mutation1 ; P < 0.05 at 30min for Mutation2 ) .	Cells expressing Mutation1 or Mutation2 lacked an insulin mediated GLUT4 redistribution (P = NS for comparison between basal state and insulin time points), a finding significantly different from PMVECs with No Mutation (P < 0.05 at all time points for Mutation1; P < 0.05 at 30min for Mutation2).	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
The mechanisms underlying ischemia- and insulin mediated GLUT-4 translocation are known to be different , raising the possibility that the intracellular destinations of GLUT-4 following these stimuli also differ .	The mechanisms underlying ischemia- and insulin mediated GLUT-4 translocation are known to be different, raising the possibility that the intracellular destinations of GLUT-4 following these stimuli also differ.	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	5	6	7	8
Therefore , we analyzed insulin actions in 3T3L1 adipocytes overexpressing T642A mutant version of AS160 and found that insulin failed to trigger acceleration of GLUT4 movement , resulting in no increase in mobile GLUT4 fraction in the cells ( XREF_FIG B and Supplemental Figure S3C ) .	Therefore, we analyzed insulin actions in 3T3L1 adipocytes overexpressing T642A mutant version of AS160 and found that insulin failed to trigger acceleration of GLUT4 movement, resulting in no increase in mobile GLUT4 fraction in the cells (XREF_FIG B and Supplemental Figure S3C).	18	25	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	24	25
As expected , insulin increased GLUT4 abundance in plasma membrane fractions , indicating its translocation to the membrane .	As expected, insulin increased GLUT4 abundance in plasma membrane fractions, indicating its translocation to the membrane.	3	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
XREF_BIBR Thus , insulin promotes the docking and fusion of GLUT4 containing vesicles to the plasma membrane .	XREF_BIBR Thus, insulin promotes the docking and fusion of GLUT4 containing vesicles to the plasma membrane.	3	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	10	11
Knockdown of Rab8A and Rab14 , but not of Rab8B or Rab10 , inhibited insulin induced GLUT4 translocation .	Knockdown of Rab8A and Rab14, but not of Rab8B or Rab10, inhibited insulin induced GLUT4 translocation.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
PI3K is responsible for the insulin stimulation of GLUT4 , the major insulin regulated glucose transporter from intracellular vesicles to the plasma membrane in insulin sensitive cells .	PI3K is responsible for the insulin stimulation of GLUT4, the major insulin regulated glucose transporter from intracellular vesicles to the plasma membrane in insulin sensitive cells.	5	12	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	8	9
The two glitazones improved insulin sensitivity and both muscle insulin stimulated glucose transport and GLUT4 total content .	The two glitazones improved insulin sensitivity and both muscle insulin stimulated glucose transport and GLUT4 total content.	4	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	14	15
For example , a previous study XREF_BIBR reported that a PI3K independent pathway , involving the activation of TC10 , is required for F-actin assembly to support the insulin stimulated GLUT4 exocytosis in adipocytes , along with several other studies that propose actin associated proteins such as N-WASP and the myosin motor Myo1c to function downstream of the wortmannin-insensitive pathway XREF_BIBR XREF_BIBR .	For example, a previous study XREF_BIBR reported that a PI3K independent pathway, involving the activation of TC10, is required for F-actin assembly to support the insulin stimulated GLUT4 exocytosis in adipocytes, along with several other studies that propose actin associated proteins such as N-WASP and the myosin motor Myo1c to function downstream of the wortmannin-insensitive pathway XREF_BIBR XREF_BIBR.	26	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	28	29	30	31
Klip and co-workers have carried out kinetic studies of GLUT4 trafficking in the L6 muscle cell line and have reported that insulin increases cell surface GLUT4 by stimulating GLUT4 exocytosis .	Klip and co-workers have carried out kinetic studies of GLUT4 trafficking in the L6 muscle cell line and have reported that insulin increases cell surface GLUT4 by stimulating GLUT4 exocytosis.	21	26	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	25	26
Insulin primarily promotes the rate of GLUT4 exocytosis and fusion with the PM , a process termed GLUT4 translocation that results in a gain in surface GLUT4 [ XREF_BIBR ] .	Insulin primarily promotes the rate of GLUT4 exocytosis and fusion with the PM, a process termed GLUT4 translocation that results in a gain in surface GLUT4 [XREF_BIBR].	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
In contrast to previous reports , in our experiments siRNA mediated knockdown of each of these three proteins had no detectable effect on GLUT4 translocation stimulated by physiological levels of insulin .	In contrast to previous reports, in our experiments siRNA mediated knockdown of each of these three proteins had no detectable effect on GLUT4 translocation stimulated by physiological levels of insulin.	23	31	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	GLUT4	GLUT4	glut4	30	31	23	24
Quantification of Mean Fluorescence Intensities ( MFI ) from multiple experiments confirmed that insulin mediated GLUT4 translocation is not altered by treatment with either BMP2 or BMP6 .	Quantification of Mean Fluorescence Intensities (MFI) from multiple experiments confirmed that insulin mediated GLUT4 translocation is not altered by treatment with either BMP2 or BMP6.	13	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Expression of AS160-4P did inhibit insulin stimulated redistribution of GLUT4 to the PM of IRAP-KD adipocytes , consistent with the hypothesis that loss of IRAP affects the efficiency , but does not completely block GLUT4 sorting to the GSV ( XREF_FIG D ) .	Expression of AS160-4P did inhibit insulin stimulated redistribution of GLUT4 to the PM of IRAP-KD adipocytes, consistent with the hypothesis that loss of IRAP affects the efficiency, but does not completely block GLUT4 sorting to the GSV (XREF_FIG D).	4	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	9	10
PIKfyve is required for insulin mediated Glut4 translocation .	PIKfyve is required for insulin mediated Glut4 translocation.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	4	5	6	7
Enhancement of Glut4 translocation upon microinjection of purified PLD into cultured adipocytes treated with insulin has been demonstrated .	Enhancement of Glut4 translocation upon microinjection of purified PLD into cultured adipocytes treated with insulin has been demonstrated.	2	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	14	15	2	3
The subcellular fractionation without homogenization described here should be useful in identifying the role of the individual GLUT4 compartments and the associated proteins in insulin induced GLUT4 recruitment in rat adipocytes .	The subcellular fractionation without homogenization described here should be useful in identifying the role of the individual GLUT4 compartments and the associated proteins in insulin induced GLUT4 recruitment in rat adipocytes.	22	27	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	24	25	26	27
Lastly , overexpression of a fragment of myosin Vb , a recently identified Rab8A interacting protein , inhibited insulin induced GLUT4 translocation and altered the subcellular distribution of GTP loaded Rab8A .	Lastly, overexpression of a fragment of myosin Vb, a recently identified Rab8A interacting protein, inhibited insulin induced GLUT4 translocation and altered the subcellular distribution of GTP loaded Rab8A.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
This elicits an increased rate of fatty acid uptake and enhanced incorporation into triacylglycerol stores and lipid intermediates to subsequently interfere with insulin induced GLUT4 recruitment ( i.e ., insulin resistance ) .	This elicits an increased rate of fatty acid uptake and enhanced incorporation into triacylglycerol stores and lipid intermediates to subsequently interfere with insulin induced GLUT4 recruitment (i.e., insulin resistance).	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	24	25
Overexpression of cortactin , a type II NPF , in L6-GLUT4myc cells increased insulin induced GLUT4 translocation .	Overexpression of cortactin, a type II NPF, in L6-GLUT4myc cells increased insulin induced GLUT4 translocation.	13	16	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
To this end , IL-4 has been shown to up-regulate GLUT-1 expression [ XREF_BIBR ] , and insulin up-regulates GLUT-4 [ XREF_BIBR ] thereby promoting glucose uptake .	To this end, IL-4 has been shown to up-regulate GLUT-1 expression [XREF_BIBR], and insulin up-regulates GLUT-4 [XREF_BIBR] thereby promoting glucose uptake.	17	21	up-regulates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	17	18	19	20
However , additional Munc18c gene deletion studies show it to be required for slow exocytosis events , such as second-phase insulin release from islets and insulin stimulated GLUT4 vesicle accumulation in skeletal muscle surface membranes , both of which involve the stimulus induced mobilization , tethering and docking , and fusion of vesicles housed in deeper and nonreadily releasable cell storage compartments .	However, additional Munc18c gene deletion studies show it to be required for slow exocytosis events, such as second-phase insulin release from islets and insulin stimulated GLUT4 vesicle accumulation in skeletal muscle surface membranes, both of which involve the stimulus induced mobilization, tethering and docking, and fusion of vesicles housed in deeper and nonreadily releasable cell storage compartments.	21	29	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	27	28
Further , protein kinase B/Akt1 plays a role in multiple signaling pathways including insulin stimulated GLUT4 membrane localization [ XREF_BIBR ] .	Further, protein kinase B/Akt1 plays a role in multiple signaling pathways including insulin stimulated GLUT4 membrane localization [XREF_BIBR].	11	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
Myosins I are involved in such diverse functions as intestinal microvillar structure and function , adaptation in the specialized hair cells of the inner ear and insulin mediated GLUT4 recycling in adipocytes .	Myosins I are involved in such diverse functions as intestinal microvillar structure and function, adaptation in the specialized hair cells of the inner ear and insulin mediated GLUT4 recycling in adipocytes.	20	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	26	27	28	29
Insulin stimulates GLUT4 redistribution to the plasma membrane ( PM ) in adipocytes and muscle cells .	Insulin stimulates GLUT4 redistribution to the plasma membrane (PM) in adipocytes and muscle cells.	0	3	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
The importance of the IRS2 isoform in insulin mediated GLUT4 redistribution has been demonstrated by the specific knockout in mice , which develop severe insulin resistance [ XREF_BIBR ] .	The importance of the IRS2 isoform in insulin mediated GLUT4 redistribution has been demonstrated by the specific knockout in mice, which develop severe insulin resistance [XREF_BIBR].	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Together , these findings suggest that p62/CE plays a key role in insulin induced GLUT4 recruitment in rat adipocytes , probably by hydrolyzing acylglycerols or acyl-CoA esters to the respective free acids that are required for GLUT4 transport vesicle budding and/or fusion .	Together, these findings suggest that p62/CE plays a key role in insulin induced GLUT4 recruitment in rat adipocytes, probably by hydrolyzing acylglycerols or acyl-CoA esters to the respective free acids that are required for GLUT4 transport vesicle budding and/or fusion.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
However , we can not rule out the possibility of enhanced insulin mediated GLUT-4 translocation from an intracellular pool to the plasma membrane of muscle and AMPK alpha2 activation in exercised diabetic mice .	However, we can not rule out the possibility of enhanced insulin mediated GLUT-4 translocation from an intracellular pool to the plasma membrane of muscle and AMPK alpha2 activation in exercised diabetic mice.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	11	12	13	14
Insulin increased PM GLUT4 and GLUT1 content 30 and 40min after treatment and the increases were partially accompanied by decrease in transporter LDM content .	Insulin increased PM GLUT4 and GLUT1 content 30 and 40min after treatment and the increases were partially accompanied by decrease in transporter LDM content.	0	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	3	4
3 Insulin stimulates glucose uptake into muscle and white adipose tissue through translocation of glucose transporter 4 ( GLUT4 ) from the cytosol to the plasma membrane .	3 Insulin stimulates glucose uptake into muscle and white adipose tissue through translocation of glucose transporter 4 (GLUT4) from the cytosol to the plasma membrane.	0	22	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	1	2	18	19
Most studies of IR focus on membrane elicited insulin signal transduction pathways that stimulate GLUT4 trafficking .	Most studies of IR focus on membrane elicited insulin signal transduction pathways that stimulate GLUT4 trafficking.	8	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	14	15
Transfections of rat adipose cells demonstrate that over-expression of wild-type NSF has no effect on total , or basal and insulin stimulated cell-surface expression of HA tagged GLUT4 .	Transfections of rat adipose cells demonstrate that over-expression of wild-type NSF has no effect on total, or basal and insulin stimulated cell-surface expression of HA tagged GLUT4.	18	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	27	28
In addition , biochemical evidence from isolated brown adipocytes has supported the essential role for IRS2 in insulin stimulated GLUT4 redistribution [ XREF_BIBR ] .	In addition, biochemical evidence from isolated brown adipocytes has supported the essential role for IRS2 in insulin stimulated GLUT4 redistribution [XREF_BIBR].	10	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Mice treated with GCs have reduced insulin stimulated glucose uptake , caused by attenuated insulin induced GLUT4 translocation to the cell membrane in myotubes .	Mice treated with GCs have reduced insulin stimulated glucose uptake, caused by attenuated insulin induced GLUT4 translocation to the cell membrane in myotubes.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
This report uncovers a new functional role for RIP140 in the adipocyte cytoplasm -- to negatively regulate insulin stimulated GLUT4 trafficking -- and determines the mechanism of this action .	This report uncovers a new functional role for RIP140 in the adipocyte cytoplasm -- to negatively regulate insulin stimulated GLUT4 trafficking -- and determines the mechanism of this action.	16	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Metformin , as a major oral anti-diabetic drug , can efficiently modulate the insulin mediated GLUT4 translocation XREF_BIBR .	Metformin, as a major oral anti-diabetic drug, can efficiently modulate the insulin mediated GLUT4 translocation XREF_BIBR.	11	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
At the termination of the 2-week myricetin treatment , insulin stimulated GLUT 4 protein expression in the membrane fraction of the soleus muscles from fructose fed rats was increased ~ 1.8-fold of that observed in their vehicle treated group ; conversely , the protein levels in the cytosolic fraction of the same samples decreased to 60 % of that observed in the vehicle treated controls ( XREF_FIG ) .	At the termination of the 2-week myricetin treatment, insulin stimulated GLUT 4 protein expression in the membrane fraction of the soleus muscles from fructose fed rats was increased ~ 1.8-fold of that observed in their vehicle treated group; conversely, the protein levels in the cytosolic fraction of the same samples decreased to 60% of that observed in the vehicle treated controls (XREF_FIG).	9	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	9	10	11	13
In addition , chronic leptin treatment normalized basal glucose transport and GLUT4 content in soleus , but not in the gastrocnemius of high-fat-fed rats XREF_BIBR , as well as the insulin stimulated GLUT4 content at the cell surface of myotubes without any reduction in total GLUT4 expression XREF_BIBR .	In addition, chronic leptin treatment normalized basal glucose transport and GLUT4 content in soleus, but not in the gastrocnemius of high-fat-fed rats XREF_BIBR, as well as the insulin stimulated GLUT4 content at the cell surface of myotubes without any reduction in total GLUT4 expression XREF_BIBR.	6	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	30	31	32	33
Insulin further increased the redistribution of GLUT4 closer to PM .	Insulin further increased the redistribution of GLUT4 closer to PM.	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
RNAi based silencing of PHLDB1 in cultured 3T3-L1 adipocytes ( XREF_FIG , C and D ) attenuated 0.1 nm insulin induced Myc-GLUT4-EGFP translocation measured by this method by 43 % as shown in XREF_FIG B. Under these conditions , knockdown of Akt resulted in similar attenuation of Myc-GLUT4-EGFP translocation consistent with the notion that effects of PHLDB1 are exerted via Akt .	RNAi based silencing of PHLDB1 in cultured 3T3-L1 adipocytes (XREF_FIG, C and D) attenuated 0.1 nm insulin induced Myc-GLUT4-EGFP translocation measured by this method by 43% as shown in XREF_FIG B. Under these conditions, knockdown of Akt resulted in similar attenuation of Myc-GLUT4-EGFP translocation consistent with the notion that effects of PHLDB1 are exerted via Akt.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Myc-GLUT4-EGFP	Myc-GLUT4-EGFP	Myc-GLUT4-EGFP	19	20	21	22
The BPA treatment enhanced basal and insulin stimulated glucose uptake , and caused an increased amount of GLUT4 protein .	The BPA treatment enhanced basal and insulin stimulated glucose uptake, and caused an increased amount of GLUT4 protein.	4	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	17	18
Under conditions chosen to optimize Clq uptake , the weak base precluded insulin induced GLUT4 translocation and the associated stimulation of glucose transport .	Under conditions chosen to optimize Clq uptake, the weak base precluded insulin induced GLUT4 translocation and the associated stimulation of glucose transport.	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Moreover , both reports suggest that insulin stimulates movement of GLUT4 from the TfnR negative pool to the plasma membrane .	Moreover, both reports suggest that insulin stimulates movement of GLUT4 from the TfnR negative pool to the plasma membrane.	6	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	10	11
The function of Munc18c in insulin stimulated exocytosis of GLUT4 containing vesicles in adipose tissue is unclear .	The function of Munc18c in insulin stimulated exocytosis of GLUT4 containing vesicles in adipose tissue is unclear.	3	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	9	10
In addition , GLUT4 intensity at the muscle plasma membrane , as detected by immunofluorescence , was not different , suggesting no defects in the insulin induced GLUT4 translocation event ( XREF_FIG ) .	In addition, GLUT4 intensity at the muscle plasma membrane, as detected by immunofluorescence, was not different, suggesting no defects in the insulin induced GLUT4 translocation event (XREF_FIG).	22	29	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	25	26	27	28
A hypothesis that accounts for most of the available literature on insulin stimulated GLUT4 translocation is that insulin action controls the access of GLUT4 vesicles to a constitutively active plasma-membrane fusion process .	A hypothesis that accounts for most of the available literature on insulin stimulated GLUT4 translocation is that insulin action controls the access of GLUT4 vesicles to a constitutively active plasma-membrane fusion process.	9	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
However , there was no concomitant drop in insulin induced GLUT4 translocation under these conditions .	However, there was no concomitant drop in insulin induced GLUT4 translocation under these conditions.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
These results suggest that unlike MyoIIA , Myo1c is not required for the insulin stimulated redistribution of perinuclear GLUT4 to the cytosol .	These results suggest that unlike MyoIIA, Myo1c is not required for the insulin stimulated redistribution of perinuclear GLUT4 to the cytosol.	10	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	18	19
RalA dependent mobilization of exocyst holocomplex assembly is critical for maintenance of apical and basolateral membrane identity in polarized epithelial cells and for insulin stimulated Glut4 delivery to the plasma membrane in adipocytes .	RalA dependent mobilization of exocyst holocomplex assembly is critical for maintenance of apical and basolateral membrane identity in polarized epithelial cells and for insulin stimulated Glut4 delivery to the plasma membrane in adipocytes.	8	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	23	24	25	26
Insulin signaling and expression of GLUT-4 , FAT and CD36 , and triglycerides were assessed in muscle biopsies , obtained before the clamp and after 30 minutes of hyperinsulinemia .	Insulin signaling and expression of GLUT-4, FAT and CD36, and triglycerides were assessed in muscle biopsies, obtained before the clamp and after 30 minutes of hyperinsulinemia.	0	9	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT-4	GLUT-4	GLUT-4	0	1	5	6
Treatment of control 3T3-L1 adipocytes with TTFA did not impair insulin stimulated HA-GLUT4 translocation ( XREF_FIG ) or insulin regulated inhibition of lipolysis ( data not shown ) , suggesting that impaired complex II activity does not cause adipocyte insulin resistance per se .	Treatment of control 3T3-L1 adipocytes with TTFA did not impair insulin stimulated HA-GLUT4 translocation (XREF_FIG) or insulin regulated inhibition of lipolysis (data not shown), suggesting that impaired complex II activity does not cause adipocyte insulin resistance per se.	9	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	HA-GLUT4	HA-GLUT4	HA-GLUT4	10	11	12	13
Insulin induces a rapid mobilization of GLUT4 containing vesicles from intracellular depots to the muscle cell surface to promote glucose uptake .	Insulin induces a rapid mobilization of GLUT4 containing vesicles from intracellular depots to the muscle cell surface to promote glucose uptake.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	6	7
Administering wortmannin to insulin stimulated cells also partially but efficiently abrogated insulin induced changes in GLUT4 movement ( Supplemental Figure S3B ) .	Administering wortmannin to insulin stimulated cells also partially but efficiently abrogated insulin induced changes in GLUT4 movement (Supplemental Figure S3B).	10	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	15	16
Since the majority of GLUT4 translocation occurs specifically within T-tubules [ XREF_BIBR , XREF_BIBR ] and cholesterol rich microdomains [ XREF_BIBR ] , T-tubule disruption and changes in cholesterol will modify insulin stimulated GLUT4 exocytosis in DM .	Since the majority of GLUT4 translocation occurs specifically within T-tubules [XREF_BIBR, XREF_BIBR] and cholesterol rich microdomains [XREF_BIBR], T-tubule disruption and changes in cholesterol will modify insulin stimulated GLUT4 exocytosis in DM.	30	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	31	32	33	34
Glut4 is directly regulated by the insulin induced intracellular signaling cascade .	Glut4 is directly regulated by the insulin induced intracellular signaling cascade.	0	7	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	6	7	0	1
The molecular basis for insulin stimulated glucose uptake is a gain in surface GLUT4 brought about by a surge in the exocytic rate of GLUT4 containing vesicles .	The molecular basis for insulin stimulated glucose uptake is a gain in surface GLUT4 brought about by a surge in the exocytic rate of GLUT4 containing vesicles.	2	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	13	14
Therefore , U-Tmod is involved in the dynamic change of F-actin structure , and regulates the cell motility in endothelia [ XREF_BIBR ] and insulin stimulated GLUT4 exocytosis in adipocytes [ XREF_BIBR ] ; while E-Tmod is widely expressed in the terminally differentiated cells , such as erythrocytes , cardiomyocytes , and skeletal muscle cells , etc [ XREF_BIBR , XREF_BIBR ] .	Therefore, U-Tmod is involved in the dynamic change of F-actin structure, and regulates the cell motility in endothelia [XREF_BIBR] and insulin stimulated GLUT4 exocytosis in adipocytes [XREF_BIBR]; while E-Tmod is widely expressed in the terminally differentiated cells, such as erythrocytes, cardiomyocytes, and skeletal muscle cells, etc [XREF_BIBR, XREF_BIBR].	24	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	24	25	26	27
MK-2206 treatment of adipocytes expressing Akt1 WT or Akt2 WT inhibited insulin induced GLUT4 translocation to the plasma membrane in a dose dependent manner ( XREF_FIG D ) .	MK-2206 treatment of adipocytes expressing Akt1 WT or Akt2 WT inhibited insulin induced GLUT4 translocation to the plasma membrane in a dose dependent manner (XREF_FIG D).	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	13	14
Much greater difficulties exist in specifying functional sites of insulin mediated GLUT4 trafficking within cells , due to heterogeneous GLUT4 distributions and the complexity of their trafficking processes .	Much greater difficulties exist in specifying functional sites of insulin mediated GLUT4 trafficking within cells, due to heterogeneous GLUT4 distributions and the complexity of their trafficking processes.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
To assess insulin stimulated GLUT4 translocation in skeletal muscle , sarcolemma and transverse tubule enriched fractions ( referred to as P2 fractions ) were prepared from insulin- or saline injected mice as described previously .	To assess insulin stimulated GLUT4 translocation in skeletal muscle, sarcolemma and transverse tubule enriched fractions (referred to as P2 fractions) were prepared from insulin- or saline injected mice as described previously.	1	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Poor insulin activated GLUT4 translocation may account for insulin resistance in ponies in previous euglycaemic , hyperinsulinaemic clamp tests .	Poor insulin activated GLUT4 translocation may account for insulin resistance in ponies in previous euglycaemic, hyperinsulinaemic clamp tests.	0	4	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	3	4
Thus , the phosphorylation of MARCKS has been implicated in neurotransmitter release { XREF_BIBR } , glucose induced secretion in isolated rat pancreatic islets { XREF_BIBR } , release of ATCH in ovine anterior pituitary cells { XREF_BIBR } , thrombin induced serotonin release from platelets { XREF_BIBR } , insulin induced Glut4 translocation to the plasma membrane in rat skeletal muscle cells { XREF_BIBR } and mucin secretion in bronchial epithelial cells { XREF_BIBR } .	Thus, the phosphorylation of MARCKS has been implicated in neurotransmitter release {XREF_BIBR}, glucose induced secretion in isolated rat pancreatic islets {XREF_BIBR}, release of ATCH in ovine anterior pituitary cells {XREF_BIBR}, thrombin induced serotonin release from platelets {XREF_BIBR}, insulin induced Glut4 translocation to the plasma membrane in rat skeletal muscle cells {XREF_BIBR} and mucin secretion in bronchial epithelial cells {XREF_BIBR}.	11	64	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	50	51	52	53
Insulin stimulates glucose uptake by recruiting glucose transporter 4 ( GLUT4 ) from an intracellular pool to the cell surface through a mechanism that is dependent on phosphatidylinositol ( PI ) 3-kinase ( PI3-K ) and cortical actin remodeling .	Insulin stimulates glucose uptake by recruiting glucose transporter 4 (GLUT4) from an intracellular pool to the cell surface through a mechanism that is dependent on phosphatidylinositol (PI) 3-kinase (PI3-K) and cortical actin remodeling.	0	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	10	11
Transfection with VAMP2-siRNA abolished the promoting effect of T3 on insulin induced GLUT4 translocation and glucose uptake ( XREF_FIG and XREF_FIG ) , suggesting that VAMP2 is indispensable for T3 to enhance insulin induced GLUT4 translocation and glucose uptake .	Transfection with VAMP2-siRNA abolished the promoting effect of T3 on insulin induced GLUT4 translocation and glucose uptake (XREF_FIG and XREF_FIG), suggesting that VAMP2 is indispensable for T3 to enhance insulin induced GLUT4 translocation and glucose uptake.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
On the other hand , ROCK1 was shown to be required for insulin induced GLUT4 translocation in cultured cells , and targeted knockout of ROCK1 caused whole body insulin resistance in mice XREF_BIBR , XREF_BIBR .	On the other hand, ROCK1 was shown to be required for insulin induced GLUT4 translocation in cultured cells, and targeted knockout of ROCK1 caused whole body insulin resistance in mice XREF_BIBR, XREF_BIBR.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Insulin stimulates glucose transport into muscle and fat cells by enhancing GLUT4 abundance in the plasma membrane through activation of phosphatidylinositol 3-kinase ( PI3K ) .	Insulin stimulates glucose transport into muscle and fat cells by enhancing GLUT4 abundance in the plasma membrane through activation of phosphatidylinositol 3-kinase (PI3K).	0	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	11	12
Similar to muscle and adipose tissue , insulin mediated Glut4 translocation has been demonstrated in the brain XREF_BIBR , XREF_BIBR , XREF_BIBR .	Similar to muscle and adipose tissue, insulin mediated Glut4 translocation has been demonstrated in the brain XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	7	8	9	10
To determine whether line 61 mice showed deficits in insulin mediated Glut4 translocation from the peri-nuclear region to cell surface , we employed a Glut4 translocation assay performed in isolated flexor digitorum brevis ( FDB ) muscle [ XREF_BIBR ] .	To determine whether line 61 mice showed deficits in insulin mediated Glut4 translocation from the peri-nuclear region to cell surface, we employed a Glut4 translocation assay performed in isolated flexor digitorum brevis (FDB) muscle [XREF_BIBR].	6	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	9	10	11	12
In the absence of insulin stimulation , results from simulation show essentially no insulin mediated GLUT4 glucose influx , which is consistent with steady state values determined in in vitro experiments ( XREF_FIG ) .	In the absence of insulin stimulation, results from simulation show essentially no insulin mediated GLUT4 glucose influx, which is consistent with steady state values determined in in vitro experiments (XREF_FIG).	7	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
More specifically , phosphorylation of Ser 237 was essential for endowing Tbc1d1 with insulin responsiveness , whereas subsequent insulin induced GLUT4 liberation required phosphorylation of Thr 596 , but not Ser 237 , under these specific conditions .	More specifically, phosphorylation of Ser 237 was essential for endowing Tbc1d1 with insulin responsiveness, whereas subsequent insulin induced GLUT4 liberation required phosphorylation of Thr 596, but not Ser 237, under these specific conditions.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
Insulin injection ( 4.3 U/kg body wt ) increased GLUT4 in the PM rich fraction ; the increase was threefold higher in TG than in non TG mice .	Insulin injection (4.3 U/kg body wt) increased GLUT4 in the PM rich fraction; the increase was threefold higher in TG than in non TG mice.	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	9	10
FFAs are esterified with glycerol 3-phosphate derived from glycolysis ( using glucose taken up via insulin stimulated GLUT4 ) .	FFAs are esterified with glycerol 3-phosphate derived from glycolysis (using glucose taken up via insulin stimulated GLUT4).	12	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	15	16	17	18
Concomitantly , insulin increased GLUT4 labeling sevenfold to a value of 3.5 x 10 ( 5 ) per cell .	Concomitantly, insulin increased GLUT4 labeling sevenfold to a value of 3.5 x 10 (5) per cell.	2	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Most of GLUT4 ( 90 % ) is in the basal state sequestered in an intracellular pool , and insulin stimulates glucose uptake mainly by recruiting this intracellular GLUT4 pool to the plasma membrane [ XREF_BIBR - XREF_BIBR ] .	Most of GLUT4 (90%) is in the basal state sequestered in an intracellular pool, and insulin stimulates glucose uptake mainly by recruiting this intracellular GLUT4 pool to the plasma membrane [XREF_BIBR - XREF_BIBR].	19	29	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	28	29
We conclude that Tpm3.1 has a role in regulating insulin stimulated GLUT4 accumulation at the PM and glucose uptake .	We conclude that Tpm3.1 has a role in regulating insulin stimulated GLUT4 accumulation at the PM and glucose uptake.	9	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Insulin stimulates glucose uptake by promoting the trafficking of GLUT4 to the plasma membrane in muscle cells , and impairment of this insulin action contributes to hyperglycemia in type 2 diabetes .	Insulin stimulates glucose uptake by promoting the trafficking of GLUT4 to the plasma membrane in muscle cells, and impairment of this insulin action contributes to hyperglycemia in type 2 diabetes.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	9	10
Doc2beta facilitates insulin stimulated GLUT4 vesicle exocytosis in 3T3-L1 adipocytes and , in islet beta cells , preferentially binds to tyrosine phosphorylated Munc18c in a manner inversely proportional to Munc18c-syntaxin 4 binding .	Doc2beta facilitates insulin stimulated GLUT4 vesicle exocytosis in 3T3-L1 adipocytes and, in islet beta cells, preferentially binds to tyrosine phosphorylated Munc18c in a manner inversely proportional to Munc18c-syntaxin 4 binding.	1	18	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Knockdown or overexpression of PIP5K1alpha modulates the insulin induced GLUT4 translocation .	Knockdown or overexpression of PIP5K1alpha modulates the insulin induced GLUT4 translocation.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
Insulin stimulates trafficking of GLUT4 to the cell surface for glucose uptake into target cells , and phosphorylation of Ser703 of the Na +/H+ exchanger NHE1 , which activates proton efflux .	Insulin stimulates trafficking of GLUT4 to the cell surface for glucose uptake into target cells, and phosphorylation of Ser703 of the Na +/H+ exchanger NHE1, which activates proton efflux.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	4	5
GLUT4 containing vesicles continuously cycle between the plasma membrane and several intracellular compartments ( e.g ., endosomes , trans-Golgi network ) , and insulin promotes GLUT4 vesicle exocytosis .	GLUT4 containing vesicles continuously cycle between the plasma membrane and several intracellular compartments (e.g., endosomes, trans-Golgi network), and insulin promotes GLUT4 vesicle exocytosis.	23	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
Indeed , AS160 has been shown to be required for insulin mediated GLUT4 redistribution and when Akt phosphorylation sites on AS160 are mutated , insulin is no longer able to signal GLUT4 redistribution [ XREF_BIBR ] .	Indeed, AS160 has been shown to be required for insulin mediated GLUT4 redistribution and when Akt phosphorylation sites on AS160 are mutated, insulin is no longer able to signal GLUT4 redistribution [XREF_BIBR].	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Regardless , our data suggest that Y521 phosphorylation of Munc18c abrogates binding to monomeric Sx4 and VAMP2 , and perhaps plays a role in insulin stimulated SNARE mediated delivery of GLUT4 to the PM .	Regardless, our data suggest that Y521 phosphorylation of Munc18c abrogates binding to monomeric Sx4 and VAMP2, and perhaps plays a role in insulin stimulated SNARE mediated delivery of GLUT4 to the PM.	20	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	24	25	30	31
The Rab10 independent pathway may be independent of AS160 as well , because insulin promotes a redistribution of GLUT4 in AS160 KO and knockdown adipocytes , revealing AS160 independent control of GLUT4 trafficking .	The Rab10 independent pathway may be independent of AS160 as well, because insulin promotes a redistribution of GLUT4 in AS160 KO and knockdown adipocytes, revealing AS160 independent control of GLUT4 trafficking.	13	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	18	19
Together , these data demonstrate that although microtubular organization may play a role in the trafficking of GLUT4 early endocytic vesicles back to the perinuclear region , they do not have a significant role in insulin stimulated GLUT4 exocytosis , initial endocytosis from the plasma membrane and/or recycling back to the plasma membrane .	Together, these data demonstrate that although microtubular organization may play a role in the trafficking of GLUT4 early endocytic vesicles back to the perinuclear region, they do not have a significant role in insulin stimulated GLUT4 exocytosis, initial endocytosis from the plasma membrane and/or recycling back to the plasma membrane.	33	47	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	35	36	37	38
This occurs through interference with the insulin stimulated transport of GLUT4 to the cell surface .	This occurs through interference with the insulin stimulated transport of GLUT4 to the cell surface.	1	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	10	11
In this regard , PI3 kinase and Akt activation is an essential step for insulin induced GLUT4 translocation and subsequent glucose uptake in skeletal muscle [ XREF_BIBR ] .	In this regard, PI3 kinase and Akt activation is an essential step for insulin induced GLUT4 translocation and subsequent glucose uptake in skeletal muscle [XREF_BIBR].	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
In Doc2b deficient cells , insulin triggered GLUT4 exocytosis is abrogated .	In Doc2b deficient cells, insulin triggered GLUT4 exocytosis is abrogated.	5	8	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	7	8
Insulin and muscle contraction increased glucose transport and plasmalemmal GLUT4 independently and additively ( positive control ) .	Insulin and muscle contraction increased glucose transport and plasmalemmal GLUT4 independently and additively (positive control).	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	9	10
A similar lack of significant GLUT4 mRNA stimulation by insulin was observed in the adipose tissue of IUGR-born subjects .	A similar lack of significant GLUT4 mRNA stimulation by insulin was observed in the adipose tissue of IUGR-born subjects.	5	10	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	5	6
Relative to baseline , insulin caused a 2.6-fold increase in GLUT 4 in the 25 % membrane fraction ( f ) , P < 0.01 , and a 40 % reduction in the 35 % f , P < 0.05 , but had no effect on GLUT 4 in the 30 % f , P = NS .	Relative to baseline, insulin caused a 2.6-fold increase in GLUT 4 in the 25% membrane fraction (f), P < 0.01, and a 40% reduction in the 35% f, P < 0.05, but had no effect on GLUT 4 in the 30% f, P = NS.	4	42	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	4	5	10	12
The mechanism of this effect could involve inhibition of insulin stimulated p38 MAP kinase and GLUT4 activation .	The mechanism of this effect could involve inhibition of insulin stimulated p38 MAP kinase and GLUT4 activation.	7	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	15	16
By blocking glucose uptake , IR reduces energy utilization by tissues dependent on GLUT4 glucose uptake ( predominantly skeletal muscle and fat ) and diverts energy access to tissues not reliant on insulin stimulated GLUT4 XREF_BIBR - XREF_BIBR .	By blocking glucose uptake, IR reduces energy utilization by tissues dependent on GLUT4 glucose uptake (predominantly skeletal muscle and fat) and diverts energy access to tissues not reliant on insulin stimulated GLUT4 XREF_BIBR - XREF_BIBR.	6	35	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	32	33	34	35
ALCAR prevented the inhibitory effect of Ang II on insulin mediated GLUT4 transport in irrelevant siRNA cells ( XREF_FIG ) .	ALCAR prevented the inhibitory effect of Ang II on insulin mediated GLUT4 transport in irrelevant siRNA cells (XREF_FIG).	1	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Treatment with a beta-adrenergic agonist increases insulin stimulated glucose transport , GLUT4 protein and mRNA .	Treatment with a beta-adrenergic agonist increases insulin stimulated glucose transport, GLUT4 protein and mRNA.	5	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	11	12
Insulin stimulates glucose transport in adipocytes and muscle by inducing the redistribution of Glut4 from intracellular locations to the plasma membrane .	Insulin stimulates glucose transport in adipocytes and muscle by inducing the redistribution of Glut4 from intracellular locations to the plasma membrane.	0	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Glut4	Glut4	Glut4	0	1	13	14
Liraglutide can enhance insulin induced GLUT4 translocation by inhibiting IRS1 serine phosphorylation in PA treated muscle cells .	Liraglutide can enhance insulin induced GLUT4 translocation by inhibiting IRS1 serine phosphorylation in PA treated muscle cells.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Despite their effect on membrane fusion , none of the constructs significantly affected the insulin stimulated accumulation of GLUT4-EGFP in the TIRF zone ( XREF_FIG ) .	Despite their effect on membrane fusion, none of the constructs significantly affected the insulin stimulated accumulation of GLUT4-EGFP in the TIRF zone (XREF_FIG).	12	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4-EGFP	GLUT4-EGFP	GLUT4-EGFP	14	15	18	19
P-Rex1 , a Rac1 specific GEF , enhanced insulin induced GLUT4 translocation downstream of PI3K in a Rac1 dependent manner in adipocytes [ XREF_BIBR ] .	P-Rex1, a Rac1 specific GEF, enhanced insulin induced GLUT4 translocation downstream of PI3K in a Rac1 dependent manner in adipocytes [XREF_BIBR].	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
However , DGKzeta knockdown significantly suppressed insulin induced GLUT4 translocation to the PM .	However, DGKzeta knockdown significantly suppressed insulin induced GLUT4 translocation to the PM.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Wortmannin , an inhibitor of PI3K , inhibited insulin stimulated GLUT4 externalization , without affecting GLUT4 translocation to the cell periphery , in Munc18c +/+ adipocytes , but it did not affect GLUT4 externalization in Munc18c-/- cells .	Wortmannin, an inhibitor of PI3K, inhibited insulin stimulated GLUT4 externalization, without affecting GLUT4 translocation to the cell periphery, in Munc18c +/+ adipocytes, but it did not affect GLUT4 externalization in Munc18c-/- cells.	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Expression of an APS mutant unable to bind Enigma increased the insulin induced Glut 4 translocation to the plasma membrane .	Expression of an APS mutant unable to bind Enigma increased the insulin induced Glut 4 translocation to the plasma membrane.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut 4	Glut 4	Glut 4	11	12	13	15
We also note that in mammalian adipocytes Rab10 and Ehbp1 are key regulators of insulin stimulated GLUT4 recycling , but their relationship has not been tested [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	We also note that in mammalian adipocytes Rab10 and Ehbp1 are key regulators of insulin stimulated GLUT4 recycling, but their relationship has not been tested [XREF_BIBR, XREF_BIBR, XREF_BIBR].	12	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Therefore , insulin stimulation of GLUT4 is critical to the regulation of neuronal metabolism and the generation of energy needed for memory and cognition .	Therefore, insulin stimulation of GLUT4 is critical to the regulation of neuronal metabolism and the generation of energy needed for memory and cognition.	2	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	5	6
20 Based on conducted studies , impaired glucose transport by defects in insulin mediated GLUT-4 translocation leads to insulin resistance .	20 Based on conducted studies, impaired glucose transport by defects in insulin mediated GLUT-4 translocation leads to insulin resistance.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	12	13	14	15
A study using knockout mice and toxin based approaches to interrogate VAMP function demonstrated that simultaneous disruption of VAMPs 2 , 3 , and 8 was required to completely block insulin stimulated GLUT4 insertion into the plasma membrane of adipocytes ; this defect could be rescued by reexpression of VAMP2 , VAMP3 , or VAMP8 alone , a result interpreted to imply plasticity in the requirement for v-SNARE proteins in GLUT4 trafficking to the plasma membrane .	A study using knockout mice and toxin based approaches to interrogate VAMP function demonstrated that simultaneous disruption of VAMPs 2, 3, and 8 was required to completely block insulin stimulated GLUT4 insertion into the plasma membrane of adipocytes; this defect could be rescued by reexpression of VAMP2, VAMP3, or VAMP8 alone, a result interpreted to imply plasticity in the requirement for v-SNARE proteins in GLUT4 trafficking to the plasma membrane.	29	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	30	31	32	33
Transient down-regulation and overexpression of Akt isoforms in adipocytes demonstrated that insulin activated PI3-kinase signals to GLUT4 primarily through Akt2 kinase , whereas Akt1 and Akt2 signal to FoxO1 .	Transient down-regulation and overexpression of Akt isoforms in adipocytes demonstrated that insulin activated PI3-kinase signals to GLUT4 primarily through Akt2 kinase, whereas Akt1 and Akt2 signal to FoxO1.	11	17	activated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	11	12	16	17
Under basal conditions , the level of AS160 expression in polarized mCCD epithelia was similar to that observed in the mouse adipocyte 3T3-L1 cell line , which is commonly used in studies of insulin stimulated GLUT4 trafficking ( data not shown ) .	Under basal conditions, the level of AS160 expression in polarized mCCD epithelia was similar to that observed in the mouse adipocyte 3T3-L1 cell line, which is commonly used in studies of insulin stimulated GLUT4 trafficking (data not shown).	31	36	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	33	34	35	36
However , at this concentration , methyl-beta-cyclodextrin perturbed CMD of hepatocyte PM and inhibited insulin induced Akt activation and glycogen synthesis but did not affect insulin induced insulin receptor kinase tyrosine phosphorylation .	However, at this concentration, methyl-beta-cyclodextrin perturbed CMD of hepatocyte PM and inhibited insulin induced Akt activation and glycogen synthesis but did not affect insulin induced insulin receptor kinase tyrosine phosphorylation.	24	29	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	25	26	27	29
In addition , Cr is biologically active as a component of chromodulin , which is part of an insulin signalling pathway and stimulates the tyrosine kinase activity of the insulin activated insulin receptor [ XREF_BIBR , XREF_BIBR ] .	In addition, Cr is biologically active as a component of chromodulin, which is part of an insulin signalling pathway and stimulates the tyrosine kinase activity of the insulin activated insulin receptor [XREF_BIBR, XREF_BIBR].	29	34	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	29	30	31	33
There was no change in erythrocyte insulin receptor binding associated with metformin treatment , but both basal and insulin stimulated insulin receptor tyrosine kinase activities of solubilized erythrocyte insulin receptors were significantly higher after 10 weeks of metformin treatment .	There was no change in erythrocyte insulin receptor binding associated with metformin treatment, but both basal and insulin stimulated insulin receptor tyrosine kinase activities of solubilized erythrocyte insulin receptors were significantly higher after 10 weeks of metformin treatment.	16	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	18	19	20	22
This insulin induced IR is a positive control for complete IR , which was accompanied by highly phosphorylated S6 ( XREF_FIG ) and did not further rerespond to insulin .	This insulin induced IR is a positive control for complete IR, which was accompanied by highly phosphorylated S6 (XREF_FIG) and did not further rerespond to insulin.	0	23	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	1	2	3	4
Some Site 1 peptides were able to activate the tyrosine kinase activity of the insulin receptor and act as agonists in the insulin dependent fat cell assay , suggesting that Site 1 marks the hotspot involved in insulin induced activation of the insulin receptor .	Some Site 1 peptides were able to activate the tyrosine kinase activity of the insulin receptor and act as agonists in the insulin dependent fat cell assay, suggesting that Site 1 marks the hotspot involved in insulin induced activation of the insulin receptor.	35	44	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	37	38	42	44
As described previously , insulin stimulated the IR homodimers more efficiently than IGF1 XREF_BIBR , whereas IGF1 was more efficient on IR/IGF1R hybrids XREF_BIBR ( XREF_FIG ) .	As described previously, insulin stimulated the IR homodimers more efficiently than IGF1 XREF_BIBR, whereas IGF1 was more efficient on IR/IGF1R hybrids XREF_BIBR (XREF_FIG).	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	7	8
We propose that increased insulin production and secretion in taurine fed mice cause an increase activation of the central IR and may be partially responsible for the increased neuronal excitability observed in taurine supplemented mice .	We propose that increased insulin production and secretion in taurine fed mice cause an increase activation of the central IR and may be partially responsible for the increased neuronal excitability observed in taurine supplemented mice.	4	20	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	19	20
Standard media for neurospheres contain micromolar insulin sufficient to activate the IGF-1R as well as the IR .	Standard media for neurospheres contain micromolar insulin sufficient to activate the IGF-1R as well as the IR.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	6	7	16	17
Insulin in muscle and endothelial cells stimulates the insulin receptor to activate phosphatidylinositide 3-kinase and protein kinase B/AKT .	Insulin in muscle and endothelial cells stimulates the insulin receptor to activate phosphatidylinositide 3-kinase and protein kinase B/AKT.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	8	10
Recent studies found that miR-21 inhibition significantly decreased body weight , adipocyte size and serum triglycerides , on the other hand , miR-21 reversed high glucose and high insulin induced IR in 3T3-L1 adipocytes , possibly through modulating the PTEN-AKT pathway [ XREF_BIBR , XREF_BIBR ] .	Recent studies found that miR-21 inhibition significantly decreased body weight, adipocyte size and serum triglycerides, on the other hand, miR-21 reversed high glucose and high insulin induced IR in 3T3-L1 adipocytes, possibly through modulating the PTEN-AKT pathway [XREF_BIBR, XREF_BIBR].	7	31	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	28	29	30	31
This acute in vivo insulin activation of the insulin receptor tyrosine kinase resulted in a greater stimulation ( 1.4-1.9-fold ) of tyrosine kinase activity in the glutamic acid : tyrosine ( 4:1 ) assay than the maximal stimulation produced by insulin treatment in vitro .	This acute in vivo insulin activation of the insulin receptor tyrosine kinase resulted in a greater stimulation (1.4-1.9-fold) of tyrosine kinase activity in the glutamic acid : tyrosine (4:1) assay than the maximal stimulation produced by insulin treatment in vitro.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	8	10
Overexpression of D.N.PKC delta abrogated insulin- induced coassociation of PKC delta and IR .	Overexpression of D.N.PKC delta abrogated insulin- induced coassociation of PKC delta and IR.	5	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin-	insulin-	insulin-	IR	IR	IR	5	6	12	13
This effect is known to be due to inability of insulin to suppress endogenous glucose production and it is associated with impairments of insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity [ XREF_BIBR ] .	This effect is known to be due to inability of insulin to suppress endogenous glucose production and it is associated with impairments of insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity [XREF_BIBR].	23	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	23	24	26	28
These data indicate that elevation of intracellular cAMP blocks the insulin stimulated MAP kinase pathway downstream of insulin receptor .	These data indicate that elevation of intracellular cAMP blocks the insulin stimulated MAP kinase pathway downstream of insulin receptor.	8	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	17	19
Overall , Nrf2 activation may impair insulin signaling and glucose uptake , which could induce IR in SKM .	Overall, Nrf2 activation may impair insulin signaling and glucose uptake, which could induce IR in SKM.	6	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	6	7	15	16
If vanadium compound ' s insulin mimetic effect is only because of its inhibition of PTPase 1B , then it would always depend on insulin induced activation of IR .	If vanadium compound 's insulin mimetic effect is only because of its inhibition of PTPase 1B, then it would always depend on insulin induced activation of IR.	22	29	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	24	25	28	29
MGF has been reported to reduce plasma glucose and insulin levels , and increase insulin sensitivity and glucose tolerance in different genetic mouse models of type 2 diabetes , diet induced IR mouse model , and streptozotocin ( STZ ) induced diabetic rats .	MGF has been reported to reduce plasma glucose and insulin levels, and increase insulin sensitivity and glucose tolerance in different genetic mouse models of type 2 diabetes, diet induced IR mouse model, and streptozotocin (STZ) induced diabetic rats.	14	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	14	15	31	32
While insulin binding of the IR may be reduced in AD brain tissue [ XREF_BIBR ] , insulin still manages to activate the catalytic domain of IR at 71-74 % of normal levels even in the hippocampal formation of AD dementia cases [ XREF_BIBR ] .	While insulin binding of the IR may be reduced in AD brain tissue [XREF_BIBR], insulin still manages to activate the catalytic domain of IR at 71-74% of normal levels even in the hippocampal formation of AD dementia cases [XREF_BIBR].	17	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	17	18	26	27
When compared with AL animals , animals randomized to CR had enhanced insulin stimulated skeletal muscle IR tyrosine kinase activity ( data not shown ) and increased IR beta-subunit phosphorylation ( XREF_FIG A ) and IRS-1 phosphorylation ( XREF_FIG B ) .	When compared with AL animals, animals randomized to CR had enhanced insulin stimulated skeletal muscle IR tyrosine kinase activity (data not shown) and increased IR beta-subunit phosphorylation (XREF_FIG A) and IRS-1 phosphorylation (XREF_FIG B).	10	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	12	13	16	17
To test if human insulin indeed can trigger InsR activation in the carp liver , carp hepatocytes were challenged with insulin ( 10 nM ) for 15 min , and in this case , a rapid phosphorylation in InsR was observed after drug treatment .	To test if human insulin indeed can trigger InsR activation in the carp liver, carp hepatocytes were challenged with insulin (10 nM) for 15 min, and in this case, a rapid phosphorylation in InsR was observed after drug treatment.	3	9	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	InsR	InsR	InsR	4	5	8	9
Phosphorylation ( pY939 ) by an insulin activated insulin receptor of a target peptide ( Y939 ) derived from an insulin receptor substrate-1 ( IRS-1 ) and its subsequent binding to another downstream target , the SH2 domain of PI-3 kinase ( SH2N ) , were detected by surface plasmon resonance ( SPR ) spectrometry .	Phosphorylation (pY939) by an insulin activated insulin receptor of a target peptide (Y939) derived from an insulin receptor substrate-1 (IRS-1) and its subsequent binding to another downstream target, the SH2 domain of PI-3 kinase (SH2N), were detected by surface plasmon resonance (SPR) spectrometry.	0	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	8	10
The liver tissue showed overexpression of the Insr and Igf-1r genes ( P > 0.001 ) in rats treated with insulin glargine in comparison with the control group .	The liver tissue showed overexpression of the Insr and Igf-1r genes (P> 0.001) in rats treated with insulin glargine in comparison with the control group.	7	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Insr	Insr	Insr	20	21	7	8
The IRR , IRR/IR and IR expressing cells were treated with alkaline media or insulin and stained with phalloidin dye and anti-HA antibody to reveal the receptor presence in particular cell .	The IRR, IRR/IR and IR expressing cells were treated with alkaline media or insulin and stained with phalloidin dye and anti-HA antibody to reveal the receptor presence in particular cell.	1	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	14	15	5	6
In human models of insulin resistance such as subjects with abdominal obesity , metabolic syndrome , obesity and type 2 diabetes , the increased oxidation of energetic substrates generated by excessive postprandial TG or FFA can activate various serine kinases that negatively affect insulin action inducing IR [ XREF_BIBR , XREF_BIBR ] .	In human models of insulin resistance such as subjects with abdominal obesity, metabolic syndrome, obesity and type 2 diabetes, the increased oxidation of energetic substrates generated by excessive postprandial TG or FFA can activate various serine kinases that negatively affect insulin action inducing IR [XREF_BIBR, XREF_BIBR].	43	50	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	43	44	46	47
Regular insulin stimulates DNA synthesis by exclusively activating InsR , whereas insulin analogues mainly signal through IGF-1R .	Regular insulin stimulates DNA synthesis by exclusively activating InsR, whereas insulin analogues mainly signal through IGF-1R.	0	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	InsR	InsR	InsR	1	2	8	9
In theory , these allosteric antibodies have the potential to activate receptors more selectively than either orthosteric antibodies or the natural ligand itself , in that they do not recognize the binding determinants within a receptor that may cross-react with multiple ligands ( e.g ., the INSR is activated not only by insulin but also by IGFs ) .	In theory, these allosteric antibodies have the potential to activate receptors more selectively than either orthosteric antibodies or the natural ligand itself, in that they do not recognize the binding determinants within a receptor that may cross-react with multiple ligands (e.g., the INSR is activated not only by insulin but also by IGFs).	45	53	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	52	53	46	47
However , when insulin stimulated insulin receptor tyrosine phosphorylation was examined in normal-glucose-tolerant insulin resistant individuals ( offspring of two diabetic parents ) at high risk for developing type 2 diabetes , a normal increase in tyrosine phosphorylation of the insulin receptor was observed [ XREF_BIBR ] .	However, when insulin stimulated insulin receptor tyrosine phosphorylation was examined in normal-glucose-tolerant insulin resistant individuals (offspring of two diabetic parents) at high risk for developing type 2 diabetes, a normal increase in tyrosine phosphorylation of the insulin receptor was observed [XREF_BIBR].	3	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	5	7
On the contrary , insulin led to a 50 % reduction in insulin receptors present in T-tubules and in sarcolemma , demonstrating that insulin induced insulin receptor internalization affects T-tubules in the muscle fibre .	On the contrary, insulin led to a 50% reduction in insulin receptors present in T-tubules and in sarcolemma, demonstrating that insulin induced insulin receptor internalization affects T-tubules in the muscle fibre.	23	27	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	23	24	25	27
reported that insulin stimulated the formation of a new beta-arrestin 2 signal complex , in which beta-arrestin 2 scaffolds Akt to insulin receptor .	reported that insulin stimulated the formation of a new beta-arrestin 2 signal complex, in which beta-arrestin 2 scaffolds Akt to insulin receptor.	2	23	stimulated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	21	23
An adjacent GPLY965 motif that contributes independently and additively with NPEY972 to insulin stimulated IR endocytosis is not conserved in IGFR ( GVLY943 ) .	An adjacent GPLY965 motif that contributes independently and additively with NPEY972 to insulin stimulated IR endocytosis is not conserved in IGFR (GVLY943).	5	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	12	13	14	15
We here show that , although TNF downregulated insulin induced insulin receptor ( IR ) and IR substrate ( IRS ) -1 phosphorylation as well as phosphoinositide 3-kinase ( PI3-kinase ) activity in pmi28 myotubes , this was , unlike in adipocytes , not sufficient to affect insulin induced glucose transport .	We here show that, although TNF downregulated insulin induced insulin receptor (IR) and IR substrate (IRS) -1 phosphorylation as well as phosphoinositide 3-kinase (PI3-kinase) activity in pmi28 myotubes, this was, unlike in adipocytes, not sufficient to affect insulin induced glucose transport.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	10	12
In order to develop an IR cell line , the HepG2 cells were initially treated with different concentrations of insulin for 36 h ( XREF_FIG ) .	In order to develop an IR cell line, the HepG2 cells were initially treated with different concentrations of insulin for 36 h (XREF_FIG).	5	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	19	20	5	6
These results demonstrate that in these beta-cells , glucose induced insulin secretion activates the beta-cell surface insulin receptor tyrosine kinase and its intracellular signal transduction pathway , suggesting a new autocrine mechanism for the regulation of beta-cell function .	These results demonstrate that in these beta-cells, glucose induced insulin secretion activates the beta-cell surface insulin receptor tyrosine kinase and its intracellular signal transduction pathway, suggesting a new autocrine mechanism for the regulation of beta-cell function.	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	glucose induced insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	16	18
While the IR is primarily activated by insulin , it will also bind to IGF-II and can bind both IGF-I and IGF-II when part of a heterodimer with IGF-IR [ XREF_BIBR - XREF_BIBR ] .	While the IR is primarily activated by insulin, it will also bind to IGF-II and can bind both IGF-I and IGF-II when part of a heterodimer with IGF-IR [XREF_BIBR - XREF_BIBR].	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	7	8	2	3
Combined , these results suggest that activation of IR signaling by both insulin and BMOV treatment involves increased association of IR with specialized , nanoscale membrane microdomains .	Combined, these results suggest that activation of IR signaling by both insulin and BMOV treatment involves increased association of IR with specialized, nanoscale membrane microdomains.	8	15	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	12	13	8	9
Insulin triggered IR autophosphorylation events have been shown to be required for insulin stimulated IR endocytosis .	Insulin triggered IR autophosphorylation events have been shown to be required for insulin stimulated IR endocytosis.	10	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	insulin	insulin	IR	IR	IR	12	13	14	15
Here we describe methods for the purification of an insulin stimulated insulin receptor serine kinase from human placenta and rat liver by sequential chromatography of solubilized membranes on wheat germ agglutinin-agarose , Mono Q , phenyl-Superose , and Superose 12 .	Here we describe methods for the purification of an insulin stimulated insulin receptor serine kinase from human placenta and rat liver by sequential chromatography of solubilized membranes on wheat germ agglutinin-agarose, Mono Q, phenyl-Superose, and Superose 12.	6	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	11	13
Tanshinone IIA enhances low-dose insulin mediated tyrosine auto-phosphorylation of the insulin receptor beta-subunit XREF_BIBR .	Tanshinone IIA enhances low-dose insulin mediated tyrosine auto-phosphorylation of the insulin receptor beta-subunit XREF_BIBR.	2	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	10	12
Insulin induces inclusion of INSR exon 11 through activation of the Ras-MAPK and ERK pathway .	Insulin induces inclusion of INSR exon 11 through activation of the Ras-MAPK and ERK pathway.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	INSR	INSR	INSR	0	1	4	5
In a review of the available research in 1999 , Wiernsperger and Bailey reported that metformin assists in glycemic control in many ways including reducing hepatic glucose output , increasing peripheral glucose utilization , decreasing fatty acid oxidation , reducing appetite and weight gain , and sensitizing peripheral tissue to insulin action , increasing the functional activity of glucose transporters , and increasing insulin mediated insulin receptor tyrosine kinase activity , which then augments a range of insulin signals .	In a review of the available research in 1999, Wiernsperger and Bailey reported that metformin assists in glycemic control in many ways including reducing hepatic glucose output, increasing peripheral glucose utilization, decreasing fatty acid oxidation, reducing appetite and weight gain, and sensitizing peripheral tissue to insulin action, increasing the functional activity of glucose transporters, and increasing insulin mediated insulin receptor tyrosine kinase activity, which then augments a range of insulin signals.	62	67	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	63	64	65	67
Furthermore , administration of GSNO ( NO donor ) prevents this improvement in insulin action and the use of an inhibitor of iNOS ( L-N6-( 1-iminoethyl ) lysine ; L-NIL ) simulates the effects of exercise on insulin action , insulin signalling and S nitrosation of IR beta , IRS1 and Akt .	Furthermore, administration of GSNO (NO donor) prevents this improvement in insulin action and the use of an inhibitor of iNOS (L-N6-(1-iminoethyl) lysine; L-NIL) simulates the effects of exercise on insulin action, insulin signalling and S nitrosation of IR beta, IRS1 and Akt.	40	47	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	40	41	46	47
In the insulin sensitive state , insulin activates the insulin receptor tyrosine kinase which leads to stimulation of insulin receptor substrate proteins and phosphatidylinositol 3-kinase ( PI3-kinase ) [ XREF_BIBR ] .	In the insulin sensitive state, insulin activates the insulin receptor tyrosine kinase which leads to stimulation of insulin receptor substrate proteins and phosphatidylinositol 3-kinase (PI3-kinase) [XREF_BIBR].	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	9	11
Sustained systemic insulin treatment of diabetic rats prevented loss of insulin receptor and Akt kinase activity , and acute intravitreal insulin administration restored insulin receptor kinase activity .	Sustained systemic insulin treatment of diabetic rats prevented loss of insulin receptor and Akt kinase activity, and acute intravitreal insulin administration restored insulin receptor kinase activity.	20	26	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	20	21	23	25
The insulin induced activation of the insulin receptor triggers the translocation of GLUT4 from intracellular vesicles to the plasma membrane , and in turn , also triggers a rapid increase in glucose uptake .	The insulin induced activation of the insulin receptor triggers the translocation of GLUT4 from intracellular vesicles to the plasma membrane, and in turn, also triggers a rapid increase in glucose uptake.	0	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	6	8
PMA ( 1 x 10 (-7) M ) did not alter insulin receptor numbers or affinity either acutely or chronically but within 60 minute inactivated insulin stimulated tyrosine kinase of the insulin receptor .	PMA (1 x 10 (-7) M) did not alter insulin receptor numbers or affinity either acutely or chronically but within 60 minute inactivated insulin stimulated tyrosine kinase of the insulin receptor.	24	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	25	26	31	33
Recently we have achieved co-purification of the insulin receptor with insulin stimulated insulin receptor serine kinase activity .	Recently we have achieved co-purification of the insulin receptor with insulin stimulated insulin receptor serine kinase activity.	3	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	12	14
In the present work , to probe further the relevance of HMGA1 for the INSR signaling system , we carried out studies in cultured HepG2 cells as well as in mice , demonstrating that phosphorylation of HMGA1 is an essential and necessary prerequisite for the insulin induced INSR downregulation either in vitro or in vivo .	In the present work, to probe further the relevance of HMGA1 for the INSR signaling system, we carried out studies in cultured HepG2 cells as well as in mice, demonstrating that phosphorylation of HMGA1 is an essential and necessary prerequisite for the insulin induced INSR downregulation either in vitro or in vivo.	44	48	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	45	46	47	48
A primary basis of type-2 diabetes is IR caused by a dysfunction of insulin signaling in target tissues .	A primary basis of type-2 diabetes is IR caused by a dysfunction of insulin signaling in target tissues.	2	14	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	7	8
Obesity is the major risk factor for metabolic syndrome and atherosclerotic cardiocerebrovascular diseases and induces insulin resistance characterized by a dysfunction of insulin to activate insulin receptor / insulin receptor substrate 1 ( IRS-1 )/phosphoinositide 3-kinase ( PI3K )/Akt pathway .	Obesity is the major risk factor for metabolic syndrome and atherosclerotic cardiocerebrovascular diseases and induces insulin resistance characterized by a dysfunction of insulin to activate insulin receptor / insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway.	15	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	15	16	25	27
INSR stimulation by insulin in CLL cells ex vivo resulted in the activation of canonical INSR signaling pathways , including the AKT-mTOR and Ras/Raf/Erk pathways , and INSR activation partially abrogated spontaneous CLL cell apoptosis ex vivo .	INSR stimulation by insulin in CLL cells ex vivo resulted in the activation of canonical INSR signaling pathways, including the AKT-mTOR and Ras/Raf/Erk pathways, and INSR activation partially abrogated spontaneous CLL cell apoptosis ex vivo.	0	6	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	3	4	0	1
Insulin induces cell glucose uptake by sequentially activating the insulin receptor ( IR ) , insulin receptor substrates ( IRS ) , PI3K , AKT and GLUT4 XREF_BIBR .	Insulin induces cell glucose uptake by sequentially activating the insulin receptor (IR), insulin receptor substrates (IRS), PI3K, AKT and GLUT4 XREF_BIBR.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	9	11
A venom insulin that efficiently targeted the insulin receptor of a fish would presumably differ from one that efficiently targeted the insulin receptor of a mollusk or a worm .	A venom insulin that efficiently targeted the insulin receptor of a fish would presumably differ from one that efficiently targeted the insulin receptor of a mollusk or a worm.	0	14	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	7	9
Addition of insulin to the DMEM incubation medium resulted in activation of the IR , measured by the immunoprecipitation of the IR with anti-IRbeta antibody ( XREF_FIG ) , followed by immunoblot analysis with anti-PY99 antibody ( XREF_FIG ) .	Addition of insulin to the DMEM incubation medium resulted in activation of the IR, measured by the immunoprecipitation of the IR with anti-IRbeta antibody (XREF_FIG), followed by immunoblot analysis with anti-PY99 antibody (XREF_FIG).	0	14	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	2	3	13	14
In addition to insulin action on brain function , central insulin sensitivity impacts peripheral tissues and contributes to overall IR .	In addition to insulin action on brain function, central insulin sensitivity impacts peripheral tissues and contributes to overall IR.	10	20	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	10	11	19	20
When an insulin receptor on the cell surface is activated by insulin , downstream signals induce a rapid increase in glucose uptake by inducing GLUT4 translocation from the storage vesicles to the plasma membrane .	When an insulin receptor on the cell surface is activated by insulin, downstream signals induce a rapid increase in glucose uptake by inducing GLUT4 translocation from the storage vesicles to the plasma membrane.	2	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	2	4
Insulin stimulated INSR , and HGF activated Met ( XREF_FIG ) .	Insulin stimulated INSR, and HGF activated Met (XREF_FIG).	0	3	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	INSR	INSR	INSR	0	1	2	3
The insulin induced activation of IR ( as measured by phosphorylation at Y1158 ) was increased in N-VFR as compared to N-Sham animals ( P < 0.0047 ) ( XREF_SUPPLEMENTARY ) but not affected by VFR in GHRKO mice .	The insulin induced activation of IR (as measured by phosphorylation at Y1158) was increased in N-VFR as compared to N-Sham animals (P < 0.0047) (XREF_SUPPLEMENTARY) but not affected by VFR in GHRKO mice.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	1	2	5	6
Under appropriate conditions , insulin can promote the reaction of the insulin receptor with the organomercurial-agarose derivative .	Under appropriate conditions, insulin can promote the reaction of the insulin receptor with the organomercurial-agarose derivative.	4	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	11	13
To determine whether the insulin induced activation of IR signaling is essential for photoreceptor differentiation , we established retinal cultures from IR knockout mice .	To determine whether the insulin induced activation of IR signaling is essential for photoreceptor differentiation, we established retinal cultures from IR knockout mice.	3	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	8	9
Insulin activates the insulin receptor , and the activated insulin receptor then phosphorylates tyrosine residues IRS-1 , which allows IRS-1 to recruit phosphatidylinositide 3-kinase and leads to phosphorylation of Akt on threonine/serine residues .	Insulin activates the insulin receptor, and the activated insulin receptor then phosphorylates tyrosine residues IRS-1, which allows IRS-1 to recruit phosphatidylinositide 3-kinase and leads to phosphorylation of Akt on threonine/serine residues.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
In the absence of glucose , the basal level of ( pro ) insulin biosynthesis in the beta-cells overexpressing the wild-type IR increased significantly ( 61 % ) compared with the beta-cells transfected with the kinase-inactive IR .	In the absence of glucose, the basal level of (pro) insulin biosynthesis in the beta-cells overexpressing the wild-type IR increased significantly (61%) compared with the beta-cells transfected with the kinase-inactive IR.	13	22	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	21	22
Our previous studies indicated that the alpha- and beta-anomers of penta-O-galloyl-D-glucopyranose ( PGG ) , 2 and 3 , act as insulin mimetics that bind to and activate the insulin receptor , stimulate glucose transport in adipocytes , and reduce blood glucose and insulin levels in diabetic and obese animals .	Our previous studies indicated that the alpha- and beta-anomers of penta-O-galloyl-D-glucopyranose (PGG), 2 and 3, act as insulin mimetics that bind to and activate the insulin receptor, stimulate glucose transport in adipocytes, and reduce blood glucose and insulin levels in diabetic and obese animals.	21	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	21	22	29	31
The majority of animal studies to date have been consistent on the effects of ENPP1 impairing insulin stimulation of insulin receptor ( IR ) activation and downstream signaling .	The majority of animal studies to date have been consistent on the effects of ENPP1 impairing insulin stimulation of insulin receptor (IR) activation and downstream signaling.	16	21	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	16	17	19	21
Recently , analysis of signaling pathways in human mammary epithelial cell lines stimulated by insulin analogs revealed that regular insulin and glargine strongly activate the IGF- insulin receptor and the MAP kinase pathway in MCF7 cells ; glargine is a strong mitogen for cells characterized by a high-IGF- insulin receptor and insulin receptor ratio [ XREF_BIBR ] .	Recently, analysis of signaling pathways in human mammary epithelial cell lines stimulated by insulin analogs revealed that regular insulin and glargine strongly activate the IGF- insulin receptor and the MAP kinase pathway in MCF7 cells; glargine is a strong mitogen for cells characterized by a high-IGF- insulin receptor and insulin receptor ratio [XREF_BIBR].	18	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	19	20	26	28
Insulin activates the insulin receptor tyrosine kinase IR , which phosphorylates and recruits different substrate adaptors including the IRS family of proteins .	Insulin activates the insulin receptor tyrosine kinase IR, which phosphorylates and recruits different substrate adaptors including the IRS family of proteins.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
In vitro , insulin stimulation of the IR increases proliferation of breast cancer cells .	In vitro, insulin stimulation of the IR increases proliferation of breast cancer cells.	3	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	7	8
MDA-MB231 human breast cancer cells are unresponsive to insulin and contain a glycoprotein inhibitor of insulin stimulated insulin receptor ( IR ) tyrosine kinase activity .	MDA-MB231 human breast cancer cells are unresponsive to insulin and contain a glycoprotein inhibitor of insulin stimulated insulin receptor (IR) tyrosine kinase activity.	13	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	15	16	17	19
Insulin induced IR internalization which increased the co-localization of IR-GFP with transferrin in apoE3 treated cells , but not in apoE4 treated cells ( XREF_FIG ) .	Insulin induced IR internalization which increased the co-localization of IR-GFP with transferrin in apoE3 treated cells, but not in apoE4 treated cells (XREF_FIG).	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	2	3
We have found that insulin triggers an enhanced activation of the insulin receptor in both the sciatic nerve and the hippocampus from diabetic rats , resulting in increased phosphorylation of GSK3 .	We have found that insulin triggers an enhanced activation of the insulin receptor in both the sciatic nerve and the hippocampus from diabetic rats, resulting in increased phosphorylation of GSK3.	4	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	11	13
GSK3beta is highly active in the basal state and is inactivated by phosphorylation at the regulatory Ser9 residue in response to insulin stimulation of the insulin receptor and insulin receptor substrate and phosphatidyl inositol 3-kinase ( PI3K )/Akt cascade ( outlined in XREF_FIG ) .	GSK3beta is highly active in the basal state and is inactivated by phosphorylation at the regulatory Ser9 residue in response to insulin stimulation of the insulin receptor and insulin receptor substrate and phosphatidyl inositol 3-kinase (PI3K)/Akt cascade (outlined in XREF_FIG).	21	27	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	21	22	25	27
Insulin and IGF1 activate insulin receptor and IGF1 receptor , which subsequently activate insulin receptor substrates through tyrosine phosphorylation .	Insulin and IGF1 activate insulin receptor and IGF1 receptor, which subsequently activate insulin receptor substrates through tyrosine phosphorylation.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	4	6
Relative to non diabetic control rats ( WKY ) , insulin stimulated insulin receptor ( IR ) autophosphorylation and insulin receptor substrate-1 ( IRS-1 ) tyrosine phosphorylation were significantly inhibited in GK skeletal muscles .	Relative to non diabetic control rats (WKY), insulin stimulated insulin receptor (IR) autophosphorylation and insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation were significantly inhibited in GK skeletal muscles.	5	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	12	14
Here , we uncover a novel Neu1 and matrix metalloproteinase-9 ( MMP-9 ) cross-talk in alliance with neuromedin B G protein coupled receptor ( GPCR ) , which is essential for insulin induced IR activation and cellular signaling .	Here, we uncover a novel Neu1 and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B G protein coupled receptor (GPCR), which is essential for insulin induced IR activation and cellular signaling.	31	34	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	31	32	33	34
Insulin receptors are expressed in many cell types including osteoblasts , chondrocytes , and osteoclasts and the activation of insulin receptor by insulin stimulation induces its downstream mediators , thus regulating cellular metabolism , growth , survival , and differentiation .	Insulin receptors are expressed in many cell types including osteoblasts, chondrocytes, and osteoclasts and the activation of insulin receptor by insulin stimulation induces its downstream mediators, thus regulating cellular metabolism, growth, survival, and differentiation.	17	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	22	23	19	21
Immunoprecipitation studies of Chinese hamster ovary cells , which overexpress the human insulin receptor when treated with insulin , showed increased amounts of p85 and PI 3-kinase activity immunoprecipitable with monoclonal anti-p85 antibody and no increase in the tyrosine phosphorylation of p85 .	Immunoprecipitation studies of Chinese hamster ovary cells, which overexpress the human insulin receptor when treated with insulin, showed increased amounts of p85 and PI 3-kinase activity immunoprecipitable with monoclonal anti-p85 antibody and no increase in the tyrosine phosphorylation of p85.	12	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	17	18	12	14
One explanation for this could be that the dissociation of syntaxin 4 occurred immediately upon insulin induced IR association with Munc18c , yielding undetectable amounts of syntaxin 4 in the coimmunoprecipitates .	One explanation for this could be that the dissociation of syntaxin 4 occurred immediately upon insulin induced IR association with Munc18c, yielding undetectable amounts of syntaxin 4 in the coimmunoprecipitates.	12	18	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	15	16	17	18
Insulin treatment induced the change of insulin receptor localization to perinuclear compartment .	Insulin treatment induced the change of insulin receptor localization to perinuclear compartment.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	6	8
This assay has been used to measure the tyrosine kinase activity of receptor which was immunocaptured from lysates of various cells overexpressing the human insulin receptor as well as the endogenous insulin receptors in the parental cells .	This assay has been used to measure the tyrosine kinase activity of receptor which was immunocaptured from lysates of various cells overexpressing the human insulin receptor as well as the endogenous insulin receptors in the parental cells.	21	32	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	31	32	24	26
In the adipose tissue , insulin induced insulin receptor ( IR ) tyrosyl phosphorylation at Tyr1162 and Tyr1163 was attenuated in HFr rats compared with controls , while EC supplementation enhanced insulin induced IR phosphorylation and restored it to control levels ( XREF_FIG ) .	In the adipose tissue, insulin induced insulin receptor (IR) tyrosyl phosphorylation at Tyr1162 and Tyr1163 was attenuated in HFr rats compared with controls, while EC supplementation enhanced insulin induced IR phosphorylation and restored it to control levels (XREF_FIG).	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	7	9
Fetuin-A is an endogenous inhibitor of the insulin stimulated insulin receptor tyrosine kinase .	Fetuin-A is an endogenous inhibitor of the insulin stimulated insulin receptor tyrosine kinase.	4	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	9	11
XREF_BIBR In a morbidly obese woman , the initial doses of insulin may need to be increased to 1.5-2.0 units/kg to overcome the combined IR of pregnancy and obesity .	XREF_BIBR In a morbidly obese woman, the initial doses of insulin may need to be increased to 1.5-2.0 units/kg to overcome the combined IR of pregnancy and obesity.	9	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	11	12	24	25
Insulin and insulin receptor ( IR ) alpha subunit binding activate insulin receptor substrates .	Insulin and insulin receptor (IR) alpha subunit binding activate insulin receptor substrates.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	11	13
This ELISA detected an increase in undercarboxylated osteocalcin in Esp-/- mice , which harbor an increase in insulin signaling in osteoblasts ( XREF_FIG ) but not in Esp-/-; InsR osb +/- mice that do not ( XREF_FIG ) .	This ELISA detected an increase in undercarboxylated osteocalcin in Esp-/- mice, which harbor an increase in insulin signaling in osteoblasts (XREF_FIG) but not in Esp-/-; InsR osb +/- mice that do not (XREF_FIG).	17	29	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	InsR	InsR	InsR	17	18	28	29
Overexpression of W.T.PKC delta caused IR to localize mainly in the internal membrane fractions , and blockade of PKC delta abrogated insulin induced IR internalization .	Overexpression of W.T.PKC delta caused IR to localize mainly in the internal membrane fractions, and blockade of PKC delta abrogated insulin induced IR internalization.	21	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	21	22	23	24
These results may suggest that the extent of AMPK activation may be a tool for insulin receptors to monitor blood glucose level , with which insulin induced insulin receptor activation determines the way to go negatively or positively toward [ Ca ( 2+ ) ] ( c ) .	These results may suggest that the extent of AMPK activation may be a tool for insulin receptors to monitor blood glucose level, with which insulin induced insulin receptor activation determines the way to go negatively or positively toward [Ca (2+)] (c).	25	29	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	25	26	27	29
High-dose insulin therapy is associated with side effects as well as insulin induced IR .	High-dose insulin therapy is associated with side effects as well as insulin induced IR.	4	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	11	12	13	14
This finding suggests that both local insulin administration and blood glucose normalization can restore retinal insulin receptor signaling , although direct activation by the ligand is more effective .	This finding suggests that both local insulin administration and blood glucose normalization can restore retinal insulin receptor signaling, although direct activation by the ligand is more effective.	6	17	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	15	17
Surrogate measures of insulin sensitivity include fasting insulin level , which increases in response to peripheral IR , and formulas based on both fasting insulin and glucose such as the homeostasis model assessment ( HOMA ) and the quantitative insulin-sensitivity check index ( QUICKI ) .	Surrogate measures of insulin sensitivity include fasting insulin level, which increases in response to peripheral IR, and formulas based on both fasting insulin and glucose such as the homeostasis model assessment (HOMA) and the quantitative insulin-sensitivity check index (QUICKI).	7	17	increases	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin level	insulin	IR	IR	ir	7	8	16	17
Our investigation of cav-2-dependent activation of IR by insulin versus IGF-1 in cav-2-transfected HEK293T cells showed that cav-2 did not affect the protein level of IR ( XREF_FIG ) ; in contrast that cav-1 has been shown to increase IR expression in cav-1-transfected HEK293T cells [ XREF_BIBR ] .	Our investigation of cav-2-dependent activation of IR by insulin versus IGF-1 in cav-2-transfected HEK293T cells showed that cav-2 did not affect the protein level of IR (XREF_FIG); in contrast that cav-1 has been shown to increase IR expression in cav-1-transfected HEK293T cells [XREF_BIBR].	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	8	9	6	7
Insulin receptor tyrosine kinase activity In normal-weight and obese diabetic patients , insulin stimulated insulin receptor tyrosine kinase activity was reduced and could not be explained by decreased insulin receptor number and binding [ XREF_BIBR ] .	Insulin receptor tyrosine kinase activity In normal-weight and obese diabetic patients, insulin stimulated insulin receptor tyrosine kinase activity was reduced and could not be explained by decreased insulin receptor number and binding [XREF_BIBR].	12	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	14	16
Taken together , we suggest that alterations in slit-diaphragm and cytoskeleton aggravate the insulin resistance induced by lipids and targeting these structures could ameliorate the IR state in podocytes .	Taken together, we suggest that alterations in slit-diaphragm and cytoskeleton aggravate the insulin resistance induced by lipids and targeting these structures could ameliorate the IR state in podocytes.	13	26	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	25	26
XREF_BIBR , XREF_BIBR Increased insulin levels ( hyperinsulinemia ) itself causes IR , preventable by rapamycin .	XREF_BIBR, XREF_BIBR Increased insulin levels (hyperinsulinemia) itself causes IR, preventable by rapamycin.	4	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	IR	IR	ir	4	5	11	12
The decreases in NO production and Akt phosphorylation with PD123319 infusion are likely secondary to decreased stimulation of the AT 2 R by ANG II and insulin receptor by insulin on the endothelium ( for NO ) and decreased insulin delivery to the muscle ( for p-Akt ) .	The decreases in NO production and Akt phosphorylation with PD123319 infusion are likely secondary to decreased stimulation of the AT 2 R by ANG II and insulin receptor by insulin on the endothelium (for NO) and decreased insulin delivery to the muscle (for p-Akt).	16	32	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	29	30	26	28
Insulin , pro insulin and IGFs with different affinities and potencies are capable of binding and activating both Ir and IGF-1R .	Insulin, pro insulin and IGFs with different affinities and potencies are capable of binding and activating both Ir and IGF-1R.	0	20	activating	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	Insulin	Insulin	Ir	Ir	Ir	0	1	18	19
Immunoprecipitation assays revealed that insulin activated the insulin receptor ( INSR ) , but not the IGF1 receptor ( IGF1R ) .	Immunoprecipitation assays revealed that insulin activated the insulin receptor (INSR), but not the IGF1 receptor (IGF1R).	4	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	7	9
However , the present study found that betatrophin levels only increased in the insulin induced model of IR , which reflected that it was insulin , but not IR , that upregulated betatrophin levels .	However, the present study found that betatrophin levels only increased in the insulin induced model of IR, which reflected that it was insulin, but not IR, that upregulated betatrophin levels.	12	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	17	18
To study the association of obesity with defects in insulin action , we investigated insulin stimulation of both insulin receptor ( IR ) autophosphorylation and subsequent glucose transport in primary skeletal muscle cell cultures obtained from both nonobese and obese nondiabetic subjects .	To study the association of obesity with defects in insulin action, we investigated insulin stimulation of both insulin receptor (IR) autophosphorylation and subsequent glucose transport in primary skeletal muscle cell cultures obtained from both nonobese and obese nondiabetic subjects.	14	20	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	14	15	18	20
Using antibodies against phospho-S1101 , we found lack of phosphorylation of this residue in DMEM- and insulin induced IR ( XREF_FIG ) .	Using antibodies against phospho-S1101, we found lack of phosphorylation of this residue in DMEM- and insulin induced IR (XREF_FIG).	12	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	16	17	18	19
Therefore , it appears that an insulin deficiency rather than hyperglycemia induces aberrant neuronal insulin receptor signaling and contributes to sensory nerve dysfunction in type 1 diabetic neuropathy .	Therefore, it appears that an insulin deficiency rather than hyperglycemia induces aberrant neuronal insulin receptor signaling and contributes to sensory nerve dysfunction in type 1 diabetic neuropathy.	6	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	14	16
Insulin stimulated PDH activity 3-4 -- fold in cells that overexpressed normal human insulin receptors , but not in cells expressing TMI receptors , composed of the ligand binding domain of the insulin receptor coupled to the transmembrane and intracellular components of the IGF-1 receptor , or CEX receptors , in which the carboxy terminal 110 amino acid portion of the insulin receptor was exchanged for the corresponding portion of the IGF-1 receptor .	Insulin stimulated PDH activity 3-4 -- fold in cells that overexpressed normal human insulin receptors, but not in cells expressing TMI receptors, composed of the ligand binding domain of the insulin receptor coupled to the transmembrane and intracellular components of the IGF-1 receptor, or CEX receptors, in which the carboxy terminal 110 amino acid portion of the insulin receptor was exchanged for the corresponding portion of the IGF-1 receptor.	0	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	32	34
In addition , no effect of mouse Grb10 was observed on the association between IRS-1 and p85 , on IRS-1-associated PI 3-kinase activity , or on insulin mediated activation of IR or IRS proteins .	In addition, no effect of mouse Grb10 was observed on the association between IRS-1 and p85, on IRS-1-associated PI 3-kinase activity, or on insulin mediated activation of IR or IRS proteins.	26	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	26	27	30	31
Both insulin and IGFs activate insulin receptor and downstream pathways ; however , insulin was shown to be more selective as a chondrogenic differentiating agent , whereas IGF-1 was shown to induce more proliferating effects .	Both insulin and IGFs activate insulin receptor and downstream pathways; however, insulin was shown to be more selective as a chondrogenic differentiating agent, whereas IGF-1 was shown to induce more proliferating effects.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	5	7
This idea is supported by a recent study that reported a significant decrease in insulin receptor mRNA in cultured DRG neurons that displayed insulin resistance when treated with high levels of insulin [ XREF_BIBR ] .	This idea is supported by a recent study that reported a significant decrease in insulin receptor mRNA in cultured DRG neurons that displayed insulin resistance when treated with high levels of insulin [XREF_BIBR].	14	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	31	32	14	16
In this study , we identified and characterized a fully human mAb , XMetD , and found it to be a novel antagonist of insulin activation of the INSR .	In this study, we identified and characterized a fully human mAb, XMetD, and found it to be a novel antagonist of insulin activation of the INSR.	24	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	24	25	28	29
We have studied how insulin mediated internalization of insulin receptors and insulin activation of the insulin receptor kinase might be inter related .	We have studied how insulin mediated internalization of insulin receptors and insulin activation of the insulin receptor kinase might be inter related.	11	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	15	17
To further test how apoE isoforms differentially affect insulin induced IR trafficking , we monitored IR internalization after insulin treatment in the absence or presence of apoE .	To further test how apoE isoforms differentially affect insulin induced IR trafficking, we monitored IR internalization after insulin treatment in the absence or presence of apoE.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	8	9	10	11
These studies of genetic manipulation of components of the insulin signaling cascade , as well as direct insulin infusion or insulin deprivation , raise the possibility that mitochondrial defects observed in some insulin resistant subjects could be a consequence of the IR itself .	These studies of genetic manipulation of components of the insulin signaling cascade, as well as direct insulin infusion or insulin deprivation, raise the possibility that mitochondrial defects observed in some insulin resistant subjects could be a consequence of the IR itself.	17	42	raise	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	17	18	41	42
Here , the findings in their report showed data to support a novel Neu1 and MMP-9 crosstalk in alliance with neuromedin B GPCR tethered to IRbeta subunit on the cell surface , all of which are essential for insulin induced IR activation and cellular signaling .	Here, the findings in their report showed data to support a novel Neu1 and MMP-9 crosstalk in alliance with neuromedin B GPCR tethered to IRbeta subunit on the cell surface, all of which are essential for insulin induced IR activation and cellular signaling.	36	41	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	38	39	40	41
INSR stimulation by insulin activated canonical INSR signaling pathways and partially abrogated ex vivo CLL cell apoptosis .	INSR stimulation by insulin activated canonical INSR signaling pathways and partially abrogated ex vivo CLL cell apoptosis.	0	4	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	3	4	0	1
Insulin initiates the regulation of cellular glucose metabolism by binding to the insulin receptor ( INSR ) on the cell surface , a process that activates the receptor ' s intrinsic kinase activity .	Insulin initiates the regulation of cellular glucose metabolism by binding to the insulin receptor (INSR) on the cell surface, a process that activates the receptor 's intrinsic kinase activity.	0	14	initiates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	12	14
The defects in insulin action were associated with an approximately 40 % reduction in insulin stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity and an approximately 50 % decrease in Akt2 activation .	The defects in insulin action were associated with an approximately 40% reduction in insulin stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity and an approximately 50% decrease in Akt2 activation.	12	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	14	15	16	18
Metformin in combination with insulin increased IR protein and gene expressions , while it had no influence on the protein expression of IGF-1R in endometrial stromal cells .	Metformin in combination with insulin increased IR protein and gene expressions, while it had no influence on the protein expression of IGF-1R in endometrial stromal cells.	2	7	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	6	7
In details , we studied i ) insulin induced IR activation in all three cell types , ii ) downstream insulin signaling and subsequent insulin action on glucose metabolism in liver- and skeletal muscle-cells and iii ) beta-cells insulin secretion and survival .	In details, we studied i) insulin induced IR activation in all three cell types, ii) downstream insulin signaling and subsequent insulin action on glucose metabolism in liver- and skeletal muscle-cells and iii) beta-cells insulin secretion and survival.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	7	8	9	10
Fructose also contributes to an increase in insulin by interfering with insulin signaling and inhibition of insulin receptor activity [ XREF_BIBR ] .	Fructose also contributes to an increase in insulin by interfering with insulin signaling and inhibition of insulin receptor activity [XREF_BIBR].	11	18	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	16	18
Insulin sensitivity varies widely in non obese , non diabetic subjects , and we have previously reported that in vivo insulin action correlates with in vitro insulin stimulated insulin receptor tyrosine kinase activity in skeletal muscle .	Insulin sensitivity varies widely in non obese, non diabetic subjects, and we have previously reported that in vivo insulin action correlates with in vitro insulin stimulated insulin receptor tyrosine kinase activity in skeletal muscle.	26	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	26	27	28	30
IR level increase , could be caused by the insulin resistance in CNS .	IR level increase, could be caused by the insulin resistance in CNS.	0	10	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	9	10	0	1
High levels of inflammatory cytokines lead to increased SOCS-1 and -3 expression in insulin sensitive tissues , which induce IR via inhibition of the insulin signaling pathway .	High levels of inflammatory cytokines lead to increased SOCS-1 and -3 expression in insulin sensitive tissues, which induce IR via inhibition of the insulin signaling pathway.	13	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	19	20
Conversely , ANG II can cause insulin resistance by interfering with the insulin stimulated insulin receptor signaling [ XREF_BIBR ] .	Conversely, ANG II can cause insulin resistance by interfering with the insulin stimulated insulin receptor signaling [XREF_BIBR].	9	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	14	16
Furthermore immunoblot analyses of tyrosine phosphorylated proteins in cell lysates showed that PTRF tyrosine phosphorylation was largely inhibited although the insulin stimulated IRS-1/2 ( 180kDa ) and the beta-subunit of insulin receptor ( 95kDa ) ( arrows ) were not affected by beta-CD treatment ( XREF_FIG ) .	Furthermore immunoblot analyses of tyrosine phosphorylated proteins in cell lysates showed that PTRF tyrosine phosphorylation was largely inhibited although the insulin stimulated IRS-1/2 (180kDa) and the beta-subunit of insulin receptor (95kDa) (arrows) were not affected by beta-CD treatment (XREF_FIG).	19	40	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	20	21	30	32
The role of insulin induced H 2 O 2 in neuronal insulin receptor activation and the origin of insulin induced H 2 O 2 in neurons remain unclear .	The role of insulin induced H 2 O 2 in neuronal insulin receptor activation and the origin of insulin induced H 2 O 2 in neurons remain unclear.	1	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	11	13
An endothelial and dendritic cell based innate immune model was used to study antigen presenting cell activation , cytokine secretion , and insulin receptor signalling pathways induced by originator and non originator insulin glargine products .	An endothelial and dendritic cell based innate immune model was used to study antigen presenting cell activation, cytokine secretion, and insulin receptor signalling pathways induced by originator and non originator insulin glargine products.	22	34	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	32	33	22	24
Insulin receptor kinase , affinity purified by adsorption and elution from immobilized insulin , is stimulated 2-3-fold by insulin in detergent solution .	Insulin receptor kinase, affinity purified by adsorption and elution from immobilized insulin, is stimulated 2-3-fold by insulin in detergent solution.	0	21	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Insulin receptor	Insulin receptor	Insulin receptor	18	19	0	2
Unexpectedly , although LRP1KO hepatocytes have decreased surface IR expression , there was no change in insulin stimulated internalization of IR , indicating that unlike in primary neurons , there may be other mechanisms that govern IR internalization in the liver .	Unexpectedly, although LRP1KO hepatocytes have decreased surface IR expression, there was no change in insulin stimulated internalization of IR, indicating that unlike in primary neurons, there may be other mechanisms that govern IR internalization in the liver.	14	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	16	17	20	21
As a consequence , mice that lacks BBS proteins exhibit hyperglycemia , insulin resistance and blunted insulin induced activation of IR signaling in insulin sensitive tissues ( liver , skeletal muscle and adipose tissue ) .	As a consequence, mice that lacks BBS proteins exhibit hyperglycemia, insulin resistance and blunted insulin induced activation of IR signaling in insulin sensitive tissues (liver, skeletal muscle and adipose tissue).	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	16	17	20	21
Insulin activated IR tyrosine kinase phosphorylated Gir which was immunoprecipitated by both the antisera .	Insulin activated IR tyrosine kinase phosphorylated Gir which was immunoprecipitated by both the antisera.	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	2	3
IRS1 belongs to the IRS family of adaptor molecules and is tyrosine phosphorylated in response to the activation of insulin receptor by insulin binding .	IRS1 belongs to the IRS family of adaptor molecules and is tyrosine phosphorylated in response to the activation of insulin receptor by insulin binding.	17	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	22	23	19	21
TPM increased anorexigenic signaling by enhancing the leptin induced leptin receptor and Janus kinase 2/signal transducer and activator of transcription 3 pathway and the insulin induced insulin receptor substrate/Akt/forkhead box O1 pathway in parallel to reduced phosphatase protein expression in the hypothalamus of obese mice .	TPM increased anorexigenic signaling by enhancing the leptin induced leptin receptor and Janus kinase 2/signal transducer and activator of transcription 3 pathway and the insulin induced insulin receptor substrate/Akt/forkhead box O1 pathway in parallel to reduced phosphatase protein expression in the hypothalamus of obese mice.	15	31	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	24	25	26	28
These indicate SA affects insulin sensitivity in multiple tissues or organs , and the insulin desensitivity of these tissues or organs collectively contribute to the whole-body IR .	These indicate SA affects insulin sensitivity in multiple tissues or organs, and the insulin desensitivity of these tissues or organs collectively contribute to the whole-body IR.	14	27	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	14	15	26	27
Insulin can stimulate both the insulin receptor ( IR ) and the insulin like growth factor-1 receptor ( IGF-1R ) , and both of these receptors are overexpressed in NSCLC patients and correlated with worse prognoses [ XREF_BIBR ] and poor responses to targeted treatments [ XREF_BIBR ] .	Insulin can stimulate both the insulin receptor (IR) and the insulin like growth factor-1 receptor (IGF-1R), and both of these receptors are overexpressed in NSCLC patients and correlated with worse prognoses [XREF_BIBR] and poor responses to targeted treatments [XREF_BIBR].	0	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	5	7
We conclude that insulin activation of erythrocyte insulin receptor kinase is not impaired in NIDDM and is not influenced by hyperglycemia .	We conclude that insulin activation of erythrocyte insulin receptor kinase is not impaired in NIDDM and is not influenced by hyperglycemia.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	7	9
A role of insulin and INSR pathway , independent of IGF-I , in regulating pituitary function is supported by the fact that ( 1 ) IGF-I and insulin significantly suppressed somatotrope function at doses ( 0.5 and 5 nM respectively ) not anticipated to activate their respective receptors , and ( 2 ) the baboon pituitary expresses INSR mRNA at levels comparable to or greater than that of tissues commonly considered as insulin sensitive ( i.e. liver , skeletal muscle , and fat ) .	A role of insulin and INSR pathway, independent of IGF-I, in regulating pituitary function is supported by the fact that (1) IGF-I and insulin significantly suppressed somatotrope function at doses (0.5 and 5 nM respectively) not anticipated to activate their respective receptors, and (2) the baboon pituitary expresses INSR mRNA at levels comparable to or greater than that of tissues commonly considered as insulin sensitive (i.e. liver, skeletal muscle, and fat).	3	58	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	3	4	57	58
In this study , we demonstrate that quercetin suppresses insulin induced dimerization of the insulin receptor ( IR ) through interfering with ligand-receptor interactions , which reduces the phosphorylation of IR and Akt .	In this study, we demonstrate that quercetin suppresses insulin induced dimerization of the insulin receptor (IR) through interfering with ligand-receptor interactions, which reduces the phosphorylation of IR and Akt.	8	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	14	16
Chronically elevated insulin levels may lead to activation of the IR , which is expressed on many cancer cells .	Chronically elevated insulin levels may lead to activation of the IR, which is expressed on many cancer cells.	2	11	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	IR	IR	ir	2	3	10	11
Insulin induced activation of the insulin receptor ( IR ) , phosphatidylinositol 3-kinase ( PI3K ) , and Akt is prevented along with IkappaB kinase ( IKK ) activation and degradation of IkappaB in the muscle tissue [ XREF_BIBR - XREF_BIBR ] .	Insulin induced activation of the insulin receptor (IR), phosphatidylinositol 3-kinase (PI3K), and Akt is prevented along with IkappaB kinase (IKK) activation and degradation of IkappaB in the muscle tissue [XREF_BIBR - XREF_BIBR].	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	5	7
Insulin does not activate the insulin receptor in these tissues at normal concentrations [ XREF_BIBR ] .	Insulin does not activate the insulin receptor in these tissues at normal concentrations [XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	5	7
Insulin activates insulin receptor kinase ( IRK ) , which is a heterotetrameric receptor composed of two extracellular alpha subunits and two transmembrane beta subunits .	Insulin activates insulin receptor kinase (IRK), which is a heterotetrameric receptor composed of two extracellular alpha subunits and two transmembrane beta subunits.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	2	4
Taken together , these results indicate that insulin rapidly increases nuclear insulin receptor appearance and activates nuclear tyrosine kinase activity .	Taken together, these results indicate that insulin rapidly increases nuclear insulin receptor appearance and activates nuclear tyrosine kinase activity.	7	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	11	13
The distribution of caveolar and noncaveolar phosphorylated IR was unaffected but insulin induced IR activation was significantly enhanced following consumption of the high-cholesterol diet ( 120 % , P < 0.001 ) .	The distribution of caveolar and noncaveolar phosphorylated IR was unaffected but insulin induced IR activation was significantly enhanced following consumption of the high-cholesterol diet (120%, P < 0.001).	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	11	12	13	14
By contrast , restoration of euglycemia with intense insulin treatment did not produce a remission in either insulin resistance or hypophosphorylation of the insulin activated insulin receptor .	By contrast, restoration of euglycemia with intense insulin treatment did not produce a remission in either insulin resistance or hypophosphorylation of the insulin activated insulin receptor.	14	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	hypophosphorylation of the insulin	insulin	insulin receptor	insulin receptor	insulin receptor	23	24	25	27
Mutations in the tyrosine kinase domain of the insulin receptor cause insulin resistance in a dominant fashion .	Mutations in the tyrosine kinase domain of the insulin receptor cause insulin resistance in a dominant fashion.	8	12	cause	Positive_activation_token_1_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	8	10
However , there are no studies available on the role of insulin induced IR signaling in the development of normal photoreceptors .	However, there are no studies available on the role of insulin induced IR signaling in the development of normal photoreceptors.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	11	12	13	14
Insulin treatment increased from 28 to 39 % the relative expression of isotype A IR mRNA , but vanadate treatment did not significantly affect this parameter .	Insulin treatment increased from 28 to 39% the relative expression of isotype A IR mRNA, but vanadate treatment did not significantly affect this parameter.	0	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	14	15
Compared with only slight coprecipitation under basal conditions , insulin stimulated approximately twofold more IR coprecipitation in both 3T3-L1 adipocyte lysates ( XREF_FIG ) and muscle extracts ( XREF_FIG ) versus unstimulated controls .	Compared with only slight coprecipitation under basal conditions, insulin stimulated approximately twofold more IR coprecipitation in both 3T3-L1 adipocyte lysates (XREF_FIG) and muscle extracts (XREF_FIG) versus unstimulated controls.	9	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	9	10	14	15
These results suggested that the IR-Munc18c association and tyrosine phosphorylation of Munc18c specifically required insulin stimulated IR kinase activity .	These results suggested that the IR-Munc18c association and tyrosine phosphorylation of Munc18c specifically required insulin stimulated IR kinase activity.	13	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	14	15	16	17
To examine the role of insulin induced IR signaling , we analyzed cultured neuronal cells isolated from newborn rodent retinas .	To examine the role of insulin induced IR signaling, we analyzed cultured neuronal cells isolated from newborn rodent retinas.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	5	6	7	8
Since 10nM insulin did not activate the insulin receptor further than the activation induced by 1nM and because 1 nM insulin corresponds to the half-maximally effective concentration ( ED50 ) for neurite outgrowth in neuronal cell culture , 1 nM as well as 0.1 nM insulin , which correspond to physiological level , were selected with a 15 min incubation for all subsequent experiments .	Since 10nM insulin did not activate the insulin receptor further than the activation induced by 1nM and because 1 nM insulin corresponds to the half-maximally effective concentration (ED50) for neurite outgrowth in neuronal cell culture, 1 nM as well as 0.1 nM insulin, which correspond to physiological level, were selected with a 15 min incubation for all subsequent experiments.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	7	9
Upon binding to the cell surface receptor , insulin activates insulin receptor ( IR ) , a heterotetrameric glycoprotein consisting of two extracellular alpha-subunits ( 135 kDa ) and two transmembrane beta-subunits ( 95 kDa ) .	Upon binding to the cell surface receptor, insulin activates insulin receptor (IR), a heterotetrameric glycoprotein consisting of two extracellular alpha-subunits (135 kDa) and two transmembrane beta-subunits (95 kDa).	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	10	12
Despite the known fact that FAA are elevated in type 2 diabetes , the high insulin concentration used during HEC obliterated the differences in FAA but not glucose disposal among the three groups , raising the likely possibility that that regional insulin resistance towards glucose metabolism not fat metabolism , may underlie the pathophysiology of IR in AA .	Despite the known fact that FAA are elevated in type 2 diabetes, the high insulin concentration used during HEC obliterated the differences in FAA but not glucose disposal among the three groups, raising the likely possibility that that regional insulin resistance towards glucose metabolism not fat metabolism, may underlie the pathophysiology of IR in AA.	41	56	underlie	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	41	42	55	56
Subsequently , the increased insulin might activate insulin receptor , which opens the K ( ATP ) channel and induces peripheral insulin release through the vagal nerve .	Subsequently, the increased insulin might activate insulin receptor, which opens the K (ATP) channel and induces peripheral insulin release through the vagal nerve.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	7	9
In contrast , insulin stimulation of IR and IRS2 knockout cells resulted in decreased PI3K and AKT activity and glucose stimulation was ineffective to activate PI3K and AKT , and instead resulted in activated extracellular signal regulated kinase ( ERK ) .	In contrast, insulin stimulation of IR and IRS2 knockout cells resulted in decreased PI3K and AKT activity and glucose stimulation was ineffective to activate PI3K and AKT, and instead resulted in activated extracellular signal regulated kinase (ERK).	3	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	6	7
Exposure of these individual cells to the promitogenic insulin analogue X10 that activates both the INSR and the IGF1R , resulted in intact downstream signaling cascades in all three cell lines , indicating functionality of the receptors .	Exposure of these individual cells to the promitogenic insulin analogue X10 that activates both the INSR and the IGF1R, resulted in intact downstream signaling cascades in all three cell lines, indicating functionality of the receptors.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	8	9	15	16
A fasting glucose to insulin ( G/I ) ratio is a simple , reliable , sensitive and specific measurement of insulin sensitivity and is a useful test for the identification of IR in women with PCOS , who have to be treated with insulin sensitizers .	A fasting glucose to insulin (G/I) ratio is a simple, reliable, sensitive and specific measurement of insulin sensitivity and is a useful test for the identification of IR in women with PCOS, who have to be treated with insulin sensitizers.	29	44	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	43	44	31	32
We examined expression of the mitogen sensitive immediate early gene , early growth response 1 ( egr-1 ) , as a model of insulin induced transcription in rat HTC-IR cells overexpressing human IR .	We examined expression of the mitogen sensitive immediate early gene, early growth response 1 (egr-1), as a model of insulin induced transcription in rat HTC-IR cells overexpressing human IR.	21	33	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin induced transcription	insulin	IR	IR	ir	23	24	32	33
Insulin and Mn/MgATP treatment of immunoaffinity purified alpha beta heterodimeric insulin receptors induced the formation of an alpha 2 beta 2 heterotetrameric insulin receptor complex .	Insulin and Mn/MgATP treatment of immunoaffinity purified alpha beta heterodimeric insulin receptors induced the formation of an alpha 2 beta 2 heterotetrameric insulin receptor complex.	0	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	22	24
Insulin and insulin like growth factors initiate signaling by binding to their cognate cell-surface receptors , namely IR and IGF1R ; although both receptors can bind insulin , IGF1 and IGF2 with differing affinities .	Insulin and insulin like growth factors initiate signaling by binding to their cognate cell-surface receptors, namely IR and IGF1R; although both receptors can bind insulin, IGF1 and IGF2 with differing affinities.	0	18	initiate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	17	18
Insulin can interact with its receptor and activate IR tyrosine kinase , leading to the activation of IRS-1 , PI3K-p85 , AKT , and GLUT4 translocation , and promoting glucose uptake and metabolism in the skeletal muscles [ XREF_BIBR , XREF_BIBR ] .	Insulin can interact with its receptor and activate IR tyrosine kinase, leading to the activation of IRS-1, PI3K-p85, AKT, and GLUT4 translocation, and promoting glucose uptake and metabolism in the skeletal muscles [XREF_BIBR, XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	8	9
In hepatocytes , chronic insulin infusion induces IR by impairing glucose uptake and the IRS-2/PI ( 3 ) K/Akt signaling pathway , which were also identified as critical nodes in the regulation of hepatocyte insulin sensitivity XREF_BIBR .	In hepatocytes, chronic insulin infusion induces IR by impairing glucose uptake and the IRS-2/PI (3) K/Akt signaling pathway, which were also identified as critical nodes in the regulation of hepatocyte insulin sensitivity XREF_BIBR.	4	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	7	8
We wanted to examine the involvement of caveolae in the early phase of insulin stimulated endocytosis of the insulin receptor in primary adipocytes .	We wanted to examine the involvement of caveolae in the early phase of insulin stimulated endocytosis of the insulin receptor in primary adipocytes.	11	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	18	20
In the present study , we investigated insulin induced IR tyrosine kinase activity towards Shc .	In the present study, we investigated insulin induced IR tyrosine kinase activity towards Shc.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	7	8	9	10
Raising amino acids from the food deprived to the fed level did not alter the insulin induced activation of IR , IRS-1 , PI 3-kinase and PKB but increased S6 phosphorylation and protein synthesis in skeletal muscle and liver .	Raising amino acids from the food deprived to the fed level did not alter the insulin induced activation of IR, IRS-1, PI 3-kinase and PKB but increased S6 phosphorylation and protein synthesis in skeletal muscle and liver.	14	28	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	15	16	19	20
Insulin stimulation of insulin receptor ( IR ) and insulin receptor substrate ( IRS ) 1 tyrosine phosphorylation was not affected by ZAG treatment ( 25 mug/ml , 24 h ) , neither in mature human SGBS ( XREF_FIG ) nor in LiSa-2 adipocytes ( XREF_FIG ) .	Insulin stimulation of insulin receptor (IR) and insulin receptor substrate (IRS) 1 tyrosine phosphorylation was not affected by ZAG treatment (25 mug/ml, 24 h), neither in mature human SGBS (XREF_FIG) nor in LiSa-2 adipocytes (XREF_FIG).	0	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
Thus a higher HOMA IR value in our study would primarily be driven by higher insulin levels .	Thus a higher HOMA IR value in our study would primarily be driven by higher insulin levels.	4	17	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	IR	IR	ir	15	16	4	5
Insulin analogues have been shown to differently activate insulin receptor isoforms and post-receptor signaling .	Insulin analogues have been shown to differently activate insulin receptor isoforms and post-receptor signaling.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	8	10
In addition to inhibiting INSR binding , XMetD also inhibited insulin induced INSR signaling by 20- to 100-fold .	In addition to inhibiting INSR binding, XMetD also inhibited insulin induced INSR signaling by 20- to 100-fold.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	10	11	12	13
Finally , only very high doses of insulin ( 500ng/ml ) could activate the INSR in LNCaP cells ( XREF_FIG C ) .	Finally, only very high doses of insulin (500ng/ml) could activate the INSR in LNCaP cells (XREF_FIG C).	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	7	8	14	15
Insulin responsiveness was measured first by the most proximal IR function activated by insulin following four hours growth of the cells in insulin deprived media .	Insulin responsiveness was measured first by the most proximal IR function activated by insulin following four hours growth of the cells in insulin deprived media.	9	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	9	10
Insulin increased insulin receptor tyrosine kinase ( IRTK ) , insulin receptor substrate 1 associated phosphatidylinositol ( PI ) 3-kinase activities , and Ser ( 473 ) phosphorylation of protein kinase B ( PKB )/Akt significantly but similarly in rested and exercised legs .	Insulin increased insulin receptor tyrosine kinase (IRTK), insulin receptor substrate 1 associated phosphatidylinositol (PI) 3-kinase activities, and Ser (473) phosphorylation of protein kinase B (PKB)/Akt significantly but similarly in rested and exercised legs.	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	2	4
Upon examination of other targets of the insulin signaling pathway , we observed a marked reduction in insulin stimulated p-tyrosine ( p-Tyr ) ( insulin receptor beta-subunit and IRS-1 ) expression levels in E4orf1-Tg sWAT and liver tissues ( XREF_FIG C ) .	Upon examination of other targets of the insulin signaling pathway, we observed a marked reduction in insulin stimulated p-tyrosine (p-Tyr) (insulin receptor beta-subunit and IRS-1) expression levels in E4orf1-Tg sWAT and liver tissues (XREF_FIG C).	15	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	17	18	24	26
We then asked whether insulin signaling in the CA contributes to the control of diapause like state by elevating or suppressing the activity of insulin receptor ( InR ) as well as two downstream elements of insulin signaling , PI3K and mTOR [ XREF_BIBR ] .	We then asked whether insulin signaling in the CA contributes to the control of diapause like state by elevating or suppressing the activity of insulin receptor (InR) as well as two downstream elements of insulin signaling, PI3K and mTOR [XREF_BIBR].	4	26	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	24	26
Insulin activated insulin receptor and promoted the proliferation of osteoclast precursors in time- and dose dependent manners .	Insulin activated insulin receptor and promoted the proliferation of osteoclast precursors in time- and dose dependent manners.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	2	4
Following insulin stimulation IR is endocytosed , and once in the endosomes , insulin is released from IR via proteolytic degradation .	Following insulin stimulation IR is endocytosed, and once in the endosomes, insulin is released from IR via proteolytic degradation.	0	15	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	1	2	3	4
In this study , we show that insulin induces INSR exon 11 inclusion in pancreatic beta cells in both human and mouse .	In this study, we show that insulin induces INSR exon 11 inclusion in pancreatic beta cells in both human and mouse.	7	10	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	7	8	9	10
We examined this inhibitor in 3T3L1 incubation where HNMPA-( AM ) 3 strongly inhibited insulin induced IR activation ( XREF_FIG ) .	We examined this inhibitor in 3T3L1 incubation where HNMPA-(AM) 3 strongly inhibited insulin induced IR activation (XREF_FIG).	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	14	15	16	17
Our results clearly demonstrated that bradykinin enhanced insulin stimulated tyrosine kinase activity of the insulin receptor and downstream insulin signal cascade through the BK2R mediated signal pathway .	Our results clearly demonstrated that bradykinin enhanced insulin stimulated tyrosine kinase activity of the insulin receptor and downstream insulin signal cascade through the BK2R mediated signal pathway.	6	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	14	16
In addition , insulin stimulated glucose disposal in skeletal muscle was significantly increased in IR Deltamyel - compared to control-mice , whereas insulin stimulated glucose uptake in brain and adipose tissue remained unaltered under clamp conditions ( XREF_FIG ) .	In addition, insulin stimulated glucose disposal in skeletal muscle was significantly increased in IR Deltamyel - compared to control-mice, whereas insulin stimulated glucose uptake in brain and adipose tissue remained unaltered under clamp conditions (XREF_FIG).	3	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	14	15
These results indicate that insulin induced IR downregulation may lead to the formation of a higher proportion of hybrid receptors , whose abundance is negatively correlated with in vivo insulin sensitivity .	These results indicate that insulin induced IR downregulation may lead to the formation of a higher proportion of hybrid receptors, whose abundance is negatively correlated with in vivo insulin sensitivity.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	6	7
These data suggest that chronic insulin treatment can induce alterations of IR beta , IRS-1 and PI 3-kinase three early steps in insulin action , which contributes significantly to insulin resistance , and may account for desensitization of insulin action .	These data suggest that chronic insulin treatment can induce alterations of IR beta, IRS-1 and PI 3-kinase three early steps in insulin action, which contributes significantly to insulin resistance, and may account for desensitization of insulin action.	5	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	5	6	11	12
Insulin has been shown to activate IR and stimulate PI3K/PDK1/AKT and GRB2/SOS/RAS kinase cascades , which are known to regulate mitochondrial function , as reviewed elsewhere [ XREF_BIBR ] .	Insulin has been shown to activate IR and stimulate PI3K/PDK1/AKT and GRB2/SOS/RAS kinase cascades, which are known to regulate mitochondrial function, as reviewed elsewhere [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	6	7
In contrast , liver-lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity .	In contrast, liver-lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity.	33	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	33	34	36	38
Nonetheless , it has been known for some time that insulin may stimulate growth of human cancer cell lines XREF_BIBR - XREF_BIBR and that 80 % of breast cancers overexpress the IR compared with normal breast tissue XREF_BIBR .	Nonetheless, it has been known for some time that insulin may stimulate growth of human cancer cell lines XREF_BIBR - XREF_BIBR and that 80% of breast cancers overexpress the IR compared with normal breast tissue XREF_BIBR.	10	32	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	10	11	31	32
6 Although basal ratios of p-ERK and ERK were reduced in the aortas of Insr +/- Irs1 +/- Apoe -/- mice , insulin stimulation resulted in significantly increased pERK and ERK ratio of insulin stimulated pERKs in Insr +/- Irs1 +/- Apoe -/- aortas compared with Insr +/+ Irs1 +/+ Apoe -/- aortas ( XREF_FIG ) .	6 Although basal ratios of p-ERK and ERK were reduced in the aortas of Insr +/- Irs1 +/- Apoe -/- mice, insulin stimulation resulted in significantly increased pERK and ERK ratio of insulin stimulated pERKs in Insr +/- Irs1 +/- Apoe -/- aortas compared with Insr +/+ Irs1 +/+ Apoe -/- aortas (XREF_FIG).	28	38	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Insr	Insr	Insr	33	34	37	38
Theoretically , once reaching brain parenchyma , insulin could potentially activate IR , IGF-1R , and the hybrid receptor , leading to cell survival and growth .	Theoretically, once reaching brain parenchyma, insulin could potentially activate IR, IGF-1R, and the hybrid receptor, leading to cell survival and growth.	7	18	potentially activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	7	8	11	12
Binding of insulin to its receptors on platelet induces auto-phosphorylation of the beta-subunits of insulin receptor and conformational changes that enhance the insulin receptor tyrosine kinase activity leading to phosphorylation of target proteins notably the IRS-1 XREF_BIBR .	Binding of insulin to its receptors on platelet induces auto-phosphorylation of the beta-subunits of insulin receptor and conformational changes that enhance the insulin receptor tyrosine kinase activity leading to phosphorylation of target proteins notably the IRS-1 XREF_BIBR.	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	14	16
The serum free media for SVZ NPs has superphysiological levels of insulin that can activate the IGF-1R in addition to the insulin receptor ( IR ) .	The serum free media for SVZ NPs has superphysiological levels of insulin that can activate the IGF-1R in addition to the insulin receptor (IR).	9	23	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	21	23
Sulfonylurea drugs have very weak anti-inflammatory effect and is not reduce insulin resistance , and insulin as monotherapy increases IR .	Sulfonylurea drugs have very weak anti-inflammatory effect and is not reduce insulin resistance, and insulin as monotherapy increases IR.	15	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	15	16	19	20
Moreover , HNMPA-( AM ) 3 treatment also reduced the insulin triggered coimmunoprecipitation of IR with Munc18c to ~ 50 % of vehicle treated control ( XREF_FIG ) .	Moreover, HNMPA-(AM) 3 treatment also reduced the insulin triggered coimmunoprecipitation of IR with Munc18c to ~ 50% of vehicle treated control (XREF_FIG).	9	16	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	10	11	14	15
As shown in XREF_FIG A , insulin activated the INSR at all doses in both cell lines , although no dose response activation pattern was observed .	As shown in XREF_FIG A, insulin activated the INSR at all doses in both cell lines, although no dose response activation pattern was observed.	6	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	6	7	9	10
Comparisons between the time courses of beta subunit autophosphorylation with those of Glu : Tyr phosphorylation both in the presence and absence of insulin confirmed that insulin can stimulate the exogenous protein kinase activity of the insulin receptor in the complete absence of beta subunit autophosphorylation .	Comparisons between the time courses of beta subunit autophosphorylation with those of Glu : Tyr phosphorylation both in the presence and absence of insulin confirmed that insulin can stimulate the exogenous protein kinase activity of the insulin receptor in the complete absence of beta subunit autophosphorylation.	26	38	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	26	27	36	38
However , both oleic and linoic acids had effects similar to that of palmitate on insulin induced IR and GLUT2 translocation ( XREF_FIG , XREF_FIG ) .	However, both oleic and linoic acids had effects similar to that of palmitate on insulin induced IR and GLUT2 translocation (XREF_FIG, XREF_FIG).	7	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	15	16	17	18
Relevant well validated experimental tools to address the insulin analogue activation of either INSR or IGF1R are missing .	Relevant well validated experimental tools to address the insulin analogue activation of either INSR or IGF1R are missing.	8	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	8	9	13	14
In the first biochemical step , the insulin hormone binds to the extracellular domain of the insulin receptor ( IR ) and activates the IR which is a membrane spanning protein tyrosine kinase complex ( PTK ) .	In the first biochemical step, the insulin hormone binds to the extracellular domain of the insulin receptor (IR) and activates the IR which is a membrane spanning protein tyrosine kinase complex (PTK).	7	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	7	8	24	25
Here we show that the maximal hyperphosphorylation of Raf-1 and MAPKK ( 10 min ) was substantially achieved after the maximal activation of MAPKKK of Raf-1 , MAPKK ( 2-5 min ) , and MAPK in Chinese hamster ovary cells overexpressing human insulin receptor ( CHO-HIR cells ) treated with insulin or 12-O-tetradecanoylphorbol-13-acetate ( TPA ) .	Here we show that the maximal hyperphosphorylation of Raf-1 and MAPKK (10 min) was substantially achieved after the maximal activation of MAPKKK of Raf-1, MAPKK (2-5 min), and MAPK in Chinese hamster ovary cells overexpressing human insulin receptor (CHO-HIR cells) treated with insulin or 12-O-tetradecanoylphorbol-13-acetate (TPA).	42	52	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	50	51	42	44
ENPP1 directly inhibits insulin induced conformational changes of the insulin receptor , and affects its activation and signaling .	ENPP1 directly inhibits insulin induced conformational changes of the insulin receptor, and affects its activation and signaling.	2	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	9	11
Insulin can activate the IR and also the insulin growth factor-1 receptor ( IGF-1R ) , which shares around 80 % homology with IR and forms hybrid receptors with it .	Insulin can activate the IR and also the insulin growth factor-1 receptor (IGF-1R), which shares around 80% homology with IR and forms hybrid receptors with it.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	4	5
Although GK diabetes did not affect insulin stimulated tyrosine phosphorylation of the insulin receptor or its content , insulin stimulated insulin receptor substrate ( IRS ) -1 tyrosine phosphorylation was severely impaired .	Although GK diabetes did not affect insulin stimulated tyrosine phosphorylation of the insulin receptor or its content, insulin stimulated insulin receptor substrate (IRS) -1 tyrosine phosphorylation was severely impaired.	5	14	stimulated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	insulin	insulin	insulin	insulin receptor	tyrosine phosphorylation of the insulin receptor	insulin receptor	6	7	12	14
Because of their different molecular structure relative to native insulin , insulin analogs may activate the insulin receptor ( IR ) and the post receptor pathways differently .	Because of their different molecular structure relative to native insulin, insulin analogs may activate the insulin receptor (IR) and the post receptor pathways differently.	11	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	16	18
Furthermore , mice with IES exposure and behavioral escape failure exhibited impaired hepatic insulin signaling via the insulin induced insulin receptor and insulin receptor substrate 1/Akt pathway , without affecting similar pathways in skeletal muscle , adipose tissue and brain .	Furthermore, mice with IES exposure and behavioral escape failure exhibited impaired hepatic insulin signaling via the insulin induced insulin receptor and insulin receptor substrate 1/Akt pathway, without affecting similar pathways in skeletal muscle, adipose tissue and brain.	13	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	19	21
These data suggest that the insulin stimulated entry of the insulin receptor into a rapid , coated pit mediated internalization pathway is saturable and requires receptor autophosphorylation and an intact juxtamembrane region .	These data suggest that the insulin stimulated entry of the insulin receptor into a rapid, coated pit mediated internalization pathway is saturable and requires receptor autophosphorylation and an intact juxtamembrane region.	4	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	10	12
Insulin induced significantly less activation of the IR --> IRS-1 --> PI3K --> Akt pathway in AD compared to healthy tissue in all brain areas our group has studied .	Insulin induced significantly less activation of the IR --> IRS-1 --> PI3K --> Akt pathway in AD compared to healthy tissue in all brain areas our group has studied.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	7	8
We also analyzed insulin induced activation of IR signaling subsequent to infusion of insulin through the portal vein .	We also analyzed insulin induced activation of IR signaling subsequent to infusion of insulin through the portal vein.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	7	8
XREF_BIBR - XREF_BIBR Once released , insulin activates the tyrosine kinase activity of the insulin receptor leading to phosphorylation of insulin receptor substrate 1 .	XREF_BIBR - XREF_BIBR Once released, insulin activates the tyrosine kinase activity of the insulin receptor leading to phosphorylation of insulin receptor substrate 1.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	14	16
Both receptors are overexpressed in leukemia cells.Studies indicate that insulin can enhance the signal of the phosphoinositide 3-kinase/Akt pathways by activating IR or IGF-1R or hybrid IR/IGF-IR receptors , resulting in the proliferation of leukemia cells .	Both receptors are overexpressed in leukemia cells.Studies indicate that insulin can enhance the signal of the phosphoinositide 3-kinase/Akt pathways by activating IR or IGF-1R or hybrid IR/IGF-IR receptors, resulting in the proliferation of leukemia cells.	9	25	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	9	10	21	22
PTP1B over-expression in muscle impairs insulin stimulated IR activation and decreases muscle glucose uptake [ XREF_BIBR ] .	PTP1B over-expression in muscle impairs insulin stimulated IR activation and decreases muscle glucose uptake [XREF_BIBR].	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	5	6	7	8
Insulin activates IR kinase and propagates two main branches of signaling via the IRS-proteins : the PI3K --> PDK1 --> AKT and GRB2 and SOS --> RAS kinase cascades .	Insulin activates IR kinase and propagates two main branches of signaling via the IRS-proteins : the PI3K --> PDK1 --> AKT and GRB2 and SOS --> RAS kinase cascades.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	2	3
In this study , we determined in vivo the insulin receptor signaling characteristics activated by insulin glulisine ( Lys ( B3 ) , Glu ( B29 ) ) at the level of insulin receptor phosphorylation , insulin receptor substrate phosphorylation , and downstream signaling elements such as phosphatidylinositol ( PI ) 3-kinase , AKT , and mitogen activated protein kinase .	In this study, we determined in vivo the insulin receptor signaling characteristics activated by insulin glulisine (Lys (B3), Glu (B29)) at the level of insulin receptor phosphorylation, insulin receptor substrate phosphorylation, and downstream signaling elements such as phosphatidylinositol (PI) 3-kinase, AKT, and mitogen activated protein kinase.	13	40	activated	Positive_regulation_syntax_3_verb	Positive_activation	Positive_regulation	insulin	insulin	insulin	insulin receptor	insulin receptor phosphorylation, insulin receptor substrate phosphorylation	insulin receptor	15	16	32	34
Insulin induces inclusion of INSR exon 11 .	Insulin induces inclusion of INSR exon 11.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	INSR	INSR	INSR	0	1	4	5
The present study demonstrates that hydrocortisone , but not insulin , stimulates insulin receptor biosynthesis by increasing the rate of transcription and that de novo protein synthesis is probably required for a maximal effect .	The present study demonstrates that hydrocortisone, but not insulin, stimulates insulin receptor biosynthesis by increasing the rate of transcription and that de novo protein synthesis is probably required for a maximal effect.	5	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	12	14
However , once the brain IR is activated by insulin the signaling effects are the same as in the periphery .	However, once the brain IR is activated by insulin the signaling effects are the same as in the periphery.	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	9	10	5	6
Insulin receptor binding to target tissues is largely unaffected by normal and GDM pregnancy ; the same is true for basal and insulin stimulated insulin receptor bound tyrosine kinase activity .	Insulin receptor binding to target tissues is largely unaffected by normal and GDM pregnancy; the same is true for basal and insulin stimulated insulin receptor bound tyrosine kinase activity.	20	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	22	23	24	26
However , chronic exogenous GH also increased the serum glucose ( p < 0.05 ) and insulin levels , although not significantly , in the GS group relative to the CS groups , and may increase the risk of IR , which was reflected by changes , although not significant , in the homeostasis model assessment of IR ( HOMA-IR ) .	However, chronic exogenous GH also increased the serum glucose (p < 0.05) and insulin levels, although not significantly, in the GS group relative to the CS groups, and may increase the risk of IR, which was reflected by changes, although not significant, in the homeostasis model assessment of IR (HOMA-IR).	4	43	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	GH also increased the serum glucose (p < 0.05) and insulin levels	insulin	IR	IR	ir	16	17	39	40
However , insulin stimulated a more rapid receptor internalization of IR and IR/IGF1R with a ~ 50 % reduction of the surface labelled IR and IR/IGF1R receptors by 30min , whereas IGF-1 led to internalization of only ~ 20 % the surface IGF1R and IGF1R/IR by 30min ( XREF_SUPPLEMENTARY ) .	However, insulin stimulated a more rapid receptor internalization of IR and IR/IGF1R with a ~ 50% reduction of the surface labelled IR and IR/IGF1R receptors by 30min, whereas IGF-1 led to internalization of only ~ 20% the surface IGF1R and IGF1R/IR by 30min (XREF_SUPPLEMENTARY).	2	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	2	3	10	11
However , insulin stimulated insulin receptor kinase activity was decreased in diabetics .	However, insulin stimulated insulin receptor kinase activity was decreased in diabetics.	2	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	4	6
Insulin activates the insulin receptor tyrosine kinase , which further activates the phosphatidylinositol 3-kinase ( PI3K ) and Akt pathways and stimulates glycogen synthesis via inhibition of glycogen synthase 3 ( GSK3 ) and also by activation of the PP1 [ XREF_BIBR , XREF_BIBR ] .	Insulin activates the insulin receptor tyrosine kinase, which further activates the phosphatidylinositol 3-kinase (PI3K) and Akt pathways and stimulates glycogen synthesis via inhibition of glycogen synthase 3 (GSK3) and also by activation of the PP1 [XREF_BIBR, XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
High levels of plasma FFAs are associated with an increase in diacylglycerol and activation of protein kinase C , leading to increased tyrosine phosphorylation of insulin receptor substrate-1 and resulting in increased insulin stimulated glucose transport activity and IR XREF_BIBR , XREF_BIBR .	High levels of plasma FFAs are associated with an increase in diacylglycerol and activation of protein kinase C, leading to increased tyrosine phosphorylation of insulin receptor substrate-1 and resulting in increased insulin stimulated glucose transport activity and IR XREF_BIBR, XREF_BIBR.	29	39	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	32	33	38	39
This increase in insulin sensitivity was associated with an increase in insulin induced insulin receptor ( IR ) tyrosine phosphorylation and , in parallel , a decrease in IR serine phosphorylation and association with PTP1B .	This increase in insulin sensitivity was associated with an increase in insulin induced insulin receptor (IR) tyrosine phosphorylation and, in parallel, a decrease in IR serine phosphorylation and association with PTP1B.	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	13	15
In the present study we measured PC-1 content , tumour necrosis factor ( TNF )-alpha gene expression , and insulin stimulation of insulin receptor tyrosine kinase activity in adipose tissue from non obese , non diabetic subjects .	In the present study we measured PC-1 content, tumour necrosis factor (TNF)-alpha gene expression, and insulin stimulation of insulin receptor tyrosine kinase activity in adipose tissue from non obese, non diabetic subjects.	19	26	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	19	20	22	24
that is well tolerated in Canadian adults and that this DRS effectively lowers blood glucose and insulin levels and reduces IR in ELD adults .	that is well tolerated in Canadian adults and that this DRS effectively lowers blood glucose and insulin levels and reduces IR in ELD adults.	10	23	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	DRS effectively lowers blood glucose and insulin levels	insulin	IR	IR	ir	16	17	20	21
Additionally , the C. elegans INS-6 insulin can bind to and activate the human InsR tyrosine kinase [ XREF_BIBR ] .	Additionally, the C. elegans INS-6 insulin can bind to and activate the human InsR tyrosine kinase [XREF_BIBR].	2	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	InsR	InsR	InsR	6	7	14	15
In contrast , insulin stimulated ATP synthase flux was severely blunted in the IR offspring ( DeltaATP flux : 5 % +/- 2 % ; p = 0.001 ) ( XREF_FIG B ) .	In contrast, insulin stimulated ATP synthase flux was severely blunted in the IR offspring (DeltaATP flux : 5% +/- 2%; p = 0.001) (XREF_FIG B).	3	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	3	4	13	14
In response to acute insulin stimulation , normal mice on CR had a 2-fold greater increase in IR activation ( as estimated by measuring IR phosphorylation at tyrosine ( Tyr ) residue 1158 [ pY1158 ] as a proxy for activation ) than the normal AL mice , while CR did not increase the already elevated insulin induced IR activation in GHRKO mice ( XREF_FIG ) .	In response to acute insulin stimulation, normal mice on CR had a 2-fold greater increase in IR activation (as estimated by measuring IR phosphorylation at tyrosine (Tyr) residue 1158 [pY1158] as a proxy for activation) than the normal AL mice, while CR did not increase the already elevated insulin induced IR activation in GHRKO mice (XREF_FIG).	52	59	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	56	57	58	59
In brief , insulin mediated IR activation triggers the sequential canonical activation cascade : IR --> Insulin Receptor Substrate ( IRS-1 ) --> Phosphatidylinositide kinase ( PI3-Kinase ) --> generating Phosphatidylinositol-( 3,4,5 )-trisphosphate ( PIP3 ) to activate --> 3-Phosphoinositide-dependent kinase-1 ( PDK-1 ) --> AKT and Protein kinase B --> Akt substrate of 160 kDa ( AS160 ) , a Rab-GAP ( GTPase activating protein ) to promote recruitment of GLUT4 vesicles to the PM [ XREF_BIBR - XREF_BIBR ] .	In brief, insulin mediated IR activation triggers the sequential canonical activation cascade : IR --> Insulin Receptor Substrate (IRS-1) --> Phosphatidylinositide kinase (PI3-Kinase) --> generating Phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) to activate --> 3-Phosphoinositide-dependent kinase-1 (PDK-1) --> AKT and Protein kinase B --> Akt substrate of 160 kDa (AS160), a Rab-GAP (GTPase activating protein) to promote recruitment of GLUT4 vesicles to the PM [XREF_BIBR - XREF_BIBR].	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	5	6
This pathway begins when insulin activates the transmembrane insulin receptor ( IR ) tyrosine kinase that phosphorylates the adaptor proteins insulin receptor substrate 1 ( IRS1 ) and IRS2 .	This pathway begins when insulin activates the transmembrane insulin receptor (IR) tyrosine kinase that phosphorylates the adaptor proteins insulin receptor substrate 1 (IRS1) and IRS2.	4	24	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	insulin	insulin	insulin	insulin receptor	insulin receptor (IR) tyrosine kinase that phosphorylates the adaptor proteins insulin receptor substrate 1	insulin receptor	4	5	8	10
The insulin mediated insulin receptor ( INSR )/phosphoinositide 3-kinase ( PI3K )/protein kinase B ( AKT ) signaling pathway is widely known as a primary pathway associated with the regulation of glucose uptake .	The insulin mediated insulin receptor (INSR)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is widely known as a primary pathway associated with the regulation of glucose uptake.	0	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	3	5
Higher glucose , C-peptide and insulin levels caused 2.8-fold , 2-fold and 3.65-fold increased risks of IR , respectively .	Higher glucose, C-peptide and insulin levels caused 2.8-fold, 2-fold and 3.65-fold increased risks of IR, respectively.	5	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	IR	IR	ir	5	6	16	17
Furthermore , insulin stimulation of the insulin receptor tyrosine kinase may not be a necessary step for all insulin signaling pathways .	Furthermore, insulin stimulation of the insulin receptor tyrosine kinase may not be a necessary step for all insulin signaling pathways.	2	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	6	8
Although it is known that insulin also activates insulin receptor in the dorsal vagal complex ( DVC ) to lower glucose production through an extracellular signal related kinase 1/2 ( Erk1/2 )-dependent and phosphatidylinositol 3-kinase ( PI3K )-independent pathway , it is unknown whether DVC insulin action regulates food intake .	Although it is known that insulin also activates insulin receptor in the dorsal vagal complex (DVC) to lower glucose production through an extracellular signal related kinase 1/2 (Erk1/2)-dependent and phosphatidylinositol 3-kinase (PI3K)-independent pathway, it is unknown whether DVC insulin action regulates food intake.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	8	10
Insulin induced a rapid , t 1/2 < 3 min , endocytosis of the insulin receptor in parallel with receptor tyrosine autophosphorylation .	Insulin induced a rapid, t 1/2 < 3 min, endocytosis of the insulin receptor in parallel with receptor tyrosine autophosphorylation.	0	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	14	16
Elevated serine kinase activity was detected in Chinese hamster ovary and insulin receptor ( IR )/IRS-1 cells and 3T3-L1 adipocytes chronically treated with insulin , and in liver and muscle of obese JCR : LA-cp rats .	Elevated serine kinase activity was detected in Chinese hamster ovary and insulin receptor (IR)/IRS-1 cells and 3T3-L1 adipocytes chronically treated with insulin, and in liver and muscle of obese JCR : LA-cp rats.	11	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	23	24	11	13
In this study , our data demonstrate that miR-21 reverses high glucose and high insulin induced IR in 3T3-L1 adipocytes , possibly through modulating the PTEN-AKT pathway , and miR-21 may be a new therapeutic target for metabolic diseases such as T2DM and obesity .	In this study, our data demonstrate that miR-21 reverses high glucose and high insulin induced IR in 3T3-L1 adipocytes, possibly through modulating the PTEN-AKT pathway, and miR-21 may be a new therapeutic target for metabolic diseases such as T2DM and obesity.	11	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	14	15	16	17
Based on this research , it can be concluded that , among children and adolescents with excess weight : 1 ) fasting plasma insulin and/or HOMA-IR CCOP enabled more diagnosis of IR as compared to FCOP ; 2 ) the frequencies of metabolic abnormalities in the subjects with IR defined with CCOP were similar to those found using FCOP ; the frequency of detection of IR by HOMA-IR was similar to that by fasting plasma insulin , regardless of the cutoff point used ; hyperglycemia was not prevalent .	Based on this research, it can be concluded that, among children and adolescents with excess weight : 1) fasting plasma insulin and/or HOMA-IR CCOP enabled more diagnosis of IR as compared to FCOP; 2) the frequencies of metabolic abnormalities in the subjects with IR defined with CCOP were similar to those found using FCOP; the frequency of detection of IR by HOMA-IR was similar to that by fasting plasma insulin, regardless of the cutoff point used; hyperglycemia was not prevalent.	21	32	enabled	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	23	24	31	32
Physiologically , insulin triggers the insulin receptor into exerting its effects , leading to the phosphorylation of insulin receptor substrate ( IRS ) proteins [ XREF_BIBR ] .	Physiologically, insulin triggers the insulin receptor into exerting its effects, leading to the phosphorylation of insulin receptor substrate (IRS) proteins [XREF_BIBR].	2	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	5	7
MDA-MB231 cells contain a factor that inhibits both basal and insulin stimulated IR tyrosine kinase activity in a concentration dependent manner .	MDA-MB231 cells contain a factor that inhibits both basal and insulin stimulated IR tyrosine kinase activity in a concentration dependent manner.	8	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	10	11	12	13
Insulin activates the insulin receptor ( INSR ) and downstream the insulin receptor substrate ( IRS ) family .	Insulin activates the insulin receptor (INSR) and downstream the insulin receptor substrate (IRS) family.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
In HepG2 cells , PANDER pretreatment significantly inhibits insulin stimulated activation of IR , IRS-1 , PI3K , and Akt .	In HepG2 cells, PANDER pretreatment significantly inhibits insulin stimulated activation of IR, IRS-1, PI3K, and Akt.	7	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	8	9	12	13
This study also found that exogenous addition of insulin stimulated canonical IR signaling pathways including AKT and mTOR and Ras/Raf/Erk in CLL B-cells in vitro .	This study also found that exogenous addition of insulin stimulated canonical IR signaling pathways including AKT and mTOR and Ras/Raf/Erk in CLL B-cells in vitro.	6	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	8	9	11	12
In contrast , we found no effect of EETs on insulin mediated IR activation at any concentration or time point ( XREF_FIG ) .	In contrast, we found no effect of EETs on insulin mediated IR activation at any concentration or time point (XREF_FIG).	4	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	10	11	12	13
This has prompted speculation that HCV may be able to affect insulin signalling inducing both hepatic and peripheral IR [ XREF_BIBR ] via several direct or indirect mechanisms ( downregulation of suppressor of cytokine signalling ( SOCS ) and protein phosphatase PPA2 , upregulation of tumour necrosis factor-alpha and induction of proinflammatory cytokines or other unknown soluble mediators ) .	This has prompted speculation that HCV may be able to affect insulin signalling inducing both hepatic and peripheral IR [XREF_BIBR] via several direct or indirect mechanisms (downregulation of suppressor of cytokine signalling (SOCS) and protein phosphatase PPA2, upregulation of tumour necrosis factor-alpha and induction of proinflammatory cytokines or other unknown soluble mediators).	11	49	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	11	12	18	19
Insulin activates the insulin receptor , triggering intracellular signalling cascades with mitogenic and antiapoptotic effects ( Calle and Kaaks , 2004 ) .	Insulin activates the insulin receptor, triggering intracellular signalling cascades with mitogenic and antiapoptotic effects (Calle and Kaaks, 2004).	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
The induction of insulin resistance modulates steady-state transcript levels in a diet induced IR mouse model .	The induction of insulin resistance modulates steady-state transcript levels in a diet induced IR mouse model.	3	15	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	13	14
In untreated fasting and control animals , muscle and liver insulin receptor tyrosine kinase activity was stimulated to similar levels by insulin added in vitro .	In untreated fasting and control animals, muscle and liver insulin receptor tyrosine kinase activity was stimulated to similar levels by insulin added in vitro.	10	22	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	21	22	10	12
Insulin stimulated insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity was enhanced in the red gastrocnemius and quadriceps of Con-RT and HF-RT animals .	Insulin stimulated insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity was enhanced in the red gastrocnemius and quadriceps of Con-RT and HF-RT animals.	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	2	4
Insulin specific cav-2-dependent activation of ERK and IR .	Insulin specific cav-2-dependent activation of ERK and IR.	0	8	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	7	8
Moreover , insulin induced dissociation of PDGF receptors from binding sites on PI 3-kinase requires a functional insulin receptor and is not prevented by vanadate treatment .	Moreover, insulin induced dissociation of PDGF receptors from binding sites on PI 3-kinase requires a functional insulin receptor and is not prevented by vanadate treatment.	2	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	17	19
IRAB-A shows both agonist and sensitizing properties and alters the kinetics and potency of insulin induced IR activation likely due to its allosteric binding .	IRAB-A shows both agonist and sensitizing properties and alters the kinetics and potency of insulin induced IR activation likely due to its allosteric binding.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	14	15	16	17
By contrast , insulin ( GLA ) dose was not correlated to serum induced activation of either IR isoform .	By contrast, insulin (GLA) dose was not correlated to serum induced activation of either IR isoform.	3	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	17	18
One important RTK is the insulin receptor that is activated by insulin XREF_BIBR .	One important RTK is the insulin receptor that is activated by insulin XREF_BIBR.	5	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	5	7
In the current study , rosiglitazone reduced plasma insulin levels and hence reduced IR .	In the current study, rosiglitazone reduced plasma insulin levels and hence reduced IR.	5	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	rosiglitazone reduced plasma insulin levels	insulin	IR	IR	ir	8	9	13	14
It has been shown that chromodulin stimulates both the tyrosine kinase activity of the insulin activated insulin receptor and the membrane phosphotyrosine phosphatase in insulin sensitive cells [ XREF_BIBR , XREF_BIBR ] .	It has been shown that chromodulin stimulates both the tyrosine kinase activity of the insulin activated insulin receptor and the membrane phosphotyrosine phosphatase in insulin sensitive cells [XREF_BIBR, XREF_BIBR].	11	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	14	15	16	18
It was found that PI3K inhibition partially reversed the insulin induced down-regulation of IGFBP1 , CTGF , INSR , DCN and LEFTY2 ( XREF_FIG ) .	It was found that PI3K inhibition partially reversed the insulin induced down-regulation of IGFBP1, CTGF, INSR, DCN and LEFTY2 (XREF_FIG).	8	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	9	10	17	18
Insulin regulated insulin receptors ( IRs ) stimulate insulin receptor substrate1 ( IRS-1 ) and interact with the downstream signals , causing a rise in HCT-116 cell proliferation .	Insulin regulated insulin receptors (IRs) stimulate insulin receptor substrate1 (IRS-1) and interact with the downstream signals, causing a rise in HCT-116 cell proliferation.	0	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	8	10
Insulin induced rapid endocytosis of IR with the plateau appeared at 5 minutes and then steadily declined , reflecting membrane recycling of IR and subsequent biotin cleavage ( XREF_SUPPLEMENTARY ) .	Insulin induced rapid endocytosis of IR with the plateau appeared at 5 minutes and then steadily declined, reflecting membrane recycling of IR and subsequent biotin cleavage (XREF_SUPPLEMENTARY).	0	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	22	23
In endothelial cell lines , this reduced binding of insulin diminishes the ability of insulin receptor to internalize insulin in cells , thereby diminishing insulin sensitivity [ XREF_BIBR ] .	In endothelial cell lines, this reduced binding of insulin diminishes the ability of insulin receptor to internalize insulin in cells, thereby diminishing insulin sensitivity [XREF_BIBR].	7	16	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	14	16
Metformin increases insulin receptor sensitivity , increases insulin uptake , thereby reducing systemic insulin levels .	Metformin increases insulin receptor sensitivity, increases insulin uptake, thereby reducing systemic insulin levels.	2	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin uptake, thereby reducing systemic insulin levels	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	2	4
Similar to its effect on insulin binding affinity , XMetS potentiated insulin dependent INSR autophosphorylation by 14-fold indicating that the enhancement of insulin binding was associated with improved insulin mediated INSR activation .	Similar to its effect on insulin binding affinity, XMetS potentiated insulin dependent INSR autophosphorylation by 14-fold indicating that the enhancement of insulin binding was associated with improved insulin mediated INSR activation.	25	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	28	29	30	31
The correction of insulin sensitivity is associated with restoration of insulin induced activation of the insulin receptor and increased insulin receptor substrate 2 ( IRS-2 ) associated PI3K in the liver [ XREF_BIBR ] .	The correction of insulin sensitivity is associated with restoration of insulin induced activation of the insulin receptor and increased insulin receptor substrate 2 (IRS-2) associated PI3K in the liver [XREF_BIBR].	8	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	15	17
Recently , it has been found that DAG activates PKCepsilon that results in inhibition of insulin stimulated insulin receptor kinase activity and in the result causes hepatic insulin resistance [ XREF_BIBR ] .	Recently, it has been found that DAG activates PKCepsilon that results in inhibition of insulin stimulated insulin receptor kinase activity and in the result causes hepatic insulin resistance [XREF_BIBR].	13	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	15	16	17	19
Of note , insulin treatment had no effect on the interaction between IRbeta and APPL1 in the in vitro pull-down assays ( XREF_FIG ) , suggesting that the stimulatory effect of insulin may be a result of insulin stimulated post-translational modification of APPL1 rather than IR in intact cells .	Of note, insulin treatment had no effect on the interaction between IRbeta and APPL1 in the in vitro pull-down assays (XREF_FIG), suggesting that the stimulatory effect of insulin may be a result of insulin stimulated post-translational modification of APPL1 rather than IR in intact cells.	35	48	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	37	38	45	46
In the positive control for IR ( insulin induced IR ) , induction of p-Akt-473 was impaired , whereas p-Akt-308 was not induced at all .	In the positive control for IR (insulin induced IR), induction of p-Akt-473 was impaired, whereas p-Akt-308 was not induced at all.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	7	8	9	10
Hepatic PIKE-A , in contrast , is responsible for IR activation , as we observed no difference in insulin induced IR activation in the muscle of both PIKE -/- and MPKO mice ( XREF_FIG ) .	Hepatic PIKE-A, in contrast, is responsible for IR activation, as we observed no difference in insulin induced IR activation in the muscle of both PIKE -/- and MPKO mice (XREF_FIG).	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	18	19	20	21
Upon insulin stimulation of baby hamster kidney cells overexpressing the IR , the catalytically inactive mutant of PTP1D , C463A , becomes tyrosine phosphorylated and coprecipitates with Grb2 .	Upon insulin stimulation of baby hamster kidney cells overexpressing the IR, the catalytically inactive mutant of PTP1D, C463A, becomes tyrosine phosphorylated and coprecipitates with Grb2.	1	11	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	1	2	10	11
Binding of insulin to its receptor results in activation of insulin receptor ( IR ) kinase , which in turn phosphorylates tyrosine residues of IR itself and insulin receptor substrates ( IRSs ) .	Binding of insulin to its receptor results in activation of insulin receptor (IR) kinase, which in turn phosphorylates tyrosine residues of IR itself and insulin receptor substrates (IRSs).	0	12	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	10	12
Thus , insulin IND-treatment evokes activation of IR in situ and enhances the scaffolding association of Kv1.3 , IR , and PSD-95 protein complexes .	Thus, insulin IND-treatment evokes activation of IR in situ and enhances the scaffolding association of Kv1.3, IR, and PSD-95 protein complexes.	2	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	2	3	18	19
The more robust insulin induced activation of IR at egr-1 in HTC-IR cells paralleled higher levels of recruitment of Pol II and phospho-Erk , suggesting that these insulin induced changes were linked .	The more robust insulin induced activation of IR at egr-1 in HTC-IR cells paralleled higher levels of recruitment of Pol II and phospho-Erk, suggesting that these insulin induced changes were linked.	0	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	7	8
While there is currently no medical treatment for LR , IR is often successfully treated with the use of insulin lowering agents or ISDs .	While there is currently no medical treatment for LR, IR is often successfully treated with the use of insulin lowering agents or ISDs.	10	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	19	20	10	11
Defects in insulin signaling through the protein kinase Akt underlie the development of IR .	Defects in insulin signaling through the protein kinase Akt underlie the development of IR.	2	14	underlie	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	2	3	13	14
Our results also suggest the possibility that the small heart phenotype of CIRKO mice is in part due to the impairment of IR signals activated by IGF-1 or IGF-2 but not by insulin .	Our results also suggest the possibility that the small heart phenotype of CIRKO mice is in part due to the impairment of IR signals activated by IGF-1 or IGF-2 but not by insulin.	22	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	32	33	22	23
Insulin is an MGF as potent as IGF-1 at physiological concentrations and requires the presence of insulin and IGF -1 hybrid receptors , stimulating INSR ( + ) IGF-1R ( + ) MMCs , unlike INSR ( + ) IGF-1R (-) or INSR (-) IGF-1R (-) MMCs .	Insulin is an MGF as potent as IGF-1 at physiological concentrations and requires the presence of insulin and IGF -1 hybrid receptors, stimulating INSR (+) IGF-1R (+) MMCs, unlike INSR (+) IGF-1R (-) or INSR (-) IGF-1R (-) MMCs.	16	28	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	16	17	24	25
Differently from the result of Akt , the phosphorylation of the insulin stimulated insulin receptor beta-subunit was not affected by Ang II , olmesartan , or PD123 ,319 .	Differently from the result of Akt, the phosphorylation of the insulin stimulated insulin receptor beta-subunit was not affected by Ang II, olmesartan, or PD123,319.	8	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	phosphorylation of the insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	13	15
In particular , it has been shown that insulin ( INS ) binding to its receptor activates the insulin receptor tyrosine kinase activity , resulting in tyrosine phosphorylation of the insulin receptor substrate-1 ( IRS1 ) .	In particular, it has been shown that insulin (INS) binding to its receptor activates the insulin receptor tyrosine kinase activity, resulting in tyrosine phosphorylation of the insulin receptor substrate-1 (IRS1).	8	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	18	20
MAD2 and BUBR1 are also required for insulin stimulated IR endocytosis in cells without genetic inactivation of p31 comet .	MAD2 and BUBR1 are also required for insulin stimulated IR endocytosis in cells without genetic inactivation of p31 comet.	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	7	8	9	10
Increases in DAG induced either by insulin , glucose and/or fatty acids may then activate cPKCs and nPKCs , which are known to phosphorylate and diminish activity of the insulin receptor , and perhaps other insulin signaling factors .	Increases in DAG induced either by insulin, glucose and/or fatty acids may then activate cPKCs and nPKCs, which are known to phosphorylate and diminish activity of the insulin receptor, and perhaps other insulin signaling factors.	3	31	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	29	31
In wheat germ agglutinin purified receptors , 125I labeled porcine insulin binding , basal and insulin stimulated insulin receptor kinase activities for both the autophosphorylation of the beta-subunit and the phosphorylation of the artificial substrate poly ( Glu Tyr ) 4:1 , were found identical in diabetic and control rats , treated or not with vanadate .	In wheat germ agglutinin purified receptors, 125I labeled porcine insulin binding, basal and insulin stimulated insulin receptor kinase activities for both the autophosphorylation of the beta-subunit and the phosphorylation of the artificial substrate poly (Glu Tyr) 4:1, were found identical in diabetic and control rats, treated or not with vanadate.	8	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	15	16	17	19
Thus , our results suggest that the local concentration of monomeric insulin within the islet is in the picomolar ' sweet spot ' range of insulin doses that activate the insulin receptor and have the most potent effects on -cells in vitro .	Thus, our results suggest that the local concentration of monomeric insulin within the islet is in the picomolar ' sweet spot ' range of insulin doses that activate the insulin receptor and have the most potent effects on -cells in vitro.	25	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	25	26	30	32
The absence of insulin signaling in insulin receptor knock-out mice contributes to reduced muscle mass and function though decreased protein synthesis .	The absence of insulin signaling in insulin receptor knock-out mice contributes to reduced muscle mass and function though decreased protein synthesis.	3	9	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	6	8
As can be recalled , any defects in the insulin signaling cascade can cause IR [ XREF_BIBR , XREF_BIBR ] .	As can be recalled, any defects in the insulin signaling cascade can cause IR [XREF_BIBR, XREF_BIBR].	9	16	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	9	10	14	15
Binding of insulin to its receptor ( IR ) activates IR tyrosine kinase , which then phosphorylates IR substrates ( IRSs ) .	Binding of insulin to its receptor (IR) activates IR tyrosine kinase, which then phosphorylates IR substrates (IRSs).	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	2	3	10	11
For example , cytokines such as TNFalpha , IL-1 , and IL-6 have been shown to increase the activity of serine kinases and/or suppressor of cytokine signaling ( SOCS ) pathways which together inactivate and degrade insulin receptor substrates which leads to IR .	For example, cytokines such as TNFalpha, IL-1, and IL-6 have been shown to increase the activity of serine kinases and/or suppressor of cytokine signaling (SOCS) pathways which together inactivate and degrade insulin receptor substrates which leads to IR.	36	43	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	36	37	42	43
Metformin improves insulin sensitivity by increasing insulin mediated insulin receptor tyrosine kinase activity , which activates post-receptor insulin signalling pathways .	Metformin improves insulin sensitivity by increasing insulin mediated insulin receptor tyrosine kinase activity, which activates post-receptor insulin signalling pathways.	1	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	8	10
Fifteen-minute bpV ( phen ) pretreatment produced a significant reduction ( 75 % ; P < 0.001 ) in maximal insulin stimulated endosomal IR exogenous kinase activity and decreased IR autophosphorylating activity by 4.3-fold in this subcellular fraction .	Fifteen-minute bpV (phen) pretreatment produced a significant reduction (75%; P < 0.001) in maximal insulin stimulated endosomal IR exogenous kinase activity and decreased IR autophosphorylating activity by 4.3-fold in this subcellular fraction.	9	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	20	21	23	24
We report here that micromolar concentrations of H ( 2 ) O ( 2 ) dramatically inhibit insulin induced IR tyrosine phosphorylation ( pretreatment with 500 microM H ( 2 ) O ( 2 ) for 5 min inhibits insulin induced IR tyrosine phosphorylation to 8 % ) , insulin receptor substrate 1 phosphorylation , as well as insulin downstream signaling such as activation of phosphatidylinositol 3-kinase ( inhibited to 57 % ) , glucose transport ( inhibited to 36 % ) , and mitogen activated protein kinase activation ( inhibited to 7.2 % ) .	We report here that micromolar concentrations of H (2) O (2) dramatically inhibit insulin induced IR tyrosine phosphorylation (pretreatment with 500 microM H (2) O (2) for 5 min inhibits insulin induced IR tyrosine phosphorylation to 8%), insulin receptor substrate 1 phosphorylation, as well as insulin downstream signaling such as activation of phosphatidylinositol 3-kinase (inhibited to 57%), glucose transport (inhibited to 36%), and mitogen activated protein kinase activation (inhibited to 7.2%).	17	84	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	17	18	19	20
We examined the effect of insulin sensitizer ( rosiglitazone ) on FFA induced IR .	We examined the effect of insulin sensitizer (rosiglitazone) on FFA induced IR.	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	5	6	13	14
Both insulin and IGF1 activate the PI3K/Akt/mTOR/HIF-1alpha pathway by binding to the IGF1 receptor ( IGF1R ) and insulin receptor ( IR ) , respectively .	Both insulin and IGF1 activate the PI3K/Akt/mTOR/HIF-1alpha pathway by binding to the IGF1 receptor (IGF1R) and insulin receptor (IR), respectively.	0	20	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	18	20
The identity of the sites of insulin stimulated serine phosphorylation in the human insulin receptor was examined by synthesizing peptides that together encompassed all the serine residues of the cytosolic portion of the beta-subunit and testing them as substrates for phosphorylation by a preparation of human insulin receptor copurified with insulin stimulated insulin receptor serine kinase activity .	The identity of the sites of insulin stimulated serine phosphorylation in the human insulin receptor was examined by synthesizing peptides that together encompassed all the serine residues of the cytosolic portion of the beta-subunit and testing them as substrates for phosphorylation by a preparation of human insulin receptor copurified with insulin stimulated insulin receptor serine kinase activity.	48	54	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	50	51	52	54
Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS , hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies .	Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies.	32	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	32	33	35	37
Moreover , serine phosphorylation of the insulin receptor and insulin receptor substrates can also lead to IR .	Moreover, serine phosphorylation of the insulin receptor and insulin receptor substrates can also lead to IR.	2	17	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	serine phosphorylation of the insulin receptor and insulin	insulin	IR	IR	ir	9	10	16	17
Basal and insulin stimulated insulin receptor kinase activities were also found normal for both the autophosphorylation of the beta subunit of the insulin receptor and the phosphorylation of the artificial substrate poly ( Glu Tyr ) 4:1 .	Basal and insulin stimulated insulin receptor kinase activities were also found normal for both the autophosphorylation of the beta subunit of the insulin receptor and the phosphorylation of the artificial substrate poly (Glu Tyr) 4:1.	0	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	4	6
Indeed , free fatty acids ( FFAs ) can inhibit insulin activation of insulin receptor substrate-1-associated phosphatidylinositol-3-kinase activity in skeletal muscle .	Indeed, free fatty acids (FFAs) can inhibit insulin activation of insulin receptor substrate-1-associated phosphatidylinositol-3-kinase activity in skeletal muscle.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	13	15
Schubert [ XREF_BIBR ] hypothesized that neuronal insulin resistance contributes to defects in neuronal function and exhibited the evidence in insulin receptor knockout ( NIRKO ) mice .	Schubert [XREF_BIBR] hypothesized that neuronal insulin resistance contributes to defects in neuronal function and exhibited the evidence in insulin receptor knockout (NIRKO) mice.	7	22	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	20	22
We found that insulin stimulates THP-1 cell chemotaxis in a dose dependent and insulin receptor dependent manner .	We found that insulin stimulates THP-1 cell chemotaxis in a dose dependent and insulin receptor dependent manner.	3	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	13	15
Insulin induced insulin receptor ( IR ) tyrosine kinase activation and insulin cell survival responses have been reported to be under the regulation of a membrane associated mammalian neuraminidase-1 ( Neu1 ) .	Insulin induced insulin receptor (IR) tyrosine kinase activation and insulin cell survival responses have been reported to be under the regulation of a membrane associated mammalian neuraminidase-1 (Neu1).	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	2	4
Pre-teen IR and insulin level and rapidly increasing IR during adolescence identify girls who are at greater risk of future impaired fasting glucose and T2DM .	Pre-teen IR and insulin level and rapidly increasing IR during adolescence identify girls who are at greater risk of future impaired fasting glucose and T2DM.	3	9	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin level	insulin	IR	IR	ir	3	4	8	9
No differences in basal or insulin induced IR activation and PI3K and Akt signalling were evident in muscle in vivo ( XREF_FIG ) .	No differences in basal or insulin induced IR activation and PI3K and Akt signalling were evident in muscle in vivo (XREF_FIG).	1	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	5	6	7	8
Insulin also increased IR kinase activity ; the half-maximal effect occurred at approximately 500-600 microU/ml insulin with a maximal 10-fold stimulation over basal .	Insulin also increased IR kinase activity; the half-maximal effect occurred at approximately 500-600 microU/ml insulin with a maximal 10-fold stimulation over basal.	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	3	4
Fetuin-A , a natural inhibitor of the insulin stimulated insulin receptor tyrosine kinase , induces insulin resistance in rodents [ XREF_BIBR ] .	Fetuin-A, a natural inhibitor of the insulin stimulated insulin receptor tyrosine kinase, induces insulin resistance in rodents [XREF_BIBR].	4	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	9	11
Systemic and ocular insulin administration restores defective retinal insulin receptor signaling 31 .	Systemic and ocular insulin administration restores defective retinal insulin receptor signaling 31.	3	10	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	8	10
The insulin receptor signaling pathway was partially activated under physiological conditions , further activated by intravenous insulin injection , and was attenuated in streptozotocin induced diabetic rats .	The insulin receptor signaling pathway was partially activated under physiological conditions, further activated by intravenous insulin injection, and was attenuated in streptozotocin induced diabetic rats.	1	17	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	16	17	1	3
Generally , the increase in the above mentioned adipokine levels can have a negative effect on insulin production , secretion and cell signalling , which may induce IR in MI .	Generally, the increase in the above mentioned adipokine levels can have a negative effect on insulin production, secretion and cell signalling, which may induce IR in MI.	16	29	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	16	17	27	28
Besides the contribution of bradykinin to an impaired blood pressure , it also enhances insulin stimulated tyrosine kinase activity of the insulin receptor , with subsequent GLUT-4 translocation in skeletal muscle tissue , thus giving a theoretical boosting effect during exercise [ XREF_BIBR ] .	Besides the contribution of bradykinin to an impaired blood pressure, it also enhances insulin stimulated tyrosine kinase activity of the insulin receptor, with subsequent GLUT-4 translocation in skeletal muscle tissue, thus giving a theoretical boosting effect during exercise [XREF_BIBR].	14	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	14	15	21	23
Glyburide ' s actions were mediated without altering the following : ( 1 ) 125I-insulin binding ; ( 2 ) the electrophoretic mobility of the affinity labeled alpha-subunit or the autophosphorylated beta-subunit of the insulin receptor ; and ( 3 ) the insulin stimulated insulin receptor kinase activity using histone or the beta-subunit of the insulin receptor as phosphoacceptors .	Glyburide 's actions were mediated without altering the following : (1) 125I-insulin binding; (2) the electrophoretic mobility of the affinity labeled alpha-subunit or the autophosphorylated beta-subunit of the insulin receptor; and (3) the insulin stimulated insulin receptor kinase activity using histone or the beta-subunit of the insulin receptor as phosphoacceptors.	14	47	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	42	43	44	46
Insulin signaling regulates Abeta and tau , and Abeta has negative effects on insulin signaling ; therefore , dysfunctional insulin signaling can enhance Abeta and tau pathology , and increased Abeta production can further exacerbate IR .	Insulin signaling regulates Abeta and tau, and Abeta has negative effects on insulin signaling; therefore, dysfunctional insulin signaling can enhance Abeta and tau pathology, and increased Abeta production can further exacerbate IR.	19	36	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	19	20	35	36
Rat primary hepatocytes with IR induced by high concentration of human insulin were used in which the incorporation rates of 14C-2-deoxyglucose and 14C-acetate were determined to estimate the insulin sensitivity of the cells and IDE activity was assessed .	Rat primary hepatocytes with IR induced by high concentration of human insulin were used in which the incorporation rates of 14C-2-deoxyglucose and 14C-acetate were determined to estimate the insulin sensitivity of the cells and IDE activity was assessed.	2	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	11	12	4	5
High concentrations of insulin ( > = 1mug/mL ) not only activate IR but also activate IGF-1R [ XREF_BIBR , XREF_BIBR ] .	High concentrations of insulin (> = 1mug/mL) not only activate IR but also activate IGF-1R [XREF_BIBR, XREF_BIBR].	1	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	12	13
Depletion of MAD2 or BUBR1 partially blocked IR endocytosis induced by insulin .	Depletion of MAD2 or BUBR1 partially blocked IR endocytosis induced by insulin.	7	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	11	12	7	8
For biotinylation assays to measure insulin induced INSR membrane trafficking , HeLa cells carrying NS or shRNAs against MARCH1 or CBL or NEDD4 were used .	For biotinylation assays to measure insulin induced INSR membrane trafficking, HeLa cells carrying NS or shRNAs against MARCH1 or CBL or NEDD4 were used.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	5	6	7	8
Insulin induced INSR downregulation is mediated by HMGA1 phosphorylation .	Insulin induced INSR downregulation is mediated by HMGA1 phosphorylation.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	INSR	INSR	INSR	0	1	2	3
Furthermore , it correlated with a 35 % reduction in insulin stimulated insulin receptor kinase activity after acute leptin pretreatment .	Furthermore, it correlated with a 35% reduction in insulin stimulated insulin receptor kinase activity after acute leptin pretreatment.	8	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	12	14
A lyophilized lysate from insulin stimulated human IR transfected Chinese hamster ovary cells provided by the manufacturer served as a quantitative standard ; 1 unit of standard is equivalent to the amount of IR [ Tyr1162/1163 ] derived from 0.6 etag of IR ( beta-subunit ) in transfected Chinese hamster ovary cells stimulated with 100nM insulin .	A lyophilized lysate from insulin stimulated human IR transfected Chinese hamster ovary cells provided by the manufacturer served as a quantitative standard; 1 unit of standard is equivalent to the amount of IR [Tyr1162/1163] derived from 0.6 etag of IR (beta-subunit) in transfected Chinese hamster ovary cells stimulated with 100nM insulin.	2	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	7	8
Fetuin-A is an endogenous inhibitor of the insulin stimulated insulin receptor tyrosine kinase recently shown that high levels of circulating fetuin-A are associated with insulin resistance in humans suggesting that fetuin-A may represent a novel mechanism involved in the pathophysiology of type 2 diabetes ( T2DM ) .	Fetuin-A is an endogenous inhibitor of the insulin stimulated insulin receptor tyrosine kinase recently shown that high levels of circulating fetuin-A are associated with insulin resistance in humans suggesting that fetuin-A may represent a novel mechanism involved in the pathophysiology of type 2 diabetes (T2DM).	4	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	9	11
Based on this , we suggest that , in comparison to nondiabetic sporadic AD cases , sporadic AD cases with concomitant diabetic conditions may respond better to therapeutic strategies such as intranasal insulin administration that are designed to directly target IR in the brain .	Based on this, we suggest that, in comparison to nondiabetic sporadic AD cases, sporadic AD cases with concomitant diabetic conditions may respond better to therapeutic strategies such as intranasal insulin administration that are designed to directly target IR in the brain.	32	43	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	32	33	40	41
This combination of test results suggested that the patient ' s severe hypoglycemia was most likely caused by exogenous insulin or perhaps insulin receptor antibodies .	This combination of test results suggested that the patient 's severe hypoglycemia was most likely caused by exogenous insulin or perhaps insulin receptor antibodies.	16	24	caused	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	19	20	22	24
Maximal effects of insulin on glucose production and utilization occurred at plasma insulin concentrations causing 11 and 49 % insulin receptor occupancy , respectively .	Maximal effects of insulin on glucose production and utilization occurred at plasma insulin concentrations causing 11 and 49% insulin receptor occupancy, respectively.	1	21	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	19	21
Partial restoration of liver insulin signaling in the insulin receptor knockout mice fails to normalize insulin action on hepatic glucose production , supporting the importance of hypothalamic insulin signaling in glucose homeostasis .	Partial restoration of liver insulin signaling in the insulin receptor knockout mice fails to normalize insulin action on hepatic glucose production, supporting the importance of hypothalamic insulin signaling in glucose homeostasis.	4	10	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	8	10
Most clinical and experimental data support the concept that INSR activation ( primarily by insulin ) leads to metabolic types of action .	Most clinical and experimental data support the concept that INSR activation (primarily by insulin) leads to metabolic types of action.	9	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	14	15	9	10
Insulin dependent activation of the insulin receptor in adipocytes increases leptin mRNA expression within a few hours [ XREF_BIBR ] .	Insulin dependent activation of the insulin receptor in adipocytes increases leptin mRNA expression within a few hours [XREF_BIBR].	0	13	activation	Positive_regulation_syntax_3_noun	Positive_activation	Positive_regulation	Insulin	Insulin	insulin	insulin receptor	insulin receptor in adipocytes increases leptin mRNA expression	insulin receptor	0	1	5	7
Insulin triggered tyrosine kinase activation of IR by a 5.0-fold in vector control .	Insulin triggered tyrosine kinase activation of IR by a 5.0-fold in vector control.	0	7	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	6	7
Herein we have used subcellular fractionation to demonstrate that in primary adipocytes insulin stimulation induced rapid insulin receptor endocytosis by way of caveolae .	Herein we have used subcellular fractionation to demonstrate that in primary adipocytes insulin stimulation induced rapid insulin receptor endocytosis by way of caveolae.	12	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	16	18
Insulin caused 10 % of the plasma membrane insulin receptor to be translocated to a compartment resistant to extracellular trypsin .	Insulin caused 10% of the plasma membrane insulin receptor to be translocated to a compartment resistant to extracellular trypsin.	0	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	8	10
In parallel we observed that GSNO 50 muM induced S nitrosation of the crucial proteins , IR and Akt , for insulin signaling IR and Akt .	In parallel we observed that GSNO 50 muM induced S nitrosation of the crucial proteins, IR and Akt, for insulin signaling IR and Akt.	8	25	signaling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	21	22	23	24
In contrast a positive control IgG , in the presence of insulin , did induce both INSR internalization and downregulation by greater than 50 % .	In contrast a positive control IgG, in the presence of insulin, did induce both INSR internalization and downregulation by greater than 50%.	9	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	11	12	16	17
Insulin activates insulin receptor ( IR ) , which is a tyrosine kinase that phosphorylates and recruits different substrate adaptors such as the IRS family of proteins .	Insulin activates insulin receptor (IR), which is a tyrosine kinase that phosphorylates and recruits different substrate adaptors such as the IRS family of proteins.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	2	4
Physiologically , insulin can bind to its receptor and lead to IR tyrosine kinase activation , which phosphorylates the downstream IR substrate family members , such as IRS-1 .	Physiologically, insulin can bind to its receptor and lead to IR tyrosine kinase activation, which phosphorylates the downstream IR substrate family members, such as IRS-1.	2	14	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	2	3	11	12
In the same study it was also shown that both systemic and intravitreal insulin administration restored deficient insulin receptor signaling [ XREF_BIBR ] .	In the same study it was also shown that both systemic and intravitreal insulin administration restored deficient insulin receptor signaling [XREF_BIBR].	13	19	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	17	19
Insulin signaling and molecular basis of IR .	Insulin signaling and molecular basis of IR.	0	7	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	6	7
In favorable food conditions different insulin peptides activate the DAF-2 insulin receptor .	In favorable food conditions different insulin peptides activate the DAF-2 insulin receptor.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	10	12
To test whether this interaction modulates insulin receptor activation , CHO IR cells , which stably express insulin receptor , were treated with insulin , and active insulin receptor was purified using WGA conjugated agarose beads .	To test whether this interaction modulates insulin receptor activation, CHO IR cells, which stably express insulin receptor, were treated with insulin, and active insulin receptor was purified using WGA conjugated agarose beads.	17	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	23	24	17	19
Despite these differences , denervated soleus and plantaris muscles exhibited comparable decreases in insulin stimulated activities of the insulin receptor ( approximately 40 % ) and phosphatidylinositol 3-kinase ( approximately 50 % ) and a pronounced decrease in GLUT-4 .	Despite these differences, denervated soleus and plantaris muscles exhibited comparable decreases in insulin stimulated activities of the insulin receptor (approximately 40%) and phosphatidylinositol 3-kinase (approximately 50%) and a pronounced decrease in GLUT-4.	9	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	18	20
High levels of insulin activate the insulin receptor ( IR ) , but not the IGF1R , in tumors in MRK mice .	High levels of insulin activate the insulin receptor (IR), but not the IGF1R, in tumors in MRK mice.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	6	8
Four hours after exercise , insulin stimulated glucose uptake was improved ( approximately 70 % , P < 0.001 ) independent of diet composition and despite normal insulin stimulated regulation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase , Akt , GSK-3 , and glycogen synthase .	Four hours after exercise, insulin stimulated glucose uptake was improved (approximately 70%, P < 0.001) independent of diet composition and despite normal insulin stimulated regulation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase, Akt, GSK-3, and glycogen synthase.	10	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	27	28	31	33
Basal and maximally insulin stimulated insulin receptor tyrosine kinase activity , tested in a cell-free system , was similar for both autophosphorylation and phosphorylation of exogenous substrates in the absence or in the presence of PMB .	Basal and maximally insulin stimulated insulin receptor tyrosine kinase activity, tested in a cell-free system, was similar for both autophosphorylation and phosphorylation of exogenous substrates in the absence or in the presence of PMB.	0	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	5	7
The insulin receptor tyrosine kinase activity was stimulated by insulin , Mg2+ ( half-maximum response at approximately 5.6-10.6 nM and approximately 8.5 mM , respectively ) and by the physiological polyamines , spermine and spermidine .	The insulin receptor tyrosine kinase activity was stimulated by insulin, Mg2+ (half-maximum response at approximately 5.6-10.6 nM and approximately 8.5 mM, respectively) and by the physiological polyamines, spermine and spermidine.	1	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	1	3
Insulin is a known stimulator of both insulin receptor ( IR ) and IGF-1R signaling necessary for adipogenic differentiation .	Insulin is a known stimulator of both insulin receptor (IR) and IGF-1R signaling necessary for adipogenic differentiation.	0	9	is a known stimulator	Positive_activation_copula_1	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	7	9
Insulin administration activates the insulin receptor kinase ( IRK ) in both plasma membrane ( PM ) and endosomes ( ENs ) raising the possibility of transmembrane signaling occurring in the endosomal compartment .	Insulin administration activates the insulin receptor kinase (IRK) in both plasma membrane (PM) and endosomes (ENs) raising the possibility of transmembrane signaling occurring in the endosomal compartment.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	4	6
Other genes related with the adipose tissue are adiponectin , an insulin sensitizing protein that also promotes fatty acid oxidation , insulin receptor and insulin receptor substrate 1 ( IRS-1 ) , key proteins from the insulin signalling pathway , and cannabinoid receptor 1 ( CB1R ) and osteocalcin , which are related with energy metabolism .	Other genes related with the adipose tissue are adiponectin, an insulin sensitizing protein that also promotes fatty acid oxidation, insulin receptor and insulin receptor substrate 1 (IRS-1), key proteins from the insulin signalling pathway, and cannabinoid receptor 1 (CB1R) and osteocalcin, which are related with energy metabolism.	11	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	21	23
Beyond its systemic metabolic actions , insulin signals endothelial cells via analogous pathways downstream of the insulin receptor .	Beyond its systemic metabolic actions, insulin signals endothelial cells via analogous pathways downstream of the insulin receptor.	6	18	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	16	18
Consistent with cell culture experiments , overexpression of GPx1 in mice decreased the insulin mediated activation of the insulin receptor and Akt , suggesting that a loss of intracellular ROS preserves phosphatase activity [ XREF_BIBR ] .	Consistent with cell culture experiments, overexpression of GPx1 in mice decreased the insulin mediated activation of the insulin receptor and Akt, suggesting that a loss of intracellular ROS preserves phosphatase activity [XREF_BIBR].	13	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	18	20
This was then followed by a rapid dephosphorylation of these molecules , which was related to the insulin induced increase of SHP-1 association to IR and of SHP-1 activity .	This was then followed by a rapid dephosphorylation of these molecules, which was related to the insulin induced increase of SHP-1 association to IR and of SHP-1 activity.	14	25	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	17	18	24	25
Insulin stimulation of insulin receptor and insulin-receptor substrate-1 ( IRS-1 ) tyrosine phosphorylation as well as activation of phosphatidylinositol 3-kinase ( PI-3 kinase ) and Akt ( also known as protein kinase B , PKB ) were all substantially reduced with severe obesity .	Insulin stimulation of insulin receptor and insulin-receptor substrate-1 (IRS-1) tyrosine phosphorylation as well as activation of phosphatidylinositol 3-kinase (PI-3 kinase) and Akt (also known as protein kinase B, PKB) were all substantially reduced with severe obesity.	0	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
We found that LMPTP deletion enhanced insulin induced liver IR signaling , suggesting LMPTP acts by suppressing IR activation in the liver .	We found that LMPTP deletion enhanced insulin induced liver IR signaling, suggesting LMPTP acts by suppressing IR activation in the liver.	6	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	6	7	9	10
Insulin induces multiprotein complex formation of RACK1 , IR , and STAT3 .	Insulin induces multiprotein complex formation of RACK1, IR, and STAT3.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	8	9
In fact , in positive control ( insulin induced IR ) , there was no response ( even paradoxical decrease of S636/639 phosphorylation in response to insulin ) .	In fact, in positive control (insulin induced IR), there was no response (even paradoxical decrease of S636/639 phosphorylation in response to insulin).	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	7	8	9	10
While it might be tempting to suspect that an insulin initiated turnover in IR could decrease the amount of IR available for signaling , most insulin resistant patients do not exhibit reduced skeletal muscle IR expression XREF_BIBR .	While it might be tempting to suspect that an insulin initiated turnover in IR could decrease the amount of IR available for signaling, most insulin resistant patients do not exhibit reduced skeletal muscle IR expression XREF_BIBR.	8	20	decrease	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	insulin	insulin	insulin	IR	amount of IR	ir	9	10	19	20
Hence , the mechanism for XMetS differs from the proposed mechanism by which insulin activates the INSR via intramolecular crosslinking XREF_BIBR .	Hence, the mechanism for XMetS differs from the proposed mechanism by which insulin activates the INSR via intramolecular crosslinking XREF_BIBR.	13	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	13	14	16	17
In contrast to insulin mediated activation of IR , IR-A48 binding has little effect on the MAPK pathway and proliferation of cancer cells .	In contrast to insulin mediated activation of IR, IR-A48 binding has little effect on the MAPK pathway and proliferation of cancer cells.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	7	8
Next , we directly addressed whether insulin induced activation of IR leads to GRK2 phosphorylation of beta 2 AR in cardiac muscle cells .	Next, we directly addressed whether insulin induced activation of IR leads to GRK2 phosphorylation of beta 2 AR in cardiac muscle cells.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	6	7	10	11
The oligopeptide chromodulin binds chromic ions in response to an insulin mediated chromic ion flux , and the metal saturated oligopeptide can bind to an insulin stimulated insulin receptor , activating the receptor ' s tyrosine kinase activity .	The oligopeptide chromodulin binds chromic ions in response to an insulin mediated chromic ion flux, and the metal saturated oligopeptide can bind to an insulin stimulated insulin receptor, activating the receptor 's tyrosine kinase activity.	22	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	25	26	27	29
Although we did not observe consistent effects of antimiR-128-1 treatment on Abca1 expression across the treated animals in the short-term study ( data not shown ) , we found potent de-repression of other targets such as the insulin signaling components Irs1 and the insulin receptor ( Insr ) , with a concomitant increase in insulin signaling output , as evidenced by elevated phosphorylated Akt ( XREF_FIG ) .	Although we did not observe consistent effects of antimiR-128-1 treatment on Abca1 expression across the treated animals in the short-term study (data not shown), we found potent de-repression of other targets such as the insulin signaling components Irs1 and the insulin receptor (Insr), with a concomitant increase in insulin signaling output, as evidenced by elevated phosphorylated Akt (XREF_FIG).	33	45	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	37	38	43	45
We examined whether prolonged insulin exposure induces a change in IR activity , membrane localization or structure that may render the IR less capable of being re-activated upon re-stimulation .	We examined whether prolonged insulin exposure induces a change in IR activity, membrane localization or structure that may render the IR less capable of being re-activated upon re-stimulation.	4	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	10	11
Moreover , PC-1 ( ENPP1 ) overexpression [ corrected ] in cultured cells in vitro and in transgenic mice in vivo , [ corrected ] impairs insulin stimulation of insulin receptor ( IR ) activation and downstream signaling .	Moreover, PC-1 (ENPP1) overexpression [corrected] in cultured cells in vitro and in transgenic mice in vivo, [corrected] impairs insulin stimulation of insulin receptor (IR) activation and downstream signaling.	26	31	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	26	27	29	31
We also used retinal organ cultures to demonstrate insulin activation of the insulin receptor and subsequent binding of p85 , measured through GST pull-down assays with p85 fusion proteins .	We also used retinal organ cultures to demonstrate insulin activation of the insulin receptor and subsequent binding of p85, measured through GST pull-down assays with p85 fusion proteins.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	12	14
The overexpression of Insr and Igf-1r genes in liver and colon of rats treated with insulin glargine observed in this study probably related with the increased affinity of glargine toward these receptors and with the subsequent increase of both metabolic and mitogenic pathways in hepatocytes and colonocytes .	The overexpression of Insr and Igf-1r genes in liver and colon of rats treated with insulin glargine observed in this study probably related with the increased affinity of glargine toward these receptors and with the subsequent increase of both metabolic and mitogenic pathways in hepatocytes and colonocytes.	1	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Insr	Insr	Insr	15	16	3	4
At the concentration identified as increasing epiblast cell number and proportion , insulin is known to activate the insulin receptor [ XREF_BIBR ] .	At the concentration identified as increasing epiblast cell number and proportion, insulin is known to activate the insulin receptor [XREF_BIBR].	12	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	18	20
Under our experimental conditions , insulin activates the insulin receptor in fibroblasts but not the insulin like growth factor 1 receptor ( Figs XREF_FIG and XREF_FIG ) .	Under our experimental conditions, insulin activates the insulin receptor in fibroblasts but not the insulin like growth factor 1 receptor (Figs XREF_FIG and XREF_FIG).	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	8	10
For enriched pathways of NIDDM , as stated previously , the insulin receptor can be activated by insulin .	For enriched pathways of NIDDM, as stated previously, the insulin receptor can be activated by insulin.	11	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	17	18	11	13
Activation of IR by insulin in retinal organ cultures .	Activation of IR by insulin in retinal organ cultures.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	2	3
Removal of Grb14 from fractions of insulin treated rats by KCl treatment led to an increase of in vivo insulin stimulated IR tyrosine kinase activity , indicating that endogenous Grb14 exerts a negative feedback control on IR catalytic activity .	Removal of Grb14 from fractions of insulin treated rats by KCl treatment led to an increase of in vivo insulin stimulated IR tyrosine kinase activity, indicating that endogenous Grb14 exerts a negative feedback control on IR catalytic activity.	15	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	19	20	21	22
Insulin extraction from the portal circulation by the liver causes insulin receptor activation and lipogenic effects , which further drives fat accumulation and potential reductions in SHBG .	Insulin extraction from the portal circulation by the liver causes insulin receptor activation and lipogenic effects, which further drives fat accumulation and potential reductions in SHBG.	0	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	10	12
We provide such a demonstration here by showing that the hippocampal formation ( HF ) and , to a lesser degree , the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR --> IRS-1 --> PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R --> IRS-2 --> PI3K signaling pathway .	We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR --> IRS-1 --> PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R --> IRS-2 --> PI3K signaling pathway.	35	45	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	35	36	39	40
The administration of a single dose of insulin ( 1.5 microgram/100 g , body weight ) induced a time dependent activation of the insulin receptor kinase in these structures .	The administration of a single dose of insulin (1.5 microgram/100 g, body weight) induced a time dependent activation of the insulin receptor kinase in these structures.	5	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	23	25
Insulin initiates its pleiotropic effects by activating the insulin receptor tyrosine kinase to phosphorylate several intracellular proteins .	Insulin initiates its pleiotropic effects by activating the insulin receptor tyrosine kinase to phosphorylate several intracellular proteins.	0	11	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	8	10
It is worthy to note that insulin induced phosphorylation of Akt was reduced in all models of IR , no matter whether or not the IR was caused by insulin .	It is worthy to note that insulin induced phosphorylation of Akt was reduced in all models of IR, no matter whether or not the IR was caused by insulin.	24	30	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	29	30	25	26
Leptin treatment at this dose improved insulin stimulated insulin receptor and insulin receptor substrate 2 ( IRS-2 ) phosphorylation , IRS-2-associated PI3K activity , and Akt activity in liver .	Leptin treatment at this dose improved insulin stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2-associated PI3K activity, and Akt activity in liver.	5	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	8	10
While there is currently no medical treatment for LR , IR and PCOS are often successfully treated with the use of insulin lowering agents ( ISDs ) XREF_BIBR , XREF_BIBR .	While there is currently no medical treatment for LR, IR and PCOS are often successfully treated with the use of insulin lowering agents (ISDs) XREF_BIBR, XREF_BIBR.	10	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	21	22	10	11
Insulin activates insulin receptor , to phosphorylate its own receptor and IRS , thereby dissociating IRS from insulin receptor to activate PI3K .	Insulin activates insulin receptor, to phosphorylate its own receptor and IRS, thereby dissociating IRS from insulin receptor to activate PI3K.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	2	4
Several detergents ( Anapoe-NID-P40 , 1,2-diheptanoyl-sn-glycero-3-phosphocholine , Anapoe-C10E9 , MEGA-10 , and n-undecyl-N , N-dimethylamine-oxide ) gave high insulin stimulated IR activity , but also led to IR autophosphorylation in the basal state .	Several detergents (Anapoe-NID-P40, 1,2-diheptanoyl-sn-glycero-3-phosphocholine, Anapoe-C10E9, MEGA-10, and n-undecyl-N, N-dimethylamine-oxide) gave high insulin stimulated IR activity, but also led to IR autophosphorylation in the basal state.	16	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	18	19	20	21
Activation of IR by insulin resulted in a rapid and transient increase of tyrosine phosphorylation of IR , its substrates IRS-1 and Shc , and also of SHP-1 .	Activation of IR by insulin resulted in a rapid and transient increase of tyrosine phosphorylation of IR, its substrates IRS-1 and Shc, and also of SHP-1.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	2	3
Moreover , these studies support the hypothesis that DAG induced PKCepsilon activation , resulting in inhibition of insulin stimulated insulin receptor kinase activity , represents the root cause of hepatic insulin resistance in all of these conditions .	Moreover, these studies support the hypothesis that DAG induced PKCepsilon activation, resulting in inhibition of insulin stimulated insulin receptor kinase activity, represents the root cause of hepatic insulin resistance in all of these conditions.	15	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	17	18	19	21
Insulin activates the insulin receptor substrates ( IRS )/phosphatidylinositol 3-kinase ( PI3-K )/protein kinase B ( PKB or Akt )/endothelial nitric oxide synthase ( eNOS ) pathway [ XREF_BIBR ] , leading to increased nitric oxide ( NO ) production and the dilation of peripheral resistance arteries and precapillary terminal arterioles , as well as increased total blood flow [ XREF_BIBR ] and muscle microvascular perfusion [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Insulin activates the insulin receptor substrates (IRS)/phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB or Akt)/endothelial nitric oxide synthase (eNOS) pathway [XREF_BIBR], leading to increased nitric oxide (NO) production and the dilation of peripheral resistance arteries and precapillary terminal arterioles, as well as increased total blood flow [XREF_BIBR] and muscle microvascular perfusion [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
Interestingly , a mixture of insulin and 4548-G05 provoked much more robust IR and Akt phosphorylations than insulin or 4548-G05 per se , indicating a synergistic effect of 4548-G05 on insulin mediated IR activation ( XREF_FIG ) .	Interestingly, a mixture of insulin and 4548-G05 provoked much more robust IR and Akt phosphorylations than insulin or 4548-G05 per se, indicating a synergistic effect of 4548-G05 on insulin mediated IR activation (XREF_FIG).	23	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	30	31	32	33
We previously demonstrated that intravitreal injection of insulin restores retinal IR activity XREF_BIBR .	We previously demonstrated that intravitreal injection of insulin restores retinal IR activity XREF_BIBR.	5	12	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	7	8	10	11
( b ) In all cell lines , insulin stimulated insulin receptor tyrosine kinase activity .	(b) In all cell lines, insulin stimulated insulin receptor tyrosine kinase activity.	8	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	10	12
Therefore , these studies indicated that XMetD was a highly effective inhibitor of insulin mediated INSR signaling in vitro .	Therefore, these studies indicated that XMetD was a highly effective inhibitor of insulin mediated INSR signaling in vitro.	11	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	INSR	INSR	INSR	13	14	15	16
Insulin induces IR activation and through a complex cascade of signal transduction events increases the uptake of glucose by inducing the translocation of GLUT4 from these vesicles to the plasma membrane .	Insulin induces IR activation and through a complex cascade of signal transduction events increases the uptake of glucose by inducing the translocation of GLUT4 from these vesicles to the plasma membrane.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	2	3
Metformin did not augment maximal or submaximal insulin stimulated IR activation .	Metformin did not augment maximal or submaximal insulin stimulated IR activation.	3	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	7	8	9	10
Comparable results were obtained when either beta 2 AR- or beta 2 AR- and IR expressing cells were concomitantly treated with isoproterenol and insulin ( see XREF_FIG ) .	Comparable results were obtained when either beta 2 AR- or beta 2 AR- and IR expressing cells were concomitantly treated with isoproterenol and insulin (see XREF_FIG).	12	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	23	24	14	15
In the white gastrocnemius , insulin activation of insulin receptor tyrosine kinase and phosphoinositide 3-kinase was unaffected by glycogen levels , whereas protein kinase B activity was significantly higher in LG compared with HG .	In the white gastrocnemius, insulin activation of insulin receptor tyrosine kinase and phosphoinositide 3-kinase was unaffected by glycogen levels, whereas protein kinase B activity was significantly higher in LG compared with HG.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	8	10
Insulin alone is able to produce molecular activation of insulin receptor substrates ( IRSs )/phosphatidylinositol 3-kinase ( PI 3-kinase )/Akt and mitogen activated protein ( MAP ) kinase signaling pathways in hypothalamus , whereas leptin alone activates MAP kinase and IRSs/PI 3-kinase signaling with no effect on Akt .	Insulin alone is able to produce molecular activation of insulin receptor substrates (IRSs)/phosphatidylinositol 3-kinase (PI 3-kinase)/Akt and mitogen activated protein (MAP) kinase signaling pathways in hypothalamus, whereas leptin alone activates MAP kinase and IRSs/PI 3-kinase signaling with no effect on Akt.	0	11	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	9	11
The ability to modulate the balance of eicosanoid vasodilators and vasoconstrictors may be valuable for early treatment of IR , a notion that is supported by improved insulin sensitivity found in animal models of metabolic disease .	The ability to modulate the balance of eicosanoid vasodilators and vasoconstrictors may be valuable for early treatment of IR, a notion that is supported by improved insulin sensitivity found in animal models of metabolic disease.	16	28	supported	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	27	28	18	19
Other therapeutical approaches could be ( 1 ) the small molecule insulin mimetic demethylasterriquinone B 1 ( DAQB 1 ) that does not competitively inhibit IDE and modulates IR [ XREF_BIBR ] , ( 2 ) the delivery of insulin antibodies , or ( 3 ) insulin inhibiting peptides into the brain [ XREF_BIBR ] .	Other therapeutical approaches could be (1) the small molecule insulin mimetic demethylasterriquinone B 1 (DAQB 1) that does not competitively inhibit IDE and modulates IR [XREF_BIBR], (2) the delivery of insulin antibodies, or (3) insulin inhibiting peptides into the brain [XREF_BIBR].	4	47	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	11	12	28	29
However , selective IGF-I stimulation of the IGF-1R invitro under conditions where insulin levels are sufficient only to stimulate the insulin receptor but not the IGF-IR revealed roles for IGF signalling per se in OPC proliferation and protein synthesis as well as survival .	However, selective IGF-I stimulation of the IGF-1R invitro under conditions where insulin levels are sufficient only to stimulate the insulin receptor but not the IGF-IR revealed roles for IGF signalling per se in OPC proliferation and protein synthesis as well as survival.	12	22	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	20	22
At 4 ng/ml insulin , adenosine deaminase decreased insulin activation of insulin receptor kinase by 25 % , a reduction that equalled the effect of adenosine deaminase on insulin stimulation of 2-deoxyglucose transport .	At 4 ng/ml insulin, adenosine deaminase decreased insulin activation of insulin receptor kinase by 25%, a reduction that equalled the effect of adenosine deaminase on insulin stimulation of 2-deoxyglucose transport.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	11	13
The change during fasting of the insulin stimulated tyrosine kinase activity of the insulin receptor is specific to certain tissue .	The change during fasting of the insulin stimulated tyrosine kinase activity of the insulin receptor is specific to certain tissue.	3	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	13	15
A similar curve has also been observed for IGF-I activation of the IGF-1R XREF_BIBR , XREF_BIBR and is seen for insulin activating the IR XREF_BIBR , XREF_BIBR .	A similar curve has also been observed for IGF-I activation of the IGF-1R XREF_BIBR, XREF_BIBR and is seen for insulin activating the IR XREF_BIBR, XREF_BIBR.	18	24	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	20	21	23	24
In cultured cells , XMetS markedly enhanced insulin binding affinity leading to potentiation of insulin stimulated INSR signaling resulting in enhanced glucose transport .	In cultured cells, XMetS markedly enhanced insulin binding affinity leading to potentiation of insulin stimulated INSR signaling resulting in enhanced glucose transport.	12	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	14	15	16	17
The low dose insulin restores retinal insulin receptor activity without changing blood glucose levels , and phloridzin normalizes blood glucose levels without affecting systemic or local insulin levels .	The low dose insulin restores retinal insulin receptor activity without changing blood glucose levels, and phloridzin normalizes blood glucose levels without affecting systemic or local insulin levels.	0	8	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	6	8
Because insulin activated IR internalization remains intact in LRP1KO hepatocytes , interaction of IR with LRP1 primarily controls IR expression at the plasma membrane , but not its endocytosis .	Because insulin activated IR internalization remains intact in LRP1KO hepatocytes, interaction of IR with LRP1 primarily controls IR expression at the plasma membrane, but not its endocytosis.	0	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	1	2	3	4
In addition , insulin causes IR by inducing lipogenesis and increasing lipid metabolites that are known to diminish insulin sensitivity .	In addition, insulin causes IR by inducing lipogenesis and increasing lipid metabolites that are known to diminish insulin sensitivity.	3	6	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	5	6
Interestingly , even in the context of HFD , ROS production can also promote insulin sensitivity ; mice lacking the H 2 O 2 scavenger glutathione peroxidase 1 are protected from HFD induced insulin resistance due to increased oxidation of PTEN , a redox sensitive PTP , thus enabling increased signaling downstream of the insulin receptor .	Interestingly, even in the context of HFD, ROS production can also promote insulin sensitivity; mice lacking the H 2 O 2 scavenger glutathione peroxidase 1 are protected from HFD induced insulin resistance due to increased oxidation of PTEN, a redox sensitive PTP, thus enabling increased signaling downstream of the insulin receptor.	31	56	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	HFD induced insulin	insulin	insulin receptor	insulin receptor	insulin receptor	33	34	54	56
Insulin and Igf signalling is mediated vaitwo intracellular insulin receptor substrates ( Irs1 and Irs2 ) ; null mutations in either Irs1 or Irs2 result in peripheral insulin resistance but only Irs2 /- mice are incapable enhancing beta-cell replication to compensate for peripheral insulin resistance [ XREF_BIBR ] .	Insulin and Igf signalling is mediated vaitwo intracellular insulin receptor substrates (Irs1 and Irs2); null mutations in either Irs1 or Irs2 result in peripheral insulin resistance but only Irs2 /- mice are incapable enhancing beta-cell replication to compensate for peripheral insulin resistance [XREF_BIBR].	0	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	8	10
Furthermore , a high-cholesterol diet can induce an enhanced insulin induced insulin receptor activation , impair the downstream molecules IRS-1 and Akt activities , and abolish an induction of caveolin-1 tyrosine phosphorylation under the insulin stimulation .	Furthermore, a high-cholesterol diet can induce an enhanced insulin induced insulin receptor activation, impair the downstream molecules IRS-1 and Akt activities, and abolish an induction of caveolin-1 tyrosine phosphorylation under the insulin stimulation.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	11	13
Briefly , insulin activates the insulin receptor tyrosine kinase ( IR ) , which phosphorylates and recruits different substrate adaptors such as the insulin receptor substrate ( IRS ) family of proteins .	Briefly, insulin activates the insulin receptor tyrosine kinase (IR), which phosphorylates and recruits different substrate adaptors such as the insulin receptor substrate (IRS) family of proteins.	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	5	7
Intravenous insulin stimulated insulin receptor tyrosine kinase activity by 7-fold in control muscle versus < or = 1.5-fold in muscle from transgenic mice .	Intravenous insulin stimulated insulin receptor tyrosine kinase activity by 7-fold in control muscle versus < or = 1.5-fold in muscle from transgenic mice.	0	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	3	5
This is supported by evidence that chemical inhibition of LMPTP activity increases insulin induced activation of the liver IR and downstream signaling pathways , and improves glucose tolerance in obese mice .	This is supported by evidence that chemical inhibition of LMPTP activity increases insulin induced activation of the liver IR and downstream signaling pathways, and improves glucose tolerance in obese mice.	12	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	12	13	18	19
Serum AHSG is a natural endogenous inhibitor of the insulin stimulated insulin receptor tyrosin kinase activity [ XREF_BIBR - XREF_BIBR ] , insulin receptor auto-phosporylation , and insulin substrate 1 phosporylation [ XREF_BIBR ] .	Serum AHSG is a natural endogenous inhibitor of the insulin stimulated insulin receptor tyrosin kinase activity [XREF_BIBR - XREF_BIBR], insulin receptor auto-phosporylation, and insulin substrate 1 phosporylation [XREF_BIBR].	6	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	11	13
The results above showed that insulin induced SA synthesis and extracellular high SA level reduced insulin sensitivity in HepG2 cells , so we asked whether intracellular SA could be increased also and might be associated with IR induced by prolonged insulin treatment .	The results above showed that insulin induced SA synthesis and extracellular high SA level reduced insulin sensitivity in HepG2 cells, so we asked whether intracellular SA could be increased also and might be associated with IR induced by prolonged insulin treatment.	34	41	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	40	41	36	37
A peptide inhibitor of IR which efficiently blocks insulin induced IR activation i.e. HNMPA-( AM ) 3 [ XREF_BIBR , XREF_BIBR ] was used by us to show dmp ' s IR independent effect .	A peptide inhibitor of IR which efficiently blocks insulin induced IR activation i.e. HNMPA-(AM) 3 [XREF_BIBR, XREF_BIBR] was used by us to show dmp 's IR independent effect.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	8	9	10	11
Reciprocally , insulin activation of the insulin receptor repressed CAR activation and induction of its target CYP2B6 gene in HepG2 cells .	Reciprocally, insulin activation of the insulin receptor repressed CAR activation and induction of its target CYP2B6 gene in HepG2 cells.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	6	8
We have previously demonstrated that diabetes significantly increases retinal cell death within 4 weeks after the onset of hyperglycemia , systemic insulin administration restores depressed insulin receptor signaling and cell death , and intravitreal insulin injection restores retinal insulin receptor activity XREF_BIBR .	We have previously demonstrated that diabetes significantly increases retinal cell death within 4 weeks after the onset of hyperglycemia, systemic insulin administration restores depressed insulin receptor signaling and cell death, and intravitreal insulin injection restores retinal insulin receptor activity XREF_BIBR.	21	27	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	21	22	25	27
Even a small increase in NAC levels above a threshold value completely prevents insulin stimulated insulin receptor activation .	Even a small increase in NAC levels above a threshold value completely prevents insulin stimulated insulin receptor activation.	12	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	15	17
While most insulin analogues primarily activated the INSR , the mitogenic activation pattern of glargine was highly similar to IGF1 and insulin AspB10 , known to bind IGF1R and induce carcinogenesis .	While most insulin analogues primarily activated the INSR, the mitogenic activation pattern of glargine was highly similar to IGF1 and insulin AspB10, known to bind IGF1R and induce carcinogenesis.	2	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	2	3	7	8
We have previously shown that young and healthy , low birth weight men , exhibit multiple abnormalities in their skeletal muscle in the insulin signalling metabolic pathway downstream of the insulin receptor , under fasting conditions XREF_BIBR .	We have previously shown that young and healthy, low birth weight men, exhibit multiple abnormalities in their skeletal muscle in the insulin signalling metabolic pathway downstream of the insulin receptor, under fasting conditions XREF_BIBR.	23	32	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	23	24	30	32
The terminal residues A1-A4 of the insulin A-chain are shown to be important for the slow binding phase , as insulin lacking these amino acids is unable to induce a conformational change of IR and has a severely impaired binding affinity .	The terminal residues A1-A4 of the insulin A-chain are shown to be important for the slow binding phase, as insulin lacking these amino acids is unable to induce a conformational change of IR and has a severely impaired binding affinity.	20	34	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	20	21	33	34
Insulin resistance expressed in Psammomys at stages B and C was demonstrated by nonsuppression of the hepatic gluconeogenesis enzyme phosphoenolpyruvate carboxykinase by the endogenous hyperinsulinemia and by the reduced capacity of insulin to activate muscle and liver tyrosine kinase of the insulin receptor .	Insulin resistance expressed in Psammomys at stages B and C was demonstrated by nonsuppression of the hepatic gluconeogenesis enzyme phosphoenolpyruvate carboxykinase by the endogenous hyperinsulinemia and by the reduced capacity of insulin to activate muscle and liver tyrosine kinase of the insulin receptor.	0	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	41	43
ENPP1 does not appear to affect insulin binding , but inhibits the insulin induced conformational change of the IR alpha subunits .	ENPP1 does not appear to affect insulin binding, but inhibits the insulin induced conformational change of the IR alpha subunits.	11	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	12	13	18	19
It is noteworthy that although the high concentration of 50nM insulin induced IR in vitro , this might not be duplicated in vivo since the serum insulin level as high as 50nM has rarely been reported in human .	It is noteworthy that although the high concentration of 50nM insulin induced IR in vitro, this might not be duplicated in vivo since the serum insulin level as high as 50nM has rarely been reported in human.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	10	11	12	13
Here , we proposed and demonstrated that high insulin concentrations promote the liberation of the alpha portion of the IR from hepatocytes , and that a protease inhibitor can prevent this process .	Here, we proposed and demonstrated that high insulin concentrations promote the liberation of the alpha portion of the IR from hepatocytes, and that a protease inhibitor can prevent this process.	8	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	8	9	19	20
More detailed information is required to elucidate the exact mechanisms as to how insulin analogues may activate the IR and IGF1R and how this activation may be linked to mitogenesis .	More detailed information is required to elucidate the exact mechanisms as to how insulin analogues may activate the IR and IGF1R and how this activation may be linked to mitogenesis.	13	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	18	19
Taken together , these results suggest that insulin stimulates the association of insulin receptor with syndecan-1 and the complex formation of syndecan-1 and integrin could play an important role in ERK I/II-ALP signaling pathway in osteoblast cells .	Taken together, these results suggest that insulin stimulates the association of insulin receptor with syndecan-1 and the complex formation of syndecan-1 and integrin could play an important role in ERK I/II-ALP signaling pathway in osteoblast cells.	7	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	12	14
Fibroin did not prevent the insulin induced downregulation of the insulin receptor or the tyrosine kinase activity associated with the receptor .	Fibroin did not prevent the insulin induced downregulation of the insulin receptor or the tyrosine kinase activity associated with the receptor.	4	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	10	12
At a physiological concentration , insulin activates the IR but does not affect either glucose metabolism or DNA synthesis , whereas IGF-I both activates the receptor and elicits biological effect .	At a physiological concentration, insulin activates the IR but does not affect either glucose metabolism or DNA synthesis, whereas IGF-I both activates the receptor and elicits biological effect.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	5	6	8	9
To test the capacity of insulin to work through a classical insulin-receptor pathway in the ovary , cultured swine granulosa cells were treated with insulin and/or increasing concentrations of insulin-receptor antiserum .	To test the capacity of insulin to work through a classical insulin-receptor pathway in the ovary, cultured swine granulosa cells were treated with insulin and/or increasing concentrations of insulin-receptor antiserum.	11	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin-receptor	insulin-receptor	insulin-receptor	24	25	11	12
Since many investigators studying insulin action use 3T3-L1 adipocytes , we compared CAR adipocytes versus regular adipocytes and showed that the two cell lines were similar with respect to insulin stimulation of insulin receptor , MAPK , and Akt phosphorylation and basal- and insulin stimulated glucose transport .	Since many investigators studying insulin action use 3T3-L1 adipocytes, we compared CAR adipocytes versus regular adipocytes and showed that the two cell lines were similar with respect to insulin stimulation of insulin receptor, MAPK, and Akt phosphorylation and basal- and insulin stimulated glucose transport.	29	34	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	29	30	32	34
At this meeting , which was industry independent like the preceding one in 2007 , the following issues were discussed a ) association between certain cancers and endogenous insulin production in humans , b ) growth promoting effects of insulin in animal experiments , c ) mitogenic and anti-apoptotic activity of pharmaceutic insulin and insulin analogues in in vitro experiments , d ) potential mechanisms of insulin action on cell growth , mediated by IGF-1 receptor and insulin receptor signaling , and e ) IGF-1 receptor targeting for inhibition of tumor growth .	At this meeting, which was industry independent like the preceding one in 2007, the following issues were discussed a) association between certain cancers and endogenous insulin production in humans, b) growth promoting effects of insulin in animal experiments, c) mitogenic and anti-apoptotic activity of pharmaceutic insulin and insulin analogues in in vitro experiments, d) potential mechanisms of insulin action on cell growth, mediated by IGF-1 receptor and insulin receptor signaling, and e) IGF-1 receptor targeting for inhibition of tumor growth.	66	79	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	66	67	77	79
Using isolated rat insulin receptor , LMWCr has been shown to bind to insulin activated insulin receptor with a dissociation constant of circa 250 pM , resulting in the increase of its tyrosine protein kinase activity .	Using isolated rat insulin receptor, LMWCr has been shown to bind to insulin activated insulin receptor with a dissociation constant of circa 250 pM, resulting in the increase of its tyrosine protein kinase activity.	11	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	15	17
As shown in XREF_FIG by real-time PCR and Western blotting analyses , compared to the untreated control ( the 1 st column , or well ) , insulin significantly increased the steady state level of transcript and the abundance of protein of InsR ( the 2 nd column , or well ) .	As shown in XREF_FIG by real-time PCR and Western blotting analyses, compared to the untreated control (the 1 st column, or well), insulin significantly increased the steady state level of transcript and the abundance of protein of InsR (the 2 nd column, or well).	27	47	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	InsR	InsR	InsR	27	28	42	43
Insulin activates the insulin receptor ( IR ) protein tyrosine kinase and downstream phosphatidylinositol-3-kinase ( PI3K )/Akt signalling in muscle to promote glucose uptake .	Insulin activates the insulin receptor (IR) protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
45 Elevated ROS stimulates serine/threonine phosphorylation of insulin receptor substrate-1 , preventing tyrosine phosphorylation and the subsequent insulin signaling cascade leading to IR .	45 Elevated ROS stimulates serine/threonine phosphorylation of insulin receptor substrate-1, preventing tyrosine phosphorylation and the subsequent insulin signaling cascade leading to IR.	12	23	leading	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	tyrosine phosphorylation and the subsequent insulin	insulin	IR	IR	ir	17	18	22	23
Insulin stimulated insulin receptor ( IR ) tyrosyl phosphorylation and phosphatidylinositol 3 '-kinase activity were impaired by 35 % and 40-60 % in muscle of PTP1B overexpressing mice compared with controls .	Insulin stimulated insulin receptor (IR) tyrosyl phosphorylation and phosphatidylinositol 3 '-kinase activity were impaired by 35% and 40-60% in muscle of PTP1B overexpressing mice compared with controls.	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	2	4
Increased free fatty acids in the circulation can also induce fatty liver and adipose accumulation , and reduce the response to insulin thereby causing IR [ XREF_BIBR ] .	Increased free fatty acids in the circulation can also induce fatty liver and adipose accumulation, and reduce the response to insulin thereby causing IR [XREF_BIBR].	17	26	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	21	22	24	25
Taken together , these recent studies suggest a revised model of insulin action in muscle and fat cells , wherein insulin stimulated IR emits a coordinated signal to evoke SNARE assembly steps in concert with vesicle mobilization to the PM , culminating in SNARE core complex assembly and GLUT4 vesicle fusion .	Taken together, these recent studies suggest a revised model of insulin action in muscle and fat cells, wherein insulin stimulated IR emits a coordinated signal to evoke SNARE assembly steps in concert with vesicle mobilization to the PM, culminating in SNARE core complex assembly and GLUT4 vesicle fusion.	20	23	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	20	21	22	23
Inhibition of insulin induced insulin receptor tyrosine phosphorylation by hypoxia is rapid and reversible .	Inhibition of insulin induced insulin receptor tyrosine phosphorylation by hypoxia is rapid and reversible.	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	4	6
demonstrated that insulin mediated downregulation of the IR , by shifting IR : IGF-1R stoichiometry in favor of IGF-1R led to a higher proportion of hybrid receptors in skeletal muscle in these patients .	demonstrated that insulin mediated downregulation of the IR, by shifting IR : IGF-1R stoichiometry in favor of IGF-1R led to a higher proportion of hybrid receptors in skeletal muscle in these patients.	2	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	2	3	7	8
Furthermore , insulin stimulated insulin receptor and Akt Ser ( 473 ) phosphorylation and phosphatidylinositol 3-kinase activity were 1.6-2.5-fold greater in skeletal muscle from C/EBPbeta (-/-) mice compared with WT mice .	Furthermore, insulin stimulated insulin receptor and Akt Ser (473) phosphorylation and phosphatidylinositol 3-kinase activity were 1.6-2.5-fold greater in skeletal muscle from C/EBPbeta (-/-) mice compared with WT mice.	2	13	stimulated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	insulin	insulin	insulin	insulin receptor	insulin receptor and Akt Ser (473) phosphorylation	insulin receptor	2	3	4	6
Previously , we demonstrated that insulin receptor knock-out mice ( Insr (-/-) ) could be rescued from diabetes by reconstitution of insulin signaling in liver , brain , and pancreatic beta cells ( L1 mice ) .	Previously, we demonstrated that insulin receptor knock-out mice (Insr (-/-)) could be rescued from diabetes by reconstitution of insulin signaling in liver, brain, and pancreatic beta cells (L1 mice).	5	22	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	21	22	5	7
The possible mechanisms include insulin mediated activation of the insulin receptor and/or its downstream molecules , ultimately effecting GLUT4 expression and translocation .	The possible mechanisms include insulin mediated activation of the insulin receptor and/or its downstream molecules, ultimately effecting GLUT4 expression and translocation.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	9	11
The results of our study show that in the setting of endogenous hyperinsulinemia , insulin causes IR , but not IGF-IR , phosphorylation .	The results of our study show that in the setting of endogenous hyperinsulinemia, insulin causes IR, but not IGF-IR, phosphorylation.	14	20	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	14	15	16	17
* IR and PCOS are often successfully treated with the use of insulin lowering agents .	* IR and PCOS are often successfully treated with the use of insulin lowering agents.	1	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	12	13	1	2
Several reports showed the involvement of stimulation of IR by insulin or IGF-2 in cancer cell progression [ XREF_BIBR , XREF_BIBR ] suggesting that IGF-1R and IR both are therapeutic targets and inhibition of both receptors may be required for optimal tumor growth inhibition .	Several reports showed the involvement of stimulation of IR by insulin or IGF-2 in cancer cell progression [XREF_BIBR, XREF_BIBR] suggesting that IGF-1R and IR both are therapeutic targets and inhibition of both receptors may be required for optimal tumor growth inhibition.	2	12	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	10	11	8	9
As a result , insulin stimulated GLUT4 translocation is impaired , resulting in IR .	As a result, insulin stimulated GLUT4 translocation is impaired, resulting in IR.	4	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	13	14
Insulin treatment activated the insulin receptor substrate-1-associated ( IRS-1-associated ) phosphoinositide 3-kinase ( PI 3-kinase ) 6.1-fold in lean , 3.7-fold in obese , and 2.4-fold in diabetic subjects .	Insulin treatment activated the insulin receptor substrate-1-associated (IRS-1-associated) phosphoinositide 3-kinase (PI 3-kinase) 6.1-fold in lean, 3.7-fold in obese, and 2.4-fold in diabetic subjects.	0	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	4	6
Interestingly , h-LRP1 -/- hepatocytes had significantly lower levels of IR expression at the cell surface ; however , the extent of insulin stimulated IR internalization was similar between h-LRP1 -/- and h-LRP1 +/+ hepatocytes .	Interestingly, h-LRP1 -/- hepatocytes had significantly lower levels of IR expression at the cell surface; however, the extent of insulin stimulated IR internalization was similar between h-LRP1 -/- and h-LRP1 +/+ hepatocytes.	20	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	22	23	24	25
At physiological levels ( ~ 25 ng/ml ; 4.4 nM ) , insulin activates only the insulin receptor .	At physiological levels (~ 25 ng/ml; 4.4 nM), insulin activates only the insulin receptor.	12	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	16	18
Our results indicated that insulin activated the INSR , but not the IGF1R in PCa cells ( even at high doses ) .	Our results indicated that insulin activated the INSR, but not the IGF1R in PCa cells (even at high doses).	4	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	4	5	7	8
Insulin rapidly induces the association of insulin receptor with syndecan-1 .	Insulin rapidly induces the association of insulin receptor with syndecan-1.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	6	8
The binding of insulin triggers the activation of the cell surface insulin receptor ( IR ) and , as a consequence , the receptor becomes phosphorylated at several tyrosine residues located in the cytoplasmic portion of its beta-subunit .	The binding of insulin triggers the activation of the cell surface insulin receptor (IR) and, as a consequence, the receptor becomes phosphorylated at several tyrosine residues located in the cytoplasmic portion of its beta-subunit.	1	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	11	13
Okadaic acid activated the kinase activity of the insulin stimulated insulin receptor , but not the basal activity of the insulin receptor without the addition of insulin .	Okadaic acid activated the kinase activity of the insulin stimulated insulin receptor, but not the basal activity of the insulin receptor without the addition of insulin.	5	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	10	12
We further found that MBNL1 is also up-regulated by insulin ( XREF_SUPPLEMENTARY ) and thus it is likely that both factors contribute to insulin induced INSR exon 11 inclusion .	We further found that MBNL1 is also up-regulated by insulin (XREF_SUPPLEMENTARY) and thus it is likely that both factors contribute to insulin induced INSR exon 11 inclusion.	21	26	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	23	24	25	26
Our study indicated that atorvastatin might inhibit IR induced by insulin through the TG lowering role of ApoAV .	Our study indicated that atorvastatin might inhibit IR induced by insulin through the TG lowering role of ApoAV.	6	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	10	11	7	8
Importantly , however , insulin stimulated the internalization of IR to a similar extent in both WT and LRP1KO hepatocytes under BSA and palmitate treated conditions .	Importantly, however, insulin stimulated the internalization of IR to a similar extent in both WT and LRP1KO hepatocytes under BSA and palmitate treated conditions.	4	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	9	10
The reason for the differential tall stature in overweight and obese prepubertal children is not fully known , but suggested mechanisms include : insulin stimulation of both the insulin receptor and the insulin like factor-I receptor [ XREF_BIBR ] , the stimulatory effects of leptin on the hypothalamic-pituitary-gonadal axis [ XREF_BIBR - XREF_BIBR ] , skeletal growth centers [ XREF_BIBR ] , and the activity of enzymes essential for the synthesis of adrenal androgens [ XREF_BIBR ] .	The reason for the differential tall stature in overweight and obese prepubertal children is not fully known, but suggested mechanisms include : insulin stimulation of both the insulin receptor and the insulin like factor-I receptor [XREF_BIBR], the stimulatory effects of leptin on the hypothalamic-pituitary-gonadal axis [XREF_BIBR - XREF_BIBR], skeletal growth centers [XREF_BIBR], and the activity of enzymes essential for the synthesis of adrenal androgens [XREF_BIBR].	23	30	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	23	24	28	30
The peptide sequences provide a range of substrates to facilitate the study , purification , and characterization of the insulin stimulated insulin receptor serine kinase or kinases , and the identification of a major site of insulin stimulated serine phosphorylation will help elucidate the function of the insulin receptor serine phosphorylation .	The peptide sequences provide a range of substrates to facilitate the study, purification, and characterization of the insulin stimulated insulin receptor serine kinase or kinases, and the identification of a major site of insulin stimulated serine phosphorylation will help elucidate the function of the insulin receptor serine phosphorylation.	11	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	19	20	21	23
COS7 cells were transiently transfected with insulin receptor or Y1158F and treated with insulin .	COS7 cells were transiently transfected with insulin receptor or Y1158F and treated with insulin.	6	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	6	8
Insulin activated IR ( WT ) , and not IR ( Delta43 ) , phosphorylated PDK-1 at tyrosines 9 , 373 , and 376 .	Insulin activated IR (WT), and not IR (Delta43), phosphorylated PDK-1 at tyrosines 9, 373, and 376.	0	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	2	3
Activation of Insr by insulin will normally initiate a cascade that involves activation of IRS and eventually PI3K , which mediate the intracellular actions of insulin .	Activation of Insr by insulin will normally initiate a cascade that involves activation of IRS and eventually PI3K, which mediate the intracellular actions of insulin.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Insr	Insr	Insr	4	5	2	3
Vertebrate insulin has earlier been shown to activate the Drosophila insulin receptor XREF_BIBR , and , based on the proposed cooperation between IDGF2 and insulin in stimulating imaginal disc cell growth , it has been suggested that IDGF2 might function as a cofactor of Drosophila insulin XREF_BIBR .	Vertebrate insulin has earlier been shown to activate the Drosophila insulin receptor XREF_BIBR, and, based on the proposed cooperation between IDGF2 and insulin in stimulating imaginal disc cell growth, it has been suggested that IDGF2 might function as a cofactor of Drosophila insulin XREF_BIBR.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	10	12
In the present study , we have shown that in normal human mammary epithelial cells insulin activates the canonical IR pathway to increase glucose uptake , and that oncogene over expression causes insulin-independence of transformed breast epithelial cells , in part by allowing for high level glucose uptake in the absence of insulin .	In the present study, we have shown that in normal human mammary epithelial cells insulin activates the canonical IR pathway to increase glucose uptake, and that oncogene over expression causes insulin-independence of transformed breast epithelial cells, in part by allowing for high level glucose uptake in the absence of insulin.	13	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	15	16	19	20
These results suggest that PTP-1B appears not only to interact with and dephosphorylate the insulin stimulated IR in a perinuclear endosome compartment but is also involved in maintaining the IR in a dephosphorylated state during its biosynthesis .	These results suggest that PTP-1B appears not only to interact with and dephosphorylate the insulin stimulated IR in a perinuclear endosome compartment but is also involved in maintaining the IR in a dephosphorylated state during its biosynthesis.	12	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	dephosphorylate the insulin	insulin	IR	IR	ir	14	15	16	17
These studies raise the possibility that major unidentified signaling nodes exist within the insulin signaling cascade , whose inhibition via the fatty acid and PKCtheta pathway triggers IR .	These studies raise the possibility that major unidentified signaling nodes exist within the insulin signaling cascade, whose inhibition via the fatty acid and PKCtheta pathway triggers IR.	13	28	triggers	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	27	28
The insulin induced IR reduction was greatly reversed by MG-132 , a proteasomal inhibitor , but not by chloroquine , a lysosomal inhibitor .	The insulin induced IR reduction was greatly reversed by MG-132, a proteasomal inhibitor, but not by chloroquine, a lysosomal inhibitor.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	1	2	3	4
Greater IR phosphorylation was observed in tumours from the mice treated with AspB10 insulin ( XREF_FIG ) than the other insulin analogues .	Greater IR phosphorylation was observed in tumours from the mice treated with AspB10 insulin (XREF_FIG) than the other insulin analogues.	1	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	1	2
Increased insulin concentration can cause peripheral IR by mediating its own signaling pathway through : ( 1 ) diminishing insulin receptors affinity and insulin receptor ' s kinase activity , ( 2 ) reducing the number of insulin receptors exposed on the cell surface by promoting internalization and degradation of hormone occupied receptors [ XREF_BIBR ] .	Increased insulin concentration can cause peripheral IR by mediating its own signaling pathway through : (1) diminishing insulin receptors affinity and insulin receptor 's kinase activity, (2) reducing the number of insulin receptors exposed on the cell surface by promoting internalization and degradation of hormone occupied receptors [XREF_BIBR].	1	7	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	1	2	6	7
IGF1R , INSR and IGF1R and INSR hybrid receptors are activated by both IGFs and insulin ligands , which exhibit different affinities for the various receptor types .	IGF1R, INSR and IGF1R and INSR hybrid receptors are activated by both IGFs and insulin ligands, which exhibit different affinities for the various receptor types.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	15	16	2	3
Insulin treatment activates the insulin receptor tyrosine kinase initiated by phosphorylation of insulin receptor substrate and followed by the association of SH2 containing proteins including PI3K .	Insulin treatment activates the insulin receptor tyrosine kinase initiated by phosphorylation of insulin receptor substrate and followed by the association of SH2 containing proteins including PI3K.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	4	6
Protein kinase C zeta ( PKC zeta ) plays an important role in insulin induced glycometabolism and insulin receptor ( IR ) associated signaling pathways .	Protein kinase C zeta (PKC zeta) plays an important role in insulin induced glycometabolism and insulin receptor (IR) associated signaling pathways.	11	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	17	19
Studies of antibodies that inhibit insulin activation of the INSR , including both spontaneously occurring human autoantibodies and mouse mAbs , have been reported .	Studies of antibodies that inhibit insulin activation of the INSR, including both spontaneously occurring human autoantibodies and mouse mAbs, have been reported.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	5	6	9	10
Our in vitro findings suggest that insulin may directly modulate skeletal growth by activating the insulin receptor directly at the growth plate .	Our in vitro findings suggest that insulin may directly modulate skeletal growth by activating the insulin receptor directly at the growth plate.	6	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	15	17
The G i -activating effect of C-terminal peptide 1325-1345 is supported by the data obtained later on direct interaction between insulin activated IR with G i2 protein and the blocking of this interaction by PT [ XREF_BIBR , XREF_BIBR ] .	The G i -activating effect of C-terminal peptide 1325-1345 is supported by the data obtained later on direct interaction between insulin activated IR with G i2 protein and the blocking of this interaction by PT [XREF_BIBR, XREF_BIBR].	18	26	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	20	21	22	23
Insulin increases the binding of PLCgamma1 to the activated IR in an SH2 domain independent manner .	Insulin increases the binding of PLCgamma1 to the activated IR in an SH2 domain independent manner.	0	13	increases	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	9	10
We found that insulin stimulation could cause InsR activation in LSKs ( XREF_FIG ) .	We found that insulin stimulation could cause InsR activation in LSKs (XREF_FIG).	3	8	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	InsR	InsR	InsR	3	4	7	8
Binding of insulin to its receptor ( IR ) activates the IR tyrosine kinase , which then phosphorylates IR substrates ( IRSs ) .	Binding of insulin to its receptor (IR) activates the IR tyrosine kinase, which then phosphorylates IR substrates (IRSs).	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	2	3	11	12
Taken together , these studies show that insulin stimulates THP-1 cell chemotaxis in a dose- and insulin receptor dependent manner .	Taken together, these studies show that insulin stimulates THP-1 cell chemotaxis in a dose- and insulin receptor dependent manner.	7	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	16	18
After binding to its receptor , insulin activates INSR tyrosine kinase activity and phosphorylates downstream signaling molecules that includes the insulin receptor substrate ( IRS ) family leading to glucose homeostasis and energy storage [ XREF_BIBR - XREF_BIBR ] .	After binding to its receptor, insulin activates INSR tyrosine kinase activity and phosphorylates downstream signaling molecules that includes the insulin receptor substrate (IRS) family leading to glucose homeostasis and energy storage [XREF_BIBR - XREF_BIBR].	6	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	6	7	8	9
This insulin induced insulin receptor trafficking was not affected by treatment of the cells with PI3-kinase inhibitor ( wortmannin ) , whereas treatment with MEK [ mitogen activated protein ( MAP ) kinase-Erk kinase ] inhibitor ( PD98059 ) partly inhibited the process in a dose dependent manner .	This insulin induced insulin receptor trafficking was not affected by treatment of the cells with PI3-kinase inhibitor (wortmannin), whereas treatment with MEK [mitogen activated protein (MAP) kinase-Erk kinase] inhibitor (PD98059) partly inhibited the process in a dose dependent manner.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	3	5
Insulin acting as a mitogen promotes neoplasm in the epithelial tissues through insulin receptor ( IR ) signalling .	Insulin acting as a mitogen promotes neoplasm in the epithelial tissues through insulin receptor (IR) signalling.	0	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	12	14
For example , miR-148a-5p , enriched in MetS-EVs may lead to downregulation of Thyroid Stimulating Hormone Receptor ( TSHR ) and Neuromedin B Receptor ( NMBR ) that modulate leptin expression , energy balance , and adiposity , and play a role in insulin induced insulin receptor activation [ XREF_BIBR ] .	For example, miR-148a-5p, enriched in MetS-EVs may lead to downregulation of Thyroid Stimulating Hormone Receptor (TSHR) and Neuromedin B Receptor (NMBR) that modulate leptin expression, energy balance, and adiposity, and play a role in insulin induced insulin receptor activation [XREF_BIBR].	41	47	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	43	44	45	47
These data suggested that the potentiation of insulin mediated INSR activation by XMetS also translated to an enhancement of downstream signaling .	These data suggested that the potentiation of insulin mediated INSR activation by XMetS also translated to an enhancement of downstream signaling.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	7	8	9	10
The insulin receptor ( IR ) is activated by insulin and plays a key role in the regulation of glucose homeostasis .	The insulin receptor (IR) is activated by insulin and plays a key role in the regulation of glucose homeostasis.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	1	3
The transcription of peroxisome proliferator activator receptor ( PPAR ) gamma and of the human insulin receptor gene was directly activated by calcitriol ; in vitro , vitamin D acceleration of glucose transport was mediated by insulin and vitamin D activated insulin receptor gene transcription [ XREF_BIBR - XREF_BIBR ] .	The transcription of peroxisome proliferator activator receptor (PPAR) gamma and of the human insulin receptor gene was directly activated by calcitriol; in vitro, vitamin D acceleration of glucose transport was mediated by insulin and vitamin D activated insulin receptor gene transcription [XREF_BIBR - XREF_BIBR].	34	46	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	36	37	41	43
Phosphorylation of serine 1078 of the insulin receptor to high stoichiometry by the kinase did not affect insulin stimulated exogenous protein tyrosine kinase activity of the insulin receptor .	Phosphorylation of serine 1078 of the insulin receptor to high stoichiometry by the kinase did not affect insulin stimulated exogenous protein tyrosine kinase activity of the insulin receptor.	16	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	17	18	26	28
In the central nervous system , intracerebroventricular insulin treatment activated hypothalamic InsR substrate-PI3K signaling [ XREF_BIBR ] .	In the central nervous system, intracerebroventricular insulin treatment activated hypothalamic InsR substrate-PI3K signaling [XREF_BIBR].	7	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	InsR	InsR	InsR	7	8	11	12
Although the cells transfected with the mutant receptor failed to respond to insulin mediated insulin receptor down-regulation , they were able to down-regulate their insulin like growth factor I receptors in response to insulin like growth factor I or high concentrations of insulin and were sensitive to monoclonal antibody induced down-regulation of their insulin receptors .	Although the cells transfected with the mutant receptor failed to respond to insulin mediated insulin receptor down-regulation, they were able to down-regulate their insulin like growth factor I receptors in response to insulin like growth factor I or high concentrations of insulin and were sensitive to monoclonal antibody induced down-regulation of their insulin receptors.	10	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	14	16
Also , inhibition was restricted to the IGF receptor , because IGFBP-3 failed to inhibit the tyrosine kinase activity of the insulin receptor stimulated by physiological concentrations of insulin .	Also, inhibition was restricted to the IGF receptor, because IGFBP-3 failed to inhibit the tyrosine kinase activity of the insulin receptor stimulated by physiological concentrations of insulin.	21	29	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	28	29	21	23
In contrast to the sensitizing effect of XMetS on insulin stimulation of the INSR , the antibody had no effect on enhancing IGF-1-mediated IGF-1R autophosphorylation .	In contrast to the sensitizing effect of XMetS on insulin stimulation of the INSR, the antibody had no effect on enhancing IGF-1-mediated IGF-1R autophosphorylation.	9	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	9	10	13	14
Thus , the above studies indicated that inhibition of insulin stimulated INSR activation by XMetD resulted in greatly diminished metabolic signal activation .	Thus, the above studies indicated that inhibition of insulin stimulated INSR activation by XMetD resulted in greatly diminished metabolic signal activation.	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	INSR	INSR	INSR	9	10	11	12
In addition , chronically treated , down-regulated cells demonstrated a significant decrease in the level of insulin receptor tyrosine phosphorylation compared to cells acutely treated with insulin .	In addition, chronically treated, down-regulated cells demonstrated a significant decrease in the level of insulin receptor tyrosine phosphorylation compared to cells acutely treated with insulin.	16	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	26	27	16	18
Insulin mediated suppression of hepatic glucose production is still preserved in IR , however , suppression of VLDL-TG secretion is less pronounced 4 , indicating a rise in TG which may represent an early manifestation of IR .	Insulin mediated suppression of hepatic glucose production is still preserved in IR, however, suppression of VLDL-TG secretion is less pronounced 4, indicating a rise in TG which may represent an early manifestation of IR.	0	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	11	12
The effects of adenosine deaminase on both insulin activation of insulin receptor kinase and insulin stimulation of 2-deoxyglucose transport were reversed by the addition of N6-phenylisopropyl-adenosine , a nonhydrolyzable adenosine analog .	The effects of adenosine deaminase on both insulin activation of insulin receptor kinase and insulin stimulation of 2-deoxyglucose transport were reversed by the addition of N6-phenylisopropyl-adenosine, a nonhydrolyzable adenosine analog.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	10	12
The initial study that characterized insulin signaling in Insr +/- Irs1 +/- mice demonstrated that heterozygosity for Insr and Irs1 genes caused reduced IR and IRS-1 protein expression in proportion to gene dosage in Insr +/- Irs1 +/- mice .	The initial study that characterized insulin signaling in Insr +/- Irs1 +/- mice demonstrated that heterozygosity for Insr and Irs1 genes caused reduced IR and IRS-1 protein expression in proportion to gene dosage in Insr +/- Irs1 +/- mice.	5	9	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Insr	Insr	Insr	5	6	8	9
Meanwhile , chronic exogenous GH may elevate serum glucose and insulin levels in vivo , and thus increase the risk of IR .	Meanwhile, chronic exogenous GH may elevate serum glucose and insulin levels in vivo, and thus increase the risk of IR.	4	22	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	GH may elevate serum glucose and insulin levels	insulin	IR	IR	ir	10	11	21	22
Higher concentrations of insulin are hypothesized to stimulate cell proliferation through increased production of bioavailable IGF-1 by activating target genes downstream of the insulin receptor , which comprise a signaling network that dictates cell growth , survival and proliferation .	Higher concentrations of insulin are hypothesized to stimulate cell proliferation through increased production of bioavailable IGF-1 by activating target genes downstream of the insulin receptor, which comprise a signaling network that dictates cell growth, survival and proliferation.	1	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	23	25
A sensitive microtiter well based assay for the measurement of insulin activation of insulin receptor kinase in intact human circulating mononuclear cells has been developed and characterized .	A sensitive microtiter well based assay for the measurement of insulin activation of insulin receptor kinase in intact human circulating mononuclear cells has been developed and characterized.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	13	15
The effect of insulin on cancer cells has furthermore been shown to activate an IR subtype ( IR-A ) that is expressed by fetal tissues and cancer cells .	The effect of insulin on cancer cells has furthermore been shown to activate an IR subtype (IR-A) that is expressed by fetal tissues and cancer cells.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	3	4	14	15
The mechanisms responsible for a lower insulin response to a post-exercise meal may include : 1 ) diminished insulin secretion due to high alpha-adrenergic tone , 2 ) improved insulin receptor activation by insulin in muscle and fat tissue following interval training , or 3 ) increased clearance of insulin from circulation by the liver , however , we found no difference in insulin sensitivity or beta-cell function in response to the mixed meal following either IntEx or ModEx .	The mechanisms responsible for a lower insulin response to a post-exercise meal may include : 1) diminished insulin secretion due to high alpha-adrenergic tone, 2) improved insulin receptor activation by insulin in muscle and fat tissue following interval training, or 3) increased clearance of insulin from circulation by the liver, however, we found no difference in insulin sensitivity or beta-cell function in response to the mixed meal following either IntEx or ModEx.	29	38	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	33	34	29	31
However , PKC activation did not alter insulin stimulated or basal amino acid transport even though PKC activation inhibited insulin stimulation of the insulin receptor tyrosine kinase .	However, PKC activation did not alter insulin stimulated or basal amino acid transport even though PKC activation inhibited insulin stimulation of the insulin receptor tyrosine kinase.	19	26	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	19	20	23	25
Insulin elicits its functions through binding to the IR , which exists in two isoforms , IR-A and IR-B , resulting from the alternative splicing of the IR gene .	Insulin elicits its functions through binding to the IR, which exists in two isoforms, IR-A and IR-B, resulting from the alternative splicing of the IR gene.	0	11	elicits	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	8	9
ENPP1 , an ectonucleotide pyrophosphatase phosphodiesterase , has a role in the insulin resistance by directly inhibiting insulin induced conformational changes of the insulin receptor , thereby affecting its activation and downstream signaling , which resulted in fasting hyper-insulinemia , a strong predictor for the subsequent development of obesity in children XREF_BIBR , XREF_BIBR .	ENPP1, an ectonucleotide pyrophosphatase phosphodiesterase, has a role in the insulin resistance by directly inhibiting insulin induced conformational changes of the insulin receptor, thereby affecting its activation and downstream signaling, which resulted in fasting hyper-insulinemia, a strong predictor for the subsequent development of obesity in children XREF_BIBR, XREF_BIBR.	17	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	17	18	23	25
Thus , MAD2 and BUBR1 are required for untimely IR internalization in cells with a compromised p31 comet function and for insulin triggered IR endocytosis .	Thus, MAD2 and BUBR1 are required for untimely IR internalization in cells with a compromised p31 comet function and for insulin triggered IR endocytosis.	20	24	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	21	22	23	24
The autophagy is turned on when insulin signaling activates an insulin receptor effector , called IRS-2 , which then turns on a PI3K .	The autophagy is turned on when insulin signaling activates an insulin receptor effector, called IRS-2, which then turns on a PI3K.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	10	12
Remarkably , whereas BMX deletion decreased insulin stimulated activation of InsR , these adaptations ( which also include increased abundance of InsR ) actually increased sensitivity to insulin in vitro and in vivo in Bmx - mice .	Remarkably, whereas BMX deletion decreased insulin stimulated activation of InsR, these adaptations (which also include increased abundance of InsR) actually increased sensitivity to insulin in vitro and in vivo in Bmx - mice.	5	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	InsR	InsR	InsR	6	7	10	11
Chronic insulin ( CI ) treatment of adipocytes and palmitic acid ( PAL ) exposure of myotubes were used to induce IR in the presence , or not , of LCn-3PUFA .	Chronic insulin (CI) treatment of adipocytes and palmitic acid (PAL) exposure of myotubes were used to induce IR in the presence, or not, of LCn-3PUFA.	1	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	1	2	21	22
However , in the presence of apoE4 , the internalization of IR did not approach plateau until 30 minutes and without obvious decline over time ( XREF_SUPPLEMENTARY ) , indicating that apoE4 inhibited insulin induced IR trafficking .	However, in the presence of apoE4, the internalization of IR did not approach plateau until 30 minutes and without obvious decline over time (XREF_SUPPLEMENTARY), indicating that apoE4 inhibited insulin induced IR trafficking.	33	36	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	33	34	35	36
Insulin activates the insulin receptor tyrosine kinase to phosphorylate signaling molecules such as insulin receptor substrate-1 ( IRS-1 ) .	Insulin activates the insulin receptor tyrosine kinase to phosphorylate signaling molecules such as insulin receptor substrate-1 (IRS-1).	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
The expression levels of IR and IGF-IR mRNA in Reh cells treated with insulin were obviously increased compared with the control group .	The expression levels of IR and IGF-IR mRNA in Reh cells treated with insulin were obviously increased compared with the control group.	4	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	4	5
It is noteworthy that betaCD treatment did not significantly change insulin induced activation , i.e ., autophosphorylation , of either A- or B-type insulin receptor ( unpublished data ) .	It is noteworthy that betaCD treatment did not significantly change insulin induced activation, i.e., autophosphorylation, of either A- or B-type insulin receptor (unpublished data).	10	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	23	25
Insulin receptor activation by insulin may also explain the suboptimal therapeutic benefit of monoclonal antibodies targeting IGF1R .	Insulin receptor activation by insulin may also explain the suboptimal therapeutic benefit of monoclonal antibodies targeting IGF1R.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Insulin receptor	Insulin receptor	Insulin receptor	4	5	0	2
Firstly , physiological doses of insulin , 0.1 and 1 nM , were able to activate the insulin receptor in sciatic nerve and hippocampus from control rats , leading to activation of AKT and phosphorylation ( deactivation ) of GSK3 within 15 min as it was shown for activation of hypothalamic PI3K .	Firstly, physiological doses of insulin, 0.1 and 1 nM, were able to activate the insulin receptor in sciatic nerve and hippocampus from control rats, leading to activation of AKT and phosphorylation (deactivation) of GSK3 within 15 min as it was shown for activation of hypothalamic PI3K.	3	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	17	19
While not directly answering that question , Stx6 knockdown in adipocytes inhibited the insulin stimulated re-exocytosis of Insulin Receptor Amino Peptidase ( IRAP ) that had been surface labeled and equilibrated with internal stores for 6h .	While not directly answering that question, Stx6 knockdown in adipocytes inhibited the insulin stimulated re-exocytosis of Insulin Receptor Amino Peptidase (IRAP) that had been surface labeled and equilibrated with internal stores for 6h.	11	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Insulin Receptor	Insulin Receptor	Insulin Receptor	13	14	17	19
Both insulin and sorbitol induced hyperosmotic shock increased intrinsic tyrosine kinase activity of insulin receptor ( IR ) followed by transient tyrosine phosphorylation of insulin-receptor substrate-1 ( IRS-1 ) and Cbl .	Both insulin and sorbitol induced hyperosmotic shock increased intrinsic tyrosine kinase activity of insulin receptor (IR) followed by transient tyrosine phosphorylation of insulin-receptor substrate-1 (IRS-1) and Cbl.	0	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	13	15
As insulin could stimulate proliferation of the hepatocytes and the effect might increase levels of betatrophin , we then detected betatrophin mRNA expression normalized to beta-actin in all these models and found that betatrophin expression was only increased in the IR model induced by insulin .	As insulin could stimulate proliferation of the hepatocytes and the effect might increase levels of betatrophin, we then detected betatrophin mRNA expression normalized to beta-actin in all these models and found that betatrophin expression was only increased in the IR model induced by insulin.	40	45	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	44	45	40	41
In animal models , treatment of type 2 diabetes mellitus rats with BBR lowered fasting blood glucose and fasting serum insulin , increased insulin sensitivity , and elevated InsR mRNA as well as PKC activity in the liver .	In animal models, treatment of type 2 diabetes mellitus rats with BBR lowered fasting blood glucose and fasting serum insulin, increased insulin sensitivity, and elevated InsR mRNA as well as PKC activity in the liver.	16	29	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	InsR	InsR	InsR	20	21	28	29
Further , IGF-1R downregulation sensitizes breast cancer cells to insulin action , MAB391 treatment results in a compensatory increase in InsR phosphorylation , and IGF-1R knockout can sensitize cells to insulin mediated activation of InsR , AKT , and MAPK .	Further, IGF-1R downregulation sensitizes breast cancer cells to insulin action, MAB391 treatment results in a compensatory increase in InsR phosphorylation, and IGF-1R knockout can sensitize cells to insulin mediated activation of InsR, AKT, and MAPK.	30	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	InsR	InsR	InsR	30	31	34	35
However , because of the low binding affinity of insulin to IGF-1R , physiological concentrations of insulin ( 100-500 pmol/L ) selectively activate IR to release NO and increase microvascular perfusion in vivo .	However, because of the low binding affinity of insulin to IGF-1R, physiological concentrations of insulin (100-500 pmol/L) selectively activate IR to release NO and increase microvascular perfusion in vivo.	14	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	16	17	23	24
We found an enrichment of loci associated with higher risk of both type 2 diabetes and coronary heart disease , including those encompassing the proximal insulin signalling INSR , IRS1 and PIK3R1 genes ( 11/53 loci associated with both diseases at p < 0.05 ; two tailed binomial probability of observing this proportion of loci by chance p = 8.5 x 10 -22 ; XREF_SUPPLEMENTARY ) .	We found an enrichment of loci associated with higher risk of both type 2 diabetes and coronary heart disease, including those encompassing the proximal insulin signalling INSR, IRS1 and PIK3R1 genes (11/53 loci associated with both diseases at p < 0.05; two tailed binomial probability of observing this proportion of loci by chance p = 8.5 x 10 -22; XREF_SUPPLEMENTARY).	25	32	signalling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	25	26	27	28
In addition , C ( 2 ) and C ( 6 ) ceramides , but not C ( 2 ) D ( inactive ) ceramide or vehicle , inhibited insulin stimulated signaling downstream of the IR and IRS-1 .	In addition, C (2) and C (6) ceramides, but not C (2) D (inactive) ceramide or vehicle, inhibited insulin stimulated signaling downstream of the IR and IRS-1.	28	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	29	30	35	36
Since the silencing of gC1qR by small RNA interference abolished adipogenesis and blocked insulin induced activation of insulin receptor , insulin receptor substrate-1 ( IRS-1 ) , Akt , and Erk1/2 , we can conclude that gC1qR is an essential molecule involved in adipogenesis and insulin signaling .	Since the silencing of gC1qR by small RNA interference abolished adipogenesis and blocked insulin induced activation of insulin receptor, insulin receptor substrate-1 (IRS-1), Akt, and Erk1/2, we can conclude that gC1qR is an essential molecule involved in adipogenesis and insulin signaling.	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	17	19
The PI3K/Akt/mTOR pathway has a critical role in insulin signaling and glucose homeostasis downstream of the insulin receptor .	The PI3K/Akt/mTOR pathway has a critical role in insulin signaling and glucose homeostasis downstream of the insulin receptor.	8	18	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	16	18
In beta-cells , FoxO1 is constitutively phosphorylated , and therefore cytoplasmic , presumably reflecting activation of insulin receptor signalling by endogenously produced insulin [ XREF_BIBR ] .	In beta-cells, FoxO1 is constitutively phosphorylated, and therefore cytoplasmic, presumably reflecting activation of insulin receptor signalling by endogenously produced insulin [XREF_BIBR].	16	23	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	22	23	16	18
The supraphysiological concentration of insulin used to routinely culture MCF10A cells causes activation of both the IR and IGF-IR XREF_BIBR .	The supraphysiological concentration of insulin used to routinely culture MCF10A cells causes activation of both the IR and IGF-IR XREF_BIBR.	2	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	4	5	16	17
It has been suggested that most of the effects observed in vitro with supraphysiological doses of insulin are mediated by IGF1R , XREF_BIBR but our data indicate that physiological concentrations of insulin in fact activate IR holoreceptors when IGF1R levels are low .	It has been suggested that most of the effects observed in vitro with supraphysiological doses of insulin are mediated by IGF1R, XREF_BIBR but our data indicate that physiological concentrations of insulin in fact activate IR holoreceptors when IGF1R levels are low.	29	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	31	32	35	36
This increase in insulin sensitivity was associated with an increase in insulin induced insulin receptor ( IR ) tyrosine phosphorylation and parallel decrease in IR serine phosphorylation and association with PTP1B .	This increase in insulin sensitivity was associated with an increase in insulin induced insulin receptor (IR) tyrosine phosphorylation and parallel decrease in IR serine phosphorylation and association with PTP1B.	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	13	15
When nutrient intake is sufficient , the insulin receptor on WAT is activated by insulin released from the pancreas , which leads to a dephosphorylation cascade and inactivation of hormone sensitive lipase ( HSL ) , favoring storage of triglycerides ( TGs ) in LDs .	When nutrient intake is sufficient, the insulin receptor on WAT is activated by insulin released from the pancreas, which leads to a dephosphorylation cascade and inactivation of hormone sensitive lipase (HSL), favoring storage of triglycerides (TGs) in LDs.	7	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	14	15	7	9
There are several causes of resistance to exogenous insulin that do not lead to IR , such as improper handling and administration of insulin .	There are several causes of resistance to exogenous insulin that do not lead to IR, such as improper handling and administration of insulin.	5	21	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	8	9	14	15
As shown previously a high-fat diet leads to net accumulation of DAG content in liver leading to activation of PKCepsilon and inhibition of insulin stimulated insulin receptor kinase activity and hepatic insulin resistance .	As shown previously a high-fat diet leads to net accumulation of DAG content in liver leading to activation of PKCepsilon and inhibition of insulin stimulated insulin receptor kinase activity and hepatic insulin resistance.	14	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	23	24	25	27
This fully human allosteric IgG2 monoclonal antibody acts as an allosteric inhibitor of insulin dependent activation of the insulin receptor ( XOMA Corporation ) .	This fully human allosteric IgG2 monoclonal antibody acts as an allosteric inhibitor of insulin dependent activation of the insulin receptor (XOMA Corporation).	13	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	18	20
We thus asked how the mTOR system responds to changes in IR activation induced by insulin .	We thus asked how the mTOR system responds to changes in IR activation induced by insulin.	11	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	15	16	11	12
The use of different beta-cell lines expressing or not the insulin receptor ( IR ( +/+ ) and IR (-/-) ) or with a reconstituted expression of IR isoform A or B ( Rec A and Rec B ) revealed that both phosphatidylinositol 3 , kinase , Akt , TSC , and mTOR complex 1 and MAPK kinase and ERK pathways mediate insulin signaling in IR ( +/+ )-, IRA-, or IRB expressing cells .	The use of different beta-cell lines expressing or not the insulin receptor (IR (+/+) and IR (-/-)) or with a reconstituted expression of IR isoform A or B (Rec A and Rec B) revealed that both phosphatidylinositol 3, kinase, Akt, TSC, and mTOR complex 1 and MAPK kinase and ERK pathways mediate insulin signaling in IR (+/+)-, IRA-, or IRB expressing cells.	62	69	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	62	63	65	66
We previously reported that the pharmacological inhibition and knockdown of glycogen synthase kinase-3 ( GSK-3 ) facilitates the insulin induced complex formation of human Grb14 ( hGrb14 ) and IR , suggesting that GSK-3 suppresses hGrb14 recruitment to IR .	We previously reported that the pharmacological inhibition and knockdown of glycogen synthase kinase-3 (GSK-3) facilitates the insulin induced complex formation of human Grb14 (hGrb14) and IR, suggesting that GSK-3 suppresses hGrb14 recruitment to IR.	16	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	18	19	29	30
Treatment of these extracts with an antibody to PC-1 significantly reduced their ability to inhibit insulin stimulated IR tyrosine kinase activity .	Treatment of these extracts with an antibody to PC-1 significantly reduced their ability to inhibit insulin stimulated IR tyrosine kinase activity.	14	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	15	16	17	18
Normally , distributed control of glucose uptake occurs via recruitment of the facilitative glucose transporter GLUT4 to the cell surface coupled to phosphorylation of the sugar by hexokinase II in response to insulin receptor activation by the insulin hormone .	Normally, distributed control of glucose uptake occurs via recruitment of the facilitative glucose transporter GLUT4 to the cell surface coupled to phosphorylation of the sugar by hexokinase II in response to insulin receptor activation by the insulin hormone.	32	38	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	37	38	32	34
There was no difference in insulin receptor kinase activity induced by insulin between TG and control rats ; however , insulin dependent insulin receptor substrate-2 tyrosine phosphorylation , glycogen synthase activation , and expression of enzymes that induce lipid synthesis were potentiated in hepatocytes of TG rats .	There was no difference in insulin receptor kinase activity induced by insulin between TG and control rats; however, insulin dependent insulin receptor substrate-2 tyrosine phosphorylation, glycogen synthase activation, and expression of enzymes that induce lipid synthesis were potentiated in hepatocytes of TG rats.	5	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	5	7
In this study we found that insulin signaling , through activation of the Ras-MAPK pathway , up-regulates the splicing factor SRSF1 and induces inclusion of INSR exon 11 to generate elevated levels of the INSR-B isoform ( XREF_FIG and XREF_FIG ) .	In this study we found that insulin signaling, through activation of the Ras-MAPK pathway, up-regulates the splicing factor SRSF1 and induces inclusion of INSR exon 11 to generate elevated levels of the INSR-B isoform (XREF_FIG and XREF_FIG).	6	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	6	7	25	26
Insulin receptor tyrosine kinase is stimulated by insulin in vivo , and this provides a mechanism by which the signal from insulin is transmitted into target cells .	Insulin receptor tyrosine kinase is stimulated by insulin in vivo, and this provides a mechanism by which the signal from insulin is transmitted into target cells.	0	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Insulin receptor	Insulin receptor	Insulin receptor	7	8	0	2
Insulin activates lipoprotein lipase ( LPL ) activity which in turn accelerates chylomicron degradation thus lowering TGs levels [ XREF_BIBR ] .	Insulin activates lipoprotein lipase (LPL) activity which in turn accelerates chylomicron degradation thus lowering TGs levels [XREF_BIBR].	0	4	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	2	4
Insulin and glucose infusion upregulate LPL activity in adipose tissue [ XREF_BIBR ] , whereas LPL activity at skeletal muscle can remain consistently high throughout the day [ XREF_BIBR ] .	Insulin and glucose infusion upregulate LPL activity in adipose tissue [XREF_BIBR], whereas LPL activity at skeletal muscle can remain consistently high throughout the day [XREF_BIBR].	0	6	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	5	6
Severe hypertriglyceridemia can be acutely treated with glucose insulin infusion , 6 or intravenous heparin infusion 7 as both insulin and heparin stimulate LPL activity .	Severe hypertriglyceridemia can be acutely treated with glucose insulin infusion, 6 or intravenous heparin infusion 7 as both insulin and heparin stimulate LPL activity.	18	24	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	19	20	23	24
LPL activity in primary cultures of cardiomyocytes from control rats is stimulated by the combination of insulin ( Ins ) and dexamethasone ( Dex ) .	LPL activity in primary cultures of cardiomyocytes from control rats is stimulated by the combination of insulin (Ins) and dexamethasone (Dex).	0	23	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	16	17	0	1
Increased insulin levels lead to activation of the enzyme lipoprotein lipase in adipose tissue , which in turn can lead to an increased clearance of lipoprotein particles and an inhibition of lipoprotein output from liver .	Increased insulin levels lead to activation of the enzyme lipoprotein lipase in adipose tissue, which in turn can lead to an increased clearance of lipoprotein particles and an inhibition of lipoprotein output from liver.	1	11	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	1	2	9	11
There was a slight reduction in LPL translation level in the deletion mutants compared to the LPL wild type and insulin treatment increased the LPL translation in wild type as shown in a representative of three repeated experiments in COS-1 cells ( XREF_FIG ) .	There was a slight reduction in LPL translation level in the deletion mutants compared to the LPL wild type and insulin treatment increased the LPL translation in wild type as shown in a representative of three repeated experiments in COS-1 cells (XREF_FIG).	20	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	20	21	24	25
Insulin , added the day after preparation , produced a dose dependent ( 1-400 ng/ml ) increase in lipoprotein lipase releasable from cells by heparin at 2 , 4 , and 24 h. Insulin also increased intracellular enzyme measured as deoxycholate-detergent-solubilized activity extracted from previously heparin released cells .	Insulin, added the day after preparation, produced a dose dependent (1-400 ng/ml) increase in lipoprotein lipase releasable from cells by heparin at 2, 4, and 24 h. Insulin also increased intracellular enzyme measured as deoxycholate-detergent-solubilized activity extracted from previously heparin released cells.	0	20	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	18	20
Under normal circumstances insulin activates the enzyme lipoprotein lipase which hydrolyses triacylglycerols .	Under normal circumstances insulin activates the enzyme lipoprotein lipase which hydrolyses triacylglycerols.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	7	9
Chylomicrone is mainly metabolized by LPL , which is activated by insulin signaling .	Chylomicrone is mainly metabolized by LPL, which is activated by insulin signaling.	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	11	12	5	6
Insulin significantly increased LPL activity in bovine but not in ovine adipose tissue , and it had no effect on G6PDH activity in the two species .	Insulin significantly increased LPL activity in bovine but not in ovine adipose tissue, and it had no effect on G6PDH activity in the two species.	0	4	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	3	4
Under normal conditions , insulin activates lipoprotein lipase which hydrolyzes triglycerides .	Under normal conditions, insulin activates lipoprotein lipase which hydrolyzes triglycerides.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	6	8
These results might be explained if the amelioration of insulin resistance increased LPL in adipose tissue .	These results might be explained if the amelioration of insulin resistance increased LPL in adipose tissue.	9	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	9	10	12	13
Insulin stimulates LPL activity and inhibits HSL activity .	Insulin stimulates LPL activity and inhibits HSL activity.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	2	3
Exogenous sources can be reduced by low-fat diets and fasting ; endogenous sources can be reduced by lipid lowering medications and limited alcohol intake [ XREF_BIBR , XREF_BIBR ] ; clearance can be promoted by insulin and heparin enhancement of lipoprotein lipase activity [ XREF_BIBR , XREF_BIBR ] , although heparin use remains controversial [ XREF_BIBR ] .	Exogenous sources can be reduced by low-fat diets and fasting; endogenous sources can be reduced by lipid lowering medications and limited alcohol intake [XREF_BIBR, XREF_BIBR]; clearance can be promoted by insulin and heparin enhancement of lipoprotein lipase activity [XREF_BIBR, XREF_BIBR], although heparin use remains controversial [XREF_BIBR].	35	42	enhancement	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	35	36	40	42
Heparin and insulin stimulate lipoprotein-lipase activity and accelerate chylomicron degradation .	Heparin and insulin stimulate lipoprotein-lipase activity and accelerate chylomicron degradation.	0	5	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein-lipase	lipoprotein-lipase	lipoprotein-lipase	2	3	4	5
Chronic ( 12-day ) insulin treatment of SHR-diabetic rats reduced the augmented heparin-releasable LPL activity and increased cell associated LPL activity .	Chronic (12-day) insulin treatment of SHR-diabetic rats reduced the augmented heparin-releasable LPL activity and increased cell associated LPL activity.	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	4	5	19	20
LPL activity is increased by insulin infusion which degrades TG rich chylomicrons and VLDL particles .	LPL activity is increased by insulin infusion which degrades TG rich chylomicrons and VLDL particles.	0	6	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	5	6	0	1
Thus , the greater insulin concentrations induced by three meals may be increasing adipose tissue lipoprotein lipase activity to a greater extent , thus promoting greater postprandial TAG clearance .	Thus, the greater insulin concentrations induced by three meals may be increasing adipose tissue lipoprotein lipase activity to a greater extent, thus promoting greater postprandial TAG clearance.	4	17	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	15	17
In differentiated 3T3-L1 adipocytes , GIP , in the presence of insulin , increased LPL activity and triglyceride accumulation through a pathway involving increased phosphorylation of protein kinase B ( PKB ) and reductions in phosphorylated LKB1 and AMP activated protein kinase ( AMPK ) .	In differentiated 3T3-L1 adipocytes, GIP, in the presence of insulin, increased LPL activity and triglyceride accumulation through a pathway involving increased phosphorylation of protein kinase B (PKB) and reductions in phosphorylated LKB1 and AMP activated protein kinase (AMPK).	9	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	11	12	14	15
Under normal circumstances , insulin activates the enzyme lipoprotein lipase , which hydrolyses triglycerides .	Under normal circumstances, insulin activates the enzyme lipoprotein lipase, which hydrolyses triglycerides.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	8	10
Heparin and insulin stimulate lipoprotein-lipase activity and accelerate chylomicron degradation [ XREF_BIBR ] .	Heparin and insulin stimulate lipoprotein-lipase activity and accelerate chylomicron degradation [XREF_BIBR].	0	5	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein-lipase	lipoprotein-lipase	lipoprotein-lipase	2	3	4	5
The normal insulin mediated stimulation of LPL activity has been shown to be blunted in insulin resistance .	The normal insulin mediated stimulation of LPL activity has been shown to be blunted in insulin resistance.	0	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	2	3	6	7
In type 2 DM , the relative insulin deficiency and decreased adiponectin causes decrease lipoprotein lipase activity resulting in high levels of low-density lipoprotein ( LDL ) , triglyceride and low levels of high-density lipoprotein ( HDL ) .	In type 2 DM, the relative insulin deficiency and decreased adiponectin causes decrease lipoprotein lipase activity resulting in high levels of low-density lipoprotein (LDL), triglyceride and low levels of high-density lipoprotein (HDL).	5	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	7	8	14	16
Inhibition of postprandial insulin , GIP and GLP-1 secretion acutely did not reduce post-heparin LPL activity either in lean or obese subjects .	Inhibition of postprandial insulin, GIP and GLP-1 secretion acutely did not reduce post-heparin LPL activity either in lean or obese subjects.	0	15	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	3	4	14	15
Under normal condition , insulin activates the enzyme lipoprotein lipase , which hydrolyses triglycerides .	Under normal condition, insulin activates the enzyme lipoprotein lipase, which hydrolyses triglycerides.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	8	10
Furthermore , the magnitude of the adipose LPL stimulation by insulin was not modulated by the endogenous serum T3 .	Furthermore, the magnitude of the adipose LPL stimulation by insulin was not modulated by the endogenous serum T3.	7	11	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	10	11	7	8
Sodium selenate ( selenate ) , as well as insulin , increased the lipoprotein lipase ( LPL ) activity in isolated rat fat pads in a time- and dose dependent manner .	Sodium selenate (selenate), as well as insulin, increased the lipoprotein lipase (LPL) activity in isolated rat fat pads in a time- and dose dependent manner.	1	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	9	10	13	15
Moreover , insulin is a potent activator of lipoprotein lipase , which enhances the catabolism of TG rich lipoproteins [ XREF_BIBR ] .	Moreover, insulin is a potent activator of lipoprotein lipase, which enhances the catabolism of TG rich lipoproteins [XREF_BIBR].	2	10	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	8	10
At diestrus and proestrus , LPL activity was increased with an increase in plasma insulin levels , suggesting that plasma insulin was the predominant up-regulator of LPL .	At diestrus and proestrus, LPL activity was increased with an increase in plasma insulin levels, suggesting that plasma insulin was the predominant up-regulator of LPL.	19	27	was the predominant up-regulator	Positive_activation_copula_1	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	20	21	26	27
Heparin stimulates the release of endothelial lipoprotein lipase into circulation , while insulin activates lipoprotein lipase , therefore increasing the clearance of chylomicrons from plasma .	Heparin stimulates the release of endothelial lipoprotein lipase into circulation, while insulin activates lipoprotein lipase, therefore increasing the clearance of chylomicrons from plasma.	12	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	12	13	14	16
Both high plasma glucose and high plasma insulin in the presence of normal glucose significantly increased LPL activity within 4 hours .	Both high plasma glucose and high plasma insulin in the presence of normal glucose significantly increased LPL activity within 4 hours.	3	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	7	8	16	17
XREF_BIBR Insulin activates lipoprotein lipase , while heparin leads to the release of endothelial lipoprotein lipases .	XREF_BIBR Insulin activates lipoprotein lipase, while heparin leads to the release of endothelial lipoprotein lipases.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	1	2	3	5
Under normal conditions , insulin activates the enzyme lipoprotein lipase and hydrolyzes triglycerides .	Under normal conditions, insulin activates the enzyme lipoprotein lipase and hydrolyzes triglycerides.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	8	10
Under postprandial conditions , insulin enhances LPL activity and triglyceride uptake in adipose tissue [ XREF_BIBR ] .	Under postprandial conditions, insulin enhances LPL activity and triglyceride uptake in adipose tissue [XREF_BIBR].	4	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	4	5	6	7
Importantly , insulin upregulates LPL activity in glial cells at the same time point where the lowest Angptl4 expression was detected , suggesting that Angptl4 may play a role in LPL activity in glial cells and perhaps in the interplay known to exist between glial cells and neurons XREF_BIBR .	Importantly, insulin upregulates LPL activity in glial cells at the same time point where the lowest Angptl4 expression was detected, suggesting that Angptl4 may play a role in LPL activity in glial cells and perhaps in the interplay known to exist between glial cells and neurons XREF_BIBR.	2	5	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	2	3	4	5
Importantly , IFN-gamma has been found to inhibit insulin mediated upregulation of fatty acid synthase ( FAS ) and lipoprotein lipase and was associated with a downregulation of phosphatidylinositol 3-kinase regulatory subunit alpha expression ( a key component of insulin signalling ) .	Importantly, IFN-gamma has been found to inhibit insulin mediated upregulation of fatty acid synthase (FAS) and lipoprotein lipase and was associated with a downregulation of phosphatidylinositol 3-kinase regulatory subunit alpha expression (a key component of insulin signalling).	7	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	8	9	19	21
Insulin is an important activator of the lipoprotein lipase , an enzyme found on capillary walls responsible for lipid hydrolysis and degradation and involved in the depuration of triacylglycerol .	Insulin is an important activator of the lipoprotein lipase, an enzyme found on capillary walls responsible for lipid hydrolysis and degradation and involved in the depuration of triacylglycerol.	0	9	is an important activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	7	9
In addition , insulin increased lipoprotein lipase mass associated with cell membranes and decreased that in the incubation medium , whereas isoproterenol induced a decrease in both cell membranes and medium .	In addition, insulin increased lipoprotein lipase mass associated with cell membranes and decreased that in the incubation medium, whereas isoproterenol induced a decrease in both cell membranes and medium.	3	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	5	7
We have suggested that the differential effects of fructose and glucose on regional adipose deposition may be explained in part by the increased sensitivity of SAT relative to VAT to insulin stimulated lipoprotein lipase ( LPL ) activation [ XREF_BIBR ] , and by our reported observations that insulin responses were decreased in subjects consuming fructose and increased in subjects consuming glucose [ XREF_BIBR ] .	We have suggested that the differential effects of fructose and glucose on regional adipose deposition may be explained in part by the increased sensitivity of SAT relative to VAT to insulin stimulated lipoprotein lipase (LPL) activation [XREF_BIBR], and by our reported observations that insulin responses were decreased in subjects consuming fructose and increased in subjects consuming glucose [XREF_BIBR].	28	34	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	30	31	32	34
The acute effect of fat feeding on the insulin mediated stimulatory response of adipose tissue lipoprotein lipase ( ATLPL ) was examined in normal-weight subjects .	The acute effect of fat feeding on the insulin mediated stimulatory response of adipose tissue lipoprotein lipase (ATLPL) was examined in normal-weight subjects.	5	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	8	9	15	17
Insulin increases the levels of LPL mRNA and LPL activity in abdominal SAT but not VAT XREF_BIBR , XREF_BIBR .	Insulin increases the levels of LPL mRNA and LPL activity in abdominal SAT but not VAT XREF_BIBR, XREF_BIBR.	0	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	5	6
XREF_BIBR Insulin resistance alters the ability of insulin to activate LPL .	XREF_BIBR Insulin resistance alters the ability of insulin to activate LPL.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	1	2	10	11
The insulin stimulation of LPL activity in adipocytes from septic rats appears to be mediated by an increase in LPL synthesis .	The insulin stimulation of LPL activity in adipocytes from septic rats appears to be mediated by an increase in LPL synthesis.	1	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	1	2	4	5
The physiologic insulin mediated stimulation of LPL activity within skeletal muscle and adipose tissue is also altered in obese subjects with insulin-resistance [ XREF_BIBR , XREF_BIBR ] .	The physiologic insulin mediated stimulation of LPL activity within skeletal muscle and adipose tissue is also altered in obese subjects with insulin-resistance [XREF_BIBR, XREF_BIBR].	0	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	2	3	6	7
Isoproterenol , a beta-adrenergic agonist , decreases LPL enzyme activity , whereas insulin increases LPL activity .	Isoproterenol, a beta-adrenergic agonist, decreases LPL enzyme activity, whereas insulin increases LPL activity.	12	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	12	13	14	15
LPL in adipocytes is activated by insulin .	LPL in adipocytes is activated by insulin.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	6	7	0	1
Insulin like growth factor-I therapy decreases and insulin therapy increases LPL activity in adipose tissue of hypophysectomized rats , whereas these therapies have no effect on LPL activity in muscle tissue .	Insulin like growth factor-I therapy decreases and insulin therapy increases LPL activity in adipose tissue of hypophysectomized rats, whereas these therapies have no effect on LPL activity in muscle tissue.	7	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	7	8	10	11
Insulin stimulated adipose LPL in the Tx-diabetic group .	Insulin stimulated adipose LPL in the Tx-diabetic group.	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	3	4
Since CET is activated by insulin sensitive lipoprotein lipase ( LPL ) , which normally increases postprandially , we queried whether iatrogenic hyperinsulinism from ISC stimulated LPL and CET by studying well controlled IDDM patients after ISC and then 6 months after lowering systemic insulin levels by intraperitoneal ( IP ) insulin delivery .	Since CET is activated by insulin sensitive lipoprotein lipase (LPL), which normally increases postprandially, we queried whether iatrogenic hyperinsulinism from ISC stimulated LPL and CET by studying well controlled IDDM patients after ISC and then 6 months after lowering systemic insulin levels by intraperitoneal (IP) insulin delivery.	3	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	5	6	7	9
Adipocyte derived LPL is essential for efficient fatty acid uptake and storage , and insulin triggers PI3K mediated induction of LPL activity .	Adipocyte derived LPL is essential for efficient fatty acid uptake and storage, and insulin triggers PI3K mediated induction of LPL activity.	14	21	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	14	15	20	21
The maximum activity of LPL induced by insulin or insulin plus dexamethasone was higher in the SQ than in the OM depot of women , and this was associated with higher levels of LPL mRNA .	The maximum activity of LPL induced by insulin or insulin plus dexamethasone was higher in the SQ than in the OM depot of women, and this was associated with higher levels of LPL mRNA.	2	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	7	8	4	5
The insulin stimulation of LPL activity during sepsis could not be attributed to insulin like growth factor-I ( IGF-I ) as adipocytes from septic rats appeared to be IGF-I resistant .	The insulin stimulation of LPL activity during sepsis could not be attributed to insulin like growth factor-I (IGF-I) as adipocytes from septic rats appeared to be IGF-I resistant.	1	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	1	2	4	5
Because the anti-lipolytic action and the stimulation of lipoprotein lipase by insulin , resistance to this hormone contributes to the increase in lipolysis and in serum NEFA concentrations .	Because the anti-lipolytic action and the stimulation of lipoprotein lipase by insulin, resistance to this hormone contributes to the increase in lipolysis and in serum NEFA concentrations.	6	12	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	11	12	8	10
The rise of plasma NEFA was probably related to the marked removal of plasma triglycerides , by insulin activation of lipoprotein lipase , and consequent saturation of the pathways of fatty acid incorporation into adipose tissue .	The rise of plasma NEFA was probably related to the marked removal of plasma triglycerides, by insulin activation of lipoprotein lipase, and consequent saturation of the pathways of fatty acid incorporation into adipose tissue.	17	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	17	18	20	22
Under normal circumstances insulin activated enzyme lipoprotein lipase and hydrolyses triglycerides .	Under normal circumstances insulin activated enzyme lipoprotein lipase and hydrolyses triglycerides.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	6	8
Heparin and insulin are known to stimulate lipoprotein lipase activity [ XREF_BIBR - XREF_BIBR ] .	Heparin and insulin are known to stimulate lipoprotein lipase activity [XREF_BIBR - XREF_BIBR].	0	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	7	9
Adipose lipoprotein lipase ( LPL ) activity per pad or per fat cell was increased by insulin .	Adipose lipoprotein lipase (LPL) activity per pad or per fat cell was increased by insulin.	1	17	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	16	17	1	3
Thus , insulin appears to stimulate adipose tissue lipoprotein lipase activity in humans .	Thus, insulin appears to stimulate adipose tissue lipoprotein lipase activity in humans.	2	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	8	10
ICV insulin augments adipocyte size , fat mass and adipose lipoprotein lipase expression [ XREF_BIBR ] .	ICV insulin augments adipocyte size, fat mass and adipose lipoprotein lipase expression [XREF_BIBR].	0	14	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	1	2	10	12
Additionally , 1 wk of insulin treatment increased LPL secretion by macrophages , but to only one-half of control , while normalizing adipose tissue LPL activity .	Additionally, 1 wk of insulin treatment increased LPL secretion by macrophages, but to only one-half of control, while normalizing adipose tissue LPL activity.	5	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	5	6	8	9
Insulin from 10 (-11) M to 10 (-9) M was able to modulate the rate of LPL secretion from 2- to 4-fold .	Insulin from 10 (-11) M to 10 (-9) M was able to modulate the rate of LPL secretion from 2- to 4-fold.	0	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	16	17
These results do not support the involvement of cyclic GMP in the insulin stimulation of lipoprotein lipase in adipose tissue .	These results do not support the involvement of cyclic GMP in the insulin stimulation of lipoprotein lipase in adipose tissue.	12	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	12	13	15	17
GIP is known to target adipose tissue and stimulate lipoprotein lipase , lipogenesis , fatty acid and glucose uptake , insulin induced fatty acid incorporation whilst inhibiting glucagon and adrenergic receptor mediated lipolysis XREF_BIBR , XREF_BIBR , XREF_BIBR .	GIP is known to target adipose tissue and stimulate lipoprotein lipase, lipogenesis, fatty acid and glucose uptake, insulin induced fatty acid incorporation whilst inhibiting glucagon and adrenergic receptor mediated lipolysis XREF_BIBR, XREF_BIBR, XREF_BIBR.	9	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	20	21	9	11
Insulin stimulates LPL and inhibits HSL ; the opposite is true for catecholamines .	Insulin stimulates LPL and inhibits HSL; the opposite is true for catecholamines.	0	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	2	3
Interestingly , insulin exposure either together or after exposure to BPA considerably increased the cellular content of triacylglycerol , lipoprotein lipase and glycerol-3-phosphate dehydrogenase in comparison to insulin alone [ XREF_BIBR ] .	Interestingly, insulin exposure either together or after exposure to BPA considerably increased the cellular content of triacylglycerol, lipoprotein lipase and glycerol-3-phosphate dehydrogenase in comparison to insulin alone [XREF_BIBR].	2	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	19	21
Whereas insulin stimulates LPL by increasing the level of LPL mRNA , glucose stimulates LPL translation and post-translational processing .	Whereas insulin stimulates LPL by increasing the level of LPL mRNA, glucose stimulates LPL translation and post-translational processing.	1	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	1	2	3	4
Thus , insulin enhanced the activation of lipoprotein lipase and promoted the synthesis of adipocytes .	Thus, insulin enhanced the activation of lipoprotein lipase and promoted the synthesis of adipocytes.	2	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	7	9
Insulin potentiates lipoprotein lipase ' s ( LPL ) ability to degrade chylomicrons that house triglycerides , whereas heparin stimulates release of LPL from the endothelial membrane .	Insulin potentiates lipoprotein lipase 's (LPL) ability to degrade chylomicrons that house triglycerides, whereas heparin stimulates release of LPL from the endothelial membrane.	0	5	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	2	4
There is resistance to insulin stimulation of LPL ; however , LPL activity in fasted obese subjects is increased and remains so following weight reduction .	There is resistance to insulin stimulation of LPL; however, LPL activity in fasted obese subjects is increased and remains so following weight reduction.	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	4	5	7	8
[ XREF_BIBR ] It is proposed that insulin increases lipoprotein lipase activity which degrades chylomicrons thus reducing serum triglycerides .	[XREF_BIBR] It is proposed that insulin increases lipoprotein lipase activity which degrades chylomicrons thus reducing serum triglycerides.	7	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	7	8	9	11
Preincubation of isolated rat adipose cells with wortmannin completely abrogated the stimulation of LPL activity by insulin , while preincubation with rapamycin caused approximately a 60 % inhibition of insulin stimulated LPL activity .	Preincubation of isolated rat adipose cells with wortmannin completely abrogated the stimulation of LPL activity by insulin, while preincubation with rapamycin caused approximately a 60% inhibition of insulin stimulated LPL activity.	27	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	29	30	31	32
As insulin concentrations were not significantly different across conditions post-lunch , this suggests the reduction in plasma triglyceride concentration was not mediated by insulin stimulated lipoprotein lipase activity .	As insulin concentrations were not significantly different across conditions post-lunch, this suggests the reduction in plasma triglyceride concentration was not mediated by insulin stimulated lipoprotein lipase activity.	21	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	23	24	25	27
Moreover , adipose tissue LPL was restored to normal by insulin supplementation ( from 460 +/- 60 to 860 +/- 150 mU per total epididymal fat in U and U+ rats , respectively ) .	Moreover, adipose tissue LPL was restored to normal by insulin supplementation (from 460 +/- 60 to 860 +/- 150 mU per total epididymal fat in U and U+ rats, respectively).	2	11	restored	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	10	11	4	5
Insulin is a potent stimulator of adipose tissue lipoprotein lipase ( LPL ) .	Insulin is a potent stimulator of adipose tissue lipoprotein lipase (LPL).	0	10	is a potent stimulator	Positive_activation_copula_1	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	8	10
Even in an insulin resistant state , insulin is able to stimulate fatty acid synthesis in liver , activate lipoprotein lipase , and prevent lipolysis in adipose tissues , which all facilitate adipose tissue enlargement .	Even in an insulin resistant state, insulin is able to stimulate fatty acid synthesis in liver, activate lipoprotein lipase, and prevent lipolysis in adipose tissues, which all facilitate adipose tissue enlargement.	7	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	7	8	19	21
Insulin also stimulates adipose lipoprotein lipase , which would increase the supply of fatty acids for esterification in adipose tissue .	Insulin also stimulates adipose lipoprotein lipase, which would increase the supply of fatty acids for esterification in adipose tissue.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	4	6
Activation of PPARgamma2 and LPL increases insulin sensitivity XREF_BIBR and lowers serum triglycerides XREF_BIBR , respectively .	Activation of PPARgamma2 and LPL increases insulin sensitivity XREF_BIBR and lowers serum triglycerides XREF_BIBR, respectively.	0	7	increases	Positive_activation_token_1_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	6	7	4	5
Insulin treatment is often considered helpful in lowering SHTG , because insulin activates LPL leading to an acceleration of chylomicron degradation .	Insulin treatment is often considered helpful in lowering SHTG, because insulin activates LPL leading to an acceleration of chylomicron degradation.	11	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	11	12	13	14
The mechanism of action behind this form of treatment suggests that insulin increases lipoprotein lipase ( LPL ) activity which can degrade chylomicrons and thus reduce serum triglycerides [ XREF_BIBR ] .	The mechanism of action behind this form of treatment suggests that insulin increases lipoprotein lipase (LPL) activity which can degrade chylomicrons and thus reduce serum triglycerides [XREF_BIBR].	11	15	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	11	12	13	15
One injection of insulin also increased LPL secretion by macrophages to one-half of control and normalized adipose tissue LPL activity , even though plasma glucose and triglyceride levels were not affected .	One injection of insulin also increased LPL secretion by macrophages to one-half of control and normalized adipose tissue LPL activity, even though plasma glucose and triglyceride levels were not affected.	1	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	3	4	6	7
Insulin and glucose dependent insulinotropic polypeptide caused a significant stimulation of lipoprotein lipase activity over a dose range of 0.25-4 nmol/L and 4-8 nmol/L , respectively .	Insulin and glucose dependent insulinotropic polypeptide caused a significant stimulation of lipoprotein lipase activity over a dose range of 0.25-4 nmol/L and 4-8 nmol/L, respectively.	0	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	11	13
Our experiments on LPL translation ( XREF_FIG ) show that insulin treatment increased LPL translation of the wild type construct , but not those constructs containing 5 bp or 19 bp deletions , suggesting that insulin regulation via IRE is at the level of protein translation as well as LPL mRNA expression .	Our experiments on LPL translation (XREF_FIG) show that insulin treatment increased LPL translation of the wild type construct, but not those constructs containing 5 bp or 19 bp deletions, suggesting that insulin regulation via IRE is at the level of protein translation as well as LPL mRNA expression.	10	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	10	11	13	14
The patient exhibited insulin resistance , carbohydrate intolerance , striking fasting- and glucose stimulated hyperinsulinemia , hyperglucagonemia , type V hyperlipoproteinemia , and lipoprotein lipase deficiency on a normal diet .	The patient exhibited insulin resistance, carbohydrate intolerance, striking fasting- and glucose stimulated hyperinsulinemia, hyperglucagonemia, type V hyperlipoproteinemia, and lipoprotein lipase deficiency on a normal diet.	3	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	23	25
The pathophysiology of mTOR inhibitors causing dyslipidemia may involve the impaired clearance of lipids from the bloodstream via stimulation of insulin stimulated lipoprotein lipase ( LPL ) XREF_BIBR , XREF_BIBR .	The pathophysiology of mTOR inhibitors causing dyslipidemia may involve the impaired clearance of lipids from the bloodstream via stimulation of insulin stimulated lipoprotein lipase (LPL) XREF_BIBR, XREF_BIBR.	18	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	20	21	22	24
Perilipin 1 , G0S2 and lipoprotein lipase were increased by high insulin .	Perilipin 1, G0S2 and lipoprotein lipase were increased by high insulin.	5	12	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	11	12	5	7
IGF-I and a high insulin concentration ( 70 nM ) stimulated only the heparin-releasable ( HR ) component of LPL activity and immunoreactive mass , and neither IGF-I nor insulin affected LPL specific activity .	IGF-I and a high insulin concentration (70 nM) stimulated only the heparin-releasable (HR) component of LPL activity and immunoreactive mass, and neither IGF-I nor insulin affected LPL specific activity.	4	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	4	5	19	20
Angptl4 independent mechanisms in the regulation of LPL activity are suggested further by the observation that insulin deficiency alone ( STZ mice ) could increase LPL activity independently of normal or diminished expression of Angptl4 XREF_BIBR .	Angptl4 independent mechanisms in the regulation of LPL activity are suggested further by the observation that insulin deficiency alone (STZ mice) could increase LPL activity independently of normal or diminished expression of Angptl4 XREF_BIBR.	16	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	16	17	25	26
A previous study showed that insulin activates lipoprotein lipase and hydrolyzes normal conditions .	A previous study showed that insulin activates lipoprotein lipase and hydrolyzes normal conditions.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	5	6	7	9
In isolated rat adipocytes , inhibition of PI3K completely blocks the stimulation of LPL activity by insulin , while inhibition of mTOR partially inhibits insulin stimulated LPL activity [ XREF_BIBR ] .	In isolated rat adipocytes, inhibition of PI3K completely blocks the stimulation of LPL activity by insulin, while inhibition of mTOR partially inhibits insulin stimulated LPL activity [XREF_BIBR].	23	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	24	25	26	27
Insulin stimulates LPL , and a significantly higher acute insulin response to glucose challenge has been observed in AA compared to EA individuals , even after adjustment for obesity , body fat distribution , and behavioral factors [ XREF_BIBR ] .	Insulin stimulates LPL, and a significantly higher acute insulin response to glucose challenge has been observed in AA compared to EA individuals, even after adjustment for obesity, body fat distribution, and behavioral factors [XREF_BIBR].	0	3	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	2	3
The data indicate that intensive insulin therapy induces antiatherogenic changes in serum lipids and lipoproteins and suggest that the induction of LPL by insulin is the major factor responsible for redistribution of HDL particles from HDL3 to HDL2 .	The data indicate that intensive insulin therapy induces antiatherogenic changes in serum lipids and lipoproteins and suggest that the induction of LPL by insulin is the major factor responsible for redistribution of HDL particles from HDL3 to HDL2.	19	24	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	23	24	21	22
During feasting , increased insulin activates LPL to promote adipogenesis .	During feasting, increased insulin activates LPL to promote adipogenesis.	3	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	4	5	6	7
The results suggest that dexamethasone , in the presence of insulin , may specifically induce lipoprotein lipase synthesis in adipose tissue .	The results suggest that dexamethasone, in the presence of insulin, may specifically induce lipoprotein lipase synthesis in adipose tissue.	8	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	10	11	15	17
The liver is known to be involved in the uptake and metabolism of free fatty acids as well as synthesis of cholesterol , triglycerides , and phospholipids ; triglycerides are hydrolyzed by the lipoprotein lipase which is activated by insulin [ XREF_BIBR ] .	The liver is known to be involved in the uptake and metabolism of free fatty acids as well as synthesis of cholesterol, triglycerides, and phospholipids; triglycerides are hydrolyzed by the lipoprotein lipase which is activated by insulin [XREF_BIBR].	33	41	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	39	40	33	35
Lipoprotein lipase ( LPL ) activity in cultured ventricular cardiomyocytes from adult rat hearts was stimulated by the combination of insulin ( 100 nM ) and dexamethasone ( 100 nM ) during an overnight ( 16 h ) incubation .	Lipoprotein lipase (LPL) activity in cultured ventricular cardiomyocytes from adult rat hearts was stimulated by the combination of insulin (100 nM) and dexamethasone (100 nM) during an overnight (16 h) incubation.	0	29	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Lipoprotein lipase	Lipoprotein lipase	Lipoprotein lipase	20	21	0	2
Refeeding after prolonged fasting activates the P-adrenergic pathway in lean rats , which transiently counteracts insulin mediated modulation of lipoprotein lipase .	Refeeding after prolonged fasting activates the P-adrenergic pathway in lean rats, which transiently counteracts insulin mediated modulation of lipoprotein lipase.	14	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	15	16	19	21
While insulin administration stimulated LPL activity of adipose tissue 3h after injection , no response was observed in red or white muscles .	While insulin administration stimulated LPL activity of adipose tissue 3h after injection, no response was observed in red or white muscles.	1	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	1	2	4	5
Insulin increases the activity of lipoprotein lipase in adipose tissue and reduces the activity of hormone sensitive lipase , which is a lipolytic enzyme .	Insulin increases the activity of lipoprotein lipase in adipose tissue and reduces the activity of hormone sensitive lipase, which is a lipolytic enzyme.	0	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	5	7
Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms XREF_BIBR , XREF_BIBR .	Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms XREF_BIBR, XREF_BIBR.	15	26	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	15	16	22	23
At a maximal dose , insulin increased heparin-releasable and total LPL activity ( approximately 7-fold ) by specifically increasing the rate of LPL synthesis ( approximately 5-fold ) determined by pulse labeling with [ 35S ] methionine and [ 35S ] cysteine and immunoprecipitation .	At a maximal dose, insulin increased heparin-releasable and total LPL activity (approximately 7-fold) by specifically increasing the rate of LPL synthesis (approximately 5-fold) determined by pulse labeling with [35S] methionine and [35S] cysteine and immunoprecipitation.	5	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	5	6	10	11
Since insulin is an activator of LPL , it has been suggested that the diminution of LPL activity may be due to a relative insulin deficiency and/or insulin resistance .	Since insulin is an activator of LPL, it has been suggested that the diminution of LPL activity may be due to a relative insulin deficiency and/or insulin resistance.	1	7	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	1	2	6	7
Interestingly , insulin stimulated LPL activity both intrinsic and in the media from glial cells after 6h was significantly increased ( XREF_FIG F , Supplementary Figure1D ) , at the same time point , where mRNA expression of Angptl4 was at its lowest .	Interestingly, insulin stimulated LPL activity both intrinsic and in the media from glial cells after 6h was significantly increased (XREF_FIG F, Supplementary Figure1D), at the same time point, where mRNA expression of Angptl4 was at its lowest.	2	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	2	3	4	5
Insulin , which does not affect LPL gene transcription , increases LPL enzyme activity and steady state mRNA levels .	Insulin, which does not affect LPL gene transcription, increases LPL enzyme activity and steady state mRNA levels.	0	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin, which does not affect LPL gene transcription	insulin	LPL	LPL	lpl	0	1	11	12
As insulin stimulates LPL , the higher acute insulin response to glucose seen in AA may be another part of this story .	As insulin stimulates LPL, the higher acute insulin response to glucose seen in AA may be another part of this story.	1	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	1	2	3	4
Insulin is a potent activator of the lipoprotein lipase , promoting the catabolism of triglyceride rich lipoproteins ( Chylomicrons , VLDL ) .	Insulin is a potent activator of the lipoprotein lipase, promoting the catabolism of triglyceride rich lipoproteins (Chylomicrons, VLDL).	0	9	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	7	9
These findings suggest that insulin stimulates the secretion of active lipoprotein lipase and a reuptake of inactive secreted enzyme , and isoproterenol decreases the activity by enzyme degradation .	These findings suggest that insulin stimulates the secretion of active lipoprotein lipase and a reuptake of inactive secreted enzyme, and isoproterenol decreases the activity by enzyme degradation.	4	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	10	12
The PI3K and mTOR pathway has previously been implicated in the insulin mediated increase in LPL activity in adipocytes XREF_BIBR , and our studies extend this to transcriptional inhibition through Sp1 and Sp3 .	The PI3K and mTOR pathway has previously been implicated in the insulin mediated increase in LPL activity in adipocytes XREF_BIBR, and our studies extend this to transcriptional inhibition through Sp1 and Sp3.	11	16	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	11	12	15	16
At the adipocyte level cortisol and insulin promote lipid accumulation by expressing lipoprotein lipase activity , while T , GH and probably estrogens exert opposite effects .	At the adipocyte level cortisol and insulin promote lipid accumulation by expressing lipoprotein lipase activity, while T, GH and probably estrogens exert opposite effects.	4	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	7	12	14
Replacement of insulin ( 24 h ) in insulin deficient rats decreased 14CO2 production , increased the uptake of [ 14C ] lipid into the mammary gland and tended to increase total lipoprotein lipase activity .	Replacement of insulin (24 h) in insulin deficient rats decreased 14CO2 production, increased the uptake of [14C] lipid into the mammary gland and tended to increase total lipoprotein lipase activity.	0	34	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	32	34
As mentioned , insulin stimulates LPL activity , and insulin resistance is thought to depress LPL activity [ XREF_BIBR , XREF_BIBR ] , one of the mechanisms through which insulin resistance is thought to lead to increased TG .	As mentioned, insulin stimulates LPL activity, and insulin resistance is thought to depress LPL activity [XREF_BIBR, XREF_BIBR], one of the mechanisms through which insulin resistance is thought to lead to increased TG.	3	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	3	4	5	6
[ XREF_BIBR ] It is well known that insulin activates enzyme lipoprotein lipase , which hydrolyzes triglyceride under normal conditions .	[XREF_BIBR] It is well known that insulin activates enzyme lipoprotein lipase, which hydrolyzes triglyceride under normal conditions.	8	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	8	9	11	13
Insulin deficiency leads to fall in lipoprotein lipase activity .	Insulin deficiency leads to fall in lipoprotein lipase activity.	0	8	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	6	8
Under usual metabolic conditions , insulin induces lipoprotein lipase , which is the enzyme that hydrolyses triglycerides to produce glycerol and fatty acids .	Under usual metabolic conditions, insulin induces lipoprotein lipase, which is the enzyme that hydrolyses triglycerides to produce glycerol and fatty acids.	5	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	5	6	7	9
It has been suggested that insulin increases the stability of Lpl mRNA and the activity of Lpl in mouse 3T3-L1 adipocytes and human primary pre-adipocytes [ XREF_BIBR ] .	It has been suggested that insulin increases the stability of Lpl mRNA and the activity of Lpl in mouse 3T3-L1 adipocytes and human primary pre-adipocytes [XREF_BIBR].	5	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Lpl	Lpl	Lpl	5	6	10	11
Normally , triglycerides are hydrolyzed by the enzyme lipoprotein lipase which is activated by insulin .	Normally, triglycerides are hydrolyzed by the enzyme lipoprotein lipase which is activated by insulin.	8	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	14	15	8	10
The inverse relationship between insulin stimulated adipose tissue lipoprotein lipase activity and basal enzyme activity suggests that adipose tissue itself is the main regulator of the lipase response to insulin .	The inverse relationship between insulin stimulated adipose tissue lipoprotein lipase activity and basal enzyme activity suggests that adipose tissue itself is the main regulator of the lipase response to insulin.	2	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	8	10
Under normal circumstances insulin activates lipoprotein lipase enzyme and hydrolyses triglycerides .	Under normal circumstances insulin activates lipoprotein lipase enzyme and hydrolyses triglycerides.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	5	7
Dexamethasone added in the presence of insulin increased heparin-releasable and total LPL activity approximately 8-fold but did not alter rates of LPL synthesis compared with insulin alone .	Dexamethasone added in the presence of insulin increased heparin-releasable and total LPL activity approximately 8-fold but did not alter rates of LPL synthesis compared with insulin alone.	4	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	6	7	11	12
In patients with type1 diabetes with good glycemic control , insulin upregulates lipoprotein lipase , increasing the production of small HDL particles [ XREF_BIBR , XREF_BIBR ] , frequently to higher than normal HDL cholesterol levels [ XREF_BIBR ] .	In patients with type1 diabetes with good glycemic control, insulin upregulates lipoprotein lipase, increasing the production of small HDL particles [XREF_BIBR, XREF_BIBR], frequently to higher than normal HDL cholesterol levels [XREF_BIBR].	10	14	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	10	11	12	14
Insulin activates LPL in adipose tissue but decreases in muscle .	Insulin activates LPL in adipose tissue but decreases in muscle.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	2	3
It is known that glucose toxicity and strong insulin resistance induce inactivation of LPL , which results in chylomicronemia .	It is known that glucose toxicity and strong insulin resistance induce inactivation of LPL, which results in chylomicronemia.	8	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	8	9	13	14
Under normal circumstances , insulin induces and activates lipoprotein lipase to hydrolyze triglycerides .	Under normal circumstances, insulin induces and activates lipoprotein lipase to hydrolyze triglycerides.	4	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	8	10
Insulin activates lipoprotein lipase , while heparin leads to the release of endothelial lipoprotein lipases .	Insulin activates lipoprotein lipase, while heparin leads to the release of endothelial lipoprotein lipases.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	2	4
The insulin activation of LPL serves to increase TAG uptake and storage after a single meal which eventually results in lower glycerol concentration .	The insulin activation of LPL serves to increase TAG uptake and storage after a single meal which eventually results in lower glycerol concentration.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	1	2	4	5
Heparin and insulin activate lipoprotein lipase ( LPL ) , thereby reducing plasma triglyceride levels .	Heparin and insulin activate lipoprotein lipase (LPL), thereby reducing plasma triglyceride levels.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	4	6
It is concluded that insulin is able to modulate the rate of LPL secretion independently of the synthesis of new enzyme molecules on a short-term basis and within a physiological range of concentrations .	It is concluded that insulin is able to modulate the rate of LPL secretion independently of the synthesis of new enzyme molecules on a short-term basis and within a physiological range of concentrations.	4	13	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	4	5	12	13
Insulin alone and together with dexamethasone increased lipoprotein lipase synthesis in adipose tissue incubated in vitro .	Insulin alone and together with dexamethasone increased lipoprotein lipase synthesis in adipose tissue incubated in vitro.	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	7	9
XREF_BIBR Insulin is found to increase the endothelial LPL activity .	XREF_BIBR Insulin is found to increase the endothelial LPL activity.	0	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	1	2	8	9
The model presented by Jelic 4 included insulin activation of LPL .	The model presented by Jelic 4 included insulin activation of LPL.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	7	8	10	11
Insulin increased levels of LPL mRNA and LPL activity in abdominal SQ but not OM adipose tissue .	Insulin increased levels of LPL mRNA and LPL activity in abdominal SQ but not OM adipose tissue.	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	4	5
Insulin ( 500 microU/ml ) increased lipoprotein lipase activity in adipose tissue from diabetic rats .	Insulin (500 microU/ml) increased lipoprotein lipase activity in adipose tissue from diabetic rats.	0	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	6	8
Heparin and insulin stimulate lipoprotein lipase activity .	Heparin and insulin stimulate lipoprotein lipase activity.	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	4	6
In states of insulin resistance , elevated insulin levels do not fully suppress the hormone sensitive lipase ( HSL ) , which hydrolyzes free fatty acids from adipocyte TG and activates lipoprotein lipase ( LPL ) XREF_BIBR .	In states of insulin resistance, elevated insulin levels do not fully suppress the hormone sensitive lipase (HSL), which hydrolyzes free fatty acids from adipocyte TG and activates lipoprotein lipase (LPL) XREF_BIBR.	7	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	7	8	31	33
XREF_BIBR The association between exercise , increased LPL activity and the consequent PPL response mediated particularly by insulin should be further evaluated .	XREF_BIBR The association between exercise, increased LPL activity and the consequent PPL response mediated particularly by insulin should be further evaluated.	7	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	17	18	7	8
Insulin stimulates lipoprotein lipase and inhibits hormone sensitive lipase in the post-prandial state [ XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	Insulin stimulates lipoprotein lipase and inhibits hormone sensitive lipase in the post-prandial state [XREF_BIBR, XREF_BIBR] (XREF_FIG).	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	2	4
Cortisol and insulin stimulate LPL activity ; within the adipose tissue capillary walls , LPL breaks down the triglyceride contained in its carrier lipoprotein .	Cortisol and insulin stimulate LPL activity; within the adipose tissue capillary walls, LPL breaks down the triglyceride contained in its carrier lipoprotein.	0	5	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	2	3	4	5
Alternatively , insulin resistance may prevent degradation of apoB by reducing the activity of lipoprotein lipase , the rate limiting and major mediator of VLDL clearance , thereby increasing VLDL levels .	Alternatively, insulin resistance may prevent degradation of apoB by reducing the activity of lipoprotein lipase, the rate limiting and major mediator of VLDL clearance, thereby increasing VLDL levels.	2	16	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	14	16
Insulin promotes the synthesis of lipoprotein lipase ( LPL ) , which is exported to the endothelial cell plasma membrane .	Insulin promotes the synthesis of lipoprotein lipase (LPL), which is exported to the endothelial cell plasma membrane.	0	20	promotes	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Insulin	Insulin	insulin	lipoprotein lipase	lipoprotein lipase (LPL), which is exported to the endothelial cell plasma membrane	lipoprotein lipase	0	1	5	7
Insulin and hydrocortisone together increased the lipoprotein lipase ( lpl ) activity several times .	Insulin and hydrocortisone together increased the lipoprotein lipase (lpl) activity several times.	0	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	6	8
Insulin in combination with dexamethasone ( INS and DEX ) increased heparin-releasable LPL activity by 71 % over the control level ( 566 +/-85 versus 331 +/-48 nmol/h .	Insulin in combination with dexamethasone (INS and DEX) increased heparin-releasable LPL activity by 71% over the control level (566 +/-85 versus 331 +/-48 nmol/h.	0	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	12	13
Insulin promotes the synthesis of LPL and stimulates the uptake of fatty acids released from triglyceride hydrolysis by LPL itself [ XREF_BIBR , XREF_BIBR ] .	Insulin promotes the synthesis of LPL and stimulates the uptake of fatty acids released from triglyceride hydrolysis by LPL itself [XREF_BIBR, XREF_BIBR].	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	5	6
Insulin increases lipoprotein lipase which in turn accelerates chylomicron and VLDL metabolism to glycerol and FFA .	Insulin increases lipoprotein lipase which in turn accelerates chylomicron and VLDL metabolism to glycerol and FFA.	0	4	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	2	4
Thus , insulin increased two cellular pools of adipocyte lipoprotein lipase in a dose dependent manner , but had no direct effect on enzyme secretion .	Thus, insulin increased two cellular pools of adipocyte lipoprotein lipase in a dose dependent manner, but had no direct effect on enzyme secretion.	2	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	9	11
It is concluded that adipose tissue lipoprotein lipase activity in man is increased by physiological insulin levels during hyperglycaemia and also by supraphysiological insulin levels during euglycaemia , but is not influenced by physiological hyperinsulinaemia without hyperglycaemia .	It is concluded that adipose tissue lipoprotein lipase activity in man is increased by physiological insulin levels during hyperglycaemia and also by supraphysiological insulin levels during euglycaemia, but is not influenced by physiological hyperinsulinaemia without hyperglycaemia.	6	17	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	15	16	6	8
The mechanisms by which insulin and glucocorticoids modulate lipoprotein lipase ( LPL ) synthesis and degradation were examined in human adipose tissue fragments maintained in organ culture .	The mechanisms by which insulin and glucocorticoids modulate lipoprotein lipase (LPL) synthesis and degradation were examined in human adipose tissue fragments maintained in organ culture.	4	10	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	8	10
In the fed state , insulin activates LPL in adipose tissue and thereby set the switch to uptake of free fatty acids ( FFA ) into the adipocytes which will then be stored in lipid droplets .	In the fed state, insulin activates LPL in adipose tissue and thereby set the switch to uptake of free fatty acids (FFA) into the adipocytes which will then be stored in lipid droplets.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	5	6	7	8
It is well known that insulin activates enzyme lipoprotein lipase , which hydrolyzes triglyceride under normal conditions .	It is well known that insulin activates enzyme lipoprotein lipase, which hydrolyzes triglyceride under normal conditions.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	5	6	8	10
Heparin and insulin stimulate lipoprotein lipase activity and accelerate chylomicron degradation .	Heparin and insulin stimulate lipoprotein lipase activity and accelerate chylomicron degradation.	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	4	6
Under in vitro experimental conditions in which insulin increases adipose tissue lipoprotein lipase , cyclic GMP or dibutyryl cyclic GMP has no effect on this enzyme in rat adipose tissue fragments , or on either the intra- or extracellular forms of this enzyme in isolated fat cells .	Under in vitro experimental conditions in which insulin increases adipose tissue lipoprotein lipase, cyclic GMP or dibutyryl cyclic GMP has no effect on this enzyme in rat adipose tissue fragments, or on either the intra- or extracellular forms of this enzyme in isolated fat cells.	7	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	7	8	11	13
The depressed activity of insulin mediated lipoprotein lipase ( LPL ) made the clearance rate of lipoprotein descend , which is the main cause of hypertriglyceridemia in T2DM disease [ XREF_BIBR ] .	The depressed activity of insulin mediated lipoprotein lipase (LPL) made the clearance rate of lipoprotein descend, which is the main cause of hypertriglyceridemia in T2DM disease [XREF_BIBR].	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	6	8
Although insulin increased total LPL activity ( secreted and cell associated ; P < 0.001 ) in 3T3-L1 adipocytes , ASP moderately stimulated secreted LPL activity ( P = 0.04 ; 5 % of total LPL activity ) .	Although insulin increased total LPL activity (secreted and cell associated; P < 0.001) in 3T3-L1 adipocytes, ASP moderately stimulated secreted LPL activity (P = 0.04; 5% of total LPL activity).	1	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	1	2	4	5
It is well known that under normal circumstances insulin activates the enzyme lipoprotein lipase which hydrolyses the triglycerides .	It is well known that under normal circumstances insulin activates the enzyme lipoprotein lipase which hydrolyses the triglycerides.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	8	9	12	14
Insulin , however , increased lipoprotein lipase synthesis independent of nuclear events .	Insulin, however, increased lipoprotein lipase synthesis independent of nuclear events.	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	5	7
The results indicate that insulin and glucagon cause reciprocal changes of lipoprotein lipase activity in rat adipose tissue .	The results indicate that insulin and glucagon cause reciprocal changes of lipoprotein lipase activity in rat adipose tissue.	4	13	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	11	13
Insulin mediated LPL activity and TG uptake .	Insulin mediated LPL activity and TG uptake.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	2	3
Insulin stimulated LPL synthesis as a result of a general increase in protein synthesis , and this effect was more marked in the obese fat cells .	Insulin stimulated LPL synthesis as a result of a general increase in protein synthesis, and this effect was more marked in the obese fat cells.	0	3	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	2	3
In 3T3-L1 adipocytes , insulin elicits the rapid release of LPL through mechanisms that are independent of energy metabolism and protein synthesis .	In 3T3-L1 adipocytes, insulin elicits the rapid release of LPL through mechanisms that are independent of energy metabolism and protein synthesis.	4	11	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	4	5	10	11
Insulin is known to activate lipoprotein lipase which catalyses the hydrolytic breakdown of lipids during normal physiological status [ XREF_BIBR ] .	Insulin is known to activate lipoprotein lipase which catalyses the hydrolytic breakdown of lipids during normal physiological status [XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	5	7
Daily injections of insulin for 7 days increased LPL activity in adipose tissue but had no effect on heart LPL activity .	Daily injections of insulin for 7 days increased LPL activity in adipose tissue but had no effect on heart LPL activity.	1	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	3	4	8	9
Adipocyte derived LPL is required for efficient fatty acid uptake and storage [ XREF_BIBR ] , and insulin infusion in humans increases adipose tissue LPL activity within a few hours [ XREF_BIBR , XREF_BIBR ] .	Adipocyte derived LPL is required for efficient fatty acid uptake and storage [XREF_BIBR], and insulin infusion in humans increases adipose tissue LPL activity within a few hours [XREF_BIBR, XREF_BIBR].	17	25	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	17	18	24	25
Another mechanism may be related to insulin sensitivity , which stimulates lipoprotein lipase activity and TG clearance , and , as it was shown , by the weight loss ( which improves insulin sensitivity ) the fat induced postprandial TG clearance was improved as well [ XREF_BIBR ] .	Another mechanism may be related to insulin sensitivity, which stimulates lipoprotein lipase activity and TG clearance, and, as it was shown, by the weight loss (which improves insulin sensitivity) the fat induced postprandial TG clearance was improved as well [XREF_BIBR].	6	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	7	11	13
Adipose tissue LPL activity is increased by insulin but inhibited by GH and sex steroids .	Adipose tissue LPL activity is increased by insulin but inhibited by GH and sex steroids.	2	8	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	7	8	2	3
Finally , in vitro studies using fat pads revealed that insulin significantly stimulated the proportion of LPL in active conformation at the extracellular level .	Finally, in vitro studies using fat pads revealed that insulin significantly stimulated the proportion of LPL in active conformation at the extracellular level.	10	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	10	11	16	17
Replacement of insulin ( 24 h ) in the combined hormone deficient rats increased uptake of [ 14C ] lipid and lipoprotein lipase approx .	Replacement of insulin (24 h) in the combined hormone deficient rats increased uptake of [14C] lipid and lipoprotein lipase approx.	0	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	21	23
Cortisol and insulin stimulate lipid uptake by activating lipoprotein lipase , and this process is facilitated by high concentrations of cortisol-activate enzyme 11-beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptors .	Cortisol and insulin stimulate lipid uptake by activating lipoprotein lipase, and this process is facilitated by high concentrations of cortisol-activate enzyme 11-beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptors.	0	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	8	10
Heparin and insulin stimulate LPL activity .	Heparin and insulin stimulate LPL activity.	0	5	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	2	3	4	5
This exocyst complex is stabilized at the PM by the insulin induced activations of protein kinase B ( PKB )/AKT and the small GTPase TC10 , along with the action of the lipid raft localized synapse associated protein 97 .	This exocyst complex is stabilized at the PM by the insulin induced activations of protein kinase B (PKB)/AKT and the small GTPase TC10, along with the action of the lipid raft localized synapse associated protein 97.	4	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	10	11	14	17
Insulin activation of phosphatidylinositol-3-kinase and protein kinase B ( PKB ) ( Akt ) can inhibit TGF-beta1 signaling via the formation of a PKB and Smad3 complex .	Insulin activation of phosphatidylinositol-3-kinase and protein kinase B (PKB) (Akt) can inhibit TGF-beta1 signaling via the formation of a PKB and Smad3 complex.	0	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	5	8
Here we show that insulin activates phosphatidylinositol 3-kinase ( PI3K ) and protein kinase B ( PKB ) , and results in an induction of long-term depression ( LTD ) in hippocampal CA1 neurones .	Here we show that insulin activates phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB), and results in an induction of long-term depression (LTD) in hippocampal CA1 neurones.	4	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	4	5	12	15
Insulin and IGF pathway-mitogen activated protein kinase kinase and MAP kinase cascade , TGF-beta signaling pathway , Angiogenesis , Insulin and IGF pathway protein kinase B signaling cascade , PI3 kinase pathway , Wnt signaling pathway were found to be the most enriched biological pathways as revealed by the PANTHER analysis .	Insulin and IGF pathway-mitogen activated protein kinase kinase and MAP kinase cascade, TGF-beta signaling pathway, Angiogenesis, Insulin and IGF pathway protein kinase B signaling cascade, PI3 kinase pathway, Wnt signaling pathway were found to be the most enriched biological pathways as revealed by the PANTHER analysis.	0	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	23	26
Consistent with the notion of Par6 proteins as negative regulators of Akt1 , earlier findings have shown that engineered Par6 activity perturbs insulin stimulated Akt1 activity in myoblasts .	Consistent with the notion of Par6 proteins as negative regulators of Akt1, earlier findings have shown that engineered Par6 activity perturbs insulin stimulated Akt1 activity in myoblasts.	21	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	22	23	24	25
Second , we show that insulin stimulates the enzymatic activity of Akt1 and Akt3 15- and 7-fold , respectively .	Second, we show that insulin stimulates the enzymatic activity of Akt1 and Akt3 15- and 7-fold, respectively.	5	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	5	6	11	12
We found that insulin activates both Akt1 and Akt2 in adipocytes , but differentially regulates the subcellular distribution of these Akt isoforms .	We found that insulin activates both Akt1 and Akt2 in adipocytes, but differentially regulates the subcellular distribution of these Akt isoforms.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	3	4	6	7
IGF-Ir/dn blocked Akt-1 activation induced by IGF-I , IGF-II , and des ( 1-3 ) IGF-I , but not by insulin .	IGF-Ir/dn blocked Akt-1 activation induced by IGF-I, IGF-II, and des (1-3) IGF-I, but not by insulin.	2	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt-1	Akt-1	Akt-1	20	21	2	3
Basal and insulin stimulated activity of Akt1 kinase and uptake of 2-deoxy-D-glucose ( 2-DG ) were measured in soleus ( slow-twitch ) and plantaris ( fast-twitch ) muscles of rats at 1 and 3 days after sectioning the sciatic nerve in one hindlimb of the animals .	Basal and insulin stimulated activity of Akt1 kinase and uptake of 2-deoxy-D-glucose (2-DG) were measured in soleus (slow-twitch) and plantaris (fast-twitch) muscles of rats at 1 and 3 days after sectioning the sciatic nerve in one hindlimb of the animals.	0	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	2	3	6	7
Akt1 and Akt2 were not activated by insulin stimulation in 3T3-L1 adipocytes .	Akt1 and Akt2 were not activated by insulin stimulation in 3T3-L1 adipocytes.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	7	8	0	1
Immunoblotting using anti-phosphorylated Akt1 antibody revealed Thr 308 already to be maximally phosphorylated at 1 min but completely dephosphorylated at 5 min , with insulin stimulation , whereas insulin induced Akt1 activation was maintained even after dephosphorylation of Thr 308 .	Immunoblotting using anti-phosphorylated Akt1 antibody revealed Thr 308 already to be maximally phosphorylated at 1 min but completely dephosphorylated at 5 min, with insulin stimulation, whereas insulin induced Akt1 activation was maintained even after dephosphorylation of Thr 308.	28	31	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	28	29	30	31
Western blot analyses showed that insulin induced the activation of protein kinase B ( Akt ) .	Western blot analyses showed that insulin induced the activation of protein kinase B (Akt).	5	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	5	6	10	13
Insulin activates both Akt1 and Akt2 in 3T3-L1 and primary rat adipocytes XREF_BIBR , XREF_BIBR , demonstrating that the failure of Akt1 to regulate GLUT4 translocation to the plasma membrane is not due to differential activation of the Akt isoforms by insulin .	Insulin activates both Akt1 and Akt2 in 3T3-L1 and primary rat adipocytes XREF_BIBR, XREF_BIBR, demonstrating that the failure of Akt1 to regulate GLUT4 translocation to the plasma membrane is not due to differential activation of the Akt isoforms by insulin.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt1	Akt1	Akt1	0	1	3	4
The insulin stimulated Akt1 activity was also enhanced by wt-PDK1 expression but was maintained even at 15 min .	The insulin stimulated Akt1 activity was also enhanced by wt-PDK1 expression but was maintained even at 15 min.	0	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	1	2	3	4
There was also no change in insulin stimulated protein kinase B activity ( 1.3 +/- 0.1 vs. 1.4 +/- 0.2-fold stimulation with insulin ) with training .	There was also no change in insulin stimulated protein kinase B activity (1.3 +/- 0.1 vs. 1.4 +/- 0.2-fold stimulation with insulin) with training.	4	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	6	7	8	11
These genes and RAPTOR itself comprised a network centered on the insulin mediated control of AKT1 , which we have described previously and is important in both epidermal skin barrier function and UV protection ( see Fig E2 , A , in this article ' s Online Repository at www.jacionline.org ) .	These genes and RAPTOR itself comprised a network centered on the insulin mediated control of AKT1, which we have described previously and is important in both epidermal skin barrier function and UV protection (see Fig E2, A, in this article 's Online Repository at www.jacionline.org).	8	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT1	AKT1	AKT1	11	12	15	16
Expression of kinase defective PKC-lambda , in addition to inhibition of atypical PKC enzyme activity , was attended by paradoxical increases in GLUT4 and GLUT1 glucose transporter levels and insulin stimulated protein kinase B enzyme activity .	Expression of kinase defective PKC-lambda, in addition to inhibition of atypical PKC enzyme activity, was attended by paradoxical increases in GLUT4 and GLUT1 glucose transporter levels and insulin stimulated protein kinase B enzyme activity.	17	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	29	30	31	34
Although the mTAb1 epitope contains a consensus site for protein kinase B , neither agent inhibited the activation of protein kinase B produced by insulin .	Although the mTAb1 epitope contains a consensus site for protein kinase B, neither agent inhibited the activation of protein kinase B produced by insulin.	19	25	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	24	25	19	22
These experiments demonstrated that activation of PKBalpha by insulin or insulin like growth factor-1 ( IGF-1 ) results from phosphorylation of both Thr308 and Ser473 , that phosphorylation of both residues is critical to generate a high level of PKBalpha activity and that the phosphorylation of Thr308 in vivo is not dependent on phosphorylation of Ser473 or vice versa .	These experiments demonstrated that activation of PKBalpha by insulin or insulin like growth factor-1 (IGF-1) results from phosphorylation of both Thr308 and Ser473, that phosphorylation of both residues is critical to generate a high level of PKBalpha activity and that the phosphorylation of Thr308 in vivo is not dependent on phosphorylation of Ser473 or vice versa.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKBalpha	PKBalpha	PKBalpha	8	9	6	7
Our previous results revealed a new pathway in which amino acids permit insulin induced activation of the protein kinase B ( PKB )/mTOR pathway in freshly isolated adipocytes when phosphatidylinositol 3-kinase ( PI3K ) is inhibited .	Our previous results revealed a new pathway in which amino acids permit insulin induced activation of the protein kinase B (PKB)/mTOR pathway in freshly isolated adipocytes when phosphatidylinositol 3-kinase (PI3K) is inhibited.	12	20	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	12	13	17	20
Insulin induced signaling includes activation of PI3 kinase and protein kinase B ( PKB )/Akt .	Insulin induced signaling includes activation of PI3 kinase and protein kinase B (PKB)/Akt.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	9	12
Phosphatidylinositol 3-kinase and protein kinase B were activated by insulin but not by TPA .	Phosphatidylinositol 3-kinase and protein kinase B were activated by insulin but not by TPA.	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	9	10	3	6
Administration of an ARB or tempol to this model prevented the activation of insulin stimulated protein kinase B , which is required for phosphorylation and activation of phosphoinositol 3-kinase , and prevented coronary artery adventitial fibrosis .	Administration of an ARB or tempol to this model prevented the activation of insulin stimulated protein kinase B, which is required for phosphorylation and activation of phosphoinositol 3-kinase, and prevented coronary artery adventitial fibrosis.	11	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	13	14	15	18
Insulin mediated activation of protein kinase B , a kinase involved in insulin induced glucose uptake , was apparently not altered by OPC3911 .	Insulin mediated activation of protein kinase B, a kinase involved in insulin induced glucose uptake, was apparently not altered by OPC3911.	0	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	4	7
Insulin increased Akt1 activity 3.9-fold in glycerol infused rats , and this was impaired 41 % in lipid infused rats .	Insulin increased Akt1 activity 3.9-fold in glycerol infused rats, and this was impaired 41% in lipid infused rats.	0	3	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt1	Akt1	Akt1	0	1	2	3
XREF_BIBR , XREF_BIBR Insulin stimulates the activation of protein kinase B and this protein signals the release of NO from endothelial cells .	XREF_BIBR, XREF_BIBR Insulin stimulates the activation of protein kinase B and this protein signals the release of NO from endothelial cells.	2	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	3	4	8	11
Insulin stimulated human muscle from obese , insulin resistant individuals display a decrease in Akt2 activity but not Akt1 compared to lean , healthy counterparts [ XREF_BIBR ] .	Insulin stimulated human muscle from obese, insulin resistant individuals display a decrease in Akt2 activity but not Akt1 compared to lean, healthy counterparts [XREF_BIBR].	0	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt1	Akt1	Akt1	0	1	18	19
Expression of a dominant negative mutant of Akt1 or class I PI3K inhibited the insulin stimulation of PI3K and Akt1 signaling without affecting phosphorylation of IkappaBalpha .	Expression of a dominant negative mutant of Akt1 or class I PI3K inhibited the insulin stimulation of PI3K and Akt1 signaling without affecting phosphorylation of IkappaBalpha.	14	20	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	14	15	19	20
In the present study , the effects of long-term TNF-alpha ( 1 ng/ml ) exposure on the components of insulin signaling pathway in HepG2 and HepG2 cells overexpressing constitutively active Akt1 and PKB-alpha ( HepG2-CA-Akt and PKB ) have been investigated .	In the present study, the effects of long-term TNF-alpha (1 ng/ml) exposure on the components of insulin signaling pathway in HepG2 and HepG2 cells overexpressing constitutively active Akt1 and PKB-alpha (HepG2-CA-Akt and PKB) have been investigated.	19	33	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB-alpha	PKB-alpha	PKB-alpha	19	20	32	33
The data demonstrate that 1 ) there is a close , direct correlation between the magnitude of insulin stimulated activity of Akt1 kinase and the level of glucose uptake in muscles with different fiber populations , 2 ) insulin activates three isoforms of Akt kinase in skeletal muscle , and 3 ) exercise in vivo is associated with activation of Akt1 but not Akt2 and Akt3 kinases in contracting muscles .	The data demonstrate that 1) there is a close, direct correlation between the magnitude of insulin stimulated activity of Akt1 kinase and the level of glucose uptake in muscles with different fiber populations, 2) insulin activates three isoforms of Akt kinase in skeletal muscle, and 3) exercise in vivo is associated with activation of Akt1 but not Akt2 and Akt3 kinases in contracting muscles.	15	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	17	18	21	22
Insulin induced Akt1 activation was much higher compared to Akt3 .	Insulin induced Akt1 activation was much higher compared to Akt3.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt1	Akt1	Akt1	0	1	2	3
Insulin induced the activation of PKBalpha in rat skeletal muscle in vivo , with little activation of PKBbeta .	Insulin induced the activation of PKBalpha in rat skeletal muscle in vivo, with little activation of PKBbeta.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	PKBalpha	PKBalpha	PKBalpha	0	1	5	6
Rapamycin and dibutyryl-cAMP , which inhibited basal signaling via mammalian target of rapamycin ( mTOR ) , restored insulin induced PKB- but not IRbeta phosphorylation .	Rapamycin and dibutyryl-cAMP, which inhibited basal signaling via mammalian target of rapamycin (mTOR), restored insulin induced PKB- but not IRbeta phosphorylation.	18	24	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB-	PKB-	PKB-	18	19	20	21
We have investigated the effect of short interfering RNA ( siRNA ) mediated knockdown of IRS-1 on insulin signaling cascade in primary human hepatocellular carcinoma HepG2 cell line and HepG2 cells overexpressing Akt1 and PKB-alpha ( HepG2-CA-Akt and PKB ) .	We have investigated the effect of short interfering RNA (siRNA) mediated knockdown of IRS-1 on insulin signaling cascade in primary human hepatocellular carcinoma HepG2 cell line and HepG2 cells overexpressing Akt1 and PKB-alpha (HepG2-CA-Akt and PKB).	17	35	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB-alpha	PKB-alpha	PKB-alpha	17	18	34	35
Insulin mediated activation of protein kinase B ( AKT ) promotes glucose uptake in adipocytes by leading vesicle of glucose transporter 4 ( GLUT4 ) to moving into the plasma membrane [ XREF_BIBR - XREF_BIBR ] .	Insulin mediated activation of protein kinase B (AKT) promotes glucose uptake in adipocytes by leading vesicle of glucose transporter 4 (GLUT4) to moving into the plasma membrane [XREF_BIBR - XREF_BIBR].	0	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	4	7
Insulin and IGF -1 activates a downstream signaling cascade of phosphoinositide 3-kinase ( PI3K ) and protein kinase B ( PKB , also known as AKT ) , leading to activation of FoxO transcription factors that activate or suppress an array of target genes ( XREF_FIG ) .	Insulin and IGF -1 activates a downstream signaling cascade of phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB, also known as AKT), leading to activation of FoxO transcription factors that activate or suppress an array of target genes (XREF_FIG).	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	16	19
Heart tissue NADPH oxidase ( NOX ) activity and immunohistochemical analysis of subunits NOX2 , Rac1 , and p22 ( phox ) , heart tissue malondialdehyde , and insulin stimulated protein kinase B ( Akt ) activation were measured .	Heart tissue NADPH oxidase (NOX) activity and immunohistochemical analysis of subunits NOX2, Rac1, and p22 (phox), heart tissue malondialdehyde, and insulin stimulated protein kinase B (Akt) activation were measured.	10	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	28	29	30	33
In contrast , activation of Akt1 by insulin was completely inhibited by 100 nM wortmannin at all time points investigated .	In contrast, activation of Akt1 by insulin was completely inhibited by 100 nM wortmannin at all time points investigated.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	7	8	5	6
For example , OGT regulates insulin signaling through O GlcNAcylation of several important insulin signaling molecules , e.g ., IRS-1 , PI3K , PDK1 , and AKT1 , leading to attenuation of insulin signaling responses in glycogen synthesis , activation of gluconeogenic genes and glucose transporter GLUT4 translocation , thus contributing to insulin resistance in type II diabetes [ XREF_BIBR , XREF_BIBR ] .	For example, OGT regulates insulin signaling through O GlcNAcylation of several important insulin signaling molecules, e.g., IRS-1, PI3K, PDK1, and AKT1, leading to attenuation of insulin signaling responses in glycogen synthesis, activation of gluconeogenic genes and glucose transporter GLUT4 translocation, thus contributing to insulin resistance in type II diabetes [XREF_BIBR, XREF_BIBR].	9	27	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT1	AKT1	AKT1	13	14	26	27
We have already shown that chronic exposure to the ketone body beta-hydroxybutyrate ( OHB ) decreases insulin mediated activation of protein kinase B ( PKB ) and glucose uptake in cardiomyocytes .	We have already shown that chronic exposure to the ketone body beta-hydroxybutyrate (OHB) decreases insulin mediated activation of protein kinase B (PKB) and glucose uptake in cardiomyocytes.	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	16	17	20	23
To determine whether SWELL1 silencing in mature adipocytes in vivo also disrupts insulin-PI3K-AKT signaling we examined insulin stimulated pAKT2 and pAKT1 in iWAT of mice 7 days after direct iWAT injection with Ad-shSCR-mCherry and Ad-shSWELL 1-mCherry .	To determine whether SWELL1 silencing in mature adipocytes in vivo also disrupts insulin-PI3K-AKT signaling we examined insulin stimulated pAKT2 and pAKT1 in iWAT of mice 7 days after direct iWAT injection with Ad-shSCR-mCherry and Ad-shSWELL 1-mCherry.	15	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	pAKT1	pAKT1	pAKT1	16	17	20	21
We found that , although insulin signaling was impaired in muscle , insulin activation of IRS-1 and PI3K , IRS-2 and PI3K , protein kinase B , and aPKC was largely intact in liver and that rosiglitazone improved insulin signaling to aPKC in muscle by improving responsiveness to PI-3 ,4,5-( PO4 ) 3 .	We found that, although insulin signaling was impaired in muscle, insulin activation of IRS-1 and PI3K, IRS-2 and PI3K, protein kinase B, and aPKC was largely intact in liver and that rosiglitazone improved insulin signaling to aPKC in muscle by improving responsiveness to PI-3,4,5-(PO4) 3.	12	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	12	13	23	26
Insulin increased activities of insulin receptor substrate ( IRS )-1-dependent phosphatidylinositol ( PI ) 3-kinase and its downstream effectors , atypical protein kinase Cs ( aPKCs ) ( zeta/lambda/iota ) and protein kinase B ( PKB ) in muscles of nondiabetic monkeys .	Insulin increased activities of insulin receptor substrate (IRS)-1-dependent phosphatidylinositol (PI) 3-kinase and its downstream effectors, atypical protein kinase Cs (aPKCs) (zeta/lambda/iota) and protein kinase B (PKB) in muscles of nondiabetic monkeys.	0	34	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	31	34
In this report , we examined the relative amounts of expression , location , and translocation upon insulin stimulation of PKBalpha in normal primary hepatocytes and carcinoma cells , HepG2 cells .	In this report, we examined the relative amounts of expression, location, and translocation upon insulin stimulation of PKBalpha in normal primary hepatocytes and carcinoma cells, HepG2 cells.	17	21	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKBalpha	PKBalpha	PKBalpha	17	18	20	21
The results indicated that insulin activated the Akt1 and the Akt3 isoforms , but not Akt2 ( XREF_FIG ) .	The results indicated that insulin activated the Akt1 and the Akt3 isoforms, but not Akt2 (XREF_FIG).	4	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	4	5	7	8
Insulin activates two major signaling pathways : the phosphoinositide 3-kinase ( PI3K ) / protein kinase B ( Akt ) and methyl ethyl ketone ( MEK ) / ERK pathways .	Insulin activates two major signaling pathways : the phosphoinositide 3-kinase (PI3K) / protein kinase B (Akt) and methyl ethyl ketone (MEK) / ERK pathways.	0	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	14	17
Chronic treatment with BMOV normalized plasma glucose levels in STZ-diabetic rats and decreased plasma insulin levels in fatty Zucker rats but did not have any effect on basal or insulin induced PKBalpha and PKBbeta activities .	Chronic treatment with BMOV normalized plasma glucose levels in STZ-diabetic rats and decreased plasma insulin levels in fatty Zucker rats but did not have any effect on basal or insulin induced PKBalpha and PKBbeta activities.	29	34	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKBalpha	PKBalpha	PKBalpha	29	30	31	32
Soleus muscle exhibited a 105 % higher abundance of Akt1 kinase , a 101 % higher insulin stimulated activity of Akt1 kinase , and 83 % higher insulin stimulated 2-deoxyglucose uptake compared with plantaris muscle .	Soleus muscle exhibited a 105% higher abundance of Akt1 kinase, a 101% higher insulin stimulated activity of Akt1 kinase, and 83% higher insulin stimulated 2-deoxyglucose uptake compared with plantaris muscle.	2	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	16	17	20	21
At 1 day after surgery , the insulin stimulated activity of Akt1 kinase in denervated soleus and plantaris muscles remained unchanged , but the insulin stimulated 2-DG uptake by these muscles was reduced by 71 and 61 % , respectively , compared with the corresponding muscles of the contralateral sham ( control ) hindlimb .	At 1 day after surgery, the insulin stimulated activity of Akt1 kinase in denervated soleus and plantaris muscles remained unchanged, but the insulin stimulated 2-DG uptake by these muscles was reduced by 71 and 61%, respectively, compared with the corresponding muscles of the contralateral sham (control) hindlimb.	6	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	7	8	11	12
In obese rats , insulin stimulated Akt1 activity decreased 30 % in muscle and 21 % in adipose tissue but increased 37 % in liver compared with lean littermates .	In obese rats, insulin stimulated Akt1 activity decreased 30% in muscle and 21% in adipose tissue but increased 37% in liver compared with lean littermates.	4	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	4	5	6	7
Insulin selectively activated Akt1 ( XREF_FIG , top panel ) , whereas TGFbeta activated Akt2 ( XREF_FIG , third panel ) .	Insulin selectively activated Akt1 (XREF_FIG, top panel), whereas TGFbeta activated Akt2 (XREF_FIG, third panel).	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt1	Akt1	Akt1	0	1	3	4
In contrast , a significant increase in insulin stimulated PKBalpha activity was observed in the liver of fatty Zucker rats ( fatty : 15.7-fold vs. lean : 7.6-fold ) .	In contrast, a significant increase in insulin stimulated PKBalpha activity was observed in the liver of fatty Zucker rats (fatty : 15.7-fold vs. lean : 7.6-fold).	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKBalpha	PKBalpha	PKBalpha	7	8	9	10
The postprandial increase of glucose and insulin activates mTOR and consequently protein kinase B ( Akt ) through mTORC2 .	The postprandial increase of glucose and insulin activates mTOR and consequently protein kinase B (Akt) through mTORC2.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	6	7	11	14
In summary , our data show that phosphorylation of Thr308 during insulin mediated Akt1 activation is an essential prerequisite to exclude Akt1 from the nuclear compartment .	In summary, our data show that phosphorylation of Thr308 during insulin mediated Akt1 activation is an essential prerequisite to exclude Akt1 from the nuclear compartment.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	11	12	13	14
These results indicate that Akt1 and 3 are similarly stimulated by insulin and this stimulation is inhibited by prior activation of protein kinase C through a mechanism that is independent of the presence of the pleckstrin homology domain .	These results indicate that Akt1 and 3 are similarly stimulated by insulin and this stimulation is inhibited by prior activation of protein kinase C through a mechanism that is independent of the presence of the pleckstrin homology domain.	4	12	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	11	12	4	5
Increased serine phosphorylation of IRS-1 inhibits the tyrosine kinase activity of the insulin receptor on IRS-1 and the activity of insulin stimulated phosphatidylinositol 3-kinase ( PI 3-kinase ) , resulting in decreased activity of insulin stimulated protein kinase B ( PKB , also known as AKT ) .	Increased serine phosphorylation of IRS-1 inhibits the tyrosine kinase activity of the insulin receptor on IRS-1 and the activity of insulin stimulated phosphatidylinositol 3-kinase (PI 3-kinase), resulting in decreased activity of insulin stimulated protein kinase B (PKB, also known as AKT).	32	39	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	34	35	36	39
Insulin treatment increased the number of AKT1 peaks from 9 to 15 ( XREF_FIG ) .	Insulin treatment increased the number of AKT1 peaks from 9 to 15 (XREF_FIG).	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT1	AKT1	AKT1	0	1	6	7
Insulin also causes inactivation of glycogen synthase kinase-3 ( GSK-3 ) and activation of protein kinase B , both processes being sufficiently rapid to account for the effects of insulin on GS .	Insulin also causes inactivation of glycogen synthase kinase-3 (GSK-3) and activation of protein kinase B, both processes being sufficiently rapid to account for the effects of insulin on GS.	0	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	14	17
To elucidate the mechanism of how insulin signaling induces RDS , bronchoalveolar epithelium specific Akt1 transgenic ( TG ) mice were generated .	To elucidate the mechanism of how insulin signaling induces RDS, bronchoalveolar epithelium specific Akt1 transgenic (TG) mice were generated.	6	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	6	7	14	15
Insulin induced activation of protein kinase B , the activity of which is controlled by the lipid products of PI 3-kinase , was also potentiated by adenosine .	Insulin induced activation of protein kinase B, the activity of which is controlled by the lipid products of PI 3-kinase, was also potentiated by adenosine.	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	4	7
Insulin activated endogenous protein kinase B alpha ( also known as RAC and Akt kinase ) activity 12-fold in L6 myotubes , while after transfection into 293 cells PKBalpha was activated 20- and 50-fold in response to insulin and IGF-1 respectively .	Insulin activated endogenous protein kinase B alpha (also known as RAC and Akt kinase) activity 12-fold in L6 myotubes, while after transfection into 293 cells PKBalpha was activated 20- and 50-fold in response to insulin and IGF-1 respectively.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B alpha	protein kinase B alpha	protein kinase B alpha	0	1	3	7
Insulin stimulation of phosphatidylinositol 3-kinase and protein kinase B-alpha activities was similar for L6-GLUT-4myc myoblasts and myotubes .	Insulin stimulation of phosphatidylinositol 3-kinase and protein kinase B-alpha activities was similar for L6-GLUT-4myc myoblasts and myotubes.	0	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B-alpha	protein kinase B-alpha	protein kinase B-alpha	0	1	6	9
In this study , we demonstrate that protein kinase B , a serine/threonine kinase stimulated by PI 3-kinase , is activated by both insulin and okadaic acid in isolated adipocytes , in parallel with their effects on Glut 4 translocation .	In this study, we demonstrate that protein kinase B, a serine/threonine kinase stimulated by PI 3-kinase, is activated by both insulin and okadaic acid in isolated adipocytes, in parallel with their effects on Glut 4 translocation.	7	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	23	24	7	10
Here we demonstrate in 293-EBNA cells overexpressing S662A and S731A-IRS -1 that insulin stimulated protein kinase B activity is not augmented , whereas without insulin treatment , basal activity is increased compared with that in cells overexpressing wild-type IRS-1 .	Here we demonstrate in 293-EBNA cells overexpressing S662A and S731A-IRS -1 that insulin stimulated protein kinase B activity is not augmented, whereas without insulin treatment, basal activity is increased compared with that in cells overexpressing wild-type IRS-1.	12	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	12	13	14	17
Activation of CB1R inhibits insulin signaling by elevating inhibitory serine 307 phosphorylation of insulin receptor substrate 1 ( IRS1 ) and by stimulating the dephosphorylation of insulin activated protein kinase B ( PKB and AKT ) through upregulation of the S/T phosphatase PH domain and leucine rich repeats protein phosphatase 1 ( PHLPP1 ) [ XREF_BIBR ] .	Activation of CB1R inhibits insulin signaling by elevating inhibitory serine 307 phosphorylation of insulin receptor substrate 1 (IRS1) and by stimulating the dephosphorylation of insulin activated protein kinase B (PKB and AKT) through upregulation of the S/T phosphatase PH domain and leucine rich repeats protein phosphatase 1 (PHLPP1) [XREF_BIBR].	24	31	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	dephosphorylation of insulin	insulin	protein kinase B	protein kinase B	protein kinase b	26	27	28	31
Moreover , hepatic activation of protein kinase B by insulin , measured by Western blot , was reduced by 54 % .	Moreover, hepatic activation of protein kinase B by insulin, measured by Western blot, was reduced by 54%.	3	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	9	10	5	8
Interestingly , while the insulin stimulated phosphotyrosine derived PI 3-kinase activity was not changed , insulin stimulated protein kinase B activation was increased by 41 % in this tissue .	Interestingly, while the insulin stimulated phosphotyrosine derived PI 3-kinase activity was not changed, insulin stimulated protein kinase B activation was increased by 41% in this tissue.	15	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	15	16	17	20
We believe that the decrease in IRS-1 phosphorylation at this inhibitory site ( Ser 307 ) in GHRKO mice underpins the insulin stimulated elevations in the activation of downstream PI3K and IRS , AKT1 and AKT2 in the absence of increased IR activation upstream .	We believe that the decrease in IRS-1 phosphorylation at this inhibitory site (Ser 307) in GHRKO mice underpins the insulin stimulated elevations in the activation of downstream PI3K and IRS, AKT1 and AKT2 in the absence of increased IR activation upstream.	19	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT1	AKT1	AKT1	21	22	33	34
These results suggest that insulin specifically activates the Akt1 and also induces a weak activation of Akt3 isoforms .	These results suggest that insulin specifically activates the Akt1 and also induces a weak activation of Akt3 isoforms.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	4	5	8	9
Similarly , there was no effect on the insulin stimulation of protein kinase B ( PKB ) and inhibition of glycogen synthase kinase 3 ( GSK-3 ) .	Similarly, there was no effect on the insulin stimulation of protein kinase B (PKB) and inhibition of glycogen synthase kinase 3 (GSK-3).	8	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	8	9	11	14
Local insulin treatment totally restored Akt1 activity ( XREF_FIG ) , while phloridzin treatment partially restored both Akt1 and Akt3 activities ( XREF_FIG ) .	Local insulin treatment totally restored Akt1 activity (XREF_FIG), while phloridzin treatment partially restored both Akt1 and Akt3 activities (XREF_FIG).	1	6	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	1	2	5	6
Compared with controls , insulin enhanced the intestinal activity of MAP kinase-2 and protein kinase B by two- and fivefold , respectively , but did not enhance p70/S6 ribosomal kinase .	Compared with controls, insulin enhanced the intestinal activity of MAP kinase-2 and protein kinase B by two- and fivefold, respectively, but did not enhance p70/S6 ribosomal kinase.	4	26	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	4	5	13	16
In conclusion ( i ) in STZ-diabetic rats PKB activity was normal up to 9 weeks of diabetes ; ( ii ) in fatty Zucker rats insulin induced activation of PKBalpha ( but not PKBbeta ) was markedly altered in both tissues ; ( iii ) changes in PKBalpha activity were tissue specific ; ( iv ) the glucoregulatory effects of BMOV were independent of PKB activity .	In conclusion (i) in STZ-diabetic rats PKB activity was normal up to 9 weeks of diabetes; (ii) in fatty Zucker rats insulin induced activation of PKBalpha (but not PKBbeta) was markedly altered in both tissues; (iii) changes in PKBalpha activity were tissue specific; (iv) the glucoregulatory effects of BMOV were independent of PKB activity.	20	34	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKBalpha	PKBalpha	PKBalpha	26	27	30	31
Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin .	Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin.	10	16	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	10	11	13	16
The greater level of p85 recruitment to PM was associated with a higher level of insulin induced recruitment of Akt1 to this compartment ( 4.0-fold in PM vs. 2.4-fold in EN ) .	The greater level of p85 recruitment to PM was associated with a higher level of insulin induced recruitment of Akt1 to this compartment (4.0-fold in PM vs. 2.4-fold in EN).	13	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	level of insulin	insulin	Akt1	Akt1	akt1	15	16	19	20
Additionally , insulin administration increased the activities of Akt1 , Akt2 , and Akt3 kinases in calf muscles and caused a sevenfold augmentation in 2-deoxyglucose uptake by these muscles .	Additionally, insulin administration increased the activities of Akt1, Akt2, and Akt3 kinases in calf muscles and caused a sevenfold augmentation in 2-deoxyglucose uptake by these muscles.	2	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	2	3	8	9
At 3 days , the insulin stimulated activity of Akt1 kinase in the denervated soleus and plantaris muscles was 86 and 71 % lower , respectively , than in their sham counterparts .	At 3 days, the insulin stimulated activity of Akt1 kinase in the denervated soleus and plantaris muscles was 86 and 71% lower, respectively, than in their sham counterparts.	4	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	5	6	9	10
Furthermore , insulin activation of protein kinase B ( PKB ) was compared with immunoblotting of serine residues at position 473 .	Furthermore, insulin activation of protein kinase B (PKB) was compared with immunoblotting of serine residues at position 473.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	2	3	5	8
Protein kinase B ( PKB ) is involved in signaling to a multitude of important cellular events and is activated by insulin and growth factors , including insulin like growth factor I ( IGF-I ) .	Protein kinase B (PKB) is involved in signaling to a multitude of important cellular events and is activated by insulin and growth factors, including insulin like growth factor I (IGF-I).	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Protein kinase B	Protein kinase B	Protein kinase B	21	22	0	3
In this model , proximal insulin signaling , including insulin receptor substrate ( IRS )-1-bound phosphatidylinositol 3-kinase ( PI 3-kinase ) activation , is preserved , but insulin stimulated protein kinase B ( Akt ) activation is markedly impaired .	In this model, proximal insulin signaling, including insulin receptor substrate (IRS)-1-bound phosphatidylinositol 3-kinase (PI 3-kinase) activation, is preserved, but insulin stimulated protein kinase B (Akt) activation is markedly impaired.	27	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	27	28	29	32
Insulin stimulates phosphatidylinositol 3-kinase ( PI3K ) and thereby AKT1 .	Insulin stimulates phosphatidylinositol 3-kinase (PI3K) and thereby AKT1.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	AKT1	AKT1	AKT1	0	1	9	10
Although IL-1beta stimulation suppresses the insulin activation of protein kinase B , the major upstream regulator of IGFBP1 mRNA transcription , the induction of IGFBP1 by IL-1beta did not require an intact insulin response element .	Although IL-1beta stimulation suppresses the insulin activation of protein kinase B, the major upstream regulator of IGFBP1 mRNA transcription, the induction of IGFBP1 by IL-1beta did not require an intact insulin response element.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	5	6	8	11
Insulin mediated Akt1 translocation and activation in mitochondria represents a signal mechanism linking extracellular fuel supply and hormonal response to coordinate bioenergetic supply and demand in cardiac muscle .	Insulin mediated Akt1 translocation and activation in mitochondria represents a signal mechanism linking extracellular fuel supply and hormonal response to coordinate bioenergetic supply and demand in cardiac muscle.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt1	Akt1	Akt1	0	1	2	3
Basal protein kinase B ( PKB ) activity was elevated about twofold in FF rats and was not further stimulated by insulin .	Basal protein kinase B (PKB) activity was elevated about twofold in FF rats and was not further stimulated by insulin.	1	22	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	21	22	1	4
They verified that AKT2 was distributed among cytosolic , plasma membrane and low density membrane fractions under basal conditions and discovered that insulin increased the plasma membrane levels for AKT2 , but not AKT1 .	They verified that AKT2 was distributed among cytosolic, plasma membrane and low density membrane fractions under basal conditions and discovered that insulin increased the plasma membrane levels for AKT2, but not AKT1.	22	34	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT1	AKT1	AKT1	22	23	33	34
In obese rodent models , insulin stimulated AKT1 activity was reported to decrease in muscle and adipose tissue but increased in liver , in contrast , AKT2 activity was decreased in muscle and liver but increased in adipose tissue [ XREF_BIBR ] .	In obese rodent models, insulin stimulated AKT1 activity was reported to decrease in muscle and adipose tissue but increased in liver, in contrast, AKT2 activity was decreased in muscle and liver but increased in adipose tissue [XREF_BIBR].	5	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT1	AKT1	AKT1	5	6	7	8
Cell and rodent studies have demonstrated that insulin in the hepatocyte acts via the insulin receptor and insulin receptor substrate-2 to activate downstream signaling ( phosphoinositide 3-kinase and protein kinase B ) , ultimately dislocating FoxO1 from the nucleus of the cell .	Cell and rodent studies have demonstrated that insulin in the hepatocyte acts via the insulin receptor and insulin receptor substrate-2 to activate downstream signaling (phosphoinositide 3-kinase and protein kinase B), ultimately dislocating FoxO1 from the nucleus of the cell.	7	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	7	8	28	31
In contrast , osmotic shock pretreatment markedly inhibited the insulin stimulation of protein kinase B ( PKB ) and p70S6 kinase activities .	In contrast, osmotic shock pretreatment markedly inhibited the insulin stimulation of protein kinase B (PKB) and p70S6 kinase activities.	9	15	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	9	10	12	15
Selective activation of protein kinase B caused by the release of insulin growth factor-1 from muscle fibers during passive stretch promotes myosatellite cell proliferation and induces skeletal muscle hypertrophy .	Selective activation of protein kinase B caused by the release of insulin growth factor-1 from muscle fibers during passive stretch promotes myosatellite cell proliferation and induces skeletal muscle hypertrophy.	3	13	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	11	12	3	6
In obese , insulin resistant Zucker rats , Akt2 expression is reduced by more than half , while Akt1 expression remains unaffected in muscle ; however , both insulin stimulated Akt1 and Akt2 activity is significantly diminished in muscle but not adipose [ XREF_BIBR ] .	In obese, insulin resistant Zucker rats, Akt2 expression is reduced by more than half, while Akt1 expression remains unaffected in muscle; however, both insulin stimulated Akt1 and Akt2 activity is significantly diminished in muscle but not adipose [XREF_BIBR].	27	41	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	28	29	30	31
Insulin stimulates glucose transport and certain other metabolic processes by activating atypical PKC isoforms ( lambda , zeta , iota ) and protein kinase B ( PKB ) through increases in D3-polyphosphoinositides derived from the action of PI3K .	Insulin stimulates glucose transport and certain other metabolic processes by activating atypical PKC isoforms (lambda, zeta, iota) and protein kinase B (PKB) through increases in D3-polyphosphoinositides derived from the action of PI3K.	0	25	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	22	25
The results indicate that insulin activates Akt1 and Akt3 isoforms , but not Akt2 ( XREF_FIG ) .	The results indicate that insulin activates Akt1 and Akt3 isoforms, but not Akt2 (XREF_FIG).	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	4	5	6	7
Insulin treatment of NMuMG cells or MEFs resulted in activation of both Akt1 and Akt2 , assessed by phosphorylation at Ser 473 and Thr 408 , with Akt1 activation seeming more prominent than Akt2 activation due to much higher total amounts of Akt1 ( XREF_SUPPLEMENTARY ) .	Insulin treatment of NMuMG cells or MEFs resulted in activation of both Akt1 and Akt2, assessed by phosphorylation at Ser 473 and Thr 408, with Akt1 activation seeming more prominent than Akt2 activation due to much higher total amounts of Akt1 (XREF_SUPPLEMENTARY).	0	14	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt1	Akt1	Akt1	0	1	12	13
Furthermore , we have shown for the first time that treatment with the CB1 inverse agonist SR141716 alone can improve insulin sensitivity in skeletal muscle as determined by its ability to enhance both insulin stimulated PKB- and ERK1/2 directed signaling .	Furthermore, we have shown for the first time that treatment with the CB1 inverse agonist SR141716 alone can improve insulin sensitivity in skeletal muscle as determined by its ability to enhance both insulin stimulated PKB- and ERK1/2 directed signaling.	31	38	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB-	PKB-	PKB-	33	34	35	36
XREF_BIBR , XREF_BIBR Elevated levels of insulin also upregulates Akt-1 and this induces mammalian target of rapamycin ( mTOR ) that in turn activates the p70 ribosomal subunit S6 kinase-1 and promotes protein synthesis contributing to cardiac hypertrophy .	XREF_BIBR, XREF_BIBR Elevated levels of insulin also upregulates Akt-1 and this induces mammalian target of rapamycin (mTOR) that in turn activates the p70 ribosomal subunit S6 kinase-1 and promotes protein synthesis contributing to cardiac hypertrophy.	4	10	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	Akt-1	Akt-1	akt-1	6	7	9	10
Insulin treatment of retinal explants results in specific activation of Akt1 and Akt3 , but not of Akt2 .	Insulin treatment of retinal explants results in specific activation of Akt1 and Akt3, but not of Akt2.	0	12	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt1	Akt1	Akt1	0	1	10	11
Insulin dependent activation of protein kinase B ( Akt ) regulates this process , in part , by inhibiting FoxO1 dependent hepatic gluconeogenesis by direct phosphorylation and subsequent cytoplasmic exclusion .	Insulin dependent activation of protein kinase B (Akt) regulates this process, in part, by inhibiting FoxO1 dependent hepatic gluconeogenesis by direct phosphorylation and subsequent cytoplasmic exclusion.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	4	7
Insulin stimulation of Akt1 and Akt2 signaling in CF airway cells was diminished compared with that observed in airway cells expressing wild-type CFTR .	Insulin stimulation of Akt1 and Akt2 signaling in CF airway cells was diminished compared with that observed in airway cells expressing wild-type CFTR.	0	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	Akt1	Akt1	Akt1	0	1	3	4
In primary cultures of human hepatocytes , glucocorticoids increased insulin stimulated p-ser473akt and protein kinase B. Similarly , glucocorticoids enhanced insulin stimulated p-ser473akt and protein kinase B and increased Insulin receptor substrate 2 mRNA expression in sc , but not omental , intact human adipocytes , suggesting a depot-specificity of action .	In primary cultures of human hepatocytes, glucocorticoids increased insulin stimulated p-ser473akt and protein kinase B. Similarly, glucocorticoids enhanced insulin stimulated p-ser473akt and protein kinase B and increased Insulin receptor substrate 2 mRNA expression in sc, but not omental, intact human adipocytes, suggesting a depot-specificity of action.	19	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	20	21	24	27
Akt1 and Akt2 activations by insulin have a similar time course and are maximal by 2.5 min in adipocytes of both lean and obese rats .	Akt1 and Akt2 activations by insulin have a similar time course and are maximal by 2.5 min in adipocytes of both lean and obese rats.	0	6	activations	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	5	6	0	1
Along these lines , recent studies have demonstrated a significant improvement in the insulin mediated activation of protein kinase B ( AKT )/mammalian target of rapamycin ( mTOR ) in the soleus muscle of aged rats [ XREF_BIBR ] , and may be partially responsible for the preservation of muscle function in the elderly when challenged by the deleterious influence of bedrest [ XREF_BIBR * ] .	Along these lines, recent studies have demonstrated a significant improvement in the insulin mediated activation of protein kinase B (AKT)/mammalian target of rapamycin (mTOR) in the soleus muscle of aged rats [XREF_BIBR], and may be partially responsible for the preservation of muscle function in the elderly when challenged by the deleterious influence of bedrest [XREF_BIBR *].	13	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	13	14	17	20
2-APB did not inhibit the insulin mediated activation of protein kinase B or extracellular signal related kinase 1/2 in whole muscles .	2-APB did not inhibit the insulin mediated activation of protein kinase B or extracellular signal related kinase 1/2 in whole muscles.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	5	6	9	12
Insulin also activated protein kinase B ( PKB ) , which may lie upstream of p70 S6k and 4E-BP1 , with the activation of the different isoforms being in the order alpha > beta > gamma .	Insulin also activated protein kinase B (PKB), which may lie upstream of p70 S6k and 4E-BP1, with the activation of the different isoforms being in the order alpha> beta> gamma.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	3	6
The relatively high blood insulin levels in Pten +/- Akt2 -/- mice may elevate the activity of Akt1 , and possibly Akt3 , thus , limiting the reduction of total Akt activity and preventing this activity from dropping to a threshold level required to inhibit tumorigenesis .	The relatively high blood insulin levels in Pten +/- Akt2 -/- mice may elevate the activity of Akt1, and possibly Akt3, thus, limiting the reduction of total Akt activity and preventing this activity from dropping to a threshold level required to inhibit tumorigenesis.	4	18	elevate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin levels	insulin	Akt1	Akt1	akt1	4	5	17	18
Previous studies have revealed that insulin dependent activation of protein kinase B ( Akt ) regulates metabolic processes via discrete transcriptional effectors .	Previous studies have revealed that insulin dependent activation of protein kinase B (Akt) regulates metabolic processes via discrete transcriptional effectors.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	5	6	9	12
Insulin dose dependently activated protein kinase B ( PKB ) but did not change atypical protein kinase C ( aPKC ) activity in control cells .	Insulin dose dependently activated protein kinase B (PKB) but did not change atypical protein kinase C (aPKC) activity in control cells.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	4	7
It must also be noted that it has previously been shown that while there is no defect in insulin ' s regulation of hepatic glycogen metabolism in dysmetabolic monkeys [ XREF_BIBR ] , there is a defect in insulin stimulated protein kinase B ( PKB and Akt ) activity [ XREF_BIBR ] , perhaps suggesting that hepatic insulin resistance in them may manifest in the regulation of gluconeogenesis via PKB and forkhead box protein O1 [ XREF_BIBR ] .	It must also be noted that it has previously been shown that while there is no defect in insulin 's regulation of hepatic glycogen metabolism in dysmetabolic monkeys [XREF_BIBR], there is a defect in insulin stimulated protein kinase B (PKB and Akt) activity [XREF_BIBR], perhaps suggesting that hepatic insulin resistance in them may manifest in the regulation of gluconeogenesis via PKB and forkhead box protein O1 [XREF_BIBR].	36	43	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	38	39	40	43
Regarding insulin sensitivity , darunavir and darunavir and ritonavir had no significant effect on insulin activation of protein kinase B ( Akt and PKB ) and MAP kinase and of glucose transport , whereas lopinavir and ritonavir and atazanavir and ritonavir partly impaired the effect of insulin .	Regarding insulin sensitivity, darunavir and darunavir and ritonavir had no significant effect on insulin activation of protein kinase B (Akt and PKB) and MAP kinase and of glucose transport, whereas lopinavir and ritonavir and atazanavir and ritonavir partly impaired the effect of insulin.	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	14	15	17	20
Mechanistically , we find that mutp53 augments insulin induced AKT1 activation by binding and inhibiting the tumor suppressor DAB2IP ( DAB2 interacting protein ) in the cytoplasm .	Mechanistically, we find that mutp53 augments insulin induced AKT1 activation by binding and inhibiting the tumor suppressor DAB2IP (DAB2 interacting protein) in the cytoplasm.	6	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT1	AKT1	AKT1	7	8	9	10
Furthermore , we detected the IGF-IR , p85 , and Akt in CEMs in OPCs during steady-state stimulation of the IGF-IR ( standard media with micromolar levels of insulin that activate the IGF-IR ) and phosphorylated IGF-IR and Akt with IGF-I stimulation .	Furthermore, we detected the IGF-IR, p85, and Akt in CEMs in OPCs during steady-state stimulation of the IGF-IR (standard media with micromolar levels of insulin that activate the IGF-IR) and phosphorylated IGF-IR and Akt with IGF-I stimulation.	26	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	IGF-IR	IGF-IR	igf-ir	28	29	32	33
Both in vivo and in vitro studies have demonstrated that insulin does not stimulate rates of mammary lipogenesis in the lactating cow [ see review ] , but the high insulin dose in the current experiment is expected to stimulate the IGF-I receptor .	Both in vivo and in vitro studies have demonstrated that insulin does not stimulate rates of mammary lipogenesis in the lactating cow [see review], but the high insulin dose in the current experiment is expected to stimulate the IGF-I receptor.	30	43	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-I receptor	IGF-I receptor	IGF-I receptor	30	31	41	43
Thus our in vitro experiments showed that insulin glargine was able to activate the IGF-IR more strongly than human insulin and insulin detemir , yet still significantly less strong than IGF-I .	Thus our in vitro experiments showed that insulin glargine was able to activate the IGF-IR more strongly than human insulin and insulin detemir, yet still significantly less strong than IGF-I.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	7	8	14	15
Insulin acts mainly through its own receptor , but can also activate the IGF-I receptor ( IGF-IR ) .	Insulin acts mainly through its own receptor, but can also activate the IGF-I receptor (IGF-IR).	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IGF-I receptor	IGF-I receptor	IGF-I receptor	0	1	13	15
Since IGF-1R could be activated also by insulin , we examined whether insulin could mimic the effect of IGF-1 and inhibit Cl channels in the TAL .	Since IGF-1R could be activated also by insulin, we examined whether insulin could mimic the effect of IGF-1 and inhibit Cl channels in the TAL.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	7	8	1	2
Based on this in vitro functional data , we hypothesized that the increased serum levels of insulin in patients with type 2 diabetes may activate the IGF-1R in skin and lead to a decreased frequency of skin cancer in these patients .	Based on this in vitro functional data, we hypothesized that the increased serum levels of insulin in patients with type 2 diabetes may activate the IGF-1R in skin and lead to a decreased frequency of skin cancer in these patients.	14	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	IGF-1R	IGF-1R	igf-1r	16	17	26	27
This apparent paradox is likely explained by the inclusion of high concentrations of insulin ( 20 mug/ml or 3.44 muM ) in the basal WIT-L medium ; the Kd of insulin for IGF1R is 200-400 nM , XREF_BIBR , XREF_BIBR making it likely that insulin is stimulating IGF1R in lymphoblasts under these conditions .	This apparent paradox is likely explained by the inclusion of high concentrations of insulin (20 mug/ml or 3.44 muM) in the basal WIT-L medium; the Kd of insulin for IGF1R is 200-400 nM, XREF_BIBR, XREF_BIBR making it likely that insulin is stimulating IGF1R in lymphoblasts under these conditions.	44	48	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	44	45	47	48
Homology between IGF1R and the insulin receptor ( INSR ) allows IGF signaling through INSR , although with lower affinity ; and vice versa , insulin ( and pro insulin ) can activate IGF1R .	Homology between IGF1R and the insulin receptor (INSR) allows IGF signaling through INSR, although with lower affinity; and vice versa, insulin (and pro insulin) can activate IGF1R.	25	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	25	26	33	34
IR gene expression was increased after treatment with insulin ( 2.9-fold change , p = 0.027 ) and further after metformin treatment ( 4.7-fold change , p < 0.001 ) , and in IGF-1R , the group treated with insulin ( 1.83-fold change ) and metformin ( 1.78-fold change ) showed more expression , than control group ( p < 0.001 ) .	IR gene expression was increased after treatment with insulin (2.9-fold change, p = 0.027) and further after metformin treatment (4.7-fold change, p < 0.001), and in IGF-1R, the group treated with insulin (1.83-fold change) and metformin (1.78-fold change) showed more expression, than control group (p < 0.001).	32	50	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	39	40	33	34
By binding to hybrid receptors , insulin may stimulate specific IGF-IR signaling pathways .	By binding to hybrid receptors, insulin may stimulate specific IGF-IR signaling pathways.	6	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	6	7	10	11
Stimulation of IGF1R by insulin may lead to inappropriate lamellar epidermal cell proliferation and lamellar weakening , a potential mechanism for hyperinsulinemic laminitis .	Stimulation of IGF1R by insulin may lead to inappropriate lamellar epidermal cell proliferation and lamellar weakening, a potential mechanism for hyperinsulinemic laminitis.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	4	5	2	3
In addition , in certain cell types , insulin activates the IGF-IR at physiological concentrations .	In addition, in certain cell types, insulin activates the IGF-IR at physiological concentrations.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	8	9	11	12
It is well known that at higher concentrations , insulin stimulates the IGF-I receptor .	It is well known that at higher concentrations, insulin stimulates the IGF-I receptor.	9	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-I receptor	IGF-I receptor	IGF-I receptor	9	10	12	14
Consequently it is hard to draw any conclusion from these in vitro results for the role of an insulin mediated IGF1R promoted cell growth in vivo .	Consequently it is hard to draw any conclusion from these in vitro results for the role of an insulin mediated IGF1R promoted cell growth in vivo.	15	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	18	19	20	21
By contrast , insulin was unable to activate the IGF1R in either cell line , regardless of the IGF1R levels .	By contrast, insulin was unable to activate the IGF1R in either cell line, regardless of the IGF1R levels.	3	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	3	4	9	10
Furthermore , immunoprecipitation ( IP ) assays revealed that insulin was unable to activate the IGF1R in P69 cells ( XREF_FIG B ) .	Furthermore, immunoprecipitation (IP) assays revealed that insulin was unable to activate the IGF1R in P69 cells (XREF_FIG B).	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	9	10	15	16
Alterations in the IGF and IGF-1R axis caused by insulin resistance contribute to the development of CRC [ XREF_BIBR ] .	Alterations in the IGF and IGF-1R axis caused by insulin resistance contribute to the development of CRC [XREF_BIBR].	3	10	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	9	10	5	6
Furthermore , the media used in our experiments to initiate differentiation contains micromolar levels of insulin , known to stimulate the IGF-IR , and as such can be considered IGF-I supplemented .	Furthermore, the media used in our experiments to initiate differentiation contains micromolar levels of insulin, known to stimulate the IGF-IR, and as such can be considered IGF-I supplemented.	13	22	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	IGF-IR	IGF-IR	igf-ir	15	16	21	22
By using the IGF-I KIRA assay , we compared IGF-IR activation in vitro induced by human insulin , two short acting insulin analogs ( insulin aspart and insulin lispro ) and two long acting insulin analogs ( insulin glargine and insulin detemir ) .	By using the IGF-I KIRA assay, we compared IGF-IR activation in vitro induced by human insulin, two short acting insulin analogs (insulin aspart and insulin lispro) and two long acting insulin analogs (insulin glargine and insulin detemir).	9	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	16	17	9	10
However , insulin concentrations more than 10 times that normal human plasma could significantly enhance overall IGF-IR complex concentration in cartilage .	However, insulin concentrations more than 10 times that normal human plasma could significantly enhance overall IGF-IR complex concentration in cartilage.	2	18	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	2	3	16	17
NRP-152 cells require IGF-I ( or a level of insulin that activates the IGF-I receptor ) , for growth and survival XREF_BIBR through mechanisms that remain incompletely understood XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	NRP-152 cells require IGF-I (or a level of insulin that activates the IGF-I receptor), for growth and survival XREF_BIBR through mechanisms that remain incompletely understood XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-I receptor	IGF-I receptor	IGF-I receptor	9	10	13	15
Micromolar levels of insulin can stimulate the IGF-1R ( and IGF-1R/IR hybrid receptors ) that suggests that either IGF-I or IGF-II will promote the growth of NSPs in 4.4 nM insulin containing media [ XREF_BIBR ] .	Micromolar levels of insulin can stimulate the IGF-1R (and IGF-1R/IR hybrid receptors) that suggests that either IGF-I or IGF-II will promote the growth of NSPs in 4.4 nM insulin containing media [XREF_BIBR].	1	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	IGF-1R	IGF-1R	igf-1r	3	4	7	8
By using the same IGF-I KIRA assay in another in vitro experiment , we compared IGF-IR activation induced by insulin glargine and insulin NPH .	By using the same IGF-I KIRA assay in another in vitro experiment, we compared IGF-IR activation induced by insulin glargine and insulin NPH.	15	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	19	20	15	16
IGF-1R can also heterodimerize with the insulin receptor and be activated by insulin [ XREF_BIBR ] .	IGF-1R can also heterodimerize with the insulin receptor and be activated by insulin [XREF_BIBR].	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	12	13	0	1
Insulin Receptor Phosphorylation by Endogenous Insulin or the Insulin Analog AspB10 Promotes Mammary Tumor Growth Independent of the IGF-I Receptor .	Insulin Receptor Phosphorylation by Endogenous Insulin or the Insulin Analog AspB10 Promotes Mammary Tumor Growth Independent of the IGF-I Receptor.	0	20	Promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin Receptor Phosphorylation by Endogenous Insulin	insulin	IGF-I Receptor	IGF-I Receptor	igf-i receptor	5	6	18	20
Ganitumab potently inhibited baseline and IGF-I-, IGF-II-, and insulin induced IGF-IR and IGF-IR and insulin hybrid receptor signaling in vitro and in vivo .	Ganitumab potently inhibited baseline and IGF-I-, IGF-II-, and insulin induced IGF-IR and IGF-IR and insulin hybrid receptor signaling in vitro and in vivo.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	8	9	10	11
Depending on the availability of IGF and insulin ligands and the ratios of these receptors , IGFs can activate IR and , conversely , insulin activates IGF1R [ XREF_BIBR ] .	Depending on the availability of IGF and insulin ligands and the ratios of these receptors, IGFs can activate IR and, conversely, insulin activates IGF1R [XREF_BIBR].	24	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	24	25	26	27
By binding to hybrid receptors , insulin may stimulate specific IGF-IR signalling pathways .	By binding to hybrid receptors, insulin may stimulate specific IGF-IR signalling pathways.	6	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	6	7	10	11
As insulin at high concentration may activate IGF-I receptor , thus we examined the effects of insulin at lower doses ( close to physiological concentrations ) on GH induced STAT5 activation .	As insulin at high concentration may activate IGF-I receptor, thus we examined the effects of insulin at lower doses (close to physiological concentrations) on GH induced STAT5 activation.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-I receptor	IGF-I receptor	IGF-I receptor	1	2	7	9
It is therefore tempting to speculate that the greater mitogenic effects of insulin and insulin analogues are solely based on the growth promoting activity of the IR itself , and that IGF1R activation by insulin analogues may be less relevant under therapeutic conditions than previously discussed .	It is therefore tempting to speculate that the greater mitogenic effects of insulin and insulin analogues are solely based on the growth promoting activity of the IR itself, and that IGF1R activation by insulin analogues may be less relevant under therapeutic conditions than previously discussed.	31	35	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	34	35	31	32
Insulin induced tyrosine autophosphorylation of the IR beta-chain was augmented in IGF-IR -- deficient cells .	Insulin induced tyrosine autophosphorylation of the IR beta-chain was augmented in IGF-IR -- deficient cells.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IGF-IR	IGF-IR	IGF-IR	0	1	11	12
Insulin growth factor I binding activates the IGF-I receptor ( IGF-I R ) , a receptor tyrosine kinase .	Insulin growth factor I binding activates the IGF-I receptor (IGF-I R), a receptor tyrosine kinase.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IGF-I receptor	IGF-I receptor	IGF-I receptor	0	1	7	9
Tumors in mice treated with glargine ( an insulin analogue that induces only a mild IGF1R activation in the MG ) also developed earlier compared to vehicle- and insulin treated animals , but this trend was not significant [ XREF_BIBR ] .	Tumors in mice treated with glargine (an insulin analogue that induces only a mild IGF1R activation in the MG) also developed earlier compared to vehicle- and insulin treated animals, but this trend was not significant [XREF_BIBR].	8	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	8	9	15	16
XREF_BIBR Insulin resistance and the consequently compensatory hyperinsulinaemia affect the metabolic pathways , overstimulate the mitogenic pathway and activate IGF-1R .	XREF_BIBR Insulin resistance and the consequently compensatory hyperinsulinaemia affect the metabolic pathways, overstimulate the mitogenic pathway and activate IGF-1R.	1	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IGF-1R	IGF-1R	IGF-1R	1	2	19	20
Despite exposure to high glucose , insulin stimulated p-IGF-1R was maintained and IGF-1-stimulated p-IGF-1R was increased by 82 % in GM3S -/- KCs ( XREF_FIG , lanes 11 vs. 5 and 12 vs. 6 , respectively ) .	Despite exposure to high glucose, insulin stimulated p-IGF-1R was maintained and IGF-1-stimulated p-IGF-1R was increased by 82% in GM3S -/- KCs (XREF_FIG, lanes 11 vs. 5 and 12 vs. 6, respectively).	6	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	p-IGF-1R	p-IGF-1R	p-IGF-1R	6	7	8	9
Although IGF-IR is highly specific to IGF-I and -II , insulin can still activate IGF-IR at higher tissue concentrations ( i.e. > 10 nM or ) XREF_BIBR .	Although IGF-IR is highly specific to IGF-I and -II, insulin can still activate IGF-IR at higher tissue concentrations (i.e.> 10 nM or) XREF_BIBR.	10	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	10	11	14	15
Thus all these data are reassuring and suggest that insulin glargine compared to human insulin ( at least in low doses ) does not increase IGF-IR signaling in vivo .	Thus all these data are reassuring and suggest that insulin glargine compared to human insulin (at least in low doses) does not increase IGF-IR signaling in vivo.	9	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	9	10	25	26
The aim of this study was to evaluate gene and protein expression of an insulin receptor ( IR ) , insulin like growth factor-1 ( IGF1 ) receptor ( IGF1R ) and aromatase in granulosa cells treated with metformin and insulin .	The aim of this study was to evaluate gene and protein expression of an insulin receptor (IR), insulin like growth factor-1 (IGF1) receptor (IGF1R) and aromatase in granulosa cells treated with metformin and insulin.	27	41	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	40	41	29	30
Linking mere IGF1R activation by insulin glargine and by [ Asp B10 ] insulin in vitro and tumor promoting activity in vivo ignores the fact that the IR activity profile of both molecules differ completely .	Linking mere IGF1R activation by insulin glargine and by [Asp B10] insulin in vitro and tumor promoting activity in vivo ignores the fact that the IR activity profile of both molecules differ completely.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	5	6	2	3
High concentrations of insulin are known to activate the IGF-IR and our previous findings demonstrate that the IR , and to lesser extent the IGF-IR , are activated in hyperplastic mammary tumor tissue extracted from type 2 diabetic mice .	High concentrations of insulin are known to activate the IGF-IR and our previous findings demonstrate that the IR, and to lesser extent the IGF-IR, are activated in hyperplastic mammary tumor tissue extracted from type 2 diabetic mice.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	3	4	9	10
Confocal imaging experiments showed that insulin glargine , but not regular insulin induced IGF-IR internalisation similarly to IGF-I .	Confocal imaging experiments showed that insulin glargine, but not regular insulin induced IGF-IR internalisation similarly to IGF-I.	6	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	11	12	13	14
Similarly , IP assays revealed that insulin ( between 5 and 500ng/ml ) did not activate the IGF1R in P69 cells .	Similarly, IP assays revealed that insulin (between 5 and 500ng/ml) did not activate the IGF1R in P69 cells.	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	6	7	17	18
Nevertheless , this supraphysiological concentration of insulin can stimulate IGF-IR , which is known to mediate VSMC migration [ XREF_BIBR ] .	Nevertheless, this supraphysiological concentration of insulin can stimulate IGF-IR, which is known to mediate VSMC migration [XREF_BIBR].	4	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	6	7	9	10
In the current study , neither glargine nor ( A21Gly , DiD-Arg ) insulin activated IGF1R in any tissue at any dose tested .	In the current study, neither glargine nor (A21Gly,DiD-Arg) insulin activated IGF1R in any tissue at any dose tested.	6	18	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	13	14	15	16
Thus , IGF1R activation by insulin analogues may be less relevant than previously realized .	Thus, IGF1R activation by insulin analogues may be less relevant than previously realized.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	5	6	2	3
To rule out cross-reactivity between these two proteins and to determine whether the effects of IGF-1 on IGF-1R were specific , monolayers were treated with insulin ( 15 microg/ml ) for 16 hours .	To rule out cross-reactivity between these two proteins and to determine whether the effects of IGF-1 on IGF-1R were specific, monolayers were treated with insulin (15 microg/ml) for 16 hours.	15	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	25	26	17	18
Likewise , insulin , at physiological levels , will not activate the IGF-1R [ XREF_BIBR ] .	Likewise, insulin, at physiological levels, will not activate the IGF-1R [XREF_BIBR].	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	2	3	12	13
IGF-1 and insulin have very similar molecular structures and high concentrations of insulin will activate the IGF-1R .	IGF-1 and insulin have very similar molecular structures and high concentrations of insulin will activate the IGF-1R.	10	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	12	13	16	17
The IGF-IR activation induced by insulin glargine was significantly lower compared to pure IGF-I over the whole range of concentrations tested .	The IGF-IR activation induced by insulin glargine was significantly lower compared to pure IGF-I over the whole range of concentrations tested.	1	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-IR	IGF-IR	IGF-IR	5	6	1	2
The basic growth supporting medium ( GM ) for neurospheres , although not containing IGF-I , is supplemented with high levels of insulin , which at this concentration stimulates IGF-IR .	The basic growth supporting medium (GM) for neurospheres, although not containing IGF-I, is supplemented with high levels of insulin, which at this concentration stimulates IGF-IR.	20	30	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	IGF-IR	IGF-IR	igf-ir	22	23	29	30
A high level of insulin stimulates the insulin and IGF-1R signaling pathway via insulin receptor substrates ( IRS ) .	A high level of insulin stimulates the insulin and IGF-1R signaling pathway via insulin receptor substrates (IRS).	2	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	level of insulin	insulin	IGF-1R	IGF-1R	igf-1r	4	5	9	10
Insulin activates IGF-I receptor , known to have growth promoting effects .	Insulin activates IGF-I receptor, known to have growth promoting effects.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	IGF-I receptor	IGF-I receptor	IGF-I receptor	0	1	2	4
In the presence of the IRAK4 inhibitor , the disappearance of the endogenous IRAK1 signal was reduced , demonstrating efficacy of the inhibitor to prevent IRAK1 activation , whereas the smearing seen in the GFP immunoblot was significantly decreased , demonstrating that IRAK4 induces IRAK1 modifications ( XREF_FIG C ) .	In the presence of the IRAK4 inhibitor, the disappearance of the endogenous IRAK1 signal was reduced, demonstrating efficacy of the inhibitor to prevent IRAK1 activation, whereas the smearing seen in the GFP immunoblot was significantly decreased, demonstrating that IRAK4 induces IRAK1 modifications (XREF_FIG C).	42	45	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	42	43	44	45
Once activated , IRAK4 triggers further activation of IRAK1 and IRAK2 .	Once activated, IRAK4 triggers further activation of IRAK1 and IRAK2.	3	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	3	4	8	9
In the MyD88 signaling pathway , stimulation of TLRs triggers its association with MyD88 , which in turn recruits IL-1R-associated kinase 4 ( IRAK4 ) , allowing the assembly of IRAK1 .	In the MyD88 signaling pathway, stimulation of TLRs triggers its association with MyD88, which in turn recruits IL-1R-associated kinase 4 (IRAK4), allowing the assembly of IRAK1.	20	31	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	23	24	30	31
IRAK1 , which interacts with MyD88 and IRAK4 and is activated by IRAK4 , has been shown to be indispensable for the early phase activation of PKD1 XREF_BIBR , XREF_BIBR .	IRAK1, which interacts with MyD88 and IRAK4 and is activated by IRAK4, has been shown to be indispensable for the early phase activation of PKD1 XREF_BIBR, XREF_BIBR.	0	19	activated	Positive_regulation_syntax_2_verb	Positive_activation	Positive_regulation	IRAK4	IRAK4	irak4	IRAK1	IRAK1, which interacts with MyD88 and IRAK4	irak1	12	13	0	1
Following TLR or IL-1R stimulation , MYD88 is recruited to the activated receptor complex as a homodimer and its association with IRAK4 activates IRAK1 and IRAK2 .	Following TLR or IL-1R stimulation, MYD88 is recruited to the activated receptor complex as a homodimer and its association with IRAK4 activates IRAK1 and IRAK2.	19	25	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	21	22	23	24
Myddosome formation promotes IRAK4 autoactivation , which initially activates IRAK1 and , at later time points , IRAK2 .	Myddosome formation promotes IRAK4 autoactivation, which initially activates IRAK1 and, at later time points, IRAK2.	3	17	initially activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	3	4	9	10
XREF_FIG B illustrates that , in contrast to the WT IRAK-4 construct that enhanced IL-1-induced IRAK-1 kinase activity in the HEK293T cells , overexpression of the mutant not only failed to enhance endogenous kinase activity , but also inhibited it .	XREF_FIG B illustrates that, in contrast to the WT IRAK-4 construct that enhanced IL-1-induced IRAK-1 kinase activity in the HEK293T cells, overexpression of the mutant not only failed to enhance endogenous kinase activity, but also inhibited it.	10	17	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK-4	IRAK-4	IRAK-4	IRAK-1	IRAK-1	IRAK-1	10	11	15	16
Upon activation of TLR , IRAK4 undergoes autophosphorylation which then phosphorylate and activate IRAK1 .	Upon activation of TLR, IRAK4 undergoes autophosphorylation which then phosphorylate and activate IRAK1.	5	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	5	6	13	14
IRAK4 in turn phosphorylates and activate IRAK1 , which then recruits E3 ligase TRAF6 that functions together with dimeric ubiquitin conjugating enzyme complex UBC13 and UEV1A to induce its auto-polyubiquitinating and other neighboring target proteins via K63 linked polyubiquitin chains .	IRAK4 in turn phosphorylates and activate IRAK1, which then recruits E3 ligase TRAF6 that functions together with dimeric ubiquitin conjugating enzyme complex UBC13 and UEV1A to induce its auto-polyubiquitinating and other neighboring target proteins via K63 linked polyubiquitin chains.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	0	1	6	7
In the MyD88 dependent pathway , TLR binding leads to MyD88 forming a complex with IRAK kinases [ XREF_BIBR ] , such that IRAK4 activates IRAK1 [ XREF_BIBR , XREF_BIBR ] .	In the MyD88 dependent pathway, TLR binding leads to MyD88 forming a complex with IRAK kinases [XREF_BIBR], such that IRAK4 activates IRAK1 [XREF_BIBR, XREF_BIBR].	23	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	23	24	25	26
During Myddosome formation , IRAK4 activates IRAK1 , which is then autophosphorylated at several sites and released from MyD88 .	During Myddosome formation, IRAK4 activates IRAK1, which is then autophosphorylated at several sites and released from MyD88.	4	16	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IRAK4	IRAK4	irak4	IRAK1	IRAK1, which is then autophosphorylated	irak1	4	5	6	7
XREF_FIG C demonstrates that , unlike WT IRAK-4 , this more truncated form of IRAK-4 also failed to augment endogenous IRAK-1 kinase activity and inhibited endogenous basal and IL-1-induced IRAK-1 activity , although less than observed upon overexpression of pRK7-IRAK4 ( M # 1 ) .	XREF_FIG C demonstrates that, unlike WT IRAK-4, this more truncated form of IRAK-4 also failed to augment endogenous IRAK-1 kinase activity and inhibited endogenous basal and IL-1-induced IRAK-1 activity, although less than observed upon overexpression of pRK7-IRAK4 (M # 1).	12	30	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRAK-4	IRAK-4	IRAK-4	IRAK-1	IRAK-1	IRAK-1	14	15	29	30
IRAK4 activates its effectors IRAK2 and IRAK1 to induce activation of NF-kappaB and other transcription factors required for the generation of proinflammatory cytokines and reactive oxygen species ( ROS ) and the activation of MAPK .	IRAK4 activates its effectors IRAK2 and IRAK1 to induce activation of NF-kappaB and other transcription factors required for the generation of proinflammatory cytokines and reactive oxygen species (ROS) and the activation of MAPK.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	0	1	6	7
IRAK4 activates IRAK1 by phosphorylation .	IRAK4 activates IRAK1 by phosphorylation.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	0	1	2	3
MyD88 recruits and promotes the interaction between IL-1R-associated kinases ( IRAK ) -4 and IRAK-1 , resulting in the phosphorylation and activation of IRAK-1 by IRAK-4 [ XREF_BIBR , XREF_BIBR ] .	MyD88 recruits and promotes the interaction between IL-1R-associated kinases (IRAK) -4 and IRAK-1, resulting in the phosphorylation and activation of IRAK-1 by IRAK-4 [XREF_BIBR, XREF_BIBR].	19	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IRAK-4	IRAK-4	IRAK-4	IRAK-1	IRAK-1	IRAK-1	25	26	23	24
Although overexpression of the WT IRAK-4 vector in HEK293T cells augmented IRAK-1 kinase activity induced by IL-1 , overexpression of the mutant forms inhibited endogenous IRAK-1 kinase activity modestly , indicating that these molecules do not function normally and can interfere with WT IRAK-4 ( i.e ., exhibit dominant negative activity ) when coexpressed with a normal IRAK-4 gene .	Although overexpression of the WT IRAK-4 vector in HEK293T cells augmented IRAK-1 kinase activity induced by IL-1, overexpression of the mutant forms inhibited endogenous IRAK-1 kinase activity modestly, indicating that these molecules do not function normally and can interfere with WT IRAK-4 (i.e., exhibit dominant negative activity) when coexpressed with a normal IRAK-4 gene.	1	13	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK-4	overexpression of the WT IRAK-4	irak-4	IRAK-1	IRAK-1	irak-1	5	6	11	12
IRAK-4 and IRAK-1 are proximal protein kinases in TLR signalling pathways ; IRAK-1 is activated via its phosphorylation by IRAK-4 .	IRAK-4 and IRAK-1 are proximal protein kinases in TLR signalling pathways; IRAK-1 is activated via its phosphorylation by IRAK-4.	12	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IRAK-4	IRAK-4	IRAK-4	IRAK-1	IRAK-1	IRAK-1	19	20	12	13
In contrast to overexpression of WT IRAK-4 , which reproducibly enhanced endogenous IRAK-1 kinase activity in HEK293T cells , both mutated forms not only failed to augment endogenous IRAK-1 kinase activity but also were modestly inhibitory .	In contrast to overexpression of WT IRAK-4, which reproducibly enhanced endogenous IRAK-1 kinase activity in HEK293T cells, both mutated forms not only failed to augment endogenous IRAK-1 kinase activity but also were modestly inhibitory.	3	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK-4	overexpression of WT IRAK-4	irak-4	IRAK-1	IRAK-1	irak-1	6	7	12	13
In the MyD88 dependent TLR signaling pathway , MyD88 ( myeloid differentiation primary response gene 88 ) recruits IRAK4 ( IL-1 receptor associated kinase 4 ) and activate IRAK1 .	In the MyD88 dependent TLR signaling pathway, MyD88 (myeloid differentiation primary response gene 88) recruits IRAK4 (IL-1 receptor associated kinase 4) and activate IRAK1.	17	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	18	19	28	29
It would therefore appear that IRAK1 is activated when it interacts with IRAK4 , perhaps by IRAK4 induced IRAK1 dimerization [ XREF_BIBR , XREF_BIBR ] .	It would therefore appear that IRAK1 is activated when it interacts with IRAK4, perhaps by IRAK4 induced IRAK1 dimerization [XREF_BIBR, XREF_BIBR].	10	19	induced	Positive_early_activation	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	16	17	18	19
In this case , SpPelle may be finally activated via the kinase domain of SpTube in a similar manner to IRAK1 activated by IRAK4 XREF_BIBR .	In this case, SpPelle may be finally activated via the kinase domain of SpTube in a similar manner to IRAK1 activated by IRAK4 XREF_BIBR.	8	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	23	24	20	21
IRAK4 then activates IRAK-1 by phosphorylation .	IRAK4 then activates IRAK-1 by phosphorylation.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK-1	IRAK-1	IRAK-1	0	1	3	4
Then , IRAK4 activates IRAK1 and IRAK2 .	Then, IRAK4 activates IRAK1 and IRAK2.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	2	3	4	5
These results indicate that IRAK-1 and IRAK-2 are sequentially activated by IRAK-4 , and are essential for the TLR signaling .	These results indicate that IRAK-1 and IRAK-2 are sequentially activated by IRAK-4, and are essential for the TLR signaling.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IRAK-4	IRAK-4	IRAK-4	IRAK-1	IRAK-1	IRAK-1	11	12	4	5
IRAK4 , in turn , activates IRAK1 via phosphorylation [ XREF_BIBR ] .	IRAK4, in turn, activates IRAK1 via phosphorylation [XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	0	1	6	7
The IL-1 receptor associated kinase 4 ( IRAK4 ) binds to MyD88 and activates IRAK1 and IRAK2 .	The IL-1 receptor associated kinase 4 (IRAK4) binds to MyD88 and activates IRAK1 and IRAK2.	4	16	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	7	8	14	15
Having established relationships between increased IRAK4 mediated IRAK1 activation and lupus manifestations , we sought to address the role of IRAK4 kinase activity in murine lupus .	Having established relationships between increased IRAK4 mediated IRAK1 activation and lupus manifestations, we sought to address the role of IRAK4 kinase activity in murine lupus.	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	5	6	7	8
Receptor engagement induces MyD88 to activate IL-1R associated kinase-4 ( IRAK-4 ) , which in turn activates IRAK-1 and IRAK-2 .	Receptor engagement induces MyD88 to activate IL-1R associated kinase-4 (IRAK-4), which in turn activates IRAK-1 and IRAK-2.	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK-4	IRAK-4	IRAK-4	IRAK-1	IRAK-1	IRAK-1	10	11	17	18
In a typical ligand induced signaling cascade , IRAK1 is recruited to the receptor via MyD88 and is activated through phosphorylation by IRAK4 [ XREF_BIBR ] .	In a typical ligand induced signaling cascade, IRAK1 is recruited to the receptor via MyD88 and is activated through phosphorylation by IRAK4 [XREF_BIBR].	8	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	22	23	8	9
XREF_BIBR In the MyD88 dependent pathway , MyD88 recruits and promotes interaction between interleukin-1 receptor associated kinase ( IRAK ) -4 and IRAK-1 , resulting in phosphorylation and activation of IRAK-1 by IRAK-4 .	XREF_BIBR In the MyD88 dependent pathway, MyD88 recruits and promotes interaction between interleukin-1 receptor associated kinase (IRAK) -4 and IRAK-1, resulting in phosphorylation and activation of IRAK-1 by IRAK-4.	24	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IRAK-4	IRAK-4	IRAK-4	IRAK-1	IRAK-1	IRAK-1	32	33	30	31
Since the insulin activation of TC10 requires the appropriate COOH-terminal domain targeting sequences ( XREF_FIG ) , we next determined the effect of Cav3 and DGV on insulin stimulated TC10 activation ( XREF_FIG ) .	Since the insulin activation of TC10 requires the appropriate COOH-terminal domain targeting sequences (XREF_FIG), we next determined the effect of Cav3 and DGV on insulin stimulated TC10 activation (XREF_FIG).	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	2	3	5	6
TC10 alpha transfected into myoblasts is activated by insulin despite the lack of CAP expression and Cbl phosphorylation .	TC10 alpha transfected into myoblasts is activated by insulin despite the lack of CAP expression and Cbl phosphorylation.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	8	9	0	1
Although insulin activated the wild-type TC10 protein and a TC10 and H-Ras chimera that were targeted to lipid raft microdomains , it was unable to activate a TC10 and K-Ras chimera that was directed to the nonlipid raft domains .	Although insulin activated the wild-type TC10 protein and a TC10 and H-Ras chimera that were targeted to lipid raft microdomains, it was unable to activate a TC10 and K-Ras chimera that was directed to the nonlipid raft domains.	1	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	1	2	5	6
In contrast , the activation of TC10 by insulin in adipocytes is not reproduced by other growth factors and requires the assembly of established signaling components in a spatially restricted subcompartment of the plasma membrane .	In contrast, the activation of TC10 by insulin in adipocytes is not reproduced by other growth factors and requires the assembly of established signaling components in a spatially restricted subcompartment of the plasma membrane.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	8	9	6	7
IGF-1 and insulin activate TC10 through a GTP exchange factor in neurons and adipocytes XREF_BIBR , XREF_BIBR .	IGF-1 and insulin activate TC10 through a GTP exchange factor in neurons and adipocytes XREF_BIBR, XREF_BIBR.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	2	3	4	5
In contrast , TC10 and K-Ras was not significantly activated by insulin ( 0.9 +/- 0.1 ) .	In contrast, TC10 and K-Ras was not significantly activated by insulin (0.9 +/- 0.1).	3	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	11	12	3	4
Atypical protein kinase C ( PKCzeta and lambda ) is a convergent downstream target of the insulin stimulated phosphatidylinositol 3-kinase and TC10 signaling pathways .	Atypical protein kinase C (PKCzeta and lambda) is a convergent downstream target of the insulin stimulated phosphatidylinositol 3-kinase and TC10 signaling pathways.	13	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	16	17	21	22
TC10 activation by insulin is catalyzed by the exchange factor C3G , which is translocated to lipid rafts along with its binding partner CrkII as a consequence of Cbl tyrosine phosphorylation by the insulin receptor .	TC10 activation by insulin is catalyzed by the exchange factor C3G, which is translocated to lipid rafts along with its binding partner CrkII as a consequence of Cbl tyrosine phosphorylation by the insulin receptor.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	3	4	0	1
Thus , these data demonstrate that the upstream pathway required for insulin dependent activation of TC10 is also confined to the same specific lipid raft microdomain defined by the COOH-terminal H-Ras and TC10 targeting sequences .	Thus, these data demonstrate that the upstream pathway required for insulin dependent activation of TC10 is also confined to the same specific lipid raft microdomain defined by the COOH-terminal H-Ras and TC10 targeting sequences.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	11	12	15	16
What role caveolin binding plays in the activation of TC10 by insulin remains uncertain .	What role caveolin binding plays in the activation of TC10 by insulin remains uncertain.	4	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	11	12	9	10
Previous works have demonstrated that insulin stimulation results in the activation of TC10 .	Previous works have demonstrated that insulin stimulation results in the activation of TC10.	5	13	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	5	6	12	13
Since insulin mediated activation of TC10 promotes the exocytic processes of GLUT4 , it may associate with the development of type 2 diabetes .	Since insulin mediated activation of TC10 promotes the exocytic processes of GLUT4, it may associate with the development of type 2 diabetes.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	1	2	5	6
It is therefore possible that this phosphorylation event may modulate the TC10-Caveolin interaction and therefore could play a role in the insulin mediated activation of TC10 .	It is therefore possible that this phosphorylation event may modulate the TC10-Caveolin interaction and therefore could play a role in the insulin mediated activation of TC10.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	21	22	25	26
However , insulin was unable to activate the TC10 and K-Ras chimera under the identical conditions ( XREF_FIG C , lanes 1-5 ) .	However, insulin was unable to activate the TC10 and K-Ras chimera under the identical conditions (XREF_FIG C, lanes 1-5).	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	2	3	8	9
Coexpression of HA-TC10/WT with Cav3/WT had no significant effect on the insulin stimulation of TC10 activation ( XREF_FIG A , lanes 1-5 ) .	Coexpression of HA-TC10/WT with Cav3/WT had no significant effect on the insulin stimulation of TC10 activation (XREF_FIG A, lanes 1-5).	11	15	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	11	12	14	15
However , in the presence of Cav3 and DGV insulin was only able to activate TC10 1.0 +/- 0.1-fold .	However, in the presence of Cav3 and DGV insulin was only able to activate TC10 1.0 +/- 0.1-fold.	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	9	10	15	16
In addition , cholesterol depletion with methyl-beta-cyclodextrin ( MbetaCD ) disperses proteins associated with plasma membrane lipid raft microdomains and prevents insulin stimulated TC10 activation without affecting PI 3-kinase activation or PI 3-kinase-dependent downstream signaling .	In addition, cholesterol depletion with methyl-beta-cyclodextrin (MbetaCD) disperses proteins associated with plasma membrane lipid raft microdomains and prevents insulin stimulated TC10 activation without affecting PI 3-kinase activation or PI 3-kinase-dependent downstream signaling.	20	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	21	22	23	24
We show here that IGF-1 ( and not insulin ) triggers robust and significant activation of TC10 in growth cones isolated from fetal brain .	We show here that IGF-1 (and not insulin) triggers robust and significant activation of TC10 in growth cones isolated from fetal brain.	4	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	8	9	16	17
These data indicate that PtdIns-3-P is specifically produced downstream from insulin mediated activation of TC10 to promote the plasma membrane translocation of GLUT4 .	These data indicate that PtdIns-3-P is specifically produced downstream from insulin mediated activation of TC10 to promote the plasma membrane translocation of GLUT4.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	10	11	14	15
In adipocytes and PC12 cells , insulin and NGF , respectively , activate TC10 , which recruits exo70 to the plasmalemma .	In adipocytes and PC12 cells, insulin and NGF, respectively, activate TC10, which recruits exo70 to the plasmalemma.	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	6	7	13	14
APS initiates the insulin induced TC10 cascade which participates to GLUT4 translocation to the plasma membrane .	APS initiates the insulin induced TC10 cascade which participates to GLUT4 translocation to the plasma membrane.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	3	4	5	6
Similarly , insulin activated the TC10 and H-Ras chimera over the same time frame ( XREF_FIG B , lanes 1-5 ) .	Similarly, insulin activated the TC10 and H-Ras chimera over the same time frame (XREF_FIG B, lanes 1-5).	2	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	2	3	5	6
Using a GST-Pak1 pull down assay to precipitate the GTP bound TC10 protein , we observed that insulin produced a time dependent activation of the expressed wild-type TC10 protein ( XREF_FIG A , lanes 1-5 ) .	Using a GST-Pak1 pull down assay to precipitate the GTP bound TC10 protein, we observed that insulin produced a time dependent activation of the expressed wild-type TC10 protein (XREF_FIG A, lanes 1-5).	17	28	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	17	18	27	28
In contrast , expression of Cav3 and DGV resulted in marked inhibition in the time and extent of insulin stimulated TC10 activation ( XREF_FIG B , lanes 1-5 ) .	In contrast, expression of Cav3 and DGV resulted in marked inhibition in the time and extent of insulin stimulated TC10 activation (XREF_FIG B, lanes 1-5).	14	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	18	19	20	21
Quantitation of these data demonstrated that insulin activated TC10/WT and TC10 and H-Ras 1.7 +/- 0.4- and 1.7 +/- 0.3-fold , respectively .	Quantitation of these data demonstrated that insulin activated TC10/WT and TC10 and H-Ras 1.7 +/- 0.4- and 1.7 +/- 0.3-fold, respectively.	6	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	6	7	10	11
Nevertheless , the data presented here clearly demonstrate that the specific COOH-terminal targeting sequences of TC10 are essential for the insulin dependent activation of TC10 and regulation of GLUT4 translocation .	Nevertheless, the data presented here clearly demonstrate that the specific COOH-terminal targeting sequences of TC10 are essential for the insulin dependent activation of TC10 and regulation of GLUT4 translocation.	20	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	TC10	TC10	TC10	20	21	24	25
Expression of genes related to insulin-receptor signaling Irs1 and Irs2 were significantly decreased in diabetic mice while the expression of Foxo1 was not changed .	Expression of genes related to insulin-receptor signaling Irs1 and Irs2 were significantly decreased in diabetic mice while the expression of Foxo1 was not changed.	3	9	signaling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin-receptor	insulin-receptor	insulin-receptor	Irs1	Irs1	Irs1	5	6	7	8
Insulin induces tyrosine phosphorylation of the insulin receptor and IRS-1 and -2 , increases binding of activated IRS-1 and -2 to the regulatory subunit of PI3 kinase , and activates Akt ( XREF_FIG ) .	Insulin induces tyrosine phosphorylation of the insulin receptor and IRS-1 and -2, increases binding of activated IRS-1 and -2 to the regulatory subunit of PI3 kinase, and activates Akt (XREF_FIG).	0	19	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin receptor	Insulin induces tyrosine phosphorylation of the insulin receptor	insulin receptor	IRS-1	IRS-1	irs-1	6	8	17	18
The insulin receptor is phosphorylated and activates IRS-1 after it binds to insulin .	The insulin receptor is phosphorylated and activates IRS-1 after it binds to insulin.	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin receptor	insulin receptor is phosphorylated	insulin receptor	IRS-1	IRS-1	irs-1	1	3	7	8
Insulin receptor signaling stimulated the association of IRS-1 with p85 alpha protein , and p85 alpha associated PI 3-kinase activity in 3T3-L1 adipocytes , and in transfected Chinese hamster ovary cells ( CHO-T ) and COS-1 cells expressing high levels of human insulin receptors .	Insulin receptor signaling stimulated the association of IRS-1 with p85 alpha protein, and p85 alpha associated PI 3-kinase activity in 3T3-L1 adipocytes, and in transfected Chinese hamster ovary cells (CHO-T) and COS-1 cells expressing high levels of human insulin receptors.	0	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin receptor	Insulin receptor	Insulin receptor	IRS-1	IRS-1	IRS-1	0	2	7	8
Here , we report that insulin induces tyrosine phosphorylation of the insulin receptor and IRS-1 and -2 , increases binding of activated IRS-1 and -2 to the regulatory subunit of PI3K , and activates protein kinase B/Akt , a downstream target of PI3K .	Here, we report that insulin induces tyrosine phosphorylation of the insulin receptor and IRS-1 and -2, increases binding of activated IRS-1 and -2 to the regulatory subunit of PI3K, and activates protein kinase B/Akt, a downstream target of PI3K.	5	24	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin receptor	insulin induces tyrosine phosphorylation of the insulin receptor	insulin receptor	IRS-1	IRS-1	irs-1	11	13	22	23
Animals randomized to PMI 5011 appeared to have increased skeletal muscle protein abundance of IRS-1 , IRS-2 , IR beta-subunit , PI 3-kinase ( p85 ) , and GLUT4 compared to control ( XREF_FIG ) .	Animals randomized to PMI 5011 appeared to have increased skeletal muscle protein abundance of IRS-1, IRS-2, IR beta-subunit, PI 3-kinase (p85), and GLUT4 compared to control (XREF_FIG).	8	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	IR	IR	IRS-1	IRS-1	IRS-1	18	19	14	15
Within a timeframe similar to the tyrosine phosphorylation and activation of IRS-1 by IR in skeletal muscle and adipose cells , Munc18c is rapidly bound by IR and phosphorylated at Tyr521 within 5 min [ XREF_BIBR , XREF_BIBR ] .	Within a timeframe similar to the tyrosine phosphorylation and activation of IRS-1 by IR in skeletal muscle and adipose cells, Munc18c is rapidly bound by IR and phosphorylated at Tyr521 within 5 min [XREF_BIBR, XREF_BIBR].	3	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IR	IR	IR	IRS-1	IRS-1	IRS-1	13	14	11	12
We also demonstrated that TNF-alpha simultaneously produced insulin resistance by uncoupling insulin receptor activity toward insulin receptor substrate-1 ( IRS-1 ) and suppressing insulin sensitive glucose transport .	We also demonstrated that TNF-alpha simultaneously produced insulin resistance by uncoupling insulin receptor activity toward insulin receptor substrate-1 (IRS-1) and suppressing insulin sensitive glucose transport.	6	18	produced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	insulin receptor	insulin receptor	insulin receptor	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	11	13	15	18
In that pathway ( XREF_FIG ) , insulin binding of the insulin receptor ( IR ) at the cell surface activates IRS-1 intracellularly , which in turn activates PI3K , then Akt and , finally , the many downstream targets of Akt , including mTOR [ XREF_BIBR , XREF_BIBR ] .	In that pathway (XREF_FIG), insulin binding of the insulin receptor (IR) at the cell surface activates IRS-1 intracellularly, which in turn activates PI3K, then Akt and, finally, the many downstream targets of Akt, including mTOR [XREF_BIBR, XREF_BIBR].	12	48	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	IR	IR	IRS-1	IRS-1	IRS-1	14	15	21	22
In normal insulin signal transduction , autophosphorylation of the insulin receptor on tyrosine 1150/1151 leads to activation of IRS-1 or IRS-2 , which phosphorylate Akt , a potent anti-apoptotic factor , thus preventing apoptosis of cells .	In normal insulin signal transduction, autophosphorylation of the insulin receptor on tyrosine 1150/1151 leads to activation of IRS-1 or IRS-2, which phosphorylate Akt, a potent anti-apoptotic factor, thus preventing apoptosis of cells.	6	20	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	insulin receptor	autophosphorylation of the insulin receptor on tyrosine 1150/1151	insulin receptor	IRS-1	IRS-1	irs-1	9	11	18	19
Autophosphorylation is a hallmark of IR activation , which in turn activates the IRS-1 and phosphoinositide 3-kinase/Akt and mitogen activated protein kinase and ERK cascades .	Autophosphorylation is a hallmark of IR activation, which in turn activates the IRS-1 and phosphoinositide 3-kinase/Akt and mitogen activated protein kinase and ERK cascades.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	IR	IR	IRS-1	IRS-1	IRS-1	5	6	13	14
Phosphorylation of IR activates the IRS-1 and IRS-2 , which are major substrates of IR that play a central key role in metabolic actions of insulin [ XREF_BIBR , XREF_BIBR ] .	Phosphorylation of IR activates the IRS-1 and IRS-2, which are major substrates of IR that play a central key role in metabolic actions of insulin [XREF_BIBR, XREF_BIBR].	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	Phosphorylation of IR	ir	IRS-1	IRS-1	irs-1	2	3	5	6
XREF_FIG shows a representative Western blot of INSR downstream activation of IRS-1 and FAK in AA and CA breast tissue samples .	XREF_FIG shows a representative Western blot of INSR downstream activation of IRS-1 and FAK in AA and CA breast tissue samples.	7	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	INSR	INSR	INSR	IRS-1	IRS-1	IRS-1	7	8	11	12
Hepatic insulin resistance represents a paradox in hepatic steatosis since insulin receptor activation of insulin receptor substrate-1 ( IRS-1 ) is active and accounts for increased DNL , yet insulin does not inhibit insulin receptor substrate-2 , which controls liver gluconeogenesis [ XREF_BIBR ] .	Hepatic insulin resistance represents a paradox in hepatic steatosis since insulin receptor activation of insulin receptor substrate-1 (IRS-1) is active and accounts for increased DNL, yet insulin does not inhibit insulin receptor substrate-2, which controls liver gluconeogenesis [XREF_BIBR].	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin receptor	insulin receptor	insulin receptor	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	10	12	14	17
Tyrosine phosphorylation of insulin receptor proteins induces the cytoplasmic binding activity of insulin receptor substrate-1 ( IRS-1 ) to insulin receptor .	Tyrosine phosphorylation of insulin receptor proteins induces the cytoplasmic binding activity of insulin receptor substrate-1 (IRS-1) to insulin receptor.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin receptor	Tyrosine phosphorylation of insulin receptor	insulin receptor	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	3	5	12	15
In this signaling pathway ( XREF_FIG and XREF_FIG ) , insulin binding of the IR at the cell surface activates IRS-1 intracellularly , which in turn activates phosphatidylinositol-3-kinase ( PI3K ) and then Akt , which inhibits many downstream molecules , including the apoptosis inducing molecules BAD and caspase-9 , forkhead box containing transcription factors of the O family ( FoxO1 and FoxO3 ) , glycogen synthase kinase-3 ( GSK-3 ) , and the mammalian target-of and rapamycin complex 1 ( mTORC1 ) [ XREF_BIBR , XREF_BIBR ] .	In this signaling pathway (XREF_FIG and XREF_FIG), insulin binding of the IR at the cell surface activates IRS-1 intracellularly, which in turn activates phosphatidylinositol-3-kinase (PI3K) and then Akt, which inhibits many downstream molecules, including the apoptosis inducing molecules BAD and caspase-9, forkhead box containing transcription factors of the O family (FoxO1 and FoxO3), glycogen synthase kinase-3 (GSK-3), and the mammalian target-of and rapamycin complex 1 (mTORC1) [XREF_BIBR, XREF_BIBR].	11	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	IR	IR	IRS-1	IRS-1	IRS-1	14	15	20	21
Metformin ( 1 micro g/ml ) increased IR tyrosine phosphorylation by 78 % ( P = 0.0007 ) in 30 min in human hepatocytes and Huh7 cells and increased IRS-2 but not IRS-1 activation , and the downstream increase in deoxyglucose uptake was mediated via increased translocation of GLUT-1 to the plasma membrane .	Metformin (1 micro g/ml) increased IR tyrosine phosphorylation by 78% (P = 0.0007) in 30 min in human hepatocytes and Huh7 cells and increased IRS-2 but not IRS-1 activation, and the downstream increase in deoxyglucose uptake was mediated via increased translocation of GLUT-1 to the plasma membrane.	0	33	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	Metformin (1 micro g/ml) increased IR tyrosine phosphorylation	ir	IRS-1	IRS-1	irs-1	7	8	32	33
In one pathway , tyrosine phosphorylation of IR induces IRS-1 to bind Src-homology-2 ( SH2 ) domain containing proteins including p85 , the regulatory subunit of class I phosphatidylinositol-3 kinase ( PI3K ) , targeting PI3K to the PM .	In one pathway, tyrosine phosphorylation of IR induces IRS-1 to bind Src-homology-2 (SH2) domain containing proteins including p85, the regulatory subunit of class I phosphatidylinositol-3 kinase (PI3K), targeting PI3K to the PM.	4	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	tyrosine phosphorylation of IR	ir	IRS-1	IRS-1	irs-1	7	8	9	10
IR causes downregulation of IRS-1 signaling , thereby leading to excess free fatty acids accumulation in the liver .	IR causes downregulation of IRS-1 signaling, thereby leading to excess free fatty acids accumulation in the liver.	0	5	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	IR	IR	IRS-1	IRS-1	IRS-1	0	1	4	5
Ramipril treatment also increased dephosphorylation of insulin receptor by muscle CF ( 22.0 +/-1.0 %/60 min compared to 16.8 +/-1.5 %/60 min ; P < 0.05 ) , and of IRS-1 by liver MF ( 37.2 +/-1.7 %/7.5 min compared to 33.8 +/-1.7 %/7.5 min ; P < 0.05 ) and CF ( 36.8 +/-1.0 %/7.5 min compared to 33.2 +/-1.0 %/7.5 min ; P < 0.05 ) .	Ramipril treatment also increased dephosphorylation of insulin receptor by muscle CF (22.0 +/-1.0%/60 min compared to 16.8 +/-1.5%/60 min; P < 0.05), and of IRS-1 by liver MF (37.2 +/-1.7%/7.5 min compared to 33.8 +/-1.7%/7.5 min; P < 0.05) and CF (36.8 +/-1.0%/7.5 min compared to 33.2 +/-1.0%/7.5 min; P < 0.05).	3	51	increased	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	insulin receptor	dephosphorylation of insulin receptor by muscle CF	insulin receptor	IRS-1	IRS-1	irs-1	6	8	30	31
Here , we report that APS enhanced ligand dependent multi ubiquitination of the insulin receptor ( IR ) in CHO cells overexpressing the IR .	Here, we report that APS enhanced ligand dependent multi ubiquitination of the insulin receptor (IR) in CHO cells overexpressing the IR.	5	24	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	APS enhanced ligand dependent multi ubiquitination of the insulin receptor (IR	ir	IR	IR	ir	16	17	23	24
Expression of K IR in capillaries in electrically active tissues may allow K IR to sense extracellular K + , contributing to functional hyperemia .	Expression of K IR in capillaries in electrically active tissues may allow K IR to sense extracellular K +, contributing to functional hyperemia.	0	15	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	Expression of K IR	ir	IR	IR	ir	3	4	13	14
These findings may be attributed to the fact that although aberrant over-expression of the IR in breast cancer cells significantly increases the effects of insulin on such cells , IR over-expression causes a certain degree of insulin receptor saturation on the cell membrane .	These findings may be attributed to the fact that although aberrant over-expression of the IR in breast cancer cells significantly increases the effects of insulin on such cells, IR over-expression causes a certain degree of insulin receptor saturation on the cell membrane.	29	38	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	IR over-expression	ir	insulin receptor	insulin receptor	insulin receptor	29	30	36	38
Ischemia reperfusion ( IR ) induced the expression of NLRP3 in mice renal tissues , and NLRP3 gene knockout mouse model can remarkably ameliorate IR induced AKI including acute tubule necrosis , expression of IL-18 and IL-1beta , alleviate impaired function and reduce mortality XREF_BIBR XREF_BIBR .	Ischemia reperfusion (IR) induced the expression of NLRP3 in mice renal tissues, and NLRP3 gene knockout mouse model can remarkably ameliorate IR induced AKI including acute tubule necrosis, expression of IL-18 and IL-1beta, alleviate impaired function and reduce mortality XREF_BIBR XREF_BIBR.	0	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ischemia reperfusion	Ischemia reperfusion	Ischemia reperfusion	IR	IR	IR	0	2	24	25
Significantly , APS mediated IR ubiquitination enhanced IR internalization but it did not affect receptor degradation , suggesting a more prevalent role of APS in regulating early events of IR endocytosis than receptor sorting .	Significantly, APS mediated IR ubiquitination enhanced IR internalization but it did not affect receptor degradation, suggesting a more prevalent role of APS in regulating early events of IR endocytosis than receptor sorting.	2	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	APS mediated IR ubiquitination	ir	IR	IR	ir	4	5	7	8
Inhibitory effects of ethanol on insulin signaling are due to reduced ligand binding to the insulin receptor , reduced tyrosine phosphorylation and activation of insulin receptor tyrosine kinase , and inhibition of signaling through IRS-1 , PI3 Kinase-Akt , PRAS40-mTOR-S6Kinase , and Erk MAPK .	Inhibitory effects of ethanol on insulin signaling are due to reduced ligand binding to the insulin receptor, reduced tyrosine phosphorylation and activation of insulin receptor tyrosine kinase, and inhibition of signaling through IRS-1, PI3 Kinase-Akt, PRAS40-mTOR-S6Kinase, and Erk MAPK.	18	27	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin receptor	phosphorylation and activation of insulin receptor tyrosine	insulin receptor	insulin receptor	insulin receptor	insulin receptor	24	26	24	26
In the current study , we compared the lesions of atherosclerosis after feeding on HFFD for 8 and 16 weeks in an attempt to investigate the short-term effects of HFFD induced IR on the early-stage lesions as well as the long-term effects of HFFD induced IR on the advanced lesions of atherosclerosis .	In the current study, we compared the lesions of atherosclerosis after feeding on HFFD for 8 and 16 weeks in an attempt to investigate the short-term effects of HFFD induced IR on the early-stage lesions as well as the long-term effects of HFFD induced IR on the advanced lesions of atherosclerosis.	29	46	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	HFFD induced IR	ir	IR	IR	ir	31	32	45	46
Reduced insulin receptor phosphorylation by ectopic expression of dominant negative insulin receptor ( dnIR ) , which contains a point mutation to abolish insulin receptor binding to ATP , or decrease insulin receptor protein by morpholino mediated knockdown in tectal neurons , severely decreases their glutamatergic synaptic input and reduces their responses to natural light stimuli .	Reduced insulin receptor phosphorylation by ectopic expression of dominant negative insulin receptor (dnIR), which contains a point mutation to abolish insulin receptor binding to ATP, or decrease insulin receptor protein by morpholino mediated knockdown in tectal neurons, severely decreases their glutamatergic synaptic input and reduces their responses to natural light stimuli.	1	28	abolish	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	insulin receptor	insulin receptor phosphorylation by ectopic expression of dominant negative insulin receptor	insulin receptor	insulin receptor	insulin receptor binding to ATP	insulin receptor	1	3	23	25
PTP1B targets and dephosphorylates the IR at the sites pY1162 and pY1163 , thus diminishing IR activity , insulin signaling and metabolic action XREF_BIBR .	PTP1B targets and dephosphorylates the IR at the sites pY1162 and pY1163, thus diminishing IR activity, insulin signaling and metabolic action XREF_BIBR.	0	16	diminishing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IR	PTP1B targets and dephosphorylates the IR	ir	IR	IR	ir	5	6	15	16
Based on the facts that MDA is produced by oxidation of cell membranes , and oxidative phosphorylation of insulin receptor on the cell surface induces IR XREF_BIBR , XREF_BIBR , the hypothesis that mitochondrial dysfunction by exposure to phthalates induces oxidative stress leading to the production of IR is plausible .	Based on the facts that MDA is produced by oxidation of cell membranes, and oxidative phosphorylation of insulin receptor on the cell surface induces IR XREF_BIBR, XREF_BIBR, the hypothesis that mitochondrial dysfunction by exposure to phthalates induces oxidative stress leading to the production of IR is plausible.	16	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin receptor	phosphorylation of insulin receptor	insulin receptor	IR	IR	ir	18	20	25	26
Also , DRP1 alone was able to induce IR in healthy rodents and inhibiting DRP1 was sufficient to reverse HFD induced IR .	Also, DRP1 alone was able to induce IR in healthy rodents and inhibiting DRP1 was sufficient to reverse HFD induced IR.	7	22	induce	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IR	DRP1 was sufficient to reverse HFD induced IR	ir	IR	IR	ir	21	22	8	9
However , chronic insulin treatment ( 24 h ) did not decrease IR expression or impair IR effects on glycogen synthesis in GRK2 deficient cells .	However, chronic insulin treatment (24 h) did not decrease IR expression or impair IR effects on glycogen synthesis in GRK2 deficient cells.	3	17	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IR	insulin treatment (24 h) did not decrease IR expression	ir	IR	IR	ir	12	13	16	17
Oct4 mediated IR resistance was not due to the induction of apoptosis or cell-cycle arrest , but to IR induced premature senescence .	Oct4 mediated IR resistance was not due to the induction of apoptosis or cell-cycle arrest, but to IR induced premature senescence.	0	20	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	IR	Oct4 mediated IR	ir	IR	IR	ir	2	3	18	19
Therefore , the dephosphorylation of IR and IRS-1 by PTP1B can modulate insulin receptor and IRS protein activities that contribute to insulin resistance ( XREF_FIG ) .	Therefore, the dephosphorylation of IR and IRS-1 by PTP1B can modulate insulin receptor and IRS protein activities that contribute to insulin resistance (XREF_FIG).	3	14	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	dephosphorylation of IR	ir	insulin receptor	insulin receptor	insulin receptor	5	6	12	14
Normally , insulin causes phosphorylation events through IR autophosphorylation , which enhances IR kinase activity , followed by activation of phosphatidylinositide-3-kinase ( PI3K ) and subsequent Akt phosphorylation cascade , which plays a central role in the control of cell growth , survival , and metabolism [ XREF_BIBR ] .	Normally, insulin causes phosphorylation events through IR autophosphorylation, which enhances IR kinase activity, followed by activation of phosphatidylinositide-3-kinase (PI3K) and subsequent Akt phosphorylation cascade, which plays a central role in the control of cell growth, survival, and metabolism [XREF_BIBR].	7	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	IR autophosphorylation	ir	IR	IR	ir	7	8	12	13
As expected , ALA elicited a pronounced phosphorylation of insulin receptor , suggesting that ALA could activate insulin receptor .	As expected, ALA elicited a pronounced phosphorylation of insulin receptor, suggesting that ALA could activate insulin receptor.	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin receptor	phosphorylation of insulin receptor, suggesting that ALA	insulin receptor	insulin receptor	insulin receptor	insulin receptor	9	11	17	19
APS mediated ubiquitination of the IR induced enhancement of the IR internalization , but did not affect the IR degradation .	APS mediated ubiquitination of the IR induced enhancement of the IR internalization, but did not affect the IR degradation.	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	APS mediated ubiquitination of the IR	ir	IR	IR	ir	5	6	10	11
Among them , IRAK-1 , IRAK-2 , and IRAK-4 positively regulate TRAF6 activity , while IRAK-M limits TLR and IL-1R-medaited immune responses .	Among them, IRAK-1, IRAK-2, and IRAK-4 positively regulate TRAF6 activity, while IRAK-M limits TLR and IL-1R-medaited immune responses.	3	12	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	IRAK-1	IRAK-1	IRAK-1	TRAF6	TRAF6	TRAF6	3	4	11	12
MyD88 recruits IRAK1 and IRAK2 , and IRAK kinases phosphorylate and activate the protein TRAF6 , which in turn polyubiquitinates the protein TGFbeta activated kinase ( TAK1 ) as well as itself in order to facilitate binding to IKKbeta .	MyD88 recruits IRAK1 and IRAK2, and IRAK kinases phosphorylate and activate the protein TRAF6, which in turn polyubiquitinates the protein TGFbeta activated kinase (TAK1) as well as itself in order to facilitate binding to IKKbeta.	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK	IRAK	IRAK	TRAF6	TRAF6	TRAF6	7	8	14	15
Conversely , in situations where the MyD88 adaptor protein binds , it mediates association of the receptor complex with IRAK protein kinase [ XREF_BIBR ] , which in turn activates TRAF6 through phosphorylation [ XREF_BIBR ] for propagation of the signal .	Conversely, in situations where the MyD88 adaptor protein binds, it mediates association of the receptor complex with IRAK protein kinase [XREF_BIBR], which in turn activates TRAF6 through phosphorylation [XREF_BIBR] for propagation of the signal.	19	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK	IRAK	IRAK	TRAF6	TRAF6	TRAF6	19	20	30	31
The goal of this study was to understand how IRAK activates the intermediate proteins TRAF6 , TAK1 , TAB1 , and TAB2 .	The goal of this study was to understand how IRAK activates the intermediate proteins TRAF6, TAK1, TAB1, and TAB2.	9	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK	IRAK	IRAK	TRAF6	TRAF6	TRAF6	9	10	14	15
IRAK proteins are then able to directly interact with and activate TRAF6 .	IRAK proteins are then able to directly interact with and activate TRAF6.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK	IRAK	IRAK	TRAF6	TRAF6	TRAF6	0	1	11	12
PA up-regulated the mRNA expression of MyD88 , IRAK1 , and TRAF6 , and no significant differences in PA induced MyD88 , IRAK1 , and TRAF6 mRNA expression were detected between inhibitor negative control and miR-132 inhibitor transfected cells ( XREF_FIG A ) .	PA up-regulated the mRNA expression of MyD88, IRAK1, and TRAF6, and no significant differences in PA induced MyD88, IRAK1, and TRAF6 mRNA expression were detected between inhibitor negative control and miR-132 inhibitor transfected cells (XREF_FIG A).	4	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	expression of MyD88, IRAK1	irak1	TRAF6	TRAF6	traf6	8	9	25	26
TRAF6 then binds to and is activated by IRAK1 .	TRAF6 then binds to and is activated by IRAK1.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IRAK1	IRAK1	IRAK1	TRAF6	TRAF6	TRAF6	8	9	0	1
MAL and MyD88 pair to enhance the activation of IRAK1 , which in turn activates Traf6 and IRAK4 leading to the activation of nuclear factor ( NF )-kappaB .	MAL and MyD88 pair to enhance the activation of IRAK1, which in turn activates Traf6 and IRAK4 leading to the activation of nuclear factor (NF)-kappaB.	7	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	IRAK1	IRAK1	Traf6	Traf6	Traf6	9	10	15	16
After IRAK kinases activate TRAF6 , its binding to TAK1 and IKKbeta ultimately frees Nf-kappaB to diffuse into the nucleus [ XREF_BIBR ] .	After IRAK kinases activate TRAF6, its binding to TAK1 and IKKbeta ultimately frees Nf-kappaB to diffuse into the nucleus [XREF_BIBR].	1	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK	IRAK	IRAK	TRAF6	TRAF6	TRAF6	1	2	4	5
Lastly , the importance of TRAF6 in primary MDS is described in our recent publication , in which genetic and pharmacologic inhibition of IRAK1 suppresses TRAF6 activation and the MDS clone .	Lastly, the importance of TRAF6 in primary MDS is described in our recent publication, in which genetic and pharmacologic inhibition of IRAK1 suppresses TRAF6 activation and the MDS clone.	21	26	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	IRAK1	IRAK1	TRAF6	TRAF6	TRAF6	23	24	25	26
IRAK1 is phosphorylated , leading to its rapid dissociation from Tollip , and causing IRAK1 induced TRAF6 activation [ XREF_BIBR ] .	IRAK1 is phosphorylated, leading to its rapid dissociation from Tollip, and causing IRAK1 induced TRAF6 activation [XREF_BIBR].	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	IRAK1	IRAK1	IRAK1	TRAF6	TRAF6	TRAF6	14	15	16	17
MyD88 , an adapter protein , recruits the IL-1R associated kinase 4 ( IRAK4 ) , which initiates a signaling cascade by phosphorylating and activating IRAK1 , which , in turn , activates and recruits TRAF6 to the IL-1R complex .	MyD88, an adapter protein, recruits the IL-1R associated kinase 4 (IRAK4), which initiates a signaling cascade by phosphorylating and activating IRAK1, which, in turn, activates and recruits TRAF6 to the IL-1R complex.	8	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	IL-1R associated kinase 4 (IRAK4), which initiates a signaling cascade by phosphorylating and activating IRAK1	irak1	TRAF6	TRAF6	traf6	25	26	35	36
XREF_BIBR , XREF_BIBR IL-33 binding to extracellular domain of ST2L results in the recruitment of MYD88 to the TIR domain of ST2L , inducing inflammatory mediators by activating transcription factor AP-1 or IRAK mediated TRAF6 , subsequent mitogen activated protein kinase ( MAPK ) , and IKK and NF-kappaB .	XREF_BIBR, XREF_BIBR IL-33 binding to extracellular domain of ST2L results in the recruitment of MYD88 to the TIR domain of ST2L, inducing inflammatory mediators by activating transcription factor AP-1 or IRAK mediated TRAF6, subsequent mitogen activated protein kinase (MAPK), and IKK and NF-kappaB.	27	37	mediated	Positive_early_activation	Positive_activation	Positive_activation	IRAK	IRAK	IRAK	TRAF6	TRAF6	TRAF6	32	33	34	35
Expression of IRAK-1 , but not MyD88 , induced the oligomerization of TRAF6 , and IRAK-1 and the TRAF6 dominant negative mutant were associated with TRAF6 .	Expression of IRAK-1, but not MyD88, induced the oligomerization of TRAF6, and IRAK-1 and the TRAF6 dominant negative mutant were associated with TRAF6.	0	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK-1	Expression of IRAK-1	irak-1	TRAF6	TRAF6	traf6	2	3	12	13
In addition , a small molecule inhibitor of IRAK1 suppresses TRAF6 and NF-kappaB activation , and induces apoptosis of primary MDS propagating cells , but is less effective as a single agent in primary AML .	In addition, a small molecule inhibitor of IRAK1 suppresses TRAF6 and NF-kappaB activation, and induces apoptosis of primary MDS propagating cells, but is less effective as a single agent in primary AML.	6	13	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	IRAK1	IRAK1	TRAF6	TRAF6	TRAF6	8	9	10	11
Once IRAK4 complexes with MyD88 , it phosphorylates IRAK1 , allowing IRAK1 to autophosphorylate and recruit the ubiquitin ligase TRAF6 .	Once IRAK4 complexes with MyD88, it phosphorylates IRAK1, allowing IRAK1 to autophosphorylate and recruit the ubiquitin ligase TRAF6.	7	20	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	phosphorylates IRAK1	irak1	TRAF6	TRAF6	traf6	8	9	19	20
TLR-4 activates MYD88 and IRAK , which activate TRAF6 , which leads to activation of NFkappaB and p38 .	TLR-4 activates MYD88 and IRAK, which activate TRAF6, which leads to activation of NFkappaB and p38.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK	IRAK	IRAK	TRAF6	TRAF6	TRAF6	4	5	8	9
XREF_BIBR , XREF_BIBR , XREF_BIBR More specifically , TAK1 is phosphorylated following IRAK mediated activation of TRAF6 .	XREF_BIBR, XREF_BIBR, XREF_BIBR More specifically, TAK1 is phosphorylated following IRAK mediated activation of TRAF6.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	IRAK	IRAK	IRAK	TRAF6	TRAF6	TRAF6	12	13	16	17
We found that knockdown of Src and PKCzeta could inhibit CHIP mediated increase in the phosphorylated levels of IRAK1 and TBK1 ( XREF_FIG ) , indicating that CHIP may promote the activation of Src and PKCzeta , which , in turn , phosphorylated and activated IRAK1 and TBK1 .	We found that knockdown of Src and PKCzeta could inhibit CHIP mediated increase in the phosphorylated levels of IRAK1 and TBK1 (XREF_FIG), indicating that CHIP may promote the activation of Src and PKCzeta, which, in turn, phosphorylated and activated IRAK1 and TBK1.	5	47	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IRAK1	Src and PKCzeta could inhibit CHIP mediated increase in the phosphorylated levels of IRAK1	irak1	IRAK1	IRAK1	irak1	18	19	45	46
However , the phosphorylation of one or more threonine residues in IRAK1 enables IRAK1 to interact with the Forkhead associated domains of Pellino isoforms [ XREF_BIBR ] , which is likely to facilitate the IRAK1 catalyzed phosphorylation of these proteins and their conversion into active E3 ligases .	However, the phosphorylation of one or more threonine residues in IRAK1 enables IRAK1 to interact with the Forkhead associated domains of Pellino isoforms [XREF_BIBR], which is likely to facilitate the IRAK1 catalyzed phosphorylation of these proteins and their conversion into active E3 ligases.	3	14	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	phosphorylation of one or more threonine residues in IRAK1	irak1	IRAK1	IRAK1	irak1	11	12	13	14
Upon IRAK recruitment , IRAK4 phosphorylates IRAK1 at key serine and threonine residues , and enables IRAK1 to eventually activate tumor necrosis factor receptor associated factor 6 ( TRAF6 ) that subsequently activates transforming growth factor-beta-activated protein kinase 1 ( TAK1 ) , a member of the mitogen activated protein ( MAP ) kinase kinase kinase ( MAP3K ) family .	Upon IRAK recruitment, IRAK4 phosphorylates IRAK1 at key serine and threonine residues, and enables IRAK1 to eventually activate tumor necrosis factor receptor associated factor 6 (TRAF6) that subsequently activates transforming growth factor-beta-activated protein kinase 1 (TAK1), a member of the mitogen activated protein (MAP) kinase kinase kinase (MAP3K) family.	4	17	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	IRAK4 phosphorylates IRAK1 at key serine and threonine residues	irak1	IRAK1	IRAK1	irak1	6	7	16	17
IRAK4 then phosphorylates IRAK1 , allowing IRAK1 to interact with TNF receptor associated factor 6 ( TRAF6 ) to assemble into a signaling complex .	IRAK4 then phosphorylates IRAK1, allowing IRAK1 to interact with TNF receptor associated factor 6 (TRAF6) to assemble into a signaling complex.	2	12	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	phosphorylates IRAK1	irak1	IRAK1	IRAK1	irak1	3	4	6	7
IRAK-4 is thought to phosphorylate IRAK-1 , which allows IRAK-1 to initiate an auto-phosphorylation cascade occurring in three sequential steps .	IRAK-4 is thought to phosphorylate IRAK-1, which allows IRAK-1 to initiate an auto-phosphorylation cascade occurring in three sequential steps.	0	11	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK-1	IRAK-4 is thought to phosphorylate IRAK-1	irak-1	IRAK-1	IRAK-1	irak-1	5	6	9	10
They also do not support the conclusion that the phosphorylation of IRAK1 by IRAK4 or autophosphorylation enhances the intrinsic catalytic activity of IRAK1 [ XREF_BIBR ] .	They also do not support the conclusion that the phosphorylation of IRAK1 by IRAK4 or autophosphorylation enhances the intrinsic catalytic activity of IRAK1 [XREF_BIBR].	9	24	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	phosphorylation of IRAK1	irak1	IRAK1	IRAK1	irak1	11	12	22	23
IRAK-4 phosphorylates IRAK-1 that is in association with TLR2 , allowing IRAK-1 to interact with TRAF6 XREF_BIBR .	IRAK-4 phosphorylates IRAK-1 that is in association with TLR2, allowing IRAK-1 to interact with TRAF6 XREF_BIBR.	0	13	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK-1	IRAK-4 phosphorylates IRAK-1	irak-1	IRAK-1	IRAK-1	irak-1	2	3	11	12
In addition , IRAK1 T209 phosphorylation increased over time in the Jurkat T-cell line upon IL-1beta stimulation , suggesting a functional IRAK1 pathway .	In addition, IRAK1 T209 phosphorylation increased over time in the Jurkat T-cell line upon IL-1beta stimulation, suggesting a functional IRAK1 pathway.	3	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	IRAK1 T209 phosphorylation	irak1	IRAK1	IRAK1	irak1	3	4	21	22
The lack of IRAK expression in IRAK deficient EF cells enabled us to evaluate the importance of IRAK in IL-1 signaling .	The lack of IRAK expression in IRAK deficient EF cells enabled us to evaluate the importance of IRAK in IL-1 signaling.	3	18	enabled	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK	IRAK expression	irak	IRAK	IRAK	irak	3	4	17	18
The phosphorylation of IRAK1 is a multistep process and results in the activation of IRAK1 .	The phosphorylation of IRAK1 is a multistep process and results in the activation of IRAK1.	1	15	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	IRAK1	phosphorylation of IRAK1	irak1	IRAK1	IRAK1	irak1	3	4	14	15
Upon critical phosphorylations of IRAK-1 by IRAK-4 XREF_BIBR , IRAK-1 is partially activated and is able to get fully activated by autophosphorylation .	Upon critical phosphorylations of IRAK-1 by IRAK-4 XREF_BIBR, IRAK-1 is partially activated and is able to get fully activated by autophosphorylation.	2	19	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	IRAK-1	phosphorylations of IRAK-1 by IRAK-4	irak-1	IRAK-1	IRAK-1	irak-1	4	5	9	10
We also examined whether TLR stimulation could augment p-IRAK levels in cells that expressed IRAK or induce p-IRAK in cells deficient in this protein .	We also examined whether TLR stimulation could augment p-IRAK levels in cells that expressed IRAK or induce p-IRAK in cells deficient in this protein.	4	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-IRAK	TLR stimulation could augment p-IRAK levels	p-irak	p-IRAK	p-IRAK	p-irak	8	9	17	18
Pellino 3b mediated Lys-63-linked IRAK polyubiquitination competed with Lys-48-linked IRAK polyubiquitination for the same ubiquitination site , Lys 134 of IRAK , thereby blocking IL-1-induced IRAK degradation .	Pellino 3b mediated Lys-63-linked IRAK polyubiquitination competed with Lys-48-linked IRAK polyubiquitination for the same ubiquitination site, Lys 134 of IRAK, thereby blocking IL-1-induced IRAK degradation.	0	26	blocking	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK	Pellino 3b mediated Lys-63-linked IRAK polyubiquitination competed with Lys-48-linked IRAK polyubiquitination for the same ubiquitination site, Lys 134 of IRAK	irak	IRAK	IRAK	irak	20	21	25	26
Thiazolidinediones induce expression of C/EBP alpha mRNA and protein , while insulin stimulates a rapid decline in C/EBP alpha mRNA and protein .	Thiazolidinediones induce expression of C/EBP alpha mRNA and protein, while insulin stimulates a rapid decline in C/EBP alpha mRNA and protein.	11	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	C/EBP alpha	C/EBP alpha	C/EBP alpha	11	12	17	19
After the adipogenic program is initiated , insulin stimulates PPARgamma- and C/EBPalpha expressing cells to accumulate and store the lipid that they produce [ XREF_BIBR ] .	After the adipogenic program is initiated, insulin stimulates PPARgamma- and C/EBPalpha expressing cells to accumulate and store the lipid that they produce [XREF_BIBR].	7	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	C/EBPalpha	C/EBPalpha	C/EBPalpha	7	8	11	12
Insulin also promotes adipogenic effects by upregulating both PPARgamma and C/EBP-alpha in adipocytes [ XREF_BIBR , XREF_BIBR ] .	Insulin also promotes adipogenic effects by upregulating both PPARgamma and C/EBP-alpha in adipocytes [XREF_BIBR, XREF_BIBR].	0	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	C/EBP-alpha	C/EBP-alpha	C/EBP-alpha	0	1	10	11
Previously we showed that two transcription factors are required for insulin induction of SREBP-1c , namely , LXRalpha and C/EBPbeta .	Previously we showed that two transcription factors are required for insulin induction of SREBP-1c, namely, LXRalpha and C/EBPbeta.	10	20	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	C/EBPbeta	C/EBPbeta	C/EBPbeta	10	11	19	20
During adipogenic differentiation , C/EBP-beta and C/EBP-delta are induced immediately by glucorticoids and insulin , and then they activate PPARgamma and C/EBP-alpha .	During adipogenic differentiation, C/EBP-beta and C/EBP-delta are induced immediately by glucorticoids and insulin, and then they activate PPARgamma and C/EBP-alpha.	4	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	C/EBP-beta	C/EBP-beta	C/EBP-beta	13	14	4	5
Moreover , in liver tissue , both C/EBPbeta LAP and LIP isoforms are rapidly increased in H4IIE rat hepatoma cells treated with 10 nM insulin ; however , in diabetic mouse liver , LAP expression is downregulated by elevation of insulin concentration ( XREF_FIG ) .	Moreover, in liver tissue, both C/EBPbeta LAP and LIP isoforms are rapidly increased in H4IIE rat hepatoma cells treated with 10 nM insulin; however, in diabetic mouse liver, LAP expression is downregulated by elevation of insulin concentration (XREF_FIG).	10	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	LIP	LIP	LIP	24	25	10	11
This is important since insulin is known to modulate the expression of two isoforms of C/EBP beta , LAP and LIP XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	This is important since insulin is known to modulate the expression of two isoforms of C/EBP beta, LAP and LIP XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	4	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	C/EBP beta	C/EBP beta	C/EBP beta	4	5	15	17
3T3-L1 cells transfected with Cebpb or Cebpb and Creb3l4 were treated with insulin containing media every 2 days .	3T3-L1 cells transfected with Cebpb or Cebpb and Creb3l4 were treated with insulin containing media every 2 days.	2	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	insulin	insulin	insulin	Cebpb	Cebpb	Cebpb	12	13	4	5
By contrast , IR phosphorylation was significantly decreased in K/R cells consistent with the inability of insulin to suppress activity of PTP1B K/R XREF_BIBR .	By contrast, IR phosphorylation was significantly decreased in K/R cells consistent with the inability of insulin to suppress activity of PTP1B K/R XREF_BIBR.	3	23	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IR	IR phosphorylation	ir	PTP1B	PTP1B	ptp1b	3	4	21	22
We have also reported enhanced insulin receptor neuroprective signaling in PTP1B deficient mice [ XREF_BIBR ] .	We have also reported enhanced insulin receptor neuroprective signaling in PTP1B deficient mice [XREF_BIBR].	5	12	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin receptor	insulin receptor	insulin receptor	PTP1B	PTP1B	PTP1B	5	7	10	11
However , overexpression of PTP1B in HepG2 cells led to diminished insulin induced IR phosphorylation , supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes .	However, overexpression of PTP1B in HepG2 cells led to diminished insulin induced IR phosphorylation, supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes.	2	21	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	overexpression of PTP1B in HepG2 cells led to diminished insulin induced IR phosphorylation	ir	PTP1B	PTP1B	ptp1b	13	14	20	21
Upon growth factor stimulation , the SH2 domains of p85 bind to the phospho-tyrosine residues on the receptor protein kinases or adaptor proteins such as insulin receptor substrate 1 ( IRS1 ) , thereby activating the lipid kinase activity of PI3Kalpha .	Upon growth factor stimulation, the SH2 domains of p85 bind to the phospho-tyrosine residues on the receptor protein kinases or adaptor proteins such as insulin receptor substrate 1 (IRS1), thereby activating the lipid kinase activity of PI3Kalpha.	25	41	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	PI3Kalpha	PI3Kalpha	PI3Kalpha	25	29	40	41
Furthermore , we found that IR activates P-FAK , which persists for at least 8 hours post-IR ( XREF_FIG ) .	Furthermore, we found that IR activates P-FAK, which persists for at least 8 hours post-IR (XREF_FIG).	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	IR	IR	P-FAK	P-FAK	P-FAK	5	6	7	8
We noted for the first time that IR activates FAK and that FAK depletion promotes the hyperactivation of checkpoint kinase CHK2 , a known downstream target of ATM and ATR and G 2 / M effectors of cell cycle arrest or apoptosis in response to DNA damage .	We noted for the first time that IR activates FAK and that FAK depletion promotes the hyperactivation of checkpoint kinase CHK2, a known downstream target of ATM and ATR and G 2 / M effectors of cell cycle arrest or apoptosis in response to DNA damage.	7	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	IR	IR	FAK	FAK	FAK	7	8	9	10
Also , there are decreased insulin stimulated tyrosine phosphorylation of IRS-1 and IRS-2 ; decreased binding of grb2 and the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 and IRS-2 , and a marked inhibition of insulin stimulated phosphatidylinositol 3-kinase [ XREF_BIBR ] .	Also, there are decreased insulin stimulated tyrosine phosphorylation of IRS-1 and IRS-2; decreased binding of grb2 and the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 and IRS-2, and a marked inhibition of insulin stimulated phosphatidylinositol 3-kinase [XREF_BIBR].	5	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRS-1	insulin stimulated tyrosine phosphorylation of IRS-1	irs-1	grb2	grb2	grb2	10	11	17	18
However , expression of IRS1 increased the extent of Grb2 associated with IRS1 with a concomitant reduction in the amount of Grb2 associated with Shc .	However, expression of IRS1 increased the extent of Grb2 associated with IRS1 with a concomitant reduction in the amount of Grb2 associated with Shc.	2	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRS1	expression of IRS1	irs1	Grb2	Grb2	grb2	4	5	9	10
Ro-31-8425 , identified in this screen to upregulate CD11a expression , enhanced MSC firm adhesion to ICAM-1 , promoted targeting of systemically infused MSCs to sites of inflammation and boosted their therapeutic impact .	Ro-31-8425, identified in this screen to upregulate CD11a expression, enhanced MSC firm adhesion to ICAM-1, promoted targeting of systemically infused MSCs to sites of inflammation and boosted their therapeutic impact.	0	17	enhanced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CD11a	Ro-31-8425, identified in this screen to upregulate CD11a expression	cd11a	ICAM-1	ICAM-1	icam-1	8	9	16	17
Neutrophil and monocyte adhesion to myometrial and cervical endothelium will be promoted during parturition by the increased CD11a and CD11b expression which we demonstrated : CD11a and b mediate binding to ICAM-1 , which we previously showed was up-regulated in endothelium of human cervix and myometrium during labour .	Neutrophil and monocyte adhesion to myometrial and cervical endothelium will be promoted during parturition by the increased CD11a and CD11b expression which we demonstrated : CD11a and b mediate binding to ICAM-1, which we previously showed was up-regulated in endothelium of human cervix and myometrium during labour.	25	36	mediate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CD11a	CD11a	CD11a	ICAM-1	ICAM-1	ICAM-1	25	26	31	32
The receptor profile of thymic B-cell lymphoma was reminiscent of the expressional status of normal thymic medullary B cells in some aspects but deviated in others : Assuming that , in terms of differentiation , thymic B-cell lymphoma is related to the asteroid variant of thymic medullary B cells , a propensity to down-regulate and lose VLA-4 , CD11a , CD44 , and LECAM-1 would have to be supposed in conjunction with a tendency to overexpress ICAM-1 and LFA-3 .	The receptor profile of thymic B-cell lymphoma was reminiscent of the expressional status of normal thymic medullary B cells in some aspects but deviated in others : Assuming that, in terms of differentiation, thymic B-cell lymphoma is related to the asteroid variant of thymic medullary B cells, a propensity to down-regulate and lose VLA-4, CD11a, CD44, and LECAM-1 would have to be supposed in conjunction with a tendency to overexpress ICAM-1 and LFA-3.	53	78	overexpress	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CD11a	CD11a	CD11a	ICAM-1	ICAM-1	ICAM-1	58	59	76	77
Activated STAT1 and STAT2 reach the nucleus where they bind to the interferon regulator factor 9 ( IRF-9 ) to form a complex that will promote the transcription of a series of interferon stimulated genes ( ISG ) .	Activated STAT1 and STAT2 reach the nucleus where they bind to the interferon regulator factor 9 (IRF-9) to form a complex that will promote the transcription of a series of interferon stimulated genes (ISG).	0	34	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRF-9	IRF-9	IRF-9	STAT2	STAT2	STAT2	17	18	3	4
We found that in the absence of IRF9 , endogenous CypA fails to precipitate both endogenous STAT1 and STAT2 ( XREF_FIG ) , suggesting that the presence of IRF9 facilitates and mediates the co-precipitation of STAT1 and STAT2 by CypA .	We found that in the absence of IRF9, endogenous CypA fails to precipitate both endogenous STAT1 and STAT2 (XREF_FIG), suggesting that the presence of IRF9 facilitates and mediates the co-precipitation of STAT1 and STAT2 by CypA.	26	38	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRF9	IRF9	IRF9	STAT2	STAT2	STAT2	28	29	37	38
IRAK1 can directly use Stat3 as a substrate and cause Stat3 serine 727 phosphorylation .	IRAK1 can directly use Stat3 as a substrate and cause Stat3 serine 727 phosphorylation.	0	11	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRAK1	IRAK1	IRAK1	Stat3	Stat3	Stat3	0	1	10	11
We have previously shown that the IL-1 receptor associated kinase 1 ( IRAK-1 ) selectively activates STAT3 and inactivates NFAT .	We have previously shown that the IL-1 receptor associated kinase 1 (IRAK-1) selectively activates STAT3 and inactivates NFAT.	9	17	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IRAK-1	IRAK-1	IRAK-1	STAT3	STAT3	STAT3	12	13	16	17
XREF_BIBR The IRS4 protein binds to and is activated by the intracellular domain of tyrosine kinase receptors , most notably the insulin , IGF-1 and leptin receptors ( IR , IGF1R and LEPR ) .	XREF_BIBR The IRS4 protein binds to and is activated by the intracellular domain of tyrosine kinase receptors, most notably the insulin, IGF-1 and leptin receptors (IR, IGF1R and LEPR).	2	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IR	IR	IR	IRS4	IRS4	IRS4	28	29	2	3
Loss of IRF8 and IRF1 activity leads to reduced basal and IFN-gamma-induced expression of different subsets of genes that play critical roles in macrophage activity and function , and that we tentatively designate the IRF8 and IRF1 regulome .	Loss of IRF8 and IRF1 activity leads to reduced basal and IFN-gamma-induced expression of different subsets of genes that play critical roles in macrophage activity and function, and that we tentatively designate the IRF8 and IRF1 regulome.	2	37	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IRF1	IRF1	IRF1	IRF8	IRF8	IRF8	4	5	34	35
Here , we showed that Cdk5 disruption sensitizes MB to CD4 + T cell dependent rejection via posttranslational modification of IRF2BP2 , which increases IRF2 and IRF2BP2 abundance and sustains PD-L1 transcriptional repression after IFN-gamma stimulation .	Here, we showed that Cdk5 disruption sensitizes MB to CD4 + T cell dependent rejection via posttranslational modification of IRF2BP2, which increases IRF2 and IRF2BP2 abundance and sustains PD-L1 transcriptional repression after IFN-gamma stimulation.	18	29	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IRF2BP2	IRF2BP2	IRF2BP2	IRF2	IRF2	IRF2	20	21	24	25
At the biochemical level , insulin signaling can be inhibited by increasing serine/threonine phosphorylation of the IR or IRS1 , which reduces insulin induced tyrosine phosphorylation of IRS1 and suppresses the interaction of p85alpha of PI3K , resulting in decreased Akt phosphorylation and activation .	At the biochemical level, insulin signaling can be inhibited by increasing serine/threonine phosphorylation of the IR or IRS1, which reduces insulin induced tyrosine phosphorylation of IRS1 and suppresses the interaction of p85alpha of PI3K, resulting in decreased Akt phosphorylation and activation.	5	35	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRS1	insulin signaling can be inhibited by increasing serine/threonine phosphorylation of the IR or IRS1	irs1	p85alpha	p85alpha	p85alpha	18	19	33	34
ITCH mediates binding of TNFAIP3 and Tax1BP1 with substrates 17 .	ITCH mediates binding of TNFAIP3 and Tax1BP1 with substrates 17.	0	6	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ITCH	ITCH	ITCH	TNFAIP3	TNFAIP3	TNFAIP3	0	1	4	5
Recently , we showed that during NIS there is a dramatic and specific upregulation of JAG1 that can activate NOTCH1 signalling and drive NIS in adjacent cells ( ' lateral induction ' ) 9 .	Recently, we showed that during NIS there is a dramatic and specific upregulation of JAG1 that can activate NOTCH1 signalling and drive NIS in adjacent cells (' lateral induction ') 9.	13	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	NOTCH1	NOTCH1	NOTCH1	15	16	19	20
In human glioma cells , forced ID4 expression can drive malignant transformation by stimulating expression of cyclin E , resulting in a hyperproliferative profile , as well as jagged1 , which activates Notch1 activation to drive astrocytes into a neural stem like state [ XREF_BIBR ] .	In human glioma cells, forced ID4 expression can drive malignant transformation by stimulating expression of cyclin E, resulting in a hyperproliferative profile, as well as jagged1, which activates Notch1 activation to drive astrocytes into a neural stem like state [XREF_BIBR].	13	33	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	jagged1	jagged1	jagged1	Notch1	Notch1	Notch1	28	29	32	33
In contrast , N1 10-24 decoy significantly blocked JAG1 induced Notch1 signaling ( XREF_FIG ) .	In contrast, N1 10-24 decoy significantly blocked JAG1 induced Notch1 signaling (XREF_FIG).	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch1	Notch1	Notch1	8	9	10	11
An additional Notch ligand , Jag1 , is induced by proinflammatory signaling and activates Notch1 in an endothelial-intrinsic manner [ XREF_BIBR , XREF_BIBR ] .	An additional Notch ligand, Jag1, is induced by proinflammatory signaling and activates Notch1 in an endothelial-intrinsic manner [XREF_BIBR, XREF_BIBR].	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch1	Notch1	Notch1	5	6	14	15
Stimulation of naive CD4 + T cells with Delta1 involving interactions with Notch3 promotes the differentiation toward the Th1 pathway , whereas Jagged1 mediated Notch1 activation is critical in driving Th2 differentiation .	Stimulation of naive CD4 + T cells with Delta1 involving interactions with Notch3 promotes the differentiation toward the Th1 pathway, whereas Jagged1 mediated Notch1 activation is critical in driving Th2 differentiation.	22	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	22	23	24	25
Expression of N1 1-24 and N1 1-36 decoys significantly blocked both DLL4- and JAG1 induced Notch1 signaling ( XREF_FIG ) .	Expression of N1 1-24 and N1 1-36 decoys significantly blocked both DLL4- and JAG1 induced Notch1 signaling (XREF_FIG).	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch1	Notch1	Notch1	13	14	15	16
The O linked fucose on Thr466 also contacts DLL4 directly in the Notch1 and DLL4 complex , but O fucosylation of Thr311 exhibits greater importance in functional assays probing Jag1 induced Notch1 signaling , suggesting that discrimination among ligands can be encoded by different combinations of sugar modifications of the receptor 7 .	The O linked fucose on Thr466 also contacts DLL4 directly in the Notch1 and DLL4 complex, but O fucosylation of Thr311 exhibits greater importance in functional assays probing Jag1 induced Notch1 signaling, suggesting that discrimination among ligands can be encoded by different combinations of sugar modifications of the receptor 7.	28	32	induced	Positive_early_activation	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch1	Notch1	Notch1	29	30	31	32
Treatment of total BMSCs and c-Kit POS / NKX2.5 POS BMSCs with exogenous Jagged1 activated Notch1 signalling and drove multi-lineage differentiation , with a tendency towards cardiac lineage differentiation in c-Kit POS / NKX2.5 POS BMSCs .	Treatment of total BMSCs and c-Kit POS / NKX2.5 POS BMSCs with exogenous Jagged1 activated Notch1 signalling and drove multi-lineage differentiation, with a tendency towards cardiac lineage differentiation in c-Kit POS / NKX2.5 POS BMSCs.	10	16	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	13	14	15	16
Furthermore , we investigated whether Jagged1 induced Notch1 signaling played a key role in this process .	Furthermore, we investigated whether Jagged1 induced Notch1 signaling played a key role in this process.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	5	6	7	8
NOTCH1 , a master regulator of T cell development , is activated by its ligands Jagged-1 and the delta like ligand ( DLL ) family , which initiate the proteolytic cleavage of the NOTCH1 intracellular domain ( ICN1 ) , its nuclear translocation , and transcription of NOTCH1 target genes .	NOTCH1, a master regulator of T cell development, is activated by its ligands Jagged-1 and the delta like ligand (DLL) family, which initiate the proteolytic cleavage of the NOTCH1 intracellular domain (ICN1), its nuclear translocation, and transcription of NOTCH1 target genes.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jagged-1	Jagged-1	Jagged-1	NOTCH1	NOTCH1	NOTCH1	15	16	0	1
We found that NOTCH1 signaling , including Jagged1 and HES1 , but not NOTCH2 signaling was significantly inhibited by CD54 knockdown in both LNCaP and PC3 cells .	We found that NOTCH1 signaling, including Jagged1 and HES1, but not NOTCH2 signaling was significantly inhibited by CD54 knockdown in both LNCaP and PC3 cells.	3	14	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	NOTCH1	NOTCH1	NOTCH1	7	8	3	4
Our results suggest that targeting JAG1 can block Notch1 activation in HTLV-I-transformed cells and represents a new target for immunotherapy in ATL patients .	Our results suggest that targeting JAG1 can block Notch1 activation in HTLV-I-transformed cells and represents a new target for immunotherapy in ATL patients.	4	9	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAG1	JAG1	JAG1	Notch1	Notch1	Notch1	5	6	8	9
Non mutated Notch1 is highly expressed in Hodgkin lymphoma ( HL ) and anaplastic large cell lymphoma ( ALCL ) cells , and tumor associated JAG1 , overexpressed by bystander cells as well as by neighboring tumor cells , induces Notch1 activation and promotes tumor cell proliferation and survival .	Non mutated Notch1 is highly expressed in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) cells, and tumor associated JAG1, overexpressed by bystander cells as well as by neighboring tumor cells, induces Notch1 activation and promotes tumor cell proliferation and survival.	23	43	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAG1	JAG1, overexpressed	jag1	Notch1	Notch1	notch1	25	26	40	41
Interestingly , a model in which fringe could block Jagged1 induced Notch1 signaling yet allow Jagged1 to mediate PDZ dependent intracellular signaling has been proposed .	Interestingly, a model in which fringe could block Jagged1 induced Notch1 signaling yet allow Jagged1 to mediate PDZ dependent intracellular signaling has been proposed.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	9	10	11	12
We identify two specific mutations that reduce ligand ( JAGGED1 ) induced NOTCH1 signaling .	We identify two specific mutations that reduce ligand (JAGGED1) induced NOTCH1 signaling.	7	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAGGED1	JAGGED1	JAGGED1	NOTCH1	NOTCH1	NOTCH1	9	10	12	13
XREF_BIBR LFNG acts like a double edged sword : by promoting both the Delta1 ligand activated NOTCH1/2 receptors and decreasing the Jagged1 ligand activated NOTCH1 signalling , it contributes to the normal and tumour suppressor effect of NOTCH1 .	XREF_BIBR LFNG acts like a double edged sword : by promoting both the Delta1 ligand activated NOTCH1/2 receptors and decreasing the Jagged1 ligand activated NOTCH1 signalling, it contributes to the normal and tumour suppressor effect of NOTCH1.	21	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	NOTCH1	NOTCH1	NOTCH1	21	22	24	25
TCR activation induces shedding of CD46 from the surface , thus enabling activation of Notch1 by Jagged1 , which is also required for IFN-gamma production .	TCR activation induces shedding of CD46 from the surface, thus enabling activation of Notch1 by Jagged1, which is also required for IFN-gamma production.	11	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	16	17	14	15
In the presence of MFng , Dll4 becomes a Notch1 superactivator , but Jag1 and Jag2 activate Notch1 quite poorly , and do not affect the response to Dll4 .	In the presence of MFng, Dll4 becomes a Notch1 superactivator, but Jag1 and Jag2 activate Notch1 quite poorly, and do not affect the response to Dll4.	13	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch1	Notch1	Notch1	13	14	17	18
NOTCH1 receptor activated by Jagged1 or Delta like 1 ( DLL1 ) is cleaved by ADAM metallopeptidase domain 17 ( ADAM17 ) and PSEN1 to intracellular domain of NOTCH1 .	NOTCH1 receptor activated by Jagged1 or Delta like 1 (DLL1) is cleaved by ADAM metallopeptidase domain 17 (ADAM17) and PSEN1 to intracellular domain of NOTCH1.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	NOTCH1	NOTCH1	NOTCH1	4	5	0	1
The arterial programme depends on Dll4 and the haemogenic endothelium and HSC on Jag1 mediated Notch1 signalling .	The arterial programme depends on Dll4 and the haemogenic endothelium and HSC on Jag1 mediated Notch1 signalling.	3	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch1	Notch1	Notch1	13	14	15	16
Given that cells used in this study ( HeLa and U2OS ) express JAG1 , a ligand that activates Notch1 , we anticipated that increased Notch1 presence at the cell surface should also increase endogenous signaling .	Given that cells used in this study (HeLa and U2OS) express JAG1, a ligand that activates Notch1, we anticipated that increased Notch1 presence at the cell surface should also increase endogenous signaling.	12	20	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch1	Notch1	Notch1	13	14	19	20
In addition , there is a critical role for Jagged1 mediated Notch1 activation , necessary for controlling GATA2 transcription factor expression within the AGM for maintenance of intraembryonic hematopoiesis independently of its role in arterial development in the mouse [ XREF_BIBR ] .	In addition, there is a critical role for Jagged1 mediated Notch1 activation, necessary for controlling GATA2 transcription factor expression within the AGM for maintenance of intraembryonic hematopoiesis independently of its role in arterial development in the mouse [XREF_BIBR].	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	9	10	11	12
SiHa cells , for example , lack Jagged1 activated Notch1 signalling ( Veeraraghavalu et al , 2005 ) , yet they exhibit RhoC activity , which may be regulated by another signalling pathway .	SiHa cells, for example, lack Jagged1 activated Notch1 signalling (Veeraraghavalu et al, 2005), yet they exhibit RhoC activity, which may be regulated by another signalling pathway.	7	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	7	8	9	10
In addition , activation of Notch1 by Jagged1 or administration of peroxynitrite scavenger reduced production of peroxynitrite and attenuated MI/R injury .	In addition, activation of Notch1 by Jagged1 or administration of peroxynitrite scavenger reduced production of peroxynitrite and attenuated MI/R injury.	3	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	7	8	5	6
Exposure of P1 cells to 1muM or greater Jagged-1 for 12 h increased the NICD to approximately seven-fold compared with the untreated cells ( XREF_FIG ) .	Exposure of P1 cells to 1muM or greater Jagged-1 for 12 h increased the NICD to approximately seven-fold compared with the untreated cells (XREF_FIG).	0	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged-1	Jagged-1	Jagged-1	NICD	NICD	NICD	8	9	14	15
He believed lateral positive induction occurred between adjacent ghost cells leading to activation of Notch1 by its cognate Jagged1 ligand which in turn exerted lateral inhibitory effect on the neighboring tumoral epithelium blocking them from adopting the same cell fate .	He believed lateral positive induction occurred between adjacent ghost cells leading to activation of Notch1 by its cognate Jagged1 ligand which in turn exerted lateral inhibitory effect on the neighboring tumoral epithelium blocking them from adopting the same cell fate.	10	19	leading	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	18	19	14	15
JAG1 enhances the chemoresistance of ovarian cancer cells by activating Notch1 signaling activity .	JAG1 enhances the chemoresistance of ovarian cancer cells by activating Notch1 signaling activity.	0	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch1	Notch1	Notch1	0	1	10	11
Later , myeloid progenitors with strong clonogenic potential emerging upon contact with Jagged1 upregulated Notch1 and Deltex and downregulated Notch signaling modulators , whereas T/NK progenitors originated by Delta1 strikingly upregulated Notch3 and Deltex and , to a lesser extent , Hes1 , Lunatic Fringe , and Numb .	Later, myeloid progenitors with strong clonogenic potential emerging upon contact with Jagged1 upregulated Notch1 and Deltex and downregulated Notch signaling modulators, whereas T/NK progenitors originated by Delta1 strikingly upregulated Notch3 and Deltex and, to a lesser extent, Hes1, Lunatic Fringe, and Numb.	8	16	upregulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	12	13	14	15
A study of a Gmd deficient mammalian cell line , Lec13 , revealed that Jagged-1 dependent activation of Notch1 was reduced in the mutant cells , suggesting that O-fucose positively regulates Notch1 activation by Jagged-1 in this context [ XREF_BIBR , XREF_BIBR ] .	A study of a Gmd deficient mammalian cell line, Lec13, revealed that Jagged-1 dependent activation of Notch1 was reduced in the mutant cells, suggesting that O-fucose positively regulates Notch1 activation by Jagged-1 in this context [XREF_BIBR, XREF_BIBR].	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Jagged-1	Jagged-1	Jagged-1	Notch1	Notch1	Notch1	14	15	18	19
Hence , we speculated that JAG1 mediated Notch1 signaling activity is involved in ovarian cancer oncogenesis and chemoresistance .	Hence, we speculated that JAG1 mediated Notch1 signaling activity is involved in ovarian cancer oncogenesis and chemoresistance.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch1	Notch1	Notch1	5	6	7	8
Furthermore , they show that Jagged1 mediated Notch1 activation enhances TGF-beta-induced Smad3 transcription and translocation to the nucleus , a key component of TGF-beta mediated signaling [ XREF_BIBR ] .	Furthermore, they show that Jagged1 mediated Notch1 activation enhances TGF-beta-induced Smad3 transcription and translocation to the nucleus, a key component of TGF-beta mediated signaling [XREF_BIBR].	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	5	6	7	8
Exogenous recombinant Jagged1 activated Notch1 signalling in both total BMSCs and c-Kit POS / NKX2.5 POS BMSCs as evidenced by upregulation of Hes1 and NICD , while the Notch1 inhibitor DAPT attenuated this effect .	Exogenous recombinant Jagged1 activated Notch1 signalling in both total BMSCs and c-Kit POS / NKX2.5 POS BMSCs as evidenced by upregulation of Hes1 and NICD, while the Notch1 inhibitor DAPT attenuated this effect.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	2	3	4	5
More recently a distinctive role for the different Notch receptors has been explored , suggesting that Jag1 mediated Notch1 and Notch3 activation stimulates differentiation of hepatoblasts towards the biliary phenotype and inhibits hepatocytic differentiation .	More recently a distinctive role for the different Notch receptors has been explored, suggesting that Jag1 mediated Notch1 and Notch3 activation stimulates differentiation of hepatoblasts towards the biliary phenotype and inhibits hepatocytic differentiation.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch1	Notch1	Notch1	16	17	18	19
Activation of Notch1 signaling by Jagged1 may also contribute to vessel stability when the VEGF and VEGFR2 pathway is inhibited .	Activation of Notch1 signaling by Jagged1 may also contribute to vessel stability when the VEGF and VEGFR2 pathway is inhibited.	2	6	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	5	6	2	3
Here , we report that the loss of miR-199b-5p due to progressive epigenetic silencing leads to the activation of the JAG1 mediated Notch1 signaling cascade , thereby leading to the development of acquired chemoresistance in ovarian cancer .	Here, we report that the loss of miR-199b-5p due to progressive epigenetic silencing leads to the activation of the JAG1 mediated Notch1 signaling cascade, thereby leading to the development of acquired chemoresistance in ovarian cancer.	17	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch1	Notch1	Notch1	20	21	22	23
Notch1 signaling may therefore be activated in tumor cells by Jagged1 through homotypic or heterotypic cell-cell interactions , and it seems likely that these interactions contribute to lymphomagenesis in vivo .	Notch1 signaling may therefore be activated in tumor cells by Jagged1 through homotypic or heterotypic cell-cell interactions, and it seems likely that these interactions contribute to lymphomagenesis in vivo.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	10	11	0	1
In this review , we discuss how during trabecular formation and ventricular compaction , Dll4-Notch1 signals from chamber endocardium to regulate cardiomyocyte proliferation and differentiation in a noncell autonomous fashion and how , at later stages , myocardial Jag1 and Jag2 activate Notch1 in chamber endocardium to sustain chamber patterning and compaction with simultaneous coronary vessel development mediated by Dll4-Notch1 .	In this review, we discuss how during trabecular formation and ventricular compaction, Dll4-Notch1 signals from chamber endocardium to regulate cardiomyocyte proliferation and differentiation in a noncell autonomous fashion and how, at later stages, myocardial Jag1 and Jag2 activate Notch1 in chamber endocardium to sustain chamber patterning and compaction with simultaneous coronary vessel development mediated by Dll4-Notch1.	37	47	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch1	Notch1	Notch1	38	39	42	43
Interestingly , Notch1 was recently implicated in endothelial cell senescence , with activation of Notch1 by Jagged1 proposed to increase cellular lifespan , corresponding to suppression of p53 , p21 cip1 , and p16 35 .	Interestingly, Notch1 was recently implicated in endothelial cell senescence, with activation of Notch1 by Jagged1 proposed to increase cellular lifespan, corresponding to suppression of p53, p21 cip1, and p16 35.	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	16	17	14	15
These findings demonstrate that Jagged1 triggered Notch1 signalling induced differentiation of total BMSCs and c-Kit POS / NKX2.5 POS BMSCs into cardiomyocyte , SMC , and endothelial cell lineages .	These findings demonstrate that Jagged1 triggered Notch1 signalling induced differentiation of total BMSCs and c-Kit POS / NKX2.5 POS BMSCs into cardiomyocyte, SMC, and endothelial cell lineages.	4	7	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	4	5	6	7
The evidence that in the setting of neurons a soluble form of Jagged1 can induce Notch1 pathway activation is in stark contrast to the reported requirement in stem cells of a membrane bound ligand to exercise a pulling force on the extracellular portion of the Notch to activate the receptor .	The evidence that in the setting of neurons a soluble form of Jagged1 can induce Notch1 pathway activation is in stark contrast to the reported requirement in stem cells of a membrane bound ligand to exercise a pulling force on the extracellular portion of the Notch to activate the receptor.	10	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	12	13	15	16
In cells transfected with ERalpha siRNA , Jagged-1 did not increase the binding of Notch-1 or ERalpha on the same promoter in the presence or absence of E 2 ( XREF_FIG ) .	In cells transfected with ERalpha siRNA, Jagged-1 did not increase the binding of Notch-1 or ERalpha on the same promoter in the presence or absence of E 2 (XREF_FIG).	7	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged-1	Jagged-1	Jagged-1	Notch-1	Notch-1	Notch-1	7	8	14	15
In contrast , transcription factors of vascular cells are down-regulated by Jagged1 activation of the Notch1 pathway .	In contrast, transcription factors of vascular cells are down-regulated by Jagged1 activation of the Notch1 pathway.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	11	12	15	16
These results suggested cardiac Notch1 signaling pathway was activated by Jagged1 .	These results suggested cardiac Notch1 signaling pathway was activated by Jagged1.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	10	11	4	5
Jagged1 induced Notch1 activation in c-Kit POS / NKX2.5 POS BMSCs was stronger than that in total BMSCs , as indicated by increased immunofluorescence signals and Hes1 levels in Jagged1 treated cells .	Jagged1 induced Notch1 activation in c-Kit POS / NKX2.5 POS BMSCs was stronger than that in total BMSCs, as indicated by increased immunofluorescence signals and Hes1 levels in Jagged1 treated cells.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	0	1	2	3
40 Downregulation of pro angiogenic Notch ligand , JAG1 , enables NOTCH1 receptor to act as a tumor suppressor via its sequestration of CTNNB1 , hence avoiding conflict with its potential angiogenic contribution via JAG1 activation .	40 Downregulation of pro angiogenic Notch ligand, JAG1, enables NOTCH1 receptor to act as a tumor suppressor via its sequestration of CTNNB1, hence avoiding conflict with its potential angiogenic contribution via JAG1 activation.	6	12	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	NOTCH1	NOTCH1	NOTCH1	8	9	11	12
Although both ligands were efficient in inducing Notch2 cleavage and activation in CD4 + T or reporter cells , the presence of Lunatic Fringe in CD4 + T cells inhibited Jag1 activation of Notch1 receptor .	Although both ligands were efficient in inducing Notch2 cleavage and activation in CD4 + T or reporter cells, the presence of Lunatic Fringe in CD4 + T cells inhibited Jag1 activation of Notch1 receptor.	30	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch1	Notch1	Notch1	30	31	33	34
Jagged1 induced Notch1 signalling led to enhanced NKX2.5 , cTnT , SM22alpha , and vWF expression , while inhibition of Notch1 signalling by DAPT reduced their expression at both mRNA and protein levels .	Jagged1 induced Notch1 signalling led to enhanced NKX2.5, cTnT, SM22alpha, and vWF expression, while inhibition of Notch1 signalling by DAPT reduced their expression at both mRNA and protein levels.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	0	1	2	3
NICD overexpression was used as a positive control for the activation of CBF-1 luciferase reporter activity , and immobilized Jagged-1 was used as a positive control to stimulate canonical Notch signaling and nuclear NICD accumulation .	NICD overexpression was used as a positive control for the activation of CBF-1 luciferase reporter activity, and immobilized Jagged-1 was used as a positive control to stimulate canonical Notch signaling and nuclear NICD accumulation.	19	34	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged-1	Jagged-1	Jagged-1	NICD	NICD	NICD	19	20	33	34
For example , the Weinmaster group showed that Lunatic fringe does not appear to inhibit binding of Jagged1 to Notch1 , even though it inhibits Jagged1 mediated Notch1 signaling in cell based assays [ XREF_BIBR , XREF_BIBR ] .	For example, the Weinmaster group showed that Lunatic fringe does not appear to inhibit binding of Jagged1 to Notch1, even though it inhibits Jagged1 mediated Notch1 signaling in cell based assays [XREF_BIBR, XREF_BIBR].	25	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	25	26	27	28
In contrast , the shear stress that results from blood flow may potentiate Notch and Jag interactions between the endothelial cells lining the vessels , where Notch1 activation by Jag1 is critical for preventing aortic valve calcification .	In contrast, the shear stress that results from blood flow may potentiate Notch and Jag interactions between the endothelial cells lining the vessels, where Notch1 activation by Jag1 is critical for preventing aortic valve calcification.	26	30	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch1	Notch1	Notch1	29	30	26	27
Activation of Notch-1 by Jagged-1 was found to result in upregulation of uPA signaling which resulted in breast cancer progression .	Activation of Notch-1 by Jagged-1 was found to result in upregulation of uPA signaling which resulted in breast cancer progression.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Jagged-1	Jagged-1	Jagged-1	Notch-1	Notch-1	Notch-1	4	5	2	3
Yet , loss of both Jagged1 and Notch1 in the bone marrow had no effect on HSC homeostasis , on hematopoietic reconstitution after genotoxic insult , or in the number of cells of different stem and progenitor subsets after bone marrow transplant thus excluding an essential role for Jagged1 mediated Notch1 signaling on HSC self-renewal or differentiation [ XREF_BIBR ] .	Yet, loss of both Jagged1 and Notch1 in the bone marrow had no effect on HSC homeostasis, on hematopoietic reconstitution after genotoxic insult, or in the number of cells of different stem and progenitor subsets after bone marrow transplant thus excluding an essential role for Jagged1 mediated Notch1 signaling on HSC self-renewal or differentiation [XREF_BIBR].	46	51	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	48	49	50	51
Jagged1 induced activation of Notch1 signalling in c-Kit POS / NKX2.5 POS BMSCs facilitated predominately cardiomyocyte differentiation , while differentiation into endothelial and SMC lineages was much weaker .	Jagged1 induced activation of Notch1 signalling in c-Kit POS / NKX2.5 POS BMSCs facilitated predominately cardiomyocyte differentiation, while differentiation into endothelial and SMC lineages was much weaker.	0	13	induced	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	0	1	4	5
In light of these observations , our recent data suggest a feed-forward loop whereby ET-1 signaling through ETB R increases Jagged1 levels , which then can activate Notch1 signaling in adjacent astrocytes .	In light of these observations, our recent data suggest a feed-forward loop whereby ET-1 signaling through ETB R increases Jagged1 levels, which then can activate Notch1 signaling in adjacent astrocytes.	1	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	light of these observations, our recent data suggest a feed-forward loop whereby ET-1 signaling through ETB R increases Jagged1 levels	jagged1	Notch1	Notch1	notch1	20	21	27	28
Our results suggest that Notch may play an oncogenic role in the tumorigenesis of CCOT where Notch1 signal activation induced by Jagged1 is necessary for specification of ghost cell fate .	Our results suggest that Notch may play an oncogenic role in the tumorigenesis of CCOT where Notch1 signal activation induced by Jagged1 is necessary for specification of ghost cell fate.	16	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	21	22	16	17
Since JAG1 can activate NOTCH1 , BCC cell apoptosis was examined in cells induced with recombinant JAG1 .	Since JAG1 can activate NOTCH1, BCC cell apoptosis was examined in cells induced with recombinant JAG1.	1	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	NOTCH1	NOTCH1	NOTCH1	1	2	4	5
This is in line with previous data showing that Jagged1 expression and Notch1 signaling are induced by an increase in synaptic activity and is further supported by evidence that a soluble peptide of Jagged1 can potentiate LTP and activate Notch1 in neuronal cultures ( data not shown ) .	This is in line with previous data showing that Jagged1 expression and Notch1 signaling are induced by an increase in synaptic activity and is further supported by evidence that a soluble peptide of Jagged1 can potentiate LTP and activate Notch1 in neuronal cultures (data not shown).	31	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	33	34	39	40
In light of these results , the observed reduction of Jagged1 in AD may cause a reduction in Notch1 activity , underlying the memory decline .	In light of these results, the observed reduction of Jagged1 in AD may cause a reduction in Notch1 activity, underlying the memory decline.	8	19	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	10	11	18	19
Interestingly , it has been shown that stromal cells within lymph nodes expressed the NOTCH1 ligand JAGGED1 that induced NOTCH1 activation in CLL cells , suggesting that an aberrant NOTCH1 activity might contribute to CLL development .	Interestingly, it has been shown that stromal cells within lymph nodes expressed the NOTCH1 ligand JAGGED1 that induced NOTCH1 activation in CLL cells, suggesting that an aberrant NOTCH1 activity might contribute to CLL development.	12	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAGGED1	JAGGED1	JAGGED1	NOTCH1	NOTCH1	NOTCH1	16	17	19	20
Notch1 activation by Jagged1 or increased Notch signaling by constitutive expression of its activated form markedly stimulated proliferative signaling such as G1/S cyclins and p38 MAPK and promote immature cardiomyocytes expansion .	Notch1 activation by Jagged1 or increased Notch signaling by constitutive expression of its activated form markedly stimulated proliferative signaling such as G1/S cyclins and p38 MAPK and promote immature cardiomyocytes expansion.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	3	4	0	1
In addition to Notch receptor activation by endothelial expressed ligands , VSMC expressed Jag-1 activates Notch1 on endothelial cells to promote proliferation , and thereby represents the importance of heterotypic cell signaling between vascular cells via Notch .	In addition to Notch receptor activation by endothelial expressed ligands, VSMC expressed Jag-1 activates Notch1 on endothelial cells to promote proliferation, and thereby represents the importance of heterotypic cell signaling between vascular cells via Notch.	13	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jag-1	Jag-1	Jag-1	Notch1	Notch1	Notch1	13	14	15	16
Targeting JAG1 induced Notch1 activation , by Notch1 RNA interference or by a gamma-secretase inhibitor , suppressed cervical cancer invasiveness .	Targeting JAG1 induced Notch1 activation, by Notch1 RNA interference or by a gamma-secretase inhibitor, suppressed cervical cancer invasiveness.	0	4	induced	Positive_early_activation	Positive_activation	Negative_activation	JAG1	JAG1	JAG1	Notch1	Notch1	Notch1	1	2	3	4
Activation of Notch1 by Jagged1 also attenuated MI/R injury .	Activation of Notch1 by Jagged1 also attenuated MI/R injury.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	4	5	2	3
Taken together , our results indicate that Jagged1 mediated activation of Notch1 is responsible for regulating GATA2 expression in the AGM , which in turn is essential for definitive haematopoiesis in the mouse .	Taken together, our results indicate that Jagged1 mediated activation of Notch1 is responsible for regulating GATA2 expression in the AGM, which in turn is essential for definitive haematopoiesis in the mouse.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	7	8	11	12
Notch1 , when activated by transmembrane ligands Jagged1 , is cleaved by the Presenilin gamma and secretase complex , which liberates Notch1 intracellular domain ( NICD ) fragments .	Notch1, when activated by transmembrane ligands Jagged1, is cleaved by the Presenilin gamma and secretase complex, which liberates Notch1 intracellular domain (NICD) fragments.	0	10	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	7	8	0	1
Intramyocardial injection of the Notch1 ligand Jagged1 induced Notch1 activation and protected against I/R injury [ XREF_BIBR ] .	Intramyocardial injection of the Notch1 ligand Jagged1 induced Notch1 activation and protected against I/R injury [XREF_BIBR].	1	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	6	7	8	9
This appears to be due , in part , to the IL-1beta-dependent increase in Jagged1 levels [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] , because Jagged1 silencing decreased Notch1 activation and was associated with a decrease in VCAM1 expression .	This appears to be due, in part, to the IL-1beta-dependent increase in Jagged1 levels [XREF_BIBR, XREF_BIBR - XREF_BIBR], because Jagged1 silencing decreased Notch1 activation and was associated with a decrease in VCAM1 expression.	25	29	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	25	26	28	29
Jagged1 triggered Notch1 signalling activation induces multi-lineage differentiation .	Jagged1 triggered Notch1 signalling activation induces multi-lineage differentiation.	0	4	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	0	1	2	3
It is likely that the increased Jagged1 release in AVICs of stenotic valves mediates the enhanced Notch1 activation and the augmented inflammatory response to TLR4 stimulation .	It is likely that the increased Jagged1 release in AVICs of stenotic valves mediates the enhanced Notch1 activation and the augmented inflammatory response to TLR4 stimulation.	6	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	6	7	16	17
Jagged1 activated Notch1 signalling predominantly induces cardiomyocyte differentiation in c-Kit POS / NKX2.5 POS BMSCs .	Jagged1 activated Notch1 signalling predominantly induces cardiomyocyte differentiation in c-Kit POS / NKX2.5 POS BMSCs.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	0	1	2	3
In the BM niche ECs trigger self-renewal and repopulation of progenitor cells through Notch ligand Jag1 activating Notch1 and Notch2 receptors in stem cells XREF_BIBR XREF_BIBR .	In the BM niche ECs trigger self-renewal and repopulation of progenitor cells through Notch ligand Jag1 activating Notch1 and Notch2 receptors in stem cells XREF_BIBR XREF_BIBR.	5	20	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch1	Notch1	Notch1	15	16	17	18
When cultured on the biomaterial , hESCs had increased Hey1 expression compared to culture on the nanoparticles alone , indicating a jagged-1 mediated activation of Notch1 signaling .	When cultured on the biomaterial, hESCs had increased Hey1 expression compared to culture on the nanoparticles alone, indicating a jagged-1 mediated activation of Notch1 signaling.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	jagged-1	jagged-1	jagged-1	Notch1	Notch1	Notch1	21	22	25	26
Notch signaling occurs through a single transmembrane receptor , notch1 , which is activated by the ligands Jagged1 ,2 and Delta like 1 , on adjacent cells .	Notch signaling occurs through a single transmembrane receptor, notch1, which is activated by the ligands Jagged1,2 and Delta like 1, on adjacent cells.	7	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	notch1	notch1	notch1	17	18	9	10
This is supported by studies showing that Notch signaling induced by Jagged may result in decreased signal intensity in the presence of Fringe , where Jagged1 activates Notch2 but not Notch1 .	This is supported by studies showing that Notch signaling induced by Jagged may result in decreased signal intensity in the presence of Fringe, where Jagged1 activates Notch2 but not Notch1.	25	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	25	26	30	31
Jagged1 activated Notch1 signalling and promoted differentiation of both total BMSCs and c-Kit POS / NKX2.5 POS BMSCs into cardiomyocyte , SMC , and endothelial cell lineages .	Jagged1 activated Notch1 signalling and promoted differentiation of both total BMSCs and c-Kit POS / NKX2.5 POS BMSCs into cardiomyocyte, SMC, and endothelial cell lineages.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	0	1	2	3
Modeling of the fucose analogs into this structure revealed no steric clash between Notch1 and Jag1 at either EGF8 or EGF12 , consistent with lack of effect of the analogs on Jag1 mediated Notch1 activation ( XREF_SUPPLEMENTARY ) .	Modeling of the fucose analogs into this structure revealed no steric clash between Notch1 and Jag1 at either EGF8 or EGF12, consistent with lack of effect of the analogs on Jag1 mediated Notch1 activation (XREF_SUPPLEMENTARY).	8	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch1	Notch1	Notch1	31	32	33	34
Thus , the results suggested that Jagged1 activated Notch1 signaling pathway that modulates cardiac AMPK signaling cascade , which is a critical regulator of cardiac metabolic-shift under stress conditions , and Notch1 signaling may be feedback regulated by AMPK signaling pathway .	Thus, the results suggested that Jagged1 activated Notch1 signaling pathway that modulates cardiac AMPK signaling cascade, which is a critical regulator of cardiac metabolic-shift under stress conditions, and Notch1 signaling may be feedback regulated by AMPK signaling pathway.	6	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	6	7	8	9
Given that JAG1 is known to activate Notch 1 signaling , we determined whether Notch-downstream genes were upregulated by the addition of JAG1 to the EC/monocyte co-cultures .	Given that JAG1 is known to activate Notch 1 signaling, we determined whether Notch-downstream genes were upregulated by the addition of JAG1 to the EC/monocyte co-cultures.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch 1	Notch 1	Notch 1	2	3	7	9
In classical IL-6 signaling , the cytokine engages its receptor IL-6Ra at the cell surface , which is followed by the recruitment of the signal transducing receptor gp130 and activation of a Janus kinase ( JAK1 ) that activates STAT3 by phosphorylation .	In classical IL-6 signaling, the cytokine engages its receptor IL-6Ra at the cell surface, which is followed by the recruitment of the signal transducing receptor gp130 and activation of a Janus kinase (JAK1) that activates STAT3 by phosphorylation.	33	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	35	36	39	40
MPA treatment triggered tyrosine phosphorylation of JAK1 and JAK2 and activated the downstream target STAT3 .	MPA treatment triggered tyrosine phosphorylation of JAK1 and JAK2 and activated the downstream target STAT3.	0	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	MPA treatment triggered tyrosine phosphorylation of JAK1	jak1	STAT3	STAT3	stat3	6	7	14	15
XREF_BIBR JAK1 is a major activator of STAT3 in many cell systems XREF_BIBR and , in the highly metastatic U2A fibrosarcoma cells , was required for invasion , XREF_BIBR , XREF_BIBR with loss of JAK1 expression suppressing metastasis to a lesser extent .	XREF_BIBR JAK1 is a major activator of STAT3 in many cell systems XREF_BIBR and, in the highly metastatic U2A fibrosarcoma cells, was required for invasion, XREF_BIBR, XREF_BIBR with loss of JAK1 expression suppressing metastasis to a lesser extent.	0	24	is a major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	1	2	7	8
STAT3 is canonically activated by JAKs ( JAK1 , JAK2 , JAK3 , and Tyk2 ) , which in turn are activated by a large number of cytokine and growth factors , including IL-10 , IL-6 , and EGF , and it is well known to play a crucial role in myogenic proliferation and differentiation [ XREF_BIBR , XREF_BIBR ] .	STAT3 is canonically activated by JAKs (JAK1, JAK2, JAK3, and Tyk2), which in turn are activated by a large number of cytokine and growth factors, including IL-10, IL-6, and EGF, and it is well known to play a crucial role in myogenic proliferation and differentiation [XREF_BIBR, XREF_BIBR].	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	7	8	0	1
JAK1 led to STAT3 activation , which belonged to cytokine signal transduction pathway and found in prostate cancer [ XREF_BIBR ] .	JAK1 led to STAT3 activation, which belonged to cytokine signal transduction pathway and found in prostate cancer [XREF_BIBR].	0	4	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	0	1	3	4
By contrast , type I cytokines + DEX stimulate tyrosine phosphorylation of Janus kinase 1 ( JAK1 ) , which in turn activate STAT3 through tyrosine phosphorylation .	By contrast, type I cytokines + DEX stimulate tyrosine phosphorylation of Janus kinase 1 (JAK1), which in turn activate STAT3 through tyrosine phosphorylation.	3	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Janus kinase 1	type I cytokines + DEX stimulate tyrosine phosphorylation of Janus kinase 1	janus kinase 1	STAT3	STAT3	stat3	12	15	23	24
Since STAT3 is activated and phosphorylated by JAK1 or JAK2 36 , we performed siRNA knockdown of JAK1 and JAK2 in HCC-70 , HCC-38 and MDA-436 cells .	Since STAT3 is activated and phosphorylated by JAK1 or JAK2 36, we performed siRNA knockdown of JAK1 and JAK2 in HCC-70, HCC-38 and MDA-436 cells.	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	7	8	1	2
JAK1 activates STAT3 activity which is stopped rapidly by the major negative regulator suppressor of cytokine signaling 3 ( SOCS3 ) in normal cells .	JAK1 activates STAT3 activity which is stopped rapidly by the major negative regulator suppressor of cytokine signaling 3 (SOCS3) in normal cells.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	0	1	2	3
In addition , phosphorylation of JAK1 , JAK2 , and TYK2 , which can also activate STAT3 , were studied .	In addition, phosphorylation of JAK1, JAK2, and TYK2, which can also activate STAT3, were studied.	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	phosphorylation of JAK1	jak1	STAT3	STAT3	stat3	5	6	16	17
Interestingly , the increased phosphorylation of JAK1 in SOCS3 DSB and DSB ES cells did not lead to increased STAT3 activation .	Interestingly, the increased phosphorylation of JAK1 in SOCS3 DSB and DSB ES cells did not lead to increased STAT3 activation.	4	20	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	JAK1	phosphorylation of JAK1	jak1	STAT3	STAT3	stat3	6	7	19	20
JAK1 Activates STAT3 Activity in Non-Small-Cell Lung Cancer cells and IL-6 Neutralizing Antibodies can Suppress JAK1-STAT3 Signaling .	JAK1 Activates STAT3 Activity in Non-Small-Cell Lung Cancer cells and IL-6 Neutralizing Antibodies can Suppress JAK1-STAT3 Signaling.	0	3	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	0	1	2	3
In addition to JAK3 , STAT3 can also be activated by the kinases JAK1 and TYK2 that are activated by IL-10 signalling pathway .	In addition to JAK3, STAT3 can also be activated by the kinases JAK1 and TYK2 that are activated by IL-10 signalling pathway.	5	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	13	14	5	6
The MUC1-C cytoplasmic domain interacted directly with JAK1 and STAT3 , and MUC1-C was necessary for JAK1 mediated STAT3 activation .	The MUC1-C cytoplasmic domain interacted directly with JAK1 and STAT3, and MUC1-C was necessary for JAK1 mediated STAT3 activation.	16	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	16	17	18	19
IL-10-induced STAT3 activation by the JAK1 adaptor is a key element mediating its well-known anti-inflammatory properties .	IL-10-induced STAT3 activation by the JAK1 adaptor is a key element mediating its well-known anti-inflammatory properties.	1	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	5	6	1	2
Ruxolitinib ( INCB018424 ) , a well characterized inhibitor of JAK1 and JAK2 ,21 strongly suppressed STAT3 P-Y705 but unexpectedly did not suppress IL-1beta release from THP-1 cells treated with R837 .	Ruxolitinib (INCB018424), a well characterized inhibitor of JAK1 and JAK2,21 strongly suppressed STAT3 P-Y705 but unexpectedly did not suppress IL-1beta release from THP-1 cells treated with R837.	8	17	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	10	11	16	17
The Janus kinases JAK1 and 3 activate and sustain different STAT3 , 5 levels .	The Janus kinases JAK1 and 3 activate and sustain different STAT3, 5 levels.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	3	4	10	11
Upon IL-10 binding to its receptor , Janus kinase 1 ( JAK1 ) and tyrosine kinase 2 ( TYK2 ) are phosphorylated and lead to activation of STAT3 .	Upon IL-10 binding to its receptor, Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) are phosphorylated and lead to activation of STAT3.	7	28	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Janus kinase 1	Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) are phosphorylated	janus kinase 1	STAT3	STAT3	stat3	7	10	27	28
Neither Jak1 nor Tyk2 ( the upstream activators of STAT3 ) was activated in pSS CD3 ( + ) lymphocytes , suggesting that the constitutive activation of STAT3 observed in pSS patients might not depend on cytokine stimulation but instead might be the result of an abnormal inactivation of pSTAT3 .	Neither Jak1 nor Tyk2 (the upstream activators of STAT3) was activated in pSS CD3 (+) lymphocytes, suggesting that the constitutive activation of STAT3 observed in pSS patients might not depend on cytokine stimulation but instead might be the result of an abnormal inactivation of pSTAT3.	0	11	activators	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Jak1	Jak1	Jak1	STAT3	STAT3	STAT3	1	2	9	10
In order to further investigate the involvement of the JAK and STAT pathway in enhancing colon cancer cell survival and the mechanism of RKIP phosphorylation , we examined whether JAK 1 and 2 overexpression could stimulate STAT3 activation and thereby negate the inhibitory effects of CPT .	In order to further investigate the involvement of the JAK and STAT pathway in enhancing colon cancer cell survival and the mechanism of RKIP phosphorylation, we examined whether JAK 1 and 2 overexpression could stimulate STAT3 activation and thereby negate the inhibitory effects of CPT.	29	40	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK 1	JAK 1	JAK 1	STAT3	STAT3	STAT3	29	31	36	37
Neutralizing anti-IL-15Rbeta mAb totally inhibited the phosphorylation of JAK1 and inhibited that of STAT3 by 50 % .	Neutralizing anti-IL-15Rbeta mAb totally inhibited the phosphorylation of JAK1 and inhibited that of STAT3 by 50%.	1	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK1	anti-IL-15Rbeta mAb totally inhibited the phosphorylation of JAK1	jak1	STAT3	STAT3	stat3	8	9	13	14
miRNA-449a and miRNA-107 target expression of IL-6R and JAK1 , respectively , in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes .	miRNA-449a and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes.	4	22	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK1	expression of IL-6R and JAK1	jak1	STAT3	STAT3	stat3	8	9	21	22
JAK1 and JAK2 , but not JAK3 , could potently activate STAT3 in two CRC derived cell lines , and this activation was partially reversed by the iron chelator deferoxamine ( DFO ) ( XREF_FIG ) .	JAK1 and JAK2, but not JAK3, could potently activate STAT3 in two CRC derived cell lines, and this activation was partially reversed by the iron chelator deferoxamine (DFO) (XREF_FIG).	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	0	1	11	12
These data strongly suggest that JAK1 kinase can direct regulate STAT3 activity by inhibition of PY-STAT3 without interruption of phosphorylated serine STAT3 .	These data strongly suggest that JAK1 kinase can direct regulate STAT3 activity by inhibition of PY-STAT3 without interruption of phosphorylated serine STAT3.	5	11	direct regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	5	6	10	11
Furthermore , the FDA approved drug ruxolitinib , a potent inhibitor of JAK1 ( IC 50 value of 3.3 nM ) and JAK2 ( IC 50 value 2.8 nM ) , blocked STAT3 and STAT5 activation in a human erythroleukemia cell line ( HEL ) expressing JAK2 V617F .	Furthermore, the FDA approved drug ruxolitinib, a potent inhibitor of JAK1 (IC 50 value of 3.3 nM) and JAK2 (IC 50 value 2.8 nM), blocked STAT3 and STAT5 activation in a human erythroleukemia cell line (HEL) expressing JAK2 V617F.	10	35	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	12	13	32	33
JAK1 and TYK2 leads to STAT3 activation , Akt dependent NF-kappaB activation and phosphorylation of extracellular signal regulated kinase 1/2 ( ERK1/2 ) and mitogen activated kinase , p38 .	JAK1 and TYK2 leads to STAT3 activation, Akt dependent NF-kappaB activation and phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2) and mitogen activated kinase, p38.	0	6	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	0	1	5	6
Inhibition of JAK1 by siRNA mediated knockdown or small molecule inhibitors targeting JAK1 and JAK2 partially reduces STAT3 activation in human dermal fibroblasts .	Inhibition of JAK1 by siRNA mediated knockdown or small molecule inhibitors targeting JAK1 and JAK2 partially reduces STAT3 activation in human dermal fibroblasts.	0	18	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	2	3	17	18
XREF_BIBR , XREF_BIBR Especially noteworthy is a reported autoinductive loop between MUC1-C and STAT3 in breast cancer cells , in which MUC1-C facilitates JAK1 mediated STAT3 activation through complex formation , leading to activation of MUC1 gene .	XREF_BIBR, XREF_BIBR Especially noteworthy is a reported autoinductive loop between MUC1-C and STAT3 in breast cancer cells, in which MUC1-C facilitates JAK1 mediated STAT3 activation through complex formation, leading to activation of MUC1 gene.	23	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	23	24	25	26
Neither the jak1 , 2 , 3/JAK ( Janus kinase ) , nor IL-2 are drivers of STAT3 , even though STAT3 expresses domains for IL-2 binding .	Neither the jak1, 2, 3/JAK (Janus kinase), nor IL-2 are drivers of STAT3, even though STAT3 expresses domains for IL-2 binding.	0	18	are drivers	Positive_activation_copula_1	Positive_activation	Positive_activation	jak1	jak1	jak1	STAT3	STAT3	STAT3	2	3	17	18
The specificity of this STAT3i is demonstrated by the fact that it reduced JAK1 increased STAT3 activity ( XREF_SUPPLEMENTARY ) , but not HIF-1alpha induced P2.1 luciferase activity ( XREF_SUPPLEMENTARY ) .	The specificity of this STAT3i is demonstrated by the fact that it reduced JAK1 increased STAT3 activity (XREF_SUPPLEMENTARY), but not HIF-1alpha induced P2.1 luciferase activity (XREF_SUPPLEMENTARY).	13	16	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	13	14	15	16
The Janus Kinases ( JAK1 and JAK2 ) are important activators of STAT-3 .	The Janus Kinases (JAK1 and JAK2) are important activators of STAT-3.	4	13	are important activators	Positive_activation_copula_1	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT-3	STAT-3	STAT-3	4	5	12	13
IL-10 and STAT3 signaling is initiated by binding of IL-10 to the IL-10R and subsequent tyrosine phosphorylation of the IL-10R by Janus kinase 1 .	IL-10 and STAT3 signaling is initiated by binding of IL-10 to the IL-10R and subsequent tyrosine phosphorylation of the IL-10R by Janus kinase 1.	2	24	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Janus kinase 1	Janus kinase 1	Janus kinase 1	STAT3	STAT3	STAT3	21	24	2	3
To determine whether the observed drug effects are conveyed through decreased tyrosine or serine phosphorylation of STAT3 , the cells were treated with ruxolitinib ( JAK1 and JAK2 inhibitor ) , luminespib ( Hsp90 inhibitor ) , INK128 ( mTORC1 and mTORC2 inhibitor ) and temsirolimus ( mTORC1 inhibitor ) for 8 h. Ruxolitinib effectively inhibited Y705 phosphorylation of WT STAT3 but not mutant STAT3 .	To determine whether the observed drug effects are conveyed through decreased tyrosine or serine phosphorylation of STAT3, the cells were treated with ruxolitinib (JAK1 and JAK2 inhibitor), luminespib (Hsp90 inhibitor), INK128 (mTORC1 and mTORC2 inhibitor) and temsirolimus (mTORC1 inhibitor) for 8 h. Ruxolitinib effectively inhibited Y705 phosphorylation of WT STAT3 but not mutant STAT3.	11	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	25	26	16	17
JAK1 activates STAT3 in lung cancer cell lines .	JAK1 activates STAT3 in lung cancer cell lines.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	0	1	2	3
In addition , MPA promoted strong Stat3 transcriptional activation in C4HD and T47D cells that was inhibited by RU486 and by blockage of Jak1 , Jak2 , and Src activities .	In addition, MPA promoted strong Stat3 transcriptional activation in C4HD and T47D cells that was inhibited by RU486 and by blockage of Jak1, Jak2, and Src activities.	6	25	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak1	Jak1	Jak1	Stat3	Stat3	Stat3	23	24	6	7
Overexpression of JAK1 and IL6ST can directly activate STAT3 .	Overexpression of JAK1 and IL6ST can directly activate STAT3.	0	9	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	Overexpression of JAK1	jak1	STAT3	STAT3	stat3	2	3	8	9
The gp130 family stimulates STAT1 , STAT3 , and STAT5 via JAK1 , JAK2 , and TYK2 , except IL-12 and IL-23 , which stimulate STAT3 and STAT4 via JAK2 and TYK2 [ XREF_BIBR - XREF_BIBR ] .	The gp130 family stimulates STAT1, STAT3, and STAT5 via JAK1, JAK2, and TYK2, except IL-12 and IL-23, which stimulate STAT3 and STAT4 via JAK2 and TYK2 [XREF_BIBR - XREF_BIBR].	11	31	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	11	12	25	26
It is known that STAT3 is activated by JAK1 and JAK2 in neuron cell lines [ XREF_BIBR ] .	It is known that STAT3 is activated by JAK1 and JAK2 in neuron cell lines [XREF_BIBR].	4	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	8	9	4	5
Binding of IL-21 to the IL-21R alpha/gamma chain complex activates the JAK1 and JAK3 pathways which then activates STAT3 , as well as STAT1 , STAT5a and STAT5b to a lesser extent XREF_BIBR XREF_BIBR .	Binding of IL-21 to the IL-21R alpha/gamma chain complex activates the JAK1 and JAK3 pathways which then activates STAT3, as well as STAT1, STAT5a and STAT5b to a lesser extent XREF_BIBR XREF_BIBR.	11	19	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	11	12	18	19
There are three major approaches to inhibit STAT3 signaling : inhibition of tyrosine kinases , such as JAK1 and 2 , that are responsible for STAT3 activation ( AG- 490 , ruxolitinib , etc. ) , STAT3 dimerization inhibitors that target its SH2 domain ( Static , S3I-M2001 , STAT3 inhibitory peptide , etc. ) and non specific compounds that indirectly inhibit STAT3 , such as resveratrol and curcumin , which inhibit many other targets ( XREF_FIG ) .	There are three major approaches to inhibit STAT3 signaling : inhibition of tyrosine kinases, such as JAK1 and 2, that are responsible for STAT3 activation (AG- 490, ruxolitinib, etc.), STAT3 dimerization inhibitors that target its SH2 domain (Static, S3I-M2001, STAT3 inhibitory peptide, etc.) and non specific compounds that indirectly inhibit STAT3, such as resveratrol and curcumin, which inhibit many other targets (XREF_FIG).	7	19	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	17	18	7	8
Moreover , STAT5 and STAT3 activation could be triggered by constitutively active JAK1 and JAK3 [ XREF_BIBR ] .	Moreover, STAT5 and STAT3 activation could be triggered by constitutively active JAK1 and JAK3 [XREF_BIBR].	2	14	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	12	13	4	5
To determine whether JAK1 , JAK2 or both activate STAT3 , we knocked down the expression of each individual JAK kinase with siRNA .	To determine whether JAK1, JAK2 or both activate STAT3, we knocked down the expression of each individual JAK kinase with siRNA.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	3	4	9	10
STAT3 is activated by the tyrosine kinases JAK1 and JAK2 in response to gp130 or IL-22R signalling and is subject to feedback inhibition by SOCS3 .	STAT3 is activated by the tyrosine kinases JAK1 and JAK2 in response to gp130 or IL-22R signalling and is subject to feedback inhibition by SOCS3.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	7	8	0	1
Our results demonstrate that matrine decreased the levels of phosphoryalted JAK1 ( p-JAK1 ) and phosphoryalted STAT3 ( p-STAT3 ) in a dose dependent manner , thus inhibiting the JAK1 and STAT3 signaling pathway ( XREF_FIG ) .	Our results demonstrate that matrine decreased the levels of phosphoryalted JAK1 (p-JAK1) and phosphoryalted STAT3 (p-STAT3) in a dose dependent manner, thus inhibiting the JAK1 and STAT3 signaling pathway (XREF_FIG).	4	33	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK1	matrine decreased the levels of phosphoryalted JAK1	jak1	STAT3	STAT3	stat3	10	11	31	32
( eg , the increased kinase activity of JAK1 increases the transcriptional activity of STAT3 ) .	(eg, the increased kinase activity of JAK1 increases the transcriptional activity of STAT3).	6	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	8	9	14	15
To delineate the mechanism by which RKIP inhibits c-Src- and JAK1 and 2 mediated STAT3 activation , a series of RKIP deletion constructs ( XREF_FIG , upper panel ) were examined for their ability to inhibit JAK1 mediated STAT3 activation .	To delineate the mechanism by which RKIP inhibits c-Src- and JAK1 and 2 mediated STAT3 activation, a series of RKIP deletion constructs (XREF_FIG, upper panel) were examined for their ability to inhibit JAK1 mediated STAT3 activation.	35	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	36	37	38	39
As shown in XREF_FIG , JAK1 GQM-DVP was able to activate STAT3 after IL-6 stimulation , however this activation was prolonged compared to wild-type JAK .	As shown in XREF_FIG, JAK1 GQM-DVP was able to activate STAT3 after IL-6 stimulation, however this activation was prolonged compared to wild-type JAK.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	5	6	11	12
IL-9 protects the T cell lymphoma BW5147 cell line against dexamethasone induced apoptosis , an effect that is dependent on Jak1 mediated Stat3 and Stat5 activation .	IL-9 protects the T cell lymphoma BW5147 cell line against dexamethasone induced apoptosis, an effect that is dependent on Jak1 mediated Stat3 and Stat5 activation.	18	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jak1	Jak1	Jak1	Stat3	Stat3	Stat3	20	21	22	23
We first reported that AZD1480 , an ATP competitive inhibitor of JAK1 and JAK2 inactivated STAT3 mediated signaling and inhibited tumor growth in pediatric solid tumors such as NB , Ewing sarcoma , and rhabdomyosarcoma in vitro and in vivo .	We first reported that AZD1480, an ATP competitive inhibitor of JAK1 and JAK2 inactivated STAT3 mediated signaling and inhibited tumor growth in pediatric solid tumors such as NB, Ewing sarcoma, and rhabdomyosarcoma in vitro and in vivo.	9	17	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	11	12	15	16
IL-22 has been demonstrated to exert its biological effects via binding to the heterodimeric receptor complex , including IL-22R1 and IL-10R2 , and IL-22 activates Jak1 and Tyk2 , which further activates STAT-1 , STAT-3 and STAT-5 XREF_BIBR .	IL-22 has been demonstrated to exert its biological effects via binding to the heterodimeric receptor complex, including IL-22R1 and IL-10R2, and IL-22 activates Jak1 and Tyk2, which further activates STAT-1, STAT-3 and STAT-5 XREF_BIBR.	24	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak1	Jak1	Jak1	STAT-3	STAT-3	STAT-3	25	26	34	35
In contrast , the dimeric IFNgamma receptor consists of the interferon gamma receptor 1 ( IFNGR1 ) and IFNGR2 and activates the receptor associated tyrosine kinases , JAK1 and JAK2 , which solely activate STAT1 .	In contrast, the dimeric IFNgamma receptor consists of the interferon gamma receptor 1 (IFNGR1) and IFNGR2 and activates the receptor associated tyrosine kinases, JAK1 and JAK2, which solely activate STAT1.	25	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	27	28	34	35
Likewise , when IFNgamma binds to IFNGR1 and IFNGR2 , JAK1 and JAK2 are activated , which in turn activate STAT1 .	Likewise, when IFNgamma binds to IFNGR1 and IFNGR2, JAK1 and JAK2 are activated, which in turn activate STAT1.	10	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	10	11	20	21
XREF_BIBR , XREF_BIBR The IFNalpha receptor is comprised of IFNalphaR1 and IFNalphaR2 chains containing JAK1 and TYK2 , where activation leads to STAT1 : STAT2 dimerization and transcription of antiviral immune molecules .	XREF_BIBR, XREF_BIBR The IFNalpha receptor is comprised of IFNalphaR1 and IFNalphaR2 chains containing JAK1 and TYK2, where activation leads to STAT1 : STAT2 dimerization and transcription of antiviral immune molecules.	13	23	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	14	15	22	23
Phosphorylation of JAK1 and JAK2 will subsequently promote the phosphorylation and nuclear translocation of STAT1 .	Phosphorylation of JAK1 and JAK2 will subsequently promote the phosphorylation and nuclear translocation of STAT1.	0	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	Phosphorylation of JAK1	jak1	STAT1	STAT1	stat1	2	3	14	15
The IFNgamma receptor is comprised of IFNgammaR1 and IFNgammaR2 chains containing JAK1 and JAK2 , where activation induces STAT1 : STAT1 dimerization and inflammatory and antibacterial immune responses .	The IFNgamma receptor is comprised of IFNgammaR1 and IFNgammaR2 chains containing JAK1 and JAK2, where activation induces STAT1 : STAT1 dimerization and inflammatory and antibacterial immune responses.	10	27	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	11	12	18	19
As we employed cells with similar genetic background but differing in JAK1 expression ( LNCaP versus LNCaP-JAK1 ) , we could identify the roles of JAK1 mediated activation of STAT1 or STAT3 in the induction of antiviral state or cytostasis ; as neither cytostasis nor antiviral state occurred in LNCaP cells .	As we employed cells with similar genetic background but differing in JAK1 expression (LNCaP versus LNCaP-JAK1), we could identify the roles of JAK1 mediated activation of STAT1 or STAT3 in the induction of antiviral state or cytostasis; as neither cytostasis nor antiviral state occurred in LNCaP cells.	25	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	25	26	29	30
To investigate functional effects of the P733L and P832S mutations , we measured JAK1 mediated activation of STAT1 and STAT2 proteins in response to stimulation with cytokines IFN-alpha and IFN-gamma .	To investigate functional effects of the P733L and P832S mutations, we measured JAK1 mediated activation of STAT1 and STAT2 proteins in response to stimulation with cytokines IFN-alpha and IFN-gamma.	13	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	13	14	17	18
For example , IFN-gamma uses JAK1 and JAK2 , which activate mainly STAT1 , whereas IL-6 binding to the IL-6 receptor alpha chain and gp130 activates primarily JAK1 and STAT3 .	For example, IFN-gamma uses JAK1 and JAK2, which activate mainly STAT1, whereas IL-6 binding to the IL-6 receptor alpha chain and gp130 activates primarily JAK1 and STAT3.	4	13	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	5	6	12	13
For example , other than Jak2 , Stat1 can be activated by either Jak1 or Tyk2 XREF_BIBR .	For example, other than Jak2, Stat1 can be activated by either Jak1 or Tyk2 XREF_BIBR.	7	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak1	Jak1	Jak1	Stat1	Stat1	Stat1	13	14	7	8
Although STAT1 activation is primarily induced upon tyrosine phosphorylation by Jak1 and Jak2 ( the IFN-gamma receptor associated tyrosine kinases ) , the full activation of STAT1 is thought to involve serine phosphorylation by unidentified protein kinases .	Although STAT1 activation is primarily induced upon tyrosine phosphorylation by Jak1 and Jak2 (the IFN-gamma receptor associated tyrosine kinases), the full activation of STAT1 is thought to involve serine phosphorylation by unidentified protein kinases.	1	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak1	Jak1	Jak1	STAT1	STAT1	STAT1	10	11	1	2
Signaling through the IFNAR elicits activation of JAK1 and TYK2 , which subsequently activate STAT1 and STAT2 .	Signaling through the IFNAR elicits activation of JAK1 and TYK2, which subsequently activate STAT1 and STAT2.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	7	8	14	15
We then used pharmacological inhibition of JAK1 and siRNA mediated targeting of STAT1 to investigate signaling events relevant to transcription .	We then used pharmacological inhibition of JAK1 and siRNA mediated targeting of STAT1 to investigate signaling events relevant to transcription.	4	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	6	7	12	13
XREF_BIBR Engagement of the type I IFN receptor ( IFNAR1 and IFNAR2 complex ) and the type III IFN receptor ( IL-28Ralpha and IFNLR1 coupled with IL10R2 ) stimulates the phosphorylation of receptor associated JAK1 and TYK2 kinases , which primarily activate STAT1 , STAT2 , and the interferon regulatory factor IRF9 ( p48 ) to form the IFN stimulated gene factor 3 ( ISGF3 ) transcription complex .	XREF_BIBR Engagement of the type I IFN receptor (IFNAR1 and IFNAR2 complex) and the type III IFN receptor (IL-28Ralpha and IFNLR1 coupled with IL10R2) stimulates the phosphorylation of receptor associated JAK1 and TYK2 kinases, which primarily activate STAT1, STAT2, and the interferon regulatory factor IRF9 (p48) to form the IFN stimulated gene factor 3 (ISGF3) transcription complex.	34	56	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	34	35	42	43
In our study , residual JAK1 activity in GSH depleted cardiac myocytes ( XREF_FIG ) may have been sufficient to activate STAT1 .	In our study, residual JAK1 activity in GSH depleted cardiac myocytes (XREF_FIG) may have been sufficient to activate STAT1.	5	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	5	6	21	22
Finally , in other cell types the correlation between JAK1 activation and the induction of STAT1 has suggested that JAK1 may activate STAT1 .	Finally, in other cell types the correlation between JAK1 activation and the induction of STAT1 has suggested that JAK1 may activate STAT1.	19	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	19	20	22	23
In the present study , EGCG markedly attenuated the seawater induced phosphorylation of JAK1 , JAK2 , and STAT1 in vitro , attenuated the increase of STAT1 and p-STAT1 , reduced the proinflammatory cytokines , and increased anti-inflammatory cytokines in vivo and vitro .	In the present study, EGCG markedly attenuated the seawater induced phosphorylation of JAK1, JAK2, and STAT1 in vitro, attenuated the increase of STAT1 and p-STAT1, reduced the proinflammatory cytokines, and increased anti-inflammatory cytokines in vivo and vitro.	5	28	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK1	EGCG markedly attenuated the seawater induced phosphorylation of JAK1	jak1	STAT1	STAT1	stat1	13	14	26	27
These results established that the interaction of USP18 and STAT2 is responsible for recruitment of USP18 to IFNAR2 and is critical for the negative effect of USP18 on type I IFN induced JAK1 phosphorylation ( XREF_FIG ) , which is upstream of type I IFN induced STAT1 activation .	These results established that the interaction of USP18 and STAT2 is responsible for recruitment of USP18 to IFNAR2 and is critical for the negative effect of USP18 on type I IFN induced JAK1 phosphorylation (XREF_FIG), which is upstream of type I IFN induced STAT1 activation.	30	47	induced	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	JAK1	IFN induced JAK1 phosphorylation	jak1	STAT1	STAT1	stat1	32	33	46	47
Binding of IFNgamma to the type II IFN receptor results in the rapid autophosphorylation and activation of the receptor associated JAK1 and JAK2 , which in turn activates cytoplasmic STAT1 by phosphorylation at Tyr 701 .	Binding of IFNgamma to the type II IFN receptor results in the rapid autophosphorylation and activation of the receptor associated JAK1 and JAK2, which in turn activates cytoplasmic STAT1 by phosphorylation at Tyr 701.	19	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	20	21	29	30
Activation of STAT1 by JAK1 or JAK2 promotes T H 1 differentiation via the upregulation of T-bet resulting in the production of IFN-gamma .	Activation of STAT1 by JAK1 or JAK2 promotes T H 1 differentiation via the upregulation of T-bet resulting in the production of IFN-gamma.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	4	5	2	3
Luteolin promoted IFN-beta-induced Janus kinase and signal transducer and activator of transcription ( JAK and STAT ) pathway activation by enhancing the phosphorylation of Jak1 , Tyk2 , and STAT1/2 , thereby promoting STAT1 accumulation in the nucleus and endogenous IFN-alpha-regulated gene expression .	Luteolin promoted IFN-beta-induced Janus kinase and signal transducer and activator of transcription (JAK and STAT) pathway activation by enhancing the phosphorylation of Jak1, Tyk2, and STAT1/2, thereby promoting STAT1 accumulation in the nucleus and endogenous IFN-alpha-regulated gene expression.	22	34	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak1	phosphorylation of Jak1	jak1	STAT1	STAT1	stat1	24	25	33	34
The observation that IL-2 and IFN alpha activate JAK1 to a comparable degree , but only IFN alpha activates STAT1 , indicates that JAK1 activation is not the only determining factor for STAT1 activation .	The observation that IL-2 and IFN alpha activate JAK1 to a comparable degree, but only IFN alpha activates STAT1, indicates that JAK1 activation is not the only determining factor for STAT1 activation.	8	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	8	9	19	20
Tyk2 and Jak1 , that in turn phosphorylate and activate STAT1 and STAT2 , leading to the formation of a transcription complex in association with IFN regulatory factor 9 ( IRF9 ) .	Tyk2 and Jak1, that in turn phosphorylate and activate STAT1 and STAT2, leading to the formation of a transcription complex in association with IFN regulatory factor 9 (IRF9).	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak1	Jak1	Jak1	STAT1	STAT1	STAT1	2	3	10	11
Subsequent activation of JAK1 and TYK2 tyrosine kinases mediate activation of the STAT1 and STAT2 factors that together with IRF9 form the heterotrimeric ISGF3 complex that binds to the ISRE element to enhance gene expression ( XREF_FIG , right ) .	Subsequent activation of JAK1 and TYK2 tyrosine kinases mediate activation of the STAT1 and STAT2 factors that together with IRF9 form the heterotrimeric ISGF3 complex that binds to the ISRE element to enhance gene expression (XREF_FIG, right).	3	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	3	4	12	13
The functional role of JAK1 and JAK2 activation of STAT1 was confirmed when expression of STAT1 was reduced by stable transduction with two different STAT1-shRNAs .	The functional role of JAK1 and JAK2 activation of STAT1 was confirmed when expression of STAT1 was reduced by stable transduction with two different STAT1-shRNAs.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	4	5	9	10
JAK1 and TYK2 will phosphorylate and activate STAT1 and STAT2 respectively , leading to the formation of the ternary interferon stimulated gene factor 3 ( ISGF3 ) complex , composed of STAT1 , STAT2 and interferon regulatory factor 9 ( IRF9 ) .	JAK1 and TYK2 will phosphorylate and activate STAT1 and STAT2 respectively, leading to the formation of the ternary interferon stimulated gene factor 3 (ISGF3) complex, composed of STAT1, STAT2 and interferon regulatory factor 9 (IRF9).	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	0	1	7	8
The activation of the IL-27 specific subunit WSX-1 drives the tyrosine phosphorylation of JAK1 that further activates Stat1 .	The activation of the IL-27 specific subunit WSX-1 drives the tyrosine phosphorylation of JAK1 that further activates Stat1.	4	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	IL-27 specific subunit WSX-1 drives the tyrosine phosphorylation of JAK1	jak1	Stat1	Stat1	stat1	13	14	17	18
STAT1 is then activated via phosphorylation at tyrosine residue 701 by JAK1 .	STAT1 is then activated via phosphorylation at tyrosine residue 701 by JAK1.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	11	12	0	1
To explore whether premature expression of Jagged1 , GDF9 and BMP15 accelerated primordial follicle formation , CMV or Notch2 promoter driven-Nobox overexpression vectors were transfected into fetal mouse ovaries ; or GDF9 , BMP15 , and Jagged1 were added to the culture system .	To explore whether premature expression of Jagged1, GDF9 and BMP15 accelerated primordial follicle formation, CMV or Notch2 promoter driven-Nobox overexpression vectors were transfected into fetal mouse ovaries; or GDF9, BMP15, and Jagged1 were added to the culture system.	4	19	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	expression of Jagged1	jagged1	Notch2	Notch2	notch2	6	7	18	19
Possibly , within smooth muscle cells Notch2 is activated by the Jagged1 ligand on neighboring endothelial cells to establish the first wave of Notch activation and differentiation .	Possibly, within smooth muscle cells Notch2 is activated by the Jagged1 ligand on neighboring endothelial cells to establish the first wave of Notch activation and differentiation.	6	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch2	Notch2	Notch2	11	12	6	7
Additionally , in vitro studies revealed that GCP derived Jag1 activates Notch2 signaling , which also supports proliferation [ XREF_BIBR ] .	Additionally, in vitro studies revealed that GCP derived Jag1 activates Notch2 signaling, which also supports proliferation [XREF_BIBR].	8	12	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch2	Notch2	Notch2	9	10	11	12
We also found that both fringe proteins reduced Jagged1 triggered Notch2 signaling , whereas neither affected Delta1 triggered Notch2 signaling .	We also found that both fringe proteins reduced Jagged1 triggered Notch2 signaling, whereas neither affected Delta1 triggered Notch2 signaling.	8	11	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch2	Notch2	Notch2	8	9	10	11
There is evidence that Jag1 protein from the portal vein mesenchyme activates Notch2 in the adjacent BECs to induce tubulogenesis.Jag1 - hepatoblast specific conditional mouse knockouts , demonstrate no effect on bile duct development but Jag1 expression in portal vein mesenchyme is crucial for tubulogenesis [ XREF_BIBR , XREF_BIBR ] .	There is evidence that Jag1 protein from the portal vein mesenchyme activates Notch2 in the adjacent BECs to induce tubulogenesis.Jag1 - hepatoblast specific conditional mouse knockouts, demonstrate no effect on bile duct development but Jag1 expression in portal vein mesenchyme is crucial for tubulogenesis [XREF_BIBR, XREF_BIBR].	4	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch2	Notch2	Notch2	4	5	12	13
Microdeletions of the JAG1 gene that disrupt the NOTCH2 pathway are usually associated with this syndrome , but in rare cases in which JAG1 is not mutated , patients present an inactivating mutation on one of their NOTCH2 allele .	Microdeletions of the JAG1 gene that disrupt the NOTCH2 pathway are usually associated with this syndrome, but in rare cases in which JAG1 is not mutated, patients present an inactivating mutation on one of their NOTCH2 allele.	3	9	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAG1	JAG1	JAG1	NOTCH2	NOTCH2	NOTCH2	3	4	8	9
Jag-1 selective activation of Notch2 is required to inhibit VSMC proliferation .	Jag-1 selective activation of Notch2 is required to inhibit VSMC proliferation.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Jag-1	Jag-1	Jag-1	Notch2	Notch2	Notch2	0	1	4	5
In murine quiescent LSK cells , treatment with Dll1 or Jagged-1 activated Notch-2 and inhibited myeloid differentiation .	In murine quiescent LSK cells, treatment with Dll1 or Jagged-1 activated Notch-2 and inhibited myeloid differentiation.	6	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Jagged-1	Jagged-1	Jagged-1	Notch-2	Notch-2	Notch-2	10	11	12	13
Third , premature expression of GDF9 , BMP15 and Jagged1 by Nobox overexpression or addition of purified protein accelerated germline cell cysts breakdown and primordial follicle assembly and activated the Notch2 signaling pathway .	Third, premature expression of GDF9, BMP15 and Jagged1 by Nobox overexpression or addition of purified protein accelerated germline cell cysts breakdown and primordial follicle assembly and activated the Notch2 signaling pathway.	3	32	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	expression of GDF9, BMP15 and Jagged1	jagged1	Notch2	Notch2	notch2	9	10	30	31
Correspondingly , compromised Jagged1 induced mineral deposition was observed in the NOTCH2 knockdown hDPs at day 14 .	Correspondingly, compromised Jagged1 induced mineral deposition was observed in the NOTCH2 knockdown hDPs at day 14.	2	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	NOTCH2	NOTCH2	NOTCH2	3	4	11	12
At least in one system the activation of Notch2 by Jag1 was enhanced , not suppressed , by Lfng modification and subsequent glycosylation [ XREF_BIBR ] .	At least in one system the activation of Notch2 by Jag1 was enhanced, not suppressed, by Lfng modification and subsequent glycosylation [XREF_BIBR].	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch2	Notch2	Notch2	10	11	8	9
These data demonstrate Jag-1 activation of Notch2 likely results in stabilization of the existing pool of p27 kip1 .	These data demonstrate Jag-1 activation of Notch2 likely results in stabilization of the existing pool of p27 kip1.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Jag-1	Jag-1	Jag-1	Notch2	Notch2	Notch2	3	4	6	7
This occurs via endothelial Jagged1 dependent activation of the Notch2 receptor in lymphoma cells .	This occurs via endothelial Jagged1 dependent activation of the Notch2 receptor in lymphoma cells.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch2	Notch2	Notch2	4	5	9	10
We previously showed that Notch2 activation by Jagged1 mediates a unique function in human VSMC to suppress proliferation 6 .	We previously showed that Notch2 activation by Jagged1 mediates a unique function in human VSMC to suppress proliferation 6.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch2	Notch2	Notch2	7	8	4	5
Furthermore , without affecting NOTCH1 , which has been described as anti-proliferative receptor in MB [ XREF_BIBR ] , JAG1 appears to specifically mediate pro survival NOTCH2 signals in MB .	Furthermore, without affecting NOTCH1, which has been described as anti-proliferative receptor in MB [XREF_BIBR], JAG1 appears to specifically mediate pro survival NOTCH2 signals in MB.	19	27	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	NOTCH2	NOTCH2	NOTCH2	19	20	26	27
XREF_BIBR - XREF_BIBR During development , Notch receptors ( predominantly Notch2 ) are activated by the Jagged1 ligand , which is produced by cells in the portal vein mesenchyme .	XREF_BIBR - XREF_BIBR During development, Notch receptors (predominantly Notch2) are activated by the Jagged1 ligand, which is produced by cells in the portal vein mesenchyme.	7	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch2	Notch2	Notch2	16	17	10	11
Similarly , expansion and aggressiveness of B-cell lymphomas is induced by an angiocrine mechanism involving endothelial Jag1 activating Notch2 in malignant lymphoma cells XREF_BIBR .	Similarly, expansion and aggressiveness of B-cell lymphomas is induced by an angiocrine mechanism involving endothelial Jag1 activating Notch2 in malignant lymphoma cells XREF_BIBR.	13	23	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch2	Notch2	Notch2	16	17	18	19
Although Jag1 could still activate Notch2 in the presence of Lfng , previous studies indicated that NICD1 , and not NICD2 , triggered robust Th2 responses ( Amsen et al ., 2003 , Amsen et al ., 2007 ; Fang et al ., 2007 ) .	Although Jag1 could still activate Notch2 in the presence of Lfng, previous studies indicated that NICD1, and not NICD2, triggered robust Th2 responses (Amsen et al., 2003, Amsen et al., 2007; Fang et al., 2007).	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch2	Notch2	Notch2	1	2	5	6
By contrast , JAG1 activation of Notch2 is potentiated by Lfng , thereby expanding the ligand-receptor combinations that are differentially modified by the Fringe enzymes .	By contrast, JAG1 activation of Notch2 is potentiated by Lfng, thereby expanding the ligand-receptor combinations that are differentially modified by the Fringe enzymes.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch2	Notch2	Notch2	3	4	6	7
XREF_BIBR - XREF_BIBR Here , we show that JAGGED1 specifically activates NOTCH3 in mural cells , and this activity is both necessary and sufficient for the expression of smooth muscle genes in three distinct mural cell populations .	XREF_BIBR - XREF_BIBR Here, we show that JAGGED1 specifically activates NOTCH3 in mural cells, and this activity is both necessary and sufficient for the expression of smooth muscle genes in three distinct mural cell populations.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAGGED1	JAGGED1	JAGGED1	NOTCH3	NOTCH3	NOTCH3	8	9	11	12
Jagged1 expression by endothelial cells induces mural cells ( pericytes in the microvasculature or smooth muscle cells in larger vessels ) to express Notch3 and Jagged1 , which subsequently promotes and maintains the differentiation phenotype of mural cells [ XREF_BIBR ] , whereas platelet derived growth factor ( PDGF ) and angiotensin II downregulate Notch3 and Jagged1 expression in vascular smooth muscle cells [ XREF_BIBR ] .	Jagged1 expression by endothelial cells induces mural cells (pericytes in the microvasculature or smooth muscle cells in larger vessels) to express Notch3 and Jagged1, which subsequently promotes and maintains the differentiation phenotype of mural cells [XREF_BIBR], whereas platelet derived growth factor (PDGF) and angiotensin II downregulate Notch3 and Jagged1 expression in vascular smooth muscle cells [XREF_BIBR].	0	31	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1 expression	jagged1	Notch3	Notch3	notch3	0	1	23	24
Notch3 activation by endothelial Jag1 is further supported by enhanced expression of Notch3 in SMC cocultured with Jag1 expressing endothelial cells , suggesting a positive feedback loop .	Notch3 activation by endothelial Jag1 is further supported by enhanced expression of Notch3 in SMC cocultured with Jag1 expressing endothelial cells, suggesting a positive feedback loop.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch3	Notch3	Notch3	4	5	0	1
Importantly , we found that DNM mediated endocytosis was required for selectively activating Jag1 mediated Notch3 signaling .	Importantly, we found that DNM mediated endocytosis was required for selectively activating Jag1 mediated Notch3 signaling.	13	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch3	Notch3	Notch3	13	14	15	16
LS180 cells were treated for 48 h with siRNA specifically targeting mRNA degradation of APJ or Notch3 , and subsequently treated with APL13 or JAG1 , respectively .	LS180 cells were treated for 48 h with siRNA specifically targeting mRNA degradation of APJ or Notch3, and subsequently treated with APL13 or JAG1, respectively.	12	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	JAG1	JAG1	JAG1	Notch3	Notch3	Notch3	24	25	16	17
Therefore , we next evaluated whether Jagged-1 stimulation could induce Notch3 proteolysis in NICD3 negative SKOV3 cells .	Therefore, we next evaluated whether Jagged-1 stimulation could induce Notch3 proteolysis in NICD3 negative SKOV3 cells.	6	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged-1	Jagged-1	Jagged-1	Notch3	Notch3	Notch3	6	7	10	11
We found that silencing Notch3 significantly enhanced the sensitivity of OVCAR3 cells to treatment with paclitaxel ( p < 0.01 , XREF_SUPPLEMENTARY ) Dynamin Dependent Endocytosis Is Required for Jag1 Mediated Notch3 Activation .	We found that silencing Notch3 significantly enhanced the sensitivity of OVCAR3 cells to treatment with paclitaxel (p < 0.01, XREF_SUPPLEMENTARY) Dynamin Dependent Endocytosis Is Required for Jag1 Mediated Notch3 Activation.	27	32	Mediated	Positive_early_activation	Positive_activation	Positive_activation	Jag1	Jag1	Jag1	Notch3	Notch3	Notch3	29	30	31	32
Cleaved Notch3 is a key determinant of Notch3 biology , and DNM mediated endocytosis is required for Jagged1 mediated Notch3 activation .	Cleaved Notch3 is a key determinant of Notch3 biology, and DNM mediated endocytosis is required for Jagged1 mediated Notch3 activation.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch3	Notch3	Notch3	17	18	19	20
A previous study by Chen et al revealed that Jagged1 promoted the pathogenesis of ovarian cancer by activating Notch-3 .	A previous study by Chen et al revealed that Jagged1 promoted the pathogenesis of ovarian cancer by activating Notch-3.	9	19	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch-3	Notch-3	Notch-3	9	10	18	19
Importantly , dynasore prevented Jagged-1-stimulated cleaved Notch3 expression in the NICD3 negative cells ( SKOV3 cells , HeyA8 and 2774 ) , suggesting that endocytosis was required for Jagged1 mediated Notch3 activation ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Importantly, dynasore prevented Jagged-1-stimulated cleaved Notch3 expression in the NICD3 negative cells (SKOV3 cells, HeyA8 and 2774), suggesting that endocytosis was required for Jagged1 mediated Notch3 activation (XREF_FIG, XREF_SUPPLEMENTARY).	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch3	Notch3	Notch3	28	29	30	31
Our results demonstrated that Jagged1 activation of Notch3 resulted in a significant decrease in cell proliferation while concomitantly promoting Hem-pericyte maturation .	Our results demonstrated that Jagged1 activation of Notch3 resulted in a significant decrease in cell proliferation while concomitantly promoting Hem-pericyte maturation.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch3	Notch3	Notch3	4	5	7	8
JAG1 activates primarily Notch3 in ovarian cancer and promotes proliferation and dissemination within the intraperitoneal cavity .	JAG1 activates primarily Notch3 in ovarian cancer and promotes proliferation and dissemination within the intraperitoneal cavity.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch3	Notch3	Notch3	0	1	3	4
Prior studies found that Jag-1 activation of Notch3 in VSMC leads to maturation and quiescence 14 .	Prior studies found that Jag-1 activation of Notch3 in VSMC leads to maturation and quiescence 14.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Jag-1	Jag-1	Jag-1	Notch3	Notch3	Notch3	4	5	7	8
Then , the pericytes located on plexus vessels that receive blood flow induced Jagged-1 upregulate Notch3 and differentiate into caSMCs .	Then, the pericytes located on plexus vessels that receive blood flow induced Jagged-1 upregulate Notch3 and differentiate into caSMCs.	13	17	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged-1	Jagged-1	Jagged-1	Notch3	Notch3	Notch3	13	14	15	16
Jagged1 Is a Transcriptional Target of Notch3 and Contributes to Its Own Transcriptional Activation .	Jagged1 Is a Transcriptional Target of Notch3 and Contributes to Its Own Transcriptional Activation.	0	8	Is a Transcriptional Target	Positive_activation_copula_1	Positive_activation	Positive_activation	Jagged1	Jagged1	Jagged1	Notch3	Notch3	Notch3	0	1	6	7
Finally , in the coculture system , Jagged-1 expressed by the feeder cells induced promoter activation of candidate Notch3 target genes , Hes5 and Pbx1 .	Finally, in the coculture system, Jagged-1 expressed by the feeder cells induced promoter activation of candidate Notch3 target genes, Hes5 and Pbx1.	7	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged-1	Jagged-1 expressed	jagged-1	Notch3	Notch3	notch3	7	8	18	19
In addition , Jagged1 expressed by endothelial cells specifically activates Notch3 in mural cells and this activity is both necessary and sufficient for the expression of smooth muscle genes .	In addition, Jagged1 expressed by endothelial cells specifically activates Notch3 in mural cells and this activity is both necessary and sufficient for the expression of smooth muscle genes.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1 expressed	jagged1	Notch3	Notch3	notch3	3	4	10	11
XREF_BIBR , XREF_BIBR In studies most relevant to vascular development , endothelial Jagged1 expression activates Notch3 in mural cells resulting in increased Jagged1 expression , and Jagged1 protein is decreased in retinal blood vessels of Notch3 knockout animals .	XREF_BIBR, XREF_BIBR In studies most relevant to vascular development, endothelial Jagged1 expression activates Notch3 in mural cells resulting in increased Jagged1 expression, and Jagged1 protein is decreased in retinal blood vessels of Notch3 knockout animals.	12	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged1	Jagged1 expression	jagged1	Notch3	Notch3	notch3	12	13	15	16
Thus , JAG1 expression specifically depends on Notch3 function in NE-SMCs and raises the possibility that it in turn activates Notch3 .	Thus, JAG1 expression specifically depends on Notch3 function in NE-SMCs and raises the possibility that it in turn activates Notch3.	2	21	raises	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAG1	JAG1 expression	jag1	Notch3	Notch3	notch3	2	3	20	21
Hence , JAG1 induced Notch3 signaling , along with transactivation of NF-kappaB-p65 by OX40L , could co-operatively regulate Treg proliferation and Foxp3 expression .	Hence, JAG1 induced Notch3 signaling, along with transactivation of NF-kappaB-p65 by OX40L, could co-operatively regulate Treg proliferation and Foxp3 expression.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch3	Notch3	Notch3	2	3	4	5
Examination of NOTCH3 expression by Western blot and qPCR revealed that knockdown of JAGGED1 in endothelial cells significantly abrogated the induction of NOTCH3 in fibroblasts ( XREF_FIG ) .	Examination of NOTCH3 expression by Western blot and qPCR revealed that knockdown of JAGGED1 in endothelial cells significantly abrogated the induction of NOTCH3 in fibroblasts (XREF_FIG).	11	23	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAGGED1	JAGGED1	JAGGED1	NOTCH3	NOTCH3	NOTCH3	13	14	22	23
To further determine if Jagged-1 expressed by the feeder cells could stimulate Notch3 signaling in tumor cells , we performed promoter reporter assays in which A2780 cell was transiently transfected with reporter plasmids containing promoter regions of candidate Notch3 downstream target genes including Hes1 , Hes5 , and Pbx1 ( Park et al , unpublished observation ) , and the transfected cells were cocultured with J cells or L cells .	To further determine if Jagged-1 expressed by the feeder cells could stimulate Notch3 signaling in tumor cells, we performed promoter reporter assays in which A2780 cell was transiently transfected with reporter plasmids containing promoter regions of candidate Notch3 downstream target genes including Hes1, Hes5, and Pbx1 (Park et al, unpublished observation), and the transfected cells were cocultured with J cells or L cells.	4	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged-1	Jagged-1 expressed	jagged-1	Notch3	Notch3	notch3	4	5	12	13
The lack of ITK in mice is mitigated by the ability of TXK to activate PLCG1 [ XREF_BIBR ] .	The lack of ITK in mice is mitigated by the ability of TXK to activate PLCG1 [XREF_BIBR].	1	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ITK	ITK	ITK	PLCG1	PLCG1	PLCG1	3	4	15	16
ITK mediates signaling by activating phospholipase Cgamma1 , resulting in activation of downstream targets such as , nuclear factor of activated T-cells ( NFAT ) , NFkappaB , and mitogen activated protein kinase pathway [ XREF_BIBR ] .	ITK mediates signaling by activating phospholipase Cgamma1, resulting in activation of downstream targets such as, nuclear factor of activated T-cells (NFAT), NFkappaB, and mitogen activated protein kinase pathway [XREF_BIBR].	0	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ITK	ITK	ITK	phospholipase Cgamma1	phospholipase Cgamma1	phospholipase Cgamma1	0	1	5	7
As mentioned above , Itk is a critical activator of PLCgamma1 .	As mentioned above, Itk is a critical activator of PLCgamma1.	4	11	is a critical activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Itk	Itk	Itk	PLCgamma1	PLCgamma1	PLCgamma1	4	5	10	11
Following TCR and CD3 cross linking , ITK activation increases PLC-gamma1 activation and Ca 2+ influx XREF_BIBR - XREF_BIBR .	Following TCR and CD3 cross linking, ITK activation increases PLC-gamma1 activation and Ca 2+ influx XREF_BIBR - XREF_BIBR.	7	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ITK	ITK	ITK	PLC-gamma1	PLC-gamma1	PLC-gamma1	7	8	10	11
Itk promotes activation of phospholipase-Cgamma1 ( PLCgamma1 ) .	Itk promotes activation of phospholipase-Cgamma1 (PLCgamma1).	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Itk	Itk	Itk	phospholipase-Cgamma1	phospholipase-Cgamma1	phospholipase-Cgamma1	0	1	4	5
These studies demonstrate that the loss of Itk and Rlk impairs TCR dependent signaling , causing defects in phospholipase C-gamma1 , p38 , and ERK activation as well as defects in calcium flux and cytokine production in vitro and expansion and effector cytokine production by CD8 ( + ) T cells in response to viral infection .	These studies demonstrate that the loss of Itk and Rlk impairs TCR dependent signaling, causing defects in phospholipase C-gamma1, p38, and ERK activation as well as defects in calcium flux and cytokine production in vitro and expansion and effector cytokine production by CD8 (+) T cells in response to viral infection.	5	20	causing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Itk	loss of Itk	itk	phospholipase C-gamma1	phospholipase C-gamma1	phospholipase c-gamma1	7	8	18	20
Itk deficient T cells display defective Ca 2 + influx and PLCgamma1 activation , whereas overexpression of Itk leads to stimulation of PLCgamma1 activity .	Itk deficient T cells display defective Ca 2 + influx and PLCgamma1 activation, whereas overexpression of Itk leads to stimulation of PLCgamma1 activity.	15	23	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Itk	overexpression of Itk	itk	PLCgamma1	PLCgamma1	plcgamma1	17	18	22	23
Downstream of the TcR , Itk activates PLCgamma1 and regulates increases in intracellular Ca 2+ , and the absence of Itk preferentially affects influx of extracellular calcium from the outside of the cell .	Downstream of the TcR, Itk activates PLCgamma1 and regulates increases in intracellular Ca 2+, and the absence of Itk preferentially affects influx of extracellular calcium from the outside of the cell.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Itk	Itk	Itk	PLCgamma1	PLCgamma1	PLCgamma1	5	6	7	8
Subsequently , Itk activates phospholipase C-gamma1 , leading to calcium mobilization and extracellular signal regulated kinase and mitogen activated protein kinase activation .	Subsequently, Itk activates phospholipase C-gamma1, leading to calcium mobilization and extracellular signal regulated kinase and mitogen activated protein kinase activation.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Itk	Itk	Itk	phospholipase C-gamma1	phospholipase C-gamma1	phospholipase C-gamma1	2	3	4	6
Interestingly , because Itk functions upstream of HS1 in the actin-regulatory pathway , this suggests that Itk may promote PLCgamma1 activation in two ways : via its kinase activity and through SH2 domain mediated adaptor functions .	Interestingly, because Itk functions upstream of HS1 in the actin-regulatory pathway, this suggests that Itk may promote PLCgamma1 activation in two ways : via its kinase activity and through SH2 domain mediated adaptor functions.	16	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Itk	Itk	Itk	PLCgamma1	PLCgamma1	PLCgamma1	16	17	19	20
Itk activated PLCgamma1 cleaves membrane phosphatidyl inositol ( 4,5 ) bisphosphate ( PIP 2 ) into two secondary messengers , inositol 1,4,5-trisphosphate ( IP 3 ) and diacylglycerol ( DAG ) .	Itk activated PLCgamma1 cleaves membrane phosphatidyl inositol (4,5) bisphosphate (PIP 2) into two secondary messengers, inositol 1,4,5-trisphosphate (IP 3) and diacylglycerol (DAG).	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Itk	Itk	Itk	PLCgamma1	PLCgamma1	PLCgamma1	0	1	2	3
These phosphorylated scaffolds then bind Inducible T cell kinase ( Itk ) , which activates PLCgamma1 and thereby generates inositol triphosphate ( IP 3 ) and diacylglycerol ( DAG ) as second messengers to trigger Ca 2+ mobilization and protein kinase Ctheta ( PKCtheta ) activation , respectively .	These phosphorylated scaffolds then bind Inducible T cell kinase (Itk), which activates PLCgamma1 and thereby generates inositol triphosphate (IP 3) and diacylglycerol (DAG) as second messengers to trigger Ca 2+ mobilization and protein kinase Ctheta (PKCtheta) activation, respectively.	8	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Itk	Itk	Itk	PLCgamma1	PLCgamma1	PLCgamma1	10	11	15	16
ITK modulates T-cell signaling by activating PLCgamma1 and regulating the extent of Ca ( 2 ) + flux .	ITK modulates T-cell signaling by activating PLCgamma1 and regulating the extent of Ca (2) + flux.	0	7	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ITK	ITK	ITK	PLCgamma1	PLCgamma1	PLCgamma1	0	1	6	7
ITK activates PLCgamma1 , generating inositol 1,4,5-trisphosphate ( IP3 ) , which leads to intracellular calcium release and diacylglycerol , which , via RASGRP and PKCdelta , ultimately results in activation and induction of the NFkappaB , mTOR , and MAPK and ERK pathways .	ITK activates PLCgamma1, generating inositol 1,4,5-trisphosphate (IP3), which leads to intracellular calcium release and diacylglycerol, which, via RASGRP and PKCdelta, ultimately results in activation and induction of the NFkappaB, mTOR, and MAPK and ERK pathways.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ITK	ITK	ITK	PLCgamma1	PLCgamma1	PLCgamma1	0	1	2	3
Pharmacological inhibition of Ca 2+ / CaM activity or mutation of the CaM binding beta3 and beta4 loop disrupts Itk dependent activation of PLCgamma1 and downstream Ca 2+ responses , indicating that CaM participates in a positive feedback loop whereby binding of CaM to the Itk PH domain enhances further Itk activation and downstream Ca 2+ responses .	Pharmacological inhibition of Ca 2+ / CaM activity or mutation of the CaM binding beta3 and beta4 loop disrupts Itk dependent activation of PLCgamma1 and downstream Ca 2+ responses, indicating that CaM participates in a positive feedback loop whereby binding of CaM to the Itk PH domain enhances further Itk activation and downstream Ca 2+ responses.	19	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Itk	Itk	Itk	PLCgamma1	PLCgamma1	PLCgamma1	19	20	23	24
The binding of PLC-gamma1 to pTyr 136 of LAT is stabilized by the adaptors GADS and SLP-76 , and formation of a LAT , PLC , gamma1 , GADS , and SLP-76 complex seems to be required for the phosphorylation and activation of PLC-gamma1 by Itk on LAT .	The binding of PLC-gamma1 to pTyr 136 of LAT is stabilized by the adaptors GADS and SLP-76, and formation of a LAT, PLC, gamma1, GADS, and SLP-76 complex seems to be required for the phosphorylation and activation of PLC-gamma1 by Itk on LAT.	36	47	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Itk	Itk	Itk	PLC-gamma1	PLC-gamma1	PLC-gamma1	45	46	43	44
Mutation of SLP-76 at Y 145 , in general , phenocopies the loss of Itk , likely because other Tec family kinases , such as Rlk , can only partially compensate for the lack of Itk mediated PLC-gamma1 activation .	Mutation of SLP-76 at Y 145, in general, phenocopies the loss of Itk, likely because other Tec family kinases, such as Rlk, can only partially compensate for the lack of Itk mediated PLC-gamma1 activation.	33	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	Itk	Itk	Itk	PLC-gamma1	PLC-gamma1	PLC-gamma1	35	36	37	38
Together , these results indicate that CaM binds to the membrane proximal EpoR cytoplasmic region and plays an essential role in activation of Jak2 mediated EpoR signaling .	Together, these results indicate that CaM binds to the membrane proximal EpoR cytoplasmic region and plays an essential role in activation of Jak2 mediated EpoR signaling.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	EpoR	EpoR	EpoR	23	24	25	26
XREF_BIBR , XREF_BIBR A second major subgroup accounting for about 20 % of CRLF2-intact Ph like ALL is comprised of cases with genomic rearrangements that produce JAK2 fusion genes analogous to ABL-class fusions or rearrangements targeting the erythropoietin receptor ( EPOR ) .	XREF_BIBR, XREF_BIBR A second major subgroup accounting for about 20% of CRLF2-intact Ph like ALL is comprised of cases with genomic rearrangements that produce JAK2 fusion genes analogous to ABL-class fusions or rearrangements targeting the erythropoietin receptor (EPOR).	26	39	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	erythropoietin receptor	erythropoietin receptor	erythropoietin receptor	26	27	37	39
Given that this mutant lacks the phospho-degron motif needed for the recruitment of beta-Trcp E3 ubiquitin ligase , which has been shown to play a key role in EpoR downregulation and degradation [ XREF_BIBR ] , it is plausible that sustained activation of JAK2 results from dissociation of its ability to signal forward from JAK2 mediated elimination of EpoR [ XREF_BIBR ; XREF_BIBR ] .	Given that this mutant lacks the phospho-degron motif needed for the recruitment of beta-Trcp E3 ubiquitin ligase, which has been shown to play a key role in EpoR downregulation and degradation [XREF_BIBR], it is plausible that sustained activation of JAK2 results from dissociation of its ability to signal forward from JAK2 mediated elimination of EpoR [XREF_BIBR; XREF_BIBR].	51	60	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	EpoR	EpoR	EpoR	54	55	58	59
Similar to the mouse described by Frenzel et al ., homozygous JAK2 YY1007/1008FF alleles caused embryonic lethality and defective EpoR signaling , whereas heterozygous mice appeared phenotypically normal .	Similar to the mouse described by Frenzel et al., homozygous JAK2 YY1007/1008FF alleles caused embryonic lethality and defective EpoR signaling, whereas heterozygous mice appeared phenotypically normal.	4	20	caused	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	EpoR	EpoR	EpoR	11	12	19	20
The Levine laboratory reported that type I JAK2 inhibitors can induce a state of persistent JAK2 signaling in EPOR- or MPL expressing myeloid cells that involves heterodimerization and trans-phosphorylation of JAK2 by JAK1 or TYK2 .	The Levine laboratory reported that type I JAK2 inhibitors can induce a state of persistent JAK2 signaling in EPOR- or MPL expressing myeloid cells that involves heterodimerization and trans-phosphorylation of JAK2 by JAK1 or TYK2.	15	20	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	EPOR-	EPOR-	EPOR-	15	16	18	19
41 EPO appears to promote neuroprotection through binding to EpoR and activating JAK-2 and NF-kB and PI3K signaling pathway .	41 EPO appears to promote neuroprotection through binding to EpoR and activating JAK-2 and NF-kB and PI3K signaling pathway.	4	18	activating	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	JAK-2	JAK-2	JAK-2	EpoR	EpoR	EpoR	12	13	9	10
Structurally unrelated CaM antagonists , W-13 and CMZ , inhibited activation of Jak2 mediated EpoR signaling pathways , whereas W-12 , a W-13 analog , did not show any significant inhibitory effect .	Structurally unrelated CaM antagonists, W-13 and CMZ, inhibited activation of Jak2 mediated EpoR signaling pathways, whereas W-12, a W-13 analog, did not show any significant inhibitory effect.	10	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	EpoR	EpoR	EpoR	12	13	14	15
The anemia was felt to be due to tofacitinib inhibition of JAK2 signaling in the erythropoietin receptor signaling cascade , a hypothesis supported by the observation that tofacitinib inhibits proliferation of human polycythemia vera cell lines at clinically relevant concentrations .	The anemia was felt to be due to tofacitinib inhibition of JAK2 signaling in the erythropoietin receptor signaling cascade, a hypothesis supported by the observation that tofacitinib inhibits proliferation of human polycythemia vera cell lines at clinically relevant concentrations.	11	18	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	erythropoietin receptor	erythropoietin receptor	erythropoietin receptor	11	12	15	17
Binding studies using various EpoR mutants in hematopoietic cells showed that CaM binds the membrane proximal 65-amino-acid cytoplasmic region ( amino acids 258-312 ) of EpoR that is critical for activation of Jak2 mediated EpoR signaling .	Binding studies using various EpoR mutants in hematopoietic cells showed that CaM binds the membrane proximal 65-amino-acid cytoplasmic region (amino acids 258-312) of EpoR that is critical for activation of Jak2 mediated EpoR signaling.	30	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	EpoR	EpoR	EpoR	32	33	34	35
In the case of the family of the 15 or more type 1 IFN subtypes , all acting through the same heterodimeric receptor , JAK1 and TYK2 kinases activate STAT1alpha and STAT2 in conjunction with the receptor cytoplasmic domains .	In the case of the family of the 15 or more type 1 IFN subtypes, all acting through the same heterodimeric receptor, JAK1 and TYK2 kinases activate STAT1alpha and STAT2 in conjunction with the receptor cytoplasmic domains.	24	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT2	STAT2	STAT2	24	25	31	32
JAK1 and TYK2 phosphorylate and activate the latent transcription factors STAT1 and STAT2 , which translocate to the nucleus and associate with IRF-9 to trigger antiviral gene transcription .	JAK1 and TYK2 phosphorylate and activate the latent transcription factors STAT1 and STAT2, which translocate to the nucleus and associate with IRF-9 to trigger antiviral gene transcription.	0	24	activate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	JAK1	JAK1	jak1	STAT2	STAT2, which translocate to the nucleus	stat2	0	1	12	13
The activated JAK1 and Tyk2 kinases then activate STAT2 by phosphorylating Tyr 690 .	The activated JAK1 and Tyk2 kinases then activate STAT2 by phosphorylating Tyr 690.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT2	STAT2	STAT2	2	3	8	9
JAK1 and Tyk2 in turn activate their downstream effectors , signal transducer and activator of transcription ( STAT ) 1 and STAT2 [ XREF_BIBR ] .	JAK1 and Tyk2 in turn activate their downstream effectors, signal transducer and activator of transcription (STAT) 1 and STAT2 [XREF_BIBR].	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT2	STAT2	STAT2	0	1	21	22
Cdc42 activation is mediated by the Rho guanine-nucleotide-exchange factor ( GEF ) intersectin-1 ( ITSN1 ) , which is recruited to the virus prior to its actin based motility .	Cdc42 activation is mediated by the Rho guanine-nucleotide-exchange factor (GEF) intersectin-1 (ITSN1), which is recruited to the virus prior to its actin based motility.	0	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	intersectin-1	intersectin-1	intersectin-1	Cdc42	Cdc42	Cdc42	12	13	0	1
Silencing of intersectin-1 prevents secretagogue induced activation of Cdc42 revealing intersectin-1L as the factor integrating Cdc42 activation to the exocytotic pathway .	Silencing of intersectin-1 prevents secretagogue induced activation of Cdc42 revealing intersectin-1L as the factor integrating Cdc42 activation to the exocytotic pathway.	0	9	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	intersectin-1	intersectin-1	intersectin-1	Cdc42	Cdc42	Cdc42	2	3	8	9
Intersectin-1 activates Cdc42 , another member of the RhoGTPases , which can regulate F-actin polymerization and assembly of branched filaments via N-WASP and the Arp2/3 complex [ XREF_BIBR ] .	Intersectin-1 activates Cdc42, another member of the RhoGTPases, which can regulate F-actin polymerization and assembly of branched filaments via N-WASP and the Arp2/3 complex [XREF_BIBR].	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Intersectin-1	Intersectin-1	Intersectin-1	Cdc42	Cdc42	Cdc42	0	1	2	3
Map , SopE and ITSN induce similar structural alterations in Cdc42 despite their lack of overall structural and sequence homology ( XREF_FIG ) .	Map, SopE and ITSN induce similar structural alterations in Cdc42 despite their lack of overall structural and sequence homology (XREF_FIG).	0	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ITSN	ITSN	ITSN	Cdc42	Cdc42	Cdc42	4	5	10	11
Cdc42 activation by Intersectin-L then leads to N-WASP activation and the stimulation of actin polymerization .	Cdc42 activation by Intersectin-L then leads to N-WASP activation and the stimulation of actin polymerization.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Intersectin-L	Intersectin-L	Intersectin-L	Cdc42	Cdc42	Cdc42	3	4	0	1
Cdc42 is locally activated by the RhoGEF intersectin-1 , which is recruited to CEV by interacting with three Asn-Pro-Phe ( NPF ) motifs toward the C terminus of A36 .	Cdc42 is locally activated by the RhoGEF intersectin-1, which is recruited to CEV by interacting with three Asn-Pro-Phe (NPF) motifs toward the C terminus of A36.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	intersectin-1	intersectin-1	intersectin-1	Cdc42	Cdc42	Cdc42	7	8	0	1
Structural comparison showed that Map and ITSN induce similar conformational changes around switch 1 and beta2-3 of Cdc42 ( XREF_FIG ) .	Structural comparison showed that Map and ITSN induce similar conformational changes around switch 1 and beta2-3 of Cdc42 (XREF_FIG).	4	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ITSN	ITSN	ITSN	Cdc42	Cdc42	Cdc42	6	7	17	18
Dll1 and Jag2 increase notch1 activation in adjacent SC cells .	Dll1 and Jag2 increase notch1 activation in adjacent SC cells.	0	5	increase	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Jag2	Jag2	Jag2	notch1	notch1	notch1	2	3	4	5
The ligand-competitive LBD antibodies were able to block Jag2 stimulated Notch1 activity completely ( XREF_FIG and XREF_TABLE ) .	The ligand-competitive LBD antibodies were able to block Jag2 stimulated Notch1 activity completely (XREF_FIG and XREF_TABLE).	7	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jag2	Jag2	Jag2	Notch1	Notch1	Notch1	8	9	10	11
Our in vitro data predicted that forced endocardial MFng expression would hamper Jag1- and Jag2 mediated Notch1 activation , producing a chamber phenotype similar to that caused by inactivation of both ligands ( XREF_FIG and XREF_SUPPLEMENTARY ) or Mib1 inactivation .	Our in vitro data predicted that forced endocardial MFng expression would hamper Jag1- and Jag2 mediated Notch1 activation, producing a chamber phenotype similar to that caused by inactivation of both ligands (XREF_FIG and XREF_SUPPLEMENTARY) or Mib1 inactivation.	11	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jag2	Jag2	Jag2	Notch1	Notch1	Notch1	14	15	16	17
N1 10-24 decoy blocked JAG1 and JAG2 mediated NOTCH1 signaling , angiogenic sprouting in vitro and retinal angiogenesis , demonstrating JAG dependent Notch signal activation promotes angiogenesis .	N1 10-24 decoy blocked JAG1 and JAG2 mediated NOTCH1 signaling, angiogenic sprouting in vitro and retinal angiogenesis, demonstrating JAG dependent Notch signal activation promotes angiogenesis.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAG2	JAG2	JAG2	NOTCH1	NOTCH1	NOTCH1	6	7	8	9
Each receptor pair can activate JAK1 or JAK3 which activate STAT6 leading to transcriptional changes associated with the M2a state , including ; CD206 ( mannose receptor ) , scavenger receptors ( SRs ) , and suppressor of cytokine release 1 ( SOCS1 ) .	Each receptor pair can activate JAK1 or JAK3 which activate STAT6 leading to transcriptional changes associated with the M2a state, including; CD206 (mannose receptor), scavenger receptors (SRs), and suppressor of cytokine release 1 (SOCS1).	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT6	STAT6	STAT6	5	6	10	11
Proliferation results from a signaling pathway in which the engagement of the IL-13 receptor activates JAK1 , which in turn activates STAT6 .	Proliferation results from a signaling pathway in which the engagement of the IL-13 receptor activates JAK1, which in turn activates STAT6.	14	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT6	STAT6	STAT6	15	16	21	22
Taken together , our results show that IL-13Ralpha ' is a novel functional component of the IL-4R system and that JAK1 and JAK2 mediate IL-4-induced optimal activation of STAT6 in nonhematopoietic cells .	Taken together, our results show that IL-13Ralpha ' is a novel functional component of the IL-4R system and that JAK1 and JAK2 mediate IL-4-induced optimal activation of STAT6 in nonhematopoietic cells.	20	31	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT6	STAT6	STAT6	20	21	28	29
Alternatively , Itk could activate or inhibit a downstream effector of CD28 signaling .	Alternatively, Itk could activate or inhibit a downstream effector of CD28 signaling.	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Itk	Itk	Itk	CD28	CD28	CD28	2	3	11	12
We show that Itk forms an inducible complex with CD28 , mediated by the SH3 domain of Itk and the diproline motifs of CD28 .	We show that Itk forms an inducible complex with CD28, mediated by the SH3 domain of Itk and the diproline motifs of CD28.	4	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Itk	Itk	Itk	CD28	CD28	CD28	17	18	9	10
These experiments were done in the absence of ligand ( after extensive washing of the cells ) , which suggests that JAK2 inhibition decreased ligand independent turnover of EGFR , thus resulting in an increase in the steady-state cell surface EGFR and pEGFR abundance .	These experiments were done in the absence of ligand (after extensive washing of the cells), which suggests that JAK2 inhibition decreased ligand independent turnover of EGFR, thus resulting in an increase in the steady-state cell surface EGFR and pEGFR abundance.	21	29	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	EGFR	EGFR	EGFR	21	22	28	29
Overexpression of JAK2 strongly enhanced EGFR Tyr 1068 phosphorylation in both cell types , and G5-7 partially reduced JAK2 induced EGFR Tyr 1068 phosphorylation in both cell types ( XREF_FIG ) .	Overexpression of JAK2 strongly enhanced EGFR Tyr 1068 phosphorylation in both cell types, and G5-7 partially reduced JAK2 induced EGFR Tyr 1068 phosphorylation in both cell types (XREF_FIG).	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	EGFR	EGFR	EGFR	18	19	20	21
JAK2 inhibition increases the surface abundance of EGFR by decreasing the association of EGFR with SOCS5 .	JAK2 inhibition increases the surface abundance of EGFR by decreasing the association of EGFR with SOCS5.	0	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	EGFR	EGFR	EGFR	0	1	7	8
Depletion of JAK2 increased the abundance of total EGFR , pEGFR , and pERK ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Depletion of JAK2 increased the abundance of total EGFR, pEGFR, and pERK (XREF_FIG and XREF_SUPPLEMENTARY).	0	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	EGFR	EGFR	EGFR	2	3	8	9
The combination showed synergistic effects on JAK2 mediated EGFR TKI resistant PC-9 and ER3 cells in some cases .	The combination showed synergistic effects on JAK2 mediated EGFR TKI resistant PC-9 and ER3 cells in some cases.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	EGFR	EGFR	EGFR	6	7	8	9
Endothelial deployed jagged-2 triggered Notch2 and Hey1 , while tempering Notch2 and Hes1 signaling in HSPCs .	Endothelial deployed jagged-2 triggered Notch2 and Hey1, while tempering Notch2 and Hes1 signaling in HSPCs.	1	6	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	jagged-2	jagged-2	jagged-2	Notch2	Notch2	Notch2	2	3	4	5
Disruption of cis inhibition [ XREF_BIBR ] of Notch2 mediated signaling by expression of the ligand Jag2 in granulosa cells is an alternative model to explain the requirement for Notch2 function in somatic granulosa cells .	Disruption of cis inhibition [XREF_BIBR] of Notch2 mediated signaling by expression of the ligand Jag2 in granulosa cells is an alternative model to explain the requirement for Notch2 function in somatic granulosa cells.	8	19	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Jag2	expression of the ligand Jag2	jag2	Notch2	Notch2	notch2	16	17	8	9
For the downstream signaling events , endothelial jagged-2 activates the Notch2 and Hey1 signaling axis in HSPCs , and balances the upward trend of Notch2 and Hes1 signals in HSPCs .	For the downstream signaling events, endothelial jagged-2 activates the Notch2 and Hey1 signaling axis in HSPCs, and balances the upward trend of Notch2 and Hes1 signals in HSPCs.	6	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	jagged-2	jagged-2	jagged-2	Notch2	Notch2	Notch2	7	8	10	11
Taken together , our results show that basal stem and progenitor cells regulate the maintenance of their own progeny through a mechanism in which basal stem cell produced Jag2 activates Notch2 in daughter secretory progenitor cells to prevent secretory cell differentiation into post-mitotic ciliated cells .	Taken together, our results show that basal stem and progenitor cells regulate the maintenance of their own progeny through a mechanism in which basal stem cell produced Jag2 activates Notch2 in daughter secretory progenitor cells to prevent secretory cell differentiation into post-mitotic ciliated cells.	28	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jag2	Jag2	Jag2	Notch2	Notch2	Notch2	28	29	30	31
Finally , jagged-2 triggers Notch2 and Hey1 signaling in HSPCs to maintain HSPC function during recovery following myelosuppressive stress .	Finally, jagged-2 triggers Notch2 and Hey1 signaling in HSPCs to maintain HSPC function during recovery following myelosuppressive stress.	2	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	jagged-2	jagged-2	jagged-2	Notch2	Notch2	Notch2	2	3	4	5
Although other studies have shown a role for Jagged2 mediated activation of Notch3 in Treg expansion , such an interaction was not likely in the present study due to little or no expression of Jagged2 ( less than 1 % of the cells ) on GM-BMDCs .	Although other studies have shown a role for Jagged2 mediated activation of Notch3 in Treg expansion, such an interaction was not likely in the present study due to little or no expression of Jagged2 (less than 1% of the cells) on GM-BMDCs.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged2	Jagged2	Jagged2	Notch3	Notch3	Notch3	8	9	12	13
However , from the FTOC experiments it is obvious that at least part of human gammadelta T cells require Jagged2 mediated Notch3 activation for their development .	However, from the FTOC experiments it is obvious that at least part of human gammadelta T cells require Jagged2 mediated Notch3 activation for their development.	19	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged2	Jagged2	Jagged2	Notch3	Notch3	Notch3	19	20	21	22
Overall , these findings clearly illustrate that Jagged2 mediated Notch3 activation is critical for human gammadelta T cell development .	Overall, these findings clearly illustrate that Jagged2 mediated Notch3 activation is critical for human gammadelta T cell development.	7	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Jagged2	Jagged2	Jagged2	Notch3	Notch3	Notch3	7	8	9	10
ERK , Akt , and Jak2 mediate Gab2 induced HepG2 cell proliferation and migration .	ERK, Akt, and Jak2 mediate Gab2 induced HepG2 cell proliferation and migration.	0	8	mediate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Gab2	Gab2	Gab2	5	6	7	8
The Bcr-Abl kinase inhibitor imatinib mesylate ( 1 microM ) and two Jak2 kinase inhibitors strongly inhibited agar colony formation and the activation of Gab2 caused by Jak2 .	The Bcr-Abl kinase inhibitor imatinib mesylate (1 microM) and two Jak2 kinase inhibitors strongly inhibited agar colony formation and the activation of Gab2 caused by Jak2.	22	28	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Gab2	Gab2	Gab2	27	28	24	25
We have shown that inhibition of Jak2 by either Jak2 specific siRNA treatment or the Jak kinase inhibitor AG490 reduced levels of pTyr ( YxxM ) Gab2 .	We have shown that inhibition of Jak2 by either Jak2 specific siRNA treatment or the Jak kinase inhibitor AG490 reduced levels of pTyr (YxxM) Gab2.	4	27	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Gab2	Gab2	Gab2	6	7	26	27
Disruption of Jak2 dependent , G-CSF-stimulated Gab2 phosphorylation by mutation of Y643 inhibited the interaction of Gab2 with Shp2 , the activation of Erk1/2 , and the proliferation of cells in response to G-CSF .	Disruption of Jak2 dependent, G-CSF-stimulated Gab2 phosphorylation by mutation of Y643 inhibited the interaction of Gab2 with Shp2, the activation of Erk1/2, and the proliferation of cells in response to G-CSF.	2	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2 dependent, G-CSF-stimulated Gab2 phosphorylation	jak2	Gab2	Gab2	gab2	2	3	16	17
As JAK3 signals in conjunction with JAK1 , which plays a dominant role in signaling via common gamma-chain containing cytokine receptor complexes , we tested the effect of JAK1 depletion on JAK inhibitor induced phospho-JAK3 induction .	As JAK3 signals in conjunction with JAK1, which plays a dominant role in signaling via common gamma-chain containing cytokine receptor complexes, we tested the effect of JAK1 depletion on JAK inhibitor induced phospho-JAK3 induction.	28	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK1	JAK1	JAK1	phospho-JAK3	phospho-JAK3	phospho-JAK3	28	29	34	35
The ITGB8 protein , associated with ITGAV and a metalloprotease , activates transforming growth factor beta-1 ( TGF-beta1 ) in epithelial cells or neurons [ XREF_BIBR , XREF_BIBR ] .	The ITGB8 protein, associated with ITGAV and a metalloprotease, activates transforming growth factor beta-1 (TGF-beta1) in epithelial cells or neurons [XREF_BIBR, XREF_BIBR].	1	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ITGB8	ITGB8	ITGB8	transforming growth factor beta-1	transforming growth factor beta-1	transforming growth factor beta-1	1	2	12	16
Itgb8 deletion reduces activated TGF-beta1 in both the developmental and adult brain [ XREF_BIBR , XREF_BIBR ] .	Itgb8 deletion reduces activated TGF-beta1 in both the developmental and adult brain [XREF_BIBR, XREF_BIBR].	0	13	reduces activated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Itgb8	Itgb8	Itgb8	TGF-beta1	TGF-beta1	TGF-beta1	0	1	4	5
In this report , we have demonstrated that Itgb8 is selectively expressed on tTreg and mediates the release of active TGF-beta1 from the latent TGF , beta1 , and GARP complex .	In this report, we have demonstrated that Itgb8 is selectively expressed on tTreg and mediates the release of active TGF-beta1 from the latent TGF, beta1, and GARP complex.	8	21	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Itgb8	Itgb8 is selectively expressed	itgb8	TGF-beta1	TGF-beta1	tgf-beta1	8	9	20	21
CD11b mediates binding of leukocytes to intercellular adhesion molecule ( ICAM-1 and CD54 ) that is up-regulated in the uterine endothelium during human TL 29 .	CD11b mediates binding of leukocytes to intercellular adhesion molecule (ICAM-1 and CD54) that is up-regulated in the uterine endothelium during human TL 29.	0	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD11b	CD11b	CD11b	ICAM-1	ICAM-1	ICAM-1	0	1	10	11
CD11b promotes allograft rejection and targeting CD11b and CD18 or its ligand ICAM1 with antagonists that block the adhesion of leukocytes to endothelial cell surfaces reduces inflammatory injury , suggesting that the integrin CD11b and CD18 is an important innate immune cell target for developing novel therapeutics against inflammation and transplant rejection .	CD11b promotes allograft rejection and targeting CD11b and CD18 or its ligand ICAM1 with antagonists that block the adhesion of leukocytes to endothelial cell surfaces reduces inflammatory injury, suggesting that the integrin CD11b and CD18 is an important innate immune cell target for developing novel therapeutics against inflammation and transplant rejection.	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD11b	CD11b	CD11b	ICAM1	ICAM1	ICAM1	0	1	12	13
Coincubation of neutrophils with alpha-Toc and pretreatment of HUVEC with alpha-Toc significantly reduced PAF induced CD11b and CD18 expression and IL-1 beta induced upregulation of ICAM-1 and VCAM-1 , respectively .	Coincubation of neutrophils with alpha-Toc and pretreatment of HUVEC with alpha-Toc significantly reduced PAF induced CD11b and CD18 expression and IL-1 beta induced upregulation of ICAM-1 and VCAM-1, respectively.	13	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD11b	PAF induced CD11b and CD18 expression	cd11b	ICAM-1	ICAM-1	icam-1	15	16	25	26
Furthermore , p115RhoGEF is activated by a PLC/IP 3 / Ca 2+ / Jak2 dependent mechanism downstream of Galphaq/11 activation ( Guilluy etal .	Furthermore, p115RhoGEF is activated by a PLC/IP 3 / Ca 2+ / Jak2 dependent mechanism downstream of Galphaq/11 activation (Guilluy etal.	2	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	p115RhoGEF	p115RhoGEF	p115RhoGEF	13	14	2	3
21 AT1R stimulation activates JAK2 , which , in turn , induces Arhgef1 , the nucleotide exchange factor responsible for activation of RhoA , which subsequently activates Rho-kinase .	21 AT1R stimulation activates JAK2, which, in turn, induces Arhgef1, the nucleotide exchange factor responsible for activation of RhoA, which subsequently activates Rho-kinase.	3	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	Arhgef1	Arhgef1	Arhgef1	4	5	12	13
The IRE1alpha and TRAF2 complex can also interact with JNK ( Jun N-terminal Kinase ) , which activates transcription factor activator protein 1 ( AP-1 ) , resulting in expression of inflammatory genes .	The IRE1alpha and TRAF2 complex can also interact with JNK (Jun N-terminal Kinase), which activates transcription factor activator protein 1 (AP-1), resulting in expression of inflammatory genes.	7	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	activator protein 1	activator protein 1	activator protein 1	9	10	20	23
Whereas the Hippo pathway acts via the transcription coactivator Yki and YAP to regulate target gene expression , JNK signaling , triggered by various modulators including Rho GTPases , activates the transcription factors Jun and Fos .	Whereas the Hippo pathway acts via the transcription coactivator Yki and YAP to regulate target gene expression, JNK signaling, triggered by various modulators including Rho GTPases, activates the transcription factors Jun and Fos.	18	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	18	19	33	34
The absence of the JNK target c-Jun impairs the expression of cluster of differentiation ( CD ) 44 , galanin or alpha7beta1 integrins , molecules known to be involved in regeneration [ XREF_BIBR ] .	The absence of the JNK target c-Jun impairs the expression of cluster of differentiation (CD) 44, galanin or alpha7beta1 integrins, molecules known to be involved in regeneration [XREF_BIBR].	1	7	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	4	5	6	7
However , the JNK pathway has been shown to mediate the activation and transcription of c-Jun , which is required for IL-1-induction of MMP-13 [ XREF_BIBR ] .	However, the JNK pathway has been shown to mediate the activation and transcription of c-Jun, which is required for IL-1-induction of MMP-13 [XREF_BIBR].	3	19	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	15	16
Once activated , JNK translocates to the nucleus where it then may phosphorylate and subsequently activate the pro apoptotic transcription factor c-Jun .	Once activated, JNK translocates to the nucleus where it then may phosphorylate and subsequently activate the pro apoptotic transcription factor c-Jun.	3	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK translocates to the nucleus	jnk	c-Jun	c-Jun	c-jun	3	4	21	22
Signals transmitted through TNFR1 can trigger concomitantly the classical NF-kB signaling ( XREF_FIG ) and certain Mitogen Activated Protein Kinase ( MAPK ) pathways , such as c-Jun NH2-terminal kinase ( JNK ) signaling ( XREF_FIG ) , that ultimately activate the transcriptions factors NF-kB and Activator Protein-1 ( AP-1 ) respectively XREF_BIBR .	Signals transmitted through TNFR1 can trigger concomitantly the classical NF-kB signaling (XREF_FIG) and certain Mitogen Activated Protein Kinase (MAPK) pathways, such as c-Jun NH2-terminal kinase (JNK) signaling (XREF_FIG), that ultimately activate the transcriptions factors NF-kB and Activator Protein-1 (AP-1) respectively XREF_BIBR.	27	48	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Jun NH2-terminal kinase	c-Jun NH2-terminal kinase	c-Jun NH2-terminal kinase	Activator Protein-1	Activator Protein-1	Activator Protein-1	27	30	46	48
JUN encodes the transcription factor c-Jun , which can be activated and phosphorylated by c-Jun N-terminal kinases ( JNK ) .	JUN encodes the transcription factor c-Jun, which can be activated and phosphorylated by c-Jun N-terminal kinases (JNK).	1	19	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	18	19	5	6
A downstream target of MTK1 is Jun N-terminal kinase ( JNK ) , which in turn activates c-Jun .	A downstream target of MTK1 is Jun N-terminal kinase (JNK), which in turn activates c-Jun.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	10	11	17	18
Following translocation to the nucleus , JNK activates the transcription factor c-Jun and ATF-2 , leading to the formation of Jun and ATF-2 complex activator protein-1 ( AP-1 ) .	Following translocation to the nucleus, JNK activates the transcription factor c-Jun and ATF-2, leading to the formation of Jun and ATF-2 complex activator protein-1 (AP-1).	6	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	6	7	11	12
Likewise , phosphorylated c-Jun bound to the TAC element , suggesting that c-Jun is activated by JNK to transactivate the TNF-alpha promoter in LPS treated monocytes .	Likewise, phosphorylated c-Jun bound to the TAC element, suggesting that c-Jun is activated by JNK to transactivate the TNF-alpha promoter in LPS treated monocytes.	12	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	16	17	12	13
The neurotoxin 1-methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine ( MPTP ) , which induces selective neuronal loss in the midbrain similar to that seen in PD , also induces JNK mediated activation of c-Jun and generates a COX-2 response in C57BL/6J mice .	The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces selective neuronal loss in the midbrain similar to that seen in PD, also induces JNK mediated activation of c-Jun and generates a COX-2 response in C57BL/6J mice.	25	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	25	26	29	30
JNK has been found to promote cell survival by regulating c-Jun and cell death by regulating c-Myc and p53 activity .	JNK has been found to promote cell survival by regulating c-Jun and cell death by regulating c-Myc and p53 activity.	0	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	10	11
c-Jun N-terminal kinase inhibition after hemorrhage before resuscitation resulted in a reduced activation of c-Jun .	c-Jun N-terminal kinase inhibition after hemorrhage before resuscitation resulted in a reduced activation of c-Jun.	0	15	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun	c-Jun	c-Jun	0	3	14	15
c-Jun is exclusively activated by JNK and the c-fos activation can be regulated by JNK and ERK signal pathways .	c-Jun is exclusively activated by JNK and the c-fos activation can be regulated by JNK and ERK signal pathways.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	5	6	0	1
Unexpectedly , a significantly high level of phosphorylated c-Jun , but not of its classical activator phospho-JNK , was detected in EGFR-TKI-resistant cells , suggesting that c-Jun is not activated by JNK in EGFR-TKI-resistant cells but may be induced by TOPK either via direct interaction or via an intermediate kinase [ XREF_BIBR ] .	Unexpectedly, a significantly high level of phosphorylated c-Jun, but not of its classical activator phospho-JNK, was detected in EGFR-TKI-resistant cells, suggesting that c-Jun is not activated by JNK in EGFR-TKI-resistant cells but may be induced by TOPK either via direct interaction or via an intermediate kinase [XREF_BIBR].	26	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	31	32	26	27
c-Jun is activated by the c-Jun N-terminal kinase ( JNK ) , a member of the mitogen activated protein kinase pathway that responds to stress and cytokines .	c-Jun is activated by the c-Jun N-terminal kinase (JNK), a member of the mitogen activated protein kinase pathway that responds to stress and cytokines.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun	c-Jun	c-Jun	5	8	0	1
p44/42 can lead to activation of the Fos and Jun components of AP-1 while JNK activates the Jun component of AP-1 .	p44/42 can lead to activation of the Fos and Jun components of AP-1 while JNK activates the Jun component of AP-1.	14	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	14	15	17	18
The c-Jun NH ( 2 )-terminal kinase ( JNK ) phosphorylates and activates members of the activator protein-1 ( AP-1 ) group of transcription factors and is implicated in oncogenic transformation .	The c-Jun NH (2)-terminal kinase (JNK) phosphorylates and activates members of the activator protein-1 (AP-1) group of transcription factors and is implicated in oncogenic transformation.	6	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	activator protein-1	activator protein-1	activator protein-1	8	9	16	18
JNK is the major activator of c-jun , a transcription factor that regulates expression of numerous cell death genes .	JNK is the major activator of c-jun, a transcription factor that regulates expression of numerous cell death genes.	0	10	is the major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	0	1	6	7
Later , LPLI promotes phosphorylation of Jun N-terminal kinase ( JNK ) and results in an activation of the transcription factor activator protein-1 ( AP-1 ) .	Later, LPLI promotes phosphorylation of Jun N-terminal kinase (JNK) and results in an activation of the transcription factor activator protein-1 (AP-1).	2	23	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	JNK	LPLI promotes phosphorylation of Jun N-terminal kinase (JNK	jnk	activator protein-1	activator protein-1	activator protein-1	10	11	21	23
In addition , the type of apoptotic stimuli plays a greater role in defining whether JNK activated c-Jun is required for apoptosis .	In addition, the type of apoptotic stimuli plays a greater role in defining whether JNK activated c-Jun is required for apoptosis.	15	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	15	16	17	18
XREF_BIBR We demonstrate that PDGF signaling in hBMSCs activates JNK , which , in turn , activates c-Jun , a component of the AP-1 complex that is implicated in many cellular processes , including proliferation , differentiation , and cellular transformation .	XREF_BIBR We demonstrate that PDGF signaling in hBMSCs activates JNK, which, in turn, activates c-Jun, a component of the AP-1 complex that is implicated in many cellular processes, including proliferation, differentiation, and cellular transformation.	8	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	9	10	17	18
JNKs activation of c-Jun can result in the transcription of ERKs phosphatases , which are involved in ERKs inactivation .	JNKs activation of c-Jun can result in the transcription of ERKs phosphatases, which are involved in ERKs inactivation.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNKs	JNKs	JNKs	c-Jun	c-Jun	c-Jun	0	1	3	4
These results suggest that activated JNK can , in turn , activate not only jun but also raf that , in turn , activates MEK that can then cross-activate JNK in a positive feedback loop .	These results suggest that activated JNK can, in turn, activate not only jun but also raf that, in turn, activates MEK that can then cross-activate JNK in a positive feedback loop.	4	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	jun	jun	jun	5	6	14	15
JNK activates the oncoprotein c-Jun , thereby forming the activator protein-1 ( AP-1 ) transcription factor as a homodimer or heterodimer 45 .	JNK activates the oncoprotein c-Jun, thereby forming the activator protein-1 (AP-1) transcription factor as a homodimer or heterodimer 45.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	4	5
In line with our data , levels of the JNK target c-Jun and of phospho-c-Jun were increased in Jnk2 -/- fibroblasts , with p54 JNK nearly lost XREF_BIBR .	In line with our data, levels of the JNK target c-Jun and of phospho-c-Jun were increased in Jnk2 -/- fibroblasts, with p54 JNK nearly lost XREF_BIBR.	6	12	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	9	10	11	12
Thus , we evaluated the role of JNK , p38 , and ERK MAPKs in this response process , being JNK the main activator of c-Jun upon several different stimuli .	Thus, we evaluated the role of JNK, p38, and ERK MAPKs in this response process, being JNK the main activator of c-Jun upon several different stimuli.	3	29	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	20	21	25	26
For instance , the JNK and p38 cascades mostly mediate activation of the members of the transcription factor AP-1 - a heterodimeric complex composed of proteins of the Jun , Fos , Maf and ATF sub-groups .	For instance, the JNK and p38 cascades mostly mediate activation of the members of the transcription factor AP-1 - a heterodimeric complex composed of proteins of the Jun, Fos, Maf and ATF sub-groups.	4	19	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	4	5	16	19
The apoptosis attributed to glutamate was shown to be preceded by an increase in activator protein-1 ( AP-1 ) caused by activation of c-Jun N-terminal kinase ( JNK ) and p38 mitogen activated protein kinase ( MAP kinase ) and phosphorylation of c-Jun ( Ser63 ) and p53 ( Ser15 ) .	The apoptosis attributed to glutamate was shown to be preceded by an increase in activator protein-1 (AP-1) caused by activation of c-Jun N-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAP kinase) and phosphorylation of c-Jun (Ser63) and p53 (Ser15).	14	26	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	activator protein-1	activator protein-1	activator protein-1	23	26	14	16
Interestingly , although JNK phosphorylates and activates c-Jun in response to reovirus infection , c-Jun activation is not required for apoptosis .	Interestingly, although JNK phosphorylates and activates c-Jun in response to reovirus infection, c-Jun activation is not required for apoptosis.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	7	8
As the activating transcription factor-2 ( ATF-2 ) and c-Jun are activated by c-Jun N-terminal kinase ( JNK ) , these 2 proteins may be competitors in signal transduction cascades .	As the activating transcription factor-2 (ATF-2) and c-Jun are activated by c-Jun N-terminal kinase (JNK), these 2 proteins may be competitors in signal transduction cascades.	4	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun	c-Jun	c-Jun	13	16	9	10
Furthermore , IFNgamma reduced JNK phosphorylation , which tightly was associated with decreased phosphorylation of downstream factors c-Jun and Smad3 and decreased binding activity of c-Jun and Smad3 in the preprpET-1 promoter .	Furthermore, IFNgamma reduced JNK phosphorylation, which tightly was associated with decreased phosphorylation of downstream factors c-Jun and Smad3 and decreased binding activity of c-Jun and Smad3 in the preprpET-1 promoter.	2	27	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	IFNgamma reduced JNK phosphorylation	jnk	c-Jun	c-Jun	c-jun	4	5	25	26
ATF-2 is activated by both JNK and p38 , but c-Jun is only activated by JNK XREF_BIBR .	ATF-2 is activated by both JNK and p38, but c-Jun is only activated by JNK XREF_BIBR.	10	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	15	16	10	11
JNK control the transcriptional activation of c-Jun .	JNK control the transcriptional activation of c-Jun.	0	7	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	6	7
Activator Protein-1 ( AP-1 ) Is Activated by c-Jun N-Terminal Kinase ( JNK ) in CRC Tissues .	Activator Protein-1 (AP-1) Is Activated by c-Jun N-Terminal Kinase (JNK) in CRC Tissues.	0	11	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Jun N-Terminal Kinase	c-Jun N-Terminal Kinase	c-Jun N-Terminal Kinase	Activator Protein-1	Activator Protein-1	Activator Protein-1	8	11	0	2
The two MKKs have distinct mechanisms , with MKK4 contributing to JNK mediated activation of c-Jun and the ATF2/c and Jun complex .	The two MKKs have distinct mechanisms, with MKK4 contributing to JNK mediated activation of c-Jun and the ATF2/c and Jun complex.	11	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	11	12	15	16
Since it is well-known that c-Jun , which is activated by JNK ( c-Jun N-terminal kinase ) , binds to the AP-1 site XREF_BIBR and it has been reported that the activation of JNK dependent ATF2 ( activated transcription factor 2 ) is important for the signaling from mitochondria to nucleus during the both genetic and metabolic stresses of mitochondria XREF_BIBR , XREF_BIBR , we therefore investigated the effect of mtUPR on the phosphorylation of JNK1 and JNK2 ( XREF_FIG ) .	Since it is well-known that c-Jun, which is activated by JNK (c-Jun N-terminal kinase), binds to the AP-1 site XREF_BIBR and it has been reported that the activation of JNK dependent ATF2 (activated transcription factor 2) is important for the signaling from mitochondria to nucleus during the both genetic and metabolic stresses of mitochondria XREF_BIBR, XREF_BIBR, we therefore investigated the effect of mtUPR on the phosphorylation of JNK1 and JNK2 (XREF_FIG).	5	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	11	12	5	6
JNK also activates c-Jun , a component of the transcription complex AP-1 that cooperates with TGF-beta-induced Smads in mediating TGF-beta-induced transcription responses , such as plasminogen activator like-urokinase ( uPA ) expression , and plays an important role in EMT [ XREF_BIBR ] .	JNK also activates c-Jun, a component of the transcription complex AP-1 that cooperates with TGF-beta-induced Smads in mediating TGF-beta-induced transcription responses, such as plasminogen activator like-urokinase (uPA) expression, and plays an important role in EMT [XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	3	4
5 Upon phosphorylation , JNK translocates into the nucleus and activates the transcription factors Jun , Fos and FoxO , which will finally induce cell death .	5 Upon phosphorylation, JNK translocates into the nucleus and activates the transcription factors Jun, Fos and FoxO, which will finally induce cell death.	4	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	4	5	14	15
The activation levels of ERK , the p38 target MK-2 and the JNK target c-jun in cell lysates were assessed by immunoblotting with phospho specific antibodies .	The activation levels of ERK, the p38 target MK-2 and the JNK target c-jun in cell lysates were assessed by immunoblotting with phospho specific antibodies.	2	17	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	12	13	14	15
MEKK along with JNKK activate JNK which phosphorylates and transcriptionally activates c-Jun [ XREF_BIBR ] .	MEKK along with JNKK activate JNK which phosphorylates and transcriptionally activates c-Jun [XREF_BIBR].	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	5	6	11	12
In the same study , an examination of various JNK deficient mice showed that both JNK2 and JNK3 , but not JNK1 , were required for MPTP induced c-Jun activation and DAergic cell demise .	In the same study, an examination of various JNK deficient mice showed that both JNK2 and JNK3, but not JNK1, were required for MPTP induced c-Jun activation and DAergic cell demise.	6	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	9	10	28	29
Our findings suggest that the JNK potentiated Akt and FoxO3a and JNK mediated c-Jun pathways co-operatively trigger Puma expression , which determines the threshold for overcoming chemoresistance in ovarian cancer cells .	Our findings suggest that the JNK potentiated Akt and FoxO3a and JNK mediated c-Jun pathways co-operatively trigger Puma expression, which determines the threshold for overcoming chemoresistance in ovarian cancer cells.	7	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	11	12	13	14
c-Jun is activated through phosphorylation by the JNK pathways [ XREF_BIBR , XREF_BIBR ] .	c-Jun is activated through phosphorylation by the JNK pathways [XREF_BIBR, XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	7	8	0	1
Pharmacological inhibition of JNK prevented this TD induced rise in Puma ( XREF_FIG ) , consistent with a known role of c-Jun in promoting Puma expression and providing a mechanism for the somatic requirement for JNK signaling that we observed ( XREF_FIG ) .	Pharmacological inhibition of JNK prevented this TD induced rise in Puma (XREF_FIG), consistent with a known role of c-Jun in promoting Puma expression and providing a mechanism for the somatic requirement for JNK signaling that we observed (XREF_FIG).	1	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	21	22
This indicates that JNK activation of c-Jun by procyanidin leads to the induction of apoptosis of OA cells and suggests a role for a c-Jun-mediated transcriptional program .	This indicates that JNK activation of c-Jun by procyanidin leads to the induction of apoptosis of OA cells and suggests a role for a c-Jun-mediated transcriptional program.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	6	7
The homophilic interactions of CD151 increased motility and MMP-9 expression of CD151 transfected MelJuSo cells , along with FAK-, Src-, p38 MAPK-, and JNK mediated activation of c-Jun in an adhesion dependent manner .	The homophilic interactions of CD151 increased motility and MMP-9 expression of CD151 transfected MelJuSo cells, along with FAK-, Src-, p38 MAPK-, and JNK mediated activation of c-Jun in an adhesion dependent manner.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	23	24	27	28
JNK is a potent activator of the transcription factor c-jun , required for B cell IL-6 production by CD40 XREF_BIBR , XREF_BIBR , XREF_BIBR .	JNK is a potent activator of the transcription factor c-jun, required for B cell IL-6 production by CD40 XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	11	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	0	1	9	10
It is possible that ERK counteracts the JNK induced activation of c-Jun by preserving phosphorylation at the Ser243 site .	It is possible that ERK counteracts the JNK induced activation of c-Jun by preserving phosphorylation at the Ser243 site.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	7	8	11	12
In doxorubicin induced cytotoxicity , JNK activated c-Jun / ATF2 to upregulate PKC delta transcripts .	In doxorubicin induced cytotoxicity, JNK activated c-Jun / ATF2 to upregulate PKC delta transcripts.	3	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	5	6	7	8
A single stimulation of cells with cytokines causes rapid ERK1/2 activation , which returns to baseline in 4 h. Repeated stimulation leads to sustained activation of ERK1/2 but not Jun N-terminal protein kinase ( JNK ) , p38 , or STAT6 .	A single stimulation of cells with cytokines causes rapid ERK1/2 activation, which returns to baseline in 4 h. Repeated stimulation leads to sustained activation of ERK1/2 but not Jun N-terminal protein kinase (JNK), p38, or STAT6.	21	35	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	34	35	29	30
JNK activation induces the translocation of transcription factors AP-1 , c-Jun , ATF-2 and ELK-1 to the nucleus to regulate inflammatory gene transcription .	JNK activation induces the translocation of transcription factors AP-1, c-Jun, ATF-2 and ELK-1 to the nucleus to regulate inflammatory gene transcription.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	10	11
Dexamethasone did not inhibit the antigen induced phosphorylation of JNK but inhibited that of c-Jun .	Dexamethasone did not inhibit the antigen induced phosphorylation of JNK but inhibited that of c-Jun.	0	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	Dexamethasone did not inhibit the antigen induced phosphorylation of JNK	jnk	c-Jun	c-Jun	c-jun	9	10	14	15
JNK activated c-Jun is a signal transducing transcription factor of the AP-1 family that is implicated in cell cycle progression , differentiation and cell transformation [ XREF_BIBR ] .	JNK activated c-Jun is a signal transducing transcription factor of the AP-1 family that is implicated in cell cycle progression, differentiation and cell transformation [XREF_BIBR].	0	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	2	3
Normally JNK activates the oncoprotein c-Jun through phosphorylation on Ser 63 and Ser73 , leading to activation of the activator protein-1 ( AP1 ) transcription factor complex as a homodimer , or as a heterodimer with Fos XREF_BIBR .	Normally JNK activates the oncoprotein c-Jun through phosphorylation on Ser 63 and Ser73, leading to activation of the activator protein-1 (AP1) transcription factor complex as a homodimer, or as a heterodimer with Fos XREF_BIBR.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	1	2	5	6
p38 MAPK and JNK may each preferentially phosphorylate and activate different transcription factors , e.g ., ATF-2 and c-Jun , respectively , which may interact in a transcription complex to regulate FasL expression .	p38 MAPK and JNK may each preferentially phosphorylate and activate different transcription factors, e.g., ATF-2 and c-Jun, respectively, which may interact in a transcription complex to regulate FasL expression.	1	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	18	19
It is possible that Jnk mediated protein activation , classically of c-Jun , is not sufficient to address the AP1 elements in the promoters without activation of interacting proteins like c-fos , which is not a Jnk substrate XREF_BIBR .	It is possible that Jnk mediated protein activation, classically of c-Jun, is not sufficient to address the AP1 elements in the promoters without activation of interacting proteins like c-fos, which is not a Jnk substrate XREF_BIBR.	4	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jnk	Jnk	Jnk	c-Jun	c-Jun	c-Jun	4	5	11	12
MDP is transferred into the cytoplasm , where it activates c-Jun N-terminal kinases ( JNKs ) , which up-regulate activator protein-1 ( API ) .	MDP is transferred into the cytoplasm, where it activates c-Jun N-terminal kinases (JNKs), which up-regulate activator protein-1 (API).	12	21	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNKs	JNKs	JNKs	activator protein-1	activator protein-1	activator protein-1	14	15	19	21
JNK is also able to activate the transcription factors activator protein-1 and Elk-1 , further increasing the transcription of specific genes , proliferation , differentiation and apoptosis , which are involved in the regulation of many cellular activities .	JNK is also able to activate the transcription factors activator protein-1 and Elk-1, further increasing the transcription of specific genes, proliferation, differentiation and apoptosis, which are involved in the regulation of many cellular activities.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	activator protein-1	activator protein-1	activator protein-1	0	1	9	11
Regarding signaling pathways , ribotoxic agents activate p38 MAPK and Jun N-terminal kinase ( JNK ) , which are involved in pro apoptotic caspase 3 activation in intestinal epithelia [ XREF_BIBR , XREF_BIBR ] .	Regarding signaling pathways, ribotoxic agents activate p38 MAPK and Jun N-terminal kinase (JNK), which are involved in pro apoptotic caspase 3 activation in intestinal epithelia [XREF_BIBR, XREF_BIBR].	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	14	15	10	11
To confirm the direct involvement of JNK mediated c-Jun signaling in miR-21 gene upregulation , JNK activity was blocked by a JNK Inhibitor , 420116 , and c-Jun was downregulated by c-Jun small interfering RNA ( siRNA ) , followed by the miR-21 promoter specific ChIP assay as described above .	To confirm the direct involvement of JNK mediated c-Jun signaling in miR-21 gene upregulation, JNK activity was blocked by a JNK Inhibitor, 420116, and c-Jun was downregulated by c-Jun small interfering RNA (siRNA), followed by the miR-21 promoter specific ChIP assay as described above.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	6	7	8	9
This result was surprising because a previous study discounted the JNK target c-Jun as a significant regulator of axon degeneration ( as opposed to cell body degeneration ) .	This result was surprising because a previous study discounted the JNK target c-Jun as a significant regulator of axon degeneration (as opposed to cell body degeneration).	8	13	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	10	11	12	13
Classically JNK activity can result in transactivation of c-Jun , a component of the activator protein-1 ( AP-1 ) transcription factor complex and JNK phosphorylation is caused by cytokines including Tumor Necrosis Factor ( TNF ) and interleukin-1beta .	Classically JNK activity can result in transactivation of c-Jun, a component of the activator protein-1 (AP-1) transcription factor complex and JNK phosphorylation is caused by cytokines including Tumor Necrosis Factor (TNF) and interleukin-1beta.	6	27	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK phosphorylation	jnk	c-Jun	c-Jun	c-jun	23	24	8	9
JNK in turn activates Jun and leads to the expression of pro survival factors , such as Bcl-2 .	JNK in turn activates Jun and leads to the expression of pro survival factors, such as Bcl-2.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	0	1	4	5
Inhibition of p38 and JNK reduced GnRH induction of c-Jun by 57 % and 54 % , respectively ( XREF_FIG ) .	Inhibition of p38 and JNK reduced GnRH induction of c-Jun by 57% and 54%, respectively (XREF_FIG).	0	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	4	5	9	10
Thus , these newly described pathways act concomitantly with the activation of c-Jun by JNK and MAPKs , thereby contributing to the complexity of AP1 driven gene transcription regulation .	Thus, these newly described pathways act concomitantly with the activation of c-Jun by JNK and MAPKs, thereby contributing to the complexity of AP1 driven gene transcription regulation.	4	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	14	15	12	13
Examination of various JNK deficient mice shows that both JNK2 and JNK3 , but not JNK1 , are required for MPTP induced c-Jun activation and dopaminergic cell demise .	Examination of various JNK deficient mice shows that both JNK2 and JNK3, but not JNK1, are required for MPTP induced c-Jun activation and dopaminergic cell demise.	0	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	22	23
The induction of Annexin A2 was mTOR independent , and was mediated at the transcriptional level by JNK activated c-Jun binding to the Annexin A2 promoter .	The induction of Annexin A2 was mTOR independent, and was mediated at the transcriptional level by JNK activated c-Jun binding to the Annexin A2 promoter.	11	20	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	17	18	19	20
ERK activates AP-1 transcriptional activity by the phosphorylation of c-Fos , while c-Jun activation is induced by JNK .	ERK activates AP-1 transcriptional activity by the phosphorylation of c-Fos, while c-Jun activation is induced by JNK.	12	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	17	18	12	13
JNKs , on the other hand , enhance the transcriptional activity of c-Jun by NH 2 -terminal phosphorylation .	JNKs, on the other hand, enhance the transcriptional activity of c-Jun by NH 2 -terminal phosphorylation.	0	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNKs	JNKs	JNKs	c-Jun	c-Jun	c-Jun	0	1	12	13
In the nuclear apoptosis pathway , activated JNK translocates to the nucleus and activates c-Jun , leading to the formation of activator protein 1 ( AP-1 ) .	In the nuclear apoptosis pathway, activated JNK translocates to the nucleus and activates c-Jun, leading to the formation of activator protein 1 (AP-1).	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK translocates to the nucleus	jnk	c-Jun	c-Jun	c-jun	7	8	14	15
An upstream mitogen activated protein ( MAP ) kinase pathway that activates Jun N-terminal kinase ( JNK ) can activate c-Jun .	An upstream mitogen activated protein (MAP) kinase pathway that activates Jun N-terminal kinase (JNK) can activate c-Jun.	14	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	16	17	20	21
B cells from lyn-/- mice have increased expression of the protein product of the early response gene egr-1 , enhanced activation of Jun N-terminal kinase ( JNK ) , and elevated calcium responses upon BCR cross linking .	B cells from lyn-/- mice have increased expression of the protein product of the early response gene egr-1, enhanced activation of Jun N-terminal kinase (JNK), and elevated calcium responses upon BCR cross linking.	19	27	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	26	27	22	23
Chronic UV irradiation results in markedly increased reactive oxygen species ( ROS ) levels that trigger the release of proinflammatory cytokines and growth factors , and stimulate mitogen activated protein kinases ( MAPKs ) such as extracellular signal regulated kinase ( ERK ) , p38 kinase , and c-Jun N-terminal kinase ( JNK ) , which converge to stimulate activator protein-1 ( AP-1 ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Chronic UV irradiation results in markedly increased reactive oxygen species (ROS) levels that trigger the release of proinflammatory cytokines and growth factors, and stimulate mitogen activated protein kinases (MAPKs) such as extracellular signal regulated kinase (ERK), p38 kinase, and c-Jun N-terminal kinase (JNK), which converge to stimulate activator protein-1 (AP-1) [XREF_BIBR, XREF_BIBR, XREF_BIBR].	48	61	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	activator protein-1	activator protein-1	activator protein-1	48	51	59	61
JNK activation leads to inhibition of the pro survival gene Bcl2 and activation of the apoptotic genes BAX , Cytochrome C , Bim and Bmf , and c-Jun .	JNK activation leads to inhibition of the pro survival gene Bcl2 and activation of the apoptotic genes BAX, Cytochrome C, Bim and Bmf, and c-Jun.	0	28	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	27	28
Gene regulation by JNK mediated c-Jun signaling generally requires specific phosphorylation of these two molecules [ XREF_BIBR , XREF_BIBR ] .	Gene regulation by JNK mediated c-Jun signaling generally requires specific phosphorylation of these two molecules [XREF_BIBR, XREF_BIBR].	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	5	6
Our current results reveal that rVvhA uniquely regulates apoptotic cell death through activation of a JNK mediated c-Jun pathway , and such activation was inhibited by melatonin treatment .	Our current results reveal that rVvhA uniquely regulates apoptotic cell death through activation of a JNK mediated c-Jun pathway, and such activation was inhibited by melatonin treatment.	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	15	16	17	18
c-Jun , a basic leucine zipper transcription factor , is mainly activated through double phosphorylation by the JNK pathway [ XREF_BIBR ] .	c-Jun, a basic leucine zipper transcription factor, is mainly activated through double phosphorylation by the JNK pathway [XREF_BIBR].	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	17	18	0	1
Alternatively , there are also reports about JNK independent activation of Jun [ XREF_BIBR , XREF_BIBR ] which would be supportive to hypothesis that in our case JNK independent effect of MP on Jun activation took place .	Alternatively, there are also reports about JNK independent activation of Jun [XREF_BIBR, XREF_BIBR] which would be supportive to hypothesis that in our case JNK independent effect of MP on Jun activation took place.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	7	8	11	12
Activation of JNK activates Bax , PUMA , and Bim and activates the transcription factor c-Jun to actuate a PCD genomic response .	Activation of JNK activates Bax, PUMA, and Bim and activates the transcription factor c-Jun to actuate a PCD genomic response.	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	2	3	15	16
To definitively establish whether JNK activity is essential for statin dependent leukemic cell differentiation , the effects of targeting JNK , using a peptide inhibitor ( GRKKRRQRRR-PP-RPKRPTTLNLFPQVPRSQD-NH 2 ) known to block JNK activation and downstream engagement of c-jun , were determined .	To definitively establish whether JNK activity is essential for statin dependent leukemic cell differentiation, the effects of targeting JNK, using a peptide inhibitor (GRKKRRQRRR-PP-RPKRPTTLNLFPQVPRSQD-NH 2) known to block JNK activation and downstream engagement of c-jun, were determined.	32	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	32	33	38	39
In our study , suppression of JNK activity slightly inhibited activation of ATF-2 or Elk-1 but dramatically inhibited activation of c-Jun .	In our study, suppression of JNK activity slightly inhibited activation of ATF-2 or Elk-1 but dramatically inhibited activation of c-Jun.	6	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	6	7	20	21
Phosphorylation of JNKs leads to increased c-Jun activation , an important component of the AP-1 complex involved in cytokine gene expression .	Phosphorylation of JNKs leads to increased c-Jun activation, an important component of the AP-1 complex involved in cytokine gene expression.	0	7	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	JNKs	Phosphorylation of JNKs	jnks	c-Jun	c-Jun	c-jun	2	3	6	7
According to previous supporting evidences [ XREF_BIBR , XREF_BIBR ] , P42/44 ERK activation attributes to an increased proliferation on endothelial cells ; AKT is responsible for the survival of endothelial cell ; JNK activation induces proliferation and migration on endothelial cells by promoting nuclear activation of c-Jun ; and eNOS plays a key role in vascular permeability and migration activities on endothelial cells .	According to previous supporting evidences [XREF_BIBR, XREF_BIBR], P42/44 ERK activation attributes to an increased proliferation on endothelial cells; AKT is responsible for the survival of endothelial cell; JNK activation induces proliferation and migration on endothelial cells by promoting nuclear activation of c-Jun; and eNOS plays a key role in vascular permeability and migration activities on endothelial cells.	33	48	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	33	34	47	48
Hrk mRNA and protein are preferentially upregulated by 2-ME , and Hrk induction is dependent on the JNK activation of c-Jun .	Hrk mRNA and protein are preferentially upregulated by 2-ME, and Hrk induction is dependent on the JNK activation of c-Jun.	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	17	18	20	21
JNKs can phosphorylate and then activate transcription factor AP-1 XREF_BIBR .	JNKs can phosphorylate and then activate transcription factor AP-1 XREF_BIBR.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNKs	JNKs	JNKs	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	0	1	6	9
In contrast , JNK pathway induced MDR1 activation in hypoxia is independent of the activator protein 1 site .	In contrast, JNK pathway induced MDR1 activation in hypoxia is independent of the activator protein 1 site.	3	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	activator protein 1	activator protein 1	activator protein 1	3	4	14	17
Finally , inhibition of JNK , reduced activation of c-Jun , and low percentage of cell death in presence of ROT indicates that c-Jun activation is also required for ROT induced cell death [ XREF_BIBR ] .	Finally, inhibition of JNK, reduced activation of c-Jun, and low percentage of cell death in presence of ROT indicates that c-Jun activation is also required for ROT induced cell death [XREF_BIBR].	2	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	4	5	9	10
As reported , JNK phosphorylation activates the transcriptional potential of c-Jun , a critical part of AP-1 .	As reported, JNK phosphorylation activates the transcriptional potential of c-Jun, a critical part of AP-1.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK phosphorylation	jnk	c-Jun	c-Jun	c-jun	3	4	10	11
HBx activation of JNK and sustained activation of c-jun , should they occur in the context of hepatitis B virus infection , might play a role in viral transformation and pathogenesis .	HBx activation of JNK and sustained activation of c-jun, should they occur in the context of hepatitis B virus infection, might play a role in viral transformation and pathogenesis.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	3	4	8	9
MAP kinases including p38 and c-Jun N-terminal kinases ( JNK ) activate transcription factor AP-1 .	MAP kinases including p38 and c-Jun N-terminal kinases (JNK) activate transcription factor AP-1.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	9	10	12	15
The increased expression of JNK could activate c-Jun and indirectly stimulate the Nrf2-ARE pathway ( XREF_FIG ) .	The increased expression of JNK could activate c-Jun and indirectly stimulate the Nrf2-ARE pathway (XREF_FIG).	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	expression of JNK	jnk	c-Jun	c-Jun	c-jun	4	5	7	8
Dvl activation of the Rho GTPase family member Rac1 leads to Jnk activation and stimulation of the transcription factors c-Jun and ATF2 .	Dvl activation of the Rho GTPase family member Rac1 leads to Jnk activation and stimulation of the transcription factors c-Jun and ATF2.	11	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Jnk	Jnk	Jnk	c-Jun	c-Jun	c-Jun	11	12	19	20
Based on these research findings , the authors concluded that JNK activation of c-Jun by procyanidin leads to the induction of apoptosis of OA cells .	Based on these research findings, the authors concluded that JNK activation of c-Jun by procyanidin leads to the induction of apoptosis of OA cells.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	10	11	13	14
Taken together , our results suggest that JNK mediated c-Jun activation is one of the first cell body reactions in response to nerve injury and that this activation and subsequent ATF3 induction are associated with axonal outgrowth .	Taken together, our results suggest that JNK mediated c-Jun activation is one of the first cell body reactions in response to nerve injury and that this activation and subsequent ATF3 induction are associated with axonal outgrowth.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	7	8	9	10
Activation of the NF-kappaB and Jun transcription factors by IKKbeta and JNK which leads to the up-regulation of the pro inflammatory genes tnf , il6 , il1beta and ccl2 is central to this process XREF_BIBR .	Activation of the NF-kappaB and Jun transcription factors by IKKbeta and JNK which leads to the up-regulation of the pro inflammatory genes tnf, il6, il1beta and ccl2 is central to this process XREF_BIBR.	0	12	Activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	11	12	5	6
In RALA hepatocytes death was blocked by the c-Jun dominant negative TAM67 , suggesting that JNK induced activation of c-Jun mediates cell death [ XREF_BIBR ] .	In RALA hepatocytes death was blocked by the c-Jun dominant negative TAM67, suggesting that JNK induced activation of c-Jun mediates cell death [XREF_BIBR].	15	20	induced	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	15	16	19	20
Jun is activated through phosphorylation at Ser 63 and Ser 73 by JNK [ XREF_BIBR , XREF_BIBR ] .	Jun is activated through phosphorylation at Ser 63 and Ser 73 by JNK [XREF_BIBR, XREF_BIBR].	0	16	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	12	13	0	1
Furthermore , downregulation of HA/CD44 activated JNK and c-Jun signaling ( by JNK I nhibitor and c-Jun siRNA ) and miR-21 production ( by anti-miR-21 inhibitor ) not only reduces Bcl2 upregulation , but also inhibits the expression of survival proteins ( e.g ., c-IAP1 , c-IAP2 and XIAP ) .	Furthermore, downregulation of HA/CD44 activated JNK and c-Jun signaling (by JNK I nhibitor and c-Jun siRNA) and miR-21 production (by anti-miR-21 inhibitor) not only reduces Bcl2 upregulation, but also inhibits the expression of survival proteins (e.g., c-IAP1, c-IAP2 and XIAP).	6	14	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	12	13	8	9
[ XREF_BIBR ] ERK that is stimulated by the Raf and MAPK kinase ( MEK ) 1/2 axis eventually activates c-Fos while JNK activates c-Jun and activator protein-1 ( AP-1 ) .	[XREF_BIBR] ERK that is stimulated by the Raf and MAPK kinase (MEK) 1/2 axis eventually activates c-Fos while JNK activates c-Jun and activator protein-1 (AP-1).	22	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	activator protein-1	activator protein-1	activator protein-1	22	23	26	28
Recent studies have described the activation of a stress induced signal cascade , c-Jun N-terminal kinase ( JNK )-mediated activation of c-Jun , and an increase in the expression of a downstream effector , cyclooxygenase 2 ( COX-2 ) , in postmortem PD brains .	Recent studies have described the activation of a stress induced signal cascade, c-Jun N-terminal kinase (JNK)-mediated activation of c-Jun, and an increase in the expression of a downstream effector, cyclooxygenase 2 (COX-2), in postmortem PD brains.	17	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	17	18	21	22
SP600125 ( 25 muM ) , a JNK blocker , inhibited the upregulation of AP-1 Luc and p21 Luc in the c-fos and c-jun transfected cells .	SP600125 (25 muM), a JNK blocker, inhibited the upregulation of AP-1 Luc and p21 Luc in the c-fos and c-jun transfected cells.	7	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	7	8	23	24
Taken together , these data suggests that cannabinoid receptor 2 activation inhibits leukocyte migration to a wound site by suppressing the JNK mediated activation of c-Jun , thereby decreasing alox5 expression .	Taken together, these data suggests that cannabinoid receptor 2 activation inhibits leukocyte migration to a wound site by suppressing the JNK mediated activation of c-Jun, thereby decreasing alox5 expression.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	21	22	25	26
XREF_BIBR - XREF_BIBR ) Similarly , JNK mediated activation of c-Jun is important for axonal outgrowth of neurons in axotomized rat nodose and dorsal root ganglia ( DRG ) and mouse DRG .	XREF_BIBR - XREF_BIBR) Similarly, JNK mediated activation of c-Jun is important for axonal outgrowth of neurons in axotomized rat nodose and dorsal root ganglia (DRG) and mouse DRG.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	6	7	10	11
Likewise , numerous studies have reported that many kinases , such as mitogen activated protein kinase kinase ( MKK ) , phosphorylate stress activated protein kinase and Jun-amino-terminal kinase SAPK and JNK , which in turn activate c-Jun to regulate gene transcription 34 .	Likewise, numerous studies have reported that many kinases, such as mitogen activated protein kinase kinase (MKK), phosphorylate stress activated protein kinase and Jun-amino-terminal kinase SAPK and JNK, which in turn activate c-Jun to regulate gene transcription 34.	23	38	activate	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	31	32	37	38
MAPK activation during challenge is also productive as c-Jun , a transcription factor that is modulated through phosphorylation by SAPK and JNK , is activated .	MAPK activation during challenge is also productive as c-Jun, a transcription factor that is modulated through phosphorylation by SAPK and JNK, is activated.	8	24	modulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	21	22	8	9
c-Jun NH2-terminal kinases ( JNKs ) potentiate transcriptional activity of c-Jun by phosphorylating serines 63 and 73 .	c-Jun NH2-terminal kinases (JNKs) potentiate transcriptional activity of c-Jun by phosphorylating serines 63 and 73.	2	11	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNKs	JNKs	JNKs	c-Jun	c-Jun	c-Jun	4	5	10	11
However , closer inspections , applying the criteria outlined above , identified key components of the proapoptotic JNK-p53 stress activated pathway , including the JNK target c-Jun and two p53 targets , p21 and PUMA , to be potentially involved in the observed neuroprotection due to HDAC1/2 depletion ( XREF_FIG ) and ( XREF_FIG ) ) .	However, closer inspections, applying the criteria outlined above, identified key components of the proapoptotic JNK-p53 stress activated pathway, including the JNK target c-Jun and two p53 targets, p21 and PUMA, to be potentially involved in the observed neuroprotection due to HDAC1/2 depletion (XREF_FIG) and (XREF_FIG)).	20	34	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	24	25	26	27
Thus it appears whether JNK activation of c-Jun is required for the apoptotic signaling appears to be very much dependent on the cell type in which JNK is activated .	Thus it appears whether JNK activation of c-Jun is required for the apoptotic signaling appears to be very much dependent on the cell type in which JNK is activated.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	4	5	7	8
JNKs were initially identified as the kinases that phosphorylated and eventually activated the transactivation domain of the transcription factor c-Jun in response to the exposure of cells to ultraviolet ( UV ) treatment .	JNKs were initially identified as the kinases that phosphorylated and eventually activated the transactivation domain of the transcription factor c-Jun in response to the exposure of cells to ultraviolet (UV) treatment.	0	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNKs	JNKs	JNKs	c-Jun	c-Jun	c-Jun	0	1	19	20
Second , loss of DLK alone was sufficient to generate a significant reduction in the phosphorylation of the stress specific JNK target c-Jun downstream of glutamate receptor hyper-activation without affecting overall JNK activity ( XREF_FIG ) .	Second, loss of DLK alone was sufficient to generate a significant reduction in the phosphorylation of the stress specific JNK target c-Jun downstream of glutamate receptor hyper-activation without affecting overall JNK activity (XREF_FIG).	18	23	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	20	21	22	23
Here , we report that R7E retinopathy is improved upon breeding with the JunAA knock-in mice , in which JNK mediated activation of c-Jun is compromised .	Here, we report that R7E retinopathy is improved upon breeding with the JunAA knock-in mice, in which JNK mediated activation of c-Jun is compromised.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	19	20	23	24
These data suggest that Src is upstream of JNK , and phosphorylation of JNK leads to the activation of the nuclear protein c-jun .	These data suggest that Src is upstream of JNK, and phosphorylation of JNK leads to the activation of the nuclear protein c-jun.	11	23	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	JNK	phosphorylation of JNK	jnk	c-jun	c-jun	c-jun	13	14	22	23
We show that PGE2 induced MMP-9 expression is mediated primarily through the EP2 and EP4 --> cAMP --> protein kinase A ( PKA )/PI3K --> ERK signaling pathway , leading to c-Fos expression , and through JNK mediated activation of c-Jun in a PKA/PI3K/ERK independent manner .	We show that PGE2 induced MMP-9 expression is mediated primarily through the EP2 and EP4 --> cAMP --> protein kinase A (PKA)/PI3K --> ERK signaling pathway, leading to c-Fos expression, and through JNK mediated activation of c-Jun in a PKA/PI3K/ERK independent manner.	36	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	36	37	40	41
The transcriptional activation of the TRE3/4 site is mediated through the transcriptional activation of c-Jun by JNK .	The transcriptional activation of the TRE3/4 site is mediated through the transcriptional activation of c-Jun by JNK.	8	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	16	17	14	15
JNK can be activated by various stressors , thereby activating the phosphorylated serine/threonine protein kinase in the amino activated region of c-Jun , a kind of nuclear factor [ XREF_BIBR XREF_BIBR XREF_BIBR ] .	JNK can be activated by various stressors, thereby activating the phosphorylated serine/threonine protein kinase in the amino activated region of c-Jun, a kind of nuclear factor [XREF_BIBR XREF_BIBR XREF_BIBR].	0	31	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	21	22
These findings suggest that a relatively small amount of JNK is enough to activate c-Jun and suppress MafA .	These findings suggest that a relatively small amount of JNK is enough to activate c-Jun and suppress MafA.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	amount of JNK	jnk	c-Jun	c-Jun	c-jun	9	10	14	15
JNK activated c-Jun , a component of the AP-1 transcription factor complex , after infection with Legionella .	JNK activated c-Jun, a component of the AP-1 transcription factor complex, after infection with Legionella.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	2	3
It could therefore be possible that in ATF2 mutant embryos JNK activated c-Jun leads to cell loss of motoneurons by apoptosis .	It could therefore be possible that in ATF2 mutant embryos JNK activated c-Jun leads to cell loss of motoneurons by apoptosis.	10	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	10	11	12	13
Phosphorylation of c-Jun at Ser 63/73 by the c-Jun N-terminal kinase ( JNK ) potentiates the transactivation function of c-Jun .	Phosphorylation of c-Jun at Ser 63/73 by the c-Jun N-terminal kinase (JNK) potentiates the transactivation function of c-Jun.	0	20	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	Phosphorylation of c-Jun at Ser 63/73 by the c-Jun N-terminal kinase (JNK	jnk	c-Jun	c-Jun	c-jun	12	13	19	20
Lee and colleagues demonstrated in vitro that retinoic acid inhibited Jun N-terminal kinase ( JNK ) , which phosphorylates and thus activates c-Jun , and that the inhibitory effect of retinoic acid on JNK activity was through the induction of mitogen activated protein ( MAP ) kinase phosphatase 1 ( MKP-1 ) [ XREF_BIBR , XREF_BIBR ] .	Lee and colleagues demonstrated in vitro that retinoic acid inhibited Jun N-terminal kinase (JNK), which phosphorylates and thus activates c-Jun, and that the inhibitory effect of retinoic acid on JNK activity was through the induction of mitogen activated protein (MAP) kinase phosphatase 1 (MKP-1) [XREF_BIBR, XREF_BIBR].	12	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	14	15	22	23
JNK subsequently activates the transcription factor AP-1 .	JNK subsequently activates the transcription factor AP-1.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	0	1	4	7
In stressful conditions such as nerve injury , JNK activating Jun transcription factor and the p38 MAPK are stimulated [ XREF_BIBR ] .	In stressful conditions such as nerve injury, JNK activating Jun transcription factor and the p38 MAPK are stimulated [XREF_BIBR].	8	18	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	8	9	10	11
On the other hand , c-Jun N-terminal kinase ( JNK ) is retrogradely transported in injured axons to activate c-Jun in the nucleus after peripheral nerve injury , as blockade of retrograde transport inhibits c-Jun activation .	On the other hand, c-Jun N-terminal kinase (JNK) is retrogradely transported in injured axons to activate c-Jun in the nucleus after peripheral nerve injury, as blockade of retrograde transport inhibits c-Jun activation.	5	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun	c-Jun	c-Jun	5	8	19	20
SERPINA1 is transcriptionally regulated at least by two tissue specific regulatory regions located in the 5 '-UTR : the liver specific regulatory region located upstream of the noncoding exon 1C and a second regulatory region upstream of exon 1A that controls expression in monocytes.25 The liver specific regulatory region at the 5 '-UTR contains two putative binding sites for AP-126 that is composed of c-Jun and c-FOS.27 Therefore , we hypothesized that expression and accumulation of ATZ are dependent upon increased JNK mediated activation of c-Jun and subsequent SERPINA1 transcriptional up-regulation .	SERPINA1 is transcriptionally regulated at least by two tissue specific regulatory regions located in the 5 '-UTR : the liver specific regulatory region located upstream of the noncoding exon 1C and a second regulatory region upstream of exon 1A that controls expression in monocytes.25 The liver specific regulatory region at the 5 '-UTR contains two putative binding sites for AP-126 that is composed of c-Jun and c-FOS.27 Therefore, we hypothesized that expression and accumulation of ATZ are dependent upon increased JNK mediated activation of c-Jun and subsequent SERPINA1 transcriptional up-regulation.	81	90	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	81	82	85	86
Both JNK1/2 and p38 MAPK target to ATF2 ( ATF subfamily ) , while JNK1/2 also targets to c-Jun and JunD [ XREF_BIBR ] .	Both JNK1/2 and p38 MAPK target to ATF2 (ATF subfamily), while JNK1/2 also targets to c-Jun and JunD [XREF_BIBR].	14	20	targets	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	JNK1/2	JNK1/2	JNK1/2	c-Jun	c-Jun	c-Jun	14	15	18	19
These data are in agreement with the recently proposed model for the conversion of short- to long-term synaptic plasticity and memory , in which a JNK activated transcription factor AP-1 , containing c-Jun and c-Fos components , functions at the top of a hierarchy of transcription factors known to regulate long-term neural plasticity .	These data are in agreement with the recently proposed model for the conversion of short- to long-term synaptic plasticity and memory, in which a JNK activated transcription factor AP-1, containing c-Jun and c-Fos components, functions at the top of a hierarchy of transcription factors known to regulate long-term neural plasticity.	24	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	25	26	27	30
JNK may be particularly important because of its unique ability to activate c-jun , a key AP-1 component [ XREF_BIBR ] .	JNK may be particularly important because of its unique ability to activate c-jun, a key AP-1 component [XREF_BIBR].	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	0	1	12	13
Phosphorylation at residues Ser 63 and Ser 73 by c-Jun N-terminal kinases ( JNKs ) was shown to enhance the transactivation activity of c-Jun Many molecular and genetic studies have provided evidence that AP-1 activity may also be implicated in the development and progression of prostate cancer .	Phosphorylation at residues Ser 63 and Ser 73 by c-Jun N-terminal kinases (JNKs) was shown to enhance the transactivation activity of c-Jun Many molecular and genetic studies have provided evidence that AP-1 activity may also be implicated in the development and progression of prostate cancer.	0	24	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNKs	JNKs	JNKs	c-Jun	c-Jun	c-Jun	13	14	23	24
Generally , JNK is activated by ROS in cells ; the activated JNK consequently activates the c-Jun and c-Fos proteins , inducing the transcriptional activity of AP-1 , which promotes the expression of target genes .	Generally, JNK is activated by ROS in cells; the activated JNK consequently activates the c-Jun and c-Fos proteins, inducing the transcriptional activity of AP-1, which promotes the expression of target genes.	10	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	12	13	16	17
First , IRE1 mediated activation of JNK induces the expression of pro inflammatory genes by directly influencing the transcription factor activator protein 1 ( AP1 ) XREF_BIBR ( XREF_FIG ) .	First, IRE1 mediated activation of JNK induces the expression of pro inflammatory genes by directly influencing the transcription factor activator protein 1 (AP1) XREF_BIBR (XREF_FIG).	2	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	IRE1 mediated activation of JNK	jnk	activator protein 1	activator protein 1	activator protein 1	6	7	20	23
This implies that activation of JNK by JSI-124 also activates c-Jun in these cells .	This implies that activation of JNK by JSI-124 also activates c-Jun in these cells.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	5	6	10	11
In its phosphorylated from , JNK can activate c-Jun ( via phosphorylation on Ser63/73 ) , which then translocates into the nucleus to constitute the AP-1 transcription factor .	In its phosphorylated from, JNK can activate c-Jun (via phosphorylation on Ser63/73), which then translocates into the nucleus to constitute the AP-1 transcription factor.	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	5	6	8	9
These results suggested that modulation of JNK activation and expression of c-jun through ERK might have been essentially involved in androgen mediated sensitization to 4-HPR-induced apoptosis in prostate cancer cells .	These results suggested that modulation of JNK activation and expression of c-jun through ERK might have been essentially involved in androgen mediated sensitization to 4-HPR-induced apoptosis in prostate cancer cells.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	6	7	11	12
c-Jun N-terminal kinase activates c-Jun by phosphorylation of 2 serine residues at the 63 and 73 positions of the NH2 terminus of c-Jun .	c-Jun N-terminal kinase activates c-Jun by phosphorylation of 2 serine residues at the 63 and 73 positions of the NH2 terminus of c-Jun.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun	c-Jun	c-Jun	0	3	4	5
On the other hand , c-Jun activated by JNK phosphorylation regulates multiple target genes that contain AP1 binding sites related with cell cycle , apoptosis and MMPs expression .	On the other hand, c-Jun activated by JNK phosphorylation regulates multiple target genes that contain AP1 binding sites related with cell cycle, apoptosis and MMPs expression.	5	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK phosphorylation	jnk	c-Jun	c-Jun	c-jun	8	9	5	6
The c-Jun NH 2 -terminal kinases ( JNKs ) phosphorylate and activate members of the activator protein-1 ( AP-1 ) transcription factor family and other cellular factors implicated in regulating altered gene expression , cellular survival ( apoptosis ) , differentiation and proliferation in response to cytokines , growth factors and oxidative stress and cancerogenesis .	The c-Jun NH 2 -terminal kinases (JNKs) phosphorylate and activate members of the activator protein-1 (AP-1) transcription factor family and other cellular factors implicated in regulating altered gene expression, cellular survival (apoptosis), differentiation and proliferation in response to cytokines, growth factors and oxidative stress and cancerogenesis.	1	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNKs	JNKs	JNKs	activator protein-1	activator protein-1	activator protein-1	7	8	15	17
During ER stress , autophosphorylation of IRE1alpha triggers its binding to TNF receptor associated factor 2 ( TRAF2 ) , and the IRE1alpha and TRAF2 complex can interact with JNK , which activates transcription factor AP-1 , resulting in the expression of inflammatory genes .	During ER stress, autophosphorylation of IRE1alpha triggers its binding to TNF receptor associated factor 2 (TRAF2), and the IRE1alpha and TRAF2 complex can interact with JNK, which activates transcription factor AP-1, resulting in the expression of inflammatory genes.	27	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	29	30	33	36
However , JNK specific inhibition does not affect neuronal survival , but instead dramatically reduces neuritogenesis , c-Jun activation , and ATF-3 induction suggesting that JNK mediated c-Jun activation and subsequent ATF-3 induction are necessary for promoting axonal outgrowth of sensory neurons in rat dorsal root ganglia .	However, JNK specific inhibition does not affect neuronal survival, but instead dramatically reduces neuritogenesis, c-Jun activation, and ATF-3 induction suggesting that JNK mediated c-Jun activation and subsequent ATF-3 induction are necessary for promoting axonal outgrowth of sensory neurons in rat dorsal root ganglia.	25	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	25	26	27	28
Furthermore , we determined whether ROS , ASK1 , and JNK mediated denbinobin induced c-Jun activation .	Furthermore, we determined whether ROS, ASK1, and JNK mediated denbinobin induced c-Jun activation.	5	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	10	11	14	15
In differentiated PC12 cells , JNK signaling can induce apoptosis and c-Jun mediates this response .	In differentiated PC12 cells, JNK signaling can induce apoptosis and c-Jun mediates this response.	5	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	5	6	11	12
Since c-Jun N-terminal kinase ( JNK ) is responsible for activation of c-Jun by phosphorylation , a JNK inhibitor SP600125 was used to test whether c-Jun expression and phosphorylation are inhibited .	Since c-Jun N-terminal kinase (JNK) is responsible for activation of c-Jun by phosphorylation, a JNK inhibitor SP600125 was used to test whether c-Jun expression and phosphorylation are inhibited.	1	13	is responsible for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun	c-Jun	c-Jun	1	4	12	13
In the present study ; in vitro data indicated JNK dependent activation of ATF2 and c-Jun to be essential for areca nut mediated TGF-beta signaling in epithelial cells .	In the present study; in vitro data indicated JNK dependent activation of ATF2 and c-Jun to be essential for areca nut mediated TGF-beta signaling in epithelial cells.	9	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	9	10	15	16
Indeed , unlike c-Jun , which is activated by JNK , JUNB is not directly induced by JNK [ XREF_BIBR ] .	Indeed, unlike c-Jun, which is activated by JNK, JUNB is not directly induced by JNK [XREF_BIBR].	2	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	9	10	3	4
All three stimuli increased PGHS-2 and IL-8 mRNA expression in a MAPK dependent manner , but while the MAPK inhibitors reduced the IL-1beta-induced activation of activating transcription factor ( ATF )-2, liver activating protein ( LAP ) and c-jun , the stretch induced increase in LAP was unaffected by MAPK-inhibition and only JNK inhibition appeared to reduce c-jun activation .	All three stimuli increased PGHS-2 and IL-8 mRNA expression in a MAPK dependent manner, but while the MAPK inhibitors reduced the IL-1beta-induced activation of activating transcription factor (ATF)-2, liver activating protein (LAP) and c-jun, the stretch induced increase in LAP was unaffected by MAPK-inhibition and only JNK inhibition appeared to reduce c-jun activation.	52	58	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	52	53	57	58
It is likely that , in response to integrin ligation , JNK not only acts on preexisting Jun and ATF2 and ATF2 and ATF2 dimers , thereby promoting the CRE dependent transcription of c-Jun , but also activates the Fos and Jun dimers formed in response to the coordinated action of both integrins and growth factor receptors .	It is likely that, in response to integrin ligation, JNK not only acts on preexisting Jun and ATF2 and ATF2 and ATF2 dimers, thereby promoting the CRE dependent transcription of c-Jun, but also activates the Fos and Jun dimers formed in response to the coordinated action of both integrins and growth factor receptors.	11	42	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	11	12	41	42
The extent of GFP-SCG10 phosphorylation by JNK in intact cells compared favorably to that of the well characterized JNK target c-Jun .	The extent of GFP-SCG10 phosphorylation by JNK in intact cells compared favorably to that of the well characterized JNK target c-Jun.	17	21	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	18	19	20	21
The JNK activity specific inhibitor , SP600125 , and siRNA directed against JNK were used to block JNK and c-Jun pathway .	The JNK activity specific inhibitor, SP600125, and siRNA directed against JNK were used to block JNK and c-Jun pathway.	1	20	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	1	2	19	20
The JNK mediated phosphorylation of c-Jun is apparently not required for the demyelinating effects of c-Jun in cell culture [ XREF_BIBR ] , which suggests that either JNK activates c-Jun indirectly , or perhaps JNK independent function of c-Jun could play a role in its activity .	The JNK mediated phosphorylation of c-Jun is apparently not required for the demyelinating effects of c-Jun in cell culture [XREF_BIBR], which suggests that either JNK activates c-Jun indirectly, or perhaps JNK independent function of c-Jun could play a role in its activity.	26	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	27	28	29	30
Meanwhile , simvastatin induced JNK mediated c-Jun and ATF-2 activation .	Meanwhile, simvastatin induced JNK mediated c-Jun and ATF-2 activation.	3	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	4	5	6	7
On the basis of these results , we concluded that JNK activation was suppressed by Chk1 , including p-p46 JNK and p-p54 JNK , which also resulted in the repressed expression of the JNK signaling molecules c-Jun , p-c-Jun , p21 WAF1 , gamma-H2AX , and H2AX .	On the basis of these results, we concluded that JNK activation was suppressed by Chk1, including p-p46 JNK and p-p54 JNK, which also resulted in the repressed expression of the JNK signaling molecules c-Jun, p-c-Jun, p21 WAF1, gamma-H2AX, and H2AX.	13	46	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	19	20	36	37
This activation of JNK in turn activates the transcription factors c-Jun and activating transcription factor-3 ( ATF-3 ) .	This activation of JNK in turn activates the transcription factors c-Jun and activating transcription factor-3 (ATF-3).	1	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	10	11
ChIP assays demonstrated that p53 was bound to the Wip1 promoter a short time after UV radiation exposure , and JNK activated c-jun was bound later .	ChIP assays demonstrated that p53 was bound to the Wip1 promoter a short time after UV radiation exposure, and JNK activated c-jun was bound later.	20	24	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	20	21	22	23
JNK activates c-jun transcriptional activity by promoting its phosphorylation XREF_BIBR .	JNK activates c-jun transcriptional activity by promoting its phosphorylation XREF_BIBR.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	0	1	2	3
This pathway is similar to that used for posttranslational activation of c-jun by JNK .	This pathway is similar to that used for posttranslational activation of c-jun by JNK.	6	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	13	14	11	12
Phosphorylation of the transcription factor c-Jun on serine 63 and serine 73 in its N-terminal transactivation domain by activated JNK augments c-Jun transcriptional activity [ XREF_BIBR , XREF_BIBR ] .	Phosphorylation of the transcription factor c-Jun on serine 63 and serine 73 in its N-terminal transactivation domain by activated JNK augments c-Jun transcriptional activity [XREF_BIBR, XREF_BIBR].	16	23	augments	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	19	20	21	22
Intriguingly , these transcription factors are all known targets of JNK and p38 , of which c-Jun can be activated by JNK MAPK , while c-Fos and GATA2 can be activated by p38 MAPK [ XREF_BIBR - XREF_BIBR ] .	Intriguingly, these transcription factors are all known targets of JNK and p38, of which c-Jun can be activated by JNK MAPK, while c-Fos and GATA2 can be activated by p38 MAPK [XREF_BIBR - XREF_BIBR].	16	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK MAPK	JNK MAPK	JNK MAPK	c-Jun	c-Jun	c-Jun	21	23	16	17
Moreover , the JNK activated the AP-1 transcriptional factors ( c-Jun , JunB and c-Fos ) [ XREF_BIBR ] .	Moreover, the JNK activated the AP-1 transcriptional factors (c-Jun, JunB and c-Fos) [XREF_BIBR].	2	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	10	11
In addition , ERK dependent c-Jun activation is known to induce neuronal differentiation , while JNK mediated c-Jun activation is involved in induction of apoptosis , suggesting that the upstream molecules involved in c-Jun activation affect c-Jun-mediated cellular events .	In addition, ERK dependent c-Jun activation is known to induce neuronal differentiation, while JNK mediated c-Jun activation is involved in induction of apoptosis, suggesting that the upstream molecules involved in c-Jun activation affect c-Jun-mediated cellular events.	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	15	16	17	18
Our evidence suggests that Tollo signaling at the NMJ occurs through JNK activation of the transcription factors Jun and Fos rather than via the canonical NF-kappaB pathway .	Our evidence suggests that Tollo signaling at the NMJ occurs through JNK activation of the transcription factors Jun and Fos rather than via the canonical NF-kappaB pathway.	11	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	11	12	17	18
Using a two-hybrid approach , we show that SAPK and JNK stimulates c-Jun transactivation in yeast and that this depends on both catalytic activity and physical interaction between the kinase and its substrate .	Using a two-hybrid approach, we show that SAPK and JNK stimulates c-Jun transactivation in yeast and that this depends on both catalytic activity and physical interaction between the kinase and its substrate.	8	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	10	11	12	13
JNK activates the transcription factor AP-1 , which is also a mediator of inflammation .	JNK activates the transcription factor AP-1, which is also a mediator of inflammation.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	0	1	3	6
Since both c-Jun and ATF-2 are activated by JNK , and targets and competitors in the same signal transduction cascade , we could speculate that ATF-2 may compete with c-Jun for JNK phosphorylation .	Since both c-Jun and ATF-2 are activated by JNK, and targets and competitors in the same signal transduction cascade, we could speculate that ATF-2 may compete with c-Jun for JNK phosphorylation.	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	8	9	2	3
Retinoic acid has been shown to protect against oxidative stress induced apoptosis by inhibition of the c-jun N-terminal kinase ( JNK ) activator protein 1 ( AP-1 ) pathway in glomerular [ XREF_BIBR ] and mesangial cells [ XREF_BIBR ] .	Retinoic acid has been shown to protect against oxidative stress induced apoptosis by inhibition of the c-jun N-terminal kinase (JNK) activator protein 1 (AP-1) pathway in glomerular [XREF_BIBR] and mesangial cells [XREF_BIBR].	10	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	c-jun N-terminal kinase	c-jun N-terminal kinase	c-jun N-terminal kinase	activator protein 1	activator protein 1	activator protein 1	16	19	22	25
JNK and p38 MAPK phosphorylation enhances the activity of c-Jun and ATF2 proteins , which in turn activate AP-1 target genes [ XREF_BIBR ] .	JNK and p38 MAPK phosphorylation enhances the activity of c-Jun and ATF2 proteins, which in turn activate AP-1 target genes [XREF_BIBR].	0	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK and p38 MAPK phosphorylation	jnk	c-Jun	c-Jun	c-jun	0	1	9	10
The pharmacologic inhibitor of JNK or JNKi inhibits UV induced JNK and c-Jun activation and attenuates a UV induced decrease of collagen type I. Quercetin , a well known antioxidant , also protects against a UV- and H ( 2 ) O ( 2 )-induced decrease of collagen type I in a dose dependent manner .	The pharmacologic inhibitor of JNK or JNKi inhibits UV induced JNK and c-Jun activation and attenuates a UV induced decrease of collagen type I. Quercetin, a well known antioxidant, also protects against a UV- and H (2) O (2)-induced decrease of collagen type I in a dose dependent manner.	2	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	4	5	12	13
WNT-5A activates ERK1/2 in intestinal epithelial cells via ROR2 [ XREF_BIBR ] , whereas it activates JNK mediated c-Jun transcriptional activity to induce production of receptor activator of nuclear factor-kappaB ( RANK ) , a regulator of osteoclast differentiation and activation , in osteoclast precursor cells via ROR2 [ XREF_BIBR ] .	WNT-5A activates ERK1/2 in intestinal epithelial cells via ROR2 [XREF_BIBR], whereas it activates JNK mediated c-Jun transcriptional activity to induce production of receptor activator of nuclear factor-kappaB (RANK), a regulator of osteoclast differentiation and activation, in osteoclast precursor cells via ROR2 [XREF_BIBR].	15	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	16	17	18	19
JNK activates the activator protein 1 ( AP1 ) component , c-Jun , and glucocorticoid and JNK regulated targets of AP1 , in the acini , may include beta4 integrin expression .	JNK activates the activator protein 1 (AP1) component, c-Jun, and glucocorticoid and JNK regulated targets of AP1, in the acini, may include beta4 integrin expression.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	activator protein 1	activator protein 1	activator protein 1	0	1	3	6
As c-Jun is activated through double phosphorylation by the JNK pathway , when JNK inhibitor ( SP600125 ) was used to block the activation of JNK , the arsenite induced activations of c-Jun and miR-21 were decreased .	As c-Jun is activated through double phosphorylation by the JNK pathway, when JNK inhibitor (SP600125) was used to block the activation of JNK, the arsenite induced activations of c-Jun and miR-21 were decreased.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	9	10	1	2
Specifically , activated JNK enhances chondrogenesis by activating the transcription factor activator protein-1 ( AP-1 ) , which upregulates the expression of transforming growth factor beta ( TGFbeta ) .	Specifically, activated JNK enhances chondrogenesis by activating the transcription factor activator protein-1 (AP-1), which upregulates the expression of transforming growth factor beta (TGFbeta).	2	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	activator protein-1	activator protein-1	activator protein-1	3	4	11	13
The MAP kinase JNK is thought to contribute to activation of the AP1 complex by activating Jun .	The MAP kinase JNK is thought to contribute to activation of the AP1 complex by activating Jun.	0	17	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	3	4	16	17
We next tested whether impaired NF-kappaB and JNK activation in Plxna4 -/- macrophages causes defective binding of the downstream transcription factors , p65 and c-Jun , to the promoter regions of Tnfa and Il6 .	We next tested whether impaired NF-kappaB and JNK activation in Plxna4 -/- macrophages causes defective binding of the downstream transcription factors, p65 and c-Jun, to the promoter regions of Tnfa and Il6.	7	25	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	7	8	24	25
In contrast , JNK activates the transcription factor c-Jun in response to pro inflammatory cytokines and exposure of cells to several forms of environmental stress .	In contrast, JNK activates the transcription factor c-Jun in response to pro inflammatory cytokines and exposure of cells to several forms of environmental stress.	3	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	8	9
Finally , the inhibitor of JNK blocked the upregulation of both c-Jun and Hrk in the GCL after retinal explantation .	Finally, the inhibitor of JNK blocked the upregulation of both c-Jun and Hrk in the GCL after retinal explantation.	3	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	5	6	11	12
Studies have shown that c-Jun activity is upregulated by the phosphorylation of c-Jun NH2-terminal kinases ( JNK ) [ XREF_BIBR ] .	Studies have shown that c-Jun activity is upregulated by the phosphorylation of c-Jun NH2-terminal kinases (JNK) [XREF_BIBR].	4	17	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	phosphorylation of c-Jun NH2-terminal kinases (JNK	jnk	c-Jun	c-Jun	c-jun	16	17	4	5
During bacterial infection , the rapid activation of JNK initiates nuclear factor activator protein-1 ( AP-1 ) to regulate pro inflammatory cytokines expression , which could trigger excessive inflammation .	During bacterial infection, the rapid activation of JNK initiates nuclear factor activator protein-1 (AP-1) to regulate pro inflammatory cytokines expression, which could trigger excessive inflammation.	6	14	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	activator protein-1	activator protein-1	activator protein-1	8	9	12	14
The phosphorylation of Ser63 or Ser73 by JNK potentiates the ability of c-Jun to activate transcription [ XREF_BIBR ] .	The phosphorylation of Ser63 or Ser73 by JNK potentiates the ability of c-Jun to activate transcription [XREF_BIBR].	1	13	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	phosphorylation of Ser63 or Ser73 by JNK	jnk	c-Jun	c-Jun	c-jun	7	8	12	13
In the present study , we investigated if the previously observed JNK mediated activation of c-Jun and induction of ATF3 could be ascribed to axonal transport of JNK signaling components , or if axonal transport of the transcription factors themselves contributes to the nuclear changes in injured sensory neurons .	In the present study, we investigated if the previously observed JNK mediated activation of c-Jun and induction of ATF3 could be ascribed to axonal transport of JNK signaling components, or if axonal transport of the transcription factors themselves contributes to the nuclear changes in injured sensory neurons.	11	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	11	12	15	16
JNK phosphorylation leads to the activation of c-Jun and AP-1 , a transcription factor composed of heterodimers of family members , which include Jun , Fos and ATF [ XREF_BIBR ] .	JNK phosphorylation leads to the activation of c-Jun and AP-1, a transcription factor composed of heterodimers of family members, which include Jun, Fos and ATF [XREF_BIBR].	0	13	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK phosphorylation	jnk	c-Jun	c-Jun	c-jun	0	1	7	8
JNK and Src are upstream activators of PKCdelta and phosphorylation of JNK leads to the activation of c-jun .	JNK and Src are upstream activators of PKCdelta and phosphorylation of JNK leads to the activation of c-jun.	9	18	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	JNK	phosphorylation of JNK	jnk	c-jun	c-jun	c-jun	11	12	17	18
In the JNK cascade , the phosphorylation of c-Jun N-terminal kinase ( JNK ) drives the activation of the oncoprotein c-Jun , which dimerizes to form the activator protein-1 ( AP-1 ) transcription factor .	In the JNK cascade, the phosphorylation of c-Jun N-terminal kinase (JNK) drives the activation of the oncoprotein c-Jun, which dimerizes to form the activator protein-1 (AP-1) transcription factor.	6	25	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	phosphorylation of c-Jun N-terminal kinase	c-jun n-terminal kinase	c-Jun	c-Jun	c-jun	8	11	20	21
The active JNK pathway promotes the activation of the transcription factor activator protein 1 ( AP-1 ) , which is related to the gene expression of pro inflammatory cytokines and may act directly on the insulin signaling pathway [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The active JNK pathway promotes the activation of the transcription factor activator protein 1 (AP-1), which is related to the gene expression of pro inflammatory cytokines and may act directly on the insulin signaling pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	activator protein 1	activator protein 1	activator protein 1	2	3	11	14
This suggests that c-Fos and c-Jun translocation was upregulated by P38 and JNK phosphorylation , respectively .	This suggests that c-Fos and c-Jun translocation was upregulated by P38 and JNK phosphorylation, respectively.	3	14	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK phosphorylation	jnk	c-Jun	c-Jun	c-jun	12	13	5	6
Our data demonstrate the existence of a new E1A pathway , which results in JNK dependent activation of the transcription factor c-Jun .	Our data demonstrate the existence of a new E1A pathway, which results in JNK dependent activation of the transcription factor c-Jun.	14	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	14	15	21	22
JNK signaling can affect microtubule sliding and initial regeneration through two possible mechanisms : 1 ) JNK or another component of JNK kinase pathway could directly phosphorylate and regulate the activity of an essential regulator of microtubule sliding ; 2 ) JNK can activate Jun and Fos dependent transcription of a gene encoding an essential player regulating microtubule sliding .	JNK signaling can affect microtubule sliding and initial regeneration through two possible mechanisms : 1) JNK or another component of JNK kinase pathway could directly phosphorylate and regulate the activity of an essential regulator of microtubule sliding; 2) JNK can activate Jun and Fos dependent transcription of a gene encoding an essential player regulating microtubule sliding.	41	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	41	42	44	45
Similarly , JNK mediated activation of c-Jun is important for axonal outgrowth of neurons in axotomized rat nodose and dorsal root ganglia ( DRG ) and mouse DRG [ XREF_BIBR , XREF_BIBR ] .	Similarly, JNK mediated activation of c-Jun is important for axonal outgrowth of neurons in axotomized rat nodose and dorsal root ganglia (DRG) and mouse DRG [XREF_BIBR, XREF_BIBR].	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	2	3	6	7
It is well known that c-Jun can be activated through double phosphorylation on serine 63 and 73 by the JNK pathway but has also a phosphorylation independent function [ XREF_BIBR , XREF_BIBR ] .	It is well known that c-Jun can be activated through double phosphorylation on serine 63 and 73 by the JNK pathway but has also a phosphorylation independent function [XREF_BIBR, XREF_BIBR].	5	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	19	20	5	6
Previous studies revealed different mechanisms in various experimental models , such as stabilization of hypoxia inducible factor ( HIF )-1alpha by the subgenomic replicon of HCV [ XREF_BIBR , XREF_BIBR ] , increased activity of Jun amino-terminal kinases ( JNK ) , mitogen activated protein kinase ( MAPK ) , or androgen receptor pathways by the HCV core protein [ XREF_BIBR , XREF_BIBR ] , and increased angiopoietin ( ANG ) -2 expression by the HCV infection [ XREF_BIBR ] .	Previous studies revealed different mechanisms in various experimental models, such as stabilization of hypoxia inducible factor (HIF)-1alpha by the subgenomic replicon of HCV [XREF_BIBR, XREF_BIBR], increased activity of Jun amino-terminal kinases (JNK), mitogen activated protein kinase (MAPK), or androgen receptor pathways by the HCV core protein [XREF_BIBR, XREF_BIBR], and increased angiopoietin (ANG) -2 expression by the HCV infection [XREF_BIBR].	32	40	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	39	40	35	36
In contrast , the apoptosis of hippocampal neurons , cerebellar granule neuron , or developing neurons appear to require a mechanism involving the activation of c-Jun by JNK .	In contrast, the apoptosis of hippocampal neurons, cerebellar granule neuron, or developing neurons appear to require a mechanism involving the activation of c-Jun by JNK.	21	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	27	28	25	26
JNK phosphorylation activates c-Jun and triggers activation of multiple downstream effectors related to proapoptotic signalling and certain cytotoxicities but its sequestration in a complex with GSTpi blocks these events .	JNK phosphorylation activates c-Jun and triggers activation of multiple downstream effectors related to proapoptotic signalling and certain cytotoxicities but its sequestration in a complex with GSTpi blocks these events.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK phosphorylation	jnk	c-Jun	c-Jun	c-jun	0	1	3	4
IL-1beta induced cPLA2 protein and mRNA expression , PGE2 production , and phosphorylation of p42 and p44 MAPK , p38 MAPK ( ATF2 ) , and JNK ( c-Jun ) in a time- and concentration dependent manner , determined by Western blotting , RT-PCR , and ELISA , which was attenuated by the inhibitors of MEK1/2 ( U0126 ) , p38 MAPK ( SB202190 ) , and JNK ( SP600125 ) , or transfection with dominant negative mutants of MEK1/2 , p38 , and JNK , respectively .	IL-1beta induced cPLA2 protein and mRNA expression, PGE2 production, and phosphorylation of p42 and p44 MAPK, p38 MAPK (ATF2), and JNK (c-Jun) in a time- and concentration dependent manner, determined by Western blotting, RT-PCR, and ELISA, which was attenuated by the inhibitors of MEK1/2 (U0126), p38 MAPK (SB202190), and JNK (SP600125), or transfection with dominant negative mutants of MEK1/2, p38, and JNK, respectively.	26	69	attenuated	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	67	68	28	29
For example , in NIH 3T3 mouse fibroblasts , platelet derived growth factor ( PDGF )-stimulated JNK1/2 dependent activation of c-Jun and p42 and p44 MAPK dependent activation of c-Fos leads to the expression of c-myc that regulates normal and aberrant cell growth [ XREF_BIBR , XREF_BIBR ] .	For example, in NIH 3T3 mouse fibroblasts, platelet derived growth factor (PDGF)-stimulated JNK1/2 dependent activation of c-Jun and p42 and p44 MAPK dependent activation of c-Fos leads to the expression of c-myc that regulates normal and aberrant cell growth [XREF_BIBR, XREF_BIBR].	16	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK1/2	JNK1/2	JNK1/2	c-Jun	c-Jun	c-Jun	16	17	20	21
In this section , we revealed inhibition of myelin genes by MKK7 and JNK mediated activation of c-Jun .	In this section, we revealed inhibition of myelin genes by MKK7 and JNK mediated activation of c-Jun.	11	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	13	14	17	18
GnRH induced induction and activation of the JNK target c-Jun was inhibited after chelation of intracellular calcium , whereas induction of c-Fos , a known target of ERK , was unaffected .	GnRH induced induction and activation of the JNK target c-Jun was inhibited after chelation of intracellular calcium, whereas induction of c-Fos, a known target of ERK, was unaffected.	2	10	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	7	8	9	10
It has been shown that transcription factor AP-1 can be activated via the Raf and ERK pathway by UVA , the JNK cascade and receptors for EGF , TNF and IL-1 by UVB , and p53 via DNA damage induced by UVC , In fact , XREF_BIBR predicted that any receptor whose activation mechanism involves multimerization could be activated by UV .	It has been shown that transcription factor AP-1 can be activated via the Raf and ERK pathway by UVA, the JNK cascade and receptors for EGF, TNF and IL-1 by UVB, and p53 via DNA damage induced by UVC, In fact, XREF_BIBR predicted that any receptor whose activation mechanism involves multimerization could be activated by UV.	5	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	21	22	5	8
However , in stressed cells , JNK phosphorylates and activates associated c-Jun and p53 proteins and enhances their transcriptional regulation of stress responsive genes [ XREF_BIBR , XREF_BIBR ] .	However, in stressed cells, JNK phosphorylates and activates associated c-Jun and p53 proteins and enhances their transcriptional regulation of stress responsive genes [XREF_BIBR, XREF_BIBR].	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	6	7	11	12
On the other hand , the CD28 coreceptor via the PI3K pathway activates MEKK and JNK allowing the production of c-jun .	On the other hand, the CD28 coreceptor via the PI3K pathway activates MEKK and JNK allowing the production of c-jun.	12	21	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	15	16	20	21
The IL-6 modulation of Caco-2 TJ permeability was regulated by JNK signaling pathway activation of transcription factor AP-1 ; which , in turn , caused a sequential activation of claudin-2 gene and subsequent increase in gene transcription and protein expression and increase in Caco-2 TJ permeability .	The IL-6 modulation of Caco-2 TJ permeability was regulated by JNK signaling pathway activation of transcription factor AP-1; which, in turn, caused a sequential activation of claudin-2 gene and subsequent increase in gene transcription and protein expression and increase in Caco-2 TJ permeability.	10	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	10	11	15	18
Hence , as JNK activates the transcription factors c-Jun and ATF-2 and is a prerequisite for the production of IFN-beta , the up-regulation of Jdp2 is most likely to affect the activity of c-Jun and ATF-2 .	Hence, as JNK activates the transcription factors c-Jun and ATF-2 and is a prerequisite for the production of IFN-beta, the up-regulation of Jdp2 is most likely to affect the activity of c-Jun and ATF-2.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	3	4	8	9
Phosphorylation of JNK can modulate the transcriptional activity of activator protein-1 ( AP-1 ) , which is an important transcription factor in osteoclastogenesis XREF_BIBR .	Phosphorylation of JNK can modulate the transcriptional activity of activator protein-1 (AP-1), which is an important transcription factor in osteoclastogenesis XREF_BIBR.	0	11	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	Phosphorylation of JNK	jnk	activator protein-1	activator protein-1	activator protein-1	2	3	9	11
One of the MAPK elements is JNK , that is phosphorylated in PD and activates the transcription factor of c-jun .	One of the MAPK elements is JNK, that is phosphorylated in PD and activates the transcription factor of c-jun.	4	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK, that is phosphorylated	jnk	c-jun	c-jun	c-jun	6	7	19	20
Ets activates ERK1/2 XREF_BIBR , p38 MAPK activates the transcription factor SP-1 XREF_BIBR , and JNK activates c-Jun , a component of the AP-1 transcription factors XREF_BIBR .	Ets activates ERK1/2 XREF_BIBR, p38 MAPK activates the transcription factor SP-1 XREF_BIBR, and JNK activates c-Jun, a component of the AP-1 transcription factors XREF_BIBR.	15	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	15	16	17	18
Expression of TauT is negatively regulated by p53 and positively regulated by c-Jun , which is mediated by the JNK signaling pathway .	Expression of TauT is negatively regulated by p53 and positively regulated by c-Jun, which is mediated by the JNK signaling pathway.	10	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	19	20	12	13
Given the hypoxia induced increase in c-Jun and ATF2 , transcription factors that are induced by JNK and p38 respectively , we elected to further study the MAPK family members JNK and p38 , both of which have been implicated in obesity and metabolic disease [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Given the hypoxia induced increase in c-Jun and ATF2, transcription factors that are induced by JNK and p38 respectively, we elected to further study the MAPK family members JNK and p38, both of which have been implicated in obesity and metabolic disease [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	18	induced	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	16	17	6	7
JNK is involved in a multitude of processes and can activate the transcription factors jun , fos and ATF2 [ XREF_BIBR ] .	JNK is involved in a multitude of processes and can activate the transcription factors jun, fos and ATF2 [XREF_BIBR].	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	jun	jun	jun	0	1	14	15
Much well documented evidence has established that the JNK signaling pathway activates c-Jun by phosphorylation and in turn phosphorylated c-Jun moves to the nucleus and combines with c-fos to form AP1 transcription factor to activate the expression of many target genes related to cell proliferation and invasion ,28 , 29 for example , MMP9 .	Much well documented evidence has established that the JNK signaling pathway activates c-Jun by phosphorylation and in turn phosphorylated c-Jun moves to the nucleus and combines with c-fos to form AP1 transcription factor to activate the expression of many target genes related to cell proliferation and invasion,28, 29 for example, MMP9.	8	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	8	9	12	13
As demonstrated by immunoblotting with anti-phospho-Ser63 c-Jun , after incubation or not with the SP600125 specific JNK inhibitor , a strong JNK dependent activation of c-Jun was found in onco-Vav- and D797N expressing cells , while a weaker activation was noticed for wt-Vav1 .	As demonstrated by immunoblotting with anti-phospho-Ser63 c-Jun, after incubation or not with the SP600125 specific JNK inhibitor, a strong JNK dependent activation of c-Jun was found in onco-Vav- and D797N expressing cells, while a weaker activation was noticed for wt-Vav1.	21	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	21	22	25	26
JNK activated c-jun induces the expression of stress associated genes [ XREF_BIBR ] .	JNK activated c-jun induces the expression of stress associated genes [XREF_BIBR].	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	0	1	2	3
High c-Jun mRNA level is associated with shorter disease-free survival ( DFS ) of patients with TNBC , and c-Jun activation correlates with JNK activation c-Jun , a transcription factor and a substrate of JNK , ERK , and p38 , has been implicated in progression of different cancers XREF_BIBR - XREF_BIBR .	High c-Jun mRNA level is associated with shorter disease-free survival (DFS) of patients with TNBC, and c-Jun activation correlates with JNK activation c-Jun, a transcription factor and a substrate of JNK, ERK, and p38, has been implicated in progression of different cancers XREF_BIBR - XREF_BIBR.	21	32	activation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	23	24	25	26
A report by XREF_BIBR demonstrated that JNK signals can directly activate the transcription factor AP-1 or indirectly activate NFkappaB through downstream proinflammatory cytokines .	A report by XREF_BIBR demonstrated that JNK signals can directly activate the transcription factor AP-1 or indirectly activate NFkappaB through downstream proinflammatory cytokines.	6	15	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	6	7	12	15
We demonstrate in the present study that cyclic stretching of vascular smooth muscle cells dramatically activates Jun N-terminal kinase ( JNK )/stress-activated protein kinase ( SAPK ) through an autocrine mechanism .	We demonstrate in the present study that cyclic stretching of vascular smooth muscle cells dramatically activates Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) through an autocrine mechanism.	15	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Jun	Jun	Jun	20	21	16	17
Bak upregulation was elicited by p38 MAPK mediated ATF-2 activation and JNK mediated c-Jun activation .	Bak upregulation was elicited by p38 MAPK mediated ATF-2 activation and JNK mediated c-Jun activation.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	11	12	13	14
In this report we demonstrate a JNK independent activation of c-Jun in vivo directed by the constitutive photomorphogenesis ( COP9 ) signalosome .	In this report we demonstrate a JNK independent activation of c-Jun in vivo directed by the constitutive photomorphogenesis (COP9) signalosome.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	6	7	10	11
JNK can also promote both cell survival by regulating c-Jun and cell death via regulating c-myc and p53 activity [ XREF_BIBR - XREF_BIBR ] .	JNK can also promote both cell survival by regulating c-Jun and cell death via regulating c-myc and p53 activity [XREF_BIBR - XREF_BIBR].	0	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	9	10
Particularly , JNK pathway has been shown to mediate the activation and transcription of c-Jun which is required for IL-1-induced MMP-13 upregulation [ XREF_BIBR ] making c-Jun a potential therapeutic target for OA treatment .	Particularly, JNK pathway has been shown to mediate the activation and transcription of c-Jun which is required for IL-1-induced MMP-13 upregulation [XREF_BIBR] making c-Jun a potential therapeutic target for OA treatment.	2	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	2	3	14	15
In particular , this would include JNK signaling , known to activate transcription factor AP-1 , ultimately leading to the increased transcription of TSPO [ XREF_BIBR ] .	In particular, this would include JNK signaling, known to activate transcription factor AP-1, ultimately leading to the increased transcription of TSPO [XREF_BIBR].	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	6	7	12	15
The observation that pharmacological inhibition of JNK and p38 MAPKs during SeV infection significantly decreased downstream ATF-2 and c-Jun activation and cytokine induction confirmed the previously documented existence of a JNK-p38 and AP-1 signaling axis critical for virus induced cytokine production XREF_BIBR , XREF_BIBR , XREF_BIBR .	The observation that pharmacological inhibition of JNK and p38 MAPKs during SeV infection significantly decreased downstream ATF-2 and c-Jun activation and cytokine induction confirmed the previously documented existence of a JNK-p38 and AP-1 signaling axis critical for virus induced cytokine production XREF_BIBR, XREF_BIBR, XREF_BIBR.	6	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	6	7	18	19
JNK activates the transcription factor c-Jun by phosphorylation of serine 63 and 73 .	JNK activates the transcription factor c-Jun by phosphorylation of serine 63 and 73.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	0	1	5	6
Furthermore , the mGluR5 dependent JNK activation specifically activated c-Jun , but not activating transcription factor-2 or JunD , and increased activator protein-1 ( AP-1 )-mediated endogenous transcriptional activity .	Furthermore, the mGluR5 dependent JNK activation specifically activated c-Jun, but not activating transcription factor-2 or JunD, and increased activator protein-1 (AP-1)-mediated endogenous transcriptional activity.	5	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	5	6	9	10
This could be important for sustaining ifnbeta gene transcription in mouse BMDM , since the JNK dependent activation of the transcription factors c-Jun and ATF2 has been reported to co-ordinate the adenovirus mediated induction of primary IRF3 responsive transcripts in conjunction with activated IRF3 [ XREF_BIBR ] .	This could be important for sustaining ifnbeta gene transcription in mouse BMDM, since the JNK dependent activation of the transcription factors c-Jun and ATF2 has been reported to co-ordinate the adenovirus mediated induction of primary IRF3 responsive transcripts in conjunction with activated IRF3 [XREF_BIBR].	15	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	15	16	22	23
It has been demonstrated that c-Jun activation by JNK is essential for SC migration and proliferation in vitro .	It has been demonstrated that c-Jun activation by JNK is essential for SC migration and proliferation in vitro.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	8	9	5	6
Activation of JNK in eye progenitors was sufficient to activate Jra and Kayak ( c-Jun and c-fos homologues ) and trigger non autonomous glia migration .	Activation of JNK in eye progenitors was sufficient to activate Jra and Kayak (c-Jun and c-fos homologues) and trigger non autonomous glia migration.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	2	3	14	15
Interestingly , besides reducing Nrf2 activation , JNK inhibition and autophagy induction reduced also c-Jun activation , suggesting that defective autophagy and redox sensitive JNK activation previously associated with KRIT1 loss-of-function XREF_BIBR , XREF_BIBR contribute to upregulation of both c-Jun and Nrf2 redox sensitive pathways ( XREF_FIG a ) .	Interestingly, besides reducing Nrf2 activation, JNK inhibition and autophagy induction reduced also c-Jun activation, suggesting that defective autophagy and redox sensitive JNK activation previously associated with KRIT1 loss-of-function XREF_BIBR, XREF_BIBR contribute to upregulation of both c-Jun and Nrf2 redox sensitive pathways (XREF_FIG a).	7	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	7	8	14	15
Of note , the JNK target c-Jun as a subunit of the transcription factor AP-1 controls the expression of carnitine palmitoyltransferase 42 which is upregulated in stretch stimulated VSMCs and may therefore promote the generation of palmitoylated NFAT5 in VSMCs exposed to biomechanical stretch .	Of note, the JNK target c-Jun as a subunit of the transcription factor AP-1 controls the expression of carnitine palmitoyltransferase 42 which is upregulated in stretch stimulated VSMCs and may therefore promote the generation of palmitoylated NFAT5 in VSMCs exposed to biomechanical stretch.	3	32	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	4	5	6	7
At the transcriptional level , RNA-seq analysis showed that the JNK target c-Jun was increased in both HDAC1/2 mutants and controls after injury , but the basal level and the upregulation were lower in the mutant ( XREF_FIG and XREF_FIG ) .	At the transcriptional level, RNA-seq analysis showed that the JNK target c-Jun was increased in both HDAC1/2 mutants and controls after injury, but the basal level and the upregulation were lower in the mutant (XREF_FIG and XREF_FIG).	9	14	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	10	11	12	13
Robust and reproducible induction of stress induced JNK activity was observed as early as 30 min after application of 100 microM NMDA , as measured by phosphorylation of the stress specific JNK target c-Jun ( XREF_FIG ) .	Robust and reproducible induction of stress induced JNK activity was observed as early as 30 min after application of 100 microM NMDA, as measured by phosphorylation of the stress specific JNK target c-Jun (XREF_FIG).	24	35	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	31	32	33	34
For instance , CEP-1347 and KT-7515 , a potent inhibitor of the SAPK and JNK pathway by regulating the transcriptional activity of c-jun , blocked Abeta-induction of Cyclin D1 and the Bcl-2 family members DP5 and Bim genes , and promoted cell survival .	For instance, CEP-1347 and KT-7515, a potent inhibitor of the SAPK and JNK pathway by regulating the transcriptional activity of c-jun, blocked Abeta-induction of Cyclin D1 and the Bcl-2 family members DP5 and Bim genes, and promoted cell survival.	12	25	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	14	15	22	23
c-jun is activated upon phosphorylation by c-jun N-terminal kinase ( JNK ) , which responds to diverse biological stress signals .	c-jun is activated upon phosphorylation by c-jun N-terminal kinase (JNK), which responds to diverse biological stress signals.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-jun N-terminal kinase	c-jun N-terminal kinase	c-jun N-terminal kinase	c-jun	c-jun	c-jun	6	9	0	1
In Drosophila , the Jun N-terminal Kinase ( JNK ) pathway activates the transcription factor Activator Protein-1 ( AP-1 ) and induces expression of stress response genes XREF_BIBR .	In Drosophila, the Jun N-terminal Kinase (JNK) pathway activates the transcription factor Activator Protein-1 (AP-1) and induces expression of stress response genes XREF_BIBR.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Activator Protein-1	Activator Protein-1	Activator Protein-1	8	9	15	17
Among JAKs , JAK2 is expressed at a high level in the central nerve system ( CNS ) , and can specifically activate STAT3 .	Among JAKs, JAK2 is expressed at a high level in the central nerve system (CNS), and can specifically activate STAT3.	3	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2 is expressed	jak2	STAT3	STAT3	stat3	3	4	23	24
Stat3 is activated by both Jak2 and Src family kinases .	Stat3 is activated by both Jak2 and Src family kinases.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	5	6	0	1
Interrogation of the signaling cascade revealed that STAT3 was activated by JAK2 , in the same manner as in nucleated cells .	Interrogation of the signaling cascade revealed that STAT3 was activated by JAK2, in the same manner as in nucleated cells.	7	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	11	12	7	8
We therefore directly tested whether drug inhibition of AURKA ( with alisertib ) , JAK2 ( an upstream activator of STAT3 , with ruxolitinib ) or PDK1 ( with GSK2334470 ) enhanced ganetespib activity .	We therefore directly tested whether drug inhibition of AURKA (with alisertib), JAK2 (an upstream activator of STAT3, with ruxolitinib) or PDK1 (with GSK2334470) enhanced ganetespib activity.	6	21	activator	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	14	15	20	21
Leptin promotes the physical interaction of JAK2 and ROCK1 , thereby increasing phosphorylation of JAK2 and downstream activation of Stat3 and FOXO1 .	Leptin promotes the physical interaction of JAK2 and ROCK1, thereby increasing phosphorylation of JAK2 and downstream activation of Stat3 and FOXO1.	12	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAK2	phosphorylation of JAK2	jak2	Stat3	Stat3	stat3	14	15	19	20
XREF_BIBR TG101348 disrupts JAK2 induced phospho-STAT3 signaling in cultured and primary cells from patients with JAK2 V617F -positive myeloproliferative disorders .	XREF_BIBR TG101348 disrupts JAK2 induced phospho-STAT3 signaling in cultured and primary cells from patients with JAK2 V617F -positive myeloproliferative disorders.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	phospho-STAT3	phospho-STAT3	phospho-STAT3	3	4	5	6
STAT3 Tyr705 phoshorylation mediated by JAK2 is involved in STAT3 dimerization and its subsequent translocation to the nucleus and interaction with genomic DNA .	STAT3 Tyr705 phoshorylation mediated by JAK2 is involved in STAT3 dimerization and its subsequent translocation to the nucleus and interaction with genomic DNA.	0	6	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	5	6	0	1
Gp130 activation induces the phosphorylation of JAK kinase 1 ( JAK1 ) and JAK2 , which in turn phosphorylate STAT3 at Y705 , triggering its homodimerization , nuclear translocation , DNA binding and the transactivation of pro inflammatory STAT3 target genes .	Gp130 activation induces the phosphorylation of JAK kinase 1 (JAK1) and JAK2, which in turn phosphorylate STAT3 at Y705, triggering its homodimerization, nuclear translocation, DNA binding and the transactivation of pro inflammatory STAT3 target genes.	0	40	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	Gp130 activation induces the phosphorylation of JAK kinase 1 (JAK1) and JAK2	jak2	STAT3	STAT3	stat3	13	14	38	39
As STAT3 is activated by Janus kinase 2 ( JAK2 ) , JAK2 mRNA expression was determined in PhIP treated MCF-7 cells and a dose dependent increase was seen .	As STAT3 is activated by Janus kinase 2 (JAK2), JAK2 mRNA expression was determined in PhIP treated MCF-7 cells and a dose dependent increase was seen.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Janus kinase 2	Janus kinase 2	Janus kinase 2	STAT3	STAT3	STAT3	5	8	1	2
At some tissues , RBP is recognized by STRA6 , a plasma membrane protein that serves a dual role : it transports retinol from extracellular RBP into cells and it transduces a signaling cascade mediated by the Janus kinase JAK2 and the transcription factors STAT3 and STAT5 .	At some tissues, RBP is recognized by STRA6, a plasma membrane protein that serves a dual role : it transports retinol from extracellular RBP into cells and it transduces a signaling cascade mediated by the Janus kinase JAK2 and the transcription factors STAT3 and STAT5.	30	46	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	39	40	44	45
JAK2 mediated activation of STAT3 promotes growth and survival of a variety of human lymphomas .	JAK2 mediated activation of STAT3 promotes growth and survival of a variety of human lymphomas.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	0	1	4	5
In canonical Stat3 pathways , Stat3 is activated by Jak2 , which is in turn activated by receptors such as the epidermal growth factor receptor ( EGFR ) XREF_BIBR XREF_BIBR ( XREF_SUPPLEMENTARY ) .	In canonical Stat3 pathways, Stat3 is activated by Jak2, which is in turn activated by receptors such as the epidermal growth factor receptor (EGFR) XREF_BIBR XREF_BIBR (XREF_SUPPLEMENTARY).	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	9	10	5	6
Because JAK2 mediates STAT3 activation , we tested the effects of AG490 .	Because JAK2 mediates STAT3 activation, we tested the effects of AG490.	1	4	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	1	2	3	4
XREF_BIBR , XREF_BIBR , XREF_BIBR JAK2 though mediates the activation of STAT3 and NFkappaB , PI3 and AKT kinases , and the expression c-MYC and survivin promoting the survival of CEL cells , XREF_BIBR and JAK1 is another important inducer of STAT5 signaling .	XREF_BIBR, XREF_BIBR, XREF_BIBR JAK2 though mediates the activation of STAT3 and NFkappaB, PI3 and AKT kinases, and the expression c-MYC and survivin promoting the survival of CEL cells, XREF_BIBR and JAK1 is another important inducer of STAT5 signaling.	0	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	5	6	11	12
ApoA-I-ABCA1 interactions have also been shown to trigger JAK2 mediated activation of STAT3 , which can suppress LPS induced pro inflammatory gene expression of TNFalpha and IL-6 in macrophages [ XREF_BIBR , XREF_BIBR ] .	ApoA-I-ABCA1 interactions have also been shown to trigger JAK2 mediated activation of STAT3, which can suppress LPS induced pro inflammatory gene expression of TNFalpha and IL-6 in macrophages [XREF_BIBR, XREF_BIBR].	8	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	12	13
JAK2 in turn activates STAT3 , a promoter of transcription .	JAK2 in turn activates STAT3, a promoter of transcription.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	0	1	4	5
Furthermore , in ER negative , Her-2 positive tumours , no response was observed to trastuzumab in patients with STAT3 activation [ XREF_BIBR ] and that JAK2 drives a JAK1 and STAT3 independent signaling program in triple negative breast cancer [ XREF_BIBR ] , demonstrated that there are different activators and targets for STAT3 in different subgroups of breast cancer .	Furthermore, in ER negative, Her-2 positive tumours, no response was observed to trastuzumab in patients with STAT3 activation [XREF_BIBR] and that JAK2 drives a JAK1 and STAT3 independent signaling program in triple negative breast cancer [XREF_BIBR], demonstrated that there are different activators and targets for STAT3 in different subgroups of breast cancer.	26	34	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	26	27	31	32
Here we show that the ABCA1 mediated activation of JAK2 also activates STAT3 , which is independent of the lipid transport function of ABCA1 .	Here we show that the ABCA1 mediated activation of JAK2 also activates STAT3, which is independent of the lipid transport function of ABCA1.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	ABCA1 mediated activation of JAK2	jak2	STAT3	STAT3	stat3	9	10	12	13
In this study , we demonstrate that HER2 and HER3 facilitates WASF3 phospho activation and promotes WASF3 transcription through JAK2 activation of STAT3 in response to NRG .	In this study, we demonstrate that HER2 and HER3 facilitates WASF3 phospho activation and promotes WASF3 transcription through JAK2 activation of STAT3 in response to NRG.	19	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	19	20	22	23
In peritoneal macrophages , the alpha7nAChR can recruit the tyrosine kinase Jak2 , which activates STAT3 and subsequent signaling cascades .	In peritoneal macrophages, the alpha7nAChR can recruit the tyrosine kinase Jak2, which activates STAT3 and subsequent signaling cascades.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	STAT3	STAT3	STAT3	11	12	15	16
Therefore , p-JAK2 activates not only STAT3 but also different intracellular receptors and forms multiprotein complexes [ XREF_BIBR ] .	Therefore, p-JAK2 activates not only STAT3 but also different intracellular receptors and forms multiprotein complexes [XREF_BIBR].	2	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-JAK2	p-JAK2	p-JAK2	STAT3	STAT3	STAT3	2	3	6	7
All available inhibitors of JAK2 interfere with the ATP binding pocket and thus block JAK2 kinase activity and the resultant activation of the STAT1 , STAT3 and STAT5 pathways .	All available inhibitors of JAK2 interfere with the ATP binding pocket and thus block JAK2 kinase activity and the resultant activation of the STAT1, STAT3 and STAT5 pathways.	2	28	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	4	5	25	26
It has been well studied that p- Janus activated kinase 2 ( Jak2 ) could activate STAT3 , and the Jak2 and STAT3 signaling pathway is involved in the development of cancers and EMT [ XREF_BIBR ] .	It has been well studied that p- Janus activated kinase 2 (Jak2) could activate STAT3, and the Jak2 and STAT3 signaling pathway is involved in the development of cancers and EMT [XREF_BIBR].	9	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	STAT3	STAT3	STAT3	12	13	16	17
Subsequently , JAK2 tyrosine kinase will be activated , which in turn activates STAT3 .	Subsequently, JAK2 tyrosine kinase will be activated, which in turn activates STAT3.	2	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	2	3	13	14
It was found that loss of Jak2 significantly attenuated STAT3 , 4 , 5 and 6 activation in BMDCs as manifested by the significant decreased levels for phosphorylated STAT3 ( pSTAT3 , XREF_FIG ) , pSTAT4 ( XREF_FIG ) , pSTAT5 ( XREF_FIG ) and pSTAT6 ( XREF_FIG ) .	It was found that loss of Jak2 significantly attenuated STAT3, 4, 5 and 6 activation in BMDCs as manifested by the significant decreased levels for phosphorylated STAT3 (pSTAT3, XREF_FIG), pSTAT4 (XREF_FIG), pSTAT5 (XREF_FIG) and pSTAT6 (XREF_FIG).	4	16	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	loss of Jak2	jak2	STAT3	STAT3	stat3	6	7	9	10
Combination of an anti-EGFR agent Iressa and a JAK2 and STAT3 inhibitor synergistically suppressed STAT3 activation and potently killed glioblastoma cell lines that expressed EGFR or EGFRvIII .	Combination of an anti-EGFR agent Iressa and a JAK2 and STAT3 inhibitor synergistically suppressed STAT3 activation and potently killed glioblastoma cell lines that expressed EGFR or EGFRvIII.	8	15	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	14	15
Similarly in this study , over-expression of JAK2 via intrathecal injection of vector induced the up-regulation of both JAK2 and STAT3 protein , which suggested the activated JAK2 and STAT3 signaling .	Similarly in this study, over-expression of JAK2 via intrathecal injection of vector induced the up-regulation of both JAK2 and STAT3 protein, which suggested the activated JAK2 and STAT3 signaling.	5	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	over-expression of JAK2	jak2	STAT3	STAT3	stat3	7	8	20	21
The inhibition of Jak2 blocked Stat3 activation and induced the activation of PARP cleavage ( XREF_FIG ) .	The inhibition of Jak2 blocked Stat3 activation and induced the activation of PARP cleavage (XREF_FIG).	1	6	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	3	4	5	6
Taken together , these results underline the crucial role of JAK2 in AKR1C1 provoked STAT3 activation and metastasis , and suggest that AKR1C1 may facilitate the activation of STAT3 by JAK2 via modulating their interaction .	Taken together, these results underline the crucial role of JAK2 in AKR1C1 provoked STAT3 activation and metastasis, and suggest that AKR1C1 may facilitate the activation of STAT3 by JAK2 via modulating their interaction.	24	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	30	31	28	29
We found that JAK2 drives a JAK1 and STAT3 independent signaling program that can be overcome using JAK2 specific inhibitors in combination with chemotherapy in order to reduce tumor initiating stem like cells and to suppress tumor growth and progression .	We found that JAK2 drives a JAK1 and STAT3 independent signaling program that can be overcome using JAK2 specific inhibitors in combination with chemotherapy in order to reduce tumor initiating stem like cells and to suppress tumor growth and progression.	3	11	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	3	4	8	9
These data show that selective degradation of JAK2 in DU145 prostate cells was sufficient to abrogate subsequent activation of STAT3 signaling .	These data show that selective degradation of JAK2 in DU145 prostate cells was sufficient to abrogate subsequent activation of STAT3 signaling.	5	20	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	7	8	19	20
Alternatively , downstream signaling towards NFkappaB may involve JAK2 activation of STAT3 [ XREF_BIBR - XREF_BIBR ] .	Alternatively, downstream signaling towards NFkappaB may involve JAK2 activation of STAT3 [XREF_BIBR - XREF_BIBR].	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	11	12
The apoA-I and ABCA1 mediated activation of JAK2 then activates downstream STAT3 , which is independent of the lipid transport function of ABCA1 .	The apoA-I and ABCA1-mediated activation of JAK2 then activates downstream STAT3, which is independent of the lipid transport function of ABCA1.	1	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	ABCA1-mediated activation of JAK2	jak2	STAT3	STAT3	stat3	7	8	11	12
Knockdown of JAK1 inhibited P-STAT3 but not P-STAT6 , whereas knockdown of JAK2 inhibited P-STAT6 but not P-STAT3 ( XREF_FIG ) .	Knockdown of JAK1 inhibited P-STAT3 but not P-STAT6, whereas knockdown of JAK2 inhibited P-STAT6 but not P-STAT3 (XREF_FIG).	10	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	P-STAT3	P-STAT3	P-STAT3	12	13	17	18
Therefore , AGE-RAGE interaction activates Jak-2 and Jak-3 resulting in activation of Stat-3 and the expression of matrix-metallopeptidase 13 ( MMP-13 , collagen III ) and ADAMST 4/5 ( cleavage of proteoglycan aggrecan ) .	Therefore, AGE-RAGE interaction activates Jak-2 and Jak-3 resulting in activation of Stat-3 and the expression of matrix-metallopeptidase 13 (MMP-13, collagen III) and ADAMST 4/5 (cleavage of proteoglycan aggrecan).	5	13	resulting in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Jak-2	Jak-2	Jak-2	Stat-3	Stat-3	Stat-3	5	6	12	13
Abnormally elevated levels of the direct JAK2 targets STAT3 and STAT5 were observed in hematopoietic stem and progenitor cells ( HSPC ) from individual MF or sAML patients , including both JAK2 mutant and JAK2 wild-type patients .	Abnormally elevated levels of the direct JAK2 targets STAT3 and STAT5 were observed in hematopoietic stem and progenitor cells (HSPC) from individual MF or sAML patients, including both JAK2 mutant and JAK2 wild-type patients.	2	10	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	6	7	8	9
Study on signal transduction through Mp1 revealed that Tpo induces activation of JAK2 and Tyk2 , which in turn activate STAT1 , STAT3 and STAT5 .	Study on signal transduction through Mp1 revealed that Tpo induces activation of JAK2 and Tyk2, which in turn activate STAT1, STAT3 and STAT5.	10	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	12	13	22	23
STAT3 is Primarily Activated by JAK2 in NSCLC .	STAT3 is Primarily Activated by JAK2 in NSCLC.	0	7	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	5	6	0	1
In addition , knockdown of Jak2 in RAW 264.7 cells or lack of Jak2 in PMs diminishes chemokine expression and appears to disrupt STAT3 signaling .	In addition, knockdown of Jak2 in RAW 264.7 cells or lack of Jak2 in PMs diminishes chemokine expression and appears to disrupt STAT3 signaling.	11	24	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	Jak2 in PMs diminishes chemokine expression	jak2	STAT3	STAT3	stat3	13	14	23	24
STAT3 Is Activated by JAK2 Independent of Key Oncogenic Driver Mutations in Non Small Cell Lung Carcinoma .	STAT3 Is Activated by JAK2 Independent of Key Oncogenic Driver Mutations in Non Small Cell Lung Carcinoma.	0	5	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	4	5	0	1
Among the plethora of kinase receptors that stimulate STATs , janus kinases ( JAK ) , in particular JAK2 driving STAT3 and STAT5 activation , have been reported to have significant roles in breast cancer .	Among the plethora of kinase receptors that stimulate STATs, janus kinases (JAK), in particular JAK2 driving STAT3 and STAT5 activation, have been reported to have significant roles in breast cancer.	11	23	driving	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	18	19	20	21
Both immunofluorescence and western blotting results showed that Shk inhibited activated STAT3 without inhibiting JAK2 ( XREF_SUPPLEMENTARY , XREF_SUPPLEMENTARY ) confirming that Shk inhibits JAK2 mediated activation of STAT3 possibly by binding directly to STAT3 .	Both immunofluorescence and western blotting results showed that Shk inhibited activated STAT3 without inhibiting JAK2 (XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY) confirming that Shk inhibits JAK2 mediated activation of STAT3 possibly by binding directly to STAT3.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	24	25	28	29
AG490 or JAK2 siRNA blocked melatonin mediated cardio-protection by inhibiting JAK2 and STAT3 signaling .	AG490 or JAK2 siRNA blocked melatonin mediated cardio-protection by inhibiting JAK2 and STAT3 signaling.	0	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	2	3	12	13
Jak2 activity is enhanced upon SOCS2 downregulation and causes the reactivation of Stat3 .	Jak2 activity is enhanced upon SOCS2 downregulation and causes the reactivation of Stat3.	0	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	0	1	12	13
Upon this condition , phosphorylation of downstream signalling elements was also strongly reduced , with the exception of pSTAT3 in A549 cells , consistently with the presence of constitutively activated JAK2 mediated STAT3 pathway [ XREF_BIBR ] .	Upon this condition, phosphorylation of downstream signalling elements was also strongly reduced, with the exception of pSTAT3 in A549 cells, consistently with the presence of constitutively activated JAK2 mediated STAT3 pathway [XREF_BIBR].	26	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	30	31	32	33
In addition , inhibition of JAK2 does not only block the activation of STAT3 but also the activity of STAT1 in B-cell lymphoma [ XREF_BIBR ] .	In addition, inhibition of JAK2 does not only block the activation of STAT3 but also the activity of STAT1 in B-cell lymphoma [XREF_BIBR].	3	14	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	5	6	13	14
When cells receive the pro proliferative stimulation , STAT3 will be activated by JAK2 , and the activated STAT3 modulates the cell survival and proliferation via its down-stream targets .	When cells receive the pro proliferative stimulation, STAT3 will be activated by JAK2, and the activated STAT3 modulates the cell survival and proliferation via its down-stream targets.	8	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	13	14	8	9
Consistent with the activation of STAT3 being mediated by JAK2 , treatment of cultures with AG490 prevented both the translocation of STAT3 and activation of nuclear STAT3 ( XREF_FIG C ) .	Consistent with the activation of STAT3 being mediated by JAK2, treatment of cultures with AG490 prevented both the translocation of STAT3 and activation of nuclear STAT3 (XREF_FIG C).	3	10	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	9	10	5	6
JAK2 blockade reduces STAT1 and STAT3 and JAK2 phosphorylation in LPS stimulated hepatoma cells .	JAK2 blockade reduces STAT1 and STAT3 and JAK2 phosphorylation in LPS stimulated hepatoma cells.	0	6	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	0	1	5	6
Inhibition of c-Src and Janus kinase 2 and 3 activities abolished STAT3 activation induced by Galpha14QL , but no physical association between Galpha14QL and c-Src could be detected by coimmunoprecipitation .	Inhibition of c-Src and Janus kinase 2 and 3 activities abolished STAT3 activation induced by Galpha14QL, but no physical association between Galpha14QL and c-Src could be detected by coimmunoprecipitation.	4	12	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Janus kinase 2	Janus kinase 2	Janus kinase 2	STAT3	STAT3	STAT3	4	7	11	12
Thus , MUC1-C is dispensable for JAK1- and JAK2 mediated STAT3 activation in fibroblasts .	Thus, MUC1-C is dispensable for JAK1- and JAK2 mediated STAT3 activation in fibroblasts.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	10	11
The phosphorylating signal transducer JAK2 activates STAT3 in response to cytokines and growth factors .	The phosphorylating signal transducer JAK2 activates STAT3 in response to cytokines and growth factors.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	4	5	6	7
We further show that genetic or pharmacologic inhibition of the gp130 and JAK2 signaling pathway disrupts activation of STAT3 .	We further show that genetic or pharmacologic inhibition of the gp130 and JAK2 signaling pathway disrupts activation of STAT3.	12	19	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	12	13	18	19
Since both JAK2 and ABL1 activate STAT3 and STAT5 XREF_BIBR , XREF_BIBR , SPI1 expression may be mediated through STAT3 or STAT5 .	Since both JAK2 and ABL1 activate STAT3 and STAT5 XREF_BIBR, XREF_BIBR, SPI1 expression may be mediated through STAT3 or STAT5.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	2	3	6	7
Stat3 can also be activated by Jak2 in addition to Src ) , it seems desirable to suppress the pathway at multiple levels to achieve a maximal effect under a variety of cellular conditions .	Stat3 can also be activated by Jak2 in addition to Src), it seems desirable to suppress the pathway at multiple levels to achieve a maximal effect under a variety of cellular conditions.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	6	7	0	1
Signalling through alpha7 induces recruitment to and phosphor ylation of Jak2 by alpha7 and subsequent Jak2 induced activation of STAT3 [ XREF_BIBR ] .	Signalling through alpha7 induces recruitment to and phosphor ylation of Jak2 by alpha7 and subsequent Jak2 induced activation of STAT3 [XREF_BIBR].	8	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	STAT3	STAT3	STAT3	10	11	19	20
Hyperactivation of the STAT3 inducer JAK2 can make malignant cells sensitive to metabolic inhibition : 3-hydroxy-3-methyl-glutaryl coenzyme A ( HMG-CoA ) reductase inhibitors - widely used to treat hypercholesterolemia - induce apoptosis and inhibit JAK2-V617F-dependent neoplastic cell growth .	Hyperactivation of the STAT3 inducer JAK2 can make malignant cells sensitive to metabolic inhibition : 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors - widely used to treat hypercholesterolemia - induce apoptosis and inhibit JAK2-V617F-dependent neoplastic cell growth.	0	6	inducer	Positive_activation_token_1_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	5	6	3	4
Phosphorylation of JAK2 ( p-JAK2 ) then activates the STAT3 proteins .	Phosphorylation of JAK2 (p-JAK2) then activates the STAT3 proteins.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	Phosphorylation of JAK2	jak2	STAT3	STAT3	stat3	2	3	9	10
A combined pre-insult and immediate post-insult blockade of JAK2 with systemically applied WP1066 inhibited the HI induced forebrain STAT3 ( 705 )-phosphorylation and reduced HI-brain damage based on some evidence for astroglial and microglial post-HI response .	A combined pre-insult and immediate post-insult blockade of JAK2 with systemically applied WP1066 inhibited the HI induced forebrain STAT3 (705)-phosphorylation and reduced HI-brain damage based on some evidence for astroglial and microglial post-HI response.	6	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	18	19
Under paclitaxel treatment DRG derived neurons were shown to express higher levels of p-JAK2 which in turn activates p-STAT3 , known to be involved in neuropathic pain and synaptic plasticity [ XREF_BIBR - XREF_BIBR ] .	Under paclitaxel treatment DRG derived neurons were shown to express higher levels of p-JAK2 which in turn activates p-STAT3, known to be involved in neuropathic pain and synaptic plasticity [XREF_BIBR - XREF_BIBR].	11	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-JAK2	levels of p-JAK2	p-jak2	p-STAT3	p-STAT3	p-stat3	13	14	18	19
MicroRNA-101 inhibits JAK2 transcription by targeting JAK2 3 ' UTR [ XREF_BIBR ] , and inhibits STAT3 activation in ECs to abrogate vascular formation .	MicroRNA-101 inhibits JAK2 transcription by targeting JAK2 3 ' UTR [XREF_BIBR], and inhibits STAT3 activation in ECs to abrogate vascular formation.	0	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	MicroRNA-101 inhibits JAK2 transcription	jak2	STAT3	STAT3	stat3	2	3	16	17
In vitro , IL-6 binding to the IL-6 receptor promotes Janus kinase 2 ( JAK2 ) phosphorylation to activate signal transducer and activator transcription 3 ( STAT3 ) , leading to its nuclear translocation ( XREF_FIG ) [ XREF_BIBR ] .	In vitro, IL-6 binding to the IL-6 receptor promotes Janus kinase 2 (JAK2) phosphorylation to activate signal transducer and activator transcription 3 (STAT3), leading to its nuclear translocation (XREF_FIG) [XREF_BIBR].	3	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Janus kinase 2	IL-6 binding to the IL-6 receptor promotes Janus kinase 2 (JAK2) phosphorylation	janus kinase 2	STAT3	STAT3	stat3	10	13	26	27
Application of ruxolitinib to JAK2 V617F -expressing cell lines inhibited phosphorylation of the JAK2 targets STAT3 , STAT5 , and extracellular signal regulated kinase ( ERK ) and promoted apoptosis in a dose dependent manner [ XREF_BIBR ] .	Application of ruxolitinib to JAK2 V617F -expressing cell lines inhibited phosphorylation of the JAK2 targets STAT3, STAT5, and extracellular signal regulated kinase (ERK) and promoted apoptosis in a dose dependent manner [XREF_BIBR].	10	21	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	phosphorylation of the JAK2	jak2	STAT3	STAT3	stat3	13	14	15	16
To test whether the deregulated STAT3 signaling by STAT3 M206K mutation can be blocked by an inhibitor of the JAK2 signaling pathway , we treated STAT3alpha WT and STAT3alpha M206K stably transfected HEK-283T cells with TG101348 , an inhibitor of JAK2 XREF_BIBR , XREF_BIBR , XREF_BIBR .	To test whether the deregulated STAT3 signaling by STAT3 M206K mutation can be blocked by an inhibitor of the JAK2 signaling pathway, we treated STAT3alpha WT and STAT3alpha M206K stably transfected HEK-283T cells with TG101348, an inhibitor of JAK2 XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	21	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	19	20	5	6
This result lead us to evaluate STAT3 activity , as JAK2 activation is known to induce STAT3 activation .	This result lead us to evaluate STAT3 activity, as JAK2 activation is known to induce STAT3 activation.	10	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	10	11	16	17
Membrane anchored PC1 indeed caused JAK2 dependent activation of STAT3 by tyrosine phosphorylation , and the membrane proximal part of the cytoplasmic tail of PC1 was identified as the JAK2 binding site .	Membrane anchored PC1 indeed caused JAK2 dependent activation of STAT3 by tyrosine phosphorylation, and the membrane proximal part of the cytoplasmic tail of PC1 was identified as the JAK2 binding site.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	5	6	9	10
When leptin binds to the b isoform of the leptin receptor ( LepRb or ObRb ) , JAK2 is activated and leads to the activation of STAT3 , STAT5 and SHP2 .	When leptin binds to the b isoform of the leptin receptor (LepRb or ObRb), JAK2 is activated and leads to the activation of STAT3, STAT5 and SHP2.	17	30	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	17	18	26	27
If proteins X and Y interact , JAK2 will activate STAT3 in trans , leading to STAT3 dependent reporter gene activity .	If proteins X and Y interact, JAK2 will activate STAT3 in trans, leading to STAT3 dependent reporter gene activity.	7	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	7	8	10	11
The phosphorylated STAT then translocates into the nucleus to initiate transcription of effector genes involved in apoptosis , cell cycle progression , and proteasomal degradation.8 Among the JAK family of kinases , JAK2 is the most extensively studied because of its critical pathogenic role in myeloproliferative neoplasia ( MPN ) of humans.9 , 10 Deregulated JAK and STAT signaling also is implicated in lymphomagenesis ,11 and JAK2 mediated activation of STAT3 promotes growth and survival in a variety of lymphomas in humans.5 , 6 , 7 Constitutively activated STAT3 promotes cell proliferation and survival in the active B cell like ( ABC ) subtype of DLBCL in humans.7 In addition , constitutively activated STAT3 is correlated with more advanced clinical stage and overall poor survival of DLBCL in humans.12 , 13 Although the JAK and STAT pathway plays a critical role in DLBCL of humans , no studies have evaluated this pathway in DLBCL of dogs .	The phosphorylated STAT then translocates into the nucleus to initiate transcription of effector genes involved in apoptosis, cell cycle progression, and proteasomal degradation.8 Among the JAK family of kinases, JAK2 is the most extensively studied because of its critical pathogenic role in myeloproliferative neoplasia (MPN) of humans.9, 10 Deregulated JAK and STAT signaling also is implicated in lymphomagenesis,11 and JAK2 mediated activation of STAT3 promotes growth and survival in a variety of lymphomas in humans.5, 6, 7 Constitutively activated STAT3 promotes cell proliferation and survival in the active B cell like (ABC) subtype of DLBCL in humans.7 In addition, constitutively activated STAT3 is correlated with more advanced clinical stage and overall poor survival of DLBCL in humans.12, 13 Although the JAK and STAT pathway plays a critical role in DLBCL of humans, no studies have evaluated this pathway in DLBCL of dogs.	66	155	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	66	67	70	71
JAK2 activates STAT3 , a transcription factor , which has been shown to exert its anti-inflammatory effects through IL-10 .	JAK2 activates STAT3, a transcription factor, which has been shown to exert its anti-inflammatory effects through IL-10.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	0	1	2	3
Biochemical inhibition of JAK2 by P6 , albeit at higher concentrations , similarly down-regulated constitutive STAT3 activity but did not influence total JAK2 protein levels .	Biochemical inhibition of JAK2 by P6, albeit at higher concentrations, similarly down-regulated constitutive STAT3 activity but did not influence total JAK2 protein levels.	1	16	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	3	4	15	16
In addition , LAR deficiency enhanced H ( 2 ) O ( 2 )-induced phosphorylation of Janus kinase 2 ( JAK2 ) , signal transducer and activator of transcription 3 ( STAT3 ) , and p38 mitogen activated protein kinase ( MAPK ) .	In addition, LAR deficiency enhanced H (2) O (2)-induced phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and p38 mitogen activated protein kinase (MAPK).	3	32	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Janus kinase 2	LAR deficiency enhanced H (2) O (2)-induced phosphorylation of Janus kinase 2	janus kinase 2	STAT3	STAT3	stat3	16	19	31	32
We further confirm the roles of Jak2 and STAT3 in ATPgammaS induced responses by using siRNAs of Jak2 and STAT3 .	We further confirm the roles of Jak2 and STAT3 in ATPgammaS induced responses by using siRNAs of Jak2 and STAT3.	4	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	Jak2	Jak2	STAT3	STAT3	STAT3	6	7	19	20
Thrombopoietin , erythropoietin , granulocyte macrophage colony stimulating factor ( GM-CSF ) , interleukin 5 ( IL-5 ) and interleukin 3 ( IL-3 ) , and other factors signal through JAK2.2 Activation of JAK2 promotes recruitment and phosphorylation of the transcription factor STAT3 , which then leads to STAT3 dimerization and translocation into the nucleus where they activate downstream target genes important in cell proliferation , differentiation , and apoptosis.3 JAK2 mediated STAT3 activation promotes growth and survival of a variety of human lymphomas.4 , 5 , 6 In diffuse large B-cell lymphoma ( DLBCL ) of humans , JAK2-STAT3 is constitutively activated and promotes lymphoma cell proliferation and survival.6 We have observed that STAT3 expression and activity are upregulated in dogs with DLBCL ( unpublished data ) .	Thrombopoietin, erythropoietin, granulocyte macrophage colony stimulating factor (GM-CSF), interleukin 5 (IL-5) and interleukin 3 (IL-3), and other factors signal through JAK2.2 Activation of JAK2 promotes recruitment and phosphorylation of the transcription factor STAT3, which then leads to STAT3 dimerization and translocation into the nucleus where they activate downstream target genes important in cell proliferation, differentiation, and apoptosis.3 JAK2 mediated STAT3 activation promotes growth and survival of a variety of human lymphomas.4, 5, 6 In diffuse large B-cell lymphoma (DLBCL) of humans, JAK2-STAT3 is constitutively activated and promotes lymphoma cell proliferation and survival.6 We have observed that STAT3 expression and activity are upregulated in dogs with DLBCL (unpublished data).	70	126	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	70	71	72	73
BBMD3 directly targeted autophosphorylation of Jak2 in vitro and in cells , and inhibited constitutive activation of Stat3 , followed by down-regulation of survival proteins such as Mcl-1 and Bcl-x L in human melanoma cells ( XREF_FIG , XREF_FIG and XREF_FIG ) .	BBMD3 directly targeted autophosphorylation of Jak2 in vitro and in cells, and inhibited constitutive activation of Stat3, followed by down-regulation of survival proteins such as Mcl-1 and Bcl-x L in human melanoma cells (XREF_FIG, XREF_FIG and XREF_FIG).	0	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	BBMD3 directly targeted autophosphorylation of Jak2	jak2	Stat3	Stat3	stat3	5	6	17	18
Inhibition of JAK2 activity with AG490 , XREF_BIBR , XREF_BIBR cucurbitacin-I ( JSI-124 ) , XREF_BIBR WP1066 , XREF_BIBR inhibitor 2 , XREF_BIBR sorafenib , XREF_BIBR curcumin XREF_BIBR or WP1193 XREF_BIBR downregulates STAT3 activity , inhibits the proliferation and migratory and invasive behavior of glioma cell lines and stimulates their progression toward apoptosis .	Inhibition of JAK2 activity with AG490, XREF_BIBR, XREF_BIBR cucurbitacin-I (JSI-124), XREF_BIBR WP1066, XREF_BIBR inhibitor 2, XREF_BIBR sorafenib, XREF_BIBR curcumin XREF_BIBR or WP1193 XREF_BIBR downregulates STAT3 activity, inhibits the proliferation and migratory and invasive behavior of glioma cell lines and stimulates their progression toward apoptosis.	2	33	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	2	3	32	33
P6 strongly suppressed the phosphorylation of JAK2 and STAT3 and diminished STAT3 activity in EMF stimulated microglia .	P6 strongly suppressed the phosphorylation of JAK2 and STAT3 and diminished STAT3 activity in EMF stimulated microglia.	0	12	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	P6 strongly suppressed the phosphorylation of JAK2	jak2	STAT3	STAT3	stat3	6	7	11	12
When the leptin receptor is phosphorylated , cytosolic STAT3 is activated through subsequent phosphorylation by JAK2 and recruited .	When the leptin receptor is phosphorylated, cytosolic STAT3 is activated through subsequent phosphorylation by JAK2 and recruited.	7	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	15	16	8	9
STAT3 is activated by JAK2 through phosphorylation of its tyrosine residues .	STAT3 is activated by JAK2 through phosphorylation of its tyrosine residues.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	4	5	0	1
Because Jak2 was not mutated nor significantly activated in the AME positive cells , it is possible that the basal level of Jak2 kinase activity could be sufficient by itself to activate the Stat3 protein that accumulates in the cell at a level higher than normal .	Because Jak2 was not mutated nor significantly activated in the AME positive cells, it is possible that the basal level of Jak2 kinase activity could be sufficient by itself to activate the Stat3 protein that accumulates in the cell at a level higher than normal.	22	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	22	23	33	34
Initiation of ephrin-B1 signaling can activate RhoA and JAK2 induced STAT3 transcriptional activity , which can modulate the expression of genes involved in cell migration and invasion [ XREF_BIBR - XREF_BIBR ] ( XREF_FIG ) .	Initiation of ephrin-B1 signaling can activate RhoA and JAK2 induced STAT3 transcriptional activity, which can modulate the expression of genes involved in cell migration and invasion [XREF_BIBR - XREF_BIBR] (XREF_FIG).	5	12	induced	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	10	11
To understand how sanguinarine inhibits Stat3 activation , we examined the effect of sanguinarine on Jak2 , a kinase that activates Stat3 , and found that sanguinarine effectively inhibits Jak2 phosphorylation , suggesting that inhibition of Stat3 activation by sanguinarine is through suppression of Jak2 expression .	To understand how sanguinarine inhibits Stat3 activation, we examined the effect of sanguinarine on Jak2, a kinase that activates Stat3, and found that sanguinarine effectively inhibits Jak2 phosphorylation, suggesting that inhibition of Stat3 activation by sanguinarine is through suppression of Jak2 expression.	9	22	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	15	16	21	22
Then , we treated 97L-Oct4 cells with AZD1480 ( AstraZeneca , Waltham , MA , USA ) , a Jak2 specific inhibitor which blocks Stat3 activation and its downstream signaling .	Then, we treated 97L-Oct4 cells with AZD1480 (AstraZeneca, Waltham, MA, USA), a Jak2 specific inhibitor which blocks Stat3 activation and its downstream signaling.	19	25	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	19	20	24	25
Jak2 contributes to Stat3 mediated oncogenesis .	Jak2 contributes to Stat3 mediated oncogenesis.	0	4	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	0	1	3	4
Marrero reported that , in cultured rat VSMCs , JAK2 mediated STAT-3 activation is substantially involved in the angiotensin II ( AII ) - or platelet derived growth factor ( PDGF )-induced proliferation [ XREF_BIBR ] .	Marrero reported that, in cultured rat VSMCs, JAK2 mediated STAT-3 activation is substantially involved in the angiotensin II (AII) - or platelet derived growth factor (PDGF)-induced proliferation [XREF_BIBR].	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT-3	STAT-3	STAT-3	9	10	11	12
Signal transducer and activator of transcription 3 ( STAT3 ) binds to Janus kinase 2 ( JAK2 ) to initiate the JAK2 and STAT3 signal transduction pathway , which plays an important role in cancer cell proliferation , immune regulation , reproduction , lipid metabolism , and other physiological processes of the organism .	Signal transducer and activator of transcription 3 (STAT3) binds to Janus kinase 2 (JAK2) to initiate the JAK2 and STAT3 signal transduction pathway, which plays an important role in cancer cell proliferation, immune regulation, reproduction, lipid metabolism, and other physiological processes of the organism.	12	26	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Janus kinase 2	Janus kinase 2	Janus kinase 2	STAT3	STAT3	STAT3	12	15	23	24
ABCA1 mediated activation of JAK2 activates STAT3 independently of the lipid transport function of ABCA1 .	ABCA1 mediated activation of JAK2 activates STAT3 independently of the lipid transport function of ABCA1.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	ABCA1 mediated activation of JAK2	jak2	STAT3	STAT3	stat3	4	5	6	7
Consistently , pharmacological inhibition of JAK2 with Fedratinib or AZD1480 suppressed activation of STAT3 but not PKC ( XREF_FIG ) .	Consistently, pharmacological inhibition of JAK2 with Fedratinib or AZD1480 suppressed activation of STAT3 but not PKC (XREF_FIG).	3	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	5	6	13	14
STAT3 is principally activated by nonreceptor tyrosine kinase JAK2 [ XREF_BIBR ] .	STAT3 is principally activated by nonreceptor tyrosine kinase JAK2 [XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	0	1
Many growth factors and cytokines , including IL-6 and epidermal growth factor , activate Janus kinase 2 ( Jak2 ) , which subsequently activates STAT3 by phosphorylation of the tyrosine residue in the transactivation domain .	Many growth factors and cytokines, including IL-6 and epidermal growth factor, activate Janus kinase 2 (Jak2), which subsequently activates STAT3 by phosphorylation of the tyrosine residue in the transactivation domain.	14	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Janus kinase 2	Janus kinase 2	Janus kinase 2	STAT3	STAT3	STAT3	14	17	24	25
For example , JAK2 can differentially activate STAT1 , STAT3 , STAT6 and/or STAT6 depending on the receptor context XREF_BIBR , while negative regulators are able to act on multiple receptors , JAKs and STATs XREF_BIBR , including the ability to cross-talk between different receptors XREF_BIBR .	For example, JAK2 can differentially activate STAT1, STAT3, STAT6 and/or STAT6 depending on the receptor context XREF_BIBR, while negative regulators are able to act on multiple receptors, JAKs and STATs XREF_BIBR, including the ability to cross-talk between different receptors XREF_BIBR.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	3	4	9	10
c-Src depletion led to STAT3 activation , which was inhibited by specific knockdown of JAK2 and TYK2 ( XREF_FIG ) .	c-Src depletion led to STAT3 activation, which was inhibited by specific knockdown of JAK2 and TYK2 (XREF_FIG).	4	18	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	14	15	4	5
JAK2 mediates STAT6 , but not STAT3 activation in breast cancer cells .	JAK2 mediates STAT6, but not STAT3 activation in breast cancer cells.	0	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	0	1	6	7
Inhibition of Janus kinase 2 ( JAK 2 ) by specific pharmacological antagonists , AG490 , attenuated the activation of JAK2 and STAT3 pathway and induction of GFAP and other pro inflammatory factors , respectively .	Inhibition of Janus kinase 2 (JAK 2) by specific pharmacological antagonists, AG490, attenuated the activation of JAK2 and STAT3 pathway and induction of GFAP and other pro inflammatory factors, respectively.	2	23	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Janus kinase 2	Janus kinase 2	Janus kinase 2	STAT3	STAT3	STAT3	2	5	22	23
XREF_BIBR , XREF_BIBR Constitutively activating mutations within the STAT3 gene ( exon 21 ; SH2 domain ) have also been identified in large granular lymphocytic leukemias , XREF_BIBR whereas aberrant activation of the JAK2 kinase -- an upstream activator of STAT3 -- has also been directly implicated in several hematopoietic malignancies and myeloproliferative disorders , primarily due to genetic abnormalities ( somatic activating mutation ) in the JAK2 kinase ( V617F exon 12 ) or in the thrombopoietin receptor ( MPL ) resulting in STAT3/5 hyperactivation .	XREF_BIBR, XREF_BIBR Constitutively activating mutations within the STAT3 gene (exon 21; SH2 domain) have also been identified in large granular lymphocytic leukemias, XREF_BIBR whereas aberrant activation of the JAK2 kinase -- an upstream activator of STAT3 -- has also been directly implicated in several hematopoietic malignancies and myeloproliferative disorders, primarily due to genetic abnormalities (somatic activating mutation) in the JAK2 kinase (V617F exon 12) or in the thrombopoietin receptor (MPL) resulting in STAT3/5 hyperactivation.	33	41	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	33	34	40	41
In the research of vascular smooth muscle cells ( VSMCs ) , Li J and colleagues found that the inhibition of JAK2 and STAT3 could significantly attenuate H 2 O 2 -induced apoptosis and block the H 2 O 2 -induced activation of STAT3 , and their data indicated that leukocyte antigen related protein regulates the Fyn/JAK2/STAT3 and Fyn and p38 MAPK pathways , which are involved in ROS induced apoptosis XREF_BIBR .	In the research of vascular smooth muscle cells (VSMCs), Li J and colleagues found that the inhibition of JAK2 and STAT3 could significantly attenuate H 2 O 2 -induced apoptosis and block the H 2 O 2 -induced activation of STAT3, and their data indicated that leukocyte antigen related protein regulates the Fyn/JAK2/STAT3 and Fyn and p38 MAPK pathways, which are involved in ROS induced apoptosis XREF_BIBR.	19	44	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	21	22	43	44
Pharmacological targeting of Jak2 by AZD1480 suppresses IL-6-induced Stat3 and ERK1/2 signaling and development of a migratory PC cell phenotype .	Pharmacological targeting of Jak2 by AZD1480 suppresses IL-6-induced Stat3 and ERK1/2 signaling and development of a migratory PC cell phenotype.	1	19	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	3	4	8	9
JAK2 and TYK2 are not involved in LIF induced STAT3 activity and self-renewal of mESCs , but instead play a role in the early lineage decision of mESCs to various differentiated cell types [ XREF_BIBR ] .	JAK2 and TYK2 are not involved in LIF induced STAT3 activity and self-renewal of mESCs, but instead play a role in the early lineage decision of mESCs to various differentiated cell types [XREF_BIBR].	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	0	1	9	10
Reports showed cholinergic agonists inhibited the production of pro inflammation cytokines via activating the alpha7 nAChR expressed on macrophages and/or splenocytes XREF_BIBR , XREF_BIBR , XREF_BIBR , and resulting in the inhibition of the JAK2 induced STAT3 tyrosine phosphorylation XREF_BIBR , XREF_BIBR .	Reports showed cholinergic agonists inhibited the production of pro inflammation cytokines via activating the alpha7 nAChR expressed on macrophages and/or splenocytes XREF_BIBR, XREF_BIBR, XREF_BIBR, and resulting in the inhibition of the JAK2 induced STAT3 tyrosine phosphorylation XREF_BIBR, XREF_BIBR.	31	37	induced	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	34	35	36	37
MPL signals via its association with JAK2 and TYK2 , resulting in phosphorylation of both MPL and JAK2 and TYK2 and consequent activation of the STAT3 , STAT5 , ERK and MAPK , and PI3K and AKT signaling pathways .	MPL signals via its association with JAK2 and TYK2, resulting in phosphorylation of both MPL and JAK2 and TYK2 and consequent activation of the STAT3, STAT5, ERK and MAPK, and PI3K and AKT signaling pathways.	0	38	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	JAK2	MPL signals via its association with JAK2 and TYK2, resulting in phosphorylation of both MPL and JAK2	jak2	STAT3	STAT3	stat3	17	18	25	26
Reduction of Jak2 protein expression by siRNAs 1 and 2 inhibited Stat3 signaling compared to a non silencing control siRNA ( XREF_FIG ) .	Reduction of Jak2 protein expression by siRNAs 1 and 2 inhibited Stat3 signaling compared to a non silencing control siRNA (XREF_FIG).	2	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2 protein expression	jak2	Stat3	Stat3	stat3	2	3	11	12
The activation of STAT3 by JAK2 in VSMCs is induced in response to various growth factors , cytokines and hormones , such as platelet derived growth factor ( PDGF )-BB , angiotensin II , vascular endothelial growth factor ( VEGF ) and interleukin-6 .	The activation of STAT3 by JAK2 in VSMCs is induced in response to various growth factors, cytokines and hormones, such as platelet derived growth factor (PDGF)-BB, angiotensin II, vascular endothelial growth factor (VEGF) and interleukin-6.	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	5	6	3	4
Here , we report that ERK2 activated by its upstream kinase , MEK1 , represses Stat3 transcriptional activity induced by Src or Jak-2 .	Here, we report that ERK2 activated by its upstream kinase, MEK1, represses Stat3 transcriptional activity induced by Src or Jak-2.	15	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak-2	Jak-2	Jak-2	Stat3	Stat3	Stat3	22	23	15	16
Results also showed that in human gastric cancer SGC7901 cells , the specific inhibition of JAK2 attenuated the activation of both JAK2 and STAT3 ( XREF_FIG ) .	Results also showed that in human gastric cancer SGC7901 cells, the specific inhibition of JAK2 attenuated the activation of both JAK2 and STAT3 (XREF_FIG).	13	25	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	15	16	23	24
MEF-Stat3-YFP cells were employed as a model of Stat3 mediated oncogenesis to address whether Jak2 inhibition can suppress the growth of a Stat3 dependent tumor .	MEF-Stat3-YFP cells were employed as a model of Stat3 mediated oncogenesis to address whether Jak2 inhibition can suppress the growth of a Stat3 dependent tumor.	14	24	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	14	15	22	23
Genetic or pharmacologic inhibition of the gp130 and JAK2 signaling pathway disrupts activation of STAT3 [ XREF_BIBR ] .	Genetic or pharmacologic inhibition of the gp130 and JAK2 signaling pathway disrupts activation of STAT3 [XREF_BIBR].	8	16	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	14	15
Pharmacological suppression of JAK2 by its inhibitor AG490 robustly protected against tissue damage , attenuated JAK2 and STAT3 signaling and inflammatory responses .	Pharmacological suppression of JAK2 by its inhibitor AG490 robustly protected against tissue damage, attenuated JAK2 and STAT3 signaling and inflammatory responses.	1	18	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	3	4	17	18
Our previous study showed that stimulation of breast cancer cells with cytokines such as IL6 leads to JAK2 activation of STAT3 , which directly promotes WASF3 transcription XREF_BIBR , XREF_BIBR .	Our previous study showed that stimulation of breast cancer cells with cytokines such as IL6 leads to JAK2 activation of STAT3, which directly promotes WASF3 transcription XREF_BIBR, XREF_BIBR.	17	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	17	18	20	21
Loss of Jak2 Impairs the Activation of STAT3 , 4 , 5 , and 6 .	Loss of Jak2 Impairs the Activation of STAT3, 4, 5, and 6.	0	14	Impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	Loss of Jak2	jak2	STAT3	STAT3	stat3	2	3	7	8
Tkip also inhibited constitutive ( DU145 ) and IL-6-induced ( LNCaP ) activation of STAT3 , consistent with the fact that STAT3 activation is mediated by JAK2 .	Tkip also inhibited constitutive (DU145) and IL-6-induced (LNCaP) activation of STAT3, consistent with the fact that STAT3 activation is mediated by JAK2.	21	27	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	26	27	21	22
In the present study , we designed a screen of STAT3 and CCND2 inhibitors , through which a novel small molecule compound called SC99 was found to inhibit STAT3 via JAK2 , a kinase that activates STAT3 , and displayed oral potency in the treatment of MM .	In the present study, we designed a screen of STAT3 and CCND2 inhibitors, through which a novel small molecule compound called SC99 was found to inhibit STAT3 via JAK2, a kinase that activates STAT3, and displayed oral potency in the treatment of MM.	28	37	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	30	31	36	37
These data indicate that strong STAT3 activation seen in a subset PDAC cell lines is mediated by JAK2 and may predict sensitivity to JAK2 inhibitors .	These data indicate that strong STAT3 activation seen in a subset PDAC cell lines is mediated by JAK2 and may predict sensitivity to JAK2 inhibitors.	5	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	17	18	5	6
For example , in response to erythropoietin or thrombopoietin receptor binding , JAK2 mediated activation of STAT3 or STAT5 supports the survival , proliferation , and differentiation of erythroid cells or megakaryocyte-erythroid progenitor cells , respectively .	For example, in response to erythropoietin or thrombopoietin receptor binding, JAK2 mediated activation of STAT3 or STAT5 supports the survival, proliferation, and differentiation of erythroid cells or megakaryocyte-erythroid progenitor cells, respectively.	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	12	13	16	17
Moreover , JAK2 activated STAT3 pathway has tumor promoting activity [ XREF_BIBR - XREF_BIBR ] .	Moreover, JAK2 activated STAT3 pathway has tumor promoting activity [XREF_BIBR - XREF_BIBR].	2	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	2	3	4	5
Evidence supports that , in breast cancer , JAK2 activates STAT3 and is found to be significantly activated when compared to non neoplastic breast tissue [ XREF_BIBR , XREF_BIBR ] .	Evidence supports that, in breast cancer, JAK2 activates STAT3 and is found to be significantly activated when compared to non neoplastic breast tissue [XREF_BIBR, XREF_BIBR].	8	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	10	11
Stat3 is activated by Janus Kinases ( Jaks ) , predominantly by Jak2 .	Stat3 is activated by Janus Kinases (Jaks), predominantly by Jak2.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	12	13	0	1
Activation of STAT3 by JAK2 regulates a variety of biological responses , including proliferation , survival , differentiation , and inflammation .	Activation of STAT3 by JAK2 regulates a variety of biological responses, including proliferation, survival, differentiation, and inflammation.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	4	5	2	3
Combination of an anti-EGFR agent Iressa and a JAK2 and STAT3 inhibitor synergistically suppressed STAT3 activation and potently killed GBM cell lines that expressed EGFR [ XREF_BIBR ] .	Combination of an anti-EGFR agent Iressa and a JAK2 and STAT3 inhibitor synergistically suppressed STAT3 activation and potently killed GBM cell lines that expressed EGFR [XREF_BIBR].	8	15	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	14	15
Notably , active JNK can promote Bim activity by posttranslationally modifying the molecule .	Notably, active JNK can promote Bim activity by posttranslationally modifying the molecule.	2	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	3	4	6	7
Previous studies have shown that JNK can activate Bim through phosphorylation to trigger Bax dependent mitochondrial apoptosis [ XREF_BIBR , XREF_BIBR ] .	Previous studies have shown that JNK can activate Bim through phosphorylation to trigger Bax dependent mitochondrial apoptosis [XREF_BIBR, XREF_BIBR].	5	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	5	6	8	9
While it has been suggested that JNK generates the proapoptotic Bid cleavage product jBid XREF_BIBR several other reports indicate that JNK activates the BH3-only protein Bim XREF_BIBR , XREF_BIBR .	While it has been suggested that JNK generates the proapoptotic Bid cleavage product jBid XREF_BIBR several other reports indicate that JNK activates the BH3-only protein Bim XREF_BIBR, XREF_BIBR.	20	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	20	21	25	26
The rescue of cells from apoptosis and inhibition of Bim expression by p38 inhibitor treatment is not due to generalized rescue of stress signaling as inhibition of JNK , which is also activated by PTK6 shRNA expression , does not block apoptosis or Bim induction .	The rescue of cells from apoptosis and inhibition of Bim expression by p38 inhibitor treatment is not due to generalized rescue of stress signaling as inhibition of JNK, which is also activated by PTK6 shRNA expression, does not block apoptosis or Bim induction.	25	44	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	27	28	43	44
These data suggest upon treatment with IRE1alpha inhibitors , BIM was activated by JNK phosphorylation as well as heterodimerization with BAX to promote cell apoptosis of pancreatic cancer cells .	These data suggest upon treatment with IRE1alpha inhibitors, BIM was activated by JNK phosphorylation as well as heterodimerization with BAX to promote cell apoptosis of pancreatic cancer cells.	9	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK phosphorylation	jnk	BIM	BIM	bim	13	14	9	10
In support of this view , it was recently shown that JNK contributes to TNF-R1-induced PCD signalling in hepatocytes by activating another proapoptotic BH3-only proteins , Bim rather than Bid .	In support of this view, it was recently shown that JNK contributes to TNF-R1-induced PCD signalling in hepatocytes by activating another proapoptotic BH3-only proteins, Bim rather than Bid.	11	27	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	11	12	26	27
These results strongly indicate that the anisomycin promoted apoptosis in Jurkat T cells through the JNK dependent activation of Bim and Bcl-xL .	These results strongly indicate that the anisomycin promoted apoptosis in Jurkat T cells through the JNK dependent activation of Bim and Bcl-xL.	15	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	15	16	19	20
Dysfunction of mitochondrial complex I associated with Parkinson ' s disease leads to degeneration of dopaminergic neurons of the substantia nigra pars compacta ( SNpc ) through a mechanism involving JNK dependent activation of Bim with consequent Bax translocation to the mitochondria and apoptosis [ XREF_BIBR ] .	Dysfunction of mitochondrial complex I associated with Parkinson 's disease leads to degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) through a mechanism involving JNK dependent activation of Bim with consequent Bax translocation to the mitochondria and apoptosis [XREF_BIBR].	30	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	30	31	34	35
Among the apoptosis inducing substrates of JNK are Bcl-2 and Bim , which are inhibited and activated , respectively , by JNK phosphorylation [ XREF_BIBR , XREF_BIBR ] .	Among the apoptosis inducing substrates of JNK are Bcl-2 and Bim, which are inhibited and activated, respectively, by JNK phosphorylation [XREF_BIBR, XREF_BIBR].	7	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	JNK	JNK phosphorylation	jnk	Bim	Bim	bim	21	22	10	11
JNK mediates Bim and Puma activation .	JNK mediates Bim and Puma activation.	0	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	0	1	2	3
For example , Bim is activated by CHOP and JNK , whereas Puma and Noxa are activated by ER stress mediated p53 up-regulation .	For example, Bim is activated by CHOP and JNK, whereas Puma and Noxa are activated by ER stress mediated p53 up-regulation.	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	9	10	3	4
On the other hand , JNK was found to activate proapoptotic Bad , Bim , and Bax through different mechanisms .	On the other hand, JNK was found to activate proapoptotic Bad, Bim, and Bax through different mechanisms.	5	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	5	6	13	14
The JNK pathway mediates BIM activation in cell apoptosis .	The JNK pathway mediates BIM activation in cell apoptosis.	1	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	BIM	BIM	BIM	1	2	4	5
In the UV irradiation study , JNK up-regulates Bim through ERK activation .	In the UV irradiation study, JNK up-regulates Bim through ERK activation.	6	9	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	6	7	8	9
JNK induces activation of Bim .	JNK induces activation of Bim.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	0	1	4	5
Conversely JNK has been reported to activate the pro apoptotic BCL-2 family protein BIM and inhibit BCL-2 .	Conversely JNK has been reported to activate the pro apoptotic BCL-2 family protein BIM and inhibit BCL-2.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	BIM	BIM	BIM	1	2	13	14
Inhibition of the MAPK p38 and JNK reduced both up-regulation of Bim and apoptosis .	Inhibition of the MAPK p38 and JNK reduced both up-regulation of Bim and apoptosis.	0	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	6	7	11	12
Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK and c-Jun-mediated induction of the BH3-only protein BIM .	Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK and c-Jun-mediated induction of the BH3-only protein BIM.	12	21	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	BIM	BIM	BIM	12	13	20	21
As JNK can activate Bim , a BH3 domain-only protein capable of binding to and activating Bax , its role in lipoapoptosis was also examined .	As JNK can activate Bim, a BH3 domain-only protein capable of binding to and activating Bax, its role in lipoapoptosis was also examined.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	1	2	4	5
The proapoptotic activity of Bim is negatively regulated by ERK-1 phosphorylation , while phosphorylation by JNK enhances Bim activity possibly by dissociation from intracellular sequestration [ XREF_BIBR ] .	The proapoptotic activity of Bim is negatively regulated by ERK-1 phosphorylation, while phosphorylation by JNK enhances Bim activity possibly by dissociation from intracellular sequestration [XREF_BIBR].	13	18	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	15	16	17	18
43 The functional role of JNK in apoptosis is not clear , although JNK has been shown in vitro to activate the pro apoptotic protein BIM and deactivate the anti-apoptotic protein BCL-2 , an anti-apoptotic protein that functions as an inhibitor of the pro apoptotic proteins BAX and BAK .	43 The functional role of JNK in apoptosis is not clear, although JNK has been shown in vitro to activate the pro apoptotic protein BIM and deactivate the anti-apoptotic protein BCL-2, an anti-apoptotic protein that functions as an inhibitor of the pro apoptotic proteins BAX and BAK.	13	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	BIM	BIM	BIM	13	14	25	26
28 As the activation of JNK by Abeta has been shown 29 and the active form of JNK has been reported to be increased in vulnerable neurons in AD , 30 it is plausible that the activation of JNK and subsequent activation of Bim and Bax mediated apoptosis pathway might be the mechanism causing neuronal cell death in oligomeric Abeta treated neurons and AD .	28 As the activation of JNK by Abeta has been shown 29 and the active form of JNK has been reported to be increased in vulnerable neurons in AD, 30 it is plausible that the activation of JNK and subsequent activation of Bim and Bax mediated apoptosis pathway might be the mechanism causing neuronal cell death in oligomeric Abeta treated neurons and AD.	38	44	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	38	39	43	44
In agreement with this notion , we have recently shown that JNK phosphorylates the pro apoptotic Bcl-2 homolog Bim , and that JNK activated Bim critically regulates Fas induced hepatocyte apoptosis .	In agreement with this notion, we have recently shown that JNK phosphorylates the pro apoptotic Bcl-2 homolog Bim, and that JNK activated Bim critically regulates Fas induced hepatocyte apoptosis.	22	26	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	22	23	24	25
XREF_BIBR , XREF_BIBR , XREF_BIBR This is likely due to the fact that TNFalpha can activate several other death effector mechanisms , among which c-Jun N-terminal kinase and Bim , another BH3-only molecule that can be activated by c-Jun N-terminal kinase , turn out to be crucial players .	XREF_BIBR, XREF_BIBR, XREF_BIBR This is likely due to the fact that TNFalpha can activate several other death effector mechanisms, among which c-Jun N-terminal kinase and Bim, another BH3-only molecule that can be activated by c-Jun N-terminal kinase, turn out to be crucial players.	26	47	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	Bim	Bim	Bim	38	41	28	29
These earlier studies also concluded that Erk , rather than Jnk , positively regulated Bim .	These earlier studies also concluded that Erk, rather than Jnk, positively regulated Bim.	6	15	positively regulated	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Jnk	Jnk	Jnk	Bim	Bim	Bim	10	11	14	15
TRAIL treatment in these cells results in JNK mediated activation of Bim , translocation of Bim and Bax to the lysosomes , and Bim and Bax dependent LMP upstream of mitochondrial dysfunction .	TRAIL treatment in these cells results in JNK mediated activation of Bim, translocation of Bim and Bax to the lysosomes, and Bim and Bax dependent LMP upstream of mitochondrial dysfunction.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	7	8	11	12
Activation of JNK by stress signal has been shown to activate pro apoptotic protein BIM .	Activation of JNK by stress signal has been shown to activate pro apoptotic protein BIM.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	BIM	BIM	BIM	2	3	14	15
17 Similarly , JNK target-sites in the BH3-only proteins Bim and Bmf , proposed to promote their apoptotic potential , were shown to be largely dispensable for cell death signaling in vivo .	17 Similarly, JNK target-sites in the BH3-only proteins Bim and Bmf, proposed to promote their apoptotic potential, were shown to be largely dispensable for cell death signaling in vivo.	3	11	target-sites	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	3	4	9	10
Instead , Bax mitochondrial translocation in this model relies mainly on the JNK dependent activation of the BH3-only protein Bim .	Instead, Bax mitochondrial translocation in this model relies mainly on the JNK dependent activation of the BH3-only protein Bim.	12	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	12	13	19	20
Combined activation of JNK and p38 appears to promote the transcriptional induction and possibly also activation of the BH3-only proteins Bim and Puma .	Combined activation of JNK and p38 appears to promote the transcriptional induction and possibly also activation of the BH3-only proteins Bim and Puma.	1	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	3	4	20	21
JNK dependent activation of Bim and Bmf .	JNK dependent activation of Bim and Bmf.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	0	1	4	5
JNK activates the proapoptotic protein Bim by phosphorylation , while inhibiting the antiapoptotic protein Bcl-2 [ XREF_BIBR ] .	JNK activates the proapoptotic protein Bim by phosphorylation, while inhibiting the antiapoptotic protein Bcl-2 [XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	0	1	5	6
IRE1alpha mediated JNK activation represses anti-apoptotic BCL2 activity and enhances pro apoptotic BIM function , thereby favoring cell death .	IRE1alpha mediated JNK activation represses anti-apoptotic BCL2 activity and enhances pro apoptotic BIM function, thereby favoring cell death.	0	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	IRE1alpha mediated JNK	jnk	BIM	BIM	bim	2	3	12	13
Upon free fatty acid stimulation , pro apoptotic Bim is activated by JNK to induce mitochondrial dysfunction .	Upon free fatty acid stimulation, pro apoptotic Bim is activated by JNK to induce mitochondrial dysfunction.	6	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	12	13	8	9
Mechanistic analysis demonstrated that JNK promoted anoikis requires the pro apoptotic BCL2 family proteins BAK and BAX and the BH3-only proteins BIM and BMF .	Mechanistic analysis demonstrated that JNK promoted anoikis requires the pro apoptotic BCL2 family proteins BAK and BAX and the BH3-only proteins BIM and BMF.	4	23	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	BIM	BIM	BIM	4	5	21	22
Despite the coexistence of both pathways in at least 30 % of the population , Bim mRNA and protein expression was increased only by the JNK and c-Jun signaling pathway , whereas Noxa and Puma mRNA and Puma protein expression was entirely JNK and c-Jun independent .	Despite the coexistence of both pathways in at least 30% of the population, Bim mRNA and protein expression was increased only by the JNK and c-Jun signaling pathway, whereas Noxa and Puma mRNA and Puma protein expression was entirely JNK and c-Jun independent.	15	29	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	25	26	15	16
Phosphorylation of JNK leads to the activation of pro death protein BIM and inhibition of anti-death protein BCL-2 XREF_BIBR .	Phosphorylation of JNK leads to the activation of pro death protein BIM and inhibition of anti-death protein BCL-2 XREF_BIBR.	0	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	JNK	Phosphorylation of JNK	jnk	BIM	BIM	bim	2	3	11	12
ROS activated the JNK signalling and overexpression of the proapoptotic Bim not followed by cytochrome c or AIF release to activate the downstream apoptotic cascade .	ROS activated the JNK signalling and overexpression of the proapoptotic Bim not followed by cytochrome c or AIF release to activate the downstream apoptotic cascade.	3	12	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	3	4	10	11
Studies have shown that the activation of JNK inhibits antiapoptotic protein BCL-2 [ XREF_BIBR ] and induces proapoptotic protein Bim [ XREF_BIBR , XREF_BIBR ] .	Studies have shown that the activation of JNK inhibits antiapoptotic protein BCL-2 [XREF_BIBR] and induces proapoptotic protein Bim [XREF_BIBR, XREF_BIBR].	5	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	7	8	19	20
The ROS and JNK signaling pathway has been shown to upregulate Bim and lead to Bax mediated apoptosis .	The ROS and JNK signaling pathway has been shown to upregulate Bim and lead to Bax mediated apoptosis.	3	12	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	3	4	11	12
To further confirm that the JNK signaling pathway mediates BIM activation and subsequent cell apoptosis , we utilized the dominant negative mutant of c-Jun , TAM67 , which was cloned into the pGFP-C2 plasmid .	To further confirm that the JNK signaling pathway mediates BIM activation and subsequent cell apoptosis, we utilized the dominant negative mutant of c-Jun, TAM67, which was cloned into the pGFP-C2 plasmid.	5	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	BIM	BIM	BIM	5	6	9	10
These findings strongly prove that anisomycin promotes the apoptosis in Jurkat T cells through the JNK dependent activation of Bim and Bcl-xL .	These findings strongly prove that anisomycin promotes the apoptosis in Jurkat T cells through the JNK dependent activation of Bim and Bcl-xL.	15	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	15	16	19	20
Here we present that Bim is up-regulated by JNK in response to oxidative stress .	Here we present that Bim is up-regulated by JNK in response to oxidative stress.	4	10	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	8	9	4	5
We next examined the phosphorylation ( activation ) state of the JNK and c-Jun pathway which can directly upregulate bim mRNA or function post-transcriptionally to increase Bim activity by phosphorylation .	We next examined the phosphorylation (activation) state of the JNK and c-Jun pathway which can directly upregulate bim mRNA or function post-transcriptionally to increase Bim activity by phosphorylation.	11	20	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	bim	bim	bim	11	12	19	20
XREF_BIBR , XREF_BIBR , XREF_BIBR In summary , our studies demonstrate a critical role of JNK mediated Bim activation in the TRAIL mediated enhancement of chemotherapy induced apoptosis in liver derived cells lines , further supporting the importance of the TRAIL-JNK-Bim axis in regulating apoptosis .	XREF_BIBR, XREF_BIBR, XREF_BIBR In summary, our studies demonstrate a critical role of JNK mediated Bim activation in the TRAIL mediated enhancement of chemotherapy induced apoptosis in liver derived cells lines, further supporting the importance of the TRAIL-JNK-Bim axis in regulating apoptosis.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	15	16	17	18
There are also hints that JNK activity can directly modulate function of BH3-only protein Bim , hence strongly influencing mitochondrial pro apoptotic signaling ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	There are also hints that JNK activity can directly modulate function of BH3-only protein Bim, hence strongly influencing mitochondrial pro apoptotic signaling (XREF_FIG) [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	15	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	5	6	14	15
38 In line with this notion , we recently observed that Fas induced hepatocyte apoptosis and liver destruction is substantially regulated via a TRAIL initiated JNK mediated activation of Bim .	38 In line with this notion, we recently observed that Fas induced hepatocyte apoptosis and liver destruction is substantially regulated via a TRAIL initiated JNK mediated activation of Bim.	25	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	25	26	29	30
JNK activation by IRE1 suppresses antiapoptotic BCL2 activity and accelerates the action of proapoptotic BIM , leading to cell death [ XREF_BIBR ] .	JNK activation by IRE1 suppresses antiapoptotic BCL2 activity and accelerates the action of proapoptotic BIM, leading to cell death [XREF_BIBR].	0	15	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	BIM	BIM	BIM	0	1	14	15
Indeed , TRAIL induced LMP in cholangiocarcinoma cells requires JNK mediated activation of Bim and Bax .	Indeed, TRAIL induced LMP in cholangiocarcinoma cells requires JNK mediated activation of Bim and Bax.	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	9	10	13	14
In this context , post-translational activation of Bax relied on JNK dependent activation of the BH3-only protein Bim [ XREF_BIBR ] .	In this context, post-translational activation of Bax relied on JNK dependent activation of the BH3-only protein Bim [XREF_BIBR].	10	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	10	11	17	18
Previous studies demonstrated that TAM67 inhibited the JNK pathway mediated activation of BIM and subsequent caspase cleavage XREF_BIBR , XREF_BIBR .	Previous studies demonstrated that TAM67 inhibited the JNK pathway mediated activation of BIM and subsequent caspase cleavage XREF_BIBR, XREF_BIBR.	7	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	BIM	BIM	BIM	7	8	12	13
JNK activates Bax , Bim , and Bad by phosphorylation and upregulates Bim , PUMA , and DP5 in hepatocytes and neurons .	JNK activates Bax, Bim, and Bad by phosphorylation and upregulates Bim, PUMA, and DP5 in hepatocytes and neurons.	0	17	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	0	1	12	13
The Phosphorylation of JNK activates BIM , Bak , Bax and inhibits the Bcl-2 and Bcl-xL ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	The Phosphorylation of JNK activates BIM, Bak, Bax and inhibits the Bcl-2 and Bcl-xL (XREF_FIG) [XREF_BIBR, XREF_BIBR].	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	Phosphorylation of JNK	jnk	BIM	BIM	bim	3	4	5	6
Collectively , these results show that caspase-8-dependent activation of Bid plus JNK induced activation of Bim cooperate in TNFalpha mediated hepatocyte destruction in LPS+ G alN injected mice .	Collectively, these results show that caspase-8-dependent activation of Bid plus JNK induced activation of Bim cooperate in TNFalpha mediated hepatocyte destruction in LPS+G alN injected mice.	9	16	induced	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	11	12	15	16
Concanavalin A Induced Hepatitis Requires Caspase-8 and Involves JNK Mediated Activation of Bim .	Concanavalin A Induced Hepatitis Requires Caspase-8 and Involves JNK Mediated Activation of Bim.	7	13	Mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	8	9	12	13
Second , by recruiting ASK1 via the adaptor TRAF2 , it enables the phosphorylation of the stress kinase JNK , which in turn : ( i ) activates pro apoptotic Bim and Bad proteins while inhibiting anti-apoptotic protein Bcl-2 ; and also ( ii ) translocates to the nucleus to activate the transcription factor complex AP-1 , which contributes to induction of pro apoptotic genes such as TNF-alpha , Fas-L and Bak XREF_BIBR , XREF_BIBR .	Second, by recruiting ASK1 via the adaptor TRAF2, it enables the phosphorylation of the stress kinase JNK, which in turn : (i) activates pro apoptotic Bim and Bad proteins while inhibiting anti-apoptotic protein Bcl-2; and also (ii) translocates to the nucleus to activate the transcription factor complex AP-1, which contributes to induction of pro apoptotic genes such as TNF-alpha, Fas-L and Bak XREF_BIBR, XREF_BIBR.	4	33	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	JNK	ASK1 via the adaptor TRAF2, it enables the phosphorylation of the stress kinase JNK	jnk	Bim	Bim	bim	18	19	30	31
Specifically , JNK activates pro apoptotic Bim and inactivates anti-apoptotic Bcl-2 proteins .	Specifically, JNK activates pro apoptotic Bim and inactivates anti-apoptotic Bcl-2 proteins.	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	2	3	6	7
Moreover , JNK activation may promote dissociation of Bim from the disrupted microtubules into the cytoplasm and degradation of Bcl-2 , resulting in apoptosis XREF_BIBR XREF_BIBR .	Moreover, JNK activation may promote dissociation of Bim from the disrupted microtubules into the cytoplasm and degradation of Bcl-2, resulting in apoptosis XREF_BIBR XREF_BIBR.	2	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	2	3	8	9
Meanwhile , inhibition of JNK and c-JUN attenuated the Bim luciferase activity .	Meanwhile, inhibition of JNK and c-JUN attenuated the Bim luciferase activity.	2	11	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	4	5	9	10
In Parkinson ' s disease for instance , excessive ROS production due to mitochondrial Complex I dysfunction is responsible for JNK mediated activation of Bim that leads to degeneration of dopaminergic neurons of the substantia nigra pars compacta ( SNpc ) [ XREF_BIBR ] .	In Parkinson 's disease for instance, excessive ROS production due to mitochondrial Complex I dysfunction is responsible for JNK mediated activation of Bim that leads to degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) [XREF_BIBR].	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	Bim	Bim	Bim	20	21	24	25
Thus , TNFalpha contributes to JNK signaling in infected cells and promotes MAP4K4 expression most likely via JNK mediated ATF2 activation XREF_BIBR , while MAP4K4 in turn is needed for TNFalpha induced JNK activation .	Thus, TNFalpha contributes to JNK signaling in infected cells and promotes MAP4K4 expression most likely via JNK mediated ATF2 activation XREF_BIBR, while MAP4K4 in turn is needed for TNFalpha induced JNK activation.	13	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	17	18	19	20
IL-18 induced phosphorylation of JNK , PKCdelta , p38 MAPK , and activating transcription factor 2 ( ATF-2 ) in RA ST fibroblasts in a time dependent manner , with JNK-2 being upstream of PKCdelta , ATF-2 , and NFkappaB .	IL-18 induced phosphorylation of JNK, PKCdelta, p38 MAPK, and activating transcription factor 2 (ATF-2) in RA ST fibroblasts in a time dependent manner, with JNK-2 being upstream of PKCdelta, ATF-2, and NFkappaB.	0	22	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	IL-18 induced phosphorylation of JNK	jnk	ATF-2	ATF-2	atf-2	4	5	17	18
In turn , JNK activated ATF-2 and AP-1 for interaction with CRE1 and CRE2 and AP-1 , respectively .	In turn, JNK activated ATF-2 and AP-1 for interaction with CRE1 and CRE2/AP-1, respectively.	3	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF-2	ATF-2	ATF-2	3	4	5	6
Taken together , our findings demonstrate that JNK mediated ATF2 activation contributes to dopaminergic neuronal death in an MPTP model of PD .	Taken together, our findings demonstrate that JNK mediated ATF2 activation contributes to dopaminergic neuronal death in an MPTP model of PD.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	7	8	9	10
Using phosphorylation specific and total protein antibodies for p66Shc and JNK1/2 as well as for the p38 substrate MAPKAP kinase 2 ( MK2 ) and the JNK1/2 target ATF2 changes in signaling were analyzed .	Using phosphorylation specific and total protein antibodies for p66Shc and JNK1/2 as well as for the p38 substrate MAPKAP kinase 2 (MK2) and the JNK1/2 target ATF2 changes in signaling were analyzed.	26	29	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK1/2	JNK1/2	JNK1/2	ATF2	ATF2	ATF2	26	27	28	29
Calcineurin , ERK1 , and ERK2 were increased resulting in nuclear translocation of transcription factors such as NFATc- and JNK activated ATF2 .	Calcineurin, ERK1, and ERK2 were increased resulting in nuclear translocation of transcription factors such as NFATc- and JNK activated ATF2.	14	22	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	19	20	21	22
The activating transcription factor-2 ( ATF-2 ) protein is essential for the normal development of mammalian brain and is activated by c-Jun N-terminal kinase ( JNK ) .	The activating transcription factor-2 (ATF-2) protein is essential for the normal development of mammalian brain and is activated by c-Jun N-terminal kinase (JNK).	1	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	activating transcription factor-2	activating transcription factor-2	activating transcription factor-2	21	24	1	4
One example of a bifan is the two MAP-kinases , p38 , and JNK that phosphorylate and activate the two transcription factors ATF2 and Elk-1 .	One example of a bifan is the two MAP-kinases, p38, and JNK that phosphorylate and activate the two transcription factors ATF2 and Elk-1.	8	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	13	14	22	23
ATF2 , a member of the basic helix-loop-helix ( HLH ) family of transcription factors , is activated via phosphorylation by c-Jun N-terminal kinase or p38 in response to stimuli including stress and cytokines .	ATF2, a member of the basic helix-loop-helix (HLH) family of transcription factors, is activated via phosphorylation by c-Jun N-terminal kinase or p38 in response to stimuli including stress and cytokines.	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	ATF2	ATF2	ATF2	21	24	0	1
These data provide evidence that in the absence of TGF-beta signaling , the suppression of cell proliferation during the early stages of wound healing is maintained through the JNK activation of ATF2 .	These data provide evidence that in the absence of TGF-beta signaling, the suppression of cell proliferation during the early stages of wound healing is maintained through the JNK activation of ATF2.	28	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	28	29	31	32
Whereas ATF-2 is activated by both the p38 and JNK MAPK , c-Jun is only phosphorylated by JNK XREF_BIBR .	Whereas ATF-2 is activated by both the p38 and JNK MAPK, c-Jun is only phosphorylated by JNK XREF_BIBR.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK MAPK	JNK MAPK	JNK MAPK	ATF-2	ATF-2	ATF-2	9	11	1	2
A slight activation of JNK was observed in DT40 cells overexpressing ATF2 , but this activity was not altered in CEFs .	A slight activation of JNK was observed in DT40 cells overexpressing ATF2, but this activity was not altered in CEFs.	2	12	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	4	5	11	12
Interestingly , on a second level of action , GR represses the increase in transcriptional activity of c-Jun : ATF2 induced by c-Jun N-terminal kinase ( JNK )-dependent phosphorylation .	Interestingly, on a second level of action, GR represses the increase in transcriptional activity of c-Jun : ATF2 induced by c-Jun N-terminal kinase (JNK)-dependent phosphorylation.	12	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase (JNK)-dependent phosphorylation	c-jun n-terminal kinase	ATF2	ATF2	atf2	22	25	19	20
In this study we have identified areca nut induced JNK mediated activation of ATF2 and c-Jun transcription factors .	In this study we have identified areca nut induced JNK mediated activation of ATF2 and c-Jun transcription factors.	9	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	9	10	13	14
In addition , JNK activates the transcription factors AP-1 and ATF2 , which are involved in bone formation [ XREF_BIBR , XREF_BIBR ] .	In addition, JNK activates the transcription factors AP-1 and ATF2, which are involved in bone formation [XREF_BIBR, XREF_BIBR].	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	3	4	10	11
Although JNK , p38MAPK and ERK1/2 all activate ATF2 , the marked ATF2 activation in 2-month-old CHIP -/- -livers most closely mirrored their temporal JNK1 activation profile .	Although JNK, p38MAPK and ERK1/2 all activate ATF2, the marked ATF2 activation in 2-month-old CHIP -/- -livers most closely mirrored their temporal JNK1 activation profile.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	1	2	8	9
This , in turn , activates Ca 2+ -dependent protein kinase C ( PKC ) , CamKIV , JNK , and MAPK , which then activate the transcription factors ATF2 , CEBP and delta , CREB , Egr-1 , and CHOP [ XREF_BIBR ] .	This, in turn, activates Ca 2+ -dependent protein kinase C (PKC), CamKIV, JNK, and MAPK, which then activate the transcription factors ATF2, CEBP and delta, CREB, Egr-1, and CHOP [XREF_BIBR].	11	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	18	19	29	30
In contrast , JNK mediated activation of ATF2 and c-Jun has also been implicated in the stress induced transcription of several genes involved in DNA repair .	In contrast, JNK mediated activation of ATF2 and c-Jun has also been implicated in the stress induced transcription of several genes involved in DNA repair.	3	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	3	4	7	8
This event , in addition to the activation of ATF2 by c-Jun N-terminal kinase ( JNK ) , increases interleukin-6 ( IL-6 ) production .	This event, in addition to the activation of ATF2 by c-Jun N-terminal kinase (JNK), increases interleukin-6 (IL-6) production.	7	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	ATF2	ATF2	ATF2	11	14	9	10
Stimulation through CD158j in CD4 + CD28 null T cells led to increased IFN-gamma expression ( XREF_FIG ) , possibly mediated through JNK induced activation of ATF-2 and c-Jun .	Stimulation through CD158j in CD4 + CD28 null T cells led to increased IFN-gamma expression (XREF_FIG), possibly mediated through JNK induced activation of ATF-2 and c-Jun.	20	28	induced	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	ATF-2	ATF-2	ATF-2	22	23	26	27
JAK2 activates the downstream molecule STAT1 after the cells are stimulated by LPS and are activated .	JAK2 activates the downstream molecule STAT1 after the cells are stimulated by LPS and are activated.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT1	STAT1	STAT1	0	1	5	6
Functional prolactin receptor signaling was further demonstrated in the activation of JAK2 and phosphorylation activation of the transcription factors Stat1 , -3 , and -5 a. Surprisingly , prolactin stimulated a sustained activation of Raf-B , without activation of the MAP kinases ERK1 or -2 .	Functional prolactin receptor signaling was further demonstrated in the activation of JAK2 and phosphorylation activation of the transcription factors Stat1, -3, and -5 a. Surprisingly, prolactin stimulated a sustained activation of Raf-B, without activation of the MAP kinases ERK1 or -2.	11	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAK2	JAK2 and phosphorylation	jak2	Stat1	Stat1	stat1	11	12	19	20
The parallel in vitro culture data support our in vivo findings , and suggest that liver IRI proceeds via JAK2 mediated STAT-1 activation pathways .	The parallel in vitro culture data support our in vivo findings, and suggest that liver IRI proceeds via JAK2 mediated STAT-1 activation pathways.	17	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT-1	STAT-1	STAT-1	19	20	21	22
In silico analysis and chromatin immunoprecipitation assays revealed that the downstream mediator of JAK2 signaling STAT1 binds to the TFEB promoter .	In silico analysis and chromatin immunoprecipitation assays revealed that the downstream mediator of JAK2 signaling STAT1 binds to the TFEB promoter.	11	16	signaling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT1	STAT1	STAT1	13	14	15	16
The subsequent phosphorylation of JAK2 triggers STAT1 activation and increased production and release of IL-6 .	The subsequent phosphorylation of JAK2 triggers STAT1 activation and increased production and release of IL-6.	2	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	phosphorylation of JAK2	jak2	STAT1	STAT1	stat1	4	5	6	7
The type of activated STAT could also play a role since MPL and JAK2 can activate STAT1 , 2 , 3 , and 5 , which may have markedly different effects on HSC and MK biology XREF_BIBR - XREF_BIBR .	The type of activated STAT could also play a role since MPL and JAK2 can activate STAT1, 2, 3, and 5, which may have markedly different effects on HSC and MK biology XREF_BIBR - XREF_BIBR.	11	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT1	STAT1	STAT1	13	14	16	17
Inhibition of Jak-2 is known to block STAT-1 activation as well as matrix metalloproteinase 13 in chondrocytes , resulting in the protection of chondrocytes and cartilage in OA [ XREF_BIBR ] .	Inhibition of Jak-2 is known to block STAT-1 activation as well as matrix metalloproteinase 13 in chondrocytes, resulting in the protection of chondrocytes and cartilage in OA [XREF_BIBR].	0	8	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak-2	Jak-2	Jak-2	STAT-1	STAT-1	STAT-1	2	3	7	8
Suppressor of cytokine signaling 1 ( SOCS1 ) suppresses the Janus kinase 2 ( JAK2 ) pathway , thereby downregulating signal transducer and activator of transcription 1 ( STAT1 ) .	Suppressor of cytokine signaling 1 (SOCS1) suppresses the Janus kinase 2 (JAK2) pathway, thereby downregulating signal transducer and activator of transcription 1 (STAT1).	10	29	downregulating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Janus kinase 2	Janus kinase 2	Janus kinase 2	STAT1	STAT1	STAT1	10	13	28	29
Jak2 activates STAT1 ( red ) via a phosphorylation of its Tyr 701 residue .	Jak2 activates STAT1 (red) via a phosphorylation of its Tyr 701 residue.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	STAT1	STAT1	STAT1	0	1	2	3
Janus kinase 2 activity , previously reported to be required for IFN-gamma-mediated Ser727 phosphorylation , was not needed for LPS mediated Ser727 phosphorylation , and activation of Janus kinase 2 did not cause the appearance of STAT1 Ser727 kinase activity .	Janus kinase 2 activity, previously reported to be required for IFN-gamma-mediated Ser727 phosphorylation, was not needed for LPS mediated Ser727 phosphorylation, and activation of Janus kinase 2 did not cause the appearance of STAT1 Ser727 kinase activity.	27	39	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Janus kinase 2	Janus kinase 2	Janus kinase 2	STAT1	STAT1	STAT1	27	30	36	37
In the developing Drosophila retina , JNK activates Foxo and AP-1 in response to UV induced DNA damage , inducing expression of the pro apoptotic protein head-involution defective ( Hid ) .	In the developing Drosophila retina, JNK activates Foxo and AP-1 in response to UV induced DNA damage, inducing expression of the pro apoptotic protein head-involution defective (Hid).	6	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Foxo	Foxo	Foxo	6	7	8	9
Supporting this idea , our results show that inhibiting JNK function in enterocytes can attenuate , although not completely inhibit , this Foxo activation .	Supporting this idea, our results show that inhibiting JNK function in enterocytes can attenuate, although not completely inhibit, this Foxo activation.	9	23	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Foxo	Foxo	Foxo	9	10	22	23
For instance , hydrogen peroxide inhibits FoxO activity by activating the phosphoinositide 3 kinase protein B pathway by affecting insulin-mimetic effects XREF_BIBR , whereas reactive oxygen species ( ROS )-activated macrophage stimulating 1 , mitogen activated protein kinase , and c-Jun N-terminal kinase activate the FoxO protein via phosphorylation and breakage of binding to the 14-3-3 protein XREF_BIBR , XREF_BIBR .	For instance, hydrogen peroxide inhibits FoxO activity by activating the phosphoinositide 3 kinase protein B pathway by affecting insulin-mimetic effects XREF_BIBR, whereas reactive oxygen species (ROS)-activated macrophage stimulating 1, mitogen activated protein kinase, and c-Jun N-terminal kinase activate the FoxO protein via phosphorylation and breakage of binding to the 14-3-3 protein XREF_BIBR, XREF_BIBR.	40	46	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	FoxO	FoxO	FoxO	40	43	45	46
Our results suggest that , as in bilaterians , JNK increases FoxO activity and cellular resistance to stress in Hydra .	Our results suggest that, as in bilaterians, JNK increases FoxO activity and cellular resistance to stress in Hydra.	9	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FoxO	FoxO	FoxO	9	10	11	12
Oxidative Stress Activates JNK which Activates Foxo .	Oxidative Stress Activates JNK which Activates Foxo.	2	7	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Foxo	Foxo	Foxo	3	4	6	7
In addition , C-Jun N-terminal protein kinase ( JNK ) can promote FOXO nuclear localization , leading to apoptosis .	In addition, C-Jun N-terminal protein kinase (JNK) can promote FOXO nuclear localization, leading to apoptosis.	3	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FOXO	FOXO	FOXO	8	9	12	13
Likewise , FoxO is negatively regulated by the PI3K and Akt pathway and activated by the JNK pathway .	Likewise, FoxO is negatively regulated by the PI3K and Akt pathway and activated by the JNK pathway.	2	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FoxO	FoxO	FoxO	16	17	2	3
Some heat shock proteins are also induced by the JNK signaling pathway and the transcription factor Foxo , which are also implicated in lifespan determination [ XREF_BIBR ] .	Some heat shock proteins are also induced by the JNK signaling pathway and the transcription factor Foxo, which are also implicated in lifespan determination [XREF_BIBR].	6	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Foxo	Foxo	Foxo	9	10	16	17
JNK mediated activation of Foxo in Insulin Producing Cells ( IPCs ) of flies , for example , represses the expression of insulin like peptide 2 ( dilp2 ) , regulating growth and longevity XREF_BIBR .	JNK mediated activation of Foxo in Insulin Producing Cells (IPCs) of flies, for example, represses the expression of insulin like peptide 2 (dilp2), regulating growth and longevity XREF_BIBR.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	Foxo	Foxo	Foxo	0	1	4	5
JNK stimulates the activity of FoxO transcription factors through direct phosphorylation [ XREF_BIBR , XREF_BIBR ] .	JNK stimulates the activity of FoxO transcription factors through direct phosphorylation [XREF_BIBR, XREF_BIBR].	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FoxO	FoxO	FoxO	0	1	5	6
FOXO activation by ROS is probably mediated by the JNK MAPK pathway : in fact , oxidative stress induced by treatment of cells with H 2 O 2 results in the activation of the small GTPase Ral that determines the phosphorylation and activation of JNK and JNK mediated phosphorylation of FOXO1 [ XREF_BIBR ] .	FOXO activation by ROS is probably mediated by the JNK MAPK pathway : in fact, oxidative stress induced by treatment of cells with H 2 O 2 results in the activation of the small GTPase Ral that determines the phosphorylation and activation of JNK and JNK mediated phosphorylation of FOXO1 [XREF_BIBR].	0	11	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK MAPK	JNK MAPK	JNK MAPK	FOXO	FOXO	FOXO	9	11	0	1
JNK activation modulates the activity of the FOXO transcription factor , sending it to the nucleus and initiating transcription .	JNK activation modulates the activity of the FOXO transcription factor, sending it to the nucleus and initiating transcription.	0	9	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FOXO	FOXO	FOXO	0	1	7	8
FoxO proteins are also activated through the phosphorylation by JNK and Mst1 , and JNK and Mst1 are activated by phophorylation ( XREF_FIG ) XREF_BIBR , XREF_BIBR .	FoxO proteins are also activated through the phosphorylation by JNK and Mst1, and JNK and Mst1 are activated by phophorylation (XREF_FIG) XREF_BIBR, XREF_BIBR.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FoxO	FoxO	FoxO	9	10	0	1
Although ROS can also affect acetylation of FOXO through p300 and CBP and inhibition of JNK may have multiple effects , including suppression of c-Jun activity , JNK activation of FOXO is likely the major means by which the ROS signalling function induced by P. gingivalis is relayed to FOXO1 .	Although ROS can also affect acetylation of FOXO through p300 and CBP and inhibition of JNK may have multiple effects, including suppression of c-Jun activity, JNK activation of FOXO is likely the major means by which the ROS signalling function induced by P. gingivalis is relayed to FOXO1.	27	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	FOXO	FOXO	FOXO	27	28	30	31
JNK-1 , a C. elegans homolog of JNK , is known to activate DAF-16 FoxO to extend lifespan [ XREF_BIBR ] .	JNK-1, a C. elegans homolog of JNK, is known to activate DAF-16 FoxO to extend lifespan [XREF_BIBR].	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FoxO	FoxO	FoxO	7	8	14	15
These findings indicate that FoxO proteins were not activated by JNK and Mst1 .	These findings indicate that FoxO proteins were not activated by JNK and Mst1.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FoxO	FoxO	FoxO	10	11	4	5
This may be associated with the JNK mediated activation of FoxO factors and the ability of JNK to inhibit insulin signaling [ XREF_BIBR ] .	This may be associated with the JNK mediated activation of FoxO factors and the ability of JNK to inhibit insulin signaling [XREF_BIBR].	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	FoxO	FoxO	FoxO	6	7	10	11
It is conceivable that increased JNK expression and function perturbs the capacity of high pAKT levels to inhibit FOXO function [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It is conceivable that increased JNK expression and function perturbs the capacity of high pAKT levels to inhibit FOXO function [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	19	perturbs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK expression	jnk	FOXO	FOXO	foxo	5	6	18	19
This pathway , by which FOXO inhibits TORC1 in flies , manifests in conditions of oxidative stress , whereby FOXO is activated by stress inducible kinases , JNK or MST1 .	This pathway, by which FOXO inhibits TORC1 in flies, manifests in conditions of oxidative stress, whereby FOXO is activated by stress inducible kinases, JNK or MST1.	19	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FOXO	FOXO	FOXO	27	28	19	20
JNK is a potent activator of FoxO and thus contributes to the inhibition of TCF via FoxO .	JNK is a potent activator of FoxO and thus contributes to the inhibition of TCF via FoxO.	0	9	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	JNK	JNK	JNK	FoxO	FoxO	FoxO	0	1	6	7
A mitogen activated kinase member JNK also modulates FoxO and plays a role in the ageing process [ XREF_BIBR ] .	A mitogen activated kinase member JNK also modulates FoxO and plays a role in the ageing process [XREF_BIBR].	0	10	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FoxO	FoxO	FoxO	5	6	8	9
Since JNK can activate the transcription factor Foxo , we also tested whether Foxo regulates NLaz transcription .	Since JNK can activate the transcription factor Foxo, we also tested whether Foxo regulates NLaz transcription.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Foxo	Foxo	Foxo	1	2	7	8
Pharmacological inhibition of JNK augmented the myeloid maturation and apoptotic effects of Akt activation or FOXO inhibition .	Pharmacological inhibition of JNK augmented the myeloid maturation and apoptotic effects of Akt activation or FOXO inhibition.	1	16	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FOXO	FOXO	FOXO	3	4	15	16
Cell autonomous activation of Foxo by JNK signaling has been described in mice and flies , and it likely plays an important role in cytoprotection and/or apoptosis in response to local insults .	Cell autonomous activation of Foxo by JNK signaling has been described in mice and flies, and it likely plays an important role in cytoprotection and/or apoptosis in response to local insults.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Foxo	Foxo	Foxo	6	7	4	5
Collectively , Jak2 and Stat5a co-overexpression cooperatively reverses epithelial-mesenchymal transition and promotes differentiation in human breast cancer cells , which may provide a mechanism to explain the invasive suppressor role of PRL activated Stat5a in mammary cancer cells .	Collectively, Jak2 and Stat5a co-overexpression cooperatively reverses epithelial-mesenchymal transition and promotes differentiation in human breast cancer cells, which may provide a mechanism to explain the invasive suppressor role of PRL activated Stat5a in mammary cancer cells.	2	34	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2 and Stat5a co-overexpression	jak2	Stat5a	Stat5a	stat5a	2	3	33	34
Consistent with our findings in cell culture models , JAK1/2 inhibition in melanomas in vivo using ruxolitinib blocked constitutive P-STAT3 and P-STAT5 , whereas JAK2 specific inhibition using NVP-BSK805 blocked only P-STAT5 .	Consistent with our findings in cell culture models, JAK1/2 inhibition in melanomas in vivo using ruxolitinib blocked constitutive P-STAT3 and P-STAT5, whereas JAK2 specific inhibition using NVP-BSK805 blocked only P-STAT5.	24	32	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	P-STAT5	P-STAT5	P-STAT5	24	25	31	32
We and others have shown that the main role of JAK2 in the epithelium is to activate STAT5a and STAT5b in response to PRL signaling .	We and others have shown that the main role of JAK2 in the epithelium is to activate STAT5a and STAT5b in response to PRL signaling.	8	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT5a	STAT5a	STAT5a	10	11	17	18
P-STAT5 is also activated by JAK2 kinase and can therefore be used as a measure of JAK2 kinase activity .	P-STAT5 is also activated by JAK2 kinase and can therefore be used as a measure of JAK2 kinase activity.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	P-STAT5	P-STAT5	P-STAT5	5	6	0	1
Although STAT5A is potently activated by PRLR and JAK2 signaling , STAT5A also forms complexes with other receptors in MECs [ XREF_BIBR , XREF_BIBR ] .	Although STAT5A is potently activated by PRLR and JAK2 signaling, STAT5A also forms complexes with other receptors in MECs [XREF_BIBR, XREF_BIBR].	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT5A	STAT5A	STAT5A	8	9	1	2
Both Stat5a and Stat5b are activated by Jak2 phosphorylation on a specific tyrosine residue .	Both Stat5a and Stat5b are activated by Jak2 phosphorylation on a specific tyrosine residue.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak2	Jak2 phosphorylation	jak2	Stat5a	Stat5a	stat5a	7	8	1	2
JAK2- activated STAT5a and b ( phospho-forms ) associate as tetramer of homodimers or heterodimers with a functional GAS element in the non coding exon 1 ( hE1 3 ) corresponding to the hPIII promoter [ XREF_BIBR ] .	JAK2- activated STAT5a and b (phospho-forms) associate as tetramer of homodimers or heterodimers with a functional GAS element in the non coding exon 1 (hE1 3) corresponding to the hPIII promoter [XREF_BIBR].	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2-	JAK2-	JAK2-	STAT5a	STAT5a	STAT5a	0	1	2	3
The lead compound Inhibitor of Stat5-002 ( IST5-002 ) prevented both Jak2 and Bcr-Abl-mediated phosphorylation and dimerization of Stat5a/b , and selectively inhibited transcriptional activity of Stat5a ( IC 50 1.5 muM ) and Stat5b ( IC 50 3.5 muM ) .	The lead compound Inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl-mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC 50 1.5 muM) and Stat5b (IC 50 3.5 muM).	5	39	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl-mediated phosphorylation	jak2	Stat5a	Stat5a	stat5a	11	12	26	27
As discussed before , increased ROS levels result in JNK mediated activation of FOXO4 leading to cellular senescence .	As discussed before, increased ROS levels result in JNK mediated activation of FOXO4 leading to cellular senescence.	9	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	FOXO4	FOXO4	FOXO4	9	10	13	14
It has been shown that JNK activates FOXO4 activity through phosphorylation at Thr447 and Thr451 XREF_BIBR .	It has been shown that JNK activates FOXO4 activity through phosphorylation at Thr447 and Thr451 XREF_BIBR.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FOXO4	FOXO4	FOXO4	5	6	7	8
When we examined whether HBX bypasses JNK signaling that targets Foxo4 , we found that the activity of JNK but not of ERK is required for the up-regulation of Foxo4 even in the presence of HBX .	When we examined whether HBX bypasses JNK signaling that targets Foxo4, we found that the activity of JNK but not of ERK is required for the up-regulation of Foxo4 even in the presence of HBX.	6	11	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Foxo4	Foxo4	Foxo4	6	7	10	11
The important role of JNK in FOXO4 activation by PKG is consistent with previous studies showing that PKG activates JNK in colon cancer cells , and that JNK activates FOXO4 .	The important role of JNK in FOXO4 activation by PKG is consistent with previous studies showing that PKG activates JNK in colon cancer cells, and that JNK activates FOXO4.	27	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FOXO4	FOXO4	FOXO4	27	28	29	30
Although , the specific role of FOXO4 in these models of senescence was not accessed , it is tempting to speculate that increased ROS levels due to FOXO1 and FOXO3 inactivation might be involved in specific JNK mediated activation of FOXO4 and induction of senescence as shown for the aforementioned study .	Although, the specific role of FOXO4 in these models of senescence was not accessed, it is tempting to speculate that increased ROS levels due to FOXO1 and FOXO3 inactivation might be involved in specific JNK mediated activation of FOXO4 and induction of senescence as shown for the aforementioned study.	36	44	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	FOXO4	FOXO4	FOXO4	36	37	40	41
ROS regulation of JNK mediated activation of FOXO4 and Akt mediated inactivation of FOXOs might lead to differential activation states of FOXO4 versus FOXO1 and 3 , explaining the antagonistic role of FOXOs in senescence .	ROS regulation of JNK mediated activation of FOXO4 and Akt mediated inactivation of FOXOs might lead to differential activation states of FOXO4 versus FOXO1 and 3, explaining the antagonistic role of FOXOs in senescence.	3	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	FOXO4	FOXO4	FOXO4	3	4	7	8
Our study revealed that alphaMSH could blunt the phosphorylation of Akt and JNK and specifically , Akt phosphorylation activates Foxo1 and Foxo3a , while JNK phosphorylation stimulates Foxo4 .	Our study revealed that alphaMSH could blunt the phosphorylation of Akt and JNK and specifically, Akt phosphorylation activates Foxo1 and Foxo3a, while JNK phosphorylation stimulates Foxo4.	24	28	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK phosphorylation	jnk	Foxo4	Foxo4	foxo4	24	25	27	28
Since JNK phosphorylation has been reported to activate FOXO4 and FOXO1 we tested the effect of a JNK inhibitor on the process .	Since JNK phosphorylation has been reported to activate FOXO4 and FOXO1 we tested the effect of a JNK inhibitor on the process.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK phosphorylation	jnk	FOXO4	FOXO4	foxo4	1	2	8	9
In vertebrates , JNK phosphorylates the insulin-receptor substrate ( IRS ) , inhibiting insulin signal transduction [ XREF_BIBR , XREF_BIBR ] ; JNK can also activate FoxO4 directly by phosphorylation [ XREF_BIBR ] .	In vertebrates, JNK phosphorylates the insulin-receptor substrate (IRS), inhibiting insulin signal transduction [XREF_BIBR, XREF_BIBR]; JNK can also activate FoxO4 directly by phosphorylation [XREF_BIBR].	22	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	FoxO4	FoxO4	FoxO4	22	23	26	27
Then JNK mediated linker phosphorylation of Smad3 inactivated cytostatic Smad3 signaling and facilitated hepatocarciongenesis [ XREF_BIBR ] .	Then JNK mediated linker phosphorylation of Smad3 inactivated cytostatic Smad3 signaling and facilitated hepatocarciongenesis [XREF_BIBR].	1	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Smad3	Smad3	Smad3	1	2	9	10
Smad3 is normally activated by TGF-beta , but JNK , via the linker phosphorylation pathway , also enables Smad3 to induce HSC proliferation [ XREF_BIBR , XREF_BIBR ] .	Smad3 is normally activated by TGF-beta, but JNK, via the linker phosphorylation pathway, also enables Smad3 to induce HSC proliferation [XREF_BIBR, XREF_BIBR].	8	19	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Smad3	Smad3	Smad3	8	9	18	19
P38 MAPK and c-Jun N-terminal kinase ( JNK ) can activate Smad 3 [ XREF_BIBR , XREF_BIBR ] and p38 MAPK also strengthens interaction between Smad3 and coactivators [ XREF_BIBR ] .	P38 MAPK and c-Jun N-terminal kinase (JNK) can activate Smad 3 [XREF_BIBR, XREF_BIBR] and p38 MAPK also strengthens interaction between Smad3 and coactivators [XREF_BIBR].	1	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	Smad 3	Smad 3	Smad 3	7	8	11	13
This finding supports the postulate that JNK mediated Smad3 linker region phosphorylation is an important mechanism by which reduced eNOS expression promotes renal fibrosis .	This finding supports the postulate that JNK mediated Smad3 linker region phosphorylation is an important mechanism by which reduced eNOS expression promotes renal fibrosis.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	Smad3	Smad3	Smad3	6	7	8	9
XREF_BIBR Further it was shown that activation of Smad3 by JNK is necessary to mediate TGFbeta -induced EMT .	XREF_BIBR Further it was shown that activation of Smad3 by JNK is necessary to mediate TGFbeta -induced EMT.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JNK	JNK	JNK	Smad3	Smad3	Smad3	10	11	8	9
In addition , this pathway can be deregulated in the context of active RAS signaling , through JNK mediated SMAD3 signaling [ XREF_BIBR ] .	In addition, this pathway can be deregulated in the context of active RAS signaling, through JNK mediated SMAD3 signaling [XREF_BIBR].	7	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK	JNK	JNK	SMAD3	SMAD3	SMAD3	17	18	19	20
However , JNK can also activate the M2 phenotype transcription factor SMAD3 [ XREF_BIBR ] .	However, JNK can also activate the M2 phenotype transcription factor SMAD3 [XREF_BIBR].	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	SMAD3	SMAD3	SMAD3	2	3	11	12
In contrast , JAK3 increases PLD2 lipase activity via Tyr415 phosphorylation .	In contrast, JAK3 increases PLD2 lipase activity via Tyr415 phosphorylation.	3	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK3	JAK3	JAK3	PLD2	PLD2	PLD2	3	4	5	6
XREF_FIG indicate that : ( a ) JAK3 ( as well as EGFR ) overexpression augments endogenous PLD2 activity in MDA-MB-231 cells ; ( b ) PLD activity is maximal when PLD2 is co-expressed along with JAK3 or with EGFR , which are negated by dsRNA silencing ; and ( c ) apigenin does not inhibit PLD2 activity directly but it negates the increasing effect it receives from JAK3 ( but slightly less form EGFR ) .	XREF_FIG indicate that : (a) JAK3 (as well as EGFR) overexpression augments endogenous PLD2 activity in MDA-MB-231 cells; (b) PLD activity is maximal when PLD2 is co-expressed along with JAK3 or with EGFR, which are negated by dsRNA silencing; and (c) apigenin does not inhibit PLD2 activity directly but it negates the increasing effect it receives from JAK3 (but slightly less form EGFR).	1	18	augments	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	JAK3	JAK3	JAK3	PLD2	PLD2	PLD2	7	8	17	18
However , when we tested a new cell line , the highly invasive MDA-MB-231 human breast cancer cell line , we unexpectedly found that JAK3 did not activate PLD2 as it had for the other cancer cells .	However, when we tested a new cell line, the highly invasive MDA-MB-231 human breast cancer cell line, we unexpectedly found that JAK3 did not activate PLD2 as it had for the other cancer cells.	24	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK3	JAK3	JAK3	PLD2	PLD2	PLD2	24	25	28	29
JAK3 activates PLD2 to a greater extent in highly invasive MTLn3 cells than in MCF-7 cells .	JAK3 activates PLD2 to a greater extent in highly invasive MTLn3 cells than in MCF-7 cells.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK3	JAK3	JAK3	PLD2	PLD2	PLD2	0	1	2	3
Whereas JAK3 and Fes marginally activate PLD2 in non transformed cells , these kinases greatly enhance ( > 200 % ) PLD activity following protein protein interaction through the SH2 domain and the Tyr 415 residue of PLD2 .	Whereas JAK3 and Fes marginally activate PLD2 in non transformed cells, these kinases greatly enhance (> 200%) PLD activity following protein protein interaction through the SH2 domain and the Tyr 415 residue of PLD2.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK3	JAK3	JAK3	PLD2	PLD2	PLD2	1	2	6	7
We confirm that ruxolitinib or TG101348 suppresses JAK2 activation of STAT4 by IL12p70 .	We confirm that ruxolitinib or TG101348 suppresses JAK2 activation of STAT4 by IL12p70.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT4	STAT4	STAT4	7	8	10	11
To exclude a generalized hypo-responsiveness of Rap1b -/- NK cells , we stimulated the NK cells with IL-12 and IL-18 that initiate the Tyk2 and JAK2 mediated Stat4 pathway .	To exclude a generalized hypo-responsiveness of Rap1b -/- NK cells, we stimulated the NK cells with IL-12 and IL-18 that initiate the Tyk2 and JAK2 mediated Stat4 pathway.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	Stat4	Stat4	Stat4	25	26	27	28
IL-12 signaling leads to activation of STAT4 by JAK2 and Tyk2 XREF_BIBR , XREF_BIBR .	IL-12 signaling leads to activation of STAT4 by JAK2 and Tyk2 XREF_BIBR, XREF_BIBR.	4	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT4	STAT4	STAT4	8	9	6	7
IL-12 signaling leads to activation of STAT4 by Jak kinase Jak2 and Tyk2 .	IL-12 signaling leads to activation of STAT4 by Jak kinase Jak2 and Tyk2.	2	12	leads	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	STAT4	STAT4	STAT4	10	11	6	7
The signalling through the IL12 and IL23 receptor also share intracellular mechanisms , where both receptors bind the Jak2 kinase , which in turn activates the STAT4 transcription factor .	The signalling through the IL12 and IL23 receptor also share intracellular mechanisms, where both receptors bind the Jak2 kinase, which in turn activates the STAT4 transcription factor.	18	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	STAT4	STAT4	STAT4	18	19	26	27
The first step is that IL-12 activates the receptor associated kinases Jak2 and Tyk2 , which subsequently activate the transcription factor Stat4 .	The first step is that IL-12 activates the receptor associated kinases Jak2 and Tyk2, which subsequently activate the transcription factor Stat4.	9	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat4	Stat4	Stat4	11	12	21	22
SCF induced activation of JAK2 in human MCs results in STAT5 and STAT6 activation .	SCF induced activation of JAK2 in human MCs results in STAT5 and STAT6 activation.	0	14	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	JAK2	SCF induced activation of JAK2	jak2	STAT6	STAT6	stat6	4	5	12	13
XREF_BIBR , XREF_BIBR - XREF_BIBR Specifically , SCF induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6 .	XREF_BIBR, XREF_BIBR - XREF_BIBR Specifically, SCF induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6.	7	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	SCF induced activation of JAK2	jak2	STAT6	STAT6	stat6	11	12	23	24
Among such factors , we paid special attention to MEF-2A and STAT6 factors , which are known to be activated by p38alpha [ XREF_BIBR ] and Jak2 [ XREF_BIBR ] , respectively .	Among such factors, we paid special attention to MEF-2A and STAT6 factors, which are known to be activated by p38alpha [XREF_BIBR] and Jak2 [XREF_BIBR], respectively.	9	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	STAT6	STAT6	STAT6	26	27	11	12
Inhibition of JAK2 and subsequent reduction of pSTAT6 resulted in reduction of cell viability also in all PMBL cell lines by about 35 % ( taken the mean between three cell lines ) .	Inhibition of JAK2 and subsequent reduction of pSTAT6 resulted in reduction of cell viability also in all PMBL cell lines by about 35% (taken the mean between three cell lines).	2	8	reduction	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	pSTAT6	pSTAT6	pSTAT6	2	3	7	8
In normal cells , JAK activation occurs in a sequential manner : JAK3 activates JAK1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , and the presence of both molecules is necessary for the correct activation of the IL-2 signalling pathway .	In normal cells, JAK activation occurs in a sequential manner : JAK3 activates JAK1 [XREF_BIBR, XREF_BIBR, XREF_BIBR], and the presence of both molecules is necessary for the correct activation of the IL-2 signalling pathway.	12	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK3	JAK3	JAK3	JAK1	JAK1	JAK1	12	13	14	15
In the baculovirus coexpression system , Raf-1 was activated by JAK2 in the presence of p21ras .	In the baculovirus coexpression system, Raf-1 was activated by JAK2 in the presence of p21ras.	6	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	Raf-1	Raf-1	Raf-1	10	11	6	7
When Lyn is inhibited , Jak2 induces Raf-1 activation .	When Lyn is inhibited, Jak2 induces Raf-1 activation.	5	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Raf-1	Raf-1	Raf-1	5	6	7	8
Interestingly , JNK inhibition fully blocked both TDP-43 and hnRNP K SG accumulation .	Interestingly, JNK inhibition fully blocked both TDP-43 and hnRNP K SG accumulation.	2	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	hnRNP K	hnRNP K	hnRNP K	2	3	9	11
Further support for an hnRNP-TDP-43 association was found in our model where we showed that JNK inhibition blocked localization of both TDP-43 and hnRNP K to SGs .	Further support for an hnRNP-TDP-43 association was found in our model where we showed that JNK inhibition blocked localization of both TDP-43 and hnRNP K to SGs.	15	25	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	hnRNP K	hnRNP K	hnRNP K	15	16	23	25
JNK inhibition blocks association of hnRNP K and TDP-43 with SGs .	JNK inhibition blocks association of hnRNP K and TDP-43 with SGs.	0	7	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	hnRNP K	hnRNP K	hnRNP K	0	1	5	7
It has also been demonstrated that JNK modulates hnRNP K accumulation through phosphorylation of the protein XREF_BIBR .	It has also been demonstrated that JNK modulates hnRNP K accumulation through phosphorylation of the protein XREF_BIBR.	6	10	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	hnRNP K	hnRNP K	hnRNP K	6	7	8	10
Both JNK inhibition and hnRNP K knockdown inhibited axon outgrowth and translation of hnRNP K regulated cytoskeletal RNAs ( tau and neurofilament medium ) , effects that were alleviated by expressing phosphomimetic , but not phosphodeficient , forms of hnRNP K. Immunohistochemical and biochemical analyses indicated that JNK phosphorylation of hnRNP K occurred within the cytoplasm and was necessary for the translational initiation of hnRNP K targeted RNAs but not for hnRNP K intracellular localization or RNA binding .	Both JNK inhibition and hnRNP K knockdown inhibited axon outgrowth and translation of hnRNP K regulated cytoskeletal RNAs (tau and neurofilament medium), effects that were alleviated by expressing phosphomimetic, but not phosphodeficient, forms of hnRNP K. Immunohistochemical and biochemical analyses indicated that JNK phosphorylation of hnRNP K occurred within the cytoplasm and was necessary for the translational initiation of hnRNP K targeted RNAs but not for hnRNP K intracellular localization or RNA binding.	1	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	hnRNP K	hnRNP K	hnRNP K	1	2	13	15
Indeed , SIRT1 deacetylates MyoD and P/CAF , an acetyltrans-ferase that activates MyoD .	Indeed, SIRT1 deacetylates MyoD and P/CAF, an acetyltrans-ferase that activates MyoD.	2	13	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	P/CAF	SIRT1 deacetylates MyoD and P/CAF	p/caf	MyoD	MyoD	myod	6	7	12	13
This triggers the JAK-2 and STAT , PI 3 K/Rac-1/NADPH oxidase/H 2 O 2 pathways , enhancing the retention of SHP-1 and SHP-2 and abrogating their inhibitory effects XREF_BIBR .	This triggers the JAK-2 and STAT, PI 3 K/Rac-1/NADPH oxidase/H 2 O 2 pathways, enhancing the retention of SHP-1 and SHP-2 and abrogating their inhibitory effects XREF_BIBR.	2	24	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK-2	JAK-2	JAK-2	SHP-2	SHP-2	SHP-2	3	4	22	23
However , JAK2 can also activate Erk1/2 and PI3K and Akt independently of SHP2 XREF_BIBR .	However, JAK2 can also activate Erk1/2 and PI3K and Akt independently of SHP2 XREF_BIBR.	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	SHP2	SHP2	SHP2	2	3	13	14
However , it has been reported that JAK2 can also activate Erk1/2 and PI3K and Akt independently of SHP2 XREF_BIBR .	However, it has been reported that JAK2 can also activate Erk1/2 and PI3K and Akt independently of SHP2 XREF_BIBR.	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	SHP2	SHP2	SHP2	7	8	18	19
In PC , Stat5a/b is activated by the upstream kinase Jak2 and by other tyrosine kinases such as Src and growth factor receptors .	In PC, Stat5a/b is activated by the upstream kinase Jak2 and by other tyrosine kinases such as Src and growth factor receptors.	3	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Jak2	Jak2	Jak2	Stat5a/b	Stat5a/b	Stat5a/b	10	11	3	4
In normal T cells , LTalpha is seemingly induced by IL-2 through a JAK3 mediated activation of STAT5a [ XREF_BIBR ] , whereas our findings suggest that both STAT5a and STAT5b are involved in malignant LTalpha production .	In normal T cells, LTalpha is seemingly induced by IL-2 through a JAK3 mediated activation of STAT5a [XREF_BIBR], whereas our findings suggest that both STAT5a and STAT5b are involved in malignant LTalpha production.	13	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK3	JAK3	JAK3	STAT5a	STAT5a	STAT5a	13	14	17	18
Together these observations suggest that some polycomb repressed sites rely more specifically on KDM2B mediated RING1B occupancy for normal H2AK119ub1 and polycomb mediated gene repression .	Together these observations suggest that some polycomb repressed sites rely more specifically on KDM2B mediated RING1B occupancy for normal H2AK119ub1 and polycomb mediated gene repression.	9	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	KDM2B	KDM2B	KDM2B	RING1B	RING1B	RING1B	13	14	15	16
KDM2B targets RING1B to CGIs .	KDM2B targets RING1B to CGIs.	0	4	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	KDM2B	KDM2B	KDM2B	RING1B	RING1B	RING1B	0	1	2	3
Transfection of c-Jun and two activators of c-Jun ( LiCl and sodium valproate ) increased MTHFR expression , whereas a reported inhibitor of c-Jun ( SP600125 ) and a dominant negative derivative of c-Jun N-terminal kinase-1 reduced MTHFR activation .	Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression, whereas a reported inhibitor of c-Jun (SP600125) and a dominant negative derivative of c-Jun N-terminal kinase-1 reduced MTHFR activation.	21	38	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Jun	c-Jun	c-Jun	MTHFR	MTHFR	MTHFR	23	24	37	38
Finally , p/CAF enhanced the activity of the Smad3 143-248 mutant again in agreement with the physical interaction data of XREF_FIG .	Finally, p/CAF enhanced the activity of the Smad3 143-248 mutant again in agreement with the physical interaction data of XREF_FIG.	2	9	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p/CAF	p/CAF	p/CAF	Smad3	Smad3	Smad3	2	3	8	9
It appears that SCF exposure over time can induce epigenetic downregulation of KIT , suggesting the existence of a fine tuned balance between different consequences of KIT activation .	It appears that SCF exposure over time can induce epigenetic downregulation of KIT, suggesting the existence of a fine tuned balance between different consequences of KIT activation.	3	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	3	4	12	13
In Ba/F3-Kit , SCF induced Kit activation resulted in a rapid phospholipase Cgamma ( PLCgamma ) tyrosine phosphorylation followed by diacylglycerol release and protein kinase C ( PKC ) stimulation .	In Ba/F3-Kit, SCF induced Kit activation resulted in a rapid phospholipase Cgamma (PLCgamma) tyrosine phosphorylation followed by diacylglycerol release and protein kinase C (PKC) stimulation.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	3	4	5	6
We found two phosphorylation sites in KIT , both known to be phosphorylated when KIT is activated by SCF [ XREF_BIBR ] : KIT 703 and KIT 747 .	We found two phosphorylation sites in KIT, both known to be phosphorylated when KIT is activated by SCF [XREF_BIBR] : KIT 703 and KIT 747.	14	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	18	19	14	15
Activation of KIT by SCF has been shown to enhance mast cell degranulation induced by IgE crosslinking .	Activation of KIT by SCF has been shown to enhance mast cell degranulation induced by IgE crosslinking.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	4	5	2	3
Exogenous soluble SCF modulated KIT receptor mRNA and protein expression , stimulated growth of MCC-1 cells , upregulated endogenous activation of KIT , AKT , and of extracellular signal regulated kinase ( ERK ) 1/2 signaling pathway .	Exogenous soluble SCF modulated KIT receptor mRNA and protein expression, stimulated growth of MCC-1 cells, upregulated endogenous activation of KIT, AKT, and of extracellular signal regulated kinase (ERK) 1/2 signaling pathway.	0	6	modulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	2	3	4	5
We propose a negative feedback loop controlling the SCF-KIT signaling pathway , in which SCF activates KIT .	We propose a negative feedback loop controlling the SCF-KIT signaling pathway, in which SCF activates KIT.	14	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	14	15	16	17
SCF stimulation of Kit is essential for ICC maintenance XREF_BIBR , XREF_BIBR , and Ca 2+ activated Cl - channels ( Ano1 ) expressed on ICC were identified as the key conductance responsible for the pacemaker activity 18 .	SCF stimulation of Kit is essential for ICC maintenance XREF_BIBR, XREF_BIBR, and Ca 2+ activated Cl - channels (Ano1) expressed on ICC were identified as the key conductance responsible for the pacemaker activity 18.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	0	1	3	4
We also observed that intravitreal injection of SCF significantly increased retinal vascular leakage of EB in the WT mice , whereas SCF failed to induce retinal vascular hyperpermeability in the cKit mutant ( Kit w-sh and w-sh ) mice that exhibited a low amount of cKit expressing endothelial cells due to a mutation in the 5 ' regulatory element of the cKit encoding gene ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	We also observed that intravitreal injection of SCF significantly increased retinal vascular leakage of EB in the WT mice, whereas SCF failed to induce retinal vascular hyperpermeability in the cKit mutant (Kit w-sh and w-sh) mice that exhibited a low amount of cKit expressing endothelial cells due to a mutation in the 5 ' regulatory element of the cKit encoding gene (XREF_FIG) [XREF_BIBR, XREF_BIBR].	21	36	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	21	22	33	34
Thus SCF may activate the wild-type species of KIT in GISTs without mutations , and may also modulate the fraction of activated KIT in GISTs with heterozygous mutations .	Thus SCF may activate the wild-type species of KIT in GISTs without mutations, and may also modulate the fraction of activated KIT in GISTs with heterozygous mutations.	1	24	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	1	2	22	23
These data indicate that SCF stimulation of Kit leads to activation of STAT-5 DNA binding with kinetics distinct from Epo mediated stimulation .	These data indicate that SCF stimulation of Kit leads to activation of STAT-5 DNA binding with kinetics distinct from Epo mediated stimulation.	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	4	5	7	8
Overall , our results indicated that SCF induced KIT activation is a novel essential pathway for the proliferation of GISTs .	Overall, our results indicated that SCF induced KIT activation is a novel essential pathway for the proliferation of GISTs.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	6	7	8	9
Glutathione S-transferase-pulldown ( GST-pulldown ) assays showed that the C-terminal or N-terminal SH2 domains of p85 ( SH2c or SH2n ) were associated with SCF stimulated Kit ( wt ) and Kit ( D814Y ) ( XREF_FIG ) .	Glutathione S-transferase-pulldown (GST-pulldown) assays showed that the C-terminal or N-terminal SH2 domains of p85 (SH2c or SH2n) were associated with SCF stimulated Kit (wt) and Kit (D814Y) (XREF_FIG).	22	31	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	24	25	26	27
KIT belongs to the type III subfamily of tyrosine kinases and gets activated by its ligand stem cell factor ( SCF ) , which is expressed as a membrane bound or soluble form XREF_BIBR XREF_BIBR XREF_BIBR .	KIT belongs to the type III subfamily of tyrosine kinases and gets activated by its ligand stem cell factor (SCF), which is expressed as a membrane bound or soluble form XREF_BIBR XREF_BIBR XREF_BIBR.	0	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	stem cell factor	stem cell factor (SCF), which is expressed	stem cell factor	KIT	KIT	kit	16	19	0	1
The development of MCp and their tissue maturation is dependent on the stimulation of Kit by stem cell factor , which is a lineage specific requirement .	The development of MCp and their tissue maturation is dependent on the stimulation of Kit by stem cell factor, which is a lineage specific requirement.	12	19	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	Kit	Kit	Kit	16	19	14	15
The Kit signaling pathway , activated by the Kit-ligand stem cell factor , was the first pathway associated with the control of ICC survival and proliferation .	The Kit signaling pathway, activated by the Kit-ligand stem cell factor, was the first pathway associated with the control of ICC survival and proliferation.	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	Kit	Kit	Kit	9	12	1	2
KITLG initiates multiple cellular responses by activating its receptor KIT .	KITLG initiates multiple cellular responses by activating its receptor KIT.	0	10	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KITLG	KITLG	KITLG	KIT	KIT	KIT	0	1	9	10
Similarly to the anti-D5 antibodies of this study , the anti-KIT D4 antibody inhibited SCF induced WT KIT activation .	Similarly to the anti-D5 antibodies of this study, the anti-KIT D4 antibody inhibited SCF induced WT KIT activation.	14	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	14	15	17	18
Importantly , human myeloid leukaemia cells express the Kit receptor and their proliferation is upregulated by SCF XREF_BIBR - XREF_BIBR , although mast cells are the only terminally differentiated hematopoietic cells that continue to express Kit XREF_BIBR , XREF_BIBR , XREF_BIBR .	Importantly, human myeloid leukaemia cells express the Kit receptor and their proliferation is upregulated by SCF XREF_BIBR - XREF_BIBR, although mast cells are the only terminally differentiated hematopoietic cells that continue to express Kit XREF_BIBR, XREF_BIBR, XREF_BIBR.	8	17	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	16	17	8	9
Physiologically , KIT is activated by its ligand stem cell factor ( SCF ) and regulates growth and differentiation of interstitial cells of Cajal ( ICC ) , the potential progenitor cell of GIST .	Physiologically, KIT is activated by its ligand stem cell factor (SCF) and regulates growth and differentiation of interstitial cells of Cajal (ICC), the potential progenitor cell of GIST.	2	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	KIT	KIT	KIT	8	11	2	3
In this respect , SCF mediated activation of KIT potently induces mast cell chemotaxis and adhesion to extracellular matrix , supporting a role for SCF in mast cell homing to their tissues of residence in vivo .	In this respect, SCF mediated activation of KIT potently induces mast cell chemotaxis and adhesion to extracellular matrix, supporting a role for SCF in mast cell homing to their tissues of residence in vivo.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	4	5	8	9
Hypoxia upregulates HIF-1alpha and VEGF XREF_BIBR , and activation of KIT by SCF signaling may also result in expression of HIF-1alpha XREF_BIBR .	Hypoxia upregulates HIF-1alpha and VEGF XREF_BIBR, and activation of KIT by SCF signaling may also result in expression of HIF-1alpha XREF_BIBR.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	12	13	10	11
It has been proposed that SCF induced Kit dimerization proceeds via a conformational change that exposes a key receptor dimerization site in the fourth of the five immunoglobulin ( Ig )-like domains in Kit .	It has been proposed that SCF induced Kit dimerization proceeds via a conformational change that exposes a key receptor dimerization site in the fourth of the five immunoglobulin (Ig)-like domains in Kit.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	5	6	7	8
After SCF induced KIT dimerization and activation of its intrinsic kinase activity , phosphorylated tyrosine residues recruit SH2-domain containing proteins , including cytosolic adaptors SHC and GRB2 , SFKs ( LYN and FYN ) , PLCgamma , and PI3K .	After SCF induced KIT dimerization and activation of its intrinsic kinase activity, phosphorylated tyrosine residues recruit SH2-domain containing proteins, including cytosolic adaptors SHC and GRB2, SFKs (LYN and FYN), PLCgamma, and PI3K.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	1	2	3	4
There was a robust baseline level of pKIT Y721 , and SCF further increased pKIT Y721 and pAKT , whereas FGF10 increased pERK1/2 ( XREF_FIG G ) .	There was a robust baseline level of pKIT Y721, and SCF further increased pKIT Y721 and pAKT, whereas FGF10 increased pERK1/2 (XREF_FIG G).	11	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	pKIT	pKIT	pKIT	11	12	14	15
Binding of SCF induces KIT dimerization , inherent tyrosine kinase activation , and resulting activation of downstream signaling pathways , including the PI3-kinase , MAPK , and Ras and ERK pathways [ XREF_BIBR ] .	Binding of SCF induces KIT dimerization, inherent tyrosine kinase activation, and resulting activation of downstream signaling pathways, including the PI3-kinase, MAPK, and Ras and ERK pathways [XREF_BIBR].	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	2	3	4	5
We first compared the effects of FcepsilonRI aggregation , induced by the addition of streptavidin ( SA ) to biotinylated human ( hu ) IgE sensitized cells , and KIT activation , induced by the addition of SCF , on huMC degranulation and chemotaxis .	We first compared the effects of FcepsilonRI aggregation, induced by the addition of streptavidin (SA) to biotinylated human (hu) IgE sensitized cells, and KIT activation, induced by the addition of SCF, on huMC degranulation and chemotaxis.	29	38	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	37	38	29	30
These data suggest that SCF induced KIT activation is an independent mechanism in GISTs , regardless of KIT autophosphorylation .	These data suggest that SCF induced KIT activation is an independent mechanism in GISTs, regardless of KIT autophosphorylation.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	4	5	6	7
The first three immunoglobulin ( Ig )-like loops of the extracellular domain form the binding site for stem cell factor ( SCF ) or KIT ligand , while the fourth and fifth loops play a role in stabilizing the SCF induced KIT dimer .	The first three immunoglobulin (Ig)-like loops of the extracellular domain form the binding site for stem cell factor (SCF) or KIT ligand, while the fourth and fifth loops play a role in stabilizing the SCF induced KIT dimer.	38	42	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	39	40	41	42
Both STI571 and AG1296 inhibited SCF dependent activation of KIT ( WT ) and SCF independent activation of KIT ( G559 ) more efficiently , whereas SCF independent activation of KIT ( V814 ) was scarcely affected .	Both STI571 and AG1296 inhibited SCF dependent activation of KIT (WT) and SCF independent activation of KIT (G559) more efficiently, whereas SCF independent activation of KIT (V814) was scarcely affected.	26	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	26	27	30	31
SCF induced Kit signaling is implicated in several physiological processes , including the development and differentiation of ICCs XREF_BIBR , XREF_BIBR , hematopoietic stem cells XREF_BIBR , and mast cells XREF_BIBR , XREF_BIBR .	SCF induced Kit signaling is implicated in several physiological processes, including the development and differentiation of ICCs XREF_BIBR, XREF_BIBR, hematopoietic stem cells XREF_BIBR, and mast cells XREF_BIBR, XREF_BIBR.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	0	1	2	3
Furthermore , SCF enhanced the invasive ability of KIT positive cell lines .	Furthermore, SCF enhanced the invasive ability of KIT positive cell lines.	2	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	2	3	8	9
Since in vivo development of MC is also considered to depend primarily on SCF activation of KIT in MC progenitors , this observation may have clinical implications and may explain why MC decrease in number during treatment with imatinib .	Since in vivo development of MC is also considered to depend primarily on SCF activation of KIT in MC progenitors, this observation may have clinical implications and may explain why MC decrease in number during treatment with imatinib.	13	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	13	14	16	17
SCF activates its receptor KIT by inducing KIT dimerization , which leads to conformational changes in the membrane proximal immunoglobulin like domains [ XREF_BIBR ) .	SCF activates its receptor KIT by inducing KIT dimerization, which leads to conformational changes in the membrane proximal immunoglobulin like domains [XREF_BIBR).	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	0	1	4	5
In contrast to degranulation and the slight chemotactic response observed in mouse bone marrow derived MCs ( BMMCs ) [ XREF_BIBR ] , such FcepsilonRI aggregation failed to evoke huMC chemotaxis whereas SCF induced KIT activation markedly promoted this response ( XREF_FIG ) .	In contrast to degranulation and the slight chemotactic response observed in mouse bone marrow derived MCs (BMMCs) [XREF_BIBR], such FcepsilonRI aggregation failed to evoke huMC chemotaxis whereas SCF induced KIT activation markedly promoted this response (XREF_FIG).	32	35	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	32	33	34	35
Emerging data have demonstrated the crucial role of SCF mediated KIT signaling in mast cell development XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Emerging data have demonstrated the crucial role of SCF mediated KIT signaling in mast cell development XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	8	9	10	11
Activation of Kit by SCF contributes to regulation of the self-renewal , survival , and differentiation of HSCs as well as maturation , survival , proliferation , migration , and functional responses of MCs .	Activation of Kit by SCF contributes to regulation of the self-renewal, survival, and differentiation of HSCs as well as maturation, survival, proliferation, migration, and functional responses of MCs.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	4	5	2	3
These results suggest that glyceollins successfully suppressed SCF induced c-kit activation and downstream kinase signaling pathways involved in the function of melanocytes and melanin synthesis .	These results suggest that glyceollins successfully suppressed SCF induced c-kit activation and downstream kinase signaling pathways involved in the function of melanocytes and melanin synthesis.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	c-kit	c-kit	c-kit	7	8	9	10
For example , mast cell homeostasis , at least in the human , is dependent on the continued activation of KIT by SCF .	For example, mast cell homeostasis, at least in the human, is dependent on the continued activation of KIT by SCF.	14	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	22	23	20	21
Effect of imatinib treatment on SCF expression and SCF stimulated KIT activation in GIST cells .	Effect of imatinib treatment on SCF expression and SCF stimulated KIT activation in GIST cells.	3	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	8	9	10	11
The results suggest a correlation between dimerization affinity and biological activity , consistent with a model in which SCF dimerization mediates dimerization of its receptor , Kit , and subsequent signal transduction .	The results suggest a correlation between dimerization affinity and biological activity, consistent with a model in which SCF dimerization mediates dimerization of its receptor, Kit, and subsequent signal transduction.	18	27	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	18	19	26	27
The activity of STA-9090 against BMCMCs was not unexpected , as our prior studies demonstrated that these cells are dependent on SCF induced Kit signaling for proliferation and survival in vitro [ XREF_BIBR ] .	The activity of STA-9090 against BMCMCs was not unexpected, as our prior studies demonstrated that these cells are dependent on SCF induced Kit signaling for proliferation and survival in vitro [XREF_BIBR].	19	24	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	21	22	23	24
These responses follow antigen mediated aggregation of immunoglobulin E ( IgE )-occupied high affinity receptors for IgE ( FcepsilonRI ) on the mast cell surface , a response which can be further enhanced following stem cell factor induced ligation of the mast cell growth factor receptor KIT .	These responses follow antigen mediated aggregation of immunoglobulin E (IgE)-occupied high affinity receptors for IgE (FcepsilonRI) on the mast cell surface, a response which can be further enhanced following stem cell factor induced ligation of the mast cell growth factor receptor KIT.	34	47	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	KIT	KIT	KIT	34	37	46	47
Indeed , our data in the heterozygous KIT mutant GIST-T1 cells indicate that autocrine and paracrine KITLG mediated KIT signaling may account for ~ 40 % of baseline proliferation even in cells with a secondary , imatinib resistant mutation and can be inhibited with antibodies or RNAi targeting KITLG .	Indeed, our data in the heterozygous KIT mutant GIST-T1 cells indicate that autocrine and paracrine KITLG mediated KIT signaling may account for ~ 40% of baseline proliferation even in cells with a secondary, imatinib resistant mutation and can be inhibited with antibodies or RNAi targeting KITLG.	13	42	mediated	Positive_early_activation	Positive_activation	Positive_activation	KITLG	KITLG	KITLG	KIT	KIT	KIT	16	17	18	19
Activation of KIT by SCF induces KIT dimerization and initiation of intrinsic tyrosine kinase activity , resulting in autophosphorylation of tyrosine residues that act as docking sites for signaling proteins containing either Src homology 2 ( SH2 ) or phospho-tyrosine binding ( PTB ) domains .	Activation of KIT by SCF induces KIT dimerization and initiation of intrinsic tyrosine kinase activity, resulting in autophosphorylation of tyrosine residues that act as docking sites for signaling proteins containing either Src homology 2 (SH2) or phospho-tyrosine binding (PTB) domains.	2	7	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	4	5	6	7
As downregulating Exosc8 abrogated SCF induced Kit signaling , we tested whether Exosc8 is required for Kit expression in the erythroblast plasma membrane .	As downregulating Exosc8 abrogated SCF induced Kit signaling, we tested whether Exosc8 is required for Kit expression in the erythroblast plasma membrane.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	4	5	6	7
Similar to its ineffectiveness in wild-type GISTs , imatinib also failed to inhibit SCF induced KIT activation in GISTs with mutant KIT .	Similar to its ineffectiveness in wild-type GISTs, imatinib also failed to inhibit SCF induced KIT activation in GISTs with mutant KIT.	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	13	14	15	16
Based on the crystal structure , SCF homodimer interacts with the D1-D3 region of KIT to induce KIT dimerization .	Based on the crystal structure, SCF homodimer interacts with the D1-D3 region of KIT to induce KIT dimerization.	6	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	6	7	17	18
Interestingly , comparison of the crystal structure of the dimeric D5 of T417I , Delta418 ,419 mutant to the corresponding region in the EM envelope of SCF stimulated KIT dimer shows a very good fit between the model of D5 : D5 dimer and the volume of the EM reconstruction in this region .	Interestingly, comparison of the crystal structure of the dimeric D5 of T417I, Delta418,419 mutant to the corresponding region in the EM envelope of SCF stimulated KIT dimer shows a very good fit between the model of D5 : D5 dimer and the volume of the EM reconstruction in this region.	24	29	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	26	27	28	29
In mast cells , SCF induced KIT activation leads to recruitment of SHP2 to the juxtamembrane domain of KIT via the adaptor protein Gab2 [ XREF_BIBR ] .	In mast cells, SCF induced KIT activation leads to recruitment of SHP2 to the juxtamembrane domain of KIT via the adaptor protein Gab2 [XREF_BIBR].	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	4	5	6	7
Finally , expression of SCF , which stimulates the Kit receptor on HSCs , and which is long known to activate a signaling pathway absolutely required for HSC development , maturation and function , has also been studied by knock-in reporter mice [ XREF_BIBR ] .	Finally, expression of SCF, which stimulates the Kit receptor on HSCs, and which is long known to activate a signaling pathway absolutely required for HSC development, maturation and function, has also been studied by knock-in reporter mice [XREF_BIBR].	2	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	expression of SCF	scf	Kit	Kit	kit	4	5	9	10
In contrast to Kit ( D814Y ) , in R and pt18 cells , SCF stimulation of Kit ( wt ) did not activate STAT5 ( XREF_FIG ) , as previously described XREF_BIBR XREF_BIBR .	In contrast to Kit (D814Y), in R and pt18 cells, SCF stimulation of Kit (wt) did not activate STAT5 (XREF_FIG), as previously described XREF_BIBR XREF_BIBR.	14	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	14	15	17	18
Thus , we propose that serum SCF and SCF secreted from mast cells could contribute to in vivo tumor progression of KIT positive pancreatic cancer .	Thus, we propose that serum SCF and SCF secreted from mast cells could contribute to in vivo tumor progression of KIT positive pancreatic cancer.	5	24	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	6	7	21	22
In KIT positive lines , KIT was activated by stem cell factor ( SCF ) .	In KIT positive lines, KIT was activated by stem cell factor (SCF).	5	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	KIT	KIT	KIT	9	12	5	6
Reportedly , endogenous KITLG co-expression leads to activation of KIT receptors in glioma cell lines and other cancers [ XREF_BIBR - XREF_BIBR ] .	Reportedly, endogenous KITLG co-expression leads to activation of KIT receptors in glioma cell lines and other cancers [XREF_BIBR - XREF_BIBR].	3	10	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	KITLG	KITLG co-expression	kitlg	KIT	KIT	kit	3	4	9	10
KIT expression is significantly higher in AML blasts than in normal bone marrow cells , and one-third of the AML blasts co-express KIT and SCF , thereby suggesting autocrine and paracrine stimulation of KIT by SCF [ XREF_BIBR ] .	KIT expression is significantly higher in AML blasts than in normal bone marrow cells, and one-third of the AML blasts co-express KIT and SCF, thereby suggesting autocrine and paracrine stimulation of KIT by SCF [XREF_BIBR].	31	37	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	35	36	33	34
Under normal conditions , CD117 is activated ( phosphorylated ) by binding of the ligand - stem cell factor .	Under normal conditions, CD117 is activated (phosphorylated) by binding of the ligand - stem cell factor.	4	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	CD117	CD117	CD117	16	19	4	5
Unlike the BCR , KIT possesses inherent catalytic activity which is increased upon SCF induced KIT dimerization .	Unlike the BCR, KIT possesses inherent catalytic activity which is increased upon SCF induced KIT dimerization.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	13	14	15	16
Whereas wildtype KIT is activated by the stem cell factor SCF , PDGFRA can be activated by PDGFA , PDGFB , and PDGFC XREF_BIBR , XREF_BIBR .	Whereas wildtype KIT is activated by the stem cell factor SCF, PDGFRA can be activated by PDGFA, PDGFB, and PDGFC XREF_BIBR, XREF_BIBR.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	10	11	2	3
SCF Induced KIT Trafficking from Early to Late Endosomes Is Impaired in CALM -/- MEFs .	SCF Induced KIT Trafficking from Early to Late Endosomes Is Impaired in CALM -/- MEFs.	0	10	Induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	0	1	2	3
Mast cell growth , development , and survival , are driven by stem cell factor ( SCF )-dependent activation of its receptor KIT .	Mast cell growth, development, and survival, are driven by stem cell factor (SCF)-dependent activation of its receptor KIT.	12	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	KIT	KIT	KIT	12	15	22	23
The binding of KIT ligand promotes KIT dimerization , and activates its intrinsic tyrosine kinase activity , thereby resulting in a transphosphorylation at several critical tyrosine residues and an activation of downstream signal transduction molecules ( Blume-Jensen et al , 1991 ) .	The binding of KIT ligand promotes KIT dimerization, and activates its intrinsic tyrosine kinase activity, thereby resulting in a transphosphorylation at several critical tyrosine residues and an activation of downstream signal transduction molecules (Blume-Jensen et al, 1991).	3	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KIT ligand	KIT ligand	KIT ligand	KIT	KIT	KIT	3	5	6	7
In mature terminally differentiated human mast cells , SCF mediated KIT activation skews this balance to pro survival .	In mature terminally differentiated human mast cells, SCF mediated KIT activation skews this balance to pro survival.	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	8	9	10	11
This observation illustrates that SCF induced KIT activation is an essential process for the expansion of mast cells from their progenitor cells and their subsequent maturation and survival in their resident tissues .	This observation illustrates that SCF induced KIT activation is an essential process for the expansion of mast cells from their progenitor cells and their subsequent maturation and survival in their resident tissues.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	4	5	6	7
Autocrine and paracrine activation of KIT signaling by KITLG plays a role in several tumors and hematologic malignancies [ XREF_BIBR ] .	Autocrine and paracrine activation of KIT signaling by KITLG plays a role in several tumors and hematologic malignancies [XREF_BIBR].	5	9	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	KITLG	KITLG	KITLG	KIT	KIT	KIT	8	9	5	6
Previous studies have demonstrated that activation of Kit by stem cell factor ( SCF ) , its natural ligand , or by gain-of-function point mutation in its intracellular domain , confers significant protection against apoptosis induced by growth factor deprivation or radiation .	Previous studies have demonstrated that activation of Kit by stem cell factor (SCF), its natural ligand, or by gain-of-function point mutation in its intracellular domain, confers significant protection against apoptosis induced by growth factor deprivation or radiation.	5	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	Kit	Kit	Kit	9	12	7	8
Spermatogenesis requires coordinated germ cell proliferation and apoptosis , partly governed by KITLG mediated KIT signaling via the PI3K pathway in mammals .	Spermatogenesis requires coordinated germ cell proliferation and apoptosis, partly governed by KITLG mediated KIT signaling via the PI3K pathway in mammals.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	KITLG	KITLG	KITLG	KIT	KIT	KIT	12	13	14	15
Recently the crystal structure of the KIT ectodomain was characterized , showing that KIT dimerization is driven by bivalent binding of KIT ligand and stabilized by lateral D4-D4 and D5-D5 interactions of two neighboring KIT ectodomains .	Recently the crystal structure of the KIT ectodomain was characterized, showing that KIT dimerization is driven by bivalent binding of KIT ligand and stabilized by lateral D4-D4 and D5-D5 interactions of two neighboring KIT ectodomains.	13	23	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	KIT ligand	KIT ligand	KIT ligand	KIT	KIT	KIT	21	23	13	14
We also found that the introduction of exogenous SCF potently increased KIT kinase activity , stimulated cell proliferation ( P < 0.01 ) and inhibited apoptosis ( P < 0.01 ) induced by serum starvation , while a KIT immunoblocking antibody suppressed proliferation ( P = 0.01 ) and promoted apoptosis ( P < 0.01 ) in cultured GIST cells .	We also found that the introduction of exogenous SCF potently increased KIT kinase activity, stimulated cell proliferation (P < 0.01) and inhibited apoptosis (P < 0.01) induced by serum starvation, while a KIT immunoblocking antibody suppressed proliferation (P = 0.01) and promoted apoptosis (P < 0.01) in cultured GIST cells.	5	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	8	9	11	12
Previous in vitro data have reported that SCF treatment of GIST cells with heterozygous KIT mutation induced a stronger KIT tyrosine phosphorylation , XREF_BIBR while it did not in GIST cells with homozygous KIT mutation .	Previous in vitro data have reported that SCF treatment of GIST cells with heterozygous KIT mutation induced a stronger KIT tyrosine phosphorylation, XREF_BIBR while it did not in GIST cells with homozygous KIT mutation.	7	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	7	8	19	20
To investigate the role of autocrine and paracrine KITLG-KIT signaling in GIST proliferation , we examined the effect of KITLG immunoneutralization and RNAi mediated knock-down in GIST cells expressing or lacking WT KIT .	To investigate the role of autocrine and paracrine KITLG-KIT signaling in GIST proliferation, we examined the effect of KITLG immunoneutralization and RNAi mediated knock-down in GIST cells expressing or lacking WT KIT.	19	33	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KITLG	KITLG	KITLG	KIT	KIT	KIT	19	20	32	33
Stem cell factor ( SCF ) , also produced by mast cells , activates the mast cell Kit receptor ( CD117 ) , vascular endothelial growth factors ( VEGFs ) act on VEGFR-1 and VEGFR-2 , angiopoietin 1 ( Ang1 ) acts on Tie2 receptor , and CXCL8/IL -8 acts on CXCR1 and CXCR2 .	Stem cell factor (SCF), also produced by mast cells, activates the mast cell Kit receptor (CD117), vascular endothelial growth factors (VEGFs) act on VEGFR-1 and VEGFR-2, angiopoietin 1 (Ang1) acts on Tie2 receptor, and CXCL8/IL -8 acts on CXCR1 and CXCR2.	2	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	4	5	17	18
To further dissect the mechanism underlying exosome complex dependent expression of Kit and establishment of SCF induced Kit signaling , we tested whether exosome complex disruption influenced other genes downregulated during erythroid maturation .	To further dissect the mechanism underlying exosome complex dependent expression of Kit and establishment of SCF induced Kit signaling, we tested whether exosome complex disruption influenced other genes downregulated during erythroid maturation.	9	18	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	15	16	17	18
Stem cell factor ( SCF ) was secreted by differentiated tumor cells and supported the clonogenic capacity of KIT ( + ) colonosphere cells .	Stem cell factor (SCF) was secreted by differentiated tumor cells and supported the clonogenic capacity of KIT (+) colonosphere cells.	2	20	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	4	5	18	19
These residues are both known to be phosphorylated when SCF induces KIT activation [ XREF_BIBR ] .	These residues are both known to be phosphorylated when SCF induces KIT activation [XREF_BIBR].	9	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	9	10	11	12
Kit is activated by stem cell factor ( SCF ) , but the source of SCF in the bowel wall is unclear and controversy exists about whether enteric neurons express the SCF required for ICC development .	Kit is activated by stem cell factor (SCF), but the source of SCF in the bowel wall is unclear and controversy exists about whether enteric neurons express the SCF required for ICC development.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	Kit	Kit	Kit	4	7	0	1
KIT stimulation by KITLG also triggers oncogenic signaling pathways resulting in unrestricted proliferation , cell survival , migration and apoptosis [ XREF_BIBR ] .	KIT stimulation by KITLG also triggers oncogenic signaling pathways resulting in unrestricted proliferation, cell survival, migration and apoptosis [XREF_BIBR].	0	4	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	KITLG	KITLG	KITLG	KIT	KIT	KIT	3	4	0	1
Because SCF blocked partially all three anti-KIT D5 antibodies binding to KIT ( XREF_FIG ) , it is likely that these antibodies bind a region involved in D5 homotypic interactions implicated in SCF induced KIT homodimerization and that the binding of SCF renders their epitope inaccessible .	Because SCF blocked partially all three anti-KIT D5 antibodies binding to KIT (XREF_FIG), it is likely that these antibodies bind a region involved in D5 homotypic interactions implicated in SCF induced KIT homodimerization and that the binding of SCF renders their epitope inaccessible.	30	35	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	32	33	34	35
In our previous study , we showed that SCF treatment conferred moderate crizotinib resistance in H3122 cells overexpressing KIT .	In our previous study, we showed that SCF treatment conferred moderate crizotinib resistance in H3122 cells overexpressing KIT.	8	19	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	8	9	18	19
In addition to its role in mast cell development and homeostasis , SCF induced KIT activation may contribute to the homing of mast cells to their sites of residence in vivo , as suggested by its potent chemotactic properties for both mouse and human mast cells and its ability to promote adhesion of mast cells to extracellular matix proteins .	In addition to its role in mast cell development and homeostasis, SCF induced KIT activation may contribute to the homing of mast cells to their sites of residence in vivo, as suggested by its potent chemotactic properties for both mouse and human mast cells and its ability to promote adhesion of mast cells to extracellular matix proteins.	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	12	13	14	15
Furthermore , SCF mediated KIT activation , particularly in conjunction with aggregation of the high affinity IgE receptor ( FcepsilonRI ) , also promotes the generation of multiple cytokines and chemokines .	Furthermore, SCF mediated KIT activation, particularly in conjunction with aggregation of the high affinity IgE receptor (FcepsilonRI), also promotes the generation of multiple cytokines and chemokines.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	2	3	4	5
Because spontaneous , SCF independent dimerization of wild-type KIT ( XREF_FIG and XREF_FIG ) caused neither autophosphorylation nor cytokine independent growth in IC-2 WT cells , N508I mutation probably results in the conformational changes of KIT for activation .	Because spontaneous, SCF independent dimerization of wild-type KIT (XREF_FIG and XREF_FIG) caused neither autophosphorylation nor cytokine independent growth in IC-2 WT cells, N508I mutation probably results in the conformational changes of KIT for activation.	3	37	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	3	4	35	36
Interestingly , autocrine SCF stimulation of Kit receptor seems to be an important step in melanoma genesis in its early phases , but it is down-regulated in later stages XREF_BIBR , XREF_BIBR .	Interestingly, autocrine SCF stimulation of Kit receptor seems to be an important step in melanoma genesis in its early phases, but it is down-regulated in later stages XREF_BIBR, XREF_BIBR.	3	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	3	4	6	7
In addition , SCF activation of KIT is critical for recruiting mast cells to sites of infection or injury , where they release a mix of pro inflammatory substances .	In addition, SCF activation of KIT is critical for recruiting mast cells to sites of infection or injury, where they release a mix of pro inflammatory substances.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	3	4	6	7
This mutation leads to stem cell factor independent activation of KIT and triggers autonomous , uncontrolled growth of neoplastic MC .	This mutation leads to stem cell factor independent activation of KIT and triggers autonomous, uncontrolled growth of neoplastic MC.	1	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	KIT	KIT	KIT	4	7	10	11
Our data , together with those findings , suggest that increased expression of SCF and KIT at the cell surface due to imatinib treatment results in abundant SCF and KIT signaling activation .	Our data, together with those findings, suggest that increased expression of SCF and KIT at the cell surface due to imatinib treatment results in abundant SCF and KIT signaling activation.	11	32	signaling activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	SCF	expression of SCF	scf	KIT	KIT	kit	13	14	29	30
These findings provide direct evidence that activation of KIT signaling by endogenous KITLG contributes to the proliferation of GIST cells expressing WT receptors .	These findings provide direct evidence that activation of KIT signaling by endogenous KITLG contributes to the proliferation of GIST cells expressing WT receptors.	8	13	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	KITLG	KITLG	KITLG	KIT	KIT	KIT	12	13	8	9
Activation of KIT by SCF also triggers activation of the MAPKs , extracellular-signal-regulated kinase 1 and 2 ( ERK1 and ERK2 ) , JNK and p38 .	Activation of KIT by SCF also triggers activation of the MAPKs, extracellular-signal-regulated kinase 1 and 2 (ERK1 and ERK2), JNK and p38.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	4	5	2	3
However , little is known regarding whether stem cell factor ( SCF ) , the KIT ligand , is able to induce the proliferation of GIST cells by activating the wild-type KIT receptor in GISTs .	However, little is known regarding whether stem cell factor (SCF), the KIT ligand, is able to induce the proliferation of GIST cells by activating the wild-type KIT receptor in GISTs.	7	32	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	stem cell factor	stem cell factor	stem cell factor	KIT	KIT	KIT	7	10	31	32
We have recently shown that the extracellular region of the EM 3D reconstruction of intact KIT dimer is very similar to the crystal structure of the extracellular regions of SCF stimulated KIT dimers except for the dimerization interface of D5 contacts .	We have recently shown that the extracellular region of the EM 3D reconstruction of intact KIT dimer is very similar to the crystal structure of the extracellular regions of SCF stimulated KIT dimers except for the dimerization interface of D5 contacts.	27	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	29	30	31	32
SCF ( 100 ng/ml ) was added to human skin mast cells to induce Kit internalization , and after 24 h actinomycin D or cycloheximide was added to inhibit global transcription and translation , respectively .	SCF (100 ng/ml) was added to human skin mast cells to induce Kit internalization, and after 24 h actinomycin D or cycloheximide was added to inhibit global transcription and translation, respectively.	0	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	0	1	14	15
SCF induced KIT dimerization results in KIT autophosphorylation , thereby recruiting critical signaling molecules into the receptor signaling complex where they become phosphorylated , allowing their regulation of downstream processes required for mast cell growth and function .	SCF induced KIT dimerization results in KIT autophosphorylation, thereby recruiting critical signaling molecules into the receptor signaling complex where they become phosphorylated, allowing their regulation of downstream processes required for mast cell growth and function.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	0	1	2	3
Binding of the soluble form of SCF causes KIT activation , internalization , and degradation , whereas binding of the membrane bound form of SCF results in prolonged KIT activation [ XREF_BIBR ] .	Binding of the soluble form of SCF causes KIT activation, internalization, and degradation, whereas binding of the membrane bound form of SCF results in prolonged KIT activation [XREF_BIBR].	4	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	6	7	8	9
SCF induced KIT stimulation is dependent on salt bridge mediated D4 homotypic contacts and dimerization of isolated D4D5 is prevented by compromising salt bridge formation between neighboring D4 species .	SCF induced KIT stimulation is dependent on salt bridge mediated D4 homotypic contacts and dimerization of isolated D4D5 is prevented by compromising salt bridge formation between neighboring D4 species.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	0	1	2	3
Once bound to KIT , SCF causes KIT tyrosine phosphorylation and formation of docking sites for SH2 domain containing molecules , such as LYN and FYN , SFKs that are recruited to phosphorylated Y567 of the KIT .	Once bound to KIT, SCF causes KIT tyrosine phosphorylation and formation of docking sites for SH2 domain containing molecules, such as LYN and FYN, SFKs that are recruited to phosphorylated Y567 of the KIT.	3	8	causes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	5	6	7	8
Development of MCs is crucially dependent on SCF induced Kit dimerization and auto-phosphorylation .	Development of MCs is crucially dependent on SCF induced Kit dimerization and auto-phosphorylation.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	Kit	Kit	Kit	7	8	9	10
Thus , this study has demonstrated that SCF may activate wild-type KIT in GISTs and participate in the activation of heterozygous KIT mutants .	Thus, this study has demonstrated that SCF may activate wild-type KIT in GISTs and participate in the activation of heterozygous KIT mutants.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	7	8	11	12
XREF_BIBR Thus , SCF may activate wild-type KIT in nonmutated GISTs and modulate the fraction of activated KIT in heterozygous GISTs .	XREF_BIBR Thus, SCF may activate wild-type KIT in nonmutated GISTs and modulate the fraction of activated KIT in heterozygous GISTs.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	3	4	7	8
In addition to being essential for melanocyte development , it has recently been reported that the hereto unidentified coupling of MC1R activation to MAPK proceeds via MC1R coupled KIT activation of MAPK [ XREF_BIBR ] .	In addition to being essential for melanocyte development, it has recently been reported that the hereto unidentified coupling of MC1R activation to MAPK proceeds via MC1R coupled KIT activation of MAPK [XREF_BIBR].	28	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	KIT	KIT	KIT	MAPK	MAPK	MAPK	28	29	31	32
Here we suggest that SCF and c-kit activates three different downstream pathways , adenylyl cyclase , p38 MAPK and MEK and ERK MAPK pathways .	Here we suggest that SCF and c-kit activates three different downstream pathways, adenylyl cyclase, p38 MAPK and MEK and ERK MAPK pathways.	4	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-kit	c-kit	c-kit	ERK MAPK	ERK MAPK	ERK MAPK	6	7	21	23
1 KITLG and KIT , which triggers the Ras and MAPK signaling pathway , plays crucial roles in melanin synthesis .	1 KITLG and KIT, which triggers the Ras and MAPK signaling pathway, plays crucial roles in melanin synthesis.	1	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KIT	KIT	KIT	MAPK	MAPK	MAPK	3	4	10	11
KIT is activated by extracellular binding of its ligand , stem cell factor , and leads to KIT dimerization , tyrosine kinase activation , and subsequent activation of downstream signaling pathways : PI3K-AKT , MAPK , and JAK-STAT .	KIT is activated by extracellular binding of its ligand, stem cell factor, and leads to KIT dimerization, tyrosine kinase activation, and subsequent activation of downstream signaling pathways : PI3K-AKT, MAPK, and JAK-STAT.	0	35	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	KIT	KIT	KIT	MAPK	MAPK	MAPK	0	1	34	35
It has been suggested that an autocrine and paracrine activation of KIT receptors in MCC cell lines occurs via stem cell factor ( SCF ) and induces the MAPK pathway and AKT activation .	It has been suggested that an autocrine and paracrine activation of KIT receptors in MCC cell lines occurs via stem cell factor (SCF) and induces the MAPK pathway and AKT activation.	11	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KIT	KIT	KIT	MAPK	MAPK	MAPK	11	12	28	29
MAPK Activation Kit was used to explore MAPK phosphorylation .	MAPK Activation Kit was used to explore MAPK phosphorylation.	0	6	Activation	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Kit	Kit	Kit	MAPK	MAPK	MAPK	2	3	0	1
Interestingly , the Erk1/2 pathway can also be activated by SCF in KIT expressing spermatogonia to stimulate their proliferation .	Interestingly, the Erk1/2 pathway can also be activated by SCF in KIT expressing spermatogonia to stimulate their proliferation.	3	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	KIT	KIT	KIT	Erk1/2	Erk1/2	Erk1/2	12	13	3	4
The MAPK pathway is stimulated by GNAQ via PKC and ( reminiscent of BRAF mutations ) GNAQ mutations and KIT , BRAF , and NRAS mutations appear to be mutually exclusive .	The MAPK pathway is stimulated by GNAQ via PKC and (reminiscent of BRAF mutations) GNAQ mutations and KIT, BRAF, and NRAS mutations appear to be mutually exclusive.	1	21	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	KIT	KIT	KIT	MAPK	MAPK	MAPK	19	20	1	2
Taken together these results suggest that coexpression of SCF and Kit may enhance responsiveness to erbB ligands by enhancing activation of the MAPK and PI3K pathways .	Taken together these results suggest that coexpression of SCF and Kit may enhance responsiveness to erbB ligands by enhancing activation of the MAPK and PI3K pathways.	6	25	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kit	coexpression of SCF and Kit	kit	MAPK	MAPK	mapk	10	11	22	23
Additionally , SFKs and ERK are activated by KIT activation XREF_BIBR .	Additionally, SFKs and ERK are activated by KIT activation XREF_BIBR.	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	KIT	KIT	KIT	ERK	ERK	ERK	8	9	4	5
Although KIT overexpression was associated with retained receptor activity and STAT3 activation , KIT downregulation correlated with decreased STAT3 levels and increased ERK signaling .	Although KIT overexpression was associated with retained receptor activity and STAT3 activation, KIT downregulation correlated with decreased STAT3 levels and increased ERK signaling.	13	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KIT	KIT	KIT	ERK	ERK	ERK	13	14	22	23
Previous studies showed that Kit activates Erk in various cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Previous studies showed that Kit activates Erk in various cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kit	Kit	Kit	Erk	Erk	Erk	4	5	6	7
In GIST , Kit ( mut ) on the Golgi activates the PI3K-Akt pathway , STAT5 and Erk .	In GIST, Kit (mut) on the Golgi activates the PI3K-Akt pathway, STAT5 and Erk.	3	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kit	Kit	Kit	Erk	Erk	Erk	3	4	17	18
Furthermore , KIT and SFK independent activation of ERK would be involved in imatinib resistance when the neoplastic cells are exposed to higher concentrations of imatinib .	Furthermore, KIT and SFK independent activation of ERK would be involved in imatinib resistance when the neoplastic cells are exposed to higher concentrations of imatinib.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	KIT	KIT	KIT	ERK	ERK	ERK	2	3	8	9
Results of our M-COPA treatment assay show that Kit can activate Erk not only on the ER but also on other compartments .	Results of our M-COPA treatment assay show that Kit can activate Erk not only on the ER but also on other compartments.	8	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kit	Kit	Kit	Erk	Erk	Erk	8	9	11	12
172 Although KIT activates Src kinases , PLCgamma 1 , PI3K and the MAPK cascade , XREF_BIBR , XREF_BIBR , XREF_BIBR it does not appear to be able to recruit and activate Syk , phosphorylate LAT 130 or activate PKC 172 at least to the same extent as that produced by the FcepsilonRI .	172 Although KIT activates Src kinases, PLCgamma 1, PI3K and the MAPK cascade, XREF_BIBR, XREF_BIBR, XREF_BIBR it does not appear to be able to recruit and activate Syk, phosphorylate LAT 130 or activate PKC 172 at least to the same extent as that produced by the FcepsilonRI.	2	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KIT	KIT	KIT	MAPK	MAPK	MAPK	2	3	13	14
In the presence of active BCR-ABL1 , KIT activation of AKT ( downstream of PI3K ) and ERK1/2 ( downstream of MEK ) was weak and short lived .	In the presence of active BCR-ABL1, KIT activation of AKT (downstream of PI3K) and ERK1/2 (downstream of MEK) was weak and short lived.	7	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	KIT	KIT	KIT	ERK1/2	ERK1/2	ERK1/2	7	8	17	18
Dual inhibition of ROS1 and KIT was required to maximally inhibit AKT and ERK1/2 at both 24 and 72 hours , suggesting that either oncogene was sufficient to activate these signaling pathways in CUTO2 cells .	Dual inhibition of ROS1 and KIT was required to maximally inhibit AKT and ERK1/2 at both 24 and 72 hours, suggesting that either oncogene was sufficient to activate these signaling pathways in CUTO2 cells.	1	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	KIT	KIT	KIT	ERK1/2	ERK1/2	ERK1/2	5	6	13	14
The activated K-ras activates BRAF as a primary downstream target protein .	The activated K-ras activates BRAF as a primary downstream target protein.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	K-ras	K-ras	K-ras	BRAF	BRAF	BRAF	2	3	4	5
This experiment confirms observations reported by others that KRAS activation of BRAF requires a negatively charged lipid environment , while a neutral lipid such as phosphatidylcholine was unable to support KRAS activation of BRAF [ XREF_BIBR ] ; for further assay development we chose phosphatidylserine ( PS ) .	This experiment confirms observations reported by others that KRAS activation of BRAF requires a negatively charged lipid environment, while a neutral lipid such as phosphatidylcholine was unable to support KRAS activation of BRAF [XREF_BIBR]; for further assay development we chose phosphatidylserine (PS).	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	BRAF	BRAF	BRAF	8	9	11	12
Stimulation of KRAS via GTPase activity activates BRAF .	Stimulation of KRAS via GTPase activity activates BRAF.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	BRAF	BRAF	BRAF	2	3	7	8
Deletion of oncogenic K-Ras failed to reduce the activation state of B-Raf or ERK1/2 , despite the requirement of oncogenic K-Ras for tumorigenesis .	Deletion of oncogenic K-Ras failed to reduce the activation state of B-Raf or ERK1/2, despite the requirement of oncogenic K-Ras for tumorigenesis.	0	13	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	K-Ras	K-Ras	K-Ras	B-Raf	B-Raf	B-Raf	3	4	11	12
RAP1 was also able to enhance KRAS stimulated BRAF kinase activity in an additive manner .	RAP1 was also able to enhance KRAS stimulated BRAF kinase activity in an additive manner.	6	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	BRAF	BRAF	BRAF	6	7	8	9
One explanation for this difference may be the efficiency of Cre mediated recombination of the conditional BRaf CA and KRas LSL alleles , which is not readily measurable in the lung epithelium .	One explanation for this difference may be the efficiency of Cre mediated recombination of the conditional BRaf CA and KRas LSL alleles, which is not readily measurable in the lung epithelium.	11	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRas	KRas	KRas	BRaf	BRaf	BRaf	19	20	16	17
On the other hand , the p. 469G > A and p. 601K > E mutations found in AAH samples are activating , and enhance the ability of BRAF to phosphorylate and activate MEK XREF_BIBR XREF_BIBR , while deactivating D594 mutations result in the hyperactivation of MEK signalling in the presence of activated KRAS XREF_BIBR .	On the other hand, the p. 469G> A and p. 601K> E mutations found in AAH samples are activating, and enhance the ability of BRAF to phosphorylate and activate MEK XREF_BIBR XREF_BIBR, while deactivating D594 mutations result in the hyperactivation of MEK signalling in the presence of activated KRAS XREF_BIBR.	24	54	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	BRAF	BRAF	BRAF	53	54	28	29
XREF_FIG shows that KRAS activation of wildtype BRAF is dependent on the presence of protein prenylation , PS , and the presence of a GTP analogue ( GTPgammaS , which hydrolyzes at a lower rate than GTP ) .	XREF_FIG shows that KRAS activation of wildtype BRAF is dependent on the presence of protein prenylation, PS, and the presence of a GTP analogue (GTPgammaS, which hydrolyzes at a lower rate than GTP).	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	BRAF	BRAF	BRAF	3	4	7	8
K-Ras activates downstream signaling Raf ( B-Raf , Raf-1 , A-Raf ) , ERK , and MEK , which translocate into the cell nucleus , regulate transcription factors , and alter gene expression with the end result of promoting cell growth XREF_BIBR , XREF_BIBR .	K-Ras activates downstream signaling Raf (B-Raf, Raf-1, A-Raf), ERK, and MEK, which translocate into the cell nucleus, regulate transcription factors, and alter gene expression with the end result of promoting cell growth XREF_BIBR, XREF_BIBR.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	K-Ras	K-Ras	K-Ras	B-Raf	B-Raf	B-Raf	0	1	6	7
XREF_BIBR , XREF_BIBR BRAF is activated by KRAS and regulates the mitogen activated protein kinase cascade , including the extracellular signal regulated kinase signaling pathway , which affects cell proliferation , cell-cycle arrest , terminal differentiation , and apoptosis ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR BRAF is activated by KRAS and regulates the mitogen activated protein kinase cascade, including the extracellular signal regulated kinase signaling pathway, which affects cell proliferation, cell-cycle arrest, terminal differentiation, and apoptosis (XREF_FIG).	2	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	BRAF	BRAF	BRAF	7	8	3	4
As KRAS activates both BRAF and PI3K , it would be interesting to determine the role of KRAS in the context of HIF activity and aggressive phenotype in thyroid tumours and thyroid carcinoma cell lines harbouring this mutation .	As KRAS activates both BRAF and PI3K, it would be interesting to determine the role of KRAS in the context of HIF activity and aggressive phenotype in thyroid tumours and thyroid carcinoma cell lines harbouring this mutation.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	BRAF	BRAF	BRAF	1	2	4	5
EGFR mediated signaling involves two main intracellular cascades : on one side KRAS activates BRAF , which in turn triggers the mitogen activated protein kinases .	EGFR mediated signaling involves two main intracellular cascades : on one side KRAS activates BRAF, which in turn triggers the mitogen activated protein kinases.	12	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	BRAF	BRAF	BRAF	12	13	14	15
Of the four core GEMM signatures generated ( Apc , Tp53 , Braf , Kras ) , the Kras signature score produced the highest hazard ratios for OS and SAR in the PETACC-3 dataset , and among the highest hazard ratios for OS , RFS and SAR in the GSE14333 dataset ( XREF_TABLE ) , suggesting that it is most indicative of advanced disease .	Of the four core GEMM signatures generated (Apc, Tp53, Braf, Kras), the Kras signature score produced the highest hazard ratios for OS and SAR in the PETACC-3 dataset, and among the highest hazard ratios for OS, RFS and SAR in the GSE14333 dataset (XREF_TABLE), suggesting that it is most indicative of advanced disease.	6	22	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kras	Kras	Kras	Braf	Braf	Braf	18	19	12	13
As a control to assess inhibition of the KRAS activation of BRAF , we added the RAS-Binding-Domain ( RBD ) of CRAF and showed that this blocked the activation with an IC 50 of 0.013 muM ( XREF_FIG ) .	As a control to assess inhibition of the KRAS activation of BRAF, we added the RAS-Binding-Domain (RBD) of CRAF and showed that this blocked the activation with an IC 50 of 0.013 muM (XREF_FIG).	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	BRAF	BRAF	BRAF	8	9	11	12
Also , significant is the observation that in PCa overexpression of VEGF and VEGR-1 there was an associated overexpression of VEGFR-2 .	Also, significant is the observation that in PCa overexpression of VEGF and VEGR-1 there was an associated overexpression of VEGFR-2.	15	21	was an associated overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	VEGFR-2	overexpression of VEGFR-2	vegfr-2	VEGFR-2	VEGFR-2	vegfr-2	20	21	20	21
Over-expression of RNF121 promoted ubiquitination of VEGFR-2 , inhibited its maturation resulted a significantly reduced VEGFR-2 presence at the cell surface .	Over-expression of RNF121 promoted ubiquitination of VEGFR-2, inhibited its maturation resulted a significantly reduced VEGFR-2 presence at the cell surface.	0	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR-2	Over-expression of RNF121 promoted ubiquitination of VEGFR-2	vegfr-2	VEGFR-2	VEGFR-2	vegfr-2	6	7	15	16
Ethanol dose-dependently increased Flk-1 expression , in the absence of any effect on VEGF-A levels , and activated Flk-1 and downstream Akt .	Ethanol dose-dependently increased Flk-1 expression, in the absence of any effect on VEGF-A levels, and activated Flk-1 and downstream Akt.	0	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Flk-1	Ethanol dose-dependently increased Flk-1 expression	flk-1	Flk-1	Flk-1	flk-1	3	4	18	19
AXT107 reduces VEGF induced phosphorylation of VEGFR2 at low doses and , at higher doses , enhances degradation of VEGFR2 .	AXT107 reduces VEGF induced phosphorylation of VEGFR2 at low doses and, at higher doses, enhances degradation of VEGFR2.	0	20	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFR2	AXT107 reduces VEGF induced phosphorylation of VEGFR2	vegfr2	VEGFR2	VEGFR2	vegfr2	6	7	19	20
we found that autocrine VEGF induced high VEGFR2 expression , promoted phosphorylation of VEGFR2 , and further enhanced internalization of pVEGFR2 in gastric cancer cells .	we found that autocrine VEGF induced high VEGFR2 expression, promoted phosphorylation of VEGFR2, and further enhanced internalization of pVEGFR2 in gastric cancer cells.	4	21	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR2	VEGF induced high VEGFR2 expression	vegfr2	pVEGFR2	pVEGFR2	pvegfr2	7	8	20	21
Ligation of VEGFR-2 triggers strong proangiogenic signals including p38MAPK and ERK , Src and FAK , and Akt and eNOS through VEGFR-2 phosphorylation , which promote angiogenesis and VEGFR-2 internalization .	Ligation of VEGFR-2 triggers strong proangiogenic signals including p38MAPK and ERK, Src and FAK, and Akt and eNOS through VEGFR-2 phosphorylation, which promote angiogenesis and VEGFR-2 internalization.	21	29	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR-2	VEGFR-2 phosphorylation	vegfr-2	VEGFR-2	VEGFR-2	vegfr-2	21	22	28	29
More recently , NRP-1 has been found to be expressed on ECs , and coexpression of NRP-1 and VEGFR-2 on ECs enhances the biological activity of VEGFR-2 in response to the VEGF-165 isoform ( Soker et al , 1998 ; Whitaker et al , 2001 ) .	More recently, NRP-1 has been found to be expressed on ECs, and coexpression of NRP-1 and VEGFR-2 on ECs enhances the biological activity of VEGFR-2 in response to the VEGF-165 isoform (Soker et al, 1998; Whitaker et al, 2001).	14	28	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR-2	coexpression of NRP-1 and VEGFR-2	vegfr-2	VEGFR-2	VEGFR-2	vegfr-2	18	19	26	27
In the example shown in XREF_FIG and XREF_FIG , vascular endothelial growth factor receptor-2 ( VEGFR2 ) overexpressing porcine aortic endothelial ( PAE and KDR ) and VEGFR2 non expressing PAE cells , stained with red and green quantum dots ( cell cytosolic stain ) , respectively , were mixed with peptoid displaying library beads .	In the example shown in XREF_FIG and XREF_FIG, vascular endothelial growth factor receptor-2 (VEGFR2) overexpressing porcine aortic endothelial (PAE and KDR) and VEGFR2 non expressing PAE cells, stained with red and green quantum dots (cell cytosolic stain), respectively, were mixed with peptoid displaying library beads.	2	30	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR2	VEGFR2 non expressing	vegfr2	KDR	KDR	kdr	27	28	24	25
Compared to the vector control , VEGFR2 expression in HUVEC induced autophosphorylaton of VEGFR2-WT .	Compared to the vector control, VEGFR2 expression in HUVEC induced autophosphorylaton of VEGFR2-WT.	6	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR2	VEGFR2 expression	vegfr2	VEGFR2-WT	VEGFR2-WT	vegfr2-wt	6	7	13	14
XREF_BIBR There is a twofold overexpression of VEGF and VEGFR-2 in MTC when compared to normal thyroid tissue .	XREF_BIBR There is a twofold overexpression of VEGF and VEGFR-2 in MTC when compared to normal thyroid tissue.	2	10	is a twofold overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	VEGFR-2	overexpression of VEGF and VEGFR-2	vegfr-2	VEGFR-2	VEGFR-2	vegfr-2	9	10	9	10
Another report by Catena et al demonstrated that recombinant human VEGF 165 b-PP ( produced in Pichia Pastoris ) was able to induce VEGFR2 Y1175 phosphorylation even more than that of VEGF 165 a and recombinant human VEGF 165 b-HS ( produced in Chinese Hamster Ovarian cells ) was able to induce VEGFR2 Y1175 to the same extent as VEGF 165 a in HUVECs .	Another report by Catena et al demonstrated that recombinant human VEGF 165 b-PP (produced in Pichia Pastoris) was able to induce VEGFR2 Y1175 phosphorylation even more than that of VEGF 165 a and recombinant human VEGF 165 b-HS (produced in Chinese Hamster Ovarian cells) was able to induce VEGFR2 Y1175 to the same extent as VEGF 165 a in HUVECs.	10	53	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR2	VEGF 165 b-PP (produced in Pichia Pastoris) was able to induce VEGFR2 Y1175 phosphorylation	vegfr2	VEGFR2	VEGFR2	vegfr2	23	24	52	53
According to our results , undifferentiated ES cells and iPSCs expressed KDR at low levels , while culture condition changed to erythrocyte differentiation media , expression of KDR significantly increased on day 14 in all lines ( XREF_FIG , p < = 0.01 ) .	According to our results, undifferentiated ES cells and iPSCs expressed KDR at low levels, while culture condition changed to erythrocyte differentiation media, expression of KDR significantly increased on day 14 in all lines (XREF_FIG, p < = 0.01).	10	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KDR	expression of KDR	kdr	KDR	KDR	kdr	27	28	11	12
We further discovered that forced expression of Flk1 can rescue that of the Flk1 , but not Etv2 mutant cells .	We further discovered that forced expression of Flk1 can rescue that of the Flk1, but not Etv2 mutant cells.	5	19	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Flk1	expression of Flk1	flk1	Flk1	Flk1	flk1	7	8	13	14
Decursin inhibited VEGF induced phosphorylation of VEGFR-2 , blocking the VEGFR-2 signaling pathway .	Decursin inhibited VEGF induced phosphorylation of VEGFR-2, blocking the VEGFR-2 signaling pathway.	0	12	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFR-2	Decursin inhibited VEGF induced phosphorylation of VEGFR-2	vegfr-2	VEGFR-2	VEGFR-2	vegfr-2	6	7	10	11
In this model , sustained VEGFR2 ubiquitination in the absence of USP8 promotes generation of a novel 120 kDa VEGFR2 proteolytic fragment .	In this model, sustained VEGFR2 ubiquitination in the absence of USP8 promotes generation of a novel 120 kDa VEGFR2 proteolytic fragment.	5	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR2	VEGFR2 ubiquitination	vegfr2	VEGFR2	VEGFR2	vegfr2	5	6	19	20
Furthermore , YKL-40 not only increased the expression of Flk-1 and KDR ( phosphatidylinositol 3-kinase/akt signal ) , VEGF receptor 2 which mediates VEGF angiogenesis [ XREF_BIBR ] , but also activated the tyrosine phosphorylated form of Flk-1 and KDR , possibly leading to a synergistic effect on angiogenic signaling activation .	Furthermore, YKL-40 not only increased the expression of Flk-1 and KDR (phosphatidylinositol 3-kinase/akt signal), VEGF receptor 2 which mediates VEGF angiogenesis [XREF_BIBR], but also activated the tyrosine phosphorylated form of Flk-1 and KDR, possibly leading to a synergistic effect on angiogenic signaling activation.	2	39	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Flk-1	YKL-40 not only increased the expression of Flk-1	flk-1	Flk-1	Flk-1	flk-1	9	10	37	38
Pep 234 ( a mammalian KISS1 antagonist ) antagonizes Kiss1r signaling activated by Kiss1 and Kiss2 , and pep 359 ( a novel analog ) antagonizes Kiss2 activation of both receptors .	Pep 234 (a mammalian KISS1 antagonist) antagonizes Kiss1r signaling activated by Kiss1 and Kiss2, and pep 359 (a novel analog) antagonizes Kiss2 activation of both receptors.	9	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Kiss1	Kiss1	Kiss1	Kiss1r	Kiss1r	Kiss1r	13	14	9	10
[ XREF_BIBR ] Data from mammals are consistent with the concept that KISS1 gene product activates the GPR54 on hypothalamic GnRH neurons .	[XREF_BIBR] Data from mammals are consistent with the concept that KISS1 gene product activates the GPR54 on hypothalamic GnRH neurons.	12	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KISS1	KISS1	KISS1	GPR54	GPR54	GPR54	12	13	17	18
Because of the important function of kisspeptin in the regulation of puberty onset , alterations in KISS1 gene might contribute to the pathogenesis of CPP , as could alterations in GPR54 gene .	Because of the important function of kisspeptin in the regulation of puberty onset, alterations in KISS1 gene might contribute to the pathogenesis of CPP, as could alterations in GPR54 gene.	16	31	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KISS1	KISS1	KISS1	GPR54	GPR54	GPR54	16	17	30	31
Importantly , biologically active peptide fragments of kisspeptin1 ( kiss1 ) and kisspeptin2 ( kiss2 ) have been shown to activate both kiss1r and kiss2r in fish XREF_BIBR , XREF_BIBR .	Importantly, biologically active peptide fragments of kisspeptin1 (kiss1) and kisspeptin2 (kiss2) have been shown to activate both kiss1r and kiss2r in fish XREF_BIBR, XREF_BIBR.	7	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	kiss1	kiss1	kiss1	kiss1r	kiss1r	kiss1r	9	10	22	23
Activation of GPR54 by KP-10 led to binding of NFATc4 to the BMP2 promoter .	Activation of GPR54 by KP-10 led to binding of NFATc4 to the BMP2 promoter.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	KP-10	KP-10	KP-10	GPR54	GPR54	GPR54	4	5	2	3
Dlx5 and Runx2 expressions were higher in GPR54 -/- cells treated with C.M than in those treated with KP-10 .	Dlx5 and Runx2 expressions were higher in GPR54 -/- cells treated with C.M than in those treated with KP-10.	7	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	KP-10	KP-10	KP-10	GPR54	GPR54	GPR54	18	19	7	8
In cancer , KISS1 induced KISS1R signaling is known to inhibit tumor angiogenesis and metastasis .	In cancer, KISS1 induced KISS1R signaling is known to inhibit tumor angiogenesis and metastasis.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	KISS1	KISS1	KISS1	KISS1R	KISS1R	KISS1R	3	4	5	6
Expression of Dlx5 and Runx2 was increased in GPR54 -/- cells treated with C.M , but not in those treated with KP-10 .	Expression of Dlx5 and Runx2 was increased in GPR54 -/- cells treated with C.M, but not in those treated with KP-10.	6	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	KP-10	KP-10	KP-10	GPR54	GPR54	GPR54	21	22	8	9
Together , our results suggest that kisspeptin-10 may activate GPR54 via a ligand transportation pathway incorporating a lipid membrane .	Together, our results suggest that kisspeptin-10 may activate GPR54 via a ligand transportation pathway incorporating a lipid membrane.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	kisspeptin-10	kisspeptin-10	kisspeptin-10	GPR54	GPR54	GPR54	6	7	9	10
KiSS1 induced GPR54 activates Galphaq/11 and PLCbeta , and affects phosphorylation of PKCs and the intracellular calcium level [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	KiSS1 induced GPR54 activates Galphaq/11 and PLCbeta, and affects phosphorylation of PKCs and the intracellular calcium level [XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR].	0	9	induced	Positive_early_activation	Positive_activation	Positive_activation	KiSS1	KiSS1	KiSS1	GPR54	GPR54	GPR54	0	1	2	3
Thus , together with our study , KiSS1 induced GPR54 signaling seems to gain complexity under different biological conditions .	Thus, together with our study, KiSS1 induced GPR54 signaling seems to gain complexity under different biological conditions.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	KiSS1	KiSS1	KiSS1	GPR54	GPR54	GPR54	7	8	9	10
Therefore , it will be interesting to understand a functional relationship between KiSS1 induced GPR54 signaling and the TNFalpha-TNFR-mediated proinflammatory cytokine mediated signaling in our future research .	Therefore, it will be interesting to understand a functional relationship between KiSS1 induced GPR54 signaling and the TNFalpha-TNFR-mediated proinflammatory cytokine mediated signaling in our future research.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	KiSS1	KiSS1	KiSS1	GPR54	GPR54	GPR54	12	13	14	15
To understand the underlying mechanism , we showed that activation of KISS1R by kisspeptin-10 led to RhoA activation and RhoA dependent gene expression through Galphaq-p63RhoGEF signaling pathway .	To understand the underlying mechanism, we showed that activation of KISS1R by kisspeptin-10 led to RhoA activation and RhoA dependent gene expression through Galphaq-p63RhoGEF signaling pathway.	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	kisspeptin-10	kisspeptin-10	kisspeptin-10	KISS1R	KISS1R	KISS1R	13	14	11	12
Kisspeptin-10 can also activate Kiss1R and influence the binding efficiency of SDF-1 and CXCL12 with its cell surface receptor , CXCR4 , thereby inhibiting metastasis .	Kisspeptin-10 can also activate Kiss1R and influence the binding efficiency of SDF-1 and CXCL12 with its cell surface receptor, CXCR4, thereby inhibiting metastasis.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kisspeptin-10	Kisspeptin-10	Kisspeptin-10	Kiss1R	Kiss1R	Kiss1R	0	1	4	5
The aim of the present study was to investigate whether Kiss-1R activation by kisspeptin-10 ( Kp-10 ) could modulate invitro proliferation and progesterone ( P4 ) secretion of bovine primary placental cell lines isolated from cotyledons of fetuses in the first trimester of pregnancy .	The aim of the present study was to investigate whether Kiss-1R activation by kisspeptin-10 (Kp-10) could modulate invitro proliferation and progesterone (P4) secretion of bovine primary placental cell lines isolated from cotyledons of fetuses in the first trimester of pregnancy.	10	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	kisspeptin-10	kisspeptin-10	kisspeptin-10	Kiss-1R	Kiss-1R	Kiss-1R	13	14	10	11
In addition , we found several known activating mutations , including two KRAS activating mutations , 8 PIK3CA activating mutations and one EGFR activating mutation ( out of 4 EGFR mutations in our samples ) .	In addition, we found several known activating mutations, including two KRAS activating mutations, 8 PIK3CA activating mutations and one EGFR activating mutation (out of 4 EGFR mutations in our samples).	4	19	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	PIK3CA	PIK3CA	PIK3CA	12	13	17	18
KRAS independently controls survival through BRAF but can also activate PIK3CA that induces AKT and cell cycle progression .	KRAS independently controls survival through BRAF but can also activate PIK3CA that induces AKT and cell cycle progression.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	PIK3CA	PIK3CA	PIK3CA	0	1	10	11
Genetically engineered mouse models indicate that even without an RTK signal , oncogenic K-Ras can induce senescence ( oncogene induced senescence , OIS ) or proliferation and differentiation [ XREF_BIBR ] ; but not full PI3Kalpha activation .	Genetically engineered mouse models indicate that even without an RTK signal, oncogenic K-Ras can induce senescence (oncogene induced senescence, OIS) or proliferation and differentiation [XREF_BIBR]; but not full PI3Kalpha activation.	12	36	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	K-Ras	K-Ras	K-Ras	PI3Kalpha	PI3Kalpha	PI3Kalpha	13	14	35	36
As a key factor , we suggest that because only KRas4B binds calmodulin , only KRas can fully activate PI3Kalpha and Akt signaling .	As a key factor, we suggest that because only KRas4B binds calmodulin, only KRas can fully activate PI3Kalpha and Akt signaling.	14	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRas	KRas	KRas	PI3Kalpha	PI3Kalpha	PI3Kalpha	15	16	19	20
Of the PI3K genes , only p110alpha and p110gamma are activated by Kras , whereas p110delta is activated by Rras and TC21 .	Of the PI3K genes, only p110alpha and p110gamma are activated by Kras, whereas p110delta is activated by Rras and TC21.	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Kras	Kras	Kras	p110alpha	p110alpha	p110alpha	12	13	6	7
Activation of PIK3CA by K-Ras and other growth stimuli receptors , such as EGFR , promotes cell tumor cell growth and prepares the cell for the next phase of cell cycle progression [ XREF_BIBR ] .	Activation of PIK3CA by K-Ras and other growth stimuli receptors, such as EGFR, promotes cell tumor cell growth and prepares the cell for the next phase of cell cycle progression [XREF_BIBR].	0	9	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	K-Ras	K-Ras	K-Ras	PIK3CA	PIK3CA	PIK3CA	4	5	2	3
Furthermore , we observed that KRAS induced mutations in SMAD4 , upregulation and downregulation in APC , downregulation in PIK3CA , and downregulation in KRAS .	Furthermore, we observed that KRAS induced mutations in SMAD4, upregulation and downregulation in APC, downregulation in PIK3CA, and downregulation in KRAS.	5	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	PIK3CA	PIK3CA	PIK3CA	5	6	19	20
Phosphorylation of other KIT tyrosine residues activates specific downstream signaling pathways and contributes to KIT mediated cell response as well .	Phosphorylation of other KIT tyrosine residues activates specific downstream signaling pathways and contributes to KIT mediated cell response as well.	0	15	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	KIT	Phosphorylation of other KIT tyrosine residues	kit	KIT	KIT	kit	3	4	14	15
These results are in line with previous published data , wherein it was demonstrated , by luciferase assay , that both miRNA221 and miRNA222 were direct regulators of KIT expression , targeting the 3 ' UTR of KIT mRNA [ XREF_BIBR , XREF_BIBR ] , and that the levels of this two miRNAs were significantly lower in KIT expressing GISTs , compared to KIT negative GISTs [ XREF_BIBR , XREF_BIBR ] .	These results are in line with previous published data, wherein it was demonstrated, by luciferase assay, that both miRNA221 and miRNA222 were direct regulators of KIT expression, targeting the 3 ' UTR of KIT mRNA [XREF_BIBR, XREF_BIBR], and that the levels of this two miRNAs were significantly lower in KIT expressing GISTs, compared to KIT negative GISTs [XREF_BIBR, XREF_BIBR].	28	38	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KIT	KIT expression	kit	KIT	KIT	kit	28	29	37	38
Most GISTs carry mutations in the proto-oncogene c-kit , which constitutively activates KIT kinase when translated ; this gain-of-function mutation in the c-kit gene is considered to be the cause of GISTs [ XREF_BIBR ] .	Most GISTs carry mutations in the proto-oncogene c-kit, which constitutively activates KIT kinase when translated; this gain-of-function mutation in the c-kit gene is considered to be the cause of GISTs [XREF_BIBR].	6	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	proto-oncogene c-kit	proto-oncogene c-kit	proto-oncogene c-kit	KIT	KIT	KIT	6	8	12	13
We also show that flavopiridol suppresses KIT mRNA expression through positive transcriptional elongation factor inhibition and decreases KIT promoter activity .	We also show that flavopiridol suppresses KIT mRNA expression through positive transcriptional elongation factor inhibition and decreases KIT promoter activity.	4	19	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	KIT	flavopiridol suppresses KIT mRNA expression	kit	KIT	KIT	kit	6	7	17	18
Sunitinib ( SU ) treatment alone inhibited phosphorylation of KIT and AKT in GIST430 , but not in GIST48 ( XREF_FIG ) , which is expected as SU potently inhibits secondary KIT exon 13 mutations ( GIST430 ) but not kinase loop mutations in exon 17 ( GIST48 ) .	Sunitinib (SU) treatment alone inhibited phosphorylation of KIT and AKT in GIST430, but not in GIST48 (XREF_FIG), which is expected as SU potently inhibits secondary KIT exon 13 mutations (GIST430) but not kinase loop mutations in exon 17 (GIST48).	0	32	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	KIT	Sunitinib (SU) treatment alone inhibited phosphorylation of KIT	kit	KIT	KIT	kit	9	10	31	32
KIT , which is a growth factor transmembrane receptor , is the product of the proto-oncogene c-kit ( chromosome 4 ) .	KIT, which is a growth factor transmembrane receptor, is the product of the proto-oncogene c-kit (chromosome 4).	0	17	is the product	Positive_activation_copula_1	Positive_activation	Positive_activation	KIT	KIT	KIT	proto-oncogene c-kit	proto-oncogene c-kit	proto-oncogene c-kit	0	1	15	17
Overexpression of CD117 in CD117 high NSCLC supports exploring KIT as a therapeutic target in this subset of patients .	Overexpression of CD117 in CD117 high NSCLC supports exploring KIT as a therapeutic target in this subset of patients.	0	10	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD117	Overexpression of CD117	cd117	KIT	KIT	kit	2	3	9	10
RRAS proteins , unlike HRAS , KRAS , and NRAS activate PI3Kgamma .	RRAS proteins, unlike HRAS, KRAS, and NRAS activate PI3Kgamma.	6	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	PI3Kgamma	PI3Kgamma	PI3Kgamma	6	7	11	12
56 As described below , PLCG1 activation by VEGFR2 acts as a driver for a subset of angiosarcomas and leads to resistance to VEGF and VEGFR targeted therapies .	56 As described below, PLCG1 activation by VEGFR2 acts as a driver for a subset of angiosarcomas and leads to resistance to VEGF and VEGFR targeted therapies.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGFR2	VEGFR2	VEGFR2	PLCG1	PLCG1	PLCG1	8	9	5	6
XREF_BIBR - XREF_BIBR Autophosphorylation of VEGFR2 leads to the recruitment of PLCG1 , binding of PLCG1 at its N-terminal SH2 domain , and subsequent activation of PLCG1 .	XREF_BIBR - XREF_BIBR Autophosphorylation of VEGFR2 leads to the recruitment of PLCG1, binding of PLCG1 at its N-terminal SH2 domain, and subsequent activation of PLCG1.	3	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	VEGFR2	Autophosphorylation of VEGFR2	vegfr2	PLCG1	PLCG1	plcg1	5	6	11	12
Given our observation that KMT2D silencing suppresses ER activation , we hypothesized that loss of function of KMT2D might augment the therapeutic activity of BYL719 in ER positive cells .	Given our observation that KMT2D silencing suppresses ER activation, we hypothesized that loss of function of KMT2D might augment the therapeutic activity of BYL719 in ER positive cells.	4	8	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	KMT2D	KMT2D	KMT2D	ER	ER	ER	4	5	7	8
Toska and colleagues identified that the epigenetic regulator KMT2D enhances ERalpha activity in BYL719 treated PIK3CA mutant breast cancer , leading to a rationale for targeting the epigenome and PI3K signaling .	Toska and colleagues identified that the epigenetic regulator KMT2D enhances ERalpha activity in BYL719 treated PIK3CA mutant breast cancer, leading to a rationale for targeting the epigenome and PI3K signaling.	5	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KMT2D	KMT2D	KMT2D	ERalpha	ERalpha	ERalpha	8	9	10	11
Disrupting the interaction between ERalpha and the MLL2 complex with small interfering RNAs specific against MLL2 or an MLL2 fragment representing the interacting region with ERalpha significantly inhibited the ERalpha transcription activity .	Disrupting the interaction between ERalpha and the MLL2 complex with small interfering RNAs specific against MLL2 or an MLL2 fragment representing the interacting region with ERalpha significantly inhibited the ERalpha transcription activity.	7	31	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MLL2	MLL2	MLL2	ERalpha	ERalpha	ERalpha	7	8	29	30
Inhibition of MLL2 also inhibit ER target gene expression [ XREF_BIBR ] .	Inhibition of MLL2 also inhibit ER target gene expression [XREF_BIBR].	0	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MLL2	MLL2	MLL2	ER	ER	ER	2	3	5	6
How the 300N-terminal region of KNL1 is able to mediate Bub1 and Aurora B kinase activities remains to be addressed .	How the 300N-terminal region of KNL1 is able to mediate Bub1 and Aurora B kinase activities remains to be addressed.	3	14	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KNL1	KNL1	KNL1	Bub1	Bub1	Bub1	5	6	10	11
Here we found that KNL1 mediated Bub1 accumulation to kinetochores is not a requirement for its activity at kinetochores .	Here we found that KNL1 mediated Bub1 accumulation to kinetochores is not a requirement for its activity at kinetochores.	4	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	KNL1	KNL1	KNL1	Bub1	Bub1	Bub1	4	5	6	7
As Kit is known to activate SFK signaling we investigated the effect of imatinib treatment on SFK signaling in mouse GIST .	As Kit is known to activate SFK signaling we investigated the effect of imatinib treatment on SFK signaling in mouse GIST.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kit	Kit	Kit	SFK	SFK	SFK	1	2	6	7
To investigate the role of Kit mediated SFK signaling in mouse GIST we performed quantitative PCR for all SFKs expressed in tumor tissue .	To investigate the role of Kit mediated SFK signaling in mouse GIST we performed quantitative PCR for all SFKs expressed in tumor tissue.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	Kit	Kit	Kit	SFK	SFK	SFK	5	6	7	8
The Kit autophosphorylation site Kit Y567 is a known docking site for SFKs and SFK docking is a mechanism of Kit mediated SFK signaling .	The Kit autophosphorylation site Kit Y567 is a known docking site for SFKs and SFK docking is a mechanism of Kit mediated SFK signaling.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	Kit	Kit	Kit	SFK	SFK	SFK	20	21	22	23
EC KLF2 and KLF4 increase thrombomodulin and tissue plasminogen activator expression ( tPA ) and decrease plasminogen activator inhibitor ( PAI-1 ) and cytokine stimulated tissue factor expression XREF_BIBR , XREF_BIBR , consistent with an anti-thrombotic effect .	EC KLF2 and KLF4 increase thrombomodulin and tissue plasminogen activator expression (tPA) and decrease plasminogen activator inhibitor (PAI-1) and cytokine stimulated tissue factor expression XREF_BIBR, XREF_BIBR, consistent with an anti-thrombotic effect.	1	24	increase	Positive_activation_token_1_verb	Positive_activation	Positive_activation	KLF4	KLF4	KLF4	thrombomodulin	thrombomodulin	thrombomodulin	3	4	5	6
DNMT inhibition by the chemical inhibitors 5Aza and RG108 rescued Klf4 expression and reversed the d-flow-induced suppression of the downstream targets eNOS and thrombomodulin .	DNMT inhibition by the chemical inhibitors 5Aza and RG108 rescued Klf4 expression and reversed the d-flow-induced suppression of the downstream targets eNOS and thrombomodulin.	0	24	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Klf4	DNMT inhibition by the chemical inhibitors 5Aza and RG108 rescued Klf4 expression	klf4	thrombomodulin	thrombomodulin	thrombomodulin	10	11	23	24
Interestingly , previous reports have shown that oncogenic KRas activity causes increased MINK1 activity and expression XREF_BIBR , and that MAP4K4 expression is heightened in tumor cell lines and tumor tissues compared with their normal counterparts XREF_BIBR , XREF_BIBR .	Interestingly, previous reports have shown that oncogenic KRas activity causes increased MINK1 activity and expression XREF_BIBR, and that MAP4K4 expression is heightened in tumor cell lines and tumor tissues compared with their normal counterparts XREF_BIBR, XREF_BIBR.	8	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRas	KRas	KRas	MINK1	MINK1	MINK1	8	9	12	13
KLF11 mediates TGF-beta and Smad signaling through downregulation of Smad7 by recruiting the transcriptional repressor Sin3A to the Smad7 promoter .	KLF11 mediates TGF-beta and Smad signaling through downregulation of Smad7 by recruiting the transcriptional repressor Sin3A to the Smad7 promoter.	0	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	KLF11	KLF11	KLF11	Sin3A	Sin3A	Sin3A	0	1	15	16
The most obvious explanation is that the BubR1 and Bub3 complex binds directly to MELTp motifs in KNL1 and this would be in agreement with the previous observations that a KNL1 protein without active MELT repeats does not support BubR1 and Bub3 kinetochore localization XREF_BIBR XREF_BIBR .	The most obvious explanation is that the BubR1 and Bub3 complex binds directly to MELTp motifs in KNL1 and this would be in agreement with the previous observations that a KNL1 protein without active MELT repeats does not support BubR1 and Bub3 kinetochore localization XREF_BIBR XREF_BIBR.	30	45	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KNL1	KNL1	KNL1	BubR1	BubR1	BubR1	30	31	39	40
In the Npnt promoter , there are eight copies of CACCC motifs which are Klf2 binding sites , and Npnt promoter activity is directly activated by Klf2 .	In the Npnt promoter, there are eight copies of CACCC motifs which are Klf2 binding sites, and Npnt promoter activity is directly activated by Klf2.	19	27	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Klf2	Klf2	Klf2	Npnt	Npnt	Npnt	26	27	19	20
Oncogenic KIT induced aggressive systemic mastocytosis requires SHP2 and PTPN11 phosphatase for disease progression in mice .	Oncogenic KIT induced aggressive systemic mastocytosis requires SHP2 and PTPN11 phosphatase for disease progression in mice.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KIT	KIT	KIT	PTPN11	PTPN11	PTPN11	1	2	9	10
Initially , we made use of HCT116 colon cancer cells expressing in wild-type cells a mutant active K-RAS D13 or mutant forms of H-RAS V12 that specifically activated RAF-1 or PI3K .	Initially, we made use of HCT116 colon cancer cells expressing in wild-type cells a mutant active K-RAS D13 or mutant forms of H-RAS V12 that specifically activated RAF-1 or PI3K.	17	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	K-RAS	K-RAS	K-RAS	RAF-1	RAF-1	RAF-1	17	18	28	29
Thus , retrovirus mediated delivery of the oncogenic KRAS caused activation of RAF-1 and ERK and PI3K and AKT signaling pathways , the major downstream effectors of KRAS .	Thus, retrovirus mediated delivery of the oncogenic KRAS caused activation of RAF-1 and ERK and PI3K and AKT signaling pathways, the major downstream effectors of KRAS.	4	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRAS	KRAS	KRAS	RAF-1	RAF-1	RAF-1	8	9	12	13
Gal3 is also known to serve as a binding partner of activated K-Ras , through which it enhances PI3K and Raf-1 activation .	Gal3 is also known to serve as a binding partner of activated K-Ras, through which it enhances PI3K and Raf-1 activation.	9	21	enhances	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	K-Ras	K-Ras	K-Ras	Raf-1	Raf-1	Raf-1	12	13	20	21
KRas protein expression occurs frequently in malignancies ; however , new research suggests that KRas alone is not sufficient to induce glioblastoma genesis , additional activation of Raf-1 , BRAF ( serine/threonine protein kinase B-Raf ) , ATRX mutation , and TP53 mutation is necessary for glioblastoma oncogenesis [ XREF_BIBR , XREF_BIBR ] .	KRas protein expression occurs frequently in malignancies; however, new research suggests that KRas alone is not sufficient to induce glioblastoma genesis, additional activation of Raf-1, BRAF (serine/threonine protein kinase B-Raf), ATRX mutation, and TP53 mutation is necessary for glioblastoma oncogenesis [XREF_BIBR, XREF_BIBR].	14	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KRas	KRas	KRas	Raf-1	Raf-1	Raf-1	14	15	27	28
K-Ras activates Raf-1 more effectively than H-Ras and N-Ras XREF_BIBR , XREF_BIBR and activates Rac more efficiently than H-Ras , 33 whereas , H-Ras is a more potent activator of PI 3-kinase than K-Ras 32 and more active in cell transformation than either N- or K-Ras in murine fibroblasts .	K-Ras activates Raf-1 more effectively than H-Ras and N-Ras XREF_BIBR, XREF_BIBR and activates Rac more efficiently than H-Ras, 33 whereas, H-Ras is a more potent activator of PI 3-kinase than K-Ras 32 and more active in cell transformation than either N- or K-Ras in murine fibroblasts.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	K-Ras	K-Ras	K-Ras	Raf-1	Raf-1	Raf-1	0	1	2	3
Multiple lines of evidence demonstrate that downstream proteins , such as the G proteins Rac and Rho , are upregulated in pancreatic cancer , and K-ras activated Raf-1 and Rac more effectively than the other ras isoforms , Ha-ras and N-ras .	Multiple lines of evidence demonstrate that downstream proteins, such as the G proteins Rac and Rho, are upregulated in pancreatic cancer, and K-ras activated Raf-1 and Rac more effectively than the other ras isoforms, Ha-ras and N-ras.	25	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	K-ras	K-ras	K-ras	Raf-1	Raf-1	Raf-1	25	26	27	28
In addition , in radioresistant cervical cancer cells , IR induces K-Ras activation that promotes the c-Raf and p38 pathway to increase cell migration and metastatic potential [ XREF_BIBR ] .	In addition, in radioresistant cervical cancer cells, IR induces K-Ras activation that promotes the c-Raf and p38 pathway to increase cell migration and metastatic potential [XREF_BIBR].	11	19	promotes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	K-Ras	K-Ras	K-Ras	c-Raf	c-Raf	c-Raf	11	12	16	17
ITK is subsequently activated by Lck which phosphorylates tyrosine 512 in the conserved activation loop within the kinase domain XREF_BIBR .	ITK is subsequently activated by Lck which phosphorylates tyrosine 512 in the conserved activation loop within the kinase domain XREF_BIBR.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lck	Lck	Lck	ITK	ITK	ITK	5	6	0	1
The tyrosine kinase Itk is activated by Lck and plays an important role in Th cell differentiation [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	The tyrosine kinase Itk is activated by Lck and plays an important role in Th cell differentiation [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lck	Lck	Lck	Itk	Itk	Itk	7	8	3	4
PLCgamma1 activation also requires Itk , which is activated by both SLP-76 and Lck [ XREF_BIBR , XREF_BIBR ] .	PLCgamma1 activation also requires Itk, which is activated by both SLP-76 and Lck [XREF_BIBR, XREF_BIBR].	3	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lck	Lck	Lck	Itk	Itk	Itk	13	14	4	5
These full-length Itk mutants were co-expressed with Lck in Sf9 cells since Lck , by phosphorylating Y511 in the Itk activation loop , is required to activate Itk XREF_BIBR .	These full-length Itk mutants were co-expressed with Lck in Sf9 cells since Lck, by phosphorylating Y511 in the Itk activation loop, is required to activate Itk XREF_BIBR.	12	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lck	Lck	Lck	Itk	Itk	Itk	12	13	27	28
Itk is recruited to the signaling complex via its PH domain interacting with phosphatidylinositol ( 3,4,5 ) triphosphate ( PIP 3 ) , generated at the plasma membrane by the enzyme PI3K , activated by Lck and regulated by ItpkB .	Itk is recruited to the signaling complex via its PH domain interacting with phosphatidylinositol (3,4,5) triphosphate (PIP 3), generated at the plasma membrane by the enzyme PI3K, activated by Lck and regulated by ItpkB.	0	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lck	Lck	Lck	Itk	Itk	Itk	35	36	0	1
Itk is directly activated by Lck and in turn plays a role in the activation of PLCgamma1 , Ca 2+ mobilization and activation of ERK and MAPK XREF_BIBR .	Itk is directly activated by Lck and in turn plays a role in the activation of PLCgamma1, Ca 2+ mobilization and activation of ERK and MAPK XREF_BIBR.	0	6	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lck	Lck	Lck	Itk	Itk	Itk	5	6	0	1
Upon its recruitment to the LAT and SLP -76 complex , ITK is activated upon phosphorylation of its activation loop ( Y511 ) by LCK .	Upon its recruitment to the LAT and SLP -76 complex, ITK is activated upon phosphorylation of its activation loop (Y511) by LCK.	11	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LCK	LCK	LCK	ITK	ITK	ITK	24	25	11	12
Since previous studies indicate that LCK associates inducibly with LAT XREF_BIBR and with SLP-76 XREF_BIBR , XREF_BIBR , it is reasonable to envision that interaction with this signalosome brings ITK into close proximity to LCK , which activates ITK by transphosphorylation on Tyr 511 of its activation loop XREF_BIBR .	Since previous studies indicate that LCK associates inducibly with LAT XREF_BIBR and with SLP-76 XREF_BIBR, XREF_BIBR, it is reasonable to envision that interaction with this signalosome brings ITK into close proximity to LCK, which activates ITK by transphosphorylation on Tyr 511 of its activation loop XREF_BIBR.	32	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LCK	LCK	LCK	ITK	ITK	ITK	34	35	38	39
These data suggest a new model where LAT tyrosine 132 serves as a catalyst for the phosphorylation of PLC-gamma1 , but that activated PLC-gamma1 functions at multiple cellular regions .	These data suggest a new model where LAT tyrosine 132 serves as a catalyst for the phosphorylation of PLC-gamma1, but that activated PLC-gamma1 functions at multiple cellular regions.	7	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	LAT	LAT	PLC-gamma1	PLC-gamma1	PLC-gamma1	7	8	23	24
LAT phosphorylation activates PLCgamma1 , leading to cleavage of phosphatidylinositol into inositol trisphosphate ( IP3 ) and diacylglycerol ( DAG ) [ XREF_BIBR , XREF_BIBR ] .	LAT phosphorylation activates PLCgamma1, leading to cleavage of phosphatidylinositol into inositol trisphosphate (IP3) and diacylglycerol (DAG) [XREF_BIBR, XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	LAT phosphorylation	lat	PLCgamma1	PLCgamma1	plcgamma1	0	1	3	4
Additionally , the activation of PLC-gamma1 by LAT leads to the formation of DAG ( diacylglycerol ) , a molecule critical for the recruitment of RasGRP1 ( Ras guanyl releasing protein 1 ) .	Additionally, the activation of PLC-gamma1 by LAT leads to the formation of DAG (diacylglycerol), a molecule critical for the recruitment of RasGRP1 (Ras guanyl releasing protein 1).	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LAT	LAT	LAT	PLC-gamma1	PLC-gamma1	PLC-gamma1	7	8	5	6
First , Lck activates Zap-70 , which in turn phosphorylates and recruits the scaffold protein LAT ( Linker for Activation of T Cells ) , promoting PLCgamma1 ( Phospholipase C gamma1 ) activity that cleaves phosphatidylinositol 4,5-biphosphate ( PIP2 ) into the second messengers diacylgylcerol ( DAG ) and inositol triphosphate ( IP3 ) .	First, Lck activates Zap-70, which in turn phosphorylates and recruits the scaffold protein LAT (Linker for Activation of T Cells), promoting PLCgamma1 (Phospholipase C gamma1) activity that cleaves phosphatidylinositol 4,5-biphosphate (PIP2) into the second messengers diacylgylcerol (DAG) and inositol triphosphate (IP3).	2	32	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	Lck activates Zap-70, which in turn phosphorylates and recruits the scaffold protein LAT	lat	PLCgamma1	PLCgamma1	plcgamma1	15	16	26	27
However , retaining LAT alone in lipid rafts effectively restored phospholipase Cgamma1 and calcium signaling in PUFA treated T cells .	However, retaining LAT alone in lipid rafts effectively restored phospholipase Cgamma1 and calcium signaling in PUFA treated T cells.	2	12	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	LAT	LAT	phospholipase Cgamma1	phospholipase Cgamma1	phospholipase Cgamma1	3	4	10	12
The formation of the LAT , Gads , and SLP-76 complex enables the activation of Phospholipase C-gamma1 , resulting in calcium mobilization .	The formation of the LAT, Gads, and SLP-76 complex enables the activation of Phospholipase C-gamma1, resulting in calcium mobilization.	1	17	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	LAT	LAT	Phospholipase C-gamma1	Phospholipase C-gamma1	Phospholipase C-gamma1	4	5	15	17
Not surprisingly , knowing the critical role of LAT as a docking protein , mutating the four distal tyrosine residues on LAT , which mediate binding to Gads , Grb2 , and PLC-gamma1 , renders Jurkat T cells completely unresponsive to receptor engagement .	Not surprisingly, knowing the critical role of LAT as a docking protein, mutating the four distal tyrosine residues on LAT, which mediate binding to Gads, Grb2, and PLC-gamma1, renders Jurkat T cells completely unresponsive to receptor engagement.	19	33	mediate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	LAT	LAT	LAT	PLC-gamma1	PLC-gamma1	PLC-gamma1	21	22	32	33
To assess whether the moderate phosphorylation of LAT induced by ANC28.1 was sufficient to activate PLCgamma1 , we investigated the phosphorylation status of Y 783 of PLCgamma1 which correlates with its enzymatic activity XREF_BIBR .	To assess whether the moderate phosphorylation of LAT induced by ANC28.1 was sufficient to activate PLCgamma1, we investigated the phosphorylation status of Y 783 of PLCgamma1 which correlates with its enzymatic activity XREF_BIBR.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	phosphorylation of LAT	lat	PLCgamma1	PLCgamma1	plcgamma1	7	8	15	16
Besides this , LAT stimulates 1 critical protein phospholipase-C-gamma1 that play important role for the production of the second messengers diacylglycerol ( DAG ) and inositol triphosphate ( IP 3 ) .	Besides this, LAT stimulates 1 critical protein phospholipase-C-gamma1 that play important role for the production of the second messengers diacylglycerol (DAG) and inositol triphosphate (IP 3).	3	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	LAT	LAT	phospholipase-C-gamma1	phospholipase-C-gamma1	phospholipase-C-gamma1	3	4	8	9
Together , these observations show that commencement LAT tyrosine 132 phosphorylation initiates PLC-gamma1 activation , but that the LAT and PLC-gamma 1 interaction is catalytic .	Together, these observations show that commencement LAT tyrosine 132 phosphorylation initiates PLC-gamma1 activation, but that the LAT and PLC-gamma 1 interaction is catalytic.	7	13	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	LAT	LAT	PLC-gamma1	PLC-gamma1	PLC-gamma1	7	8	12	13
TCR ligation leads to rapid LAT phosphorylation , thereby allowing the recruitment of PLC-gamma1 to the cellular membrane , where it is phosphorylated on Tyr783 , a hallmark of its enzymatic activation .	TCR ligation leads to rapid LAT phosphorylation, thereby allowing the recruitment of PLC-gamma1 to the cellular membrane, where it is phosphorylated on Tyr783, a hallmark of its enzymatic activation.	0	14	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	TCR ligation leads to rapid LAT phosphorylation	lat	PLC-gamma1	PLC-gamma1	plc-gamma1	5	6	13	14
Cbp and PAG regulates membrane localization of Csk , a protein kinase that phosphorylates Lck at Tyr 505 inducing Lck ' s kinase domain into an inactive conformation .	Cbp and PAG regulates membrane localization of Csk, a protein kinase that phosphorylates Lck at Tyr 505 inducing Lck 's kinase domain into an inactive conformation.	7	20	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lck	Csk, a protein kinase that phosphorylates Lck at Tyr 505	lck	Lck	Lck	lck	14	15	19	20
We demonstrated that , despite a moderate over-expression of the total form of Lck protein , Lck was significantly de-phosphorylated in the inhibitory residue Lck Y505 , thus causing Lck over-activation .	We demonstrated that, despite a moderate over-expression of the total form of Lck protein, Lck was significantly de-phosphorylated in the inhibitory residue Lck Y505, thus causing Lck over-activation.	16	30	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lck	Lck was significantly de-phosphorylated	lck	Lck	Lck	lck	16	17	29	30
FAK deficient T cells also have decreased Lck Y505 phosphorylation , the site that is directly phosphorylated by Csk to suppress Lck function , while the magnitude and kinetics of phosphorylation of the Lck substrates , Lck Y394 and TCRzeta-ITAM Y142 , are higher and faster , respectively [ XREF_BIBR ] .	FAK deficient T cells also have decreased Lck Y505 phosphorylation, the site that is directly phosphorylated by Csk to suppress Lck function, while the magnitude and kinetics of phosphorylation of the Lck substrates, Lck Y394 and TCRzeta-ITAM Y142, are higher and faster, respectively [XREF_BIBR].	0	22	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lck	FAK deficient T cells also have decreased Lck Y505 phosphorylation, the site that is directly phosphorylated by Csk	lck	Lck	Lck	lck	7	8	21	22
However , following association with a strong agonist pMHC , the MAP kinase ERK is rapidly activated and phosphorylates Lck at Ser 59 , inhibiting the binding of SHP-1 and the subsequent inhibition of Lck kinase activity .	However, following association with a strong agonist pMHC, the MAP kinase ERK is rapidly activated and phosphorylates Lck at Ser 59, inhibiting the binding of SHP-1 and the subsequent inhibition of Lck kinase activity.	11	36	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Lck	MAP kinase ERK is rapidly activated and phosphorylates Lck at Ser 59	lck	Lck	Lck	lck	19	20	34	35
Upon being activated , CSK phosphorylation is removed and LCK autophosphorylation leads to LCK activation and further phosphorylates ZAP70 to initiate further downstream signalling .	Upon being activated, CSK phosphorylation is removed and LCK autophosphorylation leads to LCK activation and further phosphorylates ZAP70 to initiate further downstream signalling.	9	14	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	LCK	LCK autophosphorylation	lck	LCK	LCK	lck	9	10	13	14
Overexpression of the Lck PM transporter Unc119 restores Nef induced subversions of Lck trafficking and TCR signaling .	Overexpression of the Lck PM transporter Unc119 restores Nef induced subversions of Lck trafficking and TCR signaling.	0	13	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lck	Overexpression of the Lck	lck	Lck	Lck	lck	3	4	12	13
The total Lck protein level was up-regulated ( mean FC = 1.79 , range 1.42-2.48 , p < 0.01 ; mean FC = 1.97 , range 1.10-3.02 , p < 0.05 ; mean FC = 1.12 , range 1.06-1.40 , n.s ., in LY5.1 FL , B6BAFL and FLB6-67 cells , respectively ) , and PAX5 and ETV6 induced a statistically significant de-phosphorylation of the Lck inhibitory domain ( Lck Y505 ) , causing Lck over-activation .	The total Lck protein level was up-regulated (mean FC = 1.79, range 1.42-2.48, p < 0.01; mean FC = 1.97, range 1.10-3.02, p < 0.05; mean FC = 1.12, range 1.06-1.40, n.s., in LY5.1 FL, B6BAFL and FLB6-67 cells, respectively), and PAX5 and ETV6 induced a statistically significant de-phosphorylation of the Lck inhibitory domain (Lck Y505), causing Lck over-activation.	55	75	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lck	PAX5 and ETV6 induced a statistically significant de-phosphorylation of the Lck inhibitory domain (Lck Y505	lck	Lck	Lck	lck	65	66	74	75
It has been shown that RSPO1 stimulates Wnt and beta-catenin signaling by preventing DKK1 and Kremen- or RNF43 and ZNRF3 mediated turnover of LRP6 on the cell surface XREF_BIBR , XREF_BIBR .	It has been shown that RSPO1 stimulates Wnt and beta-catenin signaling by preventing DKK1 and Kremen- or RNF43 and ZNRF3 mediated turnover of LRP6 on the cell surface XREF_BIBR, XREF_BIBR.	13	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Kremen-	Kremen-	Kremen-	LRP6	LRP6	LRP6	15	16	23	24
Although RSpo1 does not directly activate LRP6 , it interferes with DKK1 and Kremen mediated internalization of LRP6 through an interaction with Kremen , resulting in increased LRP6 levels on the cell surface .	Although RSpo1 does not directly activate LRP6, it interferes with DKK1 and Kremen mediated internalization of LRP6 through an interaction with Kremen, resulting in increased LRP6 levels on the cell surface.	13	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kremen	Kremen	Kremen	LRP6	LRP6	LRP6	13	14	17	18
While in this complex , Kremen triggers the internalization of LRP6 inhibiting Wnt signaling .	While in this complex, Kremen triggers the internalization of LRP6 inhibiting Wnt signaling.	5	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kremen	Kremen	Kremen	LRP6	LRP6	LRP6	5	6	10	11
Mechanistically R-spondin1 may compete with Dickkopf-1 ( DKK1 ) for binding to Kremen , which allows LRP6 to become available to upregulate Wnt signaling XREF_BIBR .	Mechanistically R-spondin1 may compete with Dickkopf-1 (DKK1) for binding to Kremen, which allows LRP6 to become available to upregulate Wnt signaling XREF_BIBR.	3	18	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kremen	Kremen	Kremen	LRP6	LRP6	LRP6	12	13	16	17
In addition , Dkk1 bridges Lrp6 and another transmembrane protein , Kremen , inducing endocytosis of Lrp6 .	In addition, Dkk1 bridges Lrp6 and another transmembrane protein, Kremen, inducing endocytosis of Lrp6.	9	17	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Kremen	Kremen	Kremen	Lrp6	Lrp6	Lrp6	11	12	16	17
Given the importance of CD28 basic residue clusters for binding to Lck , we examined the role of these motifs in the recruitment of PKCtheta as a critical downstream target of Lck mediated CD28 signaling .	Given the importance of CD28 basic residue clusters for binding to Lck, we examined the role of these motifs in the recruitment of PKCtheta as a critical downstream target of Lck mediated CD28 signaling.	29	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	Lck	Lck	Lck	CD28	CD28	CD28	31	32	33	34
ZAP-70 mediates the phosphorylation of LAT thereby allowing GRB2 and GADS to recruit critical ligands that drive the formation of the LAT signalosome [ XREF_BIBR , XREF_BIBR ] .	ZAP-70 mediates the phosphorylation of LAT thereby allowing GRB2 and GADS to recruit critical ligands that drive the formation of the LAT signalosome [XREF_BIBR, XREF_BIBR].	3	12	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	phosphorylation of LAT	lat	GRB2	GRB2	grb2	5	6	8	9
The first one involves the adapters LAT , SLP-76 , and Nck , which synergistically activate Vav1 , a GEF for Rac1 and Cdc42 .	The first one involves the adapters LAT, SLP-76, and Nck, which synergistically activate Vav1, a GEF for Rac1 and Cdc42.	3	19	synergistically activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	LAT	LAT	Vav1	Vav1	Vav1	6	7	16	17
Finally , LAT and SLP76 containing complexes activate the guanine nucleotide exchange factor VAV which , in turn , controls the Rho family GTPases .	Finally, LAT and SLP76 containing complexes activate the guanine nucleotide exchange factor VAV which, in turn, controls the Rho family GTPases.	2	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAT	LAT	LAT	VAV	VAV	VAV	2	3	13	14
KSR1 enhances Raf-1 activity in a kinase independent manner XREF_BIBR .	KSR1 enhances Raf-1 activity in a kinase independent manner XREF_BIBR.	0	3	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	KSR1	KSR1	KSR1	Raf-1	Raf-1	Raf-1	0	1	2	3
ZAP-70 is tyrosine phosphorylated and activated by Lck , going on to phosphorylate the adaptor protein LAT ( XREF_FIG ) .	ZAP-70 is tyrosine phosphorylated and activated by Lck, going on to phosphorylate the adaptor protein LAT (XREF_FIG).	0	18	activated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Lck	Lck	Lck	LAT	LAT	LAT	7	8	16	17
Consistent with this notion , a kinome-wide siRNA knock-down screen showed that down-regulation of PAK3 and the scaffold protein MAPKSP1 , which enhances MEK activation , impaired infection of human hepatocytes by P. berghei [ XREF_BIBR , XREF_BIBR ] .	Consistent with this notion, a kinome-wide siRNA knock-down screen showed that down-regulation of PAK3 and the scaffold protein MAPKSP1, which enhances MEK activation, impaired infection of human hepatocytes by P. berghei [XREF_BIBR, XREF_BIBR].	10	35	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPKSP1	MAPKSP1	MAPKSP1	MEK	MEK	MEK	19	20	23	24
One model proposes that during positive energy balance and excess body fat gain , leptin resistance is caused by elevated plasma leptin levels , resulting in chronic overstimulation of the leptin receptor and associated SOCS-3 induction .	One model proposes that during positive energy balance and excess body fat gain, leptin resistance is caused by elevated plasma leptin levels, resulting in chronic overstimulation of the leptin receptor and associated SOCS-3 induction.	17	32	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin levels	leptin	leptin receptor	leptin receptor	leptin receptor	21	22	30	32
This conserved tertiary structure of leptin shows that leptin is constrained by the structure of the receptor binding pocket , and can explain why frog leptin can activate mouse leptin receptor in vitro .	This conserved tertiary structure of leptin shows that leptin is constrained by the structure of the receptor binding pocket, and can explain why frog leptin can activate mouse leptin receptor in vitro.	24	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	25	26	29	31
In addition , in leptin receptor deficient mice ( db/db ) and in mice treated with a leptin antagonist , leptin accumulates in the median eminence but fails to appear in the mediobasal hypothalamus , providing evidence that leptin ' s signaling cascade begins in tanycytes in the median eminence , and then transitions to hypothalamic nuclei and neurons .	In addition, in leptin receptor deficient mice (db/db) and in mice treated with a leptin antagonist, leptin accumulates in the median eminence but fails to appear in the mediobasal hypothalamus, providing evidence that leptin 's signaling cascade begins in tanycytes in the median eminence, and then transitions to hypothalamic nuclei and neurons.	4	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	17	18	4	6
Leptin treatment in these animals resulted in downregulation of these miRNAs , upregulation of the leptin receptor , reduction in body weight and restoration of insulin sensitivity .	Leptin treatment in these animals resulted in downregulation of these miRNAs, upregulation of the leptin receptor, reduction in body weight and restoration of insulin sensitivity.	0	17	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Leptin	Leptin	Leptin	leptin receptor	leptin receptor	leptin receptor	0	1	15	17
The mechanism of leptin induced leptin receptor activation remains unclear .	The mechanism of leptin induced leptin receptor activation remains unclear.	1	7	induced	Positive_early_activation	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	3	4	5	7
Leptin- and leptin receptor deficient mice are protected from thrombosis , as are mice treated with a leptin neutralizing antibody , while exogenously administered leptin enhances thrombosis .	Leptin- and leptin receptor deficient mice are protected from thrombosis, as are mice treated with a leptin neutralizing antibody, while exogenously administered leptin enhances thrombosis.	0	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	17	18	2	4
Firstly , leptin induces neurogenesis and angiogenesis after stroke and leads to increased leptin receptor and pAMPK concentrations .	Firstly, leptin induces neurogenesis and angiogenesis after stroke and leads to increased leptin receptor and pAMPK concentrations.	2	15	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	2	3	13	15
We show that leptin directly regulates a population of leptin receptor ( LepRb )-expressing inhibitory neurons in the LHA , and that leptin action via these LHA LepRb neurons decreases feeding and body weight .	We show that leptin directly regulates a population of leptin receptor (LepRb)-expressing inhibitory neurons in the LHA, and that leptin action via these LHA LepRb neurons decreases feeding and body weight.	3	15	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	3	4	9	11
Despite attaining normal serum leptin levels , leptin failed to reduce food intake or activate hypothalamic leptin receptor ( LRb ) signaling such as Stat3 ( signal transducer and activator of transcription-3 ) [ XREF_BIBR ] .	Despite attaining normal serum leptin levels, leptin failed to reduce food intake or activate hypothalamic leptin receptor (LRb) signaling such as Stat3 (signal transducer and activator of transcription-3) [XREF_BIBR].	7	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	7	8	16	18
In the current study , we explored the mechanisms underlying leptin induced cardioprotection further with reference to the leptin receptor ( OB-R ) and obesity .	In the current study, we explored the mechanisms underlying leptin induced cardioprotection further with reference to the leptin receptor (OB-R) and obesity.	9	20	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	10	11	18	20
These concentrations of leptin can activate leptin receptor XREF_BIBR , XREF_BIBR .	These concentrations of leptin can activate leptin receptor XREF_BIBR, XREF_BIBR.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	3	4	6	8
However , after long-term exposure to a high-fat diet ( > 20 weeks ) , animals become resistant to leptin , even when it is infused directly into the brain , thus suggesting that in these animals , the leptin receptors lack the ability to activate leptin receptor signaling pathways [ XREF_BIBR ] .	However, after long-term exposure to a high-fat diet (> 20 weeks), animals become resistant to leptin, even when it is infused directly into the brain, thus suggesting that in these animals, the leptin receptors lack the ability to activate leptin receptor signaling pathways [XREF_BIBR].	39	51	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	39	40	46	48
To study leptin receptor signalling , the cells were treated with 40ng/mL of leptin in combination with SHLA or Lan-2 at a concentration of 1000mug/mL for 0 , 5 , 15 , 30 and 60min .	To study leptin receptor signalling, the cells were treated with 40ng/mL of leptin in combination with SHLA or Lan-2 at a concentration of 1000mug/mL for 0, 5, 15, 30 and 60min.	2	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	13	14	2	4
In addition , leptin receptor ( Ob-Rb ) was upregulated by leptin .	In addition, leptin receptor (Ob-Rb) was upregulated by leptin.	3	12	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	11	12	3	5
Furthermore , this study also demonstrated that leptin receptor mRNA was significantly increased by amylin and leptin coinfusion both centrally and peripherally , i.e ., in white adipose tissue and liver .	Furthermore, this study also demonstrated that leptin receptor mRNA was significantly increased by amylin and leptin coinfusion both centrally and peripherally, i.e., in white adipose tissue and liver.	7	17	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	16	17	7	9
Also , the absence of leptin signaling in leptin receptor knockout mice resulted in decreased neutrophil recruitment in acute lung injury XREF_BIBR .	Also, the absence of leptin signaling in leptin receptor knockout mice resulted in decreased neutrophil recruitment in acute lung injury XREF_BIBR.	5	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	5	6	8	10
Moreover , the threshold for sweet taste has also been related to the action of leptin on taste cells such that an increase in plasma leptin levels activates the leptin receptor , thus reducing the sweet taste information conveyed to the brain .	Moreover, the threshold for sweet taste has also been related to the action of leptin on taste cells such that an increase in plasma leptin levels activates the leptin receptor, thus reducing the sweet taste information conveyed to the brain.	25	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin levels	leptin	leptin receptor	leptin receptor	leptin receptor	25	26	29	31
Leptin signals through the short as well as the long form of the leptin receptor .	Leptin signals through the short as well as the long form of the leptin receptor.	0	15	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Leptin	Leptin	Leptin	leptin receptor	leptin receptor	leptin receptor	0	1	13	15
This is in contrast to the condition of obesity during the non pregnant state in which free leptin increases and levels of soluble leptin receptor remain constant .	This is in contrast to the condition of obesity during the non pregnant state in which free leptin increases and levels of soluble leptin receptor remain constant.	17	25	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	17	18	23	25
The peripheral hormone leptin signals the status of body energy stores to the central nervous system by binding and activating the leptin receptor ( LepRb ) on neurons that control energy balance and metabolism .	The peripheral hormone leptin signals the status of body energy stores to the central nervous system by binding and activating the leptin receptor (LepRb) on neurons that control energy balance and metabolism.	0	23	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	3	4	21	23
Leptin activates the long form of the leptin receptor ( LepRb ) on CNS neurons to mediate most leptin action , including the suppression of feeding .	Leptin activates the long form of the leptin receptor (LepRb) on CNS neurons to mediate most leptin action, including the suppression of feeding.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Leptin	Leptin	Leptin	leptin receptor	leptin receptor	leptin receptor	0	1	7	9
Most physiological functions of leptin are mediated centrally through leptin responsive neurons expressing the long isoform of leptin receptor ( LepRb ) distributed throughout the hypothalamus , and most predominantly in the arcuate nucleus XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Most physiological functions of leptin are mediated centrally through leptin responsive neurons expressing the long isoform of leptin receptor (LepRb) distributed throughout the hypothalamus, and most predominantly in the arcuate nucleus XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	2	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	4	5	17	19
Obese , diabetic C57BL/Ks db/db mice that lack the long-form leptin receptor exhibit no decrease in body weight or food intake when treated with leptin .	Obese, diabetic C57BL/Ks db/db mice that lack the long-form leptin receptor exhibit no decrease in body weight or food intake when treated with leptin.	10	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	24	25	10	12
For example , it was demonstrated in this study that the ability of leptin to reduce food intake is partially inhibited following was loss of astrocytic leptin-receptor signaling in adult mice .	For example, it was demonstrated in this study that the ability of leptin to reduce food intake is partially inhibited following was loss of astrocytic leptin-receptor signaling in adult mice.	11	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin-receptor	leptin-receptor	leptin-receptor	13	14	26	27
Of them , both prolonged feeding with a high-fat diet ( HFD ) and disruption of leptin signaling in leptin deficient ob/ob and leptin receptor deficient db/db hyperphagic mice were shown to result in obesity , insulin resistance , oxidative stress , changes in lipid and glucose homeostasis , and hepatic steatosis .	Of them, both prolonged feeding with a high-fat diet (HFD) and disruption of leptin signaling in leptin deficient ob/ob and leptin receptor deficient db/db hyperphagic mice were shown to result in obesity, insulin resistance, oxidative stress, changes in lipid and glucose homeostasis, and hepatic steatosis.	16	28	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	16	17	23	25
Moreover , LEP F also produced an increase of granulocyte and macrophage colony forming units and activated leptin receptor .	Moreover, LEP F also produced an increase of granulocyte and macrophage colony forming units and activated leptin receptor.	2	19	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LEP	LEP	LEP	leptin receptor	leptin receptor	leptin receptor	2	3	17	19
At the signaling level , leptin activates the leptin receptor , which has multiple splicing isoforms , although the long isoform mediates all known leptin actions .	At the signaling level, leptin activates the leptin receptor, which has multiple splicing isoforms, although the long isoform mediates all known leptin actions.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	5	6	8	10
A structurally similar membrane receptor to gp130 ( leptin receptor , OB-R ) is activated by the hormone leptin and also results in phosphorylation of STAT3 and the induction of responsive genes 71 .	A structurally similar membrane receptor to gp130 (leptin receptor, OB-R) is activated by the hormone leptin and also results in phosphorylation of STAT3 and the induction of responsive genes 71.	8	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	18	19	8	10
Leptin is mainly secreted by the adipose tissue and circulates to the brain to activate the long signaling-competent isoform of the leptin receptor ( OBR ) in the feeding centers of the hypothalamus , particularly the arcuate nucleus ( ARC ) .	Leptin is mainly secreted by the adipose tissue and circulates to the brain to activate the long signaling-competent isoform of the leptin receptor (OBR) in the feeding centers of the hypothalamus, particularly the arcuate nucleus (ARC).	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Leptin	Leptin	Leptin	leptin receptor	leptin receptor	leptin receptor	0	1	21	23
Therefore , leptin mediated resistance to amebiasis appears to function via its actions on intestinal epithelium , and requires leptin receptor signaling through both the STAT3 and SHP2 and ERK pathways .	Therefore, leptin mediated resistance to amebiasis appears to function via its actions on intestinal epithelium, and requires leptin receptor signaling through both the STAT3 and SHP2 and ERK pathways.	2	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	2	3	19	21
We investigated the role of leptin in LPS induced toxicity using leptin deficient ( ob/ob ) and leptin receptor deficient ( db/db ) mice .	We investigated the role of leptin in LPS induced toxicity using leptin deficient (ob/ob) and leptin receptor deficient (db/db) mice.	3	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	5	6	17	19
Leptin is one of the most important hormones secreted by adipose tissue and it regulates appetite , bone mass , basal metabolism , reproductive function and insulin secretion by binding and activating the long form of leptin receptor 26 .	Leptin is one of the most important hormones secreted by adipose tissue and it regulates appetite, bone mass, basal metabolism, reproductive function and insulin secretion by binding and activating the long form of leptin receptor 26.	0	38	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Leptin	Leptin	Leptin	leptin receptor	leptin receptor	leptin receptor	0	1	36	38
Leptin signals through several splice variants of the leptin receptor .	Leptin signals through several splice variants of the leptin receptor.	0	10	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Leptin	Leptin	Leptin	leptin receptor	leptin receptor	leptin receptor	0	1	8	10
SH-SY5Y , a human neuroblastoma cell line stably transfected with the Ob-Rb leptin receptor ( SH-SY5Y-ObRb ) , was treated with leptin .	SH-SY5Y, a human neuroblastoma cell line stably transfected with the Ob-Rb leptin receptor (SH-SY5Y-ObRb), was treated with leptin.	12	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	21	22	12	14
We investigated whether Otsuka Long-Evans Tokushima Fatty ( OLETF ) rats , which are a strain of hyperphagia induced obese rats , develop leptin resistance and whether caloric restriction reversed this leptin resistance induced leptin receptor ( ObRb ) deficit .	We investigated whether Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are a strain of hyperphagia induced obese rats, develop leptin resistance and whether caloric restriction reversed this leptin resistance induced leptin receptor (ObRb) deficit.	31	36	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	31	32	34	36
Thus , constant leptin overexpression induces leptin receptor desensitization that disrupts energy homeostasis characterized by an obese phenotype , whereas circadian expression may permit persistent leptin receptor activity that maintains energy homeostasis .	Thus, constant leptin overexpression induces leptin receptor desensitization that disrupts energy homeostasis characterized by an obese phenotype, whereas circadian expression may permit persistent leptin receptor activity that maintains energy homeostasis.	3	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin overexpression	leptin	leptin receptor	leptin receptor	leptin receptor	3	4	6	8
In conclusion , leptin induces neurogenesis and angiogenesis after stroke and leads to increased leptin receptor and pAMPK concentrations .	In conclusion, leptin induces neurogenesis and angiogenesis after stroke and leads to increased leptin receptor and pAMPK concentrations.	3	16	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	3	4	14	16
This Peregrine falcon leptin protein activates the chicken leptin receptor in vitro as determined through STAT3 driven luciferase production in CHO cells ( XREF_FIG ) .	This Peregrine falcon leptin protein activates the chicken leptin receptor in vitro as determined through STAT3 driven luciferase production in CHO cells (XREF_FIG).	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	3	4	8	10
The first set of studies examined expression of the leptin receptor ( OB-R ) in RA-SY5Y cells treated with 400 ng/ml leptin or placebo .	The first set of studies examined expression of the leptin receptor (OB-R) in RA-SY5Y cells treated with 400 ng/ml leptin or placebo.	9	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	21	22	9	11
In addition , leptin receptor ( OB-Rb ) was also upregulated by leptin in breast cancer cells .	In addition, leptin receptor (OB-Rb) was also upregulated by leptin in breast cancer cells.	3	16	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	12	13	3	5
Previous reports have shown that some synthetic sequences of leptin molecules can activate leptin receptor .	Previous reports have shown that some synthetic sequences of leptin molecules can activate leptin receptor.	9	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	9	10	13	15
Leptin mediates its effect by binding to and activating several specific leptin receptor isoforms including the main signaling isoform i.e. the long leptin receptor isoform ( ObRb ) .	Leptin mediates its effect by binding to and activating several specific leptin receptor isoforms including the main signaling isoform i.e. the long leptin receptor isoform (ObRb).	0	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Leptin	Leptin	Leptin	leptin receptor	leptin receptor	leptin receptor	0	1	11	13
This was done by evaluating some parameters of the following processes known to modulate leptin sensitivity : Leptin transport through the blood brain barrier ( BBB ) ; Activation of the neuronal leptin receptor ; Expression levels of various factors known to influence the neuronal leptin receptor activation ; Gene expression levels of the main hypothalamic neuropeptides involved in the anorexigenic effect of leptin .	This was done by evaluating some parameters of the following processes known to modulate leptin sensitivity : Leptin transport through the blood brain barrier (BBB); Activation of the neuronal leptin receptor; Expression levels of various factors known to influence the neuronal leptin receptor activation; Gene expression levels of the main hypothalamic neuropeptides involved in the anorexigenic effect of leptin.	13	40	Activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	14	15	32	34
Likewise , the mutant mCherry tagged leptin did not bind to or cause internalization of the leptin receptor , whereas the wild-type hormone exerted these functions ( XREF_FIG E ) .	Likewise, the mutant mCherry tagged leptin did not bind to or cause internalization of the leptin receptor, whereas the wild-type hormone exerted these functions (XREF_FIG E).	6	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	6	7	16	18
XREF_BIBR Metreleptin is a recombinant human leptin analog that binds to and activates the leptin receptor , and it is the only US Food and Drug Administration approved treatment for patients with CGL or AGL as an adjunct to diet and as replacement therapy to treat complications of leptin deficiency .	XREF_BIBR Metreleptin is a recombinant human leptin analog that binds to and activates the leptin receptor, and it is the only US Food and Drug Administration approved treatment for patients with CGL or AGL as an adjunct to diet and as replacement therapy to treat complications of leptin deficiency.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	6	7	14	16
Here , we show that intracerebroventricular administration of leptin reduces feed intake , modulates the expression of feeding related hypothalamic neuropeptides , activates leptin receptor and signal transducer and activator of transcription ( Ob-Rb and STAT ) pathway , and significantly increases the expression of autophagy related proteins ( Atg3 , Atg5 , Atg7 , beclin1 , and LC3B ) in chicken hypothalamus , liver , and muscle .	Here, we show that intracerebroventricular administration of leptin reduces feed intake, modulates the expression of feeding related hypothalamic neuropeptides, activates leptin receptor and signal transducer and activator of transcription (Ob-Rb and STAT) pathway, and significantly increases the expression of autophagy related proteins (Atg3, Atg5, Atg7, beclin1, and LC3B) in chicken hypothalamus, liver, and muscle.	6	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	8	9	23	25
Furthermore , leptin treatment of hypoxic cells increased the expression of the long and signaling form of the leptin receptor ( ObRL ) , which was augmented on co-incubation with VEGF .	Furthermore, leptin treatment of hypoxic cells increased the expression of the long and signaling form of the leptin receptor (ObRL), which was augmented on co-incubation with VEGF.	2	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	2	3	18	20
Typically , leptin activates POMC neurons and leptin receptor ( LepR )-expressing neurons of ventral premammilary nucleus ( PMV ) , known to release of anorexigenic hormones .	Typically, leptin activates POMC neurons and leptin receptor (LepR)-expressing neurons of ventral premammilary nucleus (PMV), known to release of anorexigenic hormones.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	2	3	7	9
We first performed a dose response curve to determine the amount of leptin needed to activate the leptin receptor at the hypothalamus .	We first performed a dose response curve to determine the amount of leptin needed to activate the leptin receptor at the hypothalamus.	10	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	amount of leptin	leptin	leptin receptor	leptin receptor	leptin receptor	12	13	17	19
Leptin ( 100 nM ) significantly increased mRNA and protein expression of both the long form ( ObRb ) and the short form ( ObRt ) leptin receptor in M2 macrophages ( All P < 0.01 ) .	Leptin (100 nM) significantly increased mRNA and protein expression of both the long form (ObRb) and the short form (ObRt) leptin receptor in M2 macrophages (All P < 0.01).	0	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Leptin	Leptin	Leptin	leptin receptor	leptin receptor	leptin receptor	0	1	26	28
Interestingly , leptin ( 1 nM , 24 hours ) also significantly increased both leptin receptor ( LEPR ) and androgen receptor ( AR ) mRNA .	Interestingly, leptin (1 nM, 24 hours) also significantly increased both leptin receptor (LEPR) and androgen receptor (AR) mRNA.	2	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	2	3	14	16
Neurons in the VMH express the leptin receptor , are activated by leptin ( as measured by induction of either pSTAT3 or cFos ) , and leptin rapidly depolarizes and increases the firing rate of steroidogenic factor-1 ( SF1 )-containing neurons in this brain area .	Neurons in the VMH express the leptin receptor, are activated by leptin (as measured by induction of either pSTAT3 or cFos), and leptin rapidly depolarizes and increases the firing rate of steroidogenic factor-1 (SF1)-containing neurons in this brain area.	6	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	12	13	6	8
Leptin mediates it effect on food intake by activating the leptin receptor which leads to the activation of the Janus kinase 2 ( JAK2 )/STAT3 pathway .	Leptin mediates it effect on food intake by activating the leptin receptor which leads to the activation of the Janus kinase 2 (JAK2)/STAT3 pathway.	0	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Leptin	Leptin	Leptin	leptin receptor	leptin receptor	leptin receptor	0	1	10	12
LEP activates the leptin receptor in different tissues and basically acts as a mitogen , survival factor and regulator of metabolism , feeding behavior and energy homeostasis .	LEP activates the leptin receptor in different tissues and basically acts as a mitogen, survival factor and regulator of metabolism, feeding behavior and energy homeostasis.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LEP	LEP	LEP	leptin receptor	leptin receptor	leptin receptor	0	1	3	5
Leptin resistance is induced by several defects involving the leptin receptor , in BBB transport , cellular transduction , the induction of feedback inhibitors , and biological systems with changes in cellular networks [ XREF_BIBR ] ; overactive leptin receptor signaling results in its intense phosphorylation via the ( Janus kinase ) JAK-2 and STAT-3 pathway , which improves suppression of cytokine signaling 3 ( SOCS-3 ) expression [ XREF_BIBR ] .	Leptin resistance is induced by several defects involving the leptin receptor, in BBB transport, cellular transduction, the induction of feedback inhibitors, and biological systems with changes in cellular networks [XREF_BIBR]; overactive leptin receptor signaling results in its intense phosphorylation via the (Janus kinase) JAK-2 and STAT-3 pathway, which improves suppression of cytokine signaling 3 (SOCS-3) expression [XREF_BIBR].	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Leptin	Leptin	Leptin	leptin receptor	leptin receptor	leptin receptor	0	1	9	11
The action of SHLA , Lan1 and Lan2 on leptin stimulated leptin receptor ( ObR ) gene and protein in different cell lines .	The action of SHLA, Lan1 and Lan2 on leptin stimulated leptin receptor (ObR) gene and protein in different cell lines.	5	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	9	10	11	13
gp130 and OSMR is activated only by OSM , but gp130 and LIFR can be activated by either LIF , OSM or both .	gp130 and OSMR is activated only by OSM, but gp130 and LIFR can be activated by either LIF, OSM or both.	10	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	18	19	10	11
In contrast , LIF does not activate STAT3 , ERK , or the gp130 receptor in human N tera-2/D1 EC cells , although all receptor components are expressed .	In contrast, LIF does not activate STAT3, ERK, or the gp130 receptor in human N tera-2/D1 EC cells, although all receptor components are expressed.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	3	4	13	14
However , the LIF induced down-regulation of RPE65 required a functional gp130 and STAT3 cascade intrinsic to RPE .	However, the LIF induced down-regulation of RPE65 required a functional gp130 and STAT3 cascade intrinsic to RPE.	2	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	3	4	11	12
gp130 and LIFR can be activated by LIF or OSM , but gp130 and OSMR is activated by OSM only .	gp130 and LIFR can be activated by LIF or OSM, but gp130 and OSMR is activated by OSM only.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	7	8	0	1
LIF stimulated OPC proliferation requires gp130 signaling within OPCs .	LIF stimulated OPC proliferation requires gp130 signaling within OPCs.	0	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	0	1	5	6
In the presence of ligand , the monomeric subunits associate to form the functional receptor complexes : LIF induces the formation of a heterodimeric receptor ( LIFR plus gp130 ) , and CNTF also induces the formation of a heteromultimeric receptor .	In the presence of ligand, the monomeric subunits associate to form the functional receptor complexes : LIF induces the formation of a heterodimeric receptor (LIFR plus gp130), and CNTF also induces the formation of a heteromultimeric receptor.	17	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	17	18	28	29
Upon binding to the LIF receptor ( LIFR ) , LIF causes heterodimerization of the low-affinity LIFR and gp130 , which acts as the main receptor for intracellular signal transduction ( XREF_FIG ) .	Upon binding to the LIF receptor (LIFR), LIF causes heterodimerization of the low-affinity LIFR and gp130, which acts as the main receptor for intracellular signal transduction (XREF_FIG).	10	21	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	10	11	18	19
As exogenous LIF has been shown to increase endogenous gp130 ligand production and receptor number , only the autoregulatory positive feedback loop can account for the relative increase in pStat3 with local cell density XREF_BIBR .	As exogenous LIF has been shown to increase endogenous gp130 ligand production and receptor number, only the autoregulatory positive feedback loop can account for the relative increase in pStat3 with local cell density XREF_BIBR.	1	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	2	3	9	10
LIF activation of gp130 activates ERK5 via a Gab1 and Shp2 complex , and specifically induces an eccentric hypertrophic phenotype XREF_BIBR , whereas gp130 activation primarily of STAT3 promotes concentric hypertrophy XREF_BIBR .	LIF activation of gp130 activates ERK5 via a Gab1 and Shp2 complex, and specifically induces an eccentric hypertrophic phenotype XREF_BIBR, whereas gp130 activation primarily of STAT3 promotes concentric hypertrophy XREF_BIBR.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	0	1	3	4
LIF induced OPC proliferation is dramatically reduced when gp130 is ablated from the OL lineage , suggesting that their proliferation requires LIF induced gp130 signaling in these cells .	LIF induced OPC proliferation is dramatically reduced when gp130 is ablated from the OL lineage, suggesting that their proliferation requires LIF induced gp130 signaling in these cells.	21	24	induced	Positive_early_activation	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	21	22	23	24
LIF signals through a receptor consisting of gp130 and the low affinity LIF receptor ( LIFR ) , while the CNTF receptor consists of gp130 , LIFR , and the low affinity CNTF receptor ( CNTFR ) .	LIF signals through a receptor consisting of gp130 and the low affinity LIF receptor (LIFR), while the CNTF receptor consists of gp130, LIFR, and the low affinity CNTF receptor (CNTFR).	0	35	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	0	1	24	25
While LIF alone activated gp130 and STAT3 pathway and mimicked anti-fibrotic effects of the extract of endothelial progenitor cells in cultured fibroblasts , the effect was not entirely reproducible in vivo , probably due to the variable expression of LIF receptor .	While LIF alone activated gp130 and STAT3 pathway and mimicked anti-fibrotic effects of the extract of endothelial progenitor cells in cultured fibroblasts, the effect was not entirely reproducible in vivo, probably due to the variable expression of LIF receptor.	1	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	1	2	4	5
XREF_BIBR , XREF_BIBR Although cholinergic sympathetic neurons do not project to the heart , and constitute only a small proportion overall of sympathetic neurons , it is noteworthy that in heart failure , transdifferentiation of adrenergic neurons into cholinergic neurons , probably through LIF and CT-1 activation of gp130 receptors , has been demonstrated in the adult rat .	XREF_BIBR, XREF_BIBR Although cholinergic sympathetic neurons do not project to the heart, and constitute only a small proportion overall of sympathetic neurons, it is noteworthy that in heart failure, transdifferentiation of adrenergic neurons into cholinergic neurons, probably through LIF and CT-1 activation of gp130 receptors, has been demonstrated in the adult rat.	43	49	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	43	44	48	49
LIF activates gp130 and STAT3 dependent signaling , leading to increased transcription of stem cell state regulators while simultaneously inhibiting differentiation [ XREF_BIBR , XREF_BIBR ] .	LIF activates gp130 and STAT3 dependent signaling, leading to increased transcription of stem cell state regulators while simultaneously inhibiting differentiation [XREF_BIBR, XREF_BIBR].	0	6	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	0	1	2	3
These results suggest that LIF activates gp130 and induces myocardial hypertrophy by acting as an autocrine and paracrine factor in cardiac myocytes .	These results suggest that LIF activates gp130 and induces myocardial hypertrophy by acting as an autocrine and paracrine factor in cardiac myocytes.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	4	5	6	7
Additionally , CNTF- and LIF mediated gp130 receptor activation appears to be neuroprotective as loss of endogenous CNTF , antagonism of LIF , and disruption of gp130 and LIFR-beta signaling all result in increased disease severity in MOG induced experimental autoimmune encephalomyelitis ( EAE ) , an animal model of MS .	Additionally, CNTF- and LIF mediated gp130 receptor activation appears to be neuroprotective as loss of endogenous CNTF, antagonism of LIF, and disruption of gp130 and LIFR-beta signaling all result in increased disease severity in MOG induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS.	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	LIF	LIF	LIF	gp130	gp130	gp130	4	5	6	7
Whereas OSM binding to the OSMR has been shown to promote cancer cell malignancy and reduce long-term survival in patients with breast cancer [ XREF_BIBR ] , LIF activation of the LIFR suppresses tumor growth and metastasis [ XREF_BIBR ] .	Whereas OSM binding to the OSMR has been shown to promote cancer cell malignancy and reduce long-term survival in patients with breast cancer [XREF_BIBR], LIF activation of the LIFR suppresses tumor growth and metastasis [XREF_BIBR].	27	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LIF	LIF	LIF	LIFR	LIFR	LIFR	27	28	31	32
As shown in XREF_FIG , the expression levels of LIFR in adipocytes treated with LIF dramatically decreased within 1-hr as previously reported [ XREF_BIBR ] .	As shown in XREF_FIG, the expression levels of LIFR in adipocytes treated with LIF dramatically decreased within 1-hr as previously reported [XREF_BIBR].	7	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	LIF	LIF	LIF	LIFR	LIFR	LIFR	14	15	9	10
LIF signals through the heterodimeric complex of common glycoprotein 130 ( gp130 ) and LIF receptor ( LIFR ) subunits .	LIF signals through the heterodimeric complex of common glycoprotein 130 (gp130) and LIF receptor (LIFR) subunits.	0	16	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LIF	LIF	LIF	LIF receptor	LIF receptor	LIF receptor	0	1	14	16
Binding of LIF to its receptor on the plasma membrane induces heterodimerization of the LIF receptor with another membrane protein , gp130 .	Binding of LIF to its receptor on the plasma membrane induces heterodimerization of the LIF receptor with another membrane protein, gp130.	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	LIF receptor	LIF receptor	LIF receptor	2	3	14	16
Therefore increasing in the expression of LIFr in stem cells treated with LIF can be due to positive feedback between LIF and LIFr .	Therefore increasing in the expression of LIFr in stem cells treated with LIF can be due to positive feedback between LIF and LIFr.	4	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	LIF	LIF	LIF	LIFr	LIFr	LIFr	12	13	6	7
Signal transducer and activator of transcription 3 signaling in cardiac myocytes in context is best illustrated by the induction of phosphorylation events downstream of LIF induced dimerization of its membrane receptor LIFR with gp130 .	Signal transducer and activator of transcription 3 signaling in cardiac myocytes in context is best illustrated by the induction of phosphorylation events downstream of LIF induced dimerization of its membrane receptor LIFR with gp130.	22	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIF	LIF	LIF	LIFR	LIFR	LIFR	24	25	31	32
Because LFng did not prevent interactions between Dll3 and N1 , it seemed that LFng enhancement of Dll1 signaling in combination with Dll3-inhibitory effects could account for LFng reversing Dll3 cis inhibition .	Because LFng did not prevent interactions between Dll3 and N1, it seemed that LFng enhancement of Dll1 signaling in combination with Dll3-inhibitory effects could account for LFng reversing Dll3 cis inhibition.	14	18	enhancement	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LFng	LFng	LFng	Dll1	Dll1	Dll1	14	15	17	18
We have observed that both RFNG and LFNG can increase the presence of DLL1 and DLL4 on the plasma membrane .	We have observed that both RFNG and LFNG can increase the presence of DLL1 and DLL4 on the plasma membrane.	5	15	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LFNG	LFNG	LFNG	DLL1	DLL1	DLL1	7	8	13	14
More importantly , tests in the human embryonic kidney 293 cell line show that Lfng expression significantly potentiates the response of Notch1 to Dll1 , inhibits its response to Jag1 , but enhances the responses of Notch2 to both ligands .	More importantly, tests in the human embryonic kidney 293 cell line show that Lfng expression significantly potentiates the response of Notch1 to Dll1, inhibits its response to Jag1, but enhances the responses of Notch2 to both ligands.	14	24	potentiates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Lfng	Lfng expression	lfng	Dll1	Dll1	dll1	14	15	23	24
In vitro LFNG may enhance DLL1 mediated signalling and inhibits Jagged1 mediated signalling through Notch1 , or potentiate both Jagged1- and DLL1 mediated signalling via Notch2 [ XREF_BIBR ] indicating a complex modulation of Notch activity by differential glycosylation .	In vitro LFNG may enhance DLL1 mediated signalling and inhibits Jagged1 mediated signalling through Notch1, or potentiate both Jagged1- and DLL1 mediated signalling via Notch2 [XREF_BIBR] indicating a complex modulation of Notch activity by differential glycosylation.	0	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LFNG	LFNG	LFNG	DLL1	DLL1	DLL1	2	3	5	6
We have previously reported that the glycosyltransferase LFng enhances Dll1 induced N signaling by using CSL reporter assays .	We have previously reported that the glycosyltransferase LFng enhances Dll1 induced N signaling by using CSL reporter assays.	5	10	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LFng	LFng	LFng	Dll1	Dll1	Dll1	7	8	9	10
Although LFng enhanced Dll1 activation of N1 and suppressed J1 activation of N1 as previously reported , neither rDll3 nor mDll3 activated N1 in the presence or absence of LFng ( XREF_FIG D ) .	Although LFng enhanced Dll1 activation of N1 and suppressed J1 activation of N1 as previously reported, neither rDll3 nor mDll3 activated N1 in the presence or absence of LFng (XREF_FIG D).	1	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LFng	LFng	LFng	Dll1	Dll1	Dll1	1	2	3	4
Conversely , LFng enhancement of Dll1 induced N signaling was suppressed by Dll3 in a dose dependent manner ( XREF_FIG B ) .	Conversely, LFng enhancement of Dll1 induced N signaling was suppressed by Dll3 in a dose dependent manner (XREF_FIG B).	2	6	enhancement	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LFng	LFng	LFng	Dll1	Dll1	Dll1	2	3	5	6
In co-culture NOTCH signaling assays , LFNG generally enhances DLL1 induced , but inhibits JAG1 induced , NOTCH signaling .	In co-culture NOTCH signaling assays, LFNG generally enhances DLL1 induced, but inhibits JAG1 induced, NOTCH signaling.	6	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LFNG	LFNG	LFNG	DLL1	DLL1	DLL1	6	7	9	10
Overexpression of Lfng significantly enhanced the N1-NLuc response to Dll1 and suppressed its response to Jag1 .	Overexpression of Lfng significantly enhanced the N1-NLuc response to Dll1 and suppressed its response to Jag1.	0	10	enhanced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Lfng	Overexpression of Lfng	lfng	Dll1	Dll1	dll1	2	3	9	10
In addition , we provide evidence that distinct modes of Notch signaling from NSC derivatives expressing Jag1 and Dll1 ligands , most likely mediated by Lfng , directly affect the NSC cell cycle .	In addition, we provide evidence that distinct modes of Notch signaling from NSC derivatives expressing Jag1 and Dll1 ligands, most likely mediated by Lfng, directly affect the NSC cell cycle.	18	26	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lfng	Lfng	Lfng	Dll1	Dll1	Dll1	25	26	18	19
Thus , Lfng prolongs Notch1 signaling to promote self-renewal more than differentiation during the early stages of beta-selection .	Thus, Lfng prolongs Notch1 signaling to promote self-renewal more than differentiation during the early stages of beta-selection.	2	5	prolongs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lfng	Lfng	Lfng	Notch1	Notch1	Notch1	2	3	4	5
Lunatic Fringe ( Lfng ) enhances Notch1 activation by Delta like 4 ( DL4 ) to promote Notch1 dependent T-lineage commitment of thymus seeding progenitors .	Lunatic Fringe (Lfng) enhances Notch1 activation by Delta like 4 (DL4) to promote Notch1 dependent T-lineage commitment of thymus seeding progenitors.	1	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lfng	Lfng	Lfng	Notch1	Notch1	Notch1	3	4	6	7
Another possibility is that weak or low-threshold Notch1 signals may be sufficient to maintain glucose metabolism in resting DN3a thymocytes , whereas much stronger , Lfng enhanced Notch1 signals may be required to induce proliferation of DN3b thymocytes at the onset of beta-selection .	Another possibility is that weak or low-threshold Notch1 signals may be sufficient to maintain glucose metabolism in resting DN3a thymocytes, whereas much stronger, Lfng enhanced Notch1 signals may be required to induce proliferation of DN3b thymocytes at the onset of beta-selection.	23	28	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Lfng	Lfng	Lfng	Notch1	Notch1	Notch1	25	26	27	28
Lfng modulates the activity of the Notch1 receptor by glycosylation and frucosylation of the N-terminal extracellular EGF domains .	Lfng modulates the activity of the Notch1 receptor by glycosylation and frucosylation of the N-terminal extracellular EGF domains.	0	7	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lfng	Lfng	Lfng	Notch1	Notch1	Notch1	0	1	6	7
Removal of Lfng both diminishes the intensity of Dll-Notch signaling and augments the production of NICD following Jag-Notch binding .	Removal of Lfng both diminishes the intensity of Dll-Notch signaling and augments the production of NICD following Jag-Notch binding.	0	18	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lfng	Lfng	Lfng	NICD	NICD	NICD	2	3	15	16
Dll3 also cell autonomously attenuated the enhancement of Dll1 induced N signaling that was mediated by the modulator LFng , and Dll3 inhibition was reversed by LFng .	Dll3 also cell autonomously attenuated the enhancement of Dll1 induced N signaling that was mediated by the modulator LFng, and Dll3 inhibition was reversed by LFng.	21	27	reversed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	LFng	LFng	LFng	Dll3	Dll3	Dll3	26	27	21	22
To determine whether LFng modification of N enables Dll3 to function as an activating ligand , NIH 3T3 cells were cotransfected with either alkaline phosphatase tagged LFng or secreted alkaline phosphatase with N1 and a CSL reporter .	To determine whether LFng modification of N enables Dll3 to function as an activating ligand, NIH 3T3 cells were cotransfected with either alkaline phosphatase tagged LFng or secreted alkaline phosphatase with N1 and a CSL reporter.	3	9	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LFng	LFng	LFng	Dll3	Dll3	Dll3	3	4	8	9
LFng does not enable Dll3 to activate N1 signaling .	LFng does not enable Dll3 to activate N1 signaling.	0	5	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LFng	LFng	LFng	Dll3	Dll3	Dll3	0	1	4	5
We found that LFng modification of N did not enable Dll3 to function in trans as an activating ligand .	We found that LFng modification of N did not enable Dll3 to function in trans as an activating ligand.	3	11	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LFng	LFng	LFng	Dll3	Dll3	Dll3	3	4	10	11
These data indicate that Lmo2 may accelerate Tal1 mediated leukemogenesis by enhancing the sequestration and/or inhibition of the E47 and HEB heterodimer .	These data indicate that Lmo2 may accelerate Tal1 mediated leukemogenesis by enhancing the sequestration and/or inhibition of the E47 and HEB heterodimer.	4	8	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lmo2	Lmo2	Lmo2	Tal1	Tal1	Tal1	4	5	7	8
Though the mechanism by which LDB1 and Lmo2 mediate Scl and TAL1 function is unclear , ETO-2 is an attractive candidate for differentially controlling Scl and TAL1 activity during hematopoiesis .	Though the mechanism by which LDB1 and Lmo2 mediate Scl and TAL1 function is unclear, ETO-2 is an attractive candidate for differentially controlling Scl and TAL1 activity during hematopoiesis.	5	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lmo2	Lmo2	Lmo2	TAL1	TAL1	TAL1	7	8	11	12
For example , the ability of the Lmo2 protein to interact with other proteins led to the identification of a multimeric protein complex in erythroid cells , comprising Tal1 and Scl , E47 , Ldb1 , and GATA1 in addition to Lmo2 , which binds specifically to a bipartite DNA sequence [ XREF_BIBR ] .	For example, the ability of the Lmo2 protein to interact with other proteins led to the identification of a multimeric protein complex in erythroid cells, comprising Tal1 and Scl, E47, Ldb1, and GATA1 in addition to Lmo2, which binds specifically to a bipartite DNA sequence [XREF_BIBR].	7	37	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lmo2	Lmo2	Lmo2	Tal1	Tal1	Tal1	7	8	28	29
It has previously been shown that the interaction of LMO2 with TAL1 directly increases the stability of TAL1 and E2A heterodimer .	It has previously been shown that the interaction of LMO2 with TAL1 directly increases the stability of TAL1 and E2A heterodimer.	7	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LMO2	LMO2	LMO2	TAL1	TAL1	TAL1	9	10	17	18
This study reveals that Tal1 and Lmo2 synergy does not require the DNA binding properties of TAL1 , suggesting that Lmo2 does not contribute to leukemia by enhancing or altering the transcriptional activity of the Tal1 and E47 or HEB heterodimer .	This study reveals that Tal1 and Lmo2 synergy does not require the DNA binding properties of TAL1, suggesting that Lmo2 does not contribute to leukemia by enhancing or altering the transcriptional activity of the Tal1 and E47 or HEB heterodimer.	20	40	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lmo2	Lmo2	Lmo2	Tal1	Tal1	Tal1	20	21	35	36
To determine how Lmo2 contributes to TAL1 mediated leukemogenesis and to understand the basis for the TAL1 and LMO oncogene cooperativity , we asked whether the DNA binding properties of TAL1 were required to cooperate with Lmo2 to cause disease in mice .	To determine how Lmo2 contributes to TAL1 mediated leukemogenesis and to understand the basis for the TAL1 and LMO oncogene cooperativity, we asked whether the DNA binding properties of TAL1 were required to cooperate with Lmo2 to cause disease in mice.	3	7	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Lmo2	Lmo2	Lmo2	TAL1	TAL1	TAL1	3	4	6	7
Individual mutations of these tyrosine residues demonstrated that tyrosines 753 and 759 , but not 743 , were responsible for Lck induced activation of PLCgamma2 .	Individual mutations of these tyrosine residues demonstrated that tyrosines 753 and 759, but not 743, were responsible for Lck induced activation of PLCgamma2.	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	Lck	Lck	Lck	PLCgamma2	PLCgamma2	PLCgamma2	20	21	24	25
22 have suggested that activation of PLCgamma-2 by Lck is mediated by phosphorylation of tyrosines located in the SH2-SH3 linker region .	22 have suggested that activation of PLCgamma-2 by Lck is mediated by phosphorylation of tyrosines located in the SH2-SH3 linker region.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Lck	Lck	Lck	PLCgamma-2	PLCgamma-2	PLCgamma-2	8	9	6	7
A mutant form of PLCgamma2 , in which all three tyrosines at positions 743 , 753 , and 759 in the SH2-SH3 linker region were replaced by phenylalanines , exhibited decreased Lck induced phosphorylation and completely abolished the Lck dependent activation of PLCgamma2 .	A mutant form of PLCgamma2, in which all three tyrosines at positions 743, 753, and 759 in the SH2-SH3 linker region were replaced by phenylalanines, exhibited decreased Lck induced phosphorylation and completely abolished the Lck dependent activation of PLCgamma2.	38	43	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Lck	Lck	Lck	PLCgamma2	PLCgamma2	PLCgamma2	38	39	42	43
These data show that constitutive phosphorylation of LRRK2 modulates its recruitment , in an ARHGEF7 dependent manner , to TGN46 positive Golgi organelles and suggest that CK1alpha has physiologically relevant effects on LRRK2 phenotypes .	These data show that constitutive phosphorylation of LRRK2 modulates its recruitment, in an ARHGEF7 dependent manner, to TGN46 positive Golgi organelles and suggest that CK1alpha has physiologically relevant effects on LRRK2 phenotypes.	5	16	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	phosphorylation of LRRK2	lrrk2	ARHGEF7	ARHGEF7	arhgef7	7	8	14	15
A subsequent study found that LRIG1 mediated Met destabilization is c-Cbl independent , despite Met being a well-known target of c-Cbl .	A subsequent study found that LRIG1 mediated Met destabilization is c-Cbl independent, despite Met being a well-known target of c-Cbl.	5	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRIG1	LRIG1	LRIG1	c-Cbl	c-Cbl	c-Cbl	5	6	10	11
In alpha-synuclein and LRRK2 double mutant mice , overexpression of LRRK2 promoted and knockout of LRRK2 suppressed the abnormal aggregation and somatic accumulation of alpha-synuclein as well as the progressive loss of cortical and striatal neurons of the forebrain induced by overexpression of Ala53Thr alpha-synuclein .	In alpha-synuclein and LRRK2 double mutant mice, overexpression of LRRK2 promoted and knockout of LRRK2 suppressed the abnormal aggregation and somatic accumulation of alpha-synuclein as well as the progressive loss of cortical and striatal neurons of the forebrain induced by overexpression of Ala53Thr alpha-synuclein.	13	25	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	15	16	24	25
LRRK2 overexpression also promoted abnormal somatic accumulation of alpha-synuclein in striatal neurons of A53T alpha-synuclein transgenic mice .	LRRK2 overexpression also promoted abnormal somatic accumulation of alpha-synuclein in striatal neurons of A53T alpha-synuclein transgenic mice.	0	9	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2 overexpression	lrrk2	alpha-synuclein	alpha-synuclein	alpha-synuclein	0	1	8	9
Therefore , we next examined p62 in LRRK2 silenced neurons , and we did not observe changes in its protein levels , concluding that LRRK2 modulation of alpha-synuclein is independent of p62 , at least in these conditions .	Therefore, we next examined p62 in LRRK2 silenced neurons, and we did not observe changes in its protein levels, concluding that LRRK2 modulation of alpha-synuclein is independent of p62, at least in these conditions.	24	28	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	24	25	27	28
LRRK2 may also modulate autophagy by affecting alpha-synuclein , encoded by one of the PD related genes , SNCA .	LRRK2 may also modulate autophagy by affecting alpha-synuclein, encoded by one of the PD related genes, SNCA.	0	9	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	0	1	7	8
LRRK2 modulates alpha-synuclein trafficking .	LRRK2 modulates alpha-synuclein trafficking.	0	3	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	0	1	2	3
The ability of aggregated alpha-synuclein to inhibit autophagy suggests a synergistic mechanism in which LRRK2 inhibits degradation of alpha-synuclein , which leads to the accumulation of oligomeric and aggregated alpha-synuclein , which adds to age related autophagic inhibition associated with LRRK2 expression .	The ability of aggregated alpha-synuclein to inhibit autophagy suggests a synergistic mechanism in which LRRK2 inhibits degradation of alpha-synuclein, which leads to the accumulation of oligomeric and aggregated alpha-synuclein, which adds to age related autophagic inhibition associated with LRRK2 expression.	14	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	14	15	18	19
Because alpha-synuclein in Lewy bodies is present in fibrillar structures 96 , we might infer that LRRK2 can promote the aggregation or deposition of alpha-synuclein , i.e. that LRRK2 is a director and alpha-synuclein is an actor in PD pathogenesis .	Because alpha-synuclein in Lewy bodies is present in fibrillar structures 96, we might infer that LRRK2 can promote the aggregation or deposition of alpha-synuclein, i.e. that LRRK2 is a director and alpha-synuclein is an actor in PD pathogenesis.	16	25	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	16	17	24	25
Administration of a selective LRRK2 kinase inhibitor slowed the propagation of alpha-synuclein in culture and reduced synucleinopathy lesions in a transgenic mouse model .	Administration of a selective LRRK2 kinase inhibitor slowed the propagation of alpha-synuclein in culture and reduced synucleinopathy lesions in a transgenic mouse model.	4	12	slowed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	4	5	11	12
Transcriptional stimulation of SNCA by LRRK2 was also translated into a mild but significant increase in SNCA protein expression .	Transcriptional stimulation of SNCA by LRRK2 was also translated into a mild but significant increase in SNCA protein expression.	1	6	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	SNCA	SNCA	SNCA	5	6	3	4
By contrast , inhibition of LRRK2 expression prevented the disintegration of the Golgi apparatus in neurons overexpressing alpha-syn and suppressed the accumulation of alpha-syn in cell bodies .	By contrast, inhibition of LRRK2 expression prevented the disintegration of the Golgi apparatus in neurons overexpressing alpha-syn and suppressed the accumulation of alpha-syn in cell bodies.	5	24	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2 expression	lrrk2	alpha-syn	alpha-syn	alpha-syn	5	6	23	24
On the other hand , LRRK2 over-expression enhances alpha-synuclein-mediated neuropathology by promoting the abnormal aggregation and toxicity of alpha-synuclein , while alpha-synuclein cytotoxicity was abrogated by genetic ablation of LRRK2 [ XREF_BIBR , XREF_BIBR ] .	On the other hand, LRRK2 over-expression enhances alpha-synuclein-mediated neuropathology by promoting the abnormal aggregation and toxicity of alpha-synuclein, while alpha-synuclein cytotoxicity was abrogated by genetic ablation of LRRK2 [XREF_BIBR, XREF_BIBR].	21	33	abrogated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	29	30	21	22
Furthermore , the excessive LRRK2 expression promotes somatic accumulation of alpha-synuclein , accompanied with impaired microtubule dynamics , Golgi organization and the UPS pathways .	Furthermore, the excessive LRRK2 expression promotes somatic accumulation of alpha-synuclein, accompanied with impaired microtubule dynamics, Golgi organization and the UPS pathways.	4	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2 expression	lrrk2	alpha-synuclein	alpha-synuclein	alpha-synuclein	4	5	10	11
Activation of the ERK pathway mediates the induction of SNCA by LRRK2 , since treatment with the specific inhibitor of the ERK pathway U0126 completely suppresses the transcriptional up-regulation of SNCA elicited by LRRK2 .	Activation of the ERK pathway mediates the induction of SNCA by LRRK2, since treatment with the specific inhibitor of the ERK pathway U0126 completely suppresses the transcriptional up-regulation of SNCA elicited by LRRK2.	5	12	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	SNCA	SNCA	SNCA	11	12	9	10
Over-expression of [ wt ] LRRK2 significantly increased the levels of endogenous SNCA mRNA about 2-fold compared to mock transfected cells ( relative quantity [ RQ ] ; wt 1.756 +/-0.136 , n = 23 , vs Mock 1.000 +/-0.2849 , n = 12 ; p < 0.01 ) ( XREF_FIG ) .	Over-expression of [wt] LRRK2 significantly increased the levels of endogenous SNCA mRNA about 2-fold compared to mock transfected cells (relative quantity [RQ]; wt 1.756 +/-0.136, n = 23, vs Mock 1.000 +/-0.2849, n = 12; p < 0.01) (XREF_FIG).	0	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	Over-expression of [wt] LRRK2	lrrk2	SNCA	SNCA	snca	5	6	12	13
However , the slow kinetics of alpha-synuclein phosphorylation by LRRK2 makes it unlikely that LRRK2 contributes alpha-synuclein via direct interaction as the enzyme and the substrate [ XREF_BIBR , XREF_BIBR ] .	However, the slow kinetics of alpha-synuclein phosphorylation by LRRK2 makes it unlikely that LRRK2 contributes alpha-synuclein via direct interaction as the enzyme and the substrate [XREF_BIBR, XREF_BIBR].	14	19	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	14	15	16	17
Up-regulation of SNCA by LRRK2 was also consistently observed at the protein level by enzyme linked immunosorbent assay ( ELISA ) .	Up-regulation of SNCA by LRRK2 was also consistently observed at the protein level by enzyme linked immunosorbent assay (ELISA).	0	5	Up-regulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	SNCA	SNCA	SNCA	4	5	2	3
In transgenic mice , an interaction between LRRK2 and alpha-synuclein has been suggested by XREF_BIBR who demonstrated that the presence of excess WT/G2019S LRRK2 can accelerate the progression of A53T alpha-synuclein mediated neuropathology in a CAMKII driven inducible model , and promote the formation of high molecular weight alpha-synuclein aggregates -- with ablation of LRRK2 acting to modulate pathology .	In transgenic mice, an interaction between LRRK2 and alpha-synuclein has been suggested by XREF_BIBR who demonstrated that the presence of excess WT/G2019S LRRK2 can accelerate the progression of A53T alpha-synuclein mediated neuropathology in a CAMKII driven inducible model, and promote the formation of high molecular weight alpha-synuclein aggregates -- with ablation of LRRK2 acting to modulate pathology.	19	49	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	23	24	48	49
Genetic regulation of SNCA expression levels is linked to the development of neuropathology , thus , induction of SNCA by LRRK2 points towards SNCA up-regulation as a potential pathogenic mechanism in patients with LRRK2 associated PD .	Genetic regulation of SNCA expression levels is linked to the development of neuropathology, thus, induction of SNCA by LRRK2 points towards SNCA up-regulation as a potential pathogenic mechanism in patients with LRRK2 associated PD.	16	21	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	SNCA	SNCA	SNCA	20	21	18	19
ERK activation mediates LRRK2 induced transcriptional up-regulation of SNCA .	ERK activation mediates LRRK2 induced transcriptional up-regulation of SNCA.	2	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	SNCA	SNCA	SNCA	3	4	8	9
The excessive LRRK2 expression seems to enhance the accumulation of alpha-synuclein protein and neuropathology when alpha-synuclein is also overexpressed in neurons ; loss of LRRK2 seems to alleviate the alpha-synuclein evoked neuropathology .	The excessive LRRK2 expression seems to enhance the accumulation of alpha-synuclein protein and neuropathology when alpha-synuclein is also overexpressed in neurons; loss of LRRK2 seems to alleviate the alpha-synuclein evoked neuropathology.	2	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2 expression	lrrk2	alpha-synuclein protein	alpha-synuclein protein	alpha-synuclein protein	2	3	10	12
According to our results , these mechanisms might imply transcriptional up-regulation of SNCA by LRRK2 , since over-expressed wild-type and G2019S LRRK2 stimulate by almost 2-fold endogenous SNCA transcription in transiently transfected HEK293 cells .	According to our results, these mechanisms might imply transcriptional up-regulation of SNCA by LRRK2, since over-expressed wild-type and G2019S LRRK2 stimulate by almost 2-fold endogenous SNCA transcription in transiently transfected HEK293 cells.	8	15	up-regulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	SNCA	SNCA	SNCA	14	15	12	13
Overexpression of LRRK2 in A53T alpha-synuclein transgenic mice caused earlier and more widespread somatic accumulation of alpha-synuclein .	Overexpression of LRRK2 in A53T alpha-synuclein transgenic mice caused earlier and more widespread somatic accumulation of alpha-synuclein.	0	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	Overexpression of LRRK2	lrrk2	alpha-synuclein	alpha-synuclein	alpha-synuclein	2	3	16	17
Potent LRRK2 kinase inhibitors , which are being developed for clinical use , block the increased alpha-synuclein aggregation in G2019S-LRRK2-expressing neurons .	Potent LRRK2 kinase inhibitors, which are being developed for clinical use, block the increased alpha-synuclein aggregation in G2019S-LRRK2-expressing neurons.	1	17	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	1	2	16	17
For example , whereas some studies suggest that the loss of LRRK2 function reduces the aggregation and thereby toxicity of alpha-synuclein [ XREF_BIBR ] , others have demonstrated the accumulation of alpha-synuclein-positive inclusions ( albeit in kidneys ) following the ablation of LRRK2 in animals [ XREF_BIBR ] .	For example, whereas some studies suggest that the loss of LRRK2 function reduces the aggregation and thereby toxicity of alpha-synuclein [XREF_BIBR], others have demonstrated the accumulation of alpha-synuclein-positive inclusions (albeit in kidneys) following the ablation of LRRK2 in animals [XREF_BIBR].	11	22	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	11	12	20	21
Moreover , LRRK2 promoted the abnormal aggregation and somatic accumulation of alpha-synuclein in A53T mice , which likely results from the impairment of microtubule dynamics , Golgi organization , and the ubiquitin-proteasome pathway .	Moreover, LRRK2 promoted the abnormal aggregation and somatic accumulation of alpha-synuclein in A53T mice, which likely results from the impairment of microtubule dynamics, Golgi organization, and the ubiquitin-proteasome pathway.	2	14	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	2	3	11	12
LRRK2 enhances age dependent alpha-synuclein toxicity in C. elegans .	LRRK2 enhances age dependent alpha-synuclein toxicity in C. elegans.	0	5	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	0	1	4	5
BTK is activated by the Lyn and SYK protein kinases following activation of the B cell receptor .	BTK is activated by the Lyn and SYK protein kinases following activation of the B cell receptor.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	BTK	BTK	BTK	5	6	0	1
BTK is activated by Lyn or Syk , which triggers the activation of phospholipase Cgamma ( PLCgamma ) to promote Ca 2+ influx XREF_BIBR .	BTK is activated by Lyn or Syk, which triggers the activation of phospholipase Cgamma (PLCgamma) to promote Ca 2+ influx XREF_BIBR.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	BTK	BTK	BTK	4	5	0	1
Both proteins are involved in the induction of Ca 2+ mobilization [ XREF_BIBR ] and the accepted model of FcepsilonRI signaling involves Lyn in the phosphorylation of both in an indirect manner : LAT1 via Lyn mediated Syk activation and PLC-gamma1 via Lyn mediated Btk activation [ XREF_BIBR ] .	Both proteins are involved in the induction of Ca 2+ mobilization [XREF_BIBR] and the accepted model of FcepsilonRI signaling involves Lyn in the phosphorylation of both in an indirect manner : LAT1 via Lyn mediated Syk activation and PLC-gamma1 via Lyn mediated Btk activation [XREF_BIBR].	38	47	mediated	Positive_early_activation	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	42	43	44	45
XREF_BIBR , XREF_BIBR BTK is activated following phosphorylation by SYK and LYN .	XREF_BIBR, XREF_BIBR BTK is activated following phosphorylation by SYK and LYN.	2	12	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	LYN	LYN	LYN	BTK	BTK	BTK	11	12	3	4
In fact , Btk is activated by the upstream Src family kinases Blk , Lyn , and Fyn , and in turn , phosphorylates phospholipase-Cgamma ( PLCgamma ) leading to calcium mobilization and activation of nuclear factor kappaB ( NF-kappaB ) , and mitogen activated protein kinase ( MAPK ) pathways .	In fact, Btk is activated by the upstream Src family kinases Blk, Lyn, and Fyn, and in turn, phosphorylates phospholipase-Cgamma (PLCgamma) leading to calcium mobilization and activation of nuclear factor kappaB (NF-kappaB), and mitogen activated protein kinase (MAPK) pathways.	3	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	14	15	3	4
This system was used to determine whether the net effect of Lyn is to activate or inhibit Btk function .	This system was used to determine whether the net effect of Lyn is to activate or inhibit Btk function.	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	11	12	17	18
LYN and SYK have been shown to activate BTK in B cells XREF_BIBR XREF_BIBR .	LYN and SYK have been shown to activate BTK in B cells XREF_BIBR XREF_BIBR.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LYN	LYN	LYN	BTK	BTK	BTK	0	1	8	9
Btk is activated during BCR signaling by the concerted action of Syk and Lyn kinases , BLNK and PI ( 3,4,5 ) P 3 [ XREF_BIBR ] .	Btk is activated during BCR signaling by the concerted action of Syk and Lyn kinases, BLNK and PI (3,4,5) P 3 [XREF_BIBR].	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	13	14	0	1
BTK is activated by kinases Blk , Lyn , and Fyn and then activates PLCgamma which subsequently leads to Ca2+ activation of NF-kappaB and MAP kinase pathways .	BTK is activated by kinases Blk, Lyn, and Fyn and then activates PLCgamma which subsequently leads to Ca2+ activation of NF-kappaB and MAP kinase pathways.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	BTK	BTK	BTK	7	8	0	1
A number of cell signaling studies clearly show that Btk is activated by Lyn , a Src family kinase , through phosphorylation on activation loop tyrosine 551 ( Y ( 551 ) ) .	A number of cell signaling studies clearly show that Btk is activated by Lyn, a Src family kinase, through phosphorylation on activation loop tyrosine 551 (Y (551)).	9	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	13	14	9	10
These observations thus support our conclusion that the PI3K dependent , Lyn mediated activation of Btk may be part of a signaling pathway , downstream of LAT2 , which controls the amplification and/or maintenance of the PLC gamma1 -dependent calcium signal initially dependent upon interactions of PLC gamma1 with LAT and SLP-76 .	These observations thus support our conclusion that the PI3K dependent, Lyn mediated activation of Btk may be part of a signaling pathway, downstream of LAT2, which controls the amplification and/or maintenance of the PLC gamma1 -dependent calcium signal initially dependent upon interactions of PLC gamma1 with LAT and SLP-76.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	11	12	15	16
In the B cell antigen receptor ( BCR ) signaling pathway , BCR aggregation activates the protein tyrosine kinases Lyn and Syk , which in turn activate Btk .	In the B cell antigen receptor (BCR) signaling pathway, BCR aggregation activates the protein tyrosine kinases Lyn and Syk, which in turn activate Btk.	14	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	19	20	27	28
MAML1 , in turn , recruits and activates the p300 HAT .	MAML1, in turn, recruits and activates the p300 HAT.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300 HAT	p300 HAT	p300 HAT	0	1	9	11
In conclusion , we provide evidence that the transcriptional coactivator MAML1 acts cooperatively with EGR1 to increase transcriptional activity of the EGR1 and p300 promoters in embryonic kidney cells .	In conclusion, we provide evidence that the transcriptional coactivator MAML1 acts cooperatively with EGR1 to increase transcriptional activity of the EGR1 and p300 promoters in embryonic kidney cells.	7	24	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300	p300	p300	10	11	23	24
MAML1 and EGR1 synergistically activate the p300 promoter .	MAML1 and EGR1 synergistically activate the p300 promoter.	0	7	synergistically activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300	p300	p300	0	1	6	7
MAML1 directly enhances p300 HAT activity , and this coincides with the translocation of MAML1 , p300 and acetylated histones to nuclear bodies .	MAML1 directly enhances p300 HAT activity, and this coincides with the translocation of MAML1, p300 and acetylated histones to nuclear bodies.	0	5	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300 HAT	p300 HAT	p300 HAT	0	1	3	5
Since we found that MAML1 enhances p300 autoacetylation , and HAT activity , we also investigated if MAML1 increases p300 transcriptional activity of a reporter gene in cell culture .	Since we found that MAML1 enhances p300 autoacetylation, and HAT activity, we also investigated if MAML1 increases p300 transcriptional activity of a reporter gene in cell culture.	17	21	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300	p300	p300	17	18	19	20
As shown in XREF_FIG D , MAML1 1-1016 strongly enhances p300 transcriptional coactivation , while MAML1 1-625 only moderately enhances p300 activity .	As shown in XREF_FIG D, MAML1 1-1016 strongly enhances p300 transcriptional coactivation, while MAML1 1-625 only moderately enhances p300 activity.	15	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300	p300	p300	15	16	20	21
We show in this report that MAML1 enhances p300 activity , and have investigated the molecular mechanisms and function for this interplay .	We show in this report that MAML1 enhances p300 activity, and have investigated the molecular mechanisms and function for this interplay.	6	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300	p300	p300	6	7	8	9
We show that MAML1 physically interacted with , and acted cooperatively with EGR1 to increase transcriptional activity of the EGR1 and p300 promoters , which both contain EGR1 binding sites .	We show that MAML1 physically interacted with, and acted cooperatively with EGR1 to increase transcriptional activity of the EGR1 and p300 promoters, which both contain EGR1 binding sites.	3	22	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300	p300	p300	3	4	21	22
We also found that full-length MAML1 potentiates p300 dependent transcription coactivation , and is even more pronounced for p300 lacking the activation loop .	We also found that full-length MAML1 potentiates p300 dependent transcription coactivation, and is even more pronounced for p300 lacking the activation loop.	4	16	potentiates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300	p300	p300	5	6	7	8
Interestingly , expression of MAML1 strongly upregulates p300 catalytic activity in vivo , and forms large nuclear foci containing p300 and acetylated histones .	Interestingly, expression of MAML1 strongly upregulates p300 catalytic activity in vivo, and forms large nuclear foci containing p300 and acetylated histones.	2	9	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	expression of MAML1	maml1	p300	p300	p300	4	5	7	8
The p300 HAT activity and coactivator function is potentiated by MAML1 .	The p300 HAT activity and coactivator function is potentiated by MAML1.	1	11	potentiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300 HAT	p300 HAT	p300 HAT	10	11	1	3
EGR1 alone activated the p300-luc reporter in the presence of TPA , and co-transfection of MAML1 with EGR1 strongly increased the activity of the p300 reporter ( XREF_FIG ) .	EGR1 alone activated the p300-luc reporter in the presence of TPA, and co-transfection of MAML1 with EGR1 strongly increased the activity of the p300 reporter (XREF_FIG).	13	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300	p300	p300	15	16	24	25
We also found that , in cell culture , MAML1 potentiates p300 dependent transcription coactivation to a greater extent when p300 lacks the activation loop .	We also found that, in cell culture, MAML1 potentiates p300 dependent transcription coactivation to a greater extent when p300 lacks the activation loop.	9	12	potentiates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p300	p300	p300	9	10	11	12
Finally , we demonstrated that TCDD induced active TGFbeta1 was significantly blocked by LTBP knockdown .	Finally, we demonstrated that TCDD induced active TGFbeta1 was significantly blocked by LTBP knockdown.	7	14	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	LTBP	LTBP	LTBP	TGFbeta1	TGFbeta1	TGFbeta1	13	14	8	9
Intriguingly , LTBP1 increases TGF-beta1 and TGF-beta2 at the same time in glioma cells [ XREF_BIBR ] .	Intriguingly, LTBP1 increases TGF-beta1 and TGF-beta2 at the same time in glioma cells [XREF_BIBR].	2	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LTBP1	LTBP1	LTBP1	TGF-beta1	TGF-beta1	TGF-beta1	2	3	4	5
Mechanical loading of LTBP-1 fibrils enhances TGF-beta1 release .	Mechanical loading of LTBP-1 fibrils enhances TGF-beta1 release.	3	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LTBP-1	LTBP-1	LTBP-1	TGF-beta1	TGF-beta1	TGF-beta1	3	4	6	7
Our data demonstrated that inhibition of LTBP1 expression by miR-M4-5p induced a significant decrease of TGF-beta1 secretion and activation , following a significant increase in the expression of c-Myc , a well-known oncogene .	Our data demonstrated that inhibition of LTBP1 expression by miR-M4-5p induced a significant decrease of TGF-beta1 secretion and activation, following a significant increase in the expression of c-Myc, a well-known oncogene.	6	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LTBP1	LTBP1 expression	ltbp1	TGF-beta1	TGF-beta1	tgf-beta1	6	7	15	16
Furthermore , TCDD induced active TGFbeta1 release was significantly inhibited by LTBP1 knockdown .	Furthermore, TCDD induced active TGFbeta1 release was significantly inhibited by LTBP1 knockdown.	5	12	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	LTBP1	LTBP1	LTBP1	TGFbeta1	TGFbeta1	TGFbeta1	11	12	5	6
HtrA1 may facilitate keloid pathogenesis through the activation of TGF-beta1 mediated by LTBP-1 cleavage .	HtrA1 may facilitate keloid pathogenesis through the activation of TGF-beta1 mediated by LTBP-1 cleavage.	7	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LTBP-1	LTBP-1	LTBP-1	TGF-beta1	TGF-beta1	TGF-beta1	12	13	9	10
Coexpression of MAML1 with NICD and CSL proteins in cells induces proteolytic destruction of NICD , indicating that it might also help in the disassembly of the enhancer complex following signaling .	Coexpression of MAML1 with NICD and CSL proteins in cells induces proteolytic destruction of NICD, indicating that it might also help in the disassembly of the enhancer complex following signaling.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	Coexpression of MAML1	maml1	NICD	NICD	nicd	2	3	14	15
Transfection of MAML1 in vehicle treated-cells caused Notch-1 and MAML1 to be strongly associated to the HEY1 promoter , while p53 , as expected , was undetectable .	Transfection of MAML1 in vehicle treated-cells caused Notch-1 and MAML1 to be strongly associated to the HEY1 promoter, while p53, as expected, was undetectable.	0	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	Notch-1	Notch-1	Notch-1	2	3	7	8
Moreover , co-transfection of the dominant negative MAML1 ( dn-MAML1 ) abrogated the ability of NICD to suppress Klf4 promoter activity in a dose dependent manner ( XREF_FIG ; lanes 4-7 ) .	Moreover, co-transfection of the dominant negative MAML1 (dn-MAML1) abrogated the ability of NICD to suppress Klf4 promoter activity in a dose dependent manner (XREF_FIG; lanes 4-7).	2	16	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	NICD	NICD	NICD	7	8	15	16
Considering that Lyn is key Src kinase in CLL XREF_BIBR , it can be assumed that Lyn itself mediates HS1 redistribution .	Considering that Lyn is key Src kinase in CLL XREF_BIBR, it can be assumed that Lyn itself mediates HS1 redistribution.	16	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	HS1	HS1	HS1	16	17	19	20
HS1 Nuclear Escape after B Cell Receptor Engagement is Mediated by Lyn Kinase .	HS1 Nuclear Escape after B Cell Receptor Engagement is Mediated by Lyn Kinase.	0	12	Mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	HS1	HS1	HS1	11	12	0	1
In contrast , dasatinib , a dual Bcr-Abl and Src kinase inhibitor , inhibited the phosphorylation of both BCR-ABL and Lyn , and induced apoptosis of the Bcr-Abl cell line overexpressing p53/56 Lyn .	In contrast, dasatinib, a dual Bcr-Abl and Src kinase inhibitor, inhibited the phosphorylation of both BCR-ABL and Lyn, and induced apoptosis of the Bcr-Abl cell line overexpressing p53/56 Lyn.	3	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lyn	dasatinib, a dual Bcr-Abl and Src kinase inhibitor, inhibited the phosphorylation of both BCR-ABL and Lyn	lyn	Lyn	Lyn	lyn	20	21	32	33
The results also clearly demonstrate that bt/VWF mediated agglutination induced TxA2 production is dependent on signaling apparently initiated by Lyn , enhanced by Src , and propagated through Syk , SLP-76 , PI3K , PLCgamma2 , and protein kinase C ( PKC ) .	The results also clearly demonstrate that bt/VWF mediated agglutination induced TxA2 production is dependent on signaling apparently initiated by Lyn, enhanced by Src, and propagated through Syk, SLP-76, PI3K, PLCgamma2, and protein kinase C (PKC).	17	38	initiated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Lyn	Lyn	Lyn	PLCgamma2	PLCgamma2	PLCgamma2	19	20	34	35
Given the recent evidence of cross-talk between the p53 and Notch signal transduction pathways , we have investigated whether MAML1 may also be a transcriptional coactivator of p53 .	Given the recent evidence of cross-talk between the p53 and Notch signal transduction pathways, we have investigated whether MAML1 may also be a transcriptional coactivator of p53.	19	28	be a transcriptional coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	p53	p53	p53	19	20	27	28
Overexpression of wild-type MAML1 as well as a mutant , defective in Notch signaling , enhanced the p53 dependent gene induction in mammalian cells , whereas MAML1 knockdown reduced the p53 dependent gene expression .	Overexpression of wild-type MAML1 as well as a mutant, defective in Notch signaling, enhanced the p53 dependent gene induction in mammalian cells, whereas MAML1 knockdown reduced the p53 dependent gene expression.	0	20	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	Overexpression of wild-type MAML1	maml1	p53	p53	p53	3	4	17	18
More recently , it has been revealed that miR-200 members target Notch pathway components , such as Jagged-1 and the mastermind like co-activators Maml-2 and Maml-3 , thereby mediating enhanced Notch activation by ZEB1 in PC cells [ XREF_BIBR ] .	More recently, it has been revealed that miR-200 members target Notch pathway components, such as Jagged-1 and the mastermind like co-activators Maml-2 and Maml-3, thereby mediating enhanced Notch activation by ZEB1 in PC cells [XREF_BIBR].	20	31	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Maml-3	Maml-3	Maml-3	Notch	Notch	Notch	25	26	30	31
We show that miR-200 members target Notch pathway components , such as Jagged1 ( Jag1 ) and the mastermind like coactivators Maml2 and Maml3 , thereby mediating enhanced Notch activation by ZEB1 .	We show that miR-200 members target Notch pathway components, such as Jagged1 (Jag1) and the mastermind like coactivators Maml2 and Maml3, thereby mediating enhanced Notch activation by ZEB1.	18	29	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Maml3	Maml3	Maml3	Notch	Notch	Notch	23	24	28	29
LT-alpha is strongly upregulated in intrahepatic lymphocytes after PH and can also activate lymphotoxin beta receptor ( LTbetaR ) , another receptor on hepatocytes , when co-expressed with LT-beta .	LT-alpha is strongly upregulated in intrahepatic lymphocytes after PH and can also activate lymphotoxin beta receptor (LTbetaR), another receptor on hepatocytes, when co-expressed with LT-beta.	0	27	activate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	LT-alpha	LT-alpha	lt-alpha	lymphotoxin beta receptor	lymphotoxin beta receptor (LTbetaR), another receptor on hepatocytes, when co-expressed	lymphotoxin beta receptor	0	1	13	16
This suggests that Lymphotoxin beta receptor ( LTbetaR ) activation by LTalpha , LTbeta and/or LIGHT could play a key role in ELS assembly and pro tumorigenic processes XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	This suggests that Lymphotoxin beta receptor (LTbetaR) activation by LTalpha, LTbeta and/or LIGHT could play a key role in ELS assembly and pro tumorigenic processes XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	LTalpha	LTalpha	LTalpha	Lymphotoxin beta receptor	Lymphotoxin beta receptor	Lymphotoxin beta receptor	11	12	3	6
Additionally , it has been shown that overexpression of Maged1 in HEK293 cells activates p53 dependent transactivation of the p21 CIP1 and WAF1 promoter [ XREF_BIBR ] .	Additionally, it has been shown that overexpression of Maged1 in HEK293 cells activates p53 dependent transactivation of the p21 CIP1 and WAF1 promoter [XREF_BIBR].	7	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Maged1	overexpression of Maged1	maged1	WAF1	WAF1	waf1	9	10	22	23
In control experiments , neither MAML1 alone nor p300 alone stimulated baseline CBF-1 transcriptional activity in amounts up to 100 ng .	In control experiments, neither MAML1 alone nor p300 alone stimulated baseline CBF-1 transcriptional activity in amounts up to 100 ng.	4	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAML1	MAML1	MAML1	CBF-1	CBF-1	CBF-1	5	6	12	13
Also , MAGEs can alter the subcellular localization of the ligase allowing it to find novel substrates , such as MAGEL2 directing TRIM27 to endosomes for ubiquitination WASH .	Also, MAGEs can alter the subcellular localization of the ligase allowing it to find novel substrates, such as MAGEL2 directing TRIM27 to endosomes for ubiquitination WASH.	16	23	directing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAGEL2	MAGEL2	MAGEL2	TRIM27	TRIM27	TRIM27	20	21	22	23
Simultaneously , TAK-1 phosphorylates members of the mitogen activated protein kinase ( MAPK ) kinase i.e. MKK family including MKK4 , MKK3 , or MKK6 which , in turn , activate c-Jun N-terminal kinase ( JNK ) and p38 MAPK .	Simultaneously, TAK-1 phosphorylates members of the mitogen activated protein kinase (MAPK) kinase i.e. MKK family including MKK4, MKK3, or MKK6 which, in turn, activate c-Jun N-terminal kinase (JNK) and p38 MAPK.	17	34	activate	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	19	20	31	34
Simultaneous disruption of the Mkk4 and Mkk7 genes was required to block JNK activation caused by exposure of cells to environmental stress .	Simultaneous disruption of the Mkk4 and Mkk7 genes was required to block JNK activation caused by exposure of cells to environmental stress.	4	13	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mkk4	Mkk4	Mkk4	JNK	JNK	JNK	4	5	12	13
The mechanism of saturated FFA stimulated JNK activation is mediated by the MAP kinase kinases ( MAP2K ) MKK4 and MKK7 .	The mechanism of saturated FFA stimulated JNK activation is mediated by the MAP kinase kinases (MAP2K) MKK4 and MKK7.	6	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	18	19	6	7
It was also found that TNF induced NF-kappaB activation was abrogated in cells deleted of MKK4 gene which is a dual-specificity kinase that activates both JNK and p38 MAPK [ XREF_BIBR ] .	It was also found that TNF induced NF-kappaB activation was abrogated in cells deleted of MKK4 gene which is a dual-specificity kinase that activates both JNK and p38 MAPK [XREF_BIBR].	15	28	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	15	16	25	26
A variety of environmental stresses , such as osmotic shock , UV radiation , and heat shock , or the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 reportedly induce activation of c-Jun amino-terminal kinases ( JNK ) , which are usually activated by SEK1 and MKK4 .	A variety of environmental stresses, such as osmotic shock, UV radiation, and heat shock, or the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 reportedly induce activation of c-Jun amino-terminal kinases (JNK), which are usually activated by SEK1 and MKK4.	33	45	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	43	44	35	36
Disruption of the Map2k4 gene or the Map2k7 gene in hepatocytes partially suppressed JNK signaling , indicated by reduced phosphorylation of JNK and cJun ( XREF_FIG ) .	Disruption of the Map2k4 gene or the Map2k7 gene in hepatocytes partially suppressed JNK signaling, indicated by reduced phosphorylation of JNK and cJun (XREF_FIG).	3	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Map2k4	Map2k4	Map2k4	JNK	JNK	JNK	3	4	13	14
JNK is activated through phosphorylation of the Thr-Pro-Tyr motif in its activation loop by MAPK kinases ( MAPKKs ) MKK4 and MKK7 .	JNK is activated through phosphorylation of the Thr-Pro-Tyr motif in its activation loop by MAPK kinases (MAPKKs) MKK4 and MKK7.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	19	20	0	1
ERK1 and ERK2 are activated by MEK1 and MEK2 , p38 by MKK3 and MKK6 , while JNK is activated by MKK4 and MKK7 .	ERK1 and ERK2 are activated by MEK1 and MEK2, p38 by MKK3 and MKK6, while JNK is activated by MKK4 and MKK7.	17	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	21	22	17	18
It has been reported that JNK is activated following phosphorylation by MKK4 and MKK7 , and that it is responsible for the phosphorylation of c-Jun XREF_BIBR , XREF_BIBR .	It has been reported that JNK is activated following phosphorylation by MKK4 and MKK7, and that it is responsible for the phosphorylation of c-Jun XREF_BIBR, XREF_BIBR.	5	13	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	11	12	5	6
Dual phosphorylation of MKK4 ( pMKK4 ) at S257 and T261 enhances the MKK4 induced upregulation of JNK and p38 , which are involved in the regulation of apoptosis in various cells .	Dual phosphorylation of MKK4 (pMKK4) at S257 and T261 enhances the MKK4 induced upregulation of JNK and p38, which are involved in the regulation of apoptosis in various cells.	1	23	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pMKK4	phosphorylation of MKK4 (pMKK4) at S257	pmkk4	JNK	JNK	jnk	5	6	17	18
Both JNK1/2 and p38 MAPK can be activated by MKK4 .	Both JNK1/2 and p38 MAPK can be activated by MKK4.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK1/2	JNK1/2	JNK1/2	9	10	1	2
The present study assessed the hypothesis that , in addition to ERK1/2 , c-Jun NH2-terminal kinase ( JNK ) and p38 mitogen activated protein kinase ( p38MAPK ) , the other two mammalian members of MAPKs that are originally identified as stress activated protein kinases , are activated specifically by MAPK kinase 4 ( MAP2K4 ) or MAP2K6 and play a pro life role in RVLM during experimental brain stem death .	The present study assessed the hypothesis that, in addition to ERK1/2, c-Jun NH2-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38MAPK), the other two mammalian members of MAPKs that are originally identified as stress activated protein kinases, are activated specifically by MAPK kinase 4 (MAP2K4) or MAP2K6 and play a pro life role in RVLM during experimental brain stem death.	13	55	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAP2K4	MAP2K4	MAP2K4	c-Jun NH2-terminal kinase	c-Jun NH2-terminal kinase	c-Jun NH2-terminal kinase	54	55	13	16
Collectively , these results imply that MKK4 and Hep might work together rather than in parallel , for instance in the same complex , to mediate Wnd triggered JNK activation and cell death in Drosophila .	Collectively, these results imply that MKK4 and Hep might work together rather than in parallel, for instance in the same complex, to mediate Wnd triggered JNK activation and cell death in Drosophila.	6	29	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	6	7	28	29
The previous findings that SAPKs and JNKs could be activated by both MKK4 dependent and MKK4 independent signaling cascades 232425 , suggested that cells can sense particular stresses and trigger distinct signaling paths in response .	The previous findings that SAPKs and JNKs could be activated by both MKK4 dependent and MKK4 independent signaling cascades 232425, suggested that cells can sense particular stresses and trigger distinct signaling paths in response.	4	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	12	13	6	7
Activation of MMP-1 promoter by C2-ceramide is also effectively inhibited by kinase deficient forms of ERK1/2 kinase ( MEK1/2 ) activator Raf-1 , ERK1 and ERK2 , SAPK and JNK activator SEK1 , or SAPKbeta .	Activation of MMP-1 promoter by C2-ceramide is also effectively inhibited by kinase deficient forms of ERK1/2 kinase (MEK1/2) activator Raf-1, ERK1 and ERK2, SAPK and JNK activator SEK1, or SAPKbeta.	16	32	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	31	32	29	30
JNK or p38 MAPK activities are increased upon phosphorylation by MAPK kinase ( MKK4 and MKK7 or MKK3 and MKK6 ) [ XREF_BIBR ] .	JNK or p38 MAPK activities are increased upon phosphorylation by MAPK kinase (MKK4 and MKK7 or MKK3 and MKK6) [XREF_BIBR].	0	19	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	13	14	0	1
SPRK is capable of activating MKK4 by phosphorylation of serine and threonine residues , and mutant forms of MKK4 that lack the phosphorylation sites Ser ( 254 ) and Thr ( 258 ) block SPRK induced JNK activation .	SPRK is capable of activating MKK4 by phosphorylation of serine and threonine residues, and mutant forms of MKK4 that lack the phosphorylation sites Ser (254) and Thr (258) block SPRK induced JNK activation.	16	37	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	18	19	36	37
The upstream MKK4 and MKK7 kinases mediate JNK activation via dual phosphorylation at Thr 183 and Tyr 185 .	The upstream MKK4 and MKK7 kinases mediate JNK activation via dual phosphorylation at Thr 183 and Tyr 185.	0	8	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	2	3	7	8
JNK is activated via dual phosphorylation by MKK4 and MMK7 .	JNK is activated via dual phosphorylation by MKK4 and MMK7.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	7	8	0	1
The results indicate that Galpha ( 12 ) attenuates the activation of MKK3 and MKK4 , which are known to stimulate only p38MAPK or p38MAPK and JNK , respectively .	The results indicate that Galpha (12) attenuates the activation of MKK3 and MKK4, which are known to stimulate only p38MAPK or p38MAPK and JNK, respectively.	10	27	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	14	15	26	27
These effects , which required the phosphatase activity of JSP-1 , were blocked by expression of a dominant negative mutant form of MKK4 , a MAP2K that phosphorylates and activates JNK , suggesting that the site of action of the phosphatase is upstream of MKK4 in the JNK signaling cascade .	These effects, which required the phosphatase activity of JSP-1, were blocked by expression of a dominant negative mutant form of MKK4, a MAP2K that phosphorylates and activates JNK, suggesting that the site of action of the phosphatase is upstream of MKK4 in the JNK signaling cascade.	20	31	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	22	23	30	31
Ohtsuka et al reported that the combination of anti-death receptor antibodies and chemotherapy agents led to a synergistic activation of the JNK and p38 MAP kinase which was mediated by MEK4 in breast , prostate and colon cancer cells .	Ohtsuka et al reported that the combination of anti-death receptor antibodies and chemotherapy agents led to a synergistic activation of the JNK and p38 MAP kinase which was mediated by MEK4 in breast, prostate and colon cancer cells.	18	38	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK4	MEK4	MEK4	JNK	JNK	JNK	30	31	21	22
On the basis that JNK activation is mediated by two upstream MAPK kinases ( MKKs ) , MKK4 and MKK7 , and that both MKKs are activated by the further upstream MAPK and Erk kinase kinase 1 ( MEKK1 ) , we next sought to investigate whether the MEKK1-MKK4/7 signaling pathway is also negatively involved in TLR2 induction .	On the basis that JNK activation is mediated by two upstream MAPK kinases (MKKs), MKK4 and MKK7, and that both MKKs are activated by the further upstream MAPK and Erk kinase kinase 1 (MEKK1), we next sought to investigate whether the MEKK1-MKK4/7 signaling pathway is also negatively involved in TLR2 induction.	4	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	17	18	4	5
In contrast , neither of the JNK activators MKK4 or MKK7 showed a significant increase in activity during ischaemia in the perfused heart ( XREF_FIG C and D ) .	In contrast, neither of the JNK activators MKK4 or MKK7 showed a significant increase in activity during ischaemia in the perfused heart (XREF_FIG C and D).	3	11	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	8	9	6	7
Overexpression of a dominant negative mutant form of SEK1 , an upstream activator of JNK , likewise suppressed JNK activation and inhibited apoptosis .	Overexpression of a dominant negative mutant form of SEK1, an upstream activator of JNK, likewise suppressed JNK activation and inhibited apoptosis.	6	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	8	9	18	19
MKK4 activates MAPK members of the JNK and p38 families , whereas MKK7 only activates JNK family members .	MKK4 activates MAPK members of the JNK and p38 families, whereas MKK7 only activates JNK family members.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	0	1	6	7
JNK is activated by JNK activating kinase ( JNKK1 and JNKK2 ) , a subfamily of the dual specificity MAP kinase kinase ( MEK ) family , through phosphorylation on threonine ( Thr ) 183 and tyrosine ( Tyr ) 185 residues .	JNK is activated by JNK activating kinase (JNKK1 and JNKK2), a subfamily of the dual specificity MAP kinase kinase (MEK) family, through phosphorylation on threonine (Thr) 183 and tyrosine (Tyr) 185 residues.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNKK1	JNKK1	JNKK1	JNK	JNK	JNK	8	9	0	1
The interaction between ephrinB1 and CNK1 links p115RhoGEF and RhoA with MKK4 ( an ephrinB1 associated protein ) that promotes JNK activation as well as cell migration .	The interaction between ephrinB1 and CNK1 links p115RhoGEF and RhoA with MKK4 (an ephrinB1 associated protein) that promotes JNK activation as well as cell migration.	9	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	11	12	20	21
The MAPK kinases MKK4 and MKK7 are known to activate JNK by phosphorylation at residues Thr183 and Tyr185 [ XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR ] .	The MAPK kinases MKK4 and MKK7 are known to activate JNK by phosphorylation at residues Thr183 and Tyr185 [XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR].	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	3	4	10	11
In the presence of oxidative stress and inflammation , the MAPK kinases , MKK4 and MKK7 activate JNK proteins via phosphorylation [ XREF_BIBR ] .	In the presence of oxidative stress and inflammation, the MAPK kinases, MKK4 and MKK7 activate JNK proteins via phosphorylation [XREF_BIBR].	11	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	13	14	17	18
The JNKs are activated by the MAPKKs ( MKK4 and MKK7 ) .	The JNKs are activated by the MAPKKs (MKK4 and MKK7).	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	8	9	1	2
However , MKK4 is preferably an activator of JNK and MKK3 and MKK6 are the predominant activator of the p38 pathway [ XREF_BIBR ] .	However, MKK4 is preferably an activator of JNK and MKK3 and MKK6 are the predominant activator of the p38 pathway [XREF_BIBR].	2	10	is preferably an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	2	3	8	9
Over-expression of constitutively active MKK4 , an upstream protein kinase that directly activates JNK , also inhibited apo A-I promoter activity , while over-expression of a dominant negative MKK4 de-repressed apo A-I promoter activity in TNF alpha treated cells .	Over-expression of constitutively active MKK4, an upstream protein kinase that directly activates JNK, also inhibited apo A-I promoter activity, while over-expression of a dominant negative MKK4 de-repressed apo A-I promoter activity in TNF alpha treated cells.	0	14	directly activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MKK4	Over-expression of constitutively active MKK4	mkk4	JNK	JNK	jnk	4	5	13	14
Recent work in synoviocytes from patients with rheumatoid arthritis has shown that IL-1 activation of JNK by MKK4 and MKK7 requires the upstream activity of the TGF-beta activated kinase 1 ( TAK1 ) [ XREF_BIBR ] .	Recent work in synoviocytes from patients with rheumatoid arthritis has shown that IL-1 activation of JNK by MKK4 and MKK7 requires the upstream activity of the TGF-beta activated kinase 1 (TAK1) [XREF_BIBR].	13	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	17	18	15	16
Furthermore , overexpression of a dominant inhibitory form of SEK1 , the upstream kinase regulator of JNK , inhibited both JNK activation and p21 accumulation .	Furthermore, overexpression of a dominant inhibitory form of SEK1, the upstream kinase regulator of JNK, inhibited both JNK activation and p21 accumulation.	7	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	9	10	20	21
MKK4 in shear induced JNK activation .	MKK4 in shear induced JNK activation.	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	0	1	4	5
Both MKK4 and MKK7 , by preferentially phosphorylating different residues in the activating loop , synergistically activate JNK .	Both MKK4 and MKK7, by preferentially phosphorylating different residues in the activating loop, synergistically activate JNK.	0	18	synergistically activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	1	2	17	18
Although SEK1 -/- thymocytes failed to induce SAPK and JNK in response to PMA/Ca 2+ ionophore , SEK1 -/- RAG2 -/- thymocytes proliferated and made IL-2 after PMA/Ca 2+ ionophore and CD3 and CD28 stimulation , albeit at significantly lower levels compared to SEK1 +/+ RAG2 -/- thymocytes , implying that CD28 costimulation and PMA/Ca 2+ ionophore triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation .	Although SEK1 -/- thymocytes failed to induce SAPK and JNK in response to PMA/Ca 2+ ionophore, SEK1 -/- RAG2 -/- thymocytes proliferated and made IL-2 after PMA/Ca 2+ ionophore and CD3 and CD28 stimulation, albeit at significantly lower levels compared to SEK1 +/+ RAG2 -/- thymocytes, implying that CD28 costimulation and PMA/Ca 2+ ionophore triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation.	1	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	1	2	9	10
MKK4 is less specific and can activate both p38 and JNK .	MKK4 is less specific and can activate both p38 and JNK.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	0	1	10	11
This was controlled by activated mitogen activated protein kinase 4 ( MKK4 ) mediated upregulation of c-Jun N-terminal kinase ( JNK ) and suppression of Akt .	This was controlled by activated mitogen activated protein kinase 4 (MKK4) mediated upregulation of c-Jun N-terminal kinase (JNK) and suppression of Akt.	8	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	11	12	16	19
Because the p38alpha MAPK are activated by MKK3 and MKK6 and JNK are directly activated by MKK4 and MKK7 , we thus knockdown the MKK3/6 and MKK4/7 respectively to investigate possible mechanisms of p38alpha MAPK and JNK involved in the liver steatosis .	Because the p38alpha MAPK are activated by MKK3 and MKK6 and JNK are directly activated by MKK4 and MKK7, we thus knockdown the MKK3/6 and MKK4/7 respectively to investigate possible mechanisms of p38alpha MAPK and JNK involved in the liver steatosis.	11	18	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	16	17	11	12
Thus , NBR1 appears to function as an organizer of a MEKK3 and MKK4 cassette that is required to activate JNK and an obesity induced inflammatory response .	Thus, NBR1 appears to function as an organizer of a MEKK3 and MKK4 cassette that is required to activate JNK and an obesity induced inflammatory response.	11	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	13	14	20	21
While MKK4 can activate both p38MAPK and JNK , MKK7 is specifically involved in the activation of JNKs .	While MKK4 can activate both p38MAPK and JNK, MKK7 is specifically involved in the activation of JNKs.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	1	2	7	8
In contrast to the intrinsic activity of Hep CA ( strong ) and Hep WT ( weak ) ( XREF_FIG and XREF_FIG ) XREF_BIBR , wild type Mkk4 does not activate the JNK pathway when overexpressed in S2 cells ( XREF_FIG ) or in fly eyes ( data not shown ) .	In contrast to the intrinsic activity of Hep CA (strong) and Hep WT (weak) (XREF_FIG and XREF_FIG) XREF_BIBR, wild type Mkk4 does not activate the JNK pathway when overexpressed in S2 cells (XREF_FIG) or in fly eyes (data not shown).	25	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mkk4	Mkk4	Mkk4	JNK	JNK	JNK	27	28	32	33
The MKK4 and 7 are known to activate JNK .	The MKK4 and 7 are known to activate JNK.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	1	2	8	9
While SEK1 and MKK4 can activate both the SAPK and JNK and p38 subgroups of the MAPK superfamily , MKK7 is specific for the SAPK and JNK subgroup .	While SEK1 and MKK4 can activate both the SAPK and JNK and p38 subgroups of the MAPK superfamily, MKK7 is specific for the SAPK and JNK subgroup.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	1	2	10	11
MKK4 and MKK7 , which is also called c-jun N-terminal kinase kinase 2 ( JNKK2 ) or stress activated protein kinase and extracellular signal regulated protein kinase kinase 2 ( SEK2 ) , are two upstream kinases of JNK pathway and directly activate the JNKs by phosphorylating the Tyr and Thr residue .	MKK4 and MKK7, which is also called c-jun N-terminal kinase kinase 2 (JNKK2) or stress activated protein kinase and extracellular signal regulated protein kinase kinase 2 (SEK2), are two upstream kinases of JNK pathway and directly activate the JNKs by phosphorylating the Tyr and Thr residue.	0	45	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	0	1	44	45
JNK is activated through phosphorylation by the upstream MAPKK proteins MKK4 and MKK7 .	JNK is activated through phosphorylation by the upstream MAPKK proteins MKK4 and MKK7.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	10	11	0	1
MKK7 , but not MKK4 , mediated JNK and c-Jun activation and proliferation in NB cells .	MKK7, but not MKK4, mediated JNK and c-Jun activation and proliferation in NB cells.	0	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	4	5	7	8
MKK4 , another important element of stress activated MAPK signaling pathways , phosphorylates and activates both JNK1/2 and p38 but not ERK1/2 in response to cellular stresses and inflammatory cytokines .	MKK4, another important element of stress activated MAPK signaling pathways, phosphorylates and activates both JNK1/2 and p38 but not ERK1/2 in response to cellular stresses and inflammatory cytokines.	0	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK1/2	JNK1/2	JNK1/2	0	1	16	17
On the other hand , AvrA targeting MKK4 and MKK7 inhibits JNK signaling and thus slows down apoptosis [ XREF_BIBR , XREF_BIBR ] .	On the other hand, AvrA targeting MKK4 and MKK7 inhibits JNK signaling and thus slows down apoptosis [XREF_BIBR, XREF_BIBR].	5	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	7	8	11	12
Furthermore , MKK4 and MKK7 ( upstream activators of JNK ) were found not to respond to PE stimulation in the absence of Pak1 ( XREF_FIG ) .	Furthermore, MKK4 and MKK7 (upstream activators of JNK) were found not to respond to PE stimulation in the absence of Pak1 (XREF_FIG).	2	15	activators	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	2	3	9	10
The results of our in vitro kinase assays ( XREF_FIG D ) provide further evidence that MKK4 and MKK7 must cooperate to fully activate SAPKs and JNKs .	The results of our in vitro kinase assays (XREF_FIG D) provide further evidence that MKK4 and MKK7 must cooperate to fully activate SAPKs and JNKs.	16	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	16	17	26	27
Activation of JNK1/2 by MAP2K4 is responsible for cell survival in primary human umbilical vein endothelial cells mediated by vascular endothelial growth factor receptor-3 [ XREF_BIBR ] .	Activation of JNK1/2 by MAP2K4 is responsible for cell survival in primary human umbilical vein endothelial cells mediated by vascular endothelial growth factor receptor-3 [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MAP2K4	MAP2K4	MAP2K4	JNK1/2	JNK1/2	JNK1/2	4	5	2	3
In contrast , dual phosphorylation at serine 257 ( S257 ) and threonine 261 ( T261 ) might further enhance MKK4 induced JNK and p38 signaling [ XREF_BIBR ] .	In contrast, dual phosphorylation at serine 257 (S257) and threonine 261 (T261) might further enhance MKK4 induced JNK and p38 signaling [XREF_BIBR].	19	25	induced	Positive_early_activation	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	20	21	22	23
Mixed lineage kinases ( MLKs ) phosphorylate and activate the JNK kinases MKK4 and MKK7 , which in turn phosphorylate and activate JNKs .	Mixed lineage kinases (MLKs) phosphorylate and activate the JNK kinases MKK4 and MKK7, which in turn phosphorylate and activate JNKs.	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	Mixed lineage kinases (MLKs) phosphorylate and activate the JNK kinases MKK4	mkk4	JNKs	JNKs	jnks	12	13	22	23
JNK , which is also known as stress activated protein kinase ( SAPK ) , is activated by the upstream MKK4 and MKK7 kinases via dual phosphorylation of the Thr-Pro-Tyr motif 18 .	JNK, which is also known as stress activated protein kinase (SAPK), is activated by the upstream MKK4 and MKK7 kinases via dual phosphorylation of the Thr-Pro-Tyr motif 18.	0	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	20	21	0	1
The activated MKK7 and the basal activity of MKK4 cooperatively mediate the full activation of JNK in response to TNFalpha [ XREF_BIBR , XREF_BIBR ] .	The activated MKK7 and the basal activity of MKK4 cooperatively mediate the full activation of JNK in response to TNFalpha [XREF_BIBR, XREF_BIBR].	6	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	8	9	15	16
JNK is activated by upstream MAP2Ks ( MKK4 and MKK7 kinases ) , which directly phosphorylate the Thr-Pro-Tyr motif .	JNK is activated by upstream MAP2Ks (MKK4 and MKK7 kinases), which directly phosphorylate the Thr-Pro-Tyr motif.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	7	8	0	1
MAP3K9 , also known as MLK1 , is an essential component of the MAPK and JNK signal transduction pathway ; once activated , MAP3K9 acts as an upstream activator of the MKK and JNK signal transduction cascade through phosphorylating MAP2K4 and MKK4 and MAP2K7 and MKK7 , which in turn activates the JNKs .	MAP3K9, also known as MLK1, is an essential component of the MAPK and JNK signal transduction pathway; once activated, MAP3K9 acts as an upstream activator of the MKK and JNK signal transduction cascade through phosphorylating MAP2K4 and MKK4 and MAP2K7 and MKK7, which in turn activates the JNKs.	38	53	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K4	phosphorylating MAP2K4	map2k4	JNKs	JNKs	jnks	39	40	52	53
MLK3 stimulates the MAPKKs MKK3/6 and MKK4 , which finally activate p38 and JNK MAPKs in the last steps of initiating HSC proliferation [ XREF_BIBR - XREF_BIBR ] .	MLK3 stimulates the MAPKKs MKK3/6 and MKK4, which finally activate p38 and JNK MAPKs in the last steps of initiating HSC proliferation [XREF_BIBR - XREF_BIBR].	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	6	7	13	14
In Drosophila , TAK1 , Rac1 , mixed-lineage kinases ( MLKs ) , or MKK4 initiates the JNK pathway .	In Drosophila, TAK1, Rac1, mixed-lineage kinases (MLKs), or MKK4 initiates the JNK pathway.	3	18	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	14	15	17	18
The combination of the antibodies and chemotherapy agents led to a synergistical activation of the JNK and p38 MAP kinase , which was mediated by MKK4 .	The combination of the antibodies and chemotherapy agents led to a synergistical activation of the JNK and p38 MAP kinase, which was mediated by MKK4.	12	26	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	25	26	15	16
Although SAPK and JNK activation by H2O2 was mediated by two upstream mitogen activated protein kinase ( MAPK ) kinases MKK4 and MKK7 , only MKK7 played such a role in serum withdrawal and C2-ceramide .	Although SAPK and JNK activation by H2O2 was mediated by two upstream mitogen activated protein kinase (MAPK) kinases MKK4 and MKK7, only MKK7 played such a role in serum withdrawal and C2-ceramide.	1	22	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	20	21	3	4
JNKs are activated by the upstream kinases MAPK-Kinase 4 ( MKK4 ) and MKK7 and regulate the phosphorylation of various substrates including the nuclear transcription factors c-Jun and c-Fos XREF_BIBR - XREF_BIBR .	JNKs are activated by the upstream kinases MAPK-Kinase 4 (MKK4) and MKK7 and regulate the phosphorylation of various substrates including the nuclear transcription factors c-Jun and c-Fos XREF_BIBR - XREF_BIBR.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	10	11	0	1
JNK was needed for guggulsterone induced apoptosis , inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 ( activator of JNK ) abolished the activity .	JNK was needed for guggulsterone induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity.	19	26	activator	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	21	22	25	26
XREF_BIBR - XREF_BIBR ) The MKK4 and MKK7 MAPKKs have been shown to activate JNK , and the MKK3 and MKK6 MAPKKs serve as the major activators of the p38 MAPK .	XREF_BIBR - XREF_BIBR) The MKK4 and MKK7 MAPKKs have been shown to activate JNK, and the MKK3 and MKK6 MAPKKs serve as the major activators of the p38 MAPK.	5	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	5	6	14	15
This last result confirms previous reports indicating that both , Mkk4 and Hep , are required to mediate JNK activation upon commercial LPS treatment XREF_BIBR , XREF_BIBR .	This last result confirms previous reports indicating that both, Mkk4 and Hep, are required to mediate JNK activation upon commercial LPS treatment XREF_BIBR, XREF_BIBR.	10	19	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mkk4	Mkk4	Mkk4	JNK	JNK	JNK	10	11	18	19
XREF_BIBR , XREF_BIBR In mammals , MKK4 ( MAP2K4 ) and MKK7 ( MAP2K7 ) phosphorylate and activate JNK , whereas MKK3 ( MAP2K3 ) , MKK4 , and MKK6 ( MAP2K6 ) activate p38 .	XREF_BIBR, XREF_BIBR In mammals, MKK4 (MAP2K4) and MKK7 (MAP2K7) phosphorylate and activate JNK, whereas MKK3 (MAP2K3), MKK4, and MKK6 (MAP2K6) activate p38.	6	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K4	MAP2K4	MAP2K4	JNK	JNK	JNK	8	9	18	19
MKK4 is the critical activator of SAPKs and JNKs in response to anisomycin and heat shock , whereas SAPK and JNK activation in response to osmolarity changes , UV irradiation , gamma irradiation , or ceramide is independent of MKK4 , at least in these cells .	MKK4 is the critical activator of SAPKs and JNKs in response to anisomycin and heat shock, whereas SAPK and JNK activation in response to osmolarity changes, UV irradiation, gamma irradiation, or ceramide is independent of MKK4, at least in these cells.	0	9	is the critical activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	0	1	8	9
On the other hand , miR-92a overexpression inhibited the activation of the JNK and C-JUN pathway through the targeting of mitogen activated protein kinase kinase 4 ( MKK4 ) , which activates JNK and stress activated protein kinase and a direct target of miR-92a .	On the other hand, miR-92a overexpression inhibited the activation of the JNK and C-JUN pathway through the targeting of mitogen activated protein kinase kinase 4 (MKK4), which activates JNK and stress activated protein kinase and a direct target of miR-92a.	21	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	27	28	32	33
MAP kinase kinase-4 ( MKK-4 ) activates JNK by phosphorylation .	MAP kinase kinase-4 (MKK-4) activates JNK by phosphorylation.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP kinase kinase-4	MAP kinase kinase-4	MAP kinase kinase-4	JNK	JNK	JNK	0	3	7	8
On the other hand , transfection of A431 cells with either a constitutively active SEK1 , which activates JNK , or with dominant negative SEK1 or dominant negative MEKK1 , both of which deactivate JNK , did not affect the level of HIF-1alpha in the cells ( XREF_FIG ) .	On the other hand, transfection of A431 cells with either a constitutively active SEK1, which activates JNK, or with dominant negative SEK1 or dominant negative MEKK1, both of which deactivate JNK, did not affect the level of HIF-1alpha in the cells (XREF_FIG).	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	14	15	18	19
For instance , MKK7 exclusively activates JNK while MKK4 activates p38 MAPK and JNK .	For instance, MKK7 exclusively activates JNK while MKK4 activates p38 MAPK and JNK.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	8	9	13	14
Although SEK1 -/- thymocytes failed to induce SAPK and JNK in response to PMA/Ca 2+ ionophore , SEK1 -/- RAG2 -/- thymocytes proliferated and made IL-2 after PMA/Ca 2+ ionophores and CD3 and CD28 stimulation , albeit at significantly lower levels compared to SEK1 +/+ RAG2 -/- thymocytes , indicating that CD28 costimulation and PMA/Ca 2+ ionophore triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation .	Although SEK1 -/- thymocytes failed to induce SAPK and JNK in response to PMA/Ca 2+ ionophore, SEK1 -/- RAG2 -/- thymocytes proliferated and made IL-2 after PMA/Ca 2+ ionophores and CD3 and CD28 stimulation, albeit at significantly lower levels compared to SEK1 +/+ RAG2 -/- thymocytes, indicating that CD28 costimulation and PMA/Ca 2+ ionophore triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation.	1	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	1	2	9	10
Because JNK isoforms are required for brain development , and MKK4 and MKK7 activate all JNK isoforms , it is not surprising that disruption of Mkk4 and/or Mkk7 results in severe defects in mouse development .	Because JNK isoforms are required for brain development, and MKK4 and MKK7 activate all JNK isoforms, it is not surprising that disruption of Mkk4 and/or Mkk7 results in severe defects in mouse development.	10	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	10	11	15	16
Unlike JNKK1 that activates both JNK and p38 MAP kinases , JNKK2 stimulated only JNK .	Unlike JNKK1 that activates both JNK and p38 MAP kinases, JNKK2 stimulated only JNK.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNKK1	JNKK1	JNKK1	JNK	JNK	JNK	1	2	5	6
SEK1 -/- RAG2 -/- thymocytes failed to induce SAPK / JNK in response to PMA/Ca 2+ ionophore .	SEK1 -/- RAG2 -/- thymocytes failed to induce SAPK / JNK in response to PMA/Ca 2+ ionophore.	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	0	1	10	11
31 However , the upstream signaling molecules for MKK4 mediated JNK activation by Akt are unknown .	31 However, the upstream signaling molecules for MKK4 mediated JNK activation by Akt are unknown.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	8	9	10	11
ASK1 , a MAPK kinase kinase ( MAPKKK ) , phosphorylates SEK1 and MKK4 or MKK3 and MKK6 , which in turn activates JNK or p38 MAPK , respectively .	ASK1, a MAPK kinase kinase (MAPKKK), phosphorylates SEK1 and MKK4 or MKK3 and MKK6, which in turn activates JNK or p38 MAPK, respectively.	0	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	ASK1, a MAPK kinase kinase (MAPKKK), phosphorylates SEK1	sek1	JNK	JNK	jnk	11	12	23	24
MKK3/6 and MKK4 are responsible for activating p38 , but only MKK4 activates JNK .	MKK3/6 and MKK4 are responsible for activating p38, but only MKK4 activates JNK.	10	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	11	12	13	14
The mitogen activated protein kinase kinase 4 ( MKK4 ) is activated via phosphorylation of Ser 257 and Thr 261 by upstream MAP3Ks and activates JNK and p38 MAPKs in response to cellular stress .	The mitogen activated protein kinase kinase 4 (MKK4) is activated via phosphorylation of Ser 257 and Thr 261 by upstream MAP3Ks and activates JNK and p38 MAPKs in response to cellular stress.	2	28	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	8	9	25	26
These MKK isoforms did not activate the ERK subgroup of MAP kinases , but MKK4 did activate JNK .	These MKK isoforms did not activate the ERK subgroup of MAP kinases, but MKK4 did activate JNK.	14	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	14	15	17	18
Since MKK4 is the upstream activator of JNK1/2 , these data suggest that the activation of JNK is a central event in the transmission of survival signals downstream of FN and FAK when serum is absent .	Since MKK4 is the upstream activator of JNK1/2, these data suggest that the activation of JNK is a central event in the transmission of survival signals downstream of FN and FAK when serum is absent.	1	8	is the upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK1/2	JNK1/2	JNK1/2	1	2	7	8
The MKK4 and MKK7 MAPKKs have been shown to activate JNK , and the MKK3 and MKK6 MAPKKs serve as the major activators of p38 MAPK .	The MKK4 and MKK7 MAPKKs have been shown to activate JNK, and the MKK3 and MKK6 MAPKKs serve as the major activators of p38 MAPK.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	1	2	10	11
In contrast , overexpression of wild type SEK1 enhanced Ras activation of JNK and transforming activity .	In contrast, overexpression of wild type SEK1 enhanced Ras activation of JNK and transforming activity.	3	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	overexpression of wild type SEK1	sek1	JNK	JNK	jnk	7	8	12	13
The upstream activators of p38 are poorly understood ; however , recent studies have resulted in the cloning and characterization of members of the p38 MAPKK module , most notably MKK4 , which can activate both JNK and p38 , and MKK3 and MKK6 , either of which specifically activate p38 .	The upstream activators of p38 are poorly understood; however, recent studies have resulted in the cloning and characterization of members of the p38 MAPKK module, most notably MKK4, which can activate both JNK and p38, and MKK3 and MKK6, either of which specifically activate p38.	17	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	30	31	36	37
JNK MAPKs are activated by two upstream MAPKKs , MKK4 and MKK7 , and the top tier of the JNK cascade shares many MAPKKKs with p38 ( XREF_FIG ) .	JNK MAPKs are activated by two upstream MAPKKs, MKK4 and MKK7, and the top tier of the JNK cascade shares many MAPKKKs with p38 (XREF_FIG).	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	9	10	0	1
JNKs are activated by their upstream MAP2Ks , MKK4 and MKK7 , through dual phosphorylation of threonine and tyrosine in the TPY motif found in the activation loop [ XREF_BIBR , XREF_BIBR ] .	JNKs are activated by their upstream MAP2Ks, MKK4 and MKK7, through dual phosphorylation of threonine and tyrosine in the TPY motif found in the activation loop [XREF_BIBR, XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	8	9	0	1
To determine whether the induction of MKK4 accounts for the arsenite induced JNK activation and cell apoptosis , DN-MKK4 was stably introduced into the WT MEFs ( XREF_FIG ) .	To determine whether the induction of MKK4 accounts for the arsenite induced JNK activation and cell apoptosis, DN-MKK4 was stably introduced into the WT MEFs (XREF_FIG).	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	6	7	12	13
MKK4 activates both JNK and p38 kinases and MKK7 activates only JNK .	MKK4 activates both JNK and p38 kinases and MKK7 activates only JNK.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	0	1	11	12
Consistent with a previous report [ XREF_BIBR ] , ectopic JNK activation by expression of a constitutively active JNKK transgene ( hep CA ) for a short pulse of 6h with 6h recovery at 18degreesC ( TS6hR6h ) is sufficient to induce dAtg1 expression in wing imaginal discs .	Consistent with a previous report [XREF_BIBR], ectopic JNK activation by expression of a constitutively active JNKK transgene (hep CA) for a short pulse of 6h with 6h recovery at 18degreesC (TS6hR6h) is sufficient to induce dAtg1 expression in wing imaginal discs.	10	19	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	JNKK	expression of a constitutively active JNKK	jnkk	JNK	JNK	jnk	18	19	10	11
In contrast to mammals , it seems that in Drosophila both MAPKKs , Hep and Mkk7 and Mkk4 , are required to induce JNK upon TNF or pro inflammatory stimulation .	In contrast to mammals, it seems that in Drosophila both MAPKKs, Hep and Mkk7 and Mkk4, are required to induce JNK upon TNF or pro inflammatory stimulation.	13	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mkk4	Mkk4	Mkk4	JNK	JNK	JNK	17	18	23	24
The major upstream activators of ERK1/2 are two MAP kinase kinases ( MAPKK ) , MEK1 and MEK2 , while p38 kinases are directly activated by MKK6 and MKK3 , and JNKs are directly activated by MKK4 and MKK7 1 .	The major upstream activators of ERK1/2 are two MAP kinase kinases (MAPKK), MEK1 and MEK2, while p38 kinases are directly activated by MKK6 and MKK3, and JNKs are directly activated by MKK4 and MKK7 1.	31	38	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	36	37	31	32
Together , our data demonstrate for the first time that MKK4 is an essential activator of JNK required for the normal development of the brain .	Together, our data demonstrate for the first time that MKK4 is an essential activator of JNK required for the normal development of the brain.	10	17	is an essential activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	10	11	16	17
JNK is activated by the MAP2K isoforms MKK4 and MKK7 [ XREF_BIBR ] .	JNK is activated by the MAP2K isoforms MKK4 and MKK7 [XREF_BIBR].	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	7	8	0	1
Since MKK4 and MKK7 , the downstream kinases of ASK1 , can activate JNK , we investigated whether DUSP22 could interact with MAPKs including JNK and two JNK activators , MKK4 and MKK7 .	Since MKK4 and MKK7, the downstream kinases of ASK1, can activate JNK, we investigated whether DUSP22 could interact with MAPKs including JNK and two JNK activators, MKK4 and MKK7.	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	1	2	13	14
YopJ has also been shown to inhibit phosphorylation of MKK4 and SEK1 and attenuates JNK signaling and subsequent EGR1 activation [ XREF_BIBR ] .	YopJ has also been shown to inhibit phosphorylation of MKK4 and SEK1 and attenuates JNK signaling and subsequent EGR1 activation [XREF_BIBR].	0	21	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SEK1	YopJ has also been shown to inhibit phosphorylation of MKK4 and SEK1	sek1	JNK	JNK	jnk	11	12	14	15
XREF_BIBR , XREF_BIBR In some cell types , MKK4 activates JNK primarily in response to stress stimuli , whereas MKK7 signaling is triggered by release of inflammatory cytokines .	XREF_BIBR, XREF_BIBR In some cell types, MKK4 activates JNK primarily in response to stress stimuli, whereas MKK7 signaling is triggered by release of inflammatory cytokines.	8	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	8	9	10	11
It therefore can be hypothesized that , at both low dose and high dose , ATM could have induced resistant cell apoptosis through MKK4 mediated activation of JNK , which , however , was not evident at low dose .	It therefore can be hypothesized that, at both low dose and high dose, ATM could have induced resistant cell apoptosis through MKK4 mediated activation of JNK, which, however, was not evident at low dose.	23	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	23	24	27	28
JNK is activated through phosphorylation of both residues Threonine 183 and Tyrosine 185 , by the dual specificity enzymes MKK4 and MKK7 XREF_BIBR .	JNK is activated through phosphorylation of both residues Threonine 183 and Tyrosine 185, by the dual specificity enzymes MKK4 and MKK7 XREF_BIBR.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	19	20	0	1
The finding that MKK4 alone can not activate SAPKS and JNKs in BMMCs may be explained in two ways .	The finding that MKK4 alone can not activate SAPKS and JNKs in BMMCs may be explained in two ways.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	3	4	10	11
This hypothesis is in line with our biochemical data on SEK1 independent activation of SAPKs and JNKs in lymph node T cells in response to PMA/Ca 2+ ionophore stimulation .	This hypothesis is in line with our biochemical data on SEK1 independent activation of SAPKs and JNKs in lymph node T cells in response to PMA/Ca 2+ ionophore stimulation.	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNKs	JNKs	JNKs	10	11	16	17
For instance , ERK1 and ERK2 is activated by MEK1 and MEK2 , JNK is activated by MEK4 and MEK7 and p38 MAPK is activated by MEK3 and MEK6 [ XREF_BIBR , XREF_BIBR ] .	For instance, ERK1 and ERK2 is activated by MEK1 and MEK2, JNK is activated by MEK4 and MEK7 and p38 MAPK is activated by MEK3 and MEK6 [XREF_BIBR, XREF_BIBR].	13	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK4	MEK4	MEK4	JNK	JNK	JNK	17	18	13	14
Signals transmitted from membrane receptors activate MKK4 and MKK7 , which then activate JNK via dual phosphorylation on the ThrProTyr ( TPY ) motif .	Signals transmitted from membrane receptors activate MKK4 and MKK7, which then activate JNK via dual phosphorylation on the ThrProTyr (TPY) motif.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	6	7	13	14
In the presence of any oxidative stress stimuli , ASK1 activates SEK1 , which in turn activates JNK1/2 .	In the presence of any oxidative stress stimuli, ASK1 activates SEK1, which in turn activates JNK1/2.	10	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK1/2	JNK1/2	JNK1/2	11	12	17	18
We further showed that mechanistically , phosphorylation of MAP2K4 or MAP2K6 is upstream to activation of JNK or p38MAPK during the pro life phase , with nuclear activation of transcription factors ATF-2 or c-Jun as the downstream signals .	We further showed that mechanistically, phosphorylation of MAP2K4 or MAP2K6 is upstream to activation of JNK or p38MAPK during the pro life phase, with nuclear activation of transcription factors ATF-2 or c-Jun as the downstream signals.	6	18	is upstream to activation	Positive_activation_copula_1	Positive_activation	Positive_activation	MAP2K4	phosphorylation of MAP2K4	map2k4	JNK	JNK	jnk	8	9	16	17
MKK4 induced JNK activation .	MKK4 induced JNK activation.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	0	1	2	3
Biochemical studies demonstrated that the phosphorylation of MKK4 activates JNK [ XREF_BIBR ] .	Biochemical studies demonstrated that the phosphorylation of MKK4 activates JNK [XREF_BIBR].	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	phosphorylation of MKK4	mkk4	JNK	JNK	jnk	7	8	9	10
These data suggest that selective MKK7 blockade could suppress arthritis and potentially decrease adverse effects by permitting non pathogenic MKK4 mediated JNK activation .	These data suggest that selective MKK7 blockade could suppress arthritis and potentially decrease adverse effects by permitting non pathogenic MKK4 mediated JNK activation.	16	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	19	20	21	22
Furthermore , MKK-3 and -6 are specific for p38 whereas MKK-4 also activates JNKs .	Furthermore, MKK-3 and -6 are specific for p38 whereas MKK-4 also activates JNKs.	10	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK-4	MKK-4	MKK-4	JNKs	JNKs	JNKs	10	11	13	14
As expected based upon our previous experience , increased MEKK1 activity by TRAIL was repressed by caspase 8 activation ( XREF_FIG ) , and SEK1 mediated the MEKK1 signaling cascade to JNK during TRAIL treatment ( XREF_FIG ) .	As expected based upon our previous experience, increased MEKK1 activity by TRAIL was repressed by caspase 8 activation (XREF_FIG), and SEK1 mediated the MEKK1 signaling cascade to JNK during TRAIL treatment (XREF_FIG).	24	32	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	24	25	31	32
As shown in XREF_FIG , increased activation of the upstream JNK activator MKK4 as well as downstream targets of JNK , c-Jun , and ATF-2 were readily detected in PDGF D expressing mPrE and BPH-1 cells ( XREF_FIG ) .	As shown in XREF_FIG, increased activation of the upstream JNK activator MKK4 as well as downstream targets of JNK, c-Jun, and ATF-2 were readily detected in PDGF D expressing mPrE and BPH-1 cells (XREF_FIG).	6	17	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	12	13	10	11
Upon stimulation , Mekk1 phosphorylates Mkk4 and Mkk7 ( MAPKKs ) , which then phosphorylate and activate JNK .	Upon stimulation, Mekk1 phosphorylates Mkk4 and Mkk7 (MAPKKs), which then phosphorylate and activate JNK.	3	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mkk4	Mekk1 phosphorylates Mkk4	mkk4	JNK	JNK	jnk	5	6	17	18
JNK , a member of the mitogen activated protein kinases ( MAPKs ) , is activated by the MAPK kinases SEK1 and MKK7 in response to environmental stresses .	JNK, a member of the mitogen activated protein kinases (MAPKs), is activated by the MAPK kinases SEK1 and MKK7 in response to environmental stresses.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	20	21	0	1
JNK is activated through phosphorylation on Thr183 and Tyr185 residues by MAPK kinase MKK4 and JNKK1 or MKK7 and JNKK2 11 .	JNK is activated through phosphorylation on Thr183 and Tyr185 residues by MAPK kinase MKK4 and JNKK1 or MKK7 and JNKK2 11.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNKK1	JNKK1	JNKK1	JNK	JNK	JNK	15	16	0	1
Dominant negative SEK1 can block JNK activation by LPS , but not by Salmonella .	Dominant negative SEK1 can block JNK activation by LPS, but not by Salmonella.	0	6	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	2	3	5	6
Disruption of the MKK4 gene blocked JNK activation caused by : ( i ) the mitogen activated protein kinase kinase kinase MEKK1 , and ( ii ) treatment with anisomycin or heat shock .	Disruption of the MKK4 gene blocked JNK activation caused by : (i) the mitogen activated protein kinase kinase kinase MEKK1, and (ii) treatment with anisomycin or heat shock.	3	7	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	3	4	6	7
The c-Jun NH2-terminal kinase ( JNK ) activation was evaluated by anti-phosphorylated JNK antibody and inhibited by the JNK specific inhibitor SP600125 or dominant negative SEK1 expression .	The c-Jun NH2-terminal kinase (JNK) activation was evaluated by anti-phosphorylated JNK antibody and inhibited by the JNK specific inhibitor SP600125 or dominant negative SEK1 expression.	1	27	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	SEK1	SEK1 expression	sek1	c-Jun NH2-terminal kinase	c-Jun NH2-terminal kinase	c-jun nh2-terminal kinase	25	26	1	4
To date , only MKK4 and MKK7 have been found to mediate JNK activation .	To date, only MKK4 and MKK7 have been found to mediate JNK activation.	3	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	4	5	12	13
p38 may be activated by the canonical MAP2Ks MKK3 or MKK6 , both of which are expressed in pancreatic cancer , or by MKK4 that also activates JNK ; it may undergo autophosphorylation as well although this mechanism appears specific to activated T-lymphocytes .	p38 may be activated by the canonical MAP2Ks MKK3 or MKK6, both of which are expressed in pancreatic cancer, or by MKK4 that also activates JNK; it may undergo autophosphorylation as well although this mechanism appears specific to activated T-lymphocytes.	3	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	23	24	27	28
Two MAPK kinases , MKK4 and MKK7 , synergistically activate JNK .	Two MAPK kinases, MKK4 and MKK7, synergistically activate JNK.	2	11	synergistically activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	4	5	10	11
MKK3 and MKK6 are known potential constituents of p38 MAPK signaling pathway , whereas SEK1 and MEK1 are upstream activators of SAPK and JNK and ERK pathways , respectively .	MKK3 and MKK6 are known potential constituents of p38 MAPK signaling pathway, whereas SEK1 and MEK1 are upstream activators of SAPK and JNK and ERK pathways, respectively.	14	24	are upstream activators	Positive_activation_copula_1	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	14	15	23	24
JNK is most often activated by MKK4 and MKK7 and can be inhibited by compounds such as SP600125 which inhibits all 3 isoforms [ XREF_BIBR ] .	JNK is most often activated by MKK4 and MKK7 and can be inhibited by compounds such as SP600125 which inhibits all 3 isoforms [XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	6	7	0	1
Downstream of MAP3K , in various contexts MKK4 activates both JNK and p38 kinases and MKK7 activates only JNK .	Downstream of MAP3K, in various contexts MKK4 activates both JNK and p38 kinases and MKK7 activates only JNK.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	7	8	18	19
For example , although both MEK4 and MEK7 activate JNK , only MEK7 appears to mediate JNK dependent inflammatory responses in immune cells .	For example, although both MEK4 and MEK7 activate JNK, only MEK7 appears to mediate JNK dependent inflammatory responses in immune cells.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK4	MEK4	MEK4	JNK	JNK	JNK	5	6	9	10
We therefore hypothesized that chronic MAP2K4 expression would increase activation of p38 MAPK and/or JNK .	We therefore hypothesized that chronic MAP2K4 expression would increase activation of p38 MAPK and/or JNK.	5	15	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K4	MAP2K4 expression	map2k4	JNK	JNK	jnk	5	6	14	15
Here we use morpholino mediated knockdown of the zebrafish orthologs of the Jnk activators Mkk4 and Mkk7 to examine the effect of Jnk signaling abrogation on early vertebrate embryogenesis .	Here we use morpholino mediated knockdown of the zebrafish orthologs of the Jnk activators Mkk4 and Mkk7 to examine the effect of Jnk signaling abrogation on early vertebrate embryogenesis.	9	16	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Mkk4	Mkk4	Mkk4	Jnk	Jnk	Jnk	14	15	12	13
Furthermore , mitogen activated protein kinase kinase 4 ( MKK4 ) , a kinase that activates JNK and stress activated protein kinase , was found to be directly targeted by miR-92a .	Furthermore, mitogen activated protein kinase kinase 4 (MKK4), a kinase that activates JNK and stress activated protein kinase, was found to be directly targeted by miR-92a.	4	28	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	9	10	16	17
23 Active ASK1 in turn directly phosphorylates MKK4 and leads to JNK activation .	23 Active ASK1 in turn directly phosphorylates MKK4 and leads to JNK activation.	2	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	MKK4	ASK1 in turn directly phosphorylates MKK4	mkk4	JNK	JNK	jnk	7	8	11	12
Similarly , upstream kinases such as MKK4 ( also known as MAPKK4 ) that can also activate JNKs can induce dormancy in other systems XREF_BIBR , XREF_BIBR .	Similarly, upstream kinases such as MKK4 (also known as MAPKK4) that can also activate JNKs can induce dormancy in other systems XREF_BIBR, XREF_BIBR.	3	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	6	7	17	18
Therefore , MKK4 mediated activation of JNK and Sab mediated recruitment of JNK to the mitochondrial outer membrane ( which sustains JNK activation ) are required for acetaminophen induced hepatocyte death ( XREF_FIG ) 29 .	Therefore, MKK4 mediated activation of JNK and Sab mediated recruitment of JNK to the mitochondrial outer membrane (which sustains JNK activation) are required for acetaminophen induced hepatocyte death (XREF_FIG) 29.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	2	3	6	7
Therefore , we showed that it is possible to prevent JNK activation in excitotoxicity by specific inhibition of MKK7 , preserving the physiological role of JNK driven by MKK4 .	Therefore, we showed that it is possible to prevent JNK activation in excitotoxicity by specific inhibition of MKK7, preserving the physiological role of JNK driven by MKK4.	23	29	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	28	29	25	26
It is established that JNK activation is mediated by the protein kinases MKK4 and MKK7 .	It is established that JNK activation is mediated by the protein kinases MKK4 and MKK7.	4	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	12	13	4	5
Experiments both in vivo and in vitro indicate that MKK4 and MKK7 activate JNKs synergistically , where the tyrosine residue is preferentially phosphorylated by MKK4 , while the threonine residue is phosphorylated by MKK7 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Experiments both in vivo and in vitro indicate that MKK4 and MKK7 activate JNKs synergistically, where the tyrosine residue is preferentially phosphorylated by MKK4, while the threonine residue is phosphorylated by MKK7 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	9	10	13	14
Surprisingly , levels of the phosphorylated MAPKKs , P-MEK1/2 and P-MKK4 ( activators of the Erk and JNK pathways , respectively ) were increased in all five brain regions , and much more dramatically ( P-MEK1/2 , 4.5 to > 100-fold ; P-MKK4 , 12 to ~ 300-fold ) .	Surprisingly, levels of the phosphorylated MAPKKs, P-MEK1/2 and P-MKK4 (activators of the Erk and JNK pathways, respectively) were increased in all five brain regions, and much more dramatically (P-MEK1/2, 4.5 to> 100-fold; P-MKK4, 12 to ~ 300-fold).	2	18	activators	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	P-MKK4	levels of the phosphorylated MAPKKs, P-MEK1/2 and P-MKK4	p-mkk4	JNK	JNK	jnk	10	11	17	18
Sek1 ( JNKK and MKK4 ) is a direct activator of SAPKs and JNKs in response to environmental stresses or mitogenic factors .	Sek1 (JNKK and MKK4) is a direct activator of SAPKs and JNKs in response to environmental stresses or mitogenic factors.	0	14	is a direct activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Sek1	Sek1	Sek1	JNKs	JNKs	JNKs	0	1	13	14
MKK7 is a specific upstream kinase of JNKs , while MKK4 activates both JNKs and another MAPK , p38 5 .	MKK7 is a specific upstream kinase of JNKs, while MKK4 activates both JNKs and another MAPK, p38 5.	10	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	10	11	13	14
Also , JNK can be activated through its phosphorylation by MKK4 and MKK7 at threonine , tyrosine .	Also, JNK can be activated through its phosphorylation by MKK4 and MKK7 at threonine, tyrosine.	2	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	10	11	2	3
In mammals , MKK4 and MKK7 ( the mammalian orthologs of Drosophila dMKK4 and HEP , respectively ) have been reported to activate JNK synergistically XREF_BIBR .	In mammals, MKK4 and MKK7 (the mammalian orthologs of Drosophila dMKK4 and HEP, respectively) have been reported to activate JNK synergistically XREF_BIBR.	3	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	3	4	23	24
Like all other MAPK members , JNKs are activated by dual protein kinases ( MKK4 and more specifically , MKK7 ) , which in turn are regulated by an array of upstream MAP3Ks ( see description in section 3.1.2 ) [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Like all other MAPK members, JNKs are activated by dual protein kinases (MKK4 and more specifically, MKK7), which in turn are regulated by an array of upstream MAP3Ks (see description in section 3.1.2) [XREF_BIBR, XREF_BIBR - XREF_BIBR].	6	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	14	15	6	7
As is well known , the JNK and p38 MAPKs are activated by MKK4 and MKK7 , and consequently capacitate the nuclear import of p-c-Jun and p-ATF2 , eventually resulting in alteration of gene transcription .	As is well known, the JNK and p38 MAPKs are activated by MKK4 and MKK7, and consequently capacitate the nuclear import of p-c-Jun and p-ATF2, eventually resulting in alteration of gene transcription.	6	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	13	14	6	7
In Drosophila , the single JNK homolog , Basket ( bsk ) , is activated by the MAP2Ks Hemipterous ( hep ) and Mkk4 XREF_BIBR , XREF_BIBR .	In Drosophila, the single JNK homolog, Basket (bsk), is activated by the MAP2Ks Hemipterous (hep) and Mkk4 XREF_BIBR, XREF_BIBR.	5	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mkk4	Mkk4	Mkk4	JNK	JNK	JNK	23	24	5	6
It is known that JNK is activated predominantly by MKK4 and MKK7 [ XREF_BIBR ] .	It is known that JNK is activated predominantly by MKK4 and MKK7 [XREF_BIBR].	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	9	10	4	5
In addition to p38 MAPK , MAP2K4 can also either activate JNK , or both proteins , dependent upon the model system XREF_BIBR .	In addition to p38 MAPK, MAP2K4 can also either activate JNK, or both proteins, dependent upon the model system XREF_BIBR.	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K4	MAP2K4	MAP2K4	JNK	JNK	JNK	6	7	11	12
The MKKKs phosphorylate and activate MKK4 and MKK7 , which , in turn activate JNKs by dual phosphorylation .	The MKKKs phosphorylate and activate MKK4 and MKK7, which, in turn activate JNKs by dual phosphorylation.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	5	6	14	15
The JNK activity stimulated by low Cd doses was partially suppressed by expression of a dominant negative form of MKK7 , but not a dominant negative form of MKK4 , indicating that MKK7 is involved in JNK activation by Cd .	The JNK activity stimulated by low Cd doses was partially suppressed by expression of a dominant negative form of MKK7, but not a dominant negative form of MKK4, indicating that MKK7 is involved in JNK activation by Cd.	1	29	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	28	29	1	2
MKK7 primarily activates JNK , but MKK4 activates JNK and p38 4 .	MKK7 primarily activates JNK, but MKK4 activates JNK and p38 4.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	6	7	8	9
Although JNK activation by MEK7 and MEK4 is reportedly synergistic in non cardiac cells , MEK7 is required for JNK activation and responds to pro inflammatory cytokines [ XREF_BIBR ] .	Although JNK activation by MEK7 and MEK4 is reportedly synergistic in non cardiac cells, MEK7 is required for JNK activation and responds to pro inflammatory cytokines [XREF_BIBR].	1	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK4	MEK4	MEK4	JNK	JNK	JNK	6	7	1	2
Co-expression of dominant negative MKK7 but not MKK4 and ZAK significantly attenuates JNK and SAPK activation .	Co-expression of dominant negative MKK7 but not MKK4 and ZAK significantly attenuates JNK and SAPK activation.	0	15	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	Co-expression of dominant negative MKK7 but not MKK4	mkk4	JNK	JNK	jnk	7	8	12	13
We found that MKK7 , and not MKK4 , mediates the activation of JNK signaling in excitotoxic neuronal death 3 and cerebral ischemia .	We found that MKK7, and not MKK4, mediates the activation of JNK signaling in excitotoxic neuronal death 3 and cerebral ischemia.	3	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	7	8	13	14
SB-399885 had a main effect on total expression of the dual specificity kinase MKK4 , which activates JNK and p38 , and showed a small but significant increase ( F ( 2,50 ) = 3.770 , P < = 0.05 ) of 16 % in the frontal cortex following administration of the highest dose to isolation reared rats ( P < = 0.05 versus isolate vehicle ; Fig .	SB-399885 had a main effect on total expression of the dual specificity kinase MKK4, which activates JNK and p38, and showed a small but significant increase (F (2,50) = 3.770, P < = 0.05) of 16% in the frontal cortex following administration of the highest dose to isolation reared rats (P < = 0.05 versus isolate vehicle; Fig.	7	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	expression of the dual specificity kinase MKK4	mkk4	JNK	JNK	jnk	13	14	17	18
JNKs can be activated by the upstream MKK4 and MKK7 kinases [ XREF_BIBR , XREF_BIBR ] .	JNKs can be activated by the upstream MKK4 and MKK7 kinases [XREF_BIBR, XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNKs	JNKs	JNKs	7	8	0	1
MKK1 and MKK2 activate ERK1/2 , MKK4 and MKK7 activate JNK , and MKK3 and MKK6 activate p38 .	MKK1 and MKK2 activate ERK1/2, MKK4 and MKK7 activate JNK, and MKK3 and MKK6 activate p38.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	6	7	10	11
ASK1 is activated during the cellular response to ROS and then activates MAPK kinase 4 ( MKK4 )/MKK7 and MKK3 / MKK6 , which in turn activate JNK and p38 kinase , respectively .	ASK1 is activated during the cellular response to ROS and then activates MAPK kinase 4 (MKK4)/MKK7 and MKK3 / MKK6, which in turn activate JNK and p38 kinase, respectively.	11	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	16	17	27	28
Of note , although XREF_BIBR , XREF_BIBR ) argue that AKT phosphorylates and inhibits GSK3beta , which subsequently stabilizes CRMP2 and microtubules to prevent axonal degeneration , XREF_BIBR claim that AKT promotes axonal survival by phosphorylation of MKK4 at serine 78 , which suppresses MKK4 mediated activation of prodegenerative JNK signaling .	Of note, although XREF_BIBR, XREF_BIBR) argue that AKT phosphorylates and inhibits GSK3beta, which subsequently stabilizes CRMP2 and microtubules to prevent axonal degeneration, XREF_BIBR claim that AKT promotes axonal survival by phosphorylation of MKK4 at serine 78, which suppresses MKK4 mediated activation of prodegenerative JNK signaling.	44	50	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	44	45	49	50
Whether reduced JNK activity caused by loss of MAP2K4 or MAP3K1 phenocopies the effects of compound JNK deficiency on breast cancer is unclear .	Whether reduced JNK activity caused by loss of MAP2K4 or MAP3K1 phenocopies the effects of compound JNK deficiency on breast cancer is unclear.	2	11	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAP2K4	MAP2K4	MAP2K4	JNK	JNK	JNK	8	9	2	3
The interactions between MAP kinase and its immediate upstream kinase ( MAPKK ) are highly specific : for instance , p42 and p44 MAP kinases are phosphorylated solely by MAP and ERK kinase ( MEK ) 1 and 2 ; p38 MAP kinase is selectively activated by MAP kinase kinases ( MKK ) 3 and 6 , while JNK is activated by MKK7 and MKK4 in most conditions , however MKK4 can sometimes activate p38 MAP kinase when over expressed .	The interactions between MAP kinase and its immediate upstream kinase (MAPKK) are highly specific : for instance, p42 and p44 MAP kinases are phosphorylated solely by MAP and ERK kinase (MEK) 1 and 2; p38 MAP kinase is selectively activated by MAP kinase kinases (MKK) 3 and 6, while JNK is activated by MKK7 and MKK4 in most conditions, however MKK4 can sometimes activate p38 MAP kinase when over expressed.	58	65	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	64	65	58	59
Overexpression of a dominant negative SEK1 significantly inhibited SAPK and JNK activation , whereas NFkappaB stimulation by HPK1 remained unaffected .	Overexpression of a dominant negative SEK1 significantly inhibited SAPK and JNK activation, whereas NFkappaB stimulation by HPK1 remained unaffected.	0	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SEK1	Overexpression of a dominant negative SEK1	sek1	JNK	JNK	jnk	5	6	10	11
Furthermore , activation of JNK by overexpression of a constitutively active JNKK ( hep CA ) in a dronc -/- background does not result in the generation of ROS ( XREF_SUPPLEMENTARY ) .	Furthermore, activation of JNK by overexpression of a constitutively active JNKK (hep CA) in a dronc -/- background does not result in the generation of ROS (XREF_SUPPLEMENTARY).	2	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JNKK	overexpression of a constitutively active JNKK	jnkk	JNK	JNK	jnk	11	12	4	5
JIP-1 potentiates the activation of JNK by MKK7 .	JIP-1 potentiates the activation of JNK by MKK7.	1	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	7	8	5	6
In mammals , Mkk7 is a specific activator of JNKs while Mkk4 can also phosphorylate p38 MAPKs XREF_BIBR .	In mammals, Mkk7 is a specific activator of JNKs while Mkk4 can also phosphorylate p38 MAPKs XREF_BIBR.	3	10	is a specific activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Mkk7	Mkk7	Mkk7	JNKs	JNKs	JNKs	3	4	9	10
XREF_BIBR MKK4 also activates p38 , whereas MAP2K7 specifically activates JNK which , in turn , activates substrates such as transcription factors or proapoptotic proteins .	XREF_BIBR MKK4 also activates p38, whereas MAP2K7 specifically activates JNK which, in turn, activates substrates such as transcription factors or proapoptotic proteins.	7	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K7	MAP2K7	MAP2K7	JNK	JNK	JNK	7	8	10	11
Apart from this , MKK7 is independent and specific to trigger JNK signal pathway activity while the additional phosphorylation by MKK4 ensures optimal JNK activation .	Apart from this, MKK7 is independent and specific to trigger JNK signal pathway activity while the additional phosphorylation by MKK4 ensures optimal JNK activation.	4	14	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	4	5	11	12
Mitogen activated protein kinase kinase 7 ( MKK7 )-mediated activation of JNK also resulted in accumulation of dSesn ( XREF_SUPPLEMENTARY ) , as did overexpression of Mst1 ( mammalian STE20 like kinase 1 ) , another protein kinase that phosphorylates FoxO , ( XREF_SUPPLEMENTARY ) .	Mitogen activated protein kinase kinase 7 (MKK7)-mediated activation of JNK also resulted in accumulation of dSesn (XREF_SUPPLEMENTARY), as did overexpression of Mst1 (mammalian STE20 like kinase 1), another protein kinase that phosphorylates FoxO, (XREF_SUPPLEMENTARY).	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	7	8	11	12
Two upstream kinases in the MAP kinase cascade , MAPK kinase ( MKK ) 4 and MKK7 modulate JNK function in FLS .	Two upstream kinases in the MAP kinase cascade, MAPK kinase (MKK) 4 and MKK7 modulate JNK function in FLS.	7	19	modulate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	16	17	18	19
Unlike other MAPK subfamilies , the monophosphorylation of MKK7 on the Thr residue is sufficient and specific to activate JNK pathway which , in turn , activates substrates like transcription factors or pro apoptotic proteins .	Unlike other MAPK subfamilies, the monophosphorylation of MKK7 on the Thr residue is sufficient and specific to activate JNK pathway which, in turn, activates substrates like transcription factors or pro apoptotic proteins.	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	monophosphorylation of MKK7 on the Thr	mkk7	JNK	JNK	jnk	8	9	19	20
Together , these findings indicate that parthenolide potentiates HDACI lethality in human AML cells through a process involving NF-kappaB inhibition and subsequent MKK7 dependent activation of the SAPK and JNK pathway .	Together, these findings indicate that parthenolide potentiates HDACI lethality in human AML cells through a process involving NF-kappaB inhibition and subsequent MKK7 dependent activation of the SAPK and JNK pathway.	22	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	22	23	29	30
TAK1 phosphorylates either the IKK complex , which leads to activation of the NF-kappaB pathway , or the MKK7 that activates the c-Jun N-terminal kinase ( JNK ) signaling pathway [ XREF_BIBR ] .	TAK1 phosphorylates either the IKK complex, which leads to activation of the NF-kappaB pathway, or the MKK7 that activates the c-Jun N-terminal kinase (JNK) signaling pathway [XREF_BIBR].	1	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	phosphorylates either the IKK complex, which leads to activation of the NF-kappaB pathway, or the MKK7	mkk7	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-jun n-terminal kinase	18	19	22	25
In summary , the present findings indicate that the NF-kappaB inhibitor PTL markedly increases the antileukaemic activity of the clinically relevant pan-HDACIs vorinostat and LBH589 through the MKK7 dependent induction of SAPK and JNK activation and apoptosis .	In summary, the present findings indicate that the NF-kappaB inhibitor PTL markedly increases the antileukaemic activity of the clinically relevant pan-HDACIs vorinostat and LBH589 through the MKK7 dependent induction of SAPK and JNK activation and apoptosis.	27	34	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	27	28	33	34
Thus , MKK7 is an essential activator of SAPKs and JNKs in mast cells and its function is not redundant with that of MKK4 .	Thus, MKK7 is an essential activator of SAPKs and JNKs in mast cells and its function is not redundant with that of MKK4.	2	11	is an essential activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNKs	JNKs	JNKs	2	3	10	11
We then examined the effect of expression of dominant negative MKK7 ( KL-MKK7 ) on the Fas induced activation of JNK and SAPK .	We then examined the effect of expression of dominant negative MKK7 (KL-MKK7) on the Fas induced activation of JNK and SAPK.	6	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	expression of dominant negative MKK7	mkk7	JNK	JNK	jnk	10	11	20	21
JNKK2 ( KM ) , in which methionine ( Met ) replaces ( Lys ) 149 in the ATP binding domain of c-Jun NH 2 -terminal kinase kinase2 ( JNKK2 ) that stimulates JNK activation , has been demonstrated to result in the inactivation of JNK .	JNKK2 (KM), in which methionine (Met) replaces (Lys) 149 in the ATP binding domain of c-Jun NH 2 -terminal kinase kinase2 (JNKK2) that stimulates JNK activation, has been demonstrated to result in the inactivation of JNK.	15	34	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	JNKK2	JNKK2	JNKK2	JNK	JNK	JNK	29	30	33	34
These results implied that the SAPK and JNK activators MKK7 and MKK4 operate independently and that different stresses utilize distinct MAPK signaling pathways to activate SAPKs and JNKs .	These results implied that the SAPK and JNK activators MKK7 and MKK4 operate independently and that different stresses utilize distinct MAPK signaling pathways to activate SAPKs and JNKs.	5	12	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	9	10	7	8
Mechanistic insight into cell-cycle arrest induction suggested that this inhibitory effect is through MKP-1 upregulation and MKK7 deactivation , both of which would concertedly deactivate JNK and c-Jun cascade , thereby leading to cyclin D1 downregulation .	Mechanistic insight into cell-cycle arrest induction suggested that this inhibitory effect is through MKP-1 upregulation and MKK7 deactivation, both of which would concertedly deactivate JNK and c-Jun cascade, thereby leading to cyclin D1 downregulation.	16	28	deactivate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	16	17	25	26
MKK7 exclusively activates JNKs and MKK4 is unique in its ability to phosphorylate and activate two MAP kinase groups : JNKs and p38 .	MKK7 exclusively activates JNKs and MKK4 is unique in its ability to phosphorylate and activate two MAP kinase groups : JNKs and p38.	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNKs	JNKs	JNKs	0	1	20	21
To further assess the role of JNK in cPLA 2 phosphorylation , TALL-104 CTLs were transfected with a dominant negative JNKK2 , which was shown to prevent JNK activation .	To further assess the role of JNK in cPLA 2 phosphorylation, TALL-104 CTLs were transfected with a dominant negative JNKK2, which was shown to prevent JNK activation.	15	28	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNKK2	JNKK2	JNKK2	JNK	JNK	JNK	20	21	27	28
MKK7 is a requisite activator of JNK in this pathway .	MKK7 is a requisite activator of JNK in this pathway.	0	9	is a requisite activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	0	1	6	7
Mammals possess seven MKKs , where MKK1/2 , MKK3/6 , MKK7 activate ERK , p38 , and JNK , respectively , MKK4 phosphorylates both p38 and JNK , and MKK5 activates ERK5 .	Mammals possess seven MKKs, where MKK1/2, MKK3/6, MKK7 activate ERK, p38, and JNK, respectively, MKK4 phosphorylates both p38 and JNK, and MKK5 activates ERK5.	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	10	11	17	18
Expression of MKK7 in cultured cells causes activation of the JNK signal transduction pathway .	Expression of MKK7 in cultured cells causes activation of the JNK signal transduction pathway.	0	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	Expression of MKK7	mkk7	JNK	JNK	jnk	2	3	10	11
HDACI induced decreased Raf-1 expression leads to the inactivation of MEK/ERK/Fra -1 cascades , whereas the HDACI mediated decrease in MKK7 and increase in MKP-1 synergistically inactivate JNK and c-Jun activities .	HDACI induced decreased Raf-1 expression leads to the inactivation of MEK/ERK/Fra -1 cascades, whereas the HDACI mediated decrease in MKK7 and increase in MKP-1 synergistically inactivate JNK and c-Jun activities.	18	30	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	20	21	27	28
Serum regulates Gc action through MKK7 activated JNK .	Serum regulates Gc action through MKK7 activated JNK.	3	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	5	6	7	8
ASK-1 and MKK7 induced JNK activation .	ASK-1 and MKK7 induced JNK activation.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	2	3	4	5
MKK7 can activate JNK through the phosphorylation of Thr 183 and Tyr 185 sites within the VIII region of JNK , thereby transducing extracellular stimulation signals into the cell and nucleus to trigger a series of cellular biological responses .	MKK7 can activate JNK through the phosphorylation of Thr 183 and Tyr 185 sites within the VIII region of JNK, thereby transducing extracellular stimulation signals into the cell and nucleus to trigger a series of cellular biological responses.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	0	1	3	4
The homologue in vertebrates , MKK7 , cooperates with MKK4 to activate JNK and Bsk [ XREF_BIBR ] .	The homologue in vertebrates, MKK7, cooperates with MKK4 to activate JNK and Bsk [XREF_BIBR].	3	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	5	6	12	13
Therefore , it is likely that MKK7 mediates the activation of JNK in DP thymocytes in response to anti-CD3 mAb treatment in vivo .	Therefore, it is likely that MKK7 mediates the activation of JNK in DP thymocytes in response to anti-CD3 mAb treatment in vivo.	6	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	6	7	11	12
MAP2K4 can phosphorylate both JNKs and p38 MAPK , while MAP2K7 only activates JNK .	MAP2K4 can phosphorylate both JNKs and p38 MAPK, while MAP2K7 only activates JNK.	10	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K7	MAP2K7	MAP2K7	JNK	JNK	JNK	10	11	13	14
However , constitutive JNK activation alone did not replicate the effects of DBPT in DLD-1 cells , and excessive JNK activation by adenovirus encoding MKK7 had little influence on DBPT induced apoptosis .	However, constitutive JNK activation alone did not replicate the effects of DBPT in DLD-1 cells, and excessive JNK activation by adenovirus encoding MKK7 had little influence on DBPT induced apoptosis.	19	25	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	24	25	19	20
This proposition is supported by findings showing that expression of MKK7 which mediates JNK activation by mixed-lineage kinases is increased after METH treatment .	This proposition is supported by findings showing that expression of MKK7 which mediates JNK activation by mixed-lineage kinases is increased after METH treatment.	8	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	expression of MKK7	mkk7	JNK	JNK	jnk	10	11	13	14
This suggests that TNF-alpha signals through MKK4 , but not MKK7 , to activate the p54 JNK and ROCK plays a role in the signaling events leading to MKK4 and JNK activation .	This suggests that TNF-alpha signals through MKK4, but not MKK7, to activate the p54 JNK and ROCK plays a role in the signaling events leading to MKK4 and JNK activation.	4	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	10	11	16	17
These results suggest that excess activation of ERK by CA MKK2 and JNK by CA MKK7 in v-Rel transformed cells , instead of further promoting the oncogenic potential of v-Rel , is inhibitory to the growth of transformed cells in soft agar .	These results suggest that excess activation of ERK by CA MKK2 and JNK by CA MKK7 in v-Rel transformed cells, instead of further promoting the oncogenic potential of v-Rel, is inhibitory to the growth of transformed cells in soft agar.	5	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	15	16	12	13
Although MKK7 is the primary activator of JNK in FLS after TNF or IL-1 activation , numerous studies show that the relative hierarchy of MKK4 and MKK7 depends on the cell lineage and the mode of stimulation .	Although MKK7 is the primary activator of JNK in FLS after TNF or IL-1 activation, numerous studies show that the relative hierarchy of MKK4 and MKK7 depends on the cell lineage and the mode of stimulation.	1	9	is the primary activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	1	2	7	8
Mouse embryo fibroblasts that lack MKK7 ( upstream activator of JNK ) undergo cellular senescence and G2/M growth arrest , further support our finding that reduced expression of JNK1 may be one of the contributing factors for G2/M arrest caused by knock-down of Orc6 expression XREF_BIBR .	Mouse embryo fibroblasts that lack MKK7 (upstream activator of JNK) undergo cellular senescence and G2/M growth arrest, further support our finding that reduced expression of JNK1 may be one of the contributing factors for G2/M arrest caused by knock-down of Orc6 expression XREF_BIBR.	5	12	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	5	6	10	11
Furthermore , JNK interacted with PER2 at both the exogenous and endogenous levels , and MKK7 mediated JNK activation increased the half-life of PER2 protein by inhibiting its ubiquitination .	Furthermore, JNK interacted with PER2 at both the exogenous and endogenous levels, and MKK7 mediated JNK activation increased the half-life of PER2 protein by inhibiting its ubiquitination.	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	15	16	17	18
Moreover , JNK inhibition by SP600125 or MKK7 siRNA knockdown antagonized the effects of p38 inhibition by SB202190 .	Moreover, JNK inhibition by SP600125 or MKK7 siRNA knockdown antagonized the effects of p38 inhibition by SB202190.	2	9	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	7	8	2	3
It has been shown that MAP2K7 mediates JNK activation during the deletion of CD4 and CD8 double positive thymocytes , MAP2K7 is an essential regulator of stress induced SAPK and JNK activation in mast cells and negatively regulates proliferation in hematopoietic cells , and MAP2K7 sequesters JNK1 in the cytosol , preventing pro survival functions in Jurkat cells .	It has been shown that MAP2K7 mediates JNK activation during the deletion of CD4 and CD8 double positive thymocytes, MAP2K7 is an essential regulator of stress induced SAPK and JNK activation in mast cells and negatively regulates proliferation in hematopoietic cells, and MAP2K7 sequesters JNK1 in the cytosol, preventing pro survival functions in Jurkat cells.	5	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K7	MAP2K7	MAP2K7	JNK	JNK	JNK	5	6	7	8
We propose a model in which growth cone localization of MKK7 mRNA , and possibly its translation at this subcellular localization triggers a spatio-temporal JNK signaling module in the neurite to specifically regulate mt bundling and neurite elongation .	We propose a model in which growth cone localization of MKK7 mRNA, and possibly its translation at this subcellular localization triggers a spatio-temporal JNK signaling module in the neurite to specifically regulate mt bundling and neurite elongation.	10	26	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	10	11	24	25
Although MKK7 can also be critical in activation of JNK 50 and JNK activation is often regulated by MKK4 and/or MKK7 following their activation by ASK1 , XREF_BIBR , XREF_BIBR we could neither detect activation of MKK7 , nor did MKK7 knockdown showed any influence on mCD40L killing .	Although MKK7 can also be critical in activation of JNK 50 and JNK activation is often regulated by MKK4 and/or MKK7 following their activation by ASK1, XREF_BIBR, XREF_BIBR we could neither detect activation of MKK7, nor did MKK7 knockdown showed any influence on mCD40L killing.	1	10	be critical in activation	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	1	2	9	10
XREF_BIBR So we speculate that miR-125b suppressed EMT through JNK pathway which was modulated by MAP2K7 activation .	XREF_BIBR So we speculate that miR-125b suppressed EMT through JNK pathway which was modulated by MAP2K7 activation.	9	16	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAP2K7	MAP2K7	MAP2K7	JNK	JNK	JNK	15	16	9	10
Furthermore , we provide evidence that MEK7 induced JNK1/2 activation regulates Akt-Ser 473 phosphorylation and PLB-Akt interactions in myocytes .	Furthermore, we provide evidence that MEK7 induced JNK1/2 activation regulates Akt-Ser 473 phosphorylation and PLB-Akt interactions in myocytes.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK7	MEK7	MEK7	JNK1/2	JNK1/2	JNK1/2	6	7	8	9
The JNK pathway may instead function to control c-Jun protein levels , in part by modulating the activity of several transcription factors that together regulate the c-jun promoter , which is a situation that would explain the effects of the JNK activator MKK7 in our experiments .	The JNK pathway may instead function to control c-Jun protein levels, in part by modulating the activity of several transcription factors that together regulate the c-jun promoter, which is a situation that would explain the effects of the JNK activator MKK7 in our experiments.	37	43	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	42	43	40	41
Moreover , the effects of MKK7 mediated JNK activation on phosphorylated Ser and Thr Pro motifs and Pin1 binding ability of Grb7 were markedly reduced with the Grb7 S194A mutant in comparison to wild-type Grb7 ( XREF_FIG ) .	Moreover, the effects of MKK7 mediated JNK activation on phosphorylated Ser and Thr-Pro motifs and Pin1 binding ability of Grb7 were markedly reduced with the Grb7 S194A mutant in comparison to wild-type Grb7 (XREF_FIG).	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	5	6	7	8
Indeed , we detected JNK1 , JIP1 and the upstream JNK activator MAP kinase kinase-7 ( MKK7 ) in GluR2L and GluR4 immunoprecipitates from rat brain membranes ( XREF_FIG ) .	Indeed, we detected JNK1, JIP1 and the upstream JNK activator MAP kinase kinase-7 (MKK7) in GluR2L and GluR4 immunoprecipitates from rat brain membranes (XREF_FIG).	10	15	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MAP kinase kinase-7	MAP kinase kinase-7	MAP kinase kinase-7	JNK	JNK	JNK	12	15	10	11
While MKK3 and MKK6 specifically phosphorylate and activate p38 , MKK7 activates JNK .	While MKK3 and MKK6 specifically phosphorylate and activate p38, MKK7 activates JNK.	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	10	11	12	13
Consistent with the role for JNK in mitosis , MKK7 , an upstream kinase that activates JNK is shown to regulate G2/M phase of cell cycle , and affects cell proliferation and senescence XREF_BIBR .	Consistent with the role for JNK in mitosis, MKK7, an upstream kinase that activates JNK is shown to regulate G2/M phase of cell cycle, and affects cell proliferation and senescence XREF_BIBR.	0	17	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	9	10	16	17
While MKK7 is a specific activator of JNKs , MKK4 can also phosphorylate the TGY motif of p38 MAP kinases [ XREF_BIBR ] .	While MKK7 is a specific activator of JNKs, MKK4 can also phosphorylate the TGY motif of p38 MAP kinases [XREF_BIBR].	1	8	is a specific activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNKs	JNKs	JNKs	1	2	7	8
Therefore , we evaluated whether targeting MKK7 using anti-sense oligonucleotides ( ASO ) would decrease JNK activation and severity in K/BxN serum transfer arthritis .	Therefore, we evaluated whether targeting MKK7 using anti-sense oligonucleotides (ASO) would decrease JNK activation and severity in K/BxN serum transfer arthritis.	5	16	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	6	7	15	16
Because MKK4 activates both JNK and p38 , whereas MKK7 activates only JNK activity , we set out to investigate the subcellular organization of MKK7 .	Because MKK4 activates both JNK and p38, whereas MKK7 activates only JNK activity, we set out to investigate the subcellular organization of MKK7.	9	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	9	10	12	13
JNK activation is mediated by the upstream MKK7 kinases via phosphorylation .	JNK activation is mediated by the upstream MKK7 kinases via phosphorylation.	0	8	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	7	8	0	1
While MKK7 is a specific activator of JNKs , MKK4 can also phosphorylate p38 MAPKs under some circumstances [ XREF_BIBR ] .	While MKK7 is a specific activator of JNKs, MKK4 can also phosphorylate p38 MAPKs under some circumstances [XREF_BIBR].	1	8	is a specific activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNKs	JNKs	JNKs	1	2	7	8
In the brain , MKK7 is a specific activator of JNK , and mice with brain specific conditional knockout ( cKO ) of MKK7 exhibit hypoactive axon formation in the developing brain .	In the brain, MKK7 is a specific activator of JNK, and mice with brain specific conditional knockout (cKO) of MKK7 exhibit hypoactive axon formation in the developing brain.	4	11	is a specific activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	4	5	10	11
To determine the role of the SAPK and JNK activator MKK7 in hematopoietic cells , we mutated both mkk7 alleles in ES cells using two selectable markers and generated mkk7 deficient chimeric mice via rag1 complementation .	To determine the role of the SAPK and JNK activator MKK7 in hematopoietic cells, we mutated both mkk7 alleles in ES cells using two selectable markers and generated mkk7 deficient chimeric mice via rag1 complementation.	3	11	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	10	11	8	9
The rationale for targeting MKKs instead of downstream JNK is based on studies that demonstrated the expression of MKK-4 and MKK-7 in RA synovial tissue [ XREF_BIBR ] and that MKK-7 activates JNK in fibroblast like synoviocytes after IL-1 and TNFalpha stimulation [ XREF_BIBR ] .	The rationale for targeting MKKs instead of downstream JNK is based on studies that demonstrated the expression of MKK-4 and MKK-7 in RA synovial tissue [XREF_BIBR] and that MKK-7 activates JNK in fibroblast like synoviocytes after IL-1 and TNFalpha stimulation [XREF_BIBR].	30	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK-7	MKK-7	MKK-7	JNK	JNK	JNK	30	31	32	33
LPS and peptidoglycan induced JNK activation was mediated by MKK7 primarily , similar to the results observed with TNFalpha , resulting in the activation of cJun .	LPS and peptidoglycan induced JNK activation was mediated by MKK7 primarily, similar to the results observed with TNFalpha, resulting in the activation of cJun.	4	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	9	10	4	5
Previous observations have shown that after JNK activation by overexpression of its direct activator MKK7 , JNK mediated GR phosphorylation results in a decrease of GR dependent transcriptional activity XREF_BIBR XREF_BIBR .	Previous observations have shown that after JNK activation by overexpression of its direct activator MKK7, JNK mediated GR phosphorylation results in a decrease of GR dependent transcriptional activity XREF_BIBR XREF_BIBR.	6	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MKK7	overexpression of its direct activator MKK7	mkk7	JNK	JNK	jnk	14	15	6	7
Our present studies show that MEK7 expression in keratinocytes markedly activates p38alpha and modestly activates JNK .	Our present studies show that MEK7 expression in keratinocytes markedly activates p38alpha and modestly activates JNK.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK7	MEK7 expression	mek7	JNK	JNK	jnk	5	6	15	16
The FLAG tagged constructs encode JNK fused to a constitutively active upstream mitogen activated protein kinase kinase 7 ( MKK7 ) , which persistently activates the JNK moiety [ XREF_BIBR ] .	The FLAG tagged constructs encode JNK fused to a constitutively active upstream mitogen activated protein kinase kinase 7 (MKK7), which persistently activates the JNK moiety [XREF_BIBR].	13	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	19	20	26	27
MKK7 Activates a Spatio-Temporal JNK Signaling Module in the Neurite Shaft .	MKK7 Activates a Spatio-Temporal JNK Signaling Module in the Neurite Shaft.	0	6	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	0	1	4	5
MKK7 is the primary activator of JNK in TNF , LPS , and PGN responses .	MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses.	0	14	is the primary activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	0	1	6	7
JIP3 binds to JNK and other components of the JNK module , including the MKKK , MLK3 and MKK7 , in a manner that facilitates JNK signalling and activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	JIP3 binds to JNK and other components of the JNK module, including the MKKK, MLK3 and MKK7, in a manner that facilitates JNK signalling and activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	19	module	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	18	19	9	10
MKK4 activates both JNK and p38 , whereas MKK7 activates only JNK .	MKK4 activates both JNK and p38, whereas MKK7 activates only JNK.	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	8	9	11	12
IBV induced JNK activation was mediated by MKK7 , and required both its ATP binding and phosphorylation sites .	IBV induced JNK activation was mediated by MKK7, and required both its ATP binding and phosphorylation sites.	2	8	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	7	8	2	3
Among them , Map3k1 , Map2k3 and Daxx activate p38 MAPK which in turn activates p53 [ XREF_BIBR - XREF_BIBR ] ; Map2k7 together with Map3k1 activate JNK which in turn activates p53 [ XREF_BIBR , XREF_BIBR ] ; Sae1 , Uba2 , Pias1 and Pias2 are sumoylation ligases that prime p53 for inducing apoptosis [ XREF_BIBR ] ; Mdm2 is a ubiquitin ligase for p53 that primes it for degradation .	Among them, Map3k1, Map2k3 and Daxx activate p38 MAPK which in turn activates p53 [XREF_BIBR - XREF_BIBR]; Map2k7 together with Map3k1 activate JNK which in turn activates p53 [XREF_BIBR, XREF_BIBR]; Sae1, Uba2, Pias1 and Pias2 are sumoylation ligases that prime p53 for inducing apoptosis [XREF_BIBR]; Mdm2 is a ubiquitin ligase for p53 that primes it for degradation.	22	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Map2k7	Map2k7	Map2k7	JNK	JNK	JNK	22	23	27	28
Loss of MKK7 in ES cells abrogates , but does not abolish , SAPK and JNK activation in response to osmolarity changes , UV irradiation , heat shock , or anisomycin 10 .	Loss of MKK7 in ES cells abrogates, but does not abolish, SAPK and JNK activation in response to osmolarity changes, UV irradiation, heat shock, or anisomycin 10.	0	16	abolish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK7	Loss of MKK7	mkk7	JNK	JNK	jnk	2	3	15	16
Our results show that growth cone MKK7 mRNA localization also modulates this JNK signaling module in hippocampal neurons .	Our results show that growth cone MKK7 mRNA localization also modulates this JNK signaling module in hippocampal neurons.	6	14	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	6	7	12	13
In contrast , disruption of the Mkk7 gene alone was sufficient to prevent JNK activation caused by proinflammatory cytokines .	In contrast, disruption of the Mkk7 gene alone was sufficient to prevent JNK activation caused by proinflammatory cytokines.	6	14	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mkk7	Mkk7	Mkk7	JNK	JNK	JNK	6	7	13	14
Of note , apoptosis depended on MKK7 driven JNK activation , underscoring the potential of a molecule that could interfere with the capacity of GADD45beta to downregulate MKK7 activity .	Of note, apoptosis depended on MKK7 driven JNK activation, underscoring the potential of a molecule that could interfere with the capacity of GADD45beta to downregulate MKK7 activity.	4	9	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	6	7	8	9
MEKK2 can phosphorylate and activate MAP2K proteins MKK7 and MEK5 , thereby promoting activation of JNK and ERK5 , respectively [ XREF_BIBR ] .	MEKK2 can phosphorylate and activate MAP2K proteins MKK7 and MEK5, thereby promoting activation of JNK and ERK5, respectively [XREF_BIBR].	7	21	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	7	8	15	16
Taken together , these results reinforce the contention that p85alpha R348 * mediates the nuclear accumulation of MLK3 and MKK7 thereby promoting activation of the JNK signaling cascade in the nucleus .	Taken together, these results reinforce the contention that p85alpha R348 * mediates the nuclear accumulation of MLK3 and MKK7 thereby promoting activation of the JNK signaling cascade in the nucleus.	15	27	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	19	20	25	26
Here , we identify MKK7 and JNKK2 -- a specific and essential activator of JNK -- as a target of Gadd45 beta , and in fact , of NF-kappa B itself .	Here, we identify MKK7 and JNKK2 -- a specific and essential activator of JNK -- as a target of Gadd45 beta, and in fact, of NF-kappa B itself.	4	30	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	4	5	14	15
XREF_BIBR MAP2K7 is able to specifically activate the JNK pathway without affecting ERK and p38 activities .	XREF_BIBR MAP2K7 is able to specifically activate the JNK pathway without affecting ERK and p38 activities.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K7	MAP2K7	MAP2K7	JNK	JNK	JNK	1	2	8	9
SENP3 mediated deSUMOylation of MKK7 potentiates JNK activation .	SENP3 mediated deSUMOylation of MKK7 potentiates JNK activation.	0	7	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	SENP3 mediated deSUMOylation of MKK7	mkk7	JNK	JNK	jnk	4	5	6	7
Consistent with the studies above , it was shown that transgenic mice in which a sustained JNK activation is specifically driven in beta-cells by a constitutive active mutant of the JNK activating kinase MKK7 develop glucose intolerance , reduced insulin secretion , and defective insulin signaling in their beta-cells XREF_BIBR .	Consistent with the studies above, it was shown that transgenic mice in which a sustained JNK activation is specifically driven in beta-cells by a constitutive active mutant of the JNK activating kinase MKK7 develop glucose intolerance, reduced insulin secretion, and defective insulin signaling in their beta-cells XREF_BIBR.	16	34	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	33	34	16	17
MAP2K4 and MAP2K7 have been shown to have different functions in response to extracellular stimuli because the deletion of both genes is required to block JNK activation in mouse embryonic fibroblasts in response to environmental stress such as UV irradiation and anisomycin , whereas the deletion of MAP2K7 alone is sufficient to inhibit JNK activation induced by pro inflammatory cytokines such as TNFalpha and IL1alpha .	MAP2K4 and MAP2K7 have been shown to have different functions in response to extracellular stimuli because the deletion of both genes is required to block JNK activation in mouse embryonic fibroblasts in response to environmental stress such as UV irradiation and anisomycin, whereas the deletion of MAP2K7 alone is sufficient to inhibit JNK activation induced by pro inflammatory cytokines such as TNFalpha and IL1alpha.	45	54	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K7	MAP2K7	MAP2K7	JNK	JNK	JNK	47	48	53	54
Thus , Agrin appears to activate musk primarily via the Rac and JNK dependent shunt pathway : ( a ) only interfering with JNK but not abolishing NRG and ErbB signaling abolished Agrin induced musk expression , and ( b ) forced overexpression of MKK7 , which activates JNK but not ERK and p38 MAPKs , induced musk , again suggesting convergence of the NRG and ErbB and the shunt pathways .	Thus, Agrin appears to activate musk primarily via the Rac and JNK dependent shunt pathway : (a) only interfering with JNK but not abolishing NRG and ErbB signaling abolished Agrin induced musk expression, and (b) forced overexpression of MKK7, which activates JNK but not ERK and p38 MAPKs, induced musk, again suggesting convergence of the NRG and ErbB and the shunt pathways.	29	54	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	ErbB signaling abolished Agrin induced musk expression, and (b) forced overexpression of MKK7	mkk7	JNK	JNK	jnk	44	45	48	49
We noted that the mutant form of MEK1 , MEK1 K64R , is resistant to MEK1 SUMOylation , thereby activating the ERK signaling pathway .	We noted that the mutant form of MEK1, MEK1 K64R, is resistant to MEK1 SUMOylation, thereby activating the ERK signaling pathway.	5	23	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	7	8	21	22
In contrast , ERK pathway induction is depending on binding of the Grb2 and Sos complex to Tyr 1068 and mediated by MEK1 phosphorylation , which was not increased in the present material [ XREF_BIBR , XREF_BIBR ] .	In contrast, ERK pathway induction is depending on binding of the Grb2 and Sos complex to Tyr 1068 and mediated by MEK1 phosphorylation, which was not increased in the present material [XREF_BIBR, XREF_BIBR].	3	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1 phosphorylation	mek1	ERK	ERK	erk	22	23	3	4
Up to now , it is clear that cardiac defeat mediated by LMNA mutation could be ameliorated by manipulation of the Akt and mTOR pathway by facilitating clearance of accumulated mutant protein through the process of autophagy and MEK1 mediated Erk1/2 by inhibition of apoptotic stress responses .	Up to now, it is clear that cardiac defeat mediated by LMNA mutation could be ameliorated by manipulation of the Akt and mTOR pathway by facilitating clearance of accumulated mutant protein through the process of autophagy and MEK1 mediated Erk1/2 by inhibition of apoptotic stress responses.	34	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	Erk1/2	Erk1/2	Erk1/2	38	39	40	41
Expression of constitutively active MEK1 , the kinase that activates ERKs , or overexpression of ERK2 , but not JNK1 , inhibited Stat3 activation .	Expression of constitutively active MEK1, the kinase that activates ERKs, or overexpression of ERK2, but not JNK1, inhibited Stat3 activation.	0	11	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK1	Expression of constitutively active MEK1	mek1	ERKs	ERKs	erks	4	5	10	11
Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients .	Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients.	5	18	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	17	18	5	6
Western blot analysis displayed an obvious decrease of MAPK1 , p-MAPK1 and Slug expression by si-MAPK1-1 or si-MAPK1-2 transfection , as well as an apparent decline of MAP2K1 , p-MAP2K1 and Slug expression after trsnafection with si-MAP2K1-1 or si-MAP2K1-2 in A549 and A549 and DPP cells , indicating that MAPK1 and MAP2K1 knockdown could effectively suppress MAPK and Slug pathway .	Western blot analysis displayed an obvious decrease of MAPK1, p-MAPK1 and Slug expression by si-MAPK1-1 or si-MAPK1-2 transfection, as well as an apparent decline of MAP2K1, p-MAP2K1 and Slug expression after trsnafection with si-MAP2K1-1 or si-MAP2K1-2 in A549 and A549 and DPP cells, indicating that MAPK1 and MAP2K1 knockdown could effectively suppress MAPK and Slug pathway.	49	59	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K1	MAP2K1	MAP2K1	MAPK	MAPK	MAPK	51	52	56	57
Since even high expression of CA MKK1 did not strongly increase ERK activity , only CA MKK2 and CA MKK7 were used in these studies .	Since even high expression of CA MKK1 did not strongly increase ERK activity, only CA MKK2 and CA MKK7 were used in these studies.	3	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK1	expression of CA MKK1	mkk1	ERK	ERK	erk	6	7	11	12
This suggests that both MEK1 and MEK2 are required for ET-1 to activate ERK1/2 in HASMCs .	This suggests that both MEK1 and MEK2 are required for ET-1 to activate ERK1/2 in HASMCs.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	4	5	13	14
Co-expression of either a constitutive Erk2 , or MEK1 ( an activator of endogenous Erks ) reversed this repression ( XREF_FIG ) .	Co-expression of either a constitutive Erk2, or MEK1 (an activator of endogenous Erks) reversed this repression (XREF_FIG).	0	16	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	Erks	Erks	Erks	8	9	14	15
However , in vivo expression of a constitutively active form of MEK1 ( an upstream activator of MAPK and ERK ) in the mouse lens results in several defects including macrophthalmia , cataracts and lens rupture [ XREF_BIBR ] .	However, in vivo expression of a constitutively active form of MEK1 (an upstream activator of MAPK and ERK) in the mouse lens results in several defects including macrophthalmia, cataracts and lens rupture [XREF_BIBR].	9	24	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	11	12	17	18
Oncogenic mutations of NRAS , KRAS , BRAF , MEK1 , and NF1 drive the ERK dependent growth of many human cancers .	Oncogenic mutations of NRAS, KRAS, BRAF, MEK1, and NF1 drive the ERK dependent growth of many human cancers.	1	17	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	9	10	15	16
Trametinib ( Mekinist , GlaxoSmithKline ) is an oral MEK1 and MEK2 inhibitor targeting the MAPK pathway downstream .	Trametinib (Mekinist, GlaxoSmithKline) is an oral MEK1 and MEK2 inhibitor targeting the MAPK pathway downstream.	0	16	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	9	10	15	16
Inhibition of MEK1 by its specific inhibitor , PD98059 substantially inhibited Erk activation .	Inhibition of MEK1 by its specific inhibitor, PD98059 substantially inhibited Erk activation.	0	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	Erk	Erk	Erk	2	3	11	12
For example , ERK phosphorylates and inhibits SOS , Raf , and MEK1 , thereby reducing ERK activation .	For example, ERK phosphorylates and inhibits SOS, Raf, and MEK1, thereby reducing ERK activation.	3	17	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	ERK phosphorylates and inhibits SOS, Raf, and MEK1	mek1	ERK	ERK	erk	12	13	16	17
In addition , 15 ( S )-HETE , through MEK1 dependent activation of ERK1/2 and JNK1 , stimulates the angiogenic differentiation of HRMVECs and basement membrane matrix plug angiogenesis .	In addition, 15 (S)-HETE, through MEK1 dependent activation of ERK1/2 and JNK1, stimulates the angiogenic differentiation of HRMVECs and basement membrane matrix plug angiogenesis.	9	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	9	10	13	14
Conversely , enforced activation of ERK by overexpression of MEK-1 and Q56P sensitized cells to DNA damage induced apoptosis .	Conversely, enforced activation of ERK by overexpression of MEK-1 and Q56P sensitized cells to DNA damage induced apoptosis.	3	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK-1	overexpression of MEK-1	mek-1	ERK	ERK	erk	9	10	5	6
Genetic deletion of DARPP-32 ( a key effector of the PKA cascade ) and inhibitors of MEK1 ( an upstream activator of ERK1/2 ) each block sensitization to drugs of abuse .	Genetic deletion of DARPP-32 (a key effector of the PKA cascade) and inhibitors of MEK1 (an upstream activator of ERK1/2) each block sensitization to drugs of abuse.	14	24	activator	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	16	17	22	23
In non transformed cells , MEK1 ablation increases both ERK and AKT signaling by disabling negative feedback steps in the pathways [ XREF_BIBR , XREF_BIBR ] .	In non transformed cells, MEK1 ablation increases both ERK and AKT signaling by disabling negative feedback steps in the pathways [XREF_BIBR, XREF_BIBR].	5	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	5	6	9	10
Studies from the Garraway group indicate that up-regulation of the MAP3K , Cot1 , and acquired mutation in MEK1 provide other routes to promote re-activation of the ERK1/2 pathway in relapsing tumors .	Studies from the Garraway group indicate that up-regulation of the MAP3K, Cot1, and acquired mutation in MEK1 provide other routes to promote re-activation of the ERK1/2 pathway in relapsing tumors.	15	28	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	18	19	27	28
Additionally , the expression of a constitutively active form of MEK1 , activating the ERK MAPK pathway , in mouse epidermis results in skin polyps , which are mostly formed by cells not carrying oncogenic MEK1 62 .	Additionally, the expression of a constitutively active form of MEK1, activating the ERK MAPK pathway, in mouse epidermis results in skin polyps, which are mostly formed by cells not carrying oncogenic MEK1 62.	8	16	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK MAPK	ERK MAPK	ERK MAPK	10	11	14	16
Furthermore , MEK1 deficient BMDMs were stimulated with LPS in the presence or absence of RA to assess ERK activation .	Furthermore, MEK1 deficient BMDMs were stimulated with LPS in the presence or absence of RA to assess ERK activation.	2	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	2	3	18	19
While there is some overlap in their specificity , ERK is usually activated by MEK1 and 2 , p38 by MKK3 and 6 , and JNK by MKK4 and 7 .	While there is some overlap in their specificity, ERK is usually activated by MEK1 and 2, p38 by MKK3 and 6, and JNK by MKK4 and 7.	9	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	14	15	9	10
Overexpression of the ERK pathway was found to be independent of MEK1/2 XREF_BIBR as pharmacological inhibitors of MEK1 ( PD98059 ) , MEK1/2 ( U0126 ) and dominant negative DN-MEK1/2 failed to abolish ERK activity .	Overexpression of the ERK pathway was found to be independent of MEK1/2 XREF_BIBR as pharmacological inhibitors of MEK1 (PD98059), MEK1/2 (U0126) and dominant negative DN-MEK1/2 failed to abolish ERK activity.	15	34	abolish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	17	18	33	34
RAF activation in turn activates the serine/threonine kinases MEK1 and MEK2 , which in turn activate ERK .	RAF activation in turn activates the serine/threonine kinases MEK1 and MEK2, which in turn activate ERK.	4	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	8	9	16	17
The 50-kDa ERK was shown to be stimulated by Con A , and inhibition of MEK1 down-regulated the 50-kDa ERK as was shown for ERK1 ,2 .	The 50-kDa ERK was shown to be stimulated by Con A, and inhibition of MEK1 down-regulated the 50-kDa ERK as was shown for ERK1,2.	13	20	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	15	16	19	20
It is not likely that the transdominant negative mutant of TRAF6 nonspecifically diminished the activity of the ERK dependent activator and reporter , because activation of the ERK dependent reporter mediated by coexpression of catalytically active MEK1 in the 293 cell line was not prevented by coexpression of TRAF-C of TRAF6 ( data not shown ) .	It is not likely that the transdominant negative mutant of TRAF6 nonspecifically diminished the activity of the ERK dependent activator and reporter, because activation of the ERK dependent reporter mediated by coexpression of catalytically active MEK1 in the 293 cell line was not prevented by coexpression of TRAF-C of TRAF6 (data not shown).	27	41	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	coexpression of catalytically active MEK1	mek1	ERK	ERK	erk	36	37	27	28
Furthermore , inhibitors of PI3K ( LY294002 and Wortmannin ) , MEK1 ( PD98059 and U0126 ) , and Src family tyrosine kinases ( PP2 ) decreased IGF-I-induced proliferation , and blocked ERK1/2 activation .	Furthermore, inhibitors of PI3K (LY294002 and Wortmannin), MEK1 (PD98059 and U0126), and Src family tyrosine kinases (PP2) decreased IGF-I-induced proliferation, and blocked ERK1/2 activation.	2	33	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	11	12	32	33
Most cancer was associated with constitutive activation of ERK signaling , which was activated ERK1/2 by MEK1 and MEK2 upon activation of receptor tyrosine kinase .	Most cancer was associated with constitutive activation of ERK signaling, which was activated ERK1/2 by MEK1 and MEK2 upon activation of receptor tyrosine kinase.	8	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	16	17	8	9
In cells cultured from affected bone of Melo-10 with lower mutant allele frequency of 10 % , the activation of ERK1/2 by MEK1 was equivocal .	In cells cultured from affected bone of Melo-10 with lower mutant allele frequency of 10%, the activation of ERK1/2 by MEK1 was equivocal.	18	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	22	23	20	21
Addition of either PD169316 ( a p38 inhibitor ) or SP600125 ( a JNK inhibitor ) induced formation of domes ( a phenomenon dependent on TJ barrier function ) and enhanced transepithelial electrical resistance , whereas U0126 ( an inhibitor of the ERK1/2 activators MEK1 and MEK2 ) had no significant effect .	Addition of either PD169316 (a p38 inhibitor) or SP600125 (a JNK inhibitor) induced formation of domes (a phenomenon dependent on TJ barrier function) and enhanced transepithelial electrical resistance, whereas U0126 (an inhibitor of the ERK1/2 activators MEK1 and MEK2) had no significant effect.	39	46	activators	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	44	45	42	43
As such , U0126 , a specific inhibitor of MEK1 , has been commonly used to block the Ras-MEK-ERK pathway , especially ERK1/2 activation .	As such, U0126, a specific inhibitor of MEK1, has been commonly used to block the Ras-MEK-ERK pathway, especially ERK1/2 activation.	7	23	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	9	10	22	23
XREF_BIBR GTP loaded RAS can recruit RAF ( ARAF , BRAF , and CRAF ) to the cell membrane resulting in activation ; activated RAF can phosphorylate and activate MEK ( MEK1 and MEK2 ) , which phosphorylates and activates ERK ( ERK1 and ERK2 ) as part of a signaling cascade to modulate cell proliferation , differentiation , apoptosis , and migration XREF_BIBR , XREF_BIBR , XREF_BIBR ( XREF_FIG ) .	XREF_BIBR GTP loaded RAS can recruit RAF (ARAF, BRAF, and CRAF) to the cell membrane resulting in activation; activated RAF can phosphorylate and activate MEK (MEK1 and MEK2), which phosphorylates and activates ERK (ERK1 and ERK2) as part of a signaling cascade to modulate cell proliferation, differentiation, apoptosis, and migration XREF_BIBR, XREF_BIBR, XREF_BIBR (XREF_FIG).	24	47	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	RAF can phosphorylate and activate MEK (MEK1	mek1	ERK	ERK	erk	31	32	40	41
To date , only Mek1 and Mek2 are known to activate Erk1/2 , which in turn phosphorylate over 160 proteins , including numerous cytoplasmic and nuclear targets , such as kinases , phosphatases , transcription factors , and cytoskeletal proteins .	To date, only Mek1 and Mek2 are known to activate Erk1/2, which in turn phosphorylate over 160 proteins, including numerous cytoplasmic and nuclear targets, such as kinases, phosphatases, transcription factors, and cytoskeletal proteins.	3	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek1	Mek1	Mek1	Erk1/2	Erk1/2	Erk1/2	4	5	11	12
This is noteworthy as transgenic mice designed to suprabasally express active MEK1 ( the upstream activator of ERK ) or beta4 integrin phenocopy the caspase-8 knockout mouse XREF_BIBR , XREF_BIBR .	This is noteworthy as transgenic mice designed to suprabasally express active MEK1 (the upstream activator of ERK) or beta4 integrin phenocopy the caspase-8 knockout mouse XREF_BIBR, XREF_BIBR.	9	22	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	11	12	17	18
To determine whether CPX inhibition of LEC tube formation is really attributed to inhibition of ERK1/2 pathway , we generated recombinant adenoviral vector ( Ad-MKK1-R4F ) expressing Flag tagged constitutively active MKK1 , which activates ERK1/2 .	To determine whether CPX inhibition of LEC tube formation is really attributed to inhibition of ERK1/2 pathway, we generated recombinant adenoviral vector (Ad-MKK1-R4F) expressing Flag tagged constitutively active MKK1, which activates ERK1/2.	28	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK1	MKK1	MKK1	ERK1/2	ERK1/2	ERK1/2	31	32	35	36
Consistently with these data , a constitutively active form of MEK1 induced ERK1/2 activation and caused spontaneous epileptic seizures when conditionally expressed in the murine brain .	Consistently with these data, a constitutively active form of MEK1 induced ERK1/2 activation and caused spontaneous epileptic seizures when conditionally expressed in the murine brain.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	10	11	12	13
The phosphorylation of RAF transmits the signal to MEK1 and MEK2 , which further activates ERK ( XREF_FIG ) .	The phosphorylation of RAF transmits the signal to MEK1 and MEK2, which further activates ERK (XREF_FIG).	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	8	9	15	16
Conversely , silencing of the B family regulatory subunits Balpha and Bdelta led to hyperactivation of ERK stimulated by constitutively active MEK1 .	Conversely, silencing of the B family regulatory subunits Balpha and Bdelta led to hyperactivation of ERK stimulated by constitutively active MEK1.	14	22	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	21	22	16	17
The canonical pathway for FGF signalling showed likewise an up regulation of the majority of the genes including some of the kinases from the MAPK signalling like MAPK1 , MAP2K1 and MAP3K5 .	The canonical pathway for FGF signalling showed likewise an up regulation of the majority of the genes including some of the kinases from the MAPK signalling like MAPK1, MAP2K1 and MAP3K5.	24	30	signalling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MAP2K1	MAP2K1	MAP2K1	MAPK	MAPK	MAPK	29	30	24	25
Taken together , in normal cells , MEK1 SUMOylation attenuates the activity of MEK1 toward ERK , thereby inhibiting the ERK pathway .	Taken together, in normal cells, MEK1 SUMOylation attenuates the activity of MEK1 toward ERK, thereby inhibiting the ERK pathway.	8	21	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	SUMOylation attenuates the activity of MEK1	mek1	ERK	ERK	erk	13	14	20	21
The function of the ERK pathway in bRG formation was tested by expressing the ERK activator Mek1 DD in the E14.5 mouse cortex through in utero electroporation .	The function of the ERK pathway in bRG formation was tested by expressing the ERK activator Mek1 DD in the E14.5 mouse cortex through in utero electroporation.	14	17	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Mek1	Mek1	Mek1	ERK	ERK	ERK	16	17	14	15
Artificial Erk activation by expression of constitutively active Mek1 and B-Raf failed to block ephrin-A5 effects on growth cones , and inhibitors of the Erk pathway also failed to inhibit collapse by ephrin-A5 .	Artificial Erk activation by expression of constitutively active Mek1 and B-Raf failed to block ephrin-A5 effects on growth cones, and inhibitors of the Erk pathway also failed to inhibit collapse by ephrin-A5.	1	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Mek1	expression of constitutively active Mek1	mek1	Erk	Erk	erk	8	9	1	2
To date , several scaffold proteins have been identified that facilitate MAPK activation in mammalian cells , such as the kinase suppressor of Ras 1 ( KSR1 ) and the MEK1 partner ( LAMTOR3 and MP1 ) , which is recruited to late endosomes by the adapter protein LAMTOR2 and p14 XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	To date, several scaffold proteins have been identified that facilitate MAPK activation in mammalian cells, such as the kinase suppressor of Ras 1 (KSR1) and the MEK1 partner (LAMTOR3 and MP1), which is recruited to late endosomes by the adapter protein LAMTOR2 and p14 XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	11	31	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	30	31	11	12
To further verify whether CPT inhibition of LEC tube formation is truly attributed to inhibition of ERK1/2 pathway , we generated recombinant adenoviral vector ( Ad-MKK1-R4F ) expressing Flag tagged constitutively active MKK1 , which activates ERK1/2 .	To further verify whether CPT inhibition of LEC tube formation is truly attributed to inhibition of ERK1/2 pathway, we generated recombinant adenoviral vector (Ad-MKK1-R4F) expressing Flag tagged constitutively active MKK1, which activates ERK1/2.	29	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK1	MKK1	MKK1	ERK1/2	ERK1/2	ERK1/2	32	33	36	37
Therefore , further research should be conducted to investigate whether and how Ha-annexin regulates plant defense hormone biosynthesis and signaling downstream of MKK1 and NPK1 to modulate MAPK .	Therefore, further research should be conducted to investigate whether and how Ha-annexin regulates plant defense hormone biosynthesis and signaling downstream of MKK1 and NPK1 to modulate MAPK.	17	28	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK1	MKK1	MKK1	MAPK	MAPK	MAPK	22	23	27	28
To assess the specificity of our sensor to PKC-MAPK pathway activation , we used the small-molecule inhibitor PD98059 XREF_BIBR , XREF_BIBR , which has been shown to abolish shear dependent induction of EGR-1 by blocking MEK1 activation of ERK1/2 needed for EGR-1 transcription 35 .	To assess the specificity of our sensor to PKC-MAPK pathway activation, we used the small-molecule inhibitor PD98059 XREF_BIBR, XREF_BIBR, which has been shown to abolish shear dependent induction of EGR-1 by blocking MEK1 activation of ERK1/2 needed for EGR-1 transcription 35.	35	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	35	36	38	39
Accordingly , MEK1 and MEK2 knockdown diminished macrophage mediated increase in ERK activation of melanoma cells ( XREF_FIG ) .	Accordingly, MEK1 and MEK2 knockdown diminished macrophage mediated increase in ERK activation of melanoma cells (XREF_FIG).	2	12	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	2	3	11	12
The MEK1 transgene produces constitutive ERK1/2 activation in the heart , bringing into question the simple interpretation that MEK1-ERK1/2 signaling is truly capable of inducing hypertrophy in vivo under real physiologic conditions .	The MEK1 transgene produces constitutive ERK1/2 activation in the heart, bringing into question the simple interpretation that MEK1-ERK1/2 signaling is truly capable of inducing hypertrophy in vivo under real physiologic conditions.	1	6	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	1	2	5	6
Erdheim-Chester disease ( ECD ) is a rare non Langerhans cell histiocytosis that most commonly affects adults and is driven by a high frequency of mutations in BRAF , MAP2K1 , and kinases promoting MAPK signaling .	Erdheim-Chester disease (ECD) is a rare non Langerhans cell histiocytosis that most commonly affects adults and is driven by a high frequency of mutations in BRAF, MAP2K1, and kinases promoting MAPK signaling.	19	35	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K1	MAP2K1	MAP2K1	MAPK	MAPK	MAPK	29	30	34	35
To evaluate the influence of hydrogen peroxide ( H ( 2 ) O ( 2 ) ) on mouse photoreceptor derived 661W cell survival and to determine the effect of PD98059 , an inhibitor for MEK1 ( the direct upstream activator of ERK1/2 ) , and S3I201 , a STAT3- specific inhibitor on 661W cell survival after H ( 2 ) O ( 2 ) exposure .	To evaluate the influence of hydrogen peroxide (H (2) O (2)) on mouse photoreceptor derived 661W cell survival and to determine the effect of PD98059, an inhibitor for MEK1 (the direct upstream activator of ERK1/2), and S3I201, a STAT3- specific inhibitor on 661W cell survival after H (2) O (2) exposure.	33	43	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	35	36	42	43
In order to determine the relationship between these two phenomena , we have inhibited integrin induced signaling by a specific FAK inhibitor , 1,2,4,5-Benzenetetramine tetrahydrochloride , and the MAPK induced signaling by the specific MEK1 and MEK2 inhibitor PD98059 .	In order to determine the relationship between these two phenomena, we have inhibited integrin induced signaling by a specific FAK inhibitor, 1,2,4,5-Benzenetetramine tetrahydrochloride, and the MAPK induced signaling by the specific MEK1 and MEK2 inhibitor PD98059.	27	38	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	34	35	28	29
A Cre dependent constitutively-active Map2k1 S217/222Q ( ca-Map2k1 ) overexpressing line was crossed with Neurod6-Cre and Emx1-Cre mice to induce gain-of-function ERK and MAPK signaling .	A Cre dependent constitutively-active Map2k1 S217/222Q (ca-Map2k1) overexpressing line was crossed with Neurod6-Cre and Emx1-Cre mice to induce gain-of-function ERK and MAPK signaling.	4	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Map2k1	Map2k1	Map2k1	MAPK	MAPK	MAPK	4	5	23	24
These results may be expected , because although the docking motif of MEK is important for the ERK-MEK interaction , there are other mechanisms to ensure the activation of Erk by MEK1 , such as scaffold protein facilitation and the MEK catalytic site interacting with the Erk activation loop .	These results may be expected, because although the docking motif of MEK is important for the ERK-MEK interaction, there are other mechanisms to ensure the activation of Erk by MEK1, such as scaffold protein facilitation and the MEK catalytic site interacting with the Erk activation loop.	25	42	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	Erk	Erk	Erk	31	32	29	30
ERK1/2 activity in 1E8-KA-MEK1 transfectants was significantly suppressed by dominant negative MEK1 transfection .	ERK1/2 activity in 1E8-KA-MEK1 transfectants was significantly suppressed by dominant negative MEK1 transfection.	0	12	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	11	12	0	1
In the present study , we constructed a replication defective adenovirus vector carrying mutated form of MEK1 ( CA-MEK virus ) , which constitutively activate ERK pathway , and investigated its effect on thoracic spinal cord injury model in young adult rats as well as neurite outgrowth in vitro .	In the present study, we constructed a replication defective adenovirus vector carrying mutated form of MEK1 (CA-MEK virus), which constitutively activate ERK pathway, and investigated its effect on thoracic spinal cord injury model in young adult rats as well as neurite outgrowth in vitro.	14	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	16	17	25	26
Thus , MEK1 plays stage specific and contrary roles in myogenesis , and MEK1 activated at the mid-stage promotes muscle differentiation independent of ERK .	Thus, MEK1 plays stage specific and contrary roles in myogenesis, and MEK1 activated at the mid-stage promotes muscle differentiation independent of ERK.	13	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	13	14	23	24
Treatment of A431 cells with PD 098509 , a synthetic inhibitor of MEK1 , inhibited MAPK activity without inducing G ( 1 ) arrest or increasing the levels of p27 .	Treatment of A431 cells with PD 098509, a synthetic inhibitor of MEK1, inhibited MAPK activity without inducing G (1) arrest or increasing the levels of p27.	10	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	12	13	15	16
These cascades consist of at least three protein kinases that are activated sequentially : a MAPK kinase kinase such as Raf-1 activates a MAPK kinase such as MEK1 , which in turn activates a MAPK such as ERK .	These cascades consist of at least three protein kinases that are activated sequentially : a MAPK kinase kinase such as Raf-1 activates a MAPK kinase such as MEK1, which in turn activates a MAPK such as ERK.	24	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	27	28	34	35
Pretreatment of collagen gel cultures with U0126 , a selective inhibitor of the ERK activators MEK1 and MEK2 [ XREF_BIBR ] , attenuated TGF-beta1-induced branching tubulogenesis in a dose dependent manner , a 63 % inhibition being observed at 20 muM .	Pretreatment of collagen gel cultures with U0126, a selective inhibitor of the ERK activators MEK1 and MEK2 [XREF_BIBR], attenuated TGF-beta1-induced branching tubulogenesis in a dose dependent manner, a 63% inhibition being observed at 20 muM.	10	19	activators	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	15	16	13	14
Ras , a small G protein , is an important signaling mediator which leads to activation of mitogen activated protein kinase kinases 1,2 ( MEK1 ,2 ) which activate ERKs .	Ras, a small G protein, is an important signaling mediator which leads to activation of mitogen activated protein kinase kinases 1,2 (MEK1,2) which activate ERKs.	21	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERKs	ERKs	ERKs	24	25	29	30
However , NIC1 phosphorylation levels were greatly increased when the MEK and ERK pathway was activated by the presence of a MEK1 CA ( XREF_FIG right ) .	However, NIC1 phosphorylation levels were greatly increased when the MEK and ERK pathway was activated by the presence of a MEK1 CA (XREF_FIG right).	10	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	21	22	12	13
PD98059 , an inhibitor of ERK activating kinase MEK-1 , and SB203580 , an inhibitor of p38 protein kinase , abolished the stimulation of AA release and MAPK activities .	PD98059, an inhibitor of ERK activating kinase MEK-1, and SB203580, an inhibitor of p38 protein kinase, abolished the stimulation of AA release and MAPK activities.	3	28	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK-1	MEK-1	MEK-1	MAPK	MAPK	MAPK	8	9	27	28
Of particular relevance , knock-out of the ERK activator MEK1 displaces late endosomes to the periphery [ XREF_BIBR , XREF_BIBR ] .	Of particular relevance, knock-out of the ERK activator MEK1 displaces late endosomes to the periphery [XREF_BIBR, XREF_BIBR].	4	10	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	9	10	7	8
The key effector kinases of this pathway are extracellular signal regulated kinases 1 and 2 ( ERK1/2 ) , which are activated by mitogen kinase kinase 1 ( MEK1 ) ;.	The key effector kinases of this pathway are extracellular signal regulated kinases 1 and 2 (ERK1/2), which are activated by mitogen kinase kinase 1 (MEK1);.	11	30	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	28	29	16	17
Interestingly , in the latter study , we found that constitutively active forms of Mek1 and Mek2 activated Erk1/2 similarly , although only active Mek1 induced hyperplasia .	Interestingly, in the latter study, we found that constitutively active forms of Mek1 and Mek2 activated Erk1/2 similarly, although only active Mek1 induced hyperplasia.	12	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek1	Mek1	Mek1	Erk1/2	Erk1/2	Erk1/2	14	15	18	19
In genetically altered mice , concentric , compensated cardiac hypertrophy results from the overexpression of active MAPK kinase 1 ( MEK1 ) , which activates ERK , while dilated cardiomyopathy and premature death is reported in mice with over-activation of p38 or JNK .	In genetically altered mice, concentric, compensated cardiac hypertrophy results from the overexpression of active MAPK kinase 1 (MEK1), which activates ERK, while dilated cardiomyopathy and premature death is reported in mice with over-activation of p38 or JNK.	13	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	overexpression of active MAPK kinase 1 (MEK1	mek1	ERK	ERK	erk	20	21	25	26
To confirm the requirement for the p42 and p44 MAPK pathway in stimulating this promoter , we overexpressed WT MEK1 ( an upstream activator of p42 and p44 MAPK ) or dnMEK1 with the Brn-3b reporter construct using cotransfection protocols .	To confirm the requirement for the p42 and p44 MAPK pathway in stimulating this promoter, we overexpressed WT MEK1 (an upstream activator of p42 and p44 MAPK) or dnMEK1 with the Brn-3b reporter construct using cotransfection protocols.	17	31	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	19	20	28	29
Given that extracellular signal regulated kinase ( ERK ) signaling is a major driving force for mESC differentiation and that MEK 1 also activates ERK signaling , the crosstalk between JNK and ERK signaling is worth being further studied .	Given that extracellular signal regulated kinase (ERK) signaling is a major driving force for mESC differentiation and that MEK 1 also activates ERK signaling, the crosstalk between JNK and ERK signaling is worth being further studied.	20	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK 1	MEK 1	MEK 1	ERK	ERK	ERK	20	22	24	25
ERK is activated by MEK1 and MEK2 .	ERK is activated by MEK1 and MEK2.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	4	5	0	1
In search of additional signaling pathways activated by NIK , we now demonstrate that NIK activates MEK1 phosphorylation and induces the Erk1 and Erk2 MAPK pathway .	In search of additional signaling pathways activated by NIK, we now demonstrate that NIK activates MEK1 phosphorylation and induces the Erk1 and Erk2 MAPK pathway.	14	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	NIK activates MEK1 phosphorylation	mek1	MAPK	MAPK	mapk	16	17	24	25
The MEK1 p.D67N mutant is activating as demonstrated by increased ERK phosphorylation as compared to empty vector and wildtype MEK1 , two controls which do not activate ERK .	The MEK1 p.D67N mutant is activating as demonstrated by increased ERK phosphorylation as compared to empty vector and wildtype MEK1, two controls which do not activate ERK.	5	28	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	19	20	27	28
The level of ERK1/2 activation by MEK1 generally correlated with mutant allele frequency .	The level of ERK1/2 activation by MEK1 generally correlated with mutant allele frequency.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	6	7	3	4
These findings reveal a new function for NIK as a MEK1 dependent activator of the MAPK pathway and implicate both the I kappa B kinase and MAPK signaling cascades in NIK induced differentiation of PC12 cells .	These findings reveal a new function for NIK as a MEK1 dependent activator of the MAPK pathway and implicate both the I kappa B kinase and MAPK signaling cascades in NIK induced differentiation of PC12 cells.	10	16	activator	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	10	11	15	16
This effect was seen with the BRAF inhibitor vemurafenib and subsequent MAPK pathway inhibitors trametinib ( MEK1/2 inhibitor ) and SCH772984 ( ERK1/2 inhibitor ) , but interestingly not with the CRAF inhibitor GW5074 or with PD98059 that is a non ATP competing MEK antagonist specifically inhibiting MEK1 mediated activation of the MAPK pathway .	This effect was seen with the BRAF inhibitor vemurafenib and subsequent MAPK pathway inhibitors trametinib (MEK1/2 inhibitor) and SCH772984 (ERK1/2 inhibitor), but interestingly not with the CRAF inhibitor GW5074 or with PD98059 that is a non ATP competing MEK antagonist specifically inhibiting MEK1 mediated activation of the MAPK pathway.	47	53	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	47	48	52	53
To validate this hypothesis , we transfected C33A cells with a RRM2 expression vector , followed by treatment with U0126 ( 10muM ) , an inhibitor for MEK1 ( the upstream activator of ERK1/2 ) .	To validate this hypothesis, we transfected C33A cells with a RRM2 expression vector, followed by treatment with U0126 (10muM), an inhibitor for MEK1 (the upstream activator of ERK1/2).	25	34	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	27	28	33	34
Mitogen activated protein kinase kinases ( MEK ) MEK1 and MEK4/7 activate ERK1/2 and JNK1/2 respectively .	Mitogen activated protein kinase kinases (MEK) MEK1 and MEK4/7 activate ERK1/2 and JNK1/2 respectively.	8	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	8	9	12	13
BRAF V600E phosphorylates and activates the kinases MEK1 and MEK2 , which in turn phosphorylate and activate the kinases ERK1 and ERK2 , stimulating the MAPK pathway to promote cancer 3 .	BRAF V600E phosphorylates and activates the kinases MEK1 and MEK2, which in turn phosphorylate and activate the kinases ERK1 and ERK2, stimulating the MAPK pathway to promote cancer 3.	5	26	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	7	8	25	26
We show that T cells from allergic asthmatic patients express increased levels of MEK1 , which drives ERK1/2 activation .	We show that T cells from allergic asthmatic patients express increased levels of MEK1, which drives ERK1/2 activation.	11	18	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	levels of MEK1	mek1	ERK1/2	ERK1/2	erk1/2	13	14	17	18
MAP2K1 is the upstream activator of MAPK , thus occupying a central role in the MAPK pathway .	MAP2K1 is the upstream activator of MAPK, thus occupying a central role in the MAPK pathway.	0	7	is the upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MAP2K1	MAP2K1	MAP2K1	MAPK	MAPK	MAPK	0	1	6	7
As expected , the kinase inactive MEK-1 , though being phosphorylated by C-Raf , did not result in ERK activation ( XREF_FIG , pERK blot , compare lanes 9 , 10 with 11 , 12 ) .	As expected, the kinase inactive MEK-1, though being phosphorylated by C-Raf, did not result in ERK activation (XREF_FIG, pERK blot, compare lanes 9, 10 with 11, 12).	3	20	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	MEK-1	MEK-1	MEK-1	ERK	ERK	ERK	6	7	18	19
Consistently , overexpression of MEK1 and constitutively active JNKK in U87 cells led to ERK and JNK activation , respectively , which was accompanied with markedly increased GFAP production .	Consistently, overexpression of MEK1 and constitutively active JNKK in U87 cells led to ERK and JNK activation, respectively, which was accompanied with markedly increased GFAP production.	2	17	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	MEK1	overexpression of MEK1	mek1	ERK	ERK	erk	4	5	14	15
To examine the role of ERK1/2 signaling in the whole heart , TG mice expressing activated MEK1 , which directly mediates ERK1/2 activation , were crossed into the I61Q TG background .	To examine the role of ERK1/2 signaling in the whole heart, TG mice expressing activated MEK1, which directly mediates ERK1/2 activation, were crossed into the I61Q TG background.	14	22	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	16	17	21	22
All of these effects are independent of the mitogen activated protein kinase ( MAPK ) pathway since none of them is blocked by PD098059 , the specific inhibitor of the MAPK activating kinase MEK1 .	All of these effects are independent of the mitogen activated protein kinase (MAPK) pathway since none of them is blocked by PD098059, the specific inhibitor of the MAPK activating kinase MEK1.	11	34	blocked	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	33	34	13	14
Overexpression of active MAP kinase kinase 1 ( MEK1 ) , which activates ERK results in concentric , compensated cardiac hypertrophy .	Overexpression of active MAP kinase kinase 1 (MEK1), which activates ERK results in concentric, compensated cardiac hypertrophy.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP kinase kinase 1	Overexpression of active MAP kinase kinase 1	map kinase kinase 1	ERK	ERK	erk	3	7	13	14
For example , in developing axons , local activation of p38 and Erk MAP kinases by the MAPKK MEK1 and MEK2 is differentially required for BDNF and netrin-1 induced growth cone turning and slit-2 induced growth cone collapse .	For example, in developing axons, local activation of p38 and Erk MAP kinases by the MAPKK MEK1 and MEK2 is differentially required for BDNF and netrin-1 induced growth cone turning and slit-2 induced growth cone collapse.	8	20	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	Erk	Erk	Erk	18	19	12	13
ERK1 and -2 are closely related MAPK isoforms that are activated by Mek1 or -2 and regulate signaling pathways that control cell motility , invasion , and cytoskeleton remodeling during migration in culture .	ERK1 and -2 are closely related MAPK isoforms that are activated by Mek1 or -2 and regulate signaling pathways that control cell motility, invasion, and cytoskeleton remodeling during migration in culture.	6	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mek1	Mek1	Mek1	MAPK	MAPK	MAPK	12	13	6	7
The autosomal dominant , human syndromes Noonan , Costello , cardiofaciocutaneous , and LEOPARD result from mutations in PTPN11 , HRAS , RAF1 , BRAF , MEK1 , and MEK2 that activate ERK1/2 signaling .	The autosomal dominant, human syndromes Noonan, Costello, cardiofaciocutaneous, and LEOPARD result from mutations in PTPN11, HRAS, RAF1, BRAF, MEK1, and MEK2 that activate ERK1/2 signaling.	14	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	26	27	32	33
The specificity of leptin mediated ERK activation was assessed by using U0126 , an inhibitor of the upstream kinase ( MEK1 ) that selectively activates ERK1/2 .	The specificity of leptin mediated ERK activation was assessed by using U0126, an inhibitor of the upstream kinase (MEK1) that selectively activates ERK1/2.	11	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	20	21	25	26
Neither wild-type MEK1 ( XREF_FIG ; WT-MEK ) nor the irrelevant transfection control beta-galactosidase ( not shown ) stimulated ERK activation ( XREF_FIG , top ) or gap junctional coupling ( XREF_FIG , bottom ) .	Neither wild-type MEK1 (XREF_FIG; WT-MEK) nor the irrelevant transfection control beta-galactosidase (not shown) stimulated ERK activation (XREF_FIG, top) or gap junctional coupling (XREF_FIG, bottom).	0	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	2	3	19	20
Similarly , Wagle and co-workers demonstrated activating mutations in MEK1 and subsequent reactivation of the MAPK pathway following treatment of melanoma with PLX40 [ XREF_BIBR ] .	Similarly, Wagle and co-workers demonstrated activating mutations in MEK1 and subsequent reactivation of the MAPK pathway following treatment of melanoma with PLX40 [XREF_BIBR].	9	16	reactivation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	9	10	15	16
Furthermore , our results have shown that MEK1 medicated activation of ERK plays an essential role in viral production , whereas MEK2 is dispensable although the latter also contributes to the virus induced ERK activation ( XREF_FIG and XREF_FIG ) .	Furthermore, our results have shown that MEK1 medicated activation of ERK plays an essential role in viral production, whereas MEK2 is dispensable although the latter also contributes to the virus induced ERK activation (XREF_FIG and XREF_FIG).	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	7	8	11	12
Moreover , conditional sustained activation of Mapk signaling by expression of a gain-of-function Mek1 ( DD ) allele ( by Krox20-cre ) rescues hair cycle deficits and restores quiescence of the stem cells .	Moreover, conditional sustained activation of Mapk signaling by expression of a gain-of-function Mek1 (DD) allele (by Krox20-cre) rescues hair cycle deficits and restores quiescence of the stem cells.	6	17	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Mek1	expression of a gain-of-function Mek1	mek1	Mapk	Mapk	mapk	13	14	6	7
Here , we demonstrate that under conditions of energetic and ER stress , only MEK1 activated ERKs , and ERK2 not ERK1 induced cell death through an ATF4 dependent regulation of c-Fos , Trb3 , and Bid expression .	Here, we demonstrate that under conditions of energetic and ER stress, only MEK1 activated ERKs, and ERK2 not ERK1 induced cell death through an ATF4 dependent regulation of c-Fos, Trb3, and Bid expression.	13	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERKs	ERKs	ERKs	14	15	16	17
In turn , MEK1 activates ERK1/2 through dual phosphorylation of a critical Thr-X-Tyr motif in the ERK activation loop .	In turn, MEK1 activates ERK1/2 through dual phosphorylation of a critical Thr-X-Tyr motif in the ERK activation loop.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	3	4	5	6
This suggests that there is MEK1 independent activation of MAPK in the SCF induced ovarian cancer cell growth process , and that MEK1 still plays a crucial role in maintaining the malignant properties of ovarian cancer cells even when it fails to activate MAPK as expected .	This suggests that there is MEK1 independent activation of MAPK in the SCF induced ovarian cancer cell growth process, and that MEK1 still plays a crucial role in maintaining the malignant properties of ovarian cancer cells even when it fails to activate MAPK as expected.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	5	6	9	10
In Arabidopsis , overexpression of MKK1 enhances the activity of the MAPK cascade , which is also activated by ROS XREF_BIBR , XREF_BIBR .	In Arabidopsis, overexpression of MKK1 enhances the activity of the MAPK cascade, which is also activated by ROS XREF_BIBR, XREF_BIBR.	3	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK1	overexpression of MKK1	mkk1	MAPK	MAPK	mapk	5	6	11	12
In contrast , expression of constitutively active MEK1 , which activates ERK pathway , enhanced RXRE dependent activation .	In contrast, expression of constitutively active MEK1, which activates ERK pathway, enhanced RXRE dependent activation.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	expression of constitutively active MEK1	mek1	ERK	ERK	erk	7	8	11	12
To determine whether ERK activation was necessary for activation of caspase-8 , MEK1 and -2 ( activators of ERK ) were inhibited using the specific inhibitor U0126 .	To determine whether ERK activation was necessary for activation of caspase-8, MEK1 and -2 (activators of ERK) were inhibited using the specific inhibitor U0126.	12	21	activators	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	12	13	18	19
These data provide evidence that activation of MAPK by MEK1 is important for the proliferation of NP cells .	These data provide evidence that activation of MAPK by MEK1 is important for the proliferation of NP cells.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	9	10	7	8
As shown in XREF_FIG , MEK1 overexpression enhanced ERK1/2 activation .	As shown in XREF_FIG, MEK1 overexpression enhanced ERK1/2 activation.	5	9	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1 overexpression	mek1	ERK1/2	ERK1/2	erk1/2	5	6	8	9
Details are as follows : Ras activates Raf , that can phosphorylate MEK1 and MEK2 , which in turn activate ERK1/2 .	Details are as follows : Ras activates Raf, that can phosphorylate MEK1 and MEK2, which in turn activate ERK1/2.	5	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	Ras activates Raf, that can phosphorylate MEK1	mek1	ERK1/2	ERK1/2	erk1/2	12	13	20	21
MEK1 drives ERK1/2 activation and T cell proliferation .	MEK1 drives ERK1/2 activation and T cell proliferation.	0	3	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	0	1	2	3
Conditional expression of a dominant negative form of MEK1 in the postnatal murine forebrain inhibited ERK activation and caused selective deficits in hippocampal memory retention and the translation dependent , transcription independent phase of hippocampal L-LTP .	Conditional expression of a dominant negative form of MEK1 in the postnatal murine forebrain inhibited ERK activation and caused selective deficits in hippocampal memory retention and the translation dependent, transcription independent phase of hippocampal L-LTP.	6	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	8	9	15	16
In particular , we found various kinases that are implicated in Mapk signaling , such as Mapk1 ( Erk2 ) , Map2k1 ( Mek1 ) , Map2k2 ( Mek2 ) , Map3k3 and Pyk2 ( Ptk2b ) , that have a strong propensity for binding to either danusertib or bosutinib but not to the other inhibitors tested ( XREF_FIG and XREF_SUPPLEMENTARY ) .	In particular, we found various kinases that are implicated in Mapk signaling, such as Mapk1 (Erk2), Map2k1 (Mek1), Map2k2 (Mek2), Map3k3 and Pyk2 (Ptk2b), that have a strong propensity for binding to either danusertib or bosutinib but not to the other inhibitors tested (XREF_FIG and XREF_SUPPLEMENTARY).	11	33	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Map2k1	Map2k1	Map2k1	Mapk	Mapk	Mapk	21	22	11	12
The ERKs are activated by the MEK1 and MEK2 , and the p38 is activated by the MKK3 and MKK6 .	The ERKs are activated by the MEK1 and MEK2, and the p38 is activated by the MKK3 and MKK6.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERKs	ERKs	ERKs	6	7	1	2
ATP induced TNF-alpha release was inhibited by PD 098059 , an inhibitor of extracellular signal regulated protein kinase ( ERK ) kinase 1 ( MEK1 ) , which activates ERK , and also by SB 203580 , an inhibitor of p38 mitogen activated protein kinase .	ATP induced TNF-alpha release was inhibited by PD 098059, an inhibitor of extracellular signal regulated protein kinase (ERK) kinase 1 (MEK1), which activates ERK, and also by SB 203580, an inhibitor of p38 mitogen activated protein kinase.	21	30	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	24	25	29	30
MEK1 can activate the transcription factor ERK , a key activator of proliferation signals [ XREF_BIBR ] .	MEK1 can activate the transcription factor ERK, a key activator of proliferation signals [XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	0	1	6	7
Transfection with MEK1 was used as a positive control for activation , showing that LRRK2 activation of the ERK pathway was comparable in intensity to that of the specific ERK1/2 activator MEK1 ( XREF_FIG ) .	Transfection with MEK1 was used as a positive control for activation, showing that LRRK2 activation of the ERK pathway was comparable in intensity to that of the specific ERK1/2 activator MEK1 (XREF_FIG).	25	33	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	31	32	29	30
For example , MEK1 and MEK2 activate Erk1/2 and gain of function MEK2 mutations , cause Cardiofaciocutaneous ( CFC ) syndrome , a component of which is ASD .	For example, MEK1 and MEK2 activate Erk1/2 and gain of function MEK2 mutations, cause Cardiofaciocutaneous (CFC) syndrome, a component of which is ASD.	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	Erk1/2	Erk1/2	Erk1/2	3	4	7	8
Second , expression of constitutively active MEK1 induced sustained stimulation of ERK in OCLs and dramatically promoted their survival , and the apoptosis inducing effect of AxRas DN was completely rescued by coinfection with AxMEK CA .	Second, expression of constitutively active MEK1 induced sustained stimulation of ERK in OCLs and dramatically promoted their survival, and the apoptosis inducing effect of AxRas DN was completely rescued by coinfection with AxMEK CA.	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	expression of constitutively active MEK1	mek1	ERK	ERK	erk	6	7	11	12
For example , MEK1 and MEK2 activate ERK1/2 ; MKK4 and MKK7 for JNKs ; MKK3 and MKK6 for p38 ; and MEK5 for ERK5 .	For example, MEK1 and MEK2 activate ERK1/2; MKK4 and MKK7 for JNKs; MKK3 and MKK6 for p38; and MEK5 for ERK5.	3	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	3	4	7	8
of the MAPK activator Mek1 .	of the MAPK activator Mek1.	0	5	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Mek1	Mek1	Mek1	MAPK	MAPK	MAPK	4	5	2	3
Sustained activation of ERK by overexpression of constitutively active MEK1 was sufficient to expand CD44 + / CD24 - populations in cells in which EGFR activity was blocked by either erlotinib , an EGFR kinase inhibitor , or BB-94 , a metalloprotease inhibitor that prevents generation of soluble EGFR ligands .	Sustained activation of ERK by overexpression of constitutively active MEK1 was sufficient to expand CD44 + / CD24 - populations in cells in which EGFR activity was blocked by either erlotinib, an EGFR kinase inhibitor, or BB-94, a metalloprotease inhibitor that prevents generation of soluble EGFR ligands.	1	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK1	overexpression of constitutively active MEK1	mek1	ERK	ERK	erk	9	10	3	4
The dual-specificity kinases MEK1 and MEK2 act downstream of RAS and RAF to induce ERK activation , which is generally considered protumorigenic .	The dual-specificity kinases MEK1 and MEK2 act downstream of RAS and RAF to induce ERK activation, which is generally considered protumorigenic.	0	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	3	4	14	15
To test this possibility , we examined the effects of PD98059 , a specific inhibitor of the ERK1/2 activator MEK-1 , on this effect .	To test this possibility, we examined the effects of PD98059, a specific inhibitor of the ERK1/2 activator MEK-1, on this effect.	14	20	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK-1	MEK-1	MEK-1	ERK1/2	ERK1/2	ERK1/2	19	20	17	18
Because RAF is upstream of MEK1 and ERK1/2 XREF_BIBR , XREF_BIBR , the MEK1 independent increase of ERK1/2 activity at 6 h and 96 h upon Sorafenib treatment was unexpected .	Because RAF is upstream of MEK1 and ERK1/2 XREF_BIBR, XREF_BIBR, the MEK1 independent increase of ERK1/2 activity at 6 h and 96 h upon Sorafenib treatment was unexpected.	13	18	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	13	14	17	18
The development of MEK inhibitors highlights this point XREF_BIBR : since activated MEK1 and MEK2 phosphorylate and activate ERK ( MAPK1 ) , the differential deregulation of MAPK1 in AC ( inactivated ) and SqCC ( activated ) tumors may be an important consideration in determining the efficacy of this treatment against lung cancer subtypes XREF_BIBR .	The development of MEK inhibitors highlights this point XREF_BIBR : since activated MEK1 and MEK2 phosphorylate and activate ERK (MAPK1), the differential deregulation of MAPK1 in AC (inactivated) and SqCC (activated) tumors may be an important consideration in determining the efficacy of this treatment against lung cancer subtypes XREF_BIBR.	11	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	12	13	18	19
These individual kinases are activated upstream by additional MAPKs , specifically : ERK is activated by MAPK kinase 1 ( MKK1 ) and MKK2 ; p38 MAPK by MKK3 , MKK4 , and MKK6 ; and JNK by MKK4 and MKK7 .	These individual kinases are activated upstream by additional MAPKs, specifically : ERK is activated by MAPK kinase 1 (MKK1) and MKK2; p38 MAPK by MKK3, MKK4, and MKK6; and JNK by MKK4 and MKK7.	12	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK1	MKK1	MKK1	ERK	ERK	ERK	20	21	12	13
MEK-1 by itself did not activate ERK ( XREF_FIG , lanes 16 and 33 ) .	MEK-1 by itself did not activate ERK (XREF_FIG, lanes 16 and 33).	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK-1	MEK-1	MEK-1	ERK	ERK	ERK	0	1	6	7
The expression of a constitutively active Mek1 ( Map2k1 ) , Mek1 DD , which specifically activates ERK , rescues both cerebellar foliation and BG generation , demonstrating the critical role of ERK signaling in BG induction and the essential role of BG in cerebellar foliation .	The expression of a constitutively active Mek1 (Map2k1), Mek1 DD, which specifically activates ERK, rescues both cerebellar foliation and BG generation, demonstrating the critical role of ERK signaling in BG induction and the essential role of BG in cerebellar foliation.	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek1	Mek1	Mek1	ERK	ERK	ERK	11	12	17	18
Expression of activated MEK1 restored ERK activity but not that of AKT .	Expression of activated MEK1 restored ERK activity but not that of AKT.	0	6	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	Expression of activated MEK1	mek1	ERK	ERK	erk	3	4	5	6
Renalase also improved PDAC survival in an ERK- and STAT3 dependent manner because pre-treating with U0126 , an inhibitor of the MAP kinase MEK1 and AG490 , a compound inhibits JAK2 , Erk2 and STAT3 activity , abrogated its protective effect .	Renalase also improved PDAC survival in an ERK- and STAT3 dependent manner because pre-treating with U0126, an inhibitor of the MAP kinase MEK1 and AG490, a compound inhibits JAK2, Erk2 and STAT3 activity, abrogated its protective effect.	2	38	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK-	ERK-	ERK-	23	24	7	8
This observation complies with results reported by others showing that a specific inhibitor of the ERK1/2 activator MEK1 blocked gastrin induced anti-apoptosis in AR42J cells [ XREF_BIBR ] .	This observation complies with results reported by others showing that a specific inhibitor of the ERK1/2 activator MEK1 blocked gastrin induced anti-apoptosis in AR42J cells [XREF_BIBR].	12	18	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	17	18	15	16
We now report that loss of constitutively active MEK1 ( caMEK1 ) and , thus , loss of active ERK1/2 in C7caMEK1 cells is associated with increased MEK2 protein expression , reexpression of ERK1 protein , and epithelial redifferentiation of these cells .	We now report that loss of constitutively active MEK1 (caMEK1) and, thus, loss of active ERK1/2 in C7caMEK1 cells is associated with increased MEK2 protein expression, reexpression of ERK1 protein, and epithelial redifferentiation of these cells.	4	22	loss	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	MEK1	loss of constitutively active MEK1	mek1	ERK1/2	ERK1/2	erk1/2	8	9	19	20
We additionally showed p-ERK overexpression by immunohistochemistry in all MAP2K1 mutated cases supporting MAPK and ERK pathway activation , in keeping with activating mutations of this pathway .	We additionally showed p-ERK overexpression by immunohistochemistry in all MAP2K1 mutated cases supporting MAPK and ERK pathway activation, in keeping with activating mutations of this pathway.	2	17	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K1	MAP2K1	MAP2K1	ERK	ERK	ERK	9	10	15	16
To evaluate ERK involvement , we blocked the upstream MAP ERK kinase ( MEK1 ) that activates ERK by phosphorylation of tyrosine and threonine residues on ERK .	To evaluate ERK involvement, we blocked the upstream MAP ERK kinase (MEK1) that activates ERK by phosphorylation of tyrosine and threonine residues on ERK.	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	13	14	17	18
Consistently , increased p-ERK1/2 levels were shown to be associated with spontaneous epileptic seizures in mice expressing a constitutively active form of MEK1 , which activates ERK1/2 .	Consistently, increased p-ERK1/2 levels were shown to be associated with spontaneous epileptic seizures in mice expressing a constitutively active form of MEK1, which activates ERK1/2.	20	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	22	23	26	27
Transient expression of an activated MEK1 construct in U937 cells was found to stimulate MAPK and SAPK activity , as well as enhancing AP1-, SRE- and c-Jun-mediated transcriptional activity .	Transient expression of an activated MEK1 construct in U937 cells was found to stimulate MAPK and SAPK activity, as well as enhancing AP1-, SRE- and c-Jun-mediated transcriptional activity.	5	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	5	6	14	15
MEKK2/3 activates MEK5 , which activates ERK5 .	MEKK2/3 activates MEK5, which activates ERK5.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	2	3	6	7
Interest in the ERK5 pathway has been fuelled by reports that the activation of ERK5 by MKK5 can be blocked in vivo by the kinase inhibitors PD184352 , PD 98059 and U0126 .	Interest in the ERK5 pathway has been fuelled by reports that the activation of ERK5 by MKK5 can be blocked in vivo by the kinase inhibitors PD184352, PD 98059 and U0126.	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MKK5	MKK5	MKK5	ERK5	ERK5	ERK5	16	17	14	15
To test the requirement of kinase activity of ERK5 , or ERK5 activation by upstream MEK5 for kinase recruitment and gene activation , we infected MCF-7 cells with adenovirus containing a dominant negative ERK5 ( ERK5-DN ) ( XREF_FIG ) or a dominant negative MEK5 ( MEK5-DN ) ( XREF_FIG ) construct .	To test the requirement of kinase activity of ERK5, or ERK5 activation by upstream MEK5 for kinase recruitment and gene activation, we infected MCF-7 cells with adenovirus containing a dominant negative ERK5 (ERK5-DN) (XREF_FIG) or a dominant negative MEK5 (MEK5-DN) (XREF_FIG) construct.	11	16	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	15	16	11	12
Subsequently , activated MEK5 ( pMEK5 ) specifically activates ERK5 , and then the activated ERK5 phosphorylates substrates including MEF2 , c-Fos , Fra 1 , Sap-1 , c-Myc and NF-kappaB , most of which are oncogene [ XREF_BIBR ] .	Subsequently, activated MEK5 (pMEK5) specifically activates ERK5, and then the activated ERK5 phosphorylates substrates including MEF2, c-Fos, Fra 1, Sap-1, c-Myc and NF-kappaB, most of which are oncogene [XREF_BIBR].	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	3	4	9	10
MEK5 , then , activates ERK5 .	MEK5, then, activates ERK5.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	0	1	5	6
ERK5 is exclusively activated by its upstream kinase MEK5 at presence of some growth factors like granulocyte colony stimulating factor ( G-CSF ) , nerve growth factor ( NGF ) , fibroblast growth factor ( FGF ) , and platelet derived growth factor ( PDGF ) , or in the circumstance of oxidative and hyperosmotic stress [ XREF_BIBR ] .	ERK5 is exclusively activated by its upstream kinase MEK5 at presence of some growth factors like granulocyte colony stimulating factor (G-CSF), nerve growth factor (NGF), fibroblast growth factor (FGF), and platelet derived growth factor (PDGF), or in the circumstance of oxidative and hyperosmotic stress [XREF_BIBR].	0	50	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	8	9	0	1
It appears that there are at least four subgroups in this family ; MEK1 and MEK2 subgroup that activates ERK1 and ERK2 , MEK5 that activates ERK5 and BMK1 , MKK3 that activates p38 , and MKK4 that activates p38 and Jun kinase .	It appears that there are at least four subgroups in this family; MEK1 and MEK2 subgroup that activates ERK1 and ERK2, MEK5 that activates ERK5 and BMK1, MKK3 that activates p38, and MKK4 that activates p38 and Jun kinase.	19	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	23	24	26	27
Further , we also demonstrated that ERK5 activation , mediated by MEK5 , promoted NF-kappaB activation via increased targeting of IkappaB to degradation .	Further, we also demonstrated that ERK5 activation, mediated by MEK5, promoted NF-kappaB activation via increased targeting of IkappaB to degradation.	6	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	11	12	6	7
This C-terminal extension encodes an ERK5 docking site required for MEK5 activation of ERK5 .	This C-terminal extension encodes an ERK5 docking site required for MEK5 activation of ERK5.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	10	11	13	14
Silencing of MEKK3 and MEK5 reduced ERK5 activation as shown by a bandshift and phosphorylation of Thr 218 / Tyr 220 .	Silencing of MEKK3 and MEK5 reduced ERK5 activation as shown by a bandshift and phosphorylation of Thr 218 / Tyr 220.	0	7	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	4	5	6	7
Upon exposure to various stimuli , ERK5 is activated by phosphorylation downstream of MEK5 XREF_BIBR .	Upon exposure to various stimuli, ERK5 is activated by phosphorylation downstream of MEK5 XREF_BIBR.	6	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	phosphorylation downstream of MEK5	mek5	ERK5	ERK5	erk5	13	14	6	7
MAPK and ERK kinase 5 ( MEK5 ) phosphorylates the TEY motif and activates ERK5 kinase activity .	MAPK and ERK kinase 5 (MEK5) phosphorylates the TEY motif and activates ERK5 kinase activity.	3	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	6	7	14	15
ERK5 is a new member of the MAPK family and is activated by MEK5 , and MEK5 is activated by MEKK2/3 .	ERK5 is a new member of the MAPK family and is activated by MEK5, and MEK5 is activated by MEKK2/3.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	13	14	0	1
Hence , suppression of MEK5 specifically inhibits activation of ERK5 .	Hence, suppression of MEK5 specifically inhibits activation of ERK5.	2	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	4	5	9	10
However , ERK5 is selectively activated by its upstream kinase MEK5 and ERK5-null mice are embryonic lethal , suggesting that ERK5 has unique biological functions that can not be compensated for by ERK1/2 .	However, ERK5 is selectively activated by its upstream kinase MEK5 and ERK5-null mice are embryonic lethal, suggesting that ERK5 has unique biological functions that can not be compensated for by ERK1/2.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	10	11	2	3
Biochemically , ERK5 is specifically activated by MEK5 , a MAP kinase kinase XREF_BIBR , XREF_BIBR .	Biochemically, ERK5 is specifically activated by MEK5, a MAP kinase kinase XREF_BIBR, XREF_BIBR.	2	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	7	8	2	3
With overexpression of either of these dominant negative kinases , we observed a dose dependent decrease in gene stimulation , enrichment of pMAPK substrates and pERK5 recruitment , implying that activation of ERK5 by MEK5 as well as ERK5 kinase activity are both required for chromatin related functions of ERK5 .	With overexpression of either of these dominant negative kinases, we observed a dose dependent decrease in gene stimulation, enrichment of pMAPK substrates and pERK5 recruitment, implying that activation of ERK5 by MEK5 as well as ERK5 kinase activity are both required for chromatin related functions of ERK5.	30	40	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	34	35	32	33
Nevertheless , combined pharmacological inhibition of BRAFV600E and MEK5 is required to decrease nuclear ERK5 , that is critical for the regulation of cell proliferation .	Nevertheless, combined pharmacological inhibition of BRAFV600E and MEK5 is required to decrease nuclear ERK5, that is critical for the regulation of cell proliferation.	4	18	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	8	9	14	15
ERK1/2 can be activated by MAPK and ERK kinase 1/2 ( MEK1/2 ) [ XREF_BIBR ] , whereas ERK5 ( BMK1 ) , a recently identified member of the mammalian MAPK family , is activated not by MEK1 or MEK2 but by MEK5 [ XREF_BIBR ] .	ERK1/2 can be activated by MAPK and ERK kinase 1/2 (MEK1/2) [XREF_BIBR], whereas ERK5 (BMK1), a recently identified member of the mammalian MAPK family, is activated not by MEK1 or MEK2 but by MEK5 [XREF_BIBR].	18	44	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	42	43	18	19
It has been demonstrated that ERK5 is activated in response to a variety of stimuli upon phosphorylation by its upstream kinase MEK 5 , which specifically recognizes the TEY motif in the N-terminal half , whereas the phosphotyrosine specific phosphatase PTP-SL ( protein tyrosinephosphatase STEP like ) is able to dephosphorylate ERK5 , thereby hindering its translocation to the nucleus [ XREF_BIBR ] .	It has been demonstrated that ERK5 is activated in response to a variety of stimuli upon phosphorylation by its upstream kinase MEK 5, which specifically recognizes the TEY motif in the N-terminal half, whereas the phosphotyrosine specific phosphatase PTP-SL (protein tyrosinephosphatase STEP like) is able to dephosphorylate ERK5, thereby hindering its translocation to the nucleus [XREF_BIBR].	5	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK 5	MEK 5	MEK 5	ERK5	ERK5	ERK5	21	23	5	6
MEK5 then activates ERK5 on threonine and tyrosine residues in the loop sequence motif ( TEY ) identical to ERK1 and ERK2 .	MEK5 then activates ERK5 on threonine and tyrosine residues in the loop sequence motif (TEY) identical to ERK1 and ERK2.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	0	1	3	4
Expression of constitutive-active ( ca ) MEK5 with wild-type ( wt ) ERK5 in HeLa cells , which activates ERK5 in transfected cells , increased the number of cells that are positive for the mitotic markers p-MPM-2 and p-histone H3 ( XREF_FIG ) .	Expression of constitutive-active (ca) MEK5 with wild-type (wt) ERK5 in HeLa cells, which activates ERK5 in transfected cells, increased the number of cells that are positive for the mitotic markers p-MPM-2 and p-histone H3 (XREF_FIG).	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	Expression of constitutive-active (ca) MEK5	mek5	ERK5	ERK5	erk5	6	7	19	20
These stimuli activate a cascade in which the MAPK kinase kinases MEKK3 or MEKK2 activate MKK5 , which in turn activates ERK5 [ XREF_BIBR , XREF_BIBR ] .	These stimuli activate a cascade in which the MAPK kinase kinases MEKK3 or MEKK2 activate MKK5, which in turn activates ERK5 [XREF_BIBR, XREF_BIBR].	14	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK5	MKK5	MKK5	ERK5	ERK5	ERK5	15	16	21	22
Activation of MEKK2/3 activates MEK5 , which in turn activates ERK5 .	Activation of MEKK2/3 activates MEK5, which in turn activates ERK5.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	4	5	10	11
All these results indicated that BMK1 activation induced by either MEK5 overexpression or EGF stimulation is essential for the proliferation of prostate cancer cells .	All these results indicated that BMK1 activation induced by either MEK5 overexpression or EGF stimulation is essential for the proliferation of prostate cancer cells.	5	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5 overexpression	mek5	BMK1	BMK1	bmk1	10	11	5	6
We find that the atypical protein kinase C ( PKCzeta ) , previously reported to interact with the ERK5 activator MEK5 and to be involved in epidermal growth factor mediated ERK5 stimulation , plays a crucial role in the activation of the ERK5 pathway by G ( q )-coupled GPCR .	We find that the atypical protein kinase C (PKCzeta), previously reported to interact with the ERK5 activator MEK5 and to be involved in epidermal growth factor mediated ERK5 stimulation, plays a crucial role in the activation of the ERK5 pathway by G (q)-coupled GPCR.	15	21	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	20	21	18	19
Conversely , treatment of inhibitors of c-Abl , Src , or MEK5 inhibited activation of MEK5 and ERK5 and myogenesis of C2C12 myoblasts .	Conversely, treatment of inhibitors of c-Abl, Src, or MEK5 inhibited activation of MEK5 and ERK5 and myogenesis of C2C12 myoblasts.	4	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	11	12	17	18
Following the activation of BMK1 induced by the overexpression of MEK5 in the RWPE-2 cells ( XREF_FIG ) , it was found that this proliferation phenotype was also induced in MEK5 overexpressing cells .	Following the activation of BMK1 induced by the overexpression of MEK5 in the RWPE-2 cells (XREF_FIG), it was found that this proliferation phenotype was also induced in MEK5 overexpressing cells.	2	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	overexpression of MEK5	mek5	BMK1	BMK1	bmk1	10	11	4	5
Activated ERK5 also phosphorylates MEK5 at residues 129 , 137 , 142 and 149 which are located in the region that is thought to interact with ERK5 .	Activated ERK5 also phosphorylates MEK5 at residues 129, 137, 142 and 149 which are located in the region that is thought to interact with ERK5.	0	10	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	phosphorylates MEK5 at residues 129, 137	mek5	ERK5	ERK5	erk5	4	5	1	2
ERK5 , the last MAP kinase family member discovered , is activated by the upstream kinase MEK5 in response to growth factors and stress stimulation .	ERK5, the last MAP kinase family member discovered, is activated by the upstream kinase MEK5 in response to growth factors and stress stimulation.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	16	17	0	1
ERK5 is activated through phosphorylation by the MAPK kinase Mek5 ( MAP2K5 ) .	ERK5 is activated through phosphorylation by the MAPK kinase Mek5 (MAP2K5).	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mek5	Mek5	Mek5	ERK5	ERK5	ERK5	9	10	0	1
While oncogenic RAS or BRAF cause sustained activation of the MEK1/2-ERK 1/2 pathway , ERK5 is directly activated by MEK5 .	While oncogenic RAS or BRAF cause sustained activation of the MEK1/2-ERK 1/2 pathway, ERK5 is directly activated by MEK5.	14	20	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	19	20	14	15
The MAPK kinase MEK5 activates the MAPK ERK5 .	The MAPK kinase MEK5 activates the MAPK ERK5.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	3	4	7	8
Lastly , but importantly , enzyme ERK5 is activated by MEK5 [ XREF_BIBR ] ( XREF_FIG ) .	Lastly, but importantly, enzyme ERK5 is activated by MEK5 [XREF_BIBR] (XREF_FIG).	5	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	10	11	6	7
MEK5 activates ERK5 by phosphorylation , and the known upstream regulators are MEKK2 and MEKK3 .	MEK5 activates ERK5 by phosphorylation, and the known upstream regulators are MEKK2 and MEKK3.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	0	1	2	3
Other well studied pathways include the c-Jun N-terminal kinases ( JNKs ) activated by MEK4 and MEK7 , and ERK5 which is activated by MEK5 .	Other well studied pathways include the c-Jun N-terminal kinases (JNKs) activated by MEK4 and MEK7, and ERK5 which is activated by MEK5.	4	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	24	25	19	20
XREF_BIBR found that overexpressed ERK5 in ( cell type ) localizes in the cytoplasm in resting cells but when it is co-expressed with MEK5 , which activates ERK5 , ERK5 translocates to the nucleus .	XREF_BIBR found that overexpressed ERK5 in (cell type) localizes in the cytoplasm in resting cells but when it is co-expressed with MEK5, which activates ERK5, ERK5 translocates to the nucleus.	21	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	23	24	27	28
ERK5 , a mitogen activated protein kinase ( MAPK ) , is activated upon a double phosphorylation by the unique MAPK-ERK kinase 5 ( MEK5 ) .	ERK5, a mitogen activated protein kinase (MAPK), is activated upon a double phosphorylation by the unique MAPK-ERK kinase 5 (MEK5).	0	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	24	25	0	1
However , additional kinases in this cascade include ERK5 , which is activated by MEK5 , and ERK3/4 .	However, additional kinases in this cascade include ERK5, which is activated by MEK5, and ERK3/4.	7	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	14	15	8	9
Since ERK5 is activated by MEK5 , we tried to examine the effect of ERK5 activation on c-Myc expression by introducing dominant negative MEK5A or constitute active MEK5D into human colon cancer cells DLD-1 XREF_BIBR .	Since ERK5 is activated by MEK5, we tried to examine the effect of ERK5 activation on c-Myc expression by introducing dominant negative MEK5A or constitute active MEK5D into human colon cancer cells DLD-1 XREF_BIBR.	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	5	6	1	2
In particular , one study shows that both U0126 and PD98059 block MEK5 , the kinase that activates ERK5 in addition to ERK1/2 .	In particular, one study shows that both U0126 and PD98059 block MEK5, the kinase that activates ERK5 in addition to ERK1/2.	11	20	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	12	13	18	19
For gain of function studies , a constitutively active MEK5 ( CA-MEK5 ) lentivirus was used to activate ERK5 .	For gain of function studies, a constitutively active MEK5 (CA-MEK5) lentivirus was used to activate ERK5.	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	9	10	18	19
MEK5 is Activated by Shear Stress , Activates ERK5 and Induces KLF4 to Modulate TNF Responses in Human Dermal Microvascular Endothelial Cells .	MEK5 is Activated by Shear Stress, Activates ERK5 and Induces KLF4 to Modulate TNF Responses in Human Dermal Microvascular Endothelial Cells.	0	10	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	0	1	8	9
Dominant negative MEK5 ( DNMEK5 ) and ERK5 siRNA ( siERK5 ) were used to downregulate ERK5 .	Dominant negative MEK5 (DNMEK5) and ERK5 siRNA (siERK5) were used to downregulate ERK5.	0	17	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	2	3	16	17
MEK5 activates MAPK7 through phosphorylation [ XREF_BIBR , XREF_BIBR ] , which results in expression of Kruppel like factor-2 and 4 ( KLF2 and KLF4 ) , transcription factors that drive the expression of atheroprotective genes [ XREF_BIBR , XREF_BIBR ] .	MEK5 activates MAPK7 through phosphorylation [XREF_BIBR, XREF_BIBR], which results in expression of Kruppel like factor-2 and 4 (KLF2 and KLF4), transcription factors that drive the expression of atheroprotective genes [XREF_BIBR, XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	MAPK7	MAPK7	MAPK7	0	1	2	3
Here , we describe a constitutively active form of the MAP kinase kinase , MEK5 ( D ) , which selectively activates BMK1 but not other MAP kinases in vivo .	Here, we describe a constitutively active form of the MAP kinase kinase, MEK5 (D), which selectively activates BMK1 but not other MAP kinases in vivo.	12	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	BMK1	BMK1	BMK1	14	15	22	23
Interestingly , overexpression of a constitutively active MEK5 was not sufficient to drive ERK5 to the TSS of E2 regulated genes or increase mRNA output of these genes , suggesting that ERalpha activation is required for ERK5 activity at the chromatin ( XREF_SUPPLEMENTARY ) .	Interestingly, overexpression of a constitutively active MEK5 was not sufficient to drive ERK5 to the TSS of E2 regulated genes or increase mRNA output of these genes, suggesting that ERalpha activation is required for ERK5 activity at the chromatin (XREF_SUPPLEMENTARY).	2	14	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	overexpression of a constitutively active MEK5	mek5	ERK5	ERK5	erk5	7	8	13	14
The MAPKK MEK5 activates ERK5 in different physiological contexts 35 .	The MAPKK MEK5 activates ERK5 in different physiological contexts 35.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	2	3	4	5
For gain of function study , constitutively active human recombinant MEK5 ( CAMEK5 , 20MOI ) adenovirus ( Cell Biolabs , San Diego , CA ) was used to activate ERK5 .	For gain of function study, constitutively active human recombinant MEK5 (CAMEK5, 20MOI) adenovirus (Cell Biolabs, San Diego, CA) was used to activate ERK5.	7	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	10	11	30	31
ERK5 is activated by the upstream MEK 5 kinase in responses to LV eccentric hypertrophy .	ERK5 is activated by the upstream MEK 5 kinase in responses to LV eccentric hypertrophy.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK 5	MEK 5	MEK 5	ERK5	ERK5	ERK5	6	8	0	1
IF data demonstrated that PML isoforms I-IV and VI colocalized with MEK5 activated BMK1 and that PML IV colocalization was that most robust .	IF data demonstrated that PML isoforms I-IV and VI colocalized with MEK5 activated BMK1 and that PML IV colocalization was that most robust.	9	14	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	BMK1	BMK1	BMK1	11	12	13	14
Extracellular-signal-regulated kinase 5 ( ERK5 ; also called big MAP kinase 1 ) is a member of the MAPK family and is activated by MEK5 upstream kinase via phosphorylation of TEY motif and C-terminal transcriptional domain .	Extracellular-signal-regulated kinase 5 (ERK5; also called big MAP kinase 1) is a member of the MAPK family and is activated by MEK5 upstream kinase via phosphorylation of TEY motif and C-terminal transcriptional domain.	0	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	Extracellular-signal-regulated kinase 5	Extracellular-signal-regulated kinase 5	Extracellular-signal-regulated kinase 5	24	25	0	3
When ERK5 is activated by MEK5 catalyzed dual phosphorylation , it initiates responses that lead to activation of transcription factors such as MEF2A , MEF2C and MEF2D [ XREF_BIBR ] which , in turn , leads to synthesis of other transcription factors such as KLF2 [ XREF_BIBR ] and KLF4 , although an obligatory role for ERK5 in the MEK5 dependent induction of KLF4 has recently been challenged [ XREF_BIBR ] .	When ERK5 is activated by MEK5 catalyzed dual phosphorylation, it initiates responses that lead to activation of transcription factors such as MEF2A, MEF2C and MEF2D [XREF_BIBR] which, in turn, leads to synthesis of other transcription factors such as KLF2 [XREF_BIBR] and KLF4, although an obligatory role for ERK5 in the MEK5 dependent induction of KLF4 has recently been challenged [XREF_BIBR].	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	5	6	1	2
MKK5 is the specific activator of ERK5 , which fulfills non redundant physiological roles compared with its ERK1/2 paralogs .	MKK5 is the specific activator of ERK5, which fulfills non redundant physiological roles compared with its ERK1/2 paralogs.	0	9	is the specific activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK5	MKK5	MKK5	ERK5	ERK5	ERK5	0	1	6	7
Although MEK5 is known to mediate BDNF stimulation of ERK5 in central nervous system neurons , other upstream signaling components have not been identified .	Although MEK5 is known to mediate BDNF stimulation of ERK5 in central nervous system neurons, other upstream signaling components have not been identified.	1	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	1	2	9	10
According to the canonical signaling scheme , MEK5 specifically activates ERK5 by phosphorylation of the ERK5 TEY motif .	According to the canonical signaling scheme, MEK5 specifically activates ERK5 by phosphorylation of the ERK5 TEY motif.	7	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	7	8	10	11
Thus , we checked the effect of MEK5 activation in ERK5 sumoylation and found that CA-MEK5alpha inhibits sumoylation of both wild type as well as kinase dead mutant form of ERK5 , suggesting the novel mechanism of MEK5 activation of ERK5 via reduction of ERK5 sumoylation which is not related to phosphorylation of TEY motif .	Thus, we checked the effect of MEK5 activation in ERK5 sumoylation and found that CA-MEK5alpha inhibits sumoylation of both wild type as well as kinase dead mutant form of ERK5, suggesting the novel mechanism of MEK5 activation of ERK5 via reduction of ERK5 sumoylation which is not related to phosphorylation of TEY motif.	37	42	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	37	38	40	41
A specific ERK5 upstream kinase , MEK5 , and c-Src tyrosine kinase have both been shown to mediate ERK5 activation in response to oxidative stress .	A specific ERK5 upstream kinase, MEK5, and c-Src tyrosine kinase have both been shown to mediate ERK5 activation in response to oxidative stress.	4	19	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	6	7	18	19
4 However , additional kinases in this cascade include ERK5 , which is activated by MEK5 , and ERK3/4 .	4 However, additional kinases in this cascade include ERK5, which is activated by MEK5, and ERK3/4.	8	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	15	16	9	10
MEK5 is the upstream activator of ERK5 in many epithelial cells .	MEK5 is the upstream activator of ERK5 in many epithelial cells.	0	10	is the upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	0	1	6	7
Another aPKC substrate is MEK5 , which activates the MAP kinase ERK5 .	Another aPKC substrate is MEK5, which activates the MAP kinase ERK5.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	4	5	11	12
A dominant negative form of MEK5 blocked the activation of BMK1 and ERK5 by MEKK2 , whereas activation of c-Jun N-terminal kinase ( JNK ) was unaffected , showing that MEK5 is a specific downstream effector of MEKK2 in the BMK1 and ERK5 pathway .	A dominant negative form of MEK5 blocked the activation of BMK1 and ERK5 by MEKK2, whereas activation of c-Jun N-terminal kinase (JNK) was unaffected, showing that MEK5 is a specific downstream effector of MEKK2 in the BMK1 and ERK5 pathway.	3	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	5	6	12	13
MEK5 is a specific activator of ERK5 .	MEK5 is a specific activator of ERK5.	0	7	is a specific activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	0	1	6	7
MEK5 Mediated ERK5 Activation .	MEK5 Mediated ERK5 Activation.	0	3	Mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	0	1	2	3
MEK1 and MEK2 in turn activate the ERK1 and ERK2 MAPKs via phosphorylation .	MEK1 and MEK2 in turn activate the ERK1 and ERK2 MAPKs via phosphorylation.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	0	1	9	10
To ascertain if activation of ERK1 and ERK2 contributes to APRIL promoted axon growth , we examined whether PD98059 , a selective inhibitor of MEK1 and MEK2 , the kinases that phosphorylate and activate ERK1 and ERK2 , could prevent the APRIL promoted axon growth .	To ascertain if activation of ERK1 and ERK2 contributes to APRIL promoted axon growth, we examined whether PD98059, a selective inhibitor of MEK1 and MEK2, the kinases that phosphorylate and activate ERK1 and ERK2, could prevent the APRIL promoted axon growth.	22	37	activate	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	24	25	36	37
Another molecule of EGFR signaling cascade RAF1 protein , can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2 , which in turn phosphorylate to activate the serine/threonine specific protein kinases , ERK1 and ERK2 .	Another molecule of EGFR signaling cascade RAF1 protein, can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2.	12	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	18	19	36	37
We report here the development of a simple , 96-well plate , quantitative in vitro assay measuring purified ERK2 catalytic activation by a constitutive MEK-1 mutant ( S218E S222E ) .	We report here the development of a simple, 96-well plate, quantitative in vitro assay measuring purified ERK2 catalytic activation by a constitutive MEK-1 mutant (S218E S222E).	18	25	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK-1	MEK-1	MEK-1	ERK2	ERK2	ERK2	24	25	18	19
The actual densitometric band intensity results for three experiments were quantitated and are shown in XREF_FIG B. To investigate whether ERK2 activation was coincidental with or causal for the alterations in import observed , import cocktail was pretreated with 20 muM PD98059 , a specific inhibitor for the ERK2 activator MEK1 , as described in Materials and Methods .	The actual densitometric band intensity results for three experiments were quantitated and are shown in XREF_FIG B. To investigate whether ERK2 activation was coincidental with or causal for the alterations in import observed, import cocktail was pretreated with 20 muM PD98059, a specific inhibitor for the ERK2 activator MEK1, as described in Materials and Methods.	45	51	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	50	51	48	49
Once activated , Raf-1 can phosphorylate and thereby activate the dual specificity protein kinases MEK1 and MEK2 , which in turn phosphorylate and activate the serine/threonine protein kinases ERK1 and ERK2 [ XREF_BIBR ] .	Once activated, Raf-1 can phosphorylate and thereby activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate and activate the serine/threonine protein kinases ERK1 and ERK2 [XREF_BIBR].	3	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	Raf-1 can phosphorylate and thereby activate the dual specificity protein kinases MEK1	mek1	ERK2	ERK2	erk2	14	15	30	31
This surprising result was first shown by Kholodenko and co-workers in their computational studies of the distributive dual phosphorylation and dephosphosphorylation of the ERK2 mitogen activated protein kinase ( MAPK ) kinase by the MAPK kinase MEK1 and the MAPK phosphatase MKP3 [ XREF_BIBR ] .	This surprising result was first shown by Kholodenko and co-workers in their computational studies of the distributive dual phosphorylation and dephosphosphorylation of the ERK2 mitogen activated protein kinase (MAPK) kinase by the MAPK kinase MEK1 and the MAPK phosphatase MKP3 [XREF_BIBR].	23	41	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	36	37	23	24
ERK1 and ERK2 , which are both widely expressed in multiple cell types including various joint tissues and are most commonly found together , are activated by MKK1 and MKK2 respectively , which are also referred to as MAP and ERK kinases or MEKs 1 and 2 [ XREF_BIBR ] .	ERK1 and ERK2, which are both widely expressed in multiple cell types including various joint tissues and are most commonly found together, are activated by MKK1 and MKK2 respectively, which are also referred to as MAP and ERK kinases or MEKs 1 and 2 [XREF_BIBR].	0	30	activated	Positive_regulation_syntax_2_verb	Positive_activation	Positive_regulation	MKK1	MKK1	mkk1	ERK2	ERK2, which are both widely expressed	erk2	27	28	2	3
RAF phosphorylates and activates MEK1 and MEK2 that in turn phosphorylate and activate ERK1 and ERK2 kinases .	RAF phosphorylates and activates MEK1 and MEK2 that in turn phosphorylate and activate ERK1 and ERK2 kinases.	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	RAF phosphorylates and activates MEK1	mek1	ERK2	ERK2	erk2	4	5	15	16
ERK-1 and ERK-2 are activated by highly homologous dual specificity kinases MEK-1 and MEK-2 [ XREF_BIBR ] .	ERK-1 and ERK-2 are activated by highly homologous dual specificity kinases MEK-1 and MEK-2 [XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK-1	MEK-1	MEK-1	ERK-2	ERK-2	ERK-2	11	12	2	3
Once activated , RAF kinases phosphorylate and activate the MEK ( mitogen activated or extracellular signal related protein kinase kinase ) kinases , MEK1 and MEK2 , which subsequently phosphorylate and activate ERK1 and ERK2 .	Once activated, RAF kinases phosphorylate and activate the MEK (mitogen activated or extracellular signal related protein kinase kinase) kinases, MEK1 and MEK2, which subsequently phosphorylate and activate ERK1 and ERK2.	21	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	23	24	34	35
The targets for phosphorylation of Raf-1 include the kinases MEK1 and MEK2 that in turn activate the MAP kinases ERK1 and ERK2 .	The targets for phosphorylation of Raf-1 include the kinases MEK1 and MEK2 that in turn activate the MAP kinases ERK1 and ERK2.	6	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	9	10	21	22
Upon activation by GTP bound RAS , the serine/threonine kinase RAF triggers downstream signaling by phosphorylating MEK1 and MEK2 , which in turn phosphorylate and activate ERK1 and ERK2 .	Upon activation by GTP bound RAS, the serine/threonine kinase RAF triggers downstream signaling by phosphorylating MEK1 and MEK2, which in turn phosphorylate and activate ERK1 and ERK2.	10	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	RAF triggers downstream signaling by phosphorylating MEK1	mek1	ERK2	ERK2	erk2	16	17	28	29
In the MAPK pathway , MEK1 and MEK2 are the only activators of ERK2 , processing inputs from multiple upstream kinases [ XREF_BIBR ] .	In the MAPK pathway, MEK1 and MEK2 are the only activators of ERK2, processing inputs from multiple upstream kinases [XREF_BIBR].	5	16	are the only activators	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	5	6	13	14
Oocyte maturation is triggered by steroids in a transcription independent fashion that involves an unusual positive feedback loop whereby MOS ( a germ cell specific Raf ) activates MEK1 , which in turn activates ERK2 .	Oocyte maturation is triggered by steroids in a transcription independent fashion that involves an unusual positive feedback loop whereby MOS (a germ cell specific Raf) activates MEK1, which in turn activates ERK2.	27	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	28	29	34	35
Our study found that MAPK1 and MAP2K1 knockdown suppressed p-MAPK1 , p-MAP2K1 and Slug involved in MAPK and Slug pathway .	Our study found that MAPK1 and MAP2K1 knockdown suppressed p-MAPK1, p-MAP2K1 and Slug involved in MAPK and Slug pathway.	4	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K1	MAP2K1	MAP2K1	p-MAPK1	p-MAPK1	p-MAPK1	6	7	9	10
Active Ras recruits Raf kinases to the membrane where they catalyse the phosphorylation , and therefore activation , of MEK1 and MEK2 , which then activate ERK1 and ERK2 .	Active Ras recruits Raf kinases to the membrane where they catalyse the phosphorylation, and therefore activation, of MEK1 and MEK2, which then activate ERK1 and ERK2.	7	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	19	20	28	29
Activation of p21 ras leads to recruitment and activation of Raf-1 , which then activates MEK-1 and MEK-2 , which subsequently activate ERK-1 and ERK-2 .	Activation of p21 ras leads to recruitment and activation of Raf-1, which then activates MEK-1 and MEK-2, which subsequently activate ERK-1 and ERK-2.	14	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK-1	MEK-1	MEK-1	ERK-2	ERK-2	ERK-2	15	16	24	25
To investigate if ERK1 and ERK2 activation is responsible for the enhanced neurite growth brought about by TNFR1-Fc , we examined whether U0126 , a selective MEK1 and MEK2 inhibitor that interferes with MEK1 and MEK2 dependent activation of ERK1 and ERK2 27 , could prevent the increase in neurite growth .	To investigate if ERK1 and ERK2 activation is responsible for the enhanced neurite growth brought about by TNFR1-Fc, we examined whether U0126, a selective MEK1 and MEK2 inhibitor that interferes with MEK1 and MEK2 dependent activation of ERK1 and ERK2 27, could prevent the increase in neurite growth.	33	42	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	33	34	41	42
37 Both c-Myc expression and MEK1 induced ERK2 nuclear localization are required for TGF-beta-induced EMT in prostate cancer .	37 Both c-Myc expression and MEK1 induced ERK2 nuclear localization are required for TGF-beta-induced EMT in prostate cancer.	0	9	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	5	6	7	8
MEK1 and MEK2 activate the serine/threonine specific protein kinases ERK1 and ERK2 .	MEK1 and MEK2 activate the serine/threonine specific protein kinases ERK1 and ERK2.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	0	1	11	12
Therefore , the mechanism of ERK2 activation by MEK1 in vitro is nonprocessive .	Therefore, the mechanism of ERK2 activation by MEK1 in vitro is nonprocessive.	5	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	8	9	5	6
MEK1 activated ERK2 accumulated in the nucleus and induced proliferation .	MEK1 activated ERK2 accumulated in the nucleus and induced proliferation.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	0	1	2	3
Thus , one may speculate that MKK1 and MKK2 may trigger not only Erk1 and Erk2 signaling pathways .	Thus, one may speculate that MKK1 and MKK2 may trigger not only Erk1 and Erk2 signaling pathways.	6	17	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK1	MKK1	MKK1	Erk2	Erk2	Erk2	6	7	15	16
These observations reinforce the notion that MEK1 and MEK2 isoforms activate ERK1 and ERK2 indiscriminately .	These observations reinforce the notion that MEK1 and MEK2 isoforms activate ERK1 and ERK2 indiscriminately.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	6	7	13	14
MEK1 and MEK2 in turn activate the ERK1 and ERK2 mitogen activated protein ( MAP ) kinases via phosphorylation .	MEK1 and MEK2 in turn activate the ERK1 and ERK2 mitogen activated protein (MAP) kinases via phosphorylation.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	0	1	9	10
Map2k1 activates Mapk3 and Mapk1 , and plays an important role in the epithelial-to-mesenchymal transition .	Map2k1 activates Mapk3 and Mapk1, and plays an important role in the epithelial-to-mesenchymal transition.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Map2k1	Map2k1	Map2k1	Mapk1	Mapk1	Mapk1	0	1	4	5
To unveil the compensating nuclear export of ERK2 , we induced EGFP-ERK2 nuclear translocation by C-MEK1-DD photoactivation and then blocked MEK1 induced ERK2 nuclear translocation by addition of the MEK1 inhibitor U0126 .	To unveil the compensating nuclear export of ERK2, we induced EGFP-ERK2 nuclear translocation by C-MEK1-DD photoactivation and then blocked MEK1 induced ERK2 nuclear translocation by addition of the MEK1 inhibitor U0126.	20	24	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	20	21	22	23
MEK1 and MEK2 specifically phosphorylate and activate the ERK1 and ERK2 MAPKs .	MEK1 and MEK2 specifically phosphorylate and activate the ERK1 and ERK2 MAPKs.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	0	1	10	11
Activated Raf-1 can phosphorylate MEK1 and MEK2 , which in turn activate ERK1 and ERK2 .	Activated Raf-1 can phosphorylate MEK1 and MEK2, which in turn activate ERK1 and ERK2.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	phosphorylate MEK1	mek1	ERK2	ERK2	erk2	4	5	14	15
In this cascade , Raf , a MAP kinase , activates MEK1 and MEK2 , dual specificity kinases , which activate ERK1 and ERK2 ( extracellular-signal regulated kinases 1 and 2 ) and JNK1 and JNK2 ( c-jun N-terminal kinases 1 and 2 ) , the final result being the activation of multiple transcription factors among which AP-1 , the complex of c-jun and c-fos has a prominent role in the effects of the path-way in cell proliferation ( XREF_FIG ) .	In this cascade, Raf, a MAP kinase, activates MEK1 and MEK2, dual specificity kinases, which activate ERK1 and ERK2 (extracellular-signal regulated kinases 1 and 2) and JNK1 and JNK2 (c-jun N-terminal kinases 1 and 2), the final result being the activation of multiple transcription factors among which AP-1, the complex of c-jun and c-fos has a prominent role in the effects of the path-way in cell proliferation (XREF_FIG).	10	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	11	12	23	24
In a previous study , we have demonstrated that a constitutively active form of MEK1 activates Erk1 and Erk2 kinases , which phosphorylate co-transfected NF-M in NIH 3T3 cells .	In a previous study, we have demonstrated that a constitutively active form of MEK1 activates Erk1 and Erk2 kinases, which phosphorylate co-transfected NF-M in NIH 3T3 cells.	12	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	Erk2	Erk2	Erk2	14	15	18	19
TLR4 induced ERK activation has been shown to depend on IKK mediated phosphorylation of p105 ( NF-kappaB1 ) , leading to its degradation and hence release of the TPL2 kinase , which is constitutively associated with p105 , and subsequent TPL2 mediated phosphorylation and activation of MEK1 , which in turn activates ERK1 and ERK2 .	TLR4 induced ERK activation has been shown to depend on IKK mediated phosphorylation of p105 (NF-kappaB1), leading to its degradation and hence release of the TPL2 kinase, which is constitutively associated with p105, and subsequent TPL2 mediated phosphorylation and activation of MEK1, which in turn activates ERK1 and ERK2.	42	55	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	phosphorylation and activation of MEK1	mek1	ERK2	ERK2	erk2	46	47	54	55
Constitutively active MAPKK-1 fully activates ERK-2 and the transcription factor Elk-1 , but does not substitute for activated p21ras and synergize with calcium and calcineurin signals to induce NFAT .	Constitutively active MAPKK-1 fully activates ERK-2 and the transcription factor Elk-1, but does not substitute for activated p21ras and synergize with calcium and calcineurin signals to induce NFAT.	1	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPKK-1	MAPKK-1	MAPKK-1	ERK-2	ERK-2	ERK-2	2	3	5	6
MEK1 mediated ERK2 nuclear translocation and proliferation were shown to depend on phosphorylation of S298 and T292 sites in the MEK1 proline rich domain .	MEK1 mediated ERK2 nuclear translocation and proliferation were shown to depend on phosphorylation of S298 and T292 sites in the MEK1 proline rich domain.	0	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	0	1	2	3
XREF_BIBR Once activated , Raf-1 phosphorylates the MAPKs MEK1 and MEK2 , that finally stimulate ERK1 and ERK2 .	XREF_BIBR Once activated, Raf-1 phosphorylates the MAPKs MEK1 and MEK2, that finally stimulate ERK1 and ERK2.	4	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	Raf-1 phosphorylates the MAPKs MEK1	mek1	ERK2	ERK2	erk2	8	9	17	18
Active RAF phosphorylates and activates the MEK1 and MEK2 kinases which in turn activate ERK1 and ERK2 .	Active RAF phosphorylates and activates the MEK1 and MEK2 kinases which in turn activate ERK1 and ERK2.	1	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	RAF phosphorylates and activates the MEK1	mek1	ERK2	ERK2	erk2	6	7	16	17
Following its activation , RAS recruits RAF to the membrane where it is activated and , subsequently , RAF phosphorylates MEK1 and MEK2 , which activate ERK1 and ERK2 [ XREF_BIBR ] .	Following its activation, RAS recruits RAF to the membrane where it is activated and, subsequently, RAF phosphorylates MEK1 and MEK2, which activate ERK1 and ERK2 [XREF_BIBR].	18	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	RAF phosphorylates MEK1	mek1	ERK2	ERK2	erk2	20	21	28	29
Active RAFs then phosphorylate and activate MEK1 and MEK2 kinases , which in turn phosphorylate and activate ERK1 and ERK2 kinases .	Active RAFs then phosphorylate and activate MEK1 and MEK2 kinases, which in turn phosphorylate and activate ERK1 and ERK2 kinases.	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	6	7	19	20
Expression of the dominant negative MEK1 inhibited platelet derived growth factor ( PDGF )-induced ERK2 activation , whereas expression of the constitutively active MEK1 induced ERK2 activation , suggesting that MEK1 is required and sufficient for ERK activation in these cells .	Expression of the dominant negative MEK1 inhibited platelet derived growth factor (PDGF)-induced ERK2 activation, whereas expression of the constitutively active MEK1 induced ERK2 activation, suggesting that MEK1 is required and sufficient for ERK activation in these cells.	18	26	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	23	24	25	26
The in vitro activation of ERK2 by MKK1 induces a large conformational transition of the activation segment ( DFG-APE ) , but neither induces self association of ERK2 nor destabilizes the stability of the ERK2.Ets-1 complex .	The in vitro activation of ERK2 by MKK1 induces a large conformational transition of the activation segment (DFG-APE), but neither induces self association of ERK2 nor destabilizes the stability of the ERK2.Ets-1 complex.	0	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MKK1	MKK1	MKK1	ERK2	ERK2	ERK2	7	8	5	6
MEK1 and MEK2 activate ERK1 and ERK2 ( extracellular signal regulated kinases 1 and 2 ) .	MEK1 and MEK2 activate ERK1 and ERK2 (extracellular signal regulated kinases 1 and 2).	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	0	1	6	7
Once activated , Raf-1 phosphorylates the MAPK kinases MEK1 and MEK2 , that finally stimulate ERK1 and ERK2 .	Once activated, Raf-1 phosphorylates the MAPK kinases MEK1 and MEK2, that finally stimulate ERK1 and ERK2.	3	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	Raf-1 phosphorylates the MAPK kinases MEK1	mek1	ERK2	ERK2	erk2	8	9	17	18
When localised to the plasma membrane , the Raf kinases become active and catalyse the phosphorylation and activation of MEK1 and MEK2 , which in turn activate ERK1 and ERK2 .	When localised to the plasma membrane, the Raf kinases become active and catalyse the phosphorylation and activation of MEK1 and MEK2, which in turn activate ERK1 and ERK2.	15	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	phosphorylation and activation of MEK1	mek1	ERK2	ERK2	erk2	19	20	29	30
In the MAPK signal pathway , MAPKK1 is known to activate Erk1 and MAPKK4 is known to activate JUN [ XREF_BIBR , XREF_BIBR ] .	In the MAPK signal pathway, MAPKK1 is known to activate Erk1 and MAPKK4 is known to activate JUN [XREF_BIBR, XREF_BIBR].	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPKK1	MAPKK1	MAPKK1	Erk1	Erk1	Erk1	6	7	11	12
The ERK1 and ERK2 MAP kinases are activated by the MAP2K isoforms MKK1 and MKK2 [ XREF_BIBR ] .	The ERK1 and ERK2 MAP kinases are activated by the MAP2K isoforms MKK1 and MKK2 [XREF_BIBR].	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK1	MKK1	MKK1	ERK1	ERK1	ERK1	12	13	1	2
MEK1 and 2 phosphorylate and activate MAP kinases , ERK1 and 2 [ XREF_BIBR ] .	MEK1 and 2 phosphorylate and activate MAP kinases, ERK1 and 2 [XREF_BIBR].	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1	ERK1	ERK1	0	1	9	10
Expression of active Mek1 restored sustained serum induced ERK1 ,2 activity in Rh -/- fibroblasts ( XREF_FIG ) .	Expression of active Mek1 restored sustained serum induced ERK1,2 activity in Rh -/- fibroblasts (XREF_FIG).	0	10	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek1	Expression of active Mek1	mek1	ERK1	ERK1	erk1	3	4	8	9
For example , from the complex sentence ' Active Raf-2 phosphorylates and activates MEK1 , which phosphorylates and activates the MAP kinases signal regulated kinases , ERK1 and ERK2 ( PMID-8557975 ) ' , iSimp produces multiple simple sentences , including ' Active Raf-2 phosphorylates MEK1 ' , ' MEK1 phosphorylates ERK1 ' , ' MEK1 activates ERK1 ' and so forth .	For example, from the complex sentence ' Active Raf-2 phosphorylates and activates MEK1, which phosphorylates and activates the MAP kinases signal regulated kinases, ERK1 and ERK2 (PMID-8557975) ', iSimp produces multiple simple sentences, including ' Active Raf-2 phosphorylates MEK1 ', ' MEK1 phosphorylates ERK1 ', ' MEK1 activates ERK1 ' and so forth.	55	58	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1	ERK1	ERK1	55	56	57	58
PD98059 is a specific inhibitor of ERK-1 ,2 activation by MEK-1 ,2 .	PD98059 is a specific inhibitor of ERK-1,2 activation by MEK-1,2.	6	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK-1	MEK-1	MEK-1	ERK-1	ERK-1	ERK-1	10	11	6	7
MEK1 activates ERK1 via phosphorylation .	MEK1 activates ERK1 via phosphorylation.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1	ERK1	ERK1	0	1	2	3
Similarly to MAPK3 , MAP2K1 ( MEK1 ) mediates FGF stimulated endothelial-cell proliferation in tumor models [ XREF_BIBR ] .	Similarly to MAPK3, MAP2K1 (MEK1) mediates FGF stimulated endothelial-cell proliferation in tumor models [XREF_BIBR].	1	9	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK3	MAPK3	MAPK3	6	7	2	3
For example , given a complex sentence such as ' Active Raf-2 phosphorylates and activates MEK1 , which phosphorylates and activates the MAP kinases signal regulated kinases , ERK1 and ERK2 , ( PMID-8557975 ) ' iSimp produces multiple simple sentences , including ' Active Raf-2 phosphorylates MEK1 ' , ' MEK1 phosphorylates ERK1 , ' MEK1 activates ERK1 ' and so forth .	For example, given a complex sentence such as ' Active Raf-2 phosphorylates and activates MEK1, which phosphorylates and activates the MAP kinases signal regulated kinases, ERK1 and ERK2, (PMID-8557975) ' iSimp produces multiple simple sentences, including ' Active Raf-2 phosphorylates MEK1 ', ' MEK1 phosphorylates ERK1, ' MEK1 activates ERK1 ' and so forth.	56	59	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1	ERK1	ERK1	56	57	58	59
Coinfection with Raf-1 activates Mek1 > 150-fold , and coinfection with Raf-1 and Mek1 activates Erk1 approximately 90-fold .	Coinfection with Raf-1 activates Mek1> 150-fold, and coinfection with Raf-1 and Mek1 activates Erk1 approximately 90-fold.	9	16	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Mek1	Mek1	Mek1	Erk1	Erk1	Erk1	13	14	15	16
Activation of ERK-1 by MEK1 and p38 by MKK6 has been well established to be involved in the regulation of osteoclastogenesis [ XREF_BIBR ] .	Activation of ERK-1 by MEK1 and p38 by MKK6 has been well established to be involved in the regulation of osteoclastogenesis [XREF_BIBR].	0	8	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK-1	ERK-1	ERK-1	4	5	2	3
Numerous other significant changes in gene expression of important angiogenesis and vasoreactive signal molecules were observed related to G protein signaling including cell division control protein 42 ( CDC42 , Cdc42 , 1.22-fold , p = 0.047 ) and RAC2 ( Rac2 , 6.65-fold , p = 0.009 ) , ERK1/2 and MAPK signaling including MEK2 ( Map2k2 , 1.57-fold , p = 0.005 ) and p38MAPK ( Mapk13 , 5.57-fold , p = 0.002 ) , phosphoinositol signaling , and phospholipase signaling ( XREF_TABLE , p < 0.05 ) .	Numerous other significant changes in gene expression of important angiogenesis and vasoreactive signal molecules were observed related to G protein signaling including cell division control protein 42 (CDC42, Cdc42, 1.22-fold, p = 0.047) and RAC2 (Rac2, 6.65-fold, p = 0.009), ERK1/2 and MAPK signaling including MEK2 (Map2k2, 1.57-fold, p = 0.005) and p38MAPK (Mapk13, 5.57-fold, p = 0.002), phosphoinositol signaling, and phospholipase signaling (XREF_TABLE, p < 0.05).	50	68	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	MAPK	MAPK	MAPK	55	56	52	53
It was found that the activity of both MEK1 and MEK2 was initially inhibited by selumetinib treatment of TNBC cells and tumors , but with continued administration of selumetinib MEK1 remained inhibited but MEK2 escaped inhibition allowing reactivation of ERK .	It was found that the activity of both MEK1 and MEK2 was initially inhibited by selumetinib treatment of TNBC cells and tumors, but with continued administration of selumetinib MEK1 remained inhibited but MEK2 escaped inhibition allowing reactivation of ERK.	33	40	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	ERK	ERK	ERK	33	34	39	40
RAS-GTP binds to and activates the three RAF kinase family members which phosphorylate their main substrates , the serine/threonine kinases MEK1 and MEK2 , which in turn activate the two ERK kinases .	RAS-GTP binds to and activates the three RAF kinase family members which phosphorylate their main substrates, the serine/threonine kinases MEK1 and MEK2, which in turn activate the two ERK kinases.	4	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	ERK	ERK	ERK	22	23	30	31
Ectopic expression of LT resistant MKK2 and MKK4 variants partially restored Erk1/2 and JNK1/2 signaling in LT exposed cells , enabling the cells to maintain relatively normal c-Jun protein levels and cell proliferation .	Ectopic expression of LT resistant MKK2 and MKK4 variants partially restored Erk1/2 and JNK1/2 signaling in LT exposed cells, enabling the cells to maintain relatively normal c-Jun protein levels and cell proliferation.	1	14	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK2	expression of LT resistant MKK2	mkk2	Erk1/2	Erk1/2	erk1/2	5	6	11	12
Map and Erk kinase 1 ( MEK1 ) and MEK2 activate the Erk / MAP kinases and have been implicated in cell growth and differentiation .	Map and Erk kinase 1 (MEK1) and MEK2 activate the Erk / MAP kinases and have been implicated in cell growth and differentiation.	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	Erk	Erk	Erk	9	10	12	13
Moreover , CA MKK2 expression , either alone or in the context of c-Rel overexpression , resulted in stronger ERK activation than CA MKK1 .	Moreover, CA MKK2 expression, either alone or in the context of c-Rel overexpression, resulted in stronger ERK activation than CA MKK1.	3	21	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	MKK2	MKK2 expression	mkk2	ERK	ERK	erk	3	4	19	20
Regulation of the ERK pathway is associated with the dual-specificity kinases MEK1 and MEK2 which activate ERK1/2 through their phosphorylation [ XREF_BIBR ] .	Regulation of the ERK pathway is associated with the dual-specificity kinases MEK1 and MEK2 which activate ERK1/2 through their phosphorylation [XREF_BIBR].	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	ERK1/2	ERK1/2	ERK1/2	13	14	16	17
ERK activation by CA MKK2 was more efficient than that mediated by CA MKK1 , perhaps as a result of the higher expression of CA MKK2 .	ERK activation by CA MKK2 was more efficient than that mediated by CA MKK1, perhaps as a result of the higher expression of CA MKK2.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MKK2	MKK2	MKK2	ERK	ERK	ERK	4	5	0	1
Once activated , Raf phosphorylates and activates its major substrates mitogen activated extracellular signal regulated kinase activating kinases ( MEK ) family which includes MEK1 and MEK2 , which in turn phosphorylate and activate the MAPKs ( ERK1 and ERK2 ) .	Once activated, Raf phosphorylates and activates its major substrates mitogen activated extracellular signal regulated kinase activating kinases (MEK) family which includes MEK1 and MEK2, which in turn phosphorylate and activate the MAPKs (ERK1 and ERK2).	11	39	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	extracellular signal regulated kinase	extracellular signal regulated kinase	extracellular signal regulated kinase	26	27	12	16
K-RAS and MEK-2 are up-stream activators of ERK that drives proliferative signals in colon cancer .	K-RAS and MEK-2 are up-stream activators of ERK that drives proliferative signals in colon cancer.	0	8	are up-stream activators	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK-2	MEK-2	MEK-2	ERK	ERK	ERK	2	3	7	8
Through functional assays of the MAPK pathway , we show that the deletion and the resultant haploinsufficiency of MEK2 causes dysregulation of the Ras and MAPK pathway , and we propose that haploinsufficiency of MEK2 may be a mechanism for a novel RASopathy phenotype .	Through functional assays of the MAPK pathway, we show that the deletion and the resultant haploinsufficiency of MEK2 causes dysregulation of the Ras and MAPK pathway, and we propose that haploinsufficiency of MEK2 may be a mechanism for a novel RASopathy phenotype.	16	26	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	MAPK	MAPK	MAPK	18	19	25	26
The up-regulation of MEK2 and MAPK20-1 in CDC Robin further supports that these genes function together in MAPK signaling in this genotype .	The up-regulation of MEK2 and MAPK20-1 in CDC Robin further supports that these genes function together in MAPK signaling in this genotype.	1	18	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	MAPK	MAPK	MAPK	3	4	17	18
The resultant stabilization of MEK2 thereby up-regulates ERK1/2 to provide a sustained proliferative and oncogenic signal .	The resultant stabilization of MEK2 thereby up-regulates ERK1/2 to provide a sustained proliferative and oncogenic signal.	2	8	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	ERK1/2	ERK1/2	ERK1/2	4	5	7	8
Based on these observations and on the finding that MKK2 is a substrate of XopAU phosphorylation in vitro , we hypothesize that the growth inhibition phenotype caused by co-expression of MKK2 and XopAU in yeast is a result of MKK2 activation by XopAU and subsequent MKK2 initiation of yeast MAPK cascades involved in cell cycle arrest .	Based on these observations and on the finding that MKK2 is a substrate of XopAU phosphorylation in vitro, we hypothesize that the growth inhibition phenotype caused by co-expression of MKK2 and XopAU in yeast is a result of MKK2 activation by XopAU and subsequent MKK2 initiation of yeast MAPK cascades involved in cell cycle arrest.	45	50	initiation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MKK2	MKK2	MKK2	MAPK	MAPK	MAPK	45	46	49	50
ERK is activated by MAP kinase kinase1 ( MKK1 ) and MKK2 , JNK by MKK4 and MKK7 , and p38 MAP kinase by MKK3 , MKK4 , and MKK6 .	ERK is activated by MAP kinase kinase1 (MKK1) and MKK2, JNK by MKK4 and MKK7, and p38 MAP kinase by MKK3, MKK4, and MKK6.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK2	MKK2	MKK2	ERK	ERK	ERK	11	12	0	1
However , in tobacco , the MKK1 and MKK2 mediated MAPK pathway plays a different role in plant immune responses .	However, in tobacco, the MKK1 and MKK2 mediated MAPK pathway plays a different role in plant immune responses.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	MKK2	MKK2	MKK2	MAPK	MAPK	MAPK	8	9	10	11
However , despite similar expression levels , CA MKK2 activated ERK much more strongly than CA MKK1 ( 30-fold increase by CA MKK2 compared to 2.5-fold increase by CA MKK1 ) .	However, despite similar expression levels, CA MKK2 activated ERK much more strongly than CA MKK1 (30-fold increase by CA MKK2 compared to 2.5-fold increase by CA MKK1).	7	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK2	MKK2	MKK2	ERK	ERK	ERK	8	9	10	11
We used constituitvely active ( CA ) MKK1 and CA MKK2 to further activate ERK and CA MKK7 for JNK activation .	We used constituitvely active (CA) MKK1 and CA MKK2 to further activate ERK and CA MKK7 for JNK activation.	9	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK2	MKK2	MKK2	ERK	ERK	ERK	10	11	14	15
ERK1/2 are activated by MAP kinase kinase ( MKK ) and MKK2 , JNK by MKK4 and MKK7 , and p38 by MKK3 , MKK4 , and MKK6 .	ERK1/2 are activated by MAP kinase kinase (MKK) and MKK2, JNK by MKK4 and MKK7, and p38 by MKK3, MKK4, and MKK6.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK2	MKK2	MKK2	ERK1/2	ERK1/2	ERK1/2	11	12	0	1
RAF kinases phosphorylate and activate MEK1 and/or MEK2 , which in turn phosphorylate and activate ERK1 and/or ERK2 .	RAF kinases phosphorylate and activate MEK1 and/or MEK2, which in turn phosphorylate and activate ERK1 and/or ERK2.	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	ERK2	ERK2	ERK2	7	8	17	18
Mitogen activated protein ( MAP )/ERK kinase ( MEK ) 1 and MEK2 are the upstream activators of the MAP kinases , ERK1 and ERK2 .	Mitogen activated protein (MAP)/ERK kinase (MEK) 1 and MEK2 are the upstream activators of the MAP kinases, ERK1 and ERK2.	10	25	are the upstream activators	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	ERK2	ERK2	ERK2	12	13	24	25
We assessed PKA dependent phosphorylation of the GluR1 subunit of the AMPA receptor and the MEK2 dependent activation of ERK2 protein kinase following treatment with forskolin , as two important downstream effectors of dopamine signaling .	We assessed PKA dependent phosphorylation of the GluR1 subunit of the AMPA receptor and the MEK2 dependent activation of ERK2 protein kinase following treatment with forskolin, as two important downstream effectors of dopamine signaling.	4	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK2	phosphorylation of the GluR1 subunit of the AMPA receptor and the MEK2	mek2	ERK2	ERK2	erk2	15	16	19	20
Activated RAF kinases phosphorylate and activate the dual specificity kinases MEK 1 and MEK 2 ( MEK 1/2 ) , which in turn phosphorylate and activate ERK 1 and ERK 2 ( ERK 1/2 ) , the terminal effector kinases of this pathway [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	Activated RAF kinases phosphorylate and activate the dual specificity kinases MEK 1 and MEK 2 (MEK 1/2), which in turn phosphorylate and activate ERK 1 and ERK 2 (ERK 1/2), the terminal effector kinases of this pathway [XREF_BIBR; XREF_BIBR; XREF_BIBR].	5	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK 2	MEK 2	MEK 2	ERK 2	ERK 2	ERK 2	13	15	29	31
Conversely , MEK2 activated ERK2 was retained in the cytoplasm and allowed survival .	Conversely, MEK2 activated ERK2 was retained in the cytoplasm and allowed survival.	2	11	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	ERK2	ERK2	ERK2	2	3	4	5
For example , upstream elements such as the tyrosine phosphorylated insulin receptor and IRS1 , as well as Akt regulatory sites , were found in the most rapid cluster ( cluster A ) , while MEK1 and MEK2 mediated activation of ERK1 and ERK2 ( cluster C ) and the ERK substrate p90RSK ( cluster J ) were slower ( XREF_FIG ) .	For example, upstream elements such as the tyrosine phosphorylated insulin receptor and IRS1, as well as Akt regulatory sites, were found in the most rapid cluster (cluster A), while MEK1 and MEK2 mediated activation of ERK1 and ERK2 (cluster C) and the ERK substrate p90RSK (cluster J) were slower (XREF_FIG).	35	55	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK2	MEK2	MEK2	ERK1	ERK1	ERK1	37	38	41	42
Interestingly , CA MKK7 expression primarily resulted in activation of the JNK1 isoform in a v-Rel cell line ( XREF_FIG , XREF_FIG ) , while mainly JNK2 was activated in primary spleen cells ( XREF_FIG ) .	Interestingly, CA MKK7 expression primarily resulted in activation of the JNK1 isoform in a v-Rel cell line (XREF_FIG, XREF_FIG), while mainly JNK2 was activated in primary spleen cells (XREF_FIG).	3	12	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	MKK7	MKK7 expression	mkk7	JNK1	JNK1	jnk1	3	4	11	12
MEKK1 is a protein kinase of the STE11 family , phosphorylates and activates MKK4 and MKK7 , which in turn activate JNK1 , JNK2 and JNK3 [ XREF_BIBR ] .	MEKK1 is a protein kinase of the STE11 family, phosphorylates and activates MKK4 and MKK7, which in turn activate JNK1, JNK2 and JNK3 [XREF_BIBR].	12	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK1	JNK1	JNK1	15	16	21	22
F1P activates dual-specificity mitogen activated protein kinase 7 ( MKK7 ) , which subsequently stimulates JNK-1 , a hepatic enzyme considered to act as a bridge between hepatic metabolism and inflammation .	F1P activates dual-specificity mitogen activated protein kinase 7 (MKK7), which subsequently stimulates JNK-1, a hepatic enzyme considered to act as a bridge between hepatic metabolism and inflammation.	3	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK-1	JNK-1	JNK-1	9	10	15	16
Investigating the molecular basis of activation of the c-Jun N-terminal kinase ( JNK ) subgroup of MAPK by the MAPKKK MEKK2 , we found that strong and specific JNK1 activation by MEKK2 was mediated by the MAPKK JNK kinase 2 ( JNKK2 ) rather than by JNKK1 through formation of a tripartite complex consisting of MEKK2 , JNKK2 , and JNK1 .	Investigating the molecular basis of activation of the c-Jun N-terminal kinase (JNK) subgroup of MAPK by the MAPKKK MEKK2, we found that strong and specific JNK1 activation by MEKK2 was mediated by the MAPKK JNK kinase 2 (JNKK2) rather than by JNKK1 through formation of a tripartite complex consisting of MEKK2, JNKK2, and JNK1.	28	40	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK kinase 2	JNK kinase 2	JNK kinase 2	JNK1	JNK1	JNK1	37	40	28	29
JIP3 was shown to bind to MLK3 and MKK7 inducing JNK1 activation in neurons .	JIP3 was shown to bind to MLK3 and MKK7 inducing JNK1 activation in neurons.	4	11	inducing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK1	JNK1	JNK1	8	9	10	11
When JNK1 activation was inhibited by MKK7 knockdown , the phosphorylation was blocked in cells .	When JNK1 activation was inhibited by MKK7 knockdown, the phosphorylation was blocked in cells.	1	7	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK1	JNK1	JNK1	6	7	1	2
In the JNK pathway , the TAK1-, MEKK1-, or MLK-MAP3Ks activate the MAP2K4 or MAP2K7 , which activates JNK1 , 2 or 3 , for instance , and lead to the control of cell apoptosis or the development of the immune system XREF_BIBR .	In the JNK pathway, the TAK1-, MEKK1-, or MLK-MAP3Ks activate the MAP2K4 or MAP2K7, which activates JNK1, 2 or 3, for instance, and lead to the control of cell apoptosis or the development of the immune system XREF_BIBR.	10	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP2K7	MAP2K7	MAP2K7	JNK1	JNK1	JNK1	14	15	18	19
JNK1 and JNK2 are activated by MKK4 and MKK7 ( see Introduction ) , suggesting a potential role for TAB2/3 in directing TAK1 complexes to one or both of these substrates .	JNK1 and JNK2 are activated by MKK4 and MKK7 (see Introduction), suggesting a potential role for TAB2/3 in directing TAK1 complexes to one or both of these substrates.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK1	JNK1	JNK1	8	9	0	1
Moreover , dominant negative MKK7 , but not dominant negative MKK4 and SEK1 , blocked JNK1 activation and apoptosis induced by parthenolide and HDACI regimens .	Moreover, dominant negative MKK7, but not dominant negative MKK4 and SEK1, blocked JNK1 activation and apoptosis induced by parthenolide and HDACI regimens.	2	16	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK1	JNK1	JNK1	4	5	15	16
The present results indicated that PTL markedly increases the anti-leukaemic activity of clinically relevant HDACIs , including vorinostat and LBH589 ( panobinostat ) , through a mechanism involving attenuation of HDACI mediated NF-kappaB activation and resulting MKK7- rather than MKK4 and SEK1 dependent activation of JNK1 .	The present results indicated that PTL markedly increases the anti-leukaemic activity of clinically relevant HDACIs, including vorinostat and LBH589 (panobinostat), through a mechanism involving attenuation of HDACI mediated NF-kappaB activation and resulting MKK7- rather than MKK4 and SEK1 dependent activation of JNK1.	39	46	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	JNK1	JNK1	JNK1	41	42	45	46
MKK4 is primarily activated by environmental stress and preferentially phosphorylates tyrosine ( Y ) residue 185 in the JNK1 activation motif ( TPY ) , whereas MKK7 , which is primarily activated by cytokines ( TNFandIL-1 ) , preferentially phosphorylates threonine ( T ) residue 183 .	MKK4 is primarily activated by environmental stress and preferentially phosphorylates tyrosine (Y) residue 185 in the JNK1 activation motif (TPY), whereas MKK7, which is primarily activated by cytokines (TNFandIL-1), preferentially phosphorylates threonine (T) residue 183.	0	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK1	JNK1	JNK1	0	1	18	19
39 MAPK8 encodes the c_JUN N-terminal protein kinase JNK1 , which is activated by JNKK1 ( or the MAP2K4 product ) and regulates the activity of c-Jun and c-Myc as well as the proapoptotic Bcl-2 family protein .	39 MAPK8 encodes the c_JUN N-terminal protein kinase JNK1, which is activated by JNKK1 (or the MAP2K4 product) and regulates the activity of c-Jun and c-Myc as well as the proapoptotic Bcl-2 family protein.	2	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNKK1	JNKK1	JNKK1	JNK1	JNK1	JNK1	14	15	8	9
The above evidence is indicative of a localised MKK4 dependent activation of JNK1 during cell migration , requiring the localised action of the aPKC , Kibra , and Exocyst complex .	The above evidence is indicative of a localised MKK4 dependent activation of JNK1 during cell migration, requiring the localised action of the aPKC, Kibra, and Exocyst complex.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK1	JNK1	JNK1	8	9	12	13
These confirmed that it was p-JNK2 , activated by MKK4 and MKK7 , contributed to the metastasis inhibition .	These confirmed that it was p-JNK2, activated by MKK4 and MKK7, contributed to the metastasis inhibition.	1	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	p-JNK2	p-JNK2	p-JNK2	9	10	5	6
Activation of SAPK requires a functional HPK1 kinase domain and HPK1 signals via the SH3 containing mixed lineage kinase MLK-3 and the known SAPK activator SEK1 .	Activation of SAPK requires a functional HPK1 kinase domain and HPK1 signals via the SH3 containing mixed lineage kinase MLK-3 and the known SAPK activator SEK1.	15	26	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	SAPK	SAPK	SAPK	25	26	23	24
The transient SAPK activity was suppressed by expression of a dominant negative form of MKK4 .	The transient SAPK activity was suppressed by expression of a dominant negative form of MKK4.	2	15	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	SAPK	SAPK	SAPK	14	15	2	3
These results imply that SEPW1 silencing increases MKK4 , which activates p38gamma , p38delta , and JNK2 to phosphorylate p53 on Ser 33 and cause a transient G ( 1 ) arrest .	These results imply that SEPW1 silencing increases MKK4, which activates p38gamma, p38delta, and JNK2 to phosphorylate p53 on Ser 33 and cause a transient G (1) arrest.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK2	JNK2	JNK2	7	8	16	17
However , recent genetic evidence suggests that SEK1 and SEK1 mediated SAPK activation have no role in the induction of cell death in lymphocytes , but rather protect T cells from CD95 ( FAS ) and CD3 mediated apotosis .	However, recent genetic evidence suggests that SEK1 and SEK1 mediated SAPK activation have no role in the induction of cell death in lymphocytes, but rather protect T cells from CD95 (FAS) and CD3 mediated apotosis.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	SEK1	SEK1	SEK1	SAPK	SAPK	SAPK	9	10	11	12
To determine the functional capabilities of T1A peptide we took advantage of the availability of purified MKK4 and MKK7 , both of which activate JNK3 XREF_BIBR and were shown to bind full-length arrestin-3 XREF_BIBR .	To determine the functional capabilities of T1A peptide we took advantage of the availability of purified MKK4 and MKK7, both of which activate JNK3 XREF_BIBR and were shown to bind full-length arrestin-3 XREF_BIBR.	13	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK3	JNK3	JNK3	16	17	24	25
In contrast , MKK4 activated JNK3 alpha 1 had no increase in Vmax compared to nonactivated levels and had no phosphorylation on the basis of mass spectrometry .	In contrast, MKK4 activated JNK3 alpha 1 had no increase in Vmax compared to nonactivated levels and had no phosphorylation on the basis of mass spectrometry.	3	18	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK3	JNK3	JNK3	3	4	5	6
As could be expected ( XREF_FIG ) , the activation of JNK3 by MKK7 demonstrated biphasic dependence on arrestin-3 concentration , similar to that observed with MKK4 .	As could be expected (XREF_FIG), the activation of JNK3 by MKK7 demonstrated biphasic dependence on arrestin-3 concentration, similar to that observed with MKK4.	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK3	JNK3	JNK3	13	14	11	12
Measuring catalysis under Vmax conditions showed MKK4 + MKK7 activated JNK3 alpha 1 had Vmax 715-fold greater than nonactivated JNK3 alpha 1 and MKK7 activated JNK3 alpha 1 had Vmax 250-fold greater than nonactivated JNK3 alpha 1 .	Measuring catalysis under Vmax conditions showed MKK4 + MKK7 activated JNK3 alpha 1 had Vmax 715-fold greater than nonactivated JNK3 alpha 1 and MKK7 activated JNK3 alpha 1 had Vmax 250-fold greater than nonactivated JNK3 alpha 1.	6	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK3	JNK3	JNK3	8	9	10	11
Even addition of a constitutively active form of MKK7 ( MKK7DE ) induced only moderate SAPKbeta and JNK3 kinase activity .	Even addition of a constitutively active form of MKK7 (MKK7DE) induced only moderate SAPKbeta and JNK3 kinase activity.	6	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK3	JNK3	JNK3	8	9	17	18
PAK6 activation by MKK6 was also blocked by mutation of an autophosphorylated serine ( serine 560 ) in the PAK6 activation loop , indicating that phosphorylation of this site is necessary for MKK6 mediated activation .	PAK6 activation by MKK6 was also blocked by mutation of an autophosphorylated serine (serine 560) in the PAK6 activation loop, indicating that phosphorylation of this site is necessary for MKK6 mediated activation.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MKK6	MKK6	MKK6	PAK6	PAK6	PAK6	3	4	0	1
In addition , while serine 560 phosphorylation is known to be required for PAK6 activation via MKK6 , PAK6 is also directly activated by MKK6 at tyrosine 566 [ XREF_BIBR ] .	In addition, while serine 560 phosphorylation is known to be required for PAK6 activation via MKK6, PAK6 is also directly activated by MKK6 at tyrosine 566 [XREF_BIBR].	18	25	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK6	MKK6	MKK6	PAK6	PAK6	PAK6	24	25	18	19
Moreover , PAK6 was directly activated by MKK6 , and mutation of tyrosine 566 in a consensus MKK6 site ( threonine-proline-tyrosine , TPY ) in the activation loop of the PAK6 kinase domain prevented activation by MKK6 .	Moreover, PAK6 was directly activated by MKK6, and mutation of tyrosine 566 in a consensus MKK6 site (threonine-proline-tyrosine, TPY) in the activation loop of the PAK6 kinase domain prevented activation by MKK6.	2	8	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK6	MKK6	MKK6	PAK6	PAK6	PAK6	7	8	2	3
PAK4 and PAK5 were similarly activated by MKK6 , consistent with a conserved TPY motif in their activation domains .	PAK4 and PAK5 were similarly activated by MKK6, consistent with a conserved TPY motif in their activation domains.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MKK6	MKK6	MKK6	PAK5	PAK5	PAK5	7	8	2	3
With K63 polyubiquitination of RIP1 by cIAP1 and cIAP2 , complex I recruits , phosphorylates , and ubiquitinates the MAP3Ks TAK1 , MEKK1 , or MLK3 , which in turn activate MKK4 and MKK7 , leading to activation of JNK and other downstream effectors including IkappaB kinase ( IKK ) XREF_BIBR , XREF_BIBR .	With K63 polyubiquitination of RIP1 by cIAP1 and cIAP2, complex I recruits, phosphorylates, and ubiquitinates the MAP3Ks TAK1, MEKK1, or MLK3, which in turn activate MKK4 and MKK7, leading to activation of JNK and other downstream effectors including IkappaB kinase (IKK) XREF_BIBR, XREF_BIBR.	14	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK3	phosphorylates, and ubiquitinates the MAP3Ks TAK1, MEKK1, or MLK3	mlk3	MKK4	MKK4	mkk4	25	26	31	32
Using the above approach , we determined the role of MLK3 in OGD induced activation of MKK4 and JNK and cell death .	Using the above approach, we determined the role of MLK3 in OGD induced activation of MKK4 and JNK and cell death.	8	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK3	MLK3	MLK3	MKK4	MKK4	MKK4	10	11	16	17
Moreover , the the over-expressed MAP2K3 ( MKK3 ) causes the over-expressed MAPK12 ( P38 ) , and then causes the down-expressed ELK4 ( Sap1a ) .	Moreover, the the over-expressed MAP2K3 (MKK3) causes the over-expressed MAPK12 (P38), and then causes the down-expressed ELK4 (Sap1a).	5	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK3	MKK3	MKK3	MAPK12	MAPK12	MAPK12	7	8	12	13
Together , these results suggest a linear cascade in which DLK and LZK activate MKK4 and MKK7 , which in turn , leads to JNK1-3 activation and , ultimately , cell death .	Together, these results suggest a linear cascade in which DLK and LZK activate MKK4 and MKK7, which in turn, leads to JNK1-3 activation and, ultimately, cell death.	10	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LZK	LZK	LZK	MKK7	MKK7	MKK7	12	13	16	17
In response to environmental stress , JNK is activated by phosphorylation of residues in its activation loop by MKK4 and MKK7 , which in turn are activated by MLK .	In response to environmental stress, JNK is activated by phosphorylation of residues in its activation loop by MKK4 and MKK7, which in turn are activated by MLK.	8	29	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MLK	MLK	MLK	MKK7	MKK7	MKK7	28	29	20	21
SKK3 was the only activator of SAPK4 that was induced when KB cells were exposed to a cellular stress or stimulated with interleukin-1 .	SKK3 was the only activator of SAPK4 that was induced when KB cells were exposed to a cellular stress or stimulated with interleukin-1.	0	7	was the only activator	Positive_activation_copula_1	Positive_activation	Positive_activation	SKK3	SKK3	SKK3	SAPK4	SAPK4	SAPK4	0	1	6	7
These findings indicate that SKK3 mediates the activation of SAPK4 .	These findings indicate that SKK3 mediates the activation of SAPK4.	4	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SKK3	SKK3	SKK3	SAPK4	SAPK4	SAPK4	4	5	9	10
These experiments indicate that SAPKK3 mediates the activation of SAPK3 in several mammalian cells .	These experiments indicate that SAPKK3 mediates the activation of SAPK3 in several mammalian cells.	4	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SAPKK3	SAPKK3	SAPKK3	SAPK3	SAPK3	SAPK3	4	5	9	10
Co-transfection with SAPKK3 induced SAPK3 activity and greatly enhanced activation in response to osmotic shock .	Co-transfection with SAPKK3 induced SAPK3 activity and greatly enhanced activation in response to osmotic shock.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	SAPKK3	SAPKK3	SAPKK3	SAPK3	SAPK3	SAPK3	2	3	4	5
SAPK3 and SAPK2 were activated at similar rates in vitro by SAPKK3 ( also termed MKK6 ) , and SAPKK3 was the only activator of SAPK3 that was induced when KB or 293 cells were exposed to cellular stresses or stimulated with IL-1 or TNF .	SAPK3 and SAPK2 were activated at similar rates in vitro by SAPKK3 (also termed MKK6), and SAPKK3 was the only activator of SAPK3 that was induced when KB or 293 cells were exposed to cellular stresses or stimulated with IL-1 or TNF.	19	26	was the only activator	Positive_activation_copula_1	Positive_activation	Positive_activation	SAPKK3	SAPKK3	SAPKK3	SAPK3	SAPK3	SAPK3	19	20	25	26
Mixed lineage kinase 3 ( MLK3 ) and IB2 synergistically activate p38delta but not the MAPKs JNK-1 and p38alpha .	Mixed lineage kinase 3 (MLK3) and IB2 synergistically activate p38delta but not the MAPKs JNK-1 and p38alpha.	0	18	synergistically activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK3	MLK3	MLK3	JNK-1	JNK-1	JNK-1	5	6	16	17
MAP3K11 kinase preferentially activates MAPK8 and JNK kinase , and functions as a positive regulator of the JNK signaling pathway ; it is found to be involved in the transcription activity of NF-kappaB XREF_BIBR .	MAP3K11 kinase preferentially activates MAPK8 and JNK kinase, and functions as a positive regulator of the JNK signaling pathway; it is found to be involved in the transcription activity of NF-kappaB XREF_BIBR.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K11	MAP3K11	MAP3K11	MAPK8	MAPK8	MAPK8	0	1	4	5
CEP-1347 blocked JNK1 activation induced by members of the mixed lineage kinase ( MLK ) family ( MLK3 , MLK2 , MLK1 , dual leucine zipper kinase , and leucine zipper kinase ) .	CEP-1347 blocked JNK1 activation induced by members of the mixed lineage kinase (MLK) family (MLK3, MLK2, MLK1, dual leucine zipper kinase, and leucine zipper kinase).	2	31	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MLK3	MLK3	MLK3	JNK1	JNK1	JNK1	17	18	2	3
In addition , MLK3 induced JNK1 activation was found to be suppressed by the kinase negative form of DLK , which bound to MLK3 .	In addition, MLK3 induced JNK1 activation was found to be suppressed by the kinase negative form of DLK, which bound to MLK3.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	MLK3	MLK3	MLK3	JNK1	JNK1	JNK1	3	4	5	6
We can not rule out the possibility that other MEK kinases are activated by adhesion to FN , however , PAK1 phosphorylation of MEK1 would be required for MEKK to activate MEK1 because MEK1 S298A was not phosphorylated on the activating sites upon plating on FN ( XREF_FIG ) .	We can not rule out the possibility that other MEK kinases are activated by adhesion to FN, however, PAK1 phosphorylation of MEK1 would be required for MEKK to activate MEK1 because MEK1 S298A was not phosphorylated on the activating sites upon plating on FN (XREF_FIG).	20	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	PAK1 phosphorylation of MEK1	mek1	MEK1	MEK1	mek1	23	24	31	32
MEK-1 phosphorylation catalyzed by Raf , MEKK , or autophosphorylation resulted in activation of MEK-1 kinase activity measured by phosphorylation of a mutant kinase inactive MAPK .	MEK-1 phosphorylation catalyzed by Raf, MEKK, or autophosphorylation resulted in activation of MEK-1 kinase activity measured by phosphorylation of a mutant kinase inactive MAPK.	0	16	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	MEK-1	MEK-1 phosphorylation	mek-1	MEK-1	MEK-1	mek-1	0	1	14	15
In response to epidermal growth factor , nerve growth factor , and platelet derived growth factor , B-Raf and Raf-1 are activated , phosphorylate recombinant kinase-inactive MEK-1 , and activate wild-type MEK-1 .	In response to epidermal growth factor, nerve growth factor, and platelet derived growth factor, B-Raf and Raf-1 are activated, phosphorylate recombinant kinase-inactive MEK-1, and activate wild-type MEK-1.	17	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK-1	B-Raf and Raf-1 are activated, phosphorylate recombinant kinase-inactive MEK-1	mek-1	MEK-1	MEK-1	mek-1	26	27	31	32
The constitutively active mutant Rac1QL activated Mirk in several cell types through MKK3 , which in turn activated Mirk by phosphorylation .	The constitutively active mutant Rac1QL activated Mirk in several cell types through MKK3, which in turn activated Mirk by phosphorylation.	5	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK3	MKK3	MKK3	Mirk	Mirk	Mirk	12	13	18	19
Endogenous Mirk , p38 , and MKK3 co-migrate within 500-700-kDa protein complexes , which accumulate when nuclear export is blocked by leptomycin B. Stable overexpression of Mirk increases the fraction of Mirk protein and p38 protein within these 500-700 kDa complexes , suggesting that the complexes act as nuclear depots for Mirk and p38 .	Endogenous Mirk, p38, and MKK3 co-migrate within 500-700-kDa protein complexes, which accumulate when nuclear export is blocked by leptomycin B. Stable overexpression of Mirk increases the fraction of Mirk protein and p38 protein within these 500-700 kDa complexes, suggesting that the complexes act as nuclear depots for Mirk and p38.	6	32	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK3	MKK3	MKK3	Mirk	Mirk	Mirk	6	7	31	32
The MAPK kinase MKK3 was also shown to activate Mirk as a protein kinase , implicating Mirk in the biological response to certain stress agents .	The MAPK kinase MKK3 was also shown to activate Mirk as a protein kinase, implicating Mirk in the biological response to certain stress agents.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK3	MKK3	MKK3	Mirk	Mirk	Mirk	3	4	9	10
MAP2K6 is an upstream activator of MAPK11 , its major downstream effector .	MAP2K6 is an upstream activator of MAPK11, its major downstream effector.	0	11	is an upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MAP2K6	MAP2K6	MAP2K6	MAPK11	MAPK11	MAPK11	0	1	6	7
Co-expression of the MLK3 upstream regulator Cdc42 with MLK3 is sufficient to induce homodimerization and autophosphorylation of MLK3 as well as kinase dependent activation of its downstream signaling effectors .	Co-expression of the MLK3 upstream regulator Cdc42 with MLK3 is sufficient to induce homodimerization and autophosphorylation of MLK3 as well as kinase dependent activation of its downstream signaling effectors.	0	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK3	Co-expression of the MLK3	mlk3	MLK3	MLK3	mlk3	3	4	17	18
These results suggest oxidative stress stimulates an ERK1/2 dependent phosphorylation of MLK3 on Ser 705 and Ser 758 , which promotes MLK3 dependent B-Raf and ERK1/2 activation ; this positive feedback loop ( PFL ) enhances the invasion of colon cancer cells .	These results suggest oxidative stress stimulates an ERK1/2 dependent phosphorylation of MLK3 on Ser 705 and Ser 758, which promotes MLK3 dependent B-Raf and ERK1/2 activation; this positive feedback loop (PFL) enhances the invasion of colon cancer cells.	7	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK3	ERK1/2 dependent phosphorylation of MLK3 on Ser 705 and Ser 758	mlk3	MLK3	MLK3	mlk3	11	12	21	22
These results indicate that MLK3 could be degraded via a ubiquitin-proteosome pathway and that K48 linked ubiquitination of MLK3 may function to target MLK3 for proteosomal degradation .	These results indicate that MLK3 could be degraded via a ubiquitin-proteosome pathway and that K48 linked ubiquitination of MLK3 may function to target MLK3 for proteosomal degradation.	14	24	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK3	K48 linked ubiquitination of MLK3	mlk3	MLK3	MLK3	mlk3	18	19	23	24
Overexpression of MKK4 decreased proliferation and promoted a senescent phenotype in young WI-38 human diploid fibroblasts and conversely , when MKK4 levels were lowered by several microRNAs targeting the MKK4 mRNA , the senescent phenotype was ameliorated and cells proliferated more rapidly [ XREF_BIBR ] .	Overexpression of MKK4 decreased proliferation and promoted a senescent phenotype in young WI-38 human diploid fibroblasts and conversely, when MKK4 levels were lowered by several microRNAs targeting the MKK4 mRNA, the senescent phenotype was ameliorated and cells proliferated more rapidly [XREF_BIBR].	20	30	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	MKK4 levels	mkk4	MKK4	MKK4	mkk4	20	21	29	30
Exogenous MKK4 expression partially restored the ability of Mkk4 (-/-) ESCs to differentiate into cardiomyocytes .	Exogenous MKK4 expression partially restored the ability of Mkk4 (-/-) ESCs to differentiate into cardiomyocytes.	1	10	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4 expression	mkk4	Mkk4	Mkk4	mkk4	1	2	8	9
Both MLK3 and TRAF2 are required for TNF induced SAPK and JNK activation .	Both MLK3 and TRAF2 are required for TNF induced SAPK and JNK activation.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK3	MLK3	MLK3	SAPK	SAPK	SAPK	1	2	9	10
In the same cell system , MLK3 preferentially activates the c-Jun NH2-terminal kinase and stress activated protein kinase ( JNK and SAPK ) mitogen activated protein kinase cascade and to a lesser degree the extracellular signal regulated kinase ( ERK ) pathway .	In the same cell system, MLK3 preferentially activates the c-Jun NH2-terminal kinase and stress activated protein kinase (JNK and SAPK) mitogen activated protein kinase cascade and to a lesser degree the extracellular signal regulated kinase (ERK) pathway.	6	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK3	MLK3	MLK3	SAPK	SAPK	SAPK	6	7	21	22
In support of this role , we demonstrate that MLK-3 can specifically activate the SAPK and JNK and p38/RK pathways , but has no effect on the activation of ERKs .	In support of this role, we demonstrate that MLK-3 can specifically activate the SAPK and JNK and p38/RK pathways, but has no effect on the activation of ERKs.	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK-3	MLK-3	MLK-3	SAPK	SAPK	SAPK	9	10	14	15
Finally , kinase dead mutants of MLK-3 blocked activation of the SAPK pathway by a newly identified mammalian analog of Ste20 , germinal center kinase , but not by MEKK , suggesting that MLK-3 functions to activate the SAPK and JNK and p38/RK cascades in response to stimuli transduced by Ste20 like kinases .	Finally, kinase dead mutants of MLK-3 blocked activation of the SAPK pathway by a newly identified mammalian analog of Ste20, germinal center kinase, but not by MEKK, suggesting that MLK-3 functions to activate the SAPK and JNK and p38/RK cascades in response to stimuli transduced by Ste20 like kinases.	4	12	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MLK-3	MLK-3	MLK-3	SAPK	SAPK	SAPK	6	7	11	12
MLK3 activates MKK3 and MKK6 , which in turn phosphorylate and activate p38 .	MLK3 activates MKK3 and MKK6, which in turn phosphorylate and activate p38.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK3	MLK3	MLK3	MKK3	MKK3	MKK3	0	1	2	3
Mirk is activated by phosphorylation by the stress activated SAPK kinases MKK3 and MKK6 .	Mirk is activated by phosphorylation by the stress activated SAPK kinases MKK3 and MKK6.	8	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK6	MKK6	MKK6	SAPK	SAPK	SAPK	13	14	9	10
Recently , it has been shown that another signal molecule , cancer Osaka thyroid oncogene and tumor progression locus 2 ( Cot and Tpl2 ) kinase , activates Mek and Erk and plays a role in the Erk pathway , similar to MAP3K signal molecule Raf kinase .	Recently, it has been shown that another signal molecule, cancer Osaka thyroid oncogene and tumor progression locus 2 (Cot and Tpl2) kinase, activates Mek and Erk and plays a role in the Erk pathway, similar to MAP3K signal molecule Raf kinase.	14	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor progression locus 2	tumor progression locus 2	tumor progression locus 2	Erk	Erk	Erk	16	20	30	31
Consequently , Tpl-2 was liberated from p105 , thereby stimulating activation of the MEK and ERK MAPK cascade .	Consequently, Tpl-2 was liberated from p105, thereby stimulating activation of the MEK and ERK MAPK cascade.	2	17	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl-2	Tpl-2	Tpl-2	ERK MAPK	ERK MAPK	ERK MAPK	2	3	15	17
However , our findings suggest that neither classical NF-kappaB signalling utilizing NF-kappaB1 nor Tpl2 mediated activation of ERK and MAPK influences the AOM and DSS model .	However, our findings suggest that neither classical NF-kappaB signalling utilizing NF-kappaB1 nor Tpl2 mediated activation of ERK and MAPK influences the AOM and DSS model.	13	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK	ERK	ERK	13	14	17	18
TAK1 acts as a MAP3K for the p38 and JNK pathways and via IKK it controls the activation of Tpl2 , the MAP3K that activates ERK1/2 downstream of TLRs .	TAK1 acts as a MAP3K for the p38 and JNK pathways and via IKK it controls the activation of Tpl2, the MAP3K that activates ERK1/2 downstream of TLRs.	17	28	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK1/2	ERK1/2	ERK1/2	19	20	25	26
In human adipocytes , pharmacological inhibition of Tpl2 also inhibited ERK1/2 activation induced by IL-1beta and TNF-alpha , whereas insulin effect was not significantly modified ( XREF_FIG C ) .	In human adipocytes, pharmacological inhibition of Tpl2 also inhibited ERK1/2 activation induced by IL-1beta and TNF-alpha, whereas insulin effect was not significantly modified (XREF_FIG C).	5	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK1/2	ERK1/2	ERK1/2	7	8	10	11
MAPK activation induced by the Tpl-2 protein is blocked by dominant negative mutants of Ras and Raf-1 , whereas a kinase deficient Tpl-2 mutant down regulates mitogenic signals induced by v-Ha-Ras or v-Raf .	MAPK activation induced by the Tpl-2 protein is blocked by dominant negative mutants of Ras and Raf-1, whereas a kinase deficient Tpl-2 mutant down regulates mitogenic signals induced by v-Ha-Ras or v-Raf.	0	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tpl-2	Tpl-2	Tpl-2	MAPK	MAPK	MAPK	5	6	0	1
Notably , COT could independently activate the MAPK and ERK pathway [ XREF_BIBR ] .	Notably, COT could independently activate the MAPK and ERK pathway [XREF_BIBR].	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT	COT	MAPK	MAPK	MAPK	2	3	7	8
In these cells p38gamma and p38delta are necessary to maintain steady-state levels of TPL-2 , the MKK kinase that mediates ERK1/2 activation in response to TLR stimulation .	In these cells p38gamma and p38delta are necessary to maintain steady-state levels of TPL-2, the MKK kinase that mediates ERK1/2 activation in response to TLR stimulation.	11	21	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TPL-2	levels of TPL-2	tpl-2	ERK1/2	ERK1/2	erk1/2	13	14	20	21
The IKK complex therefore regulates two of the key regulatory steps required for TPL-2 activation of ERK-1/2 , underlining the close linkage of ERK-1/2 MAP kinase activation to upregulation of NF-kappaB-dependent transcription .	The IKK complex therefore regulates two of the key regulatory steps required for TPL-2 activation of ERK-1/2, underlining the close linkage of ERK-1/2 MAP kinase activation to upregulation of NF-kappaB-dependent transcription.	13	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	ERK-1/2	ERK-1/2	ERK-1/2	13	14	16	17
COT activates ERK primarily through MEK dependent mechanisms that do not require RAF signaling .	COT activates ERK primarily through MEK dependent mechanisms that do not require RAF signaling.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT	COT	ERK	ERK	ERK	0	1	2	3
However , the results presented in XREF_FIG E , and the observation that Tpl2 overexpression increases ERK1/2 activity , suggest that Tpl2 expression could be rate limiting for the activation of ERK pathway .	However, the results presented in XREF_FIG E, and the observation that Tpl2 overexpression increases ERK1/2 activity, suggest that Tpl2 expression could be rate limiting for the activation of ERK pathway.	13	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2 overexpression	tpl2	ERK1/2	ERK1/2	erk1/2	13	14	16	17
Cot and Tpl2 activated ERK , but not JNK and p38 MAPK , in the LPS treated macrophages .	Cot and Tpl2 activated ERK, but not JNK and p38 MAPK, in the LPS treated macrophages.	0	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cot	Cot	Cot	ERK	ERK	ERK	0	1	4	5
Exogenous expression of TPL-2 in p38gamma and delta -/- macrophages not only increased ERK1/2 activation , but also rescued TPL-2-dependent TNFalpha production in response to LPS .	Exogenous expression of TPL-2 in p38gamma and delta -/- macrophages not only increased ERK1/2 activation, but also rescued TPL-2-dependent TNFalpha production in response to LPS.	1	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL-2	expression of TPL-2	tpl-2	ERK1/2	ERK1/2	erk1/2	3	4	13	14
In the TLR and TNFR pathways , TPL2 mediates ERK1/2 activation ; however TPL2 is dispensable for ERK activation in IL-17 signaling [ XREF_BIBR , XREF_BIBR ] .	In the TLR and TNFR pathways, TPL2 mediates ERK1/2 activation; however TPL2 is dispensable for ERK activation in IL-17 signaling [XREF_BIBR, XREF_BIBR].	7	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL2	TPL2	TPL2	ERK1/2	ERK1/2	ERK1/2	7	8	9	10
Here , we showed that Tpl2 mediated GPCR signals induced by thrombin or S1P not only activate ERK as previously shown , but also stimulate the release of Ca 2+ from the ER .	Here, we showed that Tpl2 mediated GPCR signals induced by thrombin or S1P not only activate ERK as previously shown, but also stimulate the release of Ca 2+ from the ER.	5	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK	ERK	ERK	5	6	17	18
This observation was attributed to the steady-state level of tumor progression locus 2 , the MKK kinase that mediates ERK1/2 activation after TLR4 stimulation in the cell , maintained by p38 kinases .	This observation was attributed to the steady-state level of tumor progression locus 2, the MKK kinase that mediates ERK1/2 activation after TLR4 stimulation in the cell, maintained by p38 kinases.	7	20	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	tumor progression locus 2	level of tumor progression locus 2	tumor progression locus 2	ERK1/2	ERK1/2	erk1/2	9	13	19	20
Recruitment of 14-3-3 to the phosphorylated C terminus stimulated TPL-2 MEK-1 kinase activity , which was essential for TPL-2 activation of ERK-1/2 .	Recruitment of 14-3-3 to the phosphorylated C terminus stimulated TPL-2 MEK-1 kinase activity, which was essential for TPL-2 activation of ERK-1/2.	18	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	ERK-1/2	ERK-1/2	ERK-1/2	18	19	21	22
TPL-2 ( COT , MAP3K8 ) kinase activates the MEK1/2-ERK 1/2 MAPK signaling pathway in innate immune responses following TLR , TNFR1 and IL-1R stimulation .	TPL-2 (COT, MAP3K8) kinase activates the MEK1/2-ERK 1/2 MAPK signaling pathway in innate immune responses following TLR, TNFR1 and IL-1R stimulation.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	MAPK	MAPK	MAPK	0	1	11	12
In contrast , TPL2 has been described as an exclusive MAP3K of MKK1/2 triggering activation of the classical ERKs , ERK1/2 .	In contrast, TPL2 has been described as an exclusive MAP3K of MKK1/2 triggering activation of the classical ERKs, ERK1/2.	3	20	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL2	TPL2	TPL2	ERKs	ERKs	ERKs	3	4	18	19
Interestingly , even though COT appears to activate ERK through MEK , these cell lines and cell lines overxpressing exogenous COT were also resistant to MEK inhibitors .	Interestingly, even though COT appears to activate ERK through MEK, these cell lines and cell lines overxpressing exogenous COT were also resistant to MEK inhibitors.	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT	COT	ERK	ERK	ERK	4	5	8	9
In vitro studies using Tpl2 overexpressing cells have shown that Tpl2 activates ERK , JNK , p38 , and the transcription factors NFAT ( nuclear factor of activated T cells ) and NF-kappaB [ XREF_BIBR , XREF_BIBR ] .	In vitro studies using Tpl2 overexpressing cells have shown that Tpl2 activates ERK, JNK, p38, and the transcription factors NFAT (nuclear factor of activated T cells) and NF-kappaB [XREF_BIBR, XREF_BIBR].	10	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK	ERK	ERK	10	11	12	13
P105-free TPL2 activates MEK1/2 , and ultimately the ERK1/2 pathway .	P105-free TPL2 activates MEK1/2, and ultimately the ERK1/2 pathway.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL2	TPL2	TPL2	ERK1/2	ERK1/2	ERK1/2	1	2	8	9
These results indicate that TPL-2 activated p38alpha and ERK1/2 following the initial interaction of M. tuberculosis and L. monocytogenes bacteria with macrophages .	These results indicate that TPL-2 activated p38alpha and ERK1/2 following the initial interaction of M. tuberculosis and L. monocytogenes bacteria with macrophages.	4	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	ERK1/2	ERK1/2	ERK1/2	4	5	8	9
In accordance with prior observations XREF_BIBR , these data raised the possibility that COT may activate ERK through MEK independent and MEK dependent mechanisms .	In accordance with prior observations XREF_BIBR, these data raised the possibility that COT may activate ERK through MEK independent and MEK dependent mechanisms.	13	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT	COT	ERK	ERK	ERK	13	14	16	17
In keeping with this , we show that TPL-2 activation of ERK is required for TLR4 and TLR9 induction of IL-10 , but negatively regulates IFN-beta production via both IL-10-dependent and -independent mechanisms .	In keeping with this, we show that TPL-2 activation of ERK is required for TLR4 and TLR9 induction of IL-10, but negatively regulates IFN-beta production via both IL-10-dependent and -independent mechanisms.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	ERK	ERK	ERK	8	9	11	12
Although KSR is a positive regulator of the Ras and mitogen activated protein ( MAP ) kinase pathway , the role of KSR in Cot mediated MAPK activation has not been identified .	Although KSR is a positive regulator of the Ras and mitogen activated protein (MAP) kinase pathway, the role of KSR in Cot mediated MAPK activation has not been identified.	22	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cot	Cot	Cot	MAPK	MAPK	MAPK	24	25	26	27
Moreover , it was suggested that not only LPS but also Tpl2 requires the Ras pathway to activate Erk .	Moreover, it was suggested that not only LPS but also Tpl2 requires the Ras pathway to activate Erk.	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	Erk	Erk	Erk	11	12	18	19
Our data support MAP3K8 induced activation of different MAPK signaling pathways in response to different profiles of shear stress , possibly as a consequence of shear induced IL1B expression .	Our data support MAP3K8 induced activation of different MAPK signaling pathways in response to different profiles of shear stress, possibly as a consequence of shear induced IL1B expression.	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K8	MAP3K8	MAP3K8	MAPK	MAPK	MAPK	3	4	8	9
Consequently , TPL-2 activation of the ERK1/2 MAP kinase pathway requires TPL-2 release from p105 , which is triggered by IkappaB kinase ( IKK )-induced proteolysis of p105 by the proteasome [ XREF_BIBR - XREF_BIBR ] .	Consequently, TPL-2 activation of the ERK1/2 MAP kinase pathway requires TPL-2 release from p105, which is triggered by IkappaB kinase (IKK)-induced proteolysis of p105 by the proteasome [XREF_BIBR - XREF_BIBR].	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	ERK1/2	ERK1/2	ERK1/2	2	3	6	7
Overexpression of Tpl2 activates ERK , JNK and p38 MAPK pathways , as well as transcription factors such as nuclear factor of activated T cells and NF-kappaB .	Overexpression of Tpl2 activates ERK, JNK and p38 MAPK pathways, as well as transcription factors such as nuclear factor of activated T cells and NF-kappaB.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Overexpression of Tpl2	tpl2	ERK	ERK	erk	2	3	4	5
TPL2 deletion in the obese state prevents MAPK activation , proinflammatory cytokine expression , and the accumulation of immune cells in peripheral tissues , resulting in reduced hepatic steatosis and improved insulin sensitivity .	TPL2 deletion in the obese state prevents MAPK activation, proinflammatory cytokine expression, and the accumulation of immune cells in peripheral tissues, resulting in reduced hepatic steatosis and improved insulin sensitivity.	0	8	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL2	TPL2	TPL2	MAPK	MAPK	MAPK	0	1	7	8
TPL-2 is an upstream activator of ERK , and decreased ERK phosphorylation and IL-10 down-regulation has been shown previously in TPL-2 -/- macrophages after TLR activation [ XREF_BIBR ] .	TPL-2 is an upstream activator of ERK, and decreased ERK phosphorylation and IL-10 down-regulation has been shown previously in TPL-2 -/- macrophages after TLR activation [XREF_BIBR].	0	9	is an upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	ERK	ERK	ERK	0	1	6	7
Tpl2 is activated by various signals , including GPCR mediated signals , to phosphorylate and activate MEK and thereby activate ERK .	Tpl2 is activated by various signals, including GPCR mediated signals, to phosphorylate and activate MEK and thereby activate ERK.	0	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK	ERK	ERK	0	1	20	21
Cot and tpl2 mediates Erk1/2 activation in the macrophagic cell line RAW , peritoneal macrophages , and bone marrow derived macrophages ( BMDM ) upon engagement of lipopolysaccharide ( LPS ) to TLR4 .	Cot and tpl2 mediates Erk1/2 activation in the macrophagic cell line RAW, peritoneal macrophages, and bone marrow derived macrophages (BMDM) upon engagement of lipopolysaccharide (LPS) to TLR4.	0	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tpl2	tpl2	tpl2	Erk1/2	Erk1/2	Erk1/2	2	3	4	5
hKSR2DeltaCA1 has been described as a regulator of proto-oncogene Cot induced MAPK signaling .	hKSR2DeltaCA1 has been described as a regulator of proto-oncogene Cot induced MAPK signaling.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Cot	Cot	Cot	MAPK	MAPK	MAPK	9	10	11	12
As the MAPK pathway MKK1 and MKK2-ERK 1/ERK2 is not only activated by RAF1 , but also by the protein kinase TPL2 , we asked whether this protein kinase contributed to the activation of ERK1 and ERK2 in response to PsaDM .	As the MAPK pathway MKK1 and MKK2-ERK 1/ERK2 is not only activated by RAF1, but also by the protein kinase TPL2, we asked whether this protein kinase contributed to the activation of ERK1 and ERK2 in response to PsaDM.	2	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TPL2	TPL2	TPL2	MAPK	MAPK	MAPK	21	22	2	3
Increased expression of MAP3K8 or COT can stimulate the MAPK pathway to bypass BRAF inhibition ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	Increased expression of MAP3K8 or COT can stimulate the MAPK pathway to bypass BRAF inhibition (XREF_FIG) [XREF_BIBR, XREF_BIBR].	1	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	expression of MAP3K8 or COT	cot	MAPK	MAPK	mapk	5	6	9	10
TLR3 signaling can also activate tumor progression locus 2 ( Tpl2 and cot , MAP3K8 ) , a cytoplasmic serine/threonine protein kinase that mediates ERK dependent signaling in hematopoietic cells .	TLR3 signaling can also activate tumor progression locus 2 (Tpl2 and cot, MAP3K8), a cytoplasmic serine/threonine protein kinase that mediates ERK dependent signaling in hematopoietic cells.	5	26	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	tumor progression locus 2	tumor progression locus 2	tumor progression locus 2	ERK	ERK	ERK	5	9	24	25
Mechanisms of primary resistance include RAC1P29S mutations ( RAC 1 regulates cell proliferation and migration ) , COT overexpression ( COT activates ERK through mechanism that does not depend on RAF signaling ) , alterations in RTK signaling ( RTK activation can signal either through CRAF or through the PI3K pathway ) , and alterations in the PI3K-AKT-mTOR pathway ( loss of function of PTEN ) .	Mechanisms of primary resistance include RAC1P29S mutations (RAC 1 regulates cell proliferation and migration), COT overexpression (COT activates ERK through mechanism that does not depend on RAF signaling), alterations in RTK signaling (RTK activation can signal either through CRAF or through the PI3K pathway), and alterations in the PI3K-AKT-mTOR pathway (loss of function of PTEN).	20	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT	COT	ERK	ERK	ERK	20	21	22	23
The results (-densitometric analyses shown in XREF_FIG ) confirm preferential activation of ERK by Tpl2 signal in astrocytes as in microglia .	The results (-densitometric analyses shown in XREF_FIG) confirm preferential activation of ERK by Tpl2 signal in astrocytes as in microglia.	10	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK	ERK	ERK	14	15	12	13
The binding of lipopolysaccharide to Toll like receptors causes phosphorylation of Cot and Tp12 to activate the MAPK cascade .	The binding of lipopolysaccharide to Toll like receptors causes phosphorylation of Cot and Tp12 to activate the MAPK cascade.	1	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cot	binding of lipopolysaccharide to Toll like receptors causes phosphorylation of Cot	cot	MAPK	MAPK	mapk	11	12	17	18
A variety of events occur triggering this resistance including the presence of NRAS mutations , COT mediated MAPK activation , redirection of signaling through CRAF , PI3kinase pathway signaling via PTEN loss , PDGFR upregulation or AKT3 upregulation , secretion of hepatocyte growth factor , increased activation of FGFR3 , and a variety of other events [ XREF_BIBR - XREF_BIBR ] .	A variety of events occur triggering this resistance including the presence of NRAS mutations, COT mediated MAPK activation, redirection of signaling through CRAF, PI3kinase pathway signaling via PTEN loss, PDGFR upregulation or AKT3 upregulation, secretion of hepatocyte growth factor, increased activation of FGFR3, and a variety of other events [XREF_BIBR - XREF_BIBR].	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	COT	COT	COT	MAPK	MAPK	MAPK	15	16	17	18
For example , it is observed that the kinase Cot can activate the ERK MAPK independent of the corresponding MAP3K ( Raf ) XREF_BIBR .	For example, it is observed that the kinase Cot can activate the ERK MAPK independent of the corresponding MAP3K (Raf) XREF_BIBR.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cot	Cot	Cot	ERK MAPK	ERK MAPK	ERK MAPK	9	10	13	15
For example , the induction of MCP-1 expression by LPS in macrophages is dependent on Tpl2 and ERK signalling , as has previously been shown using both Tpl2 deficient macrophages and small molecule inhibitors targeting ERK1/2 XREF_BIBR .	For example, the induction of MCP-1 expression by LPS in macrophages is dependent on Tpl2 and ERK signalling, as has previously been shown using both Tpl2 deficient macrophages and small molecule inhibitors targeting ERK1/2 XREF_BIBR.	27	36	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK1/2	ERK1/2	ERK1/2	27	28	35	36
Another mechanism leading to resistance was by overexpression of mitogen activated protein kinase 8 ( MAP3K8 ) , which encodes the protein kinase COT that activates ERK through phosphorylation in a RAF independent manner , leading to resistance to RAF inhibition [ XREF_BIBR ] .	Another mechanism leading to resistance was by overexpression of mitogen activated protein kinase 8 (MAP3K8), which encodes the protein kinase COT that activates ERK through phosphorylation in a RAF independent manner, leading to resistance to RAF inhibition [XREF_BIBR].	19	27	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	COT	COT	COT	ERK	ERK	ERK	23	24	26	27
Studies have consistently shown that Tpl2 and Cot mediated ERK activation is essential for LPS induced TNFalpha production in macrophages involving post-transcriptional regulation of TNFalpha mRNA translocation and/or processing of pre-TNFalpha to its processed mature form .	Studies have consistently shown that Tpl2 and Cot mediated ERK activation is essential for LPS induced TNFalpha production in macrophages involving post-transcriptional regulation of TNFalpha mRNA translocation and/or processing of pre-TNFalpha to its processed mature form.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cot	Cot	Cot	ERK	ERK	ERK	7	8	9	10
In addition , we demonstrate that hKSR-2 co-immunoprecipitates with Cot and that co-expression of hKSR-2 with Cot significantly reduces Cot mediated MAPK and NF-kappaB activation .	In addition, we demonstrate that hKSR-2 co-immunoprecipitates with Cot and that co-expression of hKSR-2 with Cot significantly reduces Cot mediated MAPK and NF-kappaB activation.	18	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Cot	Cot	Cot	MAPK	MAPK	MAPK	19	20	21	22
Map3K8 is an upsteam activator of ERK , which is inducible by IL-12 and T cell receptor dependent signals .	Map3K8 is an upsteam activator of ERK, which is inducible by IL-12 and T cell receptor dependent signals.	0	10	is an upsteam activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Map3K8	Map3K8	Map3K8	ERK	ERK	ERK	0	1	6	7
It is clear that an inhibition of Tpl2 most effectively suppresses the activation of ERK in agreement with Tpl2-depdenent activation of ERK in other systems .	It is clear that an inhibition of Tpl2 most effectively suppresses the activation of ERK in agreement with Tpl2-depdenent activation of ERK in other systems.	5	16	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK	ERK	ERK	7	8	14	15
COT was demonstrated to induce ERK via MEK but independent of Raf [ XREF_BIBR ] .	COT was demonstrated to induce ERK via MEK but independent of Raf [XREF_BIBR].	0	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT	COT	ERK	ERK	ERK	0	1	5	6
IkappaB kinase ( IKK ) complex phosphorylation of the TPL-2 C terminus regulates full-length TPL-2 activation of ERK-1/2 by a mechanism that has remained obscure .	IkappaB kinase (IKK) complex phosphorylation of the TPL-2 C terminus regulates full-length TPL-2 activation of ERK-1/2 by a mechanism that has remained obscure.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	ERK-1/2	ERK-1/2	ERK-1/2	14	15	17	18
It has been proposed that ERK is activated by an upstream kinase Tpl2 [ XREF_BIBR ] via a pathway mediated by a NF-kappaB member p105 , in which IKK and NEMO participates in the phosphorylation and degradation of the inhibitor p105 to release active Tpl2 [ XREF_BIBR ] .	It has been proposed that ERK is activated by an upstream kinase Tpl2 [XREF_BIBR] via a pathway mediated by a NF-kappaB member p105, in which IKK and NEMO participates in the phosphorylation and degradation of the inhibitor p105 to release active Tpl2 [XREF_BIBR].	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK	ERK	ERK	12	13	5	6
Cot and tpl2 has emerged as an interesting new anti-inflammatory target by its capacity to activate Erk1/2 , without involving the RAF proteins , during the innate immune response .	Cot and tpl2 has emerged as an interesting new anti-inflammatory target by its capacity to activate Erk1/2, without involving the RAF proteins, during the innate immune response.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tpl2	tpl2	tpl2	Erk1/2	Erk1/2	Erk1/2	2	3	16	17
p38gamma and p38delta were necessary to maintain steady-state levels of tumor progression locus 2 ( TPL2 ) , the MKK kinase that mediates ERK1/2 activation after TLR4 stimulation .	p38gamma and p38delta were necessary to maintain steady-state levels of tumor progression locus 2 (TPL2), the MKK kinase that mediates ERK1/2 activation after TLR4 stimulation.	10	24	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	tumor progression locus 2	tumor progression locus 2	tumor progression locus 2	ERK1/2	ERK1/2	ERK1/2	10	14	23	24
Additionally , overexpression of CRAF or the COT can also lead to MAPK reactivation .	Additionally, overexpression of CRAF or the COT can also lead to MAPK reactivation.	2	13	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	COT	overexpression of CRAF or the COT	cot	MAPK	MAPK	mapk	7	8	12	13
In this connection , it is interesting to note that our , and the previously reported findings of others , coincide with regard to the MEK and ERK module , which is apparently activated by Cot1 and Tpl2 pathway in both scenarios , as siCot1 results in a decrease in phosphorylation of MEK and ERK ( XREF_FIG ) .	In this connection, it is interesting to note that our, and the previously reported findings of others, coincide with regard to the MEK and ERK module, which is apparently activated by Cot1 and Tpl2 pathway in both scenarios, as siCot1 results in a decrease in phosphorylation of MEK and ERK (XREF_FIG).	25	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK	ERK	ERK	37	38	27	28
Several pharmaceutical companies have carried out screens using the isolated TPL-2 kinase domain and MKK1 substrate to identify inhibitors that block TPL-2 activation of ERK1/2 in cultured macrophages [ XREF_BIBR , XREF_BIBR ] .	Several pharmaceutical companies have carried out screens using the isolated TPL-2 kinase domain and MKK1 substrate to identify inhibitors that block TPL-2 activation of ERK1/2 in cultured macrophages [XREF_BIBR, XREF_BIBR].	21	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	ERK1/2	ERK1/2	ERK1/2	21	22	24	25
In response to TLRs , the ERK1/2 - MKK1/2 cascade is activated by the upstream kinase Tpl2 .	In response to TLRs, the ERK1/2 - MKK1/2 cascade is activated by the upstream kinase Tpl2.	5	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK1/2	ERK1/2	ERK1/2	16	17	6	7
These findings confirm that MAP3K8 is able to reactivate MAPK signaling despite BRAF inhibition and that targeting RAF and MEK in combination may be an effective anti-melanoma treatment strategy .	These findings confirm that MAP3K8 is able to reactivate MAPK signaling despite BRAF inhibition and that targeting RAF and MEK in combination may be an effective anti-melanoma treatment strategy.	4	10	reactivate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K8	MAP3K8	MAP3K8	MAPK	MAPK	MAPK	4	5	9	10
These data suggest that Tpl-2 activates the MAPK cascade , perhaps through its participation in the assembly of Ras and Raf-1-containing multimolecular complexes .	These data suggest that Tpl-2 activates the MAPK cascade, perhaps through its participation in the assembly of Ras and Raf-1-containing multimolecular complexes.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl-2	Tpl-2	Tpl-2	MAPK	MAPK	MAPK	4	5	7	8
Tpl2 is selectively involved in inflammatory cytokine induced ERK1/2 activation in adipocytes and is implicated in their deleterious effects on adipocyte functions .	Tpl2 is selectively involved in inflammatory cytokine induced ERK1/2 activation in adipocytes and is implicated in their deleterious effects on adipocyte functions.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK1/2	ERK1/2	ERK1/2	0	1	8	9
Indeed , recombinant COT induced pThr202 and Tyr204 phosphorylation of ERK1 in vitro ( XREF_SUPPLEMENTARY ) suggesting that in certain contexts , COT expression may potentiate ERK activation in a MEK independent manner .	Indeed, recombinant COT induced pThr202 and Tyr204 phosphorylation of ERK1 in vitro (XREF_SUPPLEMENTARY) suggesting that in certain contexts, COT expression may potentiate ERK activation in a MEK independent manner.	22	27	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT expression	cot	ERK	ERK	erk	22	23	26	27
12 In addition , compounds were tested in RPMI-7951 cells , which also contain mutated B-Raf and are resistant to B-Raf inhibitors due to the overexpression of MAP3K8 ( the gene encoding COT and Tpl2 ) that provides an alternative mechanism to indirectly or directly activate ERK proteins .	12 In addition, compounds were tested in RPMI-7951 cells, which also contain mutated B-Raf and are resistant to B-Raf inhibitors due to the overexpression of MAP3K8 (the gene encoding COT and Tpl2) that provides an alternative mechanism to indirectly or directly activate ERK proteins.	25	47	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K8	overexpression of MAP3K8	map3k8	ERK	ERK	erk	27	28	46	47
It was also shown that COT activated ERK through both MEK dependent and independent mechanisms [ XREF_BIBR ] .	It was also shown that COT activated ERK through both MEK dependent and independent mechanisms [XREF_BIBR].	5	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT	COT	ERK	ERK	ERK	5	6	7	8
Experimentally , over-expression of the Cot protein has been shown to potently stimulate the activity of the c-jun promoter utilizing JNK dependent and also two members of the MAPK family , p38gamma ( ERK6 ) and ERK5 .	Experimentally, over-expression of the Cot protein has been shown to potently stimulate the activity of the c-jun promoter utilizing JNK dependent and also two members of the MAPK family, p38gamma (ERK6) and ERK5.	2	33	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cot	over-expression of the Cot	cot	MAPK	MAPK	mapk	5	6	28	29
In fact , we could postulate that COT activates ERK primarily through MEK dependent mechanisms , resulting in increased ERK dependent transcriptional output without RAF signaling .	In fact, we could postulate that COT activates ERK primarily through MEK dependent mechanisms, resulting in increased ERK dependent transcriptional output without RAF signaling.	7	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT	COT	ERK	ERK	ERK	7	8	9	10
COT can activate ERK both via MEK and independently of MEK , and increased COT levels have been identified as a driver of resistance to BRAFi [ XREF_BIBR ] .	COT can activate ERK both via MEK and independently of MEK, and increased COT levels have been identified as a driver of resistance to BRAFi [XREF_BIBR].	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT	COT	ERK	ERK	ERK	0	1	3	4
TPL-2 also mediates ERK1/2 activation by tumour necrosis factor ( TNF ) receptor 1 ( TNF-R1 ) and interleukin-1 receptor , emphasizing the important role of TPL-2 in innate immune responses [ XREF_BIBR ] .	TPL-2 also mediates ERK1/2 activation by tumour necrosis factor (TNF) receptor 1 (TNF-R1) and interleukin-1 receptor, emphasizing the important role of TPL-2 in innate immune responses [XREF_BIBR].	0	4	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	ERK1/2	ERK1/2	ERK1/2	0	1	3	4
MEK and ERK can also be activated independently of Raf by the COT and TPL2 kinase and by mos during meiotic maturation .	MEK and ERK can also be activated independently of Raf by the COT and TPL2 kinase and by mos during meiotic maturation.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	COT	COT	COT	ERK	ERK	ERK	12	13	2	3
We demonstrate that Tpl2 is expressed in INS-1E beta-cells , mouse and human islets , is activated and upregulated by cytokines and mediates ERK1/2 , JNK and p38 activation .	We demonstrate that Tpl2 is expressed in INS-1E beta-cells, mouse and human islets, is activated and upregulated by cytokines and mediates ERK1/2, JNK and p38 activation.	3	28	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2 is expressed	tpl2	ERK1/2	ERK1/2	erk1/2	3	4	23	24
XREF_BIBR Both CRAF and Cot 1 bypass BRAF signaling , activating the MAPK pathway .	XREF_BIBR Both CRAF and Cot 1 bypass BRAF signaling, activating the MAPK pathway.	4	13	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cot	Cot	Cot	MAPK	MAPK	MAPK	4	5	12	13
Tpl2 was reported to activate ERK1/2 through phosphorylation of MEK3/6 [ XREF_BIBR ] .	Tpl2 was reported to activate ERK1/2 through phosphorylation of MEK3/6 [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK1/2	ERK1/2	ERK1/2	0	1	5	6
Alternatively , degradation of DOK3 may indirectly intersect the Tpl2 mediated ERK activation signaling pathway , as LPS stimulation induced more rapid degradation of IkappaBalpha in DOK3 deficient BMM compared to wild type , which can cause more NF-kappaB1 p105 degradation and the release of Tpl2 from the ABIN-2-NF , kappaB1 , and Tpl2 complex XREF_BIBR , XREF_BIBR .	Alternatively, degradation of DOK3 may indirectly intersect the Tpl2 mediated ERK activation signaling pathway, as LPS stimulation induced more rapid degradation of IkappaBalpha in DOK3 deficient BMM compared to wild type, which can cause more NF-kappaB1 p105 degradation and the release of Tpl2 from the ABIN-2-NF, kappaB1, and Tpl2 complex XREF_BIBR, XREF_BIBR.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK	ERK	ERK	9	10	11	12
The MAPK pathways MEK and ERK , JNK and p38MAPK as well as the NF-kappaB p65 pathway can be directly activated by MAP3K8 .	The MAPK pathways MEK and ERK, JNK and p38MAPK as well as the NF-kappaB p65 pathway can be directly activated by MAP3K8.	3	23	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAP3K8	MAP3K8	MAP3K8	ERK	ERK	ERK	22	23	5	6
XREF_BIBR - XREF_BIBR , XREF_BIBR TPL2 mediated activation of additional MAPK or NFkappaB pathways can depend on the cell type , stimulus and species .	XREF_BIBR - XREF_BIBR, XREF_BIBR TPL2 mediated activation of additional MAPK or NFkappaB pathways can depend on the cell type, stimulus and species.	5	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TPL2	TPL2	TPL2	MAPK	MAPK	MAPK	5	6	10	11
14 In both situations , however , Thr290 phosphorylation was required for TPL2 mediated ERK activation .	14 In both situations, however, Thr290 phosphorylation was required for TPL2 mediated ERK activation.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TPL2	TPL2	TPL2	ERK	ERK	ERK	12	13	14	15
The authors showed that loss of Tpl2 specifically blocks the activation of Erk among MAP kinases and NF-kappaB and that inhibition of MEK , and thereby inhibition of Erk , suppressed TNF-alpha production upon LPS signaling .	The authors showed that loss of Tpl2 specifically blocks the activation of Erk among MAP kinases and NF-kappaB and that inhibition of MEK, and thereby inhibition of Erk, suppressed TNF-alpha production upon LPS signaling.	4	13	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tpl2	loss of Tpl2	tpl2	Erk	Erk	erk	6	7	12	13
In addition IKKbeta also phosphorylates p105 , and this is required for the activation of Tpl2 , which is then able to activate the ERK1/2 pathway .	In addition IKKbeta also phosphorylates p105, and this is required for the activation of Tpl2, which is then able to activate the ERK1/2 pathway.	13	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	ERK1/2	ERK1/2	ERK1/2	15	16	24	25
Since the activation of NFAT is MAPK dependent these findings suggested that the activation of MAPK by Tpl-2 is either independent or only partially dependent on MEK1 and MEK2 .	Since the activation of NFAT is MAPK dependent these findings suggested that the activation of MAPK by Tpl-2 is either independent or only partially dependent on MEK1 and MEK2.	13	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tpl-2	Tpl-2	Tpl-2	MAPK	MAPK	MAPK	17	18	15	16
Functionally , TPL2 activation induces ERK , JNK , and NF-kappaB signaling pathways in both stimulus- and cell type specific manners XREF_BIBR , XREF_BIBR .	Functionally, TPL2 activation induces ERK, JNK, and NF-kappaB signaling pathways in both stimulus- and cell type specific manners XREF_BIBR, XREF_BIBR.	2	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL2	TPL2	TPL2	ERK	ERK	ERK	2	3	5	6
K63 linked polyubiquitination thereby results in binding and activation of TAK1 , which then activates IKK2 .	K63 linked polyubiquitination thereby results in binding and activation of TAK1, which then activates IKK2.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKK2	IKK2	IKK2	10	11	15	16
Given that TAK1 activates IKKbeta via phosphorylation of S177 in the activation loop of IKKbeta , phosphorylation of IKKbeta at S177 by PKCepsilon might activate IKKbeta , thereby inducing PKM2 expression .	Given that TAK1 activates IKKbeta via phosphorylation of S177 in the activation loop of IKKbeta, phosphorylation of IKKbeta at S177 by PKCepsilon might activate IKKbeta, thereby inducing PKM2 expression.	2	6	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	2	3	4	5
SmPellino inhibited signalling induced by the upstream proteins MyD88 , IRAK-1 , TRAF-6 and TAK-1 and TAB-1 , but not IKKbeta , which is downstream of Pellino proteins .	SmPellino inhibited signalling induced by the upstream proteins MyD88, IRAK-1, TRAF-6 and TAK-1 and TAB-1, but not IKKbeta, which is downstream of Pellino proteins.	1	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAK-1	TAK-1	TAK-1	IKKbeta	IKKbeta	IKKbeta	14	15	20	21
The conjugation of Ub to RIPK1 and components of complex-I promotes TAK1 mediated activation of IKK2 , JNK , ERK , and p38alpha .	The conjugation of Ub to RIPK1 and components of complex-I promotes TAK1 mediated activation of IKK2, JNK, ERK, and p38alpha.	11	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKK2	IKK2	IKK2	11	12	15	16
TAK1 promotes downstream activation of the IkappaB kinases ( IKK ) : IKKalpha and IKKbeta .	TAK1 promotes downstream activation of the IkappaB kinases (IKK) : IKKalpha and IKKbeta.	0	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	0	1	14	15
Although TAK1 has more frequently been associated with the canonical NF-kappaB pathway rather than the NIK- dependent non canonical pathway we identified , there is ample precedent that TAK1 can activate NIK , and that TAK1 and TRAF6-ubiquitin conjugates activate IKKalpha as well as IKKbeta .	Although TAK1 has more frequently been associated with the canonical NF-kappaB pathway rather than the NIK- dependent non canonical pathway we identified, there is ample precedent that TAK1 can activate NIK, and that TAK1 and TRAF6-ubiquitin conjugates activate IKKalpha as well as IKKbeta.	35	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	35	36	44	45
TAB1 induced TAK1 activation promoted the dissociation of active forms of IKKalpha and IKKbeta from active TAK1 , whereas the IKK mutants remained to interact with active TAK1 .	TAB1 induced TAK1 activation promoted the dissociation of active forms of IKKalpha and IKKbeta from active TAK1, whereas the IKK mutants remained to interact with active TAK1.	0	14	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAB1 induced TAK1	tak1	IKKbeta	IKKbeta	ikkbeta	2	3	13	14
Pandey et al found that b utein suppressed the NF-kappaB activation induced by various inflammatory agents and carcinogens ; and inhibited the NF-kappaB reporter activity induced by TNFR1 , TRADD , TRAF2 , NIK , TAK1 and TAB1 , and IKK-beta .	Pandey et al found that b utein suppressed the NF-kappaB activation induced by various inflammatory agents and carcinogens; and inhibited the NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, TAK1 and TAB1, and IKK-beta.	20	41	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKK-beta	IKK-beta	IKK-beta	35	36	40	41
TAK1 activation stimulates both the IKKbeta and NFkappaB and JNK and AP1 pathways , and the TLR and TNF-alpha signaling pathways converge at this step .	TAK1 activation stimulates both the IKKbeta and NFkappaB and JNK and AP1 pathways, and the TLR and TNF-alpha signaling pathways converge at this step.	0	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	0	1	5	6
TAK1 then activates the IkappaB kinase ( IKK ) complex , which consists of two catalytic subunits , IKKalpha and IKKbeta , and regulatory subunit NF-kappaB essential modulator ( NEMO , also known as IKKgamma ) .	TAK1 then activates the IkappaB kinase (IKK) complex, which consists of two catalytic subunits, IKKalpha and IKKbeta, and regulatory subunit NF-kappaB essential modulator (NEMO, also known as IKKgamma).	0	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	0	1	20	21
Consequently , TAK1 activates the p38alpha and JNK MAP kinase pathways , as well as the canonical IKKs , IKKalpha and IKKbeta .	Consequently, TAK1 activates the p38alpha and JNK MAP kinase pathways, as well as the canonical IKKs, IKKalpha and IKKbeta.	2	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	2	3	21	22
LUBAC mediated linear ubiquitylation of different components of this complex appears to stabilize or reinforce complex-I formation and promote TAK1 dependent activation of IKK2 .	LUBAC mediated linear ubiquitylation of different components of this complex appears to stabilize or reinforce complex-I formation and promote TAK1 dependent activation of IKK2.	19	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKK2	IKK2	IKK2	19	20	23	24
TAK1 activated IKKalpha and IKKbeta in the presence of TAB1 .	TAK1 activated IKKalpha and IKKbeta in the presence of TAB1.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	0	1	4	5
It is unclear if PP1 is activated by gp120 , or if PP1 activity is required for Tak1 activation of IKK-2 .	It is unclear if PP1 is activated by gp120, or if PP1 activity is required for Tak1 activation of IKK-2.	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tak1	Tak1	Tak1	IKK-2	IKK-2	IKK-2	17	18	20	21
Butein inhibited TNF induced NF-kappaB activation in a dose- and time dependent manner , suppressed the NF-kappaB activation induced by various carcinogens and inflammatory agents , and inhibited the NF-kappaB reporter activity induced by TNFR1 , TRADD , TRAF2 , NIK , TAK1 and TAB1 , and IKK-beta .	Butein inhibited TNF induced NF-kappaB activation in a dose- and time dependent manner, suppressed the NF-kappaB activation induced by various carcinogens and inflammatory agents, and inhibited the NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, TAK1 and TAB1, and IKK-beta.	27	48	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKK-beta	IKK-beta	IKK-beta	42	43	47	48
TAK1 phosphorylates and activate IKKbeta , resulting in phosphorylation and degradation of IkappaBalpha , and activation of NF-kappaB activation [ XREF_BIBR , XREF_BIBR ] .	TAK1 phosphorylates and activate IKKbeta, resulting in phosphorylation and degradation of IkappaBalpha, and activation of NF-kappaB activation [XREF_BIBR, XREF_BIBR].	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	0	1	4	5
Binding of NEMO to stimulus induced polyubiquitin chains brings IKKs in close proximity to each other ( allowing for trans-autophosphorylation ) and to the IKK-kinase TAK1 , which then activates IKK2 through phosphorylation of its activation loop serines .	Binding of NEMO to stimulus induced polyubiquitin chains brings IKKs in close proximity to each other (allowing for trans-autophosphorylation) and to the IKK-kinase TAK1, which then activates IKK2 through phosphorylation of its activation loop serines.	12	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKK2	IKK2	IKK2	25	26	30	31
Inhibition of TAK1 by 5Z-7 also blocked the activation of IKKbeta occurring downstream of TAK1 in response to TNFalpha stimulation as expected .	Inhibition of TAK1 by 5Z-7 also blocked the activation of IKKbeta occurring downstream of TAK1 in response to TNFalpha stimulation as expected.	0	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	2	3	10	11
The activated TAK1 then triggers the activation of the IKKbeta , which leads to activation of transcription factors NF-kappaB and up-regulation of many genes encoding proinflammatory cytokines , chemokines , adhesion molecules , and proteolytic enzymes .	The activated TAK1 then triggers the activation of the IKKbeta, which leads to activation of transcription factors NF-kappaB and up-regulation of many genes encoding proinflammatory cytokines, chemokines, adhesion molecules, and proteolytic enzymes.	0	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	2	3	9	10
This leads to the recruitment of the TAB1 , TAB2 , and TAK1 complex and subsequent activation of TAK1 , which in turn activates IKKbeta by phosphorylation [ XREF_BIBR , XREF_BIBR ] .	This leads to the recruitment of the TAB1, TAB2, and TAK1 complex and subsequent activation of TAK1, which in turn activates IKKbeta by phosphorylation [XREF_BIBR, XREF_BIBR].	16	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	18	19	24	25
After assembly of the signaling components to these polyubiquitin chains , TAK1 activates IKKbeta , resulting in the phosphorylation of the IkappaB proteins .	After assembly of the signaling components to these polyubiquitin chains, TAK1 activates IKKbeta, resulting in the phosphorylation of the IkappaB proteins.	11	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	11	12	13	14
TAK1 induces activation of IKKbeta leading to phosphorylation and subsequent activation of IKKbeta , which phosphorylates IkappaB .	TAK1 induces activation of IKKbeta leading to phosphorylation and subsequent activation of IKKbeta, which phosphorylates IkappaB.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	0	1	4	5
The polyubiquitinated RIP1 triggers activation of TAK1 , which in turn activates IKKalpha and IKKbeta .	The polyubiquitinated RIP1 triggers activation of TAK1, which in turn activates IKKalpha and IKKbeta.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	6	7	14	15
As examined by DNA binding , we found that butein suppressed tumor necrosis factor ( TNF )-induced NF-kappaB activation in a dose- and time dependent manner ; suppressed the NF-kappaB activation induced by various inflammatory agents and carcinogens ; and inhibited the NF-kappaB reporter activity induced by TNFR1 , TRADD , TRAF2 , NIK , TAK1 and TAB1 , and IKK-beta .	As examined by DNA binding, we found that butein suppressed tumor necrosis factor (TNF)-induced NF-kappaB activation in a dose- and time dependent manner; suppressed the NF-kappaB activation induced by various inflammatory agents and carcinogens; and inhibited the NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, TAK1 and TAB1, and IKK-beta.	40	61	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKK-beta	IKK-beta	IKK-beta	55	56	60	61
If this were the case , active TAK1 would be unable to activate IKKbeta because NEMO is required to recruit polyubiquitin chain scaffolds to mediate TAK1 dependent IKK activation [ XREF_BIBR ] .	If this were the case, active TAK1 would be unable to activate IKKbeta because NEMO is required to recruit polyubiquitin chain scaffolds to mediate TAK1 dependent IKK activation [XREF_BIBR].	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	7	8	13	14
Consequently , TAK1 is pivotal to induce the c-Kit-mediated activation of IKK2 , STAT3/5 in primary- and tumor-mast cells .	Consequently, TAK1 is pivotal to induce the c-Kit-mediated activation of IKK2, STAT3/5 in primary- and tumor-mast cells.	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKK2	IKK2	IKK2	2	3	11	12
It has been shown that purified TAK1 together with TAB1 and TAB2 is sufficient to phosphorylate and thus activate IKKbeta in a test tube .	It has been shown that purified TAK1 together with TAB1 and TAB2 is sufficient to phosphorylate and thus activate IKKbeta in a test tube.	5	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	6	7	19	20
Following activation , TAK1 activates the downstream MAPKs ( JNK , p38 and ERK ) and IKKbeta by phosphorylation .	Following activation, TAK1 activates the downstream MAPKs (JNK, p38 and ERK) and IKKbeta by phosphorylation.	3	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	3	4	16	17
Polyubiquitinated RIP2 then recruits the TAK1 kinase complex via TAB2/3 mediated interaction , leading to IKKbeta activation by TAK1 catalysed phosphorylation .	Polyubiquitinated RIP2 then recruits the TAK1 kinase complex via TAB2/3 mediated interaction, leading to IKKbeta activation by TAK1 catalysed phosphorylation.	13	21	leading	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TAK1	TAK1 catalysed phosphorylation	tak1	IKKbeta	IKKbeta	ikkbeta	18	19	15	16
TAK1 activates the IKK kinase complex ( IKKbeta and IKKalpha ) leading to NF-kappaB transcription factor activation .	TAK1 activates the IKK kinase complex (IKKbeta and IKKalpha) leading to NF-kappaB transcription factor activation.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	0	1	7	8
One recent study reported that K63 linked chains are good substrate for M1 linked poly-ubiquitylation [ XREF_BIBR ] , suggesting a model in which hybrid K63/M1 linked poly-ubiquitin chains on RIPK1 allow close proximity between the TAB2/3-TAK 1 and NEMO-IKKalpha-IKKbeta complexes , and thereby facilitate TAK1 catalyzed activation of IKKalpha and IKKbeta ( XREF_FIG ) .	One recent study reported that K63 linked chains are good substrate for M1 linked poly-ubiquitylation [XREF_BIBR], suggesting a model in which hybrid K63/M1 linked poly-ubiquitin chains on RIPK1 allow close proximity between the TAB2/3-TAK 1 and NEMO-IKKalpha-IKKbeta complexes, and thereby facilitate TAK1 catalyzed activation of IKKalpha and IKKbeta (XREF_FIG).	45	52	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	45	46	51	52
TAK1 activates IKK2 by phosphorylation of two serine residues in the activation loop [ XREF_BIBR ] .	TAK1 activates IKK2 by phosphorylation of two serine residues in the activation loop [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKK2	IKK2	IKK2	0	1	2	3
However , IKKbeta is also induced by a TAK1 independent mechanism XREF_BIBR , XREF_BIBR .	However, IKKbeta is also induced by a TAK1 independent mechanism XREF_BIBR, XREF_BIBR.	2	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	8	9	2	3
Tak1 in turn activates a complex of IKKbeta , IKKalpha and NEMO .	Tak1 in turn activates a complex of IKKbeta, IKKalpha and NEMO.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tak1	Tak1	Tak1	IKKbeta	IKKbeta	IKKbeta	0	1	7	8
In addition , TAK1 significantly enhanced the JNK1/2 and IKKbeta activations ( XREF_FIG ) .	In addition, TAK1 significantly enhanced the JNK1/2 and IKKbeta activations (XREF_FIG).	3	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	3	4	9	10
We show that TAK1 physically interacts with NIK and with IKK2 , and both XIAP or active TAK1 can stimulate IKK2 kinase activity .	We show that TAK1 physically interacts with NIK and with IKK2, and both XIAP or active TAK1 can stimulate IKK2 kinase activity.	14	22	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKK2	IKK2	IKK2	17	18	20	21
Since Tak1 is known to activate IKK-2 , and PP1 has been found to interact with the IKK complex to positively regulate IKK-2 activation , the activation of IKK-2 by gp120 was tested .	Since Tak1 is known to activate IKK-2, and PP1 has been found to interact with the IKK complex to positively regulate IKK-2 activation, the activation of IKK-2 by gp120 was tested.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tak1	Tak1	Tak1	IKK-2	IKK-2	IKK-2	1	2	6	7
TAK1 interacts via TAB2 with TRAF6 to activate JNK and IKKbeta and NF-kappaB signaling ( see Introduction ) .	TAK1 interacts via TAB2 with TRAF6 to activate JNK and IKKbeta and NF-kappaB signaling (see Introduction).	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	0	1	10	11
In this study , we observed that RASSF1A increased ASK1 mRNA and protein level but inhibited phosphorylation of ASK1 ( inactivation of ASK1 ) .	In this study, we observed that RASSF1A increased ASK1 mRNA and protein level but inhibited phosphorylation of ASK1 (inactivation of ASK1).	7	23	inactivation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	ASK1	RASSF1A increased ASK1 mRNA and protein level but inhibited phosphorylation of ASK1	ask1	ASK1	ASK1	ask1	18	19	22	23
However , Akt mediated phosphorylation of ASK1 at Thr 838 activates ASK1 and causes the subsequent downstream activation of p38 MAPK , leading to apoptosis [ XREF_BIBR ] .	However, Akt mediated phosphorylation of ASK1 at Thr 838 activates ASK1 and causes the subsequent downstream activation of p38 MAPK, leading to apoptosis [XREF_BIBR].	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	Akt mediated phosphorylation of ASK1 at Thr 838	ask1	ASK1	ASK1	ask1	6	7	11	12
Data showed that G alpha13Q226L reduced the rate of ASK1 degradation , decreased ASK1 ubiquitination , and reduced association of ASK1 with an E3 ubiquitin ligase CHIP , previously shown to mediate ASK1 degradation .	Data showed that G alpha13Q226L reduced the rate of ASK1 degradation, decreased ASK1 ubiquitination, and reduced association of ASK1 with an E3 ubiquitin ligase CHIP, previously shown to mediate ASK1 degradation.	3	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	G alpha13Q226L reduced the rate of ASK1 degradation, decreased ASK1 ubiquitination	ask1	ASK1	ASK1	ask1	13	14	20	21
Antioxidants EUK8 and N-acetyl cystenine significantly decreased apoptosis by inhibiting the ASK1 dephosphorylation at Ser ( 967 ) and subsequently increased the interaction of ASK1 with thioredoxin or 14-3-3 proteins .	Antioxidants EUK8 and N-acetyl cystenine significantly decreased apoptosis by inhibiting the ASK1 dephosphorylation at Ser (967) and subsequently increased the interaction of ASK1 with thioredoxin or 14-3-3 proteins.	1	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	EUK8 and N-acetyl cystenine significantly decreased apoptosis by inhibiting the ASK1 dephosphorylation at Ser	ask1	ASK1	ASK1	ask1	11	12	24	25
These results suggest that dephosphorylation of ASK1 at Ser 966 in wounded cells promotes dissociation of ASK1 from the FAK , CXCR4 , and PP5 complex .	These results suggest that dephosphorylation of ASK1 at Ser 966 in wounded cells promotes dissociation of ASK1 from the FAK, CXCR4, and PP5 complex.	4	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	dephosphorylation of ASK1 at Ser 966	ask1	ASK1	ASK1	ask1	6	7	16	17
When the Map3k5 -/- RAW264.7 cells were rescued by overexpression of ASK1 , K13-ASK1 or ASK1-K716A ( Lys716 mutated into Ala , kinase activity inactive ) , we found that ASK1 , but not K13-ASK1 or ASK1-K716A , could rescue the impaired IL-6 and IFNbeta production and the inhibited antiviral response ( XREF_FIG ) .	When the Map3k5 -/- RAW264.7 cells were rescued by overexpression of ASK1, K13-ASK1 or ASK1-K716A (Lys716 mutated into Ala, kinase activity inactive), we found that ASK1, but not K13-ASK1 or ASK1-K716A, could rescue the impaired IL-6 and IFNbeta production and the inhibited antiviral response (XREF_FIG).	2	15	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ASK1	overexpression of ASK1	ask1	Map3k5	Map3k5	map3k5	11	12	2	3
ROS activate upstream kinases such as glycogen synthase kinase 3 beta ( GSK3beta ) , RIPK1 , Protein kinase C alpha ( PKCalpha ) , higher order mitogen activated protein kinases ( MAPKs ) such as Mixed-lineage kinase 3 ( MLK3 ) , apoptosis signal regulating kinase 1 ( ASK1 ) and mitogen activated protein kinase kinase 4 ( MKK4 ) , ultimately leading to JNK activation .	ROS activate upstream kinases such as glycogen synthase kinase 3 beta (GSK3beta), RIPK1, Protein kinase C alpha (PKCalpha), higher order mitogen activated protein kinases (MAPKs) such as Mixed-lineage kinase 3 (MLK3), apoptosis signal regulating kinase 1 (ASK1) and mitogen activated protein kinase kinase 4 (MKK4), ultimately leading to JNK activation.	27	50	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	apoptosis signal regulating kinase 1	apoptosis signal regulating kinase 1	apoptosis signal regulating kinase 1	49	50	43	48
Assessments of p38 activity in our model conflicted with previously published data in which SLK phosphorylation of ASK1 was postulated to activate ASK1 , resulting in subsequent activation of p38 .	Assessments of p38 activity in our model conflicted with previously published data in which SLK phosphorylation of ASK1 was postulated to activate ASK1, resulting in subsequent activation of p38.	14	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	SLK phosphorylation of ASK1	ask1	ASK1	ASK1	ask1	17	18	22	23
In our observation , 5 '-AMP attenuated the methylation of ASK1 and enhanced the ubiquitination of ASK1 , which accelerate ASK1 degradation , leading to an inhibition of MAPKs cascade .	In our observation, 5 '-AMP attenuated the methylation of ASK1 and enhanced the ubiquitination of ASK1, which accelerate ASK1 degradation, leading to an inhibition of MAPKs cascade.	4	19	enhanced	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ASK1	5 '-AMP attenuated the methylation of ASK1	ask1	ASK1	ubiquitination of ASK1	ask1	10	11	16	17
The present results show that casticin treatment induced ASK1 phosphorylation , which increased ASK1 activity .	The present results show that casticin treatment induced ASK1 phosphorylation, which increased ASK1 activity.	5	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	casticin treatment induced ASK1 phosphorylation	ask1	ASK1	ASK1	ask1	8	9	13	14
MELK , as an upstream kinase of ASK1 , phosphorylates threonine 838 in an activation loop of human ASK1 , thereby stimulating ASK1 kinase activity .	MELK, as an upstream kinase of ASK1, phosphorylates threonine 838 in an activation loop of human ASK1, thereby stimulating ASK1 kinase activity.	9	24	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	phosphorylates threonine 838 in an activation loop of human ASK1	ask1	ASK1	ASK1	ask1	18	19	22	23
This was triggered by attenuating apoptosis signal regulated kinase 1 ( ASK1 ) methylation and increasing ubiquitination mediated ASK1 protein degradation .	This was triggered by attenuating apoptosis signal regulated kinase 1 (ASK1) methylation and increasing ubiquitination mediated ASK1 protein degradation.	11	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	ASK1) methylation and increasing ubiquitination	ask1	ASK1	ASK1	ask1	11	12	18	19
3.3 TAK1 K72R mutation abolishes Lys 48 -linked TAK1 polyubiquitination and enhances persistent TAK1 activation .	3.3 TAK1 K72R mutation abolishes Lys 48 -linked TAK1 polyubiquitination and enhances persistent TAK1 activation.	1	10	abolishes	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	TAK1	TAK1	tak1	TAK1	TAK1 polyubiquitination	tak1	1	2	8	9
Overexpression of TAK1 and TAB1 produces an active form of TAK1 and we found that it induced a slower migrating additional RIPK3 band ( XREF_FIG ) .	Overexpression of TAK1 and TAB1 produces an active form of TAK1 and we found that it induced a slower migrating additional RIPK3 band (XREF_FIG).	0	11	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	Overexpression of TAK1	tak1	TAK1	TAK1	tak1	2	3	10	11
Co-expression of TAK1 together with TAK1 binding protein 1 ( TAB1 ) highly activates TAK1 .	Co-expression of TAK1 together with TAK1 binding protein 1 (TAB1) highly activates TAK1.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	Co-expression of TAK1	tak1	TAK1	TAK1	tak1	2	3	14	15
TAB1 induces TAK1 autophosphorylation and thereby catalytically activates TAK1 kinase activity in vitro .	TAB1 induces TAK1 autophosphorylation and thereby catalytically activates TAK1 kinase activity in vitro.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAB1 induces TAK1 autophosphorylation	tak1	TAK1	TAK1	tak1	2	3	8	9
The orthotopic xenograft studies in SCID mice showed that suppression of TAK1 signaling by dn-TAK1 reduces tumor growth and formation of lung metastases .	The orthotopic xenograft studies in SCID mice showed that suppression of TAK1 signaling by dn-TAK1 reduces tumor growth and formation of lung metastases.	11	15	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	dn-TAK1	dn-TAK1	dn-TAK1	TAK1	TAK1	TAK1	14	15	11	12
In other systems TGF-beta1 has been shown to activate a TGF-beta-activated kinase 1 ( TAK1 ) , which in turn , activates p38 .	In other systems TGF-beta1 has been shown to activate a TGF-beta-activated kinase 1 (TAK1), which in turn, activates p38.	8	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	14	15	10	13
The subsequent phosphorylation of the TAK1 complex induces TAK1 to activate the inhibitor of NF-kappaB kinase complex , which then degrades inhibitor of NF-kappaB to release NF-kappaB , allowing the transcription factor to translocate to the nucleus , resulting in the production of proinflammatory cytokines , such as TNF-alpha and IL-6 .	The subsequent phosphorylation of the TAK1 complex induces TAK1 to activate the inhibitor of NF-kappaB kinase complex, which then degrades inhibitor of NF-kappaB to release NF-kappaB, allowing the transcription factor to translocate to the nucleus, resulting in the production of proinflammatory cytokines, such as TNF-alpha and IL-6.	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	phosphorylation of the TAK1	tak1	TAK1	TAK1	tak1	5	6	8	9
The mitogen activated protein kinase kinase kinase transforming growth factor-beta-activated kinase 1 ( TAK1 ) was implicated in the processes of inflammation and fibrosis .	The mitogen activated protein kinase kinase kinase transforming growth factor-beta-activated kinase 1 (TAK1) was implicated in the processes of inflammation and fibrosis.	1	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	transforming growth factor-beta-activated kinase 1	transforming growth factor-beta-activated kinase 1	transforming growth factor-beta-activated kinase 1	13	14	7	12
Western blot analysis showed that there was a remarkable upregulation of TAK1 , p-TAK1 at Ser412 and p-IKK ( Ser180/181 ) in primary ovarian cancer cells from omentum ( OMC ) as compared with primary ovarian cancer cells from the ovaries ( OVC ) .	Western blot analysis showed that there was a remarkable upregulation of TAK1, p-TAK1 at Ser412 and p-IKK (Ser180/181) in primary ovarian cancer cells from omentum (OMC) as compared with primary ovarian cancer cells from the ovaries (OVC).	6	15	was a remarkable upregulation	Positive_activation_copula_1	Positive_activation	Positive_activation	p-TAK1	p-TAK1	p-TAK1	TAK1	TAK1	TAK1	13	14	11	12
These data support the notion that polyubiquitination of TAK1 may cause conformational change of the TAK1 that exposes the critical phosphorylation site ( Thr 187 ) in the activation loop of TAK1 for auto-phosphorylation .	These data support the notion that polyubiquitination of TAK1 may cause conformational change of the TAK1 that exposes the critical phosphorylation site (Thr 187) in the activation loop of TAK1 for auto-phosphorylation.	6	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	polyubiquitination of TAK1	tak1	TAK1	TAK1	tak1	8	9	15	16
It is reported that k63 linked polyubiquitination of TGF-beta-activated kinase 1 ( TAK1 ) directly regulates TAK1 activity to activate p38 and MAPK pathway [ XREF_BIBR ] .	It is reported that k63 linked polyubiquitination of TGF-beta-activated kinase 1 (TAK1) directly regulates TAK1 activity to activate p38 and MAPK pathway [XREF_BIBR].	4	17	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta-activated kinase 1	k63 linked polyubiquitination of TGF-beta-activated kinase 1	tgf-beta-activated kinase 1	TAK1	TAK1	tak1	8	11	16	17
We activated TAK1 using TAK1 binding protein 1 ( TAB1 ) , which is a constitutively associated TAK1 binding partner , and co-overexpression of TAK1 and TAB1 highly activates TAK1 .	We activated TAK1 using TAK1 binding protein 1 (TAB1), which is a constitutively associated TAK1 binding partner, and co-overexpression of TAK1 and TAB1 highly activates TAK1.	22	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	co-overexpression of TAK1	tak1	TAK1	TAK1	tak1	24	25	29	30
Importantly , this report highlights a hitherto unknown feedback regulation loop between polyubiquitination and phosphorylation of TAK1 that dynamically modulates TAK1 activation , and shows how post-translational modification regulates the selection of MAPK activation in TLR4 signaling .	Importantly, this report highlights a hitherto unknown feedback regulation loop between polyubiquitination and phosphorylation of TAK1 that dynamically modulates TAK1 activation, and shows how post-translational modification regulates the selection of MAPK activation in TLR4 signaling.	10	24	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	phosphorylation of TAK1	tak1	TAK1	TAK1	tak1	16	17	20	21
We show here that knock-out or knockdown of Tak1 ( TGFbeta activated kinase 1 ) and Jnk2 ( c-Jun N-terminal kinase 2 ) perturbs neuronal migration during cortical development and that the migration defects incurred by knock-out and/or knockdown of Tbetar2 ( type II TGF-beta receptor ) or Tak1 can be partially rescued by expression of TAK1 and JNK2 , respectively .	We show here that knock-out or knockdown of Tak1 (TGFbeta activated kinase 1) and Jnk2 (c-Jun N-terminal kinase 2) perturbs neuronal migration during cortical development and that the migration defects incurred by knock-out and/or knockdown of Tbetar2 (type II TGF-beta receptor) or Tak1 can be partially rescued by expression of TAK1 and JNK2, respectively.	4	58	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAK1	expression of TAK1	tak1	Tak1	Tak1	tak1	56	57	48	49
XREF_BIBR ) CagA also associates with TNF receptor associated factor 6 ( TRAF6 ) and TGF-beta-activated kinase 1 ( TAK1 ) to induce TAK1 polyubiquitination , which in turn activates TAK1 .	XREF_BIBR) CagA also associates with TNF receptor associated factor 6 (TRAF6) and TGF-beta-activated kinase 1 (TAK1) to induce TAK1 polyubiquitination, which in turn activates TAK1.	2	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	CagA also associates with TNF receptor associated factor 6 (TRAF6) and TGF-beta-activated kinase 1 (TAK1) to induce TAK1 polyubiquitination	tak1	TAK1	TAK1	tak1	23	24	30	31
This infers that the phosphorylation of TAK1 at Ser412 increase the kinase activity of TAK1 in ovarian cancer cells .	This infers that the phosphorylation of TAK1 at Ser412 increase the kinase activity of TAK1 in ovarian cancer cells.	4	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	phosphorylation of TAK1 at Ser412	tak1	TAK1	TAK1	tak1	6	7	14	15
In the first instance , we suppressed TAK1 expression in human SCC A5RT3 cell line using lentiviral mediated RNAi ( designated herein A5RT3 TAK1 ) .	In the first instance, we suppressed TAK1 expression in human SCC A5RT3 cell line using lentiviral mediated RNAi (designated herein A5RT3 TAK1).	7	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1 expression	tak1	TAK1	TAK1	tak1	7	8	23	24
When co-transfected with K63-only ubiquitin , wild-type TAK1 was moderately ubiquitinated in the absence of CagA and co-expression of CagA significantly enhanced TAK1 ubiquitination ( XREF_FIG ) .	When co-transfected with K63-only ubiquitin, wild-type TAK1 was moderately ubiquitinated in the absence of CagA and co-expression of CagA significantly enhanced TAK1 ubiquitination (XREF_FIG).	21	24	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1 ubiquitination	tak1	TAK1	TAK1	tak1	22	23	22	23
The mitogen activated protein kinase kinase kinase transforming growth factor-beta-activated kinase 1 ( TAK1 ) has emerged as an interesting therapeutic target for inflammatory diseases and cancer .	The mitogen activated protein kinase kinase kinase transforming growth factor-beta-activated kinase 1 (TAK1) has emerged as an interesting therapeutic target for inflammatory diseases and cancer.	1	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	transforming growth factor-beta-activated kinase 1	transforming growth factor-beta-activated kinase 1	transforming growth factor-beta-activated kinase 1	13	14	7	12
Activation of JNKK1 by MEKK1 was demonstrated in vitro [ XREF_BIBR ] .	Activation of JNKK1 by MEKK1 was demonstrated in vitro [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	JNKK1	JNKK1	JNKK1	4	5	2	3
Furthermore , activation of MEKK1 increases SEK1 and MKK4 but not MKK3 or MKK6 activity .	Furthermore, activation of MEKK1 increases SEK1 and MKK4 but not MKK3 or MKK6 activity.	2	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	MKK4	MKK4	MKK4	4	5	8	9
MAP2K4-EE phosphorylated the kinase-dead p38 MAPK substrate albeit at a higher concentration compared to that of MAP3K1 activated and phosphorylated murine MAP2K4 ( MAP2K4-AC ) .	MAP2K4-EE phosphorylated the kinase-dead p38 MAPK substrate albeit at a higher concentration compared to that of MAP3K1 activated and phosphorylated murine MAP2K4 (MAP2K4-AC).	14	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K1	MAP3K1	MAP3K1	MAP2K4	MAP2K4	MAP2K4	16	17	21	22
Some likely results of this exercise in logic modeling could be the predictions that , in contrast to other cells , in these cancer cells the tumor necrosis factor-alpha receptor does not activate phosphoinositide 3-kinase , both Map3K1 and Map3K7 are required to activate MKK4 , an inhibitory link from ERK to SOS-1 may be present , and so on .	Some likely results of this exercise in logic modeling could be the predictions that, in contrast to other cells, in these cancer cells the tumor necrosis factor-alpha receptor does not activate phosphoinositide 3-kinase, both Map3K1 and Map3K7 are required to activate MKK4, an inhibitory link from ERK to SOS-1 may be present, and so on.	36	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Map3K1	Map3K1	Map3K1	MKK4	MKK4	MKK4	37	38	44	45
In contrast , MEKK1 activates SKK1 and MKK4 more efficiently than MLK2 , but barely activates SKK4 and MKK7 .	In contrast, MEKK1 activates SKK1 and MKK4 more efficiently than MLK2, but barely activates SKK4 and MKK7.	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	SKK1	SKK1	SKK1	3	4	5	6
However , it is believed that in most cells the sequential stimulation of the Ras like monomeric GTP binding protein , Rac , perhaps by Ras itself , leads to the activation of MEKK1 , a MAPKKK that then activates the MAPKK , MEK4 , also called SEK or JNK kinase , culminating in the activation of c-jun kinase ( JNK ) / MAPK .	However, it is believed that in most cells the sequential stimulation of the Ras like monomeric GTP binding protein, Rac, perhaps by Ras itself, leads to the activation of MEKK1, a MAPKKK that then activates the MAPKK, MEK4, also called SEK or JNK kinase, culminating in the activation of c-jun kinase (JNK) / MAPK.	31	52	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	MEK4	MEK4	MEK4	33	34	43	44
The MEKK MEKK1 is activated by the FLS2 kinase , MEKK1 activates MKK4 and MKK5 , two MKKs that activate MPK3 and MPK6 , two MAPKs that activate the effector proteins WRKY22 and WRKY29 resulting in an immune response .	The MEKK MEKK1 is activated by the FLS2 kinase, MEKK1 activates MKK4 and MKK5, two MKKs that activate MPK3 and MPK6, two MAPKs that activate the effector proteins WRKY22 and WRKY29 resulting in an immune response.	10	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	MKK4	MKK4	MKK4	10	11	12	13
Upon ERK5 stimulation , two members of the MAPKKK family , MEKK2 and MEKK3 , activate MEK5 , a MAPKK that is specific for ERK5 [ XREF_BIBR ] .	Upon ERK5 stimulation, two members of the MAPKKK family, MEKK2 and MEKK3, activate MEK5, a MAPKK that is specific for ERK5 [XREF_BIBR].	5	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK2	MEKK2	MEKK2	MEK5	MEK5	MEK5	11	12	16	17
We also showed that the nuclear MEK5 is activated by MEKK2 , which translocates into the nucleus upon EGF stimulation .	We also showed that the nuclear MEK5 is activated by MEKK2, which translocates into the nucleus upon EGF stimulation.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEKK2	MEKK2	MEKK2	MEK5	MEK5	MEK5	10	11	6	7
Mekk2 has been shown to activate the Mek5 and Erk5 pathway .	Mekk2 has been shown to activate the Mek5 and Erk5 pathway.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mekk2	Mekk2	Mekk2	Mek5	Mek5	Mek5	0	1	7	8
Furthermore , although both BRAF and MAP3K2 are required for tumor growth and metastasis in KRAS mutated MDA-MB-231 breast cancer cells , in that context BRAF contributed to MEK1/2 --> ERK1/2 activation whereas MAP3K2 contributed to MEK5 --> ERK5 activation [ XREF_BIBR ] .	Furthermore, although both BRAF and MAP3K2 are required for tumor growth and metastasis in KRAS mutated MDA-MB-231 breast cancer cells, in that context BRAF contributed to MEK1/2 --> ERK1/2 activation whereas MAP3K2 contributed to MEK5 --> ERK5 activation [XREF_BIBR].	33	37	contributed	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MAP3K2	MAP3K2	MAP3K2	MEK5	MEK5	MEK5	33	34	36	37
It is activated by the upstream MEK5 , which is activated by the MEKK2 or MEKK3 .	It is activated by the upstream MEK5, which is activated by the MEKK2 or MEKK3.	2	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEKK2	MEKK2	MEKK2	MEK5	MEK5	MEK5	13	14	6	7
Mek5 in turn is activated through phosphorylation by the MAPK kinase kinases MEKK2 ( MAP3K2 ) and MEKK3 ( MAP3K3 ) .	Mek5 in turn is activated through phosphorylation by the MAPK kinase kinases MEKK2 (MAP3K2) and MEKK3 (MAP3K3).	0	15	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	MAP3K2	phosphorylation by the MAPK kinase kinases MEKK2 (MAP3K2	map3k2	Mek5	Mek5	mek5	14	15	0	1
MEK5 is activated via the dual phosphorylation of its Serine 311 and Threonine 315 by MEKK2 ,3/Tpl2 .	MEK5 is activated via the dual phosphorylation of its Serine 311 and Threonine 315 by MEKK2,3/Tpl2.	0	16	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	MEKK2	phosphorylation of its Serine 311 and Threonine 315 by MEKK2	mekk2	MEK5	MEK5	mek5	15	16	0	1
MEK5 can be activated by both MEKK2 and MEKK3 .	MEK5 can be activated by both MEKK2 and MEKK3.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEKK2	MEKK2	MEKK2	MEK5	MEK5	MEK5	6	7	0	1
We describe an alternative pathway by which MEKK2 activates MEK5 and big MAP kinase1 and extracellular signal regulated kinase 5 in addition to MKK7 and JNK , and interruption of this pathway inhibits TNF-alpha promoter activation .	We describe an alternative pathway by which MEKK2 activates MEK5 and big MAP kinase1 and extracellular signal regulated kinase 5 in addition to MKK7 and JNK, and interruption of this pathway inhibits TNF-alpha promoter activation.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK2	MEKK2	MEKK2	MEK5	MEK5	MEK5	7	8	9	10
ASK-1 , a member of the MAPKKK family , activates both MKK4 and MKK7-JNK and MKK3 and MKK6-p 38 MAPK signaling cascades .	ASK-1, a member of the MAPKKK family, activates both MKK4 and MKK7-JNK and MKK3 and MKK6-p 38 MAPK signaling cascades.	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK-1	ASK-1	ASK-1	MKK4	MKK4	MKK4	0	1	11	12
ASK1 is an important activator of the MKK4 and JNK signaling pathway under conditions such as oxidative stress and DNA damage , although MKK4 and JNK may also be activated via other MKKKs .	ASK1 is an important activator of the MKK4 and JNK signaling pathway under conditions such as oxidative stress and DNA damage, although MKK4 and JNK may also be activated via other MKKKs.	0	13	is an important activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	MKK4	MKK4	MKK4	0	1	7	8
ASK1 activates SEK1 and MKK4 and MKK3 following induction by various stimuli , thus promoting JNK- and p38 MAPK dependent cell death XREF_BIBR .	ASK1 activates SEK1 and MKK4 and MKK3 following induction by various stimuli, thus promoting JNK- and p38 MAPK dependent cell death XREF_BIBR.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	SEK1	SEK1	SEK1	0	1	2	3
ASK1 activates the MKK4 and JNK and MKK6 and p38 MAPK pathways through their phosphorylation .	ASK1 activates the MKK4 and JNK and MKK6 and p38 MAPK pathways through their phosphorylation.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	MKK4	MKK4	MKK4	0	1	3	4
Furthermore , MAPKKK5 that was immunoprecipitated from transfected 293 cells was able to phosphorylate and activate MKK4 in vitro , suggesting that MAPKKK5 may be an upstream activator of MKK4 in the c-Jun N-terminal kinase pathway .	Furthermore, MAPKKK5 that was immunoprecipitated from transfected 293 cells was able to phosphorylate and activate MKK4 in vitro, suggesting that MAPKKK5 may be an upstream activator of MKK4 in the c-Jun N-terminal kinase pathway.	22	35	be an upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MAPKKK5	MAPKKK5	MAPKKK5	MKK4	MKK4	MKK4	22	23	29	30
SEK-1 is activated by the MAPKKK NSY-1 ( ortholog of ASK1 ) and activates the p38 MAPKs PMK-1 and PMK-2 .	SEK-1 is activated by the MAPKKK NSY-1 (ortholog of ASK1) and activates the p38 MAPKs PMK-1 and PMK-2.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	SEK-1	SEK-1	SEK-1	10	11	0	1
DJ-1 negatively regulates JNK activation through its inhibitory effect on apoptosis signal regulating kinase 1 ( ASK1 ) XREF_BIBR , XREF_BIBR , XREF_BIBR , a mitogen activated protein kinase kinase kinase 5 ( MAP3K5 ) that activates the MKK4 and MKK7-JNK apoptotic axis XREF_BIBR .	DJ-1 negatively regulates JNK activation through its inhibitory effect on apoptosis signal regulating kinase 1 (ASK1) XREF_BIBR, XREF_BIBR, XREF_BIBR, a mitogen activated protein kinase kinase kinase 5 (MAP3K5) that activates the MKK4 and MKK7-JNK apoptotic axis XREF_BIBR.	26	43	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K5	MAP3K5	MAP3K5	MKK4	MKK4	MKK4	33	34	38	39
ASK1 was first identified as a member of the MAPKKK family and was found to activate the MAPKK 4 ( MKK4 )-JNK and MKK3/6-p 38 pathways but not the MAP and ERK kinase ( MEK )-extracellular signal regulated kinase ( ERK ) pathway .	ASK1 was first identified as a member of the MAPKKK family and was found to activate the MAPKK 4 (MKK4)-JNK and MKK3/6-p 38 pathways but not the MAP and ERK kinase (MEK)-extracellular signal regulated kinase (ERK) pathway.	0	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	MKK4	MKK4	MKK4	0	1	20	21
These studies , and our results , suggest that phosphorylation of TAB1 by p38 may specify its function in the noncanonical p38 pathway and likely limit its role in TAK1 dependent activation of MKK3 and MKK6 .	These studies, and our results, suggest that phosphorylation of TAB1 by p38 may specify its function in the noncanonical p38 pathway and likely limit its role in TAK1 dependent activation of MKK3 and MKK6.	29	36	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	MKK6	MKK6	MKK6	29	30	35	36
As Tak1 kinase is able to target and activate both Mkk6 and Mkk3 , that themselves are known to be the only targeting and activating enzymes of p38-Mapks [ XREF_BIBR , XREF_BIBR ] , we wanted to test if any of the reported Tak1 mediated inhibitory effects on PrE derivation [ XREF_BIBR ] were mediated by p38-Mapk14/11 .	As Tak1 kinase is able to target and activate both Mkk6 and Mkk3, that themselves are known to be the only targeting and activating enzymes of p38-Mapks [XREF_BIBR, XREF_BIBR], we wanted to test if any of the reported Tak1 mediated inhibitory effects on PrE derivation [XREF_BIBR] were mediated by p38-Mapk14/11.	1	22	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tak1	Tak1	Tak1	Mkk6	Mkk6	Mkk6	1	2	10	11
Moreover , TAK1 activates members of the MAP kinase kinase 3 ( MKK3 ) and MKK6 to activate an alternative closely related pathway that phosphorylates c-Jun N-terminal Kinase ( JNK ) and p38 .	Moreover, TAK1 activates members of the MAP kinase kinase 3 (MKK3) and MKK6 to activate an alternative closely related pathway that phosphorylates c-Jun N-terminal Kinase (JNK) and p38.	2	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	MKK6	MKK6	MKK6	2	3	15	16
XREF_BIBR - XREF_BIBR The MAP kinase pathway is also activated in response to NOD ligands through TAK1 , which is a protein that activates MAPKK 6 to then activate p38 , extracellular-signal regulated kinase , and c-Jun N-terminal kinase to induce activator protein 1 dependent transcription .	XREF_BIBR - XREF_BIBR The MAP kinase pathway is also activated in response to NOD ligands through TAK1, which is a protein that activates MAPKK 6 to then activate p38, extracellular-signal regulated kinase, and c-Jun N-terminal kinase to induce activator protein 1 dependent transcription.	9	28	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	MAPKK 6	MAPKK 6	MAPKK 6	16	17	24	26
Furthermore , TAK-1 can also activate MKK3 and MKK6 , two enzymes upstream of JNK , MAPK , and p38 .	Furthermore, TAK-1 can also activate MKK3 and MKK6, two enzymes upstream of JNK, MAPK, and p38.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK-1	TAK-1	TAK-1	MKK6	MKK6	MKK6	2	3	8	9
Dual specificity MAPK Kinases 3 and 6 ( MKK3 and MKK6 ) transduce the signal from TAK1 to p38 , and in kidney fibroblasts TAK1 overexpression activated MKK3 and p38 resulting in enhanced ECM gene expression [ XREF_BIBR , XREF_BIBR ] .	Dual specificity MAPK Kinases 3 and 6 (MKK3 and MKK6) transduce the signal from TAK1 to p38, and in kidney fibroblasts TAK1 overexpression activated MKK3 and p38 resulting in enhanced ECM gene expression [XREF_BIBR, XREF_BIBR].	24	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1 overexpression	tak1	MKK3	MKK3	mkk3	24	25	27	28
Transient overexpression of TAK1 with TAB1 enhanced the activation of MKK3 and p38 MAPK with or without TGF-beta ( 1 ) stimulation , whereas a dominant negative mutant of TAK1 ( TAK1DN ) suppressed TGF-beta ( 1 )-induced activation of MKK3 and p38 MAPK .	Transient overexpression of TAK1 with TAB1 enhanced the activation of MKK3 and p38 MAPK with or without TGF-beta (1) stimulation, whereas a dominant negative mutant of TAK1 (TAK1DN) suppressed TGF-beta (1)-induced activation of MKK3 and p38 MAPK.	27	43	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	MKK3	MKK3	MKK3	29	30	40	41
Activated TAK1 activates MKK4 and MKK7 , which leads to JNK activation [ XREF_BIBR ] .	Activated TAK1 activates MKK4 and MKK7, which leads to JNK activation [XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	MKK4	MKK4	MKK4	1	2	3	4
In addition , TAK1 knockdown modestly inhibited MKK4 and MKK7 kinase activity ( average inhibition : MKK4 , 28 +/- 4 % ( p = 0.01 ) ; MKK7 , 28 +/- 8 % ( p = 0.03 ) ; n = 3 each ; Figure XREF_FIG ) .	In addition, TAK1 knockdown modestly inhibited MKK4 and MKK7 kinase activity (average inhibition : MKK4, 28 +/- 4% (p = 0.01); MKK7, 28 +/- 8% (p = 0.03); n = 3 each; Figure XREF_FIG).	3	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	MKK4	MKK4	MKK4	3	4	7	8
In larval fatbodies , activation of TAK1 by infection not only promotes Relish nuclear localization , but also activates Hemipterous ( JNKK ) , which phosphorylates and activates Basket ( JNK ) .	In larval fatbodies, activation of TAK1 by infection not only promotes Relish nuclear localization, but also activates Hemipterous (JNKK), which phosphorylates and activates Basket (JNK).	4	29	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TAK1	TAK1	tak1	JNKK	JNKK), which phosphorylates and activates Basket	jnkk	6	7	21	22
TAK1 knockdown significantly inhibited the kinase activity of MKK4 , MKK7 , and JNK .	TAK1 knockdown significantly inhibited the kinase activity of MKK4, MKK7, and JNK.	0	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	MKK4	MKK4	MKK4	0	1	8	9
It has been shown that MEKK3 induces activation of the MEK5 and ERK5 pathways through growth factor induced cellular stimulation and oxidative stress [ XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	It has been shown that MEKK3 induces activation of the MEK5 and ERK5 pathways through growth factor induced cellular stimulation and oxidative stress [XREF_BIBR, XREF_BIBR] (XREF_FIG).	5	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK3	MEKK3	MEKK3	MEK5	MEK5	MEK5	5	6	10	11
To determine whether MEKK3 regulates Klf and Adamts gene expression through the ERK5 MAPK pathway we cultured wild-type E10.5 explanted hearts in the presence of BIX02189 , a highly specific inhibitor of MEK5 , the MAPK2K that is activated by MEKK3 and in turn activates ERK5 .	To determine whether MEKK3 regulates Klf and Adamts gene expression through the ERK5 MAPK pathway we cultured wild-type E10.5 explanted hearts in the presence of BIX02189, a highly specific inhibitor of MEK5, the MAPK2K that is activated by MEKK3 and in turn activates ERK5.	30	41	activated	Positive_activation_syntax_6_verb	Positive_activation	Negative_activation	MEKK3	MEKK3	MEKK3	MEK5	MEK5	MEK5	40	41	32	33
It has been shown that MEKK3 induces activation of the MEK5 and ERK5 pathways through growth factor induced cellular stimulation and oxidative stress .	It has been shown that MEKK3 induces activation of the MEK5 and ERK5 pathways through growth factor induced cellular stimulation and oxidative stress.	5	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK3	MEKK3	MEKK3	MEK5	MEK5	MEK5	5	6	10	11
MEKK3 , identified as a CCM2 binding partner in the osmosensing complex ( Uhlik etal , 2003 ) , activates MEK5 that , in turn , through ERK5 dual phosphorylation , induces transcription factors MEF2A , MEF2C , and MEF2D to regulate their target genes ( Kato etal , 1997 ; Sohn etal , 2005 ) .	MEKK3, identified as a CCM2 binding partner in the osmosensing complex (Uhlik etal, 2003), activates MEK5 that, in turn, through ERK5 dual phosphorylation, induces transcription factors MEF2A, MEF2C, and MEF2D to regulate their target genes (Kato etal, 1997; Sohn etal, 2005).	0	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK3	MEKK3	MEKK3	MEK5	MEK5	MEK5	0	1	20	21
The MAPKKK , ASK1 , was strongly activated late during ischaemia , with a similar time course to that of MKK6 and in ischaemic neonatal cardiac myocytes ASK1 expression preferentially activated MKK6 rather than MKK3 .	The MAPKKK, ASK1, was strongly activated late during ischaemia, with a similar time course to that of MKK6 and in ischaemic neonatal cardiac myocytes ASK1 expression preferentially activated MKK6 rather than MKK3.	27	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	ASK1 expression	ask1	MKK3	MKK3	mkk3	27	28	34	35
Of the MAPK family members , ASK1 activates two different kinases : MAPKK-SEK1 ( MKK4 ) and MKK3 and MAPKK6 ( MKK6 ) .	Of the MAPK family members, ASK1 activates two different kinases : MAPKK-SEK1 (MKK4) and MKK3 and MAPKK6 (MKK6).	6	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	MKK3	MKK3	MKK3	6	7	17	18
By binding to ASK1 , DJ-1 may disrupt ASK1 homo-oligomerization and activation , thus inhibiting H 2 O 2 -induced ASK1 activation of MKK3 and p38 .	By binding to ASK1, DJ-1 may disrupt ASK1 homo-oligomerization and activation, thus inhibiting H 2 O 2 -induced ASK1 activation of MKK3 and p38.	20	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	MKK3	MKK3	MKK3	20	21	23	24
A kinase assay was used to determine ASK1 activity.AGE incubation significantly activated ASK1 , MKK3 , and MKK6 , which led to activation of p38 MAPK , resulting in upregulated fibrotic response in HCSMCs .	A kinase assay was used to determine ASK1 activity.AGE incubation significantly activated ASK1, MKK3, and MKK6, which led to activation of p38 MAPK, resulting in upregulated fibrotic response in HCSMCs.	7	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	MKK3	MKK3	MKK3	7	8	14	15
MTK1 overexpression also activated the MKK3 , MKK6 and SEK1 MAPKKs , but not the MEK1 MAPKK .	MTK1 overexpression also activated the MKK3, MKK6 and SEK1 MAPKKs, but not the MEK1 MAPKK.	0	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTK1	MTK1 overexpression	mtk1	MKK6	MKK6	mkk6	0	1	7	8
Seven days after transfection , we assessed phosphorylation ( i.e. activation ) of the MEKK4 targets MKK3 , MKK6 , and MKK4 .	Seven days after transfection, we assessed phosphorylation (i.e. activation) of the MEKK4 targets MKK3, MKK6, and MKK4.	7	19	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK4	phosphorylation (i.e. activation) of the MEKK4	mekk4	MKK6	MKK6	mkk6	14	15	18	19
In addition to its activation of MKK4 and MKK7 , MEKK4 can also activate MKK3 or MKK6 to activate p38 MAPK pathway , which depends on the receptor activated and availability of other signaling molecules [ XREF_BIBR ] .	In addition to its activation of MKK4 and MKK7, MEKK4 can also activate MKK3 or MKK6 to activate p38 MAPK pathway, which depends on the receptor activated and availability of other signaling molecules [XREF_BIBR].	10	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK4	MEKK4	MEKK4	MKK6	MKK6	MKK6	10	11	16	17
Furthermore , MTK1 phosphorylated and activated MKK6 and SEK1 in vitro .	Furthermore, MTK1 phosphorylated and activated MKK6 and SEK1 in vitro.	2	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTK1	MTK1 phosphorylated	mtk1	MKK6	MKK6	mkk6	2	3	6	7
Wildtype and activated Cot phosphorylate and activate MEK-1 and SEK-1 in vitro .	Wildtype and activated Cot phosphorylate and activate MEK-1 and SEK-1 in vitro.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cot	Cot	Cot	MEK-1	MEK-1	MEK-1	3	4	7	8
MAP3K8 encodes mitogen activated protein kinase kinase kinase 8 ( MAP3K8 ) which has been shown to cause lung cancer and can directly activate MEK1 [ XREF_BIBR ] .	MAP3K8 encodes mitogen activated protein kinase kinase kinase 8 (MAP3K8) which has been shown to cause lung cancer and can directly activate MEK1 [XREF_BIBR].	0	26	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K8	MAP3K8	MAP3K8	MEK1	MEK1	MEK1	0	1	24	25
Tpl2 activates MEK1 ( mitogen activated kinase kinase or ERK kinase ) , MEK2 ( also called MAP2K1 and MAP2K2 , respectively ) , MKK3 and MKK6 ( also called MAP2K3 and MAP2K6 , respectively ) [ XREF_BIBR , XREF_BIBR ] .	Tpl2 activates MEK1 (mitogen activated kinase kinase or ERK kinase), MEK2 (also called MAP2K1 and MAP2K2, respectively), MKK3 and MKK6 (also called MAP2K3 and MAP2K6, respectively) [XREF_BIBR, XREF_BIBR].	0	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	MEK1	MEK1	MEK1	0	1	2	3
MAP3K5 activates MAP2K6 which in turn activates p38 in response to inflammatory cytokines .	MAP3K5 activates MAP2K6 which in turn activates p38 in response to inflammatory cytokines.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K5	MAP3K5	MAP3K5	MAP2K6	MAP2K6	MAP2K6	0	1	2	3
MKK6 activation in ischaemic cells was also increased by expression of ASK1 but the fold effect appeared lower than that for MKK3 due to the higher basal MKK6 activity ( XREF_FIG C ) .	MKK6 activation in ischaemic cells was also increased by expression of ASK1 but the fold effect appeared lower than that for MKK3 due to the higher basal MKK6 activity (XREF_FIG C).	0	12	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ASK1	expression of ASK1	ask1	MKK6	MKK6	mkk6	11	12	0	1
Expression of Gadd45alpha and Gadd45gamma activates MEKK4 and MTK1 which then activates MKK4 .	Expression of Gadd45alpha and Gadd45gamma activates MEKK4 and MTK1 which then activates MKK4.	5	13	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEKK4	MEKK4	MEKK4	MKK4	MKK4	MKK4	6	7	12	13
Transient transfection assays demonstrated that JNKK2 potentiated the stimulation of c-Jun transcriptional activity by MEKK1 .	Transient transfection assays demonstrated that JNKK2 potentiated the stimulation of c-Jun transcriptional activity by MEKK1.	5	15	potentiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	JNKK2	JNKK2	JNKK2	14	15	5	6
Scaffolding of MEKK1 , MKK7 , and JNK complex by neuron specific JNK interacting protein 3 may activate MKK7 .	Scaffolding of MEKK1, MKK7, and JNK complex by neuron specific JNK interacting protein 3 may activate MKK7.	2	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	MKK7	MKK7	MKK7	2	3	18	19
However , activation of the JNK and caspase-8 pathways is tightly regulated by NF-kappaB target gene products at several levels : TRAF2 and cIAP1/2 suppress RIP1 mediated caspase-8 activation by ubiquitinating RIP1 ; cFLIP limits caspase-8 activity by competing for FADD interaction ; X linked IAP ( XIAP ) and GADD45beta inhibits prolonged JNK activation by suppressing MEKK1 mediated MKK7 activation ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	However, activation of the JNK and caspase-8 pathways is tightly regulated by NF-kappaB target gene products at several levels : TRAF2 and cIAP1/2 suppress RIP1 mediated caspase-8 activation by ubiquitinating RIP1; cFLIP limits caspase-8 activity by competing for FADD interaction; X linked IAP (XIAP) and GADD45beta inhibits prolonged JNK activation by suppressing MEKK1 mediated MKK7 activation (XREF_FIG) [XREF_BIBR, XREF_BIBR].	57	60	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	MKK7	MKK7	MKK7	57	58	59	60
Since SKK4 and MKK7 ( but not SKK1 and MKK4 ) is activated by interleukin-1 and tumour necrosis factor in several cells and tissues , we suggest that MEKK1 does not mediate the activation of SKK4 and MKK7 and SAPK1 and JNK induced by these pro inflammatory cytokines .	Since SKK4 and MKK7 (but not SKK1 and MKK4) is activated by interleukin-1 and tumour necrosis factor in several cells and tissues, we suggest that MEKK1 does not mediate the activation of SKK4 and MKK7 and SAPK1 and JNK induced by these pro inflammatory cytokines.	28	38	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	MKK7	MKK7	MKK7	28	29	37	38
The signal transduction kinase MEK ( mitogen activated protein ( MAP ) or extracellular signal regulated ( Erk ) kinase ) -1 is activated via phosphorylation by MEKK ( MEK kinase ) and raf kinases .	The signal transduction kinase MEK (mitogen activated protein (MAP) or extracellular signal regulated (Erk) kinase) -1 is activated via phosphorylation by MEKK (MEK kinase) and raf kinases.	1	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEKK	MEKK	MEKK	MEK	MEK	MEK	27	28	4	5
High-level expression of MEKK in COS-7 cells or using vaccinia virus vectors also activates MEK and MAPK , indicating that MEKK and Raf provide alternative means of activating the MAPK signalling pathway .	High-level expression of MEKK in COS-7 cells or using vaccinia virus vectors also activates MEK and MAPK, indicating that MEKK and Raf provide alternative means of activating the MAPK signalling pathway.	1	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK	expression of MEKK	mekk	MEK	MEK	mek	3	4	14	15
Furthermore , ATP did not activate B-Raf , the major isoform of Raf in the brain , nor other Mek activators such as Mek kinase 1 ( MekK1 ) and MekK2/3 .	Furthermore, ATP did not activate B-Raf, the major isoform of Raf in the brain, nor other Mek activators such as Mek kinase 1 (MekK1) and MekK2/3.	19	26	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Mek kinase 1	Mek kinase 1	Mek kinase 1	Mek	Mek	Mek	23	26	19	20
Spc1 and StyI is activated by Wis1 , a MAPK kinase ( MEK ) , which is itself activated by Wik1/Wak1/Wis4 , a MEK kinase ( MEKK ) .	Spc1 and StyI is activated by Wis1, a MAPK kinase (MEK), which is itself activated by Wik1/Wak1/Wis4, a MEK kinase (MEKK).	10	27	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MEKK	MEKK	MEKK	MEK	MEK	MEK	26	27	12	13
The serine/threonine kinases RAF and MEKK ( MAPK kinase kinase ) phosphorylate and activate MEK , in turn , during intracellular signaling ( 6 ) .	The serine/threonine kinases RAF and MEKK (MAPK kinase kinase) phosphorylate and activate MEK, in turn, during intracellular signaling (6).	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK	MEKK	MEKK	MEK	MEK	MEK	5	6	14	15
The second cascade activated by flg22 is defined by the MAPKKK MEKK1 , which activates MKK1 and MKK2 that act redundantly on MPK4 [ XREF_BIBR , XREF_BIBR ] .	The second cascade activated by flg22 is defined by the MAPKKK MEKK1, which activates MKK1 and MKK2 that act redundantly on MPK4 [XREF_BIBR, XREF_BIBR].	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	MKK1	MKK1	MKK1	11	12	15	16
In the flg22 response , it has been well investigated that MEKK1 activates the MKK1 and MKK2-MPK 4 pathway ( Meng & Zhang , 2013 ) .	In the flg22 response, it has been well investigated that MEKK1 activates the MKK1 and MKK2-MPK 4 pathway (Meng & Zhang, 2013).	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	MKK1	MKK1	MKK1	11	12	14	15
It can be concluded that both MKK1 and MKK2 interact in similar regulation towards MPK4 activation , once both MKK1 and MKK2 have been induced by MEKK1 .	It can be concluded that both MKK1 and MKK2 interact in similar regulation towards MPK4 activation, once both MKK1 and MKK2 have been induced by MEKK1.	18	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	MKK1	MKK1	MKK1	26	27	19	20
However , in addition to its capacity to phosphorylate MEK1 in vitro , MEKK-C interacts with MEK1 in the two-hybrid system , and expression of mouse MEKK1 or MEKK-C in mammalian cells causes constitutive activation of both MEK1 and MEK2 .	However, in addition to its capacity to phosphorylate MEK1 in vitro, MEKK-C interacts with MEK1 in the two-hybrid system, and expression of mouse MEKK1 or MEKK-C in mammalian cells causes constitutive activation of both MEK1 and MEK2.	23	39	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK1	expression of mouse MEKK1	mekk1	MEK1	MEK1	mek1	26	27	37	38
ATP also inhibited the activation of cRaf-1 by other growth factors , epidermal growth factor and platelet derived growth factor , as well as other MEK1 activators stimulated by FGF-2 , MEK kinase 1 ( MEKK1 ) and MEKK2 .	ATP also inhibited the activation of cRaf-1 by other growth factors, epidermal growth factor and platelet derived growth factor, as well as other MEK1 activators stimulated by FGF-2, MEK kinase 1 (MEKK1) and MEKK2.	25	36	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	MEK1	MEK1	MEK1	35	36	25	26
Coexpression of MEKK2 or MEKK3 with MKK4 in COS-7 cells resulted in activation of MKK4 , as assessed by enhanced autophosphorylation and by its ability to phosphorylate and activate recombinant JNK1 or p38 in vitro .	Coexpression of MEKK2 or MEKK3 with MKK4 in COS-7 cells resulted in activation of MKK4, as assessed by enhanced autophosphorylation and by its ability to phosphorylate and activate recombinant JNK1 or p38 in vitro.	0	15	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	MEKK2	Coexpression of MEKK2	mekk2	MKK4	MKK4	mkk4	2	3	14	15
These data indicate that MKK3 is preferentially activated by MEKK3 , whereas MKK4 is activated both by MEKK2 and MEKK3 .	These data indicate that MKK3 is preferentially activated by MEKK3, whereas MKK4 is activated both by MEKK2 and MEKK3.	12	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEKK2	MEKK2	MEKK2	MKK4	MKK4	MKK4	17	18	12	13
Consistent with these findings , SKRP1 expression increased the ASK1-MKK7 complexes in a dose dependent manner and specifically enhanced the activation of MKK7 by ASK1 .	Consistent with these findings, SKRP1 expression increased the ASK1-MKK7 complexes in a dose dependent manner and specifically enhanced the activation of MKK7 by ASK1.	18	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	MKK7	MKK7	MKK7	24	25	22	23
Since proteasome inhibitors abolish ASK1 supported accumulation of Daxx , it suggests that Daxx accumulation or degradation is proteasome dependent .	Since proteasome inhibitors abolish ASK1 supported accumulation of Daxx, it suggests that Daxx accumulation or degradation is proteasome dependent.	4	9	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	Daxx	Daxx	Daxx	4	5	8	9
The JNK kinase kinase Apoptosis Signal Regulating Kinase 1 ( ASK1 ) sequesters Daxx in the cytoplasm and thus inhibits the repressive activity of Daxx in transcription [ XREF_BIBR ] .	The JNK kinase kinase Apoptosis Signal Regulating Kinase 1 (ASK1) sequesters Daxx in the cytoplasm and thus inhibits the repressive activity of Daxx in transcription [XREF_BIBR].	4	16	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Apoptosis Signal Regulating Kinase 1	Apoptosis Signal Regulating Kinase 1	Apoptosis Signal Regulating Kinase 1	Daxx	Daxx	Daxx	4	9	13	14
ASK1 sequestered Daxx in the cytoplasm and inhibited the repressive activity of Daxx in transcription .	ASK1 sequestered Daxx in the cytoplasm and inhibited the repressive activity of Daxx in transcription.	0	7	sequestered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	ASK1	ASK1	Daxx	Daxx	Daxx	0	1	2	3
We examined TGF-beta-receptor 1 , TGF-beta inducible transcription factor 1 ( TIEG1 ) , NADPHoxidase 4 ( Nox4 ) , cytochrome c , caspase-3 ( active form and pro enzyme ) , apoptosis inducing protein Daxx , apoptosis signal regulating kinase 1 ( ASK1 ) , glycogen synthase kinase-3 beta phosphorylated on serine 9 ( p-GSK-3beta ) , and beta-catenin .	We examined TGF-beta-receptor 1, TGF-beta inducible transcription factor 1 (TIEG1), NADPHoxidase 4 (Nox4), cytochrome c, caspase-3 (active form and pro enzyme), apoptosis inducing protein Daxx, apoptosis signal regulating kinase 1 (ASK1), glycogen synthase kinase-3 beta phosphorylated on serine 9 (p-GSK-3beta), and beta-catenin.	32	44	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASK1	ASK1	ASK1	Daxx	Daxx	Daxx	43	44	35	36
In vitro studies using recombinant MKK4 protein demonstrate that it was not able to interact with purified NBR1 in a pull-down assay but that the addition of recombinant MEKK3 allowed the co-precipitation of MKK4 and NBR1 ( XREF_SUPPLEMENTARY ) .	In vitro studies using recombinant MKK4 protein demonstrate that it was not able to interact with purified NBR1 in a pull-down assay but that the addition of recombinant MEKK3 allowed the co-precipitation of MKK4 and NBR1 (XREF_SUPPLEMENTARY).	25	37	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK3	MEKK3	MEKK3	MKK4	MKK4	MKK4	28	29	33	34
ZF7 of A20 directly inhibits the TAK1 dependent activation of NEMO by binding to ubiquitin chains 136 , 137 , 138 .	ZF7 of A20 directly inhibits the TAK1 dependent activation of NEMO by binding to ubiquitin chains 136, 137, 138.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	NEMO	NEMO	NEMO	6	7	10	11
This provides a potential direct connection with the IL-1 receptor complex through the upstream kinase , MAPK-ERK kinase kinase ( MEKK3 ) , which is known to activate MKK3 [ XREF_BIBR ] , and has been shown to be an important transducer of the MyD88 , IRAK , and TRAF6 complex in IL-1R-TLR4 signaling [ XREF_BIBR ] .	This provides a potential direct connection with the IL-1 receptor complex through the upstream kinase, MAPK-ERK kinase kinase (MEKK3), which is known to activate MKK3 [XREF_BIBR], and has been shown to be an important transducer of the MyD88, IRAK, and TRAF6 complex in IL-1R-TLR4 signaling [XREF_BIBR].	18	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK3	MEKK3	MEKK3	MKK3	MKK3	MKK3	20	21	28	29
After activation by AKT1 , MAP3K8 activates MAP3K14 , which in turn contributes in the activation and subsequent ubiquitination of NFKBIA [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	After activation by AKT1, MAP3K8 activates MAP3K14, which in turn contributes in the activation and subsequent ubiquitination of NFKBIA [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K8	MAP3K8	MAP3K8	MAP3K14	MAP3K14	MAP3K14	5	6	7	8
MLK2 and MEKK1 also activated SKK2 and MKK3 and SKK3 and MKK6 , the direct upstream activators of SAPK2a and p38 .	MLK2 and MEKK1 also activated SKK2 and MKK3 and SKK3 and MKK6, the direct upstream activators of SAPK2a and p38.	0	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK1	MEKK1	MEKK1	SKK3	SKK3	SKK3	2	3	9	10
Importantly , immunoprecipitates of either MEKK3 or MEKK2 directly activated recombinant MKK7 and MKK6 in vitro .	Importantly, immunoprecipitates of either MEKK3 or MEKK2 directly activated recombinant MKK7 and MKK6 in vitro.	2	14	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK3	MEKK3	MEKK3	MKK6	MKK6	MKK6	5	6	13	14
MEKK2 , a closely related homologue of MEKK3 , also activated MKK7 and MKK6 in COS-7 cells .	MEKK2, a closely related homologue of MEKK3, also activated MKK7 and MKK6 in COS-7 cells.	5	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEKK3	MEKK3	MEKK3	MKK6	MKK6	MKK6	7	8	13	14
An interesting gene located in this region is the mitogen activated protein kinase kinase kinase 4 ( MAP3K4 ) , a major mediator of environmental stresses that activate the CSBP2 MAPK pathway , which , in turn , regulates the expression of TNF and several cytokines , and controls the initiation of the G2/M checkpoint after UV radiation [ XREF_BIBR ] .	An interesting gene located in this region is the mitogen activated protein kinase kinase kinase 4 (MAP3K4), a major mediator of environmental stresses that activate the CSBP2 MAPK pathway, which, in turn, regulates the expression of TNF and several cytokines, and controls the initiation of the G2/M checkpoint after UV radiation [XREF_BIBR].	10	31	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MAP3K4	MAP3K4	MAP3K4	CSBP2	CSBP2	CSBP2	17	18	29	30
However , K260 methylation promotes dissociation of MAP3K2 from its negative regulator , the PP2A protein phosphatase , thereby enhancing MEK1/2 --> ERK1/2 signaling in tumor cells .	However, K260 methylation promotes dissociation of MAP3K2 from its negative regulator, the PP2A protein phosphatase, thereby enhancing MEK1/2 --> ERK1/2 signaling in tumor cells.	3	23	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K2	methylation promotes dissociation of MAP3K2	map3k2	MEK1/2	MEK1/2	mek1/2	7	8	20	21
Through an unbiased screen , the serine/threonine MAP kinase kinase kinase ( MAP3K ) COT kinase ( encoded by MAP3K8 ) was shown to activate MEK in the presence of BRAF inhibition 113 .	Through an unbiased screen, the serine/threonine MAP kinase kinase kinase (MAP3K) COT kinase (encoded by MAP3K8) was shown to activate MEK in the presence of BRAF inhibition 113.	14	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT	COT	MEK	MEK	MEK	14	15	25	26
MEK dependent mechanisms include mutations in NRAS , MEK1 and MEK2 XREF_BIBR , loss of RAS regulation by NF1 XREF_BIBR XREF_BIBR , COT overexpression driving MEK signaling XREF_BIBR , and genetic alterations in BRAF itself , such as truncation or amplification XREF_BIBR .	MEK dependent mechanisms include mutations in NRAS, MEK1 and MEK2 XREF_BIBR, loss of RAS regulation by NF1 XREF_BIBR XREF_BIBR, COT overexpression driving MEK signaling XREF_BIBR, and genetic alterations in BRAF itself, such as truncation or amplification XREF_BIBR.	22	27	driving	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT overexpression	cot	MEK	MEK	mek	22	23	25	26
Although the majority of TPL-2 in these cells was complexed with ABIN-2 , the pool of TPL-2 which could activate MEK after LPS stimulation was not , and LPS activation of TPL-2 was found to correlate with its release from ABIN-2 .	Although the majority of TPL-2 in these cells was complexed with ABIN-2, the pool of TPL-2 which could activate MEK after LPS stimulation was not, and LPS activation of TPL-2 was found to correlate with its release from ABIN-2.	14	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	MEK	MEK	MEK	16	17	20	21
p105 inhibits Tpl2 mediated activation of the MEK and ERK ( mitogen activated protein kinase kinase and extracellular regulated kinase ) pathway and this inhibition is abrogated following IKK induced proteolysis of p105 [ XREF_BIBR ] .	p105 inhibits Tpl2 mediated activation of the MEK and ERK (mitogen activated protein kinase kinase and extracellular regulated kinase) pathway and this inhibition is abrogated following IKK induced proteolysis of p105 [XREF_BIBR].	2	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	MEK	MEK	MEK	2	3	7	8
Our data show that , although MEK may be activated directly through its phosphorylation by Tpl2 , its activation is modulated by PLCbeta 3 -induced PKC signals .	Our data show that, although MEK may be activated directly through its phosphorylation by Tpl2, its activation is modulated by PLCbeta 3 -induced PKC signals.	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	MEK	MEK	MEK	15	16	6	7
We further analyzed the expression of several RTKs ( KIT , PDGFRB , MET , IGF1R , EGFR ) , the alternative MEK activator COT and BRAF on a transcriptional level .	We further analyzed the expression of several RTKs (KIT, PDGFRB, MET, IGF1R, EGFR), the alternative MEK activator COT and BRAF on a transcriptional level.	22	25	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	COT	COT	COT	MEK	MEK	MEK	24	25	22	23
In contrast , MEK kinase was fully activated by TPL2 through TLR2 signaling pathways in HEK293T cells after PAUF and LPS treatment ( XREF_FIG , lanes 8 and 9 ) .	In contrast, MEK kinase was fully activated by TPL2 through TLR2 signaling pathways in HEK293T cells after PAUF and LPS treatment (XREF_FIG, lanes 8 and 9).	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TPL2	TPL2	TPL2	MEK	MEK	MEK	9	10	3	4
One possible explanation for this observation is that high COT levels might contribute to MEK inhibitor resistance by causing MEK hyperactivation , similar to the mechanism observed for BRAF amplification [ XREF_BIBR ] .	One possible explanation for this observation is that high COT levels might contribute to MEK inhibitor resistance by causing MEK hyperactivation, similar to the mechanism observed for BRAF amplification [XREF_BIBR].	9	20	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COT	COT levels	cot	MEK	MEK	mek	9	10	19	20
Both shRNA mediated and pharmacological silencing of Mapk14 ( p38alpha ) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14 dependent activation of Mek-Erk and Atf2 signaling .	Both shRNA mediated and pharmacological silencing of Mapk14 (p38alpha) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14 dependent activation of Mek-Erk and Atf2 signaling.	25	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mapk14	Mapk14	Mapk14	Atf2	Atf2	Atf2	25	26	31	32
62 CAMK2 activates p38 ( MAPK14 ) that activates transcription factors MEF2 and ATF2 , which participate in metabolic transcription through PPARGC1A .	62 CAMK2 activates p38 (MAPK14) that activates transcription factors MEF2 and ATF2, which participate in metabolic transcription through PPARGC1A.	3	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK14	MAPK14	MAPK14	ATF2	ATF2	ATF2	5	6	13	14
Recent reports have attempted to unveil the complex mechanisms that underlie the development of resistance to sorafenib , the unique effective therapy for advanced HCC , including crosstalks of PI3 K/Akt 27 and JAK-STAT signalling , hypoxia inducible pathways 6 and epithelial to mesenchymal transition events 28 or Mapk14 dependent activation of Mek-Erk and Atf2 signalling .	Recent reports have attempted to unveil the complex mechanisms that underlie the development of resistance to sorafenib, the unique effective therapy for advanced HCC, including crosstalks of PI3 K/Akt 27 and JAK-STAT signalling, hypoxia inducible pathways 6 and epithelial to mesenchymal transition events 28 or Mapk14 dependent activation of Mek-Erk and Atf2 signalling.	48	55	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mapk14	Mapk14	Mapk14	Atf2	Atf2	Atf2	48	49	54	55
We report that the kinase GLK ( MAP4K3 ) directly activated PKC-theta during TCR signaling .	We report that the kinase GLK (MAP4K3) directly activated PKC-theta during TCR signaling.	3	12	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLK	GLK	GLK	PKC-theta	PKC-theta	PKC-theta	5	6	11	12
These data indicate that GLK activates PKC-theta independent or downstream of PDK1 .	These data indicate that GLK activates PKC-theta independent or downstream of PDK1.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLK	GLK	GLK	PKC-theta	PKC-theta	PKC-theta	4	5	6	7
Thus , GLK is a direct activator of PKC-theta , and activation of GLK-PKC-theta-IKK could be used as new diagnostic biomarkers and therapeutic targets for systemic lupus erythematosus .	Thus, GLK is a direct activator of PKC-theta, and activation of GLK-PKC-theta-IKK could be used as new diagnostic biomarkers and therapeutic targets for systemic lupus erythematosus.	2	9	is a direct activator	Positive_activation_copula_1	Positive_activation	Positive_activation	GLK	GLK	GLK	PKC-theta	PKC-theta	PKC-theta	2	3	8	9
GLK signaling in T cells induces kinase activities of PKCtheta , IKKalpha , and IKKbeta .	GLK signaling in T cells induces kinase activities of PKCtheta, IKKalpha, and IKKbeta.	0	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLK	GLK	GLK	PKCtheta	PKCtheta	PKCtheta	0	1	9	10
Additionally , overexpression of the PKCtheta-activator GLK enhances PKCtheta activity and subsequent stimulation of IKK leading to autoimmunity in systemic lupus erythematosus [ XREF_BIBR ] .	Additionally, overexpression of the PKCtheta-activator GLK enhances PKCtheta activity and subsequent stimulation of IKK leading to autoimmunity in systemic lupus erythematosus [XREF_BIBR].	2	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLK	overexpression of the PKCtheta-activator GLK	glk	PKCtheta	PKCtheta	pkctheta	6	7	8	9
In addition , Tax1 modulates the activity of kinases that activate the IKK complex , such as MEK kinase 1 ( MEKK1 ; also known as MAP3K1 ) , NIK and TGFbeta activated kinase 1 ( TAK1 ; also known as MAP3K7 ) .	In addition, Tax1 modulates the activity of kinases that activate the IKK complex, such as MEK kinase 1 (MEKK1; also known as MAP3K1), NIK and TGFbeta activated kinase 1 (TAK1; also known as MAP3K7).	29	41	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NIK	NIK	NIK	TAK1	TAK1	TAK1	29	30	36	37
Activated TAK1 phosphorylates NIK , which stimulates IKK-alpha activity .	Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity.	0	6	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NIK	phosphorylates NIK	nik	TAK1	TAK1	tak1	3	4	1	2
Many kinases have been implicated to be involved in the activation phosphorylation : NF-kappaB-inducing kinase ( NIK ) XREF_BIBR , XREF_BIBR , mitogen activated protein kinase and ERK kinase kinases 1 ( MEKK1 ) XREF_BIBR , MEKK2/3 XREF_BIBR , XREF_BIBR , Hematopoietic progenitor kinase-1 ( HPK1 ) XREF_BIBR , Mixed-lineage kinase 3 ( MLK3 ) XREF_BIBR , TGF-beta activated kinase 1 ( TAK1 ) XREF_BIBR .	Many kinases have been implicated to be involved in the activation phosphorylation : NF-kappaB-inducing kinase (NIK) XREF_BIBR, XREF_BIBR, mitogen activated protein kinase and ERK kinase kinases 1 (MEKK1) XREF_BIBR, MEKK2/3 XREF_BIBR, XREF_BIBR, Hematopoietic progenitor kinase-1 (HPK1) XREF_BIBR, Mixed-lineage kinase 3 (MLK3) XREF_BIBR, TGF-beta activated kinase 1 (TAK1) XREF_BIBR.	14	64	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NIK	NIK	NIK	TAK1	TAK1	TAK1	16	17	62	63
JNK3 is hypothesized to act upstream of the proapoptotic BCL2 family as JNK3 mediated increases in BIM and PUMA expression were absent in JNK3 gene knock-out mice .	JNK3 is hypothesized to act upstream of the proapoptotic BCL2 family as JNK3 mediated increases in BIM and PUMA expression were absent in JNK3 gene knock-out mice.	12	17	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK3	JNK3	JNK3	BIM	BIM	BIM	12	13	16	17
In lung cancer , HIP-55 overexpression appears to be correlated with reduced HPK1 levels , which may lead to diminished HPK1 tumor suppressor activity .	In lung cancer, HIP-55 overexpression appears to be correlated with reduced HPK1 levels, which may lead to diminished HPK1 tumor suppressor activity.	12	23	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HPK1	HPK1 levels	hpk1	HPK1	HPK1	hpk1	12	13	20	21
Our findings also demonstrate that c-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity .	Our findings also demonstrate that c-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity.	5	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HPK1	c-Abl phosphorylates HPK1	hpk1	HPK1	HPK1	hpk1	7	8	12	13
Knockdown of Pdcd4 up-regulates MAP4K1 expression ( XREF_FIG ) and stimulates MAP4K1 promoter activity ( XREF_FIG ) .	Knockdown of Pdcd4 up-regulates MAP4K1 expression (XREF_FIG) and stimulates MAP4K1 promoter activity (XREF_FIG).	2	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MAP4K1	Pdcd4 up-regulates MAP4K1 expression	map4k1	MAP4K1	MAP4K1	map4k1	4	5	11	12
HPK1 binds and phosphorylates MEKK1 directly , whereas JNK1 activation by HPK1 is inhibited by a dominant negative MEKK1 or MKK4 and SEK mutant .	HPK1 binds and phosphorylates MEKK1 directly, whereas JNK1 activation by HPK1 is inhibited by a dominant negative MEKK1 or MKK4 and SEK mutant.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HPK1	HPK1	HPK1	JNK1	JNK1	JNK1	11	12	8	9
Expression of HPK1 activates JNK1 specifically , and it elevates strongly AP-1-mediated transcriptional activity in vivo .	Expression of HPK1 activates JNK1 specifically, and it elevates strongly AP-1-mediated transcriptional activity in vivo.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HPK1	Expression of HPK1	hpk1	JNK1	JNK1	jnk1	2	3	4	5
MSK1 is activated in vitro by MAPK2 and ERK2 or SAPK2 and p38 .	MSK1 is activated in vitro by MAPK2 and ERK2 or SAPK2 and p38.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SAPK2	SAPK2	SAPK2	MSK1	MSK1	MSK1	10	11	0	1
In accordance with the NF-kappaB activation pathway , NIK caused MEKK1 activation resulting in IkappaB kinase phosphorylation , thus linking TNF-alpha downstream signaling molecules .	In accordance with the NF-kappaB activation pathway, NIK caused MEKK1 activation resulting in IkappaB kinase phosphorylation, thus linking TNF-alpha downstream signaling molecules.	8	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NIK	NIK	NIK	MEKK1	MEKK1	MEKK1	8	9	10	11
Interestingly , HPK1 also phosphorylated MLK-3 activation loop in vitro , and Ser281 was found to be the major phosphorylation site , indicating that HPK1 also activates MLK-3 via phosphorylation of the kinase activation loop .	Interestingly, HPK1 also phosphorylated MLK-3 activation loop in vitro, and Ser281 was found to be the major phosphorylation site, indicating that HPK1 also activates MLK-3 via phosphorylation of the kinase activation loop.	24	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HPK1	HPK1	HPK1	MLK-3	MLK-3	MLK-3	24	25	27	28
MK2 is activated by p38alpha in response to many stimuli , including cytokines and bacterial infection .	MK2 is activated by p38alpha in response to many stimuli, including cytokines and bacterial infection.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p38alpha	p38alpha	p38alpha	MK2	MK2	MK2	4	5	0	1
have shown that activation of the downstream MAPK14 targets MAPKAPK2 and MK2 and MAPKAPK3 and MK3 activates amino acid starvation induced autophagy via BECN1 phosphorylation .	have shown that activation of the downstream MAPK14 targets MAPKAPK2 and MK2 and MAPKAPK3 and MK3 activates amino acid starvation induced autophagy via BECN1 phosphorylation.	3	10	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MAPK14	MAPK14	MAPK14	MAPKAPK2	MAPKAPK2	MAPKAPK2	7	8	9	10
Likewise , the phosphorylation of p53 by mitogen activated protein kinase 14 ( Mapk14 ) , also known as p38 , activates p53 ( Harris and Levine , 2005 ) .	Likewise, the phosphorylation of p53 by mitogen activated protein kinase 14 (Mapk14), also known as p38, activates p53 (Harris and Levine, 2005).	3	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mapk14	phosphorylation of p53 by mitogen activated protein kinase 14 (Mapk14	mapk14	p53	p53	p53	13	14	22	23
The apoptotic response is also mediated by the stress activated p38 kinase ( MAPK14 ) , which modulates p53 activity through TP63 phosphorylation XREF_BIBR .	The apoptotic response is also mediated by the stress activated p38 kinase (MAPK14), which modulates p53 activity through TP63 phosphorylation XREF_BIBR.	11	19	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK14	MAPK14	MAPK14	p53	p53	p53	13	14	18	19
MAPK14 and MAPK11 phosphorylate and activate MEF-2A and MEF-2C , and MAPK7 is capable of phosphorylating and activating MEF-2A , MEF-2C and MEF-2D [ XREF_BIBR , XREF_BIBR ] .	MAPK14 and MAPK11 phosphorylate and activate MEF-2A and MEF-2C, and MAPK7 is capable of phosphorylating and activating MEF-2A, MEF-2C and MEF-2D [XREF_BIBR, XREF_BIBR].	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK14	MAPK14	MAPK14	MEF-2C	MEF-2C	MEF-2C	0	1	8	9
In conclusion , the present study suggests that MAPK15 overexpression may contribute to the malignant transformation of gastric mucosa by prolonging the stability of c-Jun .	In conclusion, the present study suggests that MAPK15 overexpression may contribute to the malignant transformation of gastric mucosa by prolonging the stability of c-Jun.	8	25	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK15	MAPK15 overexpression	mapk15	c-Jun	c-Jun	c-jun	8	9	24	25
87 MAPK14 has also been shown to activate MYOD1 as well as MYF5 and MEF2 .	87 MAPK14 has also been shown to activate MYOD1 as well as MYF5 and MEF2.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK14	MAPK14	MAPK14	MYOD1	MYOD1	MYOD1	1	2	8	9
This event involves the MAPK14 mediated enhancement of HIF1A protein stability .	This event involves the MAPK14 mediated enhancement of HIF1A protein stability.	3	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK14	MAPK14	MAPK14	HIF1A	HIF1A	HIF1A	4	5	8	9
Kaur et al ., have reported activation of PAK6 by MAPK14 and PAK6 was found to be inhibited in presence of MAPK14 antagonist [ XREF_BIBR ] .	Kaur et al., have reported activation of PAK6 by MAPK14 and PAK6 was found to be inhibited in presence of MAPK14 antagonist [XREF_BIBR].	5	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MAPK14	MAPK14	MAPK14	PAK6	PAK6	PAK6	10	11	8	9
However , coexpression of the GFP-ERK2 with its upstream activator , MEK1 , resulted in a cytosolic retention of the GFP-ERK2 , which was the result of its association with MEK1 , and was reversed upon stimulation .	However, coexpression of the GFP-ERK2 with its upstream activator, MEK1, resulted in a cytosolic retention of the GFP-ERK2, which was the result of its association with MEK1, and was reversed upon stimulation.	2	34	retention	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	GFP-ERK2	coexpression of the GFP-ERK2	gfp-erk2	GFP-ERK2	GFP-ERK2	gfp-erk2	5	6	20	21
Note that we used a clone expressing a low level of GFP-ERK2 compared with endogenous ERK ( XREF_FIG ) because overexpression of GFP-ERK2 sometimes causes abnormal ERK2 localization patterns XREF_BIBR .	Note that we used a clone expressing a low level of GFP-ERK2 compared with endogenous ERK (XREF_FIG) because overexpression of GFP-ERK2 sometimes causes abnormal ERK2 localization patterns XREF_BIBR.	20	29	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GFP-ERK2	overexpression of GFP-ERK2	gfp-erk2	ERK2	ERK2	erk2	22	23	26	27
Finally , coexpression of PTP-SL and ERK2 in COS-7 cells resulted in the retention of ERK2 in the cytoplasm in a KIM dependent manner .	Finally, coexpression of PTP-SL and ERK2 in COS-7 cells resulted in the retention of ERK2 in the cytoplasm in a KIM dependent manner.	2	16	retention	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	ERK2	coexpression of PTP-SL and ERK2	erk2	ERK2	ERK2	erk2	6	7	15	16
ERK2 levels were not higher in the brains of these animals , but in primary neurons isolated from the knock-out animals , enhanced ERK2 activation was observed , despite an equivalent activation of the upstream kinase MEK .	ERK2 levels were not higher in the brains of these animals, but in primary neurons isolated from the knock-out animals, enhanced ERK2 activation was observed, despite an equivalent activation of the upstream kinase MEK.	0	24	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2 levels	erk2	ERK2	ERK2	erk2	0	1	23	24
The c. 961G > A MAPK1 mutation resulted in constitutive ERK2 activation .	The c. 961G> A MAPK1 mutation resulted in constitutive ERK2 activation.	5	12	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	MAPK1	MAPK1	MAPK1	ERK2	ERK2	ERK2	5	6	10	11
As expected , the ectopic expression of MAPK1 with mutant 3 ' UTR rescued the function of MAPK1 and exhibited a stronger ability to promote cell proliferation and resistance than the expression of wild-type gene when contransfected with miR-20a ( XREF_FIG ) .	As expected, the ectopic expression of MAPK1 with mutant 3 ' UTR rescued the function of MAPK1 and exhibited a stronger ability to promote cell proliferation and resistance than the expression of wild-type gene when contransfected with miR-20a (XREF_FIG).	5	18	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK1	expression of MAPK1	mapk1	MAPK1	MAPK1	mapk1	7	8	17	18
NO modulation of the signaling pathway was shown by its inhibitory effect on shear stress induced ERK1 and ERK2 phosphorylation and activity .	NO modulation of the signaling pathway was shown by its inhibitory effect on shear stress induced ERK1 and ERK2 phosphorylation and activity.	15	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2 phosphorylation	erk2	ERK2	ERK2	erk2	18	19	18	19
Phosphorylation of MAPK1 at T185 and/or Y187 is reported to activate MAPK1 XREF_BIBR .	Phosphorylation of MAPK1 at T185 and/or Y187 is reported to activate MAPK1 XREF_BIBR.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK1	Phosphorylation of MAPK1 at T185 and/or Y187	mapk1	MAPK1	MAPK1	mapk1	2	3	11	12
Consistent with reduced activity of BRAF , which lies upstream of ERK2 , we observed decreased phosphorylation of the ERK2 peptide containing residues T183 and Y185 .	Consistent with reduced activity of BRAF, which lies upstream of ERK2, we observed decreased phosphorylation of the ERK2 peptide containing residues T183 and Y185.	15	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK2	phosphorylation of the ERK2 peptide containing residues T183	erk2	ERK2	ERK2	erk2	19	20	19	20
This is further supported by the data showing that A beta causes phosphorylation of ERK-1 and ERK-2 , which , in turn , activates Elk-1 .	This is further supported by the data showing that A beta causes phosphorylation of ERK-1 and ERK-2, which, in turn, activates Elk-1.	9	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK-2	A beta causes phosphorylation of ERK-1 and ERK-2	erk-2	Elk-1	Elk-1	elk-1	16	17	24	25
In conclusion , we demonstrated that the SLFs play a central role in inner ear inflammation by up-regulation of CXCL2 through c-Jun activation mediated by a MEK1 and ERK2 dependent signaling pathway .	In conclusion, we demonstrated that the SLFs play a central role in inner ear inflammation by up-regulation of CXCL2 through c-Jun activation mediated by a MEK1 and ERK2 dependent signaling pathway.	21	31	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	c-Jun	c-Jun	c-Jun	28	29	21	22
In this study , we showed that the SLFs up-regulate CXCL2 in response to NTHi via ERK2 dependent activation of the c-Jun , which is involved in inner ear inflammation secondary to OM .	In this study, we showed that the SLFs up-regulate CXCL2 in response to NTHi via ERK2 dependent activation of the c-Jun, which is involved in inner ear inflammation secondary to OM.	16	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	c-Jun	c-Jun	c-Jun	16	17	21	22
ERK2 Dependent Activation of c-Jun is Required for Nontypeable H. influenzae Induced CXCL2 Up-Regulation in Inner Ear Fibrocytes .	ERK2 Dependent Activation of c-Jun is Required for Nontypeable H. influenzae Induced CXCL2 Up-Regulation in Inner Ear Fibrocytes.	0	5	Activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	c-Jun	c-Jun	c-Jun	0	1	4	5
In contrast to LPS , this study showed that NTHi up-regulates CXCL2 only via c-Jun activation mediated by ERK2 phosphorylation .	In contrast to LPS, this study showed that NTHi up-regulates CXCL2 only via c-Jun activation mediated by ERK2 phosphorylation.	14	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK2	ERK2 phosphorylation	erk2	c-Jun	c-Jun	c-jun	18	19	14	15
These results suggested that MEK1 and ERK2 mediated activation of c-Jun is involved in NTHi induced CXCL2 up-regulation in the SLFs .	These results suggested that MEK1 and ERK2 mediated activation of c-Jun is involved in NTHi induced CXCL2 up-regulation in the SLFs.	4	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	c-Jun	c-Jun	c-Jun	6	7	10	11
It is possible this is done via the hypoxia inducible factor 1 alpha ( HIF1A ) gene as MAPK1 can activate HIF1A and this transcription factor is known to mediate VEGF expression [ XREF_BIBR , XREF_BIBR ] .	It is possible this is done via the hypoxia inducible factor 1 alpha (HIF1A) gene as MAPK1 can activate HIF1A and this transcription factor is known to mediate VEGF expression [XREF_BIBR, XREF_BIBR].	18	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK1	MAPK1	MAPK1	HIF1A	HIF1A	HIF1A	18	19	21	22
Phosphorylation by ERK1 and/or ERK2 ( MAPK3 and MAPK1 , respectively ; hereafter ERK ) stimulates the transcriptional activity of HIF-1alpha by inhibiting its CRM1 ( XPO1 )-dependent nuclear export .	Phosphorylation by ERK1 and/or ERK2 (MAPK3 and MAPK1, respectively; hereafter ERK) stimulates the transcriptional activity of HIF-1alpha by inhibiting its CRM1 (XPO1)-dependent nuclear export.	0	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	Phosphorylation by ERK1 and/or ERK2	erk2	HIF-1alpha	HIF-1alpha	hif-1alpha	4	5	20	21
It has been shown that HIF-1alpha Ser 641/643 phosphorylation by p42 MAPK ( ERK2 ) promotes HIF-1alpha nuclear accumulation and transcriptional activity [ XREF_BIBR ] .	It has been shown that HIF-1alpha Ser 641/643 phosphorylation by p42 MAPK (ERK2) promotes HIF-1alpha nuclear accumulation and transcriptional activity [XREF_BIBR].	6	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	HIF-1alpha	HIF-1alpha	HIF-1alpha	13	14	16	17
Silencing of ERK2 indeed reduced ER to Golgi transport of endogenous transferrin receptor in HeLa cells ( XREF_FIG ) .	Silencing of ERK2 indeed reduced ER to Golgi transport of endogenous transferrin receptor in HeLa cells (XREF_FIG).	0	6	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	ER	ER	ER	2	3	5	6
A major mechanism by which ERK1 and ERK2 mediate c-fos induction , is phosphorylation of TCFs [ XREF_BIBR ] .	A major mechanism by which ERK1 and ERK2 mediate c-fos induction, is phosphorylation of TCFs [XREF_BIBR].	5	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	c-fos	c-fos	c-fos	7	8	9	10
However , we observed a comparable change in the ERK2 knockdown animals , indicating c-fos was activated by ERK2 independent mechanisms .	However, we observed a comparable change in the ERK2 knockdown animals, indicating c-fos was activated by ERK2 independent mechanisms.	14	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	c-fos	c-fos	c-fos	18	19	14	15
CINDy confirmed previous predictions of modulatory interactions , such as MYC activity modulation by the STK38 , MAPK1 and CSNK2A1 proteins in B-cell lymphoma XREF_BIBR , but it also inferred a large number of established post-translational regulatory interactions that could not be detected by MINDy ( XREF_SUPPLEMENTARY ) , as well as several novel predictions .	CINDy confirmed previous predictions of modulatory interactions, such as MYC activity modulation by the STK38, MAPK1 and CSNK2A1 proteins in B-cell lymphoma XREF_BIBR, but it also inferred a large number of established post-translational regulatory interactions that could not be detected by MINDy (XREF_SUPPLEMENTARY), as well as several novel predictions.	10	20	modulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MAPK1	MAPK1	MAPK1	MYC	MYC	MYC	17	18	10	11
MEK1 and MEK2 phosphorylate ERK1 and ERK2 , which activate PI3K and c-Myc to alter cancer metabolism .	MEK1 and MEK2 phosphorylate ERK1 and ERK2, which activate PI3K and c-Myc to alter cancer metabolism.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	MEK1 and MEK2 phosphorylate ERK1 and ERK2	erk2	c-Myc	c-Myc	c-myc	6	7	12	13
Through chromatin immunoprecipitation assays and inhibition of ERK1 and ERK2 , it was found that ERK1 and ERK2 targeted Mediator Complex Subunit 1 that was recruited to the CYP24 but not the TRPV6 promoter in response to 1,25 D [ XREF_BIBR ] .	Through chromatin immunoprecipitation assays and inhibition of ERK1 and ERK2, it was found that ERK1 and ERK2 targeted Mediator Complex Subunit 1 that was recruited to the CYP24 but not the TRPV6 promoter in response to 1,25 D [XREF_BIBR].	15	23	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	Mediator Complex Subunit 1	Mediator Complex Subunit 1	Mediator Complex Subunit 1	17	18	19	23
These investigators demonstrated that Mnk1 can interact with and undergo phosphorylation by Erk2 or p38 MAPK on Thr197 and Thr202 in mice and Thr209 and Thr214 in humans , whereas Mnk2 could only interact with and be activated by Erk2 [ XREF_BIBR ] .	These investigators demonstrated that Mnk1 can interact with and undergo phosphorylation by Erk2 or p38 MAPK on Thr197 and Thr202 in mice and Thr209 and Thr214 in humans, whereas Mnk2 could only interact with and be activated by Erk2 [XREF_BIBR].	30	41	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Erk2	Erk2	Erk2	Mnk2	Mnk2	Mnk2	39	40	30	31
In contrast , the activation of the ERK2 signaling pathway failed to activate Nur77 although ERK2 is also able to phosphorylate Nur77 .	In contrast, the activation of the ERK2 signaling pathway failed to activate Nur77 although ERK2 is also able to phosphorylate Nur77.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	Nur77	Nur77	Nur77	7	8	13	14
ERK2 activation upon EGF treatment causes Nur77 nuclear localization and prevents its cytosolic induction of apoptosis [ XREF_BIBR ] , but the opposite phenotype occurs in T-cells .	ERK2 activation upon EGF treatment causes Nur77 nuclear localization and prevents its cytosolic induction of apoptosis [XREF_BIBR], but the opposite phenotype occurs in T-cells.	0	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	Nur77	Nur77	Nur77	0	1	6	7
Contrary to the effects observed with the ca and wt forms of ERK2 , increasing doses of the K52R mutant did not further enhance the nurr1 induced activity of the NBRE3x construct ( XREF_FIG ) .	Contrary to the effects observed with the ca and wt forms of ERK2, increasing doses of the K52R mutant did not further enhance the nurr1 induced activity of the NBRE3x construct (XREF_FIG).	10	26	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	nurr1	nurr1	nurr1	12	13	25	26
Notably , co-expression of HA-Bmf and ERK2 CA significantly increased mobility shift of Bmf further supporting a role for activated ERK2 to phosphorylate Bmf .	Notably, co-expression of HA-Bmf and ERK2 CA significantly increased mobility shift of Bmf further supporting a role for activated ERK2 to phosphorylate Bmf.	2	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	co-expression of HA-Bmf and ERK2	erk2	Bmf	Bmf	bmf	6	7	13	14
Our results suggest that Erk2 induced PARP1 activation mediates this activity of Erk .	Our results suggest that Erk2 induced PARP1 activation mediates this activity of Erk.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Erk2	Erk2	Erk2	PARP1	PARP1	PARP1	4	5	6	7
Lastly , siRNA mediated gene silencing of the specific MAPKs showed that knockdown of ERK1 , ERK2 and JNK inhibited PARP cleavage , while siERK2 and siJNK rendered tumor cells more resistant to autophagy as assessed by LC3II accumulation ( XREF_FIG ) .	Lastly, siRNA mediated gene silencing of the specific MAPKs showed that knockdown of ERK1, ERK2 and JNK inhibited PARP cleavage, while siERK2 and siJNK rendered tumor cells more resistant to autophagy as assessed by LC3II accumulation (XREF_FIG).	12	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	PARP	PARP	PARP	16	17	20	21
As shown in XREF_FIG , only ERK2 knockdown suppressed PARP cleavage .	As shown in XREF_FIG, only ERK2 knockdown suppressed PARP cleavage.	6	10	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	PARP	PARP	PARP	6	7	9	10
Phosphorylated ERK1/2 , particularly ERK2 , can activate PARP-1 through a direct interaction that is unrelated to DNA binding or DNA damage XREF_BIBR .	Phosphorylated ERK1/2, particularly ERK2, can activate PARP-1 through a direct interaction that is unrelated to DNA binding or DNA damage XREF_BIBR.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	PARP-1	PARP-1	PARP-1	4	5	8	9
ERK1 and 2 , activated by signaling from growth factor receptors and certain cytokine receptors , activate the transcription factors Elk-1 and c-Myc .	ERK1 and 2, activated by signaling from growth factor receptors and certain cytokine receptors, activate the transcription factors Elk-1 and c-Myc.	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1	ERK1	ERK1	Elk-1	Elk-1	Elk-1	0	1	20	21
In cells , MP1 enhanced the specific binding and activation of ERK1 with MEK1 and enhanced ERK1 activation of the nuclear substrate Elk1 in a luciferase reporter assay .	In cells, MP1 enhanced the specific binding and activation of ERK1 with MEK1 and enhanced ERK1 activation of the nuclear substrate Elk1 in a luciferase reporter assay.	16	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1	ERK1	ERK1	Elk1	Elk1	Elk1	16	17	22	23
ERK1 activates the Elk1 and CREB transcription factors via phosphorylation .	ERK1 activates the Elk1 and CREB transcription factors via phosphorylation.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1	ERK1	ERK1	Elk1	Elk1	Elk1	0	1	3	4
C5b-9 activated ERK1 , which in turn activated Elk1 in myotubes .	C5b-9 activated ERK1, which in turn activated Elk1 in myotubes.	1	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1	ERK1	ERK1	Elk1	Elk1	Elk1	2	3	8	9
In HEK293-CD14-MD2 cells expressing TLR4 , fibrinogen induced robust phosphorylation of ERK1 , p38alpha and JNK and activated transcription factors NFkappaB , Elk-1 and AP-1 ( activator protein-1 ) .	In HEK293-CD14-MD2 cells expressing TLR4, fibrinogen induced robust phosphorylation of ERK1, p38alpha and JNK and activated transcription factors NFkappaB, Elk-1 and AP-1 (activator protein-1).	6	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1	fibrinogen induced robust phosphorylation of ERK1	erk1	Elk-1	Elk-1	elk-1	11	12	22	23
Finally in the case of MAPK and ERK to TOR cross-talk , facilitated by the activation of RPS6KA1 by MAPK1 in the mouse , we found orthologues in both other organisms but no interaction in the fly .	Finally in the case of MAPK and ERK to TOR cross-talk, facilitated by the activation of RPS6KA1 by MAPK1 in the mouse, we found orthologues in both other organisms but no interaction in the fly.	12	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MAPK1	MAPK1	MAPK1	RPS6KA1	RPS6KA1	RPS6KA1	19	20	17	18
Nonetheless , the results of XREF_FIG suggest that manipulation of mTORC1 signaling by KSHV is being effected through the release from inhibition by TSC2 that is induced by ERK2 mediated activation of RSK1 .	Nonetheless, the results of XREF_FIG suggest that manipulation of mTORC1 signaling by KSHV is being effected through the release from inhibition by TSC2 that is induced by ERK2 mediated activation of RSK1.	28	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	RSK1	RSK1	RSK1	28	29	32	33
OL specific knockout of Erk2 resulted in delayed MBP translation and decreased activation of p70S6K and its downstream target S6RP , both important regulators of translation , during a critical window when pre-myelinating OLs were transitioning to mature OLs capable of generating new myelin sheaths .	OL specific knockout of Erk2 resulted in delayed MBP translation and decreased activation of p70S6K and its downstream target S6RP, both important regulators of translation, during a critical window when pre-myelinating OLs were transitioning to mature OLs capable of generating new myelin sheaths.	2	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk2	Erk2	Erk2	p70S6K	p70S6K	p70S6K	4	5	14	15
CREB is directly activated by an intermediary kinase , MSK1 , which is activated by MAPK1 ,2 .	CREB is directly activated by an intermediary kinase, MSK1, which is activated by MAPK1,2.	7	16	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MAPK1	MAPK1	MAPK1	MSK1	MSK1	MSK1	15	16	9	10
ATF-2 , a member of ATF/CREB family of transcription factors , is activated by Jun N-terminal kinase ( JNK ) , p38 , or extracellular-signal-regulated kinase 1 ( ERK1 ) through phosphorylation events at Thr69 and Thr71 [ XREF_BIBR ] .	ATF-2, a member of ATF/CREB family of transcription factors, is activated by Jun N-terminal kinase (JNK), p38, or extracellular-signal-regulated kinase 1 (ERK1) through phosphorylation events at Thr69 and Thr71 [XREF_BIBR].	0	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	extracellular-signal-regulated kinase 1	extracellular-signal-regulated kinase 1	extracellular-signal-regulated kinase 1	ATF-2	ATF-2	ATF-2	24	27	0	1
Moreover , IGF-I partially restored growth in ER positive cells treated with PI-3K and ERK1 and ERK2 inhibitors , whereas it had no protective effects in ER negative cells .	Moreover, IGF-I partially restored growth in ER positive cells treated with PI-3K and ERK1 and ERK2 inhibitors, whereas it had no protective effects in ER negative cells.	7	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ERK1	ERK1	ERK1	ER	ER	ER	14	15	7	8
XREF_BIBR In contrast , when the RSK2 proteins were activated by active ERK2 , RSK2 recovers the ability to phosphorylate NFAT3-261-365 .	XREF_BIBR In contrast, when the RSK2 proteins were activated by active ERK2, RSK2 recovers the ability to phosphorylate NFAT3-261-365.	6	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	RSK2	RSK2	RSK2	12	13	6	7
Briefly , ERK2 activated RSK2 CTD ( 5 nM ) was incubated with varying concentrations of each inhibitor for 30 minutes in the presence of 100 muM ATP and 10 mM GSH .	Briefly, ERK2 activated RSK2 CTD (5 nM) was incubated with varying concentrations of each inhibitor for 30 minutes in the presence of 100 muM ATP and 10 mM GSH.	2	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	RSK2	RSK2	RSK2	2	3	4	5
Immunoprecipitated HA-RSK2 and HA-RSK2 ( ( 1-729 ) ) could be activated to the same extent in vitro by active ERK2 , demonstrating that HA-RSK2 ( ( 1-729 ) ) was properly folded .	Immunoprecipitated HA-RSK2 and HA-RSK2 ((1-729)) could be activated to the same extent in vitro by active ERK2, demonstrating that HA-RSK2 ((1-729)) was properly folded.	0	32	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	HA-RSK2	HA-RSK2	HA-RSK2	20	21	1	2
It has previously been shown that Erk2 activation of the Sp1 transcription factor is important for EGF-induced-gastrin promoter activation .	It has previously been shown that Erk2 activation of the Sp1 transcription factor is important for EGF-induced-gastrin promoter activation.	6	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Erk2	Erk2	Erk2	Sp1	Sp1	Sp1	6	7	10	11
Pretreatment of the extracts with recombinant Erk2 stimulated Sp1 binding ; whereas dephosphorylation reduced but did not eliminate Sp1 binding .	Pretreatment of the extracts with recombinant Erk2 stimulated Sp1 binding; whereas dephosphorylation reduced but did not eliminate Sp1 binding.	3	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Erk2	Erk2	Erk2	Sp1	Sp1	Sp1	6	7	8	9
Two new major spots , presumably representing phosphorylated protein , were observed for Prdx6 that had been treated with ERK2 ( XREF_FIG ) .	Two new major spots, presumably representing phosphorylated protein, were observed for Prdx6 that had been treated with ERK2 (XREF_FIG).	11	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	Prdx6	Prdx6	Prdx6	19	20	13	14
Both ERK2 and S1P further activate SPHK1 , with ERK2 phosphorylation of SPHK1 increasing its affinity for the plasma membrane .	Both ERK2 and S1P further activate SPHK1, with ERK2 phosphorylation of SPHK1 increasing its affinity for the plasma membrane.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	SPHK1	SPHK1	SPHK1	1	2	6	7
Thus , the enhancement of the Rsk1 dependent phosphorylation of BimEL is not due to the activation of Rsk1 by Erk1 ; instead it is promoted by the phosphorylation of BimEL on Ser69 by Erk1 .	Thus, the enhancement of the Rsk1 dependent phosphorylation of BimEL is not due to the activation of Rsk1 by Erk1; instead it is promoted by the phosphorylation of BimEL on Ser69 by Erk1.	13	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Erk1	Erk1	Erk1	Rsk1	Rsk1	Rsk1	20	21	18	19
ERK1 and phospho-ERK1 or ERK2 and phospho-ERK2 were inhibited by knockdown of ERK1 or ERK2 , respectively .	ERK1 and phospho-ERK1 or ERK2 and phospho-ERK2 were inhibited by knockdown of ERK1 or ERK2, respectively.	0	14	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1	ERK1	ERK1	phospho-ERK1	phospho-ERK1	phospho-ERK1	12	13	2	3
In contrast the JNK inhibitor SP600125 and the ERK1 ,2 inhibitor UO126 resulted in increase of HIF-1alpha and P-glycoprotein in the control as well as the hyperthermia treated samples , indicating negative regulation of intrinsic HIF-1alpha and P-glycoprotein expression by ERK1 ,2 and JNK signaling cascades .	In contrast the JNK inhibitor SP600125 and the ERK1,2 inhibitor UO126 resulted in increase of HIF-1alpha and P-glycoprotein in the control as well as the hyperthermia treated samples, indicating negative regulation of intrinsic HIF-1alpha and P-glycoprotein expression by ERK1,2 and JNK signaling cascades.	8	18	increase	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	ERK1	ERK1	ERK1	HIF-1alpha	HIF-1alpha	HIF-1alpha	8	9	16	17
Along with our previous report that ERK1 promotes HDAC6 activity , we propose that HDAC6 and ERK1 may form a positive feed-forward loop , which might play a role in cancer .	Along with our previous report that ERK1 promotes HDAC6 activity, we propose that HDAC6 and ERK1 may form a positive feed-forward loop, which might play a role in cancer.	6	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1	ERK1	ERK1	HDAC6	HDAC6	HDAC6	6	7	8	9
RSK-B is a p38alphaMAPK substrate , and activated by p38alphaMAPK and , more weakly , by ERK1 .	RSK-B is a p38alphaMAPK substrate, and activated by p38alphaMAPK and, more weakly, by ERK1.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK1	ERK1	ERK1	RSK-B	RSK-B	RSK-B	16	17	0	1
Combined phosphorylation at Thr163 und Thr92 through ERK-1 increases Mcl1 stability through association with Pin-1 [ XREF_BIBR ] whereas phosphorylation at Thr163 together with Ser159 by JNK and GSK-3beta decreases Mcl1 stability as well as binding to Bim [ XREF_BIBR , XREF_BIBR ] .	Combined phosphorylation at Thr163 und Thr92 through ERK-1 increases Mcl1 stability through association with Pin-1 [XREF_BIBR] whereas phosphorylation at Thr163 together with Ser159 by JNK and GSK-3beta decreases Mcl1 stability as well as binding to Bim [XREF_BIBR, XREF_BIBR].	5	10	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ERK-1	ERK-1	ERK-1	Mcl1	Mcl1	Mcl1	7	8	9	10
Importantly , Mef2C protein has been shown to be a target of MAPK ( mitogen activated protein kinase ) signaling ; a p38MAPK recombinant protein and ERK5 ( Extracellular-signal-regulated kinase 5 ) activate Mef2C by phosphorylation of serine and threonine residues in the transactivation domain - p38MAPK phosphorylates Thr293 , Thr300 and Ser387 ; ERK5 phosphorylates Ser387 .	Importantly, Mef2C protein has been shown to be a target of MAPK (mitogen activated protein kinase) signaling; a p38MAPK recombinant protein and ERK5 (Extracellular-signal-regulated kinase 5) activate Mef2C by phosphorylation of serine and threonine residues in the transactivation domain - p38MAPK phosphorylates Thr293, Thr300 and Ser387; ERK5 phosphorylates Ser387.	24	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	Mef2C	Mef2C	Mef2C	26	27	33	34
More importantly , activation of ERK5 pathway by either serum or EGF stimulates the transactivation activity of the MEF2A , MEF2C , and MEF2D transcription factors .	More importantly, activation of ERK5 pathway by either serum or EGF stimulates the transactivation activity of the MEF2A, MEF2C, and MEF2D transcription factors.	5	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	MEF2C	MEF2C	MEF2C	5	6	20	21
In addition , mimetics of the ERK5 C-terminal phosphorylated at Thr732 and Ser769/773/775 can promote activity of the AP-1 and MEF2C transcription factors independently of ERK5 kinase activity [ XREF_BIBR ] .	In addition, mimetics of the ERK5 C-terminal phosphorylated at Thr732 and Ser769/773/775 can promote activity of the AP-1 and MEF2C transcription factors independently of ERK5 kinase activity [XREF_BIBR].	3	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	MEF2C	MEF2C	MEF2C	6	7	20	21
Serum is also a potent stimulator of BMK1 induced MEF2C phosphorylation , since a dominant negative form of BMK1 specifically inhibits serum induced activation of MEF2C .	Serum is also a potent stimulator of BMK1 induced MEF2C phosphorylation, since a dominant negative form of BMK1 specifically inhibits serum induced activation of MEF2C.	16	26	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BMK1	BMK1	BMK1	MEF2C	MEF2C	MEF2C	18	19	25	26
Next , HEK293 cells were co-transfected with pMEF2 and luciferase and mycERK5-WT or mycERK-T732A , then stimulated with EGF ( 100 ng/ml ) for 6 h. Although EGF significantly increased MEF2 activity in cells overexpressing ERK5-WT , this effect of EGF was significantly reduced in cells expressing ER-32A ( XREF_FIG ) , suggesting that ERK1/2 dependent phosphorylation of ERK5 at Thr732 enhances MEF2C activation .	Next, HEK293 cells were co-transfected with pMEF2 and luciferase and mycERK5-WT or mycERK-T732A, then stimulated with EGF (100 ng/ml) for 6 h. Although EGF significantly increased MEF2 activity in cells overexpressing ERK5-WT, this effect of EGF was significantly reduced in cells expressing ER-32A (XREF_FIG), suggesting that ERK1/2 dependent phosphorylation of ERK5 at Thr732 enhances MEF2C activation.	54	63	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK1/2 dependent phosphorylation of ERK5 at Thr732	erk5	MEF2C	MEF2C	mef2c	58	59	62	63
Conclusions : HSYA suppress HSC activation by ERK5 mediated MEF2C down-regulation and makes it a potential candidate for prevention and treatment of hepatic fibrogenesis .	Conclusions : HSYA suppress HSC activation by ERK5 mediated MEF2C down-regulation and makes it a potential candidate for prevention and treatment of hepatic fibrogenesis.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	MEF2C	MEF2C	MEF2C	7	8	9	10
During muscle differentiation of C2C12 myoblasts , Klf2 and Klf4 are upregulated by ERK5 , a member of extracellular signal regulated kinase ( ERK ) family , at least in part through activation of Sp1 , which transactivates Klf2 and Klf4 transcription .	During muscle differentiation of C2C12 myoblasts, Klf2 and Klf4 are upregulated by ERK5, a member of extracellular signal regulated kinase (ERK) family, at least in part through activation of Sp1, which transactivates Klf2 and Klf4 transcription.	7	16	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	Klf2	Klf2	Klf2	13	14	7	8
Activation of ERK5 by FT-277 and GGTI-298 lead to increase in eNOS , THBD , and KLF2 .	Activation of ERK5 by FT-277 and GGTI-298 lead to increase in eNOS, THBD, and KLF2.	0	17	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF2	KLF2	KLF2	2	3	16	17
However siRNA knockdown of ERK5 reduced KLF2 induction by both pitavastatin and the dual drug treatment confirming the role of ERK5 itself .	However siRNA knockdown of ERK5 reduced KLF2 induction by both pitavastatin and the dual drug treatment confirming the role of ERK5 itself.	2	7	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF2	KLF2	KLF2	4	5	6	7
S-flow-induced ERK5 activation in ECs up-regulates PPARs and KLF2 transcriptional activity , elicits anti-inflammatory responses , and maintains normal vascular reactivity and endothelial barrier function .	S-flow-induced ERK5 activation in ECs up-regulates PPARs and KLF2 transcriptional activity, elicits anti-inflammatory responses, and maintains normal vascular reactivity and endothelial barrier function.	1	10	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF2	KLF2	KLF2	1	2	8	9
Erk5 expression in Erk5 -/- mESCs promotes Klf2 induction upon LIF withdrawal , which requires Erk5 kinase activity ( D200A ) and upstream phosphorylation by Mek5 ( T219A Y221F ; XREF_FIG C ) .	Erk5 expression in Erk5 -/- mESCs promotes Klf2 induction upon LIF withdrawal, which requires Erk5 kinase activity (D200A) and upstream phosphorylation by Mek5 (T219A Y221F; XREF_FIG C).	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk5	Erk5 expression	erk5	Klf2	Klf2	klf2	0	1	7	8
As explained above , s-flow has a vasoprotective effect via ERK5 mediated KLF2 and eNOS expression XREF_BIBR , XREF_BIBR .	As explained above, s-flow has a vasoprotective effect via ERK5 mediated KLF2 and eNOS expression XREF_BIBR, XREF_BIBR.	8	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF2	KLF2	KLF2	10	11	12	13
The work suggests that the effect of SUMOylation on Erk5 activation of the KLF2 promoter is independent of Erk5 phosphorylation .	The work suggests that the effect of SUMOylation on Erk5 activation of the KLF2 promoter is independent of Erk5 phosphorylation.	5	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Erk5	effect of SUMOylation on Erk5	erk5	KLF2	KLF2	klf2	9	10	13	14
Because ERK5 enhances MEF2 activity and subsequently KLF2 promoter activity in ECs 19 , we also tested the effect of p90RSK activation in this context .	Because ERK5 enhances MEF2 activity and subsequently KLF2 promoter activity in ECs 19, we also tested the effect of p90RSK activation in this context.	1	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF2	KLF2	KLF2	1	2	7	8
Thus , it is mechanistically possible that statin- and FTI-277 and GGTI-298-mediated activation of ERK5 , leading to the phosphorylation of MEF2 , transcriptionally activates KLF2 and its downstream targets such as eNOS and THBD .	Thus, it is mechanistically possible that statin- and FTI-277 and GGTI-298-mediated activation of ERK5, leading to the phosphorylation of MEF2, transcriptionally activates KLF2 and its downstream targets such as eNOS and THBD.	12	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF2	KLF2	KLF2	14	15	25	26
Similar to the Gal4-ERK5 reporter , H 2 O 2 inhibited ERK5 induced KLF2 promoter activity .	Similar to the Gal4-ERK5 reporter, H 2 O 2 inhibited ERK5 induced KLF2 promoter activity.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF2	KLF2	KLF2	11	12	13	14
A previous study showed that Klf2 and Klf4 are induced by ERK5 signaling and contribute to muscle cell fusion .	A previous study showed that Klf2 and Klf4 are induced by ERK5 signaling and contribute to muscle cell fusion.	5	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	Klf2	Klf2	Klf2	11	12	5	6
50 Map3k1 and Itch also form a complex within T cells as Itch is activated by Mapk8 phosphorylation .	50 Map3k1 and Itch also form a complex within T cells as Itch is activated by Mapk8 phosphorylation.	12	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mapk8	Mapk8 phosphorylation	mapk8	Itch	Itch	itch	16	17	12	13
XREF_BIBR , XREF_BIBR However , the induction of apoptosis by Mapk8/9 is a complicated process in cells and numerous mechanisms have been proposed to account for it , including activation of Itch by Mapk8 phosphorylation and Lys48 linked poly-Ub transfer onto cellular FLICE ( FADD like IL-1beta-converting enzyme )-inhibitory protein ( c-Flip ) leading to c-Flip proteasomal degradation and the promotion of apoptosis , 27 the control of p53 stability and cell death by Mapk8/9 phosphorylation of p53 at Ser6 , 28 and Mapk8/9 phosphorylation and regulation of B-cell lymphoma 2 family members to promote cell death .	XREF_BIBR, XREF_BIBR However, the induction of apoptosis by Mapk8/9 is a complicated process in cells and numerous mechanisms have been proposed to account for it, including activation of Itch by Mapk8 phosphorylation and Lys48 linked poly-Ub transfer onto cellular FLICE (FADD like IL-1beta-converting enzyme)-inhibitory protein (c-Flip) leading to c-Flip proteasomal degradation and the promotion of apoptosis, 27 the control of p53 stability and cell death by Mapk8/9 phosphorylation of p53 at Ser6, 28 and Mapk8/9 phosphorylation and regulation of B-cell lymphoma 2 family members to promote cell death.	29	36	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Mapk8	Mapk8 phosphorylation	mapk8	Itch	Itch	itch	33	34	31	32
These observations suggested that Jnk1 may modulate ITCH activity in vivo .	These observations suggested that Jnk1 may modulate ITCH activity in vivo.	4	8	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jnk1	Jnk1	Jnk1	ITCH	ITCH	ITCH	4	5	7	8
MEKK1 activity is also required for JNK1 dependent activation of the HECT domain E3 Itch and subsequent JunB and c-Jun degradation in T cells .	MEKK1 activity is also required for JNK1 dependent activation of the HECT domain E3 Itch and subsequent JunB and c-Jun degradation in T cells.	6	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	Itch	Itch	Itch	6	7	14	15
Erk5 activation mediates KLF4 upregulation and KLF4 dependent EndMT in the absence of Ccm1 .	Erk5 activation mediates KLF4 upregulation and KLF4 dependent EndMT in the absence of Ccm1.	0	4	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk5	Erk5	Erk5	KLF4	KLF4	KLF4	0	1	3	4
Activated ERK5 promoted KLF4 upregulation through MEF2A and MEF2C transcription factors in CCM1 KO ECs , since both Mef2A andMef2C knockdown in CCM1 KO ECs reduced significantly KLF4 ( Fig XREF_FIG F top and middle panels , respectively ) .	Activated ERK5 promoted KLF4 upregulation through MEF2A and MEF2C transcription factors in CCM1 KO ECs, since both Mef2A andMef2C knockdown in CCM1 KO ECs reduced significantly KLF4 (Fig XREF_FIG F top and middle panels, respectively).	1	4	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF4	KLF4	KLF4	1	2	3	4
Therefore , although Erk5 modulates Klf4 , it does not directly impact LIF signaling .	Therefore, although Erk5 modulates Klf4, it does not directly impact LIF signaling.	3	6	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Erk5	Erk5	Erk5	Klf4	Klf4	Klf4	3	4	5	6
MEK5 activation by LSS inhibits inflammatory responses in microvascular ECs , in part through ERK5 dependent induction of KLF4 .	MEK5 activation by LSS inhibits inflammatory responses in microvascular ECs, in part through ERK5 dependent induction of KLF4.	14	19	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF4	KLF4	KLF4	14	15	18	19
For example , in C2C12 mouse myoblast , ERK5 activation of KLF4 was shown to be essential for the cell fusion into myotubes with little effect on the differentiation program [ XREF_BIBR ] .	For example, in C2C12 mouse myoblast, ERK5 activation of KLF4 was shown to be essential for the cell fusion into myotubes with little effect on the differentiation program [XREF_BIBR].	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF4	KLF4	KLF4	8	9	11	12
To establish ERK5 mediated KLF4 upregulation and KLF4 dependent EndMT as common molecular nodes in CCM , we analyzed ERK5 activation , KLF4 amount , and EndMT marker expression in WT , CCM2 KO , or CCM3 KO ECs treated with XMD8-92 or vehicle as control .	To establish ERK5 mediated KLF4 upregulation and KLF4 dependent EndMT as common molecular nodes in CCM, we analyzed ERK5 activation, KLF4 amount, and EndMT marker expression in WT, CCM2 KO, or CCM3 KO ECs treated with XMD8-92 or vehicle as control.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	KLF4	KLF4	KLF4	2	3	4	5
Mechanistically , induction of MKK7 and a JNK1 dependent activation of the AP1 transcription factor ATF2 and the Ets factor ELK1 are crucial for increased regeneration of hepatocytes with MKK4 silencing .	Mechanistically, induction of MKK7 and a JNK1 dependent activation of the AP1 transcription factor ATF2 and the Ets factor ELK1 are crucial for increased regeneration of hepatocytes with MKK4 silencing.	7	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	ATF2	ATF2	ATF2	7	8	15	16
JNK1 activates c-Jun and ATF2 , two major components of the AP-1 TF complex , as well as C/EBPbeta and Jun B [ XREF_BIBR ] .	JNK1 activates c-Jun and ATF2, two major components of the AP-1 TF complex, as well as C/EBPbeta and Jun B [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	ATF2	ATF2	ATF2	0	1	4	5
ERK5 is a known activator of MEF2A , -C , and -D .	ERK5 is a known activator of MEF2A, -C, and -D.	0	11	is a known activator	Positive_activation_copula_1	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	MEF2A	MEF2A	MEF2A	0	1	6	7
Since both p38 and ERK5 activate MEF-2 by phosphorylation [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] , it is highly likely that activation of these signaling pathways by Tax activate MEF-2 .	Since both p38 and ERK5 activate MEF-2 by phosphorylation [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR], it is highly likely that activation of these signaling pathways by Tax activate MEF-2.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	MEF-2	MEF-2	MEF-2	4	5	6	7
MEK5 induction of KLF4 is mediated by ERK5 .	MEK5 induction of KLF4 is mediated by ERK5.	0	8	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	MEK5	MEK5	MEK5	7	8	0	1
Activated MEK5 phosphorylates ERK5 , which then translocates into the nuclease to activate gene transcription .	Activated MEK5 phosphorylates ERK5, which then translocates into the nuclease to activate gene transcription.	0	7	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	phosphorylates ERK5	erk5	MEK5	MEK5	mek5	3	4	1	2
Inhibition of ERK5 abrogated the effects of MEK5 activity on tumorigenicity of A549 spheres through hypoxia inducible factor 1alpha ( HIF1alpha )-mediated upregulation of apoptosis associated genes BCL2 interacting protein 3 ( BNIP3 ) and BNIP3 like ( BNIP3L ) .	Inhibition of ERK5 abrogated the effects of MEK5 activity on tumorigenicity of A549 spheres through hypoxia inducible factor 1alpha (HIF1alpha)-mediated upregulation of apoptosis associated genes BCL2 interacting protein 3 (BNIP3) and BNIP3 like (BNIP3L).	0	8	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	MEK5	MEK5	MEK5	2	3	7	8
Furthermore , the presence of selumetinib failed to increase ERK5 dependent activation of the MEF2D luciferase reporter ( XREF_FIG ) .	Furthermore, the presence of selumetinib failed to increase ERK5 dependent activation of the MEF2D luciferase reporter (XREF_FIG).	9	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	MEF2D	MEF2D	MEF2D	9	10	14	15
Overexpression of JNK-1 promotes DAF-16 and FOXO nuclear localization under conditions of stress [ XREF_BIBR ] .	Overexpression of JNK-1 promotes DAF-16 and FOXO nuclear localization under conditions of stress [XREF_BIBR].	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK-1	Overexpression of JNK-1	jnk-1	FOXO	FOXO	foxo	2	3	6	7
Therefore , inhibition of MAPK6 hydroxylation by various prolyl hydroxylase inhibitors decreases MAPK6 protein stability in cells .	Therefore, inhibition of MAPK6 hydroxylation by various prolyl hydroxylase inhibitors decreases MAPK6 protein stability in cells.	2	14	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK6	inhibition of MAPK6 hydroxylation by various prolyl hydroxylase inhibitors	mapk6	MAPK6	MAPK6	mapk6	4	5	12	13
Therefore , ERK3 phosphorylation and association with MK5 might be necessary to allow ERK3 function in T lymphocytes .	Therefore, ERK3 phosphorylation and association with MK5 might be necessary to allow ERK3 function in T lymphocytes.	2	14	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK3	ERK3 phosphorylation	erk3	ERK3	ERK3	erk3	2	3	13	14
As expected , ERK3 overexpression greatly increased HeLa cell migration ( ERK3 WT versus empty vector ( EV ) , Fig .	As expected, ERK3 overexpression greatly increased HeLa cell migration (ERK3 WT versus empty vector (EV), Fig.	3	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK3	ERK3 overexpression	erk3	ERK3	ERK3	erk3	3	4	11	12
During growth factor induced cell stimulation , BMK1 activates SGK by phosphorylation at serine 78 .	During growth factor induced cell stimulation, BMK1 activates SGK by phosphorylation at serine 78.	7	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMK1	BMK1	BMK1	SGK	SGK	SGK	7	8	9	10
ERK3 promotes the interactions of SRC3 with CBP and SP1 .	ERK3 promotes the interactions of SRC3 with CBP and SP1.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK3	ERK3	ERK3	SRC3	SRC3	SRC3	0	1	5	6
Indeed , overexpression of ERK3 ( XREF_FIG ) enhanced the interactions of SRC-3 with CBP and SP1 ( XREF_FIG ) .	Indeed, overexpression of ERK3 (XREF_FIG) enhanced the interactions of SRC-3 with CBP and SP1 (XREF_FIG).	2	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK3	overexpression of ERK3	erk3	SRC-3	SRC-3	src-3	4	5	12	13
JunD is activated by JNK1 and has a major role in mediating increased AP-1 transcriptional activity .	JunD is activated by JNK1 and has a major role in mediating increased AP-1 transcriptional activity.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	JunD	JunD	JunD	4	5	0	1
By contrast , JNK1 represses T H 2 polarization by inhibiting nuclear factor of activated T cells c1 ( NFATc1 ) and promoting the degradation of JunB .	By contrast, JNK1 represses T H 2 polarization by inhibiting nuclear factor of activated T cells c1 (NFATc1) and promoting the degradation of JunB.	3	27	represses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	JunB	JunB	JunB	3	4	26	27
It has been shown that ERK1 contributes to apoptosis by activating the tumor suppressor p53 XREF_BIBR , XREF_BIBR .	It has been shown that ERK1 contributes to apoptosis by activating the tumor suppressor p53 XREF_BIBR, XREF_BIBR.	5	15	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1	ERK1	ERK1	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	5	6	12	15
Interestingly , constitutive active IRF3 ( 5D ) can be inhibited by SP600125 ; JNK1 can synergize the action of IRF3 ( 5D ) , but not the S173A-IRF3 ( 5D ) mutant .	Interestingly, constitutive active IRF3 (5D) can be inhibited by SP600125; JNK1 can synergize the action of IRF3 (5D), but not the S173A-IRF3 (5D) mutant.	14	22	synergize	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	IRF3	IRF3	IRF3	14	15	20	21
Silencing of JNK-1 with validated siRNAs ( XREF_FIG ) prevented the shift in the size of Bim and Bmf ( XREF_FIG ) , indicating a role of JNK-1 in post-translational modification of Bim-L and Bmf in Ngo infected cells .	Silencing of JNK-1 with validated siRNAs (XREF_FIG) prevented the shift in the size of Bim and Bmf (XREF_FIG), indicating a role of JNK-1 in post-translational modification of Bim-L and Bmf in Ngo infected cells.	0	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK-1	JNK-1	JNK-1	Bmf	Bmf	Bmf	2	3	18	19
JNK1 phosphorylation leads to activator protein 1 ( AP1 ) activation , a transcription factor complex known to induce TF transcription .	JNK1 phosphorylation leads to activator protein 1 (AP1) activation, a transcription factor complex known to induce TF transcription.	0	7	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	JNK1	JNK1 phosphorylation	jnk1	activator protein 1	activator protein 1	activator protein 1	0	1	4	7
Stable inhibition of JNK-1 and JNK-2 in MCF-7 cells blocks flavonoid induced activation of AP-1 , Elk , and c-Jun .	Stable inhibition of JNK-1 and JNK-2 in MCF-7 cells blocks flavonoid induced activation of AP-1, Elk, and c-Jun.	1	20	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK-1	JNK-1	JNK-1	c-Jun	c-Jun	c-Jun	3	4	19	20
Overexpression of JNK1 in jnk (-/-) fibroblasts restored the ability of cytokines and Jun proteins to interfere with SMAD signaling .	Overexpression of JNK1 in jnk (-/-) fibroblasts restored the ability of cytokines and Jun proteins to interfere with SMAD signaling.	0	14	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	Overexpression of JNK1	jnk1	Jun	Jun	jun	2	3	13	14
Carbachol activation of JNK1 resulted in induction of c-Jun ( protein ) transcriptional activity and in stimulation of parietal cell mRNA content of c-jun .	Carbachol activation of JNK1 resulted in induction of c-Jun (protein) transcriptional activity and in stimulation of parietal cell mRNA content of c-jun.	1	10	resulted in induction	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	c-Jun	c-Jun	c-Jun	3	4	8	9
Moreover , chronic ER stress triggers inflammation via IRE1alpha , resulting in stimulation of IkappaB kinase ( IKK ) and c-jun N-terminal protein kinase 1 ( JNK1 ) that activate nuclear factor-kappaB ( NF-kappaB ) and activator protein 1 ( AP-1 ) , respectively , XREF_BIBR events that are also linked to insulin resistance .	Moreover, chronic ER stress triggers inflammation via IRE1alpha, resulting in stimulation of IkappaB kinase (IKK) and c-jun N-terminal protein kinase 1 (JNK1) that activate nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1), respectively, XREF_BIBR events that are also linked to insulin resistance.	10	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	activator protein 1	activator protein 1	activator protein 1	26	27	36	39
6 Alcohol mediated activation of JNK1 upregulates c-Jun and enhances the activity of AP-1 .	6 Alcohol mediated activation of JNK1 upregulates c-Jun and enhances the activity of AP-1.	1	8	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	Alcohol mediated activation of JNK1	jnk1	c-Jun	c-Jun	c-jun	5	6	7	8
In a study of diffuse axonal injury , JNK1 activates the downstream factor c-Jun and in turn activates ATF-3 , promoting axonal regeneration .	In a study of diffuse axonal injury, JNK1 activates the downstream factor c-Jun and in turn activates ATF-3, promoting axonal regeneration.	8	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	c-Jun	c-Jun	c-Jun	8	9	13	14
JNK1 and JNK2 , both serine/threonine protein kinases that are activated by stress can positively activate c-jun , a key component for stimulating AP-1 binding sites [ XREF_BIBR ] , including the AP-1 site in the IFN-beta promoter .	JNK1 and JNK2, both serine/threonine protein kinases that are activated by stress can positively activate c-jun, a key component for stimulating AP-1 binding sites [XREF_BIBR], including the AP-1 site in the IFN-beta promoter.	0	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	c-jun	c-jun	c-jun	0	1	16	17
78 JNK1 increases c-Jun activity and stability , whereas JNK2 binds preferentially to c-Jun in nonstimulated cells and directs it toward degradation .	78 JNK1 increases c-Jun activity and stability, whereas JNK2 binds preferentially to c-Jun in nonstimulated cells and directs it toward degradation.	0	4	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	c-Jun	c-Jun	c-Jun	1	2	3	4
CD105 resulted in high phosphorylation of JNK1 , which is able to activate c-Jun .	CD105 resulted in high phosphorylation of JNK1, which is able to activate c-Jun.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	CD105 resulted in high phosphorylation of JNK1	jnk1	c-Jun	c-Jun	c-jun	6	7	13	14
JNK1 also upregulates c-Jun which suppresses p53 [ XREF_BIBR ] .	JNK1 also upregulates c-Jun which suppresses p53 [XREF_BIBR].	0	5	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	c-Jun	c-Jun	c-Jun	0	1	3	4
XREF_BIBR , XREF_BIBR Both JNKs phosphorylate c-Jun , but JNK1 positively regulates c-Jun stability , whereas JNK2 negatively regulates it .	XREF_BIBR, XREF_BIBR Both JNKs phosphorylate c-Jun, but JNK1 positively regulates c-Jun stability, whereas JNK2 negatively regulates it.	9	13	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	c-Jun	c-Jun	c-Jun	9	10	12	13
Alcohol activated JNK1 increases c-Jun activity to augment Pol III gene transcription .	Alcohol activated JNK1 increases c-Jun activity to augment Pol III gene transcription.	2	5	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	c-Jun	c-Jun	c-Jun	2	3	4	5
JNK1 mediates the majority of c-jun phosphorylation and JNK2 mainly regulates c-jun stability .	JNK1 mediates the majority of c-jun phosphorylation and JNK2 mainly regulates c-jun stability.	0	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	c-jun	c-jun	c-jun	0	1	11	12
Transfection of dominant negative JNK1 blocked SAPK and JNK activation in colon cancer cell line HT29 and rendered it sensitive to oxaliplatin under hypoxia .	Transfection of dominant negative JNK1 blocked SAPK and JNK activation in colon cancer cell line HT29 and rendered it sensitive to oxaliplatin under hypoxia.	0	9	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	SAPK	SAPK	SAPK	4	5	6	7
In the LNZ plantaris , Jnk1 phosphorylation increased 115.2 +/- 31.9 % , 140.0 +/- 27.9 % , and 105.4 +/- 34.5 % , and Jnk2 by 354.2 +/- 140.3 % , 472.8 +/- 49.7 % , and 153.0 +/- 70.0 % from baseline at 0 , 1 , and 3 hours , respectively , ( P < .05 ) .	In the LNZ plantaris, Jnk1 phosphorylation increased 115.2 +/- 31.9%, 140.0 +/- 27.9%, and 105.4 +/- 34.5%, and Jnk2 by 354.2 +/- 140.3%, 472.8 +/- 49.7%, and 153.0 +/- 70.0% from baseline at 0, 1, and 3 hours, respectively, (P <.05).	5	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Jnk1	Jnk1 phosphorylation	jnk1	Jnk2	Jnk2	jnk2	5	6	25	26
XREF_BIBR , XREF_BIBR The ALDH1L1 induced phosphorylation of p53 is accomplished by JNK2 , which is activated through phosphorylation by JNK1 .	XREF_BIBR, XREF_BIBR The ALDH1L1 induced phosphorylation of p53 is accomplished by JNK2, which is activated through phosphorylation by JNK1.	10	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	JNK2	JNK2	JNK2	20	21	12	13
In addition , SP600125 and the silence of JNK1 gene could synergistically increase apoptosis induced by HCPT , instead of the silence of JNK2 gene .	In addition, SP600125 and the silence of JNK1 gene could synergistically increase apoptosis induced by HCPT, instead of the silence of JNK2 gene.	8	24	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	JNK2	JNK2	JNK2	8	9	23	24
JNK1 activation in Jnk2 -/- hepatocytes stabilizes the anti-apoptotic protein Mcl-1 to prevent its degradation and block TNF mediated apoptosis 28 .	JNK1 activation in Jnk2 -/- hepatocytes stabilizes the anti-apoptotic protein Mcl-1 to prevent its degradation and block TNF mediated apoptosis 28.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	Jnk2	Jnk2	Jnk2	0	1	3	4
While both JNK1 and JNK2 shRNA displayed specific targeting effects in both B16-RCKD and 4T1-RCKD clones , the JNK1 shRNA increased Jnk2 mRNA and JNK2 protein in 4T1 cells , indicating a potential role of JNK1 in repressing JNK2 expression under steady-state conditions .	While both JNK1 and JNK2 shRNA displayed specific targeting effects in both B16-RCKD and 4T1-RCKD clones, the JNK1 shRNA increased Jnk2 mRNA and JNK2 protein in 4T1 cells, indicating a potential role of JNK1 in repressing JNK2 expression under steady-state conditions.	18	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	Jnk2	Jnk2	Jnk2	18	19	21	22
In all cases where JNK2 silencing induced apoptosis we found that co-silencing JNK1 with JNK2 rescued JNK2 depleted cells from apoptosis ( XREF_FIG ) .	In all cases where JNK2 silencing induced apoptosis we found that co-silencing JNK1 with JNK2 rescued JNK2 depleted cells from apoptosis (XREF_FIG).	11	17	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	JNK2	JNK2	JNK2	12	13	16	17
IFNbeta increased JNK activation in hepatocytes ( XREF_FIG ) ; interestingly , anti-IFNbeta Ab inhibited LPS and HSC induced activation of JNK1 , but strongly increased JNK2 activation beyond that by LPS and HSC ( XREF_FIG ) .	IFNbeta increased JNK activation in hepatocytes (XREF_FIG); interestingly, anti-IFNbeta Ab inhibited LPS and HSC induced activation of JNK1, but strongly increased JNK2 activation beyond that by LPS and HSC (XREF_FIG).	12	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	anti-IFNbeta Ab inhibited LPS and HSC induced activation of JNK1	jnk1	JNK2	JNK2	jnk2	21	22	26	27
JNK1 and JNK2 both mediate insulin resistance in high fat diet fed mice , but the JNK isoforms have distinct effects on steatohepatitis with JNK1 promoting steatosis and hepatitis and JNK2 inhibiting hepatocyte cell death by blocking the mitochondrial death pathway .	JNK1 and JNK2 both mediate insulin resistance in high fat diet fed mice, but the JNK isoforms have distinct effects on steatohepatitis with JNK1 promoting steatosis and hepatitis and JNK2 inhibiting hepatocyte cell death by blocking the mitochondrial death pathway.	18	31	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	JNK2	JNK2	JNK2	24	25	30	31
In turn , PRAK directly phosphorylates and activates p53 leading to cellular senescence 54 .	In turn, PRAK directly phosphorylates and activates p53 leading to cellular senescence 54.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRAK	PRAK	PRAK	p53	p53	p53	3	4	8	9
MK5 has been shown to stimulate the transcriptional activity of p53 by direct phosphorylation of p53 at Ser 37 [ XREF_BIBR ] .	MK5 has been shown to stimulate the transcriptional activity of p53 by direct phosphorylation of p53 at Ser 37 [XREF_BIBR].	0	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK5	MK5	MK5	p53	p53	p53	0	1	10	11
In MEFs derived from Deltaex8 mice , H-Ras-G12V-induced p21 WAF expression was significantly decreased and it was postulated that the presence of MK5 and PRAK stimulates the activity of p53 by phosphorylation of serine 37 to increase p21 WAF1 expression [ XREF_BIBR ] .	In MEFs derived from Deltaex8 mice, H-Ras-G12V-induced p21 WAF expression was significantly decreased and it was postulated that the presence of MK5 and PRAK stimulates the activity of p53 by phosphorylation of serine 37 to increase p21 WAF1 expression [XREF_BIBR].	20	30	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK5	MK5	MK5	p53	p53	p53	22	23	29	30
Furthermore , we show that PRAK activates p53 by direct phosphorylation .	Furthermore, we show that PRAK activates p53 by direct phosphorylation.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRAK	PRAK	PRAK	p53	p53	p53	5	6	7	8
Furthermore , p38 and PRAK could activate p53 in response to oncogenic Ras to mediate cellular senescence .	Furthermore, p38 and PRAK could activate p53 in response to oncogenic Ras to mediate cellular senescence.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRAK	PRAK	PRAK	p53	p53	p53	4	5	7	8
We previously showed that in a skin cancer model , PRAK suppressed carcinogenesis by inducing the tumor suppressing activity of p53 through phosphorylation of p53 at Ser37 .	We previously showed that in a skin cancer model, PRAK suppressed carcinogenesis by inducing the tumor suppressing activity of p53 through phosphorylation of p53 at Ser37.	10	21	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PRAK	PRAK	PRAK	p53	p53	p53	10	11	20	21
A previous study has shown that MK2 can promote cytoplasmic accumulation of HuR in HeLa cells [ XREF_BIBR ] .	A previous study has shown that MK2 can promote cytoplasmic accumulation of HuR in HeLa cells [XREF_BIBR].	6	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	6	7	12	13
We found that TNF-alpha stimulation induced cytoplasmic accumulation of HuR , which was significantly suppressed by MK2 silencing .	We found that TNF-alpha stimulation induced cytoplasmic accumulation of HuR, which was significantly suppressed by MK2 silencing.	7	17	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	16	17	9	10
The activation of p38 and MK2 pathway by Kaposin B also induces accumulation of HuR , an ARE stabilizing AREBP , leading to the overexpression of ARE containing trasncripts [ XREF_BIBR ] .	The activation of p38 and MK2 pathway by Kaposin B also induces accumulation of HuR, an ARE stabilizing AREBP, leading to the overexpression of ARE containing trasncripts [XREF_BIBR].	3	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	5	6	14	15
MK2 promotes cytoplasmic accumulation of HuR .	MK2 promotes cytoplasmic accumulation of HuR.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	0	1	5	6
In this study , we found that knockdown of MK2 by siRNA did not affect the expression but significantly impaired the cytoplasmic accumulation of HuR after TNF-alpha stimulation in HPMECs .	In this study, we found that knockdown of MK2 by siRNA did not affect the expression but significantly impaired the cytoplasmic accumulation of HuR after TNF-alpha stimulation in HPMECs.	7	25	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	9	10	24	25
Furthermore , it has been reported that active MK2 induces cytoplasmic accumulation of HuR , which correlates with increased stability of urokinase plasminogen activator ( uPA ) and uPA receptor mRNAs that have AREs in their 3 '-UTR [ XREF_BIBR , XREF_BIBR ] .	Furthermore, it has been reported that active MK2 induces cytoplasmic accumulation of HuR, which correlates with increased stability of urokinase plasminogen activator (uPA) and uPA receptor mRNAs that have AREs in their 3 '-UTR [XREF_BIBR, XREF_BIBR].	7	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	8	9	13	14
Therefore , we asked if activated MK2 can promote cytoplasmic localization of HuR protein in LECs and transfected LECs with vectors expressing a wild type , constitutively active ( EE ) or dominant negative ( K76R ) form of MK2 protein XREF_BIBR .	Therefore, we asked if activated MK2 can promote cytoplasmic localization of HuR protein in LECs and transfected LECs with vectors expressing a wild type, constitutively active (EE) or dominant negative (K76R) form of MK2 protein XREF_BIBR.	5	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	6	7	12	13
These results suggest that MK2 promotes cytoplasmic accumulation of HuR after TNF-alpha stimulation in HPMECs .	These results suggest that MK2 promotes cytoplasmic accumulation of HuR after TNF-alpha stimulation in HPMECs.	4	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	4	5	9	10
It is thus possible that activation of p38 MAPK and MK2 by TNF-alpha stimulation may promote the cytoplasmic accumulation of HuR in HPMECs .	It is thus possible that activation of p38 MAPK and MK2 by TNF-alpha stimulation may promote the cytoplasmic accumulation of HuR in HPMECs.	5	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	10	11	20	21
MK2 may directly interact and phosphorylate and activate LIMK1 XREF_BIBR .	MK2 may directly interact and phosphorylate and activate LIMK1 XREF_BIBR.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	LIMK1	LIMK1	LIMK1	0	1	8	9
Although p38 phosphorylated LIMK1 at Ser 310 , it failed to activate LIMK1 directly ; however , MK2 activated LIMK1 by phosphorylation at Ser 323 .	Although p38 phosphorylated LIMK1 at Ser 310, it failed to activate LIMK1 directly; however, MK2 activated LIMK1 by phosphorylation at Ser 323.	17	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	LIMK1	LIMK1	LIMK1	17	18	19	20
In this study , we demonstrate that activation of LIMK1 by MAPKAPK-2 ( MK2 ; a downstream kinase of p38 MAPK ) represents a novel signaling pathway in VEGF-A-induced cell migration .	In this study, we demonstrate that activation of LIMK1 by MAPKAPK-2 (MK2; a downstream kinase of p38 MAPK) represents a novel signaling pathway in VEGF-A-induced cell migration.	7	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MAPKAPK-2	MAPKAPK-2	MAPKAPK-2	LIMK1	LIMK1	LIMK1	11	12	9	10
Moreover , it was reported that MK2 activation of LIMK1 through phosphorylation of Ser323 is required in VEGF induced actin remodeling and cell migration XREF_BIBR .	Moreover, it was reported that MK2 activation of LIMK1 through phosphorylation of Ser323 is required in VEGF induced actin remodeling and cell migration XREF_BIBR.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MK2	MK2	MK2	LIMK1	LIMK1	LIMK1	6	7	9	10
Our findings suggest that in bladder cancer , JNK2 promotes p53 stability and downstream apoptosis signaling through phosphorylation of p53 at Thr81 site rather than at Ser6 site .	Our findings suggest that in bladder cancer, JNK2 promotes p53 stability and downstream apoptosis signaling through phosphorylation of p53 at Thr81 site rather than at Ser6 site.	8	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK2	JNK2	JNK2	p53	p53	p53	8	9	10	11
Based on these results , we hypothesized that JNK2 may promote p53 stability and biological activity in bladder cancer .	Based on these results, we hypothesized that JNK2 may promote p53 stability and biological activity in bladder cancer.	8	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK2	JNK2	JNK2	p53	p53	p53	8	9	11	12
JNK2 promotes stability and pro apoptotic activity of p53 through p53 phosphorylation at Thr81 .	JNK2 promotes stability and pro apoptotic activity of p53 through p53 phosphorylation at Thr81.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK2	JNK2	JNK2	p53	p53	p53	0	1	8	9
Since our results indicate that JNK2 promotes p53 stability through phosphorylation of p53 at Thr81 , and that phosphatase treatment increases the MDM2-p53 interaction ( XREF_SUPPLEMENTARY ) , we constructed a p53 Thr81Ala mutant to determine whether p53 phosphorylation at Thr81 is important for blocking the MDM2-p53 interaction .	Since our results indicate that JNK2 promotes p53 stability through phosphorylation of p53 at Thr81, and that phosphatase treatment increases the MDM2-p53 interaction (XREF_SUPPLEMENTARY), we constructed a p53 Thr81Ala mutant to determine whether p53 phosphorylation at Thr81 is important for blocking the MDM2-p53 interaction.	5	8	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK2	JNK2	JNK2	p53	p53	p53	5	6	7	8
We show here that 2-ME2 treatment of leukemia cells promoted a p53 independent apoptotic response characterized by Bcl-2 downregulation and phosphorylation mediated by JNK and SAPK , Bak up-regulation , proteolytic cleavages of caspases-9 , -3 and PARP-1 .	We show here that 2-ME2 treatment of leukemia cells promoted a p53 independent apoptotic response characterized by Bcl-2 downregulation and phosphorylation mediated by JNK and SAPK, Bak up-regulation, proteolytic cleavages of caspases-9, -3 and PARP-1.	9	26	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	SAPK	SAPK	SAPK	p53	p53	p53	25	26	11	12
XREF_BIBR , XREF_BIBR These authors hypothesized a positive feedback loop between wtp53 and JNK and SAPK explaining a possible activation of p53 through JNK and SAPK , which then induces a p53 dependent apoptosis .	XREF_BIBR, XREF_BIBR These authors hypothesized a positive feedback loop between wtp53 and JNK and SAPK explaining a possible activation of p53 through JNK and SAPK, which then induces a p53 dependent apoptosis.	16	33	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SAPK	SAPK	SAPK	p53	p53	p53	25	26	31	32
An interaction between SIRT1 and JNK1 was observed only when cells were treated with the known JNK1 activators anisomycin or H 2 O 2 ( XREF_FIG ) .	An interaction between SIRT1 and JNK1 was observed only when cells were treated with the known JNK1 activators anisomycin or H 2 O 2 (XREF_FIG).	1	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	SIRT1	SIRT1	SIRT1	16	17	3	4
Interestingly , the activation of SIRT1 by JNK1 specifically deacetylated histone H3 but not p53 , a major target of SIRT1 .	Interestingly, the activation of SIRT1 by JNK1 specifically deacetylated histone H3 but not p53, a major target of SIRT1.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	SIRT1	SIRT1	SIRT1	7	8	5	6
While our data can not exclude the possibility that SIRT1 protein is targeted by JNK1 for proteasomal degradation , the presence of the ~ 80 kD SIRT1 species , only detected by the carboxy-terminal antibody , points to a more specific proteolytic mechanism , that could be triggered by HFD .	While our data can not exclude the possibility that SIRT1 protein is targeted by JNK1 for proteasomal degradation, the presence of the ~ 80 kD SIRT1 species, only detected by the carboxy-terminal antibody, points to a more specific proteolytic mechanism, that could be triggered by HFD.	9	17	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	SIRT1	SIRT1	SIRT1	14	15	9	10
XREF_BIBR , XREF_BIBR Furthermore , SIRT1 is regulated in response to oxidative stress through phosphorylation at Ser27 , Ser47 and Thr530 by the JNK1 kinase , which stimulates SIRT1 activity and nuclear localization .	XREF_BIBR, XREF_BIBR Furthermore, SIRT1 is regulated in response to oxidative stress through phosphorylation at Ser27, Ser47 and Thr530 by the JNK1 kinase, which stimulates SIRT1 activity and nuclear localization.	23	29	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	SIRT1	SIRT1	SIRT1	23	24	28	29
Interestingly , our study showed that JNK2 knockdown but not JNK1 knockdown largely suppressed activation of ATF-2 , suggesting that JNK2 might promote CSC phenotype in TNBC through both ATF-2 and c-Jun , which form heterodimers and stimulate CRE dependent transcription 33 .	Interestingly, our study showed that JNK2 knockdown but not JNK1 knockdown largely suppressed activation of ATF-2, suggesting that JNK2 might promote CSC phenotype in TNBC through both ATF-2 and c-Jun, which form heterodimers and stimulate CRE dependent transcription 33.	6	17	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK2	JNK2	JNK2	ATF-2	ATF-2	ATF-2	6	7	16	17
Finally , Rac1 GTPase and Jun N-terminal kinase 2 ( JNK2 ) have also been shown to promote beta-catenin nuclear localization upon Wnt signaling , although the mechanism by which this is accomplished is unclear .	Finally, Rac1 GTPase and Jun N-terminal kinase 2 (JNK2) have also been shown to promote beta-catenin nuclear localization upon Wnt signaling, although the mechanism by which this is accomplished is unclear.	3	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	10	11	18	19
MAPK9 is a first neighbour of a colon cancer related protein , beta-catenin , and inhibition of MAPK9 was found to down-regulate beta-catenin .	MAPK9 is a first neighbour of a colon cancer related protein, beta-catenin, and inhibition of MAPK9 was found to down-regulate beta-catenin.	15	23	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK9	MAPK9	MAPK9	beta-catenin	beta-catenin	beta-catenin	17	18	22	23
In conclusion , our present data demonstrate that activated JNK2 promoted beta-catenin degradation and inhibited the canonical Wnt and beta-catenin signaling in vitro , and that JNK2 deficiency upregulated beta-catenin signaling in vivo , in which GSK3beta is likely to play a critical role .	In conclusion, our present data demonstrate that activated JNK2 promoted beta-catenin degradation and inhibited the canonical Wnt and beta-catenin signaling in vitro, and that JNK2 deficiency upregulated beta-catenin signaling in vivo, in which GSK3beta is likely to play a critical role.	8	14	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	9	10	11	12
The in vivo data provided additional evidence that GSK3beta is involved in JNK2 mediated beta-catenin regulation .	The in vivo data provided additional evidence that GSK3beta is involved in JNK2 mediated beta-catenin regulation.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	12	13	14	15
To determine whether the decrease of beta-catenin protein induced by JNK2 activation is due to increased proteasomal degradation , a proteasomal inhibitor MG132 XREF_BIBR was used to treat HEK293T cells after transfection with MKK7-JNK2 and beta-catenin .	To determine whether the decrease of beta-catenin protein induced by JNK2 activation is due to increased proteasomal degradation, a proteasomal inhibitor MG132 XREF_BIBR was used to treat HEK293T cells after transfection with MKK7-JNK2 and beta-catenin.	6	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	10	11	6	7
This phosphorylation is likely to have converted p53 into an apoptotic target because p53 breakdown correlated with caspase-3 activity , was inhibited by a caspase-3 inhibitor in a dose dependent manner , and was inhibited by transfection of dominant negative JNK1 .	This phosphorylation is likely to have converted p53 into an apoptotic target because p53 breakdown correlated with caspase-3 activity, was inhibited by a caspase-3 inhibitor in a dose dependent manner, and was inhibited by transfection of dominant negative JNK1.	13	41	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	p53	p53	p53	40	41	13	14
Interestingly , co-silencing of JNK1 with JNK2 abrogated the rise in p53 ( XREF_FIG ) implying that JNK1 and JNK2 exert co-ordinated effects upon the turnover of p53 .	Interestingly, co-silencing of JNK1 with JNK2 abrogated the rise in p53 (XREF_FIG) implying that JNK1 and JNK2 exert co-ordinated effects upon the turnover of p53.	2	15	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	p53	p53	p53	4	5	11	12
To determine whether increased Bim expression was a mechanism of the increased hepatic injury that resulted from JNK2 inhibition , liver injury was compared in HFD fed wild-type and bim -/- mice treated with the JNK2 ASO .	To determine whether increased Bim expression was a mechanism of the increased hepatic injury that resulted from JNK2 inhibition, liver injury was compared in HFD fed wild-type and bim -/- mice treated with the JNK2 ASO.	27	36	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	JNK2	JNK2	JNK2	bim	bim	bim	35	36	29	30
We therefore , examined if knockdown of JNK1 prevents downregulation of Mcl-1 caused by S6K2 deficiency .	We therefore, examined if knockdown of JNK1 prevents downregulation of Mcl-1 caused by S6K2 deficiency.	5	12	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	Mcl-1	Mcl-1	Mcl-1	7	8	11	12
Our results show that JNK , in fact , negatively regulates Mcl-1 in both T47D and HCC1428 breast cancer cells , and knockdown of JNK1 partially reversed Mcl-1 downregulation caused by S6K2 deficiency ( XREF_FIG ) .	Our results show that JNK, in fact, negatively regulates Mcl-1 in both T47D and HCC1428 breast cancer cells, and knockdown of JNK1 partially reversed Mcl-1 downregulation caused by S6K2 deficiency (XREF_FIG).	22	28	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	Mcl-1	Mcl-1	Mcl-1	24	25	27	28
The combined knockdown of JNK1 and S6K2 attenuated S6K2 mediated downregulation of Mcl-1 from 2.8-fold ( 1 vs 0.35 ) to 1.7-fold ( 1.88 vs 1.13 ) .	The combined knockdown of JNK1 and S6K2 attenuated S6K2 mediated downregulation of Mcl-1 from 2.8-fold (1 vs 0.35) to 1.7-fold (1.88 vs 1.13).	2	14	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	Mcl-1	Mcl-1	Mcl-1	4	5	12	13
In human HCCs , JNK1 upregulates c-Myc and downregulates p21 ; JNK1 also regulates expression of factors that control the cell cycle , proliferation and metabolism , through methylation of histone H3 lysine 4 and 9 by MLL3 and EZH2 XREF_BIBR , XREF_BIBR .	In human HCCs, JNK1 upregulates c-Myc and downregulates p21; JNK1 also regulates expression of factors that control the cell cycle, proliferation and metabolism, through methylation of histone H3 lysine 4 and 9 by MLL3 and EZH2 XREF_BIBR, XREF_BIBR.	4	8	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	c-Myc	c-Myc	c-Myc	4	5	6	7
Our data also suggests that JNK1 increases the stability of total Myc , as Myc protein levels were increased in wild-type INS-1 cells by IL-1beta from 16h to 24h ; additionally , we found that Myc mRNA expression was increased at 12h .	Our data also suggests that JNK1 increases the stability of total Myc, as Myc protein levels were increased in wild-type INS-1 cells by IL-1beta from 16h to 24h; additionally, we found that Myc mRNA expression was increased at 12h.	5	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	Myc	Myc	Myc	5	6	11	12
Indeed , we could detect recruitment of phospho-SRF to the SRE sites located in the promoter region of CYLD , suggesting that SRF activation by p38 and MK2 are responsible for upregulation of CYLD levels .	Indeed, we could detect recruitment of phospho-SRF to the SRE sites located in the promoter region of CYLD, suggesting that SRF activation by p38 and MK2 are responsible for upregulation of CYLD levels.	22	28	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MK2	MK2	MK2	SRF	SRF	SRF	27	28	22	23
Following the identification of MK2 mediated PIAS1 phosphorylation sites , we used the PIAS1 phosphorylation mutants to assay for NF-kappaB transactivation .	Following the identification of MK2 mediated PIAS1 phosphorylation sites, we used the PIAS1 phosphorylation mutants to assay for NF-kappaB transactivation.	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	MK2	MK2	MK2	PIAS1	PIAS1	PIAS1	4	5	6	7
In this study we have uncovered a novel mechanism in ECs through which an inflammatory kinase MK2 can promote transrepression activity of PIAS1 through its S522 phosphorylation .	In this study we have uncovered a novel mechanism in ECs through which an inflammatory kinase MK2 can promote transrepression activity of PIAS1 through its S522 phosphorylation.	13	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	PIAS1	PIAS1	PIAS1	16	17	22	23
Phosphorylation of MST1 on S82 by JNK1 enhances MST1 mediated pro apoptotic signaling [ XREF_BIBR ] .	Phosphorylation of MST1 on S82 by JNK1 enhances MST1 mediated pro apoptotic signaling [XREF_BIBR].	4	9	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	MST1	MST1	MST1	6	7	8	9
In conclusion , the present study demonstrated that moscatilin increases ROS generation and subsequently activates the JNK and SAPK pathway , which modulates the Bax and Bcl2 ratio , thus leading to the caspase dependent mitochondrial apoptotic pathway .	In conclusion, the present study demonstrated that moscatilin increases ROS generation and subsequently activates the JNK and SAPK pathway, which modulates the Bax and Bcl2 ratio, thus leading to the caspase dependent mitochondrial apoptotic pathway.	16	27	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SAPK	SAPK	SAPK	Bax	Bax	Bax	18	19	24	25
JNK1 and CREB inhibition blocked 15-HETE-induced STAT3 activation and VAF changes .	JNK1 and CREB inhibition blocked 15-HETE-induced STAT3 activation and VAF changes.	0	7	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	STAT3	STAT3	STAT3	0	1	6	7
Taking into account that up-regulation of c-Fos upon osmostress required p38 activity and that Elk1 was targeted by the SAPK , we assessed the possibility that Elk1 recruitment to the c-Fos promoter was regulated by p38 .	Taking into account that up-regulation of c-Fos upon osmostress required p38 activity and that Elk1 was targeted by the SAPK, we assessed the possibility that Elk1 recruitment to the c-Fos promoter was regulated by p38.	14	20	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SAPK	SAPK	SAPK	Elk1	Elk1	Elk1	19	20	14	15
Depletion of ERK2 and JNK1 and not ERK1 elicited an increase of Paxillin patches .	Depletion of ERK2 and JNK1 and not ERK1 elicited an increase of Paxillin patches.	0	13	elicited	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	Paxillin	Paxillin	Paxillin	4	5	12	13
5-LO can be activated by an increase in intracellular Ca2+ concentration , diacylglycerols , phosphorylation by MAPKAP kinase-2 and ERK .	5-LO can be activated by an increase in intracellular Ca2+ concentration, diacylglycerols, phosphorylation by MAPKAP kinase-2 and ERK.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPKAP kinase-2	MAPKAP kinase-2	MAPKAP kinase-2	5-LO	5-LO	5-LO	16	18	0	1
Extensive in vitro kinase assays and experiments utilizing a phospho-Plk1-S326 antibody support the notion that MK2 targets Plk1 at S326 .	Extensive in vitro kinase assays and experiments utilizing a phospho-Plk1-S326 antibody support the notion that MK2 targets Plk1 at S326.	13	18	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	Plk1	Plk1	Plk1	15	16	17	18
( 2 ) PD98059 , a potent selective inhibitor of MAPK and ERK kinase ( MEK ) and GF109203X , a specific inhibitor of protein kinase C ( PKC ) abolished AVP4-8-evoked MAPK activity on astrocytes .	(2) PD98059, a potent selective inhibitor of MAPK and ERK kinase (MEK) and GF109203X, a specific inhibitor of protein kinase C (PKC) abolished AVP4-8-evoked MAPK activity on astrocytes.	8	33	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	15	16	32	33
ERK1/2 Activation Induced by N. caninum Is Mediated by MEK1/2 Activation in PMphi .	ERK1/2 Activation Induced by N. caninum Is Mediated by MEK1/2 Activation in PMphi.	0	10	Mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	9	10	0	1
MEK1/2 inhibition completely suppressed the transient activation of ERK1/2 and completely blocked apoptosis , demonstrating the role of the MEK-ERK module in mediating oxidative-stress-induced RPE cell death .	MEK1/2 inhibition completely suppressed the transient activation of ERK1/2 and completely blocked apoptosis, demonstrating the role of the MEK-ERK module in mediating oxidative-stress-induced RPE cell death.	0	9	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	0	1	8	9
Activated ( phosphorylated ) Raf activates MAPKK ( MEK ) , which in turn activates MAPK ( also called extracellular signal regulated kinase , ERK ) .	Activated (phosphorylated) Raf activates MAPKK (MEK), which in turn activates MAPK (also called extracellular signal regulated kinase, ERK).	6	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	8	9	15	16
By phosphorylating at Ser and Thr residues , MEK activates ERK1/2 , which then phosphorylates cytoplasmic and nuclear substrates .	By phosphorylating at Ser and Thr residues, MEK activates ERK1/2, which then phosphorylates cytoplasmic and nuclear substrates.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	8	9	10	11
A pharmacological inhibitor of MEK activity inhibits LPA stimulated WT Hic-5 cell migration and ERK phosphorylation , suggesting Hic-5 enhances migration via MEK activation of ERK .	A pharmacological inhibitor of MEK activity inhibits LPA stimulated WT Hic-5 cell migration and ERK phosphorylation, suggesting Hic-5 enhances migration via MEK activation of ERK.	22	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	22	23	25	26
The ERK activator MEK was reported to regulate JNK activity in rat intestine cell line ( IEC-6 ) and in human astrocyte cell line ( U-251 ) [ XREF_BIBR , XREF_BIBR ] .	The ERK activator MEK was reported to regulate JNK activity in rat intestine cell line (IEC-6) and in human astrocyte cell line (U-251) [XREF_BIBR, XREF_BIBR].	0	7	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	1	2
Mek inhibition with either of these compounds abolished Mek and Erk but not Akt activation ( XREF_FIG M-2P ) , in line with the notion that Erk phosphorylation was Mek dependent .	Mek inhibition with either of these compounds abolished Mek and Erk but not Akt activation (XREF_FIG M-2P), in line with the notion that Erk phosphorylation was Mek dependent.	0	11	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	0	1	10	11
A possible explanation for this discrepancy is that overexpression of MEK causes excessive Erk activation that far exceeds what is seen in PHN in vivo and overcomes the protective role of Erk observed in vivo .	A possible explanation for this discrepancy is that overexpression of MEK causes excessive Erk activation that far exceeds what is seen in PHN in vivo and overcomes the protective role of Erk observed in vivo.	8	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	overexpression of MEK	mek	Erk	Erk	erk	10	11	13	14
ERK1/2 is activated and phosphorylated by MEK1/2 .	ERK1/2 is activated and phosphorylated by MEK1/2.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	6	7	0	1
MEK resides in the upstream region of the ERK pathway , and induces ERK1/2 through phosphorylating its threonine and tyrosine .	MEK resides in the upstream region of the ERK pathway, and induces ERK1/2 through phosphorylating its threonine and tyrosine.	0	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	0	1	13	14
The activated BRAF leads to phosphorylation and activation of MEK1/2 , which in turn activates ERK1/2 to phosphorylate downstream targets in the cytoplasm and nucleus XREF_BIBR XREF_BIBR .	The activated BRAF leads to phosphorylation and activation of MEK1/2, which in turn activates ERK1/2 to phosphorylate downstream targets in the cytoplasm and nucleus XREF_BIBR XREF_BIBR.	2	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	BRAF leads to phosphorylation and activation of MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	9	10	15	16
The MEK dependent activation of p42 MAPK stimulates the accumulation of the Mos oncoprotein , which in turn activates MEK , thereby closing the feedback loop .	The MEK dependent activation of p42 MAPK stimulates the accumulation of the Mos oncoprotein, which in turn activates MEK, thereby closing the feedback loop.	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	1	2	6	7
In addition , MAPKs are activated by specific MAPK kinases ( MEKs ) ; specifically , MEK1/2 activates ERK1/2 , MEK3/6 activates p38 MAPK , and MEK4/7 activates JNK1/2 30 .	In addition, MAPKs are activated by specific MAPK kinases (MEKs); specifically, MEK1/2 activates ERK1/2, MEK3/6 activates p38 MAPK, and MEK4/7 activates JNK1/2 30.	16	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	16	17	18	19
Consistent with this premise , FSH stimulated ERK activation is inhibited by the cell-permeable protein kinase A specific inhibitor peptide Myr-PKI as well as by inhibitors of MEK , Src , a Ca ( 2+ ) channel blocker , and chelation of extracellular Ca ( 2+ ) .	Consistent with this premise, FSH stimulated ERK activation is inhibited by the cell-permeable protein kinase A specific inhibitor peptide Myr-PKI as well as by inhibitors of MEK, Src, a Ca (2+) channel blocker, and chelation of extracellular Ca (2+).	7	28	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	27	28	7	8
GTP bound Ras further activates the first serine threonine kinase ( Raf ) , which in turn activates Mek and then finally Erk is activated by Mek .	GTP bound Ras further activates the first serine threonine kinase (Raf), which in turn activates Mek and then finally Erk is activated by Mek.	22	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	26	27	22	23
While the underlying mechanisms responsible for DNA damage induced ERK activation remain elusive , the accumulating evidence indicates that MEK mediates ERK activation in DDR .	While the underlying mechanisms responsible for DNA damage induced ERK activation remain elusive, the accumulating evidence indicates that MEK mediates ERK activation in DDR.	19	22	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	19	20	21	22
Combined targeting of MEK and PI3K blocked the activation of both the MAPK and PI3K pathways and caused growth inhibition and cell death more effectively than any of the other treatments .	Combined targeting of MEK and PI3K blocked the activation of both the MAPK and PI3K pathways and caused growth inhibition and cell death more effectively than any of the other treatments.	1	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	3	4	12	13
Western blotting of zebrafish embryonic lysates for total ERK protein and phospho-ERK confirmed that all BRAF and MEK alleles caused ERK activation in the zebrafish embryo .	Western blotting of zebrafish embryonic lysates for total ERK protein and phospho-ERK confirmed that all BRAF and MEK alleles caused ERK activation in the zebrafish embryo.	15	21	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	17	18	20	21
The prototypic mitogen activated protein kinase ( MAPK ) 4 pathway consists of a three tiered module composed of a MAPK ( ERK1/2 ) , which is activated via phosphorylation by a MAPK kinase ( MEK1/2 ) , which in turn is phosphorylated by a MAPK kinase kinase ( Raf ) .	The prototypic mitogen activated protein kinase (MAPK) 4 pathway consists of a three tiered module composed of a MAPK (ERK1/2), which is activated via phosphorylation by a MAPK kinase (MEK1/2), which in turn is phosphorylated by a MAPK kinase kinase (Raf).	17	43	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2), which in turn is phosphorylated	mek1/2	MAPK	MAPK	mapk	35	36	20	21
Pharmacological inhibitors of MEK1/2 potently inhibit ERK1/2 activation .	Pharmacological inhibitors of MEK1/2 potently inhibit ERK1/2 activation.	1	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	3	4	6	7
ERK1/2 is activated by MEK1/2 [ XREF_BIBR ] , and we confirmed that the inhibition of ERK1/2 signaling using the MEK1/2 inhibitor , U0126 , or ERK1/2 siRNA significantly attenuated EGF induced cancer cell migration and invasion in a dose dependent manner .	ERK1/2 is activated by MEK1/2 [XREF_BIBR], and we confirmed that the inhibition of ERK1/2 signaling using the MEK1/2 inhibitor, U0126, or ERK1/2 siRNA significantly attenuated EGF induced cancer cell migration and invasion in a dose dependent manner.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	4	5	0	1
Both the effects of HNP1-3 on wound closure and ERK1/2 activation were blocked by specific inhibitors of the mitogen activated protein kinase kinase MEK , whereas inhibitors of epidermal growth factor receptor tyrosine kinase , phosphatidylinositol 3-kinase , and Src did block defensin enhanced wound closure but not ERK1/2 activation .	Both the effects of HNP1-3 on wound closure and ERK1/2 activation were blocked by specific inhibitors of the mitogen activated protein kinase kinase MEK, whereas inhibitors of epidermal growth factor receptor tyrosine kinase, phosphatidylinositol 3-kinase, and Src did block defensin enhanced wound closure but not ERK1/2 activation.	9	24	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	23	24	9	10
Expression of MEK in these cells promoted a four- to fivefold increase in cell migration and significantly increased ERK activity compared with mock transfected control cells ( XREF_FIG A ) .	Expression of MEK in these cells promoted a four- to fivefold increase in cell migration and significantly increased ERK activity compared with mock transfected control cells (XREF_FIG A).	0	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	Expression of MEK	mek	ERK	ERK	erk	2	3	18	19
To identify the effector ( s ) of the EGFR induced signalling pathway on which NPM1 may act , and to determine whether NPM1 action is direct or not on the EGF gene promoter , we performed transfection assays with a constitutively active form of MEKK1 ( caMEKK1 ) : caMEKK1 phosphorylates ERK1/2 kinase MEK1/2 , and thereby , constitutively activates ERK1/2 in the absence of MEK1/2 inhibition .	To identify the effector (s) of the EGFR induced signalling pathway on which NPM1 may act, and to determine whether NPM1 action is direct or not on the EGF gene promoter, we performed transfection assays with a constitutively active form of MEKK1 (caMEKK1) : caMEKK1 phosphorylates ERK1/2 kinase MEK1/2, and thereby, constitutively activates ERK1/2 in the absence of MEK1/2 inhibition.	50	62	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	caMEKK1 phosphorylates ERK1/2 kinase MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	54	55	61	62
However , the protection elicited by all three treatments were prevented by the inclusion of a selective inhibitor of mitogen activated protein kinase kinase ( MEK ) , the upstream kinase that activates ERK1/2 .	However, the protection elicited by all three treatments were prevented by the inclusion of a selective inhibitor of mitogen activated protein kinase kinase (MEK), the upstream kinase that activates ERK1/2.	23	34	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	25	26	33	34
The analysis of melanomas from patients relapsed on BRAF inhibitor treatment revealed the vast complexity of the MAPK signaling network and over the last years a plethora of mechanisms have been identified that allow cells to bypass BRAF inhibition by activating other signaling nodes eventually re-establishing MEK activity and hence reactivation of ERK [ for a detailed review see Lito et al ., XREF_BIBR ] , which is thought to occur in > 70 % of patients .	The analysis of melanomas from patients relapsed on BRAF inhibitor treatment revealed the vast complexity of the MAPK signaling network and over the last years a plethora of mechanisms have been identified that allow cells to bypass BRAF inhibition by activating other signaling nodes eventually re-establishing MEK activity and hence reactivation of ERK [for a detailed review see Lito et al., XREF_BIBR], which is thought to occur in> 70% of patients.	46	57	reactivation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	46	47	52	53
Specifically , MEK1/2 , MEK3/6 and MEK4/7 activate ERKs , p38 MAPK and JNKs , respectively .	Specifically, MEK1/2, MEK3/6 and MEK4/7 activate ERKs, p38 MAPK and JNKs, respectively.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERKs	ERKs	ERKs	2	3	8	9
Targeting MEK with PD-901 alone potently inhibited ERK signaling and tumor growth , and overcame the resistance when given together with PF-384 in vivo .	Targeting MEK with PD-901 alone potently inhibited ERK signaling and tumor growth, and overcame the resistance when given together with PF-384 in vivo.	0	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	1	2	7	8
Moreover , treatment of cells with epidermal growth factor ( EGF ) that activates MEK and ERK , as well as genetic ERK activation by a constitutively active MEK ( MEK CA ) , increased T562 phosphorylation levels ; pharmacological or genetic MEK inhibition using the selective U0126 inhibitor or byexpressing a dominant negative MEK mutant ( MEK DN ) ; and reduced T562 phosphorylation ; finally , in Mfn1 -/- cells re-expressing the MFN1 T562A mutant , phosphorylation was undetectable even in the presence of EGF ( XREF_FIG G ) .	Moreover, treatment of cells with epidermal growth factor (EGF) that activates MEK and ERK, as well as genetic ERK activation by a constitutively active MEK (MEK CA), increased T562 phosphorylation levels; pharmacological or genetic MEK inhibition using the selective U0126 inhibitor or byexpressing a dominant negative MEK mutant (MEK DN); and reduced T562 phosphorylation; finally, in Mfn1 -/- cells re-expressing the MFN1 T562A mutant, phosphorylation was undetectable even in the presence of EGF (XREF_FIG G).	22	30	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	28	29	22	23
As shown in XREF_FIG and XREF_FIG , intrahippocampal infusion of fluoxetine into P15 mice caused a significant increase in PSD95 expression and synaptogenesis and this effect was eliminated upon inhibition of the Erk activator MEK with U0126 and PKCalpha with Ro 31-8220 .	As shown in XREF_FIG and XREF_FIG, intrahippocampal infusion of fluoxetine into P15 mice caused a significant increase in PSD95 expression and synaptogenesis and this effect was eliminated upon inhibition of the Erk activator MEK with U0126 and PKCalpha with Ro 31-8220.	29	35	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	Erk	Erk	Erk	34	35	32	33
Furthermore , inhibition of MEK1/2 by pretreatment of NRVM with two structurally distinct inhibitors , PD98059 ( 30 microM ) or UO126 ( 3 microM ) , inhibited the activation of ERK and p90RSK and abolished the stimulation of NHE activity by sustained ( 3 min ) intracellular acidosis .	Furthermore, inhibition of MEK1/2 by pretreatment of NRVM with two structurally distinct inhibitors, PD98059 (30 microM) or UO126 (3 microM), inhibited the activation of ERK and p90RSK and abolished the stimulation of NHE activity by sustained (3 min) intracellular acidosis.	2	33	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	4	5	31	32
It further set out to characterize the hypothetical role of nuclear-export signal ( NES )-dependent relocation of ERK after nuclear entry and the potential involvement of the ERK activator MEK .	It further set out to characterize the hypothetical role of nuclear-export signal (NES)-dependent relocation of ERK after nuclear entry and the potential involvement of the ERK activator MEK.	24	30	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	29	30	27	28
PD98059 , a mitogen activated protein kinase kinase ( MEK ) inhibitor which inhibits the ERK pathway , abolished the GTPP induced increase in the expression of mRNA for GAP-43 but not for NF-L ( XREF_FIG ) .	PD98059, a mitogen activated protein kinase kinase (MEK) inhibitor which inhibits the ERK pathway, abolished the GTPP induced increase in the expression of mRNA for GAP-43 but not for NF-L (XREF_FIG).	9	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	15	16
ERK , once activated by MEK , has numerous cytosolic and nuclear substrates XREF_BIBR .	ERK, once activated by MEK, has numerous cytosolic and nuclear substrates XREF_BIBR.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	5	6	0	1
Active PAK1 can phosphorylate the serine/threonine kinases RAF and MEK , thereby activating ERK and JNK .	Active PAK1 can phosphorylate the serine/threonine kinases RAF and MEK, thereby activating ERK and JNK.	1	15	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	PAK1 can phosphorylate the serine/threonine kinases RAF and MEK	mek	ERK	ERK	erk	9	10	13	14
MEK activates ERK1/2 through phosphorylation of threonine and tyrosine which in turn inactivate apoptosis through inhibition of some pro apoptotic proteins such as Bim , Bad , caspase 9 .	MEK activates ERK1/2 through phosphorylation of threonine and tyrosine which in turn inactivate apoptosis through inhibition of some pro apoptotic proteins such as Bim, Bad, caspase 9.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	0	1	2	3
In many cases , Erk is activated via phosphorylation by the MAPKK MEK .	In many cases, Erk is activated via phosphorylation by the MAPKK MEK.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk	Erk	Erk	12	13	4	5
In cultured neonatal cardiomyocytes both PD98059 and U126 , specific inhibitors of MEK1/2 , were able to block myofibril reorganization and Erk1/2 activation upon stimulation with NRG [ XREF_BIBR , XREF_BIBR ] .	In cultured neonatal cardiomyocytes both PD98059 and U126, specific inhibitors of MEK1/2, were able to block myofibril reorganization and Erk1/2 activation upon stimulation with NRG [XREF_BIBR, XREF_BIBR].	10	22	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	Erk1/2	Erk1/2	Erk1/2	12	13	21	22
The lower incidence of squamoproliferative lesions during combined inhibition with BRAF and MEK is possibly related to blocking of paradoxical MAPK signaling downstream of CRAF by MEK inhibition .	The lower incidence of squamoproliferative lesions during combined inhibition with BRAF and MEK is possibly related to blocking of paradoxical MAPK signaling downstream of CRAF by MEK inhibition.	17	27	blocking	Negative_activation_syntax_3_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	26	27	20	21
When we treated ARPE-19 cells with 4HPR , c-Raf and MEK1/2 kinase were activated resulting in activation of the downstream effector ERK1/2 and of SAPK and JNK .	When we treated ARPE-19 cells with 4HPR, c-Raf and MEK1/2 kinase were activated resulting in activation of the downstream effector ERK1/2 and of SAPK and JNK.	8	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	10	11	21	22
ANG II significantly increased aldosterone release , and this effect was inhibited by the LO inhibitor baicalein , as well as a specific p38 MAPK inhibitor , SB202190 , but not by PD098059 , a specific inhibitor of the ERK activator MEK .	ANG II significantly increased aldosterone release, and this effect was inhibited by the LO inhibitor baicalein, as well as a specific p38 MAPK inhibitor, SB202190, but not by PD098059, a specific inhibitor of the ERK activator MEK.	36	42	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	41	42	39	40
ERK1/2 is a member of the mitogen activated protein kinase ( MAPK ) family and ERK1/2 can be activated by MEK through a cascade of upstream kinases .	ERK1/2 is a member of the mitogen activated protein kinase (MAPK) family and ERK1/2 can be activated by MEK through a cascade of upstream kinases.	13	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	20	21	15	16
Apart from PI3K , Raf-1 also stimulates the downstream kinase MEK , which in turn activates ERK1/2 .	Apart from PI3K, Raf-1 also stimulates the downstream kinase MEK, which in turn activates ERK1/2.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	10	11	16	17
Treatment with PD-98059 ( an inhibitor specific to the ERK1/2 activator MEK1/2 ) significantly suppressed the phosphorylation of MLCK , suggesting a role for ERK1/2 in regulating the activity of MLCK .	Treatment with PD-98059 (an inhibitor specific to the ERK1/2 activator MEK1/2) significantly suppressed the phosphorylation of MLCK, suggesting a role for ERK1/2 in regulating the activity of MLCK.	6	12	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	11	12	9	10
Secondly , in addition to the predominant MEK activators Raf-1 and B-Raf , MEK kinase-1 and A-Raf are able to phosphorylate MEK and thus activate the ERK pathway , although the biochemical potency of A-Raf is much weaker than that of Raf-1 or B-Raf .	Secondly, in addition to the predominant MEK activators Raf-1 and B-Raf, MEK kinase-1 and A-Raf are able to phosphorylate MEK and thus activate the ERK pathway, although the biochemical potency of A-Raf is much weaker than that of Raf-1 or B-Raf.	13	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK kinase-1 and A-Raf are able to phosphorylate MEK	mek	ERK	ERK	erk	21	22	26	27
Moreover , direct ERK activation by overexpression of constitutively active MEK has been shown to promote autophagy without any further stimulus .	Moreover, direct ERK activation by overexpression of constitutively active MEK has been shown to promote autophagy without any further stimulus.	3	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	overexpression of constitutively active MEK	mek	ERK	ERK	erk	10	11	3	4
Activated RAF subsequently carries out a chain of phosphorylation reactions to its downstream substrates , namely , MEK and ERK , initiating the activation of the canonical MAPK pathway XREF_BIBR .	Activated RAF subsequently carries out a chain of phosphorylation reactions to its downstream substrates, namely, MEK and ERK, initiating the activation of the canonical MAPK pathway XREF_BIBR.	0	29	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	17	18	27	28
Activation of MAPK by MEK may result in the activation of cytosolic phospholipase A 2 ( cPLA 2 ) [ XREF_BIBR ] and subsequent production of arachidonic acid and prostaglandins .	Activation of MAPK by MEK may result in the activation of cytosolic phospholipase A 2 (cPLA 2) [XREF_BIBR] and subsequent production of arachidonic acid and prostaglandins.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	4	5	2	3
After activation by RAS binding and protein recruitment to the cell membrane , these kinases phosphorylate and activate MEK , that in turn activates ERK and the effectors of the MAPK cascade .	After activation by RAS binding and protein recruitment to the cell membrane, these kinases phosphorylate and activate MEK, that in turn activates ERK and the effectors of the MAPK cascade.	17	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	18	19	24	25
An inhibitor of the dual-specificity ERK kinase ( MEK ) , PD-98059 , completely abolished PMA induced ERK activation .	An inhibitor of the dual-specificity ERK kinase (MEK), PD-98059, completely abolished PMA induced ERK activation.	6	18	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	8	9	17	18
These cells displayed high levels of ERK activation , that is , at least in part , independent of the conventional RAF/MEK/ERK pathway , as MEK activation was low and inhibition of MEK did not significantly block activation of ERK .	These cells displayed high levels of ERK activation, that is, at least in part, independent of the conventional RAF/MEK/ERK pathway, as MEK activation was low and inhibition of MEK did not significantly block activation of ERK.	30	40	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	32	33	39	40
In these cells , ERK are activated by a Raf and MEK dependent pathway , a P13K and Raf independent pathway and a third undetermined pathway .	In these cells, ERK are activated by a Raf and MEK dependent pathway, a P13K and Raf independent pathway and a third undetermined pathway.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	11	12	4	5
MEK inhibition with PD0325901 blocks this feedback activation of ERK , while the PI3K inhibitor GDC-0941 does not ( XREF_SUPPLEMENTARY ) .	MEK inhibition with PD0325901 blocks this feedback activation of ERK, while the PI3K inhibitor GDC-0941 does not (XREF_SUPPLEMENTARY).	0	16	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	9	10
In a human epidermoid carcinoma cell line ( i.e. A431 ) , 12 ( S )-HETE activates extracellular signal regulated kinases 1/2 ( ERK1/2 ) , which is mediated by upstream kinases MEK and Raf .	In a human epidermoid carcinoma cell line (i.e. A431), 12 (S)-HETE activates extracellular signal regulated kinases 1/2 (ERK1/2), which is mediated by upstream kinases MEK and Raf.	20	34	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	32	33	23	24
As shown in Figure XREF_FIG , shRNA mediated stable knockdown of MEK1/2 or ERK1/2 almost blocked ERK activation ( p-ERK1/2 ) in 786-0 cells .	As shown in Figure XREF_FIG, shRNA mediated stable knockdown of MEK1/2 or ERK1/2 almost blocked ERK activation (p-ERK1/2) in 786-0 cells.	9	17	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	11	12	16	17
In contrast , the dual specific protein kinase MEK activates MAPK through a two-site phosphorylation mechanism that is fully distributive .	In contrast, the dual specific protein kinase MEK activates MAPK through a two-site phosphorylation mechanism that is fully distributive.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	8	9	10	11
Raf activates the MAPK and ERK kinase ( MEK ) 1/2 dual-specificity protein kinases , which then activate ERK1/2 .	Raf activates the MAPK and ERK kinase (MEK) 1/2 dual-specificity protein kinases, which then activate ERK1/2.	6	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	8	9	18	19
The mitogen activated protein kinase ( MAPK ) cascade is a large group of conserved protein serine/threonine kinases which consist of three distinct tiers of protein kinases ; a mitogen activated extracellular signal regulated kinase kinase kinase ( MEKK ) , which activates a mitogen activated extracellular signal regulated kinase kinase ( MEK ) that subsequently activates a MAPK .	The mitogen activated protein kinase (MAPK) cascade is a large group of conserved protein serine/threonine kinases which consist of three distinct tiers of protein kinases; a mitogen activated extracellular signal regulated kinase kinase kinase (MEKK), which activates a mitogen activated extracellular signal regulated kinase kinase (MEK) that subsequently activates a MAPK.	50	59	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	52	53	58	59
PI3K , MEK , and JAK are involved in humanin mediated AKT , ERK , and STAT3 activation .	PI3K, MEK, and JAK are involved in humanin mediated AKT, ERK, and STAT3 activation.	0	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	2	3	13	14
Inhibition of MEK1/2 with UO 126 completely abolished ERK1/2 activation and reduced cell proliferation by 33-43 % .	Inhibition of MEK1/2 with UO 126 completely abolished ERK1/2 activation and reduced cell proliferation by 33-43%.	0	9	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	2	3	8	9
MEK1/2 inhibition is able to produce a sustained and deep MAPK inhibition in thyroid [ XREF_BIBR ] .	MEK1/2 inhibition is able to produce a sustained and deep MAPK inhibition in thyroid [XREF_BIBR].	0	11	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	0	1	10	11
In particular , MEK is an attractive drug target because of its high selectivity to ERK .	In particular, MEK is an attractive drug target because of its high selectivity to ERK.	3	16	target	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	15	16
Here we have investigated the role of ERK activation in the behavioral sensitization induced by repeated administration of psychostimulants in mice , using SL327 , a brain penetrating selective inhibitor of MAP-kinase and ERK kinase ( MEK ) , the enzyme that selectively activates ERK .	Here we have investigated the role of ERK activation in the behavioral sensitization induced by repeated administration of psychostimulants in mice, using SL327, a brain penetrating selective inhibitor of MAP-kinase and ERK kinase (MEK), the enzyme that selectively activates ERK.	34	45	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	36	37	44	45
Here we demonstrate that the mixed lineage kinases ( MLK1-4 ) are MEK kinases that reactivate the MEK and ERK pathway in the presence of RAF inhibitors .	Here we demonstrate that the mixed lineage kinases (MLK1-4) are MEK kinases that reactivate the MEK and ERK pathway in the presence of RAF inhibitors.	12	20	reactivate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	12	13	19	20
The present study demonstrates that LTA can induce SP-A expression via MEK dependent activation of the protein kinase ERK1/2 signaling pathway .	The present study demonstrates that LTA can induce SP-A expression via MEK dependent activation of the protein kinase ERK1/2 signaling pathway.	11	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	11	12	18	19
The concentration of U0126 was 5 muM which can inhibit the initial activation of ERK1/2 mediated by MEK1/2 up to ~ 50 % [ XREF_BIBR ] .	The concentration of U0126 was 5 muM which can inhibit the initial activation of ERK1/2 mediated by MEK1/2 up to ~ 50% [XREF_BIBR].	12	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	17	18	14	15
Inhibition of BRAF and MEK within the MAPK pathway did not inhibit ERK activation , which was in contrast partially inhibited by a direct ERK inhibitor .	Inhibition of BRAF and MEK within the MAPK pathway did not inhibit ERK activation, which was in contrast partially inhibited by a direct ERK inhibitor.	0	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	4	5	12	13
Considering that Mek1/2 inhibition suppresses Mapk signaling to a greater extent than Src inhibition 21 , our results imply that the degree of Mapk signaling dictates the epigenetic state and chromosomal stability of ESCs .	Considering that Mek1/2 inhibition suppresses Mapk signaling to a greater extent than Src inhibition 21, our results imply that the degree of Mapk signaling dictates the epigenetic state and chromosomal stability of ESCs.	2	6	suppresses	Negative_activation_syntax_5_verb	Positive_activation	Positive_activation	Mek1/2	Mek1/2	Mek1/2	Mapk	Mapk	Mapk	2	3	5	6
In PTC cells with a BRAF mutation , the only known substrates of BRAF are MEK1/2 , which activate ERK1/2 .	In PTC cells with a BRAF mutation, the only known substrates of BRAF are MEK1/2, which activate ERK1/2.	2	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	15	16	19	20
Role of hBVR in Activation of ERK1/2 by MEK1/2 and PKCdelta .	Role of hBVR in Activation of ERK1/2 by MEK1/2 and PKCdelta.	0	10	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	8	9	6	7
Clinically available inhibitors of MEK in contrast effectively block MEK induced ERK activation .	Clinically available inhibitors of MEK in contrast effectively block MEK induced ERK activation.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	11	12
The MEK1/2 selective inhibitor , AZD6244 ( ARRY-142886 ) , blocks ERK1/2 activation and is currently undergoing clinical evaluation .	The MEK1/2 selective inhibitor, AZD6244 (ARRY-142886), blocks ERK1/2 activation and is currently undergoing clinical evaluation.	1	12	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	1	2	11	12
Overexpression of NRX selectively suppresses the Wnt-beta-catenin pathway and ablation of NRX by RNA-interference ( RNAi ) results in activation of TCF , accelerated cell proliferation and enhancement of oncogenicity through cooperation with mitogen activated extracellular signal regulated kinase kinase ( MEK ) or Ras .	Overexpression of NRX selectively suppresses the Wnt-beta-catenin pathway and ablation of NRX by RNA-interference (RNAi) results in activation of TCF, accelerated cell proliferation and enhancement of oncogenicity through cooperation with mitogen activated extracellular signal regulated kinase kinase (MEK) or Ras.	23	42	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	extracellular signal regulated kinase	extracellular signal regulated kinase	extracellular signal regulated kinase	41	42	35	39
ERK1/2 are the only known substrates of MEK1/2 [ XREF_BIBR ] , and MEK1/2 inhibition by selumetinib reduced ERK1/2 activity to basal levels , confirming that MEK1/2 is a main activator of ERK1/2 , and MEK1/2 inhibition is an effective means of blocking MEK1/2-ERK 1/2 pathway in AML-stromal cell co-cultures .	ERK1/2 are the only known substrates of MEK1/2 [XREF_BIBR], and MEK1/2 inhibition by selumetinib reduced ERK1/2 activity to basal levels, confirming that MEK1/2 is a main activator of ERK1/2, and MEK1/2 inhibition is an effective means of blocking MEK1/2-ERK 1/2 pathway in AML-stromal cell co-cultures.	13	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	13	14	18	19
These results are consistent with the interpretation that MEK activates ERK , ERK2 then activates MLCK , and MLCK activates myosin .	These results are consistent with the interpretation that MEK activates ERK, ERK2 then activates MLCK, and MLCK activates myosin.	8	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	8	9	10	11
In cells incubated with EGF or platelet derived growth factor-AA , Raf activation and the subsequent stimulation of ERK reduced Akt signaling , whereas Mek inhibition , which blocked ERK activation , enhanced Akt and turned transient effects into sustained responses .	In cells incubated with EGF or platelet derived growth factor-AA, Raf activation and the subsequent stimulation of ERK reduced Akt signaling, whereas Mek inhibition, which blocked ERK activation, enhanced Akt and turned transient effects into sustained responses.	24	30	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	ERK	ERK	ERK	24	25	29	30
In our present study we demonstrated that direct inhibition of MEK with CI-1040 blocked activation of ERK1/2 and effectively radiosensitized the lapatinib resistant SUM185 cells with 45 % fewer colonies surviving radiation plus CI-1040 treatment relative to control cells treated with radiation alone .	In our present study we demonstrated that direct inhibition of MEK with CI-1040 blocked activation of ERK1/2 and effectively radiosensitized the lapatinib resistant SUM185 cells with 45% fewer colonies surviving radiation plus CI-1040 treatment relative to control cells treated with radiation alone.	8	17	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	10	11	16	17
Raf can then phosphorylate MEK , which activates ERK through phosphorylation in two different residues .	Raf can then phosphorylate MEK, which activates ERK through phosphorylation in two different residues.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	Raf can then phosphorylate MEK	mek	ERK	ERK	erk	4	5	8	9
The classical MAPK cascade ( XREF_FIG ) consists of a three-kinase module that includes an MEK kinase ( Raf kinases ) , which activates an MAPK and ERK kinase ( MEK ) , which in turn activates a mitogen responsive ERK1/2 corresponding to the classical MAPK .	The classical MAPK cascade (XREF_FIG) consists of a three-kinase module that includes an MEK kinase (Raf kinases), which activates an MAPK and ERK kinase (MEK), which in turn activates a mitogen responsive ERK1/2 corresponding to the classical MAPK.	15	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	15	16	25	26
Consistently , MEK induced ERK activation in PC12 cells induces c-Jun expression , while JNK signalling does not .	Consistently, MEK induced ERK activation in PC12 cells induces c-Jun expression, while JNK signalling does not.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	2	3	4	5
First , MEK activates ERK ( XREF_FIG -1 ) .	First, MEK activates ERK (XREF_FIG -1).	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	2	3	4	5
Treatment with PD98059 , a potent inhibitor of MEK , did not inhibit the activation of ERK1/2 , proposing a MEK independent signaling mechanism .	Treatment with PD98059, a potent inhibitor of MEK, did not inhibit the activation of ERK1/2, proposing a MEK independent signaling mechanism.	6	17	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	8	9	16	17
On the other hand , GLP-1-induced ERK1/2 phosphorylation was inhibited by preincubation with the selective inhibitor of MEK1/2 ( the upstream activator of ERK1/2 ) and with PI3K inhibitor LY294002 , suggesting that PI3K activation is also required for the GLP-1-induced activation of ERK1/2 .	On the other hand, GLP-1-induced ERK1/2 phosphorylation was inhibited by preincubation with the selective inhibitor of MEK1/2 (the upstream activator of ERK1/2) and with PI3K inhibitor LY294002, suggesting that PI3K activation is also required for the GLP-1-induced activation of ERK1/2.	15	24	activator	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	17	18	23	24
Activated RAF kinases phosphorylate and activate MEK1/2 , which in turn phosphorylate and activate ERK1/2 , leading to cellular proliferation , survival , and differentiation , and to an inhibitory feedback toward upstream components of the pathway .	Activated RAF kinases phosphorylate and activate MEK1/2, which in turn phosphorylate and activate ERK1/2, leading to cellular proliferation, survival, and differentiation, and to an inhibitory feedback toward upstream components of the pathway.	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	6	7	14	15
Ligand ( such as LPS ) binding to TLR4 activates the Ras-c-Raf-mitogen-activated protein kinase ERK kinase 1/2 ( MEK1/2 ) system which in turn activates the ERK1/2 signaling component .	Ligand (such as LPS) binding to TLR4 activates the Ras-c-Raf-mitogen-activated protein kinase ERK kinase 1/2 (MEK1/2) system which in turn activates the ERK1/2 signaling component.	18	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	18	19	26	27
Indeed , concomitant pharmacological blockade of MEK and EGFR induced prolonged ERK inhibition and severely impaired the growth of resistant tumor cells .	Indeed, concomitant pharmacological blockade of MEK and EGFR induced prolonged ERK inhibition and severely impaired the growth of resistant tumor cells.	4	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	11	12
This is followed by Raf activation of MEK , a dual specificity kinase , MEK activation of the Erk MAP Kinase , and finally migration of Erk to the nucleus where it phosphorylates and activates ETS family transcription factors that contribute to cell cycle control and proliferation .	This is followed by Raf activation of MEK, a dual specificity kinase, MEK activation of the Erk MAP Kinase, and finally migration of Erk to the nucleus where it phosphorylates and activates ETS family transcription factors that contribute to cell cycle control and proliferation.	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk	Erk	Erk	14	15	18	19
In the animal cap , which does not receive endogenous Ras signaling in wild type embryos , MEK variants caused ectopic ERK activation ( XREF_FIG and XREF_SUPPLEMENTARY ) .	In the animal cap, which does not receive endogenous Ras signaling in wild type embryos, MEK variants caused ectopic ERK activation (XREF_FIG and XREF_SUPPLEMENTARY).	17	22	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	17	18	21	22
Subsequently , MEK1/2 activates ERK1/2 by phosphorylating both Thr202 and Tyr204 residues .	Subsequently, MEK1/2 activates ERK1/2 by phosphorylating both Thr202 and Tyr204 residues.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	2	3	4	5
RTK mediated activation of the Ras GTPase leads to the activation of these kinases through phosphorylation loops : Raf activates MEK , MEK activates ERK and ERK activates p90 ribosomal S6 kinase ( RSK ) [ XREF_BIBR ] .	RTK mediated activation of the Ras GTPase leads to the activation of these kinases through phosphorylation loops : Raf activates MEK, MEK activates ERK and ERK activates p90 ribosomal S6 kinase (RSK) [XREF_BIBR].	22	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	22	23	24	25
In this way , it facilitates the interaction of RAF with its substrate MEK1/2 , which in turn activates ERK1/2 to relay the signals ( XREF_FIG ) .	In this way, it facilitates the interaction of RAF with its substrate MEK1/2, which in turn activates ERK1/2 to relay the signals (XREF_FIG).	5	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	13	14	19	20
Late ERK activation was reversed by inhibition of MEK after the end of DOX treatment .	Late ERK activation was reversed by inhibition of MEK after the end of DOX treatment.	1	9	reversed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	8	9	1	2
In turn , Raf phosphorylates and activates the dual-specificity threonine and tyrosine kinases MEK1/2 , which phosphorylate and activate the serine/threonine kinases ERK1/2 .	In turn, Raf phosphorylates and activates the dual-specificity threonine and tyrosine kinases MEK1/2, which phosphorylate and activate the serine/threonine kinases ERK1/2.	3	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	Raf phosphorylates and activates the dual-specificity threonine and tyrosine kinases MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	13	14	22	23
As a direct downstream substrate of Ras , Raf activation leads to the phosphorylation of MEK , the kinase that activates ERK .	As a direct downstream substrate of Ras, Raf activation leads to the phosphorylation of MEK, the kinase that activates ERK.	8	22	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	Raf activation leads to the phosphorylation of MEK	mek	ERK	ERK	erk	15	16	21	22
Finally , the ability of TPO to induce the IEX-1 gene expression was inhibited by U0126 , a specific inhibitor of the ERKs activator MEK and AML1 transcriptional activity was shown to be modulated by TPO through ERK dependent phosphorylation .	Finally, the ability of TPO to induce the IEX-1 gene expression was inhibited by U0126, a specific inhibitor of the ERKs activator MEK and AML1 transcriptional activity was shown to be modulated by TPO through ERK dependent phosphorylation.	19	28	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERKs	ERKs	ERKs	24	25	22	23
The MEK mediated activation of ERK through phosphorylation of ERK threonine and tyrosine residues has been well established .	The MEK mediated activation of ERK through phosphorylation of ERK threonine and tyrosine residues has been well established.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	1	2	5	6
As shown in XREF_FIG , the inhibition of MEK resulted in an increased L1CAM protein level , indicating unperturbed sensitivity of L1CAM to Erk1/2 inhibition in OIS cells , supporting the suppressive role of the Ras and MAPK pathway on L1CAM expression .	As shown in XREF_FIG, the inhibition of MEK resulted in an increased L1CAM protein level, indicating unperturbed sensitivity of L1CAM to Erk1/2 inhibition in OIS cells, supporting the suppressive role of the Ras and MAPK pathway on L1CAM expression.	6	38	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	8	9	37	38
U0126 inhibits mitogen activated protein and extracellular signal regulated kinase kinase ( MEK ) which activates ERK1/2 , and AktiIV controls activity of Akt .	U0126 inhibits mitogen activated protein and extracellular signal regulated kinase kinase (MEK) which activates ERK1/2, and AktiIV controls activity of Akt.	10	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	12	13	16	17
Chemical inhibitors of MEK activated ERK1/2 attenuated insulin enhanced CYP17 transcriptional activity by 76-80 % .	Chemical inhibitors of MEK activated ERK1/2 attenuated insulin enhanced CYP17 transcriptional activity by 76-80%.	1	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	3	4	5	6
In the absence of physiological Cu , cells may die because MEK activation of the ERK1/2 survival pathway requires Cu supplementation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In the absence of physiological Cu, cells may die because MEK activation of the ERK1/2 survival pathway requires Cu supplementation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	11	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	11	12	15	16
Given that ERK activity is activated by the upstream kinase MEK , we determined the expression and activation of MEK1/2 in response to estrogen deprivation .	Given that ERK activity is activated by the upstream kinase MEK, we determined the expression and activation of MEK1/2 in response to estrogen deprivation.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	10	11	2	3
PD98059 is a potent inhibitor of MEK , the kinase that activates ERK .	PD98059 is a potent inhibitor of MEK, the kinase that activates ERK.	4	13	activates	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	12	13
The same group recently published that MAPK and ERK pathway activation by the downstream effector MEK instead of BRAF is also capable of driving gliomagenesis in this setting , but the induced tumors were again of higher grades [ XREF_BIBR ] .	The same group recently published that MAPK and ERK pathway activation by the downstream effector MEK instead of BRAF is also capable of driving gliomagenesis in this setting, but the induced tumors were again of higher grades [XREF_BIBR].	6	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	15	16	8	9
The active RAS recruits RAFs to the cellular membrane , where the activated RAFs phosphorylate MEK 1/2 , which in turn , activates ERK 1/2 XREF_BIBR .	The active RAS recruits RAFs to the cellular membrane, where the activated RAFs phosphorylate MEK 1/2, which in turn, activates ERK 1/2 XREF_BIBR.	14	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK 1/2	phosphorylate MEK 1/2	mek 1/2	ERK 1/2	ERK 1/2	erk 1/2	15	17	23	25
The data suggested that the ERK activation by the upstream activating kinase MEK was critical for IGFBP3 induced motility .	The data suggested that the ERK activation by the upstream activating kinase MEK was critical for IGFBP3 induced motility.	5	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	12	13	5	6
NSCLC cells expressing an EGFR mutant exhibit reduced death response to gefitinib when ERK activation is augmented by constitutively active MEK .	NSCLC cells expressing an EGFR mutant exhibit reduced death response to gefitinib when ERK activation is augmented by constitutively active MEK.	13	21	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	20	21	13	14
Furthermore , NE stimulated the expression and secretion of basic fibroblast growth factor ( bFGF ) , which further promoted the cell survival via MEK dependent activation of Erk1/2 .	Furthermore, NE stimulated the expression and secretion of basic fibroblast growth factor (bFGF), which further promoted the cell survival via MEK dependent activation of Erk1/2.	24	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk1/2	Erk1/2	Erk1/2	24	25	28	29
RAF kinases function by specifically phosphorylating MEK1/2 within the kinase activation loop leading to the subsequent activation of MEK1/2 , which in turn activates ERK1/2 .	RAF kinases function by specifically phosphorylating MEK1/2 within the kinase activation loop leading to the subsequent activation of MEK1/2, which in turn activates ERK1/2.	16	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	18	19	24	25
Melatonin is effective in preventing the ischemic brain injury induced down-regulation of Raf-1 , MEK1/2 and ERK1/2 phosphorylation 57 , suggesting that the activation of Raf/MEK/ERK cascade can be mediated by Melatonin .	Melatonin is effective in preventing the ischemic brain injury induced down-regulation of Raf-1, MEK1/2 and ERK1/2 phosphorylation 57, suggesting that the activation of Raf/MEK/ERK cascade can be mediated by Melatonin.	9	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2 and ERK1/2 phosphorylation	mek1/2	ERK1/2	ERK1/2	erk1/2	14	15	16	17
ERK1/2 are activated through phosphorylation by upstream MAPK and ERK kinases MEK1/2 , which are tyrosine and threonine protein kinases that are also essential for development and normal proliferation in adult cells XREF_BIBR , XREF_BIBR .	ERK1/2 are activated through phosphorylation by upstream MAPK and ERK kinases MEK1/2, which are tyrosine and threonine protein kinases that are also essential for development and normal proliferation in adult cells XREF_BIBR, XREF_BIBR.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	11	12	0	1
Currently , the MEK1/2 inhibitors as described above are employed as inhibitors of its downstream effector ERK1/2 , as MEK1/2 is known to activate ERK1/2 selectively [ XREF_BIBR ] ( XREF_TABLE ) .	Currently, the MEK1/2 inhibitors as described above are employed as inhibitors of its downstream effector ERK1/2, as MEK1/2 is known to activate ERK1/2 selectively [XREF_BIBR] (XREF_TABLE).	19	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	19	20	24	25
While regulation of cell proliferation is mostly mediated by activation of the p38- and MEK driven MAPK signaling cascades , most of the published work suggests a more prominent role of AXL in the PI3K/AKT/mTOR and JAK and STAT pathways in tumor cell survival [ XREF_BIBR * * , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	While regulation of cell proliferation is mostly mediated by activation of the p38- and MEK driven MAPK signaling cascades, most of the published work suggests a more prominent role of AXL in the PI3K/AKT/mTOR and JAK and STAT pathways in tumor cell survival [XREF_BIBR **, XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	18	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	14	15	16	17
This may indicate that the effect of MEK1/2 inhibition may be caused either by ERK1/2 independent signals activated by MEK1/2 or by off-target effects of the inhibitor .	This may indicate that the effect of MEK1/2 inhibition may be caused either by ERK1/2 independent signals activated by MEK1/2 or by off-target effects of the inhibitor.	14	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	19	20	14	15
Rescue is mimicked by expression of ( mitogen activated protein kinase kinase ) MEK which increases ( extracellular signal related kinase ) ERK activity [ XREF_BIBR ] .	Rescue is mimicked by expression of (mitogen activated protein kinase kinase) MEK which increases (extracellular signal related kinase) ERK activity [XREF_BIBR].	4	25	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	expression of (mitogen activated protein kinase kinase) MEK	mek	ERK	ERK	erk	13	14	22	23
MEK or PI3K inhibitors suppressed ERK or Akt activation , respectively , and induced apoptosis in the v-ErbB : ER responsive cells .	MEK or PI3K inhibitors suppressed ERK or Akt activation, respectively, and induced apoptosis in the v-ErbB : ER responsive cells.	0	8	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	5	6
In its central portion MEK activates ERK , leading to increased collagen expression .	In its central portion MEK activates ERK, leading to increased collagen expression.	0	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	4	5	6	7
MAPKK kinase and MEKK phosphorylates and activates its downstream protein kinase , MAPK kinase and MEK , which in turn activates MAPK .	MAPKK kinase and MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase and MEK, which in turn activates MAPK.	10	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	15	16	21	22
In NRAS driven cells , downstream inhibition of MEK should prevent ERK activation and lead to cell death .	In NRAS driven cells, downstream inhibition of MEK should prevent ERK activation and lead to cell death.	6	12	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	8	9	11	12
Most lung adenocarcinomas harbor a genetic lesion encoding a product capable of hyperactivating MAPK signaling , including oncogenic KRAS , BRAF , EGFR , MEK , ERBB2 , MET , ALK , RET and ROS1 , among other events in the MAPK pathway 11 .	Most lung adenocarcinomas harbor a genetic lesion encoding a product capable of hyperactivating MAPK signaling, including oncogenic KRAS, BRAF, EGFR, MEK, ERBB2, MET, ALK, RET and ROS1, among other events in the MAPK pathway 11.	13	25	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	24	25	13	14
Consequently , an MAPK kinase kinase ( MAP3K , MKKK , or MEKK ) phosphorylates an MAPK kinase ( MAP2K , MKK , or MEK ) , which in turn activates an MAPK .	Consequently, an MAPK kinase kinase (MAP3K, MKKK, or MEKK) phosphorylates an MAPK kinase (MAP2K, MKK, or MEK), which in turn activates an MAPK.	3	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MAPK kinase kinase (MAP3K, MKKK, or MEKK) phosphorylates an MAPK kinase (MAP2K, MKK, or MEK	mek	MAPK	MAPK	mapk	24	25	32	33
Because MEK activates Erk1/2 , we investigated the role of Erk1/2 in the regulation of mesangial cell hypertrophy .	Because MEK activates Erk1/2, we investigated the role of Erk1/2 in the regulation of mesangial cell hypertrophy.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk1/2	Erk1/2	Erk1/2	1	2	3	4
U0126 , a specific inhibitor of ERK upstream kinase MEK1/2 , almost significantly inhibited activation of ERK induced by Kidney replenishing herb .	U0126, a specific inhibitor of ERK upstream kinase MEK1/2, almost significantly inhibited activation of ERK induced by Kidney replenishing herb.	4	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	9	10	16	17
In C. intestinalis , the FGF and MAPK pathway , mediated in part by MEK dependent phosphorylation and activation of Ets.b , is both necessary and sufficient for TVC specification .	In C. intestinalis, the FGF and MAPK pathway, mediated in part by MEK dependent phosphorylation and activation of Ets.b, is both necessary and sufficient for TVC specification.	5	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK dependent phosphorylation	mek	MAPK	MAPK	mapk	14	15	7	8
Furthermore , treatments that interfere with ERK signaling such as the MEK and ERK inhibitors SL327 , U0126 or PD98059 , impair long-term memory retention .	Furthermore, treatments that interfere with ERK signaling such as the MEK and ERK inhibitors SL327, U0126 or PD98059, impair long-term memory retention.	6	19	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	11	12	6	7
The ERK activator MEK , which possesses a NES-sequence , was apparently not involved in nuclear export , as it did not seem to enter the nucleus .	The ERK activator MEK, which possesses a NES-sequence, was apparently not involved in nuclear export, as it did not seem to enter the nucleus.	0	13	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	1	2
Such ERK activation , as well as 24 hrs memory , is reduced by inhibition of NMDA receptor and MEK1/2 ( XREF_FIG ) .	Such ERK activation, as well as 24 hrs memory, is reduced by inhibition of NMDA receptor and MEK1/2 (XREF_FIG).	1	20	reduced	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	19	20	1	2
In 3T3-L1 cells , IRS1 serine 636/639 phosphorylation causes IRS1 degradation [ XREF_BIBR ] which is dependent on MEK1/2 induced ERK activation in human skeletal muscle cells [ XREF_BIBR ] .	In 3T3-L1 cells, IRS1 serine 636/639 phosphorylation causes IRS1 degradation [XREF_BIBR] which is dependent on MEK1/2 induced ERK activation in human skeletal muscle cells [XREF_BIBR].	16	21	induced	Positive_early_activation	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	18	19	20	21
About 50 % of melanoma cells harbour mutation in BRAF kinase protein , which will lead to the deregulated activation of its downstream ERK / MEK effectors .	About 50% of melanoma cells harbour mutation in BRAF kinase protein, which will lead to the deregulated activation of its downstream ERK / MEK effectors.	19	26	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	25	26	23	24
Inhibition of the mitogenactivated protein kinase ( MEK ) pathway with PD98059 attenuated stretch induced increase in MMP-2 production and ERK activity .	Inhibition of the mitogenactivated protein kinase (MEK) pathway with PD98059 attenuated stretch induced increase in MMP-2 production and ERK activity.	7	21	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	7	8	20	21
NGF and EGF stimulation of PC12 cells stabilized m4 muscarinic acetylcholine receptor mRNA in a MEK ( the upstream activator of MAPK ) and protein synthesis dependent manner .	NGF and EGF stimulation of PC12 cells stabilized m4 muscarinic acetylcholine receptor mRNA in a MEK (the upstream activator of MAPK) and protein synthesis dependent manner.	12	22	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	15	16	21	22
The core elements of the ERK signaling pathway comprise a three tiered protein kinase cascade including the raf kinases ( B-Raf and Raf1 ) that phosphorylate and activate the MAP kinase kinases , MEK1/2 , which in turn activate ERK1/2 .	The core elements of the ERK signaling pathway comprise a three tiered protein kinase cascade including the raf kinases (B-Raf and Raf1) that phosphorylate and activate the MAP kinase kinases, MEK1/2, which in turn activate ERK1/2.	31	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	33	34	39	40
The question remains on whether ERK1/2 was activated by MEK1/2 and whether P90RSK and Nrf2 activation occurs downstream of the ERK1/2 pathway .	The question remains on whether ERK1/2 was activated by MEK1/2 and whether P90RSK and Nrf2 activation occurs downstream of the ERK1/2 pathway.	5	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	9	10	5	6
MEK + PI3K and AKT inhibition : Combined targeting of MAPK and PI3K and AKT signaling has a significant rationale as dual inhibition was required to restrain tumor growth in NRAS-mutant models [ XREF_BIBR , XREF_BIBR ] .	MEK + PI3K and AKT inhibition : Combined targeting of MAPK and PI3K and AKT signaling has a significant rationale as dual inhibition was required to restrain tumor growth in NRAS-mutant models [XREF_BIBR, XREF_BIBR].	0	16	targeting	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	0	1	10	11
To evaluate the role of ERK 1/2 on the expression and function of ABCG2 , the expression of mitogen activated protein kinase ( MAPK )/ERK kinase ( MEK ) , which preferentially activates ERK , was upregulated by transfection with the recombinant sense expression vector pcDNA3.1-MEK and downregulated by pretreatment with U0126 , a specific MEK inhibitor .	To evaluate the role of ERK 1/2 on the expression and function of ABCG2, the expression of mitogen activated protein kinase (MAPK)/ERK kinase (MEK), which preferentially activates ERK, was upregulated by transfection with the recombinant sense expression vector pcDNA3.1-MEK and downregulated by pretreatment with U0126, a specific MEK inhibitor.	25	34	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	27	28	33	34
PMA induced ERK activation was mediated by MEK1/2 and was detected for up to 6 hours after treatment .	PMA induced ERK activation was mediated by MEK1/2 and was detected for up to 6 hours after treatment.	2	8	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	7	8	2	3
Co-inhibition of BRAF V600E and MEK prevents recovery of MAPK signaling .	Co-inhibition of BRAF V600E and MEK prevents recovery of MAPK signaling.	0	10	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	5	6	9	10
Our CFC MEK variants can not induce ERK unless they are phosphorylated by RAF at two key serine residues in the regulatory loop .	Our CFC MEK variants can not induce ERK unless they are phosphorylated by RAF at two key serine residues in the regulatory loop.	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	2	3	7	8
Combined inhibition of Raf and Mek maximally inhibited MAPK signaling .	Combined inhibition of Raf and Mek maximally inhibited MAPK signaling.	1	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	MAPK	MAPK	MAPK	5	6	8	9
However , a dose of a mitogen activated and extracellular-signal-regulated kinase ( MEK ) inhibitor , ineffective in wild-type controls , blocks MAPK activation , LTP and contextual learning in K-ras +/- mutants .	However, a dose of a mitogen-activated and extracellular-signal-regulated kinase (MEK) inhibitor, ineffective in wild-type controls, blocks MAPK activation, LTP and contextual learning in K-ras +/- mutants.	12	23	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	12	13	22	23
We observed that neither U0126 , which blocks activation of Erk1/2 by MEK , nor JNK inhibitor 1 , which blocks activation of the JNK family of MAPKs that are also involved in alternative splicing , substantially affected Sam68 mediated selection of the 5 ' splice site in the Bcl-x minigene .	We observed that neither U0126, which blocks activation of Erk1/2 by MEK, nor JNK inhibitor 1, which blocks activation of the JNK family of MAPKs that are also involved in alternative splicing, substantially affected Sam68 mediated selection of the 5 ' splice site in the Bcl-x minigene.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk1/2	Erk1/2	Erk1/2	12	13	10	11
ERK1/2 can be activated transiently or persistently by MEK1/2 and upstream MAP3Ks in conjunction with regulation and involvement of scaffolding proteins and phosphatases .	ERK1/2 can be activated transiently or persistently by MEK1/2 and upstream MAP3Ks in conjunction with regulation and involvement of scaffolding proteins and phosphatases.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	8	9	0	1
The ERK1/2 pathway , activated by MEK1/2 , XREF_BIBR plays key roles in the regulation of multiple biological activities , including cell proliferation , differentiation , cell cycle transition and survival , and constitutive activation of the ERK1/2 pathway contributes to tumorigenesis , or cancer growth , and increases the cell death threshold .	The ERK1/2 pathway, activated by MEK1/2, XREF_BIBR plays key roles in the regulation of multiple biological activities, including cell proliferation, differentiation, cell cycle transition and survival, and constitutive activation of the ERK1/2 pathway contributes to tumorigenesis, or cancer growth, and increases the cell death threshold.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	6	7	1	2
In the MAPK pathway MEK is a downstream target and the only known substrate for BRAF .	In the MAPK pathway MEK is a downstream target and the only known substrate for BRAF.	0	9	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	4	5	2	3
In addition , calcium activates mitogen activated protein kinase kinase ( MEK ) , which activates ERK XREF_BIBR .	In addition, calcium activates mitogen activated protein kinase kinase (MEK), which activates ERK XREF_BIBR.	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	11	12	16	17
Activated RAF kinases phosphorylate and activate MEK1/2 , which in turn phosphorylate and activate ERK1/2 , leading to cellular proliferation , survival , and differentiation , and to an inhibitory feedback toward upstream components of the pathway ( XREF_FIG ) .	Activated RAF kinases phosphorylate and activate MEK1/2, which in turn phosphorylate and activate ERK1/2, leading to cellular proliferation, survival, and differentiation, and to an inhibitory feedback toward upstream components of the pathway (XREF_FIG).	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	6	7	14	15
To explore the role of MAPK activation on PGI 2 and cAMP production by BK and IGF-1 in VSMC , cells were pretreated for 30 min with PD 98059 ( 20 muM , NEN-Biolabs , Beverly , MA ) , a specific cell permeable inhibitor of the MAPK activator MEK followed by BK ( 10 -8 M ) or IGF-1 ( 10 -8 M ) stimulation for 10 min .	To explore the role of MAPK activation on PGI 2 and cAMP production by BK and IGF-1 in VSMC, cells were pretreated for 30 min with PD 98059 (20 muM, NEN-Biolabs, Beverly, MA), a specific cell permeable inhibitor of the MAPK activator MEK followed by BK (10 -8 M) or IGF-1 (10 -8 M) stimulation for 10 min.	44	50	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	49	50	47	48
Ectopic MEK and ERK is sufficient to drive excess vulval induction [ XREF_BIBR ] and inhibition of MEK alone is sufficient to block the MEK and ERK induced phenotype [ XREF_BIBR ] .	Ectopic MEK and ERK is sufficient to drive excess vulval induction [XREF_BIBR] and inhibition of MEK alone is sufficient to block the MEK and ERK induced phenotype [XREF_BIBR].	15	27	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	17	18	26	27
In addition , when the cells were treated with U0126 , an MEK specific inhibitor , as shown in lane 5 , U0126 completely inhibited the activation of MAPK ( second panel ) and p90RSK ( third panel ) , indicating that activation of MEK is required for activation of MAPK and p90RSK stimulated by LPA .	In addition, when the cells were treated with U0126, an MEK specific inhibitor, as shown in lane 5, U0126 completely inhibited the activation of MAPK (second panel) and p90RSK (third panel), indicating that activation of MEK is required for activation of MAPK and p90RSK stimulated by LPA.	12	37	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	12	13	28	29
Cadmium or TNFalpha treatment have been clearly associated with ERK activation and autophagic programmed cell death ; moreover , direct ERK activation by the overexpression of active MEK may promote autophagy without any other stimulus .	Cadmium or TNFalpha treatment have been clearly associated with ERK activation and autophagic programmed cell death; moreover, direct ERK activation by the overexpression of active MEK may promote autophagy without any other stimulus.	20	28	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	overexpression of active MEK	mek	ERK	ERK	erk	27	28	20	21
Examples of these reactions are : the processive phosphorylation module of MEK kinaseand the distributive phosphorylation module of ERK kinasewhere , and are protein binding , dissociation and activation rate constants , respectively .	Examples of these reactions are : the processive phosphorylation module of MEK kinaseand the distributive phosphorylation module of ERK kinasewhere, and are protein binding, dissociation and activation rate constants, respectively.	11	19	module	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	11	12	18	19
Extracellular signal regulated kinases ( ERKs ) , activated by MEK , activate transcription factors such as Elk-1 directly or activate c-fos and SRF through RSK [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Extracellular signal regulated kinases (ERKs), activated by MEK, activate transcription factors such as Elk-1 directly or activate c-fos and SRF through RSK [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERKs	ERKs	ERKs	10	11	5	6
RNA sequencing reveals upregulation of MLKs in drug resistant tumor specimens and biochemical assays have also shown that catalytic activity of MLK1 , -2 , -3 , and/or -4 is required for direct phosphorylation of MEK , in a Raf independent manner , leading to reactivation of ERK signaling and decreased sensitivity to the B-Raf inhibitor [ XREF_BIBR ] .	RNA sequencing reveals upregulation of MLKs in drug resistant tumor specimens and biochemical assays have also shown that catalytic activity of MLK1, -2, -3, and/or -4 is required for direct phosphorylation of MEK, in a Raf independent manner, leading to reactivation of ERK signaling and decreased sensitivity to the B-Raf inhibitor [XREF_BIBR].	33	48	leading to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	MEK	phosphorylation of MEK	mek	ERK	ERK	erk	35	36	47	48
Activation of ERK by overexpression of MEK causes decreased energy expenditure and systemic insulin resistance 45 .	Activation of ERK by overexpression of MEK causes decreased energy expenditure and systemic insulin resistance 45.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	overexpression of MEK	mek	ERK	ERK	erk	6	7	2	3
XREF_BIBR In recent years , lots of clinical data suggest that combined BRAF and MEK inhibition can block paradoxical activation of the MAPK pathway induced by single-agent BRAF inhibitors , and an opportunity to investigate a regimen combining a BRAF inhibitor with an MEK inhibitor was provided by the fact of MEK inhibition having been validated as a therapeutic approach in the same patient population .	XREF_BIBR In recent years, lots of clinical data suggest that combined BRAF and MEK inhibition can block paradoxical activation of the MAPK pathway induced by single-agent BRAF inhibitors, and an opportunity to investigate a regimen combining a BRAF inhibitor with an MEK inhibitor was provided by the fact of MEK inhibition having been validated as a therapeutic approach in the same patient population.	14	23	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	14	15	22	23
Inhibition of MEK ( mitogen activated protein kinase ( MAPK )/ERK kinase ) after DOX treatment reversed the late ERK activation .	Inhibition of MEK (mitogen activated protein kinase (MAPK)/ERK kinase) after DOX treatment reversed the late ERK activation.	0	20	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	2	3	19	20
Importantly , expression of mutationally activated MEK in cells without functional ErbB2 was sufficient to promote cell migration and sustained ERK activation ( XREF_FIG D ) .	Importantly, expression of mutationally activated MEK in cells without functional ErbB2 was sufficient to promote cell migration and sustained ERK activation (XREF_FIG D).	2	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	expression of mutationally activated MEK	mek	ERK	ERK	erk	6	7	20	21
In addition , IRS1 and IRS2 can activate rat sarcoma viral oncogene homolog ( RAS ) and , subsequentially , the MAPK pathway , including mitogen and extracellular signal regulated kinase ( MEK ) and extracellular signal regulated kinase ( ERK ) [ XREF_BIBR ] .	In addition, IRS1 and IRS2 can activate rat sarcoma viral oncogene homolog (RAS) and, subsequentially, the MAPK pathway, including mitogen and extracellular signal regulated kinase (MEK) and extracellular signal regulated kinase (ERK) [XREF_BIBR].	7	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	32	33	21	22
The provision of small molecule inhibitors of MEK in the blood meal reproducibly reduced ERK activation in the A. stephensi midgut and enhanced nitric oxide synthase ( NOS ) transcription within 24h after infection , resulting in the production of inflammatory levels of reactive oxygen and nitrogen species in the midgut lumen [ XREF_BIBR ] that are directly toxic to P. falciparum [ XREF_BIBR ] and leading to significant reductions in oocyst numbers on the midgut epithelium [ XREF_BIBR ] .	The provision of small molecule inhibitors of MEK in the blood meal reproducibly reduced ERK activation in the A. stephensi midgut and enhanced nitric oxide synthase (NOS) transcription within 24h after infection, resulting in the production of inflammatory levels of reactive oxygen and nitrogen species in the midgut lumen [XREF_BIBR] that are directly toxic to P. falciparum [XREF_BIBR] and leading to significant reductions in oocyst numbers on the midgut epithelium [XREF_BIBR].	5	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	7	8	14	15
This process resembles the activation of ERK , which is activated by MEK phosphorylation of its activatory residues , which are dephosphorylated by either PP2A and PTP-SL or dual specificity phosphatases XREF_BIBR , XREF_BIBR .	This process resembles the activation of ERK, which is activated by MEK phosphorylation of its activatory residues, which are dephosphorylated by either PP2A and PTP-SL or dual specificity phosphatases XREF_BIBR, XREF_BIBR.	4	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK phosphorylation of its activatory residues, which are dephosphorylated	mek	ERK	ERK	erk	12	13	6	7
Regardless of the upstream activators , the involvement of ERK appears to be necessary for post-training 0.2 mg/kg E 2 to enhance object memory consolidation , as demonstrated by the fact that systemic MEK inhibition by SL327 completely blocked dorsal hippocampal ERK activation ( XREF_FIG ) and that dorsal hippocampal infusion of the MEK inhibitor U0126 completely blocked the E 2 -induced enhancement of object memory consolidation ( XREF_FIG ) .	Regardless of the upstream activators, the involvement of ERK appears to be necessary for post-training 0.2 mg/kg E 2 to enhance object memory consolidation, as demonstrated by the fact that systemic MEK inhibition by SL327 completely blocked dorsal hippocampal ERK activation (XREF_FIG) and that dorsal hippocampal infusion of the MEK inhibitor U0126 completely blocked the E 2 -induced enhancement of object memory consolidation (XREF_FIG).	33	42	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	33	34	41	42
In addition to PI3K and mTOR , MEK activation of ERK has also been known to activate HIFs and in turn be reactivated by HIFs ( Minet et al ., 2000 ; Mottet et al ., 2002 ) .	In addition to PI3K and mTOR, MEK activation of ERK has also been known to activate HIFs and in turn be reactivated by HIFs (Minet et al., 2000; Mottet et al., 2002).	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	7	8	10	11
TPL2 can then phosphorylate MEK1/2 which in turn activates ERK1/2 .	TPL2 can then phosphorylate MEK1/2 which in turn activates ERK1/2.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	TPL2 can then phosphorylate MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	4	5	9	10
Following radiation , ERK1/2 is activated through dual tyrosine and threonine phosphorylation by MEK1/2 and the activation , in turn , leads to the phosphorylation and activation of over 160 substrates .	Following radiation, ERK1/2 is activated through dual tyrosine and threonine phosphorylation by MEK1/2 and the activation, in turn, leads to the phosphorylation and activation of over 160 substrates.	3	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	13	14	3	4
In vivo , activated MEK activates ERK kinase dominantly in the cytosol by phosphorylating threonine and tyrosine residues in the activation loop [ XREF_BIBR ] .	In vivo, activated MEK activates ERK kinase dominantly in the cytosol by phosphorylating threonine and tyrosine residues in the activation loop [XREF_BIBR].	3	7	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	4	5	6	7
Moreover , the sequence of a Platynereis dumerilii MAP kinase kinase homolog has been reported XREF_BIBR ( GenBank : CAJ38794.1 ) , indicating that MAPK activation by MEK is conserved .	Moreover, the sequence of a Platynereis dumerilii MAP kinase kinase homolog has been reported XREF_BIBR (GenBank : CAJ38794.1), indicating that MAPK activation by MEK is conserved.	24	28	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	27	28	24	25
ERK can be activated by Ref mediated MEK signaling .	ERK can be activated by Ref mediated MEK signaling.	0	8	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MEK	Ref mediated MEK	mek	ERK	ERK	erk	7	8	0	1
In the absence of Mek1/2 , only scattered , single cyclin D1 positive cells were very rarely detected in UB ( XREF_SUPPLEMENTARY ) , supporting the idea that MEK1/2 activated ERK functions in the G1/S transition phase during epithelial branching morphogenesis .	In the absence of Mek1/2, only scattered, single cyclin D1 positive cells were very rarely detected in UB (XREF_SUPPLEMENTARY), supporting the idea that MEK1/2 activated ERK functions in the G1/S transition phase during epithelial branching morphogenesis.	28	31	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	28	29	30	31
The activation of MEK is essential to somatic cell survival and stimulates MAPK signaling , which is important for DNA synthesis and mitogenesis of differentiated cells XREF_BIBR , XREF_BIBR .	The activation of MEK is essential to somatic cell survival and stimulates MAPK signaling, which is important for DNA synthesis and mitogenesis of differentiated cells XREF_BIBR, XREF_BIBR.	1	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	3	4	12	13
However , neither ERK inhibition by MEK blockade nor MLK inhibition abolished SLFN12 effects on DPP4 or PSA , suggesting that SLFN12 acts in prostate cancer cells independently of ERK and MLK .	However, neither ERK inhibition by MEK blockade nor MLK inhibition abolished SLFN12 effects on DPP4 or PSA, suggesting that SLFN12 acts in prostate cancer cells independently of ERK and MLK.	3	7	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	3	4
Inhibition of Mek ( proximal activator of Erk ) also blocked stimulation of Erk and adhesion by formylmethionyl-leucyl-phenylalanineand arachidonic acid .	Inhibition of Mek (proximal activator of Erk) also blocked stimulation of Erk and adhesion by formylmethionyl-leucyl-phenylalanineand arachidonic acid.	0	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	2	3	13	14
ERK activation is mediated by at least three different pathways : a Raf and MEK dependent pathway , a PI3K and Raf independent pathway that strongly activates MEK , and a third undetermined pathway that directly activates ERK proteins [ XREF_BIBR ] .	ERK activation is mediated by at least three different pathways : a Raf and MEK dependent pathway, a PI3K and Raf independent pathway that strongly activates MEK, and a third undetermined pathway that directly activates ERK proteins [XREF_BIBR].	0	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	14	15	0	1
Given the role of MEK signaling in cancer and MAPK dependent diseases , we sought to determine if this pathway could be inhibited safely by examining the downstream molecular consequences .	Given the role of MEK signaling in cancer and MAPK dependent diseases, we sought to determine if this pathway could be inhibited safely by examining the downstream molecular consequences.	4	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	4	5	9	10
We previously reported that activation of the MEK1/2/ERK1/2 pathway represents an important compensatory , cytoprotective response to Chk1 inhibitors in human leukemia and multiple myeloma cells , and that interruption of MEK1/2 kinase function by either pharmacologic or genetic means blocked Chk1-inhibitor-induced ERK1/2 activation and potentiated apoptosis [ XREF_BIBR ] .	We previously reported that activation of the MEK1/2/ERK1/2 pathway represents an important compensatory, cytoprotective response to Chk1 inhibitors in human leukemia and multiple myeloma cells, and that interruption of MEK1/2 kinase function by either pharmacologic or genetic means blocked Chk1-inhibitor-induced ERK1/2 activation and potentiated apoptosis [XREF_BIBR].	31	43	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	31	32	42	43
Since MEK induces activation of Map2k1 and Erk , ectopic expression of CA-MEK in endothelial cells should alleviate the phenotype of kdrl MO injected embryos .	Since MEK induces activation of Map2k1 and Erk, ectopic expression of CA-MEK in endothelial cells should alleviate the phenotype of kdrl MO injected embryos.	1	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk	Erk	Erk	1	2	7	8
It is known that ERK1/2 are activated by MEK1/2 dependent phosphorylation in the TEY motif of the activation loop .	It is known that ERK1/2 are activated by MEK1/2 dependent phosphorylation in the TEY motif of the activation loop.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2 dependent phosphorylation	mek1/2	ERK1/2	ERK1/2	erk1/2	8	9	4	5
Pre-treatment of cells with PD98059 , an inhibitor of MEK1/2 , significantly inhibited ERK1/2 kinase activity ( XREF_FIG ) .	Pre-treatment of cells with PD98059, an inhibitor of MEK1/2, significantly inhibited ERK1/2 kinase activity (XREF_FIG).	7	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	9	10	13	14
To determine if MEK inhibition prevents VS-5584-induced ERK activation , we treated PDAC cell lines BxPC-3 and HPAC with VS-5584 and the MEK inhibitor GSK1120212 ( approved by the US FDA for the treatment of metastatic melanoma ) alone or in combination .	To determine if MEK inhibition prevents VS-5584-induced ERK activation, we treated PDAC cell lines BxPC-3 and HPAC with VS-5584 and the MEK inhibitor GSK1120212 (approved by the US FDA for the treatment of metastatic melanoma) alone or in combination.	3	8	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	7	8
Activated BRAF in the MAPK signal transduction pathway propagates signaling by phosphorylating MAPKKs , MEK1/2 XREF_BIBR , XREF_BIBR .	Activated BRAF in the MAPK signal transduction pathway propagates signaling by phosphorylating MAPKKs, MEK1/2 XREF_BIBR, XREF_BIBR.	0	15	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	14	15	4	5
Inhibition of the ERK pathway by retroviral mediated overexpression of a dominant negative MEK ( an upstream activator of ERK ) in fetal thymic organ culture causes impaired differentiation of DN into DP thymocytes .	Inhibition of the ERK pathway by retroviral mediated overexpression of a dominant negative MEK (an upstream activator of ERK) in fetal thymic organ culture causes impaired differentiation of DN into DP thymocytes.	8	25	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	overexpression of a dominant negative MEK	mek	ERK	ERK	erk	13	14	19	20
To further investigate a role for ERK1/2 in HSPB1 dependent BIM degradation we used a pharmacological approach to inhibit MEK1/2 , the upstream kinase that activates ERK1/2 .	To further investigate a role for ERK1/2 in HSPB1 dependent BIM degradation we used a pharmacological approach to inhibit MEK1/2, the upstream kinase that activates ERK1/2.	18	27	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	19	20	26	27
Interestingly , when we co-transfected five different oncogenic serine/threonine kinases , including IKKalpha , IKKbeta , myristoylated-AKT , MEKDD , or CDC2 ; only constitutively active MEK ( MEKDD ) , which activates ERK , significantly reversed the effects of XPO5 ( XREF_FIG ) .	Interestingly, when we co-transfected five different oncogenic serine/threonine kinases, including IKKalpha, IKKbeta, myristoylated-AKT, MEKDD, or CDC2; only constitutively active MEK (MEKDD), which activates ERK, significantly reversed the effects of XPO5 (XREF_FIG).	12	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	26	27	33	34
Unexpectedly , two MEK ( MAP kinase kinase ) inhibitors ( PD 98059 and U 0126 ) enhanced dendritic growth , and a ligand , basic FGF , that activates the ERK pathway inhibited the growth of these processes .	Unexpectedly, two MEK (MAP kinase kinase) inhibitors (PD 98059 and U 0126) enhanced dendritic growth, and a ligand, basic FGF, that activates the ERK pathway inhibited the growth of these processes.	2	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	31	32
ERK is activated via phosphorylation by its upstream kinase MEK ( MAP kinase or ERK kinase ) .	ERK is activated via phosphorylation by its upstream kinase MEK (MAP kinase or ERK kinase).	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	0	1
Also , activated Mek expression in NRCMs and in transgenic mice increased Erk1/2 [ XREF_BIBR ] and Nfat activity in a calcineurin independent manner [ XREF_BIBR ] .	Also, activated Mek expression in NRCMs and in transgenic mice increased Erk1/2 [XREF_BIBR] and Nfat activity in a calcineurin independent manner [XREF_BIBR].	3	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek expression	mek	Erk1/2	Erk1/2	erk1/2	3	4	12	13
A pathway of Sos , Ras , Raf , and MEK can activate ERK1/2 , but it is not known if AKT interacts with one of these compounds or interacts with the pathway at the level of ERK1/2 .	A pathway of Sos, Ras, Raf, and MEK can activate ERK1/2, but it is not known if AKT interacts with one of these compounds or interacts with the pathway at the level of ERK1/2.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	10	11	13	14
Combined BRAF V600E and MEK inhibition prevents reactivation of the MAPK signaling , which correlates with decreased cell viability and augmented cell cycle arrest .	Combined BRAF V600E and MEK inhibition prevents reactivation of the MAPK signaling, which correlates with decreased cell viability and augmented cell cycle arrest.	4	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	4	5	10	11
Combination MEK inhibition and lapatinib treatment suppressed MEK and ERK signaling , increasing overall cytotoxicity , apoptosis , and inhibition of tumor growth relative to the single agent treatments ( XREF_FIG ) .	Combination MEK inhibition and lapatinib treatment suppressed MEK and ERK signaling, increasing overall cytotoxicity, apoptosis, and inhibition of tumor growth relative to the single agent treatments (XREF_FIG).	1	10	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	1	2	9	10
XREF_BIBR The dual specific protein kinase MEK activates MAPK by sequentially phosphorylating Tyr185 prior to Thr183 in the activation loop of MAPK using a distributive mechanism .	XREF_BIBR The dual specific protein kinase MEK activates MAPK by sequentially phosphorylating Tyr185 prior to Thr183 in the activation loop of MAPK using a distributive mechanism.	0	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	6	7	8	9
Constitutive expression of MEK or ERK rescued MAPK activation during DNo treatment in HeLa cells ( XREF_FIG ) , whereas transfection of cells with a construct encoding dominant negative ERK reduced phosphorylated ERK levels below those of untreated or DNo treated control cells ( XREF_FIG ) .	Constitutive expression of MEK or ERK rescued MAPK activation during DNo treatment in HeLa cells (XREF_FIG), whereas transfection of cells with a construct encoding dominant negative ERK reduced phosphorylated ERK levels below those of untreated or DNo treated control cells (XREF_FIG).	1	8	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	expression of MEK	mek	MAPK	MAPK	mapk	3	4	7	8
Raf , in turn , activates MAPK kinase ( MEK ) and phosphorylated MEK activates ERK1/2 [ XREF_BIBR ] .	Raf, in turn, activates MAPK kinase (MEK) and phosphorylated MEK activates ERK1/2 [XREF_BIBR].	12	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	13	14	15	16
Taken together with the observation that lack of MAPK activity both in vivo and in vitro intensifies E-cadherin localization on cell surfaces , and recent evidence for cross-talk between FA and AJ , we suggest that MEK1/2 activated ERK1/2 regulates cellular adhesion by phosphorylating paxillin at Ser83 , which facilitates normal FA dynamics and composition .	Taken together with the observation that lack of MAPK activity both in vivo and in vitro intensifies E-cadherin localization on cell surfaces, and recent evidence for cross-talk between FA and AJ, we suggest that MEK1/2 activated ERK1/2 regulates cellular adhesion by phosphorylating paxillin at Ser83, which facilitates normal FA dynamics and composition.	36	47	activated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	MEK1/2	MEK1/2	mek1/2	ERK1/2	ERK1/2 regulates cellular adhesion by phosphorylating paxillin at Ser83	erk1/2	36	37	38	39
ERK isoforms , ERK1 and ERK2 , are activated through the phosphorylation of tyrosine and threonine residues by the upstream kinase MEK .	ERK isoforms, ERK1 and ERK2, are activated through the phosphorylation of tyrosine and threonine residues by the upstream kinase MEK.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	21	22	0	1
The first step in MAPK activation by MEK must be the formation of a MEK x MAPK enzyme and substrate complex , followed by phosphorylation producing monophosphorylated MAPK ( pMAPK ) .	The first step in MAPK activation by MEK must be the formation of a MEK x MAPK enzyme and substrate complex, followed by phosphorylation producing monophosphorylated MAPK (pMAPK).	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	7	8	4	5
Subsequently , Raf activates MEK ( MAPK and extracellular signal regulated kinase kinase ) , which then activates ERK ( extracellular signal regulated kinase ) .	Subsequently, Raf activates MEK (MAPK and extracellular signal regulated kinase kinase), which then activates ERK (extracellular signal regulated kinase).	3	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	4	5	18	19
CA MEK overexpression induced ERK activation is evident at 3 h in low potassium cultures ( XREF_FIG D ) .	CA MEK overexpression induced ERK activation is evident at 3 h in low potassium cultures (XREF_FIG D).	1	5	induced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK overexpression	mek	ERK	ERK	erk	1	2	4	5
A study of the impact of inhibition of ERK1/2 activation by an MEK inhibition U0126 on HGF stimulated cell motility is warranted to test this hypothesis .	A study of the impact of inhibition of ERK1/2 activation by an MEK inhibition U0126 on HGF stimulated cell motility is warranted to test this hypothesis.	8	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	12	13	8	9
MEK mediated ERK activation occurring before accumulation of p-p38 MAPK and the consequent inhibition of MEK , may be sufficient to induce long lasting effects such as the persistent increase in basal excitability 12 .	MEK mediated ERK activation occurring before accumulation of p-p38 MAPK and the consequent inhibition of MEK, may be sufficient to induce long lasting effects such as the persistent increase in basal excitability 12.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	2	3
Subsequently , MEK1/2 activates extracellular receptor kinase 1/2 ( ERK1/2 ) by phosphorylating Thr202 and Tyr204 .	Subsequently, MEK1/2 activates extracellular receptor kinase 1/2 (ERK1/2) by phosphorylating Thr202 and Tyr204.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	2	3	9	10
The upstream regulator of ERK , MEK1/2 , can activate p44 and p42 ERK and MAP kinase by phosphorylation of both threonine and tyrosine residues at sites located within the activation loop of kinase subdomain VIII .	The upstream regulator of ERK, MEK1/2, can activate p44 and p42 ERK and MAP kinase by phosphorylation of both threonine and tyrosine residues at sites located within the activation loop of kinase subdomain VIII.	2	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	6	7	13	14
These data suggest that MEK1 is likely to be the major MEK that mediates prolonged ERK1/2 signaling and is required for expression of p21 CIP1 mRNA .	These data suggest that MEK1 is likely to be the major MEK that mediates prolonged ERK1/2 signaling and is required for expression of p21 CIP1 mRNA.	4	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	11	12	15	16
Active Raf in turn phosphorylates and activates MEK 1/2 ( Mitogen activated Protein Kinase- and Extracellular Signal Regulated Kinase-Kinase ) which in turn phosphorylate and activate ERK1/2 .	Active Raf in turn phosphorylates and activates MEK 1/2 (Mitogen activated Protein Kinase- and Extracellular Signal Regulated Kinase-Kinase) which in turn phosphorylate and activate ERK1/2.	1	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK 1/2	Raf in turn phosphorylates and activates MEK 1/2	mek 1/2	ERK1/2	ERK1/2	erk1/2	7	9	26	27
Finally , RNAi-knockdown of the upstream kinase , MEK , blocked stimulation of MAPK in response to both stimuli , indicating that MAPK phosphorylation by phosphate is mediated by MEK .	Finally, RNAi-knockdown of the upstream kinase, MEK, blocked stimulation of MAPK in response to both stimuli, indicating that MAPK phosphorylation by phosphate is mediated by MEK.	6	14	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	8	9	13	14
Upon addition of beta-estradiol to these cells , the Raf-1 kinase moiety of the chimera is unmasked and rapidly phosphorylates MEK , which in turn activates p42 and p44 MAPK .	Upon addition of beta-estradiol to these cells, the Raf-1 kinase moiety of the chimera is unmasked and rapidly phosphorylates MEK, which in turn activates p42 and p44 MAPK.	9	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	Raf-1 kinase moiety of the chimera is unmasked and rapidly phosphorylates MEK	mek	MAPK	MAPK	mapk	20	21	29	30
Upon activation , RAF phosphorylates and activates MEK , which activates ERK and RSK pathway .	Upon activation, RAF phosphorylates and activates MEK, which activates ERK and RSK pathway.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	RAF phosphorylates and activates MEK	mek	ERK	ERK	erk	7	8	11	12
MEK activates ERKs by dual phosphorylation on the threonine and tyrosine residues of the sequence T 185 EY 187 ( sequence of human ERK2 ) .	MEK activates ERKs by dual phosphorylation on the threonine and tyrosine residues of the sequence T 185 EY 187 (sequence of human ERK2).	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERKs	ERKs	ERKs	0	1	2	3
In our studies , the inhibitor of MEK 1/2 SL327 prevents the ERK 1/2 activation by H 2 O 2 in PC12 cells under conditions of our experiments ( XREF_FIG ) .	In our studies, the inhibitor of MEK 1/2 SL327 prevents the ERK 1/2 activation by H 2 O 2 in PC12 cells under conditions of our experiments (XREF_FIG).	7	14	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK 1/2	MEK 1/2	MEK 1/2	ERK 1/2	ERK 1/2	ERK 1/2	7	9	12	14
Most primary human melanomas exhibit loss of expression of the CDKN2A locus in addition to activation of canonical MAPK signaling including RAS , RAF , MEK , and ERK .	Most primary human melanomas exhibit loss of expression of the CDKN2A locus in addition to activation of canonical MAPK signaling including RAS, RAF, MEK, and ERK.	18	26	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	25	26	18	19
Upon activation , Raf proteins phosphorylate and activate downstream MEK kinases that then phosphorylate and activate ERK MAP kinases .	Upon activation, Raf proteins phosphorylate and activate downstream MEK kinases that then phosphorylate and activate ERK MAP kinases.	9	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	16	17
Ras is activated by an external stimulus , via one of many growth factor receptors ; it then binds to and activates Raf-1 to become Raf-1 * , or activated Raf , which in turn activates MAPK and ERK Kinase ( MEK ) which in turn activates Extracellular signal Regulated Kinase ( ERK ) .	Ras is activated by an external stimulus, via one of many growth factor receptors; it then binds to and activates Raf-1 to become Raf-1 *, or activated Raf, which in turn activates MAPK and ERK Kinase (MEK) which in turn activates Extracellular signal Regulated Kinase (ERK).	39	51	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	Extracellular signal Regulated Kinase	Extracellular signal Regulated Kinase	Extracellular signal Regulated Kinase	41	42	47	51
The ERK1/2 pathway , which is activated by the Ras-mitogen-activated protein kinase and ERK kinase ( MEK ) and eventually leads to gene transcription or mRNA translation , plays critical roles in synaptic plasticity .	The ERK1/2 pathway, which is activated by the Ras-mitogen-activated protein kinase and ERK kinase (MEK) and eventually leads to gene transcription or mRNA translation, plays critical roles in synaptic plasticity.	1	17	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	16	17	1	2
The mechanism by which MEK1/2 typically activates ERK1/2 is initiated by Ras .	The mechanism by which MEK1/2 typically activates ERK1/2 is initiated by Ras.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	4	5	7	8
64 In the case of SYK inhibition in AML , however , MEK inhibition , but not PI3K inhibition , attenuates the feedback activation of MAPK .	64 In the case of SYK inhibition in AML, however, MEK inhibition, but not PI3K inhibition, attenuates the feedback activation of MAPK.	12	26	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	12	13	25	26
However , suppression of this pathway by blocking FGF receptor activity or by more direct disruption of MAPK signalling using a small molecule inhibitor of the MAPK activator MEK , uncouples this differentiation signal and shifts the balance in favour of ES cell self-renewal .	However, suppression of this pathway by blocking FGF receptor activity or by more direct disruption of MAPK signalling using a small molecule inhibitor of the MAPK activator MEK, uncouples this differentiation signal and shifts the balance in favour of ES cell self-renewal.	23	29	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	28	29	26	27
As previously demonstrated , MEK1/2 inhibition led to decreased P-p70 S6K and P-ERK1/2 with little or no effect on P-AKT , P-PRAS40 , P-rpS6 , or P-4E-BP1 .	As previously demonstrated, MEK1/2 inhibition led to decreased P-p70 S6K and P-ERK1/2 with little or no effect on P-AKT, P-PRAS40, P-rpS6, or P-4E-BP1.	4	13	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	P-ERK1/2	P-ERK1/2	P-ERK1/2	4	5	12	13
ERK proteins are members of the conserved proline directed serine/threonine MAP ( Mitogen Activated Protein ) kinase family , and are directly activated by MEK via dual phosphorylation on the threonine ( T ) and tyrosine ( Y ) of the conserved TEY motif .	ERK proteins are members of the conserved proline directed serine/threonine MAP (Mitogen Activated Protein) kinase family, and are directly activated by MEK via dual phosphorylation on the threonine (T) and tyrosine (Y) of the conserved TEY motif.	0	27	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	24	25	0	1
Although MAPK kinases follow specific signal transduction pathways to phosphorylate their cognate MAPKs ( e.g ., MEK1/2 activates ERK1/2 but not JNK ) , p38 MAPK displays selectivity between cognate and noncognate docking sites that might explain the interference between two signal transduction pathways [ XREF_BIBR ] .	Although MAPK kinases follow specific signal transduction pathways to phosphorylate their cognate MAPKs (e.g., MEK1/2 activates ERK1/2 but not JNK), p38 MAPK displays selectivity between cognate and noncognate docking sites that might explain the interference between two signal transduction pathways [XREF_BIBR].	14	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	16	17	18	19
Recent work on ERK activation by MEK reveals that crowding has a strong effect on reaction kinetics .	Recent work on ERK activation by MEK reveals that crowding has a strong effect on reaction kinetics.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	3	4
By phosphorylating at Ser and Thr residues , MEK activates ERK1/2 , which then phosphorylates cytoplasmic and nuclear substrates , such as CREB .	By phosphorylating at Ser and Thr residues, MEK activates ERK1/2, which then phosphorylates cytoplasmic and nuclear substrates, such as CREB.	8	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	8	9	10	11
Indeed , while MEK independent activation of ERK is widely accepted ( Levin-Salomon etal ., 2008 ; Simard etal ., 2015 ) , uncoupling MEK downstream signaling to ERK remains controversial .	Indeed, while MEK independent activation of ERK is widely accepted (Levin-Salomon etal., 2008; Simard etal., 2015), uncoupling MEK downstream signaling to ERK remains controversial.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	7	8
Consistent with their ability to activate Rac1 , expression of either full-length murine p120 or of the N-terminally truncated p120 mutant ( DeltaN ) rescued both Raf and MEK phosphorylation at these sites , induced activation of ERK1/2 , increased expression of cyclin D1 , and inhibited p27 .	Consistent with their ability to activate Rac1, expression of either full-length murine p120 or of the N-terminally truncated p120 mutant (DeltaN) rescued both Raf and MEK phosphorylation at these sites, induced activation of ERK1/2, increased expression of cyclin D1, and inhibited p27.	28	40	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK phosphorylation	mek	ERK1/2	ERK1/2	erk1/2	28	29	37	38
Downstream from RAS , RAF activates MEK1/2 and MEK5/6 , which activate ERK and p38 , respectively .	Downstream from RAS, RAF activates MEK1/2 and MEK5/6, which activate ERK and p38, respectively.	5	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	6	7	12	13
In vitro analyses offer mechanistic support for the role of mechanical stimuli in promoting a MEK dependent activation of ERK1/2 .	In vitro analyses offer mechanistic support for the role of mechanical stimuli in promoting a MEK dependent activation of ERK1/2.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	15	16	19	20
Mxi2 potently up-regulates ERK mediated activation of the transcription factors Elk1 and HIF1alpha but has no effect on the activity of ERK cytoplasmic substrates RSK2 and cPLA ( 2 ) , induced by epidermal growth factor or by MEK .	Mxi2 potently up-regulates ERK mediated activation of the transcription factors Elk1 and HIF1alpha but has no effect on the activity of ERK cytoplasmic substrates RSK2 and cPLA (2), induced by epidermal growth factor or by MEK.	21	39	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	38	39	21	22
MAPK is activated by MAPK kinase ( MEK or MAPKK ) , which is activated in turn by MEK kinase ( MEKK or MAPKKK ) .	MAPK is activated by MAPK kinase (MEK or MAPKK), which is activated in turn by MEK kinase (MEKK or MAPKKK).	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	7	8	0	1
Furthermore , not only can immunopurified KSR1 phosphorylate c-Raf-1 in vitro but it also transactivates c-Raf-1 towards MEK1 , as measured by direct MEK1 phosphorylation and MEK induced ERK and MAPK activation [ XREF_BIBR - XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Furthermore, not only can immunopurified KSR1 phosphorylate c-Raf-1 in vitro but it also transactivates c-Raf-1 towards MEK1, as measured by direct MEK1 phosphorylation and MEK induced ERK and MAPK activation [XREF_BIBR - XREF_BIBR, XREF_BIBR - XREF_BIBR].	26	31	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	26	27	28	29
The results of this experiment indicate that ERK activation by MEK is required , in both normal and dwarf cells , for the induction of egr-1 expression by H 2 O 2 .	The results of this experiment indicate that ERK activation by MEK is required, in both normal and dwarf cells, for the induction of egr-1 expression by H 2 O 2.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	10	11	7	8
Within the ERK signaling pathway , CRAF is a wild-type RAF isotype , and can transmit signals from GTP bound RAS to MEK , which activates ERK .	Within the ERK signaling pathway, CRAF is a wild-type RAF isotype, and can transmit signals from GTP bound RAS to MEK, which activates ERK.	19	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	22	23	26	27
MEK in turn activates ERK-type MAPK and downstream effectors that maintain M-phase promoting factor ( MPF ) activity XREF_BIBR - XREF_BIBR .	MEK in turn activates ERK-type MAPK and downstream effectors that maintain M-phase promoting factor (MPF) activity XREF_BIBR - XREF_BIBR.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	0	1	5	6
Phosphorylation by MEK activates MAPK and ERK in the cytoplasm , and phospho-ERK is thought to enter the nucleus readily to modulate transcription .	Phosphorylation by MEK activates MAPK and ERK in the cytoplasm, and phospho-ERK is thought to enter the nucleus readily to modulate transcription.	0	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	2	3	4	5
We pre-treated primary B cells with either an inhibitor of MEK kinases ( the upstream activators of Erk ) , with two different JNK inhibitors or with a p38 inhibitor .	We pre-treated primary B cells with either an inhibitor of MEK kinases (the upstream activators of Erk), with two different JNK inhibitors or with a p38 inhibitor.	10	18	activators	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk	Erk	Erk	10	11	17	18
XREF_BIBR ERK is itself activated by the MAP kinase kinase MEK1/2 , whose activity can be stimulated downstream by growth factor receptors .	XREF_BIBR ERK is itself activated by the MAP kinase kinase MEK1/2, whose activity can be stimulated downstream by growth factor receptors.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	10	11	1	2
MEK1/2 in turn activates ERK1/2 by phosphorylation of the Thr and Tyr residues in the conserved Thr-Glu-Tyr motif within its regulatory loop .	MEK1/2 in turn activates ERK1/2 by phosphorylation of the Thr and Tyr residues in the conserved Thr-Glu-Tyr motif within its regulatory loop.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	0	1	4	5
It also controls ERK pathway activity by anchoring inactive ERK proteins in the nucleus , preventing MEK mediated reactivation of ERK in the cytoplasm 8 .	It also controls ERK pathway activity by anchoring inactive ERK proteins in the nucleus, preventing MEK mediated reactivation of ERK in the cytoplasm 8.	16	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	16	17	20	21
Inhibition of MEK1/2 caused modest reductions in basal MAPK activity and transiently suppressed UCN-01-stimulated MAPK activity below that of MEK1/2 inhibitor alone .	Inhibition of MEK1/2 caused modest reductions in basal MAPK activity and transiently suppressed UCN-01-stimulated MAPK activity below that of MEK1/2 inhibitor alone.	0	15	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	2	3	14	15
The dual specificity mitogen actived protein ( MAP ) kinase and ERK kinase ( MEK ) activates ERK1/2 in response to angII , but the MEK activating kinases remain undefined .	The dual specificity mitogen actived protein (MAP) kinase and ERK kinase (MEK) activates ERK1/2 in response to angII, but the MEK activating kinases remain undefined.	9	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	14	15	17	18
Once activated , all Raf family members ( A-Raf , B-Raf , and c-Raf ( Raf-1 ) [ XREF_BIBR ] ) are capable of activating MEK1/2 , which in turn activates ERK1/2 .	Once activated, all Raf family members (A-Raf, B-Raf, and c-Raf (Raf-1) [XREF_BIBR]) are capable of activating MEK1/2, which in turn activates ERK1/2.	22	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	25	26	31	32
Activated Raf phosphorylates and activates the dual specificity mitogen activated protein kinase ( MAPK ) MEK , which in turn stimulates the ERK subset of MAPKs : extracellular related kinase ( ERK ) 1 and ERK2 .	Activated Raf phosphorylates and activates the dual specificity mitogen activated protein kinase (MAPK) MEK, which in turn stimulates the ERK subset of MAPKs : extracellular related kinase (ERK) 1 and ERK2.	11	35	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	15	16	22	23
Erk1/2 activation , however , was significantly reduced by inhibition of MEK1/2 in both cell types .	Erk1/2 activation, however, was significantly reduced by inhibition of MEK1/2 in both cell types.	0	12	reduced	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	Erk1/2	Erk1/2	Erk1/2	11	12	0	1
MLKs are direct MEK kinases that activate the ERK pathway .	MLKs are direct MEK kinases that activate the ERK pathway.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	8	9
Importantly , ERK activation is required for the protective effect of bisphosphonates since their effect was abolished by ERK pharmacological inhibitors and by transfection of a dominant negative form of MEK , the kinase that activates ERKs .	Importantly, ERK activation is required for the protective effect of bisphosphonates since their effect was abolished by ERK pharmacological inhibitors and by transfection of a dominant negative form of MEK, the kinase that activates ERKs.	28	37	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERKs	ERKs	ERKs	30	31	36	37
The MEK1/2 then activates the MAPK ( extracellular signal related kinase 1/2 [ ERK1/2 ] ) signaling transduction pathway , resulting in activation of a variety of transcription factors that regulate cellular proliferation , differentiation , and apoptosis .	The MEK1/2 then activates the MAPK (extracellular signal related kinase 1/2 [ERK1/2]) signaling transduction pathway, resulting in activation of a variety of transcription factors that regulate cellular proliferation, differentiation, and apoptosis.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	1	2	5	6
Importantly , significant induction of LAMTOR3 , the gene that encodes MEK partner-1 ( MP1 ) , which activates ERK1 [ XREF_BIBR ] and ERK1/2 [ XREF_BIBR ] , was upregulated in F3.EGFRviii spheres in our PCR array , and was also upregulated in GSCs ( or spheres ) .	Importantly, significant induction of LAMTOR3, the gene that encodes MEK partner-1 (MP1), which activates ERK1 [XREF_BIBR] and ERK1/2 [XREF_BIBR], was upregulated in F3.EGFRviii spheres in our PCR array, and was also upregulated in GSCs (or spheres).	11	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	11	12	24	25
Since MEK must be activated in order to activate ERK , this compound blocks the activation of ERK ( XREF_FIG ) .	Since MEK must be activated in order to activate ERK, this compound blocks the activation of ERK (XREF_FIG).	1	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	1	2	9	10
Inhibition of MEK1/2 relieves this feedback loop by inactivating ERK1/2 , subsequently leading to C-Raf activation when Ras activity is available 111 .	Inhibition of MEK1/2 relieves this feedback loop by inactivating ERK1/2, subsequently leading to C-Raf activation when Ras activity is available 111.	0	10	relieves	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	2	3	9	10
In ADPKD cells , cyclic AMP dependent cell proliferation is mediated by activation of B-Raf which stimulates MEK , which in turn , activates mitogen activated protein kinase ERK , which then translocates to the nucleus to activate genes involved in cell proliferation .	In ADPKD cells, cyclic AMP dependent cell proliferation is mediated by activation of B-Raf which stimulates MEK, which in turn, activates mitogen activated protein kinase ERK, which then translocates to the nucleus to activate genes involved in cell proliferation.	16	36	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	MEK	MEK	mek	ERK	ERK, which then translocates to the nucleus	erk	17	18	28	29
Finally , the synaptically generated retrograde signal resulting in persistent MAPK activation at the soma requires tyrosine kinase ( TK ) and MEK activity ( the upstream activator of MAPK ) in the synaptic compartment .	Finally, the synaptically generated retrograde signal resulting in persistent MAPK activation at the soma requires tyrosine kinase (TK) and MEK activity (the upstream activator of MAPK) in the synaptic compartment.	22	30	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	22	23	29	30
However , in our system it is unlikely that dephosphorylation of ERK is upregulated in suspended cells , as ERK activation mediated by active versions of either Raf or MEK was unaltered in suspension versus adherent conditions .	However, in our system it is unlikely that dephosphorylation of ERK is upregulated in suspended cells, as ERK activation mediated by active versions of either Raf or MEK was unaltered in suspension versus adherent conditions.	19	30	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	29	30	19	20
XREF_BIBR , XREF_BIBR However , we have also observed that pharmacological inhibition of MEK signaling -- upstream activators of ERK1/2 -- blocks ER-stress induced activation of JUN , whereas a chemical inhibitor of JNK does not .	XREF_BIBR, XREF_BIBR However, we have also observed that pharmacological inhibition of MEK signaling -- upstream activators of ERK1/2 -- blocks ER-stress induced activation of JUN, whereas a chemical inhibitor of JNK does not.	13	20	activators	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	13	14	19	20
ERK1/2 is activated by MEK1/2 , which is downstream of the Ras and Raf pathway and has been implicated in mitogenesis , cell differentiation , and stress responses XREF_BIBR .	ERK1/2 is activated by MEK1/2, which is downstream of the Ras and Raf pathway and has been implicated in mitogenesis, cell differentiation, and stress responses XREF_BIBR.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	4	5	0	1
Raf1 phosphorylates Mek1/2 , which then activate Erk1/2 .	Raf1 phosphorylates Mek1/2, which then activate Erk1/2.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek1/2	Raf1 phosphorylates Mek1/2	mek1/2	Erk1/2	Erk1/2	erk1/2	2	3	7	8
ERK1/2 can be positively activated by MEK1/2 through phosphorylation of Thr and Tyr residues , namely Thr202 and Tyr204 of ERK1 and Thr173 and Tyr185 of ERK2 , respectively .	ERK1/2 can be positively activated by MEK1/2 through phosphorylation of Thr and Tyr residues, namely Thr202 and Tyr204 of ERK1 and Thr173 and Tyr185 of ERK2, respectively.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	6	7	0	1
Among other actions , RAF activates another kinase MEK , which activates yet another kinase MAPK .	Among other actions, RAF activates another kinase MEK, which activates yet another kinase MAPK.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	8	9	15	16
Each MAPK cascade consists of three kinase modulates which include an MEK kinase ( MEKK ) , a mitogen-activate protein kinase and extracellular signal regulated kinase ( MEK ) , and a mitogen activated protein kinase ( MAPK ) [ XREF_BIBR - XREF_BIBR ] .	Each MAPK cascade consists of three kinase modulates which include an MEK kinase (MEKK), a mitogen-activate protein kinase and extracellular signal regulated kinase (MEK), and a mitogen activated protein kinase (MAPK) [XREF_BIBR - XREF_BIBR].	7	28	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	extracellular signal regulated kinase	extracellular signal regulated kinase	extracellular signal regulated kinase	27	28	22	26
MEK1/2 silencing restores the ability of cetuximab to inhibit MAPK and cell proliferation [ XREF_BIBR ] .	MEK1/2 silencing restores the ability of cetuximab to inhibit MAPK and cell proliferation [XREF_BIBR].	0	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	0	1	9	10
The ERK1/2 pathway comprises the small GTPase RAS , which activates the RAF protein kinases ( MKKKs ) , which in turn activate MEK1/2 ( MAPK or ERK kinase , a MKK ) , which finally activates ERK1/2 ( the MAPK ) .	The ERK1/2 pathway comprises the small GTPase RAS, which activates the RAF protein kinases (MKKKs), which in turn activate MEK1/2 (MAPK or ERK kinase, a MKK), which finally activates ERK1/2 (the MAPK).	22	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	23	24	37	38
RAF kinases phosphorylate MEK ( mitogen activated protein kinase ) which then activates ERK ( extracellular signal regulated kinase ) .	RAF kinases phosphorylate MEK (mitogen activated protein kinase) which then activates ERK (extracellular signal regulated kinase).	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	RAF kinases phosphorylate MEK	mek	ERK	ERK	erk	3	4	13	14
BRAF ( a proto-oncogene ) encoding a Ser Thr kinase protein which is a downstream effector protein in the RAS/RAF/ERK signaling pathway can directly phosphorylate the MEK and even activate the ERK to affect the cells proliferation and survival [ XREF_BIBR - XREF_BIBR ] .	BRAF (a proto-oncogene) encoding a Ser Thr kinase protein which is a downstream effector protein in the RAS/RAF/ERK signaling pathway can directly phosphorylate the MEK and even activate the ERK to affect the cells proliferation and survival [XREF_BIBR - XREF_BIBR].	0	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	BRAF (a proto-oncogene) encoding a Ser Thr kinase protein which is a downstream effector protein in the RAS/RAF/ERK signaling pathway can directly phosphorylate the MEK	mek	ERK	ERK	erk	26	27	31	32
BRAF , a member of the RAF family proteins , is a serine threonine kinase that , upon binding to RAS , phosphorilates MEK ( mitogen activated protein kinase kinase ) activating the MAPK ( mitogen activated protein kinases ) cascade ( XREF_FIG ) .	BRAF, a member of the RAF family proteins, is a serine threonine kinase that, upon binding to RAS, phosphorilates MEK (mitogen activated protein kinase kinase) activating the MAPK (mitogen activated protein kinases) cascade (XREF_FIG).	22	40	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	23	24	33	34
The contribution of ERK1/2 to CD24 induced motility and invasion was examined using a specific inhibitor of the upstream ERK1/2 activator MEK1/2 ( U0126 ) .	The contribution of ERK1/2 to CD24 induced motility and invasion was examined using a specific inhibitor of the upstream ERK1/2 activator MEK1/2 (U0126).	15	23	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	21	22	19	20
Since MEK activation of ERK1/2 involves phosphorylation on its threonine and tyrosine residues , we evaluated the ability of PMA to phosphorylate ERK1/2 .	Since MEK activation of ERK1/2 involves phosphorylation on its threonine and tyrosine residues, we evaluated the ability of PMA to phosphorylate ERK1/2.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	1	2	4	5
Complete ERK activation by the kinase MEK requires dual phosphorylation at T and Y within the activation motif TEY .	Complete ERK activation by the kinase MEK requires dual phosphorylation at T and Y within the activation motif TEY.	1	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	1	2
Direct inhibition of MEK inhibits ERK signalling .	Direct inhibition of MEK inhibits ERK signalling.	1	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	5	6
ATRA induced differentiation is driven by a sustained MAP kinase signal such that inhibition of MEK activity blocks ERK and c-Raf activation , preventing differentiation .	ATRA induced differentiation is driven by a sustained MAP kinase signal such that inhibition of MEK activity blocks ERK and c-Raf activation, preventing differentiation.	15	21	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	15	16	18	19
Inhibition of either PKA or MEK1/2 blocked ERK1/2 activation by glucagon .	Inhibition of either PKA or MEK1/2 blocked ERK1/2 activation by glucagon.	0	8	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	5	6	7	8
PD98059 and U0126 , two distinct inhibitors of MEK , block the activation of ERK by GW5074 but have no effect on its ability to prevent cell death .	PD98059 and U0126, two distinct inhibitors of MEK, block the activation of ERK by GW5074 but have no effect on its ability to prevent cell death.	6	15	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	8	9	14	15
Once activated , Raf-1 phosphorylates MEK1/2 , which then activates the downstream effector ERK1/2 .	Once activated, Raf-1 phosphorylates MEK1/2, which then activates the downstream effector ERK1/2.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	Raf-1 phosphorylates MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	5	6	13	14
Alternatively , MEK1/2 inhibition does effectively inhibit ERK activity , but often fails to inhibit alternative upstream EGFR signaling components such as RAS and AKT .	Alternatively, MEK1/2 inhibition does effectively inhibit ERK activity, but often fails to inhibit alternative upstream EGFR signaling components such as RAS and AKT.	2	8	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	2	3	7	8
No changes were apparent at 1 or 2 days , but at 7 days , the protein expression of cyclins A , B1 , C , D1 , E , and the phosphorylated form of MAPK signaler MEK ( P-MEK1/2 ) decreased at 500 and 1000muM concentrations ( XREF_FIG ) .	No changes were apparent at 1 or 2 days, but at 7 days, the protein expression of cyclins A, B1, C, D1, E, and the phosphorylated form of MAPK signaler MEK (P-MEK1/2) decreased at 500 and 1000muM concentrations (XREF_FIG).	33	39	signaler	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	37	38	35	36
However , cyclin E expression is ineffectual in rescuing these effects when ERK activation is blocked by treatment with PD98059 , a selective inhibitor of MEK activation of ERK .	However, cyclin E expression is ineffectual in rescuing these effects when ERK activation is blocked by treatment with PD98059, a selective inhibitor of MEK activation of ERK.	25	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	25	26	28	29
ERK1/2 can be activated by MEK1/2 kinase and we further examined its expression and activation by western blot analysis .	ERK1/2 can be activated by MEK1/2 kinase and we further examined its expression and activation by western blot analysis.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	5	6	0	1
In a final series of experiments , we explored whether dual BRAF and MEK inhibition blocked the MAPK dependent escape from PLX4720 therapy and asked whether this prevented the onset of resistance .	In a final series of experiments, we explored whether dual BRAF and MEK inhibition blocked the MAPK dependent escape from PLX4720 therapy and asked whether this prevented the onset of resistance.	13	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	13	14	17	18
Interestingly , treatment with PD98059 prevented Akt phosphorylation ( Additional file 1 : Figure S1 in the Supplementary Material available online at http://dx.doi.org/10.1155/2015/404368 ) suggesting that inhibition of MEK is enough to prevent the PI3K and Akt and ERK activation .	Interestingly, treatment with PD98059 prevented Akt phosphorylation (Additional file 1 : Figure S1 in the Supplementary Material available online at http://dx.doi.org/10.1155/2015/404368) suggesting that inhibition of MEK is enough to prevent the PI3K and Akt and ERK activation.	26	39	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	28	29	38	39
Targeting of MEK and ERK signaling by MEK inhibition was shown to be effective in treating KRAS mutated T-ALL in a murine model [ XREF_BIBR ] .	Targeting of MEK and ERK signaling by MEK inhibition was shown to be effective in treating KRAS mutated T-ALL in a murine model [XREF_BIBR].	2	8	signaling	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	7	8	4	5
ERK , once activated by MEK , has numerous cytosolic and nuclear substrates [ XREF_BIBR ] .	ERK, once activated by MEK, has numerous cytosolic and nuclear substrates [XREF_BIBR].	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	5	6	0	1
MEK1/2 activates ERK1/2 kinases through phoshorylation of threonine 183 ( Thr183 ) and tyrosine 185 ( Tyr185 ) at the Thr-Glu-Tyr site [ XREF_BIBR ] .	MEK1/2 activates ERK1/2 kinases through phoshorylation of threonine 183 (Thr183) and tyrosine 185 (Tyr185) at the Thr-Glu-Tyr site [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	0	1	2	3
Therefore , inhibition of MEK may decrease MKP-1 expression prolonging the DOX induced decrease in MKP-1 , and thereby contribute to the enhancement of DOX induced late ERK activation .	Therefore, inhibition of MEK may decrease MKP-1 expression prolonging the DOX induced decrease in MKP-1, and thereby contribute to the enhancement of DOX induced late ERK activation.	2	28	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	4	5	27	28
Next , the ERK pathway was activated by over-expressing MEK CA in Fao cells and the effect on protein degradation of MKP-3 S159AS197A was examined .	Next, the ERK pathway was activated by over-expressing MEK CA in Fao cells and the effect on protein degradation of MKP-3 S159AS197A was examined.	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	3	4
This result indicates that the GnRH induced down-regulation of miR-125b would allow the Galphaq/11 mediated MEK1/2 induced activation of ERK1/2 and its stimulatory action on miR-132/212 gene transcription .	This result indicates that the GnRH induced down-regulation of miR-125b would allow the Galphaq/11 mediated MEK1/2 induced activation of ERK1/2 and its stimulatory action on miR-132/212 gene transcription.	15	23	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	15	16	19	20
ERK 1/2 is activated by MEK1/2 , which is activated by Raf , Ras , and growth factors or mitogens ; Raf activity , as the main effecter of Ras , is suppressed by cyclic AMP dependent kinase ( PKA ) in a normal cell .	ERK 1/2 is activated by MEK1/2, which is activated by Raf, Ras, and growth factors or mitogens; Raf activity, as the main effecter of Ras, is suppressed by cyclic AMP dependent kinase (PKA) in a normal cell.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK 1/2	ERK 1/2	ERK 1/2	5	6	0	2
Activated MEK activates ERK , which induces several proliferative and survival processes , one of which is activation of the cyclin D and CDK4/6 complex ( discussed above ) upon translocation to the nucleus .	Activated MEK activates ERK, which induces several proliferative and survival processes, one of which is activation of the cyclin D and CDK4/6 complex (discussed above) upon translocation to the nucleus.	0	17	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	1	2	3	4
Moreover , inhibition of MEK with U1026 also prevented both Epi and Phe induced ERK activation ( XREF_FIG ) .	Moreover, inhibition of MEK with U1026 also prevented both Epi and Phe induced ERK activation (XREF_FIG).	2	15	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	4	5	14	15
MAPKs are activated by specific MAPK kinases ( MEKs ) ; specifically , MEK1/2 , MEK3/6 , and MEK4/7 activate ERKs , p38 MAPK , and JNKs , respectively [ XREF_BIBR ] .	MAPKs are activated by specific MAPK kinases (MEKs); specifically, MEK1/2, MEK3/6, and MEK4/7 activate ERKs, p38 MAPK, and JNKs, respectively [XREF_BIBR].	13	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERKs	ERKs	ERKs	13	14	20	21
As expected , MEK1/2 inhibition led to decreased P-ERK , P-rpS6 , and P-4E-BP1 with no effect on P-AKT .	As expected, MEK1/2 inhibition led to decreased P-ERK, P-rpS6, and P-4E-BP1 with no effect on P-AKT.	3	13	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	P-ERK	P-ERK	P-ERK	3	4	8	9
Free TPL2 phosphorylates MEK1/2 , which then activates ERK1/2 .	Free TPL2 phosphorylates MEK1/2, which then activates ERK1/2.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	TPL2 phosphorylates MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	3	4	8	9
Thus , ERK inhibition by MEK and ERK inhibitors is an attractive therapeutic strategy in treating pancreatic cancer .	Thus, ERK inhibition by MEK and ERK inhibitors is an attractive therapeutic strategy in treating pancreatic cancer.	2	8	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	5	6	2	3
However , Mek independent activation of Erk1/2 has been noted in a number of cell types , including fibroblasts and breast cancer cell lines .	However, Mek independent activation of Erk1/2 has been noted in a number of cell types, including fibroblasts and breast cancer cell lines.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk1/2	Erk1/2	Erk1/2	2	3	6	7
MEK in turn then activates ERK1/2 .	MEK in turn then activates ERK1/2.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	0	1	5	6
In these prior studies the net effect of increased activation of Mek and Raf-1 by Pak1 was increased ERK activation in response to different stimuli .	In these prior studies the net effect of increased activation of Mek and Raf-1 by Pak1 was increased ERK activation in response to different stimuli.	9	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	ERK	ERK	ERK	11	12	18	19
By pharmacological blocking using the selective inhibitors SP600125 ( JNK1/2/3 ) , PD98059 ( MEK ; activator of ERK1/2 ) , SB202190 ( p38alpha and beta ) , and wedelolactone ( IkappaB kinase ) , we observed that EPs 7630 induced production of TNF-alpha in monocytes was strongly dependent on p38 activity and at least partly dependent on the activation of Erk1/2 and NF-kappaB ( XREF_FIG ) .	By pharmacological blocking using the selective inhibitors SP600125 (JNK1/2/3), PD98059 (MEK; activator of ERK1/2), SB202190 (p38alpha and beta), and wedelolactone (IkappaB kinase), we observed that EPs 7630 induced production of TNF-alpha in monocytes was strongly dependent on p38 activity and at least partly dependent on the activation of Erk1/2 and NF-kappaB (XREF_FIG).	12	19	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	14	15	18	19
We propose that Rapgef2 binds and is directly activated by cAMP , leading to GTP loading of Rap1 , activation of B-Raf , and the subsequent activation of ERK by MEK , leading to long-term functional effects , including activation of the nuclear transcription factor Elk1 , gene transcription in neuronal and endocrine cells , and altered cellular morphology ; however , this hypothesis awaits further experimental confirmation , including the demonstration that mutations in Rapgef2 that impair cAMP binding in vitro correspondingly impair Rapgef2 dependent cAMP initiated activation of ERK in intact cells .	We propose that Rapgef2 binds and is directly activated by cAMP, leading to GTP loading of Rap1, activation of B-Raf, and the subsequent activation of ERK by MEK, leading to long-term functional effects, including activation of the nuclear transcription factor Elk1, gene transcription in neuronal and endocrine cells, and altered cellular morphology; however, this hypothesis awaits further experimental confirmation, including the demonstration that mutations in Rapgef2 that impair cAMP binding in vitro correspondingly impair Rapgef2 dependent cAMP initiated activation of ERK in intact cells.	12	31	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	30	31	28	29
As opposed to the Mek1/2 induced activation of Erk1/2 that results from growth factor receptor tyrosine kinase ( RTK ) activation , p38-Mapk isoforms are classically known to be activated by extracellular stimuli such as proinflammatory cytokines and physical stresses , mediated by specific phosphorylation events , catalysed by distinct Mapkks .	As opposed to the Mek1/2 induced activation of Erk1/2 that results from growth factor receptor tyrosine kinase (RTK) activation, p38-Mapk isoforms are classically known to be activated by extracellular stimuli such as proinflammatory cytokines and physical stresses, mediated by specific phosphorylation events, catalysed by distinct Mapkks.	1	10	induced	Positive_early_activation	Positive_activation	Positive_activation	Mek1/2	Mek1/2	Mek1/2	Erk1/2	Erk1/2	Erk1/2	4	5	8	9
Ras activates serine/threonine protein kinase Raf , which in turn activates another serine/threonine protein kinase MEK that triggers MAPK .	Ras activates serine/threonine protein kinase Raf, which in turn activates another serine/threonine protein kinase MEK that triggers MAPK.	10	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	15	16	18	19
Enhanced neutrophil motility and morphological change were inhibited by MEK [ mitogen activated protein kinase ( MAPK )/extracellular signal regulated kinase ( ERK ) kinase ] inhibitors ( PD98059 and U0126 ) , and a phosphatidylinositol 3-kinase ( PI3K ) inhibitor ( wortmannin ) , but not by a p38 MAPK inhibitor ( SB203580 ) .	Enhanced neutrophil motility and morphological change were inhibited by MEK [mitogen activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) kinase] inhibitors (PD98059 and U0126), and a phosphatidylinositol 3-kinase (PI3K) inhibitor (wortmannin), but not by a p38 MAPK inhibitor (SB203580).	9	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	9	10	16	17
ERK is activated due to phosphorylation by MEK which itself is phosphorylated by Raf .	ERK is activated due to phosphorylation by MEK which itself is phosphorylated by Raf.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK which itself is phosphorylated	mek	ERK	ERK	erk	7	8	0	1
RAF kinases phosphorylate and activate MEK kinases ( MEK1 and MEK2 ) , which in turn phosphorylate and activate ERK kinases ( ERK1 and ERK2 ) .	RAF kinases phosphorylate and activate MEK kinases (MEK1 and MEK2), which in turn phosphorylate and activate ERK kinases (ERK1 and ERK2).	5	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	5	6	19	20
The B-Raf kinase is activated by GTP-Ras in response to growth factors and phosphorylates MEK , which in turn activates ERK to phosphorylate downstream targets such as kinases and transcription factors that promote cell division [ XREF_BIBR ] .	The B-Raf kinase is activated by GTP-Ras in response to growth factors and phosphorylates MEK, which in turn activates ERK to phosphorylate downstream targets such as kinases and transcription factors that promote cell division [XREF_BIBR].	1	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	B-Raf kinase is activated by GTP-Ras in response to growth factors and phosphorylates MEK	mek	ERK	ERK	erk	14	15	20	21
Our model predicts that in all cell lines that depend on MAPK signalling , Mek inhibition at higher doses will abrogate Erk signalling .	Our model predicts that in all cell lines that depend on MAPK signalling, Mek inhibition at higher doses will abrogate Erk signalling.	14	22	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	14	15	21	22
NT3 stimulated phosphorylation of extracellular signal regulated kinase ( ERK ) 1/2 and ERK5 in the cortical progenitors , and the effects of NT3 on the increase in total BrdU positive cells and Pax6- and BrdU positive cells were diminished by an MEK inhibitor , suggesting the involvement of MEK mediated ERK signal transduction in the NT3 actions .	NT3 stimulated phosphorylation of extracellular signal regulated kinase (ERK) 1/2 and ERK5 in the cortical progenitors, and the effects of NT3 on the increase in total BrdU positive cells and Pax6- and BrdU-positive cells were diminished by an MEK inhibitor, suggesting the involvement of MEK mediated ERK signal transduction in the NT3 actions.	47	53	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	49	50	51	52
Activated Raf phosphorylates MEK , which in turn activates ERK .	Activated Raf phosphorylates MEK, which in turn activates ERK.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	phosphorylates MEK	mek	ERK	ERK	erk	3	4	9	10
MEK DD expression induced ERK activation ( XREF_FIG ) , as expected , and suppressed IFNgamma mediated PD-L1 and MHC-II expression ( XREF_FIG ) .	MEK DD expression induced ERK activation (XREF_FIG), as expected, and suppressed IFNgamma mediated PD-L1 and MHC-II expression (XREF_FIG).	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK DD expression	mek	ERK	ERK	erk	0	1	4	5
Interestingly , acute activation of Myc triggered the phosphorylation of the Mek targets Erk1/2 in a Mek dependent manner ( XREF_FIG ) , and treatment of cells with a Mek1 inhibitor attenuated Myc induced cleavage of the apoptosis effector PARP , as well as activation of p53 and the DNA damage response proteins RAD17 and gammaH2AX ( see below ) ( XREF_FIG ) .	Interestingly, acute activation of Myc triggered the phosphorylation of the Mek targets Erk1/2 in a Mek dependent manner (XREF_FIG), and treatment of cells with a Mek1 inhibitor attenuated Myc induced cleavage of the apoptosis effector PARP, as well as activation of p53 and the DNA damage response proteins RAD17 and gammaH2AX (see below) (XREF_FIG).	5	18	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Myc triggered the phosphorylation of the Mek	mek	Erk1/2	Erk1/2	erk1/2	11	12	13	14
Combined BRAF V600E and MEK inhibition prevents rebound of MAPK activation , resulting in enhanced antitumor efficacy and also reduces the risk of secondary malignancy development .	Combined BRAF V600E and MEK inhibition prevents rebound of MAPK activation, resulting in enhanced antitumor efficacy and also reduces the risk of secondary malignancy development.	4	10	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	4	5	9	10
To confirm this , we blocked the MEK induced ERK1/2 activation by preincubating with PD98059 ( 0-25 microM ) and then determined whether [ Pt ( acac ) 2 ( DMS ) ] would still effect cell migration .	To confirm this, we blocked the MEK induced ERK1/2 activation by preincubating with PD98059 (0-25 microM) and then determined whether [Pt (acac) 2 (DMS)] would still effect cell migration.	6	21	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	7	8	9	10
This was also determined to be a key component in the action of bradykinin in trabecular meshwork cells as inhibition of MEK with U0126 completely blocked bradykinin stimulation of ERK1/2 activity .	This was also determined to be a key component in the action of bradykinin in trabecular meshwork cells as inhibition of MEK with U0126 completely blocked bradykinin stimulation of ERK1/2 activity.	19	30	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	21	22	29	30
MEK phosphorylates and activates MAPK ( a mitogen activated protein kinase ) .	MEK phosphorylates and activates MAPK (a mitogen activated protein kinase).	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	0	1	4	5
ERK regulating kinase ( MEK ) has been shown to activate ERKs , but MEK independent activation has also been reported [ XREF_BIBR , XREF_BIBR ] .	ERK regulating kinase (MEK) has been shown to activate ERKs, but MEK independent activation has also been reported [XREF_BIBR, XREF_BIBR].	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERKs	ERKs	ERKs	4	5	11	12
The ERK pathway acts via the activation of Raf ( MAPKKK ) , which phosphorylates and activates MEK ( MAPKK ) , which then activates ERK ( MAPK ) through phosphorylation and dissociates from ERK [ XREF_BIBR , XREF_BIBR ] .	The ERK pathway acts via the activation of Raf (MAPKKK), which phosphorylates and activates MEK (MAPKK), which then activates ERK (MAPK) through phosphorylation and dissociates from ERK [XREF_BIBR, XREF_BIBR].	8	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	Raf (MAPKKK), which phosphorylates and activates MEK	mek	ERK	ERK	erk	17	18	25	26
MEK finally activates the two ERK isoforms ERK1 and ERK2 by phosphorylation .	MEK finally activates the two ERK isoforms ERK1 and ERK2 by phosphorylation.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	5	6
To determine the MAPK signaling pathway ( s ) involved in opioid inhibition of neurogenesis and astrogenesis from RA induced NPs , U0126 ( which blocks MEK activation of ERK ) and SB23906 ( p38 inhibitor ) were used ( XREF_FIG ) .	To determine the MAPK signaling pathway (s) involved in opioid inhibition of neurogenesis and astrogenesis from RA induced NPs, U0126 (which blocks MEK activation of ERK) and SB23906 (p38 inhibitor) were used (XREF_FIG).	26	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	26	27	29	30
The downstream target of Raf-1 isoforms is MEK , a dual function kinase that activates the Erk kinases .	The downstream target of Raf-1 isoforms is MEK, a dual function kinase that activates the Erk kinases.	2	17	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk	Erk	Erk	7	8	16	17
Raf can then activate MEK ( a MAPK kinase ) , which then activates MAPK , also known as ERK1/2 .	Raf can then activate MEK (a MAPK kinase), which then activates MAPK, also known as ERK1/2.	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	4	5	14	15
Moreover , transient ERK1/2 activation was observed , and inhibition of MEK1/2 completely suppressed ERK1/2 activation and blocked RPE apoptosis induced by tBHP .	Moreover, transient ERK1/2 activation was observed, and inhibition of MEK1/2 completely suppressed ERK1/2 activation and blocked RPE apoptosis induced by tBHP.	9	15	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	11	12	14	15
MEK1/2 phosphorylates and activates ERK1/2 via the phosphorylation of the Thr and Tyr residues within their activation loop .	MEK1/2 phosphorylates and activates ERK1/2 via the phosphorylation of the Thr and Tyr residues within their activation loop.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	0	1	4	5
To further determine the mechanism by which pERK is negatively regulated by LiCl in the presence of LPS , we examined the phosphorylation of status of MEK1/2 ( immediate upstream activator of ERK1/2 ) .	To further determine the mechanism by which pERK is negatively regulated by LiCl in the presence of LPS, we examined the phosphorylation of status of MEK1/2 (immediate upstream activator of ERK1/2).	24	33	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	26	27	32	33
Sur-8 expression enhances Ras- or EGF induced Raf and ERK activation but has no effect on ERK activation induced by active Raf or MEK .	Sur-8 expression enhances Ras- or EGF induced Raf and ERK activation but has no effect on ERK activation induced by active Raf or MEK.	16	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	23	24	16	17
Furthermore , phosphorylation levels of MEK1/2 were decreased in later symptomatic stages.14 MEK1/2 is activated after phosphorylation and may lead to ERK1/2 activation in response to a variety of hormones , growth factors , and oxidative stress , which can regulate transcription and translation.23 , 24 When ERK signaling cascade is early activated , it can lead to increased cell proliferation and TTR aggregates expression levels .	Furthermore, phosphorylation levels of MEK1/2 were decreased in later symptomatic stages.14 MEK1/2 is activated after phosphorylation and may lead to ERK1/2 activation in response to a variety of hormones, growth factors, and oxidative stress, which can regulate transcription and translation.23, 24 When ERK signaling cascade is early activated, it can lead to increased cell proliferation and TTR aggregates expression levels.	9	22	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	12	13	21	22
Alternatively , through the activation of Raf-1 , an upstream activator of MEK , PP2A may induce MEK and ERK pathway activation .	Alternatively, through the activation of Raf-1, an upstream activator of MEK, PP2A may induce MEK and ERK pathway activation.	10	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	12	13	19	20
This morphology can be reverted to a more normal morphology with pharmacologic inhibitors of Ras signaling , for example , inhibitors of MEK activation of ERK [ XREF_BIBR , XREF_BIBR ] .	This morphology can be reverted to a more normal morphology with pharmacologic inhibitors of Ras signaling, for example, inhibitors of MEK activation of ERK [XREF_BIBR, XREF_BIBR].	22	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	22	23	25	26
Furthermore , fluoxetine induced activation of both the cAMP response element binding ( CREB ) protein and extracellular signal regulated protein kinases ( ERK1/2 ) , which was abolished by the selective inhibitor of MAP kinase kinase ( MEK ) 1,4-diamino-2 ,3-dicyano-1 ,4-bis ( 2-aminophenylthio ) butadiene ( U0126 ) , and increased cyclin D1 expression .	Furthermore, fluoxetine induced activation of both the cAMP response element binding (CREB) protein and extracellular signal regulated protein kinases (ERK1/2), which was abolished by the selective inhibitor of MAP kinase kinase (MEK) 1,4-diamino-2,3-dicyano-1,4-bis (2-aminophenylthio) butadiene (U0126), and increased cyclin D1 expression.	21	39	abolished	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	38	39	23	24
Since ERK1/2 are activated by MEK1/2 and p90RSK is an important downstream substrate of ERK1/2 , our results corroborate the susceptibility of the p44/42 MAPK ( ERK1/2 ) signaling pathway to oxidative stress caused by GPx-1 deficiency .	Since ERK1/2 are activated by MEK1/2 and p90RSK is an important downstream substrate of ERK1/2, our results corroborate the susceptibility of the p44/42 MAPK (ERK1/2) signaling pathway to oxidative stress caused by GPx-1 deficiency.	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	5	6	1	2
As it is known that the activation of ERK by MEK follows a distributed mechanism , we use a full , mass action description for ERK activation .	As it is known that the activation of ERK by MEK follows a distributed mechanism, we use a full, mass action description for ERK activation.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	10	11	8	9
An ERK1/2 cascade module , including MEK1/2 and Rsk , are found in complexes bound to these promoters .	An ERK1/2 cascade module, including MEK1/2 and Rsk, are found in complexes bound to these promoters.	1	8	module	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	6	7	1	2
ERK1/2 can be activated transiently or persistently by MEK1/2 and upstream MAP3Ks in conjunction with regulation and involvement of scaffolding proteins and phosphatases [ XREF_BIBR ] .	ERK1/2 can be activated transiently or persistently by MEK1/2 and upstream MAP3Ks in conjunction with regulation and involvement of scaffolding proteins and phosphatases [XREF_BIBR].	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	8	9	0	1
Members of the Raf family are activated by the Ras family of GTPases , and translocate to the cell membrane upon activation whereupon it activates MEK ( MAPKK ) , initiating a MAPK cascade .	Members of the Raf family are activated by the Ras family of GTPases, and translocate to the cell membrane upon activation whereupon it activates MEK (MAPKK), initiating a MAPK cascade.	24	33	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	25	26	32	33
Inhibition of Mek ( proximal activator of Erk ) also blocked stimulation of Erk and neutrophil aggregation by FMLP and arachidonic acid .	Inhibition of Mek (proximal activator of Erk) also blocked stimulation of Erk and neutrophil aggregation by FMLP and arachidonic acid.	0	16	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	2	3	13	14
MEK kinases phosphorylate and activate ERK1/2 .	MEK kinases phosphorylate and activate ERK1/2.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	0	1	5	6
Taken together , these data suggest that initial ERK1/2 activation at early time points is exclusively mediated by MEK , but at later times MEK ' s contribution becomes less , since the MEK independent pathway accounts for more than 40 % of remaining ERK1/2 phosphorylation .	Taken together, these data suggest that initial ERK1/2 activation at early time points is exclusively mediated by MEK, but at later times MEK 's contribution becomes less, since the MEK independent pathway accounts for more than 40% of remaining ERK1/2 phosphorylation.	8	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	18	19	8	9
Although the mechanism of crosstalk between PKA and ERK pathways has not yet been clarified , it is possible that PKA pathway facilitates MEK1/2 which activates the ERK1/2 pathway .	Although the mechanism of crosstalk between PKA and ERK pathways has not yet been clarified, it is possible that PKA pathway facilitates MEK1/2 which activates the ERK1/2 pathway.	22	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	23	24	27	28
Moreover , although inhibiting Mek abolished Erk ( but not Akt ) activation ( data not shown ) , inhibiting Raf in fMLF stimulated mouse neutrophils reproducibly caused partial Erk inhibition ( data not shown ) .	Moreover, although inhibiting Mek abolished Erk (but not Akt) activation (data not shown), inhibiting Raf in fMLF stimulated mouse neutrophils reproducibly caused partial Erk inhibition (data not shown).	3	14	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	4	5	6	7
MAPK and ERK kinase ( MEK ) inhibitors blocked ERK activation confirming that MEK lies upstream of ERK in haemocytes .	MAPK and ERK kinase (MEK) inhibitors blocked ERK activation confirming that MEK lies upstream of ERK in haemocytes.	5	10	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	5	6	9	10
The CAM dependent step in the Erk1/2 activation cascade is downstream of Ras activation , because inhibitors of CAM antagonize Erk1/2 activation induced by constitutively activated mutants of Ras and c-Src but not by constitutively activated mutants of Raf and MEK ( mitogen and extracellular signal regulated kinase ) .	The CAM dependent step in the Erk1/2 activation cascade is downstream of Ras activation, because inhibitors of CAM antagonize Erk1/2 activation induced by constitutively activated mutants of Ras and c-Src but not by constitutively activated mutants of Raf and MEK (mitogen and extracellular signal regulated kinase).	20	41	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk1/2	Erk1/2	Erk1/2	40	41	20	21
Because ERK1/2 is activated by the upstream protein kinase MEK , MEK inhibitors such as U0126 have been frequently used to analyze the function of ERK1/2 signaling in a wide array of biological processes .	Because ERK1/2 is activated by the upstream protein kinase MEK, MEK inhibitors such as U0126 have been frequently used to analyze the function of ERK1/2 signaling in a wide array of biological processes.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	9	10	1	2
While ERK1/2 is directly activated by MEK , a MAPKK , p38 MAPK is directly activated by MKK3 and MKK6 , all of which are regulated by the small G protein Ras [ XREF_BIBR ] .	While ERK1/2 is directly activated by MEK, a MAPKK, p38 MAPK is directly activated by MKK3 and MKK6, all of which are regulated by the small G protein Ras [XREF_BIBR].	1	7	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	6	7	1	2
MEK activates MAPK via phosphorylation .	MEK activates MAPK via phosphorylation.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	0	1	2	3
A highly selective inhibitor of MEK1/2 , U0126 , was used to inhibit Erk activation .	A highly selective inhibitor of MEK1/2, U0126, was used to inhibit Erk activation.	3	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	Erk	Erk	Erk	5	6	13	14
ERK is a downstream component of a conserved signaling module that is activated by the serine/threonine kinase , Raf , which activates the MAPK and ERK kinase ( MEK ) 1/2 protein kinases , which , in turn , activate ERK1/2 .	ERK is a downstream component of a conserved signaling module that is activated by the serine/threonine kinase, Raf, which activates the MAPK and ERK kinase (MEK) 1/2 protein kinases, which, in turn, activate ERK1/2.	26	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	28	29	40	41
These findings suggest that the increase in L-Arg-dependent nitric oxide production in Galphai Q204L transfected cells is due to activation of ERK by MEK .	These findings suggest that the increase in L-Arg-dependent nitric oxide production in Galphai Q204L transfected cells is due to activation of ERK by MEK.	17	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	23	24	21	22
Previous approaches primarily cover the inhibitors of upstream ERK activators such as Raf and Ras and MEK XREF_BIBR .	Previous approaches primarily cover the inhibitors of upstream ERK activators such as Raf and Ras and MEK XREF_BIBR.	8	17	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	16	17	8	9
To demonstrate that the appearance of p59 Lck indeed depends on Erk mediated phosphorylation , T cells were stimulated with iAbs for 30 min in the presence or absence of U0126 or MEK Inhibitor I , inhibitors of the Erk activator MEK .	To demonstrate that the appearance of p59 Lck indeed depends on Erk mediated phosphorylation, T cells were stimulated with iAbs for 30 min in the presence or absence of U0126 or MEK Inhibitor I, inhibitors of the Erk activator MEK.	36	42	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	Erk	Erk	Erk	41	42	39	40
XREF_BIBR MEK 1/2 activates the ERK family of MAPKs , and ERK activation also is known to enhance prosurvival signaling .	XREF_BIBR MEK 1/2 activates the ERK family of MAPKs, and ERK activation also is known to enhance prosurvival signaling.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK 1/2	MEK 1/2	MEK 1/2	ERK	ERK	ERK	1	3	5	6
It has been reported that direct activation of ERK by MEK can promote autophagy without other signals .	It has been reported that direct activation of ERK by MEK can promote autophagy without other signals.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	10	11	8	9
Under normal circumstances , the serine/threonine kinase BRAF is activated by NRAS ( neuroblastoma RAS viral oncogene homolog ) [ XREF_BIBR , XREF_BIBR ] and in turn phosphorylates the downstream proteins MEK1/2 ( MAP2K , mitogen activated protein kinase kinase ) , which then activate ERK1/2 [ XREF_BIBR ] .	Under normal circumstances, the serine/threonine kinase BRAF is activated by NRAS (neuroblastoma RAS viral oncogene homolog) [XREF_BIBR, XREF_BIBR] and in turn phosphorylates the downstream proteins MEK1/2 (MAP2K, mitogen activated protein kinase kinase), which then activate ERK1/2 [XREF_BIBR].	27	47	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	phosphorylates the downstream proteins MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	31	32	45	46
In the ERK1/2 pathway , signal is transduced by activated receptor tyrosine kinases , the small G protein Ras , Raf , and MAPK and ERK kinase1/2 ( MEK1/2 ) , which then activate ERK1/2 through phosphorylation .	In the ERK1/2 pathway, signal is transduced by activated receptor tyrosine kinases, the small G protein Ras, Raf, and MAPK and ERK kinase1/2 (MEK1/2), which then activate ERK1/2 through phosphorylation.	26	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	28	29	34	35
MEK1/2 activates the ERK1/2 proteins through dual phosphorylation of threonine and tyrosine located within a TXY motif on the activation lip found on MAP kinase family members [ XREF_BIBR ] .	MEK1/2 activates the ERK1/2 proteins through dual phosphorylation of threonine and tyrosine located within a TXY motif on the activation lip found on MAP kinase family members [XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	0	1	3	4
Every MAPK is activated by specific MAPKKs ( MEK1/2 for ERK1/2 , MKK3/6 for p38 , MKK4/7 [ JNKK1/2 ] for the JNKs , and MEK5 for ERK5 ) ; however , each MAPKK may be activated by more than one MAPKKK .	Every MAPK is activated by specific MAPKKs (MEK1/2 for ERK1/2, MKK3/6 for p38, MKK4/7 [JNKK1/2] for the JNKs, and MEK5 for ERK5); however, each MAPKK may be activated by more than one MAPKKK.	0	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	8	9	1	2
Raf serine/threonine kinases phosphorylate and activate the MEK1/2 dual-specificity protein kinases , which then phosphorylate and activate ERK1/2 .	Raf serine/threonine kinases phosphorylate and activate the MEK1/2 dual-specificity protein kinases, which then phosphorylate and activate ERK1/2.	7	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	7	8	17	18
We also found the reduced phospho activation downstream target MEK1/2 , which stimulates ERK1/2 .	We also found the reduced phospho activation downstream target MEK1/2, which stimulates ERK1/2.	2	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	9	10	13	14
MEK1/2 inhibition by 10muM U0126 inhibited MAPK , as expected , in all mesothelioma cell lines but had little impact on S6 phosphorylation ( XREF_FIG ) .	MEK1/2 inhibition by 10muM U0126 inhibited MAPK, as expected, in all mesothelioma cell lines but had little impact on S6 phosphorylation (XREF_FIG).	0	7	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	0	1	6	7
MEK kinases phosphorylate and activate MAPK .	MEK kinases phosphorylate and activate MAPK.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	0	1	5	6
MEK is the upstream activator of ERK ; the MEK inhibitors U0126 and PD98059 were used to confirm the ERK knockdown experiment and the role of ERK in MSC proliferation .	MEK is the upstream activator of ERK; the MEK inhibitors U0126 and PD98059 were used to confirm the ERK knockdown experiment and the role of ERK in MSC proliferation.	0	7	is the upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	6	7
However , therapies targeting mutated BRaf or MEK1/2 proteins invariably lead to drug resistance due to alternative mechanisms to activate ERK1/2 and recent efforts to directly inhibit ERK1/2 proteins are being tested [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	However, therapies targeting mutated BRaf or MEK1/2 proteins invariably lead to drug resistance due to alternative mechanisms to activate ERK1/2 and recent efforts to directly inhibit ERK1/2 proteins are being tested [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	23	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	7	8	20	21
Raf activates Mitogen activated protein kinase kinase ( MEK ) , which activates ERK .	Raf activates Mitogen activated protein kinase kinase (MEK), which activates ERK.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	8	9	13	14
XREF_BIBR , XREF_BIBR In turn , Raf activates MEK1/2 , which subsequently activate MAP kinases ERK1/2 .	XREF_BIBR, XREF_BIBR In turn, Raf activates MEK1/2, which subsequently activate MAP kinases ERK1/2.	7	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	8	9	15	16
Furthermore , Erk activation can be rescued by over-expression of constitutively activated Mek or Raf .	Furthermore, Erk activation can be rescued by over-expression of constitutively activated Mek or Raf.	2	14	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mek	over-expression of constitutively activated Mek	mek	Erk	Erk	erk	12	13	2	3
Activated Raf phosphorylates MEK , which in turn , activates ERK .	Activated Raf phosphorylates MEK, which in turn, activates ERK.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	phosphorylates MEK	mek	ERK	ERK	erk	3	4	10	11
Thus , a combination of MEK and CRAF inhibitors may also prevent the non MAPK pathways downstream of CRAF .	Thus, a combination of MEK and CRAF inhibitors may also prevent the non MAPK pathways downstream of CRAF.	5	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	5	6	14	15
Inhibition of MEK activated ERK1/2 blocked hyaluronan secretion .	Inhibition of MEK activated ERK1/2 blocked hyaluronan secretion.	0	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	2	3	4	5
In fact , in both ALK- and EGFR driven NSCLC , upfront combination ALK and MEK or EGFR and MEK inhibition has been shown to prevent the emergence of MAPK pathway addicted resistance mechanisms .	In fact, in both ALK- and EGFR driven NSCLC, upfront combination ALK and MEK or EGFR and MEK inhibition has been shown to prevent the emergence of MAPK pathway addicted resistance mechanisms.	17	30	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	19	20	29	30
It should be noted that both ERK inhibitors that we tested actually inhibit MEK1/2 , the upstream kinases that activate ERK1/2 .	It should be noted that both ERK inhibitors that we tested actually inhibit MEK1/2, the upstream kinases that activate ERK1/2.	12	21	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	13	14	20	21
MAPKs are phosphorylated by upstream MAPK kinases ( MEKs ) , which in turn are activated by MEK kinases .	MAPKs are phosphorylated by upstream MAPK kinases (MEKs), which in turn are activated by MEK kinases.	5	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	17	18	5	6
This synthesis was completely inhibited by PD98059 and U0126 that prevent activation of MEK1/2 upstream activator of ERK1/2 , whereas the selective p38 inhibitor SB203580 had no effect .	This synthesis was completely inhibited by PD98059 and U0126 that prevent activation of MEK1/2 upstream activator of ERK1/2, whereas the selective p38 inhibitor SB203580 had no effect.	13	18	activator	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	13	14	17	18
MEK1/2 directly activates ERK1/2 by phosphorylating the threonine-glutamate-tyrosine ( TEY ) motif located within their activation loops .	MEK1/2 directly activates ERK1/2 by phosphorylating the threonine-glutamate-tyrosine (TEY) motif located within their activation loops.	0	4	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	0	1	3	4
40 Moreover , as the Raf-MEK-ERK pathway ( Raf activates MEK , which then activates ERK ) is a classical signaling in cells , 39 how GA activates ERK warrants further study .	40 Moreover, as the Raf-MEK-ERK pathway (Raf activates MEK, which then activates ERK) is a classical signaling in cells, 39 how GA activates ERK warrants further study.	9	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	10	11	15	16
The phosphorylation and activation of MEK1/2 can result in activation of the ERK1/2 pathway [ XREF_BIBR ] that then stimulates the expression and activity of a number of transcription factors , including members of the Jun and Fos families [ XREF_BIBR - XREF_BIBR ] .	The phosphorylation and activation of MEK1/2 can result in activation of the ERK1/2 pathway [XREF_BIBR] that then stimulates the expression and activity of a number of transcription factors, including members of the Jun and Fos families [XREF_BIBR - XREF_BIBR].	1	13	result in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	MEK1/2	phosphorylation and activation of MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	5	6	12	13
MEK and ERK signaling is activated by beta-AR and MEK and ERK activation is also a key intracellular signaling pathway involved in BLA dependent memory consolidation .	MEK and ERK signaling is activated by beta-AR and MEK and ERK activation is also a key intracellular signaling pathway involved in BLA dependent memory consolidation.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	2	3
Moreover , ammonia induces ERK activation XREF_BIBR and the effect of S100B release was totally abolished by MEK and ERK inhibitor , indicating that cAMP and PKA and ERK are involved in this effect .	Moreover, ammonia induces ERK activation XREF_BIBR and the effect of S100B release was totally abolished by MEK and ERK inhibitor, indicating that cAMP and PKA and ERK are involved in this effect.	4	20	abolished	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	17	18	4	5
In NRAS Q61K -expressing M249-R4 cells , ERK activation by MEK is resistant to BRAF inhibition , but the cells still respond to MEK inhibition ( XREF_FIG C ) .	In NRAS Q61K -expressing M249-R4 cells, ERK activation by MEK is resistant to BRAF inhibition, but the cells still respond to MEK inhibition (XREF_FIG C).	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	10	11	7	8
As the model input , we take cytoplasmic dually phosphorylated MEK ( ppMEK ) , which activates ERK , and this input is estimated directly from data ( XREF_FIG ) .	As the model input, we take cytoplasmic dually phosphorylated MEK (ppMEK), which activates ERK, and this input is estimated directly from data (XREF_FIG).	9	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	10	11	17	18
Furthermore , stress caused by lack of ERK1/2 and the resulting upregulation of p38 pathways may perpetuate the attenuation of ERK1/2 signalling by promoting the dephosphorylation of MEK1/2 , the MAPK kinases that activate ERK [ XREF_BIBR , XREF_BIBR ] .	Furthermore, stress caused by lack of ERK1/2 and the resulting upregulation of p38 pathways may perpetuate the attenuation of ERK1/2 signalling by promoting the dephosphorylation of MEK1/2, the MAPK kinases that activate ERK [XREF_BIBR, XREF_BIBR].	25	38	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK1/2	dephosphorylation of MEK1/2	mek1/2	ERK	ERK	erk	27	28	34	35
MAPKs are specifically regulated by a MAPK kinase ( MAPKK ) XREF_BIBR , i.e ., ERK1/2 is activated by MEK1/2 , p38 by MKK3 , and JNK1/2 by MKK4 , among others .	MAPKs are specifically regulated by a MAPK kinase (MAPKK) XREF_BIBR, i.e., ERK1/2 is activated by MEK1/2, p38 by MKK3, and JNK1/2 by MKK4, among others.	14	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	19	20	15	16
The combination of three inhibitors called 3i , which includes SU5402 ( inhibiting FGF receptor tyrosine kinase ) , PD184352 ( inhibiting MEK which activates ERK by phosphorylation ) and CHIR99021 ( inhibiting GSK3 ) , is sufficient to derive and maintain mESCs in the absence of LIF and FBS ( XREF_FIG ) [ XREF_BIBR ] .	The combination of three inhibitors called 3i, which includes SU5402 (inhibiting FGF receptor tyrosine kinase), PD184352 (inhibiting MEK which activates ERK by phosphorylation) and CHIR99021 (inhibiting GSK3), is sufficient to derive and maintain mESCs in the absence of LIF and FBS (XREF_FIG) [XREF_BIBR].	21	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	22	23	25	26
Only PD98059 was able to significantly reverse the effects of angiotensin on the ECR2-TAC1prom-Luc construct , suggesting that MAPK control of ECR2-TAC1prom is modulated by the MEK and ERK pathway .	Only PD98059 was able to significantly reverse the effects of angiotensin on the ECR2-TAC1prom-Luc construct, suggesting that MAPK control of ECR2-TAC1prom is modulated by the MEK and ERK pathway.	18	29	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	26	27	18	19
It is possible that there could be independent cytoplasmic ternary complexes , depending on whether it is MEK1/2 or PKCdelta that is activating ERK1/2 .	It is possible that there could be independent cytoplasmic ternary complexes, depending on whether it is MEK1/2 or PKCdelta that is activating ERK1/2.	10	24	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	17	18	23	24
MEK activates ERK by phosphorylation ( phospho-ERK ) on both a threonine and a tyrosine residue .	MEK activates ERK by phosphorylation (phospho-ERK) on both a threonine and a tyrosine residue.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	2	3
In the MAPK pathway , ERK phosphorylation is a sign of ERK activation by MEK XREF_BIBR , XREF_BIBR .	In the MAPK pathway, ERK phosphorylation is a sign of ERK activation by MEK XREF_BIBR, XREF_BIBR.	11	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	14	15	11	12
The specific Mek inhibitor , PD98059 , blocked the activation of the Erks by ACTH and basic fibroblast growth factor , indicating that Mek is the upstream activator of Erk .	The specific Mek inhibitor, PD98059, blocked the activation of the Erks by ACTH and basic fibroblast growth factor, indicating that Mek is the upstream activator of Erk.	23	30	is the upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	23	24	29	30
11 Phosphorylation of these residues was shown to be MEK dependent , but it remains unaddressed whether this is mediated by MEK itself or its target ERK1/2 .	11 Phosphorylation of these residues was shown to be MEK dependent, but it remains unaddressed whether this is mediated by MEK itself or its target ERK1/2.	19	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	21	22	26	27
TACE activity is linked to TCR triggering by the signaling effector MEK , which in turn activates the kinase Erk .	TACE activity is linked to TCR triggering by the signaling effector MEK, which in turn activates the kinase Erk.	3	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk	Erk	Erk	11	12	19	20
PD0325901 , a potent and specific allosteric inhibitor of MEK , also abrogated ERK over-activation induced by increasing doses of NPV-BEZ235 ( XREF_FIG and XREF_FIG ) .	PD0325901, a potent and specific allosteric inhibitor of MEK, also abrogated ERK over-activation induced by increasing doses of NPV-BEZ235 (XREF_FIG and XREF_FIG).	7	14	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	13	14
Taken together these results support the previous findings that CDK5 acts to attenuate MEK XREF_BIBR , XREF_BIBR , XREF_BIBR , which coordinates with PKA to activate ERK XREF_BIBR .	Taken together these results support the previous findings that CDK5 acts to attenuate MEK XREF_BIBR, XREF_BIBR, XREF_BIBR, which coordinates with PKA to activate ERK XREF_BIBR.	13	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	13	14	26	27
A MEK specific inhibitor , PD98059 , inhibited heat shock ERK MAPK activation by > 75 % .	A MEK specific inhibitor, PD98059, inhibited heat shock ERK MAPK activation by> 75%.	1	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK MAPK	ERK MAPK	ERK MAPK	1	2	10	12
We also report a prolonged MEK dependent activation of ERK1/2 and increased c-FOS expression induced by TRAIL in this system .	We also report a prolonged MEK dependent activation of ERK1/2 and increased c-FOS expression induced by TRAIL in this system.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	5	6	9	10
However , several positive and negative feedback loops within the core kinase module ( Raf , MEK , and ERK ) triggered by active MEK or ERK , respectively , were reported .	However, several positive and negative feedback loops within the core kinase module (Raf, MEK, and ERK) triggered by active MEK or ERK, respectively, were reported.	12	26	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	24	25	19	20
XREF_BIBR RAF kinases stimulate the phosphorylation of MEK proteins , which in turn phosphorylate and activate the protein kinase ERK .	XREF_BIBR RAF kinases stimulate the phosphorylation of MEK proteins, which in turn phosphorylate and activate the protein kinase ERK.	1	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	RAF kinases stimulate the phosphorylation of MEK	mek	ERK	ERK	erk	7	8	19	20
Physiologic feedback inhibition of RAF and MEK signaling down-regulates ERK output in RTK cells ; evasion of this feedback in mutant BRAF cells is associated with increased transcriptional output and MEK and ERK dependent transformation .	Physiologic feedback inhibition of RAF and MEK signaling down-regulates ERK output in RTK cells; evasion of this feedback in mutant BRAF cells is associated with increased transcriptional output and MEK and ERK dependent transformation.	4	10	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	9	10
Finally , the selective inhibitor of MAPK kinase ( MEK ) , PD98059 , abolished the apoptosis protective effect of ADM and prevented ADM activation of ERK1/2 .	Finally, the selective inhibitor of MAPK kinase (MEK), PD98059, abolished the apoptosis protective effect of ADM and prevented ADM activation of ERK1/2.	4	27	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	9	10	26	27
Activated Plk1 may promote the phosphorylation and activation of MEK1/2 , which subsequently activates ERK1/2 and smooth muscle cell proliferation .	Activated Plk1 may promote the phosphorylation and activation of MEK1/2, which subsequently activates ERK1/2 and smooth muscle cell proliferation.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	phosphorylation and activation of MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	9	10	14	15
MEK and ERK inhibition completely suppressed 17-AAG-induced transient ERK activation .	MEK and ERK inhibition completely suppressed 17-AAG-induced transient ERK activation.	0	9	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	8	9
The MAPK pathway converges at MEK , which in turn activates ERK1/2 .	The MAPK pathway converges at MEK, which in turn activates ERK1/2.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	5	6	11	12
When epidermal growth factor ( EGF ) binds to its receptor ( EGFR ) , it can trigger the activation of Ras , which can then activate c-Raf , a serine/threonine kinase that can phosphorylate MEK , allowing it to activate ERK1/2 .	When epidermal growth factor (EGF) binds to its receptor (EGFR), it can trigger the activation of Ras, which can then activate c-Raf, a serine/threonine kinase that can phosphorylate MEK, allowing it to activate ERK1/2.	27	42	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	c-Raf, a serine/threonine kinase that can phosphorylate MEK	mek	ERK1/2	ERK1/2	erk1/2	35	36	41	42
In general , PC12 cells were first transfected with pcDNA-GFP alone or pCDNA-M6Ab-GFP , then treated with a different inhibitor , such as U0126 ( for MEK1/2 that prevents activation of MAPK by MEK ) or KN-62 ( a CaMKII inhibitor ) in the presence of NGF .	In general, PC12 cells were first transfected with pcDNA-GFP alone or pCDNA-M6Ab-GFP, then treated with a different inhibitor, such as U0126 (for MEK1/2 that prevents activation of MAPK by MEK) or KN-62 (a CaMKII inhibitor) in the presence of NGF.	28	34	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	33	34	31	32
ERK1/2 are activated directly by the upstream MEK1/2 , which are dual-specificity protein kinases .	ERK1/2 are activated directly by the upstream MEK1/2, which are dual-specificity protein kinases.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	7	8	0	1
As expected , the use of U0126 , a specific inhibitor of MEK1/2 , abolished all downstream ERK1/2 signal transduction ( XREF_FIG ) .	As expected, the use of U0126, a specific inhibitor of MEK1/2, abolished all downstream ERK1/2 signal transduction (XREF_FIG).	10	19	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	12	13	17	18
Thus , activation of FGF-1- and HRGbeta1 specific signaling causes MEK dependent prolonged activation of ERK1/2 , which is incompletely susceptible to known MEK inhibitors .	Thus, activation of FGF-1- and HRGbeta1 specific signaling causes MEK dependent prolonged activation of ERK1/2, which is incompletely susceptible to known MEK inhibitors.	10	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	10	11	15	16
Raf-1 activates the dual specific kinase MEK , which in turn activates ERK .	Raf-1 activates the dual specific kinase MEK, which in turn activates ERK.	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	12	13
This model describes the activation of ERK by MEK .	This model describes the activation of ERK by MEK.	2	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	8	9	6	7
Preincubation of U118 cells with the selective MEK1/2 inhibitor U0126 , which inhibits MEK1/2 mediated activation of ERK1/2 , led to a switch from necrosis to caspase dependent apoptosis following edelfosine treatment .	Preincubation of U118 cells with the selective MEK1/2 inhibitor U0126, which inhibits MEK1/2 mediated activation of ERK1/2, led to a switch from necrosis to caspase dependent apoptosis following edelfosine treatment.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	13	14	17	18
RAF activates the kinase MEK ( MAP kinase extracellular signal regulated kinase ) which then activates ERK ( extracellular signal regulated kinase , Figure XREF_FIG ) .	RAF activates the kinase MEK (MAP kinase extracellular signal regulated kinase) which then activates ERK (extracellular signal regulated kinase, Figure XREF_FIG).	1	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	4	5	16	17
We chose to explore the MEK and ERK module of the MAPK pathway for several reasons .	We chose to explore the MEK and ERK module of the MAPK pathway for several reasons.	5	12	module	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	5	6	11	12
Pharmacological blockade of MEK or Akt completely prevented PGE 2 -mediated activation of ERK1/2 and Akt , respectively , confirming that these inhibitors selectively blocked their target pathways ( XREF_FIG ) .	Pharmacological blockade of MEK or Akt completely prevented PGE 2 -mediated activation of ERK1/2 and Akt, respectively, confirming that these inhibitors selectively blocked their target pathways (XREF_FIG).	1	15	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	3	4	13	14
Effectors for Ras include the serine/threonine kinase Raf-1 , which via MEK activates ERK , and the GTPase Rac , which via different MKKs activates JNK and p38 .	Effectors for Ras include the serine/threonine kinase Raf-1, which via MEK activates ERK, and the GTPase Rac, which via different MKKs activates JNK and p38.	10	14	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	11	12	13	14
Putative downstream targets specific to MEK1/2 dependent activation of ERK1/2 were initially identified in SS RBCs , in which 36 unique phosphopeptides ( from 21 unique phosphoproteins ) decreased in abundance upon treatment with U0126 .	Putative downstream targets specific to MEK1/2 dependent activation of ERK1/2 were initially identified in SS RBCs, in which 36 unique phosphopeptides (from 21 unique phosphoproteins) decreased in abundance upon treatment with U0126.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	5	6	9	10
Furthermore , both PLX4720 and AZ628 can promote RAF dimerization , but only PLX4720 causes paradoxical MAPK pathway activation that is only partially reversed by MEK inhibition , consistent with our observation that PLX4720 in combination with AZD6244 displays no synergy and has a limited antiproliferative effect .	Furthermore, both PLX4720 and AZ628 can promote RAF dimerization, but only PLX4720 causes paradoxical MAPK pathway activation that is only partially reversed by MEK inhibition, consistent with our observation that PLX4720 in combination with AZD6244 displays no synergy and has a limited antiproliferative effect.	16	26	reversed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	25	26	16	17
Likewise , in the absence of evidence for a distributed mechanism of ERK kinase ( MEK ) activation by Raf , we use a simplified , one-step description , whereas a distributed mechanism of ERK activation by MEK and deactivation by MKP3 is described as a two-step process .	Likewise, in the absence of evidence for a distributed mechanism of ERK kinase (MEK) activation by Raf, we use a simplified, one-step description, whereas a distributed mechanism of ERK activation by MEK and deactivation by MKP3 is described as a two-step process.	34	41	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	37	38	34	35
MEK inhibition will decrease ERK1/2 activity and reduce RSK activation .	MEK inhibition will decrease ERK1/2 activity and reduce RSK activation.	0	5	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	0	1	4	5
Since ERK1/2 are activated by MEK1/2 and p90RSK is an important downstream substrate of ERK1/2 , we tested further whether MEK1/2 and p90RSK are also activated by MCSF .	Since ERK1/2 are activated by MEK1/2 and p90RSK is an important downstream substrate of ERK1/2, we tested further whether MEK1/2 and p90RSK are also activated by MCSF.	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	5	6	1	2
Pharmacological inhibition of the ERK activating kinase , MEK , immediately after extinction trials prevented ERK-1/2 activation and impaired extinction recall .	Pharmacological inhibition of the ERK activating kinase, MEK, immediately after extinction trials prevented ERK-1/2 activation and impaired extinction recall.	6	16	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK-1/2	ERK-1/2	ERK-1/2	8	9	15	16
These pathways are often depicted in a modular and highly structured manner in which a MAPK kinase kinase ( MAP3K ) such as Raf activates a MAPK kinase ( MAP2K ) such as MEK , which in turn activates a MAPK such as ERK1 ( XREF_FIG ) .	These pathways are often depicted in a modular and highly structured manner in which a MAPK kinase kinase (MAP3K) such as Raf activates a MAPK kinase (MAP2K) such as MEK, which in turn activates a MAPK such as ERK1 (XREF_FIG).	27	43	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	33	34	40	41
Cisplatin treatment caused sustained activation of ERK1/2 , which was prevented by PD98059 and U0126 , inhibitors of ERK1/2 upstream kinase MEK1/2 .	Cisplatin treatment caused sustained activation of ERK1/2, which was prevented by PD98059 and U0126, inhibitors of ERK1/2 upstream kinase MEK1/2.	4	22	prevented	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	21	22	6	7
Although not a screen hit , MEK target ERK showed up-regulated expression with a trend to increased activation in RCC4B20 cells .	Although not a screen hit, MEK target ERK showed up-regulated expression with a trend to increased activation in RCC4B20 cells.	6	9	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	8	9
Blocking MEK ( NGF+ MEK i ) inhibited ERK and thus several downstream targets , including the uPAR feedback .	Blocking MEK (NGF+MEK i) inhibited ERK and thus several downstream targets, including the uPAR feedback.	0	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	1	2	8	9
In addition , pharmacologic inhibition of the Erk activator Mek in zebrafish results in defective cranio-facial development , outflow tract blockage in the heart with concomitant pericardial edema , and increased vascular permeability .	In addition, pharmacologic inhibition of the Erk activator Mek in zebrafish results in defective cranio-facial development, outflow tract blockage in the heart with concomitant pericardial edema, and increased vascular permeability.	4	11	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	Mek	Mek	Mek	Erk	Erk	Erk	9	10	7	8
MEK inhibition caused acute ERK activity loss , resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases ( RTKs ) .	MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs).	0	6	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	4	5
While ERK inhibitors have not been effective in clinical testing , compounds that inhibit MEK ( an upstream activator of ERK ) including selumetinib ( formerly AZD6244 ) , and the more potent compound pimasertib ( formerly AS703026 , EMD Serono , Inc ., Rockland , MA ) have displayed clinical activity in phase II trials for melanoma and ovarian cancer .	While ERK inhibitors have not been effective in clinical testing, compounds that inhibit MEK (an upstream activator of ERK) including selumetinib (formerly AZD6244), and the more potent compound pimasertib (formerly AS703026, EMD Serono, Inc., Rockland, MA) have displayed clinical activity in phase II trials for melanoma and ovarian cancer.	13	34	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	14	15	20	21
The RAF phosphorylates two serine residues on the kinase mitogen protein kinase-1 and -2 ( MEK1/2 ) ; MEK then activates ERK1/2 by phosphorylation of threonine and tyrosine residues , which are separated by one amino acid ( threonine 183 and tyrosine 185 of ERK1/2 ) .	The RAF phosphorylates two serine residues on the kinase mitogen protein kinase-1 and -2 (MEK1/2); MEK then activates ERK1/2 by phosphorylation of threonine and tyrosine residues, which are separated by one amino acid (threonine 183 and tyrosine 185 of ERK1/2).	18	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	18	19	21	22
Additionally , MEK activation of ERK may also activate some unknown factors besides calcineurin that directly regulate NFAT3 activity .	Additionally, MEK activation of ERK may also activate some unknown factors besides calcineurin that directly regulate NFAT3 activity.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	2	3	5	6
PD 98059 , an inhibitor of the ERK activator MEK ( mitogen activated protein kinase kinase ) and bisindolylmaleimide I , an inhibitor of PKC activation , each blocked aldosterone stimulated hypertrophy .	PD 98059, an inhibitor of the ERK activator MEK (mitogen activated protein kinase kinase) and bisindolylmaleimide I, an inhibitor of PKC activation, each blocked aldosterone stimulated hypertrophy.	4	10	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	7	8
As shown in XREF_FIG A , inhibitors of the ERK activator MEK ( PD98059 ) , or PI-3K ( wortmannin ) were each able to reverse the antiapoptotic effect of alpha M beta 2 clustering with either 19c F ( ab ' ) 2 or rhICAM-1 coated beads ( XREF_FIG A ) .	As shown in XREF_FIG A, inhibitors of the ERK activator MEK (PD98059), or PI-3K (wortmannin) were each able to reverse the antiapoptotic effect of alpha M beta 2 clustering with either 19c F (ab ') 2 or rhICAM-1 coated beads (XREF_FIG A).	6	13	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	11	12	9	10
I tested four different inhibitors of MEK1/2 ( MEK ) , the kinase that activates ERK1/2 , in a model of human SSRBC adhesion to TNFalpha activated endothelial cells ( ECs ) .	I tested four different inhibitors of MEK1/2 (MEK), the kinase that activates ERK1/2, in a model of human SSRBC adhesion to TNFalpha activated endothelial cells (ECs).	6	16	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	8	9	15	16
ACTH and basic fibroblast growth factor each increased Mek phosphorylation and stimulated Mek activity in both cell lines and also activated the Erks at concentrations that paralleled their effects on Mek .	ACTH and basic fibroblast growth factor each increased Mek phosphorylation and stimulated Mek activity in both cell lines and also activated the Erks at concentrations that paralleled their effects on Mek.	12	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erks	Erks	Erks	12	13	22	23
These data suggest that ERK1/2 is activated by the upstream kinase MEK1/2 , as reported in a variety of cell types [ XREF_BIBR , XREF_BIBR ] .	These data suggest that ERK1/2 is activated by the upstream kinase MEK1/2, as reported in a variety of cell types [XREF_BIBR, XREF_BIBR].	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	11	12	4	5
ERK1/2 activation was mediated by MEK1/2 , and the protein synthesis inhibitor cycloheximide did not alter the pattern of RA induced ERK1/2 phosphorylation .	ERK1/2 activation was mediated by MEK1/2, and the protein synthesis inhibitor cycloheximide did not alter the pattern of RA induced ERK1/2 phosphorylation.	0	6	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	5	6	0	1
We found that the concurrent inhibition of PI3K and Akt and MEK kinases blocked ERK1/2 activation in a synergistic , but not additive manner after 5 minutes of EGF addition to the media ( XREF_FIG , right panel ) .	We found that the concurrent inhibition of PI3K and Akt and MEK kinases blocked ERK1/2 activation in a synergistic, but not additive manner after 5 minutes of EGF addition to the media (XREF_FIG, right panel).	11	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	11	12	14	15
Interestingly , a ROS scavenger NAC inhibited the phosphorylation of c-Raf and MEK and prevented the activation of the ERK signaling pathway .	Interestingly, a ROS scavenger NAC inhibited the phosphorylation of c-Raf and MEK and prevented the activation of the ERK signaling pathway.	5	21	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	NAC inhibited the phosphorylation of c-Raf and MEK	mek	ERK	ERK	erk	12	13	19	20
MEK and ERK inhibitors prevented ERK activation , implying their activity in these treatments , with U0126 being more potent than PD98059 ( XREF_FIG C ) .	MEK and ERK inhibitors prevented ERK activation, implying their activity in these treatments, with U0126 being more potent than PD98059 (XREF_FIG C).	0	6	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	5	6
The Ras/Raf/Mek/Erk pathway is often drawn in a linear manner such that Ras activates Raf , which in turn activates Mek , which in turn activates Erk .	The Ras/Raf/Mek/Erk pathway is often drawn in a linear manner such that Ras activates Raf, which in turn activates Mek, which in turn activates Erk.	19	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	20	21	26	27
Inhibition of MAPK and ERK kinase ( MEK ) with specific , small molecules suppresses MAPK signaling and has shown promising results in patients with NRAS mutant melanoma .	Inhibition of MAPK and ERK kinase (MEK) with specific, small molecules suppresses MAPK signaling and has shown promising results in patients with NRAS mutant melanoma.	0	16	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	7	8	15	16
BRAF functions by phosphorylating and activating MEK1/2 , which in turn phosphorylates and activates ERK1/2 , leading to cellular proliferation ( cyclin D , RBL2 ) , survival ( Bim , MCl-1 ) , and differentiation .	BRAF functions by phosphorylating and activating MEK1/2, which in turn phosphorylates and activates ERK1/2, leading to cellular proliferation (cyclin D, RBL2), survival (Bim, MCl-1), and differentiation.	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	phosphorylating and activating MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	6	7	14	15
Activated by RAS , the RAF phosphorylates and activates downstream MEK , which then activates ERK subsequently and ultimately results in the activation of transcription factors .	Activated by RAS, the RAF phosphorylates and activates downstream MEK, which then activates ERK subsequently and ultimately results in the activation of transcription factors.	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	Activated by RAS, the RAF phosphorylates and activates downstream MEK	mek	ERK	ERK	erk	10	11	15	16
Expression of MEK DN caused mitochondrial elongation , whereas activation of ERK by MEK CA resulted in fragmentation ( XREF_FIG A and 2B ) .	Expression of MEK DN caused mitochondrial elongation, whereas activation of ERK by MEK CA resulted in fragmentation (XREF_FIG A and 2B).	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	13	14	11	12
As MI mediated ERK activation was observed in neutrophils ( XREF_FIG ) , we used PD98059 and U0126 , which inhibits MEK1/2 ( the upstream activator of ERK1/2 ) , to analyze the role of these MAPK pathways in p47phox phosphorylation in neutrophils .	As MI mediated ERK activation was observed in neutrophils (XREF_FIG), we used PD98059 and U0126, which inhibits MEK1/2 (the upstream activator of ERK1/2), to analyze the role of these MAPK pathways in p47phox phosphorylation in neutrophils.	20	28	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	21	22	27	28
ERK has two highly homologous isoforms ( ERK1/2 ) that are activated by the dual-specificity kinase , MEK , through phosphorylation of specific tyrosine and threonine residues on the conserved TEY motif in its activation loop [ XREF_BIBR , XREF_BIBR ] .	ERK has two highly homologous isoforms (ERK1/2) that are activated by the dual-specificity kinase, MEK, through phosphorylation of specific tyrosine and threonine residues on the conserved TEY motif in its activation loop [XREF_BIBR, XREF_BIBR].	5	18	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	17	18	7	8
Activated RAF kinases phosphorylate and activate MEK1/2 , which in turn activate ERK1/2 .	Activated RAF kinases phosphorylate and activate MEK1/2, which in turn activate ERK1/2.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	6	7	12	13
Activation of c-Met with HGF triggered the signaling via the ERK cascade mediated by sequential phosphorylation of MEK1/2 and MAPK and induction of cholangiocarcinoma cell invasion .	Activation of c-Met with HGF triggered the signaling via the ERK cascade mediated by sequential phosphorylation of MEK1/2 and MAPK and induction of cholangiocarcinoma cell invasion.	10	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	phosphorylation of MEK1/2	mek1/2	ERK	ERK	erk	17	18	10	11
In wildtype cells , Ras activity leads to engagement and activation of Raf , which in turn activates mitogen activated protein kinase kinase ( MEK ) , which activates extracellular signal regulated kinase ( Erk ) .	In wildtype cells, Ras activity leads to engagement and activation of Raf, which in turn activates mitogen activated protein kinase kinase (MEK), which activates extracellular signal regulated kinase (Erk).	22	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	extracellular signal regulated kinase	extracellular signal regulated kinase	extracellular signal regulated kinase	24	25	29	33
These viruses stimulated the generation of both egr-1 mRNA and its gene product , throughout their entire replication cycles , via the requirement of MEK [ mitogen activated protein kinase and ERK ( extracellular-signal-regulated kinase ) kinase ]/ERK pathway .	These viruses stimulated the generation of both egr-1 mRNA and its gene product, throughout their entire replication cycles, via the requirement of MEK [mitogen activated protein kinase and ERK (extracellular-signal-regulated kinase) kinase]/ERK pathway.	24	32	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	24	25	31	32
In a previous study , we found that PTGER2 mediated activation of ERK1/2 in endometrial epithelial cells is mediated via sequential transactivation of the EGFR and activation of the MAPK kinase kinase Raf , which results in the sequential phosphorylation of the MAPK and ERK protein serine kinase 1/2 ( MEK ) , which in turn activates ERK1/2 .	In a previous study, we found that PTGER2 mediated activation of ERK1/2 in endometrial epithelial cells is mediated via sequential transactivation of the EGFR and activation of the MAPK kinase kinase Raf, which results in the sequential phosphorylation of the MAPK and ERK protein serine kinase 1/2 (MEK), which in turn activates ERK1/2.	29	58	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MAPK kinase kinase Raf, which results in the sequential phosphorylation of the MAPK and ERK protein serine kinase 1/2 (MEK	mek	ERK1/2	ERK1/2	erk1/2	50	51	57	58
MEK activates a MAPK .	MEK activates a MAPK.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	0	1	3	4
This recapitulates the Erk1/2 inhibition induced G1 arrest by MEK inhibition that is characterized by decreased expression of cyclin D1 and accumulation of p27 Kip1 XREF_BIBR - XREF_BIBR .	This recapitulates the Erk1/2 inhibition induced G1 arrest by MEK inhibition that is characterized by decreased expression of cyclin D1 and accumulation of p27 Kip1 XREF_BIBR - XREF_BIBR.	3	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk1/2	Erk1/2	Erk1/2	9	10	3	4
Since MEK activation is required for ERK activation , MEK inhibition blocks ERK activation .	Since MEK activation is required for ERK activation, MEK inhibition blocks ERK activation.	9	13	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	12	13
It has also been reported that combination BRAF inhibition and MEK inhibition prevents MAPK pathway reactivation and an improved reduction in pERK in glioma models .	It has also been reported that combination BRAF inhibition and MEK inhibition prevents MAPK pathway reactivation and an improved reduction in pERK in glioma models.	10	15	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	10	11	13	14
Raf phosphorylates and activates the kinases MEK1/2 , which activate ERK1/2 .	Raf phosphorylates and activates the kinases MEK1/2, which activate ERK1/2.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	Raf phosphorylates and activates the kinases MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	6	7	10	11
Our previous study showed that MEK kinase , which specially activated downstream ERK kinase , is an important and potential target against EV-A71 .	Our previous study showed that MEK kinase, which specially activated downstream ERK kinase, is an important and potential target against EV-A71.	5	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	5	6	12	13
This activated form phosphorylates in turn a MAPK kinase ( MP2K or MKK or MEK ) , which finally activates a MAPK .	This activated form phosphorylates in turn a MAPK kinase (MP2K or MKK or MEK), which finally activates a MAPK.	3	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	phosphorylates in turn a MAPK kinase (MP2K or MKK or MEK	mek	MAPK	MAPK	mapk	14	15	21	22
In metazoans , the protein Ras , Raf and MEK act sequentially to activate ERK [ XREF_BIBR ] .	In metazoans, the protein Ras, Raf and MEK act sequentially to activate ERK [XREF_BIBR].	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	14	15
ERK1/2 as one of MAPK proteins can be activated transiently or persistently by MEK1/2 and upstream MAP3Ks .	ERK1/2 as one of MAPK proteins can be activated transiently or persistently by MEK1/2 and upstream MAP3Ks.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	13	14	0	1
Concomitant inhibition of MEK with ERBB3 by a pan-ERBB inhibitor afatinib negated ERK reactivation and upregulation of AKT , leading to cell death in vitro and tumor regressions in vivo .	Concomitant inhibition of MEK with ERBB3 by a pan-ERBB inhibitor afatinib negated ERK reactivation and upregulation of AKT, leading to cell death in vitro and tumor regressions in vivo.	1	13	negated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	12	13
Inhibition of B-Raf or MEK in B-Raf-mutant cancer cells suppresses ERK activation accompanied by downregulation of DR5 expression and decreased cell sensitivity to DR5 activation induced apoptosis , as we recently demonstrated XREF_BIBR .	Inhibition of B-Raf or MEK in B-Raf-mutant cancer cells suppresses ERK activation accompanied by downregulation of DR5 expression and decreased cell sensitivity to DR5 activation induced apoptosis, as we recently demonstrated XREF_BIBR.	0	11	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	4	5	10	11
ERK can be activated by Ref mediated MEK signaling [ XREF_BIBR ] .	ERK can be activated by Ref mediated MEK signaling [XREF_BIBR].	0	8	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	MEK	Ref mediated MEK	mek	ERK	ERK	erk	7	8	0	1
We investigated the effects of transformation on serum and growth factor stimulation of Erk1 and Erk2 , and show that stimulation of these MAP kinases , as well as the Erk activator Mek , is delayed in oncogene transformed cells .	We investigated the effects of transformation on serum and growth factor stimulation of Erk1 and Erk2, and show that stimulation of these MAP kinases, as well as the Erk activator Mek, is delayed in oncogene transformed cells.	20	35	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	32	33	30	31
To confirm a role for MAPK signaling in patients with relapsed ALL , we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse .	To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse.	16	24	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	19	20	21	22
For each branch , the MAPK component is specifically activated by a distinct MAP2K : MEK1/2 for ERK1/2 , MKK3/6 for p38 , and MKK4/7 for JNKs .	For each branch, the MAPK component is specifically activated by a distinct MAP2K : MEK1/2 for ERK1/2, MKK3/6 for p38, and MKK4/7 for JNKs.	5	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	15	16	5	6
Consistent with this observation , MEK1/2 , an upstream kinase of ERK1/2 , induces activation of ERK1/2 and enhances TGF-beta-mediated transcription processes XREF_BIBR ; XREF_BIBR .	Consistent with this observation, MEK1/2, an upstream kinase of ERK1/2, induces activation of ERK1/2 and enhances TGF-beta-mediated transcription processes XREF_BIBR; XREF_BIBR.	5	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	5	6	16	17
To determine if inhibition of cell proliferation induced by PME-1 depletion correlates with ERK pathway inactivation , we analyzed the effect of PME-1 shRNA on proliferation of cell clones in which ERK pathway activity was activated either by H-Ras V12 , B-Raf E600 , or MEK DD overexpression .	To determine if inhibition of cell proliferation induced by PME-1 depletion correlates with ERK pathway inactivation, we analyzed the effect of PME-1 shRNA on proliferation of cell clones in which ERK pathway activity was activated either by H-Ras V12, B-Raf E600, or MEK DD overexpression.	31	48	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK DD overexpression	mek	ERK	ERK	erk	45	46	31	32
Combination of FGFR inhibition and MEK inhibition suppresses feedback activation of ERK and induces cell death in mesenchymal like KRAS mutant lung cancer cell lines .	Combination of FGFR inhibition and MEK inhibition suppresses feedback activation of ERK and induces cell death in mesenchymal like KRAS mutant lung cancer cell lines.	5	12	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	5	6	11	12
To determine if ERK activation is responsible for reducing SERCA2 mRNA during hypertrophy , we inhibited MEK , the upstream kinase that activates ERK1/2 , with two different pharmacologic inhibitors , PD98059 and U0126 ( XREF_FIG ) .	To determine if ERK activation is responsible for reducing SERCA2 mRNA during hypertrophy, we inhibited MEK, the upstream kinase that activates ERK1/2, with two different pharmacologic inhibitors, PD98059 and U0126 (XREF_FIG).	15	24	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	16	17	23	24
To determine whether the Erk activation was associated with the inhibitory effect of GGF , co-cultures were treated with GGF along with increasing concentrations of U0126 , a specific inhibitor of Erk activator Mek1/2 , and maintained under myelinating condition .	To determine whether the Erk activation was associated with the inhibitory effect of GGF, co-cultures were treated with GGF along with increasing concentrations of U0126, a specific inhibitor of Erk activator Mek1/2, and maintained under myelinating condition.	29	34	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	Mek1/2	Mek1/2	Mek1/2	Erk	Erk	Erk	33	34	31	32
The suppression of AICAR induced maturation by MEK inhibitors must , therefore , be occurring by actions unrelated to MEK stimulation of MAPK ; consequently , it would be prudent to consider this possible non specific action of the inhibitors when they are used to block MAPK activation in mouse oocytes .	The suppression of AICAR induced maturation by MEK inhibitors must, therefore, be occurring by actions unrelated to MEK stimulation of MAPK; consequently, it would be prudent to consider this possible non specific action of the inhibitors when they are used to block MAPK activation in mouse oocytes.	19	23	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	19	20	22	23
Among the downstream effectors of Ras , the most well characterized is the Ras-Raf-MAPK signaling pathway , in which Ras interaction with the serine/threonine kinase Raf causes a cascade of kinase activation , with Raf activating the mitogen activated protein kinase kinases ( MAPKK , or MEK ) and MEK activating the ERK MAPK , which then translocates to the nucleus to phosphorylate and activate transcription factors to carry out the commands of Ras .	Among the downstream effectors of Ras, the most well characterized is the Ras-Raf-MAPK signaling pathway, in which Ras interaction with the serine/threonine kinase Raf causes a cascade of kinase activation, with Raf activating the mitogen activated protein kinase kinases (MAPKK, or MEK) and MEK activating the ERK MAPK, which then translocates to the nucleus to phosphorylate and activate transcription factors to carry out the commands of Ras.	38	61	activating	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	MEK	MEK	mek	ERK MAPK	ERK MAPK, which then translocates to the nucleus	erk mapk	49	50	52	54
As expected , inhibition of Mek using U0126 entirely blocks Erk signaling in treated embryos ( XREF_FIG C ) .	As expected, inhibition of Mek using U0126 entirely blocks Erk signaling in treated embryos (XREF_FIG C).	3	11	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	5	6	10	11
Once activated , MEK kinases phosphorylate and activate ERK kinases , which phosphorylate a multitude of key cellular substrates involved in cell proliferation and survival .	Once activated, MEK kinases phosphorylate and activate ERK kinases, which phosphorylate a multitude of key cellular substrates involved in cell proliferation and survival.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	8	9
ERK 1/2 are activated by MEK1/2 , which are activated by Raf , Ras , and growth factors or mitogens ; Raf activity , as the main effector of Ras , is suppressed by cyclic AMP dependent kinase ( PKA ) in a normal cell [ XREF_BIBR ] .	ERK 1/2 are activated by MEK1/2, which are activated by Raf, Ras, and growth factors or mitogens; Raf activity, as the main effector of Ras, is suppressed by cyclic AMP dependent kinase (PKA) in a normal cell [XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK 1/2	ERK 1/2	ERK 1/2	5	6	0	2
This result is in agreement with that from Soares et al ., who showed that MEK1/2 inhibition suppressed the enhanced ERK activation induced by PI3K and mTOR dual inhibitors and enhanced the effects of growth inhibition due to BEZ235 in pancreatic cancer cells .	This result is in agreement with that from Soares et al., who showed that MEK1/2 inhibition suppressed the enhanced ERK activation induced by PI3K and mTOR dual inhibitors and enhanced the effects of growth inhibition due to BEZ235 in pancreatic cancer cells.	15	21	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	15	16	20	21
MEK1/2 can activate MAPK pathways upon stimulation by variety of extra- and intracellular signals , and MAPK signaling can control cell proliferation and differentiation .	MEK1/2 can activate MAPK pathways upon stimulation by variety of extra- and intracellular signals, and MAPK signaling can control cell proliferation and differentiation.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	0	1	3	4
In this study , inhibitors of MEK ( PB98059 ) and PI3K ( LY294002 ) were applied to abolish the activation of ERK and AKT by low dose berberine .	In this study, inhibitors of MEK (PB98059) and PI3K (LY294002) were applied to abolish the activation of ERK and AKT by low dose berberine.	4	24	abolish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	22	23
In particular , treatment with selumetinib , an inhibitor of mitogen activated protein kinase kinase 1/2 ( MEK1/2 ) , the enzyme that activates ERK1/2 , improves left ventricular ejection fraction ( fractional shortening ) , decreases cardiac fibrosis and prolongs survival in these mice [ XREF_BIBR ] .	In particular, treatment with selumetinib, an inhibitor of mitogen activated protein kinase kinase 1/2 (MEK1/2), the enzyme that activates ERK1/2, improves left ventricular ejection fraction (fractional shortening), decreases cardiac fibrosis and prolongs survival in these mice [XREF_BIBR].	11	25	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	17	18	24	25
Trametinib , an FDA approved drug for the treatment of melanoma , is one such potent and highly specific inhibitor of the Mek kinase , preventing activation of Erk by Ras .	Trametinib, an FDA approved drug for the treatment of melanoma, is one such potent and highly specific inhibitor of the Mek kinase, preventing activation of Erk by Ras.	22	29	preventing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	22	23	28	29
Activation of these pathways by ATP seemed to be independent , since LY294002 and U0126 , inhibitors of PI3K and MEK , did not block the activation of ERK and AKT , respectively , although each compound blocked its respective target .	Activation of these pathways by ATP seemed to be independent, since LY294002 and U0126, inhibitors of PI3K and MEK, did not block the activation of ERK and AKT, respectively, although each compound blocked its respective target.	16	30	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	20	21	28	29
In the classic MAPK ( Raf-1 -ERK1/2 ) pathway , Ras activates Raf-1 to phosphorylate MEK1/2 , which in turn activates ERK1/2 by phosphorylation .	In the classic MAPK (Raf-1 -ERK1/2) pathway, Ras activates Raf-1 to phosphorylate MEK1/2, which in turn activates ERK1/2 by phosphorylation.	14	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	phosphorylate MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	15	16	21	22
Activation of Nrf2 could also result from the MEK mediated activation of ERK kinase , in addition to Keap1 inactivation , at this later time .	Activation of Nrf2 could also result from the MEK mediated activation of ERK kinase, in addition to Keap1 inactivation, at this later time.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	8	9	12	13
The intracellular molecule MEK is able to activate the ERK1/2 pathway which is also involved in EC survival , proliferation and migration XREF_BIBR .	The intracellular molecule MEK is able to activate the ERK1/2 pathway which is also involved in EC survival, proliferation and migration XREF_BIBR.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	3	4	9	10
Nevertheless , since ERK1 and ERK2 are both activated by MEK , inhibiting MEK will inhibit both ERKs , rendering it difficult to ascribe each isoform a unique physiological function .	Nevertheless, since ERK1 and ERK2 are both activated by MEK, inhibiting MEK will inhibit both ERKs, rendering it difficult to ascribe each isoform a unique physiological function.	12	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERKs	ERKs	ERKs	13	14	17	18
When epidermal growth factor ( EGF ) binds to its tyrosine kinase receptor ( EGFR ) , it can trigger the activation of Ras , which can then activate c-Raf , a serine/threonine kinase that can phosphorylate MEK , allowing it to activate ERK1/2 XREF_BIBR , XREF_BIBR .	When epidermal growth factor (EGF) binds to its tyrosine kinase receptor (EGFR), it can trigger the activation of Ras, which can then activate c-Raf, a serine/threonine kinase that can phosphorylate MEK, allowing it to activate ERK1/2 XREF_BIBR, XREF_BIBR.	29	44	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	c-Raf, a serine/threonine kinase that can phosphorylate MEK	mek	ERK1/2	ERK1/2	erk1/2	37	38	43	44
XREF_BIBR , XREF_BIBR - XREF_BIBR Raf activates MEK1/2 and MEK1/2 activates ERK1/2 through activation loop phosphorylation , while ERK negatively regulates SOS to negatively regulate the pathway .	XREF_BIBR, XREF_BIBR - XREF_BIBR Raf activates MEK1/2 and MEK1/2 activates ERK1/2 through activation loop phosphorylation, while ERK negatively regulates SOS to negatively regulate the pathway.	7	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	7	8	11	12
Autoactivation rendered by these mutations increased kinase activity of ERK2 about 50-fold in vitro , which is substantially lower than the levels of MEK1/2 mediated ERK1/2 activation ; MEK1/2 can increase ERK1/2 activity over 1,000-fold .	Autoactivation rendered by these mutations increased kinase activity of ERK2 about 50-fold in vitro, which is substantially lower than the levels of MEK1/2 mediated ERK1/2 activation; MEK1/2 can increase ERK1/2 activity over 1,000-fold.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	23	24	25	26
Upon stimulation , activated Raf kinase activates MEK1/2 , which in turn activates ERK1/2 to phosphorylate substrates in the cytoplasm or to translocate to the nucleus to phosphorylate transcription factors and regulate target gene expression .	Upon stimulation, activated Raf kinase activates MEK1/2, which in turn activates ERK1/2 to phosphorylate substrates in the cytoplasm or to translocate to the nucleus to phosphorylate transcription factors and regulate target gene expression.	6	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	7	8	13	14
Activated Raf then phosphorylates Mek1/2 , which in turn activates Erk1/2 , leading to the phosphorylation of > 160 known nuclear and cytosolic Erk1/2 substrates .	Activated Raf then phosphorylates Mek1/2, which in turn activates Erk1/2, leading to the phosphorylation of> 160 known nuclear and cytosolic Erk1/2 substrates.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek1/2	phosphorylates Mek1/2	mek1/2	Erk1/2	Erk1/2	erk1/2	4	5	10	11
The phosphorylation of MEK1/2 and MKK4 , the upstream enzymes of ERK and JNK , respectively , was also strikingly suppressed by Pc-ME in LPS challenges of 2 , 3 , and 5min ( XREF_FIG ) , confirming the MAPK inhibitory activity of this extract .	The phosphorylation of MEK1/2 and MKK4, the upstream enzymes of ERK and JNK, respectively, was also strikingly suppressed by Pc-ME in LPS challenges of 2, 3, and 5min (XREF_FIG), confirming the MAPK inhibitory activity of this extract.	1	41	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	phosphorylation of MEK1/2	mek1/2	MAPK	MAPK	mapk	3	4	39	40
These data show that the T202 is the likely site of phosphorylation , and the phosphorylation of Erk1 by PKM2-SAICAR appears distinct from the MEK mediated Erk1/2 activation .	These data show that the T202 is the likely site of phosphorylation, and the phosphorylation of Erk1 by PKM2-SAICAR appears distinct from the MEK mediated Erk1/2 activation.	21	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk1/2	Erk1/2	Erk1/2	24	25	26	27
Raf is the first member of a cascade of three kinases in the MAPK pathway , with Raf activating MEK and MEK activating the terminal MAPK , Erk [ XREF_BIBR ] .	Raf is the first member of a cascade of three kinases in the MAPK pathway, with Raf activating MEK and MEK activating the terminal MAPK, Erk [XREF_BIBR].	4	29	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	21	22	25	26
Mixed lineage kinases ( MLK1-4 ) are MEK kinases that are able to independently reactivate the MEK and ERK pathway , even in the presence of RAF inhibitors .	Mixed lineage kinases (MLK1-4) are MEK kinases that are able to independently reactivate the MEK and ERK pathway, even in the presence of RAF inhibitors.	7	19	reactivate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	7	8	18	19
In agreement with this function , the capacity of NT-3 to induce eIF4E phosphorylation in the OLGs was significantly reduced by PD98059 , an inhibitor that blocks MEK , the kinase that activates ERK1/2 ( XREF_FIG ) .	In agreement with this function, the capacity of NT-3 to induce eIF4E phosphorylation in the OLGs was significantly reduced by PD98059, an inhibitor that blocks MEK, the kinase that activates ERK1/2 (XREF_FIG).	26	35	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	27	28	33	34
MEK1/2 is an upstream activator of ERK1/2 and is activated when phosphorylated at residues Ser 218 and Ser 222 .	MEK1/2 is an upstream activator of ERK1/2 and is activated when phosphorylated at residues Ser 218 and Ser 222.	0	9	is an upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	0	1	6	7
Notably , these tumors eventually resumed growth , and a fraction of them escaped PI3K dependence by compensatory ERK activation , which can be blocked by combined inhibition of Her2 and MEK .	Notably, these tumors eventually resumed growth, and a fraction of them escaped PI3K dependence by compensatory ERK activation, which can be blocked by combined inhibition of Her2 and MEK.	18	32	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	31	32	18	19
Although ERK 1/2 is activated by the separate MEK 1/2 pathway , these two MAP kinases share a number of structural and functional properties that suggest common activities .	Although ERK 1/2 is activated by the separate MEK 1/2 pathway, these two MAP kinases share a number of structural and functional properties that suggest common activities.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK 1/2	MEK 1/2	MEK 1/2	ERK 1/2	ERK 1/2	ERK 1/2	8	10	1	3
First , we investigated the role of MEK in PMA and s/s induced ERK activation .	First, we investigated the role of MEK in PMA and s/s induced ERK activation.	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	7	8	13	14
Finally , ERK activation by MEK CA over-expression in primary hepatocytes decreased glucose output whereas reduced ERK expression in primary hepatocytes increased glucose output ( XREF_FIG ) .	Finally, ERK activation by MEK CA over-expression in primary hepatocytes decreased glucose output whereas reduced ERK expression in primary hepatocytes increased glucose output (XREF_FIG).	2	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK CA over-expression	mek	ERK	ERK	erk	5	6	2	3
Western blot analysis demonstrated that cisplatin treatment induced time dependent activation of ERK , which was inhibited by chemical inhibitors of the MEK signaling pathway ( PD98059 and U0126 ) and N-acetylcysteine .	Western blot analysis demonstrated that cisplatin treatment induced time dependent activation of ERK, which was inhibited by chemical inhibitors of the MEK signaling pathway (PD98059 and U0126) and N-acetylcysteine.	10	24	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	22	23	12	13
Additionally , DARPP-32 appears to be required for an increase in phosphorylation of MEK , a dual specificity kinase which directly phosphorylates and thus activates ERK kinases .	Additionally, DARPP-32 appears to be required for an increase in phosphorylation of MEK, a dual specificity kinase which directly phosphorylates and thus activates ERK kinases.	11	26	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	phosphorylation of MEK	mek	ERK	ERK	erk	13	14	25	26
The MEK proteins then phosphorylate and activate the MAPK and ERK proteins : ERK1 and ERK2 .	The MEK proteins then phosphorylate and activate the MAPK and ERK proteins : ERK1 and ERK2.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	1	2	8	9
U0126 , a specific inhibitor of MEK ( the MAPK and ERK kinase ) , effectively blocked beta , beta-dimethylacrylshikonin-induced ERK activation and attenuated beta , beta-dimethylacrylshikonin-induced apoptosis , suggesting the pro apoptotic effects of beta , beta-dimethylacrylshikonin in SGC-7901 cells are mediated by the sustained activation of the ERK1/2 signaling pathway .	U0126, a specific inhibitor of MEK (the MAPK and ERK kinase), effectively blocked beta,beta-dimethylacrylshikonin-induced ERK activation and attenuated beta,beta-dimethylacrylshikonin-induced apoptosis, suggesting the pro apoptotic effects of beta,beta-dimethylacrylshikonin in SGC-7901 cells are mediated by the sustained activation of the ERK1/2 signaling pathway.	4	21	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	20	21
Furthermore , compound C also suppressed TGF-beta-stimulated phosphorylation of MEK1/2 , an upstream kinase that activates p44 and p42 MAPK ( XREF_FIG ) .	Furthermore, compound C also suppressed TGF-beta-stimulated phosphorylation of MEK1/2, an upstream kinase that activates p44 and p42 MAPK (XREF_FIG).	2	21	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK1/2	compound C also suppressed TGF-beta-stimulated phosphorylation of MEK1/2	mek1/2	MAPK	MAPK	mapk	9	10	19	20
Treatment of MiaPaCa-2 cells with U0126 , a preferential inhibitor of MEK , abrogated ERK over-activation induced by NPV-BEZ235 ( XREF_FIG ) .	Treatment of MiaPaCa-2 cells with U0126, a preferential inhibitor of MEK, abrogated ERK over-activation induced by NPV-BEZ235 (XREF_FIG).	9	15	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	11	12	14	15
The MAPK is activated by MEK , which is activated in turn by MEK kinase .	The MAPK is activated by MEK, which is activated in turn by MEK kinase.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	5	6	1	2
The ERK pathway represents the prototypical example of a mitogen activated protein kinase ( MAPK ) cascade where ERK ( a MAPK ) is activated by MEK , a MAPK kinase ( MAPKK ) , which in turn is activated by RAF , a MAPKK kinase ( MAPKKK ) .	The ERK pathway represents the prototypical example of a mitogen activated protein kinase (MAPK) cascade where ERK (a MAPK) is activated by MEK, a MAPK kinase (MAPKK), which in turn is activated by RAF, a MAPKK kinase (MAPKKK).	18	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	26	27	18	19
Given that MEK1/2 are exquisitely specific activators of ERK1/2 and their strategic position in the MAPK and ERK ( RAS-RAF-MEK-ERK ) pathway , they are thus considered as potentially drug targets in cancer .	Given that MEK1/2 are exquisitely specific activators of ERK1/2 and their strategic position in the MAPK and ERK (RAS-RAF-MEK-ERK) pathway, they are thus considered as potentially drug targets in cancer.	2	9	are exquisitely specific activators	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	2	3	8	9
Mek then phosphorylates and thus activates a protein kinase Erk [ XREF_BIBR ] which phosphorylates diverse cellular proteins and thereby controls their activity .	Mek then phosphorylates and thus activates a protein kinase Erk [XREF_BIBR] which phosphorylates diverse cellular proteins and thereby controls their activity.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	Erk	Erk	Erk	0	1	9	10
In certain studies , the KIAA1549 : BRAF fusion gene was also found to function through MEK dependent activation of both MAPK and mTOR pathways and the injection of neural stem cells containing the fusion were sufficient to induce glioma like lesions in mice .	In certain studies, the KIAA1549 : BRAF fusion gene was also found to function through MEK dependent activation of both MAPK and mTOR pathways and the injection of neural stem cells containing the fusion were sufficient to induce glioma like lesions in mice.	16	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	16	17	21	22
Inhibition of either cAMP dependent protein kinase ( PKA ) or MEK completely blocked ERK1/2 activation by glucagon .	Inhibition of either cAMP dependent protein kinase (PKA) or MEK completely blocked ERK1/2 activation by glucagon.	0	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	11	12	14	15
MEK and PI3K inhibitors block sEcad induced ERK and Akt and mTOR activation and oncogenic signaling .	MEK and PI3K inhibitors block sEcad induced ERK and Akt and mTOR activation and oncogenic signaling.	0	15	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	7	8
However , ERK1/2 activation was mediated by both MEK1/2 dependent and MEK1/2 independent PKCzeta regulated mechanisms in hypoxia exposed Fib-H .	However, ERK1/2 activation was mediated by both MEK1/2 dependent and MEK1/2 independent PKCzeta regulated mechanisms in hypoxia exposed Fib-H.	2	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	8	9	2	3
MAPKs are activated by specific MAPK kinases ( MAPKKs or MEKs ) ; specifically , MEK1/2 activates ERK1/2 , MEK3/6 activates p38 MAPK , and MEK4/7 activates JNK1/2 [ XREF_BIBR ] .	MAPKs are activated by specific MAPK kinases (MAPKKs or MEKs); specifically, MEK1/2 activates ERK1/2, MEK3/6 activates p38 MAPK, and MEK4/7 activates JNK1/2 [XREF_BIBR].	15	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	15	16	17	18
AZD6244 and ARRY-142886 , a novel , orally active , potent , selective , and ATP-uncompetitive MAP and ERK kinase ( MEK ) 1/2 inhibitor , targets the crucial MEK kinase in the RAS and ERK signaling pathway .	AZD6244/ARRY-142886, a novel, orally active, potent, selective, and ATP-uncompetitive MAP and ERK kinase (MEK) 1/2 inhibitor, targets the crucial MEK kinase in the RAS and ERK signaling pathway.	16	37	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	21	22	35	36
Less attention has been paid to a possible role of ERK in AD and our findings strongly support a role for calpain mediated ERK activation in the hyperphosphorylation of neurofilament proteins and tau seen in AD brain , which is known to be dependent on MEK 1/2 , the upstream regulator of ERK 1/2 .	Less attention has been paid to a possible role of ERK in AD and our findings strongly support a role for calpain mediated ERK activation in the hyperphosphorylation of neurofilament proteins and tau seen in AD brain, which is known to be dependent on MEK 1/2, the upstream regulator of ERK 1/2.	22	47	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK 1/2	MEK 1/2	MEK 1/2	ERK	ERK	ERK	45	47	23	24
Therefore , downstream MAPK inhibition , such as MEK inhibition , was recognized as a promising target option .	Therefore, downstream MAPK inhibition, such as MEK inhibition, was recognized as a promising target option.	3	9	inhibition	Negative_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	8	9	3	4
Although a definitive evidence of ERK activation by PKC or PKA in the dorsal horn is lacking , there is strong evidence supporting the view that PKC and PKA may directly ( MEK mediated ) or indirectly ( Raf mediated ) activate ERK .	Although a definitive evidence of ERK activation by PKC or PKA in the dorsal horn is lacking, there is strong evidence supporting the view that PKC and PKA may directly (MEK mediated) or indirectly (Raf mediated) activate ERK.	21	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	32	33	42	43
Firstly , MEK 1/2 inhibition targets the hyperactive MAPK .	Firstly, MEK 1/2 inhibition targets the hyperactive MAPK.	2	9	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK 1/2	MEK 1/2	MEK 1/2	MAPK	MAPK	MAPK	2	4	8	9
Raf1 has been widely reported as a key effector of the small G protein Ras , and after activation , Raf can phosphorylate MEK , which then activates ERK .	Raf1 has been widely reported as a key effector of the small G protein Ras, and after activation, Raf can phosphorylate MEK, which then activates ERK.	20	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	Raf can phosphorylate MEK	mek	ERK	ERK	erk	23	24	28	29
In this cascade , in an amino acid dependent manner , Raf-1 activates MEK1/2 ( MAPK and ERK kinase ) , which activates ERK1/2 ( extracellular signal regulated kinase 1 and ERK2 mitogen activated kinase ) .	In this cascade, in an amino acid dependent manner, Raf-1 activates MEK1/2 (MAPK and ERK kinase), which activates ERK1/2 (extracellular signal regulated kinase 1 and ERK2 mitogen activated kinase).	12	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	13	14	23	24
ATM dependent phosphorylation of p53 on Ser15 and activation of ERK1/2 by MEK dependent Thr202 and Tyr204 phosphorylation were relatively similar in both rho 0 and rho + HSF following alpha irradiation ( XREF_FIG ) .	ATM dependent phosphorylation of p53 on Ser15 and activation of ERK1/2 by MEK dependent Thr202 and Tyr204 phosphorylation were relatively similar in both rho 0 and rho + HSF following alpha irradiation (XREF_FIG).	6	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK	MEK dependent Thr202 and Tyr204 phosphorylation	mek	ERK1/2	ERK1/2	erk1/2	12	13	10	11
If initially ERK is in its off state , adding [ MEK ] causes a gradual increase in the ERK activity , and only after [ MEK ] increases over a threshold , ERK switches to its on state ( XREF_FIG , Going up ) .	If initially ERK is in its off state, adding [MEK] causes a gradual increase in the ERK activity, and only after [MEK] increases over a threshold, ERK switches to its on state (XREF_FIG, Going up).	11	20	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	11	12	19	20
Recently , we showed that blocking ERK signalling in male Lmna H222P and H222P mice , using a small molecule inhibitor of extracellular signal regulated kinase kinase ( MEK ) that activates ERK , induced normal LV diameters and cardiac ejection fraction ( EF ) at an age of 16 weeks , when placebo treated mice had significant abnormalities in these parameters [ XREF_BIBR ] .	Recently, we showed that blocking ERK signalling in male Lmna H222P and H222P mice, using a small molecule inhibitor of extracellular signal regulated kinase kinase (MEK) that activates ERK, induced normal LV diameters and cardiac ejection fraction (EF) at an age of 16 weeks, when placebo treated mice had significant abnormalities in these parameters [XREF_BIBR].	26	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	28	29	32	33
This is expected , as ERK is a downstream target of Ras and U0126 is a more selective inhibitor of ERK activation by MEK1/2 .	This is expected, as ERK is a downstream target of Ras and U0126 is a more selective inhibitor of ERK activation by MEK1/2.	20	24	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	23	24	20	21
Since MEK is the downstream effector of BRAF , MEK inhibition is an attractive strategy to block activation of the MAPK pathway and could also potentially block reactivation of the MAPK pathway in BRAF inhibitor resistant disease XREF_BIBR .	Since MEK is the downstream effector of BRAF, MEK inhibition is an attractive strategy to block activation of the MAPK pathway and could also potentially block reactivation of the MAPK pathway in BRAF inhibitor resistant disease XREF_BIBR.	9	31	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	9	10	30	31
To determine if ERK activation alone could facilitate BAFFR expression to levels similarly driven by caNRAS and could also promote the differentiation of BCR-low B cells , we conducted in vitro experiments with a constitutively active form of MEK ( caMEK ) , the kinase that directly activates ERK .	To determine if ERK activation alone could facilitate BAFFR expression to levels similarly driven by caNRAS and could also promote the differentiation of BCR-low B cells, we conducted in vitro experiments with a constitutively active form of MEK (caMEK), the kinase that directly activates ERK.	36	49	directly activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	38	39	48	49
Upon the activation of Ras ( a GTPase ) , Raf-1 acts as an MAPK kinase kinase and phosphorylates and activates MEK1/2 , which then activates ERK1/2 .	Upon the activation of Ras (a GTPase), Raf-1 acts as an MAPK kinase kinase and phosphorylates and activates MEK1/2, which then activates ERK1/2.	10	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	Raf-1 acts as an MAPK kinase kinase and phosphorylates and activates MEK1/2	mek1/2	ERK1/2	ERK1/2	erk1/2	21	22	26	27
As the kinase for Erk1/2 is MEK1/2 , we further investigated the role of MEK1/2 in hypoxia induced activation of MAPK 42/44 .	As the kinase for Erk1/2 is MEK1/2, we further investigated the role of MEK1/2 in hypoxia induced activation of MAPK 42/44.	12	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	14	15	20	21
In contrast , FGF2 stimulation or overexpression of constitutively active Ras , Raf , or MEK enhances the activity of the TGF-beta1-induced Ras -- ERK pathway .	In contrast, FGF2 stimulation or overexpression of constitutively active Ras, Raf, or MEK enhances the activity of the TGF-beta1-induced Ras -- ERK pathway.	4	25	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	15	16	24	25
6 The three Raf kinases can all activate MEK1/2 , which in turn activates ERK1/2 , resulting in the phosphorylation of target proteins , including fos in , the nucleus and the transcription factors activator protein 1 ( AP-1 ) and nuclear factor of activated T-cells ( NFAT ) , which eventually lead to cell proliferation , differentiation and survival .	6 The three Raf kinases can all activate MEK1/2, which in turn activates ERK1/2, resulting in the phosphorylation of target proteins, including fos in, the nucleus and the transcription factors activator protein 1 (AP-1) and nuclear factor of activated T-cells (NFAT), which eventually lead to cell proliferation, differentiation and survival.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	8	9	14	15
Consistent with this possibility , a preliminary report by White and colleagues has shown that electrical coupling mediated by Cx50 ( the mammalian ortholog of Cx45.6 ) between paired Xenopus oocytes is increased when ERK function is directly upregulated by coexpression of constitutively active MEK .	Consistent with this possibility, a preliminary report by White and colleagues has shown that electrical coupling mediated by Cx50 (the mammalian ortholog of Cx45.6) between paired Xenopus oocytes is increased when ERK function is directly upregulated by coexpression of constitutively active MEK.	34	45	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	coexpression of constitutively active MEK	mek	ERK	ERK	erk	44	45	34	35
Mek1/2 are direct substrates of Raf kinases and phosphorylated Mek1/2 activate downstream Erk1/2 .	Mek1/2 are direct substrates of Raf kinases and phosphorylated Mek1/2 activate downstream Erk1/2.	8	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mek1/2	phosphorylated Mek1/2	mek1/2	Erk1/2	Erk1/2	erk1/2	9	10	12	13
Formation of the Ras and RAF complex leads to activation of RAF and phosphorylation and activation of MEK that , in turn , activates MAPK isoforms ( also known as ERK ) , including MAPK3 and MAPK1 .	Formation of the Ras and RAF complex leads to activation of RAF and phosphorylation and activation of MEK that, in turn, activates MAPK isoforms (also known as ERK), including MAPK3 and MAPK1.	15	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	17	18	24	25
U0126 , a highly selective inhibitor of MEK1/2 had the same potency as SL327 ( another selective inhibitor of MEK1/2 ) , and completely inhibited ET-1-induced activation of ERK1/2 , whereas , PD98059 , a selective MEK1 inhibitor , only partially inhibited ET-1-induced activation of ERK1/2 .	U0126, a highly selective inhibitor of MEK1/2 had the same potency as SL327 (another selective inhibitor of MEK1/2), and completely inhibited ET-1-induced activation of ERK1/2, whereas, PD98059, a selective MEK1 inhibitor, only partially inhibited ET-1-induced activation of ERK1/2.	5	29	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	7	8	28	29
However , PD098059 mediated inhibition of MEK dependent stimulation of ERK did not alter the hypertrophic response of either agonist .	However, PD098059 mediated inhibition of MEK dependent stimulation of ERK did not alter the hypertrophic response of either agonist.	6	11	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	10	11
An inhibitor of the MAPK activator MEK , PD 098059 , effectively blocked ATP- and 2-chloroadenosine-induced DNA synthesis , thereby indicating that the ERK and MAPK cascade mediates mitogenic signaling by P2 and P1 purinergic receptors in human fetal astrocytes .	An inhibitor of the MAPK activator MEK, PD 098059, effectively blocked ATP- and 2-chloroadenosine-induced DNA synthesis, thereby indicating that the ERK and MAPK cascade mediates mitogenic signaling by P2 and P1 purinergic receptors in human fetal astrocytes.	1	7	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	6	7	4	5
Activated Raf phosphorylates and activates MEK1/2 , which then activates Erk .	Activated Raf phosphorylates and activates MEK1/2, which then activates Erk.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	Erk	Erk	Erk	5	6	10	11
MEK kinases further activate ERK1/2 via phosphorylation .	MEK kinases further activate ERK1/2 via phosphorylation.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	0	1	4	5
Activation of ERK1/2 by MEK1/2 phosphorylation leads to two fundamental changes XREF_BIBR , XREF_BIBR .	Activation of ERK1/2 by MEK1/2 phosphorylation leads to two fundamental changes XREF_BIBR, XREF_BIBR.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2 phosphorylation	mek1/2	ERK1/2	ERK1/2	erk1/2	4	5	2	3
MEK ( Scholl et al , 2005 ) is the same as MAPKs and can activate ERK .	MEK (Scholl et al, 2005) is the same as MAPKs and can activate ERK.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	16	17
ERK phosphorylation in MAPT mutant neurons was blocked by treatment with PD98059 , a specific inhibitor of MEK mediated activation of ERK ( XREF_FIG B and 4C ) .	ERK phosphorylation in MAPT mutant neurons was blocked by treatment with PD98059, a specific inhibitor of MEK mediated activation of ERK (XREF_FIG B and 4C).	17	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	17	18	21	22
MAPK signal amplification was also apparent in lung tissue lysates after PLX4720 treatment and was significantly diminished by Mek inhibition ( XREF_FIG ) .	MAPK signal amplification was also apparent in lung tissue lysates after PLX4720 treatment and was significantly diminished by Mek inhibition (XREF_FIG).	0	19	diminished	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Mek	Mek	Mek	MAPK	MAPK	MAPK	18	19	0	1
The ERK activation and apoptotic effects of chelerythrine were greatly abrogated by the pharmaceutical inhibitors of MEK , but not by those of c-Jun NH ( 2 ) kinase or p38 .	The ERK activation and apoptotic effects of chelerythrine were greatly abrogated by the pharmaceutical inhibitors of MEK, but not by those of c-Jun NH (2) kinase or p38.	1	17	abrogated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	16	17	1	2
In these breast cancer cells , ERK over-activation was completely prevented by inhibitors of MEK or HER2 , suggesting clear combinatorial strategies to circumvent resistance to PI3K and Akt inhibition .	In these breast cancer cells, ERK over-activation was completely prevented by inhibitors of MEK or HER2, suggesting clear combinatorial strategies to circumvent resistance to PI3K and Akt inhibition.	6	16	prevented	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	14	15	6	7
Ras activates raf , and raf phosphorylates and activates MEK , which in turn activates ERK1 and ERK2 .	Ras activates raf, and raf phosphorylates and activates MEK, which in turn activates ERK1 and ERK2.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	raf phosphorylates and activates MEK	mek	ERK2	ERK2	erk2	9	10	17	18
In the ERK signaling pathway , ERK1 or ERK2 ( ERK1/2 ) is activated by MEK1/2 , which in turn is activated by a Raf isoform such as A-Raf , B-Raf , or Raf-1 ( also known as C-Raf ) and also by TRAF-2 and TRAF-6 .	In the ERK signaling pathway, ERK1 or ERK2 (ERK1/2) is activated by MEK1/2, which in turn is activated by a Raf isoform such as A-Raf, B-Raf, or Raf-1 (also known as C-Raf) and also by TRAF-2 and TRAF-6.	6	41	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK2	ERK2	ERK2	15	16	8	9
Despite the intrinsic interest of MAP2Ks , as dual specificity kinases assuming a central role in MAP kinase modules , only one structural study has been reported , on the ERK2 activators MEK1/2 .	Despite the intrinsic interest of MAP2Ks, as dual specificity kinases assuming a central role in MAP kinase modules, only one structural study has been reported, on the ERK2 activators MEK1/2.	26	33	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK2	ERK2	ERK2	32	33	30	31
The fact that MEK is an activator of both Erk1 and Erk2 and is a bona fide proto-oncogene might imply that simultaneous activation of both Erk1 and Erk2 would give rise to a more efficient transformation .	The fact that MEK is an activator of both Erk1 and Erk2 and is a bona fide proto-oncogene might imply that simultaneous activation of both Erk1 and Erk2 would give rise to a more efficient transformation.	3	12	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk2	Erk2	Erk2	3	4	11	12
ERK1 and ERK2 are activated upon phosphorylation by MEK , which is itself activated when phosphorylated by Raf [ XREF_BIBR ] .	ERK1 and ERK2 are activated upon phosphorylation by MEK, which is itself activated when phosphorylated by Raf [XREF_BIBR].	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	8	9	2	3
We did not observe enhanced inhibition of Erk1 and Erk2 or AKT phosphorylation in mutant RAS expressing cells treated with the combination of MEK and IGF-1R inhibitors , as compared to either agent alone ( XREF_SUPPLEMENTARY ) .	We did not observe enhanced inhibition of Erk1 and Erk2 or AKT phosphorylation in mutant RAS expressing cells treated with the combination of MEK and IGF-1R inhibitors, as compared to either agent alone (XREF_SUPPLEMENTARY).	5	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk2	Erk2	Erk2	23	24	9	10
ERK2 is activated by the upstream kinases MEK1/2 , which phosphorylate both tyrosine 185 and threonine 183 .	ERK2 is activated by the upstream kinases MEK1/2, which phosphorylate both tyrosine 185 and threonine 183.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK2	ERK2	ERK2	7	8	0	1
Immature Xenopus oocytes can be induced into maturation by treatment with the hormone progesterone , which acts via the MAPK signaling cascade : binding of progesterone to its receptor leads to the accumulation of active Mos , which activates MEK , which in turn activates ERK2 ( also known as p42 MAPK ) .	Immature Xenopus oocytes can be induced into maturation by treatment with the hormone progesterone, which acts via the MAPK signaling cascade : binding of progesterone to its receptor leads to the accumulation of active Mos, which activates MEK, which in turn activates ERK2 (also known as p42 MAPK).	38	48	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	39	40	45	46
ERK1 and ERK2 account for most , if not all , effects mediated by MEK1/2 , and thus MEK1/2 and ERK1/2 are usually inseparable in addressing their physiological effects .	ERK1 and ERK2 account for most, if not all, effects mediated by MEK1/2, and thus MEK1/2 and ERK1/2 are usually inseparable in addressing their physiological effects.	0	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK2	ERK2	ERK2	14	15	2	3
MEK then activates p42mapk and ( at least in mammals ) p44mapk , members of the mitogen activated protein ( MAP ) kinase family .	MEK then activates p42mapk and (at least in mammals) p44mapk, members of the mitogen activated protein (MAP) kinase family.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	p42mapk	p42mapk	p42mapk	0	1	3	4
Active Ras binds to Raf , a serine and tyrosine protein kinase which phosphorylates and activates MEK ( mitogen activated protein kinase kinase ) , which in turn activates Erk-1 and Erk-2 through phosphorylation .	Active Ras binds to Raf, a serine and tyrosine protein kinase which phosphorylates and activates MEK (mitogen activated protein kinase kinase), which in turn activates Erk-1 and Erk-2 through phosphorylation.	4	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	Raf, a serine and tyrosine protein kinase which phosphorylates and activates MEK	mek	Erk-2	Erk-2	erk-2	16	17	31	32
MEK activates ERK1 and ERK2 isoforms resulting in cell proliferation .	MEK activates ERK1 and ERK2 isoforms resulting in cell proliferation.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	0	1	4	5
Since MEK phosphorylation activates ERK1 and ERK2 ( ERKs ) , ERK activity can be indirectly assayed by measuring MEK phosphorylation of ERKs using phospho specific antibodies .	Since MEK phosphorylation activates ERK1 and ERK2 (ERKs), ERK activity can be indirectly assayed by measuring MEK phosphorylation of ERKs using phospho specific antibodies.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK phosphorylation	mek	ERK2	ERK2	erk2	1	2	6	7
Since MAP kinase kinase ( MEK ) proteins phosphorylate and activate MAPK1 , we postulated that small molecular weight inhibitors of MEK1/2 might be able to sensitize pancreatic cancer cells to the treatment of erlotinib .	Since MAP kinase kinase (MEK) proteins phosphorylate and activate MAPK1, we postulated that small molecular weight inhibitors of MEK1/2 might be able to sensitize pancreatic cancer cells to the treatment of erlotinib.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK1	MAPK1	MAPK1	5	6	11	12
RAF1 subsequently phosphorylates the MAPKKs , MEK1/2 , which in turn activate the MAP kinases ERK1 and ERK2 ( v1.71 ) .	RAF1 subsequently phosphorylates the MAPKKs, MEK1/2, which in turn activate the MAP kinases ERK1 and ERK2 (v1.71).	4	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK2	ERK2	ERK2	6	7	17	18
In the present study , in order to investigate the involvement of MAPKs in memory reconsolidation processes we administered immediately after retrieval , different doses of SL327 ( an inhibitor of MEK , a kinase that activates both ERK1 and ERK2 ) both in C57BL/6 ( C57 ) mice and ERK1 mutant mice tested in a fear conditioning task .	In the present study, in order to investigate the involvement of MAPKs in memory reconsolidation processes we administered immediately after retrieval, different doses of SL327 (an inhibitor of MEK, a kinase that activates both ERK1 and ERK2) both in C57BL/6 (C57) mice and ERK1 mutant mice tested in a fear conditioning task.	29	41	activates	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	31	32	40	41
ERK1 and ERK2 are activated by MEK1/2 via sequential phosphorylation of Tyr and Thr residues on the activation loop , which induces activation conformational changes .	ERK1 and ERK2 are activated by MEK1/2 via sequential phosphorylation of Tyr and Thr residues on the activation loop, which induces activation conformational changes.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK2	ERK2	ERK2	6	7	2	3
As the last downstream kinases in the Ras-Raf-MEK-ERK1/2 MAP kinase cascade , ERK1 and ERK2 are directly activated by MEK XREF_BIBR .	As the last downstream kinases in the Ras-Raf-MEK-ERK1/2 MAP kinase cascade, ERK1 and ERK2 are directly activated by MEK XREF_BIBR.	12	20	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	19	20	14	15
Although MEK inhibition prevented S-1-P activation of ERK1 and ERK2 and slightly but significantly inhibited basal Caco-2 proliferation , MEK inhibition did not block the S-1-P mitogenic effect .	Although MEK inhibition prevented S-1-P activation of ERK1 and ERK2 and slightly but significantly inhibited basal Caco-2 proliferation, MEK inhibition did not block the S-1-P mitogenic effect.	1	10	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	1	2	9	10
Upon its subsequent phosphorylation , Raf-1 then activates ( phosphorylates ) MAP / ERK kinase 1 and 2 ( MEK1/2 ) , which , in turn , activate ( phosphorylate ) ERK1 and ERK2 ( p44 MAPK and p42 MAPK , respectively ) .	Upon its subsequent phosphorylation, Raf-1 then activates (phosphorylates) MAP / ERK kinase 1 and 2 (MEK1/2), which, in turn, activate (phosphorylate) ERK1 and ERK2 (p44 MAPK and p42 MAPK, respectively).	11	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK2	ERK2	ERK2	19	20	33	34
In other experiments , p42MAPK activation by MEK or by Mos inhibited Cdc2 activation by cyclin B. PD098059 , a specific inhibitor of MEK , blocked the effects of MEK ( QP ) and Mos .	In other experiments, p42MAPK activation by MEK or by Mos inhibited Cdc2 activation by cyclin B. PD098059, a specific inhibitor of MEK, blocked the effects of MEK (QP) and Mos.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	p42MAPK	p42MAPK	p42MAPK	7	8	4	5
Collectively these observations indicate that MEK activates indistinctively ERK1 and ERK2 and that both compete each other for the upstream activating kinase .	Collectively these observations indicate that MEK activates indistinctively ERK1 and ERK2 and that both compete each other for the upstream activating kinase.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	5	6	10	11
Ras then activates the MAP kinase kinase Raf , which in turn activates the MAP kinase MEK , which then activates the MAP kinases Erk1 and Erk2 .	Ras then activates the MAP kinase kinase Raf, which in turn activates the MAP kinase MEK, which then activates the MAP kinases Erk1 and Erk2.	12	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	Erk2	Erk2	Erk2	16	17	26	27
Genetic deletion of the secreted ligand Fgf4 or the MEK target ERK2 mimics MEK inhibition and impedes ESC differentiation along multiple lineages [ XREF_BIBR , XREF_BIBR ] .	Genetic deletion of the secreted ligand Fgf4 or the MEK target ERK2 mimics MEK inhibition and impedes ESC differentiation along multiple lineages [XREF_BIBR, XREF_BIBR].	1	12	target	Positive_activation_token_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	9	10	11	12
Once RAF proteins are activated and phosphorylated by different protein kinases , they phosphorylate MEK , which in turn activates ERK-1 and ERK-2 [ XREF_BIBR ] .	Once RAF proteins are activated and phosphorylated by different protein kinases, they phosphorylate MEK, which in turn activates ERK-1 and ERK-2 [XREF_BIBR].	13	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	phosphorylate MEK	mek	ERK-2	ERK-2	erk-2	14	15	22	23
Pharmacologic inhibition of MEK1/2 abolished activation of ERK2 , but reduced cell proliferation by only 32 % , showing that MEK and ERK participates in the signaling involved in RPE cell growth .	Pharmacologic inhibition of MEK1/2 abolished activation of ERK2, but reduced cell proliferation by only 32%, showing that MEK and ERK participates in the signaling involved in RPE cell growth.	1	8	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK2	ERK2	ERK2	3	4	7	8
Early responses to RA include the MEK dependent activation of ERK2 within 4 hours of RA treatment .	Early responses to RA include the MEK dependent activation of ERK2 within 4 hours of RA treatment.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	6	7	10	11
Upon activation , Ras recruits Raf-1 , a serine/threonine kinase , to phosphorylate MEK ( MAPK and Erk kinase ) , which in turn activates Erk1 and Erk2 .	Upon activation, Ras recruits Raf-1, a serine/threonine kinase, to phosphorylate MEK (MAPK and Erk kinase), which in turn activates Erk1 and Erk2.	3	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	Ras recruits Raf-1, a serine/threonine kinase, to phosphorylate MEK	mek	Erk2	Erk2	erk2	13	14	27	28
This results in the activation of Ras and the sequential phosphorylation and the activation of Raf , MEK , finally activates ERK1 and ERK2 [ XREF_BIBR - XREF_BIBR ] .	This results in the activation of Ras and the sequential phosphorylation and the activation of Raf, MEK, finally activates ERK1 and ERK2 [XREF_BIBR - XREF_BIBR].	13	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	17	18	23	24
These data suggest that beta-arrestins function both as scaffolds to enhance cRaf-1 and MEK dependent activation of ERK2 , and as targeting proteins that direct activated ERK to specific subcellular locations .	These data suggest that beta-arrestins function both as scaffolds to enhance cRaf-1 and MEK dependent activation of ERK2, and as targeting proteins that direct activated ERK to specific subcellular locations.	11	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	13	14	17	18
In addition , in another recent paper in ERK1 KO mice , it has been shown that systemic MEK inhibition with SL327 attenuated pain induced spontaneous behaviors similarly in wild-type and ERK1 KO mice , indicating that unrelated signaling pathways do not functionally compensate for the loss of ERK1 .	In addition, in another recent paper in ERK1 KO mice, it has been shown that systemic MEK inhibition with SL327 attenuated pain induced spontaneous behaviors similarly in wild-type and ERK1 KO mice, indicating that unrelated signaling pathways do not functionally compensate for the loss of ERK1.	18	33	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1	ERK1	ERK1	18	19	31	32
First , p38MAPK is known as the target of stress activated MAP2K ( MAP2K3 , MAP2K4 and MAP2K6 in particular ) , whereas MEK targets MAPK3 ( among which ERK ) involved in growth .	First, p38MAPK is known as the target of stress activated MAP2K (MAP2K3, MAP2K4 and MAP2K6 in particular), whereas MEK targets MAPK3 (among which ERK) involved in growth.	23	31	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK3	MAPK3	MAPK3	23	24	25	26
This is a system of protein kinases where a member of RAF ( A-RAF , B-RAF , and C-RAF ) kinase phosphorylates and activates the MEK kinases ( MEK1 and 2 ) which phosphorylates to further activate ERK1 and 2 , which in turn phosphorylate to activate a number of substrates that are key components in cell cycle regulation .	This is a system of protein kinases where a member of RAF (A-RAF, B-RAF, and C-RAF) kinase phosphorylates and activates the MEK kinases (MEK1 and 2) which phosphorylates to further activate ERK1 and 2, which in turn phosphorylate to activate a number of substrates that are key components in cell cycle regulation.	11	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	RAF (A-RAF, B-RAF, and C-RAF) kinase phosphorylates and activates the MEK	mek	ERK1	ERK1	erk1	25	26	37	38
To understand whether MEK targets ERK1 and ERK2 both contribute to Noxa regulation , we silenced each of them in D13/+ HME cells and found that only ERK2 down-regulation reduced Noxa levels , while ERK1 silencing marginally increased accumulation of Noxa .	To understand whether MEK targets ERK1 and ERK2 both contribute to Noxa regulation, we silenced each of them in D13/+ HME cells and found that only ERK2 down-regulation reduced Noxa levels, while ERK1 silencing marginally increased accumulation of Noxa.	3	7	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1	ERK1	ERK1	3	4	5	6
Additionally , systemic MEK inhibition with SL327 attenuated formalin induced spontaneous behaviors similarly in WT and ERK1 KO mice , indicating that unrelated signaling pathways do not functionally compensate for the loss of ERK1 .	Additionally, systemic MEK inhibition with SL327 attenuated formalin induced spontaneous behaviors similarly in WT and ERK1 KO mice, indicating that unrelated signaling pathways do not functionally compensate for the loss of ERK1.	3	18	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1	ERK1	ERK1	3	4	16	17
MEK is a specific activator of ERK1 and 2 , which function as essential regulators of cell growth and differentiation in eukaryotic cells ( Nishida and Gotoh 1993 ) .	MEK is a specific activator of ERK1 and 2, which function as essential regulators of cell growth and differentiation in eukaryotic cells (Nishida and Gotoh 1993).	0	7	is a specific activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1	ERK1	ERK1	0	1	6	7
MEK inhibition attenuates formalin induced spontaneous behaviors similarly in WT and ERK1 KO littermates .	MEK inhibition attenuates formalin induced spontaneous behaviors similarly in WT and ERK1 KO littermates.	0	13	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1	ERK1	ERK1	0	1	11	12
Intriguingly , a recent report showed that Mff stimulates the GTPase activity of DLP1 in vitro , suggesting that the self-assembly of DLP1 is facilitated by Mff .	Intriguingly, a recent report showed that Mff stimulates the GTPase activity of DLP1 in vitro, suggesting that the self-assembly of DLP1 is facilitated by Mff.	7	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	DLP1	DLP1	DLP1	7	8	13	14
However , the ability of Mff to bind Drp1 is markedly impaired , thereby reducing Mff mediated Drp1 accumulation on mitochondria in the absence of MIEFs .	However, the ability of Mff to bind Drp1 is markedly impaired, thereby reducing Mff mediated Drp1 accumulation on mitochondria in the absence of MIEFs.	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	15	16	17	18
XREF_FIG , Mff overexpression induced Drp1 accumulation on mitochondria was significantly reduced in MIEF1/2 DKO cells .	XREF_FIG, Mff overexpression induced Drp1 accumulation on mitochondria was significantly reduced in MIEF1/2 DKO cells.	2	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff overexpression	mff	Drp1	Drp1	drp1	2	3	5	6
Mff suppression or actin polymerization inhibition eliminates all detectable Drp1 oligomers , including the ER bound population .	Mff suppression or actin polymerization inhibition eliminates all detectable Drp1 oligomers, including the ER bound population.	0	10	eliminates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	0	1	9	10
XREF_BIBR Mitochondrial fission factor ( MFF ) promoted this fission process by interacting with dynamin related protein 1 ( Drp1 ) in mammalian cells , XREF_BIBR and we found different expression of MFF in CG6 .	XREF_BIBR Mitochondrial fission factor (MFF) promoted this fission process by interacting with dynamin related protein 1 (Drp1) in mammalian cells, XREF_BIBR and we found different expression of MFF in CG6.	1	23	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mitochondrial fission factor	Mitochondrial fission factor	Mitochondrial fission factor	Drp1	Drp1	Drp1	1	4	19	20
Recent studies have demonstrated that , in addition to FIS1 , mitochondrial fission factor ( Mff ) , mitochondrial dynamics proteins of 49 and 51 kDa ( MiD49 and MiD51 , respectively ) have been proposed to promote mitochondrial fission by recruiting the Drp1 [ XREF_BIBR ] .	Recent studies have demonstrated that, in addition to FIS1, mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51, respectively) have been proposed to promote mitochondrial fission by recruiting the Drp1 [XREF_BIBR].	13	45	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	15	16	43	44
Interestingly , exogenous expression of Mff alone led to a significant accumulation of Drp1 on mitochondria in the presence of endogenous MIEF1/2 , while simultaneous knockdown of endogenous MIEF1/2 by siRNA greatly reduced Mff mediated Drp1 accumulation on mitochondria .	Interestingly, exogenous expression of Mff alone led to a significant accumulation of Drp1 on mitochondria in the presence of endogenous MIEF1/2, while simultaneous knockdown of endogenous MIEF1/2 by siRNA greatly reduced Mff mediated Drp1 accumulation on mitochondria.	33	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	33	34	35	36
Although Mff stimulation of the intrinsically cooperative Drp1-short isoform is relatively modest , CL independent , and even counter-productive at high CL concentrations , Mff stimulation of the much less cooperative longest Drp1 isoform ( Drp1-long ) is robust and occurs synergistically with increasing CL content .	Although Mff stimulation of the intrinsically cooperative Drp1-short isoform is relatively modest, CL independent, and even counter-productive at high CL concentrations, Mff stimulation of the much less cooperative longest Drp1 isoform (Drp1-long) is robust and occurs synergistically with increasing CL content.	24	33	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	24	25	32	33
These beautiful biochemical data suggest that Mff and actin filaments together drive the oligomeric maturation of Drp1 .	These beautiful biochemical data suggest that Mff and actin filaments together drive the oligomeric maturation of Drp1.	6	17	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	6	7	16	17
However , the combination of Mff and actin filaments causes a substantial increase in Drp1 activity , far beyond the additive effects of either Mff or actin alone ( XREF_FIG ) .	However, the combination of Mff and actin filaments causes a substantial increase in Drp1 activity, far beyond the additive effects of either Mff or actin alone (XREF_FIG).	5	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	5	6	14	15
First , both siRNA based knockdown and CRISPR and Cas9 based knockout revealed that absence of MIEF1/2 diminishes Mff-Drp1 binding and Mff induced Drp1 accumulation on mitochondria .	First, both siRNA based knockdown and CRISPR and Cas9 based knockout revealed that absence of MIEF1/2 diminishes Mff-Drp1 binding and Mff induced Drp1 accumulation on mitochondria.	19	24	induced	Positive_early_activation	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	21	22	23	24
Evidence shows that phosphorylation of MFF by AMPK may increase the association of Drp1 with mitochondria to induce mitochondrial fission 9 .	Evidence shows that phosphorylation of MFF by AMPK may increase the association of Drp1 with mitochondria to induce mitochondrial fission 9.	3	14	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MFF	phosphorylation of MFF	mff	Drp1	Drp1	drp1	5	6	13	14
Depletion of hFis1 or Mfn2 alone did not produce a significant relocalization of Drp1 to mitochondria , whereas silencing of Mff reduced mitochondrial localization of Drp1 ( XREF_FIG ; XREF_SUPPLEMENTARY ) , in line with a recent report .	Depletion of hFis1 or Mfn2 alone did not produce a significant relocalization of Drp1 to mitochondria, whereas silencing of Mff reduced mitochondrial localization of Drp1 (XREF_FIG; XREF_SUPPLEMENTARY), in line with a recent report.	18	27	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	20	21	25	26
Furthermore , we found that MiD51 can suppress Mff dependent enhancement of Drp1 GTPase activity .	Furthermore, we found that MiD51 can suppress Mff dependent enhancement of Drp1 GTPase activity.	8	14	enhancement	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	8	9	12	13
MFF mediates mitochondrial fission by recruiting DRP1 , and MFF downregulation is responsible for mitochondrial elongation .	MFF mediates mitochondrial fission by recruiting DRP1, and MFF downregulation is responsible for mitochondrial elongation.	0	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MFF	MFF	MFF	DRP1	DRP1	DRP1	0	1	6	7
Finally , Mff would stimulate the GTPase activity of the assembled Drp1 oligomer to promote fission .	Finally, Mff would stimulate the GTPase activity of the assembled Drp1 oligomer to promote fission.	2	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	2	3	11	12
Collectively , these results further support an important role for MIEFs in regulating Mff mediated Drp1 recruitment to and Mff induced Drp1 accumulation on mitochondria .	Collectively, these results further support an important role for MIEFs in regulating Mff mediated Drp1 recruitment to and Mff induced Drp1 accumulation on mitochondria.	13	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	13	14	15	16
Mitochondrial fission factor ( Mff ) , a tail anchored membrane protein of the mitochondrial outer membrane that recruits Drp1 to sites of ensuing fission , differentially stimulates the disparate Drp1 isoforms and alleviates the autoinhibitory effect imposed by these sequences on Drp1 function .	Mitochondrial fission factor (Mff), a tail anchored membrane protein of the mitochondrial outer membrane that recruits Drp1 to sites of ensuing fission, differentially stimulates the disparate Drp1 isoforms and alleviates the autoinhibitory effect imposed by these sequences on Drp1 function.	2	31	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	4	5	30	31
Whereas Mff overexpression enhanced Drp1 localization to mitochondria and resulted in mitochondrial fragmentation , mtHsp40 L overexpression caused mitochondrial fragmentation without enhanced Drp1 translocation to mitochondria ( XREF_FIG ) .	Whereas Mff overexpression enhanced Drp1 localization to mitochondria and resulted in mitochondrial fragmentation, mtHsp40 L overexpression caused mitochondrial fragmentation without enhanced Drp1 translocation to mitochondria (XREF_FIG).	1	5	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff overexpression	mff	Drp1	Drp1	drp1	1	2	4	5
Furthermore , MIEFs regulate the association of Drp1 with Mff as well as Mff induced Drp1 accumulation on mitochondria .	Furthermore, MIEFs regulate the association of Drp1 with Mff as well as Mff induced Drp1 accumulation on mitochondria.	5	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	13	14	15	16
Thus , MIEFs can regulate the interaction between Drp1 and Mff , and also Mff induced Drp1 accumulation on mitochondria .	Thus, MIEFs can regulate the interaction between Drp1 and Mff, and also Mff induced Drp1 accumulation on mitochondria.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	14	15	16	17
As expected , exogenous expression of Mff in Mff-null cells rescued mitochondrial morphology and restored mitochondrial Drp1 puncta ( Supplemental Figure S2 , B and D ) .	As expected, exogenous expression of Mff in Mff-null cells rescued mitochondrial morphology and restored mitochondrial Drp1 puncta (Supplemental Figure S2, B and D).	4	17	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	expression of Mff	mff	Drp1	Drp1	drp1	6	7	16	17
Overexpression of Mff stimulates mitochondrial recruitment of Drp1 and mitochondrial fragmentation and silencing of Mff results in mitochondrial elongation [ XREF_BIBR , XREF_BIBR ] .	Overexpression of Mff stimulates mitochondrial recruitment of Drp1 and mitochondrial fragmentation and silencing of Mff results in mitochondrial elongation [XREF_BIBR, XREF_BIBR].	0	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Overexpression of Mff	mff	Drp1	Drp1	drp1	2	3	7	8
Independently to Fis1 , mitochondrial fission factor ( Mff ) knockdown released the Drp1 foci from the mitochondrial outer membrane accompanied by mitochondrial elongation , whereas Mff overexpression stimulated mitochondrial recruitment of Drp1 accompanied by mitochondrial fission .	Independently to Fis1, mitochondrial fission factor (Mff) knockdown released the Drp1 foci from the mitochondrial outer membrane accompanied by mitochondrial elongation, whereas Mff overexpression stimulated mitochondrial recruitment of Drp1 accompanied by mitochondrial fission.	26	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff overexpression	mff	Drp1	Drp1	drp1	26	27	32	33
Previous studies have shown interactions with Mff stimulate Drp1 GTPase activity XREF_BIBR , XREF_BIBR , while interactions with MiD51 have been shown to reduce Drp1 GTPase activity 50 .	Previous studies have shown interactions with Mff stimulate Drp1 GTPase activity XREF_BIBR, XREF_BIBR, while interactions with MiD51 have been shown to reduce Drp1 GTPase activity 50.	3	9	stimulate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	6	7	8	9
MFF then acts to promote Drp 1 mediated fission events .	MFF then acts to promote Drp 1 mediated fission events.	0	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MFF	MFF	MFF	Drp 1	Drp 1	Drp 1	0	1	5	7
However , in the presence of a vast molar excess of the isolated Drp1 VD in the reaction mixture , the Mff stimulation of Drp1 GTPase activity was significantly diminished ( ~ 25 % ) .	However, in the presence of a vast molar excess of the isolated Drp1 VD in the reaction mixture, the Mff stimulation of Drp1 GTPase activity was significantly diminished (~ 25%).	21	26	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	21	22	24	25
Furthermore , knockdown of Mff decreased mitochondrial localization of DLP1 , and targeting Mff to the plasma membrane redistributed DLP1 to the new location , strongly suggesting that Mff recruits DLP1 [ XREF_BIBR ] .	Furthermore, knockdown of Mff decreased mitochondrial localization of DLP1, and targeting Mff to the plasma membrane redistributed DLP1 to the new location, strongly suggesting that Mff recruits DLP1 [XREF_BIBR].	2	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	DLP1	DLP1	DLP1	4	5	9	10
Regardless , the fold-increase in Mff stimulation of Drp1 GTPase activity over the corresponding basal GTPase activity was quantitatively similar between Drp1 WT and Drp1 R247A .	Regardless, the fold-increase in Mff stimulation of Drp1 GTPase activity over the corresponding basal GTPase activity was quantitatively similar between Drp1 WT and Drp1 R247A.	5	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	5	6	8	9
Mff alone causes only a slight increase in Drp1 GTPase activity at the concentrations tested .	Mff alone causes only a slight increase in Drp1 GTPase activity at the concentrations tested.	0	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	0	1	8	9
Recently , activated AMPK was reported to phosphorylate mitochondria fission factor ( MFF ) , which increases Drp1 localization to the mitochondria and promotes mitochondrial fission .	Recently, activated AMPK was reported to phosphorylate mitochondria fission factor (MFF), which increases Drp1 localization to the mitochondria and promotes mitochondrial fission.	10	18	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MFF	MFF	MFF	Drp1	Drp1	Drp1	12	13	17	18
MIEFs regulate Mff mediated recruitment of Drp1 from the cytoplasm to mitochondria and affect Mff induced Drp1 accumulation on mitochondria .	MIEFs regulate Mff mediated recruitment of Drp1 from the cytoplasm to mitochondria and affect Mff induced Drp1 accumulation on mitochondria.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	14	15	16	17
Thus , Mff stimulates Drp1 cooperative GTPase activity via the nucleation of higher-order Drp1 self-assembly XREF_BIBR , XREF_BIBR .	Thus, Mff stimulates Drp1 cooperative GTPase activity via the nucleation of higher-order Drp1 self-assembly XREF_BIBR, XREF_BIBR.	2	5	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	2	3	4	5
In line with this , depletion of MIEF1/2 by siRNA treatment or by CRISPR and Cas9 based knockout impaired the physical association of Mff with Drp1 , resulting in a decrease of Mff induced Drp1 accumulation on mitochondria .	In line with this, depletion of MIEF1/2 by siRNA treatment or by CRISPR and Cas9 based knockout impaired the physical association of Mff with Drp1, resulting in a decrease of Mff induced Drp1 accumulation on mitochondria.	30	35	induced	Positive_early_activation	Positive_activation	Negative_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	32	33	34	35
In line with this , in the presence of endogenous MIEFs , elevated levels of Mff induced a significant accumulation of Drp1 on mitochondria , whereas absence of endogenous MIEFs greatly reduced Mff overexpression induced accumulation of Drp1 on mitochondria .	In line with this, in the presence of endogenous MIEFs, elevated levels of Mff induced a significant accumulation of Drp1 on mitochondria, whereas absence of endogenous MIEFs greatly reduced Mff overexpression induced accumulation of Drp1 on mitochondria.	32	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff overexpression	mff	Drp1	Drp1	drp1	32	33	37	38
Indeed , illustrating the functional hierarchy by which Mff and MiD49 contribute to Drp1 mediated mitochondrial fission and also supporting our current model , abnormal accumulation of MiD49 in Mff -/- / MARCH5 -/- cells compensated for and overcame the loss of Mff , leading to fragmented mitochondrial morphology .	Indeed, illustrating the functional hierarchy by which Mff and MiD49 contribute to Drp1 mediated mitochondrial fission and also supporting our current model, abnormal accumulation of MiD49 in Mff -/- / MARCH5 -/- cells compensated for and overcame the loss of Mff, leading to fragmented mitochondrial morphology.	8	14	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	8	9	13	14
Additionally , Mff also appears to increase the Drp1 GTPase activity and may thereby promote Drp1 spiral compaction and consequently the severing of mitochondria [ XREF_BIBR , XREF_BIBR ] .	Additionally, Mff also appears to increase the Drp1 GTPase activity and may thereby promote Drp1 spiral compaction and consequently the severing of mitochondria [XREF_BIBR, XREF_BIBR].	2	14	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	2	3	8	9
We found that c-Met activates FAK and Pyk2 and that FAK and Pyk2 mediate the effects of c-Met on medulloblastoma cell migration , invasion and proliferation .	We found that c-Met activates FAK and Pyk2 and that FAK and Pyk2 mediate the effects of c-Met on medulloblastoma cell migration, invasion and proliferation.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	3	4	5	6
Based on the above results showing that c-Met activates FAK and Pyk2 and that FAK and Pyk2 mediate the effects of c-Met in medulloblastoma cells , we hypothesized that combined inhibition of c-Met and FAK could have greater inhibitory effects on medulloblatoma malignancy than single inhibitions .	Based on the above results showing that c-Met activates FAK and Pyk2 and that FAK and Pyk2 mediate the effects of c-Met in medulloblastoma cells, we hypothesized that combined inhibition of c-Met and FAK could have greater inhibitory effects on medulloblatoma malignancy than single inhibitions.	7	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	7	8	9	10
Overall , the above data show that c-Met activates FAK and Pyk2 in a time dependent manner .	Overall, the above data show that c-Met activates FAK and Pyk2 in a time dependent manner.	7	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	7	8	9	10
Evidence indicate that the two signaling pathways , integrin and ECM and HGF and c-MET , cooperate synergistically to induce FAK activation in an adhesion dependent manner , leading to enhanced cell adhesion and motility of tumor cells .	Evidence indicate that the two signaling pathways, integrin and ECM and HGF and c-MET, cooperate synergistically to induce FAK activation in an adhesion dependent manner, leading to enhanced cell adhesion and motility of tumor cells.	8	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-MET	c-MET	c-MET	FAK	FAK	FAK	14	15	20	21
These data shows that there is a crosstalk between integrin beta1 and c-MET signaling pathways , and it reaches consensus with Beviglia ' s results that the two signaling pathways , integrin and ECM and c-MET and HGF , cooperate synergistically to induce FAK activation in an adhesion dependent manner , leading to enhanced cell adhesion and motility [ XREF_BIBR ] .	These data shows that there is a crosstalk between integrin beta1 and c-MET signaling pathways, and it reaches consensus with Beviglia 's results that the two signaling pathways, integrin and ECM and c-MET and HGF, cooperate synergistically to induce FAK activation in an adhesion dependent manner, leading to enhanced cell adhesion and motility [XREF_BIBR].	29	44	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-MET	c-MET	c-MET	FAK	FAK	FAK	35	36	43	44
Our results provide evidence that the 2 signaling pathways , integrin and ECM and c-Met and HGF , cooperate synergistically to induce FAK activation in an adhesion dependent manner , leading to enhanced cell adhesion and motility .	Our results provide evidence that the 2 signaling pathways, integrin and ECM and c-Met and HGF, cooperate synergistically to induce FAK activation in an adhesion dependent manner, leading to enhanced cell adhesion and motility.	8	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	14	15	22	23
XREF_BIBR , XREF_BIBR Recently , investigators have demonstrated that alpha5beta1 integrin binds to activate c-Met , which initiates Src and FAK signaling and promotes migration in ovarian cancer cells .	XREF_BIBR, XREF_BIBR Recently, investigators have demonstrated that alpha5beta1 integrin binds to activate c-Met, which initiates Src and FAK signaling and promotes migration in ovarian cancer cells.	13	23	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	14	15	20	21
To confirm that c-Met activates FAK and/or Pyk2 as observed on the protein arrays , the effect of HGF on FAK and Pyk2 phosphorylations in medulloblastoma cells was assessed by immunoblotting .	To confirm that c-Met activates FAK and/or Pyk2 as observed on the protein arrays, the effect of HGF on FAK and Pyk2 phosphorylations in medulloblastoma cells was assessed by immunoblotting.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	3	4	5	6
c-Met activates FAK and Pyk2 in medulloblastoma cells in a time dependent manner .	c-Met activates FAK and Pyk2 in medulloblastoma cells in a time dependent manner.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	0	1	2	3
Our study shows for the first time that c-Met activates FAK and Pyk2 and that FAK and Pyk2 mediate the effects of c-Met in medulloblastoma .	Our study shows for the first time that c-Met activates FAK and Pyk2 and that FAK and Pyk2 mediate the effects of c-Met in medulloblastoma.	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	8	9	10	11
Constitutive signaling of c-Met stimulates pp125 FAK and Rho activation , leading to tumor progression .	Constitutive signaling of c-Met stimulates pp125 FAK and Rho activation, leading to tumor progression.	1	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	3	4	6	7
c-Met activates FAK and Pyk2 as revealed by protein arrays .	c-Met activates FAK and Pyk2 as revealed by protein arrays.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	0	1	2	3
To determine if c-Met directly associated with and activated FAK and Src , lysates from alpha 5 beta 1 -integrin antibody or IgG , treated HeyA8 cells were immunoprecipitated with anti c-Met antibody .	To determine if c-Met directly associated with and activated FAK and Src, lysates from alpha 5 beta 1 -integrin antibody or IgG, treated HeyA8 cells were immunoprecipitated with anti c-Met antibody.	3	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	3	4	9	10
We found that c-Met activates FAK and Pyk2 in several medulloblastoma cell lines .	We found that c-Met activates FAK and Pyk2 in several medulloblastoma cell lines.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	3	4	5	6
Our study shows for the first time that HGF and c-Met activates FAK and Pyk2 in medulloblastoma .	Our study shows for the first time that HGF and c-Met activates FAK and Pyk2 in medulloblastoma.	8	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	FAK	FAK	FAK	10	11	12	13
The discovery of MXD1 and MXD2 added a new level of complexity to the earlier model by showing that MAX acts to mediate the activity of both MYC and MXD proteins which appeared to antagonize each other .	The discovery of MXD1 and MXD2 added a new level of complexity to the earlier model by showing that MAX acts to mediate the activity of both MYC and MXD proteins which appeared to antagonize each other.	19	30	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAX	MAX	MAX	MYC	MYC	MYC	19	20	27	28
Furthermore , Max associated with the 7SL RNA locus in a WSTF dependent manner and the same pattern was observed in WSTF KD cells overexpressing c-Myc .	Furthermore, Max associated with the 7SL RNA locus in a WSTF dependent manner and the same pattern was observed in WSTF KD cells overexpressing c-Myc.	2	26	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max	Max	c-Myc	c-Myc	c-Myc	2	3	25	26
The results indicated that Max siRNA treatment reduces Myc repression of C/EBPdelta promoter activity and this reduction in Myc repression is comparable to Miz1 siRNA treatment .	The results indicated that Max siRNA treatment reduces Myc repression of C/EBPdelta promoter activity and this reduction in Myc repression is comparable to Miz1 siRNA treatment.	4	9	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max	Max	Myc	Myc	Myc	4	5	8	9
Myc and Max dimers activate gene transcription , while Mad and Max and Mnt and Max complexes are Myc and Max antagonists and act as repressors .	Myc and Max dimers activate gene transcription, while Mad and Max and Mnt and Max complexes are Myc and Max antagonists and act as repressors.	0	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max	Max	Myc	Myc	Myc	2	3	18	19
As Max protein mediates the transcriptional effects of c-Myc our results are compatible with a mediator role of Max in modulating the cell sensitivity to the proliferative signal c-Myc .	As Max protein mediates the transcriptional effects of c-Myc our results are compatible with a mediator role of Max in modulating the cell sensitivity to the proliferative signal c-Myc.	1	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max	Max	c-Myc	c-Myc	c-Myc	1	2	8	9
To determine if Max is required for Myc repression of C/EBPdelta promoter activity HC11 cells were treated with Max siRNA and C/EBPdelta promoter driven luciferase activity assessed .	To determine if Max is required for Myc repression of C/EBPdelta promoter activity HC11 cells were treated with Max siRNA and C/EBPdelta promoter driven luciferase activity assessed.	7	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Max	Max	Max	Myc	Myc	Myc	18	19	7	8
Taken together , these results indicated that Delta Max promotes glycolytic gene expression in a Myc dependent fashion .	Taken together, these results indicated that Delta Max promotes glycolytic gene expression in a Myc dependent fashion.	7	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max	Max	Myc	Myc	Myc	8	9	15	16
Using Saccharomyces cerevisiae , we have shown that the Max bHLH/LZ domain enables Myc to activate transcription through CACGTG and CACATG sequences in vivo , and that the number and context of such sites determines the level of activation .	Using Saccharomyces cerevisiae, we have shown that the Max bHLH/LZ domain enables Myc to activate transcription through CACGTG and CACATG sequences in vivo, and that the number and context of such sites determines the level of activation.	9	14	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max	Max	Myc	Myc	Myc	9	10	13	14
All MYC proteins heterodimerize with the obligatory bHLHZip protein MAX , which enables the MYC : MAX heterodimer to bind so called E-box DNA sequences ( CACGTG and similar sequences ) situated in regulatory regions of target genes [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	All MYC proteins heterodimerize with the obligatory bHLHZip protein MAX, which enables the MYC : MAX heterodimer to bind so called E-box DNA sequences (CACGTG and similar sequences) situated in regulatory regions of target genes [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	17	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein MAX	protein MAX	protein MAX	MYC	MYC	MYC	8	10	14	15
Conversely , HIF2alpha can bind and stabilize the MYC : MAX heterodimer , promoting MYC induced transcriptional changes .	Conversely, HIF2alpha can bind and stabilize the MYC : MAX heterodimer, promoting MYC induced transcriptional changes.	10	15	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAX	MAX	MAX	MYC	MYC	MYC	10	11	14	15
mTORC1 splices the MYC interacting protein MAX , which enhances c-Myc action .	mTORC1 splices the MYC interacting protein MAX, which enhances c-Myc action.	4	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein MAX	protein MAX	protein MAX	c-Myc	c-Myc	c-Myc	5	7	10	11
Rather , c-Myc needs a partner , such as Max , which heterodimerizes with c-Myc via its own b-HLH-Zip motif to mediate Myc function .	Rather, c-Myc needs a partner, such as Max, which heterodimerizes with c-Myc via its own b-HLH-Zip motif to mediate Myc function.	5	23	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max	Max	Myc	Myc	Myc	9	10	22	23
Previous studies have demonstrated that MAX may impair MYC function by impairing the ability of MYC to bind to DNA .	Previous studies have demonstrated that MAX may impair MYC function by impairing the ability of MYC to bind to DNA.	5	9	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAX	MAX	MAX	MYC	MYC	MYC	5	6	8	9
HUWE1 also ubiquitinates and degrades the HDAC2 histone deacetylase , which associates with the MXD and MAX repressive complex that antagonizes MYC transactivation , and it is possible that degradation of chromatin bound HDAC2 is also a critical activity of HUWE1 .	HUWE1 also ubiquitinates and degrades the HDAC2 histone deacetylase, which associates with the MXD and MAX repressive complex that antagonizes MYC transactivation, and it is possible that degradation of chromatin bound HDAC2 is also a critical activity of HUWE1.	16	22	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAX	MAX	MAX	MYC	MYC	MYC	16	17	21	22
A Max expression vector was found to augment the cotransforming activity of L-Myc as well as that of c-Myc .	A Max expression vector was found to augment the cotransforming activity of L-Myc as well as that of c-Myc.	1	19	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max	Max	c-Myc	c-Myc	c-Myc	1	2	18	19
These data raise the possibility that compensatory induction of Max could increase c-Myc activity .	These data raise the possibility that compensatory induction of Max could increase c-Myc activity.	7	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max	Max	c-Myc	c-Myc	c-Myc	9	10	12	13
Another study showed the positive effect of SIRT1 on MYC by demonstrating that the SIRT1 mediated deacetylation of MYC could promote the association with its essential partner MYC associated factor X , thereby promoting the transcriptional activity of MYC [ XREF_BIBR ] .	Another study showed the positive effect of SIRT1 on MYC by demonstrating that the SIRT1 mediated deacetylation of MYC could promote the association with its essential partner MYC associated factor X, thereby promoting the transcriptional activity of MYC [XREF_BIBR].	20	40	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MYC associated factor X	MYC associated factor X	MYC associated factor X	MYC	MYC	MYC	27	31	38	39
Through the HLHZip domain , MYC heterodimerizes with the bHLHZip protein MAX , which enables the MYC : MAX complex to bind E-box regulatory DNA elements throughout the genome , thereby controlling transcription of a large group of specific genes XREF_BIBR - XREF_BIBR .	Through the HLHZip domain, MYC heterodimerizes with the bHLHZip protein MAX, which enables the MYC : MAX complex to bind E-box regulatory DNA elements throughout the genome, thereby controlling transcription of a large group of specific genes XREF_BIBR - XREF_BIBR.	6	17	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein MAX	protein MAX	protein MAX	MYC	MYC	MYC	10	12	16	17
The presence of Mnt-Max complexes before c-Myc synthesis during cell cycle entry suggested that the availability of Max for newly synthesized c-Myc is , at least in part , a function of the stability of the Mnt and Max complex .	The presence of Mnt-Max complexes before c-Myc synthesis during cell cycle entry suggested that the availability of Max for newly synthesized c-Myc is, at least in part, a function of the stability of the Mnt and Max complex.	15	22	synthesized	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max	Max	c-Myc	c-Myc	c-Myc	17	18	21	22
We knocked down c-MET expression by siRNA against the c-MET gene , to confirm whether c-MET overexpression activated c-MET signaling resulting in resistance to the cytotoxic anticancer drugs .	We knocked down c-MET expression by siRNA against the c-MET gene, to confirm whether c-MET overexpression activated c-MET signaling resulting in resistance to the cytotoxic anticancer drugs.	15	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-MET	c-MET overexpression	c-met	c-MET	c-MET	c-met	15	16	18	19
This is in line with other reports indicating that increase of c-Met expression enhances both the biologic effects of HGF and c-Met signaling in various cell types .	This is in line with other reports indicating that increase of c-Met expression enhances both the biologic effects of HGF and c-Met signaling in various cell types.	11	22	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met expression	c-met	c-Met	c-Met	c-met	11	12	21	22
Data from the Catalog of Somatic Mutations in Cancer ( COSMIC ) database revealed a low prevalence of MET mutations in prostate cancer ( 3.6 % ) , in which c-MET activation was especially mediated by c-MET overexpression in the setting of androgen deprivation .	Data from the Catalog of Somatic Mutations in Cancer (COSMIC) database revealed a low prevalence of MET mutations in prostate cancer (3.6%), in which c-MET activation was especially mediated by c-MET overexpression in the setting of androgen deprivation.	30	38	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-MET	c-MET overexpression	c-met	c-MET	c-MET	c-met	36	37	30	31
The addition of a minimum of 1 ng/mL recombinant human HGF to cultured HNSCC cells induced c-Met phosphorylation and activated two key downstream effector molecules of HGF and c-Met , AKT and p44 and p42 MAPK , in a concentration dependent fashion ( data not shown ) .	The addition of a minimum of 1 ng/mL recombinant human HGF to cultured HNSCC cells induced c-Met phosphorylation and activated two key downstream effector molecules of HGF and c-Met, AKT and p44 and p42 MAPK, in a concentration dependent fashion (data not shown).	10	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	HGF to cultured HNSCC cells induced c-Met phosphorylation	c-met	c-Met	c-Met	c-met	16	17	28	29
Targeting of c-Met expressing cells could downregulate the HGF receptor protein .	Targeting of c-Met expressing cells could downregulate the HGF receptor protein.	2	10	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Met	c-Met	c-Met	HGF receptor	HGF receptor	HGF receptor	2	3	8	10
The ubiquitous co-expression of matriptase and c-Met in the epithelial compartment of both human HNSCC and mouse squamous cell carcinoma established above suggested that dysregulated matriptase could promote c-Met signaling during squamous cell carcinogenesis by proteolytic conversion of stromal cell derived , single-chain proHGF/SF to active double-chain HGF/SF on the surface of c-Met expressing keratinocytes .	The ubiquitous co-expression of matriptase and c-Met in the epithelial compartment of both human HNSCC and mouse squamous cell carcinoma established above suggested that dysregulated matriptase could promote c-Met signaling during squamous cell carcinogenesis by proteolytic conversion of stromal cell derived, single-chain proHGF/SF to active double-chain HGF/SF on the surface of c-Met expressing keratinocytes.	2	29	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	co-expression of matriptase and c-Met	c-met	c-Met	c-Met	c-met	6	7	28	29
Reintroducing miR-199a-3p inhibited c-Met expression and led to attenuated activation of c-Met downstream signaling pathways including STAT3 , mTOR and ERK1/2 .	Reintroducing miR-199a-3p inhibited c-Met expression and led to attenuated activation of c-Met downstream signaling pathways including STAT3, mTOR and ERK1/2.	1	14	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Met	miR-199a-3p inhibited c-Met expression	c-met	c-Met	c-Met	c-met	3	4	11	12
( 2 ) Overexpression of c-MET Overexpression of c-MET in tumour tissue has been noted in many cancers , such as lung cancer , stomach cancer , breast cancer , kidney cancer , colon cancer , and HCC .	(2) Overexpression of c-MET Overexpression of c-MET in tumour tissue has been noted in many cancers, such as lung cancer, stomach cancer, breast cancer, kidney cancer, colon cancer, and HCC.	3	11	Overexpression	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	c-MET	Overexpression of c-MET	c-met	c-MET	c-MET	c-met	5	6	8	9
The co-expression of E-cadherin and c-Met observed in human gastric carcinoma tissues supports the findings of an association of c-Met with E-cadherin in gastric carcinoma cell lines ( XREF_FIG ) .	The co-expression of E-cadherin and c-Met observed in human gastric carcinoma tissues supports the findings of an association of c-Met with E-cadherin in gastric carcinoma cell lines (XREF_FIG).	1	20	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	co-expression of E-cadherin and c-Met	c-met	c-Met	c-Met	c-met	5	6	19	20
This RAP80 recruiting ubiquitinylation is performed by the E2 ubiquitin conjugase Ubc13 and the E3 ligase RNF8 , which are targeted to breaks by MDC1 [ XREF_BIBR - XREF_BIBR ] .	This RAP80 recruiting ubiquitinylation is performed by the E2 ubiquitin conjugase Ubc13 and the E3 ligase RNF8, which are targeted to breaks by MDC1 [XREF_BIBR - XREF_BIBR].	5	28	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MDC1	MDC1	MDC1	RNF8	RNF8	RNF8	24	25	16	17
The phosphorylation of MDC1 promotes the recruitment of RNF8 , and RNF8 , in conjunction with the E2 conjugating enzyme UBC13 , adds a lysine ( K ) 63 linked ubiquitin chain to histone H1 ; this chain serves as a scaffold for recruitment of ubiquitin binding proteins and does not induce protein degradation [ XREF_BIBR ] [ XREF_BIBR - XREF_BIBR ] .	The phosphorylation of MDC1 promotes the recruitment of RNF8, and RNF8, in conjunction with the E2 conjugating enzyme UBC13, adds a lysine (K) 63 linked ubiquitin chain to histone H1; this chain serves as a scaffold for recruitment of ubiquitin binding proteins and does not induce protein degradation [XREF_BIBR] [XREF_BIBR - XREF_BIBR].	1	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	phosphorylation of MDC1	mdc1	RNF8	RNF8	rnf8	3	4	8	9
ATM mediated phosphorylation of MDC1 promotes the recruitment of the RNF8 E3 ligase which targets H2A-type histones .	ATM mediated phosphorylation of MDC1 promotes the recruitment of the RNF8 E3 ligase which targets H2A-type histones.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	ATM mediated phosphorylation of MDC1	mdc1	RNF8	RNF8	rnf8	4	5	10	11
XREF_BIBR Subsequent phosphorylation of MDC1 ( on its TQXF motifs ) by ATM promotes binding of the E3 ubiquitin ligase RNF8 .	XREF_BIBR Subsequent phosphorylation of MDC1 (on its TQXF motifs) by ATM promotes binding of the E3 ubiquitin ligase RNF8.	2	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	phosphorylation of MDC1	mdc1	RNF8	RNF8	rnf8	4	5	20	21
Upon IR , ATM dependent recruitment and Ser 139 phosphorylation of mediator of DNA damage checkpoint 1 ( MDC1 ) promotes RNF8 and RNF168 to accumulate at DSBs , which modify L3MBTL1 and JMJD2A with multi ubiquitination .	Upon IR, ATM dependent recruitment and Ser 139 phosphorylation of mediator of DNA damage checkpoint 1 (MDC1) promotes RNF8 and RNF168 to accumulate at DSBs, which modify L3MBTL1 and JMJD2A with multi ubiquitination.	16	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	MDC1	MDC1	RNF8	RNF8	RNF8	18	19	21	22
For instance , ATM mediated phosphorylation of MDC1 stimulates the recruitment of the H2A ubiquitin ligases RNF8 and RNF168 .	For instance, ATM mediated phosphorylation of MDC1 stimulates the recruitment of the H2A ubiquitin ligases RNF8 and RNF168.	3	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	ATM mediated phosphorylation of MDC1	mdc1	RNF8	RNF8	rnf8	7	8	16	17
This phosphorylation of MDC1 leads to the phosphorylation dependent recruitment of RNF8 to the sites of DNA double strand breaks ( DSBs ) , where RNF8 binds to the E2 , Ubc13 , and catalyses the formation of lysine 63 linked polyubiquitin chains ( K63-Ubs ) on histones [ XREF_BIBR - XREF_BIBR ] .	This phosphorylation of MDC1 leads to the phosphorylation dependent recruitment of RNF8 to the sites of DNA double strand breaks (DSBs), where RNF8 binds to the E2, Ubc13, and catalyses the formation of lysine 63 linked polyubiquitin chains (K63-Ubs) on histones [XREF_BIBR - XREF_BIBR].	1	12	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	phosphorylation of MDC1	mdc1	RNF8	RNF8	rnf8	3	4	11	12
Phosphorylation of MDC1 by these kinases promotes the recruitment of RNF8 , which causes a feedback loop that promotes further ATM activation via RNF8 and another DSB response associated E3 ligase , CHFR [ XREF_BIBR ] .	Phosphorylation of MDC1 by these kinases promotes the recruitment of RNF8, which causes a feedback loop that promotes further ATM activation via RNF8 and another DSB response associated E3 ligase, CHFR [XREF_BIBR].	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	Phosphorylation of MDC1	mdc1	RNF8	RNF8	rnf8	2	3	10	11
With the discovery of the mechanism by which MDC1 mediates accumulation and retention of the MRN complex in gamma-H2AX-containing damaged chromatin regions , an important step in the hierarchy of events that lead to the formation of nuclear foci at sites of DSBs has been resolved .	With the discovery of the mechanism by which MDC1 mediates accumulation and retention of the MRN complex in gamma-H2AX-containing damaged chromatin regions, an important step in the hierarchy of events that lead to the formation of nuclear foci at sites of DSBs has been resolved.	8	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	MDC1	MDC1	MRN	MRN	MRN	8	9	15	16
To test whether the SDT repeats of MDC1 mediate NBS1 accumulation at sites of DSBs in vivo , we introduced the same SDT mutations as before ( XREF_FIG ) in the tagged full-length mouse MDC1 cDNA followed by transient transfection of MDC1 -/- MEFs with those mutants and assessment of MDC1 and NBS1 foci formation by indirect immunofluorescence .	To test whether the SDT repeats of MDC1 mediate NBS1 accumulation at sites of DSBs in vivo, we introduced the same SDT mutations as before (XREF_FIG) in the tagged full-length mouse MDC1 cDNA followed by transient transfection of MDC1 -/- MEFs with those mutants and assessment of MDC1 and NBS1 foci formation by indirect immunofluorescence.	5	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	MDC1	MDC1	NBS1	NBS1	NBS1	7	8	9	10
Importantly , kinetic measurements in living cells extended these results by showing that the MDC1 knockdown abolished MRN retention at DSBs from the earliest stages after DNA damage and that in the absence of MDC1 , NBS1 could not concentrate at the DSB flanking chromatin despite the fact that H2AX was efficiently phosphorylated in these compartments .	Importantly, kinetic measurements in living cells extended these results by showing that the MDC1 knockdown abolished MRN retention at DSBs from the earliest stages after DNA damage and that in the absence of MDC1, NBS1 could not concentrate at the DSB flanking chromatin despite the fact that H2AX was efficiently phosphorylated in these compartments.	14	18	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	MDC1	MDC1	MRN	MRN	MRN	14	15	17	18
Previously , we and others have shown that MDC1 mediates accumulation of the MRN complex at sites of DSBs .	Previously, we and others have shown that MDC1 mediates accumulation of the MRN complex at sites of DSBs.	8	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDC1	MDC1	MDC1	MRN	MRN	MRN	8	9	13	14
In summary , these results suggest that an acidic region near the N terminus of MDC1 mediates MRN accumulation at sites of DSBs .	In summary, these results suggest that an acidic region near the N terminus of MDC1 mediates MRN accumulation at sites of DSBs.	13	18	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MDC1	MDC1	MDC1	MRN	MRN	MRN	15	16	17	18
MDM2 has been reported to activate Notch1 signaling pathway during tumorigenesis 26 , thus we wondered whether MDM2 promotes GMC dysfunction via Notch1 signaling activation in GMCs with high glucose treatment .	MDM2 has been reported to activate Notch1 signaling pathway during tumorigenesis 26, thus we wondered whether MDM2 promotes GMC dysfunction via Notch1 signaling activation in GMCs with high glucose treatment.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDM2	MDM2	MDM2	Notch1	Notch1	Notch1	0	1	6	7
It is widely accepted that MDM2 promotes aberrant activation of Notch1 signaling via ubiquitinating and degrading of Numb XREF_BIBR , XREF_BIBR , XREF_BIBR .	It is widely accepted that MDM2 promotes aberrant activation of Notch1 signaling via ubiquitinating and degrading of Numb XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDM2	MDM2	MDM2	Notch1	Notch1	Notch1	5	6	10	11
MDM2 has been found promoting Notch1 activation through direct or indirect pathways in previous studies , but how it regulates Notch1 in DN has not been clarified .	MDM2 has been found promoting Notch1 activation through direct or indirect pathways in previous studies, but how it regulates Notch1 in DN has not been clarified.	0	6	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDM2	MDM2	MDM2	Notch1	Notch1	Notch1	0	1	5	6
As MDM2 modulates the activation of Notch1 signaling pathway while Numb is not implicated , we explored other possible mechanisms .	As MDM2 modulates the activation of Notch1 signaling pathway while Numb is not implicated, we explored other possible mechanisms.	1	8	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDM2	MDM2	MDM2	Notch1	Notch1	Notch1	1	2	6	7
MDM2 is suggested to modulate Notch1 signaling pathway through other mechanisms .	MDM2 is suggested to modulate Notch1 signaling pathway through other mechanisms.	0	7	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDM2	MDM2	MDM2	Notch1	Notch1	Notch1	0	1	5	6
Instead , our findings suggest that MDM2 mediated Notch1 activation is one of the potential mechanisms responsible for high glucose induced GMC proliferation and ECM accumulation .	Instead, our findings suggest that MDM2 mediated Notch1 activation is one of the potential mechanisms responsible for high glucose induced GMC proliferation and ECM accumulation.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	MDM2	MDM2	MDM2	Notch1	Notch1	Notch1	6	7	8	9
Pretreatment with the ADAM17 ( a disintegrin and metalloproteinase-17 ) inhibitor TAPI-0 ( tumor necrosis factor alpha protease inhibitor-0 ) reduced LPS induced production of soluble Mer protein in bronchoalveolar lavage ( BAL ) fluid , restored membrane bound Mer expression , and increased Mer activation in alveolar macrophages and lungs after LPS treatment .	Pretreatment with the ADAM17 (a disintegrin and metalloproteinase-17) inhibitor TAPI-0 (tumor necrosis factor alpha protease inhibitor-0) reduced LPS induced production of soluble Mer protein in bronchoalveolar lavage (BAL) fluid, restored membrane bound Mer expression, and increased Mer activation in alveolar macrophages and lungs after LPS treatment.	26	41	restored	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Mer	Mer	mer	Mer	Mer expression	mer	26	27	39	40
UNC2025 blocks MERTK phosphorylation in cells with an IC 50 of 2.6 nM , thereby preventing MERTK activation and downstream intracellular signaling .	UNC2025 blocks MERTK phosphorylation in cells with an IC 50 of 2.6 nM, thereby preventing MERTK activation and downstream intracellular signaling.	0	17	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MERTK	UNC2025 blocks MERTK phosphorylation	mertk	MERTK	MERTK	mertk	2	3	16	17
The novel finding of Mer expression in the nucleus -- and especially the presence of nuclear localization and export sequences -- broadens the realm of potential approaches to target Mer for therapeutic purposes .	The novel finding of Mer expression in the nucleus -- and especially the presence of nuclear localization and export sequences -- broadens the realm of potential approaches to target Mer for therapeutic purposes.	4	32	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mer	Mer expression	mer	Mer	Mer	mer	4	5	29	30
The purpose of the present study was to examine whether pharmacologically restored membrane bound Mer expression upregulates the Mer signaling pathways and suppresses lung inflammatory responses .	The purpose of the present study was to examine whether pharmacologically restored membrane bound Mer expression upregulates the Mer signaling pathways and suppresses lung inflammatory responses.	14	20	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mer	Mer expression	mer	Mer	Mer	mer	14	15	18	19
We found that c-Met signaling in primary keratinocytes activates Erk1/2 , Akt , Gab1 , and PAK1/2 .	We found that c-Met signaling in primary keratinocytes activates Erk1/2, Akt, Gab1, and PAK1/2.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	Gab1	Gab1	Gab1	3	4	13	14
This suggests that Gab1 expressed in this hybrid form is efficiently phosphorylated and associates with signaling molecules similar to Gab1 proteins stimulated by activated c-Met .	This suggests that Gab1 expressed in this hybrid form is efficiently phosphorylated and associates with signaling molecules similar to Gab1 proteins stimulated by activated c-Met.	19	25	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Met	c-Met	c-Met	Gab1	Gab1	Gab1	24	25	19	20
MFng downregulation after E11.5 would allow Jag1 and Jag2 myocardial signalling to activate endocardial Notch1 .	MFng downregulation after E11.5 would allow Jag1 and Jag2 myocardial signalling to activate endocardial Notch1.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MFng	MFng	MFng	Notch1	Notch1	Notch1	0	1	14	15
Since knockdown of Mfng decreased Notch1 and Notch4 activation in MDA-MB231 , we tested whether Mfng controls Pik3cg expression through Notch1 or Notch4 .	Since knockdown of Mfng decreased Notch1 and Notch4 activation in MDA-MB231, we tested whether Mfng controls Pik3cg expression through Notch1 or Notch4.	1	8	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mfng	Mfng	Mfng	Notch1	Notch1	Notch1	3	4	5	6
Thus , modulation of Notch1 activation by Mfng is context dependent : enhanced in MDA-MB231 , but inhibited in C0321 and in mouse mammary gland during involution .	Thus, modulation of Notch1 activation by Mfng is context dependent : enhanced in MDA-MB231, but inhibited in C0321 and in mouse mammary gland during involution.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Mfng	Mfng	Mfng	Notch1	Notch1	Notch1	7	8	4	5
MDK stimulation of Notch 2 leads to activation of STAT3 by hairy and enhancer of split-1 ( Hes1 ) [ XREF_BIBR ] .	MDK stimulation of Notch 2 leads to activation of STAT3 by hairy and enhancer of split-1 (Hes1) [XREF_BIBR].	0	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MDK	MDK	MDK	Notch 2	Notch 2	Notch 2	0	1	3	5
We further found that MK activates Notch2 signaling leading to protein/protein interactions between Hes1 and Jak2 and Stat3 intermediates .	We further found that MK activates Notch2 signaling leading to protein/protein interactions between Hes1 and Jak2 and Stat3 intermediates.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MK	MK	MK	Notch2	Notch2	Notch2	4	5	6	7
Previous studies have reported that replication stress induced MDK expression activates Notch-2 , which drives EMT and chemoresistance in pancreatic cancer .	Previous studies have reported that replication stress induced MDK expression activates Notch-2, which drives EMT and chemoresistance in pancreatic cancer.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDK	MDK expression	mdk	Notch-2	Notch-2	notch-2	8	9	11	12
The MDK induced crosstalk of Notch2 and Janus kinase 2/signal transducer and activator of transcription 3 signaling pathways regulates cell plasticity and motility , thereby contributing to EMT in human keratinocytes .	The MDK induced crosstalk of Notch2 and Janus kinase 2/signal transducer and activator of transcription 3 signaling pathways regulates cell plasticity and motility, thereby contributing to EMT in human keratinocytes.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDK	MDK	MDK	Notch2	Notch2	Notch2	1	2	5	6
MDK stimulates Notch2 signaling guiding to protein/protein communications between Jak2 and Stat3 and Hes1 , suggesting that MDK mediated interaction of Notch2/Jak2/Stat3 signaling pathways and controlled cell motility and tumorigenicity .	MDK stimulates Notch2 signaling guiding to protein/protein communications between Jak2 and Stat3 and Hes1, suggesting that MDK mediated interaction of Notch2/Jak2/Stat3 signaling pathways and controlled cell motility and tumorigenicity.	0	3	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDK	MDK	MDK	Notch2	Notch2	Notch2	0	1	2	3
Gwl activates ENSA and Arpp19 , which are phosphorylation dependent inhibitors of PP2A [ XREF_BIBR , XREF_BIBR ] .	Gwl activates ENSA and Arpp19, which are phosphorylation dependent inhibitors of PP2A [XREF_BIBR, XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Gwl	Gwl	Gwl	ENSA	ENSA	ENSA	0	1	2	3
Through this mechanism , menin drives MLL and MLL-fusion proteins to target genes .	Through this mechanism, menin drives MLL and MLL-fusion proteins to target genes.	4	9	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	menin	menin	menin	MLL	MLL	MLL	4	5	6	7
Menin is required for maintenance of homeotic genes regulated by MLL1 and MLL2 , such as Hoxa9 , Hoxc6 , Hoxc8 [ XREF_BIBR , XREF_BIBR ] , and conditional menin knockout significantly reduces binding of MLL1 to the Hoxa9 locus [ XREF_BIBR ] .	Menin is required for maintenance of homeotic genes regulated by MLL1 and MLL2, such as Hoxa9, Hoxc6, Hoxc8 [XREF_BIBR, XREF_BIBR], and conditional menin knockout significantly reduces binding of MLL1 to the Hoxa9 locus [XREF_BIBR].	29	36	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	menin	menin	menin	MLL1	MLL1	MLL1	29	30	35	36
39 Menin is known to interact with MLL ; however , MLL was hardly detected in GBX2 promoter by ChIP in both cell types ( XREF_SUPPLEMENTARY ) , in contrast to its occupancy at HoxA9 region , 40 indicating that menin might not target MLL for the regulation of GBX2 .	39 Menin is known to interact with MLL; however, MLL was hardly detected in GBX2 promoter by ChIP in both cell types (XREF_SUPPLEMENTARY), in contrast to its occupancy at HoxA9 region, 40 indicating that menin might not target MLL for the regulation of GBX2.	40	45	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	menin	menin	menin	MLL	MLL	MLL	40	41	44	45
Moreover , forced expression of MEF2A in 10T1/2 cells rescues MyoD dependent myogenic conversion in the presence of constitutively active Raf kinase and partially restores transactivation of a myogenin promoter dependent reporter gene in L6 muscle cells containing activated Raf kinase .	Moreover, forced expression of MEF2A in 10T1/2 cells rescues MyoD dependent myogenic conversion in the presence of constitutively active Raf kinase and partially restores transactivation of a myogenin promoter dependent reporter gene in L6 muscle cells containing activated Raf kinase.	3	13	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEF2A	expression of MEF2A	mef2a	MyoD	MyoD	myod	5	6	10	11
Indeed , Xenopus Mef2a can activate the Myod promoter .	Indeed, Xenopus Mef2a can activate the Myod promoter.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mef2a	Mef2a	Mef2a	Myod	Myod	Myod	3	4	7	8
A Notch ligand , Jagged1 , was also present in the P2 fraction , suggesting that Mib1 mediated Jagged1 endocytosis [ XREF_BIBR ] might occur to activate Notch signaling at synapses .	A Notch ligand, Jagged1, was also present in the P2 fraction, suggesting that Mib1 mediated Jagged1 endocytosis [XREF_BIBR] might occur to activate Notch signaling at synapses.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Mib1	Mib1	Mib1	Jagged1	Jagged1	Jagged1	16	17	18	19
ERK1/2 , the substrate of MEK undergoes phosphorylation at T202 and Y204 , and as we reported previously [ XREF_BIBR ] , MEK enables GSK-3beta activation through phosphorylation of its domain at tyrosine 216 .	ERK1/2, the substrate of MEK undergoes phosphorylation at T202 and Y204, and as we reported previously [XREF_BIBR], MEK enables GSK-3beta activation through phosphorylation of its domain at tyrosine 216.	22	25	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	GSK-3beta	GSK-3beta	GSK-3beta	22	23	24	25
It suggests that inhibition of MEK ( possible activator of GSK-3beta ) might lead to drop of GSK-3beta activity and GSK-3beta is engaged in the assembly of these protein partners .	It suggests that inhibition of MEK (possible activator of GSK-3beta) might lead to drop of GSK-3beta activity and GSK-3beta is engaged in the assembly of these protein partners.	3	11	activator	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	GSK-3beta	GSK-3beta	GSK-3beta	5	6	10	11
Therefore , Gli2 and MEF2C enhance MyoD activity and physically form a protein complex with MyoD protein during skeletal myogenesis .	Therefore, Gli2 and MEF2C enhance MyoD activity and physically form a protein complex with MyoD protein during skeletal myogenesis.	2	7	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEF2C	MEF2C	MEF2C	MyoD	MyoD	MyoD	4	5	6	7
Here , we show that Gli2 , MEF2C , and MyoD form a protein complex and enhance MyoD activity on skeletal muscle related promoters .	Here, we show that Gli2, MEF2C, and MyoD form a protein complex and enhance MyoD activity on skeletal muscle related promoters.	5	18	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEF2C	MEF2C	MEF2C	MyoD	MyoD	MyoD	7	8	17	18
Studies from the Dilworth laboratory showed that phosphorylation of MEF2D by p38 alpha and beta kinases mediates the recruitment of the Ash2L containing mixed-lineage leukemia ( MLL ) methyltransferase complex ( functionally related to Trithorax group [ TrxG ] ) to the chromatin of muscle genes , thereby promoting H3-K4 trimethylation ( H3K4 me3 ) , an epigenetic event that promotes transcription [ XREF_BIBR ] .	Studies from the Dilworth laboratory showed that phosphorylation of MEF2D by p38 alpha and beta kinases mediates the recruitment of the Ash2L containing mixed-lineage leukemia (MLL) methyltransferase complex (functionally related to Trithorax group [TrxG]) to the chromatin of muscle genes, thereby promoting H3-K4 trimethylation (H3K4 me3), an epigenetic event that promotes transcription [XREF_BIBR].	7	22	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEF2D	phosphorylation of MEF2D	mef2d	Ash2L	Ash2L	ash2l	9	10	21	22
p38alpha and beta kinases phosphorylate MEF2D mediating the recruitment of the Trithorax enzymatic subunit Ash2L to the chromatin of muscle genes [ XREF_BIBR ] .	p38alpha and beta kinases phosphorylate MEF2D mediating the recruitment of the Trithorax enzymatic subunit Ash2L to the chromatin of muscle genes [XREF_BIBR].	0	15	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEF2D	p38alpha and beta kinases phosphorylate MEF2D	mef2d	Ash2L	Ash2L	ash2l	5	6	14	15
However , MAST2 has been shown tobind the C-terminus of PTEN through a unique PDZ domain , target the C-terminus of PTEN for phosphorylation and modulate PTEN activity [ XREF_BIBR , XREF_BIBR ] .	However, MAST2 has been shown tobind the C-terminus of PTEN through a unique PDZ domain, target the C-terminus of PTEN for phosphorylation and modulate PTEN activity [XREF_BIBR, XREF_BIBR].	2	27	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAST2	MAST2	MAST2	PTEN	PTEN	PTEN	2	3	26	27
However , the decrease in Jagged1 triggered Notch2 signaling by mFng was again greater than that by lFng .	However, the decrease in Jagged1 triggered Notch2 signaling by mFng was again greater than that by lFng.	7	11	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	mFng	mFng	mFng	Notch2	Notch2	Notch2	10	11	7	8
Specifically , it was shown that the presence of Dystrophin enhances MARK2 ( Par1b ) protein levels and that MARK2 then mediates the asymmetric localization of the PARD3 polarity protein , which functions to properly guide asymmetric cell division in proliferating satellite cells .	Specifically, it was shown that the presence of Dystrophin enhances MARK2 (Par1b) protein levels and that MARK2 then mediates the asymmetric localization of the PARD3 polarity protein, which functions to properly guide asymmetric cell division in proliferating satellite cells.	19	29	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MARK2	MARK2	MARK2	PARD3	PARD3	PARD3	19	20	27	28
Mib1 , as it promotes Trans-activation , induces the endocytosis of Dll1 and may therefore reduce the amount of Dll1 available for Cis-inhibition .	Mib1, as it promotes Trans-activation, induces the endocytosis of Dll1 and may therefore reduce the amount of Dll1 available for Cis-inhibition.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mib1	Mib1	Mib1	Dll1	Dll1	Dll1	0	1	11	12
The inhibition of Akt by XN would explain the inhibition of mTOR , since mTOR is a downstream target of Akt .	The inhibition of Akt by XN would explain the inhibition of mTOR, since mTOR is a downstream target of Akt.	14	21	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	14	15	20	21
Activated Akt activates mTOR followed by phosphorylation of ribosomal protein S6 kinase ( S6K ) .	Activated Akt activates mTOR followed by phosphorylation of ribosomal protein S6 kinase (S6K).	0	4	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	3	4	1	2
Targeted silencing of Akt showed that Akt does not regulate mTOR activation in PC-3 cells , but targeted silencing of mTOR sensitized PC-3 cells to CDDO-Me mediated growth inhibition .	Targeted silencing of Akt showed that Akt does not regulate mTOR activation in PC-3 cells, but targeted silencing of mTOR sensitized PC-3 cells to CDDO-Me mediated growth inhibition.	0	21	Targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	20	21	3	4
Consistently , the PI3K and mTOR targets Akt and S6 appeared to be intrinsically phosphorylated ( i.e. activated ) and fully sensitive to SOM230 treatment in CAFs while not constitutively activated and hence not inhibited by SOM230 in PaSCs ( Fig XREF_FIG ) .	Consistently, the PI3K and mTOR targets Akt and S6 appeared to be intrinsically phosphorylated (i.e. activated) and fully sensitive to SOM230 treatment in CAFs while not constitutively activated and hence not inhibited by SOM230 in PaSCs (Fig XREF_FIG).	3	14	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	7	8
AKT is activated via phosphorylation by mTORC1 ( mTOR complex 1 ) and signals through a variety of effectors , including mTORC2 and Forkhead and winged helix box lass O ( FOXO ) , influencing the function of proteins involved in cell proliferation , differentiation and apoptosis .	AKT is activated via phosphorylation by mTORC1 (mTOR complex 1) and signals through a variety of effectors, including mTORC2 and Forkhead and winged helix box lass O (FOXO), influencing the function of proteins involved in cell proliferation, differentiation and apoptosis.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	8	9	0	1
Thus in cells with constitutive K-RAS activity , short-term inhibition of PI3K and mTOR suppresses AKT activity that rebounds by 24 h ; the rebound being due to ERK1/2 pathway signaling .	Thus in cells with constitutive K-RAS activity, short-term inhibition of PI3K and mTOR suppresses AKT activity that rebounds by 24 h; the rebound being due to ERK1/2 pathway signaling.	9	16	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	13	14	15	16
Alterations of the PI3K and Akt pathway induced by inhibitors of the mammalian target of rapamycin ( mTOR ) ( e.g ., temsirolimus and everolimus [ RAD001 ] ) appear to reverse resistance of lymphoblasts to anthracyclines and vinca alkaloids in vitro ; combination therapy trials incorporating everolimus into hyper-CVAD and rituximab are planned [ XREF_BIBR ] .	Alterations of the PI3K and Akt pathway induced by inhibitors of the mammalian target of rapamycin (mTOR) (e.g., temsirolimus and everolimus [RAD001]) appear to reverse resistance of lymphoblasts to anthracyclines and vinca alkaloids in vitro; combination therapy trials incorporating everolimus into hyper-CVAD and rituximab are planned [XREF_BIBR].	3	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	12	16	5	6
Conditional cell reprogramming involves non canonical beta-catenin activation and mTOR mediated inactivation of Akt .	Conditional cell reprogramming involves non canonical beta-catenin activation and mTOR mediated inactivation of Akt.	7	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	9	10	13	14
We find that Nod2 stimulation by MDP leads to phosphorylation of the mTOR substrate p70 S6 kinase 20 ( XREF_SUPPLEMENTARY ) and of the upstream mTOR activator Akt ( data not shown ) .	We find that Nod2 stimulation by MDP leads to phosphorylation of the mTOR substrate p70 S6 kinase 20 (XREF_SUPPLEMENTARY) and of the upstream mTOR activator Akt (data not shown).	7	29	activator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	25	26	27	28
Everolimus is an inhibitor of mTOR , which mediates PI3K and Akt signaling .	Everolimus is an inhibitor of mTOR, which mediates PI3K and Akt signaling.	3	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	11	12
mTOR activates Akt by phosphorylating Ser473 through mTOR complex 2 .	mTOR activates Akt by phosphorylating Ser473 through mTOR complex 2.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	2	3
To determine the mechanism by which miR-204 may exhibit its tumor growth and metastasis suppressor activity , we examined the effect of miR-204 on AKT and mTOR signaling as both BDNF and Ezrin have been shown to activate AKT pathway XREF_BIBR , and selective activation of AKT by mTOR has been shown to regulate cancer cell migration and invasion XREF_BIBR .	To determine the mechanism by which miR-204 may exhibit its tumor growth and metastasis suppressor activity, we examined the effect of miR-204 on AKT and mTOR signaling as both BDNF and Ezrin have been shown to activate AKT pathway XREF_BIBR, and selective activation of AKT by mTOR has been shown to regulate cancer cell migration and invasion XREF_BIBR.	44	49	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	48	49	46	47
Thus , mTOR is a target of AKT but vice versa , mTOR also targets AKT forming a signaling axis referred to as the AKT and mTOR pathway .	Thus, mTOR is a target of AKT but vice versa, mTOR also targets AKT forming a signaling axis referred to as the AKT and mTOR pathway.	2	8	is a target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	7	8
Pharmacological inhibition of mTOR , a downstream effecter of Akt , blocked the morphological effects of DISC1 suppression and Akt over-activation .	Pharmacological inhibition of mTOR, a downstream effecter of Akt, blocked the morphological effects of DISC1 suppression and Akt over-activation.	1	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	3	4	19	20
mTOR complex-2 ( TORC2 ) phosphorylates key residues to activate AKT and other kinases .	mTOR complex-2 (TORC2) phosphorylates key residues to activate AKT and other kinases.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	10	11
Previous studies have reported that mTOR plays a key role in controlling cell growth , proliferation and metabolism , and mediates the PI3K and AKT signaling pathway , which is frequently dysregulated in human cancers .	Previous studies have reported that mTOR plays a key role in controlling cell growth, proliferation and metabolism, and mediates the PI3K and AKT signaling pathway, which is frequently dysregulated in human cancers.	5	26	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	5	6	24	25
The reason for this inconsistency is not clear but may be due to mTOR activation independent of AKT by 17beta-estradiol [ XREF_BIBR ] that was used for the maintenance of estrogen dependent MCF7 xenograft tumor growth in vivo .	The reason for this inconsistency is not clear but may be due to mTOR activation independent of AKT by 17beta-estradiol [XREF_BIBR] that was used for the maintenance of estrogen dependent MCF7 xenograft tumor growth in vivo.	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	13	14	17	18
Conversely , mTOR activating oncogenic signals -- such as oncogenic receptor tyrosine kinases , class I PI3Ks and AKT -- inhibit autophagy .	Conversely, mTOR activating oncogenic signals -- such as oncogenic receptor tyrosine kinases, class I PI3Ks and AKT -- inhibit autophagy.	2	20	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	18	19
Cytarabine reduced the phosphorylation of the major negative regulator of autophagy , mammalian target of rapamycin ( mTOR ) , and its downstream target p70S6 kinase in REH cells , which was associated with downregulation of mTOR activator Akt and activation of extracellular signal- regulated kinase .	Cytarabine reduced the phosphorylation of the major negative regulator of autophagy, mammalian target of rapamycin (mTOR), and its downstream target p70S6 kinase in REH cells, which was associated with downregulation of mTOR activator Akt and activation of extracellular signal- regulated kinase.	34	39	activator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	36	37	38	39
While the removal of the repetitive oxidative stress did not rescue the cells ( XREF_FIG ) , exogenous NPD1 successfully protected the cells against apoptosis ( XREF_FIG ) and reinstated the phosphorylation of both Akt and p70S6K ( XREF_FIG ) , indicating that the activation of PI3K and Akt and/or mTOR and p70S6K pathways may be the underlying mechanism of NPD1 mediated survival of RPE cells during oxidative stress .	While the removal of the repetitive oxidative stress did not rescue the cells (XREF_FIG), exogenous NPD1 successfully protected the cells against apoptosis (XREF_FIG) and reinstated the phosphorylation of both Akt and p70S6K (XREF_FIG), indicating that the activation of PI3K and Akt and/or mTOR and p70S6K pathways may be the underlying mechanism of NPD1 mediated survival of RPE cells during oxidative stress.	44	53	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	50	51	48	49
Next , to elucidate the possible mechanism , we studied the Akt and mTOR pathway , which is regarded as critical to regulate HIF-1alpha , and found that THC could reduce the phosphorylation of Akt and mTOR , ultimately inhibiting the Akt and mTOR pathway .	Next, to elucidate the possible mechanism, we studied the Akt and mTOR pathway, which is regarded as critical to regulate HIF-1alpha, and found that THC could reduce the phosphorylation of Akt and mTOR, ultimately inhibiting the Akt and mTOR pathway.	28	44	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	THC could reduce the phosphorylation of Akt and mTOR	mtor	Akt	Akt	akt	36	37	41	42
Cell lines with activating PI3K mutations show mTOR inhibition ( as measured by phosphorylation of RPS6 ) and , less reliably , inhibition of Akt .	Cell lines with activating PI3K mutations show mTOR inhibition (as measured by phosphorylation of RPS6) and, less reliably, inhibition of Akt.	7	25	inhibition	Negative_activation_syntax_7_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	7	8	24	25
Regulation of Akt activation by mTOR has received much attention , as has , in particular , the role of mTORC2 .	Regulation of Akt activation by mTOR has received much attention, as has, in particular, the role of mTORC2.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	2	3
mTOR inhibitors exert antitumor effects on several malignancies but AKT reactivation by mTOR inhibition attenuates the antitumor effects of mTOR inhibitors .	mTOR inhibitors exert antitumor effects on several malignancies but AKT reactivation by mTOR inhibition attenuates the antitumor effects of mTOR inhibitors.	9	13	reactivation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	12	13	9	10
We hypothesized , therefore , that Akt activation in IPF lung fibroblasts is mediated by the mTORC2 component of the mTOR pathway .	We hypothesized, therefore, that Akt activation in IPF lung fibroblasts is mediated by the mTORC2 component of the mTOR pathway.	6	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	20	21	6	7
Activation of PI3K leads to the generation of the second messenger PIP3 that activates phosphotidylinositol dependent kinase PDK1 , which in turn activates AKT and downstream mediators , including the mTOR and p70S6K signaling cascades .	Activation of PI3K leads to the generation of the second messenger PIP3 that activates phosphotidylinositol dependent kinase PDK1, which in turn activates AKT and downstream mediators, including the mTOR and p70S6K signaling cascades.	23	34	mediators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	30	31	23	24
The activation of the mature oocyte to initiate post-fertilisation or parthenogenetic cleavage cycles also involves the activity of Akt and PKCalpha , which can be stimulated by activated Ras and likely mTOR [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , both central regulators of senescence implicated in cancer [ XREF_BIBR , XREF_BIBR ] .	The activation of the mature oocyte to initiate post-fertilisation or parthenogenetic cleavage cycles also involves the activity of Akt and PKCalpha, which can be stimulated by activated Ras and likely mTOR [XREF_BIBR, XREF_BIBR, XREF_BIBR], both central regulators of senescence implicated in cancer [XREF_BIBR, XREF_BIBR].	16	37	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	31	32	18	19
Treatment of PC3 cells with PP242 , an mTOR ATP site inhibitor , significantly inhibits the activity of the three primary downstream mTOR effectors 4EBP1 , p70S6K1/2 and AKT .	Treatment of PC3 cells with PP242, an mTOR ATP site inhibitor, significantly inhibits the activity of the three primary downstream mTOR effectors 4EBP1, p70S6K1/2 and AKT.	8	29	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	8	9	28	29
It has been proposed that dual blockage of mTOR and upstream targets , such as PI3K and IGF1R , may enhance antitumor activity by preventing Akt overactivation .	It has been proposed that dual blockage of mTOR and upstream targets, such as PI3K and IGF1R, may enhance antitumor activity by preventing Akt overactivation.	8	26	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	8	9	25	26
We show that in Drosophila and human cells the target of rapamycin ( TOR ) kinase and its associated protein rictor are necessary for Ser473 phosphorylation and that a reduction in rictor or mammalian TOR ( mTOR ) expression inhibited an Akt and PKB effector .	We show that in Drosophila and human cells the target of rapamycin (TOR) kinase and its associated protein rictor are necessary for Ser473 phosphorylation and that a reduction in rictor or mammalian TOR (mTOR) expression inhibited an Akt and PKB effector.	36	44	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR) expression	mtor	PKB	PKB	pkb	36	37	43	44
For example , we have shown that pharmacological suppression of mammalian target of rapamycin ( mTOR ) , which is downstream from PI3K and a central node within the PI3K/AKT/mTOR axis , results in activation of both AKT and ERK , and can account for decreased efficacy of mTOR inhibitors .	For example, we have shown that pharmacological suppression of mammalian target of rapamycin (mTOR), which is downstream from PI3K and a central node within the PI3K/AKT/mTOR axis, results in activation of both AKT and ERK, and can account for decreased efficacy of mTOR inhibitors.	10	39	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	10	14	37	38
It is known that mTOR is a downstream target of Akt and a central regulator of protein synthesis , cell growth , and cell cycle progression .	It is known that mTOR is a downstream target of Akt and a central regulator of protein synthesis, cell growth, and cell cycle progression.	4	11	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	10	11
Therefore , the active mTOR signalling is needed to activate the PI3K-AKT pathway for NK cell lineage specification .	Therefore, the active mTOR signalling is needed to activate the PI3K-AKT pathway for NK cell lineage specification.	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	PI3K-AKT	PI3K-AKT	PI3K-AKT	4	5	11	12
GSK-3beta and mTOR are important downstream targets of Akt .	GSK-3beta and mTOR are important downstream targets of Akt.	0	9	are important downstream targets	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	8	9
Further studies are needed to determine whether SREBP-1 is regulated by mTOR in cancer , to dissect its metabolic consequences , and to determine whether mTOR kinase inhibitors can block PI3K and Akt mediated lipogenesis through SREBP-1 .	Further studies are needed to determine whether SREBP-1 is regulated by mTOR in cancer, to dissect its metabolic consequences, and to determine whether mTOR kinase inhibitors can block PI3K and Akt mediated lipogenesis through SREBP-1.	25	33	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	25	26	32	33
This result is in line with previous findings showing that inhibition of mTOR alone is not sufficient to abolish Akt signaling and that the combination of an mTOR inhibitor with an RTK inhibitor is more likely to have anti-tumor activity .	This result is in line with previous findings showing that inhibition of mTOR alone is not sufficient to abolish Akt signaling and that the combination of an mTOR inhibitor with an RTK inhibitor is more likely to have anti-tumor activity.	10	20	abolish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	12	13	19	20
Rapamycin and AKT inhibitor uniformly abrogated mTOR inhibition induced AKT activation but failed to induce antitumor responses in a subset of head and neck cancers ex vivo XREF_BIBR .	Rapamycin and AKT inhibitor uniformly abrogated mTOR inhibition induced AKT activation but failed to induce antitumor responses in a subset of head and neck cancers ex vivo XREF_BIBR.	6	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	6	7	9	10
Dual inhibition of PI3K and mTOR with BEZ235 could overcome acquired resistance to bortezomib in mantle cell lymphoma cells and suppress the activated Akt and mTOR pathway [ XREF_BIBR ] .	Dual inhibition of PI3K and mTOR with BEZ235 could overcome acquired resistance to bortezomib in mantle cell lymphoma cells and suppress the activated Akt and mTOR pathway [XREF_BIBR].	1	28	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	23	24
Idarubicin induced mTOR repression was associated with the activation of the mTOR inhibitor AMP activated protein kinase and down-regulation of the mTOR activator Akt .	Idarubicin induced mTOR repression was associated with the activation of the mTOR inhibitor AMP activated protein kinase and down-regulation of the mTOR activator Akt.	16	24	activator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	21	22	23	24
We found expression of mTOR , which signals downstream of Ras activated PI3K-Akt and Ras-ERK pathways and promotes effector T cell function [ XREF_BIBR - XREF_BIBR , XREF_BIBR ] was significantly downregulated in atorvastatin treated and stimulated T cells .	We found expression of mTOR, which signals downstream of Ras activated PI3K-Akt and Ras-ERK pathways and promotes effector T cell function [XREF_BIBR - XREF_BIBR, XREF_BIBR] was significantly downregulated in atorvastatin treated and stimulated T cells.	2	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	expression of mTOR	mtor	PI3K-Akt	PI3K-Akt	pi3k-akt	4	5	12	13
AKT is fully activated upon phosphorylation of serine 473 by the TORC2 complex of the mTOR protein kinase .	AKT is fully activated upon phosphorylation of serine 473 by the TORC2 complex of the mTOR protein kinase.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	15	16	0	1
The mTOR signaling pathway is mainly activated downstream of the PI3K and Akt pathway in a variety of circumstances and plays key roles in regulation of cell proliferation , apoptosis , autophagy , and metabolism of a variety of cells [ XREF_BIBR , XREF_BIBR ] .	The mTOR signaling pathway is mainly activated downstream of the PI3K and Akt pathway in a variety of circumstances and plays key roles in regulation of cell proliferation, apoptosis, autophagy, and metabolism of a variety of cells [XREF_BIBR, XREF_BIBR].	1	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	1	2	12	13
Recent data have characterized a negative feedback loop , wherein mammalian target of rapamycin ( mTOR ) blocks additional activation of the Akt and mTOR pathway through inhibition insulin receptor substrate 1 ( IRS-1 ) function .	Recent data have characterized a negative feedback loop, wherein mammalian target of rapamycin (mTOR) blocks additional activation of the Akt and mTOR pathway through inhibition insulin receptor substrate 1 (IRS-1) function.	13	25	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	15	16	22	23
AKT is completely activated upon its phosphorylation at Ser473 by mTOR complex 2 ( mTORC2 ) , a serine/threonine kinase , when it targets many proteins associated with cell survival or cell death depending on the cellular context , including mTORC1 [ XREF_BIBR ] .	AKT is completely activated upon its phosphorylation at Ser473 by mTOR complex 2 (mTORC2), a serine/threonine kinase, when it targets many proteins associated with cell survival or cell death depending on the cellular context, including mTORC1 [XREF_BIBR].	0	11	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	10	11	0	1
In accordance with this , mTOR inhibition induces AKT activation [ XREF_BIBR ] , probably due to negative feedback by p70S6K1 .	In accordance with this, mTOR inhibition induces AKT activation [XREF_BIBR], probably due to negative feedback by p70S6K1.	5	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	5	6	8	9
Both PDK1 and mTOR subsequently activate Akt through phosphorylation at distinct sites .	Both PDK1 and mTOR subsequently activate Akt through phosphorylation at distinct sites.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	3	4	6	7
Phosphorylation of mTOR signaling target of Akt , mTOR , Rictor , Raptor , S6K and S6 were analyzed .	Phosphorylation of mTOR signaling target of Akt, mTOR, Rictor, Raptor, S6K and S6 were analyzed.	0	16	target	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	Phosphorylation of mTOR	mtor	Akt	Akt	akt	2	3	6	7
mTOR is a downstream target of PI3 and Akt and was shown to regulate glycolytic metabolism [ XREF_BIBR ] .	mTOR is a downstream target of PI3 and Akt and was shown to regulate glycolytic metabolism [XREF_BIBR].	0	13	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	8	9
Detailed biochemical analysis revealed these combinations acted to suppress mTOR induced reactivation of AKT after long term duvelisib exposure , preventing both mTORC1 and mTORC2 mediated survival and growth signals .	Detailed biochemical analysis revealed these combinations acted to suppress mTOR induced reactivation of AKT after long term duvelisib exposure, preventing both mTORC1 and mTORC2 mediated survival and growth signals.	8	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	9	10	13	14
Such an increase in mTOR activity after irradiation may be attributed to radiation induced activation of Akt XREF_BIBR .	Such an increase in mTOR activity after irradiation may be attributed to radiation induced activation of Akt XREF_BIBR.	4	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	16	17
Given this , we tested the effect of inhibitors targeting the key mTOR activating kinases AKT [ XREF_BIBR - XREF_BIBR ] and ERK [ XREF_BIBR ] .	Given this, we tested the effect of inhibitors targeting the key mTOR activating kinases AKT [XREF_BIBR - XREF_BIBR] and ERK [XREF_BIBR].	9	22	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	12	13	15	16
Different studies demonstrated that AKT and mTOR pathway is hyperactive in TNBC XREF_BIBR , XREF_BIBR , so targeting AKT and mTOR pathway using suitable inhibitors is a promising choice for TNBC treatment 1 .	Different studies demonstrated that AKT and mTOR pathway is hyperactive in TNBC XREF_BIBR, XREF_BIBR, so targeting AKT and mTOR pathway using suitable inhibitors is a promising choice for TNBC treatment 1.	6	19	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	6	7	18	19
Deletion of PTEN results in over-activation of the Akt and downstream Akt targets such as mammalian target of rapamycin ( mTOR ) , which plays a critical role in the regulation of cell growth , mRNA translation , and ribosomal biogenesis .	Deletion of PTEN results in over-activation of the Akt and downstream Akt targets such as mammalian target of rapamycin (mTOR), which plays a critical role in the regulation of cell growth, mRNA translation, and ribosomal biogenesis.	11	19	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	15	19	11	12
It has been shown that mTOR is an important mediator downstream of PI-3K and Akt for eIF4E phosphorylation .	It has been shown that mTOR is an important mediator downstream of PI-3K and Akt for eIF4E phosphorylation.	5	15	is an important mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	14	15
Thus , mTOR kinase inhibition has been proposed to prevent the feedback loop activation of Akt that may attenuate the response of patients with rapamycin therapy .	Thus, mTOR kinase inhibition has been proposed to prevent the feedback loop activation of Akt that may attenuate the response of patients with rapamycin therapy.	2	16	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	15	16
There was also the observation that combined inhibition of the class I PI3Ks and mTor eliminated the increased Akt signaling that an mTor inhibitor alone often caused .	There was also the observation that combined inhibition of the class I PI3Ks and mTor eliminated the increased Akt signaling that an mTor inhibitor alone often caused.	7	19	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTor	mTor	mTor	Akt	Akt	Akt	14	15	18	19
The biphasic inhibition and subsequent mTOR independent reactivation of AKT is likely due to parallel changes in T308 phosphorylation .	The biphasic inhibition and subsequent mTOR independent reactivation of AKT is likely due to parallel changes in T308 phosphorylation.	5	10	reactivation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	5	6	9	10
Activation of survival pathways is involved in hormone escape XREF_BIBR , such as Her-2 and neu ( a growth factor receptor tyrosine kinase ) , mTOR and AKT ( target of rapamycin and AKT ) , or ERK1 ,2 ( extracellular-signal-regulated kinase ) , all implicated in AR phosphorylation XREF_BIBR , XREF_BIBR .	Activation of survival pathways is involved in hormone escape XREF_BIBR, such as Her-2 and neu (a growth factor receptor tyrosine kinase), mTOR and AKT (target of rapamycin and AKT), or ERK1,2 (extracellular-signal-regulated kinase), all implicated in AR phosphorylation XREF_BIBR, XREF_BIBR.	9	34	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	25	26	33	34
This combined inhibition of p110alpha and mTOR eliminated the increased Akt signaling often observed using allosteric inhibitors of mTOR as monotherapy ( XREF_FIG ) and likely antagonizing the potential efficacy of mTOR inhibitors .	This combined inhibition of p110alpha and mTOR eliminated the increased Akt signaling often observed using allosteric inhibitors of mTOR as monotherapy (XREF_FIG) and likely antagonizing the potential efficacy of mTOR inhibitors.	2	11	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	6	7	10	11
Here , we show that simultaneous inhibition of mTOR signaling to both S6K1 and 4E-BP1 is sufficient to reduce AKT induced muscle growth and render it insensitive to the mTORC1-inhibitor rapamycin .	Here, we show that simultaneous inhibition of mTOR signaling to both S6K1 and 4E-BP1 is sufficient to reduce AKT induced muscle growth and render it insensitive to the mTORC1-inhibitor rapamycin.	8	20	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	8	9	19	20
mTOR mediates downstream signaling of PI3K and Akt by increased Akt phosphorylation [ XREF_BIBR ] .	mTOR mediates downstream signaling of PI3K and Akt by increased Akt phosphorylation [XREF_BIBR].	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	7	8
Accordingly , co-targeting mTOR and PI3K and Akt signaling prevents mTOR inhibition initiated Akt activation and enhances antitumor effects both in cell cultures and in animal xenograft models , suggesting an effective cancer therapeutic strategy .	Accordingly, co-targeting mTOR and PI3K and Akt signaling prevents mTOR inhibition initiated Akt activation and enhances antitumor effects both in cell cultures and in animal xenograft models, suggesting an effective cancer therapeutic strategy.	2	14	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	3	4	13	14
This mTOR blockade in turn suppresses activation of Akt , a protein kinase with a major role in maintaining neuron survival , and it is this action that appears to underlie , at least in part , the pro apoptotic actions of PD toxins and RTP801 .	This mTOR blockade in turn suppresses activation of Akt, a protein kinase with a major role in maintaining neuron survival, and it is this action that appears to underlie, at least in part, the pro apoptotic actions of PD toxins and RTP801.	1	12	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	1	2	8	9
Gastrodin could protect against H/R injury of myocardial cells in neonatal rats by reducing the level of autophagy through the activation of mTOR signals in PI3K-Akt pathway .	Gastrodin could protect against H/R injury of myocardial cells in neonatal rats by reducing the level of autophagy through the activation of mTOR signals in PI3K-Akt pathway.	22	26	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	PI3K-Akt	PI3K-Akt	PI3K-Akt	22	23	25	26
mTOR is the downstream target of Akt signaling and Akt may directly phosphorylate its Serine 2448 .	mTOR is the downstream target of Akt signaling and Akt may directly phosphorylate its Serine 2448.	0	10	is the downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	9	10
Given that mTOR , p70S6K , and 4E-BP1 are all downstream targets of the kinase Akt , we next tested whether miR-21 deficiency also affected TLR induced Akt activation .	Given that mTOR, p70S6K, and 4E-BP1 are all downstream targets of the kinase Akt, we next tested whether miR-21 deficiency also affected TLR induced Akt activation.	2	16	are all downstream targets	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	15	16
Further , mTOR can increase the activity of Akt and thus enhance the effect of this signaling pathway .	Further, mTOR can increase the activity of Akt and thus enhance the effect of this signaling pathway.	2	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	8	9
This could perhaps be due to the slower time course of activation due to insulin activation of PI3K which in turn activated AKT , but not subsequently mTOR .	This could perhaps be due to the slower time course of activation due to insulin activation of PI3K which in turn activated AKT, but not subsequently mTOR.	15	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	27	28	22	23
However , this inhibition of Akt signaling was attributed to statin mediated activation of mTOR kinase , which inhibits Akt by a negative feedback loop utilizing IRS1/2 [ XREF_BIBR , XREF_BIBR ] .	However, this inhibition of Akt signaling was attributed to statin mediated activation of mTOR kinase, which inhibits Akt by a negative feedback loop utilizing IRS1/2 [XREF_BIBR, XREF_BIBR].	10	20	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	statin mediated activation of mTOR	mtor	Akt	Akt	akt	14	15	19	20
Pharmacologic inhibition of PARP-1 promotes Akt activity and mTOR signaling resulting in decreased cell death , although these results are contradicted by a recent report showing PHLPP1 mediated downregulation of Akt activity and increased cell death following PARP inhibition .	Pharmacologic inhibition of PARP-1 promotes Akt activity and mTOR signaling resulting in decreased cell death, although these results are contradicted by a recent report showing PHLPP1 mediated downregulation of Akt activity and increased cell death following PARP inhibition.	8	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	8	9	30	31
Blocking PI3K may decrease the upregulation of Akt signaling induced by mTOR inhibition .	Blocking PI3K may decrease the upregulation of Akt signaling induced by mTOR inhibition.	7	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	11	12	7	8
Initial characterization ex vivo of primary mammary tumor cells confirmed that inhibition of mTOR by AZD8055 significantly reduced AKT , mTORC1 and mTORC2 and glycolytic activities [ XREF_BIBR ] .	Initial characterization ex vivo of primary mammary tumor cells confirmed that inhibition of mTOR by AZD8055 significantly reduced AKT, mTORC1 and mTORC2 and glycolytic activities [XREF_BIBR].	11	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	13	14	18	19
Recent studies have determined that mTOR mediates the activation of the protein kinase Akt in several cell types , but little is known about the association between mTOR and Akt in vascular endothelial cells .	Recent studies have determined that mTOR mediates the activation of the protein kinase Akt in several cell types, but little is known about the association between mTOR and Akt in vascular endothelial cells.	5	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	13	14
Given that mTOR is a downstream target of the Akt and Erk 1/2 pathways as previously mentioned , and VEGF-B has been shown to upregulate these pathways in a PD model system [ XREF_BIBR ] , it is possible that VEGF-B ' s protective effects involve mTOR downstream of increased Akt and Erk , reducing apoptosis and protecting neurons from injury ( XREF_FIG ) .	Given that mTOR is a downstream target of the Akt and Erk 1/2 pathways as previously mentioned, and VEGF-B has been shown to upregulate these pathways in a PD model system [XREF_BIBR], it is possible that VEGF-B 's protective effects involve mTOR downstream of increased Akt and Erk, reducing apoptosis and protecting neurons from injury (XREF_FIG).	2	11	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	9	10
The Akt downstream target mTORC1 was likewise activated as indicated by both mTOR phosphorylation and phosphorylation of the mTORC1 target p70 S6K ( XREF_FIG ) .	The Akt downstream target mTORC1 was likewise activated as indicated by both mTOR phosphorylation and phosphorylation of the mTORC1 target p70 S6K (XREF_FIG).	0	14	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	mTOR	mTOR phosphorylation	mtor	Akt	Akt	akt	12	13	1	2
Our data show that mTOR kinase inhibition does initially inhibit AKT activity , but this inhibition is limited by relief of feedback inhibition of receptor tyrosine kinases , leading to induction of PI3K activity .	Our data show that mTOR kinase inhibition does initially inhibit AKT activity, but this inhibition is limited by relief of feedback inhibition of receptor tyrosine kinases, leading to induction of PI3K activity.	4	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	4	5	10	11
We and others have previously discovered that , in addition to inhibiting the kinase activity of mTOR , rapamycin and RAD001 can also activate Akt and ERK1/2 survival signaling pathways , this effect contributes to resistance of lung and breast cancer cells to mTOR inhibition .	We and others have previously discovered that, in addition to inhibiting the kinase activity of mTOR, rapamycin and RAD001 can also activate Akt and ERK1/2 survival signaling pathways, this effect contributes to resistance of lung and breast cancer cells to mTOR inhibition.	14	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	16	17	24	25
AKT is fully activated upon further phosphorylation at Ser473 by the mTOR complex 2 ( mTORC2 ) [ XREF_BIBR , XREF_BIBR ] .	AKT is fully activated upon further phosphorylation at Ser473 by the mTOR complex 2 (mTORC2) [XREF_BIBR, XREF_BIBR].	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	11	12	0	1
It was observed that combined inhibition of the Class I PI3Ks and mTor eliminated the increased Akt signaling seen with mTor-rictor inhibitors .	It was observed that combined inhibition of the Class I PI3Ks and mTor eliminated the increased Akt signaling seen with mTor-rictor inhibitors.	5	17	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTor	mTor	mTor	Akt	Akt	Akt	12	13	16	17
S6K , Akt , and 4E-BP1 were modulated by mTOR mediators only in the presence of increased eIF4E .	S6K, Akt, and 4E-BP1 were modulated by mTOR mediators only in the presence of increased eIF4E.	0	10	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	9	10	2	3
Downstream , ATF6alpha induces survival through the up-regulation of Rheb and activation of mTOR signaling independent of Akt .	Downstream, ATF6alpha induces survival through the up-regulation of Rheb and activation of mTOR signaling independent of Akt.	13	18	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	13	14	17	18
Thus , mTOR kinase inhibition should prevent the feedback activation of AKT signaling that has attenuated the response of patients with rapamycin therapy .	Thus, mTOR kinase inhibition should prevent the feedback activation of AKT signaling that has attenuated the response of patients with rapamycin therapy.	2	12	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	11	12
Mammalian target of rapamycin can either positively or negatively regulate AKT signalling , and this is dependent on the composition of the mTOR signalling complex .	Mammalian target of rapamycin can either positively or negatively regulate AKT signalling, and this is dependent on the composition of the mTOR signalling complex.	0	11	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	AKT	AKT	AKT	0	4	10	11
Like pan-PI3K and mTOR inhibitors , mTOR kinase inhibitors fully block both mTORC1 and mTORC2 and generally prevent the acute PI3K and AKT rebound effect of rapalogs .	Like pan-PI3K and mTOR inhibitors, mTOR kinase inhibitors fully block both mTORC1 and mTORC2 and generally prevent the acute PI3K and AKT rebound effect of rapalogs.	6	24	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	6	7	22	23
[ XREF_BIBR ] On the other hand , inhibition of mTOR ( downstream target of Akt ) using RAD001 ( Novartis , NY , USA ) has been shown to improve the response to Trastuzumab in the breast cancer models of PTEN-loss and provide some clinical benefit in a phase I/II study , involving a small number of patients .	[XREF_BIBR] On the other hand, inhibition of mTOR (downstream target of Akt) using RAD001 (Novartis, NY, USA) has been shown to improve the response to Trastuzumab in the breast cancer models of PTEN-loss and provide some clinical benefit in a phase I/II study, involving a small number of patients.	8	17	target	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	10	11	15	16
Testosterone treatment on L6 myotubes increased mTOR and p70 phosphorylation but failed to increase Akt activation .	Testosterone treatment on L6 myotubes increased mTOR and p70 phosphorylation but failed to increase Akt activation.	0	15	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	Testosterone treatment on L6 myotubes increased mTOR and p70 phosphorylation	mtor	Akt	Akt	akt	6	7	14	15
Note that mTOR itself activates Akt and downregulates insulin signaling , inhibiting IRS-1 [ XREF_BIBR ] .	Note that mTOR itself activates Akt and downregulates insulin signaling, inhibiting IRS-1 [XREF_BIBR].	0	7	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	5	6
Raptor bound mTOR ( mTORC1 ) governs cap dependent mRNA translation , whereas mTOR , rictor , and mSin1 ( mTORC2 ) activate the survival and proliferative kinase Akt .	Raptor bound mTOR (mTORC1) governs cap dependent mRNA translation, whereas mTOR, rictor, and mSin1 (mTORC2) activate the survival and proliferative kinase Akt.	13	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	13	14	28	29
eEF1A1 expression has clear effects on the proliferation enhancement and apoptosis inhibition of Jurkat cells , which may be intervened by the up-regulation of PI3K/Akt/NF-kappaB and PI3K and Akt / mTOR signaling pathway XREF_BIBR .	eEF1A1 expression has clear effects on the proliferation enhancement and apoptosis inhibition of Jurkat cells, which may be intervened by the up-regulation of PI3K/Akt/NF-kappaB and PI3K and Akt / mTOR signaling pathway XREF_BIBR.	22	33	up-regulation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	30	31	28	29
Rapamycin-insensitive mTOR Complex 2 ( mTORC2 ) activates Akt and also regulates actin cytoskeleton .	Rapamycin-insensitive mTOR Complex 2 (mTORC2) activates Akt and also regulates actin cytoskeleton.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	1	2	8	9
The data strongly suggest that the mTOR mediated network in PTEN-null tumor is independent of AKT activity .	The data strongly suggest that the mTOR mediated network in PTEN-null tumor is independent of AKT activity.	5	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	6	7	15	16
For example , it is has been suggested that tumors resulting from TSC1/2 loss are relatively benign since increased activity of the mTOR negative feedback loop inhibits Akt .	For example, it is has been suggested that tumors resulting from TSC1/2 loss are relatively benign since increased activity of the mTOR negative feedback loop inhibits Akt.	22	28	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	22	23	27	28
The AKT target mTOR was also inhibited as shown by a decrease in mTOR phosphorylation at serine 2448 followed by P70S6K downregulation .	The AKT target mTOR was also inhibited as shown by a decrease in mTOR phosphorylation at serine 2448 followed by P70S6K downregulation.	0	6	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	3	4	1	2
Inhibition of MTOR by rapamycin decreased basal levels of protein O GlcNAcylation , decreased AKT activation and partially reversed the effect of thiamet G on alpha-synuclein monomer accumulation .	Inhibition of MTOR by rapamycin decreased basal levels of protein O GlcNAcylation, decreased AKT activation and partially reversed the effect of thiamet G on alpha-synuclein monomer accumulation.	0	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MTOR	MTOR	MTOR	AKT	AKT	AKT	2	3	14	15
Considering mTOR inhibition leads to macroautophagy and the ability of HBSS to inhibit Akt and mTOR signaling , we used mTOR inhibitor rapamycin to check the role of mTOR inhibition in HIF-1alpha expression .	Considering mTOR inhibition leads to macroautophagy and the ability of HBSS to inhibit Akt and mTOR signaling, we used mTOR inhibitor rapamycin to check the role of mTOR inhibition in HIF-1alpha expression.	1	16	inhibit	Negative_activation_syntax_5_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	1	2	13	14
In addition , mTOR can also activate Akt , which results in an increase in cell survival and proliferation .	In addition, mTOR can also activate Akt, which results in an increase in cell survival and proliferation.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	3	4	7	8
Activated mTOR complexes ( mTORC1 ) , downstream of PI3K-AKT , result in increased ribosomal protein synthesis and further AKT activation ( mTORC2 ) .	Activated mTOR complexes (mTORC1), downstream of PI3K-AKT, result in increased ribosomal protein synthesis and further AKT activation (mTORC2).	1	21	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	1	2	19	20
The increased phosphorylations of PI3K , AKT and mTOR , and the up-regulation of CXCL8 induced by miR-204 suppression were all abolished by addition of LY294002 and AZD8055 ( inhibitors of PI3K and AKT and mTOR , respectively ) .	The increased phosphorylations of PI3K, AKT and mTOR, and the up-regulation of CXCL8 induced by miR-204 suppression were all abolished by addition of LY294002 and AZD8055 (inhibitors of PI3K and AKT and mTOR, respectively).	2	34	inhibitors	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	mTOR	phosphorylations of PI3K, AKT and mTOR, and the up-regulation of CXCL8 induced by miR-204 suppression were all abolished by addition of LY294002	mtor	AKT	AKT	akt	8	9	33	34
As shown in Figure XREF_FIG , phosphorylation of the mTOR targets AKT S473 and the pS6 is prominent in all HNSCC cell lines .	As shown in Figure XREF_FIG, phosphorylation of the mTOR targets AKT S473 and the pS6 is prominent in all HNSCC cell lines.	6	12	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of the mTOR	mtor	AKT	AKT	akt	9	10	11	12
Early clinical trials of everolimus , an inhibitor of mammalian target of rapamycin ( mTOR ) which activates the AKT pathway , [ XREF_BIBR ] failed to show activity against GBM which was attributed to p-glycoprotein-mediated mutli-drug resistance pathway expression , [ XREF_BIBR ] drug detoxification , and/or the redundancy of growth pathways that circumvented inhibition of AKT .	Early clinical trials of everolimus, an inhibitor of mammalian target of rapamycin (mTOR) which activates the AKT pathway, [XREF_BIBR] failed to show activity against GBM which was attributed to p-glycoprotein-mediated mutli-drug resistance pathway expression, [XREF_BIBR] drug detoxification, and/or the redundancy of growth pathways that circumvented inhibition of AKT.	12	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	14	15	19	20
SRC and mTOR inhibition in HCC2429 synergistically inactivate AKT and reduce cell survival .	SRC and mTOR inhibition in HCC2429 synergistically inactivate AKT and reduce cell survival.	0	9	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	8	9
Akt signaling is induced by PI3K , which generates the lipid messenger phosphatidylinositol-3 ,4,5-trisphosphate ( PtdIns ( 3,4,5 ) P 3 ) and recruits Akt to the plasma membrane , as well as by the mTOR complex 2 ( mTORC2 ) , which activates Akt at the plasma membrane ( Box 1 ) .	Akt signaling is induced by PI3K, which generates the lipid messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns (3,4,5) P 3) and recruits Akt to the plasma membrane, as well as by the mTOR complex 2 (mTORC2), which activates Akt at the plasma membrane (Box 1).	35	45	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	35	36	44	45
Targeted silencing of Akt showed that Akt did not regulate mTOR activation in PC-3 cells , but targeted silencing of mTOR sensitized PC-3 cells to CDDO-Me mediated growth inhibition .	Targeted silencing of Akt showed that Akt did not regulate mTOR activation in PC-3 cells, but targeted silencing of mTOR sensitized PC-3 cells to CDDO-Me mediated growth inhibition.	0	21	Targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	20	21	3	4
CDK2-cyclin A2 or mTOR activate AKT via phosphorylation of the C-terminal residues S477 and T479 .	CDK2-cyclin A2 or mTOR activate AKT via phosphorylation of the C-terminal residues S477 and T479.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	3	4	5	6
The mTOR signaling pathway is mainly activated downstream of the PI3K and Akt pathway in a variety of circumstances and plays key roles in regulation of survival , growth , and metabolism of a variety of cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The mTOR signaling pathway is mainly activated downstream of the PI3K and Akt pathway in a variety of circumstances and plays key roles in regulation of survival, growth, and metabolism of a variety of cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	1	2	12	13
Both mTOR and BAD are the phosphorylating targets of Akt .	Both mTOR and BAD are the phosphorylating targets of Akt.	0	10	are the phosphorylating targets	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	1	2	9	10
Activated AKT indirectly activates mTOR through a phosphorylation of a number of targets downstream .	Activated AKT indirectly activates mTOR through a phosphorylation of a number of targets downstream.	0	7	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	4	5	1	2
These result argued that mTORC1 control of PtdIns ( 3,4,5 ) P 3 dominated mTORC2 control of Akt in CTLs , such that catalytic inhibitors of mTOR did not effectively disrupt Akt activity .	These result argued that mTORC1 control of PtdIns (3,4,5) P 3 dominated mTORC2 control of Akt in CTLs, such that catalytic inhibitors of mTOR did not effectively disrupt Akt activity.	24	32	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	26	27	31	32
We investigated whether EGb 761 regulates Akt downstream targets , including mTOR , p70S6 kinase , and S6 phosphorylation .	We investigated whether EGb 761 regulates Akt downstream targets, including mTOR, p70S6 kinase, and S6 phosphorylation.	6	19	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	mTOR	mTOR, p70S6 kinase, and S6 phosphorylation	mtor	Akt	Akt	akt	11	12	6	7
Receptor mediated activation of PI3K family kinases generates inositol phospholipids that activate the protein kinase Akt , which phosphorylates multiple substrates including Foxo transcription factors , glycogen synthase kinase ( GSK3beta ) , and the mammalian target of rapamycin ( mTOR ) .	Receptor mediated activation of PI3K family kinases generates inositol phospholipids that activate the protein kinase Akt, which phosphorylates multiple substrates including Foxo transcription factors, glycogen synthase kinase (GSK3beta), and the mammalian target of rapamycin (mTOR).	9	41	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	40	41	15	16
There is an ever growing interest in an Akt pathway that is activated by mTOR , rather than PI3K , because deregulation of mTOR is an emerging theme in diverse human diseases [ reviewed in [ XREF_BIBR ] ] .	There is an ever growing interest in an Akt pathway that is activated by mTOR, rather than PI3K, because deregulation of mTOR is an emerging theme in diverse human diseases [reviewed in [XREF_BIBR]].	8	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	14	15	8	9
Downstream , the PI3K-Akt pathway is mediated by the serine/threonine kinase mTOR , which regulates basic cellular functions such as cellular growth and proliferation .	Downstream, the PI3K-Akt pathway is mediated by the serine/threonine kinase mTOR, which regulates basic cellular functions such as cellular growth and proliferation.	3	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	PI3K-Akt	PI3K-Akt	PI3K-Akt	11	12	3	4
mTOR is a downstream target of Akt , and we hypothesized that mTOR signaling was activated in ECs of SAS-R tumors .	mTOR is a downstream target of Akt, and we hypothesized that mTOR signaling was activated in ECs of SAS-R tumors.	0	7	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	6	7
Rac1 Regulates mTOR Signaling Independently of the PI3K and Akt Pathway .	Rac1 Regulates mTOR Signaling Independently of the PI3K and Akt Pathway.	2	10	Signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	9	10
Knockout of the mTOR signaling molecule rictor prevents Akt from inactivating GSK3 upon TLR4 stimulation , correlating with increased FoxO1 activity and pro inflammatory gene expression .	Knockout of the mTOR signaling molecule rictor prevents Akt from inactivating GSK3 upon TLR4 stimulation, correlating with increased FoxO1 activity and pro inflammatory gene expression.	3	9	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	3	4	8	9
Furthermore , mTOR independent targets of Akt ( e.g ., Forkhead box ( FOXO ) , GSK-3beta ) can also contribute to increased cell proliferation and survival [ XREF_BIBR ] .	Furthermore, mTOR independent targets of Akt (e.g., Forkhead box (FOXO), GSK-3beta) can also contribute to increased cell proliferation and survival [XREF_BIBR].	2	11	targets	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	6	7
mTOR kinase inhibitors reduced AKT downstream function and inhibited proliferation of diverse cancer cell lines .	mTOR kinase inhibitors reduced AKT downstream function and inhibited proliferation of diverse cancer cell lines.	0	6	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	4	5
Third , the incomplete suppression of Nf1 deficient glial cell proliferation in vivo following 5mg/kg/day rapamycin treatment reflects mTOR mediated AKT activation , such that combined 5mg/kg/day rapamycin and PI3-Kinase ( PI3K ) inhibition or dual PI3K and mTOR inhibition recapitulates the growth suppressive effects of 20mg/kg/day rapamycin .	Third, the incomplete suppression of Nf1 deficient glial cell proliferation in vivo following 5mg/kg/day rapamycin treatment reflects mTOR mediated AKT activation, such that combined 5mg/kg/day rapamycin and PI3-Kinase (PI3K) inhibition or dual PI3K and mTOR inhibition recapitulates the growth suppressive effects of 20mg/kg/day rapamycin.	17	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	18	19	20	21
Therefore , the functional relationship between ERK and Akt after ischemic insults and whether mTOR is the downstream target of Akt that regulates neuron survival in ischemic brain injury require further investigation .	Therefore, the functional relationship between ERK and Akt after ischemic insults and whether mTOR is the downstream target of Akt that regulates neuron survival in ischemic brain injury require further investigation.	14	21	is the downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	14	15	20	21
On the other hand , mTOR complex 2 ( mTORC2 ) again activates AKT and can induce the expression of HIF-2alpha [ XREF_BIBR ] , an anti-apoptotic transcription factor , highly important in tumorigenesis [ XREF_BIBR ] .	On the other hand, mTOR complex 2 (mTORC2) again activates AKT and can induce the expression of HIF-2alpha [XREF_BIBR], an anti-apoptotic transcription factor, highly important in tumorigenesis [XREF_BIBR].	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	5	6	13	14
mTOR is a critical target of AKT that subsequently activates proteins such as S6 kinase , impacting protein translation and progression of the cell cycle [ XREF_BIBR - XREF_BIBR ] .	mTOR is a critical target of AKT that subsequently activates proteins such as S6 kinase, impacting protein translation and progression of the cell cycle [XREF_BIBR - XREF_BIBR].	0	7	is a critical target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	6	7
Rapamycin inhibits mTOR complex1 ( mTORC1 ) that is a master growth regulator and promotes protein synthesis [ XREF_BIBR ] , while KU0063794 inhibits mTOR complex 2 ( mTORC2 ) that can activate Akt for cellular survival as well as mTORC1 [ XREF_BIBR ] .	Rapamycin inhibits mTOR complex1 (mTORC1) that is a master growth regulator and promotes protein synthesis [XREF_BIBR], while KU0063794 inhibits mTOR complex 2 (mTORC2) that can activate Akt for cellular survival as well as mTORC1 [XREF_BIBR].	24	42	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	24	25	33	34
Kinases phosphorylated within 2h of pseudovirus addition included focal adhesion kinase ( FAK ) , many of the SRC family kinases ( SFKs ) , as well as PI3K and AKT targets , including MTOR , PRAS40 , and WNK1 ( XREF_FIG ) .	Kinases phosphorylated within 2h of pseudovirus addition included focal adhesion kinase (FAK), many of the SRC family kinases (SFKs), as well as PI3K and AKT targets, including MTOR, PRAS40, and WNK1 (XREF_FIG).	28	41	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	MTOR	MTOR	MTOR	AKT	AKT	AKT	34	35	30	31
Recently , the inhibition of mTOR has been shown to reverse Akt dependent prostate intraepithelial neoplasia .	Recently, the inhibition of mTOR has been shown to reverse Akt dependent prostate intraepithelial neoplasia.	3	13	reverse	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	11	12
For example , in insulin secreting beta-cells overactivated by nutrients and insulin , mTOR causes cellular hypertrophy/hyperplasia/hyperfunction and secondary insensitivity to IGF-1 and deactivation of Akt , leading to beta-cell death [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	For example, in insulin secreting beta-cells overactivated by nutrients and insulin, mTOR causes cellular hypertrophy/hyperplasia/hyperfunction and secondary insensitivity to IGF-1 and deactivation of Akt, leading to beta-cell death [XREF_BIBR, XREF_BIBR, XREF_BIBR].	13	26	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	13	14	25	26
As the Jak and STAT signaling path , the Akt signaling is triggered by receptor tyrosine kinases that increase PI3K levels , activating AKT , phosphorylating several targets including mTOR .	As the Jak and STAT signaling path, the Akt signaling is triggered by receptor tyrosine kinases that increase PI3K levels, activating AKT, phosphorylating several targets including mTOR.	23	30	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	29	30	23	24
Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in profound cell death and tumor regression in vivo .	Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in profound cell death and tumor regression in vivo.	3	12	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	3	4	11	12
Importantly , we found that curcumin reduced Akt , mTOR and P70S6K phosphorylation , effectively suppressing the activity of the Akt and mTOR pathway in HKCs .	Importantly, we found that curcumin reduced Akt, mTOR and P70S6K phosphorylation, effectively suppressing the activity of the Akt and mTOR pathway in HKCs.	5	23	suppressing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	curcumin reduced Akt, mTOR and P70S6K phosphorylation	mtor	Akt	Akt	akt	9	10	20	21
IGF in the mTOR signaling pathway , and interleukin 7 receptor ( IL7R ) in the JAK-STAT signaling pathway may activate the PI3K-AKT network [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	IGF in the mTOR signaling pathway, and interleukin 7 receptor (IL7R) in the JAK-STAT signaling pathway may activate the PI3K-AKT network [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	22	23
mTOR is a downstream target of Akt that integrates signals from multiple pathways , including nutrients ( e.g ., amino acids and glucose ) , growth factors ( e.g ., insulin and insulin like growth factor 1 ) , hormones ( e.g ., leptin ) , and stresses ( e.g ., starvation , hypoxia , and DNA damage ) to regulate a wide variety of eukaryotic cellular functions , such as translation , transcription , protein turnover , cell growth , differentiation , cell survival , metabolism , energy balance , and stress response .	mTOR is a downstream target of Akt that integrates signals from multiple pathways, including nutrients (e.g., amino acids and glucose), growth factors (e.g., insulin and insulin like growth factor 1), hormones (e.g., leptin), and stresses (e.g., starvation, hypoxia, and DNA damage) to regulate a wide variety of eukaryotic cellular functions, such as translation, transcription, protein turnover, cell growth, differentiation, cell survival, metabolism, energy balance, and stress response.	0	57	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	6	7
In this study , we hypothesized that the mammalian target of rapamycin ( mTOR ) pathway , which functions downstream of AKT , mediates the oncogenic effects of activated PI3K and AKT in ALK+ ALCL .	In this study, we hypothesized that the mammalian target of rapamycin (mTOR) pathway, which functions downstream of AKT, mediates the oncogenic effects of activated PI3K and AKT in ALK+ ALCL.	11	32	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	13	14	31	32
Likewise , chronic ER stress obstructs activation of Akt by mTOR complex 2 .	Likewise, chronic ER stress obstructs activation of Akt by mTOR complex 2.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	10	11	8	9
After 72 h incubation with EVE , there was no recovery of mTOR activation or feedback activation of AKT .	After 72 h incubation with EVE, there was no recovery of mTOR activation or feedback activation of AKT.	12	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	12	13	18	19
mTOR is an important target of Akt and exist in two distinct functional complexes , mTOR complex I and mTOR complex II [ XREF_BIBR ] .	mTOR is an important target of Akt and exist in two distinct functional complexes, mTOR complex I and mTOR complex II [XREF_BIBR].	0	8	is an important target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	6	7
Activated AKT induces the activation of the mTOR pathway promoting cell proliferation and inducing inhibition of proapoptotic proteins .	Activated AKT induces the activation of the mTOR pathway promoting cell proliferation and inducing inhibition of proapoptotic proteins.	0	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	7	8	1	2
Testosterone ( T ) sensitivity of Akt and mTORC1 signaling was examined in C 2 C 12 myotubes , and mTOR phosphorylation was induced independent of Akt activation at low T concentrations , while a higher T concentration was required to activate Akt signaling .	Testosterone (T) sensitivity of Akt and mTORC1 signaling was examined in C 2 C 12 myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling.	20	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR phosphorylation	mtor	Akt	Akt	akt	20	21	26	27
These include PI3K inhibitors , AKT inhibitors , and inhibitors of downstream effectors such as mTOR ( mammalian target of rapamycin ) , a serine threonine kinase that mediates PI3K-AKT signaling .	These include PI3K inhibitors, AKT inhibitors, and inhibitors of downstream effectors such as mTOR (mammalian target of rapamycin), a serine threonine kinase that mediates PI3K-AKT signaling.	12	30	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	PI3K-AKT	PI3K-AKT	PI3K-AKT	15	16	29	30
Further , a combination of SRC and mTOR inhibition synergistically blocked activation of AKT and induced apoptosis .	Further, a combination of SRC and mTOR inhibition synergistically blocked activation of AKT and induced apoptosis.	5	14	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	7	8	13	14
mTOR is a downstream target of Akt , which is activated by RTK activation and PTEN loss .	mTOR is a downstream target of Akt, which is activated by RTK activation and PTEN loss.	0	10	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	6	7
As part of complex 2 ( mTORC2 ) , mTOR is a critical activator of Akt .	As part of complex 2 (mTORC2), mTOR is a critical activator of Akt.	9	16	is a critical activator	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	9	10	15	16
mTOR is a downstream target of Akt and may be responsible for Akt ' s regulation of cell growth .	mTOR is a downstream target of Akt and may be responsible for Akt 's regulation of cell growth.	0	10	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	6	7
Several observations also suggest that mTOR dependent activation of Akt is implicated in the production of VEGF [ XREF_BIBR ] , in angiogenesis [ XREF_BIBR ] , and in other EC-responses pertinent to pro inflammation [ XREF_BIBR , XREF_BIBR ] .	Several observations also suggest that mTOR dependent activation of Akt is implicated in the production of VEGF [XREF_BIBR], in angiogenesis [XREF_BIBR], and in other EC-responses pertinent to pro inflammation [XREF_BIBR, XREF_BIBR].	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	9	10
The phosphoinositide 3-kinase AKT ( PI3K-AKT ) network , which is activated by the mTOR or JAK-STAT signaling pathways , mediates intracellular signals to regulate a variety of cellular responses , including antiapoptosis , proliferation , and cell cycling [ XREF_BIBR ] .	The phosphoinositide 3-kinase AKT (PI3K-AKT) network, which is activated by the mTOR or JAK-STAT signaling pathways, mediates intracellular signals to regulate a variety of cellular responses, including antiapoptosis, proliferation, and cell cycling [XREF_BIBR].	5	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	PI3K-AKT	PI3K-AKT	PI3K-AKT	14	15	5	6
It is well known that activated mTOR , a key downstream effector in the Akt pathway , is able to induce suppression of multiple Akt downstream targets .	It is well known that activated mTOR, a key downstream effector in the Akt pathway, is able to induce suppression of multiple Akt downstream targets.	5	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	6	7	24	25
mTOR pathway induces de novo EGFR and Akt protein synthesis .	mTOR pathway induces de novo EGFR and Akt protein synthesis.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	7	8
Mechanistically , deficiency of mTOR activity in HSC enriched population results in reduced activation of S6K1 and increased activation of Akt at Ser 473 .	Mechanistically, deficiency of mTOR activity in HSC enriched population results in reduced activation of S6K1 and increased activation of Akt at Ser 473.	4	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	20	21
Inhibition of mTOR ( mammalian target of rapamycin ) , a downstream effector of the PI3K and Akt pathway , blocked the effects of Akt on morphogenesis and oncogene driven proliferation .	Inhibition of mTOR (mammalian target of rapamycin), a downstream effector of the PI3K and Akt pathway, blocked the effects of Akt on morphogenesis and oncogene driven proliferation.	0	25	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	24	25
Both NF-kappaB and mTOR are targets of Akt and Akt regulates the activation of NF-kappaB and mTOR through activation of IKKalpha and small GTPase Rheb , respectively .	Both NF-kappaB and mTOR are targets of Akt and Akt regulates the activation of NF-kappaB and mTOR through activation of IKKalpha and small GTPase Rheb, respectively.	1	9	are targets	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	3	4	7	8
Furthermore , rapamycin , a specific inhibitor of mTOR , blocked the activation of mTOR and p70S6K but not PI3K and Akt .	Furthermore, rapamycin, a specific inhibitor of mTOR, blocked the activation of mTOR and p70S6K but not PI3K and Akt.	6	22	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	8	9	21	22
14 However , IGF-1R inhibition suppresses mTOR induced Akt activation and sensitises tumour cells to mTOR inhibitors .	14 However, IGF-1R inhibition suppresses mTOR induced Akt activation and sensitises tumour cells to mTOR inhibitors.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	6	7	8	9
Because one of the major activities of AKT is to promote cell survival , we sought to investigate whether UVB induced mTOR activation of AKT dependent pathways plays a role in preventing cell death following high dose UVB .	Because one of the major activities of AKT is to promote cell survival, we sought to investigate whether UVB induced mTOR activation of AKT dependent pathways plays a role in preventing cell death following high dose UVB.	19	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	UVB induced mTOR	mtor	AKT	AKT	akt	21	22	24	25
PI3K and mTOR dual inhibitors target the active sites of both proteins inhibiting the pathway both upstream and downstream of Akt , overcoming the mTORC1-p70S6K-IRS1 negative feedback loop , and blocking PI3K independent mTOR activation XREF_BIBR , XREF_BIBR ( XREF_FIG ) .	PI3K and mTOR dual inhibitors target the active sites of both proteins inhibiting the pathway both upstream and downstream of Akt, overcoming the mTORC1-p70S6K-IRS1 negative feedback loop, and blocking PI3K independent mTOR activation XREF_BIBR, XREF_BIBR (XREF_FIG).	0	21	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	20	21
Collectively , our results suggest that EGFR blockade decreases mTOR activation in an Akt independent manner .	Collectively, our results suggest that EGFR blockade decreases mTOR activation in an Akt independent manner.	9	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	9	10	13	14
mTOR is another downstream target of Akt , and inhibition of the PI3K/Akt/mTOR pathway has been shown to initiate autophagy [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	mTOR is another downstream target of Akt, and inhibition of the PI3K/Akt/mTOR pathway has been shown to initiate autophagy [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	7	is another downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	6	7
On stimulation , phosphorylation of the activation loop ( A-loop ) and hydrophobic motif ( HM ) of Akt by the kinase phosphoinositide dependent kinase 1 ( PDK1 ) and the mammalian target of rapamycin complex 2 ( mTORC2 ) , respectively , results in Akt activation .	On stimulation, phosphorylation of the activation loop (A-loop) and hydrophobic motif (HM) of Akt by the kinase phosphoinositide dependent kinase 1 (PDK1) and the mammalian target of rapamycin complex 2 (mTORC2), respectively, results in Akt activation.	3	47	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	mammalian target of rapamycin	phosphorylation of the activation loop (A-loop) and hydrophobic motif (HM) of Akt by the kinase phosphoinositide dependent kinase 1 (PDK1) and the mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	akt	31	35	45	46
In addition , recent preclinical studies have shown that dual inhibition of mTOR with rapamycin and Akt with perifosine prevents mTOR inhibition initiated Akt activation and significantly enhances antitumor effects in lung cancer [ XREF_BIBR ] and multiple myeloma [ XREF_BIBR ] .	In addition, recent preclinical studies have shown that dual inhibition of mTOR with rapamycin and Akt with perifosine prevents mTOR inhibition initiated Akt activation and significantly enhances antitumor effects in lung cancer [XREF_BIBR] and multiple myeloma [XREF_BIBR].	20	24	initiated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	20	21	23	24
Activated AKT downstream of the IL-2 receptor phosphorylates tuberous sclerosis complex proteins ( TSC ) , inhibiting the GTPase activating protein activity that TSC has on the GTP binding protein Rheb , an mTOR activator .	Activated AKT downstream of the IL-2 receptor phosphorylates tuberous sclerosis complex proteins (TSC), inhibiting the GTPase activating protein activity that TSC has on the GTP binding protein Rheb, an mTOR activator.	0	34	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	33	34	1	2
The mTOR pathway is most typically activated downstream of the PI3-K and Akt pathway in response to growth factors signaling through tyrosine kinase receptors ( e.g ., the binding of IGF to its receptor ) ( XREF_FIG ) .	The mTOR pathway is most typically activated downstream of the PI3-K and Akt pathway in response to growth factors signaling through tyrosine kinase receptors (e.g., the binding of IGF to its receptor) (XREF_FIG).	1	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	1	2	12	13
Considering the complexity and feedbacks present in mTOR signaling and involvement of PI3K and Akt in mTOR activation , dual inhibitors such as NVP-BEZ235 or other drugs with similar mechanisms may prove preferable to rapamycin in treatment of epilepsy .	Considering the complexity and feedbacks present in mTOR signaling and involvement of PI3K and Akt in mTOR activation, dual inhibitors such as NVP-BEZ235 or other drugs with similar mechanisms may prove preferable to rapamycin in treatment of epilepsy.	7	15	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	7	8	14	15
The serine/threonine kinase mTOR is mainly activated downstream of the PI3K and Akt pathway and forms the two multi protein complexes , mTORC1 and mTORC2 , to regulate various cellular events , such as proliferation , apoptosis , and autophagy [ XREF_BIBR , XREF_BIBR ] .	The serine/threonine kinase mTOR is mainly activated downstream of the PI3K and Akt pathway and forms the two multi protein complexes, mTORC1 and mTORC2, to regulate various cellular events, such as proliferation, apoptosis, and autophagy [XREF_BIBR, XREF_BIBR].	0	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	3	4	12	13
As discussed previously , mTOR activity can be positively modulated by the Class I PI3K and Akt pathway .	As discussed previously, mTOR activity can be positively modulated by the Class I PI3K and Akt pathway.	4	17	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	16	17
mTOR is a downstream mediator of P13K and Akt and , as a result of its position , it has a central role in controlling cellular growth and division .	mTOR is a downstream mediator of P13K and Akt and, as a result of its position, it has a central role in controlling cellular growth and division.	0	9	is a downstream mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	8	9
A critical downstream target of AKT is mTOR that mediates PI3K- and AKT dependent oncogenesis , especially in the pathogenesis of prostate cancer [ XREF_BIBR , XREF_BIBR ] .	A critical downstream target of AKT is mTOR that mediates PI3K- and AKT dependent oncogenesis, especially in the pathogenesis of prostate cancer [XREF_BIBR, XREF_BIBR].	3	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	7	8	12	13
However , these quiescent tumour cells maintained mTOR activation independently of AKT by upregulating the small GTPase RHEB via the transcription factor ATF6alpha .	However, these quiescent tumour cells maintained mTOR activation independently of AKT by upregulating the small GTPase RHEB via the transcription factor ATF6alpha.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	7	8	11	12
In fact , preclinical studies have demonstrated that inhibition of PI3K and mTOR with the dual inhibitor NVP-BEZ235 prevented Akt hyperphosphorilation associated with mTOR inhibitors .	In fact, preclinical studies have demonstrated that inhibition of PI3K and mTOR with the dual inhibitor NVP-BEZ235 prevented Akt hyperphosphorilation associated with mTOR inhibitors.	8	20	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	12	13	19	20
We also observed decreased phosphorylation of AKT , consistent with a decrease in muscle growth , and , accordingly , decreased phosphorylation of proteins downstream of the AKT target mTOR ( Fig S3B-D ) .	We also observed decreased phosphorylation of AKT, consistent with a decrease in muscle growth, and, accordingly, decreased phosphorylation of proteins downstream of the AKT target mTOR (Fig S3B-D).	23	32	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	29	30	27	28
Silencing mTOR or raptor , but not rictor , is sufficient to abolish Akt dependent incorporation of glucose , pyruvate , or acetate into cellular lipids .	Silencing mTOR or raptor, but not rictor, is sufficient to abolish Akt dependent incorporation of glucose, pyruvate, or acetate into cellular lipids.	0	15	abolish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	1	2	13	14
Taken together , the sex specific increase seen in brains of rapamycin treated mice in our comprehensive measures of proteasome activity could be linked to a sex dependent change in AKT signaling driven by mTOR regulation of the heat-shock pathway through activated rp-s6 ( as we observed in treated female brains ; Figure XREF_FIG ) .	Taken together, the sex specific increase seen in brains of rapamycin treated mice in our comprehensive measures of proteasome activity could be linked to a sex dependent change in AKT signaling driven by mTOR regulation of the heat-shock pathway through activated rp-s6 (as we observed in treated female brains; Figure XREF_FIG).	30	35	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	34	35	30	31
Dual inhibitors of PI3K and mTOR target the active sites of both holoenzymes to inhibit the pathway both upstream and downstream of AKT , thus avoiding the problem of AKT activation following abolition of the mTORC1-S6K-IRS-1 or S6K-mTORC2-AKT negative feedback loops .	Dual inhibitors of PI3K and mTOR target the active sites of both holoenzymes to inhibit the pathway both upstream and downstream of AKT, thus avoiding the problem of AKT activation following abolition of the mTORC1-S6K-IRS-1 or S6K-mTORC2-AKT negative feedback loops.	1	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	5	6	22	23
Rapamycin , an inhibitor of mTOR , blocked tumour growth and tumour vascular permeability by changing the activation status of AKT in endothelial cells XREF_BIBR .	Rapamycin, an inhibitor of mTOR, blocked tumour growth and tumour vascular permeability by changing the activation status of AKT in endothelial cells XREF_BIBR.	3	21	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	5	6	20	21
Akt activation is mediated by mTOR and is also required for the senescence associated secretory phenotype ( SASP ) .	Akt activation is mediated by mTOR and is also required for the senescence associated secretory phenotype (SASP).	0	6	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	0	1
Activated AKT triggers downstream mTOR and p70S6K1 signaling resulting in the induction of pro angiogenic factors such as VEGF and b-FGF , thereby inducing neovascularization to promote tumor growth XREF_BIBR .	Activated AKT triggers downstream mTOR and p70S6K1 signaling resulting in the induction of pro angiogenic factors such as VEGF and b-FGF, thereby inducing neovascularization to promote tumor growth XREF_BIBR.	0	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	4	5	1	2
As increased expression of alternative growth factor receptors , PTEN-loss or mutant PIK3CA expression result in hyperactive PI3K-Akt signaling , inhibitors of PI3K , Akt , and mTOR ( downstream target of Akt ) as single drugs or in combination with Trastuzumab and/or chemotherapy are also being explored .	As increased expression of alternative growth factor receptors, PTEN-loss or mutant PIK3CA expression result in hyperactive PI3K-Akt signaling, inhibitors of PI3K, Akt, and mTOR (downstream target of Akt) as single drugs or in combination with Trastuzumab and/or chemotherapy are also being explored.	20	33	target	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	27	28	32	33
Moreover , the phosphorylation of mTOR and its direct substrate p70 S6 kinase was augmented by HSV-1 infection , while the mTOR stimulator Akt and inhibitor AMPK activated protein kinase ( AMPK ) were accordingly activated and suppressed , respectively .	Moreover, the phosphorylation of mTOR and its direct substrate p70 S6 kinase was augmented by HSV-1 infection, while the mTOR stimulator Akt and inhibitor AMPK activated protein kinase (AMPK) were accordingly activated and suppressed, respectively.	20	37	stimulator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	21	22	23	24
mTOR is major downstream target of Akt , and inhibition of the PI3K/Akt/mTOR pathway has been shown to initiate autophagy and apoptosis [ XREF_BIBR , XREF_BIBR ] .	mTOR is major downstream target of Akt, and inhibition of the PI3K/Akt/mTOR pathway has been shown to initiate autophagy and apoptosis [XREF_BIBR, XREF_BIBR].	0	7	is major downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	6	7
However , resistance to these inhibitors appears to develop over time , possibly due to the accumulation of additional mutations in the mTOR pathway 30 or through negative feedback of the pathway itself , as inhibiting mTOR signaling can also upregulate AKT signaling through insulin like growth factor receptor 1 ( IGF-1R ) 31 .	However, resistance to these inhibitors appears to develop over time, possibly due to the accumulation of additional mutations in the mTOR pathway 30 or through negative feedback of the pathway itself, as inhibiting mTOR signaling can also upregulate AKT signaling through insulin like growth factor receptor 1 (IGF-1R) 31.	36	42	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	36	37	41	42
Akt is fully activated upon its phosphorylation at Ser473 by mTOR complex 2 ( mTORC2 ) [ XREF_BIBR , XREF_BIBR ] .	Akt is fully activated upon its phosphorylation at Ser473 by mTOR complex 2 (mTORC2) [XREF_BIBR, XREF_BIBR].	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	10	11	0	1
The phosphorylation ratio for the Akt target mTOR ( df = 6 ; F = 4.18 ; p < 0.01 ) increased significantly 2 h and 8 h after refeeding ( XREF_FIG ) .	The phosphorylation ratio for the Akt target mTOR (df = 6; F = 4.18; p < 0.01) increased significantly 2 h and 8 h after refeeding (XREF_FIG).	2	8	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	7	8	5	6
As discussed earlier , mTOR is a target of AKT and , through its activity in the TORC1 and TORC2 complexes , can stimulate four pivotal processes that regulate progression from G0 to G1 : increased mRNA translation , increased glycolysis and consequent ATP accumulation , degradation of the cyclin dependent kinase ( Cdk ) inhibitor p27 Kip1 and promotion , in combination with the transcriptional regulators NFAT and AP1 , of IL-2 and IL-2 receptor alpha ( IL-2Ralpha ) expression .	As discussed earlier, mTOR is a target of AKT and, through its activity in the TORC1 and TORC2 complexes, can stimulate four pivotal processes that regulate progression from G0 to G1 : increased mRNA translation, increased glycolysis and consequent ATP accumulation, degradation of the cyclin dependent kinase (Cdk) inhibitor p27 Kip1 and promotion, in combination with the transcriptional regulators NFAT and AP1, of IL-2 and IL-2 receptor alpha (IL-2Ralpha) expression.	4	23	is a target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	4	5	9	10
However , in female trisomic mice , levels of 9 of 13 components ( S6 was not measured ) were significantly increased ; of these , AKT and pAKT were increased by 66 and 45 % , respectively , and pMTOR and pS6 each by ~ 30 % .	However, in female trisomic mice, levels of 9 of 13 components (S6 was not measured) were significantly increased; of these, AKT and pAKT were increased by 66 and 45%, respectively, and pMTOR and pS6 each by ~ 30%.	26	43	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	pMTOR	pMTOR	pMTOR	AKT	AKT	AKT	40	41	26	27
Inhibitors of mTOR , for example , NVP-BEZ235 and miRNAs , block the AKT and mTOR signaling pathway and suppress tumor cells ' growth in many malignant tumors [ XREF_BIBR - XREF_BIBR ] , including glioma .	Inhibitors of mTOR, for example, NVP-BEZ235 and miRNAs, block the AKT and mTOR signaling pathway and suppress tumor cells ' growth in many malignant tumors [XREF_BIBR - XREF_BIBR], including glioma.	0	17	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	13	14
Further , the PI3K/Akt/mTOR axis plays a central role in cellular proteostasis as mTOR activation inhibits autophagy , and mTOR is a direct target of the kinase Akt , which is regulated by PI3K .	Further, the PI3K/Akt/mTOR axis plays a central role in cellular proteostasis as mTOR activation inhibits autophagy, and mTOR is a direct target of the kinase Akt, which is regulated by PI3K.	19	31	is a direct target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	19	20	27	28
Alternatively , it was recently demonstrated that mTOR Complex 2 ( mTORC2 ) can activate AKT through direct phosphorylation at its serine 473 site ( p ( ser473 ) AKT ) XREF_BIBR , XREF_BIBR .	Alternatively, it was recently demonstrated that mTOR Complex 2 (mTORC2) can activate AKT through direct phosphorylation at its serine 473 site (p (ser473) AKT) XREF_BIBR, XREF_BIBR.	7	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	7	8	15	16
Briefly , insulin binding to IR-alpha induces dimerization and autophosphorylation of IR-beta , which subsequently triggers Akt phosphorylation at Ser473 ; mTOR is a downstream target of Akt .	Briefly, insulin binding to IR-alpha induces dimerization and autophosphorylation of IR-beta, which subsequently triggers Akt phosphorylation at Ser473; mTOR is a downstream target of Akt.	21	28	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	21	22	27	28
Thus , mTOR mediated AKT and SGK activation promote p27 phosphorylation at T157 and T198 , impairing p27 nuclear import and driving cellular proliferation and migration .	Thus, mTOR mediated AKT and SGK activation promote p27 phosphorylation at T157 and T198, impairing p27 nuclear import and driving cellular proliferation and migration.	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	4	5
Accordingly , combined inhibition of mTOR kinase ( e.g ., with AZD8055 ) and the induced RTKs ( e.g ., with laptinib ) fully abolished Akt signaling and resulted in substantial cell death and tumor regression in vivo [ XREF_BIBR ] .	Accordingly, combined inhibition of mTOR kinase (e.g., with AZD8055) and the induced RTKs (e.g., with laptinib) fully abolished Akt signaling and resulted in substantial cell death and tumor regression in vivo [XREF_BIBR].	5	26	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	25	26
In agreement with previous reports that mTORC2 regulates Akt activity [ XREF_BIBR ] , we found that mTOR is critical for activation of Akt by IL-4 and that inhibition of Akt partially interferes with induction of protection .	In agreement with previous reports that mTORC2 regulates Akt activity [XREF_BIBR], we found that mTOR is critical for activation of Akt by IL-4 and that inhibition of Akt partially interferes with induction of protection.	17	24	is critical for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	17	18	23	24
Taken together these observations demonstrate first , that mTOR regulates the phosphorylation and activation of Akt in endothelial cells and , second , that a major effect of mTOR inhibition in endothelial cells is to suppress Akt inducible pro survival signals .	Taken together these observations demonstrate first, that mTOR regulates the phosphorylation and activation of Akt in endothelial cells and, second, that a major effect of mTOR inhibition in endothelial cells is to suppress Akt inducible pro survival signals.	28	37	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	28	29	36	37
mTOR is a downstream target of the AKT and PI3K signaling pathway .	mTOR is a downstream target of the AKT and PI3K signaling pathway.	0	11	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	7	8
In this study , we have shown that activation of beta-catenin and/or AKT increases mTOR activity and that inhibition of that activity with rapamycin suppresses the tumor burden by controlling cell proliferation and death .	In this study, we have shown that activation of beta-catenin and/or AKT increases mTOR activity and that inhibition of that activity with rapamycin suppresses the tumor burden by controlling cell proliferation and death.	10	15	increases	Positive_activation_token_1_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	14	15	12	13
Hypoxia impairs mTOR signaling independent of Akt during regeneration .	Hypoxia impairs mTOR signaling independent of Akt during regeneration.	2	7	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	6	7
The mTOR complex containing Rictor positively regulates AKT activity via phosphorylation on serine 473 and recent data suggests that variable Rictor expression levels may also regulate brain region specific stem cell proliferation and gliomagenesis in a manner dependent on selective AKT hyperactivity XREF_BIBR .	The mTOR complex containing Rictor positively regulates AKT activity via phosphorylation on serine 473 and recent data suggests that variable Rictor expression levels may also regulate brain region specific stem cell proliferation and gliomagenesis in a manner dependent on selective AKT hyperactivity XREF_BIBR.	1	8	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	1	2	7	8
The mTOR is a direct target of Akt and its activity has been regulated by direct phosphorylation of Ser2448 on mTOR correlating with its activation .	The mTOR is a direct target of Akt and its activity has been regulated by direct phosphorylation of Ser2448 on mTOR correlating with its activation.	0	8	is a direct target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	1	2	7	8
Finally , combined inhibition of mTOR kinase ( TORC1/2 ) and RTKs prevented the rebound of T308 P-AKT and resulted in enhanced cell death and tumor regressions in vivo [ XREF_BIBR ] .	Finally, combined inhibition of mTOR kinase (TORC1/2) and RTKs prevented the rebound of T308 P-AKT and resulted in enhanced cell death and tumor regressions in vivo [XREF_BIBR].	5	18	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	P-AKT	P-AKT	P-AKT	5	6	17	18
It was reported recently that mTOR ( a downstream target of Akt ) is also involved in the induction of type I IFN by TLR ligands in pDCs XREF_BIBR .	It was reported recently that mTOR (a downstream target of Akt) is also involved in the induction of type I IFN by TLR ligands in pDCs XREF_BIBR.	5	15	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	11	12
Dual PI3K and mTOR inhibition enhanced the effect of radiation by inhibiting AKT and mTOR signaling pathways and caused G1 phase arrest , which is associated with downregulation of cyclin D1/CDK4 activity , leading to growth inhibition .	Dual PI3K and mTOR inhibition enhanced the effect of radiation by inhibiting AKT and mTOR signaling pathways and caused G1 phase arrest, which is associated with downregulation of cyclin D1/CDK4 activity, leading to growth inhibition.	3	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	3	4	12	13
These data indicate that mTOR inhibition by rapamycin induces negative feedback activation of Akt that is IGF-1R and PI3K dependent .	These data indicate that mTOR inhibition by rapamycin induces negative feedback activation of Akt that is IGF-1R and PI3K dependent.	4	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	13	14
Downstream effectors of the PI3K pathway include AKT ( protein kinase B ) , a serine threonine kinase , directly activated by PI3K and the mTOR ( mammalian target of rapamycin ) , another serine threonine kinase leading to an increased translation of various mRNAs encoding cell cycle regulators , including MYC and cyclin D1 and a potential target of therapeutic inhibition .	Downstream effectors of the PI3K pathway include AKT (protein kinase B), a serine threonine kinase, directly activated by PI3K and the mTOR (mammalian target of rapamycin), another serine threonine kinase leading to an increased translation of various mRNAs encoding cell cycle regulators, including MYC and cyclin D1 and a potential target of therapeutic inhibition.	6	58	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	25	26	7	8
Mammalian target of rapamycin ( mTOR ) inhibitors mediate AKT activation through a type 1 insulin like growth factor receptor ( IGF-1R )-dependent mechanism .	Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin like growth factor receptor (IGF-1R)-dependent mechanism.	5	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	5	6	9	10
Indeed , we previously showed that this effect operates in RCC , and is responsible for AKT activation when this feedback loop is blocked by mTOR inhibition [ XREF_BIBR ] .	Indeed, we previously showed that this effect operates in RCC, and is responsible for AKT activation when this feedback loop is blocked by mTOR inhibition [XREF_BIBR].	16	28	blocked	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	25	26	16	17
In addition to potentially supporting the authors ' conclusion that mTOR promotes mitochondrial biogenesis in an Akt independent manner , increased mTOR phosphorylation in our current study implies mTOR may contribute to exercise induced increases in brain mtDNA copy number and PGC-1alpha protein .	In addition to potentially supporting the authors ' conclusion that mTOR promotes mitochondrial biogenesis in an Akt independent manner, increased mTOR phosphorylation in our current study implies mTOR may contribute to exercise induced increases in brain mtDNA copy number and PGC-1alpha protein.	10	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	10	11	16	17
Further , inhibition of mTOR activity using the pharmacologic inhibitor KU63794 prevented the strain induced association of both rictor and Akt with immunoprecipitated vinculin ( XREF_FIG ) .	Further, inhibition of mTOR activity using the pharmacologic inhibitor KU63794 prevented the strain induced association of both rictor and Akt with immunoprecipitated vinculin (XREF_FIG).	4	21	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	20	21
Therefore , our results suggested that the transcriptional activity of the FASN promoter and the expression of FASN in breast cancer cells were regulated by the PI3K and AKT signaling pathway , mediated by mTOR family members .	Therefore, our results suggested that the transcriptional activity of the FASN promoter and the expression of FASN in breast cancer cells were regulated by the PI3K and AKT signaling pathway, mediated by mTOR family members.	28	36	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	34	35	28	29
By using pathway analysis , we identified associations between all of the five miRNAs with the PTEN-AKT-mTOR pathway , in which PTEN suppresses the oncogenic AKT , and mTOR mediates the oncogenic effects of AKT .	By using pathway analysis, we identified associations between all of the five miRNAs with the PTEN-AKT-mTOR pathway, in which PTEN suppresses the oncogenic AKT, and mTOR mediates the oncogenic effects of AKT.	28	35	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	28	29	34	35
Immune precipitation of mTOR followed by analysis by mass spectrometry allowed identification of the protein PRAS40 ( proline rich AKT and PKB substrate 40 kDa ) XREF_BIBR .	Immune precipitation of mTOR followed by analysis by mass spectrometry allowed identification of the protein PRAS40 (proline rich AKT and PKB substrate 40 kDa) XREF_BIBR.	1	26	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	3	4	19	20
These data suggest a delay in the onset of TNFalpha regulation following Ron activation by HGFL .	These data suggest a delay in the onset of TNFalpha regulation following Ron activation by HGFL.	12	16	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	15	16	12	13
Activation of RON by MSP led to a significant increase in ciliary beat frequency of human nasal cilia .	Activation of RON by MSP led to a significant increase in ciliary beat frequency of human nasal cilia.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	4	5	2	3
To test whether Zt/g4 blocks MSP induced RON activation and downstream signaling transduction , 5 nM MSP was added to induce RON activation with or without 8 microg/ml Zt/g4 treatment ( XREF_FIG ) .	To test whether Zt/g4 blocks MSP induced RON activation and downstream signaling transduction, 5 nM MSP was added to induce RON activation with or without 8 microg/ml Zt/g4 treatment (XREF_FIG).	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	5	6	7	8
To investigate the relevance of Tyr 654 and Tyr 670 phosphorylation of beta-catenin on nuclear localization in response to Ron activation , the T47D-WT and T47D-DM cells were treated with HGFL or vehicle .	To investigate the relevance of Tyr 654 and Tyr 670 phosphorylation of beta-catenin on nuclear localization in response to Ron activation, the T47D-WT and T47D-DM cells were treated with HGFL or vehicle.	19	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	30	31	19	20
Pro MSP , MSP alpha chain , or MSP-NK2 failed to activate RON , consistent with their inability to bind to the RON receptor .	Pro MSP, MSP alpha chain, or MSP-NK2 failed to activate RON, consistent with their inability to bind to the RON receptor.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	3	4	12	13
The regulation of Ron activation and subsequent signaling by HGFL represent a novel and specific target for cancer therapeutics .	The regulation of Ron activation and subsequent signaling by HGFL represent a novel and specific target for cancer therapeutics.	3	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	9	10	3	4
As the kinase activity and phosphorylation status of Ron were significantly reduced in the mammary tumors of the MMTV-Ron HGFL-/- mice , the expression of downstream signaling pathways regulated in response to HGFL mediated Ron activation was examined .	As the kinase activity and phosphorylation status of Ron were significantly reduced in the mammary tumors of the MMTV-Ron HGFL-/- mice, the expression of downstream signaling pathways regulated in response to HGFL mediated Ron activation was examined.	28	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	32	33	34	35
In contrast , MSP induced RON activation or RON overexpression have been shown to induce EMT in various cancer cells including colon , breast , and pancreas [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	In contrast, MSP induced RON activation or RON overexpression have been shown to induce EMT in various cancer cells including colon, breast, and pancreas [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	3	4	5	6
Activation of RON by MSP in mature exudate macrophages inhibits LPS- and IFN-gamma-induced iNOS synthesis .	Activation of RON by MSP in mature exudate macrophages inhibits LPS- and IFN-gamma-induced iNOS synthesis.	0	8	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	4	5	2	3
RON activation by MSP failed to induce a significant cytokine or chemokine response , with the exception of a limited amount of IL-6 production .	RON activation by MSP failed to induce a significant cytokine or chemokine response, with the exception of a limited amount of IL-6 production.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	3	4	0	1
These data suggest that although the MSP independent activation of RON is not sufficient to promote migration on its own , the expression of RON in MCF-10A cells confers an intrinsic migratory advantage of these cells compared to 10A/Vector cells in response to EGF or HGF .	These data suggest that although the MSP independent activation of RON is not sufficient to promote migration on its own, the expression of RON in MCF-10A cells confers an intrinsic migratory advantage of these cells compared to 10A/Vector cells in response to EGF or HGF.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	6	7	10	11
To confirm that MSP induces Ron dependent signaling in primary macrophages , we examined the phosphorylation of Gab1 and Gab2 , two adaptors that are recruited to Ron and mediate signaling downstream of Ron .	To confirm that MSP induces Ron dependent signaling in primary macrophages, we examined the phosphorylation of Gab1 and Gab2, two adaptors that are recruited to Ron and mediate signaling downstream of Ron.	2	7	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	3	4	5	6
Our in vivo and in vitro data collectively show that RON activation by MSP stimulates survival and bone resorption in mature osteoclasts through activation of SRC signaling , even in the absence of functional RANKL .	Our in vivo and in vitro data collectively show that RON activation by MSP stimulates survival and bone resorption in mature osteoclasts through activation of SRC signaling, even in the absence of functional RANKL.	10	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	13	14	10	11
Hyal2 does not directly modulate the basal or MSP induced RON and Stk activity , although it is possible that adaptor proteins might mediate such signaling in other cell types .	Hyal2 does not directly modulate the basal or MSP induced RON and Stk activity, although it is possible that adaptor proteins might mediate such signaling in other cell types.	4	12	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	8	9	10	11
Second , MSP induced RON activation dissociated RSK2 from Erk1/2 , and caused RSK2 phosphorylation and subsequent nuclear translocation .	Second, MSP induced RON activation dissociated RSK2 from Erk1/2, and caused RSK2 phosphorylation and subsequent nuclear translocation.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	2	3	4	5
Microarray and qRT-PCR analyses demonstrated that a number of proinflammatory cytokines including IL-6 and TNF-alpha were moderately induced in Kupffer cells following Ron activation by HGFL .	Microarray and qRT-PCR analyses demonstrated that a number of proinflammatory cytokines including IL-6 and TNF-alpha were moderately induced in Kupffer cells following Ron activation by HGFL.	22	26	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	25	26	22	23
However , we find no evidence for direct regulation of the basal or MSP induced RON and Stk activity by Hyal2 in rat fibroblasts .	However, we find no evidence for direct regulation of the basal or MSP induced RON and Stk activity by Hyal2 in rat fibroblasts.	8	18	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	13	14	15	16
Having demonstrated that MSP induced RON signaling results in disruption of the plectin-ITGB4 interaction , we sought to investigate its relevance to pancreatic cancer cell migration .	Having demonstrated that MSP induced RON signaling results in disruption of the plectin-ITGB4 interaction, we sought to investigate its relevance to pancreatic cancer cell migration.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	3	4	5	6
As MSP was detected in human urine samples , MSP induced RON activation and signaling transduction may be a key event in bladder tumorigenesis and invasion .	As MSP was detected in human urine samples, MSP induced RON activation and signaling transduction may be a key event in bladder tumorigenesis and invasion.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	9	10	11	12
In this report , we demonstrate that activation of RON signaling by HGFL induces VEGF production in murine and human pancreatic cancer cells and that conditioned media from these cells results in tubule formation in human microvascular endothelial cells .	In this report, we demonstrate that activation of RON signaling by HGFL induces VEGF production in murine and human pancreatic cancer cells and that conditioned media from these cells results in tubule formation in human microvascular endothelial cells.	9	13	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	RON	RON	RON	12	13	9	10
MSP dependent activation of RON induces downstream signalling pathways involved in wound healing , liver regeneration , bone resorption , embryogenesis and the immune response [ XREF_BIBR - XREF_BIBR ] .	MSP dependent activation of RON induces downstream signalling pathways involved in wound healing, liver regeneration, bone resorption, embryogenesis and the immune response [XREF_BIBR - XREF_BIBR].	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	4	5
These prior studies and our results support the contention that the epithelial and stromal cell-type specific HGFL mediated Ron activation promotes the phosphorylation of STAT3 and subsequently influences the number of macrophages recruited to the developing mammary gland .	These prior studies and our results support the contention that the epithelial and stromal cell-type specific HGFL mediated Ron activation promotes the phosphorylation of STAT3 and subsequently influences the number of macrophages recruited to the developing mammary gland.	10	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	16	17	18	19
MSP activates the RON receptor protein-tyrosine kinase , which results in cell migration , shape change , or proliferation .	MSP activates the RON receptor protein-tyrosine kinase, which results in cell migration, shape change, or proliferation.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	3	4
In pancreatic cells , MSP induced RON signaling leads to disruption of plectin-integrin alpha6beta4 interaction , HPC disassembly and enhanced cell migration .	In pancreatic cells, MSP induced RON signaling leads to disruption of plectin-integrin alpha6beta4 interaction, HPC disassembly and enhanced cell migration.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	4	5	6	7
Second , our data demonstrate that HGFL induced Ron activation leads to beta-catenin nuclear localization and increased beta-catenin reporter activity , and that tyrosine residues 654 and 670 of beta-catenin are important for these processes .	Second, our data demonstrate that HGFL induced Ron activation leads to beta-catenin nuclear localization and increased beta-catenin reporter activity, and that tyrosine residues 654 and 670 of beta-catenin are important for these processes.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	6	7	8	9
We also show that the MSP gene is expressed in the tongue , the target of the hypoglossal nerve , and that MSP induces biosynthesis of Ron receptor in the motoneuron somata .	We also show that the MSP gene is expressed in the tongue, the target of the hypoglossal nerve, and that MSP induces biosynthesis of Ron receptor in the motoneuron somata.	22	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	22	23	26	27
To further investigate if the inhibition of p-Akt was through the MSP and Ron system , samples treated with MSP +/- the indicated hinge compound were harvested , immunoprecipitated with a Ron antibody , and immunoblotted with PY20 , a phosphotyrosine specific antibody , to determine levels of MSP induced Ron phosphorylation .	To further investigate if the inhibition of p-Akt was through the MSP and Ron system, samples treated with MSP +/- the indicated hinge compound were harvested, immunoprecipitated with a Ron antibody, and immunoblotted with PY20, a phosphotyrosine specific antibody, to determine levels of MSP induced Ron phosphorylation.	11	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	19	20	13	14
The study presented here demonstrates that RSK2 , a downstream signaling protein of the Ras-Erk1/2 pathway , is the principal molecule that links MSP activated RON signaling to complete EMT .	The study presented here demonstrates that RSK2, a downstream signaling protein of the Ras-Erk1/2 pathway, is the principal molecule that links MSP activated RON signaling to complete EMT.	22	26	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	23	24	25	26
We observed a statistically significant difference in the level of IL-12p40 suppression by MSP between wild-type and Grb2 +/- macrophages indicating that the recruitment of Grb2 to the second docking site tyrosine in Ron may play a role in the inhibition of LPS induced IL-12p40 after MSP stimulation of Ron ( XREF_FIG ) .	We observed a statistically significant difference in the level of IL-12p40 suppression by MSP between wild-type and Grb2 +/- macrophages indicating that the recruitment of Grb2 to the second docking site tyrosine in Ron may play a role in the inhibition of LPS induced IL-12p40 after MSP stimulation of Ron (XREF_FIG).	46	51	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	46	47	49	50
Here , we confirmed the expression of Ron on CNS microglia and MSP dependent activation of Ron is able to attenuate microglial inflammation .	Here, we confirmed the expression of Ron on CNS microglia and MSP dependent activation of Ron is able to attenuate microglial inflammation.	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	12	13	16	17
Studies showed that MSP mediated Ron activation significantly increased cell migration and invasion XREF_BIBR , XREF_BIBR .	Studies showed that MSP mediated Ron activation significantly increased cell migration and invasion XREF_BIBR, XREF_BIBR.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	3	4	5	6
Activation of Ron by HGFL in this system leads to keratinocyte spreading , migration and subsequent wound healing [ XREF_BIBR ] .	Activation of Ron by HGFL in this system leads to keratinocyte spreading, migration and subsequent wound healing [XREF_BIBR].	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	4	5	2	3
To ensure that Ron is activated by MSP , we examined MAPK signalling post MSP as a sensitive readout of Ron activation .	To ensure that Ron is activated by MSP, we examined MAPK signalling post MSP as a sensitive readout of Ron activation.	3	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	7	8	3	4
Activation of RON by MSP exerts dual functions on macrophages .	Activation of RON by MSP exerts dual functions on macrophages.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	4	5	2	3
Macrophage stimulating protein ( MSP ) activates RON by autophosphorylation and upregulating RON kinase activity .	Macrophage stimulating protein (MSP) activates RON by autophosphorylation and upregulating RON kinase activity.	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	4	5	7	8
MSP stimulation of RON has been associated with anti-apoptotic activity in epithelial cells .	MSP stimulation of RON has been associated with anti-apoptotic activity in epithelial cells.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	3	4
Although we have previously shown that Ron activation by HGFL induces NF-kappaB signaling in various cancers of epithelial origin , we did not observe NF-kappaB activation ( detected by phosphorylation of NF-kappaB ) in Kupffer cells after Ron activation by HGFL ( data not shown ) .	Although we have previously shown that Ron activation by HGFL induces NF-kappaB signaling in various cancers of epithelial origin, we did not observe NF-kappaB activation (detected by phosphorylation of NF-kappaB) in Kupffer cells after Ron activation by HGFL (data not shown).	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	9	10	6	7
These data indicate that activation of Ron signaling by HGFL leads to repression of TNFalpha production following LPS-exposure at both the protein and transcript levels .	These data indicate that activation of Ron signaling by HGFL leads to repression of TNFalpha production following LPS-exposure at both the protein and transcript levels.	6	10	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	9	10	6	7
These data suggest that MSP stimulation of RON may promote the activation of additional Src independent pathways compared to the pathways activated by MSP independent signaling of RON .	These data suggest that MSP stimulation of RON may promote the activation of additional Src independent pathways compared to the pathways activated by MSP independent signaling of RON.	23	28	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	23	24	27	28
It has been demonstrated that activation of RON by HGFL and MSP may assist in implantation , thereby improving trophoblast function and viability [ XREF_BIBR ] .	It has been demonstrated that activation of RON by HGFL and MSP may assist in implantation, thereby improving trophoblast function and viability [XREF_BIBR].	5	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	RON	RON	RON	9	10	7	8
Functional studies showed that Ron can be activated by its ligand MSP to initiate a cascade of molecular signaling , including PI3K and Akt , MAPK , beta-catenin , JNK and FAK pathways to regulate various cellular functions XREF_BIBR .	Functional studies showed that Ron can be activated by its ligand MSP to initiate a cascade of molecular signaling, including PI3K and Akt, MAPK, beta-catenin, JNK and FAK pathways to regulate various cellular functions XREF_BIBR.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	11	12	4	5
MSP was required , however , to induce RON mediated migration and proliferation , implying that RON possesses two distinct modes of signaling .	MSP was required, however, to induce RON mediated migration and proliferation, implying that RON possesses two distinct modes of signaling.	0	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	8	9
MSP dependent and MSP independent activation of RON give rise to distinct biological consequences .	MSP dependent and MSP independent activation of RON give rise to distinct biological consequences.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	3	4	7	8
The current model for the MSP mediated activation of RON begins with the binding of MSP to the receptor , leading to the formation of signaling-competent 2:2 MSP : RON complex on the cell surface .	The current model for the MSP mediated activation of RON begins with the binding of MSP to the receptor, leading to the formation of signaling-competent 2:2 MSP : RON complex on the cell surface.	2	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	5	6	9	10
MSP activation induces RON mediated cell dissociation , migration and matrix invasion .	MSP activation induces RON mediated cell dissociation, migration and matrix invasion.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	3	4
Knockdown of beta-catenin in the T47D cells also abolished the ability of HGFL to induce cyclin D1 levels ( data not shown ) demonstrating the specificity of HGFL induced Ron activation on beta-catenin for the induction of cyclin D1 under these conditions .	Knockdown of beta-catenin in the T47D cells also abolished the ability of HGFL to induce cyclin D1 levels (data not shown) demonstrating the specificity of HGFL induced Ron activation on beta-catenin for the induction of cyclin D1 under these conditions.	25	30	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	27	28	29	30
These microarray studies are consistent with prior studies , which have documented HGFL induced Ron activation as a suppressor of LPS mediated inflammation .	These microarray studies are consistent with prior studies, which have documented HGFL induced Ron activation as a suppressor of LPS mediated inflammation.	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	12	13	14	15
Msp can promote the migration of RON ( + ) cancer cells in paracrine secretion manner and inhibit the proliferation , migration and invasion of human non small cell lung cancer cells PC14 in an unknown way .	Msp can promote the migration of RON (+) cancer cells in paracrine secretion manner and inhibit the proliferation, migration and invasion of human non small cell lung cancer cells PC14 in an unknown way.	0	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Msp	Msp	Msp	RON	RON	RON	0	1	6	7
Interestingly , our studies identified Mefv , a gene that codes for the anti-inflammatory protein pyrin , as an HGFL stimulated Ron dependent gene .	Interestingly, our studies identified Mefv, a gene that codes for the anti-inflammatory protein pyrin, as an HGFL stimulated Ron dependent gene.	18	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	19	20	21	22
Our experiment found that MSP induced Ron activation increased survivin but not XIAP mRNA expression .	Our experiment found that MSP induced Ron activation increased survivin but not XIAP mRNA expression.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	4	5	6	7
Given the similarities between the Ron and Met receptor tyrosine kinases , we sought to examine the role of HGFL induced Ron activation on beta-catenin nuclear localization and the importance of beta-catenin Tyr 654 and Tyr 670 in this process .	Given the similarities between the Ron and Met receptor tyrosine kinases, we sought to examine the role of HGFL induced Ron activation on beta-catenin nuclear localization and the importance of beta-catenin Tyr 654 and Tyr 670 in this process.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	19	20	21	22
Activation of RON by MSP results in cell migration , shape change , and proliferation .	Activation of RON by MSP results in cell migration, shape change, and proliferation.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	4	5	2	3
The activation of RON by MSP leads to the activation of several pathways resulting in tumour progression and metastasis , through cell adhesion , invasion , motility and proliferation together with inhibited apoptosis .	The activation of RON by MSP leads to the activation of several pathways resulting in tumour progression and metastasis, through cell adhesion, invasion, motility and proliferation together with inhibited apoptosis.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	5	6	3	4
In addition , we wanted to explore whether Hyal2 might modulate MSP induction of RON and Stk activity .	In addition, we wanted to explore whether Hyal2 might modulate MSP induction of RON and Stk activity.	11	17	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	11	12	14	15
A previous study reported that MSP stimulation activates Ron downstream signaling PI3K and Akt and MAPK in pancreatic cancer cells XREF_BIBR .	A previous study reported that MSP stimulation activates Ron downstream signaling PI3K and Akt and MAPK in pancreatic cancer cells XREF_BIBR.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	5	6	8	9
Ribosomal protein S6 kinase-2 ( RSK2 ) , a downstream signaling protein of the Ras-Erk1/2 pathway , was shown to be the principal molecule linking MSP induced RON signaling to EMT .	Ribosomal protein S6 kinase-2 (RSK2), a downstream signaling protein of the Ras-Erk1/2 pathway, was shown to be the principal molecule linking MSP induced RON signaling to EMT.	24	28	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	25	26	27	28
Binding of MSP to its receptor , RON , activates RON and leads to cellular growth , motility , and invasion .	Binding of MSP to its receptor, RON, activates RON and leads to cellular growth, motility, and invasion.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	2	3	10	11
We considered possible molecular differences between MSP dependent and MSP independent RON signaling in MCF-10A cells by looking at the activation of MAPK ( Erk 1/2 ) and AKT , which are known to be important for MSP driven activation of RON in other cell systems .	We considered possible molecular differences between MSP dependent and MSP independent RON signaling in MCF-10A cells by looking at the activation of MAPK (Erk 1/2) and AKT, which are known to be important for MSP driven activation of RON in other cell systems.	6	45	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	6	7	41	42
We have further shown that MSP dependent activation of Ron attenuates obesity induced chronic inflammation .	We have further shown that MSP dependent activation of Ron attenuates obesity induced chronic inflammation.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	5	6	9	10
HGFL induced Ron receptor activation in peritoneal macrophages induces spreading , chemotaxis and phagocytosis .	HGFL induced Ron receptor activation in peritoneal macrophages induces spreading, chemotaxis and phagocytosis.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	0	1	2	3
In addition , HGFL mediated Ron activation induces both beta-catenin nuclear localization and transcriptional activity , with Tyr 654 and Tyr 670 residues of beta-catenin being critical for these processes .	In addition, HGFL mediated Ron activation induces both beta-catenin nuclear localization and transcriptional activity, with Tyr 654 and Tyr 670 residues of beta-catenin being critical for these processes.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	3	4	5	6
The studies herein suggest a novel mechanism whereby HGFL induced Ron receptor activation promotes the expression of anti-inflammatory genes while inhibiting genes involved in inflammation with a net effect of diminished inflammation in macrophages .	The studies herein suggest a novel mechanism whereby HGFL induced Ron receptor activation promotes the expression of anti-inflammatory genes while inhibiting genes involved in inflammation with a net effect of diminished inflammation in macrophages.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	8	9	10	11
These data suggest that activation of the NF-kappaB pathway is dependent on HGFL mediated Ron signaling and may drive changes in apoptosis .	These data suggest that activation of the NF-kappaB pathway is dependent on HGFL mediated Ron signaling and may drive changes in apoptosis.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	12	13	14	15
2.5 HGFL mediated Ron signaling in the mammary gland is associated with increased STAT3 mRNA expression and phosphorylation status .	2.5 HGFL mediated Ron signaling in the mammary gland is associated with increased STAT3 mRNA expression and phosphorylation status.	0	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	1	2	3	4
Identification of Mefv ( pyrin ) and Lcn2 as novel downstream effectors of HGFL induced Ron activation .	Identification of Mefv (pyrin) and Lcn2 as novel downstream effectors of HGFL induced Ron activation.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	13	14	15	16
The activation of Ron by HGFL in primary peritoneal macrophages is through the NF-kappaB pathway [ XREF_BIBR ] .	The activation of Ron by HGFL in primary peritoneal macrophages is through the NF-kappaB pathway [XREF_BIBR].	1	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	5	6	3	4
Altogether , these in vivo and in vitro data support a model in which ( 1 ) MSP expressing bone metastatic tumors activate RON on mature osteoclasts to promote both survival and bone resorption through a pathway separate from and parallel to RANK signaling ; and ( 2 ) SRC kinase functions downstream of RON to promote osteolysis ( XREF_FIG ) .	Altogether, these in vivo and in vitro data support a model in which (1) MSP expressing bone metastatic tumors activate RON on mature osteoclasts to promote both survival and bone resorption through a pathway separate from and parallel to RANK signaling; and (2) SRC kinase functions downstream of RON to promote osteolysis (XREF_FIG).	17	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP expressing	msp	RON	RON	ron	17	18	23	24
HGFL stimulated Ron activation leads to the induction of diverse downstream signaling cascades , which play important roles in a variety of biological processes such as inflammation and cancer .	HGFL stimulated Ron activation leads to the induction of diverse downstream signaling cascades, which play important roles in a variety of biological processes such as inflammation and cancer.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	0	1	2	3
Comoglio et al [ XREF_BIBR ] have shown that MSP may promote the release of RON from the liver , adrenal glands and spinal ganglia in humans .	Comoglio et al [XREF_BIBR] have shown that MSP may promote the release of RON from the liver, adrenal glands and spinal ganglia in humans.	9	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	9	10	15	16
Activation of Ron by MSP induces a wide array of biological effects through various signaling cascades including the JNK , MAPK , beta-catenin , and PI3K-Akt pathways , which have been shown to mediate a variety of cell behaviors including motility and cell survival [ XREF_BIBR ] .	Activation of Ron by MSP induces a wide array of biological effects through various signaling cascades including the JNK, MAPK, beta-catenin, and PI3K-Akt pathways, which have been shown to mediate a variety of cell behaviors including motility and cell survival [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	4	5	2	3
Considering their structural similarities , it is reasoned that the RON Er80 may have the ability to regulate MSP induced RON mediated activities .	Considering their structural similarities, it is reasoned that the RON Er80 may have the ability to regulate MSP induced RON mediated activities.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	18	19	20	21
MSP stimulation of RON was required for RON mediated cell migration and proliferation , which suggests that MSP independent functions of RON are not solely a consequence of increased RON expression levels .	MSP stimulation of RON was required for RON mediated cell migration and proliferation, which suggests that MSP independent functions of RON are not solely a consequence of increased RON expression levels.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	3	4
MSP stimulation of RON induces conformational changes that could potentially expose alternative residues to activate distinct pathways , or alter the signal intensity and duration .	MSP stimulation of RON induces conformational changes that could potentially expose alternative residues to activate distinct pathways, or alter the signal intensity and duration.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	3	4
Activation patterns changed during FBS starvation and RON ligand MSP alone did not lead to further RON activation suggesting different activation mechanisms .	Activation patterns changed during FBS starvation and RON ligand MSP alone did not lead to further RON activation suggesting different activation mechanisms.	7	17	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	9	10	16	17
In conclusion , we show that HGFL expression enhances Ron driven mammary tumorigenesis .	In conclusion, we show that HGFL expression enhances Ron driven mammary tumorigenesis.	6	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGFL	HGFL expression	hgfl	Ron	Ron	ron	6	7	9	10
Alternatively , it may be that the basal and MSP induced phenotypes of the RON and Stk expressing cells are mediated by separate signaling pathways , as has been found for the related receptor tyrosine kinase MET [ XREF_BIBR ] .	Alternatively, it may be that the basal and MSP induced phenotypes of the RON and Stk expressing cells are mediated by separate signaling pathways, as has been found for the related receptor tyrosine kinase MET [XREF_BIBR].	7	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	9	10	14	15
These data indicate that MSP independent activation of RON is not sufficient for cell proliferation however , due to the increased expression level of RON , MSP can act as a mitogen in 10A/RON cells .	These data indicate that MSP independent activation of RON is not sufficient for cell proliferation however, due to the increased expression level of RON, MSP can act as a mitogen in 10A/RON cells.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	4	5	8	9
Therefore only monomers of full length MSP are required to activate Ron and induce Ron homodimerization [ XREF_BIBR ] .	Therefore only monomers of full length MSP are required to activate Ron and induce Ron homodimerization [XREF_BIBR].	2	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	6	7	14	15
XREF_BIBR However , a recent study reported that SU11274 inhibits both c-MET signaling and MSP induced RON signaling .	XREF_BIBR However, a recent study reported that SU11274 inhibits both c-MET signaling and MSP induced RON signaling.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	14	15	16	17
In cultured human renal glomerular endothelial cells , macrophage stimulating protein 1 induced RON downstream signaling , resulting in increased phosphorylation of ERK and AKT kinases , expression Von Willebrand factor , increased cell motility , and re-organization of F-actin .	In cultured human renal glomerular endothelial cells, macrophage stimulating protein 1 induced RON downstream signaling, resulting in increased phosphorylation of ERK and AKT kinases, expression Von Willebrand factor, increased cell motility, and re-organization of F-actin.	8	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	macrophage stimulating protein	macrophage stimulating protein	macrophage stimulating protein	RON	RON	RON	8	11	13	14
During an inflammatory cascade , the MSP dependent activation of Ron on tissue resident macrophages has been shown to support anti-inflammatory processes and subsequent tissue repair .	During an inflammatory cascade, the MSP dependent activation of Ron on tissue resident macrophages has been shown to support anti-inflammatory processes and subsequent tissue repair.	6	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	6	7	10	11
Multiple reports indicate that the role of HGFL stimulated Ron activation in macrophages is to limit the inflammatory response , shown by a reduction in nitric oxide production and cytokine and chemokine responses following macrophage activation [ XREF_BIBR - XREF_BIBR ] .	Multiple reports indicate that the role of HGFL stimulated Ron activation in macrophages is to limit the inflammatory response, shown by a reduction in nitric oxide production and cytokine and chemokine responses following macrophage activation [XREF_BIBR - XREF_BIBR].	5	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	7	8	9	10
Lowy and his colleagues recently showed that MSP stimulated RON was unable to activate IGF1-R but that IGF1 or EGF treatment caused phosphorylation of RON [ XREF_BIBR , XREF_BIBR ] .	Lowy and his colleagues recently showed that MSP stimulated RON was unable to activate IGF1-R but that IGF1 or EGF treatment caused phosphorylation of RON [XREF_BIBR, XREF_BIBR].	7	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	7	8	9	10
Additionally , we have recently demonstrated that MSP induced RON activation results in up-regulation of VEGF expression and secretion by pancreatic cancer cells .	Additionally, we have recently demonstrated that MSP induced RON activation results in up-regulation of VEGF expression and secretion by pancreatic cancer cells.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	7	8	9	10
HGFL dependent activation of Ron leads to inhibition of the classically activated M1 macrophage pro inflammatory phenotype though inhibition of iNOS and inflammatory cytokine production and promotion of M2 anti-inflammatory phenotype as evidenced by increased arginase 1 production [ XREF_BIBR , XREF_BIBR ] .	HGFL dependent activation of Ron leads to inhibition of the classically activated M1 macrophage pro inflammatory phenotype though inhibition of iNOS and inflammatory cytokine production and promotion of M2 anti-inflammatory phenotype as evidenced by increased arginase 1 production [XREF_BIBR, XREF_BIBR].	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	0	1	4	5
Furthermore , the MSP independent activation of RON does not appear to promote additive proliferative effects with EGFR stimulation .	Furthermore, the MSP independent activation of RON does not appear to promote additive proliferative effects with EGFR stimulation.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	3	4	7	8
Ron can be activated by its ligand macrophage stimulating protein ( MSP ) , thereby activating oncogenic signaling pathways .	Ron can be activated by its ligand macrophage stimulating protein (MSP), thereby activating oncogenic signaling pathways.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	macrophage stimulating protein	macrophage stimulating protein	macrophage stimulating protein	Ron	Ron	Ron	7	10	0	1
Our results indicate that Ron activation by HGFL pretreatment prior to the LPS challenge is able to decrease TNFalpha production in both primary alveolar macrophages and in MH-S cells in vitro .	Our results indicate that Ron activation by HGFL pretreatment prior to the LPS challenge is able to decrease TNFalpha production in both primary alveolar macrophages and in MH-S cells in vitro.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	7	8	4	5
In RON expressing macrophages treated with macrophage stimulating protein , LPS induced prostaglandin E ( 2 ) ( PGE ( 2 ) ) production was significantly reduced .	In RON expressing macrophages treated with macrophage stimulating protein, LPS induced prostaglandin E (2) (PGE (2)) production was significantly reduced.	1	9	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	macrophage stimulating protein	macrophage stimulating protein	macrophage stimulating protein	RON	RON	RON	6	9	1	2
IMC-RON8 downregulates the expression of Ron , and inhibits MSP stimulated Ron activation , leading to attenuated phosphorylation of Akt and ERK and expression of survivin mRNA .	IMC-RON8 downregulates the expression of Ron, and inhibits MSP stimulated Ron activation, leading to attenuated phosphorylation of Akt and ERK and expression of survivin mRNA.	8	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	9	10	11	12
Furthermore , MSP stimulation of the RON receptor on primary macrophages inhibits the response of these cells to IFN-gamma through inhibition of STAT1 tyrosine phosphorylation induced by IFN-gamma .	Furthermore, MSP stimulation of the RON receptor on primary macrophages inhibits the response of these cells to IFN-gamma through inhibition of STAT1 tyrosine phosphorylation induced by IFN-gamma.	2	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	2	3	6	7
MSP independent tyrosine phosphorylation of RON is not unique to MCF-10A cells , as we can recapitulate the MSP independent activation of RON by expressing RON in HeLa cells ( XREF_SUPPLEMENTARY ) .	MSP independent tyrosine phosphorylation of RON is not unique to MCF-10A cells, as we can recapitulate the MSP independent activation of RON by expressing RON in HeLa cells (XREF_SUPPLEMENTARY).	18	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	18	19	22	23
MSP was unable to reactivate full-length RON and its downstream signaling when they were suppressed by PF .	MSP was unable to reactivate full-length RON and its downstream signaling when they were suppressed by PF.	0	10	reactivate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	6	7
Further , to test the effect of HGFL mediated Ron activation on NLRP3 inflammasome activity , IL-1beta protein levels secreted by TK +/+ Kupffer cells following LPS and LPS-HGFL treatments were measured .	Further, to test the effect of HGFL mediated Ron activation on NLRP3 inflammasome activity, IL-1beta protein levels secreted by TK +/+ Kupffer cells following LPS and LPS-HGFL treatments were measured.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	7	8	9	10
Thus , RON can be activated without MSP by ligand stimulation of RON associated receptors , and MSP activated RON can cause ligand independent activation of RON associated receptors .	Thus, RON can be activated without MSP by ligand stimulation of RON associated receptors, and MSP activated RON can cause ligand independent activation of RON associated receptors.	17	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	17	18	19	20
Human mAb IMC-41A10 efficiently reduced MSP mediated Ron activation and its downstream PI3K and Akt and MAPK activation XREF_BIBR .	Human mAb IMC-41A10 efficiently reduced MSP mediated Ron activation and its downstream PI3K and Akt and MAPK activation XREF_BIBR.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	5	6	7	8
Although it is possible that MSP dimers could be physiologically relevant , the current evidence supports the model of a monomer of MSP activating Ron .	Although it is possible that MSP dimers could be physiologically relevant, the current evidence supports the model of a monomer of MSP activating Ron.	20	25	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	22	23	24	25
MSP 689R and 689C variants induce similar RON signaling .	MSP 689R and 689C variants induce similar RON signaling.	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	7	8
Activation of RON by macrophage stimulating protein ( MSP ) results in cell migration and initiates changes in the morphology of RON-cDNA-transfected MDCK cells .	Activation of RON by macrophage stimulating protein (MSP) results in cell migration and initiates changes in the morphology of RON-cDNA-transfected MDCK cells.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	macrophage stimulating protein	macrophage stimulating protein	macrophage stimulating protein	RON	RON	RON	4	7	2	3
Additionally , MSP stimulation induced the RON receptor to complex with plectin and Integrin beta 4 ( ITGB4 ) .	Additionally, MSP stimulation induced the RON receptor to complex with plectin and Integrin beta 4 (ITGB4).	2	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	2	3	6	7
In addition to beta-catenin accumulation , we have also shown that HGFL induced Ron activation results in increased levels of both cyclin D1 and c-myc .	In addition to beta-catenin accumulation, we have also shown that HGFL induced Ron activation results in increased levels of both cyclin D1 and c-myc.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	11	12	13	14
Stimulation with MSP activates Ron and its downstream signaling , including PI3K and Akt and MAPK and promotes cell migration and invasion .	Stimulation with MSP activates Ron and its downstream signaling, including PI3K and Akt and MAPK and promotes cell migration and invasion.	0	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MSP	MSP	MSP	Ron	Ron	Ron	2	3	4	5
MSP stimulation of RON can increase epithelial cell migration ; however , it is not clear whether RON mediated migration can occur in the absence of MSP .	MSP stimulation of RON can increase epithelial cell migration; however, it is not clear whether RON mediated migration can occur in the absence of MSP.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	3	4
To investigate the role of HGFL induced Ron activation on beta-catenin dependent reporter activity , we utilized T47D and R7 breast cancer cell lines along with cell lines containing variations in Ron and beta-catenin expression .	To investigate the role of HGFL induced Ron activation on beta-catenin dependent reporter activity, we utilized T47D and R7 breast cancer cell lines along with cell lines containing variations in Ron and beta-catenin expression.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	5	6	7	8
HGFL mediated RON signaling supports breast cancer stem cell phenotypes via activation of non canonical beta-catenin signaling .	HGFL mediated RON signaling supports breast cancer stem cell phenotypes via activation of non canonical beta-catenin signaling.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	RON	RON	RON	0	1	2	3
These data imply that MSP independent activation of RON improves 10A/RON cell survival in the absence of growth factors , and that MSP does not significantly contribute to this effect .	These data imply that MSP independent activation of RON improves 10A/RON cell survival in the absence of growth factors, and that MSP does not significantly contribute to this effect.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	4	5	8	9
MSP stimulation of the RON receptor inhibits IL-12p40 production by primary macrophages in response to LPS .	MSP stimulation of the RON receptor inhibits IL-12p40 production by primary macrophages in response to LPS.	0	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	0	1	4	5
Macrophage stimulating protein 1 binds to and activates RON kinase , a cell surface receptor tyrosine kinase .	Macrophage stimulating protein 1 binds to and activates RON kinase, a cell surface receptor tyrosine kinase.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Macrophage stimulating protein	Macrophage stimulating protein	Macrophage stimulating protein	RON	RON	RON	0	3	8	9
In the present study , we have identified Mefv ( pyrin ) as a gene downstream of HGFL induced Ron activation in Kupffer cells , both by microarray as well as by qRT-PCR .	In the present study, we have identified Mefv (pyrin) as a gene downstream of HGFL induced Ron activation in Kupffer cells, both by microarray as well as by qRT-PCR.	14	20	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	17	18	19	20
MIF induced CD74 signaling complexes with CXCR2 , CXCR4 , or CXCR7 promote chemokine expression and chemotaxis .	MIF induced CD74 signaling complexes with CXCR2, CXCR4, or CXCR7 promote chemokine expression and chemotaxis.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	0	1	2	3
Moreover , our study suggests that CXCR4 and CD74 complexes are responsive to MIF , as MIF triggered CD74 dependent AKT activation in T cells was blocked by AMD3100 , a small molecule inhibitor of CXCR4 , as well as by CD74 and CXCR4 antibodies .	Moreover, our study suggests that CXCR4 and CD74 complexes are responsive to MIF, as MIF triggered CD74 dependent AKT activation in T cells was blocked by AMD3100, a small molecule inhibitor of CXCR4, as well as by CD74 and CXCR4 antibodies.	16	26	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	16	17	18	19
These observations suggested that MIF induced responses are not completely coordinated with CD74 dependent responses and , therefore , it is likely that MIF induces responses to P. aeruginosa infection through an alternate means such as use of receptors in addition to CD74 .	These observations suggested that MIF induced responses are not completely coordinated with CD74 dependent responses and, therefore, it is likely that MIF induces responses to P. aeruginosa infection through an alternate means such as use of receptors in addition to CD74.	23	43	induces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	23	24	42	43
Importantly , MIF released from the ischaemic heart can induce AMPK activation via binding to CD74 , which promotes glucose uptake and protects the heart during ischemia and reperfusion by metabolic pathways XREF_BIBR , XREF_BIBR .	Importantly, MIF released from the ischaemic heart can induce AMPK activation via binding to CD74, which promotes glucose uptake and protects the heart during ischemia and reperfusion by metabolic pathways XREF_BIBR, XREF_BIBR.	2	22	induce	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	2	3	15	16
The conclusion that there are CD74 independent cellular response pathways that are induced by MIF supported by the observation that when the CD74 KO mice were therapeutically treated with antisera to MIF after the onset of disease there were further reductions in corneal pathology and bacterial burdens , consistent with previously published data XREF_BIBR that inhibiting MIF biologically reduced disease pathology in the infected C57BL6 mice .	The conclusion that there are CD74 independent cellular response pathways that are induced by MIF supported by the observation that when the CD74 KO mice were therapeutically treated with antisera to MIF after the onset of disease there were further reductions in corneal pathology and bacterial burdens, consistent with previously published data XREF_BIBR that inhibiting MIF biologically reduced disease pathology in the infected C57BL6 mice.	22	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	31	32	22	23
In contrast , exogenous MIF induced leukocyte adhesion and transmigration were severely impaired in Cd74 -/- mice , suggesting an alternative mechanism underlying MIF- versus CCL2 and MIF induced leukocyte adhesion in vivo .	In contrast, exogenous MIF induced leukocyte adhesion and transmigration were severely impaired in Cd74 -/- mice, suggesting an alternative mechanism underlying MIF- versus CCL2 and MIF induced leukocyte adhesion in vivo.	3	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	Cd74	Cd74	Cd74	4	5	14	15
Indeed this MIF ortholog induced ERK1/2 kinases activation in a CD74 dependent manner , subsequently resulting in the inhibition of macrophage apoptosis in vitro .	Indeed this MIF ortholog induced ERK1/2 kinases activation in a CD74 dependent manner, subsequently resulting in the inhibition of macrophage apoptosis in vitro.	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	2	3	10	11
While the similarity of the effects of CD74 deficiency to those of MIF deficiency suggests CD74 as an essential participant in the actions of MIF , the participation of CD74 in responses to non MIF stimulation in the form of CCL2 , and the differences in in vitro responses between MIF -/- and CD74 -/- cells , suggest the possibility that while the effects of CD74 overlap with those of MIF , they are independent .	While the similarity of the effects of CD74 deficiency to those of MIF deficiency suggests CD74 as an essential participant in the actions of MIF, the participation of CD74 in responses to non MIF stimulation in the form of CCL2, and the differences in in vitro responses between MIF -/- and CD74 -/- cells, suggest the possibility that while the effects of CD74 overlap with those of MIF, they are independent.	34	55	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	34	35	53	54
MIF induced CD74 signaling in B cells requires formation of a complex with CD44 , a molecule shown to be increased in both B6 and MRL unstimulated anergic B cells .	MIF induced CD74 signaling in B cells requires formation of a complex with CD44, a molecule shown to be increased in both B6 and MRL unstimulated anergic B cells.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	0	1	2	3
In atherogenic monocyte recruitment , MIF induced monocyte adhesion involves CD74 and CXCR2 , which form a signaling receptor complex .	In atherogenic monocyte recruitment, MIF induced monocyte adhesion involves CD74 and CXCR2, which form a signaling receptor complex.	5	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	5	6	10	11
The release of endogenous MIF from ischemic myocardium has been shown to stimulate AMPK activation in a CD74 dependent , autcrine and paracrine manner , leading to enhanced glucose uptake and a beneficial tissue protective response 5 .	The release of endogenous MIF from ischemic myocardium has been shown to stimulate AMPK activation in a CD74 dependent, autcrine and paracrine manner, leading to enhanced glucose uptake and a beneficial tissue protective response 5.	1	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	4	5	17	18
This study enhances our understanding of MIF mediated CD74 activation and aids in the development of novel therapeutics .	This study enhances our understanding of MIF mediated CD74 activation and aids in the development of novel therapeutics.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	6	7	8	9
To identify inflammation related factors downstream of MIF and CD74 axis , we performed transcriptome analysis on astrocytes treated with 2.0 mug/ml MIF for 12 , 24 and 48 h , after knockdown of CD74 siRNA or scramble for 48 h.	To identify inflammation related factors downstream of MIF and CD74 axis, we performed transcriptome analysis on astrocytes treated with 2.0 mug/ml MIF for 12, 24 and 48 h, after knockdown of CD74 siRNA or scramble for 48 h.	7	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	22	23	9	10
CD74 activation by its ligand MIF signals through NF-kappaB in chronic lymphocytic leukemia ( CLL ) cells .	CD74 activation by its ligand MIF signals through NF-kappaB in chronic lymphocytic leukemia (CLL) cells.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	5	6	0	1
Our present findings confirm our hypothesis since : 1 ) increased MIF serum levels were observed in an additional group of prostate cancer patients when compared to patients with no documented prostate cancer ; 2 ) MIF mRNA was increased in prostate cancer tissue suggesting increased MIF synthesis in prostate cancer ; 3 ) CD74 , recently described as a receptor for MIF [ XREF_BIBR ] , is localized to prostatic epithelia ; 4 ) prostatic epithelial cells in vitro secrete MIF , with much greater secretion observed in prostate cancer cells .	Our present findings confirm our hypothesis since : 1) increased MIF serum levels were observed in an additional group of prostate cancer patients when compared to patients with no documented prostate cancer; 2) MIF mRNA was increased in prostate cancer tissue suggesting increased MIF synthesis in prostate cancer; 3) CD74, recently described as a receptor for MIF [XREF_BIBR], is localized to prostatic epithelia; 4) prostatic epithelial cells in vitro secrete MIF, with much greater secretion observed in prostate cancer cells.	46	55	synthesis	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	46	47	54	55
Using a novel approach , we elucidate the mechanistic details that control activation of CD74 by MIF surface residues and identify structural parameters of inhibitors that reduce CD74 biologic activation .	Using a novel approach, we elucidate the mechanistic details that control activation of CD74 by MIF surface residues and identify structural parameters of inhibitors that reduce CD74 biologic activation.	12	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	16	17	14	15
In renal cells , MIF activates CD74 to promote a proinflammatory response [ XREF_BIBR ] .	In renal cells, MIF activates CD74 to promote a proinflammatory response [XREF_BIBR].	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	4	5	6	7
Additionally , MIF effects were inhibited by an AMPK inhibitor compound C and siRNA targeting MIF receptor CD74 , suggesting the involvement of CD74 dependent AMPK activation .	Additionally, MIF effects were inhibited by an AMPK inhibitor compound C and siRNA targeting MIF receptor CD74, suggesting the involvement of CD74 dependent AMPK activation.	2	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MIF	MIF	MIF	CD74	CD74	CD74	2	3	17	18
In addition , MIF has been implicated to mediate the regulation of CD74 dependent ERK mitogen activated protein kinase ( MAPK ) signaling and the activation of cytosolic phospholipase A2 .	In addition, MIF has been implicated to mediate the regulation of CD74 dependent ERK mitogen activated protein kinase (MAPK) signaling and the activation of cytosolic phospholipase A2.	3	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	3	4	12	13
Finally , MIF stimulated CD74 dependent AKT activation was blocked by anti-CXCR4 and anti-CD74 antibodies and AMD3100 , whereas CXCL12 stimulated AKT activation was not reduced by anti-CD74 .	Finally, MIF stimulated CD74 dependent AKT activation was blocked by anti-CXCR4 and anti-CD74 antibodies and AMD3100, whereas CXCL12 stimulated AKT activation was not reduced by anti-CD74.	2	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	2	3	4	5
Unmodified MIF was shown to induce activation of ERK1/2 and AKT by binding its receptors CD74 and CXCR4 , which could be blocked by CXCR4 and CD74 neutralizing antibodies .	Unmodified MIF was shown to induce activation of ERK1/2 and AKT by binding its receptors CD74 and CXCR4, which could be blocked by CXCR4 and CD74 neutralizing antibodies.	0	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	1	2	15	16
Bonnie et al reported that MIF can activate CD74 on human MSCs and inhibit their migration .	Bonnie et al reported that MIF can activate CD74 on human MSCs and inhibit their migration.	5	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	5	6	8	9
In atherogenic monocyte recruitment , MIF induced monocyte adhesion involves CD74 and CXCR2 , which form a signalling receptor complex .	In atherogenic monocyte recruitment, MIF induced monocyte adhesion involves CD74 and CXCR2, which form a signalling receptor complex.	5	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	5	6	10	11
XREF_FIG a-c , the mRNA and protein levels of CD74 were the same whether treated with hypoxia/SD or MIF .	XREF_FIG a-c, the mRNA and protein levels of CD74 were the same whether treated with hypoxia/SD or MIF.	7	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	18	19	9	10
In the absence of a MIF-CD74 co-crystal structure , we used a novel approach to identify MIF residues that activate CD74 .	In the absence of a MIF-CD74 co-crystal structure, we used a novel approach to identify MIF residues that activate CD74.	16	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	16	17	20	21
However , intratracheal or intranasal administration of recombinant MIF activates CD74 on the surface of alveolar macrophages , leading to p44 and p42 MAPK signaling and the secretion of two neutrophil recruiting chemokines , MIP-2 and KC .	However, intratracheal or intranasal administration of recombinant MIF activates CD74 on the surface of alveolar macrophages, leading to p44 and p42 MAPK signaling and the secretion of two neutrophil recruiting chemokines, MIP-2 and KC.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	8	9	10	11
Furthermore , MIF mediates neutrophil accumulation in MIF triggered lung inflammation by inducing the chemokines Cxcl1 and Cxcl2 and Mip2 in alveolar macrophages through Cd74 and extracellular signal regulated kinase ( Erk ) signaling and can promote neutrophil chemotaxis in particular in the presence of actively expressed surface CD74 .	Furthermore, MIF mediates neutrophil accumulation in MIF triggered lung inflammation by inducing the chemokines Cxcl1 and Cxcl2 and Mip2 in alveolar macrophages through Cd74 and extracellular signal regulated kinase (Erk) signaling and can promote neutrophil chemotaxis in particular in the presence of actively expressed surface CD74.	2	49	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	2	3	48	49
However , topical inhibition of MIF by application of specific antibody onto the cornea promoted further recovery from the disease , suggesting that in addition to previously described MIF induced CD74 dependent pathways , sensitization to disease occurs via MIF triggered CD74 independent pathways .	However, topical inhibition of MIF by application of specific antibody onto the cornea promoted further recovery from the disease, suggesting that in addition to previously described MIF induced CD74 dependent pathways, sensitization to disease occurs via MIF triggered CD74 independent pathways.	37	43	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	39	40	41	42
Our recent study showed that activation of CD74 by MIF on CLL cells initiates a signaling cascade that can be observed from the very early stages of the disease .	Our recent study showed that activation of CD74 by MIF on CLL cells initiates a signaling cascade that can be observed from the very early stages of the disease.	5	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	9	10	7	8
MIF induced CD74 asssociated c-Met activation , which was blocked by knocking down CD74 expression using siRNA .	MIF induced CD74 asssociated c-Met activation, which was blocked by knocking down CD74 expression using siRNA.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	0	1	2	3
B cells from CLL patients have higher cell surface levels of CD74 than do normal B cells , and it was shown that the activation of CD74 by MIF in CLL cells activates NF-kappaB and induces secretion of IL-8 , which promotes cell survival and tumor progression [ XREF_BIBR , XREF_BIBR ] .	B cells from CLL patients have higher cell surface levels of CD74 than do normal B cells, and it was shown that the activation of CD74 by MIF in CLL cells activates NF-kappaB and induces secretion of IL-8, which promotes cell survival and tumor progression [XREF_BIBR, XREF_BIBR].	24	31	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	28	29	26	27
Stimulation of CD74 by MIF induced a signaling cascade leading to up-regulation of Bcl-2 expression , resulting in a significant increased survival of CEC .	Stimulation of CD74 by MIF induced a signaling cascade leading to up-regulation of Bcl-2 expression, resulting in a significant increased survival of CEC.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	4	5	2	3
CD74 stimulation by its ligand MIF induces cell survival .	CD74 stimulation by its ligand MIF induces cell survival.	0	6	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	5	6	0	1
We show in this study that MIF induced CD74 activation initiates a signaling cascade that results in upregulation of TAp63 , which directly regulates CLL survival .	We show in this study that MIF induced CD74 activation initiates a signaling cascade that results in upregulation of TAp63, which directly regulates CLL survival.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	6	7	8	9
Furthermore , in T. gondii infected females , it is possible that CD74 can be activated by MIF from T. gondii ( TgMIF ) .	Furthermore, in T. gondii infected females, it is possible that CD74 can be activated by MIF from T. gondii (TgMIF).	12	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	17	18	12	13
However , topical inhibition of MIF using antibodies applied to the cornea further promoted recovery from disease , suggesting that in addition to MIF dependent signaling events , MIF triggered CD74 independent signaling pathways regulate sensitization to P. aeruginosa induced infection .	However, topical inhibition of MIF using antibodies applied to the cornea further promoted recovery from disease, suggesting that in addition to MIF dependent signaling events, MIF triggered CD74 independent signaling pathways regulate sensitization to P. aeruginosa induced infection.	28	33	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	28	29	30	31
Due to the lack of an intracellular domain , the activation of CD74 by MIF relies on the recruitment of coreceptors such as CD44 or CXCR2 and CXCR4 [ XREF_BIBR ] .	Due to the lack of an intracellular domain, the activation of CD74 by MIF relies on the recruitment of coreceptors such as CD44 or CXCR2 and CXCR4 [XREF_BIBR].	10	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	14	15	12	13
It increases tumor cell survival in B-CLL via secreted MIF that triggers the CD74 and CD44-IL 8-Bcl2 axis and the ERK pathway .	It increases tumor cell survival in B-CLL via secreted MIF that triggers the CD74 and CD44-IL 8-Bcl2 axis and the ERK pathway.	8	21	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	9	10	13	14
The in vitro studies suggested that exogenous MIF derived from the tumour microenvironment promotes proliferation , adhesion , and invasion of CD74 + invasive breast cancer cells .	The in vitro studies suggested that exogenous MIF derived from the tumour microenvironment promotes proliferation, adhesion, and invasion of CD74 + invasive breast cancer cells.	6	26	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	7	8	21	22
A functional interplay between CD74 and CXCR4 was addressed in a MIF triggered CD74 dependent signaling assay by applying a CXCR4 specific small molecule inhibitor and by comparing the effects of MIF and CXCL12 in the presence versus absence of blocking anti-CD74 and anti-CXCR4 antibodies .	A functional interplay between CD74 and CXCR4 was addressed in a MIF triggered CD74 dependent signaling assay by applying a CXCR4 specific small molecule inhibitor and by comparing the effects of MIF and CXCL12 in the presence versus absence of blocking anti-CD74 and anti-CXCR4 antibodies.	8	27	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	11	12	13	14
CD74 does not have a typical signal transducing cytosolic domain , but may utilize a signal transducing coreceptor pathway in which recruitment of CD44 activates non receptor tyrosine kinases [ XREF_BIBR ] A previous study demonstrated that stimulation of CD74 by MIF recruits the tyrosine kinase receptor c-Met to the CD74 and CD44 complex and thereby enables induction of a signaling cascade within the cell to promote B cell survival [ XREF_BIBR ] .	CD74 does not have a typical signal transducing cytosolic domain, but may utilize a signal transducing coreceptor pathway in which recruitment of CD44 activates non receptor tyrosine kinases [XREF_BIBR] A previous study demonstrated that stimulation of CD74 by MIF recruits the tyrosine kinase receptor c-Met to the CD74 and CD44 complex and thereby enables induction of a signaling cascade within the cell to promote B cell survival [XREF_BIBR].	37	42	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	41	42	39	40
Since MIF or MIF-2 activation of CD74 is tissue protective in heart ischemia and liver injury induced by activation of the Fas receptor or metabolic disorders , a similar protective effect maybe hypothesized in ischemic acute kidney injury or metabolic kidney diseases characterized by increased CD74 expression , such as diabetic nephropathy or Fabry disease .	Since MIF or MIF-2 activation of CD74 is tissue protective in heart ischemia and liver injury induced by activation of the Fas receptor or metabolic disorders, a similar protective effect maybe hypothesized in ischemic acute kidney injury or metabolic kidney diseases characterized by increased CD74 expression, such as diabetic nephropathy or Fabry disease.	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	1	2	6	7
However , the protection was not comparable to what was previously observed in infected MIF KO mice , suggesting that MIF triggered CD74 independent pathways , as well as a MIF independent effects from loss of CD74 , could contribute to the pathologic response to acute P. aeruginosa keratitis in the absence of this molecule .	However, the protection was not comparable to what was previously observed in infected MIF KO mice, suggesting that MIF triggered CD74 independent pathways, as well as a MIF independent effects from loss of CD74, could contribute to the pathologic response to acute P. aeruginosa keratitis in the absence of this molecule.	20	30	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	20	21	22	23
Moreover , we recently demonstrated that CD74 stimulation by MIF recruits the tyrosine kinase receptor , c-Met , to the CD74 and CD44 complex and thereby enables the induction of its signaling cascade within the cell .	Moreover, we recently demonstrated that CD74 stimulation by MIF recruits the tyrosine kinase receptor, c-Met, to the CD74 and CD44 complex and thereby enables the induction of its signaling cascade within the cell.	6	10	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	9	10	6	7
Previous reports have highlighted the importance of MIF induced CD74 regulated inflammatory responses during autoimmune inflammation XREF_BIBR XREF_BIBR .	Previous reports have highlighted the importance of MIF induced CD74 regulated inflammatory responses during autoimmune inflammation XREF_BIBR XREF_BIBR.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	7	8	9	10
These findings support the concept that a chemical moiety of an MIF inhibitor outside the active site is important for reducing MIF activation of CD74 .	These findings support the concept that a chemical moiety of an MIF inhibitor outside the active site is important for reducing MIF activation of CD74.	21	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	21	22	24	25
XREF_BIBR , XREF_BIBR , XREF_BIBR MIF triggers the activation of the MAPK and PI3K pathways by binding its membrane receptor CD74 , resulting in the inhibition of cell apoptosis .	XREF_BIBR, XREF_BIBR, XREF_BIBR MIF triggers the activation of the MAPK and PI3K pathways by binding its membrane receptor CD74, resulting in the inhibition of cell apoptosis.	0	21	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	5	6	20	21
MIF promotes CD74 dependent CSC proliferation .	MIF promotes CD74 dependent CSC proliferation.	0	5	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	0	1	2	3
MIF also directly enhances B cell survival in a CD74 dependent mechanism .	MIF also directly enhances B cell survival in a CD74 dependent mechanism.	0	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	0	1	9	10
The reported findings provide fundamental insights on an allosteric and dynamic mechanism that controls the MIF induced activation of CD74 .	The reported findings provide fundamental insights on an allosteric and dynamic mechanism that controls the MIF induced activation of CD74.	14	20	induced	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	15	16	19	20
Our results demonstrated that MIF activated CD74 dependent c-Met , and this was linked to activation of the Akt pathway and enhancement of cell survival by MIF .	Our results demonstrated that MIF activated CD74 dependent c-Met, and this was linked to activation of the Akt pathway and enhancement of cell survival by MIF.	4	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	4	5	6	7
MIF activates CD74 to increase inflammatory cytokines in podocytes and tubular cells and proliferation in glomerular parietal epithelial cells and cyst cells .	MIF activates CD74 to increase inflammatory cytokines in podocytes and tubular cells and proliferation in glomerular parietal epithelial cells and cyst cells.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	0	1	2	3
In ischemic cardiomyocytes , MIF activates the CD74 and AMP kinase pathway , resulting in an increase of glucose uptake via the translocation of GLUT4 .	In ischemic cardiomyocytes, MIF activates the CD74 and AMP kinase pathway, resulting in an increase of glucose uptake via the translocation of GLUT4.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	4	5	7	8
We also show for the first time that MIF mediated triggering of the canonical JNK/c-Jun/AP -1 pathway is co-dependent on the interaction of MIF with its receptors CD74 and CXCR4 and involves an upstream activation of a SRC-type kinase and PI3K .	We also show for the first time that MIF mediated triggering of the canonical JNK/c-Jun/AP -1 pathway is co-dependent on the interaction of MIF with its receptors CD74 and CXCR4 and involves an upstream activation of a SRC-type kinase and PI3K.	8	29	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	8	9	27	28
Given recent promise in the design of inhibitors of the MIF : CD74 interaction , there is significant interest in defining the molecular basis for MIF activation of CD74 .	Given recent promise in the design of inhibitors of the MIF : CD74 interaction, there is significant interest in defining the molecular basis for MIF activation of CD74.	25	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	25	26	28	29
To study the effect of MIF mediated CD74 dependent ERK1/2 activation on the CEP degeneration .	To study the effect of MIF mediated CD74 dependent ERK1/2 activation on the CEP degeneration.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	5	6	7	8
MIF Signal Transduction Initiated by Binding to CD74 .	MIF Signal Transduction Initiated by Binding to CD74.	0	8	Initiated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	0	1	7	8
Examining the differences between MIF activation of CXCR4 receptors versus MIF activation of CD74 receptors then might provide insights into the actual mechanism for MIF mediated effects in the bladder and possibly other sites .	Examining the differences between MIF activation of CXCR4 receptors versus MIF activation of CD74 receptors then might provide insights into the actual mechanism for MIF mediated effects in the bladder and possibly other sites.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	10	11	13	14
CD74 , CD44 and CXCR4 are upregulated in renal cells in diseased kidneys and MIF activation of CD74 in kidney cells promotes an inflammatory response .	CD74, CD44 and CXCR4 are upregulated in renal cells in diseased kidneys and MIF activation of CD74 in kidney cells promotes an inflammatory response.	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MIF	MIF	MIF	CD74	CD74	CD74	14	15	17	18
Latent TGF-beta1 synthesized in dental pulp is primarily activated by MMP11 and to a lesser extent by MMP2 .	Latent TGF-beta1 synthesized in dental pulp is primarily activated by MMP11 and to a lesser extent by MMP2.	0	18	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGF-beta1	TGF-beta1	TGF-beta1	17	18	1	2
XREF_BIBR Communally , MMP-2 , -9 , and -14 also activate TGF-beta1 secreted from the malignant hepatocyte , a key modulator of EMT in HCC .	XREF_BIBR Communally, MMP-2, -9, and -14 also activate TGF-beta1 secreted from the malignant hepatocyte, a key modulator of EMT in HCC.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	3	4	11	12
Interestingly , in old untreated rings or VSMCs , the increased TGF-beta1 , fibronectin , and collagen were also substantially reduced by inhibition of MMP-2 .	Interestingly, in old untreated rings or VSMCs, the increased TGF-beta1, fibronectin, and collagen were also substantially reduced by inhibition of MMP-2.	9	25	reduced	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	24	25	11	12
As expected from our proposed model of MMP2 mediated TGFbeta-1 activation , there was no significant correlation between MMP2 and TGFbeta-1 expression ( XREF_FIG ) .	As expected from our proposed model of MMP2 mediated TGFbeta-1 activation, there was no significant correlation between MMP2 and TGFbeta-1 expression (XREF_FIG).	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGFbeta-1	TGFbeta-1	TGFbeta-1	7	8	9	10
The activity of MMP-2 becomes increased within the aortic wall with advancing aging and cleaves and activates TGF-beta1 and pro-ET-1 , contributing to their increased bioavailability in the vascular cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The activity of MMP-2 becomes increased within the aortic wall with advancing aging and cleaves and activates TGF-beta1 and pro-ET-1, contributing to their increased bioavailability in the vascular cells [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	3	4	17	18
Similarly , MMP-14 and MMP-2 proteolytically activate TGF-beta1 .	Similarly, MMP-14 and MMP-2 proteolytically activate TGF-beta1.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	4	5	7	8
Active MMP-2 increases the active form of TGF-beta1 by its proteolytic effects on its latent forms , LAP and LTBP-1 XREF_BIBR .	Active MMP-2 increases the active form of TGF-beta1 by its proteolytic effects on its latent forms, LAP and LTBP-1 XREF_BIBR.	0	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	1	2	7	8
Latent TGF-beta1 synthesized in odontoblasts is also secreted in dentin matrix and primarily activated by MMP2 and MMP20 and to a lesser extent by MMP11 .	Latent TGF-beta1 synthesized in odontoblasts is also secreted in dentin matrix and primarily activated by MMP2 and MMP20 and to a lesser extent by MMP11.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGF-beta1	TGF-beta1	TGF-beta1	15	16	1	2
Furthermore , in vitro , MMP2 , MMP3 , and MMP7 induce the release of TGFbeta1 from decorin , a proteoglycan that sequester TGFbeta in the matrix .	Furthermore, in vitro, MMP2, MMP3, and MMP7 induce the release of TGFbeta1 from decorin, a proteoglycan that sequester TGFbeta in the matrix.	5	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGFbeta1	TGFbeta1	TGFbeta1	5	6	15	16
However , many studies have reported that increasing angII can induce MMP2 upregulation and activity , which activates TGF-beta1 and Smad signaling , and is associated with a central arterial wall stiffness , such as fibrosis and vascular calcification [ XREF_BIBR ] .	However, many studies have reported that increasing angII can induce MMP2 upregulation and activity, which activates TGF-beta1 and Smad signaling, and is associated with a central arterial wall stiffness, such as fibrosis and vascular calcification [XREF_BIBR].	11	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGF-beta1	TGF-beta1	TGF-beta1	11	12	18	19
In contrast , latent TGF-beta1 synthesized in odontoblasts is mainly activated by MMP2 .	In contrast, latent TGF-beta1 synthesized in odontoblasts is mainly activated by MMP2.	3	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGF-beta1	TGF-beta1	TGF-beta1	12	13	4	5
MMP2 has also been shown to increase the conversion of TGFB1 precursor subunits to the active form of TGFB1 XREF_BIBR .	MMP2 has also been shown to increase the conversion of TGFB1 precursor subunits to the active form of TGFB1 XREF_BIBR.	0	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGFB1	TGFB1	TGFB1	0	1	10	11
Because TGF-beta1 is activated by MMP-2 , we next analyzed MMP-2 production in our experimental conditions .	Because TGF-beta1 is activated by MMP-2, we next analyzed MMP-2 production in our experimental conditions.	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	5	6	1	2
Overall , our data indicate that MMP2 promotes TGFbeta1 dependent PrCa cell migration in alpha v beta 6 -expressing PC3 cells .	Overall, our data indicate that MMP2 promotes TGFbeta1 dependent PrCa cell migration in alpha v beta 6 -expressing PC3 cells.	6	9	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGFbeta1	TGFbeta1	TGFbeta1	6	7	8	9
To determine whether reduction of MMP-2 production could inhibit TGF-beta1 activation , we next transfected a GFP expressing shRNA construct against MMP-2 mRNA into HK-2 cells prior to HCMV infection and raTGF-beta1 stimulation .	To determine whether reduction of MMP-2 production could inhibit TGF-beta1 activation, we next transfected a GFP expressing shRNA construct against MMP-2 mRNA into HK-2 cells prior to HCMV infection and raTGF-beta1 stimulation.	5	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	5	6	9	10
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR In particular , MMP-14 and MMP-2 can act in sequence to activate one another and cause subsequent release of TGFbeta1 from its latency complex .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR In particular, MMP-14 and MMP-2 can act in sequence to activate one another and cause subsequent release of TGFbeta1 from its latency complex.	12	29	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGFbeta1	TGFbeta1	TGFbeta1	14	15	28	29
Latent TGF-beta1 synthesized in odontoblasts is primarily activated by MMP2 and MMP20 in both odontoblasts and dentin .	Latent TGF-beta1 synthesized in odontoblasts is primarily activated by MMP2 and MMP20 in both odontoblasts and dentin.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGF-beta1	TGF-beta1	TGF-beta1	9	10	1	2
MCP-1 maintains its level indirectly via its effect to activate MMP-2 , which activates TGF-beta1 , which , in turn , increases MCP-1 .	MCP-1 maintains its level indirectly via its effect to activate MMP-2, which activates TGF-beta1, which, in turn, increases MCP-1.	9	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	10	11	14	15
We demonstrated that rh-latent TGF-beta1 was dramatically activated by MMP2 and MMP11 in vitro .	We demonstrated that rh-latent TGF-beta1 was dramatically activated by MMP2 and MMP11 in vitro.	3	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGF-beta1	TGF-beta1	TGF-beta1	9	10	4	5
In addition , MMP9 and MMP2 can directly process TGF-beta into an active ligand and induce TGF-beta1 production in the airway epithelium and peribronchiolar fibroblast proliferation XREF_BIBR .	In addition, MMP9 and MMP2 can directly process TGF-beta into an active ligand and induce TGF-beta1 production in the airway epithelium and peribronchiolar fibroblast proliferation XREF_BIBR.	3	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGF-beta1	TGF-beta1	TGF-beta1	5	6	16	17
Previous studies in several mammalian cell types have shown that latent TGF-beta1 can be activated in vitro by MMP-2 and by activators of MMP-2 [ XREF_BIBR , XREF_BIBR ] .	Previous studies in several mammalian cell types have shown that latent TGF-beta1 can be activated in vitro by MMP-2 and by activators of MMP-2 [XREF_BIBR, XREF_BIBR].	10	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	18	19	11	12
In this system , MMP-2 mediates the extracellular activation of TGF-beta1 in HCMV infected cells , and can be recapitulated by transient transfection of the HCMV IE1 or IE2 open reading frames into renal epithelial cells stimulated to undergo EMT .	In this system, MMP-2 mediates the extracellular activation of TGF-beta1 in HCMV infected cells, and can be recapitulated by transient transfection of the HCMV IE1 or IE2 open reading frames into renal epithelial cells stimulated to undergo EMT.	4	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	4	5	10	11
Epithelial-mesenchymal transition ( EMT ) occurs in the irradiated lungs of Bama minipigs , and MMP2 and MMP9 may contribute to EMT in AE2 cells by regulating TGFbeta1 .	Epithelial-mesenchymal transition (EMT) occurs in the irradiated lungs of Bama minipigs, and MMP2 and MMP9 may contribute to EMT in AE2 cells by regulating TGFbeta1.	15	28	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGFbeta1	TGFbeta1	TGFbeta1	15	16	27	28
It is well known that MMP-2 , -9 , and -14 activate TGF-beta1 , which is a key modulator of epithelial-mesenchymal transition in HCC [ XREF_BIBR ] .	It is well known that MMP-2, -9, and -14 activate TGF-beta1, which is a key modulator of epithelial-mesenchymal transition in HCC [XREF_BIBR].	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	5	6	12	13
This is indeed noteworthy since MMP2 activates latent TGF-beta1 and is a major driver of TGF-beta1-mediated fibrosis .	This is indeed noteworthy since MMP2 activates latent TGF-beta1 and is a major driver of TGF-beta1-mediated fibrosis.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGF-beta1	TGF-beta1	TGF-beta1	5	6	8	9
Since MMP-2 can activate TGFbeta1 and since TGFbeta1 has direct effects on esophageal epithelial cell function XREF_BIBR , XREF_BIBR , we were curious to know if there was a potential positive feedback loop for TGFbeta1 via MMP-2 .	Since MMP-2 can activate TGFbeta1 and since TGFbeta1 has direct effects on esophageal epithelial cell function XREF_BIBR, XREF_BIBR, we were curious to know if there was a potential positive feedback loop for TGFbeta1 via MMP-2.	1	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGFbeta1	TGFbeta1	TGFbeta1	1	2	4	5
For example , since MMP2 activates TGF-beta1 by cleaving the latency associated peptide , the loss of MMP2 activity alone is likely to result in reduced levels of TGF-beta1 [ XREF_BIBR , XREF_BIBR ] .	For example, since MMP2 activates TGF-beta1 by cleaving the latency associated peptide, the loss of MMP2 activity alone is likely to result in reduced levels of TGF-beta1 [XREF_BIBR, XREF_BIBR].	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	TGF-beta1	TGF-beta1	TGF-beta1	4	5	6	7
At the same time , MMP-2 up-regulates TGF beta-1 , MMP-9 , and VEGFR-1 .	At the same time, MMP-2 up-regulates TGF beta-1, MMP-9, and VEGFR-1.	5	9	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF beta-1	TGF beta-1	TGF beta-1	5	6	7	9
Inflammatory stimuli , MMP-2 and MMP-9 promote the release of TGF-beta1 from this complex in its mature form , which binds to its receptor and then activates downstream signaling pathways .	Inflammatory stimuli, MMP-2 and MMP-9 promote the release of TGF-beta1 from this complex in its mature form, which binds to its receptor and then activates downstream signaling pathways.	1	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	3	4	10	11
TGF-beta1 is released in the ECM in a latent form and activated by MMP-2 or MMP-9 , which are richly expressed in the tumor microenvironment [ XREF_BIBR ] .	TGF-beta1 is released in the ECM in a latent form and activated by MMP-2 or MMP-9, which are richly expressed in the tumor microenvironment [XREF_BIBR].	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MMP-2	MMP-2 or MMP-9, which are richly expressed	mmp-2	TGF-beta1	TGF-beta1	tgf-beta1	13	14	0	1
Phospho-p38 , MMP-2 and MMP-9 increased after 3 days exposure to TGF-beta1 and remained high with loss-of-STMN1 expression , suggesting that their expression was regulated , in part , by TGF-beta signaling .	Phospho-p38, MMP-2 and MMP-9 increased after 3 days exposure to TGF-beta1 and remained high with loss-of-STMN1 expression, suggesting that their expression was regulated, in part, by TGF-beta signaling.	0	12	increased	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	2	3	11	12
Our prior studies have demonstrated that MMP-2 and MCP-1 concurrently increase within the aged rat arterial wall , and that MMP-2 activates TGF-beta1 signaling via proteolysis XREF_BIBR , XREF_BIBR .	Our prior studies have demonstrated that MMP-2 and MCP-1 concurrently increase within the aged rat arterial wall, and that MMP-2 activates TGF-beta1 signaling via proteolysis XREF_BIBR, XREF_BIBR.	20	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	20	21	22	23
MMP-2 is predicted to up-regulate TGF-beta1 , MMP-9 , and VEGFR-1 .	MMP-2 is predicted to up-regulate TGF-beta1, MMP-9, and VEGFR-1.	0	10	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	0	1	5	6
We find that nuclease deficient Mre11 maintains interactions within MRN and supports activation of the ATM kinase .	We find that nuclease deficient Mre11 maintains interactions within MRN and supports activation of the ATM kinase.	3	16	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	5	6	15	16
However , for reasons that are not clear , the knockdown of MRE11 did not prevent the activation of ATM , as it does in live cells .	However, for reasons that are not clear, the knockdown of MRE11 did not prevent the activation of ATM, as it does in live cells.	10	20	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	ATM	ATM	ATM	12	13	19	20
New data suggest that the Mre11 complex can directly activate the ATM checkpoint kinase at DNA breaks .	New data suggest that the Mre11 complex can directly activate the ATM checkpoint kinase at DNA breaks.	5	13	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	5	6	11	12
In somatic cells , the ATM kinase is activated by the MRE11 complex to participate in the DNA damage response by phosphorylating multiple substrates , including the checkpoint mediator kinase CHK2 [ XREF_BIBR ] .	In somatic cells, the ATM kinase is activated by the MRE11 complex to participate in the DNA damage response by phosphorylating multiple substrates, including the checkpoint mediator kinase CHK2 [XREF_BIBR].	5	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	ATM	ATM	ATM	11	12	5	6
Expression of human MRE11 in Mre11-KD cells restored the activation of ATM and ATR .	Expression of human MRE11 in Mre11-KD cells restored the activation of ATM and ATR.	0	13	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRE11	Expression of human MRE11	mre11	ATM	ATM	atm	3	4	11	12
53BP1 dependent amplification of MRE11 and NBS1 increases the concentration of ATM at heterochromatic breaks , which in turn leads to phosphorylation of KAP1 .	53BP1 dependent amplification of MRE11 and NBS1 increases the concentration of ATM at heterochromatic breaks, which in turn leads to phosphorylation of KAP1.	2	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	ATM	ATM	ATM	4	5	11	12
These data indicate that the essential role of Nbs1 is via its interaction with Mre11 , that most of the Nbs1 protein is dispensable for Mre11 complex functions , and suggest that Mre11 and Rad50 directly activate ATM .	These data indicate that the essential role of Nbs1 is via its interaction with Mre11, that most of the Nbs1 protein is dispensable for Mre11 complex functions, and suggest that Mre11 and Rad50 directly activate ATM.	32	38	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	32	33	37	38
Interestingly , the lack of either Sae2 or Mre11 nuclease activity enhances Tel1 and ATM activation at DSBs by increasing MRX persistence at DSBs XREF_BIBR XREF_BIBR , suggesting that Sae2 and Mre11 nuclease can inhibit Tel1 and ATM signaling activity .	Interestingly, the lack of either Sae2 or Mre11 nuclease activity enhances Tel1 and ATM activation at DSBs by increasing MRX persistence at DSBs XREF_BIBR XREF_BIBR, suggesting that Sae2 and Mre11 nuclease can inhibit Tel1 and ATM signaling activity.	8	15	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	8	9	14	15
Moreover , the molecular basis of DSB end resection in yeast mre11-nuclease deficient mutants and Mre11 nuclease independent activation of ATM in mammals remains unknown and adds a new dimension to many unanswered questions about the mechanism of DSB repair .	Moreover, the molecular basis of DSB end resection in yeast mre11-nuclease deficient mutants and Mre11 nuclease independent activation of ATM in mammals remains unknown and adds a new dimension to many unanswered questions about the mechanism of DSB repair.	15	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	15	16	20	21
The corresponding MRE11 phosphosite mutant enables normal ATM signalling through substrates such as SMC1 , the phosphorylation of which is implicated in cell cycle control , genome stability and cell survival .	The corresponding MRE11 phosphosite mutant enables normal ATM signalling through substrates such as SMC1, the phosphorylation of which is implicated in cell cycle control, genome stability and cell survival.	2	8	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	ATM	ATM	ATM	2	3	7	8
The precise mechanism by which the Mre11 complex promotes ATM activation remains elusive but it may include a variety of activities including molecular bridging , DNA end-recognition and processing , modifications in chromatin structure , and direct protein protein interactions .	The precise mechanism by which the Mre11 complex promotes ATM activation remains elusive but it may include a variety of activities including molecular bridging, DNA end-recognition and processing, modifications in chromatin structure, and direct protein protein interactions.	6	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	6	7	9	10
Therefore , we propose that the distinct conformations of Mre11 bound to DNA represent a critical signal within the cell to mediate downstream signaling pathways , with symmetric Mre11 activating ATM signaling and asymmetric Mre11 initiating ATR signaling .	Therefore, we propose that the distinct conformations of Mre11 bound to DNA represent a critical signal within the cell to mediate downstream signaling pathways, with symmetric Mre11 activating ATM signaling and asymmetric Mre11 initiating ATR signaling.	10	31	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	28	29	30	31
ATM is recruited to DSBs and activated by the MRN complex ( Mre11 , Rad50 , and NBS1 ) through the association with NBS1 .	ATM is recruited to DSBs and activated by the MRN complex (Mre11, Rad50, and NBS1) through the association with NBS1.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	12	13	0	1
Our data has elucidated multiple roles for the Mre11 complex in apoptosis ; activation of ATM and the facilitation of ATM activity through the C-terminus of Nbs1 ( XREF_FIG ) .	Our data has elucidated multiple roles for the Mre11 complex in apoptosis; activation of ATM and the facilitation of ATM activity through the C-terminus of Nbs1 (XREF_FIG).	8	16	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	8	9	15	16
ATM is activated by the MRN sensor complex ( MRE11 , RAD50 and NBS1 ) that recognizes DSB structures ( XREF_FIG ) [ XREF_BIBR ] .	ATM is activated by the MRN sensor complex (MRE11, RAD50 and NBS1) that recognizes DSB structures (XREF_FIG) [XREF_BIBR].	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	ATM	ATM	ATM	9	10	0	1
Collectively , our findings demonstrate that ATM is activated by Rag DSBs in Mre11 ATLD1 and ATLD1 and Nbs1 m/m abl pre-B cells .	Collectively, our findings demonstrate that ATM is activated by Rag DSBs in Mre11 ATLD1 and ATLD1 and Nbs1 m/m abl pre-B cells.	6	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	13	14	6	7
Upon DNA DSBs , Mre11 , along with the MRN complex recruits ATM to the DSBs and activates ATM kinase activity .	Upon DNA DSBs, Mre11, along with the MRN complex recruits ATM to the DSBs and activates ATM kinase activity.	4	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	4	5	18	19
Control experiments showed that , as expected , MRE11 knockdown inhibited ATM activation in response to the DSB producer bleomycin .	Control experiments showed that, as expected, MRE11 knockdown inhibited ATM activation in response to the DSB producer bleomycin.	8	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	ATM	ATM	ATM	8	9	11	12
Following ATM activation , the Mre11 complex promotes ATM activity on many of its substrates .	Following ATM activation, the Mre11 complex promotes ATM activity on many of its substrates.	5	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	5	6	8	9
Atm activation is stimulated by expression of the Mre11 , Rad50 , and nibrin complex .	Atm activation is stimulated by expression of the Mre11, Rad50, and nibrin complex.	0	10	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mre11	expression of the Mre11	mre11	Atm	Atm	atm	8	9	0	1
In addition , the difference in the response to knockdown of MRE11 and the inhibition of MRE11 with Mirin further suggests that the effects of Mirin are a result of the inhibition of MRE11 3 '-5' exonuclease activity , and not MRE11 mediated activation of ATM .	In addition, the difference in the response to knockdown of MRE11 and the inhibition of MRE11 with Mirin further suggests that the effects of Mirin are a result of the inhibition of MRE11 3 '-5' exonuclease activity, and not MRE11 mediated activation of ATM.	41	46	mediated	Positive_early_activation	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	ATM	ATM	ATM	41	42	45	46
ATM activation is promoted by the heterotrimeric complex Mre11 , Rad50 , and Nbs1 that may directly recognize DNA double strand breaks , whereas ATR is activated through binding to RPA coated ssDNA and TopBP1 .	ATM activation is promoted by the heterotrimeric complex Mre11, Rad50, and Nbs1 that may directly recognize DNA double strand breaks, whereas ATR is activated through binding to RPA coated ssDNA and TopBP1.	0	13	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	8	9	0	1
iv ) ATM , in turn , is activated by MRE11 ( MRN ) and the ' TIP60 complex ' .	iv) ATM, in turn, is activated by MRE11 (MRN) and the ' TIP60 complex '.	2	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	ATM	ATM	ATM	10	11	2	3
In contrast , knockdown of MRE11 prevents the activation of ATM , which is required for protection of DSBs , thereby promoting the excessive processing of DSBs .	In contrast, knockdown of MRE11 prevents the activation of ATM, which is required for protection of DSBs, thereby promoting the excessive processing of DSBs.	3	14	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	ATM	ATM	ATM	5	6	10	11
Given that ATM is activated by RAG induced DSBs in the MRE11 and NBS1 mutants , it appears that the MRE11 complex plays a direct role in stabilizing the DNA end complex , rather than indirectly by activating ATM .	Given that ATM is activated by RAG induced DSBs in the MRE11 and NBS1 mutants, it appears that the MRE11 complex plays a direct role in stabilizing the DNA end complex, rather than indirectly by activating ATM.	2	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	ATM	ATM	ATM	11	12	2	3
Because Mre11 is required to activate ataxia telangiectasia mutated ( ATM ) , its loss causes a repair defect in this process , precluding analysis by siRNA .	Because Mre11 is required to activate ataxia telangiectasia mutated (ATM), its loss causes a repair defect in this process, precluding analysis by siRNA.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	1	2	6	9
To address MKL1 mediated activation of SRF , cells were transfected with a construct comprising three serum response elements ( SRE ) with a mutated Ets motif .	To address MKL1 mediated activation of SRF, cells were transfected with a construct comprising three serum response elements (SRE) with a mutated Ets motif.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	2	3	6	7
MKL1 is a co-activator of SRF , which in turn is a master regulator of genes encoding many cytoskeletal proteins 136 .	MKL1 is a co-activator of SRF, which in turn is a master regulator of genes encoding many cytoskeletal proteins 136.	0	13	is a co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	0	1	5	6
An essential link is the MKL1 dependent activation of serum response factor ( SRF ) , which translates changes in the ratio of G- and F-actin into mRNA transcription .	An essential link is the MKL1 dependent activation of serum response factor (SRF), which translates changes in the ratio of G- and F-actin into mRNA transcription.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	serum response factor	serum response factor	serum response factor	5	6	9	12
Dominant negative MKL1 inhibits serum induction of SRF target genes .	Dominant negative MKL1 inhibits serum induction of SRF target genes.	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	2	3	7	8
NFAT signaling 1 and MKL1 dependent activation of SRF dependent genes 2 , 3 represent typical examples of gene expression reliance on nuclear import of transcriptional regulators .	NFAT signaling 1 and MKL1 dependent activation of SRF dependent genes 2, 3 represent typical examples of gene expression reliance on nuclear import of transcriptional regulators.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	4	5	8	9
XREF_BIBR MKL1 mediates the TCF independent activation of serum response factor ( SRF ) , which controls vascular smooth muscle cell and cardiomyocyte differentiation .	XREF_BIBR MKL1 mediates the TCF independent activation of serum response factor (SRF), which controls vascular smooth muscle cell and cardiomyocyte differentiation.	0	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	serum response factor	serum response factor	serum response factor	1	2	8	11
We further found that overexpression of Mkl1 , which could activate Srf , preferentially downregulated cell-type-specific genes similar to Srf overexpression .	We further found that overexpression of Mkl1, which could activate Srf, preferentially downregulated cell-type-specific genes similar to Srf overexpression.	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mkl1	overexpression of Mkl1	mkl1	Srf	Srf	srf	6	7	11	12
Mkl1 , as well as the Rbm15-Mkl1 fusion protein , activate a subset of endogenous serum response factor ( SRF ) target genes in an SRF dependent manner in non hematopoietic cell lines XREF_BIBR - XREF_BIBR .	Mkl1, as well as the Rbm15-Mkl1 fusion protein, activate a subset of endogenous serum response factor (SRF) target genes in an SRF dependent manner in non hematopoietic cell lines XREF_BIBR - XREF_BIBR.	0	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mkl1	Mkl1	Mkl1	SRF	SRF	SRF	0	1	25	26
Upon polymerization of actin ( F-Actin formation ) , MRTF-A is released from monomeric actin and translocates to the nucleus , associating with SRF to activate SRF target genes .	Upon polymerization of actin (F-Actin formation), MRTF-A is released from monomeric actin and translocates to the nucleus, associating with SRF to activate SRF target genes.	9	28	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MRTF-A	MRTF-A is released from monomeric actin and translocates to the nucleus	mrtf-a	SRF	SRF	srf	9	10	26	27
Nuclear MKL1 stimulates Hh signalling in an SRF independent manner , most likely through the presence of one of its direct interactors , the histone demethylase JMJD1A .	Nuclear MKL1 stimulates Hh signalling in an SRF independent manner, most likely through the presence of one of its direct interactors, the histone demethylase JMJD1A.	0	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	1	2	7	8
MKL1 is a co-activator of serum response factor ( SRF ) , which is a master regulator of genes encoding numerous cytoskeletal proteins , including both Vinculin and Actin .	MKL1 is a co-activator of serum response factor (SRF), which is a master regulator of genes encoding numerous cytoskeletal proteins, including both Vinculin and Actin.	0	8	is a co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	serum response factor	serum response factor	serum response factor	0	1	5	8
MRTF-A ( myocardin related transcription factor A ) , also termed MKL1 , MAL and BSAC , is a transcriptional co-activator of SRF ( serum response factor ) , which is ubiquitously expressed in a wide range of tissues [ XREF_BIBR ] .	MRTF-A (myocardin related transcription factor A), also termed MKL1, MAL and BSAC, is a transcriptional co-activator of SRF (serum response factor), which is ubiquitously expressed in a wide range of tissues [XREF_BIBR].	0	33	is a transcriptional co-activator	Positive_regulation_copula_1	Positive_activation	Positive_regulation	MRTF-A	MRTF-A	mrtf-a	SRF	SRF (serum response factor), which is ubiquitously expressed	srf	0	1	22	23
We describe a mechanism by which an interaction between CCTepsilon and the cotranscriptional activator MRTF-A modulates SRF signaling .	We describe a mechanism by which an interaction between CCTepsilon and the cotranscriptional activator MRTF-A modulates SRF signaling.	7	17	modulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MRTF-A	MRTF-A	MRTF-A	SRF	SRF	SRF	14	15	16	17
In addition , inhibition of endogenous MKL1 by overexpression of a dominant negative MKL1 mutant or by small interfering RNA reduced BDNF activation of SRF driven transcription .	In addition, inhibition of endogenous MKL1 by overexpression of a dominant negative MKL1 mutant or by small interfering RNA reduced BDNF activation of SRF driven transcription.	3	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	6	7	24	25
MKL1 is regulated by the actin cytoskeleton [ XREF_BIBR ] , and activates the transcription factor SRF [ XREF_BIBR - XREF_BIBR ] .	MKL1 is regulated by the actin cytoskeleton [XREF_BIBR], and activates the transcription factor SRF [XREF_BIBR - XREF_BIBR].	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	0	1	16	17
MRTF-A is a co-activator of the transcription factor serum response factor ( SRF ) , which controls , for instance , the expression of many cytoskeletal genes .	MRTF-A is a co-activator of the transcription factor serum response factor (SRF), which controls, for instance, the expression of many cytoskeletal genes.	0	11	is a co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MRTF-A	MRTF-A	MRTF-A	serum response factor	serum response factor	serum response factor	0	1	8	11
Nevertheless , although overexpression of either wild-type MRTF-A or MRTF26A potentiated activity of the SRF reporter gene similarly in unstimulated cells , MRTF26A exhibited significantly reduced activity following serum or CD stimulation ( XREF_FIG ) .	Nevertheless, although overexpression of either wild-type MRTF-A or MRTF26A potentiated activity of the SRF reporter gene similarly in unstimulated cells, MRTF26A exhibited significantly reduced activity following serum or CD stimulation (XREF_FIG).	3	16	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRTF-A	overexpression of either wild-type MRTF-A	mrtf-a	SRF	SRF	srf	7	8	14	15
XREF_BIBR , XREF_BIBR Serum- or mechanically induced polymerization of actin releases G-actin from MKL1 and allows the translocation of MKL1 to the nucleus , where it , together with SRF , activates SRF and MKL1 target genes ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR Serum- or mechanically induced polymerization of actin releases G-actin from MKL1 and allows the translocation of MKL1 to the nucleus, where it, together with SRF, activates SRF and MKL1 target genes (XREF_FIG).	17	38	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MKL1	translocation of MKL1 to the nucleus	mkl1	SRF	SRF	srf	19	20	32	33
All four MKL1 isoforms increased SRF mediated transcriptional responses ( XREF_FIG B and C ) .	All four MKL1 isoforms increased SRF mediated transcriptional responses (XREF_FIG B and C).	2	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	2	3	5	6
MKL1 is a transcriptional coactivator of serum response factor , with the translocation of MKL1 and RBM15 being a leading cause of acute megakaryoblastic leukemia .	MKL1 is a transcriptional coactivator of serum response factor, with the translocation of MKL1 and RBM15 being a leading cause of acute megakaryoblastic leukemia.	0	9	is a transcriptional coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	serum response factor	serum response factor	serum response factor	0	1	6	9
These results suggest that neuronal MKL1 contributes to SRF regulated gene expression induced by BDNF or synaptic activity .	These results suggest that neuronal MKL1 contributes to SRF regulated gene expression induced by BDNF or synaptic activity.	4	9	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	5	6	8	9
MRTF-A has been shown to translocate to the nucleus and activate SRF in response to Rho signaling and actin polymerization .	MRTF-A has been shown to translocate to the nucleus and activate SRF in response to Rho signaling and actin polymerization.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRTF-A	MRTF-A	MRTF-A	SRF	SRF	SRF	0	1	11	12
MRTF-A is a transcriptional coactivator of SRF linking actin dynamics with transcription of SRF dependent genes encoding contractile and cytoskeletal proteins XREF_BIBR XREF_BIBR XREF_BIBR .	MRTF-A is a transcriptional coactivator of SRF linking actin dynamics with transcription of SRF dependent genes encoding contractile and cytoskeletal proteins XREF_BIBR XREF_BIBR XREF_BIBR.	0	7	is a transcriptional coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	MRTF-A	MRTF-A	MRTF-A	SRF	SRF	SRF	0	1	6	7
Megakaryoblastic leukemia 1 ( MKL1 ) , identified as part of the t ( 1 ; 22 ) translocation specific to acute megakaryoblastic leukemia , is highly expressed in differentiated muscle cells and promotes muscle differentiation by activating serum response factor ( SRF ) .	Megakaryoblastic leukemia 1 (MKL1), identified as part of the t (1; 22) translocation specific to acute megakaryoblastic leukemia, is highly expressed in differentiated muscle cells and promotes muscle differentiation by activating serum response factor (SRF).	1	41	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	serum response factor	serum response factor	serum response factor	4	5	38	41
TGFbeta1 regulated Smads coupled with synthesis and polymerization of G-actin monomers into stress fibers and the associated release and nuclear uptake of MRTF-A may augment SRF action and amplify transcriptional output from the SMalphaA promoter .	TGFbeta1 regulated Smads coupled with synthesis and polymerization of G-actin monomers into stress fibers and the associated release and nuclear uptake of MRTF-A may augment SRF action and amplify transcriptional output from the SMalphaA promoter.	20	26	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRTF-A	MRTF-A	MRTF-A	SRF	SRF	SRF	22	23	25	26
Both MKL1 and -2 are coactivators of the transcription factor serum response factor ( SRF ) , which regulates genes involved in many biological processes , including cell growth and migration .	Both MKL1 and -2 are coactivators of the transcription factor serum response factor (SRF), which regulates genes involved in many biological processes, including cell growth and migration.	0	13	are coactivators	Positive_activation_copula_1	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	serum response factor	serum response factor	serum response factor	1	2	10	13
MKL1 potentiates SRF dependent transactivation of genes specific to cells of the muscle lineage thereby playing a key role in the phenotypic modulation of smooth muscle cells .	MKL1 potentiates SRF dependent transactivation of genes specific to cells of the muscle lineage thereby playing a key role in the phenotypic modulation of smooth muscle cells.	0	4	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	0	1	2	3
MRTF-A accumulation activates SRF and MRTF-A-dependent gene transcription XREF_BIBR .	MRTF-A accumulation activates SRF and MRTF-A-dependent gene transcription XREF_BIBR.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRTF-A	MRTF-A	MRTF-A	SRF	SRF	SRF	0	1	3	4
In contrast , the transcription regulator myocardin related transcription factor ( MRTF-A ) , which stimulates SRF activity through the CArG box rather than the TCF site , has been implicated in the mechanical regulation of myofibroblast differentiation ( see below ) and JunB expression during epidermal stem cell and .	In contrast, the transcription regulator myocardin related transcription factor (MRTF-A), which stimulates SRF activity through the CArG box rather than the TCF site, has been implicated in the mechanical regulation of myofibroblast differentiation (see below) and JunB expression during epidermal stem cell and.	9	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRTF-A	MRTF-A	MRTF-A	SRF	SRF	SRF	11	12	16	17
This element thus contains the CArG box and is selectively activated by MKL1 activated SRF and not by Ras-ERK-mediated activation of SRF [ XREF_BIBR ] .	This element thus contains the CArG box and is selectively activated by MKL1 activated SRF and not by Ras-ERK-mediated activation of SRF [XREF_BIBR].	10	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	12	13	14	15
The functional properties of rat MKL1 isoforms indicates that the novel MKL1 isoform , MELODY , in addition to rat FLMKL1 , BSAC , MKL1met isoforms strongly enhanced SRF coactivation ( XREF_FIG B and C ) .	The functional properties of rat MKL1 isoforms indicates that the novel MKL1 isoform, MELODY, in addition to rat FLMKL1, BSAC, MKL1met isoforms strongly enhanced SRF coactivation (XREF_FIG B and C).	11	29	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	SRF	SRF	SRF	11	12	28	29
Importantly , among many effects , MMP9 is also able to activate TGF-beta1 contributing to enhance the pool of active TGF-beta1 [ XREF_BIBR ] .	Importantly, among many effects, MMP9 is also able to activate TGF-beta1 contributing to enhance the pool of active TGF-beta1 [XREF_BIBR].	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP9	MMP9	MMP9	TGF-beta1	TGF-beta1	TGF-beta1	6	7	12	13
The TGF-beta 1 , in turn stimulates the elaboration of additional uPA and activates additional MMP-9 which activates more TGF-beta 1 .	The TGF-beta 1, in turn stimulates the elaboration of additional uPA and activates additional MMP-9 which activates more TGF-beta 1.	13	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGF-beta 1	TGF-beta 1	TGF-beta 1	15	16	19	21
Precedent for such a proteolytic mechanism is that plasmin and MMP-9 have each been shown to activate TGF-beta1 and TGF-beta2 , respectively , by cleavage of LAP .	Precedent for such a proteolytic mechanism is that plasmin and MMP-9 have each been shown to activate TGF-beta1 and TGF-beta2, respectively, by cleavage of LAP.	8	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGF-beta1	TGF-beta1	TGF-beta1	10	11	17	18
Interestingly , MMP-9 activation of TGF-beta1 led to the increase in fibrosis in the atherosclerosis model previously described [ XREF_BIBR ] and may be a similar mechanism by which MMP-9 is increasing fibrosis in this model system .	Interestingly, MMP-9 activation of TGF-beta1 led to the increase in fibrosis in the atherosclerosis model previously described [XREF_BIBR] and may be a similar mechanism by which MMP-9 is increasing fibrosis in this model system.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGF-beta1	TGF-beta1	TGF-beta1	2	3	5	6
XREF_BIBR , XREF_BIBR Among its various activities , MMP-9 is known to activate precursor IL-1beta and latent TGF-beta1 into their active forms .	XREF_BIBR, XREF_BIBR Among its various activities, MMP-9 is known to activate precursor IL-1beta and latent TGF-beta1 into their active forms.	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGF-beta1	TGF-beta1	TGF-beta1	8	9	17	18
MMP-9 knockdown was shown to inhibit the effects of TGF-beta1 on E-cadherin and vimentin expression ( XREF_FIG ) .	MMP-9 knockdown was shown to inhibit the effects of TGF-beta1 on E-cadherin and vimentin expression (XREF_FIG).	0	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGF-beta1	TGF-beta1	TGF-beta1	0	1	9	10
MMP-9 is a downstream mediator of TGF-beta1 , and we demonstrated that the inhibition of its expression prevents TGF-beta1-induced EMT and reduces cell invasion and metastasis .	MMP-9 is a downstream mediator of TGF-beta1, and we demonstrated that the inhibition of its expression prevents TGF-beta1-induced EMT and reduces cell invasion and metastasis.	0	7	is a downstream mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGF-beta1	TGF-beta1	TGF-beta1	0	1	6	7
As discussed earlier , MMP-9 is a potential activator of latent TGFbeta1 and , hence , might be a pro fibrotic mediator .	As discussed earlier, MMP-9 is a potential activator of latent TGFbeta1 and, hence, might be a pro fibrotic mediator.	4	12	is a potential activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGFbeta1	TGFbeta1	TGFbeta1	4	5	11	12
However , keratinocyte MMP-9 production was enhanced by interleukin-1 beta , transforming growth factor beta-1 , and tumor necrosis factor-alpha .	However, keratinocyte MMP-9 production was enhanced by interleukin-1 beta, transforming growth factor beta-1, and tumor necrosis factor-alpha.	3	19	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	transforming growth factor beta-1	transforming growth factor beta-1	transforming growth factor beta-1	3	4	11	15
Inhibition of MMP-9 reduced active TGF-beta1 and reduced several TGF-beta1-driven responses , including activity of a Smad3 reporter gene and production of fibronectin .	Inhibition of MMP-9 reduced active TGF-beta1 and reduced several TGF-beta1-driven responses, including activity of a Smad3 reporter gene and production of fibronectin.	0	6	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGF-beta1	TGF-beta1	TGF-beta1	2	3	5	6
Inhibition of MMP-9 production and activity by an MMP-2 and MMP-9-specific inhibitor blocked the synergistic effect of EGF and TGF-beta1 on cell migration .	Inhibition of MMP-9 production and activity by an MMP-2 and MMP-9-specific inhibitor blocked the synergistic effect of EGF and TGF-beta1 on cell migration.	2	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGF-beta1	TGF-beta1	TGF-beta1	2	3	19	20
Elevated MMP-9 levels would contribute to the cardiac fibrosis common in HFpEP and thought to contribute to LV stiffness by activating TGF-beta1 and allowing for cardiac myofibroblast migration .	Elevated MMP-9 levels would contribute to the cardiac fibrosis common in HFpEP and thought to contribute to LV stiffness by activating TGF-beta1 and allowing for cardiac myofibroblast migration.	1	22	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9 levels	mmp-9	TGF-beta1	TGF-beta1	tgf-beta1	1	2	21	22
Like MMP-3 , MMP-9 can activate latent TGFbeta1 .	Like MMP-3, MMP-9 can activate latent TGFbeta1.	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGFbeta1	TGFbeta1	TGFbeta1	3	4	7	8
However , MMP-9 may also modulate inflammatory reaction by interference with cytokine and chemokine network , e.g ., via catalytic activation of IL-8 , release of latent transforming growth factor-beta1 and , possibly , IL-13 .	However, MMP-9 may also modulate inflammatory reaction by interference with cytokine and chemokine network, e.g., via catalytic activation of IL-8, release of latent transforming growth factor-beta1 and, possibly, IL-13.	2	34	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	transforming growth factor-beta1	transforming growth factor-beta1	transforming growth factor-beta1	2	3	27	30
This demonstrates that MMP-9 does not require CD44 to activate TGF-beta 1 in vivo in the lung .	This demonstrates that MMP-9 does not require CD44 to activate TGF-beta 1 in vivo in the lung.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGF-beta 1	TGF-beta 1	TGF-beta 1	3	4	10	12
Taken together , these data suggest that MMP-9 is the downstream target of TGF-beta1 and that TGF-beta1-induced downregulation of E-cadherin expression is largely mediated by MMP-9 .	Taken together, these data suggest that MMP-9 is the downstream target of TGF-beta1 and that TGF-beta1-induced downregulation of E-cadherin expression is largely mediated by MMP-9.	7	14	is the downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	MMP-9	MMP-9	MMP-9	TGF-beta1	TGF-beta1	TGF-beta1	7	8	13	14
For example , in atherosclerosis , MIF activates CXCR2 and CXCR4 , playing a major role in regulating inflammatory cell recruitment .	For example, in atherosclerosis, MIF activates CXCR2 and CXCR4, playing a major role in regulating inflammatory cell recruitment.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	6	7	10	11
CCL2 induces the transendothelial migration of monocytes , thereby facilitating tissue injury , and MIF itself directly activates the chemokine receptor CXCR4 , which is expressed in association with CD74 .	CCL2 induces the transendothelial migration of monocytes, thereby facilitating tissue injury, and MIF itself directly activates the chemokine receptor CXCR4, which is expressed in association with CD74.	14	26	directly activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	MIF	MIF	mif	CXCR4	CXCR4, which is expressed	cxcr4	14	15	21	22
We recently demonstrated that the unique N-terminal Pro 2 residue of MIF and its N like loop region that MIF shares with classical chemokines are important determinants of the MIF and CXCR4 interface and that MIF activates CXCR4 by partial allosteric agonism compared with CXCL12 35 .	We recently demonstrated that the unique N-terminal Pro 2 residue of MIF and its N like loop region that MIF shares with classical chemokines are important determinants of the MIF and CXCR4 interface and that MIF activates CXCR4 by partial allosteric agonism compared with CXCL12 35.	35	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	35	36	37	38
Our studies did not test whether MIF could antagonize suppression of CXCR4 by GCs in light of recent reports that MIF can modulate chemokine signaling via CXCR4 .	Our studies did not test whether MIF could antagonize suppression of CXCR4 by GCs in light of recent reports that MIF can modulate chemokine signaling via CXCR4.	6	12	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	6	7	11	12
With an N like loop and the Pro 2 residue previously identified to support MIF and CXCR4 binding 35 , the current study completes the picture as to how an ACK such as MIF engages a classical chemokine receptor ( CKR ) such as CXCR4 and will help to mechanistically understand differences versus similarities between MIF mediated CXCR4 signaling and that of the cognate ligand .	With an N like loop and the Pro 2 residue previously identified to support MIF and CXCR4 binding 35, the current study completes the picture as to how an ACK such as MIF engages a classical chemokine receptor (CKR) such as CXCR4 and will help to mechanistically understand differences versus similarities between MIF mediated CXCR4 signaling and that of the cognate ligand.	53	58	mediated	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	55	56	57	58
Therefore , these results suggest that MIF promotes the homing of CXCR4 + OCPs to the bone lesions area , while SDF-1 is engaged in the recruitment of OCPs to healthy bone via ligation with CXCR4 + OCPs .	Therefore, these results suggest that MIF promotes the homing of CXCR4 + OCPs to the bone lesions area, while SDF-1 is engaged in the recruitment of OCPs to healthy bone via ligation with CXCR4 + OCPs.	6	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	6	7	11	12
MIF has also been shown to activate the chemokine receptors CXCR2 and CXCR4 , and has a role in the development of atherosclerosis .	MIF has also been shown to activate the chemokine receptors CXCR2 and CXCR4, and has a role in the development of atherosclerosis.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	0	1	12	13
We recently demonstrated that MIF activates CXCR4 signaling in this system .	We recently demonstrated that MIF activates CXCR4 signaling in this system.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	4	5	6	7
Overall , ablation or reduction of MIF mediated CXCR4 dependent cell responses by R87A-L88A-R89A-MIF in the yeast and JVM-3 lymphocyte assays suggests that the RLR sequence is critically involved in the MIF and CXCR4 interface .	Overall, ablation or reduction of MIF mediated CXCR4 dependent cell responses by R87A-L88A-R89A-MIF in the yeast and JVM-3 lymphocyte assays suggests that the RLR sequence is critically involved in the MIF and CXCR4 interface.	2	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	6	7	8	9
MIF has also been reported to activate the chemokine receptors CXCR2 and CXCR4 [ XREF_BIBR ] to exert its chemokine like function .	MIF has also been reported to activate the chemokine receptors CXCR2 and CXCR4 [XREF_BIBR] to exert its chemokine like function.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	0	1	12	13
Migration toward CXCL12 and MIF caused CXCR4 internalization and enhanced CXCR7 surface expression ( XREF_FIG ) whereas MCP-1 did not modulate CXCR4-CXCR7 surface expression on migrating monocytes .	Migration toward CXCL12 and MIF caused CXCR4 internalization and enhanced CXCR7 surface expression (XREF_FIG) whereas MCP-1 did not modulate CXCR4-CXCR7 surface expression on migrating monocytes.	0	7	caused	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	4	5	6	7
12 The chemokine receptors CXCR2 and CXCR4 , either alone or in a complex with CD74 , also are activated by MIF leading to a variety of biological responses .	12 The chemokine receptors CXCR2 and CXCR4, either alone or in a complex with CD74, also are activated by MIF leading to a variety of biological responses.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	21	22	6	7
MIF modulates the functions of human neutrophils by inducing chemokine CXC motif receptor 2 ( CXCR2 )-dependent chemotaxis , enhancing neutrophil survival and promoting the release of chemokine C-C Motif Ligand 4 ( CCL4 ) and MMP-9 .	MIF modulates the functions of human neutrophils by inducing chemokine CXC motif receptor 2 (CXCR2)-dependent chemotaxis, enhancing neutrophil survival and promoting the release of chemokine C-C Motif Ligand 4 (CCL4) and MMP-9.	0	17	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR2	CXCR2	CXCR2	0	1	15	16
Also , MIF triggered CXCR2 dependent calcium transients .	Also, MIF triggered CXCR2 dependent calcium transients.	2	7	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR2	CXCR2	CXCR2	2	3	4	5
Interestingly , the anti-inflammatory drug AV411 ( Ibudilast ) and its analog AV1013 , both allosteric inhibitors of MIF ' s tautomerase activity , were found to inhibit MIF mediated CXCR2 dependent chemotaxis of monocytes .	Interestingly, the anti-inflammatory drug AV411 (Ibudilast) and its analog AV1013, both allosteric inhibitors of MIF 's tautomerase activity, were found to inhibit MIF mediated CXCR2 dependent chemotaxis of monocytes.	27	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR2	CXCR2	CXCR2	28	29	30	31
In vitro , MIF modulated functions of human neutrophils by inducing chemokine CXC motif receptor 2 ( CXCR2 )-dependent chemotaxis , enhancing neutrophil survival and promoting release of chemokine C-C Motif Ligand 4 ( CCL4 ) and matrix metalloprotease 9 ( MMP9 ) .	In vitro, MIF modulated functions of human neutrophils by inducing chemokine CXC motif receptor 2 (CXCR2)-dependent chemotaxis, enhancing neutrophil survival and promoting release of chemokine C-C Motif Ligand 4 (CCL4) and matrix metalloprotease 9 (MMP9).	1	19	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR2	CXCR2	CXCR2	3	4	17	18
MIF activates CXCR2 and CD74 receptors , and as recently reported , may also bind to the stromal derived factor-1 ( SDF-1 )-binding receptor CXCR4 .	MIF activates CXCR2 and CD74 receptors, and as recently reported, may also bind to the stromal derived factor-1 (SDF-1)-binding receptor CXCR4.	0	4	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MIF	MIF	MIF	CXCR2	CXCR2	CXCR2	0	1	2	3
The mTOR and p70S6K are important downstream targets of Akt and protein kinase B ( Akt and PKB ) , controlling cellular activities such as cell proliferation , protein synthesis , etc ..	The mTOR and p70S6K are important downstream targets of Akt and protein kinase B (Akt and PKB), controlling cellular activities such as cell proliferation, protein synthesis, etc..	0	14	are important downstream targets	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	protein kinase B	protein kinase B	protein kinase B	1	2	11	14
The observed changes are related with phosphorylation status of mammalian target of rapamycin ( mTOR ) substrates ( 4E binding protein 1 and p70S6 kinase ) , mTOR regulators adenosine monophosphate activated protein kinase and protein kinase B ( Akt ) ( p < 0.001 ) ; a reduced mTOR network activity in the liver is associated with an altered lipid metabolism ( XREF_FIG ) .	The observed changes are related with phosphorylation status of mammalian target of rapamycin (mTOR) substrates (4E binding protein 1 and p70S6 kinase), mTOR regulators adenosine monophosphate activated protein kinase and protein kinase B (Akt) (p < 0.001); a reduced mTOR network activity in the liver is associated with an altered lipid metabolism (XREF_FIG).	27	38	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	protein kinase B	protein kinase B	protein kinase B	27	28	35	38
mTOR is a downstream target of Akt1 , and to examine the importance of mTOR in mediating FGFR1 induced VSMC phenotypic modulation , we used a specific mTOR inhibitor , rapamycin [ XREF_BIBR ] .	mTOR is a downstream target of Akt1, and to examine the importance of mTOR in mediating FGFR1 induced VSMC phenotypic modulation, we used a specific mTOR inhibitor, rapamycin [XREF_BIBR].	0	7	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt1	Akt1	Akt1	0	1	6	7
Further analysis of mammary carcinomas revealed changes in the phosphorylation states of mammalian target of rapamycin ( mTOR ) substrates ( 4E binding protein 1 and p70S6 kinase ) and mTOR regulators adenosine monophosphate activated protein kinase and protein kinase B ( Akt ) ( P < 0.001 ) .	Further analysis of mammary carcinomas revealed changes in the phosphorylation states of mammalian target of rapamycin (mTOR) substrates (4E binding protein 1 and p70S6 kinase) and mTOR regulators adenosine monophosphate activated protein kinase and protein kinase B (Akt) (P < 0.001).	30	41	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	protein kinase B	protein kinase B	protein kinase B	30	31	38	41
Rapamycin treatment of Akt1 structures prevented the increased cell size , overgrown , and filled structures , indicating that Raptor and mTOR signaling was mediating the effects of Akt1 in these cells [ XREF_BIBR ] .	Rapamycin treatment of Akt1 structures prevented the increased cell size, overgrown, and filled structures, indicating that Raptor and mTOR signaling was mediating the effects of Akt1 in these cells [XREF_BIBR].	21	33	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt1	Akt1	Akt1	21	22	28	29
Using siRNA , rapamycin ( Rap ) , and adenoviral expression for FKBP12 resistant and constitutively active TGF-beta type I receptor ( ALK5 ) , we demonstrate that mammalian target of Rap ( mTOR ) mediates Akt1 suppression of phospho activation of S3 .	Using siRNA, rapamycin (Rap), and adenoviral expression for FKBP12 resistant and constitutively active TGF-beta type I receptor (ALK5), we demonstrate that mammalian target of Rap (mTOR) mediates Akt1 suppression of phospho activation of S3.	31	37	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt1	Akt1	Akt1	33	34	36	37
Mammalian Tor ( mTOR ) pathway was activated , confirmed by Frap1 , Rheb and Akt1 up-regulation .	Mammalian Tor (mTOR) pathway was activated, confirmed by Frap1, Rheb and Akt1 up-regulation.	0	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mammalian Tor	Mammalian Tor	Mammalian Tor	Akt1	Akt1	Akt1	0	2	15	16
Most recently , we reported that lentiviral vector gene transfer of the Akt isoforms Akt1 and Akt3 attenuated brain injury by promoting both p-PRAS40 and p-mTOR protein levels , and mTOR inhibition by rapamycin abolished the protective effects Akt1 and Akt3 gene transfer .	Most recently, we reported that lentiviral vector gene transfer of the Akt isoforms Akt1 and Akt3 attenuated brain injury by promoting both p-PRAS40 and p-mTOR protein levels, and mTOR inhibition by rapamycin abolished the protective effects Akt1 and Akt3 gene transfer.	30	42	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt1	Akt1	Akt1	30	31	38	39
This activation triggers a cascade of signals that stimulates protein kinase B ( AKT ) and the mammalian Target of Rapamycin ( mTOR ) .	This activation triggers a cascade of signals that stimulates protein kinase B (AKT) and the mammalian Target of Rapamycin (mTOR).	6	23	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	protein kinase B	protein kinase B	protein kinase B	22	23	9	12
These data show that resistance to IGF-1R inhibition by mAbs is associated with Akt and mTOR directed enhanced synthesis of EGFR , Akt1 , and survivin .	These data show that resistance to IGF-1R inhibition by mAbs is associated with Akt and mTOR directed enhanced synthesis of EGFR, Akt1, and survivin.	15	23	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt1	Akt1	Akt1	15	16	22	23
Expression of MRAP2 alongside MC2R promotes MC2R trafficking to the cell surface to a similar extent as MRAP ; however , the resultant complex has an extremely low affinity for ACTH binding .	Expression of MRAP2 alongside MC2R promotes MC2R trafficking to the cell surface to a similar extent as MRAP; however, the resultant complex has an extremely low affinity for ACTH binding.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRAP2	Expression of MRAP2	mrap2	MC2R	MC2R	mc2r	2	3	6	7
In vitro , MRAP2 has been shown to enable MC2R trafficking to the cell surface and subsequent signaling .	In vitro, MRAP2 has been shown to enable MC2R trafficking to the cell surface and subsequent signaling.	1	10	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRAP2	MRAP2	MRAP2	MC2R	MC2R	MC2R	3	4	9	10
A second MRAP protein , called MRAP2 , also modulates MC2R activity .	A second MRAP protein, called MRAP2, also modulates MC2R activity.	0	11	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein	protein	protein	MC2R	MC2R	MC2R	3	4	10	11
MRAP is essential for MC2R to respond to ACTH and although the presence of MRAP2 can enable MC2R to respond to ACTH this is unlikely to be of physiological significance .	MRAP is essential for MC2R to respond to ACTH and although the presence of MRAP2 can enable MC2R to respond to ACTH this is unlikely to be of physiological significance.	12	18	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRAP2	MRAP2	MRAP2	MC2R	MC2R	MC2R	14	15	17	18
In vitro MRAP2 appears to have a qualitatively similar ability to MRAP , enabling MC2R trafficking from the endoplasmic reticulum to the cell surface and the formation of a functional ACTH receptor .	In vitro MRAP2 appears to have a qualitatively similar ability to MRAP, enabling MC2R trafficking from the endoplasmic reticulum to the cell surface and the formation of a functional ACTH receptor.	0	15	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRAP2	MRAP2	MRAP2	MC2R	MC2R	MC2R	2	3	14	15
This suggests that although MRAP2 can enable MC2R function , this is not its role in vivo .	This suggests that although MRAP2 can enable MC2R function, this is not its role in vivo.	4	8	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRAP2	MRAP2	MRAP2	MC2R	MC2R	MC2R	4	5	7	8
That MRAP2 does not promote efficient MC2R signaling even though it supports trafficking of MC2R to the plasma membrane raised the question of the physiological role of MRAP2 .	That MRAP2 does not promote efficient MC2R signaling even though it supports trafficking of MC2R to the plasma membrane raised the question of the physiological role of MRAP2.	0	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRAP2	MRAP2	MRAP2	MC2R	MC2R	MC2R	1	2	6	7
Although both MRAP and MRAP2 allow MC2R to reach the cell surface , only MRAP enables the receptor to signal effectively .	Although both MRAP and MRAP2 allow MC2R to reach the cell surface, only MRAP enables the receptor to signal effectively.	2	8	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRAP2	MRAP2	MRAP2	MC2R	MC2R	MC2R	4	5	6	7
Here , we demonstrate that MRAP2 does indeed enable functioning of the MC2R in response to ACTH stimulation in vitro ; however , much higher concentrations of ACTH are required to generate the same amount of cAMP in the presence of MRAP2 compared with MRAP .	Here, we demonstrate that MRAP2 does indeed enable functioning of the MC2R in response to ACTH stimulation in vitro; however, much higher concentrations of ACTH are required to generate the same amount of cAMP in the presence of MRAP2 compared with MRAP.	5	14	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRAP2	MRAP2	MRAP2	MC2R	MC2R	MC2R	5	6	12	13
By using a potent small molecular weight inhibitor of Mnk1 , the upstream kinase for eIF-4E , we observed a rapid dephosphorylation of eIF-4E within 45 min after addition of the inhibitor , suggesting a high turnover of phosphate on eIF-4E mediated by Mnk1 and a yet unidentified phosphatase .	By using a potent small molecular weight inhibitor of Mnk1, the upstream kinase for eIF-4E, we observed a rapid dephosphorylation of eIF-4E within 45 min after addition of the inhibitor, suggesting a high turnover of phosphate on eIF-4E mediated by Mnk1 and a yet unidentified phosphatase.	33	48	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mnk1	Mnk1	Mnk1	eIF-4E	eIF-4E	eIF-4E	43	44	40	41
Conversely , activated Mnk1 promoted the onset of tumour development in a similar manner to eIF4E .	Conversely, activated Mnk1 promoted the onset of tumour development in a similar manner to eIF4E.	2	16	promoted	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Mnk1	Mnk1	Mnk1	eIF4E	eIF4E	eIF4E	3	4	15	16
MNK1 and MNK2 kinases phosphorylate and augment activity of eIF4E .	MNK1 and MNK2 kinases phosphorylate and augment activity of eIF4E.	0	10	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MNK1	MNK1	MNK1	eIF4E	eIF4E	eIF4E	0	1	9	10
However , we found that the level of MRE11 in XRCC1-FLAG IP was unaffected by siRNA mediated depletion of LIG3 or NBS1 , strongly suggesting direct interaction between XRCC1 and MRE11 rather than indirect association via LIG3-NBS1 interaction .	However, we found that the level of MRE11 in XRCC1-FLAG IP was unaffected by siRNA mediated depletion of LIG3 or NBS1, strongly suggesting direct interaction between XRCC1 and MRE11 rather than indirect association via LIG3-NBS1 interaction.	6	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MRE11	level of MRE11	mre11	NBS1	NBS1	nbs1	8	9	21	22
Phosphorylation of Mre11 SQ/TQ motifs modulates the affinity of MRN for DNA .	Phosphorylation of Mre11 SQ/TQ motifs modulates the affinity of MRN for DNA.	0	11	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Phosphorylation of Mre11	mre11	MRN	MRN	mrn	2	3	9	10
Our findings support a model in which Mre11 phosphorylation by PIKKs triggers MRN inactivation via disassembly from chromatin thus down-regulating the DNA damage response and allowing for recovery .	Our findings support a model in which Mre11 phosphorylation by PIKKs triggers MRN inactivation via disassembly from chromatin thus down-regulating the DNA damage response and allowing for recovery.	7	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11 phosphorylation	mre11	MRN	MRN	mrn	7	8	12	13
PIKK dependent phosphorylation of Mre11 induces MRN complex inactivation by disassembly from chromatin .	PIKK dependent phosphorylation of Mre11 induces MRN complex inactivation by disassembly from chromatin.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	PIKK dependent phosphorylation of Mre11	mre11	MRN	MRN	mrn	4	5	6	7
Inactivation of Mre11 nuclease activities or elimination of Ctp1 increases the ChIP signal of MRN subunits at the HO DSB , suggesting that DNA end processing by the MRN and Ctp1 complex is required for its departure from the DSB .	Inactivation of Mre11 nuclease activities or elimination of Ctp1 increases the ChIP signal of MRN subunits at the HO DSB, suggesting that DNA end processing by the MRN and Ctp1 complex is required for its departure from the DSB.	2	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	MRN	MRN	MRN	2	3	14	15
Mre11 expressed from cDNA successfully reconstituted levels of Rad50 and NBS1 ( XREF_FIG ) and supported the ability of MRN to activate the ATM kinase as determined by relative levels of ATM autophosphorylation ( XREF_FIG ) XREF_BIBR , XREF_BIBR .	Mre11 expressed from cDNA successfully reconstituted levels of Rad50 and NBS1 (XREF_FIG) and supported the ability of MRN to activate the ATM kinase as determined by relative levels of ATM autophosphorylation (XREF_FIG) XREF_BIBR, XREF_BIBR.	0	20	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	MRN	MRN	MRN	0	1	19	20
These data indicate that ActRIIB activation by activin A or myostatin rapidly activates both p38 MAPK and Akt in myotubes in a parallel fashion .	These data indicate that ActRIIB activation by activin A or myostatin rapidly activates both p38 MAPK and Akt in myotubes in a parallel fashion.	4	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	myostatin	myostatin	myostatin	ActRIIB	ActRIIB	ActRIIB	10	11	4	5
Liberation of myostatin allows it to bind ActRIIB , the high-affinity type-2 activin receptor , on muscle membranes .	Liberation of myostatin allows it to bind ActRIIB, the high-affinity type-2 activin receptor, on muscle membranes.	0	17	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	myostatin	myostatin	myostatin	ActRIIB	ActRIIB	ActRIIB	2	3	7	8
Neither MOB1A nor MST2 alone activated LATS2 ( XREF_FIG ) .	Neither MOB1A nor MST2 alone activated LATS2 (XREF_FIG).	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MOB1A	MOB1A	MOB1A	LATS2	LATS2	LATS2	1	2	6	7
Expression of MST2 and MOB1A was sufficient to induce maximal LATS2 activation ( XREF_FIG ) .	Expression of MST2 and MOB1A was sufficient to induce maximal LATS2 activation (XREF_FIG).	0	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MOB1A	Expression of MST2 and MOB1A	mob1a	LATS2	LATS2	lats2	4	5	10	11
The amount of HA tagged trout MC2R on the cell surface was increased by trout MRAP , whereas co-expression of MC1R variants had no significant effect ( XREF_FIG , right ) .	The amount of HA tagged trout MC2R on the cell surface was increased by trout MRAP, whereas co-expression of MC1R variants had no significant effect (XREF_FIG, right).	5	22	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRAP	MRAP	MRAP	MC2R	MC2R	MC2R	15	16	6	7
MinK increases hERG currents by an unknown mechanism .	MinK increases hERG currents by an unknown mechanism.	0	3	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MinK	MinK	MinK	hERG	hERG	hERG	0	1	2	3
Although MinK most likely functions as the accessory subunit for KCNQ1 to form I Ks channels in the heart [ XREF_BIBR , XREF_BIBR ] , MinK can also modulate hERG1 channel density when overexpressed in heterologous expression systems [ XREF_BIBR , XREF_BIBR ] .	Although MinK most likely functions as the accessory subunit for KCNQ1 to form I Ks channels in the heart [XREF_BIBR, XREF_BIBR], MinK can also modulate hERG1 channel density when overexpressed in heterologous expression systems [XREF_BIBR, XREF_BIBR].	25	31	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MinK	MinK	MinK	hERG1	hERG1	hERG1	25	26	29	30
MMP-14 and MMP-2 promote the cleavage of LAMC2 to the pro migratory gamma2 ' and gamma2xfragments .	MMP-14 and MMP-2 promote the cleavage of LAMC2 to the pro migratory gamma2 ' and gamma2xfragments.	0	8	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP-2	MMP-2	MMP-2	LAMC2	LAMC2	LAMC2	2	3	7	8
Altogether , MMP14 and MMP2 promote the cleavage of LAMC2 to the pro migratory gamma2 ' and gamma2x fragments .	Altogether, MMP14 and MMP2 promote the cleavage of LAMC2 to the pro migratory gamma2 ' and gamma2x fragments.	2	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	LAMC2	LAMC2	LAMC2	4	5	9	10
Both MMP14 and MMP2 promote the cleavage of LAMC2 into promigratory gamma2 ' and gamma2x fragments , which in turn stimulates migration , invasion , and VM in melanoma cells XREF_BIBR .	Both MMP14 and MMP2 promote the cleavage of LAMC2 into promigratory gamma2 ' and gamma2x fragments, which in turn stimulates migration, invasion, and VM in melanoma cells XREF_BIBR.	1	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MMP2	MMP2	MMP2	LAMC2	LAMC2	LAMC2	3	4	8	9
Proteasome inhibition ( XREF_SUPPLEMENTARY ) , suppression of Nedd4 ( XREF_SUPPLEMENTARY ) , or phosphomimetic mutation of the mTOR sites ( XREF_SUPPLEMENTARY ) rescued the decrease in Grb10 protein caused by mTOR inhibition .	Proteasome inhibition (XREF_SUPPLEMENTARY), suppression of Nedd4 (XREF_SUPPLEMENTARY), or phosphomimetic mutation of the mTOR sites (XREF_SUPPLEMENTARY) rescued the decrease in Grb10 protein caused by mTOR inhibition.	27	32	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Grb10	Grb10	Grb10	31	32	27	28
Grb10 is also highly abundant in the TSC2 -/- cells with hyperactive mTORC1 signaling ( XREF_FIG , XREF_SUPPLEMENTARY ) , and chronic mTOR inhibition decreased Grb10 protein abundance ( XREF_SUPPLEMENTARY ) without significantly affecting mRNA levels ( XREF_SUPPLEMENTARY ) .	Grb10 is also highly abundant in the TSC2 -/- cells with hyperactive mTORC1 signaling (XREF_FIG, XREF_SUPPLEMENTARY), and chronic mTOR inhibition decreased Grb10 protein abundance (XREF_SUPPLEMENTARY) without significantly affecting mRNA levels (XREF_SUPPLEMENTARY).	22	27	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Grb10	Grb10	Grb10	22	23	25	26
Overall , MNK2 promotes tumor proliferation , migration , invasion and metastasis in NSCLC in vitro and in vivo via 4EBP1/eIF4E and ERK and eIF4E pathway .	Overall, MNK2 promotes tumor proliferation, migration, invasion and metastasis in NSCLC in vitro and in vivo via 4EBP1/eIF4E and ERK and eIF4E pathway.	2	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MNK2	MNK2	MNK2	eIF4E	eIF4E	eIF4E	2	3	24	25
To determine whether MMP cleaved OPN has cell adhesion ability , we used a B16-BL6 mouse melanoma cell adhesion assay with OPN or OPN treated with MMP-3 or -7 .	To determine whether MMP cleaved OPN has cell adhesion ability, we used a B16-BL6 mouse melanoma cell adhesion assay with OPN or OPN treated with MMP-3 or -7.	19	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	MMP-3	MMP-3	MMP-3	OPN	OPN	OPN	26	27	21	22
We found that secretion of endothelin , a tissue inhibitor of metalloproteinase-1 ( TIMP-1 ) , Serpin E1 , IFN-gamma inducible- protein-10 ( IP-10 ) , matrix metalloproteinase-3 ( MMP-3 ) , stromal cell derived factor 1 ( SDF-1 ) , osteopontin and insulin like growth factor binding protein 9 were significantly upregulated in MCPIP1 overexpressing MSCs when compared with Puro cells ( XREF_FIG ) .	We found that secretion of endothelin, a tissue inhibitor of metalloproteinase-1 (TIMP-1), Serpin E1, IFN-gamma inducible- protein-10 (IP-10), matrix metalloproteinase-3 (MMP-3), stromal cell derived factor 1 (SDF-1), osteopontin and insulin like growth factor binding protein 9 were significantly upregulated in MCPIP1 overexpressing MSCs when compared with Puro cells (XREF_FIG).	27	53	upregulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MMP-3	MMP-3	MMP-3	osteopontin	osteopontin	osteopontin	29	30	41	42
MLF1 induces p53 dependent cell cycle arrest in murine embryonic fibroblasts .	MLF1 induces p53 dependent cell cycle arrest in murine embryonic fibroblasts.	0	3	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MLF1	MLF1	MLF1	p53	p53	p53	0	1	2	3
In the absence of co-expressed MOB1B and MST2 , LATS1 kinase activity was not above background levels ( XREF_FIG ) , whereas the co-expression of MOB1B and MST2 dramatically activated LATS1 , consistent with previous findings .	In the absence of co-expressed MOB1B and MST2, LATS1 kinase activity was not above background levels (XREF_FIG), whereas the co-expression of MOB1B and MST2 dramatically activated LATS1, consistent with previous findings.	23	31	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MOB1B	co-expression of MOB1B	mob1b	LATS1	LATS1	lats1	25	26	30	31
Although expression of the constitutively active form of S6K1 ( S6K1 T389E ) is not sufficient to induce dendritic growth , mTOR activated S6K1 may contribute to dendritogenesis ( Malik etal .	Although expression of the constitutively active form of S6K1 (S6K1 T389E) is not sufficient to induce dendritic growth, mTOR activated S6K1 may contribute to dendritogenesis (Malik etal.	21	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	21	22	23	24
AKT induces activation of the mammalian target of rapamycin ( mTOR ) , which then activates S6K1 , ultimately stimulating protein synthesis .	AKT induces activation of the mammalian target of rapamycin (mTOR), which then activates S6K1, ultimately stimulating protein synthesis.	8	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	10	11	16	17
In addition , activation of p70S6K by mTOR in astrocytes has been shown to be cytoprotective .	In addition, activation of p70S6K by mTOR in astrocytes has been shown to be cytoprotective.	3	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	7	8	5	6
In non neuronal cells of the nervous system , activation of p70S6K by mTOR in astrocytes is cytoprotective through expression of Bcl-2 and Bcl-x L expression to block BAD activity that can result in apoptosis XREF_BIBR .	In non neuronal cells of the nervous system, activation of p70S6K by mTOR in astrocytes is cytoprotective through expression of Bcl-2 and Bcl-x L expression to block BAD activity that can result in apoptosis XREF_BIBR.	9	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	13	14	11	12
Under basal conditions , TSC2 negatively regulates mTOR , so that Akt mediated TSC2 phosphorylation activates mTOR , which in turns activates p70S6K and 4E-BP1 , promoting translation of mRNAs important to cancer cell growth [ XREF_BIBR , XREF_BIBR ] .	Under basal conditions, TSC2 negatively regulates mTOR, so that Akt mediated TSC2 phosphorylation activates mTOR, which in turns activates p70S6K and 4E-BP1, promoting translation of mRNAs important to cancer cell growth [XREF_BIBR, XREF_BIBR].	15	24	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	16	17	22	23
In summary , both the mTOR downstream targets of p70S6K and eIF4E were involved in regulating UC cell proliferation , and inhibiting both p70S6K and eIF4E phosphorylation by rapamycin showed a more potent anti-proliferative effect than inhibiting p70S6K or 4E-BP1 phosphorylation alone .	In summary, both the mTOR downstream targets of p70S6K and eIF4E were involved in regulating UC cell proliferation, and inhibiting both p70S6K and eIF4E phosphorylation by rapamycin showed a more potent anti-proliferative effect than inhibiting p70S6K or 4E-BP1 phosphorylation alone.	5	11	targets	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	5	6	9	10
In contrast , the absence of mTOR Serine 2448 phosphorylation concomitant with increased mTORC1 and mTORC2 mediated p70S6K activity , increased LC3 , delayed increase in lysosome activity and exacerbation of autophagosome accumulation typifies massive , unrestrained autophagy .	In contrast, the absence of mTOR Serine 2448 phosphorylation concomitant with increased mTORC1 and mTORC2 mediated p70S6K activity, increased LC3, delayed increase in lysosome activity and exacerbation of autophagosome accumulation typifies massive, unrestrained autophagy.	6	18	mediated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	6	7	17	18
Among its targets , AKT controls the activation of the downstream pathway effector , the mammalian target of rapamycin ( mTOR ) , which activates two key substrates 4EBP1 and p70S6K .	Among its targets, AKT controls the activation of the downstream pathway effector, the mammalian target of rapamycin (mTOR), which activates two key substrates 4EBP1 and p70S6K.	15	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	p70S6K	p70S6K	p70S6K	15	19	30	31
We also demonstrated that ectopic expression of wild-type mTOR , constitutively activate S6K1 , or downregulated 4E-BP1 partially prevented rotenone induced neuronal apoptosis , suggesting that rotenone induced neuronal loss in PD may be prevented by activating mTOR signalling XREF_BIBR .	We also demonstrated that ectopic expression of wild-type mTOR, constitutively activate S6K1, or downregulated 4E-BP1 partially prevented rotenone induced neuronal apoptosis, suggesting that rotenone induced neuronal loss in PD may be prevented by activating mTOR signalling XREF_BIBR.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	expression of wild-type mTOR	mtor	S6K1	S6K1	s6k1	8	9	12	13
The Akt activates many downstream factors , including mTOR , which in turn activates 4EBP1 and p70S6K1 .	The Akt activates many downstream factors, including mTOR, which in turn activates 4EBP1 and p70S6K1.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K1	p70S6K1	p70S6K1	8	9	16	17
Ac-LA inhibited phosphorylation of downstream targets of the Akt signaling pathway , which was followed by inhibition of the mTOR target p70 ribosomal six protein kinase and the nuclear accumulation of p65 and NF-kappaB , beta-catenin , and c-myc , as well as loss of the mitochondrial membrane potential .	Ac-LA inhibited phosphorylation of downstream targets of the Akt signaling pathway, which was followed by inhibition of the mTOR target p70 ribosomal six protein kinase and the nuclear accumulation of p65 and NF-kappaB, beta-catenin, and c-myc, as well as loss of the mitochondrial membrane potential.	18	25	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70	p70	p70	19	20	21	22
Notably , the PI3K regulatory subunit PI3K p85 and an MTOR target p70S6K showed a statistical significance ( P < 0.05 ) .	Notably, the PI3K regulatory subunit PI3K p85 and an MTOR target p70S6K showed a statistical significance (P < 0.05).	3	13	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MTOR	MTOR	MTOR	p70S6K	p70S6K	p70S6K	10	11	12	13
Inhibitors of mTOR , PI3K , and Ca ( ++ ) impair p70S6K activity , whereas inhibitors of JNK and PKC stimulate p70S6K activity .	Inhibitors of mTOR, PI3K, and Ca (++) impair p70S6K activity, whereas inhibitors of JNK and PKC stimulate p70S6K activity.	0	13	impair	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	2	3	12	13
3.3 Rapamycin inhibits mTOR mediated p70S6K and 4E-BP1 pathways .	3.3 Rapamycin inhibits mTOR mediated p70S6K and 4E-BP1 pathways.	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	3	4	5	6
hsBAFF elevates proliferation and survival in the cells , also in part , via activating mTOR mediated S6K1 and 4E-BP1 pathways [ XREF_BIBR , XREF_BIBR ] .	hsBAFF elevates proliferation and survival in the cells, also in part, via activating mTOR mediated S6K1 and 4E-BP1 pathways [XREF_BIBR, XREF_BIBR].	2	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	15	16	17	18
One of the candidates that reconciled the effects of Akt1 and Mek1 pathways in the regulation of ECM remodeling was p70 S6-kinase ( p70S6K ) , which is activated by both Akt1 and mTOR and Mek1/ERK1/2 pathways through phosphorylation at specific Threonine421 and Serine424 residues on p70S6K , respectively .	One of the candidates that reconciled the effects of Akt1 and Mek1 pathways in the regulation of ECM remodeling was p70 S6-kinase (p70S6K), which is activated by both Akt1 and mTOR and Mek1/ERK1/2 pathways through phosphorylation at specific Threonine421 and Serine424 residues on p70S6K, respectively.	20	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70	p70	p70	33	34	20	21
Inhibition of PI ( 3 ) kinase or mTOR with LY294002 or rapamycin blocked p70S6K activation , prevented formation of large elongated contractile phenotype myocytes , and blocked accumulation of SM22 and smMHC .	Inhibition of PI (3) kinase or mTOR with LY294002 or rapamycin blocked p70S6K activation, prevented formation of large elongated contractile phenotype myocytes, and blocked accumulation of SM22 and smMHC.	6	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	8	9	14	15
Consistently , we found that rapamycin dramatically blocked activation of mTOR mediated S6K1 and 4E-BP1 with a concomitant reduction of CaMKII phosphorylaiton in Cd exposed PC12 cells and primary neurons ( XREF_FIG ) .	Consistently, we found that rapamycin dramatically blocked activation of mTOR mediated S6K1 and 4E-BP1 with a concomitant reduction of CaMKII phosphorylaiton in Cd exposed PC12 cells and primary neurons (XREF_FIG).	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	10	11	12	13
Previously , we found that rotenone could negatively regulate mTOR mediated p70S6K and 4E-BP1/Eif4E pathways , that leads to caspase-3 dependent neuronal apoptosis in vitro XREF_BIBR .	Previously, we found that rotenone could negatively regulate mTOR mediated p70S6K and 4E-BP1/Eif4E pathways, that leads to caspase-3 dependent neuronal apoptosis in vitro XREF_BIBR.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	9	10	11	12
mTOR mediated S6K1 and 4E-BP1 pathways are critical for cell survival .	mTOR mediated S6K1 and 4E-BP1 pathways are critical for cell survival.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	0	1	2	3
XREF_BIBR Many studies indicate that mTOR activation and subsequent regulation of p70S6 kinase via Akt signaling contributes to resistance , and a number of promising clinical trials have been initiated based on this premise .	XREF_BIBR Many studies indicate that mTOR activation and subsequent regulation of p70S6 kinase via Akt signaling contributes to resistance, and a number of promising clinical trials have been initiated based on this premise.	5	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6 kinase	p70S6 kinase	p70S6 kinase	5	6	11	13
PD toxins activates AMPK , leading to inhibition of mTOR mediated S6K1 and 4E-BP1 pathways , as well as cell death .	PD toxins activates AMPK, leading to inhibition of mTOR mediated S6K1 and 4E-BP1 pathways, as well as cell death.	5	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	9	10	11	12
We found that both FRAP and insulin activated p70 S6 kinase ( p70 ( s6k ) ) serine phosphorylated IRS-1 between residues 511 and 772 ( IRS-1 ( 511-772 ) ) .	We found that both FRAP and insulin activated p70 S6 kinase (p70 (s6k)) serine phosphorylated IRS-1 between residues 511 and 772 (IRS-1 (511-772)).	3	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FRAP	FRAP	FRAP	p70	p70	p70	4	5	12	13
Inhibition of mTOR inactivates S6K1 and stabilises IRS-1 associated with receptors , thus alleviating this negative regulation .	Inhibition of mTOR inactivates S6K1 and stabilises IRS-1 associated with receptors, thus alleviating this negative regulation.	0	5	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	2	3	4	5
However , inhibition of mTOR in ATF3 deficient BMMs reduced p70S6K activity and downregulated HMGB1 and TLR4 , and this was accompanied by the downregulation of pro inflammatory cytokines .	However, inhibition of mTOR in ATF3 deficient BMMs reduced p70S6K activity and downregulated HMGB1 and TLR4, and this was accompanied by the downregulation of pro inflammatory cytokines.	2	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	4	5	10	11
Although p70S6K can also be activated by mTOR independent pathways such as PDK-1 , MAPK and SAPK ( stress activated protein kinase ) , the mTORC1 mediated phosphorylation at T389 is required for its complete activation XREF_BIBR .	Although p70S6K can also be activated by mTOR independent pathways such as PDK-1, MAPK and SAPK (stress activated protein kinase), the mTORC1 mediated phosphorylation at T389 is required for its complete activation XREF_BIBR.	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	7	8	1	2
When inactive , S6K1 associates with the eIF3 complex , while the S6K1 activator mTOR and raptor does not .	When inactive, S6K1 associates with the eIF3 complex, while the S6K1 activator mTOR and raptor does not.	11	17	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	14	15	12	13
The protein levels of p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 were significantly increased in the hippocampal tissues of AD rats as compared with control rats ( P < 0.05 , n = 6-10 in each group ) .	The protein levels of p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 were significantly increased in the hippocampal tissues of AD rats as compared with control rats (P < 0.05, n = 6-10 in each group).	2	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p-S6K1	p-S6K1	p-S6K1	6	7	8	9
In addition , inhibition of mTOR by rapamycin inactivates S6K1 , blocking translation of mRNA species containing 5 ' terminal oligopyrimidine tracts , although this remains controversial .	In addition, inhibition of mTOR by rapamycin inactivates S6K1, blocking translation of mRNA species containing 5 ' terminal oligopyrimidine tracts, although this remains controversial.	3	11	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	5	6	9	10
mTOR activates S6K1 and EBP1 .	mTOR activates S6K1 and EBP1.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	0	1	2	3
mTOR activates p70S6K , which controls translation of mRNA to generate proteins such as hypoxia inducible factor-1 ( HIF-1 ) .	mTOR activates p70S6K, which controls translation of mRNA to generate proteins such as hypoxia inducible factor-1 (HIF-1).	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	0	1	2	3
mTOR activates both p70S6K and endothelial nitric oxide synthase ( eNOS ) .	mTOR activates both p70S6K and endothelial nitric oxide synthase (eNOS).	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	0	1	3	4
Upon stimulation , mTOR induces activation of S6K1 with subsequent phosphorylation of S6 ribosomal protein ( S6rp ) resulting in an increase in mRNA translation and cell proliferation .	Upon stimulation, mTOR induces activation of S6K1 with subsequent phosphorylation of S6 ribosomal protein (S6rp) resulting in an increase in mRNA translation and cell proliferation.	3	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	3	4	7	8
In cancer cells it has been shown that mTOR activates its downstream effector 4E-BP1 and p70S6K , which subsequently leads to translation of pro apoptotic proteins XREF_BIBR , XREF_BIBR as well as phosphorylates and inactivation of the anti-apoptotic protein Bcl-2 28 .	In cancer cells it has been shown that mTOR activates its downstream effector 4E-BP1 and p70S6K, which subsequently leads to translation of pro apoptotic proteins XREF_BIBR, XREF_BIBR as well as phosphorylates and inactivation of the anti-apoptotic protein Bcl-2 28.	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	8	9	15	16
In addition , mTOR dependent activation of dendritic S6K1 was shown to be necessary for the induction phase of protein-synthesis-dependent synaptic plasticity .	In addition, mTOR dependent activation of dendritic S6K1 was shown to be necessary for the induction phase of protein-synthesis-dependent synaptic plasticity.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	3	4	8	9
This suggests that , under these growth conditions , the mTOR mediated activation of p70 S6K1 may have partially contributed to the rapamycin sensitive component of the OV induced increase in TCTP .	This suggests that, under these growth conditions, the mTOR mediated activation of p70 S6K1 may have partially contributed to the rapamycin sensitive component of the OV induced increase in TCTP.	9	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70 S6K1	p70 S6K1	p70 S6K1	10	11	14	16
Previously , mTOR itself and mTOR mediated activation of S6K-1 have been reported as potential mechanisms for inhibiting insulin action through direct phosphorylation of IRS1 .	Previously, mTOR itself and mTOR mediated activation of S6K-1 have been reported as potential mechanisms for inhibiting insulin action through direct phosphorylation of IRS1.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K-1	S6K-1	S6K-1	5	6	9	10
The results indicate that PD stresses activate AMPK and inactivate Akt , causing neuronal cell death via inhibiting mTOR mediated S6K1 and 4E-BP1 pathways .	The results indicate that PD stresses activate AMPK and inactivate Akt, causing neuronal cell death via inhibiting mTOR mediated S6K1 and 4E-BP1 pathways.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	18	19	20	21
Akt is an insulin stimulated upstream signal kinase which triggers release of GLUT4 for glucose transport and downstream activation of protein synthesis via mTOR mediated p70S6K activation [ XREF_BIBR ] .	Akt is an insulin stimulated upstream signal kinase which triggers release of GLUT4 for glucose transport and downstream activation of protein synthesis via mTOR mediated p70S6K activation [XREF_BIBR].	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	23	24	25	26
By promoting phosphorylation of S6 , mTOR activates S6K1 .	By promoting phosphorylation of S6, mTOR activates S6K1.	6	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	6	7	8	9
Our results indicate that mTOR may be responsible for activation of S6K1 in absence of eIF3 , since treatment with rapamycin was able to entirely abrogate S6K1 activity in eIF3 depleted cells .	Our results indicate that mTOR may be responsible for activation of S6K1 in absence of eIF3, since treatment with rapamycin was able to entirely abrogate S6K1 activity in eIF3 depleted cells.	4	12	be responsible for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	4	5	11	12
MTOR has two downstream targets : the p70 S6K1 , which activity is up-regulated by MTOR and is known to play an important role in cell proliferation and cell cycle progression XREF_BIBR , and 4EBP1 , which is negatively regulated by MTOR XREF_BIBR .	MTOR has two downstream targets : the p70 S6K1, which activity is up-regulated by MTOR and is known to play an important role in cell proliferation and cell cycle progression XREF_BIBR, and 4EBP1, which is negatively regulated by MTOR XREF_BIBR.	7	16	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTOR	MTOR	MTOR	p70 S6K1	p70 S6K1	p70 S6K1	15	16	7	9
Treatment with SIR , the mTOR inhibitor , reduced phosphorylation of the mTOR targets p70S6 kinase ( XREF_FIG ) and S6 ( XREF_FIG ) , indicating that SIR was effective at the level of the ovary ( XREF_FIG , P < 0.05 ) .	Treatment with SIR, the mTOR inhibitor, reduced phosphorylation of the mTOR targets p70S6 kinase (XREF_FIG) and S6 (XREF_FIG), indicating that SIR was effective at the level of the ovary (XREF_FIG, P < 0.05).	9	16	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of the mTOR	mtor	p70S6 kinase	p70S6 kinase	p70s6 kinase	12	13	14	16
As expected , dephosphorylation of ERK1/2 as well as the mTOR targets p70 ( S6 kinase ) and the S6 ribosomal protein , an important regulator of mRNA translation , was found to be enhanced with the dual treatment as compared to each treatment alone .	As expected, dephosphorylation of ERK1/2 as well as the mTOR targets p70 (S6 kinase) and the S6 ribosomal protein, an important regulator of mRNA translation, was found to be enhanced with the dual treatment as compared to each treatment alone.	3	15	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	dephosphorylation of ERK1/2 as well as the mTOR	mtor	p70	p70	p70	10	11	12	13
Rapamycin ' s capacity to preserve Thr308 phosphorylation may reflect the well described pathway in which mTOR activated p70S6 kinase phosphorylates , and consequentially destabilizes , IRS-1 , a scaffold protein involved in growth factor activation of PI3K and Akt .	Rapamycin 's capacity to preserve Thr308 phosphorylation may reflect the well described pathway in which mTOR activated p70S6 kinase phosphorylates, and consequentially destabilizes, IRS-1, a scaffold protein involved in growth factor activation of PI3K and Akt.	16	20	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6 kinase	p70S6 kinase	p70S6 kinase	16	17	18	20
Phosphorylation of mTOR also leads to activation of p70S6K , which enhances protein translation XREF_BIBR - XREF_BIBR , XREF_BIBR - XREF_BIBR .	Phosphorylation of mTOR also leads to activation of p70S6K, which enhances protein translation XREF_BIBR - XREF_BIBR, XREF_BIBR - XREF_BIBR.	0	11	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	mTOR	Phosphorylation of mTOR	mtor	p70S6K	p70S6K	p70s6k	2	3	8	9
We recently showed that SNAT2 activity in PHTs is regulated at the posttranslational level by the mechanistic target of rapamycin ( mTOR ) , and p38 MAPK has been shown to regulate the downstream activation of the mTOR target S6K1 .	We recently showed that SNAT2 activity in PHTs is regulated at the posttranslational level by the mechanistic target of rapamycin (mTOR), and p38 MAPK has been shown to regulate the downstream activation of the mTOR target S6K1.	34	40	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	37	38	39	40
Activation of S6K1 by mTOR leads to phosphorylation of rpS6 and eIF4B which is thought to promote preferential translation of TOP mRNAs and mRNAs with highly structured 5 '-UTRs , respectively .	Activation of S6K1 by mTOR leads to phosphorylation of rpS6 and eIF4B which is thought to promote preferential translation of TOP mRNAs and mRNAs with highly structured 5 '-UTRs, respectively.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	4	5	2	3
S6K1 , a major downstream target of mTOR , is activated by growth factors such as insulin , and by mTOR , which is itself regulated by AA [ XREF_BIBR ] .	S6K1, a major downstream target of mTOR, is activated by growth factors such as insulin, and by mTOR, which is itself regulated by AA [XREF_BIBR].	0	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	20	21	0	1
Prolonged activation of S6 kinase 1 ( S6K1 , a major downstream substrate of mTORC1 ) caused by mTOR hyperactivation phosphorylates and dampens the insulin receptor substrate ( IRS1 ) , leading to insulin desensitization and inhibition of Akt activity ( XREF_FIG ) .	Prolonged activation of S6 kinase 1 (S6K1, a major downstream substrate of mTORC1) caused by mTOR hyperactivation phosphorylates and dampens the insulin receptor substrate (IRS1), leading to insulin desensitization and inhibition of Akt activity (XREF_FIG).	5	19	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	18	19	7	8
In case that eIF3-complex represents a platform for activation of S6K1 by mTOR , we expected to see a reduction of S6K1 signaling .	In case that eIF3-complex represents a platform for activation of S6K1 by mTOR, we expected to see a reduction of S6K1 signaling.	4	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	12	13	10	11
During denervation there is an increase of muscle proteins related to proteolysis , such as atrogin-1 and MAFbx and MuRF1 ( Muscle RING Finger 1 ) , as well as the reduction in the expression of proteins related to protein synthesis , such as AKT and mTOR ( serine/threonine specific protein kinase and Mammalian Target of Rapamycin , respectively ) , which in turns modulate the 4EBP1 p70S6K1 .	During denervation there is an increase of muscle proteins related to proteolysis, such as atrogin-1 and MAFbx and MuRF1 (Muscle RING Finger 1), as well as the reduction in the expression of proteins related to protein synthesis, such as AKT and mTOR (serine/threonine specific protein kinase and Mammalian Target of Rapamycin, respectively), which in turns modulate the 4EBP1 p70S6K1.	36	68	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K1	p70S6K1	p70S6K1	46	47	67	68
Many cancer driving mutations including those in PTEN , PIK3CA , and TSC1/2 lead to the activation of the AKT and mTOR pathway that in turn stimulate p70S6K , implicating these kinases as potential targets for anti-melanoma drugs [ XREF_BIBR ] .	Many cancer driving mutations including those in PTEN, PIK3CA, and TSC1/2 lead to the activation of the AKT and mTOR pathway that in turn stimulate p70S6K, implicating these kinases as potential targets for anti-melanoma drugs [XREF_BIBR].	19	28	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	21	22	27	28
Also , mTOR can directly activate p70S6K1 , which can then activate a downstream target , ribosomal protein S6 ( S6 ) , leading to the initiation of protein synthesis .	Also, mTOR can directly activate p70S6K1, which can then activate a downstream target, ribosomal protein S6 (S6), leading to the initiation of protein synthesis.	2	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K1	p70S6K1	p70S6K1	2	3	6	7
CYP significantly increased the protein levels of p-mTOR- and mTOR mediated p-S6K1 and p-4E-BP1 in the superficial dorsal horn as compared with control rats .	CYP significantly increased the protein levels of p-mTOR- and mTOR mediated p-S6K1 and p-4E-BP1 in the superficial dorsal horn as compared with control rats.	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p-S6K1	p-S6K1	p-S6K1	9	10	11	12
Our results demonstrated that combined treatment with rapamycin and melatonin blocked the negative feedback loop from the specific downstream effector of mTOR activation S6K1 to Akt signalling , which decreased cell viability , proliferation , and clonogenic capacity .	Our results demonstrated that combined treatment with rapamycin and melatonin blocked the negative feedback loop from the specific downstream effector of mTOR activation S6K1 to Akt signalling, which decreased cell viability, proliferation, and clonogenic capacity.	19	24	activation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	21	22	23	24
Since S6K1 activation by mTOR results in p44/42 mapk - and Akt reduced activity in HUVECs [ XREF_BIBR ] and insulin dependent activation of p44/42 mapk inhibits AMPK in the rat skeletal muscle cell line L6 [ XREF_BIBR ] , a functional dependency between p44/42 mapk , AMPK , and mTOR activity may also be a phenomenon involved in impaired insulin sensitivity in the foetoplacental vasculature .	Since S6K1 activation by mTOR results in p44/42 mapk - and Akt reduced activity in HUVECs [XREF_BIBR] and insulin dependent activation of p44/42 mapk inhibits AMPK in the rat skeletal muscle cell line L6 [XREF_BIBR], a functional dependency between p44/42 mapk, AMPK, and mTOR activity may also be a phenomenon involved in impaired insulin sensitivity in the foetoplacental vasculature.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	4	5	1	2
However , mTOR can be activated directly by amino acids , causing a subsequent stimulation of p70S6K activity [ XREF_BIBR , XREF_BIBR ] .	However, mTOR can be activated directly by amino acids, causing a subsequent stimulation of p70S6K activity [XREF_BIBR, XREF_BIBR].	2	17	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	2	3	16	17
Downregulation of the oncogenic transcription factor Myc , E2F1 , and mTOR target p70S6K also was highlighted after KPT-185+ AZD-2014 treatment .	Downregulation of the oncogenic transcription factor Myc, E2F1, and mTOR target p70S6K also was highlighted after KPT-185+ AZD-2014 treatment.	0	14	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	11	12	13	14
XREF_BIBR The phosphorylated form of Akt and mTOR targeting p70S6 kinase ( p70S6K ) and eukaryotic initiation factor 4E binding protein 1 ( 4E-BP1 ) were shown to be highly upregulated in the matrix groups , particularly in the DEX-BGN matrix ( XREF_FIG ) .	XREF_BIBR The phosphorylated form of Akt and mTOR targeting p70S6 kinase (p70S6K) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1) were shown to be highly upregulated in the matrix groups, particularly in the DEX-BGN matrix (XREF_FIG).	3	11	targeting	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6 kinase	p70S6 kinase	p70S6 kinase	7	8	9	11
mTOR signaling inhibition by nonspecific allosteric inhibitors such as rapamycin suppressed p70S6 kinase activity but paradoxically also increased the activation of AKT and eIF4E , which attenuated the therapeutic efficacy of these agents .	mTOR signaling inhibition by nonspecific allosteric inhibitors such as rapamycin suppressed p70S6 kinase activity but paradoxically also increased the activation of AKT and eIF4E, which attenuated the therapeutic efficacy of these agents.	0	13	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6 kinase	p70S6 kinase	p70S6 kinase	0	1	11	13
mTOR activation stimulated translation initiation processes involving both eIF4E/4E binding protein ( 4EBP ) and p70S6 kinase and ribosomal S6 protein .	mTOR activation stimulated translation initiation processes involving both eIF4E/4E binding protein (4EBP) and p70S6 kinase and ribosomal S6 protein.	0	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6 kinase	p70S6 kinase	p70S6 kinase	0	1	15	17
We demonstrated that both the mTOR downstream targets of p70S6K and eIF4E were involved in regulating KU-7-luc cell proliferation , and that inhibiting both p70S6K and eIF4E phosphorylation by rapamycin showed a more potent anti-proliferative effect than inhibiting p70S6K or 4E-BP1 phosphorylation alone .	We demonstrated that both the mTOR downstream targets of p70S6K and eIF4E were involved in regulating KU-7-luc cell proliferation, and that inhibiting both p70S6K and eIF4E phosphorylation by rapamycin showed a more potent anti-proliferative effect than inhibiting p70S6K or 4E-BP1 phosphorylation alone.	5	11	targets	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	5	6	9	10
Consistent with these data , we found that rotenone inhibited mTOR mediated p70S6K and 4E-BP1 activity , and triggered neuronal apoptosis , as detected by increased expression of cleaved-caspase-3 in vivo ( XREF_FIG ) .	Consistent with these data, we found that rotenone inhibited mTOR mediated p70S6K and 4E-BP1 activity, and triggered neuronal apoptosis, as detected by increased expression of cleaved-caspase-3 in vivo (XREF_FIG).	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	10	11	12	13
Our previous work suggested that the mTOR dependent activation of S6K1 and/or 4EBP play important roles in ( + ) strand RNA virus gene expression [ XREF_BIBR ] .	Our previous work suggested that the mTOR dependent activation of S6K1 and/or 4EBP play important roles in (+) strand RNA virus gene expression [XREF_BIBR].	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	6	7	10	11
Taken together , mTOR activates p70S6K and 4E-BP1 to induce cytokines and upon rapamycin inhibition of mTOR , it can no longer phosphorylate p70S6K and 4E-BP1 to down modulate proinflammatory cytokine IL-1beta and TNFalpha .	Taken together, mTOR activates p70S6K and 4E-BP1 to induce cytokines and upon rapamycin inhibition of mTOR, it can no longer phosphorylate p70S6K and 4E-BP1 to down modulate proinflammatory cytokine IL-1beta and TNFalpha.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	3	4	5	6
Akt has been previously shown to activate mammalian target of rapamycin ( mTOR ) , which in turn activates p70S6 kinase to induce TIMP-3 upon TGF-beta stimulation [ XREF_BIBR ] .	Akt has been previously shown to activate mammalian target of rapamycin (mTOR), which in turn activates p70S6 kinase to induce TIMP-3 upon TGF-beta stimulation [XREF_BIBR].	10	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6 kinase	p70S6 kinase	p70S6 kinase	12	13	19	21
Activation of MTOR then activates RPS6KB1 , which activates proteins responsible for protein synthesis .	Activation of MTOR then activates RPS6KB1, which activates proteins responsible for protein synthesis.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTOR	MTOR	MTOR	RPS6KB1	RPS6KB1	RPS6KB1	2	3	5	6
Recently we have demonstrated that rapamycin inhibits F-action reorganization and cell motility by inhibition of mTOR mediated S6K1 and 4E-BP1/eIF4E pathways XREF_BIBR , XREF_BIBR .	Recently we have demonstrated that rapamycin inhibits F-action reorganization and cell motility by inhibition of mTOR mediated S6K1 and 4E-BP1/eIF4E pathways XREF_BIBR, XREF_BIBR.	13	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	15	16	17	18
The activation of S6K1 by mTOR occurs in response to cellular energy status , nutrient levels , and mitogens .	The activation of S6K1 by mTOR occurs in response to cellular energy status, nutrient levels, and mitogens.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	5	6	3	4
CXCL12 induced the mTOR targets p-S6K1 and p-4EBP1 in BON cells and the CXCL12-induction was inhibited by the specific CXCR4 antagonist , AMD3100 .	CXCL12 induced the mTOR targets p-S6K1 and p-4EBP1 in BON cells and the CXCL12-induction was inhibited by the specific CXCR4 antagonist, AMD3100.	2	10	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p-S6K1	p-S6K1	p-S6K1	3	4	5	6
Activation of p70S6K by mTOR phosphorylation leads to the degradation of PDCD4 , a protein that interferes with eIF4A and eIF4G interaction and the activation of eIF4B ( XREF_FIG ) .	Activation of p70S6K by mTOR phosphorylation leads to the degradation of PDCD4, a protein that interferes with eIF4A and eIF4G interaction and the activation of eIF4B (XREF_FIG).	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR phosphorylation	mtor	p70S6K	p70S6K	p70s6k	4	5	2	3
In skeletal muscle , activation of Akt by IGF-1 stimulates protein translation through induction of mammalian target of rapamycin ( mTOR ) , which activates p70S6K and inactivates the inhibitor of translational initiation 4EBP1 , and GSK-3beta , which stimulates the initiation factor eIF2B .	In skeletal muscle, activation of Akt by IGF-1 stimulates protein translation through induction of mammalian target of rapamycin (mTOR), which activates p70S6K and inactivates the inhibitor of translational initiation 4EBP1, and GSK-3beta, which stimulates the initiation factor eIF2B.	18	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	20	21	25	26
A recent report showed that long-term treatment with rapamycin , an inhibitor of the mTOR pathway XREF_BIBR , or ablation of the mTOR target S6K1 XREF_BIBR extends lifespan in mice , possibly by delaying aging .	A recent report showed that long-term treatment with rapamycin, an inhibitor of the mTOR pathway XREF_BIBR, or ablation of the mTOR target S6K1 XREF_BIBR extends lifespan in mice, possibly by delaying aging.	22	25	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	22	23	24	25
Though the principal site required for mTOR dependent activation of p70S6K is Thr389 , which resides in a region between catalytic and auto-inhibitory domains [ XREF_BIBR ] , full activation of p70S6K is achieved through hierarchical phosphorylation of seven Ser/Thr sites targeted by mTOR , PDK1 , and other PI ( 3 ) kinase dependent kinases [ XREF_BIBR ] .	Though the principal site required for mTOR dependent activation of p70S6K is Thr389, which resides in a region between catalytic and auto-inhibitory domains [XREF_BIBR], full activation of p70S6K is achieved through hierarchical phosphorylation of seven Ser/Thr sites targeted by mTOR, PDK1, and other PI (3) kinase dependent kinases [XREF_BIBR].	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	6	7	10	11
Major downstream targets of mTOR are p70S6K and 4E-BP1 , which is activated by mTOR and then dissociates from the eukaryotic translation factor ( eIF-4E ) and activates protein synthesis [ XREF_BIBR ] .	Major downstream targets of mTOR are p70S6K and 4E-BP1, which is activated by mTOR and then dissociates from the eukaryotic translation factor (eIF-4E) and activates protein synthesis [XREF_BIBR].	2	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	14	15	6	7
Recently , our group has unveiled that human soluble BAFF ( hsBAFF ) promotes cell proliferation and survival not only in an Erk1/2 dependent nmanner , but also partially via activation of mTOR mediated S6K1 and 4E-BP1 pathways in normal and neoplastic B-lymphoid cells [ XREF_BIBR - XREF_BIBR ] .	Recently, our group has unveiled that human soluble BAFF (hsBAFF) promotes cell proliferation and survival not only in an Erk1/2 dependent nmanner, but also partially via activation of mTOR mediated S6K1 and 4E-BP1 pathways in normal and neoplastic B-lymphoid cells [XREF_BIBR - XREF_BIBR].	30	37	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	32	33	34	35
OXL significantly increased the protein levels of p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 in the DRG tissues as compared with control rats ( n = 8-10 ) .	OXL significantly increased the protein levels of p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 in the DRG tissues as compared with control rats (n = 8-10).	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p-S6K1	p-S6K1	p-S6K1	9	10	11	12
These studies provide primary evidence that PI ( 3 ) kinase and mTOR activate p70S6K in airway myocytes leading to the accumulation of contractile apparatus proteins , differentiation , and growth of large , elongated contractile phenotype airway smooth muscle cells .	These studies provide primary evidence that PI (3) kinase and mTOR activate p70S6K in airway myocytes leading to the accumulation of contractile apparatus proteins, differentiation, and growth of large, elongated contractile phenotype airway smooth muscle cells.	10	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	12	13	14	15
PD toxin induced neuronal cell death is related to inhibition of mTOR mediated S6K1 and 4E-BP1 pathways .	PD toxin induced neuronal cell death is related to inhibition of mTOR mediated S6K1 and 4E-BP1 pathways.	9	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	11	12	13	14
To investigate the mechanistic link between mTOR and DMC induced autophagy , we assessed the activation status of the Akt and mTOR signaling axis by examining the phosphorylation status of Akt at Thr308 , Ser473 , and mTOR , and the mTOR target p70S6K in DMC treated MCF-7 cells .	To investigate the mechanistic link between mTOR and DMC induced autophagy, we assessed the activation status of the Akt and mTOR signaling axis by examining the phosphorylation status of Akt at Thr308, Ser473, and mTOR, and the mTOR target p70S6K in DMC treated MCF-7 cells.	25	44	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	41	42	43	44
Moreover , mTOR is able to activate the p70S6K ( through T389 phosphorylation ) which activates the 40S ribosomal protein S6 via phosphorylation at S240/244 [ XREF_BIBR ] , a required process for translation and cell growth .	Moreover, mTOR is able to activate the p70S6K (through T389 phosphorylation) which activates the 40S ribosomal protein S6 via phosphorylation at S240/244 [XREF_BIBR], a required process for translation and cell growth.	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	2	3	8	9
This observation was significant since the mTOR integrates mitogenic signals and intracellular nutrient levels to activate 4EBP1 and p70S6K that control protein translation and cell cycle progression .	This observation was significant since the mTOR integrates mitogenic signals and intracellular nutrient levels to activate 4EBP1 and p70S6K that control protein translation and cell cycle progression.	5	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	6	7	18	19
In this case , activation was independent of nutrient signaling , and although the stimulus was a known oxidant , the concept that mTOR activates p70S6K in response to oxidation ( oxidative stress ) is consistent with our model .	In this case, activation was independent of nutrient signaling, and although the stimulus was a known oxidant, the concept that mTOR activates p70S6K in response to oxidation (oxidative stress) is consistent with our model.	23	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	23	24	25	26
In addition , suppression of mTOR activity by rapamycin decreased the level of activity of p70S6K , induced upregulation of p53 and caspase 3 , and led to increase of apoptosis in K562R IMT cells .	In addition, suppression of mTOR activity by rapamycin decreased the level of activity of p70S6K, induced upregulation of p53 and caspase 3, and led to increase of apoptosis in K562R IMT cells.	5	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	5	6	15	16
p70 ribosomal protein S6 kinase activity was induced by K-Ras in a PI3K- and mTOR dependent manner .	p70 ribosomal protein S6 kinase activity was induced by K-Ras in a PI3K- and mTOR dependent manner.	0	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70	p70	p70	14	15	0	1
Rapamycin , a specific inhibitor of FRAP and mTOR ( the upstream kinase of p70S6K ) , also blocked p70S6K activation , indicating the involvement of FRAP and mTOR activation .	Rapamycin, a specific inhibitor of FRAP and mTOR (the upstream kinase of p70S6K), also blocked p70S6K activation, indicating the involvement of FRAP and mTOR activation.	4	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FRAP	FRAP	FRAP	p70S6K	p70S6K	p70S6K	6	7	19	20
Our mechanistic data showed that sertraline not only blocked mTOR phosphorylation , but also suppressed its downstream effector p70S6K .	Our mechanistic data showed that sertraline not only blocked mTOR phosphorylation, but also suppressed its downstream effector p70S6K.	5	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	sertraline not only blocked mTOR phosphorylation	mtor	p70S6K	p70S6K	p70s6k	9	10	18	19
While no previous studies have addressed the mechanism by which PI-3-kinase blocks lactogenic differentiation , we demonstrated that the inhibition of PI-3-K , Akt or mTOR blocked the activation of p70S6 kinase and its downstream targets .	While no previous studies have addressed the mechanism by which PI-3-kinase blocks lactogenic differentiation, we demonstrated that the inhibition of PI-3-K, Akt or mTOR blocked the activation of p70S6 kinase and its downstream targets.	19	32	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6 kinase	p70S6 kinase	p70S6 kinase	25	26	30	32
PEC treatment also induced an acute decrease in the phosphorylation of the mTOR targets p70 ribosomal protein S6 kinase ( p-p70S6K ) , 4E-BP1 and p-eIF4E , revealing a potent inhibitory effect of PEC on PI3K/AKT/mTOR signaling leading to cell cycle arrest , autophagy and apoptosis in human gastric cancer cells treated with PEC .	PEC treatment also induced an acute decrease in the phosphorylation of the mTOR targets p70 ribosomal protein S6 kinase (p-p70S6K), 4E-BP1 and p-eIF4E, revealing a potent inhibitory effect of PEC on PI3K/AKT/mTOR signaling leading to cell cycle arrest, autophagy and apoptosis in human gastric cancer cells treated with PEC.	9	15	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of the mTOR	mtor	p70	p70	p70	12	13	14	15
mTOR can be activated in distinct ways , thereby activating p70S6K .	mTOR can be activated in distinct ways, thereby activating p70S6K.	0	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	0	1	10	11
In summary , we have identified that rotenone induced [ Ca 2+ ] i elevation inhibits mTOR mediated S6K1 and 4E-BP1 pathways contributing to neuronal apoptosis , through stimulating phosphorylation of CaMKII .	In summary, we have identified that rotenone induced [Ca 2+] i elevation inhibits mTOR mediated S6K1 and 4E-BP1 pathways contributing to neuronal apoptosis, through stimulating phosphorylation of CaMKII.	15	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	16	17	18	19
In the present research we further found that NS5A increased phosphorylation levels of two mTOR targeted substrates , S6K1 and 4EBP1 , in Huh7 in the absence of serum .	In the present research we further found that NS5A increased phosphorylation levels of two mTOR targeted substrates, S6K1 and 4EBP1, in Huh7 in the absence of serum.	8	19	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	NS5A increased phosphorylation levels of two mTOR	mtor	S6K1	S6K1	s6k1	14	15	18	19
In conclusion , in SCI , spinal p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 are upregulated , which results in mechanical and thermal hypersensitivity .	In conclusion, in SCI, spinal p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 are upregulated, which results in mechanical and thermal hypersensitivity.	7	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p-S6K1	p-S6K1	p-S6K1	9	10	11	12
Activation of p70S6 kinase by mTOR enables the former to catalyze phosphorylation of Ser366 on eEF2 kinase [ XREF_BIBR ] , thereby inactivating it ( XREF_FIG ) .	Activation of p70S6 kinase by mTOR enables the former to catalyze phosphorylation of Ser366 on eEF2 kinase [XREF_BIBR], thereby inactivating it (XREF_FIG).	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6 kinase	p70S6 kinase	p70S6 kinase	5	6	2	4
On the one hand , mTOR phosphorylates and activates p70S6K ( p70 ribosomal protein S6 kinase ) , furthermore , to involve in phosphorylation and inactivation of Bcl-2 [ XREF_BIBR , XREF_BIBR ] .	On the one hand, mTOR phosphorylates and activates p70S6K (p70 ribosomal protein S6 kinase), furthermore, to involve in phosphorylation and inactivation of Bcl-2 [XREF_BIBR, XREF_BIBR].	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	5	6	9	10
The aim of the present study was to investigate differences between the mTOR targets S6K1 and S6K2 and their individual potentials as new clinical targets in breast cancer , as well as further explore the importance of the S6K2/4EBP1 co-expression .	The aim of the present study was to investigate differences between the mTOR targets S6K1 and S6K2 and their individual potentials as new clinical targets in breast cancer, as well as further explore the importance of the S6K2/4EBP1 co-expression.	9	33	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	12	13	14	15
This was reflected by decreased phosphorylation levels of the downstream mTOR target p70S6K .	This was reflected by decreased phosphorylation levels of the downstream mTOR target p70S6K.	6	13	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	10	11	12	13
The mechanism by which PI3K and FRAP cooperate to induce p70S6K activation remains unclear .	The mechanism by which PI3K and FRAP cooperate to induce p70S6K activation remains unclear.	4	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FRAP	FRAP	FRAP	p70S6K	p70S6K	p70S6K	6	7	10	11
A homozygous deletion of the mTOR target S6K1 ( ribosomal protein S6 kinase 1 ) in mice was found to lead to hyperinsulinemia and glucose intolerance XREF_BIBR .	A homozygous deletion of the mTOR target S6K1 (ribosomal protein S6 kinase 1) in mice was found to lead to hyperinsulinemia and glucose intolerance XREF_BIBR.	2	16	target	Positive_activation_token_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	5	6	7	8
Consistent with previous reports that transcription inhibitors such as a-amanitin activate the mTOR signalling pathway [ XREF_BIBR ] , activation of the downstream mTOR target p70S6K following a-amanitin treatment was detected in our cell lines .	Consistent with previous reports that transcription inhibitors such as a-amanitin activate the mTOR signalling pathway [XREF_BIBR], activation of the downstream mTOR target p70S6K following a-amanitin treatment was detected in our cell lines.	19	28	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	23	24	25	26
Lanatoside C markedly reduced phosphorylation of Akt and its downstream effectors as well as mTOR and its downstream effectors , such as the mTOR activated kinase p70S6K and the eukaryotic translation initiation factors 4EBP and eIF4E , in a concentration dependent manner in both Hep3B and HA22T cells ( XREF_FIG ) .	Lanatoside C markedly reduced phosphorylation of Akt and its downstream effectors as well as mTOR and its downstream effectors, such as the mTOR activated kinase p70S6K and the eukaryotic translation initiation factors 4EBP and eIF4E, in a concentration dependent manner in both Hep3B and HA22T cells (XREF_FIG).	3	31	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	23	24	26	27
The stimulation of mTOR complex1 ( mTORC1 ) by the activation of PI3K and Akt subsequently induces activation of p70 ribosomal S6 protein kinases 1/2 and inhibition of eukaryotic initiation factor 4E bonding proteins , triggering the translational response of the mTOR cascade ( Wang et al ., 2017 ) .	The stimulation of mTOR complex1 (mTORC1) by the activation of PI3K and Akt subsequently induces activation of p70 ribosomal S6 protein kinases 1/2 and inhibition of eukaryotic initiation factor 4E bonding proteins, triggering the translational response of the mTOR cascade (Wang et al., 2017).	3	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70	p70	p70	3	4	19	20
Both activation of AMPK and inactivation of Akt contribute to suppression of mTOR mediated S6K1 and 4E-BP1 pathways , thereby leading to neuronal cell death in the context of PD .	Both activation of AMPK and inactivation of Akt contribute to suppression of mTOR mediated S6K1 and 4E-BP1 pathways, thereby leading to neuronal cell death in the context of PD.	10	17	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	12	13	14	15
To demonstrate the importance of mTOR mediated S6K1 and 4E-BP1 pathways in the pathogenesis of PD , first of all , we tested whether overexpression of mTOR has any protective effect on PD toxins induced cell death .	To demonstrate the importance of mTOR mediated S6K1 and 4E-BP1 pathways in the pathogenesis of PD, first of all, we tested whether overexpression of mTOR has any protective effect on PD toxins induced cell death.	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	5	6	7	8
89 mTOR activation increases protein synthesis by simultaneously activating p70 ribosomal protein S6 kinase ( p70S6K ) and inhibiting the translational repressor 4E binding protein 1 ( 4E-BP1 ) .	89 mTOR activation increases protein synthesis by simultaneously activating p70 ribosomal protein S6 kinase (p70S6K) and inhibiting the translational repressor 4E binding protein 1 (4E-BP1).	1	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70	p70	p70	1	2	9	10
The mammalian target of rapamycin ( mTOR ) signaling pathway determines the core route from PI3K to AKT and which diverges at mTOR XREF_BIBR , where it activates either ribosomal S6 kinase 1 ( S6K1 ) or the eukaryotic translation initiation factor 4E ( eIF4E ) XREF_BIBR .	The mammalian target of rapamycin (mTOR) signaling pathway determines the core route from PI3K to AKT and which diverges at mTOR XREF_BIBR, where it activates either ribosomal S6 kinase 1 (S6K1) or the eukaryotic translation initiation factor 4E (eIF4E) XREF_BIBR.	22	46	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	22	23	34	35
To further confirm that MDM4 effect on pS6K1 are mediated through regulation of mTOR , the knockdown of mTOR prevented the upregulation of pS6K1 by siMDM4 .	To further confirm that MDM4 effect on pS6K1 are mediated through regulation of mTOR, the knockdown of mTOR prevented the upregulation of pS6K1 by siMDM4.	16	24	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	pS6K1	pS6K1	pS6K1	18	19	23	24
XREF_BIBR , XREF_BIBR Besides , activated PDK1 may positively regulate mTOR mediated S6K1 .	XREF_BIBR, XREF_BIBR Besides, activated PDK1 may positively regulate mTOR mediated S6K1.	9	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	10	11	12	13
A recent report showed that microencapsulated rapamycin , an inhibitor of the mTOR pathway XREF_BIBR , or genetic ablation of the mTOR target S6K1 XREF_BIBR extends lifespan in mice , possibly by retarding aging .	A recent report showed that microencapsulated rapamycin, an inhibitor of the mTOR pathway XREF_BIBR, or genetic ablation of the mTOR target S6K1 XREF_BIBR extends lifespan in mice, possibly by retarding aging.	21	24	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	21	22	23	24
The signaling of mTOR modulates the activation of two major downstream components : eIF4E binding protein 1 and p70S6K XREF_BIBR , XREF_BIBR .	The signaling of mTOR modulates the activation of two major downstream components : eIF4E binding protein 1 and p70S6K XREF_BIBR, XREF_BIBR.	1	19	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	3	4	18	19
Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes mediated mTOR activation can selectively activate S6K1 without activating S6K2 .	Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes mediated mTOR activation can selectively activate S6K1 without activating S6K2.	35	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	35	36	40	41
Collectively , our findings suggest that rotenone elevation of mitochondrial H 2 O 2 - and [ Ca 2+ ] i -mediated CaMKII phosphorylation inhibits mTOR mediated S6K1 and 4E-BP1 pathways , leading to neuronal apoptosis ; activation of mTOR pathway , in turn , can partially prevent rotenone from increasing mitochondrial H 2 O 2 and [ Ca 2+ ] i , thereby attenuating rotenone induced neuronal apoptosis .	Collectively, our findings suggest that rotenone elevation of mitochondrial H 2 O 2 - and [Ca 2+] i -mediated CaMKII phosphorylation inhibits mTOR mediated S6K1 and 4E-BP1 pathways, leading to neuronal apoptosis; activation of mTOR pathway, in turn, can partially prevent rotenone from increasing mitochondrial H 2 O 2 and [Ca 2+] i, thereby attenuating rotenone induced neuronal apoptosis.	24	47	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	25	26	27	28
To examine whether Cd induced [ Ca 2+ ] i elevation is correlated to the activation of MAPK and mTOR pathways , PC12 , SH-SY5Y , and primary neurons were preincubated with and without BAPTA/AM for 30 min , followed by treatment with Cd ( 10 and 20 microM ) for 4 h. Western blot analysis showed that BAPTA/AM significantly blocked Cd induced phosphorylation of JNK , Erk1/2 , and p38 MAPK ( XREF_FIG ) , as well as phosphorylation of mTOR , and mTOR mediated S6K1 and 4E-BP1 ( XREF_FIG ) .	To examine whether Cd induced [Ca 2+] i elevation is correlated to the activation of MAPK and mTOR pathways, PC12, SH-SY5Y, and primary neurons were preincubated with and without BAPTA/AM for 30 min, followed by treatment with Cd (10 and 20 microM) for 4 h. Western blot analysis showed that BAPTA/AM significantly blocked Cd induced phosphorylation of JNK, Erk1/2, and p38 MAPK (XREF_FIG), as well as phosphorylation of mTOR, and mTOR mediated S6K1 and 4E-BP1 (XREF_FIG).	84	90	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	84	85	86	87
Unexpectedly , induction of ER stress assessed by p-eiF2a , or DR5 , or inhibition of the prototypic mTOR target S6K1 was similar in RKO , VACO432 cells irrespective of BRAF status .	Unexpectedly, induction of ER stress assessed by p-eiF2a, or DR5, or inhibition of the prototypic mTOR target S6K1 was similar in RKO, VACO432 cells irrespective of BRAF status.	14	21	target	Positive_activation_token_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	18	19	20	21
One well characterized negative feedback loop involves the tuberous sclerosis complex ( TSC ) , the Rheb RAS superfamily member , the kinase mTOR , and the mTOR target p70 ribosomal S6 kinase ( p70S6K ) that inhibits insulin receptor substrate 1 ( IRS1 ) and insulin like growth factor receptor ( IGFR ) signaling .	One well characterized negative feedback loop involves the tuberous sclerosis complex (TSC), the Rheb RAS superfamily member, the kinase mTOR, and the mTOR target p70 ribosomal S6 kinase (p70S6K) that inhibits insulin receptor substrate 1 (IRS1) and insulin like growth factor receptor (IGFR) signaling.	10	32	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70	p70	p70	27	28	29	30
Given that p70S6K is activated by mTOR , an Akt regulated kinase , Akt2 may indeed regulate not only the expression but also the functional activity of PDCD4 .	Given that p70S6K is activated by mTOR, an Akt regulated kinase, Akt2 may indeed regulate not only the expression but also the functional activity of PDCD4.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	6	7	2	3
In agreement with a role of NAADP in autophagy regulation by glutamate , we observed that NAADP treatment induces AMPK phosphorylation , while no effect was observed on the mTOR target p70S6K .	In agreement with a role of NAADP in autophagy regulation by glutamate, we observed that NAADP treatment induces AMPK phosphorylation, while no effect was observed on the mTOR target p70S6K.	26	32	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	29	30	31	32
The results indicate that rotenone induction of H2O2 inhibits mTOR mediated S6K1 and 4E-BP1/eIF4E pathways , resulting in caspase dependent and -independent apoptosis in neuronal cells .	The results indicate that rotenone induction of H2O2 inhibits mTOR mediated S6K1 and 4E-BP1/eIF4E pathways, resulting in caspase dependent and -independent apoptosis in neuronal cells.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	9	10	11	12
The mTOR pathway includes two complexes : mTOR complex 1 ( mTORC1 ) , which requires raptor and activates S6K1 , and mTORC2 , which requires rictor and activates AKT .	The mTOR pathway includes two complexes : mTOR complex 1 (mTORC1), which requires raptor and activates S6K1, and mTORC2, which requires rictor and activates AKT.	7	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	7	8	19	20
Moreover , inhibition of mTOR pathway signaling by rapamycin blocked S6K1 and augmented the cytocidal effects of the Hh pathway inhibitor .	Moreover, inhibition of mTOR pathway signaling by rapamycin blocked S6K1 and augmented the cytocidal effects of the Hh pathway inhibitor.	4	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	4	5	10	11
17 Akt and the mTOR target p70S6K can phosphory-late ERalpha serine 167 , which increases both its ligand dependent and ligand independent transcriptional activity .	17 Akt and the mTOR target p70S6K can phosphory-late ERalpha serine 167, which increases both its ligand dependent and ligand independent transcriptional activity.	1	8	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	4	5	6	7
We now demonstrate that SCF activates phosphoinositide 3-kinase ( PI3-K ) and p70 S6 kinase ( p70S6K ) and that rapamycin , a FRAP and mammalian target of rapamycin dependent inhibitor of p70S6K , completely inhibited bromodeoxyuridine incorporation induced by SCF in primary cultures of spermatogonia .	We now demonstrate that SCF activates phosphoinositide 3-kinase (PI3-K) and p70 S6 kinase (p70S6K) and that rapamycin, a FRAP and mammalian target of rapamycin dependent inhibitor of p70S6K, completely inhibited bromodeoxyuridine incorporation induced by SCF in primary cultures of spermatogonia.	23	33	inhibitor	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	p70S6K	p70S6K	p70S6K	25	29	32	33
S6K1 ( p70 ribosomal S6 kinase 1 ) is activated by insulin and growth factors via the PI3K ( phosphoinositide 3-kinase ) and mTOR ( mammalian target of rapamycin ) signalling pathways .	S6K1 (p70 ribosomal S6 kinase 1) is activated by insulin and growth factors via the PI3K (phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin) signalling pathways.	0	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	23	24	0	1
Once induced , mTOR increases cell growth and proliferation through activation of two effector molecules p70S6K and 4EBP1 leading to a global increase in protein translation .	Once induced, mTOR increases cell growth and proliferation through activation of two effector molecules p70S6K and 4EBP1 leading to a global increase in protein translation.	3	18	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	3	4	15	16
Concomitantly , mTOR mediates the activation of p70S6K , which in turn phosphorylates the 40S ribosomal protein S6 kinase at Ser235 and Ser236 , leading to the promotion of mRNA translation .	Concomitantly, mTOR mediates the activation of p70S6K, which in turn phosphorylates the 40S ribosomal protein S6 kinase at Ser235 and Ser236, leading to the promotion of mRNA translation.	2	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	2	3	7	8
Since S6K1 is activated upon phosphorylation by mTOR , this observation further demonstrates the importance of this pathway .	Since S6K1 is activated upon phosphorylation by mTOR, this observation further demonstrates the importance of this pathway.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	7	8	1	2
However , Akt signaling was transient and returned to base line after 30 minutes while the phosphorylation of the mTOR targets p70S6K and rpS6 continued to increase over the 2 hour time course .	However, Akt signaling was transient and returned to base line after 30 minutes while the phosphorylation of the mTOR targets p70S6K and rpS6 continued to increase over the 2 hour time course.	16	26	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of the mTOR	mtor	p70S6K	p70S6K	p70s6k	19	20	21	22
While expression of CA-Akt caused a constitutive activation of p70S6 kinase ( p70S6K ) in HC11 cells , the inhibition of either PI-3-kinase or mTOR abolished the activation of p70S6K by EGF .	While expression of CA-Akt caused a constitutive activation of p70S6 kinase (p70S6K) in HC11 cells, the inhibition of either PI-3-kinase or mTOR abolished the activation of p70S6K by EGF.	19	30	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	24	25	29	30
Moreover , hsBAFF also augments proliferation and survival in the cells , at least in part , through activating mTOR mediated S6K1 and 4E-BP1 pathways [ XREF_BIBR , XREF_BIBR ] .	Moreover, hsBAFF also augments proliferation and survival in the cells, at least in part, through activating mTOR mediated S6K1 and 4E-BP1 pathways [XREF_BIBR, XREF_BIBR].	18	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	19	20	21	22
We found that cardiac activation of mTORC1 and mTORC2 was impaired in p38gamma and delta -/-, p38gamma -/- and p38delta -/- mice , as assessed by the phosphorylation of the mTOR targets p70S6K , S6 and FOXO1/3a and by mTOR autophosphorylation on Ser 2481 ( XREF_FIG , XREF_SUPPLEMENTARY ) ; in contrast , no changes were detected in the expression or activation of p38alpha ( XREF_SUPPLEMENTARY ) .	We found that cardiac activation of mTORC1 and mTORC2 was impaired in p38gamma and delta -/-, p38gamma -/- and p38delta -/- mice, as assessed by the phosphorylation of the mTOR targets p70S6K, S6 and FOXO1/3a and by mTOR autophosphorylation on Ser 2481 (XREF_FIG, XREF_SUPPLEMENTARY); in contrast, no changes were detected in the expression or activation of p38alpha (XREF_SUPPLEMENTARY).	27	36	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of the mTOR	mtor	p70S6K	p70S6K	p70s6k	30	31	32	33
Alternatively or in addition , enhancement of cytotoxicity may directly involve p70S6 kinase , which is activated by mTOR .	Alternatively or in addition, enhancement of cytotoxicity may directly involve p70S6 kinase, which is activated by mTOR.	11	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6 kinase	p70S6 kinase	p70S6 kinase	18	19	11	13
Elevated IL-17 production in Tsc1-/- Treg cells was reversed by in vivo knockdown of the mTOR target S6K1 .	Elevated IL-17 production in Tsc1-/- Treg cells was reversed by in vivo knockdown of the mTOR target S6K1.	12	18	target	Positive_activation_token_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	15	16	17	18
Lastly , it has been known that ELF2AK helps S6K1 activated by mTOR to promote mRNA translation XREF_BIBR , XREF_BIBR .	Lastly, it has been known that ELF2AK helps S6K1 activated by mTOR to promote mRNA translation XREF_BIBR, XREF_BIBR.	8	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	12	13	9	10
Phosphorylation levels of its substrates ( indicators of mTOR kinase activity ) - p70 S6 kinase 1 ( p70 S6K1 - at position T389 ) and eukaryotic initiation factor 4E binding protein 1 ( eIF4E-BP1 at position S65 ) were also significantly upregulated by all the employed ligands as well as phosphorylation of S2448 mTOR .	Phosphorylation levels of its substrates (indicators of mTOR kinase activity) - p70 S6 kinase 1 (p70 S6K1 - at position T389) and eukaryotic initiation factor 4E binding protein 1 (eIF4E-BP1 at position S65) were also significantly upregulated by all the employed ligands as well as phosphorylation of S2448 mTOR.	18	55	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of S2448 mTOR	mtor	p70 S6K1	p70 S6K1	p70 s6k1	54	55	18	20
In our experimental model , constitutive activation of the mTOR target p70S6K , which may be phosphorylated by Akt dependent and Akt independent mechanisms , invariably correlates with lack of response to EGFR antagonists .	In our experimental model, constitutive activation of the mTOR target p70S6K, which may be phosphorylated by Akt dependent and Akt independent mechanisms, invariably correlates with lack of response to EGFR antagonists.	6	17	target	Positive_regulation_token_1_verb	Positive_activation	Positive_regulation	mTOR	mTOR	mtor	p70S6K	p70S6K, which may be phosphorylated	p70s6k	9	10	11	12
Specifically , we studied the effect of Fludro on the mTOR target p70S6K and found a time dependent increase of its phosphorylation at Thr389 , compared to basal .	Specifically, we studied the effect of Fludro on the mTOR target p70S6K and found a time dependent increase of its phosphorylation at Thr389, compared to basal.	3	13	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	10	11	12	13
We have shown that rapamycin inhibits cell motility by suppression of mTOR mediated S6K1 and 4E-BP1 pathways [ XREF_BIBR ] , and identified that rapamycin inhibition of cell motility is related to its prevention of F-actin reorganization [ XREF_BIBR , XREF_BIBR ] .	We have shown that rapamycin inhibits cell motility by suppression of mTOR mediated S6K1 and 4E-BP1 pathways [XREF_BIBR], and identified that rapamycin inhibition of cell motility is related to its prevention of F-actin reorganization [XREF_BIBR, XREF_BIBR].	9	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	11	12	13	14
In conclusion , in OXL rats , p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 are upregulated in sensory nerves , which result in mechanical pain and cold hypersensitivity .	In conclusion, in OXL rats, p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 are upregulated in sensory nerves, which result in mechanical pain and cold hypersensitivity.	7	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p-S6K1	p-S6K1	p-S6K1	9	10	11	12
As p70S6K activation is modulated by mTOR , p70S6K may be essential for the regulation of HIF-1alpha induction in the mechanism of adaptive T cell development .	As p70S6K activation is modulated by mTOR, p70S6K may be essential for the regulation of HIF-1alpha induction in the mechanism of adaptive T cell development.	1	7	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	6	7	1	2
MAFbx could control cell growth by interacting with eIF3f for further degradation by the 26S proteasome , preventing the activation of S6K1 by mTOR .	MAFbx could control cell growth by interacting with eIF3f for further degradation by the 26S proteasome, preventing the activation of S6K1 by mTOR.	17	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	23	24	21	22
As rapamycin inhibited mSin1 phosphorylation within 2 h , and mTORC1 is sensitive to acute rapamycin treatment [ XREF_BIBR , XREF_BIBR ] , we next reasoned that rapamycin induced dephosphorylation of mSin1 is most likely by targeting mTORC1 , although mTOR mediated S6K1 pathway had been ruled out in this event .	As rapamycin inhibited mSin1 phosphorylation within 2 h, and mTORC1 is sensitive to acute rapamycin treatment [XREF_BIBR, XREF_BIBR], we next reasoned that rapamycin induced dephosphorylation of mSin1 is most likely by targeting mTORC1, although mTOR mediated S6K1 pathway had been ruled out in this event.	40	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	40	41	42	43
mTOR signaling activates p70S6 kinase which in turn phosphorylates Ser235 , Ser236 , Ser240 and Ser244 of S6 43 .	mTOR signaling activates p70S6 kinase which in turn phosphorylates Ser235, Ser236, Ser240 and Ser244 of S6 43.	0	18	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	mTOR	mTOR	mtor	p70S6 kinase	p70S6 kinase which in turn phosphorylates Ser235, Ser236, Ser240 and Ser244 of S6	p70s6 kinase	0	1	3	5
XREF_BIBR Another line of evidence supporting a key role for autophagy in regulating longevity is data that inhibition of the mammalian target of rapamycin ( mTOR ) significantly increases lifespan in several organisms and observations that long-term treatment with rapamycin , an inhibitor of the mTOR pathway XREF_BIBR , or ablation of the mTOR target p70S6K XREF_BIBR extends lifespan in mice and may prevent congnitive deficits in a mouse model of Alzheimer ' s disease .	XREF_BIBR Another line of evidence supporting a key role for autophagy in regulating longevity is data that inhibition of the mammalian target of rapamycin (mTOR) significantly increases lifespan in several organisms and observations that long-term treatment with rapamycin, an inhibitor of the mTOR pathway XREF_BIBR, or ablation of the mTOR target p70S6K XREF_BIBR extends lifespan in mice and may prevent congnitive deficits in a mouse model of Alzheimer 's disease.	53	56	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	53	54	55	56
Overexpression of wild-type mTOR or constitutively active S6K1 , or downregulation of 4E-BP1 in PC12 cells partially prevented cell death in response to the PD toxins , revealing that mTOR mediated S6K1 and 4E-BP1 pathways due to the PD toxins were inhibited , leading to neuronal cell death .	Overexpression of wild-type mTOR or constitutively active S6K1, or downregulation of 4E-BP1 in PC12 cells partially prevented cell death in response to the PD toxins, revealing that mTOR mediated S6K1 and 4E-BP1 pathways due to the PD toxins were inhibited, leading to neuronal cell death.	29	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	29	30	31	32
It was recently demonstrated that long-term treatment with rapamycin , an inhibitor of the mTOR pathway XREF_BIBR , or ablation of the mTOR target p70S6K XREF_BIBR extends lifespan in mice , possibly by delaying aging .	It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway XREF_BIBR, or ablation of the mTOR target p70S6K XREF_BIBR extends lifespan in mice, possibly by delaying aging.	22	25	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	22	23	24	25
Moreover , sulforaphane treatment significantly attenuated rotenone inhibited mTOR mediated p70S6K and 4E-BP1 signalling pathway , as well as neuronal apoptosis .	Moreover, sulforaphane treatment significantly attenuated rotenone inhibited mTOR mediated p70S6K and 4E-BP1 signalling pathway, as well as neuronal apoptosis.	7	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	8	9	10	11
This was associated with enhanced phosphorylation of signaling proteins AKT , mTOR and mTOR target S6K1 in Foxo3-null erythroblast precursors at levels markedly higher than the control .	This was associated with enhanced phosphorylation of signaling proteins AKT, mTOR and mTOR target S6K1 in Foxo3-null erythroblast precursors at levels markedly higher than the control.	8	26	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	13	14	15	16
Instead , we still observe mTOR localization to the hybrid early and late endosomes in hVps39 knockdown cells , but mTOR does not signal to S6K1 .	Instead, we still observe mTOR localization to the hybrid early and late endosomes in hVps39 knockdown cells, but mTOR does not signal to S6K1.	20	26	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	20	21	25	26
Furthermore , inhibition of both S6K1 and S6K2 by the mTOR specific inhibitor , rapamycin , is not sufficient to achieve a complete dephosphorylation of rpS6 , as it is still phosphorylated at two of its five phosphorylatable serine residues by RSK XREF_BIBR .	Furthermore, inhibition of both S6K1 and S6K2 by the mTOR specific inhibitor, rapamycin, is not sufficient to achieve a complete dephosphorylation of rpS6, as it is still phosphorylated at two of its five phosphorylatable serine residues by RSK XREF_BIBR.	2	12	inhibition	Negative_activation_syntax_1_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	10	11	5	6
In CYP-rats , spinal p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 are upregulated , which results in mechanical pain and bladder hyperactivity .	In CYP-rats, spinal p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 are upregulated, which results in mechanical pain and bladder hyperactivity.	4	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p-S6K1	p-S6K1	p-S6K1	6	7	8	9
The inhibition of mTOR kinase prevents S6K1 activity , and then suppresses C2C12 myoblast differentiation [ XREF_BIBR ] .	The inhibition of mTOR kinase prevents S6K1 activity, and then suppresses C2C12 myoblast differentiation [XREF_BIBR].	3	7	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	3	4	6	7
To further confirm that eIF3f mediates activation of S6K1 by mTOR , an eIF3f mutant deleted of the C-terminal domain was transfected in mouse primary muscle cells and the phosphorylation of downstream targets of mTOR was assessed .	To further confirm that eIF3f mediates activation of S6K1 by mTOR, an eIF3f mutant deleted of the C-terminal domain was transfected in mouse primary muscle cells and the phosphorylation of downstream targets of mTOR was assessed.	5	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	10	11	8	9
The activation of p70S6K1 by mTOR enhances the translation of mRNAs that bear a 5 ' terminal oligopyrimidine tract , which encodes proteins related with the translational apparatus like ribosomal proteins , elongation factors eEF1A , eEF2 and the poly A binding protein .	The activation of p70S6K1 by mTOR enhances the translation of mRNAs that bear a 5 ' terminal oligopyrimidine tract, which encodes proteins related with the translational apparatus like ribosomal proteins, elongation factors eEF1A, eEF2 and the poly A binding protein.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K1	p70S6K1	p70S6K1	5	6	3	4
The findings indicate that H 2 O 2 inhibits mTOR mediated S6K1 and 4E-BP1 signaling pathways in the neuronal cells .	The findings indicate that H 2 O 2 inhibits mTOR mediated S6K1 and 4E-BP1 signaling pathways in the neuronal cells.	8	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	9	10	11	12
mTOR inhibition reduces S6K1 activity , causing an increase in IRS1/2 and enhanced activation of IGFR1 dependent Akt activity [ XREF_BIBR ] .	mTOR inhibition reduces S6K1 activity, causing an increase in IRS1/2 and enhanced activation of IGFR1 dependent Akt activity [XREF_BIBR].	0	4	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	0	1	3	4
Because p70S6K activity can be enhanced by mTOR , we decided to investigate this pathway in more detail .	Because p70S6K activity can be enhanced by mTOR, we decided to investigate this pathway in more detail.	1	8	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	7	8	1	2
The mTOR kinase responds to both nutrient and growth factor signals to activate p70S6K and 4EBP1 to increase protein translation as part of a cell growth response [ XREF_BIBR ] .	The mTOR kinase responds to both nutrient and growth factor signals to activate p70S6K and 4EBP1 to increase protein translation as part of a cell growth response [XREF_BIBR].	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	1	2	13	14
In summary , the transcriptome of post-mortem SN tissue of donors with Braak alpha-synuclein stages 0 to 6 revealed a consistent deregulation of pathways related to macroautophagy and protein synthesis , including EIF2 signaling , mTOR signaling and regulation of eIF4 and p70S6K signaling during the progression of PD pathology .	In summary, the transcriptome of post-mortem SN tissue of donors with Braak alpha-synuclein stages 0 to 6 revealed a consistent deregulation of pathways related to macroautophagy and protein synthesis, including EIF2 signaling, mTOR signaling and regulation of eIF4 and p70S6K signaling during the progression of PD pathology.	35	43	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	35	36	42	43
Western blotting showed that 5-FU significantly decreased the phosphorylation of AKT and mTOR and subsequently inhibited the activation of p70S6K , an important kinase downstream target of mTOR .	Western blotting showed that 5-FU significantly decreased the phosphorylation of AKT and mTOR and subsequently inhibited the activation of p70S6K, an important kinase downstream target of mTOR.	4	25	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	5-FU significantly decreased the phosphorylation of AKT and mTOR	mtor	p70S6K	p70S6K	p70s6k	12	13	19	20
Apoptosis in astrocytes is prevented following activation of p70S6K by mTOR that can lead to increased expression of Bcl-2 and Bcl-x L expression to block BAD activity that can result in apoptosis .	Apoptosis in astrocytes is prevented following activation of p70S6K by mTOR that can lead to increased expression of Bcl-2 and Bcl-x L expression to block BAD activity that can result in apoptosis.	4	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	10	11	8	9
ATM and ATR are activated upon recruitment to the DNA lesion by the MRN complex of proteins .	ATM and ATR are activated upon recruitment to the DNA lesion by the MRN complex of proteins.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	13	14	0	1
A view supported by the upregulation of the genes MRE11 , RAD50 , and NBN of the MRN complex that triggers the ATM and CHEK2 pathway XREF_BIBR , XREF_BIBR .	A view supported by the upregulation of the genes MRE11, RAD50, and NBN of the MRN complex that triggers the ATM and CHEK2 pathway XREF_BIBR, XREF_BIBR.	2	28	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NBN	NBN	NBN	ATM	ATM	ATM	14	15	22	23
MDC1 in turn recruits the MRN complex ( MRE11-RAD50-NBS1 ) and the MRN complex further activates ATM .	MDC1 in turn recruits the MRN complex (MRE11-RAD50-NBS1) and the MRN complex further activates ATM.	12	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	12	13	16	17
Upon MRN mediated ATM recruitment , a lysine acetyl-transferase 5 ( also known as a Tip60 , hereinafter referred to as KAT5 ) , which binds to ATM indirectly , interacts with histone H3 trimethylated at lysine 9 ( H3K9m3 ) .	Upon MRN mediated ATM recruitment, a lysine acetyl-transferase 5 (also known as a Tip60, hereinafter referred to as KAT5), which binds to ATM indirectly, interacts with histone H3 trimethylated at lysine 9 (H3K9m3).	0	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	3	4
MRN is proposed to tether together broken DNA ends and promote ATM activation via mediating the recruitment of ATM to sites of DNA damage .	MRN is proposed to tether together broken DNA ends and promote ATM activation via mediating the recruitment of ATM to sites of DNA damage.	0	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	11	12
To determine if ROS are important for ATM stimulation by resveratrol in vitro , the disulfide specific reducing agent TCEP was added to reactions in which ATM is activated by a combination of MRN , DNA , and resveratrol ( XREF_FIG ) .	To determine if ROS are important for ATM stimulation by resveratrol in vitro, the disulfide specific reducing agent TCEP was added to reactions in which ATM is activated by a combination of MRN, DNA, and resveratrol (XREF_FIG).	26	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	33	34	26	27
Once recruited to a break , MRN activates ataxia telangiectasia mutated kinase ( ATM ) resulting in deposition of histone gamma-H2AX and in recruitment of the mediator of DNA damage checkpoint 1 ( MDC1 ) , RNF8 , RNF168 and 53BP1 .	Once recruited to a break, MRN activates ataxia telangiectasia mutated kinase (ATM) resulting in deposition of histone gamma-H2AX and in recruitment of the mediator of DNA damage checkpoint 1 (MDC1), RNF8, RNF168 and 53BP1.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	6	7	8	11
DSBs , generated by genotoxic agents such as ionizing radiation , are first sensed by the MRN complex , which then recruits ATM to sites of damage via the C-terminal ATM-interaction domain of Nbs1 and promotes ATM kinase activation .	DSBs, generated by genotoxic agents such as ionizing radiation, are first sensed by the MRN complex, which then recruits ATM to sites of damage via the C-terminal ATM-interaction domain of Nbs1 and promotes ATM kinase activation.	16	38	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	16	17	36	37
Nbs1 also contains a C-terminal ATM binding domain that promotes MRN mediated activation of ATM .	Nbs1 also contains a C-terminal ATM binding domain that promotes MRN mediated activation of ATM.	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	10	11	14	15
Complementation of the NBS cell line with the wild-type NBS1 restored ATM localization to laser induced DSBs ( XREF_FIG ) .	Complementation of the NBS cell line with the wild-type NBS1 restored ATM localization to laser induced DSBs (XREF_FIG).	5	12	restored	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	9	10	11	12
Different studies identified a number of ATM targets including c-abl , TP53 , CHK-2 , NBS1 and BRCA1 ( Shiloh , 2003 ) .	Different studies identified a number of ATM targets including c-abl, TP53, CHK-2, NBS1 and BRCA1 (Shiloh, 2003).	6	16	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	15	16	6	7
Following DSBs in DNA , Nbs1 interacts with phosphorylated H2AX ( gammaH2AX ) and is responsible for the nuclear translocation of the Mre11 and Rad50 repair complex to the sites of DNA damage to sense DNA strand breaks and activate ATM XREF_BIBR , XREF_BIBR , XREF_BIBR .	Following DSBs in DNA, Nbs1 interacts with phosphorylated H2AX (gammaH2AX) and is responsible for the nuclear translocation of the Mre11 and Rad50 repair complex to the sites of DNA damage to sense DNA strand breaks and activate ATM XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	5	6	40	41
Consistent with previous results , the incubation of dimeric ATM with MRN caused HA-ATM to dissociate into the supernatant ( XREF_FIG ) .	Consistent with previous results, the incubation of dimeric ATM with MRN caused HA-ATM to dissociate into the supernatant (XREF_FIG).	6	14	caused	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	HA-ATM	HA-ATM	HA-ATM	11	12	13	14
The re-expression of wild-type NBS1 in these cells resulted in enhanced ATM activation and the recruitment of activated ATM to DSBs .	The re-expression of wild-type NBS1 in these cells resulted in enhanced ATM activation and the recruitment of activated ATM to DSBs.	1	13	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	NBS1	re-expression of wild-type NBS1	nbs1	ATM	ATM	atm	4	5	11	12
In this context , we draw a distinction between ATM activation and ATM activities : in the former circumstance , a properly assembled and localized complex is required for ATM activation whereas in the latter , Nbs1 potentiates ATM activity by promoting access of the active kinase to its downstream effectors .	In this context, we draw a distinction between ATM activation and ATM activities : in the former circumstance, a properly assembled and localized complex is required for ATM activation whereas in the latter, Nbs1 potentiates ATM activity by promoting access of the active kinase to its downstream effectors.	36	39	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	36	37	38	39
ATM is also activated by oxidation in an MRN independent manner .	ATM is also activated by oxidation in an MRN independent manner.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	8	9	0	1
MRN binds to DSBs and leads to further activation of ATM [ XREF_BIBR , XREF_BIBR ] .	MRN binds to DSBs and leads to further activation of ATM [XREF_BIBR, XREF_BIBR].	0	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	10	11
Although MRN complex activate ATM kinase 3 , deletion of Nbs1 retained accumulation of Mre11 at cytoplasmic compartment , presumably inactivating the MRN function 36 ( see XREF_FIG ) .	Although MRN complex activate ATM kinase 3, deletion of Nbs1 retained accumulation of Mre11 at cytoplasmic compartment, presumably inactivating the MRN function 36 (see XREF_FIG).	1	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	4	5
MRN complex also activates ATM kinase in response to DSBs .	MRN complex also activates ATM kinase in response to DSBs.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	4	5
A forward chemical genetic screen identified Mirin ( XREF_FIG ) , a molecule that inhibits MRN dependent activation of ATM and blocks the Mre11 exonuclease activity .	A forward chemical genetic screen identified Mirin (XREF_FIG), a molecule that inhibits MRN dependent activation of ATM and blocks the Mre11 exonuclease activity.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	15	16	19	20
Mirin prevents MRN dependent activation of ATM without affecting ATM protein kinase activity , and it inhibits Mre11 associated exonuclease activity .	Mirin prevents MRN dependent activation of ATM without affecting ATM protein kinase activity, and it inhibits Mre11 associated exonuclease activity.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	2	3	6	7
The first phase is initiated by sensor proteins belonging to the MRN complex , that activate the ATM protein which target HRR proteins to obtain the second response phase -- repair .	The first phase is initiated by sensor proteins belonging to the MRN complex, that activate the ATM protein which target HRR proteins to obtain the second response phase -- repair.	11	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	17	18
MRN complex recruits ATM to broken DNA molecules and fully activates ATM .	MRN complex recruits ATM to broken DNA molecules and fully activates ATM.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	11	12
In addition , the MRN complex at the sites of DSBs promotes the activation of the ATM kinase which is mutated in the genetic disease Ataxia-telangiectasia ( A-T ) XREF_BIBR , XREF_BIBR .	In addition, the MRN complex at the sites of DSBs promotes the activation of the ATM kinase which is mutated in the genetic disease Ataxia-telangiectasia (A-T) XREF_BIBR, XREF_BIBR.	4	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	4	5	16	17
Nbs1 is required to activate ATM and is also a substrate for ATM kinase activity .	Nbs1 is required to activate ATM and is also a substrate for ATM kinase activity.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	0	1	5	6
In ILB1 cells there was a very modest increase in the amount of ATM present at these sites over time , consistent with the evidence that NBN stimulates the activation of ATM but is not obligatory for its activation ( XREF_FIG , first panel ) .	In ILB1 cells there was a very modest increase in the amount of ATM present at these sites over time, consistent with the evidence that NBN stimulates the activation of ATM but is not obligatory for its activation (XREF_FIG, first panel).	26	32	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NBN	NBN	NBN	ATM	ATM	ATM	26	27	31	32
MRE11 is a component of the MRN complex , and ATM binds to and is activated by the MRN complex .	MRE11 is a component of the MRN complex, and ATM binds to and is activated by the MRN complex.	10	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	18	19	10	11
In contrast , neither MRN ( Mre11-Rad50-Nbs1 ) nor ATM ( ataxia-telangiectasia mutated ) , contributes to the initial response to S23906 .	In contrast, neither MRN (Mre11-Rad50-Nbs1) nor ATM (ataxia-telangiectasia mutated), contributes to the initial response to S23906.	3	16	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	4	5	9	10
As Nbs1 is important for activation of ATM following DSBs XREF_BIBR , XREF_BIBR , we considered that this factor might also affect end utilization .	As Nbs1 is important for activation of ATM following DSBs XREF_BIBR, XREF_BIBR, we considered that this factor might also affect end utilization.	1	10	is important for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	1	2	7	8
MRN functions to activate ATM , and thus the primary function of MRN in V ( D ) J recombination may be to activate ATM in response to Rag mediated DSBs .	MRN functions to activate ATM, and thus the primary function of MRN in V (D) J recombination may be to activate ATM in response to Rag mediated DSBs.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	4	5
The assembly of virus genomes in nascent domains within the nucleus triggers the MRN independent activation of ATM .	The assembly of virus genomes in nascent domains within the nucleus triggers the MRN independent activation of ATM.	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	13	14	17	18
While recent work on the cellular level has indicated that MRN activates ATM , the biochemical relationship between these proteins has yet to be fully understood .	While recent work on the cellular level has indicated that MRN activates ATM, the biochemical relationship between these proteins has yet to be fully understood.	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	10	11	12	13
In the S-phase checkpoint response and in meiosis , Nbs1 activates ATM , and ATM then performs a wide variety of functions , including phosphorylating H2AX .	In the S-phase checkpoint response and in meiosis, Nbs1 activates ATM, and ATM then performs a wide variety of functions, including phosphorylating H2AX.	9	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	9	10	11	12
Our results provide molecular insights into how Skp2 and the MRN complex coordinate to activate ATM , and identify Skp2-mediatetd NBS1 ubiquitination as a vital event for ATM activation in response to DNA damage .	Our results provide molecular insights into how Skp2 and the MRN complex coordinate to activate ATM, and identify Skp2-mediatetd NBS1 ubiquitination as a vital event for ATM activation in response to DNA damage.	10	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	10	11	15	16
Further , L1CAM , via c-Myc , regulates expression of NBS1 , a critical component of the MRE11-RAD50-NBS1 ( MRN ) complex that activates ataxia telangiectasia mutated ( ATM ) kinase and early checkpoint response .	Further, L1CAM, via c-Myc, regulates expression of NBS1, a critical component of the MRE11-RAD50-NBS1 (MRN) complex that activates ataxia telangiectasia mutated (ATM) kinase and early checkpoint response.	8	27	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	NBS1	expression of NBS1	nbs1	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	10	11	24	27
The MRN complex also aides in the activation of the DNA damage kinase ATM .	The MRN complex also aides in the activation of the DNA damage kinase ATM.	1	14	aides	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	13	14
Another function of the MRN complex is to activate ATM , a crucial mediator of the cellular response to DNA damage .	Another function of the MRN complex is to activate ATM, a crucial mediator of the cellular response to DNA damage.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	4	5	9	10
ATM is also activated by oxidative stress independently of DSBs , MRN or CHK2 , although the downstream pathways reliant on this ATM activation are unclear .	ATM is also activated by oxidative stress independently of DSBs, MRN or CHK2, although the downstream pathways reliant on this ATM activation are unclear.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	0	1
Here we show that MRN binds to viral genomes and activates a localized ATM anti-viral response that prevents viral replication at the earliest stages .	Here we show that MRN binds to viral genomes and activates a localized ATM anti-viral response that prevents viral replication at the earliest stages.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	4	5	13	14
Here we identify such an allele and characterize the responses of ATM that rely on MRN dependent activation of ATM .	Here we identify such an allele and characterize the responses of ATM that rely on MRN dependent activation of ATM.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	15	16	19	20
As expected , Mirin inhibits MRN dependent activation of ATM and homology dependent repair of DSBs [ XREF_BIBR ] .	As expected, Mirin inhibits MRN dependent activation of ATM and homology dependent repair of DSBs [XREF_BIBR].	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	5	6	9	10
In response to cellular genome breaks , MRE11/RAD50/NBS1 ( MRN ) activates a global ATM DNA damage response ( DDR ) that prevents cellular replication .	In response to cellular genome breaks, MRE11/RAD50/NBS1 (MRN) activates a global ATM DNA damage response (DDR) that prevents cellular replication.	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	9	10	14	15
XREF_BIBR The MRN ( Mre11-Rad50-Nbs1 ) complex stimulates the kinase activity of ATM , especially in the presence of double stranded DNA ends .	XREF_BIBR The MRN (Mre11-Rad50-Nbs1) complex stimulates the kinase activity of ATM, especially in the presence of double stranded DNA ends.	2	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	2	3	12	13
However , adenoviral proteins such as the E1B-55K and E4ORF6 complex not only degrade p53 but also block signaling through degradation of the MRN ( Mre11/RAD50/NBS1 ) complex which activates ATM .	However, adenoviral proteins such as the E1B-55K and E4ORF6 complex not only degrade p53 but also block signaling through degradation of the MRN (Mre11/RAD50/NBS1) complex which activates ATM.	23	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	23	24	30	31
More specifically , mirin was found to block the MRN dependent activation of ATM without affecting the kinase activity and to abolish MRE11 nuclease activity ( 100 microM ) .	More specifically, mirin was found to block the MRN dependent activation of ATM without affecting the kinase activity and to abolish MRE11 nuclease activity (100 microM).	9	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	9	10	13	14
NBS1 is a subunit in the MRN complex that activates ATM in response to DSB XREF_BIBR - XREF_BIBR .	NBS1 is a subunit in the MRN complex that activates ATM in response to DSB XREF_BIBR - XREF_BIBR.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	6	7	10	11
We have also demonstrated that ATM can be activated by oxidative stress independently of MRN or DNA damage .	We have also demonstrated that ATM can be activated by oxidative stress independently of MRN or DNA damage.	5	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	14	15	5	6
The S-phase checkpoint also required NBS1 phosphorylation by ATR , while NBS1 modulated ATM in its response to the combination treatment .	The S-phase checkpoint also required NBS1 phosphorylation by ATR, while NBS1 modulated ATM in its response to the combination treatment.	11	14	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	11	12	13	14
We therefore tested the effect of mirin , which prevents MRN dependent activation of ATM without affecting ATM protein kinase activity and it inhibits Mre11 associated exonuclease activity XREF_BIBR , XREF_BIBR .	We therefore tested the effect of mirin, which prevents MRN dependent activation of ATM without affecting ATM protein kinase activity and it inhibits Mre11 associated exonuclease activity XREF_BIBR, XREF_BIBR.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	10	11	14	15
Our studies of the effects of MRN on ATM activity in vitro indicated that MRN stimulates ATM through multiple protein protein contacts , and that this interaction increases the affinity of ATM for its substrates .	Our studies of the effects of MRN on ATM activity in vitro indicated that MRN stimulates ATM through multiple protein protein contacts, and that this interaction increases the affinity of ATM for its substrates.	14	17	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	14	15	16	17
MRN makes multiple contacts with ATM and appears to stimulate ATM activity by facilitating the stable binding of substrates .	MRN makes multiple contacts with ATM and appears to stimulate ATM activity by facilitating the stable binding of substrates.	0	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	10	11
At low doses of radiation the presence of functional MRN complex enhances activation of ATM , although there are also MRN independent mechanisms of ATM activation .	At low doses of radiation the presence of functional MRN complex enhances activation of ATM, although there are also MRN independent mechanisms of ATM activation.	9	15	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	9	10	14	15
Also Rad50 in the model is a subunit of the MRN complex , which solely activates ATM .	Also Rad50 in the model is a subunit of the MRN complex, which solely activates ATM.	10	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	10	11	16	17
The MRN complex in turn can further stimulate ATM activity leading to rapid spreading of gamma-H2AX around the DNA break , and therefore the amplification of the DDR signal .	The MRN complex in turn can further stimulate ATM activity leading to rapid spreading of gamma-H2AX around the DNA break, and therefore the amplification of the DDR signal.	1	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	8	9
These results suggest that MRN dependent generation of ssDNA oligos , which constitute a unique signal of ongoing DSB repair not encountered in normal DNA metabolism , stimulates ATM activity .	These results suggest that MRN dependent generation of ssDNA oligos, which constitute a unique signal of ongoing DSB repair not encountered in normal DNA metabolism, stimulates ATM activity.	4	29	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	4	5	28	29
Moreover , ATM , which is activated after DNA damage by the MRN complex , is activated by Aurora B in mitosis in the absence of either DNA damage or the MRN complex .	Moreover, ATM, which is activated after DNA damage by the MRN complex, is activated by Aurora B in mitosis in the absence of either DNA damage or the MRN complex.	2	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	12	13	2	3
In addition to its role in tethering DNA ends , the MRN complex also recruits and activates the catalytic function of the ATM protein kinase through direct interaction of ATM and Nbs1 [ XREF_BIBR , XREF_BIBR ] .	In addition to its role in tethering DNA ends, the MRN complex also recruits and activates the catalytic function of the ATM protein kinase through direct interaction of ATM and Nbs1 [XREF_BIBR, XREF_BIBR].	11	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	22	23
A preference for long DNA molecules is also observed with MRN stimulation of ATM .	A preference for long DNA molecules is also observed with MRN stimulation of ATM.	10	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	10	11	13	14
The MRE11-RAD50-NBS1 ( MRN ) complex ( Rad32-Rad50-Nbs1 in Schizosaccharomyces pombe ) recruits and activates the checkpoint kinase ataxia telangiectasia mutated ( ATM ; Tel1 in S. pombe ) at sites of double stranded breaks ( DSBs ) via its DSB unwinding and nucleolytic activities .	The MRE11-RAD50-NBS1 (MRN) complex (Rad32-Rad50-Nbs1 in Schizosaccharomyces pombe) recruits and activates the checkpoint kinase ataxia telangiectasia mutated (ATM; Tel1 in S. pombe) at sites of double stranded breaks (DSBs) via its DSB unwinding and nucleolytic activities.	1	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	3	4	18	21
Mirin prevents MRN dependent activation of ATM without affecting ATM protein kinase activity and inhibits Mre11 associated exonuclease activity .	Mirin prevents MRN dependent activation of ATM without affecting ATM protein kinase activity and inhibits Mre11 associated exonuclease activity.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	2	3	6	7
We found that six representative homeodomain proteins ( NKX3.1 , NKX2.2 , TTF1 , NKX2.5 , HOXB7 , and CDX2 ) physically and functionally interact with ATM and with the Mre11-Rad50-Nbs1 ( MRN ) complex that activates ATM in combination with DNA double-strand breaks .	We found that six representative homeodomain proteins (NKX3.1, NKX2.2, TTF1, NKX2.5, HOXB7, and CDX2) physically and functionally interact with ATM and with the Mre11-Rad50-Nbs1 (MRN) complex that activates ATM in combination with DNA double-strand breaks.	32	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	32	33	37	38
In contrast , similarly high levels of the DelCC MRN mutant could not activate ATM ( XREF_FIG E ) , indicating that the coils are essential for MRN stimulation of ATM .	In contrast, similarly high levels of the DelCC MRN mutant could not activate ATM (XREF_FIG E), indicating that the coils are essential for MRN stimulation of ATM.	27	31	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	27	28	30	31
The Y2755A mutant ATM protein was tested in an MRN and DNA dependent assay , and was found to be unable to phosphorylate p53 in the presence of N6-( furfuryl )-ATP alone , demonstrating that MRN requires ATP to activate ATM ( XREF_FIG D ) .	The Y2755A mutant ATM protein was tested in an MRN and DNA dependent assay, and was found to be unable to phosphorylate p53 in the presence of N6-(furfuryl)-ATP alone, demonstrating that MRN requires ATP to activate ATM (XREF_FIG D).	35	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	35	36	40	41
In response to DNA damage , a protein complex which contains MRE11 , RAD50 , and NBS1 ( MRN complex ) binds to and activates ATM protein kinase which initiates a downstream signal transduction cascade essential for coordinating cell cycle progression with DNA repair .	In response to DNA damage, a protein complex which contains MRE11, RAD50, and NBS1 (MRN complex) binds to and activates ATM protein kinase which initiates a downstream signal transduction cascade essential for coordinating cell cycle progression with DNA repair.	18	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	18	19	25	26
DSBs are detected by the Mre , Rad , and NBS1 complex which activates ATM for NHEJ repairs ( blue box ) .	DSBs are detected by the Mre, Rad, and NBS1 complex which activates ATM for NHEJ repairs (blue box).	10	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	10	11	14	15
NBS1 activates ATM as part of the MRN complex that consists of Mre11 ( the exonuclease mutated in ataxia telangiectasia like disorder , ATLD ) , Rad50 , and NBS1 .	NBS1 activates ATM as part of the MRN complex that consists of Mre11 (the exonuclease mutated in ataxia telangiectasia like disorder, ATLD), Rad50, and NBS1.	0	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	0	1	2	3
NBS1 , H2AX , the checkpoint kinase CHK2 , and the trimeric replication protein A ( RPA ) are important downstream targets of ATM .	NBS1, H2AX, the checkpoint kinase CHK2, and the trimeric replication protein A (RPA) are important downstream targets of ATM.	0	24	are important downstream targets	Positive_activation_copula_1	Positive_activation	Positive_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	0	1	23	24
Our studies reveal adenovirus infection as a powerful system to identify MRN independent mechanisms that activate ATM .	Our studies reveal adenovirus infection as a powerful system to identify MRN independent mechanisms that activate ATM.	11	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	16	17
The MRN complex is thought to activate ATM at DNA break sites .	The MRN complex is thought to activate ATM at DNA break sites.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	7	8
The first step is damage recognition involving the NBS1 mediated activation of ATM kinase by self phosphorylation , including a serine 1981 phosphorylation site [ XREF_BIBR ] .	The first step is damage recognition involving the NBS1 mediated activation of ATM kinase by self phosphorylation, including a serine 1981 phosphorylation site [XREF_BIBR].	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	8	9	12	13
It is possible that loss of MRN during AAV/Ad co-infection limits the ATM response during AAV infection .	It is possible that loss of MRN during AAV/Ad co-infection limits the ATM response during AAV infection.	4	13	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MRN	loss of MRN	mrn	ATM	ATM	atm	6	7	12	13
The MRN complex bound to DNA ends may directly activate ATM and/or initiate the nucleation of ATM at DSBs that leads to its activation .	The MRN complex bound to DNA ends may directly activate ATM and/or initiate the nucleation of ATM at DSBs that leads to its activation.	1	17	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	16	17
However , the C-terminal region of Nbs1 is sufficient to activate ATM in Nbs1 depleted Xenopus extracts .	However, the C-terminal region of Nbs1 is sufficient to activate ATM in Nbs1 depleted Xenopus extracts.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	6	7	11	12
Nbs1 could also be important for such ATM dependent mechanisms of end tethering , since Nbs1 activates ATM kinase activity following DSBs XREF_BIBR .	Nbs1 could also be important for such ATM dependent mechanisms of end tethering, since Nbs1 activates ATM kinase activity following DSBs XREF_BIBR.	15	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	15	16	17	18
RNF168 deficiency impairs 53BP1 mediated sustained signalling of ATM , a non canonical pathway complementing the canonical ATM activation cascade initiated by the MRN complex .	RNF168 deficiency impairs 53BP1 mediated sustained signalling of ATM, a non canonical pathway complementing the canonical ATM activation cascade initiated by the MRN complex.	17	24	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	23	24	17	18
The MRN complex is thought to be the sensor and initiator of the DSB response pathway , and activates ATM and downstream DSB signalling , by tethering broken DNA ends together and recruiting ATM which facilitates ATM activation .	The MRN complex is thought to be the sensor and initiator of the DSB response pathway, and activates ATM and downstream DSB signalling, by tethering broken DNA ends together and recruiting ATM which facilitates ATM activation.	1	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	19	20
Following DNA damage , ATM is activated and recruited by the MRN protein complex [ meiotic recombination 11 ( Mre11 )/DNA repair protein Rad50 and Nijmegen breakage syndrome 1 proteins ] to sites of DNA damage where ATM phosphorylates multiple substrates to trigger cell-cycle arrest .	Following DNA damage, ATM is activated and recruited by the MRN protein complex [meiotic recombination 11 (Mre11)/DNA repair protein Rad50 and Nijmegen breakage syndrome 1 proteins] to sites of DNA damage where ATM phosphorylates multiple substrates to trigger cell-cycle arrest.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	4	5
MRN senses replicating virus genomes and activates a local ATM DDR that prevents viral DNA replication .	MRN senses replicating virus genomes and activates a local ATM DDR that prevents viral DNA replication.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	9	10
In response to DSBs , ATM is directly activated by the MRN ( MRE11-RAD50-NBS1 ) complex , which is required to recruit ATM to DSBs , whereas ATR activation and recruitment to DSBs requires the formation of RPA coated SSBs , which arise from 5 '-3' resection of DSB ends .	In response to DSBs, ATM is directly activated by the MRN (MRE11-RAD50-NBS1) complex, which is required to recruit ATM to DSBs, whereas ATR activation and recruitment to DSBs requires the formation of RPA coated SSBs, which arise from 5 '-3' resection of DSB ends.	5	15	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	5	6
Further confirmation that phosphorylated NBS1 S432/3 mediates ATM signaling and C-NHEJ-mediated fusion of telomeres lacking TRF2 comes from our finding that endogenous phospho-NBS1 S432 co-localizes with Myc-MRE11 on dysfunctional telomeres in U2OS cells ( S5A ) .	Further confirmation that phosphorylated NBS1 S432/3 mediates ATM signaling and C-NHEJ-mediated fusion of telomeres lacking TRF2 comes from our finding that endogenous phospho-NBS1 S432 co-localizes with Myc-MRE11 on dysfunctional telomeres in U2OS cells (S5A).	3	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NBS1	phosphorylated NBS1	nbs1	ATM	ATM	atm	4	5	7	8
The MRN complex is believed to be the primary sensor of DSBs and promotes the activation of ATM kinase , which in turn initiates downstream DSB signalling .	The MRN complex is believed to be the primary sensor of DSBs and promotes the activation of ATM kinase, which in turn initiates downstream DSB signalling.	1	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	17	18
Nbs1 and ATMIN activate ATM in a DNA damage dependent and -independent manner , respectively XREF_BIBR , XREF_BIBR , XREF_BIBR .	Nbs1 and ATMIN activate ATM in a DNA damage dependent and -independent manner, respectively XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	0	1	4	5
We conclude that MRN activates a localized ATM DDR that restricts viral genome replication .	We conclude that MRN activates a localized ATM DDR that restricts viral genome replication.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	3	4	7	8
Another key function of the MRN complex is to trigger the monomerization of the inactive ATM dimer , resulting in an active , autophosphorylated monomer .	Another key function of the MRN complex is to trigger the monomerization of the inactive ATM dimer, resulting in an active, autophosphorylated monomer.	5	16	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	5	6	15	16
The MRN complex is recruited to the DNA damage site and activates ATM .	The MRN complex is recruited to the DNA damage site and activates ATM.	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	12	13
DSBs are recognized by the Mre11-Rad50-Nbs1 ( MRN ) complex , which promotes ATM activation at the sites of DNA damage [ XREF_BIBR ] .	DSBs are recognized by the Mre11-Rad50-Nbs1 (MRN) complex, which promotes ATM activation at the sites of DNA damage [XREF_BIBR].	7	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	7	8	13	14
The Mre11-Rad50-Nbs1 ( MRN ) complex senses DSBs and recruits and activates ATM .	The Mre11-Rad50-Nbs1 (MRN) complex senses DSBs and recruits and activates ATM.	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	3	4	12	13
It is worth noting that MRN complex further stimulates ATM activity , which results in a rapid spreading of gammaH2AX around the sites of DNA damage , and thereby amplifying DDR signal [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It is worth noting that MRN complex further stimulates ATM activity, which results in a rapid spreading of gammaH2AX around the sites of DNA damage, and thereby amplifying DDR signal [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	5	6	9	10
As Mre11 in the model is a subunit of the MRN complex , which solely activates ATM , the blocked pathways are the same as in the Ataxia telangiectasia simulation .	As Mre11 in the model is a subunit of the MRN complex, which solely activates ATM, the blocked pathways are the same as in the Ataxia telangiectasia simulation.	10	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	10	11	16	17
Loss of the C-terminal domain abrogated the effect of NKX3.1 on ATM activation by the MRN complex ( XREF_SUPPLEMENTARY ) , in contrast to the effect seen with the full-length NKX3.1 ( XREF_FIG ) .	Loss of the C-terminal domain abrogated the effect of NKX3.1 on ATM activation by the MRN complex (XREF_SUPPLEMENTARY), in contrast to the effect seen with the full-length NKX3.1 (XREF_FIG).	5	16	abrogated	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	MRN	MRN	MRN	ATM	ATM	ATM	15	16	11	12
MRN also activates ATM signaling , initiating the DNA damage response including cell cycle arrest .	MRN also activates ATM signaling, initiating the DNA damage response including cell cycle arrest.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	3	4
MRN targets TIP60 together with ATM to DNA where TIP60 interacts with trimethylated histone H3 to acetylate ATM and thereby promote ATM kinase activity [ XREF_BIBR , XREF_BIBR ] .	MRN targets TIP60 together with ATM to DNA where TIP60 interacts with trimethylated histone H3 to acetylate ATM and thereby promote ATM kinase activity [XREF_BIBR, XREF_BIBR].	0	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	21	22
XREF_BIBR DSBs are immediately sensed by the Mre11-Rad50-Nbs1 ( MRN ) complex and ATM is recruited by the C-terminus of Nbs1 , thereby activating ATM kinase .	XREF_BIBR DSBs are immediately sensed by the Mre11-Rad50-Nbs1 (MRN) complex and ATM is recruited by the C-terminus of Nbs1, thereby activating ATM kinase.	18	25	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	20	21	24	25
It has been suggested that the shift from the catalytically inactive dimer to the active monomeric form of ATM may be induced by chromatin alterations due to DNA breaks , and that interaction with the MRN complex ( MRE11/RAD50/NBN ) -- which is also a downstream target of ATM -- aids in this .	It has been suggested that the shift from the catalytically inactive dimer to the active monomeric form of ATM may be induced by chromatin alterations due to DNA breaks, and that interaction with the MRN complex (MRE11/RAD50/NBN) -- which is also a downstream target of ATM -- aids in this.	35	49	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	35	36	48	49
The MRE11-RAD50-NBS1 ( MRN ) complex detects DSBs and recruits ATM to promote ATM mediated gammaH2AX , which surrounds the DNA lesions and forms visualized foci XREF_BIBR , XREF_BIBR .	The MRE11-RAD50-NBS1 (MRN) complex detects DSBs and recruits ATM to promote ATM mediated gammaH2AX, which surrounds the DNA lesions and forms visualized foci XREF_BIBR, XREF_BIBR.	1	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	3	4	13	14
Phosphorylation of Nbs1 is critical for MRN stimulation of ATM activity toward Chk2 , but not p53 .	Phosphorylation of Nbs1 is critical for MRN stimulation of ATM activity toward Chk2, but not p53.	6	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	6	7	9	10
In summary , our study reveals that Skp2 has critical functions for allowing the MRN complex to recruit ATM to the DNA repair foci and to activate ATM .	In summary, our study reveals that Skp2 has critical functions for allowing the MRN complex to recruit ATM to the DNA repair foci and to activate ATM.	14	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	14	15	27	28
In response to DSBs , ATM is activated via recruitment to DNA lesions by the MRN complex and acetylation by TIP60 [ XREF_BIBR ] .	In response to DSBs, ATM is activated via recruitment to DNA lesions by the MRN complex and acetylation by TIP60 [XREF_BIBR].	5	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	15	16	5	6
MRN stimulates ATM activity in vitro leading to the activation of p53 and CHK2 , in a kinase assay with purified recombinant components .	MRN stimulates ATM activity in vitro leading to the activation of p53 and CHK2, in a kinase assay with purified recombinant components.	0	3	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	2	3
In contrast to the localized MRN dependent activation of ATM at virus genomes , global ATM phosphorylation has no impact on viral genome replication , capsid protein expression or total virus titres ( XREF_FIG , XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY ) .	In contrast to the localized MRN dependent activation of ATM at virus genomes, global ATM phosphorylation has no impact on viral genome replication, capsid protein expression or total virus titres (XREF_FIG, XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	5	6	9	10
Our results are in consistence with recent reports that MDM2 may negatively regulate genomic stability independent of p53 by directly binding to Nbs1 of the MRN complex to impair MRN complex mediated ATM activation and subsequent DNA damage response in other model systems XREF_BIBR - XREF_BIBR , XREF_BIBR .	Our results are in consistence with recent reports that MDM2 may negatively regulate genomic stability independent of p53 by directly binding to Nbs1 of the MRN complex to impair MRN complex mediated ATM activation and subsequent DNA damage response in other model systems XREF_BIBR - XREF_BIBR, XREF_BIBR.	29	33	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	29	30	32	33
MRN activates the ATM kinase , resulting in activation and coordination of subsequent checkpoint and repair processes .	MRN activates the ATM kinase, resulting in activation and coordination of subsequent checkpoint and repair processes.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	3	4
When ATM is activated by MRN , its phosphorylation level oscillates during DSBs repair , due to the activity of phosphatases [ XREF_BIBR ] .	When ATM is activated by MRN, its phosphorylation level oscillates during DSBs repair, due to the activity of phosphatases [XREF_BIBR].	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	5	6	1	2
These data would suggest that the MRN complex activates ATM in response to FEN1 inhibition but ATM is not required for H2AX phosphorylation in this situation .	These data would suggest that the MRN complex activates ATM in response to FEN1 inhibition but ATM is not required for H2AX phosphorylation in this situation.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	6	7	9	10
Tethering and concentrating the MRN complex in a small region of chromatin is sufficient to activate ATM in the absence of DNA damage XREF_BIBR .	Tethering and concentrating the MRN complex in a small region of chromatin is sufficient to activate ATM in the absence of DNA damage XREF_BIBR.	4	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	4	5	16	17
The Mre11/Rad50/NBS1 ( MRN ) protein complex and ATMIN protein mediate ATM kinase signaling in response to ionizing radiation ( IR ) and chromatin changes , respectively .	The Mre11/Rad50/NBS1 (MRN) protein complex and ATMIN protein mediate ATM kinase signaling in response to ionizing radiation (IR) and chromatin changes, respectively.	1	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	3	4	11	12
TRF2 has long been known to block MRN activated ATM signaling and recent data indicate that it acts through its ability to alter telomere structure into the t-loop configuration which has been proposed to block the MRN complex from accessing the telomere end .	TRF2 has long been known to block MRN activated ATM signaling and recent data indicate that it acts through its ability to alter telomere structure into the t-loop configuration which has been proposed to block the MRN complex from accessing the telomere end.	7	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	7	8	9	10
Subsequent studies have revealed that MRX and MRN drives the localization of Tel1 and ATM to the site of damage through direct interaction between Tel1 and ATM with Xrs2 and Nbs1 XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Subsequent studies have revealed that MRX and MRN drives the localization of Tel1 and ATM to the site of damage through direct interaction between Tel1 and ATM with Xrs2 and Nbs1 XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	5	17	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	7	8	14	15
L1CAM regulates expression of NBS1 , a critical component of the MRE11-RAD50-NBS1 ( MRN ) complex that activates ataxia telangiectasia mutated ( ATM ) kinase and early checkpoint response .	L1CAM regulates expression of NBS1, a critical component of the MRE11-RAD50-NBS1 (MRN) complex that activates ataxia telangiectasia mutated (ATM) kinase and early checkpoint response.	2	21	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	NBS1	expression of NBS1	nbs1	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	4	5	18	21
ATM is activated by MRN and further amplifies the signaling via phosphorylation of downstream transducers and effectors , such as H2AX and Chk2 [ XREF_BIBR ] .	ATM is activated by MRN and further amplifies the signaling via phosphorylation of downstream transducers and effectors, such as H2AX and Chk2 [XREF_BIBR].	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	4	5	0	1
It remains possible that other substrates of ATM may function directly in stabilizing coding ends but may not be phosphorylated and activated in MRN deficient cells as MRN is required to activate ATM .	It remains possible that other substrates of ATM may function directly in stabilizing coding ends but may not be phosphorylated and activated in MRN deficient cells as MRN is required to activate ATM.	27	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	27	28	32	33
DSB-repair-associated cell-cycle signalling occurs through NBS1 mediated activation of the ATM kinase .	DSB-repair-associated cell-cycle signalling occurs through NBS1 mediated activation of the ATM kinase.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	5	6	10	11
We show that MRN binds to adenovirus genomes and activates a localized ATM response that specifically prevents viral DNA replication .	We show that MRN binds to adenovirus genomes and activates a localized ATM response that specifically prevents viral DNA replication.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	3	4	12	13
The enhanced phosphorylation of Chk2 ( a downstream substrate of ATM ) 15 min after IR exposure of NBS1 comp ( + NBS1 ) cells ( XREF_FIG , top panel , lane 4 ) is consistent with the significantly enhanced IR induced NBS1 dependent activation of ATM at 15 min ( XREF_FIG , top panel ) .	The enhanced phosphorylation of Chk2 (a downstream substrate of ATM) 15 min after IR exposure of NBS1 comp (+ NBS1) cells (XREF_FIG, top panel, lane 4) is consistent with the significantly enhanced IR induced NBS1 dependent activation of ATM at 15 min (XREF_FIG, top panel).	40	47	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NBS1	IR induced NBS1	nbs1	ATM	ATM	atm	42	43	46	47
Although MRN complex can activate ATM kinase activity directly in an in vitro kinase assay and is critical for ATM activation in vivo upon DSBs , the mechanism of how MRN complex recruits ATM to the DNA repair foci for its activation upon genotoxic stress remains elusive .	Although MRN complex can activate ATM kinase activity directly in an in vitro kinase assay and is critical for ATM activation in vivo upon DSBs, the mechanism of how MRN complex recruits ATM to the DNA repair foci for its activation upon genotoxic stress remains elusive.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	5	6
A C-terminal 147-amino-acid fragment of Nbs1 that has the Mre11- and ATM binding domains can restore ATM activation in an Nbs1 depleted extract .	A C-terminal 147-amino-acid fragment of Nbs1 that has the Mre11- and ATM binding domains can restore ATM activation in an Nbs1 depleted extract.	3	17	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	5	6	16	17
A key function of the MRN complex is associated with the C-terminal domain of NBS1 protein , which recruits the protein kinase ataxia telangiectasia mutated ( ATM ) to the site of DSBs , therefore activating the ATM kinase function , initiating the signaling cascade [ XREF_BIBR ] .	A key function of the MRN complex is associated with the C-terminal domain of NBS1 protein, which recruits the protein kinase ataxia telangiectasia mutated (ATM) to the site of DSBs, therefore activating the ATM kinase function, initiating the signaling cascade [XREF_BIBR].	5	39	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	5	6	37	38
Hence , ATMIN and NBS1 mediate all ATM signaling by DSBs , and increased ATMIN dependent ATM signaling explains the different phenotypes of nbs1- and atm-mutant cells .	Hence, ATMIN and NBS1 mediate all ATM signaling by DSBs, and increased ATMIN dependent ATM signaling explains the different phenotypes of nbs1- and atm-mutant cells.	2	8	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	4	5	7	8
The first is proposed to be localized MRN mediated ATM activation associated with blocking of viral genome replication at the earliest stages of the viral life cycle , prior to MRN inhibition by viral proteins .	The first is proposed to be localized MRN mediated ATM activation associated with blocking of viral genome replication at the earliest stages of the viral life cycle, prior to MRN inhibition by viral proteins.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	7	8	9	10
Interestingly , this ATP bound state has been implicated in unwinding DNA ends , and is required for MRN mediated ATM activation in vitro .	Interestingly, this ATP bound state has been implicated in unwinding DNA ends, and is required for MRN mediated ATM activation in vitro.	18	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	18	19	20	21
However , the fact that ATM can be activated by IR treatment in cells lacking Nbs1 or BRCA1 but can not be recruited to the DSB sites suggests that the MRN complex may increase the accumulation of ATM at the DSB sites on the chromatin XREF_BIBR , XREF_BIBR but other factors can activate ATM activity in an MRN independent manner .	However, the fact that ATM can be activated by IR treatment in cells lacking Nbs1 or BRCA1 but can not be recruited to the DSB sites suggests that the MRN complex may increase the accumulation of ATM at the DSB sites on the chromatin XREF_BIBR, XREF_BIBR but other factors can activate ATM activity in an MRN independent manner.	30	38	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	30	31	37	38
NBS1 associates with ATM via its C-terminal region , which promotes the recruitment of ATM to DSBs , where ATM is activated by the MRN complex by yet to be defined mechanisms possibly involving the formation of ssDNA oligos during end resection ( XREF_FIG ) .	NBS1 associates with ATM via its C-terminal region, which promotes the recruitment of ATM to DSBs, where ATM is activated by the MRN complex by yet to be defined mechanisms possibly involving the formation of ssDNA oligos during end resection (XREF_FIG).	19	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	24	25	19	20
The MRN complex activates ATM in response to DSBs by recruiting it to the sites of damage .	The MRN complex activates ATM in response to DSBs by recruiting it to the sites of damage.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	4	5
In response to DNA damage , ATM signalling is mediated by the MRN complex , which forms foci at sites of DSBs , facilitating interactions between ATM and Nbs1 XREF_BIBR , and thereby enhancing ATM phosphorylation .	In response to DNA damage, ATM signalling is mediated by the MRN complex, which forms foci at sites of DSBs, facilitating interactions between ATM and Nbs1 XREF_BIBR, and thereby enhancing ATM phosphorylation.	6	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	12	13	6	7
In yeast , mouse , and Drosophila melanogaster , Nbs1 activation of ATM has been shown to inhibit Spo11 activity , thus providing a negative feedback loop to control DSB formation .	In yeast, mouse, and Drosophila melanogaster, Nbs1 activation of ATM has been shown to inhibit Spo11 activity, thus providing a negative feedback loop to control DSB formation.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	9	10	12	13
The MRN complex activates the ATM kinase , which explains the similarity in cellular phenotypes of both syndromes [ XREF_BIBR , XREF_BIBR ] .	The MRN complex activates the ATM kinase, which explains the similarity in cellular phenotypes of both syndromes [XREF_BIBR, XREF_BIBR].	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	5	6
Telomeres rendered dysfunctional from the removal of TRF2 signals through the MRN complex , which activates ATM to promote C-NHEJ-mediated repair .	Telomeres rendered dysfunctional from the removal of TRF2 signals through the MRN complex, which activates ATM to promote C-NHEJ-mediated repair.	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	16	17
ATM is activated in response to DNA damage by the MRN complex and it plays a key role in DDR ( XREF_FIG and XREF_FIG ) .	ATM is activated in response to DNA damage by the MRN complex and it plays a key role in DDR (XREF_FIG and XREF_FIG).	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	10	11	0	1
In response to DSBs , ATM is conically activated by the MRN ( Mre11 , Rad50 , Nbs1 ) complex , which serves as a sensor of DNA damage , and by acetylation via the TIP60 acetyltransferase [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	In response to DSBs, ATM is conically activated by the MRN (Mre11, Rad50, Nbs1) complex, which serves as a sensor of DNA damage, and by acetylation via the TIP60 acetyltransferase [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] (XREF_FIG).	5	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	5	6
The MRN complex stimulates the kinase activity of ATM [ XREF_BIBR ] and participates in 5 ' --> 3 ' resection .	The MRN complex stimulates the kinase activity of ATM [XREF_BIBR] and participates in 5 ' --> 3 ' resection.	1	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	8	9
We propose that conformational changes in the MRN complex that occur upon binding to damaged DNA are transmitted through the FXF and Y-HEAT interface to activate ATM .	We propose that conformational changes in the MRN complex that occur upon binding to damaged DNA are transmitted through the FXF and Y-HEAT interface to activate ATM.	7	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	7	8	26	27
This is consistent with the fact that the MRN complex is needed to activate ATM .	This is consistent with the fact that the MRN complex is needed to activate ATM.	8	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	8	9	14	15
In other words , nuclease defective MRN that can localize to DSBs can still activate ATM , but its lack of nuclease activity may prevent the accumulation of ssDNA oligonucleotides that amplify the ATM signal to detectable levels .	In other words, nuclease defective MRN that can localize to DSBs can still activate ATM, but its lack of nuclease activity may prevent the accumulation of ssDNA oligonucleotides that amplify the ATM signal to detectable levels.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	6	7	15	16
Using Mus musculus cells harboring targeted mutant alleles of Mre11 and/or Ku70 , together with pharmacologic kinase inhibition we demonstrate that ATM can in fact be activated by DSBs in the absence of MRN .	Using Mus musculus cells harboring targeted mutant alleles of Mre11 and/or Ku70, together with pharmacologic kinase inhibition we demonstrate that ATM can in fact be activated by DSBs in the absence of MRN.	21	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	33	34	21	22
The MRN complex acts as a DNA damage sensor , maintains genome stability during DNA replication , promotes homology dependent DNA repair and activates ATM .	The MRN complex acts as a DNA damage sensor, maintains genome stability during DNA replication, promotes homology dependent DNA repair and activates ATM.	1	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	24	25
Since ATM kinase is activated by the MRN complex at the DNA damage site this provides a simple explanation for the transient nature of B-Myb recruitment to these sites .	Since ATM kinase is activated by the MRN complex at the DNA damage site this provides a simple explanation for the transient nature of B-Myb recruitment to these sites.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	7	8	1	2
A prior report suggesting that mutant p53 actually blocked MRN activation of ATM and the G2/M checkpoint did not , however , address the effect of ATM on mutant p53 abundance .	A prior report suggesting that mutant p53 actually blocked MRN activation of ATM and the G2/M checkpoint did not, however, address the effect of ATM on mutant p53 abundance.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	9	10	12	13
MRN functions to target ATM and the Tip60 acetyltransferase to DSBs .	MRN functions to target ATM and the Tip60 acetyltransferase to DSBs.	0	8	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	4	5
It is known that the MRN complex containing nuclease-inactive Mre11 fails to promote ATM activation .	It is known that the MRN complex containing nuclease-inactive Mre11 fails to promote ATM activation.	5	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	5	6	13	14
In purified systems , MRN may still activate ATM , but the absence of the normal mechanism for ATM inactivation may reduce or eliminate the normal in vivo requirement for acetylation of ATM by Tip60 .	In purified systems, MRN may still activate ATM, but the absence of the normal mechanism for ATM inactivation may reduce or eliminate the normal in vivo requirement for acetylation of ATM by Tip60.	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	4	5	8	9
We hypothesized that the assembly of virus genome domains within the nucleus ( XREF_FIG ) triggers the MRN independent activation of ATM .	We hypothesized that the assembly of virus genome domains within the nucleus (XREF_FIG) triggers the MRN independent activation of ATM.	17	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	17	18	21	22
The DDR is initiated by proteins that directly bind to DNA DSBs such as Ku70 and Ku80 , which activate DNA-PKcs and the MRN complex , which activates ATM .	The DDR is initiated by proteins that directly bind to DNA DSBs such as Ku70 and Ku80, which activate DNA-PKcs and the MRN complex, which activates ATM.	23	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	23	24	28	29
MRN deficient cells do not activate ATM when TRF2 is removed from telomeres .	MRN deficient cells do not activate ATM when TRF2 is removed from telomeres.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	6	7
While the exact details of ATM activation by the MRN complex are not fully understood , the function of MRN as a sensor of DNA damage provides insight .	While the exact details of ATM activation by the MRN complex are not fully understood, the function of MRN as a sensor of DNA damage provides insight.	5	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	9	10	5	6
The signaling triggered by DSBs specifically involves the MRE11/RAD50/NBS1 ( MRN ) complex , which activates the Ataxia telangiectasia mutated ( ATM ) kinase upon its recruitment to DSBs .	The signaling triggered by DSBs specifically involves the MRE11/RAD50/NBS1 (MRN) complex, which activates the Ataxia telangiectasia mutated (ATM) kinase upon its recruitment to DSBs.	10	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	Ataxia telangiectasia mutated	Ataxia telangiectasia mutated	Ataxia telangiectasia mutated	10	11	17	20
The equivalent W248R allele in fission yeast allows Mre11 to form an MRN complex that efficiently binds double-strand breaks , activates Tel1 and ATM and maintains telomeres ; yet , it causes hypersensitivity to ionizing radiation and collapsed replication forks , increased Rad52 foci , defective Chk1 signaling and meiotic failure .	The equivalent W248R allele in fission yeast allows Mre11 to form an MRN complex that efficiently binds double-strand breaks, activates Tel1 and ATM and maintains telomeres; yet, it causes hypersensitivity to ionizing radiation and collapsed replication forks, increased Rad52 foci, defective Chk1 signaling and meiotic failure.	12	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	12	13	23	24
Recently it was reported that ubiquitination of NBS1 by SCF-Skp2 E3 ligase trigger the recruitment and activation of ATM on DSB formed upon IR treatment .	Recently it was reported that ubiquitination of NBS1 by SCF-Skp2 E3 ligase trigger the recruitment and activation of ATM on DSB formed upon IR treatment.	5	19	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NBS1	ubiquitination of NBS1	nbs1	ATM	ATM	atm	7	8	18	19
In response to DSBs , the MRN complex activates two PIKK kinases : ATM and ATR .	In response to DSBs, the MRN complex activates two PIKK kinases : ATM and ATR.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	6	7	13	14
Nbs1 is critical for activation of ATM , but little is known about the binding of Nbs1 to the MR complex , how the Rad50 coils and hook affect this interaction , and whether ATP regulates Nbs1 association .	Nbs1 is critical for activation of ATM, but little is known about the binding of Nbs1 to the MR complex, how the Rad50 coils and hook affect this interaction, and whether ATP regulates Nbs1 association.	0	7	is critical for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	0	1	6	7
MRN mediated ATM stimulation regulates DNA end resection .	MRN mediated ATM stimulation regulates DNA end resection.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	2	3
Once ATM is activated by MRN , its phosphorylation level oscillates during the repair process , due to the activity of different phosphatases [ XREF_BIBR ] .	Once ATM is activated by MRN, its phosphorylation level oscillates during the repair process, due to the activity of different phosphatases [XREF_BIBR].	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	5	6	1	2
Failure of proper DSBs repair would initial apoptosis , and MRN complex deficiency induced apoptosis by activating ATM and the corresponding downstream pathway [ XREF_BIBR , XREF_BIBR ] .	Failure of proper DSBs repair would initial apoptosis, and MRN complex deficiency induced apoptosis by activating ATM and the corresponding downstream pathway [XREF_BIBR, XREF_BIBR].	10	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	10	11	17	18
Once located at the DSB , MRN activates the ATM kinase and tethers the DNA ends .	Once located at the DSB, MRN activates the ATM kinase and tethers the DNA ends.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	6	7	9	10
MRN promotes monomerization of ATM and increases the affinity of ATM for its substrates .	MRN promotes monomerization of ATM and increases the affinity of ATM for its substrates.	0	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	10	11
ATM is rapidly activated by the binding of MRN to DSBs , and in turn , ATM phosphorylates MRN and several downstream effectors of DSB repair .	ATM is rapidly activated by the binding of MRN to DSBs, and in turn, ATM phosphorylates MRN and several downstream effectors of DSB repair.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	8	9	0	1
Although Nbs1 is a phosphorylation target of ATM , some evidence suggests that it also acts upstream of ATM in the DSB response pathway .	Although Nbs1 is a phosphorylation target of ATM, some evidence suggests that it also acts upstream of ATM in the DSB response pathway.	1	8	is a phosphorylation target	Positive_activation_copula_1	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	1	2	7	8
gamma-H2AX , a known marker of DSBs , is highly expressed following radiation and plays vital roles in initiating DNA damage response by interaction with the MRE11-RAD50-NBS1 ( MRN ) complex , which activates the ataxia telangiectasia mutated ( ATM ) kinase and/or ataxia telangiectasia and Rad3 related ( ATR ) kinase [ XREF_BIBR ] .	gamma-H2AX, a known marker of DSBs, is highly expressed following radiation and plays vital roles in initiating DNA damage response by interaction with the MRE11-RAD50-NBS1 (MRN) complex, which activates the ataxia telangiectasia mutated (ATM) kinase and/or ataxia telangiectasia and Rad3 related (ATR) kinase [XREF_BIBR].	28	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	28	29	35	38
Here we show that Skp2 E3 ligase is a key component for the MRN complex mediated ATM activation in response to DSBs .	Here we show that Skp2 E3 ligase is a key component for the MRN complex mediated ATM activation in response to DSBs.	13	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	13	14	16	17
Mirin is an inhibitor of MRE11 exonuclease activity that also blocks MRN activation of ATM during dsDNA break repair [ XREF_BIBR , XREF_BIBR ] .	Mirin is an inhibitor of MRE11 exonuclease activity that also blocks MRN activation of ATM during dsDNA break repair [XREF_BIBR, XREF_BIBR].	11	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	14	15
The MRN complex isolated from the extract containing DSBs is bound to ssDNA oligos and stimulates ATM activity .	The MRN complex isolated from the extract containing DSBs is bound to ssDNA oligos and stimulates ATM activity.	1	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	1	2	16	17
Additionally , the MRN complex can activate and signal via the ATM kinase , allowing ATM to regulate MRE11 nuclease to promote DNA microhomology mediated end joining over degradation .	Additionally, the MRN complex can activate and signal via the ATM kinase, allowing ATM to regulate MRE11 nuclease to promote DNA microhomology mediated end joining over degradation.	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	3	4	15	16
The Nbs1 interaction with Mre11 is critical for MRN localization to the nucleus and DSBs [ XREF_BIBR , XREF_BIBR ] and the interaction with ATM is critical for MRN dependent activation of ATM following DSBs [ XREF_BIBR , XREF_BIBR ] .	The Nbs1 interaction with Mre11 is critical for MRN localization to the nucleus and DSBs [XREF_BIBR, XREF_BIBR] and the interaction with ATM is critical for MRN dependent activation of ATM following DSBs [XREF_BIBR, XREF_BIBR].	28	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	28	29	32	33
In this respect , the MRN complex induces the ATM DNA-damage response to facilitate the repair of damaged DNA at early stages of DNA damage 58 , whereas if the damaged DNA can not be repaired , FOXO3 triggers a cell death program by promoting the ATM-Chk2-p53 apoptotic mechanism .	In this respect, the MRN complex induces the ATM DNA-damage response to facilitate the repair of damaged DNA at early stages of DNA damage 58, whereas if the damaged DNA can not be repaired, FOXO3 triggers a cell death program by promoting the ATM-Chk2-p53 apoptotic mechanism.	5	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	5	6	9	10
It has been shown that NBS1-ATM interaction is crucial for the MRN mediated ATM recruitment to DSBs .	It has been shown that NBS1-ATM interaction is crucial for the MRN mediated ATM recruitment to DSBs.	10	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	13	14
XREF_BIBR The nuclease activity of the MRN complex results in 3 ' ssDNA which along with its interaction with the C-terminus of Nbs1 stimulates ATM kinase activity and ultimately promotes homologous recombination ( HR ) ( XREF_FIG ) .	XREF_BIBR The nuclease activity of the MRN complex results in 3 ' ssDNA which along with its interaction with the C-terminus of Nbs1 stimulates ATM kinase activity and ultimately promotes homologous recombination (HR) (XREF_FIG).	20	26	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	22	23	24	25
Growing evidence suggests that ATM activation at DNA damage sites is mediated through direct recruitment by MRN , and to what extent other posttranslational modifications of ATM , such as acetylation at lysine 3016 , may function remains to be determined .	Growing evidence suggests that ATM activation at DNA damage sites is mediated through direct recruitment by MRN, and to what extent other posttranslational modifications of ATM, such as acetylation at lysine 3016, may function remains to be determined.	4	36	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	16	17	4	5
MRN and ATM are associated through multiple protein protein interactions , and MRN contributes to ATM kinase activity by increasing the affinity of ATM for its substrates ( 5 ) .	MRN and ATM are associated through multiple protein protein interactions, and MRN contributes to ATM kinase activity by increasing the affinity of ATM for its substrates (5).	12	24	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	12	13	23	24
Our data strongly suggest that MRN specifically activates ATM .	Our data strongly suggest that MRN specifically activates ATM.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	5	6	8	9
BMI1 interacts with NBS1 ; this association alters the binding of NBS1 and ATM [ XREF_BIBR ] , which likely attenuates NBS1 mediated ATM activation .	BMI1 interacts with NBS1; this association alters the binding of NBS1 and ATM [XREF_BIBR], which likely attenuates NBS1 mediated ATM activation.	20	24	mediated	Positive_early_activation	Positive_activation	Negative_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	21	22	23	24
Because conditional deletion of Nbs1 nearly abolishes ATM activity , there are likely to be other regions within Nbs1 or within the MRN complex that can compensate for the lack of the extreme C terminus .	Because conditional deletion of Nbs1 nearly abolishes ATM activity, there are likely to be other regions within Nbs1 or within the MRN complex that can compensate for the lack of the extreme C terminus.	2	8	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	4	5	7	8
The MRN complex recruits ATM at the DSB sites , and the interaction with NBS1 activates ATM kinase , resulting in the phosphorylation of the target proteins .	The MRN complex recruits ATM at the DSB sites, and the interaction with NBS1 activates ATM kinase, resulting in the phosphorylation of the target proteins.	12	17	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	14	15	16	17
In the genome , activation of ATM by MRN is amplified over a mega-base region leading to formation of DNA damage foci , cell cycle arrest , and DNA repair .	In the genome, activation of ATM by MRN is amplified over a mega-base region leading to formation of DNA damage foci, cell cycle arrest, and DNA repair.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	8	9	6	7
MRN ( MRE11/RAD50/NBS ) helps to activate ATM in response to DNA double strand breaks ( DSBs ) and also facilitates ATR activation by catalyzing the formation and extension of DNA single strand breaks ( SSBs ) .	MRN (MRE11/RAD50/NBS) helps to activate ATM in response to DNA double strand breaks (DSBs) and also facilitates ATR activation by catalyzing the formation and extension of DNA single strand breaks (SSBs).	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	0	1	7	8
The DNA damage response at these dysfunctional telomeres is not only completely dependent on ATM , but also requires a DNA end binding complex [ ; the MRN ( Mre11/Rad50/Nbs1 ) complex ] that senses double-strand breaks and activates ATM .	The DNA damage response at these dysfunctional telomeres is not only completely dependent on ATM, but also requires a DNA end binding complex [; the MRN (Mre11/Rad50/Nbs1) complex] that senses double-strand breaks and activates ATM.	27	40	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	27	28	39	40
At damaged chromatin , ATM is activated and recruited by the MRN complex ( Mre11-NBS1-Rad50 ) to DNA breaks .	At damaged chromatin, ATM is activated and recruited by the MRN complex (Mre11-NBS1-Rad50) to DNA breaks.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	4	5
FOXM1 can be seen in indirect control of chromatin structure modifying genes in FOXM1 induced NBS1 activation of ATM XREF_BIBR .	FOXM1 can be seen in indirect control of chromatin structure modifying genes in FOXM1 induced NBS1 activation of ATM XREF_BIBR.	13	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NBS1	FOXM1 induced NBS1	nbs1	ATM	ATM	atm	15	16	18	19
As ATM activation requires the MRN complex in Xenopus egg extract at low doses of DSBs , we were intrigued to know whether the MRN complex was promoting ATM activity induced by ssDNA oligos .	As ATM activation requires the MRN complex in Xenopus egg extract at low doses of DSBs, we were intrigued to know whether the MRN complex was promoting ATM activity induced by ssDNA oligos.	24	29	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	24	25	28	29
Since the MRN complex is required to activate ATM upon DNA damage , we tested the impact of ATM inhibition on mitotic chromosome alignment .	Since the MRN complex is required to activate ATM upon DNA damage, we tested the impact of ATM inhibition on mitotic chromosome alignment.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	2	3	8	9
However , purified MRN can activate ATM in an in vitro biochemical system which appears to lack Tip60 XREF_BIBR , XREF_BIBR , indicating that MRN plays an active role in upregulating ATM kinase activity .	However, purified MRN can activate ATM in an in vitro biochemical system which appears to lack Tip60 XREF_BIBR, XREF_BIBR, indicating that MRN plays an active role in upregulating ATM kinase activity.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	3	4	6	7
ATM activation induced by MRN complex promotes cell-cycle checkpoint induction ; subsequently phosphorylate downstream cdc25c and cdk1 and cyclinB complex to induce G2/M arrest [ XREF_BIBR ] .	ATM activation induced by MRN complex promotes cell-cycle checkpoint induction; subsequently phosphorylate downstream cdc25c and cdk1 and cyclinB complex to induce G2/M arrest [XREF_BIBR].	0	5	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	4	5	0	1
Upon viral infection , local but not global ATM activation and signaling are initiated by the MRN complex owing to the small size of viral DNA .	Upon viral infection, local but not global ATM activation and signaling are initiated by the MRN complex owing to the small size of viral DNA.	8	17	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	16	17	8	9
Mirin is an inhibitor of the MRN complex , which prevents MRN dependent activation of ATM without affecting ATM protein kinase activity and inhibits MRE11 associated exonuclease activity .	Mirin is an inhibitor of the MRN complex, which prevents MRN dependent activation of ATM without affecting ATM protein kinase activity and inhibits MRE11 associated exonuclease activity.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	15	16
While the biological function of ATM activation by double-strand breaks and MRN is well established , the role of ATMIN dependent ATM activation is enigmatic .	While the biological function of ATM activation by double-strand breaks and MRN is well established, the role of ATMIN dependent ATM activation is enigmatic.	5	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	11	12	5	6
The MRE11-RAD50-NBS1 ( MRN ) complex serves as the initial DSB sensor , both recruiting and activating ATM .	The MRE11-RAD50-NBS1 (MRN) complex serves as the initial DSB sensor, both recruiting and activating ATM.	1	18	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	3	4	17	18
This occurs as the MRN complex binds to and activates ATM , which in turn phosphorylates several effector proteins , including checkpoint protein 2 ( Chk2 ) and p53 .	This occurs as the MRN complex binds to and activates ATM, which in turn phosphorylates several effector proteins, including checkpoint protein 2 (Chk2) and p53.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	4	5	10	11
A forward chemical genetic screen has already identified an inhibitor of MRN that prevents MRN dependent activation of ATM , the G2/M checkpoint , and homology directed repair in mammalian cells [ XREF_BIBR ] .	A forward chemical genetic screen has already identified an inhibitor of MRN that prevents MRN dependent activation of ATM, the G2/M checkpoint, and homology directed repair in mammalian cells [XREF_BIBR].	14	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	14	15	18	19
The response begins when DNA damage is detected , typically via the Mre11-Rad50-Nbs1 ( MRN ) sensor complex , activating the apical kinases Ataxia-Telangiectasia Mutated kinase ( ATM ) , the DNA dependent Protein Kinase ( DNA-PK ) and/or ATR ( ATM and Rad3 related ) .	The response begins when DNA damage is detected, typically via the Mre11-Rad50-Nbs1 (MRN) sensor complex, activating the apical kinases Ataxia-Telangiectasia Mutated kinase (ATM), the DNA dependent Protein Kinase (DNA-PK) and/or ATR (ATM and Rad3 related).	12	44	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	14	15	41	42
We then determined whether elevated Mdm2 binds more Nbs1 to abrogate MRN induced Atm activation .	We then determined whether elevated Mdm2 binds more Nbs1 to abrogate MRN induced Atm activation.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	MRN	MRN	MRN	Atm	Atm	Atm	11	12	13	14
MRN activates the Atm signaling kinase at DSBs XREF_BIBR , and the effect of MRN deficiency on V ( D ) J recombination mimicks that of Atm deficiency XREF_BIBR .	MRN activates the Atm signaling kinase at DSBs XREF_BIBR, and the effect of MRN deficiency on V (D) J recombination mimicks that of Atm deficiency XREF_BIBR.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	Atm	Atm	Atm	0	1	3	4
It was recently shown that the MRN ( Mre11-Rad50-Nbs1 )-mediated cooperative binding of ATM to DNA greatly stimulated the ATM kinase activity .	It was recently shown that the MRN (Mre11-Rad50-Nbs1)-mediated cooperative binding of ATM to DNA greatly stimulated the ATM kinase activity.	6	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRN	MRN	MRN	ATM	ATM	ATM	6	7	19	20
Other studies showed that the C-terminal fragment of nibrin was sufficient to stimulate ATM activation at early times after irradiation .	Other studies showed that the C-terminal fragment of nibrin was sufficient to stimulate ATM activation at early times after irradiation.	6	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	nibrin	nibrin	nibrin	ATM	ATM	ATM	8	9	13	14
One example is a class of drugs that inhibit the mammalian target of rapamycin ( mTOR ) enzyme .	One example is a class of drugs that inhibit the mammalian target of rapamycin (mTOR) enzyme.	6	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	15	16	10	14
In addition to TSC2-Rheb-mTOR co-localisation , we next sought to examine whether mTOR translocation to the plasma membrane may serve to direct mTOR and LAMP2 to other substrates involved in the initiation of protein synthesis .	In addition to TSC2-Rheb-mTOR co-localisation, we next sought to examine whether mTOR translocation to the plasma membrane may serve to direct mTOR and LAMP2 to other substrates involved in the initiation of protein synthesis.	12	24	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR translocation to the plasma membrane	mtor	mTOR	mTOR	mtor	12	13	22	23
Rapamycin suppressed the phosphorylation of mTOR in the cells and also suppressed the phosphorylation of molecules downstream of mTOR , including P70 S6K and 4E-BP-1 .	Rapamycin suppressed the phosphorylation of mTOR in the cells and also suppressed the phosphorylation of molecules downstream of mTOR, including P70 S6K and 4E-BP-1.	0	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	Rapamycin suppressed the phosphorylation of mTOR	mtor	mTOR	mTOR	mtor	5	6	18	19
Moreover , the level of CTNNB1 , mTOR , and AREG was also increased by 3-, 6-, and 1.4-times in NASH and fibrotic liver tissue , suggesting activation of the Wnt and beta-catenin , mTOR , and EGF signaling pathways at the preneoplastic stage of hepatocarcinogenesis .	Moreover, the level of CTNNB1, mTOR, and AREG was also increased by 3-, 6-, and 1.4-times in NASH and fibrotic liver tissue, suggesting activation of the Wnt and beta-catenin, mTOR, and EGF signaling pathways at the preneoplastic stage of hepatocarcinogenesis.	3	35	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	level of CTNNB1, mTOR	mtor	mTOR	mTOR	mtor	7	8	34	35
Direct cellular effects of metformin involve inhibition of ATP production , increased AMP kinase ( AMPK ) activity , and inhibition of the mammalian target of rapamycin ( mTOR ) , a complex that couples protein synthesis to external growth factors and intracellular energy stores .	Direct cellular effects of metformin involve inhibition of ATP production, increased AMP kinase (AMPK) activity, and inhibition of the mammalian target of rapamycin (mTOR), a complex that couples protein synthesis to external growth factors and intracellular energy stores.	11	32	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	28	29	23	27
Phospho-mTOR expression is correlated with poor survival , supporting the potential of mTOR for targeted therapy .	Phospho-mTOR expression is correlated with poor survival, supporting the potential of mTOR for targeted therapy.	0	13	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Phospho-mTOR	Phospho-mTOR expression	phospho-mtor	mTOR	mTOR	mtor	0	1	12	13
A third category of dual inhibitors targeting both PI3K and mammalian target of rapamycin ( mTOR ) are also being investigated .	A third category of dual inhibitors targeting both PI3K and mammalian target of rapamycin (mTOR) are also being investigated.	2	16	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	15	16	10	14
The landscape for RCC treatment has changed dramatically in recent years , vascular endothelial growth factor ( VEGF ) receptor tyrosine phosphorylation inhibitors ( TKIs ) and drugs that inhibit mammalian target of rapamycin ( mTOR ) signaling have become the mainstay for the management of metastatic RCC based on improved progression-free survival or/and overall survival outcomes [ XREF_BIBR ] .	The landscape for RCC treatment has changed dramatically in recent years, vascular endothelial growth factor (VEGF) receptor tyrosine phosphorylation inhibitors (TKIs) and drugs that inhibit mammalian target of rapamycin (mTOR) signaling have become the mainstay for the management of metastatic RCC based on improved progression-free survival or/and overall survival outcomes [XREF_BIBR].	27	36	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	35	36	30	34
Growth factor receptor bound protein 10 ( GRB10 ) is a recently discovered substrate of mTOR that is activated by mTOR phosphorylation and negatively controls insulin-PI3K-AKT signaling pathway by inhibiting the insulin receptor in its active form [ XREF_BIBR ] .	Growth factor receptor bound protein 10 (GRB10) is a recently discovered substrate of mTOR that is activated by mTOR phosphorylation and negatively controls insulin-PI3K-AKT signaling pathway by inhibiting the insulin receptor in its active form [XREF_BIBR].	13	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR phosphorylation	mtor	mTOR	mTOR	mtor	20	21	15	16
AKT mediated threonine phosphorylation and mTOR mediated serine phosphorylation of AKTS1 relieves inhibition of mTOR XREF_BIBR .	AKT mediated threonine phosphorylation and mTOR mediated serine phosphorylation of AKTS1 relieves inhibition of mTOR XREF_BIBR.	0	15	relieves	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	AKT mediated threonine phosphorylation and mTOR mediated serine phosphorylation of AKTS1	mtor	mTOR	mTOR	mtor	5	6	14	15
The majority of DES used in clinical practice are designed to elute pharmacologic agents such as sirolimus that inhibit the mammalian target of rapamycin ( mTOR ) , a member of the phosphatidylinositol kinase related family of serine/threonine kinase .	The majority of DES used in clinical practice are designed to elute pharmacologic agents such as sirolimus that inhibit the mammalian target of rapamycin (mTOR), a member of the phosphatidylinositol kinase related family of serine/threonine kinase.	16	26	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	25	26	20	24
For all primary tumor xenografts , the overall phosphorylation of mTOR , S6K1 , 4EBP1 and eIF4E proteins was decreased by 53 % , 33 % , 62 % and 64 % , respectively , in rapamycin treated tumors compared with tumors in the pretreatment and control groups , supporting decreased mTOR pathway activity after treatment .	For all primary tumor xenografts, the overall phosphorylation of mTOR, S6K1, 4EBP1 and eIF4E proteins was decreased by 53%, 33%, 62% and 64%, respectively, in rapamycin treated tumors compared with tumors in the pretreatment and control groups, supporting decreased mTOR pathway activity after treatment.	8	53	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of mTOR	mtor	mTOR	mTOR	mtor	10	11	51	52
FLCN forms a complex with novel folliculin interacting proteins 1 and 2 ( FNIP1 and FNIP2 ) , and 5 '-AMP-activated protein kinase ( AMPK ) , a kinase that negatively regulates mammalian target of rapamycin ( mTOR ) XREF_BIBR , XREF_BIBR .	FLCN forms a complex with novel folliculin interacting proteins 1 and 2 (FNIP1 and FNIP2), and 5 '-AMP-activated protein kinase (AMPK), a kinase that negatively regulates mammalian target of rapamycin (mTOR) XREF_BIBR, XREF_BIBR.	8	38	negatively regulates	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	37	38	32	36
Similarly , phosphorylation of the eukaryotic initiation factor 4E binding protein , a direct mTOR target , was reduced in TIF-IA D1RCre mice , supporting that upregulation of PTEN impairs mTOR function in MSNs ( XREF_FIG ) .	Similarly, phosphorylation of the eukaryotic initiation factor 4E binding protein, a direct mTOR target, was reduced in TIF-IA D1RCre mice, supporting that upregulation of PTEN impairs mTOR function in MSNs (XREF_FIG).	2	31	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of the eukaryotic initiation factor 4E binding protein, a direct mTOR	mtor	mTOR	mTOR	mtor	14	15	30	31
The current drugs that specifically target the tyrosine kinase activity of EGFR or selectively inhibit the mammalian target of rapamycin ( mTOR ) , a PI3K and AKT downstream signal transducer showed little efficacy in treatment of primary glioblastoma [ XREF_BIBR ] .	The current drugs that specifically target the tyrosine kinase activity of EGFR or selectively inhibit the mammalian target of rapamycin (mTOR), a PI3K and AKT downstream signal transducer showed little efficacy in treatment of primary glioblastoma [XREF_BIBR].	2	22	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	21	22	16	20
Evidence from in vitro and in vivo studies suggests that the diabetic therapy metformin may also have anti-cancer activity via effects on blood insulin and glucose , cancer cell proliferation and apoptosis , and cancer stem cell growth by activating the adenosine monophosphate activated protein kinase ( AMPK )/liver kinase B-1 ( LKB1 ) pathway , inhibiting the mammalian target of rapamycin ( mTOR ) , and lowering insulin like growth factor-1 ( IGF-1 ) levels .	Evidence from in vitro and in vivo studies suggests that the diabetic therapy metformin may also have anti-cancer activity via effects on blood insulin and glucose, cancer cell proliferation and apoptosis, and cancer stem cell growth by activating the adenosine monophosphate activated protein kinase (AMPK)/liver kinase B-1 (LKB1) pathway, inhibiting the mammalian target of rapamycin (mTOR), and lowering insulin like growth factor-1 (IGF-1) levels.	45	64	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	63	64	58	62
The current study involved structural computational biology approaches to explore compounds from a diverse pool of naphthoquinone analogs that can inhibit key cancer signaling proteins phosphoinositide 3-kinase ( PI3K ) , protein kinase B , PKB ( AKT ) , and mammalian target of rapamycin ( mTOR ) .	The current study involved structural computational biology approaches to explore compounds from a diverse pool of naphthoquinone analogs that can inhibit key cancer signaling proteins phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT), and mammalian target of rapamycin (mTOR).	17	47	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	46	47	41	45
The majority of DES used in clinical practice are designed to elute pharmacologic agents which could disrupt smooth muscle cell proliferation , such as sirolimus that inhibits the mammalian target of rapamycin ( mTOR ) , a member of the phosphatidylinositol kinase related family of serine/threonine kinase .	The majority of DES used in clinical practice are designed to elute pharmacologic agents which could disrupt smooth muscle cell proliferation, such as sirolimus that inhibits the mammalian target of rapamycin (mTOR), a member of the phosphatidylinositol kinase related family of serine/threonine kinase.	24	34	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	33	34	28	32
The discovery of small molecule inhibitors that selectively target PI3K or PI3K and mammalian target of rapamycin ( mTOR ) provides an opportunity to pharmacologically determine the contribution of these key signaling nodes in VEGF-A-driven tumor angiogenesis in vivo .	The discovery of small molecule inhibitors that selectively target PI3K or PI3K and mammalian target of rapamycin (mTOR) provides an opportunity to pharmacologically determine the contribution of these key signaling nodes in VEGF-A-driven tumor angiogenesis in vivo.	5	19	target	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	18	19	13	17
Both mTOR and TORC2 phosphorylations were increased in livers from these rats , demonstrating activation of mTOR and TORC2 by central nesfatin-1 in vivo .	Both mTOR and TORC2 phosphorylations were increased in livers from these rats, demonstrating activation of mTOR and TORC2 by central nesfatin-1 in vivo.	1	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR and TORC2 phosphorylations	mtor	mTOR	mTOR	mtor	1	2	16	17
To address a specificity of the nuclear mTOR purification , we isolated mTOR from cells carrying a low level of mTOR attained by expression of the shRNAs targeting mTOR .	To address a specificity of the nuclear mTOR purification, we isolated mTOR from cells carrying a low level of mTOR attained by expression of the shRNAs targeting mTOR.	18	29	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	level of mTOR	mtor	mTOR	mTOR	mtor	20	21	28	29
One possible mechanism involves cPKCgamma mediated phosphorylation of mTOR at Ser 2481 , dependent on Ser 2448 , that triggers mTOR reactivation following inhibition of autophagy ( XREF_FIG ) .	One possible mechanism involves cPKCgamma mediated phosphorylation of mTOR at Ser 2481, dependent on Ser 2448, that triggers mTOR reactivation following inhibition of autophagy (XREF_FIG).	4	21	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	cPKCgamma mediated phosphorylation of mTOR at Ser 2481	mtor	mTOR	mTOR	mtor	8	9	20	21
Furthermore , overexpression of mTOR ( pmTOR ) upregulated mTOR , AP-1 , and VEGF , while overexpression of AP-1 ( pAP-1 ) upregulated AP-1 and VEGF .	Furthermore, overexpression of mTOR (pmTOR) upregulated mTOR, AP-1, and VEGF, while overexpression of AP-1 (pAP-1) upregulated AP-1 and VEGF.	2	14	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	overexpression of mTOR	mtor	mTOR	mTOR	mtor	4	5	9	10
Inhibition of mTOR with rapamycin ameliorated the damage and suppressed hyperglycemia elevated p-MTOR , p-P70S6K and p-S6 .	Inhibition of mTOR with rapamycin ameliorated the damage and suppressed hyperglycemia elevated p-MTOR, p-P70S6K and p-S6.	0	16	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p-MTOR	p-MTOR	p-MTOR	2	3	12	13
Two agents that inhibit mammalian target of rapamycin ( mTOR ) , temsirolimus and everolimus , are approved for treating patients with advanced kidney cancer [ XREF_BIBR , XREF_BIBR ] .	Two agents that inhibit mammalian target of rapamycin (mTOR), temsirolimus and everolimus, are approved for treating patients with advanced kidney cancer [XREF_BIBR, XREF_BIBR].	1	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	9	10	4	8
Autophagy is regulated by multiple pathways that are either dependent or independent of mTOR ( mechanistic target of rapamycin ; a.k.a. mammalian target of rapamycin ) , a master regulatory molecules that impacts several cellular functions .	Autophagy is regulated by multiple pathways that are either dependent or independent of mTOR (mechanistic target of rapamycin; a.k.a. mammalian target of rapamycin), a master regulatory molecules that impacts several cellular functions.	9	25	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	13	14	21	25
Furthermore , it was demonstrated that Fyn knockdown induces phosphorylation of AMPK , inhibits downstream phosphorylation of mTOR , and activate the AMPK and mTOR signaling pathway .	Furthermore, it was demonstrated that Fyn knockdown induces phosphorylation of AMPK, inhibits downstream phosphorylation of mTOR, and activate the AMPK and mTOR signaling pathway.	6	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	Fyn knockdown induces phosphorylation of AMPK, inhibits downstream phosphorylation of mTOR	mtor	mTOR	mTOR	mtor	17	18	24	25
We have previously shown that CM harvested from glioma cells under basal conditions ( C-CM ) , as well as CM from glioma cells activated with LPS and IFNgamma ( LI-CM ) , increased the phosphorylation of mTOR at ser 2448 , an index of mTORC activation , in microglial cells in 2-h experiments [ XREF_BIBR ] .	We have previously shown that CM harvested from glioma cells under basal conditions (C-CM), as well as CM from glioma cells activated with LPS and IFNgamma (LI-CM), increased the phosphorylation of mTOR at ser 2448, an index of mTORC activation, in microglial cells in 2-h experiments [XREF_BIBR].	33	41	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of mTOR at ser 2448	mtor	mTOR	mTOR	mtor	37	38	37	38
However , inhibition of mTOR by rapamycin pretreatment downregulated phospho-mTOR , phospho-p70S6K , and HIF-1alpha and upregulated PHD1 after LPS stimulation .	However, inhibition of mTOR by rapamycin pretreatment downregulated phospho-mTOR, phospho-p70S6K, and HIF-1alpha and upregulated PHD1 after LPS stimulation.	2	14	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	phospho-mTOR	phospho-mTOR	phospho-mTOR	4	5	9	10
When mTOR signaling was enhanced by either mTOR overexpression or deletion of tuberous sclerosis 1 , Klotho mRNA was further decreased in phosphate treated VSMCs , suggesting a vital association between mTOR signaling and Klotho expression .	When mTOR signaling was enhanced by either mTOR overexpression or deletion of tuberous sclerosis 1, Klotho mRNA was further decreased in phosphate treated VSMCs, suggesting a vital association between mTOR signaling and Klotho expression.	1	9	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR overexpression	mtor	mTOR	mTOR	mtor	7	8	1	2
Additional phosphorylation at Ser473 leads to full AKT activation and phosphorylation of mTOR at Ser2448 leads to full activation of the mTOR protein .	Additional phosphorylation at Ser473 leads to full AKT activation and phosphorylation of mTOR at Ser2448 leads to full activation of the mTOR protein.	10	22	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of mTOR at Ser2448	mtor	mTOR	mTOR	mtor	12	13	21	22
Responsive to the PI3K and AKT pathway is the mammalian target of rapamycin ( mTOR ) , a major effector that is specifically implicated in the regulation of cell growth as a result of nutrient availability and cellular bioenergetics .	Responsive to the PI3K and AKT pathway is the mammalian target of rapamycin (mTOR), a major effector that is specifically implicated in the regulation of cell growth as a result of nutrient availability and cellular bioenergetics.	7	19	is the mammalian target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	14	15	9	13
In addition to Foxo proteins , Akt phosphorylates mammalian target of rapamycin ( mTOR ) and activates the mTOR complex 1 ( mTORC1 ) , a crucial stimulator of cell anabolism and an inhibitor of cell catabolism [ XREF_BIBR ] .	In addition to Foxo proteins, Akt phosphorylates mammalian target of rapamycin (mTOR) and activates the mTOR complex 1 (mTORC1), a crucial stimulator of cell anabolism and an inhibitor of cell catabolism [XREF_BIBR].	6	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	Akt phosphorylates mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mtor	8	12	18	19
mTOR is the mammalian target of rapamycin and an important protein kinase that regulates cellular functions , such as cell growth , cell proliferation , protein synthesis , and transcription [ XREF_BIBR ] .	mTOR is the mammalian target of rapamycin and an important protein kinase that regulates cellular functions, such as cell growth, cell proliferation, protein synthesis, and transcription [XREF_BIBR].	0	7	is the mammalian target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	3	7
Targeted gene silencing of mTOR in human U937 macrophages resulted in approximately 60 % reduction of mTOR protein expression ( XREF_FIG ) .	Targeted gene silencing of mTOR in human U937 macrophages resulted in approximately 60% reduction of mTOR protein expression (XREF_FIG).	0	19	Targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR protein expression	mtor	mTOR	mTOR	mtor	16	17	4	5
The term ' Rapalogs ' describes a class of allosteric inhibitors that target the mammalian target of rapamycin ( mTOR ) pathway .	The term ' Rapalogs ' describes a class of allosteric inhibitors that target the mammalian target of rapamycin (mTOR) pathway.	10	20	target	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	19	20	14	18
Akt can phosphorylate mTOR directly at threonine 2446 and serine 2448 , but can also activate mTOR indirectly via phosphorylation of TSC2 ( Majumder and Sellers , 2005 ) .	Akt can phosphorylate mTOR directly at threonine 2446 and serine 2448, but can also activate mTOR indirectly via phosphorylation of TSC2 (Majumder and Sellers, 2005).	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	Akt can phosphorylate mTOR directly at threonine 2446	mtor	mTOR	mTOR	mtor	3	4	16	17
In vitro and preclinical data demonstrate that mammalian target of rapamycin ( mTOR ) inhibition attenuates the mTOR mediated intracellular signaling pathway involved in AMR related kidney damage .	In vitro and preclinical data demonstrate that mammalian target of rapamycin (mTOR) inhibition attenuates the mTOR mediated intracellular signaling pathway involved in AMR related kidney damage.	7	18	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mTOR	7	11	17	18
Nelfinavir was also found to increase the expression of the mammalian target of rapamycin ( mTOR ) inhibitor AMP activated protein kinase ( AMPK ) and inhibited the panobinostat activated mTOR pathway .	Nelfinavir was also found to increase the expression of the mammalian target of rapamycin (mTOR) inhibitor AMP activated protein kinase (AMPK) and inhibited the panobinostat activated mTOR pathway.	0	31	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mammalian target of rapamycin	Nelfinavir was also found to increase the expression of the mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mtor	10	14	30	31
Although the level of mTOR seen in lysates was unchanged ( XREF_FIG , right panels ) , the amount of total mTOR associated with Raptor was enhanced in p53 deficient cells ( XREF_FIG , left panels , and 3D ) , apparently reflecting a redistribution of cellular mTOR into mTORC1 complexes .	Although the level of mTOR seen in lysates was unchanged (XREF_FIG, right panels), the amount of total mTOR associated with Raptor was enhanced in p53 deficient cells (XREF_FIG, left panels, and 3D), apparently reflecting a redistribution of cellular mTOR into mTORC1 complexes.	18	48	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	amount of total mTOR	mtor	mTOR	mTOR	mtor	21	22	47	48
Recently we have observed that on one hand , cadmium , a heavy metal polluted in the environment , induces oxidative stress and neuronal cell death by activating mTOR , which can be prevented by pre-treatment with rapamycin , a specific mTOR inhibitor [ XREF_BIBR , XREF_BIBR ] ; on the other hand , hydrogen peroxide induces neuronal cell death by inhibiting mTOR , which can be attenuated by overexpression of mTOR [ XREF_BIBR ] .	Recently we have observed that on one hand, cadmium, a heavy metal polluted in the environment, induces oxidative stress and neuronal cell death by activating mTOR, which can be prevented by pre-treatment with rapamycin, a specific mTOR inhibitor [XREF_BIBR, XREF_BIBR]; on the other hand, hydrogen peroxide induces neuronal cell death by inhibiting mTOR, which can be attenuated by overexpression of mTOR [XREF_BIBR].	56	73	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	overexpression of mTOR	mtor	mTOR	mTOR	mtor	71	72	62	63
Subsequently , it was reported [ XREF_BIBR ] that DIM could inactivate both mammalian target of rapamycin ( mTOR ) and Akt activity in PDGF-D-over-expressing prostate cancer cells , PC3 .	Subsequently, it was reported [XREF_BIBR] that DIM could inactivate both mammalian target of rapamycin (mTOR) and Akt activity in PDGF-D-over-expressing prostate cancer cells, PC3.	6	19	inactivate	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	18	19	13	17
MTOR is a mammalian target of rapamycin , serine/threonine protein kinase that regulates cell growth , cell proliferation , cell motility , cell survival , protein synthesis , and transcription .	MTOR is a mammalian target of rapamycin, serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription.	0	7	is a mammalian target	Positive_activation_copula_1	Positive_activation	Positive_activation	MTOR	MTOR	MTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	3	7
Among the innovative molecules used to manage neuroendocrine tumors , there is growing interest in combining the somatostatin analogs octreotide or pasireotide ( SOM230 ) and everolimus ( RAD001 ) , an inhibitor that targets the protein kinase mammalian target of rapamycin ( mTOR ) .	Among the innovative molecules used to manage neuroendocrine tumors, there is growing interest in combining the somatostatin analogs octreotide or pasireotide (SOM230) and everolimus (RAD001), an inhibitor that targets the protein kinase mammalian target of rapamycin (mTOR).	32	44	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	43	44	38	42
PKB and Akt activity has been linked to increased mTOR activation through several mechanisms , including direct phosphorylation of mTOR by PKB and Akt [ XREF_BIBR , XREF_BIBR ] , PKB and Akt mediated phosphorylation of TSC2 , and inhibition of AMP kinase , which prevents the phosphorylation and inhibition of TSC2 [ XREF_BIBR ] .	PKB and Akt activity has been linked to increased mTOR activation through several mechanisms, including direct phosphorylation of mTOR by PKB and Akt [XREF_BIBR, XREF_BIBR], PKB and Akt mediated phosphorylation of TSC2, and inhibition of AMP kinase, which prevents the phosphorylation and inhibition of TSC2 [XREF_BIBR].	9	23	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	mTOR	phosphorylation of mTOR	mtor	mTOR	mTOR	mtor	19	20	9	10
AKT phosphorylates FRAP1 ( mTOR ) at S2448 increasing FRAP1 kinase activity , and decreased FRAP1 S2448 phosphorylation was observed in the breast cancer cell lines [ XREF_BIBR ] .	AKT phosphorylates FRAP1 (mTOR) at S2448 increasing FRAP1 kinase activity, and decreased FRAP1 S2448 phosphorylation was observed in the breast cancer cell lines [XREF_BIBR].	0	11	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FRAP1	AKT phosphorylates FRAP1 (mTOR) at S2448	frap1	FRAP1	FRAP1	frap1	2	3	9	10
Autophagy is regulated by multiple , complex networks and pathways that are either dependent or independent of mTOR ( mechanistic target of rapamycin ; a.k.a. mammalian target of rapamycin ) , a master regulatory molecule that impacts several cellular functions .	Autophagy is regulated by multiple, complex networks and pathways that are either dependent or independent of mTOR (mechanistic target of rapamycin; a.k.a. mammalian target of rapamycin), a master regulatory molecule that impacts several cellular functions.	13	34	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	17	18	25	29
The mechanism by which the drug rapamycin inhibits the mechanistic target of rapamycin ( mTOR ) is of intense interest because of its likely relevance in cancer biology , aging , and other age related diseases .	The mechanism by which the drug rapamycin inhibits the mechanistic target of rapamycin (mTOR) is of intense interest because of its likely relevance in cancer biology, aging, and other age related diseases.	1	15	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	14	15	9	13
The activation of autophagy is concurrently aided by AMPK mediated inhibition of mammalian target of rapamycin ( mTOR ) , a known suppressor of autophagy [ XREF_BIBR ] .	The activation of autophagy is concurrently aided by AMPK mediated inhibition of mammalian target of rapamycin (mTOR), a known suppressor of autophagy [XREF_BIBR].	9	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	17	18	12	16
Further , the mTORC1 complex acts on RHEB ( Ras homolog enriched in brain ) to phosphorylate mTOR at Ser2448 and thus resulting in mTOR activation .	Further, the mTORC1 complex acts on RHEB (Ras homolog enriched in brain) to phosphorylate mTOR at Ser2448 and thus resulting in mTOR activation.	3	26	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	mTOR	mTORC1 complex acts on RHEB (Ras homolog enriched in brain) to phosphorylate mTOR at Ser2448	mtor	mTOR	mTOR	mtor	17	18	24	25
AMPK directly phosphorylates the negative regulators of mTOR , the tuberous sclerosis complex ( TSC ) proteins , thereby enhancing their negative regulation of mTOR [ XREF_BIBR ] .	AMPK directly phosphorylates the negative regulators of mTOR, the tuberous sclerosis complex (TSC) proteins, thereby enhancing their negative regulation of mTOR [XREF_BIBR].	0	26	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	AMPK directly phosphorylates the negative regulators of mTOR	mtor	mTOR	mTOR	mtor	7	8	24	25
It appears that hypoxia alone , in the absence of NAC , induces an increase in mTOR protein expression , or indeed a reduction in mTOR degradation , while phosphorylation of mTOR is induced by hypoxia , and to a greater extent by hypoxia concomitant with NAC supplementation .	It appears that hypoxia alone, in the absence of NAC, induces an increase in mTOR protein expression, or indeed a reduction in mTOR degradation, while phosphorylation of mTOR is induced by hypoxia, and to a greater extent by hypoxia concomitant with NAC supplementation.	10	26	reduction	Negative_activation_syntax_7_noun	Positive_activation	Positive_activation	mTOR	NAC, induces an increase in mTOR protein expression	mtor	mTOR	mTOR	mtor	16	17	25	26
The results ( XREF_FIG ) show that as expected , MTOR protein expression was blocked by the siRNA targeting Mtor , compared to non targeting siRNA ( XREF_FIG ) .	The results (XREF_FIG) show that as expected, MTOR protein expression was blocked by the siRNA targeting Mtor, compared to non targeting siRNA (XREF_FIG).	10	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTOR	MTOR protein expression	mtor	Mtor	Mtor	mtor	10	11	19	20
Tuberin dependent stimulation of GTP hydrolysis of Rheb blocks phosphorylation of mTOR ( Ser 2448 ) , which antagonizes the mTOR signaling pathway .	Tuberin dependent stimulation of GTP hydrolysis of Rheb blocks phosphorylation of mTOR (Ser 2448), which antagonizes the mTOR signaling pathway.	0	22	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	Tuberin dependent stimulation of GTP hydrolysis of Rheb blocks phosphorylation of mTOR (Ser 2448	mtor	mTOR	mTOR	mtor	11	12	20	21
Furthermore , the phosphorylation level of PI3K/Akt/mTOR/p70S6K ( where mTOR is mammalian target of rapamycin ; p70S6K is ribosomal protein S6 kinase beta-1 ) proteins was significantly higher in the heart of Epi treated animals .	Furthermore, the phosphorylation level of PI3K/Akt/mTOR/p70S6K (where mTOR is mammalian target of rapamycin; p70S6K is ribosomal protein S6 kinase beta-1) proteins was significantly higher in the heart of Epi treated animals.	9	15	is mammalian target	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	9	10	11	15
This is in agreement with previous studies showing that curcumin can inhibit phosphorylation of mTOR and its downstream effectors phosphorylation of p70 S6 kinase 1 ( S6K1 ) and eukaryotic initiation factor 4E ( eIF4E ) binding protein 1 ( 4E-BP1 ) , and disrupt the mTOR complex XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	This is in agreement with previous studies showing that curcumin can inhibit phosphorylation of mTOR and its downstream effectors phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), and disrupt the mTOR complex XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	9	47	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	curcumin can inhibit phosphorylation of mTOR	mtor	mTOR	mTOR	mtor	14	15	46	47
An increase in SRSF1 expression was recently found to enhance relative levels of pro oncogenic isoforms generated from the Mnk2 and RON genes which impair the p38-mitogen-activated protein kinase ( MAPK ) and mammalian target of rapamycin ( mTOR ) signaling pathways , consequently enhancing the migratory and invasive activities of different cancer cells [ XREF_BIBR , XREF_BIBR ] .	An increase in SRSF1 expression was recently found to enhance relative levels of pro oncogenic isoforms generated from the Mnk2 and RON genes which impair the p38-mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, consequently enhancing the migratory and invasive activities of different cancer cells [XREF_BIBR, XREF_BIBR].	22	39	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	38	39	33	37
Thus , these studies indicate that MTP and LPGAT1 might be required for miR-30c to modulate media apoB and hepatic lipogenesis , respectively .	Thus, these studies indicate that MTP and LPGAT1 might be required for miR-30c to modulate media apoB and hepatic lipogenesis, respectively.	6	20	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	6	7	17	18
The Mttp gene plays a critical role in production of apolipoprotein B containing lipoproteins , and loss of Mttp activity dramatically reduces secretion of ApoB containing lipoproteins into the plasma XREF_BIBR .	The Mttp gene plays a critical role in production of apolipoprotein B containing lipoproteins, and loss of Mttp activity dramatically reduces secretion of ApoB containing lipoproteins into the plasma XREF_BIBR.	18	25	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mttp	Mttp	Mttp	ApoB	ApoB	ApoB	18	19	24	25
However , if PDI ' s only role in ApoB biogenesis was through the MTP complex , we predicted that increased recovery of ApoB would be evident because the MTP complex promotes ApoB secretion and escape from ERAD .	However, if PDI 's only role in ApoB biogenesis was through the MTP complex, we predicted that increased recovery of ApoB would be evident because the MTP complex promotes ApoB secretion and escape from ERAD.	29	33	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	ApoB	ApoB	ApoB	29	30	32	33
Moreover , inhibition of MTP by a synthetic MTP-inhibitor lowers atherogenic apoB containing lipoproteins in patients with homozygous familial hypercholesterolemia [ XREF_BIBR ] .	Moreover, inhibition of MTP by a synthetic MTP-inhibitor lowers atherogenic apoB containing lipoproteins in patients with homozygous familial hypercholesterolemia [XREF_BIBR].	2	12	lowers	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	4	5	11	12
Unexpectedly , expression of MTP mRNA and protein in CHO cells did not allow apoB containing lipoproteins to be assembled and secreted by CHO cells expressing apoB53 .	Unexpectedly, expression of MTP mRNA and protein in CHO cells did not allow apoB containing lipoproteins to be assembled and secreted by CHO cells expressing apoB53.	2	15	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	expression of MTP	mtp	apoB	apoB	apob	4	5	14	15
In contrast , pharmacological MTTP inhibition , or conditional genetic deletion , blocks both apoB and lipoprotein secretion from hepatocytes and enterocytes .	In contrast, pharmacological MTTP inhibition, or conditional genetic deletion, blocks both apoB and lipoprotein secretion from hepatocytes and enterocytes.	4	17	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MTTP	MTTP	MTTP	apoB	apoB	apoB	4	5	14	15
Although it has been shown that treatment with an MTTP inhibitor impairs the production of HCV particles XREF_BIBR , in this study , we found that knockout of MTTP abrogated the secretion of ApoB but not the production of infectious HCV particles .	Although it has been shown that treatment with an MTTP inhibitor impairs the production of HCV particles XREF_BIBR, in this study, we found that knockout of MTTP abrogated the secretion of ApoB but not the production of infectious HCV particles.	26	34	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MTTP	MTTP	MTTP	ApoB	ApoB	ApoB	28	29	33	34
Further , expression of an insect ( Drosophila ) MTP ortholog in a heterologous system supported secretion of human apoB as a high-density , lipid-poor particle [ XREF_BIBR , XREF_BIBR ] and in mice as triglyceride-poor VLDL as well as phospholipid rich HDL [ XREF_BIBR ] .	Further, expression of an insect (Drosophila) MTP ortholog in a heterologous system supported secretion of human apoB as a high-density, lipid-poor particle [XREF_BIBR, XREF_BIBR] and in mice as triglyceride-poor VLDL as well as phospholipid rich HDL [XREF_BIBR].	2	20	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	expression of an insect (Drosophila) MTP	mtp	apoB	apoB	apob	9	10	19	20
MTP inhibition reduced the number of apoB containing lipoproteins that were secreted from the cells .	MTP inhibition reduced the number of apoB containing lipoproteins that were secreted from the cells.	0	7	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	0	1	6	7
The CMs and VLDLs are lipoprotein particles whose assembly in the enterocytes and hepatocytes , respectively , require two major players : ( a ) apolipoprotein B ( apoB ) , the structural component of the lipoproteins , and ( b ) microsomal triglyceride transfer protein ( Mtp ) , an ER-resident protein that is thought to transfer lipids to apoB while the apoB transcript is being translated , thus allowing apoB to fold correctly and assemble a primordial lipoprotein particle [ XREF_BIBR - XREF_BIBR ] .	The CMs and VLDLs are lipoprotein particles whose assembly in the enterocytes and hepatocytes, respectively, require two major players : (a) apolipoprotein B (apoB), the structural component of the lipoproteins, and (b) microsomal triglyceride transfer protein (Mtp), an ER-resident protein that is thought to transfer lipids to apoB while the apoB transcript is being translated, thus allowing apoB to fold correctly and assemble a primordial lipoprotein particle [XREF_BIBR - XREF_BIBR].	33	76	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mtp	Mtp	Mtp	apoB	apoB	apoB	47	48	71	72
MTP , found in the endoplasmic reticulum of hepatocytes and enterocytes , mediates the formation of apoB containing lipoproteins in the liver and in the intestine [ XREF_BIBR ] .	MTP, found in the endoplasmic reticulum of hepatocytes and enterocytes, mediates the formation of apoB containing lipoproteins in the liver and in the intestine [XREF_BIBR].	0	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	0	1	16	17
We hypothesized that reduced apoB secretion in the setting of half-normal MTP levels might be caused by a reduced MTP : apoB ratio in the endoplasmic reticulum , which would reduce the number of apoB-MTP interactions .	We hypothesized that reduced apoB secretion in the setting of half-normal MTP levels might be caused by a reduced MTP : apoB ratio in the endoplasmic reticulum, which would reduce the number of apoB-MTP interactions.	4	22	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	19	20	4	5
The genetic defect underlying abetalipoproteinemia suggests that inhibiting MTP may reduce circulating concentrations of cholesterol and apoB containing lipoproteins ( XREF_FIG ) .	The genetic defect underlying abetalipoproteinemia suggests that inhibiting MTP may reduce circulating concentrations of cholesterol and apoB containing lipoproteins (XREF_FIG).	7	17	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	8	9	16	17
Inhibition of MTP decreases apoB and viral glycoproteins secretion .	Inhibition of MTP decreases apoB and viral glycoproteins secretion.	0	8	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	2	3	4	5
Phospholipid transfer activity of MTP promoted biogenesis of both apoB48 and apoB100 containing VLDL in addition to a phospholipid rich apoB48 containing HDL-size particle .	Phospholipid transfer activity of MTP promoted biogenesis of both apoB48 and apoB100 containing VLDL in addition to a phospholipid rich apoB48 containing HDL-size particle.	2	12	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB100	apoB100	apoB100	4	5	11	12
Here we have examined whether MTP is both necessary and sufficient to mediate the secretion of apoB containing lipoproteins from cells that do not normally express either of these proteins .	Here we have examined whether MTP is both necessary and sufficient to mediate the secretion of apoB containing lipoproteins from cells that do not normally express either of these proteins.	5	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	5	6	16	17
Using either Ld cells or COS cells stably transduced with MTP or MTPv1 and transiently transfected with apoB48 , we found that both isoforms of MTP supported apoB secretion ( XREF_FIG ) .	Using either Ld cells or COS cells stably transduced with MTP or MTPv1 and transiently transfected with apoB48, we found that both isoforms of MTP supported apoB secretion (XREF_FIG).	23	28	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	25	26	27	28
Immunoblotting and ELISA analyses revealed that exogenous expression of MTTP rescued the secretion of ApoB into the supernatants of EM-KO cells ( XREF_FIG ) , while expression of ApoE or MTTP in both BE-KO and EM-KO cells exhibited no effect on the intracellular RNA replication ( XREF_FIG ) .	Immunoblotting and ELISA analyses revealed that exogenous expression of MTTP rescued the secretion of ApoB into the supernatants of EM-KO cells (XREF_FIG), while expression of ApoE or MTTP in both BE-KO and EM-KO cells exhibited no effect on the intracellular RNA replication (XREF_FIG).	7	15	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTTP	expression of MTTP	mttp	ApoB	ApoB	apob	9	10	14	15
In contrast , MTP HKD did not affect apoB100 , apoB48 , and apoE levels in LDL ( XREF_FIG ) , and increased apoB48 in TL ( XREF_FIG ) .	In contrast, MTP HKD did not affect apoB100, apoB48, and apoE levels in LDL (XREF_FIG), and increased apoB48 in TL (XREF_FIG).	3	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB48	apoB48	apoB48	3	4	23	24
Although apoB containing lipoproteins are largely composed of triglycerides , drosophila MTP , which can not transfer triglycerides but can transfer phospholipids , can support apoB secretion .	Although apoB containing lipoproteins are largely composed of triglycerides, drosophila MTP, which can not transfer triglycerides but can transfer phospholipids, can support apoB secretion.	10	26	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	11	12	25	26
These observations suggest that the residual MTP activity ( ~ 60 % of full activity ) in L-Ire1alpha-KO hepatocytes is sufficient to support co-translational lipidation of apoB100 and prevent its degradation , a key component of the first step of VLDL assembly which is crucial for apoB secretion .	These observations suggest that the residual MTP activity (~ 60% of full activity) in L-Ire1alpha-KO hepatocytes is sufficient to support co-translational lipidation of apoB100 and prevent its degradation, a key component of the first step of VLDL assembly which is crucial for apoB secretion.	6	27	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB100	apoB100	apoB100	6	7	26	27
Co- and post-translational lipidation of apoB mediated by MTP is a critical step in VLDL assembly [ XREF_BIBR - XREF_BIBR ] and intracellular abundance of apoB protein is mainly regulated by the availability of lipid substrates , including TG , cholesterol , and phospholipids .	Co- and post-translational lipidation of apoB mediated by MTP is a critical step in VLDL assembly [XREF_BIBR - XREF_BIBR] and intracellular abundance of apoB protein is mainly regulated by the availability of lipid substrates, including TG, cholesterol, and phospholipids.	3	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	8	9	5	6
Although expression of MTP in cells allowed apoB to completely enter the endoplasmic reticulum , it was degraded by a proteolytic process that was inhibited by dithiothreitol ( 1 mM ) and chloroquine ( 100 microM ) , but resistant to N-acetyl-leucyl-leucyl-norleucinal .	Although expression of MTP in cells allowed apoB to completely enter the endoplasmic reticulum, it was degraded by a proteolytic process that was inhibited by dithiothreitol (1 mM) and chloroquine (100 microM), but resistant to N-acetyl-leucyl-leucyl-norleucinal.	1	10	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	expression of MTP	mtp	apoB	apoB	apob	3	4	7	8
MTP mediated lipid transfer allows apoB to fold correctly and evade intracellular degradation via the ubiquitin-proteosome system and other pathways .	MTP mediated lipid transfer allows apoB to fold correctly and evade intracellular degradation via the ubiquitin-proteosome system and other pathways.	0	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	0	1	5	6
This apoB accumulation was suppressed by inhibition of MTP activity , suggesting that these apoB ERAD substrates require at least partial lipidation to enter this particular pathway .	This apoB accumulation was suppressed by inhibition of MTP activity, suggesting that these apoB ERAD substrates require at least partial lipidation to enter this particular pathway.	1	9	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	8	9	1	2
Our study constitutes the initial demonstration that adenovirus mediated transfer of lMTP markedly stimulates MTP expression which in turn stimulates apoB-100 production .	Our study constitutes the initial demonstration that adenovirus mediated transfer of lMTP markedly stimulates MTP expression which in turn stimulates apoB-100 production.	14	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP expression	mtp	apoB-100	apoB-100	apob-100	14	15	20	21
Upregulation of MTTP may promote apoB100 secretion , which together with a decreased TG availability may favor the targeting of apoB100 to IDL and LDL rather than VLDL [ XREF_BIBR ] .	Upregulation of MTTP may promote apoB100 secretion, which together with a decreased TG availability may favor the targeting of apoB100 to IDL and LDL rather than VLDL [XREF_BIBR].	0	6	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTTP	MTTP	MTTP	apoB100	apoB100	apoB100	2	3	5	6
apoB-100 is a major protein component of VLDL , which is present on the surface of VLDL , whereas microsomal triglyceride transfer protein ( MTP ) , a luminal ER protein , mediates the assembly of apoB-100 with neutral lipids .	apoB-100 is a major protein component of VLDL, which is present on the surface of VLDL, whereas microsomal triglyceride transfer protein (MTP), a luminal ER protein, mediates the assembly of apoB-100 with neutral lipids.	22	37	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB-100	apoB-100	apoB-100	24	25	36	37
To determine whether the enzymatic activities of PDI are important for MTP stimulated apoB secretion , the wild type PDI subunit was replaced with an active site mutant , mPDI ( Cys36 --> Ser and Cys380 --> Ser ) , lacking both disulfide shuffling and redox activities .	To determine whether the enzymatic activities of PDI are important for MTP stimulated apoB secretion, the wild type PDI subunit was replaced with an active site mutant, mPDI (Cys36 --> Ser and Cys380 --> Ser), lacking both disulfide shuffling and redox activities.	11	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	11	12	13	14
Apo B-100 and Apo B-48 mutations caused by APOB100 and MTP ( microsomal triglyceride transfer protein ) gene defects are associated with metabolic disorders like abetalipoproteinaemia , hypobetalipoproteinemia and hypercholesterolemia [ XREF_BIBR - XREF_BIBR ] .	Apo B-100 and Apo B-48 mutations caused by APOB100 and MTP (microsomal triglyceride transfer protein) gene defects are associated with metabolic disorders like abetalipoproteinaemia, hypobetalipoproteinemia and hypercholesterolemia [XREF_BIBR - XREF_BIBR].	0	11	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	Apo B-100	Apo B-100	Apo B-100	10	11	0	2
FoxO1 gain-of-function , resulting from either FoxO1 transgenic expression or adenovirus mediated FoxO1 production in the liver , augments hepatic MTP expression and promotes apoB secretion , contributing to a significant induction in both the number and size of VLDL-TG particles .	FoxO1 gain-of-function, resulting from either FoxO1 transgenic expression or adenovirus mediated FoxO1 production in the liver, augments hepatic MTP expression and promotes apoB secretion, contributing to a significant induction in both the number and size of VLDL-TG particles.	0	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	FoxO1 gain-of-function, resulting from either FoxO1 transgenic expression or adenovirus mediated FoxO1 production in the liver, augments hepatic MTP expression	mtp	apoB	apoB	apob	20	21	24	25
Cotransfection of apoB-41 and the MTP 97-kDa subunit in C127 cells enhanced apoB secretion by approximately 5-fold relative to apoB-41 transfection alone , suggesting that MTP is limiting in these cells .	Cotransfection of apoB-41 and the MTP 97-kDa subunit in C127 cells enhanced apoB secretion by approximately 5-fold relative to apoB-41 transfection alone, suggesting that MTP is limiting in these cells.	5	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	5	6	12	13
ApoB is the key component of VLDL particles and microsomal triacylglycerol transfer protein ( MTP ) allows for the addition of TG to apoB , forming the VLDL particle .	ApoB is the key component of VLDL particles and microsomal triacylglycerol transfer protein (MTP) allows for the addition of TG to apoB, forming the VLDL particle.	12	24	allows	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	14	15	23	24
When apoB100 lipidation was blocked by an inhibitor of MTP ( MTPI ) , recovery of cellular apoB100 was markedly reduced , but LAC was only partially ( approximately 50 % ) effective in reversing the induced degradation .	When apoB100 lipidation was blocked by an inhibitor of MTP (MTPI), recovery of cellular apoB100 was markedly reduced, but LAC was only partially (approximately 50%) effective in reversing the induced degradation.	1	11	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB100	apoB100	apoB100	9	10	1	2
Hepatic MTP knockdown decreases but does not eliminate hepatic secretion of apoB containing lipoproteins .	Hepatic MTP knockdown decreases but does not eliminate hepatic secretion of apoB containing lipoproteins.	1	12	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	1	2	11	12
Stable expression of a MTP transgene restored the secretion of both apoB-100 and apoB-48 in L35 cells , indicating that MTP is essential for the secretion of both forms of apoB .	Stable expression of a MTP transgene restored the secretion of both apoB-100 and apoB-48 in L35 cells, indicating that MTP is essential for the secretion of both forms of apoB.	4	14	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB-48	apoB-48	apoB-48	4	5	13	14
Myocardin is a coactivator of serum response factor , which upregulates SM contractile proteins .	Myocardin is a coactivator of serum response factor, which upregulates SM contractile proteins.	0	8	is a coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	serum response factor	serum response factor	serum response factor	0	1	5	8
In SRF deficient embryonic stem cells , myocardin and MRTFs are unable to activate SRF dependent reporter genes , confirming their dependence on SRF .	In SRF deficient embryonic stem cells, myocardin and MRTFs are unable to activate SRF dependent reporter genes, confirming their dependence on SRF.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	myocardin	myocardin	myocardin	SRF	SRF	SRF	7	8	14	15
Acetylation of myocardin by p300 enhances the association of myocardin and SRF as well as the formation of the myocardin-SRF-CArG box ternary complex .	Acetylation of myocardin by p300 enhances the association of myocardin and SRF as well as the formation of the myocardin-SRF-CArG box ternary complex.	0	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	myocardin	Acetylation of myocardin	myocardin	SRF	SRF	srf	2	3	11	12
Myocardin ( Myocd ) is a transcriptional coactivator of SRF , and Myocd-SRF interaction is crucial for the differentiation of SM lineage .	Myocardin (Myocd) is a transcriptional coactivator of SRF, and Myocd-SRF interaction is crucial for the differentiation of SM lineage.	0	10	is a transcriptional coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	SRF	SRF	SRF	0	1	9	10
Such increases in MYOCD may activate SRF , whose promoter region is controlled by two CArG elements XREF_BIBR .	Such increases in MYOCD may activate SRF, whose promoter region is controlled by two CArG elements XREF_BIBR.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MYOCD	MYOCD	MYOCD	SRF	SRF	SRF	3	4	6	7
Myocardin stimulates SRF activity by forming a ternary complex with SRF on DNA and presents its strong transcriptional activation domain to SRF , which otherwise is a very weak activator of transcription .	Myocardin stimulates SRF activity by forming a ternary complex with SRF on DNA and presents its strong transcriptional activation domain to SRF, which otherwise is a very weak activator of transcription.	0	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	SRF	SRF	SRF	0	1	2	3
Another SRF cofactor , myocardin was also used in the transfection assay ; myocardin overexpression induced SRF gene promoter activity by approximately 5-fold ( P < 0.01 , n = 3 ) , while p49 and STRAP repressed the SRF-promoter activity that was induced by myocardin plasmid transfection ( P < 0.01 , n = 3 ) .	Another SRF cofactor, myocardin was also used in the transfection assay; myocardin overexpression induced SRF gene promoter activity by approximately 5-fold (P < 0.01, n = 3), while p49 and STRAP repressed the SRF-promoter activity that was induced by myocardin plasmid transfection (P < 0.01, n = 3).	13	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	myocardin	myocardin overexpression	myocardin	SRF	SRF	srf	13	14	16	17
SRF can be activated by at least two families of coactivators , p62TCF and myocardin and MKL .	SRF can be activated by at least two families of coactivators, p62TCF and myocardin and MKL.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	myocardin	myocardin	myocardin	SRF	SRF	SRF	14	15	0	1
These findings identify a novel mechanism that regulates levels of MYOCD dependent activation of the SRF genetic program differentially in cardiac and smooth muscle .	These findings identify a novel mechanism that regulates levels of MYOCD dependent activation of the SRF genetic program differentially in cardiac and smooth muscle.	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MYOCD	MYOCD	MYOCD	SRF	SRF	SRF	10	11	15	16
Myocardin and MRTFs comprise a previously uncharacterized family of SRF cofactors with the potential to modulate SRF target genes in a wide range of tissues .	Myocardin and MRTFs comprise a previously uncharacterized family of SRF cofactors with the potential to modulate SRF target genes in a wide range of tissues.	0	18	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	SRF	SRF	SRF	0	1	16	17
Myocardin related transcription factors ( MRTFs ) are robust coactivators of serum response factor ( SRF ) .	Myocardin related transcription factors (MRTFs) are robust coactivators of serum response factor (SRF).	0	14	are robust coactivators	Positive_activation_copula_1	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	serum response factor	serum response factor	serum response factor	0	1	11	14
There are previous reports of MYOCD working to stimulate gene expression in an SRF independent manner through distinct cis regulatory elements .	There are previous reports of MYOCD working to stimulate gene expression in an SRF independent manner through distinct cis regulatory elements.	3	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MYOCD	MYOCD	MYOCD	SRF	SRF	SRF	5	6	13	14
Myocardin is a transcriptional co-activator of serum response factor ( SRF ) and can be degraded through ubiquitin-proteasome system .	Myocardin is a transcriptional co-activator of serum response factor (SRF) and can be degraded through ubiquitin-proteasome system.	0	15	is a transcriptional co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	serum response factor	serum response factor	serum response factor	0	1	6	9
Because Myocd is a coactivator of SRF in regulating SMC marker gene transcription XREF_BIBR , XREF_BIBR , we sought to determine if DOCK2 alters Myocd and SRF activated SMC marker gene transcription .	Because Myocd is a coactivator of SRF in regulating SMC marker gene transcription XREF_BIBR, XREF_BIBR, we sought to determine if DOCK2 alters Myocd and SRF activated SMC marker gene transcription.	1	8	is a coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	Myocd	Myocd	Myocd	SRF	SRF	SRF	1	2	6	7
Myocardin is a coactivator of serum response factor ( SRF ) , which together promotes smooth muscle differentiation .	Myocardin is a coactivator of serum response factor (SRF), which together promotes smooth muscle differentiation.	0	8	is a coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	serum response factor	serum response factor	serum response factor	0	1	5	8
KLF4 inhibits myocardin expression , a potent coactivator of serum response factor ( SRF ) [ XREF_BIBR , XREF_BIBR ] , and prevents SRF and myocardin from associating with mesenchymal gene promoters [ XREF_BIBR ] .	KLF4 inhibits myocardin expression, a potent coactivator of serum response factor (SRF) [XREF_BIBR, XREF_BIBR], and prevents SRF and myocardin from associating with mesenchymal gene promoters [XREF_BIBR].	0	25	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	myocardin	KLF4 inhibits myocardin expression	myocardin	SRF	SRF	srf	2	3	23	24
Moreover , we found that inhibition of SRF and myocardin with a specific inhibitor , CCG-100602 , not only dramatically reduced SRF and myocardin activity in aortic VSMCs from SHR , attenuating the transcription of its downstream stiffness associated genes , but also significantly decreased the intrinsic stiffness of VSMCs from SHR TA .	Moreover, we found that inhibition of SRF and myocardin with a specific inhibitor, CCG-100602, not only dramatically reduced SRF and myocardin activity in aortic VSMCs from SHR, attenuating the transcription of its downstream stiffness associated genes, but also significantly decreased the intrinsic stiffness of VSMCs from SHR TA.	5	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	myocardin	myocardin	myocardin	SRF	SRF	SRF	9	10	21	22
The recent discovery of the myocardin family explained the old enigma of how SRF could fulfill these separate ( growth promoting and myogenic ) roles : binding of myocardin proteins confers muscle specificity to and enhances the activity of SRF .	The recent discovery of the myocardin family explained the old enigma of how SRF could fulfill these separate (growth promoting and myogenic) roles : binding of myocardin proteins confers muscle specificity to and enhances the activity of SRF.	28	40	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	myocardin	myocardin	myocardin	SRF	SRF	SRF	28	29	39	40
Myocardin related transcription factors ( MRTFs ) are key coactivators of SRF that link actin dynamics to SRF mediated gene transcription .	Myocardin related transcription factors (MRTFs) are key coactivators of SRF that link actin dynamics to SRF mediated gene transcription.	0	12	are key coactivators	Positive_activation_copula_1	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	SRF	SRF	SRF	0	1	11	12
MYOCD gene transfer upregulated both MYOCD and SRF ( XREF_FIG ) and decreased Abeta clearance by 65 % ( XREF_FIG ) .	MYOCD gene transfer upregulated both MYOCD and SRF (XREF_FIG) and decreased Abeta clearance by 65% (XREF_FIG).	0	8	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MYOCD	MYOCD	MYOCD	SRF	SRF	SRF	0	1	7	8
Myocardin and Myocardin Related Transcription Factors A and B ( MRTF-A/MAL/MKL1 and MRTF-B and MKL2 ) are essential for SRF function and enhance SRF activity .	Myocardin and Myocardin Related Transcription Factors A and B (MRTF-A/MAL/MKL1 and MRTF-B and MKL2) are essential for SRF function and enhance SRF activity.	0	24	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	SRF	SRF	SRF	0	1	23	24
In primary HSCs from normal and fibrotic rat liver , we demonstrate that myocardin , a canonical SRF cofactor , is upregulated in hepatic myofibroblasts and differentially regulates SM alpha-actin , gamma-actin , and beta-actins through activation of an ATTA box in the SM alpha-actin and a CCAAT box in gamma-actin and beta-actin promoters , respectively ; moreover , myocardin differentially activated serum response factor ( SRF ) in CArG boxes of actin promoters .	In primary HSCs from normal and fibrotic rat liver, we demonstrate that myocardin, a canonical SRF cofactor, is upregulated in hepatic myofibroblasts and differentially regulates SM alpha-actin, gamma-actin, and beta-actins through activation of an ATTA box in the SM alpha-actin and a CCAAT box in gamma-actin and beta-actin promoters, respectively; moreover, myocardin differentially activated serum response factor (SRF) in CArG boxes of actin promoters.	59	65	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	myocardin	myocardin	myocardin	serum response factor	serum response factor	serum response factor	59	60	62	65
By contrast , myocardin induced transactivation was not observed in SRF (-/-) ES cells but could be rescued by forced expression of SRF or the SRF DNA binding domain .	By contrast, myocardin induced transactivation was not observed in SRF (-/-) ES cells but could be rescued by forced expression of SRF or the SRF DNA binding domain.	3	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	myocardin	myocardin	myocardin	SRF	SRF	SRF	3	4	10	11
Myocardin is a coactivator of serum response factor ( SRF ) required for vascular smooth muscle cell ( VSMC ) differentiation .	Myocardin is a coactivator of serum response factor (SRF) required for vascular smooth muscle cell (VSMC) differentiation.	0	8	is a coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	serum response factor	serum response factor	serum response factor	0	1	5	8
Myocardin is a coactivator of serum response factor which specifically expressed in cardiac and smooth muscle cells [ XREF_BIBR ] , and promoter variation of this gene was proposed as a biomarker of cardiac hypertrophy [ XREF_BIBR ] .	Myocardin is a coactivator of serum response factor which specifically expressed in cardiac and smooth muscle cells [XREF_BIBR], and promoter variation of this gene was proposed as a biomarker of cardiac hypertrophy [XREF_BIBR].	0	11	is a coactivator	Positive_regulation_copula_1	Positive_activation	Positive_regulation	Myocardin	Myocardin	myocardin	serum response factor	serum response factor which specifically expressed	serum response factor	0	1	5	8
Myocardin is a transcriptional co-activator of serum response factor ( Srf ) , which is a key regulator of the expression of smooth and cardiac muscle genes .	Myocardin is a transcriptional co-activator of serum response factor (Srf), which is a key regulator of the expression of smooth and cardiac muscle genes.	0	9	is a transcriptional co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	serum response factor	serum response factor	serum response factor	0	1	6	9
Myocardin related transcription factors A and B ( MRTFs ) activate serum response factor driven transcription in response to Rho signaling and changes in actin dynamics .	Myocardin related transcription factors A and B (MRTFs) activate serum response factor driven transcription in response to Rho signaling and changes in actin dynamics.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	serum response factor	serum response factor	serum response factor	0	1	11	14
MYOCD upregulated SRF , as reported previously XREF_BIBR , by augmenting SRF promoter activity , most likely in a CArG dependent manner ( data not shown ) .	MYOCD upregulated SRF, as reported previously XREF_BIBR, by augmenting SRF promoter activity, most likely in a CArG dependent manner (data not shown).	0	5	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MYOCD	MYOCD	MYOCD	SRF	SRF	SRF	0	1	2	3
Myocardin is a coactivator of SRF and KLF4 can affect both myocardin and SRF .	Myocardin is a coactivator of SRF and KLF4 can affect both myocardin and SRF.	0	7	is a coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	Myocardin	Myocardin	Myocardin	SRF	SRF	SRF	0	1	5	6
The MyD88 and IRAK1 genes produce long proinflammatory mRNAs ( MyD88 L and IRAK1 ) and shorter anti-inflammatory mRNAs ( MyD88 S and IRAK1c ) .	The MyD88 and IRAK1 genes produce long proinflammatory mRNAs (MyD88 L and IRAK1) and shorter anti-inflammatory mRNAs (MyD88 S and IRAK1c).	1	14	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK1	IRAK1	IRAK1	1	2	13	14
Specifically involved is MyD88 protein activation of the complex IRAK ( IL-1 receptor associated Kinase ) -TRAF 6 ( TNF receptor associated factor ) , the latter belongs to the ubiquitin ligases class ( E3 ligases ) and appearsto be essential for the NF-kappaB uncoupling , its inhibitory protein ( Ikappa-B ) .	Specifically involved is MyD88 protein activation of the complex IRAK (IL-1 receptor associated Kinase) -TRAF 6 (TNF receptor associated factor), the latter belongs to the ubiquitin ligases class (E3 ligases) and appearsto be essential for the NF-kappaB uncoupling, its inhibitory protein (Ikappa-B).	3	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK	IRAK	IRAK	3	4	9	10
This level of MyD88 is enough to drive IRAK , TRAF6 , and NFkB to the high level of 7 , which is enough to keep the pro inflammatory cytokines high , but not enough to drive PPARg low , so the IFNg autocrine bridge can be crossed .	This level of MyD88 is enough to drive IRAK, TRAF6, and NFkB to the high level of 7, which is enough to keep the pro inflammatory cytokines high, but not enough to drive PPARg low, so the IFNg autocrine bridge can be crossed.	1	13	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	level of MyD88	myd88	IRAK	IRAK	irak	3	4	8	9
Indeed , we found that overexpression of myeloid differentiation primary response gene 88 ( MyD88 ) , an adaptor molecule that drives TLR signaling , induced IRAK1 expression and that piceatannol , a Syk inhibitor , successfully suppressed the MyD88 dependent upregulation of IRAK1 under LPS treatment conditions .	Indeed, we found that overexpression of myeloid differentiation primary response gene 88 (MyD88), an adaptor molecule that drives TLR signaling, induced IRAK1 expression and that piceatannol, a Syk inhibitor, successfully suppressed the MyD88 dependent upregulation of IRAK1 under LPS treatment conditions.	39	44	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK1	IRAK1	IRAK1	39	40	43	44
As MyD88 binds to IRAK-1KD and was recently reported to bind IRAK-4 , the simplest explanation for the observed finding was that MyD88 modulates contact of IRAK-1 and IRAK-4 .	As MyD88 binds to IRAK-1KD and was recently reported to bind IRAK-4, the simplest explanation for the observed finding was that MyD88 modulates contact of IRAK-1 and IRAK-4.	22	28	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK-1	IRAK-1	IRAK-1	22	23	26	27
Upon stimulation , Myd88 is recruited to the TLR as a dimer , and activates the kinases IRAK1 and IRAK4 .	Upon stimulation, Myd88 is recruited to the TLR as a dimer, and activates the kinases IRAK1 and IRAK4.	3	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Myd88	Myd88	Myd88	IRAK1	IRAK1	IRAK1	3	4	17	18
Ligands of MyD88 associated TLRs induce activation of IRAK4 and IRAK1 , followed by TRAF6 associated signaling that leads to nuclear translocation of the transcription factors NF-kappaB and IRF5 .	Ligands of MyD88 associated TLRs induce activation of IRAK4 and IRAK1, followed by TRAF6 associated signaling that leads to nuclear translocation of the transcription factors NF-kappaB and IRF5.	2	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK1	IRAK1	IRAK1	2	3	10	11
MyD88 activates the downstream signaling molecule IRAK , which then interacts with TRAF6 .	MyD88 activates the downstream signaling molecule IRAK, which then interacts with TRAF6.	0	13	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	MyD88	MyD88	myd88	IRAK	IRAK, which then interacts with TRAF6	irak	0	1	6	7
MyD88 activates IL-1R-associated kinases ( IRAK1 and IRAK4 ) and TNF receptor associated factor 6 ( TRAF6 ) .	MyD88 activates IL-1R-associated kinases (IRAK1 and IRAK4) and TNF receptor associated factor 6 (TRAF6).	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK1	IRAK1	IRAK1	0	1	5	6
MyD88 activates the IL-1 receptor associated kinases ( IRAKs ) IRAK4 and IRAK1 , which finally activates IKK-NF-kappaB and mitogen activated protein kinases .	MyD88 activates the IL-1 receptor associated kinases (IRAKs) IRAK4 and IRAK1, which finally activates IKK-NF-kappaB and mitogen activated protein kinases.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK1	IRAK1	IRAK1	0	1	12	13
In this study , we identified that MALAT1 up-regulated the expression of MyD88 through increasing the H3 histone acetylation of MyD88 promoter , thereby increasing IRAK1 and TRAF6 protein .	In this study, we identified that MALAT1 up-regulated the expression of MyD88 through increasing the H3 histone acetylation of MyD88 promoter, thereby increasing IRAK1 and TRAF6 protein.	7	28	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MALAT1 up-regulated the expression of MyD88	myd88	IRAK1	IRAK1	irak1	12	13	25	26
MyD88 activates the IRAK complex , containing the protein kinase IRAK4 , leading to activation of the IkappaB kinase ( IKK ) complex .	MyD88 activates the IRAK complex, containing the protein kinase IRAK4, leading to activation of the IkappaB kinase (IKK) complex.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK	IRAK	IRAK	0	1	3	4
In accordance with previous results [ XREF_BIBR , XREF_BIBR ] , we showed that the overexpression of MyD88 , but not TRIF , triggered IRAK1 upregulation ( XREF_FIG ) , indicating that MyD88 is required for IRAK1 expression and activation .	In accordance with previous results [XREF_BIBR, XREF_BIBR], we showed that the overexpression of MyD88, but not TRIF, triggered IRAK1 upregulation (XREF_FIG), indicating that MyD88 is required for IRAK1 expression and activation.	15	25	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	overexpression of MyD88	myd88	IRAK1	IRAK1	irak1	17	18	24	25
MyD88 activates IL-1R associated kinases ( IRAKs ) , IRAK-1 and IRAK-4 , and TNF-receptor associated factor-6 ( TRAF-6 ) [ XREF_BIBR , XREF_BIBR ] .	MyD88 activates IL-1R associated kinases (IRAKs), IRAK-1 and IRAK-4, and TNF-receptor associated factor-6 (TRAF-6) [XREF_BIBR, XREF_BIBR].	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK-1	IRAK-1	IRAK-1	0	1	9	10
Upon binding with one of the TIR receptor complexes , MyD88 homodimers activate the IRAK complex , which phosphorylates downstream kinases and transcription factors including NF-kappaB , further triggering the inflammatory response .	Upon binding with one of the TIR receptor complexes, MyD88 homodimers activate the IRAK complex, which phosphorylates downstream kinases and transcription factors including NF-kappaB, further triggering the inflammatory response.	10	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK	IRAK	IRAK	10	11	14	15
MyD88 recruits and activates IRAK -- 4 , which further activates IRAK -1 .	MyD88 recruits and activates IRAK -- 4, which further activates IRAK -1.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK	IRAK	IRAK	0	1	4	5
The TIR domain of MyD88 can combine with the TIR domain of TLR or IL-1R to activate Interleukin receptor associated kinase ( IRAK )-1/4 and TNF receptor associated factor-6 ( TRAF-6 ) .	The TIR domain of MyD88 can combine with the TIR domain of TLR or IL-1R to activate Interleukin receptor associated kinase (IRAK)-1/4 and TNF receptor associated factor-6 (TRAF-6).	2	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK	IRAK	IRAK	4	5	22	23
mTOR activates Stat3 by phosphorylation at serine 727 under insulin stimulation , which translocates to the nucleus of MPPs to bind to the promoter of Ikaros , leading to its transcription priming .	mTOR activates Stat3 by phosphorylation at serine 727 under insulin stimulation, which translocates to the nucleus of MPPs to bind to the promoter of Ikaros, leading to its transcription priming.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Stat3	Stat3	Stat3	0	1	2	3
These data suggest that mTOR acts as an upstream factor to activate Stat3 by its phosphorylation .	These data suggest that mTOR acts as an upstream factor to activate Stat3 by its phosphorylation.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Stat3	Stat3	Stat3	4	5	12	13
The phosphoinositide 3-kinase ( PI3K ) pathway was also activated , leading to m-TOR mediated activation of STAT3 .	The phosphoinositide 3-kinase (PI3K) pathway was also activated, leading to m-TOR mediated activation of STAT3.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	m-TOR	m-TOR	m-TOR	STAT3	STAT3	STAT3	13	14	17	18
In addition , we found that rapamycin decreased basal p-STAT3 levels and IL-6-induced p-STAT3 ; this was consistent with other reports that mTOR activated STAT3 .	In addition, we found that rapamycin decreased basal p-STAT3 levels and IL-6-induced p-STAT3; this was consistent with other reports that mTOR activated STAT3.	22	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	22	23	24	25
Activated PI3K stimulates Akt and mTOR , and mTOR signaling then activates NF-kappaB and STAT3 .	Activated PI3K stimulates Akt and mTOR, and mTOR signaling then activates NF-kappaB and STAT3.	8	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	8	9	14	15
mTOR activation results in subsequent activation of S6K and STAT3 , as well as suppression ( i.e ., phosphorylation ) of 4E-BP1 , leading to cell cycle progression and inhibition of apoptosis .	mTOR activation results in subsequent activation of S6K and STAT3, as well as suppression (i.e., phosphorylation) of 4E-BP1, leading to cell cycle progression and inhibition of apoptosis.	0	10	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	0	1	9	10
Accordingly , we observed increased signal transducer and activator of transcription 3 ( STAT3 ) and mammalian target of rapamycin ( mTOR ) phosphorylation in tubules with preneoplastic phenotypes .	Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) phosphorylation in tubules with preneoplastic phenotypes.	4	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin (mTOR) phosphorylation	mammalian target of rapamycin	STAT3	STAT3	stat3	16	20	13	14
Activation of mTOR pathway in mononuclear phagocytic cells enhances STAT3 activity and in turn IL-10 production but reduces the activation of the transcription factor NF-kappaB , the master regulator of proinflammatory responses XREF_BIBR .	Activation of mTOR pathway in mononuclear phagocytic cells enhances STAT3 activity and in turn IL-10 production but reduces the activation of the transcription factor NF-kappaB, the master regulator of proinflammatory responses XREF_BIBR.	2	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	2	3	9	10
According to previous studies , mTOR as a serine kinase positively activates STAT3 .	According to previous studies, mTOR as a serine kinase positively activates STAT3.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	5	6	12	13
Expression of a kinase dead PKC-eta ( PKC-etaKR ) construct reduced the basal and PMA evoked proliferation of PKC-eta-expressing U-251 GBM cells , as well as abrogated the PMA induced activation of Akt , mTOR , and the mTOR targets 4E-BP1 and STAT-3 .	Expression of a kinase dead PKC-eta (PKC-etaKR) construct reduced the basal and PMA evoked proliferation of PKC-eta-expressing U-251 GBM cells, as well as abrogated the PMA induced activation of Akt, mTOR, and the mTOR targets 4E-BP1 and STAT-3.	30	43	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	STAT-3	STAT-3	STAT-3	34	35	42	43
Our results show a novel pathway in which FRAP is recruited to promote gliogenesis by activating Stat3 .	Our results show a novel pathway in which FRAP is recruited to promote gliogenesis by activating Stat3.	8	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FRAP	FRAP	FRAP	Stat3	Stat3	Stat3	8	9	16	17
In related studies , the activation of mTOR in mononuclear phagocytes increased the activity of signal transducer and activator of transcription 3 ( STAT3 ) and the production of IL-10 , but decreased the production of pro inflammatory molecules ( such as IL-12 ) and nuclear factor-kappaB ( NF-kappaB ) activation ; mTOR inhibition had reciprocal effects XREF_BIBR .	In related studies, the activation of mTOR in mononuclear phagocytes increased the activity of signal transducer and activator of transcription 3 (STAT3) and the production of IL-10, but decreased the production of pro inflammatory molecules (such as IL-12) and nuclear factor-kappaB (NF-kappaB) activation; mTOR inhibition had reciprocal effects XREF_BIBR.	5	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	7	8	23	24
These data provide a novel mechanism whereby p27 deregulation by oncogenic PI3K and mTOR activates pSTAT3 to drive human cancer progression .	These data provide a novel mechanism whereby p27 deregulation by oncogenic PI3K and mTOR activates pSTAT3 to drive human cancer progression.	8	16	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	pSTAT3	pSTAT3	pSTAT3	13	14	15	16
21 CNTF has been shown to stimulate mTOR activation of STAT3 , hence implicating CNTF and mTOR as transcriptional regulators in neuroblastoma cells .	21 CNTF has been shown to stimulate mTOR activation of STAT3, hence implicating CNTF and mTOR as transcriptional regulators in neuroblastoma cells.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	7	8	10	11
To determine whether mTOR activates Stat3 upon insulin stimulation in MPPs , we performed immunoblotting with MPP cell lysates obtained from different treatments .	To determine whether mTOR activates Stat3 upon insulin stimulation in MPPs, we performed immunoblotting with MPP cell lysates obtained from different treatments.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Stat3	Stat3	Stat3	3	4	5	6
These results are all consistent with the conclusion that BMP4 causes glial differentiation by FRAP mediated Stat3 activation and smooth muscle differentiation by a FRAP independent , SMAD mediated mechanism .	These results are all consistent with the conclusion that BMP4 causes glial differentiation by FRAP mediated Stat3 activation and smooth muscle differentiation by a FRAP independent, SMAD mediated mechanism.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	FRAP	FRAP	FRAP	Stat3	Stat3	Stat3	14	15	16	17
Binding to MyD88 enables IRAK4 to phosphorylate the subsequently recruited IRAK1 , thereby inducing the activation of its kinase activity .	Binding to MyD88 enables IRAK4 to phosphorylate the subsequently recruited IRAK1, thereby inducing the activation of its kinase activity.	0	5	enables	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK4	IRAK4	IRAK4	2	3	4	5
In turn , MyD88 induced events resulted in successive activation of nuclear factor-kappaB and mitogen activated protein kinase by association with the signal adaptors IL-1R-associated kinase ( IRAK ) 1 , IRAK4 , and TNF receptor activated factor 6 , respectively , eventually leading to expression of appropriate genes , such as Il4 , Il13 , Ifngamma , Tnf , and Fasl , involved in cell differentiation , growth , survival , and apoptosis .	In turn, MyD88 induced events resulted in successive activation of nuclear factor-kappaB and mitogen activated protein kinase by association with the signal adaptors IL-1R-associated kinase (IRAK) 1, IRAK4, and TNF receptor activated factor 6, respectively, eventually leading to expression of appropriate genes, such as Il4, Il13, Ifngamma, Tnf, and Fasl, involved in cell differentiation, growth, survival, and apoptosis.	3	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK4	IRAK4	IRAK4	3	4	31	32
The addition of MyD88 , however , significantly enhanced IRAK-4-induced IRAK-1KD phosphorylation , suggesting that MyD88 stimulates IRAK-4 ' s activity ( XREF_FIG ) .	The addition of MyD88, however, significantly enhanced IRAK-4-induced IRAK-1KD phosphorylation, suggesting that MyD88 stimulates IRAK-4 's activity (XREF_FIG).	15	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK-4	IRAK-4	IRAK-4	15	16	17	18
The first step in LPS activation of TLR4 is formation of a ternary complex with LPS binding protein and CD14 , which then interacts with TLR4 and the adaptor protein MD2 , leading to activation of MyD88 , which activates IRAK-4 and TRAF6 .	The first step in LPS activation of TLR4 is formation of a ternary complex with LPS binding protein and CD14, which then interacts with TLR4 and the adaptor protein MD2, leading to activation of MyD88, which activates IRAK-4 and TRAF6.	34	42	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK-4	IRAK-4	IRAK-4	36	37	40	41
Myd88 sequentially activates IRAK4 , TRAF6 , TAK1 , and NF-kB and MAP kinases , upregulating inflammatory cytokines and interferons ( IFNs ) .	Myd88 sequentially activates IRAK4, TRAF6, TAK1, and NF-kB and MAP kinases, upregulating inflammatory cytokines and interferons (IFNs).	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Myd88	Myd88	Myd88	IRAK4	IRAK4	IRAK4	0	1	3	4
TLR signaling via JNK involves the TLR adaptor MyD88 , which activates IRAK4 and TRAF6 , in turn activating TAK1 .	TLR signaling via JNK involves the TLR adaptor MyD88, which activates IRAK4 and TRAF6, in turn activating TAK1.	4	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK4	IRAK4	IRAK4	8	9	12	13
LPS caused a MyD88 dependent activation of IRAK4 .	LPS caused a MyD88 dependent activation of IRAK4.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK4	IRAK4	IRAK4	3	4	7	8
It is well-known that IRAK4 is activated by upstream signaling adaptor MyD88 docking via their shared death domains and complexes with IRAK1 to activate downstream E3 ubiquitin ligase TRAF6 .	It is well-known that IRAK4 is activated by upstream signaling adaptor MyD88 docking via their shared death domains and complexes with IRAK1 to activate downstream E3 ubiquitin ligase TRAF6.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK4	IRAK4	IRAK4	11	12	4	5
In vertebrates , MyD88 then activates IRAK4 via the interaction between the death domain of MyD88 and the death domain of IRAK4 .	In vertebrates, MyD88 then activates IRAK4 via the interaction between the death domain of MyD88 and the death domain of IRAK4.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyD88	MyD88	MyD88	IRAK4	IRAK4	IRAK4	3	4	6	7
83 MYOD1 activates p21 ( CDKN1A ) to arrest the cell cycle and promotes differentiation of muscle progenitors .	83 MYOD1 activates p21 (CDKN1A) to arrest the cell cycle and promotes differentiation of muscle progenitors.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MYOD1	MYOD1	MYOD1	p21	p21	p21	1	2	3	4
For example , independent of its role as a transcriptional activator of muscle specific genes , MyoD can induce p21 during myogenic differentiation .	For example, independent of its role as a transcriptional activator of muscle specific genes, MyoD can induce p21 during myogenic differentiation.	16	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyoD	MyoD	MyoD	p21	p21	p21	16	17	19	20
Unexpectedly , loss of MyoD expression did not impede IGF mediated survival , revealing a second pathway involving activation by PI3-kinase of Akt , and subsequent induction of p21 .	Unexpectedly, loss of MyoD expression did not impede IGF mediated survival, revealing a second pathway involving activation by PI3-kinase of Akt, and subsequent induction of p21.	4	29	impede	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MyoD	MyoD expression	myod	p21	p21	p21	4	5	28	29
One pathway involves stimulation of MyoD expression by PI3-kinase , and subsequent induction of p21 by MyoD ; the other involves activation of Akt by PI3-kinase , followed by stimulation of p21 expression .	One pathway involves stimulation of MyoD expression by PI3-kinase, and subsequent induction of p21 by MyoD; the other involves activation of Akt by PI3-kinase, followed by stimulation of p21 expression.	2	17	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MyoD	MyoD	MyoD	p21	p21	p21	16	17	14	15
In normal muscle , the CDIs p21 and the p16 INK4 -related protein p18 are highly expressed , with p21 being induced by MyoD expression .	In normal muscle, the CDIs p21 and the p16 INK4 -related protein p18 are highly expressed, with p21 being induced by MyoD expression.	16	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MyoD	MyoD expression	myod	p21	p21	p21	23	24	19	20
Ectopic TWIST2 suppressed the p21 and MCK promoters activated by the exogenous addition of E2A and MyoD and this inhibitory effect of TWIST2 was cancelled by the introduction of short hairpin RNA ( shRNA ) against TWIST2 .	Ectopic TWIST2 suppressed the p21 and MCK promoters activated by the exogenous addition of E2A and MyoD and this inhibitory effect of TWIST2 was cancelled by the introduction of short hairpin RNA (shRNA) against TWIST2.	4	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MyoD	MyoD	MyoD	p21	p21	p21	16	17	4	5
These results indicate that MyoD promotes muscle cell survival by inducing p21 .	These results indicate that MyoD promotes muscle cell survival by inducing p21.	4	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyoD	MyoD	MyoD	p21	p21	p21	4	5	11	12
Ectopic expression of MyoD induced p21 , and inhibition of p21 blocked MyoD mediated survival , thus defining one PI3-kinase-dependent pathway as leading first to MyoD , and then to p21 and survival .	Ectopic expression of MyoD induced p21, and inhibition of p21 blocked MyoD mediated survival, thus defining one PI3-kinase-dependent pathway as leading first to MyoD, and then to p21 and survival.	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	MyoD	MyoD	MyoD	p21	p21	p21	3	4	5	6
MyoD can promote cell cycle arrest by activation of the cyclin dependent kinase inhibitor p21 XREF_BIBR , which inhibits a wide range of CDKs essential for cell cycle progression XREF_BIBR .	MyoD can promote cell cycle arrest by activation of the cyclin dependent kinase inhibitor p21 XREF_BIBR, which inhibits a wide range of CDKs essential for cell cycle progression XREF_BIBR.	0	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyoD	MyoD	MyoD	p21	p21	p21	0	1	14	15
Forced expression of MyoD induces p21 , and inhibition of p21 expression blocks MyoD mediated survival , thus defining one pathway as leading through PI3-kinase to MyoD , and then to p21 and survival .	Forced expression of MyoD induces p21, and inhibition of p21 expression blocks MyoD mediated survival, thus defining one pathway as leading through PI3-kinase to MyoD, and then to p21 and survival.	1	6	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MyoD	expression of MyoD	myod	p21	p21	p21	3	4	5	6
This MyoD mediated induction of p21 during differentiation does not require p53 .	This MyoD mediated induction of p21 during differentiation does not require p53.	0	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyoD	MyoD	MyoD	p21	p21	p21	1	2	5	6
Our observations that mTOR inhibition suppresses SGK1 activity and , conversely , that dominant negative SGK1 inhibits mTOR activity suggest the existence of a feedforward loop between SGK1 and mTOR in laforin deficient cells ; the activation of one results in the activation of the other .	Our observations that mTOR inhibition suppresses SGK1 activity and, conversely, that dominant negative SGK1 inhibits mTOR activity suggest the existence of a feedforward loop between SGK1 and mTOR in laforin deficient cells; the activation of one results in the activation of the other.	3	7	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	SGK1	SGK1	SGK1	3	4	6	7
Rapamycin , an inhibitior of mTOR , can inhibit SGK1 activity downstream of the mTORC1 complex [ XREF_BIBR ] and may , as a result , increase FoxO mediated transcription of anti-oxidant gene targets .	Rapamycin, an inhibitior of mTOR, can inhibit SGK1 activity downstream of the mTORC1 complex [XREF_BIBR] and may, as a result, increase FoxO mediated transcription of anti-oxidant gene targets.	3	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	SGK1	SGK1	SGK1	5	6	9	10
Both mTOR complexes may activate SGK .	Both mTOR complexes may activate SGK.	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	SGK	SGK	SGK	1	2	5	6
SGK1 is activated by insulin and growth factors via phosphatidylinositol-3-kinase , 3-phosphoinositide dependent kinase PDK1 and mTOR .	SGK1 is activated by insulin and growth factors via phosphatidylinositol-3-kinase, 3-phosphoinositide dependent kinase PDK1 and mTOR.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	SGK1	SGK1	SGK1	16	17	0	1
The mTOR complex 2 also promotes the activity of SGK1 , another important kinase in the control of cell proliferation [ XREF_BIBR ] .	The mTOR complex 2 also promotes the activity of SGK1, another important kinase in the control of cell proliferation [XREF_BIBR].	1	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	SGK1	SGK1	SGK1	1	2	9	10
As mTOR is a critical activator of SGK1 , we investigated whether proliferation of Akt-inhibitor-resistant cells would be sensitive to mTOR inhibitors .	As mTOR is a critical activator of SGK1, we investigated whether proliferation of Akt-inhibitor-resistant cells would be sensitive to mTOR inhibitors.	1	8	is a critical activator	Positive_activation_copula_1	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	SGK1	SGK1	SGK1	1	2	7	8
Once it is active , mTOR can also modulate Raptor activity that can be blocked by rapamycin .	Once it is active, mTOR can also modulate Raptor activity that can be blocked by rapamycin.	5	10	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Raptor	Raptor	Raptor	5	6	9	10
Rapalog induced inhibition of phosphorylation of mTOR residues Ser2448 and Ser2481 is therefore required to inhibit mTORC1 and Raptor addicted cell growth and survival that was independent of AKT activation .	Rapalog induced inhibition of phosphorylation of mTOR residues Ser2448 and Ser2481 is therefore required to inhibit mTORC1 and Raptor addicted cell growth and survival that was independent of AKT activation.	4	19	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of mTOR residues Ser2448 and Ser2481	mtor	Raptor	Raptor	raptor	6	7	18	19
That lipin 1 did not interact with mTOR alone and that mTOR did not increase the abundance of raptor copurifying with lipin 1 suggest that lipin 1 interacts with mTORC1 via raptor .	That lipin 1 did not interact with mTOR alone and that mTOR did not increase the abundance of raptor copurifying with lipin 1 suggest that lipin 1 interacts with mTORC1 via raptor.	11	19	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	raptor	raptor	raptor	11	12	18	19
In contrast , knockdown of mTOR significantly reduced the binding of raptor as well as mTOR to CaM ( XREF_FIG ) , suggesting that the interaction between mTOR and CaM is independent of raptor .	In contrast, knockdown of mTOR significantly reduced the binding of raptor as well as mTOR to CaM (XREF_FIG), suggesting that the interaction between mTOR and CaM is independent of raptor.	3	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	raptor	raptor	raptor	5	6	11	12
On the other hand , targeted induction of the WNT7B gene in osteoblasts dramatically enhanced bone mass due to increased osteoblast number , activity , and significantly stimulated bone formation , but not when the cofactor for mTOR signaling Raptor was absent [ XREF_BIBR ] .	On the other hand, targeted induction of the WNT7B gene in osteoblasts dramatically enhanced bone mass due to increased osteoblast number, activity, and significantly stimulated bone formation, but not when the cofactor for mTOR signaling Raptor was absent [XREF_BIBR].	35	40	signaling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Raptor	Raptor	Raptor	37	38	39	40
A proximal 11q13 core including S6K2 was identified as involved in the coamplification and coexpression with 8p12 , suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression .	A proximal 11q13 core including S6K2 was identified as involved in the coamplification and coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression.	19	26	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K2	S6K2	S6K2	22	23	24	25
While expression of an mTOR variant targeted to the nucleus increases activation of S6K2 , nuclear localization of S6K2 is not indispensable for activation of this kinase .	While expression of an mTOR variant targeted to the nucleus increases activation of S6K2, nuclear localization of S6K2 is not indispensable for activation of this kinase.	1	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	expression of an mTOR	mtor	S6K2	S6K2	s6k2	4	5	13	14
Mtss1 drives enhanced Rac1 activation during cell-cell junction stabilization .	Mtss1 drives enhanced Rac1 activation during cell-cell junction stabilization.	0	4	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mtss1	Mtss1	Mtss1	Rac1	Rac1	Rac1	0	1	3	4
Mtss1 induces Rac1 , but not Cdc42 , activation via the IMD but not directly as a Rac1-GEF XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Mtss1 induces Rac1, but not Cdc42, activation via the IMD but not directly as a Rac1-GEF XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mtss1	Mtss1	Mtss1	Rac1	Rac1	Rac1	0	1	2	3
This suggests that Mtss1 activation of Rac1 is dependent on cell-cell contacts and provides a potential mechanism for how Mtss1 drives F-actin formation to maintain strong E-cadherin contacts .	This suggests that Mtss1 activation of Rac1 is dependent on cell-cell contacts and provides a potential mechanism for how Mtss1 drives F-actin formation to maintain strong E-cadherin contacts.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mtss1	Mtss1	Mtss1	Rac1	Rac1	Rac1	3	4	6	7
In sum , these data are consistent with a mechanism whereby miR-23a downregulates MTSS1 , which decreases RHOB and increases RAC1 and SRC activity .	In sum, these data are consistent with a mechanism whereby miR-23a downregulates MTSS1, which decreases RHOB and increases RAC1 and SRC activity.	12	23	increases	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MTSS1	MTSS1	MTSS1	RAC1	RAC1	RAC1	13	14	20	21
Because we did not succeed in establishing CD8+ lymphoma cell lines , we utilized previously generated MYC induced Dnmt3a +/+ and Dnmt3a -/- T cell lymphoma cell lines [ XREF_BIBR ] , along with MSCV-IRES-p53-GFP overexpressing both p53 and EGFP [ XREF_BIBR ] , to evaluate the role of p53 in lymphomagenesis .	Because we did not succeed in establishing CD8+ lymphoma cell lines, we utilized previously generated MYC induced Dnmt3a +/+ and Dnmt3a -/- T cell lymphoma cell lines [XREF_BIBR], along with MSCV-IRES-p53-GFP overexpressing both p53 and EGFP [XREF_BIBR], to evaluate the role of p53 in lymphomagenesis.	15	21	induced	Positive_early_activation	Positive_activation	Positive_activation	MYC	MYC	MYC	Dnmt3a	Dnmt3a	Dnmt3a	16	17	18	19
In addition , we find that Myc can target Dnmt3a selectively to the promoter of p21Cip1 .	In addition, we find that Myc can target Dnmt3a selectively to the promoter of p21Cip1.	6	10	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Myc	Myc	Myc	Dnmt3a	Dnmt3a	Dnmt3a	6	7	9	10
In order to identify new druggable targets in the Hh pathway , we used the scaffold protein MIM , which potentiates Gli dependent activation downstream of Smo 9 , as bait in a biased proteomics screen of factors involved in Hh signaling and ciliogenesis .	In order to identify new druggable targets in the Hh pathway, we used the scaffold protein MIM, which potentiates Gli dependent activation downstream of Smo 9, as bait in a biased proteomics screen of factors involved in Hh signaling and ciliogenesis.	13	23	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MIM	MIM	MIM	Gli	Gli	Gli	17	18	21	22
Interestingly , BRG1 associates with both MyoD and Mef2 which targets BRG1 based chromatin remodeling activity to myogenic specific gene promoters to regulate protein expression at different stages of skeletal muscle differentiation [ XREF_BIBR ] .	Interestingly, BRG1 associates with both MyoD and Mef2 which targets BRG1 based chromatin remodeling activity to myogenic specific gene promoters to regulate protein expression at different stages of skeletal muscle differentiation [XREF_BIBR].	3	12	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyoD	MyoD	MyoD	BRG1	BRG1	BRG1	6	7	11	12
These results indicate that , although mainly induced from late G1 to S phase , Chk1 activation can also be induced by DNA damage during G2/M phase and attenuated by hMYH disruption [ XREF_BIBR ] .	These results indicate that, although mainly induced from late G1 to S phase, Chk1 activation can also be induced by DNA damage during G2/M phase and attenuated by hMYH disruption [XREF_BIBR].	15	33	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	hMYH	hMYH	hMYH	Chk1	Chk1	Chk1	30	31	15	16
ARA70 is a coactivator of androgen receptor ( AR ) , a ligand dependent transcription factor that plays an important role in prostate cancer .	ARA70 is a coactivator of androgen receptor (AR), a ligand dependent transcription factor that plays an important role in prostate cancer.	0	7	is a coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	androgen receptor	androgen receptor	androgen receptor	0	1	5	7
While all three coactivators ARA70 , steroid receptor coactivator 1 , and RAC3 and ACTR can enhance androgen receptor ( AR ) transcriptional activity at 1 nM dihydrotestosterone , we here demonstrate that only ARA70 can induce AR transcriptional activity > 30-fold in the presence of 10 nM 17beta-estradiol ( E2 ) , but not diethylstilbestrol .	While all three coactivators ARA70, steroid receptor coactivator 1, and RAC3 and ACTR can enhance androgen receptor (AR) transcriptional activity at 1 nM dihydrotestosterone, we here demonstrate that only ARA70 can induce AR transcriptional activity> 30-fold in the presence of 10 nM 17beta-estradiol (E2), but not diethylstilbestrol.	33	39	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	34	35	37	38
Overexpression of NcoA4 has been shown to enhance AR transactivation induced by ligands other than active androgens , which may have negative implications for the success of hormonal therapies used in the treatment of prostate cancer .	Overexpression of NcoA4 has been shown to enhance AR transactivation induced by ligands other than active androgens, which may have negative implications for the success of hormonal therapies used in the treatment of prostate cancer.	0	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NcoA4	Overexpression of NcoA4	ncoa4	AR	AR	ar	2	3	8	9
These results clearly demonstrated that PSA , without its protease activity , could enhance ARA70 induced AR transactivation and stimulate cell growth .	These results clearly demonstrated that PSA, without its protease activity, could enhance ARA70 induced AR transactivation and stimulate cell growth.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	14	15	16	17
The changes in expression pattern of AR and AR cofactors and in particular the remarkable increase in AR , ARA160 and ARA70 support the role of AR cofactors in modulating prostate cancer cell growth from androgen dependence to androgen independence .	The changes in expression pattern of AR and AR cofactors and in particular the remarkable increase in AR, ARA160 and ARA70 support the role of AR cofactors in modulating prostate cancer cell growth from androgen dependence to androgen independence.	15	27	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	21	22	26	27
We further showed that increased PSA could enhance ARA70 induced AR transactivation via modulating p53 pathway that result in the decreased apoptosis and increased cell proliferation in prostate cancer cells .	We further showed that increased PSA could enhance ARA70 induced AR transactivation via modulating p53 pathway that result in the decreased apoptosis and increased cell proliferation in prostate cancer cells.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	8	9	10	11
Here we show that ARA70 interacts with and promotes AR activity via the consensus FXXLF motif within the ARA70-N2 domain ( amino acids 176-401 ) .	Here we show that ARA70 interacts with and promotes AR activity via the consensus FXXLF motif within the ARA70-N2 domain (amino acids 176-401).	4	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	4	5	9	10
Therefore , the presence of ARA70 in the testosterone and E2 producing Leydig cells may enhance the overall activity of AR during critical stages of male sex organ development .	Therefore, the presence of ARA70 in the testosterone and E2 producing Leydig cells may enhance the overall activity of AR during critical stages of male sex organ development.	3	21	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	5	6	20	21
Using an in vitro mutagenesis and a double negative selection in yeast two-hybrid screening , we have identified a dominant negative AR coregulator ARA70 ( dARA70N ) , which can inhibit AR transcriptional activity by inactivating the normal function of ARA70 in the LNCaP cells .	Using an in vitro mutagenesis and a double negative selection in yeast two-hybrid screening, we have identified a dominant negative AR coregulator ARA70 (dARA70N), which can inhibit AR transcriptional activity by inactivating the normal function of ARA70 in the LNCaP cells.	17	33	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	23	24	31	32
Mechanisms by which PSA enhanced ARA70 induced AR transactivation results in the increased prostate cancer cell growth .	Mechanisms by which PSA enhanced ARA70 induced AR transactivation results in the increased prostate cancer cell growth.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	5	6	7	8
Deletion of amino acids 321-441 of NcoA4 diminishes the potentiation of AR transactivation by only 50 % of that achieved with wild-type NcoA4 [ XREF_BIBR ] , suggesting that additional regions of NcoA4 contribute to AR-NcoA4 interaction or to NcoA4 coactivator activity .	Deletion of amino acids 321-441 of NcoA4 diminishes the potentiation of AR transactivation by only 50% of that achieved with wild-type NcoA4 [XREF_BIBR], suggesting that additional regions of NcoA4 contribute to AR-NcoA4 interaction or to NcoA4 coactivator activity.	4	12	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NcoA4	NcoA4	NcoA4	AR	AR	AR	6	7	11	12
For example , a coactivator protein known as ARA70 was shown to increase AR responsiveness to estradiol , suggesting that ARA70 can induce AR activity using an alternative ligand [ XREF_BIBR ] .	For example, a coactivator protein known as ARA70 was shown to increase AR responsiveness to estradiol, suggesting that ARA70 can induce AR activity using an alternative ligand [XREF_BIBR].	20	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	20	21	23	24
We therefore hypothesized that PSA enhanced ARA70 induced AR transactivation might result in the increased cell growth via modulation of p53 mediated cell growth arrest and apoptosis .	We therefore hypothesized that PSA enhanced ARA70 induced AR transactivation might result in the increased cell growth via modulation of p53 mediated cell growth arrest and apoptosis.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	6	7	8	9
As early studies suggested that the higher expression level of ARA70 could enhance the antiandrogen hydroxyflutamide ( HF ) - and Delta5-androstenediol ( Adiol )-induced AR transactivation , we tested whether PSA can cooperate with ARA70 to enhance HF- or Adiol induced AR transactivation .	As early studies suggested that the higher expression level of ARA70 could enhance the antiandrogen hydroxyflutamide (HF) - and Delta5-androstenediol (Adiol)-induced AR transactivation, we tested whether PSA can cooperate with ARA70 to enhance HF- or Adiol induced AR transactivation.	8	26	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	level of ARA70	ara70	AR	AR	ar	10	11	25	26
Because ARA70 can promote the antiandrogen hydroxyflutamide ( HF )-enhanced AR transactivation , the increased ARA70 expression in hormone-refractory prostate tumors may confer the development of HF withdrawal syndrome , commonly diagnosed in patients with the later stages of prostate cancer .	Because ARA70 can promote the antiandrogen hydroxyflutamide (HF)-enhanced AR transactivation, the increased ARA70 expression in hormone-refractory prostate tumors may confer the development of HF withdrawal syndrome, commonly diagnosed in patients with the later stages of prostate cancer.	1	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	1	2	10	11
Species differences in AR potentiation by NcoA4 are also likely ; we found only a modest increase in AR transactivation ( 1.5-fold ) by full-length mouse NcoA4 [ XREF_BIBR ] .	Species differences in AR potentiation by NcoA4 are also likely; we found only a modest increase in AR transactivation (1.5-fold) by full-length mouse NcoA4 [XREF_BIBR].	3	7	potentiation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NcoA4	NcoA4	NcoA4	AR	AR	AR	6	7	3	4
As a potential facilitator of PCa progression , ARA70 induced AR transactivation may result in decreased apoptosis and increased cell proliferation in PCa cells via a PSA mediated mechanism .	As a potential facilitator of PCa progression, ARA70 induced AR transactivation may result in decreased apoptosis and increased cell proliferation in PCa cells via a PSA mediated mechanism.	8	18	induced	Positive_early_activation	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	8	9	10	11
We also found that ARA70 , ARA55 , and ARA54 , but not steroid receptor coactivator-1 ( SRC-1 ) and Rb , could significantly enhance the delta5-androstenediol-mediated AR transactivation .	We also found that ARA70, ARA55, and ARA54, but not steroid receptor coactivator-1 (SRC-1) and Rb, could significantly enhance the delta5-androstenediol-mediated AR transactivation.	4	28	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	4	5	27	28
Together , using several cell lines with either transient transfection or stable transfection of PSA , PSA-siRNA , or ARA70-siRNA to assay AR transactivation or AR endogenous target gene expression , we found PSA could promote cell growth that might go through the ARA70 induced AR transactivation .	Together, using several cell lines with either transient transfection or stable transfection of PSA, PSA-siRNA, or ARA70-siRNA to assay AR transactivation or AR endogenous target gene expression, we found PSA could promote cell growth that might go through the ARA70 induced AR transactivation.	40	46	induced	Positive_early_activation	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	43	44	45	46
Furthermore , the knockdown of ARA70 by siRNA could diminish the PSA enhanced AR activity ( XREF_FIG lane 9 vs 3 ) , suggesting that ARA70 is important for the PSA enhanced AR transactivation .	Furthermore, the knockdown of ARA70 by siRNA could diminish the PSA enhanced AR activity (XREF_FIG lane 9 vs 3), suggesting that ARA70 is important for the PSA enhanced AR transactivation.	3	14	diminish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	5	6	13	14
The molecular mechanisms by which ARA70 enhances AR transactivation involve the increase of AR expression , protein stability , and nuclear translocation .	The molecular mechanisms by which ARA70 enhances AR transactivation involve the increase of AR expression, protein stability, and nuclear translocation.	5	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	5	6	7	8
Here , we find PSA may promote hormone refractory prostate cancer growth via enhancing ARA70 induced AR transactivation without involving its protease activity .	Here, we find PSA may promote hormone refractory prostate cancer growth via enhancing ARA70 induced AR transactivation without involving its protease activity.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	14	15	16	17
As expected , we found PSA could enhance the ARA70 induced AR transactivation in the presence of 10 muM HF or 10 nM Adiol ( XREF_FIG ) .	As expected, we found PSA could enhance the ARA70 induced AR transactivation in the presence of 10 muM HF or 10 nM Adiol (XREF_FIG).	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	9	10	11	12
The increased Tissue-PSA could then go through positive feed-back regulation to further enhance ARA70 induced AR transactivation that results in the suppression of p53 expression via modulation of MDM2/HoxA5/Egr-I signaling pathways .	The increased Tissue-PSA could then go through positive feed-back regulation to further enhance ARA70 induced AR transactivation that results in the suppression of p53 expression via modulation of MDM2/HoxA5/Egr-I signaling pathways.	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	13	14	15	16
Interestingly , cotransfection of Rb and ARA70 , the first identified AR coactivator , with AR can additively induce AR transcriptional activity 13-fold ( from 5-fold to 64-fold ) .	Interestingly, cotransfection of Rb and ARA70, the first identified AR coactivator, with AR can additively induce AR transcriptional activity 13-fold (from 5-fold to 64-fold).	2	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	6	7	19	20
For example , the coactivator ARA70 can increase AR responsiveness to estradiol in prostate cancer cell lines [ XREF_BIBR ] ( XREF_FIG ) .	For example, the coactivator ARA70 can increase AR responsiveness to estradiol in prostate cancer cell lines [XREF_BIBR] (XREF_FIG).	3	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	5	6	8	9
Curiously , the second , novel locus ( locus 2 ) was within NCOA4 ( also known as ARA70 ) , which is known to enhance androgen receptor transcriptional activity in prostate cancer cells .	Curiously, the second, novel locus (locus 2) was within NCOA4 (also known as ARA70), which is known to enhance androgen receptor transcriptional activity in prostate cancer cells.	0	28	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCOA4	NCOA4	NCOA4	androgen receptor	androgen receptor	androgen receptor	13	14	26	28
Additional AR specific coactivators of note have been identified : ARA70 increases the AR activity and even facilitates the binding of estradiol to the AR , FKBP51 stabilizes the AR with HSP90 heat-shock protein complex and facilitates the binding of androgens , and TRIM24 increases AR transcriptional activity .	Additional AR specific coactivators of note have been identified : ARA70 increases the AR activity and even facilitates the binding of estradiol to the AR, FKBP51 stabilizes the AR with HSP90 heat-shock protein complex and facilitates the binding of androgens, and TRIM24 increases AR transcriptional activity.	10	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	10	11	13	14
Overall , this was first line of evidence that ZMIZ1 , rather than ZMIZ2 or ARA70 , enhances the ligand induced transactivation of AR with shorter polyQ tract in prostate cancer cells .	Overall, this was first line of evidence that ZMIZ1, rather than ZMIZ2 or ARA70, enhances the ligand induced transactivation of AR with shorter polyQ tract in prostate cancer cells.	9	24	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ARA70	ARA70	ARA70	AR	AR	AR	15	16	23	24
In this latter mechanism , N-WASP is activated by the SH3 domains of Nck .	In this latter mechanism, N-WASP is activated by the SH3 domains of Nck.	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Nck	Nck	Nck	N-WASP	N-WASP	N-WASP	13	14	5	6
Because Nck stimulates N-WASp and Arp2-3-dependent actin polymerization , we postulate that Nck modulates morphogenesis by linking spatiotemporally restricted activation of Cdc42 dependent polarity signals , junctional actin polymerization , and VE-cadherin adhesion dynamics .	Because Nck stimulates N-WASp and Arp2-3-dependent actin polymerization, we postulate that Nck modulates morphogenesis by linking spatiotemporally restricted activation of Cdc42 dependent polarity signals, junctional actin polymerization, and VE-cadherin adhesion dynamics.	1	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nck	Nck	Nck	N-WASp	N-WASp	N-WASp	1	2	3	4
In this 2:2:1 reaction scheme , Nck SH3 activation of N-WASp is described as a bimolecular interaction , the same as that used in the 1:1:1 reaction scheme .	In this 2:2:1 reaction scheme, Nck SH3 activation of N-WASp is described as a bimolecular interaction, the same as that used in the 1:1:1 reaction scheme.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Nck	Nck	Nck	N-WASp	N-WASp	N-WASp	6	7	10	11
Additionally , WASP and N-WASP are differentially activated by SH3 proteins in vitro where Grb2 and Nck1 are more potent activators of N-WASP than WASP , consistent with potentially different cellular functions .	Additionally, WASP and N-WASP are differentially activated by SH3 proteins in vitro where Grb2 and Nck1 are more potent activators of N-WASP than WASP, consistent with potentially different cellular functions.	14	23	are more potent activators	Positive_activation_copula_1	Positive_activation	Positive_activation	Nck1	Nck1	Nck1	N-WASP	N-WASP	N-WASP	16	17	22	23
Arp2/3 complexes is further stimulated by phosphatidylinositol 4,5-bisphosphate , but not by GTP-Cdc42 , suggesting that Nck and Cdc42 activate N-WASP by redundant mechanisms .	Arp2/3 complexes is further stimulated by phosphatidylinositol 4,5-bisphosphate, but not by GTP-Cdc42, suggesting that Nck and Cdc42 activate N-WASP by redundant mechanisms.	16	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nck	Nck	Nck	N-WASP	N-WASP	N-WASP	16	17	20	21
N-WASp activation by Nck1 , but not Grb2 , is important for invadopodium formation and function , suggesting that the phosphorylated cortactin-Nck1-N-WASp-Arp2/3 signaling complex may be important for actin polymerization at invadopodia .	N-WASp activation by Nck1, but not Grb2, is important for invadopodium formation and function, suggesting that the phosphorylated cortactin-Nck1-N-WASp-Arp2/3 signaling complex may be important for actin polymerization at invadopodia.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Nck1	Nck1	Nck1	N-WASp	N-WASp	N-WASp	3	4	0	1
In view of our findings , we proposed that Crk adaptors might inhibit actin polymerization at pedestals by competing with Nck activation of N-WASP [ XREF_BIBR ] .	In view of our findings, we proposed that Crk adaptors might inhibit actin polymerization at pedestals by competing with Nck activation of N-WASP [XREF_BIBR].	20	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Nck	Nck	Nck	N-WASP	N-WASP	N-WASP	20	21	23	24
WIP like proteins may be involved in the subsequent recruitment of N-WASP to a complex of Tir and Nck , but the three tandem SH3 domains of Nck1 and Nck2 likely activate N-WASP by directly binding to its PRD [ XREF_BIBR ] .	WIP like proteins may be involved in the subsequent recruitment of N-WASP to a complex of Tir and Nck, but the three tandem SH3 domains of Nck1 and Nck2 likely activate N-WASP by directly binding to its PRD [XREF_BIBR].	25	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nck1	Nck1	Nck1	N-WASP	N-WASP	N-WASP	27	28	32	33
However , N-WASP dimers created by GST-Nck will have two basic regions , and thus a greater affinity for PIP 2 vesicles , consistent with strongly cooperative activation of N-WASP by GST-Nck and PIP 2 .	However, N-WASP dimers created by GST-Nck will have two basic regions, and thus a greater affinity for PIP 2 vesicles, consistent with strongly cooperative activation of N-WASP by GST-Nck and PIP 2.	8	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	GST-Nck	GST-Nck	GST-Nck	N-WASP	N-WASP	N-WASP	31	32	29	30
XREF_BIBR showed that Nck activates N-WASP in vitro , and , interestingly , Nck and Cdc42 have redundant effects on N-WASP activity .	XREF_BIBR showed that Nck activates N-WASP in vitro, and, interestingly, Nck and Cdc42 have redundant effects on N-WASP activity.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nck	Nck	Nck	N-WASP	N-WASP	N-WASP	3	4	5	6
Nck is required for EPEC to trigger N-WASP activation and actin polymerization , indicating that recruitment of Nck by Tir is an essential step in pedestal formation .	Nck is required for EPEC to trigger N-WASP activation and actin polymerization, indicating that recruitment of Nck by Tir is an essential step in pedestal formation.	0	8	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nck	Nck	Nck	N-WASP	N-WASP	N-WASP	0	1	7	8
In the highly specialized invadopodium compartment of metastatic cells , cofilin binds cortactin in a complex with Arp2/3 , along with the Arp2/3 activator N-WASp and the N-WASp activator Nck1 ( adaptor molecule with src homology domains 2 and 3 ) [ XREF_BIBR ] .	In the highly specialized invadopodium compartment of metastatic cells, cofilin binds cortactin in a complex with Arp2/3, along with the Arp2/3 activator N-WASp and the N-WASp activator Nck1 (adaptor molecule with src homology domains 2 and 3) [XREF_BIBR].	15	42	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Nck1	Nck1	Nck1	N-WASp	N-WASp	N-WASp	29	30	27	28
The binding of NCK-1 in turn modulates the actin regulators UNC-34 Ena and VASP , WSP-1 and N-Wasp and the Arp2/3 complex .	The binding of NCK-1 in turn modulates the actin regulators UNC-34 Ena and VASP, WSP-1 and N-Wasp and the Arp2/3 complex.	1	18	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCK-1	NCK-1	NCK-1	N-Wasp	N-Wasp	N-Wasp	3	4	17	18
It ' s conceivable that one Nck molecule activates one N-WASp molecule , which in turn flips on one copy of the Arp2/3 complex .	It 's conceivable that one Nck molecule activates one N-WASp molecule, which in turn flips on one copy of the Arp2/3 complex.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nck	Nck	Nck	N-WASp	N-WASp	N-WASp	6	7	10	11
As is the case for the kinases ( s ) responsible for EPEC Tir phosphorylation , seemingly disparate observations concerning the mechanism of N-WASP activation by Nck and the role of WIP may indicate a degree of redundancy in the N-WASP activation pathway .	As is the case for the kinases (s) responsible for EPEC Tir phosphorylation, seemingly disparate observations concerning the mechanism of N-WASP activation by Nck and the role of WIP may indicate a degree of redundancy in the N-WASP activation pathway.	23	27	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Nck	Nck	Nck	N-WASP	N-WASP	N-WASP	26	27	23	24
In addition , in the highly specialized invadopodium compartment of metastatic cells , cofilin binds cortactin in a complex with Arp2/3 , the Arp2/3 activator N-WASp , and the N-WASp activator Nck1 .	In addition, in the highly specialized invadopodium compartment of metastatic cells, cofilin binds cortactin in a complex with Arp2/3, the Arp2/3 activator N-WASp, and the N-WASp activator Nck1.	18	32	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Nck1	Nck1	Nck1	N-WASp	N-WASp	N-WASp	31	32	29	30
TIF2 highly induced AR AF-2 activity on a complex promoter [ mouse mammary tumor virus ( MMTV ) ] , but it was hardly active on a minimal promoter ( GRE-TATA ) .	TIF2 highly induced AR AF-2 activity on a complex promoter [mouse mammary tumor virus (MMTV)], but it was hardly active on a minimal promoter (GRE-TATA).	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIF2	TIF2	TIF2	AR	AR	AR	0	1	3	4
NCOA2 activates AR signaling [ XREF_BIBR , XREF_BIBR ] ; its amplification occurs in 24.3 % of metastatic PCs .	NCOA2 activates AR signaling [XREF_BIBR, XREF_BIBR]; its amplification occurs in 24.3% of metastatic PCs.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCOA2	NCOA2	NCOA2	AR	AR	AR	0	1	2	3
Interestingly , SRC-1 appears to negatively influence AR activity , thereby counterbalancing the TIF2 stimulated AR activity .	Interestingly, SRC-1 appears to negatively influence AR activity, thereby counterbalancing the TIF2 stimulated AR activity.	12	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIF2	TIF2	TIF2	AR	AR	AR	13	14	15	16
AR is potentiated by the p160 family of coactivators that include SRC-1 ( NCOA1 ) , TIF2 ( NCOA2 ) , and SRC-3 ( AIB1 , NCOA3 ) .	AR is potentiated by the p160 family of coactivators that include SRC-1 (NCOA1), TIF2 (NCOA2), and SRC-3 (AIB1, NCOA3).	0	18	potentiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TIF2	TIF2	TIF2	AR	AR	AR	16	17	0	1
This naturally occurring FLNa fragment repressed AR transactivation and disrupted AR interdomain interactions and transcriptional intermediary factor 2 activated AR function in a manner reminiscent of full-length FLNa , raising the possibility that the inhibitory effects of cytoplasmic FLNa may be transduced through this fragment , which can localize to the nucleus and form part of the pre and initiation complex .	This naturally occurring FLNa fragment repressed AR transactivation and disrupted AR interdomain interactions and transcriptional intermediary factor 2 activated AR function in a manner reminiscent of full-length FLNa, raising the possibility that the inhibitory effects of cytoplasmic FLNa may be transduced through this fragment, which can localize to the nucleus and form part of the pre and initiation complex.	14	20	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	transcriptional intermediary factor 2	transcriptional intermediary factor 2	transcriptional intermediary factor 2	AR	AR	AR	14	18	19	20
Castration triggers increased expression of AR coactivators , such as TIF2 and CBP that stimulate AR activity at low androgen levels .	Castration triggers increased expression of AR coactivators, such as TIF2 and CBP that stimulate AR activity at low androgen levels.	6	16	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIF2	TIF2	TIF2	AR	AR	AR	10	11	15	16
Even in the absence of circulating androgens , overexpression of NCOA1 or NCOA2 can drive increased AR transactivation .	Even in the absence of circulating androgens, overexpression of NCOA1 or NCOA2 can drive increased AR transactivation.	8	17	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCOA2	overexpression of NCOA1 or NCOA2	ncoa2	AR	AR	ar	12	13	16	17
Overexpression of NCOA1 or NCOA2 can drive increased AR transactivation in castrate conditions , and depletion of NCOA2 prevents CRPC development in PTEN deficient mice .	Overexpression of NCOA1 or NCOA2 can drive increased AR transactivation in castrate conditions, and depletion of NCOA2 prevents CRPC development in PTEN deficient mice.	0	9	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCOA2	Overexpression of NCOA1 or NCOA2	ncoa2	AR	AR	ar	4	5	8	9
However , TIF-2 knockdown did not inhibit androgen independent nuclear localization of GFP-AR in C4-2 cells ( XREF_FIG ) .	However, TIF-2 knockdown did not inhibit androgen independent nuclear localization of GFP-AR in C4-2 cells (XREF_FIG).	2	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TIF-2	TIF-2	TIF-2	GFP-AR	GFP-AR	GFP-AR	2	3	12	13
For example , over-expression of 2 transcription factors , transcriptional intermediary factor 2 ( TIF2 ) and steroid receptor co-activator 1 ( SRC1 ) can increase AR transactivation at physiological concentrations of adrenal androgen and can provide a mechanism for ADT resistance [ XREF_BIBR ] .	For example, over-expression of 2 transcription factors, transcriptional intermediary factor 2 (TIF2) and steroid receptor co-activator 1 (SRC1) can increase AR transactivation at physiological concentrations of adrenal androgen and can provide a mechanism for ADT resistance [XREF_BIBR].	3	27	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	transcriptional intermediary factor 2	over-expression of 2 transcription factors, transcriptional intermediary factor 2	transcriptional intermediary factor 2	AR	AR	ar	9	13	26	27
AR is activated by Nuclear Receptor Co-activator 2 , and its binding location overlays with MixMD maps in XREF_FIG .	AR is activated by Nuclear Receptor Co-activator 2, and its binding location overlays with MixMD maps in XREF_FIG.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Nuclear Receptor Co-activator 2	Nuclear Receptor Co-activator 2	Nuclear Receptor Co-activator 2	AR	AR	AR	4	8	0	1
NCOA2 is amplified in approximately 6 % of patients with advanced-stage prostate cancer , and increased NCOA2 function amplifies AR pathway activity .	NCOA2 is amplified in approximately 6% of patients with advanced-stage prostate cancer, and increased NCOA2 function amplifies AR pathway activity.	0	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCOA2	NCOA2	NCOA2	AR	AR	AR	0	1	19	20
An overexpression of ARA55 or TIF2 enhanced androgen induced AR transcriptional activity in LNCaP cell .	An overexpression of ARA55 or TIF2 enhanced androgen induced AR transcriptional activity in LNCaP cell.	1	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIF2	overexpression of ARA55 or TIF2	tif2	AR	AR	ar	5	6	9	10
We interpret these data to suggest that Nek9-CTD activation of Nek7 depends on self association through the CC region , which can be mimicked by a dimeric GST tag .	We interpret these data to suggest that Nek9-CTD activation of Nek7 depends on self association through the CC region, which can be mimicked by a dimeric GST tag.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Nek9-CTD	Nek9-CTD	Nek9-CTD	Nek7	Nek7	Nek7	7	8	10	11
Nek9 is thought to activate Nek6 and Nek7 through phosphorylation and allosteric mechanisms [ XREF_BIBR , XREF_BIBR ] .	Nek9 is thought to activate Nek6 and Nek7 through phosphorylation and allosteric mechanisms [XREF_BIBR, XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nek9	Nek9	Nek9	Nek7	Nek7	Nek7	0	1	7	8
Nek9 can then stimulate Nek6 and Nek7 activity through phosphorylation of the Ser 206 and Ser 195 residues within the activation loop of Nek6 and Nek7 , respectively [ XREF_BIBR ] .	Nek9 can then stimulate Nek6 and Nek7 activity through phosphorylation of the Ser 206 and Ser 195 residues within the activation loop of Nek6 and Nek7, respectively [XREF_BIBR].	0	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nek9	Nek9	Nek9	Nek7	Nek7	Nek7	0	1	6	7
Hence , we propose that the Nek9-CTD activates Nek7 through promoting back-to-back dimerization that releases the autoinhibitory tyrosine residue , a mechanism conserved in unrelated kinase families .	Hence, we propose that the Nek9-CTD activates Nek7 through promoting back-to-back dimerization that releases the autoinhibitory tyrosine residue, a mechanism conserved in unrelated kinase families.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nek9-CTD	Nek9-CTD	Nek9-CTD	Nek7	Nek7	Nek7	6	7	8	9
We found that Nek9-CTD increased the activity of Nek7-WT to a level similar to that observed for Nek7-Y97A ( XREF_FIG A ) .	We found that Nek9-CTD increased the activity of Nek7-WT to a level similar to that observed for Nek7-Y97A (XREF_FIG A).	3	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nek9-CTD	Nek9-CTD	Nek9-CTD	Nek7-WT	Nek7-WT	Nek7-WT	3	4	8	9
In this scheme , Nek9 induces a pre-active state in Nek7 characterized by the ability of the kinase to autophosphorylate efficiently .	In this scheme, Nek9 induces a pre-active state in Nek7 characterized by the ability of the kinase to autophosphorylate efficiently.	4	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nek9	Nek9	Nek9	Nek7	Nek7	Nek7	4	5	10	11
CDK1 and PLK1 , in turn , drive activation of NEK9 , which promotes NEK6 and NEK7 activity .	CDK1 and PLK1, in turn, drive activation of NEK9, which promotes NEK6 and NEK7 activity.	8	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NEK9	NEK9	NEK9	NEK7	NEK7	NEK7	10	11	16	17
We have now shown that the noncatalytic , CTD of Nek9 directly stimulates the activity of Nek7 through release of Tyr97 autoinhibition .	We have now shown that the noncatalytic, CTD of Nek9 directly stimulates the activity of Nek7 through release of Tyr97 autoinhibition.	8	17	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nek9	Nek9	Nek9	Nek7	Nek7	Nek7	10	11	16	17
Some mitotic kinases do not become fully activated until bound to a partner protein , triggering a conformational change , which may release an autoinhibitory state ( such as postulated in Nek9 allosteric activation of Nek7 ) , reveal previously hidden additional phosphorylation sites ( such as in cyclin activation of Cdks ) or lock the protein in an active state ( such as in TPX2 stimulation of phospho-Aurora-A activity ) .	Some mitotic kinases do not become fully activated until bound to a partner protein, triggering a conformational change, which may release an autoinhibitory state (such as postulated in Nek9 allosteric activation of Nek7), reveal previously hidden additional phosphorylation sites (such as in cyclin activation of Cdks) or lock the protein in an active state (such as in TPX2 stimulation of phospho-Aurora-A activity).	31	36	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Nek9	Nek9	Nek9	Nek7	Nek7	Nek7	31	32	35	36
We find that the activation of Nek7 by Nek9-CTD unexpectedly resembles the mechanism that governs the activation of kinases from the eIF4alpha and IRE1 families .	We find that the activation of Nek7 by Nek9-CTD unexpectedly resembles the mechanism that governs the activation of kinases from the eIF4alpha and IRE1 families.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Nek9-CTD	Nek9-CTD	Nek9-CTD	Nek7	Nek7	Nek7	8	9	6	7
Previous work showed that Nek9 activates Nek6 during mitosis and possibly regulates Nek7 as well .	Previous work showed that Nek9 activates Nek6 during mitosis and possibly regulates Nek7 as well.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nek9	Nek9	Nek9	Nek6	Nek6	Nek6	4	5	6	7
Estrogen receptor ( ER ) signaling is modulated by steroid receptor coactivator 1 ( SRC-1 ) .	Estrogen receptor (ER) signaling is modulated by steroid receptor coactivator 1 (SRC-1).	0	13	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	steroid receptor coactivator 1	steroid receptor coactivator 1	steroid receptor coactivator 1	Estrogen receptor	Estrogen receptor	Estrogen receptor	9	13	0	2
In contrast , the addition of NCOA1 increased ERalpha dependent activation from 17-fold ( XREF_FIG ) to approximately 100-fold ( XREF_FIG ) .	In contrast, the addition of NCOA1 increased ERalpha dependent activation from 17-fold (XREF_FIG) to approximately 100-fold (XREF_FIG).	4	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCOA1	NCOA1	NCOA1	ERalpha	ERalpha	ERalpha	6	7	8	9
However , overexpression of either SRC-1 or SRC-3 increased AR activity in response to the partial antagonist , cyproterone acetate , whereas SRA was unable to stimulate AR activity under these conditions .	However, overexpression of either SRC-1 or SRC-3 increased AR activity in response to the partial antagonist, cyproterone acetate, whereas SRA was unable to stimulate AR activity under these conditions.	2	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-3	overexpression of either SRC-1 or SRC-3	src-3	AR	AR	ar	7	8	9	10
Hence , the decreased expression of SRC-3 could be reducing the transcriptional activity of AR .	Hence, the decreased expression of SRC-3 could be reducing the transcriptional activity of AR.	4	15	reducing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-3	expression of SRC-3	src-3	AR	AR	ar	6	7	14	15
We tested whether the addition of NBR1 would directly enhance the ability of p62 to form clusters .	We tested whether the addition of NBR1 would directly enhance the ability of p62 to form clusters.	4	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NBR1	NBR1	NBR1	p62	p62	p62	6	7	13	14
Expression of the 3 different forms of NBR1 ( wild type , nonphosphorylable , or phosphomimetic ) by electroporation in Atg7 knockout mice induced the formation of NBR1 , UB , and SQSTM1 positive speckles in a similar proportion , showing that ectopic NBR1 destabilized aggregates ( size > 1-mum diameter ) independently of its phosphorylation status to favor speckles ( size < 1-mum diameter ) ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	Expression of the 3 different forms of NBR1 (wild type, nonphosphorylable, or phosphomimetic) by electroporation in Atg7 knockout mice induced the formation of NBR1, UB, and SQSTM1 positive speckles in a similar proportion, showing that ectopic NBR1 destabilized aggregates (size> 1-mum diameter) independently of its phosphorylation status to favor speckles (size < 1-mum diameter) (XREF_FIG; XREF_SUPPLEMENTARY).	5	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NBR1	NBR1	NBR1	SQSTM1	SQSTM1	SQSTM1	7	8	32	33
The mutation inhibits the interaction of the titin kinase domain with nbr1 , a zinc finger protein that targets p62 to sarcomeres , where it binds MuRF-2 ( muscle specific RING-finger ) , a ligand for serum response transcription factor .	The mutation inhibits the interaction of the titin kinase domain with nbr1, a zinc finger protein that targets p62 to sarcomeres, where it binds MuRF-2 (muscle specific RING-finger), a ligand for serum response transcription factor.	2	20	targets	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	nbr1	nbr1	nbr1	p62	p62	p62	11	12	19	20
Pak1 can be targeted to the membrane by Nck in response to tyrosine phosphorylation , and membrane association of Pak1 is sufficient to increase its specific activity .	Pak1 can be targeted to the membrane by Nck in response to tyrosine phosphorylation, and membrane association of Pak1 is sufficient to increase its specific activity.	0	10	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Nck	Nck	Nck	Pak1	Pak1	Pak1	8	9	0	1
For this , HEK 293 cells were transfected with Myc-Cortactin alone or Myc-Cortactin and the myristoylated second SH3 domain of Nck1 ( Myr-SH3-2 ) , which was previously shown to activate PAK1 .	For this, HEK 293 cells were transfected with Myc-Cortactin alone or Myc-Cortactin and the myristoylated second SH3 domain of Nck1 (Myr-SH3-2), which was previously shown to activate PAK1.	18	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nck1	Nck1	Nck1	PAK1	PAK1	PAK1	20	21	31	32
A recombinant peptide fragment of the SMRT ( silencing mediator for retinoid and thyroid hormone receptor ) corepressor that blocks this site can inhibit BCL6 biologic functions .	A recombinant peptide fragment of the SMRT (silencing mediator for retinoid and thyroid hormone receptor) corepressor that blocks this site can inhibit BCL6 biologic functions.	6	26	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMRT	SMRT	SMRT	BCL6	BCL6	BCL6	6	7	24	25
Importantly , the SMRT peptide 1414-1430 is an inhibitor of full-length SMRT binding to BCL-6 , and reverses the repressive activities of BCL-6 in vivo .	Importantly, the SMRT peptide 1414-1430 is an inhibitor of full-length SMRT binding to BCL-6, and reverses the repressive activities of BCL-6 in vivo.	3	24	reverses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SMRT	SMRT	SMRT	BCL-6	BCL-6	BCL-6	3	4	22	23
SMRT and NCOR , in particular , are ubiquitously expressed and so would be expected to enable BCL6 functions regardless of cell context .	SMRT and NCOR, in particular, are ubiquitously expressed and so would be expected to enable BCL6 functions regardless of cell context.	0	18	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMRT	SMRT and NCOR, in particular, are ubiquitously expressed	smrt	BCL6	BCL6	bcl6	0	1	17	18
In Drosophila , neurofibromin modulates cAMP by activating the adenylyl cyclase 1 ( AC1 ) homolog , rutabaga ( rut ) [ XREF_BIBR , XREF_BIBR ] .	In Drosophila, neurofibromin modulates cAMP by activating the adenylyl cyclase 1 (AC1) homolog, rutabaga (rut) [XREF_BIBR, XREF_BIBR].	3	15	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neurofibromin	neurofibromin	neurofibromin	adenylyl cyclase 1	adenylyl cyclase 1	adenylyl cyclase 1	3	4	9	12
Together , these data and ours suggest that Nf1 simultaneously mediates the activation of both AC signaling pathways in alpha/beta neurons to facilitate new protein synthesis and the formation of long lasting memory .	Together, these data and ours suggest that Nf1 simultaneously mediates the activation of both AC signaling pathways in alpha/beta neurons to facilitate new protein synthesis and the formation of long lasting memory.	8	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nf1	Nf1	Nf1	AC	AC	AC	8	9	15	16
Further , we demonstrate that sequences in the C-terminal region of hNF1 are sufficient for NF1 and Galpha ( s )-dependent neurotransmitter stimulated AC activity , and for rescue of body size defects in Nf1 mutant flies .	Further, we demonstrate that sequences in the C-terminal region of hNF1 are sufficient for NF1 and Galpha (s)-dependent neurotransmitter stimulated AC activity, and for rescue of body size defects in Nf1 mutant flies.	13	24	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	NF1	NF1	NF1	AC	AC	AC	15	16	23	24
As a result , IFN-gamma predominates and NCOA4 is unable to up-regulate PPARgamma ( XREF_FIG ) .	As a result, IFN-gamma predominates and NCOA4 is unable to up-regulate PPARgamma (XREF_FIG).	7	14	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCOA4	NCOA4	NCOA4	PPARgamma	PPARgamma	PPARgamma	7	8	12	13
In silico simulations illustrate a down-regulation of miR-146b when ABA is administered to the system , resulting in increased concentrations of NCOA4 , which , in turn , activates PPARgamma and therefore favors IL-10 production and decreases IFN-gamma levels .	In silico simulations illustrate a down-regulation of miR-146b when ABA is administered to the system, resulting in increased concentrations of NCOA4, which, in turn, activates PPARgamma and therefore favors IL-10 production and decreases IFN-gamma levels.	19	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCOA4	NCOA4	NCOA4	PPARgamma	PPARgamma	PPARgamma	21	22	29	30
The computational simulations predicted an overexpression of miR-146b following C. difficle infection , resulting in decreased concentrations of NCOA4 , which in turn failed to activate PPARgamma .	The computational simulations predicted an overexpression of miR-146b following C. difficle infection, resulting in decreased concentrations of NCOA4, which in turn failed to activate PPARgamma.	16	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCOA4	NCOA4	NCOA4	PPARgamma	PPARgamma	PPARgamma	18	19	26	27
[ XREF_BIBR ] The importance of the SRC PR interactions has been elucidated by studies in KO mice demonstrating that steroid receptor coactivator-1 ( SRC-1 ) is the primary coactivator of PR in the uterus but SRC-3 is important in the mammary gland .	[XREF_BIBR] The importance of the SRC PR interactions has been elucidated by studies in KO mice demonstrating that steroid receptor coactivator-1 (SRC-1) is the primary coactivator of PR in the uterus but SRC-3 is important in the mammary gland.	20	34	is the primary coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	steroid receptor coactivator-1	steroid receptor coactivator-1	steroid receptor coactivator-1	PR	PR	PR	20	23	31	32
Both estrogen receptor ( ER ) and peroxisome proliferator activated receptor gamma ( PPARgamma ) regulate bone metabolism , and because steroid receptor coactivator ( SRC ) -2 ( TIF-2 ) enhances ER and PPARgamma activity , we examined the consequences of deletion of SRC-2 on bone using SRC-2 knock out ( KO ) mice .	Both estrogen receptor (ER) and peroxisome proliferator activated receptor gamma (PPARgamma) regulate bone metabolism, and because steroid receptor coactivator (SRC) -2 (TIF-2) enhances ER and PPARgamma activity, we examined the consequences of deletion of SRC-2 on bone using SRC-2 knock out (KO) mice.	23	35	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIF-2	TIF-2	TIF-2	PPARgamma	PPARgamma	PPARgamma	29	30	34	35
In addition , we examined whether RORalpha inhibits NCOA1 and NCOA2 mediated PPARgamma transcriptional activation .	In addition, we examined whether RORalpha inhibits NCOA1 and NCOA2 mediated PPARgamma transcriptional activation.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	NCOA2	NCOA2	NCOA2	PPARgamma	PPARgamma	PPARgamma	10	11	12	13
This TIF2 fragment also increases the alpha-helical content of the glucocorticoid receptor ID AF1 domain , suggesting that coactivators augment the transcriptional activity of SR agonist complexes by inducing more ordered structures beyond the LBD and AF2 region .	This TIF2 fragment also increases the alpha-helical content of the glucocorticoid receptor ID AF1 domain, suggesting that coactivators augment the transcriptional activity of SR agonist complexes by inducing more ordered structures beyond the LBD and AF2 region.	1	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIF2	TIF2	TIF2	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	1	2	10	12
Identification of this ANKS6 mutation , together with our functional data , strengthens the close relationship between NEK8 and ANKS6 , i.e. NEK8 recruits its target ANKS6 to the cilium , which in return enhances NEK8 kinase activity [ XREF_BIBR ] .	Identification of this ANKS6 mutation, together with our functional data, strengthens the close relationship between NEK8 and ANKS6, i.e. NEK8 recruits its target ANKS6 to the cilium, which in return enhances NEK8 kinase activity [XREF_BIBR].	22	37	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NEK8	NEK8 recruits its target ANKS6 to the cilium	nek8	NEK8	NEK8	nek8	22	23	35	36
The two coactivators p300 and CBP and NCoA-1 cooperatively enhance STAT5a mediated transactivation .	The two coactivators p300 and CBP and NCoA-1 cooperatively enhance STAT5a mediated transactivation.	3	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NCoA-1	NCoA-1	NCoA-1	STAT5a	STAT5a	STAT5a	7	8	10	11
Here we show that NEK2A mediated Hec1 ( highly expressed in cancer ) phosphorylation is essential for faithful kinetochore microtubule attachments in mitosis .	Here we show that NEK2A mediated Hec1 (highly expressed in cancer) phosphorylation is essential for faithful kinetochore microtubule attachments in mitosis.	4	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	NEK2A	NEK2A	NEK2A	Hec1	Hec1	Hec1	4	5	6	7
NGF activation of trkA has been proposed to activate PLC , which hydrolyzes PIP2 , relieving inhibition of TRPV1 ( XREF_FIG , bottom left ) .	NGF activation of trkA has been proposed to activate PLC, which hydrolyzes PIP2, relieving inhibition of TRPV1 (XREF_FIG, bottom left).	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	0	1	3	4
In PC12 cells , NGF activates TrkA , a receptor tyrosine kinase , and p75 NTR , a neurotrophin receptor which belongs to the tumor necrosis factor receptor subfamily .	In PC12 cells, NGF activates TrkA, a receptor tyrosine kinase, and p75 NTR, a neurotrophin receptor which belongs to the tumor necrosis factor receptor subfamily.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	6	7
Sympathetic neurons express both p75 NTR and TrkA ; while pro NGF activates p75NTR and induces cell death , mature NGF activates both p75NTR and TrkA to promote cell survival XREF_BIBR , XREF_BIBR .	Sympathetic neurons express both p75 NTR and TrkA; while pro NGF activates p75NTR and induces cell death, mature NGF activates both p75NTR and TrkA to promote cell survival XREF_BIBR, XREF_BIBR.	19	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	20	21	25	26
Thus , NGF and NT-3 , both of which predominantly activate TrkA in NGF dependent sympathetic neurons , as shown here , mediate different biological responses .	Thus, NGF and NT-3, both of which predominantly activate TrkA in NGF dependent sympathetic neurons, as shown here, mediate different biological responses.	2	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	11	12
Interestingly , the enhancement of TrkA dependent apoptotic cellular processes and cell death caused by NGF was significantly suppressed by the JNK inhibitor SP600125 , but not by the PI3K inhibitor wortmannin , indicating a JNK dependent role of NGF in TrkA induced cell-death signaling ( XREF_FIG and XREF_FIG ) .	Interestingly, the enhancement of TrkA dependent apoptotic cellular processes and cell death caused by NGF was significantly suppressed by the JNK inhibitor SP600125, but not by the PI3K inhibitor wortmannin, indicating a JNK dependent role of NGF in TrkA induced cell-death signaling (XREF_FIG and XREF_FIG).	5	16	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	15	16	5	6
We have previously performed similar studies with rat sympathetic neurons , and have demonstrated that 200 nM K252A was sufficient to completely eliminate NGF mediated TrkA activation and block NGF mediated survival .	We have previously performed similar studies with rat sympathetic neurons, and have demonstrated that 200 nM K252A was sufficient to completely eliminate NGF mediated TrkA activation and block NGF mediated survival.	22	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	23	24	25	26
The prototypic target tissue derived neurotrophin is nerve growth factor ( NGF ) , which activates its high affinity receptor neurotrophic tyrosine kinase receptor type 1 ( TrkA ) to initiate signaling that supports the survival of neurons .	The prototypic target tissue derived neurotrophin is nerve growth factor (NGF), which activates its high affinity receptor neurotrophic tyrosine kinase receptor type 1 (TrkA) to initiate signaling that supports the survival of neurons.	9	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	27	28
NGF Induced Exit of TrkA and p75 NTR from Lipid Rafts .	NGF Induced Exit of TrkA and p75 NTR from Lipid Rafts.	0	7	Induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	4	5
The primary difference between NGF and NT-3 signaling in sympathetic neurons is that NGF is able to induce endocytosis of TrkA receptors while NT-3 can not .	The primary difference between NGF and NT-3 signaling in sympathetic neurons is that NGF is able to induce endocytosis of TrkA receptors while NT-3 can not.	13	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	13	14	20	21
Previous studies with PC12 cells have shown that NGF stimulation of the TrkA receptor activates Ras , PI3K and a number of other signaling pathways to trigger neuronal differentiation ( XREF_FIG ) .	Previous studies with PC12 cells have shown that NGF stimulation of the TrkA receptor activates Ras, PI3K and a number of other signaling pathways to trigger neuronal differentiation (XREF_FIG).	8	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	12	13
NGF deficiency triggers the TrkA and p75 NTR imbalance , which then induces apoptosis , neurodegeneration , and death [ XREF_BIBR , XREF_BIBR ] .	NGF deficiency triggers the TrkA and p75 NTR imbalance, which then induces apoptosis, neurodegeneration, and death [XREF_BIBR, XREF_BIBR].	0	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	4	5
Endosomes containing activated TrkA and p75 NTR were recovered from cells treated with NGF as previously described ( XREF_FIG ) XREF_BIBR .	Endosomes containing activated TrkA and p75 NTR were recovered from cells treated with NGF as previously described (XREF_FIG) XREF_BIBR.	1	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	13	14	3	4
The main function of NGF is mediated by two membranes binding receptors : high affinity tyrosine kinase receptor TrkA and low affinity p75 NTR [ XREF_BIBR - XREF_BIBR ] .	The main function of NGF is mediated by two membranes binding receptors : high affinity tyrosine kinase receptor TrkA and low affinity p75 NTR [XREF_BIBR - XREF_BIBR].	2	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	18	19
These findings support the concept of MMP-9 and Neu1 crosstalk playing a crucial role in regulating NGF induced TrkA activation .	These findings support the concept of MMP-9 and Neu1 crosstalk playing a crucial role in regulating NGF induced TrkA activation.	15	19	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	18	19
NGF induced TrkA activation and stimulated cell proliferation of PCa cells .	NGF induced TrkA activation and stimulated cell proliferation of PCa cells.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
Like the tumor itself , sensory and sympathetic nerve fibers appear to be continually evolving by undergoing sprouting , degeneration and re-sprouting with disease progression and this sprouting and neuroma formation and cancer pain is in part driven by NGF activation of TrkA + nerve fibers .	Like the tumor itself, sensory and sympathetic nerve fibers appear to be continually evolving by undergoing sprouting, degeneration and re-sprouting with disease progression and this sprouting and neuroma formation and cancer pain is in part driven by NGF activation of TrkA + nerve fibers.	39	45	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	39	40	42	43
The TRK oncoproteins ' signal transduction has been in part elucidated , and it involves several signal transducers activated by the NGF stimulated NTRK1 receptor .	The TRK oncoproteins ' signal transduction has been in part elucidated, and it involves several signal transducers activated by the NGF stimulated NTRK1 receptor.	18	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NTRK1	NTRK1	NTRK1	21	22	23	24
PDGF induced upregulation of N- and P/Q-type Ca2+ channel currents completely mimicked upregulation of these currents caused by NGF stimulation of the endogenous TrkA receptor tyrosine kinase ( RTK ) .	PDGF induced upregulation of N- and P/Q-type Ca2+ channel currents completely mimicked upregulation of these currents caused by NGF stimulation of the endogenous TrkA receptor tyrosine kinase (RTK).	18	26	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	18	19	23	24
Collectively , these data suggest a model in which NGF stimulated TrkA dependent activation of FRS2 supports neurite outgrowth through a mechanism that likely involves the induction of p21 ( Waf1 and Cip1 ) expression and the arrest of cells at G ( 1 ) / S.	Collectively, these data suggest a model in which NGF stimulated TrkA dependent activation of FRS2 supports neurite outgrowth through a mechanism that likely involves the induction of p21 (Waf1 and Cip1) expression and the arrest of cells at G (1) / S.	9	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	11	12
The effect of LAs on NGF stimulated TrkA activity was examined to analyze autophosphorylation of TrkA using immunoprecipitation and immunoblotting .	The effect of LAs on NGF stimulated TrkA activity was examined to analyze autophosphorylation of TrkA using immunoprecipitation and immunoblotting.	3	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	7	8
In addition , in vitro application of NGF can augment the survival and dendritic outgrowth of cells derived from the SVZ of rats , but likely through p75 NTR and not TrkA as this same group , as well as others , was unable to detect TrkA protein or mRNA in the SVZ .	In addition, in vitro application of NGF can augment the survival and dendritic outgrowth of cells derived from the SVZ of rats, but likely through p75 NTR and not TrkA as this same group, as well as others, was unable to detect TrkA protein or mRNA in the SVZ.	5	35	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	31	32
At later developmental stages , however , the absence of NGF mediated TrkA signaling does result in diminished Runx1 expression , suggesting a role of TrkA signaling in maintaining Runx1 expression [ XREF_BIBR ] .	At later developmental stages, however, the absence of NGF mediated TrkA signaling does result in diminished Runx1 expression, suggesting a role of TrkA signaling in maintaining Runx1 expression [XREF_BIBR].	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	12	13
NGF induced rapid and extensive endocytosis of TrkA in these cells , and the receptor subsequently moved into small organelles located near the plasma membrane .	NGF induced rapid and extensive endocytosis of TrkA in these cells, and the receptor subsequently moved into small organelles located near the plasma membrane.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	7	8
NGF and NT3 similarly activate TrkA , but only NGF supports retrograde TrkA trafficking and retrograde survival in sympathetic neurons .	NGF and NT3 similarly activate TrkA, but only NGF supports retrograde TrkA trafficking and retrograde survival in sympathetic neurons.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	5	6
APP regulates NGF mediated TrkA activation and the sensitivity of neurons to the trophic action of NGF .	APP regulates NGF mediated TrkA activation and the sensitivity of neurons to the trophic action of NGF.	1	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	4	5
The function of NGF and TrkA signaling in the TrkA population of nociceptors has been extensively studied and NGF and TrkA signaling is a well established mediator of pain .	The function of NGF and TrkA signaling in the TrkA population of nociceptors has been extensively studied and NGF and TrkA signaling is a well established mediator of pain.	3	10	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	9	10
Uniquely , the Trk B receptor ( NTRK2 ) was increased by NGF , but not BDNF , with the increase reaching our threshold cut-off of three times that of untreated cells .	Uniquely, the Trk B receptor (NTRK2) was increased by NGF, but not BDNF, with the increase reaching our threshold cut-off of three times that of untreated cells.	3	16	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	12	13	3	4
Our findings suggest a feed-forward model whereby NGF , secreted by the pancreatic vasculature in response to glucose , activates beta-cell TrkA receptors to acutely promote glucose stimulated insulin secretion in beta-cells ( XREF_FIG ) .	Our findings suggest a feed-forward model whereby NGF, secreted by the pancreatic vasculature in response to glucose, activates beta-cell TrkA receptors to acutely promote glucose stimulated insulin secretion in beta-cells (XREF_FIG).	7	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	21	22
In PC12 cells , overexpression of Pincher enhanced TrkA internalization induced by NGF via a clathrin independent macropinocytosis process .	In PC12 cells, overexpression of Pincher enhanced TrkA internalization induced by NGF via a clathrin independent macropinocytosis process.	8	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	8	9
Interestingly , DeltaTrkA did not activate MAPK and ERK [ XREF_BIBR ] , while a strong activation of ERK was observed by TRKA activated by NGF [ XREF_BIBR ] and in HMC-1 cells .	Interestingly, DeltaTrkA did not activate MAPK and ERK [XREF_BIBR], while a strong activation of ERK was observed by TRKA activated by NGF [XREF_BIBR] and in HMC-1 cells.	20	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TRKA	TRKA	TRKA	25	26	22	23
In contrast , NGF was unable to stimulate the association of TrkA with a glutathione S-transferase fusion protein containing a mutant SH2 Bbeta ( R555E ) with a defective SH2 domain .	In contrast, NGF was unable to stimulate the association of TrkA with a glutathione S-transferase fusion protein containing a mutant SH2 Bbeta (R555E) with a defective SH2 domain.	3	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	11	12
Although the signals generated by NGF stimulation of TrkA involve many of the same pathways that are stimulated by other RTKs , its more simplified endodomain structure with only two defined docking sites makes it an attractive target to devolve how individual signaling pathways are regulated in terms of downstream responses .	Although the signals generated by NGF stimulation of TrkA involve many of the same pathways that are stimulated by other RTKs, its more simplified endodomain structure with only two defined docking sites makes it an attractive target to devolve how individual signaling pathways are regulated in terms of downstream responses.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	8	9
Our data showed that SgG2 blocks NGF induced TrkA retrograde transport and disturbs growth cone morphology .	Our data showed that SgG2 blocks NGF induced TrkA retrograde transport and disturbs growth cone morphology.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	8	9
XREF_FIG ) , suggesting that the TrkA and p75 NTR imbalance caused by NGF deficiency occurred in the APP and PS1 mice .	XREF_FIG), suggesting that the TrkA and p75 NTR imbalance caused by NGF deficiency occurred in the APP and PS1 mice.	5	14	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	13	14	6	7
The NGF activated Trk A stimulates downstream signaling pathways leading to neuronal differentiation and promoting cell survival .	The NGF activated Trk A stimulates downstream signaling pathways leading to neuronal differentiation and promoting cell survival.	0	4	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	1	2	3	4
Thus , somewhat surprisingly , depolarization was able to increase Akt activity to levels similar to NGF induced TrkA activation at doses where both NGF and KCl mediate maximal survival .	Thus, somewhat surprisingly, depolarization was able to increase Akt activity to levels similar to NGF induced TrkA activation at doses where both NGF and KCl mediate maximal survival.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	18	19
Downregulation of p75NTR might shift binding of necdin to TrkA , facilitating robust NGF mediated TrkA activation and and signaling ( XREF_FIG ) .	Downregulation of p75NTR might shift binding of necdin to TrkA, facilitating robust NGF mediated TrkA activation and and signaling (XREF_FIG).	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	13	14	15	16
The present study examined the effects of CH ( 3 ) Hg on ( 125 ) I-nerve growth factor ( NGF ) binding to the TrkA receptor , NGF induced activation of the TrkA receptor , and neurite outgrowth in an in vitro model of differentiation using PC12 cells .	The present study examined the effects of CH (3) Hg on (125) I-nerve growth factor (NGF) binding to the TrkA receptor, NGF induced activation of the TrkA receptor, and neurite outgrowth in an in vitro model of differentiation using PC12 cells.	18	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	20	21	33	34
Importantly , PACA increased NGF levels and subsequently induced TrkA activation in MPTP treated mice .	Importantly, PACA increased NGF levels and subsequently induced TrkA activation in MPTP treated mice.	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	PACA increased NGF levels	ngf	TrkA	TrkA	trka	4	5	9	10
The neurotrophin , NGF , secreted by peripheral target tissues , supports survival of sympathetic and sensory neurons by regulating endocytosis and retrograde vesicular trafficking of NGF : TrkA complexes .	The neurotrophin, NGF, secreted by peripheral target tissues, supports survival of sympathetic and sensory neurons by regulating endocytosis and retrograde vesicular trafficking of NGF : TrkA complexes.	1	29	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	28	29
In this work , we found that the activation of TrkA by NGF induced the proteolysis of ApoER2 , specifically affecting the shedding of the receptor and resulting in the accumulation of its CTF .	In this work, we found that the activation of TrkA by NGF induced the proteolysis of ApoER2, specifically affecting the shedding of the receptor and resulting in the accumulation of its CTF.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	10	11
However , study had shown that NGF activated TrkA signaling pathway and regulated cJun N-terminal kinase 2 to reduce caspase-2/3 in olfactory bulb .	However, study had shown that NGF activated TrkA signaling pathway and regulated cJun N-terminal kinase 2 to reduce caspase-2/3 in olfactory bulb.	6	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	8	9
TrkA increased the ICP values and NGF enhanced TrkA ' s effect .	TrkA increased the ICP values and NGF enhanced TrkA 's effect.	4	9	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	8	9
Using receptor activated immunoprecipitation followed by analysis of the immune complexes by SDS-PAGE and immunoblotting , we show that NGF induces the association of TrkA with c-Crk-II in a multimeric complex that also includes SHC and PLC-gamma 1 .	Using receptor activated immunoprecipitation followed by analysis of the immune complexes by SDS-PAGE and immunoblotting, we show that NGF induces the association of TrkA with c-Crk-II in a multimeric complex that also includes SHC and PLC-gamma 1.	19	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	19	20	24	25
The drug completely inhibited the transphosphorylation of NGF induced TrkA in those cell bodies , indicating that foretinib acts by also inhibiting an as yet unidentified cell death pathway .	The drug completely inhibited the transphosphorylation of NGF induced TrkA in those cell bodies, indicating that foretinib acts by also inhibiting an as yet unidentified cell death pathway.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	9	10
Furthermore , no physical interaction between endogenous TrkA and Tiam1 was detected in PC12 cells treated with NGF ( XREF_SUPPLEMENTARY ) .	Furthermore, no physical interaction between endogenous TrkA and Tiam1 was detected in PC12 cells treated with NGF (XREF_SUPPLEMENTARY).	4	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	17	18	7	8
We found that NGF by itself slightly increased both TrkA and p75 NTR in rafts ( XREF_FIG , left plots ) , but after in vitro reactions that promote microtubule polymerization , p75 NTR was sorted away from rafts , while NGF and TrkA were sorted into rafts ( XREF_FIG , right plots and XREF_FIG ) .	We found that NGF by itself slightly increased both TrkA and p75 NTR in rafts (XREF_FIG, left plots), but after in vitro reactions that promote microtubule polymerization, p75 NTR was sorted away from rafts, while NGF and TrkA were sorted into rafts (XREF_FIG, right plots and XREF_FIG).	3	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	9	10
In line with the modulatory role of NGF on amyloid precursor protein ( APP ) secretory pathway ( s ) in NGF responsive cells , the ectopic administration of NGF stimulates the binding of its high-affinity receptor TrK kinase A ( TrkA ) to Amyloid Precursor Protein ( APP ) in in vitro cholinergic septal neurons favoring its subcellular localization in Golgi compartment -- via downregulation in phosphorylation at the threonine 668 ( T668 ) -- which , in turn , reduces susceptibility to BACE cleavage and promotes the anti-amyloidogenic processing .	In line with the modulatory role of NGF on amyloid precursor protein (APP) secretory pathway (s) in NGF responsive cells, the ectopic administration of NGF stimulates the binding of its high-affinity receptor TrK kinase A (TrkA) to Amyloid Precursor Protein (APP) in in vitro cholinergic septal neurons favoring its subcellular localization in Golgi compartment -- via downregulation in phosphorylation at the threonine 668 (T668) -- which, in turn, reduces susceptibility to BACE cleavage and promotes the anti-amyloidogenic processing.	27	38	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrK	TrK	TrK	29	30	37	38
Activation of TrkA by NGF triggers signal transduction cascades involving phosphatidylinositol 3-kinase/AKT ( PI3K and AKT ) and mitogen activated protein kinase and extracellular-signal-regulated kinases ( MAPK and ERK ) pathways .	Activation of TrkA by NGF triggers signal transduction cascades involving phosphatidylinositol 3-kinase/AKT (PI3K and AKT) and mitogen activated protein kinase and extracellular-signal-regulated kinases (MAPK and ERK) pathways.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	2	3
However , NGF has been shown to cause trkA activation in 1 min and maximum Erk activation 1.5 min after exposure .	However, NGF has been shown to cause trkA activation in 1 min and maximum Erk activation 1.5 min after exposure.	2	9	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	2	3	8	9
XREF_BIBR , XREF_BIBR Consequentially , NGF activation of TrkA modulates the activity of both ligand and voltage gated ion channels involved in nociception via the following mechanisms .	XREF_BIBR, XREF_BIBR Consequentially, NGF activation of TrkA modulates the activity of both ligand and voltage gated ion channels involved in nociception via the following mechanisms.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	8	9
The latter effect suggests that downstream retrograde survival signals can arise from alterations in one or more kinase activities in the distal axons without activation of TrkA by NGF .	The latter effect suggests that downstream retrograde survival signals can arise from alterations in one or more kinase activities in the distal axons without activation of TrkA by NGF.	10	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	28	29	26	27
However , experiments in cell lines revealed that induction of the NGF-TrkA signaling produced a phenotype of dramatic suppression of cell proliferation through inhibition of cell division and pronounced intracellular vacuolization , in a way straightly dependent on NGF activation of TrkA .	However, experiments in cell lines revealed that induction of the NGF-TrkA signaling produced a phenotype of dramatic suppression of cell proliferation through inhibition of cell division and pronounced intracellular vacuolization, in a way straightly dependent on NGF activation of TrkA.	38	42	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	38	39	41	42
We first examined NGF induced changes in tyrosine phosphorylation , to determine how overexpression of SHP-1 affects NGF mediated TrkA survival signals .	We first examined NGF induced changes in tyrosine phosphorylation, to determine how overexpression of SHP-1 affects NGF mediated TrkA survival signals.	17	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	17	18	19	20
Furthermore , how the dimeric and possibly oligomeric p75NTR forms relate to the respective NGF activated TrkA forms at the cell membrane still needs exploration .	Furthermore, how the dimeric and possibly oligomeric p75NTR forms relate to the respective NGF activated TrkA forms at the cell membrane still needs exploration.	10	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	14	15	16	17
Our preliminary results ( see XREF_SUPPLEMENTARY ) demonstrate that chronic ECS treatment results in a robust increase in the overall level of tyrosine phosphorylation in some of the same brain regions where both NGF and TrkA were found to be upregulated ( i.e ., perirhinal cortex ) , suggesting that NGF activation of TrkA may contribute to this effect .	Our preliminary results (see XREF_SUPPLEMENTARY) demonstrate that chronic ECS treatment results in a robust increase in the overall level of tyrosine phosphorylation in some of the same brain regions where both NGF and TrkA were found to be upregulated (i.e., perirhinal cortex), suggesting that NGF activation of TrkA may contribute to this effect.	50	54	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	50	51	53	54
have recently shown in vitro that NGF specifically enhances the binding of TrkA , but not p75 NTR , to microtubules in detergent resistance membranes , and that this binding does not require phosphorylation of TrkA .	have recently shown in vitro that NGF specifically enhances the binding of TrkA, but not p75 NTR, to microtubules in detergent resistance membranes, and that this binding does not require phosphorylation of TrkA.	6	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	12	13
XREF_BIBR , XREF_BIBR In addition , NGF can promote the ability of neurotrophic tyrosine kinase receptor type 1 ( TrkA ) to retard neuronal apoptosis .	XREF_BIBR, XREF_BIBR In addition, NGF can promote the ability of neurotrophic tyrosine kinase receptor type 1 (TrkA) to retard neuronal apoptosis.	6	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	19	20
In this context , it has been demonstrated that NGF causes TrkA to specifically attract microtubules to lipid rafts and that this mechanism is important for endocytosis , signal transduction and axon growth .	In this context, it has been demonstrated that NGF causes TrkA to specifically attract microtubules to lipid rafts and that this mechanism is important for endocytosis, signal transduction and axon growth.	9	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	11	12
Although TrkA can be activated by both NGF and Neurotrophin 3 during development , NGF is the only ligand that activates TrkA in mature sympathetic neurons , and thus is crucial for maintaining sympathetic neuron health and stimulating axon regeneration .	Although TrkA can be activated by both NGF and Neurotrophin 3 during development, NGF is the only ligand that activates TrkA in mature sympathetic neurons, and thus is crucial for maintaining sympathetic neuron health and stimulating axon regeneration.	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	1	2
Activation of trkA by NGF would facilitate trafficking of TRPV1 to the plasma membrane , increasing channel current ( XREF_FIG ) .	Activation of trkA by NGF would facilitate trafficking of TRPV1 to the plasma membrane, increasing channel current (XREF_FIG).	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	4	5	2	3
Increased CHD5 Expression by NGF induced Activation of TrkA .	Increased CHD5 Expression by NGF induced Activation of TrkA.	2	9	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	8	9
During insulin or NGF stimulation TrkA , insulin receptor substrate-1 ( IRS-1 ) , INSR ( and presumably other proteins ) forms a complex in PC12 cells .	During insulin or NGF stimulation TrkA, insulin receptor substrate-1 (IRS-1), INSR (and presumably other proteins) forms a complex in PC12 cells.	0	9	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
The MAPK and AKT pathways are two major effectors of NGF induced TrkA signaling in different cell models [ XREF_BIBR ] , although this function has not been elucidated for MM cells yet .	The MAPK and AKT pathways are two major effectors of NGF induced TrkA signaling in different cell models [XREF_BIBR], although this function has not been elucidated for MM cells yet.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	12	13
Here we demonstrate that extended C2-ceramide exposure dramatically increases NGF induced trkA activation and further show that C2-ceramide augments trkA tyrosine phosphorylation even in the absence of neurotrophin .	Here we demonstrate that extended C2-ceramide exposure dramatically increases NGF induced trkA activation and further show that C2-ceramide augments trkA tyrosine phosphorylation even in the absence of neurotrophin.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	9	10	11	12
Exogenous 5 was observed to raise the level of NGF mediated TrkA activation by 43 % relative to NGF control based on Western Blotting ( XREF_FIG ) , further confirming that 5 functions through the NGF and TrkA pathway .	Exogenous 5 was observed to raise the level of NGF mediated TrkA activation by 43% relative to NGF control based on Western Blotting (XREF_FIG), further confirming that 5 functions through the NGF and TrkA pathway.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	11	12
We hypothesized that the removal of one or both of the cysteines would affect NGF induced signaling of the trkA receptor .	We hypothesized that the removal of one or both of the cysteines would affect NGF induced signaling of the trkA receptor.	13	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	14	15	19	20
Furthermore , mRME-1 overexpressed in TrkA-PC12 cells did not act like Pincher to enhance NGF induced TrkA internalization ( unpublished data ) .	Furthermore, mRME-1 overexpressed in TrkA-PC12 cells did not act like Pincher to enhance NGF induced TrkA internalization (unpublished data).	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	14	15	16	17
Thereafter we investigated the effect of the selected peptide on NGF stimulated TrkA activity and the expression of transient receptor potential channel 1 in PC12 cells .	Thereafter we investigated the effect of the selected peptide on NGF stimulated TrkA activity and the expression of transient receptor potential channel 1 in PC12 cells.	8	13	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	12	13
It has recently been shown that breast cancer NGF can stimulate TrkA signaling in tumor associated macrophages , increasing IL-10 production .	It has recently been shown that breast cancer NGF can stimulate TrkA signaling in tumor associated macrophages, increasing IL-10 production.	6	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	11	12
TrkA dependent apoptosis in neuronal cells is triggered by the depletion of NGF , resulted in spontaneous regression in NB .	TrkA dependent apoptosis in neuronal cells is triggered by the depletion of NGF, resulted in spontaneous regression in NB.	0	13	triggered	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	0	1
In contrast , NGF stimulation of chimeric TrkA receptor produced little sensitization of TRPV1 currents at 100ng/mL but normal sensitization at 1,000 ng/mL ( XREF_FIG C ) .	In contrast, NGF stimulation of chimeric TrkA receptor produced little sensitization of TRPV1 currents at 100ng/mL but normal sensitization at 1,000 ng/mL (XREF_FIG C).	3	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	7	8
We show that the Akt and PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U.V .-induced apoptosis , but that apoptosis induced by c-Myc is also blocked by a novel , Akt and PKB independent , pathway .	We show that the Akt and PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U.V.-induced apoptosis, but that apoptosis induced by c-Myc is also blocked by a novel, Akt and PKB independent, pathway.	11	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	13	14
The E2 cells express a level of endogenous TrkA that is similar at the protein level to the level of TrkA in TA25 yet fail to activate TrkA when treated with NGF .	The E2 cells express a level of endogenous TrkA that is similar at the protein level to the level of TrkA in TA25 yet fail to activate TrkA when treated with NGF.	18	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	31	32	20	21
In addition , TrkA dependent cellular processes such as ERK phosphorylation , JNK phosphorylation , PARP cleavage , caspase-7 activation and caspase-8 cleavage were strongly enhanced by NGF and were significantly suppressed by SP600125 , but not by wortmannin , indicating that NGF enhances TrkA dependent apoptotic signaling in a JNK dependent manner ( XREF_FIG ) .	In addition, TrkA dependent cellular processes such as ERK phosphorylation, JNK phosphorylation, PARP cleavage, caspase-7 activation and caspase-8 cleavage were strongly enhanced by NGF and were significantly suppressed by SP600125, but not by wortmannin, indicating that NGF enhances TrkA dependent apoptotic signaling in a JNK dependent manner (XREF_FIG).	42	47	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	42	43	44	45
These results suggest that NGF promotes endocytosis of TrkA receptors by activation of a PLC-gamma and calcineurin signaling pathway .	These results suggest that NGF promotes endocytosis of TrkA receptors by activation of a PLC-gamma and calcineurin signaling pathway.	4	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	8	9
Mutation of the nuclear localization signal has no effect on NGF induced activation of TrkA and ERKs 1/2 but prevents SH2B1beta from enhancing NGF induced neurite outgrowth .	Mutation of the nuclear localization signal has no effect on NGF induced activation of TrkA and ERKs 1/2 but prevents SH2B1beta from enhancing NGF induced neurite outgrowth.	8	15	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	14	15
While NGF promotes retrograde transport of TrkA signaling endosomes to activate pro survival signaling pathways in neuronal soma , NT-3 does not [ XREF_BIBR ] .	While NGF promotes retrograde transport of TrkA signaling endosomes to activate pro survival signaling pathways in neuronal soma, NT-3 does not [XREF_BIBR].	1	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	6	7
Taken together , these findings indicate that NGF , but not NT3 , activates a TrkA-Rac1-cofilin signaling module associated with the TrkA endosome that mediates F-actin severing and the formation of retrograde transport-competent TrkA signaling endosomes .	Taken together, these findings indicate that NGF, but not NT3, activates a TrkA-Rac1-cofilin signaling module associated with the TrkA endosome that mediates F-actin severing and the formation of retrograde transport-competent TrkA signaling endosomes.	7	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	33	34
The neurotrophins NGF and NT-3 activate cell surface TrkA , which responds by recruiting MTs to detergent resistant cell surface lipid rafts and reorganising the assembly of MTs required for neuritogenesis , axon genesis , and growth cone formation , resulting in neuronal differentiation [ XREF_BIBR - XREF_BIBR ] .	The neurotrophins NGF and NT-3 activate cell surface TrkA, which responds by recruiting MTs to detergent resistant cell surface lipid rafts and reorganising the assembly of MTs required for neuritogenesis, axon genesis, and growth cone formation, resulting in neuronal differentiation [XREF_BIBR - XREF_BIBR].	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	8	9
Although both NGF and proNGF are able to bind to and activate TrkA and p75NTR , they do so with different affinities .	Although both NGF and proNGF are able to bind to and activate TrkA and p75NTR, they do so with different affinities.	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	12	13
NGF and Neurotrophin-3 Both Activate TrkA on Sympathetic Neurons but Differentially Regulate Survival and Neuritogenesis .	NGF and Neurotrophin-3 Both Activate TrkA on Sympathetic Neurons but Differentially Regulate Survival and Neuritogenesis.	0	11	Activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	5	6
8 The activation of TrkA by NGF thus initiates the chronic pain phenotype by increasing nociceptor sensitivity to further stimulus .	8 The activation of TrkA by NGF thus initiates the chronic pain phenotype by increasing nociceptor sensitivity to further stimulus.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	4	5
Furthermore , stimulation of Plexin-B1 specific signaling through NGF mediated activation of TrkA and Plexin-B 1 chimeric receptors promoted I-kappaB phosphorylation and degradation .	Furthermore, stimulation of Plexin-B1 specific signaling through NGF mediated activation of TrkA and Plexin-B 1 chimeric receptors promoted I-kappaB phosphorylation and degradation.	8	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	12	13
According to this model , activation of TrkA by NGF stimulates and translocates SphK1 from the cytosol to the plasma membrane , where its substrate sphingosine resides , to generate S1P in a spatially and temporally restricted manner .	According to this model, activation of TrkA by NGF stimulates and translocates SphK1 from the cytosol to the plasma membrane, where its substrate sphingosine resides, to generate S1P in a spatially and temporally restricted manner.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	7	8
Coexpression of p75 is required for high-affinity activation of TrkA by NGF , and the precise ratio of p75 : TrkA expression has been found to exquisitely regulate TrkA activation by NGF in PC12 and transfected Chinese hamster ovary cells .	Coexpression of p75 is required for high-affinity activation of TrkA by NGF, and the precise ratio of p75 : TrkA expression has been found to exquisitely regulate TrkA activation by NGF in PC12 and transfected Chinese hamster ovary cells.	7	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	9	10
Rapid TRPV1 sensitization via NGF activation of TrkA receptors can be reconstituted in human and animal derived celllines as well as Xenopus laevis oocytes .	Rapid TRPV1 sensitization via NGF activation of TrkA receptors can be reconstituted in human and animal derived celllines as well as Xenopus laevis oocytes.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	7	8
NGF activated TrkA initiates survival signaling by binding to and phosphorylating on tyrosine proteins such as Shc , FRS-2 , rAPS , and SH2-B that activate the Ras-PI 3-kinase and Ras-MAPK signaling pathways and PLC-gamma1 , which regulates protein kinase C activity and intracellular calcium levels .	NGF activated TrkA initiates survival signaling by binding to and phosphorylating on tyrosine proteins such as Shc, FRS-2, rAPS, and SH2-B that activate the Ras-PI 3-kinase and Ras-MAPK signaling pathways and PLC-gamma1, which regulates protein kinase C activity and intracellular calcium levels.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
Each neurotrophin binds with high affinity to Trk receptors : NGF activates TrkA , and BDNF interacts with TrkB .	Each neurotrophin binds with high affinity to Trk receptors : NGF activates TrkA, and BDNF interacts with TrkB.	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	12	13
The addition of LAR wedge peptide inhibited LAR co-immunoprecipitation with TrkA , augmented NGF induced activation of TrkA , ERK , and AKT , and in the absence of exogenous NGF , induced activation of TrkA , ERK , and AKT .	The addition of LAR wedge peptide inhibited LAR co-immunoprecipitation with TrkA, augmented NGF induced activation of TrkA, ERK, and AKT, and in the absence of exogenous NGF, induced activation of TrkA, ERK, and AKT.	13	22	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	13	14	17	18
In conclusion , it is conceivable from these data that beta1 integrin links TrkA with AR in regulating the neuritogenesis triggered by androgens or NGF in PC12 cells .	In conclusion, it is conceivable from these data that beta1 integrin links TrkA with AR in regulating the neuritogenesis triggered by androgens or NGF in PC12 cells.	10	25	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	24	25	13	14
These data demonstrate that even in the adult bone marrow , NGF released by these endogenous cells can induce a 10-70 fold increase in the density of TrkA + sensory nerve fibers in the bone marrow .	These data demonstrate that even in the adult bone marrow, NGF released by these endogenous cells can induce a 10-70 fold increase in the density of TrkA + sensory nerve fibers in the bone marrow.	11	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	27	28
The gating of TRPV1 is rapidly and potently enhanced when PKA or PKC are activated by a variety of inflammatory mediators , and also when TrkA is activated by the binding of NGF .	The gating of TRPV1 is rapidly and potently enhanced when PKA or PKC are activated by a variety of inflammatory mediators, and also when TrkA is activated by the binding of NGF.	25	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	32	33	25	26
We therefore investigated whether NGF induced TrkA could activate Arf6 , using GST-GGA3 PBD pull-down assays that specifically bound the GTP bound ( active ) form of Arf .	We therefore investigated whether NGF induced TrkA could activate Arf6, using GST-GGA3 PBD pull-down assays that specifically bound the GTP bound (active) form of Arf.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	6	7
It was reported that the NGF deficiency would lead to a TrkA and p75 NTR imbalance in AD brain , which might be one of possible mechanisms of neurodegeneration .	It was reported that the NGF deficiency would lead to a TrkA and p75 NTR imbalance in AD brain, which might be one of possible mechanisms of neurodegeneration.	5	15	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	11	12
Nogo-p4 binding with NgR1 suppresses TrkA signaling induced by low concentrations of NGF in differentiated PC12 cells .	Nogo-p4 binding with NgR1 suppresses TrkA signaling induced by low concentrations of NGF in differentiated PC12 cells.	5	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	5	6
The observations that NGF activates TrkA autophosporylation on Y490 , the Shc binding site , and phosphorylation and activation of Akt in neurons from Linx tEGFP and tEGFP mice suggest that ligand dependent activation of cell surface TrkA and at least some TrkA effectors occurs normally in the absence of Linx ( XREF_FIG ) .	The observations that NGF activates TrkA autophosporylation on Y490, the Shc binding site, and phosphorylation and activation of Akt in neurons from Linx tEGFP and tEGFP mice suggest that ligand dependent activation of cell surface TrkA and at least some TrkA effectors occurs normally in the absence of Linx (XREF_FIG).	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
These results confirm that BVNP-0197 inhibits NGF mediated TrkA signaling invitro and may be targeted for further therapeutic development .	These results confirm that BVNP-0197 inhibits NGF mediated TrkA signaling invitro and may be targeted for further therapeutic development.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	8	9
6 TrKA is specifically activated by NGF , whereas TrKB and TrKC are primarily receptors for BDNF and NT-3 respectively .	6 TrKA is specifically activated by NGF, whereas TrKB and TrKC are primarily receptors for BDNF and NT-3 respectively.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrKA	TrKA	TrKA	6	7	1	2
NGF targeted TrkA and activated the RAS/RAF/MAPK downstream signalling cascades to produce neuritogenic activity .	NGF targeted TrkA and activated the RAS/RAF/MAPK downstream signalling cascades to produce neuritogenic activity.	0	4	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
Our previous results showed that SgG2 impairs NGF induced TrkA retrograde transport in primary culture of neurons grown in microfluidic devices [ XREF_BIBR ] .	Our previous results showed that SgG2 impairs NGF induced TrkA retrograde transport in primary culture of neurons grown in microfluidic devices [XREF_BIBR].	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	9	10
This suggests that SOD2 involvement in neuronal differentiation must depend upon additional factors not activated by TrkAIII , which would include Ras/MAPK/Erk signalling induced by NGF activated TrkA but not spontaneously active TrkAIII in SH-SY5Y cells XREF_BIBR .	This suggests that SOD2 involvement in neuronal differentiation must depend upon additional factors not activated by TrkAIII, which would include Ras/MAPK/Erk signalling induced by NGF activated TrkA but not spontaneously active TrkAIII in SH-SY5Y cells XREF_BIBR.	23	28	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	25	26	27	28
The biological effects of rearranged TRK oncogenes recapitulate that of NGF stimulated wild type NTRK1 receptor .	The biological effects of rearranged TRK oncogenes recapitulate that of NGF stimulated wild type NTRK1 receptor.	9	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NTRK1	NTRK1	NTRK1	10	11	14	15
Moreover , USP36 depletion leads to enhanced total and surface TrkA expression that results in increased NGF mediated TrkA activation and signaling that augments PC12 cell differentiation .	Moreover, USP36 depletion leads to enhanced total and surface TrkA expression that results in increased NGF mediated TrkA activation and signaling that augments PC12 cell differentiation.	13	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	18	19
Intriguingly , NGF independent activation of TrkA can be induced by various stimuli including amyloid-beta XREF_BIBR , XREF_BIBR , proteosome inhibitors such as MG-132 and lactacystin XREF_BIBR , XREF_BIBR , and dorsomorphin , a selective inhibitor of bone morphogenetic protein signaling XREF_BIBR .	Intriguingly, NGF independent activation of TrkA can be induced by various stimuli including amyloid-beta XREF_BIBR, XREF_BIBR, proteosome inhibitors such as MG-132 and lactacystin XREF_BIBR, XREF_BIBR, and dorsomorphin, a selective inhibitor of bone morphogenetic protein signaling XREF_BIBR.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	6	7
Our findings revealed that curcumin exerts its protective effect against injured neurons through stimulating NGF release which further activates TrkA and PI3K and Akt cell survival signaling .	Our findings revealed that curcumin exerts its protective effect against injured neurons through stimulating NGF release which further activates TrkA and PI3K and Akt cell survival signaling.	14	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	14	15	19	20
These results support the importance of the CS-E motif in NGF stimulated Trk activation .	These results support the importance of the CS-E motif in NGF stimulated Trk activation.	8	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	10	11	12	13
These data indicate that NGF activation of the TrkA signal transduction pathway via HIF-1alpha drives VEGF transcription .	These data indicate that NGF activation of the TrkA signal transduction pathway via HIF-1alpha drives VEGF transcription.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	8	9
K252a acts as a specific and potent inhibitor of Trk receptor , inhibits the phosphorylation of NGF induced TrkA , and selectively blocks the activities of NGF in PC-12 cells XREF_BIBR .	K252a acts as a specific and potent inhibitor of Trk receptor, inhibits the phosphorylation of NGF induced TrkA, and selectively blocks the activities of NGF in PC-12 cells XREF_BIBR.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	18	19
The activation of PLC-gamma downstream of TrkA activation by NGF relieves this constitutive inhibition by hydrolyzing PIP2 to inositol 1,4,5-trisphosphate ( IP3 ) and diacylglycerol .	The activation of PLC-gamma downstream of TrkA activation by NGF relieves this constitutive inhibition by hydrolyzing PIP2 to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol.	6	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	6	7
Nerve growth factor ( NGF ) stimulates TRKA ; brain derived growth factor ( BDGF ) and neurotrpphins-4/5 activate TRKB whileneurotrpphins-3 activates TRKC .	Nerve growth factor (NGF) stimulates TRKA; brain derived growth factor (BDGF) and neurotrpphins-4/5 activate TRKB whileneurotrpphins-3 activates TRKC.	2	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TRKA	TRKA	TRKA	4	5	7	8
While the neurotrophin NGF stimulates TrkA in sympathetic neurons to promote axon maintenance and process outgrowth , its precursor protein ProNGF , which is elevated in the human heart after MI 77 , activates the p75 neurotrophin receptor ( p75NTR ; also called TNF receptor super family 16 , TNFRS16 ) , to trigger axon degeneration XREF_BIBR , XREF_BIBR ( XREF_FIG ) .	While the neurotrophin NGF stimulates TrkA in sympathetic neurons to promote axon maintenance and process outgrowth, its precursor protein ProNGF, which is elevated in the human heart after MI 77, activates the p75 neurotrophin receptor (p75NTR; also called TNF receptor super family 16, TNFRS16), to trigger axon degeneration XREF_BIBR, XREF_BIBR (XREF_FIG).	1	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
The trkA receptor , when activated by NGF , can activate several intracellular signaling cascades , including the Erk1/2 signaling pathway .	The trkA receptor, when activated by NGF, can activate several intracellular signaling cascades, including the Erk1/2 signaling pathway.	1	8	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	7	8	1	2
Also , NGF activation of TrkA + sensory nerve fibers leads to an increase in the expression of the neuropeptides including BDNF , CGRP and SP .	Also, NGF activation of TrkA + sensory nerve fibers leads to an increase in the expression of the neuropeptides including BDNF, CGRP and SP.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	5	6
37-39 While it is well known that NGF is neuroprotective through activation of TrkA , they showed that proNGF promoted neuroinflammation and cell death by activation of p75 NTR .	37-39 While it is well known that NGF is neuroprotective through activation of TrkA, they showed that proNGF promoted neuroinflammation and cell death by activation of p75 NTR.	7	14	is neuroprotective through activation	Positive_activation_copula_1	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	13	14
Effect of Cav-1 and Cav-2 on NGF Induced TrkA and p75 NTR Internalization .	Effect of Cav-1 and Cav-2 on NGF Induced TrkA and p75 NTR Internalization.	0	12	Induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	8	9
Taken together , our data indicate that NECC2 is a novel component of caveolae in PC12 cells , and support a role for this protein as a molecular scaffold modulating NGF mediated TrkA signal transduction .	Taken together, our data indicate that NECC2 is a novel component of caveolae in PC12 cells, and support a role for this protein as a molecular scaffold modulating NGF mediated TrkA signal transduction.	26	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	30	31	32	33
HEK293 cells were transiently transfected with either rat or chimeric TrkA construct to assess NGF stimulated TrkA activation ( XREF_SUPPLEMENTARY ) .	HEK293 cells were transiently transfected with either rat or chimeric TrkA construct to assess NGF stimulated TrkA activation (XREF_SUPPLEMENTARY).	13	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	14	15	16	17
We conclude therefore that the effect of BDNF on cdk1 phosphorylation does not require a previous activation of TrkA by NGF .	We conclude therefore that the effect of BDNF on cdk1 phosphorylation does not require a previous activation of TrkA by NGF.	13	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	20	21	18	19
NGF enhances TrkA dependent cancer cell death in a JNK dependent manner .	NGF enhances TrkA dependent cancer cell death in a JNK dependent manner.	0	3	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
Nerve growth factor ( NGF ) activates TrkA to trigger signaling events that promote the survival , differentiation and maintenance of neurons .	Nerve growth factor (NGF) activates TrkA to trigger signaling events that promote the survival, differentiation and maintenance of neurons.	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	7	8
Nerve Growth Factor ( NGF ) is produced by innate immune cells during inflammation and activates its receptor TrkA in nociceptor neurons ( XREF_FIG ) .	Nerve Growth Factor (NGF) is produced by innate immune cells during inflammation and activates its receptor TrkA in nociceptor neurons (XREF_FIG).	2	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	18	19
In contrast , the neuraminidase inhibitor , 2-deoxy-2 ,3-dehydro-N-acetylneuraminic acid , specific for plasma membrane ganglioside Neu3 and Neu2 sialidases has no inhibitory effect on NGF induced pTrkA .	In contrast, the neuraminidase inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid, specific for plasma membrane ganglioside Neu3 and Neu2 sialidases has no inhibitory effect on NGF induced pTrkA.	23	28	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	pTrkA	pTrkA	pTrkA	25	26	27	28
The differences in biological responses seen here may instead be due to NGF inducing a strong acute TrkA activation that does not occur with NT-3 .	The differences in biological responses seen here may instead be due to NGF inducing a strong acute TrkA activation that does not occur with NT-3.	10	18	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	17	18
By RT-CES monitoring , we observed that higher concentrations of NGF 25-100 ng/ml ) increased the CI of both TrkA and TrkA and p75 cells in serum-free medium .	By RT-CES monitoring, we observed that higher concentrations of NGF 25-100 ng/ml) increased the CI of both TrkA and TrkA and p75 cells in serum-free medium.	8	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	19	20
This apparently obvious approach is not as trivial as it may seem because NGF induced NTRK1 activation leads to cell type specific biological effects , such as the differentiation of neuronal cells , the apoptosis of medulloblastoma cells and the mitogenesis of non neuronal cells ( Muragaki et al , 1997 ) .	This apparently obvious approach is not as trivial as it may seem because NGF induced NTRK1 activation leads to cell type specific biological effects, such as the differentiation of neuronal cells, the apoptosis of medulloblastoma cells and the mitogenesis of non neuronal cells (Muragaki et al, 1997).	13	16	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	NTRK1	NTRK1	NTRK1	13	14	15	16
In this model , p75NTR would provide a direct death signal independent of Trk or Trk signaling , and sympathetic neurons would be rescued from death only if NGF activated TrkA to sufficient levels to silence this death signal .	In this model, p75NTR would provide a direct death signal independent of Trk or Trk signaling, and sympathetic neurons would be rescued from death only if NGF activated TrkA to sufficient levels to silence this death signal.	28	31	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	28	29	30	31
NGF was found to induce trkA mRNA 36 h after the addition of NGF , while no trkA mRNA was detected in the absence of NGF .	NGF was found to induce trkA mRNA 36 h after the addition of NGF, while no trkA mRNA was detected in the absence of NGF.	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	0	1	5	6
These results raise the possibility that the clathrin independent internalization of NGF and TrkA by Pincher may selectively mediate the formation of the critical NGF and TrkA signaling endosome .	These results raise the possibility that the clathrin independent internalization of NGF and TrkA by Pincher may selectively mediate the formation of the critical NGF and TrkA signaling endosome.	9	28	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	26	27
These results suggest that simvastatin is neurotoxic and PC12 cells elicited a protective response , involving a transient activation of a Trk mediated intracellular signal transduction pathway by an autocrine secretion of NGF , although these responses did not persist against pro apoptotic signals and resulted in an apoptosis of the PC12 cells .	These results suggest that simvastatin is neurotoxic and PC12 cells elicited a protective response, involving a transient activation of a Trk mediated intracellular signal transduction pathway by an autocrine secretion of NGF, although these responses did not persist against pro apoptotic signals and resulted in an apoptosis of the PC12 cells.	18	33	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	32	33	21	22
Given that stimulation of TrkA by NGF induces auto-phosphorylation of this receptor and promotes ERK1/2 activation , we thought it likely that NGF and TrkA interactions might differentially activate downstream signaling between the 2 phenotypes .	Given that stimulation of TrkA by NGF induces auto-phosphorylation of this receptor and promotes ERK1/2 activation, we thought it likely that NGF and TrkA interactions might differentially activate downstream signaling between the 2 phenotypes.	2	7	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	4	5
Moreover , activation of TRKA by NGF strongly rescues KIT inhibition induced cell death of mast cell lines and primary mast cells from patients with SM , and this rescue effect can be efficiently blocked by entrectinib ( a new pan TRK specific inhibitor ) .	Moreover, activation of TRKA by NGF strongly rescues KIT inhibition induced cell death of mast cell lines and primary mast cells from patients with SM, and this rescue effect can be efficiently blocked by entrectinib (a new pan TRK specific inhibitor).	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TRKA	TRKA	TRKA	6	7	4	5
The NGF activated TrkA stimulates downstream signaling pathways , which results in neuronal differentiation and promoting cell survival [ XREF_BIBR ] .	The NGF activated TrkA stimulates downstream signaling pathways, which results in neuronal differentiation and promoting cell survival [XREF_BIBR].	0	15	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	3	4
NGF ( 100ng/ml ) also failed to induce significant death of NT SH-SY5Y , pcDNA SH-SY5Y or TrkA SH-SY5Y cells ( XREF_FIG ) .	NGF (100ng/ml) also failed to induce significant death of NT SH-SY5Y, pcDNA SH-SY5Y or TrkA SH-SY5Y cells (XREF_FIG).	0	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	17	18
In this study , we examined the effect of GM1 on NGF induced TrkA dimerization in Trk-PC12 ( 6-24 ) cells .	In this study, we examined the effect of GM1 on NGF induced TrkA dimerization in Trk-PC12 (6-24) cells.	5	14	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	13	14
The mechanism through which NGF sensitised TrkA expressing SH-SY5Y cells to TRAIL induced apoptosis ( XREF_FIG ) did not result , however , from NGF downregulation of cFLIP expression , but rather from cFLIP sequestration by NGF activated TrkA receptors .	The mechanism through which NGF sensitised TrkA expressing SH-SY5Y cells to TRAIL induced apoptosis (XREF_FIG) did not result, however, from NGF downregulation of cFLIP expression, but rather from cFLIP sequestration by NGF activated TrkA receptors.	34	39	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	36	37	38	39
We identify cFLIP as the major mediator of the TRAIL resistant SH-SY5Y phenotype and provide evidence that NGF sensitization to TRAIL induced apoptosis results from cFLIP sequestration by NGF activated TrkA .	We identify cFLIP as the major mediator of the TRAIL resistant SH-SY5Y phenotype and provide evidence that NGF sensitization to TRAIL induced apoptosis results from cFLIP sequestration by NGF activated TrkA.	26	31	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	28	29	30	31
NGF would promote survival of NTRK1 expressing cells .	NGF would promote survival of NTRK1 expressing cells.	0	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NTRK1	NTRK1	NTRK1	0	1	5	6
NGF activation of the high-affinity NGF receptor trkA can generate production and release of SP , while SP , in turn , can promote the production and release of NGF [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	NGF activation of the high-affinity NGF receptor trkA can generate production and release of SP, while SP, in turn, can promote the production and release of NGF [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	0	1	7	8
NGF is believed to activate TrkA by bridging two TrkA monomers , leading to TrkA transphosphorylation .	NGF is believed to activate TrkA by bridging two TrkA monomers, leading to TrkA transphosphorylation.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	5	6
Thus the lack of , or inhibition of , PTPsigma would increase NGF induced TrkA signaling , thereby enhancing sympathetic axon growth .	Thus the lack of, or inhibition of, PTPsigma would increase NGF induced TrkA signaling, thereby enhancing sympathetic axon growth.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	14	15
We also suggest that differential activation of TrkA by NGF and NT-3 may lead to differing profiles of downstream substrate activation , and that NT-3 may simply not activate pathways essential to survival as efficiently as NGF does .	We also suggest that differential activation of TrkA by NGF and NT-3 may lead to differing profiles of downstream substrate activation, and that NT-3 may simply not activate pathways essential to survival as efficiently as NGF does.	5	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	7	8
Ras was not required for NGF induced activation of Trk or tyrosine phosphorylation of PLC-gamma 1 .	Ras was not required for NGF induced activation of Trk or tyrosine phosphorylation of PLC-gamma 1.	3	11	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	5	6	9	10
Furthermore , STX8 modulates downstream NGF induced TrkA signaling and , consequently , the survival of NGF dependent dorsal root ganglia neurons .	Furthermore, STX8 modulates downstream NGF induced TrkA signaling and, consequently, the survival of NGF dependent dorsal root ganglia neurons.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	7	8
NGF is a member of the neurotrophin family of growth factors , and can activate two receptors : TrkA and the p75 neurotrophin receptor ( p75 NTR ) .	NGF is a member of the neurotrophin family of growth factors, and can activate two receptors : TrkA and the p75 neurotrophin receptor (p75 NTR).	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	18	19
The MAPK pathway , in particular the ERK1/2 branch , has been found to be favored following NGF induced Trk activation ( Segal 2003 ) and is also widely implicated in neurite outgrowth ( Thomas and Huganir 2004 ) .	The MAPK pathway, in particular the ERK1/2 branch, has been found to be favored following NGF induced Trk activation (Segal 2003) and is also widely implicated in neurite outgrowth (Thomas and Huganir 2004).	15	29	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	17	18	19	20
One possible explanation might be that since NGF uniquely promotes TrkA endocytosis in nerve terminals for carrying retrograde survival signals back to neuronal soma , this process has been co-opted for local control of NGF mediated axonal growth , via mechanisms that remain to be identified .	One possible explanation might be that since NGF uniquely promotes TrkA endocytosis in nerve terminals for carrying retrograde survival signals back to neuronal soma, this process has been co-opted for local control of NGF mediated axonal growth, via mechanisms that remain to be identified.	7	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	10	11
Addition of 1 nM NGF promoted maximal TrkA internalization at 15 min post NGF incubation in both control ( HEPES ) and M3 conditions ( XREF_FIG ) .	Addition of 1 nM NGF promoted maximal TrkA internalization at 15 min post NGF incubation in both control (HEPES) and M3 conditions (XREF_FIG).	0	8	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	7	8
As such , Trio may act as a platform to locally modulate Rac and RhoA activity in response to neurotrophins , wherein the mature form of NGF preferentially activates TrkA to promote the interaction of ARMS and Trio at the plasma membrane and Rac dependent neurite outgrowth .	As such, Trio may act as a platform to locally modulate Rac and RhoA activity in response to neurotrophins, wherein the mature form of NGF preferentially activates TrkA to promote the interaction of ARMS and Trio at the plasma membrane and Rac dependent neurite outgrowth.	24	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	26	27	29	30
Additionally , previous reports have demonstrated that even in the adult , NGF can induce marked sprouting of TrkA + sensory nerve fibers XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Additionally, previous reports have demonstrated that even in the adult, NGF can induce marked sprouting of TrkA + sensory nerve fibers XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	12	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	18	19
This correlated with the Topflash experiment , where treatment with EGF or NGF caused Topflash activation in RCS cells overexpressing EGFR or TRKA , respectively ( XREF_FIG ; cells treated with EGF or NGF alone ) .	This correlated with the Topflash experiment, where treatment with EGF or NGF caused Topflash activation in RCS cells overexpressing EGFR or TRKA, respectively (XREF_FIG; cells treated with EGF or NGF alone).	19	34	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NGF	NGF	NGF	TRKA	TRKA	TRKA	33	34	22	23
Additionally , expression of the dominant negative RacN17 abolished retrograde transport of TrkA induced by NGF and NT3 in the presence of bafilomycin ( XREF_FIG ) .	Additionally, expression of the dominant negative RacN17 abolished retrograde transport of TrkA induced by NGF and NT3 in the presence of bafilomycin (XREF_FIG).	10	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	15	16	12	13
Normal keratinocytes over-expressing TrkA proliferate better than control transfectants , while the NGF mimicking anti-Trk antibody induces an increased keratinocyte proliferation in Trk over-expressing cells as compared to mock transfected keratinocytes .	Normal keratinocytes over-expressing TrkA proliferate better than control transfectants, while the NGF mimicking anti-Trk antibody induces an increased keratinocyte proliferation in Trk over-expressing cells as compared to mock transfected keratinocytes.	11	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	12	13	22	23
Here , exercise may act to decrease elevated NGF associated with the high-fat diet , leading to normalized TrkA positive axonal innervation .	Here, exercise may act to decrease elevated NGF associated with the high-fat diet, leading to normalized TrkA positive axonal innervation.	6	21	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	18	19
NGF mediated TrkA signaling in PC12 cells typically activates Erk1/2 and Akt downstream signaling .	NGF mediated TrkA signaling in PC12 cells typically activates Erk1/2 and Akt downstream signaling.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
Overall , our results indicate an essential role for p75NTR in supporting NGF triggered TrkA signaling pathways mediating neuronal survival in hippocampal neurons .	Overall, our results indicate an essential role for p75NTR in supporting NGF triggered TrkA signaling pathways mediating neuronal survival in hippocampal neurons.	12	16	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	14	15
In the models we tested we see increased expression of HIF-1alpha and not HIF-2alpha upon NGF activation of TrkA .	In the models we tested we see increased expression of HIF-1alpha and not HIF-2alpha upon NGF activation of TrkA.	15	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	15	16	18	19
Application of NGF to DRG axons in compartmentalized cultures activated TrkA receptors which induced local translation of CREB mRNA .	Application of NGF to DRG axons in compartmentalized cultures activated TrkA receptors which induced local translation of CREB mRNA.	0	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	10	11
In fact , NGF can stimulate distal neurites and upregulate neurotrophic tyrosine kinase receptor type 1 ( TrkA ) for neuronal survival , growth , and differentiation in nervous system .	In fact, NGF can stimulate distal neurites and upregulate neurotrophic tyrosine kinase receptor type 1 (TrkA) for neuronal survival, growth, and differentiation in nervous system.	3	26	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	17	18
PC frequently synthesizes large amounts of NGF , which in turns stimulates TrkA 3 .	PC frequently synthesizes large amounts of NGF, which in turns stimulates TrkA 3.	0	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	PC frequently synthesizes large amounts of NGF	ngf	TrkA	TrkA	trka	6	7	12	13
In addition , NGF enhanced TrkA induced morphological changes and cell death , and this effect was significantly suppressed by the JNK inhibitor SP600125 , but not by the phosphatidylinositol 3-kinase ( PI3K ) inhibitor wortmannin .	In addition, NGF enhanced TrkA induced morphological changes and cell death, and this effect was significantly suppressed by the JNK inhibitor SP600125, but not by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin.	3	6	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
During the first two postnatal weeks , sympathetic neurons compete for limiting amounts of target derived NGF , which binds to and activates TrkA tyrosine kinase receptors on neuronal teminals , thereby mediating a retrograde neuronal survival signal .	During the first two postnatal weeks, sympathetic neurons compete for limiting amounts of target derived NGF, which binds to and activates TrkA tyrosine kinase receptors on neuronal teminals, thereby mediating a retrograde neuronal survival signal.	15	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	23	24
Our results support a model in which sortilin- and p75 dependent cleavage of proNGF occurs in peri-somatic glia , to produce NGF that activates TrkA in the adjacent neuronal soma .	Our results support a model in which sortilin- and p75 dependent cleavage of proNGF occurs in peri-somatic glia, to produce NGF that activates TrkA in the adjacent neuronal soma.	20	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	21	22	24	25
We have reported that a Neu1-MMP9 crosstalk in alliance with neuromedin GPCR Galpha i -signaling also regulates NGF induced TrkA activation , downstream cellular signaling , and cellular function [ XREF_BIBR ] .	We have reported that a Neu1-MMP9 crosstalk in alliance with neuromedin GPCR Galpha i -signaling also regulates NGF induced TrkA activation, downstream cellular signaling, and cellular function [XREF_BIBR].	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	17	18	19	20
Mature NGF , which activates both p75 NTR and TrkA , promotes cell survival .	Mature NGF, which activates both p75 NTR and TrkA, promotes cell survival.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	9	10
NGF ( 1-14 ) induces TrkA receptor internalization in PC12 cells only in the presence of CuSO 4 and ZnSO 4 .	NGF (1-14) induces TrkA receptor internalization in PC12 cells only in the presence of CuSO 4 and ZnSO 4.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	5	6
In contrast , Rab22 shRNA cells showed no response to NGF induced pTrkA endocytosis , and the percentage of cells containing intracellular pTrkA staining remained at a low background level ( < 5 % ) over the time course of NGF treatment ( XREF_FIG ) .	In contrast, Rab22 shRNA cells showed no response to NGF induced pTrkA endocytosis, and the percentage of cells containing intracellular pTrkA staining remained at a low background level (< 5%) over the time course of NGF treatment (XREF_FIG).	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	pTrkA	pTrkA	pTrkA	10	11	12	13
While NGF induced sprouting of TrkA + / GAP43 + sensory fibers appears to be involved in driving skeletal pain , previous studies have clearly demonstrated that NGF binding to TrkA in peripheral tissues can play a pivotal role in the generation and maintenance of pain .	While NGF induced sprouting of TrkA + / GAP43 + sensory fibers appears to be involved in driving skeletal pain, previous studies have clearly demonstrated that NGF binding to TrkA in peripheral tissues can play a pivotal role in the generation and maintenance of pain.	1	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	5	6
Analysis of TRK oncogenes signal transduction , performed in NIH3T3 foci , have detected the involvement of several signal transducers recruited by the NGF stimulated NTRK1 receptor , such as Shc , PLCgamma , ERK1/2 and JNK MAP kinases ( Borrello et al , 1994 , manuscript in preparation ) .	Analysis of TRK oncogenes signal transduction, performed in NIH3T3 foci, have detected the involvement of several signal transducers recruited by the NGF stimulated NTRK1 receptor, such as Shc, PLCgamma, ERK1/2 and JNK MAP kinases (Borrello et al, 1994, manuscript in preparation).	20	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NTRK1	NTRK1	NTRK1	23	24	25	26
Peptidergic DRG neurons express TrkA and p75 neurotrophin receptors that are targeted by nerve growth factor ( NGF ) .	Peptidergic DRG neurons express TrkA and p75 neurotrophin receptors that are targeted by nerve growth factor (NGF).	4	18	targeted	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	17	18	4	5
To at least partly resolve this , XREF_BIBR provided evidence that the neurotrophic actions of proNGF are indirect and involve conversion to NGF , which may be subsequently secreted to activate TrkA .	To at least partly resolve this, XREF_BIBR provided evidence that the neurotrophic actions of proNGF are indirect and involve conversion to NGF, which may be subsequently secreted to activate TrkA.	19	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	22	23	31	32
Although the initial cell-surface abundance of TrkA is significantly lower in shNHE5 cells than in shNHE1 or control cells ( time 0 , XREF_FIG ) , densitometric analysis showed that the rates of NGF induced TrkA endocytosis were comparable among the three cell lines ( XREF_FIG ) .	Although the initial cell-surface abundance of TrkA is significantly lower in shNHE5 cells than in shNHE1 or control cells (time 0, XREF_FIG), densitometric analysis showed that the rates of NGF induced TrkA endocytosis were comparable among the three cell lines (XREF_FIG).	31	36	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	33	34	35	36
NGF activation of TrkA and p75 NTR can increase microglial migration 62 and can induce macrophage mediated tumor necrosis factor ( TNF )-alpha production 63 , interleukin-1beta ( IL-1beta ) secretion and inflammasome activation XREF_BIBR , XREF_BIBR .	NGF activation of TrkA and p75 NTR can increase microglial migration 62 and can induce macrophage mediated tumor necrosis factor (TNF)-alpha production 63, interleukin-1beta (IL-1beta) secretion and inflammasome activation XREF_BIBR, XREF_BIBR.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	3	4
This implicates RAS and MAPK signaling in the NB tumour suppressing effects of NGF activated TrkA receptors and PI3K/Akt/NF-kappaB without RAS and MAPK signaling in the diametrically opposed oncogenic activity of TrkAIII , which for some reason is unable to activate the RAS and MAPK pathway , despite binding Grb-2 and Frs-2 adapter proteins involved in RAS and MAPK activation [ XREF_BIBR ] .	This implicates RAS and MAPK signaling in the NB tumour suppressing effects of NGF activated TrkA receptors and PI3K/Akt/NF-kappaB without RAS and MAPK signaling in the diametrically opposed oncogenic activity of TrkAIII, which for some reason is unable to activate the RAS and MAPK pathway, despite binding Grb-2 and Frs-2 adapter proteins involved in RAS and MAPK activation [XREF_BIBR].	11	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	13	14	15	16
Previous groups have shown that overexpression of NGF can lead to hyperinnvervation in the bladder [ XREF_BIBR ] , can cause Adelta fibers to become responsive to substance P [ XREF_BIBR ] , and can promote the sprouting of TrkA expressing nociceptors , resulting in hyperinnervation of the skin [ XREF_BIBR ] .	Previous groups have shown that overexpression of NGF can lead to hyperinnvervation in the bladder [XREF_BIBR], can cause Adelta fibers to become responsive to substance P [XREF_BIBR], and can promote the sprouting of TrkA expressing nociceptors, resulting in hyperinnervation of the skin [XREF_BIBR].	5	40	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	overexpression of NGF	ngf	TrkA	TrkA	trka	7	8	39	40
In order to be generated , the NGF induced signal requires therefore the two receptors , TrkA and p75 NTR , to be activated concomitantly .	In order to be generated, the NGF induced signal requires therefore the two receptors, TrkA and p75 NTR, to be activated concomitantly.	6	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	16	17
XREF_BIBR have shown that tyrosines in TRPV1 are phosphorylated and that the phosphorylation is enhanced when TrkA is activated by NGF .	XREF_BIBR have shown that tyrosines in TRPV1 are phosphorylated and that the phosphorylation is enhanced when TrkA is activated by NGF.	16	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	20	21	16	17
The stimulated outgrowth was confirmed in a second defective PC12 clone over-expressing the NGF receptor TrkA , treated with NGF and/or a recombinant L1CAM chimera .	The stimulated outgrowth was confirmed in a second defective PC12 clone over-expressing the NGF receptor TrkA, treated with NGF and/or a recombinant L1CAM chimera.	11	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	19	20	15	16
TrkA receptors are activated by NGF at concentrations significantly lower than the p75 neurotrophin receptor and 0.1 ng/mL NGF is sufficient to significantly activate the TrkA receptor with maximal activation at 1 ng/mL .	TrkA receptors are activated by NGF at concentrations significantly lower than the p75 neurotrophin receptor and 0.1 ng/mL NGF is sufficient to significantly activate the TrkA receptor with maximal activation at 1 ng/mL.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	0	1
Further studies revealed that NRAGE downregulates TrkA expression through a post-transcriptional manner and thereby blocks NGF induced TrkA phosphrylation at tyrosine 490 .	Further studies revealed that NRAGE downregulates TrkA expression through a post-transcriptional manner and thereby blocks NGF induced TrkA phosphrylation at tyrosine 490.	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	15	16	17	18
V-ATPase inhibition also perturbs targeting of MET ( XREF_FIG ) and EGFR to the leading edge of migratory cells similar to the impairment of NGF induced TrkA recycling by Baf .	V-ATPase inhibition also perturbs targeting of MET (XREF_FIG) and EGFR to the leading edge of migratory cells similar to the impairment of NGF induced TrkA recycling by Baf.	22	27	induced	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	24	25	26	27
15 However , NGF mediated TrkA activation is also known to induce cell death in glioblastoma and medulloblastoma .	15 However, NGF mediated TrkA activation is also known to induce cell death in glioblastoma and medulloblastoma.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
This result is in agreement with the accumulation of NGF activated TrkA in enlarged endosomes in PC12 cells overexpressing a dominant negative Rab7 mutant .	This result is in agreement with the accumulation of NGF activated TrkA in enlarged endosomes in PC12 cells overexpressing a dominant negative Rab7 mutant.	7	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	11	12
Specifically , NGF induces the transcriptional upregulation of the gene encoding NTRK1 , which results in increased NTRK1 levels and presumably reinforced NTRK1 dependent pro survival signaling ( XREF_FIG ) .	Specifically, NGF induces the transcriptional upregulation of the gene encoding NTRK1, which results in increased NTRK1 levels and presumably reinforced NTRK1 dependent pro survival signaling (XREF_FIG).	2	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NTRK1	NTRK1	NTRK1	2	3	11	12
To test the potential involvement of NHE5 in NGF induced TrkA internalization , shRNA expressing cells were treated with NGF for the indicated times , and TrkA retained on the cell surface was detected by biotinylation ( see Materials and Methods ) .	To test the potential involvement of NHE5 in NGF induced TrkA internalization, shRNA expressing cells were treated with NGF for the indicated times, and TrkA retained on the cell surface was detected by biotinylation (see Materials and Methods).	1	11	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	10	11
Furthermore , we observed that Arf6 is required for GGA3 mediated TrkA recycling and that Arf6 is activated by Src , a downstream effector of NGF activated TrkA .	Furthermore, we observed that Arf6 is required for GGA3 mediated TrkA recycling and that Arf6 is activated by Src, a downstream effector of NGF activated TrkA.	23	28	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	25	26	27	28
NGF applied to distal axons enhanced the transcytosis of TrkA receptors from cell bodies to distal axons .	NGF applied to distal axons enhanced the transcytosis of TrkA receptors from cell bodies to distal axons.	0	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	9	10
NGF enhances TrkA dependent cellular processes in a JNK dependent manner .	NGF enhances TrkA dependent cellular processes in a JNK dependent manner.	0	3	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
NGF activates TrkA and/or p75NTR , triggering signal transduction cascades .	NGF activates TrkA and/or p75NTR, triggering signal transduction cascades.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
P75 NTR can functionally antagonize downstream TrkA signaling , and increased TrkA activation by NGF may explain the increased axonal elongation in p75 NTR -/- hearts .	P75 NTR can functionally antagonize downstream TrkA signaling, and increased TrkA activation by NGF may explain the increased axonal elongation in p75 NTR -/- hearts.	11	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	14	15	11	12
We hypothesize that enhanced NGF mediated Trk A activation during the period of mechanical allodynia increases the expression of SP in DRG neurons and serves as a molecular mechanism for PDN in type 2 diabetes .	We hypothesize that enhanced NGF mediated Trk A activation during the period of mechanical allodynia increases the expression of SP in DRG neurons and serves as a molecular mechanism for PDN in type 2 diabetes.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	4	5	6	7
Co-treatment with 17-DMAG inhibited NGF mediated increase in p-TrkA , p-AKT , and p-ERK1/2 ( XREF_FIG ) .	Co-treatment with 17-DMAG inhibited NGF mediated increase in p-TrkA, p-AKT, and p-ERK1/2 (XREF_FIG).	4	15	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	p-TrkA	p-TrkA	p-TrkA	4	5	8	9
To evaluate whether the metals in the medium are essential in the TrkA signaling triggered by NGF and NGF ( 1-14 ) western blot analyses were performed in PC12 cells un-pre-treated or pre-treated 24 h before with BCS ( a membrane-impermeable extracellular strong metal chelating agent ) , in the presence or absence of CuSO 4 and ZnSO 4 .	To evaluate whether the metals in the medium are essential in the TrkA signaling triggered by NGF and NGF (1-14) western blot analyses were performed in PC12 cells un-pre-treated or pre-treated 24 h before with BCS (a membrane-impermeable extracellular strong metal chelating agent), in the presence or absence of CuSO 4 and ZnSO 4.	12	18	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	12	13
To better understand NGF mediated TrkA dependent signaling pathways during cancer cell death , we investigated the effects of NGF on the regulation of TrkA and TrkA dependent cellular proteins in TrkA inducible SK-N-MC cancer cells by western blot analysis .	To better understand NGF mediated TrkA dependent signaling pathways during cancer cell death, we investigated the effects of NGF on the regulation of TrkA and TrkA dependent cellular proteins in TrkA inducible SK-N-MC cancer cells by western blot analysis.	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
NGF activation of TrkA causes a marked increase in VEGF secretion by neuronal cells .	NGF activation of TrkA causes a marked increase in VEGF secretion by neuronal cells.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	3	4
Nerve growth factor ( NGF ) initiates the majority of its biological effects by promoting the dimerization and activation of the tyrosine kinase receptor TrkA .	Nerve growth factor (NGF) initiates the majority of its biological effects by promoting the dimerization and activation of the tyrosine kinase receptor TrkA.	2	25	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	24	25
NGF stimulated retrograde transport of trkA in the mammalian nervous system .	NGF stimulated retrograde transport of trkA in the mammalian nervous system.	0	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	0	1	5	6
For example , QDs conjugated to nerve growth factor ( NGF ) effectively activate TrkA receptors and downstream signaling cascades that promote neuronal differentiation [ XREF_BIBR ] .	For example, QDs conjugated to nerve growth factor (NGF) effectively activate TrkA receptors and downstream signaling cascades that promote neuronal differentiation [XREF_BIBR].	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	14	15
NGF stimulation promotes rapid exocytosis of TrkA receptors .	NGF stimulation promotes rapid exocytosis of TrkA receptors.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	6	7
Indeed , unlike Rab22 : S19N , the dominant negative Rab5 mutant ( Rab5 : S34N ) does not block NGF induced pTrkA endocytosis ( unpublished data ) , suggesting a Rab22 specific pathway for pTrkA endocytosis .	Indeed, unlike Rab22 : S19N, the dominant negative Rab5 mutant (Rab5 : S34N) does not block NGF induced pTrkA endocytosis (unpublished data), suggesting a Rab22 specific pathway for pTrkA endocytosis.	19	23	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	pTrkA	pTrkA	pTrkA	20	21	22	23
Sympathetic neurons express two receptors that are activated by NGF : p75 , a pan neurotrophin receptor , and the specific NGF receptor , TrkA .	Sympathetic neurons express two receptors that are activated by NGF : p75, a pan neurotrophin receptor, and the specific NGF receptor, TrkA.	7	25	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	24	25
Another possible pathway is the downregulation of NGF activation of tyrosine kinase receptor trkA which uses the phosphatidylinositol 3-kinase/phosphatidylinositol phosphate 3 ( PI3K and PIP3 ) signalling pathway to increase the expression and sensitivity of TRPV1 [ XREF_BIBR ] .	Another possible pathway is the downregulation of NGF activation of tyrosine kinase receptor trkA which uses the phosphatidylinositol 3-kinase/phosphatidylinositol phosphate 3 (PI3K and PIP3) signalling pathway to increase the expression and sensitivity of TRPV1 [XREF_BIBR].	7	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	7	8	13	14
The NGF transport hypothesis is supported by recent evidence : in PC12 cells NGF stimulates the internalization of trk into endosomes in which trk remains activated , and phosphorylated trk is retrogradely transported in the sciatic nerve .	The NGF transport hypothesis is supported by recent evidence : in PC12 cells NGF stimulates the internalization of trk into endosomes in which trk remains activated, and phosphorylated trk is retrogradely transported in the sciatic nerve.	13	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trk	trk	trk	13	14	18	19
TrkA activation by NGF is essential for the maturation , projections , and function of these neurons , as was previously described for sensory neurons in the PNS as well .	TrkA activation by NGF is essential for the maturation, projections, and function of these neurons, as was previously described for sensory neurons in the PNS as well.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	0	1
Nerve growth factor ( NGF ) initiates the activation of TrkA tyrosine kinase receptors and numerous subsequent signaling cascades .	Nerve growth factor (NGF) initiates the activation of TrkA tyrosine kinase receptors and numerous subsequent signaling cascades.	2	13	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	10	11
However , NGF is sufficient to promote terminal differentiation of a approximately 8 % of trk transfected MAH cells to postmitotic , NGF dependent neurons , whereas all cells eventually die in medium with bFGF .	However, NGF is sufficient to promote terminal differentiation of a approximately 8% of trk transfected MAH cells to postmitotic, NGF dependent neurons, whereas all cells eventually die in medium with bFGF.	2	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trk	trk	trk	2	3	15	16
Subsequently , retrograde NGF signaling enhances anterograde delivery of additional TrkA receptors by drawing on a larger intracellular pool residing in cell bodies ( XREF_FIG ) .	Subsequently, retrograde NGF signaling enhances anterograde delivery of additional TrkA receptors by drawing on a larger intracellular pool residing in cell bodies (XREF_FIG).	3	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	10	11
The receptor tyrosine kinase Kit thus contrasts with the receptor tyrosine kinase trkA , which is activated by the sprouting stimulus ( NGF ) but not by the axonal regeneration signal .	The receptor tyrosine kinase Kit thus contrasts with the receptor tyrosine kinase trkA, which is activated by the sprouting stimulus (NGF) but not by the axonal regeneration signal.	6	23	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	22	23	12	13
In contrast , after in vitro reactions , NGF caused TrkA to increase , and p75 NTR to decrease in the floating DRMs ( XREF_FIG , + in vitro reaction ) .	In contrast, after in vitro reactions, NGF caused TrkA to increase, and p75 NTR to decrease in the floating DRMs (XREF_FIG, + in vitro reaction).	8	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	10	11
The expression and sensitivity of TRPV1 receptor can be upregulated by NGF induced activation of trkA receptor which signals via the PI3K and PIP3 pathway [ XREF_BIBR ] ( see XREF_FIG ) .	The expression and sensitivity of TRPV1 receptor can be upregulated by NGF induced activation of trkA receptor which signals via the PI3K and PIP3 pathway [XREF_BIBR] (see XREF_FIG).	9	29	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	11	12	15	16
NGF induces a TrkA dimerization with subsequent tyrosine phosphorylation via its intrinsic tyrosine kinase activity , a required step for the formation of oligodendroglial processes .	NGF induces a TrkA dimerization with subsequent tyrosine phosphorylation via its intrinsic tyrosine kinase activity, a required step for the formation of oligodendroglial processes.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	3	4
To determine whether NGF promotes TrkA exocytosis , sympathetic neurons were stimulated briefly ( 5 min pulse ) with NGF , and surface levels of TrkA assessed by cell surface biotinylation .	To determine whether NGF promotes TrkA exocytosis, sympathetic neurons were stimulated briefly (5 min pulse) with NGF, and surface levels of TrkA assessed by cell surface biotinylation.	3	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
Coexpression of p75 NTR and TrkA receptors increases TrkA high affinity binding sites for NGF and NGF mediated TrkA activation .	Coexpression of p75 NTR and TrkA receptors increases TrkA high affinity binding sites for NGF and NGF mediated TrkA activation.	12	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	18	19
Since NGF activates the tyrosine kinase activity of gp140trk , the protein product of the trk proto-oncogene , we also examined the association of PtdIns 3-kinase with gp140trk .	Since NGF activates the tyrosine kinase activity of gp140trk, the protein product of the trk proto-oncogene, we also examined the association of PtdIns 3-kinase with gp140trk.	1	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	gp140trk	gp140trk	gp140trk	1	2	8	9
NGF induced TrkA dimerization and autophosphorylation , particularly on tyrosine residues 490 and 785 , signifies receptor activation and functions to trigger downstream signaling cascades , including the Ras and ERK , PLCgamma , and PI3K pathways , by recruiting signaling pathway effector proteins to the membrane ( XREF_FIG ) .	NGF induced TrkA dimerization and autophosphorylation, particularly on tyrosine residues 490 and 785, signifies receptor activation and functions to trigger downstream signaling cascades, including the Ras and ERK, PLCgamma, and PI3K pathways, by recruiting signaling pathway effector proteins to the membrane (XREF_FIG).	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
TRKA is activated by NGF , which has a well studied role in the mediation of pain , itch , and inflammation , and the development and maintenance of cholinergic , sympathetic , and sensory neurons [ XREF_BIBR ] .	TRKA is activated by NGF, which has a well studied role in the mediation of pain, itch, and inflammation, and the development and maintenance of cholinergic, sympathetic, and sensory neurons [XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TRKA	TRKA	TRKA	4	5	0	1
Thus , nerve growth factor ( NGF ) activates TrkA [ XREF_BIBR , XREF_BIBR ] , brain derived neurotrophic factor ( BDNF ) [ XREF_BIBR ] and neurotrophin-4/5 ( NT-4/5 ) [ XREF_BIBR ] binds to TrkB ; and neurotrophin-3 ( NT-3 ) [ XREF_BIBR ] reacts with TrkC , although it can also bind TrkA and TrkB with lesser affinity [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Thus, nerve growth factor (NGF) activates TrkA [XREF_BIBR, XREF_BIBR], brain derived neurotrophic factor (BDNF) [XREF_BIBR] and neurotrophin-4/5 (NT-4/5) [XREF_BIBR] binds to TrkB; and neurotrophin-3 (NT-3) [XREF_BIBR] reacts with TrkC, although it can also bind TrkA and TrkB with lesser affinity [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	9	10
NGF stimulates association of TrkA and NGF to newly polymerized microtubules with lipid rafts , but not p75 NTR .	NGF stimulates association of TrkA and NGF to newly polymerized microtubules with lipid rafts, but not p75 NTR.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	4	5
Interestingly , Sema3F can antagonize NGF stimulated TrkA signaling in sympathetic neurons .	Interestingly, Sema3F can antagonize NGF stimulated TrkA signaling in sympathetic neurons.	4	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	7	8
Taken together , these data demonstrated that TrkA is a determinant of pancreatic adenocarcinoma chemoresistance and PI3K and Akt is a key signaling component by which NGF activation of the TrkA signal transduction pathway protects pancreatic cancer cells from chemotherapy induced cell death .	Taken together, these data demonstrated that TrkA is a determinant of pancreatic adenocarcinoma chemoresistance and PI3K and Akt is a key signaling component by which NGF activation of the TrkA signal transduction pathway protects pancreatic cancer cells from chemotherapy induced cell death.	26	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	26	27	30	31
It has been known that NGF induced autophosphorylation of Y-670 , Y-674 , and Y-675 is essential for TrkA activity and causes trans-phosphorylation of TrkA at Y-490 and Y-785 , resulting in the activation of NGF mediated TrkA signaling XREF_BIBR .	It has been known that NGF induced autophosphorylation of Y-670, Y-674, and Y-675 is essential for TrkA activity and causes trans-phosphorylation of TrkA at Y-490 and Y-785, resulting in the activation of NGF mediated TrkA signaling XREF_BIBR.	9	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	35	36	37	38
We could show , with microfluidic devices , that SgG2 reduced NGF induced TrkA retrograde transport .	We could show, with microfluidic devices, that SgG2 reduced NGF induced TrkA retrograde transport.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	13	14
Moreover , specific stimulation of p75NTR by NGF activated TrkA and the MAPK ( mitogen activated protein kinase ) pathway .	Moreover, specific stimulation of p75NTR by NGF activated TrkA and the MAPK (mitogen activated protein kinase) pathway.	5	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	9	10
We have developed methods to assess target engagement for drug programs aimed at disrupting NGF induced TrkA signaling .	We have developed methods to assess target engagement for drug programs aimed at disrupting NGF induced TrkA signaling.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	14	15	16	17
SHP-1 interacts with TrkA at tyrosine 490 and controls both the basal NGF stimulated level of TrkA activity in developing peripheral neurons .	SHP-1 interacts with TrkA at tyrosine 490 and controls both the basal NGF stimulated level of TrkA activity in developing peripheral neurons.	8	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	16	17
Collectively , the results suggest that NGF produced in the injured tissue activates trkA receptors to promote the central sprouting of capsaicin sensitive primary afferents , thus increasing the number of nociceptive synapses within the immature SDH .	Collectively, the results suggest that NGF produced in the injured tissue activates trkA receptors to promote the central sprouting of capsaicin sensitive primary afferents, thus increasing the number of nociceptive synapses within the immature SDH.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	6	7	13	14
NGF promotes endocytosis of its TrkA receptors in nerve endings into signaling endosomes that are retrogradely transported to neuronal cell bodies to activate trophic signaling .	NGF promotes endocytosis of its TrkA receptors in nerve endings into signaling endosomes that are retrogradely transported to neuronal cell bodies to activate trophic signaling.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	5	6
A dominant inhibitory Pincher mutant prevents NGF induced TrkA internalization and selectively blocks cytoplasmic endosomal signaling through erk5 kinase .	A dominant inhibitory Pincher mutant prevents NGF induced TrkA internalization and selectively blocks cytoplasmic endosomal signaling through erk5 kinase.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	8	9
XREF_BIBR showed that formation of signaling endosomes containing TrkA involves a mechanism that affects actin dynamics , and that NGF , but not NT3 , could activate TrkA to form persistent , retrogradely transported signaling endosomes .	XREF_BIBR showed that formation of signaling endosomes containing TrkA involves a mechanism that affects actin dynamics, and that NGF, but not NT3, could activate TrkA to form persistent, retrogradely transported signaling endosomes.	19	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	19	20	27	28
NGF released from target cells activates TrkA on axon terminals and triggers activation of PI3K and Akt , MEK and ERK , and PLCgamma ( phospholipase C ) signaling pathways .	NGF released from target cells activates TrkA on axon terminals and triggers activation of PI3K and Akt, MEK and ERK, and PLCgamma (phospholipase C) signaling pathways.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	6	7
25 These facts suggest that NGF mediated TrkA activation could have important roles in the regulation of transcription via hnRNP K , hnRNP C1/C2 , SRSF1 , SRSF3 , BAF53A and TDP43 ; in nuclear structure via lamin B1 ; in protein stability via PSalpha1 ; and in enzymatic modification via septin-2 and PP2Acbeta in a JNK dependent manner in SK-N-MC cancer cell death signaling .	25 These facts suggest that NGF mediated TrkA activation could have important roles in the regulation of transcription via hnRNP K, hnRNP C1/C2, SRSF1, SRSF3, BAF53A and TDP43; in nuclear structure via lamin B1; in protein stability via PSalpha1; and in enzymatic modification via septin-2 and PP2Acbeta in a JNK dependent manner in SK-N-MC cancer cell death signaling.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	7	8
To better understand the NGF mediated TrkA dependent cellular processes and cell death mechanism , we investigated TrkA dependent targets regulated by NGF in TrkA inducible SK-N-MC cells through CBB staining and 2D proteomic analysis .	To better understand the NGF mediated TrkA dependent cellular processes and cell death mechanism, we investigated TrkA dependent targets regulated by NGF in TrkA inducible SK-N-MC cells through CBB staining and 2D proteomic analysis.	2	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	6	7
Down-modulation of STK25 , but not STK24 , rescued medulloblastoma cells from NGF induced TrkA dependent cell death , suggesting that STK25 is part of the death signaling pathway initiated by TrkA and CCM2 .	Down-modulation of STK25, but not STK24, rescued medulloblastoma cells from NGF induced TrkA dependent cell death, suggesting that STK25 is part of the death signaling pathway initiated by TrkA and CCM2.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	14	15
NGF stimulation caused a fraction of TrkA to rapidly associate with microtubules in lipid rafts ( XREF_FIG , XREF_FIG ) , and this association was retained in a fraction of endosomes ( XREF_FIG ) .	NGF stimulation caused a fraction of TrkA to rapidly associate with microtubules in lipid rafts (XREF_FIG, XREF_FIG), and this association was retained in a fraction of endosomes (XREF_FIG).	0	7	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	6	7
Moreover , functional interaction between p75NTR and Trk was demonstrated , in which proNGF induced PTEN via p75NTR to suppress Trk mediated survival signal in brain neurons and proNGF also inhibited NGF mediated Trk activation in PC12 cells [ XREF_BIBR , XREF_BIBR ] .	Moreover, functional interaction between p75NTR and Trk was demonstrated, in which proNGF induced PTEN via p75NTR to suppress Trk mediated survival signal in brain neurons and proNGF also inhibited NGF mediated Trk activation in PC12 cells [XREF_BIBR, XREF_BIBR].	31	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	31	32	33	34
Here we show that NGF induces TrkA and p75 NTR exit from lipid rafts in PC12 cells .	Here we show that NGF induces TrkA and p75 NTR exit from lipid rafts in PC12 cells.	4	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	6	7
In contrast , NGF mediated activation of TrkA induces its endocytosis and co-transport with downstream signaling molecules pERK1/2 and pAkt to the soma .	In contrast, NGF mediated activation of TrkA induces its endocytosis and co-transport with downstream signaling molecules pERK1/2 and pAkt to the soma.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	7	8
NGF Activates a Functional TrkA Signaling Pathway in hfNBMs .	NGF Activates a Functional TrkA Signaling Pathway in hfNBMs.	0	6	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	4	5
Y1036 prevents both BDNF- and NGF mediated trk activation , downstream activation of the p44/42 mitogen activated protein kinase pathway , and neurotrophin mediated differentiation of dorsal-root ganglion sensory neurons .	Y1036 prevents both BDNF- and NGF mediated trk activation, downstream activation of the p44/42 mitogen activated protein kinase pathway, and neurotrophin mediated differentiation of dorsal-root ganglion sensory neurons.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	trk	trk	trk	5	6	7	8
Application of NGF to distal axons of neurons grown in compartmentalized cultures supports cell survival as well as TrkA signaling within cell bodies , which in turn is required for activation of NGF and TrkA signaling effectors that promote survival .	Application of NGF to distal axons of neurons grown in compartmentalized cultures supports cell survival as well as TrkA signaling within cell bodies, which in turn is required for activation of NGF and TrkA signaling effectors that promote survival.	0	19	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	18	19
The strongest constitutively active TrkA mutants , GluAsp and AspGlu , support NGF independent neuritogenesis and cell survival to levels approximately 65 and 80-100 % , respectively , of NGF activated wild type TrkA .	The strongest constitutively active TrkA mutants, GluAsp and AspGlu, support NGF independent neuritogenesis and cell survival to levels approximately 65 and 80-100%, respectively, of NGF activated wild type TrkA.	1	34	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	33	34
NGF promotes endocytosis of TrkA receptors in distal axons into NGF : TrkA containing signalling endosomes that are retrogradely transported back to cell bodies to exert transcriptional control of neuronal survival and long-term growth XREF_BIBR .	NGF promotes endocytosis of TrkA receptors in distal axons into NGF : TrkA containing signalling endosomes that are retrogradely transported back to cell bodies to exert transcriptional control of neuronal survival and long-term growth XREF_BIBR.	0	5	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	4	5
XREF_FIG A ( characteristic Western Blot ) and XREF_FIG B ( quantitation of multiple experiments ) illustrate that exposure of PC12 cells to this anti-p75 NTR antibody almost completely abolishes NGF induced TrkA and p75 NTR exit from lipid rafts , much like Cav-1 expression .	XREF_FIG A (characteristic Western Blot) and XREF_FIG B (quantitation of multiple experiments) illustrate that exposure of PC12 cells to this anti-p75 NTR antibody almost completely abolishes NGF induced TrkA and p75 NTR exit from lipid rafts, much like Cav-1 expression.	30	36	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	30	31	32	33
While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA , its uncleaved precursor , pro NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin .	While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA, its uncleaved precursor, pro NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin.	1	21	necessary	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	15	16
Thus , strategies to interfere with NGF mediated TRKA activation and BDNF mediated p75NTR activation may prove beneficial in reducing sympathetic neuron sprouting and norepinephrine release [ XREF_BIBR - XREF_BIBR ] .	Thus, strategies to interfere with NGF mediated TRKA activation and BDNF mediated p75NTR activation may prove beneficial in reducing sympathetic neuron sprouting and norepinephrine release [XREF_BIBR - XREF_BIBR].	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TRKA	TRKA	TRKA	6	7	8	9
NGF mediated TrkA activation is known to regulate cell survival and differentiation through the ERK , PI3K-Akt and phospholipase C-gamma ( PLC-gamma ) signaling pathways , whereas NGF mediated p75NTR activation induces cell death through JNK signaling .	NGF mediated TrkA activation is known to regulate cell survival and differentiation through the ERK, PI3K-Akt and phospholipase C-gamma (PLC-gamma) signaling pathways, whereas NGF mediated p75NTR activation induces cell death through JNK signaling.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
This was in stark contrast to the activation of TrkA by NGF , which supported the sustained activation of TrkA within distal axons for over 24 hours of NGF stimulation ( XREF_FIG ) .	This was in stark contrast to the activation of TrkA by NGF, which supported the sustained activation of TrkA within distal axons for over 24 hours of NGF stimulation (XREF_FIG).	4	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	9	10
For example , upon NGF mediated activation of TrkA at an axon terminal , endosomal transport of the active NGF and TrkA complex along the axon to the cell body is required to promote signaling events in the nucleus XREF_BIBR , XREF_BIBR .	For example, upon NGF mediated activation of TrkA at an axon terminal, endosomal transport of the active NGF and TrkA complex along the axon to the cell body is required to promote signaling events in the nucleus XREF_BIBR, XREF_BIBR.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	8	9
Indeed , while both NGF and NT3 can support TrkA activation and axonal extension , NT3 is incapable of eliciting retrograde survival signaling , presumably due to its inability to form retrogradely transported TrkA signaling endosomes .	Indeed, while both NGF and NT3 can support TrkA activation and axonal extension, NT3 is incapable of eliciting retrograde survival signaling, presumably due to its inability to form retrogradely transported TrkA signaling endosomes.	3	10	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	9	10
NGF initiates the majority of its neurotrophic effects by promoting the activation of the tyrosine kinase receptor TrkA .	NGF initiates the majority of its neurotrophic effects by promoting the activation of the tyrosine kinase receptor TrkA.	0	18	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	17	18
Similarly , in sensory and sympathetic neurons , NGF induced TrkA activation in lipid rafts is required for efficient stimulation of ERK1/2 , Akt and PLCgamma for survival .	Similarly, in sensory and sympathetic neurons, NGF induced TrkA activation in lipid rafts is required for efficient stimulation of ERK1/2, Akt and PLCgamma for survival.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	10	11
Finally , the prominent expression of Tiam1 in NGF responsive neurons , such as developing sensory and sympathetic neurons as well as the neuronal cell line PC12 , led us to consider a possible role of Tiam1 in NGF induced TrkA downstream signaling and neurite extension .	Finally, the prominent expression of Tiam1 in NGF responsive neurons, such as developing sensory and sympathetic neurons as well as the neuronal cell line PC12, led us to consider a possible role of Tiam1 in NGF induced TrkA downstream signaling and neurite extension.	31	42	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	38	39	40	41
NGF also significantly increased the number of TrkA containing varicosities .	NGF also significantly increased the number of TrkA containing varicosities.	0	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	7	8
NT-3 docking on both sites 1 and 2 affords full agonism , which can be additive with NGF activation of Trk .	NT-3 docking on both sites 1 and 2 affords full agonism, which can be additive with NGF activation of Trk.	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	17	18	20	21
To better understand the mechanism of NGF mediated TrkA dependent cell death , we identified TrkA dependent targets regulated by NGF through CBB staining and a 2D proteomic analysis .	To better understand the mechanism of NGF mediated TrkA dependent cell death, we identified TrkA dependent targets regulated by NGF through CBB staining and a 2D proteomic analysis.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	8	9
NGF activates TrkA signaling pathways , thus influencing neuronal cell proliferation , differentiation , and survival [ XREF_BIBR , XREF_BIBR ] .	NGF activates TrkA signaling pathways, thus influencing neuronal cell proliferation, differentiation, and survival [XREF_BIBR, XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
It is now well established that NGF , produced in and released from target tissues , activates specifically TrkA at the distal axons of innervating neurons .	It is now well established that NGF, produced in and released from target tissues, activates specifically TrkA at the distal axons of innervating neurons.	6	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	18	19
In fact , in PC12 cells the extent of nanotopography triggered differentiation ( even in the absence of a biochemical stimulus ) was comparable to the canonical differentiation mediated by NGF induced TrkA activation .	In fact, in PC12 cells the extent of nanotopography triggered differentiation (even in the absence of a biochemical stimulus) was comparable to the canonical differentiation mediated by NGF induced TrkA activation.	28	33	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	30	31	32	33
5C3 binds specifically to the ectodomain of TrkA and mimics NGF , inducing TrkA internalization and signaling .	5C3 binds specifically to the ectodomain of TrkA and mimics NGF, inducing TrkA internalization and signaling.	5	14	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	13	14
By contrast , activation of NTRK1 by NGF binding in the soma resulted in the activation of ERK1 and ERK2 , which was not sufficient for the phosphorylation of CREB and the induction of survival signalling XREF_BIBR .	By contrast, activation of NTRK1 by NGF binding in the soma resulted in the activation of ERK1 and ERK2, which was not sufficient for the phosphorylation of CREB and the induction of survival signalling XREF_BIBR.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	NTRK1	NTRK1	NTRK1	7	8	5	6
These results indicate that the mechanisms for SPTB Numb- and NGF induced neurite outgrowth differ : SPTB Numb induced neurite outgrowth requires Ca 2+ influx but not TrkA activation , while NGF induced neurite outgrowth requires TrkA activation but not Ca 2+ influx .	These results indicate that the mechanisms for SPTB Numb- and NGF induced neurite outgrowth differ : SPTB Numb induced neurite outgrowth requires Ca 2+ influx but not TrkA activation, while NGF induced neurite outgrowth requires TrkA activation but not Ca 2+ influx.	31	37	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	31	32	36	37
NGF dissociates p75NTR and Sall2 complexes and activates TrkA , which has an obligate function in the nuclear translocation of Sall2 .	NGF dissociates p75NTR and Sall2 complexes and activates TrkA, which has an obligate function in the nuclear translocation of Sall2.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	8	9
For such reason it was important to assess cell proliferation in EOC and some molecules involved in NGF- mediated TRKA activation signaling pathway .	For such reason it was important to assess cell proliferation in EOC and some molecules involved in NGF- mediated TRKA activation signaling pathway.	15	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF-	NGF-	NGF-	TRKA	TRKA	TRKA	17	18	19	20
NGF stimulation for 30 minutes markedly increased TrkA endocytosis compared to un stimulated cells ( XREF_FIG ) .	NGF stimulation for 30 minutes markedly increased TrkA endocytosis compared to un stimulated cells (XREF_FIG).	0	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	7	8
NGF preferentially activates TrkA ; BDNF and NT-4/5 preferentially bind to TrkB ; and NT-3 signals through TrkC .	NGF preferentially activates TrkA; BDNF and NT-4/5 preferentially bind to TrkB; and NT-3 signals through TrkC.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	3	4
16:353-359) , we examined whether NGF modulates the down-regulation of TrkA .	16:353-359), we examined whether NGF modulates the down-regulation of TrkA.	5	11	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	10	11
The heteromutein ( Htm1 ) was used to study the heteroreceptor complex formation and function , in the putative absence of NGF induced TrkA dimerization .	The heteromutein (Htm1) was used to study the heteroreceptor complex formation and function, in the putative absence of NGF induced TrkA dimerization.	19	24	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	21	22	23	24
Moreover , NGF at axon terminals must be internalized and retrogradely transported to neuron cell bodies for the NGF signal to induce phosphorylation of CREB ( cAMP response element binding protein ) and to increase survival of immature neurons [ XREF_BIBR - XREF_BIBR ] ; NGF induced activation of TrkA in axon terminals was also required for survival [ XREF_BIBR - XREF_BIBR ] .	Moreover, NGF at axon terminals must be internalized and retrogradely transported to neuron cell bodies for the NGF signal to induce phosphorylation of CREB (cAMP response element binding protein) and to increase survival of immature neurons [XREF_BIBR - XREF_BIBR]; NGF induced activation of TrkA in axon terminals was also required for survival [XREF_BIBR - XREF_BIBR].	42	52	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	45	46	49	50
Overexpression of a dn form of Pincher ( PincherG68E ) has been shown to prevent NGF induced internalization of TrkA .	Overexpression of a dn form of Pincher (PincherG68E) has been shown to prevent NGF induced internalization of TrkA.	14	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	15	16	19	20
XREF_BIBR , XREF_BIBR To better understand the NGF mediated TrkA dependent signaling pathways , we investigated the roles of NGF in TrkA dependent cellular processes , morphological changes and cell death in TrkA inducible SK-N-MC cells .	XREF_BIBR, XREF_BIBR To better understand the NGF mediated TrkA dependent signaling pathways, we investigated the roles of NGF in TrkA dependent cellular processes, morphological changes and cell death in TrkA inducible SK-N-MC cells.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	9	10
NGF activates TrkA and rapidly stimulates its endocytosis XREF_BIBR , XREF_BIBR , XREF_BIBR , yet we reproducibly could not detect phosphorylated TrkA in floating DRMs under any conditions in this study , either before ( XREF_FIG ) or after in vitro reactions ( not shown ) .	NGF activates TrkA and rapidly stimulates its endocytosis XREF_BIBR, XREF_BIBR, XREF_BIBR, yet we reproducibly could not detect phosphorylated TrkA in floating DRMs under any conditions in this study, either before (XREF_FIG) or after in vitro reactions (not shown).	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
These results show that CH3Hg inhibition of NGF stimulated TrkA activation in PC12 cells decreases downstream signaling through the Raf/MEK/ERK cascade .	These results show that CH3Hg inhibition of NGF stimulated TrkA activation in PC12 cells decreases downstream signaling through the Raf/MEK/ERK cascade.	5	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	9	10
In support of our hypothesis , Noga and colleagues reported that NGF activates Trk A positive human monocyte derived dendritic cells to mediate asthma [ XREF_BIBR ] .	In support of our hypothesis, Noga and colleagues reported that NGF activates Trk A positive human monocyte derived dendritic cells to mediate asthma [XREF_BIBR].	11	14	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	11	12	13	14
Compounds that can prevent NGF mediated activation of TrkA on peripheral nociceptors will be useful in the management of pain and those capable of acting centrally to augment NGF mediated activation of TrkA could be developed as Alzheimer ' s therapeutics to support the cholinergic system .	Compounds that can prevent NGF mediated activation of TrkA on peripheral nociceptors will be useful in the management of pain and those capable of acting centrally to augment NGF mediated activation of TrkA could be developed as Alzheimer 's therapeutics to support the cholinergic system.	27	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	28	29	32	33
In cultured primary astrocyte , recombinant nerve growth factor ( NGF ) was used to activate TrkA .	In cultured primary astrocyte, recombinant nerve growth factor (NGF) was used to activate TrkA.	8	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	16	17
However , although NGF promoted the retrograde accumulation of P-TrkA , P-Erk1/2 and P-Akt in cell bodies of control neurons , there was a pronounced reduction in the levels of these signalling molecules in the cell bodies of RCAN1 expressing neurons ( XREF_FIG ) .	However, although NGF promoted the retrograde accumulation of P-TrkA, P-Erk1/2 and P-Akt in cell bodies of control neurons, there was a pronounced reduction in the levels of these signalling molecules in the cell bodies of RCAN1 expressing neurons (XREF_FIG).	3	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	P-TrkA	P-TrkA	P-TrkA	3	4	9	10
The data summarized above demonstrates that when NGF activates its high affinity receptor TRKA in human granulosa cells of normal ovary and in epithelial cells from EOC , it acts as an indirect angiogenic factor by increasing VEGF expression and also as a direct angiogenic factor by activating TRKA in endothelial cells , therefore increasing angiogenesis in EOC .	The data summarized above demonstrates that when NGF activates its high affinity receptor TRKA in human granulosa cells of normal ovary and in epithelial cells from EOC, it acts as an indirect angiogenic factor by increasing VEGF expression and also as a direct angiogenic factor by activating TRKA in endothelial cells, therefore increasing angiogenesis in EOC.	7	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TRKA	TRKA	TRKA	7	8	13	14
NGF induced NTRK1 activation causes ABL1 ( c-Abelson kinase 1 or c-Abl )-mediated phosphorylation of the adaptor protein Crk at Tyr 222 , resulting in the dissociation of paxillin and c-Abl from Crk , which is critical for NGF induced neurite out-growth .	NGF induced NTRK1 activation causes ABL1 (c-Abelson kinase 1 or c-Abl)-mediated phosphorylation of the adaptor protein Crk at Tyr 222, resulting in the dissociation of paxillin and c-Abl from Crk, which is critical for NGF induced neurite out-growth.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	NTRK1	NTRK1	NTRK1	0	1	2	3
Nerve growth factor ( NGF ) mediates the survival and differentiation of neurons by stimulating the tyrosine kinase activity of the TrkA and NGF receptor .	Nerve growth factor (NGF) mediates the survival and differentiation of neurons by stimulating the tyrosine kinase activity of the TrkA and NGF receptor.	2	24	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	21	22
Consistent with the suppression , NAC inhibited NGF induced activation of TrkA , formation of receptor complexes comprising TrkA , Shc , Grb2 , and Sos , and activation of phospholipase Cgamma and phosphatidylinositol 3-kinase .	Consistent with the suppression, NAC inhibited NGF induced activation of TrkA, formation of receptor complexes comprising TrkA, Shc, Grb2, and Sos, and activation of phospholipase Cgamma and phosphatidylinositol 3-kinase.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	11	12
Treatment with the two TrkB oligos completely inhibited BDNF induced reporter activation in TrkB cells and had minimal effect on the TrkA and TrkC cells induced by NGF and NT-3 respectively .	Treatment with the two TrkB oligos completely inhibited BDNF induced reporter activation in TrkB cells and had minimal effect on the TrkA and TrkC cells induced by NGF and NT-3 respectively.	21	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	27	28	21	22
Additionally , previous reports have demonstrated that even in the adult , NGF can induce marked sprouting of TrkA + sensory nerve fibers .	Additionally, previous reports have demonstrated that even in the adult, NGF can induce marked sprouting of TrkA + sensory nerve fibers.	12	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	18	19
NECC2 regulates NGF mediated TrkA signaling .	NECC2 regulates NGF mediated TrkA signaling.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	4	5
In PC12 cells , NGF stimulates both TrkA and p75 NTR receptors .	In PC12 cells, NGF stimulates both TrkA and p75 NTR receptors.	4	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	7	8
NGF treatment of eosinophils in culture triggered the activation of the TrkA receptor and promoted IL-4 secretion [ XREF_BIBR , XREF_BIBR ] .	NGF treatment of eosinophils in culture triggered the activation of the TrkA receptor and promoted IL-4 secretion [XREF_BIBR, XREF_BIBR].	0	12	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	11	12
Taken together , these findings define a novel molecular mechanism through which Tiam1 mediates TrkA signaling and neurite outgrowth induced by NGF .	Taken together, these findings define a novel molecular mechanism through which Tiam1 mediates TrkA signaling and neurite outgrowth induced by NGF.	14	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	21	22	14	15
On the other hand , the addition of exogenous CS-E polysaccharides into the culture medium inhibited NT-4/5-and NGF mediated TrkA activation , consistent with the mechanism that CS-E polysaccharides in solution can sequester neurotrophins away from the cell surface and prevent them from activating TrkA receptors .	On the other hand, the addition of exogenous CS-E polysaccharides into the culture medium inhibited NT-4/5-and NGF mediated TrkA activation, consistent with the mechanism that CS-E polysaccharides in solution can sequester neurotrophins away from the cell surface and prevent them from activating TrkA receptors.	16	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	17	18	19	20
This hypothesis , that NGF and NT-3 differentially activate TrkA to mediate differing neuronal responses , does not exclude the potential involvement of the TrkC and p75 receptors .	This hypothesis, that NGF and NT-3 differentially activate TrkA to mediate differing neuronal responses, does not exclude the potential involvement of the TrkC and p75 receptors.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	9	10
After injury , locally released NGF activates TrkA receptors on DRG neurons , promoting actin synthesis and assembly near lamellipodia , with axonal extension facilitated by ion transporters , which establish osmotic driving forces , and AQP1 water channels , which facilitate water entry .	After injury, locally released NGF activates TrkA receptors on DRG neurons, promoting actin synthesis and assembly near lamellipodia, with axonal extension facilitated by ion transporters, which establish osmotic driving forces, and AQP1 water channels, which facilitate water entry.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	7	8
These data indicate that the effects of ER activation on HUC proliferation at least partly involve activation of trkA by NGF .	These data indicate that the effects of ER activation on HUC proliferation at least partly involve activation of trkA by NGF.	15	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	20	21	18	19
We propose that SHP-1 regulates both basal and NGF stimulated TrkA activity .	We propose that SHP-1 regulates both basal and NGF stimulated TrkA activity.	6	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	10	11
NGF stimulation slightly increased the proportion of TrkA high expressing monocytes ( XREF_FIG ) compared to both matched controls ( +14.1 +/- 21.6 % p = 0.021 ) and proNGF ( 21.6 % p = 0.02 ) .	NGF stimulation slightly increased the proportion of TrkA high expressing monocytes (XREF_FIG) compared to both matched controls (+14.1 +/- 21.6% p = 0.021) and proNGF (21.6% p = 0.02).	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	7	8
Taken together , it indicated that NGF induced neurite outgrowth promoted by compounds 1 and 3 may be entirely TrkA dependent and partially Erk1/2 mediated .	Taken together, it indicated that NGF induced neurite outgrowth promoted by compounds 1 and 3 may be entirely TrkA dependent and partially Erk1/2 mediated.	6	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	19	20
It is known that NGF elicits the survival and proliferative effects by activating the NGF and TrkA signaling , and at the same time , the NGF and p75 NTR signaling is suppressed by the TrkA activation to elicit the anti-apoptosis effects .	It is known that NGF elicits the survival and proliferative effects by activating the NGF and TrkA signaling, and at the same time, the NGF and p75 NTR signaling is suppressed by the TrkA activation to elicit the anti-apoptosis effects.	4	17	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	16	17
We also found that TrkA interacts with AbetaPP , modulating AbetaPP processing , and that activation of TrkA by NGF induces increased Abeta production in vitro .	We also found that TrkA interacts with AbetaPP, modulating AbetaPP processing, and that activation of TrkA by NGF induces increased Abeta production in vitro.	15	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	19	20	17	18
When NGF activates TrkA in distal tissues , TrkA must be endocytosed and retrogradely transported to the neuronal cell body for a complete response to NGF to occur [ XREF_BIBR ] .	When NGF activates TrkA in distal tissues, TrkA must be endocytosed and retrogradely transported to the neuronal cell body for a complete response to NGF to occur [XREF_BIBR].	1	6	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	3	4
Although the general consensus is that NGF produces peripheral sensitization by activating TrkA , recent work suggests that p75 also contributes .	Although the general consensus is that NGF produces peripheral sensitization by activating TrkA, recent work suggests that p75 also contributes.	6	13	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	12	13
Taken together , results obtained in XREF_FIG indicate that LPC upregulates NGF induced signaling by enhancing NGF induced activation of TrkA .	Taken together, results obtained in XREF_FIG indicate that LPC upregulates NGF induced signaling by enhancing NGF induced activation of TrkA.	15	21	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	20	21
Interestingly , previous experimental evidence has shown that the levels of Ezrin are regulated upon NGF stimulation in a TrkA dependent manner and this NGF dependent activation of Ezrin results in the remodeling of the growth cones of chick embryo dorsal root ganglia neurons .	Interestingly, previous experimental evidence has shown that the levels of Ezrin are regulated upon NGF stimulation in a TrkA dependent manner and this NGF dependent activation of Ezrin results in the remodeling of the growth cones of chick embryo dorsal root ganglia neurons.	15	21	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	15	16	19	20
It has also been shown that NGF lowers the threshold and enhances the response of nociceptors to mechanical stimuli [ XREF_BIBR ] , suggesting that NGF activation of TrkA may play a role in activating and sensitizing mechanotransducers expressed by sensory nerve fibers .	It has also been shown that NGF lowers the threshold and enhances the response of nociceptors to mechanical stimuli [XREF_BIBR], suggesting that NGF activation of TrkA may play a role in activating and sensitizing mechanotransducers expressed by sensory nerve fibers.	25	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	25	26	28	29
In this review , we will overview the evidence implicating specific signaling cascades in aspects of the cellular response to the neurotrophins , specifically in response to activation of TrkA by NGF .	In this review, we will overview the evidence implicating specific signaling cascades in aspects of the cellular response to the neurotrophins, specifically in response to activation of TrkA by NGF.	6	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	31	32	29	30
Also , it has been shown that following NGF induced activation of TrkA , augmented p38 MAPK and ERK signaling in the spinal cord and lumbar and DRGs have been implicated in the pathobiology of chronic pain .	Also, it has been shown that following NGF induced activation of TrkA, augmented p38 MAPK and ERK signaling in the spinal cord and lumbar and DRGs have been implicated in the pathobiology of chronic pain.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	12	13
Previously , we reported that NGF induced TrkA endocytosis in sympathetic axons depends on TrkA mediated recruitment of Phospholipase C-gamma ( PLC-gamma ) , which then stimulates calcineurin , a calcium dependent phosphatase , to dephosphorylate the endocytic GTPase , dynamin1 .	Previously, we reported that NGF induced TrkA endocytosis in sympathetic axons depends on TrkA mediated recruitment of Phospholipase C-gamma (PLC-gamma), which then stimulates calcineurin, a calcium dependent phosphatase, to dephosphorylate the endocytic GTPase, dynamin1.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	7	8
NGF treatment induced endocytosis of pTrkA into large endosomes that contained RFP-Rab22 ( XREF_FIG and XREF_FIG ) , which correlated with a dramatic increase in neurite outgrowth .	NGF treatment induced endocytosis of pTrkA into large endosomes that contained RFP-Rab22 (XREF_FIG and XREF_FIG), which correlated with a dramatic increase in neurite outgrowth.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	pTrkA	pTrkA	pTrkA	0	1	5	6
NGF also induced TrkA dependent ruffling of the actin cytoskeleton in the macrophages .	NGF also induced TrkA dependent ruffling of the actin cytoskeleton in the macrophages.	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	3	4
NGF is the founding member of the polypeptide neurotrophin family , activates transmembrane tyrosine kinase receptor TrkA XREF_BIBR and is responsible for the survival and differentiation of sympathetic and dorsal root ganglion neurons , as well as other cells ( neuronal and non neuronal ) in both the central nervous system and the periphery XREF_BIBR .	NGF is the founding member of the polypeptide neurotrophin family, activates transmembrane tyrosine kinase receptor TrkA XREF_BIBR and is responsible for the survival and differentiation of sympathetic and dorsal root ganglion neurons, as well as other cells (neuronal and non neuronal) in both the central nervous system and the periphery XREF_BIBR.	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	16	17
These findings suggest that these targets could have an important role in NGF mediated TrkA induced cancer cell death signaling via a novel JNK dependent mechanism .	These findings suggest that these targets could have an important role in NGF mediated TrkA induced cancer cell death signaling via a novel JNK dependent mechanism.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	14	15
In PC12 cells , PACAP acts through the seven-transmembrane G protein coupled receptor PAC1 while NGF activates the TrkA receptor tyrosine kinase and p75-NTR .	In PC12 cells, PACAP acts through the seven-transmembrane G protein coupled receptor PAC1 while NGF activates the TrkA receptor tyrosine kinase and p75-NTR.	15	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	15	16	18	19
Therefore , NGF modulates pain responses and changes pain thresholds by two principal mechanisms : a direct TrkA mediated activation of pain signaling through receptors and channels on nerves such as Transient Receptor Potential cation channel subfamily V member 1 ( TRPV1 ) and TetrodoToXin ( TTX ) insensitive voltage gated sodium channel Na v , and indirectly through the TrkA mediated degranulation of mast cells and basophils .	Therefore, NGF modulates pain responses and changes pain thresholds by two principal mechanisms : a direct TrkA mediated activation of pain signaling through receptors and channels on nerves such as Transient Receptor Potential cation channel subfamily V member 1 (TRPV1) and TetrodoToXin (TTX) insensitive voltage gated sodium channel Na v, and indirectly through the TrkA mediated degranulation of mast cells and basophils.	2	19	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	17	18
Our analysis also showed a direct correlation between CHD5 expression and neuronal differentiation involving TrkA signaling , induced by NGF treatment in NB cells .	Our analysis also showed a direct correlation between CHD5 expression and neuronal differentiation involving TrkA signaling, induced by NGF treatment in NB cells.	14	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	19	20	14	15
Additionally , it has been shown that NGF drives PKC activation in TrkA expressing cells , which could also sensitize TRPV1 responses , while fibronectin mediated translocation of TRPV1 to the plasma membrane is not considered dependent upon PKC .	Additionally, it has been shown that NGF drives PKC activation in TrkA expressing cells, which could also sensitize TRPV1 responses, while fibronectin mediated translocation of TRPV1 to the plasma membrane is not considered dependent upon PKC.	7	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	12	13
Our data suggests increased NGF action during the initial period of mechanical allodynia could increase the regeneration of Trk A positive IENF which express neuropeptides such as SP and CGRP .	Our data suggests increased NGF action during the initial period of mechanical allodynia could increase the regeneration of Trk A positive IENF which express neuropeptides such as SP and CGRP.	4	21	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	4	5	18	19
One potential explanation for these results is that NGF mediated Trk activation is more sustained than NT-3-mediated activation .	One potential explanation for these results is that NGF mediated Trk activation is more sustained than NT-3-mediated activation.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	8	9	10	11
In PC12 cells , activation of TrkA by NGF induces the proteolytic processing of p75 NTR , resulting in the accumulation of the p75 NTR CTF and also its ICD [ XREF_BIBR ] .	In PC12 cells, activation of TrkA by NGF induces the proteolytic processing of p75 NTR, resulting in the accumulation of the p75 NTR CTF and also its ICD [XREF_BIBR].	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	6	7
In cultured human umbilical vein endothelial cells ( HUVECs ) , NGF activates TrkA , triggering a mitogenic response and exerting an autocrine role in HUVECs [ XREF_BIBR ] .	In cultured human umbilical vein endothelial cells (HUVECs), NGF activates TrkA, triggering a mitogenic response and exerting an autocrine role in HUVECs [XREF_BIBR].	11	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	13	14
The biological effect of T3/Y291F mutant was also investigated in PC12 cells , in which the constitutively activated TRK oncogenes recapitulate the neuronal differentiating effect of NGF stimulated NTRK1 receptor .	The biological effect of T3/Y291F mutant was also investigated in PC12 cells, in which the constitutively activated TRK oncogenes recapitulate the neuronal differentiating effect of NGF stimulated NTRK1 receptor.	24	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NTRK1	NTRK1	NTRK1	26	27	28	29
These data demonstrate that even in the adult bone marrow , NGF released by these inflammatory , immune and stromal cells can induce a 10-70 fold increase in density of TrkA + sensory nerve fibers in the bone marrow .	These data demonstrate that even in the adult bone marrow, NGF released by these inflammatory, immune and stromal cells can induce a 10-70 fold increase in density of TrkA + sensory nerve fibers in the bone marrow.	11	31	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	30	31
Nerve growth factor ( NGF ) initiates its biological effects by promoting the dimerization and activation of the tyrosine kinase receptor TrkA .	Nerve growth factor (NGF) initiates its biological effects by promoting the dimerization and activation of the tyrosine kinase receptor TrkA.	2	22	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	21	22
XREF_BIBR - XREF_BIBR NGF activates trkA receptors through receptor dimerization at the cell surface followed by receptor autophosphorylation .	XREF_BIBR - XREF_BIBR NGF activates trkA receptors through receptor dimerization at the cell surface followed by receptor autophosphorylation.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	3	4	5	6
In pancreatic cancer , overexpression of NGF may contribute to PNI by prompting the hyperplasia of nerves , restraining the apoptosis of tumor cells and specifically combining NGF and TrkA .	In pancreatic cancer, overexpression of NGF may contribute to PNI by prompting the hyperplasia of nerves, restraining the apoptosis of tumor cells and specifically combining NGF and TrkA.	4	30	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	overexpression of NGF	ngf	TrkA	TrkA	trka	6	7	29	30
For example , NGF could also promote progression by interacting with its receptors TrkA and P75 in both an autocrine and paracrine manner .	For example, NGF could also promote progression by interacting with its receptors TrkA and P75 in both an autocrine and paracrine manner.	3	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	13	14
Data indicate that : ( i ) positive cholinotrophic effects of NGF required activation of both TrkA and p75NTR receptors ; ( ii ) cAMP/RA evoked differentiation inhibited NGF effects mediated by TrkA receptors and activated its p75NTR dependent suppressing influences and ( iii ) a differentiation evoked decrease of mitochondrial acetyl-CoA and an elevation of mitochondrial Ca could augment impairment of cholinergic neurons by neurotoxic signals .	Data indicate that : (i) positive cholinotrophic effects of NGF required activation of both TrkA and p75NTR receptors; (ii) cAMP/RA evoked differentiation inhibited NGF effects mediated by TrkA receptors and activated its p75NTR dependent suppressing influences and (iii) a differentiation evoked decrease of mitochondrial acetyl-CoA and an elevation of mitochondrial Ca could augment impairment of cholinergic neurons by neurotoxic signals.	11	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	16	17
Furthermore , NGF treatment also enhanced the association of endogenous NTRAP and TrkA in PC12 cells ( XREF_FIG F ) .	Furthermore, NGF treatment also enhanced the association of endogenous NTRAP and TrkA in PC12 cells (XREF_FIG F).	2	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	12	13
Nerve growth factor ( NGF ) activates TrkA , brain derived neurotrophic factor ( BDNF ) and NT-4 activate TrkB , and NT-3 preferentially binds to TrkC ( and to the other Trk receptors , albeit with lower affinity ) .	Nerve growth factor (NGF) activates TrkA, brain derived neurotrophic factor (BDNF) and NT-4 activate TrkB, and NT-3 preferentially binds to TrkC (and to the other Trk receptors, albeit with lower affinity).	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	7	8
p75 induces the neurotrophin NGF mediated survival in neuronal cells expressing TrkA .	p75 induces the neurotrophin NGF mediated survival in neuronal cells expressing TrkA.	2	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	11	12
The activated Erk proteins predominate in the cytoplasm in lieu of their normal nuclear localization following NGF stimulation of TrkA .	The activated Erk proteins predominate in the cytoplasm in lieu of their normal nuclear localization following NGF stimulation of TrkA.	16	20	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	19	20
101 NGF activation of TrkA + has also been demonstrated to induce a remarkable reorganization of sensory and sympathetic nerve fibers .	101 NGF activation of TrkA + has also been demonstrated to induce a remarkable reorganization of sensory and sympathetic nerve fibers.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	4	5
A suggestion by Bonnington and McNaughton is that out of the three pathways activated by NGF induced TrKA receptor activation , PI3K pathway leads to the sensitization of TRPV1 .	A suggestion by Bonnington and McNaughton is that out of the three pathways activated by NGF induced TrKA receptor activation, PI3K pathway leads to the sensitization of TRPV1.	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrKA	TrKA	TrKA	15	16	17	18
The survival of dorsal root ganglion and sympathetic neurons is promoted whether nerve growth factor ( NGF ) activates TrkA receptors on the cell body or axon .	The survival of dorsal root ganglion and sympathetic neurons is promoted whether nerve growth factor (NGF) activates TrkA receptors on the cell body or axon.	14	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	19	20
Nogo-p4 did not significantly affect TrkA signaling induced by 100 ng/ml NGF , but signaling was suppressed when an NGF concentration of 5 ng/ml was used .	Nogo-p4 did not significantly affect TrkA signaling induced by 100 ng/ml NGF, but signaling was suppressed when an NGF concentration of 5 ng/ml was used.	5	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	5	6
NGF increased NGF ' s retrograde transport and MOR expression in TrkA positive DRG which was prevented by the disruption of this NGF transport .	NGF increased NGF 's retrograde transport and MOR expression in TrkA positive DRG which was prevented by the disruption of this NGF transport.	11	23	prevented	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	22	23	11	12
In oxygen induced retinopathy mouse model , NGF contributed to retinal neovascularization by activating TrkA receptor [ XREF_BIBR ] .	In oxygen induced retinopathy mouse model, NGF contributed to retinal neovascularization by activating TrkA receptor [XREF_BIBR].	7	15	contributed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	14	15
Therefore , to examine whether or not NGF secreted from B35 cells following TG-CKJ and SH-CKJ treatment can induce activation of the TrkA receptor signaling pathway , the expression levels of several protein were measured in PC12 cells cultured with CM .	Therefore, to examine whether or not NGF secreted from B35 cells following TG-CKJ and SH-CKJ treatment can induce activation of the TrkA receptor signaling pathway, the expression levels of several protein were measured in PC12 cells cultured with CM.	7	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	22	23
Intradermal injection of capsaicin and NGF produce heat hyperalgesia by activating their respective TRPV1 ( transient receptor potential vanilloid receptor-1 ) and TrkA receptors on nociceptor sensory nerve terminals .	Intradermal injection of capsaicin and NGF produce heat hyperalgesia by activating their respective TRPV1 (transient receptor potential vanilloid receptor-1) and TrkA receptors on nociceptor sensory nerve terminals.	1	23	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	22	23
NGF promotes neuronal survival and neurite outgrowth by binding and activating its receptor TrkA on axon tips .	NGF promotes neuronal survival and neurite outgrowth by binding and activating its receptor TrkA on axon tips.	0	14	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	13	14
In a recent study , activity dependent synthesis and release of BDNF was found to induce p75 NTR -dependent axon pruning that occurs in postnatal life , unless TrkA was concomitantly activated by NGF .	In a recent study, activity dependent synthesis and release of BDNF was found to induce p75 NTR -dependent axon pruning that occurs in postnatal life, unless TrkA was concomitantly activated by NGF.	28	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	33	34	28	29
NGF activation of TrkA and p75 differentially regulate firing pattern .	NGF activation of TrkA and p75 differentially regulate firing pattern.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	3	4
NGF stimulation of grafts increased the message for NGF receptors p75 and trkA in the chromaffin transplants .	NGF stimulation of grafts increased the message for NGF receptors p75 and trkA in the chromaffin transplants.	0	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	0	1	12	13
On the other hand , the activation of trkA by NGF in other cells has been implicated in several pathologies including inflammation induced hyperalgesia and several cancers .	On the other hand, the activation of trkA by NGF in other cells has been implicated in several pathologies including inflammation induced hyperalgesia and several cancers.	6	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	10	11	8	9
NGF has also been shown to activate TrkA receptor on CD34 + endothelial progenitor cells , stimulating their angiogenic behavior [ XREF_BIBR ] .	NGF has also been shown to activate TrkA receptor on CD34 + endothelial progenitor cells, stimulating their angiogenic behavior [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	7	8
High-dose NGF may induce cytoplasmic relocation of the receptor TrkA and axonal growth arrest independently of p75NTR .	High-dose NGF may induce cytoplasmic relocation of the receptor TrkA and axonal growth arrest independently of p75NTR.	0	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	9	10
Previous reports have exhaustively demonstrated that in both the developing and adult animal , NGF can induce marked sprouting of TrkA + sensory and sympathetic nerve fibers .	Previous reports have exhaustively demonstrated that in both the developing and adult animal, NGF can induce marked sprouting of TrkA + sensory and sympathetic nerve fibers.	14	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	14	15	20	21
Treatment with the V-ATPase inhibitor bafilomycin also diminished the cell-surface targeting of TrkA and suppressed NGF induced TrkA signaling in PC12 cells .	Treatment with the V-ATPase inhibitor bafilomycin also diminished the cell-surface targeting of TrkA and suppressed NGF induced TrkA signaling in PC12 cells.	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	15	16	17	18
In a subsequent study , we reported NGF and p38 dependent increased Tropomyosin receptor kinase ( Trk ) A positive nociceptive intraepidermal nerve fiber densities ( IENFDs ) , the activation of dermal CD68 positive dendritic cells , and CD207 positive Langerhans cell ( LC ) aggregations in the hind footpad skin during the period of mechanical allodynia [ XREF_BIBR , XREF_BIBR ] .	In a subsequent study, we reported NGF and p38 dependent increased Tropomyosin receptor kinase (Trk) A positive nociceptive intraepidermal nerve fiber densities (IENFDs), the activation of dermal CD68 positive dendritic cells, and CD207 positive Langerhans cell (LC) aggregations in the hind footpad skin during the period of mechanical allodynia [XREF_BIBR, XREF_BIBR].	7	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	7	8	16	17
While NGF specifically activates TrkA [ XREF_BIBR ] , BDNF and NT-4/5 interact with TrkB [ XREF_BIBR , XREF_BIBR ] .	While NGF specifically activates TrkA [XREF_BIBR], BDNF and NT-4/5 interact with TrkB [XREF_BIBR, XREF_BIBR].	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	4	5
Pincher overexpression enhances NGF induced TrkA endocytosis .	Pincher overexpression enhances NGF induced TrkA endocytosis.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
It may be possible that NGF stimulate TrkA rather than p75NTR in aggressive cancers with high malignant potential , as results of a study by Sakamoto et al ( 2001a ) showed that patients with NGF+ and p75NTR- had poorer survival in breast cancer .	It may be possible that NGF stimulate TrkA rather than p75NTR in aggressive cancers with high malignant potential, as results of a study by Sakamoto et al (2001a) showed that patients with NGF+ and p75NTR- had poorer survival in breast cancer.	5	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	7	8
Together , these data emphasize that while NGF induced sprouting of TrkA + nerve fibers may be involved in driving skeletal pain , NGF induced sensitization and alteration of the phenotype of TrkA + nerve fibers may play a significant role in the generation and maintenance of chronic arthritic joint pain .	Together, these data emphasize that while NGF induced sprouting of TrkA + nerve fibers may be involved in driving skeletal pain, NGF induced sensitization and alteration of the phenotype of TrkA + nerve fibers may play a significant role in the generation and maintenance of chronic arthritic joint pain.	7	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	11	12
Each Trk receptor interacts selectively with a different neurotrophin resulting in preferential interaction pairs : TrkA is activated by NGF , TrkB by BDNF , and TrkC by NT-3 .	Each Trk receptor interacts selectively with a different neurotrophin resulting in preferential interaction pairs : TrkA is activated by NGF, TrkB by BDNF, and TrkC by NT-3.	15	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	19	20	15	16
Our evidence of NGF promoting TrkA -but not p75- expression in HCEC may explain the observation that NGF promotes HCEC cell survival in a dose dependent manner , while the neutralizing NGF antibody has the opposite effect .	Our evidence of NGF promoting TrkA -but not p75- expression in HCEC may explain the observation that NGF promotes HCEC cell survival in a dose dependent manner, while the neutralizing NGF antibody has the opposite effect.	1	6	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
The results of our studies suggest that despite slightly weaker activation of ERK1/2 mitogen activated protein kinases , NT3 triggered TrkC seems to provide apparently stronger than NGF triggered TrkA signal for neurite elongation in differentiating PC12 cells .	The results of our studies suggest that despite slightly weaker activation of ERK1/2 mitogen activated protein kinases, NT3 triggered TrkC seems to provide apparently stronger than NGF triggered TrkA signal for neurite elongation in differentiating PC12 cells.	27	30	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	27	28	29	30
11 Activation of TrkA by NGF triggers the aforementioned signaling cascades to provide support for neurite growth and repair and maintenance of effective connectivity between the cholinergic basal forebrain , hippocampus , and the cortex for the formation of new memories .	11 Activation of TrkA by NGF triggers the aforementioned signaling cascades to provide support for neurite growth and repair and maintenance of effective connectivity between the cholinergic basal forebrain, hippocampus, and the cortex for the formation of new memories.	1	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	3	4
Alternatively this dramatic divergence of response suggests changes in the network of signaling molecules linking NGF mediated TrkA activation to TRPV1 sensitization between adult and neonatal DRG neurons .	Alternatively this dramatic divergence of response suggests changes in the network of signaling molecules linking NGF mediated TrkA activation to TRPV1 sensitization between adult and neonatal DRG neurons.	14	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	15	16	17	18
As expected , NGF enhanced the TrkA dependent downregulation of cell viability , which was further strengthened by hnRNP K siRNAs .	As expected, NGF enhanced the TrkA dependent downregulation of cell viability, which was further strengthened by hnRNP K siRNAs.	3	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	6	7
Although NGF is known to bind to and activate the receptor tyrosine kinase TrkA , many downstream targets of NGF signaling may be possibly phosphorylated by nonreceptor tyrosine kinases such as c-Src and focal adhesion kinase ( FAK ) .	Although NGF is known to bind to and activate the receptor tyrosine kinase TrkA, many downstream targets of NGF signaling may be possibly phosphorylated by nonreceptor tyrosine kinases such as c-Src and focal adhesion kinase (FAK).	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	13	14
In sympathetic neurons , both the intermediate target derived neurotrophin , NT-3 , and the final target derived factor , NGF , activate the TrkA receptor to promote axon growth .	In sympathetic neurons, both the intermediate target derived neurotrophin, NT-3, and the final target derived factor, NGF, activate the TrkA receptor to promote axon growth.	18	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	20	21	24	25
TrkA receptor binds and is activated mainly by NGF , while TrkC receptor binds and is activated by neurotrophin 3 ( NT3 ) .	TrkA receptor binds and is activated mainly by NGF, while TrkC receptor binds and is activated by neurotrophin 3 (NT3).	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	0	1
These findings not only provide the first direct experimental demonstration of trkA mediating a physiological response in an appropriate cell type , namely NGF promoted survival of embryonic neurons , but indicate that not all neurons are able to respond to a trkA mediated signal transduction event .	These findings not only provide the first direct experimental demonstration of trkA mediating a physiological response in an appropriate cell type, namely NGF promoted survival of embryonic neurons, but indicate that not all neurons are able to respond to a trkA mediated signal transduction event.	9	31	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	23	24	11	12
Neither 2-aminopurine nor 6-thioguanine inhibited the NGF dependent induction of Trk associated kinase activity .	Neither 2-aminopurine nor 6-thioguanine inhibited the NGF dependent induction of Trk associated kinase activity.	6	13	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	6	7	10	11
These data strongly suggest that activation of TRKA by NGF is important for the development of mastocytosis .	These data strongly suggest that activation of TRKA by NGF is important for the development of mastocytosis.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TRKA	TRKA	TRKA	9	10	7	8
NGF promotes survival and differentiation of PC12 cells by activating the TrkA receptor .	NGF promotes survival and differentiation of PC12 cells by activating the TrkA receptor.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	11	12
NGF activation of TrkA is also critical in inducing cellular survival and differentiation .	NGF activation of TrkA is also critical in inducing cellular survival and differentiation.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	3	4
In mouse hippocampal cells lacking p75NTR ( p75NTR-/-) activation of TrkA by NGF was not detectable .	In mouse hippocampal cells lacking p75NTR (p75NTR-/-) activation of TrkA by NGF was not detectable.	4	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	10	11
TrkA activation by NGF leads to the activation of ERK1 and 2 kinases XREF_BIBR , XREF_BIBR .	TrkA activation by NGF leads to the activation of ERK1 and 2 kinases XREF_BIBR, XREF_BIBR.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	0	1
These data on the ectopic sprouting of TrkA + sensory and sympathetic nerve fibers are interesting as they indicate how pre-emptive treatment with therapies that block NGF activation of TrkA may reduce the attendant pain , but also may block the pathologic remodeling of sensory and sympathetic nerve fibers that are themselves a major driver of chronic hypersensitivity .	These data on the ectopic sprouting of TrkA + sensory and sympathetic nerve fibers are interesting as they indicate how pre-emptive treatment with therapies that block NGF activation of TrkA may reduce the attendant pain, but also may block the pathologic remodeling of sensory and sympathetic nerve fibers that are themselves a major driver of chronic hypersensitivity.	26	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	26	27	29	30
These data raise the possibility that FAIM influences NGF induced neurite outgrowth by modulating activation of intracellular signaling pathways downstream of TrkA and p75 .	These data raise the possibility that FAIM influences NGF induced neurite outgrowth by modulating activation of intracellular signaling pathways downstream of TrkA and p75.	8	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	21	22
The process of NGF induced TrkA internalization is clearly affected by interfering with ligand binding to p75 ( NTR ) .	The process of NGF induced TrkA internalization is clearly affected by interfering with ligand binding to p75 (NTR).	1	6	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
We discovered that NGF administration in vivo activated TrkA receptors , and increased both TrkA and ChAT mRNA ; conversely , anti-NGF infusions suppressed expression of both genes .	We discovered that NGF administration in vivo activated TrkA receptors, and increased both TrkA and ChAT mRNA; conversely, anti-NGF infusions suppressed expression of both genes.	3	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	8	9
TrkA and TrkA and p75 cells were treated with a range of NGF concentrations and whole cell lysates collected for immunoblotting .	TrkA and TrkA and p75 cells were treated with a range of NGF concentrations and whole cell lysates collected for immunoblotting.	0	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	0	1
Figure XREF_FIG shows that NGF induced TrkA receptor internalization in absence of CuSO 4 and ZnSO 4 ; the presence of metal ions slightly inhibited this effect .	Figure XREF_FIG shows that NGF induced TrkA receptor internalization in absence of CuSO 4 and ZnSO 4; the presence of metal ions slightly inhibited this effect.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	6	7
NGF Causes TrkA to Specifically Attract Microtubules to Lipid Rafts .	NGF Causes TrkA to Specifically Attract Microtubules to Lipid Rafts.	0	3	Causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
In addition , the phosphorylation was very rapid and long lasting indicating a direct and sustained NGF effect and further supporting the specificity of the NGF and TrkA signaling involvement .	In addition, the phosphorylation was very rapid and long lasting indicating a direct and sustained NGF effect and further supporting the specificity of the NGF and TrkA signaling involvement.	16	29	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	27	28
Pincher function is necessary for both the NGF induced internalization of TrkA by a pinocytic process , and the sorting of long lived endosomal vesicles with NGF signaling capability .	Pincher function is necessary for both the NGF induced internalization of TrkA by a pinocytic process, and the sorting of long lived endosomal vesicles with NGF signaling capability.	6	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	11	12
In TrkA expressing normal neurons , NGF activation of TrkA stimulates increases in VEGF production that is accompanied by increases in HIF-1alpha but not HIF-1beta or HIF-2alpha .	In TrkA expressing normal neurons, NGF activation of TrkA stimulates increases in VEGF production that is accompanied by increases in HIF-1alpha but not HIF-1beta or HIF-2alpha.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	9	10
In cell fractionation studies in which 125 I-NGF is bound to PC12 cells in the cold , and the cells are washed and warmed to allow internalization of NGF bound receptors XREF_BIBR , XREF_BIBR , XREF_BIBR , NGF caused rapid internalization of TrkA into endosomes that could be recovered in organelles that emerged when cells were mechanically permeabilized by a single passage through a tight passage created by a ball whose diameter is very close to that of a surrounding cylinder .	In cell fractionation studies in which 125 I-NGF is bound to PC12 cells in the cold, and the cells are washed and warmed to allow internalization of NGF bound receptors XREF_BIBR, XREF_BIBR, XREF_BIBR, NGF caused rapid internalization of TrkA into endosomes that could be recovered in organelles that emerged when cells were mechanically permeabilized by a single passage through a tight passage created by a ball whose diameter is very close to that of a surrounding cylinder.	31	43	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	37	38	42	43
In this report , we show that androgens and NGF both induce a reciprocal cross-talk between androgen receptor ( AR ) and TrkA in prostate cancer derived LNCaP cells .	In this report, we show that androgens and NGF both induce a reciprocal cross-talk between androgen receptor (AR) and TrkA in prostate cancer derived LNCaP cells.	7	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	22	23
Consistent with these results , the number of TrkA dependent dead cells stained by trypan blue was greatly increased by NGF , and this effect was significantly suppressed by SP600125 , but not by wortmannin , indicating that NGF enhances TrkA dependent cancer cell death in a JNK dependent manner ( XREF_FIG ) .	Consistent with these results, the number of TrkA dependent dead cells stained by trypan blue was greatly increased by NGF, and this effect was significantly suppressed by SP600125, but not by wortmannin, indicating that NGF enhances TrkA dependent cancer cell death in a JNK dependent manner (XREF_FIG).	38	41	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	38	39	40	41
NGF specifically activates the receptor trkA , initiating a signal transduction cascade which ultimately blocks cell death .	NGF specifically activates the receptor trkA, initiating a signal transduction cascade which ultimately blocks cell death.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	0	1	5	6
PI3K binds to TRPV1 directly via its p85alpha subunit , which presumably recognizes the phosphorylated Y200 of TRPV1 , to enhance TRPV1 surface trafficking upon NGF stimulation of TrkA in DRG neurons [ XREF_BIBR ] .	PI3K binds to TRPV1 directly via its p85alpha subunit, which presumably recognizes the phosphorylated Y200 of TRPV1, to enhance TRPV1 surface trafficking upon NGF stimulation of TrkA in DRG neurons [XREF_BIBR].	25	29	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	25	26	28	29
Interestingly , p53 knockdown or overexpression of mutant p53 attenuates NGF mediated activation of TrkA , the high-affinity receptor for NGF and a tyrosine kinase , and activation of the mitogen activated protein kinase pathway .	Interestingly, p53 knockdown or overexpression of mutant p53 attenuates NGF mediated activation of TrkA, the high-affinity receptor for NGF and a tyrosine kinase, and activation of the mitogen activated protein kinase pathway.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	14	15
p75NTR can functionally antagonize NGF stimulated TrkA signaling in sympathetic neurons .	p75NTR can functionally antagonize NGF stimulated TrkA signaling in sympathetic neurons.	3	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	6	7
Decades of research have demonstrated that NGF directly activates and sensitizes TrkA expressing sensory neurons and that NGF activation of TrkA could play a key role in the sensitization of TrkA expressing nociceptors to mechanical , chemical and thermal stimuli .	Decades of research have demonstrated that NGF directly activates and sensitizes TrkA expressing sensory neurons and that NGF activation of TrkA could play a key role in the sensitization of TrkA expressing nociceptors to mechanical, chemical and thermal stimuli.	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	17	18	20	21
This observation suggests that infection induced release of NGF triggers survival paracrine signalling through TrkA and TrkC , in addition to neuraminidase and trans-sialidase-mediated Trk activation .	This observation suggests that infection induced release of NGF triggers survival paracrine signalling through TrkA and TrkC, in addition to neuraminidase and trans-sialidase-mediated Trk activation.	6	25	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	8	9	24	25
Anterograde TrkA transcytosis is necessary for optimal signaling and growth responses to NGF , and intriguingly , is augmented by NGF itself acting on distal axons .	Anterograde TrkA transcytosis is necessary for optimal signaling and growth responses to NGF, and intriguingly, is augmented by NGF itself acting on distal axons.	1	22	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	20	21	1	2
Mature NGF activates TrkA to mediate survival and differentiative signaling .	Mature NGF activates TrkA to mediate survival and differentiative signaling.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	3	4
We found that TrkA activation by NGF in PC12 cells induced ApoER2 processing , which was dependent on TrkA activation and metalloproteinases .	We found that TrkA activation by NGF in PC12 cells induced ApoER2 processing, which was dependent on TrkA activation and metalloproteinases.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	3	4
Surprisingly , overexpression of the GM1 synthase ( B3GALT4 ) in PC12 cells prevents NGF induced activation of TrkA , which is probably due to significant changes in the intracellular localization of the receptor [ XREF_BIBR ] .	Surprisingly, overexpression of the GM1 synthase (B3GALT4) in PC12 cells prevents NGF induced activation of TrkA, which is probably due to significant changes in the intracellular localization of the receptor [XREF_BIBR].	14	23	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	14	15	18	19
Our results also show that the signaling effector SH2-B is a substrate of NGF mediated Trk signaling in NB , whereas it is not activated by NGF in rat pheochromocytoma PC12 cells .	Our results also show that the signaling effector SH2-B is a substrate of NGF mediated Trk signaling in NB, whereas it is not activated by NGF in rat pheochromocytoma PC12 cells.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	13	14	15	16
They exert many biological effects by binding and activating specific Trk receptor tyrosine kinases ; NGF activates TrkA , BDNF and NT4/5 activate TrkB , and NT3 activates TrkC .	They exert many biological effects by binding and activating specific Trk receptor tyrosine kinases; NGF activates TrkA, BDNF and NT4/5 activate TrkB, and NT3 activates TrkC.	15	22	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	15	16	17	18
NGF activates TrkA in a graded fashion , while NT-3 activates TrkA and , to a much lesser extent , TrkC .	NGF activates TrkA in a graded fashion, while NT-3 activates TrkA and, to a much lesser extent, TrkC.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
Furthermore , TrkAIII expression also inhibits the differentiation inducing effects of NGF activated TrkA signaling by preventing RAS and MAPK activation , characterising TrkAIII as a potential pivotal regulator of NB cell differentiation in the presence of neurotrophins [ XREF_BIBR , XREF_BIBR ] .	Furthermore, TrkAIII expression also inhibits the differentiation inducing effects of NGF activated TrkA signaling by preventing RAS and MAPK activation, characterising TrkAIII as a potential pivotal regulator of NB cell differentiation in the presence of neurotrophins [XREF_BIBR, XREF_BIBR].	9	14	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	13	14
Independent of the model , TrkA activation by NGF is indeed saturable [ XREF_BIBR - XREF_BIBR ] , yet remarkable gradient sensitivity was observed experimentally over two orders of magnitude of concentration ( XREF_FIG ) .	Independent of the model, TrkA activation by NGF is indeed saturable [XREF_BIBR - XREF_BIBR], yet remarkable gradient sensitivity was observed experimentally over two orders of magnitude of concentration (XREF_FIG).	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	5	6
Similar domain specific activities have also been observed for NGF ; specifically , the precursor form of this related NT preferentially activates p75 NTR resulting in apoptosis , while mature NGF preferentially activates TrkA receptor with neurotrophic effects .	Similar domain specific activities have also been observed for NGF; specifically, the precursor form of this related NT preferentially activates p75 NTR resulting in apoptosis, while mature NGF preferentially activates TrkA receptor with neurotrophic effects.	29	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	30	31	33	34
The absence of medulloblastomas that contain NGF and TrkA is consistent with in vitro data demonstrating that NGF mediated TrkA signaling induces apoptosis .	The absence of medulloblastomas that contain NGF and TrkA is consistent with in vitro data demonstrating that NGF mediated TrkA signaling induces apoptosis.	17	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	17	18	19	20
NGF activates TrkA receptor triggering downstream signaling pathways , while p75NTR signaling is complex , inducing both survival and apoptosis mechanisms .	NGF activates TrkA receptor triggering downstream signaling pathways, while p75NTR signaling is complex, inducing both survival and apoptosis mechanisms.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
Here , we report that Nerve Growth Factor ( NGF ) promotes endocytosis of its TrkA receptors and axon growth by calcineurin mediated dephosphorylation of the endocytic GTPase , dynamin1 .	Here, we report that Nerve Growth Factor (NGF) promotes endocytosis of its TrkA receptors and axon growth by calcineurin mediated dephosphorylation of the endocytic GTPase, dynamin1.	7	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	15	16
Conversely , P-TrkA endosomes that are not Flag-TrkA positive likely represent NGF activated TrkA not bound by Flag antibody during the pulse application of Flag antibody to distal axons .	Conversely, P-TrkA endosomes that are not Flag-TrkA positive likely represent NGF activated TrkA not bound by Flag antibody during the pulse application of Flag antibody to distal axons.	11	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	11	12	13	14
Taken together , these data suggest that Ret , upon activation in distal axons , is not retrogradely transported at detectible levels to the cell bodies of sympathetic neurons , in contrast to TrkA activated by NGF .	Taken together, these data suggest that Ret, upon activation in distal axons, is not retrogradely transported at detectible levels to the cell bodies of sympathetic neurons, in contrast to TrkA activated by NGF.	31	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	36	37	33	34
XREF_BIBR ; XREF_BIBR Unlike the ligand induced dimerization mechanism for NGF activation of TrkA through 2:2 receptor complexes , XREF_BIBR ; XREF_BIBR a ligand induced conformational change in a preformed p75NTR dimer is the likely activation mechanism , XREF_BIBR raising the question of the implications of the 2:1 NGF and p75NTR versus the 2:2 NT-3 and p75NTR complexes .	XREF_BIBR; XREF_BIBR Unlike the ligand induced dimerization mechanism for NGF activation of TrkA through 2:2 receptor complexes, XREF_BIBR; XREF_BIBR a ligand induced conformational change in a preformed p75NTR dimer is the likely activation mechanism, XREF_BIBR raising the question of the implications of the 2:1 NGF and p75NTR versus the 2:2 NT-3 and p75NTR complexes.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	10	11	13	14
Both NT-3 and NGF induce similar sustained , long-term activation of TrkA , while NGF is 10-fold more efficient than NT-3 in mediating acute , short-term TrkA activity .	Both NT-3 and NGF induce similar sustained, long-term activation of TrkA, while NGF is 10-fold more efficient than NT-3 in mediating acute, short-term TrkA activity.	1	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	11	12
Thus , while NGF and NT3 similarly activate TrkA on the axonal surface and promote TrkA mediated axonal extension and TrkA internalization , these two ligands differ in their abilities to generate transport-competent signaling endosomes and retrograde survival signaling .	Thus, while NGF and NT3 similarly activate TrkA on the axonal surface and promote TrkA mediated axonal extension and TrkA internalization, these two ligands differ in their abilities to generate transport-competent signaling endosomes and retrograde survival signaling.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	8	9
NGF swiftly provokes TrkA activation and quickly induces TrkA degradation , while gambogic amid selectively upregulates TrkA protein and mRNA levels in a time dependent manner .	NGF swiftly provokes TrkA activation and quickly induces TrkA degradation, while gambogic amid selectively upregulates TrkA protein and mRNA levels in a time dependent manner.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	16	17
NGF elicits its biological effects mainly by binding the high affinity TrkA receptor ( tropomyosin related receptor A ) .	NGF elicits its biological effects mainly by binding the high affinity TrkA receptor (tropomyosin related receptor A).	0	12	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	11	12
Despite of the essential contribution of NGF for neuronal development and function , the molecular mechanisms that control NGF induced TrkA signaling are not totally understood .	Despite of the essential contribution of NGF for neuronal development and function, the molecular mechanisms that control NGF induced TrkA signaling are not totally understood.	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	18	19	20	21
The nerve growth factor ( NGF )-induced activation of TrkA is widely known to control neuronal cell survival and axonal growth .	The nerve growth factor (NGF)-induced activation of TrkA is widely known to control neuronal cell survival and axonal growth.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	5	6	9	10
Equivalent pulsatile Erk activation is not seen following NGF activation of TrkA , presumably reflecting a different combination of feedback and feedforward effects .	Equivalent pulsatile Erk activation is not seen following NGF activation of TrkA, presumably reflecting a different combination of feedback and feedforward effects.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	11	12
Here , we confirm that NGF stimulates SOD2 expression XREF_BIBR , XREF_BIBR , XREF_BIBR in TrkA SH-SY5Y cells ( this study ) , adding to observations that NGF induces Ras and MAPK signalling and neuronal differentiation in TrkA SH-SY5Y cells XREF_BIBR , and suggesting that SOD2 expression in SH-SY5Y cells could be regulated differently by spontaneously active intracellular TrkAIII and NGF activated cell surface TrkA receptors .	Here, we confirm that NGF stimulates SOD2 expression XREF_BIBR, XREF_BIBR, XREF_BIBR in TrkA SH-SY5Y cells (this study), adding to observations that NGF induces Ras and MAPK signalling and neuronal differentiation in TrkA SH-SY5Y cells XREF_BIBR, and suggesting that SOD2 expression in SH-SY5Y cells could be regulated differently by spontaneously active intracellular TrkAIII and NGF activated cell surface TrkA receptors.	60	65	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	60	61	64	65
Yet , while NGF supports TrkA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival , NT-3 can not .	Yet, while NGF supports TrkA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival, NT-3 can not.	3	6	supports	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	5	6
In contrast , NGF induced neuronal differentiation in HTLA230 cells expressing the endogenous trkA receptor gene , despite the lack of p75 expression .	In contrast, NGF induced neuronal differentiation in HTLA230 cells expressing the endogenous trkA receptor gene, despite the lack of p75 expression.	3	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	trkA	trkA	trkA	3	4	13	14
XREF_BIBR , XREF_BIBR The ACTB protein , tropomyosin 3 , dynein intermediate chain protein , vimentin , lamin A/C isoform 1 precursor , lamin B2 , hnRNPKa and heat shock 70-kDa protein 5 have been identified as NGF mediated TrkA dependent effector proteins using a DIGE ( fluorescence two-dimensional difference gel electrophoresis ) proteomic analysis in SY5Y neuroblastoma cells stably expressing ectopic TrkA .	XREF_BIBR, XREF_BIBR The ACTB protein, tropomyosin 3, dynein intermediate chain protein, vimentin, lamin A/C isoform 1 precursor, lamin B2, hnRNPKa and heat shock 70-kDa protein 5 have been identified as NGF mediated TrkA dependent effector proteins using a DIGE (fluorescence two-dimensional difference gel electrophoresis) proteomic analysis in SY5Y neuroblastoma cells stably expressing ectopic TrkA.	35	42	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	37	38	39	40
Sympathetic neurons express p75 and TrkA , both of which are activated by NGF .	Sympathetic neurons express p75 and TrkA, both of which are activated by NGF.	2	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	13	14	5	6
Moreover , evidence suggests that TrkB can promote neoangiogenesis [ XREF_BIBR ] while NGF stimulation of TrkA promotes angiogenesis in vivo [ XREF_BIBR ] .	Moreover, evidence suggests that TrkB can promote neoangiogenesis [XREF_BIBR] while NGF stimulation of TrkA promotes angiogenesis in vivo [XREF_BIBR].	13	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	13	14	16	17
Indeed , by the investigation of CREB phosphorylation on Ser 133 , we observed that the stimulation of TrkA by NGF and NGF-mimetic peptides was able to activate the canonical end of the cascade .	Indeed, by the investigation of CREB phosphorylation on Ser 133, we observed that the stimulation of TrkA by NGF and NGF-mimetic peptides was able to activate the canonical end of the cascade.	16	23	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	20	21	18	19
Another series of studies showed that NGF withdrawal induces delayed TrkA hyper-activation and Abeta production , the former dependent on the latter [ XREF_BIBR ] .	Another series of studies showed that NGF withdrawal induces delayed TrkA hyper-activation and Abeta production, the former dependent on the latter [XREF_BIBR].	6	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	6	7	10	11
NGF induced TrkA and CD44 association is involved in tumor aggressiveness and resistance to lestaurtinib .	NGF induced TrkA and CD44 association is involved in tumor aggressiveness and resistance to lestaurtinib.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	2	3
This concentration of NGF preferentially activates the TrkA signaling pathway through high affinity NGF binding sites .	This concentration of NGF preferentially activates the TrkA signaling pathway through high affinity NGF binding sites.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	7	8
Taken together , these data indicate that NGF mediated activation of TrkA receptor stimulates PI3K , which in turn increases Rac1 activity to induce transient RhoA inactivation during the initial phase of neurite outgrowth .	Taken together, these data indicate that NGF mediated activation of TrkA receptor stimulates PI3K, which in turn increases Rac1 activity to induce transient RhoA inactivation during the initial phase of neurite outgrowth.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	7	8	11	12
Thus , ubiquitination can not occur at those two sites , resulting in a non degradable IkappaBalpha that can sequester p65 in the cytoplasm and inhibit its transcriptional activity [ XREF_BIBR , XREF_BIBR ] .	Thus, ubiquitination can not occur at those two sites, resulting in a non degradable IkappaBalpha that can sequester p65 in the cytoplasm and inhibit its transcriptional activity [XREF_BIBR, XREF_BIBR].	11	25	sequester	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	16	17	20	21
Phosphorylation of IkappaBalpha by the IkappaB kinase ( IKKalpha , IKKbeta , IKKgamma ) complex induces IkappaBalpha degradation and thereby release of RelA for nuclear translocation .	Phosphorylation of IkappaBalpha by the IkappaB kinase (IKKalpha, IKKbeta, IKKgamma) complex induces IkappaBalpha degradation and thereby release of RelA for nuclear translocation.	0	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	Phosphorylation of IkappaBalpha	ikappabalpha	RelA	RelA	rela	2	3	22	23
Upon stimulation , IkappaBalpha is quickly phosphorylated and degraded allowing translocation of p65 to the nucleus where p65 transactivates target genes .	Upon stimulation, IkappaBalpha is quickly phosphorylated and degraded allowing translocation of p65 to the nucleus where p65 transactivates target genes.	3	13	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha is quickly phosphorylated	ikappabalpha	p65	p65	p65	3	4	12	13
The activation of IKKbeta leads to the phosphorylation and subsequent degradation of the inhibitor of NF-kappaB , IkappaBalpha , which enables the NF-kappaB proteins p50 and p65 to translocate to the nucleus and induce anti-apoptosis and inflammatory responses .	The activation of IKKbeta leads to the phosphorylation and subsequent degradation of the inhibitor of NF-kappaB, IkappaBalpha, which enables the NF-kappaB proteins p50 and p65 to translocate to the nucleus and induce anti-apoptosis and inflammatory responses.	15	28	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	17	18	26	27
In the current study , it was showed that GP pre-treatment could reduce the phosphorylation level of IkappaBalpha as well as inhibiting the translocation of NF-kappaB p65 to nuclei .	In the current study, it was showed that GP pre-treatment could reduce the phosphorylation level of IkappaBalpha as well as inhibiting the translocation of NF-kappaB p65 to nuclei.	9	27	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	GP pre-treatment could reduce the phosphorylation level of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	17	18	25	27
As shown in XREF_FIG , APS2-1 significantly ( P < 0.01 ) decreased the level of phosphorylation of IkappaBalpha , and inhibited the translocation of the NF-kappaB p65 subunit from the cytoplasm to the nucleus .	As shown in XREF_FIG, APS2-1 significantly (P < 0.01) decreased the level of phosphorylation of IkappaBalpha, and inhibited the translocation of the NF-kappaB p65 subunit from the cytoplasm to the nucleus.	5	28	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	APS2-1 significantly (P < 0.01) decreased the level of phosphorylation of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	18	19	26	28
As expected , Rv2299c triggered phosphorylation of p38 and ERK1/2 as well as phosphorylation and degradation of IkappaB-alpha in DCs , and induced significant translocation of p65 from the cytosol to the nucleus .	As expected, Rv2299c triggered phosphorylation of p38 and ERK1/2 as well as phosphorylation and degradation of IkappaB-alpha in DCs, and induced significant translocation of p65 from the cytosol to the nucleus.	3	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaB-alpha	Rv2299c triggered phosphorylation of p38 and ERK1/2 as well as phosphorylation and degradation of IkappaB-alpha	ikappab-alpha	p65	p65	p65	17	18	26	27
In this study , we demonstrated that 4-HNE stimulated IkappaBalpha phosphorylation and degradation , and subsequently induced nuclear translocation of NF-kappaB p65 in HPASMCs in vitro .	In this study, we demonstrated that 4-HNE stimulated IkappaBalpha phosphorylation and degradation, and subsequently induced nuclear translocation of NF-kappaB p65 in HPASMCs in vitro.	7	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	4-HNE stimulated IkappaBalpha phosphorylation	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	9	10	20	22
It has been reported that PEITC inhibits IkappaBalpha phosphorylation and decreases the nuclear translocation of p65 subunit of NF-kappaB ; 13 thus , based on this previous work and on the above mentioned results , we propose that inhibition of IkappaBalpha degradation and suppression of NF-kappaB activity ( by both IkappaBalpha association and dephosphorylation ) could be mediated , at least in part , by PTPL1 and PKCdelta , and that these signalling events contribute to apoptosis in PC3 prostate cancer cells .	It has been reported that PEITC inhibits IkappaBalpha phosphorylation and decreases the nuclear translocation of p65 subunit of NF-kappaB; 13 thus, based on this previous work and on the above mentioned results, we propose that inhibition of IkappaBalpha degradation and suppression of NF-kappaB activity (by both IkappaBalpha association and dephosphorylation) could be mediated, at least in part, by PTPL1 and PKCdelta, and that these signalling events contribute to apoptosis in PC3 prostate cancer cells.	5	16	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	PEITC inhibits IkappaBalpha phosphorylation	ikappabalpha	p65	p65	p65	7	8	15	16
Overxpression of p65 , an active subunit of NFkappaB , upregulated Sptlc2 and the blockage of NFkappaB pathway by IkappaBalpha prevented Sptlc2 upregulation ( XREF_FIG ) .	Overxpression of p65, an active subunit of NFkappaB, upregulated Sptlc2 and the blockage of NFkappaB pathway by IkappaBalpha prevented Sptlc2 upregulation (XREF_FIG).	0	20	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	19	20	2	3
TLR2 ligation also induces IkappaBalpha phosphorylation and degradation , a process that allows the canonical NFkappaB p50 and p65 transcription factor to translocate to the nucleus and drive inflammatory responses [ XREF_BIBR , XREF_BIBR ] .	TLR2 ligation also induces IkappaBalpha phosphorylation and degradation, a process that allows the canonical NFkappaB p50 and p65 transcription factor to translocate to the nucleus and drive inflammatory responses [XREF_BIBR, XREF_BIBR].	0	20	allows	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IkappaBalpha	TLR2 ligation also induces IkappaBalpha phosphorylation	ikappabalpha	p65	p65	p65	4	5	18	19
TQ mediated release of ROS in turn inhibited NFkappaB activity by dephosphorylating IkappaBalpha and decreased translocation of p65 subunit of NFkappaB in the nuclear compartment in ABC cell lines .	TQ mediated release of ROS in turn inhibited NFkappaB activity by dephosphorylating IkappaBalpha and decreased translocation of p65 subunit of NFkappaB in the nuclear compartment in ABC cell lines.	0	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	TQ mediated release of ROS in turn inhibited NFkappaB activity by dephosphorylating IkappaBalpha	ikappabalpha	p65	p65	p65	12	13	17	18
As expected , MG132 did not block phosphorylation of IkappaB-alpha but did prevent the nuclear translocation of p65 in astrocytes in response to stimulation with NMO IgG .	As expected, MG132 did not block phosphorylation of IkappaB-alpha but did prevent the nuclear translocation of p65 in astrocytes in response to stimulation with NMO IgG.	3	18	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB-alpha	MG132 did not block phosphorylation of IkappaB-alpha	ikappab-alpha	p65	p65	p65	9	10	17	18
IkappaBalpha is known to bind to NF-kappaB and block the nuclear localization signal , causing retention of the NF and kappaB dimer ( p50 and p65 ) in the cytoplasm .	IkappaBalpha is known to bind to NF-kappaB and block the nuclear localization signal, causing retention of the NF and kappaB dimer (p50 and p65) in the cytoplasm.	0	26	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	0	1	25	26
Furthermore , TMC suppressed tumor necrosis factor-alpha ( TNF-alpha ) and interleukin-1beta ( IL-1beta ) production , and the phosphorylation and degradation of IkappaB-alpha as well as the LPS stimulated nuclear translocation of p65 in macrophages .	Furthermore, TMC suppressed tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) production, and the phosphorylation and degradation of IkappaB-alpha as well as the LPS stimulated nuclear translocation of p65 in macrophages.	19	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaB-alpha	phosphorylation and degradation of IkappaB-alpha	ikappab-alpha	p65	p65	p65	23	24	33	34
EGFR activates NF-kappaB through the PI3K and Akt pathway that leads to the phosphorylation of IkappaBalpha on serines 32 and 36 , thereby promoting the nuclear translocation of the p65 subunit .	EGFR activates NF-kappaB through the PI3K and Akt pathway that leads to the phosphorylation of IkappaBalpha on serines 32 and 36, thereby promoting the nuclear translocation of the p65 subunit.	5	30	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	PI3K and Akt pathway that leads to the phosphorylation of IkappaBalpha	ikappabalpha	p65	p65	p65	15	16	29	30
Suppression of NF-kappaB activation by Rg3 was associated with suppression of IKKbeta activity and subsequently IkappaBalpha degradation and nuclear translocation of p65 .	Suppression of NF-kappaB activation by Rg3 was associated with suppression of IKKbeta activity and subsequently IkappaBalpha degradation and nuclear translocation of p65.	15	22	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	15	16	21	22
In contrast , Dyrk1A deficient mice ( on a CD1 background ) have decreased IkappaBalpha protein levels with an increased calpain activity and decreased cytoplasmic p65 sequestration in the brain .	In contrast, Dyrk1A deficient mice (on a CD1 background) have decreased IkappaBalpha protein levels with an increased calpain activity and decreased cytoplasmic p65 sequestration in the brain.	3	26	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	Dyrk1A deficient mice (on a CD1 background) have decreased IkappaBalpha protein levels	ikappabalpha	p65	p65	p65	14	15	25	26
Taken together , these findings suggest that BEX2 expression is required for both normal phosphorylation of p65 and IkappaBalpha , and the ceramide induced DNA binding of p65 in breast cancer cells .	Taken together, these findings suggest that BEX2 expression is required for both normal phosphorylation of p65 and IkappaBalpha, and the ceramide induced DNA binding of p65 in breast cancer cells.	14	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	phosphorylation of p65 and IkappaBalpha	ikappabalpha	p65	p65	p65	18	19	27	28
Furthermore , DXM inhibited LPS induced IkappaBalpha degradation and nuclear translocation of p65 .	Furthermore, DXM inhibited LPS induced IkappaBalpha degradation and nuclear translocation of p65.	2	13	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	DXM inhibited LPS induced IkappaBalpha	ikappabalpha	p65	p65	p65	6	7	12	13
PEITC also suppressed LPS induced phosphorylation and degradation of IkBa and decreased nuclear translocation of p65 .	PEITC also suppressed LPS induced phosphorylation and degradation of IkBa and decreased nuclear translocation of p65.	0	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkBa	PEITC also suppressed LPS induced phosphorylation and degradation of IkBa	ikba	p65	p65	p65	9	10	15	16
Phosphorylation of the IkappaBalpha subunit of the NF and kappaB complex by IKK leads to proteasomal degradation , allowing nuclear translocation of the p50 and p65 subunits .	Phosphorylation of the IkappaBalpha subunit of the NF and kappaB complex by IKK leads to proteasomal degradation, allowing nuclear translocation of the p50 and p65 subunits.	0	26	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	Phosphorylation of the IkappaBalpha	ikappabalpha	p65	p65	p65	3	4	25	26
Consistent with these well studied processes , our study demonstrated that URGCP upregulates the level of p-IkappaBalpha and promotes the nuclear translocation of NF-kappaB and p65 in glioma cells , suggesting that the NF-kappaB pathway plays an essential role in the URGCP induced glioma cell proliferation .	Consistent with these well studied processes, our study demonstrated that URGCP upregulates the level of p-IkappaBalpha and promotes the nuclear translocation of NF-kappaB and p65 in glioma cells, suggesting that the NF-kappaB pathway plays an essential role in the URGCP induced glioma cell proliferation.	11	26	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-IkappaBalpha	URGCP upregulates the level of p-IkappaBalpha	p-ikappabalpha	p65	p65	p65	16	17	25	26
In accord with these findings , co-administration of bortezomib resulted in increased expression of the S32/36 phosphorylated form of IkappaBalpha ( XREF_FIG ) , an NF-kappaB inhibitory protein that sequesters RelA and p65 in cytoplasm , presumably due to blockade of proteasome mediated IkappaBalpha degradation following S32/36 phosphorylation 35 .	In accord with these findings, co-administration of bortezomib resulted in increased expression of the S32/36 phosphorylated form of IkappaBalpha (XREF_FIG), an NF-kappaB inhibitory protein that sequesters RelA and p65 in cytoplasm, presumably due to blockade of proteasome mediated IkappaBalpha degradation following S32/36 phosphorylation 35.	17	32	sequesters	Negative_activation_syntax_5_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	19	20	30	31
Taken together , our findings reveal that ORI protect OVX induced bone loss via inhibiting osteoclastic bone resorption but enhancing osteoblastic bone formation through abolishing both Ifrd1 and IkappaBalpha mediated p65 nuclear translocation .	Taken together, our findings reveal that ORI protect OVX induced bone loss via inhibiting osteoclastic bone resorption but enhancing osteoblastic bone formation through abolishing both Ifrd1 and IkappaBalpha mediated p65 nuclear translocation.	26	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	28	29	30	31
Consequently , inhibition of miR-891a-5p increased IkappaBalpha level , prevented nuclear translocation of NF-kappaB p65 and ultimately suppressed the synergistic effect of Tat- and K1 induced angiogenesis .	Consequently, inhibition of miR-891a-5p increased IkappaBalpha level, prevented nuclear translocation of NF-kappaB p65 and ultimately suppressed the synergistic effect of Tat- and K1 induced angiogenesis.	4	15	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	miR-891a-5p increased IkappaBalpha level	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	6	7	13	15
Apigenin decreased the phosphorylation level of IkappaBalpha in the cytosol , and abrogated the nuclear translocation of p65 within the nucleus suggesting that it blocks the activation of NFkappaB signaling pathway in MCF-7 vec and MCF-7 HER2 cells .	Apigenin decreased the phosphorylation level of IkappaBalpha in the cytosol, and abrogated the nuclear translocation of p65 within the nucleus suggesting that it blocks the activation of NFkappaB signaling pathway in MCF-7 vec and MCF-7 HER2 cells.	0	18	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	Apigenin decreased the phosphorylation level of IkappaBalpha	ikappabalpha	p65	p65	p65	6	7	17	18
The present study shows that oleifolioside A markedly inhibits rapid phosphorylation of IkappaB-alpha with subsequent degradation by proteasomes in the cytosol ( XREF_FIG ) , as well as prevents the translocation of the p65 subunit of NF-kappaB from the cytosol to the nucleus .	The present study shows that oleifolioside A markedly inhibits rapid phosphorylation of IkappaB-alpha with subsequent degradation by proteasomes in the cytosol (XREF_FIG), as well as prevents the translocation of the p65 subunit of NF-kappaB from the cytosol to the nucleus.	5	34	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB-alpha	oleifolioside A markedly inhibits rapid phosphorylation of IkappaB-alpha	ikappab-alpha	p65	p65	p65	12	13	33	34
The phosphorylation of IkappaBalpha promotes the activation and translocation of the nuclear factor-kappaB ( NF-kappaB ) subunits p65 and p50 to the nucleus .	The phosphorylation of IkappaBalpha promotes the activation and translocation of the nuclear factor-kappaB (NF-kappaB) subunits p65 and p50 to the nucleus.	1	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	phosphorylation of IkappaBalpha	ikappabalpha	p65	p65	p65	3	4	17	18
We demonstrated , by western blot analysis , that ADA inhibited both the phosphorylation and degradation of IkBalpha thereby preventing the nuclear translocation of the p65 subunit containing the transcriptional activation domain .	We demonstrated, by western blot analysis, that ADA inhibited both the phosphorylation and degradation of IkBalpha thereby preventing the nuclear translocation of the p65 subunit containing the transcriptional activation domain.	9	26	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkBalpha	ADA inhibited both the phosphorylation and degradation of IkBalpha	ikbalpha	p65	p65	p65	17	18	25	26
In M1 , but not in M2 , ChA enhanced the phosphorylation of IkappaBalpha accompanied by consequent decreased protein levels of IkappaBalpha ( XREF_FIG ) , and caused nuclear enrichment of the p65 subunit of NFkappaB ( XREF_FIG ) .	In M1, but not in M2, ChA enhanced the phosphorylation of IkappaBalpha accompanied by consequent decreased protein levels of IkappaBalpha (XREF_FIG), and caused nuclear enrichment of the p65 subunit of NFkappaB (XREF_FIG).	8	33	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	ChA enhanced the phosphorylation of IkappaBalpha	ikappabalpha	p65	p65	p65	13	14	32	33
Further , we found that DIM inhibited IkappaBalpha phosphorylation , and blocked translocation of p65 subunit of NF-kappaB to the nucleus .	Further, we found that DIM inhibited IkappaBalpha phosphorylation, and blocked translocation of p65 subunit of NF-kappaB to the nucleus.	5	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	DIM inhibited IkappaBalpha phosphorylation	ikappabalpha	p65	p65	p65	7	8	14	15
Immunoblotting showed that ITCs suppressed LPS induced phosphorylation and degradation of IkappaBalpha and decreased nuclear translocation of p65 .	Immunoblotting showed that ITCs suppressed LPS induced phosphorylation and degradation of IkappaBalpha and decreased nuclear translocation of p65.	5	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	LPS induced phosphorylation and degradation of IkappaBalpha	ikappabalpha	p65	p65	p65	11	12	17	18
In this study , we found that overexpression of TIPE3 in MCF-7 cells substantially upregulated p-AKT and p-IkBalpha phosphorylation and promoted p65 nuclear localization .	In this study, we found that overexpression of TIPE3 in MCF-7 cells substantially upregulated p-AKT and p-IkBalpha phosphorylation and promoted p65 nuclear localization.	7	23	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-IkBalpha	overexpression of TIPE3 in MCF-7 cells substantially upregulated p-AKT and p-IkBalpha phosphorylation	p-ikbalpha	p65	p65	p65	17	18	21	22
BAY 11 , a selective inhibitor of IkappaB-alpha phosphorylation and degradation , blocked the nuclear translocation of NF-kappaB p65 protein .	BAY 11, a selective inhibitor of IkappaB-alpha phosphorylation and degradation, blocked the nuclear translocation of NF-kappaB p65 protein.	7	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaB-alpha	IkappaB-alpha phosphorylation	ikappab-alpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	7	8	17	19
In this pathway , the inhibitor of kappaB ( IkappaBalpha ) sequesters the p65 : p50 heterodimer in an inactive state in the cytoplasm .	In this pathway, the inhibitor of kappaB (IkappaBalpha) sequesters the p65 : p50 heterodimer in an inactive state in the cytoplasm.	5	16	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	9	10	13	14
Furthermore , Western blot and immunofluorescence analysis indicated that neougonin A could inhibit the phosphorylation of IkBalpha and block the translocation of NF-kB and p65 into the nucleus even at 1.25 muM ( P < 0.05 ) , but have no effect on JNK , ERK1/2 , and p38MAPK phosphorylation .	Furthermore, Western blot and immunofluorescence analysis indicated that neougonin A could inhibit the phosphorylation of IkBalpha and block the translocation of NF-kB and p65 into the nucleus even at 1.25 muM (P < 0.05), but have no effect on JNK, ERK1/2, and p38MAPK phosphorylation.	9	25	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkBalpha	neougonin A could inhibit the phosphorylation of IkBalpha	ikbalpha	p65	p65	p65	16	17	24	25
The expression level of cytosolic IkappaBalpha and IkappaBbeta did support the status of nuclear translocation of p52 , p65 and RelB in frontal cortex of both the sexes during MPTP treatment or estrogen supplement and tamoxifen supplement ( XREF_FIG ) .	The expression level of cytosolic IkappaBalpha and IkappaBbeta did support the status of nuclear translocation of p52, p65 and RelB in frontal cortex of both the sexes during MPTP treatment or estrogen supplement and tamoxifen supplement (XREF_FIG).	2	19	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	level of cytosolic IkappaBalpha	ikappabalpha	p65	p65	p65	5	6	18	19
Examination of the effects of the diterpene on NF-kappaB signaling showed that LAME inhibits the phosphorylation of IkappaBalpha and IkappaBbeta , preventing their degradation and the nuclear translocation of the NF-kappaB p65 subunit .	Examination of the effects of the diterpene on NF-kappaB signaling showed that LAME inhibits the phosphorylation of IkappaBalpha and IkappaBbeta, preventing their degradation and the nuclear translocation of the NF-kappaB p65 subunit.	12	32	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	LAME inhibits the phosphorylation of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	17	18	30	32
Mechanistically , A11 and B13 blocked the phosphorylation of IkappaBalpha and suppressed the activation of p65 and IkappaBalpha .	Mechanistically, A11 and B13 blocked the phosphorylation of IkappaBalpha and suppressed the activation of p65 and IkappaBalpha.	4	17	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	B13 blocked the phosphorylation of IkappaBalpha	ikappabalpha	p65	p65	p65	9	10	15	16
7 Indeed , the inhibition of NF-kappaB signaling in PANC-1 cells by using either RNA induced knockdown of RELA or by proteasome ( MG-132 ) and IkappaBalpha small molecule inhibitors ( BAY-117082 ) led to a significant reduction of cell cycle , cell growth and migration ( XREF_SUPPLEMENTARY ) .	7 Indeed, the inhibition of NF-kappaB signaling in PANC-1 cells by using either RNA induced knockdown of RELA or by proteasome (MG-132) and IkappaBalpha small molecule inhibitors (BAY-117082) led to a significant reduction of cell cycle, cell growth and migration (XREF_SUPPLEMENTARY).	15	29	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RELA	RELA	RELA	26	27	18	19
HSYA blocked the TNFR1 mediated phosphorylation and degradation of IkappaBalpha and also prevented the nuclear translocation of NF-kappaB p65 .	HSYA blocked the TNFR1 mediated phosphorylation and degradation of IkappaBalpha and also prevented the nuclear translocation of NF-kappaB p65.	3	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	TNFR1 mediated phosphorylation and degradation of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	9	10	17	19
POP1 is reported to inhibit cytosolic IKKalpha and beta upstream of IkBalpha phosphorylation , thus preventing nuclear translocation of p50 : p65 heterodimers in epithelial cells .	POP1 is reported to inhibit cytosolic IKKalpha and beta upstream of IkBalpha phosphorylation, thus preventing nuclear translocation of p50 : p65 heterodimers in epithelial cells.	0	22	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkBalpha	POP1 is reported to inhibit cytosolic IKKalpha and beta upstream of IkBalpha phosphorylation	ikbalpha	p65	p65	p65	11	12	21	22
Suppression of inflammatory responses is associated with IkappaBalpha independent inhibition of NF-kappaBp65 activation and selective inhibition of activation of Interferon Regulatory Factors ( IRFs ) .	Suppression of inflammatory responses is associated with IkappaBalpha independent inhibition of NF-kappaBp65 activation and selective inhibition of activation of Interferon Regulatory Factors (IRFs).	7	12	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	NF-kappaBp65	NF-kappaBp65	NF-kappaBp65	7	8	11	12
In unstimulated cells , IkappaB holds the NF and kappaB complex ( p65 and p50 ) in the cytoplasm , while LPS stimulation induces phosphorylation of IkappaB-alpha , increasing the release of p65 into the nucleus [ XREF_BIBR ] .	In unstimulated cells, IkappaB holds the NF and kappaB complex (p65 and p50) in the cytoplasm, while LPS stimulation induces phosphorylation of IkappaB-alpha, increasing the release of p65 into the nucleus [XREF_BIBR].	21	33	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaB-alpha	LPS stimulation induces phosphorylation of IkappaB-alpha	ikappab-alpha	p65	p65	p65	26	27	32	33
This occurred at the transcriptional level , since the gingerol compounds decreased LPS induced IkappaB-alpha degradation , prevented nuclear translocation of NF-kappaB p65 and reduced NF-kappaB activity in a concentration dependent manner .	This occurred at the transcriptional level, since the gingerol compounds decreased LPS induced IkappaB-alpha degradation, prevented nuclear translocation of NF-kappaB p65 and reduced NF-kappaB activity in a concentration dependent manner.	9	23	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaB-alpha	gingerol compounds decreased LPS induced IkappaB-alpha	ikappab-alpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	14	15	21	23
We next determined whether LT induced IkappaBalpha phosphorylation was sufficient to induce the nuclear translocation of the NF-kappaB p50 and p65 subunits during ETEC infection .	We next determined whether LT induced IkappaBalpha phosphorylation was sufficient to induce the nuclear translocation of the NF-kappaB p50 and p65 subunits during ETEC infection.	4	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	LT induced IkappaBalpha phosphorylation	ikappabalpha	p65	p65	p65	6	7	20	21
IkappaBalpha mediated increase in p65 ( RelA ) activity is a characteristic of canonical NF-kappaB signaling .	IkappaBalpha mediated increase in p65 (RelA) activity is a characteristic of canonical NF-kappaB signaling.	0	5	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	0	1	4	5
Specifically , translational interference of IkappaBalpha , increasing the duration of RelA nuclear localization activity , occurred in intracellular infection , whereas impairment of RelA nuclear translocation occurred during extracellular presentation , and these effects were GXM dependent [ XREF_BIBR ] .	Specifically, translational interference of IkappaBalpha, increasing the duration of RelA nuclear localization activity, occurred in intracellular infection, whereas impairment of RelA nuclear translocation occurred during extracellular presentation, and these effects were GXM dependent [XREF_BIBR].	3	14	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	5	6	11	12
Western blot analysis showed that compound 7 inhibited the LPS induced phosphorylation of IkappaBalpha and antagonized the LPS induced reduction of cytoplasmic NF-kappaB p65 and the increase of nuclear NF-kappaB p65 .	Western blot analysis showed that compound 7 inhibited the LPS induced phosphorylation of IkappaBalpha and antagonized the LPS induced reduction of cytoplasmic NF-kappaB p65 and the increase of nuclear NF-kappaB p65.	9	24	antagonized	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	LPS induced phosphorylation of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	13	14	22	24
Similar to HCT116 , only overexression of UEV1A , but not UEV1C or MMS2 was able to increase the phosphorylation of IkappaBalpha , decrease IkappaBalpha and promote more p65 into the nucleus in DLD1 cells ( XREF_SUPPLEMENTARY ) .	Similar to HCT116, only overexression of UEV1A, but not UEV1C or MMS2 was able to increase the phosphorylation of IkappaBalpha, decrease IkappaBalpha and promote more p65 into the nucleus in DLD1 cells (XREF_SUPPLEMENTARY).	7	29	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	UEV1A, but not UEV1C or MMS2 was able to increase the phosphorylation of IkappaBalpha	ikappabalpha	p65	p65	p65	21	22	28	29
One is that the down-regulation of IKKepsilon by miR-7 decreased the phosphorylation and degradation of IkappaBalpha , which blocked RELA activation .	One is that the down-regulation of IKKepsilon by miR-7 decreased the phosphorylation and degradation of IkappaBalpha, which blocked RELA activation.	11	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	phosphorylation and degradation of IkappaBalpha	ikappabalpha	RELA	RELA	rela	15	16	19	20
Furthermore , TNF-alpha-induced ICAM-1 expression , which was increased via IKKbeta and IkappaBalpha mediated activation of NF-kappaB p65 , was also inhibited by DA .	Furthermore, TNF-alpha-induced ICAM-1 expression, which was increased via IKKbeta and IkappaBalpha mediated activation of NF-kappaB p65, was also inhibited by DA.	10	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	12	13	16	18
Furthermore , ketamine suppressed the phosphorylation and degradation of IkappaB-alpha as well as the LPS stimulated nuclear translocation of NF-kappaB p65 in macrophages .	Furthermore, ketamine suppressed the phosphorylation and degradation of IkappaB-alpha as well as the LPS stimulated nuclear translocation of NF-kappaB p65 in macrophages.	5	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaB-alpha	phosphorylation and degradation of IkappaB-alpha	ikappab-alpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	9	10	19	21
As seen in XREF_FIG , relative to DMSO control propofol mediated IkappaBalpha degradation did not increase nuclear translocation of p65 at up to 4 h of propofol exposure .	As seen in XREF_FIG, relative to DMSO control propofol mediated IkappaBalpha degradation did not increase nuclear translocation of p65 at up to 4 h of propofol exposure.	9	20	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	propofol mediated IkappaBalpha	ikappabalpha	p65	p65	p65	11	12	19	20
IkappaBalpha phosphorylation triggers translocation of RelA subunit of NF-kappaB to the nucleus .	IkappaBalpha phosphorylation triggers translocation of RelA subunit of NF-kappaB to the nucleus.	0	6	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha phosphorylation	ikappabalpha	RelA	RelA	rela	0	1	5	6
However , IkappaBalpha primarily targets RelA and c-Rel-containing complexes , leaving other NF-kappaB and Rel protein complexes , such as p50 and p52 homodimers , and RelB heterodimers uninhibited .	However, IkappaBalpha primarily targets RelA and c-Rel-containing complexes, leaving other NF-kappaB and Rel protein complexes, such as p50 and p52 homodimers, and RelB heterodimers uninhibited.	2	28	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	2	3	5	6
Inhibition of IkBa phosphorylation and degradation inhibits nuclear translocation of p65 .	Inhibition of IkBa phosphorylation and degradation inhibits nuclear translocation of p65.	2	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkBa	IkBa phosphorylation	ikba	p65	p65	p65	2	3	10	11
As expected , Bay 11-7082 inhibited the IR induced phosphorylation and degradation of IkappaBalpha , and thus attenuated the translocation of p65 into the nucleus .	As expected, Bay 11-7082 inhibited the IR induced phosphorylation and degradation of IkappaBalpha, and thus attenuated the translocation of p65 into the nucleus.	7	22	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IR induced phosphorylation and degradation of IkappaBalpha	ikappabalpha	p65	p65	p65	13	14	21	22
In accordance , preliminary evaluation of NF-kappaB activation by assessment of the phosphorylation of IkBalpha and of RelA in our transduced T-ALL cell lines did not reveal any obvious differences modulated by miR-146b ( data not shown ) .	In accordance, preliminary evaluation of NF-kappaB activation by assessment of the phosphorylation of IkBalpha and of RelA in our transduced T-ALL cell lines did not reveal any obvious differences modulated by miR-146b (data not shown).	7	19	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	IkBalpha	phosphorylation of IkBalpha	ikbalpha	RelA	RelA	rela	14	15	17	18
In this scenario , the signal in these genes would be attenuated via upregulation of the repressor IkappaBalpha , which in turn would induce less nuclear RelA and less gene expression .	In this scenario, the signal in these genes would be attenuated via upregulation of the repressor IkappaBalpha, which in turn would induce less nuclear RelA and less gene expression.	13	30	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	17	18	26	27
BAY-11-7085 , an inhibitor of IkappaBalpha phosphorylation , inhibited LPS induced nuclear translocation of p65 ( XREF_FIG ) .	BAY-11-7085, an inhibitor of IkappaBalpha phosphorylation, inhibited LPS induced nuclear translocation of p65 (XREF_FIG).	5	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha phosphorylation	ikappabalpha	p65	p65	p65	5	6	14	15
By inhibiting LPS induced inhibitor kinase ( IKKalpha and beta ) phosphorylation , cis-ampelopsin E significantly decreased LPS induced IkappaBalpha phosphorylation , prevented IkappaBalpha degradation , and subsequently reduced the translocating of transcription factor p65 into the nucleus .	By inhibiting LPS induced inhibitor kinase (IKKalpha and beta) phosphorylation, cis-ampelopsin E significantly decreased LPS induced IkappaBalpha phosphorylation, prevented IkappaBalpha degradation, and subsequently reduced the translocating of transcription factor p65 into the nucleus.	17	35	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	LPS induced IkappaBalpha phosphorylation	ikappabalpha	transcription factor p65	transcription factor p65	transcription factor p65	19	20	32	35
We demonstrate here that eight melanoma cell lines exhibit increased IkappaB kinase ( IKK ) activity , enhanced phosphorylation of IkappaBalpha and p65 , and enhanced nuclear localization of p65 and p50 in comparison to normal human epidermal melanocytes .	We demonstrate here that eight melanoma cell lines exhibit increased IkappaB kinase (IKK) activity, enhanced phosphorylation of IkappaBalpha and p65, and enhanced nuclear localization of p65 and p50 in comparison to normal human epidermal melanocytes.	10	31	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaB kinase (IKK) activity, enhanced phosphorylation of IkappaBalpha	ikappabalpha	p65	p65	p65	20	21	29	30
XREF_BIBR , XREF_BIBR In our study , theaflavin inhibited LPS induced IkappaBalpha degradation and nuclear translocation of RelA in BMMs .	XREF_BIBR, XREF_BIBR In our study, theaflavin inhibited LPS induced IkappaBalpha degradation and nuclear translocation of RelA in BMMs.	7	18	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	theaflavin inhibited LPS induced IkappaBalpha	ikappabalpha	RelA	RelA	rela	11	12	17	18
When inflammation is initiated via the NF-kappaB pathway , IkappaBalpha is phosphorylated , dissociated from the cytoplasmic complex , and allowed NF-kappaB and p65 to move to the nucleus .	When inflammation is initiated via the NF-kappaB pathway, IkappaBalpha is phosphorylated, dissociated from the cytoplasmic complex, and allowed NF-kappaB and p65 to move to the nucleus.	9	25	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha is phosphorylated	ikappabalpha	p65	p65	p65	9	10	23	24
XREF_BIBR , XREF_BIBR , XREF_BIBR Treatment with PMOC sequentially inhibited IkappaBalpha phosphorylation in LPS- or CpG ODN activated whole liver cells and LPS activated RAW 264.7 cells ( XREF_SUPPLEMENTARY ) , nuclear import of NF-kappaB p65 in LPS activated RAW 264.7 cells ( XREF_SUPPLEMENTARY ) , and NF-kappaB transcriptional activity in LPS-, CpG ODN- or TNF-alpha-activated cells containing NF-kappaB-Luc reporter construct ( XREF_SUPPLEMENTARY ) .	XREF_BIBR, XREF_BIBR, XREF_BIBR Treatment with PMOC sequentially inhibited IkappaBalpha phosphorylation in LPS- or CpG ODN activated whole liver cells and LPS activated RAW 264.7 cells (XREF_SUPPLEMENTARY), nuclear import of NF-kappaB p65 in LPS activated RAW 264.7 cells (XREF_SUPPLEMENTARY), and NF-kappaB transcriptional activity in LPS-, CpG ODN- or TNF-alpha-activated cells containing NF-kappaB-Luc reporter construct (XREF_SUPPLEMENTARY).	10	36	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha phosphorylation	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	10	11	34	36
Sanguinarine blocked the tumor necrosis factor induced phosphorylation and degradation of IkappaBalpha , an inhibitory subunit of NF-kappaB , and inhibited translocation of p65 subunit to the nucleus .	Sanguinarine blocked the tumor necrosis factor induced phosphorylation and degradation of IkappaBalpha, an inhibitory subunit of NF-kappaB, and inhibited translocation of p65 subunit to the nucleus.	0	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	Sanguinarine blocked the tumor necrosis factor induced phosphorylation and degradation of IkappaBalpha	ikappabalpha	p65	p65	p65	11	12	23	24
Upon cellular activation IkappaBalpha is proteolyzed , allowing RelA dimers to enter the nucleus and activate target genes .	Upon cellular activation IkappaBalpha is proteolyzed, allowing RelA dimers to enter the nucleus and activate target genes.	3	15	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	3	4	8	9
NOD2 activates RIP2 , which in turn activates IKK through a ubiquitination dependent process that is not yet fully understood .	NOD2 activates RIP2, which in turn activates IKK through a ubiquitination dependent process that is not yet fully understood.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	0	1	2	3
Our data identify the E3-ubiquitin ligase ZNRF4 as a negative regulator of NOD2 mediated anti-bacterial and inflammatory responses during both acute and chronic stimulation by promoting RIP2 degradation .	Our data identify the E3-ubiquitin ligase ZNRF4 as a negative regulator of NOD2 mediated anti-bacterial and inflammatory responses during both acute and chronic stimulation by promoting RIP2 degradation.	10	27	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	12	13	26	27
Our results suggest that activation of CNS infiltrating dendritic cells by PGN is dependent on NOD1- and NOD2 mediated RIP2 activation .	Our results suggest that activation of CNS infiltrating dendritic cells by PGN is dependent on NOD1- and NOD2 mediated RIP2 activation.	13	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	17	18	19	20
Simultaneous activation of NOD2 by MDP leads to activation of RICK by NOD2 and the downmodulation of the TLR2 signaling pathway [ XREF_BIBR ] .	Simultaneous activation of NOD2 by MDP leads to activation of RICK by NOD2 and the downmodulation of the TLR2 signaling pathway [XREF_BIBR].	6	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RICK	RICK	RICK	12	13	10	11
After ligation of PGN , TLR2 or NOD2 activates the downstream adaptor MyD88 or RICK , respectively , eliciting the activation of the commonly used downstream signaling pathways , including extracellular signal regulated kinase 1/2 ( ERK1/2 ) , c-Jun N-terminal kinase ( JNK ) , and p38 MAPK pathways , NF-kappaB pathway and PI3K and Akt signaling pathway XREF_BIBR XREF_BIBR , accounting for the production of the downstream cytokines .	After ligation of PGN, TLR2 or NOD2 activates the downstream adaptor MyD88 or RICK, respectively, eliciting the activation of the commonly used downstream signaling pathways, including extracellular signal regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAPK pathways, NF-kappaB pathway and PI3K and Akt signaling pathway XREF_BIBR XREF_BIBR, accounting for the production of the downstream cytokines.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RICK	RICK	RICK	7	8	14	15
In summary , this study by XREF_BIBR implies a critical role of PGN induced NOD1- and NOD2 mediated RICK activation in CNS inflammatory response through its impact on the activation of peripherally derived CNS APCs and the consequent effector stage of EAE .	In summary, this study by XREF_BIBR implies a critical role of PGN induced NOD1- and NOD2 mediated RICK activation in CNS inflammatory response through its impact on the activation of peripherally derived CNS APCs and the consequent effector stage of EAE.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RICK	RICK	RICK	16	17	18	19
Finally , as shown in XREF_FIG , polyubiquitination of RICK induced by 30 min of stimulation with MDP in 293 cells stably expressing NOD2 was barely seen upon co-transfection of IRF4 ; thus the inhibitory effect of IRF4 also applies to RICK activated by NOD2 .	Finally, as shown in XREF_FIG, polyubiquitination of RICK induced by 30 min of stimulation with MDP in 293 cells stably expressing NOD2 was barely seen upon co-transfection of IRF4; thus the inhibitory effect of IRF4 also applies to RICK activated by NOD2.	39	45	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RICK	RICK	RICK	44	45	41	42
Binding to NOD2 promotes RIP2 kinase activation and this active NOD2 : RIP2 complex then activates a number of intracellular signaling pathways including the MAP Kinase pathways ( JNK , ERK , p38 ) , the NF-kappaB pathway ( XREF_FIG ) , autophagy and antigen presentation [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Binding to NOD2 promotes RIP2 kinase activation and this active NOD2 : RIP2 complex then activates a number of intracellular signaling pathways including the MAP Kinase pathways (JNK, ERK, p38), the NF-kappaB pathway (XREF_FIG), autophagy and antigen presentation [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	6	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	2	3	4	5
Binding to NOD2 promotes RIP2 kinase activation , and the NOD2 and RIP2 complex then initiates a large signaling platform .	Binding to NOD2 promotes RIP2 kinase activation, and the NOD2 and RIP2 complex then initiates a large signaling platform.	0	6	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	2	3	4	5
Interestingly , NOD2 mediated protection against T. gondii is independent of its adaptor protein RIPK2 , as RIPK2 deficient mice are completely protected [ XREF_BIBR ] .	Interestingly, NOD2 mediated protection against T. gondii is independent of its adaptor protein RIPK2, as RIPK2 deficient mice are completely protected [XREF_BIBR].	2	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIPK2	RIPK2	RIPK2	2	3	14	15
Upon recognition of agonist , NOD2 self-oligomerize to activate RICK via CARD-CARD interactions .	Upon recognition of agonist, NOD2 self-oligomerize to activate RICK via CARD-CARD interactions.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RICK	RICK	RICK	5	6	9	10
NOD1 and NOD2 receptor stimulation has been shown to induce RIP2 kinase dependent NF-kappaB activation , resulting in the transcription of pro inflammatory cytokines .	NOD1 and NOD2 receptor stimulation has been shown to induce RIP2 kinase dependent NF-kappaB activation, resulting in the transcription of pro inflammatory cytokines.	2	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	2	3	10	11
These data suggest that the MDP and NOD2 mediated component of the synergistic response is partly RIP2 independent and that GSK717 is able to inhibit both the RIP2 dependent and independent components .	These data suggest that the MDP and NOD2 mediated component of the synergistic response is partly RIP2 independent and that GSK717 is able to inhibit both the RIP2 dependent and independent components.	5	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	7	8	16	17
While RIPK2 expression could rescue NOD2 dependent signaling in the RIPK2 -/- macrophages , expression of empty vector ( XREF_FIG ) , RIPK3/2 or RIPK4/2 could not ( XREF_FIG ) , suggesting that despite the biochemical similarities between RIPK2 and RIPK4/2 , RIPK4 ' s kinase domain could not replace RIPK2 in NOD2 signaling .	While RIPK2 expression could rescue NOD2 dependent signaling in the RIPK2 -/- macrophages, expression of empty vector (XREF_FIG), RIPK3/2 or RIPK4/2 could not (XREF_FIG), suggesting that despite the biochemical similarities between RIPK2 and RIPK4/2, RIPK4 's kinase domain could not replace RIPK2 in NOD2 signaling.	5	14	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIPK2	RIPK2	RIPK2	5	6	10	11
Furthermore , ponatinib was still able to completely prevent these responses even in the cells lacking catalytic activity of RIPK2 , clearly indicating that efficient inhibition of NOD2 responses is not related to the ability of the inhibitors to block the catalytic activity of RIPK2 .	Furthermore, ponatinib was still able to completely prevent these responses even in the cells lacking catalytic activity of RIPK2, clearly indicating that efficient inhibition of NOD2 responses is not related to the ability of the inhibitors to block the catalytic activity of RIPK2.	27	45	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIPK2	RIPK2	RIPK2	27	28	44	45
Since NOD2 mediated RIPK2 activation results in the activation of ERK , we further studied the impact of CYLD on ERK1/2 dependent pathogen control and production of ROS and NO .	Since NOD2 mediated RIPK2 activation results in the activation of ERK, we further studied the impact of CYLD on ERK1/2 dependent pathogen control and production of ROS and NO.	1	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIPK2	RIPK2	RIPK2	1	2	3	4
The cytosolic pattern recognition receptor NOD1 and NOD2 also activates the RIPK2 gene XREF_BIBR .	The cytosolic pattern recognition receptor NOD1 and NOD2 also activates the RIPK2 gene XREF_BIBR.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIPK2	RIPK2	RIPK2	7	8	11	12
The second , Tyr 474 , is located in the group of residues identified by Fridh and Rittinger and is autophosphorylated following RIP2 activation by NOD2 .	The second, Tyr 474, is located in the group of residues identified by Fridh and Rittinger and is autophosphorylated following RIP2 activation by NOD2.	22	26	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	25	26	22	23
This study indicates for the first time , a model in which a bacterial trigger of NOD2 drives a RIP2 dependent activation of NF-kappaB genes while viral infection triggers an NOD2 and IPS -1 driven IRF-3 response , thus defining host-pathogen interactions of polymicrobial infection .	This study indicates for the first time, a model in which a bacterial trigger of NOD2 drives a RIP2 dependent activation of NF-kappaB genes while viral infection triggers an NOD2 and IPS -1 driven IRF-3 response, thus defining host-pathogen interactions of polymicrobial infection.	14	21	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	16	17	19	20
Since RICK is a serine threonine kinase , NOD2 activation of RICK could be regulating IRF4 function by enhancing RICK phosphorylation of IRF4 .	Since RICK is a serine threonine kinase, NOD2 activation of RICK could be regulating IRF4 function by enhancing RICK phosphorylation of IRF4.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RICK	RICK	RICK	8	9	11	12
NOD1 and NOD2 ligands increased the number of OVA specific cells producing IL-4 and IL-5 in the splenocytes of WT mice , but not in RIP2 deficient mice .	NOD1 and NOD2 ligands increased the number of OVA specific cells producing IL-4 and IL-5 in the splenocytes of WT mice, but not in RIP2 deficient mice.	0	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	2	3	25	26
Upon MDP recognition , NOD2 induces the activation of the transcription factor NF-kappaB and the mitogen activated protein kinases ( MAPKs ) via the serine threonine kinase RICK ( also called RIP2 ) .	Upon MDP recognition, NOD2 induces the activation of the transcription factor NF-kappaB and the mitogen activated protein kinases (MAPKs) via the serine threonine kinase RICK (also called RIP2).	4	32	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	4	5	31	32
Nod2 can stimulate epithelial cells , macrophages and dendritic cells by sensing muramyl dipeptide ( MDP ) , a component of bacterial peptidoglycan , and can also trigger activation of RIP2 and the canonical NF-kappaB pathway in these cells XREF_BIBR .	Nod2 can stimulate epithelial cells, macrophages and dendritic cells by sensing muramyl dipeptide (MDP), a component of bacterial peptidoglycan, and can also trigger activation of RIP2 and the canonical NF-kappaB pathway in these cells XREF_BIBR.	0	31	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nod2	Nod2	Nod2	RIP2	RIP2	RIP2	0	1	30	31
It could not support NOD2 induced signaling in RIPK2 -/- macrophages and could not replace RIPK2 ' s role in driving NOD2 induced gene expression .	It could not support NOD2 induced signaling in RIPK2 -/- macrophages and could not replace RIPK2 's role in driving NOD2 induced gene expression.	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIPK2	RIPK2	RIPK2	4	5	8	9
In particular , obtaining insight into the mechanism by which the ligand induced oligomerization of NOD2 induces RIP2 activation is an important goal since it could lead to the development of new therapies for these clinical conditions .	In particular, obtaining insight into the mechanism by which the ligand induced oligomerization of NOD2 induces RIP2 activation is an important goal since it could lead to the development of new therapies for these clinical conditions.	13	18	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	RIP2	RIP2	RIP2	15	16	17	18
NGF treatment for 6 h increased NGF receptor mRNA fourfold ; this increase was inhibited by cycloheximide .	NGF treatment for 6 h increased NGF receptor mRNA fourfold; this increase was inhibited by cycloheximide.	0	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGF receptor	NGF receptor	NGF receptor	0	1	6	8
This down-regulation does not occur when PC12nnr5 cells , which lack the high-affinity NGF receptor , p140trk , are treated with NGF .	This down-regulation does not occur when PC12nnr5 cells, which lack the high-affinity NGF receptor, p140trk, are treated with NGF.	13	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NGF	NGF	NGF	NGF receptor	NGF receptor	NGF receptor	21	22	13	15
In contrast , NGF induced L1 expression can occur in absence of p75NTR or independently of the high-affinity NGF receptor .	In contrast, NGF induced L1 expression can occur in absence of p75NTR or independently of the high-affinity NGF receptor.	3	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGF receptor	NGF receptor	NGF receptor	3	4	18	20
Although NGF and pro NGF can promote cell death by activating NGFR and use this receptor to stimulate TNF release , it is unlikely that this mechanism operates in GCs , because neither rodent nor human GCs express NGFR .	Although NGF and pro-NGF can promote cell death by activating NGFR and use this receptor to stimulate TNF release, it is unlikely that this mechanism operates in GCs, because neither rodent nor human GCs express NGFR.	1	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGFR	NGFR	NGFR	1	2	11	12
Chronic infusion of nerve growth factor ( NGF ) into the forebrain of the adult rat produced increases in NGF receptor ( NGF-R ) mRNA hybridization , NGF-R immunoreactivity , choline acetyltransferase ( ChAT ) mRNA hybridization , and neuronal hypertrophy , when compared with vehicle infusion or noninfused rat brain .	Chronic infusion of nerve growth factor (NGF) into the forebrain of the adult rat produced increases in NGF receptor (NGF-R) mRNA hybridization, NGF-R immunoreactivity, choline acetyltransferase (ChAT) mRNA hybridization, and neuronal hypertrophy, when compared with vehicle infusion or noninfused rat brain.	5	21	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGF receptor	NGF receptor	NGF receptor	7	8	19	21
Administration of NGF induced a short lasting hypertrophy of low affinity NGF receptor immunoreactive neurons within the nucleus basalis magnocellularis ( NBM ) , the horizontal limb of the diagonal band of Broca , and the medial septum .	Administration of NGF induced a short lasting hypertrophy of low affinity NGF receptor immunoreactive neurons within the nucleus basalis magnocellularis (NBM), the horizontal limb of the diagonal band of Broca, and the medial septum.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGF receptor	NGF receptor	NGF receptor	2	3	11	13
In cultures of high plating density , NGF increased the number of NGF-R and ChAT positive neurons without affecting the number of AChE positive neurons in these cultures .	In cultures of high plating density, NGF increased the number of NGF-R and ChAT positive neurons without affecting the number of AChE positive neurons in these cultures.	7	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGF-R	NGF-R	NGF-R	7	8	12	13
Low-affinity nerve growth factor receptor ( p75 NGFR ) , if demonstrated in the urothelium , could provide the means for ( 1 ) NGF mediated modulation of the urothelial response to inflammation ; ( 2 ) NGF mediated autocrine and paracrine regulation of urothelial proliferation ; and ( 3 ) p75 NGFR mediated induction of apoptosis .	Low-affinity nerve growth factor receptor (p75 NGFR), if demonstrated in the urothelium, could provide the means for (1) NGF mediated modulation of the urothelial response to inflammation; (2) NGF mediated autocrine and paracrine regulation of urothelial proliferation; and (3) p75 NGFR mediated induction of apoptosis.	37	53	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	p75 NGFR	p75 NGFR	p75 NGFR	37	38	51	53
We have found that ( 1 ) the NGF receptor molecules were localized to the cell surface of Schwann cells forming bands of Bungner ; ( 2 ) axonal regeneration into the distal portion of sciatic nerve coincided temporally and spatially with a decrease in Schwann cell expression of NGF receptor ; ( 3 ) Schwann cell NGF receptor could be induced by axotomy of NGF independent neurons , such as motoneurons and parasympathetic neurons ; and ( 4 ) the presence of axon-Schwann cell contact was inversely related to expression of Schwann cell NGF receptor .	We have found that (1) the NGF receptor molecules were localized to the cell surface of Schwann cells forming bands of Bungner; (2) axonal regeneration into the distal portion of sciatic nerve coincided temporally and spatially with a decrease in Schwann cell expression of NGF receptor; (3) Schwann cell NGF receptor could be induced by axotomy of NGF independent neurons, such as motoneurons and parasympathetic neurons; and (4) the presence of axon-Schwann cell contact was inversely related to expression of Schwann cell NGF receptor.	57	67	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGF receptor	NGF receptor	NGF receptor	65	66	57	59
In contrast to developing neurons , systemic NGF did not increase NGF receptor mRNA in nonneuronal cells of the sciatic nerve .	In contrast to developing neurons, systemic NGF did not increase NGF receptor mRNA in nonneuronal cells of the sciatic nerve.	6	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGF receptor	NGF receptor	NGF receptor	7	8	11	13
Binding of NGF enhanced lateral diffusion of NGFr in A875 cells and in PC12 cells in suspension but did not alter lateral diffusion of NGFr in COS cells or in adherent PC12 cells .	Binding of NGF enhanced lateral diffusion of NGFr in A875 cells and in PC12 cells in suspension but did not alter lateral diffusion of NGFr in COS cells or in adherent PC12 cells.	0	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGFr	NGFr	NGFr	2	3	7	8
Recent publications suggest a ligand independent activation and also a non NGF ligand activation of NGFR signaling XREF_BIBR - XREF_BIBR .	Recent publications suggest a ligand independent activation and also a non NGF ligand activation of NGFR signaling XREF_BIBR - XREF_BIBR.	11	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	NGFR	NGFR	NGFR	11	12	15	16
Treatment of PC12 cells with buthionine sulfoximine ( BSO ) reduced the levels of GSH , a major cellular reductant , and enhanced NGF induced neuronal differentiation , activation of AP-1 and the NGF receptor tyrosine kinase , TrkA .	Treatment of PC12 cells with buthionine sulfoximine (BSO) reduced the levels of GSH, a major cellular reductant, and enhanced NGF induced neuronal differentiation, activation of AP-1 and the NGF receptor tyrosine kinase, TrkA.	23	36	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGF receptor	NGF receptor	NGF receptor	23	24	33	35
More importantly , administration of dexamethasone appears to block the NGF mediated induction of NGFR when both agents are administered simultaneously .	More importantly, administration of dexamethasone appears to block the NGF mediated induction of NGFR when both agents are administered simultaneously.	8	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	NGFR	NGFR	NGFR	10	11	14	15
Here the addition of Notch1 but not Zmiz1 significantly increased binding of ICN1 or Rbpj ( XREF_SUPPLEMENTARY ) .	Here the addition of Notch1 but not Zmiz1 significantly increased binding of ICN1 or Rbpj (XREF_SUPPLEMENTARY).	2	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Notch1	Notch1	Notch1	Rbpj	Rbpj	Rbpj	4	5	14	15
The data presented in XREF_SUPPLEMENTARY demonstrates that the inhibition of Notch1 signaling significantly blocks the CSL and RBP-Jk dependent activation of Notch target gene , Hes1 gene transcription .	The data presented in XREF_SUPPLEMENTARY demonstrates that the inhibition of Notch1 signaling significantly blocks the CSL and RBP-Jk dependent activation of Notch target gene, Hes1 gene transcription.	10	19	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Notch1	Notch1	Notch1	RBP-Jk	RBP-Jk	RBP-Jk	10	11	17	18
Additionally , Notch-1 may activate through binding to CBF-1 another member of the bHLH proteins , the HESI that plays a critical role in the expansion of early T cell precursors 16 .	Additionally, Notch-1 may activate through binding to CBF-1 another member of the bHLH proteins, the HESI that plays a critical role in the expansion of early T cell precursors 16.	2	9	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Notch-1	Notch-1	Notch-1	CBF-1	CBF-1	CBF-1	2	3	8	9
Meanwhile , Notch1 knockdown decreases the binding of CBF-1 on minimal promoter of PTEN .	Meanwhile, Notch1 knockdown decreases the binding of CBF-1 on minimal promoter of PTEN.	2	9	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Notch1	Notch1	Notch1	CBF-1	CBF-1	CBF-1	2	3	8	9
As expected , the 4xwtCBF1Luc vector activity , dependent on RBPJkappa activation by NICD , showed a 6-fold increase in luciferase activity ( XREF_FIG A ) .	As expected, the 4xwtCBF1Luc vector activity, dependent on RBPJkappa activation by NICD, showed a 6-fold increase in luciferase activity (XREF_FIG A).	10	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NICD	NICD	NICD	RBPJkappa	RBPJkappa	RBPJkappa	13	14	10	11
When Notch interacts with membrane bound ligands Delta or Jagged on the surface of neighboring cells , the Notch intracellular domain ( NICD ) is proteolytically cleaved from the membrane by gamma-secretase ( XREF_FIG ) and translocates to the nucleus to complex with and activate the transcription factor CSL ( CBF1 in humans , Suppressor of Hairless in Drosophila , LAG in Caenorhabditis elegans ; also called RBP-Jkappa in mice ) .	When Notch interacts with membrane bound ligands Delta or Jagged on the surface of neighboring cells, the Notch intracellular domain (NICD) is proteolytically cleaved from the membrane by gamma-secretase (XREF_FIG) and translocates to the nucleus to complex with and activate the transcription factor CSL (CBF1 in humans, Suppressor of Hairless in Drosophila, LAG in Caenorhabditis elegans; also called RBP-Jkappa in mice).	20	66	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NICD	NICD	NICD	CBF1	CBF1	CBF1	22	23	50	51
Notch1 cytoplasmic-domain constructs transfected into cortical neurons were present in multiple phosphorylated forms , localized to the nucleus and could induce CBF1 mediated transactivation .	Notch1 cytoplasmic-domain constructs transfected into cortical neurons were present in multiple phosphorylated forms, localized to the nucleus and could induce CBF1 mediated transactivation.	0	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Notch1	Notch1	Notch1	CBF1	CBF1	CBF1	0	1	21	22
Analysis of lifespan , WBC counts , and serum TSLP levels reveal that Notch VG ; RBPj msx2LOF animals were similar to the RBPj msx2LOF animals ( XREF_FIG ) , indicating that the RBPj msx2LOF phenotype is driven by N1ICD ( or N2ICD in Msx2-Cre +/tg ; Notch1 f/f ; Notch2 +/f ; Rbpj f/f mice , data not shown ) .	Analysis of lifespan, WBC counts, and serum TSLP levels reveal that Notch VG; RBPj msx2LOF animals were similar to the RBPj msx2LOF animals (XREF_FIG), indicating that the RBPj msx2LOF phenotype is driven by N1ICD (or N2ICD in Msx2-Cre +/tg; Notch1 f/f; Notch2 +/f; Rbpj f/f mice, data not shown).	33	48	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Notch1	Notch1	Notch1	RBPj	RBPj	RBPj	47	48	33	34
In this study , by the use of reporter gene assays , we demonstrate that C-promoter binding factor-1 ( CBF-1 )-dependent gene transcription driven by the Notch-1 intracellular domain ( N1 ( ICD ) ) is potently antagonized by exogenously expressed transactivating ( TA ) p73 splice variants in SH-SY5Y neuroblastomas and in primary neurones .	In this study, by the use of reporter gene assays, we demonstrate that C-promoter binding factor-1 (CBF-1)-dependent gene transcription driven by the Notch-1 intracellular domain (N1 (ICD)) is potently antagonized by exogenously expressed transactivating (TA) p73 splice variants in SH-SY5Y neuroblastomas and in primary neurones.	17	28	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Notch-1	Notch-1	Notch-1	CBF-1	CBF-1	CBF-1	26	27	19	20
Positive feedback loops with nonlinearity can yield bistability XREF_BIBR , and both Notch1 autoregulation and NICD mediated conversion of RBP-Jkappa into a transcriptional activator that in turn upregulates Notch1 expression constitute positive feedback loops that can drive this behavior .	Positive feedback loops with nonlinearity can yield bistability XREF_BIBR, and both Notch1 autoregulation and NICD mediated conversion of RBP-Jkappa into a transcriptional activator that in turn upregulates Notch1 expression constitute positive feedback loops that can drive this behavior.	12	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Notch1	Notch1	Notch1	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	12	13	19	20
Instead , ESCO2 binds directly to the Notch Intracellular Domain ( NICD ) , a domain released upon receptor activation and cleavage , and prevents NICD activation of the transcription regulator CBF1 involved in neural progenitor cell proliferation and differentiation .	Instead, ESCO2 binds directly to the Notch Intracellular Domain (NICD), a domain released upon receptor activation and cleavage, and prevents NICD activation of the transcription regulator CBF1 involved in neural progenitor cell proliferation and differentiation.	25	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NICD	NICD	NICD	CBF1	CBF1	CBF1	25	26	31	32
Notably , our assay quantitatively measures the amount of NICD protein released from the membrane and therefore directly measures gamma-secretase activity for Notch1 cleavage , while Gillman et al 5 used a reporter based assay that relies on NICD mediated activation of CBF1 , a Notch target gene .	Notably, our assay quantitatively measures the amount of NICD protein released from the membrane and therefore directly measures gamma-secretase activity for Notch1 cleavage, while Gillman et al 5 used a reporter based assay that relies on NICD mediated activation of CBF1, a Notch target gene.	36	47	mediated	Positive_early_activation	Positive_activation	Positive_activation	NICD	NICD	NICD	CBF1	CBF1	CBF1	38	39	42	43
The canonical Notch pathway involves proteolytic liberation of the Notch-1 intracellular domain ( NIC-1 ) , which activates CSL ( CBF1 , Su ( H ) , and Lag-1 )-mediated transactivation .	The canonical Notch pathway involves proteolytic liberation of the Notch-1 intracellular domain (NIC-1), which activates CSL (CBF1, Su (H), and Lag-1)-mediated transactivation.	9	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Notch-1	Notch-1	Notch-1	CBF1	CBF1	CBF1	9	10	20	21
These experiments suggest that TDP-A activates the Notch pathway first by increasing the transcription of Notch receptors , followed by cleaving of the receptors by gamma-secretase and forming NICD which activates CBF1 , and finally leading to the activation of its downstream target genes .	These experiments suggest that TDP-A activates the Notch pathway first by increasing the transcription of Notch receptors, followed by cleaving of the receptors by gamma-secretase and forming NICD which activates CBF1, and finally leading to the activation of its downstream target genes.	27	32	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	NICD	NICD	NICD	CBF1	CBF1	CBF1	28	29	31	32
After phosphorylation , p100 is processed to selectively activate a RelB : p52 heterodimer in response to specific inducers .	After phosphorylation, p100 is processed to selectively activate a RelB : p52 heterodimer in response to specific inducers.	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p100	p100	p100	RelB	RelB	RelB	3	4	10	11
A lack of p100 promotes RelB : p50 and NFkappaB activation upon TNF stimulation .	A lack of p100 promotes RelB : p50 and NFkappaB activation upon TNF stimulation.	1	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p100	p100	p100	RelB	RelB	RelB	3	4	5	6
IAP antagonists increase osteoclast activity by stabilizing NIK , causing pro osteoclastogenic RelB and p52 mediated transcription .	IAP antagonists increase osteoclast activity by stabilizing NIK, causing pro osteoclastogenic RelB and p52 mediated transcription.	9	17	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p52	p52 mediated transcription	p52	RelB	RelB	relb	14	15	12	13
To this end , we compared global gene-expressions ( Materials and Methods ) in TNF treated MEFs of the following genotypes , namely WT fibroblasts , which primarily elicits RelA : p50 activity , Rela -/- Nfkb2 -/- cells , which exclusively activate RelB : p50 , and control NFkappaB deficient Rela -/- Relb -/- Rel -/- cells , which lack the expression of all three transcription activating NFkappaB subunits RelA , RelB and cRel .	To this end, we compared global gene-expressions (Materials and Methods) in TNF treated MEFs of the following genotypes, namely WT fibroblasts, which primarily elicits RelA : p50 activity, Rela -/- Nfkb2 -/- cells, which exclusively activate RelB : p50, and control NFkappaB deficient Rela -/- Relb -/- Rel -/- cells, which lack the expression of all three transcription activating NFkappaB subunits RelA, RelB and cRel.	32	44	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nfkb2	Nfkb2	Nfkb2	RelB	RelB	RelB	36	37	43	44
In the alternative NF-kappaB pathway , IKKalpha activation leads to the phosphorylation of p100 and its resultant processing to the active p52 form , and allows nuclear entry of the RelB and p52 heterodimer [ XREF_BIBR , XREF_BIBR ] .	In the alternative NF-kappaB pathway, IKKalpha activation leads to the phosphorylation of p100 and its resultant processing to the active p52 form, and allows nuclear entry of the RelB and p52 heterodimer [XREF_BIBR, XREF_BIBR].	6	34	allows	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	p100	IKKalpha activation leads to the phosphorylation of p100	p100	RelB	RelB and p52 heterodimer	relb	13	14	30	31
In addition to modulating RelA activity through crosstalk , Nfkb2 also mediates RelB : p52 activation in response to singular non canonical stimuli .	In addition to modulating RelA activity through crosstalk, Nfkb2 also mediates RelB : p52 activation in response to singular non canonical stimuli.	9	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nfkb2	Nfkb2	Nfkb2	RelB	RelB	RelB	9	10	12	13
RelB is sequestered in the cytosol by the inhibitory NF-kappaB protein p100 .	RelB is sequestered in the cytosol by the inhibitory NF-kappaB protein p100.	0	12	sequestered	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	p100	p100	p100	RelB	RelB	RelB	11	12	0	1
In the non canonical pathway , phosphorylation of p100 by IKKalpha triggers nuclear translocation of the RelB and p52 transcription factors for regulating gene expression .	In the non canonical pathway, phosphorylation of p100 by IKKalpha triggers nuclear translocation of the RelB and p52 transcription factors for regulating gene expression.	6	20	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p100	phosphorylation of p100	p100	RelB	RelB	relb	8	9	16	17
This is probably because the Nfkb2 gene deletion does not block the activation of RELB , which may form a dimer with p50 to partially compensate the function of RELB and p52 dimer , as mice deficient in both Nfkb1 and Nfkb2 have more severe defects in lymphoid organ development 83 .	This is probably because the Nfkb2 gene deletion does not block the activation of RELB, which may form a dimer with p50 to partially compensate the function of RELB and p52 dimer, as mice deficient in both Nfkb1 and Nfkb2 have more severe defects in lymphoid organ development 83.	5	23	block	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Nfkb2	Nfkb2	nfkb2	RELB	RELB, which may form a dimer with p50	relb	5	6	14	15
These studies also raised a mechanistic conundrum as activating mutations in the non canonical NFkappaB module do not appear to act through RelB : p52 ; rather they promote perpetuating RelB : p50 and NFkappaB response to canonical TNF signal .	These studies also raised a mechanistic conundrum as activating mutations in the non canonical NFkappaB module do not appear to act through RelB : p52; rather they promote perpetuating RelB : p50 and NFkappaB response to canonical TNF signal.	24	35	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p52	p52	p52	RelB	RelB	RelB	24	25	30	31
In the non canonical pathway , the RelB and p100 dimer is activated by IKKalpha dependent phosphorylation of p100 at a cluster of serine residues C-terminal to the ANK repeats 19 .	In the non canonical pathway, the RelB and p100 dimer is activated by IKKalpha dependent phosphorylation of p100 at a cluster of serine residues C-terminal to the ANK repeats 19.	7	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p100	phosphorylation of p100	p100	RelB	RelB	relb	18	19	7	8
In the noncanonical NF-kappaB pathway , RelB is activated by IKKalpha dependent processing of the inhibitory NFkappaB2 and p100 protein to p52 , resulting in transcriptionally active RelB and p52 heterodimers XREF_BIBR .	In the noncanonical NF-kappaB pathway, RelB is activated by IKKalpha dependent processing of the inhibitory NFkappaB2 and p100 protein to p52, resulting in transcriptionally active RelB and p52 heterodimers XREF_BIBR.	6	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p100	p100	p100	RelB	RelB	RelB	18	19	6	7
XREF_SUPPLEMENTARY , overexpressing RelA , RelB , c-Rel , or CUL4B can result in p21 down-regulation but not p50 or p52 overexpression .	XREF_SUPPLEMENTARY, overexpressing RelA, RelB, c-Rel, or CUL4B can result in p21 down-regulation but not p50 or p52 overexpression.	2	22	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p52	p52 overexpression	p52	RelB	RelB	relb	20	21	5	6
In an interdisciplinary approach , we identify that depletion of p100 , owing aberrations in the non canonical module , triggers an autoregulatory RelB pathway , which perpetuates an alternate RelB : p50 NF-kappaB activity in response to TNF .	In an interdisciplinary approach, we identify that depletion of p100, owing aberrations in the non canonical module, triggers an autoregulatory RelB pathway, which perpetuates an alternate RelB : p50 NF-kappaB activity in response to TNF.	8	24	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	10	11	23	24
Absence of p100 in mutant cells additionally triggered a late acting RelB : p50 and NFkappaB response , which was contingent upon autoregulatory Relb synthesis ( XREF_FIG - XREF_FIG ; and XREF_FIG ) .	Absence of p100 in mutant cells additionally triggered a late acting RelB : p50 and NFkappaB response, which was contingent upon autoregulatory Relb synthesis (XREF_FIG - XREF_FIG; and XREF_FIG).	0	16	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p100	p100	p100	RelB	RelB	RelB	2	3	11	12
Similarly , Lipopolysacharide ( LPS ) and CD40L are reported to activate NF inducing kinase ( NIK ) to initiate noncanonical pathway by involving IKKalpha and beta , p100 , RelB complex and phosphorylated p100 activate RelB and p52 which translocate to nucleous and interact with target kappaB element and regulate transcription .	Similarly, Lipopolysacharide (LPS) and CD40L are reported to activate NF inducing kinase (NIK) to initiate noncanonical pathway by involving IKKalpha and beta, p100, RelB complex and phosphorylated p100 activate RelB and p52 which translocate to nucleous and interact with target kappaB element and regulate transcription.	33	44	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p100	phosphorylated p100	p100	RelB	RelB	relb	34	35	36	37
p100 phosphorylation leads to its cleavage into p52 , producing an active RelB and p52 dimer that moves to the nucleus and regulates transcription ( XREF_FIG ) [ XREF_BIBR ] .	p100 phosphorylation leads to its cleavage into p52, producing an active RelB and p52 dimer that moves to the nucleus and regulates transcription (XREF_FIG) [XREF_BIBR].	0	24	leads	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	p100	p100 phosphorylation	p100	RelB	RelB and p52 dimer that moves to the nucleus and regulates transcription	relb	0	1	12	13
Both NF- B p50 and NF- B p65 , which compose the predominant heterodimer form of NF- B in the brain are involved in G-1-induced GLT-1 regulation , supported by the observation that G-1 induced the binding of these two subunits ( p50 and p65 ) to the cis-element of GLT-1 promoter and activated the NF- B luciferase reporter .	Both NF- B p50 and NF- B p65, which compose the predominant heterodimer form of NF- B in the brain are involved in G-1-induced GLT-1 regulation, supported by the observation that G-1 induced the binding of these two subunits (p50 and p65) to the cis-element of GLT-1 promoter and activated the NF- B luciferase reporter.	0	45	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p50	p50	p50	p65	p65	p65	3	4	44	45
In related experiments , FBW7 ablation abrogated loss of p105 , p100 and p65 expression in cycloheximide treated LNCaP cells ( XREF_FIG ) , and blocked the turnover of p65 after 24h of 1,25 D treatment in LNCaP cells ( XREF_SUPPLEMENTARY ) .	In related experiments, FBW7 ablation abrogated loss of p105, p100 and p65 expression in cycloheximide treated LNCaP cells (XREF_FIG), and blocked the turnover of p65 after 24h of 1,25 D treatment in LNCaP cells (XREF_SUPPLEMENTARY).	4	30	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p105	FBW7 ablation abrogated loss of p105, p100 and p65 expression	p105	p65	p65	p65	9	10	29	30
The ability of both antibodies to block OFQ/N induced increase in the NFkappaB and DNA binding complex indicates that OFQ/N induces binding of both p50 and the transcription activating p65 subunit to DNA ( XREF_FIG ) .	The ability of both antibodies to block OFQ/N induced increase in the NFkappaB and DNA binding complex indicates that OFQ/N induces binding of both p50 and the transcription activating p65 subunit to DNA (XREF_FIG).	21	30	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p50	p50	p50	p65	p65	p65	24	25	29	30
XREF_BIBR The NFkappaB family of transcription factors which is composed of five members , p65 ( REL-A ) , REL-B , cytoplasmic ( c ) REL , p50 ; p105 ( NFkappaB1 ) and p52 ; p100 ( NFkappaB2 ) , is widely activated under cytokines and/or microbial challenge .	XREF_BIBR The NFkappaB family of transcription factors which is composed of five members, p65 (REL-A), REL-B, cytoplasmic (c) REL, p50; p105 (NFkappaB1) and p52; p100 (NFkappaB2), is widely activated under cytokines and/or microbial challenge.	3	44	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p50	p50	p50	p65	p65	p65	27	28	14	15
Hence , in this system , repressive p50 homodimers may outweigh activating p65 containing dimers , while partial p50 depletion alleviates repression and promotes transcription by favoring p65 containing dimers .	Hence, in this system, repressive p50 homodimers may outweigh activating p65 containing dimers, while partial p50 depletion alleviates repression and promotes transcription by favoring p65 containing dimers.	18	28	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p50	p50	p50	p65	p65	p65	18	19	27	28
Metformin moderately reduced p50 levels compared with control cells but significantly reduced the stimulation of both p50 and p65 by succinate ( XREF_FIG ) .	Metformin moderately reduced p50 levels compared with control cells but significantly reduced the stimulation of both p50 and p65 by succinate (XREF_FIG).	0	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p50	Metformin moderately reduced p50 levels	p50	p65	p65	p65	3	4	18	19
The canonical pathway of NF-kappaB activation involves the engagement of the IkappaB kinase ( IKK ) complex , p50 and p65 dimers are released from the binding inhibitor IkappaBalpha , allowing p50 and p65 to translocate to the nucleus while the phosphorylated IkappaBalpha is ubiquitinated and targeted to the proteasome for degradation .	The canonical pathway of NF-kappaB activation involves the engagement of the IkappaB kinase (IKK) complex, p50 and p65 dimers are released from the binding inhibitor IkappaBalpha, allowing p50 and p65 to translocate to the nucleus while the phosphorylated IkappaBalpha is ubiquitinated and targeted to the proteasome for degradation.	16	35	allowing	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p50	p50	p50	p65	p65	p65	18	19	33	34
Expression of NF-kappaB proteins p105 and c-Rel increased in the cytoplasm upon stimulation and the activated subunits p50 , p65 and c-Rel translocated to the nucleus ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Expression of NF-kappaB proteins p105 and c-Rel increased in the cytoplasm upon stimulation and the activated subunits p50, p65 and c-Rel translocated to the nucleus (XREF_FIG and XREF_SUPPLEMENTARY).	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p105	Expression of NF-kappaB proteins p105	p105	p65	p65	p65	4	5	19	20
The importance of such experimental rigor is further highlighted by the recent findings of XREF_BIBR who demonstrate the non specificity of many commonly used commercial antibodies targeting the NF-kappaB subunit proteins p65 and p50 .	The importance of such experimental rigor is further highlighted by the recent findings of XREF_BIBR who demonstrate the non specificity of many commonly used commercial antibodies targeting the NF-kappaB subunit proteins p65 and p50.	19	34	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p50	p50	p50	p65	p65	p65	33	34	31	32
This allows the histidine kinase nucleoside diphosphate kinase B ( NDPK-B , also known as nm23H2 ) to activate KCa3.1 by phosphorylating histidine 358 in the C-terminus of KCa3.1 XREF_BIBR , XREF_BIBR .	This allows the histidine kinase nucleoside diphosphate kinase B (NDPK-B, also known as nm23H2) to activate KCa3.1 by phosphorylating histidine 358 in the C-terminus of KCa3.1 XREF_BIBR, XREF_BIBR.	15	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	nm23H2	nm23H2	nm23H2	KCa3.1	KCa3.1	KCa3.1	15	16	19	20
These results indicate that NDPK activation of Nm23-H1 by NMac1 treatments is crucial for suppression of invasion and migration of breast cancer cells .	These results indicate that NDPK activation of Nm23-H1 by NMac1 treatments is crucial for suppression of invasion and migration of breast cancer cells.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NMac1	NMac1	NMac1	Nm23-H1	Nm23-H1	Nm23-H1	9	10	7	8
H-89 , PP1 , U0126 and Stattic pre-treatment significantly inhibited the forskolin induced Nm23 protein expression , suggesting the possible involvement of c-Src , ERK and STAT3 in cAMP induced upregulation of Nm23 , respectively .	H-89, PP1, U0126 and Stattic pre-treatment significantly inhibited the forskolin induced Nm23 protein expression, suggesting the possible involvement of c-Src, ERK and STAT3 in cAMP induced upregulation of Nm23, respectively.	0	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nm23	H-89, PP1, U0126 and Stattic pre-treatment significantly inhibited the forskolin induced Nm23 protein expression	nm23	Nm23	Nm23	nm23	13	14	32	33
Phosphorylation of Nm23-H1 induces phosphor-Nm23-H1 to make complex with H-prune and promotes cell motility [ XREF_BIBR ] .	Phosphorylation of Nm23-H1 induces phosphor-Nm23-H1 to make complex with H-prune and promotes cell motility [XREF_BIBR].	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nm23-H1	Phosphorylation of Nm23-H1	nm23-h1	phosphor-Nm23-H1	phosphor-Nm23-H1	phosphor-nm23-h1	2	3	4	5
Phosphorylation of nm23-H1 by CK1delta and epsilon has been shown to induce complex formation of nm23-H1 with a cellular partner called h-prune .	Phosphorylation of nm23-H1 by CK1delta and epsilon has been shown to induce complex formation of nm23-H1 with a cellular partner called h-prune.	0	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	nm23-H1	Phosphorylation of nm23-H1	nm23-h1	nm23-H1	nm23-H1	nm23-h1	2	3	15	16
By immunohistochemistry , Nm23-H1 expression of metastatic lymph nodes was significantly lower than that of their primary oral cancers , supporting a role of Nm23-H1 in metastasis suppression .	By immunohistochemistry, Nm23-H1 expression of metastatic lymph nodes was significantly lower than that of their primary oral cancers, supporting a role of Nm23-H1 in metastasis suppression.	3	27	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nm23-H1	Nm23-H1 expression	nm23-h1	Nm23-H1	Nm23-H1	nm23-h1	3	4	24	25
Impact of NM23-H1 expression on repair of UVR induced DNA damage was measured initially in the NM23 deficient , VGP derived melanoma cell line WM793 .	Impact of NM23-H1 expression on repair of UVR induced DNA damage was measured initially in the NM23 deficient, VGP derived melanoma cell line WM793.	2	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NM23-H1	NM23-H1 expression	nm23-h1	NM23	NM23	nm23	2	3	16	17
These results suggest that NMac1 activates the NDPK activity of hexameric form of both Nm23-H1 and -H2 via increasing the substrate affinity with allosteric mechanism .	These results suggest that NMac1 activates the NDPK activity of hexameric form of both Nm23-H1 and -H2 via increasing the substrate affinity with allosteric mechanism.	4	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NMac1	NMac1	NMac1	Nm23-H1	Nm23-H1	Nm23-H1	4	5	14	15
XREF_FIG , NMac1 activates NDPK activity of only hexameric Nm23-H1 , but not dimeric one .	XREF_FIG, NMac1 activates NDPK activity of only hexameric Nm23-H1, but not dimeric one.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NMac1	NMac1	NMac1	Nm23-H1	Nm23-H1	Nm23-H1	2	3	9	10
To test whether NOS is expressed in primary breast tumors and whether its expression is associated with the presence of metastasis , we analyzed the expression of the inducible NOS in 22 primary breast tumors , and to investigate its association to other gene products related to the metastatic ability of tumor cells , we correlated the expression of the inducible NOS with the expression of the nm23 protein ( the product of the putative antimetastatic gene nm23 ) .	To test whether NOS is expressed in primary breast tumors and whether its expression is associated with the presence of metastasis, we analyzed the expression of the inducible NOS in 22 primary breast tumors, and to investigate its association to other gene products related to the metastatic ability of tumor cells, we correlated the expression of the inducible NOS with the expression of the nm23 protein (the product of the putative antimetastatic gene nm23).	64	78	product	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	nm23	expression of the nm23	nm23	nm23	nm23	nm23	67	68	77	78
We found that NMac1 activated NDPK activity of recombinant Nm23-H1 in a dose dependent manner , EC 50 was 10.7 microM and percentage maximum activation was 405 % assessed by curve fitting .	We found that NMac1 activated NDPK activity of recombinant Nm23-H1 in a dose dependent manner, EC 50 was 10.7 microM and percentage maximum activation was 405% assessed by curve fitting.	3	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NMac1	NMac1	NMac1	Nm23-H1	Nm23-H1	Nm23-H1	3	4	9	10
To determine whether NMac1 activates dimeric or hexameric form of Nm23-H1 , we examined the NDPK activation of identical amounts of each form purified by size exclusion chromatography , in response to NMac1 .	To determine whether NMac1 activates dimeric or hexameric form of Nm23-H1, we examined the NDPK activation of identical amounts of each form purified by size exclusion chromatography, in response to NMac1.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NMac1	NMac1	NMac1	Nm23-H1	Nm23-H1	Nm23-H1	3	4	10	11
Activation of NOD2 caused by these invading microbes appears to direct ATG16L1 to the plasma membrane adjacent to the point of bacterial entry in order to coordinate the clearance of the organism .	Activation of NOD2 caused by these invading microbes appears to direct ATG16L1 to the plasma membrane adjacent to the point of bacterial entry in order to coordinate the clearance of the organism.	0	12	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	ATG16L1	ATG16L1	ATG16L1	2	3	11	12
MDP activation of Nod2 induces Atg16L1 dependent autophagy , but not in cells expressing the disease variants of either of these susceptibility genes [ XREF_BIBR - XREF_BIBR ] .	MDP activation of Nod2 induces Atg16L1 dependent autophagy, but not in cells expressing the disease variants of either of these susceptibility genes [XREF_BIBR - XREF_BIBR].	1	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nod2	Nod2	Nod2	Atg16L1	Atg16L1	Atg16L1	3	4	5	6
In summary , the intersection of NOD2 with autophagy presents a multi pronged approach in the defense against intracellular bacteria by : 1 ) guiding ATG16L1 to the bacterial entry site to initiate autophagy , 2 ) through presentation of MHC class II antigens to T cells and shaping adaptive immune responses , and 3 ) by contributing to the activation of pro inflammatory signaling mediated by NOD2 .	In summary, the intersection of NOD2 with autophagy presents a multi pronged approach in the defense against intracellular bacteria by : 1) guiding ATG16L1 to the bacterial entry site to initiate autophagy, 2) through presentation of MHC class II antigens to T cells and shaping adaptive immune responses, and 3) by contributing to the activation of pro inflammatory signaling mediated by NOD2.	9	68	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	ATG16L1	ATG16L1	ATG16L1	67	68	25	26
Activation of NOD1 and NOD2 in the cytoplasm directs the autophagy machinery by recruiting ATG16L1 to the site of bacterial entry , although this interaction was not affected in cells with homozygous expression of the T300A variant .	Activation of NOD1 and NOD2 in the cytoplasm directs the autophagy machinery by recruiting ATG16L1 to the site of bacterial entry, although this interaction was not affected in cells with homozygous expression of the T300A variant.	0	15	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	ATG16L1	ATG16L1	ATG16L1	4	5	14	15
ATG16L1 localises to the cell membrane and this is increased at the sites of entry of Shigella by a NOD2 dependent mechanism .	ATG16L1 localises to the cell membrane and this is increased at the sites of entry of Shigella by a NOD2 dependent mechanism.	0	21	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	ATG16L1	ATG16L1	ATG16L1	19	20	0	1
Susceptibility genes for Crohn ' s disease include NOD2 , which mediates the cytosolic response to peptidoglycan fragments , IRGM , the sole human member of a large family of anti-microbial GTPases , and ATG16L1 , a core autophagy gene .	Susceptibility genes for Crohn 's disease include NOD2, which mediates the cytosolic response to peptidoglycan fragments, IRGM, the sole human member of a large family of anti-microbial GTPases, and ATG16L1, a core autophagy gene.	7	39	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NOD2	NOD2	NOD2	ATG16L1	ATG16L1	ATG16L1	8	9	34	35
For example , MST1/2 can be targeted to the plasma membrane by SAV1 , whereas NF2 promotes the plasma membrane association of LATS1 .	For example, MST1/2 can be targeted to the plasma membrane by SAV1, whereas NF2 promotes the plasma membrane association of LATS1.	15	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NF2	NF2	NF2	LATS1	LATS1	LATS1	15	16	22	23
Likewise , co-expression of NF2 and Sav promoted membrane translocation of Lats1 and Mst1 in HEK293 cells ( XREF_SUPPLEMENTARY ) .	Likewise, co-expression of NF2 and Sav promoted membrane translocation of Lats1 and Mst1 in HEK293 cells (XREF_SUPPLEMENTARY).	2	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NF2	co-expression of NF2	nf2	Lats1	Lats1	lats1	4	5	11	12
For example , MST1/2 can be targetted to the plasma membrane by SAV1 , whereas NF2 promotes the plasma membrane association of LATS1 [ XREF_BIBR ] .	For example, MST1/2 can be targetted to the plasma membrane by SAV1, whereas NF2 promotes the plasma membrane association of LATS1 [XREF_BIBR].	15	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NF2	NF2	NF2	LATS1	LATS1	LATS1	15	16	22	23
Similar observations were made in mammalian cells , as Sav1 promoted membrane association of Mst1 but not Lats1 , and conversely , NF2 promoted membrane association of Lats1 but not Mst1 ( XREF_SUPPLEMENTARY ) .	Similar observations were made in mammalian cells, as Sav1 promoted membrane association of Mst1 but not Lats1, and conversely, NF2 promoted membrane association of Lats1 but not Mst1 (XREF_SUPPLEMENTARY).	22	28	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NF2	NF2	NF2	Lats1	Lats1	Lats1	22	23	27	28
When merlin was removed from ewg mutants , almost all R8s expressed Rh5 ( XREF_FIG ) suggesting that merlin is required to activate the Hippo pathway and Warts to induce yR8 fate in ewg mutants .	When merlin was removed from ewg mutants, almost all R8s expressed Rh5 (XREF_FIG) suggesting that merlin is required to activate the Hippo pathway and Warts to induce yR8 fate in ewg mutants.	18	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	merlin	merlin	merlin	Warts	Warts	Warts	18	19	27	28
It has been reported that Nodal promotes the tumorigenicity and plasticity of metastatic melanoma in part by activating ALK4 receptor associated with crypto-1 and knockdown of Nodal stimulated tumor differentiation and regression .	It has been reported that Nodal promotes the tumorigenicity and plasticity of metastatic melanoma in part by activating ALK4 receptor associated with crypto-1 and knockdown of Nodal stimulated tumor differentiation and regression.	5	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nodal	Nodal	Nodal	ALK4	ALK4	ALK4	5	6	18	19
Nodal activates ActRIB and ALK -4 and ALK-7 .	Nodal activates ActRIB and ALK -4 and ALK-7.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nodal	Nodal	Nodal	ActRIB	ActRIB	ActRIB	0	1	2	3
In the course of investigating whether knockdown of Balpha would inhibit Activin and Nodal induced ALK4 clustering , we noticed that levels of HA-ALK4 were extremely low when Balpha was depleted ( XREF_FIG ) .	In the course of investigating whether knockdown of Balpha would inhibit Activin and Nodal induced ALK4 clustering, we noticed that levels of HA-ALK4 were extremely low when Balpha was depleted (XREF_FIG).	10	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Nodal	Nodal	Nodal	ALK4	ALK4	ALK4	13	14	15	16
Among the ligands , TGF-beta activates ALK5 , Activin activates ALK4 , Nodal activates ALK4 and ALK7 and BMPs activate ALK1 , ALK2 , ALK3 and ALK6 [ XREF_BIBR ] .	Among the ligands, TGF-beta activates ALK5, Activin activates ALK4, Nodal activates ALK4 and ALK7 and BMPs activate ALK1, ALK2, ALK3 and ALK6 [XREF_BIBR].	12	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nodal	Nodal	Nodal	ALK4	ALK4	ALK4	12	13	14	15
We also examined the endogenous P-Smad2/3 transcriptional response downstream of the Dox induced Alk4 * in TAG1 cells by examining with quantitative reverse transcription PCR ( RT-PCR ) the expression profile of the known target gene Nodal over time ( XREF_SUPPLEMENTARY ) .	We also examined the endogenous P-Smad2/3 transcriptional response downstream of the Dox induced Alk4 * in TAG1 cells by examining with quantitative reverse transcription PCR (RT-PCR) the expression profile of the known target gene Nodal over time (XREF_SUPPLEMENTARY).	12	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nodal	Nodal	Nodal	Alk4	Alk4	Alk4	36	37	13	14
Lastly , using microarray analyses and subsequent validation and functional assays , we show that merlin positively regulates the large tumor suppressor 2 ( Lats2 ) signaling pathway and down-regulates canonical and noncanonical Wnt signaling .	Lastly, using microarray analyses and subsequent validation and functional assays, we show that merlin positively regulates the large tumor suppressor 2 (Lats2) signaling pathway and down-regulates canonical and noncanonical Wnt signaling.	15	29	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Negative_activation	merlin	merlin	merlin	Lats2	Lats2	Lats2	15	16	24	25
Merlin activates Lats2 signaling pathway and inhibits canonical and noncanonical Wnt signaling .	Merlin activates Lats2 signaling pathway and inhibits canonical and noncanonical Wnt signaling.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Merlin	Merlin	Merlin	Lats2	Lats2	Lats2	0	1	2	3
Taken together , these results suggest that merlin activates Lats2 signaling and inhibits canonical and noncanonical Wnt signaling .	Taken together, these results suggest that merlin activates Lats2 signaling and inhibits canonical and noncanonical Wnt signaling.	7	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	merlin	merlin	merlin	Lats2	Lats2	Lats2	7	8	9	10
Based on our findings we hypothesize that NF2 and K-Ras and RASSF1A function to activate Mst1 in separate subcellular locations ( mitochondria vs. nucleus ) leading to engagement of different downstream effectors ( Bcl-xL vs. Lats2 and Yap ) .	Based on our findings we hypothesize that NF2 and K-Ras and RASSF1A function to activate Mst1 in separate subcellular locations (mitochondria vs. nucleus) leading to engagement of different downstream effectors (Bcl-xL vs. Lats2 and Yap).	7	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NF2	NF2	NF2	Lats2	Lats2	Lats2	7	8	35	36
We have shown recently that merlin activates the Lats2 signaling pathway in human glioblastoma cells , sensitizes the response of GBM cells to chemotherapeutic agents , and inhibits GBM growth in vivo and that merlin exerts its tumor suppressor function by inhibiting the hyaluronan-CD44 interaction .	We have shown recently that merlin activates the Lats2 signaling pathway in human glioblastoma cells, sensitizes the response of GBM cells to chemotherapeutic agents, and inhibits GBM growth in vivo and that merlin exerts its tumor suppressor function by inhibiting the hyaluronan-CD44 interaction.	5	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	merlin	merlin	merlin	Lats2	Lats2	Lats2	5	6	8	9
Nodal induces Alk7 signaling by direct binding , although at lower levels than in the presence of Cripto-1 [ XREF_BIBR ] .	Nodal induces Alk7 signaling by direct binding, although at lower levels than in the presence of Cripto-1 [XREF_BIBR].	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nodal	Nodal	Nodal	Alk7	Alk7	Alk7	0	1	2	3
Here , we show that Nodal activates ALK7 signaling and regulates beta-cell apoptosis .	Here, we show that Nodal activates ALK7 signaling and regulates beta-cell apoptosis.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nodal	Nodal	Nodal	ALK7	ALK7	ALK7	5	6	7	8
Increasing the NMB application to 2microM , NMB induced depolarization and action potential ( AP ) firing in most NMBR neurons .	Increasing the NMB application to 2microM, NMB induced depolarization and action potential (AP) firing in most NMBR neurons.	7	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NMB	NMB	NMB	NMBR	NMBR	NMBR	7	8	19	20
Overexpression of Nfil3 led to almost exclusive differentiation into NK cells ( XREF_FIG D ) , reinforcing the importance of Nfil3 for NK cell development .	Overexpression of Nfil3 led to almost exclusive differentiation into NK cells (XREF_FIG D), reinforcing the importance of Nfil3 for NK cell development.	0	21	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nfil3	Overexpression of Nfil3	nfil3	Nfil3	Nfil3	nfil3	2	3	20	21
Previous studies showed the dependence of NFIL-3 expression on new protein synthesis in IL-3-stimulated cells , however , IL-4 and IL-10 induced NFIL3 in the protein synthesis independent mechanism [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , supporting the possibility of late , Pim-1-independent transactivation of NFIL3 by Dex .	Previous studies showed the dependence of NFIL-3 expression on new protein synthesis in IL-3-stimulated cells, however, IL-4 and IL-10 induced NFIL3 in the protein synthesis independent mechanism [XREF_BIBR, XREF_BIBR, XREF_BIBR], supporting the possibility of late, Pim-1-independent transactivation of NFIL3 by Dex.	20	47	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NFIL3	IL-10 induced NFIL3	nfil3	NFIL3	NFIL3	nfil3	22	23	46	47
Further , STAT3 RNAi decreased the level of NFIL3 expression and the overexpression STAT3 increased NFIL3 mRNA and protein expression level inversely .	Further, STAT3 RNAi decreased the level of NFIL3 expression and the overexpression STAT3 increased NFIL3 mRNA and protein expression level inversely.	8	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NFIL3	NFIL3 expression	nfil3	NFIL3	NFIL3	nfil3	8	9	15	16
Some gene pathways enhance , others repress transcription of Notch-1 , while Notch-1 itself activates Myc and HIF-1alpha .	Some gene pathways enhance, others repress transcription of Notch-1, while Notch-1 itself activates Myc and HIF-1alpha.	12	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Notch-1	Notch-1	Notch-1	HIF-1alpha	HIF-1alpha	HIF-1alpha	12	13	17	18
In this study , it was shown that NICD sequesters a negative regulator of HIF-1alpha resulting in increased protein levels of HIF-1alpha and , in turn , increasing its downstream effects .	In this study, it was shown that NICD sequesters a negative regulator of HIF-1alpha resulting in increased protein levels of HIF-1alpha and, in turn, increasing its downstream effects.	8	15	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	NICD	NICD	NICD	HIF-1alpha	HIF-1alpha	HIF-1alpha	8	9	14	15
Our prior work established that Notch3 is the predominant Notch receptor in SMCs of cerebral arteries and that RBPJ activity in these cells is predominantly mediated by Notch3 signaling .	Our prior work established that Notch3 is the predominant Notch receptor in SMCs of cerebral arteries and that RBPJ activity in these cells is predominantly mediated by Notch3 signaling.	18	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Notch3	Notch3	Notch3	RBPJ	RBPJ	RBPJ	27	28	18	19
The first comprises mice expressing the R90C or C428S mutations ( or the wild type sequence ) under the control of the SM22a promoter , at about physiological levels [ XREF_BIBR , XREF_BIBR ] : the R90C mutant receptor appears to be equally potent as the wild type in rescuing the arterial defects of Notch3 mutant mice , suggesting it remains functional and does not exhibit dominant and negative activity , further retaining the ability to elicit Notch 3 mediated RBP-Jk transcription in brain arteries of TP1-nLacZ reporter mice [ XREF_BIBR ] .	The first comprises mice expressing the R90C or C428S mutations (or the wild type sequence) under the control of the SM22a promoter, at about physiological levels [XREF_BIBR, XREF_BIBR] : the R90C mutant receptor appears to be equally potent as the wild type in rescuing the arterial defects of Notch3 mutant mice, suggesting it remains functional and does not exhibit dominant and negative activity, further retaining the ability to elicit Notch 3 mediated RBP-Jk transcription in brain arteries of TP1-nLacZ reporter mice [XREF_BIBR].	77	81	mediated	Positive_early_activation	Positive_activation	Positive_activation	Notch 3	Notch 3	Notch 3	RBP-Jk	RBP-Jk	RBP-Jk	77	79	80	81
In another previous study , we identified the novel 36-residue neuropeptide neuromedin S ( NMS ) , which activates both NMUR1 and NMUR2 in a cell based assay in a manner similar to NMU 14 .	In another previous study, we identified the novel 36-residue neuropeptide neuromedin S (NMS), which activates both NMUR1 and NMUR2 in a cell based assay in a manner similar to NMU 14.	12	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NMS	NMS	NMS	NMUR2	NMUR2	NMUR2	14	15	22	23
In addition to NMU , NMUr1 and NMUr2 are activated by neuromedin S ( NMS ) , a related neuropeptide localized exclusively to the suprachiasmatic nucleus of the hypothalamus ( SCN ) , the primary circadian timing center of the brain .	In addition to NMU, NMUr1 and NMUr2 are activated by neuromedin S (NMS), a related neuropeptide localized exclusively to the suprachiasmatic nucleus of the hypothalamus (SCN), the primary circadian timing center of the brain.	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	neuromedin S	neuromedin S	neuromedin S	NMUr2	NMUr2	NMUr2	11	13	7	8
Overexpression of heregulin , a potent ligand that activates HER3 and HER4 receptors , plays a significant role in the development of chemotherapy resistance in breast cancer patients .	Overexpression of heregulin, a potent ligand that activates HER3 and HER4 receptors, plays a significant role in the development of chemotherapy resistance in breast cancer patients.	0	12	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	heregulin	Overexpression of heregulin	heregulin	HER3	HER3	her3	2	3	9	10
Altogether , these studies indicate that Affibody molecules might be used in future treatments of cancers that are dependent on heregulin induced HER3 signaling .	Altogether, these studies indicate that Affibody molecules might be used in future treatments of cancers that are dependent on heregulin induced HER3 signaling.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	20	21	22	23
In particular heregulin induced activation of ErbB3 may cause resistance to gefitinib .	In particular heregulin induced activation of ErbB3 may cause resistance to gefitinib.	0	8	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB3	ErbB3	ErbB3	2	3	6	7
In addition , Nrg1 type I , which is likely mainly produced by Schwann cells , can induce ErbB2 and ErbB3 receptor activation via autocrine signaling [ XREF_BIBR , XREF_BIBR ] .	In addition, Nrg1 type I, which is likely mainly produced by Schwann cells, can induce ErbB2 and ErbB3 receptor activation via autocrine signaling [XREF_BIBR, XREF_BIBR].	3	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB3	ErbB3	ErbB3	3	4	20	21
The aberrant tyrosine kinase activity of ErbB2 and ErbB3 receptors caused by NRG1 fusions represent an opportunity for the development of new anticancer drugs acting through inhibition of the ErbB network .	The aberrant tyrosine kinase activity of ErbB2 and ErbB3 receptors caused by NRG1 fusions represent an opportunity for the development of new anticancer drugs acting through inhibition of the ErbB network.	6	13	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	12	13	8	9
Moreover , the heregulin release also reactivated HER3 via HER2 and HER3 dimers along with downstream signalling pathways .	Moreover, the heregulin release also reactivated HER3 via HER2 and HER3 dimers along with downstream signalling pathways.	3	12	reactivated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	3	4	7	8
Previous studies have shown that Nrg1 induced activation causes ErbB3 endocytosis and subsequent degradation by the lysosome in MCF7 breast tumor cells , although the ErbB3 degradation occurs at a slower rate than that of ErbB1 [ XREF_BIBR , XREF_BIBR ] Furthermore , our recent work has revealed that , in response to Nrg1 binding , ErbB3 in Schwann cells can undergo endocytic degradation , which is associated with the termination of Nrg1 activated ErbB2 and ErbB3 receptor signaling [ XREF_BIBR , XREF_BIBR ] .	Previous studies have shown that Nrg1 induced activation causes ErbB3 endocytosis and subsequent degradation by the lysosome in MCF7 breast tumor cells, although the ErbB3 degradation occurs at a slower rate than that of ErbB1 [XREF_BIBR, XREF_BIBR] Furthermore, our recent work has revealed that, in response to Nrg1 binding, ErbB3 in Schwann cells can undergo endocytic degradation, which is associated with the termination of Nrg1 activated ErbB2 and ErbB3 receptor signaling [XREF_BIBR, XREF_BIBR].	5	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB3	ErbB3	ErbB3	5	6	9	10
We have previously shown that both antibodies inhibit NRG1 binding , NRG1 induced pHER3 stimulation , ligand induced signaling and ligand induced melanoma cell proliferation through binding to different epitopes [ XREF_BIBR , XREF_BIBR ] , one of which ( A3 ) has been mapped to the ErbB3 heterodimerization loop with other ErbBs .	We have previously shown that both antibodies inhibit NRG1 binding, NRG1 induced pHER3 stimulation, ligand induced signaling and ligand induced melanoma cell proliferation through binding to different epitopes [XREF_BIBR, XREF_BIBR], one of which (A3) has been mapped to the ErbB3 heterodimerization loop with other ErbBs.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	pHER3	pHER3	pHER3	11	12	13	14
A time course study of LINC00052 expression upon HER3 activation by NRG-1 stimulation was performed .	A time course study of LINC00052 expression upon HER3 activation by NRG-1 stimulation was performed.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	HER3	HER3	HER3	11	12	8	9
Similar to the experiments on M14 cells above , Montero-Conde and colleagues showed that NRG1 ligand could activate pHER3 and pAKT in the presence of PLX4032 , and this activation could be reversed by the addition of lapatinib .	Similar to the experiments on M14 cells above, Montero-Conde and colleagues showed that NRG1 ligand could activate pHER3 and pAKT in the presence of PLX4032, and this activation could be reversed by the addition of lapatinib.	14	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	pHER3	pHER3	pHER3	14	15	18	19
Nrg1 has been shown to increase ErbB3 and olfactory glial proliferation in culture 28 .	Nrg1 has been shown to increase ErbB3 and olfactory glial proliferation in culture 28.	0	10	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB3	ErbB3	ErbB3	0	1	6	7
Although HER3 expression was only very weakly correlated with Iressa sensitivity , the authors concluded that it is the heregulin induced HER3 activation rather than the level causing insensitivity to Iressa XREF_BIBR .	Although HER3 expression was only very weakly correlated with Iressa sensitivity, the authors concluded that it is the heregulin induced HER3 activation rather than the level causing insensitivity to Iressa XREF_BIBR.	14	22	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	19	20	21	22
Heregulin ( HRG ) , a ligand for ErbB3 , activates ErbB2 and ErbB3 , which in turn triggers downstream signals via activation of ErbB2 tyrosine kinase XREF_BIBR XREF_BIBR XREF_BIBR .	Heregulin (HRG), a ligand for ErbB3, activates ErbB2 and ErbB3, which in turn triggers downstream signals via activation of ErbB2 tyrosine kinase XREF_BIBR XREF_BIBR XREF_BIBR.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	ErbB3	ErbB3	ErbB3	0	1	13	14
On the other hand , it has been demonstrated that a naturally occurring secreted form of the human HER-3 receptor , p85-soluble ErbB3 ( sErbB3 ) , is a potent negative regulator of heregulin stimulated HER-2 , HER-3 and HER-4 activation .	On the other hand, it has been demonstrated that a naturally occurring secreted form of the human HER-3 receptor, p85-soluble ErbB3 (sErbB3), is a potent negative regulator of heregulin stimulated HER-2, HER-3 and HER-4 activation.	31	40	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER-3	HER-3	HER-3	33	34	37	38
HER3 activation by NRG-1 negatively impacts the association of HER3 and DJ-1 .	HER3 activation by NRG-1 negatively impacts the association of HER3 and DJ-1.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	HER3	HER3	HER3	3	4	0	1
The addition of pertuzumab to lapatinib inhibited NRG1 stimulated HER3 and HER4 signalling in both SK-BR-3 and BT-474 cells , although the additive effect was only seen in the parental and resistant BT-474 cells as well as BT-474 xenograft models .	The addition of pertuzumab to lapatinib inhibited NRG1 stimulated HER3 and HER4 signalling in both SK-BR-3 and BT-474 cells, although the additive effect was only seen in the parental and resistant BT-474 cells as well as BT-474 xenograft models.	6	39	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER3	HER3	HER3	7	8	9	10
Acute NRG1 treatment activates ERBB3 in liver , but not in skeletal muscle , white adipose tissue and hypothalamus of db/db mice .	Acute NRG1 treatment activates ERBB3 in liver, but not in skeletal muscle, white adipose tissue and hypothalamus of db/db mice.	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB3	ERBB3	ERBB3	1	2	4	5
We show that heregulin activates HER2 and HER3 and increases androgen dependent AR transactivation of reporter genes in CWR-R1 cells .	We show that heregulin activates HER2 and HER3 and increases androgen dependent AR transactivation of reporter genes in CWR-R1 cells.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	3	4	7	8
Taken together , these data suggest that activation of HER3 by NRG-1 triggers the dissociation of HER3 and DJ-1 in cancer cells .	Taken together, these data suggest that activation of HER3 by NRG-1 triggers the dissociation of HER3 and DJ-1 in cancer cells.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	HER3	HER3	HER3	11	12	9	10
We conclude that an NRG1 induced protein stability cascade involving USP8 and Nrdp1 mediates the down-regulation of ErbB3 .	We conclude that an NRG1 induced protein stability cascade involving USP8 and Nrdp1 mediates the down-regulation of ErbB3.	3	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	4	5	17	18
The addition of a secondary kinase inhibitor , lapatinib , blocked NRG1 induced pHER3 and pAKT activation , restoring sensitivity to PLX4032 .	The addition of a secondary kinase inhibitor, lapatinib, blocked NRG1 induced pHER3 and pAKT activation, restoring sensitivity to PLX4032.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	pHER3	pHER3	pHER3	11	12	13	14
NRG1 dependent activation of HER3 induces primary resistance to trastuzumab in HER2 overexpressing breast cancer cells .	NRG1 dependent activation of HER3 induces primary resistance to trastuzumab in HER2 overexpressing breast cancer cells.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER3	HER3	HER3	0	1	4	5
Our results demonstrate that heregulin driven ERBB3 signaling mediates resistance to letrozole in a preclinical model of ER ( + ) breast cancer , suggesting that heregulin expressing ER ( + ) breast cancer patients may benefit from the addition of seribantumab to antiendocrine therapy .	Our results demonstrate that heregulin driven ERBB3 signaling mediates resistance to letrozole in a preclinical model of ER (+) breast cancer, suggesting that heregulin expressing ER (+) breast cancer patients may benefit from the addition of seribantumab to antiendocrine therapy.	4	8	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ERBB3	ERBB3	ERBB3	4	5	6	7
HER3 can be activated by its ligand ( heregulin and HRG ) , which induces HER3 heterodimerization with EGFR , HER2 , or other RTKs .	HER3 can be activated by its ligand (heregulin and HRG), which induces HER3 heterodimerization with EGFR, HER2, or other RTKs.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	8	9	0	1
Each contained activated ErbB3 that could be co-immunoprecipitated with the p85 subunit of PI3 kinase ( XREF_FIG ) , consistent with the hypothesis that , in vivo , the PI3 kinase pathway had been engaged through NRG1 driven activation of ErbB3 .	Each contained activated ErbB3 that could be co-immunoprecipitated with the p85 subunit of PI3 kinase (XREF_FIG), consistent with the hypothesis that, in vivo, the PI3 kinase pathway had been engaged through NRG1 driven activation of ErbB3.	36	41	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	36	37	40	41
In vivo , heregulin induced HER3 and HER2 transactivation , in the absence of HER2 over-expression , is sufficient for generation of adenocarcinomas while favouring the metastatic spread of breast cancer cells in mice [ XREF_BIBR ] .	In vivo, heregulin induced HER3 and HER2 transactivation, in the absence of HER2 over-expression, is sufficient for generation of adenocarcinomas while favouring the metastatic spread of breast cancer cells in mice [XREF_BIBR].	1	8	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	3	4	5	6
It has been proposed that activation of HER3 by NRG1 contributes to melanoma development and progression , but we did not identify a correlation between HER3 activation and the expression of ligands NRG1 or NRG2 ( XREF_SUPPLEMENTARY ) .	It has been proposed that activation of HER3 by NRG1 contributes to melanoma development and progression, but we did not identify a correlation between HER3 activation and the expression of ligands NRG1 or NRG2 (XREF_SUPPLEMENTARY).	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER3	HER3	HER3	9	10	7	8
In surface plasmon resonance ( BIAcore ) studies , the designed peptides have been shown to selectively bind to the erbB receptor ectodomains and isolated subdomain IV of erbB2 with submicromolar affinities and to inhibit heregulin induced interactions of erbB3 with different erbB receptors .	In surface plasmon resonance (BIAcore) studies, the designed peptides have been shown to selectively bind to the erbB receptor ectodomains and isolated subdomain IV of erbB2 with submicromolar affinities and to inhibit heregulin induced interactions of erbB3 with different erbB receptors.	34	40	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	erbB3	erbB3	erbB3	35	36	39	40
Dimerization of HER2 : HER3 was induced by NRG1 , a ligand for HER3 .	Dimerization of HER2 : HER3 was induced by NRG1, a ligand for HER3.	0	11	induced	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER3	HER3	HER3	8	9	4	5
It is not clear whether membrane bound SMDF activates ErbB-2 and ErbB-3 at the plasma membrane or whether signalling takes place on intracellular vesicles , as we have not been able to detect the activated receptor by immunostaining ( unpublished observations ) .	It is not clear whether membrane bound SMDF activates ErbB-2 and ErbB-3 at the plasma membrane or whether signalling takes place on intracellular vesicles, as we have not been able to detect the activated receptor by immunostaining (unpublished observations).	7	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMDF	SMDF	SMDF	ErbB-3	ErbB-3	ErbB-3	7	8	11	12
Described intrinsic ( RAF/MEK/ERK pathway ) and extrinsic ( alternative pathways ) mechanisms of acquired BRAF inhibitor resistance in thyroid cancer include : RAF/MEK/ERK pathway activation brought about through alternate BRAF splicing [ XREF_BIBR ] , activation of the PI3K and AKT pathway through c-MET [ XREF_BIBR ] , autocrine NRG1- mediated HER3 receptor activation of the PI3K and AKT and RAS/RAF/MEK/ERK pathways [ XREF_BIBR ] , and autocrine IL-6-mediated JAK and STAT3 and RAS/RAF/MEK/ERK pathway activation [ XREF_BIBR ] .	Described intrinsic (RAF/MEK/ERK pathway) and extrinsic (alternative pathways) mechanisms of acquired BRAF inhibitor resistance in thyroid cancer include : RAF/MEK/ERK pathway activation brought about through alternate BRAF splicing [XREF_BIBR], activation of the PI3K and AKT pathway through c-MET [XREF_BIBR], autocrine NRG1- mediated HER3 receptor activation of the PI3K and AKT and RAS/RAF/MEK/ERK pathways [XREF_BIBR], and autocrine IL-6-mediated JAK and STAT3 and RAS/RAF/MEK/ERK pathway activation [XREF_BIBR].	46	70	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1-	NRG1-	NRG1-	HER3	HER3	HER3	50	51	52	53
ErbB3 activation is driven by the neuregulin family of ligands ( NRG1 and NRG2 , specifically ) in a subset of solid cancers [ XREF_BIBR , XREF_BIBR ] .	ErbB3 activation is driven by the neuregulin family of ligands (NRG1 and NRG2, specifically) in a subset of solid cancers [XREF_BIBR, XREF_BIBR].	0	15	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	11	12	0	1
Indeed , in the parental H3122 cells , exogenous NRG1 induced an increase of p-HER3 and p-AKT ( XREF_FIG A and B ) .	Indeed, in the parental H3122 cells, exogenous NRG1 induced an increase of p-HER3 and p-AKT (XREF_FIG A and B).	8	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	p-HER3	p-HER3	p-HER3	9	10	14	15
Addition of exogeneous NRG1 or NRG2 was sufficient to drive upregulation of p-ERBB2 and p-ERBB3 in RT112 cells ( XREF_SUPPLEMENTARY ) .	Addition of exogeneous NRG1 or NRG2 was sufficient to drive upregulation of p-ERBB2 and p-ERBB3 in RT112 cells (XREF_SUPPLEMENTARY).	0	15	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	p-ERBB3	p-ERBB3	p-ERBB3	3	4	14	15
Heregulin can bind to and induce the activation of ERBB3 .	Heregulin can bind to and induce the activation of ERBB3.	0	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	ERBB3	ERBB3	ERBB3	0	1	9	10
Up-regulated soluble NRG1 activates ErbB2 and ErbB3 and , through a positive feedback loop ( helped by ErbB2 overexpression ) , augments its expression stimulating Schwann cell proliferation XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Up-regulated soluble NRG1 activates ErbB2 and ErbB3 and, through a positive feedback loop (helped by ErbB2 overexpression), augments its expression stimulating Schwann cell proliferation XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	2	3	6	7
Whether activation of ErbB3 by heregulin results in EBP1 dissociation or ERK1 activation leads to EBP1 phosphorylation in ovarian somatic cells is under study .	Whether activation of ErbB3 by heregulin results in EBP1 dissociation or ERK1 activation leads to EBP1 phosphorylation in ovarian somatic cells is under study.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB3	ErbB3	ErbB3	5	6	3	4
We have previously generated Affibody molecules that inhibit heregulin induced signaling of the HER3 pathways .	We have previously generated Affibody molecules that inhibit heregulin induced signaling of the HER3 pathways.	8	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	8	9	13	14
Zhou et al ( 2006 ) also showed that ADAM17 protein is upregulated in NSCLC and correlated with heregulin mediated HER3 activation , leading to gefitinib insensitivity Receptors .	Zhou et al (2006) also showed that ADAM17 protein is upregulated in NSCLC and correlated with heregulin mediated HER3 activation, leading to gefitinib insensitivity Receptors.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	18	19	20	21
In particular , tumors in which NRG1 triggers ErbB3 signaling have been found to be sensitive to anti-ErbB3 antibody treatment [ XREF_BIBR ] .	In particular, tumors in which NRG1 triggers ErbB3 signaling have been found to be sensitive to anti-ErbB3 antibody treatment [XREF_BIBR].	6	9	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	6	7	8	9
Further , two studies have reported on heregulin induced activation of HER3 and HER2 dimers resulting in Src kinase activation .	Further, two studies have reported on heregulin induced activation of HER3 and HER2 dimers resulting in Src kinase activation.	5	14	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	7	8	11	12
In addition , CM from some of the primary tumor cell samples that express NRG1 RNA ( DF05 , DF14 ) activated ErbB3 in OVCAR5 cells ( which express but do not activate ErbB3 ) ( XREF_FIG ) .	In addition, CM from some of the primary tumor cell samples that express NRG1 RNA (DF05, DF14) activated ErbB3 in OVCAR5 cells (which express but do not activate ErbB3) (XREF_FIG).	14	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	14	15	22	23
Cytoplasmic Ebp1 associates with the cytoplasmic domain of ErbB3 and following heregulin activation of ErbB3 , Ebp1 dissociates from the receptor and translocates to the nucleus [ XREF_BIBR ] .	Cytoplasmic Ebp1 associates with the cytoplasmic domain of ErbB3 and following heregulin activation of ErbB3, Ebp1 dissociates from the receptor and translocates to the nucleus [XREF_BIBR].	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB3	ErbB3	ErbB3	11	12	14	15
HER3 and HER4 are activated by the heregulin or neuregulin family of growth factors [ XREF_BIBR - XREF_BIBR ] .	HER3 and HER4 are activated by the heregulin or neuregulin family of growth factors [XREF_BIBR - XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	7	8	0	1
In the EGF response , at least two tyrosine phosphorylated forms of ErbB3 are detected , but these phosphoproteins have distinctly lower apparent molecular weights compared with the heregulin stimulated ErbB3 phosphoproteins and do not complex with p85 .	In the EGF response, at least two tyrosine phosphorylated forms of ErbB3 are detected, but these phosphoproteins have distinctly lower apparent molecular weights compared with the heregulin stimulated ErbB3 phosphoproteins and do not complex with p85.	24	33	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB3	ErbB3	ErbB3	28	29	30	31
A recent study showed that in a portion ( ~ 25 % ) of ovarian cancers , NRG1 activated ERBB3 to promote cancer cell proliferation and drive tumor growth .	A recent study showed that in a portion (~ 25%) of ovarian cancers, NRG1 activated ERBB3 to promote cancer cell proliferation and drive tumor growth.	17	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB3	ERBB3	ERBB3	17	18	19	20
This antibody promotes antibody dependent cellular cytotoxicity in NRG1 positive PC and CAFs and inhibits NRG1 associated signaling pathway induction , by blocking NRG1 mediated HER3 activation .	This antibody promotes antibody dependent cellular cytotoxicity in NRG1 positive PC and CAFs and inhibits NRG1 associated signaling pathway induction, by blocking NRG1 mediated HER3 activation.	23	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER3	HER3	HER3	23	24	25	26
Besides activating ErbB4 homodimers , Nrg1 can mediate the formation of ErbB dimers consisting of ErbB3 , as well as EGFR .	Besides activating ErbB4 homodimers, Nrg1 can mediate the formation of ErbB dimers consisting of ErbB3, as well as EGFR.	5	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB3	ErbB3	ErbB3	5	6	15	16
Heregulin activated HER3 , but not HER2 , in both SPRY2 Nsi control and KD cells ( XREF_FIG ) .	Heregulin activated HER3, but not HER2, in both SPRY2 Nsi control and KD cells (XREF_FIG).	0	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	HER3	HER3	HER3	0	1	2	3
The results showed that DJ-1 was associated with clinical stage of breast cancer , and NRG-1 increased the dissociation of HER3 and DJ-1 , with promoting the level of DJ-1 in peripheral blood .	The results showed that DJ-1 was associated with clinical stage of breast cancer, and NRG-1 increased the dissociation of HER3 and DJ-1, with promoting the level of DJ-1 in peripheral blood.	15	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	HER3	HER3	HER3	15	16	20	21
Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC .	Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	HER3	HER3	HER3	0	1	2	3
HER3 is a member of the ErbB tyrosine kinase receptor family and is activated by heregulin .	HER3 is a member of the ErbB tyrosine kinase receptor family and is activated by heregulin.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	15	16	0	1
Heregulin driven ERBB3 signaling has been implicated as a mechanism of resistance to cytotoxic and antiendocrine therapies in preclinical breast cancer models .	Heregulin driven ERBB3 signaling has been implicated as a mechanism of resistance to cytotoxic and antiendocrine therapies in preclinical breast cancer models.	0	6	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	ERBB3	ERBB3	ERBB3	0	1	2	3
We conclude that stromal CAF secreted NRG-1 stimulates ErbB3 and AKT signalling and promotes pancreatic cancer cell tumourigenesis , providing a mechanism that may contribute to PDAC resistance to anti-EGFR therapy .	We conclude that stromal CAF secreted NRG-1 stimulates ErbB3 and AKT signalling and promotes pancreatic cancer cell tumourigenesis, providing a mechanism that may contribute to PDAC resistance to anti-EGFR therapy.	5	11	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	ErbB3	ErbB3	ErbB3	6	7	8	9
Based on the up-regulation of NRG1-ERBB3 signaling in BRAF V600E cutaneous melanoma cells following RAF inhibitor treatment , we tested the impact of trametinib on NRG1 induced ERBB3 signaling in UM cells .	Based on the up-regulation of NRG1-ERBB3 signaling in BRAF V600E cutaneous melanoma cells following RAF inhibitor treatment, we tested the impact of trametinib on NRG1 induced ERBB3 signaling in UM cells.	23	28	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB3	ERBB3	ERBB3	25	26	27	28
Based on an analysis of NRG1 and ErbB3 mRNA in recurrent HNSCC , post-treatment , late stage disease also appears to be enriched for NRG1 mediated ErbB3 activation [ XREF_BIBR ] ; whether Trop2 loss is a mechanism for autocrine activation of ErbB3 in this context remains to be evaluated .	Based on an analysis of NRG1 and ErbB3 mRNA in recurrent HNSCC, post-treatment, late stage disease also appears to be enriched for NRG1 mediated ErbB3 activation [XREF_BIBR]; whether Trop2 loss is a mechanism for autocrine activation of ErbB3 in this context remains to be evaluated.	24	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	24	25	26	27
Taken together , these results clearly demonstrate that DJ-1 modulates HER3 levels and impacts HER3 signaling triggered by NRG-1 .	Taken together, these results clearly demonstrate that DJ-1 modulates HER3 levels and impacts HER3 signaling triggered by NRG-1.	14	19	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	HER3	HER3	HER3	18	19	14	15
To investigate the effect of NRG1 and the well-known enteric neurotrophic factor GDNF on gene regulation of the enteric NRG1 system itself , mRNA expression of Nrg1 , ErbB2 and ErbB3 were measured by RT-qPCR in rat enteric nerve cell cultures treated with increasing concentrations of NRG1 of 2 ng/ml and 20 ng/ml and 50 ng/ml GDNF for 1 week .	To investigate the effect of NRG1 and the well-known enteric neurotrophic factor GDNF on gene regulation of the enteric NRG1 system itself, mRNA expression of Nrg1, ErbB2 and ErbB3 were measured by RT-qPCR in rat enteric nerve cell cultures treated with increasing concentrations of NRG1 of 2 ng/ml and 20 ng/ml and 50 ng/ml GDNF for 1 week.	24	56	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	46	47	30	31
Activation of HER2-HER3 signaling associated with the operation of a heregulin autocrine loop confers resistance to cetuximab , and patritumab is able to restore cetuximab sensitivity through inhibition of heregulin induced HER3 activation .	Activation of HER2-HER3 signaling associated with the operation of a heregulin autocrine loop confers resistance to cetuximab, and patritumab is able to restore cetuximab sensitivity through inhibition of heregulin induced HER3 activation.	27	32	induced	Positive_early_activation	Positive_activation	Negative_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	29	30	31	32
NDF activated ErbB-3 or ErbB-4 heterodimerize with ErbB-1 only when no ErbB-2 is available .	NDF activated ErbB-3 or ErbB-4 heterodimerize with ErbB-1 only when no ErbB-2 is available.	0	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NDF	NDF	NDF	ErbB-3	ErbB-3	ErbB-3	0	1	2	3
NRG1 activation of ERBB3 is enhanced in MEK inhibited cells in an adaptive manner .	NRG1 activation of ERBB3 is enhanced in MEK inhibited cells in an adaptive manner.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB3	ERBB3	ERBB3	0	1	3	4
Here , heregulin stimulation is shown to markedly upregulate kinase activity in erbB3 immunoprecipitates .	Here, heregulin stimulation is shown to markedly upregulate kinase activity in erbB3 immunoprecipitates.	2	13	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	erbB3	erbB3	erbB3	2	3	12	13
Conversely , HER3 and HER4 are activated by the heregulin or neuregulin family of growth factors ( XREF_FIG ) .	Conversely, HER3 and HER4 are activated by the heregulin or neuregulin family of growth factors (XREF_FIG).	2	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	9	10	2	3
Taken together , the above noted data strongly suggest that ErbB3 is activated by an NRG1 driven autocrine circuit in certain ovarian cancer cell lines and in a significant fraction of primary advanced-stage ovarian cancers .	Taken together, the above noted data strongly suggest that ErbB3 is activated by an NRG1 driven autocrine circuit in certain ovarian cancer cell lines and in a significant fraction of primary advanced-stage ovarian cancers.	10	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	15	16	10	11
Neuregulin 1 ( NRG1 ) is the predominant ligand for ERBB3 and can promote the heterodimerization of ERBB3 with other ERBB family members , resulting in activation of multiple intracellular signaling pathways .	Neuregulin 1 (NRG1) is the predominant ligand for ERBB3 and can promote the heterodimerization of ERBB3 with other ERBB family members, resulting in activation of multiple intracellular signaling pathways.	0	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB3	ERBB3	ERBB3	3	4	17	18
ID5 preferentially induced binding of the Mr 46,000 isoform of SHC to HER2 , whereas heregulin preferentially induced binding of the Mr 52,00 isoform of SHC to HER3 .	ID5 preferentially induced binding of the Mr 46,000 isoform of SHC to HER2, whereas heregulin preferentially induced binding of the Mr 52,00 isoform of SHC to HER3.	15	28	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	15	16	27	28
NRG1 fusions activates the ERBB2 and ERBB3 signaling pathway [ XREF_BIBR ] .	NRG1 fusions activates the ERBB2 and ERBB3 signaling pathway [XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB3	ERBB3	ERBB3	0	1	6	7
By means of siRNA mediated downregulation of CD44 expression and blocking experiments , we identified CD44v6 as a co-receptor for EGF- and ER induced ErbB1 activation and for NRG1 induced ErbB3 and ErbB4 activation .	By means of siRNA mediated downregulation of CD44 expression and blocking experiments, we identified CD44v6 as a co-receptor for EGF- and ER induced ErbB1 activation and for NRG1 induced ErbB3 and ErbB4 activation.	28	33	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	28	29	30	31
The dose response curve obtained was compared to that of a control , and the results clearly indicated that HER2 : HER3 heterodimerization induced by NRG1 in U2OS cell lines was inhibited by compound 9 .	The dose response curve obtained was compared to that of a control, and the results clearly indicated that HER2 : HER3 heterodimerization induced by NRG1 in U2OS cell lines was inhibited by compound 9.	21	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER3	HER3	HER3	25	26	21	22
The treatment of M14 ( a BRAF mutated melanoma cell line ) with the ligand NRG1 activated pHER3 and pAKT , inducing partial resistance to PLX4032 .	The treatment of M14 (a BRAF mutated melanoma cell line) with the ligand NRG1 activated pHER3 and pAKT, inducing partial resistance to PLX4032.	1	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	pHER3	pHER3	pHER3	15	16	17	18
This effect was occluded by the NRG1 signaling inhibitor gefitinib ( XREF_FIG ) , which blocks the signaling of the ErbB2 and ErbB3 receptors activated by NRG1 engagement 40 .	This effect was occluded by the NRG1 signaling inhibitor gefitinib (XREF_FIG), which blocks the signaling of the ErbB2 and ErbB3 receptors activated by NRG1 engagement 40.	20	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	26	27	22	23
Studies from our laboratory have identified the CMT1C associated protein SIMPLE as a positive regulator of endosome-to-lysosome trafficking required for controlling Nrg1 induced ErbB3 downregulation in Schwann cells [ XREF_BIBR , XREF_BIBR ] .	Studies from our laboratory have identified the CMT1C associated protein SIMPLE as a positive regulator of endosome-to-lysosome trafficking required for controlling Nrg1 induced ErbB3 downregulation in Schwann cells [XREF_BIBR, XREF_BIBR].	18	24	induced	Positive_early_activation	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB3	ErbB3	ErbB3	21	22	23	24
Consistent with the immunoblotting results , multiple peptides were identified by LC-MS/MS from heregulin stimulated HER3 , but no peptides were detected from the control sample , again demonstrating that only activated HER3 interacts with MTK1 .	Consistent with the immunoblotting results, multiple peptides were identified by LC-MS/MS from heregulin stimulated HER3, but no peptides were detected from the control sample, again demonstrating that only activated HER3 interacts with MTK1.	9	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	13	14	15	16
To attenuate EGFR signaling we replaced EGF in the culture medium with amphiregulin ( AREG ) , which is 100-fold less active on EGFR [ XREF_BIBR ] , and added neuregulin ( NRG1 ) , which activates ERBB3 and ERBB4 reviewed in ref [ XREF_BIBR ] .	To attenuate EGFR signaling we replaced EGF in the culture medium with amphiregulin (AREG), which is 100-fold less active on EGFR [XREF_BIBR], and added neuregulin (NRG1), which activates ERBB3 and ERBB4 reviewed in ref [XREF_BIBR].	30	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB3	ERBB3	ERBB3	32	33	37	38
Cell lines derived from these tumors expressed ErbB3 protein and either HER2 or ErbB4 [ XREF_BIBR ] ; in half of the lines ErbB3 was constitutively activated by endogenous NRG1 expression ; the others were responsive to added NRG1 [ XREF_BIBR ] .	Cell lines derived from these tumors expressed ErbB3 protein and either HER2 or ErbB4 [XREF_BIBR]; in half of the lines ErbB3 was constitutively activated by endogenous NRG1 expression; the others were responsive to added NRG1 [XREF_BIBR].	23	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG1	NRG1 expression	nrg1	ErbB3	ErbB3	erbb3	29	30	23	24
The results indicate that the heregulin toxins target ErbB4 or possibly ErbB3 but not ErbB2 .	The results indicate that the heregulin toxins target ErbB4 or possibly ErbB3 but not ErbB2.	5	12	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB3	ErbB3	ErbB3	5	6	11	12
The ORF that most strongly induced resistance to ALK inhibition in both H3122 and MGH006 was neuregulin-1 ( NRG1 ) , the ligand that activates HER3 .	The ORF that most strongly induced resistance to ALK inhibition in both H3122 and MGH006 was neuregulin-1 (NRG1), the ligand that activates HER3.	1	26	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER3	HER3	HER3	18	19	25	26
Overall , these findings suggest that ErbB3 signaling is activated by autocrine production of NRG1 in a subset of WT/WT cutaneous melanomas .	Overall, these findings suggest that ErbB3 signaling is activated by autocrine production of NRG1 in a subset of WT/WT cutaneous melanomas.	6	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	14	15	6	7
A30 RNA aptamer is specific and shows high affinity for HER3ECD and inhibits the heregulin induced activation of HER3 receptor following inhibition of growth of MCF7 cells [ XREF_BIBR ] .	A30 RNA aptamer is specific and shows high affinity for HER3ECD and inhibits the heregulin induced activation of HER3 receptor following inhibition of growth of MCF7 cells [XREF_BIBR].	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	14	15	18	19
Activation of ErbB2 and ErbB3 signaling by NRG1 specifically participates in endocardial cushion EMT via a mechanism involving hyaluronic acid ( HA ) , an important component of the cardiac jelly [ XREF_BIBR ] .	Activation of ErbB2 and ErbB3 signaling by NRG1 specifically participates in endocardial cushion EMT via a mechanism involving hyaluronic acid (HA), an important component of the cardiac jelly [XREF_BIBR].	2	8	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	7	8	4	5
While EGF , transforming growth factor ( TGF )-alpha , and amphiregulin only had a moderate effect , NDF dramatically increased the ErbB-3 phosphotyrosine content .	While EGF, transforming growth factor (TGF)-alpha, and amphiregulin only had a moderate effect, NDF dramatically increased the ErbB-3 phosphotyrosine content.	18	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NDF	NDF	NDF	ErbB-3	ErbB-3	ErbB-3	18	19	22	23
We used a HER2 blocking antibody to show that ERBB3 phosphorylation in HNSCC and colorectal cancer cells is strictly dependent on association with HER2 , but not EGFR , and that neuregulin 1 activates ERBB3 and HER2 signaling to reverse the effect of EGFR blockade on colorectal cancer cell growth .	We used a HER2 blocking antibody to show that ERBB3 phosphorylation in HNSCC and colorectal cancer cells is strictly dependent on association with HER2, but not EGFR, and that neuregulin 1 activates ERBB3 and HER2 signaling to reverse the effect of EGFR blockade on colorectal cancer cell growth.	31	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neuregulin 1	neuregulin 1	neuregulin 1	ERBB3	ERBB3	ERBB3	31	33	34	35
To determine whether Skp2 is also involved in Akt signaling activation by other ErbB family proteins , BT-474 breast cancer cells were treated with Heregulin ( HRG ) , which is known to activate ErbB2 and ErbB3 .	To determine whether Skp2 is also involved in Akt signaling activation by other ErbB family proteins, BT-474 breast cancer cells were treated with Heregulin (HRG), which is known to activate ErbB2 and ErbB3.	22	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	ErbB3	ErbB3	ErbB3	24	25	36	37
The increased expression of NRG1 increases the autocrine signaling of HER2 and HER3 in tumors .	The increased expression of NRG1 increases the autocrine signaling of HER2 and HER3 in tumors.	2	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	expression of NRG1	nrg1	HER3	HER3	her3	4	5	12	13
We have shown that phosphorylated ErbB2 and ErbB3 stimulated by heregulin , localized in the nucleus of CRC cells .	We have shown that phosphorylated ErbB2 and ErbB3 stimulated by heregulin, localized in the nucleus of CRC cells.	4	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB3	ErbB3	ErbB3	10	11	7	8
The presence of the NRG1 ligand suggests that ErbB3 targeting inhibitors , such as KTN3379 , may be useful in a large subset of HNSCC where NRG1 expression leads to ErbB3 signaling .	The presence of the NRG1 ligand suggests that ErbB3 targeting inhibitors, such as KTN3379, may be useful in a large subset of HNSCC where NRG1 expression leads to ErbB3 signaling.	26	31	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	NRG1	NRG1 expression	nrg1	ErbB3	ErbB3	erbb3	26	27	30	31
This membrane anchored NRG1 isoform activates ErbB3 and ErbB2 receptors that likely regulate SC motility around the axon , in addition to SC precursor survival and proliferation .	This membrane anchored NRG1 isoform activates ErbB3 and ErbB2 receptors that likely regulate SC motility around the axon, in addition to SC precursor survival and proliferation.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	3	4	6	7
NRG1 too is overexpressed in PCa and elicits different ErbB3 and ErbB2 activation profiles depending upon the hormone-sensitivity of the cells [ XREF_BIBR ] .	NRG1 too is overexpressed in PCa and elicits different ErbB3 and ErbB2 activation profiles depending upon the hormone-sensitivity of the cells [XREF_BIBR].	0	13	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1 too is overexpressed	nrg1	ErbB3	ErbB3	erbb3	0	1	9	10
XREF_BIBR Together , our findings suggest a pathogenic pathway ( XREF_FIG ) by which SIMPLE mutation disrupts endosome-to-lysosome trafficking and signaling attenuation of NRG1 activated ErbB2 and ErbB3 receptors in Schwann cells , causing prolonged activation of downstream signaling pathways , thereby leading to myelin infolding and demyelinating peripheral neuropathy .	XREF_BIBR Together, our findings suggest a pathogenic pathway (XREF_FIG) by which SIMPLE mutation disrupts endosome-to-lysosome trafficking and signaling attenuation of NRG1 activated ErbB2 and ErbB3 receptors in Schwann cells, causing prolonged activation of downstream signaling pathways, thereby leading to myelin infolding and demyelinating peripheral neuropathy.	18	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	23	24	27	28
XREF_BIBR , XREF_BIBR ERBB3 is activated by ligand heregulin and by heterodimerization with other ERBB family members and is thought to be active only as a heterodimer .	XREF_BIBR, XREF_BIBR ERBB3 is activated by ligand heregulin and by heterodimerization with other ERBB family members and is thought to be active only as a heterodimer.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ERBB3	ERBB3	ERBB3	8	9	3	4
Here , we report that NRG1 stimulation activated HER3 and HER4 signalling despite the inhibition incurred by lapatinib .	Here, we report that NRG1 stimulation activated HER3 and HER4 signalling despite the inhibition incurred by lapatinib.	5	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER3	HER3	HER3	5	6	8	9
Given the importance of Nrg1 activated ErbB2 and ErbB3 receptor signaling in the peripheral nervous system , it is important for future studies to elucidate the molecular mechanisms governing endocytic trafficking of Nrg1 activated ErbB2 and ErbB3 receptors in Schwann cells and determine how ErbB2 and ErbB3 trafficking affects the potency , duration , and functional outcomes of ErbB2 and ErbB3 receptor mediated signaling in the control of myelin formation and maintenance .	Given the importance of Nrg1 activated ErbB2 and ErbB3 receptor signaling in the peripheral nervous system, it is important for future studies to elucidate the molecular mechanisms governing endocytic trafficking of Nrg1 activated ErbB2 and ErbB3 receptors in Schwann cells and determine how ErbB2 and ErbB3 trafficking affects the potency, duration, and functional outcomes of ErbB2 and ErbB3 receptor mediated signaling in the control of myelin formation and maintenance.	30	37	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB3	ErbB3	ErbB3	32	33	36	37
In addition , the ability of processed and unprocessed antibodies to inhibit ligand mediated Her3 receptor phosphorylation was evaluated in MCF-7 , a cell line in which Her3 signaling can be activated by addition of heregulin .	In addition, the ability of processed and unprocessed antibodies to inhibit ligand mediated Her3 receptor phosphorylation was evaluated in MCF-7, a cell line in which Her3 signaling can be activated by addition of heregulin.	27	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	Her3	Her3	Her3	35	36	27	28
We first observed in these cells that the anti-ErbB3 antibody A3 was able to induce strong ErbB3 downregulation as previously shown in melanoma cells and that the antibody was able to decrease , albeit to a variable extent , heregulin induced pErbB3 , pAKT and pERK signaling [ XREF_BIBR ] .	We first observed in these cells that the anti-ErbB3 antibody A3 was able to induce strong ErbB3 downregulation as previously shown in melanoma cells and that the antibody was able to decrease, albeit to a variable extent, heregulin induced pErbB3, pAKT and pERK signaling [XREF_BIBR].	39	48	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	pErbB3	pErbB3	pErbB3	39	40	41	42
Binding of MM-111 to ErbB3 blocks heregulin binding and inhibits heregulin activated ErbB3 signaling 66 .	Binding of MM-111 to ErbB3 blocks heregulin binding and inhibits heregulin activated ErbB3 signaling 66.	9	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB3	ErbB3	ErbB3	10	11	12	13
High DJ-1 expression increased total HER3 as compared to the pcDNA control cells in the absence of NRG-1 , and the increase was marginalized in the presence of NRG-1 due to NRG-1 induced HER3 activation .	High DJ-1 expression increased total HER3 as compared to the pcDNA control cells in the absence of NRG-1, and the increase was marginalized in the presence of NRG-1 due to NRG-1 induced HER3 activation.	23	34	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	HER3	HER3	HER3	31	32	33	34
Heregulin ( HRG ) belongs to the family of EGFs and activates the receptor proteins ErbB3 and ErbB4 in a variety of cell types to regulate cell fate .	Heregulin (HRG) belongs to the family of EGFs and activates the receptor proteins ErbB3 and ErbB4 in a variety of cell types to regulate cell fate.	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	ErbB3	ErbB3	ErbB3	0	1	15	16
These results demonstrate that NRG1 induces ERBB3 dependent AKT activation in MA-2 and 451Lu-R cells in vitro .	These results demonstrate that NRG1 induces ERBB3 dependent AKT activation in MA-2 and 451Lu-R cells in vitro.	4	7	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB3	ERBB3	ERBB3	4	5	6	7
In contrast , HER3 and HER4 are activated by the heregulin ( neuregulin ) family of growth factors ( Hrg and Nrg 1 , 2 , 3 , 4 ) .	In contrast, HER3 and HER4 are activated by the heregulin (neuregulin) family of growth factors (Hrg and Nrg 1, 2, 3, 4).	3	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	10	11	3	4
We also confirmed that NRG1 administration activates ErbB3 selectively in the ventral DG , and this activation did not result in neurogenic changes in immature neurons , in contrast to proliferating cells as shown previously XREF_BIBR .	We also confirmed that NRG1 administration activates ErbB3 selectively in the ventral DG, and this activation did not result in neurogenic changes in immature neurons, in contrast to proliferating cells as shown previously XREF_BIBR.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	4	5	7	8
It is postulated that MM-111 could anchor to HER2 and block heregulin induced activation of HER3 to treat HER2 and HER3 driven breast cancer .	It is postulated that MM-111 could anchor to HER2 and block heregulin induced activation of HER3 to treat HER2 and HER3 driven breast cancer.	10	16	induced	Positive_early_activation	Positive_activation	Negative_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	11	12	15	16
We previously showed that the immunoglobulin like cell adhesion molecule , nectin like molecule-2 ( Necl-2 )/CADM1 , interacts with the ErbB3 and ErbB4 receptors , and that the interaction of Necl-2 with ErbB3 inhibits the Nrg1 induced ErbB3 and ErbB2 signaling in epithelial cells .	We previously showed that the immunoglobulin like cell adhesion molecule, nectin like molecule-2 (Necl-2)/CADM1, interacts with the ErbB3 and ErbB4 receptors, and that the interaction of Necl-2 with ErbB3 inhibits the Nrg1 induced ErbB3 and ErbB2 signaling in epithelial cells.	35	41	induced	Positive_early_activation	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB3	ErbB3	ErbB3	36	37	38	39
The NRG1 , ErbB3 , and activated ErbB3 status , as well as the sensitivity to ErbB3 RNAi for a panel of ovarian cancer cell lines is shown in XREF_SUPPLEMENTARY .	The NRG1, ErbB3, and activated ErbB3 status, as well as the sensitivity to ErbB3 RNAi for a panel of ovarian cancer cell lines is shown in XREF_SUPPLEMENTARY.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	1	2	7	8
It was possible that all the effects of applying sErbB4-ECD on capsaicin responsiveness were due to blockade of endogenous Nrg1 stimulation of ErbB3 receptors located on adjacent Schwann cells , rather than to direct stimulation of Type III Nrg1 back signaling .	It was possible that all the effects of applying sErbB4-ECD on capsaicin responsiveness were due to blockade of endogenous Nrg1 stimulation of ErbB3 receptors located on adjacent Schwann cells, rather than to direct stimulation of Type III Nrg1 back signaling.	19	23	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB3	ErbB3	ErbB3	19	20	22	23
For an overall assessment of potential signaling mechanisms triggered by NRG1 stimulation in ERBB3 and ERBB4 expressing cells we next investigated which KEGG pathways were significantly enriched for regulated phosphoproteins ( harboring significantly regulated phosphosites ) compared to the entire detected phosphoproteome in Ba/F3 cells .	For an overall assessment of potential signaling mechanisms triggered by NRG1 stimulation in ERBB3 and ERBB4 expressing cells we next investigated which KEGG pathways were significantly enriched for regulated phosphoproteins (harboring significantly regulated phosphosites) compared to the entire detected phosphoproteome in Ba/F3 cells.	10	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB3	ERBB3	ERBB3	10	11	13	14
We show that NRG1 can stimulate the ErbB3 receptor on macrophages in order to induce JAG1 expression , which acts as a ligand for the tumor cell Notch receptor , increasing their capacity for transendothelial migration and intravasation .	We show that NRG1 can stimulate the ErbB3 receptor on macrophages in order to induce JAG1 expression, which acts as a ligand for the tumor cell Notch receptor, increasing their capacity for transendothelial migration and intravasation.	3	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	3	4	7	8
In this study , we show that NRG1 indeed induces upregulation of p-HER3 , which abrogates the effective inhibition of downstream p-AKT achieved by ALK inhibitors in the parental H3122 cells ( XREF_FIG ) .	In this study, we show that NRG1 indeed induces upregulation of p-HER3, which abrogates the effective inhibition of downstream p-AKT achieved by ALK inhibitors in the parental H3122 cells (XREF_FIG).	7	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	p-HER3	p-HER3	p-HER3	7	8	12	13
The NRG1 induced cell dependency on ErbB3 mediated cell survival pathway prompted us to hypothesize that the presence of high NRG1 levels in the omentum promotes the growth of ErbB3 + cancer cells .	The NRG1 induced cell dependency on ErbB3 mediated cell survival pathway prompted us to hypothesize that the presence of high NRG1 levels in the omentum promotes the growth of ErbB3 + cancer cells.	20	32	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1 levels	nrg1	ErbB3	ErbB3	erbb3	20	21	29	30
Also , in MCF10A cells expressing high levels of HER2 and Neu , a kinase domain mutant of PIK3CA ( H1047R ) induced expression of Heregulin , the ligand that activates HER2 and HER3 signaling through the PI3K pathway [ XREF_BIBR ] .	Also, in MCF10A cells expressing high levels of HER2 and Neu, a kinase domain mutant of PIK3CA (H1047R) induced expression of Heregulin, the ligand that activates HER2 and HER3 signaling through the PI3K pathway [XREF_BIBR].	18	34	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Heregulin	PIK3CA (H1047R) induced expression of Heregulin	heregulin	HER3	HER3	her3	25	26	33	34
Rather , we demonstrated that chronic HER3 signaling was driven by high-level and potentially autocrine expression of the alpha and beta forms of Neuregulin 1 ( NRG1 ) , collectively known as ( HRG ) XREF_BIBR , XREF_BIBR in cell lines derived from SCCHN .	Rather, we demonstrated that chronic HER3 signaling was driven by high-level and potentially autocrine expression of the alpha and beta forms of Neuregulin 1 (NRG1), collectively known as (HRG) XREF_BIBR, XREF_BIBR in cell lines derived from SCCHN.	6	26	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Neuregulin 1	expression of the alpha and beta forms of Neuregulin 1	neuregulin 1	HER3	HER3	her3	23	25	6	7
, the NRG1 induced p-HER3 ( Tyr1307 ) was not significantly affected ( XREF_SUPPLEMENTARY ) .	, the NRG1 induced p-HER3 (Tyr1307) was not significantly affected (XREF_SUPPLEMENTARY).	1	10	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	p-HER3	p-HER3	p-HER3	2	3	4	5
Heregulin has been shown to induce the transendothelial migration of HER2 and HER3 positive breast cancer cell lines across a tight barrier of primary brain microvascular endothelia .	Heregulin has been shown to induce the transendothelial migration of HER2 and HER3 positive breast cancer cell lines across a tight barrier of primary brain microvascular endothelia.	0	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	HER3	HER3	HER3	0	1	12	13
To determine effects of DJ-1 knockdown on HER3 signaling , HER3 downstream signaling molecules were monitored by WB after cells were treated with NRG-1 .	To determine effects of DJ-1 knockdown on HER3 signaling, HER3 downstream signaling molecules were monitored by WB after cells were treated with NRG-1.	10	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	HER3	HER3	HER3	23	24	10	11
This is exemplified by phosphosites close to the x axis in XREF_FIG , which were NRG1 induced to a similar level in cells lacking ERBB3 , while phosphorylation of sites close to the diagonal line largely depended on cellular ERBB3 expression .	This is exemplified by phosphosites close to the x axis in XREF_FIG, which were NRG1 induced to a similar level in cells lacking ERBB3, while phosphorylation of sites close to the diagonal line largely depended on cellular ERBB3 expression.	4	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB3	ERBB3	ERBB3	15	16	24	25
Mechanistically , NRG1 stimulation of ErbB4 results in a sustained [ Ca 2+ ] increase in neural progenitors which involves store operated calcium entry [ XREF_BIBR ] .	Mechanistically, NRG1 stimulation of ErbB4 results in a sustained [Ca 2+] increase in neural progenitors which involves store operated calcium entry [XREF_BIBR].	2	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	2	3	5	6
For example , NRG1 treatment led to GABA release in basket cell terminals , purportedly by the activation of ErbB4 by NRG1 [ XREF_BIBR ] .	For example, NRG1 treatment led to GABA release in basket cell terminals, purportedly by the activation of ErbB4 by NRG1 [XREF_BIBR].	17	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	21	22	19	20
In the cerebellar cortex , NRG1 release by afferent fibres induces the expression of NR2C subunits during synaptogenesis through the activation of ErbB4 receptors [ XREF_BIBR ] ; in the rat prefrontal cortex and in neuronal primary cultures , NRG1 activation of ErbB4 modulates NMDAR currents and regulates trafficking and endocytosis of NMDAR subunits at excitatory synapses [ XREF_BIBR ] ; NRG1 signalling through Fyn kinase modulates NMDAR phosphorylation [ XREF_BIBR ] ; activity driven glutamatergic synapse development is impaired by genetic deficits in NRG1 and ErbB4 signalling [ XREF_BIBR ] .	In the cerebellar cortex, NRG1 release by afferent fibres induces the expression of NR2C subunits during synaptogenesis through the activation of ErbB4 receptors [XREF_BIBR]; in the rat prefrontal cortex and in neuronal primary cultures, NRG1 activation of ErbB4 modulates NMDAR currents and regulates trafficking and endocytosis of NMDAR subunits at excitatory synapses [XREF_BIBR]; NRG1 signalling through Fyn kinase modulates NMDAR phosphorylation [XREF_BIBR]; activity driven glutamatergic synapse development is impaired by genetic deficits in NRG1 and ErbB4 signalling [XREF_BIBR].	39	43	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	39	40	42	43
CGCs are an especially attractive system for investigating NRG1 and ErbB4 signaling effects because CGCs express ErbB4 and NRG1 have been shown to activate pathways downstream of ErbB4 in these cells .	CGCs are an especially attractive system for investigating NRG1 and ErbB4 signaling effects because CGCs express ErbB4 and NRG1 have been shown to activate pathways downstream of ErbB4 in these cells.	16	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	18	19	27	28
It has been reported that NRG1 passes the blood brain barrier and activates ErbB4 in the brain XREF_BIBR , XREF_BIBR .	It has been reported that NRG1 passes the blood brain barrier and activates ErbB4 in the brain XREF_BIBR, XREF_BIBR.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	5	6	13	14
Importantly , post mortem studies demonstrate that schizophrenia subjects have increased neuregulin-1 mediated activation of ErbB4 , resulting in increased suppression of NMDA-R mediated glutamate transmission .	Importantly, post mortem studies demonstrate that schizophrenia subjects have increased neuregulin-1 mediated activation of ErbB4, resulting in increased suppression of NMDA-R mediated glutamate transmission.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	neuregulin-1	neuregulin-1	neuregulin-1	ErbB4	ErbB4	ErbB4	11	12	15	16
Another study reported that the expression levels of Nrg1 and ErbB4 are similar between SCZ postmortem tissue and controls , but there is an increase in Nrg1 induced ErbB4 activation and increases in ErbB4-PSD95 interactions .	Another study reported that the expression levels of Nrg1 and ErbB4 are similar between SCZ postmortem tissue and controls, but there is an increase in Nrg1 induced ErbB4 activation and increases in ErbB4-PSD95 interactions.	24	29	induced	Positive_early_activation	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	26	27	28	29
Nrg1 has been shown to penetrate blood-brain barrier , and peripherally administered Nrg1 activates ErbB4 and leads to a persistent hyperdopaminergic state in neonatal mice .	Nrg1 has been shown to penetrate blood-brain barrier, and peripherally administered Nrg1 activates ErbB4 and leads to a persistent hyperdopaminergic state in neonatal mice.	11	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	12	13	14	15
Moreover , we extended our analysis to ERBB4 Ba/F3 cells treated with NRG1 to investigate the role and contribution of ERBB3 in ligand stimulated cells .	Moreover, we extended our analysis to ERBB4 Ba/F3 cells treated with NRG1 to investigate the role and contribution of ERBB3 in ligand stimulated cells.	7	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB4	ERBB4	ERBB4	12	13	7	8
However , we did not observe any behavioral alterations in mice treated with an anti-ErbB4 antibody that was more potent in inhibiting NRG1 mediated ErbB4 activation .	However, we did not observe any behavioral alterations in mice treated with an anti-ErbB4 antibody that was more potent in inhibiting NRG1 mediated ErbB4 activation.	22	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	22	23	24	25
In addition , it has been reported that Nrg1 increases the release of the intracellular domain of ErbB4 , ErbB4-ICD , in neural precursor cells .	In addition, it has been reported that Nrg1 increases the release of the intracellular domain of ErbB4, ErbB4-ICD, in neural precursor cells.	8	19	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	8	9	17	18
Transwell assays on NMDA and NRG1 stimulated ErbB4 transfected cells in the presence of BAPTA .	Transwell assays on NMDA and NRG1 stimulated ErbB4 transfected cells in the presence of BAPTA.	1	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	5	6	7	8
As first described in our high-throughput cell based screening studies , K252a ( 1 ) potentiates Nrg1 induced neuritogenesis in PC12 cells expressing human ErbB4 within the same dose range ( 1-100 nM ) that inhibits NGF induced neuritogenesis in the same cell line , while K252a ( 1 ) alone does not cause neurite outgrowth ( XREF_FIG ) .	As first described in our high-throughput cell based screening studies, K252a (1) potentiates Nrg1 induced neuritogenesis in PC12 cells expressing human ErbB4 within the same dose range (1-100 nM) that inhibits NGF induced neuritogenesis in the same cell line, while K252a (1) alone does not cause neurite outgrowth (XREF_FIG).	16	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	16	17	24	25
Using two different antibodies of HER4 cytoplasmic domain , we showed that exogenous heregulin stimulation increased HER4 protein ; and the mRNA levels were concordantly upregulated .	Using two different antibodies of HER4 cytoplasmic domain, we showed that exogenous heregulin stimulation increased HER4 protein; and the mRNA levels were concordantly upregulated.	13	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER4	HER4	HER4	13	14	16	17
48 Consistent with this finding , NRG1 enhances the synchrony between firing pairs of fast spiking interneurons and pyramidal neurons by activating ErbB4 .	48 Consistent with this finding, NRG1 enhances the synchrony between firing pairs of fast spiking interneurons and pyramidal neurons by activating ErbB4.	6	23	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	6	7	22	23
Trastuzumab treatment and exogenous heregulin stimulation induce the upregulation of HER4 180kDa and HER4 80kDa in HER2 positive breast cancer .	Trastuzumab treatment and exogenous heregulin stimulation induce the upregulation of HER4 180kDa and HER4 80kDa in HER2 positive breast cancer.	4	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER4	HER4	HER4	4	5	10	11
Further , NRG1 has been demonstrated to activate ErbB4 and regulate GABAergic transmission in adult brains [ XREF_BIBR ] .	Further, NRG1 has been demonstrated to activate ErbB4 and regulate GABAergic transmission in adult brains [XREF_BIBR].	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	2	3	8	9
Neuregulin 1 activated ERBB4 interacts with YAP to induce Hippo pathway targetgenes and promote cell migration .	Neuregulin 1 activated ERBB4 interacts with YAP to induce Hippo pathway targetgenes and promote cell migration.	0	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Neuregulin 1	Neuregulin 1	Neuregulin 1	ERBB4	ERBB4	ERBB4	0	2	3	4
ErbB2 is the preferred coreceptor for ErbB4 , which is activated by NRG-1 .	ErbB2 is the preferred coreceptor for ErbB4, which is activated by NRG-1.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	ErbB4	ErbB4	ErbB4	12	13	6	7
In agreement , the ErbB4 , PSD-95 , and NMDA complex was more tightly coupled in schizophrenic brains and NRG1 mediated stimulation of ErbB4 was markedly enhanced .	In agreement, the ErbB4, PSD-95, and NMDA complex was more tightly coupled in schizophrenic brains and NRG1 mediated stimulation of ErbB4 was markedly enhanced.	19	24	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	19	20	23	24
Nrg1 activation of ErbB4 on axons of cortical GABAergic interneurons has been shown to enhance activity dependent GABA release .	Nrg1 activation of ErbB4 on axons of cortical GABAergic interneurons has been shown to enhance activity dependent GABA release.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	0	1	3	4
In this study , we provide evidence that neuregulin1-beta ( a.k.a. heregulin1-beta ) , a neuregulin-1 gene isoform that preferentially binds to and activates the ErbB4 receptor , evokes an almost immediate overflow of striatal dopamine when injected into a region just dorsal to the ipsilateral substantia nigra .	In this study, we provide evidence that neuregulin1-beta (a.k.a. heregulin1-beta), a neuregulin-1 gene isoform that preferentially binds to and activates the ErbB4 receptor, evokes an almost immediate overflow of striatal dopamine when injected into a region just dorsal to the ipsilateral substantia nigra.	15	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neuregulin-1	neuregulin-1	neuregulin-1	ErbB4	ErbB4	ErbB4	15	16	25	26
Our data reveal , for the first time , that stimulation of ErbB4 signaling by NRG-1 upregulates the expression of K ( + ) channel proteins via activation of the Akt and mTOR signaling pathway and plays an important role in neuronal development and maturation .	Our data reveal, for the first time, that stimulation of ErbB4 signaling by NRG-1 upregulates the expression of K (+) channel proteins via activation of the Akt and mTOR signaling pathway and plays an important role in neuronal development and maturation.	12	16	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	ErbB4	ErbB4	ErbB4	15	16	12	13
Also , we can not rule out the hypothesis that the timing of the present study has hidden the NRG1 induced transient activation of some signalling pathways downstream ErbB4 .	Also, we can not rule out the hypothesis that the timing of the present study has hidden the NRG1 induced transient activation of some signalling pathways downstream ErbB4.	18	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	19	20	28	29
ErbB4-PSD95 interaction facilitates NRG1 mediated activation of ErbB4 .	ErbB4-PSD95 interaction facilitates NRG1 mediated activation of ErbB4.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	3	4	7	8
Enhanced NRG1 mediated ErbB4 signaling and subsequent decreased activation of NMDARs was found in postmortem human brains .	Enhanced NRG1 mediated ErbB4 signaling and subsequent decreased activation of NMDARs was found in postmortem human brains.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	1	2	3	4
Our data further indicate a significant contribution of ERBB3 in NRG1 triggered ERBB and ERBB4 signaling .	Our data further indicate a significant contribution of ERBB3 in NRG1 triggered ERBB and ERBB4 signaling.	8	15	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB4	ERBB4	ERBB4	10	11	14	15
Endocardial Nrg1 signaling mediates ligand dependent heterodimersation of ErbB2 and ErbB4 within the heart myocardium .	Endocardial Nrg1 signaling mediates ligand dependent heterodimersation of ErbB2 and ErbB4 within the heart myocardium.	1	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	1	2	10	11
A similar differential phosphorylation resulting in differential signaling has been described for ErbB4 , albeit induced by different Nrg1 ligands .	A similar differential phosphorylation resulting in differential signaling has been described for ErbB4, albeit induced by different Nrg1 ligands.	10	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	18	19	12	13
Moreover , pharmacological and genetic studies showed that the blockade of LTP by NRG1 required stimulation of ErbB4 .	Moreover, pharmacological and genetic studies showed that the blockade of LTP by NRG1 required stimulation of ErbB4.	13	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	13	14	17	18
Neuregulin-1 Stimulates ErbB4 to Enhance Excitement ( and Stability ) at the Synapse .	Neuregulin-1 Stimulates ErbB4 to Enhance Excitement (and Stability) at the Synapse.	0	3	Stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Neuregulin-1	Neuregulin-1	Neuregulin-1	ErbB4	ErbB4	ErbB4	0	1	2	3
Consistently , NRG-1 activated the ErbB4 receptor in isolated macrophages , inhibited phosphatidylinositide 3-kinase/Akt and STAT3 signaling pathways , and reduced the release of inflammatory cytokines .	Consistently, NRG-1 activated the ErbB4 receptor in isolated macrophages, inhibited phosphatidylinositide 3-kinase/Akt and STAT3 signaling pathways, and reduced the release of inflammatory cytokines.	2	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	ErbB4	ErbB4	ErbB4	2	3	5	6
This form of NRG1 has been shown previously to penetrate the blood-brain barrier and functionally activate ErbB4 in the cortex .	This form of NRG1 has been shown previously to penetrate the blood-brain barrier and functionally activate ErbB4 in the cortex.	1	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	3	4	16	17
In an excellent study with postmortem brains from patients with SZ , a marked increase in NRG1 induced activation of ErbB4 and suppression of NMDA-type glutamate receptor activation is observed , in comparison with normal controls .	In an excellent study with postmortem brains from patients with SZ, a marked increase in NRG1 induced activation of ErbB4 and suppression of NMDA-type glutamate receptor activation is observed, in comparison with normal controls.	14	27	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	16	17	20	21
At the hippocampal CA3-CA1 pathway , activity dependent release of NRG1 from presynaptic CA3 pyramidal cells activates postsynaptic ErbB4 receptors .	At the hippocampal CA3-CA1 pathway, activity dependent release of NRG1 from presynaptic CA3 pyramidal cells activates postsynaptic ErbB4 receptors.	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	10	11	18	19
However , neu differentiation factor induced heterodimers of ErbB2 and ErbB4 activated Stat5 .	However, neu differentiation factor induced heterodimers of ErbB2 and ErbB4 activated Stat5.	2	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neu differentiation factor	neu differentiation factor	neu differentiation factor	ErbB4	ErbB4	ErbB4	2	5	10	11
This was done via p63 transcriptional regulation of Nrg1 , which in turn activated ErbB4 and STAT5A in LEPs facilitating LEPs differentiation [ XREF_BIBR * ] .	This was done via p63 transcriptional regulation of Nrg1, which in turn activated ErbB4 and STAT5A in LEPs facilitating LEPs differentiation [XREF_BIBR *].	6	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	8	9	14	15
The heregulin induced cleavage of ErbB-4 could be blocked by conditions that prevent clathrin coated pit formation , suggesting that heregulin mediated ErbB-4 cleavage occurs subsequent to internalization .	The heregulin induced cleavage of ErbB-4 could be blocked by conditions that prevent clathrin coated pit formation, suggesting that heregulin mediated ErbB-4 cleavage occurs subsequent to internalization.	20	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB-4	ErbB-4	ErbB-4	20	21	22	23
ErbB2 is a coreceptor for ErbB4 , which is activated by neuregulin-1 .	ErbB2 is a coreceptor for ErbB4, which is activated by neuregulin-1.	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	neuregulin-1	neuregulin-1	neuregulin-1	ErbB4	ErbB4	ErbB4	11	12	5	6
By cell type specific gene modulation in vitro and in vivo including in a mutant DISC1 mouse model , we demonstrate that DISC1 inhibits NRG1 induced ErbB4 activation and signalling .	By cell type specific gene modulation in vitro and in vivo including in a mutant DISC1 mouse model, we demonstrate that DISC1 inhibits NRG1 induced ErbB4 activation and signalling.	24	27	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	24	25	26	27
As a result , we have shown that both ErbB4 and pErbB4 stimulated by heregulin can be detected in the cytoplasm of HCT 116 cells .	As a result, we have shown that both ErbB4 and pErbB4 stimulated by heregulin can be detected in the cytoplasm of HCT 116 cells.	9	17	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	pErbB4	pErbB4	pErbB4	14	15	11	12
NRG1 and ErbB signalling is likely an important paracrine mediator of cell-to-cell interactions that exerts a negative inotropic effect via activation of the muscarinic response and helps regenerate cardiomyocytes following cardiac ischaemia via an NRG1 mediated ErbB2 and ErbB4 signalling pathway .	NRG1 and ErbB signalling is likely an important paracrine mediator of cell-to-cell interactions that exerts a negative inotropic effect via activation of the muscarinic response and helps regenerate cardiomyocytes following cardiac ischaemia via an NRG1 mediated ErbB2 and ErbB4 signalling pathway.	0	40	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	0	1	38	39
Yet , these data suggest that NRG1 overexpression leads to altered ErbB4 + cell soma count of interneurons other than those expressing PV .	Yet, these data suggest that NRG1 overexpression leads to altered ErbB4 + cell soma count of interneurons other than those expressing PV.	6	15	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	NRG1	NRG1 overexpression	nrg1	ErbB4	ErbB4	erbb4	6	7	11	12
Thus ErbB2 may not be required for Nrg-1 induced activation of PI3-kinase and Akt , so long as Nrg-1 is available at sufficient concentration to activate ErbB4 and ErbB4 homodimers , promoting cytoprotection .	Thus ErbB2 may not be required for Nrg-1 induced activation of PI3-kinase and Akt, so long as Nrg-1 is available at sufficient concentration to activate ErbB4 and ErbB4 homodimers, promoting cytoprotection.	18	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg-1	Nrg-1	Nrg-1	ErbB4	ErbB4	ErbB4	18	19	26	27
Further , NRG1 has been demonstrated to activate ErbB4 and regulate GABAergic transmission in adult brains .	Further, NRG1 has been demonstrated to activate ErbB4 and regulate GABAergic transmission in adult brains.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	2	3	8	9
These results suggest that , at least to the limits of our detection methods , the stimulation of Nrg1 mediated neuritogenesis through K252a mediated AAK1 or siRNA silencing of AAK1 does not involving block Nrg1 induced ErbB4 endocytosis .	These results suggest that, at least to the limits of our detection methods, the stimulation of Nrg1 mediated neuritogenesis through K252a mediated AAK1 or siRNA silencing of AAK1 does not involving block Nrg1 induced ErbB4 endocytosis.	33	37	induced	Positive_early_activation	Positive_activation	Negative_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	34	35	36	37
Consistently , another study has revealed that although NRG1 induced activation of erbB4 markedly increases in the prefrontal cortex of schizophrenia patients , levels of NRG1 and erbB4 are unchanged in both patients and controls [ XREF_BIBR ] .	Consistently, another study has revealed that although NRG1 induced activation of erbB4 markedly increases in the prefrontal cortex of schizophrenia patients, levels of NRG1 and erbB4 are unchanged in both patients and controls [XREF_BIBR].	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	erbB4	erbB4	erbB4	8	9	12	13
Interestingly , we found this interaction was reduced when a kinase dead version of ErbB4 was expressed , indicating DISC1 may require NRG1 activation of ErbB4 for intracellular binding ( XREF_FIG ) .	Interestingly, we found this interaction was reduced when a kinase dead version of ErbB4 was expressed, indicating DISC1 may require NRG1 activation of ErbB4 for intracellular binding (XREF_FIG).	22	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	22	23	25	26
Comparative assessment of NRG1 stimulated ERBB4 Ba/F3 cells revealed that ERBB3 did not trigger defined signaling pathways but more broadly enhanced phosphoproteome regulation in cells expressing both receptors .	Comparative assessment of NRG1 stimulated ERBB4 Ba/F3 cells revealed that ERBB3 did not trigger defined signaling pathways but more broadly enhanced phosphoproteome regulation in cells expressing both receptors.	1	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB4	ERBB4	ERBB4	3	4	5	6
Therefore , it would be necessary to know whether Nrg1 mediated blockade of NMDAR activity enhancement requires Erbb4 in pyramidal neurons or interneurons .	Therefore, it would be necessary to know whether Nrg1 mediated blockade of NMDAR activity enhancement requires Erbb4 in pyramidal neurons or interneurons.	9	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	Erbb4	Erbb4	Erbb4	9	10	17	18
ErbB4 is capable of forming homodimers and heterodimers , and it has been shown that the neuregulin-1 ( NRG1 ) ligand promotes the homodimerization of ErbB4 as well as the heterodimerization of ErbB4 with ErbB3 .	ErbB4 is capable of forming homodimers and heterodimers, and it has been shown that the neuregulin-1 (NRG1) ligand promotes the homodimerization of ErbB4 as well as the heterodimerization of ErbB4 with ErbB3.	16	26	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	18	19	25	26
NRG1 treatment significantly increased the coprecipitated ErbB4 , whereas pretreatment with K252a abolished the interaction .	NRG1 treatment significantly increased the coprecipitated ErbB4, whereas pretreatment with K252a abolished the interaction.	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	0	1	6	7
These corridor cells express high levels of cysteine-rich-domain-containing NRG1 ( CDR-NRG1 , synonymously NRG1 type III ) that is thought to activate ErbB4 dependent signaling in TCAs , allowing further growth passing through the developing diencephalon .	These corridor cells express high levels of cysteine-rich-domain-containing NRG1 (CDR-NRG1, synonymously NRG1 type III) that is thought to activate ErbB4 dependent signaling in TCAs, allowing further growth passing through the developing diencephalon.	5	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	levels of cysteine-rich-domain-containing NRG1	nrg1	ErbB4	ErbB4	erbb4	8	9	22	23
Given our current finding that DISC1 reduces NRG1 induced ErbB4 activation , we predict that DISC1 might also reduce Kal7-Rac1 signalling .	Given our current finding that DISC1 reduces NRG1 induced ErbB4 activation, we predict that DISC1 might also reduce Kal7-Rac1 signalling.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	7	8	9	10
Increased NRG1 induced ErbB4 activity was observed in postmortem tissue samples from Schizophrenic patients causing attenuation of the NMDA receptor function .	Increased NRG1 induced ErbB4 activity was observed in postmortem tissue samples from Schizophrenic patients causing attenuation of the NMDA receptor function.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	1	2	3	4
When reagents that prevent acidification of endosomes were employed , heregulin induced ErbB-4 cleavage was sensitive to metalloprotease inhibitors .	When reagents that prevent acidification of endosomes were employed, heregulin induced ErbB-4 cleavage was sensitive to metalloprotease inhibitors.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB-4	ErbB-4	ErbB-4	10	11	12	13
NRG1 mediated ErbB4 signalling regulates many important cellular processes such as growth , differentiation and death in various cell-types , particularly in myelin producing cells , glia and neurons XREF_BIBR .	NRG1 mediated ErbB4 signalling regulates many important cellular processes such as growth, differentiation and death in various cell-types, particularly in myelin producing cells, glia and neurons XREF_BIBR.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	0	1	2	3
Increased activation of the ErbB4 receptor induced by NRG1 was previously reported in a SCZ postmortem brain study XREF_BIBR .	Increased activation of the ErbB4 receptor induced by NRG1 was previously reported in a SCZ postmortem brain study XREF_BIBR.	4	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	8	9	4	5
Bersell et al demonstrated that Neuregulin 1 stimulates cell cycle reentry , karyokinesis , and cytokinesis of rat ventricular cardiomyocytes by activating tyrosine kinase signaling downstream of the ErbB4 receptor 27 .	Bersell et al demonstrated that Neuregulin 1 stimulates cell cycle reentry, karyokinesis, and cytokinesis of rat ventricular cardiomyocytes by activating tyrosine kinase signaling downstream of the ErbB4 receptor 27.	5	29	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Neuregulin 1	Neuregulin 1	Neuregulin 1	ErbB4	ErbB4	ErbB4	5	7	28	29
Acutely , NRG1 promotes GABA release by activating ErbB4 in GABAergic neurons and thus regulates the firing of excitatory neurons and LTP .	Acutely, NRG1 promotes GABA release by activating ErbB4 in GABAergic neurons and thus regulates the firing of excitatory neurons and LTP.	2	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	2	3	8	9
Together , the results suggest that basal and NRG1 induced ErbB4 activity is similar between control and ctoNrg1 mice .	Together, the results suggest that basal and NRG1 induced ErbB4 activity is similar between control and ctoNrg1 mice.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	8	9	10	11
However , Nrg1 stimulation increases ErbB4 signaling and heightens the attenuation of NMDA receptor phosphorylation in tissue isolated from schizophrenia patients , suggesting ErbB4 signaling pathways may be hypersensitized in schizophrenia .	However, Nrg1 stimulation increases ErbB4 signaling and heightens the attenuation of NMDA receptor phosphorylation in tissue isolated from schizophrenia patients, suggesting ErbB4 signaling pathways may be hypersensitized in schizophrenia.	2	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	2	3	5	6
NRG1 activates ErbB4 and induced its proteolytic cleavage by ADAM17 , resulting in an enhanced SREBP2 cleavage and nuclear activation 15 .	NRG1 activates ErbB4 and induced its proteolytic cleavage by ADAM17, resulting in an enhanced SREBP2 cleavage and nuclear activation 15.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	0	1	2	3
In summary , NRG1 stimulation of the ErbB4 receptor exerts a sustained [ Ca 2+ ] i increase in ST14A neural progenitors ; NRG1 induced migration is Ca 2+ -dependent and can be positively modulated by activation of the NMDA receptor .	In summary, NRG1 stimulation of the ErbB4 receptor exerts a sustained [Ca 2+] i increase in ST14A neural progenitors; NRG1 induced migration is Ca 2+ -dependent and can be positively modulated by activation of the NMDA receptor.	3	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	3	4	7	8
Based on this ligand-receptor configuration , NRG1 mediates juxtacrine and paracrine signaling to ERBB4 .	Based on this ligand-receptor configuration, NRG1 mediates juxtacrine and paracrine signaling to ERBB4.	6	14	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB4	ERBB4	ERBB4	6	7	13	14
XREF_BIBR NRG1 mediated erbB4 activation has been shown to modulate interneuron function ; XREF_BIBR - XREF_BIBR however , the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood .	XREF_BIBR NRG1 mediated erbB4 activation has been shown to modulate interneuron function; XREF_BIBR - XREF_BIBR however, the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	erbB4	erbB4	erbB4	1	2	3	4
NRG1 induced ErbB4 activation is known to increase GABA release [ XREF_BIBR ] .	NRG1 induced ErbB4 activation is known to increase GABA release [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	0	1	2	3
Monitoring adapter interactions with Nrg1 activated ErbB4 receptors .	Monitoring adapter interactions with Nrg1 activated ErbB4 receptors.	2	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	4	5	6	7
In support of the interpretation that the effect of K252a mediated AAK1 inhibition does not block Nrg1 stimulated ErbB4 endocytosis , previous studies have shown that the inhibition of ErbB4 endocytosis attenuated Nrg1 induced activation of ERK1/2 , whereas we did not observe such attenuation with K252a ( 1 ) treatment ( XREF_FIG ) .	In support of the interpretation that the effect of K252a mediated AAK1 inhibition does not block Nrg1 stimulated ErbB4 endocytosis, previous studies have shown that the inhibition of ErbB4 endocytosis attenuated Nrg1 induced activation of ERK1/2, whereas we did not observe such attenuation with K252a (1) treatment (XREF_FIG).	15	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	16	17	18	19
Nrg-1 activation of ErbB4 is associated with translocation of receptor to a triton-insoluble membrane fraction , likely caveolae [ XREF_BIBR ] .	Nrg-1 activation of ErbB4 is associated with translocation of receptor to a triton-insoluble membrane fraction, likely caveolae [XREF_BIBR].	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Nrg-1	Nrg-1	Nrg-1	ErbB4	ErbB4	ErbB4	0	1	3	4
Heregulin mediated activation of HER4 initiates receptor cleavage ( releasing an 80-kDa HER4 intracellular domain , s80 ( HER4 ) , containing nuclear localization sequences ) and results in G ( 2 )-M delay by unknown signaling mechanisms .	Heregulin mediated activation of HER4 initiates receptor cleavage (releasing an 80-kDa HER4 intracellular domain, s80 (HER4), containing nuclear localization sequences) and results in G (2)-M delay by unknown signaling mechanisms.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	HER4	HER4	HER4	0	1	4	5
Neuregulin 1 ( NRG1 ) secreted by endocardial cells activates ErbB2 and ErbB4 receptors in myocardial cells to promote formation of trabecular myocardium .	Neuregulin 1 (NRG1) secreted by endocardial cells activates ErbB2 and ErbB4 receptors in myocardial cells to promote formation of trabecular myocardium.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	3	4	12	13
In HER2 negative MCF7 cells , trastuzumab treatment and heregulin stimulation also induced an upregulation of HER4 at 180kDa but no obvious increase in HER4 80kDa was detected ( XREF_SUPPLEMENTARY ) .	In HER2 negative MCF7 cells, trastuzumab treatment and heregulin stimulation also induced an upregulation of HER4 at 180kDa but no obvious increase in HER4 80kDa was detected (XREF_SUPPLEMENTARY).	9	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER4	HER4	HER4	9	10	16	17
This augmentation was significantly greater in cells expressing DISC1 shRNA compared with those with control shRNA , suggesting that DISC1 knockdown enhances activation of ErbB4 by NRG1 ( XREF_FIG ) .	This augmentation was significantly greater in cells expressing DISC1 shRNA compared with those with control shRNA, suggesting that DISC1 knockdown enhances activation of ErbB4 by NRG1 (XREF_FIG).	21	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	26	27	24	25
Here we show that NRG1 stimulated the proliferation of human HeLa cells expressing ErbB4 , where the phosphorylation relay of extracellular signal regulated kinase , a mitogen activated protein kinase ( MAPK ) , and serum response factor ( SRF ) , a transcription factor , was induced , and the c-fos transcription was activated .	Here we show that NRG1 stimulated the proliferation of human HeLa cells expressing ErbB4, where the phosphorylation relay of extracellular signal regulated kinase, a mitogen activated protein kinase (MAPK), and serum response factor (SRF), a transcription factor, was induced, and the c-fos transcription was activated.	4	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	4	5	13	14
In line with this model , NRG1 activation of ERBB4 receptors was found to be significantly enhanced in postmortem tissue from the dorsolateral prefrontal cortex ( PFC ) of schizophrenia patients .	In line with this model, NRG1 activation of ERBB4 receptors was found to be significantly enhanced in postmortem tissue from the dorsolateral prefrontal cortex (PFC) of schizophrenia patients.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB4	ERBB4	ERBB4	6	7	9	10
Here we suggest that the influence of DISC1 on NRG1 induced ErbB4 activation is likely mediated by competitive inhibition of binding of ErbB4 to PSD95 .	Here we suggest that the influence of DISC1 on NRG1 induced ErbB4 activation is likely mediated by competitive inhibition of binding of ErbB4 to PSD95.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	9	10	11	12
Immunofluorescence analysis of phosphoErbB4 and parvalbumin showed that NRG1 induced ErbB4 activation occurs in GABAergic interneurons .	Immunofluorescence analysis of phosphoErbB4 and parvalbumin showed that NRG1 induced ErbB4 activation occurs in GABAergic interneurons.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	8	9	10	11
Following peripheral administration , a mature form of NRG1 or an epidermal growth factor ( EGF )-like core domain of NRG1 ( eNRG1 ) penetrates the blood-brain barrier of the neonates and activates ErbB4 in the midbrain and neocortex XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Following peripheral administration, a mature form of NRG1 or an epidermal growth factor (EGF)-like core domain of NRG1 (eNRG1) penetrates the blood-brain barrier of the neonates and activates ErbB4 in the midbrain and neocortex XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	6	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	8	9	33	34
For instance , activation of the ErbB2 and ErbB4 tyrosine kinase receptors by the growth factor neuregulin-1 can stimulate PI3K signaling .	For instance, activation of the ErbB2 and ErbB4 tyrosine kinase receptors by the growth factor neuregulin-1 can stimulate PI3K signaling.	3	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	neuregulin-1	neuregulin-1	neuregulin-1	ErbB4	ErbB4	ErbB4	16	17	8	9
Here we have documented ErbB expression in three immortalized cell lines and shown that NRG1 induces the phosphotyrosylation of the ErbB4 receptor in these cells .	Here we have documented ErbB expression in three immortalized cell lines and shown that NRG1 induces the phosphotyrosylation of the ErbB4 receptor in these cells.	14	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	14	15	20	21
Interestingly , Nrg1 induced activation of erbB4 in mice was found to have a trend for an increase in Nrg1 +/- examined in this study ( unpublished observation ) .	Interestingly, Nrg1 induced activation of erbB4 in mice was found to have a trend for an increase in Nrg1 +/- examined in this study (unpublished observation).	2	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	erbB4	erbB4	erbB4	2	3	6	7
Heregulin stimulation ( XREF_SUPPLEMENTARY ) and trastuzumab treatment induced HER4 nuclear localisation in SKBR3 cells .	Heregulin stimulation (XREF_SUPPLEMENTARY) and trastuzumab treatment induced HER4 nuclear localisation in SKBR3 cells.	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	HER4	HER4	HER4	0	1	9	10
We found that NRG1 activated ERBB4 enhances cholesterogenic gene expression through SREBP-2 , a master regulator of cholesterol metabolism .	We found that NRG1 activated ERBB4 enhances cholesterogenic gene expression through SREBP-2, a master regulator of cholesterol metabolism.	3	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB4	ERBB4	ERBB4	3	4	5	6
A recent study demonstrated that NRG1 induced activation of ErbB4 stimulates the MAPK , PI3K , and cyclin dependent kinase-5 ( cdk5 ) pathways in cultured rat cerebellar granule neurons [ XREF_BIBR ] .	A recent study demonstrated that NRG1 induced activation of ErbB4 stimulates the MAPK, PI3K, and cyclin dependent kinase-5 (cdk5) pathways in cultured rat cerebellar granule neurons [XREF_BIBR].	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	5	6	9	10
On the other hand , NMDA could have no effect per se in ST14A cell migration , and have instead an effect when added together with other molecules , such as members of the neuregulin family , and specifically NRG1 , that has been shown to promote ErbB4 mediated neuronal migration [ XREF_BIBR - XREF_BIBR ] .	On the other hand, NMDA could have no effect per se in ST14A cell migration, and have instead an effect when added together with other molecules, such as members of the neuregulin family, and specifically NRG1, that has been shown to promote ErbB4 mediated neuronal migration [XREF_BIBR - XREF_BIBR].	21	48	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	39	40	47	48
Also , immunofluorescence data confirmed our western blot results that NRG1 induced ErbB4 activation is not dependent on TrkB activation status .	Also, immunofluorescence data confirmed our western blot results that NRG1 induced ErbB4 activation is not dependent on TrkB activation status.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	10	11	12	13
Thus , ErbB4 signaling induced by neuropsin dependent processing of NRG-1 contributes to the modulation of synaptic plasticity via regulation of GABAergic transmission .	Thus, ErbB4 signaling induced by neuropsin dependent processing of NRG-1 contributes to the modulation of synaptic plasticity via regulation of GABAergic transmission.	2	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	ErbB4	ErbB4	ErbB4	10	11	2	3
NRG1 activated ERBB4 regulation of cholesterogenic genes that we identified by transcriptional profiling could occur through an SREBP dependent or SREBP independent mechanism .	NRG1 activated ERBB4 regulation of cholesterogenic genes that we identified by transcriptional profiling could occur through an SREBP dependent or SREBP independent mechanism.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB4	ERBB4	ERBB4	0	1	2	3
We again found that NRG1 induced ErbB4 activation , measured by interneuron specific pErbB4 immunoreactivity , was significantly greater in cells expressing DISC1 shRNA compared with those with control shRNA ( XREF_SUPPLEMENTARY ) .	We again found that NRG1 induced ErbB4 activation, measured by interneuron specific pErbB4 immunoreactivity, was significantly greater in cells expressing DISC1 shRNA compared with those with control shRNA (XREF_SUPPLEMENTARY).	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	4	5	6	7
Recently , it is shown that NRG1 mediated ErbB4 signalling regulates many important cellular and molecular processes such as cellular growth , differentiation and death , particularly in myelin producing cells , glia and neurons .	Recently, it is shown that NRG1 mediated ErbB4 signalling regulates many important cellular and molecular processes such as cellular growth, differentiation and death, particularly in myelin producing cells, glia and neurons.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	6	7	8	9
By contrast , activation of either ErbB-3 or ErbB-4 by NDF did not affect tyrosine phosphorylation of c-Cbl .	By contrast, activation of either ErbB-3 or ErbB-4 by NDF did not affect tyrosine phosphorylation of c-Cbl.	3	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NDF	NDF	NDF	ErbB-4	ErbB-4	ErbB-4	10	11	8	9
To test this , we first examined whether DISC1 knockdown affects NRG1 induced ErbB4 activation in vitro .	To test this, we first examined whether DISC1 knockdown affects NRG1 induced ErbB4 activation in vitro.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	11	12	13	14
Activation of ErbB4 by Nrg1 may induce a marked increase in ErbB4 phosphorylation and lead to a sustained activation of Akt and Erk .	Activation of ErbB4 by Nrg1 may induce a marked increase in ErbB4 phosphorylation and lead to a sustained activation of Akt and Erk.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	4	5	2	3
The NRG1 induced activation of ErbB4 stimulates the mitogen activated protein kinase ( MAPK ) , phosphatidylinositol 3-kinase ( PI3K ) and cyclin dependent kinase-5 ( cdk5 ) pathways .	The NRG1 induced activation of ErbB4 stimulates the mitogen activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and cyclin dependent kinase-5 (cdk5) pathways.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	1	2	5	6
In the presented 2-cell batch assays , ErbB4 was stimulated by a full-length Nrg1 variant expressed exclusively in neighbouring cells .	In the presented 2-cell batch assays, ErbB4 was stimulated by a full-length Nrg1 variant expressed exclusively in neighbouring cells.	7	14	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	13	14	7	8
Thus , NRG1 induced activation of ErbB4 in parvalbumin expressing inhibitory interneurons may serve as a critical endogenous negative-feedback mechanism to suppress limbic epileptogenesis .	Thus, NRG1 induced activation of ErbB4 in parvalbumin expressing inhibitory interneurons may serve as a critical endogenous negative-feedback mechanism to suppress limbic epileptogenesis.	2	8	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	2	3	6	7
Subsequently , we investigated if NRG1 stimulation in ErbB4 transfected cells could elicit calcium signals .	Subsequently, we investigated if NRG1 stimulation in ErbB4 transfected cells could elicit calcium signals.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	5	6	8	9
Thus , it is possible that the activation of ErbB4 by NRG1 contributes to NR2B phosphorylation by inducing the GABA A R mediated release of BDNF from neurons , which then act on TrkB expressing neurons promoting NR2B activation via PLCgamma .	Thus, it is possible that the activation of ErbB4 by NRG1 contributes to NR2B phosphorylation by inducing the GABA A R mediated release of BDNF from neurons, which then act on TrkB expressing neurons promoting NR2B activation via PLCgamma.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	11	12	9	10
Indeed , NRG1 stimulation of ErbB4 receptors elicits long lasting increases in [ Ca 2+ ] i , with a mechanism involving store operated calcium entry ( SOCE ) .	Indeed, NRG1 stimulation of ErbB4 receptors elicits long lasting increases in [Ca 2+] i, with a mechanism involving store operated calcium entry (SOCE).	2	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	2	3	5	6
Using a postmortem tissue stimulation approach , XREF_BIBR showed a marked increase in NRG1 induced activation of ErbB4 in the prefrontal cortex in schizophrenia , although the absolute levels of NRG1 ErbB4 did not differ significantly between schizophrenia and control groups .	Using a postmortem tissue stimulation approach, XREF_BIBR showed a marked increase in NRG1 induced activation of ErbB4 in the prefrontal cortex in schizophrenia, although the absolute levels of NRG1 ErbB4 did not differ significantly between schizophrenia and control groups.	11	18	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	13	14	17	18
Finally , we used the well known phosphorylation dependent interactions of cytosolic adapter proteins to Nrg1 activated ErbB4 [ XREF_BIBR ] to show the applicability of split-TEV assays to monitor regulated interactions at the membrane of living cells .	Finally, we used the well known phosphorylation dependent interactions of cytosolic adapter proteins to Nrg1 activated ErbB4 [XREF_BIBR] to show the applicability of split-TEV assays to monitor regulated interactions at the membrane of living cells.	13	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	15	16	17	18
Here , using a new postmortem tissue stimulation approach , we show a marked increase in NRG1 induced activation of erbB4 in the prefrontal cortex in schizophrenia .	Here, using a new postmortem tissue stimulation approach, we show a marked increase in NRG1 induced activation of erbB4 in the prefrontal cortex in schizophrenia.	14	21	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	erbB4	erbB4	erbB4	16	17	20	21
ErbB4 activator Nrg1 isoform beta1 ( Nrg1beta1 ) , Specific ErbB4 siRNA , YAP siRNA and PIK3CB specific inhibitor TGX 221 were used to manipulate the proposed pathway .	ErbB4 activator Nrg1 isoform beta1 (Nrg1beta1), Specific ErbB4 siRNA, YAP siRNA and PIK3CB specific inhibitor TGX 221 were used to manipulate the proposed pathway.	0	6	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	2	3	0	1
The activation of ErbB2 and ErbB4 signaling by NRG-1 has been found to be important for cardiomyocyte survival .	The activation of ErbB2 and ErbB4 signaling by NRG-1 has been found to be important for cardiomyocyte survival.	3	9	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	ErbB4	ErbB4	ErbB4	8	9	5	6
Quantification of these results showed a significantly higher phosphorylation ratio of ERBB3 ( by 142 folds ) , but not of ERBB4 , in the liver of mice treated with NRG1 compared with controls ( p < 0.01 , XREF_FIG ) .	Quantification of these results showed a significantly higher phosphorylation ratio of ERBB3 (by 142 folds), but not of ERBB4, in the liver of mice treated with NRG1 compared with controls (p < 0.01, XREF_FIG).	19	31	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB4	ERBB4	ERBB4	30	31	21	22
ErbB4 is highly abundant in interneurons , and NRG1 mediated erbB4 activation has been shown to modulate interneuron function , but the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood .	ErbB4 is highly abundant in interneurons, and NRG1 mediated erbB4 activation has been shown to modulate interneuron function, but the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood.	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	erbB4	erbB4	erbB4	8	9	10	11
The clients of extracellular HSP90 are probably the proteins secreted into the extracellular space and/or binding to the cell surface : Extracellular HSP90 interacts with secreted matrix metalloproteinase 2 and changes matrix metalloproteinase 2 to an active form , while extracellular HSP90 binds to human epidermal growth factor receptor-2 ( HER-2 ) , a membrane receptor , and assists HER-2 and HER-3 heterodimer formation , which is necessary for heregulin induced HER-2 activation and signaling .	The clients of extracellular HSP90 are probably the proteins secreted into the extracellular space and/or binding to the cell surface : Extracellular HSP90 interacts with secreted matrix metalloproteinase 2 and changes matrix metalloproteinase 2 to an active form, while extracellular HSP90 binds to human epidermal growth factor receptor-2 (HER-2), a membrane receptor, and assists HER-2 and HER-3 heterodimer formation, which is necessary for heregulin induced HER-2 activation and signaling.	67	72	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER-2	HER-2	HER-2	69	70	71	72
For example , MUC1 forms complexes with ERBB2 and functions in promoting heregulin induced ERBB2 signalling XREF_BIBR - XREF_BIBR ( XREF_FIG ) .	For example, MUC1 forms complexes with ERBB2 and functions in promoting heregulin induced ERBB2 signalling XREF_BIBR - XREF_BIBR (XREF_FIG).	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ERBB2	ERBB2	ERBB2	12	13	14	15
Noncleavable variants of TGF-beta can activate the EGF ( ErbB1 ) receptor and plasma membrane preparations harboring human NRG1 type I stimulate ErbB2 phoshorylation and DNA synthesis in cultured cells .	Noncleavable variants of TGF-beta can activate the EGF (ErbB1) receptor and plasma membrane preparations harboring human NRG1 type I stimulate ErbB2 phoshorylation and DNA synthesis in cultured cells.	16	23	stimulate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB2	ErbB2	ErbB2	18	19	22	23
Therefore , NRG1 activation of ErbB2 and 3 can stimulate the increase of Rac1-GTP and Cdc42-GTP to enhance Schwann cell migration .	Therefore, NRG1 activation of ErbB2 and 3 can stimulate the increase of Rac1-GTP and Cdc42-GTP to enhance Schwann cell migration.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB2	ErbB2	ErbB2	2	3	5	6
In cell lines , heregulin stimulation of HER2 signaling results in NF-kappaB activation , which is blocked entirely by the specific inhibition of IKK by the NBD peptide ( XREF_FIG ) .	In cell lines, heregulin stimulation of HER2 signaling results in NF-kappaB activation, which is blocked entirely by the specific inhibition of IKK by the NBD peptide (XREF_FIG).	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	4	5	7	8
Lastly , in vitro data suggest that heregulin induced HER2 : HER3 heterodimers mediate trastuzumab insensitivity by activating signaling through the AKT-mTOR pathway , and that trastuzumab is ineffective in abrogating this signal [ XREF_BIBR ] .	Lastly, in vitro data suggest that heregulin induced HER2 : HER3 heterodimers mediate trastuzumab insensitivity by activating signaling through the AKT-mTOR pathway, and that trastuzumab is ineffective in abrogating this signal [XREF_BIBR].	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	7	8	9	10
A recent study reported that SH3TC2 regulates endocytosis of Nrg1 activated ErbB2 receptors in Schwann cells [ XREF_BIBR ] .	A recent study reported that SH3TC2 regulates endocytosis of Nrg1 activated ErbB2 receptors in Schwann cells [XREF_BIBR].	7	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB2	ErbB2	ErbB2	9	10	11	12
Activation of ErbB2 by heregulin beta1 decreases the pool of Grb7 associated to membranes .	Activation of ErbB2 by heregulin beta1 decreases the pool of Grb7 associated to membranes.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	4	5	2	3
NRG1 activation of ErbB2 and 3 promotes Schwann cell migration through Rho GTPases Rac1 and Cdc42 and the downstream JNK .	NRG1 activation of ErbB2 and 3 promotes Schwann cell migration through Rho GTPases Rac1 and Cdc42 and the downstream JNK.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB2	ErbB2	ErbB2	0	1	3	4
Here we show that Ran is subject to growth factor regulation by demonstrating that it is activated in a serum dependent manner in human breast cancer cells and , in particular , in response to heregulin , a growth factor that activates the Neu and ErbB2 tyrosine kinase .	Here we show that Ran is subject to growth factor regulation by demonstrating that it is activated in a serum dependent manner in human breast cancer cells and, in particular, in response to heregulin, a growth factor that activates the Neu and ErbB2 tyrosine kinase.	16	47	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	Neu	Neu	Neu	35	36	43	44
Our results indicate that the activation of ErbB2 by heregulin or by its overexpression requires Grb2 to stimulate the Akt pathway to propagate mitogenic signals .	Our results indicate that the activation of ErbB2 by heregulin or by its overexpression requires Grb2 to stimulate the Akt pathway to propagate mitogenic signals.	5	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	9	10	7	8
In support of this inference , we observed that whereas both ERRP and EBIP were able to inhibit heregulin induced activation of HER-2 and HER-3 in MDA-MB-453 breast cancer cells , neither rEGFR-447 nor hEGFR-501 was effective in this matter ( XREF_SUPPLEMENTARY ) .	In support of this inference, we observed that whereas both ERRP and EBIP were able to inhibit heregulin induced activation of HER-2 and HER-3 in MDA-MB-453 breast cancer cells, neither rEGFR-447 nor hEGFR-501 was effective in this matter (XREF_SUPPLEMENTARY).	18	24	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER-2	HER-2	HER-2	18	19	22	23
Heregulin is known to activate the oncogenic ERBB2 receptor [ XREF_BIBR ] .	Heregulin is known to activate the oncogenic ERBB2 receptor [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	ERBB2	ERBB2	ERBB2	0	1	7	8
We conducted in vitro experiments utilizing HER2 positive breast and gastric cell lines pharmacologically treated with recombinant heregulin or transfected with the heregulin gene .	We conducted in vitro experiments utilizing HER2 positive breast and gastric cell lines pharmacologically treated with recombinant heregulin or transfected with the heregulin gene.	6	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	17	18	6	7
As shown in XREF_FIG , HER2 was activated by heregulin but this did not significantly change the interaction of HER2 with PUMA .	As shown in XREF_FIG, HER2 was activated by heregulin but this did not significantly change the interaction of HER2 with PUMA.	5	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	9	10	5	6
Heregulin stimulated HER2 activation induced Ack1 activation and AR tyrosine phosphorylation primarily at Tyr 267 , located within the transactivation domain [ XREF_BIBR ] .	Heregulin stimulated HER2 activation induced Ack1 activation and AR tyrosine phosphorylation primarily at Tyr 267, located within the transactivation domain [XREF_BIBR].	0	15	stimulated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Heregulin	Heregulin	heregulin	HER2	HER2 activation induced Ack1 activation and AR tyrosine phosphorylation primarily at Tyr 267	her2	0	1	2	3
Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1alpha protein and VEGF mRNA expression that is dependent upon activity of PI3K , AKT ( also known as protein kinase B ) , and the downstream kinase FRAP ( FKBP-rapamycin-associated protein ) .	Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1alpha protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein).	4	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	14	15	4	5
Again , heregulin beta1 enhanced the growth of erbB2 cDNA transfected beta4-deltacyt cells , but not mock cells .	Again, heregulin beta1 enhanced the growth of erbB2 cDNA transfected beta4-deltacyt cells, but not mock cells.	2	9	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	erbB2	erbB2	erbB2	2	3	8	9
Consistent with a critical role of endosome to-lysosome trafficking in signaling attenuation [ XREF_BIBR ] , our results indicate that SIMPLE mutant induced trafficking impairment causes reduced attenuation of Nrg1 activated ErbB2 and ErbB3 receptor signaling , leading to prolonged downstream Erk signaling [ XREF_BIBR ] .	Consistent with a critical role of endosome to-lysosome trafficking in signaling attenuation [XREF_BIBR], our results indicate that SIMPLE mutant induced trafficking impairment causes reduced attenuation of Nrg1 activated ErbB2 and ErbB3 receptor signaling, leading to prolonged downstream Erk signaling [XREF_BIBR].	27	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB2	ErbB2	ErbB2	29	30	31	32
This and the fact that EBIP also inhibits growth of several other breast cancer cells that express other members of the EGFR family and also inhibits heregulin induced activation of HER-2 and HER-3 in breast cancer cells suggest that EBIP , as has been reported for ERRP could potentially be a pan-ErbB inhibitor .	This and the fact that EBIP also inhibits growth of several other breast cancer cells that express other members of the EGFR family and also inhibits heregulin induced activation of HER-2 and HER-3 in breast cancer cells suggest that EBIP, as has been reported for ERRP could potentially be a pan-ErbB inhibitor.	26	32	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER-2	HER-2	HER-2	26	27	30	31
Activation of HER2 signaling by neuregulin-1 has been shown to improve cardiac myocyte function and survival , and upregulation of this pathway in the heart may be a potential therapeutic approach .	Activation of HER2 signaling by neuregulin-1 has been shown to improve cardiac myocyte function and survival, and upregulation of this pathway in the heart may be a potential therapeutic approach.	2	6	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	neuregulin-1	neuregulin-1	neuregulin-1	HER2	HER2	HER2	5	6	2	3
To test whether BTK-C is a secondary kinase that mediates NRG1 rescue in HER2 positive breast cancer cells , we treated BT474 and SKBR3 cells with lapatinib , lapatinib and NRG1 or lapatinib and NRG1 plus AVL-292 , a BTK inhibitor that does not inhibit the EGFR family ( XREF_FIG ) .	To test whether BTK-C is a secondary kinase that mediates NRG1 rescue in HER2 positive breast cancer cells, we treated BT474 and SKBR3 cells with lapatinib, lapatinib and NRG1 or lapatinib and NRG1 plus AVL-292, a BTK inhibitor that does not inhibit the EGFR family (XREF_FIG).	10	14	rescue	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER2	HER2	HER2	10	11	13	14
Heregulin beta1 stimulation of HER2 signaling in MCF-7 cells increased Ang-2 by 20 % ( P < .05 ) .	Heregulin beta1 stimulation of HER2 signaling in MCF-7 cells increased Ang-2 by 20% (P <.05).	0	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	HER2	HER2	HER2	0	1	4	5
Phosphorylation of c-myc was observed and transiently peaked at 15 minutes following GP88 addition similar to the Her2 activator Heregulin , used as positive control .	Phosphorylation of c-myc was observed and transiently peaked at 15 minutes following GP88 addition similar to the Her2 activator Heregulin, used as positive control.	14	20	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	Her2	Her2	Her2	19	20	17	18
Importantly , they demonstrate that either amplification of ERBB2 or increased levels of the ERBB3 and ERBB4 ligand heregulin are present in patients with CRC that exhibited de novo or acquired cetuximab resistance .	Importantly, they demonstrate that either amplification of ERBB2 or increased levels of the ERBB3 and ERBB4 ligand heregulin are present in patients with CRC that exhibited de novo or acquired cetuximab resistance.	8	19	increased	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	heregulin	levels of the ERBB3 and ERBB4 ligand heregulin	heregulin	ERBB2	ERBB2	erbb2	18	19	8	9
Aberrant ERBB2 signalling , by ERBB2 amplification or heregulin production , seems to be responsible for both intrinsic and acquired resistance in cetuximab treated mCRC patients .	Aberrant ERBB2 signalling, by ERBB2 amplification or heregulin production, seems to be responsible for both intrinsic and acquired resistance in cetuximab treated mCRC patients.	1	9	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ERBB2	ERBB2	ERBB2	8	9	1	2
There is evidence that SH3TC2 is required for controlling Nrg1 induced ErbB2 endocytosis in Schwann cells [ XREF_BIBR ] , but whether SH3TC2 has a role in regulating ErbB recycling to the cell surface remains to be determined .	There is evidence that SH3TC2 is required for controlling Nrg1 induced ErbB2 endocytosis in Schwann cells [XREF_BIBR], but whether SH3TC2 has a role in regulating ErbB recycling to the cell surface remains to be determined.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB2	ErbB2	ErbB2	9	10	11	12
Furthermore , neu differentiation factor and heregulin , a ligand that indirectly activates p185erbB-2 by direct binding to erbB-3 receptors , potently stimulated the proliferation of the growth factor dependent H16N-2 cells ( which expressed c-erbB-2 and c-erbB-3 but not c-erbB-4 ) in the absence of both IGF and EGF .	Furthermore, neu differentiation factor and heregulin, a ligand that indirectly activates p185erbB-2 by direct binding to erbB-3 receptors, potently stimulated the proliferation of the growth factor dependent H16N-2 cells (which expressed c-erbB-2 and c-erbB-3 but not c-erbB-4) in the absence of both IGF and EGF.	2	14	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	neu differentiation factor	neu differentiation factor	neu differentiation factor	p185erbB-2	p185erbB-2	p185erbB-2	2	5	13	14
This involved treating MCF-7 breast cancer cells , which express low levels of ErbB2 , with heregulin , a ligand for ErbB3 and ErbB4 receptors that indirectly activates ErbB2 by heterodimerization and accelerates cell cycle progression .	This involved treating MCF-7 breast cancer cells, which express low levels of ErbB2, with heregulin, a ligand for ErbB3 and ErbB4 receptors that indirectly activates ErbB2 by heterodimerization and accelerates cell cycle progression.	9	29	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	16	17	28	29
In an effort to investigate these mechanisms , we observed that heregulin mediated activation of HER2 , or HER2 overexpression , resulted in EMT , which is accompanied with increased expression of a known EMT regulator Slug , but not TWIST or Snail .	In an effort to investigate these mechanisms, we observed that heregulin mediated activation of HER2, or HER2 overexpression, resulted in EMT, which is accompanied with increased expression of a known EMT regulator Slug, but not TWIST or Snail.	11	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	11	12	15	16
Recent data indicate that pertuzumab can abrogate signaling through AKT-mTOR in response to heregulin mediated HER2 : HER3 heterodimerization , while trastuzumab can not [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Recent data indicate that pertuzumab can abrogate signaling through AKT-mTOR in response to heregulin mediated HER2 : HER3 heterodimerization, while trastuzumab can not [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	13	14	15	16
Notably , the authors demonstrated that either amplification of ErbB2 or increased levels of the ErbB3 and ErbB4 ligand heregulin led to de novo or acquired cetuximab resistance , and Ruan et al achieved similar results in a breast cancer study .	Notably, the authors demonstrated that either amplification of ErbB2 or increased levels of the ErbB3 and ErbB4 ligand heregulin led to de novo or acquired cetuximab resistance, and Ruan et al achieved similar results in a breast cancer study.	9	20	increased	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	heregulin	levels of the ErbB3 and ErbB4 ligand heregulin	heregulin	ErbB2	ErbB2	erbb2	19	20	9	10
ERbeta downregulates heregulin induced activation of HER2 and HER3 dimer and Akt .	ERbeta downregulates heregulin induced activation of HER2 and HER3 dimer and Akt.	2	9	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	2	3	6	7
These results suggest that heregulin induces NF-kappaB independent of her2 and neu .	These results suggest that heregulin induces NF-kappaB independent of her2 and neu.	4	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	neu	neu	neu	4	5	11	12
The luminal cell line , MDA-MB-175 , which showed significant sensitivity to neratinib has previously been shown to be dependent on heregulin mediated activation of HER2 and HER3 signaling and are also more sensitive to pertuzumab treatment than trastuzumab [ XREF_BIBR ] .	The luminal cell line, MDA-MB-175, which showed significant sensitivity to neratinib has previously been shown to be dependent on heregulin mediated activation of HER2 and HER3 signaling and are also more sensitive to pertuzumab treatment than trastuzumab [XREF_BIBR].	21	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	21	22	25	26
EBIP also inhibited heregulin induced activation of HER-2 and HER-3 in MDA-MB-453 breast cancer cells .	EBIP also inhibited heregulin induced activation of HER-2 and HER-3 in MDA-MB-453 breast cancer cells.	3	9	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER-2	HER-2	HER-2	3	4	7	8
Neu differentiation factor ( NDF )/heregulin activates ErbB2 via heterodimerization with the NDF receptors ErbB3 and ErbB4 .	Neu differentiation factor (NDF)/heregulin activates ErbB2 via heterodimerization with the NDF receptors ErbB3 and ErbB4.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Neu differentiation factor	Neu differentiation factor	Neu differentiation factor	ErbB2	ErbB2	ErbB2	0	3	7	8
In order to examine further the mechanism by which the activation of ErbB2 induces Notch1 signaling , MCF-10A cells were treated with Heregulin to induce , via ErbB3 and ErbB2 heterodimerization , the activation of ErbB2 signaling .	In order to examine further the mechanism by which the activation of ErbB2 induces Notch1 signaling, MCF-10A cells were treated with Heregulin to induce, via ErbB3 and ErbB2 heterodimerization, the activation of ErbB2 signaling.	10	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	ErbB2	ErbB2	ErbB2	22	23	12	13
The present findings might be applicable to cell types other than ECs because Necl-4 was similarly up-regulated by confluence in epithelial cells in which Necl-4 negatively regulated the heregulin induced ErbB2 and ErbB3 signalling [ XREF_BIBR ] .	The present findings might be applicable to cell types other than ECs because Necl-4 was similarly up-regulated by confluence in epithelial cells in which Necl-4 negatively regulated the heregulin induced ErbB2 and ErbB3 signalling [XREF_BIBR].	27	33	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	28	29	30	31
NEDD9 is abundantly expressed in many breast cancer cell lines and hyper-phosphorylation associated with activation of NEDD9 has been detected in phosphoproteome analysis of heregulin stimulated ErbB2 positive breast adenocarcinoma MCF7 cells .	NEDD9 is abundantly expressed in many breast cancer cell lines and hyper-phosphorylation associated with activation of NEDD9 has been detected in phosphoproteome analysis of heregulin stimulated ErbB2 positive breast adenocarcinoma MCF7 cells.	22	31	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	24	25	26	27
HER2 activation by the ligand neuregulin-1 was associated with tyrosine phosphorylation of beta-catenin , dissociation of beta-catenin from E-cadherin , and decreased E-cadherin-mediated cell adhesion .	HER2 activation by the ligand neuregulin-1 was associated with tyrosine phosphorylation of beta-catenin, dissociation of beta-catenin from E-cadherin, and decreased E-cadherin-mediated cell adhesion.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	neuregulin-1	neuregulin-1	neuregulin-1	HER2	HER2	HER2	5	6	0	1
Future studies are needed to investigate how the signaling output of Nrg1 activated ErbB2 and ErbB3 receptor is determined and modulated in Schwann cells to regulate myelination in peripheral nerves .	Future studies are needed to investigate how the signaling output of Nrg1 activated ErbB2 and ErbB3 receptor is determined and modulated in Schwann cells to regulate myelination in peripheral nerves.	9	16	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB2	ErbB2	ErbB2	11	12	13	14
When PKC is activated by TPA , NDF is no longer able to activate ErbB-2 in T47D cells , leading to a blockage of cell proliferation .	When PKC is activated by TPA, NDF is no longer able to activate ErbB-2 in T47D cells, leading to a blockage of cell proliferation.	7	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NDF	NDF	NDF	ErbB-2	ErbB-2	ErbB-2	7	8	14	15
However , a therapeutical approach using soluble recombinant human Nrg1 , which stimulates ErbB2 receptors , might not be easily applied to humans due to possible side effects .	However, a therapeutical approach using soluble recombinant human Nrg1, which stimulates ErbB2 receptors, might not be easily applied to humans due to possible side effects.	5	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB2	ErbB2	ErbB2	9	10	13	14
The assay was developed for analysis of heregulin induced ErbB2 activation and utilizes the stimulation of intact receptor on the adherent breast carcinoma cell line , MCF-7 .	The assay was developed for analysis of heregulin induced ErbB2 activation and utilizes the stimulation of intact receptor on the adherent breast carcinoma cell line, MCF-7.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	7	8	9	10
Analysis of ERK1/2 signaling downstream of NRG1 activated ErbB2 and ErbB3 receptors revealed that SIMPLE depletion altered the inactivation phase of ERK1/2 phosphorylation , leading to prolonged activation of ERK1/2 signaling ( XREF_FIG ) .	Analysis of ERK1/2 signaling downstream of NRG1 activated ErbB2 and ErbB3 receptors revealed that SIMPLE depletion altered the inactivation phase of ERK1/2 phosphorylation, leading to prolonged activation of ERK1/2 signaling (XREF_FIG).	3	11	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB2	ErbB2	ErbB2	6	7	8	9
This is consistent with other reports suggesting that although cranial ganglia are defective in Nrg1 , Erbb2 and Erbb3 mutant mice , this likely arises not because of an effect on cranial NC migation , but because Nrg1 mediated ErbB2 and ErbB3 signaling is required for survival of cranial NC derived neurons .	This is consistent with other reports suggesting that although cranial ganglia are defective in Nrg1, Erbb2 and Erbb3 mutant mice, this likely arises not because of an effect on cranial NC migation, but because Nrg1 mediated ErbB2 and ErbB3 signaling is required for survival of cranial NC derived neurons.	37	42	mediated	Positive_early_activation	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB2	ErbB2	ErbB2	37	38	39	40
Heregulin ( HRG ) activates the ErbB2 via induction of heterodimerization with ErbB3 and ErbB4 receptors .	Heregulin (HRG) activates the ErbB2 via induction of heterodimerization with ErbB3 and ErbB4 receptors.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	ErbB2	ErbB2	ErbB2	0	1	6	7
In this study , we showed that Necl-4 interacted in cis with ErbB3 through their extracellular regions , recruited PTPN13 and inhibited the heregulin induced activation of the ErbB2 and ErbB3 signaling .	In this study, we showed that Necl-4 interacted in cis with ErbB3 through their extracellular regions, recruited PTPN13 and inhibited the heregulin induced activation of the ErbB2 and ErbB3 signaling.	22	31	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	23	24	28	29
MCF7 cells carry low endogenous levels of both ERBB2 and ERBB3 and represent a widely used system for NRG1 induced ERBB2 and ERBB3 signaling .	MCF7 cells carry low endogenous levels of both ERBB2 and ERBB3 and represent a widely used system for NRG1 induced ERBB2 and ERBB3 signaling.	16	23	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB2	ERBB2	ERBB2	18	19	20	21
Recent studies have shown that Nrg1 activated ErbB2 and ErbB3 receptors could undergo en-docytosis in Schwann cells [ XREF_BIBR , XREF_BIBR ] ; however , it remains to be determined whether activated ErbB2 and ErbB3 receptors trigger distinct signaling pathways at the plasma membrane and endosomes .	Recent studies have shown that Nrg1 activated ErbB2 and ErbB3 receptors could undergo en-docytosis in Schwann cells [XREF_BIBR, XREF_BIBR]; however, it remains to be determined whether activated ErbB2 and ErbB3 receptors trigger distinct signaling pathways at the plasma membrane and endosomes.	5	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB2	ErbB2	ErbB2	5	6	7	8
As shown in XREF_FIG , heregulin induced activation of HER2 in these cells and also led to enhanced PUMA protein degradation .	As shown in XREF_FIG, heregulin induced activation of HER2 in these cells and also led to enhanced PUMA protein degradation.	5	15	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	5	6	9	10
Heregulin beta-2 , a naturally occurring ligand that activates the HER2 receptor by inducing its heterodimerization with the HER4 receptor , has recently been cloned .	Heregulin beta-2, a naturally occurring ligand that activates the HER2 receptor by inducing its heterodimerization with the HER4 receptor, has recently been cloned.	0	12	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Heregulin	Heregulin	Heregulin	HER2 receptor	HER2 receptor	HER2 receptor	0	1	10	12
In contrast , HER2 positive breast cancer cells can not be rescued from ibrutinib induced growth inhibition by NRG1 .	In contrast, HER2 positive breast cancer cells can not be rescued from ibrutinib induced growth inhibition by NRG1.	3	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER2	HER2	HER2	18	19	3	4
47 Here we found that most NRG1 like activity supporting ATRA induced spermatogonial differentiation on fibroblasts was ERBB2 dependent ( XREF_FIG ) .	47 Here we found that most NRG1 like activity supporting ATRA induced spermatogonial differentiation on fibroblasts was ERBB2 dependent (XREF_FIG).	5	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ERBB2	ERBB2	ERBB2	6	7	17	18
In CWR22 xenograft derived CWR-R1 cells , heregulin stimulation of ErbB2 enhanced AR activity and cell growth .	In CWR22 xenograft derived CWR-R1 cells, heregulin stimulation of ErbB2 enhanced AR activity and cell growth.	7	11	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	7	8	10	11
HER3 is essential for HER2 driven tumourigenesis [ XREF_BIBR ] , and patients with NRG1 driven HER2 non amplified tumours have been suggested to derive clinical benefit from HER2 : HER3 directed therapies [ XREF_BIBR ] .	HER3 is essential for HER2 driven tumourigenesis [XREF_BIBR], and patients with NRG1 driven HER2 non amplified tumours have been suggested to derive clinical benefit from HER2 : HER3 directed therapies [XREF_BIBR].	12	17	driven	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER2	HER2	HER2	14	15	16	17
Aberrant ERBB2 signaling ( by ERBB2 amplification or heregulin production ) is an example of a resistance mechanism that leads to activation of a bypass signaling pathway .	Aberrant ERBB2 signaling (by ERBB2 amplification or heregulin production) is an example of a resistance mechanism that leads to activation of a bypass signaling pathway.	1	9	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ERBB2	ERBB2	ERBB2	8	9	1	2
XREF_BIBR In ErbB2 expressing cell lines , administration of the ErbB2 activator heregulin beta 1 led to increased NFkappaB activation , whereas herceptin , an anti-ErbB2 monoclonal antibody , blocked this activation and led to apoptosis .	XREF_BIBR In ErbB2 expressing cell lines, administration of the ErbB2 activator heregulin beta 1 led to increased NFkappaB activation, whereas herceptin, an anti-ErbB2 monoclonal antibody, blocked this activation and led to apoptosis.	10	13	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	12	13	10	11
Extracellular Hsp90alpha is upregulated in malignant melanomas XREF_BIBR , colorectal cancer XREF_BIBR and fibrosarcomas XREF_BIBR , and is shown to increase heregulin induced Her-2 activation and signaling XREF_BIBR .	Extracellular Hsp90alpha is upregulated in malignant melanomas XREF_BIBR, colorectal cancer XREF_BIBR and fibrosarcomas XREF_BIBR, and is shown to increase heregulin induced Her-2 activation and signaling XREF_BIBR.	20	24	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	Her-2	Her-2	Her-2	21	22	23	24
NRG1 is a ligand for HER3 and HER4 , and the release of NRG1 and other HER ligands could induce HER2 dimerisation with other HER receptors [ XREF_BIBR ] .	NRG1 is a ligand for HER3 and HER4, and the release of NRG1 and other HER ligands could induce HER2 dimerisation with other HER receptors [XREF_BIBR].	13	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER2	HER2	HER2	13	14	20	21
Competitive binding of neuregulin-1 to L929 cells overexpressing ErbB2 .	Competitive binding of neuregulin-1 to L929 cells overexpressing ErbB2.	1	9	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neuregulin-1	neuregulin-1	neuregulin-1	ErbB2	ErbB2	ErbB2	3	4	8	9
On the other hand , hMena and hMena 11a knock-down prevented EGF and NRG1 mediated HER2 and EGFR activation .	On the other hand, hMena and hMena 11a knock-down prevented EGF and NRG1 mediated HER2 and EGFR activation.	11	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER2	HER2	HER2	13	14	15	16
To determine the effects of CMT1C linked mutations on NRG1-ErbB signaling in Schwann cells , we expressed Myc tagged SIMPLE WT , SIMPLE W116G , or SIMPLE P135T in MSC80 Schwann cells by stable transfection and analyzed their effects on ERK1/2 signaling downstream of NRG1 activated ErbB2 and ErbB3 receptors .	To determine the effects of CMT1C linked mutations on NRG1-ErbB signaling in Schwann cells, we expressed Myc tagged SIMPLE WT, SIMPLE W116G, or SIMPLE P135T in MSC80 Schwann cells by stable transfection and analyzed their effects on ERK1/2 signaling downstream of NRG1 activated ErbB2 and ErbB3 receptors.	42	49	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB2	ErbB2	ErbB2	44	45	46	47
Thus , this NRG1 mediated HER2 activation serves as a potential explanation for the clinical efficacy of HER2 targeting in HER2-low tumors .	Thus, this NRG1 mediated HER2 activation serves as a potential explanation for the clinical efficacy of HER2 targeting in HER2-low tumors.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER2	HER2	HER2	3	4	5	6
XREF_BIBR As in cancer cells , Nrg1 induced activation of ERBB2 in cardiomyocytes activates the ERK and PI3K and Akt pathways that promote cardiomyocyte proliferation during development and cardiomyocyte survival during adulthood ( XREF_FIG ) .	XREF_BIBR As in cancer cells, Nrg1 induced activation of ERBB2 in cardiomyocytes activates the ERK and PI3K and Akt pathways that promote cardiomyocyte proliferation during development and cardiomyocyte survival during adulthood (XREF_FIG).	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ERBB2	ERBB2	ERBB2	6	7	10	11
Further analyses with antibodies recognizing two additional phosphorylation sites ( Y788 , Y1248 ) confirmed NRG1 driven activation of ErbB2 .	Further analyses with antibodies recognizing two additional phosphorylation sites (Y788, Y1248) confirmed NRG1 driven activation of ErbB2.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB2	ErbB2	ErbB2	15	16	19	20
Our data suggest that surface HSP90 is involved in heregulin induced HER-2 activation and signaling , leading to cytoskeletal rearrangement , essential for cell invasion .	Our data suggest that surface HSP90 is involved in heregulin induced HER-2 activation and signaling, leading to cytoskeletal rearrangement, essential for cell invasion.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER-2	HER-2	HER-2	9	10	11	12
Nrg1 mediated ErbB2 receptor activation requires the participation of ErbB3 or ErbB4 to form heterodimers .	Nrg1 mediated ErbB2 receptor activation requires the participation of ErbB3 or ErbB4 to form heterodimers.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	Nrg1	Nrg1	Nrg1	ErbB2	ErbB2	ErbB2	0	1	2	3
However , exposure of wild-type cells to NDF promoted ErbB2 tyrosine kinase activation ( XREF_FIG B ) , resulting in a significant ( greater than tenfold ) increase in cell migration on collagen ( XREF_FIG A ) and vitronectin ( data not shown ) .	However, exposure of wild-type cells to NDF promoted ErbB2 tyrosine kinase activation (XREF_FIG B), resulting in a significant (greater than tenfold) increase in cell migration on collagen (XREF_FIG A) and vitronectin (data not shown).	5	12	promoted	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NDF	NDF	NDF	ErbB2	ErbB2	ErbB2	7	8	9	10
Trastuzumab ( Herceptin ) and PD158780 were independently used to inhibit ErbB2 signaling while neuregulin-1beta ( NRG-1 ) was used to activate ErbB2 .	Trastuzumab (Herceptin) and PD158780 were independently used to inhibit ErbB2 signaling while neuregulin-1beta (NRG-1) was used to activate ErbB2.	14	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	ErbB2	ErbB2	ErbB2	16	17	22	23
These data indicated that NT-3 activated TrkA and , to a lesser degree , TrkC on NGF dependent sympathetic neurons .	These data indicated that NT-3 activated TrkA and, to a lesser degree, TrkC on NGF dependent sympathetic neurons.	4	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	4	5	14	15
TrkC receptors are activated by selective binding of its ligand NT-3 .	TrkC receptors are activated by selective binding of its ligand NT-3.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	10	11	0	1
This was not expected because it is generally believed that NT-3 primarily activates TrkC but not TrkB .	This was not expected because it is generally believed that NT-3 primarily activates TrkC but not TrkB.	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	10	11	13	14
It has also been reported that NT-3 stimulation of TrkC upregulated proneuronal genes promoting neuronal differentiation through activating the Erk1/2 MAP kinase pathway in the immature homogeneous subpopulation of human MSCs and activated the Arf6-Rac1 pathway upregulating proneuronal genes in HEK293 cells [ XREF_BIBR , XREF_BIBR ] .	It has also been reported that NT-3 stimulation of TrkC upregulated proneuronal genes promoting neuronal differentiation through activating the Erk1/2 MAP kinase pathway in the immature homogeneous subpopulation of human MSCs and activated the Arf6-Rac1 pathway upregulating proneuronal genes in HEK293 cells [XREF_BIBR, XREF_BIBR].	6	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	6	7	9	10
Taken together , these results suggest that NT3 activation of TrkC stimulates Schwann cell migration through two parallel signaling units , Ras/Tiam1/Rac1 and Dbs and Cdc42 , and that Schwann cell migration is uniquely regulated in the case of Ras and Rac1 , by two different types of small GTPases .	Taken together, these results suggest that NT3 activation of TrkC stimulates Schwann cell migration through two parallel signaling units, Ras/Tiam1/Rac1 and Dbs and Cdc42, and that Schwann cell migration is uniquely regulated in the case of Ras and Rac1, by two different types of small GTPases.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NT3	NT3	NT3	TrkC	TrkC	TrkC	7	8	10	11
NT3 , finally , primarily activates trkC receptors .	NT3, finally, primarily activates trkC receptors.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT3	NT3	NT3	trkC	trkC	trkC	0	1	6	7
An early function for NT-3 on immature DRG neurons is supported further by data presented here that demonstrate that whereas BDNF and NGF can support a subset of immature DRG neurons in vitro , activation of the trkC receptor either by NT-3 binding or via antibody mediated cross linking induces the most robust survival response .	An early function for NT-3 on immature DRG neurons is supported further by data presented here that demonstrate that whereas BDNF and NGF can support a subset of immature DRG neurons in vitro, activation of the trkC receptor either by NT-3 binding or via antibody mediated cross linking induces the most robust survival response.	34	42	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	trkC	trkC	trkC	41	42	37	38
NT-3 activates the receptor tyrosine kinase TrkC , which then stimulates three pathways in which Raf/MEK/ERK , PLCgamma/Ca 2+ , and PI3K , are key intermediates .	NT-3 activates the receptor tyrosine kinase TrkC, which then stimulates three pathways in which Raf/MEK/ERK, PLCgamma/Ca 2+, and PI3K, are key intermediates.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	0	1	6	7
Fifth , although NT-3 leads to both TrkA and TrkC activation , it is apparently the TrkA activation that is essential for neuronal survival and neuritogenesis .	Fifth, although NT-3 leads to both TrkA and TrkC activation, it is apparently the TrkA activation that is essential for neuronal survival and neuritogenesis.	3	10	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	3	4	9	10
Following neurotrophin-3 stimulation TRKC , apoptosis is prevented through the activation of the PI3K and AKT pathway .	Following neurotrophin-3 stimulation TRKC, apoptosis is prevented through the activation of the PI3K and AKT pathway.	0	7	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	neurotrophin-3	neurotrophin-3	neurotrophin-3	TRKC	TRKC	TRKC	1	2	3	4
2Cl reduces TrkC activation and signaling promoted by NT-3 , and selectively blocks ligand dependent cell survival .	2Cl reduces TrkC activation and signaling promoted by NT-3, and selectively blocks ligand dependent cell survival.	2	9	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	8	9	2	3
If the ACLs were injured , then the expression of NT-3 would decrease in the proprioceptors , thus reducing the activity of TrkC ; however , GAP-43 in the ACL would be activated , thereby starting the self healing system .	If the ACLs were injured, then the expression of NT-3 would decrease in the proprioceptors, thus reducing the activity of TrkC; however, GAP-43 in the ACL would be activated, thereby starting the self healing system.	8	23	reducing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	expression of NT-3	nt-3	TrkC	TrkC	trkc	10	11	22	23
Taken together , these results suggest that neurotrophin 3 activation of TrkC induces Schwann cell migration through the c-Jun N-terminal kinase signaling pathway .	Taken together, these results suggest that neurotrophin 3 activation of TrkC induces Schwann cell migration through the c-Jun N-terminal kinase signaling pathway.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	neurotrophin 3	neurotrophin 3	neurotrophin 3	TrkC	TrkC	TrkC	7	9	11	12
Previously , we demonstrated that neurotrophin 3 activation of TrkC inhibits Schwann cell myelination and enhances the migration of primary Schwann cells through the signaling pathway regulated by the Rho GTPases Rac1 and Cdc42 .	Previously, we demonstrated that neurotrophin 3 activation of TrkC inhibits Schwann cell myelination and enhances the migration of primary Schwann cells through the signaling pathway regulated by the Rho GTPases Rac1 and Cdc42.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	neurotrophin 3	neurotrophin 3	neurotrophin 3	TrkC	TrkC	TrkC	5	7	9	10
NT-3 may modulate the synaptogenic activity of TrkC , for example , by inducing TrkC dimerization and internalization .	NT-3 may modulate the synaptogenic activity of TrkC, for example, by inducing TrkC dimerization and internalization.	0	8	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	0	1	7	8
NGF binds and activates the TrkA receptor , BDNF and NT-4 both signal through TrkB , and NT-3 activates TrkC .	NGF binds and activates the TrkA receptor, BDNF and NT-4 both signal through TrkB, and NT-3 activates TrkC.	17	20	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	17	18	19	20
Further work by the same investigators proposed that TrkC activation by neurotrophin-3 stimulates SC migration through two parallel signaling pathways involving cdc42 or rac1 .	Further work by the same investigators proposed that TrkC activation by neurotrophin-3 stimulates SC migration through two parallel signaling pathways involving cdc42 or rac1.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	neurotrophin-3	neurotrophin-3	neurotrophin-3	TrkC	TrkC	TrkC	11	12	8	9
Both BMP2 and NT-3 promote the in vitro development of these cells , and the number of TrkC , TH , and DAT neurons is reduced in the noggin overexpressing mice .	Both BMP2 and NT-3 promote the in vitro development of these cells, and the number of TrkC, TH, and DAT neurons is reduced in the noggin overexpressing mice.	1	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	3	4	17	18
TrkA and TrkC are activated primarily by the neurotrophins nerve growth factor ( NGF ) and neurotrophin-3 ( NT-3 ) , respectively , and the activation is essential for development and maintenance of the nervous systems .	TrkA and TrkC are activated primarily by the neurotrophins nerve growth factor (NGF) and neurotrophin-3 (NT-3), respectively, and the activation is essential for development and maintenance of the nervous systems.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	neurotrophin-3	neurotrophin-3	neurotrophin-3	TrkC	TrkC	TrkC	16	17	2	3
Binding of neurotrophins to Trk receptors promotes neuronal survival and differentiation , with TrkA mediating the effects of NGF , TrkB being bound by BDNF , NT-3 and NT-4 and TrkC activated by NT-3 .	Binding of neurotrophins to Trk receptors promotes neuronal survival and differentiation, with TrkA mediating the effects of NGF, TrkB being bound by BDNF, NT-3 and NT-4 and TrkC activated by NT-3.	13	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	33	34	30	31
Neurotrophin-3 ( NT-3 ) primarily activates the TrkC tyrosine protein kinases , four related isoforms encoded by alternative splicing of trkC , a gene also widely expressed throughout the mammalian nervous system .	Neurotrophin-3 (NT-3) primarily activates the TrkC tyrosine protein kinases, four related isoforms encoded by alternative splicing of trkC, a gene also widely expressed throughout the mammalian nervous system.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Neurotrophin-3	Neurotrophin-3	Neurotrophin-3	TrkC	TrkC	TrkC	0	1	7	8
NT3 activation of Schwann cell TrkC receptor also has the ability to promote the activities of Rac1 and Cdc42 in parallel XREF_BIBR ; but their activation requires two different Dbl family GEFs .	NT3 activation of Schwann cell TrkC receptor also has the ability to promote the activities of Rac1 and Cdc42 in parallel XREF_BIBR; but their activation requires two different Dbl family GEFs.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NT3	NT3	NT3	TrkC	TrkC	TrkC	0	1	5	6
BDNF ( ID 24225 ) and neurotrophin 5 ( NTF5 , ID 25730 ) are specific to NTRK2 while NT3 mainly activates NTRK3 XREF_BIBR .	BDNF (ID 24225) and neurotrophin 5 (NTF5, ID 25730) are specific to NTRK2 while NT3 mainly activates NTRK3 XREF_BIBR.	19	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT3	NT3	NT3	NTRK3	NTRK3	NTRK3	19	20	22	23
Therefore , our data provide evidence that NT-3 supports the survival of TrkA-, TrkB- and TrkC expressing neurons in the trigeminal ganglion by activating directly each of these receptors in vivo .	Therefore, our data provide evidence that NT-3 supports the survival of TrkA-, TrkB- and TrkC expressing neurons in the trigeminal ganglion by activating directly each of these receptors in vivo.	7	16	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	7	8	15	16
In recent studies , TrkC activation by neurotrophin-3 in Schwann cells activates the Cdc42 GEF , Dbl ' s big sister ( Dbs ) , and the Rac1 GEF , Tiam1 , leading to Schwann cell migration .	In recent studies, TrkC activation by neurotrophin-3 in Schwann cells activates the Cdc42 GEF, Dbl 's big sister (Dbs), and the Rac1 GEF, Tiam1, leading to Schwann cell migration.	4	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	neurotrophin-3	neurotrophin-3	neurotrophin-3	TrkC	TrkC	TrkC	7	8	4	5
Following TrkC activation by its ligand neurotrophin-3 , protein extracts from DAOY cells were run on 2DE with subsequent MALDI-TOF-TOF analysis and quantification in order to detect downstream effectors .	Following TrkC activation by its ligand neurotrophin-3, protein extracts from DAOY cells were run on 2DE with subsequent MALDI-TOF-TOF analysis and quantification in order to detect downstream effectors.	1	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	neurotrophin-3	neurotrophin-3	neurotrophin-3	TrkC	TrkC	TrkC	6	7	1	2
BDNF and neurotrophin-4 ( NT-4 ) recognize the TrkB receptor , while NGF binds specifically with TrkA , and NT-3 activates TrkC .	BDNF and neurotrophin-4 (NT-4) recognize the TrkB receptor, while NGF binds specifically with TrkA, and NT-3 activates TrkC.	19	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	19	20	21	22
Comparisons of neonatal mice deficient in NT-3 or its cognate receptor TrkC have shown that there is a much greater deficiency in spinal sensory neurons in the former , suggesting that NT-3 may activate receptors in addition to TrkC .	Comparisons of neonatal mice deficient in NT-3 or its cognate receptor TrkC have shown that there is a much greater deficiency in spinal sensory neurons in the former, suggesting that NT-3 may activate receptors in addition to TrkC.	31	39	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	31	32	38	39
Upon TrkC activation by NT-3 , PLCgamma/Ca 2+ signaling rapidly reduced the extent of phosphorylation of this domain of SAD ( XREF_FIG ) .	Upon TrkC activation by NT-3, PLCgamma/Ca 2+ signaling rapidly reduced the extent of phosphorylation of this domain of SAD (XREF_FIG).	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	4	5	1	2
However , despite the potential for cross-talk , we did not observe any effects on colon cancer cells that lacked NTRK3 after being treated with NT-3 .	However, despite the potential for cross-talk, we did not observe any effects on colon cancer cells that lacked NTRK3 after being treated with NT-3.	19	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	NTRK3	NTRK3	NTRK3	25	26	20	21
The cytokine Neurotrophin-3 ( but not Ciliary Neurotrophic Factor ) promotes neural crest proliferation and survival in response to alcohol ; neural crest cells express the Trk-C receptor , but whether this represents repletion of absent neurotrophin or generalized trophic support was not tested .	The cytokine Neurotrophin-3 (but not Ciliary Neurotrophic Factor) promotes neural crest proliferation and survival in response to alcohol; neural crest cells express the Trk-C receptor, but whether this represents repletion of absent neurotrophin or generalized trophic support was not tested.	0	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Neurotrophin-3	Neurotrophin-3	Neurotrophin-3	Trk-C	Trk-C	Trk-C	2	3	26	27
Although both neurotrophins activate TrkB receptors , their temporal expression is different , and NT-3 activates TrkB receptors in a lower proportion and activates TrkC receptors as well XREF_BIBR .	Although both neurotrophins activate TrkB receptors, their temporal expression is different, and NT-3 activates TrkB receptors in a lower proportion and activates TrkC receptors as well XREF_BIBR.	14	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	14	15	24	25
The present study attempted to explore whether NT-3 gene modified MSCs could promote TrkC gene modified MSCs to differentiate into neural like cells in a GS scaffold and , more importantly , whether the grafted MSC derived neural like cells could maintain neural features or transdifferentiate into other neural cells such as myelin forming cells in the completely transected rat spinal cord .	The present study attempted to explore whether NT-3 gene modified MSCs could promote TrkC gene modified MSCs to differentiate into neural like cells in a GS scaffold and, more importantly, whether the grafted MSC derived neural like cells could maintain neural features or transdifferentiate into other neural cells such as myelin forming cells in the completely transected rat spinal cord.	7	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	7	8	13	14
Furthermore , cell culture paradigms revealed that NT3 activation of TrkC stimulates Ras activity and induces the Rac1-GEF TIAM1 to activate Rac1 .	Furthermore, cell culture paradigms revealed that NT3 activation of TrkC stimulates Ras activity and induces the Rac1-GEF TIAM1 to activate Rac1.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NT3	NT3	NT3	TrkC	TrkC	TrkC	7	8	10	11
The NTRK3 receptor is activated by neurotrophin-3 and activates signaling pathways involved in neuronal survival , differentiation , and synaptic plasticity .	The NTRK3 receptor is activated by neurotrophin-3 and activates signaling pathways involved in neuronal survival, differentiation, and synaptic plasticity.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	neurotrophin-3	neurotrophin-3	neurotrophin-3	NTRK3	NTRK3	NTRK3	6	7	1	2
The influence of IL-1beta on NT-3 signaling was therefore studied under conditions when NT-3 primarily activated the TrkC receptor .	The influence of IL-1beta on NT-3 signaling was therefore studied under conditions when NT-3 primarily activated the TrkC receptor.	13	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	13	14	17	18
These results suggest that growth and maturation of the Purkinje cell dendritic arbor may be influenced by neurotrophin-3 activation of trkC receptors distributed within developing dendrites .	These results suggest that growth and maturation of the Purkinje cell dendritic arbor may be influenced by neurotrophin-3 activation of trkC receptors distributed within developing dendrites.	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	neurotrophin-3	neurotrophin-3	neurotrophin-3	trkC	trkC	trkC	17	18	20	21
NPR-A is activated by ANP and BNP , thereby mediating their endocrine actions in regulating body volume homeostasis and blood pressure and their local antihypertrophic effects in the myocardium .	NPR-A is activated by ANP and BNP, thereby mediating their endocrine actions in regulating body volume homeostasis and blood pressure and their local antihypertrophic effects in the myocardium.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	4	5	0	1
XREF_BIBR Also , in cultured inner medullary collecting duct cells ANP , which like BNP activates GC-A , has been reported to promote retrieval of AQP2 from the cell membrane to the cytosol , which may be able to enhance the aquaretic actions of TLV .	XREF_BIBR Also, in cultured inner medullary collecting duct cells ANP, which like BNP activates GC-A, has been reported to promote retrieval of AQP2 from the cell membrane to the cytosol, which may be able to enhance the aquaretic actions of TLV.	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	10	11	16	17
GC-A and Npr1 is activated by atrial natriuretic peptide ( ANP ) and brain natriuretic peptide ( BNP ) and the mRNA is expressed in the subfornical organ , medial habenula , cerebellum and olfactory bulb [ XREF_BIBR , XREF_BIBR ] .	GC-A and Npr1 is activated by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and the mRNA is expressed in the subfornical organ, medial habenula, cerebellum and olfactory bulb [XREF_BIBR, XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	atrial natriuretic peptide	atrial natriuretic peptide	atrial natriuretic peptide	GC-A	GC-A	GC-A	6	9	0	1
NPR-A is activated by ANP , BNP and DNP [ XREF_BIBR ] , NPR-B shows high affinity and is activated by CNP and , finally , the NPR-C binds all natriuretic peptides [ XREF_BIBR ] .	NPR-A is activated by ANP, BNP and DNP [XREF_BIBR], NPR-B shows high affinity and is activated by CNP and, finally, the NPR-C binds all natriuretic peptides [XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	4	5	0	1
Proteolytic susceptibility was addressed with novel bioassays that measure the time required for kidney membranes or purified neutral endopeptidase to abolish ANP dependent activation of NPR-A .	Proteolytic susceptibility was addressed with novel bioassays that measure the time required for kidney membranes or purified neutral endopeptidase to abolish ANP dependent activation of NPR-A.	21	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	21	22	25	26
ANP and C-type natriuretic peptide ( CNP ) induced a concentration dependent increase in cGMP suggesting the presence of type-A ( NPR-A ) and type-B ( NPR-B ) receptors , respectively .	ANP and C-type natriuretic peptide (CNP) induced a concentration dependent increase in cGMP suggesting the presence of type-A (NPR-A) and type-B (NPR-B) receptors, respectively.	0	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	0	1	21	22
One micromolar ANP stimulated the guanylyl cyclase activity of GC-A to 72 , 66 and 61 % of the activity measured in the presence of 1 % Triton X-100 and Mn 2+ GTP in membranes from cells transfected with wild type , S487A and S487E GC-A constructs , respectively ( XREF_FIG ) .	One micromolar ANP stimulated the guanylyl cyclase activity of GC-A to 72, 66 and 61% of the activity measured in the presence of 1% Triton X-100 and Mn 2+ GTP in membranes from cells transfected with wild type, S487A and S487E GC-A constructs, respectively (XREF_FIG).	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	2	3	9	10
ANP and BNP , which are both produced by stretched atria or by diseased VMs XREF_BIBR , XREF_BIBR , activate NPR1 and can counteract pathological cardiac hypertrophy XREF_BIBR , XREF_BIBR .	ANP and BNP, which are both produced by stretched atria or by diseased VMs XREF_BIBR, XREF_BIBR, activate NPR1 and can counteract pathological cardiac hypertrophy XREF_BIBR, XREF_BIBR.	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR1	NPR1	NPR1	0	1	20	21
This study demonstrates that NPR-A activation ( by ANP and/or BNP ) plays a key role in facilitating pro inflammatory cytokine production , iNOS expression and activity and the subsequent development of vascular hyporeactivity in LPS induced murine shock .	This study demonstrates that NPR-A activation (by ANP and/or BNP) plays a key role in facilitating pro inflammatory cytokine production, iNOS expression and activity and the subsequent development of vascular hyporeactivity in LPS induced murine shock.	4	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	8	9	4	5
Both atrial natriuretic factor ( ANF ) and GTP gamma S synergistically stimulated the guanylate cyclase ( GC ) activity of GC-A and ANF-R in a dose- and time related manner .	Both atrial natriuretic factor (ANF) and GTP gamma S synergistically stimulated the guanylate cyclase (GC) activity of GC-A and ANF-R in a dose- and time related manner.	1	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	atrial natriuretic factor	atrial natriuretic factor	atrial natriuretic factor	GC-A	GC-A	GC-A	1	4	21	22
NPRA activation by atrial natriuretic peptide ( ANP ) leads to cGMP production , which plays important roles in cardiovascular homeostasis .	NPRA activation by atrial natriuretic peptide (ANP) leads to cGMP production, which plays important roles in cardiovascular homeostasis.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	atrial natriuretic peptide	atrial natriuretic peptide	atrial natriuretic peptide	NPRA	NPRA	NPRA	3	6	0	1
Thus , genetic studies in mice strongly support a role for ANP activation of NPR-A in the local inhibition of cardiac hypertrophy and BNP activation of NPR-A in the inhibition of cardiac fibrosis .	Thus, genetic studies in mice strongly support a role for ANP activation of NPR-A in the local inhibition of cardiac hypertrophy and BNP activation of NPR-A in the inhibition of cardiac fibrosis.	11	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	11	12	14	15
We also presently demonstrate that stimulation of NPR-A by ANP or BNP does not affect the 5-HT 4 -mediated inotropic response , which is in line with the previously reported lack of effect on the beta 1 -AR mediated inotropic response .	We also presently demonstrate that stimulation of NPR-A by ANP or BNP does not affect the 5-HT 4 -mediated inotropic response, which is in line with the previously reported lack of effect on the beta 1 -AR mediated inotropic response.	5	11	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	9	10	7	8
Atrial ( ANP ) and brain natriuretic peptide ( BNP ) activate NPR-A , causing production of cyclic GMP ( cGMP ) .	Atrial (ANP) and brain natriuretic peptide (BNP) activate NPR-A, causing production of cyclic GMP (cGMP).	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	2	3	12	13
The vast majority of early studies showed that either ANP or ATP alone increased cyclase activity of GC-A but when added together , ANP and ATP resulted in synergistic receptor activation .	The vast majority of early studies showed that either ANP or ATP alone increased cyclase activity of GC-A but when added together, ANP and ATP resulted in synergistic receptor activation.	8	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	9	10	17	18
NPR-A is activated by ANP and BNP , and NPR-B is activated by CNP [ XREF_BIBR ] .	NPR-A is activated by ANP and BNP, and NPR-B is activated by CNP [XREF_BIBR].	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	4	5	0	1
Indeed , previous studies as well as recent data have indicated that the KHD seems to be important for ANP dependent activation of NPR-A [ XREF_BIBR , XREF_BIBR ] .	Indeed, previous studies as well as recent data have indicated that the KHD seems to be important for ANP dependent activation of NPR-A [XREF_BIBR, XREF_BIBR].	19	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	19	20	23	24
Expression of this cDNA in COS-7 cells potentiated ANF stimulated GC-A activity .	Expression of this cDNA in COS-7 cells potentiated ANF stimulated GC-A activity.	7	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANF	ANF	ANF	GC-A	GC-A	GC-A	8	9	10	11
These data indicate that NPR-A is basally internalized by a dynamin dependent pathway and that prolonged ANP exposure stimulates both NPR-A internalization and degradation .	These data indicate that NPR-A is basally internalized by a dynamin dependent pathway and that prolonged ANP exposure stimulates both NPR-A internalization and degradation.	16	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	16	17	20	21
Transfection of CypA inhibited ANF stimulated GC-A activity , indicating that CypA functions as an endogenous inhibitor for GC-A activation .	Transfection of CypA inhibited ANF stimulated GC-A activity, indicating that CypA functions as an endogenous inhibitor for GC-A activation.	3	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANF	ANF	ANF	GC-A	GC-A	GC-A	4	5	6	7
To this end , since activation of NPR-A by ANP and BNP has been shown to increase intracellular cGMP production [ XREF_BIBR ] , we investigated if application of BNP to mouse TG cultures could increase intracellular cGMP production , as determined by ELISA .	To this end, since activation of NPR-A by ANP and BNP has been shown to increase intracellular cGMP production [XREF_BIBR], we investigated if application of BNP to mouse TG cultures could increase intracellular cGMP production, as determined by ELISA.	5	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	9	10	7	8
Collectively , these data suggest that endothelial GC-A activated by ANP prevents hematogenous pulmonary metastasis of cancer cells in mice .	Collectively, these data suggest that endothelial GC-A activated by ANP prevents hematogenous pulmonary metastasis of cancer cells in mice.	6	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	10	11	7	8
The biological effects of CNP result from its selective activation of the cell surface particulate guanylyl cyclase receptor B ( GC-B ) , which contrasts the selective activation of GC-A by ANP and BNP [ XREF_BIBR ] .	The biological effects of CNP result from its selective activation of the cell surface particulate guanylyl cyclase receptor B (GC-B), which contrasts the selective activation of GC-A by ANP and BNP [XREF_BIBR].	27	35	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	31	32	29	30
The NPR-A is activated by physiological concentrations of ANP and BNP , but not by CNP .	The NPR-A is activated by physiological concentrations of ANP and BNP, but not by CNP.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	8	9	1	2
Specifically , the GC-A receptor activated by ANP and BNP and GC-B activation by CNP mediate beneficial pleiotropic actions , which include natriuresis , vasodilatation , suppression of the renin-angiotensin-aldosterone system , inhibition of cardiomyocyte hypertrophy , retardation of fibrosis and improvement in ventricular function and structure .	Specifically, the GC-A receptor activated by ANP and BNP and GC-B activation by CNP mediate beneficial pleiotropic actions, which include natriuresis, vasodilatation, suppression of the renin-angiotensin-aldosterone system, inhibition of cardiomyocyte hypertrophy, retardation of fibrosis and improvement in ventricular function and structure.	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	7	8	3	4
GC-A was poorly activated by ANF and ATP after the rat lung membrane was pretreated with pronase , suggesting that ANF and ATP and pronase activate guanylate cyclase through the same mechanism .	GC-A was poorly activated by ANF and ATP after the rat lung membrane was pretreated with pronase, suggesting that ANF and ATP and pronase activate guanylate cyclase through the same mechanism.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANF	ANF	ANF	GC-A	GC-A	GC-A	5	6	0	1
Released in response to an increase in dietary sodium and/or an increase in intravascular volume with atrial stretch , ANP activates GC-A in endothelial cells , vascular smooth muscle and collecting duct cells to increase blood vessel permeability , induce vasorelaxation and inhibit sodium ion reabsorption that results in natriuresis , respectively .	Released in response to an increase in dietary sodium and/or an increase in intravascular volume with atrial stretch, ANP activates GC-A in endothelial cells, vascular smooth muscle and collecting duct cells to increase blood vessel permeability, induce vasorelaxation and inhibit sodium ion reabsorption that results in natriuresis, respectively.	17	22	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	19	20	21	22
Phosphorylation may be important in the regulation of both basal and ANP induced NPR-A activity in the systemic vasculature .	Phosphorylation may be important in the regulation of both basal and ANP induced NPR-A activity in the systemic vasculature.	6	14	induced	Positive_early_activation	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	11	12	13	14
Our findings show that both ANP and ANP-RR generate cGMP in human aortic endothelial cells and activate GC-A receptor with no difference between the two peptides .	Our findings show that both ANP and ANP-RR generate cGMP in human aortic endothelial cells and activate GC-A receptor with no difference between the two peptides.	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	5	6	17	18
In addition , in the previous study GC activity was poorly activated ( < 2.5 fold ) , whereas in our assays ANP stimulated GC-A 9-fold .	In addition, in the previous study GC activity was poorly activated (< 2.5 fold), whereas in our assays ANP stimulated GC-A 9-fold.	22	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	22	23	24	25
Both ANP and BNP activate guanylyl cyclase and natriuretic peptide receptor-A ( GC-A and NPRA ) , which , in response to hormone binding , produces second-messenger cGMP [ XREF_BIBR ] .	Both ANP and BNP activate guanylyl cyclase and natriuretic peptide receptor-A (GC-A and NPRA), which, in response to hormone binding, produces second-messenger cGMP [XREF_BIBR].	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPRA	NPRA	NPRA	1	2	14	15
ANP was originally shown to activate GC-A in the absence of ATP .	ANP was originally shown to activate GC-A in the absence of ATP.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	0	1	6	7
Both ANP and BNP stimulate NPRA whereas CNP activates NPRB , and all three natriuretic peptides bind to NPRC .	Both ANP and BNP stimulate NPRA whereas CNP activates NPRB, and all three natriuretic peptides bind to NPRC.	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPRA	NPRA	NPRA	1	2	5	6
In isolated venous and arterial rings , CNP activates GC-B receptors in veins while ANP and BNP activate GC-A receptors in both arteries and veins which is consistent with the less hypotensive actions of CNP as compared to ANP and BNP .	In isolated venous and arterial rings, CNP activates GC-B receptors in veins while ANP and BNP activate GC-A receptors in both arteries and veins which is consistent with the less hypotensive actions of CNP as compared to ANP and BNP.	14	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	14	15	18	19
In the absence of ATP , product formation by ANP activated GC-A was cooperative , as demonstrated by a Hill coefficient of 1.5 ( XREF_FIG ) .	In the absence of ATP, product formation by ANP activated GC-A was cooperative, as demonstrated by a Hill coefficient of 1.5 (XREF_FIG).	7	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	9	10	11	12
Human macrophages isolated by peripheral blood mononuclear cells and THP-1 monocytes , which were shown to express all three natriuretic peptide receptors ( NPR-A , NPR-B , and NPR-C ) , were treated with physiological concentrations of ANP .	Human macrophages isolated by peripheral blood mononuclear cells and THP-1 monocytes, which were shown to express all three natriuretic peptide receptors (NPR-A, NPR-B, and NPR-C), were treated with physiological concentrations of ANP.	21	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	37	38	23	24
Atrial natriuretic pepticle ( ANP ) stimulates guanylate cyclase A , which is predominantly expressed in the rat parotid gland .	Atrial natriuretic pepticle (ANP) stimulates guanylate cyclase A, which is predominantly expressed in the rat parotid gland.	0	15	stimulates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Atrial natriuretic pepticle	Atrial natriuretic pepticle	atrial natriuretic pepticle	guanylate cyclase A	guanylate cyclase A, which is predominantly expressed	guanylate cyclase a	0	3	7	10
We examined whether CypA affects the activation of GC-A by ANF .	We examined whether CypA affects the activation of GC-A by ANF.	4	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	ANF	ANF	ANF	GC-A	GC-A	GC-A	10	11	8	9
Similar effects of ANP were observed in transgenic mice overexpressing the ANP receptor GC-A in vascular endothelium cells .	Similar effects of ANP were observed in transgenic mice overexpressing the ANP receptor GC-A in vascular endothelium cells.	1	14	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	3	4	13	14
ANP stimulated intracellular accumulation of cGMP and GC activity of NPRA were drastically reduced in Npr1 miRNA expressing cells by 90 %-95% as compared with control cells .	ANP stimulated intracellular accumulation of cGMP and GC activity of NPRA were drastically reduced in Npr1 miRNA expressing cells by 90%-95% as compared with control cells.	0	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPRA	NPRA	NPRA	0	1	10	11
Conversely , atrial natriuretic peptide stimulates the guanylyl cyclase activities of NPR1 and NPR2 and can inhibit TGFbeta activity in myofibroblasts ; this inhibition has been suggested to underlie the opposing roles of atrial natriuretic peptide and TGFbeta during hypoxia induced remodeling of the pulmonary vasculature [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Conversely, atrial natriuretic peptide stimulates the guanylyl cyclase activities of NPR1 and NPR2 and can inhibit TGFbeta activity in myofibroblasts; this inhibition has been suggested to underlie the opposing roles of atrial natriuretic peptide and TGFbeta during hypoxia induced remodeling of the pulmonary vasculature [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	atrial natriuretic peptide	atrial natriuretic peptide	atrial natriuretic peptide	NPR1	NPR1	NPR1	2	5	11	12
Quercetin inhibited CNP stimulated GC-B activity , but had little effect on ANF stimulated GC-A activity in PC12 cells , suggesting that quercetin mainly activates GC-B in PC12 cells .	Quercetin inhibited CNP stimulated GC-B activity, but had little effect on ANF stimulated GC-A activity in PC12 cells, suggesting that quercetin mainly activates GC-B in PC12 cells.	10	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ANF	ANF	ANF	GC-A	GC-A	GC-A	12	13	14	15
Thus , both experimental observations and mathematical simulations of the signaling pathway suggest that in MA-10 cells calcineurin regulates ANP induced NPR-A desensitization , which , in turn , blunts ANP induced testosterone production .	Thus, both experimental observations and mathematical simulations of the signaling pathway suggest that in MA-10 cells calcineurin regulates ANP induced NPR-A desensitization, which, in turn, blunts ANP induced testosterone production.	19	22	induced	Positive_early_activation	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	19	20	21	22
ANP activation of guanylate cyclase A receptors produces cGMP , which is preferentially extruded on the basolateral side of the cells and inhibits the amiloride sensitive Na-channel activity .	ANP activation of guanylate cyclase A receptors produces cGMP, which is preferentially extruded on the basolateral side of the cells and inhibits the amiloride sensitive Na-channel activity.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ANP	ANP	ANP	guanylate cyclase A	guanylate cyclase A	guanylate cyclase A	0	1	3	6
Given the fact that ANP is well characterised to activate NPR-A , we assume that extracellular activation is key to cGMP generation .	Given the fact that ANP is well characterised to activate NPR-A, we assume that extracellular activation is key to cGMP generation.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	4	5	10	11
Studies of human NPR1 and NPR2 have shown that 1 microM ANP activates NPR1 , but has almost no effect on NPR2 .	Studies of human NPR1 and NPR2 have shown that 1 microM ANP activates NPR1, but has almost no effect on NPR2.	9	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPR1	NPR1	NPR1	11	12	13	14
Administration of atrial natriuretic peptide ( ANP ) , which activates GC-A and B , significantly suppressed TGF mediated EPFR reduction either intravenously ( 10 nmol/kg/h ) or intraluminally ( 10 (-5) mol/l in ATF ) ( 9 +/-3% and 13 +/-2% vs. 47 +/-3% of the control , p < 0.05 ) .	Administration of atrial natriuretic peptide (ANP), which activates GC-A and B, significantly suppressed TGF mediated EPFR reduction either intravenously (10 nmol/kg/h) or intraluminally (10 (-5) mol/l in ATF) (9 +/-3% and 13 +/-2% vs. 47 +/-3% of the control, p < 0.05).	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	atrial natriuretic peptide	atrial natriuretic peptide	atrial natriuretic peptide	GC-A	GC-A	GC-A	2	5	11	12
Because GC-A signaling stimulated by ANP and BNP results in a decrease in cardiac pre- and after-load , their mobilization during cardiac failure is thought to be one of the compensatory mechanisms activated in response to heart damage .	Because GC-A signaling stimulated by ANP and BNP results in a decrease in cardiac pre- and after-load, their mobilization during cardiac failure is thought to be one of the compensatory mechanisms activated in response to heart damage.	1	8	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	5	6	1	2
GC-A is activated by atrial natriuretic peptide ( ANP ) , the natriuretic factor in atrial extracts that was originally described by XREF_BIBR ( XREF_FIG ) .	GC-A is activated by atrial natriuretic peptide (ANP), the natriuretic factor in atrial extracts that was originally described by XREF_BIBR (XREF_FIG).	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	atrial natriuretic peptide	atrial natriuretic peptide	atrial natriuretic peptide	GC-A	GC-A	GC-A	4	7	0	1
These studies and our data strongly suggest that ANP mediated Npr-1 signaling has a direct inhibitory effect on cardiac hypertrophy .	These studies and our data strongly suggest that ANP mediated Npr-1 signaling has a direct inhibitory effect on cardiac hypertrophy.	8	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	ANP	ANP	ANP	Npr-1	Npr-1	Npr-1	8	9	10	11
Furthermore , quercetin had a small effect on ANF stimulated GC-A activity and had no effect on soluble guanylate cyclase activity in LLC-PK1 cells , suggesting that quercetin does not activate GC-A , GC-B or soluble guanylate cyclase in LLC-PK1 cells .	Furthermore, quercetin had a small effect on ANF stimulated GC-A activity and had no effect on soluble guanylate cyclase activity in LLC-PK1 cells, suggesting that quercetin does not activate GC-A, GC-B or soluble guanylate cyclase in LLC-PK1 cells.	6	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ANF	ANF	ANF	GC-A	GC-A	GC-A	8	9	10	11
The GC-A is activated by the atrial natriuretic peptide ( ANP ) and the brain natriuretic peptide ( BNP ) , two primarily cardiac hormones which are secreted from the atrium and ventricle during pressure or volume overload .	The GC-A is activated by the atrial natriuretic peptide (ANP) and the brain natriuretic peptide (BNP), two primarily cardiac hormones which are secreted from the atrium and ventricle during pressure or volume overload.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	atrial natriuretic peptide	atrial natriuretic peptide	atrial natriuretic peptide	GC-A	GC-A	GC-A	6	9	1	2
Basal internalization of both receptors was 8-fold higher in 293 compared with HeLa cells and ANP did not increase internalization of FLAG-GC-A .	Basal internalization of both receptors was 8-fold higher in 293 compared with HeLa cells and ANP did not increase internalization of FLAG-GC-A.	15	22	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	FLAG-GC-A	FLAG-GC-A	FLAG-GC-A	15	16	21	22
The archetypal mammalian mGC is GC-A , a critical cardiovascular regulator that is stimulated by atrial natriuretic peptide ( ANP ) and B-type natriuretic peptide ( BNP ) .	The archetypal mammalian mGC is GC-A, a critical cardiovascular regulator that is stimulated by atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP).	3	18	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	atrial natriuretic peptide	atrial natriuretic peptide	atrial natriuretic peptide	GC-A	GC-A	GC-A	15	18	5	6
Expression of these cDNAs on mammalian cells revealed that ( 1 ) GC-B is a specific receptor for CNP whereas GC-A is stimulated effectively both by ANP and BNP , and ( 2 ) the two forms of GC-B possess practically the same high binding affinity for CNP while the shorter form could not induce cGMP production by the binding of CNP .	Expression of these cDNAs on mammalian cells revealed that (1) GC-B is a specific receptor for CNP whereas GC-A is stimulated effectively both by ANP and BNP, and (2) the two forms of GC-B possess practically the same high binding affinity for CNP while the shorter form could not induce cGMP production by the binding of CNP.	20	28	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	26	27	20	21
ANP promoted the expression of NPRA and the formation of NPRA , PGRMC1 , and EGFR complex .	ANP promoted the expression of NPRA and the formation of NPRA, PGRMC1, and EGFR complex.	0	16	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANP	ANP	ANP	NPRA	NPRA	NPRA	0	1	10	11
Activation of GC-A or GC-B receptors by ANP or ANP-RR .	Activation of GC-A or GC-B receptors by ANP or ANP-RR.	0	9	Activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	7	8	2	3
Surprisingly , BDNF mRNA expression in the maternal brain was not stimulated by VPA at either 3 or 24 hr ( XREF_FIG ) ; however , expression of NT4 , which , like BDNF , activates trkB , was increased 2.8-fold in the maternal brain at 3 hr after VPA administration .	Surprisingly, BDNF mRNA expression in the maternal brain was not stimulated by VPA at either 3 or 24 hr (XREF_FIG); however, expression of NT4, which, like BDNF, activates trkB, was increased 2.8-fold in the maternal brain at 3 hr after VPA administration.	26	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT4	expression of NT4	nt4	trkB	trkB	trkb	28	29	36	37
The differential sorting most likely occurs after the early endosome where NT4 might promote TrkB sorting to the recycling endosome and a fraction of it might be degraded via the proteasome system .	The differential sorting most likely occurs after the early endosome where NT4 might promote TrkB sorting to the recycling endosome and a fraction of it might be degraded via the proteasome system.	11	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT4	NT4	NT4	TrkB	TrkB	TrkB	11	12	14	15
NT4 leads to efficient endocytosis and targeting of TrkB receptor to the early endocytic compartment .	NT4 leads to efficient endocytosis and targeting of TrkB receptor to the early endocytic compartment.	0	9	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	NT4	NT4	NT4	TrkB	TrkB	TrkB	0	1	8	9
Our data showing that NT4 activation of TrkB does not lead to significant down-regulation of the receptor thus ensuring sustained signaling , presents the first molecular evidence that could explain those findings .	Our data showing that NT4 activation of TrkB does not lead to significant down-regulation of the receptor thus ensuring sustained signaling, presents the first molecular evidence that could explain those findings.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NT4	NT4	NT4	TrkB	TrkB	TrkB	4	5	7	8
To determine how BNDF and NT4 may differentially modulate the endocytic trafficking of TrkB receptor , we first analyzed the initial endocytosis of TrkB upon ligand stimulation .	To determine how BNDF and NT4 may differentially modulate the endocytic trafficking of TrkB receptor, we first analyzed the initial endocytosis of TrkB upon ligand stimulation.	3	14	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT4	NT4	NT4	TrkB	TrkB	TrkB	5	6	13	14
Chronic exposure of NT-4 may induce trkB receptor downregulation .	Chronic exposure of NT-4 may induce trkB receptor downregulation.	1	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-4	NT-4	NT-4	trkB	trkB	trkB	3	4	6	7
However , interestingly the complete TrkB null mouse shows neuronal death in the hippocampus whereas the BDNF null does not , suggesting a key role for NT4 mediated TrkB activation .	However, interestingly the complete TrkB null mouse shows neuronal death in the hippocampus whereas the BDNF null does not, suggesting a key role for NT4 mediated TrkB activation.	21	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	NT4	NT4	NT4	TrkB	TrkB	TrkB	26	27	28	29
Although TrkB can be activated by NT4 and , in some instances , NT3 , BDNF is the most important ligand for TrkB within the brain XREF_BIBR .	Although TrkB can be activated by NT4 and, in some instances, NT3, BDNF is the most important ligand for TrkB within the brain XREF_BIBR.	1	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NT4	NT4	NT4	TrkB	TrkB	TrkB	6	7	1	2
These findings may be due to low level expression of BDNF remaining after viral infection of Cre recombinase that acts on TrkB receptors or alternatively some minor effects of neurotrophin 3 ( NT3 ) or neurotrophin 4 ( NT4 ) activating the TrkB receptor to impact lithium ' s effects on synaptic transmission .	These findings may be due to low level expression of BDNF remaining after viral infection of Cre recombinase that acts on TrkB receptors or alternatively some minor effects of neurotrophin 3 (NT3) or neurotrophin 4 (NT4) activating the TrkB receptor to impact lithium 's effects on synaptic transmission.	35	43	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT4	NT4	NT4	TrkB	TrkB	TrkB	38	39	42	43
Exposure to 30-100 ng/ml GDNF or neurturin ( NRTN ) resulted in activation of ret .	Exposure to 30-100 ng/ml GDNF or neurturin (NRTN) resulted in activation of ret.	0	15	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	NRTN	NRTN	NRTN	ret	ret	ret	8	9	14	15
Thus , based on the expression patterns of RET signaling components in the developing SC and DRGs , RET in the central projections and cell bodies of developing RA mechanoreceptors could potentially be activated in cis by NRTN / GFRa2 or in trans by GDNF / GFRa1 , which may come from neighboring DRG neurons , dorsal root entry zone cells , or dSC cells .	Thus, based on the expression patterns of RET signaling components in the developing SC and DRGs, RET in the central projections and cell bodies of developing RA mechanoreceptors could potentially be activated in cis by NRTN / GFRa2 or in trans by GDNF / GFRa1, which may come from neighboring DRG neurons, dorsal root entry zone cells, or dSC cells.	18	64	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRTN	NRTN	NRTN	RET	RET	RET	37	38	18	19
Since RA mechanoreceptors express a high level of Gfra2 but not any other Gfras , it is likely that RET in RA mechanoreceptors is activated by NRTN and GFRa2 in cis .	Since RA mechanoreceptors express a high level of Gfra2 but not any other Gfras, it is likely that RET in RA mechanoreceptors is activated by NRTN and GFRa2 in cis.	19	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRTN	NRTN	NRTN	RET	RET	RET	26	27	19	20
Additionally , we identify Ret independent signaling pathways initiated by NRTN and ARTN , which are important in altering the function of peripheral sensory neurons .	Additionally, we identify Ret independent signaling pathways initiated by NRTN and ARTN, which are important in altering the function of peripheral sensory neurons.	4	16	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRTN	NRTN	NRTN	Ret	Ret	Ret	10	11	4	5
GDNF family of ligands ( GFLs ) GDNF , Neurturin ( Nrtn ) , Artemin ( Artn ) and Persephin ( Pspn ) bind to co-receptors GFRalpha1-4 respectively and activate RET Receptor tyrosine kinase .	GDNF family of ligands (GFLs) GDNF, Neurturin (Nrtn), Artemin (Artn) and Persephin (Pspn) bind to co-receptors GFRalpha1-4 respectively and activate RET Receptor tyrosine kinase.	3	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrtn	Nrtn	Nrtn	RET	RET	RET	11	12	30	31
When the specific ligand , neurturin ( NRTN ) binds GFRA2 , the RET tyrosine kinase is activated by GFRA2 and NRTN , to elicit a biological response .	When the specific ligand, neurturin (NRTN) binds GFRA2, the RET tyrosine kinase is activated by GFRA2 and NRTN, to elicit a biological response.	13	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRTN	NRTN	NRTN	RET	RET	RET	21	22	13	14
A neurotrophic factor closely related to GDNF , neurturin , also activates the Ret receptor .	A neurotrophic factor closely related to GDNF, neurturin, also activates the Ret receptor.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neurturin	neurturin	neurturin	Ret	Ret	Ret	8	9	13	14
Thus , at E13.5 , Gfra2 and Nrtn null mice phenocopy the central projection deficit of Ret mutant mice , which suggests that RET is activated by NRTN and GFRa2 in cis for the initial growth of RA mechanosensory central projections .	Thus, at E13.5, Gfra2 and Nrtn null mice phenocopy the central projection deficit of Ret mutant mice, which suggests that RET is activated by NRTN and GFRa2 in cis for the initial growth of RA mechanosensory central projections.	23	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRTN	NRTN	NRTN	RET	RET	RET	27	28	23	24
XREF_BIBR , XREF_BIBR , XREF_BIBR This suggests that neurturin might stimulate Ret on dopaminergic neurons by low affinity binding to GFRalpha1 or supports dopaminergic neurons in a non-cell-autonomous manner .	XREF_BIBR, XREF_BIBR, XREF_BIBR This suggests that neurturin might stimulate Ret on dopaminergic neurons by low affinity binding to GFRalpha1 or supports dopaminergic neurons in a non-cell-autonomous manner.	8	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neurturin	neurturin	neurturin	Ret	Ret	Ret	8	9	11	12
Altogether , our results support the view that the loss of retrograde signalling from peripheral targets is one of the mechanisms by which CaMK1a is de novo induced in injured sensory neurons , and that its expression is negatively regulated by the Ret signalling pathway notably triggered by NRTN .	Altogether, our results support the view that the loss of retrograde signalling from peripheral targets is one of the mechanisms by which CaMK1a is de novo induced in injured sensory neurons, and that its expression is negatively regulated by the Ret signalling pathway notably triggered by NRTN.	42	49	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRTN	NRTN	NRTN	Ret	Ret	Ret	48	49	42	43
MAPK signaling is hyperactivated by mutated NRAS that can activate CRAF , a RAF isomer , and BRAF heterodimerization and pathway switching , which can bypass vemurafenib sensitivity of cancer cells [ XREF_BIBR ] .	MAPK signaling is hyperactivated by mutated NRAS that can activate CRAF, a RAF isomer, and BRAF heterodimerization and pathway switching, which can bypass vemurafenib sensitivity of cancer cells [XREF_BIBR].	3	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRAS	NRAS	NRAS	BRAF	BRAF	BRAF	6	7	17	18
NRAS overactivation potentiates BRAF and induces expression of downstream effectors [ XREF_BIBR ] .	NRAS overactivation potentiates BRAF and induces expression of downstream effectors [XREF_BIBR].	0	4	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRAS	NRAS	NRAS	BRAF	BRAF	BRAF	0	1	3	4
XREF_BIBR Interestingly , NRAS activating mutations do not co-occur with PTEN mutations , consistent with the notion that , unlike BRAF , which can not induce PI3K activation , NRAS alone stimulates both the BRAF and MAPK and PI3K pathways .	XREF_BIBR Interestingly, NRAS activating mutations do not co-occur with PTEN mutations, consistent with the notion that, unlike BRAF, which can not induce PI3K activation, NRAS alone stimulates both the BRAF and MAPK and PI3K pathways.	29	39	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRAS	NRAS	NRAS	BRAF	BRAF	BRAF	29	30	34	35
Due to the ability of Hsp90 inhibitors to target several oncogenic proteins , melanomas with activating BRAF mutations , as well as those with WT BRAF activated by NRAS alike are sensitive to inhibitors like 17AAG [ XREF_BIBR , XREF_BIBR ] .	Due to the ability of Hsp90 inhibitors to target several oncogenic proteins, melanomas with activating BRAF mutations, as well as those with WT BRAF activated by NRAS alike are sensitive to inhibitors like 17AAG [XREF_BIBR, XREF_BIBR].	22	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRAS	NRAS	NRAS	BRAF	BRAF	BRAF	28	29	25	26
Interestingly , mutant BRAF , which is present in almost 70 % of all melanomas , shows marked dependency on Hsp90 and is degraded by 17-AAG treatment , while WT BRAF activated by NRAS is also Hsp90 dependent [ XREF_BIBR ] .	Interestingly, mutant BRAF, which is present in almost 70% of all melanomas, shows marked dependency on Hsp90 and is degraded by 17-AAG treatment, while WT BRAF activated by NRAS is also Hsp90 dependent [XREF_BIBR].	29	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	NRAS	NRAS	NRAS	BRAF	BRAF	BRAF	33	34	30	31
However , whereas Neuregulin3 stimulates a modest amount of ErbB4 coupling to biological responses , Neuregulin4 fails to stimulate ErbB4 coupling to biological responses .	However, whereas Neuregulin3 stimulates a modest amount of ErbB4 coupling to biological responses, Neuregulin4 fails to stimulate ErbB4 coupling to biological responses.	15	20	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Neuregulin4	Neuregulin4	Neuregulin4	ErbB4	ErbB4	ErbB4	15	16	19	20
As a novel endocrine factor , Nrg4 acts as an autocrine , paracrine , or endocrine signal by releasing the epidermal growth factor like domain after photolytic cleavage and activates the receptor kinases ErbB3 and ErbB4 in the cardiovascular system .	As a novel endocrine factor, Nrg4 acts as an autocrine, paracrine, or endocrine signal by releasing the epidermal growth factor like domain after photolytic cleavage and activates the receptor kinases ErbB3 and ErbB4 in the cardiovascular system.	6	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg4	Nrg4	Nrg4	ErbB4	ErbB4	ErbB4	6	7	35	36
Similarly NRG4 induces heterodimerization of HER4 with HER1 , HER2 and HER3 [ XREF_BIBR ] .	Similarly NRG4 induces heterodimerization of HER4 with HER1, HER2 and HER3 [XREF_BIBR].	1	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG4	NRG4	NRG4	HER4	HER4	HER4	1	2	5	6
Mechanistically , Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner .	Mechanistically, Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg4	Nrg4	Nrg4	ErbB4	ErbB4	ErbB4	2	3	6	7
Selective responses can be invoked by particular ligand and receptor combinations ; NRG4 , which exclusively activates ErbB4 25 , signals for mouse colonocyte survival but not proliferation or migration 17 .	Selective responses can be invoked by particular ligand and receptor combinations; NRG4, which exclusively activates ErbB4 25, signals for mouse colonocyte survival but not proliferation or migration 17.	7	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG4	NRG4	NRG4	ErbB4	ErbB4	ErbB4	12	13	17	18
Nrg4 belongs to the epidermal growth factor ( EGF ) family of extracellular ligands that bind to and activate the receptor tyrosine kinases ErbB3 and ErbB4 .	Nrg4 belongs to the epidermal growth factor (EGF) family of extracellular ligands that bind to and activate the receptor tyrosine kinases ErbB3 and ErbB4.	0	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg4	Nrg4	Nrg4	ErbB4	ErbB4	ErbB4	0	1	25	26
To examine whether native Nrg4 can be released into the extracellular space to activate ErbB4 , we collected CM from HEK293 cells transiently transfected with a vector expressing full-length wild type Nrg4 and treated Min6 cells stably overexpressing ErbB4 ( ErbB4-Min6 ) .	To examine whether native Nrg4 can be released into the extracellular space to activate ErbB4, we collected CM from HEK293 cells transiently transfected with a vector expressing full-length wild type Nrg4 and treated Min6 cells stably overexpressing ErbB4 (ErbB4-Min6).	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg4	Nrg4	Nrg4	ErbB4	ErbB4	ErbB4	4	5	14	15
At the mechanistic level , Nrg4 binds to and activates the receptor tyrosine kinases ErbB3 and ErbB4 , leading to STAT5 phosphorylation in hepatocytes .	At the mechanistic level, Nrg4 binds to and activates the receptor tyrosine kinases ErbB3 and ErbB4, leading to STAT5 phosphorylation in hepatocytes.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg4	Nrg4	Nrg4	ErbB4	ErbB4	ErbB4	5	6	16	17
A recent study has shown that inhibition of NRP2 disrupts vascular endothelial growth factor C induced lymphatic endothelial cell migration , reduces tumor lymphangiogenesis , and inhibits metastasis to sentinel lymph nodes and distant organs by delaying the departure of tumor cells from the primary tumor [ XREF_BIBR ] .	A recent study has shown that inhibition of NRP2 disrupts vascular endothelial growth factor C induced lymphatic endothelial cell migration, reduces tumor lymphangiogenesis, and inhibits metastasis to sentinel lymph nodes and distant organs by delaying the departure of tumor cells from the primary tumor [XREF_BIBR].	6	15	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	NRP2	NRP2	NRP2	vascular endothelial growth factor C	vascular endothelial growth factor C	vascular endothelial growth factor C	8	9	10	15
Furthermore , it has been shown that NRP2 mediates VEGF-C induced lymphatic sprouting together with VEGFR-3 [ XREF_BIBR ] .	Furthermore, it has been shown that NRP2 mediates VEGF-C induced lymphatic sprouting together with VEGFR-3 [XREF_BIBR].	7	10	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NRP2	NRP2	NRP2	VEGF-C	VEGF-C	VEGF-C	7	8	9	10
However , the net effect of CCBE1 on the cell surface increased local VEGF-C concentration , which is also promoted by neuropilin-2 16 , syndecan-4 18 , and beta-1 integrin XREF_BIBR , XREF_BIBR , which stabilize the VEGFR-3 and VEGF-C interaction .	However, the net effect of CCBE1 on the cell surface increased local VEGF-C concentration, which is also promoted by neuropilin-2 16, syndecan-4 18, and beta-1 integrin XREF_BIBR, XREF_BIBR, which stabilize the VEGFR-3 and VEGF-C interaction.	13	22	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	neuropilin-2	neuropilin-2	neuropilin-2	VEGF-C	VEGF-C	VEGF-C	21	22	13	14
Nrp2 can promote VEGF-C signaling via VEGFR2 and VEGFR3 , and inhibition of Nrp2 modestly but significantly reduces VEGF-C-mediated activation of both receptors .	Nrp2 can promote VEGF-C signaling via VEGFR2 and VEGFR3, and inhibition of Nrp2 modestly but significantly reduces VEGF-C-mediated activation of both receptors.	0	4	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrp2	Nrp2	Nrp2	VEGF-C	VEGF-C	VEGF-C	0	1	3	4
COUP-TFII might exert its lymphangiogenic function through Nrp2 increased VEGF-C signaling [ XREF_BIBR ] .	COUP-TFII might exert its lymphangiogenic function through Nrp2 increased VEGF-C signaling [XREF_BIBR].	2	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrp2	Nrp2	Nrp2	VEGF-C	VEGF-C	VEGF-C	7	8	9	10
NRP2 enhances VEGF-C and VEGFR -3 effects in developmental lymphangiogenesis , but its role in adult and tumoral lymphangiogenesis is not known .	NRP2 enhances VEGF-C and VEGFR -3 effects in developmental lymphangiogenesis, but its role in adult and tumoral lymphangiogenesis is not known.	0	6	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRP2	NRP2	NRP2	VEGF-C	VEGF-C	VEGF-C	0	1	2	3
The interaction of NRP2 with VEGFR3 enhances VEGFC induced LEC survival and migration in vitro .	The interaction of NRP2 with VEGFR3 enhances VEGFC induced LEC survival and migration in vitro.	1	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRP2	NRP2	NRP2	VEGFC	VEGFC	VEGFC	3	4	7	8
VEGF may also regulate autophagy because it has been shown that NRP2 mediated VEGFC signalling mediated by mTOR complex 1 activates an autophagic mechanism that combats chemotherapy induced stress , which has implications for the role of VEGF signalling in therapy resistance 93 .	VEGF may also regulate autophagy because it has been shown that NRP2 mediated VEGFC signalling mediated by mTOR complex 1 activates an autophagic mechanism that combats chemotherapy induced stress, which has implications for the role of VEGF signalling in therapy resistance 93.	11	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	NRP2	NRP2	NRP2	VEGFC	VEGFC	VEGFC	11	12	13	14
130 They demonstrated that NMDARs in GABA neurons are required to release NRG2 , which activate its receptor ErbB4 on the same neuron as an autocrine signaling .	130 They demonstrated that NMDARs in GABA neurons are required to release NRG2, which activate its receptor ErbB4 on the same neuron as an autocrine signaling.	11	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG2	NRG2	NRG2	ErbB4	ErbB4	ErbB4	12	13	18	19
NRG2 promotes the association of ErbB4 with GluN2B .	NRG2 promotes the association of ErbB4 with GluN2B.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG2	NRG2	NRG2	ErbB4	ErbB4	ErbB4	0	1	5	6
A recent study reports that NRG2 , a close relative of NRG1 , is expressed in inhibitory interneurons and activates ERBB4 cell-autonomously , causing a downregulation of NMDA receptor activity in these cells ( Vullhorst etal , 2015 ) .	A recent study reports that NRG2, a close relative of NRG1, is expressed in inhibitory interneurons and activates ERBB4 cell-autonomously, causing a downregulation of NMDA receptor activity in these cells (Vullhorst etal, 2015).	5	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG2	NRG2, a close relative of NRG1, is expressed	nrg2	ERBB4	ERBB4	erbb4	5	6	20	21
For instance , down-regulations of NRG2 or NRG3 that also transduce signals via erbB4 could enhance NRG1- erbB4 signaling at all levels .	For instance, down-regulations of NRG2 or NRG3 that also transduce signals via erbB4 could enhance NRG1- erbB4 signaling at all levels.	3	18	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG2	NRG2	NRG2	erbB4	erbB4	erbB4	5	6	17	18
In turn , NRG2 promotes the physical association of ErbB4 with GluN2B containing NMDARs , which is followed by NMDAR removal from the cell surface and the downregulation of whole-cell and synaptic NMDAR currents selectively in interneurons .	In turn, NRG2 promotes the physical association of ErbB4 with GluN2B containing NMDARs, which is followed by NMDAR removal from the cell surface and the downregulation of whole-cell and synaptic NMDAR currents selectively in interneurons.	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG2	NRG2	NRG2	ErbB4	ErbB4	ErbB4	3	4	9	10
Thus Gln 43 regulates NRG2 stimulation of ErbB4 coupling to IL-3-independent proliferation [ XREF_BIBR ] .	Thus Gln 43 regulates NRG2 stimulation of ErbB4 coupling to IL-3-independent proliferation [XREF_BIBR].	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG2	NRG2	NRG2	ErbB4	ErbB4	ErbB4	4	5	7	8
Postulated mechanisms include mutation of RAS to NRAS which can activate CRAF or activation of MEK through PI3K/AKT/mTOR pathway in melanomas [ XREF_BIBR ] .	Postulated mechanisms include mutation of RAS to NRAS which can activate CRAF or activation of MEK through PI3K/AKT/mTOR pathway in melanomas [XREF_BIBR].	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRAS	NRAS	NRAS	CRAF	CRAF	CRAF	7	8	11	12
The relative ineffectiveness of BRafV600E could also be related to reports that oncogenic NRas actually targets CRaf , not BRaf .	The relative ineffectiveness of BRafV600E could also be related to reports that oncogenic NRas actually targets CRaf, not BRaf.	12	19	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRas	NRas	NRas	CRaf	CRaf	CRaf	13	14	16	17
For example , NT-4 may stimulate TrkA in some circumstances XREF_BIBR .	For example, NT-4 may stimulate TrkA in some circumstances XREF_BIBR.	3	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-4	NT-4	NT-4	TrkA	TrkA	TrkA	3	4	6	7
Such a mechanism would ensure that neurotrophins like NT-3 and NT-4 , which weakly activate TrkA ( as shown here ) would not maintain sympathetic neuron survival and circumvent the absolute requirement for NGF , thereby leading to inappropriate target innervation .	Such a mechanism would ensure that neurotrophins like NT-3 and NT-4, which weakly activate TrkA (as shown here) would not maintain sympathetic neuron survival and circumvent the absolute requirement for NGF, thereby leading to inappropriate target innervation.	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT-4	NT-4	NT-4	TrkA	TrkA	TrkA	10	11	15	16
In addition , there is some heterologous binding , with NT3 and NT4 also activating TrkA , and NT3 activating TrkB .	In addition, there is some heterologous binding, with NT3 and NT4 also activating TrkA, and NT3 activating TrkB.	7	16	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NT4	NT4	NT4	TrkA	TrkA	TrkA	12	13	15	16
In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 ( Rev-Erbalpha ) rescues Nr2e3 associated retinal degeneration in the rd7 mouse , which lacks a functional Nr2e3 gene .	In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbalpha) rescues Nr2e3 associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene.	6	17	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nr1d1	Nr1d1	Nr1d1	Nr2e3	Nr2e3	Nr2e3	11	12	16	17
These studies also determined that Nr1d1 is a direct target of NR2E3 by chromatin immunoprecipitation , suggesting that these factors function in the same transcriptional network XREF_BIBR .	These studies also determined that Nr1d1 is a direct target of NR2E3 by chromatin immunoprecipitation, suggesting that these factors function in the same transcriptional network XREF_BIBR.	5	14	is a direct target	Positive_activation_copula_1	Positive_activation	Positive_activation	Nr1d1	Nr1d1	Nr1d1	NR2E3	NR2E3	NR2E3	5	6	11	12
Modifier Genes as Therapeutics : The Nuclear Hormone Receptor Rev Erb Alpha ( Nr1d1 ) Rescues Nr2e3 Associated Retinal Disease .	Modifier Genes as Therapeutics : The Nuclear Hormone Receptor Rev Erb Alpha (Nr1d1) Rescues Nr2e3 Associated Retinal Disease.	1	17	Rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nr1d1	Nr1d1	Nr1d1	Nr2e3	Nr2e3	Nr2e3	13	14	16	17
We previously characterized the expression profile of the retinas of rd7 animals and identified 30 genes that are misregulated in Nr2e3 deficient retinas , 24 of which are directly regulated by NR2E3 , NR1D1 or co-regulated by both nuclear hormone receptors XREF_BIBR .	We previously characterized the expression profile of the retinas of rd7 animals and identified 30 genes that are misregulated in Nr2e3 deficient retinas, 24 of which are directly regulated by NR2E3, NR1D1 or co-regulated by both nuclear hormone receptors XREF_BIBR.	20	34	directly regulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	NR1D1	NR1D1	NR1D1	Nr2e3	Nr2e3	Nr2e3	33	34	20	21
Here , we demonstrate that in vivo delivery of the candidate modifier gene , Nr1d1 rescues Nr2e3 associated retinal degeneration .	Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration.	14	17	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nr1d1	Nr1d1	Nr1d1	Nr2e3	Nr2e3	Nr2e3	14	15	16	17
Our focused signaling interaction analysis identified additional signals of particular interest : Nrg2 signaling from DP may activate Erbb3 in Mc , which is involved in Mc maturation and melanoma development .	Our focused signaling interaction analysis identified additional signals of particular interest : Nrg2 signaling from DP may activate Erbb3 in Mc, which is involved in Mc maturation and melanoma development.	12	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nrg2	Nrg2	Nrg2	Erbb3	Erbb3	Erbb3	12	13	18	19
Surprisingly , A6 SCC is more responsive to glucocorticoids than to mineralocorticoids , suggesting the possibility that these cells do not contain transcriptionally active mineralocorticoid receptor ( MR ) and that glucocorticoid receptor ( GR ) mediates MR like responses in these collecting duct like cells .	Surprisingly, A6 SCC is more responsive to glucocorticoids than to mineralocorticoids, suggesting the possibility that these cells do not contain transcriptionally active mineralocorticoid receptor (MR) and that glucocorticoid receptor (GR) mediates MR like responses in these collecting duct like cells.	31	38	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	MR	MR	MR	31	33	37	38
The MR can be activated by both Aldo and cortisol ( the glucocorticoid receptor ( GR ) ligand ) ; however , hormone specificity is conferred in Aldo responsive tissues , such as the kidney , by expression of the cortisol inactivating enzyme 11beta-hydroxysteroid dehydrogenase-2 ( 11betaHSD2 ) .	The MR can be activated by both Aldo and cortisol (the glucocorticoid receptor (GR) ligand); however, hormone specificity is conferred in Aldo responsive tissues, such as the kidney, by expression of the cortisol inactivating enzyme 11beta-hydroxysteroid dehydrogenase-2 (11betaHSD2).	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	MR	MR	MR	12	14	1	2
Previous findings have suggested that NPY induces lipid synthesis in the murine preadipocyte cell line 3T3-L1 by activating NPY1R , NPY2R , or NPY5R .	Previous findings have suggested that NPY induces lipid synthesis in the murine preadipocyte cell line 3T3-L1 by activating NPY1R, NPY2R, or NPY5R.	5	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NPY	NPY	NPY	NPY2R	NPY2R	NPY2R	5	6	20	21
Gene expression analyses revealed that Npy -/- and Npy +/- rats have increased Npy1r , Npy2r , and Npy5r expressions in the whole brain relative to WT rats ( XREF_FIG ) , indicating that the dose effect of knocking out Npy results in an increase in these three receptor transcripts , possibly as a means of compensation .	Gene expression analyses revealed that Npy -/- and Npy +/- rats have increased Npy1r, Npy2r, and Npy5r expressions in the whole brain relative to WT rats (XREF_FIG), indicating that the dose effect of knocking out Npy results in an increase in these three receptor transcripts, possibly as a means of compensation.	5	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Npy	Npy	Npy	Npy2r	Npy2r	Npy2r	5	6	15	16
Other RFamide peptides , including neuropeptide AF , neuropeptide SF and RFamide related peptide also target NPFFR1 or NPFFR2 , and have been reported to activate the HPA axis and induce anxiety- or depression like behaviors .	Other RFamide peptides, including neuropeptide AF, neuropeptide SF and RFamide related peptide also target NPFFR1 or NPFFR2, and have been reported to activate the HPA axis and induce anxiety- or depression like behaviors.	8	19	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neuropeptide SF	neuropeptide SF	neuropeptide SF	NPFFR2	NPFFR2	NPFFR2	8	10	18	19
These different peptides can all activate NPFFR1 and NPFFR2 , but RFRP group displays better activity for NPFFR1 , and NPFF group preferentially activates NPFFR2 .	These different peptides can all activate NPFFR1 and NPFFR2, but RFRP group displays better activity for NPFFR1, and NPFF group preferentially activates NPFFR2.	20	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NPFF	NPFF	NPFF	NPFFR2	NPFFR2	NPFFR2	20	21	24	25
Likely , the Hh signaling pathway contributes to melanoma progression , as suggested by the delayed tumor growth of B16F0 melanoma cells in immunodeficient mice and also by tumor size reduction in a melanoma transgenic mouse model with elevated Gli-1 that was induced by oncogenic N-RAS when treated with Hh inhibitor [ XREF_BIBR ] .	Likely, the Hh signaling pathway contributes to melanoma progression, as suggested by the delayed tumor growth of B16F0 melanoma cells in immunodeficient mice and also by tumor size reduction in a melanoma transgenic mouse model with elevated Gli-1 that was induced by oncogenic N-RAS when treated with Hh inhibitor [XREF_BIBR].	12	46	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	N-RAS	N-RAS	N-RAS	Gli-1	Gli-1	Gli-1	45	46	39	40
For instance , oncogenic H- or N-Ras increase GLI1 function in melanoma cells and HH-GLI signalling is required for N-Ras-induced mouse melanoma growth .	For instance, oncogenic H- or N-Ras increase GLI1 function in melanoma cells and HH-GLI signalling is required for N-Ras-induced mouse melanoma growth.	6	9	increase	Positive_activation_token_1_verb	Positive_activation	Positive_activation	N-Ras	N-Ras	N-Ras	GLI1	GLI1	GLI1	6	7	8	9
Both NPFF and FMRFamide activated NPFF1 receptors to couple with Gi/o protein and inhibited adenylyl cyclase activity in PC-12 and rNPFF1 cells , but there were no effects on MAPKs ( ERK1/2 and p38 MAPK ) or PI3K and Akt pathway .	Both NPFF and FMRFamide activated NPFF1 receptors to couple with Gi/o protein and inhibited adenylyl cyclase activity in PC-12 and rNPFF1 cells, but there were no effects on MAPKs (ERK1/2 and p38 MAPK) or PI3K and Akt pathway.	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NPFF	NPFF	NPFF	NPFF1	NPFF1	NPFF1	1	2	5	6
The HMG domain of WHSC1 can interact with the DNA binding domain of the androgen receptor ( AR ) and , in the presence of the ligand , enhances AR mediated transcriptional activation , thereby implicating WHSC1 in the promotion of prostate carcinogenesis .	The HMG domain of WHSC1 can interact with the DNA binding domain of the androgen receptor (AR) and, in the presence of the ligand, enhances AR mediated transcriptional activation, thereby implicating WHSC1 in the promotion of prostate carcinogenesis.	2	30	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WHSC1	WHSC1	WHSC1	AR	AR	AR	4	5	29	30
Surprisingly , both studies found that SHP was able to enhance PPARalpha- and PPARgamma mediated transcriptional activity .	Surprisingly, both studies found that SHP was able to enhance PPARalpha- and PPARgamma mediated transcriptional activity.	6	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHP	SHP	SHP	PPARalpha-	PPARalpha-	PPARalpha-	6	7	11	12
With regard to time dependent ERK 1/2 activation , HEK293-AJP , HEK293-NTSR1 and HEK293-APJ and NTSR1 cells were treated with 10 -7 M NT or Apelin-13 for 0 , 5 , 15 , 20 and 30min .	With regard to time dependent ERK 1/2 activation, HEK293-AJP, HEK293-NTSR1 and HEK293-APJ and NTSR1 cells were treated with 10 -7 M NT or Apelin-13 for 0, 5, 15, 20 and 30min.	15	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NT	NT	NT	NTSR1	NTSR1	NTSR1	23	24	15	16
Previous experiments have identified that NTS could induce the internalization of NTR1 in target cells by a unique recycling cycle .	Previous experiments have identified that NTS could induce the internalization of NTR1 in target cells by a unique recycling cycle.	5	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NTS	NTS	NTS	NTR1	NTR1	NTR1	5	6	11	12
HEK293-NTSR1 and HEK293-APJ and NTSR1 cells treated with NT demonstrated maximum phosphorylation of ERK 1/2 at 10min .	HEK293-NTSR1 and HEK293-APJ and NTSR1 cells treated with NT demonstrated maximum phosphorylation of ERK 1/2 at 10min.	2	9	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NT	NT	NT	NTSR1	NTSR1	NTSR1	8	9	4	5
Therefore , we examined if NTS induced NTSR1 translocation to SMDs regulates NTSR1 and Galpha q/11 interaction .	Therefore, we examined if NTS induced NTSR1 translocation to SMDs regulates NTSR1 and Galpha q/11 interaction.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	NTS	NTS	NTS	NTSR1	NTSR1	NTSR1	5	6	7	8
Activation of LHA Nts neurons significantly increased nestlet shredding in both Nts Cre ; NtsR1 ++ and Nts Cre ; NtsR1 KOKO mice ( XREF_FIG ) , suggesting that LHA Nts neurons increases behaviors directed at objects other than food , which may contribute to their increased activity and energy expenditure ( XREF_FIG ) .	Activation of LHA Nts neurons significantly increased nestlet shredding in both Nts Cre; NtsR1 ++ and Nts Cre; NtsR1 KOKO mice (XREF_FIG), suggesting that LHA Nts neurons increases behaviors directed at objects other than food, which may contribute to their increased activity and energy expenditure (XREF_FIG).	3	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nts	Nts	Nts	NtsR1	NtsR1	NtsR1	3	4	14	15
To determine if ML314 modulated either of these processes we measured dose dependent NT mediated NTR1 internalization using a recently developed fluorogen activated reporter assay ( XREF_FIG ) and NT mediated beta-arrestin2-GFP recruitment using a translocation assay ( XREF_FIG ) XREF_BIBR - XREF_BIBR .	To determine if ML314 modulated either of these processes we measured dose dependent NT mediated NTR1 internalization using a recently developed fluorogen activated reporter assay (XREF_FIG) and NT mediated beta-arrestin2-GFP recruitment using a translocation assay (XREF_FIG) XREF_BIBR - XREF_BIBR.	11	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	NT	NT	NT	NTR1	NTR1	NTR1	13	14	15	16
In previous studies , the effects of NTS mediated NTSR1 activation were usually assessed through direct treatment of cancer cells with NTS or an NTS agonist .	In previous studies, the effects of NTS mediated NTSR1 activation were usually assessed through direct treatment of cancer cells with NTS or an NTS agonist.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	NTS	NTS	NTS	NTSR1	NTSR1	NTSR1	7	8	9	10
A similar effect was also noted between HEK293-APJ and NTSR1 cells and HEK293-NTSR1 cells treated with NT .	A similar effect was also noted between HEK293-APJ and NTSR1 cells and HEK293-NTSR1 cells treated with NT.	7	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NT	NT	NT	NTSR1	NTSR1	NTSR1	16	17	9	10
Moreover , sortilin was also known as a co receptor ( NTSR3 ) for a G protein coupled receptor , the neurotensin receptor-1 ( NTSR1 ) that is activated by neurotensin XREF_BIBR .	Moreover, sortilin was also known as a co receptor (NTSR3) for a G protein coupled receptor, the neurotensin receptor-1 (NTSR1) that is activated by neurotensin XREF_BIBR.	18	31	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	neurotensin	neurotensin	neurotensin	NTSR1	NTSR1	NTSR1	30	31	24	25
Since LHA Nts neurons project to and can activate NtsR1 expressing DA neurons , they may promote locomotor activity via NtsR1 dependent actions in the VTA .	Since LHA Nts neurons project to and can activate NtsR1 expressing DA neurons, they may promote locomotor activity via NtsR1 dependent actions in the VTA.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nts	Nts	Nts	NtsR1	NtsR1	NtsR1	2	3	9	10
Going forward it will also be important to determine if LHA Nts induced NtsR1 signaling may be a specific pathway to engage mesolimbic DA circuits that suppress appetite .	Going forward it will also be important to determine if LHA Nts induced NtsR1 signaling may be a specific pathway to engage mesolimbic DA circuits that suppress appetite.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Nts	Nts	Nts	NtsR1	NtsR1	NtsR1	11	12	13	14
D1R antagonism blunted LHA Nts induced locomotor activity in Nts Cre ; NtsR1 ++ mice , consistent with previous studies , and also in Nts Cre ; NtsR1 KOKO mice ( XREF_FIG , p = 0.06 for Nts Cre ; NtsR1 KOKO mice ) .	D1R antagonism blunted LHA Nts induced locomotor activity in Nts Cre; NtsR1 ++ mice, consistent with previous studies, and also in Nts Cre; NtsR1 KOKO mice (XREF_FIG, p = 0.06 for Nts Cre; NtsR1 KOKO mice).	3	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nts	Nts	Nts	NtsR1	NtsR1	NtsR1	4	5	12	13
Recent study indicated that NTS induced NTR1 trafficking from plasma membrane to endosomes could be regulated by microRNAs in colonic epithelial cells , thus partially affected NTS and NTR1 complex activated pro inflammatory signaling pathways [ XREF_BIBR ] .	Recent study indicated that NTS induced NTR1 trafficking from plasma membrane to endosomes could be regulated by microRNAs in colonic epithelial cells, thus partially affected NTS and NTR1 complex activated pro inflammatory signaling pathways [XREF_BIBR].	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	NTS	NTS	NTS	NTR1	NTR1	NTR1	4	5	6	7
Thus , it is suggested that NTS induced NTSR1 translocation within SMD may lead to enhanced interaction of NTSR1 with Galpha q/11 .	Thus, it is suggested that NTS induced NTSR1 translocation within SMD may lead to enhanced interaction of NTSR1 with Galpha q/11.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	NTS	NTS	NTS	NTSR1	NTSR1	NTSR1	6	7	8	9
To assess changes in the expression of miRNAs in response to NT , non transformed human colonic epithelial NCM460 cells over-expressing NTR1 ( NCM460-NTR1 ) were treated with 10 -7 M NT for 30 min or 6 hours and miRNA arrays were performed .	To assess changes in the expression of miRNAs in response to NT, non transformed human colonic epithelial NCM460 cells over-expressing NTR1 (NCM460-NTR1) were treated with 10 -7 M NT for 30 min or 6 hours and miRNA arrays were performed.	15	37	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	NT	NT	NT	NTR1	NTR1	NTR1	31	32	21	22
NT mediated NTR1 activity in the CNS is closely associated with the rewarding and motor pathways mediated by DA 47 .	NT mediated NTR1 activity in the CNS is closely associated with the rewarding and motor pathways mediated by DA 47.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	NT	NT	NT	NTR1	NTR1	NTR1	0	1	2	3
Neurotensin receptor type 1 ( NTSR1 ) , a member of the G-protein-coupled receptor ( GPCR ) family , is naturally activated by binding of a neurotensin peptide , leading to a variety of physiological effects .	Neurotensin receptor type 1 (NTSR1), a member of the G-protein-coupled receptor (GPCR) family, is naturally activated by binding of a neurotensin peptide, leading to a variety of physiological effects.	0	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	neurotensin	neurotensin	neurotensin	NTSR1	NTSR1	NTSR1	26	27	5	6
Thus , NTS stimulation induces cellular adaptation by altering the degradation process of NTSR1 .	Thus, NTS stimulation induces cellular adaptation by altering the degradation process of NTSR1.	2	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NTS	NTS	NTS	NTSR1	NTSR1	NTSR1	2	3	13	14
Indeed , after 30 min of NGF treatment , no diminution of TrkA levels was observed in cells treated with K252a compared with DMSO treated control cells , indicating that inhibition of TrkA phosphorylation slowed TrkA internalization .	Indeed, after 30 min of NGF treatment, no diminution of TrkA levels was observed in cells treated with K252a compared with DMSO treated control cells, indicating that inhibition of TrkA phosphorylation slowed TrkA internalization.	32	36	slowed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkA	TrkA phosphorylation	trka	TrkA	TrkA	trka	32	33	35	36
Together , these results indicate that TrkA and CD44 association and the subsequent RhoGTPase activation are not abolished by the inhibition of TrkA phosphorylation .	Together, these results indicate that TrkA and CD44 association and the subsequent RhoGTPase activation are not abolished by the inhibition of TrkA phosphorylation.	6	24	abolished	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	TrkA	TrkA phosphorylation	trka	TrkA	TrkA	trka	22	23	6	7
CYP induced cystitis ( 4 h , 48 h , 8 d ) increased TrkA transcript expression in detrusor of WT mice but produced no change in TrkA transcript expression in detrusor of NGF-OE mice ( XREF_FIG ) .	CYP induced cystitis (4 h, 48 h, 8 d) increased TrkA transcript expression in detrusor of WT mice but produced no change in TrkA transcript expression in detrusor of NGF-OE mice (XREF_FIG).	0	28	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkA	CYP induced cystitis (4 h, 48 h, 8 d) increased TrkA transcript expression	trka	TrkA	TrkA	trka	14	15	27	28
However , overexpression of trk in PC12 cells produced a sustained activation of trk , similar to our observations in sympathetic neurons .	However, overexpression of trk in PC12 cells produced a sustained activation of trk, similar to our observations in sympathetic neurons.	2	14	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	trk	overexpression of trk	trk	trk	trk	trk	4	5	13	14
The TrkA R685A mutation prevented receptor binding to PTP1B and suppressed PTP1B induced TrkA dephosphorylation , but did not disrupt TrkA kinase activity or downstream signaling ( XREF_SUPPLEMENTARY ) .	The TrkA R685A mutation prevented receptor binding to PTP1B and suppressed PTP1B induced TrkA dephosphorylation, but did not disrupt TrkA kinase activity or downstream signaling (XREF_SUPPLEMENTARY).	1	22	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TrkA	TrkA R685A mutation prevented receptor binding to PTP1B and suppressed PTP1B induced TrkA dephosphorylation	trka	TrkA	TrkA	trka	1	2	20	21
To test this hypothesis , we transfected HEK293 cells with plasmids encoding LINGO-1 and TrkA , achieving levels of TrkA expression sufficient to cause ligand independent TrkA activation .	To test this hypothesis, we transfected HEK293 cells with plasmids encoding LINGO-1 and TrkA, achieving levels of TrkA expression sufficient to cause ligand independent TrkA activation.	19	27	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkA	TrkA expression	trka	TrkA	TrkA	trka	19	20	26	27
Correspondingly , our results show that NUMB mediated negative regulation of EMT in TNBC cells is p53 independent .	Correspondingly, our results show that NUMB mediated negative regulation of EMT in TNBC cells is p53 independent.	6	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NUMB	NUMB	NUMB	p53	p53	p53	6	7	16	17
Previous study has demonstrated that Numb could inhibit p53 degradation and thus maintains normal apoptotic cycles of mammary epithelial cells XREF_BIBR .	Previous study has demonstrated that Numb could inhibit p53 degradation and thus maintains normal apoptotic cycles of mammary epithelial cells XREF_BIBR.	5	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	5	6	8	9
It has been shown that Numb promotes p53 stabilization blocking the function of the mouse double minute 2 ( Mdm2 ) E3-ubiquitin ligase and , interestingly , both p53 and Mdm2 are hosted in the nucleus .	It has been shown that Numb promotes p53 stabilization blocking the function of the mouse double minute 2 (Mdm2) E3-ubiquitin ligase and, interestingly, both p53 and Mdm2 are hosted in the nucleus.	5	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	5	6	7	8
Numb also inhibits MDM2 ( mouse double minute 2 ) activity and thereby increases the activity of p53 [ XREF_BIBR ] .	Numb also inhibits MDM2 (mouse double minute 2) activity and thereby increases the activity of p53 [XREF_BIBR].	0	19	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	0	1	17	18
While Numb promotes apoptosis in a p53 dependent manner , the apoptotic function is abolished when Numb is methylated by Set8 or the Lys methylation sites in Numb are mutated .	While Numb promotes apoptosis in a p53 dependent manner, the apoptotic function is abolished when Numb is methylated by Set8 or the Lys methylation sites in Numb are mutated.	1	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	1	2	6	7
Numb requires Ex3 ( Numb-1/2 isoforms ) to inhibit Mdm2 and thus increase p53 availability .	Numb requires Ex3 (Numb-1/2 isoforms) to inhibit Mdm2 and thus increase p53 availability.	0	14	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	0	1	13	14
Note that the sign of the feedback loop is positive ( shown in green ) and the p53 activation by NUMB is represented by two suppressions in series ( shown in yellow ) in the figure .	Note that the sign of the feedback loop is positive (shown in green) and the p53 activation by NUMB is represented by two suppressions in series (shown in yellow) in the figure.	17	21	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NUMB	NUMB	NUMB	p53	p53	p53	20	21	17	18
A recent literature showed the NUMB promotes apoptosis in a p53 dependent manner , the apoptotic function is abolished when Numb is methylated by Set8 or the Lys methylation sites in Numb are mutated XREF_BIBR .	A recent literature showed the NUMB promotes apoptosis in a p53 dependent manner, the apoptotic function is abolished when Numb is methylated by Set8 or the Lys methylation sites in Numb are mutated XREF_BIBR.	4	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NUMB	NUMB	NUMB	p53	p53	p53	5	6	10	11
Previous study has shown that Numb could prevent p53 degradation in human mammary cells and thus promotes cell apoptosis XREF_BIBR .	Previous study has shown that Numb could prevent p53 degradation in human mammary cells and thus promotes cell apoptosis XREF_BIBR.	5	9	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	5	6	8	9
Because Numb inhibits p53 degradation , this argues that Numb stabilizes p53 in the stem like DC .	Because Numb inhibits p53 degradation, this argues that Numb stabilizes p53 in the stem like DC.	1	4	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	1	2	3	4
These data suggest that the role of Numb in PA induced RPTC apoptosis is p53 independent , which is different from that in mammary epithelial cells .	These data suggest that the role of Numb in PA induced RPTC apoptosis is p53 independent, which is different from that in mammary epithelial cells.	5	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	7	8	14	15
So , NUMB could increase to prevent the degradation of p53 by HDM2 .	So, NUMB could increase to prevent the degradation of p53 by HDM2.	2	11	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	NUMB	NUMB	NUMB	p53	p53	p53	2	3	10	11
Extensive biochemical and biophysical studies were performed by XREF_BIBR to characterize the importance of Ex3 in Numb mediated control of Mdm2 and p53 stability .	Extensive biochemical and biophysical studies were performed by XREF_BIBR to characterize the importance of Ex3 in Numb mediated control of Mdm2 and p53 stability.	14	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	16	17	22	23
Taken together , these results show that Numb nuclear import is essential for Numb mediated p53 stabilization .	Taken together, these results show that Numb nuclear import is essential for Numb mediated p53 stabilization.	13	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	13	14	15	16
In addition , Numb promotes stability of p53 by inhibiting ligase Mdm2 [ XREF_BIBR ] .	In addition, Numb promotes stability of p53 by inhibiting ligase Mdm2 [XREF_BIBR].	3	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	p53	p53	p53	3	4	7	8
The gp130 family of cytokines are highly pleiotropic in normal development , yet an overlapping role for these cytokines in cancer continues to emerge , with studies now implicating autocrine and paracrine IL-6 , LIF and OSM mediated gp130 activation as important mediators of tumor progression and metastasis .	The gp130 family of cytokines are highly pleiotropic in normal development, yet an overlapping role for these cytokines in cancer continues to emerge, with studies now implicating autocrine and paracrine IL-6, LIF and OSM mediated gp130 activation as important mediators of tumor progression and metastasis.	34	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	OSM	OSM	OSM	gp130	gp130	gp130	36	37	38	39
However , only OSM activates the OSM receptor ( OSMR ) and gp130 complex .	However, only OSM activates the OSM receptor (OSMR) and gp130 complex.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	gp130	gp130	gp130	3	4	12	13
In mouse , human OSM activates the heterodimer of LIF receptor beta ( LIFRbeta ) and gp130 XREF_BIBR , like CNTF XREF_BIBR , XREF_BIBR .	In mouse, human OSM activates the heterodimer of LIF receptor beta (LIFRbeta) and gp130 XREF_BIBR, like CNTF XREF_BIBR, XREF_BIBR.	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	gp130	gp130	gp130	4	5	16	17
Similarly , human OSM only activates gp130 and OSMRbeta and not LIFR in human adipocytes .	Similarly, human OSM only activates gp130 and OSMRbeta and not LIFR in human adipocytes.	2	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	gp130	gp130	gp130	3	4	6	7
Oncostatin M. Oncostatin M ( OSM ) is an inflammatory cytokine that also belongs to the family of gp130 related cytokines , and as such , OSM stimulates transmembrane signaling by binding and activating either of two receptor complexes : ( 1 ) gp130 and LIFR ( leukemia inhibitor factor receptor ) heterodimers , and ( 2 ) gp130 and OSM receptor ( OSMR ) .	Oncostatin M. Oncostatin M (OSM) is an inflammatory cytokine that also belongs to the family of gp130 related cytokines, and as such, OSM stimulates transmembrane signaling by binding and activating either of two receptor complexes : (1) gp130 and LIFR (leukemia inhibitor factor receptor) heterodimers, and (2) gp130 and OSM receptor (OSMR).	26	61	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	gp130	gp130	gp130	26	27	58	59
Previous studies have reported that OSM treatment increases gp130 promoter activities and enhances the synthesis of OSMRbeta and gp130 , and to a lesser extent , LIFR in various cell lines [ 40 ] .	Previous studies have reported that OSM treatment increases gp130 promoter activities and enhances the synthesis of OSMRbeta and gp130, and to a lesser extent, LIFR in various cell lines [40].	5	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	gp130	gp130	gp130	5	6	18	19
On the molecular level this usage of OSM from different species results in the stimulation of different receptor complexes : human OSM exclusively binds to the type I gp130 and LIFR system in mouse cells ; murine OSM , however , exclusively activates the type II gp130 and OSMR system .	On the molecular level this usage of OSM from different species results in the stimulation of different receptor complexes : human OSM exclusively binds to the type I gp130 and LIFR system in mouse cells; murine OSM, however, exclusively activates the type II gp130 and OSMR system.	36	49	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	gp130	gp130	gp130	37	38	46	47
OSM can induce the formation of a dimer of gp130 with LIFR or the related protein , oncostatin M receptor .	OSM can induce the formation of a dimer of gp130 with LIFR or the related protein, oncostatin M receptor.	0	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	gp130	gp130	gp130	0	1	9	10
The blockage of UCH-L1-regulated deubiquitination of TrkB eventually results in the increased degradation of surface TrkB and decreased activation of TrkB and its downstream signaling pathways .	The blockage of UCH-L1-regulated deubiquitination of TrkB eventually results in the increased degradation of surface TrkB and decreased activation of TrkB and its downstream signaling pathways.	4	25	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkB	deubiquitination of TrkB	trkb	TrkB	TrkB	trkb	6	7	20	21
Previous studies to dissect the functional effects have shown that forced expression of TrkB in rat intestinal epithelial cells conferred anoikis resistance in vitro and allowed the TrkB expressing cells to form tumors and metastases in nude mice XREF_BIBR , XREF_BIBR .	Previous studies to dissect the functional effects have shown that forced expression of TrkB in rat intestinal epithelial cells conferred anoikis resistance in vitro and allowed the TrkB expressing cells to form tumors and metastases in nude mice XREF_BIBR, XREF_BIBR.	11	29	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkB	expression of TrkB	trkb	TrkB	TrkB	trkb	13	14	27	28
It has been documented that Abeta reduces BDNF and TrkB receptor levels and decreases TrkB mediating signalling 12 .	It has been documented that Abeta reduces BDNF and TrkB receptor levels and decreases TrkB mediating signalling 12.	5	15	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TrkB	Abeta reduces BDNF and TrkB receptor levels	trkb	TrkB	TrkB	trkb	9	10	14	15
Blocking autophosphorylation of trkB substantially reduced the interactions between p75 ( NTR ) and trkB constructs containing the intracellular , but not the extracellular , domains .	Blocking autophosphorylation of trkB substantially reduced the interactions between p75 (NTR) and trkB constructs containing the intracellular, but not the extracellular, domains.	1	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	trkB	autophosphorylation of trkB	trkb	trkB	trkB	trkb	3	4	14	15
A glycosylation of TrkB potentially mediates the stability of TrkB [ XREF_BIBR ] .	A glycosylation of TrkB potentially mediates the stability of TrkB [XREF_BIBR].	1	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkB	glycosylation of TrkB	trkb	TrkB	TrkB	trkb	3	4	9	10
These results confirm that impaired TrkB internalisation is caused by absence of HAP1 rather than decreased levels of TrkB , because HAP1 gene deletion does not affect TrkB mRNA and protein level in the cortex .	These results confirm that impaired TrkB internalisation is caused by absence of HAP1 rather than decreased levels of TrkB, because HAP1 gene deletion does not affect TrkB mRNA and protein level in the cortex.	5	19	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TrkB	levels of TrkB	trkb	TrkB	TrkB	trkb	18	19	5	6
Furthermore , the over-expression of TrkB significantly stimulated the growth of Ishikawa TrkB cells compared to Ishikawa EV or parental Ishikawa cells ( XREF_FIG ) .	Furthermore, the over-expression of TrkB significantly stimulated the growth of Ishikawa TrkB cells compared to Ishikawa EV or parental Ishikawa cells (XREF_FIG).	3	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkB	over-expression of TrkB	trkb	TrkB	TrkB	trkb	5	6	12	13
Previously published Olig2 targets Olig1 ( PS = 62.52 ) and Nkx6.2 ( PS = 53.86 ) also showed enrichment over input ( XREF_FIG ) .	Previously published Olig2 targets Olig1 (PS = 62.52) and Nkx6.2 (PS = 53.86) also showed enrichment over input (XREF_FIG).	1	11	targets	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Olig1	Olig1	Olig1	Olig2	Olig2	Olig2	4	5	2	3
The regulatory module shows that Olig1 positively regulates Olig2 in different brain tissues .	The regulatory module shows that Olig1 positively regulates Olig2 in different brain tissues.	5	12	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Olig1	Olig1	Olig1	Olig2	Olig2	Olig2	5	6	8	9
Olig1 can promote the functions of Olig2 [ XREF_BIBR , XREF_BIBR ] , and it plays an essential role in the differentiation and remyelination of OLs by maintaining Olig2 expression [ XREF_BIBR , XREF_BIBR ] .	Olig1 can promote the functions of Olig2 [XREF_BIBR, XREF_BIBR], and it plays an essential role in the differentiation and remyelination of OLs by maintaining Olig2 expression [XREF_BIBR, XREF_BIBR].	0	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Olig1	Olig1	Olig1	Olig2	Olig2	Olig2	0	1	6	7
Activation of TrkA at the cell surface leads to phosphorylation of tyrosine residues in the cytoplasmic domain , which in turn recruits signaling molecules and activates multiple signaling pathways involving PLC-gamma1 , MAPK , and PI3K .	Activation of TrkA at the cell surface leads to phosphorylation of tyrosine residues in the cytoplasmic domain, which in turn recruits signaling molecules and activates multiple signaling pathways involving PLC-gamma1, MAPK, and PI3K.	0	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkA	TrkA	TrkA	PLC-gamma1	PLC-gamma1	PLC-gamma1	2	3	30	31
While the tyrosine phosphorylation of TrkA , SHC and PLC-gamma 1 increased with time in the presence of NGF and was inhibited by the tyrosine kinase inhibitor K252a , the state of tyrosine phosphorylation of c-Crk-II did not appear to change with NGF treatment .	While the tyrosine phosphorylation of TrkA, SHC and PLC-gamma 1 increased with time in the presence of NGF and was inhibited by the tyrosine kinase inhibitor K252a, the state of tyrosine phosphorylation of c-Crk-II did not appear to change with NGF treatment.	2	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkA	tyrosine phosphorylation of TrkA	trka	PLC-gamma 1	PLC-gamma 1	plc-gamma 1	5	6	9	11
PLCgamma1 can be activated by receptor tyrosine kinases ( i.e. : PDGFR , EGFR , FGFR , Trk ) , as well as non receptor protein kinases ( Src , Syk , Tec ) or phosphatidic acid , tau protein and its analogue .	PLCgamma1 can be activated by receptor tyrosine kinases (i.e. : PDGFR, EGFR, FGFR, Trk), as well as non receptor protein kinases (Src, Syk, Tec) or phosphatidic acid, tau protein and its analogue.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Trk	Trk	Trk	PLCgamma1	PLCgamma1	PLCgamma1	17	18	0	1
Accordingly , phosphorylation of hnRNP A2/B1 by the Fyn kinase was correlated with the increased translation of a MBP mRNA reporter in oligodendrocytes XREF_BIBR and TrkB receptors were shown to activate Fyn in the hippocampus XREF_BIBR .	Accordingly, phosphorylation of hnRNP A2/B1 by the Fyn kinase was correlated with the increased translation of a MBP mRNA reporter in oligodendrocytes XREF_BIBR and TrkB receptors were shown to activate Fyn in the hippocampus XREF_BIBR.	23	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkB	TrkB	TrkB	Fyn	Fyn	Fyn	25	26	31	32
Studies in other systems have demonstrated that Fyn kinase is activated by TrkB , it phosphorylates NR2B , and contributes to BDNF induced increases in synaptic transmission .	Studies in other systems have demonstrated that Fyn kinase is activated by TrkB, it phosphorylates NR2B, and contributes to BDNF induced increases in synaptic transmission.	7	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TrkB	TrkB	TrkB	Fyn	Fyn	Fyn	12	13	7	8
Since Numb was previously shown to activate the E3 ligase Itch , resulting in Gli1 ubiquitination and degradation , we tested the idea that Sufu stabilizes Gli1 protein by antagonizing Numb and Itch , a mechanism distinct from Sufu control of Gli2/3 protein levels .	Since Numb was previously shown to activate the E3 ligase Itch, resulting in Gli1 ubiquitination and degradation, we tested the idea that Sufu stabilizes Gli1 protein by antagonizing Numb and Itch, a mechanism distinct from Sufu control of Gli2/3 protein levels.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	Itch	Itch	Itch	1	2	10	11
In signal receiving cells , Numb initiates the binding of Itch to membrane tethered NICD 49 and is a well established Notch antagonist in NPs 50 .	In signal receiving cells, Numb initiates the binding of Itch to membrane tethered NICD 49 and is a well established Notch antagonist in NPs 50.	5	11	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	Itch	Itch	Itch	5	6	10	11
We show that Numb activates the catalytic activity of Itch , releasing it from an inhibitory intramolecular interaction between its homologous to E6-AP C-terminus and WW domains .	We show that Numb activates the catalytic activity of Itch, releasing it from an inhibitory intramolecular interaction between its homologous to E6-AP C-terminus and WW domains.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	Itch	Itch	Itch	3	4	9	10
Immunoprecipitation followed by Western analysis demonstrated that activated TrkB , composed of the intracellular domain of TrkB fused to glutathione S-transferase ( GST-TrkB ( ICD ) ) , promoted the association of ShcC and Grb2 in yeast .	Immunoprecipitation followed by Western analysis demonstrated that activated TrkB, composed of the intracellular domain of TrkB fused to glutathione S-transferase (GST-TrkB (ICD)), promoted the association of ShcC and Grb2 in yeast.	7	34	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkB	TrkB	TrkB	ShcC	ShcC	ShcC	8	9	32	33
Restoring Ofd1 protein expression in Ofd1 Ofd1myc cells restored normal localization of Ift88 to the centrosome ( XREF_FIG ) .	Restoring Ofd1 protein expression in Ofd1 Ofd1myc cells restored normal localization of Ift88 to the centrosome (XREF_FIG).	1	13	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ofd1	Ofd1 protein expression	ofd1	Ift88	Ift88	ift88	1	2	12	13
We identified ETV6-NTRK3 , MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours and demonstrate that NTRK3 fusions constitutively activate the MAPK , PI3K and PLCgamma1 pathways in melanocytes .	We identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours and demonstrate that NTRK3 fusions constitutively activate the MAPK, PI3K and PLCgamma1 pathways in melanocytes.	14	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NTRK3	NTRK3	NTRK3	PLCgamma1	PLCgamma1	PLCgamma1	14	15	23	24
In humans and other mammalian species , OT and AVP target the OTR ( oxytocin receptor ) and the three vasopressin receptors V1aR , V1bR and V2R [ XREF_BIBR ] .	In humans and other mammalian species, OT and AVP target the OTR (oxytocin receptor) and the three vasopressin receptors V1aR, V1bR and V2R [XREF_BIBR].	7	26	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OT	OT	OT	OTR	OTR	OTR	7	8	12	13
Furthermore , the threshold for alteration of social behavior by OXT ligand activation of the OXTR may differ across measures of social behavior ( i.e ., offspring care , food sharing , partner preference , proximity , grooming ) .	Furthermore, the threshold for alteration of social behavior by OXT ligand activation of the OXTR may differ across measures of social behavior (i.e., offspring care, food sharing, partner preference, proximity, grooming).	10	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	OXT	OXT	OXT	OXTR	OXTR	OXTR	10	11	15	16
We have previously demonstrated that the native peptide oxytocin can activate OXTR coupling to different G protein subtypes : Gq , Gi and Go 15 .	We have previously demonstrated that the native peptide oxytocin can activate OXTR coupling to different G protein subtypes : Gq, Gi and Go 15.	5	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	OXTR	OXTR	OXTR	8	9	11	12
Since the neuronal F-11 cells could also endogenously express the canonical oxytocin receptor , we again tested whether or not OXTR mediates the oxytocin elicited Ca 2+ signals using OXTR specific siRNA .	Since the neuronal F-11 cells could also endogenously express the canonical oxytocin receptor, we again tested whether or not OXTR mediates the oxytocin elicited Ca 2+ signals using OXTR specific siRNA.	22	31	elicited	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	oxytocin	oxytocin	oxytocin	OXTR	OXTR	OXTR	23	24	29	30
Because OXT in uterine tissue activates OXTR and another member of the G protein coupled receptor ( GPCR ) family , vasopressin V 1A receptor , the local expression of this latter may also influence uterine contractility .	Because OXT in uterine tissue activates OXTR and another member of the G protein coupled receptor (GPCR) family, vasopressin V 1A receptor, the local expression of this latter may also influence uterine contractility.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXT	OXT	OXT	OXTR	OXTR	OXTR	1	2	6	7
XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR To our best knowledge , no study has directly documented the prenatal testosterone effects on OT production in supraoptic and paraventricular nucleus or OXTR sensitivity , however intranasal OT in healthy men induced the group serving tendencies only in those with higher fetal testosterone , according to their 2D :4 D ratio , XREF_BIBR which indicates the different responsiveness to OT mediated by prenatal testosterone exposure .	XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR To our best knowledge, no study has directly documented the prenatal testosterone effects on OT production in supraoptic and paraventricular nucleus or OXTR sensitivity, however intranasal OT in healthy men induced the group serving tendencies only in those with higher fetal testosterone, according to their 2D :4 D ratio, XREF_BIBR which indicates the different responsiveness to OT mediated by prenatal testosterone exposure.	20	29	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	OT	OT	OT	OXTR	OXTR	OXTR	20	21	28	29
Activation of OXTR by oxytocin is considered one of the central biological signals for social behavior .	Activation of OXTR by oxytocin is considered one of the central biological signals for social behavior.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	OXTR	OXTR	OXTR	4	5	2	3
RT-PCR analysis showed that OT administration increased oxytocin receptor mRNA ( 2 fold , P , 0.05 ) .	RT-PCR analysis showed that OT administration increased oxytocin receptor mRNA (2 fold, P, 0.05).	4	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OT	OT	OT	oxytocin receptor	oxytocin receptor	oxytocin receptor	4	5	7	9
The oxytocin receptor is a 389-amino acid G-protein-coupled receptor and is activated by the hormone oxytocin .	The oxytocin receptor is a 389-amino acid G-protein-coupled receptor and is activated by the hormone oxytocin.	1	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	15	16	1	3
We propose that OXT activation of the OXTR occurs in the posterior retina and that this may serve as a paracrine signaling pathway that contributes to communication between the cone photoreceptor and the RPE .	We propose that OXT activation of the OXTR occurs in the posterior retina and that this may serve as a paracrine signaling pathway that contributes to communication between the cone photoreceptor and the RPE.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	OXT	OXT	OXT	OXTR	OXTR	OXTR	3	4	7	8
The OTR signaling mediated by oxytocin inhibited estrogen stimulated growth of leiomyoma cells .	The OTR signaling mediated by oxytocin inhibited estrogen stimulated growth of leiomyoma cells.	1	6	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	OTR	OTR	OTR	5	6	1	2
Indeed , caffeine seemed to augment Oxt induced OTR signalling in the mouse brain ( XREF_SUPPLEMENTARY ) , although A 1 R did not interact directly with OTR ( XREF_SUPPLEMENTARY ) .	Indeed, caffeine seemed to augment Oxt induced OTR signalling in the mouse brain (XREF_SUPPLEMENTARY), although A 1 R did not interact directly with OTR (XREF_SUPPLEMENTARY).	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Oxt	Oxt	Oxt	OTR	OTR	OTR	6	7	8	9
Because recent studies have shown that OT can mediate its behavioral effects via the vasopressin Via receptor and the CeA expresses OTR and Via receptor , it is also possible that OT activated both the OTR and the Via receptor in the CeA .	Because recent studies have shown that OT can mediate its behavioral effects via the vasopressin Via receptor and the CeA expresses OTR and Via receptor, it is also possible that OT activated both the OTR and the Via receptor in the CeA.	31	39	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OT	OT	OT	OTR	OTR	OTR	31	32	35	36
XREF_BIBR - XREF_BIBR Oxytocin initiates uterine contractions by activating the oxytocin receptor ( OXTR ) , which is a G protein coupled receptor ( GPCR ) that undergoes rapid desensitization with agonist activation .	XREF_BIBR - XREF_BIBR Oxytocin initiates uterine contractions by activating the oxytocin receptor (OXTR), which is a G protein coupled receptor (GPCR) that undergoes rapid desensitization with agonist activation.	2	12	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Oxytocin	Oxytocin	Oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	3	4	10	12
Several factors contribute to the limited and controversial efficacy of oxytocin in the clinical practice : ( i ) oxytocin has a short half-life in the plasma 11 and in the cerebrospinal fluid 12 and , consequently , its pharmacological effects are short lived ; ( ii ) oxytocin does not cross the blood-brain barrier in a significant amount 12 and thus , when given by parenteral administration , it does not reach the brain ; ( iii ) intranasal oxytocin administration , considered as a wayof delivering exogenous oxytocin directly into the brain , has not yet been proven to do so 13 , leading to very poorly defined pharmacokinetics parameters ( doses , intervals , metabolites ) ; ( iv ) oxytocin binds to and activates the vasopressin V1a and V1b receptor subtypes , which are also highly expressed in the brain where they promote effects different from ( and even the opposite to ) those of the oxytocin receptor ( OXTR ) 14 ; and ( v ) oxytocin promotes OXTR coupling to a number of different G protein subtypes and beta-arrestins 15 , 16 , leading to the activation of multiple signalling pathways , whose precise roles within the brain are currently unknown .	Several factors contribute to the limited and controversial efficacy of oxytocin in the clinical practice : (i) oxytocin has a short half-life in the plasma 11 and in the cerebrospinal fluid 12 and, consequently, its pharmacological effects are short lived; (ii) oxytocin does not cross the blood-brain barrier in a significant amount 12 and thus, when given by parenteral administration, it does not reach the brain; (iii) intranasal oxytocin administration, considered as a wayof delivering exogenous oxytocin directly into the brain, has not yet been proven to do so 13, leading to very poorly defined pharmacokinetics parameters (doses, intervals, metabolites); (iv) oxytocin binds to and activates the vasopressin V1a and V1b receptor subtypes, which are also highly expressed in the brain where they promote effects different from (and even the opposite to) those of the oxytocin receptor (OXTR) 14; and (v) oxytocin promotes OXTR coupling to a number of different G protein subtypes and beta-arrestins 15, 16, leading to the activation of multiple signalling pathways, whose precise roles within the brain are currently unknown.	171	206	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	OXTR	OXTR	OXTR	171	172	173	174
Oxytocin ( OXT ) acts through its specific receptor ( OXTR ) and increased density of OXTR and/or augmented sensitivity to OXT were postulated as prerequisites of normal onset of labor .	Oxytocin (OXT) acts through its specific receptor (OXTR) and increased density of OXTR and/or augmented sensitivity to OXT were postulated as prerequisites of normal onset of labor.	0	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXT	OXT	OXT	OXTR	OXTR	OXTR	2	3	16	17
( 2 ) High concentration of OXT or VP can , respectively , activate both VP receptors and OXTR [ XREF_BIBR ] .	(2) High concentration of OXT or VP can, respectively, activate both VP receptors and OXTR [XREF_BIBR].	4	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXT	OXT	OXT	OXTR	OXTR	OXTR	6	7	18	19
In both primary myometrial and ULTR cells , knockdown of GRK6 largely prevented oxytocin induced OTR desensitization ; in contrast , selective depletion of GRKs 2 , 3 , or 5 was without effect .	In both primary myometrial and ULTR cells, knockdown of GRK6 largely prevented oxytocin induced OTR desensitization; in contrast, selective depletion of GRKs 2, 3, or 5 was without effect.	13	16	induced	Positive_early_activation	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	OTR	OTR	OTR	13	14	15	16
In this regard , there is evidence that repeated stimulation of the hypothalamic OXT neuronal system enhances its cellular and synaptic plasticity by inducing cellular hypertrophy , OXT and OXTR synthesis , and OXT release .	In this regard, there is evidence that repeated stimulation of the hypothalamic OXT neuronal system enhances its cellular and synaptic plasticity by inducing cellular hypertrophy, OXT and OXTR synthesis, and OXT release.	13	30	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXT	OXT	OXT	OXTR	OXTR	OXTR	13	14	29	30
Given that oxytocin is known to promote the onset and maintenance of maternal care and administration of an oxytocin receptor antagonist into the MPOA decreases ABN , we hypothesized that activation of central CRFR would reduce oxytocin release in the MPOA and hence impair maternal care .	Given that oxytocin is known to promote the onset and maintenance of maternal care and administration of an oxytocin receptor antagonist into the MPOA decreases ABN, we hypothesized that activation of central CRFR would reduce oxytocin release in the MPOA and hence impair maternal care.	2	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	2	3	18	20
This activity dependent depression was turned into facilitation of glutamate EPSCs by oxytocin , possibly via postsynaptic activation of the oxytocin receptor .	This activity dependent depression was turned into facilitation of glutamate EPSCs by oxytocin, possibly via postsynaptic activation of the oxytocin receptor.	5	22	activation	Positive_activation_syntax_6_noun	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	12	13	20	22
Oxytocin enhances uterine contractility by activating L-type Ca channels and oxytocin receptor .	Oxytocin enhances uterine contractility by activating L-type Ca channels and oxytocin receptor.	0	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Oxytocin	Oxytocin	Oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	0	1	10	12
The pulsatile release of oxytocin into the blood every 5 to 10 minutes causes the intermittent , oxytocin receptor mediated contraction of smooth muscle cells in the mammary glands and uterus , which elicits rhythmic milk ejection , or milk letdown , during the suckling stimulus and uterine contractions during parturition [ XREF_BIBR ] .	The pulsatile release of oxytocin into the blood every 5 to 10 minutes causes the intermittent, oxytocin receptor mediated contraction of smooth muscle cells in the mammary glands and uterus, which elicits rhythmic milk ejection, or milk letdown, during the suckling stimulus and uterine contractions during parturition [XREF_BIBR].	2	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	4	5	17	19
We did not find any differences in Oxtr mRNA in any of the regions examined ; however , reduced expression of Avpr1a in the lateral septum and BNST may also impact upon oxytocin mediated social memory processes , given that oxytocin evidently exerts some of its effects on sociability , social recognition and social communication via Avpr1a , rather than Oxtr 64 , 65 .	We did not find any differences in Oxtr mRNA in any of the regions examined; however, reduced expression of Avpr1a in the lateral septum and BNST may also impact upon oxytocin mediated social memory processes, given that oxytocin evidently exerts some of its effects on sociability, social recognition and social communication via Avpr1a, rather than Oxtr 64, 65.	30	63	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	Oxtr	Oxtr	Oxtr	32	33	60	61
Oxytocin receptor expression varies in response to early experience , and both oxytocin signaling and methylation status of the oxytocin receptor gene ( Oxtr ) in blood have been related to disordered social behavior .	Oxytocin receptor expression varies in response to early experience, and both oxytocin signaling and methylation status of the oxytocin receptor gene (Oxtr) in blood have been related to disordered social behavior.	12	21	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	12	13	19	21
Prolonged continuous oxytocin administration during labor may induce oxytocin receptor desensitization , which attenuates the response of the myometrium to further oxytocin , increasing the risk of postpartum hemorrhage .	Prolonged continuous oxytocin administration during labor may induce oxytocin receptor desensitization, which attenuates the response of the myometrium to further oxytocin, increasing the risk of postpartum hemorrhage.	2	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	2	3	8	10
In another example , homodimers of a modified oxytocin ( dOTK 2 -C8 ) activated the oxytocin receptor dimers at 0.8 pM concentrations in cellular assays , as compared to 4 nM concentrations for the monomer , dOTK [ XREF_BIBR ] .	In another example, homodimers of a modified oxytocin (dOTK 2 -C8) activated the oxytocin receptor dimers at 0.8 pM concentrations in cellular assays, as compared to 4 nM concentrations for the monomer, dOTK [XREF_BIBR].	4	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	8	9	16	18
Oxytocin increases uterine contractility by activating the oxytocin receptor ( OXTR ) , a member of the G protein coupled receptor family , which is prone to molecular desensitization .	Oxytocin increases uterine contractility by activating the oxytocin receptor (OXTR), a member of the G protein coupled receptor family, which is prone to molecular desensitization.	0	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Oxytocin	Oxytocin	Oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	0	1	7	9
Importantly , oxytocin activation of OTR is known to interfere with learning and memory .	Importantly, oxytocin activation of OTR is known to interfere with learning and memory.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	OTR	OTR	OTR	2	3	5	6
In addition , OT as well as DMSO increased OTR protein and OTR mRNA , and OTA completely inhibited the formation of cardiomyocytes in OT- and DMSO supplemented cultures .	In addition, OT as well as DMSO increased OTR protein and OTR mRNA, and OTA completely inhibited the formation of cardiomyocytes in OT- and DMSO supplemented cultures.	3	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OT	OT	OT	OTR protein	OTR protein	OTR protein	3	4	9	11
Oxytocin ( OT ) can modulate multiple physiological functions via binding to the widely distributed oxytocin receptor ( OTR ) .	Oxytocin (OT) can modulate multiple physiological functions via binding to the widely distributed oxytocin receptor (OTR).	0	17	modulate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	OT	OT	OT	oxytocin receptor	oxytocin receptor	oxytocin receptor	2	3	15	17
In the newborn rats , exogenous oxytocin could also partially reverse the effects of the competitive oxytocin receptor blockers , indicating that endogenous oxytocin levels are not saturated , and that therapeutic elevation of oxytocin levels could result in more powerful analgesia in the newborn .	In the newborn rats, exogenous oxytocin could also partially reverse the effects of the competitive oxytocin receptor blockers, indicating that endogenous oxytocin levels are not saturated, and that therapeutic elevation of oxytocin levels could result in more powerful analgesia in the newborn.	5	18	reverse	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	6	7	16	18
We tested whether oxytocin stimulation promotes beta-arrestin-mediated OXTR desensitization in vivo and activates beta-arrestin-mediated mitogen activated protein kinase ( MAPK ) growth signaling .	We tested whether oxytocin stimulation promotes beta-arrestin-mediated OXTR desensitization in vivo and activates beta-arrestin-mediated mitogen activated protein kinase (MAPK) growth signaling.	3	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	OXTR	OXTR	OXTR	3	4	7	8
OT activation of OXTR reduced secretion of IL-6 in LPS activated macrophages .	OT activation of OXTR reduced secretion of IL-6 in LPS activated macrophages.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	OT	OT	OT	OXTR	OXTR	OXTR	0	1	3	4
To test for direct effects of Oxt on KCC2 insertion and stabilization at the plasma membrane , we evaluated the pKCC2 and KCC2 ratio in Oxtr +/+ neurons treated with 100nM Oxt for 10min ( XREF_FIG A ) .	To test for direct effects of Oxt on KCC2 insertion and stabilization at the plasma membrane, we evaluated the pKCC2 and KCC2 ratio in Oxtr +/+ neurons treated with 100nM Oxt for 10min (XREF_FIG A).	25	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Oxt	Oxt	Oxt	Oxtr	Oxtr	Oxtr	31	32	25	26
In addition , OT synthesis in the PVN and OTR density in the NAc shell is reduced .	In addition, OT synthesis in the PVN and OTR density in the NAc shell is reduced.	3	10	synthesis	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	OT	OT	OT	OTR	OTR	OTR	3	4	9	10
Pretreatment of the OVX rats with estrogen augmented the oxytocin induced running activity twofold , and increased the Oxtr mRNA in the VMH threefold .	Pretreatment of the OVX rats with estrogen augmented the oxytocin induced running activity twofold, and increased the Oxtr mRNA in the VMH threefold.	8	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	Oxtr	Oxtr	Oxtr	9	10	18	19
The signaling pathway controlled by the main milking hormone , the prolactin , was active , oxytocin did not rescue the mutant mother feeding capacities and oxytocin receptor and myoepithelial cells , responsible of milk ejection were easily evidenced .	The signaling pathway controlled by the main milking hormone, the prolactin, was active, oxytocin did not rescue the mutant mother feeding capacities and oxytocin receptor and myoepithelial cells, responsible of milk ejection were easily evidenced.	16	28	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	16	17	26	28
To ascertain whether Oxt PVH neurons can directly activate Oxtr PBN neurons , we injected AAV1-DIO-ChR2 : YFP into the PVH and AAV-DIO-mCherry into the PBN of Oxt Cre +/+ : : Oxtr Cre/+ mice .	To ascertain whether Oxt PVH neurons can directly activate Oxtr PBN neurons, we injected AAV1-DIO-ChR2 : YFP into the PVH and AAV-DIO-mCherry into the PBN of Oxt Cre +/+ : : Oxtr Cre/+ mice.	3	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Oxt	Oxt	Oxt	Oxtr	Oxtr	Oxtr	3	4	9	10
PAK1 directly activates LIMK1 via phosphorylation of threonine 508 .	PAK1 directly activates LIMK1 via phosphorylation of threonine 508.	0	5	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK1	LIMK1	LIMK1	0	1	3	4
Pak1 and ROCK , respectively , activate LIMK1 and LIMK2 downstream of Rac and Rho ; however , an effector protein kinase for LIMKs downstream of Cdc42 remains to be defined .	Pak1 and ROCK, respectively, activate LIMK1 and LIMK2 downstream of Rac and Rho; however, an effector protein kinase for LIMKs downstream of Cdc42 remains to be defined.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	LIMK1	LIMK1	LIMK1	0	1	7	8
When active , PAK1 is able to phosphorylate and activate Lin-11/lsl-1/Mec-3 kinase 1 ( LIMK1 ) , which in turn inhibits cofilin by phosphorylation XREF_BIBR , XREF_BIBR .	When active, PAK1 is able to phosphorylate and activate Lin-11/lsl-1/Mec-3 kinase 1 (LIMK1), which in turn inhibits cofilin by phosphorylation XREF_BIBR, XREF_BIBR.	3	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK1	LIMK1	LIMK1	3	4	14	15
In turn , both ROCK1 and PAK1 phosphorylate and activate LIMK1 ( on Thr508 ) and LIMK2 ( on Thr505 ) .	In turn, both ROCK1 and PAK1 phosphorylate and activate LIMK1 (on Thr508) and LIMK2 (on Thr505).	4	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK1	LIMK1	LIMK1	6	7	10	11
Together with the recent finding that PAK1 , a downstream effector of Rac , also activates LIMK1 by phosphorylation at Thr 508 , these results suggest that activation of LIMK1 is one of the common targets for Rho and Rac to reorganize the actin cytoskeleton .	Together with the recent finding that PAK1, a downstream effector of Rac, also activates LIMK1 by phosphorylation at Thr 508, these results suggest that activation of LIMK1 is one of the common targets for Rho and Rac to reorganize the actin cytoskeleton.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK1	LIMK1	LIMK1	6	7	16	17
Our data support this and further show that while PAK1 is upstream of cofilin , IPA3 mediated inhibition of PAK1 fails to inhibit LIMK activation .	Our data support this and further show that while PAK1 is upstream of cofilin, IPA3 mediated inhibition of PAK1 fails to inhibit LIMK activation.	17	24	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK	LIMK	LIMK	19	20	23	24
LIMK1 , but not LIMK2 can be activated by p21 activated kinases ( PAK1 , PAK2 , and PAK4 ) , downstream of Rac and Cdc42 activation [ XREF_BIBR , XREF_BIBR ] .	LIMK1, but not LIMK2 can be activated by p21 activated kinases (PAK1, PAK2, and PAK4), downstream of Rac and Cdc42 activation [XREF_BIBR, XREF_BIBR].	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK1	LIMK1	LIMK1	13	14	0	1
The regulation of actin cytoskeletal dynamics is through the phosphorylation of cofilin at Ser 3 by LIM-Kinase ( LIMK ) , in a pathway where PAK1 activates LIMK .	The regulation of actin cytoskeletal dynamics is through the phosphorylation of cofilin at Ser 3 by LIM-Kinase (LIMK), in a pathway where PAK1 activates LIMK.	25	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK	LIMK	LIMK	25	26	27	28
PAK1 is upstream of cofilin , and activates the cofilin kinase LIMK , XREF_BIBR so one would expect its expression and activity to be increased , rather than decreased .	PAK1 is upstream of cofilin, and activates the cofilin kinase LIMK, XREF_BIBR so one would expect its expression and activity to be increased, rather than decreased.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK	LIMK	LIMK	0	1	11	12
PAK1 phosphorylation leads to the activation of LIM-kinase 1 ( LIMK1 ) [ XREF_BIBR ] , inhibition of MYLK , activation of myosin regulatory light chains ( MRLC ) [ XREF_BIBR ] .	PAK1 phosphorylation leads to the activation of LIM-kinase 1 (LIMK1) [XREF_BIBR], inhibition of MYLK, activation of myosin regulatory light chains (MRLC) [XREF_BIBR].	0	11	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	PAK1	PAK1 phosphorylation	pak1	LIMK1	LIMK1	limk1	0	1	10	11
Importantly , LIMK1 is also activated by PAK1 , which is the effector molecule of the Rac induced lamellipodia formation or cell spreading [ XREF_BIBR ] .	Importantly, LIMK1 is also activated by PAK1, which is the effector molecule of the Rac induced lamellipodia formation or cell spreading [XREF_BIBR].	2	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK1	LIMK1	LIMK1	7	8	2	3
Downstream of Rac1 , p21 activated kinase 1 ( PAK1 ) activates LIMK1 , and regulates the actin cytoskeletal reorganization through the phosphorylation of the actin depolymerizing factors cofilin and destrin and their actin depolymerizing activities [ XREF_BIBR , XREF_BIBR ] .	Downstream of Rac1, p21 activated kinase 1 (PAK1) activates LIMK1, and regulates the actin cytoskeletal reorganization through the phosphorylation of the actin depolymerizing factors cofilin and destrin and their actin depolymerizing activities [XREF_BIBR, XREF_BIBR].	6	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK1	LIMK1	LIMK1	9	10	12	13
Both Abeta oligomers and fibrillar Abeta42 treatment of hippocampal neurons can activate PAK1 , which in turn activates LIMK1 in vitro .	Both Abeta oligomers and fibrillar Abeta42 treatment of hippocampal neurons can activate PAK1, which in turn activates LIMK1 in vitro.	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK1	LIMK1	LIMK1	12	13	18	19
Rho protein effectors like ROCKI and II or PAK1 ( p21 activated kinase 1 ) are able to activate LIMK ( LIM kinases ) via phosphorylation .	Rho protein effectors like ROCKI and II or PAK1 (p21 activated kinase 1) are able to activate LIMK (LIM kinases) via phosphorylation.	2	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	LIMK	LIMK	LIMK	8	9	19	20
To determine the importance of SPAK and OSR1 in estradiol mediated enhancement of NKCC1 activation we knocked down SPAK and OSR1 expression using antisense oligonucleotides ( oligos ) directed against their respective mRNAs .	To determine the importance of SPAK and OSR1 in estradiol mediated enhancement of NKCC1 activation we knocked down SPAK and OSR1 expression using antisense oligonucleotides (oligos) directed against their respective mRNAs.	7	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	7	8	13	14
Finally , although expression of NKCC1 and KCC2 mRNA was found unaltered in a study on prefrontal cortex of schizophrenic patients , the same study found increased expression of OXSR1 and WNK3 transcripts , which act posttranscriptionally to up-regulate NKCC1 and downregulate KCC2 activity .	Finally, although expression of NKCC1 and KCC2 mRNA was found unaltered in a study on prefrontal cortex of schizophrenic patients, the same study found increased expression of OXSR1 and WNK3 transcripts, which act posttranscriptionally to up-regulate NKCC1 and downregulate KCC2 activity.	29	40	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OXSR1	OXSR1	OXSR1	NKCC1	NKCC1	NKCC1	29	30	39	40
siRNA mediated knockdown of WNK1 or OSR1 reduces intracellular K + and Cl - content and RVI in glioma cells by abolishing NKCC1 regulatory phospho activation .	siRNA mediated knockdown of WNK1 or OSR1 reduces intracellular K + and Cl - content and RVI in glioma cells by abolishing NKCC1 regulatory phospho activation.	2	25	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	6	7	22	23
In mammalian cells , under hyperosmotic or hypotonic low Cl - conditions SPAK and OSR1 have been shown to activate NKCC1 , NKCC2 and NCC by direct phosphorylation , with WNKs 1 , 3 or 4 acting upstream of SPAK and OSR1 .	In mammalian cells, under hyperosmotic or hypotonic low Cl - conditions SPAK and OSR1 have been shown to activate NKCC1, NKCC2 and NCC by direct phosphorylation, with WNKs 1, 3 or 4 acting upstream of SPAK and OSR1.	12	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	14	15	20	21
The phosphorylation triggers activation of SPAK and OSR1 , which in turn stimulates NKCC1 to maintain intracellular ionic strength and volume [ XREF_BIBR ] .	The phosphorylation triggers activation of SPAK and OSR1, which in turn stimulates NKCC1 to maintain intracellular ionic strength and volume [XREF_BIBR].	2	14	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	7	8	13	14
Kinases SPAK and OSR1 are up regulated by estradiol and activate NKCC1 in the developing hypothalamus .	Kinases SPAK and OSR1 are up regulated by estradiol and activate NKCC1 in the developing hypothalamus.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	3	4	11	12
To the best of our knowledge , this is the first report demonstrating that OSR1 and SPAK cooperatively modulate NKCC1 activity in SCs to support spermatogenesis .	To the best of our knowledge, this is the first report demonstrating that OSR1 and SPAK cooperatively modulate NKCC1 activity in SCs to support spermatogenesis.	14	20	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	14	15	19	20
The SPAK and OSR1 activates NKCC1 and the kinase function of both the WNKs and SPAK and OSR1 is required .	The SPAK and OSR1 activates NKCC1 and the kinase function of both the WNKs and SPAK and OSR1 is required.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	3	4	5	6
In mammals , the WNK activated Sterile-20 ( Ste20 )-related Proline and Alanine rich Kinase ( SPAK ) and Oxidative Stress Response Kinase 1 ( OSR1 ) have been shown to stimulate human NKCC1 through phosphorylation at T203 , T207 , T212 and T217 , whereas AMP dependent kinase ( AMPK ) inhibits NKCC1 by phosphorylation at S77 .	In mammals, the WNK activated Sterile-20 (Ste20)-related Proline and Alanine rich Kinase (SPAK) and Oxidative Stress Response Kinase 1 (OSR1) have been shown to stimulate human NKCC1 through phosphorylation at T203, T207, T212 and T217, whereas AMP dependent kinase (AMPK) inhibits NKCC1 by phosphorylation at S77.	14	34	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	25	26	33	34
For example , the SPAK and OSR1 activates NKCC1 without affecting surface expression , and the kinase function of both the WNKs and SPAK and OSR1 is required .	For example, the SPAK and OSR1 activates NKCC1 without affecting surface expression, and the kinase function of both the WNKs and SPAK and OSR1 is required.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	6	7	8	9
SPAK and OSR1 were originally identified through their ability to interact , phosphorylate , and activate NKCC1 and may also regulate NCC .	SPAK and OSR1 were originally identified through their ability to interact, phosphorylate, and activate NKCC1 and may also regulate NCC.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	2	3	16	17
Although several in vivo studies have indicated that NKCCs are controlled by OSR1 and/or SPAK XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR , no study has examined how SPAK and OSR1 -- when co-expressed -- might modulate NKCC1 activity in reproductive tissues and affect fertility .	Although several in vivo studies have indicated that NKCCs are controlled by OSR1 and/or SPAK XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR, no study has examined how SPAK and OSR1 -- when co-expressed -- might modulate NKCC1 activity in reproductive tissues and affect fertility.	25	35	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	27	28	34	35
A very recent study has revealed that OGD and Reoxygenation induced increase in phosphoactivation of NKCC1 by WNK3-SPAK and OSR1 kinases in OPC .	A very recent study has revealed that OGD and Reoxygenation induced increase in phosphoactivation of NKCC1 by WNK3-SPAK and OSR1 kinases in OPC.	10	20	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NKCC1	NKCC1	NKCC1	19	20	15	16
A conserved OXSR1 binding motif present on NKCC1 XREF_BIBR has also been detected on WNK1 and WNK4 XREF_BIBR and the activation of NKCC1 by OXSR1 is regulated through upstream interactions with WNK1 and WNK4 XREF_BIBR , XREF_BIBR - XREF_BIBR , XREF_BIBR .	A conserved OXSR1 binding motif present on NKCC1 XREF_BIBR has also been detected on WNK1 and WNK4 XREF_BIBR and the activation of NKCC1 by OXSR1 is regulated through upstream interactions with WNK1 and WNK4 XREF_BIBR, XREF_BIBR - XREF_BIBR, XREF_BIBR.	12	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	OXSR1	OXSR1	OXSR1	NKCC1	NKCC1	NKCC1	24	25	22	23
Here , we have further demonstrated that PAK1 was activated in human CRC cell lines in vitro by both Gamide and Ggly through PI3K dependent pathways , and that the activation of PAK1 contributed to gastrin stimulated activation of beta-catenin signaling and VEGF production in CRC cells , as PAK1 knockdown completely blocked these stimulatory effects of gastrins on CRC cells .	Here, we have further demonstrated that PAK1 was activated in human CRC cell lines in vitro by both Gamide and Ggly through PI3K dependent pathways, and that the activation of PAK1 contributed to gastrin stimulated activation of beta-catenin signaling and VEGF production in CRC cells, as PAK1 knockdown completely blocked these stimulatory effects of gastrins on CRC cells.	30	40	contributed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	32	33	39	40
Our analysis shows that Sox17 modulated PAK1 , which itself is known to modulate the beta-catenin pathway .	Our analysis shows that Sox17 modulated PAK1, which itself is known to modulate the beta-catenin pathway.	5	16	modulate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	6	7	15	16
We have recently shown that 5-ASA activity is mediated by inhibition of serine threonine kinase PAK1 and inhibition of PAK1 increased membranous localization of E-cadherin and beta-catenin .	We have recently shown that 5-ASA activity is mediated by inhibition of serine threonine kinase PAK1 and inhibition of PAK1 increased membranous localization of E-cadherin and beta-catenin.	13	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	15	16	26	27
Recently , PAK1 has been shown to activate beta-catenin transcriptional activities and promote EMT in podocytes [ XREF_BIBR ] .	Recently, PAK1 has been shown to activate beta-catenin transcriptional activities and promote EMT in podocytes [XREF_BIBR].	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
We have also shown here that PAK1 mediates gastrin stimulated activation of beta-catenin and VEGF production in CRC cells , as knockdown of PAK1 blocked the stimulatory effects of gastrins on both activation of beta-catenin and VEGF production .	We have also shown here that PAK1 mediates gastrin stimulated activation of beta-catenin and VEGF production in CRC cells, as knockdown of PAK1 blocked the stimulatory effects of gastrins on both activation of beta-catenin and VEGF production.	6	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	6	7	12	13
PAK1 knockdown not only reduced the transcriptional activity of beta-catenin and TCF4 but also blocked the stimulation by gastrins of the transcriptional activity of beta-catenin and TCF4 .	PAK1 knockdown not only reduced the transcriptional activity of beta-catenin and TCF4 but also blocked the stimulation by gastrins of the transcriptional activity of beta-catenin and TCF4.	0	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	0	1	9	10
Furthermore , inhibition of TLR4 or PAK1 prior to challenge with Fn significantly decreased protein abundance of P-beta-catenin S675 , C-myc and Cyclin D1 , as well as nuclear beta-catenin accumulation .	Furthermore, inhibition of TLR4 or PAK1 prior to challenge with Fn significantly decreased protein abundance of P-beta-catenin S675, C-myc and Cyclin D1, as well as nuclear beta-catenin accumulation.	2	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	P-beta-catenin	P-beta-catenin	P-beta-catenin	6	7	17	18
In the present study , both a gut derived Fn ( F01 ) strain from a CRC patient and a Fn ( ATCC10953 ) strain originating from the oral cavity was able to induce PAK1 mediated transcriptional activation of beta-catenin .	In the present study, both a gut derived Fn (F01) strain from a CRC patient and a Fn (ATCC10953) strain originating from the oral cavity was able to induce PAK1 mediated transcriptional activation of beta-catenin.	33	40	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	34	35	39	40
Therefore , PAK1 may promote tumor malignancy by activating Ras/Raf/MARK and beta-catenin and TCF4 signaling .	Therefore, PAK1 may promote tumor malignancy by activating Ras/Raf/MARK and beta-catenin and TCF4 signaling.	2	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
Especially for Epstein-Barr virus related gastric cancer , there is an inverse relation between p21 and beta-catenin , which might be mediated by PAK1 dependent interference with Wnt signaling 48 .	Especially for Epstein-Barr virus related gastric cancer, there is an inverse relation between p21 and beta-catenin, which might be mediated by PAK1 dependent interference with Wnt signaling 48.	12	25	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	23	24	16	17
Although p21 activated kinase 1 ( PAK1 ) , acting downstream of Ras , stimulates Wnt and beta-catenin signaling and is known to play an important role in CRC development and progression , the role of PAK1 in the expression of CSC markers has not previously been investigated .	Although p21 activated kinase 1 (PAK1), acting downstream of Ras, stimulates Wnt and beta-catenin signaling and is known to play an important role in CRC development and progression, the role of PAK1 in the expression of CSC markers has not previously been investigated.	3	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	6	7	17	18
However , the role of the beta-catenin signaling mediated by PAK1 in lung cancer cell stemness is not fully understood , although the PAK1 mediated stem like phenotype confers sunitinib resistance via NF-kappaB/IL -6 activation in renal cell carcinoma XREF_BIBR .	However, the role of the beta-catenin signaling mediated by PAK1 in lung cancer cell stemness is not fully understood, although the PAK1 mediated stem like phenotype confers sunitinib resistance via NF-kappaB/IL -6 activation in renal cell carcinoma XREF_BIBR.	6	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	10	11	6	7
As shown in XREF_FIG , Pak1 RNAi infection of Rb-/- MC3T3 cells increased the intensity of beta-catenin labeling in intercellular spaces , suggesting a partial restoration of adherens junctions ( top panel , arrow ) , compared to Rb-/- MC3T3 cells infected with scrambled control adenovirus ( middle panel ) .	As shown in XREF_FIG, Pak1 RNAi infection of Rb-/- MC3T3 cells increased the intensity of beta-catenin labeling in intercellular spaces, suggesting a partial restoration of adherens junctions (top panel, arrow), compared to Rb-/- MC3T3 cells infected with scrambled control adenovirus (middle panel).	5	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	beta-catenin	beta-catenin	beta-catenin	5	6	16	17
PAK1 knockdown was shown to inhibit the activation of beta-catenin in colorectal cancer , thereby inhibiting Wnt and beta-catenin signaling and proliferation [ XREF_BIBR ] .	PAK1 knockdown was shown to inhibit the activation of beta-catenin in colorectal cancer, thereby inhibiting Wnt and beta-catenin signaling and proliferation [XREF_BIBR].	0	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	0	1	9	10
3.4 Depletion of PAK1 increases cell adhesion and membranous localization of beta-catenin and E-cadherin .	3.4 Depletion of PAK1 increases cell adhesion and membranous localization of beta-catenin and E-cadherin.	1	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
Our study demonstrates that Fn significantly increases P-PAK1 protein levels , leading to beta-catenin S675 phosphorylation and nuclear accumulation , whereas inhibition of PAK1 greatly decreases the level of P-beta-catenin S675 .	Our study demonstrates that Fn significantly increases P-PAK1 protein levels, leading to beta-catenin S675 phosphorylation and nuclear accumulation, whereas inhibition of PAK1 greatly decreases the level of P-beta-catenin S675.	21	30	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	P-beta-catenin	P-beta-catenin	P-beta-catenin	23	24	29	30
PAK1 mediates the MEK and ERK , PI3K and AKT , and Wnt and beta-catenin signaling pathways in colorectal cancer cells .	PAK1 mediates the MEK and ERK, PI3K and AKT, and Wnt and beta-catenin signaling pathways in colorectal cancer cells.	0	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	0	1	14	15
PAK1 knockdown blocks gastrin stimulated activation of beta-catenin and VEGF production in CRC cells .	PAK1 knockdown blocks gastrin stimulated activation of beta-catenin and VEGF production in CRC cells.	0	10	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	0	1	7	8
Bam32 interacts with Pak1 via PLC-gamma1 and Bam32-PLC-gamma1-Pak1 complexes activate Mek-1 and Erk .	Bam32 interacts with Pak1 via PLC-gamma1 and Bam32-PLC-gamma1-Pak1 complexes activate Mek-1 and Erk.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	Mek-1	Mek-1	Mek-1	3	4	10	11
We characterized in Jurkat cells and primary T lymphocytes , a pathway dependent on Bam32-PLC-gamma1-Pak1 complexes , in which Pak1 kinase activates Raf-1 and Mek-1 , both upstream of Erk .	We characterized in Jurkat cells and primary T lymphocytes, a pathway dependent on Bam32-PLC-gamma1-Pak1 complexes, in which Pak1 kinase activates Raf-1 and Mek-1, both upstream of Erk.	19	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	Mek-1	Mek-1	Mek-1	19	20	24	25
Pak1 directly activates Raf-1 , by phosphorylating serine 338 XREF_BIBR moreover Pak1 directly activates MEK1 , phosphorylating serine 298 XREF_BIBR .	Pak1 directly activates Raf-1, by phosphorylating serine 338 XREF_BIBR moreover Pak1 directly activates MEK1, phosphorylating serine 298 XREF_BIBR.	10	15	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	MEK1	MEK1	MEK1	11	12	14	15
It regulates the PAK1 dependent activation of MEK1 in response to adhesion , thus representing a point of convergence for integrating growth factor signaling and cell adhesion to extracellular matrix ( ECM ) [ XREF_BIBR , XREF_BIBR ] .	It regulates the PAK1 dependent activation of MEK1 in response to adhesion, thus representing a point of convergence for integrating growth factor signaling and cell adhesion to extracellular matrix (ECM) [XREF_BIBR, XREF_BIBR].	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	MEK1	MEK1	MEK1	3	4	7	8
This suggests the possibility of a functional relationship between PAK1 activation and the MAPK and ERK pathway , through PAK1 activation of the ERK-activator MEK1 [ XREF_BIBR ] , similar to observations in Plasmodium infected erythrocytes , as detailed below [ XREF_BIBR ] .	This suggests the possibility of a functional relationship between PAK1 activation and the MAPK and ERK pathway, through PAK1 activation of the ERK-activator MEK1 [XREF_BIBR], similar to observations in Plasmodium infected erythrocytes, as detailed below [XREF_BIBR].	19	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	MEK1	MEK1	MEK1	19	20	24	25
PAK1 was shown to activate human MEK1 in erythrocytes upon infection with Plasmodium falciparum ( 3D7 ) and P. berghei [ XREF_BIBR ] .	PAK1 was shown to activate human MEK1 in erythrocytes upon infection with Plasmodium falciparum (3D7) and P. berghei [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	MEK1	MEK1	MEK1	0	1	6	7
This is reminiscent of PAK1 mediated activation of MEK1 : PAK1 was shown to phosphorylate MEK1 on S298 , causing its autophosphorylation on S218/222 .	This is reminiscent of PAK1 mediated activation of MEK1 : PAK1 was shown to phosphorylate MEK1 on S298, causing its autophosphorylation on S218/222.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	MEK1	MEK1	MEK1	4	5	8	9
The activation of MEK1 by PAK1 , and subsequently ERK by MEK1 , is suggested to result in the phosphorylation of FAK at Ser910 .	The activation of MEK1 by PAK1, and subsequently ERK by MEK1, is suggested to result in the phosphorylation of FAK at Ser910.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	MEK1	MEK1	MEK1	5	6	3	4
Furthermore , increased activation of the PAK1 activator Rac1 induced the formation of a triple complex of Rac1 , PAK1 , and MEK1 independent of the kinase activity of PAK1 .	Furthermore, increased activation of the PAK1 activator Rac1 induced the formation of a triple complex of Rac1, PAK1, and MEK1 independent of the kinase activity of PAK1.	6	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	MEK1	MEK1	MEK1	6	7	22	23
This demonstrates that PAK1 , like MEK1 , is activated in infected erythrocytes , and that MEK1 is activated by PAK1 as a consequence of infection .	This demonstrates that PAK1, like MEK1, is activated in infected erythrocytes, and that MEK1 is activated by PAK1 as a consequence of infection.	16	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	MEK1	MEK1	MEK1	20	21	16	17
In addition , WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1 , which in turn phosphorylate and activate NCC [ XREF_BIBR ; XREF_BIBR ] .	In addition, WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1, which in turn phosphorylate and activate NCC [XREF_BIBR; XREF_BIBR].	3	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1	osr1	NCC	NCC	ncc	11	12	19	20
With-no-lysine kinase ( WNK ) kinases phosphorylate the STE20 and SPS1 -44 related proline-alanine-rich protein kinase ( SPAK ) and the related oxidative stress related kinase 1 ( OSR1 ) , which directly activate NCC [ XREF_BIBR , XREF_BIBR ] .	With-no-lysine kinase (WNK) kinases phosphorylate the STE20 and SPS1 -44 related proline-alanine-rich protein kinase (SPAK) and the related oxidative stress related kinase 1 (OSR1), which directly activate NCC [XREF_BIBR, XREF_BIBR].	25	38	directly activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NCC	NCC	NCC	28	29	34	35
SPAK and OSR1 then directly phosphorylate and activate NCC , increasing sodium reabsorption in the DCT , which causes decreased potassium secretion by the downstream nephron , by limiting distal NaCl delivery and/or inducing structural changes .	SPAK and OSR1 then directly phosphorylate and activate NCC, increasing sodium reabsorption in the DCT, which causes decreased potassium secretion by the downstream nephron, by limiting distal NaCl delivery and/or inducing structural changes.	0	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NCC	NCC	NCC	2	3	8	9
The observation that both SPAK and OSR1 and NCC phosphorylation was increased following dietary salt restriction provided indirect evidence that SPAK and OSR1 mediated activation of NCC in vivo .	The observation that both SPAK and OSR1 and NCC phosphorylation was increased following dietary salt restriction provided indirect evidence that SPAK and OSR1 mediated activation of NCC in vivo.	22	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NCC	NCC	NCC	22	23	26	27
WNK1 can also indirectly regulates NCC activity by phosphorylating the SPAK and OSR1 kinases , which activate NCC without affecting its surface expression .	WNK1 can also indirectly regulates NCC activity by phosphorylating the SPAK and OSR1 kinases, which activate NCC without affecting its surface expression.	0	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	WNK1 can also indirectly regulates NCC activity by phosphorylating the SPAK and OSR1	osr1	NCC	NCC	ncc	12	13	17	18
WNK4 phosphorylates the kinases SPAK ( Ste20 related proline alanine rich kinase ) and OSR1 ( oxidative stress responsive kinase ) , which then phosphorylate and activate the renal Na-Cl cotransporter ( NCC ) .	WNK4 phosphorylates the kinases SPAK (Ste20 related proline alanine rich kinase) and OSR1 (oxidative stress responsive kinase), which then phosphorylate and activate the renal Na-Cl cotransporter (NCC).	0	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	WNK4 phosphorylates the kinases SPAK (Ste20 related proline alanine rich kinase) and OSR1	osr1	Na-Cl cotransporter	Na-Cl cotransporter	na-cl cotransporter	14	15	29	31
As two protein kinases , Ste20p related Proline Alanine rich kinase ( SPAK ) and Oxidative stress responsive 1 ( OxSR1 ) , phosphorylate and activate NCC , we examined their roles in norepinephrine effects .	As two protein kinases, Ste20p related Proline Alanine rich kinase (SPAK) and Oxidative stress responsive 1 (OxSR1), phosphorylate and activate NCC, we examined their roles in norepinephrine effects.	16	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OxSR1	OxSR1	OxSR1	NCC	NCC	NCC	20	21	26	27
As SPAK and OxSR1 are the major activators of NCC in vivo , we used SPAK -/- and kidney specific ( KS ) OxSR1 -/- mice to determine if either of these kinases is essential for the observed changes in NCC .	As SPAK and OxSR1 are the major activators of NCC in vivo, we used SPAK -/- and kidney specific (KS) OxSR1 -/- mice to determine if either of these kinases is essential for the observed changes in NCC.	1	10	are the major activators	Positive_activation_copula_1	Positive_activation	Positive_activation	OxSR1	OxSR1	OxSR1	NCC	NCC	NCC	3	4	9	10
The phospho mimicking T48D mutant of mouse NCC increased its protein abundance and Na + uptake , and also enhanced the phosphorylation at the N-terminal region of NCC by OSR1 .	The phospho mimicking T48D mutant of mouse NCC increased its protein abundance and Na + uptake, and also enhanced the phosphorylation at the N-terminal region of NCC by OSR1.	19	30	enhanced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NCC	NCC	NCC	29	30	27	28
Similarly , SPAK and OSR1 activates NCC intrinsic activity .	Similarly, SPAK and OSR1 activates NCC intrinsic activity.	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSR1	OSR1	OSR1	NCC	NCC	NCC	4	5	6	7
As will be discussed below , serine/threonine protein kinase 39 ( SPAK ) is one of the most important kinases contributing to activation of NCC by phosphorylation and both SPAK and OSR1 have been shown to phosphorylate NCC at these three residues , in vitro ( XREF_FIG ) .	As will be discussed below, serine/threonine protein kinase 39 (SPAK) is one of the most important kinases contributing to activation of NCC by phosphorylation and both SPAK and OSR1 have been shown to phosphorylate NCC at these three residues, in vitro (XREF_FIG).	22	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	OSR1	phosphorylation and both SPAK and OSR1	osr1	NCC	NCC	ncc	31	32	24	25
Upon phosphorylation by PAK1 , Raf-1 is targeted to the mitochondria through its interaction with the BH4 domain of Bcl-2 .	Upon phosphorylation by PAK1, Raf-1 is targeted to the mitochondria through its interaction with the BH4 domain of Bcl-2.	1	8	targeted	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	Raf-1	Raf-1	Raf-1	3	4	5	6
We observed that all group II PAKs were efficient serine 338 kinases , although only PAK1 and PAK5 significantly stimulated Raf-1 kinase activity .	We observed that all group II PAKs were efficient serine 338 kinases, although only PAK1 and PAK5 significantly stimulated Raf-1 kinase activity.	14	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	Raf-1	Raf-1	Raf-1	15	16	20	21
Interestingly , knockdown of PAK1 ( but not PAK2 or PAK4 ) completely abolished CRAF pS338 ( XREF_FIG ) , and this was accompanied by a dramatic increase in IR mediated DNA damage ( XREF_FIG ) .	Interestingly, knockdown of PAK1 (but not PAK2 or PAK4) completely abolished CRAF pS338 (XREF_FIG), and this was accompanied by a dramatic increase in IR mediated DNA damage (XREF_FIG).	2	15	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	CRAF	CRAF	CRAF	4	5	14	15
PAK1 activates CRAF pS338 and modulates radiosensitivity .	PAK1 activates CRAF pS338 and modulates radiosensitivity.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	CRAF	CRAF	CRAF	0	1	2	3
Additionally , Pak1 and Pak5 stimulate Raf-1 complexes with Bcl-2 and mitochondrial translocation of Raf-1 XREF_BIBR , XREF_BIBR , XREF_BIBR .	Additionally, Pak1 and Pak5 stimulate Raf-1 complexes with Bcl-2 and mitochondrial translocation of Raf-1 XREF_BIBR, XREF_BIBR, XREF_BIBR.	2	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	Raf-1	Raf-1	Raf-1	2	3	6	7
We showed that phosphorylation of cRaf S338 by Pak1 in Rat-1 fibroblasts activates cRaf and is necessary for the coupling of Akt1 and cRaf pathways in mediating oncogenic transformation [ XREF_BIBR , XREF_BIBR ] .	We showed that phosphorylation of cRaf S338 by Pak1 in Rat-1 fibroblasts activates cRaf and is necessary for the coupling of Akt1 and cRaf pathways in mediating oncogenic transformation [XREF_BIBR, XREF_BIBR].	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	phosphorylation of cRaf S338 by Pak1	pak1	cRaf	cRaf	craf	8	9	13	14
It has been shown that PAK1 binds to Raf-1 and that this interaction is required for PAK1 mediated Raf-1 activation .	It has been shown that PAK1 binds to Raf-1 and that this interaction is required for PAK1 mediated Raf-1 activation.	16	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	Raf-1	Raf-1	Raf-1	16	17	18	19
In the case of cyclin D 1 and Pak1 , the resistance mechanism could be explained by both cyclin D 1 and Pak1 potentiating the activity of the ER-alpha [ XREF_BIBR - XREF_BIBR ] .	In the case of cyclin D 1 and Pak1, the resistance mechanism could be explained by both cyclin D 1 and Pak1 potentiating the activity of the ER-alpha [XREF_BIBR - XREF_BIBR].	15	32	potentiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	ER-alpha	ER-alpha	ER-alpha	22	23	28	29
Pak-1 is a downstream mediator of Rac1 dependent ER transcriptional activation .	Pak-1 is a downstream mediator of Rac1 dependent ER transcriptional activation.	0	10	is a downstream mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	Pak-1	Pak-1	Pak-1	ER	ER	ER	0	1	8	9
Conversely , selective inhibition of the endogenous CRIPak resulted in an increased Pak1 activity , and consequently , increased cytoskeleton remodeling and Pak1 mediated ER transactivation activity .	Conversely, selective inhibition of the endogenous CRIPak resulted in an increased Pak1 activity, and consequently, increased cytoskeleton remodeling and Pak1 mediated ER transactivation activity.	18	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	ER	ER	ER	22	23	24	25
Our findings suggest that CRIPak is a novel negative regulator of the Pak1 and has a role in the modulation of Pak1 mediated ER transactivation in breast cancer cells .	Our findings suggest that CRIPak is a novel negative regulator of the Pak1 and has a role in the modulation of Pak1 mediated ER transactivation in breast cancer cells.	21	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	ER	ER	ER	21	22	23	24
PAK1 stimulates the PRL dependent invasion of TMX2-28 cells ( highly invasive ER negative clone of MCF-7 cells ) through Matrigel .	PAK1 stimulates the PRL dependent invasion of TMX2-28 cells (highly invasive ER negative clone of MCF-7 cells) through Matrigel.	0	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	ER	ER	ER	0	1	12	13
Moreover , knockdown of Pak1 in RL95-2 significantly down-regulated cell cycle related gene cyclin D1 and steroid receptors , ERalpha and PR , but have no effect on another cell cycle related gene CDC25A , as evaluated by qPCR ( XREF_FIG ) .	Moreover, knockdown of Pak1 in RL95-2 significantly down-regulated cell cycle related gene cyclin D1 and steroid receptors, ERalpha and PR, but have no effect on another cell cycle related gene CDC25A, as evaluated by qPCR (XREF_FIG).	2	20	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	ERalpha	ERalpha	ERalpha	4	5	19	20
XREF_BIBR , XREF_BIBR Moreover , ER activation by PAK1 induces upregulation of cyclin D1 in breast cancer cells , as well as in the mammary epithelium .	XREF_BIBR, XREF_BIBR Moreover, ER activation by PAK1 induces upregulation of cyclin D1 in breast cancer cells, as well as in the mammary epithelium.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	ER	ER	ER	8	9	5	6
These findings suggest that Pak1 could potentially regulate cyclin D 1 expression in both ER positive and ER negative breast cancer cells .	These findings suggest that Pak1 could potentially regulate cyclin D 1 expression in both ER positive and ER negative breast cancer cells.	4	17	potentially regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	ER	ER	ER	4	5	14	15
ER activation by Pak1 also induces upregulation of cyclin D 1 in breast cancer cells , as well as in the mammary epithelium [ XREF_BIBR ] .	ER activation by Pak1 also induces upregulation of cyclin D 1 in breast cancer cells, as well as in the mammary epithelium [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	ER	ER	ER	3	4	0	1
We also found that Pak1 hyperactivation increases the stimulation of downstream proliferative signaling effectors MEK1/2 and p38-MAPK in mammary tumor epithelial cells .	We also found that Pak1 hyperactivation increases the stimulation of downstream proliferative signaling effectors MEK1/2 and p38-MAPK in mammary tumor epithelial cells.	4	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	MEK1/2	MEK1/2	MEK1/2	4	5	14	15
XREF_BIBR PAK1 overexpression in mammary tissue also increases the activation of MEK1/2 and p38-MAPK in mammary tumor epithelial cells .	XREF_BIBR PAK1 overexpression in mammary tissue also increases the activation of MEK1/2 and p38-MAPK in mammary tumor epithelial cells.	1	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1 overexpression	pak1	MEK1/2	MEK1/2	mek1/2	1	2	11	12
However , other studies have shown that in a number of cell types specific downstream inhibition of Pak1 can result in the loss of ERK activation and diminished MEK and ERK pathway signaling [ XREF_BIBR - XREF_BIBR , XREF_BIBR ] .	However, other studies have shown that in a number of cell types specific downstream inhibition of Pak1 can result in the loss of ERK activation and diminished MEK and ERK pathway signaling [XREF_BIBR - XREF_BIBR, XREF_BIBR].	15	32	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	MEK	MEK	MEK	17	18	28	29
These data suggest that PAK1 can stimulate MEK activity in a kinase independent manner , probably by serving as a scaffold to facilitate interaction of C-RAF .	These data suggest that PAK1 can stimulate MEK activity in a kinase independent manner, probably by serving as a scaffold to facilitate interaction of C-RAF.	4	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	MEK	MEK	MEK	4	5	7	8
Activated Rac1 promotes Erk dependent hyperproliferation by Pak1 mediated Mek activation .	Activated Rac1 promotes Erk dependent hyperproliferation by Pak1 mediated Mek activation.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	Mek	Mek	Mek	7	8	9	10
Activated Rac1 promoted Erk dependent hyperproliferation by Pak1 mediated Mek activation independent of Mek1 phosporylation at serine 298 .	Activated Rac1 promoted Erk dependent hyperproliferation by Pak1 mediated Mek activation independent of Mek1 phosporylation at serine 298.	2	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	Mek	Mek	Mek	7	8	9	10
Pak1 has been reported to modulate activation of the Raf/MEK/ERK pathway by either directly activating Raf or priming MEK for activation of Raf in some cell types [ XREF_BIBR - XREF_BIBR ] .	Pak1 has been reported to modulate activation of the Raf/MEK/ERK pathway by either directly activating Raf or priming MEK for activation of Raf in some cell types [XREF_BIBR - XREF_BIBR].	0	19	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	MEK	MEK	MEK	0	1	18	19
When coupled with the observation that OSM and OSMR are significantly elevated in PDAC , and OSMR is induced by OSM , the unique signaling emanating from the OSMR justifies a more thorough analysis of OSM and the signaling cascades described here .	When coupled with the observation that OSM and OSMR are significantly elevated in PDAC, and OSMR is induced by OSM, the unique signaling emanating from the OSMR justifies a more thorough analysis of OSM and the signaling cascades described here.	16	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	OSMR	OSMR	OSMR	20	21	16	17
By contrast , OSM treatment stimulated robust interaction of OSMR with EGFR in the control astrocytes ( XREF_FIG ) .	By contrast, OSM treatment stimulated robust interaction of OSMR with EGFR in the control astrocytes (XREF_FIG).	3	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	OSMR	OSMR	OSMR	3	4	9	10
For this purpose , human GBM cell lines LN18 and LN229 showing basal levels of OSMR ( XREF_SUPPLEMENTARY B ) were treated with OSM ( 50 ng/ml ) for 12 hours and tested for a panel of markers .	For this purpose, human GBM cell lines LN18 and LN229 showing basal levels of OSMR (XREF_SUPPLEMENTARY B) were treated with OSM (50 ng/ml) for 12 hours and tested for a panel of markers.	13	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	OSM	OSM	OSM	OSMR	OSMR	OSMR	23	24	15	16
Moreover , OSMR is induced by OSM ligand , suggesting that a positive feedback loop is engaged to promote greater OSMR/JAK/STAT3 activation and maintain the induced mesenchymal and CSC cell state .	Moreover, OSMR is induced by OSM ligand, suggesting that a positive feedback loop is engaged to promote greater OSMR/JAK/STAT3 activation and maintain the induced mesenchymal and CSC cell state.	2	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	OSMR	OSMR	OSMR	6	7	2	3
Because OSM is required to trigger the interaction of OSMR with EGFR in astrocytes that do not express oncogenic EGFRvIII , we assessed the influence of OSM on EGFR and STAT3 signaling in these cells .	Because OSM is required to trigger the interaction of OSMR with EGFR in astrocytes that do not express oncogenic EGFRvIII, we assessed the influence of OSM on EGFR and STAT3 signaling in these cells.	1	10	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	OSMR	OSMR	OSMR	1	2	9	10
The mRNA levels of both OSMR and HGF showed a gradual increase when MSCs were treated with increasing concentrations of OSM from 0.5 to 5 ng/ml ( XREF_FIG , XREF_FIG ) .	The mRNA levels of both OSMR and HGF showed a gradual increase when MSCs were treated with increasing concentrations of OSM from 0.5 to 5 ng/ml (XREF_FIG, XREF_FIG).	2	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	OSM	OSM	OSM	OSMR	OSMR	OSMR	20	21	5	6
In a mouse model , OSMR overexpressing SCC cells treated with OSM showed significant increases in lung colonisation .	In a mouse model, OSMR overexpressing SCC cells treated with OSM showed significant increases in lung colonisation.	5	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	OSM	OSM	OSM	OSMR	OSMR	OSMR	11	12	5	6
In mouse cells , only mouse OSM is capable of activating the mouse OSM receptor ; human OSM instead activates the LIF receptor .	In mouse cells, only mouse OSM is capable of activating the mouse OSM receptor; human OSM instead activates the LIF receptor.	16	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	OSM	OSM	OSM	LIF receptor	LIF receptor	LIF receptor	17	18	21	23
Furthermore , inhibition of PKC-beta , ERK1/2 , and p90RSK by pretreatment of neuronal cells with PKC-beta inhibitor , U0126 and SL0101 , respectively abolished the activation of NHE-1 by sustained NH 4 Cl induced intracellular acidosis .	Furthermore, inhibition of PKC-beta, ERK1/2, and p90RSK by pretreatment of neuronal cells with PKC-beta inhibitor, U0126 and SL0101, respectively abolished the activation of NHE-1 by sustained NH 4 Cl induced intracellular acidosis.	2	29	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p90RSK	p90RSK	p90RSK	NHE-1	NHE-1	NHE-1	9	10	28	29
Among the kinases known to activate NHE-1 , the serine kinase p90RSK has been shown to increase NHE-1 activity by phosphorylation of a key serine 703 residue located in the cytoplasmic tail of the exchanger which serves as a docking site for the 14-3-3 adaptor protein XREF_BIBR .	Among the kinases known to activate NHE-1, the serine kinase p90RSK has been shown to increase NHE-1 activity by phosphorylation of a key serine 703 residue located in the cytoplasmic tail of the exchanger which serves as a docking site for the 14-3-3 adaptor protein XREF_BIBR.	8	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p90RSK	p90RSK	p90RSK	NHE-1	NHE-1	NHE-1	11	12	17	18
One possible pathway is through ERK1/2 and its effector p90RSK , which activates NHE1 by direct phosphorylation on Ser 703 of its C-terminal tail , after several types of stimuli .	One possible pathway is through ERK1/2 and its effector p90RSK, which activates NHE1 by direct phosphorylation on Ser 703 of its C-terminal tail, after several types of stimuli.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p90RSK	p90RSK	p90RSK	NHE1	NHE1	NHE1	9	10	13	14
Similar results were observed by overexpression of a NHE-1 S703A mutant ( XREF_FIG ) , providing evidence of a direct modulation of NHE-1 by p90RSK .	Similar results were observed by overexpression of a NHE-1 S703A mutant (XREF_FIG), providing evidence of a direct modulation of NHE-1 by p90RSK.	15	25	modulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	p90RSK	p90RSK	p90RSK	NHE-1	NHE-1	NHE-1	24	25	22	23
To gain insight into how reduction of lis-1 suppresses dhc-1 ( or195ts ) embryonic lethality , we sought to identify additional genes that when depleted by RNAi also suppressed the temperature sensitive embryonic lethality of dhc-1 ( or195ts ) .	To gain insight into how reduction of lis-1 suppresses dhc-1 (or195ts) embryonic lethality, we sought to identify additional genes that when depleted by RNAi also suppressed the temperature sensitive embryonic lethality of dhc-1 (or195ts).	5	14	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	lis-1	lis-1	lis-1	dhc-1	dhc-1	dhc-1	7	8	9	10
In the germline , depletion of the dynein associated proteins DLI-1 and LIS-1 caused diffusion of DHC-1 into the cytoplasm , whereas depletion of CAP-1 and -2 caused strong accumulation of DHC-1 in the perinuclear region .	In the germline, depletion of the dynein associated proteins DLI-1 and LIS-1 caused diffusion of DHC-1 into the cytoplasm, whereas depletion of CAP-1 and -2 caused strong accumulation of DHC-1 in the perinuclear region.	10	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIS-1	LIS-1	LIS-1	DHC-1	DHC-1	DHC-1	12	13	16	17
YB-1 activation by p90RSK is necessary to sustain the fibronectin and TGF-beta 1 dependent pro adhesive circuit in ovarian cancer cells .	YB-1 activation by p90RSK is necessary to sustain the fibronectin and TGF-beta 1 dependent pro adhesive circuit in ovarian cancer cells.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	p90RSK	p90RSK	p90RSK	YB-1	YB-1	YB-1	3	4	0	1
As also previously reported [ XREF_BIBR ] , we show that FN expression and relevant function may be regulated by the transcription and translation factor YB-1 that in turn is activated by the p90RSK .	As also previously reported [XREF_BIBR], we show that FN expression and relevant function may be regulated by the transcription and translation factor YB-1 that in turn is activated by the p90RSK.	18	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p90RSK	p90RSK	p90RSK	YB-1	YB-1	YB-1	33	34	25	26
Our data also support a novel role for Snail activation in alcohol induced , iNOS mediated intestinal hyperpermeability and that PAK1 is responsible for activation of Snail at Ser246 with alcohol stimulation .	Our data also support a novel role for Snail activation in alcohol induced, iNOS mediated intestinal hyperpermeability and that PAK1 is responsible for activation of Snail at Ser246 with alcohol stimulation.	20	27	is responsible for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	Snail	Snail	Snail	20	21	26	27
We found for the first time that Pak1 promotes transcription repression activity of Snail from E-cadherin , occludin , and aromatase promoters .	We found for the first time that Pak1 promotes transcription repression activity of Snail from E-cadherin, occludin, and aromatase promoters.	7	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	Snail	Snail	Snail	7	8	13	14
Selective depletion of PAK1 dramatically increased the nuclear and focal point accumulation of ILK , further demonstrating a role for PAK1 in ILK translocation .	Selective depletion of PAK1 dramatically increased the nuclear and focal point accumulation of ILK, further demonstrating a role for PAK1 in ILK translocation.	1	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PAK1	PAK1	PAK1	ILK	ILK	ILK	3	4	13	14
Although functional significance of this PAK1 mediated nuclear function of ILK is not very clear , this study indicates that changes in the nuclear activity of ILK are directly linked to the changes in nuclear lamins , which are critical proteins necessary for the nuclear integrity and function .	Although functional significance of this PAK1 mediated nuclear function of ILK is not very clear, this study indicates that changes in the nuclear activity of ILK are directly linked to the changes in nuclear lamins, which are critical proteins necessary for the nuclear integrity and function.	2	11	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	ILK	ILK	ILK	5	6	10	11
XREF_BIBR Among them , the Aurora kinase A and the Polo like kinase 1 ( Plk1 ) , two key players of mitosis , are directly activated via phosphorylation by PAK1 , on T288 and S342 and on S49 , respectively .	XREF_BIBR Among them, the Aurora kinase A and the Polo like kinase 1 (Plk1), two key players of mitosis, are directly activated via phosphorylation by PAK1, on T288 and S342 and on S49, respectively.	5	31	directly activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	Aurora kinase A	Aurora kinase A	Aurora kinase A	30	31	5	8
Another important regulator of dynein is a complex of interacting proteins LIS1 and NudE ( or its paralogue NudEL ; NudE and NudEL are gene products of Nde1 and Ndel1 ) .	Another important regulator of dynein is a complex of interacting proteins LIS1 and NudE (or its paralogue NudEL; NudE and NudEL are gene products of Nde1 and Ndel1).	9	30	products	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	LIS1	LIS1	LIS1	Ndel1	Ndel1	Ndel1	11	12	29	30
We propose a model in which LIS1 is a critical mediator of local NDEL1 based dynein activation at the AIS .	We propose a model in which LIS1 is a critical mediator of local NDEL1 based dynein activation at the AIS.	6	14	is a critical mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	LIS1	LIS1	LIS1	NDEL1	NDEL1	NDEL1	6	7	13	14
Our group has reported that d-flow induces phosphorylation of p90RSK , which then allows p90RSK to bind the C-terminus region of ERK5 ( amino acids 571-807 ) .	Our group has reported that d-flow induces phosphorylation of p90RSK, which then allows p90RSK to bind the C-terminus region of ERK5 (amino acids 571-807).	7	16	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p90RSK	phosphorylation of p90RSK	p90rsk	p90RSK	p90RSK	p90rsk	9	10	14	15
In contrast , no binding to c-Raf or the MEKK1 activator p65-PAK could be detected .	In contrast, no binding to c-Raf or the MEKK1 activator p65-PAK could be detected.	4	12	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	p65-PAK	p65-PAK	p65-PAK	MEKK1	MEKK1	MEKK1	11	12	9	10
Likewise , a role for Ste20p in carbohydrate metabolic processes is supported by the observation that Pak1 phosphorylates and activates phosphoglucomutase-1 ( PGM ; Ensembl : ENSG00000079739 ) XREF_BIBR .	Likewise, a role for Ste20p in carbohydrate metabolic processes is supported by the observation that Pak1 phosphorylates and activates phosphoglucomutase-1 (PGM; Ensembl : ENSG00000079739) XREF_BIBR.	16	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	phosphoglucomutase-1	phosphoglucomutase-1	phosphoglucomutase-1	16	17	20	21
PALB2 ( Partner and Localizer of BRCA2 ) protein , another key HR regulator , can also remove the inhibitory effect of RPA and promote RAD51 activity .	PALB2 (Partner and Localizer of BRCA2) protein, another key HR regulator, can also remove the inhibitory effect of RPA and promote RAD51 activity.	0	26	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	0	1	25	26
TEX15 , BRCA1 , BRCA2 and PALB2 have been suggested to mediate RAD51 and DMC1 loading onto sites of DSBs [ XREF_BIBR - XREF_BIBR ] .	TEX15, BRCA1, BRCA2 and PALB2 have been suggested to mediate RAD51 and DMC1 loading onto sites of DSBs [XREF_BIBR - XREF_BIBR].	0	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	6	7	12	13
PALB2 stimulates RAD51 mediated strand invasion of a single stranded DNA into a supercoiled plasmid to form a D-loop structure .	PALB2 stimulates RAD51 mediated strand invasion of a single stranded DNA into a supercoiled plasmid to form a D-loop structure.	0	5	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	0	1	2	3
Given this , and the fact that PALB2 associates with RAD51 , we wanted to test whether PALB2 , alone or in combination with RAD51AP1 , would enhance the recombinase function of RAD51 .	Given this, and the fact that PALB2 associates with RAD51, we wanted to test whether PALB2, alone or in combination with RAD51AP1, would enhance the recombinase function of RAD51.	17	33	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	17	18	32	33
In the conditions tested , 12 nM PALB2 stimulated RAD51 activity by approximately 7-fold ( XREF_SUPPLEMENTARY ) .	In the conditions tested, 12 nM PALB2 stimulated RAD51 activity by approximately 7-fold (XREF_SUPPLEMENTARY).	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	7	8	9	10
After RAD51 filament formation on resected DNA DSBs , PALB2 and BRCA2 stimulate RAD51 during the invasion step of HR .	After RAD51 filament formation on resected DNA DSBs, PALB2 and BRCA2 stimulate RAD51 during the invasion step of HR.	9	14	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	9	10	13	14
Subsequently , for the invasion step , only monomeric PALB2 will be present at strand breaks to stimulate RAD51 strand exchange activity .	Subsequently, for the invasion step, only monomeric PALB2 will be present at strand breaks to stimulate RAD51 strand exchange activity.	7	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	9	10	18	19
The reversion of RAD51 foci or gene targeting by PALB2 W1038X MutNES was not complete , and we believe that additional mutations are required for complete reversion .	The reversion of RAD51 foci or gene targeting by PALB2 W1038X MutNES was not complete, and we believe that additional mutations are required for complete reversion.	1	11	reversion	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	9	10	3	4
PALB2 promotes the assembly of RAD51 into a nucleoprotein filament with single-strand DNA in vitro [ XREF_BIBR , XREF_BIBR ] .	PALB2 promotes the assembly of RAD51 into a nucleoprotein filament with single-strand DNA in vitro [XREF_BIBR, XREF_BIBR].	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	0	1	5	6
Additionally , PALB2 can promote RAD51 dependent formation of a D loop [ XREF_BIBR , XREF_BIBR ] , in which invading single-strand DNA pairs with homologous DNA within an intact duplex ( XREF_FIG ) .	Additionally, PALB2 can promote RAD51 dependent formation of a D loop [XREF_BIBR, XREF_BIBR], in which invading single-strand DNA pairs with homologous DNA within an intact duplex (XREF_FIG).	2	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	2	3	5	6
In vitro data show that PALB2 , even in the absence of BRCA2 , can potentiate RAD51 strand exchange [ XREF_BIBR ] .	In vitro data show that PALB2, even in the absence of BRCA2, can potentiate RAD51 strand exchange [XREF_BIBR].	5	18	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	5	6	16	17
PALB2 stimulates RAD51 for strand invasion and homologous recombination , similar to studies reported by Dray and colleagues in the accompanying paper 33 .	PALB2 stimulates RAD51 for strand invasion and homologous recombination, similar to studies reported by Dray and colleagues in the accompanying paper 33.	0	3	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	0	1	2	3
We observed that PALB2 Delta1-40 promotes the loading of RAD51 on ssDNA better than PALB2 , in the absence ( XREF_FIG B , lanes 1-3 ) or in the presence of RPA ( lanes 4-6 ) .	We observed that PALB2 Delta1-40 promotes the loading of RAD51 on ssDNA better than PALB2, in the absence (XREF_FIG B, lanes 1-3) or in the presence of RPA (lanes 4-6).	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	3	4	9	10
Subsequently , the concomitant action of BRCA1 , PALB2 , and BRCA2 , in complex with its partner DSS1 , promotes the replacement of RPA and the loading of the recombinase RAD51 onto ssDNA .	Subsequently, the concomitant action of BRCA1, PALB2, and BRCA2, in complex with its partner DSS1, promotes the replacement of RPA and the loading of the recombinase RAD51 onto ssDNA.	4	32	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	8	9	31	32
We tested whether PALB2 enhances RAD51 mediated strand invasion using a ssDNA oligonucleotide .	We tested whether PALB2 enhances RAD51 mediated strand invasion using a ssDNA oligonucleotide.	3	6	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	3	4	5	6
Such function is accomplished by BRCA2 or PALB2 recombination mediators to overcome the inhibitory effect of RPA and allow RAD51 to nucleate on the ssDNA to promote the pre-synaptic filament assembly .	Such function is accomplished by BRCA2 or PALB2 recombination mediators to overcome the inhibitory effect of RPA and allow RAD51 to nucleate on the ssDNA to promote the pre-synaptic filament assembly.	5	21	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	7	8	19	20
Similar to reactions with oligonucleotides , PALB2 stimulated RAD51 D-loop formation ( ~ 20-fold activation compared to RAD51 alone ) ( XREF_FIG , compare lane 3 and 8 ) .	Similar to reactions with oligonucleotides, PALB2 stimulated RAD51 D-loop formation (~ 20-fold activation compared to RAD51 alone) (XREF_FIG, compare lane 3 and 8).	4	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	6	7	8	9
PALB2 strongly stimulates DNA strand invasion activity of RAD51 and stabilizes the nucleoprotein filament against a disruptive BRC3/4 polypeptide .	PALB2 strongly stimulates DNA strand invasion activity of RAD51 and stabilizes the nucleoprotein filament against a disruptive BRC3/4 polypeptide.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	0	1	8	9
These results show that PALB2 can strongly enhance RAD51 function in D-loop assays .	These results show that PALB2 can strongly enhance RAD51 function in D-loop assays.	4	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	4	5	8	9
However , this is extremely difficult as one can not distinguish between the RAD51 invasion activity promoted by PALB2 and BRCA2 and the poleta elongation activity stimulated by PALB2 and BRCA2 , as elongation is possible only after DNA invasion has occurred .	However, this is extremely difficult as one can not distinguish between the RAD51 invasion activity promoted by PALB2 and BRCA2 and the poleta elongation activity stimulated by PALB2 and BRCA2, as elongation is possible only after DNA invasion has occurred.	13	20	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	18	19	13	14
Enhancement of RAD51 activity by PALB2 and RAD51AP1 .	Enhancement of RAD51 activity by PALB2 and RAD51AP1.	0	7	Enhancement	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	5	6	2	3
Similarly , two regions of PALB2 bind RAD51 and PALB2 stimulates RAD51 for HR .	Similarly, two regions of PALB2 bind RAD51 and PALB2 stimulates RAD51 for HR.	7	13	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	9	10	11	12
The anchor role of BRCA1 is indicated by the hierarchy of the DNA damage induced focus formation : BRCA1 disruption diminishes PALB2 , BRCA2 and RAD51 foci ; PALB2 disruption reduces BRCA2 and RAD51 foci but not BRCA1 foci ; BRCA2 disruption only impairs RAD51 foci .	The anchor role of BRCA1 is indicated by the hierarchy of the DNA damage induced focus formation : BRCA1 disruption diminishes PALB2, BRCA2 and RAD51 foci; PALB2 disruption reduces BRCA2 and RAD51 foci but not BRCA1 foci; BRCA2 disruption only impairs RAD51 foci.	28	34	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	28	29	33	34
We monitored the activation of RAD51 by PALB2 , in conditions where RAD51 saturates the ssDNA substrate prior to invasion into a homologous DNA ( XREF_FIG B ) .	We monitored the activation of RAD51 by PALB2, in conditions where RAD51 saturates the ssDNA substrate prior to invasion into a homologous DNA (XREF_FIG B).	1	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	7	8	5	6
We have previously shown that PALB2 stimulates RAD51 in D-loop formation , a key step of HR .	We have previously shown that PALB2 stimulates RAD51 in D-loop formation, a key step of HR.	5	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	5	6	7	8
Although PALB2 and BRCA2 each have recombination mediator activity in the absence of the other , PALB2 also serves to promote the proper intranuclear localization of BRCA2 and thereby the ability of BRCA2 to support HR .	Although PALB2 and BRCA2 each have recombination mediator activity in the absence of the other, PALB2 also serves to promote the proper intranuclear localization of BRCA2 and thereby the ability of BRCA2 to support HR.	16	27	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	BRCA2	BRCA2	BRCA2	16	17	26	27
PALB2 supports BRCA2 stability and determines its localization in the nucleus after DNA damage [ XREF_BIBR ] .	PALB2 supports BRCA2 stability and determines its localization in the nucleus after DNA damage [XREF_BIBR].	0	5	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	BRCA2	BRCA2	BRCA2	0	1	2	3
The high expression of PALB2 may potentially promote the function of BRCA2 to cause or enhance the progress of breast cancer .	The high expression of PALB2 may potentially promote the function of BRCA2 to cause or enhance the progress of breast cancer.	2	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	expression of PALB2	palb2	BRCA2	BRCA2	brca2	4	5	11	12
PALB2 also mediates the physical interaction of BRCA2 with a carboxy-terminal fragment of BRCA1 and is required for the cooperation between BRCA1 and BRCA2 in the DNA damage responses [ XREF_BIBR ] .	PALB2 also mediates the physical interaction of BRCA2 with a carboxy-terminal fragment of BRCA1 and is required for the cooperation between BRCA1 and BRCA2 in the DNA damage responses [XREF_BIBR].	0	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	BRCA2	BRCA2	BRCA2	0	1	7	8
It was also characterized as a linker protein between BRCA1 and BRCA2 as cells treated with PALB2 siRNAs , but not a control siRNA , abolished the association between BRCA1 and BRCA2 .	It was also characterized as a linker protein between BRCA1 and BRCA2 as cells treated with PALB2 siRNAs, but not a control siRNA, abolished the association between BRCA1 and BRCA2.	7	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	PALB2	PALB2	PALB2	BRCA2	BRCA2	BRCA2	16	17	11	12
PALB2 supports BRCA2 stability and determines its localization in the nucleus after DNA damage XREF_BIBR .	PALB2 supports BRCA2 stability and determines its localization in the nucleus after DNA damage XREF_BIBR.	0	5	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	BRCA2	BRCA2	BRCA2	0	1	2	3
However , BRCA1 is not only implicated in HRR by its role in end-resection , but also due to its indirect interaction with BRCA2 , which is mediated by the PALB2 protein .	However, BRCA1 is not only implicated in HRR by its role in end-resection, but also due to its indirect interaction with BRCA2, which is mediated by the PALB2 protein.	6	31	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	BRCA2	BRCA2	BRCA2	30	31	23	24
Since PALB2 regulates the association of BRCA2 with chromatin [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , it is perhaps not surprising that the ChAM domain of PALB2 also promotes the association of BRCA2 with chromatin [ XREF_BIBR ] .	Since PALB2 regulates the association of BRCA2 with chromatin [XREF_BIBR, XREF_BIBR, XREF_BIBR], it is perhaps not surprising that the ChAM domain of PALB2 also promotes the association of BRCA2 with chromatin [XREF_BIBR].	25	34	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	BRCA2	BRCA2	BRCA2	27	28	33	34
Using extracts from these cells , we find that PALB2 mediates the physical interaction of BRCA2 with a COOH-terminal fragment of BRCA1 .	Using extracts from these cells, we find that PALB2 mediates the physical interaction of BRCA2 with a COOH-terminal fragment of BRCA1.	9	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	BRCA2	BRCA2	BRCA2	9	10	15	16
Hence , PALB2 function is not only important to target BRCA2 to chromatin but also is directly involved in the regulation of homologous recombination .	Hence, PALB2 function is not only important to target BRCA2 to chromatin but also is directly involved in the regulation of homologous recombination.	2	11	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	BRCA2	BRCA2	BRCA2	2	3	10	11
Cotransfection of c-Abl and gamma-PAK elicits phosphorylation of gamma-PAK on tyrosine and down-regulation of gamma-PAK activity , promoting accumulation of inactive gamma-PAK .	Cotransfection of c-Abl and gamma-PAK elicits phosphorylation of gamma-PAK on tyrosine and down-regulation of gamma-PAK activity, promoting accumulation of inactive gamma-PAK.	0	12	elicits	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	gamma-PAK	gamma-PAK	gamma-pak	gamma-PAK	phosphorylation of gamma-PAK on tyrosine	gamma-pak	4	5	8	9
It is known that phosphorylation of Pak2 T402 at the activation loop and/or S141 at the auto-inhibitory domain results in Pak2 activation .	It is known that phosphorylation of Pak2 T402 at the activation loop and/or S141 at the auto-inhibitory domain results in Pak2 activation.	4	22	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Pak2	phosphorylation of Pak2 T402	pak2	Pak2	Pak2	pak2	6	7	20	21
Pak inhibition reduced beta-catenin and Akt signaling in most MPSNT cells , but interestingly , did not consistently reduce activation of the Mek and Erk cascade .	Pak inhibition reduced beta-catenin and Akt signaling in most MPSNT cells, but interestingly, did not consistently reduce activation of the Mek and Erk cascade.	0	25	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak	Pak	Pak	Mek	Mek	Mek	0	1	22	23
We thus infer that P-REX1 GEF activity promotes Rac and Pak induced activation of MEK and ERK and PI3K and AKT in ER+ breast cancer cells .	We thus infer that P-REX1 GEF activity promotes Rac and Pak induced activation of MEK and ERK and PI3K and AKT in ER+ breast cancer cells.	8	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Pak	Pak	Pak	MEK	MEK	MEK	10	11	14	15
44 In accordance with a role for platelet PAK upstream of MAPK activation , we found that platelet PAK activation temporally preceded platelet MEK activation ( XREF_FIG ) and that inhibition of PAK blocked MEK and ERK activation in platelets ( XREF_FIG ) .	44 In accordance with a role for platelet PAK upstream of MAPK activation, we found that platelet PAK activation temporally preceded platelet MEK activation (XREF_FIG) and that inhibition of PAK blocked MEK and ERK activation in platelets (XREF_FIG).	30	37	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK	PAK	PAK	MEK	MEK	MEK	32	33	34	35
Along with its well-known downstream target p38 MAPK [ XREF_BIBR ] , PAK inhibition significantly reduced the activation of c-Raf , MEK and ERK1/2 following 15 min of PRL stimulation in T47D cells ( XREF_FIG ) .	Along with its well-known downstream target p38 MAPK [XREF_BIBR], PAK inhibition significantly reduced the activation of c-Raf, MEK and ERK1/2 following 15 min of PRL stimulation in T47D cells (XREF_FIG).	12	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK	PAK	PAK	MEK	MEK	MEK	12	13	21	22
The tamoxifen mediated increase in PAK4 expression may allow PAK4 to influence the tamoxifen response .	The tamoxifen mediated increase in PAK4 expression may allow PAK4 to influence the tamoxifen response.	1	11	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK4	tamoxifen mediated increase in PAK4 expression	pak4	PAK4	PAK4	pak4	5	6	9	10
Indeed , expression of kinase dead PAK4 was unable to rescue the PAK4 depletion phenotype emphasising the need for kinase activity .	Indeed, expression of kinase dead PAK4 was unable to rescue the PAK4 depletion phenotype emphasising the need for kinase activity.	2	14	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK4	expression of kinase dead PAK4	pak4	PAK4	PAK4	pak4	6	7	12	13
The Pak4 mRNA and protein levels were substantially enhanced by wt Pak4 overexpression and reduced by Pak4 depletion .	The Pak4 mRNA and protein levels were substantially enhanced by wt Pak4 overexpression and reduced by Pak4 depletion.	1	13	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Pak4	Pak4 overexpression	pak4	Pak4	Pak4	pak4	11	12	1	2
Ectopic expression of wild-type PAK4 in MDA-MB-231 cells activated PI3K and AKT signaling and resulted in the enhancement of the cell proliferation , migration , and invasion , whereas PAK4 induced effects were blocked by the PAK4 kinase inhibitor PF- 3758309 , PAK4 siRNAs or the PI3K inhibitor LY294002 .	Ectopic expression of wild-type PAK4 in MDA-MB-231 cells activated PI3K and AKT signaling and resulted in the enhancement of the cell proliferation, migration, and invasion, whereas PAK4 induced effects were blocked by the PAK4 kinase inhibitor PF- 3758309, PAK4 siRNAs or the PI3K inhibitor LY294002.	1	43	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PAK4	expression of wild-type PAK4	pak4	PAK4	PAK4	pak4	4	5	42	43
Co-expression of PAK4 and the constitutively active Cdc42HsV12 causes the redistribution of PAK4 to the brefeldin A sensitive compartment of the Golgi membrane and the subsequent induction of filopodia and actin polymerization .	Co-expression of PAK4 and the constitutively active Cdc42HsV12 causes the redistribution of PAK4 to the brefeldin A sensitive compartment of the Golgi membrane and the subsequent induction of filopodia and actin polymerization.	0	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK4	Co-expression of PAK4	pak4	PAK4	PAK4	pak4	2	3	12	13
Serines 218 and/or 222 in the MEK1 activation loop are required for PAK stimulated MEK1 activity towards ERK .	Serines 218 and/or 222 in the MEK1 activation loop are required for PAK stimulated MEK1 activity towards ERK.	10	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PAK	PAK	PAK	MEK1	MEK1	MEK1	12	13	14	15
Here we provide evidence that PAK can directly activate MEK1 by a mechanism distinct from conventional Ras and Raf mediated activation .	Here we provide evidence that PAK can directly activate MEK1 by a mechanism distinct from conventional Ras and Raf mediated activation.	5	10	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK	PAK	PAK	MEK1	MEK1	MEK1	5	6	9	10
The Rac effector PAK was shown to activate Raf and MEK1 , both downstream targets of Ras .	The Rac effector PAK was shown to activate Raf and MEK1, both downstream targets of Ras.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK	PAK	PAK	MEK1	MEK1	MEK1	3	4	10	11
The function of PALB2 as a linker of BRCA1 and BRCA2 may permit more sensitive regulation of HR and may allow BRCA1 to mediate other functions , such as checkpoint signaling , independently from HR .	The function of PALB2 as a linker of BRCA1 and BRCA2 may permit more sensitive regulation of HR and may allow BRCA1 to mediate other functions, such as checkpoint signaling, independently from HR.	1	23	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PALB2	PALB2	PALB2	BRCA1	BRCA1	BRCA1	3	4	21	22
Remarkably , 5RA-8 treatment of Hoxa1 and Pbx1 null mutants was sufficient to rescue the AP position of the r4 Hoxb1 + domain and shift it beyond the rostral aspect of the otocyst ( 4/4 ; 100 % ) ( XREF_FIG ) .	Remarkably, 5RA-8 treatment of Hoxa1 and Pbx1 null mutants was sufficient to rescue the AP position of the r4 Hoxb1 + domain and shift it beyond the rostral aspect of the otocyst (4/4; 100%) (XREF_FIG).	7	22	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pbx1	Pbx1	Pbx1	Hoxb1	Hoxb1	Hoxb1	7	8	20	21
The recent suggestion that Pak3 could stimulate Raf-1 activity by directly phosphorylating S338 through a Ras and phosphatidylinositol 3-kinase ( Pl3-K )/-Cdc42-dependent pathway has attracted much attention .	The recent suggestion that Pak3 could stimulate Raf-1 activity by directly phosphorylating S338 through a Ras and phosphatidylinositol 3-kinase (Pl3-K)/-Cdc42-dependent pathway has attracted much attention.	4	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak3	Pak3	Pak3	Raf-1	Raf-1	Raf-1	4	5	7	8
Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear beta-catenin as well as the Wnt and beta-catenin targets cyclin D1 and c-Myc .	Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear beta-catenin as well as the Wnt and beta-catenin targets cyclin D1 and c-Myc.	7	25	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK4	PAK4	PAK4	beta-catenin	beta-catenin	beta-catenin	7	8	13	14
In Drosophila , the PAK4 orthologue Mbt [ XREF_BIBR ] was suggested to target Armadillo ( homologue of beta-catenin ) , and deletion of Mbt from the eye leads to abnormal cell-cell junctions [ XREF_BIBR ] .	In Drosophila, the PAK4 orthologue Mbt [XREF_BIBR] was suggested to target Armadillo (homologue of beta-catenin), and deletion of Mbt from the eye leads to abnormal cell-cell junctions [XREF_BIBR].	4	19	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK4	PAK4	PAK4	beta-catenin	beta-catenin	beta-catenin	4	5	18	19
Pax3 augmented Lef1 dependent transactivation from this promoter .	Pax3 augmented Lef1 dependent transactivation from this promoter.	0	4	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pax3	Pax3	Pax3	Lef1	Lef1	Lef1	0	1	2	3
TOPK overexpression in PC12 cells augmented levels of antioxidative proteins ( peroxiredoxin 1 and 2 , heme oxygenase 1 and manganese superoxide dismutase ) , as well as total superoxide dismutase activity , along with inhibition of malondialdehyde and 3-nitrotyrosine upon H2O2 stimulation .	TOPK overexpression in PC12 cells augmented levels of antioxidative proteins (peroxiredoxin 1 and 2, heme oxygenase 1 and manganese superoxide dismutase), as well as total superoxide dismutase activity, along with inhibition of malondialdehyde and 3-nitrotyrosine upon H2O2 stimulation.	0	22	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TOPK	TOPK overexpression	topk	peroxiredoxin 1	peroxiredoxin 1	peroxiredoxin 1	0	1	11	13
Interestingly , Pax3 up-regulates the epithelial somite markers Meox1 and Paraxis , supporting the involvement of this transcription factor in the process of somite epithelialization .	Interestingly, Pax3 up-regulates the epithelial somite markers Meox1 and Paraxis, supporting the involvement of this transcription factor in the process of somite epithelialization.	2	10	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pax3	Pax3	Pax3	Meox1	Meox1	Meox1	2	3	8	9
AKT is likely the key mediator downstream of PI3K and PDK-1 , since nutrient receptor upregulation is maintained by a PDK1 mutant ( L155E ) that can activate AKT but not other PDK1 substrates [ XREF_BIBR ] .	AKT is likely the key mediator downstream of PI3K and PDK-1, since nutrient receptor upregulation is maintained by a PDK1 mutant (L155E) that can activate AKT but not other PDK1 substrates [XREF_BIBR].	20	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	20	21	28	29
Focusing initially on upstream signaling responsible for this , we observed a rapid and sustained Akt phosphorylation and iNOS upregulation in photostressed COH-BR1 cells , both of which effects were effectively abolished by a PI3K inhibitor ( Wo ) , thus linking PDPK1 mediated Akt activation to iNOS overexpression .	Focusing initially on upstream signaling responsible for this, we observed a rapid and sustained Akt phosphorylation and iNOS upregulation in photostressed COH-BR1 cells, both of which effects were effectively abolished by a PI3K inhibitor (Wo), thus linking PDPK1 mediated Akt activation to iNOS overexpression.	41	45	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	Akt	Akt	Akt	42	43	44	45
Thus , even the slightest fraction of PDK1 escaping GSK2334470 inhibition would be sufficient to activate Akt , which is in agreement with the observation that cytosolic Akt lacking PH domain ( DeltaPH-Akt ) was more potently inhibited that the full-length protein .	Thus, even the slightest fraction of PDK1 escaping GSK2334470 inhibition would be sufficient to activate Akt, which is in agreement with the observation that cytosolic Akt lacking PH domain (DeltaPH-Akt) was more potently inhibited that the full-length protein.	5	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	7	8	16	17
PDK1 activates Akt by phosphorylating a Ser/Thr residue in the activation loop .	PDK1 activates Akt by phosphorylating a Ser/Thr residue in the activation loop.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	2	3
PDK1 partially activates AKT by phosphorylating threonine308 .	PDK1 partially activates AKT by phosphorylating threonine308.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	3	4
Akt itself is activated upon phosphorylation of threonine 308 and serine 473 by the phosphatidyl dependent kinases PDK1 and PDK2 and rictor-mTOR , in a PI3K dependent manner .	Akt itself is activated upon phosphorylation of threonine 308 and serine 473 by the phosphatidyl dependent kinases PDK1 and PDK2 and rictor-mTOR, in a PI3K dependent manner.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	17	18	0	1
In 3T3-L1 preadipocytes , PP2A has been shown to directly inhibit Akt activity and Ser473 phosphorylation by two distinct mechanisms - without affecting the immediate upstream Akt activator PDK1 XREF_BIBR .	In 3T3-L1 preadipocytes, PP2A has been shown to directly inhibit Akt activity and Ser473 phosphorylation by two distinct mechanisms - without affecting the immediate upstream Akt activator PDK1 XREF_BIBR.	26	29	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	28	29	26	27
Akt itself is activated via phosphorylation by phosphoinositide dependent protein kinase 1 ( PDK1 ) .	Akt itself is activated via phosphorylation by phosphoinositide dependent protein kinase 1 (PDK1).	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	13	14	0	1
As with + PDK1+ NeuT , increasing PDK1 levels in the context of reduced PTEN or mutant PIK3CA enhanced activation of AKT as indicated by increased phosphorylation of T-308 and S-473 ( XREF_SUPPLEMENTARY ) .	As with + PDK1+ NeuT, increasing PDK1 levels in the context of reduced PTEN or mutant PIK3CA enhanced activation of AKT as indicated by increased phosphorylation of T-308 and S-473 (XREF_SUPPLEMENTARY).	7	22	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1 levels	pdk1	AKT	AKT	akt	7	8	21	22
PIP3 then recruits Akt and 3-phosphoinositide-dependent kinase 1 ( PDK1 ) to the plasma membrane where PDK1 activates Akt and mTORC2 .	PIP3 then recruits Akt and 3-phosphoinositide-dependent kinase 1 (PDK1) to the plasma membrane where PDK1 activates Akt and mTORC2.	16	20	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	16	17	18	19
Thus , PDK1 activation of PKB is sufficient for pre-T cell differentiation , but PDK1 substrates that interact with PDK1 via its PIF domain are required for optimal pre-T cell growth and proliferative expansion .	Thus, PDK1 activation of PKB is sufficient for pre-T cell differentiation, but PDK1 substrates that interact with PDK1 via its PIF domain are required for optimal pre-T cell growth and proliferative expansion.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	2	3	5	6
This allows the recruitment of PDK1 and AKT into the plasma membrane [ XREF_BIBR ] and subsequent activation of AKT by PDK1 .	This allows the recruitment of PDK1 and AKT into the plasma membrane [XREF_BIBR] and subsequent activation of AKT by PDK1.	17	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	21	22	19	20
Two such PH domain containing kinases , phosphoinositide dependent kinase 1 ( PDK1 ) and the serine threonine kinase Akt , are recruited to the membrane via PIP3 , where PDK1 activates Akt by phosphorylation at the threonine 308 [ XREF_BIBR , XREF_BIBR ] .	Two such PH domain containing kinases, phosphoinositide dependent kinase 1 (PDK1) and the serine threonine kinase Akt, are recruited to the membrane via PIP3, where PDK1 activates Akt by phosphorylation at the threonine 308 [XREF_BIBR, XREF_BIBR].	30	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	30	31	32	33
In addition to its activation at the plasma membrane , Akt can be activated by nuclear pools of PI3K , and PDK1 and DNA-PK .	In addition to its activation at the plasma membrane, Akt can be activated by nuclear pools of PI3K, and PDK1 and DNA-PK.	10	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	21	22	10	11
Mutation of the PIF-pocket abolished activation of S6K and SGK1 isoforms but does not affect PDK1 mediated Akt 308 phosphorylation XREF_BIBR - XREF_BIBR .	Mutation of the PIF-pocket abolished activation of S6K and SGK1 isoforms but does not affect PDK1 mediated Akt 308 phosphorylation XREF_BIBR - XREF_BIBR.	14	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	15	16	17	18
Enzymes such as phosphoinositide dependent kinase ( PDK1 ) and Akt are then recruited to the inner membrane surface by PIP3 , and Akt is subsequently activated by PDK1 as a result of this interaction .	Enzymes such as phosphoinositide dependent kinase (PDK1) and Akt are then recruited to the inner membrane surface by PIP3, and Akt is subsequently activated by PDK1 as a result of this interaction.	23	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	28	29	23	24
PIP3 subsequently activates the 3 '-phosphoinositide dependent kinase-1 ( PDK1 ) ( at the PH domain ) , which in turn phosphorylates and activates Akt , targeting the Pleckstrin homology in the Akt N-terminal region XREF_BIBR .	PIP3 subsequently activates the 3 '-phosphoinositide dependent kinase-1 (PDK1) (at the PH domain), which in turn phosphorylates and activates Akt, targeting the Pleckstrin homology in the Akt N-terminal region XREF_BIBR.	7	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	9	10	24	25
PDK1 ( phosphoinositide dependent kinase 1 ) and the complex mTORC2 activates Akt through threonine 308 and serine 473 phosphophylations , respectively [ XREF_BIBR , XREF_BIBR ] .	PDK1 (phosphoinositide dependent kinase 1) and the complex mTORC2 activates Akt through threonine 308 and serine 473 phosphophylations, respectively [XREF_BIBR, XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	12	13
We explored the importance of PDK1 , the protein kinase that activates PKB and S6K , in mediating tumorigenesis caused by the deletion of PTEN .	We explored the importance of PDK1, the protein kinase that activates PKB and S6K, in mediating tumorigenesis caused by the deletion of PTEN.	3	14	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	5	6	12	13
This modification , in conjunction with AKT phosphorylation on Thr308 by the phosphoinositide dependent kinase-1 ( PDK1 ) triggers full activation of AKT in response to mitogenic stimuli .	This modification, in conjunction with AKT phosphorylation on Thr308 by the phosphoinositide dependent kinase-1 (PDK1) triggers full activation of AKT in response to mitogenic stimuli.	14	24	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	16	17	22	23
AKT is activated by PDK and regulates downstream effectors , such as MDR1 , which regulates drug resistance [ XREF_BIBR , XREF_BIBR ] .	AKT is activated by PDK and regulates downstream effectors, such as MDR1, which regulates drug resistance [XREF_BIBR, XREF_BIBR].	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK	PDK	PDK	AKT	AKT	AKT	4	5	0	1
We also suggest that PDK1 mediated Akt activation at the leading edge is responsible for this effect .	We also suggest that PDK1 mediated Akt activation at the leading edge is responsible for this effect.	4	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	4	5	6	7
Classic AKT activation occurs at the plasma membrane and is mediated by PH-domains present both in AKT and PDK1 , which co-localizes them at PI ( 3,4,5 ) P3 binding sites presumably in close proximity to mTORC2 .	Classic AKT activation occurs at the plasma membrane and is mediated by PH-domains present both in AKT and PDK1, which co-localizes them at PI (3,4,5) P3 binding sites presumably in close proximity to mTORC2.	1	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	18	19	1	2
The resulting 3,4,5-phosphoinositide products act as second messengers to recruit Akt and protein kinase B ( PKB ) to the membrane , where PDK1 and the TORC2 complex activate PKB by phosphorylating threonine residue 308 ( T308 ) or serine residue 473 ( S473 ) , respectively .	The resulting 3,4,5-phosphoinositide products act as second messengers to recruit Akt and protein kinase B (PKB) to the membrane, where PDK1 and the TORC2 complex activate PKB by phosphorylating threonine residue 308 (T308) or serine residue 473 (S473), respectively.	23	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	23	24	29	30
It is not clear whether the nuclear localized PDK1 can activate Akt , and if the mechanism of the activation is similar to that in the cytoplasm .	It is not clear whether the nuclear localized PDK1 can activate Akt, and if the mechanism of the activation is similar to that in the cytoplasm.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	8	9	11	12
PIP 3 recruits phosphoinositide dependent kinase 1 ( PDK1 ) and AKT to the plasma membrane ( XREF_FIG ) , where PDK1 activates AKT by phosphorylating a residue localized in its activation loop ( Thr308 in human AKT1 ) .	PIP 3 recruits phosphoinositide dependent kinase 1 (PDK1) and AKT to the plasma membrane (XREF_FIG), where PDK1 activates AKT by phosphorylating a residue localized in its activation loop (Thr308 in human AKT1).	21	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	21	22	23	24
PKB is also activated via phosphorylation by PDK and , in turn , will activate the anti-apoptotic machinery , glucose metabolism ( glycogen synthesis , glycolysis and glucose uptake ) and protein synthesis .	PKB is also activated via phosphorylation by PDK and, in turn, will activate the anti-apoptotic machinery, glucose metabolism (glycogen synthesis, glycolysis and glucose uptake) and protein synthesis.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK	PDK	PDK	PKB	PKB	PKB	7	8	0	1
The AGC family Ser/Thr kinase protein kinase B ( PKB and Akt )/GSK3beta is a common downstream signaling pathway of both DNA-PKcs and 3-phosphoinositide-dependent kinase 1 ( PDK 1 ) , in which Akt is fully activated through phosphorylation of two key residues , Thr308 by PDK1 [ XREF_BIBR ] and Ser473 by DNA-PKcs [ XREF_BIBR ] in response to DNA damage .	The AGC family Ser/Thr kinase protein kinase B (PKB and Akt)/GSK3beta is a common downstream signaling pathway of both DNA-PKcs and 3-phosphoinositide-dependent kinase 1 (PDK 1), in which Akt is fully activated through phosphorylation of two key residues, Thr308 by PDK1 [XREF_BIBR] and Ser473 by DNA-PKcs [XREF_BIBR] in response to DNA damage.	33	48	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	46	47	33	34
Thus this sialidase possibly reduces the PDK1 mediated Akt and mTOR signaling .	Thus this sialidase possibly reduces the PDK1 mediated Akt and mTOR signaling.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	6	7	8	9
Membrane recruited AKT is activated through phosphorylation by PDK1 and by TOR complex 2 XREF_BIBR - XREF_BIBR .	Membrane recruited AKT is activated through phosphorylation by PDK1 and by TOR complex 2 XREF_BIBR - XREF_BIBR.	2	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	8	9	2	3
PIP3 is known to participate in bone formation via its role in Akt signaling where it is able to recruit PDK1 , which in turn activates Akt .	PIP3 is known to participate in bone formation via its role in Akt signaling where it is able to recruit PDK1, which in turn activates Akt.	19	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	20	21	26	27
PDK1 activates S6K , SGK and PKB isoforms by phosphorylating these kinases at their T-loop .	PDK1 activates S6K, SGK and PKB isoforms by phosphorylating these kinases at their T-loop.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	0	1	6	7
One of the signaling proteins , e.g ., phosphatidylinositol 3-kinase ( PI3-K ) , binds to insulin receptor substrate ( IRS ) and further activates 3-phosphoinositide-dependent protein kinase 1 ( PDK1 ) , which activates Akt , a serine kinase .	One of the signaling proteins, e.g., phosphatidylinositol 3-kinase (PI3-K), binds to insulin receptor substrate (IRS) and further activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase.	24	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	30	31	35	36
Interestingly , although it is well known that PDK1 activates AKT through activation loop phosphorylation , studies using genetic knockouts have revealed differential requirement for PDK1 and AKT in thymocyte survival XREF_BIBR .	Interestingly, although it is well known that PDK1 activates AKT through activation loop phosphorylation, studies using genetic knockouts have revealed differential requirement for PDK1 and AKT in thymocyte survival XREF_BIBR.	8	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	8	9	10	11
PDPK1 activates AKT to promote mTORC1 activation during influenza virus infection .	PDPK1 activates AKT to promote mTORC1 activation during influenza virus infection.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	AKT	AKT	AKT	0	1	2	3
PDK1 can activate AKT through phosphorylation of AKT at Thr308 [ XREF_BIBR ] .	PDK1 can activate AKT through phosphorylation of AKT at Thr308 [XREF_BIBR].	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	3	4
The activation of Akt is facilitated by receptor mediated activation of PI3-kinase which , through the production of PIP 3 , activates Phosphoinositide dependent kinase-1 ( PDK1 ) which in turn activates Akt .	The activation of Akt is facilitated by receptor mediated activation of PI3-kinase which, through the production of PIP 3, activates Phosphoinositide dependent kinase-1 (PDK1) which in turn activates Akt.	24	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	26	27	32	33
Mechanistically , this is dependent on ROS mediated hyper-phosphorylation of PI3K and subsequent downstream PDK1 mediated activation of AKT , culminating in the upregulation of cell cycle promoting genes such as CDK1 and PCNA .	Mechanistically, this is dependent on ROS mediated hyper-phosphorylation of PI3K and subsequent downstream PDK1 mediated activation of AKT, culminating in the upregulation of cell cycle promoting genes such as CDK1 and PCNA.	8	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	14	15	18	19
Using EGF stimulation as a model system for studying AKT activation , we showed that Pfn1 over-expression does not lead to impaired activation of any of the positive regulators of AKT activation including EGFR itself , PI3K or PDK1 .	Using EGF stimulation as a model system for studying AKT activation, we showed that Pfn1 over-expression does not lead to impaired activation of any of the positive regulators of AKT activation including EGFR itself, PI3K or PDK1.	30	39	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	38	39	30	31
SDF-1alpha also induces the phosphorylation of PDK1 at Ser241 ( an upstream activator of Akt ) , GSK3beta at Ser9 ( a downstream substrate of Akt ) , and myosin light chain at Ser19 ( a downstream element of the Akt signaling pathway ) .	SDF-1alpha also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3beta at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway).	0	15	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	PDK1	SDF-1alpha also induces the phosphorylation of PDK1 at Ser241	pdk1	Akt	Akt	akt	6	7	14	15
Sustained activation of Akt inhibits apoptosis in VSMCs , involving in part PDK1 while inhibition of PDK1 by antisense oligonucleotides abolishes Akt activation by p65 in endothelial cells .	Sustained activation of Akt inhibits apoptosis in VSMCs, involving in part PDK1 while inhibition of PDK1 by antisense oligonucleotides abolishes Akt activation by p65 in endothelial cells.	14	22	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	16	17	21	22
PIP3 activates phosphoinositide dependent protein kinase ( PDK ) , which phosphorylates and activates Akt ( also known as protein kinase B ) .	PIP3 activates phosphoinositide dependent protein kinase (PDK), which phosphorylates and activates Akt (also known as protein kinase B).	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK	PDK	PDK	Akt	Akt	Akt	7	8	14	15
PIP3 activates PDK1 that , in turn , activates Akt family members among other kinases .	PIP3 activates PDK1 that, in turn, activates Akt family members among other kinases.	1	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	2	3	9	10
As predicted , knockdown of PDK1 inactivated Akt and S6K , and resulted in remarkable suppression of eIF4B S422 phosphorylation but had little effect on Ser406 phosphorylation ( XREF_SUPPLEMENTARY and Figure XREF_FIG ) .	As predicted, knockdown of PDK1 inactivated Akt and S6K, and resulted in remarkable suppression of eIF4B S422 phosphorylation but had little effect on Ser406 phosphorylation (XREF_SUPPLEMENTARY and Figure XREF_FIG).	3	9	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	5	6	7	8
Initially Akt is partially activated via the IGF-1R and PI3K signaling pathway by PDK1 at T309 , however it is S473 phosphorylation by mTOR and specifically the mTORC2 complex that results in maximal activation .	Initially Akt is partially activated via the IGF-1R and PI3K signaling pathway by PDK1 at T309, however it is S473 phosphorylation by mTOR and specifically the mTORC2 complex that results in maximal activation.	1	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	13	14	1	2
Lipids phosphorylated by activated PI3K also recruit and activate the kinase PDK , which further activates AKT and PKB via .	Lipids phosphorylated by activated PI3K also recruit and activate the kinase PDK, which further activates AKT and PKB via.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK	PDK	PDK	AKT	AKT	AKT	11	12	16	17
Recruitment of PDK1 and AKT to the plasma membrane leads to the interaction of both kinases where PDK1 phosphorylates and partially activates AKT on a T308 residue [ XREF_BIBR , XREF_BIBR ] .	Recruitment of PDK1 and AKT to the plasma membrane leads to the interaction of both kinases where PDK1 phosphorylates and partially activates AKT on a T308 residue [XREF_BIBR, XREF_BIBR].	17	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	17	18	22	23
Phosphoinositide dependent kinase 1 ( PDK1 ) is at the hub of many signalling pathways , activating PKB and PKC isoenzymes , as well as p70 S6 kinase and perhaps PKA .	Phosphoinositide dependent kinase 1 (PDK1) is at the hub of many signalling pathways, activating PKB and PKC isoenzymes, as well as p70 S6 kinase and perhaps PKA.	2	20	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	5	6	17	18
It has been well established that PDK1 activates Akt and mTOR signaling in severe cardiac disease [ XREF_BIBR ] .	It has been well established that PDK1 activates Akt and mTOR signaling in severe cardiac disease [XREF_BIBR].	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	6	7	8	9
This dose likely resulted in potent or sustained activation of insulin signaling and PI3K , which would be expected to lead to S6K1 mediated negative feedback and suppression of further stimulation of 3-phosphoinositide dependent protein kinase-1 ( PDK1 ) , the kinase that targets Akt at Thr 308 .	This dose likely resulted in potent or sustained activation of insulin signaling and PI3K, which would be expected to lead to S6K1 mediated negative feedback and suppression of further stimulation of 3-phosphoinositide dependent protein kinase-1 (PDK1), the kinase that targets Akt at Thr 308.	30	45	targets	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	3-phosphoinositide dependent protein kinase-1	3-phosphoinositide dependent protein kinase-1	3-phosphoinositide dependent protein kinase-1	Akt	Akt	Akt	32	36	44	45
When stimulated , PIP3 recruits AKT to the plasma membrane where AKT is activated via phosphorylation by PDK1 and mTORC2 .	When stimulated, PIP3 recruits AKT to the plasma membrane where AKT is activated via phosphorylation by PDK1 and mTORC2.	4	19	activated	Positive_regulation_syntax_2_verb	Positive_activation	Positive_regulation	PDK1	PDK1	pdk1	AKT	recruits AKT to the plasma membrane	akt	17	18	5	6
This second messenger binds and recruits the 3-phosphoinositide-dependent protein kinase-1 ( PDK1 ) , which thereafter activates AKT and PKB , a serine/threonine kinase involved in regulating many biological processes such as cell survival , growth , and metabolism XREF_BIBR .	This second messenger binds and recruits the 3-phosphoinositide-dependent protein kinase-1 (PDK1), which thereafter activates AKT and PKB, a serine/threonine kinase involved in regulating many biological processes such as cell survival, growth, and metabolism XREF_BIBR.	9	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	11	12	19	20
Here , PDK1 phosphorylates the activation loop ( T308 ) and thereby activates Akt XREF_BIBR .	Here, PDK1 phosphorylates the activation loop (T308) and thereby activates Akt XREF_BIBR.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	2	3	13	14
The protein kinases TANK binding kinase 1 ( TBK1 ) and 3-phosphoinositide-dependent protein kinase-1 ( PDPK1 , also called PDK1 ) directly and coordinately activate AKT and its family members by phosphorylation in many cells , including HCT116 cells .	The protein kinases TANK binding kinase 1 (TBK1) and 3-phosphoinositide-dependent protein kinase-1 (PDPK1, also called PDK1) directly and coordinately activate AKT and its family members by phosphorylation in many cells, including HCT116 cells.	11	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase-1	3-phosphoinositide-dependent protein kinase-1	3-phosphoinositide-dependent protein kinase-1	AKT	AKT	AKT	11	14	25	26
Using automated nuclear translocation analysis , knockdown of Akt activators PDK1 , Rictor , and SIN1 , as well as XPO1 , led to an increase in nuclear localization of FOXO1a ( XREF_FIG , XREF_FIG , and XREF_FIG ) .	Using automated nuclear translocation analysis, knockdown of Akt activators PDK1, Rictor, and SIN1, as well as XPO1, led to an increase in nuclear localization of FOXO1a (XREF_FIG, XREF_FIG, and XREF_FIG).	6	15	activators	Positive_activation_token_1_noun	Positive_activation	Negative_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	10	11	8	9
Loss of PDK1 inhibits Akt and RSK activation .	Loss of PDK1 inhibits Akt and RSK activation.	0	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	Loss of PDK1	pdk1	Akt	Akt	akt	2	3	4	5
While PDK1 has been shown to directly activate p70S6 kinase independently of Akt [ XREF_BIBR ] , our results indicate that the activation of p70S6 kinase is dependent on Akt and mTOR in HC11 cells .	While PDK1 has been shown to directly activate p70S6 kinase independently of Akt [XREF_BIBR], our results indicate that the activation of p70S6 kinase is dependent on Akt and mTOR in HC11 cells.	1	14	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	1	2	12	13
Taken together , these studies demonstrate that AKT independent signaling initiated by PDK1 and mTORC2 downstream of PI3K contributes significantly to cancer progression .	Taken together, these studies demonstrate that AKT independent signaling initiated by PDK1 and mTORC2 downstream of PI3K contributes significantly to cancer progression.	7	17	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	12	13	7	8
They did not induce HPV16 late gene expression to the same extent as the Akt inhibitors GDC-0068 and AZD5363 , suggesting that both PI3K and PDK1 activates Akt in the C33A cells .	They did not induce HPV16 late gene expression to the same extent as the Akt inhibitors GDC-0068 and AZD5363, suggesting that both PI3K and PDK1 activates Akt in the C33A cells.	23	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	25	26	27	28
It has been shown that overexpression of PDK1 is sufficient to activate Akt ; however , for maximal activity , the presence of PIP3 is essential .	It has been shown that overexpression of PDK1 is sufficient to activate Akt; however, for maximal activity, the presence of PIP3 is essential.	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	overexpression of PDK1	pdk1	Akt	Akt	akt	7	8	12	13
PDK1 , which is upstream protein of Akt , was affected in the translocation to the plasma membrane by gingipains , and could not normally activate Akt and transmit the cascade of Akt signaling pathway .	PDK1, which is upstream protein of Akt, was affected in the translocation to the plasma membrane by gingipains, and could not normally activate Akt and transmit the cascade of Akt signaling pathway.	0	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	26	27
These signaling effectors include PDK1 , which activates Akt to promote cell proliferation and survival , and Btk , which activates PLCgamma .	These signaling effectors include PDK1, which activates Akt to promote cell proliferation and survival, and Btk, which activates PLCgamma.	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	4	5	8	9
There , Akt is directly or indirectly activated by PDK1 .	There, Akt is directly or indirectly activated by PDK1.	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	9	10	2	3
PI3K activates 3-phosphoinositide-dependent protein kinase 1 ( PDK1 ) , which activates Akt , a serine kinase .	PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase.	1	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	7	8	12	13
PIP 3 , the product of PI3K , serves as a docking site to recruit signaling proteins with pleckstrin homology domains including Akt and PDKs to the cellular membrane , where Akt is activated by PDK1 and PDK2 58 .	PIP 3, the product of PI3K, serves as a docking site to recruit signaling proteins with pleckstrin homology domains including Akt and PDKs to the cellular membrane, where Akt is activated by PDK1 and PDK2 58.	31	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	35	36	31	32
PKB is activated by both 3-phosphoinositide-dependent protein kinase 1 ( PDK1 ) and mammalian target of rapamycin protein kinase c2 ( mTORc2 ) through phosphorylation on different amino acid of PKB .	PKB is activated by both 3-phosphoinositide-dependent protein kinase 1 (PDK1) and mammalian target of rapamycin protein kinase c2 (mTORc2) through phosphorylation on different amino acid of PKB.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	10	11	0	1
Here , Akt is activated through phosphorylation at T308 by the PDK1 kinase , which is also anchored to the plasma membrane by PI ( 3,4,5 ) P3 , and through phosphorylation at S473 by mTORC2 .	Here, Akt is activated through phosphorylation at T308 by the PDK1 kinase, which is also anchored to the plasma membrane by PI (3,4,5) P3, and through phosphorylation at S473 by mTORC2.	2	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	11	12	2	3
PDK-1 efficiently phosphorylates AKT at Thr 308 , and over-expression of PDK1 is sufficient to partially activate AKT in transfected cells [ XREF_BIBR ] .	PDK-1 efficiently phosphorylates AKT at Thr 308, and over-expression of PDK1 is sufficient to partially activate AKT in transfected cells [XREF_BIBR].	9	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	over-expression of PDK1	pdk1	AKT	AKT	akt	11	12	17	18
PDK1 activates AKT suggesting that PDK1 inhibition might suppress tumor development .	PDK1 activates AKT suggesting that PDK1 inhibition might suppress tumor development.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	2	3
PIP3 binds to Akt and subsequently Akt moves to the cell membrane , where Akt is activated by PDK1 and mTORC2 phosphorylation by Thr308 and Ser473 , respectively [ XREF_BIBR ] .	PIP3 binds to Akt and subsequently Akt moves to the cell membrane, where Akt is activated by PDK1 and mTORC2 phosphorylation by Thr308 and Ser473, respectively [XREF_BIBR].	14	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1 and mTORC2 phosphorylation	pdk1	Akt	Akt	akt	18	19	14	15
Increased PDK1 potentiates AKT signaling in the setting of upstream PI3K pathway activation .	Increased PDK1 potentiates AKT signaling in the setting of upstream PI3K pathway activation.	0	4	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	1	2	3	4
While the activation of AKT by PDK1 has long been thought to be critical to the activation of mTORC-1 , recent evidence has suggested that mTORC1 can be activated in T cells independently of AKT ( and unpublished observation ) .	While the activation of AKT by PDK1 has long been thought to be critical to the activation of mTORC-1, recent evidence has suggested that mTORC1 can be activated in T cells independently of AKT (and unpublished observation).	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	6	7	4	5
Since Akt ( Thr308 ) is a target of PI3K mediated , PDK1 dependent activation of Akt , we determined if TGF-beta also induces phosphorylation of Akt at Thr308 in these cells .	Since Akt (Thr308) is a target of PI3K mediated, PDK1 dependent activation of Akt, we determined if TGF-beta also induces phosphorylation of Akt at Thr308 in these cells.	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	12	13	16	17
Consistent with this , we find combing PDK1 and mTOR inhibitors reduced Akt activation to below basal levels and markedly inhibited proliferation of all of the cell lines tested .	Consistent with this, we find combing PDK1 and mTOR inhibitors reduced Akt activation to below basal levels and markedly inhibited proliferation of all of the cell lines tested.	7	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	7	8	12	13
Through the production of phosphatidylinositol ( 3,4,5 )-trisphosphate ( PIP3 ) , PI3K activates 3-phosphoinositide-dependent protein kinase-1 ( PDK1 ) , which in turn activates Akt .	Through the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), PI3K activates 3-phosphoinositide-dependent protein kinase-1 (PDK1), which in turn activates Akt.	14	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase-1	3-phosphoinositide-dependent protein kinase-1	3-phosphoinositide-dependent protein kinase-1	Akt	Akt	Akt	14	17	25	26
This binding leads to a conformational change and activation of Akt by PDK1 and the mammalian target of rapamycin complex 2 ( mTORC2 ) by phosphorylation on two residues .	This binding leads to a conformational change and activation of Akt by PDK1 and the mammalian target of rapamycin complex 2 (mTORC2) by phosphorylation on two residues.	6	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	12	13	10	11
PDK1 and mTORC2 activate AKT by phosphorylation at two sites : Serine 473 ( S473 ) is phosphorylated by mTORC2 and Threonine 308 ( T308 ) is phosphorylated by PDK1 .	PDK1 and mTORC2 activate AKT by phosphorylation at two sites : Serine 473 (S473) is phosphorylated by mTORC2 and Threonine 308 (T308) is phosphorylated by PDK1.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	4	5
PDK1 activates AKT [ XREF_BIBR ] and SGK , a serum and glucocorticoid induced kinase with a similar structure to AKT .	PDK1 activates AKT [XREF_BIBR] and SGK, a serum and glucocorticoid induced kinase with a similar structure to AKT.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	2	3
In the PI3-K pathway , Akt ( protein Ser/Thr kinase B ) , which plays an important role in cell proliferation and insulin action in cells , is activated by PDK1 [ XREF_BIBR ] .	In the PI3-K pathway, Akt (protein Ser/Thr kinase B), which plays an important role in cell proliferation and insulin action in cells, is activated by PDK1 [XREF_BIBR].	5	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	30	31	5	6
Activation of Akt by PDK1 is measured by quantitating the phosphorylation of Akt specific substrate peptide using the IMAP assay format .	Activation of Akt by PDK1 is measured by quantitating the phosphorylation of Akt specific substrate peptide using the IMAP assay format.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	4	5	2	3
PIP3 , combined with the threonine T308 and serine S473 sites of AKT , transferred T308 and S473 to the cell membrane surface ; thus the AKT activating kinases PDK1 and PDK2 activated AKT , respectively [ XREF_BIBR , XREF_BIBR ] .	PIP3, combined with the threonine T308 and serine S473 sites of AKT, transferred T308 and S473 to the cell membrane surface; thus the AKT activating kinases PDK1 and PDK2 activated AKT, respectively [XREF_BIBR, XREF_BIBR].	25	39	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	29	30	33	34
However , deficiency of PDK1 inhibits IL-7-mediated proliferation of B cell progenitors , which could be due to PDK1 targeting Akt and other signaling molecules , such as PKC 64 .	However, deficiency of PDK1 inhibits IL-7-mediated proliferation of B cell progenitors, which could be due to PDK1 targeting Akt and other signaling molecules, such as PKC 64.	16	24	targeting	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	18	19	20	21
PDK1 is a direct downstream kinase of PI3K and activates the membrane bound Akt protein .	PDK1 is a direct downstream kinase of PI3K and activates the membrane bound Akt protein.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	13	14
PDK1 subsequently activates AKT via phosphorylation at threonine 308 .	PDK1 subsequently activates AKT via phosphorylation at threonine 308.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	3	4
To determine the involvement of phosphoinositide dependent protein kinase 1 ( PDK1 ) in the effects of S1P induced Akt activation , we examined total PDK1 and phosphorylated PDK1 ( pPDK1 ) after treatment with S1P .	To determine the involvement of phosphoinositide dependent protein kinase 1 (PDK1) in the effects of S1P induced Akt activation, we examined total PDK1 and phosphorylated PDK1 (pPDK1) after treatment with S1P.	6	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	11	12	19	20
It is therefore very likely that the PKB and SGK ancestral protein was also activated by PDK1 and TORC2 ancestral proteins .	It is therefore very likely that the PKB and SGK ancestral protein was also activated by PDK1 and TORC2 ancestral proteins.	6	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	16	17	7	8
Although KP-372-1 also has well characterized activity against the PDK1 target Akt in human cells , it is unlikely that this activity accounts for its antifungal activity because the yeast Akt ortholog , Sch9 , is not essential in either S. cerevisiae or C. albicans .	Although KP-372-1 also has well characterized activity against the PDK1 target Akt in human cells, it is unlikely that this activity accounts for its antifungal activity because the yeast Akt ortholog, Sch9, is not essential in either S. cerevisiae or C. albicans.	6	12	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	9	10	11	12
In the PI3K/PDK1/Akt relay , Akt is activated by PDK1 [ XREF_BIBR ] , and PDK1 in turn is activated by PI3K generated 3 phosphorylated phosphoinositides [ XREF_BIBR ] .	In the PI3K/PDK1/Akt relay, Akt is activated by PDK1 [XREF_BIBR], and PDK1 in turn is activated by PI3K generated 3 phosphorylated phosphoinositides [XREF_BIBR].	5	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	9	10	5	6
As an upstream protein of AKT , PDK1 may activate AKT and its downstream kinases .	As an upstream protein of AKT, PDK1 may activate AKT and its downstream kinases.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	7	8	10	11
PDK1 can activate Akt kinase on the activation loop at T308 , promoting full activity of Akt XREF_BIBR .	PDK1 can activate Akt kinase on the activation loop at T308, promoting full activity of Akt XREF_BIBR.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	3	4
Our observation of a decreased insulin stimulated phosphorylation of Akt thr308 in HIV infected lipodystrophic patients compared to control subjects , indicate that the lower glucose uptake in HIV infected patients is caused by defects involving PDK1 activation of Akt .	Our observation of a decreased insulin stimulated phosphorylation of Akt thr308 in HIV infected lipodystrophic patients compared to control subjects, indicate that the lower glucose uptake in HIV infected patients is caused by defects involving PDK1 activation of Akt.	36	40	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	36	37	39	40
PIP3 then recruits AKT to the cell membrane where phosphorylation by mTORC2 and PDK1 activates AKT .	PIP3 then recruits AKT to the cell membrane where phosphorylation by mTORC2 and PDK1 activates AKT.	9	16	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	13	14	15	16
Second , PDK1 activates AKT , which in turn activates mechanistic target of rapamycin ( mTOR ) , which then phosphorylates translation initiation factor 4E binding protein ( 4E-BP ) , releasing its inhibition of the translation initiation factor 4E ( eIF4E ) .	Second, PDK1 activates AKT, which in turn activates mechanistic target of rapamycin (mTOR), which then phosphorylates translation initiation factor 4E binding protein (4E-BP), releasing its inhibition of the translation initiation factor 4E (eIF4E).	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	2	3	4	5
PDK1 silencing in polyamine deficient cells not only prevented the induced Akt activation but also blocked the increased resistance to apoptosis .	PDK1 silencing in polyamine deficient cells not only prevented the induced Akt activation but also blocked the increased resistance to apoptosis.	0	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	11	12
PKB is then activated following phosphorylation by PDK1 at Thr 308 .	PKB is then activated following phosphorylation by PDK1 at Thr 308.	0	9	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	7	8	0	1
To determine how AMIGO2 regulates the PDK1 mediated Akt pathway , we examined the cellular localization of PDK1 in AMIGO2 knockdown ECs .	To determine how AMIGO2 regulates the PDK1 mediated Akt pathway, we examined the cellular localization of PDK1 in AMIGO2 knockdown ECs.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	6	7	8	9
This results in phosphoinositide dependent kinase 1 ( PDPK1 ) mediated activation of the kinase Akt ( protein kinase B ) .	This results in phosphoinositide dependent kinase 1 (PDPK1) mediated activation of the kinase Akt (protein kinase B).	8	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	Akt	Akt	Akt	8	9	15	16
Furthermore , studies using mammalian cells demonstrated that insulin mediated activation of PDK and mTorC2 not only activates Akt , but also stimulates the formation of the PP2A and B56 holoenzyme complex , which in turn dephosphorylates phospho-Akt .	Furthermore, studies using mammalian cells demonstrated that insulin mediated activation of PDK and mTorC2 not only activates Akt, but also stimulates the formation of the PP2A and B56 holoenzyme complex, which in turn dephosphorylates phospho-Akt.	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK	insulin mediated activation of PDK	pdk	Akt	Akt	akt	12	13	18	19
PIP3 brings PDK1 and AKT to the membrane , where PDK1 activates AKT by phosphorylation at residue threonine 308 [ XREF_BIBR , XREF_BIBR ] .	PIP3 brings PDK1 and AKT to the membrane, where PDK1 activates AKT by phosphorylation at residue threonine 308 [XREF_BIBR, XREF_BIBR].	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	10	11	12	13
Activated PDK1 stimulates Akt activity by direct binding and phosphorylation of Threonine 308 in the central catalytic domain XREF_BIBR .	Activated PDK1 stimulates Akt activity by direct binding and phosphorylation of Threonine 308 in the central catalytic domain XREF_BIBR.	0	4	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	1	2	3	4
PDK1 then activates Akt leading to the activation of its downstream targets S6kinase and S6 and the induction of hypertrophy XREF_BIBR , XREF_BIBR .	PDK1 then activates Akt leading to the activation of its downstream targets S6kinase and S6 and the induction of hypertrophy XREF_BIBR, XREF_BIBR.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	3	4
PI3K activates PDK1 , which then activates AKT and mTOR to increase tumor cell proliferation and survival .	PI3K activates PDK1, which then activates AKT and mTOR to increase tumor cell proliferation and survival.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	2	3	7	8
The activity of PI3K by its catalytic p110 subunit is required for the generation of PIP3 , which in turn recruits and phosphorylates PDK to completely activate AKT by phosphorylation XREF_BIBR XREF_BIBR .	The activity of PI3K by its catalytic p110 subunit is required for the generation of PIP3, which in turn recruits and phosphorylates PDK to completely activate AKT by phosphorylation XREF_BIBR XREF_BIBR.	22	28	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PDK	phosphorylates PDK	pdk	AKT	AKT	akt	23	24	27	28
Though it is well established that Akt is activated by PDK1 and mTORC2 upon PI3K dependent recruitment to the cytoplasmic membrane , there is increasing evidence that Akt can also be activated in distinct subcellular compartments .	Though it is well established that Akt is activated by PDK1 and mTORC2 upon PI3K dependent recruitment to the cytoplasmic membrane, there is increasing evidence that Akt can also be activated in distinct subcellular compartments.	6	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	10	11	6	7
Akt is subsequently activated through phosphorylation by intracellular kinases , 3-phosphoinoitide-dependent protein kinase 1 ( PDK1 ) and the rictor-mTORC2 ( mammalian target of rapamycin complex 2 ) , at positions Thr 308 and Ser 473 , respectively ( XREF_FIG ) .	Akt is subsequently activated through phosphorylation by intracellular kinases, 3-phosphoinoitide-dependent protein kinase 1 (PDK1) and the rictor-mTORC2 (mammalian target of rapamycin complex 2), at positions Thr 308 and Ser 473, respectively (XREF_FIG).	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	15	16	0	1
XREF_BIBR , XREF_BIBR In response to various cellular stimulations , PDK1 can activate phosphoinositide-3 kinase ( PI3-K ) and then Akt .	XREF_BIBR, XREF_BIBR In response to various cellular stimulations, PDK1 can activate phosphoinositide-3 kinase (PI3-K) and then Akt.	10	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	10	11	20	21
PDK1 phosphorylates endosome associated SGK3 at Thr 320 , whereas diversion of SGK3 to the plasma membrane , where PDK1 normally activates PKB , interferes with PDK1 phosphorylation of SGK3 .	PDK1 phosphorylates endosome associated SGK3 at Thr 320, whereas diversion of SGK3 to the plasma membrane, where PDK1 normally activates PKB, interferes with PDK1 phosphorylation of SGK3.	19	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	19	20	22	23
They also expose that a PI3K- and Akt independent pathway mediated by PDK1 and mTORC1 controls expression of HIF1 transcriptional complexes in CD8 + T cells .	They also expose that a PI3K- and Akt independent pathway mediated by PDK1 and mTORC1 controls expression of HIF1 transcriptional complexes in CD8 + T cells.	7	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	12	13	7	8
PKN2 was recently shown to be part of a ternary Rho and PDK1 protein complex enhancing Akt activation in a PI3-kinase dependent manner [ XREF_BIBR ] .	PKN2 was recently shown to be part of a ternary Rho and PDK1 protein complex enhancing Akt activation in a PI3-kinase dependent manner [XREF_BIBR].	12	17	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	12	13	16	17
Since these Akt isoforms are similarly activated by PI3K and PDK1 and share some common downstream effectors , it is postulated that the Akt isoforms may be functionally redundant .	Since these Akt isoforms are similarly activated by PI3K and PDK1 and share some common downstream effectors, it is postulated that the Akt isoforms may be functionally redundant.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	10	11	2	3
In mammals , Akt is activated by PDK phosphorylation at Thr 308 and PDK-2 and TORC-2 protein complex at Ser 473 .	In mammals, Akt is activated by PDK phosphorylation at Thr 308 and PDK-2 and TORC-2 protein complex at Ser 473.	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK	PDK phosphorylation at Thr 308	pdk	Akt	Akt	akt	7	8	3	4
Furthermore , the compound can inhibit AKT activation in these cells without affecting the canonical AKT activators PDK1 or mTOR .	Furthermore, the compound can inhibit AKT activation in these cells without affecting the canonical AKT activators PDK1 or mTOR.	12	19	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	17	18	15	16
SGK2 and SGK3 are activated in vitro by PDK1 , albeit more slowly than SGK1 , and their activation is accompanied by the phosphorylation of Thr ( 193 ) and Thr ( 253 ) respectively , the residues equivalent to the Thr in the ' activation loop ' of PKB that is targeted by PDK1 .	SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr (193) and Thr (253) respectively, the residues equivalent to the Thr in the ' activation loop ' of PKB that is targeted by PDK1.	46	55	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	54	55	49	50
The data establish that PI3K- and Akt independent mechanisms mediated by PDK1 control mTORC1 activity in CD8 + T cells .	The data establish that PI3K- and Akt independent mechanisms mediated by PDK1 control mTORC1 activity in CD8 + T cells.	4	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	11	12	6	7
One attractive hypothesis was the involvement of the SGK1 kinase , known to regulate biological activities in a manner similar to Akt , and activated like Akt by PDK1 , the major downstream effector kinase of PI3K XREF_BIBR .	One attractive hypothesis was the involvement of the SGK1 kinase, known to regulate biological activities in a manner similar to Akt, and activated like Akt by PDK1, the major downstream effector kinase of PI3K XREF_BIBR.	24	29	activated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	28	29	26	27
This leads to tyrosine phosphorylation of insulin receptor substrates ( IRS ) by tyrosine kinase , and phosphatidylinositol 3-kinase ( PI3-kinase ) activates 3-phosphoinositide-dependent protein kinase-1 ( PDK ) , which activates Akt .	This leads to tyrosine phosphorylation of insulin receptor substrates (IRS) by tyrosine kinase, and phosphatidylinositol 3-kinase (PI3-kinase) activates 3-phosphoinositide-dependent protein kinase-1 (PDK), which activates Akt.	25	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK	PDK	PDK	Akt	Akt	Akt	27	28	32	33
This indicates that PDK1 promotes proliferation in an Akt independent manner .	This indicates that PDK1 promotes proliferation in an Akt independent manner.	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	3	4	8	9
Consequently , AKT is activated by PDK1 .	Consequently, AKT is activated by PDK1.	2	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	6	7	2	3
Other potential targets downstream from PI3K include PDK1 , a kinase that activates AKT and aPKC and has several specific small molecule inhibitors .	Other potential targets downstream from PI3K include PDK1, a kinase that activates AKT and aPKC and has several specific small molecule inhibitors.	6	15	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	7	8	13	14
It is well known that PDK1 activates Akt , S6K , and serum and glucocorticoid regulated kinase ( SGK ) .	It is well known that PDK1 activates Akt, S6K, and serum and glucocorticoid regulated kinase (SGK).	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	5	6	7	8
PDK1 activates Akt , which in turn phosphorylates and inactivates the tumour suppressor complex comprising TSC1 and 2 ( tuberous sclerosis complex 1/2 ) , resulting in the activation of mTORC1 ( target of rapamycin complex 1 ) by Rheb-GTP .	PDK1 activates Akt, which in turn phosphorylates and inactivates the tumour suppressor complex comprising TSC1 and 2 (tuberous sclerosis complex 1/2), resulting in the activation of mTORC1 (target of rapamycin complex 1) by Rheb-GTP.	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	2	3
TCR-CD28-induced increases in phosphorylation of both Akt S473 , a direct target of mTORC2 , and the T308 residue , which is the most critical determinant of Akt activation by PDK1 , were attenuated in cKO T cells .	TCR-CD28-induced increases in phosphorylation of both Akt S473, a direct target of mTORC2, and the T308 residue, which is the most critical determinant of Akt activation by PDK1, were attenuated in cKO T cells.	27	31	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	30	31	27	28
The PDK1 requirement for transformation of PTEN-null thymocytes could therefore reflect that PDK1 activation of PKB is necessary for nutrient receptor expression , cell growth and proliferation and thymic development of PTEN deleted cells .	The PDK1 requirement for transformation of PTEN-null thymocytes could therefore reflect that PDK1 activation of PKB is necessary for nutrient receptor expression, cell growth and proliferation and thymic development of PTEN deleted cells.	12	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	12	13	15	16
PDK1 activates AKT by phosphorylation of the threonine site ( T308 ) in AKT .	PDK1 activates AKT by phosphorylation of the threonine site (T308) in AKT.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	2	3
After recruitment to the plasma membrane , Akt becomes phosphorylated and activated by PDK1 , and then plays an important role in diverse cellular processes including cell survival , glucose metabolism , and cytokine synthesis [ XREF_BIBR - XREF_BIBR ] .	After recruitment to the plasma membrane, Akt becomes phosphorylated and activated by PDK1, and then plays an important role in diverse cellular processes including cell survival, glucose metabolism, and cytokine synthesis [XREF_BIBR - XREF_BIBR].	7	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	13	14	7	8
Although AKT is partially activated following phosphorylation on the Thr308 residue by PDK1 , for full activation , AKT must be independently phosphorylated on Ser473 by mTOR .	Although AKT is partially activated following phosphorylation on the Thr308 residue by PDK1, for full activation, AKT must be independently phosphorylated on Ser473 by mTOR.	1	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	12	13	1	2
PDK1 is known to activate AKT at threonine 308 , but it can also activate other molecules , such as PKC and SGK [ XREF_BIBR ] .	PDK1 is known to activate AKT at threonine 308, but it can also activate other molecules, such as PKC and SGK [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	5	6
Furthermore , we reported Akt is activated by PDK1 in activated astrocytes [ XREF_BIBR ] .	Furthermore, we reported Akt is activated by PDK1 in activated astrocytes [XREF_BIBR].	4	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	8	9	4	5
PIP3 recruits the AGC kinase family member ' s 3-phosphoinositide-dependent protein kinase 1 ( PDK1 ) and AKT to the plasma membrane , where PDK1 activates AKT by Threonin 308 phosphorylation .	PIP3 recruits the AGC kinase family member 's 3-phosphoinositide-dependent protein kinase 1 (PDK1) and AKT to the plasma membrane, where PDK1 activates AKT by Threonin 308 phosphorylation.	24	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	24	25	26	27
Activated PI3K activates PDK1 , which in turn activates AKT , while PI3K can be inactivated by the PTEN tumor suppressor XREF_BIBR - XREF_BIBR .	Activated PI3K activates PDK1, which in turn activates AKT, while PI3K can be inactivated by the PTEN tumor suppressor XREF_BIBR - XREF_BIBR.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	3	4	9	10
PKB and PDK1 then are recruited to plasma membrane wherein PDK1 activates PKB as well as p70S6K .	PKB and PDK1 then are recruited to plasma membrane wherein PDK1 activates PKB as well as p70S6K.	10	16	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	10	11	12	13
The binding of PIP3 to the PH domain of AKT anchors Akt to the plasma membrane and allows to the plasma membrane and allows its phosphorylation and activation by PDK1 ( Phosphoinositide Dependent Kinase-1 ) XREF_BIBR .	The binding of PIP3 to the PH domain of AKT anchors Akt to the plasma membrane and allows to the plasma membrane and allows its phosphorylation and activation by PDK1 (Phosphoinositide Dependent Kinase-1) XREF_BIBR.	1	31	allows	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	29	30	11	12
This leads to protein kinase Akt activation by PDK1 .	This leads to protein kinase Akt activation by PDK1.	1	9	leads	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	8	9	5	6
In turn , PDK1 activates the proto-oncogenic protein kinase Akt which contains a PtdIns-3 ,4,5-P 3 - responsive PH domain .	In turn, PDK1 activates the proto-oncogenic protein kinase Akt which contains a PtdIns-3,4,5-P 3 - responsive PH domain.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	3	4	9	10
In response to PI3K activation , PDK1 and the mammalian target of rapamycin mTOR , acting in the rapamycin-insensitive TORC2 complex , activate Akt via phosphorylation of two key residues , T308 and S473 .	In response to PI3K activation, PDK1 and the mammalian target of rapamycin mTOR, acting in the rapamycin-insensitive TORC2 complex, activate Akt via phosphorylation of two key residues, T308 and S473.	6	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	6	7	23	24
Classically , Akt is activated by PDK1 , whereas PTEN is a major negative regulator of the Akt pathway XREF_BIBR .	Classically, Akt is activated by PDK1, whereas PTEN is a major negative regulator of the Akt pathway XREF_BIBR.	2	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	6	7	2	3
PDK1 activates AKT and PKC in several cell-types XREF_BIBR , XREF_BIBR .	PDK1 activates AKT and PKC in several cell-types XREF_BIBR, XREF_BIBR.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	2	3
PKB is then activated by PDK dependent phosphorylation at two phosphorylation sites , amino acid residue threonine 308 and serine 473 .	PKB is then activated by PDK dependent phosphorylation at two phosphorylation sites, amino acid residue threonine 308 and serine 473.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK	PDK dependent phosphorylation at two phosphorylation sites, amino acid residue threonine 308 and serine 473	pdk	PKB	PKB	pkb	5	6	0	1
However , PDK1 L155E does not support normal murine embryo development , indicating that PDK1 activation of PKB is not sufficient for all PDK1 functions .	However, PDK1 L155E does not support normal murine embryo development, indicating that PDK1 activation of PKB is not sufficient for all PDK1 functions.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	14	15	17	18
PDPK1 signals in a PI3K-depedent manner activating AKT , S6K ( ribosomal protein S6 kinase ) , and SGK ( serum and glucocorticoid regulated kinase ) but can also activate PKC and p90RSK independent of PI3K and PIP3 mediated activation .	PDPK1 signals in a PI3K-depedent manner activating AKT, S6K (ribosomal protein S6 kinase), and SGK (serum and glucocorticoid regulated kinase) but can also activate PKC and p90RSK independent of PI3K and PIP3 mediated activation.	0	14	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	AKT	AKT	AKT	0	1	7	8
However , most models indicate that AKT activation occurs at the plasma membrane , thus it remains mechanistically enigmatic how AKT activation by mTORC2 , PDK1 , and other AKT regulatory signals are coordinated in time and space .	However, most models indicate that AKT activation occurs at the plasma membrane, thus it remains mechanistically enigmatic how AKT activation by mTORC2, PDK1, and other AKT regulatory signals are coordinated in time and space.	20	26	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	25	26	20	21
PDK then activates both Akt ( protein kinase B ) and protein kinase C ( PKC ) , which influence expression of glucose transporter 4 ( GLUT4 ) [ XREF_BIBR , XREF_BIBR ] .	PDK then activates both Akt (protein kinase B) and protein kinase C (PKC), which influence expression of glucose transporter 4 (GLUT4) [XREF_BIBR, XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK	PDK	PDK	Akt	Akt	Akt	0	1	4	5
AKT activated by PDK1 is able to phosphorylate many protein targets at the membrane such as caspase-9 , tuberin , murine double minute 2 , and mTOR .	AKT activated by PDK1 is able to phosphorylate many protein targets at the membrane such as caspase-9, tuberin, murine double minute 2, and mTOR.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	3	4	0	1
Akt is fully activated after phosphorylation at Thr 308 and Ser 473 by PDK1 ( phosphoinositide dependent protein kinase 1 ) or mTORC2 ( mammalian target of rapamycin complex 2 ) XREF_BIBR .	Akt is fully activated after phosphorylation at Thr 308 and Ser 473 by PDK1 (phosphoinositide dependent protein kinase 1) or mTORC2 (mammalian target of rapamycin complex 2) XREF_BIBR.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	13	14	0	1
PDK1 mediated activation of AKT , the key effector of class I PI3K signaling , results in modulation of distinct signaling cascades regulating cell proliferation ( GSK3 , FOXO ) , survival ( BAD , MDM2 ) and protein synthesis and cell growth ( TSC , RHEB , mTOR ) .	PDK1 mediated activation of AKT, the key effector of class I PI3K signaling, results in modulation of distinct signaling cascades regulating cell proliferation (GSK3, FOXO), survival (BAD, MDM2) and protein synthesis and cell growth (TSC, RHEB, mTOR).	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	4	5
These results suggest that plumbagin activates NAD ( P ) H oxidase , Src , and PI3K , and that the activated PI3K or PDK1 subsequently stimulate Akt and Ras-Raf-MEK1/2-ERK1/2 in 3T3-L1 cells .	These results suggest that plumbagin activates NAD (P) H oxidase, Src, and PI3K, and that the activated PI3K or PDK1 subsequently stimulate Akt and Ras-Raf-MEK1/2-ERK1/2 in 3T3-L1 cells.	22	32	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	24	25	27	28
For example , if PDK1 constitutively activates Akt , thus activating the PI3k pathway , Akt activation occurs independently of PTEN loss or retention , resulting in PTEN independent constitutive activation of the PI3k and Akt pathway .	For example, if PDK1 constitutively activates Akt, thus activating the PI3k pathway, Akt activation occurs independently of PTEN loss or retention, resulting in PTEN independent constitutive activation of the PI3k and Akt pathway.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	4	5	7	8
In vitro experiments identified that beta-amyloid ( Abeta ) , especially oligomer preparations , specifically interrupted the PDK dependent activation of Akt .	In vitro experiments identified that beta-amyloid (Abeta), especially oligomer preparations, specifically interrupted the PDK dependent activation of Akt.	17	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK	PDK	PDK	Akt	Akt	Akt	17	18	21	22
PDK1 is a phosphorylation target of mitochondrial Akt in hypoxia .	PDK1 is a phosphorylation target of mitochondrial Akt in hypoxia.	0	9	is a phosphorylation target	Positive_activation_copula_1	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	7	8
Thereafter , Akt can be activated through phosphorylation by PDPK1 and the kinase PDPK2 .	Thereafter, Akt can be activated through phosphorylation by PDPK1 and the kinase PDPK2.	2	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	Akt	Akt	Akt	9	10	2	3
In the case of Akt , conformational change induced by PIP 3 binding to its PH domain promotes its phosphorylation by PDK1 .	In the case of Akt, conformational change induced by PIP 3 binding to its PH domain promotes its phosphorylation by PDK1.	2	22	promotes	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	21	22	4	5
PKB and SGK are both activated by PDK1 and the TORC2 complex .	PKB and SGK are both activated by PDK1 and the TORC2 complex.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	7	8	0	1
For example , phosphorylation of purified Akt on Thr308 by recombinant active PDK1 increases Akt protein kinase activity by 30-fold ( 1 , 28 , 29 ) , presumably as a result of a major conformational change in the enzyme that allows substrate binding and phosphorylation .	For example, phosphorylation of purified Akt on Thr308 by recombinant active PDK1 increases Akt protein kinase activity by 30-fold (1, 28, 29), presumably as a result of a major conformational change in the enzyme that allows substrate binding and phosphorylation.	8	17	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	12	13	14	15
Bozulic et al have recently shown that PDK1 is responsible for Akt and Thr308 phosphorylation in the DNA damage induced by ionizing radiation , and GSK3 phosphorylation after DNA damage depends on both DNA-PK-mediated and PDK1 mediated activation of Akt [ XREF_BIBR ] .	Bozulic et al have recently shown that PDK1 is responsible for Akt and Thr308 phosphorylation in the DNA damage induced by ionizing radiation, and GSK3 phosphorylation after DNA damage depends on both DNA-PK-mediated and PDK1 mediated activation of Akt [XREF_BIBR].	35	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	35	36	39	40
PDK1 phosphorylates and thereby activates Akt at threonine 308 .	PDK1 phosphorylates and thereby activates Akt at threonine 308.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	5	6
In summary , the work presented here supports the new mechanistic insight that PDK1 localization is regulated by AMIGO2 to activate Akt signaling , which regulates EC adhesion , migration , survival , and angiogenesis .	In summary, the work presented here supports the new mechanistic insight that PDK1 localization is regulated by AMIGO2 to activate Akt signaling, which regulates EC adhesion, migration, survival, and angiogenesis.	13	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	13	14	21	22
AKT is partially activated by PDK1 at threonine 308 ( Thr308 ) .	AKT is partially activated by PDK1 at threonine 308 (Thr308).	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	5	6	0	1
Primarily , PDK1 activates Akt at the front of moving cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Primarily, PDK1 activates Akt at the front of moving cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	2	3	4	5
The recruitment of Akt to the membrane and the activation of Akt through PDK1 allow Akt to be released into cytosol to activate mTOR and other downstream effectors [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The recruitment of Akt to the membrane and the activation of Akt through PDK1 allow Akt to be released into cytosol to activate mTOR and other downstream effectors [XREF_BIBR, XREF_BIBR, XREF_BIBR].	11	18	allow	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	13	14	15	16
This allows for the colocalization of Akt and PDK1 ( phosphoinositide dependent kinase 1 ) at the plasma membrane via their PtdIns ( 3,4,5 ) P 3 -binding PH ( pleckstrin homology ) domains and for efficient activation of Akt by PDK1 via phosphorylation of Akt at Thr 308 [ XREF_BIBR ] .	This allows for the colocalization of Akt and PDK1 (phosphoinositide dependent kinase 1) at the plasma membrane via their PtdIns (3,4,5) P 3 -binding PH (pleckstrin homology) domains and for efficient activation of Akt by PDK1 via phosphorylation of Akt at Thr 308 [XREF_BIBR].	37	43	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	41	42	39	40
PDK1 , in turn , activates AKT by phosphorylation at the Thr308 residue .	PDK1, in turn, activates AKT by phosphorylation at the Thr308 residue.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	0	1	6	7
The activation of PKB by PDK1 occurs in presence of vesicles containing phosphatidylinositol tri-phosphate , and results from the interaction of this second messenger with the PKB PH domains .	The activation of PKB by PDK1 occurs in presence of vesicles containing phosphatidylinositol tri-phosphate, and results from the interaction of this second messenger with the PKB PH domains.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	5	6	3	4
Further work to characterize the orchestration of cytosolic and nuclear activation of Akt by PDK1 is needed to connect or differentiate the two processes .	Further work to characterize the orchestration of cytosolic and nuclear activation of Akt by PDK1 is needed to connect or differentiate the two processes.	3	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	14	15	12	13
Activated PI3K phosphorylates and activates 3-phosphoinositide-dependent protein kinase 1 , which stimulates AKT activation .	Activated PI3K phosphorylates and activates 3-phosphoinositide-dependent protein kinase 1, which stimulates AKT activation.	2	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase 1	phosphorylates and activates 3-phosphoinositide-dependent protein kinase 1	3-phosphoinositide-dependent protein kinase 1	AKT	AKT	akt	5	9	12	13
This event is important for the activation of phosphatidylinositol dependent protein kinase 1 ( PDPK1 ) that eventually stimulates Akt .	This event is important for the activation of phosphatidylinositol dependent protein kinase 1 (PDPK1) that eventually stimulates Akt.	1	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	Akt	Akt	Akt	14	15	19	20
Akt , an important mediator in the intracellular cascade , is subsequently activated by PDK1 and acts on down-stream enzymes to stimulate proliferation and inhibit pro apoptotic signals XREF_BIBR .	Akt, an important mediator in the intracellular cascade, is subsequently activated by PDK1 and acts on down-stream enzymes to stimulate proliferation and inhibit pro apoptotic signals XREF_BIBR.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	14	15	0	1
In normal thymocytes , PDK1 activation of PKB is vital for cell growth and proliferation because PDK1 substrates such as PKB control the essential metabolic responses that allow T cells to meet the energy demands of rapid proliferation .	In normal thymocytes, PDK1 activation of PKB is vital for cell growth and proliferation because PDK1 substrates such as PKB control the essential metabolic responses that allow T cells to meet the energy demands of rapid proliferation.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	4	5	7	8
PDK1 mediated activation of PKB is thus not sufficient to deregulate thymocyte growth .	PDK1 mediated activation of PKB is thus not sufficient to deregulate thymocyte growth.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	0	1	4	5
The activation of PI3K by IPC promotes the phosphorylation of PDK1 , which in turn activates Akt to subsequently recruit a wide range of pro survival downstream targets such a GSK3beta , p70s6k and eNOS 25 .	The activation of PI3K by IPC promotes the phosphorylation of PDK1, which in turn activates Akt to subsequently recruit a wide range of pro survival downstream targets such a GSK3beta, p70s6k and eNOS 25.	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PI3K by IPC promotes the phosphorylation of PDK1	pdk1	Akt	Akt	akt	10	11	16	17
In addition to the kinase domain , PDK1 and PKB contain a pleckstrin homology ( PH ) domain that binds to the second messenger , resulting in the phosphorylation and activation of PKB by PDK1 .	In addition to the kinase domain, PDK1 and PKB contain a pleckstrin homology (PH) domain that binds to the second messenger, resulting in the phosphorylation and activation of PKB by PDK1.	25	35	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	34	35	32	33
Interestingly , Akt inhibits GSKbeta , an initiator of apoptosis whereas PDK1 partially activates Akt via phosphorylation XREF_BIBR .	Interestingly, Akt inhibits GSKbeta, an initiator of apoptosis whereas PDK1 partially activates Akt via phosphorylation XREF_BIBR.	11	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	11	12	14	15
PDK1 further activates Akt kinase , which in turn regulates activation of many substrates involved in cell growth and proliferation , e.g ., mammalian target of rapamycin ( mTOR ) and cyclins , angiogenesis via endothelial nitric oxide synthase ( eNOS ) ,, and apoptosis ( e.g ., FoxO1 , Bcl-2-associated death promoter ( BAD ) or nuclear factor kappaB ( NF-kappaB ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] ) .	PDK1 further activates Akt kinase, which in turn regulates activation of many substrates involved in cell growth and proliferation, e.g., mammalian target of rapamycin (mTOR) and cyclins, angiogenesis via endothelial nitric oxide synthase (eNOS),, and apoptosis (e.g., FoxO1, Bcl-2-associated death promoter (BAD) or nuclear factor kappaB (NF-kappaB) [XREF_BIBR, XREF_BIBR, XREF_BIBR]).	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	3	4
For example , growth factors such as insulin or insulin like growth factor lead to the activation of phosphatidylinositol 3-kinase ( PI3K ) that through the production of phosphatidylinositol -trisphosphate ( PIP3 ) will activate 3-phosphoinositide-dependent protein kinase-1 ( PDK1 ) , which in turn will activate Akt , leading to subsequent mTORC1 activation .	For example, growth factors such as insulin or insulin like growth factor lead to the activation of phosphatidylinositol 3-kinase (PI3K) that through the production of phosphatidylinositol -trisphosphate (PIP3) will activate 3-phosphoinositide-dependent protein kinase-1 (PDK1), which in turn will activate Akt, leading to subsequent mTORC1 activation.	35	48	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase-1	3-phosphoinositide-dependent protein kinase-1	3-phosphoinositide-dependent protein kinase-1	Akt	Akt	Akt	35	38	47	48
IGF-1 stimulates the phosphorylation of Thr24 , Ser256 , Ser319 , Ser322 and Ser325 in embryonic stem ( ES ) cells , but not in PDK1-/- ES cells , providing genetic evidence that PDK1 ( the upstream activator of PKB ) is required for the phosphorylation of FKHR in mammalian cells .	IGF-1 stimulates the phosphorylation of Thr24, Ser256, Ser319, Ser322 and Ser325 in embryonic stem (ES) cells, but not in PDK1-/- ES cells, providing genetic evidence that PDK1 (the upstream activator of PKB) is required for the phosphorylation of FKHR in mammalian cells.	33	42	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	33	34	39	40
PDK1 is an essential activator of the protein kinase Akt .	PDK1 is an essential activator of the protein kinase Akt.	0	10	is an essential activator	Positive_activation_copula_1	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	9	10
Overexpression of miR-375 has been shown to inhibit PDK1 expression , thereby down-regulating the PDK1 and Akt survival pathway .	Overexpression of miR-375 has been shown to inhibit PDK1 expression, thereby down-regulating the PDK1 and Akt survival pathway.	0	18	down-regulating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	Overexpression of miR-375 has been shown to inhibit PDK1 expression	pdk1	Akt	Akt	akt	8	9	16	17
The recruitment of Akt to the membrane and the activation of Akt through PDK1 allow Akt to be released into cytosol to activate mTOR and other downstream effectors .	The recruitment of Akt to the membrane and the activation of Akt through PDK1 allow Akt to be released into cytosol to activate mTOR and other downstream effectors.	11	18	allow	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	13	14	15	16
The detection of phosphorylation at these two sites has been routinely used interchangeably to interpret the activation of AKT by PDK1 .	The detection of phosphorylation at these two sites has been routinely used interchangeably to interpret the activation of AKT by PDK1.	14	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	20	21	18	19
There is accumulating evidence that PDK1 is overexpressed in particular cancer settings and activates cancer cell growth and survival independent of Akt signaling .	There is accumulating evidence that PDK1 is overexpressed in particular cancer settings and activates cancer cell growth and survival independent of Akt signaling.	5	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1 is overexpressed	pdk1	Akt	Akt	akt	5	6	21	22
Thus , the PDK1 mediated Akt A-loop ( T308 ) phosphorylation is not dependent on prior HM ( S473 ) phosphorylation by mTORC2 XREF_BIBR - XREF_BIBR .	Thus, the PDK1 mediated Akt A-loop (T308) phosphorylation is not dependent on prior HM (S473) phosphorylation by mTORC2 XREF_BIBR - XREF_BIBR.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	3	4	5	6
Increased PIP3 levels recruit two distinct serine/threonine kinases , PDK1 and mTORC2 to the membrane , which then activate the pivotal protein kinase Akt via phosphorylations within its catalytic and hydrophobic domains .	Increased PIP3 levels recruit two distinct serine/threonine kinases, PDK1 and mTORC2 to the membrane, which then activate the pivotal protein kinase Akt via phosphorylations within its catalytic and hydrophobic domains.	3	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	recruit two distinct serine/threonine kinases, PDK1 and mTORC2 to the membrane	pdk1	Akt	Akt	akt	9	10	23	24
This notion was further validated in human mammary cell lines where increased PDK1 in multiple settings of upstream activation ( due to ERBB2 or PIK3CA mutation or PTEN RNAi ) enhanced AKT activation and rendered some cell lines less sensitive to both PDK1 and PI3K inhibition .	This notion was further validated in human mammary cell lines where increased PDK1 in multiple settings of upstream activation (due to ERBB2 or PIK3CA mutation or PTEN RNAi) enhanced AKT activation and rendered some cell lines less sensitive to both PDK1 and PI3K inhibition.	11	34	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	12	13	31	32
AKT is activated by PIP3 , PDK1 and PDK2 leading to phosphorylation of a host of other proteins that affect cell proliferation , cell cycle progression and cell survival .	AKT is activated by PIP3, PDK1 and PDK2 leading to phosphorylation of a host of other proteins that affect cell proliferation, cell cycle progression and cell survival.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	6	7	0	1
XREF_BIBR , XREF_BIBR Similarly , overexpression of PDK1 in the human breast epithelial cell line MCF10A potentiates AKT signaling , indeed suggesting that PDK1 does have important AKT dependent activity in breast cancer .	XREF_BIBR, XREF_BIBR Similarly, overexpression of PDK1 in the human breast epithelial cell line MCF10A potentiates AKT signaling, indeed suggesting that PDK1 does have important AKT dependent activity in breast cancer.	5	18	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	overexpression of PDK1	pdk1	AKT	AKT	akt	7	8	17	18
Curcumin reduced phosphorylation of PDK1 and inhibited constitutive activation of Akt .	Curcumin reduced phosphorylation of PDK1 and inhibited constitutive activation of Akt.	0	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	Curcumin reduced phosphorylation of PDK1	pdk1	Akt	Akt	akt	4	5	10	11
Our findings indicate that PDK1 is independently activated in breast cancer and not only as part of the PIK3CA pathway , suggesting that PDK1 plays a specific and distinct role from the canonical PIK3 and Akt pathway and promotes oncogenesis independently of AKT .	Our findings indicate that PDK1 is independently activated in breast cancer and not only as part of the PIK3CA pathway, suggesting that PDK1 plays a specific and distinct role from the canonical PIK3 and Akt pathway and promotes oncogenesis independently of AKT.	23	43	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	23	24	42	43
Upon IRS phosphorylation a subsequent series of activation is initiated through the activation of the regulatory subunit PI3K that activates ( PDK1 ) which in turn causes Akt activation .	Upon IRS phosphorylation a subsequent series of activation is initiated through the activation of the regulatory subunit PI3K that activates (PDK1) which in turn causes Akt activation.	19	28	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	21	22	27	28
XREF_BIBR Consequently , a combination of PDK1 and mTOR inhibitors reduced Akt activation to below basal levels and markedly inhibited proliferation of the different cell lines being tested , including breast cancer cells .	XREF_BIBR Consequently, a combination of PDK1 and mTOR inhibitors reduced Akt activation to below basal levels and markedly inhibited proliferation of the different cell lines being tested, including breast cancer cells.	6	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	6	7	11	12
Regulated by a variety of extracellular signals , growth factors , cytokines and oxidative stress , serine threonine kinase Akt ( also known as protein kinase B ) is activated by PDK and is involved in the regulation of cell survival and apoptosis .	Regulated by a variety of extracellular signals, growth factors, cytokines and oxidative stress, serine threonine kinase Akt (also known as protein kinase B) is activated by PDK and is involved in the regulation of cell survival and apoptosis.	16	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK	PDK	PDK	Akt	Akt	Akt	31	32	19	20
Then lipid kinases are activated , like 3-phosphoinositide-dependent protein kinase 1 ( PDK-1 ) , which activates AKT by phosphorylation [ XREF_BIBR ] .	Then lipid kinases are activated, like 3-phosphoinositide-dependent protein kinase 1 (PDK-1), which activates AKT by phosphorylation [XREF_BIBR].	7	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase 1	3-phosphoinositide-dependent protein kinase 1	3-phosphoinositide-dependent protein kinase 1	AKT	AKT	AKT	7	11	17	18
PIP3 activates various kinases and ion channels , including phosphatidylinositol dependent kinase 1 ( PDK1 ) that , in turn , activates Akt family members among other kinases .	PIP3 activates various kinases and ion channels, including phosphatidylinositol dependent kinase 1 (PDK1) that, in turn, activates Akt family members among other kinases.	11	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	14	15	22	23
PIP3 production results in activation of PDK1 , which , in turn , activates AKT by direct phosphorylation .	PIP3 production results in activation of PDK1, which, in turn, activates AKT by direct phosphorylation.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	6	7	14	15
PIP 3 , the product of PI3K ( phosphatidylinositol 3-kinase ) , is an essential mediator of the activation of AKT by PDK1 ( 3-phosphoinositide-dependent protein kinase-1 ) [ XREF_BIBR ] .	PIP 3, the product of PI3K (phosphatidylinositol 3-kinase), is an essential mediator of the activation of AKT by PDK1 (3-phosphoinositide-dependent protein kinase-1) [XREF_BIBR].	18	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	22	23	20	21
Once it is correctly positioned in the cell membrane , Akt can be activated through the phosphorylation of its kinase domain by PDK1 at Thr 308 .	Once it is correctly positioned in the cell membrane, Akt can be activated through the phosphorylation of its kinase domain by PDK1 at Thr 308.	10	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	22	23	10	11
Collectively , these results support a model by which PDK1 deletion inhibits the activity of the Akt pathway , leading to increased Foxo1 activity and consequently , reduced Nav1.5 expression .	Collectively, these results support a model by which PDK1 deletion inhibits the activity of the Akt pathway, leading to increased Foxo1 activity and consequently, reduced Nav1.5 expression.	9	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	9	10	16	17
Canonical upstream signals leading to mTOR activation include PI3-kinase-induced generation of PIP3 which in turn activates PDK1 which then activates Akt through phosphorylatation at threonine 308 .	Canonical upstream signals leading to mTOR activation include PI3-kinase-induced generation of PIP3 which in turn activates PDK1 which then activates Akt through phosphorylatation at threonine 308.	15	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	16	17	20	21
Moreover , ES cells lacking PDK1 , which failed to activate Akt and RSK , are viable , despite the reported important role of Akt and RSK in regulating survival and proliferation .	Moreover, ES cells lacking PDK1, which failed to activate Akt and RSK, are viable, despite the reported important role of Akt and RSK in regulating survival and proliferation.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	5	6	11	12
PDK1 mediates activation of PKB , p70 S6 kinase and p90 Rsk in vivo , but is not rate limiting for activation of PKA , MSK1 and AMPK .	PDK1 mediates activation of PKB, p70 S6 kinase and p90 Rsk in vivo, but is not rate limiting for activation of PKA, MSK1 and AMPK.	0	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKB	PKB	PKB	0	1	4	5
It is known that the deacetylation by SIRT1 enhances binding of Akt and PDK1 to PIP 3 and promotes Akt activation .	It is known that the deacetylation by SIRT1 enhances binding of Akt and PDK1 to PIP 3 and promotes Akt activation.	5	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	deacetylation by SIRT1 enhances binding of Akt and PDK1	pdk1	Akt	Akt	akt	13	14	19	20
PDK1 can activate both Akt and PKC .	PDK1 can activate both Akt and PKC.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	0	1	4	5
Upstream kinases , such as PI3K , mammalian target of rapamycin complex , and PDK1 modulate Akt signaling .	Upstream kinases, such as PI3K, mammalian target of rapamycin complex, and PDK1 modulate Akt signaling.	1	17	modulate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	14	15	16	17
AKT is activated and phosphorylated through dual Ser/Thr phosphorylation by PDK1 [ XREF_BIBR ] .	AKT is activated and phosphorylated through dual Ser/Thr phosphorylation by PDK1 [XREF_BIBR].	0	12	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	10	11	0	1
It is possible that Rab11 dendritic endosomes are functionally equivalent to the apical endosomes of polarized cells , which could also serve as a platform for recruiting signaling molecules such as phosphoinositide dependent kinase-1 ( PDK1 ) , the kinase that activates Akt and atypical protein kinase C.	It is possible that Rab11 dendritic endosomes are functionally equivalent to the apical endosomes of polarized cells, which could also serve as a platform for recruiting signaling molecules such as phosphoinositide dependent kinase-1 (PDK1), the kinase that activates Akt and atypical protein kinase C.	33	47	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	35	36	42	43
Akt , a major regulator of several cell survival pathways , is activated upon phosphorylation by PDK1 and the plasma membrane localization of Akt is important for the activation [ XREF_BIBR , XREF_BIBR ] .	Akt, a major regulator of several cell survival pathways, is activated upon phosphorylation by PDK1 and the plasma membrane localization of Akt is important for the activation [XREF_BIBR, XREF_BIBR].	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	16	17	0	1
Our results are consistent with previous studies in Drosophila showing that PI3K activates PDK1 , which then activates Akt , and Akt , in turn , inhibits the activity of FOXO and its downstream targets .	Our results are consistent with previous studies in Drosophila showing that PI3K activates PDK1, which then activates Akt, and Akt, in turn, inhibits the activity of FOXO and its downstream targets.	13	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	13	14	18	19
Recently , several studies have investigated the role of PDK1 in tumors and there is evidence that PDK1 can activate other molecules involved in cell survival , senescence , and proliferation independent of its AKT phosphorylating activity [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Recently, several studies have investigated the role of PDK1 in tumors and there is evidence that PDK1 can activate other molecules involved in cell survival, senescence, and proliferation independent of its AKT phosphorylating activity [XREF_BIBR, XREF_BIBR, XREF_BIBR].	17	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	17	18	34	35
Activated growth factor receptor stimulates PI3K to convert phosphotidylinositol 4,5-bisphosphate to phosphotidylinositol 3,4,5-trisphosphate , leading to the recruitment of phosphatidylinositide dependent protein kinase 1 ( PDK1 ) and Akt to the plasma membrane followed by phosphorylation and activation of Akt by PDK1 .	Activated growth factor receptor stimulates PI3K to convert phosphotidylinositol 4,5-bisphosphate to phosphotidylinositol 3,4,5-trisphosphate, leading to the recruitment of phosphatidylinositide dependent protein kinase 1 (PDK1) and Akt to the plasma membrane followed by phosphorylation and activation of Akt by PDK1.	33	42	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	41	42	39	40
Thus , we modelled Akt activation as an OR gate where either PDK1 or mTORC2 can trigger Akt activation and their effects are additive .	Thus, we modelled Akt activation as an OR gate where either PDK1 or mTORC2 can trigger Akt activation and their effects are additive.	11	18	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	12	13	17	18
AKT is activated at first through phosphorylation of Thr 308 present in its kinase domain by activated PDK1 and then by phosporylation of Ser 473 present in its C-terminal domain by PDK2 [ XREF_BIBR , XREF_BIBR ] .	AKT is activated at first through phosphorylation of Thr 308 present in its kinase domain by activated PDK1 and then by phosporylation of Ser 473 present in its C-terminal domain by PDK2 [XREF_BIBR, XREF_BIBR].	0	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	17	18	0	1
Akt is activated by the phosphorylation of 3-phosphoinositide-dependent kinase 1 ( PDK1 ) .	Akt is activated by the phosphorylation of 3-phosphoinositide-dependent kinase 1 (PDK1).	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	phosphorylation of 3-phosphoinositide-dependent kinase 1 (PDK1	pdk1	Akt	Akt	akt	11	12	0	1
The stimulation of PI3K leads to activation of PtdIns P 3 -dependent serine/threonine kinases such as PDK1 ( phosphoinositide dependent kinase 1 ) , which can activate Akt , a key serine/threonine kinase in subsequent downstream signalling .	The stimulation of PI3K leads to activation of PtdIns P 3 -dependent serine/threonine kinases such as PDK1 (phosphoinositide dependent kinase 1), which can activate Akt, a key serine/threonine kinase in subsequent downstream signalling.	13	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	16	17	27	28
Phosphorylation of Thr308 by PDK1 increases Akt kinase activity , but the maximal activity requires phosphorylation of Ser473 by mTORC2 .	Phosphorylation of Thr308 by PDK1 increases Akt kinase activity, but the maximal activity requires phosphorylation of Ser473 by mTORC2.	0	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	Phosphorylation of Thr308 by PDK1	pdk1	Akt	Akt	akt	4	5	6	7
The binding of the PDK1 PH domain to PIP3 leads to the trans-phosphorylation of PDK1 at threonine 513 , which results in destabilization of the autoinhibition conformation and maintenance of the catalytic activity of PDK1 to finally activate Akt .	The binding of the PDK1 PH domain to PIP3 leads to the trans-phosphorylation of PDK1 at threonine 513, which results in destabilization of the autoinhibition conformation and maintenance of the catalytic activity of PDK1 to finally activate Akt.	12	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	trans-phosphorylation of PDK1 at threonine 513	pdk1	Akt	Akt	akt	14	15	38	39
Moreover , hsp90 has been reported to prevent proteasome dependent degradation of PDK1 , which is known to activate Akt .	Moreover, hsp90 has been reported to prevent proteasome dependent degradation of PDK1, which is known to activate Akt.	10	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	12	13	19	20
Mechanistically , mahanine inhibited cell-survival pathway by dephosphorylation of PIP3 dependent kinase 1 ( PDK1 ) thereby deactivation of Akt and downregulation of Bcl-xL .	Mechanistically, mahanine inhibited cell-survival pathway by dephosphorylation of PIP3 dependent kinase 1 (PDK1) thereby deactivation of Akt and downregulation of Bcl-xL.	7	21	deactivation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	PDK1	dephosphorylation of PIP3 dependent kinase 1 (PDK1	pdk1	Akt	Akt	akt	14	15	19	20
At the membrane , upstream activators such as 1 ) PDK1 ( phosphoinositide dependent protein kinase-1 ) activate Akt by phosphorylation of Thr308 in the activation loop of the Akt kinase domain and 2 ) the mammalian target of rapamycin ( mTOR ) complex-2 , which phosphorylates Ser473 in the carboxy-terminal regulatory domain of Akt XREF_BIBR - XREF_BIBR .	At the membrane, upstream activators such as 1) PDK1 (phosphoinositide dependent protein kinase-1) activate Akt by phosphorylation of Thr308 in the activation loop of the Akt kinase domain and 2) the mammalian target of rapamycin (mTOR) complex-2, which phosphorylates Ser473 in the carboxy-terminal regulatory domain of Akt XREF_BIBR - XREF_BIBR.	10	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	10	11	18	19
PI3K signaling is mediated by PDK1 , and PDK1 activates Akt signaling .	PI3K signaling is mediated by PDK1, and PDK1 activates Akt signaling.	8	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	8	9	10	11
PDK1 is constitutively active , thus , AKT and S6K can be activated downstream of PI3K by PDK1 .	PDK1 is constitutively active, thus, AKT and S6K can be activated downstream of PI3K by PDK1.	7	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	17	18	7	8
PIP3 recruits AKT and phosphoinositide depdendent kinase 1 ( PDK1 ) to the plasma membrane , allowing PDK1 to phosphorylate AKT at threonine ( T ) 308 and induce the catalytic activity of AKT .	PIP3 recruits AKT and phosphoinositide depdendent kinase 1 (PDK1) to the plasma membrane, allowing PDK1 to phosphorylate AKT at threonine (T) 308 and induce the catalytic activity of AKT.	1	23	allowing	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	PDK1	recruits AKT and phosphoinositide depdendent kinase 1 (PDK1) to the plasma membrane	pdk1	AKT	PDK1 to phosphorylate AKT at threonine	akt	9	10	20	21
PIP3 enhances the activity of 3-phosphoinositide-dependent protein kinase-l ( PDPK1 ) , further activating AKT .	PIP3 enhances the activity of 3-phosphoinositide-dependent protein kinase-l (PDPK1), further activating AKT.	7	15	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	AKT	AKT	AKT	9	10	14	15
The role of phosphorylation at Ser 3473 by mTOR complex 2 ( mTOR in complex with Rictor ; XREF_FIG ) remains poorly understood , but may precede phosphorylation at Thr 308 and promote recognition and activation of Akt by PDK1 .	The role of phosphorylation at Ser 3473 by mTOR complex 2 (mTOR in complex with Rictor; XREF_FIG) remains poorly understood, but may precede phosphorylation at Thr 308 and promote recognition and activation of Akt by PDK1.	32	40	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	39	40	37	38
Even though Akt is generally regarded as immediate downstream of PI3K pathway , the independent regulation of PI3K and Akt by KRG in this study suggests that KRG may affect the activity of other regulators of Akt activation such as mTOR2C , PDK1 and PP2A , which needs experimental verification in the future .	Even though Akt is generally regarded as immediate downstream of PI3K pathway, the independent regulation of PI3K and Akt by KRG in this study suggests that KRG may affect the activity of other regulators of Akt activation such as mTOR2C, PDK1 and PP2A, which needs experimental verification in the future.	36	43	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	42	43	36	37
This docking causes a conformational change in the AKT molecule such that T308 and S473 become available for phosphorylation by phosphoinositide dependent protein kinase-1 ( PDPK1 ) , which likewise uses a PH domain to target AKT .	This docking causes a conformational change in the AKT molecule such that T308 and S473 become available for phosphorylation by phosphoinositide dependent protein kinase-1 (PDPK1), which likewise uses a PH domain to target AKT.	23	37	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	AKT	AKT	AKT	25	26	36	37
In turn , 3-phosphoinositide-dependent kinase ( PDK1 ) activates AKT and related kinases via the phosphorylation of activation loop residues , including T308 of AKT and analogous sites within the calcium- and diacylglycerol independent atypical protein kinase C isoforms ( aPKCs ) lambda and iota and zeta [ XREF_BIBR ] .	In turn, 3-phosphoinositide-dependent kinase (PDK1) activates AKT and related kinases via the phosphorylation of activation loop residues, including T308 of AKT and analogous sites within the calcium- and diacylglycerol independent atypical protein kinase C isoforms (aPKCs) lambda and iota and zeta [XREF_BIBR].	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	6	7	9	10
Akt isoforms are major downstream effector molecules of PI3K and are activated through phosphorylation by PDK1 at threonine 308 and by mTORC2 at serine 473 .	Akt isoforms are major downstream effector molecules of PI3K and are activated through phosphorylation by PDK1 at threonine 308 and by mTORC2 at serine 473.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	15	16	0	1
Thus , the activation of Akt by PDK1 is dependent on PI-3 kinase activation , which catalyses the production of PIP 3 at the membrane .	Thus, the activation of Akt by PDK1 is dependent on PI-3 kinase activation, which catalyses the production of PIP 3 at the membrane.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	7	8	5	6
IGF-1 induced a similar phosphorylation of CRHSP24 in ES ( embryonic stem ) cells from wild-type mice or mice that express the PDK1 ( 3-phosphoinositide-dependent kinase 1 ) mutant ( PDK1 [ L155E ] ) that activates PKBalpha normally , but can not activate SGK .	IGF-1 induced a similar phosphorylation of CRHSP24 in ES (embryonic stem) cells from wild-type mice or mice that express the PDK1 (3-phosphoinositide-dependent kinase 1) mutant (PDK1 [L155E]) that activates PKBalpha normally, but can not activate SGK.	22	38	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKBalpha	PKBalpha	PKBalpha	22	23	37	38
PDK1 , phosphoinositide dependent kinase 1 , and PDK2 , phosphoinositide dependent kinase 2 , then cooperate to activate Akt1 and protein kinase B ( Akt1 and PKB ) by phosphorylation at two critical residues .	PDK1, phosphoinositide dependent kinase 1, and PDK2, phosphoinositide dependent kinase 2, then cooperate to activate Akt1 and protein kinase B (Akt1 and PKB) by phosphorylation at two critical residues.	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt1	Akt1	Akt1	0	1	19	20
PIP3 production induces the recruitment to the plasma membrane of 3-phosphoinositide-dependent protein kinase-1 ( PDK1 ) , which in turn activates protein kinaseB ( Akt ) through phosphorylation on Thr308 .	PIP3 production induces the recruitment to the plasma membrane of 3-phosphoinositide-dependent protein kinase-1 (PDK1), which in turn activates protein kinaseB (Akt) through phosphorylation on Thr308.	12	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	protein kinaseB	protein kinaseB	protein kinaseB	14	15	21	23
On membrane localization , AKT1 is activated in part through phosphorylation by PDPK1 and elicits several downstream cellular functions .	On membrane localization, AKT1 is activated in part through phosphorylation by PDPK1 and elicits several downstream cellular functions.	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	AKT1	AKT1	AKT1	12	13	4	5
PI3K converts PI ( 4,5 ) P2 , a membrane inositol phospholipid , into PI ( 3,4,5 ) P3 , which recruits 3-phosphoinositide-dependent protein kinase-1 ( PDK1 ) to the plasma membrane , where PDK1 activates protein kinase B ( AKT ) .	PI3K converts PI (4,5) P2, a membrane inositol phospholipid, into PI (3,4,5) P3, which recruits 3-phosphoinositide-dependent protein kinase-1 (PDK1) to the plasma membrane, where PDK1 activates protein kinase B (AKT).	21	39	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase-1	recruits 3-phosphoinositide-dependent protein kinase-1 (PDK1) to the plasma membrane	3-phosphoinositide-dependent protein kinase-1	protein kinase B	protein kinase B	protein kinase b	22	25	36	39
PIP3 activates 3-phosphoinositide-dependent protein kinase 1 ( PDK1 ) , which in turn activates protein kinase B ( PKB , also known as Akt ) and members of the atypical PKC family 20 .	PIP3 activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which in turn activates protein kinase B (PKB, also known as Akt) and members of the atypical PKC family 20.	1	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	protein kinase B	protein kinase B	protein kinase B	7	8	14	17
Based on the activation of TrkB receptor , another PDK1 cascade is to activate protein kinase B ( Akt ) for promoting mTOR to form mTOR complex 1 , which modulates 4E-BP1 and S6K1 activities , thereby resulting in an increase of PKC lambda ( PKClambda ) and PKMzeta .	Based on the activation of TrkB receptor, another PDK1 cascade is to activate protein kinase B (Akt) for promoting mTOR to form mTOR complex 1, which modulates 4E-BP1 and S6K1 activities, thereby resulting in an increase of PKC lambda (PKClambda) and PKMzeta.	9	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	protein kinase B	protein kinase B	protein kinase B	9	10	14	17
PIP3 activates phosphatidylinositol-3-OH kinase/3-phosphoinositide-dependent protein kinase 1 ( PDK1 ) , which activates protein kinase B ( PKB , also known as Akt ) and members of the atypical PKC family .	PIP3 activates phosphatidylinositol-3-OH kinase/3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates protein kinase B (PKB, also known as Akt) and members of the atypical PKC family.	1	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	protein kinase B	protein kinase B	protein kinase B	8	9	13	16
PDK1 mediates the cellular influence of growth factors and insulin by activating both RSK and S6K and is essential for activation of PKB and Akt1 .	PDK1 mediates the cellular influence of growth factors and insulin by activating both RSK and S6K and is essential for activation of PKB and Akt1.	0	25	is essential for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt1	Akt1	Akt1	0	1	24	25
PIP3 activates 3-phosphoinositide-dependent protein kinase 1 ( PDK1 ) , which , in turn , activates protein kinase B ( PKB , also known as Akt ) and members of the atypical PKC family .	PIP3 activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which, in turn, activates protein kinase B (PKB, also known as Akt) and members of the atypical PKC family.	2	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase 1	3-phosphoinositide-dependent protein kinase 1	3-phosphoinositide-dependent protein kinase 1	protein kinase B	protein kinase B	protein kinase B	2	6	16	19
The phosphoinositide dependent kinase PDK1 activates the serum- and glucocorticoid inducible kinase isoforms SGK1 , SGK2 , and SGK3 and protein kinase B , which in turn are known to up-regulate a variety of sodium coupled transporters .	The phosphoinositide dependent kinase PDK1 activates the serum- and glucocorticoid inducible kinase isoforms SGK1, SGK2, and SGK3 and protein kinase B, which in turn are known to up-regulate a variety of sodium coupled transporters.	0	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	protein kinase B	protein kinase B	protein kinase B	4	5	20	23
Once positioned at the cell membrane , Akt1 is activated by PDK1 through the phosphorylation of threonine 308 , which is in the activation loop of Akt XREF_BIBR .	Once positioned at the cell membrane, Akt1 is activated by PDK1 through the phosphorylation of threonine 308, which is in the activation loop of Akt XREF_BIBR.	7	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt1	Akt1	Akt1	11	12	7	8
Furthermore , EGFR-ERBB2 heterodimers lead to activation of the PI3K and AKT1 pathway [ XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) , where AKT1 is activated by PDK1 and PDK2 and , in turn , phosphorylates several target proteins .	Furthermore, EGFR-ERBB2 heterodimers lead to activation of the PI3K and AKT1 pathway [XREF_BIBR, XREF_BIBR] (XREF_FIG), where AKT1 is activated by PDK1 and PDK2 and, in turn, phosphorylates several target proteins.	23	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT1	AKT1	AKT1	27	28	23	24
All three isoforms ( PKBalpha , PKBbeta and PKBgamma ) were phosphorylated at similar rates and activated to similar extents by 3-phosphoinositide-dependent protein kinase-1 ( PDK1 ) .	All three isoforms (PKBalpha, PKBbeta and PKBgamma) were phosphorylated at similar rates and activated to similar extents by 3-phosphoinositide-dependent protein kinase-1 (PDK1).	2	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase-1	3-phosphoinositide-dependent protein kinase-1	3-phosphoinositide-dependent protein kinase-1	PKBalpha	PKBalpha	PKBalpha	21	24	4	5
These results , together with previous observations , indicate that PtdIns ( 3,4,5 ) P3 plays several roles in the PDK1 induced activation of PKBalpha .	These results, together with previous observations, indicate that PtdIns (3,4,5) P3 plays several roles in the PDK1 induced activation of PKBalpha.	17	25	induced	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKBalpha	PKBalpha	PKBalpha	20	21	24	25
Once bound , PDK1 becomes active and is allowed to activate protein kinase B ( Akt ) .	Once bound, PDK1 becomes active and is allowed to activate protein kinase B (Akt).	3	14	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	protein kinase B	protein kinase B	protein kinase B	3	4	11	14
This occurs via PPARbeta and delta dependent up-regulation of integrin linked kinase ( ILK ) and 3-phosphoinositide-dependent kinase-1 ( PDK1 ) , which activate Akt1 via phosphorylation , and through down-regulation of PTEN [ XREF_BIBR ] .	This occurs via PPARbeta and delta dependent up-regulation of integrin linked kinase (ILK) and 3-phosphoinositide-dependent kinase-1 (PDK1), which activate Akt1 via phosphorylation, and through down-regulation of PTEN [XREF_BIBR].	17	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt1	Akt1	Akt1	19	20	24	25
PKBalpha is not Activated by Calyculin A in PDK1 -/- ES Cells .	PKBalpha is not Activated by Calyculin A in PDK1 -/- ES Cells.	0	11	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKBalpha	PKBalpha	PKBalpha	8	9	0	1
Based on the presence of PDK1 protein in caput and cauda sperm , it has been hypothesized that PDK1 induces activation of Akt1 or SGK , in a molecular pathway alternative to PKA ' s , for the acquisition of sperm motility during epididymal maturation .	Based on the presence of PDK1 protein in caput and cauda sperm, it has been hypothesized that PDK1 induces activation of Akt1 or SGK, in a molecular pathway alternative to PKA 's, for the acquisition of sperm motility during epididymal maturation.	18	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt1	Akt1	Akt1	18	19	22	23
Although PDK mediated activation of Akt1 occurs at the plasma membrane , Akt1 is found in the nucleus , and it may shuttle between nucleus and cytoplasm XREF_BIBR ; XREF_BIBR ; XREF_BIBR .	Although PDK mediated activation of Akt1 occurs at the plasma membrane, Akt1 is found in the nucleus, and it may shuttle between nucleus and cytoplasm XREF_BIBR; XREF_BIBR; XREF_BIBR.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK	PDK	PDK	Akt1	Akt1	Akt1	1	2	5	6
Phosphatidylinositol 3,4,5-trisphosphate initiates a cascade of events that lead to the phosphorylation of protein 3-phosphoinositide-dependent protein kinase-1 and -2 ( PDK1/2 ) , which in turn activate protein kinase B ( PKB and Akt ) , a key downstream effector of PI3k [ XREF_BIBR , XREF_BIBR ] .	Phosphatidylinositol 3,4,5-trisphosphate initiates a cascade of events that lead to the phosphorylation of protein 3-phosphoinositide-dependent protein kinase-1 and -2 (PDK1/2), which in turn activate protein kinase B (PKB and Akt), a key downstream effector of PI3k [XREF_BIBR, XREF_BIBR].	11	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase-1	phosphorylation of protein 3-phosphoinositide-dependent protein kinase-1 and -2 (PDK1/2	3-phosphoinositide-dependent protein kinase-1	protein kinase B	protein kinase B	protein kinase b	14	17	27	30
PI3K and Akt , MAPK and Erk , and STAT3 were activated by PDGFRalpha in PTC cells .	PI3K and Akt, MAPK and Erk, and STAT3 were activated by PDGFRalpha in PTC cells.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	Erk	Erk	Erk	13	14	6	7
23 Overexpression of the PDGFRA wild-type gene activates AKT and ERK at levels optimal for tumorigenicity .	23 Overexpression of the PDGFRA wild-type gene activates AKT and ERK at levels optimal for tumorigenicity.	1	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRA	Overexpression of the PDGFRA	pdgfra	ERK	ERK	erk	4	5	10	11
PDGFRalpha signaling was previously shown to modulate the N-cadherin-mediated mesodermal cell migration in chick embryo and was also reported to promote the migration of oligodendrocyte progenitor cells by activating ERK1/2 signaling pathway .	PDGFRalpha signaling was previously shown to modulate the N-cadherin-mediated mesodermal cell migration in chick embryo and was also reported to promote the migration of oligodendrocyte progenitor cells by activating ERK1/2 signaling pathway.	0	31	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	ERK1/2	ERK1/2	ERK1/2	0	1	29	30
PDGF-AA ligation to its receptors causes PDGFRalpha dimerization , which activates the downstream Erk and Akt1 pathways , followed by endocytosis and lysosome mediated degradation of PDGFRalpha , which serve as a negative feedback mechanism XREF_BIBR , XREF_BIBR .	PDGF-AA ligation to its receptors causes PDGFRalpha dimerization, which activates the downstream Erk and Akt1 pathways, followed by endocytosis and lysosome mediated degradation of PDGFRalpha, which serve as a negative feedback mechanism XREF_BIBR, XREF_BIBR.	6	29	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	Erk	Erk	Erk	6	7	13	14
Vemurafenib resistance of melanoma cells harboring a BRAF mutation reflects ERK and AKT activation induced by PDGFRalpha up-regulation , since inhibition of its synthesis by PDGFRalpha specific shRNA causes a reduction of ERK and AKT activation and restores sensitivity to BRAF-I .	Vemurafenib resistance of melanoma cells harboring a BRAF mutation reflects ERK and AKT activation induced by PDGFRalpha up-regulation, since inhibition of its synthesis by PDGFRalpha specific shRNA causes a reduction of ERK and AKT activation and restores sensitivity to BRAF-I.	10	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	ERK	ERK	ERK	16	17	10	11
Stimulation of PDGFRalpha with its ligand , such as PDGF-AA , increases cell proliferation and activation of AKT and MAPK signaling , and neutralizing PDGFRalpha inhibited these signaling effects [ XREF_BIBR ] .	Stimulation of PDGFRalpha with its ligand, such as PDGF-AA, increases cell proliferation and activation of AKT and MAPK signaling, and neutralizing PDGFRalpha inhibited these signaling effects [XREF_BIBR].	0	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	MAPK	MAPK	MAPK	2	3	19	20
Additionally , overexpression of PDGFRalpha activates MAPK and AKT signaling pathways in cultured tumor cells obtained from a patient with pulmonary artery sarcoma .	Additionally, overexpression of PDGFRalpha activates MAPK and AKT signaling pathways in cultured tumor cells obtained from a patient with pulmonary artery sarcoma.	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRalpha	overexpression of PDGFRalpha	pdgfralpha	MAPK	MAPK	mapk	4	5	6	7
Our results showed that the knockdown of PDGFRalpha inhibited the activity of p-Erk1/2 .	Our results showed that the knockdown of PDGFRalpha inhibited the activity of p-Erk1/2.	5	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	p-Erk1/2	p-Erk1/2	p-Erk1/2	7	8	12	13
Several studies have shown that PDGFRalpha gene amplification is frequently observed and overexpression of PDGFRalpha activates the MAPK and AKT signaling pathways in pulmonary artery sarcoma .	Several studies have shown that PDGFRalpha gene amplification is frequently observed and overexpression of PDGFRalpha activates the MAPK and AKT signaling pathways in pulmonary artery sarcoma.	12	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRalpha	overexpression of PDGFRalpha	pdgfralpha	MAPK	MAPK	mapk	14	15	17	18
More importantly , NT21MP down-regulated AKT and ERK1/2 activity , which were activated by PDGFRalpha , and eventually reversed the EMT .	More importantly, NT21MP down-regulated AKT and ERK1/2 activity, which were activated by PDGFRalpha, and eventually reversed the EMT.	7	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	ERK1/2	ERK1/2	ERK1/2	14	15	7	8
These results suggest that ponatinib reduces the viability of merlin deficient HSC by inhibiting PDGFRalpha and beta dependent activation of MEK and ERK and STAT3 pathways , leading to decreased cyclin D1 expression .	These results suggest that ponatinib reduces the viability of merlin deficient HSC by inhibiting PDGFRalpha and beta dependent activation of MEK and ERK and STAT3 pathways, leading to decreased cyclin D1 expression.	14	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	ERK	ERK	ERK	14	15	22	23
XREF_BIBR previously outline that phospho-PDGFRalpha activates the Akt and ERK pathways with both pathways contributing to the invasive potential of thyroid cancer cell lines .	XREF_BIBR previously outline that phospho-PDGFRalpha activates the Akt and ERK pathways with both pathways contributing to the invasive potential of thyroid cancer cell lines.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	phospho-PDGFRalpha	phospho-PDGFRalpha	phospho-PDGFRalpha	ERK	ERK	ERK	4	5	9	10
Early studies on the downstream signaling of FIP1L1 and PDGFRalpha showed that , unlike other activated tyrosine kinases , FIP1L1 and PDGFRalpha does not appear to induce ERK1/2 activation .	Early studies on the downstream signaling of FIP1L1 and PDGFRalpha showed that, unlike other activated tyrosine kinases, FIP1L1 and PDGFRalpha does not appear to induce ERK1/2 activation.	19	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	ERK1/2	ERK1/2	ERK1/2	21	22	27	28
Since upstream regulators of RAS and MAPK activation including EGFR , PDGFRA , and HRAS were down-regulated following differentiation ( XREF_FIG ) , we explored the regulatory relationship between KLF4 and the expression of these potential target genes .	Since upstream regulators of RAS and MAPK activation including EGFR, PDGFRA, and HRAS were down-regulated following differentiation (XREF_FIG), we explored the regulatory relationship between KLF4 and the expression of these potential target genes.	4	12	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	PDGFRA	PDGFRA	PDGFRA	MAPK	MAPK	MAPK	11	12	6	7
Nilotinib inhibition of PDGFRalpha in serum decreases activation of AKT and ERK1/2 signaling .	Nilotinib inhibition of PDGFRalpha in serum decreases activation of AKT and ERK1/2 signaling.	1	12	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	ERK1/2	ERK1/2	ERK1/2	3	4	11	12
The distinction between PDGFR-A and PDGFR-B signaling is increasing with the discovery that PDGFR-A , not PDGFR-B , is localized to and activated in a specialized structure on the cell membrane , the primary cilium , where PDGFR-A can activate MAPK and Akt signaling .	The distinction between PDGFR-A and PDGFR-B signaling is increasing with the discovery that PDGFR-A, not PDGFR-B, is localized to and activated in a specialized structure on the cell membrane, the primary cilium, where PDGFR-A can activate MAPK and Akt signaling.	37	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFR-A	PDGFR-A	PDGFR-A	MAPK	MAPK	MAPK	37	38	40	41
Notably , combined knockdown of RSK2 and PDGFRalpha or S6K1 and PDGFRalpha is not sufficient to abrogate the feedback ERK reactivation mechanism ( XREF_SUPPLEMENTARY ) .	Notably, combined knockdown of RSK2 and PDGFRalpha or S6K1 and PDGFRalpha is not sufficient to abrogate the feedback ERK reactivation mechanism (XREF_SUPPLEMENTARY).	3	21	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	ERK	ERK	ERK	7	8	19	20
WNT5A mediates the protein kinase C pathway to promote invasion and metastasis XREF_BIBR , while the PDGFRA gene ( which encodes platelet derived growth factor receptor alpha ) upregulates the ERK signaling pathway in basal cell carcinoma XREF_BIBR .	WNT5A mediates the protein kinase C pathway to promote invasion and metastasis XREF_BIBR, while the PDGFRA gene (which encodes platelet derived growth factor receptor alpha) upregulates the ERK signaling pathway in basal cell carcinoma XREF_BIBR.	16	32	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRA	PDGFRA	PDGFRA	ERK	ERK	ERK	16	17	30	31
In line with these findings we also show that mainly thrombin but also factor Xa , can induce EMT by RPE via PDGF-B mediated PDGF-Rbeta signaling .	In line with these findings we also show that mainly thrombin but also factor Xa, can induce EMT by RPE via PDGF-B mediated PDGF-Rbeta signaling.	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGF-Rbeta	PDGF-Rbeta	PDGF-Rbeta	22	23	24	25
Moreover , recent studies have shown that pericyte loss caused by faulty PDGF-B signal transduction from endothelium to PDGFRbeta in pericytes leads to BBB breakdown , CBF reductions and hypoxia which in turn initiates age dependent secondary neuronal and synaptic changes associated with neuronal and synaptic dysfunction [ XREF_BIBR ] .	Moreover, recent studies have shown that pericyte loss caused by faulty PDGF-B signal transduction from endothelium to PDGFRbeta in pericytes leads to BBB breakdown, CBF reductions and hypoxia which in turn initiates age dependent secondary neuronal and synaptic changes associated with neuronal and synaptic dysfunction [XREF_BIBR].	9	20	caused	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGFRbeta	PDGFRbeta	PDGFRbeta	12	13	18	19
As PDGF-B activates both PDGFRA and PDGFRB , the latter of which is present in the vasculature , this model may be particularly sensitive to angiogenesis inhibition .	As PDGF-B activates both PDGFRA and PDGFRB, the latter of which is present in the vasculature, this model may be particularly sensitive to angiogenesis inhibition.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGFRB	PDGFRB	PDGFRB	1	2	6	7
PDGFRbeta , which is frequently activated in bone-metastatic PCa patients , is activated both by PDGF-B and PDGF-D .	PDGFRbeta, which is frequently activated in bone-metastatic PCa patients, is activated both by PDGF-B and PDGF-D.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGFRbeta	PDGFRbeta	PDGFRbeta	15	16	0	1
As the most potent growth factor of SMCs , PDGF-B induces the synthesis and secretion of PDGFR-beta and SMC progenitor cells , causing intimal thickening .	As the most potent growth factor of SMCs, PDGF-B induces the synthesis and secretion of PDGFR-beta and SMC progenitor cells, causing intimal thickening.	9	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGFR-beta	PDGFR-beta	PDGFR-beta	9	10	16	17
PDGFR-beta is activated by PDGF-B or PDGF-D .	PDGFR-beta is activated by PDGF-B or PDGF-D.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGFR-beta	PDGFR-beta	PDGFR-beta	4	5	0	1
p53 is not required for Arf dependent blockade of PDGF-B driven proliferation and repression of Pdgfrbeta protein as ectopic expression of Arf is still able to inhibit the 2-fold increase in the S-phase fraction of cells upon treatment with PDGF-B .	p53 is not required for Arf dependent blockade of PDGF-B driven proliferation and repression of Pdgfrbeta protein as ectopic expression of Arf is still able to inhibit the 2-fold increase in the S-phase fraction of cells upon treatment with PDGF-B.	7	17	driven	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PDGF-B	PDGF-B	PDGF-B	Pdgfrbeta protein	Pdgfrbeta protein	Pdgfrbeta protein	9	10	15	17
Previous studies have proposed several mechanisms through which PDGF-B induces PDGFRbeta activation in pericytes , including PDGF ligand diversity and availability as well as interplay with membrane proteins or co-receptors .	Previous studies have proposed several mechanisms through which PDGF-B induces PDGFRbeta activation in pericytes, including PDGF ligand diversity and availability as well as interplay with membrane proteins or co-receptors.	8	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGFRbeta	PDGFRbeta	PDGFRbeta	8	9	10	11
PDGF-B is secreted from ECs and promotes the proliferation and migration of PDGFRbeta positive mural cell precursors to the vessel wall .	PDGF-B is secreted from ECs and promotes the proliferation and migration of PDGFRbeta positive mural cell precursors to the vessel wall.	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGFRbeta	PDGFRbeta	PDGFRbeta	0	1	12	13
We identified 19 genes involved in TGFBR signaling ( including TGFB2 , TGFB3 , TGFBR1 and TGFBR2 ) and 50 genes involved in PDGFRB signaling ( including PDGFRB and PDGFB ) that comprised the core enrichment groups for these pathways in improvers based on GSEA results ( Additional file 8 ) .	We identified 19 genes involved in TGFBR signaling (including TGFB2, TGFB3, TGFBR1 and TGFBR2) and 50 genes involved in PDGFRB signaling (including PDGFRB and PDGFB) that comprised the core enrichment groups for these pathways in improvers based on GSEA results (Additional file 8).	23	30	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	PDGFB	PDGFB	PDGFB	PDGFRB	PDGFRB	PDGFRB	29	30	23	24
Additionally , we demonstrated that stimulation with VEGFA induced PDGFRbeta tyrosine phosphorylation in meningiomas similar to PDGFB stimulated PDGFRbeta .	Additionally, we demonstrated that stimulation with VEGFA induced PDGFRbeta tyrosine phosphorylation in meningiomas similar to PDGFB stimulated PDGFRbeta.	14	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDGFB	PDGFB	PDGFB	PDGFRbeta	PDGFRbeta	PDGFRbeta	16	17	18	19
PDGF-Rbeta signaling , initiated by the secretion of PDGF-B ligand by endothelial cells , is paramount for the recruitment of PDGF-Rbeta positive vascular smooth muscle cells and pericytes during angiogenesis [ XREF_BIBR , XREF_BIBR ] .	PDGF-Rbeta signaling, initiated by the secretion of PDGF-B ligand by endothelial cells, is paramount for the recruitment of PDGF-Rbeta positive vascular smooth muscle cells and pericytes during angiogenesis [XREF_BIBR, XREF_BIBR].	0	9	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGF-Rbeta	PDGF-Rbeta	PDGF-Rbeta	8	9	0	1
PDGFA expression in the epiblast controls N-cadherin expression and activates PDGFRalpha , which is required for migration of mesodermal cells away from the primitive streak .	PDGFA expression in the epiblast controls N-cadherin expression and activates PDGFRalpha, which is required for migration of mesodermal cells away from the primitive streak.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFA	PDGFA expression	pdgfa	PDGFRalpha	PDGFRalpha	pdgfralpha	0	1	10	11
However , SHP-2 C459S mutant retained its ability to associate with PDGFRalpha induced by PDGF-A ( XREF_FIG ) .	However, SHP-2 C459S mutant retained its ability to associate with PDGFRalpha induced by PDGF-A (XREF_FIG).	9	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDGF-A	PDGF-A	PDGF-A	PDGFRalpha	PDGFRalpha	PDGFRalpha	14	15	11	12
Exogenous PDGF-A infusion into the adult SVZ induces PDGFRalpha positive neural progenitor cells to generate glioma like lesions in the mouse brain XREF_BIBR .	Exogenous PDGF-A infusion into the adult SVZ induces PDGFRalpha positive neural progenitor cells to generate glioma like lesions in the mouse brain XREF_BIBR.	1	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-A	PDGF-A	PDGF-A	PDGFRalpha	PDGFRalpha	PDGFRalpha	1	2	8	9
Overexpression of PDGFB generates BB dimers that activate both PDGFRalpha and beta while overexpression of PDGFA only activates PDGFRalpha .	Overexpression of PDGFB generates BB dimers that activate both PDGFRalpha and beta while overexpression of PDGFA only activates PDGFRalpha.	13	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFA	overexpression of PDGFA	pdgfa	PDGFRalpha	PDGFRalpha	pdgfralpha	15	16	18	19
PDGF also has a dedifferentiating effect on mouse astrocytes , and infusion of PDGF-A into the lateral ventricle of adult mouse brain can induce the proliferation of PDGFR-alpha -- positive NSCs that may form glioma like lesions .	PDGF also has a dedifferentiating effect on mouse astrocytes, and infusion of PDGF-A into the lateral ventricle of adult mouse brain can induce the proliferation of PDGFR-alpha -- positive NSCs that may form glioma like lesions.	11	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-A	PDGF-A	PDGF-A	PDGFR-alpha	PDGFR-alpha	PDGFR-alpha	13	14	27	28
PDGF-A treatment further enhanced PDGF-Ralpha protein , associated with increased levels of AKT , suggesting a feed-forward mechanism where increased endosomal internalization leads to PDGF-Ralpha recycling in lung myofibroblasts with subsequent increase in receptor expression ( Wang etal , 2004 ; Heldin , 2013 ) ( Fig XREF_FIG D and I ) .	PDGF-A treatment further enhanced PDGF-Ralpha protein, associated with increased levels of AKT, suggesting a feed-forward mechanism where increased endosomal internalization leads to PDGF-Ralpha recycling in lung myofibroblasts with subsequent increase in receptor expression (Wang etal, 2004; Heldin, 2013) (Fig XREF_FIG D and I).	0	6	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-A	PDGF-A	PDGF-A	PDGF-Ralpha protein	PDGF-Ralpha protein	PDGF-Ralpha protein	0	1	4	6
Further analyses revealed that PDGF-A , but not PDGF-B , is required for proliferation , migration and normal differentiation of PDGFRalpha positive OPCs XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , and that over-production of PDGF-A in the CNS neurons or astrocytes induces hyper-proliferation of the PDGFRalpha positive O-2A progenitor cells in a paracrine manner XREF_BIBR , XREF_BIBR .	Further analyses revealed that PDGF-A, but not PDGF-B, is required for proliferation, migration and normal differentiation of PDGFRalpha positive OPCs XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, and that over-production of PDGF-A in the CNS neurons or astrocytes induces hyper-proliferation of the PDGFRalpha positive O-2A progenitor cells in a paracrine manner XREF_BIBR, XREF_BIBR.	33	50	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-A	PDGF-A	PDGF-A	PDGFRalpha	PDGFRalpha	PDGFRalpha	35	36	46	47
It is known that ectopic CNS expression of PDGF-A in mice elicits a dose dependent proliferation of PDGFRalpha positive oligodendrocyte precursor cells ( OPCs ) XREF_BIBR - XREF_BIBR .	It is known that ectopic CNS expression of PDGF-A in mice elicits a dose dependent proliferation of PDGFRalpha positive oligodendrocyte precursor cells (OPCs) XREF_BIBR - XREF_BIBR.	6	27	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-A	expression of PDGF-A	pdgf-a	PDGFRalpha	PDGFRalpha	pdgfralpha	8	9	17	18
Taken together , this suggests that developmental expression of PDGF-A activates PDGFRalpha in myofibroblasts precursors , which induce alpha-Sma expression and cytoskeleton remodeling .	Taken together, this suggests that developmental expression of PDGF-A activates PDGFRalpha in myofibroblasts precursors, which induce alpha-Sma expression and cytoskeleton remodeling.	7	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-A	expression of PDGF-A	pdgf-a	PDGFRalpha	PDGFRalpha	pdgfralpha	9	10	11	12
The residual PDGF-A-induced p-Akt S473 , p-Y of Dyn2 and Dyn2 association to activated PDGFRalpha in these mouse astrocytes were due to PDGF-A stimulation of endogenous PDGFRalpha in the astrocytes since these cells are not PDGFRalpha deficient .	The residual PDGF-A-induced p-Akt S473, p-Y of Dyn2 and Dyn2 association to activated PDGFRalpha in these mouse astrocytes were due to PDGF-A stimulation of endogenous PDGFRalpha in the astrocytes since these cells are not PDGFRalpha deficient.	22	29	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDGF-A	PDGF-A	PDGF-A	PDGFRalpha	PDGFRalpha	PDGFRalpha	22	23	26	27
In order to determine which signaling pathway ( s ) downstream of PDGFRalpha are necessary for its oncogenic capacity , we chose PDGF-A instead of PDGF-B since PDGF-A only stimulates PDGFRalpha but not PDGFRbeta .	In order to determine which signaling pathway (s) downstream of PDGFRalpha are necessary for its oncogenic capacity, we chose PDGF-A instead of PDGF-B since PDGF-A only stimulates PDGFRalpha but not PDGFRbeta.	27	33	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-A	PDGF-A	PDGF-A	PDGFRalpha	PDGFRalpha	PDGFRalpha	27	28	30	31
We previously reported that in LN444 and PDGFA and LN18 and PDGFA cells , autocrine PDGFA activates endogenous PDGFRalpha signaling and enhanced glioma cell tumorigenesis in mouse orthotopic xenografts .	We previously reported that in LN444 and PDGFA and LN18 and PDGFA cells, autocrine PDGFA activates endogenous PDGFRalpha signaling and enhanced glioma cell tumorigenesis in mouse orthotopic xenografts.	14	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFA	PDGFA	PDGFA	PDGFRalpha	PDGFRalpha	PDGFRalpha	15	16	18	19
PDGF-A and PDGF-C selectively activate PDGFR-alpha , whereas PDGF-B activates both PDGFR-alpha and PDGFR-beta .	PDGF-A and PDGF-C selectively activate PDGFR-alpha, whereas PDGF-B activates both PDGFR-alpha and PDGFR-beta.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-A	PDGF-A	PDGF-A	PDGFR-alpha	PDGFR-alpha	PDGFR-alpha	0	1	5	6
In fact , association of PDGFRalpha to alphavbeta3 integrin activates the Src kinase Lyn and triggers proliferation on fibronectin support .	In fact, association of PDGFRalpha to alphavbeta3 integrin activates the Src kinase Lyn and triggers proliferation on fibronectin support.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	Src	Src	Src	5	6	11	12
Twist1 was found to directly induce expression of PDGFRalpha , which then activates Src kinase to promote invadopodia formation 24 .	Twist1 was found to directly induce expression of PDGFRalpha, which then activates Src kinase to promote invadopodia formation 24.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRalpha	Twist1 was found to directly induce expression of PDGFRalpha	pdgfralpha	Src	Src	src	8	9	13	14
We assessed levels of phospho and total Src and PTEN in PASMCs treated with siRNA to PDGFRalpha , beta and alphabeta .	We assessed levels of phospho and total Src and PTEN in PASMCs treated with siRNA to PDGFRalpha, beta and alphabeta.	2	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	Src	Src	Src	16	17	7	8
Furthermore , a dominant negative SHP-2 C459S mutant inhibited PDGF-A-stimulated glioma cell migration , phosphorylation of Dyn2 and concomitantly blocked PDGFRalpha induced Src activation .	Furthermore, a dominant negative SHP-2 C459S mutant inhibited PDGF-A-stimulated glioma cell migration, phosphorylation of Dyn2 and concomitantly blocked PDGFRalpha induced Src activation.	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	Src	Src	Src	20	21	22	23
PDGFRalpha mediated Src activation appears to be dispensable for mitogenic responses in some cell types XREF_BIBR , XREF_BIBR ( XREF_FIG ) .	PDGFRalpha mediated Src activation appears to be dispensable for mitogenic responses in some cell types XREF_BIBR, XREF_BIBR (XREF_FIG).	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	Src	Src	Src	0	1	2	3
These data suggested that increased bFGF upregulates the expression of PDGFRbeta and may enhance PDGFRbeta mediated pericyte functions after brain ischemia .	These data suggested that increased bFGF upregulates the expression of PDGFRbeta and may enhance PDGFRbeta mediated pericyte functions after brain ischemia.	5	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRbeta	bFGF upregulates the expression of PDGFRbeta	pdgfrbeta	PDGFRbeta	PDGFRbeta	pdgfrbeta	10	11	14	15
Using site directed mutagenesis , we show that Abl dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity , in vitro , but serves to downregulate PDGFR mediated chemotaxis .	Using site directed mutagenesis, we show that Abl dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR mediated chemotaxis.	8	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFR-beta	Abl dependent phosphorylation of PDGFR-beta	pdgfr-beta	PDGFR-beta	PDGFR-beta	pdgfr-beta	12	13	14	15
We and others observe that Pdgfrbeta expression increases in WT mice after acute liver injury by CCl 4 , implicating PDGFRbeta in HSC activation .	We and others observe that Pdgfrbeta expression increases in WT mice after acute liver injury by CCl 4, implicating PDGFRbeta in HSC activation.	5	21	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pdgfrbeta	Pdgfrbeta expression	pdgfrbeta	PDGFRbeta	PDGFRbeta	pdgfrbeta	5	6	20	21
This is most likely caused by the increased expression and activation of PDGFRbeta in smLRP1-/- mice and an accompanying increase in PI3K association with PDGFRbeta .	This is most likely caused by the increased expression and activation of PDGFRbeta in smLRP1-/- mice and an accompanying increase in PI3K association with PDGFRbeta.	4	25	caused	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	PDGFRbeta	expression and activation of PDGFRbeta	pdgfrbeta	PDGFRbeta	PDGFRbeta	pdgfrbeta	12	13	24	25
The discovery that ARF represses Pdgfrbeta transcription via p53 XREF_BIBR and blocks Pdgfrbeta protein synthesis via miR-34a XREF_BIBR helps resolve this puzzle by showing that ARF regulates Pdgfrbeta through complementary p53 dependent and p53 independent mechanisms ( XREF_FIG ) .	The discovery that ARF represses Pdgfrbeta transcription via p53 XREF_BIBR and blocks Pdgfrbeta protein synthesis via miR-34a XREF_BIBR helps resolve this puzzle by showing that ARF regulates Pdgfrbeta through complementary p53 dependent and p53 independent mechanisms (XREF_FIG).	3	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pdgfrbeta	ARF represses Pdgfrbeta transcription	pdgfrbeta	Pdgfrbeta protein	Pdgfrbeta protein	pdgfrbeta protein	5	6	12	14
Thus , although constitutive activation of PDK1 is sufficient to activate PKCdelta in our system , it may be via an indirect rather than a direct process .	Thus, although constitutive activation of PDK1 is sufficient to activate PKCdelta in our system, it may be via an indirect rather than a direct process.	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKCdelta	PKCdelta	PKCdelta	6	7	11	12
We demonstrate herein that activated PDK1 can up-regulate PKCdelta activity and stabilize the protein , and that PDK1 associates with PKCdelta and with AKT .	We demonstrate herein that activated PDK1 can up-regulate PKCdelta activity and stabilize the protein, and that PDK1 associates with PKCdelta and with AKT.	4	11	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKCdelta	PKCdelta	PKCdelta	5	6	8	9
By a mechanistic approach , the authors further demonstrated that , among the protein kinase C ( PKC ) isoforms , PKCdelta ( also known as PRKCD ) is activated by 3-phosphoinositide-dependent protein kinase-1 ( PDPK1 ) in a KRAS dependent manner and sequentially activates p47 phox by phosphorylation on Ser348 and Ser379 , thereby causing translocation of p47 phox into the membrane fraction for NOX1 catalyzed ROS production .	By a mechanistic approach, the authors further demonstrated that, among the protein kinase C (PKC) isoforms, PKCdelta (also known as PRKCD) is activated by 3-phosphoinositide-dependent protein kinase-1 (PDPK1) in a KRAS dependent manner and sequentially activates p47 phox by phosphorylation on Ser348 and Ser379, thereby causing translocation of p47 phox into the membrane fraction for NOX1 catalyzed ROS production.	21	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase-1	3-phosphoinositide-dependent protein kinase-1	3-phosphoinositide-dependent protein kinase-1	PKCdelta	PKCdelta	PKCdelta	31	34	21	22
In this present work , we report that the balance of p21 Ras -mediated survival signaling is regulated by via a PI 3 K-AKT pathway , which is dependent upon both PDK1 and PKCdelta , and that PDK1 activates and regulates PKCdelta to determine the fate of cells containing a mutated , activated p21 Ras .	In this present work, we report that the balance of p21 Ras -mediated survival signaling is regulated by via a PI 3 K-AKT pathway, which is dependent upon both PDK1 and PKCdelta, and that PDK1 activates and regulates PKCdelta to determine the fate of cells containing a mutated, activated p21 Ras.	37	42	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKCdelta	PKCdelta	PKCdelta	37	38	41	42
Conversely , expression of a kinase-dead ( dominant negative ) PDK1 significantly suppresses PKCdelta activity .	Conversely, expression of a kinase-dead (dominant negative) PDK1 significantly suppresses PKCdelta activity.	2	14	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	expression of a kinase-dead (dominant negative) PDK1	pdk1	PKCdelta	PKCdelta	pkcdelta	10	11	13	14
PDK1 regulates PKCdelta activity , and constitutive expression of PDK1 increases PKCdelta activity in different cell types .	PDK1 regulates PKCdelta activity, and constitutive expression of PDK1 increases PKCdelta activity in different cell types.	7	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	expression of PDK1	pdk1	PKCdelta	PKCdelta	pkcdelta	9	10	11	12
Of note , PKCdelta , when it was activated by PDPK1 , directly bound to the SH3-N domain of p47 ( phox ) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47 ( phox ) C-terminal in a K-Ras-dependent manner , finally leading to its membrane translocation .	Of note, PKCdelta, when it was activated by PDPK1, directly bound to the SH3-N domain of p47 (phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47 (phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation.	3	24	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	PKCdelta	PKCdelta	PKCdelta	10	11	3	4
Of note , PDPK1 is phosphorylated on Thr505 by p38 ( also known as mitogen activated protein kinase 14 or MAPK14 ) in a KRAS dependent manner and then activates PKCdelta , which consequently binds to the SH3-N domain of p47 phox and catalyzes phosphorylation on Ser348 and Ser379 residues of the p47 phox C-terminal region .	Of note, PDPK1 is phosphorylated on Thr505 by p38 (also known as mitogen activated protein kinase 14 or MAPK14) in a KRAS dependent manner and then activates PKCdelta, which consequently binds to the SH3-N domain of p47 phox and catalyzes phosphorylation on Ser348 and Ser379 residues of the p47 phox C-terminal region.	3	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDPK1	PDPK1 is phosphorylated on Thr505	pdpk1	PKCdelta	PKCdelta	pkcdelta	3	4	30	31
p21 Ras -mediated survival signaling is therefore regulated by via a PI 3 K-AKT pathway , which is dependent upon both PDK1 and PKCdelta , and PDK1 activates and regulates PKCdelta to determine the fate of cells containing a mutated , activated p21 Ras .	p21 Ras -mediated survival signaling is therefore regulated by via a PI 3 K-AKT pathway, which is dependent upon both PDK1 and PKCdelta, and PDK1 activates and regulates PKCdelta to determine the fate of cells containing a mutated, activated p21 Ras.	26	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKCdelta	PKCdelta	PKCdelta	26	27	30	31
Despite the fact that PDGF-B can activate also PDGFRalpha in vitro , no redundancy between PDGF-A/C and PDGF-B has been implicated through comparative analysis of knockout mutants so far .	Despite the fact that PDGF-B can activate also PDGFRalpha in vitro, no redundancy between PDGF-A/C and PDGF-B has been implicated through comparative analysis of knockout mutants so far.	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGFRalpha	PDGFRalpha	PDGFRalpha	4	5	8	9
PDGF-A binds only PDGFR-alpha , whereas PDGF-B activates PDGFR-alpha , alphabeta , and beta .	PDGF-A binds only PDGFR-alpha, whereas PDGF-B activates PDGFR-alpha, alphabeta, and beta.	6	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-B	PDGF-B	PDGF-B	PDGFR-alpha	PDGFR-alpha	PDGFR-alpha	6	7	8	9
Thus , sustained overexpression of PDGF-B in astrocytic cells can , on a Tp53 null background , lead to uncontrolled expansion of Pdgfr-alpha + glial progenitor cells and initiate the development of aggressive GB like brain tumors .	Thus, sustained overexpression of PDGF-B in astrocytic cells can, on a Tp53 null background, lead to uncontrolled expansion of Pdgfr-alpha + glial progenitor cells and initiate the development of aggressive GB like brain tumors.	3	26	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGF-B	overexpression of PDGF-B	pdgf-b	Pdgfr-alpha	Pdgfr-alpha	pdgfr-alpha	5	6	22	23
PI3K and PDK1 activate Akt2 by phosphorylating at Ser474 and Thr309 , respectively XREF_BIBR .	PI3K and PDK1 activate Akt2 by phosphorylating at Ser474 and Thr309, respectively XREF_BIBR.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt2	Akt2	Akt2	2	3	4	5
The transcription of AKT2 was decreased , but its activating kinase PDPK1 was upregulated , which increases the activity of AKT2 .	The transcription of AKT2 was decreased, but its activating kinase PDPK1 was upregulated, which increases the activity of AKT2.	8	21	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	AKT2	AKT2	AKT2	11	12	20	21
This indicates that Akt2 may be activated by the cooperative mechanism of PI3K and PDK1 ( XREF_FIG ) .	This indicates that Akt2 may be activated by the cooperative mechanism of PI3K and PDK1 (XREF_FIG).	3	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt2	Akt2	Akt2	14	15	3	4
XREF_BIBR , XREF_BIBR PtdIns ( 3,4,5 ) P 3 in turn recruits downstream protein kinases PDK1 and Akt2 to the plasma membrane , in which Akt2 is activated through phosphorylation of specific residues by PDK1 and the mammalian target of rapamycin complex 2 .	XREF_BIBR, XREF_BIBR PtdIns (3,4,5) P 3 in turn recruits downstream protein kinases PDK1 and Akt2 to the plasma membrane, in which Akt2 is activated through phosphorylation of specific residues by PDK1 and the mammalian target of rapamycin complex 2.	25	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt2	Akt2	Akt2	34	35	25	26
XREF_BIBR In a positive feedback loop , both PDK1 and AKT phosphorylate and activate PAK1 XREF_BIBR XREF_BIBR ( XREF_FIG ) .	XREF_BIBR In a positive feedback loop, both PDK1 and AKT phosphorylate and activate PAK1 XREF_BIBR XREF_BIBR (XREF_FIG).	7	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PAK1	PAK1	PAK1	8	9	14	15
Therefore , to ensure a complete suppression of PAK1 activation , we used OSU-03012 , a novel Celecoxib derivative , which simultaneously inhibits PDK1 activity , thus blocking the PDK1 mediated PAK1 activation route , as well as inhibiting PAK activity via competitive inhibition of ATP binding [ XREF_BIBR ] .	Therefore, to ensure a complete suppression of PAK1 activation, we used OSU-03012, a novel Celecoxib derivative, which simultaneously inhibits PDK1 activity, thus blocking the PDK1 mediated PAK1 activation route, as well as inhibiting PAK activity via competitive inhibition of ATP binding [XREF_BIBR].	28	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PAK1	PAK1	PAK1	29	30	31	32
PDK1 activates PAK1 [ XREF_BIBR ] , and PAK1 phosphorylates ILK [ XREF_BIBR ] .	PDK1 activates PAK1 [XREF_BIBR], and PAK1 phosphorylates ILK [XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PAK1	PAK1	PAK1	0	1	2	3
PDK1 , KDR , and ZNF367 Are Targets of PAK1 in the Human SSC Line , and PAK1 Interacts with PDK1 .	PDK1, KDR, and ZNF367 Are Targets of PAK1 in the Human SSC Line, and PAK1 Interacts with PDK1.	0	14	Are Targets	Positive_activation_copula_1	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PAK1	PAK1	PAK1	0	1	9	10
Membrane localized PAK1 can also be activated by PDK1 [ XREF_BIBR ] .	Membrane localized PAK1 can also be activated by PDK1 [XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PAK1	PAK1	PAK1	8	9	2	3
Additionally , since there was no concomitant overexpression of PDGFRalpha in tumors generated from RCAS and tv-a-mediated PDGF-B expression , it will be interesting to determine whether targeted co-overexpression of PDGFRalpha and PDGF-B in the mouse brain will generate gliomas with similar histopathological characteristics as does PDGF-B alone .	Additionally, since there was no concomitant overexpression of PDGFRalpha in tumors generated from RCAS and tv-a-mediated PDGF-B expression, it will be interesting to determine whether targeted co-overexpression of PDGFRalpha and PDGF-B in the mouse brain will generate gliomas with similar histopathological characteristics as does PDGF-B alone.	4	11	was no concomitant overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	PDGFRalpha	overexpression of PDGFRalpha	pdgfralpha	PDGFRalpha	PDGFRalpha	pdgfralpha	9	10	9	10
At E10.5 , cells in the AVC also showed expression of PDGFRalpha ( that is , nuclear GFP signal in the Pdgfra tm11 ( EGFP ) Sor reporter ; XREF_FIG ) but were negative for NG2 and Cspg4 suggesting that these were primitive mesenchymal cells ( XREF_SUPPLEMENTARY ) .	At E10.5, cells in the AVC also showed expression of PDGFRalpha (that is, nuclear GFP signal in the Pdgfra tm11 (EGFP) Sor reporter; XREF_FIG) but were negative for NG2 and Cspg4 suggesting that these were primitive mesenchymal cells (XREF_SUPPLEMENTARY).	9	22	signal	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	PDGFRalpha	expression of PDGFRalpha	pdgfralpha	Pdgfra	Pdgfra	pdgfra	11	12	21	22
At any rate , our finding that PDK1 does not increase PKCtheta induced NF-kappaB or AP-1 activity ( unpublished data ) indicates that PDK1 mediated PKCtheta translocation is not sufficient to render it functional .	At any rate, our finding that PDK1 does not increase PKCtheta induced NF-kappaB or AP-1 activity (unpublished data) indicates that PDK1 mediated PKCtheta translocation is not sufficient to render it functional.	23	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKCtheta	PKCtheta	PKCtheta	23	24	25	26
PDK1 coexpression enhanced the membrane and cytoskeleton translocation of PKCtheta , and this effect was only partially sensitive to a PI3-K inhibitor ( XREF_FIG ) .	PDK1 coexpression enhanced the membrane and cytoskeleton translocation of PKCtheta, and this effect was only partially sensitive to a PI3-K inhibitor (XREF_FIG).	0	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1 coexpression	pdk1	PKCtheta	PKCtheta	pkctheta	0	1	9	10
PDK1 has been implicated in NF-kappaB regulation in T cells via its ability to activate PKCtheta , although recently the GLK , rather than PDK1 , has been suggested to be responsible for PKCtheta activation .	PDK1 has been implicated in NF-kappaB regulation in T cells via its ability to activate PKCtheta, although recently the GLK, rather than PDK1, has been suggested to be responsible for PKCtheta activation.	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKCtheta	PKCtheta	PKCtheta	0	1	15	16
PDK1 , downstream of PI3K , is believed to activate PKC-theta by phosphorylation of T538 site .	PDK1, downstream of PI3K, is believed to activate PKC-theta by phosphorylation of T538 site.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKC-theta	PKC-theta	PKC-theta	0	1	10	11
Finally , the ability of dominant negative Vav to inhibit PDK1 induced PKCtheta translocation suggests that Vav may function downstream of PDK1 .	Finally, the ability of dominant negative Vav to inhibit PDK1 induced PKCtheta translocation suggests that Vav may function downstream of PDK1.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKCtheta	PKCtheta	PKCtheta	10	11	12	13
Although PDK1 overexpression induced prominent translocation of PKCtheta to the membrane and to the cytoskeleton ( XREF_FIG ) , it itself did not undergo detectable membrane translocation upon T cell activation , even when overexpressed in T cells .	Although PDK1 overexpression induced prominent translocation of PKCtheta to the membrane and to the cytoskeleton (XREF_FIG), it itself did not undergo detectable membrane translocation upon T cell activation, even when overexpressed in T cells.	1	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1 overexpression	pdk1	PKCtheta	PKCtheta	pkctheta	1	2	7	8
This observation has implications for in vivo signaling , as it suggests that full activation of RSK2 by PDK1 alone is possible , circumventing at least in some cases the requirement for ERK .	This observation has implications for in vivo signaling, as it suggests that full activation of RSK2 by PDK1 alone is possible, circumventing at least in some cases the requirement for ERK.	14	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	RSK2	RSK2	RSK2	18	19	16	17
Knock down of class III receptor tyrosine kinase PDGFRbeta expression enhanced Src activity ; in a Src dependent fashion knock down of PDGFRbeta enhanced CD95 tyrosine phosphorylation and also suppressed the ability of sorafenib to induce CD95 tyrosine phosphorylation .	Knock down of class III receptor tyrosine kinase PDGFRbeta expression enhanced Src activity; in a Src dependent fashion knock down of PDGFRbeta enhanced CD95 tyrosine phosphorylation and also suppressed the ability of sorafenib to induce CD95 tyrosine phosphorylation.	8	12	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRbeta	PDGFRbeta expression	pdgfrbeta	Src	Src	src	8	9	11	12
We conclude that GRK5 mediates the preponderance of PDGF promoted seryl phosphorylation of the PDGFRbeta in SMCs , and , through mechanisms involving Shp2 , desensitizes PDGFRbeta inositol phosphate signaling and enhances PDGFRbeta triggered Src activation .	We conclude that GRK5 mediates the preponderance of PDGF promoted seryl phosphorylation of the PDGFRbeta in SMCs, and, through mechanisms involving Shp2, desensitizes PDGFRbeta inositol phosphate signaling and enhances PDGFRbeta triggered Src activation.	32	35	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDGFRbeta	PDGFRbeta	PDGFRbeta	Src	Src	Src	32	33	34	35
Thus molecular one potential model for drug action is that sorafenib mediated inhibition PDGFRbeta causes a compensatory activation of Src family tyrosine kinases that in turn phosphorylate and activate CD95 .	Thus molecular one potential model for drug action is that sorafenib mediated inhibition PDGFRbeta causes a compensatory activation of Src family tyrosine kinases that in turn phosphorylate and activate CD95.	12	22	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PDGFRbeta	PDGFRbeta	PDGFRbeta	Src	Src	Src	13	14	19	20
We hypothesized that HPCA brings PKCalpha to PDK1 , after which PDK1 activates PKCalpha .	We hypothesized that HPCA brings PKCalpha to PDK1, after which PDK1 activates PKCalpha.	4	14	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKCalpha	PKCalpha	PKCalpha	7	8	13	14
PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides .	PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKBgamma	PKBgamma	PKBgamma	6	7	0	1
Here we report that PDK1 promotes MAPK activation in a MEK dependent manner .	Here we report that PDK1 promotes MAPK activation in a MEK dependent manner.	4	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	MEK	MEK	MEK	4	5	10	11
An alternative pathway of PIP 3 -dependent ERK activation involves phosphoinositide dependent kinase-1 ( PDK1 ) , a target of PI3K , which can activate MEK directly and ERK indirectly through the activation of certain PKC isoforms , although it has been reported that PKCs are not involved in EGF induced ERK activation .	An alternative pathway of PIP 3 -dependent ERK activation involves phosphoinositide dependent kinase-1 (PDK1), a target of PI3K, which can activate MEK directly and ERK indirectly through the activation of certain PKC isoforms, although it has been reported that PKCs are not involved in EGF induced ERK activation.	12	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	MEK	MEK	MEK	14	15	25	26
XREF_BIBR This oncogene cooperativity seen with concurrent mutations in KRAS and PIK3CA is mediated by Ras and p110alpha interaction and signaling through PDK1 that directly mediates p90RSK activity .	XREF_BIBR This oncogene cooperativity seen with concurrent mutations in KRAS and PIK3CA is mediated by Ras and p110alpha interaction and signaling through PDK1 that directly mediates p90RSK activity.	13	27	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	p90RSK	p90RSK	p90RSK	22	23	26	27
The Rac and Cdc42 kinase , PAK1 , and the Rho kinase , PKN and PKC related kinase 1 , which are associated with invasion and metastasis , are also activated by PDK1 .	The Rac and Cdc42 kinase, PAK1, and the Rho kinase, PKN and PKC related kinase 1, which are associated with invasion and metastasis, are also activated by PDK1.	11	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	PKN	PKN	PKN	32	33	13	14
PR wild-type cells rescued PR-null cells , defective in alveologenesis [ XREF_BIBR ] , and ERalpha wild-type cells restored ductal morphogenesis of ERalpha-null epithelium [ XREF_BIBR ] .	PR wild-type cells rescued PR-null cells, defective in alveologenesis [XREF_BIBR], and ERalpha wild-type cells restored ductal morphogenesis of ERalpha-null epithelium [XREF_BIBR].	0	18	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ERalpha	ERalpha	ERalpha	0	1	15	16
Pretreatment with celastrol , followed by a pulse of NN-DNJ and celastrol , followed by another celastrol treatment , capped by a pulse of NN-DNJ and celastrol was envisioned to enhance PR directed UPR mediated L444P GC folding in the ER , generating a higher steady state concentration of folded L444P GC for the PC to act on .	Pretreatment with celastrol, followed by a pulse of NN-DNJ and celastrol, followed by another celastrol treatment, capped by a pulse of NN-DNJ and celastrol was envisioned to enhance PR directed UPR mediated L444P GC folding in the ER, generating a higher steady state concentration of folded L444P GC for the PC to act on.	30	41	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	31	32	40	41
Clearly , the RTP values of compounds 2a and 2c are far greater for the ERbeta mediated response ( OTUB2 activation in ERalpha + ERbeta cells ) than the ERalpha mediated response ( PR activation in ERalpha only cells ) .	Clearly, the RTP values of compounds 2a and 2c are far greater for the ERbeta mediated response (OTUB2 activation in ERalpha + ERbeta cells) than the ERalpha mediated response (PR activation in ERalpha only cells).	33	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PR	PR	PR	ERalpha	ERalpha	ERalpha	33	34	36	37
Progesterone receptor analysis has been used to enhance the prognostic usefulness of estrogen receptor analysis in breast cancer .	Progesterone receptor analysis has been used to enhance the prognostic usefulness of estrogen receptor analysis in breast cancer.	0	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Progesterone receptor	Progesterone receptor	Progesterone receptor	estrogen receptor	estrogen receptor	estrogen receptor	0	2	12	14
In addition , kaempferol in silico binding analysis was completed for PR , as was the activation of ER and AR signaling in vitro in order to determine receptor specificity .	In addition, kaempferol in silico binding analysis was completed for PR, as was the activation of ER and AR signaling in vitro in order to determine receptor specificity.	9	21	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	11	12	18	19
Serial sections demonstrated that areas of mammary tissue with a high proportion of TOX3 hi cells also expressed ER , the ER target progesterone receptor ( PR ) , and the ER pioneer factor FOXA1 .	Serial sections demonstrated that areas of mammary tissue with a high proportion of TOX3 hi cells also expressed ER, the ER target progesterone receptor (PR), and the ER pioneer factor FOXA1.	21	25	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	progesterone receptor	progesterone receptor	progesterone receptor	ER	ER	ER	23	25	21	22
During pregnancy , hormone responsive ERalpha + and PR + luminal cells induce the proliferation of neighbouring ERalpha - and PR - cells to drive alveologenesis 19 .	During pregnancy, hormone responsive ERalpha + and PR + luminal cells induce the proliferation of neighbouring ERalpha - and PR - cells to drive alveologenesis 19.	6	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ERalpha	ERalpha	ERalpha	8	9	17	18
In the present study , we demonstrate that elevated levels of the progesterone receptor ( PR )-B isoform in breast cancer cells induces down-regulation of estrogen receptor ( ER ) alpha mRNA and protein content , causing concomitant repression of the estrogen regulated genes insulin receptor substrate 1 , cyclin D1 , and pS2 , addressing a specific effect of PR/PR-B on ERalpha gene transcription .	In the present study, we demonstrate that elevated levels of the progesterone receptor (PR)-B isoform in breast cancer cells induces down-regulation of estrogen receptor (ER) alpha mRNA and protein content, causing concomitant repression of the estrogen regulated genes insulin receptor substrate 1, cyclin D1, and pS2, addressing a specific effect of PR/PR-B on ERalpha gene transcription.	12	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	progesterone receptor	progesterone receptor	progesterone receptor	estrogen receptor	estrogen receptor	estrogen receptor	12	14	25	27
This lack of association with ERalpha could be related to transcriptionally repressive effects on ERalpha mediated by PR signaling .	This lack of association with ERalpha could be related to transcriptionally repressive effects on ERalpha mediated by PR signaling.	8	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PR	PR	PR	ERalpha	ERalpha	ERalpha	17	18	14	15
Nevertheless , PR agonists do directly support invasiveness and metastatic potential in ER +/PR+ breast cancer cells as demonstrated using in vivo experimental models [ XREF_BIBR , XREF_BIBR ] .	Nevertheless, PR agonists do directly support invasiveness and metastatic potential in ER +/PR+ breast cancer cells as demonstrated using in vivo experimental models [XREF_BIBR, XREF_BIBR].	2	16	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	2	3	12	13
Requirement of different SRC isoforms for the regulation of Pgr gene expression by E2 activated ER is one clear example of a tissue specific hormonal effect .	Requirement of different SRC isoforms for the regulation of Pgr gene expression by E2 activated ER is one clear example of a tissue specific hormonal effect.	9	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Pgr	Pgr gene expression by E2	pgr	ER	ER	er	9	10	15	16
Two years later ( Experiment II ) , the amount of ER1s ( ER measured in cytosolic fraction ) as well as of ERhs was lower than at the beginning of Experiment I. ER could again be activated by estradiol treatment and PgR was also induced .	Two years later (Experiment II), the amount of ER1s (ER measured in cytosolic fraction) as well as of ERhs was lower than at the beginning of Experiment I. ER could again be activated by estradiol treatment and PgR was also induced.	33	43	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PgR	PgR	PgR	ER	ER	ER	42	43	33	34
In addition , the proportion of PGR positive stromal cells was significantly increased in E 2 -treated Esr1 f/- uteri in both mesometrial and anti-mesometrial poles .	In addition, the proportion of PGR positive stromal cells was significantly increased in E 2 -treated Esr1 f/- uteri in both mesometrial and anti-mesometrial poles.	4	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGR	PGR	PGR	Esr1	Esr1	Esr1	6	7	17	18
More studies are needed to directly compare the value of tracers targeting different receptors in specific patient groups -- for example GRPR , SSTR , ER , PR , and NPY1R targeted imaging in ER positive BCs and clinical studiescomparing their added value to currently available 18 F-FDG PET/CT are needed to enhance their broad application in daily clinical routine .	More studies are needed to directly compare the value of tracers targeting different receptors in specific patient groups -- for example GRPR, SSTR, ER, PR, and NPY1R targeted imaging in ER positive BCs and clinical studiescomparing their added value to currently available 18 F-FDG PET/CT are needed to enhance their broad application in daily clinical routine.	10	36	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	27	28	34	35
This PR isoform specific modulation of ER genomic activity was further reflected in the Ingenuity analyses of the isoform specific transcriptomes and the observed phenotypes .	This PR isoform specific modulation of ER genomic activity was further reflected in the Ingenuity analyses of the isoform specific transcriptomes and the observed phenotypes.	1	8	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	1	2	6	7
Both ER- and PR targeted radiotracers , but especially ER targeted radiotracers , are currently studied in clinical trials .	Both ER- and PR targeted radiotracers, but especially ER targeted radiotracers, are currently studied in clinical trials.	1	15	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	3	4	9	10
Gene expression analysis using quantitative PCR of the estrogen receptor target progesterone receptor ( PgR ) following 6hours of exposure to E2 indicated that BU MCF-7 cells are responsive to low levels of estrogen ( XREF_FIG ) .	Gene expression analysis using quantitative PCR of the estrogen receptor target progesterone receptor (PgR) following 6hours of exposure to E2 indicated that BU MCF-7 cells are responsive to low levels of estrogen (XREF_FIG).	8	13	target	Positive_activation_token_1_noun	Positive_activation	Positive_activation	progesterone receptor	progesterone receptor	progesterone receptor	estrogen receptor	estrogen receptor	estrogen receptor	11	13	8	10
The present studies were undertaken to determine the importance of the polyamine biosynthetic pathway in cellular proliferation and hormone regulated progesterone receptor synthesis in estrogen receptor containing breast cancer cells .	The present studies were undertaken to determine the importance of the polyamine biosynthetic pathway in cellular proliferation and hormone regulated progesterone receptor synthesis in estrogen receptor containing breast cancer cells.	20	26	synthesis	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	progesterone receptor	progesterone receptor	progesterone receptor	estrogen receptor	estrogen receptor	estrogen receptor	20	22	24	26
Given that PGR is a direct target of ERalpha and that PGR+ tumors are typically also ER+ 23 , we speculate that the considerable correlation of C/EBPdelta with PGR in tissues reflects the ability of ERalpha to support both PGR gene expression as well as C/EBPdelta protein stability .	Given that PGR is a direct target of ERalpha and that PGR+ tumors are typically also ER+ 23, we speculate that the considerable correlation of C/EBPdelta with PGR in tissues reflects the ability of ERalpha to support both PGR gene expression as well as C/EBPdelta protein stability.	2	9	is a direct target	Positive_activation_copula_1	Positive_activation	Positive_activation	PGR	PGR	PGR	ERalpha	ERalpha	ERalpha	2	3	8	9
Because expression profiles did not cluster by the presence or absence of tamoxifen , despite ER expression , we hypothesized that a higher positive correlation would be observed in the transcriptomes observed in response to joint therapies with a PR targeting drug and SERMs ( tamoxifen , raloxifene or bazedoxifene ) or selective estrogen receptor down regulators ( SERDs ) like fulvestrant .	Because expression profiles did not cluster by the presence or absence of tamoxifen, despite ER expression, we hypothesized that a higher positive correlation would be observed in the transcriptomes observed in response to joint therapies with a PR targeting drug and SERMs (tamoxifen, raloxifene or bazedoxifene) or selective estrogen receptor down regulators (SERDs) like fulvestrant.	36	56	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	estrogen receptor	estrogen receptor	estrogen receptor	39	40	53	55
In accord with these results , activated PR increased activated ER binding events fourfold in ER + / PR + breast cancer cells ( XREF_FIG , B and C ) and redirected ER to sites that correlated with genomic binding of PR and complexes of ER and PR ( XREF_FIG , D and E ) .	In accord with these results, activated PR increased activated ER binding events fourfold in ER + / PR + breast cancer cells (XREF_FIG, B and C) and redirected ER to sites that correlated with genomic binding of PR and complexes of ER and PR (XREF_FIG, D and E).	6	22	increased activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	7	8	15	16
Similarly , progesterone receptor ( PR ) expression is correlated with better prognosis and higher response to hormone based treatments and increases the predictive power of ER [ XREF_BIBR - XREF_BIBR ] .	Similarly, progesterone receptor (PR) expression is correlated with better prognosis and higher response to hormone based treatments and increases the predictive power of ER [XREF_BIBR - XREF_BIBR].	2	28	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	progesterone receptor	progesterone receptor	progesterone receptor	ER	ER	ER	2	4	26	27
In E-P ewes , roIFN-tau decreased oestrogen stimulated increases in ER and OTR , but not PR expression compared with control ewes .	In E-P ewes, roIFN-tau decreased oestrogen stimulated increases in ER and OTR, but not PR expression compared with control ewes.	7	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR expression	pr	ER	ER	er	16	17	10	11
Western blot analysis of CD1 MOE treated with E 2 and SERMs revealed significant ( P < 0.001 ) PR induction and disappearance of ERalpha in response to E 2 treatment .	Western blot analysis of CD1 MOE treated with E 2 and SERMs revealed significant (P < 0.001) PR induction and disappearance of ERalpha in response to E 2 treatment.	19	26	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PR	PR	PR	ERalpha	ERalpha	ERalpha	19	20	24	25
Furthermore , PRL and TGFalpha in combination blocked the mitogenic effects of estrogen , dramatically reduced progesterone receptor levels , and diminished ERalpha down-regulation in response to circulating estrogen levels , in contrast to the other genotypes .	Furthermore, PRL and TGFalpha in combination blocked the mitogenic effects of estrogen, dramatically reduced progesterone receptor levels, and diminished ERalpha down-regulation in response to circulating estrogen levels, in contrast to the other genotypes.	2	23	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	progesterone receptor	PRL and TGFalpha in combination blocked the mitogenic effects of estrogen, dramatically reduced progesterone receptor levels	progesterone receptor	ERalpha	ERalpha	eralpha	16	18	22	23
Consequently , co-doping Pr 3+ can significantly decrease the lifetime of the lower level ( Er 3+ : 4 I 13/2 ) and almost has no effect on that of the upper level ( Er 3+ : 4 I 11/2 ) , which indicates the self termination problem in the crystal can be greatly inhibited .	Consequently, co-doping Pr 3+ can significantly decrease the lifetime of the lower level (Er 3+ : 4 I 13/2) and almost has no effect on that of the upper level (Er 3+ : 4 I 11/2), which indicates the self termination problem in the crystal can be greatly inhibited.	2	24	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pr	Pr	Pr	Er	Er	Er	3	4	15	16
As demonstrated by row normalized heat maps , the patterns of gene regulation associated with joint activation of ER and PR were most similar to those induced by PR activation alone in all ER + / PR + cell models and in at least three of eight ER + / PR + patient tumors ( P1 , P3 , and P4 ) .	As demonstrated by row normalized heat maps, the patterns of gene regulation associated with joint activation of ER and PR were most similar to those induced by PR activation alone in all ER + / PR + cell models and in at least three of eight ER + / PR + patient tumors (P1, P3, and P4).	26	48	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	28	29	47	48
Interestingly , activated PR directed ER to genomic loci such that the resulting gene expression program was associated with a good clinical outcome .	Interestingly, activated PR directed ER to genomic loci such that the resulting gene expression program was associated with a good clinical outcome.	2	6	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	3	4	5	6
Further analysis verified that progestins regulate Ccnd1 , JunD , Usf1 , Gfi1 , Cyr61 , and Cdkn1b through PR mediated activation of ligand-free ER , ERK1-2 or AKT , in the absence of genomic PR binding .	Further analysis verified that progestins regulate Ccnd1, JunD, Usf1, Gfi1, Cyr61, and Cdkn1b through PR mediated activation of ligand-free ER, ERK1-2 or AKT, in the absence of genomic PR binding.	19	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	19	20	24	25
In addition , overexpression of FOXC1 reduced expression of PR , IRS1 , and XBP1 ( downstream target of ERalpha ) and significantly reduced luciferase activity caused by E2 using ERE luciferase reporter assay .	In addition, overexpression of FOXC1 reduced expression of PR, IRS1, and XBP1 (downstream target of ERalpha) and significantly reduced luciferase activity caused by E2 using ERE luciferase reporter assay.	3	20	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	PR	overexpression of FOXC1 reduced expression of PR	pr	ERalpha	ERalpha	eralpha	9	10	19	20
The PR is a transcriptional target of the ER , and would thus similarly be expected to have coexpression with Bag-1 .	The PR is a transcriptional target of the ER, and would thus similarly be expected to have coexpression with Bag-1.	0	17	is a transcriptional target	Positive_activation_copula_1	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	1	2	8	9
One report shows that higher expression of the progesterone receptor ( PR ) may be linked to the ability of MSCs to support growth of ERalpha positive MCF-7 breast cancer cells under estrogen deficiency [ XREF_BIBR ] .	One report shows that higher expression of the progesterone receptor (PR) may be linked to the ability of MSCs to support growth of ERalpha positive MCF-7 breast cancer cells under estrogen deficiency [XREF_BIBR].	5	30	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	progesterone receptor	expression of the progesterone receptor	progesterone receptor	ERalpha	ERalpha	eralpha	8	10	25	26
Therefore , upregulation of many ER target genes suggests that stromal COUP-TFII is essential for the PR mediated downregulation of ER activity in the epithelium to open up the receptivity window .	Therefore, upregulation of many ER target genes suggests that stromal COUP-TFII is essential for the PR mediated downregulation of ER activity in the epithelium to open up the receptivity window.	15	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	16	17	20	21
We have developed a model system to analyze the mechanisms underlying this cross-talk , specifically the repression of ER mediated transcriptional activity by PR complexed with agonistic or antagonistic ligands .	We have developed a model system to analyze the mechanisms underlying this cross-talk, specifically the repression of ER mediated transcriptional activity by PR complexed with agonistic or antagonistic ligands.	16	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	23	24	18	19
Another possibility is that ER and PR initiate different signal transduction pathways and the activation of the ER pathway induces ER production .	Another possibility is that ER and PR initiate different signal transduction pathways and the activation of the ER pathway induces ER production.	4	21	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	6	7	20	21
ER expression in some brain areas is blunted by progesterone , a phenomenon thought to be involved in terminating estrus behavior , so a similar PR mediated downregulation of ER may be necessary for paternal behavior in male prairie voles .	ER expression in some brain areas is blunted by progesterone, a phenomenon thought to be involved in terminating estrus behavior, so a similar PR mediated downregulation of ER may be necessary for paternal behavior in male prairie voles.	23	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	25	26	29	30
Other prominent data sets are : a recent C. elegans study related to proteome remodeling and aggregation in aging ( PXD001364 ) , the data sets entitled ' Ancient proteins resolve the evolutionary history of Darwin ' s South American ungulates ' ( PXD001411 ) , and ' Microbial life in permafrost : predictions of microbial response to natural thaw using a multi-omics approach ' ( PXD001131 ) , or the data sets ' Progesterone receptor modulates ERalpha action in breast cancer ' ( PXD002104 ) , and ' Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links ' ( PXD000490 and PXD000491 ) .	Other prominent data sets are : a recent C. elegans study related to proteome remodeling and aggregation in aging (PXD001364), the data sets entitled ' Ancient proteins resolve the evolutionary history of Darwin 's South American ungulates ' (PXD001411), and ' Microbial life in permafrost : predictions of microbial response to natural thaw using a multi-omics approach ' (PXD001131), or the data sets ' Progesterone receptor modulates ERalpha action in breast cancer ' (PXD002104), and ' Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links ' (PXD000490 and PXD000491).	74	103	modulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Progesterone receptor	Progesterone receptor	Progesterone receptor	ERalpha	ERalpha	ERalpha	74	76	77	78
PR is a transcriptional target of ER , and these two receptors show tight co-expression in normal mammary epithelial cells [ XREF_BIBR ] .	PR is a transcriptional target of ER, and these two receptors show tight co-expression in normal mammary epithelial cells [XREF_BIBR].	0	7	is a transcriptional target	Positive_activation_copula_1	Positive_activation	Positive_activation	PR	PR	PR	ER	ER	ER	0	1	6	7
Although ERalpha expression alone was sufficient to promote PgR expression in breast tumors , the levels of PgR expression were significantly potentiated in tumors coexpressing ERalpha with nuclear 4ICD ( PgR AQUA 21.7 vs. 30.0 ; p = 0.025 ) indicating that the 4ICD coactivator potentiates PgR expression in breast tumors .	Although ERalpha expression alone was sufficient to promote PgR expression in breast tumors, the levels of PgR expression were significantly potentiated in tumors coexpressing ERalpha with nuclear 4ICD (PgR AQUA 21.7 vs. 30.0; p = 0.025) indicating that the 4ICD coactivator potentiates PgR expression in breast tumors.	17	28	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PgR	PgR expression	pgr	ERalpha	ERalpha	eralpha	17	18	25	26
We did not determine whether PDK1 directly regulates SGK1 , but it was shown that PDK1 is required for PI3K mediated activation of SGK1 and that SGK1 dependent activation of NHE3 involves PI3K .	We did not determine whether PDK1 directly regulates SGK1, but it was shown that PDK1 is required for PI3K mediated activation of SGK1 and that SGK1 dependent activation of NHE3 involves PI3K.	5	9	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK1	SGK1	SGK1	5	6	8	9
The activation of SGK by PDK1 in vitro is unaffected by PtdIns ( 3,4,5 ) P3 , abolished by the mutation of Ser422 to Ala , and greatly potentiated by mutation of Ser422 to Asp ( although this mutation does not activate SGK itself ) .	The activation of SGK by PDK1 in vitro is unaffected by PtdIns (3,4,5) P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp (although this mutation does not activate SGK itself).	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK	SGK	SGK	5	6	3	4
Activation of SGK1 by PDK1 may further involve the mammalian target of rapamycin mTOR [ XREF_BIBR - XREF_BIBR ] and the serine/threonine kinase WNK1 ( with no lysine kinase 1 ) [ XREF_BIBR - XREF_BIBR ] .	Activation of SGK1 by PDK1 may further involve the mammalian target of rapamycin mTOR [XREF_BIBR - XREF_BIBR] and the serine/threonine kinase WNK1 (with no lysine kinase 1) [XREF_BIBR - XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK1	SGK1	SGK1	4	5	2	3
SGK1 , which is activated by PDK1 , contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2 .	SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK1	SGK1	SGK1	6	7	0	1
Here we show that PDK1 activates SGK in vitro by phosphorylating Thr256 .	Here we show that PDK1 activates SGK in vitro by phosphorylating Thr256.	4	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK	SGK	SGK	4	5	6	7
SGK1 is activated by activated PDK1 , which is phosphorylated by activated PI3K .	SGK1 is activated by activated PDK1, which is phosphorylated by activated PI3K.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1, which is phosphorylated	pdk1	SGK1	SGK1	sgk1	5	6	0	1
SGK1 activation by PDK1 may involve the scaffold protein Na + / H + exchanger regulating factor 2 ( NHERF2 ) , which mediates the assembly of SGK1 and PDK1 via its PDZ domains and PIF consensus sequence [ XREF_BIBR ] .	SGK1 activation by PDK1 may involve the scaffold protein Na + / H + exchanger regulating factor 2 (NHERF2), which mediates the assembly of SGK1 and PDK1 via its PDZ domains and PIF consensus sequence [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK1	SGK1	SGK1	3	4	0	1
SGK1 activation is mediated by mTORC2 dependent phosphorylation at the HM ( S422 ) and subsequent PDK1 phosphorylation at the activation loop ( T256 ) in a PIF binding pocket dependent manner .	SGK1 activation is mediated by mTORC2 dependent phosphorylation at the HM (S422) and subsequent PDK1 phosphorylation at the activation loop (T256) in a PIF binding pocket dependent manner.	0	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	phosphorylation at the HM (S422) and subsequent PDK1	pdk1	SGK1	SGK1	sgk1	16	17	0	1
The kinase signals partially through the phosphoinositide dependent kinase PDK1 , which on the one hand activates the serum- and glucocorticoid- inducible kinase SGK1 and on the other hand activates protein kinase PKCdelta .	The kinase signals partially through the phosphoinositide dependent kinase PDK1, which on the one hand activates the serum- and glucocorticoid- inducible kinase SGK1 and on the other hand activates protein kinase PKCdelta.	2	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK1	SGK1	SGK1	9	10	23	24
PDK1 dependent activation of SGK1 is triggered via PI3-kinase by insulin , IGF1 , hepatic growth factor ( HGF ) , follicle stimulating hormone ( FSH ) and thrombin [ XREF_BIBR ] .	PDK1 dependent activation of SGK1 is triggered via PI3-kinase by insulin, IGF1, hepatic growth factor (HGF), follicle stimulating hormone (FSH) and thrombin [XREF_BIBR].	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK1	SGK1	SGK1	0	1	4	5
Recently , XREF_BIBR demonstrated that PDK1 mediated SGK1 activation contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2 , which further confirms this positive feedback loop .	Recently, XREF_BIBR demonstrated that PDK1 mediated SGK1 activation contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2, which further confirms this positive feedback loop.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK1	SGK1	SGK1	5	6	7	8
Cotransfection of PDK1 with SGK caused a 6-fold activation of SGK activity , whereas kinase-dead PDK1 caused no activation .	Cotransfection of PDK1 with SGK caused a 6-fold activation of SGK activity, whereas kinase-dead PDK1 caused no activation.	0	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK	SGK	SGK	2	3	10	11
PDK1 also mediated activation of p70S6K in the absence of EGFR .	PDK1 also mediated activation of p70S6K in the absence of EGFR.	0	6	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	p70S6K	p70S6K	p70S6K	0	1	5	6
Since activated Akt and PDK1 may positively regulate mTOR and S6K1 , respectively , XREF_BIBR , we next investigated whether H 2 O 2 induction of ROS inhibits mTOR mediated phosphorylation of mTOR and S6K1 by suppressing the activity of Akt and PDK1 , respectively .	Since activated Akt and PDK1 may positively regulate mTOR and S6K1, respectively, XREF_BIBR, we next investigated whether H 2 O 2 induction of ROS inhibits mTOR mediated phosphorylation of mTOR and S6K1 by suppressing the activity of Akt and PDK1, respectively.	2	11	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	S6K1	S6K1	S6K1	4	5	10	11
Thus , S6K1 activity could be stimulated by either PDK1 or ERK , the former being consistent with the observation of elevated PIKE and p110beta levels in FXS mice 52 and latter being consistent with the observation that hypersensitivity to ERK contributes to exaggerated protein synthesis and audiogenic seizures in Fmr1 knockout mice 46 .	Thus, S6K1 activity could be stimulated by either PDK1 or ERK, the former being consistent with the observation of elevated PIKE and p110beta levels in FXS mice 52 and latter being consistent with the observation that hypersensitivity to ERK contributes to exaggerated protein synthesis and audiogenic seizures in Fmr1 knockout mice 46.	2	48	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	S6K1	S6K1	S6K1	9	10	2	3
XREF_FIG shows that expression of a single WT PDK1 allele can support activation of S6K1 in pre-T cells , but the PDK1 L155E allele can not .	XREF_FIG shows that expression of a single WT PDK1 allele can support activation of S6K1 in pre-T cells, but the PDK1 L155E allele can not.	3	15	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	expression of a single WT PDK1	pdk1	S6K1	S6K1	s6k1	8	9	14	15
Osmotic stress leads to removal of RAPTOR and the subsequent loss of PIF domain phosphorylation by TOR , which inhibits PDK1 dependent activation of S6K1 .	Osmotic stress leads to removal of RAPTOR and the subsequent loss of PIF domain phosphorylation by TOR, which inhibits PDK1 dependent activation of S6K1.	20	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	S6K1	S6K1	S6K1	20	21	24	25
p70S6K itself is activated by 3-phosphoinositide-dependent protein kinase 1 ( PDK-1 ) and mammalian target of rapamycin ( mTOR ) kinase .	p70S6K itself is activated by 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and mammalian target of rapamycin (mTOR) kinase.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	3-phosphoinositide-dependent protein kinase 1	3-phosphoinositide-dependent protein kinase 1	3-phosphoinositide-dependent protein kinase 1	p70S6K	p70S6K	p70S6K	5	9	0	1
Unlike classical autophagy signalling , this process did not involve changes to mTOR phosphorylation and it may be that components of these pathways are able to activate p70S6K directly , as PDK1 has been shown to directly phosphorylate and activate p70S6K in vitro and in vivo XREF_BIBR .	Unlike classical autophagy signalling, this process did not involve changes to mTOR phosphorylation and it may be that components of these pathways are able to activate p70S6K directly, as PDK1 has been shown to directly phosphorylate and activate p70S6K in vitro and in vivo XREF_BIBR.	31	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	p70S6K	p70S6K	p70S6K	31	32	40	41
A recent model proposed by the Blenis laboratory suggests that S6K1 is phosphorylated in the pre and initiation complex by mTOR leading to dissociation and full activation of S6K1 by PDK1 .	A recent model proposed by the Blenis laboratory suggests that S6K1 is phosphorylated in the pre and initiation complex by mTOR leading to dissociation and full activation of S6K1 by PDK1.	21	31	leading	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	S6K1	S6K1	S6K1	30	31	28	29
Knockdown of PDK1 resulted in decreased phosphorylation of S6 , a downstream effector of the PDK1 target p70S6K ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Knockdown of PDK1 resulted in decreased phosphorylation of S6, a downstream effector of the PDK1 target p70S6K (XREF_FIG and XREF_SUPPLEMENTARY).	12	21	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	p70S6K	p70S6K	p70S6K	15	16	17	18
Moreover , the fact that p70S6K , the upstream kinase of S6 ribosomal protein , is sequentially activated by both mTORC1 and PDK1 may explain why S6 phosphorylation is more sensitive to inhibition by SHR8443 than AKT , which is activated only by mTORC2 [ XREF_BIBR , XREF_BIBR ] .	Moreover, the fact that p70S6K, the upstream kinase of S6 ribosomal protein, is sequentially activated by both mTORC1 and PDK1 may explain why S6 phosphorylation is more sensitive to inhibition by SHR8443 than AKT, which is activated only by mTORC2 [XREF_BIBR, XREF_BIBR].	5	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	p70S6K	p70S6K	p70S6K	22	23	5	6
Thirdly , our data are consistent with a model in which PtdIns ( 3,4,5 ) P 3 , produced from activation of Class 1 PI3K , promotes phosphorylation of the hydrophobic motif of SGK3 by mTORC2 , thereby stimulating activation of SGK3 by PDK1 .	Thirdly, our data are consistent with a model in which PtdIns (3,4,5) P 3, produced from activation of Class 1 PI3K, promotes phosphorylation of the hydrophobic motif of SGK3 by mTORC2, thereby stimulating activation of SGK3 by PDK1.	38	44	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK3	SGK3	SGK3	43	44	41	42
On the other hand , recent studies uncovered an AKT independent signalling pathway in PIK3CA mutant cancer cell with low AKT activation that involved PDK1 dependent activation of SGK3 XREF_BIBR .	On the other hand, recent studies uncovered an AKT independent signalling pathway in PIK3CA mutant cancer cell with low AKT activation that involved PDK1 dependent activation of SGK3 XREF_BIBR.	24	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK3	SGK3	SGK3	24	25	28	29
Interestingly , like AKT , SGK3 and two other isoforms , SGK1 and SGK2 , belong to the AGC protein kinase family and are activated following their phosphorylation by PDK1 and mTORC2 .	Interestingly, like AKT, SGK3 and two other isoforms, SGK1 and SGK2, belong to the AGC protein kinase family and are activated following their phosphorylation by PDK1 and mTORC2.	5	31	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK3	SGK3	SGK3	29	30	5	6
SGK3 , similar to many other AGC kinases including Akt isoforms , is activated following phosphorylation of its catalytic domain T-loop motif ( Thr 320 ) by PDK1 and its non catalytic C-terminal hydrophobic motif ( Ser 486 ) by mTOR [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	SGK3, similar to many other AGC kinases including Akt isoforms, is activated following phosphorylation of its catalytic domain T-loop motif (Thr 320) by PDK1 and its non catalytic C-terminal hydrophobic motif (Ser 486) by mTOR [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	28	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	PDK1	phosphorylation of its catalytic domain T-loop motif (Thr 320) by PDK1	pdk1	SGK3	SGK3	sgk3	27	28	0	1
The signaling of insulin involves the serum- and glucocorticoid inducible kinase SGK3 , 10 which , similar to protein kinase B 11 and SGK1 , 12 is activated by phosphatidy-linositol-3-kinase and phosphoinositide dependent kinase PDK1 .	The signaling of insulin involves the serum- and glucocorticoid inducible kinase SGK3, 10 which, similar to protein kinase B 11 and SGK1, 12 is activated by phosphatidy-linositol-3-kinase and phosphoinositide dependent kinase PDK1.	4	35	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK3	SGK3	SGK3	34	35	11	12
A previous study showed that all SGKs are phosphorylated by PDK1 , and knockdown of PDK1 abolished Dex induced regulation of SGK2 , SGK3 , and NHE3 ( XREF_FIG and S4 ) .	A previous study showed that all SGKs are phosphorylated by PDK1, and knockdown of PDK1 abolished Dex induced regulation of SGK2, SGK3, and NHE3 (XREF_FIG and S4).	13	24	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK3	SGK3	SGK3	15	16	23	24
Phosphorylation of hydrophobic motif triggers release of Cdc37 and concomitant association of 3-phosphoinositide dependent kinase 1 ( PDK1 ) to activate SGK3 .	Phosphorylation of hydrophobic motif triggers release of Cdc37 and concomitant association of 3-phosphoinositide dependent kinase 1 (PDK1) to activate SGK3.	15	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK3	SGK3	SGK3	17	18	21	22
For example , cell lines driven by PIK3CA mutations in the helical domain ( exon 20 ) were shown to be dependent on the Akt independent PDK1 target SGK3 for tumor growth 45 .	For example, cell lines driven by PIK3CA mutations in the helical domain (exon 20) were shown to be dependent on the Akt independent PDK1 target SGK3 for tumor growth 45.	21	31	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK3	SGK3	SGK3	26	27	28	29
To confirm PDK1 dependent modulation of SGK3 and other known PDK1 substrates in PIK3CA-mutant cells , we suppressed PDK1 expression and examined the resulting phosphorylation patterns .	To confirm PDK1 dependent modulation of SGK3 and other known PDK1 substrates in PIK3CA-mutant cells, we suppressed PDK1 expression and examined the resulting phosphorylation patterns.	2	7	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK3	SGK3	SGK3	2	3	6	7
For example , PDK1 has been shown to activate SGK3 in a PI3K dependent , AKT independent fashion in breast cancer .	For example, PDK1 has been shown to activate SGK3 in a PI3K dependent, AKT independent fashion in breast cancer.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	SGK3	SGK3	SGK3	3	4	9	10
However , it was surprising that VPS34 was also co-immunoprecipitated when PDGFRB was immunoprecipitated , thus supporting the idea that the complex actually consisted of PDGFRB , Beclin 1 and VPS34 ( XREF_SUPPLEMENTARY ) .	However, it was surprising that VPS34 was also co-immunoprecipitated when PDGFRB was immunoprecipitated, thus supporting the idea that the complex actually consisted of PDGFRB, Beclin 1 and VPS34 (XREF_SUPPLEMENTARY).	6	29	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VPS34	VPS34	VPS34	Beclin 1	Beclin 1	Beclin 1	6	7	27	29
Spautin-1 has been recently reported to prevent autophagy by inhibiting the deubiquitinases USP10 and USP13 , which leads to beclin 1 and Vps34 ( or PI3KIII ) degradation [ XREF_BIBR ] .	Spautin-1 has been recently reported to prevent autophagy by inhibiting the deubiquitinases USP10 and USP13, which leads to beclin 1 and Vps34 (or PI3KIII) degradation [XREF_BIBR].	9	25	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Vps34	Vps34	Vps34	beclin 1	beclin 1	beclin 1	22	23	19	21
After verifying transient Vps34 knockdown ( XREF_FIG ) relative to appropriate scrambled siRNA controls ( siScr ) , we observed that loss of Vps34 wholly abrogated decorin evoked induction of Peg3 and Beclin 1 , when compared with decorin alone ( XREF_FIG ) .	After verifying transient Vps34 knockdown (XREF_FIG) relative to appropriate scrambled siRNA controls (siScr), we observed that loss of Vps34 wholly abrogated decorin evoked induction of Peg3 and Beclin 1, when compared with decorin alone (XREF_FIG).	21	34	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Vps34	loss of Vps34	vps34	Beclin 1	Beclin 1	beclin 1	23	24	32	34
Although PIAS1 enhanced the Smad4 dependent transcriptional activation of TGF-beta signaling , a mutant lacking the RING domain inhibited the sumoylation of Smad4 in a dominant negative manner and , as a result , abolished the transcriptional response of TGF-beta .	Although PIAS1 enhanced the Smad4 dependent transcriptional activation of TGF-beta signaling, a mutant lacking the RING domain inhibited the sumoylation of Smad4 in a dominant negative manner and, as a result, abolished the transcriptional response of TGF-beta.	1	7	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIAS1	PIAS1	PIAS1	Smad4	Smad4	Smad4	1	2	4	5
Moreover , the knockdown of PIAS1 expression attenuated the zinc induced recruitment of Smad4 on the p21 WAF1 and Cip1 promoter .	Moreover, the knockdown of PIAS1 expression attenuated the zinc induced recruitment of Smad4 on the p21 WAF1 and Cip1 promoter.	5	14	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PIAS1	PIAS1 expression	pias1	Smad4	Smad4	smad4	5	6	13	14
In conclusion , this study demonstrates for the first time that PIAS1 , a member of PIAS protein family , augments the transcriptional activity of the Smad2 and Smad4 protein complex not only in zinc induced LNCaP cell apoptosis , but also in various cancer cells .	In conclusion, this study demonstrates for the first time that PIAS1, a member of PIAS protein family, augments the transcriptional activity of the Smad2 and Smad4 protein complex not only in zinc induced LNCaP cell apoptosis, but also in various cancer cells.	11	30	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIAS1	PIAS1	PIAS1	Smad4	Smad4	Smad4	11	12	28	29
These results suggest that PIAS1 enhances Smad4 nuclear localization in the presence of zinc .	These results suggest that PIAS1 enhances Smad4 nuclear localization in the presence of zinc.	4	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIAS1	PIAS1	PIAS1	Smad4	Smad4	Smad4	4	5	6	7
If this hypothesis is correct , transient reduction of PEX3 levels should block recruitment of the PEX19 docking domain to peroxisomes .	If this hypothesis is correct, transient reduction of PEX3 levels should block recruitment of the PEX19 docking domain to peroxisomes.	9	18	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PEX3	PEX3 levels	pex3	PEX19	PEX19	pex19	9	10	16	17
For example , a fusion protein of full-length Pex3 and GFP , expressed under control of the PEX3 promoter in H. polymorpha pex19 cells , localizes to the cytosol .	For example, a fusion protein of full-length Pex3 and GFP, expressed under control of the PEX3 promoter in H. polymorpha pex19 cells, localizes to the cytosol.	17	23	promoter	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PEX3	PEX3	PEX3	pex19	pex19	pex19	17	18	22	23
The observation that PEX3 is both necessary and sufficient to mediate PEX19 docking indicates that it should also be essential for class I PMP import .	The observation that PEX3 is both necessary and sufficient to mediate PEX19 docking indicates that it should also be essential for class I PMP import.	3	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PEX3	PEX3	PEX3	PEX19	PEX19	PEX19	3	4	11	12
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Previous reports suggested PIAS1 physically interacts with Smad4 and enhances the Smad4 dependent transcriptional activation of TGF-beta signaling , whereas PIAS3 preferred to activate Smad3 .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Previous reports suggested PIAS1 physically interacts with Smad4 and enhances the Smad4 dependent transcriptional activation of TGF-beta signaling, whereas PIAS3 preferred to activate Smad3.	27	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIAS3	PIAS3	PIAS3	Smad3	Smad3	Smad3	27	28	31	32
Another interesting parallel is the PIAS3 mediated co-activation of Smad3 , where PIAS3 was shown to enhance the transcriptional activity of Smad3 by forming a ternary complex with the co-activator p300 [ XREF_BIBR ] .	Another interesting parallel is the PIAS3 mediated co-activation of Smad3, where PIAS3 was shown to enhance the transcriptional activity of Smad3 by forming a ternary complex with the co-activator p300 [XREF_BIBR].	12	22	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIAS3	PIAS3	PIAS3	Smad3	Smad3	Smad3	12	13	21	22
Here , loss of either PIAS1 or PIAS4 severely impairs K63-ub at damage sites , reduces recruitment BRCA1 and 53BP1 and causes impaired DSB repair .	Here, loss of either PIAS1 or PIAS4 severely impairs K63-ub at damage sites, reduces recruitment BRCA1 and 53BP1 and causes impaired DSB repair.	2	20	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PIAS4	loss of either PIAS1 or PIAS4	pias4	53BP1	53BP1	53bp1	7	8	19	20
Interestingly , in response to DSBs , PIAS4 also mediates SUMO1 modification of 53BP1 and BRCA1 while SUMO2/3 modification of BRCA1 is also mediated by PIAS1 .	Interestingly, in response to DSBs, PIAS4 also mediates SUMO1 modification of 53BP1 and BRCA1 while SUMO2/3 modification of BRCA1 is also mediated by PIAS1.	7	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIAS4	PIAS4	PIAS4	53BP1	53BP1	53BP1	7	8	13	14
In reporter assays Pellino3 leads to activation of c-Jun and Elk-1 , but not NF-kappaB .	In reporter assays Pellino3 leads to activation of c-Jun and Elk-1, but not NF-kappaB.	3	10	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Pellino3	Pellino3	Pellino3	c-Jun	c-Jun	c-Jun	3	4	8	9
Moreover , null alleles of Arabidopsis PEX14 still allow residual matrix protein import whereas null alleles of Arabidopsis PEX13 confer lethality , indicating a heightened importance of PEX13 versus PEX14 in early plant development .	Moreover, null alleles of Arabidopsis PEX14 still allow residual matrix protein import whereas null alleles of Arabidopsis PEX13 confer lethality, indicating a heightened importance of PEX13 versus PEX14 in early plant development.	3	28	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PEX14	PEX14	PEX14	PEX13	PEX13	PEX13	6	7	27	28
IRAK1 inhibits NLRP3 and is targeted by Pellino2 .	IRAK1 inhibits NLRP3 and is targeted by Pellino2.	0	8	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Pellino2	Pellino2	Pellino2	IRAK1	IRAK1	IRAK1	7	8	0	1
Furthermore , both Pellino proteins target kinases in manifesting these effects with Pellino3 promoting ubiquitination of RIP2 to mediate NOD2 signaling and Pellino2 targeting IRAK1 to facilitate NLRP3 inflammasome activation .	Furthermore, both Pellino proteins target kinases in manifesting these effects with Pellino3 promoting ubiquitination of RIP2 to mediate NOD2 signaling and Pellino2 targeting IRAK1 to facilitate NLRP3 inflammasome activation.	22	25	targeting	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Pellino2	Pellino2	Pellino2	IRAK1	IRAK1	IRAK1	22	23	24	25
However , we find that loss of PEX12 or PEX10 does not reduce the association of PEX5 with peroxisomes , demonstrating that these peroxins are not required for receptor docking .	However, we find that loss of PEX12 or PEX10 does not reduce the association of PEX5 with peroxisomes, demonstrating that these peroxins are not required for receptor docking.	5	17	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PEX12	loss of PEX12	pex12	PEX5	PEX5	pex5	7	8	16	17
The ability of PEX12 to bind PEX5 suggests that PEX12 may contribute to retaining PEX5 at the translocation apparatus .	The ability of PEX12 to bind PEX5 suggests that PEX12 may contribute to retaining PEX5 at the translocation apparatus.	9	18	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	PEX12	PEX12	PEX12	PEX5	PEX5	PEX5	9	10	14	15
According to one model , a downstream complex of two ATPases , PEX1 and PEX6 , and the peroxisomal membrane protein PEX26 are thought to mediate recycling of PEX5 into the cytosol [ XREF_BIBR , XREF_BIBR ] .	According to one model, a downstream complex of two ATPases, PEX1 and PEX6, and the peroxisomal membrane protein PEX26 are thought to mediate recycling of PEX5 into the cytosol [XREF_BIBR, XREF_BIBR].	10	29	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PEX6	PEX6	PEX6	PEX5	PEX5	PEX5	14	15	28	29
PEX26 contributes to peroxisome biogenesis by anchoring PEX6 and PEX1 to the membrane of the peroxisome .	PEX26 contributes to peroxisome biogenesis by anchoring PEX6 and PEX1 to the membrane of the peroxisome.	0	9	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PEX26	PEX26	PEX26	PEX6	PEX6	PEX6	0	1	7	8
In support of these results , we found that expression of PIAS1 and SUMO1 increased Akt activity , whereas expression of SENP1 reduced Akt1 activity .	In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity.	9	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIAS1	expression of PIAS1	pias1	Akt	Akt	akt	11	12	15	16
Pellino3 therefore blocks IRAK degradation and thus inhibits IL-1-induced NF-kappaB activation .	Pellino3 therefore blocks IRAK degradation and thus inhibits IL-1-induced NF-kappaB activation.	0	7	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pellino3	Pellino3	Pellino3	IRAK	IRAK	IRAK	0	1	3	4
The results demonstrated that pex14 , pex13 and pex12 mutations disrupt the proper targeting of PEX7 to peroxisomes .	The results demonstrated that pex14, pex13 and pex12 mutations disrupt the proper targeting of PEX7 to peroxisomes.	4	16	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	pex14	pex14	pex14	PEX7	PEX7	PEX7	4	5	15	16
Further investigation found that stabilization of PINK1 by BAG2 triggers Parkin mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of Parkinson ' s disease .	Further investigation found that stabilization of PINK1 by BAG2 triggers Parkin mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of Parkinson 's disease.	4	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	6	7	10	11
PINK1 activation in turn recruits and activates Parkin on OMM .	PINK1 activation in turn recruits and activates Parkin on OMM.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	7	8
The main role of PINK1 in cells is to promote Parkin mediated mitophagy by recruiting Parkin to damaged mitochondria .	The main role of PINK1 in cells is to promote Parkin mediated mitophagy by recruiting Parkin to damaged mitochondria.	2	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	4	5	10	11
While p-UB can activate PARKIN in vitro and overexpression of UB S65A delays PARKIN recruitment to mitochondria , the precise role of p-UB in PARKIN activation and its relationship to potentially direct activation of PARKIN by PINK1 is murky .	While p-UB can activate PARKIN in vitro and overexpression of UB S65A delays PARKIN recruitment to mitochondria, the precise role of p-UB in PARKIN activation and its relationship to potentially direct activation of PARKIN by PINK1 is murky.	32	37	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	36	37	34	35
PINK-1 phosporylates the ubiqutin and induces Parkin on Ser65 which is then allowed to move to mitochondria XREF_BIBR , XREF_BIBR .	PINK-1 phosporylates the ubiqutin and induces Parkin on Ser65 which is then allowed to move to mitochondria XREF_BIBR, XREF_BIBR.	0	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK-1	PINK-1	PINK-1	Parkin	Parkin	Parkin	0	1	6	7
At the mitochondrial surface , PINK1 recruits the E3 ubiquitin ligase Parkin and activates Parkin by phosphorylation XREF_BIBR , XREF_BIBR , XREF_BIBR .	At the mitochondrial surface, PINK1 recruits the E3 ubiquitin ligase Parkin and activates Parkin by phosphorylation XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	5	6	14	15
In addition , PINK1 can mediate mitophagy in a Parkin independent manner by recruiting nuclear dot protein 52kDa ( NDP52 ) and optineurin ( OPTN ) [ XREF_BIBR ] .	In addition, PINK1 can mediate mitophagy in a Parkin independent manner by recruiting nuclear dot protein 52kDa (NDP52) and optineurin (OPTN) [XREF_BIBR].	3	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	3	4	9	10
Parkin and PINK1 function in a conserved mitochondrial quality control pathway , in which PINK1 , a putative mitochondrial kinase , directs Parkin , a cytosolic E3 ubiquitin ligase , selectively to dysfunctional mitochondria to promote their isolation , immobilization and degradation by macroautophagy ( hereafter , mitophagy ) .	Parkin and PINK1 function in a conserved mitochondrial quality control pathway, in which PINK1, a putative mitochondrial kinase, directs Parkin, a cytosolic E3 ubiquitin ligase, selectively to dysfunctional mitochondria to promote their isolation, immobilization and degradation by macroautophagy (hereafter, mitophagy).	14	28	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	14	15	22	23
It had previously been shown that Rab7 , together with its GTPase activating proteins TBC1D15 and TBC1D17 , are required for Parkin mediated mitophagy downstream of PINK1 induced Parkin translocation to mitochondria .	It had previously been shown that Rab7, together with its GTPase activating proteins TBC1D15 and TBC1D17, are required for Parkin mediated mitophagy downstream of PINK1 induced Parkin translocation to mitochondria.	24	29	induced	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	26	27	28	29
Since decreased mitochondrial membrane potential ( Deltapsim ) prevents proteasomal degradation of PINK1 , it was proposed that PINK1 becomes stabilized on damaged mitochondria to activate Parkin XREF_BIBR .	Since decreased mitochondrial membrane potential (Deltapsim) prevents proteasomal degradation of PINK1, it was proposed that PINK1 becomes stabilized on damaged mitochondria to activate Parkin XREF_BIBR.	18	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	18	19	26	27
Although the studies on PINK1 phosphorylation of ubiquitin [ XREF_BIBR - XREF_BIBR ] and Parkin [ XREF_BIBR - XREF_BIBR ] suggest a novel mechanism for PINK1 activation of Parkin , the expression of phosphomimetics of ubiquitin and Parkin was insufficient to promote the mitochondrial recruitment of Parkin [ XREF_BIBR , XREF_BIBR ] .	Although the studies on PINK1 phosphorylation of ubiquitin [XREF_BIBR - XREF_BIBR] and Parkin [XREF_BIBR - XREF_BIBR] suggest a novel mechanism for PINK1 activation of Parkin, the expression of phosphomimetics of ubiquitin and Parkin was insufficient to promote the mitochondrial recruitment of Parkin [XREF_BIBR, XREF_BIBR].	25	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	25	26	28	29
This model is consistent with a role of Pink1 in controlling mitochondrial health and also does not exclude a downstream or parallel role where Pink1 can be triggered to recruit Parkin , facilitating mitophagy ( XREF_FIG ) .	This model is consistent with a role of Pink1 in controlling mitochondrial health and also does not exclude a downstream or parallel role where Pink1 can be triggered to recruit Parkin, facilitating mitophagy (XREF_FIG).	24	31	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pink1	Pink1	Pink1	Parkin	Parkin	Parkin	24	25	30	31
This study provides fundamental evidence that PINK1 phosphorylation at Ser 65 activates Parkin E3 ligase .	This study provides fundamental evidence that PINK1 phosphorylation at Ser 65 activates Parkin E3 ligase.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 phosphorylation at Ser 65	pink1	Parkin	Parkin	parkin	6	7	12	13
We developed a cell-free assay that recapitulates PINK1 dependent activation of Parkin E3 ligase activity against the established substrate Mfn1 .	We developed a cell-free assay that recapitulates PINK1 dependent activation of Parkin E3 ligase activity against the established substrate Mfn1.	7	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	7	8	11	12
Parkin contains four zinc coordinating domains ( RING0 , RING1 , IBR , and RING2 ) , although only RING1 adopts the canonical ubiquitin ligase RING domain structure , and several E2s can transfer ubiquitin to PINK1 activated Parkin .	Parkin contains four zinc coordinating domains (RING0, RING1, IBR, and RING2), although only RING1 adopts the canonical ubiquitin ligase RING domain structure, and several E2s can transfer ubiquitin to PINK1 activated Parkin.	33	39	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	36	37	38	39
We observed that MBP-PINK1 ubiquitylation was lost in mutants that led to decrease in Miro1 ubiquitylation or free chain formation ( A46P , K211N ) or both ( S65A , R275W , C431F , G430D , K161N , T415N ; XREF_FIG ) and was unaltered in mutants that had no effect or increased Parkin activity ( WT , K27N , R33Q , R42P , G328E ; XREF_FIG ) .	We observed that MBP-PINK1 ubiquitylation was lost in mutants that led to decrease in Miro1 ubiquitylation or free chain formation (A46P, K211N) or both (S65A, R275W, C431F, G430D, K161N, T415N; XREF_FIG) and was unaltered in mutants that had no effect or increased Parkin activity (WT, K27N, R33Q, R42P, G328E; XREF_FIG).	3	54	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MBP-PINK1	MBP-PINK1 ubiquitylation	mbp-pink1	Parkin	Parkin	parkin	3	4	53	54
Pink1 promotes Parkin mediated mitophagy by recruiting Parkin on mitochondria and promoting Parkin E3 ligase activity [ XREF_BIBR ] .	Pink1 promotes Parkin mediated mitophagy by recruiting Parkin on mitochondria and promoting Parkin E3 ligase activity [XREF_BIBR].	0	3	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Pink1	Pink1	Pink1	Parkin	Parkin	Parkin	0	1	2	3
Interestingly , using the phosphospecific Ser 65 antibody that is much more sensitive than the mass spectrometry approach employed in analysis of data in XREF_FIG a , we also observed phosphorylation of Parkin Ser 65 in cells not over-expressing PINK1 treated with CCCP suggesting endogenous PINK1 present in HEK293 is also able to phosphorylate Parkin ( XREF_FIG b ) .	Interestingly, using the phosphospecific Ser 65 antibody that is much more sensitive than the mass spectrometry approach employed in analysis of data in XREF_FIG a, we also observed phosphorylation of Parkin Ser 65 in cells not over-expressing PINK1 treated with CCCP suggesting endogenous PINK1 present in HEK293 is also able to phosphorylate Parkin (XREF_FIG b).	32	46	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	45	46	32	33
In the mitochondrial fraction , knockdown of PINK1 impaired the ART induced increase in Parkin , SQSTM1 , LC3 and ubiquitin levels in the mitochondria of the HeLa cells ( XREF_FIG C ) .	In the mitochondrial fraction, knockdown of PINK1 impaired the ART induced increase in Parkin, SQSTM1, LC3 and ubiquitin levels in the mitochondria of the HeLa cells (XREF_FIG C).	5	21	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	7	8	14	15
PINK1 dependent activation of Parkin is recognized as a major pathway to induce mitophagy .	PINK1 dependent activation of Parkin is recognized as a major pathway to induce mitophagy.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	4	5
Both wild-type PINK1 protein and S465D mutant protein can promote the transfer of Parkin to clustered mitochondria , while S465A , T313M , R492X mutant PINK1 had a relatively weaker role in the interaction with Parkin .	Both wild-type PINK1 protein and S465D mutant protein can promote the transfer of Parkin to clustered mitochondria, while S465A, T313M, R492X mutant PINK1 had a relatively weaker role in the interaction with Parkin.	2	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	2	3	13	14
Healthy mitochondria normally import and degrade the PD related protein Pink1 , but Pink1 exits mitochondria if the membrane potential collapses and initiates Parkin mediated mitophagy .	Healthy mitochondria normally import and degrade the PD related protein Pink1, but Pink1 exits mitochondria if the membrane potential collapses and initiates Parkin mediated mitophagy.	13	24	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pink1	Pink1	Pink1	Parkin	Parkin	Parkin	13	14	23	24
In addition , overexpression of Pink1 alone can initiate translocation of Parkin to mitochondria without mitochondrial damage XREF_BIBR .	In addition, overexpression of Pink1 alone can initiate translocation of Parkin to mitochondria without mitochondrial damage XREF_BIBR.	3	12	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pink1	overexpression of Pink1	pink1	Parkin	Parkin	parkin	5	6	11	12
PINK-1 in turn activates PARKIN , which translocates to depolarized mitochondria and promotes their degradation by mitophagy [ XREF_BIBR ] .	PINK-1 in turn activates PARKIN, which translocates to depolarized mitochondria and promotes their degradation by mitophagy [XREF_BIBR].	0	12	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	PINK-1	PINK-1	pink-1	PARKIN	PARKIN, which translocates to depolarized mitochondria	parkin	0	1	4	5
Expression of PINK1 enhanced Parkin mediated degradation of heat shock induced misfolded protein .	Expression of PINK1 enhanced Parkin mediated degradation of heat shock induced misfolded protein.	0	10	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	Expression of PINK1	pink1	Parkin	Parkin	parkin	2	3	4	5
PINK1 has been shown to activate Parkin both by direct phosphorylation and by phosphorylating ubiquitin .	PINK1 has been shown to activate Parkin both by direct phosphorylation and by phosphorylating ubiquitin.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	6	7
Parkin is activated through phosphorylation of ubiquitin by PINK1 ( do not forget that mutations in PINK1 are also associated with autosomal recessive PD ) .	Parkin is activated through phosphorylation of ubiquitin by PINK1 (do not forget that mutations in PINK1 are also associated with autosomal recessive PD).	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	8	9	0	1
Knockdown of PINK1 abolished Parkin recruitment to mitochondria and mitophagy in response to CCCP treatment [ XREF_BIBR ] , whereas overexpression of PINK1 promoted translocation of Parkin to mitochondria with normal Deltapsim [ XREF_BIBR ] .	Knockdown of PINK1 abolished Parkin recruitment to mitochondria and mitophagy in response to CCCP treatment [XREF_BIBR], whereas overexpression of PINK1 promoted translocation of Parkin to mitochondria with normal Deltapsim [XREF_BIBR].	20	27	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	overexpression of PINK1	pink1	Parkin	Parkin	parkin	22	23	26	27
PINK1 is likely to enhance Parkin function but probably is not required .	PINK1 is likely to enhance Parkin function but probably is not required.	0	11	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	5	6
Mechanistic insights into PINK1 mediated Parkin activation have recently been revealed .	Mechanistic insights into PINK1 mediated Parkin activation have recently been revealed.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	3	4	5	6
These data also support the notion that Parkin is protecting the Mutator mouse through mitophagy , where PINK1 is well established to activate Parkin activity , than through neuroprotective or transcriptional activation , where PINK1 has not been shown to be involved .	These data also support the notion that Parkin is protecting the Mutator mouse through mitophagy, where PINK1 is well established to activate Parkin activity, than through neuroprotective or transcriptional activation, where PINK1 has not been shown to be involved.	17	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	17	18	23	24
Disruption of either PINK1 or Parkin phosphorylation impaired the PINK1 and Parkin pathway , and the degeneration phenotype of photoreceptor neurons was obviously alleviated .	Disruption of either PINK1 or Parkin phosphorylation impaired the PINK1 and Parkin pathway, and the degeneration phenotype of photoreceptor neurons was obviously alleviated.	0	12	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 or Parkin phosphorylation	pink1	Parkin	Parkin	parkin	3	4	11	12
To obtain further evidence that PINK1 phosphorylation activates Parkin and to develop a more robust in vitro Parkin assay , we tested whether ubiquitylation of the proposed direct substrate Miro1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] could be deployed to assess Parkin activity .	To obtain further evidence that PINK1 phosphorylation activates Parkin and to develop a more robust in vitro Parkin assay, we tested whether ubiquitylation of the proposed direct substrate Miro1 [XREF_BIBR, XREF_BIBR, XREF_BIBR] could be deployed to assess Parkin activity.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 phosphorylation	pink1	Parkin	Parkin	parkin	5	6	8	9
PINK1 phosphorylation initiates a cascade of structural changes that result in sequential release of auto-inhibitory self-interactions and eventually liberation of Parkin enzymatic activities .	PINK1 phosphorylation initiates a cascade of structural changes that result in sequential release of auto-inhibitory self-interactions and eventually liberation of Parkin enzymatic activities.	0	22	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 phosphorylation	pink1	Parkin	Parkin	parkin	0	1	20	21
PINK1 and Parkin dependent mitophagy , which helps maintain a healthy mitochondrial network , is initiated by activation of the PINK1 kinase specifically on damaged mitochondria .	PINK1 and Parkin dependent mitophagy, which helps maintain a healthy mitochondrial network, is initiated by activation of the PINK1 kinase specifically on damaged mitochondria.	0	21	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	20	21	2	3
Once at the mitochondrial surface , Parkin is activated by PINK1 kinase activity through the phosphorylation of its serine65 .	Once at the mitochondrial surface, Parkin is activated by PINK1 kinase activity through the phosphorylation of its serine65.	6	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	10	11	6	7
PINK1 potentiates activation of PARKIN leading to the activation of mitochondrial fission and mitophagy .	PINK1 potentiates activation of PARKIN leading to the activation of mitochondrial fission and mitophagy.	0	5	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	0	1	4	5
Therefore , ROT induces a vicious cycle wherein H 2 O 2 indirectly triggers PINK-1 , which in turn activates ( > ) Parkin > NF-kappaB > p53 > Parkin .	Therefore, ROT induces a vicious cycle wherein H 2 O 2 indirectly triggers PINK-1, which in turn activates (>) Parkin> NF-kappaB> p53> Parkin.	13	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK-1	PINK-1	PINK-1	Parkin	Parkin	Parkin	14	15	23	24
The ability of a single RING-HECT hybrid E3 to synthesize both canonical and non canonical chain linkages is unusual but was confirmed in vitro using PINK1 activated PARKIN and kinetic analysis of UB chain synthesis by UB-AQUA .	The ability of a single RING-HECT hybrid E3 to synthesize both canonical and non canonical chain linkages is unusual but was confirmed in vitro using PINK1 activated PARKIN and kinetic analysis of UB chain synthesis by UB-AQUA.	25	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	25	26	27	28
However , when Parkin translocation was completely blocked by loss of PINK1 , this was not rescued by expression of either NDUFA10 or ND42 ( XREF_FIG ) .	However, when Parkin translocation was completely blocked by loss of PINK1, this was not rescued by expression of either NDUFA10 or ND42 (XREF_FIG).	3	12	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PINK1	loss of PINK1	pink1	Parkin	Parkin	parkin	11	12	3	4
Herein , PINK1 accumulates on the surface of dysfunctional mitochondria and recruits and activates cytosolic PARKIN .	Herein, PINK1 accumulates on the surface of dysfunctional mitochondria and recruits and activates cytosolic PARKIN.	2	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	2	3	15	16
The second feedforward loop involves the generation of mitochondrial polyubiquitin chains by PINK1 activated Parkin , and/or another mitochondrial E3 ligase , and their subsequent phosphorylation by PINK1 .	The second feedforward loop involves the generation of mitochondrial polyubiquitin chains by PINK1 activated Parkin, and/or another mitochondrial E3 ligase, and their subsequent phosphorylation by PINK1.	10	15	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	12	13	14	15
The absence or reduction of PINK1 in flies does not affect the ability of Parkin overexpression to impair mitochondrial motility [ XREF_BIBR ] and morphology [ XREF_BIBR ] , indicating that PINK1 phosphorylation on its substrates such as Miro is likely to stimulate Parkin function , but probably not absolutely necessary .	The absence or reduction of PINK1 in flies does not affect the ability of Parkin overexpression to impair mitochondrial motility [XREF_BIBR] and morphology [XREF_BIBR], indicating that PINK1 phosphorylation on its substrates such as Miro is likely to stimulate Parkin function, but probably not absolutely necessary.	31	44	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 phosphorylation	pink1	Parkin	Parkin	parkin	31	32	43	44
Although much progress has been made into understanding how PINK1 and Parkin are regulated , a major question remains on the cellular consequences of PINK1 directed Parkin activation after mitochondrial depolarization .	Although much progress has been made into understanding how PINK1 and Parkin are regulated, a major question remains on the cellular consequences of PINK1 directed Parkin activation after mitochondrial depolarization.	22	27	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	24	25	26	27
In addition , PINK1 induces Parkin to self-associate involving the RBR domain , which may mediate Parkin enzyme activation .	In addition, PINK1 induces Parkin to self-associate involving the RBR domain, which may mediate Parkin enzyme activation.	3	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	3	4	5	6
Accumulation of PINK1 on the OMM can also be triggered by knockdown of the mitochondrial protease Lon [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] and is sufficient to induce Parkin activity and downstream mitophagy [ XREF_BIBR , XREF_BIBR ] .	Accumulation of PINK1 on the OMM can also be triggered by knockdown of the mitochondrial protease Lon [XREF_BIBR, XREF_BIBR, XREF_BIBR] and is sufficient to induce Parkin activity and downstream mitophagy [XREF_BIBR, XREF_BIBR].	0	30	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	2	3	29	30
Mitochondrial depolarization promotes the assembly of K6 , K11 , K48 , and K63 UB chains on numerous mitochondrial proteins via PINK1 activated PARKIN ( Steps 1 and 2 ) .	Mitochondrial depolarization promotes the assembly of K6, K11, K48, and K63 UB chains on numerous mitochondrial proteins via PINK1 activated PARKIN (Steps 1 and 2).	19	28	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	21	22	23	24
The accumulated PINK1 recruits a cytosolic E3 ubiquitin ligase PARKIN and activates PARKIN by phosphorylation .	The accumulated PINK1 recruits a cytosolic E3 ubiquitin ligase PARKIN and activates PARKIN by phosphorylation.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	2	3	12	13
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin .	PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin.	0	10	Activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	9	10
It causes PINK1 accumulation that eventually induces Parkin to initiate the autophagic degradation of the damaged mitochondria .	It causes PINK1 accumulation that eventually induces Parkin to initiate the autophagic degradation of the damaged mitochondria.	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	2	3	7	8
Parkin is then recruited to the OMM and activated by PINK1 .	Parkin is then recruited to the OMM and activated by PINK1.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	10	11	0	1
While PINK1 activation of Parkin is promoted by mitochondrial membrane depolarization [ XREF_BIBR ] , Bnip3 targets mitochondria in the polarized state to autophagosomes [ XREF_BIBR ] .	While PINK1 activation of Parkin is promoted by mitochondrial membrane depolarization [XREF_BIBR], Bnip3 targets mitochondria in the polarized state to autophagosomes [XREF_BIBR].	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	1	2	4	5
Overexpression of PINK1-WT but not PINK1 mutants induced the translocation of parkin to mitochondria regardless of depolarization ( XREF_FIG ) , as reported previously .	Overexpression of PINK1-WT but not PINK1 mutants induced the translocation of parkin to mitochondria regardless of depolarization (XREF_FIG), as reported previously.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1-WT	Overexpression of PINK1-WT	pink1-wt	parkin	parkin	parkin	2	3	11	12
Parkin is activated by the protein kinase PINK1 , which is stabilized on depolarized mitochondria upon mitochondrial damage .	Parkin is activated by the protein kinase PINK1, which is stabilized on depolarized mitochondria upon mitochondrial damage.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	7	8	0	1
In brief , upon the loss of mitochondrial membrane potential , the PINK1 protein is stabilized on the outer mitochondrial membrane and thereby activates and recruits the E3 ubiquitin ligase parkin .	In brief, upon the loss of mitochondrial membrane potential, the PINK1 protein is stabilized on the outer mitochondrial membrane and thereby activates and recruits the E3 ubiquitin ligase parkin.	12	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	12	13	30	31
Pink-1 present on the OMM triggers the migration of Parkin , an E3 ubiquitin ligase from the cytosol to the mitochondrion , likely by phosphorylation events on either Pink-1 XREF_BIBR or Parkin XREF_BIBR , or both .	Pink-1 present on the OMM triggers the migration of Parkin, an E3 ubiquitin ligase from the cytosol to the mitochondrion, likely by phosphorylation events on either Pink-1 XREF_BIBR or Parkin XREF_BIBR, or both.	0	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pink-1	Pink-1	Pink-1	Parkin	Parkin	Parkin	0	1	9	10
However , Parkin clustering was fully rescued by co-transfection of PINK1 W437X together with the editing vector in 85 +/-8% of the cells positive for PINK1 , Parkin and ADAR2 expression .	However, Parkin clustering was fully rescued by co-transfection of PINK1 W437X together with the editing vector in 85 +/-8% of the cells positive for PINK1, Parkin and ADAR2 expression.	2	11	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	10	11	2	3
Despite significant advances , our understanding of how PINK1 activates PARKIN to promote substrate ubiquitylation remains incomplete .	Despite significant advances, our understanding of how PINK1 activates PARKIN to promote substrate ubiquitylation remains incomplete.	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	8	9	10	11
Thus , our study supports a model where Parkin is locally activated by PINK1 .	Thus, our study supports a model where Parkin is locally activated by PINK1.	8	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	13	14	8	9
The key question that remains is how Parkin is activated , for instance by PINK1 once it arrives at mitochondria , as Parkin activators must release a variety of safety belts that keep Parkin inactive .	The key question that remains is how Parkin is activated, for instance by PINK1 once it arrives at mitochondria, as Parkin activators must release a variety of safety belts that keep Parkin inactive.	7	15	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	14	15	7	8
Knockdown of PINK1 abolishes Parkin recruitment to mitochondria and mitophagy in response to CCCP treatment [ XREF_BIBR ] , whereas overexpression of PINK1 promotes translocation of Parkin to mitochondria with normal potential [ XREF_BIBR ] .	Knockdown of PINK1 abolishes Parkin recruitment to mitochondria and mitophagy in response to CCCP treatment [XREF_BIBR], whereas overexpression of PINK1 promotes translocation of Parkin to mitochondria with normal potential [XREF_BIBR].	20	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	overexpression of PINK1	pink1	Parkin	Parkin	parkin	22	23	26	27
The present study provides fundamental novel mechanistic insights into how PINK1 activates Parkin E3 ligase activity and suggests a dual regulatory mechanism of Parkin E3 ligase activity in which PINK1 dependent phosphorylation of Parkin at Ser 65 is required to prime Parkin for activation by ubiquitin Phospho-Ser65 .	The present study provides fundamental novel mechanistic insights into how PINK1 activates Parkin E3 ligase activity and suggests a dual regulatory mechanism of Parkin E3 ligase activity in which PINK1 dependent phosphorylation of Parkin at Ser 65 is required to prime Parkin for activation by ubiquitin Phospho-Ser65.	10	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	10	11	12	13
PINK1 mediated activation of Parkin is orchestrated by an interplay between phosphorylation and ubiquitination .	PINK1 mediated activation of Parkin is orchestrated by an interplay between phosphorylation and ubiquitination.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	4	5
Although the mechanism underlying PINK1 mediated activation of Parkin has remained elusive , Parkin Ser 65 phosphorylation by PINK1 was proposed to be involved in its activation of E3 ligase activity [ XREF_BIBR , XREF_BIBR ] .	Although the mechanism underlying PINK1 mediated activation of Parkin has remained elusive, Parkin Ser 65 phosphorylation by PINK1 was proposed to be involved in its activation of E3 ligase activity [XREF_BIBR, XREF_BIBR].	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	4	5	8	9
Similarly , expression of exogenous PINK1 at high levels leads to damage independent recruitment of Parkin to axonal mitochondria in both PINK1 +/+ and PINK1 -/- genetic backgrounds .	Similarly, expression of exogenous PINK1 at high levels leads to damage independent recruitment of Parkin to axonal mitochondria in both PINK1 +/+ and PINK1 -/- genetic backgrounds.	2	16	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	expression of exogenous PINK1	pink1	Parkin	Parkin	parkin	5	6	15	16
PINK1 overexpression increased basal Parkin accumulation on neuronal mitochondria , but did not sensitize them to depolarization induced Parkin translocation .	PINK1 overexpression increased basal Parkin accumulation on neuronal mitochondria, but did not sensitize them to depolarization induced Parkin translocation.	0	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 overexpression	pink1	Parkin	Parkin	parkin	0	1	4	5
Upon loss of inner mitochondrial membrane potential , PINK1 , a mitochondrial kinase , is selectively stabilized on the surface of the dysfunctional mitochondrion , leading to the recruitment of the E3 ubiquitin ligase Parkin 9 .	Upon loss of inner mitochondrial membrane potential, PINK1, a mitochondrial kinase, is selectively stabilized on the surface of the dysfunctional mitochondrion, leading to the recruitment of the E3 ubiquitin ligase Parkin 9.	8	35	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	8	9	34	35
Beyond PINK1 activation of Parkin , this novel modification of Ub may have other implications .	Beyond PINK1 activation of Parkin, this novel modification of Ub may have other implications.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	1	2	4	5
PINK1 activates Parkin activity leading to ubiquitination of multiple proteins , which in turn promotes clearance of mitochondria by mitophagy .	PINK1 activates Parkin activity leading to ubiquitination of multiple proteins, which in turn promotes clearance of mitochondria by mitophagy.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	2	3
Further , parkin knockdown prevents the reduction in PARIS seen with PINK1 overexpression ( XREF_FIG ) , while PINK1 knockdown abolished parkin mediated degradation of PARIS ( XREF_FIG ) .	Further, parkin knockdown prevents the reduction in PARIS seen with PINK1 overexpression (XREF_FIG), while PINK1 knockdown abolished parkin mediated degradation of PARIS (XREF_FIG).	18	22	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	18	19	21	22
Mechanistically , this Ub burst would require local activation of parkin by PINK1 in the vicinity of Mfn2 , which could be achieved by PINK1 catalyzed phosphorylation of the resulting Ub chains - events that would dually serve to activate parkin and tether it in place .	Mechanistically, this Ub burst would require local activation of parkin by PINK1 in the vicinity of Mfn2, which could be achieved by PINK1 catalyzed phosphorylation of the resulting Ub chains - events that would dually serve to activate parkin and tether it in place.	6	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	12	13	10	11
We also find that Parkin targeted to peroxisomes by PINK1 is sufficient to drive pexophagy but this was not recapitulated on lysosomes .	We also find that Parkin targeted to peroxisomes by PINK1 is sufficient to drive pexophagy but this was not recapitulated on lysosomes.	4	13	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	9	10	4	5
We and othershave shown that PINK1 and Parkin function in the same pathway , with PINK1 positively regulating Parkin to control mitochondrial integrity and quality control in Drosophila .	We and othershave shown that PINK1 and Parkin function in the same pathway, with PINK1 positively regulating Parkin to control mitochondrial integrity and quality control in Drosophila.	15	20	positively regulating	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	15	16	18	19
Genetic studies suggest that PINK1 and parkin function in a common genetic pathway with PINK1 positively regulating parkin .	Genetic studies suggest that PINK1 and parkin function in a common genetic pathway with PINK1 positively regulating parkin.	4	18	positively regulating	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	4	5	17	18
We next sought to determine the major site ( s ) of Miro1 ubiquitylation by Parkin that had been activated by PINK1 phosphorylation .	We next sought to determine the major site (s) of Miro1 ubiquitylation by Parkin that had been activated by PINK1 phosphorylation.	4	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1 phosphorylation	pink1	Parkin	Parkin	parkin	21	22	15	16
In this review , we highlight recent breakthroughs addressing the key issues of how PINK1 activates Parkin in response to mitochondrial malfunction , how Parkin localizes specifically to impaired mitochondria , and how ubiquitination and deubiquitination regulate PINK1 and Parkin mediated mitophagy .	In this review, we highlight recent breakthroughs addressing the key issues of how PINK1 activates Parkin in response to mitochondrial malfunction, how Parkin localizes specifically to impaired mitochondria, and how ubiquitination and deubiquitination regulate PINK1 and Parkin mediated mitophagy.	14	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	14	15	16	17
However , prior studies both in vitro and in vivo have painted a bewildering picture of PARKIN chain assembly , with K27 , K48 , and K63 linked chains being independently reported on various PARKIN targets or on total mitochondrial proteins , most often using overexpressed UB mutants ( in vivo ) or fragments of PARKIN not activated by PINK1 ( in vitro ) that are prone to artifacts .	However, prior studies both in vitro and in vivo have painted a bewildering picture of PARKIN chain assembly, with K27, K48, and K63 linked chains being independently reported on various PARKIN targets or on total mitochondrial proteins, most often using overexpressed UB mutants (in vivo) or fragments of PARKIN not activated by PINK1 (in vitro) that are prone to artifacts.	53	66	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	59	60	55	56
We had previously shown that , even in the absence of mitochondrial damage , PINK1 overexpression is sufficient to cause Parkin dependent arrest of mitochondrial motility .	We had previously shown that, even in the absence of mitochondrial damage, PINK1 overexpression is sufficient to cause Parkin dependent arrest of mitochondrial motility.	14	22	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 overexpression	pink1	Parkin	Parkin	parkin	14	15	20	21
Using MDS of a PINK1 activated Parkin molecule , we could further corroborate structural effects of mutations selected from each domain , but could also show that moderate local changes can translate into significant rearrangements upon activation and opening of Parkin .	Using MDS of a PINK1 activated Parkin molecule, we could further corroborate structural effects of mutations selected from each domain, but could also show that moderate local changes can translate into significant rearrangements upon activation and opening of Parkin.	1	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	4	5	6	7
The ability of Parkin overexpression to alter mitochondrial motility in the presence of PINK1 RNAi ( XREF_FIG ) or mitochondrial morphology in a PINK1 null background indicates that , although PINK1 can stimulate Parkin function , Parkin can act independently as well .	The ability of Parkin overexpression to alter mitochondrial motility in the presence of PINK1 RNAi (XREF_FIG) or mitochondrial morphology in a PINK1 null background indicates that, although PINK1 can stimulate Parkin function, Parkin can act independently as well.	30	34	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	30	31	33	34
If mitochondria re-establish membrane potential , PINK1 accumulated on the outer mitochondrial membrane is readily re-imported and degraded to deactivate Parkin , terminate mitophagy and maintain healthy organelles in the network .	If mitochondria re-establish membrane potential, PINK1 accumulated on the outer mitochondrial membrane is readily re-imported and degraded to deactivate Parkin, terminate mitophagy and maintain healthy organelles in the network.	6	21	degraded	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	6	7	20	21
PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65 .	PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65.	0	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	10	11
These data indicate that phospho-Ub stimulates Parkin ligase activity and represents a mechanism of PINK1 activation of Parkin ( XREF_FIG ) .	These data indicate that phospho-Ub stimulates Parkin ligase activity and represents a mechanism of PINK1 activation of Parkin (XREF_FIG).	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	14	15	17	18
Another new report indicates that two xenophagy pathway proteins , NDP52 and optineurin , can promote mitophagy independent of Parkin by functioning as autophagy receptors in HeLa cells after being tagged with PINK1 phosphorylated ubiquitin [ XREF_BIBR ] ( XREF_FIG ) The relationship of this PINK1 mediated Parkin independent mitophagy pathway to PINK1-Mfn2-Parkin signaling is unclear .	Another new report indicates that two xenophagy pathway proteins, NDP52 and optineurin, can promote mitophagy independent of Parkin by functioning as autophagy receptors in HeLa cells after being tagged with PINK1 phosphorylated ubiquitin [XREF_BIBR] (XREF_FIG) The relationship of this PINK1 mediated Parkin independent mitophagy pathway to PINK1-Mfn2-Parkin signaling is unclear.	42	50	mediated	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	45	46	47	48
We found that the defective parkin OMM recruitment phenotype of PINK1 -/- neurons was rescued by PINK1 WT expression ( XREF_FIG ) .	We found that the defective parkin OMM recruitment phenotype of PINK1 -/- neurons was rescued by PINK1 WT expression (XREF_FIG).	3	19	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1 WT expression	pink1	parkin	parkin	parkin	16	17	5	6
PINK1 modulates Parkin in several distinct ways : First , its mitochondrial abundance is regulated through proteolysis ; healthy mitochondria degrade PINK1 , thereby normally maintaining low levels and activity .	PINK1 modulates Parkin in several distinct ways : First, its mitochondrial abundance is regulated through proteolysis; healthy mitochondria degrade PINK1, thereby normally maintaining low levels and activity.	0	6	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	2	3
For example PINK1 activates Parkin through phosphorylation of ubiquitin and enhances Parkin mediated elimination of damaged mitochondria ( mitophagy ) .	For example PINK1 activates Parkin through phosphorylation of ubiquitin and enhances Parkin mediated elimination of damaged mitochondria (mitophagy).	2	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	2	3	11	12
More importantly , another study reported that lentiviral overexpression of wild type PINK1 in these DA neurons was able to restore the translocation of Parkin to mitochondria , further validating the association between PINK1 and Parkin [ XREF_BIBR ] .	More importantly, another study reported that lentiviral overexpression of wild type PINK1 in these DA neurons was able to restore the translocation of Parkin to mitochondria, further validating the association between PINK1 and Parkin [XREF_BIBR].	8	25	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	overexpression of wild type PINK1	pink1	Parkin	Parkin	parkin	12	13	24	25
At the outer mitochondrial membrane , PINK1 induces the ubiquitin ligase activity of Parkin by phosphorylation , thus eliciting the rapid inclusion of mitochondria in LC3 positive vacuoles and ultimately leading to their lysosomal mediated degradation .	At the outer mitochondrial membrane, PINK1 induces the ubiquitin ligase activity of Parkin by phosphorylation, thus eliciting the rapid inclusion of mitochondria in LC3 positive vacuoles and ultimately leading to their lysosomal mediated degradation.	6	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	6	7	13	14
Parkin is activated by serine/threonine protein kinase PINK1 and primarily exerts its influence in neurological disorders .	Parkin is activated by serine/threonine protein kinase PINK1 and primarily exerts its influence in neurological disorders.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	7	8	0	1
To confirm whether N-FLAG-PINK1 or DeltaN34 PINK1 activates Parkin under steady-state conditions , we tried to examine the localization and E3 activity of Parkin when these PINK1 mutants were expressed .	To confirm whether N-FLAG-PINK1 or DeltaN34 PINK1 activates Parkin under steady-state conditions, we tried to examine the localization and E3 activity of Parkin when these PINK1 mutants were expressed.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	6	7	8	9
In the absence of HECT like activity , Parkin can still be activated by PINK1 to self-associate and to form an oxyester ubiquitin enzyme intermediate but , without ubiquitination activity , does not stably attach to mitochondria .	In the absence of HECT like activity, Parkin can still be activated by PINK1 to self-associate and to form an oxyester ubiquitin enzyme intermediate but, without ubiquitination activity, does not stably attach to mitochondria.	8	34	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	14	15	8	9
YFP-Parkin C431N mitochondrial translocation was not observed in rapalog- and CCCP treated cells subjected to PINK1 siRNA , confirming that PINK1 drives Parkin self association .	YFP-Parkin C431N mitochondrial translocation was not observed in rapalog- and CCCP treated cells subjected to PINK1 siRNA, confirming that PINK1 drives Parkin self association.	20	24	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	20	21	22	23
PINK1 phosphorylated Ub serves to both activate and anchor parkin to the OMM , where it can ligate more Ub moieties that are subsequently phosphorylated .	PINK1 phosphorylated Ub serves to both activate and anchor parkin to the OMM, where it can ligate more Ub moieties that are subsequently phosphorylated.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	0	1	9	10
On the surface of mitochondria with low Deltapsi m , PINK1 accumulates , leading to the recruitment of the ubiquitin ligase Parkin , which ubiquitinylates outer membrane proteins including BCL-2 , VDAC1 , MFN1 and MFN2 .	On the surface of mitochondria with low Deltapsi m, PINK1 accumulates, leading to the recruitment of the ubiquitin ligase Parkin, which ubiquitinylates outer membrane proteins including BCL-2, VDAC1, MFN1 and MFN2.	10	24	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	10	11	21	22
Overexpression of wild-type PINK1 using an intact CMV promoter causes Parkin mitochondrial localization and activation irrespective of DeltaPsim , whereas expression of wild-type PINK1 using the CMV ( d1 ) promoter results in Parkin recruitment and activation that are dependent on a decrease in DeltaPsim .	Overexpression of wild-type PINK1 using an intact CMV promoter causes Parkin mitochondrial localization and activation irrespective of DeltaPsim, whereas expression of wild-type PINK1 using the CMV (d1) promoter results in Parkin recruitment and activation that are dependent on a decrease in DeltaPsim.	0	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	Overexpression of wild-type PINK1	pink1	Parkin	Parkin	parkin	3	4	10	11
Direct Activation of PARKIN by PINK1 Promotes Synthesis of Canonical and Non Canonical UB Chains in vitro .	Direct Activation of PARKIN by PINK1 Promotes Synthesis of Canonical and Non Canonical UB Chains in vitro.	1	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	5	6	3	4
Various models for the PINK1 mediated Parkin recruitment process have been proposed , but , until now , none have adequately explained the accumulated data .	Various models for the PINK1 mediated Parkin recruitment process have been proposed, but, until now, none have adequately explained the accumulated data.	1	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	4	5	6	7
Consistent with the mitochondrial hypothesis , it has been postulated that the role of PARK2 and PINK1 in mitochondrial quality control underlies the basis of PARK2 related PD .	Consistent with the mitochondrial hypothesis, it has been postulated that the role of PARK2 and PINK1 in mitochondrial quality control underlies the basis of PARK2 related PD.	12	27	underlies	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARK2	PARK2	PARK2	16	17	25	26
SH-SY5Y cells constitutively over expressing wild-type parkin were treated with PINK1 or control siRNA for 6 days and mtDNA relative expression measured .	SH-SY5Y cells constitutively over expressing wild-type parkin were treated with PINK1 or control siRNA for 6 days and mtDNA relative expression measured.	4	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	10	11	6	7
In response to mitochondrial damage , PINK1 induces the activation of parkin by phosphorylation .	In response to mitochondrial damage, PINK1 induces the activation of parkin by phosphorylation.	6	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	6	7	11	12
Parkin lacking the Ubl domain is still activated by PINK1 indicating that phospho-ubiquitin binding to Parkin does more than displace the Parkin Ubl domain .	Parkin lacking the Ubl domain is still activated by PINK1 indicating that phospho-ubiquitin binding to Parkin does more than displace the Parkin Ubl domain.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	9	10	0	1
Recent high-resolution crystal structures of Parkin that were mainly solved without the Ubl domain have not provided much insight into how Parkin is activated by PINK1 [ XREF_BIBR - XREF_BIBR ] .	Recent high-resolution crystal structures of Parkin that were mainly solved without the Ubl domain have not provided much insight into how Parkin is activated by PINK1 [XREF_BIBR - XREF_BIBR].	21	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	25	26	21	22
The low levels of PINK1 could enable some of the Parkin dependent routes ( PARKIN2 age effect = +2.1 ) .	The low levels of PINK1 could enable some of the Parkin dependent routes (PARKIN2 age effect = +2.1).	2	12	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	levels of PINK1	pink1	Parkin	Parkin	parkin	4	5	10	11
This approach revealed that overexpression of wild-type PINK1 in PINK1 mutant neurons restored the translocation of Parkin to mitochondria ( XREF_FIG ; right panel ) .	This approach revealed that overexpression of wild-type PINK1 in PINK1 mutant neurons restored the translocation of Parkin to mitochondria (XREF_FIG; right panel).	4	17	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	overexpression of wild-type PINK1	pink1	Parkin	Parkin	parkin	7	8	16	17
In vitro , PINK1 directly activates PARKIN ' s ability to assemble canonical and non canonical UB chains , and promotes association of PARKIN with both p-UB and poly-p-UB .	In vitro, PINK1 directly activates PARKIN 's ability to assemble canonical and non canonical UB chains, and promotes association of PARKIN with both p-UB and poly-p-UB.	1	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	3	4	23	24
On the outer mitochondrial membrane ( OMM ) , PINK1 recruits the E3 ubiquitin ligase Parkin and activates latent Parkin activity to ubiquitinate scores of OMM proteins .	On the outer mitochondrial membrane (OMM), PINK1 recruits the E3 ubiquitin ligase Parkin and activates latent Parkin activity to ubiquitinate scores of OMM proteins.	9	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	9	10	19	20
PINK1 FL phosphorylates the GTPase Miro , and thus induces Parkin dependent degeneration of Miro .	PINK1 FL phosphorylates the GTPase Miro, and thus induces Parkin dependent degeneration of Miro.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	10	11
Furthermore , disruption of PINK1 phosphorylation prevented the mitochondrial translocation of Parkin , and the absence of Parkin phosphorylation abolished PINK1 and Parkin induced cell death .	Furthermore, disruption of PINK1 phosphorylation prevented the mitochondrial translocation of Parkin, and the absence of Parkin phosphorylation abolished PINK1 and Parkin induced cell death.	4	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 phosphorylation	pink1	Parkin	Parkin	parkin	4	5	11	12
We also found that Parkin targeted to peroxisomes by PINK1 was sufficient to signal pexophagy .	We also found that Parkin targeted to peroxisomes by PINK1 was sufficient to signal pexophagy.	4	13	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	9	10	4	5
The results suggest that PINK1 stimulates Parkin associated mitochondrial clearance in GCs suffering oxidative injury .	The results suggest that PINK1 stimulates Parkin associated mitochondrial clearance in GCs suffering oxidative injury.	4	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	4	5	6	7
The mechanism of PINK1 mediated activation of Parkin has remained elusive .	The mechanism of PINK1 mediated activation of Parkin has remained elusive.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	3	4	7	8
Recent models of Parkin activation by PINK1 have highlighted a role for ubiquitin Phospho-Ser65 in binding and recruiting phosphorylated Parkin to mitochondria triggering a feed-forward amplification loop of Parkin activity at the mitochondria [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Recent models of Parkin activation by PINK1 have highlighted a role for ubiquitin Phospho-Ser65 in binding and recruiting phosphorylated Parkin to mitochondria triggering a feed-forward amplification loop of Parkin activity at the mitochondria [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	6	7	3	4
Because PINK1 acts upstream of Parkin and increases the Parkin E3 ligase activity , PINK1 and Parkin may jointly promote growth factor induced Akt signal transduction .	Because PINK1 acts upstream of Parkin and increases the Parkin E3 ligase activity, PINK1 and Parkin may jointly promote growth factor induced Akt signal transduction.	1	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	1	2	9	10
PINK1 Triggers Autocatalytic Activation of Parkin to Specify Cell Fate Decisions .	PINK1 Triggers Autocatalytic Activation of Parkin to Specify Cell Fate Decisions.	0	6	Triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	5	6
This might require PINK1 stimulated association of Parkin and Mfn2 with mitochondria , so we tested the functional significance of PINK1-Mfn2-Parkin interactions on ubiquitination .	This might require PINK1 stimulated association of Parkin and Mfn2 with mitochondria, so we tested the functional significance of PINK1-Mfn2-Parkin interactions on ubiquitination.	2	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	3	4	7	8
At the OMM , PINK1 activates the ubiquitin ligase activity of Parkin by phosphorylation .	At the OMM, PINK1 activates the ubiquitin ligase activity of Parkin by phosphorylation.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	4	5	11	12
To test if Parkin HECT like activity is activated by PINK1 in vivo , untagged C431S Parkin or C431F Parkin were expressed in cells treated with or without CCCP .	To test if Parkin HECT like activity is activated by PINK1 in vivo, untagged C431S Parkin or C431F Parkin were expressed in cells treated with or without CCCP.	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	10	11	3	4
For example , it has been shown that PINK1 can recruit the autophagy receptors NDP52 and optineurin directly to mitochondria to activate mitophagy independent of Parkin .	For example, it has been shown that PINK1 can recruit the autophagy receptors NDP52 and optineurin directly to mitochondria to activate mitophagy independent of Parkin.	8	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	8	9	25	26
Damaged and depolarized mitochondria are targeted by PTEN induced putative kinase 1 ( PINK1 ) , which drives Parkin mediated mitophagic engulfment by autophagosomes .	Damaged and depolarized mitochondria are targeted by PTEN induced putative kinase 1 (PINK1), which drives Parkin mediated mitophagic engulfment by autophagosomes.	11	19	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	13	14	18	19
Mitofusins are ubiquitinated even in yeast that lack PINK1 and Parkin supporting the idea that ubiquitinated mitofusins , among other ubiquitinated OMM proteins , may represent a starting point for the PINK1 and Parkin positive feedback ubiquitin phosphorylation cycle ( XREF_FIG ) .	Mitofusins are ubiquitinated even in yeast that lack PINK1 and Parkin supporting the idea that ubiquitinated mitofusins, among other ubiquitinated OMM proteins, may represent a starting point for the PINK1 and Parkin positive feedback ubiquitin phosphorylation cycle (XREF_FIG).	8	38	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	8	9	33	34
Moreover , when PINK1 -/- MEFs co-expressing GFP-Parkin and CMV ( d1 ) promoter driven PINK1 were treated with CCCP , autoubiquitylation of GFP-Parkin was clearly observed only following CCCP treatment ( XREF_FIG , lane 4 ) , suggesting that a defined expression level of exogenous PINK1 enables Parkin to localize specifically to depolarized mitochondria .	Moreover, when PINK1 -/- MEFs co-expressing GFP-Parkin and CMV (d1) promoter driven PINK1 were treated with CCCP, autoubiquitylation of GFP-Parkin was clearly observed only following CCCP treatment (XREF_FIG, lane 4), suggesting that a defined expression level of exogenous PINK1 enables Parkin to localize specifically to depolarized mitochondria.	43	50	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	level of exogenous PINK1	pink1	Parkin	Parkin	parkin	46	47	48	49
Many substrates of PINK1 and mechanisms for PINK1 mediated Parkin activation have been postulated .	Many substrates of PINK1 and mechanisms for PINK1 mediated Parkin activation have been postulated.	1	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	7	8	9	10
Therefore it appears that Parkin could be the main substrate of PINK1 , but the structural basis for PINK1 kinase activity targeting the Parkin Ubl remains unknown .	Therefore it appears that Parkin could be the main substrate of PINK1, but the structural basis for PINK1 kinase activity targeting the Parkin Ubl remains unknown.	18	24	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	18	19	23	24
Thus , while p-UB is capable of activating PARKIN in trans , the extent of activation is significantly lower than with PINK1 activated PARKIN across canonical and non canonical chain linkages .	Thus, while p-UB is capable of activating PARKIN in trans, the extent of activation is significantly lower than with PINK1 activated PARKIN across canonical and non canonical chain linkages.	21	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	21	22	23	24
We and other groups have reported that PINK1 activates Parkin E3 ligase activity both directly via phosphorylation of Parkin serine 65 ( Ser 65 ) -- which lies within its ubiquitin like domain ( Ubl ) -- and indirectly through phosphorylation of ubiquitin at Ser 65 .	We and other groups have reported that PINK1 activates Parkin E3 ligase activity both directly via phosphorylation of Parkin serine 65 (Ser 65) -- which lies within its ubiquitin like domain (Ubl) -- and indirectly through phosphorylation of ubiquitin at Ser 65.	7	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	7	8	9	10
Mutations in PARKIN and PINK1 cause recessive forms of PD , and these genes ( encoding parkin , an E3 ubiquitin ligase , and PINK1 , a mitochondrially targeted protein kinase ) primarily function in the quality control of mitochondria ; a collection of pathways regulating the removal of damaged proteins , lipids , and organelles from the mitochondrial reticulum to ensure its proper activity .	Mutations in PARKIN and PINK1 cause recessive forms of PD, and these genes (encoding parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrially targeted protein kinase) primarily function in the quality control of mitochondria; a collection of pathways regulating the removal of damaged proteins, lipids, and organelles from the mitochondrial reticulum to ensure its proper activity.	0	24	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	4	5	16	17
PINK1 overexpression induced PARK2 translocation in 51 % of scrambled shRNA expressing cells but in only 33 % of Becn1 shRNA expressing cells .	PINK1 overexpression induced PARK2 translocation in 51% of scrambled shRNA expressing cells but in only 33% of Becn1 shRNA expressing cells.	0	4	induced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 overexpression	pink1	PARK2	PARK2	park2	0	1	3	4
Furthermore , Parkin targeted to peroxisomes by PINK1 is sufficient to drive pexophagy , but not on lysosomes [ XREF_BIBR ] .	Furthermore, Parkin targeted to peroxisomes by PINK1 is sufficient to drive pexophagy, but not on lysosomes [XREF_BIBR].	2	9	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	7	8	2	3
PINK-1 in turn enhances Parkin activity , potentiating the fusion of mitochondria and mitophagy [ XREF_BIBR ] .	PINK-1 in turn enhances Parkin activity, potentiating the fusion of mitochondria and mitophagy [XREF_BIBR].	0	5	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK-1	PINK-1	PINK-1	Parkin	Parkin	Parkin	0	1	4	5
For example , whereas wild-type PINK1 can rescue Parkin mitochondrial localization in PINK1 -/- mouse embryonic fibroblasts ( MEFs ) , a kinase dead mutant of PINK1 can not .	For example, whereas wild-type PINK1 can rescue Parkin mitochondrial localization in PINK1 -/- mouse embryonic fibroblasts (MEFs), a kinase dead mutant of PINK1 can not.	4	10	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	5	6	8	9
PINK1 phosphorylates various mitochondrial proteins such as mitofusin2 ( mfn2 ) , which recruits the E3 ubiquitin ligase Parkin , which in turn is activated by PINK1 .	PINK1 phosphorylates various mitochondrial proteins such as mitofusin2 (mfn2), which recruits the E3 ubiquitin ligase Parkin, which in turn is activated by PINK1.	13	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	26	27	18	19
Control of mitochondrial turnover and protection against oxidative stress are mediated via the kinase activity of PINK1 targeting Parkin [ XREF_BIBR ] , HTRA2 [ XREF_BIBR ] and TRAP1 [ XREF_BIBR ] proteins .	Control of mitochondrial turnover and protection against oxidative stress are mediated via the kinase activity of PINK1 targeting Parkin [XREF_BIBR], HTRA2 [XREF_BIBR] and TRAP1 [XREF_BIBR] proteins.	14	25	targeting	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	16	17	18	19
The effects of pathogenic mutations is further complicated when one considers that PINK1 mediated activation of parkin might be altered either through decreased efficiency of phosphorylation or modulation of ubiquitination by phospho-parkin .	The effects of pathogenic mutations is further complicated when one considers that PINK1 mediated activation of parkin might be altered either through decreased efficiency of phosphorylation or modulation of ubiquitination by phospho-parkin.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	12	13	16	17
PINK1 dependent activation of Parkin is recognized as a major pathway of mitophagy .	PINK1 dependent activation of Parkin is recognized as a major pathway of mitophagy.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	4	5
Hereditary Parkinson ' s disease is commonly caused by mutations in the protein kinase PINK1 or the E3 ubiquitin ligase Parkin , which function together to eliminate damaged mitochondria .	Hereditary Parkinson 's disease is commonly caused by mutations in the protein kinase PINK1 or the E3 ubiquitin ligase Parkin, which function together to eliminate damaged mitochondria.	7	26	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	14	15	20	21
The mitochondrial kinase PINK1 activates and recruits the E3 ubiquitin ligase Parkin to de-energized mitochondria .	The mitochondrial kinase PINK1 activates and recruits the E3 ubiquitin ligase Parkin to de-energized mitochondria.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	3	4	11	12
However , the requirement of PINK1 for parkin activation was not bypassed by phosphomimetic parkin mutation , and how PINK1 accelerates the E3 activity of parkin on damaged mitochondria is still obscure .	However, the requirement of PINK1 for parkin activation was not bypassed by phosphomimetic parkin mutation, and how PINK1 accelerates the E3 activity of parkin on damaged mitochondria is still obscure.	19	28	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	19	20	25	26
Although PINK1 induced Parkin activation has been widely studied , the precise mechanism of Parkin activation is not fully elucidated .	Although PINK1 induced Parkin activation has been widely studied, the precise mechanism of Parkin activation is not fully elucidated.	1	4	induced	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	1	2	3	4
In this study we assess the role of mitochondrial factors in PINK1 mediated Parkin translocation and activation .	In this study we assess the role of mitochondrial factors in PINK1 mediated Parkin translocation and activation.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	11	12	13	14
Immunostaining showed that PA not only increased PINK1 and Parkin levels , but also promoted PINK1 and Parkin localization to mitochondria in peri-nuclear area ( XREF_FIG ) .	Immunostaining showed that PA not only increased PINK1 and Parkin levels, but also promoted PINK1 and Parkin localization to mitochondria in peri-nuclear area (XREF_FIG).	3	18	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PA not only increased PINK1 and Parkin levels	pink1	Parkin	Parkin	parkin	7	8	17	18
PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy .	PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	0	1	2	3
Although cell-free experiments indicate that this Ubl domain interaction inhibits Parkin E3 ligase activity , these experiments did not take PINK1 activation of Parkin into account .	Although cell-free experiments indicate that this Ubl domain interaction inhibits Parkin E3 ligase activity, these experiments did not take PINK1 activation of Parkin into account.	20	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	20	21	23	24
Rab8A is not required for PINK1 dependent activation of Parkin E3 ligase activity .	Rab8A is not required for PINK1 dependent activation of Parkin E3 ligase activity.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	5	6	9	10
PARKIN activation by PINK1 produces canonical and non canonical UB chains on mitochondria , and PARKIN dependent chain assembly is required for accumulation of poly-phospho-UB ( poly-p-UB ) on mitochondria .	PARKIN activation by PINK1 produces canonical and non canonical UB chains on mitochondria, and PARKIN dependent chain assembly is required for accumulation of poly-phospho-UB (poly-p-UB) on mitochondria.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	3	4	0	1
However , overexpression of wild-type PINK1 harboring kinase domain enabled Parkin to translocate .	However, overexpression of wild-type PINK1 harboring kinase domain enabled Parkin to translocate.	2	12	enabled	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	overexpression of wild-type PINK1	pink1	Parkin	Parkin	parkin	5	6	10	11
In conclusion , this study has suggested that PINK1 dependent Parkin phosphorylation at Ser65 accelerates the mitochondrial translocation of Parkin and showed that the introduction of mutations at this site also affects subsequent mitophagy processes .	In conclusion, this study has suggested that PINK1 dependent Parkin phosphorylation at Ser65 accelerates the mitochondrial translocation of Parkin and showed that the introduction of mutations at this site also affects subsequent mitophagy processes.	8	20	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 dependent Parkin phosphorylation at Ser65	pink1	Parkin	Parkin	parkin	8	9	19	20
Another mechanism that PINK1 activating Parkin is that PINK1 phosphorylates ubiquitin at Ser65 ( pS65-Ub ) , and pS65-Ub binds and activates Parkin due to Parkin ' s high affinity for pS65-Ub .	Another mechanism that PINK1 activating Parkin is that PINK1 phosphorylates ubiquitin at Ser65 (pS65-Ub), and pS65-Ub binds and activates Parkin due to Parkin 's high affinity for pS65-Ub.	3	6	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	3	4	5	6
PINK1 MEDIATED PARKIN ACTIVATION .	PINK1 MEDIATED PARKIN ACTIVATION.	0	3	MEDIATED	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	0	1	2	3
In mammals , the PINK1 kinase activates ubiquitin ligase Parkin by phosphorylating S65 of Ub and of the Parkin Ubl domain , which in turn promotes the amplification of autophagy signals necessary for the removal of damaged mitochondria .	In mammals, the PINK1 kinase activates ubiquitin ligase Parkin by phosphorylating S65 of Ub and of the Parkin Ubl domain, which in turn promotes the amplification of autophagy signals necessary for the removal of damaged mitochondria.	4	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	4	5	9	10
Increased expression of full-length PINK1 enhances recruitment of parkin to chemically depolarized mitochondria , resulting in rapid mitochondrial clearance in transformed cell lines .	Increased expression of full-length PINK1 enhances recruitment of parkin to chemically depolarized mitochondria, resulting in rapid mitochondrial clearance in transformed cell lines.	1	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	expression of full-length PINK1	pink1	parkin	parkin	parkin	4	5	8	9
Thus the mechanism underlying PINK1 mediated Parkin recruitment remained a mystery .	Thus the mechanism underlying PINK1 mediated Parkin recruitment remained a mystery.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	4	5	6	7
PINK1 senses damaged mitochondria , and recruits and activates Parkin to ubiquitinate mitochondrial outer membrane proteins including mitofusins and Miro .	PINK1 senses damaged mitochondria, and recruits and activates Parkin to ubiquitinate mitochondrial outer membrane proteins including mitofusins and Miro.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	9	10
Parkin mRNA was absent in knockout hearts , but transcript levels of upstream Parkin activators PINK1 and Mfn2 increased ( XREF_FIG ) .	Parkin mRNA was absent in knockout hearts, but transcript levels of upstream Parkin activators PINK1 and Mfn2 increased (XREF_FIG).	10	16	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	15	16	13	14
These results suggest that BECN1 is involved in CCCP or PINK1 overexpression induced PARK2 translocation to mitochondria and that this effect is not related to inhibition of PINK1 accumulation at mitochondria .	These results suggest that BECN1 is involved in CCCP or PINK1 overexpression induced PARK2 translocation to mitochondria and that this effect is not related to inhibition of PINK1 accumulation at mitochondria.	8	14	induced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 overexpression	pink1	PARK2	PARK2	park2	10	11	13	14
Stabilization of PINK1 by BAG2 triggers PARKIN mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of PD .	Stabilization of PINK1 by BAG2 triggers PARKIN mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of PD.	0	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	2	3	6	7
Transfection of these MEFS with wild-type PINK1 restored parkin translocation [ XREF_BIBR ] .	Transfection of these MEFS with wild-type PINK1 restored parkin translocation [XREF_BIBR].	3	9	restored	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	6	7	8	9
The respective editing vector against PINK1 W437X was functional to rescue the PINK1 mediated perinuclear clustering of Parkin and the mitophagy phenotype in PINK1-KO HeLa cells under transient transfection of the editing target .	The respective editing vector against PINK1 W437X was functional to rescue the PINK1 mediated perinuclear clustering of Parkin and the mitophagy phenotype in PINK1-KO HeLa cells under transient transfection of the editing target.	11	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	12	13	17	18
PINK1 is localized at the OMM , and can activate parkin by phosphorylation , which in turn ubiquitinates numerous proteins , including OMM proteins and autophagy receptors .	PINK1 is localized at the OMM, and can activate parkin by phosphorylation, which in turn ubiquitinates numerous proteins, including OMM proteins and autophagy receptors.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	0	1	10	11
While overexpression of either wild-type PINK1 or the mutant p.G411S , but not p.Q456X , effectively activated parkin in this paradigm , the p.G411S mutant showed a small , but significant reduction compared to wild-type .	While overexpression of either wild-type PINK1 or the mutant p.G411S, but not p.Q456X, effectively activated parkin in this paradigm, the p.G411S mutant showed a small, but significant reduction compared to wild-type.	1	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	overexpression of either wild-type PINK1	pink1	parkin	parkin	parkin	5	6	17	18
Overexpression of PINK1-WT or TRAF6-WT restored the translocation of parkin after knockdown of endogenous PINK1 or TRAF6 ( XREF_FIG ) .	Overexpression of PINK1-WT or TRAF6-WT restored the translocation of parkin after knockdown of endogenous PINK1 or TRAF6 (XREF_FIG).	0	10	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1-WT	Overexpression of PINK1-WT	pink1-wt	parkin	parkin	parkin	2	3	9	10
PINK1 also signals and activates intracellular Parkin to ubiquitinate defective mitochondria for mitophagy .	PINK1 also signals and activates intracellular Parkin to ubiquitinate defective mitochondria for mitophagy.	0	7	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	6	7
PINK1 activates the E3 ligase parkin ( PARK2 ) to ubiquitylate mitochondrial outer membrane proteins , providing an ' eat me ' signal for recognition by the autophagy machinery 21 .	PINK1 activates the E3 ligase parkin (PARK2) to ubiquitylate mitochondrial outer membrane proteins, providing an ' eat me ' signal for recognition by the autophagy machinery 21.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	0	1	5	6
PINK1 activated parkin and phosphorylated ubiquitin then promote ubiquitination and subsequent degradation of many mitochondrial proteins , including mitofusion 1 and 2 , TOM20 , TOM70 and VDACs [ XREF_BIBR - XREF_BIBR ] .	PINK1 activated parkin and phosphorylated ubiquitin then promote ubiquitination and subsequent degradation of many mitochondrial proteins, including mitofusion 1 and 2, TOM20, TOM70 and VDACs [XREF_BIBR - XREF_BIBR].	0	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	0	1	2	3
When mitochondrial membrane potential decreases , PINK1 is stabilized and accumulates selectively in dysfunctional mitochondria , allowing it to retrieve Parkin from the cytoplasm to the mitochondria where Parkin initiates the degradation of damaged mitochondria .	When mitochondrial membrane potential decreases, PINK1 is stabilized and accumulates selectively in dysfunctional mitochondria, allowing it to retrieve Parkin from the cytoplasm to the mitochondria where Parkin initiates the degradation of damaged mitochondria.	6	23	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	6	7	20	21
PINK1 drives Parkin self association and HECT like E3 activity upstream of mitochondrial binding .	PINK1 drives Parkin self association and HECT like E3 activity upstream of mitochondrial binding.	0	13	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	2	3
Here , we show that the relocation of Parkin to mitochondria induced by a collapse of DeltaPsi ( m ) relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria , even in cells with normal DeltaPsi ( m ) .	Here, we show that the relocation of Parkin to mitochondria induced by a collapse of DeltaPsi (m) relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal DeltaPsi (m).	30	36	causes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	33	34	35	36
Overexprsssion of parkin in pink1 null flies rescues mitochondrial phenotype , but overexpression of PINK1 does not rescue the phenotype in parkin null flies , suggesting that parkin functions in the downstream of PINK1 [ XREF_BIBR , XREF_BIBR ] .	Overexprsssion of parkin in pink1 null flies rescues mitochondrial phenotype, but overexpression of PINK1 does not rescue the phenotype in parkin null flies, suggesting that parkin functions in the downstream of PINK1 [XREF_BIBR, XREF_BIBR].	12	23	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	overexpression of PINK1	pink1	parkin	parkin	parkin	14	15	21	22
Also , parkin targeting to mitochondria was completely abolished in fibroblasts from PINK1 KO mice and could be rescued by reintroduction of wild-type PINK1 .	Also, parkin targeting to mitochondria was completely abolished in fibroblasts from PINK1 KO mice and could be rescued by reintroduction of wild-type PINK1.	2	24	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	parkin	parkin	parkin	23	24	2	3
To determine if PINK1 mediated neuroprotective effect involves Parkin , we examined whether Drosophila parkin overexpression ( parkin OE ) alleviates HD phenotype in Drosophila .	To determine if PINK1 mediated neuroprotective effect involves Parkin, we examined whether Drosophila parkin overexpression (parkin OE) alleviates HD phenotype in Drosophila.	3	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	3	4	8	9
Furthermore , given that PINK1 can activate Parkin without obvious mitochondrial translocation , one can mechanistically separate Parkin E3 activation and translocation into two distinct steps .	Furthermore, given that PINK1 can activate Parkin without obvious mitochondrial translocation, one can mechanistically separate Parkin E3 activation and translocation into two distinct steps.	4	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	4	5	7	8
Of note , the serine/threonine protein kinase PINK1 which is required to activate PARKIN appeared stabilized but not increased under KP46 treated HCT116 as compared to controls ( data not shown ) .	Of note, the serine/threonine protein kinase PINK1 which is required to activate PARKIN appeared stabilized but not increased under KP46 treated HCT116 as compared to controls (data not shown).	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	PARKIN	PARKIN	PARKIN	7	8	13	14
Co-expression of PINK1 and Parkin , or expression of mitochondria targeted Parkin induces mitochondrial aggregation in human DA neuroblastoma cells .	Co-expression of PINK1 and Parkin, or expression of mitochondria targeted Parkin induces mitochondrial aggregation in human DA neuroblastoma cells.	0	12	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	Co-expression of PINK1	pink1	Parkin	Parkin	parkin	2	3	11	12
Our results are consistent with prior studies showing that PTEN and PIK3CA activate mTOR signaling downstream of AKT in non redundant ways .	Our results are consistent with prior studies showing that PTEN and PIK3CA activate mTOR signaling downstream of AKT in non redundant ways.	9	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	11	12	17	18
In basal like breast cancer , the AKT1 , PIK3CA , and MYC loci are commonly amplified and induce constitutive Akt and c-Myc pathway signaling .	In basal like breast cancer, the AKT1, PIK3CA, and MYC loci are commonly amplified and induce constitutive Akt and c-Myc pathway signaling.	7	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	9	10	20	21
These findings show that although acute p110alpha inhibition partially diminishes AKT activation , selective p110alpha inhibitors are likely to be less immunosuppressive in vivo compared with p110delta or pan-class I inhibitors .	These findings show that although acute p110alpha inhibition partially diminishes AKT activation, selective p110alpha inhibitors are likely to be less immunosuppressive in vivo compared with p110delta or pan-class I inhibitors.	6	11	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	6	7	10	11
We predict that both Pten deficiency and constitutive activation of p110alpha * may activate AKT .	We predict that both Pten deficiency and constitutive activation of p110alpha * may activate AKT.	8	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	10	11	14	15
p110alpha inhibition partially reduced B cell receptor ( BCR )-dependent AKT activation and proliferation , and diminished survival supported by the cytokines BAFF and IL-4 .	p110alpha inhibition partially reduced B cell receptor (BCR)-dependent AKT activation and proliferation, and diminished survival supported by the cytokines BAFF and IL-4.	0	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	0	1	10	11
Because we observed that Akt localized to invadopodia , site specific and controlled activation of Akt by p110alpha and PDK1 may be required for proper invadopodia formation and cancer invasion .	Because we observed that Akt localized to invadopodia, site specific and controlled activation of Akt by p110alpha and PDK1 may be required for proper invadopodia formation and cancer invasion.	10	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Akt	Akt	Akt	17	18	15	16
Single FGFR3 or PIK3CA mutations and the different mutation combinations FGFR3-PIK3CA and AKT1 and PIK3CA-RAS can activate the AKT but not the MAPK pathway .	Single FGFR3 or PIK3CA mutations and the different mutation combinations FGFR3-PIK3CA and AKT1 and PIK3CA-RAS can activate the AKT but not the MAPK pathway.	10	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA-RAS	PIK3CA-RAS	PIK3CA-RAS	AKT	AKT	AKT	14	15	18	19
Inhibition of p110alpha reduced IGF-I-stimulated Akt activity and prevented IGF-I-mediated survival in H 2 O 2 -treated cells ; in contrast , siRNA knockdown of p110beta increased IGF-I-stimulated Akt activity .	Inhibition of p110alpha reduced IGF-I-stimulated Akt activity and prevented IGF-I-mediated survival in H 2 O 2 -treated cells; in contrast, siRNA knockdown of p110beta increased IGF-I-stimulated Akt activity.	0	6	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Akt	Akt	Akt	2	3	5	6
However , p110alpha over-expression alone is not apparently sufficient to activate AKT signalling in OCs and hence may require other alterations to be fully oncogenic .	However, p110alpha over-expression alone is not apparently sufficient to activate AKT signalling in OCs and hence may require other alterations to be fully oncogenic.	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha over-expression	p110alpha	AKT	AKT	akt	2	3	11	12
4.2 Increased PI3Kalpha Activity Upregulates K + Current and Ion Channel Subunit Expression Independent of Akt Signaling .	4.2 Increased PI3Kalpha Activity Upregulates K + Current and Ion Channel Subunit Expression Independent of Akt Signaling.	2	16	Upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	Akt	Akt	Akt	2	3	15	16
Expression of Pik3ca with E545K mutation alone was unable to cause hyperplasia or cancer in the uterus and did not activate Akt as effectively as Pten deletion in short-term cultures of mouse endometrial epithelium , likely explaining the lack of phenotype in vivo .	Expression of Pik3ca with E545K mutation alone was unable to cause hyperplasia or cancer in the uterus and did not activate Akt as effectively as Pten deletion in short-term cultures of mouse endometrial epithelium, likely explaining the lack of phenotype in vivo.	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pik3ca	Expression of Pik3ca	pik3ca	Akt	Akt	akt	2	3	21	22
Silencing p110alpha or p110delta partially inhibited Akt and PKB activation induced by anti-CD3 plus anti-ICOS antibodies .	Silencing p110alpha or p110delta partially inhibited Akt and PKB activation induced by anti-CD3 plus anti-ICOS antibodies.	0	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Akt	Akt	Akt	1	2	6	7
Unlike PIK3CA mutation , PTEN loss appears to activate PIP3 and AKT signaling preferentially through the p110beta subunit , and PI3Kalpha selective inhibitors do not inhibit PI3K and AKT signaling in these cells .	Unlike PIK3CA mutation, PTEN loss appears to activate PIP3 and AKT signaling preferentially through the p110beta subunit, and PI3Kalpha selective inhibitors do not inhibit PI3K and AKT signaling in these cells.	20	29	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	AKT	AKT	AKT	20	21	28	29
In the AKT pathway , genes associated with AKT activation including PIK3R1 , PIK3CA , and PPP2CA were coordinately up-regulated in the LTNP group ( versus VIR ) in CD4+ and CD8+ T cells .	In the AKT pathway, genes associated with AKT activation including PIK3R1, PIK3CA, and PPP2CA were coordinately up-regulated in the LTNP group (versus VIR) in CD4+ and CD8+ T cells.	8	14	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	13	14	8	9
Although p110alpha inhibition partially diminished Akt activation , it is likely that selective p110alpha inhibitors will be less immunosuppressive in vivo than p110delta or pan PI3K class I inhibitors [ XREF_BIBR ] .	Although p110alpha inhibition partially diminished Akt activation, it is likely that selective p110alpha inhibitors will be less immunosuppressive in vivo than p110delta or pan PI3K class I inhibitors [XREF_BIBR].	1	6	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Akt	Akt	Akt	1	2	5	6
XREF_FIG showed that myr-PIK3CA was able to constitutively activate AKT in low serum condition ( 1 % ) compared with wt-PIK3CA and control transfection .	XREF_FIG showed that myr-PIK3CA was able to constitutively activate AKT in low serum condition (1%) compared with wt-PIK3CA and control transfection.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	myr-PIK3CA	myr-PIK3CA	myr-PIK3CA	AKT	AKT	AKT	3	4	9	10
Our results demonstrate that IGF-1 treatment or inactivation of PTEN enhances I ( Ca , L ) via PI3Kalpha dependent increase in PKB activation .	Our results demonstrate that IGF-1 treatment or inactivation of PTEN enhances I (Ca, L) via PI3Kalpha dependent increase in PKB activation.	18	23	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	PKB	PKB	PKB	18	19	22	23
These findings are reminiscent of breast or endometrial cancer , in which PIK3CA mutations are frequently detected in the setting of low PTEN expression or mutations XREF_BIBR , XREF_BIBR , and suggest that p110alpha over-expression alone may not be sufficient to activate AKT signalling and hence requires other alterations to be fully oncogenic in OC .	These findings are reminiscent of breast or endometrial cancer, in which PIK3CA mutations are frequently detected in the setting of low PTEN expression or mutations XREF_BIBR, XREF_BIBR, and suggest that p110alpha over-expression alone may not be sufficient to activate AKT signalling and hence requires other alterations to be fully oncogenic in OC.	33	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha over-expression	p110alpha	AKT	AKT	akt	33	34	42	43
In breast cancer , a hyperactive AKT mediated by PTEN loss , PIK3CA , or AKT mutations resulted in resistance to anti-HER2 antibody , trastuzumab .	In breast cancer, a hyperactive AKT mediated by PTEN loss, PIK3CA, or AKT mutations resulted in resistance to anti-HER2 antibody, trastuzumab.	4	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	12	13	6	7
p110alpha mediates PI3K and AKT signaling and anchorage independent growth of human HER2+ , PTEN deficient breast cancer cells .	p110alpha mediates PI3K and AKT signaling and anchorage independent growth of human HER2+, PTEN deficient breast cancer cells.	0	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	0	1	4	5
These results establish that p110alpha primarily mediates PI3K and AKT signaling in HER2+ PTEN deficient breast tumors whereas p110beta conditionally mediates HER2 and PI3K signaling in the absence of p110alpha .	These results establish that p110alpha primarily mediates PI3K and AKT signaling in HER2+ PTEN deficient breast tumors whereas p110beta conditionally mediates HER2 and PI3K signaling in the absence of p110alpha.	4	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	4	5	9	10
Akt is hyperactivated in cancer cells by multiple mechanisms , including the loss of PTEN , mutations that activate the catalytic subunit of PI3K , p110alpha , mutations that activate Akt isoforms , the activation of RAS and growth factor receptors and amplification of the genes encoding the catalytic subunit of PI3K and Akt ( XREF_FIG ) .	Akt is hyperactivated in cancer cells by multiple mechanisms, including the loss of PTEN, mutations that activate the catalytic subunit of PI3K, p110alpha, mutations that activate Akt isoforms, the activation of RAS and growth factor receptors and amplification of the genes encoding the catalytic subunit of PI3K and Akt (XREF_FIG).	14	31	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Akt	Akt	Akt	25	26	30	31
Depletion of PIK3CA with two distinct shRNA hairpins in MDA-MB-468 cells also induced AKT reactivation evidenced by increased AKT phosphorylation at Ser 473 , Thr 308 and phosphorylation of PRAS40 and GSK-3beta ( XREF_FIG ) .	Depletion of PIK3CA with two distinct shRNA hairpins in MDA-MB-468 cells also induced AKT reactivation evidenced by increased AKT phosphorylation at Ser 473, Thr 308 and phosphorylation of PRAS40 and GSK-3beta (XREF_FIG).	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	2	3	13	14
Given its central node position in the canonical PI3K pathway , AKT can be activated by either upstream PIK3CA activation or PTEN inactivation .	Given its central node position in the canonical PI3K pathway, AKT can be activated by either upstream PIK3CA activation or PTEN inactivation.	11	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	18	19	11	12
This observation suggests that p110alpha over-expression alone is not sufficient to activate AKT signalling and hence requires other alterations to be fully oncogenic in NSCLCs .	This observation suggests that p110alpha over-expression alone is not sufficient to activate AKT signalling and hence requires other alterations to be fully oncogenic in NSCLCs.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha over-expression	p110alpha	AKT	AKT	akt	4	5	12	13
Akt is frequently activated by upstream PIK3CA or PTEN mutations or gene silencing .	Akt is frequently activated by upstream PIK3CA or PTEN mutations or gene silencing.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	6	7	0	1
Highlights * RA increases the expression of p110alpha subunit of PI3K , Akt and beta1 subunit of Na + / K + -ATPase * Ouabain induces activation of Akt and ERK 1/2 in differentiated SK-N-SH cells but not in non differentiated cells * 1 muM ouabain leads to a decrease in the number of cells in non differentiated SK-N-SH * Reduction of ouabain induced cell death in differentiated SK-N-SH Introduction .	Highlights * RA increases the expression of p110alpha subunit of PI3K, Akt and beta1 subunit of Na + / K + -ATPase * Ouabain induces activation of Akt and ERK 1/2 in differentiated SK-N-SH cells but not in non differentiated cells * 1 muM ouabain leads to a decrease in the number of cells in non differentiated SK-N-SH * Reduction of ouabain induced cell death in differentiated SK-N-SH Introduction.	2	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	RA increases the expression of p110alpha	p110alpha	Akt	Akt	akt	7	8	28	29
PIK3CA knockdown decreases Akt activation in GBM cell lines , and knockdown of either PIK3CA or PIK3R1 reduces FAK activity .	PIK3CA knockdown decreases Akt activation in GBM cell lines, and knockdown of either PIK3CA or PIK3R1 reduces FAK activity.	0	4	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	0	1	3	4
For example , TimeTP detected perturbation of the PI3K-Akt signaling pathway ( XREF_TABLE ) but it was not included the TF-Pathway map in time clock ( XREF_FIG ) because PI3K-Akt signaling pathway is directly activated by the modification of PIK3CA in the experiment .	For example, TimeTP detected perturbation of the PI3K-Akt signaling pathway (XREF_TABLE) but it was not included the TF-Pathway map in time clock (XREF_FIG) because PI3K-Akt signaling pathway is directly activated by the modification of PIK3CA in the experiment.	29	40	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	PI3K-Akt	PI3K-Akt	PI3K-Akt	39	40	29	30
In many cancers , PI3K and AKT pathway activation is mediated by oncogenic mutations in PIK3CA and AKT1 genes .	In many cancers, PI3K and AKT pathway activation is mediated by oncogenic mutations in PIK3CA and AKT1 genes.	6	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	15	16	6	7
Furthermore , PI3K ( p110alpha ) signalling negatively regulated GPCR stimulated extracellular responsive kinase and Akt ( via PI3K , p110 ) activation [ XREF_BIBR ] .	Furthermore, PI3K (p110alpha) signalling negatively regulated GPCR stimulated extracellular responsive kinase and Akt (via PI3K, p110) activation [XREF_BIBR].	2	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Akt	Akt	Akt	4	5	15	16
p110alpha ablation and chronic inhibition upregulates AKT signaling .	p110alpha ablation and chronic inhibition upregulates AKT signaling.	0	7	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	0	1	6	7
Tumoral mutations in PIK3CA , the catalytic subunit of PI3K , activates AKT and promotes CRC cell growth .	Tumoral mutations in PIK3CA, the catalytic subunit of PI3K, activates AKT and promotes CRC cell growth.	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	3	4	12	13
Both PIK3CA and EGFR synergize to engage oncogenic PI3K and AKT signaling , which is a key driver of many different cancer types , including PC .	Both PIK3CA and EGFR synergize to engage oncogenic PI3K and AKT signaling, which is a key driver of many different cancer types, including PC.	0	11	synergize	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	1	2	10	11
Taken together , the data showed that while E4-ORF1 and rasV12 similarly elevate p85alpha , p85beta , and p110alpha levels and activate Akt in a PI3K dependent manner in human epithelial cells , E4-ORF1 differs from rasV12 in its dependence on both a PBM and Dlg1 for these activities and in not activating the Raf and MAP kinase pathway .	Taken together, the data showed that while E4-ORF1 and rasV12 similarly elevate p85alpha, p85beta, and p110alpha levels and activate Akt in a PI3K dependent manner in human epithelial cells, E4-ORF1 differs from rasV12 in its dependence on both a PBM and Dlg1 for these activities and in not activating the Raf and MAP kinase pathway.	8	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	E4-ORF1 and rasV12 similarly elevate p85alpha, p85beta, and p110alpha levels	p110alpha	Akt	Akt	akt	18	19	22	23
Unexpectedly , these experiments revealed that PI3Kalpha mediated electrical remodeling , reflecting transcriptional upregulation of ion channel subunits , is independent of cellular hypertrophy and Akt signaling .	Unexpectedly, these experiments revealed that PI3Kalpha mediated electrical remodeling, reflecting transcriptional upregulation of ion channel subunits, is independent of cellular hypertrophy and Akt signaling.	6	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	Akt	Akt	Akt	6	7	25	26
Silencing of p110alpha or AKT resulted in markedly enhanced activation of STAT3 , and decreased AKT activity in the si-AKT group ( XREF_FIG ) .	Silencing of p110alpha or AKT resulted in markedly enhanced activation of STAT3, and decreased AKT activity in the si-AKT group (XREF_FIG).	0	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	2	3	15	16
Mutations in p110alpha , the catalytic subunit of PI3K , are often present in tumors and cause increased PIP3 production and aberrant activation of Akt .	Mutations in p110alpha, the catalytic subunit of PI3K, are often present in tumors and cause increased PIP3 production and aberrant activation of Akt.	0	25	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Akt	Akt	Akt	2	3	24	25
Our results indicate that in NHUC , rare mutant forms and all three hotspot mutant forms of PIK3CA can activate the PI3K and AKT pathway .	Our results indicate that in NHUC, rare mutant forms and all three hotspot mutant forms of PIK3CA can activate the PI3K and AKT pathway.	15	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	17	18	23	24
showed that VacA activates PI3K and p110alpha , which in turn activates Akt to phosphorylate GSK3beta .	showed that VacA activates PI3K and p110alpha, which in turn activates Akt to phosphorylate GSK3beta.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Akt	Akt	Akt	6	7	12	13
However , p110alpha overexpression may not be sufficient to activate AKT signalling and drive ovarian tumorigenesis since many tumors overexpressing PI3K presented at least one additional alteration .	However, p110alpha overexpression may not be sufficient to activate AKT signalling and drive ovarian tumorigenesis since many tumors overexpressing PI3K presented at least one additional alteration.	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha overexpression	p110alpha	AKT	AKT	akt	2	3	10	11
PIK3CA encodes the catalytic subunit p110 alpha of PI3K XREF_BIBR , and mutated PIK3CA stimulates the AKT pathway and promotes cell growth in various cancers , including CRC XREF_BIBR .	PIK3CA encodes the catalytic subunit p110 alpha of PI3K XREF_BIBR, and mutated PIK3CA stimulates the AKT pathway and promotes cell growth in various cancers, including CRC XREF_BIBR.	12	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	13	14	16	17
Somatic mutations in PIK3CA ( phosphatidylinositol-4 ,5-bisphosphonate 3-kinase [ PI3K ] , catalytic subunit alpha gene ) activate the PI3K-AKT signaling pathway and contribute to pathogenesis of various malignancies , including colorectal cancer .	Somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphonate 3-kinase [PI3K], catalytic subunit alpha gene) activate the PI3K-AKT signaling pathway and contribute to pathogenesis of various malignancies, including colorectal cancer.	1	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	19	20
Combined Her2 , p110alpha and p110beta inhibition maximally abrogated AKT activation and minimized tumor growth .	Combined Her2, p110alpha and p110beta inhibition maximally abrogated AKT activation and minimized tumor growth.	3	10	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	3	4	9	10
PI3Kalpha or PI3Kbeta can induce activation of AKT by phosphorylation .	PI3Kalpha or PI3Kbeta can induce activation of AKT by phosphorylation.	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	AKT	AKT	AKT	0	1	7	8
Amplifications , gain-of-function mutations , and activation by upstream signaling of PIK3CA lead to the dysregulated activation of AKT allowing for the constitutive upregulation of multiple AKT directed oncogenic pathways including the mammalian target of rapamycin ( mTOR ) pathway [ XREF_BIBR ] .	Amplifications, gain-of-function mutations, and activation by upstream signaling of PIK3CA lead to the dysregulated activation of AKT allowing for the constitutive upregulation of multiple AKT directed oncogenic pathways including the mammalian target of rapamycin (mTOR) pathway [XREF_BIBR].	6	27	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	11	12	26	27
Obesity , insulin and insulin like growth factor-1 influence growth and inhibit apoptosis through phosphatidylinositol 3-kinase ( PIK3CA ) , which in turn activates Akt and protein kinase B ( PKB ) via phosphorylation .	Obesity, insulin and insulin like growth factor-1 influence growth and inhibit apoptosis through phosphatidylinositol 3-kinase (PIK3CA), which in turn activates Akt and protein kinase B (PKB) via phosphorylation.	15	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	17	18	24	25
Activation of the PIK3CA pathway increases the signaling of the AKT and mTOR pathway and stimulates proliferation of the cell .	Activation of the PIK3CA pathway increases the signaling of the AKT and mTOR pathway and stimulates proliferation of the cell.	3	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	3	4	10	11
2,4,10 Somatic mutations in PIK3CA have been shown to induce oncogenic characteristics by activating AKT .	2,4,10 Somatic mutations in PIK3CA have been shown to induce oncogenic characteristics by activating AKT.	2	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	4	5	14	15
We first tested whether inhibition of p110alpha alone was sufficient to abrogate PI3K and AKT signaling both in vitro and in vivo .	We first tested whether inhibition of p110alpha alone was sufficient to abrogate PI3K and AKT signaling both in vitro and in vivo.	4	15	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	6	7	14	15
The signalling pathway modulation induced by a single copy knock-in of mutant PIK3CA ( H1047R ) in the MCF10A cells have previously been examined , and it was reported that the three main recurrent somatic PIK3CA hotspot mutations ( H1047R/E542K/E545K ) all promote constitutive AKT and ERK activation in MCF10A , leading to growth factor independent growth XREF_BIBR XREF_BIBR .	The signalling pathway modulation induced by a single copy knock-in of mutant PIK3CA (H1047R) in the MCF10A cells have previously been examined, and it was reported that the three main recurrent somatic PIK3CA hotspot mutations (H1047R/E542K/E545K) all promote constitutive AKT and ERK activation in MCF10A, leading to growth factor independent growth XREF_BIBR XREF_BIBR.	35	49	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	35	36	44	45
Mutations in PIK3CA activate the AKT and mTOR pathway and have been described in many malignancies types , including colon , breast , gastric , and brain cancers .	Mutations in PIK3CA activate the AKT and mTOR pathway and have been described in many malignancies types, including colon, breast, gastric, and brain cancers.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	2	3	5	6
Importantly , PIK3CA amplification could aberrantly activate the PI3K and Akt signaling pathway .	Importantly, PIK3CA amplification could aberrantly activate the PI3K and Akt signaling pathway.	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	2	3	10	11
These results suggest that p110alpha containing PI3Ks ( PI3Kalpha ) are required for EGF stimulated activation of PKB in MCF10a cells and this role is not redundant with other class IA PI3Ks .	These results suggest that p110alpha containing PI3Ks (PI3Kalpha) are required for EGF stimulated activation of PKB in MCF10a cells and this role is not redundant with other class IA PI3Ks.	4	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	PKB	PKB	PKB	4	5	17	18
Point mutations in the helical ( exon 9 ) and catalytic domains ( exon 20 ) of PIK3CA have previously been hypothesized to contribute to colorectal tumorigenesis by activating the PI3K and Akt signaling pathway and promoting cellular proliferation [ XREF_BIBR , XREF_BIBR ] .	Point mutations in the helical (exon 9) and catalytic domains (exon 20) of PIK3CA have previously been hypothesized to contribute to colorectal tumorigenesis by activating the PI3K and Akt signaling pathway and promoting cellular proliferation [XREF_BIBR, XREF_BIBR].	1	34	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	17	18	32	33
These results are relevant to potential cancer therapies as Akt is frequently activated by upstream PIK3CA or PTEN mutations or gene silencing .	These results are relevant to potential cancer therapies as Akt is frequently activated by upstream PIK3CA or PTEN mutations or gene silencing.	9	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	15	16	9	10
The inactivation of beta-catenin by beta-catenin siRNA transfection and the activation of PI3K and AKT signaling by p110alpha plasmid transfection abrogated cell death caused by 17-AAG and HMA .	The inactivation of beta-catenin by beta-catenin siRNA transfection and the activation of PI3K and AKT signaling by p110alpha plasmid transfection abrogated cell death caused by 17-AAG and HMA.	12	19	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	17	18	14	15
3.3 Short-term Activation of Cardiac PI3Kalpha Signaling Upregulates Repolarizing K + Currents Independent of Akt .	3.3 Short-term Activation of Cardiac PI3Kalpha Signaling Upregulates Repolarizing K + Currents Independent of Akt.	5	15	Upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	Akt	Akt	Akt	5	6	14	15
Thus mutations in PIK3CA likely activate the AKT pathway to progress , rather than initiate , WNT-medulloblastoma .	Thus mutations in PIK3CA likely activate the AKT pathway to progress, rather than initiate, WNT-medulloblastoma.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	3	4	7	8
PIK3CA and Yap co-expression promotes activation of the AKT and mTOR , ERK and MAPK , and Notch pathways in the mouse liver .	PIK3CA and Yap co-expression promotes activation of the AKT and mTOR, ERK and MAPK, and Notch pathways in the mouse liver.	0	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA and Yap co-expression	pik3ca	AKT	AKT	akt	0	1	8	9
Inhibition of PI3Kalpha reduced P-AKT and P-PRAS40 with little or no effect on P-p70 S6K .	Inhibition of PI3Kalpha reduced P-AKT and P-PRAS40 with little or no effect on P-p70 S6K.	0	6	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	P-AKT	P-AKT	P-AKT	2	3	4	5
Pharmacological studies in which p110 isoform selective inhibitors were used to treat human HER2+ , PTEN deficient breast cancer cells confirmed that specific targeting of p110alpha was sufficient to inhibit AKT activity and tumor growth .	Pharmacological studies in which p110 isoform selective inhibitors were used to treat human HER2+, PTEN deficient breast cancer cells confirmed that specific targeting of p110alpha was sufficient to inhibit AKT activity and tumor growth.	23	31	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	25	26	30	31
Akt activation can be induced by amplification of the PIK3CA gene , which has been implicated as a potential predictive oncogene in tumors [ XREF_BIBR ] .	Akt activation can be induced by amplification of the PIK3CA gene, which has been implicated as a potential predictive oncogene in tumors [XREF_BIBR].	0	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	9	10	0	1
We demonstrated that mutations in the helical ( E542K , E545A ) and kinase domain ( H1047R ) of p110alpha constitutively activate the PI3K-AKT pathway and lead to factor independent growth of early hematopoietic cells .	We demonstrated that mutations in the helical (E542K, E545A) and kinase domain (H1047R) of p110alpha constitutively activate the PI3K-AKT pathway and lead to factor independent growth of early hematopoietic cells.	3	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	PI3K-AKT	PI3K-AKT	PI3K-AKT	19	20	23	24
Several groups have documented that the AKT related kinase SGK3 is activated by PIK3CA helical domain mutations .	Several groups have documented that the AKT related kinase SGK3 is activated by PIK3CA helical domain mutations.	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	13	14	6	7
Oncogenic mutations and amplification of PIK3CA activate PI3K and Akt signalings to drive the HPV induced tumorigenesis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Oncogenic mutations and amplification of PIK3CA activate PI3K and Akt signalings to drive the HPV induced tumorigenesis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	5	6	9	10
Many of the PIK3CD mutations ( XREF_FIG ) occurred in analogous fashion to constitutively activating mutations in homologous regions of PIK3CA , which activates PI-3 kinase and AKT signaling in non hematologic cancers .	Many of the PIK3CD mutations (XREF_FIG) occurred in analogous fashion to constitutively activating mutations in homologous regions of PIK3CA, which activates PI-3 kinase and AKT signaling in non hematologic cancers.	18	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	20	21	27	28
We speculate that , under normal conditions , p110alpha mediates mTOR and p70S6K activation through Akt ; however , loss of p110alpha attenuates Akt activation , to which the cell responds by activating a yet unidentified pathway ( s ) that enhance activation of mTOR and p70S6K .	We speculate that, under normal conditions, p110alpha mediates mTOR and p70S6K activation through Akt; however, loss of p110alpha attenuates Akt activation, to which the cell responds by activating a yet unidentified pathway (s) that enhance activation of mTOR and p70S6K.	19	24	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p110alpha	loss of p110alpha	p110alpha	Akt	Akt	akt	21	22	23	24
To test whether p110alpha inhibition alone was sufficient to completely abrogate PI3K-AKT signaling , time-course experiments using BYL719 in multiple PIK3CA hot spot mutant or HER2 amplified breast cancer cell lines were performed .	To test whether p110alpha inhibition alone was sufficient to completely abrogate PI3K-AKT signaling, time-course experiments using BYL719 in multiple PIK3CA hot spot mutant or HER2 amplified breast cancer cell lines were performed.	3	12	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	11	12
Additionally , the HDACi vorinostat and the PI3Kalpha isoform agonist 55704 also promote pro survival PI3K and Akt signalling .	Additionally, the HDACi vorinostat and the PI3Kalpha isoform agonist 55704 also promote pro survival PI3K and Akt signalling.	7	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	Akt	Akt	Akt	7	8	17	18
XREF_BIBR Activated KRAS and BRAF are critical drivers in mitogen activated protein kinase ( MAPK ) signaling , while PIK3CA activates PI3K and AKT signaling , both pathways are crucial in cell proliferation , differentiation , and migration .	XREF_BIBR Activated KRAS and BRAF are critical drivers in mitogen activated protein kinase (MAPK) signaling, while PIK3CA activates PI3K and AKT signaling, both pathways are crucial in cell proliferation, differentiation, and migration.	19	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	19	20	23	24
Similarly , AKT reactivation was induced by PIK3CA depletion in MDA-MB-231 breast cancer cells in response to IGF-1 stimulation ( XREF_FIG ) .	Similarly, AKT reactivation was induced by PIK3CA depletion in MDA-MB-231 breast cancer cells in response to IGF-1 stimulation (XREF_FIG).	2	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	7	8	2	3
Mutations in PIK3R1 , PIK3CA , or PTEN activate the PI3K-AKT signalling cascade , and were reported in 4 , 6 and 15 % of paediatric T-LBL cases , respectively .	Mutations in PIK3R1, PIK3CA, or PTEN activate the PI3K-AKT signalling cascade, and were reported in 4, 6 and 15% of paediatric T-LBL cases, respectively.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	PI3K-AKT	PI3K-AKT	PI3K-AKT	4	5	10	11
We showed that PTEN loss , or PIK3CA activation mutation , AKT and PI3K overexpression decreased sensitivity S AKT , p by four to six orders of magnitude for all protein parameters and this corresponds to the transformation of the I/O response from smooth hyperbolic to switch like .	We showed that PTEN loss, or PIK3CA activation mutation, AKT and PI3K overexpression decreased sensitivity S AKT, p by four to six orders of magnitude for all protein parameters and this corresponds to the transformation of the I/O response from smooth hyperbolic to switch like.	7	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PIK3CA	PIK3CA activation mutation, AKT and PI3K overexpression	pik3ca	AKT	AKT	akt	7	8	18	19
Mutant Phosphatidylinositol 3-kinase CA ( PIK3CA ) stimulates the AKT pathway and promotes cell growth in several cancers , including ESCC and Non small cell lung cancer ( NSCLC ) being associated in these cases with poor prognosis [ XREF_BIBR ] .	Mutant Phosphatidylinositol 3-kinase CA (PIK3CA) stimulates the AKT pathway and promotes cell growth in several cancers, including ESCC and Non small cell lung cancer (NSCLC) being associated in these cases with poor prognosis [XREF_BIBR].	3	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	5	6	9	10
Furthermore , lncRNA-AWPPH promotes YBX1 mediated activation of PIK3CA transcription , upregulates PIK3CA expression , and activates PI3K and AKT pathway .	Furthermore, lncRNA-AWPPH promotes YBX1 mediated activation of PIK3CA transcription, upregulates PIK3CA expression, and activates PI3K and AKT pathway.	2	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	lncRNA-AWPPH promotes YBX1 mediated activation of PIK3CA transcription	pik3ca	AKT	AKT	akt	8	9	19	20
Altogether , our study demonstrates that PIK3CA H1047R and E545K mutants , but not wild-type PIK3CA , can fully activate the AKT signaling , leading to steatosis in the mouse liver .	Altogether, our study demonstrates that PIK3CA H1047R and E545K mutants, but not wild-type PIK3CA, can fully activate the AKT signaling, leading to steatosis in the mouse liver.	6	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	6	7	21	22
AKT pathway activation by PIK3CA and PIK3R1 mutation did not correlate with clinical activity , whereas RAS and RAF pathway mutations did segregate with resistance to AKT inhibition .	AKT pathway activation by PIK3CA and PIK3R1 mutation did not correlate with clinical activity, whereas RAS and RAF pathway mutations did segregate with resistance to AKT inhibition.	0	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	4	5	0	1
The p110delta isoform constitutively activated the Akt signaling pathway , but p110gamma activated Akt only in the presence of serum [ XREF_BIBR ] .	The p110delta isoform constitutively activated the Akt signaling pathway, but p110gamma activated Akt only in the presence of serum [XREF_BIBR].	11	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110gamma	p110gamma	p110gamma	Akt	Akt	Akt	11	12	13	14
Thus , PI3Kgamma -/- mice fail to activate AKT and ERK1/2 immediately following M I/R injury , and this lack of activation can be localized to the area at risk .	Thus, PI3Kgamma -/- mice fail to activate AKT and ERK1/2 immediately following M I/R injury, and this lack of activation can be localized to the area at risk.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	AKT	AKT	AKT	2	3	8	9
Likewise , Akt activated by PI3Kgamma contributes to pathological hypertrophy during pressure overload or beta-adrenergic receptor activation , but is dispensable for physiological growth [ XREF_BIBR - XREF_BIBR ] .	Likewise, Akt activated by PI3Kgamma contributes to pathological hypertrophy during pressure overload or beta-adrenergic receptor activation, but is dispensable for physiological growth [XREF_BIBR - XREF_BIBR].	2	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	5	6	2	3
Inhibition of PI3Kgamma prevents Akt activation and blunts the HG induced increase in HMGB1 expression by the cardiomyocytes .	Inhibition of PI3Kgamma prevents Akt activation and blunts the HG induced increase in HMGB1 expression by the cardiomyocytes.	0	5	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	2	3	4	5
Collectively , these results suggest that PI3Kgamma induced activation of Akt may be at least in part responsible for cell survival and proliferation in fibroblasts .	Collectively, these results suggest that PI3Kgamma induced activation of Akt may be at least in part responsible for cell survival and proliferation in fibroblasts.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	6	7	10	11
As PI3Kdelta and PI3Kgamma are known to activate AKT , we analysed the phosphorylation status of s473 in response to idelalisib , CZC24832 and duvelisib .	As PI3Kdelta and PI3Kgamma are known to activate AKT, we analysed the phosphorylation status of s473 in response to idelalisib, CZC24832 and duvelisib.	1	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	AKT	AKT	AKT	3	4	8	9
PI3Kgamma activates Akt and PKB after GPCR activation , leading to pathological hypertrophy .	PI3Kgamma activates Akt and PKB after GPCR activation, leading to pathological hypertrophy.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	PKB	PKB	PKB	0	1	4	5
PI3Kgamma and Akt activation following GCPR stimulation typically leads to pathological ( maladaptive ) hypertrophy [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] , whereas loss of PI3Kgamma prevents activation of Akt and PKB and ERK1/2 pathways in response to beta-AR stimulation , resulting in a marked reduction in hypertrophy [ XREF_BIBR ] .	PI3Kgamma and Akt activation following GCPR stimulation typically leads to pathological (maladaptive) hypertrophy [XREF_BIBR, XREF_BIBR - XREF_BIBR], whereas loss of PI3Kgamma prevents activation of Akt and PKB and ERK1/2 pathways in response to beta-AR stimulation, resulting in a marked reduction in hypertrophy [XREF_BIBR].	24	35	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3Kgamma	loss of PI3Kgamma	pi3kgamma	Akt	Akt	akt	26	27	30	31
Traditionally , the lipid kinase activity of PI3Kgamma activates Akt , which mediates important cellular functions .	Traditionally, the lipid kinase activity of PI3Kgamma activates Akt, which mediates important cellular functions.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	7	8	9	10
Thus , PI3Kgamma stimulates pro hypertrophic Akt and MAPK pathways during pathologic states that is somewhat protective early on , and depresses contractility through the indirect modulation of Ca 2+ regulatory proteins .	Thus, PI3Kgamma stimulates pro hypertrophic Akt and MAPK pathways during pathologic states that is somewhat protective early on, and depresses contractility through the indirect modulation of Ca 2+ regulatory proteins.	2	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	2	3	6	7
Complementation of p110gamma null mast cells with p101 and p110gamma restored the activation of Akt and cell migration , but failed to support degranulation .	Complementation of p110gamma null mast cells with p101 and p110gamma restored the activation of Akt and cell migration, but failed to support degranulation.	2	17	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110gamma	p110gamma	p110gamma	Akt	Akt	Akt	2	3	14	15
It has been reported that YAP promote the expression of the catalytic subunit of PI3K , p110gamma , which activates AKT XREF_BIBR , but whether this is occurring in mSC remains to be shown .	It has been reported that YAP promote the expression of the catalytic subunit of PI3K, p110gamma, which activates AKT XREF_BIBR, but whether this is occurring in mSC remains to be shown.	8	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110gamma	p110gamma	p110gamma	AKT	AKT	AKT	16	17	20	21
Active PI3Kgamma not only triggers activation of Akt , but also stimulates the stress activated MAPK signaling pathway and serves as an activator for phosphodiesterase 3B ( 18,19 ) .	Active PI3Kgamma not only triggers activation of Akt, but also stimulates the stress activated MAPK signaling pathway and serves as an activator for phosphodiesterase 3B (18,19).	0	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	1	2	7	8
The p110delta isoform constitutively activates the Akt signaling pathway ; p110gamma activates Akt only in the presence of serum .	The p110delta isoform constitutively activates the Akt signaling pathway; p110gamma activates Akt only in the presence of serum.	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110gamma	p110gamma	p110gamma	Akt	Akt	Akt	10	11	12	13
Although PI3Kgamma activated Akt signaling is prohypertrophic , PI3Kalpha-Akt pathway is an important mediator of physiologic growth .	Although PI3Kgamma activated Akt signaling is prohypertrophic, PI3Kalpha-Akt pathway is an important mediator of physiologic growth.	1	4	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	1	2	3	4
Furthermore , we show that PI3Kgamma specific inhibitors promote the rapid decrease in Akt and mTOR activation caused by expression of a KSHV oncogene , vGPCR , in endothelial cells thereby causing their apoptotic death and tumor regression , probably due to impaired vGPCR initiated direct and paracrine transforming mechanisms .	Furthermore, we show that PI3Kgamma specific inhibitors promote the rapid decrease in Akt and mTOR activation caused by expression of a KSHV oncogene, vGPCR, in endothelial cells thereby causing their apoptotic death and tumor regression, probably due to impaired vGPCR initiated direct and paracrine transforming mechanisms.	5	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	5	6	13	14
Overexpression of PI3K and p110gamma indeed increased cell numbers and mediated activation of Akt in PDAC cell lines .	Overexpression of PI3K and p110gamma indeed increased cell numbers and mediated activation of Akt in PDAC cell lines.	0	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110gamma	Overexpression of PI3K and p110gamma	p110gamma	Akt	Akt	akt	4	5	13	14
Our findings suggest that activation of Akt initially contributes to cardiac hypertrophy and that chronic metabolic and inflammatory stimulation and overexpression of inhibitory mediators decrease PI3Kgamma mediated Akt signaling and blunt compensatory hypertrophy after MI .	Our findings suggest that activation of Akt initially contributes to cardiac hypertrophy and that chronic metabolic and inflammatory stimulation and overexpression of inhibitory mediators decrease PI3Kgamma mediated Akt signaling and blunt compensatory hypertrophy after MI.	24	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	25	26	27	28
PKM2 stimulates the transcriptional activities of HIF , beta-catenin , STAT3 , and Oct4 [ XREF_BIBR ] .	PKM2 stimulates the transcriptional activities of HIF, beta-catenin, STAT3, and Oct4 [XREF_BIBR].	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	0	1	10	11
We also found that STAT3 was significantly activated by PKM2 overexpression .	We also found that STAT3 was significantly activated by PKM2 overexpression.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKM2	PKM2 overexpression	pkm2	STAT3	STAT3	stat3	9	10	4	5
Together with previous studies , we found that lapatinib inhibits breast cancer cell proliferation by influencing PKM2 expression and reduces Stat3 and phosphorylated Stat3 levels .	Together with previous studies, we found that lapatinib inhibits breast cancer cell proliferation by influencing PKM2 expression and reduces Stat3 and phosphorylated Stat3 levels.	8	21	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKM2	lapatinib inhibits breast cancer cell proliferation by influencing PKM2 expression	pkm2	Stat3	Stat3	stat3	16	17	20	21
Overall , our data demonstrate that PTBP1 interacts with PKM2 and promotes ALCL oncogenesis by facilitating PKM2 dependent activation of STAT3 within the nucleus .	Overall, our data demonstrate that PTBP1 interacts with PKM2 and promotes ALCL oncogenesis by facilitating PKM2 dependent activation of STAT3 within the nucleus.	16	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	16	17	20	21
Interestingly , knockdown of PKM2 substantially decreased the assembly of the oligo protein complex and assembly of stat3 in the complex ( the weak supershift ) ( XREF_FIG ) , while expression of HA-PKM2 increased assembled complex and assembly of stat3 in the complex ( XREF_FIG ) .	Interestingly, knockdown of PKM2 substantially decreased the assembly of the oligo protein complex and assembly of stat3 in the complex (the weak supershift) (XREF_FIG), while expression of HA-PKM2 increased assembled complex and assembly of stat3 in the complex (XREF_FIG).	2	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	stat3	stat3	stat3	4	5	17	18
Dimeric PKM2 can also activate Stat3 , which is known to coordinate expression of genes involved in inflammation and the hypoxic response together with HIF-alpha , suggesting that PKM2 may act as a metabolic sensor integrating these two gene expression programs 49 .	Dimeric PKM2 can also activate Stat3, which is known to coordinate expression of genes involved in inflammation and the hypoxic response together with HIF-alpha, suggesting that PKM2 may act as a metabolic sensor integrating these two gene expression programs 49.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	Stat3	Stat3	Stat3	1	2	5	6
Considering that un phosphorylated STAT3 is continuously shuttling between the cytoplasm generating a nuclear reservoir of STAT3 available for activation [ XREF_BIBR ] , PKM2 mediated STAT3 activation could contribute to macrophage activation upon metabolic reprogramming [ XREF_BIBR , XREF_BIBR ] .	Considering that un phosphorylated STAT3 is continuously shuttling between the cytoplasm generating a nuclear reservoir of STAT3 available for activation [XREF_BIBR], PKM2 mediated STAT3 activation could contribute to macrophage activation upon metabolic reprogramming [XREF_BIBR, XREF_BIBR].	24	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	24	25	26	27
In addition , dimeric PKM2 can operate as a protein kinase , thereby promoting the functions of signal transducer and activator of transcription 3 ( STAT3 ) , which control the synthesis of multiple anti-apoptotic proteins including BCL-2 , BCL-X L and MCL-1 .	In addition, dimeric PKM2 can operate as a protein kinase, thereby promoting the functions of signal transducer and activator of transcription 3 (STAT3), which control the synthesis of multiple anti-apoptotic proteins including BCL-2, BCL-X L and MCL-1.	3	26	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	4	5	25	26
The results show that inhibition of PKM2 by lapatinib reduces Stat3 and phosphorylated Stat3 levels .	The results show that inhibition of PKM2 by lapatinib reduces Stat3 and phosphorylated Stat3 levels.	4	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	Stat3	Stat3	Stat3	6	7	10	11
The nuclear localization signal ( NLS ) of PKM2 facilitates its translocation into the nucleus , thus is essential for PKM2 mediated STAT3 activation [ XREF_BIBR ] .	The nuclear localization signal (NLS) of PKM2 facilitates its translocation into the nucleus, thus is essential for PKM2 mediated STAT3 activation [XREF_BIBR].	20	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	20	21	22	23
Recent findings suggest that pyruvate kinase M2 ( PKM2 ) , a glycolysis enzyme , directly activates STAT3 [ XREF_BIBR , XREF_BIBR ] .	Recent findings suggest that pyruvate kinase M2 (PKM2), a glycolysis enzyme, directly activates STAT3 [XREF_BIBR, XREF_BIBR].	6	21	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	8	9	17	18
In one study , pyruvate kinase M2 ( PKM2 ) , a protein that is known to be essential for the Warburg effect and proliferation of cancer cells , was found to activate STAT3 via catalyzing its phosphorylation at Y705 [ XREF_BIBR , XREF_BIBR ] .	In one study, pyruvate kinase M2 (PKM2), a protein that is known to be essential for the Warburg effect and proliferation of cancer cells, was found to activate STAT3 via catalyzing its phosphorylation at Y705 [XREF_BIBR, XREF_BIBR].	6	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	8	9	33	34
The results of our study suggest the following model : the expression of nuclear PKM2 induces the initiation of STAT3 signalling , which then offsets the impact of EGFR-TKI on cell apoptosis and proliferation ( XREF_FIG ) .	The results of our study suggest the following model : the expression of nuclear PKM2 induces the initiation of STAT3 signalling, which then offsets the impact of EGFR-TKI on cell apoptosis and proliferation (XREF_FIG).	11	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKM2	expression of nuclear PKM2	pkm2	STAT3	STAT3	stat3	14	15	19	20
Increased cytoplasmic PKM2 promoted pyruvate kinase activity and lactate production ( aerobic glycolysis ) , whereas FEZF1-AS1-induced nuclear PKM2 upregulation further activated STAT3 signaling .	Increased cytoplasmic PKM2 promoted pyruvate kinase activity and lactate production (aerobic glycolysis), whereas FEZF1-AS1-induced nuclear PKM2 upregulation further activated STAT3 signaling.	18	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	18	19	22	23
We further examined whether PKM2 modulates Stat3 and Stat3 ( Tyr ( P )-705) expression under the effects of lapatinib and found that PKM2 expression was significantly reduced in lapatinib treated cells compared to control cells , and Stat3 and Stat3 ( Tyr ( P )-705) expression was also significantly reduced after treatment with lapatinib compared to control groups in both cell lines .	We further examined whether PKM2 modulates Stat3 and Stat3 (Tyr (P)-705) expression under the effects of lapatinib and found that PKM2 expression was significantly reduced in lapatinib treated cells compared to control cells, and Stat3 and Stat3 (Tyr (P)-705) expression was also significantly reduced after treatment with lapatinib compared to control groups in both cell lines.	4	21	modulates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	PKM2	PKM2	pkm2	Stat3	Stat3 (Tyr (P)-705) expression	stat3	4	5	8	9
We therefore investigated whether STAT3 was activated by nuclear PKM2 and was involved in gefitinib resistance in CRC .	We therefore investigated whether STAT3 was activated by nuclear PKM2 and was involved in gefitinib resistance in CRC.	4	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	9	10	4	5
Thus , activation of stat3 by PKM2 in malignant cancer cells potentially provides a highly plausible explanation for this long standing question .	Thus, activation of stat3 by PKM2 in malignant cancer cells potentially provides a highly plausible explanation for this long standing question.	2	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	stat3	stat3	stat3	6	7	4	5
As PIK3CA and RAS mutants stimulate mTOR downstream of EGFR , we asked whether their expression is sufficient to confer cetuximab resistance .	As PIK3CA and RAS mutants stimulate mTOR downstream of EGFR, we asked whether their expression is sufficient to confer cetuximab resistance.	1	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	mTOR	mTOR	mTOR	1	2	6	7
The PIK3CA p.Glu545Lys variation within the helical domain of the p110alpha protein was identified in tumors of the colon and brain XREF_BIBR , XREF_BIBR and constitutively activates the mTOR pathway 27 .	The PIK3CA p.Glu545Lys variation within the helical domain of the p110alpha protein was identified in tumors of the colon and brain XREF_BIBR, XREF_BIBR and constitutively activates the mTOR pathway 27.	1	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	mTOR	mTOR	mTOR	1	2	28	29
PIK3CA driven mTOR activates Bcl-2 and ultimately inhibits apoptosis [ XREF_BIBR ] , indicating that PIK3CA signaling may have an important role in the immortality of transformed cells .	PIK3CA driven mTOR activates Bcl-2 and ultimately inhibits apoptosis [XREF_BIBR], indicating that PIK3CA signaling may have an important role in the immortality of transformed cells.	0	7	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	mTOR	mTOR	mTOR	0	1	2	3
The mTOR pathway and RPS6KB are activated by PIK3CA and inhibited by PRKAG2 [ XREF_BIBR ] .	The mTOR pathway and RPS6KB are activated by PIK3CA and inhibited by PRKAG2 [XREF_BIBR].	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	mTOR	mTOR	mTOR	8	9	1	2
Oncogenic mutations in PIK3CA ( gene encoding the alpha p110 catalytic subunit ) of PI3K have been observed in GC , constitutively activating the PI3KA and mTOR pathway [ XREF_BIBR , XREF_BIBR ] .	Oncogenic mutations in PIK3CA (gene encoding the alpha p110 catalytic subunit) of PI3K have been observed in GC, constitutively activating the PI3KA and mTOR pathway [XREF_BIBR, XREF_BIBR].	1	31	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	mTOR	mTOR	mTOR	3	4	26	27
These results can be easily understood because that PIK3CA activates p-Akt , and positively regulates mTOR XREF_BIBR , XREF_BIBR .	These results can be easily understood because that PIK3CA activates p-Akt, and positively regulates mTOR XREF_BIBR, XREF_BIBR.	7	16	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	mTOR	mTOR	mTOR	8	9	15	16
The mTOR pathway is also frequently upregulated in cancer by oncogenic PIK3CA and PTEN mutations 79 , which may also contribute to Hsf1 activity .	The mTOR pathway is also frequently upregulated in cancer by oncogenic PIK3CA and PTEN mutations 79, which may also contribute to Hsf1 activity.	1	15	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	mTOR	mTOR	mTOR	11	12	1	2
Previous studies have described several genetic aberrations that might be predictive for response to mTOR inhibition such as mutations in or loss of PIK3CA , PTEN , TSC and KRAS [ XREF_BIBR - XREF_BIBR ] .	Previous studies have described several genetic aberrations that might be predictive for response to mTOR inhibition such as mutations in or loss of PIK3CA, PTEN, TSC and KRAS [XREF_BIBR - XREF_BIBR].	14	24	inhibition	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	PIK3CA	loss of PIK3CA	pik3ca	mTOR	mTOR	mtor	23	24	14	15
Inhibitors of p110alpha often also inhibit the class IV isoforms DNA-PK and mTOR , as with PI-103 , but it has been possible to remove the class IV inhibition from class I selective inhibitors as in case of GDC-0941 3 compared to PI-103 [ XREF_BIBR ] .	Inhibitors of p110alpha often also inhibit the class IV isoforms DNA-PK and mTOR, as with PI-103, but it has been possible to remove the class IV inhibition from class I selective inhibitors as in case of GDC-0941 3 compared to PI-103 [XREF_BIBR].	0	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	mTOR	mTOR	mTOR	2	3	12	13
However , class I PI3K and p110alpha signaling activates mTOR and suppresses autophagy , thus opposing the activity of class III PI3K and Vps34 .	However, class I PI3K and p110alpha signaling activates mTOR and suppresses autophagy, thus opposing the activity of class III PI3K and Vps34.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	mTOR	mTOR	mTOR	6	7	9	10
Also involved is PI3Kalpha , which activates the Akt1 and Akt2 Ser/Thr kinase , responsible for proliferation and antiapoptotic function [ XREF_BIBR - XREF_BIBR ] .	Also involved is PI3Kalpha, which activates the Akt1 and Akt2 Ser/Thr kinase, responsible for proliferation and antiapoptotic function [XREF_BIBR - XREF_BIBR].	1	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	Akt1	Akt1	Akt1	3	4	8	9
Additional genetic lesions in the PI3K and AKT pathway include mutations of PIK3R1 that lead to misregulation of p110alpha , LOH of INPP4B , activating mutations or copy number gain of the AKT1 , AKT2 and AKT3 genes , amplification of PDPK1 , as well as a plethora of genetic alterations of upstream RTKs such as HER2 .	Additional genetic lesions in the PI3K and AKT pathway include mutations of PIK3R1 that lead to misregulation of p110alpha, LOH of INPP4B, activating mutations or copy number gain of the AKT1, AKT2 and AKT3 genes, amplification of PDPK1, as well as a plethora of genetic alterations of upstream RTKs such as HER2.	18	37	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	AKT1	AKT1	AKT1	18	19	32	33
For instance , the query related to an interaction between PI3K ( PIK3CA ) and AKT ( AKT1 ) in Omnipath returns an activation of AKT1 by PIK3CA from four databases ( SignaLink3 , Laudanna_effects , Wang , Signor ) , and an inhibition of AKT1 by PIK3CA from one database ( Laudanna_effects ) .	For instance, the query related to an interaction between PI3K (PIK3CA) and AKT (AKT1) in Omnipath returns an activation of AKT1 by PIK3CA from four databases (SignaLink3, Laudanna_effects, Wang, Signor), and an inhibition of AKT1 by PIK3CA from one database (Laudanna_effects).	21	43	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT1	AKT1	AKT1	27	28	25	26
PI3K ( PIK3CA ) induces the activation of Akt1 ( alias PDK1 ) and is recognized as an important regulator of cell proliferation and survival and links to inflammation.41 Akt promotes tumorigenesis by inhibiting apoptosis by inactivating BCL2 , by stabilizing MYC , by inducing the degradation of cyclin dependent kinase ( CDK1 ) , or by triggering activity of NFkappaB signaling.42 Cytokine receptors utilize nonreceptor protein tyrosine kinases , such as JAK , to transmit their signals to the signal transducers and activators of transcription ( STATs ) .	PI3K (PIK3CA) induces the activation of Akt1 (alias PDK1) and is recognized as an important regulator of cell proliferation and survival and links to inflammation.41 Akt promotes tumorigenesis by inhibiting apoptosis by inactivating BCL2, by stabilizing MYC, by inducing the degradation of cyclin dependent kinase (CDK1), or by triggering activity of NFkappaB signaling.42 Cytokine receptors utilize nonreceptor protein tyrosine kinases, such as JAK, to transmit their signals to the signal transducers and activators of transcription (STATs).	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt1	Akt1	Akt1	2	3	8	9
We demonstrated that the PIK3CA hotspot mutation H1047R , but not E545K , selectively activates AKT2 but not AKT1 in MCF10A cells .	We demonstrated that the PIK3CA hotspot mutation H1047R, but not E545K, selectively activates AKT2 but not AKT1 in MCF10A cells.	4	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT1	AKT1	AKT1	4	5	18	19
Also involved is PI3Kalpha , which activates the Akt1 and Akt2 Ser/Thr kinase , responsible for cell proliferation and inhibition of apoptosis .	Also involved is PI3Kalpha, which activates the Akt1 and Akt2 Ser/Thr kinase, responsible for cell proliferation and inhibition of apoptosis.	1	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	Akt1	Akt1	Akt1	3	4	8	9
39 In addition , p110alpha activation of RAC1 has been shown to be necessary for KRAS mediated pancreatic tumorigenesis and p110alpha and RAC1 are increased in human PanINs and invasive ductal cancers .	39 In addition, p110alpha activation of RAC1 has been shown to be necessary for KRAS mediated pancreatic tumorigenesis and p110alpha and RAC1 are increased in human PanINs and invasive ductal cancers.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	RAC1	RAC1	RAC1	4	5	7	8
Loss of p110alpha reduced RAC1 activity and expression in these tissues .	Loss of p110alpha reduced RAC1 activity and expression in these tissues.	0	5	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p110alpha	Loss of p110alpha	p110alpha	RAC1	RAC1	rac1	2	3	4	5
Interestingly , we observed that IRGM1 enhanced F-actin polymerization and triggers epithelial mesenchymal transition ( EMT ) through a mechanism involved in PIK3CA mediated Rac1 activation .	Interestingly, we observed that IRGM1 enhanced F-actin polymerization and triggers epithelial mesenchymal transition (EMT) through a mechanism involved in PIK3CA mediated Rac1 activation.	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Rac1	Rac1	Rac1	22	23	24	25
To test if p110alpha dependent upregulation of the Rac1 pathway is present in the earliest stages of tumorigenesis , we examined RAC1 and GEF levels in primary acinar cells isolated from six to eight-week old Kras G12D and alpha -/-; Kras G12D mice .	To test if p110alpha dependent upregulation of the Rac1 pathway is present in the earliest stages of tumorigenesis, we examined RAC1 and GEF levels in primary acinar cells isolated from six to eight-week old Kras G12D and alpha -/-; Kras G12D mice.	3	9	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Rac1	Rac1	Rac1	3	4	8	9
On the other hand , more than half OC that overexpressed PIK3CA presented two or more alterations ( 14 OCs simultaneously overexpressed PIK3CA and had lost PTEN , 6 OCs overexpressed both PIK3CA and AKT1 , and 5 OCs overexpressed both PIK3CA and AKT2 ) .	On the other hand, more than half OC that overexpressed PIK3CA presented two or more alterations (14 OCs simultaneously overexpressed PIK3CA and had lost PTEN, 6 OCs overexpressed both PIK3CA and AKT1, and 5 OCs overexpressed both PIK3CA and AKT2).	31	44	overexpressed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT2	AKT2	AKT2	32	33	43	44
This evidence suggests that NRBF2 may modulate Vps15 mediated Vps34 activity independent of Atg14L .	This evidence suggests that NRBF2 may modulate Vps15 mediated Vps34 activity independent of Atg14L.	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vps15	Vps15	Vps15	Vps34	Vps34	Vps34	7	8	9	10
Moreover , both Nrbf2 MIT domain and CCD ( residues 168-209 ) facilitate Vps34-Vps15 interactions and Vps15 enhanced Vps34 activity [ XREF_BIBR ] .	Moreover, both Nrbf2 MIT domain and CCD (residues 168-209) facilitate Vps34-Vps15 interactions and Vps15 enhanced Vps34 activity [XREF_BIBR].	14	19	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Vps15	Vps15	Vps15	Vps34	Vps34	Vps34	16	17	18	19
This would be consistent with NRBF2 binding to the Vps15 WD40 domain , which is known to target Vps34 to endosomes [ XREF_BIBR ] .	This would be consistent with NRBF2 binding to the Vps15 WD40 domain, which is known to target Vps34 to endosomes [XREF_BIBR].	9	19	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vps15	Vps15	Vps15	Vps34	Vps34	Vps34	9	10	18	19
Vps15 acts to anchor the complex to the membrane whereas Vps34 is recruited and then activated by Vps15 .	Vps15 acts to anchor the complex to the membrane whereas Vps34 is recruited and then activated by Vps15.	10	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Vps15	Vps15	Vps15	Vps34	Vps34	Vps34	17	18	10	11
Myristoylation anchors Vps15 to the target membranes such as endosomal membranes and isolation membranes ( or pre-autophagosomal site ( PAS ) in yeast ) , facilitates translocation of Vps34 to these membranes , and activates the essential PI ( 3 ) K activity of Vps34 [ XREF_BIBR ] .	Myristoylation anchors Vps15 to the target membranes such as endosomal membranes and isolation membranes (or pre-autophagosomal site (PAS) in yeast), facilitates translocation of Vps34 to these membranes, and activates the essential PI (3) K activity of Vps34 [XREF_BIBR].	0	46	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vps15	Vps15	Vps15	Vps34	Vps34	Vps34	2	3	44	45
Vps34 supported by its co-enzyme Vps15 is the sole Class III phosphatidylinositol kinase and produces the docking lipid phosphatidylinositol-3 '-phosphate ( PI 3 P ) .	Vps34 supported by its co-enzyme Vps15 is the sole Class III phosphatidylinositol kinase and produces the docking lipid phosphatidylinositol-3 '-phosphate (PI 3 P).	0	14	supported	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Vps15	Vps15	Vps15	Vps34	Vps34	Vps34	5	6	0	1
Interestingly , we found that both the MIT domain and CCD are important for the function of NRBF2 in enhancing Vps15 mediated Vps34 activity under these conditions ( XREF_FIG , XREF_FIG ) .	Interestingly, we found that both the MIT domain and CCD are important for the function of NRBF2 in enhancing Vps15 mediated Vps34 activity under these conditions (XREF_FIG, XREF_FIG).	20	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vps15	Vps15	Vps15	Vps34	Vps34	Vps34	20	21	22	23
From these evidences , we could make hypothesis that cancer specific high expression of PIK3R1 increases activation of PIK3CA and as a result , negatively regulated apoptotic function cause cancer in breast .	From these evidences, we could make hypothesis that cancer specific high expression of PIK3R1 increases activation of PIK3CA and as a result, negatively regulated apoptotic function cause cancer in breast.	12	19	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3R1	expression of PIK3R1	pik3r1	PIK3CA	PIK3CA	pik3ca	14	15	18	19
This engineered mutation in p85alpha also activated recombinant p110beta but did not activate p110alpha , revealing isoform specific aspects of regulation .	This engineered mutation in p85alpha also activated recombinant p110beta but did not activate p110alpha, revealing isoform specific aspects of regulation.	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	4	5	13	14
These changes would eliminate the repression of PIK3CA caused by PIK3R1 XREF_BIBR .	These changes would eliminate the repression of PIK3CA caused by PIK3R1 XREF_BIBR.	5	11	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	PIK3R1	PIK3R1	PIK3R1	PIK3CA	PIK3CA	PIK3CA	10	11	7	8
Helical domain mutations increased catalytic activity by reducing the repression of p110alpha by p85alpha [ XREF_BIBR ] or facilitating the interaction of p110alpha with IRS-1 [ XREF_BIBR ] , whereas kinase domain mutations increase the retention of p110alpha at the plasma membrane [ XREF_BIBR ] .	Helical domain mutations increased catalytic activity by reducing the repression of p110alpha by p85alpha [XREF_BIBR] or facilitating the interaction of p110alpha with IRS-1 [XREF_BIBR], whereas kinase domain mutations increase the retention of p110alpha at the plasma membrane [XREF_BIBR].	9	15	repression	Negative_activation_token_2_noun	Positive_activation	Positive_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	13	14	11	12
XREF_BIBR , XREF_BIBR There is also evidence to suggest that mutations to the PI3K class 1 regulatory subunit p85alpha may play a key role in tumorigenicity ; mutations have been found in the p85alpha SH2 domain , which diminish regulatory function of p85alpha on p110alpha , thereby increasing p110alpha activity .	XREF_BIBR, XREF_BIBR There is also evidence to suggest that mutations to the PI3K class 1 regulatory subunit p85alpha may play a key role in tumorigenicity; mutations have been found in the p85alpha SH2 domain, which diminish regulatory function of p85alpha on p110alpha, thereby increasing p110alpha activity.	40	49	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	42	43	48	49
Recent studies have indicated that multiple functional mutations ( K379E , R503W , KS549delN , D560Y , KS549delN , N564D , and QYL579delL ) in the nSH2 and iSH2 domains of PIK3R1 activate the canonical PI3K pathway by disrupting the inhibitory contact of the C2 domain in p110alpha 32 .	Recent studies have indicated that multiple functional mutations (K379E, R503W, KS549delN, D560Y, KS549delN, N564D, and QYL579delL) in the nSH2 and iSH2 domains of PIK3R1 activate the canonical PI3K pathway by disrupting the inhibitory contact of the C2 domain in p110alpha 32.	29	48	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PIK3R1	PIK3R1	PIK3R1	p110alpha	p110alpha	p110alpha	31	32	47	48
However , inhibition of p110alpha activity potentially mediated by increased p85alpha is ineffective because myr-p110alpha is likely not removed from membrane association by p85alpha .	However, inhibition of p110alpha activity potentially mediated by increased p85alpha is ineffective because myr-p110alpha is likely not removed from membrane association by p85alpha.	4	11	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	10	11	4	5
Mutations in PIK3CD and PIK3R1 cause activated PI3K-delta syndrome ( APDS ) by dysregulation of the PI3K-AKT pathway .	Mutations in PIK3CD and PIK3R1 cause activated PI3K-delta syndrome (APDS) by dysregulation of the PI3K-AKT pathway.	0	8	cause activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3R1	PIK3R1	PIK3R1	PI3K-delta	PI3K-delta	PI3K-delta	4	5	7	8
How can delE11 p85alpha promote p110delta hyperactivation despite less stable interaction with p110delta ?	How can delE11 p85alpha promote p110delta hyperactivation despite less stable interaction with p110delta?	2	6	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p85alpha	p85alpha	p85alpha	p110delta	p110delta	p110delta	3	4	5	6
Because the net effect of the p85alpha ( del p. 434 - 475 ) is increased PI3Kdelta activity , we consider it as a GOF mutation , even though it is strictly speaking a mutation resultin in loss of inhibitory function .	Because the net effect of the p85alpha (del p. 434 - 475) is increased PI3Kdelta activity, we consider it as a GOF mutation, even though it is strictly speaking a mutation resultin in loss of inhibitory function.	3	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p85alpha	p85alpha	p85alpha	PI3Kdelta	PI3Kdelta	PI3Kdelta	6	7	16	17
Therefore , impairment of p85alpha may enhance pAKT by losing its inhibitory role of p110delta and its enhancing effect against PTEN enzymatic activity .	Therefore, impairment of p85alpha may enhance pAKT by losing its inhibitory role of p110delta and its enhancing effect against PTEN enzymatic activity.	2	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p85alpha	p85alpha	p85alpha	p110delta	p110delta	p110delta	4	5	14	15
Moreover , PRK1 activates AR even in the presence of the AR antagonist cyproterone acetate that is used in the clinical management of prostate cancer .	Moreover, PRK1 activates AR even in the presence of the AR antagonist cyproterone acetate that is used in the clinical management of prostate cancer.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRK1	PRK1	PRK1	AR	AR	AR	2	3	4	5
Degradation of PKN1 by SspH1 attenuates the AR response ( XREF_FIG A ) .	Degradation of PKN1 by SspH1 attenuates the AR response (XREF_FIG A).	0	8	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKN1	PKN1	PKN1	AR	AR	AR	2	3	7	8
Furthermore , PRK1 promotes a functional complex of AR with the co-activator TIF-2 .	Furthermore, PRK1 promotes a functional complex of AR with the co-activator TIF-2.	2	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRK1	PRK1	PRK1	AR	AR	AR	2	3	8	9
Pin1 potentiates Notch1 cleavage by gamma-secretase , leading to an increased release of the active intracellular domain and ultimately enhancing Notch1 transcriptional and tumorigenic activity .	Pin1 potentiates Notch1 cleavage by gamma-secretase, leading to an increased release of the active intracellular domain and ultimately enhancing Notch1 transcriptional and tumorigenic activity.	0	3	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pin1	Pin1	Pin1	Notch1	Notch1	Notch1	0	1	2	3
Taken together , both in vitro and in vivo studies demonstrate that activation of NOTCH1 signalling by PIN1 may potentially contribute to hepatocarcinogenesis .	Taken together, both in vitro and in vivo studies demonstrate that activation of NOTCH1 signalling by PIN1 may potentially contribute to hepatocarcinogenesis.	14	18	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PIN1	PIN1	PIN1	NOTCH1	NOTCH1	NOTCH1	17	18	14	15
Thus , Pin1 mediated NICD stabilization and/or p53 phosphorylation play vital roles in the pro apoptotic function of the p53 and NICD complex .	Thus, Pin1 mediated NICD stabilization and/or p53 phosphorylation play vital roles in the pro apoptotic function of the p53 and NICD complex.	2	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Pin1	Pin1	Pin1	NICD	NICD	NICD	2	3	4	5
Interestingly , Pin1 is a direct target of Notch1 creating a positive feedback loop .	Interestingly, Pin1 is a direct target of Notch1 creating a positive feedback loop.	2	9	is a direct target	Positive_activation_copula_1	Positive_activation	Positive_activation	Pin1	Pin1	Pin1	Notch1	Notch1	Notch1	2	3	8	9
Furthermore , Pin1 enhances Notch1 transcription activation and tumorigenic potential in breast cancer .	Furthermore, Pin1 enhances Notch1 transcription activation and tumorigenic potential in breast cancer.	2	6	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pin1	Pin1	Pin1	Notch1	Notch1	Notch1	2	3	4	5
We include the use of Omi phosphomutants to further establish the effect of PINK1 activation of OMI on our novel substrates .	We include the use of Omi phosphomutants to further establish the effect of PINK1 activation of OMI on our novel substrates.	13	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	OMI	OMI	OMI	13	14	16	17
XREF_BIBR Moreover , HtrA2 is phosphorylated in a PINK1 dependent manner in response to p38 SAPK ( Stress Activated Protein Kinase ) pathway activation , suggesting that PINK1 can modulate HtrA2 activity as part of mitochondrial stress response .	XREF_BIBR Moreover, HtrA2 is phosphorylated in a PINK1 dependent manner in response to p38 SAPK (Stress Activated Protein Kinase) pathway activation, suggesting that PINK1 can modulate HtrA2 activity as part of mitochondrial stress response.	27	31	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1	PINK1	HtrA2	HtrA2	HtrA2	27	28	30	31
Consistent with this hypothesis , over-expression of Pin1 augmented Myc ' s interaction with p300 and transcriptional activity .	Consistent with this hypothesis, over-expression of Pin1 augmented Myc 's interaction with p300 and transcriptional activity.	5	10	augmented	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Pin1	over-expression of Pin1	pin1	Myc	Myc	myc	7	8	9	10
Transient transfection with a Luciferase reporter driven by the Myc responsive Nucleolin promoter ( Ncl-Luc ) showed that Pin1 and p300 additively enhanced the transcriptional activity of Myc ( XREF_FIG ) .	Transient transfection with a Luciferase reporter driven by the Myc responsive Nucleolin promoter (Ncl-Luc) showed that Pin1 and p300 additively enhanced the transcriptional activity of Myc (XREF_FIG).	18	29	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pin1	Pin1	Pin1	Myc	Myc	Myc	18	19	27	28
Altogether , our data demonstrate that Pin1 and Abl cooperate to enhance the interaction of Myc with p300 and its resulting acetylation .	Altogether, our data demonstrate that Pin1 and Abl cooperate to enhance the interaction of Myc with p300 and its resulting acetylation.	6	16	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pin1	Pin1	Pin1	Myc	Myc	Myc	6	7	15	16
In fact , our results indicate that the lower level of PIM1 , induced by ribosomal stress , causes inactivation of AKT , inhibition of MDM2 and a consequent p53 stabilization .	In fact, our results indicate that the lower level of PIM1, induced by ribosomal stress, causes inactivation of AKT, inhibition of MDM2 and a consequent p53 stabilization.	9	26	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PIM1	level of PIM1	pim1	MDM2	MDM2	mdm2	11	12	25	26
Surprisingly , at high levels of Pim expression , as would occur in tumors , active , but not inactive , Pim-1 or Pim-2 blocks the degradation of both p53 and Mdm2 in a manner that is independent of Mdm2 phosphorylation , leading to increased p53 levels and , proportionately , p53 dependent transactivation .	Surprisingly, at high levels of Pim expression, as would occur in tumors, active, but not inactive, Pim-1 or Pim-2 blocks the degradation of both p53 and Mdm2 in a manner that is independent of Mdm2 phosphorylation, leading to increased p53 levels and, proportionately, p53 dependent transactivation.	21	32	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pim-1	Pim-1	Pim-1	Mdm2	Mdm2	Mdm2	21	22	31	32
Therefore , we predicted that Pim-2 should also cause p21 to be stabilized by phosphorylation on Thr145 in HCT116 cells .	Therefore, we predicted that Pim-2 should also cause p21 to be stabilized by phosphorylation on Thr145 in HCT116 cells.	5	10	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pim-2	Pim-2	Pim-2	p21	p21	p21	5	6	9	10
In addition , the stability of cyclin dependent kinase ( CDK ) inhibitor p21 , which inhibits G 1 / S-phase progression , was enhanced by Pim-2 phosphorylation and inhibited cell proliferation in HCT116 cells .	In addition, the stability of cyclin dependent kinase (CDK) inhibitor p21, which inhibits G 1 / S-phase progression, was enhanced by Pim-2 phosphorylation and inhibited cell proliferation in HCT116 cells.	12	29	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Pim-2	Pim-2 phosphorylation	pim-2	p21	p21	p21	26	27	13	14
To determine whether Pim-2 also causes endogenous p21 to be stabilized , we first transfected pBK and CMV-Pim-2-FLAG ( wild type and kinase dead ) into HCT116 cells .	To determine whether Pim-2 also causes endogenous p21 to be stabilized, we first transfected pBK and CMV-Pim-2-FLAG (wild type and kinase dead) into HCT116 cells.	3	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pim-2	Pim-2	Pim-2	p21	p21	p21	3	4	7	8
Thus , in the insulin sensitive tissues of the p85alpha -/- animal there are decreased p110alpha and p110beta catalytic subunits and in p110alpha +/- and p110beta +/- heterozygotes there is ~ 50 % decrease in p85 expression in liver and muscle .	Thus, in the insulin sensitive tissues of the p85alpha -/- animal there are decreased p110alpha and p110beta catalytic subunits and in p110alpha +/- and p110beta +/- heterozygotes there is ~ 50% decrease in p85 expression in liver and muscle.	9	33	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p85alpha	p85alpha	p85alpha	p110beta	p110beta	p110beta	9	10	17	18
Relatively low levels of p85alpha and beta mediated suppression of p110beta may also cause the unusually high basal activity of p110beta compared to other class I PI3K subunits .	Relatively low levels of p85alpha and beta mediated suppression of p110beta may also cause the unusually high basal activity of p110beta compared to other class I PI3K subunits.	2	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p85alpha	levels of p85alpha	p85alpha	p110beta	p110beta	p110beta	4	5	20	21
To determine the possible contribution of different molecules which are involved with intrinsic apoptotic signaling in the context of Pim-1 mediated p21 downregulation in the presence of EBNA3C , we checked the protein expression profiles of Caspase-3 , Caspase-9 , Apaf-1 , and Bcl2 in sh-Ctrl-vector transfected and Pim-1 stable knockdown EBV negative Ramos cells .	To determine the possible contribution of different molecules which are involved with intrinsic apoptotic signaling in the context of Pim-1 mediated p21 downregulation in the presence of EBNA3C, we checked the protein expression profiles of Caspase-3, Caspase-9, Apaf-1, and Bcl2 in sh-Ctrl-vector transfected and Pim-1 stable knockdown EBV negative Ramos cells.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Pim-1	Pim-1	Pim-1	p21	p21	p21	19	20	21	22
Secondly , PI3Kgamma activates the phosphoinositide dependent protein kinase 1 ( PDK1 ) , and although the latter can modulate classical ( alpha and betaI ) and novel ( delta and epsilon ) PKC isoform , activation of atypical ( zeta/lambda/tau ) PKCs , and particularly PKCzeta , is a highly specific event downstream of PI3Kgamma-PDK1 [ XREF_BIBR ] .	Secondly, PI3Kgamma activates the phosphoinositide dependent protein kinase 1 (PDK1), and although the latter can modulate classical (alpha and betaI) and novel (delta and epsilon) PKC isoform, activation of atypical (zeta/lambda/tau) PKCs, and particularly PKCzeta, is a highly specific event downstream of PI3Kgamma-PDK1 [XREF_BIBR].	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	PDK1	PDK1	PDK1	2	3	11	12
Finally , overexpression of PIM1 rescues the effect of RPS19 depletion and restores p53 to control levels .	Finally, overexpression of PIM1 rescues the effect of RPS19 depletion and restores p53 to control levels.	2	10	rescues	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PIM1	overexpression of PIM1	pim1	RPS19	RPS19	rps19	4	5	9	10
They also showed that uPA induced uPAR cleavage was strongly accelerated in the lipid rafts .	They also showed that uPA induced uPAR cleavage was strongly accelerated in the lipid rafts.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	4	5	6	7
The tumor specificity of the MSN particle was improved with the addition of both chitosan , targeting acidic pH , and urokinase plasminogen activator ( UPA ) , targeting UPAR .	The tumor specificity of the MSN particle was improved with the addition of both chitosan, targeting acidic pH, and urokinase plasminogen activator (UPA), targeting UPAR.	23	30	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UPA	UPA	UPA	UPAR	UPAR	UPAR	25	26	29	30
The data reported here indicate that phosphorylation of pro uPA may modulate uPAR signaling ability , possibly interfering with uPAR mobilization and dynamic association with other membrane partners .	The data reported here indicate that phosphorylation of pro uPA may modulate uPAR signaling ability, possibly interfering with uPAR mobilization and dynamic association with other membrane partners.	6	14	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	phosphorylation of pro uPA	upa	uPAR	uPAR	upar	9	10	12	13
The authors highlighted an association between the uPAR and PDGFRbeta receptors induced by uPA stimulation .	The authors highlighted an association between the uPAR and PDGFRbeta receptors induced by uPA stimulation.	7	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	13	14	7	8
Exogenous addition of uPA activated Notch 1 in uPAR antisense U251 MG cells and also in uPAR antisense cells transfected with siRNA against Delta and Jagged .	Exogenous addition of uPA activated Notch 1 in uPAR antisense U251 MG cells and also in uPAR antisense cells transfected with siRNA against Delta and Jagged.	1	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	3	4	8	9
Survivin production is essential for the uPA induced up-regulation of uPAR .	Survivin production is essential for the uPA induced up-regulation of uPAR.	5	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	6	7	10	11
Supported by our complementary technical approaches on MSC from two different tissue origins , we propose that when vascular injuries that are associated with tissue lesions occurred , PDGF that is released from platelets and monocytes [ XREF_BIBR ] would stimulate an autocrine loop that induces uPA increased expression and uPAR activation by uPA in MSCs .	Supported by our complementary technical approaches on MSC from two different tissue origins, we propose that when vascular injuries that are associated with tissue lesions occurred, PDGF that is released from platelets and monocytes [XREF_BIBR] would stimulate an autocrine loop that induces uPA increased expression and uPAR activation by uPA in MSCs.	45	51	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	46	47	50	51
A relevant biological result indicates that uPA is required to enhance co-immunoprecipitation of purified integrins and uPAR .	A relevant biological result indicates that uPA is required to enhance co-immunoprecipitation of purified integrins and uPAR.	6	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	6	7	16	17
In human coronary VSMC , uPA induces uPAR independent , domain dependent smooth muscle cell proliferation through transactivation of EGFR by a plasmin mediated , ADAM induced , HB-EGF-dependent process , which is mediated by the intracellular pathways involving Galphai , Gbetagamma , src and NAD [ P ] H oxidase .	In human coronary VSMC, uPA induces uPAR independent, domain dependent smooth muscle cell proliferation through transactivation of EGFR by a plasmin mediated, ADAM induced, HB-EGF-dependent process, which is mediated by the intracellular pathways involving Galphai, Gbetagamma, src and NAD [P] H oxidase.	5	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	5	6	7	8
While uPA bound to uPAR independently of its membrane localization and dimerization status , uPA induced uPAR cleavage was strongly accelerated in lipid rafts .	While uPA bound to uPAR independently of its membrane localization and dimerization status, uPA induced uPAR cleavage was strongly accelerated in lipid rafts.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	14	15	16	17
uPA induced cleavage renders uPAR ( II-III ) on the cell surface , now unable to bind uPA [ XREF_BIBR , XREF_BIBR ] .	uPA induced cleavage renders uPAR (II-III) on the cell surface, now unable to bind uPA [XREF_BIBR, XREF_BIBR].	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	0	1	4	5
Thus , uPAR overexpressing MCF-7 cells respond similarly to the parent cells when treated with uPA .	Thus, uPAR overexpressing MCF-7 cells respond similarly to the parent cells when treated with uPA.	2	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	15	16	2	3
The uPA mediated induction of uPAR is not accomplished through its receptor and requires enzymatic activity .	The uPA mediated induction of uPAR is not accomplished through its receptor and requires enzymatic activity.	0	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	1	2	5	6
Thus , uPA and uPAR mediated cell surface proteolysis and/or uPAR mediated signaling events promote inflammatory joint disease , indicating that disruption of this key proteolytic and signaling system may provide a novel therapeutic strategy to limit clinical arthritis .	Thus, uPA and uPAR mediated cell surface proteolysis and/or uPAR mediated signaling events promote inflammatory joint disease, indicating that disruption of this key proteolytic and signaling system may provide a novel therapeutic strategy to limit clinical arthritis.	2	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	2	3	10	11
uPA increases uPA-R affinity for VTN and is also able to cleave its receptor .	uPA increases uPA-R affinity for VTN and is also able to cleave its receptor.	0	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPA-R	uPA-R	uPA-R	0	1	2	3
The ability of uPA to stimulate uPAR deficient fibroblast proliferation suggested the possibility that these cells expressed an alternative uPA receptor that might stimulate their proliferation .	The ability of uPA to stimulate uPAR deficient fibroblast proliferation suggested the possibility that these cells expressed an alternative uPA receptor that might stimulate their proliferation.	1	7	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	3	4	6	7
Moreover , inhibition of uPA activity with the subsequent shift towards more full-length uPAR , reduced both migration and invasion in a uPAR dependent manner , suggesting functional relevance of the cleavage status of uPAR .	Moreover, inhibition of uPA activity with the subsequent shift towards more full-length uPAR, reduced both migration and invasion in a uPAR dependent manner, suggesting functional relevance of the cleavage status of uPAR.	4	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	4	5	22	23
Induction of uPAR by uPA represents a novel pathway by which epithelial cells can regulate uPAR dependent cellular responses that may contribute to stromal remodeling in lung injury or neoplasia .	Induction of uPAR by uPA represents a novel pathway by which epithelial cells can regulate uPAR dependent cellular responses that may contribute to stromal remodeling in lung injury or neoplasia.	0	5	Induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	4	5	2	3
The results obtained on DRG explants from transgenic mice lacking uPA gene support the assumption that uPA stimulates neurite growth via uPA and uPAR interaction and uPAR role in axons branching and neural cell migration .	The results obtained on DRG explants from transgenic mice lacking uPA gene support the assumption that uPA stimulates neurite growth via uPA and uPAR interaction and uPAR role in axons branching and neural cell migration.	16	27	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	16	17	26	27
Together these observations indicate that uPA mediated uPAR cleavage and D1 removal , occurring on the cell surface of several cell types , can play a fundamental role in the regulation of multiple uPAR functions .	Together these observations indicate that uPA mediated uPAR cleavage and D1 removal, occurring on the cell surface of several cell types, can play a fundamental role in the regulation of multiple uPAR functions.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	5	6	7	8
HEK-293 cells that stably expressed membrane associated uPAR were treated with fluorescein isothiocyanate conjugated uPA ( uPA-FITC ) in the presence and absence of compound .	HEK-293 cells that stably expressed membrane associated uPAR were treated with fluorescein isothiocyanate conjugated uPA (uPA-FITC) in the presence and absence of compound.	6	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	14	15	7	8
As observed with the 293 cells , the exogenous addition of pro uPA rescued the uPAR cell morphology in a mutant dependent manner .	As observed with the 293 cells, the exogenous addition of pro uPA rescued the uPAR cell morphology in a mutant dependent manner.	9	17	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	12	13	15	16
Exogenous addition of uPA and uPAR activate Notch 1 in uPAR antisense and in U251 MG cells .	Exogenous addition of uPA and uPAR activate Notch 1 in uPAR antisense and in U251 MG cells.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	3	4	10	11
uPA induced uPAR cleavage is performed most efficiently when uPAR is GPI anchored to the cell surface [ XREF_BIBR , XREF_BIBR ] , hence uPAR is probably cleaved before it is shed .	uPA induced uPAR cleavage is performed most efficiently when uPAR is GPI anchored to the cell surface [XREF_BIBR, XREF_BIBR], hence uPAR is probably cleaved before it is shed.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	0	1	2	3
Thus , we have demonstrated that uPA promotes cellular migration , in an integrin selective manner , by initiating a uPAR dependent signaling cascade in which Ras , MEK , ERK , and MLCK serve as essential downstream effectors .	Thus, we have demonstrated that uPA promotes cellular migration, in an integrin selective manner, by initiating a uPAR dependent signaling cascade in which Ras, MEK, ERK, and MLCK serve as essential downstream effectors.	6	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	6	7	20	21
These results suggest that uPA promotes the invasive capacity of the uPAR positive cancer cells , and that stromal cells may play an important role in cancer cell invasion by supplying uPA and/or promoting uPA production .	These results suggest that uPA promotes the invasive capacity of the uPAR positive cancer cells, and that stromal cells may play an important role in cancer cell invasion by supplying uPA and/or promoting uPA production.	4	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	4	5	11	12
uPAR interactions with integrins and VN are positively regulated by uPA [ XREF_BIBR ] , and both uPA and VN can induce uPAR mediated cytoskeletal reorganization and cell migration [ XREF_BIBR ] .	uPAR interactions with integrins and VN are positively regulated by uPA [XREF_BIBR], and both uPA and VN can induce uPAR mediated cytoskeletal reorganization and cell migration [XREF_BIBR].	16	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	17	18	22	23
Clearance of uPA , PAI-1 , and uPAR complex from the cell surface may allow for the formation of new multicomponent signaling receptors in which unliganded uPAR associates with adaptor proteins that are available in short supply .	Clearance of uPA, PAI-1, and uPAR complex from the cell surface may allow for the formation of new multicomponent signaling receptors in which unliganded uPAR associates with adaptor proteins that are available in short supply.	2	27	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	2	3	26	27
Since the short term uPA treatment causes a partial cleavage of uPA-R , that does not increase with time , the observed increase in cell adhesivity can not be related to the cleavage of uPA-R .	Since the short term uPA treatment causes a partial cleavage of uPA-R, that does not increase with time, the observed increase in cell adhesivity can not be related to the cleavage of uPA-R.	4	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPA-R	uPA-R	uPA-R	4	5	11	12
u-PAR activation by u-PA produced de novo synthesis of diacylglycerol ( DAG ) from glucose by a cytochalasin B-inhibitable mechanism , indicating the involvement of a specific glucose transporter ( GLUT ) .	u-PAR activation by u-PA produced de novo synthesis of diacylglycerol (DAG) from glucose by a cytochalasin B-inhibitable mechanism, indicating the involvement of a specific glucose transporter (GLUT).	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	u-PA	u-PA	u-PA	u-PAR	u-PAR	u-PAR	3	4	0	1
Both sodium orthovanadate and uPA induce uPAR mRNA stability , indicating that dephosphorylation could contribute to uPA induced posttranscriptional regulation of uPAR expression .	Both sodium orthovanadate and uPA induce uPAR mRNA stability, indicating that dephosphorylation could contribute to uPA induced posttranscriptional regulation of uPAR expression.	2	8	induce	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	4	5	6	7
uPA further mediates its own expression in these cells as well as that of uPAR and PAI-1 through induction of changes in mRNA stability .	uPA further mediates its own expression in these cells as well as that of uPAR and PAI-1 through induction of changes in mRNA stability.	0	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	0	1	14	15
uPA accelerated atherosclerosis and aortic dilation are largely , if not completely , independent of uPAR .	uPA accelerated atherosclerosis and aortic dilation are largely, if not completely, independent of uPAR.	0	16	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	0	1	15	16
The lack of an effect of uPA- and uPAR specific antibodies on HT 1080 cell migration , in the absence of exogenously added DIP-uPA , suggested that endogenously produced uPA is insufficient to activate autocrine uPAR signaling in these cells .	The lack of an effect of uPA- and uPAR specific antibodies on HT 1080 cell migration, in the absence of exogenously added DIP-uPA, suggested that endogenously produced uPA is insufficient to activate autocrine uPAR signaling in these cells.	28	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	29	30	35	36
The expressions of both uPA and uPAR mRNAs in the gastric cancer cell lines ( MKN45 and KATO- III ) were increased markedly ( uPA mRNA ; MKN45 : 12-fold , KATO-III : 5-fold ) ( uPAR mRNA ; MKN45 : 3-fold , KATO-III : 3-fold ) with H. pylori NCTC11637 strain stimulation , whereas the expression levels of uPA and uPAR mRNA did not increase with cagA negative strain stimulation .	The expressions of both uPA and uPAR mRNAs in the gastric cancer cell lines (MKN45 and KATO- III) were increased markedly (uPA mRNA; MKN45 : 12-fold, KATO-III : 5-fold) (uPAR mRNA; MKN45 : 3-fold, KATO-III : 3-fold) with H. pylori NCTC11637 strain stimulation, whereas the expression levels of uPA and uPAR mRNA did not increase with cagA negative strain stimulation.	1	37	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	expressions of both uPA	upa	uPAR	uPAR	upar	4	5	36	37
Since Plau gene expression is influenced by uPAR signaling XREF_BIBR , XREF_BIBR , we suspected that the upregulated Plau expression we saw in Chd4 fl/fl ; Tie2-Cre + endothelial cells was secondary to upregulated Plaur .	Since Plau gene expression is influenced by uPAR signaling XREF_BIBR, XREF_BIBR, we suspected that the upregulated Plau expression we saw in Chd4 fl/fl; Tie2-Cre + endothelial cells was secondary to upregulated Plaur.	18	35	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plau	Plau expression	plau	Plaur	Plaur	plaur	18	19	34	35
On the other hand , uPA activated uPAR influences cell migration itself , as it associates to transmembrane integrins and hence induces several signal transduction cascades XREF_BIBR .	On the other hand, uPA activated uPAR influences cell migration itself, as it associates to transmembrane integrins and hence induces several signal transduction cascades XREF_BIBR.	5	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	5	6	7	8
The modular assembly of its three LU ( Ly6 and uPAR like ) domains is inherently flexible and binding of uPA drives uPAR into its closed conformation , which presents the higher-affinity state for vitronectin thus providing an allosteric regulatory mechanism .	The modular assembly of its three LU (Ly6 and uPAR like) domains is inherently flexible and binding of uPA drives uPAR into its closed conformation, which presents the higher-affinity state for vitronectin thus providing an allosteric regulatory mechanism.	2	26	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	20	21	22	23
Inhibition of uPA activity reduces cell migration and invasion in a uPAR dependent manner .	Inhibition of uPA activity reduces cell migration and invasion in a uPAR dependent manner.	2	13	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	2	3	11	12
The identification of uPA and uPAR signaling in hemangiosarcomas has led to the development of a novel therapeutic approach targeting uPAR .	The identification of uPA and uPAR signaling in hemangiosarcomas has led to the development of a novel therapeutic approach targeting uPAR.	3	21	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	3	4	20	21
To further clarify the role of uPA as a ligand for Notch 1 in glioblastoma cells , we wanted to ascertain if uPA activates Notch 1 in uPAR antisense cells in both the presence and absence of Notch ligands , namely Delta and Jagged .	To further clarify the role of uPA as a ligand for Notch 1 in glioblastoma cells, we wanted to ascertain if uPA activates Notch 1 in uPAR antisense cells in both the presence and absence of Notch ligands, namely Delta and Jagged.	22	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	22	23	27	28
uPA can upregulate uPAR in mesothelial cells and also contributes to chemotactic and mitogenic responses induced by pleural mesothelial cells and lung fibroblasts .	uPA can upregulate uPAR in mesothelial cells and also contributes to chemotactic and mitogenic responses induced by pleural mesothelial cells and lung fibroblasts.	0	9	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	0	1	3	4
There is overexpression of uPA and uPAR in neuroblastoma , and their increased expression is associated with invasion , metastasis , and poor prognosis for neuroblastoma [ XREF_BIBR ] .	There is overexpression of uPA and uPAR in neuroblastoma, and their increased expression is associated with invasion, metastasis, and poor prognosis for neuroblastoma [XREF_BIBR].	1	7	is overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	uPA	overexpression of uPA	upa	uPAR	uPAR	upar	4	5	6	7
We found that in the absence of uPA : PAI-1 , uPAR is randomly distributed along the plasma membrane , whereas uPA : PAI-1 promotes formation of uPAR-LRP complexes and initiates redistribution of occupied uPAR to clathrin coated pits .	We found that in the absence of uPA : PAI-1, uPAR is randomly distributed along the plasma membrane, whereas uPA : PAI-1 promotes formation of uPAR-LRP complexes and initiates redistribution of occupied uPAR to clathrin coated pits.	21	35	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	21	22	34	35
We reported earlier that uPA induces its own expression as well as that of uPAR through obliteration of p53 .	We reported earlier that uPA induces its own expression as well as that of uPAR through obliteration of p53.	4	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	4	5	14	15
These results suggest that uPA by itself could mediate uPAR independent functions such as Notch 1 regulation in glioblastoma cell lines .	These results suggest that uPA by itself could mediate uPAR independent functions such as Notch 1 regulation in glioblastoma cell lines.	4	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	4	5	9	10
The uPA activates uPAR dependent cell signaling and may explain the ability of ESC cells to release from dormancy .	The uPA activates uPAR dependent cell signaling and may explain the ability of ESC cells to release from dormancy.	0	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	1	2	3	4
Thus , binding of uPA causes uPAR to act as a ligand for alpha 5 beta 1 to induce cell adhesion , intracellular signaling , and cell migration .	Thus, binding of uPA causes uPAR to act as a ligand for alpha 5 beta 1 to induce cell adhesion, intracellular signaling, and cell migration.	2	7	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	4	5	6	7
Taken together , the data support the possibility that pro uPA phosphorylation on Ser 138/303 can modulate uPAR transducing ability .	Taken together, the data support the possibility that pro uPA phosphorylation on Ser 138/303 can modulate uPAR transducing ability.	10	19	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA phosphorylation on Ser 138/303	upa	uPAR	uPAR	upar	10	11	17	18
The urokinase-type plasminogen activator receptor ( uPAR ) , which plays a critical role in cancer cell growth , survival , invasion and metastasis , contains a five amino acid sequence ( SRSRY ) between two of its three domains , which is exposed through ligand binding , and mediates chemotactic properties of uPAR .	The urokinase-type plasminogen activator receptor (uPAR), which plays a critical role in cancer cell growth, survival, invasion and metastasis, contains a five amino acid sequence (SRSRY) between two of its three domains, which is exposed through ligand binding, and mediates chemotactic properties of uPAR.	1	54	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	urokinase-type plasminogen activator	urokinase-type plasminogen activator	urokinase-type plasminogen activator	uPAR	uPAR	uPAR	1	4	53	54
During mitotic entry , Plk1 phosphorylates and partially activates Cdc25C , which , in turn , removes the inhibitory ( T14 and Y15 ) phosphorylations on Cdk1 , partially activating it .	During mitotic entry, Plk1 phosphorylates and partially activates Cdc25C, which, in turn, removes the inhibitory (T14 and Y15) phosphorylations on Cdk1, partially activating it.	4	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	Cdc25C	Cdc25C	Cdc25C	4	5	9	10
Ubiquitination of Plk1 by Chfr delays the activation of the Cdc25C phosphatase and the inactivation of the Wee1 kinase , leading to a delay in Cdc2 activation .	Ubiquitination of Plk1 by Chfr delays the activation of the Cdc25C phosphatase and the inactivation of the Wee1 kinase, leading to a delay in Cdc2 activation.	0	14	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Plk1	Ubiquitination of Plk1	plk1	Cdc25C	Cdc25C	cdc25c	2	3	10	11
However , mitotic entry is triggered by a steep increase in cyclin B-cyclin-dependent kinase 1 activity , which is promoted by PLK1 activated CDC25C .	However, mitotic entry is triggered by a steep increase in cyclin B-cyclin-dependent kinase 1 activity, which is promoted by PLK1 activated CDC25C.	19	24	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	CDC25C	CDC25C	CDC25C	21	22	23	24
The activation circuit for CDK1 involves both inhibitory phosphorylation of MYT1 on Thr 495 and an activating phosphorylation on CDC25C , which are both mediated by PLK1 .	The activation circuit for CDK1 involves both inhibitory phosphorylation of MYT1 on Thr 495 and an activating phosphorylation on CDC25C, which are both mediated by PLK1.	17	27	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	CDC25C	CDC25C	CDC25C	26	27	19	20
We also show that Polo like kinase 1 ( Plk1 ) is responsible for this phosphorylation and that constitutively active Plk1 promotes nuclear localization of Cdc25C .	We also show that Polo like kinase 1 (Plk1) is responsible for this phosphorylation and that constitutively active Plk1 promotes nuclear localization of Cdc25C.	19	26	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	Cdc25C	Cdc25C	Cdc25C	20	21	25	26
PLK1 activates Cdc2 and cyclin B complex via phosphorylation and activation of Cdc25C and is an early trigger for G2/M transition [ XREF_BIBR ] .	PLK1 activates Cdc2 and cyclin B complex via phosphorylation and activation of Cdc25C and is an early trigger for G2/M transition [XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	Cdc25C	Cdc25C	Cdc25C	0	1	12	13
Most importantly , Plk1 activates the dual specific phosphatase Cdc25C , which dephosphorylates , and thus activates , the maturation promoting factor ( MPF ) , resulting in nuclear MPF translocation .	Most importantly, Plk1 activates the dual specific phosphatase Cdc25C, which dephosphorylates, and thus activates, the maturation promoting factor (MPF), resulting in nuclear MPF translocation.	3	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	Cdc25C	Cdc25C	Cdc25C	3	4	9	10
Phosphorylation of S198 by Plk1 promotes cdc25C nuclear localization XREF_BIBR and a proteomic screen of phospho-peptides interacting with the Plk1 binding domain identified a S-phosho-TP motif present in cdc25C at T130 as a polo-box-domain ( PDB ) binding motif XREF_BIBR , XREF_BIBR .	Phosphorylation of S198 by Plk1 promotes cdc25C nuclear localization XREF_BIBR and a proteomic screen of phospho-peptides interacting with the Plk1 binding domain identified a S-phosho-TP motif present in cdc25C at T130 as a polo-box-domain (PDB) binding motif XREF_BIBR, XREF_BIBR.	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Phosphorylation of S198 by Plk1	plk1	cdc25C	cdc25C	cdc25c	4	5	6	7
PLK1 activates CDC25C and Cyclin B1 by phosphorylation , which triggers entry of cells into mitosis , [ XREF_BIBR ] .	PLK1 activates CDC25C and Cyclin B1 by phosphorylation, which triggers entry of cells into mitosis, [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	CDC25C	CDC25C	CDC25C	0	1	2	3
Overexpression of a phosphomimetic Cdc25C variant promotes mitotic entry even when Plk1 activity is inhibited , indicating that activation of Cdc25C by Plk1 is sufficient for mitotic entry [ XREF_BIBR ] .	Overexpression of a phosphomimetic Cdc25C variant promotes mitotic entry even when Plk1 activity is inhibited, indicating that activation of Cdc25C by Plk1 is sufficient for mitotic entry [XREF_BIBR].	18	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	Cdc25C	Cdc25C	Cdc25C	22	23	20	21
On the other hand , Plk1 promotes the activation of Cdk1 and cyclin B by activating Cdc25C .	On the other hand, Plk1 promotes the activation of Cdk1 and cyclin B by activating Cdc25C.	5	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	Cdc25C	Cdc25C	Cdc25C	5	6	16	17
Plk1 directly promotes mitotic entry by activating Cdc25C and Cdk1 and Cyclin B complex [ XREF_BIBR - XREF_BIBR ] .	Plk1 directly promotes mitotic entry by activating Cdc25C and Cdk1 and Cyclin B complex [XREF_BIBR - XREF_BIBR].	0	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	Cdc25C	Cdc25C	Cdc25C	0	1	7	8
We show that there is widespread coordinate overexpression of FOXM1 and PLK1 in oesophageal adenocarcinomas , thereby providing the potential for feedback potentiation of FOXM1 activity .	We show that there is widespread coordinate overexpression of FOXM1 and PLK1 in oesophageal adenocarcinomas, thereby providing the potential for feedback potentiation of FOXM1 activity.	4	12	is widespread coordinate overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	PLK1	overexpression of FOXM1 and PLK1	plk1	FOXM1	FOXM1	foxm1	11	12	9	10
Wild-type Plk1 , but not the kinase inactive mutant of Plk1 , significantly upregulated FoxM1 transcriptional activity in a concentration dependent manner ( XREF_FIG ) , suggesting a direct regulation of FoxM1 by Plk1 dependent phosphorylation .	Wild-type Plk1, but not the kinase inactive mutant of Plk1, significantly upregulated FoxM1 transcriptional activity in a concentration dependent manner (XREF_FIG), suggesting a direct regulation of FoxM1 by Plk1 dependent phosphorylation.	0	16	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	FoxM1	FoxM1	FoxM1	1	2	14	15
Accordingly , the expression levels of known FoxM1 downstream targets such as polo like kinase-1 ( PLK-1 ) , the 55-kDa centromeric protein Cep55 , and cyclin D1 were also decreased following thiostrepton treatment .	Accordingly, the expression levels of known FoxM1 downstream targets such as polo like kinase-1 (PLK-1), the 55-kDa centromeric protein Cep55, and cyclin D1 were also decreased following thiostrepton treatment.	7	27	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	polo like kinase-1	polo like kinase-1	polo like kinase-1	FoxM1	FoxM1	FoxM1	12	15	7	8
Western blot analysis showed that overexpression of the full-length FOXM1 prevented the down-regulation of FOXM1 targets such as CDC25b and PLK in response to tamoxifen treatment .	Western blot analysis showed that overexpression of the full-length FOXM1 prevented the down-regulation of FOXM1 targets such as CDC25b and PLK in response to tamoxifen treatment.	14	21	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	PLK	PLK	PLK	FOXM1	FOXM1	FOXM1	20	21	14	15
Consistent with a pro tumorigenic role , overexpressing Plk1 activates FoxM1 , stimulating transcription of several mitotic regulators favoring cell proliferation [ XREF_BIBR ] .	Consistent with a pro tumorigenic role, overexpressing Plk1 activates FoxM1, stimulating transcription of several mitotic regulators favoring cell proliferation [XREF_BIBR].	5	11	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	FoxM1	FoxM1	FoxM1	8	9	10	11
These results are consistent with those shown in XREF_FIG and indicate that phosphorylation of either Thr 596 or Ser 678 of FoxM1 can independently mediate the binding to Plk1 and this binding is essential for Plk1 dependent activation of FoxM1 .	These results are consistent with those shown in XREF_FIG and indicate that phosphorylation of either Thr 596 or Ser 678 of FoxM1 can independently mediate the binding to Plk1 and this binding is essential for Plk1 dependent activation of FoxM1.	35	40	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	FoxM1	FoxM1	FoxM1	35	36	39	40
We next investigated whether the association between Plk1 and FoxM1 is necessary for Plk1 dependent activation of FoxM1 .	We next investigated whether the association between Plk1 and FoxM1 is necessary for Plk1 dependent activation of FoxM1.	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	FoxM1	FoxM1	FoxM1	13	14	17	18
Recently , Plk1 was also shown to activate FoxM1 directly .	Recently, Plk1 was also shown to activate FoxM1 directly.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	FoxM1	FoxM1	FoxM1	2	3	8	9
After confirming the elimination of PLK1 driven FOXM1 activation by ONO1910 , we found that ONO1910 also eliminates FOXM1 activation driven by MELK in a dose dependent manner ( XREF_FIG A ) .	After confirming the elimination of PLK1 driven FOXM1 activation by ONO1910, we found that ONO1910 also eliminates FOXM1 activation driven by MELK in a dose dependent manner (XREF_FIG A).	3	8	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	FOXM1	FOXM1	FOXM1	5	6	7	8
We now show that there is also coordinate overexpression of FOXM1 and PLK1 in gastric adenocarcinomas , thereby providing the potential for feedback potentiation of FOXM1 activity .	We now show that there is also coordinate overexpression of FOXM1 and PLK1 in gastric adenocarcinomas, thereby providing the potential for feedback potentiation of FOXM1 activity.	5	13	is also coordinate overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	PLK1	overexpression of FOXM1 and PLK1	plk1	FOXM1	FOXM1	foxm1	12	13	10	11
Likewise , FOXM1 protein is sequentially targeted by PLK1 , then APC Cdh1 activity during G1 [ XREF_BIBR - XREF_BIBR ] .	Likewise, FOXM1 protein is sequentially targeted by PLK1, then APC Cdh1 activity during G1 [XREF_BIBR - XREF_BIBR].	2	13	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	FOXM1	FOXM1	FOXM1	8	9	2	3
Treatment with volasertib still reduced constitutive ER transcriptional reporter activity in the FOXM1-EE expressing cells , suggesting PLK1 mediates ER activity downstream of FOXM1 in LTED cells .	Treatment with volasertib still reduced constitutive ER transcriptional reporter activity in the FOXM1-EE expressing cells, suggesting PLK1 mediates ER activity downstream of FOXM1 in LTED cells.	17	26	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	FOXM1	FOXM1	FOXM1	17	18	23	24
In order to exclude the possibility of an off-target effect by pharmacological inhibition , we then tested the effect of the PLK1 dominant negative mutant ( PLK1 DN ) on MELK mediated FOXM1 activation .	In order to exclude the possibility of an off-target effect by pharmacological inhibition, we then tested the effect of the PLK1 dominant negative mutant (PLK1 DN) on MELK mediated FOXM1 activation.	18	33	mediated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	FOXM1	FOXM1	FOXM1	21	22	32	33
Plk1 contributes to both Cyclin B1 and Cdc25C activation and localization at the G 2 / M transition XREF_BIBR .	Plk1 contributes to both Cyclin B1 and Cdc25C activation and localization at the G 2 / M transition XREF_BIBR.	0	13	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	B1	B1	B1	0	1	5	6
However , it was possible that Plk1 could trigger the nuclear accumulation of cyclin B1 by a mechanism separate from phosphorylating cyclin B1 .	However, it was possible that Plk1 could trigger the nuclear accumulation of cyclin B1 by a mechanism separate from phosphorylating cyclin B1.	6	15	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	B1	B1	B1	6	7	14	15
Plk1 promotes activation of Cdc2 and cyclin B1 XREF_BIBR , XREF_BIBR and inhibits the activity of the Cdc2 and cyclin B1 inhibitors , Wee1 and Myt1 XREF_BIBR , XREF_BIBR , XREF_BIBR .	Plk1 promotes activation of Cdc2 and cyclin B1 XREF_BIBR, XREF_BIBR and inhibits the activity of the Cdc2 and cyclin B1 inhibitors, Wee1 and Myt1 XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	B1	B1	B1	0	1	7	8
Whereas siRNA mediated downregulation of Plk1 induced the upregulation of cyclin B1 mRNA in both cell lines , this was only followed by the increased protein translation in HS766T , but not in MiaPaca2 .	Whereas siRNA mediated downregulation of Plk1 induced the upregulation of cyclin B1 mRNA in both cell lines, this was only followed by the increased protein translation in HS766T, but not in MiaPaca2.	3	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	B1	B1	B1	5	6	11	12
If Plk1 can only enhance the activity of Cdc2 and cyclin B1 that already is phosphorylated at Thr161 , the amount of active Plk1 present would be irrelevant if CAK is the rate limiting factor in Cdc2 and cyclin B1 activation .	If Plk1 can only enhance the activity of Cdc2 and cyclin B1 that already is phosphorylated at Thr161, the amount of active Plk1 present would be irrelevant if CAK is the rate limiting factor in Cdc2 and cyclin B1 activation.	1	18	enhance	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Plk1	Plk1	plk1	B1	B1 that already is phosphorylated at Thr161	b1	1	2	11	12
Co-expression of constitutively active Plk1 stimulates nuclear entry of cyclin B1 .	Co-expression of constitutively active Plk1 stimulates nuclear entry of cyclin B1.	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Co-expression of constitutively active Plk1	plk1	B1	B1	b1	4	5	10	11
However , in conflict with this , we and others have shown that Plk1 phosphorylates cyclin B1 on Ser133 not Ser147 and that overexpressing Plk1 does not cause cyclin B1 to move into the nucleus in interphase .	However, in conflict with this, we and others have shown that Plk1 phosphorylates cyclin B1 on Ser133 not Ser147 and that overexpressing Plk1 does not cause cyclin B1 to move into the nucleus in interphase.	23	30	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	B1	B1	B1	24	25	29	30
Surprisingly , we also found that catalytically active Plk1 was unable to increase the activity of endogenous Cdc2 and cyclin B1 in P3 cardiac myocytes , suggesting that Plk1 is unable to complete with the other factors that regulate activity of the Cdc2 and cyclin B1 complex .	Surprisingly, we also found that catalytically active Plk1 was unable to increase the activity of endogenous Cdc2 and cyclin B1 in P3 cardiac myocytes, suggesting that Plk1 is unable to complete with the other factors that regulate activity of the Cdc2 and cyclin B1 complex.	7	21	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	B1	B1	B1	8	9	20	21
Over-expression of Plk1 does not increase the activity of Cdc2 and cyclin B1 in P3 cardiac myocytes .	Over-expression of Plk1 does not increase the activity of Cdc2 and cyclin B1 in P3 cardiac myocytes.	0	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Over-expression of Plk1	plk1	B1	B1	b1	2	3	12	13
Plk1 dependent phosphorylations ( T792 , T1008 and S676 ) were reported to stimulate BubR1 kinase activity , promote kinetochore microtubule attachments , monitor kinetochore tension , as well as the recruitment of Mad2 checkpoint protein to kinetochores .	Plk1 dependent phosphorylations (T792, T1008 and S676) were reported to stimulate BubR1 kinase activity, promote kinetochore microtubule attachments, monitor kinetochore tension, as well as the recruitment of Mad2 checkpoint protein to kinetochores.	0	16	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1 dependent phosphorylations	plk1	BubR1	BubR1	bubr1	0	1	14	15
In the current study , we also found that the knockdown of Plk1 in HeLa cells activates the spindle checkpoint , even though the levels of kinetochore associated Mad2 , but not BubR1 , are reduced , which is consistent with the findings of a recent study .	In the current study, we also found that the knockdown of Plk1 in HeLa cells activates the spindle checkpoint, even though the levels of kinetochore associated Mad2, but not BubR1, are reduced, which is consistent with the findings of a recent study.	10	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	BubR1	BubR1	BubR1	12	13	32	33
Phosphorylation of a conserved KARD domain n BUBR1 by PLK1 ( polo like kinase 1 ) promotes direct interaction of BUBR1 with the PP2A-B56alpha phosphatase , a potential mechanism for the recruitment of PP2A-B56alpha to the inner kinetochore prior to microtubule attachment .	Phosphorylation of a conserved KARD domain n BUBR1 by PLK1 (polo like kinase 1) promotes direct interaction of BUBR1 with the PP2A-B56alpha phosphatase, a potential mechanism for the recruitment of PP2A-B56alpha to the inner kinetochore prior to microtubule attachment.	0	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK1	Phosphorylation of a conserved KARD domain n BUBR1 by PLK1	plk1	BUBR1	BUBR1	bubr1	9	10	20	21
In contrast , ectopic expression of wild-type PLD2 enhanced Ras and MAPK activation in response to therapeutic levels of lovastatin .	In contrast, ectopic expression of wild-type PLD2 enhanced Ras and MAPK activation in response to therapeutic levels of lovastatin.	4	12	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLD2	expression of wild-type PLD2	pld2	MAPK	MAPK	mapk	7	8	11	12
While inhibition of both PLD and DGK had no effect on the overall ERK activity , inhibition of PLD2 but not PLD1 or DGK blocked the nuclear ERK activity in several cancer cell lines .	While inhibition of both PLD and DGK had no effect on the overall ERK activity, inhibition of PLD2 but not PLD1 or DGK blocked the nuclear ERK activity in several cancer cell lines.	16	28	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PLD2	PLD2	PLD2	ERK	ERK	ERK	18	19	27	28
PLD2 , and its product phosphatidic acid , can also activate MAPK .	PLD2, and its product phosphatidic acid, can also activate MAPK.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLD2	PLD2	PLD2	MAPK	MAPK	MAPK	0	1	11	12
Both isoforms of PLD , PLD1 and PLD2 , have been shown to promote activation of ERK by increasing the membrane associated pool of phosphorylated Raf .	Both isoforms of PLD, PLD1 and PLD2, have been shown to promote activation of ERK by increasing the membrane associated pool of phosphorylated Raf.	1	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLD2	PLD2	PLD2	ERK	ERK	ERK	7	8	16	17
Inhibition or siRNA mediated knockdown of Plk1 causes PICH to spread from centromeres and KTs over chromosome arms , suggesting that Plk1 normally functions to remove PICH from arms and allow its concentration at centromeres and KTs .	Inhibition or siRNA mediated knockdown of Plk1 causes PICH to spread from centromeres and KTs over chromosome arms, suggesting that Plk1 normally functions to remove PICH from arms and allow its concentration at centromeres and KTs.	4	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	PICH	PICH	PICH	6	7	8	9
A rise in Plk1 activity during early mitosis causes the release of PICH from chromosome arms , resulting in the concentration of PICH at centromeres and kinetochores .	A rise in Plk1 activity during early mitosis causes the release of PICH from chromosome arms, resulting in the concentration of PICH at centromeres and kinetochores.	3	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	PICH	PICH	PICH	3	4	12	13
That PICH targets Plk1 to the chromosome arm was further supported by overexpression studies in which GFP-PICH was found to colocalize with Plk1 on the chromosome arms .	That PICH targets Plk1 to the chromosome arm was further supported by overexpression studies in which GFP-PICH was found to colocalize with Plk1 on the chromosome arms.	0	9	targets	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	PICH	PICH	PICH	3	4	1	2
In previous studies , we had shown that depletion or inhibition of Plk1 during early mitosis results in retention of PICH on chromosome arms .	In previous studies, we had shown that depletion or inhibition of Plk1 during early mitosis results in retention of PICH on chromosome arms.	8	21	results in retention	Positive_activation_syntax_8_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	PICH	PICH	PICH	12	13	20	21
In light of these early results , it seemed plausible that recruitment of Plk1 and consequent phosphorylation of PICH by Plk1 is the mechanism through which Plk1 triggers the dissociation of PICH from chromosome arms .	In light of these early results, it seemed plausible that recruitment of Plk1 and consequent phosphorylation of PICH by Plk1 is the mechanism through which Plk1 triggers the dissociation of PICH from chromosome arms.	26	32	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	PICH	PICH	PICH	26	27	31	32
Given that PLK-1 directly modulates p53 functions as well as indirectly by modulating MDM2 functions , we wanted to determine inhibiting PLK-1 would sensitize cells to the effects of nutlin-3 , an inhibitor of MDM2 .	Given that PLK-1 directly modulates p53 functions as well as indirectly by modulating MDM2 functions, we wanted to determine inhibiting PLK-1 would sensitize cells to the effects of nutlin-3, an inhibitor of MDM2.	2	14	modulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK-1	PLK-1	PLK-1	MDM2	MDM2	MDM2	2	3	13	14
Plk1 phosphorylates S260 in MDM2 and stimulates MDM2 mediated turnover of p53 [ XREF_BIBR ] .	Plk1 phosphorylates S260 in MDM2 and stimulates MDM2 mediated turnover of p53 [XREF_BIBR].	0	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	MDM2	MDM2	MDM2	0	1	7	8
Further , the depletion of Plk1 has been correlated to reduced levels of Mdm2 , an E3 ubiquitin ligase and critical regulator of p53 , which was corroborated with the observation that phosphorylation of Mdm2 at Ser260 by Plk1 stimulates Mdm2 mediated turnover of p53 .	Further, the depletion of Plk1 has been correlated to reduced levels of Mdm2, an E3 ubiquitin ligase and critical regulator of p53, which was corroborated with the observation that phosphorylation of Mdm2 at Ser260 by Plk1 stimulates Mdm2 mediated turnover of p53.	36	42	stimulates	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	Mdm2	Mdm2	Mdm2	38	39	40	41
Furthermore we observed that treatment of cells with the conventional PKC inhibitor Go6976 ( XREF_FIG ) and specific PKCalpha knock down ( XREF_FIG ) markedly inhibited the FGF-2-mediated Akt phosphorylation , indicating that a PLCgamma1 mediated PKCalpha activation is necessary for FGF-2-mediated Akt activation .	Furthermore we observed that treatment of cells with the conventional PKC inhibitor Go6976 (XREF_FIG) and specific PKCalpha knock down (XREF_FIG) markedly inhibited the FGF-2-mediated Akt phosphorylation, indicating that a PLCgamma1 mediated PKCalpha activation is necessary for FGF-2-mediated Akt activation.	33	37	mediated	Positive_early_activation	Positive_activation	Positive_activation	PLCgamma1	PLCgamma1	PLCgamma1	PKCalpha	PKCalpha	PKCalpha	34	35	36	37
Since PLCgamma1 mediates PKCalpha activation , we investigated whether PLCgamma1 mediated PKCalpha activation was required for FGF-2-dependent Akt activation .	Since PLCgamma1 mediates PKCalpha activation, we investigated whether PLCgamma1 mediated PKCalpha activation was required for FGF-2-dependent Akt activation.	1	4	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLCgamma1	PLCgamma1	PLCgamma1	PKCalpha	PKCalpha	PKCalpha	1	2	3	4
Inhibition of PLCgamma1 phosphorylation by pretreatment with U73122 , a PLC inhibitor , dramatically decreased PKCalpha activation , as well as the degradation of ZO-1 and claudin-2 , during exposure to oxidative stress .	Inhibition of PLCgamma1 phosphorylation by pretreatment with U73122, a PLC inhibitor, dramatically decreased PKCalpha activation, as well as the degradation of ZO-1 and claudin-2, during exposure to oxidative stress.	2	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PLCgamma1	PLCgamma1 phosphorylation	plcgamma1	PKCalpha	PKCalpha	pkcalpha	2	3	15	16
Because these mutations still allow microtubule bundling , Prc1 may create a scaffold of appropriately bundled microtubules on which Plk1 can target HsCyk-4 for phosphorylation .	Because these mutations still allow microtubule bundling, Prc1 may create a scaffold of appropriately bundled microtubules on which Plk1 can target HsCyk-4 for phosphorylation.	19	23	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	HsCyk-4	HsCyk-4	HsCyk-4	19	20	22	23
XREF_BIBR , XREF_BIBR The maximum level of phosphorylation occurs in mitosis , and Plk1- and Plk2 associated phosphorylation can activate TOP2A .	XREF_BIBR, XREF_BIBR The maximum level of phosphorylation occurs in mitosis, and Plk1- and Plk2 associated phosphorylation can activate TOP2A.	13	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1-	Plk1-	Plk1-	TOP2A	TOP2A	TOP2A	13	14	20	21
Our work demonstrates that Plk1 also activates Kif2b to destabilize k-MT attachments .	Our work demonstrates that Plk1 also activates Kif2b to destabilize k-MT attachments.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	Kif2b	Kif2b	Kif2b	4	5	7	8
BI 2356 treated cells arrested in prometaphase and displayed abundant centromeric survivin-GFP , phenocopying the distribution of S20A , further indicating that Ser 20 is the principal Plk1 target of survivin .	BI 2356 treated cells arrested in prometaphase and displayed abundant centromeric survivin-GFP, phenocopying the distribution of S20A, further indicating that Ser 20 is the principal Plk1 target of survivin.	27	31	target	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	survivin	survivin	survivin	27	28	30	31
It is not necessarily relevant whether PLK1 and IAPs are direct targets of Survivin .	It is not necessarily relevant whether PLK1 and IAPs are direct targets of Survivin.	6	14	are direct targets	Positive_activation_copula_1	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	Survivin	Survivin	Survivin	6	7	13	14
Treatment with BI 2356 , however , revealed that cells arrested in prometaphase in response to the Plk1 inhibition have abundant survivin-GFP at their centromeres , a pattern closely phenocopying S20A localization and distinct from the distribution of T21A ( this study ) and T97A , lending further credence to our conclusion that Ser 20 is the principle Plk1 target of survivin .	Treatment with BI 2356, however, revealed that cells arrested in prometaphase in response to the Plk1 inhibition have abundant survivin-GFP at their centromeres, a pattern closely phenocopying S20A localization and distinct from the distribution of T21A (this study) and T97A, lending further credence to our conclusion that Ser 20 is the principle Plk1 target of survivin.	58	62	target	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	survivin	survivin	survivin	58	59	61	62
Overexpression of Plk1 and knockdown of p53 expression both enhanced the post-translational protein stability of Cep55 .	Overexpression of Plk1 and knockdown of p53 expression both enhanced the post-translational protein stability of Cep55.	0	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk1	Overexpression of Plk1	plk1	Cep55	Cep55	cep55	2	3	15	16
Consistently , overexpression of PLK1 and knockdown of its linker TP53 can enhance the stability of CEP55 which could regulates breast cancer progression and metastasis XREF_BIBR .	Consistently, overexpression of PLK1 and knockdown of its linker TP53 can enhance the stability of CEP55 which could regulates breast cancer progression and metastasis XREF_BIBR.	2	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK1	overexpression of PLK1	plk1	CEP55	CEP55	cep55	4	5	16	17
In contrast , c-Myc was not repressed by other potent and selective inhibitors of PLK or JAK lacking BET activity , including ruxolitinib , tofacitinib , and GSK-461364A ( XREF_FIG , XREF_SUPPLEMENTARY , and XREF_SUPPLEMENTARY ) .	In contrast, c-Myc was not repressed by other potent and selective inhibitors of PLK or JAK lacking BET activity, including ruxolitinib, tofacitinib, and GSK-461364A (XREF_FIG, XREF_SUPPLEMENTARY, and XREF_SUPPLEMENTARY).	3	16	repressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	PLK	PLK	PLK	c-Myc	c-Myc	c-Myc	14	15	3	4
A previous study demonstrated that PLK1 may promote tumor cell survival by regulating Myc stabilization ; inhibitors of PLK1 preferentially induced potent apoptosis level in MYCN amplified tumor cells from neuroblastoma and small cell lung cancer , and synergistically potentiated the therapeutic efficacies of Bcl-2 antagonists .	A previous study demonstrated that PLK1 may promote tumor cell survival by regulating Myc stabilization; inhibitors of PLK1 preferentially induced potent apoptosis level in MYCN amplified tumor cells from neuroblastoma and small cell lung cancer, and synergistically potentiated the therapeutic efficacies of Bcl-2 antagonists.	5	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	Myc	Myc	Myc	5	6	13	14
Several studies have shown that PLK1 induces c-Myc accumulation by direct phosphorylation [ XREF_BIBR , XREF_BIBR ] .	Several studies have shown that PLK1 induces c-Myc accumulation by direct phosphorylation [XREF_BIBR, XREF_BIBR].	5	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK1	PLK1	PLK1	c-Myc	c-Myc	c-Myc	5	6	7	8
Pin1 is also subject to post-translational modifications , including Ser16 phosphorylation , which abolishes the ability of Pin1 to interact with its substrates and Ser65 by PLK , which appears to increase Pin1 protein stability .	Pin1 is also subject to post-translational modifications, including Ser16 phosphorylation, which abolishes the ability of Pin1 to interact with its substrates and Ser65 by PLK, which appears to increase Pin1 protein stability.	19	34	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK	PLK	PLK	Pin1	Pin1	Pin1	26	27	32	33
The hypothesis that particular targets require simultaneous interaction with both the WW and the PPIase domain was tested using the known Pin1 targets Plk1 and Cdc25C .	The hypothesis that particular targets require simultaneous interaction with both the WW and the PPIase domain was tested using the known Pin1 targets Plk1 and Cdc25C.	18	25	targets	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	Pin1	Pin1	Pin1	23	24	21	22
Moreover , addition of PBX1 or the alternative TALE HOXA1 cofactor PREP1 , which normally allow HOXA1 to fully activate the HOXA1 reporter had no effect on the activation of the NF-kappaB reporter by HOXA1 .	Moreover, addition of PBX1 or the alternative TALE HOXA1 cofactor PREP1, which normally allow HOXA1 to fully activate the HOXA1 reporter had no effect on the activation of the NF-kappaB reporter by HOXA1.	2	23	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PREP1	PREP1	PREP1	HOXA1	HOXA1	HOXA1	11	12	16	17
Similarly , Pbx1a and Prep1 only modestly increased the Hoxa1- and Hoxa2 mediated reporter activations ( 1.2-fold ; XREF_FIG A and B ) .	Similarly, Pbx1a and Prep1 only modestly increased the Hoxa1- and Hoxa2 mediated reporter activations (1.2-fold; XREF_FIG A and B).	2	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Prep1	Prep1	Prep1	Hoxa1-	Hoxa1-	Hoxa1-	4	5	9	10
Our current data suggest PLCgamma1 activates Rac1 to promote migration in glioma cells and PTPmu acts to suppress migration by dephosphorylating PLCgamma1 on residue Y783 .	Our current data suggest PLCgamma1 activates Rac1 to promote migration in glioma cells and PTPmu acts to suppress migration by dephosphorylating PLCgamma1 on residue Y783.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLCgamma1	PLCgamma1	PLCgamma1	Rac1	Rac1	Rac1	4	5	6	7
The signal transduction of both PLCgamma1 and MAP and ERK mediated pathways can activate small G protein Rac1 , which is a key component in regulating cell migration XREF_BIBR , XREF_BIBR .	The signal transduction of both PLCgamma1 and MAP and ERK mediated pathways can activate small G protein Rac1, which is a key component in regulating cell migration XREF_BIBR, XREF_BIBR.	2	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLCgamma1	PLCgamma1	PLCgamma1	Rac1	Rac1	Rac1	5	6	17	18
This in vitro cooperativity of PREP1 and PBX1 might result in a precise organization of transcriptional regulation , in which PREP1 contributes to selectivity and PBX1 to affinity .	This in vitro cooperativity of PREP1 and PBX1 might result in a precise organization of transcriptional regulation, in which PREP1 contributes to selectivity and PBX1 to affinity.	20	26	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	PREP1	PREP1	PREP1	PBX1	PBX1	PBX1	20	21	25	26
Within the Prep1 and Pbx1 dimer , it is Prep1 that drives Pbx1 to bind at a specific DNA sequence [ XREF_BIBR ] , while possibly Pbx1 provides the information for the specific ( activating or repressing ) function [ XREF_BIBR ] .	Within the Prep1 and Pbx1 dimer, it is Prep1 that drives Pbx1 to bind at a specific DNA sequence [XREF_BIBR], while possibly Pbx1 provides the information for the specific (activating or repressing) function [XREF_BIBR].	5	13	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Prep1	Prep1	Prep1	Pbx1	Pbx1	Pbx1	9	10	12	13
To test the hypothesis that Plk1 kinase activity could inhibit Chk2 as part of the mechanism of checkpoint inactivation , we first examined whether the activity of Plk1 could be responsible for the inability of DNA damage to activate Chk2 during mitosis ( XREF_FIG ) .	To test the hypothesis that Plk1 kinase activity could inhibit Chk2 as part of the mechanism of checkpoint inactivation, we first examined whether the activity of Plk1 could be responsible for the inability of DNA damage to activate Chk2 during mitosis (XREF_FIG).	5	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	Chk2	Chk2	Chk2	5	6	10	11
For instance , during mitosis , Chk2 can be activated independently of ATM , likely through phosphorylation by DNA-PK , Plk1 , or MPS1 kinases [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	For instance, during mitosis, Chk2 can be activated independently of ATM, likely through phosphorylation by DNA-PK, Plk1, or MPS1 kinases [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	Chk2	Chk2	Chk2	20	21	6	7
Thus an increase in PREP-1 leads to changes in the fate determining HOXb1 and has therefore important functional consequences .	Thus an increase in PREP-1 leads to changes in the fate determining HOXb1 and has therefore important functional consequences.	2	13	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PREP-1	PREP-1	PREP-1	HOXb1	HOXb1	HOXb1	4	5	12	13
To examine the effect of vimentin phosphorylation by Plk1 on vimentin filament forming ability , soluble vimentin was treated with or without Plk1 and then incubated under conditions favoring polymerization .	To examine the effect of vimentin phosphorylation by Plk1 on vimentin filament forming ability, soluble vimentin was treated with or without Plk1 and then incubated under conditions favoring polymerization.	10	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Plk1	Plk1	Plk1	vimentin	vimentin	vimentin	22	23	10	11
121 Activation of MC4R by alpha-MSH stimulates accumulation of cAMP through increasing coupling with G alpha s.	121 Activation of MC4R by alpha-MSH stimulates accumulation of cAMP through increasing coupling with G alpha s.	1	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	5	6	3	4
When calories are replete , alpha-MSH activates MC4R to promote satiety , feeding suppression , and weight loss by energy expenditure .	When calories are replete, alpha-MSH activates MC4R to promote satiety, feeding suppression, and weight loss by energy expenditure.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	5	6	7	8
alpha-MSH activates MC4R to increase cAMP in the neurons for sensation of satiety .	alpha-MSH activates MC4R to increase cAMP in the neurons for sensation of satiety.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	0	1	2	3
Current studies indicate that orthologs of MC2R , MC3R , MC4R , and MC5R can all be stimulated by ACTH or MSH sized ligands with varying degrees of efficacy , and none of these receptors apparently requires interaction with an accessory protein to facilitate trafficking to the plasma membrane or activation once at the plasma membrane following a ligand binding event .	Current studies indicate that orthologs of MC2R, MC3R, MC4R, and MC5R can all be stimulated by ACTH or MSH sized ligands with varying degrees of efficacy, and none of these receptors apparently requires interaction with an accessory protein to facilitate trafficking to the plasma membrane or activation once at the plasma membrane following a ligand binding event.	4	21	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC4R	MC4R	MC4R	19	20	10	11
beta-MSH elicited full activation of wild-type MC4R ( EC50 = 2.78 nM ) , but no activation at Rm1 and Rm2 ( XREF_FIG ) .	beta-MSH elicited full activation of wild-type MC4R (EC50 = 2.78 nM), but no activation at Rm1 and Rm2 (XREF_FIG).	0	8	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-MSH	beta-MSH	beta-MSH	MC4R	MC4R	MC4R	0	1	6	7
When vectorial ion transport is measured across mouse or human intestinal mucosa , administration of alpha-MSH induces a MC4R specific PYY dependent anti-secretory response consistent with a role for the MC4R in paracrine inhibition of electrolyte secretion .	When vectorial ion transport is measured across mouse or human intestinal mucosa, administration of alpha-MSH induces a MC4R specific PYY dependent anti-secretory response consistent with a role for the MC4R in paracrine inhibition of electrolyte secretion.	13	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	15	16	18	19
Both mc1r and mc4r are activated by alpha-MSH and are involved in the control of the pigmentation and the modulation of food intake , respectively XREF_BIBR XREF_BIBR XREF_BIBR .	Both mc1r and mc4r are activated by alpha-MSH and are involved in the control of the pigmentation and the modulation of food intake, respectively XREF_BIBR XREF_BIBR XREF_BIBR.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	mc4r	mc4r	mc4r	7	8	3	4
By contrast , the teleost and tetrapod MC1R , MC3R , MC4R , and MC5R paralogs can be activated by either ACTH or the MSH sized polypeptides derived from POMC with varying potencies .	By contrast, the teleost and tetrapod MC1R, MC3R, MC4R, and MC5R paralogs can be activated by either ACTH or the MSH sized polypeptides derived from POMC with varying potencies.	9	25	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC4R	MC4R	MC4R	21	22	11	12
It has been shown that alpha-MSH activates PVN firing MC4R neurons in brain slices by closing the inwardly rectifying potassium channel , Kir7.1 , via the Galphas coupled signaling pathway [ XREF_BIBR ] .	It has been shown that alpha-MSH activates PVN firing MC4R neurons in brain slices by closing the inwardly rectifying potassium channel, Kir7.1, via the Galphas coupled signaling pathway [XREF_BIBR].	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	5	6	9	10
Together , these results demonstrate that alpha-MSH released by ARC POMC neuron terminals postsynaptically augments glutamatergic synaptic activity in PVH MC4R neurons .	Together, these results demonstrate that alpha-MSH released by ARC POMC neuron terminals postsynaptically augments glutamatergic synaptic activity in PVH MC4R neurons.	6	21	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	6	7	20	21
Together , the data support the hypothesis that agrp has a specific role in the regulation of somatic growth as an antagonist of alpha-MSH mediated stimulation of MC4R signaling , and that the MC4R must be inhibited by AgRP during the larval period for the normal rate of growth to occur .	Together, the data support the hypothesis that agrp has a specific role in the regulation of somatic growth as an antagonist of alpha-MSH mediated stimulation of MC4R signaling, and that the MC4R must be inhibited by AgRP during the larval period for the normal rate of growth to occur.	23	28	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	23	24	27	28
In summary , activation of the POMC expressing neurons in the hypothalamic arcuate nucleus triggers the release of alpha-MSH , which activates MC4R at the paraventricular nucleus , leading to suppressed food intake and increased energy expenditure .	In summary, activation of the POMC expressing neurons in the hypothalamic arcuate nucleus triggers the release of alpha-MSH, which activates MC4R at the paraventricular nucleus, leading to suppressed food intake and increased energy expenditure.	16	34	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	18	19	22	23
This phenomenon , combined with our findings that MC3R and MC4R activation by alphaMSH led to substantial enhancement of leptin induced STAT3 activity , is consistent with our previous observation of the interaction between the two receptors shared by urocortin and corticotropin releasing hormone -- CRHR1 and CRHR2 -- and the leptin receptor .	This phenomenon, combined with our findings that MC3R and MC4R activation by alphaMSH led to substantial enhancement of leptin induced STAT3 activity, is consistent with our previous observation of the interaction between the two receptors shared by urocortin and corticotropin releasing hormone -- CRHR1 and CRHR2 -- and the leptin receptor.	8	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	alphaMSH	alphaMSH	alphaMSH	MC4R	MC4R	MC4R	13	14	10	11
This is mediated via release of melanotropin-alpha , which stimulates melanocortin receptor-4 , resulting in appetite satiety .	This is mediated via release of melanotropin-alpha, which stimulates melanocortin receptor-4, resulting in appetite satiety.	4	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	melanotropin-alpha	melanotropin-alpha	melanotropin-alpha	melanocortin receptor-4	melanocortin receptor-4	melanocortin receptor-4	6	7	10	12
ACTH rises acutely with stress and could theoretically activate L cell MC4R to induce PYY release .	ACTH rises acutely with stress and could theoretically activate L cell MC4R to induce PYY release.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC4R	MC4R	MC4R	0	1	11	12
The MC4-R is activated by alpha-melanocyte-stimulating hormone [ alpha-MSH ; a cleavage product of pro opiomelanocortin ( POMC ) , which is expressed in the other ARC neurones ] and inhibits feeding .	The MC4-R is activated by alpha-melanocyte-stimulating hormone [alpha-MSH; a cleavage product of pro opiomelanocortin (POMC), which is expressed in the other ARC neurones] and inhibits feeding.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4-R	MC4-R	MC4-R	8	9	1	2
In HEK293 cells , dominant negative mutants of dynamin-1 prevent internalization of the MC4R when it is stimulated by alpha-MSH .	In HEK293 cells, dominant negative mutants of dynamin-1 prevent internalization of the MC4R when it is stimulated by alpha-MSH.	10	20	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	19	20	13	14
Central administration of alpha-MSH elevates blood pressure and heart rate in an SNS- and MC4R dependent manner XREF_BIBR , XREF_BIBR .	Central administration of alpha-MSH elevates blood pressure and heart rate in an SNS- and MC4R dependent manner XREF_BIBR, XREF_BIBR.	1	17	elevates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	3	4	14	15
The data indicate that , in neuronal cells , MC4R recycles constitutively and that alpha-MSH modulates MC4R residency at the plasma membrane by acting at an intracellular sorting step .	The data indicate that, in neuronal cells, MC4R recycles constitutively and that alpha-MSH modulates MC4R residency at the plasma membrane by acting at an intracellular sorting step.	14	17	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	14	15	16	17
TTP2515 blocked AgRP inhibition of alpha-MSH-induced MC4-R activation ; with TTP2515 alpha-MSH was able to activate the MC4-R even in the presence of AgRP ( XREF_FIG ) .	TTP2515 blocked AgRP inhibition of alpha-MSH-induced MC4-R activation; with TTP2515 alpha-MSH was able to activate the MC4-R even in the presence of AgRP (XREF_FIG).	11	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4-R	MC4-R	MC4-R	11	12	17	18
Further studies showed that alpha-MSH activated MC4R downstream sphingosine kinase 1 ( SphK1 ) and increased cellular sphingosine-1-phosphate ( S1P ) content in MC3T3-E1 cells and primary murine osteoblasts , which were blocked by SHU9119 or MC4R shRNAs .	Further studies showed that alpha-MSH activated MC4R downstream sphingosine kinase 1 (SphK1) and increased cellular sphingosine-1-phosphate (S1P) content in MC3T3-E1 cells and primary murine osteoblasts, which were blocked by SHU9119 or MC4R shRNAs.	4	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	4	5	6	7
AgRP affects feeding behavior and metabolism by antagonizing the melanocortin receptors , MC3R and MC4R , which are stimulated by POMC cleavage products .	AgRP affects feeding behavior and metabolism by antagonizing the melanocortin receptors, MC3R and MC4R, which are stimulated by POMC cleavage products.	10	22	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	POMC	POMC	POMC	MC4R	MC4R	MC4R	20	21	14	15
The MC4R is activated principally by alpha-MSH , leading to neuronal depolarization and action potential firing , while AgRP acts as an antagonist or biased agonist promoting neuronal hyperpolarization ( see below ) .	The MC4R is activated principally by alpha-MSH, leading to neuronal depolarization and action potential firing, while AgRP acts as an antagonist or biased agonist promoting neuronal hyperpolarization (see below).	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	6	7	1	2
Whether an alpha-MSH activation of MC4-R plays a role in the leptin induced stimulation BAT thermogenesis remains controversial .	Whether an alpha-MSH activation of MC4-R plays a role in the leptin induced stimulation BAT thermogenesis remains controversial.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4-R	MC4-R	MC4-R	2	3	5	6
Using this system , dose response analysis indicated that alpha-MSH mediates a MC4R dependent closure of Kir7.1 channels with an IC 50 of 10 -7.5 M ( XREF_FIG ) .	Using this system, dose response analysis indicated that alpha-MSH mediates a MC4R dependent closure of Kir7.1 channels with an IC 50 of 10 -7.5 M (XREF_FIG).	9	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	9	10	12	13
Several studies on mammalian MCRs [ reviewed by Gantz and Fong ] , as well as a study on bird MCRs , and studies on teleosts and cartilaginous fish MCRs indicate that MC1R , MC3R , MC4R , and MC5R can be activated by ACTH or any of the MSH sized ligands with varying degrees of efficacy .	Several studies on mammalian MCRs [reviewed by Gantz and Fong], as well as a study on bird MCRs, and studies on teleosts and cartilaginous fish MCRs indicate that MC1R, MC3R, MC4R, and MC5R can be activated by ACTH or any of the MSH sized ligands with varying degrees of efficacy.	32	50	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC4R	MC4R	MC4R	44	45	36	37
MC4R is directly activated by alpha-MSH from POMC neurons , an effect that is inhibited by AgRP from orexigenic neurons in the ARC .	MC4R is directly activated by alpha-MSH from POMC neurons, an effect that is inhibited by AgRP from orexigenic neurons in the ARC.	0	6	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	5	6	0	1
ACTH can activate all five receptor subtypes ; of the melanocortins , only ACTH activates MC2R ; ACTH as well as alpha-MSH , beta-MSH and gamma-MSH activate MC1R , MC3R , MC4R and MC5R , although with varying affinities .	ACTH can activate all five receptor subtypes; of the melanocortins, only ACTH activates MC2R; ACTH as well as alpha-MSH, beta-MSH and gamma-MSH activate MC1R, MC3R, MC4R and MC5R, although with varying affinities.	17	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-MSH	beta-MSH	beta-MSH	MC4R	MC4R	MC4R	23	24	31	32
Agouti related protein ( AgRP ) , which is released by an independent population of neurons , inhibits alphaMSH activation of MC4R .	Agouti related protein (AgRP), which is released by an independent population of neurons, inhibits alphaMSH activation of MC4R.	18	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	alphaMSH	alphaMSH	alphaMSH	MC4R	MC4R	MC4R	18	19	21	22
Wild-type MC4R was activated by alpha-MSH with an EC50 of 30.3 nM .	Wild-type MC4R was activated by alpha-MSH with an EC50 of 30.3 nM.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	5	6	1	2
If the consequence of agrp blockade is enhanced stimulation of the MC4R by the endogenous ligand , alpha-MSH , then reduction of the pomca preprohormone gene encoding alpha-MSH should also reduce the consequences of agrp blockade .	If the consequence of agrp blockade is enhanced stimulation of the MC4R by the endogenous ligand, alpha-MSH, then reduction of the pomca preprohormone gene encoding alpha-MSH should also reduce the consequences of agrp blockade.	7	18	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	17	18	11	12
GDPbetaS ( 5 mM ) blocked D1 mediated depolarization , but failed to block alpha-MSH induced depolarization of PVN MC4R neurons ( XREF_FIG ) .	GDPbetaS (5 mM) blocked D1 mediated depolarization, but failed to block alpha-MSH induced depolarization of PVN MC4R neurons (XREF_FIG).	13	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	14	15	19	20
alpha-MSH stimulation of Mc4r within the paraventricular nucleus ( PVN ) of the hypothalamus suppresses food intake and increases energy expenditure XREF_BIBR .	alpha-MSH stimulation of Mc4r within the paraventricular nucleus (PVN) of the hypothalamus suppresses food intake and increases energy expenditure XREF_BIBR.	0	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	Mc4r	Mc4r	Mc4r	0	1	3	4
Injection of alpha-MSH into the posterior VTA increases the activity of MC4R expressing dopaminergic neurons and induces ethanol self administration .	Injection of alpha-MSH into the posterior VTA increases the activity of MC4R expressing dopaminergic neurons and induces ethanol self administration.	0	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	2	3	11	12
This possibility is of interest because i ) ARC POMC neurons heavily innervate the PVH where alpha-MSH promotes satiety XREF_BIBR , XREF_BIBR , and ii ) alpha-MSH and MC4R action in other contexts can affect synaptic plasticity XREF_BIBR , XREF_BIBR .	This possibility is of interest because i) ARC POMC neurons heavily innervate the PVH where alpha-MSH promotes satiety XREF_BIBR, XREF_BIBR, and ii) alpha-MSH and MC4R action in other contexts can affect synaptic plasticity XREF_BIBR, XREF_BIBR.	16	29	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	16	17	28	29
Central administration of alpha-MSH increases BP and HR in wild-type mice , but not in Mc4r -/- mice , which maintain a normal BP despite severe obesity .	Central administration of alpha-MSH increases BP and HR in wild-type mice, but not in Mc4r -/- mice, which maintain a normal BP despite severe obesity.	3	17	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	Mc4r	Mc4r	Mc4r	3	4	15	16
ACTH ( 1-39 ) or alpha-MSH can activate MC1R , MC3R , MC4R , and MC5R , but MC2R can only be activated by ACTH and not by alpha-MSH or other analogs .	ACTH (1-39) or alpha-MSH can activate MC1R, MC3R, MC4R, and MC5R, but MC2R can only be activated by ACTH and not by alpha-MSH or other analogs.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	5	6	12	13
The MC1R is activated by alpha-MSH and antagonized by agouti signaling protein ( ASIP ) .	The MC1R is activated by alpha-MSH and antagonized by agouti signaling protein (ASIP).	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	5	6	1	2
As described above , the main extrinsic regulatory pathway in melanogenesis involves the MC1R receptor , which is activated by alphaMSH and acts through cAMP .	As described above, the main extrinsic regulatory pathway in melanogenesis involves the MC1R receptor, which is activated by alphaMSH and acts through cAMP.	13	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	alphaMSH	alphaMSH	alphaMSH	MC1R	MC1R	MC1R	20	21	13	14
These peptides did not antagonize alpha-MSH stimulation of MC1R and antagonized MC3 , 4 and 5R at markedly lower potency .	These peptides did not antagonize alpha-MSH stimulation of MC1R and antagonized MC3, 4 and 5R at markedly lower potency.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	5	6	8	9
beta-endorphin shares a precursor ( POMC ) with melanocortin ligands , such as alpha-MSH 11 , which activates MC1R and is essential for cutaneous pigmentation 12 .	beta-endorphin shares a precursor (POMC) with melanocortin ligands, such as alpha-MSH 11, which activates MC1R and is essential for cutaneous pigmentation 12.	1	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	13	14	18	19
p53 has been shown recently to regulate expression of the POMC gene in human keratinocytes , increasing secretion of alphaMSH , which stimulates MC1R function in neighboring melanocytes , leading to increased eumelanin synthesis ( see XREF_FIG ) .	p53 has been shown recently to regulate expression of the POMC gene in human keratinocytes, increasing secretion of alphaMSH, which stimulates MC1R function in neighboring melanocytes, leading to increased eumelanin synthesis (see XREF_FIG).	17	24	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alphaMSH	alphaMSH	alphaMSH	MC1R	MC1R	MC1R	19	20	23	24
The MC1R is activated by alphaMSH but is antagonized by ASIP and those interactions determine the types and amounts of melanins produced , and thus the resulting skin pigment phenotype .	The MC1R is activated by alphaMSH but is antagonized by ASIP and those interactions determine the types and amounts of melanins produced, and thus the resulting skin pigment phenotype.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	alphaMSH	alphaMSH	alphaMSH	MC1R	MC1R	MC1R	5	6	1	2
At extremely high plasma adrenocorticotropin hormone ( ACTH ) concentrations , ACTH activation of MC1R leads to hyperpigmentation observed in patients with familial glucocorticoid deficiency ( FGD ) .	At extremely high plasma adrenocorticotropin hormone (ACTH) concentrations, ACTH activation of MC1R leads to hyperpigmentation observed in patients with familial glucocorticoid deficiency (FGD).	11	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC1R	MC1R	MC1R	11	12	14	15
It is also believed that alphaMSH activation of MC1R induces protective mechanisms against damaging effects of ultraviolet radiation ( UVR ) .	It is also believed that alphaMSH activation of MC1R induces protective mechanisms against damaging effects of ultraviolet radiation (UVR).	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	alphaMSH	alphaMSH	alphaMSH	MC1R	MC1R	MC1R	5	6	8	9
Such agonists as a-melanocyte-stimulating hormone ( alpha-MSH ) or adrenocorticotropic hormone stimulate MC1R to induce increased melanocyte proliferation and dendricity 19 , 23 , melanosome transfer 24 and an elevated ratio of the darker eumelanin pigment over the red and yellow pheomelanin pigment 25 .	Such agonists as a-melanocyte-stimulating hormone (alpha-MSH) or adrenocorticotropic hormone stimulate MC1R to induce increased melanocyte proliferation and dendricity 19, 23, melanosome transfer 24 and an elevated ratio of the darker eumelanin pigment over the red and yellow pheomelanin pigment 25.	9	13	stimulate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	adrenocorticotropic hormone	adrenocorticotropic hormone	adrenocorticotropic hormone	MC1R	MC1R	MC1R	9	11	12	13
Furthermore , melanin production with ACTH ( 1-8 ) was competitively attenuated in the presence of ASP ( 87-132 )-NH 2 , a MC-1R antagonist , as well as with alpha-MSH [ XREF_FIG ] , indicating that ACTH ( 1-8 ) activates MC-1R to elicit melanogenesis .	Furthermore, melanin production with ACTH (1-8) was competitively attenuated in the presence of ASP (87-132)-NH 2, a MC-1R antagonist, as well as with alpha-MSH [XREF_FIG], indicating that ACTH (1-8) activates MC-1R to elicit melanogenesis.	37	43	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC-1R	MC-1R	MC-1R	37	38	42	43
Furthermore , we studied the mRNA expression of MC1R , Tyrp1 , Tyrp2 and Try genes in melanocytes treated with L-cysteine , alpha-MSH and nitric oxide from at least three unrelated Hanwoo phenotypes .	Furthermore, we studied the mRNA expression of MC1R, Tyrp1, Tyrp2 and Try genes in melanocytes treated with L-cysteine, alpha-MSH and nitric oxide from at least three unrelated Hanwoo phenotypes.	8	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	22	23	8	9
As seen in XREF_FIG , alphaMSH dose-dependently activated Mc1r wt with an EC 50 value of 9.2 +/- 1.1 nM .	As seen in XREF_FIG, alphaMSH dose-dependently activated Mc1r wt with an EC 50 value of 9.2 +/- 1.1 nM.	5	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alphaMSH	alphaMSH	alphaMSH	Mc1r	Mc1r	Mc1r	5	6	8	9
24 Red hair , due to lack of alpha-MSH activating MC1R in melanocytes , was initially reported as part of the clinical spectrum of congenital POMC deficiency .	24 Red hair, due to lack of alpha-MSH activating MC1R in melanocytes, was initially reported as part of the clinical spectrum of congenital POMC deficiency.	6	12	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	8	9	10	11
XREF_BIBR When the MC1R is stimulated by alpha-MSH , melanin synthesis transitions from the less protective yellow red pheomelanin to more protective brown-black eumelanin .	XREF_BIBR When the MC1R is stimulated by alpha-MSH, melanin synthesis transitions from the less protective yellow red pheomelanin to more protective brown-black eumelanin.	2	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	7	8	3	4
In macrophages , alpha-MSH activates MC1R and inhibits lipopolysaccharide ( LPS )-induced nuclear factor kappaB ( NF-kappaB ) activation XREF_BIBR .	In macrophages, alpha-MSH activates MC1R and inhibits lipopolysaccharide (LPS)-induced nuclear factor kappaB (NF-kappaB) activation XREF_BIBR.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	3	4	5	6
Increased generation of POMC derived peptides , such as alpha-melanocyte-stimulating hormone ( alphaMSH ) , betaMSH , and adrenocorticotropic hormone ( ACTH ) , in turn , increases pigmentation by activating MC1R .	Increased generation of POMC derived peptides, such as alpha-melanocyte-stimulating hormone (alphaMSH), betaMSH, and adrenocorticotropic hormone (ACTH), in turn, increases pigmentation by activating MC1R.	1	32	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC1R	MC1R	MC1R	21	22	31	32
Linear and cyclic analogues of the alpha-melanocyte stimulating hormone ( alpha-MSH ) targeting the human melanocortin receptor 1 ( MC1R ) are of pharmacological interest for detecting and treating melanoma .	Linear and cyclic analogues of the alpha-melanocyte stimulating hormone (alpha-MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma.	8	18	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	melanocortin receptor 1	melanocortin receptor 1	melanocortin receptor 1	10	11	15	18
alpha-MSH activates putative cell surface receptor MC1R and stimulates melanogenesis and proliferation of human melanocytes .	alpha-MSH activates putative cell surface receptor MC1R and stimulates melanogenesis and proliferation of human melanocytes.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	0	1	6	7
Melanocyte derived alpha-MSH , ACTH , and other peptides of POMC , stimulate the MC1R of neighbouring melanocytes , activating an intracellular signalling cascade involving the second messenger cAMP and the MITF [ XREF_BIBR ] .	Melanocyte derived alpha-MSH, ACTH, and other peptides of POMC, stimulate the MC1R of neighbouring melanocytes, activating an intracellular signalling cascade involving the second messenger cAMP and the MITF [XREF_BIBR].	2	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC1R	MC1R	MC1R	4	5	14	15
MC1R is stimulated by the proopiomelanocortin ( POMC )-derived - melanocyte stimulating hormone ( MSH ) and adrenocorticotropic hormone ( ACTH ) and , in turn , activates the rate limiting enzyme in melanin synthesis , tyrosinase .	MC1R is stimulated by the proopiomelanocortin (POMC)-derived - melanocyte stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) and, in turn, activates the rate limiting enzyme in melanin synthesis, tyrosinase.	0	27	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	proopiomelanocortin	proopiomelanocortin	proopiomelanocortin	MC1R	MC1R	MC1R	5	6	0	1
Additionally , activation of MC1R by alpha-MSH regulates intracellular redox status by up regulating the expression of antioxidant genes , including heme oxygenase-1 ( HO-1 ) , ferritin , and peroxiredoxin-1 .	Additionally, activation of MC1R by alpha-MSH regulates intracellular redox status by up regulating the expression of antioxidant genes, including heme oxygenase-1 (HO-1), ferritin, and peroxiredoxin-1.	2	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	6	7	4	5
The agonists alpha-melanocyte-stimulating hormone ( alphaMSH ) and adrenocorticotropic hormone ( ACTH ) activate MC1R to produce eumelanin , while the MC1R antagonist agouti signaling protein ( ASP ) causes melanocytes to produce pheomelanin .	The agonists alpha-melanocyte-stimulating hormone (alphaMSH) and adrenocorticotropic hormone (ACTH) activate MC1R to produce eumelanin, while the MC1R antagonist agouti signaling protein (ASP) causes melanocytes to produce pheomelanin.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	adrenocorticotropic hormone	adrenocorticotropic hormone	adrenocorticotropic hormone	MC1R	MC1R	MC1R	8	10	14	15
In other work using human melanocytes , Song and colleagues found that alphaMSH induced MC1R signaling increased levels of catalase after UV exposure .	In other work using human melanocytes, Song and colleagues found that alphaMSH induced MC1R signaling increased levels of catalase after UV exposure.	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	alphaMSH	alphaMSH	alphaMSH	MC1R	MC1R	MC1R	12	13	14	15
Interestingly , MC1R , which can be activated by alpha-MSH , ACTH , and MECO-I , has been shown to have a functional role in limiting intestinal inflammation ; deletion of that receptor produces colitis .	Interestingly, MC1R, which can be activated by alpha-MSH, ACTH, and MECO-I, has been shown to have a functional role in limiting intestinal inflammation; deletion of that receptor produces colitis.	2	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC1R	MC1R	MC1R	11	12	2	3
alpha-MSH signaling of the MC1R receptor is inhibited by the agouti signaling protein ( ASP , ASIP in humans ) that can compete with alpha-MSH in binding to MC1R .	alpha-MSH signaling of the MC1R receptor is inhibited by the agouti signaling protein (ASP, ASIP in humans) that can compete with alpha-MSH in binding to MC1R.	0	5	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	0	1	4	5
Moreover , alpha-MSH increased MC-1R immunoreactivity and lipid synthesis in SZ95 sebocytes in the presence of testosterone .	Moreover, alpha-MSH increased MC-1R immunoreactivity and lipid synthesis in SZ95 sebocytes in the presence of testosterone.	2	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC-1R	MC-1R	MC-1R	2	3	4	5
alphaMSH is then released from keratinocytes to activate MC1R in melanocytes [ XREF_BIBR ] .	alphaMSH is then released from keratinocytes to activate MC1R in melanocytes [XREF_BIBR].	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alphaMSH	alphaMSH	alphaMSH	MC1R	MC1R	MC1R	0	1	8	9
In the absence of agouti , alpha-MSH ( alpha melanocyte stimulating hormone ) stimulates Mc1r to synthesize eumelanin .	In the absence of agouti, alpha-MSH (alpha melanocyte stimulating hormone) stimulates Mc1r to synthesize eumelanin.	6	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	Mc1r	Mc1r	Mc1r	6	7	14	15
Our findings demonstrate that alpha-MSH causes MC1R desensitization , which seems to be transient , and show that the MC1R antagonists ASIP and HBD3 inhibit MC1R activity by blocking its activation by alpha-MSH , and possibly causing MC1R desensitization .	Our findings demonstrate that alpha-MSH causes MC1R desensitization, which seems to be transient, and show that the MC1R antagonists ASIP and HBD3 inhibit MC1R activity by blocking its activation by alpha-MSH, and possibly causing MC1R desensitization.	4	7	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	4	5	6	7
Activation of MC1R by alpha-MSH or ACTH increases cAMP synthesis which indirectly induces a switch from the production of pheomelanin to eumelanin synthesis [ XREF_BIBR ] ( XREF_FIG ) .	Activation of MC1R by alpha-MSH or ACTH increases cAMP synthesis which indirectly induces a switch from the production of pheomelanin to eumelanin synthesis [XREF_BIBR] (XREF_FIG).	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	4	5	2	3
The primary regulator of mitochondrial biogenesis is PGC-1alpha , which activates the transcription factors Nrf1 , Nrf2 , ERRalpha , and PPARalpha , which , in turn , regulate the transcription of mitochondrial DNA , antioxidants , and biogenesis genes .	The primary regulator of mitochondrial biogenesis is PGC-1alpha, which activates the transcription factors Nrf1, Nrf2, ERRalpha, and PPARalpha, which, in turn, regulate the transcription of mitochondrial DNA, antioxidants, and biogenesis genes.	2	31	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	PGC-1alpha	PGC-1alpha	pgc-1alpha	ERRalpha	ERRalpha, and PPARalpha, which, in turn, regulate the transcription	erralpha	7	8	18	19
This is mediated by catecholamines via beta-adrenergic signaling , which increases PGC-1alpha , a transcriptional coactivator that induces ERRalpha and NRF-1 , culminating in increased mitochondrial mass .	This is mediated by catecholamines via beta-adrenergic signaling, which increases PGC-1alpha, a transcriptional coactivator that induces ERRalpha and NRF-1, culminating in increased mitochondrial mass.	10	20	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	11	12	18	19
Mechanistically , the use of integrative metabolomics and transcriptomics revealed that PGC1alpha activates an Oestrogen related receptor alpha ( ERRalpha )-dependent transcriptional program to elicit a catabolic state and metastasis suppression .	Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1alpha activates an Oestrogen related receptor alpha (ERRalpha)-dependent transcriptional program to elicit a catabolic state and metastasis suppression.	11	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC1alpha	PGC1alpha	PGC1alpha	ERRalpha	ERRalpha	ERRalpha	11	12	19	20
Addition of PGC-1alpha upregulated ERRalpha induced promoter activity and partially alleviated the downregulation observed in the presence of XCT790 ( XREF_FIG ) .	Addition of PGC-1alpha upregulated ERRalpha induced promoter activity and partially alleviated the downregulation observed in the presence of XCT790 (XREF_FIG).	0	5	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	2	3	4	5
PGC-1alpha activated ERRalpha to cause ERRalpha coupling with ERRE in the Sirt3 promoter region , leading to Sirt3 mRNA transcription .	PGC-1alpha activated ERRalpha to cause ERRalpha coupling with ERRE in the Sirt3 promoter region, leading to Sirt3 mRNA transcription.	0	3	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	0	1	2	3
Strikingly , introduction of PGC-1alpha in HeLa cells by transient transfection induces the activity of the ESRRA promoter in a manner that is dependent on the presence of the ESRRA23 element and on its dosage .	Strikingly, introduction of PGC-1alpha in HeLa cells by transient transfection induces the activity of the ESRRA promoter in a manner that is dependent on the presence of the ESRRA23 element and on its dosage.	2	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ESRRA	ESRRA	ESRRA	4	5	16	17
Members of the PPARgamma coactivator-1 ( PGC-1 ) family , mainly PGC-1alpha and PGC-1beta , interact with and stimulate the transactivation functions of NRF-1 , NRF-2 , PPARalpha , PPARdelta , and ERRalpha to enhance mitochondrial content and the oxidative capacity of muscle .	Members of the PPARgamma coactivator-1 (PGC-1) family, mainly PGC-1alpha and PGC-1beta, interact with and stimulate the transactivation functions of NRF-1, NRF-2, PPARalpha, PPARdelta, and ERRalpha to enhance mitochondrial content and the oxidative capacity of muscle.	8	33	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	11	12	32	33
Collectively , these and later studies have established that ERRalpha activated by PGC-1alpha or PGC-1beta induces genes with roles in lipid transport [ XREF_BIBR , XREF_BIBR ] , fatty acid oxidation [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] , TCA cycle [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] , oxidative phosphorylation [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] , mitochondrial biogenesis [ XREF_BIBR , XREF_BIBR ] , mitochondrial dynamics [ XREF_BIBR , XREF_BIBR ] and oxidative stress defense [ XREF_BIBR ] ( XREF_FIG and XREF_TABLE ) .	Collectively, these and later studies have established that ERRalpha activated by PGC-1alpha or PGC-1beta induces genes with roles in lipid transport [XREF_BIBR, XREF_BIBR], fatty acid oxidation [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR], TCA cycle [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR], oxidative phosphorylation [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR], mitochondrial biogenesis [XREF_BIBR, XREF_BIBR], mitochondrial dynamics [XREF_BIBR, XREF_BIBR] and oxidative stress defense [XREF_BIBR] (XREF_FIG and XREF_TABLE).	9	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	12	13	9	10
Furthermore , previous evidence demonstrates that PGC-1alpha acts as an endogenous regulator of Sirt3 and activates Sirt3 by triggering ERRalpha to cause ERRalpha coupling with ERRE in the Sirt3 promoter region .	Furthermore, previous evidence demonstrates that PGC-1alpha acts as an endogenous regulator of Sirt3 and activates Sirt3 by triggering ERRalpha to cause ERRalpha coupling with ERRE in the Sirt3 promoter region.	6	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	6	7	19	20
Using a knock-down approach to compliment activation of ERRalpha by PGC-1alpha , we verified that these genes were regulated by ERRspPGC1 in an ERRalpha dependent manner in both ERalpha positive and ERalpha negative cell lines ( XREF_FIG ) .	Using a knock-down approach to compliment activation of ERRalpha by PGC-1alpha, we verified that these genes were regulated by ERRspPGC1 in an ERRalpha dependent manner in both ERalpha positive and ERalpha negative cell lines (XREF_FIG).	0	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	10	11	8	9
Transient transfection experiments have demonstrated that induction of the ESRRA promoter by PGC-1alpha is dependent on the presence of the ESRRA23 element , and that the strength of the activation correlates with its dosage [ XREF_BIBR ] .	Transient transfection experiments have demonstrated that induction of the ESRRA promoter by PGC-1alpha is dependent on the presence of the ESRRA23 element, and that the strength of the activation correlates with its dosage [XREF_BIBR].	9	13	promoter	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ESRRA	ESRRA	ESRRA	12	13	9	10
NRIP1 activity on mitochondrial pathways is mainly exerted through the repressive control on the transcriptional coactivator PGC-1alpha and its targets including the transcription factors NRF1 , ERRalpha , PPARs , which are repressed by NRIP1 and induced by PGC-1alpha in a dose dependent manner .	NRIP1 activity on mitochondrial pathways is mainly exerted through the repressive control on the transcriptional coactivator PGC-1alpha and its targets including the transcription factors NRF1, ERRalpha, PPARs, which are repressed by NRIP1 and induced by PGC-1alpha in a dose dependent manner.	24	43	induced	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	38	39	26	27
Specifically , it has been demonstrated that both PGC-1alpha and PGC-1beta robustly enhance ERRalpha activity when assayed on reporter genes and regulate overlapping repertoires of endogenous ERRalpha target genes .	Specifically, it has been demonstrated that both PGC-1alpha and PGC-1beta robustly enhance ERRalpha activity when assayed on reporter genes and regulate overlapping repertoires of endogenous ERRalpha target genes.	7	21	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	8	9	13	14
PGC-1alpha then activates ERRalpha to cause ERRalpha binding to ERRE in the mating-type information regulation 2 homolog 3 ( Sirt3 ) promoter regions , leading to silent Sirt3 mRNA transcription .	PGC-1alpha then activates ERRalpha to cause ERRalpha binding to ERRE in the mating-type information regulation 2 homolog 3 (Sirt3) promoter regions, leading to silent Sirt3 mRNA transcription.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	0	1	3	4
PGC-1alpha induces VEGF in a HIF independent fashion by coactivating ERR-alpha on a novel enhancer in the first intron of the VEGF gene 10 .	PGC-1alpha induces VEGF in a HIF independent fashion by coactivating ERR-alpha on a novel enhancer in the first intron of the VEGF gene 10.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERR-alpha	ERR-alpha	ERR-alpha	0	1	10	11
Interestingly , PGC-1alpha can also activate VEGF , by coactivating ERR-alpha on conserved binding sites found in the promoter and in a cluster within the first intron of the VEGF gene , driving angiogenesis in response to oxygen deprivation independently of HIF-1 [ XREF_BIBR ] .	Interestingly, PGC-1alpha can also activate VEGF, by coactivating ERR-alpha on conserved binding sites found in the promoter and in a cluster within the first intron of the VEGF gene, driving angiogenesis in response to oxygen deprivation independently of HIF-1 [XREF_BIBR].	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERR-alpha	ERR-alpha	ERR-alpha	2	3	10	11
Although the natural ligand of ERRalpha is unknown , ERRalpha can be activated by several cytokines and by PGC-1alpha .	Although the natural ligand of ERRalpha is unknown, ERRalpha can be activated by several cytokines and by PGC-1alpha.	9	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	ERRalpha	ERRalpha	ERRalpha	18	19	9	10
Interestingly , the fact that the amount of G rich signal is not rescued by POT1 overexpression experiments suggests that the POT1 positive effect on telomerase activity does not require long G-overhangs and that long G-overhangs are not absolutely required for POT1 mediated telomerase dependent over-elongation .	Interestingly, the fact that the amount of G rich signal is not rescued by POT1 overexpression experiments suggests that the POT1 positive effect on telomerase activity does not require long G-overhangs and that long G-overhangs are not absolutely required for POT1 mediated telomerase dependent over-elongation.	39	45	mediated	Positive_early_activation	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	41	42	43	44
POT1 may also positively regulate telomerase action at the telomere ; when positioned on DNA upstream of a 3 ' end in vitro , POT1 stimulates telomerase activity .	POT1 may also positively regulate telomerase action at the telomere; when positioned on DNA upstream of a 3 ' end in vitro, POT1 stimulates telomerase activity.	24	27	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	24	25	26	27
Parallel in vitro work has shown that telomere structural proteins TEBPbeta in Oxytrichia and Rap1 in Saccharomyces cerevisiae promote formation of quadruplex structures , while human POT1 protein destabilizes quadruplex structures and stimulates telomerase activity .	Parallel in vitro work has shown that telomere structural proteins TEBPbeta in Oxytrichia and Rap1 in Saccharomyces cerevisiae promote formation of quadruplex structures, while human POT1 protein destabilizes quadruplex structures and stimulates telomerase activity.	26	34	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	26	27	33	34
While stimulation by Cdc13 contrasts with the inhibitory effect of Pot1 , it should be noted that Pot1 activates telomerase in conjunction with the telomeric protein Tpp1 XREF_BIBR .	While stimulation by Cdc13 contrasts with the inhibitory effect of Pot1, it should be noted that Pot1 activates telomerase in conjunction with the telomeric protein Tpp1 XREF_BIBR.	17	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pot1	Pot1	Pot1	telomerase	telomerase	telomerase	17	18	19	20
In contrast to these genetic findings in cultured cells , biochemical studies in vitro have established that recombinant TPP1 and POT1 enhance processivity of telomerase on oligonucleotide substrates , suggesting that TPP1 and POT1 act as positive co-factors in telomerase catalysis .	In contrast to these genetic findings in cultured cells, biochemical studies in vitro have established that recombinant TPP1 and POT1 enhance processivity of telomerase on oligonucleotide substrates, suggesting that TPP1 and POT1 act as positive co-factors in telomerase catalysis.	18	27	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	20	21	24	25
The potential importance of G-quadruplex structures was implied by the recent findings that the human POT1 disrupts G-quadruplex and stimulates the telomerase activity .	The potential importance of G-quadruplex structures was implied by the recent findings that the human POT1 disrupts G-quadruplex and stimulates the telomerase activity.	13	22	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	15	16	21	22
In all , our results demonstrate that RTEL1 promotes the stability of the G rich telomeric overhang and POT1 complex thus allowing telomerase to overextend long telomeres .	In all, our results demonstrate that RTEL1 promotes the stability of the G rich telomeric overhang and POT1 complex thus allowing telomerase to overextend long telomeres.	18	24	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	18	19	22	23
TPP1 is responsible for recruiting telomerase to the telomere and , together with POT1 enhances telomerase processivity by decreasing the rate constant for dissociation from telomere DNA and increasing the rate constant for telomerase extension activity XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR .	TPP1 is responsible for recruiting telomerase to the telomere and, together with POT1 enhances telomerase processivity by decreasing the rate constant for dissociation from telomere DNA and increasing the rate constant for telomerase extension activity XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR.	4	16	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	13	14	15	16
In addition , inhibition of Pot1 by antisense oligonucleotides led to telomere shortening as well as inhibition of telomerase activity in GC cells .	In addition, inhibition of Pot1 by antisense oligonucleotides led to telomere shortening as well as inhibition of telomerase activity in GC cells.	3	19	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pot1	Pot1	Pot1	telomerase	telomerase	telomerase	5	6	18	19
Multiple studies implicate that hTEN domain is crucial for the TPP1 and POT1 mediated telomerase recruitment to telomeres that facilitates the processivity of telomerase by aiding the translocation step .	Multiple studies implicate that hTEN domain is crucial for the TPP1 and POT1 mediated telomerase recruitment to telomeres that facilitates the processivity of telomerase by aiding the translocation step.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	12	13	14	15
On the other hand , POT1 can positively regulate telomerase when it is bound internally to telomeric ssDNA .	On the other hand, POT1 can positively regulate telomerase when it is bound internally to telomeric ssDNA.	5	10	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	5	6	9	10
While TRF1/TRF2/RAP1 are inhibitory of telomerase action , POT1 and TPP1 act to stimulate telomerase activity in vitro , and TPP1 , via its interaction with TIN2 , is directly involved in recruiting telomerase to telomeres XREF_BIBR .	While TRF1/TRF2/RAP1 are inhibitory of telomerase action, POT1 and TPP1 act to stimulate telomerase activity in vitro, and TPP1, via its interaction with TIN2, is directly involved in recruiting telomerase to telomeres XREF_BIBR.	8	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	8	9	14	15
Here , we find that the POT1 with the entire TPP1 protein plus the TIN2 subunit increases telomerase processivity about three-fold .	Here, we find that the POT1 with the entire TPP1 protein plus the TIN2 subunit increases telomerase processivity about three-fold.	5	18	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	6	7	17	18
These data support the notion that the mechanism for gamma-MSH-induced natriuresis may not involve circulating gamma-MSH directly activating MC3-R in renal tubular cells , but rather may include inhibiting central neural pathways that tonically maintain renal tubular Na + absorption .	These data support the notion that the mechanism for gamma-MSH-induced natriuresis may not involve circulating gamma-MSH directly activating MC3-R in renal tubular cells, but rather may include inhibiting central neural pathways that tonically maintain renal tubular Na + absorption.	14	22	directly activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gamma-MSH	gamma-MSH	gamma-MSH	MC3-R	MC3-R	MC3-R	15	16	18	19
alpha-MSH activates melanocortin-3 and melanocortin-4 receptors ( Mc3r , Mc4r ) to exert catabolic effects .	alpha-MSH activates melanocortin-3 and melanocortin-4 receptors (Mc3r, Mc4r) to exert catabolic effects.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	Mc3r	Mc3r	Mc3r	0	1	7	8
Unlike the MSH or ACTH receptors , MC3-R is potently activated by gamma-MSH peptides , POMC products that were named for their amino acid homology with alpha- and beta-MSH , but lack melanotropic activity .	Unlike the MSH or ACTH receptors, MC3-R is potently activated by gamma-MSH peptides, POMC products that were named for their amino acid homology with alpha- and beta-MSH, but lack melanotropic activity.	7	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	gamma-MSH	gamma-MSH	gamma-MSH	MC3-R	MC3-R	MC3-R	12	13	7	8
gamma-MSH does not modulate I sc or MC3-R signaling in mouse collecting duct cells .	gamma-MSH does not modulate I sc or MC3-R signaling in mouse collecting duct cells.	0	8	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gamma-MSH	gamma-MSH	gamma-MSH	MC3-R	MC3-R	MC3-R	0	1	7	8
To distinguish between both MCR subtypes , we used gamma-MSH activating MC3R , but not MC4R with a potency similar to alpha-MSH .	To distinguish between both MCR subtypes, we used gamma-MSH activating MC3R, but not MC4R with a potency similar to alpha-MSH.	8	15	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gamma-MSH	gamma-MSH	gamma-MSH	MC3R	MC3R	MC3R	9	10	11	12
In another group of animals ( n = 7 ) , effect of MC3R stimulation by gammaMSH on sucrose free feeding was determined .	In another group of animals (n = 7), effect of MC3R stimulation by gammaMSH on sucrose free feeding was determined.	13	20	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	gammaMSH	gammaMSH	gammaMSH	MC3R	MC3R	MC3R	16	17	13	14
Since PGC-1alpha activates both peroxisome proliferator activated receptor alpha ( PPARalpha ) and nuclear respiratory factor-1 ( Nrf-1 ) to promote mitochondrial biogenesis , Sirt-1 modulates the creation of new mitochondria during tissue repair in cases of cardiac injury [ XREF_BIBR ] .	Since PGC-1alpha activates both peroxisome proliferator activated receptor alpha (PPARalpha) and nuclear respiratory factor-1 (Nrf-1) to promote mitochondrial biogenesis, Sirt-1 modulates the creation of new mitochondria during tissue repair in cases of cardiac injury [XREF_BIBR].	1	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	nuclear respiratory factor-1	nuclear respiratory factor-1	nuclear respiratory factor-1	1	2	13	16
PGC-1alpha can activate nuclear respiratory factor 1 ( NRF1 ) , leading to the transcription of both nuclear encoded mitochondrial proteins and the mitochondrial transcriptional factor Tfam .	PGC-1alpha can activate nuclear respiratory factor 1 (NRF1), leading to the transcription of both nuclear encoded mitochondrial proteins and the mitochondrial transcriptional factor Tfam.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	nuclear respiratory factor 1	nuclear respiratory factor 1	nuclear respiratory factor 1	0	1	3	7
Shadel and Clayton demonstrated that PGC-1alpha led to an activation of nuclear respiratory factor-1 ( NRF-1 ) , which binds to and activates the gene promoter of the mitochondrial electron transport system such as COX2 .	Shadel and Clayton demonstrated that PGC-1alpha led to an activation of nuclear respiratory factor-1 (NRF-1), which binds to and activates the gene promoter of the mitochondrial electron transport system such as COX2.	5	14	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	nuclear respiratory factor-1	nuclear respiratory factor-1	nuclear respiratory factor-1	5	6	11	14
Increased PGC-1alpha leads to up-regulation of target genes such as nuclear respiratory factor 1 ( Nrf-1 ) which can , in turn , stimulate the expression of OXPHOS genes and mitochondrial transcription factor A ( Tfam ) , a mitochondrial matrix protein essential for transcription of mitochondrial DNA XREF_BIBR .	Increased PGC-1alpha leads to up-regulation of target genes such as nuclear respiratory factor 1 (Nrf-1) which can, in turn, stimulate the expression of OXPHOS genes and mitochondrial transcription factor A (Tfam), a mitochondrial matrix protein essential for transcription of mitochondrial DNA XREF_BIBR.	0	14	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	nuclear respiratory factor 1	nuclear respiratory factor 1	nuclear respiratory factor 1	1	2	10	14
In most tissues , including skeletal muscle , PGC-1alpha strongly induces mitochondrial biogenesis by co-activating nuclear respiratory factor 1 ( NRF1 ) , NRF2 , estrogen related receptor alpha ( ERRalpha ) , and other transcription factors .	In most tissues, including skeletal muscle, PGC-1alpha strongly induces mitochondrial biogenesis by co-activating nuclear respiratory factor 1 (NRF1), NRF2, estrogen related receptor alpha (ERRalpha), and other transcription factors.	8	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	nuclear respiratory factor 1	nuclear respiratory factor 1	nuclear respiratory factor 1	8	9	15	19
Further studies indicated that PPARGC1A activates nuclear respiratory factor 1 ( NRF1 ) and 2 ( NRF2 ) [ XREF_BIBR ] .	Further studies indicated that PPARGC1A activates nuclear respiratory factor 1 (NRF1) and 2 (NRF2) [XREF_BIBR].	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPARGC1A	PPARGC1A	PPARGC1A	nuclear respiratory factor 1	nuclear respiratory factor 1	nuclear respiratory factor 1	4	5	6	10
PGC1alpha is a co-activator of nuclear respiratory factor 1 ( NRF1 ) and mitochondrial transcription factor ( TFAM ) , which are important for mitochondrial biogenesis [ XREF_BIBR ] , ARA at 300 mg/kg was found to increase the expressions of NRF1 and TFAM .	PGC1alpha is a co-activator of nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor (TFAM), which are important for mitochondrial biogenesis [XREF_BIBR], ARA at 300 mg/kg was found to increase the expressions of NRF1 and TFAM.	0	9	is a co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	PGC1alpha	PGC1alpha	PGC1alpha	nuclear respiratory factor 1	nuclear respiratory factor 1	nuclear respiratory factor 1	0	1	5	9
Once being activated by either phosphorylation or de-acetylation , PGC-1alpha activates nuclear respiratory factor 1 and 2 ( NRF1 and NRF2 ) , and subsequently mitochondrial transcription factor A ( Tfam ) .	Once being activated by either phosphorylation or de-acetylation, PGC-1alpha activates nuclear respiratory factor 1 and 2 (NRF1 and NRF2), and subsequently mitochondrial transcription factor A (Tfam).	5	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	nuclear respiratory factor 1	nuclear respiratory factor 1	nuclear respiratory factor 1	9	10	11	15
PGC1alpha upregulates mitochondrial biogenesis by activating nuclear respiratory factor 1 , which in turn regulates transcription of transcription factor A.	PGC1alpha upregulates mitochondrial biogenesis by activating nuclear respiratory factor 1, which in turn regulates transcription of transcription factor A.	0	16	upregulates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	PGC1alpha	PGC1alpha	pgc1alpha	nuclear respiratory factor 1	nuclear respiratory factor 1, which in turn regulates transcription	nuclear respiratory factor 1	0	1	6	10
PGC1alpha and PGC1beta modulate function of nuclear respiratory factor 1 ( NRF1 ) , NRF2 , and mitochondrial transcription factor A ( TFAM ) , thereby altering gene expression to modulate mitochondrial biogenesis and function 37 .	PGC1alpha and PGC1beta modulate function of nuclear respiratory factor 1 (NRF1), NRF2, and mitochondrial transcription factor A (TFAM), thereby altering gene expression to modulate mitochondrial biogenesis and function 37.	0	10	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC1alpha	PGC1alpha	PGC1alpha	nuclear respiratory factor 1	nuclear respiratory factor 1	nuclear respiratory factor 1	0	1	6	10
Deletion of Pofut1 , which effectively blocks NOTCH signaling through inhibition of post-translational modifications to NOTCH receptors [ XREF_BIBR ] , leads to embryonic lethality at E9.5 [ XREF_BIBR , XREF_BIBR ] .	Deletion of Pofut1, which effectively blocks NOTCH signaling through inhibition of post-translational modifications to NOTCH receptors [XREF_BIBR], leads to embryonic lethality at E9.5 [XREF_BIBR, XREF_BIBR].	0	8	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pofut1	Pofut1	Pofut1	NOTCH	NOTCH	NOTCH	2	3	7	8
Our observation of increased Pofut1 in mutant podocytes supports activation of Notch in CAGG-CreER TM +/-; Wt1 f/f transgenic mice .	Our observation of increased Pofut1 in mutant podocytes supports activation of Notch in CAGG-CreER TM +/-; Wt1 f/f transgenic mice.	1	12	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pofut1	Pofut1	Pofut1	Notch	Notch	Notch	4	5	11	12
Second , Pofut1 , an essential factor for ligand-receptor interactions , was deleted to block Notch signaling upstream of transcriptional events .	Second, Pofut1, an essential factor for ligand-receptor interactions, was deleted to block Notch signaling upstream of transcriptional events.	2	16	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pofut1	Pofut1	Pofut1	Notch	Notch	Notch	2	3	15	16
Lowe et al has demonstrated that O fucosylation of Notch catalyzed by Pofut1 regulates lymphoid and myeloid homeostasis .	Lowe et al has demonstrated that O fucosylation of Notch catalyzed by Pofut1 regulates lymphoid and myeloid homeostasis.	7	13	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Pofut1	Pofut1	Pofut1	Notch	Notch	Notch	12	13	9	10
In a recent in vitro study , we showed that Pofut1 knockdown reduces Notch signalling and affects differentiation of the mouse myoblast cell line C2C12 .	In a recent in vitro study, we showed that Pofut1 knockdown reduces Notch signalling and affects differentiation of the mouse myoblast cell line C2C12.	10	14	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pofut1	Pofut1	Pofut1	Notch	Notch	Notch	10	11	13	14
The rescue of Pofut1 expression in knockdown cells restored Notch signaling activation and a normal course in C2C12 differentiation .	The rescue of Pofut1 expression in knockdown cells restored Notch signaling activation and a normal course in C2C12 differentiation.	3	11	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pofut1	Pofut1 expression	pofut1	Notch	Notch	notch	3	4	9	10
Collectively , these data suggest that the reduced Pofut1 mRNA levels in cax mutant embryos attenuate Notch activity below a threshold required for patterning the presomitic mesoderm , leading to defects in regular somite spacing and compartmentalization that underlie the observed skeletal malformations .	Collectively, these data suggest that the reduced Pofut1 mRNA levels in cax mutant embryos attenuate Notch activity below a threshold required for patterning the presomitic mesoderm, leading to defects in regular somite spacing and compartmentalization that underlie the observed skeletal malformations.	8	17	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pofut1	Pofut1 mRNA levels	pofut1	Notch	Notch	notch	8	9	16	17
Since Notch signaling plays a critical role in stem cells of intestinal crypts , and potentially cancer stem cells , increased Notch signaling mediated by POFUT1 may function as a critical step in colon tumorigenesis .	Since Notch signaling plays a critical role in stem cells of intestinal crypts, and potentially cancer stem cells, increased Notch signaling mediated by POFUT1 may function as a critical step in colon tumorigenesis.	21	26	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	POFUT1	POFUT1	POFUT1	Notch	Notch	Notch	25	26	21	22
Interestingly , Notch activity was partially restored by overexpression of an enzymatically inactive Pofut1 ( equivalent to the R245A mutant of Ofut1 ) as well as an unrelated ER protein , alpha-glucosidase I [ XREF_BIBR ] .	Interestingly, Notch activity was partially restored by overexpression of an enzymatically inactive Pofut1 (equivalent to the R245A mutant of Ofut1) as well as an unrelated ER protein, alpha-glucosidase I [XREF_BIBR].	2	15	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Pofut1	overexpression of an enzymatically inactive Pofut1	pofut1	Notch	Notch	notch	13	14	2	3
Pofut1 deletion inactivated Notch signaling , giving rise to smaller but viable mice .	Pofut1 deletion inactivated Notch signaling, giving rise to smaller but viable mice.	0	4	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pofut1	Pofut1	Pofut1	Notch	Notch	Notch	0	1	3	4
It was important to examine whether enhanced Pofut1 deficient HSPC egress was caused by the loss of Notch receptor-ligand binding or by defective ligand induced Notch signaling .	It was important to examine whether enhanced Pofut1 deficient HSPC egress was caused by the loss of Notch receptor-ligand binding or by defective ligand induced Notch signaling.	6	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pofut1	Pofut1	Pofut1	Notch	Notch	Notch	7	8	25	26
The NOTCH modulator POFUT1 critically regulates this signaling axis .	The NOTCH modulator POFUT1 critically regulates this signaling axis.	0	5	modulator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	POFUT1	POFUT1	POFUT1	NOTCH	NOTCH	NOTCH	3	4	1	2
Like FRINGE , POFUT1 promotes NOTCH signaling through DLL4 binding 25 .	Like FRINGE, POFUT1 promotes NOTCH signaling through DLL4 binding 25.	3	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	POFUT1	POFUT1	POFUT1	NOTCH	NOTCH	NOTCH	3	4	5	6
Overexpression of an enzymatically inactive Pofut1 ( equivalent to the R245A mutant in OFut1 ) in these cells partially restores Notch activity .	Overexpression of an enzymatically inactive Pofut1 (equivalent to the R245A mutant in OFut1) in these cells partially restores Notch activity.	0	21	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pofut1	Overexpression of an enzymatically inactive Pofut1	pofut1	Notch	Notch	notch	5	6	20	21
In addition to generating the O-fucose linkage that is the substrate of the Fringe glycosyltransferases , Pofut1 provides a chaperone activity that is independent of its glycosyltransferase activity and promotes Notch maturation XREF_BIBR .	In addition to generating the O-fucose linkage that is the substrate of the Fringe glycosyltransferases, Pofut1 provides a chaperone activity that is independent of its glycosyltransferase activity and promotes Notch maturation XREF_BIBR.	16	32	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pofut1	Pofut1	Pofut1	Notch	Notch	Notch	16	17	30	31
Similarly , deletion of genes that block NOTCH signaling , such as Pofut1 and members of the gamma and secretase complex , leads to embryonic failure after gastrulation and midline formation .	Similarly, deletion of genes that block NOTCH signaling, such as Pofut1 and members of the gamma and secretase complex, leads to embryonic failure after gastrulation and midline formation.	7	20	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Pofut1	Pofut1	Pofut1	NOTCH	NOTCH	NOTCH	12	13	7	8
The metabolism of triglyceride rich lipoproteins is modulated by PPARalpha dependent stimulation of the lipoprotein lipase gene , which facilitates the release of fatty acids from lipoprotein particles , and the down-regulation of apolipoprotein C-III [ XREF_BIBR ] .	The metabolism of triglyceride rich lipoproteins is modulated by PPARalpha dependent stimulation of the lipoprotein lipase gene, which facilitates the release of fatty acids from lipoprotein particles, and the down-regulation of apolipoprotein C-III [XREF_BIBR].	9	16	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PPARalpha	PPARalpha	PPARalpha	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	9	10	14	16
The primary mechanism of action of PPAR-alpha is increasing lipoprotein lipase activity which hydrolyzes triglyceride rich lipoproteins , and reducing its inhibition ; PPAR-alpha activation represses the expression of apolipoprotein ( Apo ) C3 , which is the endogenous lipoprotein lipase repressor [ XREF_BIBR , XREF_BIBR ] .	The primary mechanism of action of PPAR-alpha is increasing lipoprotein lipase activity which hydrolyzes triglyceride rich lipoproteins, and reducing its inhibition; PPAR-alpha activation represses the expression of apolipoprotein (Apo) C3, which is the endogenous lipoprotein lipase repressor [XREF_BIBR, XREF_BIBR].	4	11	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPAR-alpha	PPAR-alpha	PPAR-alpha	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	7	9	11
Analysis of cardiac function revealed that in isolated perfused hearts , left ventricular developed pressure ( a measure of contractility ) was markedly lower in PPARalpha knockout mice overexpressing LPL compared with controls .	Analysis of cardiac function revealed that in isolated perfused hearts, left ventricular developed pressure (a measure of contractility) was markedly lower in PPARalpha knockout mice overexpressing LPL compared with controls.	25	32	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPARalpha	PPARalpha	PPARalpha	LPL	LPL	LPL	25	26	29	30
In contrast , fasted FFA levels were significantly lower in cardiac muscle of PPARalpha knockout mice with normal LPL expression (-26% ) and PPARalpha knockout mice overexpressing LPL (-38% ) compared with controls .	In contrast, fasted FFA levels were significantly lower in cardiac muscle of PPARalpha knockout mice with normal LPL expression (-26%) and PPARalpha knockout mice overexpressing LPL (-38%) compared with controls.	23	28	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPARalpha	PPARalpha	PPARalpha	LPL	LPL	LPL	23	24	27	28
Our results indicate a critical role for PPARalpha in myocardial pump function and suggest that mouse models combining different genetic effects such as PPARalpha knockout mice overexpressing muscle LPL may be useful to study cardiomyopathies .	Our results indicate a critical role for PPARalpha in myocardial pump function and suggest that mouse models combining different genetic effects such as PPARalpha knockout mice overexpressing muscle LPL may be useful to study cardiomyopathies.	23	29	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPARalpha	PPARalpha	PPARalpha	LPL	LPL	LPL	23	24	28	29
Fibrates increase triglyceride lipolysis by PPARalpha mediated activation of LPL in the liver .	Fibrates increase triglyceride lipolysis by PPARalpha mediated activation of LPL in the liver.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	PPARalpha	PPARalpha	PPARalpha	LPL	LPL	LPL	5	6	9	10
PPARalpha agonists increase the gene expresson of LPL and up regulate Apo A-I and A-II synthesis which are major apoproteins of the HDL fraction in the liver and resulting in increased serum HDL levels [ XREF_BIBR , XREF_BIBR ] .	PPARalpha agonists increase the gene expresson of LPL and up regulate Apo A-I and A-II synthesis which are major apoproteins of the HDL fraction in the liver and resulting in increased serum HDL levels [XREF_BIBR, XREF_BIBR].	0	8	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPARalpha	PPARalpha	PPARalpha	LPL	LPL	LPL	0	1	7	8
This increased PPARalpha may then act in return to up-regulate LPL .	This increased PPARalpha may then act in return to up-regulate LPL.	2	11	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPARalpha	PPARalpha	PPARalpha	LPL	LPL	LPL	2	3	10	11
The effect of fibrates on the metabolism of triglyceride rich lipoproteins is due to a PPAR-alpha dependent stimulation of lipoprotein lipase and an inhibition of apolipoprotein C-III expressions , whereas the increase in plasma HDL cholesterol depends on an overexpression of apolipoprotein A-I and apolipoprotein A-II .	The effect of fibrates on the metabolism of triglyceride rich lipoproteins is due to a PPAR-alpha dependent stimulation of lipoprotein lipase and an inhibition of apolipoprotein C-III expressions, whereas the increase in plasma HDL cholesterol depends on an overexpression of apolipoprotein A-I and apolipoprotein A-II.	15	21	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PPAR-alpha	PPAR-alpha	PPAR-alpha	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	15	16	19	21
PPARalpha also promotes plasma triglyceride clearance by mobilizing LPL activity and enhancing oxidation of fatty acids , thereby regulating plasma lipid levels [ XREF_BIBR ] .	PPARalpha also promotes plasma triglyceride clearance by mobilizing LPL activity and enhancing oxidation of fatty acids, thereby regulating plasma lipid levels [XREF_BIBR].	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPARalpha	PPARalpha	PPARalpha	LPL	LPL	LPL	0	1	8	9
Fibric acid derivatives are PPAR-alpha agonists that induce LPL gene , thus suppressing apolipoprotein C111 and thereby causing reduction in TG levels .	Fibric acid derivatives are PPAR-alpha agonists that induce LPL gene, thus suppressing apolipoprotein C111 and thereby causing reduction in TG levels.	4	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPAR-alpha	PPAR-alpha	PPAR-alpha	LPL	LPL	LPL	4	5	8	9
Although several studies demonstrate PPARalpha activators increase LPL mRNA in macrophages , conflicting evidence exists regarding LPL secretion .	Although several studies demonstrate PPARalpha activators increase LPL mRNA in macrophages, conflicting evidence exists regarding LPL secretion.	4	8	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPARalpha	PPARalpha	PPARalpha	LPL	LPL	LPL	4	5	7	8
The rat SLC-1 is activated by nanomolar concentrations of MCH and is coupled to the G protein G alpha i/o .	The rat SLC-1 is activated by nanomolar concentrations of MCH and is coupled to the G protein G alpha i/o.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MCH	MCH	MCH	SLC-1	SLC-1	SLC-1	9	10	2	3
Because the results described above indicate that MCH stimulates prodynorphin and down-regulation of MCH-R inhibits prodynorphin in the LHA , we next assessed if central MCH was able to modulate hepatic lipid metabolism when the kappaOR system is disrupted .	Because the results described above indicate that MCH stimulates prodynorphin and down-regulation of MCH-R inhibits prodynorphin in the LHA, we next assessed if central MCH was able to modulate hepatic lipid metabolism when the kappaOR system is disrupted.	7	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MCH	MCH	MCH	MCH-R	MCH-R	MCH-R	7	8	13	14
GW 803430 , a known MCHR 1 antagonist , demonstrated a potent antagonist activity towards MCH induced MCHR 1 receptor with an IC 50 value of ~ 13nM .	GW 803430, a known MCHR 1 antagonist, demonstrated a potent antagonist activity towards MCH induced MCHR 1 receptor with an IC 50 value of ~ 13nM.	13	19	induced	Positive_early_activation	Positive_activation	Positive_activation	MCH	MCH	MCH	MCHR 1	MCHR 1	MCHR 1	15	16	17	19
For example , MCH induced body weight gain and hyperphagia are not observed in MCH-R1 null mice .	For example, MCH induced body weight gain and hyperphagia are not observed in MCH-R1 null mice.	3	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MCH	MCH	MCH	MCH-R1	MCH-R1	MCH-R1	3	4	14	15
Overexpression of beta-Arrestins Rescues MCH Mediated MCHR1 Internalization .	Overexpression of beta-Arrestins Rescues MCH Mediated MCHR1 Internalization.	3	7	Mediated	Positive_early_activation	Positive_activation	Positive_activation	MCH	MCH	MCH	MCHR1	MCHR1	MCHR1	4	5	6	7
Overexpression of dominant negative beta-arrestin-2 ( 284-409 ) or dynamin I-K44A significantly prevented MCH induced internalization of MCH1R , while overexpression of dominant negative beta-arrestin-1-V53D had no effect .	Overexpression of dominant negative beta-arrestin-2 (284-409) or dynamin I-K44A significantly prevented MCH induced internalization of MCH1R, while overexpression of dominant negative beta-arrestin-1-V53D had no effect.	13	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MCH	MCH	MCH	MCH1R	MCH1R	MCH1R	13	14	17	18
The spike frequency of hypocretin and orexin neurons in the presence of hypocretin-1 alone ( 372.8 +/- 60.4 % of control , n = 6 ) and in the presence of hypocretin-1 plus MCH ( 369.4 +/- 64.4 % of control , n = 6 ) was comparable ( P > 0.05 , paired t- test , XREF_FIG ) demonstrating that the MCH mediated inhibitory effect was abolished in MCHR1 KO mice .	The spike frequency of hypocretin and orexin neurons in the presence of hypocretin-1 alone (372.8 +/- 60.4% of control, n = 6) and in the presence of hypocretin-1 plus MCH (369.4 +/- 64.4% of control, n = 6) was comparable (P> 0.05, paired t- test, XREF_FIG) demonstrating that the MCH mediated inhibitory effect was abolished in MCHR1 KO mice.	61	71	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MCH	MCH	MCH	MCHR1	MCHR1	MCHR1	62	63	69	70
Despite potent desensitization of ERK signaling by MCH in BHK-570 cells , we were unable to observe MCH mediated internalization of MCH receptor 1 ( MCHR1 ) by fluorescence microscopy .	Despite potent desensitization of ERK signaling by MCH in BHK-570 cells, we were unable to observe MCH mediated internalization of MCH receptor 1 (MCHR1) by fluorescence microscopy.	16	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MCH	MCH	MCH	MCH receptor 1	MCH receptor 1	MCH receptor 1	17	18	21	24
The MCH mediated inhibition was dose dependent , absent in MCHR1 KO mice and blocked in slices pretreated with PTX , consistent with reports that the Gi/o pathway is activated by MCH receptor stimulation in cell lines .	The MCH mediated inhibition was dose dependent, absent in MCHR1 KO mice and blocked in slices pretreated with PTX, consistent with reports that the Gi/o pathway is activated by MCH receptor stimulation in cell lines.	0	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MCH	MCH	MCH	MCHR1	MCHR1	MCHR1	1	2	10	11
Moreover , MCH mediated activation of MCHR1 on NCM460 colonocytes resulted in complete inhibition of forskolin induced increases in intracellular cAMP ( XREF_FIG ) .	Moreover, MCH mediated activation of MCHR1 on NCM460 colonocytes resulted in complete inhibition of forskolin induced increases in intracellular cAMP (XREF_FIG).	2	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	MCH	MCH	MCH	MCHR1	MCHR1	MCHR1	2	3	6	7
The MC 2 receptor is activated by subnanomolar concentrations of ACTH but not by even micromolar concentrations of MSH .	The MC 2 receptor is activated by subnanomolar concentrations of ACTH but not by even micromolar concentrations of MSH.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC 2	MC 2	MC 2	10	11	1	3
XREF_FIG indicated 500nM of alpha-MSH injection for 1h increased MC5R .	XREF_FIG indicated 500nM of alpha-MSH injection for 1h increased MC5R.	4	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC5R	MC5R	MC5R	4	5	9	10
While most of the intracellular signaling pathways associated with the melanocortin receptors are unclear , alpha-MSH stimulation of MC5r activates the JAK2 and STAT1 pathway .	While most of the intracellular signaling pathways associated with the melanocortin receptors are unclear, alpha-MSH stimulation of MC5r activates the JAK2 and STAT1 pathway.	15	19	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC5r	MC5r	MC5r	15	16	18	19
The melanocortin-1 , -3 , -4 and -5 receptors respond to the endogenous melanocortin agonists alpha-, beta-, and gamma-melanocyte stimulating hormone ( MSH ) and ACTH , but the MC 2 receptor is alone in not responding to any of the MSH peptides and is only stimulated by ACTH .	The melanocortin-1, -3, -4 and -5 receptors respond to the endogenous melanocortin agonists alpha-, beta-, and gamma-melanocyte stimulating hormone (MSH) and ACTH, but the MC 2 receptor is alone in not responding to any of the MSH peptides and is only stimulated by ACTH.	29	49	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACTH	ACTH	ACTH	MC 2	MC 2	MC 2	48	49	29	31
We also found that overexpression of hCLP46 enhances Notch activation and regulates cell proliferation in a cell type dependent manner .	We also found that overexpression of hCLP46 enhances Notch activation and regulates cell proliferation in a cell type dependent manner.	4	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hCLP46	overexpression of hCLP46	hclp46	Notch	Notch	notch	6	7	8	9
We showed that Poglut1 knockdown reduced Notch signaling and largely affected the key regulators of myogenic differentiation , with PAX7 decrease and MYOD increase .	We showed that Poglut1 knockdown reduced Notch signaling and largely affected the key regulators of myogenic differentiation, with PAX7 decrease and MYOD increase.	3	7	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Poglut1	Poglut1	Poglut1	Notch	Notch	Notch	3	4	6	7
We concluded that Poglut1 contributes to myogenesis by regulating Notch signaling and defining , directly or indirectly , the proportion of cells that commit differentiation .	We concluded that Poglut1 contributes to myogenesis by regulating Notch signaling and defining, directly or indirectly, the proportion of cells that commit differentiation.	3	10	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Poglut1	Poglut1	Poglut1	Notch	Notch	Notch	3	4	9	10
The most downregulated gene in the ginsenoside Rg1-treatment group was Poglut1 ( protein O-glucosyltransferase ) , which enhances Notch signaling activation [ XREF_BIBR ] .	The most downregulated gene in the ginsenoside Rg1-treatment group was Poglut1 (protein O-glucosyltransferase), which enhances Notch signaling activation [XREF_BIBR].	3	20	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Poglut1	Poglut1	Poglut1	Notch	Notch	Notch	10	11	18	19
Taken together , hCLP46 enhanced Notch activation and inhibited 293TRex cell proliferation through CDKI signalling .	Taken together, hCLP46 enhanced Notch activation and inhibited 293TRex cell proliferation through CDKI signalling.	3	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hCLP46	hCLP46	hCLP46	Notch	Notch	Notch	3	4	5	6
In Drosophila , Poglut1 is encoded by rumi [ XREF_BIBR ] and promotes Notch activation [ XREF_BIBR - XREF_BIBR ] .	In Drosophila, Poglut1 is encoded by rumi [XREF_BIBR] and promotes Notch activation [XREF_BIBR - XREF_BIBR].	3	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Poglut1	Poglut1	Poglut1	Notch	Notch	Notch	3	4	13	14
As a result , Wip1 inhibits ATM and p53 , but activates Mdm2 .	As a result, Wip1 inhibits ATM and p53, but activates Mdm2.	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wip1	Wip1	Wip1	Mdm2	Mdm2	Mdm2	4	5	12	13
These results confirmed that the effects of Wip1 on MdmX are at least partly dependent on Mdm2 , suggesting that Wip1 mediated stabilization of MdmX is likely Mdm2 dependent .	These results confirmed that the effects of Wip1 on MdmX are at least partly dependent on Mdm2, suggesting that Wip1 mediated stabilization of MdmX is likely Mdm2 dependent.	20	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wip1	Wip1	Wip1	Mdm2	Mdm2	Mdm2	20	21	27	28
Wip1 is also known to target Mdm2 at S395 , promoting the stability of Mdm2 and enhancing the interaction between Mdm2 and p53 .	Wip1 is also known to target Mdm2 at S395, promoting the stability of Mdm2 and enhancing the interaction between Mdm2 and p53.	0	7	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wip1	Wip1	Wip1	Mdm2	Mdm2	Mdm2	0	1	6	7
Intriguingly , these feedback regulatory pathways are again positive feedback loops in the form of double negative feedback ( XREF_FIG ) , and they are closely interlinked with the core p53-MDM2 autoregulation in that Wip1 upregulates MDM2 via inhibiting its degradation [ XREF_BIBR ] ( XREF_FIG ) .	Intriguingly, these feedback regulatory pathways are again positive feedback loops in the form of double negative feedback (XREF_FIG), and they are closely interlinked with the core p53-MDM2 autoregulation in that Wip1 upregulates MDM2 via inhibiting its degradation [XREF_BIBR] (XREF_FIG).	31	38	upregulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Wip1	Wip1	Wip1	MDM2	MDM2	MDM2	34	35	36	37
It was also shown by the group of L. Donehower that Wip1 could potentiate MDM2 function to further reduce p53 levels [ XREF_BIBR ] .	It was also shown by the group of L. Donehower that Wip1 could potentiate MDM2 function to further reduce p53 levels [XREF_BIBR].	11	15	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wip1	Wip1	Wip1	MDM2	MDM2	MDM2	11	12	14	15
Our results thus provide for the first time that Plk3 mediates UV irradiation induced c-Jun activation by phosphorylating c-Jun , suggesting that Plk3 plays an important role in mediating programmed cell death of corneal epithelial cells after UV irradiation .	Our results thus provide for the first time that Plk3 mediates UV irradiation induced c-Jun activation by phosphorylating c-Jun, suggesting that Plk3 plays an important role in mediating programmed cell death of corneal epithelial cells after UV irradiation.	9	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Plk3	Plk3	Plk3	c-Jun	c-Jun	c-Jun	9	10	14	15
PGC-1alpha was shown to modulate the mitochondrial anti-oxidant enzymes SOD2 , thioredoxin and glutathione peroxidase 1 ( GPX1 ) and thus mitigates oxidative stress .	PGC-1alpha was shown to modulate the mitochondrial anti-oxidant enzymes SOD2, thioredoxin and glutathione peroxidase 1 (GPX1) and thus mitigates oxidative stress.	0	21	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	SOD2	SOD2	SOD2	0	1	9	10
The cardio-protective effects of PGC-1 likely are due , at least in part , to its ROS lowering effects , as PGC-1alpha induces GPx1 and SOD2 in models of neurodegeneration 189 .	The cardio-protective effects of PGC-1 likely are due, at least in part, to its ROS lowering effects, as PGC-1alpha induces GPx1 and SOD2 in models of neurodegeneration 189.	21	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	SOD2	SOD2	SOD2	21	22	25	26
In vitro evidence suggests that PGC-1alpha is a powerful inducer of antioxidants GPx and SOD2 .	In vitro evidence suggests that PGC-1alpha is a powerful inducer of antioxidants GPx and SOD2.	5	15	is a powerful inducer	Positive_activation_copula_1	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	SOD2	SOD2	SOD2	5	6	14	15
PGC-1alpha activation with the PPARgamma agonist ( Pioglitazone ) or with a cAMP dependent protein kinase ( AMPK ) agonist ( AICAR ) restored normal SOD2 induction .	PGC-1alpha activation with the PPARgamma agonist (Pioglitazone) or with a cAMP dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction.	0	26	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	SOD2	SOD2	SOD2	0	1	25	26
Overexpression of the PLK2 kinase increases alpha-synuclein phosphorylation and mediates the selective clearance of alpha-synuclein through autophagic degradation and accordingly causes reduced alpha-synuclein toxicity [ XREF_BIBR ] .	Overexpression of the PLK2 kinase increases alpha-synuclein phosphorylation and mediates the selective clearance of alpha-synuclein through autophagic degradation and accordingly causes reduced alpha-synuclein toxicity [XREF_BIBR].	0	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK2	Overexpression of the PLK2	plk2	alpha-synuclein	alpha-synuclein	alpha-synuclein	3	4	14	15
More importantly PLK2 , but not other kinases , mediates quantitative conversion ( > 95 % ) of alpha-Syn to phosphorylated alpha-Syn .	More importantly PLK2, but not other kinases, mediates quantitative conversion (> 95%) of alpha-Syn to phosphorylated alpha-Syn.	2	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PLK2	PLK2	PLK2	alpha-Syn	alpha-Syn	alpha-Syn	2	3	18	19
Overexpression of pgc-1alpha has been reported to increase the mRNA levels of manganese superoxide dismutase ( MnSOD ) and glutathione peroxidase 1 ( GPx1 ) in mouse C2C12 myotubes .	Overexpression of pgc-1alpha has been reported to increase the mRNA levels of manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx1) in mouse C2C12 myotubes.	0	24	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pgc-1alpha	Overexpression of pgc-1alpha	pgc-1alpha	GPx1	GPx1	gpx1	2	3	23	24
MCHR2 is specifically activated by nanomolar concentrations of MCH , binds to MCH with high affinity , and signals through Gq protein .	MCHR2 is specifically activated by nanomolar concentrations of MCH, binds to MCH with high affinity, and signals through Gq protein.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MCH	MCH	MCH	MCHR2	MCHR2	MCHR2	8	9	0	1
Plk4 was overexpressed by two methods : transient transfection of a Plk4 expressing plasmid , and transient induction of a tet inducible Plk4 stable cell line .	Plk4 was overexpressed by two methods : transient transfection of a Plk4 expressing plasmid, and transient induction of a tet inducible Plk4 stable cell line.	0	13	overexpressed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Plk4	Plk4 expressing	plk4	Plk4	Plk4	plk4	11	12	0	1
Centriole assembly and duplication is controlled by Polo-like-kinase 4 ( Plk4 ) : these processes fail if Plk4 is downregulated and are promoted by Plk4 overexpression .	Centriole assembly and duplication is controlled by Polo-like-kinase 4 (Plk4) : these processes fail if Plk4 is downregulated and are promoted by Plk4 overexpression.	17	26	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Plk4	Plk4 overexpression	plk4	Plk4	Plk4	plk4	24	25	17	18
The analysis of peripheral myelin protein 22 ( PMP22 ) , ganglioside induced differentiation associated protein 1 ( GDAP1 ) , gap junction beta-1 protein ( GJB1 ) , and myelin protein zero ( MPZ ) genes did not reveal mutations ; however , we identified a new sequence intronic variant in the mitofusin 2 ( MFN2 ) gene of unknown pathogenic significance .	The analysis of peripheral myelin protein 22 (PMP22), ganglioside induced differentiation associated protein 1 (GDAP1), gap junction beta-1 protein (GJB1), and myelin protein zero (MPZ) genes did not reveal mutations; however, we identified a new sequence intronic variant in the mitofusin 2 (MFN2) gene of unknown pathogenic significance.	5	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PMP22	PMP22	PMP22	myelin protein zero	myelin protein zero	myelin protein zero	8	9	30	33
These genes include previously known p53 targets such as APAF1 , FAS , PLK3 and MASPIN and several genes that were not previously described as p53 transcriptional targets .	These genes include previously known p53 targets such as APAF1, FAS, PLK3 and MASPIN and several genes that were not previously described as p53 transcriptional targets.	5	14	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	PLK3	PLK3	PLK3	p53	p53	p53	13	14	5	6
The bound promoters included many known p53 transcriptional targets such as PLK3 , FAS , APAF1 , C12orf5 , PCNA , TP53INP1 , DDB2 , MASPIN , GDF15 and PIG11 .	The bound promoters included many known p53 transcriptional targets such as PLK3, FAS, APAF1, C12orf5, PCNA, TP53INP1, DDB2, MASPIN, GDF15 and PIG11.	6	29	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	PLK3	PLK3	PLK3	p53	p53	p53	11	12	6	7
We additionally reveal new mechanistic insights into the role of POFUT1 during CRC , through demonstrating that POFUT1 silencing inhibits Notch1 signaling .	We additionally reveal new mechanistic insights into the role of POFUT1 during CRC, through demonstrating that POFUT1 silencing inhibits Notch1 signaling.	17	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	POFUT1	POFUT1	POFUT1	Notch1	Notch1	Notch1	17	18	20	21
hCLP46 overexpression enhanced Notch1 activation in 293Trex cells in a ligand dependent manner , with increased Notch signalling enhancing Hes1 expression .	hCLP46 overexpression enhanced Notch1 activation in 293Trex cells in a ligand dependent manner, with increased Notch signalling enhancing Hes1 expression.	0	4	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hCLP46	hCLP46 overexpression	hclp46	Notch1	Notch1	notch1	0	1	3	4
Conversely , the stable overexpression of NIPP1 caused a redistribution of EZH2 among PcG target genes , with corresponding changes in H3K27 trimethylation ( XREF_FIG ) .	Conversely, the stable overexpression of NIPP1 caused a redistribution of EZH2 among PcG target genes, with corresponding changes in H3K27 trimethylation (XREF_FIG).	4	12	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NIPP1	overexpression of NIPP1	nipp1	EZH2	EZH2	ezh2	6	7	11	12
The knockdown of NIPP1 or PP1 reduced the association of EZH2 with a subset of its target genes , whereas the overexpression of NIPP1 resulted in a retargeting of EZH2 from fully repressed to partially active PcG targets .	The knockdown of NIPP1 or PP1 reduced the association of EZH2 with a subset of its target genes, whereas the overexpression of NIPP1 resulted in a retargeting of EZH2 from fully repressed to partially active PcG targets.	1	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	NIPP1	NIPP1	NIPP1	EZH2	EZH2	EZH2	3	4	10	11
Consistent with this notion , we show here that the loss of NIPP1 results in a reduced occupancy of EZH2 at a subset of PcG targets , whereas the overexpression of NIPP1 causes , in a PP1 dependent manner , a redistribution of EZH2 between its target genes .	Consistent with this notion, we show here that the loss of NIPP1 results in a reduced occupancy of EZH2 at a subset of PcG targets, whereas the overexpression of NIPP1 causes, in a PP1 dependent manner, a redistribution of EZH2 between its target genes.	29	47	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NIPP1	overexpression of NIPP1	nipp1	EZH2	EZH2	ezh2	31	32	43	44
Moreover , the knockdown of NIPP1 in cancer cells results in the dissociation of EZH2 from a subset of target genes , whereas the overexpression of NIPP1 causes a redistribution of EZH2 between target loci .	Moreover, the knockdown of NIPP1 in cancer cells results in the dissociation of EZH2 from a subset of target genes, whereas the overexpression of NIPP1 causes a redistribution of EZH2 between target loci.	24	34	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NIPP1	overexpression of NIPP1	nipp1	EZH2	EZH2	ezh2	26	27	31	32
It has been reported that the overexpression of PPP1R3A and its catalytic subunit in glycogen depleted cells leads to slightly higher GYS and lower glycogen phosphorylase ( PYG ) activity , resulting in increased glycogen content 24 .	It has been reported that the overexpression of PPP1R3A and its catalytic subunit in glycogen depleted cells leads to slightly higher GYS and lower glycogen phosphorylase (PYG) activity, resulting in increased glycogen content 24.	6	25	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	PPP1R3A	overexpression of PPP1R3A	ppp1r3a	GYS	GYS	gys	8	9	21	22
We therefore investigated whether PRDM16 could enhance the transcriptional activity of PPARgamma .	We therefore investigated whether PRDM16 could enhance the transcriptional activity of PPARgamma.	4	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRDM16	PRDM16	PRDM16	PPARgamma	PPARgamma	PPARgamma	4	5	11	12
Peroxisome proliferator activated receptor-gamma ( PPAR-gamma ) is the master transcriptional regulator of fat differentiation , and in concert with the PR domain containing-16 ( PRDM-16 ) activates PPAR-gamma coactivator-1alpha ( PGC-1alpha ) to induce brown selective genes [ XREF_BIBR - XREF_BIBR ] .	Peroxisome proliferator activated receptor-gamma (PPAR-gamma) is the master transcriptional regulator of fat differentiation, and in concert with the PR domain containing-16 (PRDM-16) activates PPAR-gamma coactivator-1alpha (PGC-1alpha) to induce brown selective genes [XREF_BIBR - XREF_BIBR].	23	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRDM-16	PRDM-16	PRDM-16	PPAR-gamma	PPAR-gamma	PPAR-gamma	25	26	28	29
In myocytes , in the presence of PPARgamma agonists , PRDM16 induces multiple PPARgamma target genes in adipogenesis like aP2 and adiponectin , as well as brown fat selective gene program , including Ucp1 and Cidea .	In myocytes, in the presence of PPARgamma agonists, PRDM16 induces multiple PPARgamma target genes in adipogenesis like aP2 and adiponectin, as well as brown fat selective gene program, including Ucp1 and Cidea.	10	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRDM16	PRDM16	PRDM16	PPARgamma	PPARgamma	PPARgamma	10	11	13	14
Recently , it has been demonstrated that PPARgamma induction of brown fat genes in subcutaneous WAT is mediated by activation of PRDM16 ( PR domain containing 16 ) , a process that is mediated by deacetylation of PPARgamma by sirtuin 1 ( SIRT1 ) .	Recently, it has been demonstrated that PPARgamma induction of brown fat genes in subcutaneous WAT is mediated by activation of PRDM16 (PR domain containing 16), a process that is mediated by deacetylation of PPARgamma by sirtuin 1 (SIRT1).	7	22	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PRDM16	PRDM16	PRDM16	PPARgamma	PPARgamma	PPARgamma	21	22	7	8
In PPARgamma-/- cells , PRDM16 expression induced transcription of the reporter gene only in the presence of exogenously added PPARgamma ( XREF_SUPPLEMENTARY ) .	In PPARgamma-/- cells, PRDM16 expression induced transcription of the reporter gene only in the presence of exogenously added PPARgamma (XREF_SUPPLEMENTARY).	4	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRDM16	PRDM16 expression	prdm16	PPARgamma	PPARgamma	ppargamma	4	5	19	20
PRDM16 , a key determining factor of BAT , is also a coactivator of PPARgamma that activates and regulates BAT selective gene expression .	PRDM16, a key determining factor of BAT, is also a coactivator of PPARgamma that activates and regulates BAT selective gene expression.	0	15	is also a coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	PRDM16	PRDM16	PRDM16	PPARgamma	PPARgamma	PPARgamma	0	1	14	15
Mechanistically , PRDM16 increases the transcriptional activities of PGC-1alpha , PPARgamma , and C/EBPs through direct interactions .	Mechanistically, PRDM16 increases the transcriptional activities of PGC-1alpha, PPARgamma, and C/EBPs through direct interactions.	2	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRDM16	PRDM16	PRDM16	PPARgamma	PPARgamma	PPARgamma	2	3	10	11
Furthermore , AMPKalpha1 deletion significantly downregulates Foxo3 and ROS scavenging enzymes including catalase , MnSOD , and glutathione peroxidase ( GPx-1 ) in mice erythroblasts [ XREF_BIBR ] .	Furthermore, AMPKalpha1 deletion significantly downregulates Foxo3 and ROS scavenging enzymes including catalase, MnSOD, and glutathione peroxidase (GPx-1) in mice erythroblasts [XREF_BIBR].	2	10	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AMPKalpha1	AMPKalpha1	AMPKalpha1	Foxo3	Foxo3	Foxo3	2	3	6	7
PPP3CA activates the transcription factor NFATC1 that produces muscle metabolic genes including myoglobin ( MB ) .	PPP3CA activates the transcription factor NFATC1 that produces muscle metabolic genes including myoglobin (MB).	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPP3CA	PPP3CA	PPP3CA	NFATC1	NFATC1	NFATC1	0	1	5	6
For example , XREF_BIBR found that atrogin-1 attenuates agonist induced CnA dependent activation of NFATc4 and pathological hypertrophy in cardiomyocytes .	For example, XREF_BIBR found that atrogin-1 attenuates agonist induced CnA dependent activation of NFATc4 and pathological hypertrophy in cardiomyocytes.	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CnA	CnA	CnA	NFATc4	NFATc4	NFATc4	10	11	14	15
While we do not have isolated islets from a NPY4R null mouse to provide direct evidence , it is likely that PP is activating NPY4R , leading to a decrease in somatostatin secretion .	While we do not have isolated islets from a NPY4R null mouse to provide direct evidence, it is likely that PP is activating NPY4R, leading to a decrease in somatostatin secretion.	21	25	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PP	PP	PP	NPY4R	NPY4R	NPY4R	21	22	24	25
CnA interacts with and activates myocyte enhancer factors 2C and 2D ( MEF2C and MEF2D ) , which regulate the transcription of PGC-1alpha directly [ XREF_BIBR , XREF_BIBR ] .	CnA interacts with and activates myocyte enhancer factors 2C and 2D (MEF2C and MEF2D), which regulate the transcription of PGC-1alpha directly [XREF_BIBR, XREF_BIBR].	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CnA	CnA	CnA	MEF2C	MEF2C	MEF2C	0	1	12	13
PPP3CB activated PIK3R2 , CDC26 and NFATC1 .	PPP3CB activated PIK3R2, CDC26 and NFATC1.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PPP3CB	PPP3CB	PPP3CB	NFATC1	NFATC1	NFATC1	0	1	6	7
Increased cellular stress response and suppressed AMPKalpha2 dependent induction of mitophagy regulator ULK1 in DTG mice .	Increased cellular stress response and suppressed AMPKalpha2 dependent induction of mitophagy regulator ULK1 in DTG mice.	6	15	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	AMPKalpha2	AMPKalpha2	AMPKalpha2	ULK1	ULK1	ULK1	6	7	12	13
Collectively , these results suggest that the elevated autophagy in response to gastrin treatment is both due to a direct effect on PRKAA2 , which induces the ULK1 activity , and the indirect effect via reduced mTOR activity .	Collectively, these results suggest that the elevated autophagy in response to gastrin treatment is both due to a direct effect on PRKAA2, which induces the ULK1 activity, and the indirect effect via reduced mTOR activity.	20	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRKAA2	PRKAA2	PRKAA2	ULK1	ULK1	ULK1	22	23	27	28
AMPKalpha1 activates SIRT1 and inhibits inflammation in macrophages ; furthermore , AMPKalpha1 may inhibit the activation of the nuclear factor-kappaB system , a key regulator of innate immunity and inflammation .	AMPKalpha1 activates SIRT1 and inhibits inflammation in macrophages; furthermore, AMPKalpha1 may inhibit the activation of the nuclear factor-kappaB system, a key regulator of innate immunity and inflammation.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AMPKalpha1	AMPKalpha1	AMPKalpha1	SIRT1	SIRT1	SIRT1	0	1	2	3
We hypothesis that this is related to the phosphorylation status of SIRT1 and that the AMPK-alpha1 kinase attempts to rescue SIRT1 function .	We hypothesis that this is related to the phosphorylation status of SIRT1 and that the AMPK-alpha1 kinase attempts to rescue SIRT1 function.	15	21	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AMPK-alpha1	AMPK-alpha1	AMPK-alpha1	SIRT1	SIRT1	SIRT1	15	16	20	21
These data suggest two possible scenarios : either the increased interaction of AMPK-alpha1 with the SIRT1 and DBC1 complex might attempt to promote SIRT1 activation in the striatum of HD mice through the dissociation from DBC1 , or the inability to induce SIRT1 in R6/2 mice might be due to an inhibitory retention of AMPK-alpha1 via DBC1 .	These data suggest two possible scenarios : either the increased interaction of AMPK-alpha1 with the SIRT1 and DBC1 complex might attempt to promote SIRT1 activation in the striatum of HD mice through the dissociation from DBC1, or the inability to induce SIRT1 in R6/2 mice might be due to an inhibitory retention of AMPK-alpha1 via DBC1.	10	24	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AMPK-alpha1	AMPK-alpha1	AMPK-alpha1	SIRT1	SIRT1	SIRT1	12	13	23	24
These findings indicate that P2rx7 deletion may increase PRKAA1 mediated ULK1 activity following KA injection .	These findings indicate that P2rx7 deletion may increase PRKAA1 mediated ULK1 activity following KA injection.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	PRKAA1	PRKAA1	PRKAA1	ULK1	ULK1	ULK1	8	9	10	11
We observed marked enrichment of RNA Pol II phospho-S2 in NsB after heat shock , in association with p300 and HSF1 ( XREF_FIG ) , an effect that was reduced by PKAcalpha knockdown ( XREF_FIG ) .	We observed marked enrichment of RNA Pol II phospho-S2 in NsB after heat shock, in association with p300 and HSF1 (XREF_FIG), an effect that was reduced by PKAcalpha knockdown (XREF_FIG).	16	32	reduced	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	PKAcalpha	PKAcalpha	PKAcalpha	HSF1	HSF1	HSF1	31	32	20	21
As PKAcalpha mediates the function of HSF1 through a mechanism that involves phosphorylation on serine 320 XREF_BIBR , we examined the ability of HSF1 in which S320 was replaced by either aspartate ( S320D ) or alanine ( S320A ) ( XREF_FIG ) to bind p300 .	As PKAcalpha mediates the function of HSF1 through a mechanism that involves phosphorylation on serine 320 XREF_BIBR, we examined the ability of HSF1 in which S320 was replaced by either aspartate (S320D) or alanine (S320A) (XREF_FIG) to bind p300.	1	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKAcalpha	PKAcalpha	PKAcalpha	HSF1	HSF1	HSF1	1	2	6	7
In summary , AnxA6 is a new PKCalpha scaffold to promote PKCalpha mediated EGFR inactivation through increased membrane targeting of PKCalpha and EGFR and PKCalpha complex formation .	In summary, AnxA6 is a new PKCalpha scaffold to promote PKCalpha mediated EGFR inactivation through increased membrane targeting of PKCalpha and EGFR and PKCalpha complex formation.	10	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	EGFR	EGFR	EGFR	11	12	13	14
Annexin A1 interacts with the EGF receptor and regulates its trafficking , degradation , and signalling [ XREF_BIBR ] , whereas annexin A6 promotes PKCalpha mediated EGFR inactivation through increased membrane targeting of PKCalpha and EGFR and PKCalpha complex formation [ XREF_BIBR ] .	Annexin A1 interacts with the EGF receptor and regulates its trafficking, degradation, and signalling [XREF_BIBR], whereas annexin A6 promotes PKCalpha mediated EGFR inactivation through increased membrane targeting of PKCalpha and EGFR and PKCalpha complex formation [XREF_BIBR].	23	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	EGFR	EGFR	EGFR	24	25	26	27
Protein kinase C , alpha ( PRKCA ) mediates epidermal growth factor receptor transactivation in human prostate cancer cells XREF_BIBR .	Protein kinase C, alpha (PRKCA) mediates epidermal growth factor receptor transactivation in human prostate cancer cells XREF_BIBR.	4	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRKCA	PRKCA	PRKCA	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	6	7	9	13
We have previously described the involvement of PKC-alpha in Salmonella induced PMN transmigration , thus we sought to investigate whether ezrin activation could also be mediated by PKCalpha .	We have previously described the involvement of PKC-alpha in Salmonella induced PMN transmigration, thus we sought to investigate whether ezrin activation could also be mediated by PKCalpha.	20	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	ezrin	ezrin	ezrin	27	28	20	21
We found that inhibitors specific to PKC-alpha decreased the apical localization of MRP2 , attenuated ezrin-MRP2 interactions , and significantly reduced the phosphorylation of ezrin at Thr 567 , suggesting that PKC-alpha activates ezrin during S. Typhimurium infection .	We found that inhibitors specific to PKC-alpha decreased the apical localization of MRP2, attenuated ezrin-MRP2 interactions, and significantly reduced the phosphorylation of ezrin at Thr 567, suggesting that PKC-alpha activates ezrin during S. Typhimurium infection.	31	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC-alpha	PKC-alpha	PKC-alpha	ezrin	ezrin	ezrin	31	32	33	34
PCPH and ENTPD5 expression confers to prostate cancer cells resistance against cisplatin induced apoptosis through PKCalpha mediated Bcl-2 stabilization .	PCPH and ENTPD5 expression confers to prostate cancer cells resistance against cisplatin induced apoptosis through PKCalpha mediated Bcl-2 stabilization.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	Bcl-2	Bcl-2	Bcl-2	15	16	17	18
Further studies showed that only unphosphorylated PKCalpha could bind to and activate PLD1 and that both inhibitors induced phosphorylation of PKCalpha .	Further studies showed that only unphosphorylated PKCalpha could bind to and activate PLD1 and that both inhibitors induced phosphorylation of PKCalpha.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	unphosphorylated PKCalpha	pkcalpha	PLD1	PLD1	pld1	6	7	12	13
Masahiro Oka et al reported PKCalpha mediated PLD1 activation in human melanoma cells .	Masahiro Oka et al reported PKCalpha mediated PLD1 activation in human melanoma cells.	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	5	6	7	8
PLD1 exhibits low intrinsic basal activity and is strongly and synergistically activated by members of the ARF and Rho families of monomeric G proteins as well as by PKCalpha and PKCbeta .	PLD1 exhibits low intrinsic basal activity and is strongly and synergistically activated by members of the ARF and Rho families of monomeric G proteins as well as by PKCalpha and PKCbeta.	0	30	synergistically activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	28	29	0	1
Via a parallel pathway , Galpha i or Galpha o / PKCalpha and PLC activates PLD1 and in tun mTOR that also promotes proliferation in a manner synergistic with NFATC1 .	Via a parallel pathway, Galpha i or Galpha o / PKCalpha and PLC activates PLD1 and in tun mTOR that also promotes proliferation in a manner synergistic with NFATC1.	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	11	12	15	16
It is currently unclear if the non catalytic mechanism by which PKCalpha and beta activate PLD1 in vitro accounts for PKC dependent increases in PLD activity in intact cells [ XREF_BIBR - XREF_BIBR ] .	It is currently unclear if the non catalytic mechanism by which PKCalpha and beta activate PLD1 in vitro accounts for PKC dependent increases in PLD activity in intact cells [XREF_BIBR - XREF_BIBR].	11	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	11	12	15	16
In addition , a PKCalpha specific inhibitor , RO320432 , reduced the activation of PLD1 and affected PLD1 signaling during differentiation in NSCs .	In addition, a PKCalpha specific inhibitor, RO320432, reduced the activation of PLD1 and affected PLD1 signaling during differentiation in NSCs.	4	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	4	5	14	15
PKCalpha activation of PLD1 involves N- and C-terminal PLD domains .	PKCalpha activation of PLD1 involves N- and C-terminal PLD domains.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	0	1	3	4
PLD1 is selectively activated by the GTPases Rho , Rac1 and Cdc42 as well as the PKCalpha [ XREF_BIBR ] .	PLD1 is selectively activated by the GTPases Rho, Rac1 and Cdc42 as well as the PKCalpha [XREF_BIBR].	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	16	17	0	1
These assays demonstrated that zebrafish Pld1 , similar to mammalian PLD1 enzymes , can be activated by both PKCalpha and Arf1 ( XREF_FIG ) .	These assays demonstrated that zebrafish Pld1, similar to mammalian PLD1 enzymes, can be activated by both PKCalpha and Arf1 (XREF_FIG).	4	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	Pld1	Pld1	Pld1	18	19	5	6
PLD1 is activated by PKCalpha and GTPases such as RhoA , RacI , Cdc42 , and ADP ribosylation factor ( ARF ) , whereas PLD2 is not .	PLD1 is activated by PKCalpha and GTPases such as RhoA, RacI, Cdc42, and ADP ribosylation factor (ARF), whereas PLD2 is not.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	4	5	0	1
The inhibition of phorbol ester activation of phospholipase D1 ( PLD1 ) by protein kinase C ( PKC ) inhibitors has been considered proof of phosphorylation dependent activation of PLD1 by PKCalpha .	The inhibition of phorbol ester activation of phospholipase D1 (PLD1) by protein kinase C (PKC) inhibitors has been considered proof of phosphorylation dependent activation of PLD1 by PKCalpha.	22	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	31	32	29	30
These results indicate that neither the regulatory nor catalytic domains of PKCalpha alone can bind to or activate PLD1 and that a residue in the C terminus of PKCalpha ( Phe ( 663 ) ) is required for these effects .	These results indicate that neither the regulatory nor catalytic domains of PKCalpha alone can bind to or activate PLD1 and that a residue in the C terminus of PKCalpha (Phe (663)) is required for these effects.	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	11	12	18	19
We show that the amino-terminal 325 amino acids are required for PKC-alpha activation of PLD1 but not for activation by ARF1 and RhoA .	We show that the amino-terminal 325 amino acids are required for PKC-alpha activation of PLD1 but not for activation by ARF1 and RhoA.	11	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PKC-alpha	PKC-alpha	PKC-alpha	PLD1	PLD1	PLD1	11	12	14	15
We found that protein kinase C alp ( PKCalpha ) stimulated PLD1 activity in the presence of phorbol myristate acetate ( PMA ) .	We found that protein kinase C alp (PKCalpha) stimulated PLD1 activity in the presence of phorbol myristate acetate (PMA).	6	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	8	9	11	12
Moreover , the actual proposed mechanism of PLD1 activation by the classical isoform PKCalpha is independent of the catalytic activity of PKC [ XREF_BIBR ] .	Moreover, the actual proposed mechanism of PLD1 activation by the classical isoform PKCalpha is independent of the catalytic activity of PKC [XREF_BIBR].	7	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD1	PLD1	PLD1	13	14	7	8
Loss of PKCalpha in MCF-7 cells overexpressing pre-miR-24-2 decreases downstream PKCalpha mediated gene expression .	Loss of PKCalpha in MCF-7 cells overexpressing pre-miR-24-2 decreases downstream PKCalpha mediated gene expression.	0	11	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCalpha	Loss of PKCalpha	pkcalpha	PKCalpha	PKCalpha	pkcalpha	2	3	10	11
Wild-type PKC-alpha ( wtPKC-alpha ) and inactive PKC alpha mutants were overexpressed in RPTC to selectively increase or block PKC-alpha activation .	Wild-type PKC-alpha (wtPKC-alpha) and inactive PKC alpha mutants were overexpressed in RPTC to selectively increase or block PKC-alpha activation.	0	20	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC-alpha	PKC-alpha (wtPKC-alpha) and inactive PKC alpha mutants were overexpressed	pkc-alpha	PKC-alpha	PKC-alpha	pkc-alpha	1	2	19	20
We screened potential active shRNAs that specifically target the human PKCalpha and PKCbetaII mRNA and identified two PKCalpha shRNAs and four PKCbetaII shRNAs that specifically decrease PKCalpha and PKCbetaII expression ( Supplemental Figure S1B ) .	We screened potential active shRNAs that specifically target the human PKCalpha and PKCbetaII mRNA and identified two PKCalpha shRNAs and four PKCbetaII shRNAs that specifically decrease PKCalpha and PKCbetaII expression (Supplemental Figure S1B).	7	30	target	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCalpha	PKCbetaII shRNAs that specifically decrease PKCalpha and PKCbetaII expression	pkcalpha	PKCalpha	PKCalpha	pkcalpha	26	27	10	11
Overexpression of syndecan-4 , but not a mutant lacking its cytoplasmic domain , specifically increased the level of endogenous PKC-alpha and enhanced the translocation of PKC-alpha into both detergent-insoluble and membrane fractions .	Overexpression of syndecan-4, but not a mutant lacking its cytoplasmic domain, specifically increased the level of endogenous PKC-alpha and enhanced the translocation of PKC-alpha into both detergent-insoluble and membrane fractions.	0	26	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC-alpha	Overexpression of syndecan-4, but not a mutant lacking its cytoplasmic domain, specifically increased the level of endogenous PKC-alpha	pkc-alpha	PKC-alpha	PKC-alpha	pkc-alpha	19	20	25	26
More important , overexpression of GFP-PKCalpha or PKCbetaI rescued the respective effect of siRNA of PKCalpha or PKCbetaI ( XREF_FIG E ) .	More important, overexpression of GFP-PKCalpha or PKCbetaI rescued the respective effect of siRNA of PKCalpha or PKCbetaI (XREF_FIG E).	3	20	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GFP-PKCalpha	overexpression of GFP-PKCalpha	gfp-pkcalpha	PKCalpha	PKCalpha	pkcalpha	5	6	15	16
By contrast , the expression of p-PKCalpha was increased , and increased translocation of PKCalpha from the cytoplasm to the nuclear membrane and nucleus was observed .	By contrast, the expression of p-PKCalpha was increased, and increased translocation of PKCalpha from the cytoplasm to the nuclear membrane and nucleus was observed.	4	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-PKCalpha	expression of p-PKCalpha	p-pkcalpha	PKCalpha	PKCalpha	pkcalpha	6	7	14	15
PKC-alpha activated by Abeta directly phosphorylated a recombinant MARCKS in vitro , Translocation of PKC-alpha from the cytoplasm to the membrane and accumulation of phospho-MARCKS in the cytoplasm were induced by Abeta .	PKC-alpha activated by Abeta directly phosphorylated a recombinant MARCKS in vitro, Translocation of PKC-alpha from the cytoplasm to the membrane and accumulation of phospho-MARCKS in the cytoplasm were induced by Abeta.	0	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKC-alpha	Abeta directly phosphorylated a recombinant MARCKS in vitro, Translocation of PKC-alpha	pkc-alpha	PKC-alpha	PKC-alpha	pkc-alpha	14	15	0	1
Adenoviral PKCalpha expression rescued P-PKC-alpha in Rictor-null PMECs ( XREF_FIG ) , rescued branching morphogenesis in Rictor-null organoids ( XREF_FIG ) and increased Rictor-null organoid size ( XREF_FIG ) .	Adenoviral PKCalpha expression rescued P-PKC-alpha in Rictor-null PMECs (XREF_FIG), rescued branching morphogenesis in Rictor-null organoids (XREF_FIG) and increased Rictor-null organoid size (XREF_FIG).	1	5	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha expression	pkcalpha	P-PKC-alpha	P-PKC-alpha	p-pkc-alpha	1	2	4	5
Moreover , PKCalpha mediates nephrin endocytosis in podocytes XREF_BIBR , XREF_BIBR .	Moreover, PKCalpha mediates nephrin endocytosis in podocytes XREF_BIBR, XREF_BIBR.	2	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	nephrin	nephrin	nephrin	2	3	4	5
PKC-alpha , stimulated by the high glucose concentration , induces nephrin endocytosis and leads to proteinuria while depletion of PKC-alpha stabilizes nephrin in diabetic nephropathy .	PKC-alpha, stimulated by the high glucose concentration, induces nephrin endocytosis and leads to proteinuria while depletion of PKC-alpha stabilizes nephrin in diabetic nephropathy.	0	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC-alpha	PKC-alpha	PKC-alpha	nephrin	nephrin	nephrin	0	1	10	11
PKC-alpha induces nephrin endocytosis and leads to proteinuria and the loss of PKC-alpha prevents nephrin depletion in diabetic nephropathy [ XREF_BIBR , XREF_BIBR ] .	PKC-alpha induces nephrin endocytosis and leads to proteinuria and the loss of PKC-alpha prevents nephrin depletion in diabetic nephropathy [XREF_BIBR, XREF_BIBR].	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC-alpha	PKC-alpha	PKC-alpha	nephrin	nephrin	nephrin	0	1	2	3
Podocytic PKC-Alpha Is Regulated in Murine and Human Diabetes and Mediates Nephrin Endocytosis .	Podocytic PKC-Alpha Is Regulated in Murine and Human Diabetes and Mediates Nephrin Endocytosis.	0	12	Mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC-Alpha	PKC-Alpha	PKC-Alpha	Nephrin	Nephrin	Nephrin	1	2	11	12
Recent studies have focused on the mechanisms regulating the internalization of nephrin : PKCalpha was shown to mediate nephrin endocytosis via the regulation of an interaction between nephrin and beta-arrestin2 XREF_BIBR , XREF_BIBR , XREF_BIBR .	Recent studies have focused on the mechanisms regulating the internalization of nephrin : PKCalpha was shown to mediate nephrin endocytosis via the regulation of an interaction between nephrin and beta-arrestin2 XREF_BIBR, XREF_BIBR, XREF_BIBR.	13	19	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	nephrin	nephrin	nephrin	13	14	18	19
These data suggest that PKC-alpha promotes beta-arrestin-mediated nephrin endocytosis , most likely via the clathrin dependent pathway .	These data suggest that PKC-alpha promotes beta-arrestin-mediated nephrin endocytosis, most likely via the clathrin dependent pathway.	4	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC-alpha	PKC-alpha	PKC-alpha	nephrin	nephrin	nephrin	4	5	7	8
We here tested the hypothesis that PKCalpha mediates the hyperglycemia induced downregulation of the slit-diaphragm protein nephrin .	We here tested the hypothesis that PKCalpha mediates the hyperglycemia induced downregulation of the slit-diaphragm protein nephrin.	6	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	nephrin	nephrin	nephrin	6	7	16	17
We can demonstrate that PKCalpha mediates nephrin endocytosis in podocytes and that overexpression of PKCalpha leads to an augmented endocytosis response .	We can demonstrate that PKCalpha mediates nephrin endocytosis in podocytes and that overexpression of PKCalpha leads to an augmented endocytosis response.	4	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	nephrin	nephrin	nephrin	4	5	6	7
In human melanocytes , alpha , beta , delta , epsilon and zeta isoforms of PKC are expressed , but uniquely PKC-beta activates tyrosinase , the key and the rate limiting enzyme in melanogenesis , by phosphorylating specific serine residues on its cytoplasmic domain .	In human melanocytes, alpha, beta, delta, epsilon and zeta isoforms of PKC are expressed, but uniquely PKC-beta activates tyrosinase, the key and the rate limiting enzyme in melanogenesis, by phosphorylating specific serine residues on its cytoplasmic domain.	21	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC-beta	PKC-beta	PKC-beta	tyrosinase	tyrosinase	tyrosinase	21	22	23	24
XREF_BIBR , XREF_BIBR It has been shown that plasma membrane lipids are also affected by UVR to release membrane associated diacylglycerol ( DAG ) , which activates PKC-beta In turn , PKC-beta activates tyrosinase , resulting in stimulation of melanogenesis .	XREF_BIBR, XREF_BIBR It has been shown that plasma membrane lipids are also affected by UVR to release membrane associated diacylglycerol (DAG), which activates PKC-beta In turn, PKC-beta activates tyrosinase, resulting in stimulation of melanogenesis.	26	34	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PKC-beta	PKC-beta	PKC-beta	tyrosinase	tyrosinase	tyrosinase	27	28	33	34
In melanogenesis , PKCbeta activates the tyrosinase by phosphorylation of its two serine residues .	In melanogenesis, PKCbeta activates the tyrosinase by phosphorylation of its two serine residues.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCbeta	PKCbeta	PKCbeta	tyrosinase	tyrosinase	tyrosinase	3	4	6	7
We conclude that PKC-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome associated protein .	We conclude that PKC-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome associated protein.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC-beta	PKC-beta	PKC-beta	tyrosinase	tyrosinase	tyrosinase	3	4	5	6
Activation of tyrosinase by PKC-beta was shown to be required for melanogenesis both in vivo [ XREF_BIBR ] and in vitro [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] , while conversely increased activity and/or expression of PKC-beta leads to increased pigmentation both in vitro [ XREF_BIBR ] and in vivo [ XREF_BIBR ] .	Activation of tyrosinase by PKC-beta was shown to be required for melanogenesis both in vivo [XREF_BIBR] and in vitro [XREF_BIBR, XREF_BIBR - XREF_BIBR], while conversely increased activity and/or expression of PKC-beta leads to increased pigmentation both in vitro [XREF_BIBR] and in vivo [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PKC-beta	PKC-beta	PKC-beta	tyrosinase	tyrosinase	tyrosinase	4	5	2	3
As these results support the importance of PKCalpha and epsilon in regulating Nox5 activity , our next goal was to see whether active forms of PKCalpha and epsilon are can stimulate increased Nox5 activity .	As these results support the importance of PKCalpha and epsilon in regulating Nox5 activity, our next goal was to see whether active forms of PKCalpha and epsilon are can stimulate increased Nox5 activity.	23	33	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	Nox5	Nox5	Nox5	25	26	32	33
The PKC isoform mediating this response is most likely to be PKCalpha as genetic silencing of PKCalpha reduced the ability of PMA to activate NOX5 and a constitutively active form of PKCalpha robustly increased NOX5 activity 8 .	The PKC isoform mediating this response is most likely to be PKCalpha as genetic silencing of PKCalpha reduced the ability of PMA to activate NOX5 and a constitutively active form of PKCalpha robustly increased NOX5 activity 8.	29	35	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	NOX5	NOX5	NOX5	31	32	34	35
Based on these new findings we suggest that PLD2 activity is specifically up-regulated by H2O2 and that the H2O2 induced PLD2 activation is mediated by Ca2+ influx and PKCalpha activation .	Based on these new findings we suggest that PLD2 activity is specifically up-regulated by H2O2 and that the H2O2 induced PLD2 activation is mediated by Ca2+ influx and PKCalpha activation.	20	29	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PLD2	PLD2	PLD2	28	29	20	21
We further demonstrated that PKCalpha stimulated p47 phox / NADPH oxidase 2 ( Nox2 )-dependent reactive oxygen species ( ROS ) generation and then activated the ATF2/AP -1 signals .	We further demonstrated that PKCalpha stimulated p47 phox / NADPH oxidase 2 (Nox2)-dependent reactive oxygen species (ROS) generation and then activated the ATF2/AP -1 signals.	4	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	p47	p47	p47	4	5	6	7
Based on these findings , Figure XREF_FIG depicts a model for the PKCalpha mediated activation of p47 phox / Nox2 and ROS dependent ATF2/AP -1 and p300 signaling pathway implicated in LTA induced MMP-9 expression and cell migration in RBA-1 cells .	Based on these findings, Figure XREF_FIG depicts a model for the PKCalpha mediated activation of p47 phox / Nox2 and ROS dependent ATF2/AP -1 and p300 signaling pathway implicated in LTA induced MMP-9 expression and cell migration in RBA-1 cells.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	p47	p47	p47	12	13	16	17
A study in 2005 by Wong and Jin showed that PKD was activated by VEGF downstream of PKCalpha and regulated endothelial cell proliferation [ XREF_BIBR ] .	A study in 2005 by Wong and Jin showed that PKD was activated by VEGF downstream of PKCalpha and regulated endothelial cell proliferation [XREF_BIBR].	10	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	PKD	PKD	PKD	17	18	10	11
PKC-alpha and -delta siRNA attenuated PKD activity , whereas overexpression of PKC-alpha and -delta enhanced PKD activity .	PKC-alpha and -delta siRNA attenuated PKD activity, whereas overexpression of PKC-alpha and -delta enhanced PKD activity.	0	6	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKC-alpha	PKC-alpha	PKC-alpha	PKD	PKD	PKD	0	1	5	6
PKCbeta contributes a critical role in mediating proliferation through retinoblastoma associated protein phosphorylation and permeability through phosphorylation induced endocytosis of the tight junction protein occludin .	PKCbeta contributes a critical role in mediating proliferation through retinoblastoma associated protein phosphorylation and permeability through phosphorylation induced endocytosis of the tight junction protein occludin.	0	25	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCbeta	PKCbeta	PKCbeta	occludin	occludin	occludin	0	1	24	25
We did not evaluate the role of Src in PKCbeta induced occludin modification and the relationship of this signaling pathway to PKC induced permeability remains to be determined .	We did not evaluate the role of Src in PKCbeta induced occludin modification and the relationship of this signaling pathway to PKC induced permeability remains to be determined.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	PKCbeta	PKCbeta	PKCbeta	occludin	occludin	occludin	9	10	11	12
Besides strengthening the cell-ECM adhesion , surface bound TG2 promotes receptor clustering and amplifies integrin and syndecan-4 outside-in signaling , increasing activation of multiple downstream targets , including FAK , RhoA , and PKCalpha .	Besides strengthening the cell-ECM adhesion, surface bound TG2 promotes receptor clustering and amplifies integrin and syndecan-4 outside-in signaling, increasing activation of multiple downstream targets, including FAK, RhoA, and PKCalpha.	14	34	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	syndecan-4	syndecan-4	syndecan-4	33	34	16	17
Since PMA is non specific , our results suggest that activation of PKCbetaII and PKCepsilon both induce sensitization of TRPV1 to heat .	Since PMA is non specific, our results suggest that activation of PKCbetaII and PKCepsilon both induce sensitization of TRPV1 to heat.	10	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	14	15	19	20
XREF_BIBR - XREF_BIBR Specifically , activation of PKCepsilon seems to mediate sensitization of TRPV1 to agonist stimulation via phosphorylation of TRPV1 at serine 800 ( S800 ) .	XREF_BIBR - XREF_BIBR Specifically, activation of PKCepsilon seems to mediate sensitization of TRPV1 to agonist stimulation via phosphorylation of TRPV1 at serine 800 (S800).	5	14	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	7	8	13	14
In the current study , we tested the hypothesis that inhibition of PKCepsilon attenuates the restoration of TRPV1 sensitivity induced by the TRPA1 agonists , allyl isothiocyanate ( AITC ) and the general anesthetic , propofol .	In the current study, we tested the hypothesis that inhibition of PKCepsilon attenuates the restoration of TRPV1 sensitivity induced by the TRPA1 agonists, allyl isothiocyanate (AITC) and the general anesthetic, propofol.	10	18	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	12	13	17	18
This could provide a mechanism for indirect activation of TRPV1 by PKCepsilon , since , as discussed above , PKCepsilon phosphorylates the activation loop of PKD1 thereby stimulating PKD1 activity [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	This could provide a mechanism for indirect activation of TRPV1 by PKCepsilon, since, as discussed above, PKCepsilon phosphorylates the activation loop of PKD1 thereby stimulating PKD1 activity [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	11	12	9	10
This complex is involved in PKA- and PKCepsilon induced TRPV1 sensitization in DRG neurons .	This complex is involved in PKA- and PKCepsilon induced TRPV1 sensitization in DRG neurons.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	7	8	9	10
In vitro , PKCepsilon phosphorylates Ser 502 and Ser 800 , and in HEK-293 cells , intracellular application of the epsilonV1-2 peptide inhibitor of PKCepsilon , which inhibits PKCepsilon binding to RACK2 , reduces bradykinin mediated enhancement of TRPV1 function [ XREF_BIBR ] .	In vitro, PKCepsilon phosphorylates Ser 502 and Ser 800, and in HEK-293 cells, intracellular application of the epsilonV1-2 peptide inhibitor of PKCepsilon, which inhibits PKCepsilon binding to RACK2, reduces bradykinin mediated enhancement of TRPV1 function [XREF_BIBR].	20	41	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	epsilonV1-2 peptide inhibitor of PKCepsilon, which inhibits PKCepsilon binding to RACK2	pkcepsilon	TRPV1	TRPV1	trpv1	28	29	38	39
Therefore , the present study further determined the role of PKCepsilon in LPA induced potentiation of TRPV1 current .	Therefore, the present study further determined the role of PKCepsilon in LPA induced potentiation of TRPV1 current.	8	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	10	11	16	17
The heat sensitivity of TRPV1 is almost eliminated by either knocking down PKCbetaII or mutating Thr705 ; however , neither of these manipulations affects the potentiation of TRPV1 caused by the activation of PKCepsilon .	The heat sensitivity of TRPV1 is almost eliminated by either knocking down PKCbetaII or mutating Thr705; however, neither of these manipulations affects the potentiation of TRPV1 caused by the activation of PKCepsilon.	25	34	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	33	34	27	28
EP1 agonist induced TRPV1 externalization was suppressed by inhibitors of CaMKII , PLC , PKC and PKCepsilon , while EP4 agonist induced TRPV1 externalization by inhibitors of cAMP and PKA and ERK and MAPK .	EP1 agonist induced TRPV1 externalization was suppressed by inhibitors of CaMKII, PLC, PKC and PKCepsilon, while EP4 agonist induced TRPV1 externalization by inhibitors of cAMP and PKA and ERK and MAPK.	3	17	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	16	17	3	4
PKCepsilon has been proposed to mediate sensitization of TRPV1 via direct phosphorylation of S502 and S800 .	PKCepsilon has been proposed to mediate sensitization of TRPV1 via direct phosphorylation of S502 and S800.	0	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	0	1	8	9
XREF_BIBR As TRPV1 sensitization is caused by PKCepsilon dependent phosphorylation , the likelihood that NSAIDs may decrease SP via PKCepsilon translocation inhibition can be conceived .	XREF_BIBR As TRPV1 sensitization is caused by PKCepsilon dependent phosphorylation, the likelihood that NSAIDs may decrease SP via PKCepsilon translocation inhibition can be conceived.	2	10	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon dependent phosphorylation	pkcepsilon	TRPV1	TRPV1	trpv1	7	8	2	3
PKCepsilon not only modulates TRPV1 function but also regulates prolonged response of the chronic inflammatory pain [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	PKCepsilon not only modulates TRPV1 function but also regulates prolonged response of the chronic inflammatory pain [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	8	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	0	1	4	5
Although these observations demonstrated that phosphorylation by PKCepsilon modulates TRPV1 activity , the question of whether dominant negative PKCepsilon performed a similar role in vivo remained to be explored .	Although these observations demonstrated that phosphorylation by PKCepsilon modulates TRPV1 activity, the question of whether dominant negative PKCepsilon performed a similar role in vivo remained to be explored.	5	10	modulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	7	8	9	10
The effects of DNPKCepsilon on CAPS currents provide evidence that PKCepsilon modulates basal TRPV1 responses to CAPS .	The effects of DNPKCepsilon on CAPS currents provide evidence that PKCepsilon modulates basal TRPV1 responses to CAPS.	10	14	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	10	11	13	14
As PKCepsilon phosphorylation of TRPV1 induced by PDBu slows the onset and rate of desensitization of CAPS responses , the present results showing the opposite effect with DNPKCepsilon and BIM are consistent with the idea that basal or constitutively active PKCepsilon modulates normal TRPV1 responses to CAPS .	As PKCepsilon phosphorylation of TRPV1 induced by PDBu slows the onset and rate of desensitization of CAPS responses, the present results showing the opposite effect with DNPKCepsilon and BIM are consistent with the idea that basal or constitutively active PKCepsilon modulates normal TRPV1 responses to CAPS.	36	44	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	40	41	43	44
We next examined whether NOTCH2 can be increased by SRC and STAT3 , whose activities in turn are increased by PKCdelta .	We next examined whether NOTCH2 can be increased by SRC and STAT3, whose activities in turn are increased by PKCdelta.	7	21	increased	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	SRC	SRC	SRC	20	21	9	10
Since we found that SRC and STAT3 were activated by PKCdelta , we next determined the sequence of PKCdelta signal activation events .	Since we found that SRC and STAT3 were activated by PKCdelta, we next determined the sequence of PKCdelta signal activation events.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	SRC	SRC	SRC	10	11	4	5
We were unable to detect a change in activation of the adaptor protein , Shc ; however , loss of PKCdelta significantly suppressed Src activation , which likely contributes to the suppression of ERK and downstream proliferation .	We were unable to detect a change in activation of the adaptor protein, Shc; however, loss of PKCdelta significantly suppressed Src activation, which likely contributes to the suppression of ERK and downstream proliferation.	18	24	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCdelta	loss of PKCdelta	pkcdelta	Src	Src	src	20	21	23	24
CaMKII and PKCdelta mediate the effects of IL-1beta and Src on GluA1 .	CaMKII and PKCdelta mediate the effects of IL-1beta and Src on GluA1.	0	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Src	Src	Src	2	3	9	10
PKCdelta inhibition reduced SRC , JAK2 and affected only Tyr 705 STAT3 phosphorylation , while not modulating ERK or Ser 727 STAT3 phosphorylation .	PKCdelta inhibition reduced SRC, JAK2 and affected only Tyr 705 STAT3 phosphorylation, while not modulating ERK or Ser 727 STAT3 phosphorylation.	0	5	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	SRC	SRC	SRC	0	1	3	4
Further , studies in human breast cancer cell lines support these findings and suggest that PKCdelta is essential for activation of Src and ERK downstream of the ErbB2 receptor .	Further, studies in human breast cancer cell lines support these findings and suggest that PKCdelta is essential for activation of Src and ERK downstream of the ErbB2 receptor.	15	23	is essential for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Src	Src	Src	15	16	21	22
We next examined whether the thrombin induced increase in PKCdelta activation subsequently enhanced c-Src activation .	We next examined whether the thrombin induced increase in PKCdelta activation subsequently enhanced c-Src activation.	9	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	c-Src	c-Src	c-Src	9	10	13	14
These data indicate that PKCdelta activates SRC , which in turn activates STAT3 to trigger the mesenchymal transformation underlying the infiltrative behavior of GBM cells .	These data indicate that PKCdelta activates SRC, which in turn activates STAT3 to trigger the mesenchymal transformation underlying the infiltrative behavior of GBM cells.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	SRC	SRC	SRC	4	5	6	7
PKCepsilon overexpression increases Stat3 activation after either TPA treatment or UVR exposure .	PKCepsilon overexpression increases Stat3 activation after either TPA treatment or UVR exposure.	0	4	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon overexpression	pkcepsilon	Stat3	Stat3	stat3	0	1	3	4
Additional studies are required to determine if Stat-3 activation by PKCepsilon in a HFD environment requires IL-6 .	Additional studies are required to determine if Stat-3 activation by PKCepsilon in a HFD environment requires IL-6.	7	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	Stat-3	Stat-3	Stat-3	10	11	7	8
We found in intact mouse skin in vivo that PKCepsilon , which sensitizes skin to development of SCC by UVR , leads to constitutive activation of Stat3 [ XREF_BIBR ] .	We found in intact mouse skin in vivo that PKCepsilon, which sensitizes skin to development of SCC by UVR, leads to constitutive activation of Stat3 [XREF_BIBR].	9	28	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	Stat3	Stat3	Stat3	9	10	26	27
Deletion of PKCepsilon in TRAMP mice inhibits Stat3 activation .	Deletion of PKCepsilon in TRAMP mice inhibits Stat3 activation.	0	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	Stat3	Stat3	Stat3	2	3	7	8
In this study , loss of PKCepsilon in TRAMP mice inhibited activation of Stat3 , which was manifested by significant inhibition of both pStat3Ser727 and pStat3Tyr705 protein levels as well as decreased Stat3-DNA binding activity .	In this study, loss of PKCepsilon in TRAMP mice inhibited activation of Stat3, which was manifested by significant inhibition of both pStat3Ser727 and pStat3Tyr705 protein levels as well as decreased Stat3-DNA binding activity.	4	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	loss of PKCepsilon	pkcepsilon	Stat3	Stat3	stat3	6	7	13	14
To determine whether PKCepsilon deletion in TRAMP mice inhibits Stat3 activation , we performed immunoblot analysis in excised tissue PCa lysates of TG , Het and KO mice .	To determine whether PKCepsilon deletion in TRAMP mice inhibits Stat3 activation, we performed immunoblot analysis in excised tissue PCa lysates of TG, Het and KO mice.	3	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	Stat3	Stat3	Stat3	3	4	9	10
In consistent with previous findings , deletion of PKCepsilon in FVB/N TRAMP mice down-regulated prostatic Stat3 activation and Stat3 regulated gene expressions .	In consistent with previous findings, deletion of PKCepsilon in FVB/N TRAMP mice down-regulated prostatic Stat3 activation and Stat3 regulated gene expressions.	6	16	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	Stat3	Stat3	Stat3	8	9	15	16
PKCepsilon activates Stat3 by direct phosphorylation at Ser727 residue and this regulation is important for cell invasion and motility [ XREF_BIBR , XREF_BIBR ] .	PKCepsilon activates Stat3 by direct phosphorylation at Ser727 residue and this regulation is important for cell invasion and motility [XREF_BIBR, XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	Stat3	Stat3	Stat3	0	1	2	3
PKCepsilon activates Stat3 via phosphorylation at Ser 727 which has been found to be intimately linked with prostate cancer .	PKCepsilon activates Stat3 via phosphorylation at Ser 727 which has been found to be intimately linked with prostate cancer.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	Stat3	Stat3	Stat3	0	1	2	3
The results presented indicate that PKCepsilon mediates Stat3 activation .	The results presented indicate that PKCepsilon mediates Stat3 activation.	5	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	Stat3	Stat3	Stat3	5	6	7	8
PKCepsilon mediated Stat3 activation increased mRNA and protein levels of translocator protein TSPO [ XREF_BIBR ] , a cholesterol- and drug binding protein that is primarily located at the outer mitochondrial membrane [ XREF_BIBR ] .	PKCepsilon mediated Stat3 activation increased mRNA and protein levels of translocator protein TSPO [XREF_BIBR], a cholesterol- and drug binding protein that is primarily located at the outer mitochondrial membrane [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	Stat3	Stat3	Stat3	0	1	2	3
Previous studies have shown that PKCdelta can increase STAT3 activity .	Previous studies have shown that PKCdelta can increase STAT3 activity.	5	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT3	STAT3	STAT3	5	6	8	9
Our study also showed that PKCdelta enhanced STAT3 activation causes an increase in NOTCH2 signaling .	Our study also showed that PKCdelta enhanced STAT3 activation causes an increase in NOTCH2 signaling.	5	8	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT3	STAT3	STAT3	5	6	7	8
Also , PKCdelta mediates the binding of the IL-6 transmembrane receptor gp130 to STAT3 , and it has been implicated in IL-6-induced insulin signaling .	Also, PKCdelta mediates the binding of the IL-6 transmembrane receptor gp130 to STAT3, and it has been implicated in IL-6-induced insulin signaling.	2	14	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT3	STAT3	STAT3	2	3	13	14
Thus , ET-1 can reduce eNOS expression and NO generation in fetal pulmonary artery endothelial cells through PKCdelta mediated activation of STAT3 .	Thus, ET-1 can reduce eNOS expression and NO generation in fetal pulmonary artery endothelial cells through PKCdelta mediated activation of STAT3.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT3	STAT3	STAT3	17	18	21	22
In conclusion , although extrapolation from cell culture studies to the situation in vivo is limited to a certain extent , the findings of the present study elucidate a novel pathway by which increased levels of ET-1 impairs endothelial NO production via PKCdelta mediated activation of STAT3 .	In conclusion, although extrapolation from cell culture studies to the situation in vivo is limited to a certain extent, the findings of the present study elucidate a novel pathway by which increased levels of ET-1 impairs endothelial NO production via PKCdelta mediated activation of STAT3.	42	47	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT3	STAT3	STAT3	42	43	46	47
In keeping with this notion , our finding that STAT3 can be activated by PKCdelta could explain the aberrant activation of STAT3 in GBM .	In keeping with this notion, our finding that STAT3 can be activated by PKCdelta could explain the aberrant activation of STAT3 in GBM.	9	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT3	STAT3	STAT3	14	15	9	10
Together , our results suggest that PKCdelta mediates ET-1-induced increase in STAT3 activation through increased ser727 phosphorylation .	Together, our results suggest that PKCdelta mediates ET-1-induced increase in STAT3 activation through increased ser727 phosphorylation.	6	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT3	STAT3	STAT3	6	7	11	12
Our results further indicate that PKCdelta mediated STAT3 Ser 727 phosphorylation is mainly a nuclear event .	Our results further indicate that PKCdelta mediated STAT3 Ser 727 phosphorylation is mainly a nuclear event.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT3	STAT3	STAT3	5	6	7	8
Increased ET-1 signaling reduces eNOS promoter activity via a PKCdelta mediated activation of STAT3 in ovine FPAECs .	Increased ET-1 signaling reduces eNOS promoter activity via a PKCdelta mediated activation of STAT3 in ovine FPAECs.	9	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT3	STAT3	STAT3	9	10	13	14
These authors showed that in response to oxidative stress , PKCdelta but not PKCepsilon mediates PKD activation .	These authors showed that in response to oxidative stress, PKCdelta but not PKCepsilon mediates PKD activation.	10	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	PKD	PKD	PKD	10	11	15	16
In the intestine , the protein kinase Cdelta ( PKCdelta ) TPA-1 activates the protein kinase D ( PKD ) DKF-2 upstream of the cassette XREF_BIBR ( XREF_FIG ) .	In the intestine, the protein kinase Cdelta (PKCdelta) TPA-1 activates the protein kinase D (PKD) DKF-2 upstream of the cassette XREF_BIBR (XREF_FIG).	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	protein kinase D	protein kinase D	protein kinase D	9	10	14	17
PMA induced PKD activation is mediated by PKCdelta .	PMA induced PKD activation is mediated by PKCdelta.	2	8	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	PKD	PKD	PKD	7	8	2	3
Furthermore , the finding that rottlerin , a PKCdelta specific inhibitor , blocks PKD activation suggests that PKCdelta , a member of novel PKCs , mediates Ang II induced PKD activation .	Furthermore, the finding that rottlerin, a PKCdelta specific inhibitor, blocks PKD activation suggests that PKCdelta, a member of novel PKCs, mediates Ang II induced PKD activation.	8	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	PKD	PKD	PKD	8	9	13	14
In the intestine , the protein kinase Cdelta ( PKCdelta ) TPA-1 activates the protein kinase D DKF-2 , which in turn activates the PMK-I cassette .	In the intestine, the protein kinase Cdelta (PKCdelta) TPA-1 activates the protein kinase D DKF-2, which in turn activates the PMK-I cassette.	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	protein kinase D	protein kinase D	protein kinase D	9	10	14	17
We find that PKCdelta activation of PKD is an important pathway for AngII stimulated HDAC5 phosphorylation , inhibited by E2 and DPN .	We find that PKCdelta activation of PKD is an important pathway for AngII stimulated HDAC5 phosphorylation, inhibited by E2 and DPN.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	PKD	PKD	PKD	3	4	6	7
Under oxidative stress conditions , PKD stimulation mediated by PKCdelta phosphorylation is facilitated through Src family tyrosine kinases ( reviewed in ref .	Under oxidative stress conditions, PKD stimulation mediated by PKCdelta phosphorylation is facilitated through Src family tyrosine kinases (reviewed in ref.	5	11	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta phosphorylation	pkcdelta	PKD	PKD	pkd	9	10	5	6
ATRA induced PKCdelta phosphorylation and then activated PKCdelta phosphorylated Sp1 .	ATRA induced PKCdelta phosphorylation and then activated PKCdelta phosphorylated Sp1.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	ATRA induced PKCdelta phosphorylation	pkcdelta	PKCdelta	PKCdelta	pkcdelta	2	3	7	8
Paradoxically , overexpression of kinase-dead dominant negative PKCdelta also increased plasma membrane PKCdelta and NTCP as well as Rab4 activity .	Paradoxically, overexpression of kinase-dead dominant negative PKCdelta also increased plasma membrane PKCdelta and NTCP as well as Rab4 activity.	2	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	overexpression of kinase-dead dominant negative PKCdelta	pkcdelta	PKCdelta	PKCdelta	pkcdelta	7	8	12	13
Angiotensin II apparently increased the basal expression level of PKCdelta phosphorylated at Ser ( 643 ) before hypoxia , promoted the cleavage of PKCdelta to its catalytic fragment , and fostered the progression of DNA fragmentation after hypoxia .	Angiotensin II apparently increased the basal expression level of PKCdelta phosphorylated at Ser (643) before hypoxia, promoted the cleavage of PKCdelta to its catalytic fragment, and fostered the progression of DNA fragmentation after hypoxia.	0	24	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	Angiotensin II apparently increased the basal expression level of PKCdelta	pkcdelta	PKCdelta	PKCdelta	pkcdelta	9	10	23	24
The author demonstrated that PKCdelta mediated Nrf2 activation contributed to the increase in antioxidant gene expression and consequently improved beta cell function in the presence of oxidative stress [ XREF_BIBR ] ( XREF_FIG ) .	The author demonstrated that PKCdelta mediated Nrf2 activation contributed to the increase in antioxidant gene expression and consequently improved beta cell function in the presence of oxidative stress [XREF_BIBR] (XREF_FIG).	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Nrf2	Nrf2	Nrf2	4	5	6	7
We , thus , explored the relevance of PRKCD to TAM induced Nrf2 activation .	We, thus, explored the relevance of PRKCD to TAM induced Nrf2 activation.	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRKCD	PRKCD	PRKCD	Nrf2	Nrf2	Nrf2	8	9	12	13
Nevertheless , based on the role played by ROS and tyrosine kinases in activating PKC , and the possibility that activation of Nrf2 by PKCdelta forms a negative feedback loop , it seems likely that these kinases are activated in Nrf2 -/- mice , and the increase in inflammatory response that is observed in cells lacking Nrf2 is consistent with this hypothesis .	Nevertheless, based on the role played by ROS and tyrosine kinases in activating PKC, and the possibility that activation of Nrf2 by PKCdelta forms a negative feedback loop, it seems likely that these kinases are activated in Nrf2 -/- mice, and the increase in inflammatory response that is observed in cells lacking Nrf2 is consistent with this hypothesis.	20	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Nrf2	Nrf2	Nrf2	24	25	22	23
Based on these findings , we propose that the PAR1 and PAR3 , PKCdelta , and c-Src pathways are involved in thrombin induced Nrf2 activation in human synovial fibroblasts .	Based on these findings, we propose that the PAR1 and PAR3, PKCdelta, and c-Src pathways are involved in thrombin induced Nrf2 activation in human synovial fibroblasts.	9	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Nrf2	Nrf2	Nrf2	13	14	23	24
Last , it is interesting to note that in addition to the ability of PKC enzymes to amplify ROS signaling and increase NF-kappaB and AP-1 activity , it has also been reported that PKCdelta activates Nrf2 by phosphorylating Ser 40 in the Neh2 domain of the CNC-bZIP transcription factor [ XREF_BIBR - XREF_BIBR ] ; it remains unclear , however , whether phosphorylation of Nrf2 at Ser 40 alters its activity , its subcellular localization , and/or its stability .	Last, it is interesting to note that in addition to the ability of PKC enzymes to amplify ROS signaling and increase NF-kappaB and AP-1 activity, it has also been reported that PKCdelta activates Nrf2 by phosphorylating Ser 40 in the Neh2 domain of the CNC-bZIP transcription factor [XREF_BIBR - XREF_BIBR]; it remains unclear, however, whether phosphorylation of Nrf2 at Ser 40 alters its activity, its subcellular localization, and/or its stability.	33	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Nrf2	Nrf2	Nrf2	33	34	35	36
This study demonstrates a novel mechanism in which GHRH antagonist induced cell growth inhibition and apoptosis through PKCdelta mediated activation of p53 and p21 in human endometrial cancer cells .	This study demonstrates a novel mechanism in which GHRH antagonist induced cell growth inhibition and apoptosis through PKCdelta mediated activation of p53 and p21 in human endometrial cancer cells.	17	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	p53	p53	p53	17	18	21	22
This decrease seemed to be the main signal responsible for maintaining the intracellular redox homeostasis hindering the activation of p53 induced by ROS , p38MAPK , and PKCdelta .	This decrease seemed to be the main signal responsible for maintaining the intracellular redox homeostasis hindering the activation of p53 induced by ROS, p38MAPK, and PKCdelta.	17	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	p53	p53	p53	27	28	19	20
Reporter assays demonstrated that PKCdelta induces the promoter activity of TP53 through the TP53 core promoter element ( CPE-TP53 ) and that such induction is enhanced in response to DNA damage .	Reporter assays demonstrated that PKCdelta induces the promoter activity of TP53 through the TP53 core promoter element (CPE-TP53) and that such induction is enhanced in response to DNA damage.	4	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	TP53	TP53	TP53	4	5	10	11
Consistent with these results , PKCdelta potentiates p53 dependent apoptosis by Ser ( 46 ) phosphorylation in response to genotoxic stress .	Consistent with these results, PKCdelta potentiates p53 dependent apoptosis by Ser (46) phosphorylation in response to genotoxic stress.	3	8	potentiates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	p53	p53	p53	5	6	7	8
Two reports have suggested a unique mechanism of activation of the JNK pathway by the Type I IFN receptor , involving PKCdelta dependent activation of JNK1 ( XREF_FIG ) .	Two reports have suggested a unique mechanism of activation of the JNK pathway by the Type I IFN receptor, involving PKCdelta dependent activation of JNK1 (XREF_FIG).	21	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	JNK1	JNK1	JNK1	21	22	25	26
JNK1 is known to be activated by increased PKCdelta levels in cells [ XREF_BIBR ] .	JNK1 is known to be activated by increased PKCdelta levels in cells [XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta levels	pkcdelta	JNK1	JNK1	jnk1	8	9	0	1
ERK1/2 and PKCdelta induces Drp1 mediated mitochondrial fission via increases in ROS production during hyperglycemic conditions and hypertensive neuroencephalopathy , respectively [ XREF_BIBR , XREF_BIBR ] .	ERK1/2 and PKCdelta induces Drp1 mediated mitochondrial fission via increases in ROS production during hyperglycemic conditions and hypertensive neuroencephalopathy, respectively [XREF_BIBR, XREF_BIBR].	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Drp1	Drp1	Drp1	2	3	4	5
As shown in XREF_FIG ( XREF_SUPPLEMENTARY ) , we found that siPKCdelta treatment reduces PKCd binds to DRP1 protein levels following AGE-BSA exposure , suggesting that AGE-BSA promotes DRP1 protein activated by elevated PKCdelta phosphorylated .	As shown in XREF_FIG (XREF_SUPPLEMENTARY), we found that siPKCdelta treatment reduces PKCd binds to DRP1 protein levels following AGE-BSA exposure, suggesting that AGE-BSA promotes DRP1 protein activated by elevated PKCdelta phosphorylated.	28	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta phosphorylated	pkcdelta	DRP1	DRP1	drp1	33	34	28	29
YQFM Protects against H 2 O 2 -Induced Mitochondrial Fission through Inhibiting PKCdelta Mediated Drp1 Activation .	YQFM Protects against H 2 O 2 -Induced Mitochondrial Fission through Inhibiting PKCdelta Mediated Drp1 Activation.	11	15	Mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Drp1	Drp1	Drp1	12	13	14	15
PKCdelta and Cdk1 mediate an increase in Drp1 , mitochondrial fission , and cardiomyocyte death conferred by A/R injury .	PKCdelta and Cdk1 mediate an increase in Drp1, mitochondrial fission, and cardiomyocyte death conferred by A/R injury.	0	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Drp1	Drp1	Drp1	0	1	7	8
In contrast , the high PKCepsilon expression in melanoma cells induces predominantly nuclear localization of ATF2 , which attenuates its normal cytosolic function and correlates with resistance to genotoxic stress .	In contrast, the high PKCepsilon expression in melanoma cells induces predominantly nuclear localization of ATF2, which attenuates its normal cytosolic function and correlates with resistance to genotoxic stress.	5	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon expression	pkcepsilon	ATF2	ATF2	atf2	5	6	15	16
In contrast , phosphorylation of ATF2 on threonine 52 ( T52 ) by protein kinase C epsilon ( PKCepsilon ) promotes the nuclear localization and transcriptional activity of ATF2 , rendering the cells resistant to chemotherapeutic stress .	In contrast, phosphorylation of ATF2 on threonine 52 (T52) by protein kinase C epsilon (PKCepsilon) promotes the nuclear localization and transcriptional activity of ATF2, rendering the cells resistant to chemotherapeutic stress.	3	29	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	phosphorylation of ATF2 on threonine 52 (T52) by protein kinase C epsilon (PKCepsilon	pkcepsilon	ATF2	ATF2	atf2	18	19	28	29
The ability of ATF2 to reach the mitochondria is determined by PKCepsilon , which directs ATF2 nuclear localization .	The ability of ATF2 to reach the mitochondria is determined by PKCepsilon, which directs ATF2 nuclear localization.	9	17	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	ATF2	ATF2	ATF2	11	12	15	16
It is possible that , by driving the nuclear localization and activity of ATF2 , PKCepsilon might also promote the DNA repair function of ATF2 2 , further contributing to enhanced melanoma survival during therapeutic stress -- a point that deserves further investigation .	It is possible that, by driving the nuclear localization and activity of ATF2, PKCepsilon might also promote the DNA repair function of ATF2 2, further contributing to enhanced melanoma survival during therapeutic stress -- a point that deserves further investigation.	9	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	ATF2	ATF2	ATF2	15	16	13	14
The remodeling of Cx43 induced by the activation of PKCepsilon may therefore contribute to the formation of the arrhythmogenic substrate in the diabetic heart .	The remodeling of Cx43 induced by the activation of PKCepsilon may therefore contribute to the formation of the arrhythmogenic substrate in the diabetic heart.	1	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	Cx43	Cx43	Cx43	9	10	3	4
XREF_BIBR More recently , two studies showed that HuR phosphorylation at S221 by protein kinase C ( PKC ) alpha and PKCdelta induced HuR translocation to the cytoplasm in response to ATP and angiotensin II treatment , respectively .	XREF_BIBR More recently, two studies showed that HuR phosphorylation at S221 by protein kinase C (PKC) alpha and PKCdelta induced HuR translocation to the cytoplasm in response to ATP and angiotensin II treatment, respectively.	21	24	induced	Positive_early_activation	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	HuR	HuR	HuR	21	22	23	24
This series of events is crucial to elicit the death pathway triggered by doxorubicin and is necessary to promote HuR function in post-transcriptional regulation of gene expression , because genetic ablation of PKCdelta caused the inability of HuR to bind its target mRNAs , topoisomerase IIalpha ( TOP2A ) included .	This series of events is crucial to elicit the death pathway triggered by doxorubicin and is necessary to promote HuR function in post-transcriptional regulation of gene expression, because genetic ablation of PKCdelta caused the inability of HuR to bind its target mRNAs, topoisomerase IIalpha (TOP2A) included.	30	38	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	HuR	HuR	HuR	32	33	37	38
PKCdelta mediates activation of ASMase by cisplatin .	PKCdelta mediates activation of ASMase by cisplatin.	0	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	ASMase	ASMase	ASMase	0	1	4	5
Experiment 4a : PKCepsilon activation mediates agonist independent and agonist dependent internalization of mGluR5 in acute NAc slices .	Experiment 4a : PKCepsilon activation mediates agonist independent and agonist dependent internalization of mGluR5 in acute NAc slices.	3	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCepsilon	PKCepsilon	PKCepsilon	mGluR5	mGluR5	mGluR5	3	4	13	14
Furthermore , PKCdelta mediated activation of STAT1 required the activation of JNK , as the inhibition of JNK activity by its specific inhibitor or transfection of its dominant negative mutant suppressed both serine phosphorylation of STAT1 and PLSCR1 expression but not the activation of PKCdelta .	Furthermore, PKCdelta mediated activation of STAT1 required the activation of JNK, as the inhibition of JNK activity by its specific inhibitor or transfection of its dominant negative mutant suppressed both serine phosphorylation of STAT1 and PLSCR1 expression but not the activation of PKCdelta.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT1	STAT1	STAT1	2	3	6	7
XREF_BIBR Therefore , IFNalpha treatment induces an antileukemic process through PKCdelta mediated STAT1 activation .	XREF_BIBR Therefore, IFNalpha treatment induces an antileukemic process through PKCdelta mediated STAT1 activation.	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	STAT1	STAT1	STAT1	10	11	12	13
Collectively , these results suggest that phosphorylation of serine 504 by PKCdelta modulates the biological function of tNOX .	Collectively, these results suggest that phosphorylation of serine 504 by PKCdelta modulates the biological function of tNOX.	6	18	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	phosphorylation of serine 504 by PKCdelta	pkcdelta	tNOX	tNOX	tnox	11	12	17	18
In contrast , acetylation by p300 and pCAF or phosphorylation by c-Abl , p38MAPk or PKCdelta stimulate p73 activity .	In contrast, acetylation by p300 and pCAF or phosphorylation by c-Abl, p38MAPk or PKCdelta stimulate p73 activity.	9	18	stimulate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	p73	p73	p73	15	16	17	18
PKCtheta directs the T cell receptor ( TCR ) and CD28 dependent assembly of a CBM complex ( CARMA1 , BCL10 , and MALT1 ) for efficient activation of NF-kappaB , raising the question of whether other membrane bound receptors that activate NF-kappaB also require this PKCtheta-CBM axis to control TCR independent T cell activity .	PKCtheta directs the T cell receptor (TCR) and CD28 dependent assembly of a CBM complex (CARMA1, BCL10, and MALT1) for efficient activation of NF-kappaB, raising the question of whether other membrane bound receptors that activate NF-kappaB also require this PKCtheta-CBM axis to control TCR independent T cell activity.	0	23	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	CARMA1	CARMA1	CARMA1	0	1	18	19
Phosphorylation of caspase activation and recruitment domain ( CARD ) and membrane associated guanylate kinase ( MAGUK ) domain containing protein-1 ( CARMA1 ) by activated PKC-theta promotes CARMA1 to associate with Bcl10 ( B-lymphocyte lymphoma and leukemia 10 ) and mucosa associated lymphoid tissue 1 ( MALT1 ) proteins , which leads to activation of the IKK complex .	Phosphorylation of caspase activation and recruitment domain (CARD) and membrane associated guanylate kinase (MAGUK) domain containing protein-1 (CARMA1) by activated PKC-theta promotes CARMA1 to associate with Bcl10 (B-lymphocyte lymphoma and leukemia 10) and mucosa associated lymphoid tissue 1 (MALT1) proteins, which leads to activation of the IKK complex.	19	52	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PKC-theta	PKC-theta	PKC-theta	CARMA1	CARMA1	CARMA1	26	27	28	29
PKCtheta is recruited to the OX40-TRAF2 compartment , activates CARMA1 , and then induces the CBM complex to augment IKK activities .	PKCtheta is recruited to the OX40-TRAF2 compartment, activates CARMA1, and then induces the CBM complex to augment IKK activities.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	CARMA1	CARMA1	CARMA1	0	1	9	10
Further , our data suggest that this role connects to a well established pathway in which PKC-theta activates NF-kappaB after TCR-CD28 stimulation by mobilizing a Carma1 , Bcl-10 , MALT-1 signaling complex .	Further, our data suggest that this role connects to a well established pathway in which PKC-theta activates NF-kappaB after TCR-CD28 stimulation by mobilizing a Carma1, Bcl-10, MALT-1 signaling complex.	16	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC-theta	PKC-theta	PKC-theta	Carma1	Carma1	Carma1	16	17	25	26
8 PKCtheta activates CARMA1 ( also known as CARD11 ) bringing together Bcl10 and MALT1 leading to NF-kappaB activation .	8 PKCtheta activates CARMA1 (also known as CARD11) bringing together Bcl10 and MALT1 leading to NF-kappaB activation.	0	10	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	CARMA1	CARMA1	CARMA1	1	2	3	4
PKCtheta activation leads to CARMA1 , Bcl10 , and MALT1 ( CBM ) complexes that induce NFkappaB transcriptional activation and controls T-cell proliferation .	PKCtheta activation leads to CARMA1, Bcl10, and MALT1 (CBM) complexes that induce NFkappaB transcriptional activation and controls T-cell proliferation.	0	11	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	CARMA1	CARMA1	CARMA1	0	1	4	5
T cell receptor ( TCR ) signaling to IkappaB kinase ( IKK )/NF-kappaB is controlled by PKCtheta dependent activation of the Carma1 , Bcl10 , and Malt1 ( CBM ) complex .	T cell receptor (TCR) signaling to IkappaB kinase (IKK)/NF-kappaB is controlled by PKCtheta dependent activation of the Carma1, Bcl10, and Malt1 (CBM) complex.	16	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	Carma1	Carma1	Carma1	16	17	21	22
This suggests that unlike naive T cells , in which PKCtheta activates CARMA1 , T-ALL cells may activate CARMA1 independently of PKCtheta .	This suggests that unlike naive T cells, in which PKCtheta activates CARMA1, T-ALL cells may activate CARMA1 independently of PKCtheta.	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	CARMA1	CARMA1	CARMA1	10	11	12	13
These results indicate that early in APC : T cell conjugation , CARD11 populates the area of cell : cell contact , but its occupancy at the center of the IS is reduced shortly thereafter by a redistribution to distal areas that limits the duration of its colocalization with PKCtheta , a key kinase that activates CARD11 scaffold function during TCR signaling .	These results indicate that early in APC : T cell conjugation, CARD11 populates the area of cell : cell contact, but its occupancy at the center of the IS is reduced shortly thereafter by a redistribution to distal areas that limits the duration of its colocalization with PKCtheta, a key kinase that activates CARD11 scaffold function during TCR signaling.	42	58	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	CARD11	CARD11	CARD11	49	50	56	57
In summary , our data show that PKCtheta mediated induction of insulin resistance occurring simultaneously with PKCtheta mediated HSF1 activation is responsible for EA cytotoxicity .	In summary, our data show that PKCtheta mediated induction of insulin resistance occurring simultaneously with PKCtheta mediated HSF1 activation is responsible for EA cytotoxicity.	13	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	HSF1	HSF1	HSF1	16	17	18	19
PKCtheta induces heat shock independent activation of HSF1 .	PKCtheta induces heat shock independent activation of HSF1.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	HSF1	HSF1	HSF1	0	1	7	8
Second , PKCtheta activation causes production of HSF1 , which enhances the glucose dependence of the cells .	Second, PKCtheta activation causes production of HSF1, which enhances the glucose dependence of the cells.	2	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	HSF1	HSF1	HSF1	2	3	7	8
Since dissociation of HSF1 from HSP90 is a prerequisite for HSF1 activation and nuclear translocation , these data provide a mechanistic basis to explain PKCtheta dependent activation of HSF1 by EA .	Since dissociation of HSF1 from HSP90 is a prerequisite for HSF1 activation and nuclear translocation, these data provide a mechanistic basis to explain PKCtheta dependent activation of HSF1 by EA.	24	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	HSF1	HSF1	HSF1	24	25	28	29
We previously established a link between PKCtheta and HSF1 , a transcription factor known to induce tumor glucose dependency [ XREF_BIBR , XREF_BIBR ] , namely direct phosphorylation and heat-shock-independent activation of HSF1 by PKCtheta [ XREF_BIBR ] .	We previously established a link between PKCtheta and HSF1, a transcription factor known to induce tumor glucose dependency [XREF_BIBR, XREF_BIBR], namely direct phosphorylation and heat-shock-independent activation of HSF1 by PKCtheta [XREF_BIBR].	30	36	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	HSF1	HSF1	HSF1	34	35	32	33
PKCtheta activates HSF1 by phosphorylating serine 333 in the stress responsive regulatory domain .	PKCtheta activates HSF1 by phosphorylating serine 333 in the stress responsive regulatory domain.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	HSF1	HSF1	HSF1	0	1	2	3
As the current study has demonstrated that PrKD1 increases nuclear beta-catenin and published literature supports beta-catenin as a co-activator of AR , we explored whether the PrKD1 dependent increase in nuclear beta-catenin influenced AR transcriptional activity by studying the expression of a sample of AR responsive genes .	As the current study has demonstrated that PrKD1 increases nuclear beta-catenin and published literature supports beta-catenin as a co-activator of AR, we explored whether the PrKD1 dependent increase in nuclear beta-catenin influenced AR transcriptional activity by studying the expression of a sample of AR responsive genes.	26	32	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PrKD1	PrKD1	PrKD1	beta-catenin	beta-catenin	beta-catenin	26	27	31	32
27 Notably , protein kinase D modulates the E-cadherin and beta-catenin pathway , which is critical for synaptic plasticity .	27 Notably, protein kinase D modulates the E-cadherin and beta-catenin pathway, which is critical for synaptic plasticity.	3	11	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein kinase D	protein kinase D	protein kinase D	beta-catenin	beta-catenin	beta-catenin	3	6	10	11
Down regulation of PrKD1 increases the nuclear beta-catenin .	Down regulation of PrKD1 increases the nuclear beta-catenin.	1	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PrKD1	PrKD1	PrKD1	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
Cardiac specific overexpression of PKD results in a dilated cardiomyopathy with elevated fetal genes that are normally controlled by MEF2 , supporting the pathological role of PKD [ XREF_BIBR ] .	Cardiac specific overexpression of PKD results in a dilated cardiomyopathy with elevated fetal genes that are normally controlled by MEF2, supporting the pathological role of PKD [XREF_BIBR].	2	28	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKD	overexpression of PKD	pkd	PKD	PKD	pkd	4	5	26	27
Intriguingly , prior exposure to the adenylyl cyclase activator forskolin ( 1 microM for 5 min ) or the beta-adrenergic agonist isoprenaline ( 100 nM for 5 min ) markedly attenuated ET1 induced PKD activation , but not PMA induced PKD activation .	Intriguingly, prior exposure to the adenylyl cyclase activator forskolin (1 microM for 5 min) or the beta-adrenergic agonist isoprenaline (100 nM for 5 min) markedly attenuated ET1 induced PKD activation, but not PMA induced PKD activation.	31	41	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKD	ET1 induced PKD	pkd	PKD	PKD	pkd	33	34	40	41
By using a phospho specific antibody , we show that Abl directly phosphorylates PKD at Tyr ( 463 ) in vitro , and in cells phosphorylation of this site is sufficient to mediate full activation of PKD .	By using a phospho specific antibody, we show that Abl directly phosphorylates PKD at Tyr (463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of PKD.	10	37	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKD	Abl directly phosphorylates PKD at Tyr (463	pkd	PKD	PKD	pkd	13	14	36	37
PRKCQ and PKCtheta expression is relatively greater in human triple negative tumors compared to other subtypes , further supporting PRKCQ and PKCtheta as a candidate therapeutic target for this subtype .	PRKCQ and PKCtheta expression is relatively greater in human triple negative tumors compared to other subtypes, further supporting PRKCQ and PKCtheta as a candidate therapeutic target for this subtype.	0	22	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRKCQ	PRKCQ and PKCtheta expression	prkcq	PKCtheta	PKCtheta	pkctheta	0	1	21	22
PDK1 then induces phosphorylation of PKCtheta on Thr 538 and thereby promotes the recruitment of PKCtheta to lipid rafts and induces activation of PKCtheta .	PDK1 then induces phosphorylation of PKCtheta on Thr 538 and thereby promotes the recruitment of PKCtheta to lipid rafts and induces activation of PKCtheta.	0	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCtheta	PDK1 then induces phosphorylation of PKCtheta on Thr 538	pkctheta	PKCtheta	PKCtheta	pkctheta	5	6	15	16
The preliminary data indicated that compared with the unstimulated group ( PKC theta and beta-tubulin from densitometry analysis : 0.62 ) , PHA stimulation attenuated PKC theta levels ( PKC theta and beta-tubulin from densitometry analysis : 0.32 ) and 4-HM ( 10muM ) could restore this level ( PKC theta and beta-tubulin from densitometry analysis : 0.58 ) .	The preliminary data indicated that compared with the unstimulated group (PKC theta and beta-tubulin from densitometry analysis : 0.62), PHA stimulation attenuated PKC theta levels (PKC theta and beta-tubulin from densitometry analysis : 0.32) and 4-HM (10muM) could restore this level (PKC theta and beta-tubulin from densitometry analysis : 0.58).	25	51	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKC theta	PKC theta levels	pkc theta	PKC theta	PKC theta	pkc theta	25	27	49	51
Our data suggest that the suppression of CKIP-1 can work in a resting state or against aberrant PKCtheta activation such as expression of constitutively active PKCtheta or treatment of PMA .	Our data suggest that the suppression of CKIP-1 can work in a resting state or against aberrant PKCtheta activation such as expression of constitutively active PKCtheta or treatment of PMA.	17	27	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	PKCtheta	expression of constitutively active PKCtheta	pkctheta	PKCtheta	PKCtheta	pkctheta	25	26	17	18
Activation of PKD enhances Bit1 function in anoikis , whereas inhibiting PKD function with pharmacological inhibitors or small interfering RNA compromises the ability of Bit1 to induce anoikis .	Activation of PKD enhances Bit1 function in anoikis, whereas inhibiting PKD function with pharmacological inhibitors or small interfering RNA compromises the ability of Bit1 to induce anoikis.	0	5	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKD	PKD	PKD	Bit1	Bit1	Bit1	2	3	4	5
Overexpression of constitutively active PKD or PKD activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues ( Ser5 and Ser87 ) in a form of Bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic Bit1 .	Overexpression of constitutively active PKD or PKD activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (Ser5 and Ser87) in a form of Bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic Bit1.	0	46	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKD	Overexpression of constitutively active PKD or PKD	pkd	Bit1	Bit1	bit1	6	7	45	46
Indeed , activation of PKD enhanced the mitochondrial release of Bit1 with concomitant induction of the Bit1 anoikis function .	Indeed, activation of PKD enhanced the mitochondrial release of Bit1 with concomitant induction of the Bit1 anoikis function.	2	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKD	PKD	PKD	Bit1	Bit1	Bit1	4	5	10	11
It is known that PKD can both activate PI4KB and inhibit OSBP and CERT , thus acting as a key regulator of lipid transport in the ER and Golgi membranes .	It is known that PKD can both activate PI4KB and inhibit OSBP and CERT, thus acting as a key regulator of lipid transport in the ER and Golgi membranes.	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKD	PKD	PKD	PI4KB	PI4KB	PI4KB	4	5	8	9
At the trans-Golgi network ( TGN ) , PKD activates PI4KB to generate phosphatidylinositol 4-phosphate ( PI4P ) , which mediates the Golgi membrane localization of CERT and OSBP through their pleckstrin homology ( PH ) domains , and PKD phosphorylation of CERT and OSBP inhibits their functions .	At the trans-Golgi network (TGN), PKD activates PI4KB to generate phosphatidylinositol 4-phosphate (PI4P), which mediates the Golgi membrane localization of CERT and OSBP through their pleckstrin homology (PH) domains, and PKD phosphorylation of CERT and OSBP inhibits their functions.	8	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKD	PKD	PKD	PI4KB	PI4KB	PI4KB	8	9	10	11
In addition , PKCtheta , a target of mTORC2 , activates WIP via S488 phosphorylation in lymphocytes .	In addition, PKCtheta, a target of mTORC2, activates WIP via S488 phosphorylation in lymphocytes.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCtheta	PKCtheta	PKCtheta	WIP	WIP	WIP	3	4	11	12
PKCgamma also modulate the function of GluR4 containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ( AMPA ) receptors by directly binding to GluR4 in the cerebellum ; phosphorylation by PKC seems to target the receptor to the plasma membrane [ XREF_BIBR ] .	PKCgamma also modulate the function of GluR4 containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by directly binding to GluR4 in the cerebellum; phosphorylation by PKC seems to target the receptor to the plasma membrane [XREF_BIBR].	0	7	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCgamma	PKCgamma	PKCgamma	GluR4	GluR4	GluR4	0	1	6	7
DNA-PKcs also activates Akt via phosphorylation of Ser473 , which in turn inactivates GSK-3beta via phosphorylation of Ser9 , resulting in the stabilization of c-Myc [ XREF_BIBR ] .	DNA-PKcs also activates Akt via phosphorylation of Ser473, which in turn inactivates GSK-3beta via phosphorylation of Ser9, resulting in the stabilization of c-Myc [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Akt	Akt	Akt	0	1	3	4
In parallel to the activation of DNA-PKcs by Akt1 , in the complex formed between Akt1 and DNA-PKcs , XREF_BIBR , XREF_BIBR Akt is also activated by DNA-PKcs .	In parallel to the activation of DNA-PKcs by Akt1, in the complex formed between Akt1 and DNA-PKcs, XREF_BIBR, XREF_BIBR Akt is also activated by DNA-PKcs.	19	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Akt	Akt	Akt	27	28	22	23
We next tried to indentify the intermediate player of AKT activation by PERK by focus on DNA-PKcs , a recently discovered PI3K member that can activate AKT XREF_BIBR - XREF_BIBR .	We next tried to indentify the intermediate player of AKT activation by PERK by focus on DNA-PKcs, a recently discovered PI3K member that can activate AKT XREF_BIBR - XREF_BIBR.	4	27	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	AKT	AKT	AKT	16	17	26	27
DNA-PKcs , forms a complex with PERK , mediates AKT activation by Wogonin .	DNA-PKcs, forms a complex with PERK, mediates AKT activation by Wogonin.	0	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	AKT	AKT	AKT	0	1	9	10
For example , in response to IR , DNA-PKcs promotes cell survival through phosphorylation of Thr308 and Ser473 ( this site is also phosphorylated by mTORC2 , see below ) residues of Akt ( also called PKB ) together with PDK1 and the subsequent transcriptional regulation of the p53-p21 pathway .	For example, in response to IR, DNA-PKcs promotes cell survival through phosphorylation of Thr308 and Ser473 (this site is also phosphorylated by mTORC2, see below) residues of Akt (also called PKB) together with PDK1 and the subsequent transcriptional regulation of the p53-p21 pathway.	8	37	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	PKB	PKB	PKB	8	9	36	37
Recent studies have shed lights on how DNA-PKcs activates AKT .	Recent studies have shed lights on how DNA-PKcs activates AKT.	7	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	AKT	AKT	AKT	7	8	9	10
During DNA damage due to ionizing radiation , DNA-PKcs activates Akt via phosphorylation of the hydrophobic motif at S473 .	During DNA damage due to ionizing radiation, DNA-PKcs activates Akt via phosphorylation of the hydrophobic motif at S473.	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Akt	Akt	Akt	8	9	10	11
These latter mechanisms may be driven by components of other DNA repair pathway components , for example , DNA-PKcs that drives AKT survival signaling in HGSOC , and will be discussed now .	These latter mechanisms may be driven by components of other DNA repair pathway components, for example, DNA-PKcs that drives AKT survival signaling in HGSOC, and will be discussed now.	16	30	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	AKT	AKT	AKT	18	19	21	22
We further observed that KU0060648 caused a strong and dose dependent decrease in AKT phosphorylation ( p-AKT Ser 473 ) of U87 and M059K cells using immunoblotting , which indicated that inhibition of DNA-PKcs could suppress the activation of AKT in glioma cells .	We further observed that KU0060648 caused a strong and dose dependent decrease in AKT phosphorylation (p-AKT Ser 473) of U87 and M059K cells using immunoblotting, which indicated that inhibition of DNA-PKcs could suppress the activation of AKT in glioma cells.	31	40	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	AKT	AKT	AKT	33	34	39	40
Therefore , we suggest another pathway of DNA-PKcs affecting the H2AX phosphorylation level , i.e ., DNA-PKcs activates Akt via phosphorylation on Ser473 , which in turn inactivates GSK3beta via phosphorylating Ser9 [ XREF_BIBR ] .	Therefore, we suggest another pathway of DNA-PKcs affecting the H2AX phosphorylation level, i.e., DNA-PKcs activates Akt via phosphorylation on Ser473, which in turn inactivates GSK3beta via phosphorylating Ser9 [XREF_BIBR].	14	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Akt	Akt	Akt	16	17	18	19
The DLD-1 parental and the different AKT isoform KO cell lines were treated with siRNA against DNA-PKcs and irradiated ( 4Gy ) in the presence of 10 % FBS or 0.5 % FBS .	The DLD-1 parental and the different AKT isoform KO cell lines were treated with siRNA against DNA-PKcs and irradiated (4Gy) in the presence of 10% FBS or 0.5% FBS.	6	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	AKT	AKT	AKT	16	17	6	7
Furthermore , IKBKE or IKKepsilon ( I-kappa-B kinase epsilon ) , TANK binding kinase 1 ( TBK1 ) and DNA-PKcs have been shown to directly activate Akt [ XREF_BIBR - XREF_BIBR ] .	Furthermore, IKBKE or IKKepsilon (I-kappa-B kinase epsilon), TANK binding kinase 1 (TBK1) and DNA-PKcs have been shown to directly activate Akt [XREF_BIBR - XREF_BIBR].	2	28	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Akt	Akt	Akt	19	20	26	27
Suppression of PRKDC could inhibit the AKT pathway , EMT , and the migration and invasion of CRC cells .	Suppression of PRKDC could inhibit the AKT pathway, EMT, and the migration and invasion of CRC cells.	0	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PRKDC	PRKDC	PRKDC	AKT	AKT	AKT	2	3	6	7
Interestingly , suppression of DNA-PKcs with siRNA also reduced the activation of AKT in DLD-1 but not in HCT116 .	Interestingly, suppression of DNA-PKcs with siRNA also reduced the activation of AKT in DLD-1 but not in HCT116.	2	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	AKT	AKT	AKT	4	5	12	13
Importantly , we found that DNA-PKcs , AKT and PERK form a complex in Wogonin treated cells , which is reversed by pre-treatment with DNA-PKcs inhibitor Nu 7062 ( XREF_FIG ) , based on this information , we suggest that DNA-PKcs , forms a complex with PERK , mediates AKT activation by wogonin .	Importantly, we found that DNA-PKcs, AKT and PERK form a complex in Wogonin treated cells, which is reversed by pre-treatment with DNA-PKcs inhibitor Nu 7062 (XREF_FIG), based on this information, we suggest that DNA-PKcs, forms a complex with PERK, mediates AKT activation by wogonin.	40	50	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	AKT	AKT	AKT	40	41	49	50
Finally , DNA-PKcs has been shown to activate Akt as so called PDK2 in the nucleus upon DNA damage .	Finally, DNA-PKcs has been shown to activate Akt as so called PDK2 in the nucleus upon DNA damage.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Akt	Akt	Akt	2	3	8	9
In addition , DNA-PKcs could activate Akt in response to genotoxic stresses [ XREF_BIBR ] .	In addition, DNA-PKcs could activate Akt in response to genotoxic stresses [XREF_BIBR].	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Akt	Akt	Akt	3	4	6	7
DNA-PKcs stimulates WRN helicase activity on telomeric D-loops .	DNA-PKcs stimulates WRN helicase activity on telomeric D-loops.	0	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	0	1	2	3
Equally interesting will be to determine the molecular mechanism by which DNA-PKcs stimulates the helicase activity of WRN and whether the DNA-PKcs binding partner , Ku , plays a role in this process .	Equally interesting will be to determine the molecular mechanism by which DNA-PKcs stimulates the helicase activity of WRN and whether the DNA-PKcs binding partner, Ku, plays a role in this process.	11	18	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	11	12	17	18
The results suggest that DNA-PKcs stimulates WRN helicase on a telomeric D-loop substrate , but not on a G tailed DNA duplex , an open form of a telomeric D-loop .	The results suggest that DNA-PKcs stimulates WRN helicase on a telomeric D-loop substrate, but not on a G tailed DNA duplex, an open form of a telomeric D-loop.	4	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	4	5	6	7
Interestingly , the authors have also shown that DNA-PKcs stimulates the activity of WRN towards D-loops composed of non telomeric DNA sequences , suggesting that these findings may extend to D-loop structures formed during other nuclear processes such as homologous recombination .	Interestingly, the authors have also shown that DNA-PKcs stimulates the activity of WRN towards D-loops composed of non telomeric DNA sequences, suggesting that these findings may extend to D-loop structures formed during other nuclear processes such as homologous recombination.	8	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	8	9	13	14
This study demonstrates that DNA-PKcs stimulates the apparent processivity of WRN helicase but not WRN exonuclease on telomeric and non telomeric D-loop substrates in vitro and that overexpression of WRN helicase reverses telomere G-tail shortening in vivo caused by knockdown of DNA-PKcs in U-2 OS cells .	This study demonstrates that DNA-PKcs stimulates the apparent processivity of WRN helicase but not WRN exonuclease on telomeric and non telomeric D-loop substrates in vitro and that overexpression of WRN helicase reverses telomere G-tail shortening in vivo caused by knockdown of DNA-PKcs in U-2 OS cells.	4	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	4	5	10	11
DNA-PKcs stimulates WRN helicase activity on non- telomeric D-loops .	DNA-PKcs stimulates WRN helicase activity on non- telomeric D-loops.	0	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	0	1	2	3
DNA-PKcs , a telomere associated protein , stimulates WRN helicase activity on telomeric D-loop substrates .	DNA-PKcs, a telomere associated protein, stimulates WRN helicase activity on telomeric D-loop substrates.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	0	1	8	9
In contrast , DNA-PKcs stimulates the WRN helicase but not the WRN exonuclease ; however , the WRN exonuclease is also stimulated by XRCC4 and LIG4 .	In contrast, DNA-PKcs stimulates the WRN helicase but not the WRN exonuclease; however, the WRN exonuclease is also stimulated by XRCC4 and LIG4.	3	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	3	4	6	7
DNA-PKcs stimulates WRN helicase activity on D-loop substrates .	DNA-PKcs stimulates WRN helicase activity on D-loop substrates.	0	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	0	1	2	3
DNA-PKcs does not stimulate WRN helicase on non-D-loop DNA substrates .	DNA-PKcs does not stimulate WRN helicase on non-D-loop DNA substrates.	0	5	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	0	1	4	5
These results suggest that DNA-PKcs may stimulate WRN helicase activity on D-loop structures in telomeric or non telomeric DNA because the stimulation appears to be independent of the nucleotide sequence of the DNA substrate in vitro .	These results suggest that DNA-PKcs may stimulate WRN helicase activity on D-loop structures in telomeric or non telomeric DNA because the stimulation appears to be independent of the nucleotide sequence of the DNA substrate in vitro.	4	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	4	5	7	8
These results indicate that DNA-PKcs stimulates the processivity of WRN helicase on the D-loop substrate but not on other DNA substrates examined in this study .	These results indicate that DNA-PKcs stimulates the processivity of WRN helicase on the D-loop substrate but not on other DNA substrates examined in this study.	4	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	4	5	9	10
These results suggest that DNA-PKcs stimulates WRN helicase , possibly by increasing its processivity , and that this stimulation is independent of WRN exonuclease .	These results suggest that DNA-PKcs stimulates WRN helicase, possibly by increasing its processivity, and that this stimulation is independent of WRN exonuclease.	4	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	4	5	6	7
The key points of the model are as follows : 1 ) In the absence of DNA-PKcs and WRN exonuclease , WRN helicase dissociates from DNA prior to release of a full-length invading strand , resulting in reannealing of the unwound region ; 2 ) when WRN exonuclease degrades the 3 ' tail of the invading strand , WRN helicase releases the shortened invading strand , even in the absence of DNA-PKcs ; 3 ) DNA-PKcs stimulates WRN processivity , so that exonuclease deficient WRN or WRN is able to release an intact or nearly intact invading strand from the D-loop , respectively .	The key points of the model are as follows : 1) In the absence of DNA-PKcs and WRN exonuclease, WRN helicase dissociates from DNA prior to release of a full-length invading strand, resulting in reannealing of the unwound region; 2) when WRN exonuclease degrades the 3 ' tail of the invading strand, WRN helicase releases the shortened invading strand, even in the absence of DNA-PKcs; 3) DNA-PKcs stimulates WRN processivity, so that exonuclease deficient WRN or WRN is able to release an intact or nearly intact invading strand from the D-loop, respectively.	75	102	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	75	76	77	78
However , the mechanism ( s ) of this stimulation may differ from the mechanism by which DNA-PKcs stimulates WRN helicase .	However, the mechanism (s) of this stimulation may differ from the mechanism by which DNA-PKcs stimulates WRN helicase.	17	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	17	18	19	20
The results also indicate that DNA-PKcs stimulates WRN catalyzed unwinding of non telomeric D-loop , implying that WRN and DNA-PKcs could cooperate to unwind recombination associated D-loops in genomic regions other than the telomere .	The results also indicate that DNA-PKcs stimulates WRN catalyzed unwinding of non telomeric D-loop, implying that WRN and DNA-PKcs could cooperate to unwind recombination associated D-loops in genomic regions other than the telomere.	5	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	5	6	7	8
DNA-PKcs modulates WRN processing of telomeric D-loops .	DNA-PKcs modulates WRN processing of telomeric D-loops.	0	3	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	0	1	2	3
In this issue of Aging , Kusumoto-Matsuo and colleagues [ XREF_BIBR ] report that DNA-PKcs stimulates the helicase activity of WRN towards model D loop structures in vitro .	In this issue of Aging, Kusumoto-Matsuo and colleagues [XREF_BIBR] report that DNA-PKcs stimulates the helicase activity of WRN towards model D loop structures in vitro.	14	25	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	14	15	20	21
DNA-PKcs did not stimulate WRN helicase on this DNA substrate .	DNA-PKcs did not stimulate WRN helicase on this DNA substrate.	0	5	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	0	1	4	5
They provided evidence that DNA-PKcs can specifically stimulate WRN helicase and prevent telomeric D-loop from exonuclease digestion in vitro and in vivo .	They provided evidence that DNA-PKcs can specifically stimulate WRN helicase and prevent telomeric D-loop from exonuclease digestion in vitro and in vivo.	4	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	4	5	8	9
The results show that DNA-PKcs selectively stimulates WRN helicase but not WRN exonuclease in vitro , affecting that WRN helicase unwinds and promotes the release of the full-length invading strand of a telomere D-loop model substrate .	The results show that DNA-PKcs selectively stimulates WRN helicase but not WRN exonuclease in vitro, affecting that WRN helicase unwinds and promotes the release of the full-length invading strand of a telomere D-loop model substrate.	4	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	4	5	7	8
Prolactin mediated stimulation of prolactin receptor ( PRLR ) appears to be the canonical and primary means of activating STAT5 at this stage .	Prolactin mediated stimulation of prolactin receptor (PRLR) appears to be the canonical and primary means of activating STAT5 at this stage.	0	6	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Prolactin	Prolactin	Prolactin	prolactin receptor	prolactin receptor	prolactin receptor	0	1	4	6
Based on the assumption that the prolactin receptor ( PRLR ) is activated by PRL induced sequential dimerization , potential human PRL ( hPRL ) antagonists were designed that sterically interfere with binding site 2 .	Based on the assumption that the prolactin receptor (PRLR) is activated by PRL induced sequential dimerization, potential human PRL (hPRL) antagonists were designed that sterically interfere with binding site 2.	6	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PRL	PRL	PRL	prolactin receptor	prolactin receptor	prolactin receptor	14	15	6	8
Prolactin activates the prolactin receptor associated Jak2 tyrosine kinase and downstream signaling proteins , including signal transducer and activator of transcription-5a ( Stat5a ) and Stat5b .	Prolactin activates the prolactin receptor associated Jak2 tyrosine kinase and downstream signaling proteins, including signal transducer and activator of transcription-5a (Stat5a) and Stat5b.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Prolactin	Prolactin	Prolactin	prolactin receptor	prolactin receptor	prolactin receptor	0	1	3	5
Essential role of endogenous prolactin and CDK7 in estrogen induced upregulation of the prolactin receptor in breast cancer cells .	Essential role of endogenous prolactin and CDK7 in estrogen induced upregulation of the prolactin receptor in breast cancer cells.	1	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	prolactin	prolactin	prolactin	prolactin receptor	prolactin receptor	prolactin receptor	4	5	13	15
The authors demonstrated that both estradiol and prolactin induced prolactin receptor in the gonadotropin releasing hormone ( GnRH ) neurons derived from transgenic mice expressing Green Fluorescent Protein ( GFP ) under the control of GnRH promoter ( GnRH-GFP ) and implicated it in LH suppression .	The authors demonstrated that both estradiol and prolactin induced prolactin receptor in the gonadotropin releasing hormone (GnRH) neurons derived from transgenic mice expressing Green Fluorescent Protein (GFP) under the control of GnRH promoter (GnRH-GFP) and implicated it in LH suppression.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	prolactin	prolactin	prolactin	prolactin receptor	prolactin receptor	prolactin receptor	7	8	9	11
Our studies have shown that prolactin produced in breast cancer cells through intracrine activation of PRLR and via at least two signal transduction pathways , JAK2 and STAT5 and JAK2/PI3K/MEK/ERK , up-regulates the human prolactin receptor .	Our studies have shown that prolactin produced in breast cancer cells through intracrine activation of PRLR and via at least two signal transduction pathways, JAK2 and STAT5 and JAK2/PI3K/MEK/ERK, up-regulates the human prolactin receptor.	5	36	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	prolactin	prolactin	prolactin	prolactin receptor	prolactin receptor	prolactin receptor	5	6	34	36
Nectin-4 of this apparatus further cis interacted with the prolactin receptor in the luminal cells to enhance the prolactin induced prolactin receptor signaling for alveolar development with lactogenic differentiation .	Nectin-4 of this apparatus further cis interacted with the prolactin receptor in the luminal cells to enhance the prolactin induced prolactin receptor signaling for alveolar development with lactogenic differentiation.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	prolactin	prolactin	prolactin	prolactin receptor	prolactin receptor	prolactin receptor	18	19	20	22
Since the presence of prolactin receptors was earlier demonstrated in hypothalamic dopaminergic neurons , our working hypothesis was that prolactin induced activation of prolactin receptor coupled signaling leads to increased neuronal activity in these neurons .	Since the presence of prolactin receptors was earlier demonstrated in hypothalamic dopaminergic neurons, our working hypothesis was that prolactin induced activation of prolactin receptor coupled signaling leads to increased neuronal activity in these neurons.	19	25	induced	Positive_early_activation	Positive_activation	Positive_activation	prolactin	prolactin	prolactin	prolactin receptor	prolactin receptor	prolactin receptor	19	20	23	25
Mouse prolactin failed to induce human prolactin receptor mediated biologic responses of cell clustering , proliferation , gene induction and signal transduction , including activation of Stat5 , Stat3 , Erk1/2 and Akt pathways .	Mouse prolactin failed to induce human prolactin receptor mediated biologic responses of cell clustering, proliferation, gene induction and signal transduction, including activation of Stat5, Stat3, Erk1/2 and Akt pathways.	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	prolactin	prolactin	prolactin	prolactin receptor	prolactin receptor	prolactin receptor	1	2	6	8
We previously showed that the Ig like cell-adhesion molecule nectin-4 cis -interacts with the prolactin receptor through the extracellular region and stimulates prolactin induced prolactin receptor activation and signaling , resulting in alveolar development in the mouse mammary gland .	We previously showed that the Ig like cell-adhesion molecule nectin-4 cis -interacts with the prolactin receptor through the extracellular region and stimulates prolactin induced prolactin receptor activation and signaling, resulting in alveolar development in the mouse mammary gland.	22	26	induced	Positive_early_activation	Positive_activation	Positive_activation	prolactin	prolactin	prolactin	prolactin receptor	prolactin receptor	prolactin receptor	22	23	24	26
Both the interaction of nectin-4 with the extracellular region of the prolactin receptor and the interaction of SOCS1 with the cytoplasmic region of nectin-4 were required for the stimulatory effect of nectin-4 on the prolactin induced prolactin receptor activation .	Both the interaction of nectin-4 with the extracellular region of the prolactin receptor and the interaction of SOCS1 with the cytoplasmic region of nectin-4 were required for the stimulatory effect of nectin-4 on the prolactin induced prolactin receptor activation.	25	38	induced	Positive_early_activation	Positive_activation	Positive_activation	prolactin	prolactin	prolactin	prolactin receptor	prolactin receptor	prolactin receptor	34	35	36	38
For example , loss of DNA-PKcs promotes a p53 dependent checkpoint in ATM sufficient thymocytes , but severely impairs p53 dependent apoptosis in ATM -/- thymocytes ( XREF_FIG ) .	For example, loss of DNA-PKcs promotes a p53 dependent checkpoint in ATM sufficient thymocytes, but severely impairs p53 dependent apoptosis in ATM -/- thymocytes (XREF_FIG).	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	loss of DNA-PKcs	dna-pkcs	p53	p53	p53	5	6	8	9
Taken together , our results support a model in which the upstream effectors DNA-PKcs and Atm selectively activate p53 to differentially regulate cell-cycle and apoptotic responses .	Taken together, our results support a model in which the upstream effectors DNA-PKcs and Atm selectively activate p53 to differentially regulate cell-cycle and apoptotic responses.	10	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	p53	p53	p53	13	14	18	19
In contrast , our results strongly suggest that ATM and DNA-PKcs collaborate to promote p53 activation in irradiated thymocytes and B cells undergoing CSR .	In contrast, our results strongly suggest that ATM and DNA-PKcs collaborate to promote p53 activation in irradiated thymocytes and B cells undergoing CSR.	8	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	p53	p53	p53	10	11	14	15
Prolonged absence of DNA-PKcs in MO59J cells might have caused inadequate regulation of p53 .	Prolonged absence of DNA-PKcs in MO59J cells might have caused inadequate regulation of p53.	1	14	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	p53	p53	p53	3	4	13	14
The data indicate that additional loss of DNA-PKcs in p53 deficient cells reverses anthracycline-resistance imposed by p53-deficiency , and that DNA-PKcs modulates p53 independent pathways responding to DNA damage induced by anthracyclines .	The data indicate that additional loss of DNA-PKcs in p53 deficient cells reverses anthracycline-resistance imposed by p53-deficiency, and that DNA-PKcs modulates p53 independent pathways responding to DNA damage induced by anthracyclines.	20	24	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	p53	p53	p53	20	21	22	23
These results indicate that ATR and DNA-PKcs alone induce regular p53 dynamics and are able to compensate the loss of the two other kinases .	These results indicate that ATR and DNA-PKcs alone induce regular p53 dynamics and are able to compensate the loss of the two other kinases.	4	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	p53	p53	p53	6	7	10	11
DNA-PKcs causes the Artemis : DNA and PKcs complex to favor junctions of ssDNA and dsDNA .	DNA-PKcs causes the Artemis : DNA and PKcs complex to favor junctions of ssDNA and dsDNA.	0	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	0	1	3	4
Artemis then binds and is activated through phosphorylation by DNA-PKcs .	Artemis then binds and is activated through phosphorylation by DNA-PKcs.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	9	10	0	1
Therefore , the conformational change in Artemis induced by DNA-PKcs appears to be the primary event that permits Artemis to acquire endonucleolytic activity .	Therefore, the conformational change in Artemis induced by DNA-PKcs appears to be the primary event that permits Artemis to acquire endonucleolytic activity.	4	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	9	10	6	7
DNA-PKcs promotes the hairpin opening activity of the Artemis nuclease .	DNA-PKcs promotes the hairpin opening activity of the Artemis nuclease.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	0	1	8	9
DNA-PKcs deficiency leads to a nearly complete block in coding join formation , as DNA-PKcs is required to activate Artemis , the endonuclease that opens hairpin sealed coding ends .	DNA-PKcs deficiency leads to a nearly complete block in coding join formation, as DNA-PKcs is required to activate Artemis, the endonuclease that opens hairpin sealed coding ends.	14	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	14	15	19	20
DNA-PKcs kinase activity is needed to activate Artemis and maintain it at the DNA damage site XREF_BIBR .	DNA-PKcs kinase activity is needed to activate Artemis and maintain it at the DNA damage site XREF_BIBR.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	0	1	7	8
The kinase activity of DNA-PKcs is required to activate the endonucleolytic activity of Artemis .	The kinase activity of DNA-PKcs is required to activate the endonucleolytic activity of Artemis.	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	4	5	13	14
In vitro , DNA-PKcs enables Artemis to cleave dsDNA [ XREF_BIBR ] , and it was shown to cleave stalled forks after prolonged arrest [ XREF_BIBR ] .	In vitro, DNA-PKcs enables Artemis to cleave dsDNA [XREF_BIBR], and it was shown to cleave stalled forks after prolonged arrest [XREF_BIBR].	1	7	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	3	4	5	6
Prior to joining , hairpin coding ends are nicked open through the endonuclease activity of the nuclear enzyme Artemis , which complexes with the serine/threonine kinase DNA-PKcs , which , in turn , activates Artemis by phosphorylation [ XREF_BIBR , XREF_BIBR ] .	Prior to joining, hairpin coding ends are nicked open through the endonuclease activity of the nuclear enzyme Artemis, which complexes with the serine/threonine kinase DNA-PKcs, which, in turn, activates Artemis by phosphorylation [XREF_BIBR, XREF_BIBR].	25	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	26	27	34	35
This shows that pre-autophosphorylation of DNA-PKcs is sufficient to stimulate the ssDNA endonuclease activity of Artemis , just like the dsDNA endonuclease of Artemis : DNA-PKcs ( XREF_FIG lane 4 versus lane 8 ) .	This shows that pre-autophosphorylation of DNA-PKcs is sufficient to stimulate the ssDNA endonuclease activity of Artemis, just like the dsDNA endonuclease of Artemis : DNA-PKcs (XREF_FIG lane 4 versus lane 8).	3	16	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	pre-autophosphorylation of DNA-PKcs	dna-pkcs	Artemis	Artemis	artemis	5	6	15	16
Artemis is activated by the autophosphorylation of DNA-PKcs .	Artemis is activated by the autophosphorylation of DNA-PKcs.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DNA-PKcs	autophosphorylation of DNA-PKcs	dna-pkcs	Artemis	Artemis	artemis	7	8	0	1
Presenilin 1 ( PS1 ) mediates Notch signaling activity via cleavage of Notch , liberating Notch intracellular domain ( NICD ) .	Presenilin 1 (PS1) mediates Notch signaling activity via cleavage of Notch, liberating Notch intracellular domain (NICD).	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	Notch	Notch	Notch	3	4	6	7
Ps1 mediated Notch signalling is required to induce Dll1 expression in the caudal half of the somite .	Ps1 mediated Notch signalling is required to induce Dll1 expression in the caudal half of the somite.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ps1	Ps1	Ps1	Notch	Notch	Notch	0	1	2	3
Inactivation of PS1 or PS1 and PS2 causes a prenatally lethal ' Notch phenotype , ' which has hampered investigation of PS function in adulthood seriously .	Inactivation of PS1 or PS1 and PS2 causes a prenatally lethal ' Notch phenotype, ' which has hampered investigation of PS function in adulthood seriously.	0	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	Notch	Notch	Notch	2	3	12	13
High concentration ASI reduces the level of PS-1 and inhibits Notch signal , whereas low concentration activates the Notch signal .	High concentration ASI reduces the level of PS-1 and inhibits Notch signal, whereas low concentration activates the Notch signal.	2	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PS-1	ASI reduces the level of PS-1	ps-1	Notch	Notch	notch	7	8	10	11
PS1 and PS2 mediate the cleavage of APP and Notch .	PS1 and PS2 mediate the cleavage of APP and Notch.	0	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	Notch	Notch	Notch	0	1	9	10
We tested the hypothesis that simvastatin enhances arteriogenesis after stroke by increasing PS1 activation of the Notch signaling pathway .	We tested the hypothesis that simvastatin enhances arteriogenesis after stroke by increasing PS1 activation of the Notch signaling pathway.	12	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PS1	PS1	PS1	Notch	Notch	Notch	12	13	16	17
Thus , Ps1 dependent activation of the Notch pathway is essential for caudal half somite development .	Thus, Ps1 dependent activation of the Notch pathway is essential for caudal half somite development.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Ps1	Ps1	Ps1	Notch	Notch	Notch	2	3	7	8
The assumption has been that facilitation of Notch signaling and betaAPP processing by presenilin 1 are analogous functions .	The assumption has been that facilitation of Notch signaling and betaAPP processing by presenilin 1 are analogous functions.	7	15	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	presenilin 1	presenilin 1	presenilin 1	Notch	Notch	Notch	13	15	7	8
In the current study , our specific goals were to determine whether PS1 incrementexon8 could rescue the lethal Notch deficient phenotype XREF_BIBR XREF_BIBR of the PS1-null mouse and to determine whether PS1 incrementexon8 could form complexes with wt PS1 and/or nicastrin .	In the current study, our specific goals were to determine whether PS1 incrementexon8 could rescue the lethal Notch deficient phenotype XREF_BIBR XREF_BIBR of the PS1-null mouse and to determine whether PS1 incrementexon8 could form complexes with wt PS1 and/or nicastrin.	12	22	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	Notch	Notch	Notch	12	13	18	19
Absence of PS1 ( PS1KO ) provokes a drastic reduction of APP and Notch cleavages , which are restored by the expression of human PS1 ( rPS1wt ) .	Absence of PS1 (PS1KO) provokes a drastic reduction of APP and Notch cleavages, which are restored by the expression of human PS1 (rPS1wt).	11	26	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PS1	expression of human PS1	ps1	Notch	Notch	notch	24	25	13	14
Therefore , Mesp2- and Ps1 dependent activation of Notch signalling pathways might differentially regulate Dll1 expression , resulting in the establishment of the rostro-caudal polarity of somites .	Therefore, Mesp2- and Ps1 dependent activation of Notch signalling pathways might differentially regulate Dll1 expression, resulting in the establishment of the rostro-caudal polarity of somites.	2	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Ps1	Ps1	Ps1	Notch	Notch	Notch	4	5	8	9
These data indicate that PS1 promotes Notch signaling activity , which may mediate simvastatin induced arteriogenesis after stroke .	These data indicate that PS1 promotes Notch signaling activity, which may mediate simvastatin induced arteriogenesis after stroke.	4	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	Notch	Notch	Notch	4	5	6	7
We also observed that PS1 and PS2 produce equivalent amounts of Notch intracellular domain ( NICD ) , indicating equal cleavage activity at the Notch S3-site ( the corollary of the APP epsilon-site ) .	We also observed that PS1 and PS2 produce equivalent amounts of Notch intracellular domain (NICD), indicating equal cleavage activity at the Notch S3-site (the corollary of the APP epsilon-site).	4	13	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	Notch	Notch	Notch	4	5	11	12
PS1 , like sel-12 in C. elegans , mediates LIN-12 and notch signaling .	PS1, like sel-12 in C. elegans, mediates LIN-12 and notch signaling.	0	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	notch	notch	notch	0	1	11	12
Interestingly , SFRPs and Psen1 activate Notch signaling , in some systems XREF_BIBR - XREF_BIBR .	Interestingly, SFRPs and Psen1 activate Notch signaling, in some systems XREF_BIBR - XREF_BIBR.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Psen1	Psen1	Psen1	Notch	Notch	Notch	4	5	6	7
Brain vascular phenotypes have been reported in mice lacking Notch signaling mediators such as presenilin-1 9 and Numb .	Brain vascular phenotypes have been reported in mice lacking Notch signaling mediators such as presenilin-1 9 and Numb.	9	17	mediators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	presenilin-1	presenilin-1	presenilin-1	Notch	Notch	Notch	14	15	9	10
The individual affinities of GAS6 and PROS1 toward TYRO3 , AXL , and MERTK are known : GAS6 can bind all three TAM receptors with higher affinities for AXL and TYRO3 in comparison to MERTK , whereas PROS1 can activate TYRO3 and MERTK but not AXL .	The individual affinities of GAS6 and PROS1 toward TYRO3, AXL, and MERTK are known : GAS6 can bind all three TAM receptors with higher affinities for AXL and TYRO3 in comparison to MERTK, whereas PROS1 can activate TYRO3 and MERTK but not AXL.	37	46	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PROS1	PROS1	PROS1	AXL	AXL	AXL	37	38	45	46
This is consistent with the fact that Pros1 , the only TAM ligand remaining in the Gas6 -/- Mertk -/- mice , does not activate Axl 5 , the only microglial TAM receptor remaining in these mice .	This is consistent with the fact that Pros1, the only TAM ligand remaining in the Gas6 -/- Mertk -/- mice, does not activate Axl 5, the only microglial TAM receptor remaining in these mice.	7	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pros1	Pros1	Pros1	Axl	Axl	Axl	7	8	25	26
In contrast , PROS1 can only activate TYRO3 and MER , but not AXL .	In contrast, PROS1 can only activate TYRO3 and MER, but not AXL.	3	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PROS1	PROS1	PROS1	AXL	AXL	AXL	3	4	13	14
In this capacity , while Gas6 has a high affinity for Axl ( nM ) and significantly lower affinity Tyro3 and Mertk ( uM ) , Pros1 has a preference to Tyro3 and Mertk but does not activate Axl ( XREF_TABLE ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In this capacity, while Gas6 has a high affinity for Axl (nM) and significantly lower affinity Tyro3 and Mertk (uM), Pros1 has a preference to Tyro3 and Mertk but does not activate Axl (XREF_TABLE) [XREF_BIBR, XREF_BIBR, XREF_BIBR].	26	47	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pros1	Pros1	Pros1	Axl	Axl	Axl	26	27	38	39
In summary , our study suggests that DNA-PKcs is the upstream activator of Chk2 and Brca1 .	In summary, our study suggests that DNA-PKcs is the upstream activator of Chk2 and Brca1.	7	15	is the upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Chk2	Chk2	Chk2	7	8	13	14
A possible scenario based on available data is that in the absence of ATM , DNA-PKcs can directly activate Chk2 and modify MDM2 to promote p53 dependent apoptosis .	A possible scenario based on available data is that in the absence of ATM, DNA-PKcs can directly activate Chk2 and modify MDM2 to promote p53 dependent apoptosis.	15	21	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Chk2	Chk2	Chk2	15	16	19	20
We want to determine whether inhibition of PS1 protein expression by SP600125 also inhibits Notch 1 processing and Notch 1 signaling in adult mouse brains without deleterious consequences .	We want to determine whether inhibition of PS1 protein expression by SP600125 also inhibits Notch 1 processing and Notch 1 signaling in adult mouse brains without deleterious consequences.	7	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1 protein expression	ps1	Notch 1	Notch 1	notch 1	7	8	14	16
Moreover , PSEN1 inhibition decreased Notch 1 , Notch 2 , and Notch 3 protein expressions .	Moreover, PSEN1 inhibition decreased Notch 1, Notch 2, and Notch 3 protein expressions.	2	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PSEN1	PSEN1	PSEN1	Notch 1	Notch 1	Notch 1	2	3	5	7
Both Wild-Type PS1 and PS1Deltacat Restore Normal Proteolytic Cleavage of Notch-1 and gamma-Secretase Activity .	Both Wild-Type PS1 and PS1Deltacat Restore Normal Proteolytic Cleavage of Notch-1 and gamma-Secretase Activity.	0	13	Restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	Notch-1	Notch-1	Notch-1	2	3	10	11
Interestingly , PS1 knockdown alone was sufficient to significantly diminish NICD production , whereas knockdown of PS2 did not show an obvious effect ( XREF_FIG , lanes 5-6 ) .	Interestingly, PS1 knockdown alone was sufficient to significantly diminish NICD production, whereas knockdown of PS2 did not show an obvious effect (XREF_FIG, lanes 5-6).	2	11	diminish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	NICD	NICD	NICD	2	3	10	11
These results suggest that PS1 or a PS1 containing enzyme in NCT -/- cells mediates NICD production .	These results suggest that PS1 or a PS1 containing enzyme in NCT -/- cells mediates NICD production.	4	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	NICD	NICD	NICD	4	5	15	16
Our data also suggest that inhibition of PS1 by SP600125 reduces PS1 and gamma-secretase activity and Notch 1 signaling in adult mouse brains without lethal effect or induction of apoptosis .	Our data also suggest that inhibition of PS1 by SP600125 reduces PS1 and gamma-secretase activity and Notch 1 signaling in adult mouse brains without lethal effect or induction of apoptosis.	5	18	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	Notch 1	Notch 1	Notch 1	7	8	16	18
Wild-type and p. 183G > V PS1 displayed similar levels of gamma-secretase activity , as measured by production of NICD , whereas PS1 bearing an p. 257D > A substitution , which abolishes gamma-secretase activity , was unable to produce detectable NICD ( XREF_FIG ) .	Wild-type and p. 183G> V PS1 displayed similar levels of gamma-secretase activity, as measured by production of NICD, whereas PS1 bearing an p. 257D> A substitution, which abolishes gamma-secretase activity, was unable to produce detectable NICD (XREF_FIG).	22	43	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1	PS1	NICD	NICD	NICD	22	23	41	42
In developing neurons , PS1 overexpression increased the nuclear translocation of NICD and inhibited neurite growth , whereas PS1 mutations M146V , I143T , and deletion of exon 9 ( D9 ) did not facilitate NICD nuclear translocation and had no effect on neurite growth .	In developing neurons, PS1 overexpression increased the nuclear translocation of NICD and inhibited neurite growth, whereas PS1 mutations M146V, I143T, and deletion of exon 9 (D9) did not facilitate NICD nuclear translocation and had no effect on neurite growth.	4	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PS1	PS1 overexpression	ps1	NICD	NICD	nicd	4	5	11	12
H2AX dependent NHEJ is inactivated by deletion of XRCC4 or DNA-PKcs , two genes required for C-NHEJ , pointing to the notion that H2AX dependent NHEJ is part of C-NHEJ , rather than a subtype of A-NHEJ .	H2AX dependent NHEJ is inactivated by deletion of XRCC4 or DNA-PKcs, two genes required for C-NHEJ, pointing to the notion that H2AX dependent NHEJ is part of C-NHEJ, rather than a subtype of A-NHEJ.	0	11	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	H2AX	H2AX	H2AX	10	11	0	1
DNA-PKcs may mediate H2AX dependent NHEJ as a core NHEJ factor .	DNA-PKcs may mediate H2AX dependent NHEJ as a core NHEJ factor.	0	5	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	H2AX	H2AX	H2AX	0	1	3	4
The NHEJ core factors XRCC4 and DNA-PKcs mediate H2AX dependent NHEJ .	The NHEJ core factors XRCC4 and DNA-PKcs mediate H2AX dependent NHEJ.	4	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	H2AX	H2AX	H2AX	6	7	8	9
We confirmed that activation of PROKR1 by PROK1 in human endometrial epithelial cells resulted in the induction of expression of IL-8 and we demonstrated that this induction occurred via the activation of the calcineurin and nuclear factor of activated T-cells ( NFAT ) signaling pathway .	We confirmed that activation of PROKR1 by PROK1 in human endometrial epithelial cells resulted in the induction of expression of IL-8 and we demonstrated that this induction occurred via the activation of the calcineurin and nuclear factor of activated T-cells (NFAT) signaling pathway.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PROK1	PROK1	PROK1	PROKR1	PROKR1	PROKR1	7	8	5	6
Using third trimester placental explant model , a recent study has demonstrated IL-8 induction by EG-VEGF , potentially via activation of PROKR1 [ XREF_BIBR ] .	Using third trimester placental explant model, a recent study has demonstrated IL-8 induction by EG-VEGF, potentially via activation of PROKR1 [XREF_BIBR].	11	23	activation	Positive_activation_syntax_6_noun	Positive_activation	Positive_activation	EG-VEGF	EG-VEGF	EG-VEGF	PROKR1	PROKR1	PROKR1	15	16	21	22
Gene microarray analysis on RNA extracted from Ishikawa PROKR1 cells treated with 40 nm PROK1 for 8 h revealed 49 genes to be differentially regulated .	Gene microarray analysis on RNA extracted from Ishikawa PROKR1 cells treated with 40 nm PROK1 for 8 h revealed 49 genes to be differentially regulated.	8	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PROK1	PROK1	PROK1	PROKR1	PROKR1	PROKR1	14	15	8	9
Also , Ishikawa PROKR1 cells transfected with the pNF-kappaB-Luc vector ( Promega ) and treated with 40nM PROK1 did not induce NF-kappaB-driven luciferase activity .	Also, Ishikawa PROKR1 cells transfected with the pNF-kappaB-Luc vector (Promega) and treated with 40nM PROK1 did not induce NF-kappaB-driven luciferase activity.	3	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PROK1	PROK1	PROK1	PROKR1	PROKR1	PROKR1	17	18	3	4
Expression of the TM3 mutants ( E84A , R87A , Q83A ) led to a partial rescue of NCT maturation as well as PEN2 expression and restored PS1 endoproteolysis to the same level as that seen for wild-type APH1 ( XREF_FIG A ) .	Expression of the TM3 mutants (E84A, R87A, Q83A) led to a partial rescue of NCT maturation as well as PEN2 expression and restored PS1 endoproteolysis to the same level as that seen for wild-type APH1 (XREF_FIG A).	0	28	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PEN2	Expression of the TM3 mutants (E84A, R87A, Q83A) led to a partial rescue of NCT maturation as well as PEN2 expression	pen2	PS1	PS1	ps1	23	24	27	28
Interestingly , protein levels of PEN2 was significantly increased ( ~ 200 % , p < 0.005 ) in PS1 transgenic mice as compared to that of wild type mice ( XREF_FIG ) .	Interestingly, protein levels of PEN2 was significantly increased (~ 200%, p < 0.005) in PS1 transgenic mice as compared to that of wild type mice (XREF_FIG).	3	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PEN2	levels of PEN2	pen2	PS1	PS1	ps1	5	6	19	20
Finally , we demonstrate that PEN2 is sufficient to promote the endoproteolysis of PS1 to generate the active form of gamma-secretase .	Finally, we demonstrate that PEN2 is sufficient to promote the endoproteolysis of PS1 to generate the active form of gamma-secretase.	5	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PEN2	PEN2	PEN2	PS1	PS1	PS1	5	6	13	14
For example , the mechanisms by which PROK2 promotes GnRH neuronal migration , the neuroendocrine action of PROK2 and PROKR2 system in the reproductive and other endocrine axes , and the role of other Prokr2 neuronal populations are still poorly understood .	For example, the mechanisms by which PROK2 promotes GnRH neuronal migration, the neuroendocrine action of PROK2 and PROKR2 system in the reproductive and other endocrine axes, and the role of other Prokr2 neuronal populations are still poorly understood.	7	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PROK2	PROK2	PROK2	Prokr2	PROKR2	PROKR2	7	8	19	20
We found that the Prok2 overexpression phenotype was abolished in prokr2-/- larvae ( XREF_SUPPLEMENTARY ) , but was unaffected in prokr1-/- larvae ( XREF_SUPPLEMENTARY ) , indicating that Prok2 overexpression induced behavioral effects require prokr2 but not prokr1 .	We found that the Prok2 overexpression phenotype was abolished in prokr2-/- larvae (XREF_SUPPLEMENTARY), but was unaffected in prokr1-/- larvae (XREF_SUPPLEMENTARY), indicating that Prok2 overexpression induced behavioral effects require prokr2 but not prokr1.	28	37	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Prok2	Prok2 overexpression	prok2	prokr2	prokr2	prokr2	28	29	34	35
We also found that light dependent , Prok2 induced sedation requires prokineticin receptor 2 ( prokr2 ) and is strongly suppressed in galn mutants .	We also found that light dependent, Prok2 induced sedation requires prokineticin receptor 2 (prokr2) and is strongly suppressed in galn mutants.	7	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Prok2	Prok2	Prok2	prokr2	prokr2	prokr2	7	8	15	16
A truncated mutant form of Ptc1 that is unable to interact with cyclin B1 was identified in a subset of basal cell carcinomas , and epidermal ablation of Ptc1 in mice increased nuclear cyclin B1 , which is consistent with cyclin B1 driving mitosis in these Hh dependent tumors .	A truncated mutant form of Ptc1 that is unable to interact with cyclin B1 was identified in a subset of basal cell carcinomas, and epidermal ablation of Ptc1 in mice increased nuclear cyclin B1, which is consistent with cyclin B1 driving mitosis in these Hh dependent tumors.	26	38	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ptc1	Ptc1	Ptc1	B1	B1	B1	28	29	34	35
Besides apoptosis , exogenous Ptch1 in 293T cells induces the redistribution of cyclin B1 from the nucleus to the cytoplasm , resulting in reduced cell proliferation .	Besides apoptosis, exogenous Ptch1 in 293T cells induces the redistribution of cyclin B1 from the nucleus to the cytoplasm, resulting in reduced cell proliferation.	3	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ptch1	Ptch1	Ptch1	B1	B1	B1	4	5	13	14
In these studies , cGMP-treatment or PKGI overexpression in SMC or cell lines was observed to cause PKGI proteolysis and the generation of a COOH-terminal kinase fragment with constitutive activity .	In these studies, cGMP-treatment or PKGI overexpression in SMC or cell lines was observed to cause PKGI proteolysis and the generation of a COOH-terminal kinase fragment with constitutive activity.	4	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKGI	PKGI overexpression	pkgi	PKGI	PKGI	pkgi	6	7	17	18
Since PTH ( 1-34 ) activates both Adenylate Cyclase and Protein Kinase A ( AC/PKA ) and Protein Kinase C ( PKC ) downstream of the PTH1R in osteoblastic cells , we independently determined the effect of either pathway on Jagged1 .	Since PTH (1-34) activates both Adenylate Cyclase and Protein Kinase A (AC/PKA) and Protein Kinase C (PKC) downstream of the PTH1R in osteoblastic cells, we independently determined the effect of either pathway on Jagged1.	1	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	1	2	26	27
Human PTH was also able to stimulate chicken PTH1R ( 21.4 +/-10 pmol and well at 10 -7 M ) ( Additional file XREF_SUPPLEMENTARY ) .	Human PTH was also able to stimulate chicken PTH1R (21.4 +/-10 pmol and well at 10 -7 M) (Additional file XREF_SUPPLEMENTARY).	0	23	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	1	2	8	9
Recording PTHR activation by intramolecular FRET with a receptor bio-sensor as previously described [ XREF_BIBR ] showed that , in contrast to PTHrP ( 1-36 ) , PTH ( 1-34 ) induces a stable active state of PTHR that persists well after removal of ligand .	Recording PTHR activation by intramolecular FRET with a receptor bio-sensor as previously described [XREF_BIBR] showed that, in contrast to PTHrP (1-36), PTH (1-34) induces a stable active state of PTHR that persists well after removal of ligand.	27	38	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	27	28	37	38
Stimulation of PTHR by PTH on osteoblasts leads to activation of Galphas and Galphaq , with consequent induction of cAMP and protein kinase A ( PKA ) and phospholipase C ( PLC )/PKC signaling pathways , which results in both osteoblast formation and osteoclast resorption .	Stimulation of PTHR by PTH on osteoblasts leads to activation of Galphas and Galphaq, with consequent induction of cAMP and protein kinase A (PKA) and phospholipase C (PLC)/PKC signaling pathways, which results in both osteoblast formation and osteoclast resorption.	0	6	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	4	5	2	3
PTH stimulates transport of PTH1R to cilia of NP cells .	PTH stimulates transport of PTH1R to cilia of NP cells.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	0	1	4	5
PTH reconstituted YFP fluorescence by 30 s ( XREF_FIG , upper panels ) and PTH TMR was predominantly co-localized with the YFP fluorescence ( XREF_FIG , lower panels ) , indicating PTH induced formation of PTH1R dimer or oligomer .	PTH reconstituted YFP fluorescence by 30 s (XREF_FIG, upper panels) and PTH TMR was predominantly co-localized with the YFP fluorescence (XREF_FIG, lower panels), indicating PTH induced formation of PTH1R dimer or oligomer.	31	36	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	31	32	35	36
It has been shown that , while PTH ( 1-34 ) both activates and internalizes PTH1R in distal kidney cells , PTH ( 7-34 ) induce receptor endocytosis without inducing cAMP or PLC signaling pathways .	It has been shown that, while PTH (1-34) both activates and internalizes PTH1R in distal kidney cells, PTH (7-34) induce receptor endocytosis without inducing cAMP or PLC signaling pathways.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	7	8	15	16
The internalization of LRP6 was not observed without expression of PTH1R , indicating that PTH induced internalization of LRP6 is PTH1R dependent ( XREF_FIG ) .	The internalization of LRP6 was not observed without expression of PTH1R, indicating that PTH induced internalization of LRP6 is PTH1R dependent (XREF_FIG).	14	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	14	15	20	21
Expression of the same CAM in osteoblasts by placing its expression under the control of the type I collagen promoter showed that both the osteoblast and osteoclast numbers were increased , suggesting that PTH activation of PTHR1 in osteoblasts increase both bone forming and bone resorbing activities .	Expression of the same CAM in osteoblasts by placing its expression under the control of the type I collagen promoter showed that both the osteoblast and osteoclast numbers were increased, suggesting that PTH activation of PTHR1 in osteoblasts increase both bone forming and bone resorbing activities.	33	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	33	34	36	37
We previously have shown that PTH-myc elicited PTHR 1 -mediated signaling 14 .	We previously have shown that PTH-myc elicited PTHR 1 -mediated signaling 14.	5	8	elicited	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PTH-myc	PTH-myc	PTH-myc	PTHR	PTHR	PTHR	5	6	7	8
The knockdown of pallidin blocked PTH enhanced transport of PTH1R to cilia in both mouse and human NP cells and pCREB validated in Western blot analysis .	The knockdown of pallidin blocked PTH enhanced transport of PTH1R to cilia in both mouse and human NP cells and pCREB validated in Western blot analysis.	5	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	5	6	9	10
In contrast to results from a previous study showing that PTH1R is down-regulated by PTH in cultured osteoblasts XREF_BIBR , PTH1R was slightly increased by intermittent PTH treatment in vivo as measured by IHC and Western blot analysis .	In contrast to results from a previous study showing that PTH1R is down-regulated by PTH in cultured osteoblasts XREF_BIBR, PTH1R was slightly increased by intermittent PTH treatment in vivo as measured by IHC and Western blot analysis.	10	15	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	14	15	10	11
1 PTHR1 signaling is crucial for maintaining ionized calcium ( Ca 2+ ) concentrations within a narrow range in the bloodstream , and is thus activated by parathyroid hormone ( PTH ) in response to Ca 2+ influx and efflux changes that occur on the minute timescale .	1 PTHR1 signaling is crucial for maintaining ionized calcium (Ca 2+) concentrations within a narrow range in the bloodstream, and is thus activated by parathyroid hormone (PTH) in response to Ca 2+ influx and efflux changes that occur on the minute timescale.	1	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	parathyroid hormone	parathyroid hormone	parathyroid hormone	PTHR1	PTHR1	PTHR1	27	29	1	2
The PTH1 receptor is activated by PTH and PTHrP but not by TIP39 .	The PTH1 receptor is activated by PTH and PTHrP but not by TIP39.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1 receptor	PTH1 receptor	PTH1 receptor	6	7	1	3
We next determined whether changes in the phosphorylation status of serine 368 of Cx43 contribute to binding of betaarrestin to the PTHR1 induced by PTH .	We next determined whether changes in the phosphorylation status of serine 368 of Cx43 contribute to binding of betaarrestin to the PTHR1 induced by PTH.	14	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	24	25	21	22
PTH activates PTHR by interacting with a ligand binding site localized within the N-terminal extracellular domain ( the N-domain ) and the domain comprising the seven transmembrane helices and the connecting extracellular loops ( the J-domain ) .	PTH activates PTHR by interacting with a ligand binding site localized within the N-terminal extracellular domain (the N-domain) and the domain comprising the seven transmembrane helices and the connecting extracellular loops (the J-domain).	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	0	1	2	3
After the appearance of functional PTH receptor 1 ( PTHR1 ) in Kusa 4b10 cells , they were treated with either PTH ( 1-34 ) or PTHrP ( 1-141 ) , and RNA was subjected to Affymetrix whole mouse genome array .	After the appearance of functional PTH receptor 1 (PTHR1) in Kusa 4b10 cells, they were treated with either PTH (1-34) or PTHrP (1-141), and RNA was subjected to Affymetrix whole mouse genome array.	2	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	21	22	9	10
We previously showed by recording FRET changes in HEK293 cells expressing PTHR-CFP and YFP that the rate constant of PTHR activation by PTH 1-34 follows a hyperbolic dependence on ligand concentration XREF_BIBR .	We previously showed by recording FRET changes in HEK293 cells expressing PTHR-CFP and YFP that the rate constant of PTHR activation by PTH 1-34 follows a hyperbolic dependence on ligand concentration XREF_BIBR.	19	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	22	23	19	20
PTH ( 7-84 ) and its analogue PTH ( 7-34 ) , for instance , promote PTHR internalization in both kidney and bone cells lacking the cytoplasmic PDZ adaptor protein , NHERF1 .	PTH (7-84) and its analogue PTH (7-34), for instance, promote PTHR internalization in both kidney and bone cells lacking the cytoplasmic PDZ adaptor protein, NHERF1.	0	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	0	1	16	17
Interestingly , our data showed that PTH upregulated its receptor PTH1R in STRO-1 ( + ) PDLSCs , which may result in the establishment of a positive feedback loop .	Interestingly, our data showed that PTH upregulated its receptor PTH1R in STRO-1 (+) PDLSCs, which may result in the establishment of a positive feedback loop.	6	11	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	6	7	10	11
The PTH and PTHR1 system has been shown to be an important mediator of the development of the bone marrow niche where PTH activation of PTHR1 increases the number of osteoblasts in stromal cultures , and increased the number of hematopoietic stem cells and survival of mice receiving bone marrow transplant XREF_BIBR .	The PTH and PTHR1 system has been shown to be an important mediator of the development of the bone marrow niche where PTH activation of PTHR1 increases the number of osteoblasts in stromal cultures, and increased the number of hematopoietic stem cells and survival of mice receiving bone marrow transplant XREF_BIBR.	22	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	22	23	25	26
In these cells , which are the target of the calcium sparing action of PTH , PTH ( 1-34 ) activated adenylyl cyclase ( AC ) and phospholipase C ( PLC ) and PTH1R endocytosis .	In these cells, which are the target of the calcium sparing action of PTH, PTH (1-34) activated adenylyl cyclase (AC) and phospholipase C (PLC) and PTH1R endocytosis.	16	34	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	16	17	33	34
On the other hand , PTH ( 1-31 ) activates the PTH1R without causing receptor internalization .	On the other hand, PTH (1-31) activates the PTH1R without causing receptor internalization.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	5	6	11	12
Previously , we demonstrated that NHERF1 increased PTH stimulated PTH1R coupling to Galphaq but not to Galphas or Galphai .	Previously, we demonstrated that NHERF1 increased PTH stimulated PTH1R coupling to Galphaq but not to Galphas or Galphai.	6	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	7	8	9	10
To begin to test this theory , ROS cells were transiently transfected with HA-PTHR , myc-ubiquitin and treated with PTH ( 1-34 ) or PTH ( 7-34 ) .	To begin to test this theory, ROS cells were transiently transfected with HA-PTHR, myc-ubiquitin and treated with PTH (1-34) or PTH (7-34).	11	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PTH	PTH	PTH	HA-PTHR	HA-PTHR	HA-PTHR	19	20	13	14
Human and zebrafish PTH1R are preferentially activated by both PTH and PTHrP .	Human and zebrafish PTH1R are preferentially activated by both PTH and PTHrP.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	9	10	3	4
However , it is also possible that chronic PTH stimulation may induce changes in the PTH1R that lower ligand binding affinities ; thus reducing PTH-TMR staining .	However, it is also possible that chronic PTH stimulation may induce changes in the PTH1R that lower ligand binding affinities; thus reducing PTH-TMR staining.	8	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	8	9	15	16
Interestingly , PTH activation of Pthr1 has been shown to activate the Wnt and beta-catenin signaling directly by stabilizing beta-catenin protein in osteoblasts XREF_BIBR .	Interestingly, PTH activation of Pthr1 has been shown to activate the Wnt and beta-catenin signaling directly by stabilizing beta-catenin protein in osteoblasts XREF_BIBR.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	Pthr1	Pthr1	Pthr1	2	3	5	6
PTH ( 7-34 ) induces PTH1R internalization on its own and is only a competitive inhibitor at higher concentrations [ XREF_BIBR ] .	PTH (7-34) induces PTH1R internalization on its own and is only a competitive inhibitor at higher concentrations [XREF_BIBR].	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	0	1	5	6
These observations suggested that PLCbeta is activated by pertussis toxin sensitive Gi/o Gbetagamma subunits and that adenylyl cyclase is inhibited by Galpha-subunits upon PTH induced PTH1R activation .	These observations suggested that PLCbeta is activated by pertussis toxin sensitive Gi/o Gbetagamma subunits and that adenylyl cyclase is inhibited by Galpha-subunits upon PTH induced PTH1R activation.	19	26	induced	Positive_early_activation	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	23	24	25	26
The 34 N-terminal amino-acids of the full length 84 amino-acid single polypeptide of PTH can activate the PTH1R and several downstream pathways including cAMP and protein kinase A ( PKA ) , phospholipase C ( PLC )/protein kinase C ( PKC ) , PLC independent PKC and Ca 2+ pathways , and perhaps other as well .	The 34 N-terminal amino-acids of the full length 84 amino-acid single polypeptide of PTH can activate the PTH1R and several downstream pathways including cAMP and protein kinase A (PKA), phospholipase C (PLC)/protein kinase C (PKC), PLC independent PKC and Ca 2+ pathways, and perhaps other as well.	11	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	13	14	17	18
A truncated version of PTH , PTH ( 1-34 ) , can fully activate PTH1R and has been used for osteoporosis treatments .	A truncated version of PTH, PTH (1-34), can fully activate PTH1R and has been used for osteoporosis treatments.	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	4	5	14	15
The parathyroid hormone 1 receptor ( PTH1R ) is activated by parathyroid hormone ( PTH ) and parathyroid hormone related protein ( PTHrP ) , hormones that mediate mineral ion homeostasis and tissue development , respectively .	The parathyroid hormone 1 receptor (PTH1R) is activated by parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP), hormones that mediate mineral ion homeostasis and tissue development, respectively.	1	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	parathyroid hormone	parathyroid hormone	parathyroid hormone	parathyroid hormone 1 receptor	parathyroid hormone 1 receptor	parathyroid hormone 1 receptor	11	13	1	5
The PTH1R is activated with subnanomolar potency by PTH and PTHrP , and both peptides are thought to be its physiological ligands .	The PTH1R is activated with subnanomolar potency by PTH and PTHrP, and both peptides are thought to be its physiological ligands.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	8	9	1	2
The observations described above led us to hypothesize that distinct patterns of ligand induced ubiquitination and deubiquitination could explain the difference between the complete PTHR recycling induced by PTH ( 1-34 ) and PTHR downregulation elicited by PTH ( 7-34 ) .	The observations described above led us to hypothesize that distinct patterns of ligand induced ubiquitination and deubiquitination could explain the difference between the complete PTHR recycling induced by PTH (1-34) and PTHR downregulation elicited by PTH (7-34).	24	34	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	28	29	24	25
It is of considerable interest to investigate how PTH ( 1-34 ) activation of PTH1R results in such complex metabolic effects .	It is of considerable interest to investigate how PTH (1-34) activation of PTH1R results in such complex metabolic effects.	8	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	8	9	14	15
Notably , PTH and PTHrP can stimulate PTH1R on osteoblasts to increase the ratio of RANKL and OPG ( osteoprotegrin ) , which in turn promotes osteoclastogenesis .	Notably, PTH and PTHrP can stimulate PTH1R on osteoblasts to increase the ratio of RANKL and OPG (osteoprotegrin), which in turn promotes osteoclastogenesis.	2	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	2	3	7	8
Partial homology of PTHrP and parathyroid hormone allows PTHrP to activate parathyroid hormone 1 receptor ( PTH1R ) .	Partial homology of PTHrP and parathyroid hormone allows PTHrP to activate parathyroid hormone 1 receptor (PTH1R).	3	15	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	parathyroid hormone	parathyroid hormone	parathyroid hormone	parathyroid hormone 1 receptor	parathyroid hormone 1 receptor	parathyroid hormone 1 receptor	5	7	11	15
Mammalian PTH1R is activated by both PTH and PTHrP which have similar potency and stimulate both cAMP and iCa 2+ production [ XREF_BIBR ] .	Mammalian PTH1R is activated by both PTH and PTHrP which have similar potency and stimulate both cAMP and iCa 2+ production [XREF_BIBR].	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	6	7	1	2
However , although addition of PTH did not induce PTHR-GFP internalization under these same conditions , AT1R-GFP was internalized on angiotensin II addition ( XREF_FIG ) .	However, although addition of PTH did not induce PTHR-GFP internalization under these same conditions, AT1R-GFP was internalized on angiotensin II addition (XREF_FIG).	3	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR-GFP	PTHR-GFP	PTHR-GFP	5	6	9	10
PTH ( 2-34 ) and ( 3-34 ) caused PTH1R internalization intermediate between PTH ( 1-34 ) and ( 7-34 ) .	PTH (2-34) and (3-34) caused PTH1R internalization intermediate between PTH (1-34) and (7-34).	0	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	0	1	9	10
These findings raised an important question of whether the intervention of beta-catenin interaction with PTHR in osteoblasts has a similar effect to alter PTH induced PTHR signaling .	These findings raised an important question of whether the intervention of beta-catenin interaction with PTHR in osteoblasts has a similar effect to alter PTH induced PTHR signaling.	22	26	induced	Positive_early_activation	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	23	24	25	26
Taken together , these results show that PTH induces PTH1R dependent endocytosis of TbetaRII .	Taken together, these results show that PTH induces PTH1R dependent endocytosis of TbetaRII.	7	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	7	8	9	10
Given that PTH1R can be activated by PTH and PTHrP [ XREF_BIBR ] , we sought whether PTHrP alone induced the association between PTH1R and TbetaRII in rat MCs .	Given that PTH1R can be activated by PTH and PTHrP [XREF_BIBR], we sought whether PTHrP alone induced the association between PTH1R and TbetaRII in rat MCs.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	7	8	2	3
Recently it has be shown that cAMP production that is induced in this classical way via PTH activation of PTHR is suppressed by elevated CO 2 and results in activation of the sodium-proton exchanger isoform 3 ( NHe3 ) .	Recently it has be shown that cAMP production that is induced in this classical way via PTH activation of PTHR is suppressed by elevated CO 2 and results in activation of the sodium-proton exchanger isoform 3 (NHe3).	16	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	16	17	19	20
NHERF1 blocked PTH induced dissociation of the PTH1R from Galpha ( s ) .	NHERF1 blocked PTH induced dissociation of the PTH1R from Galpha (s).	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	2	3	7	8
In contrast , NHERF2 decreased PTH induced PTH1R coupling to Galphas and increased Galphaq and Galphai activation [ XREF_BIBR ] .	In contrast, NHERF2 decreased PTH induced PTH1R coupling to Galphas and increased Galphaq and Galphai activation [XREF_BIBR].	5	12	induced	Positive_early_activation	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	5	6	7	8
In mammals and teleosts , PTH and PTHLH activate the PTH1R nearly equivalently for calcium regulation .	In mammals and teleosts, PTH and PTHLH activate the PTH1R nearly equivalently for calcium regulation.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	5	6	10	11
PTH is secreted from the parathyroid gland in response to the lowering of blood Ca 2+ concentrations and will increase Ca 2+ concentrations by stimulating the PTHR 1 XREF_BIBR , XREF_BIBR .	PTH is secreted from the parathyroid gland in response to the lowering of blood Ca 2+ concentrations and will increase Ca 2+ concentrations by stimulating the PTHR 1 XREF_BIBR, XREF_BIBR.	0	28	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	0	1	26	27
Dexamethasone dose-dependently increased PTH stimulated adenylyl cyclase activity at 72 h. Dex markedly increased PTH1R mRNA accumulation , but did not change transcriptional activity .	Dexamethasone dose-dependently increased PTH stimulated adenylyl cyclase activity at 72 h. Dex markedly increased PTH1R mRNA accumulation, but did not change transcriptional activity.	3	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	3	4	14	15
We show that the assembly of this complex occurs on endosomes in response to PTH stimulation , where it directs PTHR to retromer for recycling to the cell surface , and provide evidence that the PTHR-SNX27-retromer association is physiologically required to restrict PTH signaling in OBs , where disruption of SNX27 impairs OB activity and contributes to a severe growth and maturation deficit in the skeleton of SNX27 deficient mice .	We show that the assembly of this complex occurs on endosomes in response to PTH stimulation, where it directs PTHR to retromer for recycling to the cell surface, and provide evidence that the PTHR-SNX27-retromer association is physiologically required to restrict PTH signaling in OBs, where disruption of SNX27 impairs OB activity and contributes to a severe growth and maturation deficit in the skeleton of SNX27 deficient mice.	14	21	directs	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	14	15	20	21
Taken together , these data indicate that PTHR forms a complex with SNX27 via its PDZ-domain , which requires both the PTH induced internalization of PTHR and an intact PTHR PDZbm for SNX27-PTHR association on endosomes .	Taken together, these data indicate that PTHR forms a complex with SNX27 via its PDZ-domain, which requires both the PTH induced internalization of PTHR and an intact PTHR PDZbm for SNX27-PTHR association on endosomes.	20	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	21	22	25	26
Here , we show that PTHR recycling induced by PTH ( 7-34 ) is slower and incomplete compared with PTH ( 1-34 ) .	Here, we show that PTHR recycling induced by PTH (7-34) is slower and incomplete compared with PTH (1-34).	5	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	9	10	5	6
PTH induced proportionately similar PTHR internalization in the presence or absence of Deltae14-PTHR ( XREF_FIG ) .	PTH induced proportionately similar PTHR internalization in the presence or absence of Deltae14-PTHR (XREF_FIG).	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	0	1	4	5
Our recent study indicates that PTH induces endocytosis of PTH1R and TbetaRII , as a complex , and that this feature coordinates the signaling of both PTH and TGF-beta in coupling bone formation and resorption during the process of bone remodeling .	Our recent study indicates that PTH induces endocytosis of PTH1R and TbetaRII, as a complex, and that this feature coordinates the signaling of both PTH and TGF-beta in coupling bone formation and resorption during the process of bone remodeling.	5	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	5	6	9	10
However , PTH ( 7-34 ) , which does not activate the PTHR but promotes receptor internalization , down-regulates the PTHR by a ubiquitin sensitive pathway .	However, PTH (7-34), which does not activate the PTHR but promotes receptor internalization, down-regulates the PTHR by a ubiquitin sensitive pathway.	2	21	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	2	3	20	21
Notably , in cells expressing NHERF1 , PTH ( 1-34 ) and PTH ( 1-84 ) promote PTH1R endocytosis , whereas receptor sequestration by PTH ( 7-34 ) and PTH ( 7-84 ) is eliminated .	Notably, in cells expressing NHERF1, PTH (1-34) and PTH (1-84) promote PTH1R endocytosis, whereas receptor sequestration by PTH (7-34) and PTH (7-84) is eliminated.	7	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	7	8	17	18
When the latter assay was applied to transfected cells in 24-well plates , a strong luminescent signal was detected from HEK 293a cells expressing PTHR 1 and treated with PTH-myc ( P < 0.001 vs. control receptor expressing cells ) .	When the latter assay was applied to transfected cells in 24-well plates, a strong luminescent signal was detected from HEK 293a cells expressing PTHR 1 and treated with PTH-myc (P < 0.001 vs. control receptor expressing cells).	23	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PTH-myc	PTH-myc	PTH-myc	PTHR	PTHR	PTHR	29	30	24	25
The potential of PTH analogs that induce prolonged PTHR1 signaling for osteoporosis therapy is unclear at present .	The potential of PTH analogs that induce prolonged PTHR1 signaling for osteoporosis therapy is unclear at present.	3	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	3	4	8	9
PTH promoted internalization and recycling of the PTHR .	PTH promoted internalization and recycling of the PTHR.	0	8	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	0	1	7	8
According to this hypothesis , PTH ( 7-84 ) may contribute to hormone resistance by inducing PTH1R internalization and downregulation without accompanying activation .	According to this hypothesis, PTH (7-84) may contribute to hormone resistance by inducing PTH1R internalization and downregulation without accompanying activation.	5	17	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	5	6	16	17
These finding are consistent with a persistently activated PTHR state induced by PTH 1-34 but not by PTHrP 1-36 .	These finding are consistent with a persistently activated PTHR state induced by PTH 1-34 but not by PTHrP 1-36.	8	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	12	13	8	9
We show here that in an animal model of experimental CKD , the intermittent administration of PTH ( 1-34 ) increases bone formation and expression of renal but not bone PTH1R mRNA , while decreasing vascular calcification .	We show here that in an animal model of experimental CKD, the intermittent administration of PTH (1-34) increases bone formation and expression of renal but not bone PTH1R mRNA, while decreasing vascular calcification.	14	31	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	16	17	30	31
To investigate postreceptor mechanisms of action , MC3T3-E1 cells were induced to differentiate to optimize PTH-1 receptor expression , and differentiated MC3T3-E1 cells were treated with varying doses of PTH ( 1-34 ) for 1 h. Northern blot analysis revealed a dose dependent stimulation of steady state c-fos messenger RNA ( mRNA ) , with measurable expression at doses as low as 1 pM PTH .	To investigate postreceptor mechanisms of action, MC3T3-E1 cells were induced to differentiate to optimize PTH-1 receptor expression, and differentiated MC3T3-E1 cells were treated with varying doses of PTH (1-34) for 1 h. Northern blot analysis revealed a dose dependent stimulation of steady state c-fos messenger RNA (mRNA), with measurable expression at doses as low as 1 pM PTH.	15	36	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH-1 receptor	PTH-1 receptor	PTH-1 receptor	29	30	15	17
A shorter version of intact PTH , PTH 1-34 ( teriparatide ) , can stimulate the PTHR 1 with equivalent affinity ( K I of 4nM vs. 2nM , respectively , in a radioligand competition assay ) 11 .	A shorter version of intact PTH, PTH 1-34 (teriparatide), can stimulate the PTHR 1 with equivalent affinity (K I of 4nM vs. 2nM, respectively, in a radioligand competition assay) 11.	2	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	5	6	16	17
PTH ( 1-31 ) , however , stimulated AC and PLC but not PTH1R endocytosis .	PTH (1-31), however, stimulated AC and PLC but not PTH1R endocytosis.	0	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	0	1	13	14
PTH ( 1-34 ) activation of PTH1R stimulates adenylate cyclase ( AC )-mediated cAMP production by Galphas and increases PLC mediated [ Ca 2+ ] i ( cytosolic free Ca 2+ concentration ) by Galphaq .	PTH (1-34) activation of PTH1R stimulates adenylate cyclase (AC)-mediated cAMP production by Galphas and increases PLC mediated [Ca 2+] i (cytosolic free Ca 2+ concentration) by Galphaq.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	0	1	6	7
Human PTH activated chicken PTH1R and stimulated cAMP production with an apparently similar potency to chicken PTHrP .	Human PTH activated chicken PTH1R and stimulated cAMP production with an apparently similar potency to chicken PTHrP.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	1	2	4	5
The results support that PTH ( 1-34 ) not only activates PTH1R but can also uniquely sense Ca 2+ .	The results support that PTH (1-34) not only activates PTH1R but can also uniquely sense Ca 2+.	4	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	4	5	11	12
While the PTH and PTHrP receptor ( PTH1R ) is expressed and biologically active in VSMC XREF_BIBR , XREF_BIBR , PTH1R activation by PTH ( 1-34 ) in kidney , bone , and hematopoietic niche may also influence arteriosclerotic processes XREF_BIBR .	While the PTH and PTHrP receptor (PTH1R) is expressed and biologically active in VSMC XREF_BIBR, XREF_BIBR, PTH1R activation by PTH (1-34) in kidney, bone, and hematopoietic niche may also influence arteriosclerotic processes XREF_BIBR.	20	34	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	23	24	20	21
As with other G protein coupled receptors , stimulation of PTH1R by PTH induces a GDP-GTP exchange on the alpha-subunit of the heterotrimeric G protein .	As with other G protein coupled receptors, stimulation of PTH1R by PTH induces a GDP-GTP exchange on the alpha-subunit of the heterotrimeric G protein.	8	13	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	12	13	10	11
Paradoxically , while activation of PTH1R by PTH or PTH ( 1-34 ) results in bone resorption ( release of Ca 2+ from bone ) , intermittent injection of PTH ( 1-34 ) can enhance bone formation and is an FDA approved treatment for osteoporosis 16 .	Paradoxically, while activation of PTH1R by PTH or PTH (1-34) results in bone resorption (release of Ca 2+ from bone), intermittent injection of PTH (1-34) can enhance bone formation and is an FDA approved treatment for osteoporosis 16.	3	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	7	8	5	6
Taken together , these results raised the possibility that incomplete PTHR recycling induced by PTH ( 7-34 ) is due to a degradative process Effect of PTH ( 7-34 ) in PTHR-proteasome depended degradation .	Taken together, these results raised the possibility that incomplete PTHR recycling induced by PTH (7-34) is due to a degradative process Effect of PTH (7-34) in PTHR-proteasome depended degradation.	10	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	14	15	10	11
It was determined that simply mutating F34 to A in PTH induced PTH1R internalization in a NHERF1 independent manner .	It was determined that simply mutating F34 to A in PTH induced PTH1R internalization in a NHERF1 independent manner.	5	13	induced	Positive_early_activation	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	10	11	12	13
Zebrafish PTH1R is activated similarly by the N-terminal peptides of fugu PTHrPA , human PTHrP and PTH and zebrafish PTH1 but not zebrafish PTH2 while zebrafish PTH3R has preference for fugu PTHrPA , human PTHrP and zebrafish PTH1 and PTH2 but not for human PTH [ XREF_BIBR , XREF_BIBR ] .	Zebrafish PTH1R is activated similarly by the N-terminal peptides of fugu PTHrPA, human PTHrP and PTH and zebrafish PTH1 but not zebrafish PTH2 while zebrafish PTH3R has preference for fugu PTHrPA, human PTHrP and zebrafish PTH1 and PTH2 but not for human PTH [XREF_BIBR, XREF_BIBR].	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	16	17	1	2
A cascade of cell specific events of PTH mediates PTH1R function to regulate extracellular mineral ion homeostasis and bone remodeling .	A cascade of cell specific events of PTH mediates PTH1R function to regulate extracellular mineral ion homeostasis and bone remodeling.	5	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	7	8	9	10
PTH1R activation by PTHrP ( 1-36 ) or PTH ( 1-34 ) had no effect on proliferation but improved MC survival .	PTH1R activation by PTHrP (1-36) or PTH (1-34) had no effect on proliferation but improved MC survival.	0	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	8	9	0	1
Human ( hu ) PTH1R can be activated by PTH and PTHrP with indistinguishable potency in downstream signaling pathways , including cAMP , phospholipase C ( PLC ) , and ERK1/2 .	Human (hu) PTH1R can be activated by PTH and PTHrP with indistinguishable potency in downstream signaling pathways, including cAMP, phospholipase C (PLC), and ERK1/2.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	9	10	4	5
PTH1R is activated by PTH and PTHrP , both of which have been shown to regulate bone metabolism and differentiation .	PTH1R is activated by PTH and PTHrP, both of which have been shown to regulate bone metabolism and differentiation.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	4	5	0	1
We used it to engineer ( D )-peptide analogs of the agonists GLP-1 and PTH that successfully activate GLP1R and PTH1R , respectively .	We used it to engineer (D)-peptide analogs of the agonists GLP-1 and PTH that successfully activate GLP1R and PTH1R, respectively.	1	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	14	15	20	21
Intriguingly , despite these reduced cell surface levels , PTH induced PTHR signaling remains elevated upon SNX27 and retromer disruption .	Intriguingly, despite these reduced cell surface levels, PTH induced PTHR signaling remains elevated upon SNX27 and retromer disruption.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	9	10	11	12
These results are consistent with the conclusion that USP2 dictates receptor fate after PTHR endocytosis induced by PTH ( 1-34 ) .	These results are consistent with the conclusion that USP2 dictates receptor fate after PTHR endocytosis induced by PTH (1-34).	13	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	17	18	13	14
PTH ( 1-34 ) induced internalization of the PTH1R with a concomitant increase in the colocalization of the receptor with PLD1 in intracellular vesicles and in a perinuclear , ADP ribosylation factor-1-positive compartment .	PTH (1-34) induced internalization of the PTH1R with a concomitant increase in the colocalization of the receptor with PLD1 in intracellular vesicles and in a perinuclear, ADP ribosylation factor-1-positive compartment.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	0	1	8	9
In mammals , it has been shown that activation of PTH1R by PTH ( 1-34 ) and PTHrP ( 1-34 ) are comparable to that by the corresponding full length peptides .	In mammals, it has been shown that activation of PTH1R by PTH (1-34) and PTHrP (1-34) are comparable to that by the corresponding full length peptides.	8	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	12	13	10	11
XREF_BIBR PTHR1 , a G protein coupled receptor linked to adenylyl cyclase , is activated by the N-terminal regions of both PTH and PTHrP .	XREF_BIBR PTHR1, a G protein coupled receptor linked to adenylyl cyclase, is activated by the N-terminal regions of both PTH and PTHrP.	0	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	21	22	1	2
Conversely , PTH ( 7-34 ) rapidly stimulated PTH1R internalization without activating AC or PLC ..	Conversely, PTH (7-34) rapidly stimulated PTH1R internalization without activating AC or PLC..	2	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	2	3	8	9
PTH stimulates PTH1R to increase intracellular cAMP , which in turn activates PKA leading to phosphorylation of the cAMP response element binding protein ( CREB ) .	PTH stimulates PTH1R to increase intracellular cAMP, which in turn activates PKA leading to phosphorylation of the cAMP response element binding protein (CREB).	0	3	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	0	1	2	3
For example , PTH can induce endocytosis of a PTH1R and TGFbeta type II receptor ( TbetaRII ) complex , resulting in spatial and temporal integrated coupling of bone resorption and formation .	For example, PTH can induce endocytosis of a PTH1R and TGFbeta type II receptor (TbetaRII) complex, resulting in spatial and temporal integrated coupling of bone resorption and formation.	3	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	3	4	9	10
It is known that Na + / H + exchanger regulatory factor-1 ( NHERF1 ) , implicated in protein targeting and in the assembly of protein complexes , inhibits PTHR internalization induced by PTH ( 7-34 ) .	It is known that Na + / H + exchanger regulatory factor-1 (NHERF1), implicated in protein targeting and in the assembly of protein complexes, inhibits PTHR internalization induced by PTH (7-34).	29	35	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	33	34	29	30
Furthermore , the resistance to PTH may be explained by an abnormal interaction between PTH and the PTH1R receptor , eventually modulated by a compensatory elevation of PTH .	Furthermore, the resistance to PTH may be explained by an abnormal interaction between PTH and the PTH1R receptor, eventually modulated by a compensatory elevation of PTH.	17	28	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	27	28	17	18
It has been proposed that cAMP generation by PTH activated PTHR1 is maintained in early endosomes by a positive feedback mechanism , where arrestin dependent activation of ERK1/2 inhibits phosphodiesterases ( PDEs ) and favors the cAMP response .	It has been proposed that cAMP generation by PTH activated PTHR1 is maintained in early endosomes by a positive feedback mechanism, where arrestin dependent activation of ERK1/2 inhibits phosphodiesterases (PDEs) and favors the cAMP response.	6	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	8	9	10	11
Phosphorylated FAK Tyr 397 binds Src family kinases ( Src ) , which in turn directly phosphorylate FAK Tyr 576/577 to produce maximal FAK enzymatic activity .	Phosphorylated FAK Tyr 397 binds Src family kinases (Src), which in turn directly phosphorylate FAK Tyr 576/577 to produce maximal FAK enzymatic activity.	0	25	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Phosphorylated FAK Tyr 397 binds Src family kinases	fak	FAK	FAK	fak	1	2	23	24
Both Tpl2 and Ca 2+ stimulate phosphorylation of FAK at Tyr 397 and promote the extended residency of FAK at focal adhesions , focal adhesion disassembly and cell edge retraction .	Both Tpl2 and Ca 2+ stimulate phosphorylation of FAK at Tyr 397 and promote the extended residency of FAK at focal adhesions, focal adhesion disassembly and cell edge retraction.	1	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Tpl2 and Ca 2+ stimulate phosphorylation of FAK at Tyr 397	fak	FAK	FAK	fak	8	9	18	19
To determine whether the kinase activity of FAK is critical for MET and CAT induced HCC development , we examined whether ectopic expression of FAK or a FAK-kinase dead mutant can restore MET and CAT induced tumor formation to Alb-Cre ; Fak flox and flox ( Hep incrementFak ) mice .	To determine whether the kinase activity of FAK is critical for MET and CAT induced HCC development, we examined whether ectopic expression of FAK or a FAK-kinase dead mutant can restore MET and CAT induced tumor formation to Alb-Cre; Fak flox and flox (Hep incrementFak) mice.	22	42	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	expression of FAK	fak	Fak	Fak	fak	24	25	41	42
c-Met activation with HGF induced a strong phosphorylation of FAK at Tyr 397 and Tyr 925 , which are important for the maximal adhesion induced activation of FAK and signaling to downstream effectors .	c-Met activation with HGF induced a strong phosphorylation of FAK at Tyr 397 and Tyr 925, which are important for the maximal adhesion induced activation of FAK and signaling to downstream effectors.	7	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	phosphorylation of FAK at Tyr 397 and Tyr 925	fak	FAK	FAK	fak	9	10	27	28
FAK autophosphorylation at Tyr397 ( Y397 FAK ) creates a binding site for c-Src that phosphorylates FAK at Tyr576 ( Y576 FAK ) and Tyr577 ( Y577 FAK ) , promoting maximal FAK catalytic activity .	FAK autophosphorylation at Tyr397 (Y397 FAK) creates a binding site for c-Src that phosphorylates FAK at Tyr576 (Y576 FAK) and Tyr577 (Y577 FAK), promoting maximal FAK catalytic activity.	15	34	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	phosphorylates FAK at Tyr576 (Y576	fak	FAK	FAK	fak	16	17	32	33
Src binding and phosphorylation of FAK Y576/577 leads to full activation of FAK , which plays a critical role in regulating cell spreading and migration through regulating formation and turnover of focal adhesions XREF_BIBR .	Src binding and phosphorylation of FAK Y576/577 leads to full activation of FAK, which plays a critical role in regulating cell spreading and migration through regulating formation and turnover of focal adhesions XREF_BIBR.	3	13	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	FAK	phosphorylation of FAK	fak	FAK	FAK	fak	5	6	12	13
Src induced FAK phosphorylation at Tyr 576 and Tyr 577 further enhanced the catalytic activity of FAK .	Src induced FAK phosphorylation at Tyr 576 and Tyr 577 further enhanced the catalytic activity of FAK.	0	17	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Src induced FAK phosphorylation at Tyr 576 and Tyr 577	fak	FAK	FAK	fak	2	3	16	17
Inhibition of FAK phosphorylation using FAK inhibitor has significantly reduced the radiation induced activation of FAK by 60 % and 66 % in DAOY and D283 cells , respectively ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Inhibition of FAK phosphorylation using FAK inhibitor has significantly reduced the radiation induced activation of FAK by 60% and 66% in DAOY and D283 cells, respectively (XREF_FIG and XREF_SUPPLEMENTARY).	2	16	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK phosphorylation	fak	FAK	FAK	fak	2	3	15	16
Transient overexpression of wild-type FAK under these conditions resulted in adhesion independent FAK activation , as indicated by constitutive FAK Y397 phosphorylation in suspended cells ( XREF_FIG B ) .	Transient overexpression of wild-type FAK under these conditions resulted in adhesion independent FAK activation, as indicated by constitutive FAK Y397 phosphorylation in suspended cells (XREF_FIG B).	1	14	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	FAK	overexpression of wild-type FAK	fak	FAK	FAK	fak	4	5	12	13
The subsequent binding of FAK to Src likely contributes to Src kinase activation , which in turn promotes the phosphorylation of FAK at additional tyrosine residues to stimulate maximal FAK kinase activity .	The subsequent binding of FAK to Src likely contributes to Src kinase activation, which in turn promotes the phosphorylation of FAK at additional tyrosine residues to stimulate maximal FAK kinase activity.	2	25	contributes	Positive_regulation_syntax_7_verb	Positive_activation	Positive_regulation	FAK	binding of FAK to Src	fak	FAK	Src kinase activation, which in turn promotes the phosphorylation of FAK	fak	4	5	21	22
Phosphorylation of FAK Y925 is mediated by c-Src and promotes the binding of the Grb2 adaptor protein to FAK , leading to ERK and MAP kinase activation .	Phosphorylation of FAK Y925 is mediated by c-Src and promotes the binding of the Grb2 adaptor protein to FAK, leading to ERK and MAP kinase activation.	0	19	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	FAK	Phosphorylation of FAK Y925	fak	FAK	FAK	fak	2	3	18	19
FAK and Pyk2-CT expression and Pyk2 overexpression enhanced FAK -/ - cell motility approximately threefold over cells transfected with vector alone ( XREF_FIG B ) .	FAK and Pyk2-CT expression and Pyk2 overexpression enhanced FAK -/ - cell motility approximately threefold over cells transfected with vector alone (XREF_FIG B).	0	12	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK and Pyk2-CT expression	fak	FAK	FAK	fak	0	1	8	9
XIAP knockdown reduces shear stress enhanced phosphorylation of FAK at Y576 and induces shear stress triggered translocation of FAK into nucleus .	XIAP knockdown reduces shear stress enhanced phosphorylation of FAK at Y576 and induces shear stress triggered translocation of FAK into nucleus.	0	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	XIAP knockdown reduces shear stress enhanced phosphorylation of FAK at Y576	fak	FAK	FAK	fak	8	9	18	19
The activated Src contributes to maximal FAK activation by phosphorylation of FAK at Y576 and Y577 in the kinase activation loop and at Y861 and Y925 in the PR region of FAK .	The activated Src contributes to maximal FAK activation by phosphorylation of FAK at Y576 and Y577 in the kinase activation loop and at Y861 and Y925 in the PR region of FAK.	6	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	FAK	phosphorylation of FAK at Y576	fak	FAK	FAK	fak	11	12	6	7
XREF_BIBR note that pH regulated FAK Y397 phosphorylation required combined integrin stimulation and elevated pH to activate FAK .	XREF_BIBR note that pH regulated FAK Y397 phosphorylation required combined integrin stimulation and elevated pH to activate FAK.	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK Y397 phosphorylation	fak	FAK	FAK	fak	5	6	17	18
One possible explanation might be that FAK phosphorylation induces cleavage of FAK with the N-terminus of FAK which contains the YFP moiety thus being no longer addressed to FAs .	One possible explanation might be that FAK phosphorylation induces cleavage of FAK with the N-terminus of FAK which contains the YFP moiety thus being no longer addressed to FAs.	6	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK phosphorylation	fak	FAK	FAK	fak	6	7	11	12
FRAP analysis on migrating astrocytoma cells has demonstrated that FAK Tyr 397 autophosphorylation increases specifically the time residency of FAK at FAs but not in the cytoplasm .	FRAP analysis on migrating astrocytoma cells has demonstrated that FAK Tyr 397 autophosphorylation increases specifically the time residency of FAK at FAs but not in the cytoplasm.	9	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK Tyr 397 autophosphorylation	fak	FAK	FAK	fak	9	10	19	20
In mouse skin , the greater expression of total FAK in the epidermis of non exposed and 11 h after acute UVB treated WT mice compared to that of OPN-null mice , allows the induced-OPN to rapidly interact with integrin and activate FAK to enhance cell survival of WT keratinocytes as oppose those of OPN-null mice .	In mouse skin, the greater expression of total FAK in the epidermis of non exposed and 11 h after acute UVB treated WT mice compared to that of OPN-null mice, allows the induced-OPN to rapidly interact with integrin and activate FAK to enhance cell survival of WT keratinocytes as oppose those of OPN-null mice.	6	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	expression of total FAK	fak	FAK	FAK	fak	9	10	42	43
In Fak-/- MEFs , overexpression of FAK is able to provide protection for cells lacking signals from extracellular matrix , while co-expression of FAK and Palm-PTK6-YF induces stronger FAK and AKT activation and synergistically promotes cell survival ( XREF_FIG ) .	In Fak-/- MEFs, overexpression of FAK is able to provide protection for cells lacking signals from extracellular matrix, while co-expression of FAK and Palm-PTK6-YF induces stronger FAK and AKT activation and synergistically promotes cell survival (XREF_FIG).	21	31	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	co-expression of FAK	fak	FAK	FAK	fak	23	24	28	29
Cabozantinib resistant tumor islets have increased level of pFAK compared to those in untreated tumors ( XREF_FIG ) , supporting FAK activation in the survival of tumor cells .	Cabozantinib resistant tumor islets have increased level of pFAK compared to those in untreated tumors (XREF_FIG), supporting FAK activation in the survival of tumor cells.	0	21	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pFAK	Cabozantinib resistant tumor islets have increased level of pFAK	pfak	FAK	FAK	fak	8	9	20	21
9 Also , the expression of this full-length FAK containing bio-sensors may lead to the perturbation of the endogenous downstream signaling pathways , possibly by introducing extra enzymatic activities of FAK in host cells .	9 Also, the expression of this full-length FAK containing bio-sensors may lead to the perturbation of the endogenous downstream signaling pathways, possibly by introducing extra enzymatic activities of FAK in host cells.	4	31	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	expression of this full-length FAK	fak	FAK	FAK	fak	8	9	30	31
Specifically , FAK was phosphorylated at Y397 , a site known to be autophosphorylated upon integrin signaling and that serves as a docking site for phosphatidylinositol 3-kinase , as well as at Y576 and Y577 , which are sites that enhance FAK kinase activity when phosphorylated .	Specifically, FAK was phosphorylated at Y397, a site known to be autophosphorylated upon integrin signaling and that serves as a docking site for phosphatidylinositol 3-kinase, as well as at Y576 and Y577, which are sites that enhance FAK kinase activity when phosphorylated.	2	43	enhance	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FAK	FAK was phosphorylated at Y397, a site known to be autophosphorylated upon integrin signaling and that serves as a docking site for phosphatidylinositol 3-kinase, as well as at Y576	fak	FAK	FAK	fak	2	3	41	42
Src can be subsequently recruited to phosphorylate Tyr516 and Tyr517 in the kinase domain of FAK , causing the further activation of FAK .	Src can be subsequently recruited to phosphorylate Tyr516 and Tyr517 in the kinase domain of FAK, causing the further activation of FAK.	6	23	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	phosphorylate Tyr516 and Tyr517 in the kinase domain of FAK	fak	FAK	FAK	fak	15	16	22	23
Immunoblotting of lysates prepared from cells following 72 hours of growth in suspension showed that co-expression of Palm-PTK6-YF and FAK induces higher FAK activation ( PY576 and Y577 ) even under suspended conditions , resulting in substantially higher levels of AKT activation ( phospho-Thr-308 , phospho-Ser-473 ) and lower levels of cleaved caspase 3 ( CC3 ) and p27 ( XREF_FIG ) .	Immunoblotting of lysates prepared from cells following 72 hours of growth in suspension showed that co-expression of Palm-PTK6-YF and FAK induces higher FAK activation (PY576 and Y577) even under suspended conditions, resulting in substantially higher levels of AKT activation (phospho-Thr-308, phospho-Ser-473) and lower levels of cleaved caspase 3 (CC3) and p27 (XREF_FIG).	15	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	co-expression of Palm-PTK6-YF and FAK	fak	FAK	FAK	fak	19	20	22	23
Mitosis specific phosphorylation is responsible for the disruption of FAK and CAS binding because dephosphorylation of mitotic FAK in vitro by protein serine/threonine phosphatase 1 restores the ability of FAK to associate with CAS , though not with c-Src .	Mitosis specific phosphorylation is responsible for the disruption of FAK and CAS binding because dephosphorylation of mitotic FAK in vitro by protein serine/threonine phosphatase 1 restores the ability of FAK to associate with CAS, though not with c-Src.	14	30	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	dephosphorylation of mitotic FAK	fak	FAK	FAK	fak	17	18	29	30
Moreover , M13 caused decreased FAK levels in both BT474 and HCT116 colon cancer cells , decreased complex of FAK and Mdm-2 and activated caspase-8 in BT474 cells and HCT116 colon cancer cells .	Moreover, M13 caused decreased FAK levels in both BT474 and HCT116 colon cancer cells, decreased complex of FAK and Mdm-2 and activated caspase-8 in BT474 cells and HCT116 colon cancer cells.	5	21	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK levels	fak	FAK	FAK	fak	5	6	19	20
Subsequently , CD99CRIII3 induced FAK phosphorylation at S910 , which led to the recruitment of PTPN12 and PIN1 to FAK , followed by FAK dephosphorylation at Y397 .	Subsequently, CD99CRIII3 induced FAK phosphorylation at S910, which led to the recruitment of PTPN12 and PIN1 to FAK, followed by FAK dephosphorylation at Y397.	2	20	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	FAK	CD99CRIII3 induced FAK phosphorylation at S910	fak	FAK	FAK	fak	4	5	19	20
The much greater spreading area and slower migration of SMCs on InF , as well as a higher prevalence of stress fibers and vinculin rich focal adhesions , is an indicator of significant FAK autophosphorylation , 36 which in turn may recruit and activate c-Src and enhance overall FAK signaling .	The much greater spreading area and slower migration of SMCs on InF, as well as a higher prevalence of stress fibers and vinculin rich focal adhesions, is an indicator of significant FAK autophosphorylation, 36 which in turn may recruit and activate c-Src and enhance overall FAK signaling.	33	49	enhance	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FAK	FAK autophosphorylation	fak	FAK	FAK	fak	33	34	48	49
The ability of these sequences in FRNK to suppress proapoptotic signals in FAT should enable FRNK to be expressed in a regulated fashion and to modulate certain functions of FAK -- for instance cell spreading -- without killing the cells in which it is expressed .	The ability of these sequences in FRNK to suppress proapoptotic signals in FAT should enable FRNK to be expressed in a regulated fashion and to modulate certain functions of FAK -- for instance cell spreading -- without killing the cells in which it is expressed.	4	34	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FRNK	FRNK to suppress proapoptotic signals in FAT should enable FRNK to be expressed	frnk	FAK	FAK	fak	6	7	29	30
Phosphorylation of FAK on Tyr 576 by Src activates FAK .	Phosphorylation of FAK on Tyr 576 by Src activates FAK.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Phosphorylation of FAK on Tyr 576	fak	FAK	FAK	fak	2	3	9	10
Interestingly , Pyk2 overexpression only weakly augmented FAK- cell migration to FN whereas transient FAK expression promoted FAK- cell migration to FN efficiently compared with FAK+ cells .	Interestingly, Pyk2 overexpression only weakly augmented FAK- cell migration to FN whereas transient FAK expression promoted FAK- cell migration to FN efficiently compared with FAK+ cells.	14	19	promoted	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FAK	FAK expression	fak	FAK-	FAK-	fak-	14	15	17	18
The FAK dependent signaling cascade in the infected cells is initiated by the autophosphorylation of FAK at tyrosine 397 , which is a major phosphorylation site required for the outside-in signaling of integrins [ XREF_BIBR , XREF_BIBR ] .	The FAK dependent signaling cascade in the infected cells is initiated by the autophosphorylation of FAK at tyrosine 397, which is a major phosphorylation site required for the outside-in signaling of integrins [XREF_BIBR, XREF_BIBR].	1	16	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FAK	autophosphorylation of FAK	fak	FAK	FAK	fak	15	16	1	2
Our observations indicate that tyrosine phosphorylation of FAK induces delocalization of FAK from FAs to membrane ruffles since increased phosphorylated FAK was found at membrane ruffles after PV treatment ( XREF_FIG ) .	Our observations indicate that tyrosine phosphorylation of FAK induces delocalization of FAK from FAs to membrane ruffles since increased phosphorylated FAK was found at membrane ruffles after PV treatment (XREF_FIG).	4	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	tyrosine phosphorylation of FAK	fak	FAK	FAK	fak	7	8	11	12
The HPV infected cells also escaped from anoikis by the E6 mediated expression of FAK and the phosphorylation of paxillin , which activates FAK .	The HPV infected cells also escaped from anoikis by the E6 mediated expression of FAK and the phosphorylation of paxillin, which activates FAK.	10	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	E6 mediated expression of FAK	fak	FAK	FAK	fak	14	15	23	24
We showed that FAK can be activated by mechanical stretch and , with a 10 muM PF 573228 ( a novel small molecule inhibitor of FAK ) treatment , FAK autophosphorylation at Tyr397 is significantly decreased .	We showed that FAK can be activated by mechanical stretch and, with a 10 muM PF 573228 (a novel small molecule inhibitor of FAK) treatment, FAK autophosphorylation at Tyr397 is significantly decreased.	23	36	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK autophosphorylation at Tyr397	fak	FAK	FAK	fak	29	30	25	26
The increase in cytoskeletal FAK phosphorylation without increased FAK protein suggests autophosphorylation and increased cytoskeletal FAK activity .	The increase in cytoskeletal FAK phosphorylation without increased FAK protein suggests autophosphorylation and increased cytoskeletal FAK activity.	4	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK phosphorylation	fak	FAK	FAK	fak	4	5	15	16
Integrins and Src stimulate FAK autophosphorylation at Tyr 397 which subsequently promotes maximal FAK 576/577 Tyr P.	Integrins and Src stimulate FAK autophosphorylation at Tyr 397 which subsequently promotes maximal FAK 576/577 Tyr P.	2	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Src stimulate FAK autophosphorylation at Tyr 397	fak	FAK	FAK	fak	4	5	13	14
In contrast , the specific PtdIns 3-kinase inhibitor LY294002 induced apoptosis and markedly decreased p125 ( FAK ) expression and increased FAK proteolysis but had little effect on Y861 phosphorylation .	In contrast, the specific PtdIns 3-kinase inhibitor LY294002 induced apoptosis and markedly decreased p125 (FAK) expression and increased FAK proteolysis but had little effect on Y861 phosphorylation.	5	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	PtdIns 3-kinase inhibitor LY294002 induced apoptosis and markedly decreased p125 (FAK) expression	fak	FAK	FAK	fak	16	17	21	22
Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85 , the regulatory subunit of phosphatidylinositol-3-kinase .	Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase.	0	18	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397	fak	FAK	FAK	fak	4	5	17	18
Recently , growth factor receptor phosphorylation of FAK at Y194 within the FERM F2 lobe was shown to promote FAK activation .	Recently, growth factor receptor phosphorylation of FAK at Y194 within the FERM F2 lobe was shown to promote FAK activation.	2	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	growth factor receptor phosphorylation of FAK at Y194	fak	FAK	FAK	fak	7	8	19	20
The increase in FAK tyrosine phosphorylation was associated with increase in its kinase activity and further supported by increased phosphotyrosine accumulation on focal adhesions and increased membrane localization of FAK after stimulation by insulin .	The increase in FAK tyrosine phosphorylation was associated with increase in its kinase activity and further supported by increased phosphotyrosine accumulation on focal adhesions and increased membrane localization of FAK after stimulation by insulin.	3	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK tyrosine phosphorylation	fak	FAK	FAK	fak	3	4	29	30
Activated Src , in turn , phosphorylates FAK and further enhances FAK activity , thereby forming a positive feedback loop leading to the activation of downstream signaling molecules , such as ERK and PI3-K and AKT .	Activated Src, in turn, phosphorylates FAK and further enhances FAK activity, thereby forming a positive feedback loop leading to the activation of downstream signaling molecules, such as ERK and PI3-K and AKT.	6	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	phosphorylates FAK	fak	FAK	FAK	fak	7	8	11	12
Integrin clustering induces autophosphorylation of FAK on Tyr397 , enhancing FAK kinase activity and recruits the adhesion scaffolding protein paxillin .	Integrin clustering induces autophosphorylation of FAK on Tyr397, enhancing FAK kinase activity and recruits the adhesion scaffolding protein paxillin.	0	12	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Integrin clustering induces autophosphorylation of FAK on Tyr397	fak	FAK	FAK	fak	5	6	10	11
Studying S-> A nonphosphorylatable point mutants suggests that these sites coordinately upregulate FAK Y397 tyrosine phosphorylation , which conventionally initiates FAK activation , and mediate pressure induced cancer cell adhesion .	Studying S-> A nonphosphorylatable point mutants suggests that these sites coordinately upregulate FAK Y397 tyrosine phosphorylation, which conventionally initiates FAK activation, and mediate pressure induced cancer cell adhesion.	12	21	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK Y397 tyrosine phosphorylation	fak	FAK	FAK	fak	12	13	20	21
Given that activated Src phosphorylates FAK and enhances FAK activity and that PTP-PEST cooperates with Csk to inactivate Src through its capacity to dephosphorylate the positive regulatory Tyr of Src family kinases , PTP-PEST-induced reduction of FAK phosphorylation at Y397 may be a combined effect from direct FAK dephosphorylation and inhibition of Src activity .	Given that activated Src phosphorylates FAK and enhances FAK activity and that PTP-PEST cooperates with Csk to inactivate Src through its capacity to dephosphorylate the positive regulatory Tyr of Src family kinases, PTP-PEST-induced reduction of FAK phosphorylation at Y397 may be a combined effect from direct FAK dephosphorylation and inhibition of Src activity.	3	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Src phosphorylates FAK	fak	FAK	FAK	fak	5	6	8	9
High FAK activation caused by high adhesion or by high FAK expression stimulates proliferation , whereas minimal adhesion prevents FAK activation and yields inactive complexes that inhibit proliferation .	High FAK activation caused by high adhesion or by high FAK expression stimulates proliferation, whereas minimal adhesion prevents FAK activation and yields inactive complexes that inhibit proliferation.	1	12	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FAK	FAK expression	fak	FAK	FAK	fak	10	11	1	2
Cycloheximide , the protein synthesis inhibitor , induced PAEC apoptosis more slowly than staurosporine , but did not induce FAK dephosphorylation or rapid focal adhesion disruption , and instead caused a slower loss of focal adhesions and a marked increase in FAK proteolysis .	Cycloheximide, the protein synthesis inhibitor, induced PAEC apoptosis more slowly than staurosporine, but did not induce FAK dephosphorylation or rapid focal adhesion disruption, and instead caused a slower loss of focal adhesions and a marked increase in FAK proteolysis.	0	42	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Cycloheximide, the protein synthesis inhibitor, induced PAEC apoptosis more slowly than staurosporine, but did not induce FAK dephosphorylation	fak	FAK	FAK	fak	19	20	41	42
In both cases , ectopic FAK mRNA expression rescued the FAK morphant anteriorized phenotype .	In both cases, ectopic FAK mRNA expression rescued the FAK morphant anteriorized phenotype.	5	13	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK mRNA expression	fak	FAK	FAK	fak	5	6	10	11
We show that inhibition of FAK signalling by expression of FAK or FAK siRNA did not affect cell proliferation or survival in SCC40 and SCC38 cells .	We show that inhibition of FAK signalling by expression of FAK or FAK siRNA did not affect cell proliferation or survival in SCC40 and SCC38 cells.	5	13	signalling	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	FAK	expression of FAK	fak	FAK	FAK	fak	10	11	5	6
Finally , stretch induced FAK phosphorylation at Y397 led to activation of FAK kinase activity resulting in proliferation and differentiation of neonatal cardiac fibroblasts into myofibroblasts .	Finally, stretch induced FAK phosphorylation at Y397 led to activation of FAK kinase activity resulting in proliferation and differentiation of neonatal cardiac fibroblasts into myofibroblasts.	4	14	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	FAK	FAK phosphorylation at Y397	fak	FAK	FAK	fak	4	5	12	13
S1P and thrombin induced distinct patterns of FAK site specific phosphorylation with the FAK Y576 phosphorylation site targeted by SIP challenge and phosphorylation of three FAK sites ( Y397 , Y576 , and Y925 ) in response to thrombin stimulation .	S1P and thrombin induced distinct patterns of FAK site specific phosphorylation with the FAK Y576 phosphorylation site targeted by SIP challenge and phosphorylation of three FAK sites (Y397, Y576, and Y925) in response to thrombin stimulation.	13	26	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FAK	phosphorylation of three FAK	fak	FAK	FAK	fak	25	26	13	14
Expression of wild-type but not calpain resistant FAK rescues talin dynamics in FAK deficient cells .	Expression of wild-type but not calpain resistant FAK rescues talin dynamics in FAK deficient cells.	0	14	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Expression of wild-type but not calpain resistant FAK	fak	FAK	FAK	fak	7	8	12	13
Ectopic FAK protein expression rescues the FAK morphant phenotype .	Ectopic FAK protein expression rescues the FAK morphant phenotype.	1	8	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK protein expression	fak	FAK	FAK	fak	1	2	6	7
Stable Pyk2 and FAK-CT Expression Rescues FAK -/- Morphological Defects .	Stable Pyk2 and FAK-CT Expression Rescues FAK -/- Morphological Defects.	3	9	Rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK-CT	FAK-CT Expression	fak-ct	FAK	FAK	fak	3	4	6	7
Activated neutrophils release VEGF , which in turn phosphorylates endothelial FAK and induces FAK dependent hyperpermeability .	Activated neutrophils release VEGF, which in turn phosphorylates endothelial FAK and induces FAK dependent hyperpermeability.	3	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	VEGF, which in turn phosphorylates endothelial FAK	fak	FAK	FAK	fak	10	11	13	14
Using this approach , we demonstrated that increase in FAK phosphorylation induces delocalization of FAK from FAs to membrane ruffles .	Using this approach, we demonstrated that increase in FAK phosphorylation induces delocalization of FAK from FAs to membrane ruffles.	9	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK phosphorylation	fak	FAK	FAK	fak	9	10	14	15
In the PTC cell lines , RAP1GAP delayed FAK phosphorylation at Y576 , a site that when phosphorylated by SRC enhances FAK activity ( XREF_FIG ) .	In the PTC cell lines, RAP1GAP delayed FAK phosphorylation at Y576, a site that when phosphorylated by SRC enhances FAK activity (XREF_FIG).	8	22	enhances	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	FAK	FAK phosphorylation at Y576	fak	FAK	FAK	fak	8	9	21	22
Tricin decreased FAK protein levels and suppressed focal-adhesion-kinase ( FAK )-downstream-signal activation .	Tricin decreased FAK protein levels and suppressed focal-adhesion-kinase (FAK)-downstream-signal activation.	0	10	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	Tricin decreased FAK protein levels	fak	FAK	FAK	fak	2	3	9	10
By analyzing lysates from FN stimulated FAK -/ -, DA2 , CA3 , CB4 , SE6 , and SX4 cells using phospho specific antibodies that recognize activated JNK kinases , Pyk2 and FAK-CT expression in CA3 and CB4 cells promoted FN stimulated JNK-1 activation equally as well as FAK in DA2 cells ( XREF_FIG A , lanes 2-4 ) .	By analyzing lysates from FN stimulated FAK -/ -, DA2, CA3, CB4, SE6, and SX4 cells using phospho specific antibodies that recognize activated JNK kinases, Pyk2 and FAK-CT expression in CA3 and CB4 cells promoted FN stimulated JNK-1 activation equally as well as FAK in DA2 cells (XREF_FIG A, lanes 2-4).	30	51	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK-CT	FAK-CT expression	fak-ct	FAK	FAK	fak	32	33	48	49
Instead , elevated FAK activity is associated with PTK2 amplification , consistent with a model whereby increased FAK dimerization induced by higher FAK levels contributes to catalytic activation 9 .	Instead, elevated FAK activity is associated with PTK2 amplification, consistent with a model whereby increased FAK dimerization induced by higher FAK levels contributes to catalytic activation 9.	17	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	FAK	FAK levels	fak	FAK	FAK	fak	22	23	17	18
The SOCS proteins also promoted polyubiquitination and degradation of FAK in a SOCS box dependent manner and inhibited FAK dependent signaling events , such as cell motility on fibronectin .	The SOCS proteins also promoted polyubiquitination and degradation of FAK in a SOCS box dependent manner and inhibited FAK dependent signaling events, such as cell motility on fibronectin.	1	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	SOCS proteins also promoted polyubiquitination and degradation of FAK	fak	FAK	FAK	fak	9	10	18	19
In malignant astrocytoma , it was reported that overexpression of FAK promote FAK association with p120RasGAP thereby promoting Ras activity through a competitive inhibition [ XREF_BIBR ] .	In malignant astrocytoma, it was reported that overexpression of FAK promote FAK association with p120RasGAP thereby promoting Ras activity through a competitive inhibition [XREF_BIBR].	8	13	promote	Positive_activation_token_1_verb	Positive_activation	Positive_activation	FAK	overexpression of FAK	fak	FAK	FAK	fak	10	11	12	13
HB-EGF increased p-FAK expression , and induced p-FAK redistribution and actin reorganization in migrating RIE-1 cells .	HB-EGF increased p-FAK expression, and induced p-FAK redistribution and actin reorganization in migrating RIE-1 cells.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-FAK	HB-EGF increased p-FAK expression	p-fak	p-FAK	p-FAK	p-fak	2	3	7	8
FAK phosphorylation at Tyr576 and Tyr577 in the kinase domain [ XREF_BIBR ] promotes maximal FAK catalytic activation that prompts the formation of signaling complexes with other proteins including PI3K , Akt [ XREF_BIBR ] and ERK [ XREF_BIBR ] .	FAK phosphorylation at Tyr576 and Tyr577 in the kinase domain [XREF_BIBR] promotes maximal FAK catalytic activation that prompts the formation of signaling complexes with other proteins including PI3K, Akt [XREF_BIBR] and ERK [XREF_BIBR].	0	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK phosphorylation at Tyr576	fak	FAK	FAK	fak	0	1	15	16
Inhibition of FAK with FAK-CD demonstrated significantly higher detachment of Nf1 + / + cells , suggesting that FAK can sequester NF1 from growth inhibitory functioning , and once FAK is inhibited by FAK-CD , NF1 is released for cellular functioning .	Inhibition of FAK with FAK-CD demonstrated significantly higher detachment of Nf1 + / + cells, suggesting that FAK can sequester NF1 from growth inhibitory functioning, and once FAK is inhibited by FAK-CD, NF1 is released for cellular functioning.	29	34	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FAK-CD	FAK-CD	FAK-CD	FAK	FAK	FAK	33	34	29	30
Tyrosine phosphorylation of focal adhesion kinase ( FAK ) family members FAK and PYK2 was significantly reduced by dasatinib , and select inhibitors for these kinases PF431396 , which inhibits both FAK and PYK2 , and PF573228 , which only inhibits FAK and not PYK2 , significantly reduced matrix contraction by transdifferentiated Muller cells .	Tyrosine phosphorylation of focal adhesion kinase (FAK) family members FAK and PYK2 was significantly reduced by dasatinib, and select inhibitors for these kinases PF431396, which inhibits both FAK and PYK2, and PF573228, which only inhibits FAK and not PYK2, significantly reduced matrix contraction by transdifferentiated Muller cells.	0	44	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	Tyrosine phosphorylation of focal adhesion kinase (FAK	fak	FAK	FAK	fak	7	8	41	42
However , only WT FAK expression promoted an approximately fourfold increase in FAK -/- v-Src Matrigel cell invasion compared with Ad-TA-infected cells ( XREF_FIG B ) .	However, only WT FAK expression promoted an approximately fourfold increase in FAK -/- v-Src Matrigel cell invasion compared with Ad-TA-infected cells (XREF_FIG B).	4	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK expression	fak	FAK	FAK	fak	4	5	12	13
Although Src activation has been reported to precede FAK activation in cancer cell adhesion XREF_BIBR , it is generally understood that FAK autophosphorylation at Y397 site was required for the recruitment of Src at the FA sites to fully activate FAK XREF_BIBR XREF_BIBR XREF_BIBR .	Although Src activation has been reported to precede FAK activation in cancer cell adhesion XREF_BIBR, it is generally understood that FAK autophosphorylation at Y397 site was required for the recruitment of Src at the FA sites to fully activate FAK XREF_BIBR XREF_BIBR XREF_BIBR.	21	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	FAK autophosphorylation at Y397	fak	FAK	FAK	fak	21	22	40	41
Once activated , Src phosphorylates FAK on a number of additional tyrosine residues , leading to further increased activity of FAK .	Once activated, Src phosphorylates FAK on a number of additional tyrosine residues, leading to further increased activity of FAK.	3	21	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Src phosphorylates FAK	fak	FAK	FAK	fak	5	6	20	21
Furthermore , phosphorylation of FAK at Tyr397 increases specifically the time-residency of FAK at FAs but not in cytosol , which in turn induces disassembly of FAs as observed using Y397F FAK mutant cells [ XREF_BIBR ] .	Furthermore, phosphorylation of FAK at Tyr397 increases specifically the time-residency of FAK at FAs but not in cytosol, which in turn induces disassembly of FAs as observed using Y397F FAK mutant cells [XREF_BIBR].	2	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	phosphorylation of FAK at Tyr397	fak	FAK	FAK	fak	4	5	12	13
The overexpression of FAK also promoted the association of FAK with p120RasGAP , which is a negative regulator of Ras activity , in the U-251MG cells cultured in aggregate suspension , with this association being abrogated upon plating of the cells onto vitronectin .	The overexpression of FAK also promoted the association of FAK with p120RasGAP, which is a negative regulator of Ras activity, in the U-251MG cells cultured in aggregate suspension, with this association being abrogated upon plating of the cells onto vitronectin.	1	10	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	overexpression of FAK	fak	FAK	FAK	fak	3	4	9	10
Stable Pyk2 and FAK-CT Expression Promotes Changes in FAK -/- Cell Morphology .	Stable Pyk2 and FAK-CT Expression Promotes Changes in FAK -/- Cell Morphology.	3	11	Promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK-CT	FAK-CT Expression	fak-ct	FAK	FAK	fak	3	4	8	9
Expression of the FAK Phe 397 mutant did not promote FAK- cell migration and overexpression of p50 ( csk ) in DA2 cells inhibited migration to FN suggesting that Src family PTKs play important roles in FAK mediated motility events .	Expression of the FAK Phe 397 mutant did not promote FAK- cell migration and overexpression of p50 (csk) in DA2 cells inhibited migration to FN suggesting that Src family PTKs play important roles in FAK mediated motility events.	0	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	Expression of the FAK	fak	FAK-	FAK-	fak-	3	4	10	11
Here , we show for the first time that phosphorylation of FAK Tyr ( 407 ) increases during serum starvation , contact inhibition , and cell cycle arrest , all conditions under which activating FAK Tyr ( 397 ) phosphorylation decreases .	Here, we show for the first time that phosphorylation of FAK Tyr (407) increases during serum starvation, contact inhibition, and cell cycle arrest, all conditions under which activating FAK Tyr (397) phosphorylation decreases.	9	35	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	phosphorylation of FAK Tyr (407	fak	FAK	FAK	fak	11	12	34	35
Notably , FAK-WT re-expression promoted survival and growth of FAK shRNA expressing ID8-IP under suspended conditions ( XREF_FIG ) .	Notably, FAK-WT re-expression promoted survival and growth of FAK shRNA expressing ID8-IP under suspended conditions (XREF_FIG).	2	10	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK-WT	FAK-WT re-expression	fak-wt	FAK	FAK	fak	2	3	9	10
It was demonstrated in vitro in nontransformed intestinal epithelial cells that autophosphorylation of FAK at tyrosine 397 promotes the association of FAK with PI3K , thereby disrupting the focal adhesion complex .	It was demonstrated in vitro in nontransformed intestinal epithelial cells that autophosphorylation of FAK at tyrosine 397 promotes the association of FAK with PI3K, thereby disrupting the focal adhesion complex.	11	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	autophosphorylation of FAK at tyrosine 397	fak	FAK	FAK	fak	13	14	21	22
PTP1B can also activate Src in focal adhesions and integrin signaling [ XREF_BIBR , XREF_BIBR ] as well as in insulin signaling [ XREF_BIBR ] .	PTP1B can also activate Src in focal adhesions and integrin signaling [XREF_BIBR, XREF_BIBR] as well as in insulin signaling [XREF_BIBR].	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	0	1	4	5
In all these data suggest that PTP1B regulated EGFR activation is involved in HNE mediated Src activation .	In all these data suggest that PTP1B regulated EGFR activation is involved in HNE mediated Src activation.	6	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	6	7	15	16
Prostate cells have a propensity to undergo neuroendocrine differentiation in which Src pathway may be involved , as recent reports showed that RPTPalpha and PTP1B , phosphatases which activate Src , induce neuroendocrine differentiation [ XREF_BIBR , XREF_BIBR ] .	Prostate cells have a propensity to undergo neuroendocrine differentiation in which Src pathway may be involved, as recent reports showed that RPTPalpha and PTP1B, phosphatases which activate Src, induce neuroendocrine differentiation [XREF_BIBR, XREF_BIBR].	22	31	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	24	25	29	30
We show that reduction of PTP1B expression in MTLn3 breast cancer cells enhanced phosphorylation at the inhibitory tyrosine 529 and reduced endogenous c-Src activity .	We show that reduction of PTP1B expression in MTLn3 breast cancer cells enhanced phosphorylation at the inhibitory tyrosine 529 and reduced endogenous c-Src activity.	5	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B expression	ptp1b	c-Src	c-Src	c-src	5	6	22	23
Finally , calpain-2 can positively regulate Src activity through the proteolysis and activation of PTP1B , a phosphatase that activates Src , thereby potentially creating a feedback loop between Src and calpain-2 through PTP1B .	Finally, calpain-2 can positively regulate Src activity through the proteolysis and activation of PTP1B, a phosphatase that activates Src, thereby potentially creating a feedback loop between Src and calpain-2 through PTP1B.	10	21	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	14	15	20	21
These studies suggest that PTP1B can act as an important activator of Src by dephosphorylation at Y527 of Src and elevated PTP1B can increase tumorigenicity by activating Src .	These studies suggest that PTP1B can act as an important activator of Src by dephosphorylation at Y527 of Src and elevated PTP1B can increase tumorigenicity by activating Src.	20	28	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	21	22	27	28
If Src activation by PTP1B plays a role in ErbB2 signaling , than activation or overexpression of PTP1B should affect acinar development in a Src dependent manner .	If Src activation by PTP1B plays a role in ErbB2 signaling, than activation or overexpression of PTP1B should affect acinar development in a Src dependent manner.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	4	5	1	2
These results establish that PTP1B promotes integrin mediated responses in fibroblasts by dephosphorylating the inhibitory pTyr ( 527 ) and thereby activating the Src kinase .	These results establish that PTP1B promotes integrin mediated responses in fibroblasts by dephosphorylating the inhibitory pTyr (527) and thereby activating the Src kinase.	4	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	4	5	23	24
Functional impairment of PTP1B causes retardation of axon elongation , as well as reduction of growth cone filopodia lifetime and Src activity .	Functional impairment of PTP1B causes retardation of axon elongation, as well as reduction of growth cone filopodia lifetime and Src activity.	1	21	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	3	4	20	21
Short hairpin RNA mediated suppression of PTPalpha , for instance , reduced SRC activity by up to four-fold in human breast and colon cancer cell lines [ XREF_BIBR ] , while overexpression of PTP1B increased SRC activity and promoted anchorage dependent growth of colon cancer cells [ XREF_BIBR ] .	Short hairpin RNA mediated suppression of PTPalpha, for instance, reduced SRC activity by up to four-fold in human breast and colon cancer cell lines [XREF_BIBR], while overexpression of PTP1B increased SRC activity and promoted anchorage dependent growth of colon cancer cells [XREF_BIBR].	31	36	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	overexpression of PTP1B	ptp1b	SRC	SRC	src	33	34	35	36
Although we can not rule out the contribution of additional vitronectin receptors , like alphavbeta1 and alphavbeta5 integrins , our results implicate that PTP1B and beta3 integrin cooperate to activate Src at peripheral puncta .	Although we can not rule out the contribution of additional vitronectin receptors, like alphavbeta1 and alphavbeta5 integrins, our results implicate that PTP1B and beta3 integrin cooperate to activate Src at peripheral puncta.	23	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	23	24	30	31
PTP1B also localizes to mitochondria and enhances Src mediated mitochondrial oxidative phosphorylation [ XREF_BIBR ] .	PTP1B also localizes to mitochondria and enhances Src mediated mitochondrial oxidative phosphorylation [XREF_BIBR].	0	12	enhances	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	PTP1B	PTP1B	ptp1b	Src	Src mediated mitochondrial oxidative phosphorylation	src	0	1	7	8
A subset of PTPs can dephosphorylate Src family tyrosine kinases at the conserved autophosphorylation site ( Y416 ) , leading to Src inactivation , whereas PTP1B activates Src by dephosphorylation of a C-terminal inhibitory tyrosine residue , Y527 [ XREF_BIBR ] .	A subset of PTPs can dephosphorylate Src family tyrosine kinases at the conserved autophosphorylation site (Y416), leading to Src inactivation, whereas PTP1B activates Src by dephosphorylation of a C-terminal inhibitory tyrosine residue, Y527 [XREF_BIBR].	25	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	25	26	27	28
PTP1B mediated Src activation is required for transformation of MCF-10A by ErbB2 ( HER2 and Neu ) [ XREF_BIBR ] and contributes to tumor growth of SW48 colon cancer cells [ XREF_BIBR ] .	PTP1B mediated Src activation is required for transformation of MCF-10A by ErbB2 (HER2 and Neu) [XREF_BIBR] and contributes to tumor growth of SW48 colon cancer cells [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	0	1	2	3
Conversely , PTP1B can activate Src through dephosphorylation of Y529 , which may lead to elevated LPP phosphorylation and enhanced invadopodia formation XREF_BIBR .	Conversely, PTP1B can activate Src through dephosphorylation of Y529, which may lead to elevated LPP phosphorylation and enhanced invadopodia formation XREF_BIBR.	2	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	2	3	5	6
At the same time , PTP-1B can activate Src by dephosphorylating Src pTyr 527 , which mediates intramolecular inhibition of Src activity .	At the same time, PTP-1B can activate Src by dephosphorylating Src pTyr 527, which mediates intramolecular inhibition of Src activity.	5	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP-1B	PTP-1B	PTP-1B	Src	Src	Src	5	6	8	9
Interestingly , PTP1B may also directly activate Src kinase by dephosphorylation at Y527 and thus reversal of its constitutive autoinhibition .	Interestingly, PTP1B may also directly activate Src kinase by dephosphorylation at Y527 and thus reversal of its constitutive autoinhibition.	2	8	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	2	3	7	8
After recruitment , PTP-1B may become a substrate for c-Src and induce further c-Src activation by promoting Csk dissociation from the integrin complex and dephosphorylation of tyrosine 529 ( XREF_FIG f ) .	After recruitment, PTP-1B may become a substrate for c-Src and induce further c-Src activation by promoting Csk dissociation from the integrin complex and dephosphorylation of tyrosine 529 (XREF_FIG f).	3	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP-1B	PTP-1B	PTP-1B	c-Src	c-Src	c-Src	3	4	13	14
XREF_FIG , PTP1B overexpression in HEK293 cells caused a twofold increase of endogenous Src activity [ XREF_BIBR ] .	XREF_FIG, PTP1B overexpression in HEK293 cells caused a twofold increase of endogenous Src activity [XREF_BIBR].	2	16	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B overexpression	ptp1b	Src	Src	src	2	3	13	14
The mechanism by which PTP1B activates Src is more complicated than is currently believed , and more studies with PTP1B and the DeltaE5 PTP1B mutant isoform are needed to clarify the relationship between PTP1B and Src activation .	The mechanism by which PTP1B activates Src is more complicated than is currently believed, and more studies with PTP1B and the DeltaE5 PTP1B mutant isoform are needed to clarify the relationship between PTP1B and Src activation.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	4	5	6	7
PTP1B modulates Src activity by dephosphorylation of a regulatory tyrosine at the C-terminus of Src ( tyrosine 529 in mouse Src ) , removing the negative constraint imposed by the intramolecular interaction between the phosphorylated state of this residue and the SH2 domain XREF_BIBR , XREF_BIBR - XREF_BIBR .	PTP1B modulates Src activity by dephosphorylation of a regulatory tyrosine at the C-terminus of Src (tyrosine 529 in mouse Src), removing the negative constraint imposed by the intramolecular interaction between the phosphorylated state of this residue and the SH2 domain XREF_BIBR, XREF_BIBR - XREF_BIBR.	0	3	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	0	1	2	3
Notably , we have shown that PTP1B overexpression caused a reduction of Src phosphorylation at the inhibitory tyrosine 527 residue , suggesting that PTP1B mediated Src activation leads to an enhanced proinflammatory response in microglia .	Notably, we have shown that PTP1B overexpression caused a reduction of Src phosphorylation at the inhibitory tyrosine 527 residue, suggesting that PTP1B mediated Src activation leads to an enhanced proinflammatory response in microglia.	23	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	23	24	25	26
Calpain and PTP1B modulate c-Src activity .	Calpain and PTP1B modulate c-Src activity.	0	5	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	c-Src	c-Src	c-Src	2	3	4	5
Here we demonstrate that PTP1B activation of Src and FAK signaling downregulates RhoA-myosin activity , and as a consequence restricts contractility at the cell cortex , events that are functionally linked to the development of the lamellipodium and adhesions .	Here we demonstrate that PTP1B activation of Src and FAK signaling downregulates RhoA-myosin activity, and as a consequence restricts contractility at the cell cortex, events that are functionally linked to the development of the lamellipodium and adhesions.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	4	5	7	8
Our results suggest that early after cell contact with the matrix , PTP1B cooperates with beta3 integrins to activate a Src and FAK signaling pathway leading to the transient repression of RhoA and myosin dependent contractility , allowing adhesion and lamellipodium assembly .	Our results suggest that early after cell contact with the matrix, PTP1B cooperates with beta3 integrins to activate a Src and FAK signaling pathway leading to the transient repression of RhoA and myosin dependent contractility, allowing adhesion and lamellipodium assembly.	12	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	12	13	20	21
Here we show that protein-tyrosine phosphatase 1B ( PTPIB ) activates Src , thereby initiating the activation of a Rac dependent pathway leading to cytoskeletal remodeling .	Here we show that protein-tyrosine phosphatase 1B (PTPIB) activates Src, thereby initiating the activation of a Rac dependent pathway leading to cytoskeletal remodeling.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein-tyrosine phosphatase 1B	protein-tyrosine phosphatase 1B	protein-tyrosine phosphatase 1B	Src	Src	Src	4	7	11	12
We also provide evidence that PTP1B can activate Src , a well-known oncogene , which is known to have a role in anoikis .	We also provide evidence that PTP1B can activate Src, a well-known oncogene, which is known to have a role in anoikis.	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	5	6	8	9
Activation of ErbB2 , but not ErbB1 , increases PTP1B expression , and increased expression of PTP1B activates Src and induces a Src dependent transformed phenotype .	Activation of ErbB2, but not ErbB1, increases PTP1B expression, and increased expression of PTP1B activates Src and induces a Src dependent transformed phenotype.	2	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	ErbB2, but not ErbB1, increases PTP1B expression	ptp1b	Src	Src	src	9	10	18	19
In contrast , PTP1B potentiated SRC activity , but not by dephosphorylating SRC itself directly ; instead , PTP1B regulated the interaction between CBP and PAG and CSK .	In contrast, PTP1B potentiated SRC activity, but not by dephosphorylating SRC itself directly; instead, PTP1B regulated the interaction between CBP and PAG and CSK.	3	6	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	SRC	SRC	SRC	3	4	5	6
In addition , PTP1B has also been shown to activate Src by dephosphorylating the inhibitory Y527 site in the C-terminus of this kinase .	In addition, PTP1B has also been shown to activate Src by dephosphorylating the inhibitory Y527 site in the C-terminus of this kinase.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	3	4	10	11
PTP1B was reported to activate c-Src by dephosphorylation of the inhibitory pTyr-530 [ XREF_BIBR ] .	PTP1B was reported to activate c-Src by dephosphorylation of the inhibitory pTyr-530 [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	c-Src	c-Src	c-Src	0	1	5	6
Collectively , these results suggest that PTP1B promotes Src activation at new adhesions sites assembled within the lamellipodium .	Collectively, these results suggest that PTP1B promotes Src activation at new adhesions sites assembled within the lamellipodium.	6	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	6	7	8	9
PTP1B mediated Src activation led to an enhanced proinflammatory response in the microglial cells .	PTP1B mediated Src activation led to an enhanced proinflammatory response in the microglial cells.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	0	1	2	3
To assess whether PTP1B and alphavbeta3 cooperate to activate Src , starved WT and KO cells were plated for 10min on vitronectin and analyzed with anti-Src-pY418 .	To assess whether PTP1B and alphavbeta3 cooperate to activate Src, starved WT and KO cells were plated for 10min on vitronectin and analyzed with anti-Src-pY418.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	3	4	9	10
Our early studies show that PTP1B may activate the Src kinase , which is needed for NF-kappa-B activation and Hes1 expression [ XREF_BIBR ] .	Our early studies show that PTP1B may activate the Src kinase, which is needed for NF-kappa-B activation and Hes1 expression [XREF_BIBR].	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	5	6	9	10
Previous studies have reported that PTP1B activates endogenous c-Src in breast cancer cells by the dephosphorylation of its inhibitory tyrosine 529 .	Previous studies have reported that PTP1B activates endogenous c-Src in breast cancer cells by the dephosphorylation of its inhibitory tyrosine 529.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	c-Src	c-Src	c-Src	5	6	8	9
Our data establish the in vivo relevance of PTP-1B activation of c-Src downstream of a beta3 integrin .	Our data establish the in vivo relevance of PTP-1B activation of c-Src downstream of a beta3 integrin.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PTP-1B	PTP-1B	PTP-1B	c-Src	c-Src	c-Src	8	9	11	12
XREF_BIBR , XREF_BIBR PTP1B is a major activator of Src by dephosphorylating the inhibitory tyrosine phosphorylation site ( Y529 ) on the COOH terminus of the kinase .	XREF_BIBR, XREF_BIBR PTP1B is a major activator of Src by dephosphorylating the inhibitory tyrosine phosphorylation site (Y529) on the COOH terminus of the kinase.	0	10	is a major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	3	4	9	10
PTP1B cooperates with beta3 integrin to activate Src in the lamellipodium .	PTP1B cooperates with beta3 integrin to activate Src in the lamellipodium.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	0	1	7	8
PTEN expression was increased with decreased Akt phosphorylation by the agonists , whereas agonists actions were abolished in PTEN knockdown cells , indicating the critical role of PTEN in the anti-proliferative effects of PPARgamma activation .	PTEN expression was increased with decreased Akt phosphorylation by the agonists, whereas agonists actions were abolished in PTEN knockdown cells, indicating the critical role of PTEN in the anti-proliferative effects of PPARgamma activation.	0	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN expression	pten	PTEN	PTEN	pten	0	1	27	28
Moreover , the deletion of PTEN decreased in the MDM2 transcriptional activity of wt-PTEN DU145 cells transfected with P1 promoter .	Moreover, the deletion of PTEN decreased in the MDM2 transcriptional activity of wt-PTEN DU145 cells transfected with P1 promoter.	3	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN	PTEN	wt-PTEN	wt-PTEN	wt-PTEN	5	6	13	14
Taken together , our study identified a tumor suppressive role of Gas5 in PTC cells acting as a ceRNA , effectively becoming a sink for miR-222-3p , modulating the expression of PTEN , which lead to PTEN and AKT pathway activation and proliferation suppression .	Taken together, our study identified a tumor suppressive role of Gas5 in PTC cells acting as a ceRNA, effectively becoming a sink for miR-222-3p, modulating the expression of PTEN, which lead to PTEN and AKT pathway activation and proliferation suppression.	29	38	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	PTEN	expression of PTEN	pten	PTEN	PTEN	pten	31	32	36	37
CK2 mediates phosphorylation of the PTEN C-terminal serine threonine cluster S380-T382-T383 , which promotes PTEN stability while reducing PTEN lipid phosphatase activity .	CK2 mediates phosphorylation of the PTEN C-terminal serine threonine cluster S380-T382-T383, which promotes PTEN stability while reducing PTEN lipid phosphatase activity.	0	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	CK2 mediates phosphorylation of the PTEN C-terminal serine threonine	pten	PTEN	PTEN	pten	5	6	14	15
Using PCI for PEI mediated PTEN gene transfer was found to further enhance PTEN mRNA and protein expression as well as PTEN related cell growth inhibition reaching 89 % .	Using PCI for PEI mediated PTEN gene transfer was found to further enhance PTEN mRNA and protein expression as well as PTEN related cell growth inhibition reaching 89%.	3	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PEI mediated PTEN	pten	PTEN	PTEN	pten	5	6	13	14
Not only did overexpression of Pten restore Pten staining intensity , but it also rescued the increase in soma size seen in Pten knockdown neurons .	Not only did overexpression of Pten restore Pten staining intensity, but it also rescued the increase in soma size seen in Pten knockdown neurons.	3	8	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pten	overexpression of Pten	pten	Pten	Pten	pten	5	6	7	8
Earlier studies suggest that , while phosphorylation of PTEN at the C2 domain enhances PTEN stabilization , it also promotes a closed conformation , inhibiting PTEN activity [ XREF_BIBR , XREF_BIBR ] .	Earlier studies suggest that, while phosphorylation of PTEN at the C2 domain enhances PTEN stabilization, it also promotes a closed conformation, inhibiting PTEN activity [XREF_BIBR, XREF_BIBR].	6	15	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	phosphorylation of PTEN at the C2 domain	pten	PTEN	PTEN	pten	8	9	14	15
Re-injecting the cultured PTEN-normal 1degrees Br cells conferred a distinct PTEN loss in brain metastases ( 2degrees Brain Mets ) , but not in 2degrees MFP tumors , and PTEN levels in 2degrees Br cells were fully restored again in culture ( XREF_FIG , XREF_FIG ) , indicating a reversible non genetic PTEN loss in the brain tumor microenvironment ( TME ) .	Re-injecting the cultured PTEN-normal 1degrees Br cells conferred a distinct PTEN loss in brain metastases (2degrees Brain Mets), but not in 2degrees MFP tumors, and PTEN levels in 2degrees Br cells were fully restored again in culture (XREF_FIG, XREF_FIG), indicating a reversible non genetic PTEN loss in the brain tumor microenvironment (TME).	29	53	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN levels	pten	PTEN	PTEN	pten	29	30	52	53
Taken together , the results in XREF_FIG demonstrate that rapid , non nuclear E2/ERalpha signaling mediates PTEN phosphorylation at key negative regulatory residues , and increases PTEN stability .	Taken together, the results in XREF_FIG demonstrate that rapid, non nuclear E2/ERalpha signaling mediates PTEN phosphorylation at key negative regulatory residues, and increases PTEN stability.	13	27	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	E2/ERalpha signaling mediates PTEN phosphorylation	pten	PTEN	PTEN	pten	16	17	26	27
Increased phosphorylation of PTEN increases PTEN activity .	Increased phosphorylation of PTEN increases PTEN activity.	1	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	phosphorylation of PTEN	pten	PTEN	PTEN	pten	3	4	5	6
Our observations correlate with the previous study as both suggest that PTEN SUMOylation mediates the trafficking of PTEN to compartments outside the nucleus .	Our observations correlate with the previous study as both suggest that PTEN SUMOylation mediates the trafficking of PTEN to compartments outside the nucleus.	11	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN SUMOylation	pten	PTEN	PTEN	pten	11	12	17	18
Based on these data , we hypothesized that PTEN SUMOylation could modulate the covalent interaction of PTEN with monoubiquitin .	Based on these data, we hypothesized that PTEN SUMOylation could modulate the covalent interaction of PTEN with monoubiquitin.	8	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN SUMOylation	pten	PTEN	PTEN	pten	8	9	16	17
The phosphorylation of PTEN on three residues ( S380 , T382 , and T383 ) is likely to mediate the regulation of PTEN function XREF_BIBR .	The phosphorylation of PTEN on three residues (S380, T382, and T383) is likely to mediate the regulation of PTEN function XREF_BIBR.	1	24	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	phosphorylation of PTEN on three residues (S380	pten	PTEN	PTEN	pten	3	4	22	23
Although the LLC MVs downregulated PTEN protein levels in CD4 + T cells , overexpression of PTEN ORF rescued the downregulation of PTEN protein induced by the miR-214-loaded MVs ( XREF_FIG and XREF_FIG ) .	Although the LLC MVs downregulated PTEN protein levels in CD4 + T cells, overexpression of PTEN ORF rescued the downregulation of PTEN protein induced by the miR-214-loaded MVs (XREF_FIG and XREF_FIG).	14	23	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	overexpression of PTEN	pten	PTEN	PTEN	pten	16	17	22	23
Our observation of cytoplasmic WT1 expression and loss of PTEN expression in tubal MPT suggests its neoplastic nature and raises the possibility of WT1 or PTEN involvement in the development of MPT .	Our observation of cytoplasmic WT1 expression and loss of PTEN expression in tubal MPT suggests its neoplastic nature and raises the possibility of WT1 or PTEN involvement in the development of MPT.	9	26	raises	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN expression	pten	PTEN	PTEN	pten	9	10	25	26
Polyubiquitination of PTEN results in decreased protein stability leading to PTEN degradation by proteasome mediated decay mechanisms [ XREF_BIBR ] , whereas monoubiquitination of PTEN on Lys13 and Lys289 promotes the nuclear transport of PTEN [ XREF_BIBR , XREF_BIBR ] .	Polyubiquitination of PTEN results in decreased protein stability leading to PTEN degradation by proteasome mediated decay mechanisms [XREF_BIBR], whereas monoubiquitination of PTEN on Lys13 and Lys289 promotes the nuclear transport of PTEN [XREF_BIBR, XREF_BIBR].	22	38	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	monoubiquitination of PTEN on Lys13 and Lys289	pten	PTEN	PTEN	pten	24	25	34	35
The tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 ( PTEN ) dephosphorylates phosphatidylinositol-3 ,4,5-phosphate , down-regulating the PI3K and Akt signaling ; CK2 phosphorylates PTEN and reduces PTEN activity , leading to activation of PDK1 .	The tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylates phosphatidylinositol-3,4,5-phosphate, down-regulating the PI3K and Akt signaling; CK2 phosphorylates PTEN and reduces PTEN activity, leading to activation of PDK1.	25	31	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	CK2 phosphorylates PTEN	pten	PTEN	PTEN	pten	27	28	30	31
The expression of Pten was nearly abolished in cDCs and markedly reduced in pDCs but normal in myeloid non DCs , supporting a DC specific Pten deletion .	The expression of Pten was nearly abolished in cDCs and markedly reduced in pDCs but normal in myeloid non DCs, supporting a DC specific Pten deletion.	1	26	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pten	expression of Pten	pten	Pten	Pten	pten	3	4	25	26
We found that overexpression of PTEN effectively increased expression and phosphatase activity of PTEN , and concomitantly inhibited LPS induced fibroblast proliferation , differentiation and collagen secretion .	We found that overexpression of PTEN effectively increased expression and phosphatase activity of PTEN, and concomitantly inhibited LPS induced fibroblast proliferation, differentiation and collagen secretion.	3	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	overexpression of PTEN	pten	PTEN	PTEN	pten	5	6	13	14
Overexpression of PTEN ( and possibly PTEN G129E ) would enhance the effects of endogenous PTEN to suppress EMT .	Overexpression of PTEN (and possibly PTEN G129E) would enhance the effects of endogenous PTEN to suppress EMT.	0	16	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	Overexpression of PTEN	pten	PTEN	PTEN	pten	2	3	15	16
It creates PI-3 ,4,5-triphosphate ( PtdIns ( 3,4,5 ) P 3 ) at the plasma membrane mediated by PI3K and phosphatase and tensin homolog ( PTEN , a phosphatase that counteracts the kinase action of PI3K ) .	It creates PI-3,4,5-triphosphate (PtdIns (3,4,5) P 3) at the plasma membrane mediated by PI3K and phosphatase and tensin homolog (PTEN, a phosphatase that counteracts the kinase action of PI3K).	3	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	PTEN	PTEN	PTEN	20	24	25	26
16 Consistent with the function of the C-terminal region as a determinant of stability and nuclear translocation of PTEN , deletion of this region increases interaction of PTEN with E3 ligases NEDD4 that leads both mono- and polyubiquitylation on PTEN at the same residues K13 and K289 .	16 Consistent with the function of the C-terminal region as a determinant of stability and nuclear translocation of PTEN, deletion of this region increases interaction of PTEN with E3 ligases NEDD4 that leads both mono- and polyubiquitylation on PTEN at the same residues K13 and K289.	24	38	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN with E3 ligases NEDD4 that leads both mono- and polyubiquitylation	pten	PTEN	PTEN	pten	27	28	27	28
This shows that high expression of PRL-3 downregulates the expression of PTEN and increases the ratio of p-PTEN and PTEN .	This shows that high expression of PRL-3 downregulates the expression of PTEN and increases the ratio of p-PTEN and PTEN.	4	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	expression of PRL-3 downregulates the expression of PTEN	pten	PTEN	PTEN	pten	11	12	19	20
We also found that miR-181a/b targets phosphatase and tensin homolog ( PTEN ) , and the sponge expressing stable cells had increased PTEN activity and decreased PI3K signaling .	We also found that miR-181a/b targets phosphatase and tensin homolog (PTEN), and the sponge expressing stable cells had increased PTEN activity and decreased PI3K signaling.	4	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	PTEN	PTEN	PTEN	6	10	22	23
CK2 mediates phosphorylation of PTEN C-terminus serine/threonine cluster S380/T382/T383 , which promotes PTEN protein stability , while reducing PTEN lipid phosphatase activity against its substrate PIP3 XREF_BIBR , XREF_BIBR .	CK2 mediates phosphorylation of PTEN C-terminus serine/threonine cluster S380/T382/T383, which promotes PTEN protein stability, while reducing PTEN lipid phosphatase activity against its substrate PIP3 XREF_BIBR, XREF_BIBR.	0	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	CK2 mediates phosphorylation of PTEN	pten	PTEN	PTEN	pten	4	5	12	13
The above results demonstrated that the SIRT3 mediated deacetylation of PTEN increased MDM2 transcription and PTEN lipid phosphatase activity .	The above results demonstrated that the SIRT3 mediated deacetylation of PTEN increased MDM2 transcription and PTEN lipid phosphatase activity.	6	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	SIRT3 mediated deacetylation of PTEN	pten	PTEN	PTEN	pten	10	11	15	16
Furthermore , PTEN expression identified by western blot was markedly increased by silymarin ( XREF_FIG ) , Thus revealing mediation of PTEN in the action of silymarin .	Furthermore, PTEN expression identified by western blot was markedly increased by silymarin (XREF_FIG), Thus revealing mediation of PTEN in the action of silymarin.	2	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN expression	pten	PTEN	PTEN	pten	2	3	21	22
42 In other contexts , FAK phosphorylation of PTEN causes PTEN to enter the nucleus ( and hence , resulting in increased degradation ) .	42 In other contexts, FAK phosphorylation of PTEN causes PTEN to enter the nucleus (and hence, resulting in increased degradation).	5	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	FAK phosphorylation of PTEN	pten	PTEN	PTEN	pten	8	9	10	11
The phosphorylation of PTEN using ROCK triggers the phosphatase activity of PTEN , which results in reduction in phosphorylation of Akt , which is crucial for cell survival .	The phosphorylation of PTEN using ROCK triggers the phosphatase activity of PTEN, which results in reduction in phosphorylation of Akt, which is crucial for cell survival.	1	14	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	phosphorylation of PTEN	pten	PTEN	PTEN	pten	3	4	11	12
Of those identified , miR-21 , also termed miR-21-5p , was upregulated in HS tissue compared with NS tissue and was selected for further analysis , because a previous study had investigated the function of phosphatase and tensin homolog ( PTEN ) in hypertrophic scar and miR-21 was demonstrated to directly target PTEN .	Of those identified, miR-21, also termed miR-21-5p, was upregulated in HS tissue compared with NS tissue and was selected for further analysis, because a previous study had investigated the function of phosphatase and tensin homolog (PTEN) in hypertrophic scar and miR-21 was demonstrated to directly target PTEN.	35	53	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	PTEN	PTEN	PTEN	35	39	52	53
Gene protein expression level studies have demonstrated that in breast cancer , there is overexpression of PTEN in SKBR3 breast cancer cells , as with the ER negative cancer cells , containing the wild-type PTEN and normal expression of p53 .	Gene protein expression level studies have demonstrated that in breast cancer, there is overexpression of PTEN in SKBR3 breast cancer cells, as with the ER negative cancer cells, containing the wild-type PTEN and normal expression of p53.	13	21	is overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	PTEN	overexpression of PTEN	pten	PTEN	PTEN	pten	16	17	16	17
Overexpression of PTEN reduces the engulfment of apoptotic cells , and disruption of PTEN increases the engulfment of apoptotic cells both in vitro and in vivo .	Overexpression of PTEN reduces the engulfment of apoptotic cells, and disruption of PTEN increases the engulfment of apoptotic cells both in vitro and in vivo.	0	14	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	Overexpression of PTEN	pten	PTEN	PTEN	pten	2	3	13	14
CK2 mediates phosphorylation of PTEN C-terminus serine/threonine cluster S380/T382/T383 , which , aids PTEN protein stability , while reducing PTEN lipid phosphatase activity against the substrate PIP3 .	CK2 mediates phosphorylation of PTEN C-terminus serine/threonine cluster S380/T382/T383, which, aids PTEN protein stability, while reducing PTEN lipid phosphatase activity against the substrate PIP3.	0	15	aids	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	CK2 mediates phosphorylation of PTEN	pten	PTEN	PTEN	pten	4	5	13	14
Most notably , although Pten deletion did not render the cells completely insensitive to NOTCH inhibition with GSI , in each case mutational loss of Pten effectively impaired the response to NOTCH1 inhibition therapy and all mice harboring Pten deleted leukemias showed overt progression under therapy , a hallmark criteria of therapy resistance in the clinic , with 100 % mortality by the end of the fourth cycle of treatment .	Most notably, although Pten deletion did not render the cells completely insensitive to NOTCH inhibition with GSI, in each case mutational loss of Pten effectively impaired the response to NOTCH1 inhibition therapy and all mice harboring Pten deleted leukemias showed overt progression under therapy, a hallmark criteria of therapy resistance in the clinic, with 100% mortality by the end of the fourth cycle of treatment.	23	39	impaired	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pten	loss of Pten	pten	Pten	Pten	pten	25	26	38	39
Interestingly , esiRNA ( termed PTEN-sh-3p21 ) cleaved from PTEN-sh was identified in 293T cells and human liver tissues , which was found to target the mRNA 3 ' UTRs of protein phosphatase PPP2CA and PTEN in L-O2 cells .	Interestingly, esiRNA (termed PTEN-sh-3p21) cleaved from PTEN-sh was identified in 293T cells and human liver tissues, which was found to target the mRNA 3 ' UTRs of protein phosphatase PPP2CA and PTEN in L-O2 cells.	7	38	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN-sh	PTEN-sh	PTEN-sh	PTEN	PTEN	PTEN	9	10	35	36
The alpha isoform negatively regulates PTEN transcription and the beta isoform positively regulates PTEN mRNA post-transcriptionally through PTENP1 sense .	The alpha isoform negatively regulates PTEN transcription and the beta isoform positively regulates PTEN mRNA post-transcriptionally through PTENP1 sense.	5	14	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	PTEN	PTEN transcription	pten	PTEN	PTEN	pten	5	6	13	14
Taken together , our study results suggest that differential expression of PTEN targeting miR-19a and miR-21 modulates the PTEN protein levels and the CS and CSL phenotypes , irrespective of the patient ' s mutation status , and support their roles as genetic modifiers in CS and CSL .	Taken together, our study results suggest that differential expression of PTEN targeting miR-19a and miR-21 modulates the PTEN protein levels and the CS and CSL phenotypes, irrespective of the patient 's mutation status, and support their roles as genetic modifiers in CS and CSL.	9	26	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	expression of PTEN	pten	PTEN	PTEN	pten	11	12	18	19
This finding established that loss of USP18 expression reduced cellular PTEN levels and promoted destabilization of cytosolic PTEN [ XREF_BIBR , XREF_BIBR ] .	This finding established that loss of USP18 expression reduced cellular PTEN levels and promoted destabilization of cytosolic PTEN [XREF_BIBR, XREF_BIBR].	6	19	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	USP18 expression reduced cellular PTEN levels	pten	PTEN	PTEN	pten	10	11	17	18
Taken together , these results indicate that E2 induces PTEN phosphorylation , increases PTEN protein stability and decreases PTEN lipid phosphatase activity .	Taken together, these results indicate that E2 induces PTEN phosphorylation, increases PTEN protein stability and decreases PTEN lipid phosphatase activity.	7	21	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	E2 induces PTEN phosphorylation	pten	PTEN	PTEN	pten	9	10	18	19
The induction of PTEN expression and nuclear accumulation by genistein elicits a sequence of PTEN dependent increased nuclear p53 accumulation , enhanced PTEN and p53 physical interaction , and increased recruitment of the PTEN and p53 complex to the p53 binding sites of the PTEN promoter [ XREF_BIBR , XREF_BIBR ] .	The induction of PTEN expression and nuclear accumulation by genistein elicits a sequence of PTEN dependent increased nuclear p53 accumulation, enhanced PTEN and p53 physical interaction, and increased recruitment of the PTEN and p53 complex to the p53 binding sites of the PTEN promoter [XREF_BIBR, XREF_BIBR].	3	15	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN expression	pten	PTEN	PTEN	pten	3	4	14	15
Inhibition of PTEN phosphorylation by the CK2 inhibitor 5,6-dichloro-1-beta-d-ribofuranosyl-benzimidazole also diminished the PTEN protein content .	Inhibition of PTEN phosphorylation by the CK2 inhibitor 5,6-dichloro-1-beta-d-ribofuranosyl-benzimidazole also diminished the PTEN protein content.	0	14	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	Inhibition of PTEN phosphorylation by the CK2 inhibitor	pten	PTEN	PTEN	pten	2	3	12	13
1 In particular , PTEN phosphorylation by Casein Kinase II promotes PTEN inactivation through the stabilization of PTEN in a closed conformation .	1 In particular, PTEN phosphorylation by Casein Kinase II promotes PTEN inactivation through the stabilization of PTEN in a closed conformation.	4	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN phosphorylation	pten	PTEN	PTEN	pten	4	5	11	12
Loss of PTEN , therefore , disrupts the PI3K : PTEN balance resulting in increased Akt activation and uncontrolled cell growth .	Loss of PTEN, therefore, disrupts the PI3K : PTEN balance resulting in increased Akt activation and uncontrolled cell growth.	0	11	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	Loss of PTEN	pten	PTEN	PTEN	pten	2	3	10	11
We next investigated if the RSUME induced PTEN sumoylation modulates PTEN protein stability .	We next investigated if the RSUME induced PTEN sumoylation modulates PTEN protein stability.	5	12	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	RSUME induced PTEN sumoylation	pten	PTEN	PTEN	pten	7	8	10	11
Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation .	Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation.	2	12	driving	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	CK2 is known to phosphorylate PTEN	pten	PTEN	PTEN	pten	7	8	10	11
Sema4D induced the dephosphorylation of PTEN at Ser 380 and stimulated PTEN phosphatase activity in hippocampal neurons .	Sema4D induced the dephosphorylation of PTEN at Ser 380 and stimulated PTEN phosphatase activity in hippocampal neurons.	0	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	Sema4D induced the dephosphorylation of PTEN at Ser 380	pten	PTEN	PTEN	pten	5	6	11	12
Phosphatase and tensin homolog ( PTEN ) hamartoma tumor syndrome ( PHTS ) is caused by germ line mutations in the PTEN gene .	Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is caused by germ line mutations in the PTEN gene.	0	22	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTEN	PTEN	PTEN	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	21	22	0	4
Moreover , the deacetylation of PTEN increased the transcriptional activity of PTEN .	Moreover, the deacetylation of PTEN increased the transcriptional activity of PTEN.	3	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	deacetylation of PTEN	pten	PTEN	PTEN	pten	5	6	11	12
XREF_BIBR It was shown that phosphorylation of PTEN at S366 and T370 promotes the chromatin translocation ; PTEN co-precipitates human RAD52 protein and is required for hydrogen peroxide induced RAD52 sumoylation .	XREF_BIBR It was shown that phosphorylation of PTEN at S366 and T370 promotes the chromatin translocation; PTEN co-precipitates human RAD52 protein and is required for hydrogen peroxide induced RAD52 sumoylation.	5	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	phosphorylation of PTEN at S366 and T370	pten	PTEN	PTEN	pten	7	8	17	18
We present evidence that inhibition of insulin increased prolactin gene transcription was secondary to RPTPalpha activation of Src , reflecting its role as mediator of integrin responses .	We present evidence that inhibition of insulin increased prolactin gene transcription was secondary to RPTPalpha activation of Src, reflecting its role as mediator of integrin responses.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	Src	Src	Src	14	15	17	18
The Rptp-alpha signaling pathway that activates Fyn and Src kinases might also contribute to the proper development of the radial glial scaffold for promoting appropriate neuronal migration , but in this case , this would be through a mechanism independent of reelin signaling .	The Rptp-alpha signaling pathway that activates Fyn and Src kinases might also contribute to the proper development of the radial glial scaffold for promoting appropriate neuronal migration, but in this case, this would be through a mechanism independent of reelin signaling.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rptp-alpha	Rptp-alpha	Rptp-alpha	Src	Src	Src	1	2	8	9
CDC25A was also found in the pathway that involves the activation of Src by protein-tyrosine phosphatase alpha ( srcRPTP Pathway ) .	CDC25A was also found in the pathway that involves the activation of Src by protein-tyrosine phosphatase alpha (srcRPTP Pathway).	10	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	protein-tyrosine phosphatase alpha	protein-tyrosine phosphatase alpha	protein-tyrosine phosphatase alpha	Src	Src	Src	14	17	12	13
In that study , RPTPalpha245 , a truncated isoform of RPTPalpha that is devoid of phosphatase activity , can bind to endogenous RPTPalpha directly , which decreases RPTPalpha-Grb2 binding and increases RPTPalpha activation of Src [ XREF_BIBR ] .	In that study, RPTPalpha245, a truncated isoform of RPTPalpha that is devoid of phosphatase activity, can bind to endogenous RPTPalpha directly, which decreases RPTPalpha-Grb2 binding and increases RPTPalpha activation of Src [XREF_BIBR].	31	36	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	Src	Src	Src	31	32	34	35
The role of PTPRA in gastric cancer might be linked to its biological role in integrin signalling , cell adhesion , and activating the SRC family tyrosine kinases .	The role of PTPRA in gastric cancer might be linked to its biological role in integrin signalling, cell adhesion, and activating the SRC family tyrosine kinases.	1	27	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTPRA	PTPRA	PTPRA	SRC	SRC	SRC	3	4	24	25
Hence , the decreased RPTPalpha in PSD-95-Src complexes as observed in SCZ ( XREF_FIG ) should decrease Src activity .	Hence, the decreased RPTPalpha in PSD-95-Src complexes as observed in SCZ (XREF_FIG) should decrease Src activity.	2	18	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	Src	Src	Src	4	5	17	18
RPTPalpha serine hyperphosphorylation was proposed to mediate mitotic activation of Src .	RPTPalpha serine hyperphosphorylation was proposed to mediate mitotic activation of Src.	0	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha serine hyperphosphorylation	rptpalpha	Src	Src	src	0	1	10	11
This will lead to Src hypoactivity , since RPTPalpha enhances Src activity by decreasing phosphorylation of pY530 of Src 30 .	This will lead to Src hypoactivity, since RPTPalpha enhances Src activity by decreasing phosphorylation of pY530 of Src 30.	8	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	Src	Src	Src	8	9	10	11
RPTPalpha and PTPepsilon dephosphorylate and activate Src family kinases in various cell types in vitro and in vivo .	RPTPalpha and PTPepsilon dephosphorylate and activate Src family kinases in various cell types in vitro and in vivo.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	Src	Src	Src	0	1	6	7
Taken together , these data suggest a model whereby RPTPalpha mediates RA FLS aggressiveness by promoting constitutive activation of SRC and FAK , leading to enhanced FLS survival , increased production of critical mediators of arthritis in response to TNF and IL-1beta , and promotion of motility and invasiveness in response to PDGF .	Taken together, these data suggest a model whereby RPTPalpha mediates RA FLS aggressiveness by promoting constitutive activation of SRC and FAK, leading to enhanced FLS survival, increased production of critical mediators of arthritis in response to TNF and IL-1beta, and promotion of motility and invasiveness in response to PDGF.	9	21	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	SRC	SRC	SRC	9	10	19	20
In the present study , we determined the relationship between PTPRA expression and activation state of c-Src in SCC samples and the cell line H520 , which provided evidence that PTPRA expression has a potential to dephosphorylate the site of Tyr527 in PTK c-Src and activates the c-Src in SCC cells .	In the present study, we determined the relationship between PTPRA expression and activation state of c-Src in SCC samples and the cell line H520, which provided evidence that PTPRA expression has a potential to dephosphorylate the site of Tyr527 in PTK c-Src and activates the c-Src in SCC cells.	30	50	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTPRA	PTPRA expression	ptpra	c-Src	c-Src	c-src	30	31	47	48
Specifically on a rigid fibronectin substratum , RPTP-alpha promotes Src and Cas function and clustering to reinforce adhesion complexes and decrease axon outgrowth of hippocampal neurons .	Specifically on a rigid fibronectin substratum, RPTP-alpha promotes Src and Cas function and clustering to reinforce adhesion complexes and decrease axon outgrowth of hippocampal neurons.	7	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPTP-alpha	RPTP-alpha	RPTP-alpha	Src	Src	Src	7	8	9	10
However , it was still unclear to what extent c-Src activation by PTPRA is comparable to v-Src expression for inducing cyclin proteins .	However, it was still unclear to what extent c-Src activation by PTPRA is comparable to v-Src expression for inducing cyclin proteins.	9	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PTPRA	PTPRA	PTPRA	c-Src	c-Src	c-Src	12	13	9	10
In estrogen-receptor-negative breast cancer cell lines as well as colon cancer cell lines , siRNA mediated knockdown of PTPRA reduced Src activity and induced apoptosis XREF_BIBR .	In estrogen-receptor-negative breast cancer cell lines as well as colon cancer cell lines, siRNA mediated knockdown of PTPRA reduced Src activity and induced apoptosis XREF_BIBR.	16	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PTPRA	PTPRA	PTPRA	Src	Src	Src	18	19	20	21
We found that PTPRA overexpression can activate the c-Src signaling pathways and stimulate the G1/S transition in the cellular models .	We found that PTPRA overexpression can activate the c-Src signaling pathways and stimulate the G1/S transition in the cellular models.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTPRA	PTPRA overexpression	ptpra	c-Src	c-Src	c-src	3	4	8	9
Indeed , NRG1 , ErbB4 , PSD-95 , dysbindin-1 or RPTPalpha , each of which has been implicated for SCZ , can modulate Src kinase .	Indeed, NRG1, ErbB4, PSD-95, dysbindin-1 or RPTPalpha, each of which has been implicated for SCZ, can modulate Src kinase.	2	24	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	Src	Src	Src	10	11	23	24
Indeed , overexpression of RPTPalpha in nonneuronal cells results in persistent activation of Src , with concomitant cell transformation and tumorigenesis , and mutation of Ser180 or Ser204 blocks neoplastic transformation of cells by RPTPalpha .	Indeed, overexpression of RPTPalpha in nonneuronal cells results in persistent activation of Src, with concomitant cell transformation and tumorigenesis, and mutation of Ser180 or Ser204 blocks neoplastic transformation of cells by RPTPalpha.	2	14	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	RPTPalpha	overexpression of RPTPalpha	rptpalpha	Src	Src	src	4	5	13	14
RPTPalpha-D2 has also been shown to directly bind to Src kinase and is required for the dephosphorylation and activation of Src by RPTPalpha .	RPTPalpha-D2 has also been shown to directly bind to Src kinase and is required for the dephosphorylation and activation of Src by RPTPalpha.	13	23	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	Src	Src	Src	22	23	20	21
RPTPalpha dependent activation of Src family kinases , in particular activation of Fyn , is required for the force dependent formation of focal complexes and strengthening of alpha v / beta 3 -integrin-cytoskeleton connections during the initial phase of ECM contact .	RPTPalpha dependent activation of Src family kinases, in particular activation of Fyn, is required for the force dependent formation of focal complexes and strengthening of alpha v / beta 3 -integrin-cytoskeleton connections during the initial phase of ECM contact.	0	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	Src	Src	Src	0	1	4	5
Functional studies showed that PTPRA promoted lung cancer cell growth by modulating Src activation and cell progression .	Functional studies showed that PTPRA promoted lung cancer cell growth by modulating Src activation and cell progression.	4	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTPRA	PTPRA	PTPRA	Src	Src	Src	4	5	12	13
However , a number of independent studies including our own work have presented convincing evidence that MDK and PTN do not activate ALK .	However, a number of independent studies including our own work have presented convincing evidence that MDK and PTN do not activate ALK.	16	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTN	PTN	PTN	ALK	ALK	ALK	18	19	22	23
A different mechanism for ALK activation by PTN has also recently been suggested by Perez-Pinera and colleagues [ XREF_BIBR ] .	A different mechanism for ALK activation by PTN has also recently been suggested by Perez-Pinera and colleagues [XREF_BIBR].	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PTN	PTN	PTN	ALK	ALK	ALK	7	8	4	5
PTN upregulated anaplastic lymphoma kinase ( ALK ) , p-Glycogen Synthase Kinase ( GSK ) 3beta , beta-catenin and multidrug resistance protein 1/P-glycoprotein ( MDR1 and P-gp ) .	PTN upregulated anaplastic lymphoma kinase (ALK), p-Glycogen Synthase Kinase (GSK) 3beta, beta-catenin and multidrug resistance protein 1/P-glycoprotein (MDR1 and P-gp).	0	5	upregulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	PTN	PTN	PTN	anaplastic lymphoma kinase	anaplastic lymphoma kinase	anaplastic lymphoma kinase	0	1	2	5
Pleiotrophin signals by inactivating its receptor , the receptor protein tyrosine phosphatase ( RPTP ) beta and zeta , and , recently , PTN was found to activate anaplastic lymphoma kinase ( ALK ) through the PTN/RPTPbeta/zeta signaling pathway in PTN stimulated cells , not through a direct interaction of PTN with ALK and thus not through the PTN enforced dimerization of ALK .	Pleiotrophin signals by inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP) beta and zeta, and, recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway in PTN stimulated cells, not through a direct interaction of PTN with ALK and thus not through the PTN enforced dimerization of ALK.	0	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pleiotrophin	Pleiotrophin	Pleiotrophin	anaplastic lymphoma kinase	anaplastic lymphoma kinase	anaplastic lymphoma kinase	0	1	28	31
Our findings in this study do not support previous reports that MDK and PTN directly activate ALK , but are in agreement with other studies that show that MDK and PTN do not activate ALK .	Our findings in this study do not support previous reports that MDK and PTN directly activate ALK, but are in agreement with other studies that show that MDK and PTN do not activate ALK.	11	17	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTN	PTN	PTN	ALK	ALK	ALK	13	14	16	17
Although several groups have shown that PTN and MK activate ALK [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] some questions remain , since a number of groups have reported contradictory findings [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Although several groups have shown that PTN and MK activate ALK [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR] some questions remain, since a number of groups have reported contradictory findings [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	6	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTN	PTN	PTN	ALK	ALK	ALK	6	7	10	11
No point mutations were detected in the tyrosine kinase domain of ALK ( exons 22-25 , data not shown ) , and PTN failed to activate ALK when added to the cells ( XREF_FIG ) .	No point mutations were detected in the tyrosine kinase domain of ALK (exons 22-25, data not shown), and PTN failed to activate ALK when added to the cells (XREF_FIG).	22	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTN	PTN	PTN	ALK	ALK	ALK	22	23	26	27
Recently , PTN was found to activate anaplastic lymphoma kinase ( ALK ) through the PTN/RPTPbeta/zeta signaling pathway ; this discovery potentially is very important , since constitutive ALK activity of nucleophosmin ( NPM )-ALK fusion protein is causative of anaplastic large cell lymphomas , and , activated ALK is found in other malignant cancers .	Recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway; this discovery potentially is very important, since constitutive ALK activity of nucleophosmin (NPM)-ALK fusion protein is causative of anaplastic large cell lymphomas, and, activated ALK is found in other malignant cancers.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTN	PTN	PTN	anaplastic lymphoma kinase	anaplastic lymphoma kinase	anaplastic lymphoma kinase	2	3	7	10
More recently , Perez-Pinera and colleagues proposed an alternative mechanism by which pleiotrophin could be stimulating ALK signalling .	More recently, Perez-Pinera and colleagues proposed an alternative mechanism by which pleiotrophin could be stimulating ALK signalling.	12	17	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pleiotrophin	pleiotrophin	pleiotrophin	ALK	ALK	ALK	12	13	16	17
In conclusion , our data suggest that Alk is not activated by MDK and PTN related growth factors Miple1 and Miple 2 in vivo .	In conclusion, our data suggest that Alk is not activated by MDK and PTN related growth factors Miple1 and Miple 2 in vivo.	7	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTN	PTN	PTN	Alk	Alk	Alk	14	15	7	8
One study demonstrates indirect activation of ALK by PTN via RPTPzeta .	One study demonstrates indirect activation of ALK by PTN via RPTPzeta.	2	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PTN	PTN	PTN	ALK	ALK	ALK	8	9	6	7
PTN was reported to bind to RPTPbeta and zeta and then indirectly activate the anaplastic lymphoma kinase ( ALK ) .	PTN was reported to bind to RPTPbeta and zeta and then indirectly activate the anaplastic lymphoma kinase (ALK).	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTN	PTN	PTN	anaplastic lymphoma kinase	anaplastic lymphoma kinase	anaplastic lymphoma kinase	0	1	14	17
Anaplastic lymphoma kinase ( ALK ) , which is a receptor that is activated by pleiotrophin , was present in mural cells associated with abnormal vessels .	Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels.	2	16	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	pleiotrophin	pleiotrophin	pleiotrophin	ALK	ALK	ALK	15	16	4	5
Recently , PTN was found to activate anaplastic lymphoma kinase ( ALK ) through the PTN/RPTPbeta/zeta signaling pathway [ XREF_BIBR ] ; and the rescue of fibroblast apoptosis by PTN is mediated through ALK receptor dependent AKT and ERK activation [ XREF_BIBR ] .	Recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway [XREF_BIBR]; and the rescue of fibroblast apoptosis by PTN is mediated through ALK receptor dependent AKT and ERK activation [XREF_BIBR].	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTN	PTN	PTN	anaplastic lymphoma kinase	anaplastic lymphoma kinase	anaplastic lymphoma kinase	2	3	7	10
Whether PTN and MK are true ligands of ALK remain controversial , as some groups failed to reproduce the binding and activation of ALK by PTN [ XREF_BIBR ] [ XREF_BIBR , XREF_BIBR ] underscoring the need for further study of the roles of these potential ligands .	Whether PTN and MK are true ligands of ALK remain controversial, as some groups failed to reproduce the binding and activation of ALK by PTN [XREF_BIBR] [XREF_BIBR, XREF_BIBR] underscoring the need for further study of the roles of these potential ligands.	19	27	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PTN	PTN	PTN	ALK	ALK	ALK	25	26	23	24
For example , although certain experimental results have supported such a biological connection [ XREF_BIBR ] , several investigators have had difficulty reproducing experimental data showing the binding and activation of ALK by PTN [ XREF_BIBR - XREF_BIBR ] .	For example, although certain experimental results have supported such a biological connection [XREF_BIBR], several investigators have had difficulty reproducing experimental data showing the binding and activation of ALK by PTN [XREF_BIBR - XREF_BIBR].	27	35	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PTN	PTN	PTN	ALK	ALK	ALK	33	34	31	32
ALK is activated by its ligands , midkine ( MDK ) and pleiotrophin ( PTN ) , both of which serve as mitogenic and angiogenic factors in cancer [ XREF_BIBR , XREF_BIBR ] .	ALK is activated by its ligands, midkine (MDK) and pleiotrophin (PTN), both of which serve as mitogenic and angiogenic factors in cancer [XREF_BIBR, XREF_BIBR].	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	pleiotrophin	pleiotrophin	pleiotrophin	ALK	ALK	ALK	12	13	0	1
However , the PTH type 2 receptor ( PTH2R ) , which can be activated by PTH and TIP39 but not by PTHrP , is also present in keratinocytes XREF_BIBR , XREF_BIBR .	However, the PTH type 2 receptor (PTH2R), which can be activated by PTH and TIP39 but not by PTHrP, is also present in keratinocytes XREF_BIBR, XREF_BIBR.	6	18	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH2R	PTH2R	PTH2R	16	17	8	9
The rat PTH2R is poorly activated by PTH , and bovine hypothalamic extracts contain activity that is more potent and more efficatious at the rat PTH2R than PTH , based on stimulation of cAMP accumulation in cultured cells transfected with the PTH2R .	The rat PTH2R is poorly activated by PTH, and bovine hypothalamic extracts contain activity that is more potent and more efficatious at the rat PTH2R than PTH, based on stimulation of cAMP accumulation in cultured cells transfected with the PTH2R.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH2R	PTH2R	PTH2R	7	8	2	3
The human PTH2R is potently activated by both PTH and TIP39 .	The human PTH2R is potently activated by both PTH and TIP39.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH2R	PTH2R	PTH2R	8	9	2	3
The novel receptor was named PTH2R because of its sequence similarity to the parathyroid hormone receptor and also because the human PTH2R can be activated by parathyroid hormone .	The novel receptor was named PTH2R because of its sequence similarity to the parathyroid hormone receptor and also because the human PTH2R can be activated by parathyroid hormone.	19	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	parathyroid hormone	parathyroid hormone	parathyroid hormone	PTH2R	PTH2R	PTH2R	26	28	21	22
The human parathyroid hormone-2 receptor is activated by parathyroid hormone and a recently purified hypothalamic polypeptide , tubero-infundibular peptide of 39 residues , while the rat parathyroid hormone-2 receptor is poorly activated by parathyroid hormone and is potently activated by tubero-infundibular peptide of 39 residues .	The human parathyroid hormone-2 receptor is activated by parathyroid hormone and a recently purified hypothalamic polypeptide, tubero-infundibular peptide of 39 residues, while the rat parathyroid hormone-2 receptor is poorly activated by parathyroid hormone and is potently activated by tubero-infundibular peptide of 39 residues.	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	parathyroid hormone	parathyroid hormone	parathyroid hormone	parathyroid hormone-2 receptor	parathyroid hormone-2 receptor	parathyroid hormone-2 receptor	8	10	2	5
Although PTH partially activates PTH2R , PTH2 is likely the endogenous PTH2R ligand .	Although PTH partially activates PTH2R, PTH2 is likely the endogenous PTH2R ligand.	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH2R	PTH2R	PTH2R	1	2	4	5
Human PTH2R , which is found in the brain , pancreas , heart and kidneys , is activated by PTH and tuberoinfundibular peptide of 39 residues .	Human PTH2R, which is found in the brain, pancreas, heart and kidneys, is activated by PTH and tuberoinfundibular peptide of 39 residues.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH2R	PTH2R	PTH2R	19	20	1	2
PTH strongly activates the human PTH2 receptor but is a weak partial agonist for rat and zebrafish PTH2 receptors .	PTH strongly activates the human PTH2 receptor but is a weak partial agonist for rat and zebrafish PTH2 receptors.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH2 receptor	PTH2 receptor	PTH2 receptor	0	1	5	7
In rat , however , nanomolar concentrations of parathyroid hormone do not cause significant activation of the PTH2R .	In rat, however, nanomolar concentrations of parathyroid hormone do not cause significant activation of the PTH2R.	8	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	parathyroid hormone	parathyroid hormone	parathyroid hormone	PTH2R	PTH2R	PTH2R	8	10	17	18
Only PTH activates the PTH2 receptor .	Only PTH activates the PTH2 receptor.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH2 receptor	PTH2 receptor	PTH2 receptor	1	2	4	6
Zebrafish PTH2R binds exclusively to TIP39 while the human PTH2R is also activated by PTH [ XREF_BIBR ] .	Zebrafish PTH2R binds exclusively to TIP39 while the human PTH2R is also activated by PTH [XREF_BIBR].	7	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH2R	PTH2R	PTH2R	14	15	9	10
However , the rat PTH2R is poorly activated by PTH and it is not clear whether PTH reaches brain PTH2Rs , so PTH may not be a physiological agonist of the PTH2R .	However, the rat PTH2R is poorly activated by PTH and it is not clear whether PTH reaches brain PTH2Rs, so PTH may not be a physiological agonist of the PTH2R.	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH2R	PTH2R	PTH2R	9	10	4	5
Although the human PTH2R can be activated both by TIP39 and PTH ( as described below ) , the resulting cAMP and intracellular Ca signaling is different .	Although the human PTH2R can be activated both by TIP39 and PTH (as described below), the resulting cAMP and intracellular Ca signaling is different.	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH	PTH	PTH	PTH2R	PTH2R	PTH2R	11	12	3	4
Furthermore , overexpression of kinase active c-Src enhanced Brk induced STAT5b transcriptional activity .	Furthermore, overexpression of kinase active c-Src enhanced Brk induced STAT5b transcriptional activity.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	8	9	10	11
As the kinase-inactive c-Src did not enhance Brk mediated STAT5b transcriptional activity , c-Src kinase activity may play a role in increasing the phosphorylation and functional activation of Brk .	As the kinase-inactive c-Src did not enhance Brk mediated STAT5b transcriptional activity, c-Src kinase activity may play a role in increasing the phosphorylation and functional activation of Brk.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	7	8	9	10
c-Src overexpression enhanced Brk induced STAT5b transcriptional activity , however , indicating that Brk and c-Src together can enhance STAT5b transcriptional activity .	c-Src overexpression enhanced Brk induced STAT5b transcriptional activity, however, indicating that Brk and c-Src together can enhance STAT5b transcriptional activity.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	3	4	5	6
Likewise , the kinase inactive c-Src ( K-Src ) failed to significantly enhance Brk induced STAT5b transcriptional activity , suggesting that the kinase activity of c-Src is also necessary for this cooperation between Brk and c-Src .	Likewise, the kinase inactive c-Src (K-Src) failed to significantly enhance Brk induced STAT5b transcriptional activity, suggesting that the kinase activity of c-Src is also necessary for this cooperation between Brk and c-Src.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	13	14	15	16
While studies in the MEF5 -/- cells allowed us to characterize the role of Brk in STAT5b activation , we continued our studies in breast cancer cell lines as a means to investigate the biological relevance of Brk mediated STAT5b activation .	While studies in the MEF5 -/- cells allowed us to characterize the role of Brk in STAT5b activation, we continued our studies in breast cancer cell lines as a means to investigate the biological relevance of Brk mediated STAT5b activation.	35	40	mediated	Positive_early_activation	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	37	38	39	40
These results demonstrate not only that Brk mediates STAT5b transcriptional activity , but that Y699 is required .	These results demonstrate not only that Brk mediates STAT5b transcriptional activity, but that Y699 is required.	6	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	6	7	8	9
As previously , Brk dramatically enhanced STAT5b transcriptional activity , and the K219M Brk was also able to significantly enhance this activity .	As previously, Brk dramatically enhanced STAT5b transcriptional activity, and the K219M Brk was also able to significantly enhance this activity.	3	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	3	4	6	7
Breast tumor kinase mediates STAT5b transcriptional activity .	Breast tumor kinase mediates STAT5b transcriptional activity.	0	6	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Breast tumor kinase	Breast tumor kinase	Breast tumor kinase	STAT5b	STAT5b	STAT5b	0	3	4	5
Since our previous studies demonstrated that STAT5b , but not STAT5a , elicits a proproliferative effect in breast cancer cells [ XREF_BIBR ] , and other studies have shown that Brk also increases proliferation of breast cancer cells [ XREF_BIBR ] , we focused our efforts on Brk mediated activation of STAT5b .	Since our previous studies demonstrated that STAT5b, but not STAT5a, elicits a proproliferative effect in breast cancer cells [XREF_BIBR], and other studies have shown that Brk also increases proliferation of breast cancer cells [XREF_BIBR], we focused our efforts on Brk mediated activation of STAT5b.	45	52	mediated	Positive_early_activation	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	47	48	51	52
Breast tumor kinase mediates STAT5b activity in breast cancer cells .	Breast tumor kinase mediates STAT5b activity in breast cancer cells.	0	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Breast tumor kinase	Breast tumor kinase	Breast tumor kinase	STAT5b	STAT5b	STAT5b	0	3	4	5
Exogenous expression of Brk in the Brk negative breast cancer cell line BT-549 increased endogenous STAT5b transcriptional activity .	Exogenous expression of Brk in the Brk negative breast cancer cell line BT-549 increased endogenous STAT5b transcriptional activity.	1	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Brk	expression of Brk	brk	STAT5b	STAT5b	stat5b	3	4	15	16
PTK6 activates STAT3 [ XREF_BIBR ] and STAT5b [ XREF_BIBR ] to promote proliferation , and this may be facilitated by the signal transducing adaptor protein-2 ( STAP2 ) [ XREF_BIBR ] .	PTK6 activates STAT3 [XREF_BIBR] and STAT5b [XREF_BIBR] to promote proliferation, and this may be facilitated by the signal transducing adaptor protein-2 (STAP2) [XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	PTK6	PTK6	STAT5b	STAT5b	STAT5b	0	1	7	8
Transient transfection of Brk into the Brk negative BT-549 breast cancer cell line enhanced STAT5b transcriptional activity , as measured by a STAT5 specific luciferase reporter .	Transient transfection of Brk into the Brk negative BT-549 breast cancer cell line enhanced STAT5b transcriptional activity, as measured by a STAT5 specific luciferase reporter.	1	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	3	4	14	15
While there was a detectable basal level of transcriptional activity , Brk significantly increased endogenous STAT5b transcriptional activity , as did the constitutively active Brk ( Y447F ) .	While there was a detectable basal level of transcriptional activity, Brk significantly increased endogenous STAT5b transcriptional activity, as did the constitutively active Brk (Y447F).	11	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	11	12	15	16
We have demonstrated that the nonreceptor tyrosine kinase Brk positively regulates STAT5b activity leading to proliferation of breast cancer cells .	We have demonstrated that the nonreceptor tyrosine kinase Brk positively regulates STAT5b activity leading to proliferation of breast cancer cells.	4	12	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Brk	Brk	Brk	STAT5b	STAT5b	STAT5b	8	9	11	12
In addition , FAK inhibited PYK2 autophosphorylation and focal adhesion targeting , which might contribute to FAK mediated suppression of PYK2 ' s phenotypes .	In addition, FAK inhibited PYK2 autophosphorylation and focal adhesion targeting, which might contribute to FAK mediated suppression of PYK2 's phenotypes.	5	17	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	PYK2	PYK2 autophosphorylation	pyk2	FAK	FAK	fak	5	6	16	17
Although Pyk2 overexpression in FAK -/- MEFs enhances MAPK activation , we found that Pyk2 enhanced FAK -/- MEF proliferation was dependent on p190RhoGEF expression and was correlated with the ability of Pyk2 to stimulate RhoA activation .	Although Pyk2 overexpression in FAK -/- MEFs enhances MAPK activation, we found that Pyk2 enhanced FAK -/- MEF proliferation was dependent on p190RhoGEF expression and was correlated with the ability of Pyk2 to stimulate RhoA activation.	14	27	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Pyk2	Pyk2	Pyk2	FAK	FAK	FAK	14	15	16	17
Pyk2 tyrosine phosphorylation was enhanced by fibronectin ( FN ) stimulation of FAK- but not FAK+ cells .	Pyk2 tyrosine phosphorylation was enhanced by fibronectin (FN) stimulation of FAK- but not FAK+ cells.	0	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pyk2	Pyk2 tyrosine phosphorylation	pyk2	FAK-	FAK-	fak-	0	1	12	13
Pyk2 and FAK-CT also Rescues FAK -/- Cell Defects in FN stimulated JNK Activation .	Pyk2 and FAK-CT also Rescues FAK -/- Cell Defects in FN stimulated JNK Activation.	0	11	Rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pyk2	Pyk2	Pyk2	FAK	FAK	FAK	0	1	5	6
Notably , Ad-Pyk2 overexpression only weakly promoted FAK -/- Pyk2 shRNA MEF motility to ~ 70 % of the level of FAK -/- controls ( XREF_FIG ) .	Notably, Ad-Pyk2 overexpression only weakly promoted FAK -/- Pyk2 shRNA MEF motility to ~ 70% of the level of FAK -/- controls (XREF_FIG).	2	10	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ad-Pyk2	Ad-Pyk2 overexpression	ad-pyk2	FAK	FAK	fak	2	3	7	8
To test whether Pyk2 and FAK-CT can rescue FAK -/ - cell motility defects , Boyden chamber haptotaxis cell migration assays were conducted with immobilized FN as the stimulus .	To test whether Pyk2 and FAK-CT can rescue FAK -/ - cell motility defects, Boyden chamber haptotaxis cell migration assays were conducted with immobilized FN as the stimulus.	3	13	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pyk2	Pyk2	Pyk2	FAK	FAK	FAK	3	4	8	9
However , the presence of the FAK related Pyk2 PTK in cells without FAK reduces effects of FAK loss on p53 and angiogenesis .	However, the presence of the FAK related Pyk2 PTK in cells without FAK reduces effects of FAK loss on p53 and angiogenesis.	8	18	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pyk2	Pyk2	Pyk2	FAK	FAK	FAK	8	9	17	18
In addition , Pyk2 and Src family PTKs ( Protein-tyrosine kinases ) combine to promote fibronectin ( FN ) stimulated signaling events that promote activation of extracellular-signal-regulated kinase 2 ( ERK2 ) in the absence of FAK , and Pyk2 tyrosine phosphorylation is enhanced by fibronectin ( FN ) stimulation of FAK - cells , but not in FAK + cells [ XREF_BIBR ] .	In addition, Pyk2 and Src family PTKs (Protein-tyrosine kinases) combine to promote fibronectin (FN) stimulated signaling events that promote activation of extracellular-signal-regulated kinase 2 (ERK2) in the absence of FAK, and Pyk2 tyrosine phosphorylation is enhanced by fibronectin (FN) stimulation of FAK - cells, but not in FAK + cells [XREF_BIBR].	3	52	promote	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Pyk2	Pyk2	pyk2	FAK	Pyk2 tyrosine phosphorylation is enhanced by fibronectin (FN) stimulation of FAK	fak	3	4	51	52
Inhibition of Pyk2 by PF-431396 ( a dual inhibitor of Pyk2 and FAK ) or Pyk2 siRNA abolished DA release induced by GQ1b .	Inhibition of Pyk2 by PF-431396 (a dual inhibitor of Pyk2 and FAK) or Pyk2 siRNA abolished DA release induced by GQ1b.	8	16	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Positive_activation	Pyk2	Pyk2	Pyk2	FAK	FAK	FAK	15	16	12	13
Pyk2 promotes FAK -/- MEF proliferation , but not motility , at a level equal to FAK .	Pyk2 promotes FAK -/- MEF proliferation, but not motility, at a level equal to FAK.	0	5	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Pyk2	Pyk2	Pyk2	FAK	FAK	FAK	0	1	2	3
FAK and PYK2 kinase activity mediates FAK and PYK2 regulation of the Wnt and beta-catenin pathway .	FAK and PYK2 kinase activity mediates FAK and PYK2 regulation of the Wnt and beta-catenin pathway.	2	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PYK2	PYK2	PYK2	FAK	FAK	FAK	2	3	6	7
Interestingly , Ad-Pyk2 overexpression did not significantly promote FAK -/- p190RhoGEF shRNA MEF growth ( XREF_FIG ; P > 0.05 ) and only weakly facilitated RhoA-GTP binding upon FN plating ( XREF_FIG ) .	Interestingly, Ad-Pyk2 overexpression did not significantly promote FAK -/- p190RhoGEF shRNA MEF growth (XREF_FIG; P> 0.05) and only weakly facilitated RhoA-GTP binding upon FN plating (XREF_FIG).	2	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ad-Pyk2	Ad-Pyk2 overexpression	ad-pyk2	FAK	FAK	fak	2	3	8	9
at intervals of 5-10 min caused constant responses for at least 30 min ( XREF_FIG ) , suggesting that these repeated TIP39 challenges did not cause desensitization of the PTH2 receptor .	at intervals of 5-10 min caused constant responses for at least 30 min (XREF_FIG), suggesting that these repeated TIP39 challenges did not cause desensitization of the PTH2 receptor.	21	31	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIP39	TIP39	TIP39	PTH2 receptor	PTH2 receptor	PTH2 receptor	21	22	29	31
For example , tuberoinfundibular peptide of 39 residues ( TIP39 )-mediated activation of the parathyroid hormone 2 receptor ( PTH2R ) on glutamatergic terminals presynaptic to MnPO neurons projecting to DMH/DA increases core temperature , likely including a stimulation of BAT thermogenesis , and interruption of TIP39 signaling in MnPO reduces cold defense capability .	For example, tuberoinfundibular peptide of 39 residues (TIP39)-mediated activation of the parathyroid hormone 2 receptor (PTH2R) on glutamatergic terminals presynaptic to MnPO neurons projecting to DMH/DA increases core temperature, likely including a stimulation of BAT thermogenesis, and interruption of TIP39 signaling in MnPO reduces cold defense capability.	3	18	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	tuberoinfundibular peptide of 39 residues	tuberoinfundibular peptide of 39 residues	tuberoinfundibular peptide of 39 residues	parathyroid hormone 2 receptor	parathyroid hormone 2 receptor	parathyroid hormone 2 receptor	3	8	14	18
However , only TIP39 induces beta-arrestin and protein kinase Cbeta mobilisation and receptor internalisation of PTH2R [ XREF_BIBR ] .	However, only TIP39 induces beta-arrestin and protein kinase Cbeta mobilisation and receptor internalisation of PTH2R [XREF_BIBR].	2	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIP39	TIP39	TIP39	PTH2R	PTH2R	PTH2R	3	4	15	16
Furthermore , TIP39 induces beta-arrestin and protein kinase C-beta mobilization , PTH2R desensitization , and receptor internalization whereas PTH does not .	Furthermore, TIP39 induces beta-arrestin and protein kinase C-beta mobilization, PTH2R desensitization, and receptor internalization whereas PTH does not.	2	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIP39	TIP39	TIP39	PTH2R	PTH2R	PTH2R	2	3	11	12
PTH2R , abundant in brain and pancreas , is essentially activated by PTH2 .	PTH2R, abundant in brain and pancreas, is essentially activated by PTH2.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PTH2	PTH2	PTH2	PTH2R	PTH2R	PTH2R	12	13	0	1
The PTH2 receptor is activated by TIP39 but not by PTHrP .	The PTH2 receptor is activated by TIP39 but not by PTHrP.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TIP39	TIP39	TIP39	PTH2 receptor	PTH2 receptor	PTH2 receptor	6	7	1	3
Similar modifications of TIP39 were produced in attempts to generate a PTH2R antagonist .	Similar modifications of TIP39 were produced in attempts to generate a PTH2R antagonist.	1	12	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIP39	TIP39	TIP39	PTH2R	PTH2R	PTH2R	3	4	11	12
Tuberoinfundibular peptide of 39 residues ( TIP39 ) selectively activates the PTH2 receptor .	Tuberoinfundibular peptide of 39 residues (TIP39) selectively activates the PTH2 receptor.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tuberoinfundibular peptide of 39 residues	Tuberoinfundibular peptide of 39 residues	Tuberoinfundibular peptide of 39 residues	PTH2 receptor	PTH2 receptor	PTH2 receptor	0	5	11	13
The Pth2 ligand acts by binding and activating the Pth2r .	The Pth2 ligand acts by binding and activating the Pth2r.	1	10	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pth2	Pth2	Pth2	Pth2r	Pth2r	Pth2r	1	2	9	10
Thus , TIP39 axon terminals and the PTH2R are co-distributed in the very same brain structures allowing the presynaptic modulation of PTH2R axon terminals .	Thus, TIP39 axon terminals and the PTH2R are co-distributed in the very same brain structures allowing the presynaptic modulation of PTH2R axon terminals.	2	23	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIP39	TIP39	TIP39	PTH2R	PTH2R	PTH2R	2	3	21	22
Taken together , these findings suggest that TIP39 activation of PTH2R can influence keratinocytes differentiation .	Taken together, these findings suggest that TIP39 activation of PTH2R can influence keratinocytes differentiation.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TIP39	TIP39	TIP39	PTH2R	PTH2R	PTH2R	7	8	10	11
Tuberoinfundibular peptide of 39 residues ( TIP39 ) potently activates the parathyroid hormone-2 receptor ( PTH2-R ) .	Tuberoinfundibular peptide of 39 residues (TIP39) potently activates the parathyroid hormone-2 receptor (PTH2-R).	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tuberoinfundibular peptide of 39 residues	Tuberoinfundibular peptide of 39 residues	Tuberoinfundibular peptide of 39 residues	parathyroid hormone-2 receptor	parathyroid hormone-2 receptor	parathyroid hormone-2 receptor	0	5	11	14
Importantly , Brk and FAK phosphorylation ( activation ) can consequently lead to AKT , paxillin and MAPK activation [ XREF_BIBR , XREF_BIBR ] .	Importantly, Brk and FAK phosphorylation (activation) can consequently lead to AKT, paxillin and MAPK activation [XREF_BIBR, XREF_BIBR].	2	18	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Brk	Brk and FAK phosphorylation	brk	AKT	AKT	akt	2	3	13	14
Disruption of the Ptk6 gene in the mouse led to increased growth and impaired enterocyte differentiation that was accompanied by an increase in AKT activation and decreased nuclear localization of the AKT substrate FoxO1 [ XREF_BIBR , XREF_BIBR ] , supporting the notion that PTK6 inhibits AKT activity in normal tissue .	Disruption of the Ptk6 gene in the mouse led to increased growth and impaired enterocyte differentiation that was accompanied by an increase in AKT activation and decreased nuclear localization of the AKT substrate FoxO1 [XREF_BIBR, XREF_BIBR], supporting the notion that PTK6 inhibits AKT activity in normal tissue.	3	47	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTK6	Ptk6	Ptk6	AKT	AKT	AKT	3	4	46	47
Silencing PTK6 reduced ERK1/2 activation , but not AKT or STAT3 activation , while PTK6 overexpression increased ERK1/2 activation .	Silencing PTK6 reduced ERK1/2 activation, but not AKT or STAT3 activation, while PTK6 overexpression increased ERK1/2 activation.	0	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	1	2	8	9
Interestingly , activation of AKT by PTK6 is most evident in cells exposed to low levels of EGF ( 0.1 ng/ml versus 1ng/ml of EGF ) suggesting that under higher concentrations of EGF , the RTK and PI3K pathway may be robustly activated , masking the contribution of PTK6 mediated AKT activation .	Interestingly, activation of AKT by PTK6 is most evident in cells exposed to low levels of EGF (0.1 ng/ml versus 1ng/ml of EGF) suggesting that under higher concentrations of EGF, the RTK and PI3K pathway may be robustly activated, masking the contribution of PTK6 mediated AKT activation.	46	51	mediated	Positive_early_activation	Positive_activation	Positive_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	48	49	50	51
PTK6 directly phosphorylates and promotes AKT activation in response to EGF in BPH1 cells .	PTK6 directly phosphorylates and promotes AKT activation in response to EGF in BPH1 cells.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	0	1	5	6
XREF_BIBR - XREF_BIBR It has also been reported that PTK6 could also activate the PI3k and Akt and STAT pathway .	XREF_BIBR - XREF_BIBR It has also been reported that PTK6 could also activate the PI3k and Akt and STAT pathway.	9	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	PTK6	PTK6	Akt	Akt	Akt	9	10	16	17
Introduction of PTK6 into SYF cells sensitized these cells to physiological levels of epidermal growth factor ( EGF ) and increased AKT activation .	Introduction of PTK6 into SYF cells sensitized these cells to physiological levels of epidermal growth factor (EGF) and increased AKT activation.	0	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	2	3	21	22
Our data indicate that in addition to promoting growth factor receptor mediated activation of AKT , PTK6 can directly activate AKT to promote oncogenic signaling .	Our data indicate that in addition to promoting growth factor receptor mediated activation of AKT, PTK6 can directly activate AKT to promote oncogenic signaling.	16	21	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	16	17	20	21
Evidence in breast cancer suggests that PTK6 stimulates AKT signaling by increasing ErbB receptor signaling [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Evidence in breast cancer suggests that PTK6 stimulates AKT signaling by increasing ErbB receptor signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	6	7	8	9
Thus , we conclude that CaMKIIalpha activity is required for NCAM induced RPTPalpha mediated fyn activation .	Thus, we conclude that CaMKIIalpha activity is required for NCAM induced RPTPalpha mediated fyn activation.	11	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	fyn	fyn	fyn	12	13	14	15
In response to NCAM activation NCAM binds RPTPalpha and both molecules are recruited to lipid rafts where RPTPalpha activates fyn , a process that is regulated by PrP ( XREF_FIG ) .	In response to NCAM activation NCAM binds RPTPalpha and both molecules are recruited to lipid rafts where RPTPalpha activates fyn, a process that is regulated by PrP (XREF_FIG).	6	22	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	fyn	fyn	fyn	17	18	19	20
These data suggest parallel paths of force sensing in structural components , which might be the target of force dependent , RPTPalpha mediated activation of Fyn .	These data suggest parallel paths of force sensing in structural components, which might be the target of force dependent, RPTPalpha mediated activation of Fyn.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	Fyn	Fyn	Fyn	21	22	25	26
Furthermore , we show that BisI , a PKCdelta inhibitor , does not block RPTPalpha mediated fyn activation in response to NCAM clustering .	Furthermore, we show that BisI, a PKCdelta inhibitor, does not block RPTPalpha mediated fyn activation in response to NCAM clustering.	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	fyn	fyn	fyn	14	15	16	17
We have shown earlier that RPTPalpha dependent activation of Fyn is needed for the formation of focal complexes and contacts , suggesting that it might affect reinforcement .	We have shown earlier that RPTPalpha dependent activation of Fyn is needed for the formation of focal complexes and contacts, suggesting that it might affect reinforcement.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RPTPalpha	RPTPalpha	RPTPalpha	Fyn	Fyn	Fyn	5	6	9	10
First , Lck activity was required for TCR induced Pyk2 translocation , but not for TCR induced Pyk2 activation .	First, Lck activity was required for TCR induced Pyk2 translocation, but not for TCR induced Pyk2 activation.	7	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pyk2	TCR induced Pyk2	pyk2	Pyk2	Pyk2	pyk2	9	10	17	18
Using specific antibodies , increased phosphorylation of PYK2 tyrosine residues 402 and 580 was observed .	Using specific antibodies, increased phosphorylation of PYK2 tyrosine residues 402 and 580 was observed.	4	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PYK2	phosphorylation of PYK2 tyrosine residues 402	pyk2	PYK2	PYK2	pyk2	7	8	7	8
In this model , ET-1 mediated activation of Pyk2 , as described above , promotes the binding of the autophosphorylation site of Pyk2 ( Tyr 402 ) to the Src-homology 2 domain ( SH2 ) of c-Src .	In this model, ET-1 mediated activation of Pyk2, as described above, promotes the binding of the autophosphorylation site of Pyk2 (Tyr 402) to the Src-homology 2 domain (SH2) of c-Src.	4	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pyk2	ET-1 mediated activation of Pyk2	pyk2	Pyk2	Pyk2	pyk2	8	9	22	23
All three calmodulin antagonists blocked this increase in Pyk2 autophosphorylation ( XREF_FIG ) similar to their blockade of NMDA stimulated Pyk2 co-precipitation with PSD-95 ( XREF_FIG ) .	All three calmodulin antagonists blocked this increase in Pyk2 autophosphorylation (XREF_FIG) similar to their blockade of NMDA stimulated Pyk2 co-precipitation with PSD-95 (XREF_FIG).	8	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Pyk2	Pyk2 autophosphorylation	pyk2	Pyk2	Pyk2	pyk2	8	9	20	21
Previously , we have demonstrated that selected amino acid substitutions within the Pyk2 FERM domain inhibited Pyk2 phosphorylation and reduced the capacity of Pyk2 to stimulate glioma migration .	Previously, we have demonstrated that selected amino acid substitutions within the Pyk2 FERM domain inhibited Pyk2 phosphorylation and reduced the capacity of Pyk2 to stimulate glioma migration.	8	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pyk2	acid substitutions within the Pyk2 FERM domain inhibited Pyk2 phosphorylation	pyk2	Pyk2	Pyk2	pyk2	16	17	23	24
Correlation of the expression of Pyk2 and FAK with clinicopathological parameters : overexpression of Pyk2 was significantly associated with poor survival and tumour invasiveness .	Correlation of the expression of Pyk2 and FAK with clinicopathological parameters : overexpression of Pyk2 was significantly associated with poor survival and tumour invasiveness.	3	15	overexpression	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Pyk2	expression of Pyk2	pyk2	Pyk2	Pyk2	pyk2	5	6	14	15
We also show that Pyk2 , a tyrosine kinase involved in cytoskeleton rearrangements and B cell migration , is a downstream target of both CXCL13 and S1P signaling and that Rap activation is important for CXCL13 and S1P to stimulate tyrosine phosphorylation of Pyk2 , a modification that increases Pyk2 kinase activity .	We also show that Pyk2, a tyrosine kinase involved in cytoskeleton rearrangements and B cell migration, is a downstream target of both CXCL13 and S1P signaling and that Rap activation is important for CXCL13 and S1P to stimulate tyrosine phosphorylation of Pyk2, a modification that increases Pyk2 kinase activity.	30	51	increases	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Pyk2	Rap activation is important for CXCL13 and S1P to stimulate tyrosine phosphorylation of Pyk2	pyk2	Pyk2	Pyk2	pyk2	43	44	49	50
In keeping with the established model for FAK activation ( see above ) , we envision that phosphorylation of Pyk2 at the Y579 site results in full activation of Pyk2 .	In keeping with the established model for FAK activation (see above), we envision that phosphorylation of Pyk2 at the Y579 site results in full activation of Pyk2.	17	30	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Pyk2	phosphorylation of Pyk2 at the Y579	pyk2	Pyk2	Pyk2	pyk2	19	20	29	30
These data suggest that PTPN21 mediated inhibition of TNF-alpha-induced NF-kappaB signaling could have the same cancer promoting effects as PTPN21 mediated Src activation .	These data suggest that PTPN21 mediated inhibition of TNF-alpha-induced NF-kappaB signaling could have the same cancer promoting effects as PTPN21 mediated Src activation.	19	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	PTPN21	PTPN21	PTPN21	Src	Src	Src	19	20	21	22
The inhibitory effect of PTPN21 on the NF-kappaB signaling pathway seems controversial when compared to PTPN21 mediated activation of the Src signaling pathway and its promoting effects on cell motility and migration .	The inhibitory effect of PTPN21 on the NF-kappaB signaling pathway seems controversial when compared to PTPN21 mediated activation of the Src signaling pathway and its promoting effects on cell motility and migration.	15	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	PTPN21	PTPN21	PTPN21	Src	Src	Src	15	16	20	21
Similarly , we assume that PTPN21 mediated activation of the NF-kappaB signaling pathway might be more crucial for regulating ICAM-1 expression compared to PTPN21 mediated activation of the Src signaling pathway .	Similarly, we assume that PTPN21 mediated activation of the NF-kappaB signaling pathway might be more crucial for regulating ICAM-1 expression compared to PTPN21 mediated activation of the Src signaling pathway.	23	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	PTPN21	PTPN21	PTPN21	Src	Src	Src	23	24	28	29
SHP-2 phosphatase contributes to KRAS driven intestinal oncogenesis but prevents colitis associated cancer development .	SHP-2 phosphatase contributes to KRAS driven intestinal oncogenesis but prevents colitis associated cancer development.	0	5	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	SHP-2	SHP-2	SHP-2	KRAS	KRAS	KRAS	0	1	4	5
Since Tyr32 is conserved in human and mouse KRAS proteins , our data suggest that SHP-2 may also target KRAS in IECs , enhancing the stimulation of downstream proliferative RAS/MEK/ERK kinases .	Since Tyr32 is conserved in human and mouse KRAS proteins, our data suggest that SHP-2 may also target KRAS in IECs, enhancing the stimulation of downstream proliferative RAS/MEK/ERK kinases.	15	21	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHP-2	SHP-2	SHP-2	KRAS	KRAS	KRAS	15	16	19	20
Inhibition of SHP-2 expression also decreased the capability of KRAS cells to grow under anchorage independent conditions and to invade Matrigel .	Inhibition of SHP-2 expression also decreased the capability of KRAS cells to grow under anchorage independent conditions and to invade Matrigel.	2	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SHP-2	SHP-2 expression	shp-2	KRAS	KRAS	kras	2	3	9	10
Activated Kras alleviates the Ptpn11 requirement for colony formation by progenitors and cytokine and growth factor responsiveness of HSCs , indicating that Ras is functionally downstream of Shp2 in these cells .	Activated Kras alleviates the Ptpn11 requirement for colony formation by progenitors and cytokine and growth factor responsiveness of HSCs, indicating that Ras is functionally downstream of Shp2 in these cells.	0	5	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ptpn11	Ptpn11	Ptpn11	Kras	Kras	Kras	4	5	1	2
In our study , the results of MTT assay and colony formation assay showed that overexpression of PTK6 can enhance cell proliferation and colony formation ability and high expression of PTK6 cause poor prognosis in NPC .	In our study, the results of MTT assay and colony formation assay showed that overexpression of PTK6 can enhance cell proliferation and colony formation ability and high expression of PTK6 cause poor prognosis in NPC.	15	33	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	overexpression of PTK6	ptk6	PTK6	PTK6	ptk6	17	18	30	31
Taken together , these results suggest that miR-17 down-regulates PTK6 expression and ERK1/2 activity by directly targeting PTK6 3 ' UTR .	Taken together, these results suggest that miR-17 down-regulates PTK6 expression and ERK1/2 activity by directly targeting PTK6 3 ' UTR.	7	18	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	miR-17 down-regulates PTK6 expression	ptk6	PTK6	PTK6	ptk6	9	10	17	18
Dasatinib reduces FAK phosphorylation increasing the effects of RPI-1 inhibition in a RET and PTC1 expressing cell line .	Dasatinib reduces FAK phosphorylation increasing the effects of RPI-1 inhibition in a RET and PTC1 expressing cell line.	0	17	increasing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	Dasatinib reduces FAK phosphorylation	fak	RET	RET	ret	2	3	12	13
Fak has been shown to signal downstream of Ret , and Fak and Ret complexes have previously been identified in MCF7 cells .	Fak has been shown to signal downstream of Ret, and Fak and Ret complexes have previously been identified in MCF7 cells.	0	9	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fak	Fak	Fak	Ret	Ret	Ret	0	1	8	9
On the other hand , activation of SHP-2 protein-tyrosine phosphatase was shown to increase HoxA10 induced transcriptional repression of NOX2 and p67phox .	On the other hand, activation of SHP-2 protein-tyrosine phosphatase was shown to increase HoxA10 induced transcriptional repression of NOX2 and p67phox.	7	15	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHP-2	SHP-2	SHP-2	HoxA10	HoxA10	HoxA10	7	8	14	15
In addition , it has been recently shown that parathyroid hormone ( PTH ) and its receptor ( PTHR ) , a GPCR that can be phosphorylated by GRK5 , regulates phosphorylation of LRP6 serine 1490 to activate LRP6 in a Wnt independent fashion .	In addition, it has been recently shown that parathyroid hormone (PTH) and its receptor (PTHR), a GPCR that can be phosphorylated by GRK5, regulates phosphorylation of LRP6 serine 1490 to activate LRP6 in a Wnt independent fashion.	16	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTHR	PTHR), a GPCR that can be phosphorylated	pthr	LRP6	LRP6	lrp6	18	19	38	39
Because PTEN is known to stabilize PPM1A against degradation XREF_BIBR , we built a model to illustrate hypothetical dynamics of PTEN induced PPM1A sequestration , including delayed enzymatic activity for PPM1A .	Because PTEN is known to stabilize PPM1A against degradation XREF_BIBR, we built a model to illustrate hypothetical dynamics of PTEN induced PPM1A sequestration, including delayed enzymatic activity for PPM1A.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	PTEN	PTEN	PTEN	PPM1A	PPM1A	PPM1A	20	21	22	23
They demonstrated that , in the overloaded muscle , SRF enhances the expression of COX2 mRNA , which in turn upregulates IL-4 mRNA and ultimately secretes IL-4 protein .	They demonstrated that, in the overloaded muscle, SRF enhances the expression of COX2 mRNA, which in turn upregulates IL-4 mRNA and ultimately secretes IL-4 protein.	9	22	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	COX2	SRF enhances the expression of COX2	cox2	IL-4	IL-4	il-4	14	15	21	22
Both Rac activated PAK and Src family non receptor tyrosine kinases have been shown to play independent critical roles in podocyte physiology XREF_BIBR XREF_BIBR .	Both Rac activated PAK and Src family non receptor tyrosine kinases have been shown to play independent critical roles in podocyte physiology XREF_BIBR XREF_BIBR.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	1	2	3	4
betaPIX is a guanine nucleotide exchange factor ( GEF ) for Rac1 activating PAK and contributes to GABA A R stability .	betaPIX is a guanine nucleotide exchange factor (GEF) for Rac1 activating PAK and contributes to GABA A R stability.	6	14	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	11	12	13	14
In cultured cells , activation of Rac1 at the cell edge was sufficient to promote membrane ruffling , recruit the Rac effector PAK , and direct cell movement .	In cultured cells, activation of Rac1 at the cell edge was sufficient to promote membrane ruffling, recruit the Rac effector PAK, and direct cell movement.	4	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	6	7	22	23
Rac activates PI3K and AKT independent of JNK , and activates the MEKK-JNK cascade independent of PAK .	Rac activates PI3K and AKT independent of JNK, and activates the MEKK-JNK cascade independent of PAK.	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	0	1	16	17
Another Rac1 activity , upregulation of reactive oxygen species , in which PAK1 is also involved , has been suggested to contribute to Rac1 mediated growth regulation PAK activation in RAS mutant cancer .	Another Rac1 activity, upregulation of reactive oxygen species, in which PAK1 is also involved, has been suggested to contribute to Rac1 mediated growth regulation PAK activation in RAS mutant cancer.	1	28	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	1	2	27	28
One study found that Rac1 activated its effector PAK in mammary epithelial cells plated on basement membrane proteins , in the absence of lactogenic hormones .	One study found that Rac1 activated its effector PAK in mammary epithelial cells plated on basement membrane proteins, in the absence of lactogenic hormones.	4	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	4	5	8	9
2 As RAC1 activates PAK , which assists in the MEK and ERK pathway via phosphorylation of c-RAF and MEK1 25 , we asked if activated RAC1 affected embryonic development and if these effects were accompanied by PAK and ERK activation .	2 As RAC1 activates PAK, which assists in the MEK and ERK pathway via phosphorylation of c-RAF and MEK1 25, we asked if activated RAC1 affected embryonic development and if these effects were accompanied by PAK and ERK activation.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAC1	RAC1	RAC1	PAK	PAK	PAK	2	3	4	5
Ins and IGF-1 , like antigen ( Ag ) , also stimulates the Rac dependent activation of PAK as well as the production of hydrogen peroxide ( H2O2 ) .	Ins/IGF-1, like antigen (Ag), also stimulates the Rac dependent activation of PAK as well as the production of hydrogen peroxide (H2O2).	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	13	14	17	18
Kalirin-7 activation of the small GTPase Rac1 can lead to the activation of p21 activated kinase ( Pak ) and subsequent Pak dependent induction of actin polymerization .	Kalirin-7 activation of the small GTPase Rac1 can lead to the activation of p21 activated kinase (Pak) and subsequent Pak dependent induction of actin polymerization.	1	23	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak	Pak	Pak	6	7	21	22
However , activated Rac in non adherent cells failed to stimulate the Rac effector PAK .	However, activated Rac in non adherent cells failed to stimulate the Rac effector PAK.	2	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	3	4	14	15
This GEF domain activates Rac , which in turn activates Pak .	This GEF domain activates Rac, which in turn activates Pak.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	Pak	Pak	Pak	4	5	10	11
The activation of Rac increases the activation of PAK under environmental conditions stimulating cell death and growth .	The activation of Rac increases the activation of PAK under environmental conditions stimulating cell death and growth.	1	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	3	4	8	9
Spine actin is modulated largely by Rac1 activated PAK that activates LIM-kinase ( LIMK ) to promote actin polymerization by phosphorylating ADF and cofilin , thereby inhibiting actin depolymerizing activity .	Spine actin is modulated largely by Rac1 activated PAK that activates LIM-kinase (LIMK) to promote actin polymerization by phosphorylating ADF and cofilin, thereby inhibiting actin depolymerizing activity.	3	22	activated	Positive_regulation_token_1_verb	Positive_activation	Positive_regulation	Rac1	Rac1	rac1	PAK	PAK that activates LIM-kinase (LIMK) to promote actin polymerization by phosphorylating ADF	pak	6	7	8	9
Rac1 induced activation of PAK and downstream signaling are believed to be necessary for actin cytoskeleton reorganization and regulate GLUT4 translocation in response to insulin in cultured muscle cells .	Rac1 induced activation of PAK and downstream signaling are believed to be necessary for actin cytoskeleton reorganization and regulate GLUT4 translocation in response to insulin in cultured muscle cells.	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	0	1	4	5
Rac1 activation is known to induce PAK .	Rac1 activation is known to induce PAK.	0	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	0	1	6	7
Integrin mediated adhesion activates PAK through its effector Rac , which enables PAK to activate c-Raf by phosphorylation of serine 338 .	Integrin mediated adhesion activates PAK through its effector Rac, which enables PAK to activate c-Raf by phosphorylation of serine 338.	3	13	enables	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	8	9	12	13
Rac dependent activation of PAK promotes survival of neurons through stimulation of the mitogen activated protein kinase ( MAPK ) and phosphatidyl inositol-3 kinase ( PI3K )/Akt pathways that inhibits the activity of pro apoptotic members ( e.g ., Bad ) and enhances the expression of pro survival members ( e.g ., Bcl-xL ) of the Bcl-2 family of proteins [ XREF_BIBR - XREF_BIBR ] .	Rac dependent activation of PAK promotes survival of neurons through stimulation of the mitogen activated protein kinase (MAPK) and phosphatidyl inositol-3 kinase (PI3K)/Akt pathways that inhibits the activity of pro apoptotic members (e.g., Bad) and enhances the expression of pro survival members (e.g., Bcl-xL) of the Bcl-2 family of proteins [XREF_BIBR - XREF_BIBR].	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	0	1	4	5
Although Rac stimulates PAK in vivo , GST-Rac , as well as GST-Rho , were unable to activate LD4 associated PAK in this in vitro assay , consistent with previous reports .	Although Rac stimulates PAK in vivo, GST-Rac, as well as GST-Rho, were unable to activate LD4 associated PAK in this in vitro assay, consistent with previous reports.	1	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	1	2	3	4
Interestingly , later studies demonstrated that Rac but not Cdc42 is the major activator of Pak in R-cell growth cones XREF_BIBR , XREF_BIBR .	Interestingly, later studies demonstrated that Rac but not Cdc42 is the major activator of Pak in R-cell growth cones XREF_BIBR, XREF_BIBR.	6	22	is the major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Rac	Rac	Rac	Pak	Pak	Pak	6	7	15	16
Subsequent activation of the small GTPase Rac activates Pak and likely other effectors as well .	Subsequent activation of the small GTPase Rac activates Pak and likely other effectors as well.	1	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	Pak	Pak	Pak	6	7	8	9
Thus , when 1- and probably other fibronectin binding integrins are uncoupled from downstream signalling by detaching cells from the ECM , PAK is not activated by Rac , even though Rac-GTP ( activated by growth factor receptors ) is present in these detached cells [ XREF_BIBR ] .	Thus, when 1- and probably other fibronectin binding integrins are uncoupled from downstream signalling by detaching cells from the ECM, PAK is not activated by Rac, even though Rac-GTP (activated by growth factor receptors) is present in these detached cells [XREF_BIBR].	22	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	27	28	22	23
Activation of PAK by Rac1 or Cdc42 leads to the activation of LIMK1 , which in turn phosphorylates and inactivates cofilin , a crucial modulator of actin dynamics .	Activation of PAK by Rac1 or Cdc42 leads to the activation of LIMK1, which in turn phosphorylates and inactivates cofilin, a crucial modulator of actin dynamics.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	4	5	2	3
Nascent adhesions bound to phosphorylated paxillin thus mediate activation of Rac , which in turn activates PAK , and active PAK completes the feedback loop by phosphorylating paxillin .	Nascent adhesions bound to phosphorylated paxillin thus mediate activation of Rac, which in turn activates PAK, and active PAK completes the feedback loop by phosphorylating paxillin.	8	17	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	10	11	16	17
LIM kinase is , in turn , a substrate for PAK , which is activated by Rho and Rac GTPases .	LIM kinase is, in turn, a substrate for PAK, which is activated by Rho and Rac GTPases.	8	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	18	19	10	11
In reference to results from Vav -/- T cells showing decreased ERK activation 23 , our result is also consistent with the hypothesis that TCR stimulated tyrosine phosphorylation of Vav promotes its GEF activity toward Rac , which in turn activates PAK and ERK 10 .	In reference to results from Vav -/- T cells showing decreased ERK activation 23, our result is also consistent with the hypothesis that TCR stimulated tyrosine phosphorylation of Vav promotes its GEF activity toward Rac, which in turn activates PAK and ERK 10.	30	43	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	35	36	41	42
Rac1 activates PAK , which promotes cell division XREF_BIBR .	Rac1 activates PAK, which promotes cell division XREF_BIBR.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	0	1	2	3
Rac activates PAK , but two opposing views on the effect of PAK on MRLC phosphorylation have been published .	Rac activates PAK, but two opposing views on the effect of PAK on MRLC phosphorylation have been published.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	0	1	2	3
Subsequently , Rac activates PAK , which in turn stimulates Raf by S338 phosphorylation and MEK by S298 phosphorylation .	Subsequently, Rac activates PAK, which in turn stimulates Raf by S338 phosphorylation and MEK by S298 phosphorylation.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	2	3	4	5
Here we demonstrate that plexin-B1 , a receptor for Semaphorin4D ( Sema4D ) , and p21 activated kinase ( PAK ) can compete for the interaction with active Rac and plexin-B1 can inhibit Rac induced PAK activation .	Here we demonstrate that plexin-B1, a receptor for Semaphorin4D (Sema4D), and p21 activated kinase (PAK) can compete for the interaction with active Rac and plexin-B1 can inhibit Rac induced PAK activation.	32	36	induced	Positive_early_activation	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	33	34	35	36
It is generally understood that Rac1 would activate PAK , a kinase known to phosphorylate the specific guanine nucleotide exchange factor of Cdc42 .	It is generally understood that Rac1 would activate PAK, a kinase known to phosphorylate the specific guanine nucleotide exchange factor of Cdc42.	5	18	activate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Rac1	Rac1	rac1	PAK	PAK, a kinase known to phosphorylate the specific guanine	pak	5	6	8	9
This stimulates a series of events with Sos activating Rac , which in turn activates PAK .	This stimulates a series of events with Sos activating Rac, which in turn activates PAK.	8	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	9	10	15	16
Though Rac also activates Pak , such an idea is consistent with models which link Pak to further Rac activation via the Pak bound guanine-nucleotide exchange factor , PIX XREF_BIBR , XREF_BIBR .	Though Rac also activates Pak, such an idea is consistent with models which link Pak to further Rac activation via the Pak bound guanine-nucleotide exchange factor, PIX XREF_BIBR, XREF_BIBR.	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	Pak	Pak	Pak	1	2	4	5
Activation of Rac1 by Ang II is known to activate the PAK and JNK pathway , which may also be involved in VSMC hypertrophy and migration [ XREF_BIBR ] .	Activation of Rac1 by Ang II is known to activate the PAK and JNK pathway, which may also be involved in VSMC hypertrophy and migration [XREF_BIBR].	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	2	3	11	12
Src is responsible for suppressing alphavbeta3 dependent activation of RhoA via stimulation of p190RhoGAP , while PKCalpha is required for Rac dependent activation of PAK .	Src is responsible for suppressing alphavbeta3 dependent activation of RhoA via stimulation of p190RhoGAP, while PKCalpha is required for Rac dependent activation of PAK.	20	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	20	21	24	25
The model assumes that Rac1 activates PAK by binding to the PAK CRIB domain , causing a conformational transition of PAK .	The model assumes that Rac1 activates PAK by binding to the PAK CRIB domain, causing a conformational transition of PAK.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	4	5	6	7
Rac1 induced PAK activation has been shown to activate p38MAPK [ XREF_BIBR ] , which phosphorylates tau [ XREF_BIBR ] .	Rac1 induced PAK activation has been shown to activate p38MAPK [XREF_BIBR], which phosphorylates tau [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	0	1	2	3
PAK is directly activated by Rac-1 and mediates many of its morphological effects in endothelial cells [ XREF_BIBR ] .	PAK is directly activated by Rac-1 and mediates many of its morphological effects in endothelial cells [XREF_BIBR].	0	7	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rac-1	Rac-1	Rac-1	PAK	PAK	PAK	5	6	0	1
In response to stimuli from serum , VEGF , TNF , bFGF , histamine and thrombin , endothelial cells exhibit Rac mediated activation of PAK via phosphorylation at Ser141 resulting in its translocation to endothelial cell-barrier junctions [ XREF_BIBR ] .	In response to stimuli from serum, VEGF, TNF, bFGF, histamine and thrombin, endothelial cells exhibit Rac mediated activation of PAK via phosphorylation at Ser141 resulting in its translocation to endothelial cell-barrier junctions [XREF_BIBR].	20	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	20	21	24	25
The second mechanism is through Rac activated PAK kinases , which then phosphorylate and inactivate the microtubule destabilizing protein stathmin [ XREF_BIBR ] .	The second mechanism is through Rac activated PAK kinases, which then phosphorylate and inactivate the microtubule destabilizing protein stathmin [XREF_BIBR].	5	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	5	6	7	8
Active Rac1 leads to the activation of PAK and PI3K .	Active Rac1 leads to the activation of PAK and PI3K.	0	9	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	1	2	7	8
Rac1 activates PAK which subsequently stimulates LIM-kinase ( LIMK ) .	Rac1 activates PAK which subsequently stimulates LIM-kinase (LIMK).	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	0	1	2	3
Dominant negative Rac blocks PAK mediated release from contact inhibition , implying that PAK functions upstream of Rac in this signaling pathway .	Dominant negative Rac blocks PAK mediated release from contact inhibition, implying that PAK functions upstream of Rac in this signaling pathway.	0	6	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	2	3	4	5
Inhibition of the upstream effector Rac abrogates the oncogene induced growth and activity of Pak .	Inhibition of the upstream effector Rac abrogates the oncogene induced growth and activity of Pak.	0	15	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	Pak	Pak	Pak	5	6	14	15
It inhibits the Rac1 signaling pathway by p21 activated kinase ( PAK )-dependent and PAK independent mechanisms XREF_BIBR , and negatively modulates the LIMK and cofilin pathway XREF_BIBR , resulting in decreased cell motility .	It inhibits the Rac1 signaling pathway by p21 activated kinase (PAK)-dependent and PAK independent mechanisms XREF_BIBR, and negatively modulates the LIMK and cofilin pathway XREF_BIBR, resulting in decreased cell motility.	3	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	3	4	14	15
PAK is activated by Rac1 and it phosphorylates vimentin at Ser 38 .	PAK is activated by Rac1 and it phosphorylates vimentin at Ser 38.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	4	5	0	1
Accordingly , it has been observed to inhibit Rac1 mediated PAK activation dose dependently , whereas IPA-3 has a substantially reduced effect on already-active PAK .	Accordingly, it has been observed to inhibit Rac1 mediated PAK activation dose dependently, whereas IPA-3 has a substantially reduced effect on already-active PAK.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	8	9	10	11
The variable x i ( i = 273 or 31/118 ) represents the subset of n harboring phosphorylated paxillin ( and , implicitly , GIT1/betaPIX/PAK or CrkII and DOCK180 complexes ) , r is the density of active Rac ( activated by betaPIX or DOCK180 ) , and p is the subset of x 273 harboring Rac activated PAK .	The variable x i (i = 273 or 31/118) represents the subset of n harboring phosphorylated paxillin (and, implicitly, GIT1/betaPIX/PAK or CrkII and DOCK180 complexes), r is the density of active Rac (activated by betaPIX or DOCK180), and p is the subset of x 273 harboring Rac activated PAK.	55	59	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	56	57	58	59
Rac could be activated without cellular compensation , enabling us to probe the role of myosin and PAK in Rac mediated motility .	Rac could be activated without cellular compensation, enabling us to probe the role of myosin and PAK in Rac mediated motility.	0	18	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	0	1	17	18
Rac also activates PAK , which exerts its effects through Arp2/3 and LIMK activation or MLCK inhibition .	Rac also activates PAK, which exerts its effects through Arp2/3 and LIMK activation or MLCK inhibition.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	0	1	3	4
An activating perturbation of Rac increases the activity of PAK more than 18-fold under the cell death stimulating conditions , and 5.59-fold under the growth stimulating conditions .	An activating perturbation of Rac increases the activity of PAK more than 18-fold under the cell death stimulating conditions, and 5.59-fold under the growth stimulating conditions.	2	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK	PAK	PAK	4	5	9	10
Rac1 activation significantly increased the activity of PAK and decreased the activity of RhoA .	Rac1 activation significantly increased the activity of PAK and decreased the activity of RhoA.	0	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	0	1	7	8
PAK1 , which can be activated by Rac1 , is a potential candidate ( Sells and Chernoff 1997 ) .	PAK1, which can be activated by Rac1, is a potential candidate (Sells and Chernoff 1997).	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	7	8	0	1
We found that Rac1 activation of Pak-1 was necessary for Rac1 mediated increase in ER transcriptional activity .	We found that Rac1 activation of Pak-1 was necessary for Rac1 mediated increase in ER transcriptional activity.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak-1	Pak-1	Pak-1	3	4	6	7
Since betaPIX is a Rac and Cdc42 GEF and one of the major effectors of Rac is Pak1 , which also binds betaPIX , betaPIX coordinates Rac dependent activation of Pak1 .	Since betaPIX is a Rac and Cdc42 GEF and one of the major effectors of Rac is Pak1, which also binds betaPIX, betaPIX coordinates Rac dependent activation of Pak1.	26	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac	Rac	Rac	Pak1	Pak1	Pak1	26	27	30	31
The detailed mechanism regarding how Rac1 activates PAK1 in skeletal muscle cells remains unresolved .	The detailed mechanism regarding how Rac1 activates PAK1 in skeletal muscle cells remains unresolved.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	5	6	7	8
Moreover , Rac1 dependent activation of PAK1 is regulated by EGF mediated PI3K and Akt activation .	Moreover, Rac1 dependent activation of PAK1 is regulated by EGF mediated PI3K and Akt activation.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	2	3	6	7
If Rac1 and PIP2 coordinate to activate PAK1 , then CKIP-1 or other PH domain containing proteins may constitute the machinery required for insulin stimulated and PI3K dependent PAK1 activation and recruitment to the PM in skeletal muscle cells .	If Rac1 and PIP2 coordinate to activate PAK1, then CKIP-1 or other PH domain containing proteins may constitute the machinery required for insulin stimulated and PI3K dependent PAK1 activation and recruitment to the PM in skeletal muscle cells.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	1	2	7	8
Rac1 dependent activation of Pak1 scaffolding for PDK-Akt activity was described , but this study does not state whether Pix and Git are part of this scaffold .	Rac1 dependent activation of Pak1 scaffolding for PDK-Akt activity was described, but this study does not state whether Pix and Git are part of this scaffold.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	0	1	4	5
In vitro studies indicate that by activating PAK1 , a well known Rac target , Rac can activate ERK in T cells upon TCR stimulation 10 , and in NK cells upon interaction with the target cell 11 .	In vitro studies indicate that by activating PAK1, a well known Rac target, Rac can activate ERK in T cells upon TCR stimulation 10, and in NK cells upon interaction with the target cell 11.	6	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK1	PAK1	PAK1	15	16	7	8
PIP 2 Potentiates Rac1 mediated Pak1 Activation .	PIP 2 Potentiates Rac1 mediated Pak1 Activation.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	3	4	5	6
Treatment of mock transfected controls or cells expressing Rac1 V12 with either the pan-PKC inhibitor Go6976 or the PKC betaII specific inhibitor CGP53353 blocked pS1916 MIIA HC and localization of MIIA to FA in cells expressing Rac1 V12 , but did not block Pak1 activation induced by Rac1 V12 or baseline pS1916 MIIA in control or RacN17 transfected cells ( XREF_FIG ) .	Treatment of mock transfected controls or cells expressing Rac1 V12 with either the pan-PKC inhibitor Go6976 or the PKC betaII specific inhibitor CGP53353 blocked pS1916 MIIA HC and localization of MIIA to FA in cells expressing Rac1 V12, but did not block Pak1 activation induced by Rac1 V12 or baseline pS1916 MIIA in control or RacN17 transfected cells (XREF_FIG).	43	48	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	47	48	43	44
TGFbeta1 treatment enhances Rac1 mediated Pak1 activation in prostate cancer cells .	TGFbeta1 treatment enhances Rac1 mediated Pak1 activation in prostate cancer cells.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	3	4	5	6
Our data emphasize the importance of the extracellular matrix stroma in tissue survival and suggest that alpha6beta4 integrin dependent Rac stimulation of Pak1 could be an important mechanism mediating apoptosis-resistance in some breast tumors .	Our data emphasize the importance of the extracellular matrix stroma in tissue survival and suggest that alpha6beta4 integrin dependent Rac stimulation of Pak1 could be an important mechanism mediating apoptosis-resistance in some breast tumors.	19	23	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac	Rac	Rac	Pak1	Pak1	Pak1	19	20	22	23
Rac1 mediated PAK1 activation is manifested by PAK1 autophosphorylation at Thr 428 19 .	Rac1 mediated PAK1 activation is manifested by PAK1 autophosphorylation at Thr 428 19.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	0	1	2	3
Depletion of Rap1 in our study prevented membrane association of Tiam1 during recovery after thrombin ; this was linked to attenuation of Rac activation and Rac mediated activation of the Rac effectors PAK1 and cortactin .	Depletion of Rap1 in our study prevented membrane association of Tiam1 during recovery after thrombin; this was linked to attenuation of Rac activation and Rac mediated activation of the Rac effectors PAK1 and cortactin.	25	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK1	PAK1	PAK1	25	26	32	33
The Pak1 effect would likely be PI3K dependent because PI3K activates Rac1 , which activates Pak1 .	The Pak1 effect would likely be PI3K dependent because PI3K activates Rac1, which activates Pak1.	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	11	12	15	16
Although activation of PAK1 by Rac1 and Cdc42 is well characterized , a number of GTPase independent mechanisms may also modify PAK activity and function .	Although activation of PAK1 by Rac1 and Cdc42 is well characterized, a number of GTPase independent mechanisms may also modify PAK activity and function.	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	5	6	3	4
Moreover , combined depletion of the ERM proteins results in more significant attenuation of S1P induced Rac1 activation and activation of the Rac1 downstream target PAK1 , compared with radixin knockdown alone ( XREF_FIG ) .	Moreover, combined depletion of the ERM proteins results in more significant attenuation of S1P induced Rac1 activation and activation of the Rac1 downstream target PAK1, compared with radixin knockdown alone (XREF_FIG).	16	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	16	17	25	26
XREF_BIBR The guanine nucleotide exchange factor ( GEF ) Trio activates Rac , which in turn activates PAK1 .	XREF_BIBR The guanine nucleotide exchange factor (GEF) Trio activates Rac, which in turn activates PAK1.	10	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK1	PAK1	PAK1	11	12	17	18
Moreover , several miRNAs , such as miR-153 ( via targeting SNAI1 and ZEB2 ) , miR-101 ( via targeting enhancer of zeste homolog 2 : EZH2 ) miR-27a-3p ( via targeting yes associated protein 1 : YAP1 ) , and miR-485-5p ( via targeting p21 RAC1 activated kinase 1 : PAK1 ) are involved in EMT induction [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Moreover, several miRNAs, such as miR-153 (via targeting SNAI1 and ZEB2), miR-101 (via targeting enhancer of zeste homolog 2 : EZH2) miR-27a-3p (via targeting yes associated protein 1 : YAP1), and miR-485-5p (via targeting p21 RAC1 activated kinase 1 : PAK1) are involved in EMT induction [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	45	52	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p21 RAC1	p21 RAC1	p21 RAC1	PAK1	PAK1	PAK1	45	47	51	52
Pak1 binds the DH-PH domain of P115-RhoGEF , thus suggesting a mechanism by which Rac stimulation of Pak1 may disrupt receptor dependent Rho signaling .	Pak1 binds the DH-PH domain of P115-RhoGEF, thus suggesting a mechanism by which Rac stimulation of Pak1 may disrupt receptor dependent Rho signaling.	14	18	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac	Rac	Rac	Pak1	Pak1	Pak1	14	15	17	18
They further linked this to Rac1 mediated activation of PAK1 , which in turn led to cortactin phosphorylation and invadopodia disassembly .	They further linked this to Rac1 mediated activation of PAK1, which in turn led to cortactin phosphorylation and invadopodia disassembly.	5	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	5	6	9	10
However , our genetic data argue that CED-10 and Rac contributes significantly to the PAK-1 signaling branch , raising the possibility that the Pak , Pix , and Git complex is not entirely Rac independent .	However, our genetic data argue that CED-10 and Rac contributes significantly to the PAK-1 signaling branch, raising the possibility that the Pak, Pix, and Git complex is not entirely Rac independent.	7	15	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK-1	PAK-1	PAK-1	9	10	14	15
Vav1 support of tumor growth was associated with Rac1 activation of the PAK1 serine/threonine kinase , the NF-kappaB transcription factor , and the cyclin D1 regulator of G1 cell cycle progression .	Vav1 support of tumor growth was associated with Rac1 activation of the PAK1 serine/threonine kinase, the NF-kappaB transcription factor, and the cyclin D1 regulator of G1 cell cycle progression.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	8	9	12	13
Our experiments demonstrate that knockdown of either radixin or all ERM proteins significantly reduces Rac activation and activation of the Rac downstream target PAK1 ( XREF_FIG ) , which is a principal mediator of Rac dependent signaling to the cytoskeleton .	Our experiments demonstrate that knockdown of either radixin or all ERM proteins significantly reduces Rac activation and activation of the Rac downstream target PAK1 (XREF_FIG), which is a principal mediator of Rac dependent signaling to the cytoskeleton.	14	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK1	PAK1	PAK1	14	15	23	24
In the brain , the PAK1 activator Rac1 is known to be involved in dendritic spine formation , raising the possibility that PAK1 is involved in neuron structure and function .	In the brain, the PAK1 activator Rac1 is known to be involved in dendritic spine formation, raising the possibility that PAK1 is involved in neuron structure and function.	4	12	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	7	8	5	6
Rac1 in turn is known to activate Pak1 , which has as its principal intracellular target , LIMK1 .	Rac1 in turn is known to activate Pak1, which has as its principal intracellular target, LIMK1.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	0	1	7	8
In line with this , we found more beta-Pix binding to the COOH terminus of Rac1 and , consequently , more Rac1 activation in Pak1 -/- cells .	In line with this, we found more beta-Pix binding to the COOH terminus of Rac1 and, consequently, more Rac1 activation in Pak1 -/- cells.	21	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	21	22	24	25
For example , in cerebellar granule cell cultures neurite outgrowth mediated by the L1 cell adhesion molecule is inhibited by ethanol , and L1 signaling induced by clustering in the plasma membrane through MAP kinases requires Rac1 mediated Pak1 activation .	For example, in cerebellar granule cell cultures neurite outgrowth mediated by the L1 cell adhesion molecule is inhibited by ethanol, and L1 signaling induced by clustering in the plasma membrane through MAP kinases requires Rac1 mediated Pak1 activation.	35	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	36	37	38	39
This report shows that Rac1 binds to and stimulates the kinase activity of PAK1 approximately 2- and 4-5-fold , respectively , better than Rac2 .	This report shows that Rac1 binds to and stimulates the kinase activity of PAK1 approximately 2- and 4-5-fold, respectively, better than Rac2.	4	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	4	5	13	14
Interestingly , EHop-016 has also been shown to decrease Rac1 mediated activation of PAK1 .	Interestingly, EHop-016 has also been shown to decrease Rac1 mediated activation of PAK1.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	9	10	13	14
For example , Rac activation induces PAK1 to phosphorylate LIMK1 at Thr 508 residue .	For example, Rac activation induces PAK1 to phosphorylate LIMK1 at Thr 508 residue.	3	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK1	PAK1	PAK1	3	4	6	7
PAK1 kinase activity can also be increased in human breast tissue by the upregulation of Rac3 activity or Rac1 expression [ XREF_BIBR , XREF_BIBR ] .	PAK1 kinase activity can also be increased in human breast tissue by the upregulation of Rac3 activity or Rac1 expression [XREF_BIBR, XREF_BIBR].	0	20	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rac1	Rac1 expression	rac1	PAK1	PAK1	pak1	18	19	0	1
Here we show that Rac1 stimulates a second , kinase independent function of PAK1 .	Here we show that Rac1 stimulates a second, kinase independent function of PAK1.	4	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	4	5	13	14
Thus , Rac1 activation promotes pS1916 MIIA HC in an integrin dependent , Pak1 independent manner to promote specific association of pS1916 MIIA mini-filaments with FAs .	Thus, Rac1 activation promotes pS1916 MIIA HC in an integrin dependent, Pak1 independent manner to promote specific association of pS1916 MIIA mini-filaments with FAs.	2	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	2	3	13	14
Here we show that expression of active Ras , Raf-1 , or Rac1 in fibroblasts stimulates NFkappaB in a PAK1 dependent manner and that expression of active PAK1 can stimulate NFkappaB on its own .	Here we show that expression of active Ras, Raf-1, or Rac1 in fibroblasts stimulates NFkappaB in a PAK1 dependent manner and that expression of active PAK1 can stimulate NFkappaB on its own.	4	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	expression of active Ras, Raf-1, or Rac1	rac1	PAK1	PAK1	pak1	12	13	19	20
Our results indicated that PIAS3 mediated SUMOylation of Rac1 controlled its activation and modulated the Rac1 downstream activity of PAK1 and JNK .	Our results indicated that PIAS3 mediated SUMOylation of Rac1 controlled its activation and modulated the Rac1 downstream activity of PAK1 and JNK.	4	21	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	PIAS3 mediated SUMOylation of Rac1	rac1	PAK1	PAK1	pak1	8	9	19	20
The small GTPases , in particular Rac , are thought to regulate cofilin activity through a molecular pathway in which Rac activates the serine/threonine kinase Pak1 that in turn affects the activity of LIM kinase 1 ( LIMK1 ) [ XREF_BIBR ] [ XREF_BIBR ] .	The small GTPases, in particular Rac, are thought to regulate cofilin activity through a molecular pathway in which Rac activates the serine/threonine kinase Pak1 that in turn affects the activity of LIM kinase 1 (LIMK1) [XREF_BIBR] [XREF_BIBR].	20	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	Pak1	Pak1	Pak1	20	21	25	26
Rac1 activity has been shown to increase the activity of Pak1 , and the ability to activate Pak1 is also seen with cdc42 .	Rac1 activity has been shown to increase the activity of Pak1, and the ability to activate Pak1 is also seen with cdc42.	0	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	0	1	10	11
XREF_BIBR Thus , EHop-016 , through suppressing Rac1 mediated activation of PAK1 , might have beneficial effects not only in cancer but also in other human diseases , including cardiovascular diseases .	XREF_BIBR Thus, EHop-016, through suppressing Rac1 mediated activation of PAK1, might have beneficial effects not only in cancer but also in other human diseases, including cardiovascular diseases.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	7	8	11	12
Since the downstream effects of PKA could be blocked by dominant negative Rac1 [ XREF_BIBR ] , and because Rac1 is a direct activator of Pak1 , it is tempting to speculate that Pak1 could be downstream of PKA in affecting the function of the ER .	Since the downstream effects of PKA could be blocked by dominant negative Rac1 [XREF_BIBR], and because Rac1 is a direct activator of Pak1, it is tempting to speculate that Pak1 could be downstream of PKA in affecting the function of the ER.	19	26	is a direct activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	19	20	25	26
Instead , activation of the Rac target PAK1 is necessary for destabilization of cell-cell contacts .	Instead, activation of the Rac target PAK1 is necessary for destabilization of cell-cell contacts.	2	8	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK1	PAK1	PAK1	5	6	7	8
Thus , Rac1 mediates pS1916 MIIA HC in an integrin dependent , Pak1 independent manner .	Thus, Rac1 mediates pS1916 MIIA HC in an integrin dependent, Pak1 independent manner.	2	14	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	2	3	12	13
The results in XREF_FIG suggested that Rac1 activated Pak1 and Pak2 contribute to induction of COX-2 in papilloma cells primarily through activation of the NFkappaB pathway , not through activation of p38 .	The results in XREF_FIG suggested that Rac1 activated Pak1 and Pak2 contribute to induction of COX-2 in papilloma cells primarily through activation of the NFkappaB pathway, not through activation of p38.	6	11	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	6	7	8	9
Based on extensive mammalian work , we hypothesized that CED-10 and Rac would be required to activate PAK-1 and/or MAX-2 , and we tested this model genetically by pair-wise knockdown of putative pathway components .	Based on extensive mammalian work, we hypothesized that CED-10 and Rac would be required to activate PAK-1 and/or MAX-2, and we tested this model genetically by pair-wise knockdown of putative pathway components.	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK-1	PAK-1	PAK-1	11	12	17	18
We followed the kinetics of Rab5 activation by a Rabex-5 truncation mutant [ Rabex-5 ( 135-480 ) ] that lacks the EET domain and can only activate Rab5 via the indirect pathway upon association with Rabaptin-5 XREF_BIBR .	We followed the kinetics of Rab5 activation by a Rabex-5 truncation mutant [Rabex-5 (135-480)] that lacks the EET domain and can only activate Rab5 via the indirect pathway upon association with Rabaptin-5 XREF_BIBR.	9	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	9	10	27	28
RABGEF1 directs the downstream Rab proteins , RAB5 and RAB7A , to damaged mitochondria , that is further regulated by mitochondrial Rab-GAPs .	RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, that is further regulated by mitochondrial Rab-GAPs.	0	8	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RABGEF1	RABGEF1	RABGEF1	RAB5	RAB5	RAB5	0	1	7	8
Rabex-5 can activate Rab5 on early endosomes via direct and indirect pathways XREF_BIBR .	Rabex-5 can activate Rab5 on early endosomes via direct and indirect pathways XREF_BIBR.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	0	1	3	4
Delayed Onset of Positive Feedback Activation of Rab5 by Rabex-5 and Rabaptin-5 in Endocytosis .	Delayed Onset of Positive Feedback Activation of Rab5 by Rabex-5 and Rabaptin-5 in Endocytosis.	5	13	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	9	10	7	8
This low level of Rabex-5 ( 135-480 ) , with Rabaptin-5 , was able to increase Rab5 activity , suggesting that endogenous Rabex-5 and Rabaptin-5 level was already near or above the threshold level for the onset of the positive feedback loop in Rab5 activation and there was no delayed phase in these cells , given that Rab5 was overexpressed by 2-fold ( in the form of GFP-Rab5 ) .	This low level of Rabex-5 (135-480), with Rabaptin-5, was able to increase Rab5 activity, suggesting that endogenous Rabex-5 and Rabaptin-5 level was already near or above the threshold level for the onset of the positive feedback loop in Rab5 activation and there was no delayed phase in these cells, given that Rab5 was overexpressed by 2-fold (in the form of GFP-Rab5).	2	17	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	level of Rabex-5	rabex-5	Rab5	Rab5	rab5	4	5	16	17
Thus , upon recruitment of Rabaptin5 by Rab5 , Rabex5 is co-recruited to allow fast enrichment of activated Rab5 on endosomal membranes ( XREF_FIG lower part ) .	Thus, upon recruitment of Rabaptin5 by Rab5, Rabex5 is co-recruited to allow fast enrichment of activated Rab5 on endosomal membranes (XREF_FIG lower part).	9	21	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex5	Rabex5	Rabex5	Rab5	Rab5	Rab5	9	10	18	19
Among a long list of Rab GEFs , we can cite as examples Mon1 that has been shown to act as GEF of Rab7 and its yeast homolog Ypt7 after activation by Ccz1 , TRAPP-I that promotes activation of Ypt1p in yeast and Rab1 in mammalian cells at the surface of ER-Golgi transport vesicles , Sec2p that acts as sequential GEF for the yeast Rabs Ypt32p and Sec4p in the early stages of the secretory pathway , and Rabex-5 that activates Rab5 in early endosomes , which is necessary for membrane fusion .	Among a long list of Rab GEFs, we can cite as examples Mon1 that has been shown to act as GEF of Rab7 and its yeast homolog Ypt7 after activation by Ccz1, TRAPP-I that promotes activation of Ypt1p in yeast and Rab1 in mammalian cells at the surface of ER-Golgi transport vesicles, Sec2p that acts as sequential GEF for the yeast Rabs Ypt32p and Sec4p in the early stages of the secretory pathway, and Rabex-5 that activates Rab5 in early endosomes, which is necessary for membrane fusion.	32	82	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	78	79	81	82
Expression of full-length Rabex-5 alone showed the same slow activation kinetics as Rabex-5 ( 1-399 ) ( data not shown ) , confirming that Rabaptin-5 is limiting in the cell and overexpressed Rabex-5 mostly targets to the early endosomes and activates Rab5 via the direct pathway .	Expression of full-length Rabex-5 alone showed the same slow activation kinetics as Rabex-5 (1-399) (data not shown), confirming that Rabaptin-5 is limiting in the cell and overexpressed Rabex-5 mostly targets to the early endosomes and activates Rab5 via the direct pathway.	31	45	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	32	33	41	42
Rab22 recruits Rabex-5 to early endosomes , thus promoting Rab5 activation .	Rab22 recruits Rabex-5 to early endosomes, thus promoting Rab5 activation.	1	10	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	recruits Rabex-5 to early endosomes	rabex-5	Rab5	Rab5	rab5	2	3	9	10
Previous structural , biochemical , and biological data have demonstrated that Rabex-5 and Rabaptin-5 function together to activate Rab5 in endocytosis ; the GEF activity of Rabex-5 could be autoinhibited by its CC domain and activated by binding of the Rabaptin-5 C2-1 domain ( Rabaptin-5C21 ) to the CC domain .	Previous structural, biochemical, and biological data have demonstrated that Rabex-5 and Rabaptin-5 function together to activate Rab5 in endocytosis; the GEF activity of Rabex-5 could be autoinhibited by its CC domain and activated by binding of the Rabaptin-5 C2-1 domain (Rabaptin-5C21) to the CC domain.	11	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	11	12	18	19
In contrast , expression of a constitutively active Rab5 mutant or of Rabex-5 ( a specific Rab5 GEF that activates Rab5 ) inhibits neurite outgrowth , while expression of a dominant negative Rab5 mutant induces outgrowth [ XREF_BIBR ] .	In contrast, expression of a constitutively active Rab5 mutant or of Rabex-5 (a specific Rab5 GEF that activates Rab5) inhibits neurite outgrowth, while expression of a dominant negative Rab5 mutant induces outgrowth [XREF_BIBR].	3	21	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rabex-5	expression of a constitutively active Rab5 mutant or of Rabex-5	rabex-5	Rab5	Rab5	rab5	12	13	20	21
When the Rabex-5 and Rabaptin-5 complex is recruited to the early endosomal membrane via the interaction of the C-terminal region of Rabaptin-5 with the GTP bound Rab5 , Rabex-5 can activate Rab5 locally in a very efficient way .	When the Rabex-5 and Rabaptin-5 complex is recruited to the early endosomal membrane via the interaction of the C-terminal region of Rabaptin-5 with the GTP bound Rab5, Rabex-5 can activate Rab5 locally in a very efficient way.	28	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	28	29	31	32
Recruitment of Rab5 to early endosomes is accompanied by Rab5 activation mediated by Rabex-5 [ XREF_BIBR , XREF_BIBR ] , a Rab5 GEF whose activity is promoted by the Rab5 effector Rabaptin-5 .	Recruitment of Rab5 to early endosomes is accompanied by Rab5 activation mediated by Rabex-5 [XREF_BIBR, XREF_BIBR], a Rab5 GEF whose activity is promoted by the Rab5 effector Rabaptin-5.	9	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	13	14	9	10
Expression of Rabex-5 ( 135-480 ) alone did not show any increase in Rab5 activity and consequently there was no increase in the level of GFP-Rab5-GTP ( data now shown ) , indicating that even though Rabex-5 ( 135-480 ) may form functional complexes with endogenous Rabaptin-5 for the indirect pathway , the level of any Rabex-5 ( 135-480 ) and Rabaptin-5 complex formed in this case is likely below the threshold level for the onset of the positive feedback loop and is insufficient to activate Rab5 , as predicted by the mathematical model ( XREF_FIG ) .	Expression of Rabex-5 (135-480) alone did not show any increase in Rab5 activity and consequently there was no increase in the level of GFP-Rab5-GTP (data now shown), indicating that even though Rabex-5 (135-480) may form functional complexes with endogenous Rabaptin-5 for the indirect pathway, the level of any Rabex-5 (135-480) and Rabaptin-5 complex formed in this case is likely below the threshold level for the onset of the positive feedback loop and is insufficient to activate Rab5, as predicted by the mathematical model (XREF_FIG).	53	87	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	level of any Rabex-5	rabex-5	Rab5	Rab5	rab5	56	57	86	87
Nevertheless , the interactions between Rabex-5 and Rab5 are similar to those between Rabex-5 and Rab21 , suggesting that Rabex-5 may activate Rab5 via a similar mechanism as for Rab21 ( XREF_FIG ) .	Nevertheless, the interactions between Rabex-5 and Rab5 are similar to those between Rabex-5 and Rab21, suggesting that Rabex-5 may activate Rab5 via a similar mechanism as for Rab21 (XREF_FIG).	19	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	19	20	22	23
Overexpression of the GEFs Rabex-5 and Rin1 increased E AVG Max values and the persistence of active Rab5a on macropinosomes .	Overexpression of the GEFs Rabex-5 and Rin1 increased E AVG Max values and the persistence of active Rab5a on macropinosomes.	0	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Overexpression of the GEFs Rabex-5	rabex-5	Rab5a	Rab5a	rab5a	4	5	17	18
Rab5 on the early endosome is activated by the guanine exchange factor ( GEF ) Rabex-5 .	Rab5 on the early endosome is activated by the guanine exchange factor (GEF) Rabex-5.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	15	16	0	1
Thus , Rabex-5 can target to early endosomes via the EET domain and activate Rab5 in a Rabaptin-5-independent manner in vivo .	Thus, Rabex-5 can target to early endosomes via the EET domain and activate Rab5 in a Rabaptin-5-independent manner in vivo.	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	2	3	14	15
In addition , with expression of Rabex-5 ( 135-480 ) that can only activate Rab5 via the indirect positive feedback pathway in NF73 cells , which contains no endogenous Rabex-5 and thus lacks any direct pathway mediated Rab5 activation ( sigma = 0 ) , we have been able to identify the threshold Rabex-5 ( 135-480 ) concentration for the positive feedback pathway and determine the ratio of lambda and gamma as 10 -5 M , which reflects the affinity of the Rabex-5 , Rabaptin-5 , Rab5 , and GTP complex in the cell .	In addition, with expression of Rabex-5 (135-480) that can only activate Rab5 via the indirect positive feedback pathway in NF73 cells, which contains no endogenous Rabex-5 and thus lacks any direct pathway mediated Rab5 activation (sigma = 0), we have been able to identify the threshold Rabex-5 (135-480) concentration for the positive feedback pathway and determine the ratio of lambda and gamma as 10 -5 M, which reflects the affinity of the Rabex-5, Rabaptin-5, Rab5, and GTP complex in the cell.	4	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	expression of Rabex-5	rabex-5	Rab5	Rab5	rab5	6	7	14	15
RABGEF1 directs the downstream Rab proteins , RAB5 and RAB7A , to damaged mitochondria , whose associations are further regulated by mitochondrial Rab-GAPs .	RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs.	0	8	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RABGEF1	RABGEF1	RABGEF1	RAB5	RAB5	RAB5	0	1	7	8
Rabex-5 , a RabGEF , acts with a cofactor Rabaptin-5 to activate Rab5 on the early endosome surface .	Rabex-5, a RabGEF, acts with a cofactor Rabaptin-5 to activate Rab5 on the early endosome surface.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	0	1	12	13
The activating proteins Rabex-5 and Rabaptin-5 stimulate Rab5 on the cytosolic surface of the EE resulting in the recruitment of Rab5 effectors including the tethering factor EEA1 and the PI 3-OH kinase Vps34 .	The activating proteins Rabex-5 and Rabaptin-5 stimulate Rab5 on the cytosolic surface of the EE resulting in the recruitment of Rab5 effectors including the tethering factor EEA1 and the PI 3-OH kinase Vps34.	0	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	3	4	7	8
In this case , as the GEF activity of Rabex-5 is autoinhibited by Rabex-5CC , Rabex-5 can only activate Rab5 at the basal level .	In this case, as the GEF activity of Rabex-5 is autoinhibited by Rabex-5CC, Rabex-5 can only activate Rab5 at the basal level.	15	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	15	16	19	20
Seminal studies have demonstrated that Rabex-5 can enhance Rab5 activation via a positive feedback loop : Rabex-5 forms a heterodimeric complex with the protein Rabaptin5 containing an effector domain for Rab5 .	Seminal studies have demonstrated that Rabex-5 can enhance Rab5 activation via a positive feedback loop : Rabex-5 forms a heterodimeric complex with the protein Rabaptin5 containing an effector domain for Rab5.	5	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	5	6	8	9
When Rabex-5 , a GEF that usually activates Rab5 on early endosomes , was redirected to mitochondria , it immediately spurred the recruitment of Rab5 -- but not other Rab GTPases -- to mitochondrial membranes .	When Rabex-5, a GEF that usually activates Rab5 on early endosomes, was redirected to mitochondria, it immediately spurred the recruitment of Rab5 -- but not other Rab GTPases -- to mitochondrial membranes.	1	14	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	1	2	8	9
The previous biochemical and biological data showed that Rabex-5 functions together with Rabaptin-5 to activate Rab5 and then to promote the fusion of early endosomes in endocytosis .	The previous biochemical and biological data showed that Rabex-5 functions together with Rabaptin-5 to activate Rab5 and then to promote the fusion of early endosomes in endocytosis.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5	Rab5	Rab5	8	9	15	16
GFP-Rabex-5 and GFP-Rabex-5 ( 1-399 ) correctly targeted to RFP-Rab5-labeled early endosomes and enhanced Rab5 activity , as evidenced by the enlargement of these early endosomes ( XREF_FIG ) .	GFP-Rabex-5 and GFP-Rabex-5 (1-399) correctly targeted to RFP-Rab5-labeled early endosomes and enhanced Rab5 activity, as evidenced by the enlargement of these early endosomes (XREF_FIG).	0	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GFP-Rabex-5	GFP-Rabex-5	GFP-Rabex-5	Rab5	Rab5	Rab5	0	1	14	15
Interestingly , the activation of Rac1 required PI3K and causes the activation of PAK2 .	Interestingly, the activation of Rac1 required PI3K and causes the activation of PAK2.	3	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK2	PAK2	PAK2	5	6	13	14
In contrast , there was a dose dependent suppression of p-PAK1 and PAK2 following R-ketorolac treatment that was similar to positive controls treated with Cdc42 or Rac1 specific inhibitors .	In contrast, there was a dose dependent suppression of p-PAK1 and PAK2 following R-ketorolac treatment that was similar to positive controls treated with Cdc42 or Rac1 specific inhibitors.	8	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK2	PAK2	PAK2	26	27	12	13
Importantly , these inhibitors directly affected the activation of the Rac1 effectors p21 activated kinase ( PAK ) 1 and PAK2 .	Importantly, these inhibitors directly affected the activation of the Rac1 effectors p21 activated kinase (PAK) 1 and PAK2.	10	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK2	PAK2	PAK2	10	11	20	21
In agreement , silencing of Rac1 by shRNA blocks PAK2 activity and inhibits RANTES and CCL5 induced macrophage polarization and directional migration .	In agreement, silencing of Rac1 by shRNA blocks PAK2 activity and inhibits RANTES and CCL5 induced macrophage polarization and directional migration.	3	10	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK2	PAK2	PAK2	5	6	9	10
Small GTPase Rac1 activates Pak2 .	Small GTPase Rac1 activates Pak2.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak2	Pak2	Pak2	2	3	4	5
We show that RhoH associates with both Rac1 and the Rac1 target PAK2 , and co-localises with Rac1 in lamellipodia .	We show that RhoH associates with both Rac1 and the Rac1 target PAK2, and co-localises with Rac1 in lamellipodia.	4	13	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	PAK2	PAK2	PAK2	10	11	12	13
These observations raise the possibility that activation of PAK2 by Rac could also be essential for CCK mediated enzyme secretion and activation of ERK in pancreatic acini , subsequently resulting in growth .	These observations raise the possibility that activation of PAK2 by Rac could also be essential for CCK mediated enzyme secretion and activation of ERK in pancreatic acini, subsequently resulting in growth.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK2	PAK2	PAK2	10	11	8	9
Whereas the activation of PAK2 by Rac or CDC42 , as with PAK1 , promotes cell survival by phosphorylating Bad and Bcl-2 , apoptotic stimuli such as DNA damage lead to proteolytic cleavage of PAK2 , generating a p34 fragment .	Whereas the activation of PAK2 by Rac or CDC42, as with PAK1, promotes cell survival by phosphorylating Bad and Bcl-2, apoptotic stimuli such as DNA damage lead to proteolytic cleavage of PAK2, generating a p34 fragment.	2	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rac	Rac	Rac	PAK2	PAK2	PAK2	6	7	4	5
Together , these genetic results establish Rad50 as an innate immune sensor for DNA and reveal that the Rad50- and CARD9 mediated DNA response operates independently of ATM to induce IL-1beta .	Together, these genetic results establish Rad50 as an innate immune sensor for DNA and reveal that the Rad50- and CARD9 mediated DNA response operates independently of ATM to induce IL-1beta.	17	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad50-	Rad50-	Rad50-	ATM	ATM	ATM	18	19	27	28
The expression of RAD50 was up-regulated in this study , and RAD50 might activate ATM .	The expression of RAD50 was up-regulated in this study, and RAD50 might activate ATM.	11	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD50	RAD50	RAD50	ATM	ATM	ATM	11	12	14	15
Although a Rad50 phosphosite specific mutant ( S635G ) supported normal activation of ATM in Rad50 deficient cells , it was defective in correcting DNA damage induced signaling through the ATM dependent substrate SMC1 .	Although a Rad50 phosphosite specific mutant (S635G) supported normal activation of ATM in Rad50 deficient cells, it was defective in correcting DNA damage induced signaling through the ATM dependent substrate SMC1.	2	14	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad50	Rad50	Rad50	ATM	ATM	ATM	2	3	13	14
The hypermorphic Rad50 S variant allele constitutively activates ATM , and Rad50 S/S mice show enhanced HSC apoptotic attrition leading to bone marrow failure at a very young age .	The hypermorphic Rad50 S variant allele constitutively activates ATM, and Rad50 S/S mice show enhanced HSC apoptotic attrition leading to bone marrow failure at a very young age.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad50	Rad50	Rad50	ATM	ATM	ATM	2	3	8	9
Once activated ATM in turn phosphorylates RAD50 and NBS1 , important for cell cycle control , DNA repair and cell survival .	Once activated ATM in turn phosphorylates RAD50 and NBS1, important for cell cycle control, DNA repair and cell survival.	1	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD50	phosphorylates RAD50	rad50	ATM	ATM	atm	6	7	2	3
Because Rad50 activates the kinase ATM following nuclear DNA damage sensing 20 , we also tested the involvement of ATM in cytosolic DNA induced IL-1beta generation .	Because Rad50 activates the kinase ATM following nuclear DNA damage sensing 20, we also tested the involvement of ATM in cytosolic DNA induced IL-1beta generation.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad50	Rad50	Rad50	ATM	ATM	ATM	1	2	5	6
At replication forks stalled by UV lesions or HU , Chk1 , Claspin , and TIM1 and TIPIN are required for Rad18 mediated ubiquitinylation of PCNA that allows binding of translesion polymerases [ XREF_BIBR ] .	At replication forks stalled by UV lesions or HU, Chk1, Claspin, and TIM1 and TIPIN are required for Rad18 mediated ubiquitinylation of PCNA that allows binding of translesion polymerases [XREF_BIBR].	21	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad18	Rad18	Rad18	PCNA	PCNA	PCNA	21	22	25	26
Moreover , ING1b is required for the E3 ligase Rad18 mediated PCNA-Ub and for Rad18 and Poleta to be tethered to the chromatin at the sites of replication .	Moreover, ING1b is required for the E3 ligase Rad18 mediated PCNA-Ub and for Rad18 and Poleta to be tethered to the chromatin at the sites of replication.	6	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rad18	Rad18	Rad18	PCNA-Ub	PCNA-Ub	PCNA-Ub	9	10	11	12
In addition , we constructed Ubc12 -/- HEK293T cell and found that RAD18 could not promote PCNA NEDDylation without UBC12 .	In addition, we constructed Ubc12 -/- HEK293T cell and found that RAD18 could not promote PCNA NEDDylation without UBC12.	12	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD18	RAD18	RAD18	PCNA	PCNA	PCNA	12	13	16	17
Next , we examined whether RAD18 promotes PCNA NEDDylation by Ni 2+ pull-down assay .	Next, we examined whether RAD18 promotes PCNA NEDDylation by Ni 2+ pull-down assay.	5	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD18	RAD18	RAD18	PCNA	PCNA	PCNA	5	6	7	8
Ectopic expression of Rad18 enhanced PCNA-Ub in control cells in a time dependent manner after UV .	Ectopic expression of Rad18 enhanced PCNA-Ub in control cells in a time dependent manner after UV.	1	6	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad18	expression of Rad18	rad18	PCNA-Ub	PCNA-Ub	pcna-ub	3	4	5	6
ING1b maintains histone H4 acetylation during S phase and is required for Rad18 mediated PCNA-Ub .	ING1b maintains histone H4 acetylation during S phase and is required for Rad18 mediated PCNA-Ub.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rad18	Rad18	Rad18	PCNA-Ub	PCNA-Ub	PCNA-Ub	12	13	14	15
In contrast , knock-down of RAD18 , the ubiquitin E3 ligase that modifies PCNA XREF_BIBR - XREF_BIBR , caused diffusion of PCNA throughout the nucleus and abrogated both the number and the intensity of the eGFP-FAN1 foci .	In contrast, knock-down of RAD18, the ubiquitin E3 ligase that modifies PCNA XREF_BIBR - XREF_BIBR, caused diffusion of PCNA throughout the nucleus and abrogated both the number and the intensity of the eGFP-FAN1 foci.	3	22	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD18	RAD18	RAD18	PCNA	PCNA	PCNA	5	6	21	22
In S. cerevisiae cells there exist two different E3 enzymes , Rad18 and Rad5 , which drive the ubiquitin transfer to PCNA from the E2 Rad6 and Ubc13-Mms2 , respectively .	In S. cerevisiae cells there exist two different E3 enzymes, Rad18 and Rad5, which drive the ubiquitin transfer to PCNA from the E2 Rad6 and Ubc13-Mms2, respectively.	9	27	drive	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Rad18	Rad18	Rad18	PCNA	PCNA	PCNA	11	12	21	22
ING1b is required for Rad18 mediated PCNA-Ub .	ING1b is required for Rad18 mediated PCNA-Ub.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rad18	Rad18	Rad18	PCNA-Ub	PCNA-Ub	PCNA-Ub	4	5	6	7
XREF_FIG D , UBC12 and RAD18 but not RAD6B and RAD18 could NEDDylate PCNA , suggesting that RAD18 catalyzes PCNA NEDDylation using NEDD8 specific enzymes in vivo and vitro .	XREF_FIG D, UBC12 and RAD18 but not RAD6B and RAD18 could NEDDylate PCNA, suggesting that RAD18 catalyzes PCNA NEDDylation using NEDD8 specific enzymes in vivo and vitro.	17	20	catalyzes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RAD18	RAD18	RAD18	PCNA	PCNA	PCNA	17	18	19	20
Because unrepaired UVC induced lesions halt the ongoing progression of replication forks , they trigger RAD6 and RAD18 mediated monoubiquitinylation of PCNA followed by the assembly of TLS polymerases , including Poleta , which has been implicated in the error-free bypass of UVC induced CPDs XREF_BIBR , XREF_BIBR .	Because unrepaired UVC induced lesions halt the ongoing progression of replication forks, they trigger RAD6 and RAD18 mediated monoubiquitinylation of PCNA followed by the assembly of TLS polymerases, including Poleta, which has been implicated in the error-free bypass of UVC induced CPDs XREF_BIBR, XREF_BIBR.	15	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD18	RAD18	RAD18	PCNA	PCNA	PCNA	17	18	21	22
In addition , WT RAD18 but not the inactive enzyme mutants of RAD18 , C28F or DeltaRING could rescue PCNA NEDDylation .	In addition, WT RAD18 but not the inactive enzyme mutants of RAD18, C28F or DeltaRING could rescue PCNA NEDDylation.	3	20	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD18	RAD18	RAD18	PCNA	PCNA	PCNA	4	5	19	20
Rad18 enhanced PCNA-Ub was abrogated in ING1b KD cells at 1h and more dramatically at 6h ( XREF_FIG A ) .	Rad18 enhanced PCNA-Ub was abrogated in ING1b KD cells at 1h and more dramatically at 6h (XREF_FIG A).	0	4	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rad18	Rad18	Rad18	PCNA-Ub	PCNA-Ub	PCNA-Ub	0	1	2	3
A stalled fork triggers at least two monoubiquitinylation pathways , the RAD6 and RAD18 mediated monoubiquitinylation of PCNA and the FANC core complex mediated monoubiquitinylation of FANCD2 XREF_BIBR .	A stalled fork triggers at least two monoubiquitinylation pathways, the RAD6 and RAD18 mediated monoubiquitinylation of PCNA and the FANC core complex mediated monoubiquitinylation of FANCD2 XREF_BIBR.	11	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD18	RAD18	RAD18	PCNA	PCNA	PCNA	13	14	17	18
We further examined if ING1b is required for PCNA-Ub mediated by the Rad18 E3 ligase .	We further examined if ING1b is required for PCNA-Ub mediated by the Rad18 E3 ligase.	6	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rad18	Rad18	Rad18	PCNA-Ub	PCNA-Ub	PCNA-Ub	12	13	8	9
Indeed , RAD18 strongly enhanced PCNA NEDDylation .	Indeed, RAD18 strongly enhanced PCNA NEDDylation.	2	6	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD18	RAD18	RAD18	PCNA	PCNA	PCNA	2	3	5	6
Rad18 targets PCNA for ubiquitylation through its intrinsic SUMO binding activity and , thus , has the properties of a STUbL .	Rad18 targets PCNA for ubiquitylation through its intrinsic SUMO binding activity and, thus, has the properties of a STUbL.	0	13	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rad18	Rad18	Rad18	PCNA	PCNA	PCNA	0	1	2	3
The latter event appears to be mediated through RPA dependent recruitment of Rad18 , which together with Rad6 and the Rad5 , Mms2 , and Ubc13 complex promotes PCNA modification with mono- and polyubiquitin chains , and induces translesion synthesis- and error-free-mediated DDT , respectively .	The latter event appears to be mediated through RPA dependent recruitment of Rad18, which together with Rad6 and the Rad5, Mms2, and Ubc13 complex promotes PCNA modification with mono- and polyubiquitin chains, and induces translesion synthesis- and error-free-mediated DDT, respectively.	10	37	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad18	Rad18	Rad18	PCNA	PCNA	PCNA	12	13	28	29
Protein-tyrosine phosphatase epsilon ( PTPepsilon ) performs two potentially opposing roles : in Neu induced mammary tumors , PTPepsilon activates Src downstream of Neu , whereas in other systems PTPepsilon can indirectly down-regulate MAP kinase signaling .	Protein-tyrosine phosphatase epsilon (PTPepsilon) performs two potentially opposing roles : in Neu induced mammary tumors, PTPepsilon activates Src downstream of Neu, whereas in other systems PTPepsilon can indirectly down-regulate MAP kinase signaling.	18	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTPepsilon	PTPepsilon	PTPepsilon	Src	Src	Src	18	19	20	21
We show that Neu induces phosphorylation of RPTPepsilon exclusively at its C-terminal Y695 , and that this phosphorylation is required for activation of c-Src by RPTPepsilon .	We show that Neu induces phosphorylation of RPTPepsilon exclusively at its C-terminal Y695, and that this phosphorylation is required for activation of c-Src by RPTPepsilon.	19	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RPTPepsilon	RPTPepsilon	RPTPepsilon	c-Src	c-Src	c-Src	25	26	23	24
The receptor-type protein tyrosine phosphatase epsilon ( RPTPepsilon ) activates c-Src in mammary tumor cells induced in vivo by Neu .	The receptor-type protein tyrosine phosphatase epsilon (RPTPepsilon) activates c-Src in mammary tumor cells induced in vivo by Neu.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPTPepsilon	RPTPepsilon	RPTPepsilon	c-Src	c-Src	c-Src	7	8	10	11
We conclude that RPTPepsilon is a physiological activator of Src in Neu induced mammary tumors and suggest that pharmacological inhibition of phosphatases that activate Src may be useful to augment direct pharmacological inhibition of Src .	We conclude that RPTPepsilon is a physiological activator of Src in Neu induced mammary tumors and suggest that pharmacological inhibition of phosphatases that activate Src may be useful to augment direct pharmacological inhibition of Src.	3	11	is a physiological activator	Positive_activation_copula_1	Positive_activation	Positive_activation	RPTPepsilon	RPTPepsilon	RPTPepsilon	Src	Src	Src	3	4	9	10
We show that at the molecular level , RPTPepsilon activates Src , a known collaborator of Neu in mammary tumorigenesis .	We show that at the molecular level, RPTPepsilon activates Src, a known collaborator of Neu in mammary tumorigenesis.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPTPepsilon	RPTPepsilon	RPTPepsilon	Src	Src	Src	8	9	10	11
The non receptor isoform of protein-tyrosine phosphatase epsilon ( cyt-PTPe ) supports adhesion of bone resorbing osteoclasts by activating Src downstream of integrins .	The non receptor isoform of protein-tyrosine phosphatase epsilon (cyt-PTPe) supports adhesion of bone resorbing osteoclasts by activating Src downstream of integrins.	5	20	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	protein-tyrosine phosphatase epsilon	protein-tyrosine phosphatase epsilon	protein-tyrosine phosphatase epsilon	Src	Src	Src	5	8	19	20
However , the molecular mechanisms that control activation of c-Src by RPTPepsilon are unknown .	However, the molecular mechanisms that control activation of c-Src by RPTPepsilon are unknown.	6	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RPTPepsilon	RPTPepsilon	RPTPepsilon	c-Src	c-Src	c-Src	11	12	9	10
Rac is activated downstream of Ras and can activate JNK1 , possibly via Pak kinases to stimulate cell cycle progression .	Rac is activated downstream of Ras and can activate JNK1, possibly via Pak kinases to stimulate cell cycle progression.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	JNK1	JNK1	JNK1	0	1	9	10
In contrast , expression of a constitutively active Rac1 , an alternative guanosine triphosphatase involved in intracellular signaling , produced a high level of JNK1 activation , suggesting that Rac1 is an important upstream activator of JNK in this system .	In contrast, expression of a constitutively active Rac1, an alternative guanosine triphosphatase involved in intracellular signaling, produced a high level of JNK1 activation, suggesting that Rac1 is an important upstream activator of JNK in this system.	3	25	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	expression of a constitutively active Rac1	rac1	JNK1	JNK1	jnk1	8	9	24	25
Because a Vav dependent activation of JNK1 , which mimics Rac1 activation of JNK1 , had been demonstrated 13 31 50 , we assayed for the activation of JNK1 in cells expressing Vav-C .	Because a Vav dependent activation of JNK1, which mimics Rac1 activation of JNK1, had been demonstrated 13 31 50, we assayed for the activation of JNK1 in cells expressing Vav-C.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	JNK1	JNK1	JNK1	10	11	13	14
( ii ) The p38 MAPKs ( in mammalian brain mainly the isoforms p38alpha and p38delta ) are downstream of Rac1 , Cdc42 , and Rap1 , whereas ( iii ) the JNKS ( mainly JNK1 and JNK3 in brain ) are activated by Rac1 and Rap2 .	(ii) The p38 MAPKs (in mammalian brain mainly the isoforms p38alpha and p38delta) are downstream of Rac1, Cdc42, and Rap1, whereas (iii) the JNKS (mainly JNK1 and JNK3 in brain) are activated by Rac1 and Rap2.	32	46	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	JNK1	JNK1	JNK1	44	45	35	36
Although constitutively active Cdc42 , Rac1 , and RhoA all can activate JNK1 , only the RhoA mutant was able to promote formation of primitive endoderm , mimicking expression of the constitutively activated G alpha ( 13 ) .	Although constitutively active Cdc42, Rac1, and RhoA all can activate JNK1, only the RhoA mutant was able to promote formation of primitive endoderm, mimicking expression of the constitutively activated G alpha (13).	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	JNK1	JNK1	JNK1	5	6	12	13
In addition , many reports showed that small GTPases , Ras , Rac1 , Cdc42 and RhoA mediate the activation of JNK1 in response to various stimulants .	In addition, many reports showed that small GTPases, Ras, Rac1, Cdc42 and RhoA mediate the activation of JNK1 in response to various stimulants.	8	23	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	JNK1	JNK1	JNK1	12	13	21	22
We also found that PLC-gamma2-deficient cells exhibited impaired JNK1 activation and , interestingly , a dominant negative Rac1 ( Rac1 N17 ) blocked activation of JNK1 , suggesting a model where cooperation of PKCs and Rac1 leads to JNK1 activation .	We also found that PLC-gamma2-deficient cells exhibited impaired JNK1 activation and, interestingly, a dominant negative Rac1 (Rac1 N17) blocked activation of JNK1, suggesting a model where cooperation of PKCs and Rac1 leads to JNK1 activation.	14	26	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	JNK1	JNK1	JNK1	17	18	25	26
Recently it has been reported that Rac1 can activate JNK1 and control nuclear localization of beta-catenin in canonical Wnt signaling XREF_BIBR .	Recently it has been reported that Rac1 can activate JNK1 and control nuclear localization of beta-catenin in canonical Wnt signaling XREF_BIBR.	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	JNK1	JNK1	JNK1	6	7	9	10
The latter function of Rabaptin-5 is mediated through formation of a complex with the Rab5 guanine nucleotide exchange factor ( GEF ) Rabex-5 , which acts to increase nucleotide exchange on Rab5 , enhancing its activity and hence its ability to recruit other effectors involved in the endosomal fusion process .	The latter function of Rabaptin-5 is mediated through formation of a complex with the Rab5 guanine nucleotide exchange factor (GEF) Rabex-5, which acts to increase nucleotide exchange on Rab5, enhancing its activity and hence its ability to recruit other effectors involved in the endosomal fusion process.	2	39	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabaptin-5	Rabaptin-5	Rabaptin-5	Rabex-5	Rabex-5	Rabex-5	4	5	22	23
Later it was shown that Rabaptin-5 stimulates Rabex-5 exchange activity in vitro .	Later it was shown that Rabaptin-5 stimulates Rabex-5 exchange activity in vitro.	5	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabaptin-5	Rabaptin-5	Rabaptin-5	Rabex-5	Rabex-5	Rabex-5	5	6	7	8
Rabaptin-5 augments the Rabex-5 exchange activity , thus generating GTP bound , membrane associated Rab5 that , in turn , binds Rabaptin-5 and stabilizes the Rabex-5 .	Rabaptin-5 augments the Rabex-5 exchange activity, thus generating GTP bound, membrane associated Rab5 that, in turn, binds Rabaptin-5 and stabilizes the Rabex-5.	0	5	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabaptin-5	Rabaptin-5	Rabaptin-5	Rabex-5	Rabex-5	Rabex-5	0	1	3	4
In this case , Rabaptin-5 not only assists the recruitment of Rabex-5 to the early endosomal membrane , but also activates the GEF activity of Rabex-5 .	In this case, Rabaptin-5 not only assists the recruitment of Rabex-5 to the early endosomal membrane, but also activates the GEF activity of Rabex-5.	4	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabaptin-5	Rabaptin-5	Rabaptin-5	Rabex-5	Rabex-5	Rabex-5	4	5	25	26
First , we show that Rabaptin-5 increases the exchange activity of Rabex-5 on Rab5 .	First, we show that Rabaptin-5 increases the exchange activity of Rabex-5 on Rab5.	5	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabaptin-5	Rabaptin-5	Rabaptin-5	Rabex-5	Rabex-5	Rabex-5	5	6	11	12
Rabaptin-5 further enhances the guanine nucleotide exchange factor activity of Rabex-5 , establishing a positive feedback loop of Rab5 activation , leading to rapid recruitment of other Rab5 effectors including Vps34 , a class III phosphatidylinositol 3-kinase ( PI3K ) , and class C core vacuole and endosome tethering ( CORVET )/homotypic fusion and vacuole protein sorting ( HOPS ) , a tethering complex .	Rabaptin-5 further enhances the guanine nucleotide exchange factor activity of Rabex-5, establishing a positive feedback loop of Rab5 activation, leading to rapid recruitment of other Rab5 effectors including Vps34, a class III phosphatidylinositol 3-kinase (PI3K), and class C core vacuole and endosome tethering (CORVET)/homotypic fusion and vacuole protein sorting (HOPS), a tethering complex.	0	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabaptin-5	Rabaptin-5	Rabaptin-5	Rabex-5	Rabex-5	Rabex-5	0	1	10	11
Rabaptin5 in turn activates Rabex5 , insuring that Rab5 remains in its GTP bound form and is not extracted by the guanine-nucleotide dissociation inhibitor .	Rabaptin5 in turn activates Rabex5, insuring that Rab5 remains in its GTP bound form and is not extracted by the guanine-nucleotide dissociation inhibitor.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabaptin5	Rabaptin5	Rabaptin5	Rabex5	Rabex5	Rabex5	0	1	4	5
In another ATPase machine , FlaI , a structurally defined intermediate with bound phosphate ion ( PO 4 3-) released from ADP partially opens subunit contacts : This structure suggests that RAD50 conformational intermediates may allow MRE11 ssDNA endonuclease activity while restricting dsDNA and MRE11 exonuclease excision .	In another ATPase machine, FlaI, a structurally defined intermediate with bound phosphate ion (PO 4 3-) released from ADP partially opens subunit contacts : This structure suggests that RAD50 conformational intermediates may allow MRE11 ssDNA endonuclease activity while restricting dsDNA and MRE11 exonuclease excision.	31	39	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD50	RAD50	RAD50	MRE11	MRE11	MRE11	31	32	36	37
Upon ATP hydrolysis , RAD50 opens to allow MRE11 to carry out 3 '-5' resection toward the break , and the arms may be freed from the interlinked complex .	Upon ATP hydrolysis, RAD50 opens to allow MRE11 to carry out 3 '-5' resection toward the break, and the arms may be freed from the interlinked complex.	4	10	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD50	RAD50	RAD50	MRE11	MRE11	MRE11	4	5	8	9
Both Rad50 and Xrs2 and Nbs1 enhance the nuclease activity of Mre11 in vitro [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Both Rad50 and Xrs2 and Nbs1 enhance the nuclease activity of Mre11 in vitro [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad50	Rad50	Rad50	Mre11	Mre11	Mre11	1	2	11	12
Rad50 induces a conformational change in the Mre11 dimer .	Rad50 induces a conformational change in the Mre11 dimer.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad50	Rad50	Rad50	Mre11	Mre11	Mre11	0	1	7	8
Our analyses suggest that this mutation promotes an open RAD50 that could activate MRE11 nuclease .	Our analyses suggest that this mutation promotes an open RAD50 that could activate MRE11 nuclease.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAD50	RAD50	RAD50	MRE11	MRE11	MRE11	9	10	13	14
In the latter state , Rad50 directs the associated Mre11 DNase to initiate DNA end resection , a key step in DSB repair .	In the latter state, Rad50 directs the associated Mre11 DNase to initiate DNA end resection, a key step in DSB repair.	5	10	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad50	Rad50	Rad50	Mre11	Mre11	Mre11	5	6	9	10
In reconstitution studies the addition of Rad50 enhances the affinity of Mre11 for DNA and stimulates its nuclease activity , and this is further enhanced by the addition of Nbs1 [ XREF_BIBR ] .	In reconstitution studies the addition of Rad50 enhances the affinity of Mre11 for DNA and stimulates its nuclease activity, and this is further enhanced by the addition of Nbs1 [XREF_BIBR].	4	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad50	Rad50	Rad50	Mre11	Mre11	Mre11	6	7	11	12
In the bacteriophage T4 , Rad50 ( gene product 46 ) enhances the nuclease activity of Mre11 ( gene product 47 ) , and Mre11 and DNA in combination stimulate the ATPase activity of Rad50 .	In the bacteriophage T4, Rad50 (gene product 46) enhances the nuclease activity of Mre11 (gene product 47), and Mre11 and DNA in combination stimulate the ATPase activity of Rad50.	5	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad50	Rad50	Rad50	Mre11	Mre11	Mre11	5	6	16	17
Biochemical examples of this type of regulation are MPAK pathway [ XREF_BIBR ] , Src Family kinase pathway [ XREF_BIBR ] , and Rabaptin-5 mediated Rab5 activation in endocytosis [ XREF_BIBR ] .	Biochemical examples of this type of regulation are MPAK pathway [XREF_BIBR], Src Family kinase pathway [XREF_BIBR], and Rabaptin-5 mediated Rab5 activation in endocytosis [XREF_BIBR].	23	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rabaptin-5	Rabaptin-5	Rabaptin-5	Rab5	Rab5	Rab5	23	24	25	26
Hypoxia inducible factor ( HIF ) has also shown to repress RABEP1 transcription , which lead to impaired Rab5 mediated endosome fusion and prolonged EGF receptor half-life [ XREF_BIBR ] .	Hypoxia inducible factor (HIF) has also shown to repress RABEP1 transcription, which lead to impaired Rab5 mediated endosome fusion and prolonged EGF receptor half-life [XREF_BIBR].	0	19	lead	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	RABEP1	Hypoxia inducible factor (HIF) has also shown to repress RABEP1 transcription	rabep1	Rab5	Rab5	rab5	11	12	18	19
Lastly , serines 191 and 605 were recently identified as Rac activated JNK2 sites , and mutations of these residues appears to reduce the nuclear accumulation of beta-catenin in a murine bone marrow derived stromal cell line , ST2 .	Lastly, serines 191 and 605 were recently identified as Rac activated JNK2 sites, and mutations of these residues appears to reduce the nuclear accumulation of beta-catenin in a murine bone marrow derived stromal cell line, ST2.	8	13	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	JNK2	JNK2	JNK2	10	11	12	13
Rac1 can activate JNK2 to phosphorylate beta-catenin , which is responsible for controlling limb outgrowth in mouse embryos .	Rac1 can activate JNK2 to phosphorylate beta-catenin, which is responsible for controlling limb outgrowth in mouse embryos.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	JNK2	JNK2	JNK2	0	1	3	4
Instead , Rac and Cdc42 , but not Rho , stimulated a distinct MAP kinase , the c-Jun kinase JNK and SAPK ( Jun NH2-terminal kinase or stress activated protein kinase ) .	Instead, Rac and Cdc42, but not Rho, stimulated a distinct MAP kinase, the c-Jun kinase JNK and SAPK (Jun NH2-terminal kinase or stress activated protein kinase).	2	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	SAPK	SAPK	SAPK	2	3	21	22
For instance , in the Ras/Raf/MEK ( MAPK and ERK ) signaling pathway , Ras serves as an intermediary between the activated and phosphorylated growth factor receptor and MEK , whereas the JNK and SAPK and P38 and MAPK pathways may be directly activated by Rho and Rho related Rac , respectively .	For instance, in the Ras/Raf/MEK (MAPK and ERK) signaling pathway, Ras serves as an intermediary between the activated and phosphorylated growth factor receptor and MEK, whereas the JNK and SAPK and P38 and MAPK pathways may be directly activated by Rho and Rho related Rac, respectively.	32	50	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	SAPK	SAPK	SAPK	49	50	34	35
The first event is activation of the Src family protein tyrosine kinases ( SFKs ) Fyn and Lck through the dephosphorylation of their crucial tyrosine residues mediated by CD45 XREF_BIBR , XREF_BIBR .	The first event is activation of the Src family protein tyrosine kinases (SFKs) Fyn and Lck through the dephosphorylation of their crucial tyrosine residues mediated by CD45 XREF_BIBR, XREF_BIBR.	15	29	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CD45	CD45	CD45	Fyn	Fyn	Fyn	28	29	15	16
Thus it is likely that TS enzymatic modulation of CD45 and downstream activation of Src family kinases Lck and Fyn reduce the threshold for TCR activation of naive T cells , leading to the increased responses to subdominant TS epitopes .	Thus it is likely that TS enzymatic modulation of CD45 and downstream activation of Src family kinases Lck and Fyn reduce the threshold for TCR activation of naive T cells, leading to the increased responses to subdominant TS epitopes.	9	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CD45	CD45	CD45	Fyn	Fyn	Fyn	9	10	19	20
CD45 activates the Src family protein-tyrosine kinases , p56lck and p59fyn , by dephosphorylating a negative regulatory tyrosine in the carboxyl terminus .	CD45 activates the Src family protein-tyrosine kinases, p56lck and p59fyn, by dephosphorylating a negative regulatory tyrosine in the carboxyl terminus.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD45	CD45	CD45	p59fyn	p59fyn	p59fyn	0	1	10	11
The CD45 tyrosine phosphatase has been reported to activate the src family tyrosine kinases Lck and Fyn by dephosphorylating regulatory COOH-terminal tyrosine residues 505 and 528 , respectively .	The CD45 tyrosine phosphatase has been reported to activate the src family tyrosine kinases Lck and Fyn by dephosphorylating regulatory COOH-terminal tyrosine residues 505 and 528, respectively.	1	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD45	CD45	CD45	Fyn	Fyn	Fyn	1	2	16	17
Previous analyses have suggested that the CD45 tyrosine phosphatase activates src family tyrosine kinases p56lck and p59fyn by dephosphorylating regulatory COOH-terminal residues .	Previous analyses have suggested that the CD45 tyrosine phosphatase activates src family tyrosine kinases p56lck and p59fyn by dephosphorylating regulatory COOH-terminal residues.	6	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD45	CD45	CD45	p59fyn	p59fyn	p59fyn	6	7	16	17
This protein is recruited from the cytosol onto the surface of late endosomes by Rab9 GTPase , which enables TIP47 to bind to MPR cytoplasmic domains with enhanced affinity .	This protein is recruited from the cytosol onto the surface of late endosomes by Rab9 GTPase, which enables TIP47 to bind to MPR cytoplasmic domains with enhanced affinity.	14	20	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rab9	Rab9	Rab9	TIP47	TIP47	TIP47	14	15	19	20
Moreover , Rab9 increases the affinity of TIP47 for MPR cytoplasmic domains .	Moreover, Rab9 increases the affinity of TIP47 for MPR cytoplasmic domains.	2	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rab9	Rab9	Rab9	TIP47	TIP47	TIP47	2	3	7	8
Because Rab9 enhances the affinity of TIP47 for MPR cytoplasmic domains , it seems reasonable to propose that these proteins are packaged altogether into transport carriers .	Because Rab9 enhances the affinity of TIP47 for MPR cytoplasmic domains, it seems reasonable to propose that these proteins are packaged altogether into transport carriers.	1	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rab9	Rab9	Rab9	TIP47	TIP47	TIP47	1	2	6	7
Moreover , Rab9 increased the affinity of TIP47 for its cargo .	Moreover, Rab9 increased the affinity of TIP47 for its cargo.	2	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rab9	Rab9	Rab9	TIP47	TIP47	TIP47	2	3	7	8
Rab9 , principally localized to late endosomes , increase the interaction of TIP47 with MPRs , and hence MPRs are concentrated to Rab9 vesicles [ XREF_BIBR , XREF_BIBR ] .	Rab9, principally localized to late endosomes, increase the interaction of TIP47 with MPRs, and hence MPRs are concentrated to Rab9 vesicles [XREF_BIBR, XREF_BIBR].	0	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rab9	Rab9	Rab9	TIP47	TIP47	TIP47	0	1	12	13
Consistently , overexpression of PTPRJ activates Src and enhances cell-matrix adhesion .	Consistently, overexpression of PTPRJ activates Src and enhances cell-matrix adhesion.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTPRJ	overexpression of PTPRJ	ptprj	Src	Src	src	4	5	6	7
Expression of Dep1 in transformed rat thyroid PCMPSV cells increased Src activity via Y527 dephosphorylation ( corresponding to Y530 in human Src ) without affecting the level of phosphorylated Y416 ( Y419 in human Src ) .	Expression of Dep1 in transformed rat thyroid PCMPSV cells increased Src activity via Y527 dephosphorylation (corresponding to Y530 in human Src) without affecting the level of phosphorylated Y416 (Y419 in human Src).	0	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dep1	Expression of Dep1	dep1	Src	Src	src	2	3	10	11
In contrast to cell migration , cell-substrate adhesion was promoted by active DEP-1 and delayed or suppressed by DEP-1 C1239S , correlating with positive effects of DEP-1 on adhesion stimulated Src kinase .	In contrast to cell migration, cell-substrate adhesion was promoted by active DEP-1 and delayed or suppressed by DEP-1 C1239S, correlating with positive effects of DEP-1 on adhesion stimulated Src kinase.	24	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DEP-1	DEP-1	DEP-1	Src	Src	Src	26	27	30	31
PTX3 was shown to enhance the binding of CFH to apoptotic cells XREF_BIBR .	PTX3 was shown to enhance the binding of CFH to apoptotic cells XREF_BIBR.	0	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTX3	PTX3	PTX3	CFH	CFH	CFH	0	1	8	9
PTX3 levels were positively associated with the severity of dilatative cardiomyopathy and increased risk of HF [ XREF_BIBR ] .	PTX3 levels were positively associated with the severity of dilatative cardiomyopathy and increased risk of HF [XREF_BIBR].	0	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTX3	PTX3 levels	ptx3	HF	HF	hf	0	1	15	16
Retroviral overexpression of Rac2 in primary VSMC leads to increased migration , activation of the NADPH oxidation cascade , and increased activation of the Rac2 effector protein Pak1 and its proximal effectors , ERK1/2 , and p38 ( P < 0.05 for all ) .	Retroviral overexpression of Rac2 in primary VSMC leads to increased migration, activation of the NADPH oxidation cascade, and increased activation of the Rac2 effector protein Pak1 and its proximal effectors, ERK1/2, and p38 (P < 0.05 for all).	1	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac2	overexpression of Rac2	rac2	Pak1	Pak1	pak1	3	4	27	28
In this schema , PI-3K-activated Rac2 induces Pak1 to phosphorylate Mek at serine 298 as well as Raf1 at serine 338 , potentiating Raf1 ' s phosphorylation of Mek at serine 217/222 .	In this schema, PI-3K-activated Rac2 induces Pak1 to phosphorylate Mek at serine 298 as well as Raf1 at serine 338, potentiating Raf1 's phosphorylation of Mek at serine 217/222.	4	8	induces	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Rac2	Rac2	Rac2	Pak1	Pak1	Pak1	5	6	7	8
Activated Rac can induce new actin polymerization by stimulating the Arp2/3 complex through the Rac target IRSp53 XREF_BIBR .	Activated Rac can induce new actin polymerization by stimulating the Arp2/3 complex through the Rac target IRSp53 XREF_BIBR.	14	17	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rac	Rac	Rac	IRSp53	IRSp53	IRSp53	14	15	16	17
These data suggest that loss of RAD17 and/or RAD50 may impair BRCA1 function , and could contribute to increased sensitivity to DNA damaging agents .	These data suggest that loss of RAD17 and/or RAD50 may impair BRCA1 function, and could contribute to increased sensitivity to DNA damaging agents.	4	12	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RAD50	loss of RAD17 and/or RAD50	rad50	BRCA1	BRCA1	brca1	8	9	11	12
The PYCARD protein is known to directly activate CASP9 and BAX .	The PYCARD protein is known to directly activate CASP9 and BAX.	1	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PYCARD	PYCARD	PYCARD	BAX	BAX	BAX	1	2	10	11
Activated CRAF activated MEK and ERK , and in some experiments produced increased proliferation and migration of melanoma cells .	Activated CRAF activated MEK and ERK, and in some experiments produced increased proliferation and migration of melanoma cells.	0	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	1	2	3	4
Then , activated Raf-1 induces ERK1/2 and MEK1/2 enhancing proliferation of smooth muscle cells .	Then, activated Raf-1 induces ERK1/2 and MEK1/2 enhancing proliferation of smooth muscle cells.	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK1/2	MEK1/2	MEK1/2	3	4	7	8
Specifically , Raf-1 is a direct activator of MEK and a target of Pin1 , but phosphorylation of Raf-1 on Ser259 inhibits kinase activity leading to reduced MEK phosphorylation .	Specifically, Raf-1 is a direct activator of MEK and a target of Pin1, but phosphorylation of Raf-1 on Ser259 inhibits kinase activity leading to reduced MEK phosphorylation.	2	9	is a direct activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	2	3	8	9
8.2.8 DJ-1 Can Bind Directly to and Phosphorylate c-Raf , Which Can Then Activate MEK and ERK1/2 .	8.2.8 DJ-1 Can Bind Directly to and Phosphorylate c-Raf, Which Can Then Activate MEK and ERK1/2.	1	16	Activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Raf	DJ-1 Can Bind Directly to and Phosphorylate c-Raf	c-raf	MEK	MEK	mek	8	9	14	15
CRAF knockdown enhances the antiproliferative effect of MEK inhibition in KRAS-mutant tumors .	CRAF knockdown enhances the antiproliferative effect of MEK inhibition in KRAS-mutant tumors.	0	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	0	1	7	8
This C-RAF activation of MEK and ERK signaling was suppressed by pharmacologic MEK inhibition ( XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY ) .	This C-RAF activation of MEK and ERK signaling was suppressed by pharmacologic MEK inhibition (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	C-RAF	C-RAF	C-RAF	MEK	MEK	MEK	1	2	4	5
MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAF V600E .	MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAF V600E.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	3	4	0	1
It has been demonstrated in melanoma and lung cancer cells that MEK activated by CRAF is less sensitive to MEK inhibitors than , when the activation is via BRAF V600E [ XREF_BIBR ] .	It has been demonstrated in melanoma and lung cancer cells that MEK activated by CRAF is less sensitive to MEK inhibitors than, when the activation is via BRAF V600E [XREF_BIBR].	11	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	14	15	11	12
Previous studies demonstrated that PKA inhibits Ras and c-Raf activation of MEK and ERK MAPK signaling XREF_BIBR , XREF_BIBR .	Previous studies demonstrated that PKA inhibits Ras and c-Raf activation of MEK and ERK MAPK signaling XREF_BIBR, XREF_BIBR.	6	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	c-Raf	c-Raf	c-Raf	MEK	MEK	MEK	8	9	11	12
While in the traditional transient MAPK signaling pathway c-Raf activates Mek which promotes Erk regulation of nuclear transcription factors , in the prolonged RA/D3 associated signaling , c-Raf additionally translocates to the nucleus by 48 hours to activate its own transcription factor targets [ XREF_BIBR , XREF_BIBR ] .	While in the traditional transient MAPK signaling pathway c-Raf activates Mek which promotes Erk regulation of nuclear transcription factors, in the prolonged RA/D3 associated signaling, c-Raf additionally translocates to the nucleus by 48 hours to activate its own transcription factor targets [XREF_BIBR, XREF_BIBR].	7	12	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	c-Raf	c-Raf	c-Raf	Mek	Mek	Mek	8	9	10	11
In this pathway , Salp15 induced RAF1 activation stimulates MEK signalling , which promotes Il6 and Tnf mRNA decay and impairs nucleosome remodeling and hence transcriptional activation at the Il12a promoter .	In this pathway, Salp15 induced RAF1 activation stimulates MEK signalling, which promotes Il6 and Tnf mRNA decay and impairs nucleosome remodeling and hence transcriptional activation at the Il12a promoter.	4	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAF1	Salp15 induced RAF1	raf1	MEK	MEK	mek	6	7	9	10
ERK1 and ERK2 , the output of the cascade , are phosphorylated by MEK1 and MEK2 , and MEK1/2 are activated upstream by Raf-1 , and B-Raf XREF_BIBR .	ERK1 and ERK2, the output of the cascade, are phosphorylated by MEK1 and MEK2, and MEK1/2 are activated upstream by Raf-1, and B-Raf XREF_BIBR.	18	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK1/2	MEK1/2	MEK1/2	23	24	18	19
The resulting GTP-Ras protein activates various downstream effectors such as MAP-kinase Raf-1 which activates the MEK and ERK gene regulation cascade , a primary cell growth and anti-apoptosis pathway .	The resulting GTP-Ras protein activates various downstream effectors such as MAP-kinase Raf-1 which activates the MEK and ERK gene regulation cascade, a primary cell growth and anti-apoptosis pathway.	7	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	11	12	15	16
Raf-1 activates MEK ( MAPK kinase ) in the MAPK pathway , and the MEK inhibitor U0126 reduced calcium current by 45 % after 10-15 min , whereas the inactive analogue U0124 had no effect .	Raf-1 activates MEK (MAPK kinase) in the MAPK pathway, and the MEK inhibitor U0126 reduced calcium current by 45% after 10-15 min, whereas the inactive analogue U0124 had no effect.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	0	1	2	3
To determine whether or not Raf-1 directly activates MEK , we developed an in vitro assay with purified recombinant proteins .	To determine whether or not Raf-1 directly activates MEK, we developed an in vitro assay with purified recombinant proteins.	5	9	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	5	6	8	9
The hydrolysis of RAP1-GTP releases Raf-1 from sequestration , thereby allowing MEK / ERK signaling .	The hydrolysis of RAP1-GTP releases Raf-1 from sequestration, thereby allowing MEK / ERK signaling.	1	14	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	5	6	11	12
These results demonstrated the essential role of Ras induced conformational change in MEK activation by c-Raf .	These results demonstrated the essential role of Ras induced conformational change in MEK activation by c-Raf.	8	16	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	c-Raf	c-Raf	c-Raf	MEK	MEK	MEK	15	16	12	13
MEK and Erk activation is mediated by the upstream kinase Raf-1 .	MEK and Erk activation is mediated by the upstream kinase Raf-1.	0	11	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	10	11	0	1
The data indicate that RAF1 mediated MEK signaling networks are likely involved in DETD-35-induced cytoplasmic vacuolation death in human TNCB cells .	The data indicate that RAF1 mediated MEK signaling networks are likely involved in DETD-35-induced cytoplasmic vacuolation death in human TNCB cells.	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK	MEK	MEK	4	5	6	7
These results show that CRAF inhibition is required for PD0325901 to be effective against KRAS mutant cancers , and suggest that inhibitors like PD0325901 are less effective at inhibiting CRAF activated MEK .	These results show that CRAF inhibition is required for PD0325901 to be effective against KRAS mutant cancers, and suggest that inhibitors like PD0325901 are less effective at inhibiting CRAF activated MEK.	29	32	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	29	30	31	32
ERKs are activated by the MAPK kinase ( MEK ) which is activated by Raf-1 .	ERKs are activated by the MAPK kinase (MEK) which is activated by Raf-1.	6	15	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	14	15	8	9
Specifically , B-Raf is thought to be the main activator of MEK under normal conditions ; Raf-1 activates MEK in response to stimulus [ XREF_BIBR ] .	Specifically, B-Raf is thought to be the main activator of MEK under normal conditions; Raf-1 activates MEK in response to stimulus [XREF_BIBR].	16	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	16	17	18	19
While the build-up of a V600E BRAF , CRAF , and MEK complex ultimately limited the efficacy of combined BRAF and MEK inhibition in melanoma , this signaling complex appeared to be poised to deliver a lethal dose of signaling once both inhibitors were efficiently and acutely removed ( XREF_FIG ) .	While the build-up of a V600E BRAF, CRAF, and MEK complex ultimately limited the efficacy of combined BRAF and MEK inhibition in melanoma, this signaling complex appeared to be poised to deliver a lethal dose of signaling once both inhibitors were efficiently and acutely removed (XREF_FIG).	2	22	limited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	8	9	21	22
They also confirmed that silencing of CRAF abrogated this activation of MEK1/2 > ERK1/2 signaling .	They also confirmed that silencing of CRAF abrogated this activation of MEK1/2> ERK1/2 signaling.	4	14	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK1/2	MEK1/2	MEK1/2	6	7	11	12
We conclude that MEK is a direct substrate of Raf-1 and that the activation of MEK by Raf-1 is due to phosphorylation by Raf-1 , which is sufficient for MEK activation .	We conclude that MEK is a direct substrate of Raf-1 and that the activation of MEK by Raf-1 is due to phosphorylation by Raf-1, which is sufficient for MEK activation.	13	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	17	18	15	16
In addition , overexpression of C-Raf is not considered by-itself tumorigenic , since it does not result in C-Raf activation or activation of its downstream mediators , MEK and ERK [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, overexpression of C-Raf is not considered by-itself tumorigenic, since it does not result in C-Raf activation or activation of its downstream mediators, MEK and ERK [XREF_BIBR, XREF_BIBR, XREF_BIBR].	18	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	C-Raf	C-Raf	C-Raf	MEK	MEK	MEK	18	19	27	28
Lito and colleagues recently demonstrated that MEK activated by CRAF in melanoma and lung cancer cells is less sensitive to MEK inhibitors than when activated by BRAF V600E [ XREF_BIBR ] , which is confirmed by the response of KTC1-VEM2 cells to combination treatment with vemurafenib and the MEK inhibitor AZD6244 .	Lito and colleagues recently demonstrated that MEK activated by CRAF in melanoma and lung cancer cells is less sensitive to MEK inhibitors than when activated by BRAF V600E [XREF_BIBR], which is confirmed by the response of KTC1-VEM2 cells to combination treatment with vemurafenib and the MEK inhibitor AZD6244.	6	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	9	10	6	7
RAF-1 directly activates MEK1/2 by phosphorylation at serine residues 217 and 221 [ XREF_BIBR ] .	RAF-1 directly activates MEK1/2 by phosphorylation at serine residues 217 and 221 [XREF_BIBR].	0	4	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAF-1	RAF-1	RAF-1	MEK1/2	MEK1/2	MEK1/2	0	1	3	4
Rosner and colleagues showed that PKC phosphorylates RKIP at serine residue 153 ( S153 ) in neuronal cells , and this phosphorylation leads to dissociation of RKIP from Raf-1 and subsequent activation of MEK and ERK .	Rosner and colleagues showed that PKC phosphorylates RKIP at serine residue 153 (S153) in neuronal cells, and this phosphorylation leads to dissociation of RKIP from Raf-1 and subsequent activation of MEK and ERK.	28	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	28	29	33	34
Raf-1 and Bag1 upregulate MEK1/2 thus activating the ERK1/2 pathway [ XREF_BIBR - XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Raf-1 and Bag1 upregulate MEK1/2 thus activating the ERK1/2 pathway [XREF_BIBR - XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	5	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK1/2	MEK1/2	MEK1/2	0	1	4	5
Due to three isoenzymes of RAF ( A-RAF , B-RAF , and C-RAF ) , the inhibition of one of them such as B-RAF can induce a compensatory transactivation of C-RAF , which in turn activates downstream MEK and the subsequent pathway [ XREF_BIBR , XREF_BIBR ] .	Due to three isoenzymes of RAF (A-RAF, B-RAF, and C-RAF), the inhibition of one of them such as B-RAF can induce a compensatory transactivation of C-RAF, which in turn activates downstream MEK and the subsequent pathway [XREF_BIBR, XREF_BIBR].	28	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	C-RAF	C-RAF	C-RAF	MEK	MEK	MEK	30	31	37	38
A major downstream effector target of Ras-GTP is the MAP-kinase Raf-1 that activates the MEK and Erk gene regulation cascade .	A major downstream effector target of Ras-GTP is the MAP-kinase Raf-1 that activates the MEK and Erk gene regulation cascade.	4	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	10	11	14	15
This inhibition of Raf-1 hyperphosphorylation resulted in increased kinase activity of Raf-1 and increased phosphorylation of MEK , suggesting that the hyperphosphorylation of Raf-1 inhibits its MEK kinase activity .	This inhibition of Raf-1 hyperphosphorylation resulted in increased kinase activity of Raf-1 and increased phosphorylation of MEK, suggesting that the hyperphosphorylation of Raf-1 inhibits its MEK kinase activity.	3	17	increased	Positive_regulation_syntax_1_verb	Positive_activation	Negative_regulation	Raf-1	Raf-1 hyperphosphorylation	raf-1	MEK	phosphorylation of MEK	mek	3	4	16	17
Once fully activated , Raf-1 phosphorylates and activates MKK1 or MKK2 ( also called MEK1/2 ) .	Once fully activated, Raf-1 phosphorylates and activates MKK1 or MKK2 (also called MEK1/2).	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK1/2	MEK1/2	MEK1/2	4	5	14	15
It has been reported that activation of RAF-1 triggers movement of cytosolic MEK to endosomes .	It has been reported that activation of RAF-1 triggers movement of cytosolic MEK to endosomes.	5	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAF-1	RAF-1	RAF-1	MEK	MEK	MEK	7	8	12	13
Activation of Ras leads to the activation of Raf-1 , which will activate MEK .	Activation of Ras leads to the activation of Raf-1, which will activate MEK.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	8	9	13	14
These experiments therefore demonstrate that LSA induces PCC through a mechanism that is dependent on the kinase activity of RAF1 but independent of the classical RAF1/MEK/ERK pathway , and suggest that RAF1 could target additional substrates in addition to MEK .	These experiments therefore demonstrate that LSA induces PCC through a mechanism that is dependent on the kinase activity of RAF1 but independent of the classical RAF1/MEK/ERK pathway, and suggest that RAF1 could target additional substrates in addition to MEK.	31	40	target	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK	MEK	MEK	31	32	39	40
In addition , mitotic activation of Raf-1 does not lead to stimulation of the mitogen activated protein kinase kinase ( MAPKK or MEK ) and the extracellular signal regulated protein kinase ( ERK ) .	In addition, mitotic activation of Raf-1 does not lead to stimulation of the mitogen activated protein kinase kinase (MAPKK or MEK) and the extracellular signal regulated protein kinase (ERK).	4	23	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	6	7	22	23
In NIH 3T3 fibroblasts and COS-1 cells , mutation of serine 259 resulted in Raf-1 proteins which activated the MEK and ERK pathway as efficiently as v-Raf .	In NIH 3T3 fibroblasts and COS-1 cells, mutation of serine 259 resulted in Raf-1 proteins which activated the MEK and ERK pathway as efficiently as v-Raf.	14	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	14	15	19	20
MEK inhibition by U0126 XREF_BIBR and C-RAF inhibition by GW5074 XREF_BIBR also caused apoptosis but presented different traits .	MEK inhibition by U0126 XREF_BIBR and C-RAF inhibition by GW5074 XREF_BIBR also caused apoptosis but presented different traits.	0	7	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Positive_activation	C-RAF	C-RAF	C-RAF	MEK	MEK	MEK	6	7	0	1
SDF-1 strongly induced phosphorylation of Raf-1 on S338 , the target site for the Rac effector Paks , and enhanced the IL-3-induced activation of Raf-1 and MEK .	SDF-1 strongly induced phosphorylation of Raf-1 on S338, the target site for the Rac effector Paks, and enhanced the IL-3-induced activation of Raf-1 and MEK.	0	27	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	SDF-1 strongly induced phosphorylation of Raf-1 on S338	raf-1	MEK	MEK	mek	5	6	26	27
Raf-1 is responsive to receptor tyrosine kinase activation , and upon phosphorylation Raf-1 activates MEK and ERK kinases [ XREF_BIBR ] .	Raf-1 is responsive to receptor tyrosine kinase activation, and upon phosphorylation Raf-1 activates MEK and ERK kinases [XREF_BIBR].	10	17	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	12	13	14	15
For example , consider high-precision measurements of 23 of the 24 involved parameters , all but the rate constant for the activation of Mek by Raf1 .	For example, consider high-precision measurements of 23 of the 24 involved parameters, all but the rate constant for the activation of Mek by Raf1.	11	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Raf1	Raf1	Raf1	Mek	Mek	Mek	25	26	23	24
Post-treatment biopsies of resistant tumors have identified RTK , NRAS , COT , and C-RAF mediated activation of the MEK and ERK pathway , essentially bypassing BRAF altogether .	Post-treatment biopsies of resistant tumors have identified RTK, NRAS, COT, and C-RAF mediated activation of the MEK and ERK pathway, essentially bypassing BRAF altogether.	14	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	C-RAF	C-RAF	C-RAF	MEK	MEK	MEK	14	15	19	20
MEK and ERK MEK1 and MEK2 are activated by RAF-1 , its only known substrates [ XREF_BIBR ] .	MEK and ERK MEK1 and MEK2 are activated by RAF-1, its only known substrates [XREF_BIBR].	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RAF-1	RAF-1	RAF-1	MEK	MEK	MEK	9	10	0	1
It is also due to CRAF activation that vemurafenib paradoxically induces the MEK and ERK pathway in BRAF WT cells even though inhibiting MEK and ERK phosphorylation in BRAF tumors with a BRAF V600E mutation [ XREF_BIBR ] .	It is also due to CRAF activation that vemurafenib paradoxically induces the MEK and ERK pathway in BRAF WT cells even though inhibiting MEK and ERK phosphorylation in BRAF tumors with a BRAF V600E mutation [XREF_BIBR].	5	15	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	5	6	12	13
MAPK14 functionally antagonizes RAF1 activation of MEK ( MAP2K1 ) , which is a critical pathway that regulates chondrocyte hypertrophy .	MAPK14 functionally antagonizes RAF1 activation of MEK (MAP2K1), which is a critical pathway that regulates chondrocyte hypertrophy.	3	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK	MEK	MEK	3	4	6	7
Activated Ras activates the Raf1 kinase , which in turn activates the MAP kinase MEK .	Activated Ras activates the Raf1 kinase, which in turn activates the MAP kinase MEK.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf1	Raf1	Raf1	MEK	MEK	MEK	4	5	14	15
The increase in MAPK activity and tyrosine phosphorylation caused by 1alpha ,25 ( OH ) ( 2 ) D ( 3 ) could be abolished by Ras inhibitor peptide , compound PD 98059 , which prevents the activation of MEK by Raf-1 , or incubation of cell lysates before 1alpha ,25 ( OH ) ( 2 ) D ( 3 ) exposure with an anti-Raf-1 antibody .	The increase in MAPK activity and tyrosine phosphorylation caused by 1alpha,25 (OH) (2) D (3) could be abolished by Ras inhibitor peptide, compound PD 98059, which prevents the activation of MEK by Raf-1, or incubation of cell lysates before 1alpha,25 (OH) (2) D (3) exposure with an anti-Raf-1 antibody.	37	42	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	41	42	39	40
Since RAS activation and CRAF activity are both low in BRAF V600E tumors , in which MEK and ERK signaling is driven almost entirely by BRAF V600E , we hypothesized that the decreased MEK inhibitor sensitivity of KRAS tumors is due to ineffective inhibition of CRAF driven MEK signaling by these drugs .	Since RAS activation and CRAF activity are both low in BRAF V600E tumors, in which MEK and ERK signaling is driven almost entirely by BRAF V600E, we hypothesized that the decreased MEK inhibitor sensitivity of KRAS tumors is due to ineffective inhibition of CRAF driven MEK signaling by these drugs.	43	48	driven	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	45	46	47	48
To understand this , we performed an RNAi screen in a KRAS-mutant model and found that CRAF knockdown enhanced MEK inhibition .	To understand this, we performed an RNAi screen in a KRAS-mutant model and found that CRAF knockdown enhanced MEK inhibition.	16	20	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	16	17	19	20
Thus , activated Raf-1 alone does not support MEK and MAPK activation in macrophages .	Thus, activated Raf-1 alone does not support MEK and MAPK activation in macrophages.	2	11	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	3	4	8	9
Moreover , PP2a can dephosphorylate and inactivate MEK1 and ERK family kinases , therefore , inhibiting mitogenic signals ; this effect is obtained directly and indirectly , through the inactivation of PKCzeta enzyme [ XREF_BIBR ] , which in turn stimulates the MAPK cascade through Raf-1 independent activation of MEK [ XREF_BIBR , XREF_BIBR ] .	Moreover, PP2a can dephosphorylate and inactivate MEK1 and ERK family kinases, therefore, inhibiting mitogenic signals; this effect is obtained directly and indirectly, through the inactivation of PKCzeta enzyme [XREF_BIBR], which in turn stimulates the MAPK cascade through Raf-1 independent activation of MEK [XREF_BIBR, XREF_BIBR].	45	53	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	45	46	49	50
Active Raf-1 activates the Ras kinase ( proto oncogene Raf encoding ' s serine/threonine kinase ) , which then activates mitogen activated protein kinase ( MAPK ) kinase , also known as MEK , by serine phosphorylation .	Active Raf-1 activates the Ras kinase (proto oncogene Raf encoding 's serine/threonine kinase), which then activates mitogen activated protein kinase (MAPK) kinase, also known as MEK, by serine phosphorylation.	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	kinase	kinase	kinase	1	2	5	6
In support of this , CRAF activation of MEK has been observed following treatment with MEK inhibitors , in the setting of impaired ERK activation by dominant negative kinase suppressor of RAS ( KSR ) , and in cells overexpressing IMP .	In support of this, CRAF activation of MEK has been observed following treatment with MEK inhibitors, in the setting of impaired ERK activation by dominant negative kinase suppressor of RAS (KSR), and in cells overexpressing IMP.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	5	6	8	9
This result is expected because both C-RAF and MOS directly activate MEK .	This result is expected because both C-RAF and MOS directly activate MEK.	5	12	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	C-RAF	C-RAF	C-RAF	MEK	MEK	MEK	6	7	11	12
Second , it has been reported that PKA promotes Raf1 activation , which in turn activates MEK and finally ERK .	Second, it has been reported that PKA promotes Raf1 activation, which in turn activates MEK and finally ERK.	9	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf1	Raf1	Raf1	MEK	MEK	MEK	9	10	16	17
PD98059 has been shown to prevent the activation of MEK by c-Raf or MEK kinase by blocking the MEK activation site .	PD98059 has been shown to prevent the activation of MEK by c-Raf or MEK kinase by blocking the MEK activation site.	7	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	c-Raf	c-Raf	c-Raf	MEK	MEK	MEK	11	12	9	10
MEK kinase , which is downstream of BRAF , is activated by CRAF or members of the PI3K pathway as an escape mechanism from BRAF inhibition .	MEK kinase, which is downstream of BRAF, is activated by CRAF or members of the PI3K pathway as an escape mechanism from BRAF inhibition.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	12	13	0	1
We next determined whether upstream targeting of CRAF enhanced the effects of MEK inhibition in NRAS-mutant melanoma .	We next determined whether upstream targeting of CRAF enhanced the effects of MEK inhibition in NRAS-mutant melanoma.	5	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	7	8	12	13
CRAF knockdown may enhance the antitumor effects of MEK inhibition by inhibiting other targets of RAF in addition to MEK .	CRAF knockdown may enhance the antitumor effects of MEK inhibition by inhibiting other targets of RAF in addition to MEK.	0	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	0	1	8	9
In vitro , however , SB203580 stimulated Raf-1 activates MEK1 in a coupled assay .	In vitro, however, SB203580 stimulated Raf-1 activates MEK1 in a coupled assay.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK1	MEK1	MEK1	7	8	9	10
The activation of Mek1 by Raf-1 involves only serine phosphorylation , which is directly proportional to the extent of Mek1 activation .	The activation of Mek1 by Raf-1 involves only serine phosphorylation, which is directly proportional to the extent of Mek1 activation.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	Mek1	Mek1	Mek1	5	6	3	4
In this study , using activated MEK1 produced by in vitro activation by RAF1 ( pMEK1 ( invitro ) ) , we demonstrate that the simultaneous expression of RAF1 for production of activated MEK1 does not result in stoichiometric phosphorylation of MEK1 .	In this study, using activated MEK1 produced by in vitro activation by RAF1 (pMEK1 (invitro)), we demonstrate that the simultaneous expression of RAF1 for production of activated MEK1 does not result in stoichiometric phosphorylation of MEK1.	4	17	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK1	MEK1	MEK1	13	14	6	7
The specific activity of the [ Asp218 , Asp222 ] and [ Asp218 , Glu222 ] Mek1 mutants , 29 nanomole phosphate per minute per milligram , is similar to that of wild-type Mek1 activated by Raf-1 in vitro .	The specific activity of the [Asp218, Asp222] and [Asp218, Glu222] Mek1 mutants, 29 nanomole phosphate per minute per milligram, is similar to that of wild-type Mek1 activated by Raf-1 in vitro.	30	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	Mek1	Mek1	Mek1	36	37	33	34
Activated MEK1 mediates hyperphosphorylation of the amino terminal regulatory as well as of the carboxy terminal catalytic domain of Raf-1 .	Activated MEK1 mediates hyperphosphorylation of the amino terminal regulatory as well as of the carboxy terminal catalytic domain of Raf-1.	0	20	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK1	MEK1	MEK1	19	20	1	2
MEK1 dependent Golgi complex fragmentation is through activation by RAF1 and not MEK1 kinase 1 .	MEK1 dependent Golgi complex fragmentation is through activation by RAF1 and not MEK1 kinase 1.	7	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK1	MEK1	MEK1	9	10	12	13
We now report that RAF1 is required to activate MEK1 for Golgi complex fragmentation during mitosis and that mitotically activated MEK1 is found on the Golgi membranes in late prophase .	We now report that RAF1 is required to activate MEK1 for Golgi complex fragmentation during mitosis and that mitotically activated MEK1 is found on the Golgi membranes in late prophase.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK1	MEK1	MEK1	4	5	9	10
MEK1 is first mitotically activated by RAF1 , and then recruited to the Golgi ribbon in late prophase , where it mediates Golgi complex fragmentation .	MEK1 is first mitotically activated by RAF1, and then recruited to the Golgi ribbon in late prophase, where it mediates Golgi complex fragmentation.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK1	MEK1	MEK1	6	7	0	1
These results provide strong evidence that RAF1 mediated activation of MEK1 is required for Golgi complex fragmentation by mitotic cytosol .	These results provide strong evidence that RAF1 mediated activation of MEK1 is required for Golgi complex fragmentation by mitotic cytosol.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK1	MEK1	MEK1	6	7	10	11
RAF1 activated MEK1 is found on the Golgi apparatus in late prophase and is required for Golgi complex fragmentation in mitosis .	RAF1 activated MEK1 is found on the Golgi apparatus in late prophase and is required for Golgi complex fragmentation in mitosis.	0	14	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK1	MEK1	MEK1	0	1	2	3
To investigate further the contribution of the MEK-1 pathway , we modulated the expression of Ras and Raf-1 proteins , which are known to trigger MEK-1 activation in chondrocytes [ XREF_BIBR ] .	To investigate further the contribution of the MEK-1 pathway, we modulated the expression of Ras and Raf-1 proteins, which are known to trigger MEK-1 activation in chondrocytes [XREF_BIBR].	13	26	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	expression of Ras and Raf-1	raf-1	MEK-1	MEK-1	mek-1	17	18	25	26
RAF1 dependent activation of MEK1 is necessary for Golgi complex fragmentation .	RAF1 dependent activation of MEK1 is necessary for Golgi complex fragmentation.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK1	MEK1	MEK1	0	1	4	5
Activated Ras can activate the Ser/Thr kinase Raf-1 which can then activate the dual specificity kinases Mek1 and Mek2 .	Activated Ras can activate the Ser/Thr kinase Raf-1 which can then activate the dual specificity kinases Mek1 and Mek2.	3	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	Mek1	Mek1	Mek1	7	8	16	17
In the MAPK pathway , the small G protein , Ras activates Raf-1 which in turn activates MEK-1 resulting in the activation of p44 ( ERK1 ) and p42 ( ERK2 ) which is known to cause cellular proliferation and inhibit apoptosis [ XREF_BIBR ] .	In the MAPK pathway, the small G protein, Ras activates Raf-1 which in turn activates MEK-1 resulting in the activation of p44 (ERK1) and p42 (ERK2) which is known to cause cellular proliferation and inhibit apoptosis [XREF_BIBR].	11	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK-1	MEK-1	MEK-1	12	13	17	18
In contrast , MEK1 activation by constitutively-active Raf-1 is refractory to mutations at PAK1 phosphorylation sites .	In contrast, MEK1 activation by constitutively-active Raf-1 is refractory to mutations at PAK1 phosphorylation sites.	3	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK1	MEK1	MEK1	7	8	3	4
Furthermore , Cd treatment rapidly activated ( within 2.5 min ) raf-1 , mitogen activated protein kinase kinase , mek-1 , extracellular signal regulated kinases , erk-1/2 , ribosomal S6 kinase , rsk , and E-26 like protein kinase , elk , about 4-fold in vector transfectants .	Furthermore, Cd treatment rapidly activated (within 2.5 min) raf-1, mitogen activated protein kinase kinase, mek-1, extracellular signal regulated kinases, erk-1/2, ribosomal S6 kinase, rsk, and E-26 like protein kinase, elk, about 4-fold in vector transfectants.	11	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	raf-1	raf-1	raf-1	mek-1	mek-1	mek-1	11	12	19	20
The activation of Raf-1 initiates a MAPK cascade that comprises a sequential phosphorylation of the dual specific MAPK kinases ( MAP2K1 and MEK1 and MAP2K2 and MEK2 ) and the extracellular signal regulated kinases ( MAPK3 and ERK1 and MAPK1 and ERK2 ) .	The activation of Raf-1 initiates a MAPK cascade that comprises a sequential phosphorylation of the dual specific MAPK kinases (MAP2K1 and MEK1 and MAP2K2 and MEK2) and the extracellular signal regulated kinases (MAPK3 and ERK1 and MAPK1 and ERK2).	1	26	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MAP2K1	MAP2K1	MAP2K1	3	4	20	21
We propose that a RAF1 dependent activation of MEK1 and its presence on the Golgi apparatus in late prophase is required for Golgi complex fragmentation .	We propose that a RAF1 dependent activation of MEK1 and its presence on the Golgi apparatus in late prophase is required for Golgi complex fragmentation.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RAF1	RAF1	RAF1	MEK1	MEK1	MEK1	4	5	8	9
In addition the signal is amplified as Raf1 activates numerous MEK1 proteins .	In addition the signal is amplified as Raf1 activates numerous MEK1 proteins.	7	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf1	Raf1	Raf1	MEK1	MEK1	MEK1	7	8	10	11
Raf1 is known to directly activate MEK1 and its activity was necessary for mitotic Golgi fragmentation and entry into mitosis .	Raf1 is known to directly activate MEK1 and its activity was necessary for mitotic Golgi fragmentation and entry into mitosis.	0	7	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf1	Raf1	Raf1	MEK1	MEK1	MEK1	0	1	6	7
Pak1 , and as well Pak5 , induce phosphorylation of Raf1 at Ser338 and stimulate translocation of a subpopulation of Raf1 to the mitochondria [ XREF_BIBR - XREF_BIBR ] .	Pak1, and as well Pak5, induce phosphorylation of Raf1 at Ser338 and stimulate translocation of a subpopulation of Raf1 to the mitochondria [XREF_BIBR - XREF_BIBR].	0	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf1	Pak1, and as well Pak5, induce phosphorylation of Raf1 at Ser338	raf1	Raf1	Raf1	raf1	10	11	20	21
Recently , AKT phosphorylation of MST2 and a feedback phosphorylation of Raf-1 by LATS1 was found to enable Raf-1 to suppress both MST2 and ERK signaling [ XREF_BIBR ] .	Recently, AKT phosphorylation of MST2 and a feedback phosphorylation of Raf-1 by LATS1 was found to enable Raf-1 to suppress both MST2 and ERK signaling [XREF_BIBR].	9	19	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	phosphorylation of Raf-1	raf-1	Raf-1	Raf-1	raf-1	11	12	18	19
CRAF phosphorylation on Serine 338 ( due to P21 activated kinases ) promotes CRAF association with and inactivation of the pro apoptotic kinases ASK1 and MST2 .	CRAF phosphorylation on Serine 338 (due to P21 activated kinases) promotes CRAF association with and inactivation of the pro apoptotic kinases ASK1 and MST2.	0	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	CRAF phosphorylation on Serine 338	craf	CRAF	CRAF	craf	0	1	13	14
Coexpression of Raf-1 with v-ras p21 in Sf9 cells stimulated the autophosphorylating activity of Raf-1 .	Coexpression of Raf-1 with v-ras p21 in Sf9 cells stimulated the autophosphorylating activity of Raf-1.	0	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Coexpression of Raf-1	raf-1	Raf-1	Raf-1	raf-1	2	3	14	15
As expected , expression of constitutively active PAK1 strongly enhanced the phosphorylation of Raf-1 on serine 338 in cells and stimulated the kinase activity of Raf-1 towards MEK1 in vitro ( XREF_FIG ) .	As expected, expression of constitutively active PAK1 strongly enhanced the phosphorylation of Raf-1 on serine 338 in cells and stimulated the kinase activity of Raf-1 towards MEK1 in vitro (XREF_FIG).	3	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	expression of constitutively active PAK1 strongly enhanced the phosphorylation of Raf-1 on serine 338	raf-1	Raf-1	Raf-1	raf-1	13	14	25	26
Both MGF and GM-CSF enhanced Raf-1 phosphorylation and increased Raf-1 associated kinase activity in vitro .	Both MGF and GM-CSF enhanced Raf-1 phosphorylation and increased Raf-1 associated kinase activity in vitro.	1	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	MGF and GM-CSF enhanced Raf-1 phosphorylation	raf-1	Raf-1	Raf-1	raf-1	5	6	9	10
Raf-1 phosphorylation at Ser338 by PAK1 can induce the translocation of Raf-1 to the mitochondria where it binds to Bcl-2 and phosphorylates BAD at Ser112 , thus providing an additional mechanism in which PAK1 can regulate BAD activity and prevent apoptosis [ XREF_BIBR ] .	Raf-1 phosphorylation at Ser338 by PAK1 can induce the translocation of Raf-1 to the mitochondria where it binds to Bcl-2 and phosphorylates BAD at Ser112, thus providing an additional mechanism in which PAK1 can regulate BAD activity and prevent apoptosis [XREF_BIBR].	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1 phosphorylation at Ser338	raf-1	Raf-1	Raf-1	raf-1	0	1	11	12
Compared to the both mutant KRas cell lines , the wild-type KRas cell line BxPC-3 prevented the inhibition of c-Raf expression at the low drug concentrations of 10 and 20 mug/mL , but promoted the down-regulation of c-Raf at the high drug concentration of 30 mug/mL .	Compared to the both mutant KRas cell lines, the wild-type KRas cell line BxPC-3 prevented the inhibition of c-Raf expression at the low drug concentrations of 10 and 20 mug/mL, but promoted the down-regulation of c-Raf at the high drug concentration of 30 mug/mL.	11	38	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Raf	KRas cell line BxPC-3 prevented the inhibition of c-Raf expression	c-raf	c-Raf	c-Raf	c-raf	19	20	37	38
PAK1 and PAK5 phosphorylate Raf1 at Ser338 and stimulate translocation of a subpopulation of Raf1 to the mitochondria .	PAK1 and PAK5 phosphorylate Raf1 at Ser338 and stimulate translocation of a subpopulation of Raf1 to the mitochondria.	0	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf1	PAK1 and PAK5 phosphorylate Raf1 at Ser338	raf1	Raf1	Raf1	raf1	4	5	14	15
This model ( XREF_FIG ) is supported by our experiments showing that MEK controls NtA phosphorylation of CRAF and a recent report that MEK can activate CRAF .	This model (XREF_FIG) is supported by our experiments showing that MEK controls NtA phosphorylation of CRAF and a recent report that MEK can activate CRAF.	12	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	MEK controls NtA phosphorylation of CRAF	craf	CRAF	CRAF	craf	17	18	26	27
PAK5 phosphorylates Raf-1 on serine 338 and stimulates Raf-1 activity .	PAK5 phosphorylates Raf-1 on serine 338 and stimulates Raf-1 activity.	0	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	PAK5 phosphorylates Raf-1 on serine 338	raf-1	Raf-1	Raf-1	raf-1	2	3	8	9
Kolesnick and co-workers recently demonstrated that mammalian KSR1 purified to homogeneity directly phosphorylates Raf-1 at Thr 269 promoting Raf-1 kinase activity in vitro , consistent with their previous findings [ XREF_BIBR , XREF_BIBR ] .	Kolesnick and co-workers recently demonstrated that mammalian KSR1 purified to homogeneity directly phosphorylates Raf-1 at Thr 269 promoting Raf-1 kinase activity in vitro, consistent with their previous findings [XREF_BIBR, XREF_BIBR].	7	20	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	KSR1 purified to homogeneity directly phosphorylates Raf-1 at Thr 269	raf-1	Raf-1	Raf-1	raf-1	13	14	18	19
AKT can phosphorylate MST2 and LATS1 phosphorylates Raf-1 , which were found to enable Raf-1 to suppress ERK and MST2 signaling [ XREF_BIBR ] .	AKT can phosphorylate MST2 and LATS1 phosphorylates Raf-1, which were found to enable Raf-1 to suppress ERK and MST2 signaling [XREF_BIBR].	6	15	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	phosphorylates Raf-1	raf-1	Raf-1	Raf-1	raf-1	7	8	14	15
bFGF protection is MEK independent and involves the activation of Raf-1 by phosphorylation of S338 and Raf-1 translocation to mitochondria .	bFGF protection is MEK independent and involves the activation of Raf-1 by phosphorylation of S338 and Raf-1 translocation to mitochondria.	8	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Raf-1	phosphorylation of S338 and Raf-1	raf-1	Raf-1	Raf-1	raf-1	16	17	10	11
While there is evidence that phosphorylation of Ser388 , Ser389 , and Tyr341 on Raf-1 increases affinity of Raf-1 for RKIP , there are also results to suggest that interaction of Raf-1 with RKIP instead blocks the phosphorylation of these same residues on Raf-1 .	While there is evidence that phosphorylation of Ser388, Ser389, and Tyr341 on Raf-1 increases affinity of Raf-1 for RKIP, there are also results to suggest that interaction of Raf-1 with RKIP instead blocks the phosphorylation of these same residues on Raf-1.	5	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	phosphorylation of Ser388, Ser389, and Tyr341 on Raf-1	raf-1	Raf-1	Raf-1	raf-1	14	15	18	19
Various growth factors such as epidermal growth factor , acidic fibroblast growth factor , platelet derived growth factor , insulin , granulocyte-macrophage colony stimulating factor , interleukin ( IL )-2, IL-3 and erythropoietin have been shown to induce phosphorylation of Raf-1 , thereby activating Raf-1 kinase .	Various growth factors such as epidermal growth factor, acidic fibroblast growth factor, platelet derived growth factor, insulin, granulocyte-macrophage colony stimulating factor, interleukin (IL)-2, IL-3 and erythropoietin have been shown to induce phosphorylation of Raf-1, thereby activating Raf-1 kinase.	9	45	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	acidic fibroblast growth factor, platelet derived growth factor, insulin, granulocyte-macrophage colony stimulating factor, interleukin (IL)-2, IL-3 and erythropoietin have been shown to induce phosphorylation of Raf-1	raf-1	Raf-1	Raf-1	raf-1	40	41	44	45
These include Akt phosphorylation of MST2 and a feedback phosphorylation of Raf-1 Ser259 by LATS1 , which enables Raf-1 to suppress both MST2 and MEK signalling .	These include Akt phosphorylation of MST2 and a feedback phosphorylation of Raf-1 Ser259 by LATS1, which enables Raf-1 to suppress both MST2 and MEK signalling.	9	19	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	phosphorylation of Raf-1 Ser259 by LATS1	raf-1	Raf-1	Raf-1	raf-1	11	12	18	19
Our data also show by sequential in vitro kinase assays that TNF-alpha enhances KSR phosphorylation of Raf-1 on threonine , enhancing Raf-1 kinase activity toward MAP kinase kinase .	Our data also show by sequential in vitro kinase assays that TNF-alpha enhances KSR phosphorylation of Raf-1 on threonine, enhancing Raf-1 kinase activity toward MAP kinase kinase.	11	23	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	TNF-alpha enhances KSR phosphorylation of Raf-1 on threonine	raf-1	Raf-1	Raf-1	raf-1	16	17	21	22
XREF_BIBR At low expression , RASSF1A stimulates MST2 activity , whereas it inhibits MST2 activity at high expression ( XREF_FIG ) .	XREF_BIBR At low expression, RASSF1A stimulates MST2 activity, whereas it inhibits MST2 activity at high expression (XREF_FIG).	5	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	5	6	7	8
DNA damaged is perceived by the master sensor , ATM kinase , which phosphorylates RASSF1A on Ser 131 within its ATM consensus sequence , and triggers activation of MST2 and downstream events described above .	DNA damaged is perceived by the master sensor, ATM kinase, which phosphorylates RASSF1A on Ser 131 within its ATM consensus sequence, and triggers activation of MST2 and downstream events described above.	9	29	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	ATM kinase, which phosphorylates RASSF1A on Ser 131	rassf1a	MST2	MST2	mst2	14	15	28	29
RASSF1A overexpression itself has been observed to cause MST1 and MST2 activation , XREF_BIBR , XREF_BIBR and one report proposes that activation occurs through the ability of RASSF1A to disrupt an inhibitory interaction between MST2 and cRaf1 73 ( see below ) .	RASSF1A overexpression itself has been observed to cause MST1 and MST2 activation, XREF_BIBR, XREF_BIBR and one report proposes that activation occurs through the ability of RASSF1A to disrupt an inhibitory interaction between MST2 and cRaf1 73 (see below).	0	11	cause	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A overexpression	rassf1a	MST2	MST2	mst2	0	1	10	11
This prevents RASSF1A mediated MST2 dimerization and auto-phosphorylation on Thr180 which are both required for full activation of MST2 .	This prevents RASSF1A mediated MST2 dimerization and auto-phosphorylation on Thr180 which are both required for full activation of MST2.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	2	3	4	5
Such insights will help to construct more accurate and predictive mechanistic models of RASSF1A mediated MST2 activation , the understanding of which is essential for future therapeutic strategies targeting RASSF1A .	Such insights will help to construct more accurate and predictive mechanistic models of RASSF1A mediated MST2 activation, the understanding of which is essential for future therapeutic strategies targeting RASSF1A.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	13	14	15	16
RASSF1A has been reported to activate Mst2 , which may result in activation of YAP on p73 in the context of Fas induced apoptosis [ XREF_BIBR ] .	RASSF1A has been reported to activate Mst2, which may result in activation of YAP on p73 in the context of Fas induced apoptosis [XREF_BIBR].	0	22	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	Mst2	Mst2	Mst2	0	1	6	7
Upon a certain cue , RASSF1A activates MST2 and triggers the Hippo pathway dependent pro apoptotic process ( XREF_FIG , the upper part ) .	Upon a certain cue, RASSF1A activates MST2 and triggers the Hippo pathway dependent pro apoptotic process (XREF_FIG, the upper part).	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	5	6	7	8
RASSF1A can also induce apoptosis through an MST2 specific pathway by releasing MST2 from its inhibitor , Raf1 , and allowing for large tumor suppressor homology ( Drosophila ) ( LATS ) 1 mediated activation of the transcriptional regulator Yes associated protein ( YAP ) 1 [ XREF_BIBR ] .	RASSF1A can also induce apoptosis through an MST2 specific pathway by releasing MST2 from its inhibitor, Raf1, and allowing for large tumor suppressor homology (Drosophila) (LATS) 1 mediated activation of the transcriptional regulator Yes associated protein (YAP) 1 [XREF_BIBR].	0	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	0	1	12	13
Finally , RASSF1A has been shown to promote the interaction of Mst2 with its substrate Lats1 , leading to the activation of Lats1 and downstream Yap1 [ XREF_BIBR ] .	Finally, RASSF1A has been shown to promote the interaction of Mst2 with its substrate Lats1, leading to the activation of Lats1 and downstream Yap1 [XREF_BIBR].	2	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	Mst2	Mst2	Mst2	2	3	11	12
While it is probable that RASSF1A mediated activation of MST2 activates pro apoptotic pathways , it is surprising that the transcriptional co-activator YAP is involved in p73 activation and PUMA up-regulation , since several studies have shown that it YAP has oncogenic properties .	While it is probable that RASSF1A mediated activation of MST2 activates pro apoptotic pathways, it is surprising that the transcriptional co-activator YAP is involved in p73 activation and PUMA up-regulation, since several studies have shown that it YAP has oncogenic properties.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	5	6	9	10
For example , RASSF1A and RASSF2 activate MST2 and induce apoptosis via Hippo signaling whereas RASSF6 inhibits MST1/2 and induces apoptosis through a different pathway , despite all RASSF proteins harboring an RA domain .	For example, RASSF1A and RASSF2 activate MST2 and induce apoptosis via Hippo signaling whereas RASSF6 inhibits MST1/2 and induces apoptosis through a different pathway, despite all RASSF proteins harboring an RA domain.	3	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	3	4	7	8
To reduce the number of model parameters without significantly compromising the network dynamics properties , the MEK and ERK activation steps are lumped into a single step ; ( iii ) The MST2 module describes activation of the MST2 and LATS signalling cascade , which is mediated by the scaffold protein Ras association domain family 1 isoform A ( RASSF1A ) .	To reduce the number of model parameters without significantly compromising the network dynamics properties, the MEK and ERK activation steps are lumped into a single step; (iii) The MST2 module describes activation of the MST2 and LATS signalling cascade, which is mediated by the scaffold protein Ras association domain family 1 isoform A (RASSF1A).	35	60	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	59	60	38	39
In our in vitro kinase assay , RASSF1A activates MST2 [ XREF_BIBR ] .	In our in vitro kinase assay, RASSF1A activates MST2 [XREF_BIBR].	7	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	7	8	9	10
Raf-1 binds and inhibits MST2 kinase , whereas dissociation from Raf-1 and binding to tumor suppressor protein RASSF1A activates MST2 .	Raf-1 binds and inhibits MST2 kinase, whereas dissociation from Raf-1 and binding to tumor suppressor protein RASSF1A activates MST2.	10	20	activates	Positive_activation_token_1_verb	Positive_activation	Negative_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	17	18	19	20
Overall RASSF1A is likely to activate MST2 in vivo and the Hippo pathway ( XREF_FIG , the upper part ) .	Overall RASSF1A is likely to activate MST2 in vivo and the Hippo pathway (XREF_FIG, the upper part).	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	1	2	6	7
Because RASSF1A promotes MST1 activation and apoptosis via this hetero-dimerization , we postulated that the direct interaction of MST1 with BRAF V600E might affect MST1 kinase activity .	Because RASSF1A promotes MST1 activation and apoptosis via this hetero-dimerization, we postulated that the direct interaction of MST1 with BRAF V600E might affect MST1 kinase activity.	1	4	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST1	MST1	MST1	1	2	3	4
On the other hand , increased cardiac expression of RASSF1A , but not a SARAH domain mutant RASSF1A that is deficient for MST1 binding , augmented MST1 activation and cardiomyocyte apoptosis [ XREF_BIBR ] .	On the other hand, increased cardiac expression of RASSF1A, but not a SARAH domain mutant RASSF1A that is deficient for MST1 binding, augmented MST1 activation and cardiomyocyte apoptosis [XREF_BIBR].	7	27	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	expression of RASSF1A	rassf1a	MST1	MST1	mst1	9	10	26	27
Because RASSF1A also binds to the C-terminal domain of MST1 and increases MST1 kinase activity , the interaction between BRAF V600E and MST1 might affect MST1 kinase activity by interrupting the heterotypic interaction of MST1 with RASSF1A .	Because RASSF1A also binds to the C-terminal domain of MST1 and increases MST1 kinase activity, the interaction between BRAF V600E and MST1 might affect MST1 kinase activity by interrupting the heterotypic interaction of MST1 with RASSF1A.	1	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST1	MST1	MST1	1	2	12	13
The direct interaction of BRAF-V600E with MST1 to prevent RASSF1 mediated MST1 activation also provides an explanation for the mutually exclusive occurrence of BRAF V600E mutation and RASSF1A hypermethylation in thyroid cancer 128 , as either event may be sufficient to inactivate RASSF1-MST1-FOXO3 signalling .	The direct interaction of BRAF-V600E with MST1 to prevent RASSF1 mediated MST1 activation also provides an explanation for the mutually exclusive occurrence of BRAF V600E mutation and RASSF1A hypermethylation in thyroid cancer 128, as either event may be sufficient to inactivate RASSF1-MST1-FOXO3 signalling.	8	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	RASSF1	RASSF1	RASSF1	MST1	MST1	MST1	9	10	11	12
In this manner , RASSF1A mediates MST1 activation and induction of apoptosis .	In this manner, RASSF1A mediates MST1 activation and induction of apoptosis.	4	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RASSF1A	RASSF1A	RASSF1A	MST1	MST1	MST1	4	5	6	7
Furthermore , inhibition of the Ral signaling pathway abolishes both AFX mediated transcription and regulation of p27 ( Kip1 ) , while activation of Ral augments AFX activity .	Furthermore, inhibition of the Ral signaling pathway abolishes both AFX mediated transcription and regulation of p27 (Kip1), while activation of Ral augments AFX activity.	22	27	augments	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Ral	Ral	Ral	AFX	AFX	AFX	24	25	26	27
shRNA mediated knockdown of Rap1GDS1 selectively suppressed Cdc42 activation and inhibited both baseline and microgravity induced vasculogenesis .	shRNA mediated knockdown of Rap1GDS1 selectively suppressed Cdc42 activation and inhibited both baseline and microgravity induced vasculogenesis.	2	8	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Rap1GDS1	Rap1GDS1	Rap1GDS1	Cdc42	Cdc42	Cdc42	4	5	7	8
We demonstrated that GFR can activate Rap1 but not H-Ras in 293T cells and that the cdc25 domain of GFR is required for the activation of Rap1 .	We demonstrated that GFR can activate Rap1 but not H-Ras in 293T cells and that the cdc25 domain of GFR is required for the activation of Rap1.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GFR	GFR	GFR	H-Ras	H-Ras	H-Ras	3	4	9	10
Another study suggested that Rheb activates the mTOR complex by antagonizing its inhibitor FK506 binding protein 38 ( FKBP 38 ) .	Another study suggested that Rheb activates the mTOR complex by antagonizing its inhibitor FK506 binding protein 38 (FKBP 38).	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	4	5	7	8
Ras and Rheb also enhances mTOR and raptor signaling , stimulating p70S6 kinase- and eIF4E ( eukaryotic translation initiation factor 4E )-regulated cell growth , autophagy , metabolism , ribosome biogenesis and translation [ XREF_BIBR ] .	Ras and Rheb also enhances mTOR and raptor signaling, stimulating p70S6 kinase- and eIF4E (eukaryotic translation initiation factor 4E)-regulated cell growth, autophagy, metabolism, ribosome biogenesis and translation [XREF_BIBR].	0	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	2	3	5	6
AMPK can induce autophagy by acting via two different pathways , directly , by phosphorylating the proautophagic factor ULK1 [ XREF_BIBR , XREF_BIBR ] , and indirectly , by negatively regulating the mTOR complex targeting them TOR inhibitors tuberous sclerosis complex 1 and 2 ( TSC1/2 ) and the mTOR activator Rheb , a Ras homologue GTP binding protein enriched in the brain [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	AMPK can induce autophagy by acting via two different pathways, directly, by phosphorylating the proautophagic factor ULK1 [XREF_BIBR, XREF_BIBR], and indirectly, by negatively regulating the mTOR complex targeting them TOR inhibitors tuberous sclerosis complex 1 and 2 (TSC1/2) and the mTOR activator Rheb, a Ras homologue GTP binding protein enriched in the brain [XREF_BIBR, XREF_BIBR, XREF_BIBR].	49	52	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	51	52	49	50
Rheb is a direct activator of mTOR and the only known downstream target of Rheb is mTOR .	Rheb is a direct activator of mTOR and the only known downstream target of Rheb is mTOR.	0	7	is a direct activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	6	7
Siah1 degrades Rheb leading to reduced mTOR signaling , while ketamine , conversely , stabilizes Rheb which enhances mTOR signaling .	Siah1 degrades Rheb leading to reduced mTOR signaling, while ketamine, conversely, stabilizes Rheb which enhances mTOR signaling.	14	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	15	16	18	19
Rheb binds directly to the amino-terminal lobe of the mTOR catalytic domain , and activates mTOR kinase in a GTP dependent manner .	Rheb binds directly to the amino-terminal lobe of the mTOR catalytic domain, and activates mTOR kinase in a GTP dependent manner.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	15	16
In addition , PML recruits mTOR activator Rheb to the nucleus , thereby inhibiting mTOR [ XREF_BIBR ] .	In addition, PML recruits mTOR activator Rheb to the nucleus, thereby inhibiting mTOR [XREF_BIBR].	5	10	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	7	8	5	6
Rheb and PA : The Direct Activators of mTOR .	Rheb and PA : The Direct Activators of mTOR.	0	9	Activators	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	8	9
We found that Rheb expression significantly enhanced mTOR activity , as determined by increased phosphorylation of p70 S6 ( XREF_FIG ) .	We found that Rheb expression significantly enhanced mTOR activity, as determined by increased phosphorylation of p70 S6 (XREF_FIG).	3	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb expression	rheb	mTOR	mTOR	mtor	3	4	7	8
Active Rheb directly activates the mTOR kinase by altering substrate affinities .	Active Rheb directly activates the mTOR kinase by altering substrate affinities.	0	6	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	1	2	5	6
First , we wanted to confirm in our assays that Rheb activation of mTOR is dependent on farnesylation .	First, we wanted to confirm in our assays that Rheb activation of mTOR is dependent on farnesylation.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	10	11	13	14
Rheb activation of mTOR is more dependent on farnesylation than on postprenylation CAAX processing .	Rheb activation of mTOR is more dependent on farnesylation than on postprenylation CAAX processing.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	3	4
Through the small G protein Rheb , the TSC proteins , hamartin and tuberin , negatively regulate mammalian target of rapamycin complex 1 ( mTORC1 ) signaling .	Through the small G protein Rheb, the TSC proteins, hamartin and tuberin, negatively regulate mammalian target of rapamycin complex 1 (mTORC1) signaling.	5	21	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	5	6	17	21
Rheb activates mTOR to suppress autophagy and promote transformation [ XREF_BIBR ] .	Rheb activates mTOR to suppress autophagy and promote transformation [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	2	3
To accomplish the goal of this study , overexpression of Rheb was used as a means to induce a PI3K and PKB independent activation of mTOR signaling .	To accomplish the goal of this study, overexpression of Rheb was used as a means to induce a PI3K and PKB independent activation of mTOR signaling.	8	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	10	11	25	26
These cytotoxic effects have been attributed to FTI induced inhibition of prosurvival signaling by Akt , the Rheb target mTOR , or mitogen activated protein ( MAP ) kinases .	These cytotoxic effects have been attributed to FTI induced inhibition of prosurvival signaling by Akt, the Rheb target mTOR, or mitogen activated protein (MAP) kinases.	8	20	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	17	18	19	20
Rheb has been shown to bind directly to the amino-terminal lobe of the mammalian TOR ( mTOR ) catalytic domain and activate mTOR in a GTP dependent manner .	Rheb has been shown to bind directly to the amino-terminal lobe of the mammalian TOR (mTOR) catalytic domain and activate mTOR in a GTP dependent manner.	0	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	22	23
The TSC is a GTPase activating factor that antagonizes the function of the small GTPase rheB , which is required to activate mTOR in response to nutrients .	The TSC is a GTPase activating factor that antagonizes the function of the small GTPase rheB, which is required to activate mTOR in response to nutrients.	10	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	rheB	rheB	rheB	mTOR	mTOR	mTOR	15	16	22	23
In addition , we found that activation of mTOR by Rheb2 or a constitutively active RagB mutant ( RagB GTP ) , like overexpression of p62 itself , enhances the soft agar growth of A498 cells ( XREF_SUPPLEMENTARY ) .	In addition, we found that activation of mTOR by Rheb2 or a constitutively active RagB mutant (RagB GTP), like overexpression of p62 itself, enhances the soft agar growth of A498 cells (XREF_SUPPLEMENTARY).	6	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rheb2	Rheb2	Rheb2	mTOR	mTOR	mTOR	10	11	8	9
For instance TSC1 and TSC2 inhibits mTORC1 signaling through the inhibition of the mTOR activator Ras Homolog Enriched In Brain ( Rheb ) ; however , TSC1 and TSC2 has been demonstrated to activate mTORC2 signaling through direct contact with mTORC2 [ XREF_BIBR , XREF_BIBR ] .	For instance TSC1 and TSC2 inhibits mTORC1 signaling through the inhibition of the mTOR activator Ras Homolog Enriched In Brain (Rheb); however, TSC1 and TSC2 has been demonstrated to activate mTORC2 signaling through direct contact with mTORC2 [XREF_BIBR, XREF_BIBR].	10	20	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Ras Homolog Enriched In Brain	Ras Homolog Enriched In Brain	Ras Homolog Enriched In Brain	mTOR	mTOR	mTOR	15	20	13	14
When bound to GTP Rheb activates mTOR and when bound to GDP it inhibits mTOR .	When bound to GTP Rheb activates mTOR and when bound to GDP it inhibits mTOR.	1	7	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	4	5	6	7
ATF6 increases the expression of Rheb , which activates mTOR activity independently of AKT .	ATF6 increases the expression of Rheb, which activates mTOR activity independently of AKT.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	ATF6 increases the expression of Rheb	rheb	mTOR	mTOR	mtor	5	6	9	10
Expression of a constitutively active Rheb enhanced mTOR activity and increased the fiber size in VCP-IBM mouse skeletal muscle .	Expression of a constitutively active Rheb enhanced mTOR activity and increased the fiber size in VCP-IBM mouse skeletal muscle.	0	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Expression of a constitutively active Rheb	rheb	mTOR	mTOR	mtor	5	6	7	8
In summary , we have found that inhibition of Rce1- and Icmt catalyzed modifications does not prevent Rheb activation of mTOR , and that FTS inhibits mTOR through a mechanism that does not involve Rheb inhibition .	In summary, we have found that inhibition of Rce1- and Icmt catalyzed modifications does not prevent Rheb activation of mTOR, and that FTS inhibits mTOR through a mechanism that does not involve Rheb inhibition.	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	17	18	20	21
Rheb may activate mTOR kinase activity via direct binding [ XREF_BIBR ] and this effect has been mimicked in in vitro mTORC1 kinase assays [ XREF_BIBR , XREF_BIBR ] .	Rheb may activate mTOR kinase activity via direct binding [XREF_BIBR] and this effect has been mimicked in in vitro mTORC1 kinase assays [XREF_BIBR, XREF_BIBR].	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	3	4
The function of Rheb is to bind to and activate mTOR and thus , it is essential for coupling all upstream signals to this pathway .	The function of Rheb is to bind to and activate mTOR and thus, it is essential for coupling all upstream signals to this pathway.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	3	4	10	11
Rheb activates mTOR signaling , but the activities of TSC1 and TSC2 complexes decrease in mTOR activation .	Rheb activates mTOR signaling, but the activities of TSC1 and TSC2 complexes decrease in mTOR activation.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	2	3
Together these proteins form a heterodimer that inhibits Rheb ( Ras homolog expressed in brain ) , the GTPase that activates the mTOR pathway [ XREF_BIBR ] .	Together these proteins form a heterodimer that inhibits Rheb (Ras homolog expressed in brain), the GTPase that activates the mTOR pathway [XREF_BIBR].	7	23	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	22	23
The mechanisms by which mTORC1 is activated by amino acids are less clear but a number of studies have shown that the binding of Raptor to the Rag GTPases , a family of four related small GTPases XREF_BIBR , is necessary for mTOR to localize onto the lysosome where mTOR is activated by its upstream activator Rheb XREF_BIBR , XREF_BIBR ,.	The mechanisms by which mTORC1 is activated by amino acids are less clear but a number of studies have shown that the binding of Raptor to the Rag GTPases, a family of four related small GTPases XREF_BIBR, is necessary for mTOR to localize onto the lysosome where mTOR is activated by its upstream activator Rheb XREF_BIBR, XREF_BIBR,.	49	57	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	56	57	49	50
Rheb mediated activation of mTOR causes phosphorylation , and thus activation of , S6 ribosomal protein .	Rheb mediated activation of mTOR causes phosphorylation, and thus activation of, S6 ribosomal protein.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	4	5
Then the activated Rheb promotes mTOR complex 1 ( mTORC1 ) to phosphorylate p70S6 and 4E binding protein1 ( 4EBP1 ) , resulting in dysregulation of protein synthesis and cell survival [ XREF_BIBR ] .	Then the activated Rheb promotes mTOR complex 1 (mTORC1) to phosphorylate p70S6 and 4E binding protein1 (4EBP1), resulting in dysregulation of protein synthesis and cell survival [XREF_BIBR].	1	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	3	4	5	6
The Rheb CA -encoding vector has been used as a reliable tool to increase mTOR activity in different cell types .	The Rheb CA -encoding vector has been used as a reliable tool to increase mTOR activity in different cell types.	1	15	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	1	2	14	15
Amino acids on the other hand signal to mTORC1 through the Rag family of GTPases , by mediating the activation of mTOR by RHEB at the lysosome [ XREF_BIBR , XREF_BIBR ] .	Amino acids on the other hand signal to mTORC1 through the Rag family of GTPases, by mediating the activation of mTOR by RHEB at the lysosome [XREF_BIBR, XREF_BIBR].	17	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	23	24	21	22
An important regulator of RHEB activity is the TSC complex which inactivates RHEB by accelerating GTP hydrolysis , and it has been reported that the TSC2 protein cycles on and off the lysosomal surface in response to amino acid levels : when amino acids are withdrawn TSC2 translocates to the lysosomal surface where it inactivates RHEB causing the subsequent mTOR inactivation .	An important regulator of RHEB activity is the TSC complex which inactivates RHEB by accelerating GTP hydrolysis, and it has been reported that the TSC2 protein cycles on and off the lysosomal surface in response to amino acid levels : when amino acids are withdrawn TSC2 translocates to the lysosomal surface where it inactivates RHEB causing the subsequent mTOR inactivation.	54	60	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	55	56	59	60
AMPK has been shown to inhibit mTORC1 activity by two different mechanisms : one through activation of the TSC2 , which promotes downstream inhibition of the mTOR activator Rheb [ XREF_BIBR , XREF_BIBR ] , and the other through direct phosphorylation of Raptor at Ser792 blocking mTORC1 activation [ XREF_BIBR ] .	AMPK has been shown to inhibit mTORC1 activity by two different mechanisms : one through activation of the TSC2, which promotes downstream inhibition of the mTOR activator Rheb [XREF_BIBR, XREF_BIBR], and the other through direct phosphorylation of Raptor at Ser792 blocking mTORC1 activation [XREF_BIBR].	26	30	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	28	29	26	27
Thus , when combined , these data indicate that overexpression of Rheb induces mTOR signaling through a PI3K and PKB independent mechanism in adult skeletal muscle in vivo and that the effects of Rheb on mTOR seem to be specific to the mTORC1 complex .	Thus, when combined, these data indicate that overexpression of Rheb induces mTOR signaling through a PI3K and PKB independent mechanism in adult skeletal muscle in vivo and that the effects of Rheb on mTOR seem to be specific to the mTORC1 complex.	9	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	11	12	13	14
Ectopic expression of Rheb in MDA-MB-231 cells resulted in activation of mTOR as evidenced by about 4.9-fold increase in T389 phosphorylation of P70s6k ( XREF_FIG ) .	Ectopic expression of Rheb in MDA-MB-231 cells resulted in activation of mTOR as evidenced by about 4.9-fold increase in T389 phosphorylation of P70s6k (XREF_FIG).	1	12	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Rheb	expression of Rheb	rheb	mTOR	mTOR	mtor	3	4	11	12
The Rheb activates mTOR by antagonizing its endogenous inhibitor FKBP38 .	The Rheb activates mTOR by antagonizing its endogenous inhibitor FKBP38.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	1	2	3	4
XREF_BIBR - XREF_BIBR Rheb activates mTOR by antagonizing its endogenous inhibitor , FKBP38 , XREF_BIBR though this remains controversial .	XREF_BIBR - XREF_BIBR Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38, XREF_BIBR though this remains controversial.	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	3	4	5	6
A recent study has shown that mTOR is required to interact with late endosomes that are enriched in TMEM127 proteins , as binding to the mTOR activators Rheb and PA is necessary for its activation .	A recent study has shown that mTOR is required to interact with late endosomes that are enriched in TMEM127 proteins, as binding to the mTOR activators Rheb and PA is necessary for its activation.	25	31	activators	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	27	28	25	26
In other studies , conditional expression of the mTOR activator Rheb ( a downstream effector of Akt ) in neural progenitors has been shown to promote myelination in the brain , while conditional Rheb knockout from the same cells inhibits myelination [ XREF_BIBR ] .	In other studies, conditional expression of the mTOR activator Rheb (a downstream effector of Akt) in neural progenitors has been shown to promote myelination in the brain, while conditional Rheb knockout from the same cells inhibits myelination [XREF_BIBR].	5	11	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	10	11	8	9
During amino acid deprivation , even potent upstream activators of Rheb fail to activate mTOR .	During amino acid deprivation, even potent upstream activators of Rheb fail to activate mTOR.	8	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	10	11	14	15
Thus , rescue of HD phenotypes through Rheb mediated activation of mTOR in HD striatum appears somewhat contradictory in the face of previously published data .	Thus, rescue of HD phenotypes through Rheb mediated activation of mTOR in HD striatum appears somewhat contradictory in the face of previously published data.	5	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	7	8	11	12
XREF_BIBR Given that Rheb is able to bind the kinase domain of other phosphatidylinositol-3 kinase like kinase ( PIKK ) family members such as ataxia telangiecstasia mutated ( ATM ) and ataxia telangiecstasia and Rad3 related ( ATR ) , XREF_BIBR structural studies examining the physical interaction between Rheb and mTOR could provide helpful insight into how Rheb activates mTOR .	XREF_BIBR Given that Rheb is able to bind the kinase domain of other phosphatidylinositol-3 kinase like kinase (PIKK) family members such as ataxia telangiecstasia mutated (ATM) and ataxia telangiecstasia and Rad3 related (ATR), XREF_BIBR structural studies examining the physical interaction between Rheb and mTOR could provide helpful insight into how Rheb activates mTOR.	57	60	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	57	58	59	60
TSC1/2 negatively regulates Rheb , which directly activates mTOR .	TSC1/2 negatively regulates Rheb, which directly activates mTOR.	2	9	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	3	4	8	9
Activation of mTOR by Rheb overexpression potently enhances the activity of HIFalpha and VEGF secretion during hypoxia .	Activation of mTOR by Rheb overexpression potently enhances the activity of HIFalpha and VEGF secretion during hypoxia.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rheb	Rheb overexpression	rheb	mTOR	mTOR	mtor	4	5	2	3
Importantly , PLD mediates activation of mTOR by Rheb because knockdown of PLD1 by shRNA significantly inhibited phosphorylation of the mTOR substrate S6K in response to overexpression of Rheb in cells .	Importantly, PLD mediates activation of mTOR by Rheb because knockdown of PLD1 by shRNA significantly inhibited phosphorylation of the mTOR substrate S6K in response to overexpression of Rheb in cells.	3	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	6	7
Rheb stimulated the activation of mTOR with an essential role in the regulation of S6K and 4EBP1 [ XREF_BIBR ] .	Rheb stimulated the activation of mTOR with an essential role in the regulation of S6K and 4EBP1 [XREF_BIBR].	0	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	5	6
Overexpression of Rheb Induces mTOR Signaling through a PI3K and PKB independent Mechanism in Skeletal Muscle In Vivo .	Overexpression of Rheb Induces mTOR Signaling through a PI3K and PKB independent Mechanism in Skeletal Muscle In Vivo.	0	5	Induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Overexpression of Rheb	rheb	mTOR	mTOR	mtor	2	3	4	5
Rheb positively regulates mTOR signaling and co-immunoprecipitate with mTOR [ XREF_BIBR ] .	Rheb positively regulates mTOR signaling and co-immunoprecipitate with mTOR [XREF_BIBR].	0	4	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	3	4
In the normal state , the hamartin and tuberin complex activates the protein Ras homolog enriched in brain ( Rheb ) , which inhibits mammalian target of rapamycin ( mTOR ) .	In the normal state, the hamartin and tuberin complex activates the protein Ras homolog enriched in brain (Rheb), which inhibits mammalian target of rapamycin (mTOR).	17	28	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	19	20	24	28
The Rheb activates mTOR by antagonizing its endogenous inhibitor FKBP38 XREF_BIBR .	The Rheb activates mTOR by antagonizing its endogenous inhibitor FKBP38 XREF_BIBR.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	1	2	3	4
Thus , while these CAAX modifications are necessary for proper subcellular localization , Rheb activation of mTOR is not impaired in the absence of Rce1 or Icmt function .	Thus, while these CAAX modifications are necessary for proper subcellular localization, Rheb activation of mTOR is not impaired in the absence of Rce1 or Icmt function.	13	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	13	14	16	17
Here , we find that PLD1 , but not PLD2 , is required for Rheb activation of the mTOR pathway , as demonstrated by the effects of RNAi .	Here, we find that PLD1, but not PLD2, is required for Rheb activation of the mTOR pathway, as demonstrated by the effects of RNAi.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	14	15	18	19
To confirm the regulation role of mTOR in G9a inhibition induced autophagy , we next overexpressed Rheb , which intensively activates mTOR in TCC T24 and UMUC-3 [ XREF_BIBR ] .	To confirm the regulation role of mTOR in G9a inhibition induced autophagy, we next overexpressed Rheb, which intensively activates mTOR in TCC T24 and UMUC-3 [XREF_BIBR].	15	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	16	17	21	22
RHEB may activate mTOR either by directly binding to it 117 or by binding to the mTOR antagonist FKBP38 ( also known as FKBP8 ) 118 .	RHEB may activate mTOR either by directly binding to it 117 or by binding to the mTOR antagonist FKBP38 (also known as FKBP8) 118.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	0	1	3	4
Despite progress in the understanding of mTor signaling , there are no in vivo studies that indicate whether Rheb1 or Rheb2 is necessary to activate mTor signaling .	Despite progress in the understanding of mTor signaling, there are no in vivo studies that indicate whether Rheb1 or Rheb2 is necessary to activate mTor signaling.	18	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb2	Rheb2	Rheb2	mTor	mTor	mTor	20	21	25	26
The positive and negative control of TORC1 activity is exerted through the TSC1 : TSC2 complex , whose TSC2 subunit serves as a GAP for the small GTPase Rheb , which activates mTOR .	The positive and negative control of TORC1 activity is exerted through the TSC1 : TSC2 complex, whose TSC2 subunit serves as a GAP for the small GTPase Rheb, which activates mTOR.	23	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	28	29	32	33
As shown in XREF_FIG A , we confirmed that the overexpression of Rheb in immobilized muscles was sufficient to induce the activation of mTOR signaling , as revealed by an increase in the T389 phosphorylation of co-transfected GST-p70 .	As shown in XREF_FIG A, we confirmed that the overexpression of Rheb in immobilized muscles was sufficient to induce the activation of mTOR signaling, as revealed by an increase in the T389 phosphorylation of co-transfected GST-p70.	10	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	12	13	23	24
Our laboratory examined the effects of forced overexpression of the known mTOR activator Rheb2 that has been shown to be preferentially expressed in HSC populations [ XREF_BIBR ] .	Our laboratory examined the effects of forced overexpression of the known mTOR activator Rheb2 that has been shown to be preferentially expressed in HSC populations [XREF_BIBR].	7	21	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb2	Rheb2	Rheb2	mTOR	mTOR	mTOR	13	14	11	12
To test whether over-expression of Rheb could upregulate mTOR activity in vitro , we constructed a Myc tagged wild-type ( wtRheb ) and a HA tagged , constitutively active mutant Rheb ( caRheb ) .	To test whether over-expression of Rheb could upregulate mTOR activity in vitro, we constructed a Myc tagged wild-type (wtRheb) and a HA tagged, constitutively active mutant Rheb (caRheb).	3	9	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	over-expression of Rheb	rheb	mTOR	mTOR	mtor	5	6	8	9
Rheb has been shown to exclusively activate the mTOR pathway without affecting other signaling pathways .	Rheb has been shown to exclusively activate the mTOR pathway without affecting other signaling pathways.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	8	9
The above results suggested that Rce1- and Icmt catalyzed modifications are required for Rheb localization , but not for Rheb activation of mTOR .	The above results suggested that Rce1- and Icmt catalyzed modifications are required for Rheb localization, but not for Rheb activation of mTOR.	19	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	19	20	22	23
Indeed , we have shown , as a proof of principle , that knocking down TSC2 or overexpressing RHEB enhances mTOR activity in KO cells .	Indeed, we have shown, as a proof of principle, that knocking down TSC2 or overexpressing RHEB enhances mTOR activity in KO cells.	17	21	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	18	19	20	21
Striatal levels of Rheb , which also activates mTOR , are unaltered in Rhes deleted striatum ( XREF_SUPPLEMENTARY ) .	Striatal levels of Rheb, which also activates mTOR, are unaltered in Rhes deleted striatum (XREF_SUPPLEMENTARY).	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	levels of Rheb	rheb	mTOR	mTOR	mtor	3	4	8	9
Rheb is the upstream activator of mTOR .	Rheb is the upstream activator of mTOR.	0	7	is the upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	6	7
These results suggested Rheb activated mTOR signaling .	These results suggested Rheb activated mTOR signaling.	3	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	3	4	5	6
When compared to Rheb , the greater effect size of ca-Akt was also expected because ca-Akt has the potential to induce an increase in protein synthesis through the combined activation of mTOR signaling and the inhibition of glycogen synthase kinase-3 beta ( GSK3beta ) , while Rheb only activates mTOR signaling .	When compared to Rheb, the greater effect size of ca-Akt was also expected because ca-Akt has the potential to induce an increase in protein synthesis through the combined activation of mTOR signaling and the inhibition of glycogen synthase kinase-3 beta (GSK3beta), while Rheb only activates mTOR signaling.	46	50	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	46	47	49	50
mTOR activation by Rheb overexpression decreases the CD133+ subpopulations .	mTOR activation by Rheb overexpression decreases the CD133+ subpopulations.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Rheb	Rheb overexpression	rheb	mTOR	mTOR	mtor	3	4	0	1
Thus , the lack of an effect of Rheb on PKB ( 308 ) phosphorylation suggests that , similar to the results obtained in C2C12 myoblasts , overexpression of Rheb induces mTOR signaling through a PI3K independent mechanism in adult skeletal muscle in vivo .	Thus, the lack of an effect of Rheb on PKB (308) phosphorylation suggests that, similar to the results obtained in C2C12 myoblasts, overexpression of Rheb induces mTOR signaling through a PI3K independent mechanism in adult skeletal muscle in vivo.	27	32	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	29	30	31	32
We found that ATF6alpha induced Rheb , a small GTPase of the Ras family that directly activates the survival protein mTOR .	We found that ATF6alpha induced Rheb, a small GTPase of the Ras family that directly activates the survival protein mTOR.	3	21	directly activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rheb	ATF6alpha induced Rheb	rheb	mTOR	mTOR	mtor	5	6	20	21
By contrast , the interaction of NIX with Rheb elicited mTOR independent effects on cell growth [ XREF_BIBR ] .	By contrast, the interaction of NIX with Rheb elicited mTOR independent effects on cell growth [XREF_BIBR].	6	12	elicited	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	10	11
Rheb , in its GTP bound state , can activate mTOR .	Rheb, in its GTP bound state, can activate mTOR.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	10	11
Previous work showed Rheb can signal both mTOR dependent and -independent pathways , and we found that Rheb can signal eIF2alpha , a target implicated in AD .	Previous work showed Rheb can signal both mTOR dependent and -independent pathways, and we found that Rheb can signal eIF2alpha, a target implicated in AD.	3	8	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	3	4	7	8
Our proteomic data also suggests that the mTORC1 pathway is activated , as shown by the increased expression of several proteins in the mTOR pathway at 12 hpi , including the mTOR activator Rheb ( XREF_SUPPLEMENTARY ) .	Our proteomic data also suggests that the mTORC1 pathway is activated, as shown by the increased expression of several proteins in the mTOR pathway at 12 hpi, including the mTOR activator Rheb (XREF_SUPPLEMENTARY).	10	35	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	33	34	31	32
It has also been shown that the overexpression of Rheb is sufficient to activate mTOR signaling and that the knockdown of Rheb inhibits mTOR signaling .	It has also been shown that the overexpression of Rheb is sufficient to activate mTOR signaling and that the knockdown of Rheb inhibits mTOR signaling.	19	24	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	21	22	23	24
The proteins encoded by TSC1 ( hamartin ) and TSC2 ( tuberin ) normally form a complex that regulates the mTORC1 signaling pathway directly through inhibition of the mTOR activator rheb ( ras homologue expressed in brain ) [ XREF_BIBR ] .	The proteins encoded by TSC1 (hamartin) and TSC2 (tuberin) normally form a complex that regulates the mTORC1 signaling pathway directly through inhibition of the mTOR activator rheb (ras homologue expressed in brain) [XREF_BIBR].	25	31	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	rheb	rheb	rheb	mTOR	mTOR	mTOR	30	31	28	29
One of the major effects of the activation of mTOR by Rheb is to suppress autophagy [ XREF_BIBR ] .	One of the major effects of the activation of mTOR by Rheb is to suppress autophagy [XREF_BIBR].	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	11	12	9	10
When the hamartin and tuberin complex is not functional , elevated levels of active Rheb ( Rheb-GTP ) constitutively activate mTOR , ultimately resulting in abnormal protein translation .	When the hamartin and tuberin complex is not functional, elevated levels of active Rheb (Rheb-GTP) constitutively activate mTOR, ultimately resulting in abnormal protein translation.	11	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	levels of active Rheb	rheb	mTOR	mTOR	mtor	14	15	20	21
Furthermore , we found that the Icmt inhibitor cysmethynil did not block Rheb activation of mTOR ( data not shown ) .	Furthermore, we found that the Icmt inhibitor cysmethynil did not block Rheb activation of mTOR (data not shown).	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	12	13	15	16
Akt , Tuberin and Rheb activate mTOR when it is part of a protein complex called mTORC1 ( mTOR complex 1 ) , which is exquisitely sensitive to the drug rapamycin .	Akt, Tuberin and Rheb activate mTOR when it is part of a protein complex called mTORC1 (mTOR complex 1), which is exquisitely sensitive to the drug rapamycin.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	4	5	6	7
Interestingly , the late-phase decrease in mTOR activation we observed coincided with decreased expression of the upstream mTOR activator Rheb , suggesting a possible negative-feedback mechanism ( XREF_FIG ) .	Interestingly, the late-phase decrease in mTOR activation we observed coincided with decreased expression of the upstream mTOR activator Rheb, suggesting a possible negative-feedback mechanism (XREF_FIG).	13	20	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	19	20	17	18
More recently , Rheb was shown to activate mTOR in vitro , thus providing conclusive evidence that Rheb is an activator of mTOR [ XREF_BIBR , XREF_BIBR ] .	More recently, Rheb was shown to activate mTOR in vitro, thus providing conclusive evidence that Rheb is an activator of mTOR [XREF_BIBR, XREF_BIBR].	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	3	4	8	9
When in its GTP state , Rheb is a potent activator of mTOR .	When in its GTP state, Rheb is a potent activator of mTOR.	6	13	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	6	7	12	13
Hamartin and tuberin are involved in the regulation of cell proliferation and differentiation , forming a physical and functional complex that activates guanosine triphosphatase ( GTPase ) , keeping the protein Ras homolog enriched in brain protein ( RHEB ) inactive in order to inhibit the mammalian target of rapamycin ( mTOR ) pathway .	Hamartin and tuberin are involved in the regulation of cell proliferation and differentiation, forming a physical and functional complex that activates guanosine triphosphatase (GTPase), keeping the protein Ras homolog enriched in brain protein (RHEB) inactive in order to inhibit the mammalian target of rapamycin (mTOR) pathway.	31	50	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	31	36	46	50
In this study , we show that Rheb like-1 protein ( RhebL1 ) rescues mTOR signaling during nutrient withdrawal and that tuberous sclerosis complex-1 ( TSC ) and TSC2 impairs RhebL1 mediated signaling through mTOR .	In this study, we show that Rheb like-1 protein (RhebL1) rescues mTOR signaling during nutrient withdrawal and that tuberous sclerosis complex-1 (TSC) and TSC2 impairs RhebL1 mediated signaling through mTOR.	7	15	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	7	8	14	15
Akt1 , in turn , activates mTORC1 by inhibiting the GAP TSC1/2 complex , thus activating the GTPase Rheb , which activates mTOR .	Akt1, in turn, activates mTORC1 by inhibiting the GAP TSC1/2 complex, thus activating the GTPase Rheb, which activates mTOR.	15	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	18	19	22	23
Tuberous sclerosis complexes 1 and 2 ( TSC1 and TSC2 ; also known as Hamartin and Tuberin ) form a heterodimeric protein complex to control mTOR signalling by integrating different signalling pathways : TSC1 and TSC2 complex functions as a GTPase activating protein to inhibit the activity of Rheb , a small GTPase protein that activates mTOR activation XREF_BIBR XREF_BIBR .	Tuberous sclerosis complexes 1 and 2 (TSC1 and TSC2; also known as Hamartin and Tuberin) form a heterodimeric protein complex to control mTOR signalling by integrating different signalling pathways : TSC1 and TSC2 complex functions as a GTPase activating protein to inhibit the activity of Rheb, a small GTPase protein that activates mTOR activation XREF_BIBR XREF_BIBR.	46	59	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	48	49	56	57
Overexpression of Rheb Induces mTOR Signaling through a PI3K independent Mechanism in Skeletal Muscle Myoblasts .	Overexpression of Rheb Induces mTOR Signaling through a PI3K independent Mechanism in Skeletal Muscle Myoblasts.	0	5	Induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Overexpression of Rheb	rheb	mTOR	mTOR	mtor	2	3	4	5
Our Rheb overexpression data are consistent with this hypothesis , because mTOR signaling in Rab5CA expressing cells is not rescued by constitutive hyperactivation of endogenous Rheb in TSC2-/- MEFs , but is rescued by overexpression of Rheb .	Our Rheb overexpression data are consistent with this hypothesis, because mTOR signaling in Rab5CA expressing cells is not rescued by constitutive hyperactivation of endogenous Rheb in TSC2-/- MEFs, but is rescued by overexpression of Rheb.	11	37	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	36	37	11	12
A recent study examining both signaling pathways found that ketamine increased BDNF by generating nitric oxide , leading to the stabilization of Nitrergic Rheb , a small G protein that enhances mTOR signaling .	A recent study examining both signaling pathways found that ketamine increased BDNF by generating nitric oxide, leading to the stabilization of Nitrergic Rheb, a small G protein that enhances mTOR signaling.	20	32	enhances	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	23	24	31	32
In the endomembrane , Rheb , which is a Ras related GTP protein , activates mTOR , although the detailed mechanism of its action remains unclear .	In the endomembrane, Rheb, which is a Ras related GTP protein, activates mTOR, although the detailed mechanism of its action remains unclear.	4	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	4	5	15	16
mTORC1 activity is negatively regulated by the TSC1/2 complex , which inhibits Ras homologue enriched in brain ( Rheb ) , a small guanosine triphosphatase ( GTPase ) that activates mTOR , via its GTPase activating protein ( GAP ) activity .	mTORC1 activity is negatively regulated by the TSC1/2 complex, which inhibits Ras homologue enriched in brain (Rheb), a small guanosine triphosphatase (GTPase) that activates mTOR, via its GTPase activating protein (GAP) activity.	16	36	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	18	19	30	31
To investigate whether the DDIT4 and mTOR signaling pathway is involved in regulating the proliferation of RMCs treated with 1,25 ( OH ) 2 D 3 , we examined the expression of VDR , DDIT4 , TSC1 and TSC2 , the mTOR mediator Rheb , mTOR , and its downstream proteins 4E-BP1 and p70S6K by Western blot .	To investigate whether the DDIT4 and mTOR signaling pathway is involved in regulating the proliferation of RMCs treated with 1,25 (OH) 2 D 3, we examined the expression of VDR, DDIT4, TSC1 and TSC2, the mTOR mediator Rheb, mTOR, and its downstream proteins 4E-BP1 and p70S6K by Western blot.	41	45	mediator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	43	44	41	42
While Rce1- and Icmt catalyzed modifications were required for proper Rheb localization , surprisingly , they were dispensable for Rheb mediated activation of mTOR .	While Rce1- and Icmt catalyzed modifications were required for proper Rheb localization, surprisingly, they were dispensable for Rheb mediated activation of mTOR.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	19	20	23	24
As mTOR is an inhibitor of autophagy 121 , and RHEB activates mTOR , it may not be surprising that FTIs can induce autophagy , possibly by blocking RHEB function 122 .	As mTOR is an inhibitor of autophagy 121, and RHEB activates mTOR, it may not be surprising that FTIs can induce autophagy, possibly by blocking RHEB function 122.	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	10	11	12	13
The Rheb mediated activation of mTOR conferred marginal protection against PEITC mediated cleavage of LC3 .	The Rheb mediated activation of mTOR conferred marginal protection against PEITC mediated cleavage of LC3.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	1	2	5	6
However , evidence exists that Rheb2 can also activate mTOR .	However, evidence exists that Rheb2 can also activate mTOR.	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb2	Rheb2	Rheb2	mTOR	mTOR	mTOR	5	6	9	10
Collectively , these in vitro studies demonstrate a link between two pathways that regulate mTOR , PLD/PA and TSC2 and Rheb , and provide further insight into a mechanism by which Rheb activates mTOR .	Collectively, these in vitro studies demonstrate a link between two pathways that regulate mTOR, PLD/PA and TSC2 and Rheb, and provide further insight into a mechanism by which Rheb activates mTOR.	31	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	31	32	33	34
The effect of Akt on mTOR is indirect : Akt inhibits the tuberous sclerosis complex ( TSC ) proteins 1 and 2 , which act as a GTPase activating protein ( GAP ) to inhibit the small G protein Ras homolog enriched in brain ( Rheb ) which activates mTOR signaling .	The effect of Akt on mTOR is indirect : Akt inhibits the tuberous sclerosis complex (TSC) proteins 1 and 2, which act as a GTPase activating protein (GAP) to inhibit the small G protein Ras homolog enriched in brain (Rheb) which activates mTOR signaling.	39	50	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	mTOR	mTOR	mTOR	39	44	49	50
This mechanism results in spatial separation and thus dissociation of TSC2 from lysosome and reliefs the inhibitory effect of TSC2 on the mTOR activator Rheb , leading to activation of mTORC1-S6K1 signaling .	This mechanism results in spatial separation and thus dissociation of TSC2 from lysosome and reliefs the inhibitory effect of TSC2 on the mTOR activator Rheb, leading to activation of mTORC1-S6K1 signaling.	19	25	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	24	25	22	23
This explains why overexpressed Rheb activates mTOR in the absence of amino acids ; presumably the Rheb-mTOR interaction is driven by mass action in this case , and no longer requires the amino acid stimulated movement of mTOR to late endosomes .	This explains why overexpressed Rheb activates mTOR in the absence of amino acids; presumably the Rheb-mTOR interaction is driven by mass action in this case, and no longer requires the amino acid stimulated movement of mTOR to late endosomes.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	4	5	6	7
Akt activation leads to phosphorylation and inhibition of tuberous sclerosis protein complex , which in turn results in subsequent engagement of Ras homolog enriched in brain to activate mTOR .	Akt activation leads to phosphorylation and inhibition of tuberous sclerosis protein complex, which in turn results in subsequent engagement of Ras homolog enriched in brain to activate mTOR.	21	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	mTOR	mTOR	mTOR	21	26	28	29
Mechanistically , the TSC2 subunit serves as a GTPase activating protein ( GAP ) for the small GTPase protein Rheb , which activates the mTOR when it is GTP bound [ XREF_BIBR , XREF_BIBR ] .	Mechanistically, the TSC2 subunit serves as a GTPase activating protein (GAP) for the small GTPase protein Rheb, which activates the mTOR when it is GTP bound [XREF_BIBR, XREF_BIBR].	18	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	19	20	24	25
Since RHEB is the canonical activator of mTOR , this finding is consistent with other reports that have highlighted mTOR as a main regulator of cell size XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Since RHEB is the canonical activator of mTOR, this finding is consistent with other reports that have highlighted mTOR as a main regulator of cell size XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	1	8	is the canonical activator	Positive_activation_copula_1	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	1	2	7	8
Rheb is an activator of mTOR .	Rheb is an activator of mTOR.	0	6	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	5	6
The activation of Rheb allows mTor to be activated through association with raptor and other TORC1 complex members , stimulating TOR dependent mRNA translation through p70S6Kinase , and cap dependent translation thorough inhibition of the eiF4e repressor , 4E-BP .	The activation of Rheb allows mTor to be activated through association with raptor and other TORC1 complex members, stimulating TOR dependent mRNA translation through p70S6Kinase, and cap dependent translation thorough inhibition of the eiF4e repressor, 4E-BP.	1	8	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTor	mTor	mTor	3	4	5	6
To determine whether Rheb could induce activation of mTOR in DRG neurons , we transduced cultured adult DRG neurons using wtRheb-lentivirus .	To determine whether Rheb could induce activation of mTOR in DRG neurons, we transduced cultured adult DRG neurons using wtRheb-lentivirus.	3	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	3	4	8	9
RHEB stimulates the protein kinase mTOR , which results in activating phosphorylation of the mTOR substrates S6 kinase ( S6K ) and eukaryotic translation initiation factor 4E binding protein 1 ( 4EBP1 ) XREF_BIBR , XREF_BIBR , which is consistent with RHEB being essential for cell growth and cell cycle progression in D. melanogaster 116 .	RHEB stimulates the protein kinase mTOR, which results in activating phosphorylation of the mTOR substrates S6 kinase (S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) XREF_BIBR, XREF_BIBR, which is consistent with RHEB being essential for cell growth and cell cycle progression in D. melanogaster 116.	0	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	0	1	5	6
Rheb is unique among members of the small GTPase family in that the regulation of its function occurs predominately through its inactivation by Rheb GAPs ( e.g ., TSC2 ) rather than its activation by Rheb guanidine exchange factors ( GEFs ) ; thus , overexpression of Rheb bypasses the requirement for PI3K activation of Akt to promote mTOR activity .	Rheb is unique among members of the small GTPase family in that the regulation of its function occurs predominately through its inactivation by Rheb GAPs (e.g., TSC2) rather than its activation by Rheb guanidine exchange factors (GEFs); thus, overexpression of Rheb bypasses the requirement for PI3K activation of Akt to promote mTOR activity.	45	59	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	47	48	58	59
115 Moreover , RHEB mediation of mTOR activity is necessary for OPC differentiation into myelinating OLs .	115 Moreover, RHEB mediation of mTOR activity is necessary for OPC differentiation into myelinating OLs.	3	7	mediation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	3	4	6	7
AAV mediated transduction of SN dopamine neurons with constitutively active forms of the kinase Akt or the GTPase Rheb , both of which stimulate mTor activity , induces long-range growth that reaches striatal target and restores function .	AAV mediated transduction of SN dopamine neurons with constitutively active forms of the kinase Akt or the GTPase Rheb, both of which stimulate mTor activity, induces long-range growth that reaches striatal target and restores function.	1	35	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTor	mTor	mTor	18	19	24	25
Together , these results indicate that overexpression of Rheb induces mTOR signaling through a PI3K independent mechanism in C2C12 myoblasts .	Together, these results indicate that overexpression of Rheb induces mTOR signaling through a PI3K independent mechanism in C2C12 myoblasts.	6	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	8	9	10	11
In this study , we demonstrate that the overexpression of Rheb induces mTOR signaling through a PI3K and PKB independent mechanism and that this event is sufficient to induce a robust and cell autonomous hypertrophic response .	In this study, we demonstrate that the overexpression of Rheb induces mTOR signaling through a PI3K and PKB independent mechanism and that this event is sufficient to induce a robust and cell autonomous hypertrophic response.	8	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	10	11	12	13
Activated Rheb stimulates mTOR complex 1 ( mTORC1 ) that finally leads to an enhancement of general translation with an increase in protein synthesis and cell growth .	Activated Rheb stimulates mTOR complex 1 (mTORC1) that finally leads to an enhancement of general translation with an increase in protein synthesis and cell growth.	0	4	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	1	2	3	4
To determine whether the direct activation of mTOR by Rheb also enhances axonal growth capacity in vitro , we cultured DRG neurons from adult rats and measured axonal outgrowth 3 days following Rheb or GFP lentiviral transduction ( XREF_FIG ) .	To determine whether the direct activation of mTOR by Rheb also enhances axonal growth capacity in vitro, we cultured DRG neurons from adult rats and measured axonal outgrowth 3 days following Rheb or GFP lentiviral transduction (XREF_FIG).	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	9	10	7	8
Rheb activates mTOR by antagonizing its endogenous inhibitor , FKBP38 , though this remains controversial .	Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38, though this remains controversial.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	2	3
We have studied whether Rheb is sufficient to activate mTOR signaling and promote protein synthesis and cardiac hypertrophy in adult rat ventricular cardiomyocytes ( ARVC ) .	We have studied whether Rheb is sufficient to activate mTOR signaling and promote protein synthesis and cardiac hypertrophy in adult rat ventricular cardiomyocytes (ARVC).	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	4	5	9	10
Rheb can activate mTOR signaling pathway and participate in genesis and development of multiple cancers .	Rheb can activate mTOR signaling pathway and participate in genesis and development of multiple cancers.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	3	4
At the lysosome surface , the small GTPase Rheb activates mTOR , and active mTORC1 promotes anabolic processes and inhibits autophagy [ XREF_BIBR ] .	At the lysosome surface, the small GTPase Rheb activates mTOR, and active mTORC1 promotes anabolic processes and inhibits autophagy [XREF_BIBR].	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	10	11
Rheb leads to activation of mTOR through an unknown mechanism .	Rheb leads to activation of mTOR through an unknown mechanism.	0	6	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	5	6
To determine whether the overexpression of Rheb could induce mTOR signaling in adult skeletal muscle in vivo , mouse TA muscles were transfected with Rheb , or GFP as a control condition , and the phosphorylation of the ribosomal S6 ( S6 ) protein on the Ser235/236 residues ( P-S6 ) was evaluated as a marker of mTOR signaling .	To determine whether the overexpression of Rheb could induce mTOR signaling in adult skeletal muscle in vivo, mouse TA muscles were transfected with Rheb, or GFP as a control condition, and the phosphorylation of the ribosomal S6 (S6) protein on the Ser235/236 residues (P-S6) was evaluated as a marker of mTOR signaling.	4	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	6	7	9	10
Recent studies have shown that an mTOR containing complex , mTORC1 , is targeted to lysosomes in the presence of amino acids and activated by Rheb GTPase resident in that compartment .	Recent studies have shown that an mTOR containing complex, mTORC1, is targeted to lysosomes in the presence of amino acids and activated by Rheb GTPase resident in that compartment.	5	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	25	26	6	7
Ras homolog enriched in brain ( Rheb ) is a direct activator of mTOR and was shown to activate the mTOR pathway in many studies .	Ras homolog enriched in brain (Rheb) is a direct activator of mTOR and was shown to activate the mTOR pathway in many studies.	0	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	mTOR	mTOR	mTOR	0	5	20	21
Previous studies have shown that the small GTPase Rheb increases mTOR activity by sequestering the mTOR inhibitor FKBP-38 .	Previous studies have shown that the small GTPase Rheb increases mTOR activity by sequestering the mTOR inhibitor FKBP-38.	5	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	10	11
Skeletal muscle overexpression of Rheb increased mTOR mediated kinase events resulting in increased skeletal muscle size and protein translation independent of PI3-kinase and PKB ( AKT ) [ XREF_BIBR ] .	Skeletal muscle overexpression of Rheb increased mTOR mediated kinase events resulting in increased skeletal muscle size and protein translation independent of PI3-kinase and PKB (AKT) [XREF_BIBR].	2	7	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	4	5	6	7
Furthermore , p38 has been shown to phosphorylate Raptor on the S863 residue in response to aresnite , and the activation of mTOR by Rheb overexpression is associated with an increase in S696 , T706 , and S863 phosphorylation [ XREF_BIBR , XREF_BIBR ] .	Furthermore, p38 has been shown to phosphorylate Raptor on the S863 residue in response to aresnite, and the activation of mTOR by Rheb overexpression is associated with an increase in S696, T706, and S863 phosphorylation [XREF_BIBR, XREF_BIBR].	20	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rheb	Rheb overexpression	rheb	mTOR	mTOR	mtor	24	25	22	23
Furthermore , the intracellular levels of free Mg 2+ might play a crucial role in the regulation of the activities of the principal mTOR modulators such as Rheb and Rag GTPases [ XREF_BIBR - XREF_BIBR ] .	Furthermore, the intracellular levels of free Mg 2+ might play a crucial role in the regulation of the activities of the principal mTOR modulators such as Rheb and Rag GTPases [XREF_BIBR - XREF_BIBR].	23	30	modulators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	27	28	23	24
mTOR activation by constitutively active Rheb alters circadian rhythms in hepatocytes .	mTOR activation by constitutively active Rheb alters circadian rhythms in hepatocytes.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	5	6	0	1
Experimental data linking mutations to critical residues in the proteins suggests that Rheb is only able to activate mTOR when in its GTP bound state .	Experimental data linking mutations to critical residues in the proteins suggests that Rheb is only able to activate mTOR when in its GTP bound state.	12	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	12	13	18	19
In addition to its potential direct activation of mTOR , Rheb may indirectly stimulate mTOR through its ability to bind and activate phospholipase D ( PLD ) .	In addition to its potential direct activation of mTOR, Rheb may indirectly stimulate mTOR through its ability to bind and activate phospholipase D (PLD).	10	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	10	11	14	15
Rheb activates mTOR by antagonizing its endogenous inhibitor , FKBP38 [ XREF_BIBR ] , though this remains controversial [ XREF_BIBR ] .	Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38 [XREF_BIBR], though this remains controversial [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	2	3
Renal mTOR activation in poorly controlled diabetes may result from a combination of AKT inhibition of tuberous sclerosis complex 2 , hyperglycemia induced AMPK inhibition , and increased glucose uptake through glucose transporter 1 , in which the resulting increased glycolysis and activation of GAPDH can lead directly to Rheb activation of mTOR by reducing Rheb binding to GAPDH .	Renal mTOR activation in poorly controlled diabetes may result from a combination of AKT inhibition of tuberous sclerosis complex 2, hyperglycemia induced AMPK inhibition, and increased glucose uptake through glucose transporter 1, in which the resulting increased glycolysis and activation of GAPDH can lead directly to Rheb activation of mTOR by reducing Rheb binding to GAPDH.	49	53	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	49	50	52	53
The satiety hormone leptin may also be regulated by miR-155 : Adipocyte leptin expression is elevated by Rheb mediated mTOR activation XREF_BIBR .	The satiety hormone leptin may also be regulated by miR-155 : Adipocyte leptin expression is elevated by Rheb mediated mTOR activation XREF_BIBR.	15	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	17	18	19	20
Thus , when insulin and IGFs are present , TSC is inactive , and Rheb retains GTP and activates mTOR .	Thus, when insulin and IGFs are present, TSC is inactive, and Rheb retains GTP and activates mTOR.	14	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	14	15	19	20
It has recently been shown that Rheb activates mTOR by binding to its endogenous inhibitor FKBP38 and preventing it from association with mTOR .	It has recently been shown that Rheb activates mTOR by binding to its endogenous inhibitor FKBP38 and preventing it from association with mTOR.	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	6	7	8	9
However , Rheb mediated activation of mTOR did not impart a meaningful protection against BITC induced cleavage of LC3 ( XREF_FIG ) , LC3 puncta ( XREF_FIG ) or cell growth inhibition ( XREF_FIG ) .	However, Rheb mediated activation of mTOR did not impart a meaningful protection against BITC induced cleavage of LC3 (XREF_FIG), LC3 puncta (XREF_FIG) or cell growth inhibition (XREF_FIG).	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	2	3	6	7
Ectopic expression of Rheb in PC-3 cells resulted in activation of mTOR as evidenced by about 3.1-fold increase in T389 phosphorylation of its downstream target p70s6k ( supplemental Fig .	Ectopic expression of Rheb in PC-3 cells resulted in activation of mTOR as evidenced by about 3.1-fold increase in T389 phosphorylation of its downstream target p70s6k (supplemental Fig.	1	12	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Rheb	expression of Rheb	rheb	mTOR	mTOR	mtor	3	4	11	12
TSC1 and TSC2 form a complex that inhibits Rheb directed mTOR activation through a GTPase activating protein ( GAP ) domain in the TSC2 C terminus .	TSC1 and TSC2 form a complex that inhibits Rheb directed mTOR activation through a GTPase activating protein (GAP) domain in the TSC2 C terminus.	7	11	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	10	11
As Rheb , in turn , activates mTOR , the TSC genes function to dampen down mTOR signaling pathway activity , and , given the role of mTOR in stimulating cell growth and proliferation , normally prevent excessive growth and proliferation .	As Rheb, in turn, activates mTOR, the TSC genes function to dampen down mTOR signaling pathway activity, and, given the role of mTOR in stimulating cell growth and proliferation, normally prevent excessive growth and proliferation.	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	1	2	7	8
Protein mTOR complex 1 ( mTORC1 ) functions as a major sensor for the nutrient , energy , and redox state of a cell and is activated by ras homolog enriched in brain ( RHEB1 ) , a GTP binding protein .	Protein mTOR complex 1 (mTORC1) functions as a major sensor for the nutrient, energy, and redox state of a cell and is activated by ras homolog enriched in brain (RHEB1), a GTP binding protein.	1	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ras homolog enriched in brain	ras homolog enriched in brain	ras homolog enriched in brain	mTOR	mTOR	mTOR	28	33	1	2
The pathway from PI-3 kinase to TOR is well described , proceeding through Akt inhibition of the Tuberous Sclerosis complex , a GTPase activating protein for the ras like GTPase Rheb , and Rheb activation of mTOR complex 1 .	The pathway from PI-3 kinase to TOR is well described, proceeding through Akt inhibition of the Tuberous Sclerosis complex, a GTPase activating protein for the ras like GTPase Rheb, and Rheb activation of mTOR complex 1.	33	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	33	34	36	37
mTOR can be activated by RHEB either on the surface of the peroxisome [ XREF_BIBR ]-in response to reactive oxygen species ( ROS )-or on the surface the lysosome [ XREF_BIBR ]-in response to amino acids .	mTOR can be activated by RHEB either on the surface of the peroxisome [XREF_BIBR]-in response to reactive oxygen species (ROS)-or on the surface the lysosome [XREF_BIBR]-in response to amino acids.	0	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	5	6	0	1
This dissociation reduces the inhibitory function of the TSC1 and TSC2 complex on GTPase Rheb thus enabling the activation of the mTOR complex 1 .	This dissociation reduces the inhibitory function of the TSC1 and TSC2 complex on GTPase Rheb thus enabling the activation of the mTOR complex 1.	11	22	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	14	15	21	22
Rheb activates mTOR , while the TSC1 and TSC2 complex , by inhibiting Rheb , avidly inhibits mTOR and therefore prevents protein synthesis .	Rheb activates mTOR, while the TSC1 and TSC2 complex, by inhibiting Rheb, avidly inhibits mTOR and therefore prevents protein synthesis.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	2	3
On the other hand , ATF6 activation is crucial to long-term survival of tumors by augmenting resistance to chemotherapy , nutrient starvation and stress in quiescent squamous carcinoma cells , where ATF6 increases Rheb expression , which in turn activates mTOR activity in an Akt independent manner .	On the other hand, ATF6 activation is crucial to long-term survival of tumors by augmenting resistance to chemotherapy, nutrient starvation and stress in quiescent squamous carcinoma cells, where ATF6 increases Rheb expression, which in turn activates mTOR activity in an Akt independent manner.	33	41	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	33	34	40	41
Nitrosylated GAPDH complexes with the ubiquitin-E3-ligase Siah1 and Rheb , a small G protein that activates mTOR .	Nitrosylated GAPDH complexes with the ubiquitin-E3-ligase Siah1 and Rheb, a small G protein that activates mTOR.	0	17	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	16	17
mTOR activity is upregulated by Rheb ( Ras homology enriched in brain ) , a Ras GTPase superfamily member that acts to promote cell growth .	mTOR activity is upregulated by Rheb (Ras homology enriched in brain), a Ras GTPase superfamily member that acts to promote cell growth.	0	18	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	5	6	0	1
In the absence of polycystin-1 , disinhibition of Rheb results in activation of mTOR and increased cell growth .	In the absence of polycystin-1, disinhibition of Rheb results in activation of mTOR and increased cell growth.	8	14	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	13	14
Rheb modulates the mTOR complex and controls protein synthesis via the phosphorylation of 4E-BP1 and S6 .	Rheb modulates the mTOR complex and controls protein synthesis via the phosphorylation of 4E-BP1 and S6.	0	6	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	3	4
Instead , we found that FTS blocked Rheb activation of mTOR , but this effect was independent of inhibition of Rheb or of any other prenylated protein .	Instead, we found that FTS blocked Rheb activation of mTOR, but this effect was independent of inhibition of Rheb or of any other prenylated protein.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	7	8	10	11
In conclusion , dissociation of PRAS40 from mTORC1 and enhanced mTORC1 substrate binding results from Akt and mTORC1 activation and makes little or no contribution to mTORC1 signaling , which rather is determined by Rheb activation of mTOR catalytic activity , through mechanisms that remain to be fully elucidated .	In conclusion, dissociation of PRAS40 from mTORC1 and enhanced mTORC1 substrate binding results from Akt and mTORC1 activation and makes little or no contribution to mTORC1 signaling, which rather is determined by Rheb activation of mTOR catalytic activity, through mechanisms that remain to be fully elucidated.	34	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	34	35	37	38
Though Rheb is well known to activate mTOR , the physiologic rationale for this action has not been altogether clear .	Though Rheb is well known to activate mTOR, the physiologic rationale for this action has not been altogether clear.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	1	2	7	8
Furthermore , studies in nonskeletal muscle cells have shown that Rheb activates mTOR through a PI3K and PKB independent mechanism .	Furthermore, studies in nonskeletal muscle cells have shown that Rheb activates mTOR through a PI3K and PKB independent mechanism.	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	10	11	12	13
Rheb activates mTOR by antagonizing its endogenous inhibitor , FK506 binding protein 38 ( FKBP38 ) [ XREF_BIBR ] , though this remains controversial [ XREF_BIBR ] .	Rheb activates mTOR by antagonizing its endogenous inhibitor, FK506 binding protein 38 (FKBP38) [XREF_BIBR], though this remains controversial [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	2	3
Additionally , PLD1 , but not PLD2 , was shown to be required for the activation of mTOR by Rheb [ XREF_BIBR ] .	Additionally, PLD1, but not PLD2, was shown to be required for the activation of mTOR by Rheb [XREF_BIBR].	15	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	19	20	17	18
When the TSC complex is inhibited by AKT , RHEB activates mTOR [ XREF_BIBR ] .	When the TSC complex is inhibited by AKT, RHEB activates mTOR [XREF_BIBR].	9	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	9	10	11	12
Rheb CA expression increases mTOR activity in newborn neurons in vivo .	Rheb CA expression increases mTOR activity in newborn neurons in vivo.	0	5	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb CA expression	rheb	mTOR	mTOR	mtor	0	1	4	5
Rheb is a small GTP binding protein that activates mTOR in its GTP bound form , whereas Rheb and PI3K converge to activate mTOR to stimulate cell growth and inhibit autophagy XREF_BIBR .	Rheb is a small GTP binding protein that activates mTOR in its GTP bound form, whereas Rheb and PI3K converge to activate mTOR to stimulate cell growth and inhibit autophagy XREF_BIBR.	17	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	17	18	23	24
When Rheb is in its GTP bound form , it directly interacts with and activates mTORC1 , but the exact mechanism by which Rheb activates mTOR is unclear .	When Rheb is in its GTP bound form, it directly interacts with and activates mTORC1, but the exact mechanism by which Rheb activates mTOR is unclear.	23	26	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	23	24	25	26
TSC1 functions together with TSC2 as an inhibitor of mTOR by maintaining the mTOR activator RHEB in an inactive state .	TSC1 functions together with TSC2 as an inhibitor of mTOR by maintaining the mTOR activator RHEB in an inactive state.	11	16	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	15	16	13	14
It therefore seems possible that WSSV might likewise express one or more viral proteins that functionally replace the mTOR activator Rheb or otherwise activate the mTOR pathway .	It therefore seems possible that WSSV might likewise express one or more viral proteins that functionally replace the mTOR activator Rheb or otherwise activate the mTOR pathway.	16	21	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	20	21	18	19
Rheb activates mTOR pathway .	Rheb activates mTOR pathway.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	2	3
Activated Akt inhibits TSC ( tuberous sclerosis complex ) 1/2 , thereby relieving its inhibition of Rheb ( Ras homologue enriched in brain ) , allowing Rheb activation of mTOR .	Activated Akt inhibits TSC (tuberous sclerosis complex) 1/2, thereby relieving its inhibition of Rheb (Ras homologue enriched in brain), allowing Rheb activation of mTOR.	26	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	26	27	29	30
XREF_BIBR Exogenous expression of Rheb enhanced phosphorylation of mTOR effectors S6K and 4E-BP1 in a rapamycin dependent manner , while co-expression of Rheb with TSC2 : TSC1attentuates Rheb mediated mTOR activation .	XREF_BIBR Exogenous expression of Rheb enhanced phosphorylation of mTOR effectors S6K and 4E-BP1 in a rapamycin dependent manner, while co-expression of Rheb with TSC2 : TSC1attentuates Rheb mediated mTOR activation.	26	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	27	28	29	30
Rheb has been shown to bind directly to the kinase domain of mTOR and activate mTOR kinase activity in a GTP dependent manner [ XREF_BIBR ] .	Rheb has been shown to bind directly to the kinase domain of mTOR and activate mTOR kinase activity in a GTP dependent manner [XREF_BIBR].	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	15	16
Moreover , genes that negatively regulate the mammalian target of rapamycin ( mTOR ) , the main regulator of autophagy , such as AMPK , LKB1 , PTEN and TSC1/2 induce autophagy while , conversely , oncogenes that promote mTOR signaling , such as class I PI3K , AKT , Ras and RHEB inhibit autophagy [ XREF_BIBR , XREF_BIBR ] .	Moreover, genes that negatively regulate the mammalian target of rapamycin (mTOR), the main regulator of autophagy, such as AMPK, LKB1, PTEN and TSC1/2 induce autophagy while, conversely, oncogenes that promote mTOR signaling, such as class I PI3K, AKT, Ras and RHEB inhibit autophagy [XREF_BIBR, XREF_BIBR].	39	53	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	52	53	39	40
In contrast , although Rce and Icmt were required for proper Rheb localization , neither of the post-prenyl processing steps was required for Rheb induced mTOR activation .	In contrast, although Rce and Icmt were required for proper Rheb localization, neither of the post-prenyl processing steps was required for Rheb induced mTOR activation.	23	26	induced	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	23	24	25	26
The results indicated that overexpression of Rheb induces a significant increase in mTOR signaling in skeletal muscle myoblasts ( XREF_FIG ) .	The results indicated that overexpression of Rheb induces a significant increase in mTOR signaling in skeletal muscle myoblasts (XREF_FIG).	4	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	mTOR	mTOR	mtor	6	7	12	13
Tuberous sclerosis complexes ( TSCs ) normally inhibit Rheb directed mTOR activation , and mutations in TSC proteins ( TSC1-hamartin , TSC2-tuberin ) constitutively activate Rheb-mTOR-pS6K and increase cell size .	Tuberous sclerosis complexes (TSCs) normally inhibit Rheb directed mTOR activation, and mutations in TSC proteins (TSC1-hamartin, TSC2-tuberin) constitutively activate Rheb-mTOR-pS6K and increase cell size.	8	11	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	10	11
When free of TSC1/2 , RHEB activates mTOR within a rapamycin sensitive protein complex called mTORC1 .	When free of TSC1/2, RHEB activates mTOR within a rapamycin sensitive protein complex called mTORC1.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	5	6	7	8
Rheb mediates the activation of mTOR 20 , and mTOR is activated in Notch dependent malignancies 65 , and therefore this study suggests a potential role for the Rheb-Notch-Rheb loop in mTOR activation in non TSC malignancies without identified TSC1/2 mutations .	Rheb mediates the activation of mTOR 20, and mTOR is activated in Notch dependent malignancies 65, and therefore this study suggests a potential role for the Rheb-Notch-Rheb loop in mTOR activation in non TSC malignancies without identified TSC1/2 mutations.	0	6	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	5	6
When in its GTP bound state , Rheb has been reported to directly activate mTOR signaling .	When in its GTP bound state, Rheb has been reported to directly activate mTOR signaling.	7	15	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	7	8	14	15
mTOR is activated by the GTPase Rheb which in turn is controlled by the TSC1 and TSC2 complex .	mTOR is activated by the GTPase Rheb which in turn is controlled by the TSC1 and TSC2 complex.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	6	7	0	1
AKT promotes activation of the Rheb small GTPase , which then activates mTOR , a protein that is involved in growth factor signaling , the energy state of the cell , and nutrient and oxygen availability .	AKT promotes activation of the Rheb small GTPase, which then activates mTOR, a protein that is involved in growth factor signaling, the energy state of the cell, and nutrient and oxygen availability.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	5	6	12	13
Growth factor deprivation leads to inactivation of Akt protein kinase , activation of tuberous sclerosis 1/2 ( TSC1/2 ) , and inactivation of Rheb , thus attenuated Rheb activation of mTOR XREF_BIBR .	Growth factor deprivation leads to inactivation of Akt protein kinase, activation of tuberous sclerosis 1/2 (TSC1/2), and inactivation of Rheb, thus attenuated Rheb activation of mTOR XREF_BIBR.	27	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	27	28	30	31
Importantly , it has subsequently been demonstrated in cultured HEK293 cells that PLD1 is also essential for Rheb activation of mTOR signaling .	Importantly, it has subsequently been demonstrated in cultured HEK293 cells that PLD1 is also essential for Rheb activation of mTOR signaling.	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	17	18	20	21
To determine whether the Rheb induced mTOR signaling through a PI3K dependent mechanism , the PI3K inhibitor wortmannin was used .	To determine whether the Rheb induced mTOR signaling through a PI3K dependent mechanism, the PI3K inhibitor wortmannin was used.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	4	5	6	7
Overexpression of Rheb activates mTOR signaling via a PI3K and PKB independent mechanism and is sufficient to induce skeletal muscle hypertrophy .	Overexpression of Rheb activates mTOR signaling via a PI3K and PKB independent mechanism and is sufficient to induce skeletal muscle hypertrophy.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Overexpression of Rheb	rheb	mTOR	mTOR	mtor	2	3	4	5
Since it remained possible that FTS may disrupt Rheb interaction with mTOR , we next asked if FTS inhibits Rheb induced activation of mTOR .	Since it remained possible that FTS may disrupt Rheb interaction with mTOR, we next asked if FTS inhibits Rheb induced activation of mTOR.	19	24	induced	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	19	20	23	24
Combined , these results indicate that 1 ) Rheb induces hypertrophy through a rapamycin sensitive mechanism , 2 ) mTOR is the rapamycin sensitive element in skeletal muscle that confers Rheb induced hypertrophy , and 3 ) mTOR kinase activity is necessary for the Rheb induced hypertrophic response .	Combined, these results indicate that 1) Rheb induces hypertrophy through a rapamycin sensitive mechanism, 2) mTOR is the rapamycin sensitive element in skeletal muscle that confers Rheb induced hypertrophy, and 3) mTOR kinase activity is necessary for the Rheb induced hypertrophic response.	8	39	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	37	38
RHEB GTP activates mTOR ( mammalian target of rapamycin ) .	RHEB GTP activates mTOR (mammalian target of rapamycin).	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	0	1	3	4
RHEB promotes allosteric activation of mTOR whereas PRAS40 blocks substrate recruitment sites .	RHEB promotes allosteric activation of mTOR whereas PRAS40 blocks substrate recruitment sites.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	0	1	5	6
Hamartin and tuberin are involved in the regulation of cell proliferation and differentiation , forming a physical and functional complex that activates GTPase , keeping the protein Ras homolog enriched in brain protein ( RHEB ) inactive in order to inhibit the mammalian target of rapamycin ( mTOR ) pathway .	Hamartin and tuberin are involved in the regulation of cell proliferation and differentiation, forming a physical and functional complex that activates GTPase, keeping the protein Ras homolog enriched in brain protein (RHEB) inactive in order to inhibit the mammalian target of rapamycin (mTOR) pathway.	27	46	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	27	32	42	46
Rheb activates mTOR pathway in 293T cells and DRG .	Rheb activates mTOR pathway in 293T cells and DRG.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	2	3
To our surprise , Rheb mediated activation of mTOR fails to confer any protection against cell killing or apoptotic DNA fragmentation by BITC ( Singh SV , unpublished observations ) in either MDA-MB-231 or MCF-7 cells .	To our surprise, Rheb mediated activation of mTOR fails to confer any protection against cell killing or apoptotic DNA fragmentation by BITC (Singh SV, unpublished observations) in either MDA-MB-231 or MCF-7 cells.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	4	5	8	9
Akt phosphorylation inactivates the tuberous sclerosis complex ( TSC ) formed by hamartin ( TSC1 ) and tuberin , leading to accumulation of the GTP bound form of the small G protein Rheb that activates mTOR .	Akt phosphorylation inactivates the tuberous sclerosis complex (TSC) formed by hamartin (TSC1) and tuberin, leading to accumulation of the GTP bound form of the small G protein Rheb that activates mTOR.	26	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	32	33	35	36
Both mTOR complexes are stimulated by Ras homolog enriched in brain ( RHEB ) which is downstream from insulin , growth factor and nutrient signaling pathways .	Both mTOR complexes are stimulated by Ras homolog enriched in brain (RHEB) which is downstream from insulin, growth factor and nutrient signaling pathways.	1	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	mTOR	mTOR	mTOR	6	11	1	2
Taken together , these data suggest that Rheb activation of mTOR is more dependent on farnesylation than on Rce1- and Icmt catalyzed modifications .	Taken together, these data suggest that Rheb activation of mTOR is more dependent on farnesylation than on Rce1- and Icmt catalyzed modifications.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	7	8	10	11
Overexpression of Rheb due to a TSC1 or TSC2 mutation leads to increased mTOR activation and excessive cell growth and proliferation .	Overexpression of Rheb due to a TSC1 or TSC2 mutation leads to increased mTOR activation and excessive cell growth and proliferation.	0	14	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Rheb	Overexpression of Rheb	rheb	mTOR	mTOR	mtor	2	3	13	14
A number of studies establish that one of the functions of Rheb is to activate mTOR leading to growth .	A number of studies establish that one of the functions of Rheb is to activate mTOR leading to growth.	9	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	11	12	15	16
However , it had also been concluded that Rheb is necessary for amino acids to activate mTOR signaling .	However, it had also been concluded that Rheb is necessary for amino acids to activate mTOR signaling.	8	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	8	9	16	17
These scenarios demonstrate how signals transduced through the TSC are mediated by Rheb to affect mTOR , although the precise interactions between Rheb and mTOR have not yet been entirely elucidated .	These scenarios demonstrate how signals transduced through the TSC are mediated by Rheb to affect mTOR, although the precise interactions between Rheb and mTOR have not yet been entirely elucidated.	10	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	12	13	15	16
Rheb ( Ras homolog enriched in brain ) , a GTP binding protein , is a key activator of mTOR and is inhibited by Rheb-GTPase-activating protein ( GAP ) .	Rheb (Ras homolog enriched in brain), a GTP binding protein, is a key activator of mTOR and is inhibited by Rheb-GTPase-activating protein (GAP).	0	22	is a key activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	0	1	19	20
Overexpression of the small G protein rheb , which greatly enhances mTOR signaling , markedly increased EGFP-HDQ74 aggregates and cell death in COS-7 cells ( XREF_FIG E ) .	Overexpression of the small G protein rheb, which greatly enhances mTOR signaling, markedly increased EGFP-HDQ74 aggregates and cell death in COS-7 cells (XREF_FIG E).	0	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	rheb	Overexpression of the small G protein rheb	rheb	mTOR	mTOR	mtor	6	7	11	12
Although Rheb2 can activate mTor when over expressed in vitro , Rheb2 is not required for organismal viability , and is not essential for mTORC1 or mTORC2 signaling , or myelination ( XREF_SUPPLEMENTARY ) in brain .	Although Rheb2 can activate mTor when over expressed in vitro, Rheb2 is not required for organismal viability, and is not essential for mTORC1 or mTORC2 signaling, or myelination (XREF_SUPPLEMENTARY) in brain.	1	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb2	Rheb2	Rheb2	mTor	mTor	mTor	1	2	4	5
Both Rheb1 and Rheb2 transgenes can activate mTor in heterologous cells .	Both Rheb1 and Rheb2 transgenes can activate mTor in heterologous cells.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb2	Rheb2	Rheb2	mTor	mTor	mTor	3	4	7	8
This conclusion is reinforced by supplementary data from two studies : mice with a neo-insertion in an Mtor intron that decreases Mtor mRNA approximately 70 % show a similar selective lowering of CD44 on CD4 + T cells and CD44 levels are also reduced on naive , CD62L positive T cells that are deficient for the mTOR activator Rheb or deficient for the mTOR interacting protein Rictor .	This conclusion is reinforced by supplementary data from two studies : mice with a neo-insertion in an Mtor intron that decreases Mtor mRNA approximately 70% show a similar selective lowering of CD44 on CD4 + T cells and CD44 levels are also reduced on naive, CD62L positive T cells that are deficient for the mTOR activator Rheb or deficient for the mTOR interacting protein Rictor.	53	59	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	58	59	56	57
These observations were not unique to the MDA-MB-231 cell line because Rheb mediated activation of mTOR failed to confer any protection against BITC induced autophagy or growth inhibition in the MCF-7 cell line ( results not shown ) .	These observations were not unique to the MDA-MB-231 cell line because Rheb mediated activation of mTOR failed to confer any protection against BITC induced autophagy or growth inhibition in the MCF-7 cell line (results not shown).	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	11	12	15	16
Angiotensin I , a decapeptide , is produced by action of renin , an enzyme present in the juxtaglomerular apparatus of the kidney , on angiotensinogen .	Angiotensin I, a decapeptide, is produced by action of renin, an enzyme present in the juxtaglomerular apparatus of the kidney, on angiotensinogen.	0	14	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin I	Angiotensin I	Angiotensin I	11	12	0	2
Baro and volume receptors in the kidney participate in stimulating the release of the enzyme renin that starts a cascade of events to produce angiotensin II ( AngII ) , which initiates also drinking and ADH release .	Baro and volume receptors in the kidney participate in stimulating the release of the enzyme renin that starts a cascade of events to produce angiotensin II (AngII), which initiates also drinking and ADH release.	11	36	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	15	16	24	26
Infusion of H. 261 , the inhibitor of human renin in the baboon , lowered blood angiotensin I , plasma angiotensin II , and arterial pressure suggesting that in the sodium depleted state angiotensin II contributes to the maintenance of arterial pressure .	Infusion of H. 261, the inhibitor of human renin in the baboon, lowered blood angiotensin I, plasma angiotensin II, and arterial pressure suggesting that in the sodium depleted state angiotensin II contributes to the maintenance of arterial pressure.	6	25	lowered	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	9	10	16	18
Angiotensin II is produced from angiotensinogen by the proteolytic action of renin and angiotensin converting enzyme ; and several data point to the existence of a complete local renin-angiotensin system in adipose tissue , including angiotensin II receptors .	Angiotensin II is produced from angiotensinogen by the proteolytic action of renin and angiotensin converting enzyme; and several data point to the existence of a complete local renin-angiotensin system in adipose tissue, including angiotensin II receptors.	0	12	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin II	Angiotensin II	Angiotensin II	11	12	0	2
Another metabolic disorder is hypertension , which occurs when renin produces angiotensin I from angiotensinogen .	Another metabolic disorder is hypertension, which occurs when renin produces angiotensin I from angiotensinogen.	9	13	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	9	10	11	13
Infusion of renin into perfused hindquarters induced sustained local angiotensin I release in the presence of an intact endothelium but not after endothelium denudation .	Infusion of renin into perfused hindquarters induced sustained local angiotensin I release in the presence of an intact endothelium but not after endothelium denudation.	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	2	3	9	11
Our results demonstrate that after induction of the renin gene in Cyp1a1-Ren-2 transgenic rats inappropriate increases in plasma and kidney ANG II levels in response to very high dietary salt intake are responsible for the development of severe hypertension in this model of inducible renin transgenic rats .	Our results demonstrate that after induction of the renin gene in Cyp1a1-Ren-2 transgenic rats inappropriate increases in plasma and kidney ANG II levels in response to very high dietary salt intake are responsible for the development of severe hypertension in this model of inducible renin transgenic rats.	8	22	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	renin	renin	renin	ANG II	ANG II	ANG II	8	9	20	22
The first step of the RAS , namely , the conversion of angiotensinogen to angiotensin I ( AngI ) is activated by renin , a highly selective protease secreted from the juxtaglomerular cells in the kidneys .	The first step of the RAS, namely, the conversion of angiotensinogen to angiotensin I (AngI) is activated by renin, a highly selective protease secreted from the juxtaglomerular cells in the kidneys.	13	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	22	23	14	16
Measurements of plasma renin activity , that are based on the determination of angiotensin I whose conversion from angiotensinogen is catalyzed by renin , will be performed in blood samples of the screening test of the first 100 patients included in the GECOH study .	Measurements of plasma renin activity, that are based on the determination of angiotensin I whose conversion from angiotensinogen is catalyzed by renin, will be performed in blood samples of the screening test of the first 100 patients included in the GECOH study.	11	23	catalyzed	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	22	23	13	15
The uniqueness of the RAS lies in : The function and regulation of the highly specific enzyme renin which specifically catalyses the conversion of the prohormone angiotensinogen to Ang I by an extracellular mechanism .	The uniqueness of the RAS lies in : The function and regulation of the highly specific enzyme renin which specifically catalyses the conversion of the prohormone angiotensinogen to Ang I by an extracellular mechanism.	9	30	catalyses	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	17	18	28	30
Saline infusion may prevent CIN by inhibiting renin release and thus production of angiotensin II ( ANG II ) , a vasoconstrictor , from angiotensin I ( ANG I ) .	Saline infusion may prevent CIN by inhibiting renin release and thus production of angiotensin II (ANG II), a vasoconstrictor, from angiotensin I (ANG I).	7	15	production	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	7	8	13	15
Inhibition of renin prevents the downstream production of the potent vasoconstrictor angiotensin II , which is responsible for increasing blood pressure .	Inhibition of renin prevents the downstream production of the potent vasoconstrictor angiotensin II, which is responsible for increasing blood pressure.	0	13	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	2	3	11	13
Renin catalyzes the conversion of angiotensinogen to angiotensin I , which can be converted by ACE into angiotensin II.	Renin catalyzes the conversion of angiotensinogen to angiotensin I, which can be converted by ACE into angiotensin II.	0	9	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	0	1	7	9
Recent studies show that both prorenin and renin activate angiotensin II independent signaling cascade through ( pro ) renin receptor , a new fangled player of the old renin-angiotensin-aldosterone system .	Recent studies show that both prorenin and renin activate angiotensin II independent signaling cascade through (pro) renin receptor, a new fangled player of the old renin-angiotensin-aldosterone system.	5	11	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	7	8	9	11
Renin and prorenin not only activate the ( P ) RR but also increase the formation of Ang-II , through increase in renin activity .	Renin and prorenin not only activate the (P) RR but also increase the formation of Ang-II, through increase in renin activity.	0	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	Ang-II	Ang-II	Ang-II	0	1	17	18
Thus , renin must have caused higher angiotensin II tissue levels than indicated by the measurements in the venous effluent .	Thus, renin must have caused higher angiotensin II tissue levels than indicated by the measurements in the venous effluent.	2	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	2	3	7	9
PRA measurements are obtained through the detection and quantification of angiotensin I ( Ang I ) produced by the action of renin on its natural substrate angiotensinogen .	PRA measurements are obtained through the detection and quantification of angiotensin I (Ang I) produced by the action of renin on its natural substrate angiotensinogen.	11	22	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	21	22	13	15
The renin angiotensin aldosterone system ( RAAS ) activation , due perhaps to intrinsic renal tissue damage with areas of hypoperfusion , leading to angiotensin II mediated vasoconstriction , salt and water retention , and sympathetic hyperactivity all contribute to HTN in CKD .	The renin angiotensin aldosterone system (RAAS) activation, due perhaps to intrinsic renal tissue damage with areas of hypoperfusion, leading to angiotensin II mediated vasoconstriction, salt and water retention, and sympathetic hyperactivity all contribute to HTN in CKD.	1	26	leading	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	1	2	24	26
XREF_BIBR Renin catalyzes the conversion of angiotensinogen to angiotensin I , which is the rate limiting step in the RAS .	XREF_BIBR Renin catalyzes the conversion of angiotensinogen to angiotensin I, which is the rate limiting step in the RAS.	0	10	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	1	2	8	10
All these results suggest that renin angiotensin system modulate the renal hemodynamics responses to NO synthesis inhibition by either increasing RVR through the elevated action of intrarenal angiotensin II and/or modulating renin release .	All these results suggest that renin angiotensin system modulate the renal hemodynamics responses to NO synthesis inhibition by either increasing RVR through the elevated action of intrarenal angiotensin II and/or modulating renin release.	5	29	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	5	6	27	29
Since evidence is available that renin generates Ang II at the surface cell membrane [ XREF_BIBR ] it is important to investigate if prolonged exposure to renin plus Ao for 24 h elicited downregulation and internalization of angiotensin II AT1 receptors in myocytes treated with renin ( 128 pmol Ang I/ml/min ) plus Ao ( 110 pmol Ang I generated by renin to exhaustion ) for a period of 24 h. 5.2 .	Since evidence is available that renin generates Ang II at the surface cell membrane [XREF_BIBR] it is important to investigate if prolonged exposure to renin plus Ao for 24 h elicited downregulation and internalization of angiotensin II AT1 receptors in myocytes treated with renin (128 pmol Ang I/ml/min) plus Ao (110 pmol Ang I generated by renin to exhaustion) for a period of 24 h. 5.2.	37	53	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	45	46	37	39
Observation of developing adrenal renin suggests that there is important involvement of angiotensin II produced by renin synthesis in the morphogenesis of the adrenal gland in the fetal stage .	Observation of developing adrenal renin suggests that there is important involvement of angiotensin II produced by renin synthesis in the morphogenesis of the adrenal gland in the fetal stage.	10	17	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	16	17	12	14
This blockade of the enzyme activity of renin leads to lowered plasma renin activity and then decreased plasma angiotensin I and II [ XREF_BIBR ] .	This blockade of the enzyme activity of renin leads to lowered plasma renin activity and then decreased plasma angiotensin I and II [XREF_BIBR].	5	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	7	8	18	20
Renin levels are elevated with ACEi or ARB use and may produce Ang II through non ACE pathways .	Renin levels are elevated with ACEi or ARB use and may produce Ang II through non ACE pathways.	0	14	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin levels	renin	Ang II	Ang II	ang ii	0	1	12	14
Angiotensin I is produced from the precursor angiotensinogen by the enzymatic activity of renin , which is located in granulosa , theca and luteal cells [ XREF_BIBR , XREF_BIBR ] .	Angiotensin I is produced from the precursor angiotensinogen by the enzymatic activity of renin, which is located in granulosa, theca and luteal cells [XREF_BIBR, XREF_BIBR].	0	17	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin I	Angiotensin I	Angiotensin I	13	14	0	2
Renin is secreted by kidney and catalyzes angiotensinogen to angiotensin I , which is the rate limiting step in renin-angiotensin-aldosterone system ( RAS ) .	Renin is secreted by kidney and catalyzes angiotensinogen to angiotensin I, which is the rate limiting step in renin-angiotensin-aldosterone system (RAS).	0	11	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	0	1	9	11
Due to the strict species-specificity of the renin mediated cleavage of angiotensinogen , the human angiotensinogen protein is only cleaved into angiotensin I in the presence of human renin , so , despite a widespread expression of human angiotensinogen , RAS hyperactivity only occurs in tissues where both transgenes are active .	Due to the strict species-specificity of the renin mediated cleavage of angiotensinogen, the human angiotensinogen protein is only cleaved into angiotensin I in the presence of human renin, so, despite a widespread expression of human angiotensinogen, RAS hyperactivity only occurs in tissues where both transgenes are active.	4	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	7	8	11	12
Hemodynamics blood gases renin activity inducing angiotensin II and angiotension converting enzyme ( ACE ) and TXB2/6-ketone-PGF 1 alpha were studied through Swan-Ganz catheter before and after administration of the drug .	Hemodynamics blood gases renin activity inducing angiotensin II and angiotension converting enzyme (ACE) and TXB2/6-ketone-PGF 1 alpha were studied through Swan-Ganz catheter before and after administration of the drug.	3	16	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	3	4	6	8
Cathepsin D is also a renin like enzyme that catalyzes angiotensinogen breakdown to AngI .	Cathepsin D is also a renin like enzyme that catalyzes angiotensinogen breakdown to AngI.	1	11	catalyzes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	5	6	10	11
Ang II is usually produced by the action of renin on angiotensinogen to form Ang I , which is further cleaved by ACE to generate Ang II [ XREF_BIBR , XREF_BIBR ] .	Ang II is usually produced by the action of renin on angiotensinogen to form Ang I, which is further cleaved by ACE to generate Ang II [XREF_BIBR, XREF_BIBR].	0	10	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	9	10	0	2
The inactive form of the enzyme ; angiotensinogen , is cleaved by renin to produce an inactive angiotensin I , which is subsequently converted into its active form angiotensin II.	The inactive form of the enzyme; angiotensinogen, is cleaved by renin to produce an inactive angiotensin I, which is subsequently converted into its active form angiotensin II.	10	19	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	12	13	17	19
Inhibition of renin activity by aliskiren diminishes AngI production which is the first and rate limiting process of the RAS .	Inhibition of renin activity by aliskiren diminishes AngI production which is the first and rate limiting process of the RAS.	2	8	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	AngI	AngI	AngI	2	3	7	8
Furthermore , aliskiren , a renin inhibitor , reduced renin- and Hpr induced cleavage of Agt and Gag polyproteins .	Furthermore, aliskiren, a renin inhibitor, reduced renin- and Hpr induced cleavage of Agt and Gag polyproteins.	9	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin-	renin-	renin-	Agt	Agt	Agt	9	10	15	16
The consequences of increased renin release associated with renal sympathetic activity , increased angiotensin II and aldosterone , both act to increase salt and water retention and interfere with pharmacologic intervention [ XREF_BIBR ] .	The consequences of increased renin release associated with renal sympathetic activity, increased angiotensin II and aldosterone, both act to increase salt and water retention and interfere with pharmacologic intervention [XREF_BIBR].	4	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	4	5	13	15
Accordingly , we hypothesized that activation of V2R increases renin synthesis via PKA and CREB , independently of ANG II type 1 ( AT1 ) receptor activation in CD cells .	Accordingly, we hypothesized that activation of V2R increases renin synthesis via PKA and CREB, independently of ANG II type 1 (AT1) receptor activation in CD cells.	9	20	synthesis	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	renin	renin	renin	ANG II	ANG II	ANG II	9	10	18	20
Renin stimulates release of angiotensin I which transforms into angiotensin II.	Renin stimulates release of angiotensin I which transforms into angiotensin II.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	0	1	4	6
Renin stimulates angiotensin II ( Ang-II ) generation .	Renin stimulates angiotensin II (Ang-II) generation.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	Ang-II	Ang-II	Ang-II	0	1	5	6
ANG is produced by the action of renin on angiotensinogen to form ANG I and its subsequent conversion to the biologically active octapeptide by ANG converting enzyme .	ANG is produced by the action of renin on angiotensinogen to form ANG I and its subsequent conversion to the biologically active octapeptide by ANG converting enzyme.	2	14	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	ANG I	ANG I	ANG I	7	8	12	14
3 Genetic studies found that renin catalyzes angiotensinogen to angiotensin I ( AngI ) , which is translated into a bioactive octapeptide ( AngII ) by the action of angiotensin I converting enzyme ( ACE ) or other enzymes .	3 Genetic studies found that renin catalyzes angiotensinogen to angiotensin I (AngI), which is translated into a bioactive octapeptide (AngII) by the action of angiotensin I converting enzyme (ACE) or other enzymes.	5	8	catalyzes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	5	6	7	8
Plasma renin produces angiotensin II ( Ang II ) to constrict the arterioles and thereby ensure sufficient BP to deliver an appropriate rate of flow for cardiovascular homeostasis .	Plasma renin produces angiotensin II (Ang II) to constrict the arterioles and thereby ensure sufficient BP to deliver an appropriate rate of flow for cardiovascular homeostasis.	0	15	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	1	2	3	5
Plasma renin activity was increased , however , plasma angiotensin II and plasma aldosterone were unchanged .	Plasma renin activity was increased, however, plasma angiotensin II and plasma aldosterone were unchanged.	1	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	1	2	9	11
Circulating angiotensinogen is hydrolysed by renin to produce Angiotensin I ( Ang I ) , which is then further converted by angiotensin converting enzyme ( ACE ) to generate biological active octapeptide , Ang II.	Circulating angiotensinogen is hydrolysed by renin to produce Angiotensin I (Ang I), which is then further converted by angiotensin converting enzyme (ACE) to generate biological active octapeptide, Ang II.	3	10	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin I	Angiotensin I	Angiotensin I	5	6	8	10
XREF_BIBR The 2K1C model elevates the plasma renin activity , which activates the angiotensin II mediated hypertensive actions , XREF_BIBR and l-NAME modulates the nitric oxide ( NO ) level in smooth muscles , which lead to elevation of blood pressure .	XREF_BIBR The 2K1C model elevates the plasma renin activity, which activates the angiotensin II mediated hypertensive actions, XREF_BIBR and l-NAME modulates the nitric oxide (NO) level in smooth muscles, which lead to elevation of blood pressure.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	7	8	13	15
Renin produces decapeptide angiotensin I from angiotensinogen .	Renin produces decapeptide angiotensin I from angiotensinogen.	0	5	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	0	1	3	5
In RAS , renin catalyses the cleavage of AGT to the decapeptide angiotensin I XREF_BIBR , which is further converted into angiotensin II by ACE catalyzing , the biologically vasoconstrictive peptide of the RAS .	In RAS, renin catalyses the cleavage of AGT to the decapeptide angiotensin I XREF_BIBR, which is further converted into angiotensin II by ACE catalyzing, the biologically vasoconstrictive peptide of the RAS.	3	18	catalyses	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	3	4	12	14
Second , renin and angiotensin I accumulate during ACE inhibition and a change in the dose of an ACE inhibitor could produce sudden shifts of angiotensin I to angiotensin II.	Second, renin and angiotensin I accumulate during ACE inhibition and a change in the dose of an ACE inhibitor could produce sudden shifts of angiotensin I to angiotensin II.	2	27	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	2	3	25	27
Renin ( 10 ng/mL for 15 minutes ) caused sustained release of Ang I ( 153 +/-16 fmol/mL ) .	Renin (10 ng/mL for 15 minutes) caused sustained release of Ang I (153 +/-16 fmol/mL).	0	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	Ang I	Ang I	Ang I	0	1	12	14
Renin stimulates the transformation of angiotensinogen in the liver into angiotensin I ( Ang I ) that is further transformed into angiotensin II ( Ang II ) by the angiotensin converting enzyme ( ACE ) from the lungs .	Renin stimulates the transformation of angiotensinogen in the liver into angiotensin I (Ang I) that is further transformed into angiotensin II (Ang II) by the angiotensin converting enzyme (ACE) from the lungs.	0	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensinogen	angiotensinogen	angiotensinogen	0	1	5	6
Collectively , these results suggest that USF2 promotes renal renin expression and stimulates ANG II generation , leading to activation of the intrarenal RAS .	Collectively, these results suggest that USF2 promotes renal renin expression and stimulates ANG II generation, leading to activation of the intrarenal RAS.	6	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	USF2 promotes renal renin expression	renin	ANG II	ANG II	ang ii	9	10	13	15
To examine whether renin containing cells synthesize angiotensinogen , we have utilized a polyclonal antibody to angiotensinogen and immunoprecipitated metabolically labeled cells of two neuroblastomas known to contain renin .	To examine whether renin containing cells synthesize angiotensinogen, we have utilized a polyclonal antibody to angiotensinogen and immunoprecipitated metabolically labeled cells of two neuroblastomas known to contain renin.	3	8	synthesize	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	3	4	7	8
XREF_BIBR When released by ischemia and reperfusion ( I/R ) , this renin initiates the activation of a local renin-angiotensin system ( RAS ) ; the locally formed angiotensin II ( ANG II ) exacerbates norepinephrine ( NE ) release from cardiac sympathetic nerves and elicits reperfusion arrhythmias .	XREF_BIBR When released by ischemia and reperfusion (I/R), this renin initiates the activation of a local renin-angiotensin system (RAS); the locally formed angiotensin II (ANG II) exacerbates norepinephrine (NE) release from cardiac sympathetic nerves and elicits reperfusion arrhythmias.	11	30	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	12	13	28	30
Angiotensin I is produced by cleavage of angiotensinogen ( AGT ) by renin and is then converted to angiotensin II predominantly by angiotensin converting enzyme ( ACE ) and partly by chymase ( CMA1 ) .	Angiotensin I is produced by cleavage of angiotensinogen (AGT) by renin and is then converted to angiotensin II predominantly by angiotensin converting enzyme (ACE) and partly by chymase (CMA1).	0	13	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin I	Angiotensin I	Angiotensin I	12	13	0	2
As renin inhibition reduces the effect of Ang II on both AT 1 Rs and AT 2 Rs , and there is no evidence suggesting that it affects the kallikrein system , it is likely that if renin inhibitors do alter tissue microvascular perfusion , they exert vasomotor effects via mechanisms distinct from those of ACE inhibitors or AT 1 R blockers .	As renin inhibition reduces the effect of Ang II on both AT 1 Rs and AT 2 Rs, and there is no evidence suggesting that it affects the kallikrein system, it is likely that if renin inhibitors do alter tissue microvascular perfusion, they exert vasomotor effects via mechanisms distinct from those of ACE inhibitors or AT 1 R blockers.	1	9	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	1	2	7	9
Increasing plasma angiotensin II ( Ang II ) concentration through intravenous Ang II infusion also suppresses renin release , via the short feedback loop .	Increasing plasma angiotensin II (Ang II) concentration through intravenous Ang II infusion also suppresses renin release, via the short feedback loop.	0	17	Increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	16	17	2	4
Renin catalyzes the AGT lysis to AngI , and ACE converts AngI into bioactive AngII .	Renin catalyzes the AGT lysis to AngI, and ACE converts AngI into bioactive AngII.	0	7	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	AngI	AngI	AngI	0	1	6	7
XREF_BIBR , XREF_BIBR In addition , the soluble form of PRR is secreted into the lumen contributing further to renin driven formation of Ang I , which can be converted to Ang II by locally available ACE .	XREF_BIBR, XREF_BIBR In addition, the soluble form of PRR is secreted into the lumen contributing further to renin driven formation of Ang I, which can be converted to Ang II by locally available ACE.	16	25	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	19	20	23	25
Renin induced drinking requires brain angiotensinogen for the generation of angiotensin I and then angiotensin II to stimulate thirst .	Renin induced drinking requires brain angiotensinogen for the generation of angiotensin I and then angiotensin II to stimulate thirst.	0	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensinogen	angiotensinogen	angiotensinogen	0	1	5	6
As renin has an upstream role in the RAAS cascade , blockade of renin might inhibit the detrimental effects of both angiotensin II and aldosterone , resulting in additive beneficial hemodynamic and structural effects on the kidney .	As renin has an upstream role in the RAAS cascade, blockade of renin might inhibit the detrimental effects of both angiotensin II and aldosterone, resulting in additive beneficial hemodynamic and structural effects on the kidney.	11	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	13	14	21	23
The direct inhibition of renin is a logical target for pharmacologic suppression of the RAAS , because renin mediated cleavage of angiotensinogen to form Ang I is a rate limiting first step in the RAAS pathway .	The direct inhibition of renin is a logical target for pharmacologic suppression of the RAAS, because renin mediated cleavage of angiotensinogen to form Ang I is a rate limiting first step in the RAAS pathway.	17	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	17	18	21	22
( Pro ) renin binds to the receptor and induces tissue injuries directly , completely independent of angiotensin II ( Ang II ) .	(Pro) renin binds to the receptor and induces tissue injuries directly, completely independent of angiotensin II (Ang II).	3	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	3	4	17	19
Significantly , cathepsin D , not renin , catalyzed the AGT to Ang I conversion in VSMCs .	Significantly, cathepsin D, not renin, catalyzed the AGT to Ang I conversion in VSMCs.	3	14	catalyzed	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	6	7	12	14
Renin activates angiotensin II , which increases blood pressure by direct vasoconstriction and by causing sodium and water retention in the kidney .	Renin activates angiotensin II, which increases blood pressure by direct vasoconstriction and by causing sodium and water retention in the kidney.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin II	angiotensin II	angiotensin II	0	1	2	4
An alternative approach to RAS blockade is to inhibit the first step in the renin-angiotensin-aldosterone cascade , renin mediated cleavage of angiotensinogen to angiotensin-1 ( XREF_FIG ) .	An alternative approach to RAS blockade is to inhibit the first step in the renin-angiotensin-aldosterone cascade, renin mediated cleavage of angiotensinogen to angiotensin-1 (XREF_FIG).	17	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	17	18	21	22
Our data indicate that ouabain administered into the central nervous system produces a hypertensive effect which does not primarily involve peripheral alpha-adrenergic receptors , but appears to be due to angiotensin II produced by renin of renal origin .	Our data indicate that ouabain administered into the central nervous system produces a hypertensive effect which does not primarily involve peripheral alpha-adrenergic receptors, but appears to be due to angiotensin II produced by renin of renal origin.	28	37	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	34	35	30	32
Renin cleaves angiotensinogen to produce ANG I , a decapeptide .	Renin cleaves angiotensinogen to produce ANG I, a decapeptide.	0	7	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	ANG I	ANG I	ANG I	0	1	5	7
Thus dynamic exercise is a potent stimulus for renal nerve activation in humans , and renal sympathetic nerve activity may contribute to increased RVR both directly ( NE and , at exhaustive work loads , possibly NPY ) and indirectly ( via renin mediated ANG II formation ) .	Thus dynamic exercise is a potent stimulus for renal nerve activation in humans, and renal sympathetic nerve activity may contribute to increased RVR both directly (NE and, at exhaustive work loads, possibly NPY) and indirectly (via renin mediated ANG II formation).	6	46	mediated	Positive_early_activation	Positive_activation	Positive_activation	renin	renin	renin	ANG II	ANG II	ANG II	42	43	44	46
XREF_BIBR - XREF_BIBR The RAS cascade begins with a renin mediated cleavage of angiotensinogen ( AGN ) to the biologically inert angiotensin I. Angiotensin I is then cleaved by angiotensin converting enzyme ( ACE ) to form angiotensin II ( ATII ) , 15 which is the vasoactive end product of the RAS cascade and is a ligand for both angiotensin II receptor 1 ( ATIIR1 ) and angiotensin II receptor 2 ( ATIIR2 ) .	XREF_BIBR - XREF_BIBR The RAS cascade begins with a renin mediated cleavage of angiotensinogen (AGN) to the biologically inert angiotensin I. Angiotensin I is then cleaved by angiotensin converting enzyme (ACE) to form angiotensin II (ATII), 15 which is the vasoactive end product of the RAS cascade and is a ligand for both angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2).	8	25	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin I	Angiotensin I	Angiotensin I	9	10	23	25
Cardiac mast cell secretes renin initiating the formation of angiotensinogen .	Cardiac mast cell secretes renin initiating the formation of angiotensinogen.	3	10	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	4	5	9	10
Additionally , the first and rate limiting step in Ang-II production is primarily renin enzyme , which catalyzes angiotensinogen to the physiologically inactive decapeptide , Ang-I .	Additionally, the first and rate limiting step in Ang-II production is primarily renin enzyme, which catalyzes angiotensinogen to the physiologically inactive decapeptide, Ang-I.	13	19	catalyzes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	13	14	18	19
In the enzymatic cascade , angiotensinogen ( AGT ) is cleaved by renin to produce angiotensin I , which is further converted in the bioactive octapeptide angiotensin II ( ATII ) through the action of angiotensin I converting enzyme ( ACE ) , a membrane bound , zinc metallo-endopeptidase involved in the metabolism of many small peptides .	In the enzymatic cascade, angiotensinogen (AGT) is cleaved by renin to produce angiotensin I, which is further converted in the bioactive octapeptide angiotensin II (ATII) through the action of angiotensin I converting enzyme (ACE), a membrane bound, zinc metallo-endopeptidase involved in the metabolism of many small peptides.	10	17	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	12	13	15	17
Because the handle region peptide did not seem to inhibit the binding of renin to the ( pro ) renin receptor , the physiological production of renal angiotensin II induced by renin or receptor bound renin was probably unaffected by the handle-region-peptide-induced inhibition of receptor bound prorenin .	Because the handle region peptide did not seem to inhibit the binding of renin to the (pro) renin receptor, the physiological production of renal angiotensin II induced by renin or receptor bound renin was probably unaffected by the handle-region-peptide-induced inhibition of receptor bound prorenin.	24	34	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	31	32	27	29
Renin then catalyzes the conversion of angiotensinogen to angiotensin I , which is cleaved by the angiotensin converting enzyme into its active form , angiotensin II.	Renin then catalyzes the conversion of angiotensinogen to angiotensin I, which is cleaved by the angiotensin converting enzyme into its active form, angiotensin II.	0	10	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	0	1	8	10
Renin catalyzes the conversion of angiotensinogen to angiotensin I , which is the rate determining step .	Renin catalyzes the conversion of angiotensinogen to angiotensin I, which is the rate determining step.	0	9	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	0	1	7	9
When blood pressure is low , aldosterone is released from the zona glomerulosa in response to renin induced angiotensin II production .	When blood pressure is low, aldosterone is released from the zona glomerulosa in response to renin induced angiotensin II production.	8	20	induced	Positive_early_activation	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	16	17	18	20
XREF_BIBR Additionally , the receptor may amplify renin induced angiotensin II dependent effects .	XREF_BIBR Additionally, the receptor may amplify renin induced angiotensin II dependent effects.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	7	8	9	11
Renin catalyzes the conversion of angiotensinogen to angiotensin I ( Ang I ) , the first and rate limiting step in the renin-angiotensin-aldosterone system .	Renin catalyzes the conversion of angiotensinogen to angiotensin I (Ang I), the first and rate limiting step in the renin-angiotensin-aldosterone system.	0	17	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	0	1	7	9
Upregulation of collecting duct ( CD ) renin may lead to increased ANG II formation during ANG II dependent hypertension , thus contributing to this imbalance .	Upregulation of collecting duct (CD) renin may lead to increased ANG II formation during ANG II dependent hypertension, thus contributing to this imbalance.	7	14	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin	renin	ANG II	ANG II	ANG II	7	8	12	14
Angiotensin II is produced by cleavage of angiotensinogen by renin and angiotensin converting enzyme in the circulation .	Angiotensin II is produced by cleavage of angiotensinogen by renin and angiotensin converting enzyme in the circulation.	0	13	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin II	Angiotensin II	Angiotensin II	9	10	0	2
Indeed , when incubated with plasma from our Ren1c-/- mice , which contains high levels of mouse AGT , exogenous recombinant human renin ( 10 -12 ~ -8 M ) does not cause Ang I production even at a concentration 10,000 times higher than normal physiological levels of mouse renin , although both human and mouse renin equally activates ERK1/2 in mouse vascular smooth muscle cells ( XREF_FIG ) .	Indeed, when incubated with plasma from our Ren1c-/- mice, which contains high levels of mouse AGT, exogenous recombinant human renin (10 -12 ~ -8 M) does not cause Ang I production even at a concentration 10,000 times higher than normal physiological levels of mouse renin, although both human and mouse renin equally activates ERK1/2 in mouse vascular smooth muscle cells (XREF_FIG).	19	35	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	22	23	33	35
During Ang II dependent hypertension , enhancement of renin mRNA and protein in the collecting duct cells , as reflected in increased renin activity in the urine [ XREF_BIBR ] , may lead to increased intratubular Ang II content , thus contributing to an imbalance in the content of Ang II and Ang 1-7 via differential regulation of ACE and ACE2 leading to increased intrarenal formation of Ang II [ XREF_BIBR ] .	During Ang II dependent hypertension, enhancement of renin mRNA and protein in the collecting duct cells, as reflected in increased renin activity in the urine [XREF_BIBR], may lead to increased intratubular Ang II content, thus contributing to an imbalance in the content of Ang II and Ang 1-7 via differential regulation of ACE and ACE2 leading to increased intrarenal formation of Ang II [XREF_BIBR].	8	38	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	8	9	36	38
XREF_BIBR , XREF_BIBR Generally , renin plasma level is increased after a period of exercise , activating more Ang I and Ang II overtaking renin levels due to lactic acidosis , which inhibits angiotensinases .	XREF_BIBR, XREF_BIBR Generally, renin plasma level is increased after a period of exercise, activating more Ang I and Ang II overtaking renin levels due to lactic acidosis, which inhibits angiotensinases.	5	22	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin plasma level	renin	Ang I	Ang I	ang i	5	6	18	20
Plasma angiotensin II correlated with active renin but not with inactive renin , suggesting that the inactive renin does not produce angiotensin II in vivo .	Plasma angiotensin II correlated with active renin but not with inactive renin, suggesting that the inactive renin does not produce angiotensin II in vivo.	15	23	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	17	18	21	23
The renin-angiotensin-system can serve as an example how a proteolytic network regulates a physiological process 1 : Briefly , angiotensinogen is cleaved by renin to produce angiotensin I , which in turn is cleaved by angiotensin converting enzyme ( ACE ) to form the effector peptide angiotensin II.	The renin-angiotensin-system can serve as an example how a proteolytic network regulates a physiological process 1 : Briefly, angiotensinogen is cleaved by renin to produce angiotensin I, which in turn is cleaved by angiotensin converting enzyme (ACE) to form the effector peptide angiotensin II.	21	28	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	23	24	26	28
The first and rate limiting step in the production of AngII is the conversion of angiotensinogen into AngI , which is catalysed by the aspartyl protease renin ( EC 3.4.23.15 ) .	The first and rate limiting step in the production of AngII is the conversion of angiotensinogen into AngI, which is catalysed by the aspartyl protease renin (EC 3.4.23.15).	13	28	catalysed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	AngI	AngI	AngI	26	27	17	18
Angiotensin II is the end product of the renin-angiotensin system ( RAS ) , where renin stimulates the production of angiotensin I from angiotensinogen , which is then converted to angiotensin II by angiotensin converting enzyme ( ACE ) .	Angiotensin II is the end product of the renin-angiotensin system (RAS), where renin stimulates the production of angiotensin I from angiotensinogen, which is then converted to angiotensin II by angiotensin converting enzyme (ACE).	15	22	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	15	16	20	22
Angiotensinogen is catalytically cleaved by renin to produce angiotensin I in response to lowered blood pressure .	Angiotensinogen is catalytically cleaved by renin to produce angiotensin I in response to lowered blood pressure.	3	10	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	5	6	8	10
Plasma renin activity ( PRA ) was reduced and plasma angiotensin II increased in a dose dependent fashion after angiotensin II infusion .	Plasma renin activity (PRA) was reduced and plasma angiotensin II increased in a dose dependent fashion after angiotensin II infusion.	1	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	1	2	10	12
Renin released from JGA cells initiates the activation of the RAS by hydrolyzing circulating and tissue AGT to generate ANG I.	Renin released from JGA cells initiates the activation of the RAS by hydrolyzing circulating and tissue AGT to generate ANG I.	0	18	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	AGT	AGT	AGT	0	1	16	17
Following the pathway , Angiotensinogen becomes converted into Angiotensin I , catalyzed by Renin , which is of renal origin .	Following the pathway, Angiotensinogen becomes converted into Angiotensin I, catalyzed by Renin, which is of renal origin.	6	19	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	Angiotensin I	Angiotensin I	Angiotensin I	13	14	8	10
Plasma angiotensin II correlated significantly with APRA , TPRA , TPRC and plasma angiotensin I ( PA I ) , but not with inactive renin , which suggests that inactive renin does not produce angiotensin II in vivo .	Plasma angiotensin II correlated significantly with APRA, TPRA, TPRC and plasma angiotensin I (PA I), but not with inactive renin, which suggests that inactive renin does not produce angiotensin II in vivo.	29	36	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	30	31	34	36
The huge increase in renin concentration and activity in the plasma and tissue interstitial space stimulates the conversion of Ang I , which can ultimately lead to the build-up of Ang I , Ang II and other angiotensin metabolites in the body , through ACE dependent and -independent pathways ( XREF_FIG ) .	The huge increase in renin concentration and activity in the plasma and tissue interstitial space stimulates the conversion of Ang I, which can ultimately lead to the build-up of Ang I, Ang II and other angiotensin metabolites in the body, through ACE dependent and -independent pathways (XREF_FIG).	4	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	4	5	19	21
As a result of losartan dosing , plasma renin activity increases due to removal of the angiotensin II feedback .	As a result of losartan dosing, plasma renin activity increases due to removal of the angiotensin II feedback.	8	18	increases	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	8	9	16	18
However , pendrin null mice have elevated plasma renin concentration XREF_BIBR , XREF_BIBR , which should increase plasma angiotensin II concentration , thereby stimulating vascular contractility XREF_BIBR .	However, pendrin null mice have elevated plasma renin concentration XREF_BIBR, XREF_BIBR, which should increase plasma angiotensin II concentration, thereby stimulating vascular contractility XREF_BIBR.	8	23	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	8	9	18	20
Our data agree with previous measurements of angiotensinogen in the rat brain as assayed by renin catalyzed angiotensin I release .	Our data agree with previous measurements of angiotensinogen in the rat brain as assayed by renin catalyzed angiotensin I release.	13	19	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	15	16	17	19
Therefore , chronic direct renin inhibition with aliskiren effectively completely prevented the development of slowly progressive ANG II dependent hypertension in Cyp1a1-Ren2 rats .	Therefore, chronic direct renin inhibition with aliskiren effectively completely prevented the development of slowly progressive ANG II dependent hypertension in Cyp1a1-Ren2 rats.	4	18	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	ANG II	ANG II	ANG II	4	5	16	18
Though active angiotensin peptides are generated extracellularly in the plasma via renin mediated cleavage of angiotensinogen to angiotensin I , followed by ACE mediated cleavage to AngII , methods which enable their expression through gene transfer approaches are available .	Though active angiotensin peptides are generated extracellularly in the plasma via renin mediated cleavage of angiotensinogen to angiotensin I, followed by ACE mediated cleavage to AngII, methods which enable their expression through gene transfer approaches are available.	9	23	mediated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	11	12	17	19
AngI itself is produced by enzymatic cleavage of the angiotensinogen precursor by renin .	AngI itself is produced by enzymatic cleavage of the angiotensinogen precursor by renin.	0	13	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	AngI	AngI	AngI	12	13	0	1
According to the classical concept , the RAS consists of renin , AGT , Ang converting enzyme ( ACE ) , Ang I , Ang II , and Ang II type 1 and type 2 receptors , in which renin acts on AGT to produce Ang I which is processed to Ang II by ACE .	According to the classical concept, the RAS consists of renin, AGT, Ang converting enzyme (ACE), Ang I, Ang II, and Ang II type 1 and type 2 receptors, in which renin acts on AGT to produce Ang I which is processed to Ang II by ACE.	39	47	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	39	40	45	47
Thus , significant aldosterone release in the non volume depleted individual who does not have hyperkalemia and in absence of renin mediated AngII production indicates autonomous aldosterone production , and is generally referred to as primary aldosteronism .	Thus, significant aldosterone release in the non volume depleted individual who does not have hyperkalemia and in absence of renin mediated AngII production indicates autonomous aldosterone production, and is generally referred to as primary aldosteronism.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	renin	renin	renin	AngII	AngII	AngII	20	21	22	23
Such maintained JG renin levels together with the increased collecting duct renin may contribute to augmented intrarenal ANG II levels .	Such maintained JG renin levels together with the increased collecting duct renin may contribute to augmented intrarenal ANG II levels.	3	19	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin levels	renin	ANG II	ANG II	ang ii	3	4	17	19
Renin-angiotensin-aldosteron system Renin activates the conversion of angiotensinogen in Ang I ( angiotensin I ) , which is turn to Ang II ( angiotensin II ) and has an overwhelming importance like the growth hormone in liver fibrosis .	Renin-angiotensin-aldosteron system Renin activates the conversion of angiotensinogen in Ang I (angiotensin I), which is turn to Ang II (angiotensin II) and has an overwhelming importance like the growth hormone in liver fibrosis.	0	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin II	angiotensin II	angiotensin II	2	3	23	25
ANG II synthesis was catalyzed by renin and angiotensin converting enzyme ( ACE ) , but not chymase , as determined using specific inhibitors .	ANG II synthesis was catalyzed by renin and angiotensin converting enzyme (ACE), but not chymase, as determined using specific inhibitors.	0	10	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	ANG II	ANG II	ANG II	6	7	0	2
The plasma renin activity was variable and only increased transiently at 21 days , thus the angiotensin II dependence of this hypertension is not caused by stimulated plasma renin activity .	The plasma renin activity was variable and only increased transiently at 21 days, thus the angiotensin II dependence of this hypertension is not caused by stimulated plasma renin activity.	16	29	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	28	29	16	18
Therefore , renin activity inhibition by aliskiren and inhibition of Ang I to Ang II conversion by chymostatin , both suppressed intracellular Ang II production and likely attenuated PA or cholersterol related RAS activation in HK2 cells .	Therefore, renin activity inhibition by aliskiren and inhibition of Ang I to Ang II conversion by chymostatin, both suppressed intracellular Ang II production and likely attenuated PA or cholersterol related RAS activation in HK2 cells.	2	24	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	2	3	22	24
Furthermore , the presumed feedback downregulation of renin levels supports the importance of angiotensinogen as a determinant of angiotensin II generation .	Furthermore, the presumed feedback downregulation of renin levels supports the importance of angiotensinogen as a determinant of angiotensin II generation.	7	14	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin levels	renin	angiotensinogen	angiotensinogen	angiotensinogen	7	8	13	14
In chronic vitamin D deficient mice , the expression of renin induces more angiotensinogen to be transformed into angiotensin II , which , by combining with the angiotensin type 1 receptor , activates TGF-beta1 .	In chronic vitamin D deficient mice, the expression of renin induces more angiotensinogen to be transformed into angiotensin II, which, by combining with the angiotensin type 1 receptor, activates TGF-beta1.	8	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	expression of renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	10	11	13	14
Renin is released into the circulation immediately following hemorrhage and subsequently increases angiotensin II levels , which have a maximal effect within 30 minutes to increase TPR .	Renin is released into the circulation immediately following hemorrhage and subsequently increases angiotensin II levels, which have a maximal effect within 30 minutes to increase TPR.	0	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin II	angiotensin II	angiotensin II	0	1	12	14
Renin cleaves AGT to produce a fragment of 10 amino acids known as angiotensin I ( Ang I ) .	Renin cleaves AGT to produce a fragment of 10 amino acids known as angiotensin I (Ang I).	0	18	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	Ang I	Ang I	Ang I	0	1	16	18
Angiotensinogen is cleaved by the enzyme renin to produce angiotensin I , which is further converted into a vasoconstricting peptide , angiotensin II , the biologically active peptide of the renin angiotensin system .	Angiotensinogen is cleaved by the enzyme renin to produce angiotensin I, which is further converted into a vasoconstricting peptide, angiotensin II, the biologically active peptide of the renin angiotensin system.	2	11	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	6	7	9	11
When salbutamol was added to the hypoxic mixture , there was a significant rise in plasma renin and angiotensin II [ mean ( SEM ) maximal increase in angiotensin II of 5.6 ( 2.9 ) pg/ml and renin of 15.5 ( 6.3 ) mu-units/ml at 60 min , P < 0.05 compared with normoxia ] .	When salbutamol was added to the hypoxic mixture, there was a significant rise in plasma renin and angiotensin II [mean (SEM) maximal increase in angiotensin II of 5.6 (2.9) pg/ml and renin of 15.5 (6.3) mu-units/ml at 60 min, P < 0.05 compared with normoxia].	26	43	increase	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	37	38	28	30
Renin secretion is very significantly reduced by beta blocking agents ( propranolol ) ; conversion of angiotensin I into angiotensin II is inhibited by teprotide , captopril and their derivatives ; peripheral actions of angiotensin II are blocked by saralasin .	Renin secretion is very significantly reduced by beta blocking agents (propranolol); conversion of angiotensin I into angiotensin II is inhibited by teprotide, captopril and their derivatives; peripheral actions of angiotensin II are blocked by saralasin.	0	18	blocking	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	0	1	16	18
Biosynthesis of endogenous brain angiotensin II was stimulated by 0.1 U renin and the blood pressure was elevated 40 min after the application .	Biosynthesis of endogenous brain angiotensin II was stimulated by 0.1 U renin and the blood pressure was elevated 40 min after the application.	0	15	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	11	12	4	6
[ XREF_BIBR , XREF_BIBR ] One of the major rate limiting steps of this system is the conversion of angiotensinogen to angiotensin I , which is catalyzed by renin .	[XREF_BIBR, XREF_BIBR] One of the major rate limiting steps of this system is the conversion of angiotensinogen to angiotensin I, which is catalyzed by renin.	17	29	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	28	29	21	23
Moreover , along with its enzymatic properties , renin activates Ang II independent signaling cascade via pro renin receptors to triggers profibrotic and inflammatory injury in mesangial cells XREF_BIBR , XREF_BIBR .	Moreover, along with its enzymatic properties, renin activates Ang II independent signaling cascade via pro renin receptors to triggers profibrotic and inflammatory injury in mesangial cells XREF_BIBR, XREF_BIBR.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	8	9	10	12
Blockade of the renin angiotensin system also reduces oxidative stress and the stimulatory effects of angiotensin II on the expression of a various growth factors and cytokines known to contribute to renal injury .	Blockade of the renin angiotensin system also reduces oxidative stress and the stimulatory effects of angiotensin II on the expression of a various growth factors and cytokines known to contribute to renal injury.	3	17	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	3	4	15	17
Luminal angiotensinogen is synthesized and secreted from proximal tubular cells and is subsequently cleaved to Ang I by renin via autocrine and paracrine mechanisms .	Luminal angiotensinogen is synthesized and secreted from proximal tubular cells and is subsequently cleaved to Ang I by renin via autocrine and paracrine mechanisms.	0	23	synthesized	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	18	19	1	2
It is generally assumed that intrarenal Ang II is produced by the action of juxtaglomerular cell release of renin working on plasma angiotensinogen .	It is generally assumed that intrarenal Ang II is produced by the action of juxtaglomerular cell release of renin working on plasma angiotensinogen.	6	19	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	18	19	6	8
The CF derived exosomes up-regulated the expression of renin , angiotensinogen , AT1R , and AT2R ; downregulated angiotensin converting enzyme 2 ; and enhanced Ang II production in cultured cardiomyocytes .	The CF derived exosomes up-regulated the expression of renin, angiotensinogen, AT1R, and AT2R; downregulated angiotensin converting enzyme 2; and enhanced Ang II production in cultured cardiomyocytes.	1	27	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	CF derived exosomes up-regulated the expression of renin	renin	Ang II	Ang II	ang ii	8	9	25	27
Angiotensins are a group of hormonal peptides and include angiotensin II and angiotensin 1-7 produced by the renin angiotensin system .	Angiotensins are a group of hormonal peptides and include angiotensin II and angiotensin 1-7 produced by the renin angiotensin system.	8	19	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin 1-7	angiotensin 1-7	angiotensin 1-7	17	18	12	14
In contrast , renin inhibition limits the generation of angiotensin II and thus reduces the activation of both angiotensin type 1 and type 2 receptors .	In contrast, renin inhibition limits the generation of angiotensin II and thus reduces the activation of both angiotensin type 1 and type 2 receptors.	3	11	limits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	3	4	9	11
The precursor angiotensinogen is cleaved by renin to produce angiotensin I , which is further cleaved to Ang II by angiotensin converting enzyme [ XREF_BIBR ] .	The precursor angiotensinogen is cleaved by renin to produce angiotensin I, which is further cleaved to Ang II by angiotensin converting enzyme [XREF_BIBR].	4	11	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	6	7	9	11
Renin activates angiotensinogen , converting it into angiotensin I and then Ang II under the action of converting enzyme .	Renin activates angiotensinogen, converting it into angiotensin I and then Ang II under the action of converting enzyme.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensinogen	angiotensinogen	angiotensinogen	0	1	2	3
Plasma AGT levels are close enough to the Michaelis constant for renin that small increases in either renin or AGT may increase Ang II production and alter blood pressure XREF_BIBR .	Plasma AGT levels are close enough to the Michaelis constant for renin that small increases in either renin or AGT may increase Ang II production and alter blood pressure XREF_BIBR.	14	24	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	17	18	22	24
The diminished angiotensinogen expression might mean less locally produced RAS substrate , while the increased ( pro ) renin receptor expression might lead to a more efficient conversion of angiotensinogen to Ang-I by renin .	The diminished angiotensinogen expression might mean less locally produced RAS substrate, while the increased (pro) renin receptor expression might lead to a more efficient conversion of angiotensinogen to Ang-I by renin.	22	34	lead	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	33	34	29	30
Increasing renin secretion from kidneys will result in enhancement of angiotensin II production .	Increasing renin secretion from kidneys will result in enhancement of angiotensin II production.	1	12	result in enhancement	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	1	2	10	12
Active human renin at doses of 3 , 10 , and 30 ng/mL perfusate for 15 minutes increased Ang I release from undetectable levels ( mean +/- SEM ) to 31.9 +/- 3.3 , 147.1 +/- 26.2 , and 206.4 +/- 17.1 fmol/mL , respectively , by 9 minutes .	Active human renin at doses of 3, 10, and 30 ng/mL perfusate for 15 minutes increased Ang I release from undetectable levels (mean +/- SEM) to 31.9 +/- 3.3, 147.1 +/- 26.2, and 206.4 +/- 17.1 fmol/mL, respectively, by 9 minutes.	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	2	3	18	20
The enzyme renin cleaves the substrate AGT to produce angiotensin I ( Ang I ) .	The enzyme renin cleaves the substrate AGT to produce angiotensin I (Ang I).	0	11	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	2	3	9	11
Renin inhibition blocks production of angiotensin II , a key mediator in the regulation of body fluid volume and blood pressure .	Renin inhibition blocks production of angiotensin II, a key mediator in the regulation of body fluid volume and blood pressure.	0	10	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin II	angiotensin II	angiotensin II	0	1	5	7
14 AngII , the major bioactive component of the renin-angiotensin system ( RAS ) , is produced from angiotensinogen by the actions of renin and angiotensin converting enzyme ( ACE ) , and acts through angiotensin type 1 and type 2 receptors ( AT1R and AT2R ) .	14 AngII, the major bioactive component of the renin-angiotensin system (RAS), is produced from angiotensinogen by the actions of renin and angiotensin converting enzyme (ACE), and acts through angiotensin type 1 and type 2 receptors (AT1R and AT2R).	0	33	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	AngII	AngII	AngII	23	24	1	2
Renin release stimulates the generation of angiotensin II ( AngII ) , and the release of aldosterone from the adrenal cortex [ XREF_BIBR ] .	Renin release stimulates the generation of angiotensin II (AngII), and the release of aldosterone from the adrenal cortex [XREF_BIBR].	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	AngII	AngII	AngII	0	1	9	10
Because plasma renin activity was increased the role of angiotensin II as a renal vasoconstrictor was evaluated by utilizing two angiotensin antagonists .	Because plasma renin activity was increased the role of angiotensin II as a renal vasoconstrictor was evaluated by utilizing two angiotensin antagonists.	2	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	2	3	9	11
Angiotensin II , the major effector of the RAS , is produced by successive enzymatic cleavage of the glycoprotein AGT by the enzymes renin and angiotensin converting enzyme ( ACE ) .	Angiotensin II, the major effector of the RAS, is produced by successive enzymatic cleavage of the glycoprotein AGT by the enzymes renin and angiotensin converting enzyme (ACE).	0	29	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin II	Angiotensin II	Angiotensin II	23	24	0	2
ASO against AGT reduces intact AGT and des ( AngI ) AGT , leading to reductions of total AGT , whereas renin inhibition increases intact AGT and reduces des ( AngI ) AGT with no changes of total plasma AGT .	ASO against AGT reduces intact AGT and des (AngI) AGT, leading to reductions of total AGT, whereas renin inhibition increases intact AGT and reduces des (AngI) AGT with no changes of total plasma AGT.	21	35	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	AGT	AGT	AGT	21	22	32	33
Together , these results suggest that increased renin enhances AngII synthesis , leading to the activation of the renal RAS in USF2 ( Tg ) mice , and contributing to the development of nephropathy .	Together, these results suggest that increased renin enhances AngII synthesis, leading to the activation of the renal RAS in USF2 (Tg) mice, and contributing to the development of nephropathy.	6	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	AngII	AngII	AngII	7	8	9	10
The augmented distal tubular renin may contribute to increased intratubular ANG II levels and distal nephron sodium reabsorption in ANG II dependent hypertension .	The augmented distal tubular renin may contribute to increased intratubular ANG II levels and distal nephron sodium reabsorption in ANG II dependent hypertension.	0	17	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin	renin	ANG II	ANG II	ANG II	4	5	10	12
The classical RAS as it looked in the middle 1970s consisted of circulating renin , acting on angiotensinogen to produce angiotensin I , which in turn was converted into angiotensin II ( Ang II ) by angiotensin converting enzyme ( ACE ) .	The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin converting enzyme (ACE).	12	27	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	13	14	20	22
Renin , released from juxtaglomerular cells , causes the proteolytic cleavage of angiotensinogen to angiotensin I which is also a target of proteolytic cleavage .	Renin, released from juxtaglomerular cells, causes the proteolytic cleavage of angiotensinogen to angiotensin I which is also a target of proteolytic cleavage.	0	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensinogen	angiotensinogen	angiotensinogen	0	1	12	13
Angiotensin II is produced by enzymatic cleavage of the precursor angiotensinogen by renin and by angiotensin converting enzyme ( ACE ) , and exerts its effects in the tissues through angiotensin receptors type1 ( AGTRa ) and type 2 ( AGTR2 ) .	Angiotensin II is produced by enzymatic cleavage of the precursor angiotensinogen by renin and by angiotensin converting enzyme (ACE), and exerts its effects in the tissues through angiotensin receptors type1 (AGTRa) and type 2 (AGTR2).	0	23	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin II	Angiotensin II	Angiotensin II	12	13	0	2
Renin can induce renal disease by generating angiotensin II and , thereby , increasing fibrosis .	Renin can induce renal disease by generating angiotensin II and, thereby, increasing fibrosis.	0	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin II	angiotensin II	angiotensin II	0	1	7	9
To investigate whether plasma angiotensin II ( Ang II ) determines the effects of the renin-angiotensin system or whether tissue uptake of renin and localized production of Ang II might account for any cardiovascular , renal , hormonal or drinking effect of circulating renin .	To investigate whether plasma angiotensin II (Ang II) determines the effects of the renin-angiotensin system or whether tissue uptake of renin and localized production of Ang II might account for any cardiovascular, renal, hormonal or drinking effect of circulating renin.	22	29	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	22	23	27	29
Direct renin inhibition upstream of ACE , well-known for decades as a RAAS blocking concept , prevents the generation of Ang-I and thus , Ang-II .	Direct renin inhibition upstream of ACE, well-known for decades as a RAAS blocking concept, prevents the generation of Ang-I and thus, Ang-II.	1	25	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang-II	Ang-II	Ang-II	1	2	24	25
The active circulating autacoid , angiotensin-II , is generated by the familiar sequence of renin acting on angiotensinogen to produce angiotensin-I , which is converted into angiotensin-II in the blood vessels of the peripheral tissues .	The active circulating autacoid, angiotensin-II, is generated by the familiar sequence of renin acting on angiotensinogen to produce angiotensin-I, which is converted into angiotensin-II in the blood vessels of the peripheral tissues.	12	24	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin-I	angiotensin-I	angiotensin-I	14	15	20	21
Importantly , the interaction of a secreted extracellular domain , resulting from proteolysis of ATP6AP2 in the golgi , is able also to bind to renin thus allowing modulation of AngII without intracellular signaling .	Importantly, the interaction of a secreted extracellular domain, resulting from proteolysis of ATP6AP2 in the golgi, is able also to bind to renin thus allowing modulation of AngII without intracellular signaling.	23	31	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	AngII	AngII	AngII	25	26	30	31
ANG II is produced by the action of renin on angiotensinogen to form ANG I , which is further cleaved by angiotensin converting enzyme ( ACE ) to form ANG II.	ANG II is produced by the action of renin on angiotensinogen to form ANG I, which is further cleaved by angiotensin converting enzyme (ACE) to form ANG II.	0	12	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	ANG II	ANG II	ANG II	8	9	0	2
Angiotensin II indcued essentially similar effects on blood pressure in both groups but the greater feedback inhibition of PRA was produced by this peptide in normal or high renin essential hypertension than in low renin essential hypertension .	Angiotensin II indcued essentially similar effects on blood pressure in both groups but the greater feedback inhibition of PRA was produced by this peptide in normal or high renin essential hypertension than in low renin essential hypertension.	0	29	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin II	Angiotensin II	Angiotensin II	28	29	0	2
Increased renin activity stimulates the conversion of Ang I and ultimately Ang II , and Ang II is a key factor in the ACE and AT1R axis .	Increased renin activity stimulates the conversion of Ang I and ultimately Ang II, and Ang II is a key factor in the ACE and AT1R axis.	1	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	1	2	7	9
The major regulator of mineralocorticoid production in the adrenal is angiotensin II produced by the action of renal renin .	The major regulator of mineralocorticoid production in the adrenal is angiotensin II produced by the action of renal renin.	2	19	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	18	19	10	12
Renin stimulates the production of angiotensin I ( Ang I ) , which is then converted to angiotensin II ( Ang II ) .	Renin stimulates the production of angiotensin I (Ang I), which is then converted to angiotensin II (Ang II).	0	22	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	Ang II	Ang II	Ang II	0	1	20	22
Renin produces angiotensin I from angiotensinogen , after which it is converted to a potent vasoconstrictor , angiotensin II by angiotensin I converting enzyme ( ACE ) .	Renin produces angiotensin I from angiotensinogen, after which it is converted to a potent vasoconstrictor, angiotensin II by angiotensin I converting enzyme (ACE).	0	4	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	0	1	2	4
XREF_BIBR , XREF_BIBR AGT , a protein with 452 amino acids , is cleaved by renin to produce Ang I. Ang I is a decapeptide , which is then cleaved by ACE to produce Ang II.	XREF_BIBR, XREF_BIBR AGT, a protein with 452 amino acids, is cleaved by renin to produce Ang I. Ang I is a decapeptide, which is then cleaved by ACE to produce Ang II.	13	33	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	15	16	20	22
As a small percentage ( = ~ 2 % ) of plasma prorenin is always in the open form , i.e ., capable of generating Ang I , a 200-fold increase of plasma prorenin concentration leads to a substantial increase in Ang I generating activity , even without the help of a receptor .	As a small percentage (= ~ 2%) of plasma prorenin is always in the open form, i.e., capable of generating Ang I, a 200-fold increase of plasma prorenin concentration leads to a substantial increase in Ang I generating activity, even without the help of a receptor.	33	43	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	prorenin	prorenin	prorenin	Ang I	Ang I	Ang I	33	34	41	43
Recent studies have demonstrated that renin upregulates TGF-b1 and matrix proteins through the renin and prorenin receptors , independent of angiotensin II , which is regulated by extracellular-signal regulated kinase 1 and 2 ( ERK1/2 ) , a mitogen activated protein kinase ( MAPK ) .	Recent studies have demonstrated that renin upregulates TGF-b1 and matrix proteins through the renin and prorenin receptors, independent of angiotensin II, which is regulated by extracellular-signal regulated kinase 1 and 2 (ERK1/2), a mitogen activated protein kinase (MAPK).	5	25	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	5	6	20	22
Therefore , the present findings demonstrate that chronic renin inhibition with aliskiren prevents the development of slowly progressive ANG II dependent hypertension and the associated derangements in renal hemodynamics and excretory function in Cyp1a1-Ren2 transgenic rats .	Therefore, the present findings demonstrate that chronic renin inhibition with aliskiren prevents the development of slowly progressive ANG II dependent hypertension and the associated derangements in renal hemodynamics and excretory function in Cyp1a1-Ren2 transgenic rats.	8	31	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	ANG II	ANG II	ANG II	8	9	18	20
Renin build-up in fact not only stimulates the conversion of Ang I leading to Ang II accumulation but is also likely associated with detrimental effects directly induced by renin [ XREF_BIBR ] .	Renin build-up in fact not only stimulates the conversion of Ang I leading to Ang II accumulation but is also likely associated with detrimental effects directly induced by renin [XREF_BIBR].	0	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	Ang I	Ang I	Ang I	0	1	10	12
4 Renin catalyzes the conversion of angiotensinogen to angiotensin I ( Ang-I ) , which is then cleaved by angiotensin converting enzyme ( ACE ) to produce Ang-II .	4 Renin catalyzes the conversion of angiotensinogen to angiotensin I (Ang-I), which is then cleaved by angiotensin converting enzyme (ACE) to produce Ang-II.	0	10	catalyzes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	1	2	8	10
Normally , angiotensinogen produced in the liver is converted by renin in the kidney to produce angiotensin I , which is then metabolized to angiotensin II in the lungs by the enzyme ACE ( kininase II ) .	Normally, angiotensinogen produced in the liver is converted by renin in the kidney to produce angiotensin I, which is then metabolized to angiotensin II in the lungs by the enzyme ACE (kininase II).	8	18	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	10	11	16	18
It is now well recognized that ( pro ) renin ( PRO ) acting at its receptors ( PRR ) in the brain elicits both Ang II - dependent and independent effects on cardiovascular and fluid homeostasis , and contributes to the RAS involvement in neurogenic hypertension .	It is now well recognized that (pro) renin (PRO) acting at its receptors (PRR) in the brain elicits both Ang II - dependent and independent effects on cardiovascular and fluid homeostasis, and contributes to the RAS involvement in neurogenic hypertension.	7	39	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	9	10	25	27
Increased renin synthesis leads to an elevated angiotensin II production , which is a strong vasoconstrictor , enabling the development of hypertension and left ventricular hypertrophy [ XREF_BIBR ] .	Increased renin synthesis leads to an elevated angiotensin II production, which is a strong vasoconstrictor, enabling the development of hypertension and left ventricular hypertrophy [XREF_BIBR].	1	9	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	1	2	7	9
As an endocrine hormonal system , angiotensin II ( Ang II ) formation in the circulation results from the linear processing of the substrate angiotensinogen ( Aogen ) produced by the liver , by the renal enzyme renin .	As an endocrine hormonal system, angiotensin II (Ang II) formation in the circulation results from the linear processing of the substrate angiotensinogen (Aogen) produced by the liver, by the renal enzyme renin.	20	38	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	37	38	24	25
In dogs and rats , Phosphoryl-E decreased hypertensive responce and increase angiotensin I concentration induced by the exogenous renin .	In dogs and rats, Phosphoryl-E decreased hypertensive responce and increase angiotensin I concentration induced by the exogenous renin.	6	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	18	19	11	13
Human SRY significantly regulated human promoters of AGT , REN , ACE2 , AT2 , and MAS compared to control levels , elevating AGT and REN promoter activity while decreasing ACE2 , AT2 , and MAS .	Human SRY significantly regulated human promoters of AGT, REN, ACE2, AT2, and MAS compared to control levels, elevating AGT and REN promoter activity while decreasing ACE2, AT2, and MAS.	5	27	elevating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	REN	REN	REN	AGT	AGT	AGT	9	10	23	24
Angiotensin II ( Ang II ) is a key molecule of RAS and is produced as a result of sequential cleavage of angiotensinogen by renin and angiotensin converting enzyme ( ACE ) .	Angiotensin II (Ang II) is a key molecule of RAS and is produced as a result of sequential cleavage of angiotensinogen by renin and angiotensin converting enzyme (ACE).	0	28	produced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Angiotensin II	Angiotensin II	Angiotensin II	24	25	0	2
We investigated the antiangiogenic effect of angiotensinogen and 2 related compounds : ( 1 ) des ( angiotensin I ) angiotensinogen , the product of angiotensinogen cleavage by renin , and ( 2 ) the reactive center loop cleaved angiotensinogen , which is produced after selective and limited proteolysis by the protease V8 .	We investigated the antiangiogenic effect of angiotensinogen and 2 related compounds : (1) des (angiotensin I) angiotensinogen, the product of angiotensinogen cleavage by renin, and (2) the reactive center loop cleaved angiotensinogen, which is produced after selective and limited proteolysis by the protease V8.	23	29	product	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	28	29	25	26
Under these circumstances , the greater plasma renin activity might cause a decrease in renal blood flow but not necessarily a change in angiotensin II or aldosterone .	Under these circumstances, the greater plasma renin activity might cause a decrease in renal blood flow but not necessarily a change in angiotensin II or aldosterone.	7	26	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	7	8	23	25
Renin cleaves AGT to produce Ang I , which is then processed to Ang II by ACE .	Renin cleaves AGT to produce Ang I, which is then processed to Ang II by ACE.	0	7	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	Ang I	Ang I	Ang I	0	1	5	7
XREF_BIBR - XREF_BIBR The increase in renin activity stimulates the conversion of Ang I and Ang II , which may limit the efficacy of RAS inhibition XREF_BIBR and the increased renin can also activate the prorenin and renin receptor causing renal and cardiovascular damages independent of Ang II XREF_BIBR ( XREF_FIG ) .	XREF_BIBR - XREF_BIBR The increase in renin activity stimulates the conversion of Ang I and Ang II, which may limit the efficacy of RAS inhibition XREF_BIBR and the increased renin can also activate the prorenin and renin receptor causing renal and cardiovascular damages independent of Ang II XREF_BIBR (XREF_FIG).	6	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang I	Ang I	Ang I	6	7	12	14
Antisense inhibition of renin secretion by adenoviral delivery of renin antisense gene abolishes the cold induced increases in renin , AngII and aldosterone and prevents the development of CIH .	Antisense inhibition of renin secretion by adenoviral delivery of renin antisense gene abolishes the cold induced increases in renin, AngII and aldosterone and prevents the development of CIH.	3	21	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	AngII	AngII	AngII	3	4	20	21
Since the PRR binds both renin and prorenin leading to Ang II production , the finding of PRR in the brain provides additional evidence for the presence of a functional brain RAS .	Since the PRR binds both renin and prorenin leading to Ang II production, the finding of PRR in the brain provides additional evidence for the presence of a functional brain RAS.	4	12	leading to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	5	6	10	12
The relative contribution of plasma renin and angiotensinogen , and of locally synthesized renin ( or renin like enzyme ) and angiotensinogen , to angiotensin generation in each tissue is unknown , and probably differs between tissues .	The relative contribution of plasma renin and angiotensinogen, and of locally synthesized renin (or renin like enzyme) and angiotensinogen, to angiotensin generation in each tissue is unknown, and probably differs between tissues.	2	22	synthesized	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	5	6	21	22
Angiotensinogen ( AGT ) is initially cleaved by renin to produce angiotensin I , which is rapidly processed by angiotensin converting enzyme ( ACE ) to produce the powerful octapeptide vasopressor , angiotensin II.	Angiotensinogen (AGT) is initially cleaved by renin to produce angiotensin I, which is rapidly processed by angiotensin converting enzyme (ACE) to produce the powerful octapeptide vasopressor, angiotensin II.	6	13	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	8	9	11	13
This increase in renin production should stimulate angiotensin II release .	This increase in renin production should stimulate angiotensin II release.	3	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	3	4	7	9
Renin , an aspartate protease , cleaves the alpha-globulin angiotensinogen to produce the decapeptide angiotensin I , which is then converted to the vasoactive hormone angiotensin II by the action of a peptidase ' converting enzyme ' .	Renin, an aspartate protease, cleaves the alpha-globulin angiotensinogen to produce the decapeptide angiotensin I, which is then converted to the vasoactive hormone angiotensin II by the action of a peptidase ' converting enzyme '.	0	16	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	angiotensin I	angiotensin I	angiotensin I	0	1	14	16
Activation of NHE1 is also mediated through phosphorylation by protein kinases like , protein kinase A ( PKA ) , protein kinase C ( PKC ) , extracellular signal regulated kinases ( ERK1/2 ) and p90 ( RSK ) kinases , Rho activated kinase p160 ROCK , and Ca 2+ / calmodulin dependent kinases .	Activation of NHE1 is also mediated through phosphorylation by protein kinases like, protein kinase A (PKA), protein kinase C (PKC), extracellular signal regulated kinases (ERK1/2) and p90 (RSK) kinases, Rho activated kinase p160 ROCK, and Ca 2+ / calmodulin dependent kinases.	15	46	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	p160 ROCK	p160 ROCK	p160 ROCK	41	42	44	46
Differently , RhoA activates ROCK1 through interaction with the carboxy-terminal site .	Differently, RhoA activates ROCK1 through interaction with the carboxy-terminal site.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	2	3	4	5
The theoretical link between statins and ROCK1 goes as follows : statins inhibit the isoprenoid pathway , isoprenoids are regulators of the enzyme Rho , and Rho in turn activates ROCK1 .	The theoretical link between statins and ROCK1 goes as follows : statins inhibit the isoprenoid pathway, isoprenoids are regulators of the enzyme Rho, and Rho in turn activates ROCK1.	26	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	26	27	30	31
To confirm whether RhoA could activate ROCK1 during MC-3129-induced apoptosis , a lentivirus shRNA approach was used to stably knockdown RhoA expression .	To confirm whether RhoA could activate ROCK1 during MC-3129-induced apoptosis, a lentivirus shRNA approach was used to stably knockdown RhoA expression.	3	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	3	4	6	7
Blocking Rho activity , which reduces ROCK1 activity , has been observed to increase lamellipodium extension , possibly by counteracting contraction XREF_BIBR .	Blocking Rho activity, which reduces ROCK1 activity, has been observed to increase lamellipodium extension, possibly by counteracting contraction XREF_BIBR.	1	7	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	1	2	6	7
XREF_BIBR The two isoforms ROCK1 and ROCK2 are activated by Rho family GTPases and promote actin-myosin mediated contractile force generation via serine threonine phosphorylation of numerous down-stream targets including myosin light chain ( MLC ) , XREF_BIBR myosin binding subunit of myosin phosphatase ( MYPT ) , XREF_BIBR ezrin/radixin/moesin ( ERM ) proteins XREF_BIBR and LIM kinase ( LIMK ) .	XREF_BIBR The two isoforms ROCK1 and ROCK2 are activated by Rho family GTPases and promote actin-myosin mediated contractile force generation via serine threonine phosphorylation of numerous down-stream targets including myosin light chain (MLC), XREF_BIBR myosin binding subunit of myosin phosphatase (MYPT), XREF_BIBR ezrin/radixin/moesin (ERM) proteins XREF_BIBR and LIM kinase (LIMK).	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	10	11	4	5
Rap1 is known to stabilise endothelial junctions , whereas another small GTPase , RhoA , stimulates actomyosin contractility by MLC phosphorylation via its effector Rho-kinase 1 ( ROCK1 ) leading to increased endothelial permeability XREF_BIBR XREF_BIBR XREF_BIBR .	Rap1 is known to stabilise endothelial junctions, whereas another small GTPase, RhoA, stimulates actomyosin contractility by MLC phosphorylation via its effector Rho-kinase 1 (ROCK1) leading to increased endothelial permeability XREF_BIBR XREF_BIBR XREF_BIBR.	11	29	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	13	14	27	28
XREF_BIBR On activation by binding to GTP , Rho activates its effector molecules ( Rho kinase ROCK1 and 2 ) , which signal downstream molecules to polymerize actin fibers in the cardiovascular , pulmonary , and renal systems .	XREF_BIBR On activation by binding to GTP, Rho activates its effector molecules (Rho kinase ROCK1 and 2), which signal downstream molecules to polymerize actin fibers in the cardiovascular, pulmonary, and renal systems.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	8	9	16	17
Rho proteins mediate downstream signaling via their effectors : the serine/threonine kinases ROCK1 and ROCK 2 [ XREF_BIBR ] , or members of the mammalian diaphanous family of formins , such as mDia1 .	Rho proteins mediate downstream signaling via their effectors : the serine/threonine kinases ROCK1 and ROCK 2 [XREF_BIBR], or members of the mammalian diaphanous family of formins, such as mDia1.	0	14	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	0	1	12	13
This suggests that RhoA activation underlies the activation of ROCK1 .	This suggests that RhoA activation underlies the activation of ROCK1.	3	10	underlies	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	3	4	9	10
The type I Tgf-beta receptor may interact with a number of different molecules including RhoA , which activates ROCK1 .	The type I Tgf-beta receptor may interact with a number of different molecules including RhoA, which activates ROCK1.	12	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	14	15	18	19
The Rho effector kinases ROCK1 and 2 were shown to mediate cell contractility downstream of nocodazole induced Rho activation and expression of constitutive active ROCK1 induced Golgi fragmentation , but neither the single , nor the combined depletion of ROCK1 and ROCK2 affected Golgi associated PKD activity ( XREF_FIG ) .	The Rho effector kinases ROCK1 and 2 were shown to mediate cell contractility downstream of nocodazole induced Rho activation and expression of constitutive active ROCK1 induced Golgi fragmentation, but neither the single, nor the combined depletion of ROCK1 and ROCK2 affected Golgi associated PKD activity (XREF_FIG).	15	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rho	nocodazole induced Rho	rho	ROCK1	ROCK1	rock1	17	18	24	25
CDC42 and RAC1 promote actin nucleation mainly nucleation of highly branched to induce membrane protrusion , whereas RHOA activates ROCK1 to induce F-actin and induce actomyosin contraction and tail formation .	CDC42 and RAC1 promote actin nucleation mainly nucleation of highly branched to induce membrane protrusion, whereas RHOA activates ROCK1 to induce F-actin and induce actomyosin contraction and tail formation.	17	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RHOA	RHOA	RHOA	ROCK1	ROCK1	ROCK1	17	18	19	20
In this process , alphaL and beta2 integrin activates through Vav1 , RhoA , which subsequently activates the kinase p160 ROCK .	In this process, alphaL and beta2 integrin activates through Vav1, RhoA, which subsequently activates the kinase p160 ROCK.	10	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	p160 ROCK	p160 ROCK	p160 ROCK	12	13	19	21
RhoA directly regulates the activity of ROCK1 as we described above , and is physically proximal to Erk1/2 .	RhoA directly regulates the activity of ROCK1 as we described above, and is physically proximal to Erk1/2.	0	7	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	0	1	6	7
ROCK1 activation by the Rho GTPase RhoA results in increased MLC phosphorylation , generating contractile forces through actin-myosin interactions XREF_BIBR .	ROCK1 activation by the Rho GTPase RhoA results in increased MLC phosphorylation, generating contractile forces through actin-myosin interactions XREF_BIBR.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	4	5	0	1
In G q -deficient mouse platelets , U46619 or thrombin , but not ADP , causes shape change through activation of G 12/13 and RhoA mediated p160ROCK pathways [ XREF_BIBR , XREF_BIBR ] .	In G q -deficient mouse platelets, U46619 or thrombin, but not ADP, causes shape change through activation of G 12/13 and RhoA mediated p160ROCK pathways [XREF_BIBR, XREF_BIBR].	24	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	p160ROCK	p160ROCK	p160ROCK	24	25	26	27
Rho molecules when bounded to guanosine triphosphate , activate its effector molecules ( ROCK-1 and ROCK-2 ) .	Rho molecules when bounded to guanosine triphosphate, activate its effector molecules (ROCK-1 and ROCK-2).	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK-1	ROCK-1	ROCK-1	0	1	13	14
XREF_BIBR - XREF_BIBR The study of the regulatory activation of ROCK1 demonstrated that Rnd3 inhibits RhoA mediated ROCK1 signaling by specifically binding to ROCK1 , but not ROCK2 .	XREF_BIBR - XREF_BIBR The study of the regulatory activation of ROCK1 demonstrated that Rnd3 inhibits RhoA mediated ROCK1 signaling by specifically binding to ROCK1, but not ROCK2.	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	15	16	17	18
In addition , the activation of ROCK1 by RhoA can promote cell invasion and motility in prostate cancer and colorectal carcinoma cells .	In addition, the activation of ROCK1 by RhoA can promote cell invasion and motility in prostate cancer and colorectal carcinoma cells.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	8	9	6	7
RhoA activates the serine/threonine kinases ROCK1 and ROCK2 XREF_BIBR .	RhoA activates the serine/threonine kinases ROCK1 and ROCK2 XREF_BIBR.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	0	1	5	6
Rho associated kinase 1 ( ROCK1 ) and ROCK2 are activated by Rho GTPase and control cytoskeleton rearrangement through modulating the phosphorylation of their down-stream effector molecules .	Rho associated kinase 1 (ROCK1) and ROCK2 are activated by Rho GTPase and control cytoskeleton rearrangement through modulating the phosphorylation of their down-stream effector molecules.	3	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	12	13	5	6
Furthermore , as no apparent changes in total ROCK1 levels occurred , we found a prominent degradation via the 26S proteasome of RhoA , the key small GTPase that activates ROCK1 to be required for this bioactivity ( XREF_FIG ) .	Furthermore, as no apparent changes in total ROCK1 levels occurred, we found a prominent degradation via the 26S proteasome of RhoA, the key small GTPase that activates ROCK1 to be required for this bioactivity (XREF_FIG).	20	31	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	22	23	30	31
For example , Rho A activates ROCK1 and ROCK2 in VSMCs XREF_BIBR and ROCK can directly phosphorylate myosin light chains in vitro at Ser19 XREF_BIBR .	For example, Rho A activates ROCK1 and ROCK2 in VSMCs XREF_BIBR and ROCK can directly phosphorylate myosin light chains in vitro at Ser19 XREF_BIBR.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	3	4	6	7
Indeed , we found selenite induced activation of Erk2-HA was inhibited when the association of ROCK1 with Erk2-HA was enhanced in cells ( XREF_FIG ) , where ROCK1 was upregulated by constitutively-active RhoA expression .	Indeed, we found selenite induced activation of Erk2-HA was inhibited when the association of ROCK1 with Erk2-HA was enhanced in cells (XREF_FIG), where ROCK1 was upregulated by constitutively-active RhoA expression.	27	34	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RhoA	RhoA expression	rhoa	ROCK1	ROCK1	rock1	32	33	27	28
[ XREF_BIBR ] Accordingly , it has been also shown that RhoA activates ROCK1 and ROCK2 in SMCs [ XREF_BIBR ] and that the ROCK1 inhibitor Y-27632 , RhoA/RhoB/RhoC inhibitor C3 exoenzyme , and ROCK inhibitor fasudil block SMCs migration .	[XREF_BIBR] Accordingly, it has been also shown that RhoA activates ROCK1 and ROCK2 in SMCs [XREF_BIBR] and that the ROCK1 inhibitor Y-27632, RhoA/RhoB/RhoC inhibitor C3 exoenzyme, and ROCK inhibitor fasudil block SMCs migration.	11	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	11	12	13	14
We infer the mechanism based upon XREF_FIG and XREF_FIG , Online XREF_SUPPLEMENTARY as follows : A1 : diabetes up-regulates Thbs1 ; A2 : no change in levels of LTBP1 was detected for this comparison ; A3 : the amount of activated Tgf-beta2 may increase because the total amount of Tgf-beta2 increases , and because of increased activation due to up-regulation of Thbs1 ; A4 : since Tgf-beta2 activates Tgf-betaR1 & 2 complex ( TGFBR ) and since the amount of activated Tgf-beta2 increases , the amount of activated TGFBR increases ; A5 and A6 : since no change in the amount of SMURF2 mRNA was detected in this comparison , interaction with SMURF2 , which targets Tgf-beta1 for destruction , will not change the amount of total or activated Tgfbeta-R ; A7 : since Tgf and betaR complex indirectly activates RhoA , and since the amount of activated Tgf and betaR complex increases , the amount of activated RhoA increases ; A8 : since RhoA activates ROCK1 , and since the amount of activated RhoA increases , the amount of activated ROCK1 increases ; A9 : since ROCK1 accelerates atherogenesis ( ATHRG ) , and since the extent of ROCK1 activation increases , acceleration of atherosclerosis ( ATHRG ) ensues .	We infer the mechanism based upon XREF_FIG and XREF_FIG, Online XREF_SUPPLEMENTARY as follows : A1 : diabetes up-regulates Thbs1; A2 : no change in levels of LTBP1 was detected for this comparison; A3 : the amount of activated Tgf-beta2 may increase because the total amount of Tgf-beta2 increases, and because of increased activation due to up-regulation of Thbs1; A4 : since Tgf-beta2 activates Tgf-betaR1 & 2 complex (TGFBR) and since the amount of activated Tgf-beta2 increases, the amount of activated TGFBR increases; A5 and A6 : since no change in the amount of SMURF2 mRNA was detected in this comparison, interaction with SMURF2, which targets Tgf-beta1 for destruction, will not change the amount of total or activated Tgfbeta-R; A7 : since Tgf and betaR complex indirectly activates RhoA, and since the amount of activated Tgf and betaR complex increases, the amount of activated RhoA increases; A8 : since RhoA activates ROCK1, and since the amount of activated RhoA increases, the amount of activated ROCK1 increases; A9 : since ROCK1 accelerates atherogenesis (ATHRG), and since the extent of ROCK1 activation increases, acceleration of atherosclerosis (ATHRG) ensues.	164	209	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	164	165	166	167
XREF_BIBR , XREF_BIBR Studies of regulatory activation of ROCK1 discovered that Rnd3 inhibits RhoA mediated ROCK1 signaling by specifically binding to ROCK1 but not ROCK2 .	XREF_BIBR, XREF_BIBR Studies of regulatory activation of ROCK1 discovered that Rnd3 inhibits RhoA mediated ROCK1 signaling by specifically binding to ROCK1 but not ROCK2.	13	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	13	14	15	16
Interestingly , several studies have shown that TGF-beta can induce the Rho GTPase signaling pathway that triggers the downstream effector protein ROCK1 in pulmonary and renal fibrosis XREF_BIBR .	Interestingly, several studies have shown that TGF-beta can induce the Rho GTPase signaling pathway that triggers the downstream effector protein ROCK1 in pulmonary and renal fibrosis XREF_BIBR.	11	27	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	11	12	21	22
For example , ethanol induces RhoA mediated ROCK1 activation , 42 and lipid mediators , such as arachidonic acid ( AA ) and sphingosylphosphorylcholine ( SPC ) , can also interact with the inhibitory ROCK carboxyl-terminal domain to stimulate ROCK activity independent of RhoA .	For example, ethanol induces RhoA mediated ROCK1 activation, 42 and lipid mediators, such as arachidonic acid (AA) and sphingosylphosphorylcholine (SPC), can also interact with the inhibitory ROCK carboxyl-terminal domain to stimulate ROCK activity independent of RhoA.	4	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	5	6	7	8
We generated a mouse with muscle specific , constitutively active ROCK1 and this mouse develops obesity and insulin resistance , suggesting two separate mechanisms are responsible for insulin resistance : 1 ) ROCK1 is activated by Rho A or Rho E causing PKC activation and suppressed glycogenesis XREF_BIBR .	We generated a mouse with muscle specific, constitutively active ROCK1 and this mouse develops obesity and insulin resistance, suggesting two separate mechanisms are responsible for insulin resistance : 1) ROCK1 is activated by Rho A or Rho E causing PKC activation and suppressed glycogenesis XREF_BIBR.	32	45	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	36	37	32	33
Importantly , inhibition of RhoA ( C3 transferase ) or ROCK ( Y-27632 ) significantly attenuated the upregulation of ROCK1 and ROCK2 induced by high glucose , while Y-27632 inhibited the upregulation of RhoA ( P < 0.05 ; n = 3 ) .	Importantly, inhibition of RhoA (C3 transferase) or ROCK (Y-27632) significantly attenuated the upregulation of ROCK1 and ROCK2 induced by high glucose, while Y-27632 inhibited the upregulation of RhoA (P < 0.05; n = 3).	2	22	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	4	5	19	20
Differently , Rho-A activates ROCK1 through interaction with carboxy-terminal site .	Differently, Rho-A activates ROCK1 through interaction with carboxy-terminal site.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho-A	Rho-A	Rho-A	ROCK1	ROCK1	ROCK1	2	3	4	5
ROCK-1 , which is activated by activated RhoA , promotes cell invasion and motility in prostate cancer and colorectal carcinoma cells .	ROCK-1, which is activated by activated RhoA, promotes cell invasion and motility in prostate cancer and colorectal carcinoma cells.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK-1	ROCK-1	ROCK-1	7	8	0	1
p160ROCK is a serine/threonine kinase that is activated by RhoA and has been shown to be a critical modulator of RhoA mediated actin dynamics .	p160ROCK is a serine/threonine kinase that is activated by RhoA and has been shown to be a critical modulator of RhoA mediated actin dynamics.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	p160ROCK	p160ROCK	p160ROCK	9	10	0	1
Several S/T kinases are activated by binding of Rho GTPases , for example ROCK1 is activated by RhoA and PAK1 is activated by Rac1 and Cdc42 [ XREF_BIBR , XREF_BIBR ] .	Several S/T kinases are activated by binding of Rho GTPases, for example ROCK1 is activated by RhoA and PAK1 is activated by Rac1 and Cdc42 [XREF_BIBR, XREF_BIBR].	12	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	17	18	13	14
In another study , downstream of activated KIT D814V receptor , a PI3Kinase and RHOA mediated activation of ROCK1 was shown to induce transformation and myeloproliferative neoplasm in mice [ XREF_BIBR ] .	In another study, downstream of activated KIT D814V receptor, a PI3Kinase and RHOA mediated activation of ROCK1 was shown to induce transformation and myeloproliferative neoplasm in mice [XREF_BIBR].	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	RHOA	RHOA	RHOA	ROCK1	ROCK1	ROCK1	14	15	18	19
RHOA mediated ROCK1 activity is required for caveolin 1 induced cell contraction , which enables cancer cells to align with and potentially to migrate along the pre-existing collagen matrix in vitro 149 .	RHOA mediated ROCK1 activity is required for caveolin 1 induced cell contraction, which enables cancer cells to align with and potentially to migrate along the pre-existing collagen matrix in vitro 149.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	RHOA	RHOA	RHOA	ROCK1	ROCK1	ROCK1	0	1	2	3
Thus , activation of ROCK1 by Rho A or Rho E seems to be important for the muscle glycogenesis , whereas constitutive activation of ROCK1 suppresses irisin production to impair impairing glucose uptake and energy expenditure .	Thus, activation of ROCK1 by Rho A or Rho E seems to be important for the muscle glycogenesis, whereas constitutive activation of ROCK1 suppresses irisin production to impair impairing glucose uptake and energy expenditure.	2	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	6	7	4	5
Though these studies are interesting , the exact molecular relationship between RhoC and ROCK-1 in RCC is unclear because ROCK-1 is generally activated by RhoA .	Though these studies are interesting, the exact molecular relationship between RhoC and ROCK-1 in RCC is unclear because ROCK-1 is generally activated by RhoA.	19	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK-1	ROCK-1	ROCK-1	24	25	19	20
However , there was no proteolytic cleavage of ROCK1 in dasatinib treated cells ( data not shown ) , consistent with RhoA activation of ROCK1 as the primary mechanism .	However, there was no proteolytic cleavage of ROCK1 in dasatinib treated cells (data not shown), consistent with RhoA activation of ROCK1 as the primary mechanism.	21	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	21	22	24	25
Then , RhoA induced ROCK1 activation takes place in different sites , precluding inhibition of tubule formation by RhoA activity .	Then, RhoA induced ROCK1 activation takes place in different sites, precluding inhibition of tubule formation by RhoA activity.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	2	3	4	5
XREF_BIBR Inhibition of RhoA blocks RhoA dependent ROCK1 activation and prevents downstream actin remodeling through the ROCK1/LIMK/cofilin pathway , thus reducing cell motility .	XREF_BIBR Inhibition of RhoA blocks RhoA dependent ROCK1 activation and prevents downstream actin remodeling through the ROCK1/LIMK/cofilin pathway, thus reducing cell motility.	1	8	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	3	4	7	8
We have previously shown that SPP86 inhibits GDNF- RET induced activation of the MAPK pathway at low doses [ XREF_BIBR ] .	We have previously shown that SPP86 inhibits GDNF- RET induced activation of the MAPK pathway at low doses [XREF_BIBR].	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	8	9	13	14
As a result , RET and PTC proteins constitutively activate the MAPK pathway without any ligand binding .	As a result, RET and PTC proteins constitutively activate the MAPK pathway without any ligand binding.	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	4	5	11	12
Either BRAF mutation or RET and PTC rearrangement can activate the mitogen activated protein kinase kinase ( MEK1/2 or MAPKK ) and downstream MAPK ( ERK1/2 ) signaling transduction pathway , resulting in the activation of a variety of transcription factors that regulate cellular proliferation , differentiation , and apoptosis .	Either BRAF mutation or RET and PTC rearrangement can activate the mitogen activated protein kinase kinase (MEK1/2 or MAPKK) and downstream MAPK (ERK1/2) signaling transduction pathway, resulting in the activation of a variety of transcription factors that regulate cellular proliferation, differentiation, and apoptosis.	4	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	4	5	23	24
The activated RET kinase is known to signal via extracellular signal regulated kinase ( ERK ) and phosphoinositide 3-kinase ( PI3K ) , leading to enhanced proliferation and resistance to apoptosis .	The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis.	2	13	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	extracellular signal regulated kinase	extracellular signal regulated kinase	extracellular signal regulated kinase	2	3	9	13
Although the effects of Ret signaling on GIRK2 have not been studied , it is tempting to speculate that the modulation of Ras and Mapk signaling by Ret and DJ-1 also affects GIRK2 function and vulnerability of dopaminergic neurons .	Although the effects of Ret signaling on GIRK2 have not been studied, it is tempting to speculate that the modulation of Ras and Mapk signaling by Ret and DJ-1 also affects GIRK2 function and vulnerability of dopaminergic neurons.	22	29	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Ret	Ret	Ret	Mapk	Mapk	Mapk	27	28	24	25
This work demonstrates clear synergism between RET activation of MAPK pathways and deregulation of cell cycle progression ( XREF_TABLE ) .	This work demonstrates clear synergism between RET activation of MAPK pathways and deregulation of cell cycle progression (XREF_TABLE).	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	6	7	9	10
The authors speculated that in the double mutants , the ERK MAPK pathway might be activated by RET via an alternative pathway involving PLC-gamma , allowing kidney development to proceed normally , and they did not suggest that other signaling molecules might substitute for GDNF under these conditions .	The authors speculated that in the double mutants, the ERK MAPK pathway might be activated by RET via an alternative pathway involving PLC-gamma, allowing kidney development to proceed normally, and they did not suggest that other signaling molecules might substitute for GDNF under these conditions.	10	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RET	RET	RET	ERK MAPK	ERK MAPK	ERK MAPK	17	18	10	12
These findings are in agreement with the notion the BRAF V600E and RET over-expression activate MAPK pathway more than HRAS Q61R and with the recent results of TCGA Consortium [ XREF_BIBR ] .	These findings are in agreement with the notion the BRAF V600E and RET over-expression activate MAPK pathway more than HRAS Q61R and with the recent results of TCGA Consortium [XREF_BIBR].	12	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET over-expression	ret	MAPK	MAPK	mapk	12	13	15	16
3 Activating mutations of BRAF , RAS or RET and PTC are observed in more than two-thirds of cases of human papillary thyroid carcinoma ( PTC ) , supporting activation of the MAPK pathway as a major genetic event in PTC carcinogenesis .	3 Activating mutations of BRAF, RAS or RET and PTC are observed in more than two-thirds of cases of human papillary thyroid carcinoma (PTC), supporting activation of the MAPK pathway as a major genetic event in PTC carcinogenesis.	2	33	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	8	9	32	33
So far the main molecular finding is the activating mutations of RAS and BRAF or rearrangement of RET , both of which activate the MAPK pathway .	So far the main molecular finding is the activating mutations of RAS and BRAF or rearrangement of RET, both of which activate the MAPK pathway.	9	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	17	18	24	25
Both BRAF and RET and PTC genetic alterations result in MAPK activation , even though they are associated to different phenotypes .	Both BRAF and RET and PTC genetic alterations result in MAPK activation, even though they are associated to different phenotypes.	1	12	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	3	4	10	11
Consistent with earlier experiments , placing a His tag at the N-terminus was detrimental to the biological activity of GDNF [ XREF_BIBR ] : there was significant reduction in the ability of His tagged zGDNF to elicit RET induced MAPK signaling ( XREF_SUPPLEMENTARY ) .	Consistent with earlier experiments, placing a His tag at the N-terminus was detrimental to the biological activity of GDNF [XREF_BIBR] : there was significant reduction in the ability of His tagged zGDNF to elicit RET induced MAPK signaling (XREF_SUPPLEMENTARY).	36	40	induced	Positive_early_activation	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	37	38	39	40
Ret activates the Ras and Erk MAP kinase , PLCgamma-Ca + and PI3K-Akt signaling pathways , all of which are important for normal kidney development .	Ret activates the Ras and Erk MAP kinase, PLCgamma-Ca + and PI3K-Akt signaling pathways, all of which are important for normal kidney development.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ret	Ret	Ret	Erk	Erk	Erk	0	1	5	6
In these cancers , RET activates the ERK and MAPK , the PI3K/AKT/mTOR and the JAK and STAT3 pathways .	In these cancers, RET activates the ERK and MAPK, the PI3K/AKT/mTOR and the JAK and STAT3 pathways.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	4	5	9	10
Phosphorylation of RET induced ERK activation and the migration of pancreatic cancer cells XREF_BIBR .	Phosphorylation of RET induced ERK activation and the migration of pancreatic cancer cells XREF_BIBR.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	RET	RET	RET	ERK	ERK	ERK	2	3	4	5
Most papillary thyroid cancer expresses RET and PTC or BRAF mutants , which activate the MAPK pathway of MEK-ERK .	Most papillary thyroid cancer expresses RET and PTC or BRAF mutants, which activate the MAPK pathway of MEK-ERK.	4	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	5	6	15	16
However , constitutive activation of ERK caused by a RET and PTC oncogene may or may not be sufficient to induce all hallmarks of cancer in vivo .	However, constitutive activation of ERK caused by a RET and PTC oncogene may or may not be sufficient to induce all hallmarks of cancer in vivo.	3	12	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RET	RET	RET	ERK	ERK	ERK	9	10	5	6
RET and PTC stimulates both the PI3K and AKT and the ERK pathways by recruiting several adaptors to phosphorylated Y1062 .	RET and PTC stimulates both the PI3K and AKT and the ERK pathways by recruiting several adaptors to phosphorylated Y1062.	0	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	ERK	ERK	ERK	0	1	11	12
RET activates FAK and MAPK .	RET activates FAK and MAPK.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	0	1	4	5
These differences suggest that although both BRAF mutation and the RET and PTC1 rearrangement are able to activate the MEK and ERK signal transduction pathway , other pathways not affected by PD0325901 may be involved in PTC cells with the RET and PTC rearrangements .	These differences suggest that although both BRAF mutation and the RET and PTC1 rearrangement are able to activate the MEK and ERK signal transduction pathway, other pathways not affected by PD0325901 may be involved in PTC cells with the RET and PTC rearrangements.	7	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	ERK	ERK	ERK	10	11	21	22
These results further support that the mechanism of CAKUT pathogenesis in patients with these RET mutations ( megaureters , dysplasia and cryptorchidism , and duplication ) is at least through modulation of RET activated MAPK activity .	These results further support that the mechanism of CAKUT pathogenesis in patients with these RET mutations (megaureters, dysplasia and cryptorchidism, and duplication) is at least through modulation of RET activated MAPK activity.	30	35	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	32	33	34	35
Furthermore , we found that DHA supplementation markedly increased the levels of GDNF and GFRalpha1 and the phosphorylation of RET , and led to the activation of the MAPK pathway in hippocampus tissue .	Furthermore, we found that DHA supplementation markedly increased the levels of GDNF and GFRalpha1 and the phosphorylation of RET, and led to the activation of the MAPK pathway in hippocampus tissue.	5	29	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	RET	DHA supplementation markedly increased the levels of GDNF and GFRalpha1 and the phosphorylation of RET	ret	MAPK	MAPK	mapk	19	20	28	29
RET stimulates MAPK and Akt and PKB signalling pathways , through Ras-Raf-Merk-Erk , Ras-PI3-K/Akt/PKB in vivo and vitro ( Melillo et al , 2005 ; Mitsutake et al , 2006 ; Santoro et al , 2006 ) .	RET stimulates MAPK and Akt and PKB signalling pathways, through Ras-Raf-Merk-Erk, Ras-PI3-K/Akt/PKB in vivo and vitro (Melillo et al, 2005; Mitsutake et al, 2006; Santoro et al, 2006).	0	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	0	1	2	3
RET and PTC , Ras , and receptor tyrosine kinase could dually activate the PI3K and Akt and MAPK pathways .	RET and PTC, Ras, and receptor tyrosine kinase could dually activate the PI3K and Akt and MAPK pathways.	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	0	1	18	19
Previous studies have shown that a subset of ERalpha positive breast cancers express high levels of mRNA transcripts encoding RET and that RET signaling in ERalpha positive breast cancer cell lines can result in the activation of MAPK and AKT , which are important regulators of ERalpha phosphorylation [ XREF_BIBR , XREF_BIBR ] .	Previous studies have shown that a subset of ERalpha positive breast cancers express high levels of mRNA transcripts encoding RET and that RET signaling in ERalpha positive breast cancer cell lines can result in the activation of MAPK and AKT, which are important regulators of ERalpha phosphorylation [XREF_BIBR, XREF_BIBR].	22	39	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	22	23	37	38
Ligand activation of the RET kinase activates a cascade of signaling pathways , e.g ., JAK , MAPK , c-Jun , NH2-terminal kinase , Ras/Raf/MAPK , NF-kappaB , and the PI3K and AKT pathways 31 .	Ligand activation of the RET kinase activates a cascade of signaling pathways, e.g., JAK, MAPK, c-Jun, NH2-terminal kinase, Ras/Raf/MAPK, NF-kappaB, and the PI3K and AKT pathways 31.	4	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	4	5	17	18
In Drosophila , MAPK , Src and PI3K can be activated by constitutively active Ret overexpression in the compound eye .	In Drosophila, MAPK, Src and PI3K can be activated by constitutively active Ret overexpression in the compound eye.	3	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ret	Ret overexpression	ret	MAPK	MAPK	mapk	14	15	3	4
RET and NF1 have both shown to activate the MAPK pathway of cellular signaling via abnormal RAS activation , which is involved in a wide variety of human tumors ( XREF_FIG ) .	RET and NF1 have both shown to activate the MAPK pathway of cellular signaling via abnormal RAS activation, which is involved in a wide variety of human tumors (XREF_FIG).	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	0	1	9	10
PF573228 also inhibited RET- dependent activation of Akt and ERK1/2 in MCF7 cells to a similar degree as SPP86 .	PF573228 also inhibited RET- dependent activation of Akt and ERK1/2 in MCF7 cells to a similar degree as SPP86.	3	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RET-	RET-	RET-	ERK1/2	ERK1/2	ERK1/2	3	4	9	10
Here we show that the 3 proteins function along a linear oncogenic signaling cascade in which RET and PTC induces RAS dependent BRAF activation and RAS- and BRAF dependent ERK activation .	Here we show that the 3 proteins function along a linear oncogenic signaling cascade in which RET and PTC induces RAS dependent BRAF activation and RAS- and BRAF dependent ERK activation.	16	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	ERK	ERK	ERK	16	17	29	30
RET ligands belong to the glial cell derived neurotrophic ( GDNF ) family , and upon engagement , RET induces activation of multiple signaling pathways : PI3K , MAPK , JNK , p38 , SRC , ERK5 , PLC-gamma , and STAT [ XREF_BIBR ] .	RET ligands belong to the glial cell derived neurotrophic (GDNF) family, and upon engagement, RET induces activation of multiple signaling pathways : PI3K, MAPK, JNK, p38, SRC, ERK5, PLC-gamma, and STAT [XREF_BIBR].	18	36	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	MAPK	MAPK	MAPK	18	19	28	29
BCPAP cells express the BRAF V600E mutation , which causes selective constitutive activation of MAPK signaling , while TPC1 cells express RET and PTC1 , a gene rearrangement that causes constitutive activation of the Ret tyrosine kinase , which activates MAPK and PI3K signaling .	BCPAP cells express the BRAF V600E mutation, which causes selective constitutive activation of MAPK signaling, while TPC1 cells express RET and PTC1, a gene rearrangement that causes constitutive activation of the Ret tyrosine kinase, which activates MAPK and PI3K signaling.	34	43	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ret	Ret	Ret	MAPK	MAPK	MAPK	34	35	40	41
The absence of effect in ERK phosphorylation after BRAF inhibition by RNAi in TPC1 cell line suggests that RET and PTC1 activates ERK by a mechanism independent of wild-type BRAF .	The absence of effect in ERK phosphorylation after BRAF inhibition by RNAi in TPC1 cell line suggests that RET and PTC1 activates ERK by a mechanism independent of wild-type BRAF.	18	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	ERK	ERK	ERK	18	19	22	23
RET9 and RET51 activate PI3K and AKT and ERK signalling with different dynamics and have distinct abilities to recruit Src or Frs2 , suggesting differential activation of downstream targetsby the two main RET isoforms .	RET9 and RET51 activate PI3K and AKT and ERK signalling with different dynamics and have distinct abilities to recruit Src or Frs2, suggesting differential activation of downstream targetsby the two main RET isoforms.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET51	RET51	RET51	ERK	ERK	ERK	2	3	8	9
Using the neuroectodermic SK-N-MC cell line , we found that the Ret tyrosine kinase activity is essential for GDNF to induce phosphatidylinositol 3-kinase ( PI3K )/Akt and ERK pathways as well as cell rescue .	Using the neuroectodermic SK-N-MC cell line, we found that the Ret tyrosine kinase activity is essential for GDNF to induce phosphatidylinositol 3-kinase (PI3K)/Akt and ERK pathways as well as cell rescue.	11	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ret	Ret	Ret	ERK	ERK	ERK	11	12	27	28
The PI3K and Akt signaling can also be activated by RET and PTC or Ras .	The PI3K and Akt signaling can also be activated by RET and PTC or Ras.	1	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RET	RET	RET	Akt	Akt	Akt	10	11	3	4
Stimulation of Ret51 expressing cells also fail to induce sustained activation of Erk-MAPK and can not activate PKB-Akt ( XREF_FIG ) .	Stimulation of Ret51 expressing cells also fail to induce sustained activation of Erk-MAPK and can not activate PKB-Akt (XREF_FIG).	2	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ret51	Ret51	Ret51	PKB-Akt	PKB-Akt	PKB-Akt	2	3	17	18
The association of ShcD with RET is not an extraordinary finding for Shc family proteins since ShcC has been identified as a physiological substrate of the activated RET oncoprotein , which activates the PI3K and AKT signalling pathway and promotes cancer cell survival XREF_BIBR .	The association of ShcD with RET is not an extraordinary finding for Shc family proteins since ShcC has been identified as a physiological substrate of the activated RET oncoprotein, which activates the PI3K and AKT signalling pathway and promotes cancer cell survival XREF_BIBR.	27	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	AKT	AKT	AKT	27	28	35	36
SPP86 may thus inhibit RET- mediated Akt activation in this cell line .	SPP86 may thus inhibit RET- mediated Akt activation in this cell line.	3	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	RET-	RET-	RET-	Akt	Akt	Akt	4	5	6	7
We observed , as we have previously described , that the presence of GAS1 reduces RET phosphorylation and inhibits the activation of AKT .	We observed, as we have previously described, that the presence of GAS1 reduces RET phosphorylation and inhibits the activation of AKT.	13	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RET	GAS1 reduces RET phosphorylation	ret	AKT	AKT	akt	15	16	22	23
RET overexpression was shown to promote AKT activation , which is consistent with previous reports , however coexpression with ShcD inhibited this activation in the presence of GDNF .	RET overexpression was shown to promote AKT activation, which is consistent with previous reports, however coexpression with ShcD inhibited this activation in the presence of GDNF.	0	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET overexpression	ret	AKT	AKT	akt	0	1	6	7
IRS-1 coimmunoprecipitates with Ret and co-expression of IRS-1 results in the potentiation of Ret mediated activation of Akt ( PKB ) , a bona fide effector of PI3-K .	IRS-1 coimmunoprecipitates with Ret and co-expression of IRS-1 results in the potentiation of Ret mediated activation of Akt (PKB), a bona fide effector of PI3-K.	11	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ret	Ret	Ret	Akt	Akt	Akt	13	14	17	18
Proliferation of thyroid cancer cells OCUT1 , K1 , FTC133 , C643 , Hth7 , and TPC1 , which harbored PIK3CA , PTEN , Ras , or RET and PTC mutations that could activate the PI3K and Akt pathway , was potently inhibited by MK2206 with IC ( 50 ) values mostly below or around 0.5 mum .	Proliferation of thyroid cancer cells OCUT1, K1, FTC133, C643, Hth7, and TPC1, which harbored PIK3CA, PTEN, Ras, or RET and PTC mutations that could activate the PI3K and Akt pathway, was potently inhibited by MK2206 with IC (50) values mostly below or around 0.5 mum.	27	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	Akt	Akt	Akt	27	28	37	38
Protein RAS and fusion protein RET and PTC may activate the PI3K and AKT ( phosphatidylinositol 3-kinase/Akt ) signaling pathway through the loss of function of PTEN [ XREF_BIBR ] .	Protein RAS and fusion protein RET and PTC may activate the PI3K and AKT (phosphatidylinositol 3-kinase/Akt) signaling pathway through the loss of function of PTEN [XREF_BIBR].	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	AKT	AKT	AKT	5	6	13	14
Additionally , RET- FAK crosstalk may play a key role in facilitating PTC1 and RET and GDNF- RET induced activation of Akt and MAPK signaling in TPC1 and MCF7 cells .	Additionally, RET- FAK crosstalk may play a key role in facilitating PTC1 and RET and GDNF- RET induced activation of Akt and MAPK signaling in TPC1 and MCF7 cells.	16	24	induced	Positive_early_activation	Positive_activation	Positive_activation	RET	RET	RET	Akt	Akt	Akt	17	18	21	22
25 While RET activation principally induces the RAS-RAF-MEK-ERK mitogen activated protein kinase ( MAPK ) pathway , RET can also activate phosphatidylinositol-3-kinase and Akt ( PI3K and Akt ) , janus activated kinase and signal transducers and activators of transcription ( JAK and STAT ) , and jun-N terminal kinase ( JNK ) , among other pathways ( XREF_FIG ) .	25 While RET activation principally induces the RAS-RAF-MEK-ERK mitogen activated protein kinase (MAPK) pathway, RET can also activate phosphatidylinositol-3-kinase and Akt (PI3K and Akt), janus activated kinase and signal transducers and activators of transcription (JAK and STAT), and jun-N terminal kinase (JNK), among other pathways (XREF_FIG).	17	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	Akt	Akt	Akt	17	18	23	24
The deletion of asparagine 1059 ( delN1059 ) and the substitution of leucine 1061 ( L1061P ) , two Ret mutations identified in families affected by congenital megacolon ( Hirschsprung ' s disease ) , impair the binding of IRS-1 to Ret as well as Ret mediated Akt ( PKB ) stimulation .	The deletion of asparagine 1059 (delN1059) and the substitution of leucine 1061 (L1061P), two Ret mutations identified in families affected by congenital megacolon (Hirschsprung 's disease), impair the binding of IRS-1 to Ret as well as Ret mediated Akt (PKB) stimulation.	45	49	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ret	Ret	Ret	Akt	Akt	Akt	45	46	47	48
Ret is a potent activator of both PI3K and Akt and Ras and ERK , and the loss of cell bodies , axons , and reduced cell size in DAT-Ret mice suggest possible defects in PI3K and Akt and/or Ras and ERK signaling .	Ret is a potent activator of both PI3K and Akt and Ras and ERK, and the loss of cell bodies, axons, and reduced cell size in DAT-Ret mice suggest possible defects in PI3K and Akt and/or Ras and ERK signaling.	0	25	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Ret	Ret	Ret	Akt	Akt	Akt	0	1	9	10
In one scenario , RET phosphorylation induces SRC family kinases ( SFKs ) and PI3K and AKT activation and ultimately the upregulation of Mycn .	In one scenario, RET phosphorylation induces SRC family kinases (SFKs) and PI3K and AKT activation and ultimately the upregulation of Mycn.	4	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET phosphorylation	ret	AKT	AKT	akt	4	5	16	17
Dominant activating mutations of RET ( Rearranged during Transfection ) proto-oncogene have been identified in MTC , and constitutively active RET kinases activate the PI3K and Akt pathway [ XREF_BIBR ] .	Dominant activating mutations of RET (Rearranged during Transfection) proto-oncogene have been identified in MTC, and constitutively active RET kinases activate the PI3K and Akt pathway [XREF_BIBR].	20	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	Akt	Akt	Akt	20	21	26	27
Taken together , the results show that Ret inhibition alone significantly blocked the activation status of Fak , Stat3 and Akt .	Taken together, the results show that Ret inhibition alone significantly blocked the activation status of Fak, Stat3 and Akt.	7	21	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Ret	Ret	Ret	Akt	Akt	Akt	7	8	20	21
Interestingly , SPP86 and PF573228 inhibited RET and PTC1 and GDNF- RET induced activation of Akt and MAPK signaling to a similar degree .	Interestingly, SPP86 and PF573228 inhibited RET and PTC1 and GDNF- RET induced activation of Akt and MAPK signaling to a similar degree.	6	18	induced	Positive_early_activation	Positive_activation	Positive_activation	RET	RET	RET	Akt	Akt	Akt	11	12	15	16
Previous studies have revealed that RET activates the Raf and MEK and PI3K and Akt downstream signaling pathways , which in turn phosphorylate and activate ERK1/2 and mammalian target of rapamycin ( mTOR ) proteins , respectively .	Previous studies have revealed that RET activates the Raf and MEK and PI3K and Akt downstream signaling pathways, which in turn phosphorylate and activate ERK1/2 and mammalian target of rapamycin (mTOR) proteins, respectively.	5	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	Akt	Akt	Akt	5	6	14	15
pS473Akt levels are also high in the tumours and only Ret inhibition caused a significant decrease in Akt activity ( XREF_FIG , XREF_FIG and Supporting Information XREF_SUPPLEMENTARY D ) .	pS473Akt levels are also high in the tumours and only Ret inhibition caused a significant decrease in Akt activity (XREF_FIG, XREF_FIG and Supporting Information XREF_SUPPLEMENTARY D).	10	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ret	Ret	Ret	Akt	Akt	Akt	10	11	17	18
Activation of the Ret kinase inhibits apoptosis and promotes survival through Ret induced AKT signaling , making apoptosis and survival of neurons dependent on the presence of GFRalpha receptors [ XREF_BIBR ] .	Activation of the Ret kinase inhibits apoptosis and promotes survival through Ret induced AKT signaling, making apoptosis and survival of neurons dependent on the presence of GFRalpha receptors [XREF_BIBR].	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Ret	Ret	Ret	AKT	AKT	AKT	11	12	13	14
The activation of PKB by RET and PTC blocked the activity of the forkhead transcription factor , FKHRL1 , but a Y315F mutant of PKB failed to inhibit FKHRL1 activity .	The activation of PKB by RET and PTC blocked the activity of the forkhead transcription factor, FKHRL1, but a Y315F mutant of PKB failed to inhibit FKHRL1 activity.	1	7	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RET	RET	RET	PKB	PKB	PKB	5	6	3	4
Furthermore , it is likely that cochlear neurons behave differently from nodose neurons , in which Ret but not NCAM activates PI3K and Akt signaling upon GDNF and GFRalpha1 stimulation .	Furthermore, it is likely that cochlear neurons behave differently from nodose neurons, in which Ret but not NCAM activates PI3K and Akt signaling upon GDNF and GFRalpha1 stimulation.	16	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ret	Ret	Ret	Akt	Akt	Akt	16	17	23	24
Wild-type and truncated forms of RET and PTC activate the PI3K and AKT pathway leading to tumorigenesis [ XREF_BIBR , XREF_BIBR ] .	Wild-type and truncated forms of RET and PTC activate the PI3K and AKT pathway leading to tumorigenesis [XREF_BIBR, XREF_BIBR].	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	AKT	AKT	AKT	5	6	12	13
Ret induces the serine/threonine kinase AKT and extracellular signal regulated kinase ( ERK ) signaling which mediate pro survival and neurotrophic activities .	Ret induces the serine/threonine kinase AKT and extracellular signal regulated kinase (ERK) signaling which mediate pro survival and neurotrophic activities.	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ret	Ret	Ret	AKT	AKT	AKT	0	1	5	6
Finally , activation of the RET proto-oncogene can activate the PI3K and Akt pathway , and activating mutations of the RET protein are associated with both sporadic and hereditary MTC [ XREF_BIBR ] .	Finally, activation of the RET proto-oncogene can activate the PI3K and Akt pathway, and activating mutations of the RET protein are associated with both sporadic and hereditary MTC [XREF_BIBR].	5	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	Akt	Akt	Akt	5	6	12	13
Phospholipase D ( PLD ) was shown to be one such target several years ago ; more recent work from our laboratory and others has demonstrated that of the two mammalian PLD isozymes , PLD1 but not PLD2 is activated by RhoA and this activation proceeds through direct binding both in vitro and in vivo .	Phospholipase D (PLD) was shown to be one such target several years ago; more recent work from our laboratory and others has demonstrated that of the two mammalian PLD isozymes, PLD1 but not PLD2 is activated by RhoA and this activation proceeds through direct binding both in vitro and in vivo.	34	42	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	PLD1	PLD1	PLD1	41	42	34	35
ARF and Rho family GTPases synergize to significantly increase PLD1 activity beyond an additive response .	ARF and Rho family GTPases synergize to significantly increase PLD1 activity beyond an additive response.	0	10	synergize	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	PLD1	PLD1	PLD1	2	3	9	10
There is abundant evidence that PLD1 ( but not PLD2 ) is activated by the Rho family GTPases RhoA , Rac1 , and Cdc42 , with RhoA being the most efficacious [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	There is abundant evidence that PLD1 (but not PLD2) is activated by the Rho family GTPases RhoA, Rac1, and Cdc42, with RhoA being the most efficacious [XREF_BIBR, XREF_BIBR - XREF_BIBR].	5	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	PLD1	PLD1	PLD1	15	16	5	6
PLD1 is activated in a synergistic manner in vitro by protein kinase C-alpha , ADP ribosylation factor 1 ( ARF1 ) , and Rho family members .	PLD1 is activated in a synergistic manner in vitro by protein kinase C-alpha, ADP ribosylation factor 1 (ARF1), and Rho family members.	0	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	PLD1	PLD1	PLD1	23	24	0	1
Rho , Cdc42 , and Rac1 are binding activators of PLD1 , and stimulate substrate binding affinity ( 1/K m ) .125 Arf and Rho family GTPases synergize to significantly increase PLD1 activity beyond an additive response .	Rho, Cdc42, and Rac1 are binding activators of PLD1, and stimulate substrate binding affinity (1/K m).125 Arf and Rho family GTPases synergize to significantly increase PLD1 activity beyond an additive response.	24	32	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	PLD1	PLD1	PLD1	24	25	31	32
First , RhoA can activate PLD1 through direct interaction with its C-terminus [ XREF_BIBR ] .	First, RhoA can activate PLD1 through direct interaction with its C-terminus [XREF_BIBR].	2	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	PLD1	PLD1	PLD1	2	3	5	6
The transfection of RhoA , Cdc42 , or Rac1 can activate PLD1 , which has been implicated in the regulation of the actin cytoskeleton .	The transfection of RhoA, Cdc42, or Rac1 can activate PLD1, which has been implicated in the regulation of the actin cytoskeleton.	1	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	PLD1	PLD1	PLD1	3	4	11	12
Rho proteins , in particular RhoA , Rac1 and Cdc42 , which control actin cytoskeleton reorganization , exclusively activate PLD1 by direct interaction with its C-terminus .	Rho proteins, in particular RhoA, Rac1 and Cdc42, which control actin cytoskeleton reorganization, exclusively activate PLD1 by direct interaction with its C-terminus.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	PLD1	PLD1	PLD1	0	1	19	20
Inhibition of Rho with C3 exotoxin and a dominant negative Rho adenovirus and inhibition of ROCK with Y-27632 inhibited Cch stimulated PLD1 activity , increased protein secretion , and decreased ERK activity .	Inhibition of Rho with C3 exotoxin and a dominant negative Rho adenovirus and inhibition of ROCK with Y-27632 inhibited Cch stimulated PLD1 activity, increased protein secretion, and decreased ERK activity.	10	22	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rho	Rho	Rho	PLD1	PLD1	PLD1	10	11	21	22
PLD1 exhibits a low basal activity and is activated by Arf , RhoA and PKC [ XREF_BIBR , XREF_BIBR ] .	PLD1 exhibits a low basal activity and is activated by Arf, RhoA and PKC [XREF_BIBR, XREF_BIBR].	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	PLD1	PLD1	PLD1	12	13	0	1
RhoA activated PLD1 appears to be the intersection point between Rho and Rap signaling .	RhoA activated PLD1 appears to be the intersection point between Rho and Rap signaling.	0	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	PLD1	PLD1	PLD1	0	1	2	3
The results further substantiate our previous finding that RhoA activates PLD1 through direct interaction .	The results further substantiate our previous finding that RhoA activates PLD1 through direct interaction.	8	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	PLD1	PLD1	PLD1	8	9	10	11
In membranes , which contain both PLD1 and PLD2 , the stimulatory effect of S1P on PLD activity can best be explained by RhoA- and PKCdelta dependent activation of PLD1 ; in contrast , the effects of BK on RhoA translocation and enhancement of BK stimulated PLD activity by PKC inhibition are both consistent with PLD2 serving as its primary target .	In membranes, which contain both PLD1 and PLD2, the stimulatory effect of S1P on PLD activity can best be explained by RhoA- and PKCdelta dependent activation of PLD1; in contrast, the effects of BK on RhoA translocation and enhancement of BK stimulated PLD activity by PKC inhibition are both consistent with PLD2 serving as its primary target.	23	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RhoA-	RhoA-	RhoA-	PLD1	PLD1	PLD1	23	24	29	30
Finally , we show that recombinant D4 peptide inhibits RhoA stimulated PLD1 activation but not ARF- or PKC-alpha-stimulated PLD1 activation .	Finally, we show that recombinant D4 peptide inhibits RhoA stimulated PLD1 activation but not ARF- or PKC-alpha-stimulated PLD1 activation.	8	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	PLD1	PLD1	PLD1	9	10	11	12
However , this insert is not necessary for RhoA or Rac activation of PLD1 .	However, this insert is not necessary for RhoA or Rac activation of PLD1.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	PLD1	PLD1	PLD1	8	9	13	14
We additionally reported that PLD1 is activated in a synergistic manner by protein kinase c-alpha ( PKC-alpha ) , ADP ribosylation factor 1 ( ARF1 ) , and Rho family members .	We additionally reported that PLD1 is activated in a synergistic manner by protein kinase c-alpha (PKC-alpha), ADP ribosylation factor 1 (ARF1), and Rho family members.	4	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	PLD1	PLD1	PLD1	28	29	4	5
PLD1 , but not PLD2 , was shown to contribute to acidic pH e -induced MMP-9 signaling , with RhoA activating PLD1 [ XREF_BIBR ] .	PLD1, but not PLD2, was shown to contribute to acidic pH e -induced MMP-9 signaling, with RhoA activating PLD1 [XREF_BIBR].	16	23	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	PLD1	PLD1	PLD1	19	20	21	22
In contrast , hPLD1 activity was enhanced more readily by overexpression of RhoA .	In contrast, hPLD1 activity was enhanced more readily by overexpression of RhoA.	3	13	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RhoA	overexpression of RhoA	rhoa	hPLD1	hPLD1	hpld1	12	13	3	4
As noted above , Rho proteins , such as RhoA , are known to activate PLD1 .	As noted above, Rho proteins, such as RhoA, are known to activate PLD1.	4	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	PLD1	PLD1	PLD1	4	5	15	16
380 Rho , Cdc42 , and Rac1 selectively activate PLD1 .	380 Rho, Cdc42, and Rac1 selectively activate PLD1.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	PLD1	PLD1	PLD1	1	2	9	10
RhoA directly stimulates DIAPH1 , leading to direct interaction with profilin and stimulation of actin polymerization .	RhoA directly stimulates DIAPH1, leading to direct interaction with profilin and stimulation of actin polymerization.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	DIAPH1	DIAPH1	DIAPH1	0	1	3	4
For example , lysophosphatidic acid ( LPA )-stimulated activation of Rho promotes the activation of DIAPH1 and subsequent formation of actin filaments .	For example, lysophosphatidic acid (LPA)-stimulated activation of Rho promotes the activation of DIAPH1 and subsequent formation of actin filaments.	8	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rho	Rho	Rho	DIAPH1	DIAPH1	DIAPH1	10	11	15	16
( Pro ) renin receptor activation by renin or prorenin mediates both Ang II dependent and independent pathways .	(Pro) renin receptor activation by renin or prorenin mediates both Ang II dependent and independent pathways.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	renin	renin	renin	renin receptor	renin receptor	renin receptor	7	8	3	5
Since renin can promote intracellular signaling by direct binding to the ( pro ) renin receptor independent of angiotensin receptor activation , it is possible that renin may have direct effect on kinases that promote signaling via the PI3K and Akt pathway .	Since renin can promote intracellular signaling by direct binding to the (pro) renin receptor independent of angiotensin receptor activation, it is possible that renin may have direct effect on kinases that promote signaling via the PI3K and Akt pathway.	1	16	promote	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	renin	renin	renin	renin receptor	renin receptor	renin receptor	1	2	14	16
We revisited these areas and critically examined the relationship between elevated levels of circulating prorenin and renin induced activation of the ( pro ) renin receptor and incidences of hypertension and end-organ damage .	We revisited these areas and critically examined the relationship between elevated levels of circulating prorenin and renin induced activation of the (pro) renin receptor and incidences of hypertension and end-organ damage.	14	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	renin receptor	renin receptor	renin receptor	16	17	24	26
This could potentially be harmful because high levels of renin and prorenin may stimulate the ( pro ) renin receptor , thus inducing profibrotic effects .	This could potentially be harmful because high levels of renin and prorenin may stimulate the (pro) renin receptor, thus inducing profibrotic effects.	7	20	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	levels of renin	renin	renin receptor	renin receptor	renin receptor	9	10	18	20
Similar effect was found when renin was dialyzed inside the heart cells - an effect not necessarily related to Ang II formation , but in part related to oxidative stress probably induced by the activation of an intracellular renin receptor elicited by renin .	Similar effect was found when renin was dialyzed inside the heart cells - an effect not necessarily related to Ang II formation, but in part related to oxidative stress probably induced by the activation of an intracellular renin receptor elicited by renin.	38	43	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	renin receptor	renin receptor	renin receptor	42	43	38	40
Renin has been shown to increase TGF-beta and Col-1 mRNA abundance in an angiotensin independent manner by stimulating the ( pro ) renin receptor .	Renin has been shown to increase TGF-beta and Col-1 mRNA abundance in an angiotensin independent manner by stimulating the (pro) renin receptor.	0	24	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Renin	Renin	Renin	renin receptor	renin receptor	renin receptor	0	1	22	24
Is it possible that the activation of the intracellular renin receptor elicited by renin increases the oxidative stress through the PI3K-Akt signal pathway and reduces the gap junction permeability ?	Is it possible that the activation of the intracellular renin receptor elicited by renin increases the oxidative stress through the PI3K-Akt signal pathway and reduces the gap junction permeability?	9	14	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	renin receptor	renin receptor	renin receptor	13	14	9	11
Even though aliskiren could possibly modify pro renin molecule and prevents its conversion to active renin , preliminary evidence indicate that aliskiren does not inhibit the renin induced or pro renin induced activation of the ( pro ) renin receptor .	Even though aliskiren could possibly modify pro renin molecule and prevents its conversion to active renin, preliminary evidence indicate that aliskiren does not inhibit the renin induced or pro renin induced activation of the (pro) renin receptor.	29	40	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	renin receptor	renin receptor	renin receptor	30	31	38	40
However , drugs fail to absolutely block RAAS activity with increasing the concentration of renin because they attenuate the negative feedback effect of Ang II on renin release , and such high renin levels will activate the ( pro ) renin receptor ( ( P ) RR ) .	However, drugs fail to absolutely block RAAS activity with increasing the concentration of renin because they attenuate the negative feedback effect of Ang II on renin release, and such high renin levels will activate the (pro) renin receptor ((P) RR).	32	42	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin levels	renin	renin receptor	renin receptor	renin receptor	32	33	40	42
XREF_BIBR , XREF_BIBR As mentioned previously , high levels of renin can activate the prorenin and renin receptor , which aside from activating prorenin , can possibly initiate ERK1/2 signaling and transform growth factor-beta activation and other potentially serious complications .	XREF_BIBR, XREF_BIBR As mentioned previously, high levels of renin can activate the prorenin and renin receptor, which aside from activating prorenin, can possibly initiate ERK1/2 signaling and transform growth factor-beta activation and other potentially serious complications.	8	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	levels of renin	renin	renin receptor	renin receptor	renin receptor	10	11	16	18
indicated , for instance , that there is an intracellular renin receptor , which when activated by intracellular renin causes the translocation of a transcription factor ( PLZF ) from the cytoplasm to the nucleus and consequent activation of several genes including an enhanced transcription of the p85alpha subunit of the phosphatidylinositol-3 kinase ( PI3K-p85alpha ) .	indicated, for instance, that there is an intracellular renin receptor, which when activated by intracellular renin causes the translocation of a transcription factor (PLZF) from the cytoplasm to the nucleus and consequent activation of several genes including an enhanced transcription of the p85alpha subunit of the phosphatidylinositol-3 kinase (PI3K-p85alpha).	10	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	renin	renin	renin	renin receptor	renin receptor	renin receptor	18	19	10	12
XREF_BIBR Increased plasma renin concentration occurs to a greater extent with aliskiren than with other ACE inhibitors and ARBs , and might be an important issue because prorenin and renin have been shown to stimulate the ( pro ) renin receptor and induce fibrosis , apoptosis , and organ hypertrophy in experimental disease models .	XREF_BIBR Increased plasma renin concentration occurs to a greater extent with aliskiren than with other ACE inhibitors and ARBs, and might be an important issue because prorenin and renin have been shown to stimulate the (pro) renin receptor and induce fibrosis, apoptosis, and organ hypertrophy in experimental disease models.	27	41	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	renin receptor	renin receptor	renin receptor	29	30	39	41
Furthermore , overexpression of Rheb in HEK293cells resulted in the activation of PLD1 .	Furthermore, overexpression of Rheb in HEK293cells resulted in the activation of PLD1.	2	13	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	PLD1	PLD1	pld1	4	5	12	13
Importantly , very recent data reveals that Rheb directly interacts with and activates PLD1 [ XREF_BIBR , XREF_BIBR ] .	Importantly, very recent data reveals that Rheb directly interacts with and activates PLD1 [XREF_BIBR, XREF_BIBR].	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	PLD1	PLD1	PLD1	7	8	13	14
The overexpression of Rheb activates PLD1 in cells in the absence of mitogenic stimulation , and the knockdown of Rheb impairs serum stimulation of PLD activation .	The overexpression of Rheb activates PLD1 in cells in the absence of mitogenic stimulation, and the knockdown of Rheb impairs serum stimulation of PLD activation.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	overexpression of Rheb	rheb	PLD1	PLD1	pld1	3	4	5	6
XREF_BIBR , XREF_BIBR Rheb , a member of the Ras GTPase family , has also been reported to directly activate PLD1 in vitro .	XREF_BIBR, XREF_BIBR Rheb, a member of the Ras GTPase family, has also been reported to directly activate PLD1 in vitro.	0	21	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	PLD1	PLD1	PLD1	3	4	20	21
XREF_BIBR This group has more recently demonstrated that PLD1 is activated by the GTPase Rheb , which has been implicated in signals that activate mTOR .	XREF_BIBR This group has more recently demonstrated that PLD1 is activated by the GTPase Rheb, which has been implicated in signals that activate mTOR.	8	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	PLD1	PLD1	PLD1	14	15	8	9
And the recent finding that Rheb , which is implicated in the activation of mTORC1 , directly activates PLD1 [ XREF_BIBR ] strongly supports a role for PLD1 in the activation of mTORC1 .	And the recent finding that Rheb, which is implicated in the activation of mTORC1, directly activates PLD1 [XREF_BIBR] strongly supports a role for PLD1 in the activation of mTORC1.	5	20	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	PLD1	PLD1	PLD1	5	6	18	19
Importantly , it was recently reported that the GTPase Rheb activates PLD1 [ XREF_BIBR ] .	Importantly, it was recently reported that the GTPase Rheb activates PLD1 [XREF_BIBR].	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	PLD1	PLD1	PLD1	9	10	11	12
In vitro , BT13 stimulated phosphorylation of RET , as well as RET dependent intracellular signaling , but activated neither NGF receptor TrkA nor BDNF receptor TrkB nor intracellular signaling in the absence of RET .	In vitro, BT13 stimulated phosphorylation of RET, as well as RET dependent intracellular signaling, but activated neither NGF receptor TrkA nor BDNF receptor TrkB nor intracellular signaling in the absence of RET.	3	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	BT13 stimulated phosphorylation of RET	ret	RET	RET	ret	7	8	34	35
In additional pre-clinical studies , XREF_BIBR have shown that ZD6474 blocks in vivo phosphorylation and signaling of the RET and PTC3 and RET and MEN2B oncoproteins , inhibits the proliferative autonomy of RET and PTC3 transformed cells , and prevents the growth of two human PTC cell lines that carry spontaneous RET and PTC1 rearrangements .	In additional pre-clinical studies, XREF_BIBR have shown that ZD6474 blocks in vivo phosphorylation and signaling of the RET and PTC3 and RET and MEN2B oncoproteins, inhibits the proliferative autonomy of RET and PTC3 transformed cells, and prevents the growth of two human PTC cell lines that carry spontaneous RET and PTC1 rearrangements.	9	33	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RET	ZD6474 blocks in vivo phosphorylation and signaling of the RET	ret	RET	RET	ret	18	19	32	33
Furthermore , we show that pRb can also restore MyoD activity and muscle cell differentiation in cells with amplified MDM2 .	Furthermore, we show that pRb can also restore MyoD activity and muscle cell differentiation in cells with amplified MDM2.	5	10	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pRb	pRb	pRb	MyoD	MyoD	MyoD	5	6	9	10
Moreover , our findings may also be consistent with a second model in which pRb enhances the activation of MyoD target genes by sequestering the histone deacetylase 1 repressor away from MyoD .	Moreover, our findings may also be consistent with a second model in which pRb enhances the activation of MyoD target genes by sequestering the histone deacetylase 1 repressor away from MyoD.	14	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pRb	pRb	pRb	MyoD	MyoD	MyoD	14	15	19	20
Since MyoD activity was rescued by exogenous pRb overexpression , we evaluated the differentiation capacity of these cells .	Since MyoD activity was rescued by exogenous pRb overexpression, we evaluated the differentiation capacity of these cells.	1	9	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	pRb	pRb overexpression	prb	MyoD	MyoD	myod	7	8	1	2
Therefore , pRb likely potentiates MyoD activity via an indirect mechanism not involving binding Rb to MyoD .	Therefore, pRb likely potentiates MyoD activity via an indirect mechanism not involving binding Rb to MyoD.	2	6	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pRb	pRb	pRb	MyoD	MyoD	MyoD	2	3	5	6
Therefore , both Rb and myogenin are immediate early targets of MyoD mediated transcriptional activation during the switch to myogenic differentiation .	Therefore, both Rb and myogenin are immediate early targets of MyoD mediated transcriptional activation during the switch to myogenic differentiation.	2	12	are immediate early targets	Positive_activation_copula_1	Positive_activation	Positive_activation	Rb	Rb	Rb	MyoD	MyoD	MyoD	3	4	11	12
The idea that Rb promotes muscle differentiation by potentiating Myod1 activity was contested [ XREF_BIBR ] , and other mechanisms proposed [ XREF_BIBR , XREF_BIBR ] , but not involving E2f repression .	The idea that Rb promotes muscle differentiation by potentiating Myod1 activity was contested [XREF_BIBR], and other mechanisms proposed [XREF_BIBR, XREF_BIBR], but not involving E2f repression.	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rb	Rb	Rb	Myod1	Myod1	Myod1	3	4	9	10
Precisely how pRB augments MyoD is not known but it seems to involve influencing phosphorylation of MEF2C that is necessary for maximal transcription of late markers [ XREF_BIBR ] .	Precisely how pRB augments MyoD is not known but it seems to involve influencing phosphorylation of MEF2C that is necessary for maximal transcription of late markers [XREF_BIBR].	2	5	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pRB	pRB	pRB	MyoD	MyoD	MyoD	2	3	4	5
The transduction of exogenous TP53 or Rb genes in p53 defective myoblasts rescues MyoD activity and differentiation potential .	The transduction of exogenous TP53 or Rb genes in p53 defective myoblasts rescues MyoD activity and differentiation potential.	6	14	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rb	Rb	Rb	MyoD	MyoD	MyoD	6	7	13	14
Reelin , a large protein that regulates neuronal migration during embryonic development , activates a conserved signaling pathway that requires its receptors , very low-density lipoprotein receptor and apolipoprotein E receptor 2 , the cytoplasmic adaptor protein Disabled-1 ( Dab1 ) , and Src family kinases ( SFK ) .	Reelin, a large protein that regulates neuronal migration during embryonic development, activates a conserved signaling pathway that requires its receptors, very low-density lipoprotein receptor and apolipoprotein E receptor 2, the cytoplasmic adaptor protein Disabled-1 (Dab1), and Src family kinases (SFK).	0	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Reelin	Reelin	Reelin	very low-density lipoprotein receptor	very low-density lipoprotein receptor	very low-density lipoprotein receptor	0	1	23	27
These results suggest that binding of Reelin , which exists as a homodimer in vivo , to ApoER2 and VLDLR induces clustering of ApoER2 and VLDLR .	These results suggest that binding of Reelin, which exists as a homodimer in vivo, to ApoER2 and VLDLR induces clustering of ApoER2 and VLDLR.	4	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Reelin	Reelin	Reelin	VLDLR	VLDLR	VLDLR	6	7	25	26
Interaction with Reelin induces VLDLR and ApoER2 to bind the adaptor protein DAB1 , which leads to activation of Src family tyrosine kinases ( SFKs ) and other kinases that phosphorylate DAB1 at its tyrosine residues .	Interaction with Reelin induces VLDLR and ApoER2 to bind the adaptor protein DAB1, which leads to activation of Src family tyrosine kinases (SFKs) and other kinases that phosphorylate DAB1 at its tyrosine residues.	0	8	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Reelin	Reelin	Reelin	VLDLR	VLDLR	VLDLR	2	3	4	5
Altogether , these studies support the hypothesis that Reelin can induce Apoer2 and Vldlr dependent signaling by clustering Dab1 on the cytoplasmic leaflet of the plasma membrane , bringing it into close proximity with SFK , without the need for an additional coreceptor .	Altogether, these studies support the hypothesis that Reelin can induce Apoer2 and Vldlr dependent signaling by clustering Dab1 on the cytoplasmic leaflet of the plasma membrane, bringing it into close proximity with SFK, without the need for an additional coreceptor.	8	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Reelin	Reelin	Reelin	Vldlr	Vldlr	Vldlr	8	9	13	14
Interaction with Reelin induces VLDLR and ApoER2 to bind the adaptor protein Dab1 at an NPxY motif on their cytoplasmic tails [ XREF_BIBR , XREF_BIBR ] .	Interaction with Reelin induces VLDLR and ApoER2 to bind the adaptor protein Dab1 at an NPxY motif on their cytoplasmic tails [XREF_BIBR, XREF_BIBR].	0	8	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Reelin	Reelin	Reelin	VLDLR	VLDLR	VLDLR	2	3	4	5
Therefore , we asked whether Reelin could modulate the interaction of VLDLR with GluA1 , RasGRF1 , and/or CamKIIalpha .	Therefore, we asked whether Reelin could modulate the interaction of VLDLR with GluA1, RasGRF1, and/or CamKIIalpha.	5	12	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Reelin	Reelin	Reelin	VLDLR	VLDLR	VLDLR	5	6	11	12
Concurrent with Wg induction and pSrc upregulation , Ret expression in adult intestinal progenitors led to a small but detectable induction of pFak ( Fig XREF_FIG F ) .	Concurrent with Wg induction and pSrc upregulation, Ret expression in adult intestinal progenitors led to a small but detectable induction of pFak (Fig XREF_FIG F).	8	23	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Ret	Ret expression	ret	pFak	pFak	pfak	8	9	22	23
RET signaling has been shown to lead to phosphorylation of the adhesion dependent signaling molecules FAK , paxillin , and p130 CAS .	RET signaling has been shown to lead to phosphorylation of the adhesion dependent signaling molecules FAK, paxillin, and p130 CAS.	0	21	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	FAK	FAK	FAK	0	1	15	16
Instead , by inhibiting p65 ( RelA ) phosphorylation SINK prevents its association with the CBP and p300 and P/CAF co-activators , thus creating a negative feedback control of p65 ( RelA ) transcriptional activity [ XREF_BIBR ] .	Instead, by inhibiting p65 (RelA) phosphorylation SINK prevents its association with the CBP and p300 and P/CAF co-activators, thus creating a negative feedback control of p65 (RelA) transcriptional activity [XREF_BIBR].	2	20	prevents	Negative_activation_syntax_3_verb	Positive_activation	Positive_activation	p65	p65 (RelA) phosphorylation	p65	CBP	CBP	cbp	4	5	15	16
However , phosphorylation of RelA at Ser276 is not sufficient to promote binding of CBP , as Ser311 also needs to be phosphorylated in response to tumor necrosis factor ( TNF ) 5 .	However, phosphorylation of RelA at Ser276 is not sufficient to promote binding of CBP, as Ser311 also needs to be phosphorylated in response to tumor necrosis factor (TNF) 5.	2	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RelA	phosphorylation of RelA at Ser276	rela	CBP	CBP	cbp	4	5	14	15
Phosphorylation of p65 at serine 276 can raise the recruitment of coactivator p300 and CBP , achieving full transcriptional activation involving p65 acetylation , and the acetylation is largely contingent on prior phosphorylation [ XREF_BIBR ] .	Phosphorylation of p65 at serine 276 can raise the recruitment of coactivator p300 and CBP, achieving full transcriptional activation involving p65 acetylation, and the acetylation is largely contingent on prior phosphorylation [XREF_BIBR].	0	15	raise	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p65	Phosphorylation of p65 at serine 276	p65	CBP	CBP	cbp	2	3	14	15
However , the ' cis-only ' mouse model , in which Gfra1 is expressed under the control of the Ret promoter in a Gfra1 null background , produced no overt phenotypes in many Ret dependent developmental processes , suggesting that trans signaling may not play a major physiological role .	However, the ' cis-only ' mouse model, in which Gfra1 is expressed under the control of the Ret promoter in a Gfra1 null background, produced no overt phenotypes in many Ret dependent developmental processes, suggesting that trans signaling may not play a major physiological role.	19	25	promoter	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Ret	Ret	Ret	Gfra1	Gfra1	Gfra1	19	20	23	24
Ret also mediates GPI anchored GFRalpha1 signaling in response to GDNF , a diffusible chemoattractant in the limb - indicating that Ret is a multifunctional co-receptor for guidance molecules .	Ret also mediates GPI anchored GFRalpha1 signaling in response to GDNF, a diffusible chemoattractant in the limb - indicating that Ret is a multifunctional co-receptor for guidance molecules.	0	6	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ret	Ret	Ret	GFRalpha1	GFRalpha1	GFRalpha1	0	1	5	6
The results show that ret promotes the generation of trkA negative nociceptors and GFRalpha1- and GFRalpha2 positive DRG neuron populations .	The results show that ret promotes the generation of trkA negative nociceptors and GFRalpha1- and GFRalpha2 positive DRG neuron populations.	4	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ret	ret	ret	GFRalpha1-	GFRalpha1-	GFRalpha1-	4	5	13	14
GTP Hydrolysis of TC10 Promotes Neurite Outgrowth through Exocytic Fusion of Rab11- and L1 Containing Vesicles by Releasing Exocyst Component Exo70 .	GTP Hydrolysis of TC10 Promotes Neurite Outgrowth through Exocytic Fusion of Rab11- and L1 Containing Vesicles by Releasing Exocyst Component Exo70.	1	21	Promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TC10	Hydrolysis of TC10	tc10	Exo70	Exo70	exo70	3	4	20	21
Thus , the putative TC10 inactivation on tethered vesicles in neuronal cells can induce Exo70 release and exocyst disassembly , which contributes to vesicle fusion .	Thus, the putative TC10 inactivation on tethered vesicles in neuronal cells can induce Exo70 release and exocyst disassembly, which contributes to vesicle fusion.	4	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TC10	TC10	TC10	Exo70	Exo70	Exo70	4	5	14	15
In analogy to the mammalian system , where Exo70 is targeted at the PM by the small GTPase TC10 , our data suggest a similar role for Rac1a in Dictyostelium .	In analogy to the mammalian system, where Exo70 is targeted at the PM by the small GTPase TC10, our data suggest a similar role for Rac1a in Dictyostelium.	8	19	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TC10	TC10	TC10	Exo70	Exo70	Exo70	18	19	8	9
In addition , curcumin decreased expression of p50 and p65 proteins and NFkappaB dependent transactivation and also decreased Sp1 , Sp3 , and Sp4 transcription factors that are overexpressed in pancreatic cancer cells .	In addition, curcumin decreased expression of p50 and p65 proteins and NFkappaB dependent transactivation and also decreased Sp1, Sp3, and Sp4 transcription factors that are overexpressed in pancreatic cancer cells.	3	25	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p65	curcumin decreased expression of p50 and p65	p65	Sp1	Sp1	sp1	9	10	18	19
These results suggest that Ret can induce ERK2 activation in a p21ras dependent manner in cells derived from tissue where Ret is endogenously expressed .	These results suggest that Ret can induce ERK2 activation in a p21ras dependent manner in cells derived from tissue where Ret is endogenously expressed.	4	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ret	Ret	Ret	ERK2	ERK2	ERK2	4	5	7	8
Analysis of the kinetics of ERK2 activation and downstream events revealed that Ret and FGF receptor activation led to sustained ERK2 activation and SRE transactivation , while PDGF treatment led to transient ERK2 activation and failed to induce SRE transactivation .	Analysis of the kinetics of ERK2 activation and downstream events revealed that Ret and FGF receptor activation led to sustained ERK2 activation and SRE transactivation, while PDGF treatment led to transient ERK2 activation and failed to induce SRE transactivation.	12	21	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Ret	Ret	Ret	ERK2	ERK2	ERK2	12	13	20	21
RBM15 promotes the access of DBP5 to mRNP complexes .	RBM15 promotes the access of DBP5 to mRNP complexes.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RBM15	RBM15	RBM15	DBP5	DBP5	DBP5	0	1	5	6
We propose a model in which RBM15 directs DBP5 to NXF1-mRNP complexes at the NPC and precludes DBP5 ' s non productive engagement with other RNP , thereby acting to promote the NXF1-mRNP remodeling and serving as a specificity control of export substrate .	We propose a model in which RBM15 directs DBP5 to NXF1-mRNP complexes at the NPC and precludes DBP5 's non productive engagement with other RNP, thereby acting to promote the NXF1-mRNP remodeling and serving as a specificity control of export substrate.	6	16	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RBM15	RBM15	RBM15	DBP5	DBP5	DBP5	6	7	8	9
XREF_BIBR Quercetin treatment also decreased cytosolic p65 protein expression and prevented high glucose induced p65 and c-jun nuclear localization .	XREF_BIBR Quercetin treatment also decreased cytosolic p65 protein expression and prevented high glucose induced p65 and c-jun nuclear localization.	1	18	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p65	Quercetin treatment also decreased cytosolic p65 protein expression	p65	c-jun	c-jun	c-jun	6	7	16	17
In contrast , Rfng still allowed Notch1 availability to reach background levels at high cis-Jag1 levels .	In contrast, Rfng still allowed Notch1 availability to reach background levels at high cis-Jag1 levels.	3	7	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rfng	Rfng	Rfng	Notch1	Notch1	Notch1	3	4	6	7
Given that cIAP1 , cIAP2 and XIAP have been implicated as essential in DNA damage induced NF-kappaB activation , it is tempting to speculate that following DNA damage , the intracellular levels of these signaling components may dictate whether cells can survive through NF-kappaB-dependent anti-apoptotic gene induction or die through RIP1 mediated caspase-8 activation .	Given that cIAP1, cIAP2 and XIAP have been implicated as essential in DNA damage induced NF-kappaB activation, it is tempting to speculate that following DNA damage, the intracellular levels of these signaling components may dictate whether cells can survive through NF-kappaB-dependent anti-apoptotic gene induction or die through RIP1 mediated caspase-8 activation.	48	53	mediated	Positive_early_activation	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	50	51	52	53
It is noteworthy , however , that RIPK3 kinase inhibition 13 , or a D161N mutation in the RIPK3 kinase domain in vivo 12 , can drive lethal caspase-8-dependent apoptosis by triggering RIPK1 recruitment to RIPK3 , and RIPK1 mediated activation of caspase-8 .	It is noteworthy, however, that RIPK3 kinase inhibition 13, or a D161N mutation in the RIPK3 kinase domain in vivo 12, can drive lethal caspase-8-dependent apoptosis by triggering RIPK1 recruitment to RIPK3, and RIPK1 mediated activation of caspase-8.	38	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	38	39	42	43
RIP-1 downregulation reduced NF-kappaB transcriptional activity , blocked the cell cycle in G0/G1 phase , weakened cell proliferation , enhanced caspase-8 and caspase-3 activity , and increased cell apoptosis .	RIP-1 downregulation reduced NF-kappaB transcriptional activity, blocked the cell cycle in G0/G1 phase, weakened cell proliferation, enhanced caspase-8 and caspase-3 activity, and increased cell apoptosis.	0	23	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP-1	RIP-1	RIP-1	caspase-8	caspase-8	caspase-8	0	1	20	21
44 Indeed , the TRAF2 associated cIAPs have been found to inhibit TNF induced RIP1 mediated activation of caspase-8 by K63 ubiquitination of RIP1 .	44 Indeed, the TRAF2 associated cIAPs have been found to inhibit TNF induced RIP1 mediated activation of caspase-8 by K63 ubiquitination of RIP1.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	14	15	18	19
Although transformed MEF from ripk1 -/- mice display increased sensitivity to TNF induced apoptosis , RIPK1 has also been shown to promote FADD dependent caspase-8 activation in response to TNF and other stimuli .	Although transformed MEF from ripk1 -/- mice display increased sensitivity to TNF induced apoptosis, RIPK1 has also been shown to promote FADD dependent caspase-8 activation in response to TNF and other stimuli.	15	25	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	15	16	24	25
13 Although the mechanism by which RIP1 activates caspase-8 and triggers apoptosis after TNF stimulation has been revealed , the role of RIP1 in the induction of apoptosis by chemotherapeutic agents remains unclear .	13 Although the mechanism by which RIP1 activates caspase-8 and triggers apoptosis after TNF stimulation has been revealed, the role of RIP1 in the induction of apoptosis by chemotherapeutic agents remains unclear.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	6	7	8	9
We observed that ablation of RIPK1 rescues the embryonic lethality of casp8 -/- mice ( XREF_FIG , XREF_SUPPLEMENTARY ) , consistent with the similar rescue of embryonic lethality in fadd -/- mice on the ripk1 -/- background .	We observed that ablation of RIPK1 rescues the embryonic lethality of casp8 -/- mice (XREF_FIG, XREF_SUPPLEMENTARY), consistent with the similar rescue of embryonic lethality in fadd -/- mice on the ripk1 -/- background.	3	31	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	casp8	casp8	casp8	5	6	11	12
Only when polyubiquitination of RIPK1 is blocked by inhibition of ubiquitination enzymes cIAPs or by mutation at the polyubiquitination site of RIPK1 , RIPK1 becomes a pro apoptotic and activates caspase-8 .	Only when polyubiquitination of RIPK1 is blocked by inhibition of ubiquitination enzymes cIAPs or by mutation at the polyubiquitination site of RIPK1, RIPK1 becomes a pro apoptotic and activates caspase-8.	23	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	23	24	30	31
XREF_BIBR , XREF_BIBR In addition to activation of caspases , Smac mimetics have been described to trigger an NF-kappaB-dependent autocrine and paracrine TNFalpha loop , which induces cell death by facilitating the formation of a TNFalpha induced cytosolic complex II consisting of caspase-8 , Fas associated protein with death domain and RIP1 , which drives caspase-8 activation and cell death .	XREF_BIBR, XREF_BIBR In addition to activation of caspases, Smac mimetics have been described to trigger an NF-kappaB-dependent autocrine and paracrine TNFalpha loop, which induces cell death by facilitating the formation of a TNFalpha induced cytosolic complex II consisting of caspase-8, Fas associated protein with death domain and RIP1, which drives caspase-8 activation and cell death.	46	56	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	51	52	55	56
8 In the context of TNFR1 signaling TRAF2-cIAP1/2 complexes are also of pivotal relevance for activation of the classical NFkappaB pathway and in addition prevent RIP1 mediated caspase-8 activation .	8 In the context of TNFR1 signaling TRAF2-cIAP1/2 complexes are also of pivotal relevance for activation of the classical NFkappaB pathway and in addition prevent RIP1 mediated caspase-8 activation.	25	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	25	26	27	28
CLIPR-59 modulates ubiquitination of RIP1 , thus promoting Caspase-8 activation to induce apoptosis by TNF-alpha .	CLIPR-59 modulates ubiquitination of RIP1, thus promoting Caspase-8 activation to induce apoptosis by TNF-alpha.	0	9	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	CLIPR-59 modulates ubiquitination of RIP1	rip1	Caspase-8	Caspase-8	caspase-8	4	5	8	9
NEMO was previously reported to prevent TNF induced death of Jurkat Tcells by inhibiting RIPK1 mediated activation of caspase-8 independently of NF-kappaB .	NEMO was previously reported to prevent TNF induced death of Jurkat Tcells by inhibiting RIPK1 mediated activation of caspase-8 independently of NF-kappaB.	14	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	14	15	18	19
RIP1 has also been proposed to bind directly to caspase-8 and/or to its non catalytic homologue , c-Flip , and has been postulated to even directly activate caspase-8 in the absence of FADD during TNF signaling .	RIP1 has also been proposed to bind directly to caspase-8 and/or to its non catalytic homologue, c-Flip, and has been postulated to even directly activate caspase-8 in the absence of FADD during TNF signaling.	0	28	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	0	1	27	28
Effective RIP1 k63 polyubiquitination and persistent MKK3 and MKK6 expression during drug treatment potentiated caspase8 activity via p53-DISC conformation .	Effective RIP1 k63 polyubiquitination and persistent MKK3 and MKK6 expression during drug treatment potentiated caspase8 activity via p53-DISC conformation.	1	15	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1 k63 polyubiquitination	rip1	caspase8	caspase8	caspase8	1	2	14	15
Both RIPK1 and RIPK3 are targets of caspase-8 that cleaves the deubiquitinase CYLD and prevents the initiation of necroptosis [ XREF_BIBR ] .	Both RIPK1 and RIPK3 are targets of caspase-8 that cleaves the deubiquitinase CYLD and prevents the initiation of necroptosis [XREF_BIBR].	0	8	are targets	Positive_activation_copula_1	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	1	2	7	8
A crucial component of all three TNF response pathways is the protein kinase RIP1 , which together with the proteins TRADD , TRAF2 , TRAF5 and cIAP2 forms the TNF-receptor associated complex I. Lys 63 linked polyubiquitination of RIP1 induces NF-kappaB activation , while RIP1 deubiquitination either leads to caspase-8 dependent apoptosis , or - failing that - to caspase-8 independent necroptosis XREF_BIBR .	A crucial component of all three TNF response pathways is the protein kinase RIP1, which together with the proteins TRADD, TRAF2, TRAF5 and cIAP2 forms the TNF-receptor associated complex I. Lys 63 linked polyubiquitination of RIP1 induces NF-kappaB activation, while RIP1 deubiquitination either leads to caspase-8 dependent apoptosis, or - failing that - to caspase-8 independent necroptosis XREF_BIBR.	44	50	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	RIP1	RIP1 deubiquitination	rip1	caspase-8	caspase-8	caspase-8	44	45	49	50
RIP1 knockdown was found to suppress caspase-8 activation in both cases ( XREF_FIG ) .	RIP1 knockdown was found to suppress caspase-8 activation in both cases (XREF_FIG).	0	7	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	0	1	6	7
Instead , we found that RIPK1 promotes death receptor independent caspase-8 activation , which is required for the downstream activation of caspase-9 and -3 and the induction of cell death .	Instead, we found that RIPK1 promotes death receptor independent caspase-8 activation, which is required for the downstream activation of caspase-9 and -3 and the induction of cell death.	5	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	5	6	10	11
Generally , when receiving a death signal , RIP1 activates caspase-8 and initiates apoptosis .	Generally, when receiving a death signal, RIP1 activates caspase-8 and initiates apoptosis.	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	8	9	10	11
In the absence of ubiquitination , RIP1 associates with and activates pro caspase 8 , which leads to caspase 3 activation and apoptosis [ XREF_BIBR ] ( XREF_FIG ) .	In the absence of ubiquitination, RIP1 associates with and activates pro caspase 8, which leads to caspase 3 activation and apoptosis [XREF_BIBR] (XREF_FIG).	6	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase 8	caspase 8	caspase 8	6	7	12	14
This is evident because MIB2 RING finger mutants can still bind to RIPK1 ( XREF_FIG B ) but fail to regulate RIPK1 mediated activation of caspase-8 and cell death ( XREF_FIG A-4F ) .	This is evident because MIB2 RING finger mutants can still bind to RIPK1 (XREF_FIG B) but fail to regulate RIPK1 mediated activation of caspase-8 and cell death (XREF_FIG A-4F).	21	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	21	22	25	26
Interestingly , deletion of RIP1 blocked HMGB1 release , but not PARP or caspase 8 cleavage ( XREF_FIG ) .	Interestingly, deletion of RIP1 blocked HMGB1 release, but not PARP or caspase 8 cleavage (XREF_FIG).	2	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase 8	caspase 8	caspase 8	4	5	13	15
Deletion of RIP1 abrogated the induction of IL-8 as well as caspase-8 activity observed in wild-type Jurkat cells exposed to the defensin .	Deletion of RIP1 abrogated the induction of IL-8 as well as caspase-8 activity observed in wild-type Jurkat cells exposed to the defensin.	0	12	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	2	3	11	12
CYLD deficiency leads to hyperubiquitinated RIPK1 in the necrosome and impaired phosphorylation of RIPK1 and RIPK3 , thereby blocking caspase-8 activation .	CYLD deficiency leads to hyperubiquitinated RIPK1 in the necrosome and impaired phosphorylation of RIPK1 and RIPK3, thereby blocking caspase-8 activation.	0	20	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	CYLD deficiency leads to hyperubiquitinated RIPK1 in the necrosome and impaired phosphorylation of RIPK1	ripk1	caspase-8	caspase-8	caspase-8	13	14	19	20
However , RIPK1 can also promote the activation of caspase-8 in a FADD dependent manner .	However, RIPK1 can also promote the activation of caspase-8 in a FADD dependent manner.	2	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	2	3	9	10
The recruitment of cIAP1 and cIAP2 to TNFR1 inhibits TNFalpha dependent , RIPK1 dependent activation of caspase 8 .	The recruitment of cIAP1 and cIAP2 to TNFR1 inhibits TNFalpha dependent, RIPK1 dependent activation of caspase 8.	12	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase 8	caspase 8	caspase 8	12	13	16	18
These data imply that SM-164 and TNFalpha induced death involved RIPK1 dependent activation of caspase-8 and executioner caspases [ XREF_BIBR ] .	These data imply that SM-164 and TNFalpha-induced death involved RIPK1 dependent activation of caspase-8 and executioner caspases [XREF_BIBR].	10	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	10	11	14	15
16-20 Loss of cIAP1 and cIAP2 leads to diminished ubiquitylation of RIPK1 and activates caspase-8 .	16-20 Loss of cIAP1 and cIAP2 leads to diminished ubiquitylation of RIPK1 and activates caspase-8.	1	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	Loss of cIAP1 and cIAP2 leads to diminished ubiquitylation of RIPK1	ripk1	caspase-8	caspase-8	caspase-8	11	12	14	15
Also , RIP1 knockdown reduced IFNalpha and BV6 mediated cleavage of caspase-8 and -3 into active cleavage fragments .	Also, RIP1 knockdown reduced IFNalpha and BV6 mediated cleavage of caspase-8 and -3 into active cleavage fragments.	2	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	2	3	11	12
Depletion of MIB2 resulted in RIPK1 mediated formation of complex-II and activation of caspase-8 ( XREF_SUPPLEMENTARY K and S2L ) .	Depletion of MIB2 resulted in RIPK1 mediated formation of complex-II and activation of caspase-8 (XREF_SUPPLEMENTARY K and S2L).	5	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	5	6	13	14
This finding and the fact that caspase-8 is activated by a soluble TRADD , RIP1 , TRAF2 , and cIAP complex suggest that reduced endosomal trafficking of TNF and TNFR1 most likely contributes to caspase-8 activation by allowing time for the remodeling and dissociation of the TRADD-RIP1-TRAF2-cIPA signaling complex from the internalized TNF and TNFR1 .	This finding and the fact that caspase-8 is activated by a soluble TRADD, RIP1, TRAF2, and cIAP complex suggest that reduced endosomal trafficking of TNF and TNFR1 most likely contributes to caspase-8 activation by allowing time for the remodeling and dissociation of the TRADD-RIP1-TRAF2-cIPA signaling complex from the internalized TNF and TNFR1.	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	14	15	6	7
Additional studies are necessary to address how RIP1 , RIP3 , and cFLIP isoforms modulate the ability of various pro apoptotic stimuli to induce specific caspase-8 signaling complexes that mediate processing of IL-1beta .	Additional studies are necessary to address how RIP1, RIP3, and cFLIP isoforms modulate the ability of various pro apoptotic stimuli to induce specific caspase-8 signaling complexes that mediate processing of IL-1beta.	7	27	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	7	8	25	26
12 Consistent with a role for CLIPR-59 in modulating ubiquitin dependent RIP1 signaling , CLIPR-59 expression enhanced Caspase-8 activation induced by WT RIP1 but not RIP1 K377R ( XREF_FIG ) .	12 Consistent with a role for CLIPR-59 in modulating ubiquitin dependent RIP1 signaling, CLIPR-59 expression enhanced Caspase-8 activation induced by WT RIP1 but not RIP1 K377R (XREF_FIG).	17	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	Caspase-8	Caspase-8	Caspase-8	22	23	17	18
RIP1 deubiquitination by CYLD promotes caspase-8 activation .	RIP1 deubiquitination by CYLD promotes caspase-8 activation.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1 deubiquitination	rip1	caspase-8	caspase-8	caspase-8	0	1	5	6
Remarkably , ablation of RIPK1 also allows the normal embryonic development of caspase-8- or FADD deficient animals , although these mice succumb to early post-natal lethality ( as do RIPK1-null mice ) .	Remarkably, ablation of RIPK1 also allows the normal embryonic development of caspase-8- or FADD deficient animals, although these mice succumb to early post-natal lethality (as do RIPK1-null mice).	2	16	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8-	caspase-8-	caspase-8-	4	5	12	13
In the absence of cIAPs , RIP1 forms a complex with the death receptor complex and activates the extrinsic pathway and caspase-8 [ XREF_BIBR , XREF_BIBR ] .	In the absence of cIAPs, RIP1 forms a complex with the death receptor complex and activates the extrinsic pathway and caspase-8 [XREF_BIBR, XREF_BIBR].	6	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	6	7	21	22
Importantly , knockdown of RIP1 by RNA interference prevented the formation of the RIP1.FADD.caspase-8 complex and inhibited subsequent activation of caspase-8 , -9 , and -3 ; loss of mitochondrial membrane potential ; and apoptosis upon treatment with IAP inhibitor and lexatumumab .	Importantly, knockdown of RIP1 by RNA interference prevented the formation of the RIP1.FADD.caspase-8 complex and inhibited subsequent activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and apoptosis upon treatment with IAP inhibitor and lexatumumab.	2	34	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	4	5	20	21
RIPK1 deficiency induces TRAF2 destabilization upon stimulation and promotes formation of complex II , caspase-8 activation and apoptosis induction .	RIPK1 deficiency induces TRAF2 destabilization upon stimulation and promotes formation of complex II, caspase-8 activation and apoptosis induction.	0	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	0	1	14	15
RIP-1 or c-FLIP knockdown significantly enhanced caspase-8 and caspase-3 activity , while combined transfection further enhanced their activities ( XREF_FIG ) .	RIP-1 or c-FLIP knockdown significantly enhanced caspase-8 and caspase-3 activity, while combined transfection further enhanced their activities (XREF_FIG).	0	9	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP-1	RIP-1	RIP-1	caspase-8	caspase-8	caspase-8	0	1	6	7
Without cIAP1 , RIPK1 is cleaved by Caspase8 ; alternatively , uncleaved RIPK1 causes Caspase8 independent necroptosis .	Without cIAP1, RIPK1 is cleaved by Caspase8; alternatively, uncleaved RIPK1 causes Caspase8 independent necroptosis.	11	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	Caspase8	Caspase8	Caspase8	12	13	14	15
As described above , in the absence of cIAP proteins , caspase-8 is activated by the RIP1 containing complex II in the TNFalpha and TNFR signaling .	As described above, in the absence of cIAP proteins, caspase-8 is activated by the RIP1 containing complex II in the TNFalpha and TNFR signaling.	11	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	16	17	11	12
RIP-1 or c-FLIP L siRNA markedly induced cell apoptosis and enhanced caspase-8 and caspase-3 activities .	RIP-1 or c-FLIP L siRNA markedly induced cell apoptosis and enhanced caspase-8 and caspase-3 activities.	0	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP-1	RIP-1	RIP-1	caspase-8	caspase-8	caspase-8	0	1	11	12
However , overexpression TRAF6 or RIP1 in E1A-stable cell lines could not restore TAK1 activation and mediate FOXO3a degradation ( data not shown ) , suggesting that prevention of TAK1 activation by E1A is not mediated by those two upstream activators .	However, overexpression TRAF6 or RIP1 in E1A-stable cell lines could not restore TAK1 activation and mediate FOXO3a degradation (data not shown), suggesting that prevention of TAK1 activation by E1A is not mediated by those two upstream activators.	3	14	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	TAK1	TAK1	TAK1	5	6	13	14
In response to TLR3 signaling , TRAF6 is recruited to a complex including the adaptor TRIF , the related family member TRAF3 , and the RIP1 kinase , which activates TAK1 in response to TRAF6 activation .	In response to TLR3 signaling, TRAF6 is recruited to a complex including the adaptor TRIF, the related family member TRAF3, and the RIP1 kinase, which activates TAK1 in response to TRAF6 activation.	25	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	TAK1	TAK1	TAK1	25	26	30	31
RIPK1 induces Reactive Oxygen Species accumulation and death in Tak1 deficient macrophage .	RIPK1 induces Reactive Oxygen Species accumulation and death in Tak1 deficient macrophage.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	Tak1	Tak1	Tak1	0	1	9	10
In TRIF dependent TLR signaling , TRIF directly recruits TRAF6 and RIP1 , which work cooperatively to activate TAK1 , eventually leading to activation of NF-kappaB and AP-1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In TRIF dependent TLR signaling, TRIF directly recruits TRAF6 and RIP1, which work cooperatively to activate TAK1, eventually leading to activation of NF-kappaB and AP-1 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	TAK1	TAK1	TAK1	11	12	18	19
In order to analyze whether TAK1 curbs the cytotoxic potential of RIP1 by regulating its incorporation into TNFalpha induced complex-I , WT and TAK1 KO MEFs were stimulated with Flag-TNFalpha and complex-I was immunoprecipitated with an alpha-Flag antibody .	In order to analyze whether TAK1 curbs the cytotoxic potential of RIP1 by regulating its incorporation into TNFalpha induced complex-I, WT and TAK1 KO MEFs were stimulated with Flag-TNFalpha and complex-I was immunoprecipitated with an alpha-Flag antibody.	9	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	TAK1	TAK1	TAK1	11	12	23	24
TRIF protein recruits receptor interacting protein-1 ( RIP1 ) kinase which activates TAK1 .	TRIF protein recruits receptor interacting protein-1 (RIP1) kinase which activates TAK1.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	TAK1	TAK1	TAK1	7	8	12	13
However , RIPK1 overexpression did not activate TAK1 even with treatment with TNF , Smac mimetic , and Z-VAD ( XREF_FIG , top panel , lane 4 ) .	However, RIPK1 overexpression did not activate TAK1 even with treatment with TNF, Smac mimetic, and Z-VAD (XREF_FIG, top panel, lane 4).	2	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1 overexpression	ripk1	TAK1	TAK1	tak1	2	3	7	8
Increases in TRAF6 signalling , despite NleB inhibition of TAK1 function ( XREF_FIG ) , suggest that the effector may block RIP1 mediated activation of TAK1 to inhibit signalling in TNFR , but not TLR and IL1R pathways XREF_BIBR .	Increases in TRAF6 signalling, despite NleB inhibition of TAK1 function (XREF_FIG), suggest that the effector may block RIP1 mediated activation of TAK1 to inhibit signalling in TNFR, but not TLR and IL1R pathways XREF_BIBR.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	TAK1	TAK1	TAK1	21	22	25	26
To further investigate the contribution of RIPK1 and RIPK3 to TAK1 activation , we examined whether RIPK1 and/or RIPK3 can activate TAK1 using the overexpression system in HeLa cells ( XREF_FIG ) .	To further investigate the contribution of RIPK1 and RIPK3 to TAK1 activation, we examined whether RIPK1 and/or RIPK3 can activate TAK1 using the overexpression system in HeLa cells (XREF_FIG).	16	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	TAK1	TAK1	TAK1	16	17	21	22
The RING domains of cIAP1/2 catalyze the activating K63 linked polyubiquitination of RIP1 , which activates the TAK1 ( transforming growth factor-beta-activated kinase 1 ) kinase complex [ XREF_BIBR ] .	The RING domains of cIAP1/2 catalyze the activating K63 linked polyubiquitination of RIP1, which activates the TAK1 (transforming growth factor-beta-activated kinase 1) kinase complex [XREF_BIBR].	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	K63 linked polyubiquitination of RIP1	rip1	TAK1	TAK1	tak1	12	13	17	18
In TRIF dependent TLR3 signalling , TRIF directly recruits TRAF6 and RIP1 , which work cooperatively to activate TAK1 , eventually leading to activation of NF-kappaB and AP1 .	In TRIF dependent TLR3 signalling, TRIF directly recruits TRAF6 and RIP1, which work cooperatively to activate TAK1, eventually leading to activation of NF-kappaB and AP1.	8	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	TAK1	TAK1	TAK1	11	12	18	19
TRAF6 recruits the kinase RIP-1 , which in turn interacts with and activates the TAK1 complex , leading to activation of NF-kappaB and MAPKs and induction of inflammatory cytokines .	TRAF6 recruits the kinase RIP-1, which in turn interacts with and activates the TAK1 complex, leading to activation of NF-kappaB and MAPKs and induction of inflammatory cytokines.	1	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP-1	RIP-1	RIP-1	TAK1	TAK1	TAK1	4	5	14	15
This demonstrates that an active RIPK1 alone can not activate TAK1 .	This demonstrates that an active RIPK1 alone can not activate TAK1.	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	TAK1	TAK1	TAK1	5	6	10	11
RIPK1 dependent caspase-8 activation in Tak1 deficient fibroblasts .	RIPK1 dependent caspase-8 activation in Tak1 deficient fibroblasts.	0	7	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	Tak1	Tak1	Tak1	0	1	5	6
In a classical TNF-alpha signaling , TNF-R2 forms complex with TRAF2 and cIAP1/2 to further recruit and activate RIPK1 , which further activates TAK1 kinase activity leading to the activation of NF-kappaB and MAPK pathways .	In a classical TNF-alpha signaling, TNF-R2 forms complex with TRAF2 and cIAP1/2 to further recruit and activate RIPK1, which further activates TAK1 kinase activity leading to the activation of NF-kappaB and MAPK pathways.	17	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	TAK1	TAK1	TAK1	18	19	23	24
This work revealed that Tir-eGFP , but not eGFP , inhibited luciferase activity driven by plasmid expression of TRAF2 and RIP1 , but not TAK1 , IKKbeta ( XREF_FIG ) or IKKalpha ( not shown ) .	This work revealed that Tir-eGFP, but not eGFP, inhibited luciferase activity driven by plasmid expression of TRAF2 and RIP1, but not TAK1, IKKbeta (XREF_FIG) or IKKalpha (not shown).	13	28	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RIP1	expression of TRAF2 and RIP1	rip1	TAK1	TAK1	tak1	20	21	24	25
K 63 polyubiquitination of RIPK1 leads to its activation and recruitment of TAK1 complex and IKK complex [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	K 63 polyubiquitination of RIPK1 leads to its activation and recruitment of TAK1 complex and IKK complex [XREF_BIBR, XREF_BIBR - XREF_BIBR].	2	13	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	RIPK1	polyubiquitination of RIPK1	ripk1	TAK1	TAK1	tak1	4	5	12	13
RIPK1 activates TAK-1 via recruitment of TAK-1 complex and interaction of K 63 ubiquitin chains to TAB2 and subsequent phosphorylation of TAK1 [ XREF_BIBR ] .	RIPK1 activates TAK-1 via recruitment of TAK-1 complex and interaction of K 63 ubiquitin chains to TAB2 and subsequent phosphorylation of TAK1 [XREF_BIBR].	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	TAK-1	TAK-1	TAK-1	0	1	2	3
RIPK1 induces Tak1 deficient macrophage death through a mechanism independent of caspase activity and RIPK3 .	RIPK1 induces Tak1 deficient macrophage death through a mechanism independent of caspase activity and RIPK3.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	Tak1	Tak1	Tak1	0	1	2	3
To examine the involvement of RIPK1 , Nec-1 was used and we found that inhibition of RIPK1 also reduced TNF- and Z-VAD-induced TAK1 activation in Tab2 deficient fibroblasts ( XREF_FIG ) .	To examine the involvement of RIPK1, Nec-1 was used and we found that inhibition of RIPK1 also reduced TNF- and Z-VAD-induced TAK1 activation in Tab2 deficient fibroblasts (XREF_FIG).	14	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	TAK1	TAK1	TAK1	16	17	22	23
Furthermore , antagonizing RIN1 caused multilevel inactivation of EGFR signaling and had obvious inhibitory effects on tumorigenesis .	Furthermore, antagonizing RIN1 caused multilevel inactivation of EGFR signaling and had obvious inhibitory effects on tumorigenesis.	2	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIN1	RIN1	RIN1	EGFR	EGFR	EGFR	3	4	8	9
We demonstrate that RIN1 overexpression substantially activates EGFR signaling in ccRCC through binding to Rab25 .	We demonstrate that RIN1 overexpression substantially activates EGFR signaling in ccRCC through binding to Rab25.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIN1	RIN1 overexpression	rin1	EGFR	EGFR	egfr	3	4	7	8
Meanwhile , antagonizing RIN1 caused multilevel inactivation of EGFR signaling and had obvious inhibitory effects on tumorigenesis .	Meanwhile, antagonizing RIN1 caused multilevel inactivation of EGFR signaling and had obvious inhibitory effects on tumorigenesis.	2	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIN1	RIN1	RIN1	EGFR	EGFR	EGFR	3	4	8	9
We speculate that the role of Rab25 in EGFR trafficking and recycling to the plasma membrane might contribute to its role in RIN1 induced EGFR signaling in ccRCC .	We speculate that the role of Rab25 in EGFR trafficking and recycling to the plasma membrane might contribute to its role in RIN1 induced EGFR signaling in ccRCC.	17	25	induced	Positive_early_activation	Positive_activation	Positive_activation	RIN1	RIN1	RIN1	EGFR	EGFR	EGFR	22	23	24	25
Rab25 is responsible for RIN1 induced EGFR signaling and tumor malignancy in clear cell renal cell carcinoma cell .	Rab25 is responsible for RIN1 induced EGFR signaling and tumor malignancy in clear cell renal cell carcinoma cell.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	RIN1	RIN1	RIN1	EGFR	EGFR	EGFR	4	5	6	7
These results suggest that Rab25 might be responsible for RIN1 induced EGFR signaling and tumor malignancy in ccRCC cells .	These results suggest that Rab25 might be responsible for RIN1 induced EGFR signaling and tumor malignancy in ccRCC cells.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	RIN1	RIN1	RIN1	EGFR	EGFR	EGFR	9	10	11	12
RIN1 promotes renal cell carcinoma malignancy by activating EGFR signaling through Rab25 .	RIN1 promotes renal cell carcinoma malignancy by activating EGFR signaling through Rab25.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIN1	RIN1	RIN1	EGFR	EGFR	EGFR	0	1	8	9
Our current study revealed that overexpression of RIN1 in ccRCC cells activated the EGFR signaling pathway , thus promoting proliferation , migration and invasion of ccRCC .	Our current study revealed that overexpression of RIN1 in ccRCC cells activated the EGFR signaling pathway, thus promoting proliferation, migration and invasion of ccRCC.	5	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIN1	overexpression of RIN1	rin1	EGFR	EGFR	egfr	7	8	13	14
RIN1 activates EGFR signaling in clear cell renal cell carcinoma .	RIN1 activates EGFR signaling in clear cell renal cell carcinoma.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIN1	RIN1	RIN1	EGFR	EGFR	EGFR	0	1	2	3
RIP2 activation of the IRF5 aspartic acid substitutions showed a similar positive effect of S451D and S462D function in this assay ( XREF_FIG ) .	RIP2 activation of the IRF5 aspartic acid substitutions showed a similar positive effect of S451D and S462D function in this assay (XREF_FIG).	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RIP2	RIP2	RIP2	IRF5	IRF5	IRF5	0	1	4	5
Both IFN reporters responded to IRF5 activated by RIP2 kinase , demonstrating IRF5 involvement in the induction of diverse cytokines ( XREF_FIG ) .	Both IFN reporters responded to IRF5 activated by RIP2 kinase, demonstrating IRF5 involvement in the induction of diverse cytokines (XREF_FIG).	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RIP2	RIP2	RIP2	IRF5	IRF5	IRF5	8	9	5	6
Mycobacterium tuberculosis upregulated NOD2 - RIPK2 , which activated IRF5 and induced IFNalpha and beta XREF_BIBR .	Mycobacterium tuberculosis upregulated NOD2 - RIPK2, which activated IRF5 and induced IFNalpha and beta XREF_BIBR.	3	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK2	RIPK2	RIPK2	IRF5	IRF5	IRF5	5	6	9	10
Although the transcriptional activity of IRF5 KK/RR was 2-fold less than wt , IRF5 KK/RR was still activated by RIP2 , and activity was complete in the context of the activating mutation ( KK/RR , SS/DD ) .	Although the transcriptional activity of IRF5 KK/RR was 2-fold less than wt, IRF5 KK/RR was still activated by RIP2, and activity was complete in the context of the activating mutation (KK/RR, SS/DD).	13	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RIP2	RIP2	RIP2	IRF5	IRF5	IRF5	19	20	13	14
This suggested that distinct amino acids were phosphorylated in response to TRAF6 and RIP2 that did not alter IRF5 electrophoretic mobility , but significantly stimulated IRF5 transcriptional potential .	This suggested that distinct amino acids were phosphorylated in response to TRAF6 and RIP2 that did not alter IRF5 electrophoretic mobility, but significantly stimulated IRF5 transcriptional potential.	7	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP2	RIP2	RIP2	IRF5	IRF5	IRF5	13	14	25	26
This may be due to other transcription factors stimulated by RIP2 that can interact directly with IRF5 or augment IRF5 effects indirectly .	This may be due to other transcription factors stimulated by RIP2 that can interact directly with IRF5 or augment IRF5 effects indirectly.	8	20	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP2	RIP2 that can interact directly with IRF5	rip2	IRF5	IRF5	irf5	10	11	19	20
RIPK1 Kinase Activity Mediates Embryonic Lethality in RelA and NEMO Knockout Mice .	RIPK1 Kinase Activity Mediates Embryonic Lethality in RelA and NEMO Knockout Mice.	0	11	Mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	NEMO	NEMO	NEMO	0	1	9	10
Through the DNA damage sensor kinase ataxia telangiectasia mutated ( ATM ) , the IKK subunit NEMO and IKKgamma is phosphorylated and recruited to form a complex called the PIDDsome , consisting of RIP1 , p53 induced death domain ( PIDD ) , and NEMO in the nucleus , where RIP1 triggers NEMO activation [ XREF_BIBR - XREF_BIBR ] .	Through the DNA damage sensor kinase ataxia telangiectasia mutated (ATM), the IKK subunit NEMO and IKKgamma is phosphorylated and recruited to form a complex called the PIDDsome, consisting of RIP1, p53 induced death domain (PIDD), and NEMO in the nucleus, where RIP1 triggers NEMO activation [XREF_BIBR - XREF_BIBR].	50	53	triggers	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	NEMO	NEMO	NEMO	50	51	52	53
RIPK1 Kinase Activity Dependent Apoptosis Drives Hepatocyte Death and HCC Development in NEMO LPC-KO Mice .	RIPK1 Kinase Activity Dependent Apoptosis Drives Hepatocyte Death and HCC Development in NEMO LPC-KO Mice.	0	14	Drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	NEMO	NEMO	NEMO	0	1	12	13
RIP1 knockdown prevented NEMO deficient T cells from undergoing caspase independent cell death whereas the non targeting hairpin had no effect , confirming the hypothesis that RIP1 triggers programmed necrosis in NEMO deficient cells ( XREF_FIG ) .	RIP1 knockdown prevented NEMO deficient T cells from undergoing caspase independent cell death whereas the non targeting hairpin had no effect, confirming the hypothesis that RIP1 triggers programmed necrosis in NEMO deficient cells (XREF_FIG).	0	6	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	NEMO	NEMO	NEMO	0	1	3	4
Engagement of the TNF receptor results in assembly of multi-component receptor associated signaling complexes by adaptors including TNFR1 associated death domain ( TRADD ) , the RING domain ubiquitin ligases , such as TRAF2 , and RIP1 , which activate the IkappaB kinase ( IKK ) complex , composed of two highly homologous kinase subunits , IKKalpha and IKK1 and IKKbeta and IKK2 , and a regulatory subunit NEMO and IKKgamma .	Engagement of the TNF receptor results in assembly of multi-component receptor associated signaling complexes by adaptors including TNFR1 associated death domain (TRADD), the RING domain ubiquitin ligases, such as TRAF2, and RIP1, which activate the IkappaB kinase (IKK) complex, composed of two highly homologous kinase subunits, IKKalpha and IKK1 and IKKbeta and IKK2, and a regulatory subunit NEMO and IKKgamma.	11	70	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	NEMO	NEMO	NEMO	36	37	68	69
It is possible that the lack of RIP1 causes NEMO to bind to another molecule , which acts as a competitive antagonist .	It is possible that the lack of RIP1 causes NEMO to bind to another molecule, which acts as a competitive antagonist.	5	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	NEMO	NEMO	NEMO	7	8	9	10
However , our results showing that RIPK1 kinase activity mediates death of NEMO- or p65 deficient IECs but also embryonic lethality of NEMO- or p65 deficient mice provide invivo experimental evidence that NF-kappaB signaling also controls RIPK1 mediated cell death .	However, our results showing that RIPK1 kinase activity mediates death of NEMO- or p65 deficient IECs but also embryonic lethality of NEMO- or p65 deficient mice provide invivo experimental evidence that NF-kappaB signaling also controls RIPK1 mediated cell death.	6	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	NEMO-	NEMO-	NEMO-	6	7	12	13
RIN1 increased the kinase activity of both ABL1 and ABL2 , and this occurred in the presence or absence of ABL regulatory domains outside the SH3-SH2-tyrosine kinase domain core .	RIN1 increased the kinase activity of both ABL1 and ABL2, and this occurred in the presence or absence of ABL regulatory domains outside the SH3-SH2-tyrosine kinase domain core.	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIN1	RIN1	RIN1	ABL2	ABL2	ABL2	0	1	9	10
Indeed , RIN1 , which activates ABL1 and ABL2 by binding the SH3 and SH2 domains to relieve autoinhibition , increases the transforming ability of BCR in hematopoietic cell lines and primary bone marrow cells and enhances the leukemogenic properties of BCR-ABL1 in a murine model system .	Indeed, RIN1, which activates ABL1 and ABL2 by binding the SH3 and SH2 domains to relieve autoinhibition, increases the transforming ability of BCR in hematopoietic cell lines and primary bone marrow cells and enhances the leukemogenic properties of BCR-ABL1 in a murine model system.	2	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIN1	RIN1	RIN1	ABL2	ABL2	ABL2	2	3	8	9
Abl1 and Abl2 , close paralogs that are each directly activated by Rin1 , localize to neuronal synapses and contribute to short-term synaptic plasticity in the hippocampus .	Abl1 and Abl2, close paralogs that are each directly activated by Rin1, localize to neuronal synapses and contribute to short-term synaptic plasticity in the hippocampus.	0	14	directly activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Rin1	Rin1	Rin1	Abl2	Abl2	Abl2	12	13	2	3
The RICK ubiquitination on K209 located within its kinase domain triggers the oligomerization of RICK and the recruitment of TAK1 , in turn facilitating IKK activation .	The RICK ubiquitination on K209 located within its kinase domain triggers the oligomerization of RICK and the recruitment of TAK1, in turn facilitating IKK activation.	1	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RICK	RICK ubiquitination on K209	rick	RICK	RICK	rick	1	2	14	15
Inactivation of the ATP binding site of RIPK2 through genetic disruption of key amino acid residues ( K38 , K47 , D164 ) or by chemical inhibition decreased full-length RIPK2 levels , decreased autophosphorylation and prevented RIPK2 mediated cellular activation or apoptosis XREF_BIBR , XREF_BIBR .	Inactivation of the ATP binding site of RIPK2 through genetic disruption of key amino acid residues (K38, K47, D164) or by chemical inhibition decreased full-length RIPK2 levels, decreased autophosphorylation and prevented RIPK2 mediated cellular activation or apoptosis XREF_BIBR, XREF_BIBR.	3	39	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK2	ATP binding site of RIPK2 through genetic disruption of key amino acid residues (K38, K47, D164) or by chemical inhibition decreased full-length RIPK2 levels	ripk2	RIPK2	RIPK2	ripk2	29	30	36	37
CTRP8 and RLN2 , as well as two biologically active peptides homologous to a peptide sequence within the N-terminal region of the C1q globular domain of human CTRP8 , P59 , and P74 , activated RXFP1 by inducing cAMP signaling and PI3K-PKCzeta and PKCdelta-ERK 1/2 signaling in GB cells .	CTRP8 and RLN2, as well as two biologically active peptides homologous to a peptide sequence within the N-terminal region of the C1q globular domain of human CTRP8, P59, and P74, activated RXFP1 by inducing cAMP signaling and PI3K-PKCzeta and PKCdelta-ERK 1/2 signaling in GB cells.	0	36	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RLN2	RLN2	RLN2	RXFP1	RXFP1	RXFP1	2	3	35	36
RXFP1 activation by RLN2 in human thyroid cancer cells increased cell migration and extracellular matrix invasion resulting from enhanced collagenolytic activity through the upregulation of MMP2 and MT1-MMP and MMP14 and the increased secretion of MMP2 .	RXFP1 activation by RLN2 in human thyroid cancer cells increased cell migration and extracellular matrix invasion resulting from enhanced collagenolytic activity through the upregulation of MMP2 and MT1-MMP and MMP14 and the increased secretion of MMP2.	0	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	RLN2	RLN2	RLN2	RXFP1	RXFP1	RXFP1	3	4	0	1
FHOD1 , FHOD3 ' s closest paralog , can be activated by ROCK1 [ XREF_BIBR ] , which phosphorylates a consensus site in the DAD domain .	FHOD1, FHOD3 's closest paralog, can be activated by ROCK1 [XREF_BIBR], which phosphorylates a consensus site in the DAD domain.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	FHOD1	FHOD1	FHOD1	12	13	0	1
FHOD1 , unlike other diaphanous related formins ( DRFs ) , is activated upon phosphorylation of three residues in the DAD by ROCK1 , which releases the inhibitory interaction between DAD and DID [ XREF_BIBR , XREF_BIBR ] .	FHOD1, unlike other diaphanous related formins (DRFs), is activated upon phosphorylation of three residues in the DAD by ROCK1, which releases the inhibitory interaction between DAD and DID [XREF_BIBR, XREF_BIBR].	0	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	FHOD1	FHOD1	FHOD1	22	23	0	1
These findings indicate that ET B receptor activation may result in ROCK1 mediated LIMK2 induction following SE .	These findings indicate that ET B receptor activation may result in ROCK1 mediated LIMK2 induction following SE.	11	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	LIMK2	LIMK2	LIMK2	11	12	13	14
RIP1 and IRAKs activate TRAF6 , which is an adaptor shared by both MyD88 as well as TRIF .	RIP1 and IRAKs activate TRAF6, which is an adaptor shared by both MyD88 as well as TRIF.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	TRAF6	TRAF6	TRAF6	0	1	4	5
TRIF enlists the IKKs complex and Receptor interacting protein-1 ( RIP-1 ) , which activates TRAF3 and TRAF6 .	TRIF enlists the IKKs complex and Receptor interacting protein-1 (RIP-1), which activates TRAF3 and TRAF6.	6	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Receptor interacting protein-1	Receptor interacting protein-1	Receptor interacting protein-1	TRAF6	TRAF6	TRAF6	6	9	17	18
We next compared the sensitivities of the Ubc13 QD mutant and wild type Ubc13 to inhibition using in vitro ubiquitination assays that contained stoichiometric amounts of the E3 RNF8 , which stimulates Mms2 and Ubc13 dependent formation of Lys63 linked polyubiquitin chains 7 ( XREF_FIG ) .	We next compared the sensitivities of the Ubc13 QD mutant and wild type Ubc13 to inhibition using in vitro ubiquitination assays that contained stoichiometric amounts of the E3 RNF8, which stimulates Mms2 and Ubc13 dependent formation of Lys63 linked polyubiquitin chains 7 (XREF_FIG).	24	36	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RNF8	amounts of the E3 RNF8	rnf8	Ubc13	Ubc13	ubc13	28	29	34	35
We establish that UBC13 dependent K63 linked ubiquitylation at DSB sites is predominantly mediated by RNF8 but not RNF168 , and that H1-type linker histones , but not core histones , represent major chromatin associated targets of this modification .	We establish that UBC13 dependent K63 linked ubiquitylation at DSB sites is predominantly mediated by RNF8 but not RNF168, and that H1-type linker histones, but not core histones, represent major chromatin associated targets of this modification.	3	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RNF8	RNF8	RNF8	UBC13	UBC13	UBC13	15	16	3	4
NOD2 through interaction with RIP2 activates IKKgamma and subsequently NF-kappaB , which transcriptionally promotes inflammatory cytokines expression .	NOD2 through interaction with RIP2 activates IKKgamma and subsequently NF-kappaB, which transcriptionally promotes inflammatory cytokines expression.	2	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RIP2	RIP2	RIP2	IKKgamma	IKKgamma	IKKgamma	4	5	6	7
In a step-wise fashion , RIP2 activates NF-kappaB , and AP-1 by TAK1 ( TGF-beta activated kinase 1 ) complex , and NEMO , p38 , JNK and ERK MAPK pathway [ XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR ] .	In a step-wise fashion, RIP2 activates NF-kappaB, and AP-1 by TAK1 (TGF-beta activated kinase 1) complex, and NEMO, p38, JNK and ERK MAPK pathway [XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR].	5	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP2	RIP2	RIP2	NEMO	NEMO	NEMO	5	6	22	23
Furthermore , TC10 enhances GLUT4 vesicle trafficking and fusion to the plasma membrane by two mechanisms .	Furthermore, TC10 enhances GLUT4 vesicle trafficking and fusion to the plasma membrane by two mechanisms.	2	6	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TC10	TC10	TC10	GLUT4	GLUT4	GLUT4	2	3	4	5
In line with the possibility that RNF8 I405A functionally replaced WT RNF8 in DNA damage signaling , both RNF8 and its I405A mutant , but not DeltaFHA and DeltaRING , promoted BRCA1 and RAD18 accumulation at IRIF ( XREF_FIG C ) .	In line with the possibility that RNF8 I405A functionally replaced WT RNF8 in DNA damage signaling, both RNF8 and its I405A mutant, but not DeltaFHA and DeltaRING, promoted BRCA1 and RAD18 accumulation at IRIF (XREF_FIG C).	17	34	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RNF8	RNF8	RNF8	RAD18	RAD18	RAD18	18	19	33	34
Indeed , only reconstitution with wild-type RNF8 restored RAD18 IRIF ( XREF_FIG ) , suggesting that RAD18 also requires RNF8 E3 ligase activity to be recruited to DSB sites .	Indeed, only reconstitution with wild-type RNF8 restored RAD18 IRIF (XREF_FIG), suggesting that RAD18 also requires RNF8 E3 ligase activity to be recruited to DSB sites.	3	9	restored	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RNF8	RNF8	RNF8	RAD18	RAD18	RAD18	6	7	8	9
Subsequently RNF168 recognizes RNF8 synthesized di ubiquitinated H2A and H2AX and other yet-to-be-identified substrates via its MIU motifs and further elongate K63 linked polyubiquitin chains to reach a threshold that is required for sustained assembly of 53BP1 , BRCA1 and other DNA damage repair proteins at DSB sites XREF_BIBR , XREF_BIBR - XREF_BIBR .	Subsequently RNF168 recognizes RNF8 synthesized di ubiquitinated H2A and H2AX and other yet-to-be-identified substrates via its MIU motifs and further elongate K63 linked polyubiquitin chains to reach a threshold that is required for sustained assembly of 53BP1, BRCA1 and other DNA damage repair proteins at DSB sites XREF_BIBR, XREF_BIBR - XREF_BIBR.	2	10	synthesized	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RNF8	RNF8	RNF8	H2AX	H2AX	H2AX	3	4	9	10
Our results also demonstrated that MEOX2 activation of the p21WAF1 promoter was enhanced by RNF10 co-expression .	Our results also demonstrated that MEOX2 activation of the p21WAF1 promoter was enhanced by RNF10 co-expression.	5	16	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RNF10	RNF10 co-expression	rnf10	MEOX2	MEOX2	meox2	14	15	5	6
In non neuronal cells , activated ROCK1 induced PTEN activity resulting in an inactivation of Akt .	In non neuronal cells, activated ROCK1 induced PTEN activity resulting in an inactivation of Akt.	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	PTEN	PTEN	PTEN	6	7	8	9
7 Several studies have found that RhoA and ROCK1 activation enhances PTEN activity and suppresses Akt activation .	7 Several studies have found that RhoA and ROCK1 activation enhances PTEN activity and suppresses Akt activation.	6	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	PTEN	PTEN	PTEN	8	9	11	12
A number of evidence indicates that RhoA and ROCK1 activation enhances PTEN activity and suppresses Akt activation .	A number of evidence indicates that RhoA and ROCK1 activation enhances PTEN activity and suppresses Akt activation.	6	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	PTEN	PTEN	PTEN	8	9	11	12
Moreover , ROCK1 knockdown inhibited PTEN and promoted Akt , leading to depressed TLR4 .	Moreover, ROCK1 knockdown inhibited PTEN and promoted Akt, leading to depressed TLR4.	2	6	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	PTEN	PTEN	PTEN	2	3	5	6
Moreover , ROCK1 can activate PTEN , which in turn suppresses Akt activity and promotes caspase-3 activation XREF_BIBR .	Moreover, ROCK1 can activate PTEN, which in turn suppresses Akt activity and promotes caspase-3 activation XREF_BIBR.	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	PTEN	PTEN	PTEN	2	3	5	6
Whether this is an independent action or is secondary to activation of RhoA and ROCK is not known , but in macrophages and neutrophils , ROCK1 activates PTEN , which inactivates Akt .	Whether this is an independent action or is secondary to activation of RhoA and ROCK is not known, but in macrophages and neutrophils, ROCK1 activates PTEN, which inactivates Akt.	25	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	PTEN	PTEN	PTEN	25	26	27	28
This protein has four human isoforms ( p90RSK1-4 ) , among which , both RSK1 and RSK2 have been reported to activate and phosphorylate the regulatory associated protein of mTOR ( RAPTOR ) , which is required for the mTORC1 complex activity .	This protein has four human isoforms (p90RSK1-4), among which, both RSK1 and RSK2 have been reported to activate and phosphorylate the regulatory associated protein of mTOR (RAPTOR), which is required for the mTORC1 complex activity.	13	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RSK1	RSK1	RSK1	regulatory associated protein of mTOR	regulatory associated protein of mTOR	regulatory associated protein of mTOR	14	15	25	30
Downstream of ERK , p90 ribosomal S6 kinase 1 ( RSK1 ) also inhibits TSC1/2 and activates Raptor to promote mTORC1 activity [ XREF_BIBR , XREF_BIBR ] .	Downstream of ERK, p90 ribosomal S6 kinase 1 (RSK1) also inhibits TSC1/2 and activates Raptor to promote mTORC1 activity [XREF_BIBR, XREF_BIBR].	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RSK1	RSK1	RSK1	Raptor	Raptor	Raptor	10	11	17	18
Rabin8 is its primary GEF but RPGR has also been reported to activate RAB8 .	Rabin8 is its primary GEF but RPGR has also been reported to activate RAB8.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPGR	RPGR	RPGR	RAB8	RAB8	RAB8	6	7	13	14
Our data suggest that RPGR modulates intracellular localization and function of RAB8A .	Our data suggest that RPGR modulates intracellular localization and function of RAB8A.	4	12	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPGR	RPGR	RPGR	RAB8A	RAB8A	RAB8A	4	5	11	12
We then tested whether RPGR can potentiate the GTPase activity of RAB8A .	We then tested whether RPGR can potentiate the GTPase activity of RAB8A.	4	12	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPGR	RPGR	RPGR	RAB8A	RAB8A	RAB8A	4	5	11	12
One role for Ta3 may lie in localizing Rab8 activators such as Rabin8 33 or RPGR 42 to the BB , possibly through additional indirect steps given the lack of identification of a direct interaction between Ta3 and Rabin8 22 .	One role for Ta3 may lie in localizing Rab8 activators such as Rabin8 33 or RPGR 42 to the BB, possibly through additional indirect steps given the lack of identification of a direct interaction between Ta3 and Rabin8 22.	8	16	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	RPGR	RPGR	RPGR	Rab8	Rab8	Rab8	15	16	8	9
The anti-estrogen 4-hydroxytamoxifen blocks Rsk2 mediated activation of ERalpha , by inducing a conformation of ERalpha in which the Rsk2 docking site is masked .	The anti-estrogen 4-hydroxytamoxifen blocks Rsk2 mediated activation of ERalpha, by inducing a conformation of ERalpha in which the Rsk2 docking site is masked.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rsk2	Rsk2	Rsk2	ERalpha	ERalpha	ERalpha	4	5	8	9
For example , we have found that RSK2 stimulates the transcriptional activity of estrogen receptor alpha ( ERalpha ) [ XREF_BIBR - XREF_BIBR ] which is known to be important in the etiology of many breast cancers .	For example, we have found that RSK2 stimulates the transcriptional activity of estrogen receptor alpha (ERalpha) [XREF_BIBR - XREF_BIBR] which is known to be important in the etiology of many breast cancers.	7	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RSK2	RSK2	RSK2	estrogen receptor	estrogen receptor	estrogen receptor	7	8	13	15
Furthermore , Clark and colleagues reported that , independently of MAPK , p90 ribosomal S6 kinase 2 ( Rsk2 ) specifically activates ER-alpha by phosphorylation of Ser167 and by docking to the hormone binding domain of ER-alpha , and that the antiestrogen 4-hydroxytamoxifen blocks Rsk2 mediated activation of ER-alpha [ XREF_BIBR ] .	Furthermore, Clark and colleagues reported that, independently of MAPK, p90 ribosomal S6 kinase 2 (Rsk2) specifically activates ER-alpha by phosphorylation of Ser167 and by docking to the hormone binding domain of ER-alpha, and that the antiestrogen 4-hydroxytamoxifen blocks Rsk2 mediated activation of ER-alpha [XREF_BIBR].	44	50	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rsk2	Rsk2	Rsk2	ER-alpha	ER-alpha	ER-alpha	44	45	48	49
Coexpression of 14-3-3beta and/or ROCK1 increased the proportion of Rnd3 in the cytosolic fraction , concomitant with reduced levels of Rnd3 in the membrane fraction ( XREF_FIG C , upper left ) .	Coexpression of 14-3-3beta and/or ROCK1 increased the proportion of Rnd3 in the cytosolic fraction, concomitant with reduced levels of Rnd3 in the membrane fraction (XREF_FIG C, upper left).	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ROCK1	Coexpression of 14-3-3beta and/or ROCK1	rock1	Rnd3	Rnd3	rnd3	4	5	9	10
Again , genetic deletion of ROCK1 partially but not completely rescued Rnd3 deficiency mediated heart failure phenotype .	Again, genetic deletion of ROCK1 partially but not completely rescued Rnd3 deficiency mediated heart failure phenotype.	3	12	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ROCK1	ROCK1	ROCK1	Rnd3	Rnd3	Rnd3	5	6	11	12
To further investigate the role of ROCK1 activation in Rnd3 deficiency mediated cardiomyopathy , we created the Rnd3 +/- with ROCK1-null background mouse line , Rnd3 +/-/ROCK1-/- ( XREF_FIG ) .	To further investigate the role of ROCK1 activation in Rnd3 deficiency mediated cardiomyopathy, we created the Rnd3 +/- with ROCK1-null background mouse line, Rnd3 +/-/ROCK1-/- (XREF_FIG).	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	Rnd3	Rnd3	Rnd3	6	7	9	10
Consistent with the Rho kinase treatment result , we found that genetic loss of ROCK1 gene also partially attenuated hemodynamic stress induced cardiomyopathy in Rnd3 haploinsufficient mice .	Consistent with the Rho kinase treatment result, we found that genetic loss of ROCK1 gene also partially attenuated hemodynamic stress induced cardiomyopathy in Rnd3 haploinsufficient mice.	14	26	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ROCK1	ROCK1	ROCK1	Rnd3	Rnd3	Rnd3	14	15	24	25
This maybe due to complicated feedback loops between the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways wherein either mTORC1 inhibition leads to ERK1/2 activation by a p70S6K/PI3K/Ras dependent pathway or by the KRAS mutants activating p90 Rsk-1 which serves to activate eIF4B and rpS6 thereby bypassing mTOR dependent activation .	This maybe due to complicated feedback loops between the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways wherein either mTORC1 inhibition leads to ERK1/2 activation by a p70S6K/PI3K/Ras dependent pathway or by the KRAS mutants activating p90 Rsk-1 which serves to activate eIF4B and rpS6 thereby bypassing mTOR dependent activation.	32	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p90 Rsk-1	p90 Rsk-1	p90 Rsk-1	rpS6	rpS6	rpS6	32	34	40	41
Two of the crucial phosphorylation sites in RSK1 are Ser 380 , which provides a docking site for 3 '-phosphoinositide-dependent kinase-1 ( PDK1 ) and Ser 221 , which is phosphorylated by the docked PDK1 and is thought to activate RSK1 [ XREF_BIBR ] .	Two of the crucial phosphorylation sites in RSK1 are Ser 380, which provides a docking site for 3 '-phosphoinositide-dependent kinase-1 (PDK1) and Ser 221, which is phosphorylated by the docked PDK1 and is thought to activate RSK1 [XREF_BIBR].	4	42	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RSK1	phosphorylation sites in RSK1 are Ser 380	rsk1	RSK1	RSK1	rsk1	7	8	40	41
Phosphorylation of basal or phosphatase-2A-treated recombinant Rsk-1 in vitro with erk2 and MAP kinase increases Rsk-1 40S kinase , peptide kinase , and autophosphorylating activity , retards migration of Rsk-1 polypeptides on SDS-PAGE , and generates new sites of Rsk-1 autophosphorylation in vitro .	Phosphorylation of basal or phosphatase-2A-treated recombinant Rsk-1 in vitro with erk2 and MAP kinase increases Rsk-1 40S kinase, peptide kinase, and autophosphorylating activity, retards migration of Rsk-1 polypeptides on SDS-PAGE, and generates new sites of Rsk-1 autophosphorylation in vitro.	0	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rsk-1	Phosphorylation of basal or phosphatase-2A-treated recombinant Rsk-1	rsk-1	Rsk-1	Rsk-1	rsk-1	6	7	15	16
Herein , we report that RPL5 and RPL11 can also enhance the transcriptional activity of a p53 homolog TAp73 , but through a distinct mechanism .	Herein, we report that RPL5 and RPL11 can also enhance the transcriptional activity of a p53 homolog TAp73, but through a distinct mechanism.	5	19	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPL5	RPL5	RPL5	TAp73	TAp73	TAp73	5	6	18	19
Furthermore , ectopic expression of RPL5 or RPL11 markedly induced TAp73 transcriptional activity by antagonizing MDM2 suppression .	Furthermore, ectopic expression of RPL5 or RPL11 markedly induced TAp73 transcriptional activity by antagonizing MDM2 suppression.	3	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPL5	expression of RPL5	rpl5	TAp73	TAp73	tap73	5	6	10	11
Under physiological conditions , the expression of Wnt5a and Ror2 is regulated , leading to modulated Ror2 signaling , such as that seen in development XREF_BIBR - XREF_BIBR .	Under physiological conditions, the expression of Wnt5a and Ror2 is regulated, leading to modulated Ror2 signaling, such as that seen in development XREF_BIBR - XREF_BIBR.	5	17	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ror2	expression of Wnt5a and Ror2	ror2	Ror2	Ror2	ror2	9	10	16	17
Y-27632 decreased the expression of ROCK-II and phosphorylated ( p )-CRMP2 , and suppressed the increased ROCK-II and p-CRMP2 induced by LPS ; however , no effect on the levels of TLR4 expression was observed .	Y-27632 decreased the expression of ROCK-II and phosphorylated (p)-CRMP2, and suppressed the increased ROCK-II and p-CRMP2 induced by LPS; however, no effect on the levels of TLR4 expression was observed.	0	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ROCK-II	Y-27632 decreased the expression of ROCK-II	rock-ii	p-CRMP2	p-CRMP2	p-crmp2	5	6	18	19
We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1 , Mad2 and CENP-E under checkpoint conditions .	We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions.	19	34	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Rsk2	Rsk2	Rsk2	CENP-E	CENP-E	CENP-E	19	20	33	34
We therefore conclude that RSK1 and RSK2 are novel activators of YB-1 , able to phosphorylate the serine 102 residue .	We therefore conclude that RSK1 and RSK2 are novel activators of YB-1, able to phosphorylate the serine 102 residue.	4	12	are novel activators	Positive_activation_copula_1	Positive_activation	Positive_activation	RSK1	RSK1	RSK1	YB-1	YB-1	YB-1	4	5	11	12
Nevertheless , the mechanism by which S6K1 short isoforms activate mTOR is yet to be determined .	Nevertheless, the mechanism by which S6K1 short isoforms activate mTOR is yet to be determined.	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	6	7	10	11
As mentioned above , S6K1 and S6K2 are the downstream targets of mTOR that are the most affected by rapamycin .	As mentioned above, S6K1 and S6K2 are the downstream targets of mTOR that are the most affected by rapamycin.	4	13	are the downstream targets	Positive_activation_copula_1	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	4	5	12	13
First , mTOR signaling including Akt , p70 and ribosomal S6 kinase ( p70 and S6K ) , and autophagy were assessed .	First, mTOR signaling including Akt, p70 and ribosomal S6 kinase (p70 and S6K), and autophagy were assessed.	2	11	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	p70	p70	p70	mTOR	mTOR	mTOR	7	8	2	3
HC toxin induced Akt activation was sufficient to enhance downstream mTOR complex 1 ( mTORC1 ) signalling including p70S6K and S6 , which were consistently abolished by PI3K inhibition .	HC toxin induced Akt activation was sufficient to enhance downstream mTOR complex 1 (mTORC1) signalling including p70S6K and S6, which were consistently abolished by PI3K inhibition.	10	25	signalling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	18	19	10	11
p70S6K mediates mTOR signaling in ATF3 mediated immune regulation in vitro .	p70S6K mediates mTOR signaling in ATF3 mediated immune regulation in vitro.	0	3	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	0	1	2	3
S6K1 is a down-stream target of mTOR ; it plays an important role in cell proliferation and cell cycle progression [ XREF_BIBR ] .	S6K1 is a down-stream target of mTOR; it plays an important role in cell proliferation and cell cycle progression [XREF_BIBR].	0	7	is a down-stream target	Positive_activation_copula_1	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	0	1	6	7
Recent findings indicate that rapamycin can differentially inhibit mTOR dependent translation promoted by p70S6 kinase versus cap dependent translation regulated by 4E-BP1 .	Recent findings indicate that rapamycin can differentially inhibit mTOR dependent translation promoted by p70S6 kinase versus cap dependent translation regulated by 4E-BP1.	8	15	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p70S6 kinase	p70S6 kinase	p70S6 kinase	mTOR	mTOR	mTOR	13	15	8	9
Furthermore , the effect of n-butanol on well validated readouts of mTOR activation , such as p70S6K phosphorylation , is relatively small .	Furthermore, the effect of n-butanol on well validated readouts of mTOR activation, such as p70S6K phosphorylation, is relatively small.	11	18	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	p70S6K	p70S6K phosphorylation	p70s6k	mTOR	mTOR	mtor	16	17	11	12
Activation of mTOR signaling by leucine or overexpression of p70 ribosome protein subunit 6 kinase 1 ( S6K1 ) activated mTOR signaling in isolated T cells , while reversed the ghrelin induced inhibition of iTh17 cell differentiation .	Activation of mTOR signaling by leucine or overexpression of p70 ribosome protein subunit 6 kinase 1 (S6K1) activated mTOR signaling in isolated T cells, while reversed the ghrelin induced inhibition of iTh17 cell differentiation.	14	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	17	18	20	21
As an evidence of this notion , siRNA mediated gene silencing of PI3K and Akt inhibited the activation of p70S6K1 ( a downstream target of mTOR ) , and subsequently led to the suppression of migration , invasion and proliferation XREF_BIBR .	As an evidence of this notion, siRNA mediated gene silencing of PI3K and Akt inhibited the activation of p70S6K1 (a downstream target of mTOR), and subsequently led to the suppression of migration, invasion and proliferation XREF_BIBR.	17	26	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p70S6K1	p70S6K1	p70S6K1	mTOR	mTOR	mTOR	19	20	25	26
Correspondingly , we detected no significant effects of chronic ALD on the total , phosphorylated or phospho and total levels of proline rich Akt substrate 40kDa ( PRAS 40 ) or p70S6 kinase , which mediate mTOR signaling ( XREF_TABLE ) .	Correspondingly, we detected no significant effects of chronic ALD on the total, phosphorylated or phospho and total levels of proline rich Akt substrate 40kDa (PRAS 40) or p70S6 kinase, which mediate mTOR signaling (XREF_TABLE).	19	37	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6 kinase	levels of proline rich Akt substrate 40kDa (PRAS 40) or p70S6 kinase	p70s6 kinase	mTOR	mTOR	mtor	31	33	36	37
Activation of AMPK by the AMP mimetic 5-amino-4-imidazolecarboxamide ribose ( AICAR ) represses mTOR signaling , leading to dephosphorylation of a number of targets of mTOR signaling including S6K1 , eIF4G and 4E-BP1 [ XREF_BIBR ] .	Activation of AMPK by the AMP mimetic 5-amino-4-imidazolecarboxamide ribose (AICAR) represses mTOR signaling, leading to dephosphorylation of a number of targets of mTOR signaling including S6K1, eIF4G and 4E-BP1 [XREF_BIBR].	25	32	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	28	29	25	26
Activated mTOR further phosphorylates ribosomal p70 S6 kinase ( S6K1 ) , eukaryotic initiation factor 4E ( eIF4E ) binding protein 1 ( 4E-BP1 ) , and Akt , controlling cell proliferation , growth , and survival .	Activated mTOR further phosphorylates ribosomal p70 S6 kinase (S6K1), eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), and Akt, controlling cell proliferation, growth, and survival.	0	10	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	9	10	1	2
Consistent with the AKT data , p70S6K and p-p70S6K levels ( a major target of mTOR ) were not different between strains or with exercise training in skeletal muscle .	Consistent with the AKT data, p70S6K and p-p70S6K levels (a major target of mTOR) were not different between strains or with exercise training in skeletal muscle.	6	16	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p70S6K	p70S6K and p-p70S6K levels	p70s6k	mTOR	mTOR	mtor	6	7	15	16
POLDIP3 is a substrate for S6K1 , which is downstream of mTOR , and enhances the mTOR and S6K1 dependent translation of mRNA , which is associated with cell size XREF_BIBR , XREF_BIBR .	POLDIP3 is a substrate for S6K1, which is downstream of mTOR, and enhances the mTOR and S6K1 dependent translation of mRNA, which is associated with cell size XREF_BIBR, XREF_BIBR.	3	22	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	5	6	16	17
Akt also leads to activate the protein synthesis with mTOR mediated by eIF4 and p70S6K [ XREF_BIBR ] .	Akt also leads to activate the protein synthesis with mTOR mediated by eIF4 and p70S6K [XREF_BIBR].	4	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	14	15	9	10
p70S6K and 4E-BP1 are targets of mTOR and are positively regulated via phosphorylation XREF_BIBR .	p70S6K and 4E-BP1 are targets of mTOR and are positively regulated via phosphorylation XREF_BIBR.	0	10	are targets	Positive_activation_copula_1	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	0	1	6	7
Activation of Akt and ERK1/2 , which are required for lasting and fast antidepressant effects XREF_BIBR , stimulate 4E-BP1 or p70S6K activation in an mTOR dependent or mTOR independent manner .	Activation of Akt and ERK1/2, which are required for lasting and fast antidepressant effects XREF_BIBR, stimulate 4E-BP1 or p70S6K activation in an mTOR dependent or mTOR independent manner.	18	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	20	21	24	25
We used rapamycin and mTOR shRNA lentiviral vectors to inhibit mTOR activities , while S6K1 viral vectors , a main downstream mTOR gene , were used to promote mTOR activities .	We used rapamycin and mTOR shRNA lentiviral vectors to inhibit mTOR activities, while S6K1 viral vectors, a main downstream mTOR gene, were used to promote mTOR activities.	14	29	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	14	15	28	29
In the present study , we demonstrated that mTOR feedback activation by two S6K1 inhibitors , A77 1726 or PF-4708671 , and by S6K1 siRNA did not suppress autophagy in a motoneuron cell line .	In the present study, we demonstrated that mTOR feedback activation by two S6K1 inhibitors, A77 1726 or PF-4708671, and by S6K1 siRNA did not suppress autophagy in a motoneuron cell line.	8	24	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	23	24	8	9
As p70S6K is a downstream target of mTOR , we suggest that JNK has a crucial role in sustaining the activity of mTOR in human CCA cells .	As p70S6K is a downstream target of mTOR, we suggest that JNK has a crucial role in sustaining the activity of mTOR in human CCA cells.	1	8	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	1	2	7	8
Both 4E-BP1 and S6K1 are downstream phosphorylation targets of mTOR and stimulate mRNA translation initiation in the post-absorptive state .	Both 4E-BP1 and S6K1 are downstream phosphorylation targets of mTOR and stimulate mRNA translation initiation in the post-absorptive state.	1	10	are downstream phosphorylation targets	Positive_activation_copula_1	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	3	4	9	10
Besides localization of phosphorylated mTOR in the cytoplasm , remarkable alterations of two major mTOR targets including phosphorylation of S6K1 and catalytic substrate S6 and 4E-BP1 were observed , substantiating mTOR activation in DNA damaged cells .	Besides localization of phosphorylated mTOR in the cytoplasm, remarkable alterations of two major mTOR targets including phosphorylation of S6K1 and catalytic substrate S6 and 4E-BP1 were observed, substantiating mTOR activation in DNA damaged cells.	14	23	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	S6K1	phosphorylation of S6K1	s6k1	mTOR	mTOR	mtor	19	20	14	15
The protein kinase p70S6K is a target of mTOR and its acute phosphorylation following resistance exercise has been reported to correlate with muscle hypertrophy following training [ XREF_BIBR , XREF_BIBR ] ; however , not all studies have found a relationship [ XREF_BIBR , XREF_BIBR ] .	The protein kinase p70S6K is a target of mTOR and its acute phosphorylation following resistance exercise has been reported to correlate with muscle hypertrophy following training [XREF_BIBR, XREF_BIBR]; however, not all studies have found a relationship [XREF_BIBR, XREF_BIBR].	0	9	is a target	Positive_activation_copula_1	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	3	4	8	9
Both S6K1 and 4E-BP1/eIF4E pathways mediate mTOR dependent G1 phase transition .	Both S6K1 and 4E-BP1/eIF4E pathways mediate mTOR dependent G1 phase transition.	1	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	1	2	6	7
Activated mTOR subsequently activates p70 ribosomal protein S6 kinase ( p70S6K ) and ribosomal protein S6 ( S6 ) by phosphorylation .	Activated mTOR subsequently activates p70 ribosomal protein S6 kinase (p70S6K) and ribosomal protein S6 (S6) by phosphorylation.	0	11	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	10	11	1	2
However , it is unclear how the TOS motif in S6K1 and 4E-BP1 mediates mTOR signaling .	However, it is unclear how the TOS motif in S6K1 and 4E-BP1 mediates mTOR signaling.	8	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	10	11	14	15
Furthermore , 2-deoxyglucose activated p70S6K suggesting that phosphorylation of glucose is required for carbohydrate mediated mTOR signalling in the heart .	Furthermore, 2-deoxyglucose activated p70S6K suggesting that phosphorylation of glucose is required for carbohydrate mediated mTOR signalling in the heart.	4	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	4	5	15	16
S6K1 is a downstream target of the mTOR , and the mTOR and S6K1 pathway plays an essential role in normal cellular functions , including protein translation , synthesis , stability , cell proliferation , cell cycle progression , and cell survival XREF_BIBR .	S6K1 is a downstream target of the mTOR, and the mTOR and S6K1 pathway plays an essential role in normal cellular functions, including protein translation, synthesis, stability, cell proliferation, cell cycle progression, and cell survival XREF_BIBR.	0	8	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	0	1	7	8
p70S6K and 4E-BP1 are downstream targets of mTOR ; the inhibition and down-regulation of these molecules can induce autophagy .	p70S6K and 4E-BP1 are downstream targets of mTOR; the inhibition and down-regulation of these molecules can induce autophagy.	0	8	are downstream targets	Positive_activation_copula_1	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	0	1	7	8
Note that total protein of mTOR , S6K1 and 4E-BP1 levels was not significantly increased in SCI rats .	Note that total protein of mTOR, S6K1 and 4E-BP1 levels was not significantly increased in SCI rats.	3	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1 and 4E-BP1 levels	s6k1	mTOR	mTOR	mtor	7	8	5	6
For example , an up-regulated lncRNA termed metastasis associated lung adenocarcinoma transcript1 ( MALAT1 ) in HCC increases the expression of splicing factor SRSF1 ( serine and arginine rich splicing factor 1 ) through activating Wnt pathway , causing dys regulated apoptosis and alternative splicing of S6 kinase1 ( S6K1 ) , which further activates the mTOR pathway , and ultimately resulting in HCC progression [ XREF_BIBR ] .	For example, an up-regulated lncRNA termed metastasis associated lung adenocarcinoma transcript1 (MALAT1) in HCC increases the expression of splicing factor SRSF1 (serine and arginine rich splicing factor 1) through activating Wnt pathway, causing dys regulated apoptosis and alternative splicing of S6 kinase1 (S6K1), which further activates the mTOR pathway, and ultimately resulting in HCC progression [XREF_BIBR].	47	57	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	49	50	56	57
Unlike cytokines and EGF , which induce HIF-1alpha by Akt and mTOR dependent translation [ XREF_BIBR ] , starvation deficient of growth factors inhibits Akt and mTOR downstream signaling including 4E-BP1 and p70S6K phosphorylation .	Unlike cytokines and EGF, which induce HIF-1alpha by Akt and mTOR dependent translation [XREF_BIBR], starvation deficient of growth factors inhibits Akt and mTOR downstream signaling including 4E-BP1 and p70S6K phosphorylation.	24	34	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	p70S6K	p70S6K phosphorylation	p70s6k	mTOR	mTOR	mtor	32	33	26	27
Previous studies demonstrated that PIK3CA knock in cells do not activate the mTOR pathway in the absence of EGF despite EGF independent growth , as evidenced by resistance to the mTOR inhibitor rapamycin and the lack of p70S6K phosphorylation , a downstream substrate of mTORC1 .	Previous studies demonstrated that PIK3CA knock in cells do not activate the mTOR pathway in the absence of EGF despite EGF independent growth, as evidenced by resistance to the mTOR inhibitor rapamycin and the lack of p70S6K phosphorylation, a downstream substrate of mTORC1.	10	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K phosphorylation	p70s6k	mTOR	mTOR	mtor	37	38	12	13
Furthermore , mTOR activity is mediated by direct phosphorylation of its downstream targets S6K1 and PHAS-1 , which can ultimately result in protein synthesis .	Furthermore, mTOR activity is mediated by direct phosphorylation of its downstream targets S6K1 and PHAS-1, which can ultimately result in protein synthesis.	2	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	S6K1	phosphorylation of its downstream targets S6K1	s6k1	mTOR	mTOR	mtor	13	14	2	3
As shown in Figure XREF_FIG , Abeta induced the phosphorylation of 4EBP1 and p70S6K1 , which was blocked by rapamycin , suggesting that mTOR activation is mediated by the activation of 4EBP1 and p70S6K1 in Abeta treated SK-N-MC cells .	As shown in Figure XREF_FIG, Abeta induced the phosphorylation of 4EBP1 and p70S6K1, which was blocked by rapamycin, suggesting that mTOR activation is mediated by the activation of 4EBP1 and p70S6K1 in Abeta treated SK-N-MC cells.	23	34	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p70S6K1	p70S6K1	p70S6K1	mTOR	mTOR	mTOR	33	34	23	24
Since S6K-1 is a downstream target of mTOR associated proteins such as raptor we next investigated whether insulin stimulated glucose transport was altered in our model when Raptor was knocked-down .	Since S6K-1 is a downstream target of mTOR associated proteins such as raptor we next investigated whether insulin stimulated glucose transport was altered in our model when Raptor was knocked-down.	1	8	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	S6K-1	S6K-1	S6K-1	mTOR	mTOR	mTOR	1	2	7	8
S6K-1 is a downstream target of mTOR , a critical kinase involved in metabolic disorders and tumorigenesis [ XREF_BIBR ] .	S6K-1 is a downstream target of mTOR, a critical kinase involved in metabolic disorders and tumorigenesis [XREF_BIBR].	0	10	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	S6K-1	S6K-1	S6K-1	mTOR	mTOR	mTOR	0	1	6	7
Furthermore , expression of S6K1 ( which phosphorylates rpS6 ) and Rheb ( upstream activator of mTOR ) were significantly reduced in placentas from obese dams (-30% and -45 % , respectively , P < 0.05 ; XREF_FIG ) .	Furthermore, expression of S6K1 (which phosphorylates rpS6) and Rheb (upstream activator of mTOR) were significantly reduced in placentas from obese dams (-30% and -45%, respectively, P < 0.05; XREF_FIG).	2	17	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	S6K1	expression of S6K1	s6k1	mTOR	mTOR	mtor	4	5	16	17
We found that the phosphorylation levels of Akt and p70S6K ( immediate downstream targets of mTOR ) decreased in cells treated with FIR .	We found that the phosphorylation levels of Akt and p70S6K (immediate downstream targets of mTOR) decreased in cells treated with FIR.	5	16	targets	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p70S6K	levels of Akt and p70S6K	p70s6k	mTOR	mTOR	mtor	9	10	15	16
Activated mTOR phosphorylates p70S6K1 that promotes gene expression , while activated mTOR inhibits 4E-BP1 through phosphorylation that up-regulates gene expression .	Activated mTOR phosphorylates p70S6K1 that promotes gene expression, while activated mTOR inhibits 4E-BP1 through phosphorylation that up-regulates gene expression.	0	5	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K1	phosphorylates p70S6K1	p70s6k1	mTOR	mTOR	mtor	3	4	1	2
In a panel of NSCLC cells , the compound also attenuated mTOR downstream signaling , including the phosphorylation of p70S6K , S6 , and Akt , resulting in G1 cell cycle arrest and growth inhibition .	In a panel of NSCLC cells, the compound also attenuated mTOR downstream signaling, including the phosphorylation of p70S6K, S6, and Akt, resulting in G1 cell cycle arrest and growth inhibition.	11	21	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	p70S6K	phosphorylation of p70S6K	p70s6k	mTOR	mTOR	mtor	19	20	11	12
However , the expression of mTOR was not affected by PF-4708671 , which again indicates that S6K1 is a target of mTOR .	However, the expression of mTOR was not affected by PF-4708671, which again indicates that S6K1 is a target of mTOR.	16	22	is a target	Positive_activation_copula_1	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	16	17	21	22
Furthermore , pretreatment with PD 98059 ( a p44/42 inhibitor , 10 (-5) M ) or SP 600125 ( a JNK inhibitor , 10 (-6) M ) inhibited ZnCl ( 2 )-induced activation of mTOR , p70S6K , and 4E-BP1 .	Furthermore, pretreatment with PD 98059 (a p44/42 inhibitor, 10 (-5) M) or SP 600125 (a JNK inhibitor, 10 (-6) M) inhibited ZnCl (2)-induced activation of mTOR, p70S6K, and 4E-BP1.	27	37	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	36	37	34	35
Immunoblotting of phospho-S6 ribosomal protein , a downstream component of the mTOR substrate S6K1 in glandular homogenates revealed activation of S6K1 ( and therefore activation of mTOR ) in only the ligated state in the 3 day group .	Immunoblotting of phospho-S6 ribosomal protein, a downstream component of the mTOR substrate S6K1 in glandular homogenates revealed activation of S6K1 (and therefore activation of mTOR) in only the ligated state in the 3 day group.	18	27	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	20	21	26	27
S6K1 is a downstream target of mTOR and a serine threonine protein kinase that has been shown to be essential for protein synthesis , growth , development , and proliferation .	S6K1 is a downstream target of mTOR and a serine threonine protein kinase that has been shown to be essential for protein synthesis, growth, development, and proliferation.	0	7	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	0	1	6	7
MTOR and p70S6K1 can be activated by the dysfunction or genetic alterations of its upstream PI3K/PTEN/AKT signaling pathway or by the overexpression or amplification of p70S6K1 .	MTOR and p70S6K1 can be activated by the dysfunction or genetic alterations of its upstream PI3K/PTEN/AKT signaling pathway or by the overexpression or amplification of p70S6K1.	0	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p70S6K1	overexpression or amplification of p70S6K1	p70s6k1	MTOR	MTOR	mtor	25	26	0	1
Modulation of the alternative splicing of S6K1 , generates the oncogenic splicing isoform Iso2 , promotes activation of the mTOR pathway , leading to enhanced 4E-BP1 phosphorylation .	Modulation of the alternative splicing of S6K1, generates the oncogenic splicing isoform Iso2, promotes activation of the mTOR pathway, leading to enhanced 4E-BP1 phosphorylation.	4	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	6	7	19	20
Avila-Flores and colleagues demonstrated that over-expression of DGKzeta led to enhanced , serum induced phosphorylation of p70 S6 kinase ( p70S6K ) -- a major downstream target of mTOR -- and rendered the cells resistant to the effects of rapamycin .	Avila-Flores and colleagues demonstrated that over-expression of DGKzeta led to enhanced, serum induced phosphorylation of p70 S6 kinase (p70S6K) -- a major downstream target of mTOR -- and rendered the cells resistant to the effects of rapamycin.	14	29	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p70S6K	phosphorylation of p70 S6 kinase (p70S6K	p70s6k	mTOR	mTOR	mtor	20	21	28	29
Similarly , the levels of mTOR pathway mediators such as p-S6K1 , p-eIF-4E , and p-4E-BP-1 were either reduced or completely inhibited by CDDO-Me in a concentration dependent manner .	Similarly, the levels of mTOR pathway mediators such as p-S6K1, p-eIF-4E, and p-4E-BP-1 were either reduced or completely inhibited by CDDO-Me in a concentration dependent manner.	5	15	mediators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	p-S6K1	p-S6K1	p-S6K1	mTOR	mTOR	mTOR	10	11	5	6
Considering that ( i ) p70S6K induces S6 phosphorylation of the 40S ribosomal subunit , an essential condition for protein synthesis ; ( ii ) eIF2 is essential for the initiation of messenger RNA translation process ; and ( iii ) eIF5A and eEF1A play a central role in the elongation of the polypeptidic chain during the transcripts decoding , the data presented here lead us to suppose that a part of T3 induced insulin expression in INS-1E cells depends on the protein synthesis activation at the post-transcriptional level , as these proteins of the translational machinery were shown to be regulated by T3 .	Considering that (i) p70S6K induces S6 phosphorylation of the 40S ribosomal subunit, an essential condition for protein synthesis; (ii) eIF2 is essential for the initiation of messenger RNA translation process; and (iii) eIF5A and eEF1A play a central role in the elongation of the polypeptidic chain during the transcripts decoding, the data presented here lead us to suppose that a part of T3 induced insulin expression in INS-1E cells depends on the protein synthesis activation at the post-transcriptional level, as these proteins of the translational machinery were shown to be regulated by T3.	5	103	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	S6	S6	S6	5	6	7	8
The phosphorylation levels of S6K1 targets rpS6 ( ribosomal protein S6 ) and p-GSK3beta fell rapidly within 5 minutes and stayed low ( p-GSK3beta ) or undetectable ( p-rpS6 ) for 120 minutes .	The phosphorylation levels of S6K1 targets rpS6 (ribosomal protein S6) and p-GSK3beta fell rapidly within 5 minutes and stayed low (p-GSK3beta) or undetectable (p-rpS6) for 120 minutes.	2	13	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	rpS6	rpS6	rpS6	4	5	6	7
Phosphorylation of p70S6K in turn results in the activation of ribosomal protein S6 ( RPS6 ) and other translational regulators that further enhance translation initiation and elongation .	Phosphorylation of p70S6K in turn results in the activation of ribosomal protein S6 (RPS6) and other translational regulators that further enhance translation initiation and elongation.	0	13	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	p70S6K	Phosphorylation of p70S6K	p70s6k	ribosomal protein S6	ribosomal protein S6	ribosomal protein s6	2	3	10	13
Phosphorylation of 4EBP1 results in its release from eIF4E and promotes cap dependent translation , whereas phosphorylation of p70S6K activates the ribosomal S6 protein to enhance translation of ribosomal proteins and elongation factors .	Phosphorylation of 4EBP1 results in its release from eIF4E and promotes cap dependent translation, whereas phosphorylation of p70S6K activates the ribosomal S6 protein to enhance translation of ribosomal proteins and elongation factors.	16	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	phosphorylation of p70S6K	p70s6k	S6	S6	s6	18	19	22	23
Rapamycin suppresses mTORC1 pathway by inhibiting phosphorylation of p70S6 kinase ( p70S6K ) at Thr389 , which in turn no longer activates ribosomal protein S6 and protein synthesis machinery .	Rapamycin suppresses mTORC1 pathway by inhibiting phosphorylation of p70S6 kinase (p70S6K) at Thr389, which in turn no longer activates ribosomal protein S6 and protein synthesis machinery.	0	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6 kinase	Rapamycin suppresses mTORC1 pathway by inhibiting phosphorylation of p70S6 kinase (p70S6K) at Thr389	p70s6 kinase	ribosomal protein S6	ribosomal protein S6	ribosomal protein s6	8	10	22	25
Activated mTORC1 phosphorylates the hydrophobic motif of S6K1 , thus sequentially activating S6 to induce ribosome biogenesis [ XREF_BIBR ] .	Activated mTORC1 phosphorylates the hydrophobic motif of S6K1, thus sequentially activating S6 to induce ribosome biogenesis [XREF_BIBR].	1	13	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	mTORC1 phosphorylates the hydrophobic motif of S6K1	s6k1	S6	S6	s6	7	8	12	13
This transitory effect of rapamycin on PKCalpha and PKD phosphorylation differs from the dephosphorylation kinetics of the p70S6K target pS6 , and correlates well with DGKzeta activation .	This transitory effect of rapamycin on PKCalpha and PKD phosphorylation differs from the dephosphorylation kinetics of the p70S6K target pS6, and correlates well with DGKzeta activation.	14	20	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	pS6	pS6	pS6	17	18	19	20
Overexpression of wild-type ( WT ) p70S6K1 , and particularly F5A-E389-R3A and E389-DeltaCT , abrogated the reduction of p-S6 by rapamycin ; however , rapamycin was equally potent in increasing the level of p-Akt in these cells transfected with empty vector , WT p70S6K1 , or mutant p70S6K1 , regardless of whether p70S6K signaling was inhibited or not ( XREF_FIG ) .	Overexpression of wild-type (WT) p70S6K1, and particularly F5A-E389-R3A and E389-DeltaCT, abrogated the reduction of p-S6 by rapamycin; however, rapamycin was equally potent in increasing the level of p-Akt in these cells transfected with empty vector, WT p70S6K1, or mutant p70S6K1, regardless of whether p70S6K signaling was inhibited or not (XREF_FIG).	0	19	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K1	Overexpression of wild-type (WT) p70S6K1	p70s6k1	p-S6	p-S6	p-s6	6	7	18	19
Phosphorylation of mTOR activates key eukaryotic translation regulators , including p70-S6 kinase ( p70S6K , which directly targets ribosomal S6 protein ) and the eukaryotic translation initiation factor 4-E binding protein 1 ( 4E-BP1 ) .	Phosphorylation of mTOR activates key eukaryotic translation regulators, including p70-S6 kinase (p70S6K, which directly targets ribosomal S6 protein) and the eukaryotic translation initiation factor 4-E binding protein 1 (4E-BP1).	11	20	targets	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	S6	S6	S6	13	14	19	20
The results showed that S6K1 inhibition strongly suppressed the activation induced increase in pS6 in both WT and S6K2 -/- T cells .	The results showed that S6K1 inhibition strongly suppressed the activation induced increase in pS6 in both WT and S6K2 -/- T cells.	4	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	pS6	pS6	pS6	4	5	13	14
Phosphorylation of p70S6K leads to activation of rpS6 , which is involved in translation of 5 ' TOP dependent messenger RNAs .	Phosphorylation of p70S6K leads to activation of rpS6, which is involved in translation of 5 ' TOP dependent messenger RNAs.	0	11	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	p70S6K	Phosphorylation of p70S6K	p70s6k	rpS6	rpS6	rps6	2	3	7	8
Zinc induced p70S6K activation could only upregulate translation of total S6 and tau but not global proteins in SH-SY5Y cells .	Zinc induced p70S6K activation could only upregulate translation of total S6 and tau but not global proteins in SH-SY5Y cells.	0	12	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	Zinc induced p70S6K	p70s6k	S6	S6	s6	2	3	10	11
Both RSK and S6K1 phosphorylate and activate the ribosomal subunit S6 , which is essential for translation .	Both RSK and S6K1 phosphorylate and activate the ribosomal subunit S6, which is essential for translation.	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	S6	S6	S6	3	4	10	11
Therefore , the phosphorylation status of p70S6K target ribosomal protein S6 ( S6RP ) was examined , since its phosphorylation sites could be altered by FKBP12-RAPA-mTOR or mTOR-raptor interactions [ XREF_BIBR , XREF_BIBR ] .	Therefore, the phosphorylation status of p70S6K target ribosomal protein S6 (S6RP) was examined, since its phosphorylation sites could be altered by FKBP12-RAPA-mTOR or mTOR-raptor interactions [XREF_BIBR, XREF_BIBR].	6	11	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	ribosomal protein S6	ribosomal protein S6	ribosomal protein S6	6	7	8	11
Phosphorylation of p70 S6K1 further activates and phosphorylates downstream ribosomal S6 protein ( rpS6 ) , which plays a role in mRNA translation of proteins including elongation factors and ribosomal proteins .	Phosphorylation of p70 S6K1 further activates and phosphorylates downstream ribosomal S6 protein (rpS6), which plays a role in mRNA translation of proteins including elongation factors and ribosomal proteins.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70 S6K1	Phosphorylation of p70 S6K1	p70 s6k1	S6	S6	s6	2	4	10	11
To test this prediction , we analyzed S6 phosphorylation in 3T3 cells treated with S6K1 siRNA .	To test this prediction, we analyzed S6 phosphorylation in 3T3 cells treated with S6K1 siRNA.	7	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	S6K1	S6K1	S6K1	S6	S6	S6	14	15	7	8
We observed a potential activation of translation in both the ischemic and non ischemic myocardial territories of the HC group , including lower levels of HIF-1alpha , in conjunction with higher S6K1 levels , which activates the ribosomal protein S6 , in the ischemic myocardial territory ( XREF_SUPPLEMENTARY ) .	We observed a potential activation of translation in both the ischemic and non ischemic myocardial territories of the HC group, including lower levels of HIF-1alpha, in conjunction with higher S6K1 levels, which activates the ribosomal protein S6, in the ischemic myocardial territory (XREF_SUPPLEMENTARY).	31	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1 levels	s6k1	ribosomal protein S6	ribosomal protein S6	ribosomal protein s6	31	32	37	40
mTORC1 phosphorylates and modulates the activity of the serine/threonine ribosomal protein S6 kinase 1 ( S6K1 ) , which , in turn , phosphorilates and activate S6 , a ribosomal protein involved in translation XREF_BIBR - XREF_BIBR .	mTORC1 phosphorylates and modulates the activity of the serine/threonine ribosomal protein S6 kinase 1 (S6K1), which, in turn, phosphorilates and activate S6, a ribosomal protein involved in translation XREF_BIBR - XREF_BIBR.	0	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	mTORC1 phosphorylates and modulates the activity of the serine/threonine ribosomal protein S6 kinase 1 (S6K1	s6k1	S6	S6	s6	15	16	26	27
As a central serine/threonine protein kinase , mTOR controls protein synthesis via the phosphorylation of two downstream effectors : the p70S6K which activates RP-S6 , and the 4E-BP1 which is inactivated by phosphorylation to induce the release of eIF4E [ XREF_BIBR ] .	As a central serine/threonine protein kinase, mTOR controls protein synthesis via the phosphorylation of two downstream effectors : the p70S6K which activates RP-S6, and the 4E-BP1 which is inactivated by phosphorylation to induce the release of eIF4E [XREF_BIBR].	10	24	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	RP-S6	RP-S6	RP-S6	20	21	23	24
However , S6K1 blockade with the selective inhibitor LY2584702 caused a stronger inhibition of pS6 at all time points assessed .	However, S6K1 blockade with the selective inhibitor LY2584702 caused a stronger inhibition of pS6 at all time points assessed.	2	15	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	pS6	pS6	pS6	2	3	14	15
Another important step for BDNF stimulated dendritic protein synthesis is the phosphorylation of p70S6K , which ultimately activates the ribosomal protein S6 leading to 5 '-oligopyrimidine tract containing mRNAs translation .	Another important step for BDNF stimulated dendritic protein synthesis is the phosphorylation of p70S6K, which ultimately activates the ribosomal protein S6 leading to 5 '-oligopyrimidine tract containing mRNAs translation.	2	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	step for BDNF stimulated dendritic protein synthesis is the phosphorylation of p70S6K	p70s6k	ribosomal protein S6	ribosomal protein S6	ribosomal protein s6	13	14	19	22
XREF_BIBR The observed selective activation of p70 S6 kinase following Tiam1-spinophilin binding is likely a consequence of increased Rac1 association with p70 S6 , which was previously reported to enhance p70 S6 activation .	XREF_BIBR The observed selective activation of p70 S6 kinase following Tiam1-spinophilin binding is likely a consequence of increased Rac1 association with p70 S6, which was previously reported to enhance p70 S6 activation.	21	32	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70	p70	p70	S6	S6	S6	21	22	31	32
mTOR also controls translation via phosphorylation of RPS6 by RPS6 kinase ( S6K1 ) which activates ribosomal protein S6 to promote its 40S ribosome function .	mTOR also controls translation via phosphorylation of RPS6 by RPS6 kinase (S6K1) which activates ribosomal protein S6 to promote its 40S ribosome function.	10	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	ribosomal protein S6	ribosomal protein S6	ribosomal protein S6	12	13	16	19
Sch9 and S6K1 then targets ribosomal protein S6 and other regulators to modulate protein translation initiation and ribosome biogenesis .	Sch9 and S6K1 then targets ribosomal protein S6 and other regulators to modulate protein translation initiation and ribosome biogenesis.	0	8	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	ribosomal protein S6	ribosomal protein S6	ribosomal protein S6	2	3	5	8
Activation of the mTOR and S6K1 pathway via S6K1 phosphorylation was demonstrated to phosphorylate GLI1 , promoting GLI1 transcriptional activity and oncogenic function .	Activation of the mTOR and S6K1 pathway via S6K1 phosphorylation was demonstrated to phosphorylate GLI1, promoting GLI1 transcriptional activity and oncogenic function.	3	19	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	GLI1	GLI1	GLI1	5	6	17	18
Thus , in contrast to the canonical HH pathway , SMO inhibitors seem not to affect S6K1 mediated Gli1 activation , suggesting that the S6K1 mediated release of SuFu from Gli1 occurs independently of SMO .	Thus, in contrast to the canonical HH pathway, SMO inhibitors seem not to affect S6K1 mediated Gli1 activation, suggesting that the S6K1 mediated release of SuFu from Gli1 occurs independently of SMO.	15	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	16	17	18	19
In fact , SMO inhibitors , such as cyclopamine and GDC-0449 , had little effects on the mTOR and S6K1 mediated Gli1 activation .	In fact, SMO inhibitors, such as cyclopamine and GDC-0449, had little effects on the mTOR and S6K1 mediated Gli1 activation.	19	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	19	20	21	22
All these data indicated that Gli1 Ser84 is a key site for Gli1 activity and its phosphorylation by S6K1 enhances Gli1 function as an oncogene .	All these data indicated that Gli1 Ser84 is a key site for Gli1 activity and its phosphorylation by S6K1 enhances Gli1 function as an oncogene.	16	21	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	18	19	20	21
123 Furthermore , vismodegib was not effective in oesophageal cancer cells with overactivation of mTOR-S6K1 signalling ( a downstream target of PI3K-AKT ) , owing to SMO independent , mTOR and S6K1 mediated GLI1 activation ; combination treatment with the mTOR inhibitor everolimus and vismodegib showed better inhibitory effects on the growth of these cells in a xenograft model than either drug alone .	123 Furthermore, vismodegib was not effective in oesophageal cancer cells with overactivation of mTOR-S6K1 signalling (a downstream target of PI3K-AKT), owing to SMO independent, mTOR and S6K1 mediated GLI1 activation; combination treatment with the mTOR inhibitor everolimus and vismodegib showed better inhibitory effects on the growth of these cells in a xenograft model than either drug alone.	29	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	GLI1	GLI1	GLI1	31	32	33	34
S6K1 mediates the regulation of Gli1 by TNFalpha .	S6K1 mediates the regulation of Gli1 by TNFalpha.	0	6	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	0	1	5	6
Together , the results suggest that S6K1 mediates the regulation of Gli1 by TNFalpha and mTOR pathway through phosphorylating Gli1 at Ser84 .	Together, the results suggest that S6K1 mediates the regulation of Gli1 by TNFalpha and mTOR pathway through phosphorylating Gli1 at Ser84.	6	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	6	7	11	12
Thus , the activation of Gli1 by S6K1 is functionally involved in the TNFalpha and mTOR pathway .	Thus, the activation of Gli1 by S6K1 is functionally involved in the TNFalpha and mTOR pathway.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	7	8	5	6
From a mechanistic point of view , our results indicated that p70S6K signaling was able to activate Gli1 and up-regulate the anti-apoptotic protein Bcl2 , thereby activating a survival response in breast cancer cells challenged in hostile settings .	From a mechanistic point of view, our results indicated that p70S6K signaling was able to activate Gli1 and up-regulate the anti-apoptotic protein Bcl2, thereby activating a survival response in breast cancer cells challenged in hostile settings.	11	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	Gli1	Gli1	Gli1	11	12	17	18
S6K1 activation enhances Gli1 transcriptional activity and promotes its oncogenic function in esophageal cancer cell lines .	S6K1 activation enhances Gli1 transcriptional activity and promotes its oncogenic function in esophageal cancer cell lines.	0	5	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	0	1	3	4
Explanations to this phenomenon have been provided with the occurrence of novel Smo mutations and/or with the identification of oncogenic signaling pathways involving ERK , AKT and mTOR and S6K1 , which promote Smo independent Gli activation or non canonical Gli independent cascades .	Explanations to this phenomenon have been provided with the occurrence of novel Smo mutations and/or with the identification of oncogenic signaling pathways involving ERK, AKT and mTOR and S6K1, which promote Smo independent Gli activation or non canonical Gli independent cascades.	22	36	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli	Gli	Gli	29	30	35	36
Because our data have shown that in EAC cell lines mTOR and S6K1 mediated Gli1 activation is SMO independent , we speculated that mTOR/S6K1/Gli1 should enhance the resistance of EAC cells to SMO inhibitors .	Because our data have shown that in EAC cell lines mTOR and S6K1 mediated Gli1 activation is SMO independent, we speculated that mTOR/S6K1/Gli1 should enhance the resistance of EAC cells to SMO inhibitors.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	12	13	14	15
Furthermore , a cross-talk between the two pathways has been described in a model of esophageal cancer where mTORC1 and S6K1 promotes the oncogenic function of GLI1 , through S6K1 mediated phosphorylation of GLI1 , in a SMO independent manner [ XREF_BIBR ] .	Furthermore, a cross-talk between the two pathways has been described in a model of esophageal cancer where mTORC1 and S6K1 promotes the oncogenic function of GLI1, through S6K1 mediated phosphorylation of GLI1, in a SMO independent manner [XREF_BIBR].	18	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	GLI1	GLI1	GLI1	20	21	26	27
To investigate whether S6K1 mediates the regulation of Gli1 by TNFalpha , we knocked down S6K1 ( XREF_FIG ) and tested the regulation of Gli1 by TNFalpha .	To investigate whether S6K1 mediates the regulation of Gli1 by TNFalpha, we knocked down S6K1 (XREF_FIG) and tested the regulation of Gli1 by TNFalpha.	3	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	3	4	8	9
48 Recent studies have shown that activated mTOR and S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function , 49 but our study hold the opposite view that Gli1 transcription factor appears to be no changes treated with rapamycin , whereas silenced the expression of Gli1 with siRNAs lead to mTOR dephosphorylation then induced autophagy associated cell death suggested that Gli1 may be located at the upstream of mTOR in chondrosarcoma cells .	48 Recent studies have shown that activated mTOR and S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function, 49 but our study hold the opposite view that Gli1 transcription factor appears to be no changes treated with rapamycin, whereas silenced the expression of Gli1 with siRNAs lead to mTOR dephosphorylation then induced autophagy associated cell death suggested that Gli1 may be located at the upstream of mTOR in chondrosarcoma cells.	9	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	9	10	12	13
30 ERalpha regulation of S6K1 expression creates a positive feedforward loop , leading to activation of ERalpha by S6K1 , potentiating ERalpha positive breast cancer cell growth .	30 ERalpha regulation of S6K1 expression creates a positive feedforward loop, leading to activation of ERalpha by S6K1, potentiating ERalpha positive breast cancer cell growth.	12	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	ERalpha	ERalpha	ERalpha	18	19	16	17
In the presence of estradiol , overexpression of p70S6 kinase increased activity of the ER by approximately 1.7 fold compared to estradiol alone and glyceollin was able to block the p70S6 kinase effect ( XREF_FIG ) .	In the presence of estradiol, overexpression of p70S6 kinase increased activity of the ER by approximately 1.7 fold compared to estradiol alone and glyceollin was able to block the p70S6 kinase effect (XREF_FIG).	6	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6 kinase	overexpression of p70S6 kinase	p70s6 kinase	ER	ER	er	8	10	14	15
The resultant increase in activated S6K1 can directly activate the estrogen receptor ( ER ) to increase transcription of ER responsive genes independently of estrogen signaling , thereby rendering tumor cells unresponsive to endocrine therapy .	The resultant increase in activated S6K1 can directly activate the estrogen receptor (ER) to increase transcription of ER responsive genes independently of estrogen signaling, thereby rendering tumor cells unresponsive to endocrine therapy.	2	12	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	estrogen receptor	estrogen receptor	estrogen receptor	5	6	10	12
In summary , targeting the aberrant Akt and p70S6K activation in ER - hMEC models in vitro and in the MMTV- neu transgenic mouse model in vivo effectively inhibited Akt and S6K signaling and reduced proliferation of hMECs in vitro and ADH and MIN lesions in vivo , indicating its potential in prevention of p70S6K activated ER - breast cancer .	In summary, targeting the aberrant Akt and p70S6K activation in ER - hMEC models in vitro and in the MMTV- neu transgenic mouse model in vivo effectively inhibited Akt and S6K signaling and reduced proliferation of hMECs in vitro and ADH and MIN lesions in vivo, indicating its potential in prevention of p70S6K activated ER - breast cancer.	52	59	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	p70S6K	p70S6K	p70S6K	ER	ER	ER	54	55	56	57
We next interrogated the effect of estrogen on the RPS6KB1 promoter in ERalpha overexpressing cells using luciferase reporter assay .	We next interrogated the effect of estrogen on the RPS6KB1 promoter in ERalpha overexpressing cells using luciferase reporter assay.	9	14	promoter	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RPS6KB1	RPS6KB1	RPS6KB1	ERalpha	ERalpha	ERalpha	9	10	12	13
These data , in light of the recent report by Yee ' s group , strongly suggest that p70S6 kinase directly targets ERalpha , and that this interaction can be abrogated by glyceollin .	These data, in light of the recent report by Yee 's group, strongly suggest that p70S6 kinase directly targets ERalpha, and that this interaction can be abrogated by glyceollin.	18	23	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6 kinase	p70S6 kinase	p70S6 kinase	ERalpha	ERalpha	ERalpha	18	20	22	23
Importantly , S6K1 can promote ERalpha activation in the absence of estrogen , therefore , high expression of S6K1 might be one reason for acquiring ligand independent proliferative ability [ XREF_BIBR , XREF_BIBR ] .	Importantly, S6K1 can promote ERalpha activation in the absence of estrogen, therefore, high expression of S6K1 might be one reason for acquiring ligand independent proliferative ability [XREF_BIBR, XREF_BIBR].	2	6	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	ERalpha	ERalpha	ERalpha	2	3	5	6
In addition , p70S6K activation induced transformation of ER - human mammary epithelial cells ( hMEC ) .	In addition, p70S6K activation induced transformation of ER - human mammary epithelial cells (hMEC).	3	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	ER	ER	ER	3	4	8	9
P70S6K is responsible for translational initiation via mTORC1 , in particular regulatory associated protein of mTOR , which specifically phosphorylates p70S6K , which in turn activates eukaryotic translation initiation factor 4B ( eIF4B ) .	P70S6K is responsible for translational initiation via mTORC1, in particular regulatory associated protein of mTOR, which specifically phosphorylates p70S6K, which in turn activates eukaryotic translation initiation factor 4B (eIF4B).	19	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	phosphorylates p70S6K	p70s6k	eukaryotic translation initiation factor 4B	eukaryotic translation initiation factor 4B	eukaryotic translation initiation factor 4b	20	21	26	31
S6K1 can also activate eIF4B , a protein that helps eIF4A to unwind the secondary structure of untranslated mRNA XREF_BIBR .	S6K1 can also activate eIF4B, a protein that helps eIF4A to unwind the secondary structure of untranslated mRNA XREF_BIBR.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	eIF4B	eIF4B	eIF4B	0	1	4	5
Active p70S6K activates eIF4B by phosphorylation on S422 .	Active p70S6K activates eIF4B by phosphorylation on S422.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	eIF4B	eIF4B	eIF4B	1	2	3	4
Upon A23187 stimulation , RSK2 induced nuclear localization of NFAT3 .	Upon A23187 stimulation, RSK2 induced nuclear localization of NFAT3.	4	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RSK2	RSK2	RSK2	NFAT3	NFAT3	NFAT3	4	5	9	10
RSK2 phosphorylated NFAT3 in vitro ( Km = 3.559 microM ) , and activation of NFAT3 by RSK2 enhanced the promoter activity of NFAT3 downstream target genes in vivo .	RSK2 phosphorylated NFAT3 in vitro (Km = 3.559 microM), and activation of NFAT3 by RSK2 enhanced the promoter activity of NFAT3 downstream target genes in vivo.	0	26	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RSK2	RSK2 phosphorylated NFAT3	rsk2	NFAT3	NFAT3	nfat3	0	1	23	24
PPARgamma signaling is initiated by the formation of a heterodimer between PPARgamma and retinoid X receptor alpha ( RXRalpha ) after the binding of the ligand or agonist to the ligand binding domain ( LBD ) of PPARgamma and the subsequent dissociation of its corepressors [ XREF_BIBR , XREF_BIBR ] .	PPARgamma signaling is initiated by the formation of a heterodimer between PPARgamma and retinoid X receptor alpha (RXRalpha) after the binding of the ligand or agonist to the ligand binding domain (LBD) of PPARgamma and the subsequent dissociation of its corepressors [XREF_BIBR, XREF_BIBR].	0	17	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	retinoid X receptor alpha	retinoid X receptor alpha	retinoid X receptor alpha	PPARgamma	PPARgamma	PPARgamma	13	17	0	1
PPARgamma was also confirmed as an upregulated gene ( 1.32 fold ) in angiogenic clones by real-time PCR analysis while other genes that influence PPARgamma signaling such as retinoid X receptor alpha ( RXRA , 1.59-fold ) , nuclear receptor interacting protein 1 ( NRIP1 , 2.39-fold ) , and c-Fos ( 1.70-fold ) were upregulated on the microarray .	PPARgamma was also confirmed as an upregulated gene (1.32 fold) in angiogenic clones by real-time PCR analysis while other genes that influence PPARgamma signaling such as retinoid X receptor alpha (RXRA, 1.59-fold), nuclear receptor interacting protein 1 (NRIP1, 2.39-fold), and c-Fos (1.70-fold) were upregulated on the microarray.	24	32	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	retinoid X receptor alpha	retinoid X receptor alpha	retinoid X receptor alpha	PPARgamma	PPARgamma	PPARgamma	28	32	24	25
Here , we report that hotspot S427F/Y mutations in RXRA or focal amplification and overexpression of PPARG in bladder cancer induce the activation of the PPARgamma and RXRalpha pathway , leading to suppression of cytokine secretion from cancer cells .	Here, we report that hotspot S427F/Y mutations in RXRA or focal amplification and overexpression of PPARG in bladder cancer induce the activation of the PPARgamma and RXRalpha pathway, leading to suppression of cytokine secretion from cancer cells.	7	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RXRA	RXRA	RXRA	PPARgamma	PPARgamma	PPARgamma	9	10	25	26
Importantly , our data also demonstrate that RSPO3 causes an expansion of Lgr5 + stem cells , Paneth cells , Lgr4 + cells and LRCs .	Importantly, our data also demonstrate that RSPO3 causes an expansion of Lgr5 + stem cells, Paneth cells, Lgr4 + cells and LRCs.	7	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RSPO3	RSPO3	RSPO3	Lgr5	Lgr5	Lgr5	7	8	12	13
RSPO3 induced the expansion of Lgr5 + stem cells , Paneth cells , non Paneth cell label retaining cells and Lgr4 + cells , thus promoting both intestinal stem cell and niche compartments .	RSPO3 induced the expansion of Lgr5 + stem cells, Paneth cells, non Paneth cell label retaining cells and Lgr4 + cells, thus promoting both intestinal stem cell and niche compartments.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RSPO3	RSPO3	RSPO3	Lgr5	Lgr5	Lgr5	0	1	5	6
In mice , overexpression of the R-spondin gene Rspo3 , which potentiates Wnt signaling in the gut , promotes expansion of Lgr5 stem cells and Paneth cells , with Paneth cells located throughout adenomas and at the invasive front of adenocarcinomas [ XREF_BIBR ] .	In mice, overexpression of the R-spondin gene Rspo3, which potentiates Wnt signaling in the gut, promotes expansion of Lgr5 stem cells and Paneth cells, with Paneth cells located throughout adenomas and at the invasive front of adenocarcinomas [XREF_BIBR].	3	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rspo3	overexpression of the R-spondin gene Rspo3	rspo3	Lgr5	Lgr5	lgr5	8	9	21	22
By contrast , in a mouse model with artificial H. pylori infection , Rspo3 is upregulated to expand Lgr5 + gastric stem and progenitor cells .	By contrast, in a mouse model with artificial H. pylori infection, Rspo3 is upregulated to expand Lgr5 + gastric stem and progenitor cells.	13	24	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rspo3	Rspo3	Rspo3	Lgr5	Lgr5	Lgr5	13	14	18	19
In this study , we found that LMP1 increased the phosphorylation level of MSK1 at Thr581 and enhanced the MSK1 kinase activity .	In this study, we found that LMP1 increased the phosphorylation level of MSK1 at Thr581 and enhanced the MSK1 kinase activity.	7	21	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSK1	LMP1 increased the phosphorylation level of MSK1	msk1	MSK1	MSK1	msk1	13	14	19	20
Unlike HS treatment , as shown in XREF_FIG , IFN-gamma treatment did not induce the expression of MSK1 or activate the kinase activity of MSK1 ( XREF_FIG ) , thus preventing the specific phosphorylation of KDM3A at S264 in IFN-gamma-treated cells ( XREF_FIG ) .	Unlike HS treatment, as shown in XREF_FIG, IFN-gamma treatment did not induce the expression of MSK1 or activate the kinase activity of MSK1 (XREF_FIG), thus preventing the specific phosphorylation of KDM3A at S264 in IFN-gamma-treated cells (XREF_FIG).	9	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSK1	IFN-gamma treatment did not induce the expression of MSK1	msk1	MSK1	MSK1	msk1	17	18	24	25
Therefore , S6K1 promotes the processing of SREBP1 through an , as yet , unknown molecular mechanism .	Therefore, S6K1 promotes the processing of SREBP1 through an, as yet, unknown molecular mechanism.	2	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	SREBP1	SREBP1	SREBP1	2	3	7	8
In addition , S6K1 promotes the processing of SREBP1 in the liver and of SREBP2 in a hepatocellular carcinoma cell line [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, S6K1 promotes the processing of SREBP1 in the liver and of SREBP2 in a hepatocellular carcinoma cell line [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	SREBP1	SREBP1	SREBP1	3	4	8	9
RSUME promotes the activity of hypoxia inducible factor 1 ( HIF-1alpha ) , a master regulator of the hypoxic response ; RGS5 is an apoptotic stimulator induced by hypoxia in endothelial cells .	RSUME promotes the activity of hypoxia inducible factor 1 (HIF-1alpha), a master regulator of the hypoxic response; RGS5 is an apoptotic stimulator induced by hypoxia in endothelial cells.	0	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RSUME	RSUME	RSUME	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	10	11
Hypoxia induced RSUME protein SUMOylation can enhance the stability and activity of the HIF1alpha protein .	Hypoxia induced RSUME protein SUMOylation can enhance the stability and activity of the HIF1alpha protein.	2	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RSUME	RSUME protein SUMOylation	rsume	HIF1alpha protein	HIF1alpha protein	hif1alpha protein	2	3	13	15
In a previous study [ XREF_BIBR ] , it has been shown that the MAPK nuclear kinase , mitogen-and stress activated protein kinase 1 ( MSK1 ) , induces NF-kappaB p65 serine 276 phosphorylation upon IL-1beta treatment , as well as MAPK inhibition abolishes binding of p65 , of its coactivator CBP and of MSK1 to the kappaB intronic enhancer site of the stem cell factor gene .	In a previous study [XREF_BIBR], it has been shown that the MAPK nuclear kinase, mitogen-and stress activated protein kinase 1 (MSK1), induces NF-kappaB p65 serine 276 phosphorylation upon IL-1beta treatment, as well as MAPK inhibition abolishes binding of p65, of its coactivator CBP and of MSK1 to the kappaB intronic enhancer site of the stem cell factor gene.	19	31	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSK1	MSK1	MSK1	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	25	26	29	31
In order to gain mechanistic insight into MSK1 mediated activation of RelA and p65 and posttranslational histone modifications , we determined the downstream events i.e. the phosphorylation of RelA and p65 ( Ser276 ) and histone modifications in response to CSE using a MSK1 N- and C-terminal kinase dead mutant and siRNA mediated knock-down approaches , as well as using a stable MSK1 knock-down mouse embryonic fibroblasts ( MEFs ) .	In order to gain mechanistic insight into MSK1 mediated activation of RelA and p65 and posttranslational histone modifications, we determined the downstream events i.e. the phosphorylation of RelA and p65 (Ser276) and histone modifications in response to CSE using a MSK1 N- and C-terminal kinase dead mutant and siRNA mediated knock-down approaches, as well as using a stable MSK1 knock-down mouse embryonic fibroblasts (MEFs).	7	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	MSK1	MSK1	MSK1	RelA	RelA	RelA	7	8	11	12
Therefore , following IL6R and JAK dependent STAT3-Y705 phosphorylation , DNA damage activated MSK1 may enhance STAT3 activation by phosphorylating STAT3-S727 , which in turn translocated into the nucleus and bound to specific gene promoters such as MIR181A promoter .	Therefore, following IL6R and JAK dependent STAT3-Y705 phosphorylation, DNA damage activated MSK1 may enhance STAT3 activation by phosphorylating STAT3-S727, which in turn translocated into the nucleus and bound to specific gene promoters such as MIR181A promoter.	13	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSK1	MSK1	MSK1	STAT3	STAT3	STAT3	13	14	16	17
Importantly , RagB-C X loaded with XDP also recovered raptor , suggesting that the state induced by the nucleotide diphosphate loading of RagC promotes raptor binding ( XREF_FIG ) .	Importantly, RagB-C X loaded with XDP also recovered raptor, suggesting that the state induced by the nucleotide diphosphate loading of RagC promotes raptor binding (XREF_FIG).	20	25	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RagC	RagC	RagC	raptor	raptor	raptor	22	23	24	25
Furthermore , our study also demonstrated that the transcriptional factors MSK1 and ATF1 that activate c-jun , as well as Elk-1 that activates c-fos , were phoshosphorylated in G-1-treated cells .	Furthermore, our study also demonstrated that the transcriptional factors MSK1 and ATF1 that activate c-jun, as well as Elk-1 that activates c-fos, were phoshosphorylated in G-1-treated cells.	7	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MSK1	MSK1	MSK1	Elk-1	Elk-1	Elk-1	10	11	20	21
As mentioned above , the reduction of MSK1 in R6/2 mice may partially impair the impact of Elk-1 activation .	As mentioned above, the reduction of MSK1 in R6/2 mice may partially impair the impact of Elk-1 activation.	5	18	impair	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MSK1	MSK1	MSK1	Elk-1	Elk-1	Elk-1	7	8	17	18
RPS6KA4 ( 64.12 Mb ) encodes a member of the ribosomal S6 kinase family of serine/threonine kinases ( also known as p90S6K ; MSK2 , RSK-B ) , which is required for phosphorylation of numerous intracellular substrates in response to mitogens and stress , and is an important downstream effector of mitogen activated protein kinase ( MAPK ) for regulation of transcription factors such as CREB1 and ATF1 , and RELA ( member of the NF-kappaB family ) in response to TNF .	RPS6KA4 (64.12 Mb) encodes a member of the ribosomal S6 kinase family of serine/threonine kinases (also known as p90S6K; MSK2, RSK-B), which is required for phosphorylation of numerous intracellular substrates in response to mitogens and stress, and is an important downstream effector of mitogen activated protein kinase (MAPK) for regulation of transcription factors such as CREB1 and ATF1, and RELA (member of the NF-kappaB family) in response to TNF.	0	79	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RPS6KA4	RPS6KA4	RPS6KA4	RELA	RELA	RELA	0	1	70	71
To investigate the regulation of ERK1/2 phosphorylation by RSPO2-GPR48 and LGR4 signaling axis , we monitored ERK1/2 phosphorylation in GPR48 and LGR4-knockdown and control cells treated with exogenous RSPO2 .	To investigate the regulation of ERK1/2 phosphorylation by RSPO2-GPR48 and LGR4 signaling axis, we monitored ERK1/2 phosphorylation in GPR48 and LGR4-knockdown and control cells treated with exogenous RSPO2.	17	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	RSPO2	RSPO2	RSPO2	GPR48	GPR48	GPR48	28	29	19	20
Engagement of syndecan-4 with H/0 triggered Rac1 activation in cells already spread on 50K ( XREF_FIG ) .	Engagement of syndecan-4 with H/0 triggered Rac1 activation in cells already spread on 50K (XREF_FIG).	0	7	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	2	3	6	7
alpha 5 beta 1 integrin and syndecan-4 activate Rac1 and inhibit RhoA to regulate membrane protrusion .	alpha 5 beta 1 integrin and syndecan-4 activate Rac1 and inhibit RhoA to regulate membrane protrusion.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	6	7	8	9
Persistent migration requires polarization of signals , such as Rac1 and , although it is known that concerted engagement of fibronectin receptors , alpha5beta1 integrin and syndecan-4 , triggers Rac1 activation , it is less clear how the signal remains localized to a single protrusion as the composition of a 3D matrix changes .	Persistent migration requires polarization of signals, such as Rac1 and, although it is known that concerted engagement of fibronectin receptors, alpha5beta1 integrin and syndecan-4, triggers Rac1 activation, it is less clear how the signal remains localized to a single protrusion as the composition of a 3D matrix changes.	21	30	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	26	27	29	30
However , a recent study demonstrated that syndecan 4 dependent cell migration was dependent on the ability of PKCalpha to activate Rac [ XREF_BIBR ] .	However, a recent study demonstrated that syndecan 4 dependent cell migration was dependent on the ability of PKCalpha to activate Rac [XREF_BIBR].	7	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	syndecan 4	syndecan 4	syndecan 4	Rac	Rac	Rac	7	9	21	22
We found that syndecan-4 uptake , induced either by treatment with FGF2 or by antibody clustering , requires the integrity of plasma membrane lipid rafts for its initiation , occurs in a non-clathrin-, non-dynamin-dependent manner and involves Rac1 , which is activated by syndecan-4 clustering .	We found that syndecan-4 uptake, induced either by treatment with FGF2 or by antibody clustering, requires the integrity of plasma membrane lipid rafts for its initiation, occurs in a non-clathrin-, non-dynamin-dependent manner and involves Rac1, which is activated by syndecan-4 clustering.	36	44	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	43	44	37	38
Taken together , these results demonstrate that FGF2 endocytosis requires syndecan-4 clustering dependent activation of Rac1 and the intact CDC42 dependent macropinocytic pathway .	Taken together, these results demonstrate that FGF2 endocytosis requires syndecan-4 clustering dependent activation of Rac1 and the intact CDC42 dependent macropinocytic pathway.	10	16	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	10	11	15	16
Immortalized MEFs from wild-type syndecan-4 +/+ littermates exhibited a similar profile of Rac1 activation to primary human fibroblasts ( XREF_FIG ) , and Rac1 regulation was restored to null MEFs by the expression of full-length human syndecan-4 ( XREF_FIG ) .	Immortalized MEFs from wild-type syndecan-4 +/+ littermates exhibited a similar profile of Rac1 activation to primary human fibroblasts (XREF_FIG), and Rac1 regulation was restored to null MEFs by the expression of full-length human syndecan-4 (XREF_FIG).	23	38	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	syndecan-4	expression of full-length human syndecan-4	syndecan-4	Rac1	Rac1	rac1	36	37	23	24
Ultrasound exerts an influence downstream of syndecan-4 and PKCalpha to specifically activate Rac1 , itself a critical regulator of tissue repair , and to a lesser extent RhoA .	Ultrasound exerts an influence downstream of syndecan-4 and PKCalpha to specifically activate Rac1, itself a critical regulator of tissue repair, and to a lesser extent RhoA.	3	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	6	7	12	13
Second , knockdown of GEF-H1 , SDC1 , or SDC4 decreased BMM cell invasiveness and GEF-H1 modulated small GTPase activity of Rac1 and RhoA in conjunction with heparanase treatment .	Second, knockdown of GEF-H1, SDC1, or SDC4 decreased BMM cell invasiveness and GEF-H1 modulated small GTPase activity of Rac1 and RhoA in conjunction with heparanase treatment.	2	23	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SDC4	SDC4	SDC4	Rac1	Rac1	Rac1	9	10	21	22
Previous studies indicated that SDC-4 orchestrates the polarization of active Rac1 in the presence of chemotactic signals such as FGF-2 and that SDC-4 induces Rac1 dependent cell migration in a manner that requires both its PDZ binding domain and PKCalpha .	Previous studies indicated that SDC-4 orchestrates the polarization of active Rac1 in the presence of chemotactic signals such as FGF-2 and that SDC-4 induces Rac1 dependent cell migration in a manner that requires both its PDZ binding domain and PKCalpha.	22	25	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SDC-4	SDC-4	SDC-4	Rac1	Rac1	Rac1	22	23	24	25
Synectin appears important for syndecan-4 dependant activation of Rac at the leading edge and thereby for syndecan-4 dependant endothelial cell migration [ XREF_BIBR ] .	Synectin appears important for syndecan-4 dependant activation of Rac at the leading edge and thereby for syndecan-4 dependant endothelial cell migration [XREF_BIBR].	4	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac	Rac	Rac	4	5	8	9
It has been previously demonstrated that SDC-4 promotes endothelial cell migration in response to ligand binding by activating Rac1 and localizing it to the leading edge and that these processes are dependent on its PDZ binding domain interaction with synectin , a small intracellular scaffold protein .	It has been previously demonstrated that SDC-4 promotes endothelial cell migration in response to ligand binding by activating Rac1 and localizing it to the leading edge and that these processes are dependent on its PDZ binding domain interaction with synectin, a small intracellular scaffold protein.	6	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDC-4	SDC-4	SDC-4	Rac1	Rac1	Rac1	6	7	18	19
Sdc4 ectodomain increased generation of reactive oxygen species ( ROS ) , reduced activation of RhoA , increased activation of Rac1 , increased nuclear abundance of NFATc1 , and increased total beta3-integrin .	Sdc4 ectodomain increased generation of reactive oxygen species (ROS), reduced activation of RhoA, increased activation of Rac1, increased nuclear abundance of NFATc1, and increased total beta3-integrin.	0	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sdc4	Sdc4	Sdc4	Rac1	Rac1	Rac1	0	1	20	21
The possibility of syndecan-4 modulating the behavior of integrin and Rac1 , without the deleterious side effects associated with targeting the molecules directly , makes syndecan-4 anattractive target for wound treatment .	The possibility of syndecan-4 modulating the behavior of integrin and Rac1, without the deleterious side effects associated with targeting the molecules directly, makes syndecan-4 anattractive target for wound treatment.	1	11	modulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	3	4	10	11
Clustering of syndecan-4 ( by antibodies and by Fc-receptor-Syndecan-4 chimeras ) has been demonstrated to induce FGF2 endocytosis in a clathrin and dynamin independent process , which requires syndecan-4 independent activation of Rac1 [ XREF_BIBR ] .	Clustering of syndecan-4 (by antibodies and by Fc-receptor-Syndecan-4 chimeras) has been demonstrated to induce FGF2 endocytosis in a clathrin and dynamin independent process, which requires syndecan-4 independent activation of Rac1 [XREF_BIBR].	28	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	28	29	32	33
However , engagement of syndecan-4 did not cause Rac1 to redistribute in Coro1C knockdown Cav1 -/- cells ( XREF_FIG D ) , demonstrating that the fibronectin triggered mechanism for Rac1 redistribution is mediated by caveolin .	However, engagement of syndecan-4 did not cause Rac1 to redistribute in Coro1C knockdown Cav1 -/- cells (XREF_FIG D), demonstrating that the fibronectin triggered mechanism for Rac1 redistribution is mediated by caveolin.	2	9	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	4	5	8	9
Our results unravelled a novel regulatory mechanism of the basal Rac1 activity that was mediated by SDC4 in a phosphorylation- and PDZ interaction dependent manner in MCF-7 breast adenocarcinoma cells .	Our results unravelled a novel regulatory mechanism of the basal Rac1 activity that was mediated by SDC4 in a phosphorylation- and PDZ interaction dependent manner in MCF-7 breast adenocarcinoma cells.	10	22	mediated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	SDC4	SDC4	SDC4	Rac1	Rac1	Rac1	16	17	10	11
Upon wounding , syndecan-4 detects the appearance of fibronectin in the wound bed and mediates regulation of the small GTPases , Rac1 , RhoA and RhoG .	Upon wounding, syndecan-4 detects the appearance of fibronectin in the wound bed and mediates regulation of the small GTPases, Rac1, RhoA and RhoG.	3	22	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	3	4	21	22
In the Rac1 FRET experiments , a soluble syndecan-4 ligand caused localized Rac1 activation ( supplementary material Movie 2 ) , despite the diffuse nature of the stimulus , demonstrating the predisposition of certain regions of membrane to Rac1 activation .	In the Rac1 FRET experiments, a soluble syndecan-4 ligand caused localized Rac1 activation (supplementary material Movie 2), despite the diffuse nature of the stimulus, demonstrating the predisposition of certain regions of membrane to Rac1 activation.	8	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	8	9	12	13
Unexpectedly , a recombinant SAV1 fragment containing the SARAH domain did not stimulate the MST2 kinase activity toward MOB1 in vitro ( XREF_FIG ) .	Unexpectedly, a recombinant SAV1 fragment containing the SARAH domain did not stimulate the MST2 kinase activity toward MOB1 in vitro (XREF_FIG).	4	16	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	4	5	14	15
Next , we further explored the mechanism by which SAV1 promoted MST2 activation in human cells .	Next, we further explored the mechanism by which SAV1 promoted MST2 activation in human cells.	9	12	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	9	10	11	12
SAV1 strongly elevated the pT180 signal of MST2 WT , but did not further enhance T180 phosphorylation of MST2 3TA , suggesting that SAV1 stimulated MST2 activation through antagonizing STRIPAK SLMAP in human cells .	SAV1 strongly elevated the pT180 signal of MST2 WT, but did not further enhance T180 phosphorylation of MST2 3TA, suggesting that SAV1 stimulated MST2 activation through antagonizing STRIPAK SLMAP in human cells.	23	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	23	24	25	26
It is possible that MST1 or MST2 molecules activated as a result of homodimerization subsequently dissociate and are then targeted to different substrates or subcellular locations by RASSF or SAV1 .	It is possible that MST1 or MST2 molecules activated as a result of homodimerization subsequently dissociate and are then targeted to different substrates or subcellular locations by RASSF or SAV1.	4	30	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	29	30	6	7
Thus , SARAH mediated binding of SAV1 to MST2 is required for SAV1 induced MST2 activation .	Thus, SARAH mediated binding of SAV1 to MST2 is required for SAV1 induced MST2 activation.	12	15	induced	Positive_early_activation	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	12	13	14	15
Strikingly , the N-terminal tail of SAV1 directly binds to PP2A and inhibits its phosphatase activity , suggesting that SAV1 stimulates MST2 activation through antagonizing STRIPAK SLMAP -mediated dephosphorylation of MST2 pT180 [ XREF_BIBR ] .	Strikingly, the N-terminal tail of SAV1 directly binds to PP2A and inhibits its phosphatase activity, suggesting that SAV1 stimulates MST2 activation through antagonizing STRIPAK SLMAP -mediated dephosphorylation of MST2 pT180 [XREF_BIBR].	19	22	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	19	20	21	22
One possibility is that SAV1 may target MST2 to the plasma membrane , thus spatially separating MST2 from STRIPAK SLMAP , whose SLMAP subunit has been reported to localize to the endoplasmic reticulum .	One possibility is that SAV1 may target MST2 to the plasma membrane, thus spatially separating MST2 from STRIPAK SLMAP, whose SLMAP subunit has been reported to localize to the endoplasmic reticulum.	4	8	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	4	5	7	8
To understand how SAV1 activates MST2 , we determined the crystal structure of MST2 incrementL and D146N bound to the SARAH domain of SAV1 ( residues 291-383 ) ( XREF_FIG and XREF_TABLE ) .	To understand how SAV1 activates MST2, we determined the crystal structure of MST2 incrementL and D146N bound to the SARAH domain of SAV1 (residues 291-383) (XREF_FIG and XREF_TABLE).	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	3	4	5	6
If a major mechanism by which SAV1 promotes MST2 activation is through inhibiting STRIPAK SLMAP -mediated dephosphorylation of MST2 pT180 , then deletion of SLMAP is expected to bypass the requirement for SAV1 in MST2 activation in vivo .	If a major mechanism by which SAV1 promotes MST2 activation is through inhibiting STRIPAK SLMAP -mediated dephosphorylation of MST2 pT180, then deletion of SLMAP is expected to bypass the requirement for SAV1 in MST2 activation in vivo.	6	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	6	7	8	9
Interestingly , the SAV1 incrementN198 mutant , which contains WW1/2 and SARAH domains , could support MST2 auto-activation in the same assay .	Interestingly, the SAV1 incrementN198 mutant, which contains WW1/2 and SARAH domains, could support MST2 auto-activation in the same assay.	3	17	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	3	4	16	17
Mutations in SAV1 SARAH that disrupted its binding to MST2 ( E346A and R358A and E346A and R368A ) also diminished SAV1 stimulation of MST2 activation .	Mutations in SAV1 SARAH that disrupted its binding to MST2 (E346A and R358A and E346A and R368A) also diminished SAV1 stimulation of MST2 activation.	21	25	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	21	22	24	25
In E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice , bleomycin administration increased serum levels of all Ig isotypes , except IgA , compared with bleomycin treated wild type mice ( P < 0.05 ) .	In E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice, bleomycin administration increased serum levels of all Ig isotypes, except IgA, compared with bleomycin treated wild type mice (P < 0.05).	0	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	9	10	1	2
Moreover , E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice displayed higher frequencies of Th17 cells compared with P-selectin -/- and E-selectin -/- mice ( P < 0.05 ) .	Moreover, E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice displayed higher frequencies of Th17 cells compared with P-selectin -/- and E-selectin -/- mice (P < 0.05).	2	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	10	11	2	3
Bleomycin treated E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice had increased IgM autoantibody levels to topo I , as well as IgG autoantibody levels to topo I compared with bleomycin treated wild type mice ( P < 0.05 ) .	Bleomycin treated E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice had increased IgM autoantibody levels to topo I, as well as IgG autoantibody levels to topo I compared with bleomycin treated wild type mice (P < 0.05).	1	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	10	11	2	3
PSGL-1 and CD43 immunoprecipitated from Th17 cell lysates support major E-selectin dependent rolling under flow conditions in vitro .	PSGL-1 and CD43 immunoprecipitated from Th17 cell lysates support major E-selectin dependent rolling under flow conditions in vitro.	0	12	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	0	1	10	11
Moreover , E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice exhibited higher expression levels of IL-4 , IL-17 , and TGF-beta1 in the skin and lung and IL-6 in the lung than P-selectin -/- and E-selectin -/- mice ( P < 0.05 ) .	Moreover, E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice exhibited higher expression levels of IL-4, IL-17, and TGF-beta1 in the skin and lung and IL-6 in the lung than P-selectin -/- and E-selectin -/- mice (P < 0.05).	2	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	10	11	2	3
Based on mAb blocking studies , the authors inferred that PSGL-1 is necessary for attachment of neutrophils to P-selectin and for optimal attachment to E-selectin .	Based on mAb blocking studies, the authors inferred that PSGL-1 is necessary for attachment of neutrophils to P-selectin and for optimal attachment to E-selectin.	10	25	necessary	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	10	11	24	25
The present study is to investigate the signaling kinases responsible for the F-actin changes mediated by L-selectin and PSGL-1 during neutrophil rolling on E-selectin .	The present study is to investigate the signaling kinases responsible for the F-actin changes mediated by L-selectin and PSGL-1 during neutrophil rolling on E-selectin.	14	24	mediated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	18	19	23	24
Both CD43 and PSGL-1 isolated from Th17 cells mediated functional E-selectin rolling ( XREF_FIG ) , but only CD43- E-selectin dependent adhesion seemed to be specific for Th17 cells , in contrast to PSGL-1 which functioned as an E-selectin ligand , and also as a P-selectin ligand on both Th17 and Th1 cells ( XREF_FIG ) .	Both CD43 and PSGL-1 isolated from Th17 cells mediated functional E-selectin rolling (XREF_FIG), but only CD43- E-selectin dependent adhesion seemed to be specific for Th17 cells, in contrast to PSGL-1 which functioned as an E-selectin ligand, and also as a P-selectin ligand on both Th17 and Th1 cells (XREF_FIG).	1	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	3	4	10	11
In contrast , E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice exhibited a reduction in skin IFN-gamma expression that was significantly lower than that found in P-selectin -/- mice as well as E-selectin -/- mice ( P < 0.05 , respectively ) .	In contrast, E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice exhibited a reduction in skin IFN-gamma expression that was significantly lower than that found in P-selectin -/- mice as well as E-selectin -/- mice (P < 0.05, respectively).	3	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	11	12	3	4
Furthermore , IgG anti-topo I Ab production in E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice was greater than those in P-selectin -/- and E-selectin -/- mice ( P < 0.05 ) .	Furthermore, IgG anti-topo I Ab production in E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice was greater than those in P-selectin -/- and E-selectin -/- mice (P < 0.05).	8	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	16	17	8	9
E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice exhibited further increased numbers of neutrophils relative to bleomycin treated P-selectin -/- and E-selectin -/- mice ( P < 0.05 , respectively ) .	E-selectin -/- mice treated with anti-P-selectin mAb and PSGL-1 -/- mice exhibited further increased numbers of neutrophils relative to bleomycin treated P-selectin -/- and E-selectin -/- mice (P < 0.05, respectively).	0	9	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	E-selectin	E-selectin	E-selectin	8	9	0	1
Thus , it appears that the first 148 amino acids of PSGL-1 are sufficient to support attachment and subsequent rolling on CHO cell monolayers expressing E- or P-selectin .	Thus, it appears that the first 148 amino acids of PSGL-1 are sufficient to support attachment and subsequent rolling on CHO cell monolayers expressing E- or P-selectin.	9	28	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	P-selectin	P-selectin	P-selectin	11	12	27	28
Neutrophil P-selectin glycoprotein ligand-1 ( PSGL-1 ) mediates the initial rolling and adhesion of neutrophils to P-selectin on activated endothelium and platelets .	Neutrophil P-selectin glycoprotein ligand-1 (PSGL-1) mediates the initial rolling and adhesion of neutrophils to P-selectin on activated endothelium and platelets.	3	21	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	P-selectin	P-selectin	P-selectin	5	6	16	17
The PSGL-1 up-regulation associated with natalizumab treatment enhances the ability of patients ' CD4 + T cells to roll over P-selectin .	The PSGL-1 up-regulation associated with natalizumab treatment enhances the ability of patients ' CD4 + T cells to roll over P-selectin.	1	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	P-selectin	P-selectin	P-selectin	1	2	20	21
HL60 cells express high levels of P-selectin glycoprotein ligand-1 ( PSGL-1 , CD62P ) and exhibit rolling on P-selectin mediated primarily by PSGL-1 .	HL60 cells express high levels of P-selectin glycoprotein ligand-1 (PSGL-1, CD62P) and exhibit rolling on P-selectin mediated primarily by PSGL-1.	16	23	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	P-selectin	P-selectin	P-selectin	22	23	18	19
The best characterized selectin ligand is P-selectin glycoprotein-1 ( PSGL-1 ) that supports P-selectin- dependent rolling in vitro and in vivo .	The best characterized selectin ligand is P-selectin glycoprotein-1 (PSGL-1) that supports P-selectin- dependent rolling in vitro and in vivo.	7	15	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PSGL-1	PSGL-1	PSGL-1	P-selectin-	P-selectin-	P-selectin-	9	10	13	14
Both C2GlcNAcT-I glycosylation and PSGL-1 dimerization increased the rate of tethering to P-selectin under flow , whereas C2GlcNAcT-I levels primarily influenced tether bond strength .	Both C2GlcNAcT-I glycosylation and PSGL-1 dimerization increased the rate of tethering to P-selectin under flow, whereas C2GlcNAcT-I levels primarily influenced tether bond strength.	2	13	increased	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	PSGL-1	glycosylation and PSGL-1	psgl-1	P-selectin	P-selectin	p-selectin	4	5	12	13
SBDS mediates the release of eIF6 from the 60S ribosome which is a pre-requisite for the initiation of 80s ribosome translational activity [ XREF_BIBR ] .	SBDS mediates the release of eIF6 from the 60S ribosome which is a pre-requisite for the initiation of 80s ribosome translational activity [XREF_BIBR].	0	6	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SBDS	SBDS	SBDS	eIF6	eIF6	eIF6	0	1	5	6
The current working molecular model is that SBDS acts with EFTuD1 to promote EIF6 removal from the 60S ribosomal subunit [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The current working molecular model is that SBDS acts with EFTuD1 to promote EIF6 removal from the 60S ribosomal subunit [XREF_BIBR, XREF_BIBR, XREF_BIBR].	7	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SBDS	SBDS	SBDS	EIF6	EIF6	EIF6	7	8	13	14
SBDS binds to the 60S ribosomal subunit and promotes the dissociation of EIF6 through the GTPase EFL1 during ribosomal maturation .	SBDS binds to the 60S ribosomal subunit and promotes the dissociation of EIF6 through the GTPase EFL1 during ribosomal maturation.	0	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SBDS	SBDS	SBDS	EIF6	EIF6	EIF6	0	1	12	13
It was recently shown that SBDS couples with the GTPase EFL1 to cause the release of EIF6 from the pre-60S ribosome subunit , an essential step in the formation of the mature ribosome .	It was recently shown that SBDS couples with the GTPase EFL1 to cause the release of EIF6 from the pre-60S ribosome subunit, an essential step in the formation of the mature ribosome.	5	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SBDS	SBDS	SBDS	EIF6	EIF6	EIF6	5	6	16	17
We confirm that the number of eIF6 binding sites on 60S ribosomes is reduced , consistent with reduced generation of free 60S and with a proposed model of SBDS mediated eIF6 release in the late maturation of 60S , in cooperation with EFL1 [ XREF_BIBR ] .	We confirm that the number of eIF6 binding sites on 60S ribosomes is reduced, consistent with reduced generation of free 60S and with a proposed model of SBDS mediated eIF6 release in the late maturation of 60S, in cooperation with EFL1 [XREF_BIBR].	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	SBDS	SBDS	SBDS	eIF6	eIF6	eIF6	28	29	30	31
XREF_BIBR , XREF_BIBR , XREF_BIBR SBDS together with EFL1 , a GTPase , triggers the GTP dependent release of EIF6 from 60S preribosomes in the cytoplasm , thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating EIF6 recycling to the nucleus , where it is needed for 60S rRNA processing and nuclear export .	XREF_BIBR, XREF_BIBR, XREF_BIBR SBDS together with EFL1, a GTPase, triggers the GTP dependent release of EIF6 from 60S preribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating EIF6 recycling to the nucleus, where it is needed for 60S rRNA processing and nuclear export.	0	20	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SBDS	SBDS	SBDS	EIF6	EIF6	EIF6	5	6	19	20
To test the hypothesis that Sema3F activates Nrp2 in type I SGNs , which would lead to decreased complexity and inhibition of extension , we established cochlear explant cultures from E15.5 or E16.5 mice and maintained them in media containing control Fc or Sema3F-Fc fusion proteins for 24 hr .	To test the hypothesis that Sema3F activates Nrp2 in type I SGNs, which would lead to decreased complexity and inhibition of extension, we established cochlear explant cultures from E15.5 or E16.5 mice and maintained them in media containing control Fc or Sema3F-Fc fusion proteins for 24 hr.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sema3F	Sema3F	Sema3F	Nrp2	Nrp2	Nrp2	5	6	7	8
In these cells , SEMA3F induces a complex of NRP2 and plexin A1 , activating p190RhoGAP , which inactivates RhoA , converting GTP to GDP , resulting in loss of stress fibers and collapse of the F-actin cytoskeleton .	In these cells, SEMA3F induces a complex of NRP2 and plexin A1, activating p190RhoGAP, which inactivates RhoA, converting GTP to GDP, resulting in loss of stress fibers and collapse of the F-actin cytoskeleton.	4	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEMA3F	SEMA3F	SEMA3F	NRP2	NRP2	NRP2	4	5	9	10
These data are consistent with the hypothesis that a localized source of Sema3F in the OHC region acts to activate Nrp2 in SGN growth cones leading to decreased complexity and extension .	These data are consistent with the hypothesis that a localized source of Sema3F in the OHC region acts to activate Nrp2 in SGN growth cones leading to decreased complexity and extension.	10	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sema3F	Sema3F	Sema3F	Nrp2	Nrp2	Nrp2	12	13	20	21
In these studies , we demonstrate that repulsive signaling mediated by Sema3F in the OHC region and Nrp2 in SGNs controls , at least in part , the number of SGN fibers that terminate on OHCs .	In these studies, we demonstrate that repulsive signaling mediated by Sema3F in the OHC region and Nrp2 in SGNs controls, at least in part, the number of SGN fibers that terminate on OHCs.	9	18	mediated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Sema3F	Sema3F	Sema3F	Nrp2	Nrp2	Nrp2	11	12	17	18
Finally , we performed live cell imaging of the collapse in COS-7 cells transfected with NRP2 control or NRP2 and Plexin A3 treated with SEMA3F ( XREF_SUPPLEMENTARY ) .	Finally, we performed live cell imaging of the collapse in COS-7 cells transfected with NRP2 control or NRP2 and Plexin A3 treated with SEMA3F (XREF_SUPPLEMENTARY).	15	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	SEMA3F	SEMA3F	SEMA3F	NRP2	NRP2	NRP2	24	25	15	16
Furthermore , the fact that in flx1Delta cells , Sdh5 overexpression can partially restore flavinylation of Sdh1 leaves open the possibility that Sdh5 is indeed a FAD chaperone .	Furthermore, the fact that in flx1Delta cells, Sdh5 overexpression can partially restore flavinylation of Sdh1 leaves open the possibility that Sdh5 is indeed a FAD chaperone.	9	17	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sdh5	Sdh5 overexpression	sdh5	Sdh1	Sdh1	sdh1	9	10	16	17
The NMR studies revealed that the Sdh5 core assumes a compact 5 alpha-helical bundle and revealed a concentrated patch of conserved residues on the surface of these alpha-helices , which is theorized to be the Sdh1 binding site While it is not yet possible to define the precise mechanism by which Sdh5 supports Sdh1 flavinylation , there is sufficient data to hypothesize as to the role of Sdh5 in this process .	The NMR studies revealed that the Sdh5 core assumes a compact 5 alpha-helical bundle and revealed a concentrated patch of conserved residues on the surface of these alpha-helices, which is theorized to be the Sdh1 binding site While it is not yet possible to define the precise mechanism by which Sdh5 supports Sdh1 flavinylation, there is sufficient data to hypothesize as to the role of Sdh5 in this process.	51	54	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sdh5	Sdh5	Sdh5	Sdh1	Sdh1	Sdh1	51	52	53	54
Deletion of SDH5 caused a complete loss of FAD cofactor attachment ( flavination ) of Sdh1 , although Sdh1 was still present ( XREF_FIG ) .	Deletion of SDH5 caused a complete loss of FAD cofactor attachment (flavination) of Sdh1, although Sdh1 was still present (XREF_FIG).	0	21	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDH5	SDH5	SDH5	Sdh1	Sdh1	Sdh1	2	3	15	16
Sdh5 overexpression in WT cells did not increase Sdh1 flavination ( XREF_FIG , lane 1 versus lane 2 ) , possibly due to flavination that was already stoichiometric .	Sdh5 overexpression in WT cells did not increase Sdh1 flavination (XREF_FIG, lane 1 versus lane 2), possibly due to flavination that was already stoichiometric.	0	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sdh5	Sdh5 overexpression	sdh5	Sdh1	Sdh1	sdh1	0	1	8	9
Furthermore , the over-expression of hWW45 greatly enhanced the apoptotic efficacy of MST1 , whereas the knockdown of endogenous hWW45 by RNA interference attenuated MST1 induced apoptosis in the present study .	Furthermore, the over-expression of hWW45 greatly enhanced the apoptotic efficacy of MST1, whereas the knockdown of endogenous hWW45 by RNA interference attenuated MST1 induced apoptosis in the present study.	16	27	attenuated	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	hWW45	hWW45	hww45	MST1	MST1 induced apoptosis	mst1	19	20	24	25
Sav1 activates MST1 , which results in the downstream activation of Hippo signalling 55 .	Sav1 activates MST1, which results in the downstream activation of Hippo signalling 55.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sav1	Sav1	Sav1	MST1	MST1	MST1	0	1	2	3
When cotransfected with a Notch reporter , IC V -6 mt and DeltaE-6mt , but not N FL -6 mt , rescue Notch signaling in sdc3 -/- SCs ( XREF_FIG ) , which suggests a role for Syndecan-3 in regulating TACE mediated cleavage of Notch at the S2 site .	When cotransfected with a Notch reporter, IC V -6 mt and DeltaE-6mt, but not N FL -6 mt, rescue Notch signaling in sdc3 -/- SCs (XREF_FIG), which suggests a role for Syndecan-3 in regulating TACE mediated cleavage of Notch at the S2 site.	23	45	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	sdc3	sdc3	sdc3	Notch	Notch	Notch	25	26	44	45
The finding that Syndecan-3 promotes Notch processing and signaling represents a further step toward understanding the mechanisms that regulate SC niche function .	The finding that Syndecan-3 promotes Notch processing and signaling represents a further step toward understanding the mechanisms that regulate SC niche function.	3	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syndecan-3	Syndecan-3	Syndecan-3	Notch	Notch	Notch	3	4	5	6
Similarly , knockdown of Syndecan-3 in the SC line MM14 by transfection with a mix of three different Syndecan-3 siRNAs reduces activation of both Hes1-Luc and CSL-Luc Notch reporters ( XREF_FIG ) .	Similarly, knockdown of Syndecan-3 in the SC line MM14 by transfection with a mix of three different Syndecan-3 siRNAs reduces activation of both Hes1-Luc and CSL-Luc Notch reporters (XREF_FIG).	2	28	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Syndecan-3	Syndecan-3	Syndecan-3	Notch	Notch	Notch	4	5	27	28
MDA-9 and syntenin mediates IL-5-induced Sox4 activation through its direct interaction with IL-5Ralpha and Sox4 , supporting a potential role in B-cell development and differentiation .	MDA-9 and syntenin mediates IL-5-induced Sox4 activation through its direct interaction with IL-5Ralpha and Sox4, supporting a potential role in B-cell development and differentiation.	0	6	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDA-9	MDA-9	MDA-9	Sox4	Sox4	Sox4	0	1	5	6
It had been reported that MDA-9 and Syntenin could enhance the transcription activity of Sox4 by decreasing its proteosomal degradation [ XREF_BIBR , XREF_BIBR ] .	It had been reported that MDA-9 and Syntenin could enhance the transcription activity of Sox4 by decreasing its proteosomal degradation [XREF_BIBR, XREF_BIBR].	5	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MDA-9	MDA-9	MDA-9	Sox4	Sox4	Sox4	5	6	14	15
Consistent with the possibility that S1pr3 promotes egress of mouse Galpha13- or Arhgef1 deficient GC B cells into circulation , we found that the majority of Galpha13- or Arhgef1 deficient GC B cells in lymph from mixed chimeras were LZ phenotype ( XREF_FIG ) .	Consistent with the possibility that S1pr3 promotes egress of mouse Galpha13- or Arhgef1 deficient GC B cells into circulation, we found that the majority of Galpha13- or Arhgef1 deficient GC B cells in lymph from mixed chimeras were LZ phenotype (XREF_FIG).	5	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S1pr3	S1pr3	S1pr3	Galpha13-	Galpha13-	Galpha13-	5	6	10	11
However , when we examined circulatory fluids of these mixed chimeras , we found that loss of S1pr3 was sufficient to prevent egress of Galpha13 deficient GC B cells into lymph and blood ( XREF_FIG ) .	However, when we examined circulatory fluids of these mixed chimeras, we found that loss of S1pr3 was sufficient to prevent egress of Galpha13 deficient GC B cells into lymph and blood (XREF_FIG).	15	25	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	S1pr3	loss of S1pr3	s1pr3	Galpha13	Galpha13	galpha13	17	18	24	25
Syndecan-3 promotes this essential step in the generation of NICD by forming a complex that contains the Notch receptor at the satellite cell plasma membrane .	Syndecan-3 promotes this essential step in the generation of NICD by forming a complex that contains the Notch receptor at the satellite cell plasma membrane.	0	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syndecan-3	Syndecan-3	Syndecan-3	NICD	NICD	NICD	0	1	9	10
SBDS promotes a conformational switch in the GTPase EFL1 that displaces eIF6 from the 60S subunit by competing for an overlapping binding site .	SBDS promotes a conformational switch in the GTPase EFL1 that displaces eIF6 from the 60S subunit by competing for an overlapping binding site.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SBDS	SBDS	SBDS	EFL1	EFL1	EFL1	0	1	8	9
The binding of SHH relieves SMO inhibition , leading to activation of the GLI transcription factors .	The binding of SHH relieves SMO inhibition, leading to activation of the GLI transcription factors.	1	6	relieves	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	3	4	5	6
We determined whether Shh promotes Smo ciliary localization by inducing its phosphorylation at CK1 and GRK sites by examining ciliary localization of CFP tagged wild type or phosphorylation site mutant forms of Smo in MEF cells treated with or without Shh conditioned medium .	We determined whether Shh promotes Smo ciliary localization by inducing its phosphorylation at CK1 and GRK sites by examining ciliary localization of CFP tagged wild type or phosphorylation site mutant forms of Smo in MEF cells treated with or without Shh conditioned medium.	23	42	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	40	41	32	33
We also analyzed whether the primary cilium is required for Shh induced Smo conformational change by measuring FRET C in the wild type or Kif3a-/- MEFs transfected with wild type or mutant forms of Smo-CFP C / YFP C.	We also analyzed whether the primary cilium is required for Shh induced Smo conformational change by measuring FRET C in the wild type or Kif3a-/- MEFs transfected with wild type or mutant forms of Smo-CFP C / YFP C.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	10	11	12	13
SMANT and its analog SMANT-2 inhibited Shh induced ciliary accumulation of Smo : : EGFP with IC50 ' s of 1.1 muM and 1.6 muM , respectively ( XREF_FIG ; XREF_TABLE ) .	SMANT and its analog SMANT-2 inhibited Shh induced ciliary accumulation of Smo : : EGFP with IC50 's of 1.1 muM and 1.6 muM, respectively (XREF_FIG; XREF_TABLE).	6	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	6	7	11	12
PATCHED , a SHH receptor , inhibits the SHH signal pathway by suppressing SMO .	PATCHED, a SHH receptor, inhibits the SHH signal pathway by suppressing SMO.	3	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SHH	SHH	SHH	SMO	SMO	SMO	3	4	13	14
To determine if the level of Shh pathway activity correlates with the level of Smo phosphorylation , NIH3T3 cells transfected with Smo-Myc were treated with different levels of Shh , followed by mobility shift assay on the phospho-tag gel or western blot with PS1 .	To determine if the level of Shh pathway activity correlates with the level of Smo phosphorylation, NIH3T3 cells transfected with Smo-Myc were treated with different levels of Shh, followed by mobility shift assay on the phospho-tag gel or western blot with PS1.	19	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo-Myc	Smo-Myc	Smo-Myc	28	29	21	22
Our previous FRET analysis indicated that Shh induces a conformational change in Smo from a closed to an open conformation XREF_BIBR .	Our previous FRET analysis indicated that Shh induces a conformational change in Smo from a closed to an open conformation XREF_BIBR.	6	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	6	7	12	13
Binding of Shh to the inhibitory receptor , Patched1 ( Ptc1 ) , results in activation of Smoothened ( Smo ) and subsequent activation of Gli transcription factors .	Binding of Shh to the inhibitory receptor, Patched1 (Ptc1), results in activation of Smoothened (Smo) and subsequent activation of Gli transcription factors.	0	23	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	2	3	19	20
Moreover , Shh which activates SMO blocks axon growth produced by synaptamide ( XREF_FIG ) .	Moreover, Shh which activates SMO blocks axon growth produced by synaptamide (XREF_FIG).	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	SMO	SMO	SMO	2	3	5	6
Mutating S0 ( SA0 ) or S1 ( SA1 ) slightly reduced whereas their combined mutations ( S01 ) markedly inhibited Shh induced Smo activity ( XREF_FIG ) .	Mutating S0 (SA0) or S1 (SA1) slightly reduced whereas their combined mutations (S01) markedly inhibited Shh induced Smo activity (XREF_FIG).	20	24	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	21	22	23	24
Ptc inhibits association of beta-arrestin 2 with Smo , and this inhibition is relieved in cells treated with Shh .	Ptc inhibits association of beta-arrestin 2 with Smo, and this inhibition is relieved in cells treated with Shh.	1	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	18	19	7	8
The ability of itraconazole to suppress Shh induced accumulation of Smo in the primary cilium is consistent with direct action of itraconazole on Smo for pathway inactivation .	The ability of itraconazole to suppress Shh induced accumulation of Smo in the primary cilium is consistent with direct action of itraconazole on Smo for pathway inactivation.	5	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	6	7	10	11
To decipher the function of SHH in patterning of and cell type specification in the LE , we first irreversibly ablated SHH signaling in epithelial cells that express Shh and their progeny by ShhGFPCRE mediated removal of Smo in mutants carrying Smo floxed ( f ) alleles ( ShhGFPCRE and Smo f/f ) .	To decipher the function of SHH in patterning of and cell type specification in the LE, we first irreversibly ablated SHH signaling in epithelial cells that express Shh and their progeny by ShhGFPCRE mediated removal of Smo in mutants carrying Smo floxed (f) alleles (ShhGFPCRE and Smo f/f).	21	38	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	Smo	Smo	Smo	21	22	37	38
The presence of SHH will repress PTCH1 and activate SMO .	The presence of SHH will repress PTCH1 and activate SMO.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	3	4	9	10
The most parsimonious explanation for this result is that Shh causes Smo dispersed over the cell surface to concentrate in cilia , a result that is consistent with lateral transport or recycling models but not with directed vesicular transport .	The most parsimonious explanation for this result is that Shh causes Smo dispersed over the cell surface to concentrate in cilia, a result that is consistent with lateral transport or recycling models but not with directed vesicular transport.	9	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	9	10	11	12
There could be a basal association of CK1alpha and GRK2 with Smo in quiescent cells , and Shh could induce a change in Smo that makes the CK1 and GRK sites more accessible to the bound kinases , which may also contribute to the initiation of Smo phosphorylation .	There could be a basal association of CK1alpha and GRK2 with Smo in quiescent cells, and Shh could induce a change in Smo that makes the CK1 and GRK sites more accessible to the bound kinases, which may also contribute to the initiation of Smo phosphorylation.	17	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	17	18	23	24
Shh also activates the ERK pathway independently of Smo , probably through modulating the interaction of the SH3 interacting motif of Ptc1 CTD with SH3 containing proteins like Grb2 .	Shh also activates the ERK pathway independently of Smo, probably through modulating the interaction of the SH3 interacting motif of Ptc1 CTD with SH3 containing proteins like Grb2.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	0	1	8	9
XREF_SUPPLEMENTARY : Shh promotes fibroblast migration in a Smo dependent fashion .	XREF_SUPPLEMENTARY : Shh promotes fibroblast migration in a Smo dependent fashion.	2	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	2	3	8	9
The canonical cascade is initiated by Patched ( Ptch ) and Smoothened ( Smo ) ; Sonic Hedgehog ligand ( Shh ) binding to Ptch allows release of Smo , causing active full-length Gli to enter the nucleus and activate transcription of target genes , including Gli1 , Ptch1 , and Cyclin D1 , in a context- and cell-type dependent manner [ XREF_BIBR ] .	The canonical cascade is initiated by Patched (Ptch) and Smoothened (Smo); Sonic Hedgehog ligand (Shh) binding to Ptch allows release of Smo, causing active full-length Gli to enter the nucleus and activate transcription of target genes, including Gli1, Ptch1, and Cyclin D1, in a context- and cell-type dependent manner [XREF_BIBR].	18	29	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	20	21	28	29
This analysis showed that upon Shh-N CM stimulation , GFP-KIF13B expression , but not GFP alone , could rescue SMO accumulation in cilia compared to control conditions ( XREF_FIG ) , substantiating a requirement for KIF13B in Shh induced SMO ciliary accumulation .	This analysis showed that upon Shh-N CM stimulation, GFP-KIF13B expression, but not GFP alone, could rescue SMO accumulation in cilia compared to control conditions (XREF_FIG), substantiating a requirement for KIF13B in Shh induced SMO ciliary accumulation.	35	41	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	SMO	SMO	SMO	37	38	39	40
Despite the enrichment of Smo in the cilium in response to Shh , Smo also accumulates in cilia in cells that lack the Dync2h1 retrograde IFT motor in the absence of ligand XREF_BIBR , XREF_BIBR , suggesting that Smo trafficks through the cilium in the absence of ligand , and that Shh increases ciliary accumulation of Smo .	Despite the enrichment of Smo in the cilium in response to Shh, Smo also accumulates in cilia in cells that lack the Dync2h1 retrograde IFT motor in the absence of ligand XREF_BIBR, XREF_BIBR, suggesting that Smo trafficks through the cilium in the absence of ligand, and that Shh increases ciliary accumulation of Smo.	51	57	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	51	52	56	57
We first tested the compounds in C3H10T1/2 cells that were treated with SAG ( a small-molecule activator of Smo ) rather than Shh conditioned medium to activate the Hh pathway .	We first tested the compounds in C3H10T1/2 cells that were treated with SAG (a small-molecule activator of Smo) rather than Shh conditioned medium to activate the Hh pathway.	16	24	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	22	23	18	19
DAPT dramatically reduced Shh induced Smo accumulation within primary cilia , acting in a dose dependent manner ( XREF_FIG D-5F , 5I-5K , and S5A ) .	DAPT dramatically reduced Shh induced Smo accumulation within primary cilia, acting in a dose dependent manner (XREF_FIG D-5F, 5I-5K, and S5A).	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	3	4	5	6
Shh activates Smo activity indirectly , unlike SAG , after first binding Ptch1/2 , according to the canonical Hh signaling model .	Shh activates Smo activity indirectly, unlike SAG, after first binding Ptch1/2, according to the canonical Hh signaling model.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	0	1	2	3
In ERalpha positive gastric cancer cells , E2 induced Shh expression and promoted cellular proliferation independent of smo activity .	In ERalpha positive gastric cancer cells, E2 induced Shh expression and promoted cellular proliferation independent of smo activity.	7	18	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	E2 induced Shh expression	shh	smo	smo	smo	9	10	17	18
22-NHC inhibits Smo activated by Shh and 20-OHC , but not by SAG , and can not inhibit the constitutively active SmoM2 mutant .	22-NHC inhibits Smo activated by Shh and 20-OHC, but not by SAG, and can not inhibit the constitutively active SmoM2 mutant.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	5	6	2	3
We reasoned that if loss of CCRK leads to mild , ligand independent derepression of the Hh pathway , some Shh dependent cell fates would be rescued in Ccrk -/- Smo -/- double mutants .	We reasoned that if loss of CCRK leads to mild, ligand independent derepression of the Hh pathway, some Shh dependent cell fates would be rescued in Ccrk -/- Smo -/- double mutants.	20	33	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	20	21	30	31
Using a hairpin and cDNA lentiviral system , we show that overexpression of the Shh dependent gene Noggin , but not Sox2 or Sox18 , can partially rescue the dermal Smo knockdown hair follicle phenotype by increasing the expression of epithelial Shh .	Using a hairpin and cDNA lentiviral system, we show that overexpression of the Shh dependent gene Noggin, but not Sox2 or Sox18, can partially rescue the dermal Smo knockdown hair follicle phenotype by increasing the expression of epithelial Shh.	11	34	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	overexpression of the Shh	shh	Smo	Smo	smo	14	15	30	31
Mutations in the Shh signaling pathway that target Ptch1 , Smo and Gli1 are associated with cancers of the prostate , skin , and esophagus [ XREF_BIBR - XREF_BIBR ] .	Mutations in the Shh signaling pathway that target Ptch1, Smo and Gli1 are associated with cancers of the prostate, skin, and esophagus [XREF_BIBR - XREF_BIBR].	3	11	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	3	4	10	11
Furthermore , increasing the number of SA mutations gradually decreased the level of Shh induced Smo activity , whereas increasing the number of phospho mimetic mutations progressively increased the level of basal Smo activity .	Furthermore, increasing the number of SA mutations gradually decreased the level of Shh induced Smo activity, whereas increasing the number of phospho mimetic mutations progressively increased the level of basal Smo activity.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	13	14	15	16
On the other hand , non sterol 7TM antagonists like SANT-1 and Vismodegib prevent Shh induced Smo accumulation in cilia .	On the other hand, non sterol 7TM antagonists like SANT-1 and Vismodegib prevent Shh induced Smo accumulation in cilia.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	14	15	16	17
In this pathway , the SHH protein activates smoothened ( Smo ) by binding to its receptor , patched-1 .	In this pathway, the SHH protein activates smoothened (Smo) by binding to its receptor, patched-1.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	Smo	Smo	Smo	5	6	10	11
Shh ligand secreted from cancerous epithelial cells can activate Smo dependent signaling in adjacent stromal cells according to the canonical Hh pathway , leading to desmoplasia [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Shh ligand secreted from cancerous epithelial cells can activate Smo dependent signaling in adjacent stromal cells according to the canonical Hh pathway, leading to desmoplasia [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	0	1	9	10
In mice , overexpression of SHH , activates SMO , GLI1 or GLI2 and promotes development of basal cell carcinoma like tumors XREF_BIBR .	In mice, overexpression of SHH, activates SMO, GLI1 or GLI2 and promotes development of basal cell carcinoma like tumors XREF_BIBR.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	overexpression of SHH	shh	SMO	SMO	smo	5	6	8	9
To further analyze the requirement for Pifo in Shh induced Smo translocation to the PC , we developed a live-cell imaging system using LSM .	To further analyze the requirement for Pifo in Shh induced Smo translocation to the PC, we developed a live-cell imaging system using LSM.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	8	9	10	11
Shh may increase the rate of delivery of Smo containing vesicles to the base of the cilium , where Smo is transferred to an anterograde IFT dependent trafficking mechanism .	Shh may increase the rate of delivery of Smo containing vesicles to the base of the cilium, where Smo is transferred to an anterograde IFT dependent trafficking mechanism.	0	9	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	0	1	8	9
First , synergy is not observed between oxysterols and SHH induced SMO activation .	First, synergy is not observed between oxysterols and SHH induced SMO activation.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	9	10	11	12
This Shh induced effect depends on the pathway transducer Smoothened ( Smo ) and the transcription factor Gli1 .	This Shh induced effect depends on the pathway transducer Smoothened (Smo) and the transcription factor Gli1.	0	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	1	2	11	12
Shh induces ciliary accumulation of Smo that correlates with pathway activation , but the underlying mechanism is poorly understood XREF_BIBR , XREF_BIBR .	Shh induces ciliary accumulation of Smo that correlates with pathway activation, but the underlying mechanism is poorly understood XREF_BIBR, XREF_BIBR.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	0	1	5	6
Consistent with previous reports , we found that Smo was enriched in the cilia of wild-type MEFs treated with Shh ( XREF_FIG ) .	Consistent with previous reports, we found that Smo was enriched in the cilia of wild-type MEFs treated with Shh (XREF_FIG).	8	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	19	20	8	9
Altered Shh Signaling in the Absence of Smo Activity .	Altered Shh Signaling in the Absence of Smo Activity.	1	8	Signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	1	2	7	8
Shh induces Smo trafficking to the cell surface and the primary cilium , while the Shh and Ptch1 complex traffics to late endosomes XREF_BIBR - XREF_BIBR .	Shh induces Smo trafficking to the cell surface and the primary cilium, while the Shh and Ptch1 complex traffics to late endosomes XREF_BIBR - XREF_BIBR.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	0	1	2	3
The binding of Shh ligand to patched ( PTCH1 ) protein relieves the inhibition of smoothened ( SMO ) which is then able to relieve the sequestration of a Gli1 transcription factor by a cytoplasmic complex which includes SUFU ( suppressor of fused homolog ) .	The binding of Shh ligand to patched (PTCH1) protein relieves the inhibition of smoothened (SMO) which is then able to relieve the sequestration of a Gli1 transcription factor by a cytoplasmic complex which includes SUFU (suppressor of fused homolog).	3	24	relieves	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	SMO	SMO	SMO	3	4	17	18
Shh stimulation causes rapid accumulation of Smo in primary cilia 17 , a process blocked by some Site A Smo inhibitors , such as SANT1 .	Shh stimulation causes rapid accumulation of Smo in primary cilia 17, a process blocked by some Site A Smo inhibitors, such as SANT1.	0	7	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	0	1	6	7
DY131 , and its analog GSK4716 , inhibited Shh induced accumulation of Smo : : EGFP with IC50 ' s of 0.8 muM and 2muM respectively ( XREF_FIG , XREF_SUPPLEMENTARY , XREF_TABLE ) .	DY131, and its analog GSK4716, inhibited Shh induced accumulation of Smo : : EGFP with IC50 's of 0.8 muM and 2muM respectively (XREF_FIG, XREF_SUPPLEMENTARY, XREF_TABLE).	8	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	8	9	12	13
XREF_BIBR , XREF_BIBR , XREF_BIBR The binding of SHH relieves Smo inhibition , leading to activation of the GLI transcription factors : the activators Gli1 and Gli2 and the repressor Gli3 .	XREF_BIBR, XREF_BIBR, XREF_BIBR The binding of SHH relieves Smo inhibition, leading to activation of the GLI transcription factors : the activators Gli1 and Gli2 and the repressor Gli3.	6	11	relieves	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	Smo	Smo	Smo	8	9	10	11
Employing immunocytochemistry for myc tagged Smoothened [ XREF_BIBR ] , we found that addition of Shh peptide to UGSM-2 cells grown under limited proliferative conditions triggered a localization of exogenous wild type Smo to the primary cilium and that this localization could be blocked by cyclopamine .	Employing immunocytochemistry for myc tagged Smoothened [XREF_BIBR], we found that addition of Shh peptide to UGSM-2 cells grown under limited proliferative conditions triggered a localization of exogenous wild type Smo to the primary cilium and that this localization could be blocked by cyclopamine.	15	33	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	15	16	32	33
Binding of SHH protein to PTC releases this inhibition , allowing SMO to activate the downstream signaling cascade .	Binding of SHH protein to PTC releases this inhibition, allowing SMO to activate the downstream signaling cascade.	2	13	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	2	3	11	12
In fact , we have previously reported that cyclopamine is much less potent against Shh activated Smo compared to 20 ( S )-OHC-activated Smo , likely because the conformation adopted by Smo is different in response to these two agonists .	In fact, we have previously reported that cyclopamine is much less potent against Shh activated Smo compared to 20 (S)-OHC-activated Smo, likely because the conformation adopted by Smo is different in response to these two agonists.	12	33	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	14	15	16	17
We further found that Shh induced endocytic turnover of Ptch1 was not affected in Smo null MEFs ( XREF_FIG ) , suggesting that it is an upstream signaling event , independent of Smo function .	We further found that Shh induced endocytic turnover of Ptch1 was not affected in Smo null MEFs (XREF_FIG), suggesting that it is an upstream signaling event, independent of Smo function.	4	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	4	5	14	15
These results indicate that Shh induction initiates the formation of a Smo ciliary transport complex by increasing the affinity of Smo to Gprasp2-Pifo-Kif3b .	These results indicate that Shh induction initiates the formation of a Smo ciliary transport complex by increasing the affinity of Smo to Gprasp2-Pifo-Kif3b.	4	14	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	4	5	11	12
How stimulation with Shh allows SMO to cross this barrier is an open question .	How stimulation with Shh allows SMO to cross this barrier is an open question.	1	7	allows	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	SMO	SMO	SMO	3	4	5	6
KIF13B and CAV1 promote Shh induced ciliary SMO accumulation .	KIF13B and CAV1 promote Shh induced ciliary SMO accumulation.	4	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	SMO	SMO	SMO	4	5	7	8
The high levels of ciliary SMO in Atthog -/- and Megf8 -/- made it difficult to assess whether SHH could further increase SMO in cilia , although images taken at low gain settings revealed responsiveness to HiSHH ( XREF_FIG D and XREF_SUPPLEMENTARY C ) .	The high levels of ciliary SMO in Atthog -/- and Megf8 -/- made it difficult to assess whether SHH could further increase SMO in cilia, although images taken at low gain settings revealed responsiveness to HiSHH (XREF_FIG D and XREF_SUPPLEMENTARY C).	18	24	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	18	19	22	23
Binding of Shh to its receptor Patched1 ( Ptch1 ) causes the ciliary accumulation of Smoothened ( Smo ) and the ciliary exit of Gpr161 , thereby inducing the activation of Gli transcription factors , which move from the cilium to the nucleus and induce the Hh transcriptional program .	Binding of Shh to its receptor Patched1 (Ptch1) causes the ciliary accumulation of Smoothened (Smo) and the ciliary exit of Gpr161, thereby inducing the activation of Gli transcription factors, which move from the cilium to the nucleus and induce the Hh transcriptional program.	0	22	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	2	3	17	18
However , inactivation of Inpp5e does not disrupt Shh mediated Smo ciliary translocation , suggesting other lipid remodeling enzymes may be recruited to the ciliary base to provide this control .	However, inactivation of Inpp5e does not disrupt Shh mediated Smo ciliary translocation, suggesting other lipid remodeling enzymes may be recruited to the ciliary base to provide this control.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	8	9	10	11
It has also been shown that a systemic delivery of antifungal agent designated itraconazole , which acts as a noncompetitive inhibitor of hedgehog pathway , prevented the SHH induced SMO accumulation in the primary cilium and suppressed the growth of subcutaneously implanted primary medulloblastoma cells from a PTCH +/-; p53 -/- mouse .	It has also been shown that a systemic delivery of antifungal agent designated itraconazole, which acts as a noncompetitive inhibitor of hedgehog pathway, prevented the SHH induced SMO accumulation in the primary cilium and suppressed the growth of subcutaneously implanted primary medulloblastoma cells from a PTCH +/-; p53 -/- mouse.	26	36	induced	Positive_early_activation	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	27	28	29	30
The results showed that the Shh signaling molecules SHH , PTCH , SMO , GLI1 , and GLI2 were intact and activated in both types of cells .	The results showed that the Shh signaling molecules SHH, PTCH, SMO, GLI1, and GLI2 were intact and activated in both types of cells.	4	21	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	SMO	SMO	SMO	5	6	12	13
The SHH receptor PTC has been proposed to modulate the activity of the pathway signal transducer SMO through the activity of sterol molecules .	The SHH receptor PTC has been proposed to modulate the activity of the pathway signal transducer SMO through the activity of sterol molecules.	1	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	1	2	16	17
Activated smo transduces the Shh signal to other signaling elements such as Gil proteins .	Activated smo transduces the Shh signal to other signaling elements such as Gil proteins.	0	5	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	smo	smo	smo	4	5	1	2
We note that Shh induced Smo mobility shift was not completely abolished by silencing CK1alpha and GRK2 , likely due to an incomplete elimination of these kinase activities by the RNAi approach ( XREF_SUPPLEMENTARY ) .	We note that Shh induced Smo mobility shift was not completely abolished by silencing CK1alpha and GRK2, likely due to an incomplete elimination of these kinase activities by the RNAi approach (XREF_SUPPLEMENTARY).	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	3	4	5	6
Mutations in the 7TMD binding-site do not alter the constitutive or SHH induced signaling activity of SMO , which has led to view that this site does not regulate physiological signaling .	Mutations in the 7TMD binding-site do not alter the constitutive or SHH induced signaling activity of SMO, which has led to view that this site does not regulate physiological signaling.	9	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	11	12	16	17
During SHH stimulation SMO is recruited to replace PTCH at this structure leading to downstream activation of GLI proteins .	During SHH stimulation SMO is recruited to replace PTCH at this structure leading to downstream activation of GLI proteins.	0	7	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	1	2	3	4
This Smo and Tiam1 complex dissociates upon Shh mediated activation of Smo , thus allowing Tiam1 to activate Rac1 .	This Smo and Tiam1 complex dissociates upon Shh mediated activation of Smo, thus allowing Tiam1 to activate Rac1.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	7	8	11	12
SHH pathway is initiated with the binding of SHH ligand to PTCH receptor , causing the activation of SMO .	SHH pathway is initiated with the binding of SHH ligand to PTCH receptor, causing the activation of SMO.	0	19	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	0	1	18	19
Activation of the Shh pathway markedly upregulates the localization of Smo at the primary cilium in mouse embryonic fibroblasts and Madin-Darby Canine Kidney cells [ XREF_BIBR , XREF_BIBR ] .	Activation of the Shh pathway markedly upregulates the localization of Smo at the primary cilium in mouse embryonic fibroblasts and Madin-Darby Canine Kidney cells [XREF_BIBR, XREF_BIBR].	0	11	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	3	4	10	11
Since Shh or Smo oncogenic mutations promote Smo activation by inducing its ciliary localization , it is interesting whether Smo phosphorylation could regulate its ciliary accumulation .	Since Shh or Smo oncogenic mutations promote Smo activation by inducing its ciliary localization, it is interesting whether Smo phosphorylation could regulate its ciliary accumulation.	1	8	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	1	2	7	8
SANT-1 , SANT-2 , and GDC0449 inhibit both Hh pathway activation and Sonic hedgehog ( Shh ) induced Smo accumulation within the PC .	SANT-1, SANT-2, and GDC0449 inhibit both Hh pathway activation and Sonic hedgehog (Shh) induced Smo accumulation within the PC.	13	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	15	16	18	19
Shh stimulates activation of Erk1/2 independent Smo mediated canonical Hh signalling .	Shh stimulates activation of Erk1/2 independent Smo mediated canonical Hh signalling.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	0	1	6	7
Additionally , Shh rapidly activated PKCalpha , and led to a Smo dependent increase in Ca 2+ in the growth cone .	Additionally, Shh rapidly activated PKCalpha, and led to a Smo dependent increase in Ca 2+ in the growth cone.	2	13	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	2	3	11	12
In order to further confirm the role of Shh and Gli 1 signaling pathway in this process , the odontoblastic differentiation of AdShh transfected hDPCs was measured in the presence of Cyclopamine ( Cyc ) , which is a potent Shh and Gli 1 signaling pathway antagonist targeting the SMO protein .	In order to further confirm the role of Shh and Gli 1 signaling pathway in this process, the odontoblastic differentiation of AdShh transfected hDPCs was measured in the presence of Cyclopamine (Cyc), which is a potent Shh and Gli 1 signaling pathway antagonist targeting the SMO protein.	31	50	targeting	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	SMO	SMO	SMO	40	41	49	50
In all cases , DAPT reduced Shh induced Smo accumulation within primary cilia , suggesting that the cross-talk between the Notch and Shh pathways is conserved across germ layers and species .	In all cases, DAPT reduced Shh induced Smo accumulation within primary cilia, suggesting that the cross-talk between the Notch and Shh pathways is conserved across germ layers and species.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	6	7	8	9
A link between Hh dependent activation of Smo in the primary cilium , Gli2 trafficking and Gli2 -mediated transcriptional activation has also been demonstrated : recombinant Shh ligand caused Smo and Gli2 to accumulate within the cilium membrane and ciliary tip , respectively , and these events preceded and were necessary for Gli2 to traffick into the nucleus and trans-activate target genes .	A link between Hh dependent activation of Smo in the primary cilium, Gli2 trafficking and Gli2 -mediated transcriptional activation has also been demonstrated : recombinant Shh ligand caused Smo and Gli2 to accumulate within the cilium membrane and ciliary tip, respectively, and these events preceded and were necessary for Gli2 to traffick into the nucleus and trans-activate target genes.	26	33	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	26	27	29	30
Overall , the effects of SA or SD mutations on Shh induced FRET C correlated with their effects on Shh induced Smo activation .	Overall, the effects of SA or SD mutations on Shh induced FRET C correlated with their effects on Shh induced Smo activation.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	19	20	21	22
Overexpressed SmoEGFP was targeted to ciliary membrane independent of Shh .	Overexpressed SmoEGFP was targeted to ciliary membrane independent of Shh.	0	10	Overexpressed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	SmoEGFP	SmoEGFP	SmoEGFP	9	10	1	2
Shh overexpression activates Ccnb1 signaling in SCLC independent of Smo .	Shh overexpression activates Ccnb1 signaling in SCLC independent of Smo.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh overexpression	shh	Smo	Smo	smo	0	1	9	10
Since SMO and GLI1/2 can be activated by Shh independent stimuli , targeting them potentially target the transduction of a number of important molecular pathways .	Since SMO and GLI1/2 can be activated by Shh independent stimuli, targeting them potentially target the transduction of a number of important molecular pathways.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	SMO	SMO	SMO	8	9	1	2
In Mgrn1 -/- cells , SHH did clearly increase SMO accumulation in cilia .	In Mgrn1 -/- cells, SHH did clearly increase SMO accumulation in cilia.	5	10	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	5	6	9	10
Upon activation of the pathway , the secreted ligand sonic hedgehog ( SHH ) binds to the Patched ( PTCH ) receptor and activates the transmembrane protein Smoothened ( SMO ) .	Upon activation of the pathway, the secreted ligand sonic hedgehog (SHH) binds to the Patched (PTCH) receptor and activates the transmembrane protein Smoothened (SMO).	10	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	12	13	29	30
Shh stimulation of Smo -/- MEFs does not increase ciliary SuFu and Gli , indicating that signal dependent recruitment of SuFu and Gli requires Smo .	Shh stimulation of Smo -/- MEFs does not increase ciliary SuFu and Gli, indicating that signal dependent recruitment of SuFu and Gli requires Smo.	0	5	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	0	1	3	4
Though Smo can be activated by Shh or Ihh , only Ihh was shown in previous studies to be upregulated in the developing palatine bones .	Though Smo can be activated by Shh or Ihh, only Ihh was shown in previous studies to be upregulated in the developing palatine bones.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	6	7	1	2
We found that itraconazole treatment dramatically reduced Shh induced accumulation of Smo in the primary cilium ( XREF_FIG ) , similar to other Smo antagonists , SANT-1 and SANT-2 , but in contrast to cyclopamine which induced accumulation of Smo in the primary cilium .	We found that itraconazole treatment dramatically reduced Shh induced accumulation of Smo in the primary cilium (XREF_FIG), similar to other Smo antagonists, SANT-1 and SANT-2, but in contrast to cyclopamine which induced accumulation of Smo in the primary cilium.	7	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	7	8	11	12
Based on the interstitial specificity of Pdgfr-alpha expression , we constructed a Pdgfr-alpha-cre to establish a E12.5 - E16.5 transgenic mice with specific knockout of the key Shh signaling molecule Smo in the pulmonary interstitium with tamoxifen induction .	Based on the interstitial specificity of Pdgfr-alpha expression, we constructed a Pdgfr-alpha-cre to establish a E12.5 - E16.5 transgenic mice with specific knockout of the key Shh signaling molecule Smo in the pulmonary interstitium with tamoxifen induction.	23	31	signaling	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Smo	Smo	Smo	27	28	30	31
Finally , simultaneously mutating all CK1 and GRK sites ( SA0-5 ) completely abolished Shh induced Smo activation .	Finally, simultaneously mutating all CK1 and GRK sites (SA0-5) completely abolished Shh induced Smo activation.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	14	15	16	17
The binding of SHH protein ligand to Ptch relieves Smo suppression , leading to Hh/Gli activation that culminates in Gli2 transcription factor activation and subsequent translocation to the nucleus [ XREF_BIBR - XREF_BIBR ] .	The binding of SHH protein ligand to Ptch relieves Smo suppression, leading to Hh/Gli activation that culminates in Gli2 transcription factor activation and subsequent translocation to the nucleus [XREF_BIBR - XREF_BIBR].	3	10	relieves	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	Smo	Smo	Smo	3	4	9	10
Binding of the SHH ligand to its receptor , patched ( PTC ) , activates the transmembrane protein SMO , resulting in the modulation of the glioma associated oncogene 1 ( GLI1 ) , GLI2 and GLI3 , as well as in the processing and binding of GLI activators and repressors to SHH target genes .	Binding of the SHH ligand to its receptor, patched (PTC), activates the transmembrane protein SMO, resulting in the modulation of the glioma associated oncogene 1 (GLI1), GLI2 and GLI3, as well as in the processing and binding of GLI activators and repressors to SHH target genes.	3	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	SMO	SMO	SMO	3	4	18	19
Hence , canonical Hh signaling in PDAC is likely to occur in a paracrine fashion , whereby Shh ligand secreted from epithelial cells activates Smoothened ( Smo )-dependent downstream signaling in adjacent stromal cells , promoting desmoplasia .	Hence, canonical Hh signaling in PDAC is likely to occur in a paracrine fashion, whereby Shh ligand secreted from epithelial cells activates Smoothened (Smo)-dependent downstream signaling in adjacent stromal cells, promoting desmoplasia.	17	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	17	18	26	27
While mutating S2 to S5 either individually ( SA2 , SA3 , SA5 ) or in combinations ( SA23 , SA45 ) had little if any effect on Smo activation ( XREF_FIG ) , combined mutations of these sites with S1/S0 ( SA12 , SA13 , SA123 , SA0-3 , SA1-5 , SA0-5 ) resulted in a progressive decrease in Shh induced Smo activity ( XREF_FIG ) .	While mutating S2 to S5 either individually (SA2, SA3, SA5) or in combinations (SA23, SA45) had little if any effect on Smo activation (XREF_FIG), combined mutations of these sites with S1/S0 (SA12, SA13, SA123, SA0-3, SA1-5, SA0-5) resulted in a progressive decrease in Shh induced Smo activity (XREF_FIG).	54	63	induced	Positive_early_activation	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	60	61	62	63
Binding of SHH ligand to PTCH abolishes PTCH exerted repression of Smoothened ( SMO ) allowing SMO to become active , which activates SHH target gene transcription through the glioma associated oncogene ( Gli ) transcription factor family .	Binding of SHH ligand to PTCH abolishes PTCH exerted repression of Smoothened (SMO) allowing SMO to become active, which activates SHH target gene transcription through the glioma associated oncogene (Gli) transcription factor family.	2	27	abolishes	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	SHH	SHH	shh	SMO	SMO) allowing SMO to become active, which activates SHH target gene transcription	smo	2	3	13	14
However , more recent work using rat spinal cords demonstrated that Shh signals in a Smo dependent manner to activate axons for responsiveness to Semaphorins , which mediate repulsion upon midline crossing [ XREF_BIBR ] .	However, more recent work using rat spinal cords demonstrated that Shh signals in a Smo dependent manner to activate axons for responsiveness to Semaphorins, which mediate repulsion upon midline crossing [XREF_BIBR].	11	17	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	Smo	Smo	Smo	11	12	15	16
Phenylarsine oxide , a protein tyrosine phosphatase inhibitor , suppressed Sema4D induced contractile response in COS-7 cells expressing Plexin-B1 .	Phenylarsine oxide, a protein tyrosine phosphatase inhibitor, suppressed Sema4D induced contractile response in COS-7 cells expressing Plexin-B1.	10	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	Plexin-B1	Plexin-B1	Plexin-B1	10	11	18	19
It was earlier shown that activation of plexinB1 by sema4D can induce opposing responses on the cytoskeleton , depending on different interacting proteins , but the intracellular pathway used for inhibitory synapse formation is not known .	It was earlier shown that activation of plexinB1 by sema4D can induce opposing responses on the cytoskeleton, depending on different interacting proteins, but the intracellular pathway used for inhibitory synapse formation is not known.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	sema4D	sema4D	sema4D	plexinB1	plexinB1	plexinB1	9	10	7	8
This inhibition is most likely due to the ability of EGF to sequester ErbB-2 , making it unavailable to support Sema4D induced plexin-B1 activation .	This inhibition is most likely due to the ability of EGF to sequester ErbB-2, making it unavailable to support Sema4D induced plexin-B1 activation.	19	23	induced	Positive_early_activation	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	plexin-B1	plexin-B1	plexin-B1	20	21	22	23
In PC12 cells , Sema4D activation of PlexinB1 suppresses cell migration through inhibition of R-Ras and , subsequently , of beta1-integrin activity .	In PC12 cells, Sema4D activation of PlexinB1 suppresses cell migration through inhibition of R-Ras and, subsequently, of beta1-integrin activity.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	PlexinB1	PlexinB1	PlexinB1	4	5	7	8
For example , in cultures of cortical neurons , Sema4D activates Plexin-B1 to regulate the growth and branching of axons and dendrites .	For example, in cultures of cortical neurons, Sema4D activates Plexin-B1 to regulate the growth and branching of axons and dendrites.	9	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	Plexin-B1	Plexin-B1	Plexin-B1	9	10	11	12
The present study was designed to test the hypothesis that Plexin-B1 effects are mediated by Semaphorin-4D .	The present study was designed to test the hypothesis that Plexin-B1 effects are mediated by Semaphorin-4D.	10	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Semaphorin-4D	Semaphorin-4D	Semaphorin-4D	Plexin-B1	Plexin-B1	Plexin-B1	15	16	10	11
Inactivation of R-Ras by the RasGAP activity of plexin-B1 triggered by Sema4D was shown to cause an inhibition of cell migration through suppression of PI3K and beta1 integrin activity [ XREF_BIBR ] .	Inactivation of R-Ras by the RasGAP activity of plexin-B1 triggered by Sema4D was shown to cause an inhibition of cell migration through suppression of PI3K and beta1 integrin activity [XREF_BIBR].	6	12	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	plexin-B1	plexin-B1	plexin-B1	11	12	8	9
In neurons , the related receptor Plexin-B1 , stimulated by Sema4D , is known to act as an inactivator ( GTPase activating protein ; GAP ) for M-Ras and R-Ras .	In neurons, the related receptor Plexin-B1, stimulated by Sema4D, is known to act as an inactivator (GTPase activating protein; GAP) for M-Ras and R-Ras.	3	15	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	Plexin-B1	Plexin-B1	Plexin-B1	10	11	6	7
Furthermore , Plexin-B1 can be activated by its high-affinity ligand Sema4D , and such activation can subsequently transactivate c-MET and promote tumor growth , invasion , migration and angiogenesis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Furthermore, Plexin-B1 can be activated by its high-affinity ligand Sema4D, and such activation can subsequently transactivate c-MET and promote tumor growth, invasion, migration and angiogenesis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	Plexin-B1	Plexin-B1	Plexin-B1	10	11	2	3
We then tested whether IKKs and other components of the canonical NF-kappaB pathway are activated by Sema4D induced Plexin-B1 activation .	We then tested whether IKKs and other components of the canonical NF-kappaB pathway are activated by Sema4D induced Plexin-B1 activation.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	Plexin-B1	Plexin-B1	Plexin-B1	16	17	18	19
Stimulation of plexin-B1 by Sema4D leads to RhoA activation in a PDZ-RhoGEF and LARG dependent manner , causing remodeling of actin cytoskeleton that is important for the regulation of cell morphology and cell motility [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Stimulation of plexin-B1 by Sema4D leads to RhoA activation in a PDZ-RhoGEF and LARG dependent manner, causing remodeling of actin cytoskeleton that is important for the regulation of cell morphology and cell motility [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	plexin-B1	plexin-B1	plexin-B1	4	5	2	3
Stimulation of Plexin-B1 by Sema4D induces collapse of the growth cone through downregulation of R-Ras activity .	Stimulation of Plexin-B1 by Sema4D induces collapse of the growth cone through downregulation of R-Ras activity.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	Plexin-B1	Plexin-B1	Plexin-B1	4	5	2	3
We show here that activation of plexin-B1 by Sema4D and its subsequent tyrosine phosphorylation creates docking sites for the SH2 domains of phospholipase Cgamma ( PLCgamma ) .	We show here that activation of plexin-B1 by Sema4D and its subsequent tyrosine phosphorylation creates docking sites for the SH2 domains of phospholipase Cgamma (PLCgamma).	4	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Sema4D	Sema4D and its subsequent tyrosine phosphorylation	sema4d	plexin-B1	plexin-B1	plexin-b1	8	9	6	7
In breast cancer cells , SEMA4D activates PlexinB1 ( PLXNB1 ) to promote or inhibit metastasis in a context dependent manner .	In breast cancer cells, SEMA4D activates PlexinB1 (PLXNB1) to promote or inhibit metastasis in a context dependent manner.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEMA4D	SEMA4D	SEMA4D	PlexinB1	PlexinB1	PlexinB1	5	6	7	8
Subsequent studies have shown that Sema4D activation of PlexinB1 and PlexinA1 hinders cell attachment to adhesive substrates , resulting in cell collapse and inhibition of cell migration ( Barberis et al ., 2004 ) .	Subsequent studies have shown that Sema4D activation of PlexinB1 and PlexinA1 hinders cell attachment to adhesive substrates, resulting in cell collapse and inhibition of cell migration (Barberis et al., 2004).	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	PlexinB1	PlexinB1	PlexinB1	5	6	8	9
Here , we show that the tyrosine kinase ErbB-2 is critically involved in Sema4D induced activation of plexin-B1 and downstream signaling processes via the small GTPase RhoA .	Here, we show that the tyrosine kinase ErbB-2 is critically involved in Sema4D induced activation of plexin-B1 and downstream signaling processes via the small GTPase RhoA.	11	21	induced	Positive_early_activation	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	plexin-B1	plexin-B1	plexin-B1	13	14	17	18
Sema4D induced activation of plexin-B1 has been reported to evoke different and sometimes opposing cellular responses .	Sema4D induced activation of plexin-B1 has been reported to evoke different and sometimes opposing cellular responses.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	plexin-B1	plexin-B1	plexin-B1	0	1	4	5
Recently it was also found that activation of plexin-B1 by Sema4D activates RhoA leading to endothelial cell migration [ XREF_BIBR ] .	Recently it was also found that activation of plexin-B1 by Sema4D activates RhoA leading to endothelial cell migration [XREF_BIBR].	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	plexin-B1	plexin-B1	plexin-B1	10	11	8	9
If cleaved and shed by these cells , endogenous Sema4D may activate plexinB1 by an autocrine mechanism .	If cleaved and shed by these cells, endogenous Sema4D may activate plexinB1 by an autocrine mechanism.	8	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	plexinB1	plexinB1	plexinB1	9	10	12	13
Sema4D enhances cell motility of breast cancer cell lines expressing plexinB1 and ErbB2 and decreases motility in cells expressing plexinB1 and c-Met and the effect is reversed by switching expression of ErbB2 and c-Met XREF_BIBR .	Sema4D enhances cell motility of breast cancer cell lines expressing plexinB1 and ErbB2 and decreases motility in cells expressing plexinB1 and c-Met and the effect is reversed by switching expression of ErbB2 and c-Met XREF_BIBR.	0	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	plexinB1	plexinB1	plexinB1	0	1	10	11
Activation of plexin-B1 by Sema4D results in tyrosine phosphorylation of plexin-B1 by ErbB-2 .	Activation of plexin-B1 by Sema4D results in tyrosine phosphorylation of plexin-B1 by ErbB-2.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	plexin-B1	plexin-B1	plexin-B1	4	5	2	3
Stimulation of Plexin-B1 by Sema4D is reported to hamper integrin based adhesion and cell migration in NIH-3T3 cells .	Stimulation of Plexin-B1 by Sema4D is reported to hamper integrin based adhesion and cell migration in NIH-3T3 cells.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	Plexin-B1	Plexin-B1	Plexin-B1	4	5	2	3
For example , in HEK293 cells , Sema4D induced plexin-B1 and RhoGEF activation does not necessarily require Met , whereas ErbB-2 is strictly essential .	For example, in HEK293 cells, Sema4D induced plexin-B1 and RhoGEF activation does not necessarily require Met, whereas ErbB-2 is strictly essential.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	plexin-B1	plexin-B1	plexin-B1	7	8	9	10
To investigate if Sema4D mediates TGF-beta1 production , through binding to its receptor Plexin-B1 on tumor cells , we used siRNA system for transient silencing of Plexin-B1 in several HNSCC cell lines of the oral tongue .	To investigate if Sema4D mediates TGF-beta1 production, through binding to its receptor Plexin-B1 on tumor cells, we used siRNA system for transient silencing of Plexin-B1 in several HNSCC cell lines of the oral tongue.	3	16	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Sema4D	Sema4D	Sema4D	Plexin-B1	Plexin-B1	Plexin-B1	3	4	13	14
Taken together , these findings show that SEMA4D induces Plexin-B1 / RhoA dependent production of PDGF-B and ANGPTL4 from HUVECs while VEGF does not , suggesting a possible mechanism for differences of these two pro angiogenic proteins observed in endothelial cells [ XREF_BIBR , XREF_BIBR ] .	Taken together, these findings show that SEMA4D induces Plexin-B1 / RhoA dependent production of PDGF-B and ANGPTL4 from HUVECs while VEGF does not, suggesting a possible mechanism for differences of these two pro angiogenic proteins observed in endothelial cells [XREF_BIBR, XREF_BIBR].	7	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEMA4D	SEMA4D	SEMA4D	Plexin-B1	Plexin-B1	Plexin-B1	7	8	9	10
Enrichment for Gli2 at the Hes1 promoter was only detected in Smo agonist treated explants , with no enrichment of Gli2 detected in untreated explants , which suggested that Hes1 is a Shh dependent direct transcriptional target of Gli2 ( XREF_FIG ) .	Enrichment for Gli2 at the Hes1 promoter was only detected in Smo agonist treated explants, with no enrichment of Gli2 detected in untreated explants, which suggested that Hes1 is a Shh dependent direct transcriptional target of Gli2 (XREF_FIG).	32	40	target	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	32	33	38	39
When ptc1 +/+ fibroblasts are transfected with Shh target gene activating transcription factors gli1 or gli2 , igf2 transcription is induced more than 1500-fold ( XREF_FIG ) .	When ptc1 +/+ fibroblasts are transfected with Shh target gene activating transcription factors gli1 or gli2, igf2 transcription is induced more than 1500-fold (XREF_FIG).	7	16	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	gli2	gli2	gli2	7	8	15	16
The inhibition of primary cilia in testicular somatic cells resulted in loss of Gli-2 and Smoothened , thereby likely affecting the hedgehog signaling pathway as previous studies have shown that Gli-2 degradation is suppressed by active Shh signaling in vivo .	The inhibition of primary cilia in testicular somatic cells resulted in loss of Gli-2 and Smoothened, thereby likely affecting the hedgehog signaling pathway as previous studies have shown that Gli-2 degradation is suppressed by active Shh signaling in vivo.	30	37	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli-2	Gli-2	Gli-2	36	37	30	31
However , in most contexts , SHH activates GLI2 [ XREF_BIBR ] , while it is unclear SHH activates or represses GLI3 [ XREF_BIBR ] .	However, in most contexts, SHH activates GLI2 [XREF_BIBR], while it is unclear SHH activates or represses GLI3 [XREF_BIBR].	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	GLI2	GLI2	GLI2	6	7	8	9
Moreover , positive feedback exists between Atoh1 and Shh , whereby Atoh1 maintains granule neuron precursors in a Shh responsive state , in part through the activation of the Shh target Gli2 ; in turn Shh sustains Atoh1 expression and granule neuron precursor proliferation .	Moreover, positive feedback exists between Atoh1 and Shh, whereby Atoh1 maintains granule neuron precursors in a Shh responsive state, in part through the activation of the Shh target Gli2; in turn Shh sustains Atoh1 expression and granule neuron precursor proliferation.	26	32	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	29	30	31	32
Shh signaling is mediated at the transcriptional level by three proteins in vertebrates : Gli1 , Gli2 , and Gli3 .	Shh signaling is mediated at the transcriptional level by three proteins in vertebrates : Gli1, Gli2, and Gli3.	0	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	0	1	16	17
The absence of Shh signaling allows proteolytic processing of bifunctional Gli2 and Gli3 to form the truncated repressors Gli2R and Gli3R ( GliR ) [ XREF_BIBR , XREF_BIBR ] .	The absence of Shh signaling allows proteolytic processing of bifunctional Gli2 and Gli3 to form the truncated repressors Gli2R and Gli3R (GliR) [XREF_BIBR, XREF_BIBR].	3	12	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	3	4	10	11
In the mouse , Gli2 and Gli3 are activated directly by Shh signaling , and they in turn activate transcription of Gli1 .	In the mouse, Gli2 and Gli3 are activated directly by Shh signaling, and they in turn activate transcription of Gli1.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	11	12	4	5
Because both Gli1 and Gli2 are induced by Shh , these results establish a regulatory feedback loop triggered by Shh that restricts floor plate cells to the midline .	Because both Gli1 and Gli2 are induced by Shh, these results establish a regulatory feedback loop triggered by Shh that restricts floor plate cells to the midline.	2	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	8	9	4	5
A second cluster of target genes ( gli2 and N-myc ) is induced to a greater extent by Shh Ala than by wild type Shh .	A second cluster of target genes (gli2 and N-myc) is induced to a greater extent by Shh Ala than by wild type Shh.	2	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	gli2	gli2	gli2	18	19	7	8
For example , Gli2 is up-regulated by the activated Shh signaling in early embryos of chicken and X. laevis but not in those of mammals ; Shh down-regulates Gli3 during neurogenesis of X. laevis , but does not in the regenerating limbs of X. laevis and the mammalian skin .	For example, Gli2 is up-regulated by the activated Shh signaling in early embryos of chicken and X. laevis but not in those of mammals; Shh down-regulates Gli3 during neurogenesis of X. laevis, but does not in the regenerating limbs of X. laevis and the mammalian skin.	3	10	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	9	10	3	4
These data suggest there is a Shh dependent function required to activate Gli2 in the epidermis and a Shh dependent signal from the dermis back to the epidermis that is needed to complete the down growth necessary for follicle development .	These data suggest there is a Shh dependent function required to activate Gli2 in the epidermis and a Shh dependent signal from the dermis back to the epidermis that is needed to complete the down growth necessary for follicle development.	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	6	7	12	13
Activation of the Shh signaling cascade consistently induces Gli family transcription factors ( Gli1 and Gli2 ) , hence both Gli genes mRNA [ XREF_BIBR ] , expressed in pancreatic CSCs , stating potential involvement of Shh signaling in human pancreatic carcinogenesis .	Activation of the Shh signaling cascade consistently induces Gli family transcription factors (Gli1 and Gli2), hence both Gli genes mRNA [XREF_BIBR], expressed in pancreatic CSCs, stating potential involvement of Shh signaling in human pancreatic carcinogenesis.	3	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	3	4	15	16
Conditional deletion of ILK or Smo also inhibits SHh driven activation of Gli2 in the embryonic mouse cerebellum .	Conditional deletion of ILK or Smo also inhibits SHh driven activation of Gli2 in the embryonic mouse cerebellum.	7	13	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHh	SHh	SHh	Gli2	Gli2	Gli2	8	9	12	13
This revealed that Gli1 , Gli2 and Pifo are induced to different degrees by Shh signaling , whereas Gprasp2 was not ( XREF_FIG ) .	This revealed that Gli1, Gli2 and Pifo are induced to different degrees by Shh signaling, whereas Gprasp2 was not (XREF_FIG).	3	15	induced	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	14	15	5	6
Another example is the edge PTCH1 --> GLI1 , which has a bootstrap frequency of 48 % , suggesting that SHH signaling in Daoy cells in most cases first activates GLI2 and then GLI1 ( because of the highly stable edges PTCH1 --> GLI2 and GLI2 --> GLI1 ) .	Another example is the edge PTCH1 --> GLI1, which has a bootstrap frequency of 48%, suggesting that SHH signaling in Daoy cells in most cases first activates GLI2 and then GLI1 (because of the highly stable edges PTCH1 --> GLI2 and GLI2 --> GLI1).	20	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	GLI2	GLI2	GLI2	20	21	30	31
Indeed , a recent report demonstrated direct binding of Gli2 to HES-1 promoter in retinal progenitor cells treated with Shh .	Indeed, a recent report demonstrated direct binding of Gli2 to HES-1 promoter in retinal progenitor cells treated with Shh.	7	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	19	20	9	10
Different in vitro functions of Gli proteins suggest that Gli2 and Gli3 respond to and are activated by Shh signaling , whereas Gli1 is a transcriptional target of activated Gli2 and Gli3 [ XREF_BIBR , XREF_BIBR ] .	Different in vitro functions of Gli proteins suggest that Gli2 and Gli3 respond to and are activated by Shh signaling, whereas Gli1 is a transcriptional target of activated Gli2 and Gli3 [XREF_BIBR, XREF_BIBR].	9	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	18	19	9	10
While we do not know the mechanistic basis of this amplification , it may rely on the production of more Gli2 which is transcriptionally up-regulated by Shh signaling in fibroblasts [ XREF_BIBR ] .	While we do not know the mechanistic basis of this amplification, it may rely on the production of more Gli2 which is transcriptionally up-regulated by Shh signaling in fibroblasts [XREF_BIBR].	17	27	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	26	27	20	21
Activation of the SHH signaling cascade consistently induces Gli family transcription factors ( Gli1 and Gli2 ) , hence both Gli genes mRNA XREF_BIBR , expressed in pancreatic cancer cell lines and CSCs , stating potential involvement of SHH signaling in human pancreatic carcinogenesis .	Activation of the SHH signaling cascade consistently induces Gli family transcription factors (Gli1 and Gli2), hence both Gli genes mRNA XREF_BIBR, expressed in pancreatic cancer cell lines and CSCs, stating potential involvement of SHH signaling in human pancreatic carcinogenesis.	3	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	Gli2	Gli2	Gli2	3	4	15	16
For example , sonic hedgehog ( Shh ) activation of the transcription factors Gli2 and Gli3 is indispensable for folliculogenesis XREF_BIBR .	For example, sonic hedgehog (Shh) activation of the transcription factors Gli2 and Gli3 is indispensable for folliculogenesis XREF_BIBR.	6	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	6	7	13	14
Generally , the levels of Gli2 protein , but not mRNA , correlated with the levels of Gli2 transcriptional target Gli1 in the cells treated with SU6668 and Shh ( XREF_FIG A a ) .	Generally, the levels of Gli2 protein, but not mRNA, correlated with the levels of Gli2 transcriptional target Gli1 in the cells treated with SU6668 and Shh (XREF_FIG A a).	15	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	28	29	17	18
Finally , chromatin immunoprecipitation ( ChIP ) analysis suggests that Hes1 is a Shh dependent , direct transcriptional target of Gli2 .	Finally, chromatin immunoprecipitation (ChIP) analysis suggests that Hes1 is a Shh dependent, direct transcriptional target of Gli2.	13	21	target	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	13	14	20	21
Conversely , knockout of Bif-1 suppresses Bax and Bak conformational change , cytochrome c release , caspase activation and cell death .	Conversely, knockout of Bif-1 suppresses Bax and Bak conformational change, cytochrome c release, caspase activation and cell death.	2	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Bif-1	Bif-1	Bax	Bax	Bax	4	5	6	7
Bif-1 accelerates Bax conformational change either through a phosphorylation dependent mechanism or by directly binding Bax and enhances the kinetics of apoptosis induction in response to intrinsic apoptotic signals , resulting in an increase in outer mitochondrial membrane permeabilization [ XREF_BIBR ] .	Bif-1 accelerates Bax conformational change either through a phosphorylation dependent mechanism or by directly binding Bax and enhances the kinetics of apoptosis induction in response to intrinsic apoptotic signals, resulting in an increase in outer mitochondrial membrane permeabilization [XREF_BIBR].	0	17	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Bif-1	Bif-1	Bax	Bax	Bax	0	1	2	3
Knockout of Bif-1 suppresses Bax and Bak conformational change , cytochrome c release , caspase activation and cell death .	Knockout of Bif-1 suppresses Bax and Bak conformational change, cytochrome c release, caspase activation and cell death.	0	8	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Bif-1	Bif-1	Bax	Bax	Bax	2	3	4	5
Overexpression of Bif-1 promotes Bax activation and apoptosis , whereas inhibition of Bif-1 expression suppresses Bax and Bak conformational activation , cytochrome c release , caspase activation , and cell death in response to intrinsic apoptosis signals .	Overexpression of Bif-1 promotes Bax activation and apoptosis, whereas inhibition of Bif-1 expression suppresses Bax and Bak conformational activation, cytochrome c release, caspase activation, and cell death in response to intrinsic apoptosis signals.	0	5	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Overexpression of Bif-1	bif-1	Bax	Bax	bax	2	3	4	5
Inhibition of endogenous Bif-1 expression in HeLa cells by RNA interference abrogated the conformational change of Bax and Bak , cytochrome c release , and caspase 3 activation induced by various intrinsic death signals .	Inhibition of endogenous Bif-1 expression in HeLa cells by RNA interference abrogated the conformational change of Bax and Bak, cytochrome c release, and caspase 3 activation induced by various intrinsic death signals.	3	18	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Bif-1 expression	bif-1	Bax	Bax	bax	3	4	16	17
Since loss of Bif-1 not only suppresses Bax and Bak activation and apoptosis but also inhibits PI3KC3 activation and autophagy , it remains to be determined whether the tumor suppressor activity of Bif-1 is due to its pro apoptotic activity , pro autophagic activity , or both .	Since loss of Bif-1 not only suppresses Bax and Bak activation and apoptosis but also inhibits PI3KC3 activation and autophagy, it remains to be determined whether the tumor suppressor activity of Bif-1 is due to its pro apoptotic activity, pro autophagic activity, or both.	1	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bif-1	loss of Bif-1	bif-1	Bax	Bax	bax	3	4	7	8
Bif-1 overexpression promotes Bax activation and apoptosis .	Bif-1 overexpression promotes Bax activation and apoptosis.	0	4	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Bif-1 overexpression	bif-1	Bax	Bax	bax	0	1	3	4
Overexpression of Bif-1 in hematopoietic cells promotes Bax activation and apoptosis following IL-3 withdrawal .	Overexpression of Bif-1 in hematopoietic cells promotes Bax activation and apoptosis following IL-3 withdrawal.	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Overexpression of Bif-1	bif-1	Bax	Bax	bax	2	3	7	8
Overexpression of Bif-1 stimulates BAX and thus stimulates apoptosis .	Overexpression of Bif-1 stimulates BAX and thus stimulates apoptosis.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Overexpression of Bif-1	bif-1	BAX	BAX	bax	2	3	4	5
While Bif-1 over-expression promotes Bax activation and apoptosis , inhibition of Bif-1 expression suppresses Bax dependent apoptosis in response to intrinsic death signals .	While Bif-1 over-expression promotes Bax activation and apoptosis, inhibition of Bif-1 expression suppresses Bax dependent apoptosis in response to intrinsic death signals.	1	5	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Bif-1 over-expression	bif-1	Bax	Bax	bax	1	2	4	5
Loss of Bif-1 suppresses the activation of Bax and mitochondrial apoptosis induced by serum starvation , tunicamycin treatment , and detachment from the extracellular matrix .	Loss of Bif-1 suppresses the activation of Bax and mitochondrial apoptosis induced by serum starvation, tunicamycin treatment, and detachment from the extracellular matrix.	0	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bif-1	Loss of Bif-1	bif-1	Bax	Bax	bax	2	3	7	8
We have shown that knockout of Bif-1 suppresses Bax and Bak conformational change , cytochrome c release , caspase activation and cell death , suggesting that Bif-1 may represent a new type of Bax activator controlling the mitochondrial pathway of apoptosis .	We have shown that knockout of Bif-1 suppresses Bax and Bak conformational change, cytochrome c release, caspase activation and cell death, suggesting that Bif-1 may represent a new type of Bax activator controlling the mitochondrial pathway of apoptosis.	4	12	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Bif-1	Bif-1	Bax	Bax	Bax	6	7	8	9
Overexpression of Bif-1 promotes Bax conformational change , caspase activation , and apoptotic cell death in FL5.12 cells following interleukin-3 deprivation .	Overexpression of Bif-1 promotes Bax conformational change, caspase activation, and apoptotic cell death in FL5.12 cells following interleukin-3 deprivation.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Overexpression of Bif-1	bif-1	Bax	Bax	bax	2	3	4	5
Bif-1 , a member of the endophilin B protein family , activates the conformational change of proapoptotic proteins BAX and BAK and subsequent cytochrome c release and caspase 3 activation during apoptosis [ XREF_BIBR ] .	Bif-1, a member of the endophilin B protein family, activates the conformational change of proapoptotic proteins BAX and BAK and subsequent cytochrome c release and caspase 3 activation during apoptosis [XREF_BIBR].	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Bif-1	Bif-1	BAX	BAX	BAX	0	1	18	19
Similar is true for Bif-1 that has been shown to enhance Bax function .	Similar is true for Bif-1 that has been shown to enhance Bax function.	2	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bif-1	Bif-1	Bif-1	Bax	Bax	Bax	4	5	11	12
Several studies reported that the PI3K and Akt pathway is mediated by the SHH pathway .	Several studies reported that the PI3K and Akt pathway is mediated by the SHH pathway.	5	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	Akt	Akt	Akt	13	14	7	8
In conclusion , SHH pathway may activate PI3K and Akt pathway and inhibit the activation of the ERK pathway in neurons under oxidative stress .	In conclusion, SHH pathway may activate PI3K and Akt pathway and inhibit the activation of the ERK pathway in neurons under oxidative stress.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	Akt	Akt	Akt	3	4	9	10
Young et al XREF_BIBR reported that Shh signaling promotes metastasis and lymphangiogenesis via activation of Akt , the EMT ( epithelial to mesenchymal transition ) , and the MMP-9 pathway in gastric cancer .	Young et al XREF_BIBR reported that Shh signaling promotes metastasis and lymphangiogenesis via activation of Akt, the EMT (epithelial to mesenchymal transition), and the MMP-9 pathway in gastric cancer.	6	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Akt	Akt	Akt	6	7	15	16
These findings suggest that Shh enhances autophagy of vascular SMCs by engaging AKT activation , thus indicating a crucial role of autophagy in Shh induced cellular effects [ XREF_BIBR ] .	These findings suggest that Shh enhances autophagy of vascular SMCs by engaging AKT activation, thus indicating a crucial role of autophagy in Shh induced cellular effects [XREF_BIBR].	4	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	AKT	AKT	AKT	4	5	12	13
These results indicate that inflammatory response may inhibit the PI3K and Akt signaling while the SHH pathway may activate the PI3K and Akt signaling in vitro and in vivo .	These results indicate that inflammatory response may inhibit the PI3K and Akt signaling while the SHH pathway may activate the PI3K and Akt signaling in vitro and in vivo.	15	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	Akt	Akt	Akt	15	16	22	23
Shh has been shown to activate the ERK1/2 XREF_BIBR , PKC XREF_BIBR , ROCK XREF_BIBR , and PI3K and Akt XREF_BIBR signaling pathways , among others .	Shh has been shown to activate the ERK1/2 XREF_BIBR, PKC XREF_BIBR, ROCK XREF_BIBR, and PI3K and Akt XREF_BIBR signaling pathways, among others.	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Akt	Akt	Akt	0	1	19	20
The PI3K and Akt pathway is activated by Shh in ECs , but is not involved in Shh induced Gli1 nuclear translocation [ XREF_BIBR ] .	The PI3K and Akt pathway is activated by Shh in ECs, but is not involved in Shh induced Gli1 nuclear translocation [XREF_BIBR].	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Akt	Akt	Akt	8	9	3	4
These treatments did not affect the expression of SHH or of the WNT-TCF signature ( XREF_FIG ) , supporting the specific requirement of endogenous MEK and AKT signalling downstream of oncogenic RAS for endogenous GLI1 function in CCs .	These treatments did not affect the expression of SHH or of the WNT-TCF signature (XREF_FIG), supporting the specific requirement of endogenous MEK and AKT signalling downstream of oncogenic RAS for endogenous GLI1 function in CCs.	4	27	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	AKT	AKT	AKT	8	9	26	27
SHH signaling pathway activates the PI3K and Akt signaling pathway .	SHH signaling pathway activates the PI3K and Akt signaling pathway.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	Akt	Akt	Akt	0	1	7	8
In addition to the identification of Gfra1 as a novel modulator of Ras and MAPK , PI3K and Akt signaling in thyroid carcinogenesis of Thrb PV/PV mice , we also detected the highly activated expression of Shh ( sonic hedgehog ) that could also function to modulate the PI3K and Akt and Wnt and beta-catenin pathways .	In addition to the identification of Gfra1 as a novel modulator of Ras and MAPK, PI3K and Akt signaling in thyroid carcinogenesis of Thrb PV/PV mice, we also detected the highly activated expression of Shh (sonic hedgehog) that could also function to modulate the PI3K and Akt and Wnt and beta-catenin pathways.	34	51	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	expression of Shh	shh	Akt	Akt	akt	36	37	50	51
Hence although application of Shh activates Akt , PI3Kgamma is not required for the accelerated wound healing response to exogenous Shh .	Hence although application of Shh activates Akt, PI3Kgamma is not required for the accelerated wound healing response to exogenous Shh.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Akt	Akt	Akt	4	5	6	7
It is reasonable to consider whether these Shh induced , ROCK mediated effects support the function of other nearby cells , such as EPCs , smooth muscle cells [ XREF_BIBR - XREF_BIBR ] , and muscle derived progenitor cells [ XREF_BIBR ] , and whether Shh activation of the PI3K and Akt pathway , reported in ECs [ XREF_BIBR ] , EPCs [ XREF_BIBR ] , and fibroblasts [ XREF_BIBR ] in vitro , may also induce favorable effects .	It is reasonable to consider whether these Shh induced, ROCK mediated effects support the function of other nearby cells, such as EPCs, smooth muscle cells [XREF_BIBR - XREF_BIBR], and muscle derived progenitor cells [XREF_BIBR], and whether Shh activation of the PI3K and Akt pathway, reported in ECs [XREF_BIBR], EPCs [XREF_BIBR], and fibroblasts [XREF_BIBR] in vitro, may also induce favorable effects.	45	52	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	Akt	Akt	Akt	45	46	51	52
Interestingly , blockade of Shh cascade by cyclopamine suppressed the MPs Shh+ -induced activation of eNOS , but not that of Akt .	Interestingly, blockade of Shh cascade by cyclopamine suppressed the MPs Shh+ -induced activation of eNOS, but not that of Akt.	4	22	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Akt	Akt	Akt	4	5	21	22
Akt activators such as Kras , Shh , EGFR and PTEN have been implicated in PDA XREF_BIBR - XREF_BIBR .	Akt activators such as Kras, Shh, EGFR and PTEN have been implicated in PDA XREF_BIBR - XREF_BIBR.	0	7	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Shh	Shh	Shh	Akt	Akt	Akt	6	7	0	1
It was shown previously that Shh peptide can induce PI3K dependent activation of Akt [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It was shown previously that Shh peptide can induce PI3K dependent activation of Akt [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Akt	Akt	Akt	5	6	13	14
In this study , we report that SENP1 increases the stabilisation and transcriptional activity of HIF-1alpha in hypoxia via deSUMOylation in HCC .	In this study, we report that SENP1 increases the stabilisation and transcriptional activity of HIF-1alpha in hypoxia via deSUMOylation in HCC.	7	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP1	SENP1	SENP1	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	15	16
Transgenic overexpression of SENP1 in the mouse prostate gland increases HIF-1alpha , VEGF , and angiogenesis XREF_BIBR .	Transgenic overexpression of SENP1 in the mouse prostate gland increases HIF-1alpha, VEGF, and angiogenesis XREF_BIBR.	1	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP1	overexpression of SENP1	senp1	HIF-1alpha	HIF-1alpha	hif-1alpha	3	4	10	11
XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR With regard to deSUMOylation , here , we show that SENP1 increased the stability and transcriptional activity of HIF-1alpha by deSUMOylation at K391 or K477 residues of HIF-1alpha in HCC cells .	XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR With regard to deSUMOylation, here, we show that SENP1 increased the stability and transcriptional activity of HIF-1alpha by deSUMOylation at K391 or K477 residues of HIF-1alpha in HCC cells.	16	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP1	SENP1	SENP1	HIF-1alpha	HIF-1alpha	HIF-1alpha	16	17	24	25
Also , SENP1 overexpression initiates the HIF1alpha pathway in the prostates of transgenic mice as indicated by the elevation of HIF1 regulated VEGF protein levels at low-grade PIN ( 4 months of age ) and even more dramatic VEGF elevation at 12 months of age , when the SENP1 transgenic mice concurrently exhibit an increase in microvessel density [ XREF_BIBR ] .	Also, SENP1 overexpression initiates the HIF1alpha pathway in the prostates of transgenic mice as indicated by the elevation of HIF1 regulated VEGF protein levels at low-grade PIN (4 months of age) and even more dramatic VEGF elevation at 12 months of age, when the SENP1 transgenic mice concurrently exhibit an increase in microvessel density [XREF_BIBR].	2	7	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP1	SENP1 overexpression	senp1	HIF1alpha	HIF1alpha	hif1alpha	2	3	6	7
SENP1 positively regulated HIF-1alpha in SKOV3 cells .	SENP1 positively regulated HIF-1alpha in SKOV3 cells.	0	6	positively regulated	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	SENP1	SENP1	SENP1	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	3	4
SENP1 knockdown did not affect the non sumoylated pool of HIF-2alpha but did decrease the total pool of HIF-1alpha , consistent with the results published by Cheng et al ..	SENP1 knockdown did not affect the non sumoylated pool of HIF-2alpha but did decrease the total pool of HIF-1alpha, consistent with the results published by Cheng et al..	0	19	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP1	SENP1	SENP1	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	18	19
Altogether , these results suggest that under hypoxia , SENP1 increases the stability and transcriptional activity of HIF-1alpha in a SENPs dependent manner .	Altogether, these results suggest that under hypoxia, SENP1 increases the stability and transcriptional activity of HIF-1alpha in a SENPs dependent manner.	9	22	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP1	SENP1	SENP1	HIF-1alpha	HIF-1alpha	HIF-1alpha	9	10	17	18
SENP1 enhances HIF1alpha stability through de-SUMOylation .	SENP1 enhances HIF1alpha stability through de-SUMOylation.	0	3	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP1	SENP1	SENP1	HIF1alpha	HIF1alpha	HIF1alpha	0	1	2	3
Conversely , SUMO specific protease 1 ( SENP-1 ) was able to increase the stability of HIF-1alpha by decreasing SUMOylation of HIF-1alpha .	Conversely, SUMO specific protease 1 (SENP-1) was able to increase the stability of HIF-1alpha by decreasing SUMOylation of HIF-1alpha.	4	17	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP-1	SENP-1	SENP-1	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	16	17
SENP1 enhances the stability and transcriptional activity of HIF-1alpha through deSUMOylation .	SENP1 enhances the stability and transcriptional activity of HIF-1alpha through deSUMOylation.	0	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP1	SENP1	SENP1	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	8	9
In this study , our results show that SENP1 increases the stabilisation and transcriptional activity of HIF-1alpha under hypoxic condition via deSUMOylation .	In this study, our results show that SENP1 increases the stabilisation and transcriptional activity of HIF-1alpha under hypoxic condition via deSUMOylation.	8	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP1	SENP1	SENP1	HIF-1alpha	HIF-1alpha	HIF-1alpha	8	9	16	17
Moreover , how SENP1 modulates HIF-1alpha affecting cancer stemness is unknown .	Moreover, how SENP1 modulates HIF-1alpha affecting cancer stemness is unknown.	3	6	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SENP1	SENP1	SENP1	HIF-1alpha	HIF-1alpha	HIF-1alpha	3	4	5	6
SENP1 is a direct target of HIF-1alpha and HIF-2alpha .	SENP1 is a direct target of HIF-1alpha and HIF-2alpha.	0	8	is a direct target	Positive_activation_copula_1	Positive_activation	Positive_activation	SENP1	SENP1	SENP1	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	6	7
SH2-B is also an activator of JAK2 in response to growth hormone , whereas APS appears to be a negative regulator of JAK2 after erythropoietin ( EPO ) stimulation and inhibits platelet derived growth factor induced mitogenesis .	SH2-B is also an activator of JAK2 in response to growth hormone, whereas APS appears to be a negative regulator of JAK2 after erythropoietin (EPO) stimulation and inhibits platelet derived growth factor induced mitogenesis.	0	8	is also an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	SH2-B	SH2-B	SH2-B	JAK2	JAK2	JAK2	0	1	6	7
These proteins and pathways include : 1 ) Stat transcription factors implicated in the expression of multiple genes , including the gene encoding insulin like growth factor 1 ; 2 ) Shc adapter proteins that lead to activation of the grb2-SOS-Ras-Raf-MEK-ERK1 ,2 pathway ; 3 ) insulin receptor substrate proteins implicated in the phosphatidylinositol-3-kinase and Akt pathway ; 4 ) signal regulatory protein alpha , a transmembrane scaffold protein that recruits proteins including the tyrosine phosphatase SHP2 ; and 5 ) SH2B1 , a scaffold protein that can activate JAK2 and enhance GH regulation of the actin cytoskeleton .	These proteins and pathways include : 1) Stat transcription factors implicated in the expression of multiple genes, including the gene encoding insulin like growth factor 1; 2) Shc adapter proteins that lead to activation of the grb2-SOS-Ras-Raf-MEK-ERK1,2 pathway; 3) insulin receptor substrate proteins implicated in the phosphatidylinositol-3-kinase and Akt pathway; 4) signal regulatory protein alpha, a transmembrane scaffold protein that recruits proteins including the tyrosine phosphatase SHP2; and 5) SH2B1, a scaffold protein that can activate JAK2 and enhance GH regulation of the actin cytoskeleton.	14	90	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	SH2B1	SH2B1	SH2B1	JAK2	JAK2	JAK2	81	82	89	90
SH2B1 enhances leptin signaling by binding to and activating JAK2 .	SH2B1 enhances leptin signaling by binding to and activating JAK2.	0	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SH2B1	SH2B1	SH2B1	JAK2	JAK2	JAK2	0	1	9	10
SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/IRS1/2 signaling complex .	SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/IRS1/2 signaling complex.	0	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SH2B1	SH2B1	SH2B1	JAK2	JAK2	JAK2	0	1	7	8
Binding of the SH2 domain of SH2B1 to phospho-Tyr ( 813 ) in JAK2 enhanced leptin induction of JAK2 activity .	Binding of the SH2 domain of SH2B1 to phospho-Tyr (813) in JAK2 enhanced leptin induction of JAK2 activity.	4	19	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SH2B1	SH2B1	SH2B1	JAK2	JAK2	JAK2	6	7	18	19
These data suggest that the SH2B1 in beta-cells promotes insulin synthesis and secretion at least in part by enhancing activation of JAK2 and/or Pdx1 pathways in response to hormonal and nutritional signals .	These data suggest that the SH2B1 in beta-cells promotes insulin synthesis and secretion at least in part by enhancing activation of JAK2 and/or Pdx1 pathways in response to hormonal and nutritional signals.	4	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SH2B1	SH2B1	SH2B1	JAK2	JAK2	JAK2	5	6	21	22
SH2B1 directly enhances growth hormone signaling and promotes activation of both the JAK2 and STAT and the PI 3-kinase pathways in cultured cells XREF_BIBR , XREF_BIBR , XREF_BIBR .	SH2B1 directly enhances growth hormone signaling and promotes activation of both the JAK2 and STAT and the PI 3-kinase pathways in cultured cells XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SH2B1	SH2B1	SH2B1	JAK2	JAK2	JAK2	0	1	12	13
The SH2B adaptor protein 1 ( SH2B1 ) activates the JAK2 cytoplasmic tyrosine kinase to mediate cell signaling .	The SH2B adaptor protein 1 (SH2B1) activates the JAK2 cytoplasmic tyrosine kinase to mediate cell signaling.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SH2B1	SH2B1	SH2B1	JAK2	JAK2	JAK2	6	7	10	11
SHC1 could therefore contribute the activation of MAPK and/or the activation of the PI3K-Akt pathway in these tumors .	SHC1 could therefore contribute the activation of MAPK and/or the activation of the PI3K-Akt pathway in these tumors.	0	8	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHC1	SHC1	SHC1	MAPK	MAPK	MAPK	0	1	7	8
Recruitment of GIV ' s SH2 like domain to EGFR suppresses and terminates Shc1 mediated MAPK and ERK activation and antagonizes SHP-1-mediated receptor dephosphorylation while simultaneously triggering two other pathways in parallel -- 1 ) GIV ' s GEF function links G protein activation to ligand activated receptor , and 2 ) EGFR phosphorylates GIV on tyrosines that help recruit and activate PI3K , thereby triggering the activation of Akt kinase .	Recruitment of GIV 's SH2 like domain to EGFR suppresses and terminates Shc1 mediated MAPK and ERK activation and antagonizes SHP-1-mediated receptor dephosphorylation while simultaneously triggering two other pathways in parallel -- 1) GIV 's GEF function links G protein activation to ligand activated receptor, and 2) EGFR phosphorylates GIV on tyrosines that help recruit and activate PI3K, thereby triggering the activation of Akt kinase.	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Shc1	Shc1	Shc1	MAPK	MAPK	MAPK	13	14	15	16
SHcA 42 and SHcA 56 activate p44/42 mapk leading to increased release of vasoconstrictors , such as ET-1 .	SHcA 42 and SHcA 56 activate p44/42 mapk leading to increased release of vasoconstrictors, such as ET-1.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHcA	SHcA	SHcA	mapk	mapk	mapk	0	1	7	8
Both SHC1 phosphorylation and C. trachomatis infection have been shown to activate the MEK and ERK cascade ; however , C. trachomatis induced MEK and ERK activation has mainly been demonstrated at later infection time points , e.g ., from 12 h pi .	Both SHC1 phosphorylation and C. trachomatis infection have been shown to activate the MEK and ERK cascade; however, C. trachomatis induced MEK and ERK activation has mainly been demonstrated at later infection time points, e.g., from 12 h pi.	1	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SHC1	SHC1 phosphorylation	shc1	ERK	ERK	erk	1	2	15	16
In response to TGF-beta , TGF-beta type I receptor mediates tyrosine phosphorylation of ShcA , which then recruits Grb2 and Sos , to form a complex , initiating Ras activation and consequently ERK and MAPK signaling cascade .	In response to TGF-beta, TGF-beta type I receptor mediates tyrosine phosphorylation of ShcA, which then recruits Grb2 and Sos, to form a complex, initiating Ras activation and consequently ERK and MAPK signaling cascade.	5	36	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ShcA	TGF-beta type I receptor mediates tyrosine phosphorylation of ShcA	shca	MAPK	MAPK	mapk	13	14	34	35
In contrast , the adaptor protein ShcA ( also known as Shc1 ) can sequester TbetaRI in caveolin-1-positive compartments and promote Erk and Akt signaling while attenuating Smad3 signaling .	In contrast, the adaptor protein ShcA (also known as Shc1) can sequester TbetaRI in caveolin-1-positive compartments and promote Erk and Akt signaling while attenuating Smad3 signaling.	3	24	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ShcA	ShcA	ShcA	Erk	Erk	Erk	6	7	21	22
ShcA knockdown abolished CSR induced activation of both Erk and the uPA promoter .	ShcA knockdown abolished CSR induced activation of both Erk and the uPA promoter.	0	12	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ShcA	ShcA	ShcA	Erk	Erk	Erk	0	1	8	9
Myf5 , and not MyoD , is the target of Shh signaling in the epaxial dermomyotome , as MyoD activation by recombinant Shh protein in presomitic mesoderm explants is defective in Myf5 null embryos .	Myf5, and not MyoD, is the target of Shh signaling in the epaxial dermomyotome, as MyoD activation by recombinant Shh protein in presomitic mesoderm explants is defective in Myf5 null embryos.	18	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	MyoD	MyoD	MyoD	22	23	18	19
It is possible , but unproven that Shh induction of MyoD in these normal cells and in proliferating Shh induced medulloblastoma cells is part of an onco-fetal development program that is aberrantly activated in medulloblastoma .	It is possible, but unproven that Shh induction of MyoD in these normal cells and in proliferating Shh induced medulloblastoma cells is part of an onco-fetal development program that is aberrantly activated in medulloblastoma.	7	18	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	MyoD	MyoD	MyoD	7	8	10	11
Recent data suggests that Hedgehog signaling plays a unique role in adult myogenesis because inhibition of Shh via cyclopamine impaired the activation of Myf5 and MyoD in skeletal muscle progenitors and led to a reduction in the number of activated satellite cells and myoblasts following injury in vivo .	Recent data suggests that Hedgehog signaling plays a unique role in adult myogenesis because inhibition of Shh via cyclopamine impaired the activation of Myf5 and MyoD in skeletal muscle progenitors and led to a reduction in the number of activated satellite cells and myoblasts following injury in vivo.	14	26	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	MyoD	MyoD	MyoD	16	17	25	26
Inhibition of Shh signalling significantly impaired the up-regulation of Myf5 and MyoD after injury ( XREF_FIG ) .	Inhibition of Shh signalling significantly impaired the up-regulation of Myf5 and MyoD after injury (XREF_FIG).	2	12	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	MyoD	MyoD	MyoD	2	3	11	12
This is also supported by the evidence that Shh inhibition reduces the number of activated satellite cells at the damage site , impairs the up-regulation of Myf5 and MyoD that physiologically occurs in regenerating muscles , and increases muscle fibrosis .	This is also supported by the evidence that Shh inhibition reduces the number of activated satellite cells at the damage site, impairs the up-regulation of Myf5 and MyoD that physiologically occurs in regenerating muscles, and increases muscle fibrosis.	8	29	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	MyoD	MyoD	MyoD	8	9	28	29
This depends on the early epaxial activation of Myf5 , which is driven by Wnt and Shh signaling , without any Pax3 and/or Pax7 requirement .	This depends on the early epaxial activation of Myf5, which is driven by Wnt and Shh signaling, without any Pax3 and/or Pax7 requirement.	6	17	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Shh	Shh	Shh	Myf5	Myf5	Myf5	16	17	8	9
Subsequently , Shh and Wnt signaling lead to specification and expression of Myf5 .	Subsequently, Shh and Wnt signaling lead to specification and expression of Myf5.	2	13	lead	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	Myf5	Myf5	Myf5	2	3	12	13
In previous studies , we showed that Shh signalling , via an essential Gli binding site in the Myf5 epaxial somite ( ES ) enhancer , is required for the specification of epaxial muscle progenitor cells .	In previous studies, we showed that Shh signalling, via an essential Gli binding site in the Myf5 epaxial somite (ES) enhancer, is required for the specification of epaxial muscle progenitor cells.	7	20	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Shh	Shh	Shh	Myf5	Myf5	Myf5	7	8	18	19
For example , SGK1 activates glucose transporters SGLT1 , GLUT1 , and GLUT4 via phosphorylation and by targeting them to the plasma membrane .	For example, SGK1 activates glucose transporters SGLT1, GLUT1, and GLUT4 via phosphorylation and by targeting them to the plasma membrane.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SGK1	SGK1	SGK1	GLUT4	GLUT4	GLUT4	3	4	12	13
Remarkably , suppression of synthesis of SEPT7 by small interfering RNA abrogated the localization of CENP-E to the kinetochore and caused aberrant chromosome segregation .	Remarkably, suppression of synthesis of SEPT7 by small interfering RNA abrogated the localization of CENP-E to the kinetochore and caused aberrant chromosome segregation.	4	16	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SEPT7	SEPT7	SEPT7	CENP-E	CENP-E	CENP-E	6	7	15	16
SEPT7 has been shown to mediate the localization of CENP-E to kinetochores , which is important for proper chromosome segregation .	SEPT7 has been shown to mediate the localization of CENP-E to kinetochores, which is important for proper chromosome segregation.	0	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SEPT7	SEPT7	SEPT7	CENP-E	CENP-E	CENP-E	0	1	9	10
Mechanistically , CREB regulates the expression of Glut3 and Siah2 , the latter and LDH activity promoting the normoxic stabilization of HIF-1alpha that regulates the expression of rate limiting genes of glycolysis .	Mechanistically, CREB regulates the expression of Glut3 and Siah2, the latter and LDH activity promoting the normoxic stabilization of HIF-1alpha that regulates the expression of rate limiting genes of glycolysis.	5	22	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Siah2	expression of Glut3 and Siah2	siah2	HIF-1alpha	HIF-1alpha	hif-1alpha	9	10	21	22
Siah2 increases stability of HIF-1alpha through degradation of negative HIF-1alpha regulators .	Siah2 increases stability of HIF-1alpha through degradation of negative HIF-1alpha regulators.	0	5	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Siah2	Siah2	Siah2	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	4	5
Normally activation of plexinC1 by Sema7A leads to phosphorylation of cofilin , while binding of Sema7A to beta1-integrins triggers their phosphorylation XREF_BIBR XREF_BIBR .	Normally activation of plexinC1 by Sema7A leads to phosphorylation of cofilin, while binding of Sema7A to beta1-integrins triggers their phosphorylation XREF_BIBR XREF_BIBR.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Sema7A	Sema7A	Sema7A	plexinC1	plexinC1	plexinC1	5	6	3	4
For example , Siah1 , which belongs to the E3 ubiquitin ligase complex , is known to promote degradation of Numb , and thereby leads to activation of Notch XREF_BIBR - XREF_BIBR .	For example, Siah1, which belongs to the E3 ubiquitin ligase complex, is known to promote degradation of Numb, and thereby leads to activation of Notch XREF_BIBR - XREF_BIBR.	3	29	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Siah1	Siah1	Siah1	Notch	Notch	Notch	3	4	28	29
ShcA proteins mediate Erk1 and Erk2 activation by integrins and epidermal growth factor ( EGF ) , and are expressed as p46ShcA , p52ShcA , and p66ShcA .	ShcA proteins mediate Erk1 and Erk2 activation by integrins and epidermal growth factor (EGF), and are expressed as p46ShcA, p52ShcA, and p66ShcA.	0	6	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ShcA	ShcA	ShcA	Erk2	Erk2	Erk2	0	1	5	6
SETBP1 overexpression is believed to promote leukemogenesis by enhancing full length SET protein and then impairing the phosphatise activity of the tumor suppressor PP2A through the formation of a SETBP1 , SET , and PP2A complex [ XREF_BIBR ] .	SETBP1 overexpression is believed to promote leukemogenesis by enhancing full length SET protein and then impairing the phosphatise activity of the tumor suppressor PP2A through the formation of a SETBP1, SET, and PP2A complex [XREF_BIBR].	0	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SETBP1	SETBP1 overexpression	setbp1	SET	SET	set	0	1	11	12
Specifically , POSH promotes assembly of a complex including Rac GTPase , mixed lineage kinase ( MLK ) , MKK7 , and Jun kinase ( JNK ) .	Specifically, POSH promotes assembly of a complex including Rac GTPase, mixed lineage kinase (MLK), MKK7, and Jun kinase (JNK).	2	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	POSH	POSH	POSH	MKK7	MKK7	MKK7	2	3	19	20
In particular , how does phospho-CIN85 activate cbl ?	In particular, how does phospho-CIN85 activate cbl?	5	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	phospho-CIN85	phospho-CIN85	phospho-CIN85	cbl	cbl	cbl	5	6	7	8
As the Shoc2 signaling partners M-Ras and Raf-1 interact with the N-terminal domain of Shoc2 , we reasoned that the mechanism underlying the ability of Shoc2 to accelerate activation of the ERK1/2 pathway may be supported by this region of Shoc2 .	As the Shoc2 signaling partners M-Ras and Raf-1 interact with the N-terminal domain of Shoc2, we reasoned that the mechanism underlying the ability of Shoc2 to accelerate activation of the ERK1/2 pathway may be supported by this region of Shoc2.	1	8	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Shoc2	Shoc2	Shoc2	M-Ras	M-Ras	M-Ras	2	3	5	6
Most importantly , POSH mediated JNK1 and JNK2 activation is necessary for cell survival and plays a critical role in directing T H 1 differentiation .	Most importantly, POSH mediated JNK1 and JNK2 activation is necessary for cell survival and plays a critical role in directing T H 1 differentiation.	3	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	POSH	POSH	POSH	JNK1	JNK1	JNK1	3	4	5	6
In parallel , autophagy positive regulators such as AMBRA1 and BIF-1 promote BECLIN1 association to hVPS34 [ XREF_BIBR - XREF_BIBR ] .	In parallel, autophagy positive regulators such as AMBRA1 and BIF-1 promote BECLIN1 association to hVPS34 [XREF_BIBR - XREF_BIBR].	5	13	promote	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BIF-1	BIF-1	BIF-1	BECLIN1	BECLIN1	BECLIN1	10	11	12	13
SIRT1 then activates PGC-1alpha by deacetylation [ XREF_BIBR ] .	SIRT1 then activates PGC-1alpha by deacetylation [XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	3	4
SIRT-1 activation by resveratrol increases survival of motor neurons from transgenic ALS mice and reduces learning impairment and neurodegeneration in AD mouse models by decreasing the acetylation of SIRT1 substrates PGC-1alpha and p53 XREF_BIBR .	SIRT-1 activation by resveratrol increases survival of motor neurons from transgenic ALS mice and reduces learning impairment and neurodegeneration in AD mouse models by decreasing the acetylation of SIRT1 substrates PGC-1alpha and p53 XREF_BIBR.	0	33	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT-1	SIRT-1	SIRT-1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	30	31
In particular , SIRT1 activates PGC-1alpha by deacetylation of lysine residues , thereby enhancing mitochondrial biogenesis 15 .	In particular, SIRT1 activates PGC-1alpha by deacetylation of lysine residues, thereby enhancing mitochondrial biogenesis 15.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	3	4	5	6
While SIRT1 increases transcriptional activity of the coactivator PGC-1alpha by deacetylation , it is not known whether PPARalpha is also a direct target of SIRT1 deacetylation during fasting ( XREF_FIG ) .	While SIRT1 increases transcriptional activity of the coactivator PGC-1alpha by deacetylation, it is not known whether PPARalpha is also a direct target of SIRT1 deacetylation during fasting (XREF_FIG).	1	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	1	2	8	9
Sirt1 activates Akt1 and PGC-1alpha among other pathways and protects mice against cardiac ischemia and reperfusion injury , while Sirt3 protects against cardiac oxidative stress in a Foxo3a dependent manner , regulates cardiomyocyte metabolism through activation of AMPK and PGC-1alpha , and causes resistance to angiotensin-II driven cardiac hypertrophy and fibrosis .	Sirt1 activates Akt1 and PGC-1alpha among other pathways and protects mice against cardiac ischemia and reperfusion injury, while Sirt3 protects against cardiac oxidative stress in a Foxo3a dependent manner, regulates cardiomyocyte metabolism through activation of AMPK and PGC-1alpha, and causes resistance to angiotensin-II driven cardiac hypertrophy and fibrosis.	0	42	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	4	5
By deacetylating and thus activating PGC-1alpha , FOXO-1 and LXR , SIRT1 induces gluconeogenesis and fatty acid beta oxidation ; these actions are physiologically relevant as demonstrated by the fact that liver specific deletion ( or downregulation ) of SIRT1 causes hypoglycemia and hypersensitivity to diet induced hepatic steatosis [ XREF_BIBR - XREF_BIBR ] .	By deacetylating and thus activating PGC-1alpha, FOXO-1 and LXR, SIRT1 induces gluconeogenesis and fatty acid beta oxidation; these actions are physiologically relevant as demonstrated by the fact that liver specific deletion (or downregulation) of SIRT1 causes hypoglycemia and hypersensitivity to diet induced hepatic steatosis [XREF_BIBR - XREF_BIBR].	4	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	11	12	5	6
The deacetylase Sirtuin-1 ( SIRT1 ) can activate PGC-1alpha by means of protein deacetylation as shown in different cell types .	The deacetylase Sirtuin-1 (SIRT1) can activate PGC-1alpha by means of protein deacetylation as shown in different cell types.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	8	9
Sirt1 mediated PGC-1alpha activation could directly respond to H 2 O 2 -induced oxidative stress on the regulation of glutathione GPx1 , CAT , and Mn-SOD [ XREF_BIBR ] .	Sirt1 mediated PGC-1alpha activation could directly respond to H 2 O 2 -induced oxidative stress on the regulation of glutathione GPx1, CAT, and Mn-SOD [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	2	3
Interestingly , this SIRT1 mediated PGC-1alpha activation requires phosphorylation of PGC-1alpha by AMPK .	Interestingly, this SIRT1 mediated PGC-1alpha activation requires phosphorylation of PGC-1alpha by AMPK.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	3	4	5	6
SIRT1 activates PGC1alpha through deacetylation and promotes the transcription of target genes involved in mitochondrial biogenesis .	SIRT1 activates PGC1alpha through deacetylation and promotes the transcription of target genes involved in mitochondrial biogenesis.	0	6	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	0	1	2	3
There are several studies demonstrating that SIRT1 can enhance PGC-1alpha activation and make it act as a substrate of deacetylation [ XREF_BIBR , XREF_BIBR ] .	There are several studies demonstrating that SIRT1 can enhance PGC-1alpha activation and make it act as a substrate of deacetylation [XREF_BIBR, XREF_BIBR].	6	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	6	7	9	10
SIRT1 also activates PGC1alpha which results in mitochondriogenesis [ XREF_BIBR ] .	SIRT1 also activates PGC1alpha which results in mitochondriogenesis [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	0	1	3	4
Mechanistically , chemotherapy induced DNA damage results in increased expression of SIRT1 , which deacetylates and thereby activates PGC1alpha as a transcriptional coactivator .	Mechanistically, chemotherapy induced DNA damage results in increased expression of SIRT1, which deacetylates and thereby activates PGC1alpha as a transcriptional coactivator.	9	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	expression of SIRT1	sirt1	PGC1alpha	PGC1alpha	pgc1alpha	11	12	18	19
A number of studies have shown that SIRT1 deacetylates and positively regulates PGC-1alpha in cell culture systems and under fasting or exercise conditions in vivo XREF_BIBR , XREF_BIBR , XREF_BIBR .	A number of studies have shown that SIRT1 deacetylates and positively regulates PGC-1alpha in cell culture systems and under fasting or exercise conditions in vivo XREF_BIBR, XREF_BIBR, XREF_BIBR.	7	13	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	7	8	12	13
AMPK and SIRT1 , the two main metabolic sensors in cells , directly modulate PGC-1alpha activity through phosphorylation and deacetylation ( Nemoto etal .	AMPK and SIRT1, the two main metabolic sensors in cells, directly modulate PGC-1alpha activity through phosphorylation and deacetylation (Nemoto etal.	0	15	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	14	15
Since PGC-1alpha is activated by AMPK and SIRT1 , nutritional ketosis may initiate PGC-1alpha activity through these enzymes .	Since PGC-1alpha is activated by AMPK and SIRT1, nutritional ketosis may initiate PGC-1alpha activity through these enzymes.	1	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	7	8	1	2
SIRT1 also can modulate the PGC-1alpha repressing effect on glycolytic genes in response to fasting and pyruvate [ XREF_BIBR ] .	SIRT1 also can modulate the PGC-1alpha repressing effect on glycolytic genes in response to fasting and pyruvate [XREF_BIBR].	0	6	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	5	6
Both SIRT1 and AMPK are upstream regulators of PGC-1alpha , and directly activate PGC-1alpha by deacetylation and phosphorylation , respectively .	Both SIRT1 and AMPK are upstream regulators of PGC-1alpha, and directly activate PGC-1alpha by deacetylation and phosphorylation, respectively.	0	14	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	1	2	13	14
Because SIRT1 upregulates PGC-1alpha , this may be a compensatory mechanism to prevent mitochondrial depletion in the absence of SIRT2 .	Because SIRT1 upregulates PGC-1alpha, this may be a compensatory mechanism to prevent mitochondrial depletion in the absence of SIRT2.	1	4	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	1	2	3	4
XREF_BIBR Importantly , PGC1alpha is deacetylated and activated in mice treated with the putative Sirt1 activator Resveratrol in parallel with a substantial increase in oxygen consumption and improvement of the dysmetabolic phenotype under high-fat diet .	XREF_BIBR Importantly, PGC1alpha is deacetylated and activated in mice treated with the putative Sirt1 activator Resveratrol in parallel with a substantial increase in oxygen consumption and improvement of the dysmetabolic phenotype under high-fat diet.	3	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC1alpha	PGC1alpha	PGC1alpha	14	15	3	4
Sirtuins are essential parts within nuclear-mitochondrial communication , where SIRT1 -- located in the nucleus -- de-acetylates and activates PGC-1alpha and FOX03a , and also indirectly activates AMPK by de-acetylation and activation of the AMPK activating protein kinase LKB1 .	Sirtuins are essential parts within nuclear-mitochondrial communication, where SIRT1 -- located in the nucleus -- de-acetylates and activates PGC-1alpha and FOX03a, and also indirectly activates AMPK by de-acetylation and activation of the AMPK activating protein kinase LKB1.	9	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	9	10	19	20
However , they only could show in an MCF-7 cell line ( Breast cancer cells ) that the reduction of Sirt1 involved reduced PGC1alpha and , subsequently , reduced NRF2 and enhanced susceptibility to oxidative stress [ XREF_BIBR ] .	However, they only could show in an MCF-7 cell line (Breast cancer cells) that the reduction of Sirt1 involved reduced PGC1alpha and, subsequently, reduced NRF2 and enhanced susceptibility to oxidative stress [XREF_BIBR].	18	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC1alpha	PGC1alpha	PGC1alpha	20	21	23	24
Animal and in vivo studies indicate that resveratrol increases SIRT1 expression that stimulates PGC1alpha activity .	Animal and in vivo studies indicate that resveratrol increases SIRT1 expression that stimulates PGC1alpha activity.	7	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	resveratrol increases SIRT1 expression	sirt1	PGC1alpha	PGC1alpha	pgc1alpha	9	10	13	14
However , proofs for critical regulation of SIRT1 on oxidative stress , especially how SIRT1 directly regulates FOXOs and PGC-1alpha and their downstream antioxidant genes in fatty liver diseases still need further investigation .	However, proofs for critical regulation of SIRT1 on oxidative stress, especially how SIRT1 directly regulates FOXOs and PGC-1alpha and their downstream antioxidant genes in fatty liver diseases still need further investigation.	14	20	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	14	15	19	20
It has been shown that SIRT1 activates PGC-1alpha primarily by its deacetylation [ XREF_BIBR ] .	It has been shown that SIRT1 activates PGC-1alpha primarily by its deacetylation [XREF_BIBR].	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	7	8
Also , SIRT1 potentiates the activity of PPAR-alpha and PGC-1alpha , leading to increased lipolysis and fat loss in mature adipocytes [ XREF_BIBR ] .	Also, SIRT1 potentiates the activity of PPAR-alpha and PGC-1alpha, leading to increased lipolysis and fat loss in mature adipocytes [XREF_BIBR].	2	10	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	9	10
Thus , SIRT1 activates PGC1alpha by deacetylation while HAT inactivates PGC1alpha by acetylation .	Thus, SIRT1 activates PGC1alpha by deacetylation while HAT inactivates PGC1alpha by acetylation.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	2	3	4	5
Results demonstrate also that overexpression of SIRT1 deacetylase or suppression of GCN5 acetyltransferase activates transcriptional activity of PGC-1alpha in neurons and increases mitochondrial density .	Results demonstrate also that overexpression of SIRT1 deacetylase or suppression of GCN5 acetyltransferase activates transcriptional activity of PGC-1alpha in neurons and increases mitochondrial density.	4	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	overexpression of SIRT1	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	6	7	17	18
, and that SIRT1 mediated activation of PGC-1alpha is insufficient to confer tolerance ( i.e ., the upregulation of PGC-1alpha is necessary ) .	, and that SIRT1 mediated activation of PGC-1alpha is insufficient to confer tolerance (i.e., the upregulation of PGC-1alpha is necessary).	1	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	3	4	7	8
SIRT1 can activate PGC-1alpha by deacetylation .	SIRT1 can activate PGC-1alpha by deacetylation.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	3	4
A previous study showed that SIRT1 is a pivotal activator of PGC-1alpha in various diseases and that there are two pathways through which SIRT1 regulates PGC-1alpha : regulating PGC-1alpha and controlling activity of PGC-1alpha .	A previous study showed that SIRT1 is a pivotal activator of PGC-1alpha in various diseases and that there are two pathways through which SIRT1 regulates PGC-1alpha : regulating PGC-1alpha and controlling activity of PGC-1alpha.	5	14	is a pivotal activator	Positive_activation_copula_1	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	11	12
SIRT1 activates PGC-1alpha by deacetylation sparking a chain of signalling pathways promoting mitochondrial biogenesis and function .	SIRT1 activates PGC-1alpha by deacetylation sparking a chain of signalling pathways promoting mitochondrial biogenesis and function.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	2	3
Inhibition of SIRT1 decreases activation of PGC-1alpha leading to defective PINK1- and Parkin mediated mitophagy .	Inhibition of SIRT1 decreases activation of PGC-1alpha leading to defective PINK1- and Parkin mediated mitophagy.	0	10	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	6	7
Independent studies have shown that SIRT1 also activates PGC-1a ( Nemoto etal ., 2005 ; Rodgers etal ., 2005 ; Gerhart-Hines etal ., 2007 ) .	Independent studies have shown that SIRT1 also activates PGC-1a (Nemoto etal., 2005; Rodgers etal., 2005; Gerhart-Hines etal., 2007).	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1a	PGC-1a	PGC-1a	5	6	8	9
Because SIRT1 activates PGC-1alpha , which can improve mitochondrial bioenergetics and resistance to oxidative damage , it will be important to investigate whether SIRT1 can mitigate neurodegeneration via PGC-1alpha .	Because SIRT1 activates PGC-1alpha, which can improve mitochondrial bioenergetics and resistance to oxidative damage, it will be important to investigate whether SIRT1 can mitigate neurodegeneration via PGC-1alpha.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	1	2	3	4
Increasing SIRT1 activity could modulate PGC1alpha functions in vivo and ultimately modulates the regulation of energy homeostasis .	Increasing SIRT1 activity could modulate PGC1alpha functions in vivo and ultimately modulates the regulation of energy homeostasis.	1	6	modulate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	1	2	5	6
The effects of SIRT1 on metabolism are mediated in part by PPARgamma co-activator-1alpha ( PGC-1alpha ) , which is activated through deacetylation by SIRT1 .	The effects of SIRT1 on metabolism are mediated in part by PPARgamma co-activator-1alpha (PGC-1alpha), which is activated through deacetylation by SIRT1.	12	24	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	23	24	14	15
SIRT1 upregulates PGC-1alpha , and plays an important role in autophagy and mitophagy induction through deacetylation and activation of major autophagy proteins ( ATG5 , ATG7 , ATG8 and LC3 ) , stabilization of PINK1 , and upregulation of mitophagy receptor Nix and BNIP3L and LC3 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	SIRT1 upregulates PGC-1alpha, and plays an important role in autophagy and mitophagy induction through deacetylation and activation of major autophagy proteins (ATG5, ATG7, ATG8 and LC3), stabilization of PINK1, and upregulation of mitophagy receptor Nix and BNIP3L and LC3 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	5	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	2	3
SIRT1 activates PGC1alpha through deacetylation and regulates mitochondria biogenesis and activities 25 .	SIRT1 activates PGC1alpha through deacetylation and regulates mitochondria biogenesis and activities 25.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	0	1	2	3
As Sirt1 is a known activator of PGC1-alpha , we examined if EGCg altered Sirt1 levels in muscles of the old rats in this study .	As Sirt1 is a known activator of PGC1-alpha, we examined if EGCg altered Sirt1 levels in muscles of the old rats in this study.	1	8	is a known activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC1-alpha	PGC1-alpha	PGC1-alpha	1	2	7	8
Notably , SIRT1 dependent activation of PGC-1alpha is required for induction and maintenance of fatty acid oxidation in response to low glucose concentrations leading to the switch from glucose to fatty acid oxidation .	Notably, SIRT1 dependent activation of PGC-1alpha is required for induction and maintenance of fatty acid oxidation in response to low glucose concentrations leading to the switch from glucose to fatty acid oxidation.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	6	7
SIRT1 promotes PGC-1alpha pathway activity [ XREF_BIBR - XREF_BIBR ] , thus protein abundance of SIRT1 was measured and was 20 % higher in dystrophic muscle regardless of treatment compared to healthy muscle .	SIRT1 promotes PGC-1alpha pathway activity [XREF_BIBR - XREF_BIBR], thus protein abundance of SIRT1 was measured and was 20% higher in dystrophic muscle regardless of treatment compared to healthy muscle.	0	4	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	2	3
Recent studies indicate that SIRT1 dependent activation of PGC-1alpha plays a major role in regulating metabolic adaptations in different tissues [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Recent studies indicate that SIRT1 dependent activation of PGC-1alpha plays a major role in regulating metabolic adaptations in different tissues [XREF_BIBR, XREF_BIBR - XREF_BIBR].	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	8	9
Furthermore , as PGC1-alpha has been linked to autophagy , and Sirt1 is a known activator of PGC1-alpha we wanted to determine if either of these proteins increased with unloading or reloading .	Furthermore, as PGC1-alpha has been linked to autophagy, and Sirt1 is a known activator of PGC1-alpha we wanted to determine if either of these proteins increased with unloading or reloading.	11	18	is a known activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC1-alpha	PGC1-alpha	PGC1-alpha	11	12	17	18
Sirt 1 deacetylates , and thereby activates PGC-1alpha and indirectly stimulates mitochondrial biogenesis [ XREF_BIBR ] .	Sirt 1 deacetylates, and thereby activates PGC-1alpha and indirectly stimulates mitochondrial biogenesis [XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt 1	Sirt 1	Sirt 1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	2	7	8
In addition , SIRT1 activates PPARGC1A , a regulator of mitochondrial biogenesis .	In addition, SIRT1 activates PPARGC1A, a regulator of mitochondrial biogenesis.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PPARGC1A	PPARGC1A	PPARGC1A	3	4	5	6
In peripheral tissues , PGC1alpha activity is stimulated by the actions of the NAD dependent deacetylase SIRT1 and studies in cultured neurons have implicated SIRT1 in neuroprotection .	In peripheral tissues, PGC1alpha activity is stimulated by the actions of the NAD dependent deacetylase SIRT1 and studies in cultured neurons have implicated SIRT1 in neuroprotection.	4	18	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	16	17	4	5
In skeletal muscle , SIRT1 activates PGC-1alpha but inhibits protein tyrosine phosphatase ( PTP ) 1B ( a negative regulator of the insulin receptor signaling cascade ) and hence enhances mitochondrial activity , fatty acid beta oxidation and insulin sensitivity .	In skeletal muscle, SIRT1 activates PGC-1alpha but inhibits protein tyrosine phosphatase (PTP) 1B (a negative regulator of the insulin receptor signaling cascade) and hence enhances mitochondrial activity, fatty acid beta oxidation and insulin sensitivity.	4	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	6	7
In particular , overexpression of SIRT1 deacetylase and suppression of GCN5 acetylase increase the transcriptional activity of PGC-1alpha and prevent Exp-Htt-induced mitochondrial loss in neurons .	In particular, overexpression of SIRT1 deacetylase and suppression of GCN5 acetylase increase the transcriptional activity of PGC-1alpha and prevent Exp-Htt-induced mitochondrial loss in neurons.	3	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	overexpression of SIRT1	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	5	6	17	18
However , to date , the intracellular mechanisms that regulate SIRT1 mediated activation of PGC1alpha , inmammalian cells , have not been elucidate .	However, to date, the intracellular mechanisms that regulate SIRT1 mediated activation of PGC1alpha, inmammalian cells, have not been elucidate.	10	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	10	11	14	15
The effects of PGC-1alpha on the activation of GLUT4 gene expression are reflected in the increased ability of myocytes to transport glucose , suggesting that the SIRT1 regulated activation of PGC-1alpha influences insulin sensitization .	The effects of PGC-1alpha on the activation of GLUT4 gene expression are reflected in the increased ability of myocytes to transport glucose, suggesting that the SIRT1 regulated activation of PGC-1alpha influences insulin sensitization.	26	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	26	27	30	31
It is so far unclear how Sirt1 and GSK3b act in concert to modulate PGC-1alpha activity .	It is so far unclear how Sirt1 and GSK3b act in concert to modulate PGC-1alpha activity.	6	15	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	6	7	14	15
The increase in the activity of AMPK and SIRT1 will then activate PGC-1alpha .	The increase in the activity of AMPK and SIRT1 will then activate PGC-1alpha.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	8	9	12	13
The PPARgamma coactivator 1 alpha ( Ppargc1a or PGC-1alpha ) was identified as an important transcriptional cofactor of PPARgamma and is activated by SIRT1 .	The PPARgamma coactivator 1 alpha (Ppargc1a or PGC-1alpha) was identified as an important transcriptional cofactor of PPARgamma and is activated by SIRT1.	4	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Ppargc1a	Ppargc1a	Ppargc1a	23	24	6	7
On the other hand , SIRT1 activates FoxO1 and PGC-1alpha to increase hepatic glucose production .	On the other hand, SIRT1 activates FoxO1 and PGC-1alpha to increase hepatic glucose production.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	9	10
Since PGC-1alpha is activated by SirT1 deacetylation in response to nutrient deprivation [ XREF_BIBR ] , PGC-1alpha can potentially serve as a link between nutrient sensing pathways and the oxidant scavenging mechanisms facilitated by SirT3 ( XREF_FIG ) .	Since PGC-1alpha is activated by SirT1 deacetylation in response to nutrient deprivation [XREF_BIBR], PGC-1alpha can potentially serve as a link between nutrient sensing pathways and the oxidant scavenging mechanisms facilitated by SirT3 (XREF_FIG).	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SirT1	SirT1 deacetylation	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	5	6	1	2
We hypothesize that SIRT1 is a good point for therapeutic intervention as SIRT1 activates PGC-1alpha and potential SIRT1 activating drugs are available .	We hypothesize that SIRT1 is a good point for therapeutic intervention as SIRT1 activates PGC-1alpha and potential SIRT1 activating drugs are available.	12	17	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	12	13	14	15
PGC-1alpha and sirtuin 1 ( SIRT1 ) , which directly activates PGC-1alpha by deacetylation , are primarily Mt proteins .	PGC-1alpha and sirtuin 1 (SIRT1), which directly activates PGC-1alpha by deacetylation, are primarily Mt proteins.	0	12	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	11	12
Moroever , activation of SIRT1 and AMPK activates PGC-1a , a transcriptional regulator of mitochondrial function , antioxidant defenses , and fatty acid oxidation .	Moroever, activation of SIRT1 and AMPK activates PGC-1a, a transcriptional regulator of mitochondrial function, antioxidant defenses, and fatty acid oxidation.	2	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1a	PGC-1a	PGC-1a	4	5	8	9
For example , during fasting , increased SIRT1 activity activates PGC1alpha , allowing nutrient deprived cells to transition from glycolytic ATP production to mitochondrial oxidative ATP synthesis [ XREF_BIBR ] .	For example, during fasting, increased SIRT1 activity activates PGC1alpha, allowing nutrient deprived cells to transition from glycolytic ATP production to mitochondrial oxidative ATP synthesis [XREF_BIBR].	7	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	7	8	10	11
The liver fasting response involves activation of PGC-1alpha by SIRT1 dependent deacytylation [ XREF_BIBR ] .	The liver fasting response involves activation of PGC-1alpha by SIRT1 dependent deacytylation [XREF_BIBR].	5	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	9	10	7	8
As to the significance of the specific downregulation of renal SIRT1 expression in aged ATRAP-KO mice , SIRT1 , which is primarily expressed in the renal tubule , functions as a protein deacetylase to activate PGC-1alpha and plays an important role in mitochondrial homeostasis through proper regulation of biogenesis and autophagy mechanisms.31 , 47 , 48 Therefore , decreased renal expression of SIRT1 , a longevity promoting molecule , is often associated with mitochondrial abnormalities .	As to the significance of the specific downregulation of renal SIRT1 expression in aged ATRAP-KO mice, SIRT1, which is primarily expressed in the renal tubule, functions as a protein deacetylase to activate PGC-1alpha and plays an important role in mitochondrial homeostasis through proper regulation of biogenesis and autophagy mechanisms.31, 47, 48 Therefore, decreased renal expression of SIRT1, a longevity promoting molecule, is often associated with mitochondrial abnormalities.	17	37	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1, which is primarily expressed	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	17	18	35	36
On the other hand , the SIRT1 mediated activation of PGC1alpha is correlated with the rapid induction of hepatic fatty acid oxidation in T2 treated rats [ XREF_BIBR , XREF_BIBR ] .	On the other hand, the SIRT1 mediated activation of PGC1alpha is correlated with the rapid induction of hepatic fatty acid oxidation in T2 treated rats [XREF_BIBR, XREF_BIBR].	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	6	7	10	11
PGC-1alpha , which can be activated by SIRT1 , was repressed by MeCP2 .	PGC-1alpha, which can be activated by SIRT1, was repressed by MeCP2.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	7	8	0	1
Although Sirt1 can increase PGC1alpha activity through deacetylation , PGC1alpha can be regulated at transcriptional and post-translational levels by other factors , such as energy-sensor AMPK [ XREF_BIBR ] .	Although Sirt1 can increase PGC1alpha activity through deacetylation, PGC1alpha can be regulated at transcriptional and post-translational levels by other factors, such as energy-sensor AMPK [XREF_BIBR].	1	5	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC1alpha	PGC1alpha	PGC1alpha	1	2	4	5
We show that SIRT1 deacetylase activity is positively regulated by ATGL to promote PGC-1alpha signaling .	We show that SIRT1 deacetylase activity is positively regulated by ATGL to promote PGC-1alpha signaling.	3	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	3	4	13	14
In the liver , Sirt1 deacetylates and activates the transcriptional co-activator PGC1-alpha and the transcription factor FoxO1 to promote gluconeogenesis XREF_BIBR , XREF_BIBR .	In the liver, Sirt1 deacetylates and activates the transcriptional co-activator PGC1-alpha and the transcription factor FoxO1 to promote gluconeogenesis XREF_BIBR, XREF_BIBR.	4	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC1-alpha	PGC1-alpha	PGC1-alpha	4	5	11	12
Since AMPK senses AMP and ATP ratios and Sirt1 is NAD+ dependent , both AMPK and Sirt1 modulate PGC-1alpha activity in response to cellular energy supply .	Since AMPK senses AMP and ATP ratios and Sirt1 is NAD+ dependent, both AMPK and Sirt1 modulate PGC-1alpha activity in response to cellular energy supply.	14	19	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	16	17	18	19
The deacetylase Sirt1 activates PGC-1alpha in times of energy demand thereby switching on oxidative phosphorylation , whereas the acetyltransferase GCN5 represses PGC-1alpha in excess of energy .	The deacetylase Sirt1 activates PGC-1alpha in times of energy demand thereby switching on oxidative phosphorylation, whereas the acetyltransferase GCN5 represses PGC-1alpha in excess of energy.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	4	5
Importantly , PGC-1alpha is increased during mechanical stimulation of the endothelium by shear stress in a SIRT1 dependent manner .	Importantly, PGC-1alpha is increased during mechanical stimulation of the endothelium by shear stress in a SIRT1 dependent manner.	2	18	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	16	17	2	3
Based on these data , the SIRT1 dependent activation of PGC-1alpha is thought to contribute to an improvement in insulin sensitivity in skeletal muscle .	Based on these data, the SIRT1 dependent activation of PGC-1alpha is thought to contribute to an improvement in insulin sensitivity in skeletal muscle.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	6	7	10	11
SIRT1 activates PGC-1alpha in muscle and liver to increase mitochondrial biogenesis 98 .	SIRT1 activates PGC-1alpha in muscle and liver to increase mitochondrial biogenesis 98.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	2	3
SIRT1 positively regulates PGC-1alpha localization and transcriptional activity , and inhibition of GSK3beta would stabilize PGC-1alpha against proteasomal degradation , consistent with the observed increase in PGC-1alpha levels and increased expression of multiple PGC-1alpha gene targets in adipose tissue .	SIRT1 positively regulates PGC-1alpha localization and transcriptional activity, and inhibition of GSK3beta would stabilize PGC-1alpha against proteasomal degradation, consistent with the observed increase in PGC-1alpha levels and increased expression of multiple PGC-1alpha gene targets in adipose tissue.	0	4	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	3	4
SIRT1 and AMPK then act together to enhance the activity of PGC-1alpha , a target of both proteins and a key regulator of mitochondrial function .	SIRT1 and AMPK then act together to enhance the activity of PGC-1alpha, a target of both proteins and a key regulator of mitochondrial function.	0	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	11	12
The SIRT1 activator , resveratrol , increases the activity of PGC-1alpha and improves mitochondrial activity as a consequence of its deacetylation of PGC-1alpha , which increases its effects on liver , fat and muscle metabolism .	The SIRT1 activator, resveratrol, increases the activity of PGC-1alpha and improves mitochondrial activity as a consequence of its deacetylation of PGC-1alpha, which increases its effects on liver, fat and muscle metabolism.	1	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	1	2	10	11
In particular , the increase in ATP and NADH induces a reduction in AMPK activation and SIRT1 deacetylating potential , thus negatively modulating PGC-1alpha activity .	In particular, the increase in ATP and NADH induces a reduction in AMPK activation and SIRT1 deacetylating potential, thus negatively modulating PGC-1alpha activity.	16	24	modulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	16	17	23	24
SIRT1 activates PGC-1alpha through deacetylation leading to its translocation into the nucleus [ XREF_BIBR ] .	SIRT1 activates PGC-1alpha through deacetylation leading to its translocation into the nucleus [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	2	3
Despite the fact that sirtuin-1 ( SIRT1 ) activates PGC1alpha and mitochondrial biogenesis , we observed a surprising up-regulation of SIRT1 mRNA ( XREF_SUPPLEMENTARY ) .	Despite the fact that sirtuin-1 (SIRT1) activates PGC1alpha and mitochondrial biogenesis, we observed a surprising up-regulation of SIRT1 mRNA (XREF_SUPPLEMENTARY).	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	6	7	9	10
FOXO1 and PGC1alpha , activated by SIRT1 deacetylation , become then the major players to further support the expression of the gluconeogenic program [ XREF_BIBR , XREF_BIBR ] .	FOXO1 and PGC1alpha, activated by SIRT1 deacetylation, become then the major players to further support the expression of the gluconeogenic program [XREF_BIBR, XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1 deacetylation	sirt1	PGC1alpha	PGC1alpha	pgc1alpha	6	7	2	3
Similar results can also be found in alcoholic fatty liver diseases where activation of SIRT1 deacetylase activity by resveratrol enhances PGC-1alpha transcriptional activity and attenuates oxidative stress as judged by decreasing MDA levels XREF_BIBR .	Similar results can also be found in alcoholic fatty liver diseases where activation of SIRT1 deacetylase activity by resveratrol enhances PGC-1alpha transcriptional activity and attenuates oxidative stress as judged by decreasing MDA levels XREF_BIBR.	14	22	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	14	15	20	21
Sirt1 activates PGC-1a and negatively regulates NFAT , mTOR , and HIF-1a activity .	Sirt1 activates PGC-1a and negatively regulates NFAT, mTOR, and HIF-1a activity.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1a	PGC-1a	PGC-1a	0	1	2	3
Activation of Sirt1 through caloric restriction induces PGC-1alpha activity and enhances mitochondrial function [ XREF_BIBR , XREF_BIBR ] .	Activation of Sirt1 through caloric restriction induces PGC-1alpha activity and enhances mitochondrial function [XREF_BIBR, XREF_BIBR].	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	7	8
While acetylation of PGC1alpha suppresses its transcriptional coactivator activity , histone deacetylase sirtuin 1 ( Sirt1 ) can activate PGC1alpha and mito-biogenesis .	While acetylation of PGC1alpha suppresses its transcriptional coactivator activity, histone deacetylase sirtuin 1 (Sirt1) can activate PGC1alpha and mito-biogenesis.	12	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC1alpha	PGC1alpha	PGC1alpha	15	16	19	20
The status of SIRT1 , an NAD +-dependent deacetylase that activates PGC1alpha by removing inhibitory acetyl groups , however , was affected by OAA ( XREF_FIG ) .	The status of SIRT1, an NAD +-dependent deacetylase that activates PGC1alpha by removing inhibitory acetyl groups, however, was affected by OAA (XREF_FIG).	1	12	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	3	4	11	12
SIRT1 induced PGC-1alpha activation in hepatocytes , can result in downregulation of glycolytic pathways and the upregulation of gluconeogenic pathways to maintain the glycogen level [ XREF_BIBR ] , although the plasma glucose level increased ( glycolysis process ) during exercise ( XREF_FIG c ) .	SIRT1 induced PGC-1alpha activation in hepatocytes, can result in downregulation of glycolytic pathways and the upregulation of gluconeogenic pathways to maintain the glycogen level [XREF_BIBR], although the plasma glucose level increased (glycolysis process) during exercise (XREF_FIG c).	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	2	3
SIRT1 is activated and cooperates with pAMPK to enhance the ability of PGC-1alpha to stimulate mitochondrial biogenesis and function [ XREF_BIBR ] .	SIRT1 is activated and cooperates with pAMPK to enhance the ability of PGC-1alpha to stimulate mitochondrial biogenesis and function [XREF_BIBR].	0	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	12	13
SIRT1 enhances mitochondrial fatty acid oxidation in response to fasting by activating PPAR-alpha and PGC-1alpha in the liver .	SIRT1 enhances mitochondrial fatty acid oxidation in response to fasting by activating PPAR-alpha and PGC-1alpha in the liver.	0	15	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	14	15
In addition , AMPK also regulates Sirt1 , another metabolic sensor and a Nicotinamide adenine dinucleotide ( NAD + ) dependent type III deacetylase sirtuin , that activates PGC-1alpha and various substrates including PPARgamma .	In addition, AMPK also regulates Sirt1, another metabolic sensor and a Nicotinamide adenine dinucleotide (NAD +) dependent type III deacetylase sirtuin, that activates PGC-1alpha and various substrates including PPARgamma.	5	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	6	7	28	29
Provided that the expression of PGC-1alpha and mitochondrial OXPHOS genes is reduced in skeletal muscle of type 2 diabetes patients , the SIRT1 dependent activation of PGC-1alpha function in skeletal muscle might contribute to the improvement of insulin sensitivity .	Provided that the expression of PGC-1alpha and mitochondrial OXPHOS genes is reduced in skeletal muscle of type 2 diabetes patients, the SIRT1 dependent activation of PGC-1alpha function in skeletal muscle might contribute to the improvement of insulin sensitivity.	22	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	22	23	26	27
Sirtuins have also been implicated in the exercise response : SIRT1 activates PGC-1alpha via deacetylation and is highly expressed after endurance exercise .	Sirtuins have also been implicated in the exercise response : SIRT1 activates PGC-1alpha via deacetylation and is highly expressed after endurance exercise.	10	18	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	10	11	12	13
First of all , SIRT1 activates PGC-1alpha , a master regulator of mitochondrial metabolism and biogenesis [ XREF_BIBR ] .	First of all, SIRT1 activates PGC-1alpha, a master regulator of mitochondrial metabolism and biogenesis [XREF_BIBR].	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	6	7
In the case of CR ( a chronic stress ) , induction of SIRT1 and inhibition of GSK3beta activate and stabilize PGC-1alpha , resulting in a sustained increase in expression of genes involved in the mitochondrial energy metabolism .	In the case of CR (a chronic stress), induction of SIRT1 and inhibition of GSK3beta activate and stabilize PGC-1alpha, resulting in a sustained increase in expression of genes involved in the mitochondrial energy metabolism.	11	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	13	14	21	22
SIRT3 promotes PGC-1alpha expression while SIRT1 activates PGC-1alpha by direct deacetylation [ XREF_BIBR ] .	SIRT3 promotes PGC-1alpha expression while SIRT1 activates PGC-1alpha by direct deacetylation [XREF_BIBR].	5	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	7	8
However , Sirt1 is activated under the same conditions and activates PGC-1alpha by deacetylation .	However, Sirt1 is activated under the same conditions and activates PGC-1alpha by deacetylation.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	11	12
SIRT1 activates PGC-1alpha primarily though its ability to deacetylate this coactivator .	SIRT1 activates PGC-1alpha primarily though its ability to deacetylate this coactivator.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	2	3
Activation of SIRT1 stimulates PGC1alpha , with consequent activation of mitochondrial biogenesis and metabolism [ XREF_BIBR ] and associated improvements of insulin sensitivity and suppression of oxidative and inflammatory stress [ XREF_BIBR , XREF_BIBR ] .	Activation of SIRT1 stimulates PGC1alpha, with consequent activation of mitochondrial biogenesis and metabolism [XREF_BIBR] and associated improvements of insulin sensitivity and suppression of oxidative and inflammatory stress [XREF_BIBR, XREF_BIBR].	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	2	3	4	5
Therefore , besides the SIRT1 mediated activation of PGC-1alpha , it is plausible to postulate that the beneficial effect of resveratrol on neuronal homeostasis could be partially due to the inhibition of ERK1/2 mediated autophagic cell death .	Therefore, besides the SIRT1 mediated activation of PGC-1alpha, it is plausible to postulate that the beneficial effect of resveratrol on neuronal homeostasis could be partially due to the inhibition of ERK1/2 mediated autophagic cell death.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	8	9
In another arm of the pathway , SIRT1 is also believed to upregulate PGC1alpha and PPARalpha , which upregulates MLYCD subsequently decreasing MLYCD levels , decreasing Malonyl-CoA synthesis and relieving the repression of CPT1 .	In another arm of the pathway, SIRT1 is also believed to upregulate PGC1alpha and PPARalpha, which upregulates MLYCD subsequently decreasing MLYCD levels, decreasing Malonyl-CoA synthesis and relieving the repression of CPT1.	7	24	upregulate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	SIRT1	SIRT1	sirt1	PGC1alpha	PGC1alpha and PPARalpha, which upregulates MLYCD subsequently decreasing MLYCD levels	pgc1alpha	7	8	13	14
This result indicated that SIRT1 KD not influenced to muscle contraction induced PGC-1alpha deacetytilation and muscle energy metabolism .	This result indicated that SIRT1 KD not influenced to muscle contraction induced PGC-1alpha deacetytilation and muscle energy metabolism.	4	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	12	13
As shown in XREF_FIG B , Sirt1 over-expression relieved HA and Abeta induced down-regulation of PGC1alpha significantly .	As shown in XREF_FIG B, Sirt1 over-expression relieved HA and Abeta induced down-regulation of PGC1alpha significantly.	6	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1 over-expression	sirt1	PGC1alpha	PGC1alpha	pgc1alpha	6	7	15	16
Moreover , SIRT1 can activate PGC-1alpha ( peroxisome-proliferator-activated receptor gamma coactivator-1alpha ) .	Moreover, SIRT1 can activate PGC-1alpha (peroxisome-proliferator-activated receptor gamma coactivator-1alpha).	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	5	6
25 SIRT1 activates PGC1alpha signaling to promote mitobiogenesis as well as promotes mitophagy to selectively eliminate severely damaged mitochondria .	25 SIRT1 activates PGC1alpha signaling to promote mitobiogenesis as well as promotes mitophagy to selectively eliminate severely damaged mitochondria.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	1	2	3	4
Reduced SIRT1 deacetylation decreases activities of LKB1 , PGC1alpha , and AMPKalpha2 174 , causing decreased mitochondrial biogenesis , increased ROS production , and a profoundly disturbed circadian clock synchronization of glucose and lipid metabolism .	Reduced SIRT1 deacetylation decreases activities of LKB1, PGC1alpha, and AMPKalpha2 174, causing decreased mitochondrial biogenesis, increased ROS production, and a profoundly disturbed circadian clock synchronization of glucose and lipid metabolism.	1	9	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1 deacetylation	sirt1	PGC1alpha	PGC1alpha	pgc1alpha	1	2	8	9
SIRT1 activates PGC-1alpha , the master regulator of mitochondria biogenesis , and inhibits glycolysis [ XREF_BIBR ] .	SIRT1 activates PGC-1alpha, the master regulator of mitochondria biogenesis, and inhibits glycolysis [XREF_BIBR].	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	2	3
Moreover , SIRT1 can enhance PGC-1alpha activation , which acts as a regulator in resistance to oxidative stress and mitochondrial integrity .	Moreover, SIRT1 can enhance PGC-1alpha activation, which acts as a regulator in resistance to oxidative stress and mitochondrial integrity.	2	6	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	5	6
It is likely that SIRT1 activators including resveratrol increase AMPK thereby induce PGC1-alpha and restore mitochondrial function or increase mitochondrial biogenesis in skeletal muscle [ XREF_BIBR , XREF_BIBR ] .	It is likely that SIRT1 activators including resveratrol increase AMPK thereby induce PGC1-alpha and restore mitochondrial function or increase mitochondrial biogenesis in skeletal muscle [XREF_BIBR, XREF_BIBR].	4	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1-alpha	PGC1-alpha	PGC1-alpha	4	5	12	13
SIRT1 also activates PGC1alpha which results in mitochondrial biogenesis .	SIRT1 also activates PGC1alpha which results in mitochondrial biogenesis.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	0	1	3	4
Adiponectin is an anti-inflammatory , insulin sensitizing adipokine expressed exclusively by adipocytes that exerts beneficial effects on lipid and glucose homeostasis via multiple mechanisms , most notably via ceramidase activity and AMPK / SIRT1 dependent activation of PGC-1alpha .	Adiponectin is an anti-inflammatory, insulin sensitizing adipokine expressed exclusively by adipocytes that exerts beneficial effects on lipid and glucose homeostasis via multiple mechanisms, most notably via ceramidase activity and AMPK / SIRT1 dependent activation of PGC-1alpha.	33	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	33	34	37	38
To this end , SIRT1 also promotes PGC-1alpha activity by deacetylation [ XREF_BIBR ] , thus demonstrating a role for calorie restriction in promotion of PGC-1alpha activity .	To this end, SIRT1 also promotes PGC-1alpha activity by deacetylation [XREF_BIBR], thus demonstrating a role for calorie restriction in promotion of PGC-1alpha activity.	4	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	7	8
41 SIRT1 promotes mitochondrial function and antioxidant metabolism by activating PGC-1alpha , a master transcriptional regulator of these responses .	41 SIRT1 promotes mitochondrial function and antioxidant metabolism by activating PGC-1alpha, a master transcriptional regulator of these responses.	0	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	1	2	10	11
The SIRT1 agonist SRT1720 was used to enhance PGC1alpha activation in wild-type mice during DSS exposure .	The SIRT1 agonist SRT1720 was used to enhance PGC1alpha activation in wild-type mice during DSS exposure.	1	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	1	2	8	9
In addition to the induction of PGC-1alpha , DR increases the activity and stability of PGC-1alpha via post-translational modifications by both SIRT1 [ XREF_BIBR , XREF_BIBR ] and GSK3beta ( glycogen synthase kinase 3 beta ) [ XREF_BIBR ] .	In addition to the induction of PGC-1alpha, DR increases the activity and stability of PGC-1alpha via post-translational modifications by both SIRT1 [XREF_BIBR, XREF_BIBR] and GSK3beta (glycogen synthase kinase 3 beta) [XREF_BIBR].	4	23	increases	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	21	22	6	7
SIRT1 can activate PGC-1alpha , which in turn co-activates PPARgamma to stimulate fatty acid oxidation .	SIRT1 can activate PGC-1alpha, which in turn co-activates PPARgamma to stimulate fatty acid oxidation.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	3	4
Treatment of mice with resveratrol leads to increased mitochondrial biogenesis and increased energy expenditure in mice , possibly by SIRT1 mediated increase in PGC-1alpha activity .	Treatment of mice with resveratrol leads to increased mitochondrial biogenesis and increased energy expenditure in mice, possibly by SIRT1 mediated increase in PGC-1alpha activity.	19	24	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	19	20	23	24
This issue appeared to be resolved , in part , following the work of Amat and coworkers who reported that SIRT1 , via interaction with myogenic determining factor ( MyoD ) promotes a positive autoregulatory PGC-1alpha expression loop in vitro .	This issue appeared to be resolved, in part, following the work of Amat and coworkers who reported that SIRT1, via interaction with myogenic determining factor (MyoD) promotes a positive autoregulatory PGC-1alpha expression loop in vitro.	20	37	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	20	21	35	36
Gerhart Hines et al XREF_BIBR reported that SIRT-1 causes activation of PGC-1alpha and exhibits inhibitory effect on glucose metabolism in liver .	Gerhart Hines et al XREF_BIBR reported that SIRT-1 causes activation of PGC-1alpha and exhibits inhibitory effect on glucose metabolism in liver.	7	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT-1	SIRT-1	SIRT-1	PGC-1alpha	PGC-1alpha	PGC-1alpha	7	8	11	12
In fact , PGC-1alpha activity is conversely regulated by the Sirt1 deacetylase , which activates PGC-1alpha , and the GCN5 acetyltransferase , which represses PGC-1alpha activity .	In fact, PGC-1alpha activity is conversely regulated by the Sirt1 deacetylase, which activates PGC-1alpha, and the GCN5 acetyltransferase, which represses PGC-1alpha activity.	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	10	11	15	16
Furthermore , AMPK activates PGC1alpha ( peroxisome proliferator activated receptor gamma , coactivator 1alpha ) , a master regulator of mitochondrial biogenesis , reportedly via direct phosphorylation of PGC1alpha but also by promoting NAD + -dependent activation of PGC1alpha by Sirt1 ( sirtuin 1 ) .	Furthermore, AMPK activates PGC1alpha (peroxisome proliferator activated receptor gamma, coactivator 1alpha), a master regulator of mitochondrial biogenesis, reportedly via direct phosphorylation of PGC1alpha but also by promoting NAD + -dependent activation of PGC1alpha by Sirt1 (sirtuin 1).	26	42	promoting	Positive_regulation_syntax_3_verb	Positive_activation	Positive_regulation	Sirt1	Sirt1	sirt1	PGC1alpha	phosphorylation of PGC1alpha	pgc1alpha	40	41	28	29
Analysis of muscle specific AdipoR1 knockout mice revealed the pivotal role of adiponectin and AdipoR1 in the regulation of mitochondrial biogenesis via AMPK- and SIRT1 mediated PGC-1alpha activation as well as Ca ( 2+ )-dependent up-regulation of PGC-1alpha expression .	Analysis of muscle specific AdipoR1 knockout mice revealed the pivotal role of adiponectin and AdipoR1 in the regulation of mitochondrial biogenesis via AMPK- and SIRT1 mediated PGC-1alpha activation as well as Ca (2+)-dependent up-regulation of PGC-1alpha expression.	20	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	24	25	26	27
Additionally , Sirt1 modulates the activity of PGC-1alpha ( peroxisome proliferator activated receptor gamma coactivator-1 alpha ) which is involved in , among other things , mitochondrial biogenesis and function [ XREF_BIBR ] .	Additionally, Sirt1 modulates the activity of PGC-1alpha (peroxisome proliferator activated receptor gamma coactivator-1 alpha) which is involved in, among other things, mitochondrial biogenesis and function [XREF_BIBR].	2	19	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	7	8
Overexpression of hepatic SIRT1 restores PGC-1alpha activity , normalizes the expression of electron transport chain components , and increases mitochondrial complex IV activity .	Overexpression of hepatic SIRT1 restores PGC-1alpha activity, normalizes the expression of electron transport chain components, and increases mitochondrial complex IV activity.	0	6	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	Overexpression of hepatic SIRT1	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	3	4	5	6
Sirtuin 1 ( SIRT1 ) a member of the sirtuin family of proteins , may mediate the effect of CR by influencing PPAR-gamma , PGC1-alpha , and FOXO .	Sirtuin 1 (SIRT1) a member of the sirtuin family of proteins, may mediate the effect of CR by influencing PPAR-gamma, PGC1-alpha, and FOXO.	0	25	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1-alpha	PGC1-alpha	PGC1-alpha	3	4	24	25
In muscle , like in liver , SIRT1 mediated activation of PGC-1alpha during fasting activates peroxisome proliferators activated receptor alpha ( PPARalpha )-mediated transcription of fatty-acid catabolic genes .	In muscle, like in liver, SIRT1 mediated activation of PGC-1alpha during fasting activates peroxisome proliferators activated receptor alpha (PPARalpha)-mediated transcription of fatty-acid catabolic genes.	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	7	8	11	12
Among its many actions , SIRT1 activates PGC-1alpha via deacetylation leading to transcriptional activation of a complement of genes associated with mitochondrial biogenesis XREF_BIBR , XREF_BIBR , OXPHOS and fatty acid oxidation XREF_BIBR - XREF_BIBR .	Among its many actions, SIRT1 activates PGC-1alpha via deacetylation leading to transcriptional activation of a complement of genes associated with mitochondrial biogenesis XREF_BIBR, XREF_BIBR, OXPHOS and fatty acid oxidation XREF_BIBR - XREF_BIBR.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	7	8
Recent evidences suggest that Sirt1 could activate PGC1alpha via deacetylation with a concomitant suppression of PPARgamma expression [ XREF_BIBR , XREF_BIBR ] .	Recent evidences suggest that Sirt1 could activate PGC1alpha via deacetylation with a concomitant suppression of PPARgamma expression [XREF_BIBR, XREF_BIBR].	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC1alpha	PGC1alpha	PGC1alpha	4	5	7	8
However , treatment of chondrocytes with the SIRT1 activator , SRT1720 , restored the phosphorylation of AMPK and PGC-1alpha , suggesting that SIRT1 induced the activation of AMPK and PGC-1alpha pathway ( XREF_FIG D-F ) .	However, treatment of chondrocytes with the SIRT1 activator, SRT1720, restored the phosphorylation of AMPK and PGC-1alpha, suggesting that SIRT1 induced the activation of AMPK and PGC-1alpha pathway (XREF_FIG D-F).	22	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	22	23	29	30
Sirt-1 activation increases PGC-1alpha activity through deacetylation and may be activated through resveratrol exposure XREF_BIBR , XREF_BIBR , XREF_BIBR .	Sirt-1 activation increases PGC-1alpha activity through deacetylation and may be activated through resveratrol exposure XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	4	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt-1	Sirt-1	Sirt-1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	3	4
XREF_BIBR , XREF_BIBR , XREF_BIBR During nutrient or energy depletion ( e.g ., fasting , exercise , or calorie restriction ) , the level of cAMP and ratio of AMP and ATP increase , which trigger the signaling cascades of PKA and CREB , AMPK , and SIRT1 that can activate PGC1alpha , the master regulator of mitochondrial biogenesis .	XREF_BIBR, XREF_BIBR, XREF_BIBR During nutrient or energy depletion (e.g., fasting, exercise, or calorie restriction), the level of cAMP and ratio of AMP and ATP increase, which trigger the signaling cascades of PKA and CREB, AMPK, and SIRT1 that can activate PGC1alpha, the master regulator of mitochondrial biogenesis.	0	55	activate	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	47	48	51	52
XREF_BIBR In fact , PGC-1alpha activity is directly modulated at transcriptional and posttranslational level XREF_BIBR by two major cell metabolic sensors namely AMPK and SIRT1 , through phosphorylation and deacetylation .	XREF_BIBR In fact, PGC-1alpha activity is directly modulated at transcriptional and posttranslational level XREF_BIBR by two major cell metabolic sensors namely AMPK and SIRT1, through phosphorylation and deacetylation.	4	25	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	24	25	4	5
Activation of SIRT1 results in activation of PGC-1alpha , one of the components of mitochondrial biogenesis [ XREF_BIBR ] .	Activation of SIRT1 results in activation of PGC-1alpha, one of the components of mitochondrial biogenesis [XREF_BIBR].	0	12	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	7	8
Although there is no correlation between the total muscle content of SIRT1 and PGC-1alpha or mitochondrial biogenesis , SIRT1 activation is associated with increases in PGC-1alpha target gene expression , consistent with SIRT1 activation of PGC-1alpha through deacetylation .	Although there is no correlation between the total muscle content of SIRT1 and PGC-1alpha or mitochondrial biogenesis, SIRT1 activation is associated with increases in PGC-1alpha target gene expression, consistent with SIRT1 activation of PGC-1alpha through deacetylation.	32	36	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	32	33	35	36
We postulated that SIRT1 could activate TFAM and PGC-1alpha by deacetylation , and PGC-1alpha in turn coactivates TFAM .	We postulated that SIRT1 could activate TFAM and PGC-1alpha by deacetylation, and PGC-1alpha in turn coactivates TFAM.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	3	4	8	9
PGC-1alpha is activated by both SIRT1 through deacetylation and by AMPK through phosphorylation , resulting in improved mitochondrial function [ XREF_BIBR , XREF_BIBR ] .	PGC-1alpha is activated by both SIRT1 through deacetylation and by AMPK through phosphorylation, resulting in improved mitochondrial function [XREF_BIBR, XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	0	1
, who demonstrated that SIRT1 localizes at PGC-1alpha target gene promoters to presumably synergize PGC-1alpha action on these target genes .	, who demonstrated that SIRT1 localizes at PGC-1alpha target gene promoters to presumably synergize PGC-1alpha action on these target genes.	4	15	synergize	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	14	15
In humans , the administration of epicatechin rich cocoa to patients with type 2 diabetes and heart failure , a stimulation in mitochondrial biogenesis in skeletal muscle , as expressed by an increment in SIRT1 dependent activation of PGC-1alpha and as a higher content of porin and mitochondrial complexes I and V , was observed [ XREF_BIBR ] .	In humans, the administration of epicatechin rich cocoa to patients with type 2 diabetes and heart failure, a stimulation in mitochondrial biogenesis in skeletal muscle, as expressed by an increment in SIRT1 dependent activation of PGC-1alpha and as a higher content of porin and mitochondrial complexes I and V, was observed [XREF_BIBR].	34	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	34	35	38	39
PGC-1alpha and Nrf2 are activators of antioxidant defense genes in neurons , and Sirt1 can promote PGC-1alpha activity by deacetylation .	PGC-1alpha and Nrf2 are activators of antioxidant defense genes in neurons, and Sirt1 can promote PGC-1alpha activity by deacetylation.	13	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	13	14	16	17
As association of PGC-1alpha with the rDNA at normal and unstressed conditions requires its activation by resveratrol - a sirtuin mimetic that induces Sirt1 that in turn deacetylates and thus activates PGC-1alpha - and could be counteracted by nicotinamide , the interaction of PGC-1alpha with the rDNA might be regulated by a Sirt-1 like activity .	As association of PGC-1alpha with the rDNA at normal and unstressed conditions requires its activation by resveratrol - a sirtuin mimetic that induces Sirt1 that in turn deacetylates and thus activates PGC-1alpha - and could be counteracted by nicotinamide, the interaction of PGC-1alpha with the rDNA might be regulated by a Sirt-1 like activity.	22	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	23	24	31	32
In this regard , Schnellmann and colleagues reported that the SIRT1 activator SRT1720 could activate PGC-1alpha for mitochondrial biogenesis , leading to the accelerated recovery from ischemic AKI .	In this regard, Schnellmann and colleagues reported that the SIRT1 activator SRT1720 could activate PGC-1alpha for mitochondrial biogenesis, leading to the accelerated recovery from ischemic AKI.	10	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	10	11	15	16
For example , Sirt1 activates PGC-1alpha ( peroxisome proliferator activated receptor gamma coactivator 1-alpha ) [ XREF_BIBR ] , which is known to protect against sarcopenia [ XREF_BIBR ] , and supplementation with the sirtuin cofactor NAD + protects against age related metabolic changes in skeletal muscle in a Sirt1 dependent manner [ XREF_BIBR ] .	For example, Sirt1 activates PGC-1alpha (peroxisome proliferator activated receptor gamma coactivator 1-alpha) [XREF_BIBR], which is known to protect against sarcopenia [XREF_BIBR], and supplementation with the sirtuin cofactor NAD + protects against age related metabolic changes in skeletal muscle in a Sirt1 dependent manner [XREF_BIBR].	3	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	3	4	5	6
PGC-1alpha is a direct target of SIRT1 , which activates PGC-1alpha mainly through its ability to deacetylate its coactivator [ XREF_BIBR ] .	PGC-1alpha is a direct target of SIRT1, which activates PGC-1alpha mainly through its ability to deacetylate its coactivator [XREF_BIBR].	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	6	7	10	11
However , PGC-1alpha can be activated not only by SIRT1 but also by diverse factors such as steroid receptor coactivator-1 ( SRC-1 ) and CREB binding protein ( CBP )/P300 [ XREF_BIBR ] .	However, PGC-1alpha can be activated not only by SIRT1 but also by diverse factors such as steroid receptor coactivator-1 (SRC-1) and CREB binding protein (CBP)/P300 [XREF_BIBR].	2	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	9	10	2	3
Sirt1 induces PGC-1alpha , a regulator of energy metabolic pathways .	Sirt1 induces PGC-1alpha, a regulator of energy metabolic pathways.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	2	3
Direct phosphorylation by AMPK promotes PGC-1alpha dependent induction at the PGC-1alpha promoter level , while SIRT1 stimulates PGC-1alpha activity through deacetylation , thereby inducing mitochondrial biogenesis .	Direct phosphorylation by AMPK promotes PGC-1alpha dependent induction at the PGC-1alpha promoter level, while SIRT1 stimulates PGC-1alpha activity through deacetylation, thereby inducing mitochondrial biogenesis.	15	18	stimulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	15	16	17	18
Furthermore , activated mitochondrial function might reduce oxidative stress , and SIRT1 activates PGC-1alpha in the liver in response to fasting signals [ XREF_BIBR ] .	Furthermore, activated mitochondrial function might reduce oxidative stress, and SIRT1 activates PGC-1alpha in the liver in response to fasting signals [XREF_BIBR].	11	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	11	12	13	14
The rescue effects had been attributed at least partly to SIRT1 XREF_BIBR , XREF_BIBR on the basis that resveratrol directly or indirectly potentiates SIRT1 20 , and that SIRT1 activates PGC-1alpha by deacetylation 21 .	The rescue effects had been attributed at least partly to SIRT1 XREF_BIBR, XREF_BIBR on the basis that resveratrol directly or indirectly potentiates SIRT1 20, and that SIRT1 activates PGC-1alpha by deacetylation 21.	28	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	28	29	30	31
In addition to the direct effects of SIRT1 on FXR , SIRT1 may also indirectly increase FXR activity by activating PGC-1alpha .	In addition to the direct effects of SIRT1 on FXR, SIRT1 may also indirectly increase FXR activity by activating PGC-1alpha.	11	21	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	11	12	20	21
Collectively , activation of PGC-1alpha by SIRT1 and enhanced mitogenesis may restore energy metabolism in the failing myocardium and ameliorate heart failure .	Collectively, activation of PGC-1alpha by SIRT1 and enhanced mitogenesis may restore energy metabolism in the failing myocardium and ameliorate heart failure.	2	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	6	7	4	5
Moreover , at that time , SIRT1 can activate PGC-1alpha and FOXO1 through a deacetylation reaction , resulting in the induction of gluconeogenesis related genes .	Moreover, at that time, SIRT1 can activate PGC-1alpha and FOXO1 through a deacetylation reaction, resulting in the induction of gluconeogenesis related genes.	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	6	7	9	10
Most especially , overexpression of SIRT1 deacetylase and suppression of GCN5 acetylase increase the transcriptional activity of PGC-1alpha and prevent mitochondrial loss in neurons induced by expanded Huntingtin protein [ XREF_BIBR ] .	Most especially, overexpression of SIRT1 deacetylase and suppression of GCN5 acetylase increase the transcriptional activity of PGC-1alpha and prevent mitochondrial loss in neurons induced by expanded Huntingtin protein [XREF_BIBR].	3	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	overexpression of SIRT1	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	5	6	17	18
At the same time , SIRT1 deacetylates and thus activates PGC-1alpha and FOXO transcriptional factors to turn on genes necessary for response to long-term fasting ( XREF_FIG ) .	At the same time, SIRT1 deacetylates and thus activates PGC-1alpha and FOXO transcriptional factors to turn on genes necessary for response to long-term fasting (XREF_FIG).	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	10	11
Deacetylation by Sirt1 restores PGC-1alpha activity and increases mitochondrial biogenesis .	Deacetylation by Sirt1 restores PGC-1alpha activity and increases mitochondrial biogenesis.	0	5	restores	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	4	5
PGC-1alpha is activated by SIRT1 deacetylation and by p38 MAP kinase through phosphorylation [ XREF_BIBR , XREF_BIBR ] .	PGC-1alpha is activated by SIRT1 deacetylation and by p38 MAP kinase through phosphorylation [XREF_BIBR, XREF_BIBR].	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1 deacetylation	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	4	5	0	1
SIRT1 activates PGC1alpha by deacetylation while HAT inactivates PGC1alpha by acetylation [ XREF_BIBR ] .	SIRT1 activates PGC1alpha by deacetylation while HAT inactivates PGC1alpha by acetylation [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	0	1	2	3
We confirm that SIRT1 synergizes with PGC-1alpha to potentiate T 3 response , in accordance with recent findings of another group XREF_BIBR , but also find that SIRT1 enhances TRbeta1 activity independently of PGC-1alpha .	We confirm that SIRT1 synergizes with PGC-1alpha to potentiate T 3 response, in accordance with recent findings of another group XREF_BIBR, but also find that SIRT1 enhances TRbeta1 activity independently of PGC-1alpha.	27	34	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	27	28	33	34
In addition , SIRT1 is involved in the upregulation of mitochondrial biogenesis due to its capability to deacetylate and thus activate the PPARgamma co-activator-1alpha , which stimulates mitochondrial activity and subsequently increases glucose metabolism , which in turn improves insulin sensitivity .	In addition, SIRT1 is involved in the upregulation of mitochondrial biogenesis due to its capability to deacetylate and thus activate the PPARgamma co-activator-1alpha, which stimulates mitochondrial activity and subsequently increases glucose metabolism, which in turn improves insulin sensitivity.	3	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PPARgamma co-activator-1alpha	PPARgamma co-activator-1alpha	PPARgamma co-activator-1alpha	3	4	22	24
Hepatic deletion of Sirt1 decreased co-activation of PGC-1alpha .	Hepatic deletion of Sirt1 decreased co-activation of PGC-1alpha.	1	8	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	3	4	7	8
Further , SIRT1 potentiates PGC-1alpha transcriptional activity in promoting mitochondrial biogenesis and oxidative phosphorylation .	Further, SIRT1 potentiates PGC-1alpha transcriptional activity in promoting mitochondrial biogenesis and oxidative phosphorylation.	2	6	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	4	5
In contrast , SIRT1 deacetylation and AMPK phosphorylation of PGC-1alpha XREF_BIBR ; XREF_BIBR increases PGC-1alpha activity , thereby enhancing the expression of metabolic genes involved in hepatic fatty acid beta oxidation .	In contrast, SIRT1 deacetylation and AMPK phosphorylation of PGC-1alpha XREF_BIBR; XREF_BIBR increases PGC-1alpha activity, thereby enhancing the expression of metabolic genes involved in hepatic fatty acid beta oxidation.	3	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1 deacetylation and AMPK phosphorylation	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	3	4	14	15
In cultured podocytes BF175 increased SIRT1 mediated activation of PGC1-alpha and protected against high glucose mediated mitochondrial injury .	In cultured podocytes BF175 increased SIRT1 mediated activation of PGC1-alpha and protected against high glucose mediated mitochondrial injury.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1-alpha	PGC1-alpha	PGC1-alpha	5	6	9	10
Knockdown of SIRT1 also increased PGC-1alpha activity .	Knockdown of SIRT1 also increased PGC-1alpha activity.	0	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	5	6
The results of our current study suggest that sudachitin treatment increased serum adiponectin levels and increased Sirt1 expression , which activates PGC-1alpha in the skeletal muscle .	The results of our current study suggest that sudachitin treatment increased serum adiponectin levels and increased Sirt1 expression, which activates PGC-1alpha in the skeletal muscle.	8	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	sudachitin treatment increased serum adiponectin levels and increased Sirt1 expression	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	16	17	21	22
Interestingly , both SIRT1 and AMPK together or independently activate PGC-1alpha to induce the expression of genes involved in glucose and fatty acid metabolism and restore ATP levels [ XREF_BIBR - XREF_BIBR ] .	Interestingly, both SIRT1 and AMPK together or independently activate PGC-1alpha to induce the expression of genes involved in glucose and fatty acid metabolism and restore ATP levels [XREF_BIBR - XREF_BIBR].	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	3	4	10	11
Furthermore , in response to cellular stress adenosine monophosphate ( AMP )-activated kinase ( AMPK ) has been shown to induce mitophagy via mammalian target of rapamycin ( mTOR ) inhibition and ULK1 activation [ XREF_BIBR , XREF_BIBR ] , whereas AMPK mediated SIRT1 phosphorylation activates PGC1alpha , which stimulates mitochondrial biogenesis [ XREF_BIBR ] .	Furthermore, in response to cellular stress adenosine monophosphate (AMP)-activated kinase (AMPK) has been shown to induce mitophagy via mammalian target of rapamycin (mTOR) inhibition and ULK1 activation [XREF_BIBR, XREF_BIBR], whereas AMPK mediated SIRT1 phosphorylation activates PGC1alpha, which stimulates mitochondrial biogenesis [XREF_BIBR].	41	49	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	AMPK mediated SIRT1 phosphorylation	sirt1	PGC1alpha	PGC1alpha	pgc1alpha	43	44	46	47
Importantly , SIRT1 activates PGC-1alpha , a master regulator of mitochondrial biogenesis and energy metabolism .	Importantly, SIRT1 activates PGC-1alpha, a master regulator of mitochondrial biogenesis and energy metabolism.	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	4	5
PGC-1alpha is activated by SIRT1 , which suggests a hierarchy of signalling elements in the determination of myonuclear number .	PGC-1alpha is activated by SIRT1, which suggests a hierarchy of signalling elements in the determination of myonuclear number.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	0	1
Activation of SIRT-1 activates PGC-1alpha , which reduces plaque burden in plaque competent mice [ XREF_BIBR ] .	Activation of SIRT-1 activates PGC-1alpha, which reduces plaque burden in plaque competent mice [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT-1	SIRT-1	SIRT-1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	4	5
PGC1-alpha is also transcriptionally activated in liver by SIRT1 .	PGC1-alpha is also transcriptionally activated in liver by SIRT1.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1-alpha	PGC1-alpha	PGC1-alpha	8	9	0	1
AMPK and SIRT1 also synergistically regulate eNOS and PGC1alpha similar to that of cortactin XREF_BIBR , XREF_BIBR However , knockdown of cortactin had little effect on PGC1alpha expression in HUVECs ( XREF_SUPPLEMENTARY ) , which suggests that cortactin is not an upstream regulator of PGC1alpha .	AMPK and SIRT1 also synergistically regulate eNOS and PGC1alpha similar to that of cortactin XREF_BIBR, XREF_BIBR However, knockdown of cortactin had little effect on PGC1alpha expression in HUVECs (XREF_SUPPLEMENTARY), which suggests that cortactin is not an upstream regulator of PGC1alpha.	0	9	synergistically regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	2	3	8	9
However , results from some more recent studies indicated that resveratrol activates SIRT1 via stimulating the AMPK pathway , which is supported by observations that 1 ) resveratrol consistently increased SIRT1 and PGC-1alpha activity in mice [ XREF_BIBR , XREF_BIBR ] and SIRT1 activates PGC-1alpha , one of the major targets of AMPK signaling ; 2 ) resveratrol can not activate SIRT1 with native substrates in vitro , although it activates SIRT1 in vivo and deacetylate fluorophore tagged substrates in vitro [ XREF_BIBR , XREF_BIBR ] ; and 3 ) the abilities of resveratrol to activate SIRT1 and exert the beneficial metabolic effects in wild-type mice are lost in AMPK deficient mice [ XREF_BIBR ] .	However, results from some more recent studies indicated that resveratrol activates SIRT1 via stimulating the AMPK pathway, which is supported by observations that 1) resveratrol consistently increased SIRT1 and PGC-1alpha activity in mice [XREF_BIBR, XREF_BIBR] and SIRT1 activates PGC-1alpha, one of the major targets of AMPK signaling; 2) resveratrol can not activate SIRT1 with native substrates in vitro, although it activates SIRT1 in vivo and deacetylate fluorophore tagged substrates in vitro [XREF_BIBR, XREF_BIBR]; and 3) the abilities of resveratrol to activate SIRT1 and exert the beneficial metabolic effects in wild-type mice are lost in AMPK deficient mice [XREF_BIBR].	42	113	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	42	43	44	45
In fact , as previously mentioned , SIRT1 is a transcriptional activator of PGC-1alpha ( a transcriptional co-regulator that governs mitochondrial biogenesis and activity ) that can compensate for neuronal mitochondrial loss due to alpha-syn expression [ XREF_BIBR ] .	In fact, as previously mentioned, SIRT1 is a transcriptional activator of PGC-1alpha (a transcriptional co-regulator that governs mitochondrial biogenesis and activity) that can compensate for neuronal mitochondrial loss due to alpha-syn expression [XREF_BIBR].	7	27	is a transcriptional activator	Positive_activation_copula_1	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	7	8	13	14
Human endothelial cells were exposed to lipopolysaccharide plus peptidoglycan G to mimic a sepsis environment , with a range of concentrations of a selective synthetic agonist of silent information regulator-1 ( SIRT-1 ) which activates PGC1alpha , or bis ( 2-hydroxy-benzylidene ) acetone ( 2HBA ) which activates NFE2L2 , with and without inhibitors of these pathways .	Human endothelial cells were exposed to lipopolysaccharide plus peptidoglycan G to mimic a sepsis environment, with a range of concentrations of a selective synthetic agonist of silent information regulator-1 (SIRT-1) which activates PGC1alpha, or bis (2-hydroxy-benzylidene) acetone (2HBA) which activates NFE2L2, with and without inhibitors of these pathways.	29	47	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT-1	SIRT-1	SIRT-1	PGC1alpha	PGC1alpha	PGC1alpha	31	32	35	36
Fasting also causes SIRT1 dependent activation of PGC-1alpha in skeletal muscle but the consequence is the induction of mitochondrial fatty acid oxidation [ XREF_BIBR ] .	Fasting also causes SIRT1 dependent activation of PGC-1alpha in skeletal muscle but the consequence is the induction of mitochondrial fatty acid oxidation [XREF_BIBR].	3	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	3	4	7	8
In support of this conclusion , they reported that inhibition of SIRT1 with nicotinamide or knock down of SIRT1 markedly reduced PGC-1alpha activation and attenuated the increase in mitochondrial proteins in response to AMPK activation .	In support of this conclusion, they reported that inhibition of SIRT1 with nicotinamide or knock down of SIRT1 markedly reduced PGC-1alpha activation and attenuated the increase in mitochondrial proteins in response to AMPK activation.	9	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	11	12	21	22
Both the DN SIRT1 and the SIRT1 shRNA resulted in increased PGC-1alpha coactivator activity , measured in C 2 C 12 myotubes co-transfected with a PGC-1alpha-GAL4 fusion construct and a luciferase reporter XREF_BIBR , and enhanced the resveratrol induced increase in PGC-1alpha activity ( XREF_FIG ) .	Both the DN SIRT1 and the SIRT1 shRNA resulted in increased PGC-1alpha coactivator activity, measured in C 2 C 12 myotubes co-transfected with a PGC-1alpha-GAL4 fusion construct and a luciferase reporter XREF_BIBR, and enhanced the resveratrol induced increase in PGC-1alpha activity (XREF_FIG).	6	42	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	6	7	41	42
Additionally , studies involving quenching of ROS with resveratrol , results in deacetylation and activation of PGC1alpha by SIRT1 and Nrf2 , both of which are associated with mitochondrial biogenesis and mitigation of oxidative stress and redox homeostasis [ XREF_BIBR ] .	Additionally, studies involving quenching of ROS with resveratrol, results in deacetylation and activation of PGC1alpha by SIRT1 and Nrf2, both of which are associated with mitochondrial biogenesis and mitigation of oxidative stress and redox homeostasis [XREF_BIBR].	10	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	18	19	16	17
Another metabolic sensor , Sirt1 , an NAD+ dependent type III deacetylase sirtuin , activates PGC-1alpha and various substrates , including PPARgamma and PPARalpha , in skeletal muscle and adipocytes to contribute to energy expenditure and browning of WAT and resistance to dietary obesity .	Another metabolic sensor, Sirt1, an NAD+ dependent type III deacetylase sirtuin, activates PGC-1alpha and various substrates, including PPARgamma and PPARalpha, in skeletal muscle and adipocytes to contribute to energy expenditure and browning of WAT and resistance to dietary obesity.	2	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	15	16
SIRT1 activation of PGC-1alpha enhances mitochondrial biogenesis , optimizes mitochondrial surface and volume ratio to reduce ROS production , and mounts an antioxidant defense [ XREF_BIBR , XREF_BIBR ] .	SIRT1 activation of PGC-1alpha enhances mitochondrial biogenesis, optimizes mitochondrial surface and volume ratio to reduce ROS production, and mounts an antioxidant defense [XREF_BIBR, XREF_BIBR].	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	3	4
In the MPTP induced mouse model of PD , RV restored the cellular antioxidant defense system via SIRT1 dependent activation of PGC-1alpha , which , in turn , augmented the expression of antioxidant enzymes [ XREF_BIBR ] .	In the MPTP induced mouse model of PD, RV restored the cellular antioxidant defense system via SIRT1 dependent activation of PGC-1alpha, which, in turn, augmented the expression of antioxidant enzymes [XREF_BIBR].	17	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	17	18	21	22
Knockdown of Perilipin 5 is associated with reduced catecholamine stimulated deacetylation of PGC-1alpha ; and SIRT1 , which is present in the Perilipin 5 and PGC-1alpha complex , is well known to promote PGC-1alpha activity via deacetylation .	Knockdown of Perilipin 5 is associated with reduced catecholamine stimulated deacetylation of PGC-1alpha; and SIRT1, which is present in the Perilipin 5 and PGC-1alpha complex, is well known to promote PGC-1alpha activity via deacetylation.	15	34	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	15	16	33	34
The NAD + -dependent deacetylase SIRT1 positively regulates PGC-1alpha through deacetylation and has been implicated in neuronal protection ( Kim etal ., 2007 ; Michan etal ., 2010 ) .	The NAD + -dependent deacetylase SIRT1 positively regulates PGC-1alpha through deacetylation and has been implicated in neuronal protection (Kim etal., 2007; Michan etal., 2010).	1	9	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	8	9
For example , SIRT1 directly suppresses PPARgamma transcriptional activity , but SIRT1 also activates PGC-1alpha , which could increase the transcriptional activities of PPARgamma .	For example, SIRT1 directly suppresses PPARgamma transcriptional activity, but SIRT1 also activates PGC-1alpha, which could increase the transcriptional activities of PPARgamma.	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	11	12	14	15
Exercise induced activation of either AMPK or SIRT1 in muscle is known to activate PGC1alpha where it drives oxidative fiber remodeling by activating pro oxidative transcription factors .	Exercise induced activation of either AMPK or SIRT1 in muscle is known to activate PGC1alpha where it drives oxidative fiber remodeling by activating pro oxidative transcription factors.	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	7	8	14	15
Upon nutrient stress , the NAD + -dependent deacetylase SIRT1 activates PGC-1alpha , a reaction that is rate limited by availability of the metabolite NAD + .	Upon nutrient stress, the NAD + -dependent deacetylase SIRT1 activates PGC-1alpha, a reaction that is rate limited by availability of the metabolite NAD +.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	9	10	11	12
Therefore an important regulator of mitochondrial biogenesis is the histone deacetylase sirtuin 1 ( Sirt1 ) which can serve to activate PGC1alpha and mitochondrial biogenesis [ XREF_BIBR ] .	Therefore an important regulator of mitochondrial biogenesis is the histone deacetylase sirtuin 1 (Sirt1) which can serve to activate PGC1alpha and mitochondrial biogenesis [XREF_BIBR].	0	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC1alpha	PGC1alpha	PGC1alpha	14	15	21	22
As expected , we found no change in transcripts specific to PGC1alpha , which is activated posttranscriptionally by Sirt1 , and to two PGC1alpha partners , NRF1 and NRF2 .	As expected, we found no change in transcripts specific to PGC1alpha, which is activated posttranscriptionally by Sirt1, and to two PGC1alpha partners, NRF1 and NRF2.	9	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC1alpha	PGC1alpha	PGC1alpha	18	19	11	12
PGC-1alpha is not only an important coactivator in liver biology , but may be activated by Sirt1 .	PGC-1alpha is not only an important coactivator in liver biology, but may be activated by Sirt1.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	16	17	0	1
Although AMPK directly activates PGC-1alpha by phosphorylation , it also acts indirectly by enhancing the activity of SIRT1 , the enzyme that deacetylates and thereby activates PGC-1alpha [ XREF_BIBR ] .	Although AMPK directly activates PGC-1alpha by phosphorylation, it also acts indirectly by enhancing the activity of SIRT1, the enzyme that deacetylates and thereby activates PGC-1alpha [XREF_BIBR].	15	28	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	17	18	26	27
SIRT1 deacetylates and thereby stimulates PGC1alpha .	SIRT1 deacetylates and thereby stimulates PGC1alpha.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC1alpha	PGC1alpha	PGC1alpha	0	1	5	6
It has been shown to enhance mitochondrial biogenesis through Sirt1 , which activates PGC-1alpha , the co-activator of the nuclear respiratory factor ( Nrf ) proteins that control mitochondrial biogenesis .	It has been shown to enhance mitochondrial biogenesis through Sirt1, which activates PGC-1alpha, the co-activator of the nuclear respiratory factor (Nrf) proteins that control mitochondrial biogenesis.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	9	10	13	14
The silent information regulator protein ( Sir2 ) homologue SIRT1 is another activator of PGC-1alpha .	The silent information regulator protein (Sir2) homologue SIRT1 is another activator of PGC-1alpha.	8	15	is another activator	Positive_activation_copula_1	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	9	10	14	15
The therapeutic potential of resveratrol , a polyphenolic extract from grape skins and red wine , has been gaining increasing popularity as a CR mimetic due to its ability to induce mitochondrial biogenesis via SIRT1 mediated activation of PGC-1alpha in mice .	The therapeutic potential of resveratrol, a polyphenolic extract from grape skins and red wine, has been gaining increasing popularity as a CR mimetic due to its ability to induce mitochondrial biogenesis via SIRT1 mediated activation of PGC-1alpha in mice.	32	40	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	34	35	38	39
Thus , higher sirt1 expression in the mGHRKO mice upon fasting could result in increased activation of PGC1alpha in the mGHRKO mice .	Thus, higher sirt1 expression in the mGHRKO mice upon fasting could result in increased activation of PGC1alpha in the mGHRKO mice.	3	21	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	sirt1	sirt1 expression	sirt1	PGC1alpha	PGC1alpha	pgc1alpha	3	4	17	18
SIRT1 Silencing Decreased PGC-1alpha and Mitochondrial Electron Transport Chain Proteins after ICH Injury .	SIRT1 Silencing Decreased PGC-1alpha and Mitochondrial Electron Transport Chain Proteins after ICH Injury.	0	9	Decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	3	4
Using both of gain- and loss-of-function experiments , we showed that Sirt1 dependent activation of FoxO1 was critical in mediating shear stress induced autophagy .	Using both of gain- and loss-of-function experiments, we showed that Sirt1 dependent activation of FoxO1 was critical in mediating shear stress induced autophagy.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	FoxO1	FoxO1	FoxO1	11	12	15	16
Sirt1 is known to activate Foxo1 by deacetylation ( promoting nuclear localization ) while Akt inhibits Foxo1 by phosphorylation ( preventing nuclear translocation ) .	Sirt1 is known to activate Foxo1 by deacetylation (promoting nuclear localization) while Akt inhibits Foxo1 by phosphorylation (preventing nuclear translocation).	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	Foxo1	Foxo1	Foxo1	0	1	5	6
SIRT1 also has been demonstrated to promote the transcriptional activity of FoxO1 to up-regulate MnSOD , suppress oxidative stress in cardiomyocytes , reduce cardiac infarct volume , and improve functional recovery after ischemic and reperfusion in murine models [ XREF_BIBR ] .	SIRT1 also has been demonstrated to promote the transcriptional activity of FoxO1 to up-regulate MnSOD, suppress oxidative stress in cardiomyocytes, reduce cardiac infarct volume, and improve functional recovery after ischemic and reperfusion in murine models [XREF_BIBR].	0	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FoxO1	FoxO1	FoxO1	0	1	11	12
SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 .	SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3.	0	12	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1 overexpression	sirt1	FoxO1	FoxO1	foxo1	0	1	10	11
In addition to enhancing FOXO1 -- C/EBPalpha interactions [ XREF_BIBR ] , SIRT1 also acts to increase adiponectin transcription in adipocytes by activating FOXO1 directly through its deacetylation ( see above ) .	In addition to enhancing FOXO1 -- C/EBPalpha interactions [XREF_BIBR], SIRT1 also acts to increase adiponectin transcription in adipocytes by activating FOXO1 directly through its deacetylation (see above).	12	24	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	12	13	23	24
Exposure of the cells to Res ( 20 microM ) caused rapid activation of SIRT1 , which had a dual effect on FoxO1 function : SIRT1 increased FoxO1 ' s ability to induce cell cycle arrest , but inhibited FoxO1 ' s ability to induce cell death .	Exposure of the cells to Res (20 microM) caused rapid activation of SIRT1, which had a dual effect on FoxO1 function : SIRT1 increased FoxO1 's ability to induce cell cycle arrest, but inhibited FoxO1 's ability to induce cell death.	25	38	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FoxO1	FoxO1	FoxO1	25	26	27	28
SIRT1 can target FOXO1 to bind and deacetylate FOXO1 at residues that are acetylated by cAMP response element binding protein [ XREF_BIBR ] .	SIRT1 can target FOXO1 to bind and deacetylate FOXO1 at residues that are acetylated by cAMP response element binding protein [XREF_BIBR].	0	4	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	0	1	3	4
These results suggest that Sirt1 positively mediates nuclear localization of FoxO1 in the mouse heart in vivo .	These results suggest that Sirt1 positively mediates nuclear localization of FoxO1 in the mouse heart in vivo.	4	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	FoxO1	FoxO1	FoxO1	4	5	10	11
SIRT1 activates Foxo1 and Foxo4 which are involved in the promotion of cell-cycle arrest by induction of p27 Kip1 and in enhancing cellular defences against oxidative stress through the regulation of manganese superoxide dismutase , catalase , and GADD45 ( growth arrest and DNA damage inducible alpha ) [ XREF_BIBR , XREF_BIBR ] .	SIRT1 activates Foxo1 and Foxo4 which are involved in the promotion of cell-cycle arrest by induction of p27 Kip1 and in enhancing cellular defences against oxidative stress through the regulation of manganese superoxide dismutase, catalase, and GADD45 (growth arrest and DNA damage inducible alpha) [XREF_BIBR, XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Foxo1	Foxo1	Foxo1	0	1	2	3
In addition , Sirt1 overexpression in transgenic mice induced deacetylation and nuclear translocation of FoxO1 .	In addition, Sirt1 overexpression in transgenic mice induced deacetylation and nuclear translocation of FoxO1.	3	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1 overexpression	sirt1	FoxO1	FoxO1	foxo1	3	4	14	15
Moreover , resveratrol , a plant polyphenol activator of SIRT1 , increases FoxO1 dependent SIRT1 transcription activity and thus induces its expression .	Moreover, resveratrol, a plant polyphenol activator of SIRT1, increases FoxO1 dependent SIRT1 transcription activity and thus induces its expression.	7	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FoxO1	FoxO1	FoxO1	9	10	12	13
During prolonged fasting , FOXO1 activity supported by SIRT1 seems to be a key element in the maintenance of glucose production .	During prolonged fasting, FOXO1 activity supported by SIRT1 seems to be a key element in the maintenance of glucose production.	4	9	supported	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	8	9	4	5
SIRT1 activates FOXO1 , which forms a transcription complex with CCAAT and enhancer binding protein alpha ( C/EBPalpha ) , thus promoting adiponectin gene transcription .	SIRT1 activates FOXO1, which forms a transcription complex with CCAAT and enhancer binding protein alpha (C/EBPalpha), thus promoting adiponectin gene transcription.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	0	1	2	3
Tobita et al reported that inhibition of SIRT1 could impair AKT and FOXO1 pathways , causing increased gluconeogenesis in human hepatocytes [ XREF_BIBR ] .	Tobita et al reported that inhibition of SIRT1 could impair AKT and FOXO1 pathways, causing increased gluconeogenesis in human hepatocytes [XREF_BIBR].	5	13	impair	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	7	8	12	13
Resveratrol , a proposed SIRT1 activator ( reviewed in section X ) , prevented hypoxia induced apoptosis in cardiomyocytes through SIRT1 mediated FOXO1 regulation .	Resveratrol, a proposed SIRT1 activator (reviewed in section X), prevented hypoxia induced apoptosis in cardiomyocytes through SIRT1 mediated FOXO1 regulation.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	20	21	22	23
Specifically , SIRT1 was found to directly deacetylate and thereby activate FOXO1 [ XREF_BIBR ] and FOXO3a [ XREF_BIBR ] , which play important roles in transducing insulin signaling downstream of serine and threoine protein kinase ( Akt ) [ XREF_BIBR ] .	Specifically, SIRT1 was found to directly deacetylate and thereby activate FOXO1 [XREF_BIBR] and FOXO3a [XREF_BIBR], which play important roles in transducing insulin signaling downstream of serine and threoine protein kinase (Akt) [XREF_BIBR].	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	2	3	11	12
SIRT1 that activates FOXO1 known as longevity gene is also implicated in the development of skin aging , i.e ., SIRT1 activation --> deacetylation of FOXO1 --> increased Rab7 expression --> stimulate autophagy induction .	SIRT1 that activates FOXO1 known as longevity gene is also implicated in the development of skin aging, i.e., SIRT1 activation --> deacetylation of FOXO1 --> increased Rab7 expression --> stimulate autophagy induction.	0	10	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	0	1	3	4
Other studies suggest that SIRT1 modulation of FOXO1 is important for proper glucose homeostasis , angiogenesis , and feeding behaviors .	Other studies suggest that SIRT1 modulation of FOXO1 is important for proper glucose homeostasis, angiogenesis, and feeding behaviors.	4	8	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	4	5	7	8
Evidence showed that Sirt1 dependent activation of FOXO1 was crucial in vascular protection after the onset of oxidative stress [ XREF_BIBR ] .	Evidence showed that Sirt1 dependent activation of FOXO1 was crucial in vascular protection after the onset of oxidative stress [XREF_BIBR].	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	FOXO1	FOXO1	FOXO1	3	4	7	8
Interaction of FOXO1 ( a direct activator of ATGL ) and SIRT1 ( an activator of FOXO1 ) led to activation of FOXO1 which is linked with increased tumorigenicity of cancer cells via acylglycerol kinase [ XREF_BIBR ] .	Interaction of FOXO1 (a direct activator of ATGL) and SIRT1 (an activator of FOXO1) led to activation of FOXO1 which is linked with increased tumorigenicity of cancer cells via acylglycerol kinase [XREF_BIBR].	0	17	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	11	12	16	17
SIRT1 has been demonstrated to promote the transcriptional activity of FoxO1 to upregulate MnSOD , suppress oxidative stress in cardiac myocytes , and thereby reduce cardiac infarct volume and improve functional recovery after ischemia and reperfusion in mice [ XREF_BIBR ] .	SIRT1 has been demonstrated to promote the transcriptional activity of FoxO1 to upregulate MnSOD, suppress oxidative stress in cardiac myocytes, and thereby reduce cardiac infarct volume and improve functional recovery after ischemia and reperfusion in mice [XREF_BIBR].	0	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FoxO1	FoxO1	FoxO1	0	1	10	11
With this caveat , it ' s notable that changes in energy homeostasis are opposite in the two models , consistent with the notion that a gain of SirT1 function would promote FoxO1 activity via deacetylation XREF_BIBR , and thus with a specific role of SirT1 and FoxO1 in linking food intake with energy expenditure .	With this caveat, it 's notable that changes in energy homeostasis are opposite in the two models, consistent with the notion that a gain of SirT1 function would promote FoxO1 activity via deacetylation XREF_BIBR, and thus with a specific role of SirT1 and FoxO1 in linking food intake with energy expenditure.	28	33	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	FoxO1	FoxO1	FoxO1	28	29	32	33
RES induces SIRT1 , that may modulate Foxo1 signaling which is important in insulin signaling .	RES induces SIRT1, that may modulate Foxo1 signaling which is important in insulin signaling.	1	8	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Foxo1	Foxo1	Foxo1	2	3	7	8
Whereas SIRT1 activation enhances the transcriptional activity of FOXO1 XREF_BIBR , FOXO3a XREF_BIBR , and FOXO4 XREF_BIBR on ROS detoxifying enzymes by deacetylation , the CBP and p300 mediated acetylation of FOXOs impairs their DNA binding activity XREF_BIBR .	Whereas SIRT1 activation enhances the transcriptional activity of FOXO1 XREF_BIBR, FOXO3a XREF_BIBR, and FOXO4 XREF_BIBR on ROS detoxifying enzymes by deacetylation, the CBP and p300 mediated acetylation of FOXOs impairs their DNA binding activity XREF_BIBR.	1	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	1	2	8	9
Analyses of the acetylation status of the Sirt1 target Foxo1 in skeletal muscle and p65 in the liver show that SRT3025 increases deacetylation of Sirt1 target proteins in vivo .	Analyses of the acetylation status of the Sirt1 target Foxo1 in skeletal muscle and p65 in the liver show that SRT3025 increases deacetylation of Sirt1 target proteins in vivo.	4	17	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	Foxo1	Foxo1	Foxo1	7	8	9	10
In cardiac myocytes , SIRT1 is reported to activate FoxO1 , leading to the upregulation of Rab7 , a small GTP binding protein that mediates late autophagosome-lysosome fusion [ XREF_BIBR ] .	In cardiac myocytes, SIRT1 is reported to activate FoxO1, leading to the upregulation of Rab7, a small GTP binding protein that mediates late autophagosome-lysosome fusion [XREF_BIBR].	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FoxO1	FoxO1	FoxO1	4	5	9	10
In N43 hypothalamic cells , pharmacological inhibition of Sirt1 increases anorexigenic POMC expression but co-treatment with Sirt1 inhibitor and FoxO1 siRNA does not XREF_BIBR , suggesting that Sirt1 mediated FoxO1 deactylation is involved in the regulation of POMC mRNA and food intake .	In N43 hypothalamic cells, pharmacological inhibition of Sirt1 increases anorexigenic POMC expression but co-treatment with Sirt1 inhibitor and FoxO1 siRNA does not XREF_BIBR, suggesting that Sirt1 mediated FoxO1 deactylation is involved in the regulation of POMC mRNA and food intake.	27	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	FoxO1	FoxO1	FoxO1	27	28	29	30
However , Sirt-1 ( an activator of FoXO-1 ) reduces adipogenic differentiation potentially by deacetylating PPAR-gamma or impairing the formation of FoXO-1 and PPAR-gamma complexes [ XREF_BIBR , XREF_BIBR ] .	However, Sirt-1 (an activator of FoXO-1) reduces adipogenic differentiation potentially by deacetylating PPAR-gamma or impairing the formation of FoXO-1 and PPAR-gamma complexes [XREF_BIBR, XREF_BIBR].	2	25	reduces	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	Sirt-1	Sirt-1	sirt-1	FoXO-1	FoXO-1 and PPAR-gamma complexes	foxo-1	2	3	21	22
XREF_BIBR , XREF_BIBR Using both gain- and loss-of-function experiments , we provided evidence supporting that Sirt1 mediated FoxO1 activation was likely to have a major role in flow induced autophagy in vascular EC .	XREF_BIBR, XREF_BIBR Using both gain- and loss-of-function experiments, we provided evidence supporting that Sirt1 mediated FoxO1 activation was likely to have a major role in flow induced autophagy in vascular EC.	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	FoxO1	FoxO1	FoxO1	15	16	17	18
Hypoxia induced apoptosis in embryonic rat heart derived H9c2 cells was greatly decreased following treatment with resveratrol by activation of SIRT1 increasing the ability of FOXO1 ( Forkhead box factors regulated by insulin and Akt ) to induce cell cycle arrest .	Hypoxia induced apoptosis in embryonic rat heart derived H9c2 cells was greatly decreased following treatment with resveratrol by activation of SIRT1 increasing the ability of FOXO1 (Forkhead box factors regulated by insulin and Akt) to induce cell cycle arrest.	18	26	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	20	21	25	26
Exposure of the cells to resveratrol caused rapid activation of Sirt1 , which had a dual effect on FoxO1 function : Sirt1 increased FoxO1 ' s ability to induce cell cycle arrest , but inhibited FoxO1 ' s ability to induce cell death .	Exposure of the cells to resveratrol caused rapid activation of Sirt1, which had a dual effect on FoxO1 function : Sirt1 increased FoxO1 's ability to induce cell cycle arrest, but inhibited FoxO1 's ability to induce cell death.	21	34	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	FoxO1	FoxO1	FoxO1	21	22	23	24
It is interesting to note that SIRT1 activates FOXO1 and CCAAT and enhancer binding protein alpha interaction leading to increased adiponectin gene transcription , which is an essential factor for regulation of adipogenesis [ XREF_BIBR ] .	It is interesting to note that SIRT1 activates FOXO1 and CCAAT and enhancer binding protein alpha interaction leading to increased adiponectin gene transcription, which is an essential factor for regulation of adipogenesis [XREF_BIBR].	6	17	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	6	7	8	9
In parallel , SIRT1 activates the transcription factor FOXO1 , which induces the same switch in transcription , reinforcing gluconeogenesis .	In parallel, SIRT1 activates the transcription factor FOXO1, which induces the same switch in transcription, reinforcing gluconeogenesis.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	3	4	8	9
SIRT1 is a key metabolic sensor and regulator in cells and directly deacetylates and modulates some important metabolic regulators , including PGC-1alpha ( peroxisome proliferator activated receptor gamma coactivator 1-alpha ) , peroxisome proliferator activated receptors ( PPARs ) , p53 , and forkhead box protein O1 ( FOXO1 ) which change the expression of transcriptional programs that modulate cholesterol , lipid and energy homeostasis [ XREF_BIBR ] .	SIRT1 is a key metabolic sensor and regulator in cells and directly deacetylates and modulates some important metabolic regulators, including PGC-1alpha (peroxisome proliferator activated receptor gamma coactivator 1-alpha), peroxisome proliferator activated receptors (PPARs), p53, and forkhead box protein O1 (FOXO1) which change the expression of transcriptional programs that modulate cholesterol, lipid and energy homeostasis [XREF_BIBR].	0	47	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	forkhead box protein O1	forkhead box protein O1	forkhead box protein O1	0	1	43	47
SIRT1 activates Foxo1 and Foxo3 by deacetylation , which promotes nuclear localization of these factors XREF_BIBR , XREF_BIBR .	SIRT1 activates Foxo1 and Foxo3 by deacetylation, which promotes nuclear localization of these factors XREF_BIBR, XREF_BIBR.	0	4	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Foxo1	Foxo1	Foxo1	0	1	2	3
SIRT1 also has been demonstrated to promote the transcriptional activity of FoxO1 to upregulate MnSOD , suppress oxidative stress in cardiac myocytes , reduce cardiac infarct volume , and improve functional recovery after ischemic and reperfusion in murine models [ XREF_BIBR ] .	SIRT1 also has been demonstrated to promote the transcriptional activity of FoxO1 to upregulate MnSOD, suppress oxidative stress in cardiac myocytes, reduce cardiac infarct volume, and improve functional recovery after ischemic and reperfusion in murine models [XREF_BIBR].	0	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FoxO1	FoxO1	FoxO1	0	1	11	12
25 We demonstrated that flow decreased the acetylation level of FoxO1 in EC ; likewise , we showed that overexpression of Sirt1 induced nuclear localization of FoxO1 in EC .	25 We demonstrated that flow decreased the acetylation level of FoxO1 in EC; likewise, we showed that overexpression of Sirt1 induced nuclear localization of FoxO1 in EC.	19	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	overexpression of Sirt1	sirt1	FoxO1	FoxO1	foxo1	21	22	26	27
SIRT1 mediated activation of FOXO1 may therefore protect from obesity induced inflammation and subsequently insulin resistance .	SIRT1 mediated activation of FOXO1 may therefore protect from obesity induced inflammation and subsequently insulin resistance.	0	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	0	1	4	5
Sirt1 dependent activation of FoxO1 is critical in mediating shear induced autophagy .	Sirt1 dependent activation of FoxO1 is critical in mediating shear induced autophagy.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	FoxO1	FoxO1	FoxO1	0	1	4	5
In endothelial cells , SIRT1 modulates the transcriptional activity of Foxo1 and p53 , and activates the enzymatic activity of endothelial nitric oxide synthase ( eNOS ) .	In endothelial cells, SIRT1 modulates the transcriptional activity of Foxo1 and p53, and activates the enzymatic activity of endothelial nitric oxide synthase (eNOS).	4	15	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Foxo1	Foxo1	Foxo1	4	5	10	11
PEPCK was induced in a biphasic manner ( 1-4 h and 16-24 h ) possibly by SIRT1 activation of FOXO1 and a second phase induction activated by autofeedback regulation of SIRT1 expression via FoxO1 as described by Xiong et al ..	PEPCK was induced in a biphasic manner (1-4 h and 16-24 h) possibly by SIRT1 activation of FOXO1 and a second phase induction activated by autofeedback regulation of SIRT1 expression via FoxO1 as described by Xiong et al..	16	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	16	17	19	20
FOXO family is a kind of important acting factor of SIRT1 , and it was generally believed that SIRT1 could promote activity of FOXO1 to control cellular oxidative stress response by making FOXO1 deacetylation [ XREF_BIBR ] .	FOXO family is a kind of important acting factor of SIRT1, and it was generally believed that SIRT1 could promote activity of FOXO1 to control cellular oxidative stress response by making FOXO1 deacetylation [XREF_BIBR].	18	24	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	18	19	23	24
FOXO1 , whose activity is increased by deacetylation of SIRT1 [ XREF_BIBR , XREF_BIBR ] , also regulates thyroid hormone induced transcription of key hepatic gluconeogenic genes [ XREF_BIBR ] .	FOXO1, whose activity is increased by deacetylation of SIRT1 [XREF_BIBR, XREF_BIBR], also regulates thyroid hormone induced transcription of key hepatic gluconeogenic genes [XREF_BIBR].	0	17	increased	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	SIRT1	deacetylation of SIRT1	sirt1	FOXO1	FOXO1	foxo1	9	10	0	1
These tumors also show increased activation of AKT suggesting that SIRT1 might promote cancer by activating AKT [ XREF_BIBR , XREF_BIBR ] .	These tumors also show increased activation of AKT suggesting that SIRT1 might promote cancer by activating AKT [XREF_BIBR, XREF_BIBR].	10	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	AKT	AKT	AKT	10	11	16	17
Overall , this study suggested caspase dependent activation of both the intrinsic and extrinsic signaling pathways , probably through blockade of the SIRT1 and p53 mediated mitochondrial and Akt pathways to exert the proapoptotic effect of CCF-NLs in DBTRG-05MG GBM cells .	Overall, this study suggested caspase dependent activation of both the intrinsic and extrinsic signaling pathways, probably through blockade of the SIRT1 and p53 mediated mitochondrial and Akt pathways to exert the proapoptotic effect of CCF-NLs in DBTRG-05MG GBM cells.	19	29	mediated	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	22	23	28	29
We therefore propose that in the presence of growth ( insulin ) signaling , SIRT1 activates Akt , resulting in the phosphorylation of Foxo .	We therefore propose that in the presence of growth (insulin) signaling, SIRT1 activates Akt, resulting in the phosphorylation of Foxo.	12	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	14	15	16	17
We observed that SIRT1 inhibition abrogated the activation of Akt kinase , mTOR , phosphorylated p70S6K1 ( Thr 389 , Thr 421 and Ser 424 ) and p70S6K1 ( XREF_FIG ) , suggesting that SIRT1 regulated the p16/RB pathway through the Akt and p70S6K1 signaling pathway .	We observed that SIRT1 inhibition abrogated the activation of Akt kinase, mTOR, phosphorylated p70S6K1 (Thr 389, Thr-421 and Ser-424) and p70S6K1 (XREF_FIG), suggesting that SIRT1 regulated the p16/RB pathway through the Akt and p70S6K1 signaling pathway.	3	10	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	3	4	9	10
SirT1 is known to promote membrane localization and activation of AKT via SirT1 dependent deacetylation of two lysine residues in the PH ( pleckstrin homology ) domain of AKT XREF_BIBR .	SirT1 is known to promote membrane localization and activation of AKT via SirT1 dependent deacetylation of two lysine residues in the PH (pleckstrin homology) domain of AKT XREF_BIBR.	0	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	AKT	AKT	AKT	0	1	10	11
These findings suggest that SIRT1 upregulates insulin signaling and Akt activation at multiple levels .	These findings suggest that SIRT1 upregulates insulin signaling and Akt activation at multiple levels.	4	10	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	4	5	9	10
This model indicated SIRT1 may pose a central role in p16 repression through direct deacetylation and directly and indirectly modulating Akt and p70S6K1 signaling under the circumstance of nutrition stress ( XREF_FIG ) .	This model indicated SIRT1 may pose a central role in p16 repression through direct deacetylation and directly and indirectly modulating Akt and p70S6K1 signaling under the circumstance of nutrition stress (XREF_FIG).	3	23	modulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	3	4	20	21
SIRT1 also can increase Akt activity that is considered to be a principle pathway for cellular proliferation and survival , for the cytoprotective capacity of EPO and nicotinamide , and for mediating insulin signaling XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR .	SIRT1 also can increase Akt activity that is considered to be a principle pathway for cellular proliferation and survival, for the cytoprotective capacity of EPO and nicotinamide, and for mediating insulin signaling XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR.	0	5	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	0	1	4	5
Accordingly , later research indicated that the specific deletion of hepatic SIRT1 in mice impaired the mTorc2 and Akt signaling and resulted in hyperglycemia , oxidative damage , and insulin resistance .	Accordingly, later research indicated that the specific deletion of hepatic SIRT1 in mice impaired the mTorc2 and Akt signaling and resulted in hyperglycemia, oxidative damage, and insulin resistance.	8	19	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	11	12	18	19
Intriguingly , resveratrol treatment above 3 microM did not significantly activate AKT , suggesting that resveratrol treatment above 3 microM may have additional activity that is independent of SirT1 activation of AKT .	Intriguingly, resveratrol treatment above 3 microM did not significantly activate AKT, suggesting that resveratrol treatment above 3 microM may have additional activity that is independent of SirT1 activation of AKT.	28	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	AKT	AKT	AKT	28	29	31	32
In HCC , SIRT1 is aberrantly overexpressed and activates TERT gene promoter [ XREF_BIBR ] , YAP and TEAD4 association [ XREF_BIBR ] , c-Myc stabilization [ XREF_BIBR ] , NF-kB [ XREF_BIBR ] , wnt and beta-catenin [ XREF_BIBR ] , and PI3K and AKT [ XREF_BIBR ] signaling to stimulate cell proliferation and metastasis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In HCC, SIRT1 is aberrantly overexpressed and activates TERT gene promoter [XREF_BIBR], YAP and TEAD4 association [XREF_BIBR], c-Myc stabilization [XREF_BIBR], NF-kB [XREF_BIBR], wnt and beta-catenin [XREF_BIBR], and PI3K and AKT [XREF_BIBR] signaling to stimulate cell proliferation and metastasis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	46	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1 is aberrantly overexpressed	sirt1	AKT	AKT	akt	3	4	45	46
In another study , SIRT1 also activated Akt and PI3K signaling , by deacetylating Akt , and resulted in enhancement of cardiac hypertrophic response in cardiomyocytes [ XREF_BIBR ] .	In another study, SIRT1 also activated Akt and PI3K signaling, by deacetylating Akt, and resulted in enhancement of cardiac hypertrophic response in cardiomyocytes [XREF_BIBR].	4	17	activated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	SIRT1	SIRT1	sirt1	Akt	deacetylating Akt	akt	4	5	14	15
Role of SIRT1 mediated mitochondrial and Akt pathways in glioblastoma cell death induced by Cotinus coggygria flavonoid nanoliposomes .	Role of SIRT1 mediated mitochondrial and Akt pathways in glioblastoma cell death induced by Cotinus coggygria flavonoid nanoliposomes.	0	7	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	2	3	6	7
The increased SIRT1 expression induces neuroendocrine differentiation of prostate cancer cells by activating the Akt pathway .	The increased SIRT1 expression induces neuroendocrine differentiation of prostate cancer cells by activating the Akt pathway.	2	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1 expression	sirt1	Akt	Akt	akt	2	3	14	15
The downregulation of SIRT1 induced suppression of the AKT and MRP1 pathway in BEL/FU cells ( Figs XREF_FIG C and XREF_SUPPLEMENTARY ) , and the overexpression of SIRT1 activated the AKT and MRP1 pathway in BEL7402 cells .	The downregulation of SIRT1 induced suppression of the AKT and MRP1 pathway in BEL/FU cells (Figs XREF_FIG C and XREF_SUPPLEMENTARY), and the overexpression of SIRT1 activated the AKT and MRP1 pathway in BEL7402 cells.	25	33	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	overexpression of SIRT1	sirt1	AKT	AKT	akt	27	28	30	31
Resveratrol also acts on bone architecture by promoting a proper bone remodeling , through reducing prostaglandin E1 ( PGE1 ) , prostaglandin D2 ( PGD-2 ) , prostaglandin F 2alpha ( PGF2alpha ) and basic fibroblast growth factor 2 ( FGF-2 )-stimulated OPG production , through a mechanism involving SIRT1 activation and inhibition of Akt and MAPKs signaling .	Resveratrol also acts on bone architecture by promoting a proper bone remodeling, through reducing prostaglandin E1 (PGE1), prostaglandin D2 (PGD-2), prostaglandin F 2alpha (PGF2alpha) and basic fibroblast growth factor 2 (FGF-2)-stimulated OPG production, through a mechanism involving SIRT1 activation and inhibition of Akt and MAPKs signaling.	49	57	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	49	50	54	55
These combined data demonstrate that following low dose resveratrol treatment differentiation is induced through SirT1 direct activation of AKT ; an activity that is independent of AMPK activation .	These combined data demonstrate that following low dose resveratrol treatment differentiation is induced through SirT1 direct activation of AKT; an activity that is independent of AMPK activation.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	AKT	AKT	AKT	14	15	18	19
Sirt1 and Sirt2 inhibitors additively inhibited the constitutive AKT activity in these cells .	Sirt1 and Sirt2 inhibitors additively inhibited the constitutive AKT activity in these cells.	0	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	AKT	AKT	AKT	0	1	8	9
These inhibitors significantly blocked the phosphorylation of Akt on Thr308 in the presence of elevated SirT1 ( data not shown ) , indicating that activation of Akt by SirT1 occurs via the IGFR and PI3Kinases .	These inhibitors significantly blocked the phosphorylation of Akt on Thr308 in the presence of elevated SirT1 (data not shown), indicating that activation of Akt by SirT1 occurs via the IGFR and PI3Kinases.	24	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	Akt	Akt	Akt	28	29	26	27
But in conditions where nutrients are ample , SIRT1 promotes Akt signaling and cellular senescence .	But in conditions where nutrients are ample, SIRT1 promotes Akt signaling and cellular senescence.	8	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	8	9	10	11
SIRT1 increases Akt activity that is considered to be a principle pathway for cellular proliferation , survival , and for mediating insulin signaling [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	SIRT1 increases Akt activity that is considered to be a principle pathway for cellular proliferation, survival, and for mediating insulin signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	3	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	0	1	2	3
However , a low or high dose of resveratrol acts by targeting different signaling molecules implicated in the induction of VSMC differentiation ; the low dose stimulates differentiation through SIRT1 mediated activation of Akt , whereas high-dose resveratrol stimulates differentiation through AMPK mediated inhibition of the mTORC1 pathway , allowing activation of Akt [ XREF_BIBR ] .	However, a low or high dose of resveratrol acts by targeting different signaling molecules implicated in the induction of VSMC differentiation; the low dose stimulates differentiation through SIRT1 mediated activation of Akt, whereas high-dose resveratrol stimulates differentiation through AMPK mediated inhibition of the mTORC1 pathway, allowing activation of Akt [XREF_BIBR].	29	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	29	30	33	34
Activation of Akt by SirT1 leads to phosphorylation of MDM2 and inhibition of the proapoptotic protein p53 .	Activation of Akt by SirT1 leads to phosphorylation of MDM2 and inhibition of the proapoptotic protein p53.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	Akt	Akt	Akt	4	5	2	3
SIRT1 increases Akt activity that leads to cellular protection .	SIRT1 increases Akt activity that leads to cellular protection.	0	3	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	0	1	2	3
Using animal models carrying constitutive or tissue specific loss-of-function mutations of SIRT1 , we have previously demonstrated that liver specific disruption of SIRT1 impairs mTorc2 and Akt signaling and results in hyperglycemia , oxidative damage , and insulin resistance XREF_BIBR , XREF_BIBR .	Using animal models carrying constitutive or tissue specific loss-of-function mutations of SIRT1, we have previously demonstrated that liver specific disruption of SIRT1 impairs mTorc2 and Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance XREF_BIBR, XREF_BIBR.	20	27	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	22	23	26	27
SIRT1 activates the Akt pathway via a direct physical interaction , instead of acting through N-Myc .	SIRT1 activates the Akt pathway via a direct physical interaction, instead of acting through N-Myc.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	0	1	3	4
Low dose resveratrol induced differentiation through stimulation of SirT1 , which activated AKT to induce differentiation .	Low dose resveratrol induced differentiation through stimulation of SirT1, which activated AKT to induce differentiation.	6	13	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	AKT	AKT	AKT	8	9	12	13
It is plausible to speculate that Sirt1 activates Akt , resulting in phosphorylation of Foxo1 to inhibit Foxo activity in the presence of insulin ( Akt activity ) .	It is plausible to speculate that Sirt1 activates Akt, resulting in phosphorylation of Foxo1 to inhibit Foxo activity in the presence of insulin (Akt activity).	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	Akt	Akt	Akt	6	7	8	9
In addition , Sirt1 may directly activate Akt and IGF signaling to suppress autophagy and promote cellular senescence ( Pillai etal ., 2014 ) , indicating a dual regulatory role for the longevity gene for autophagy and aging with various Akt status .	In addition, Sirt1 may directly activate Akt and IGF signaling to suppress autophagy and promote cellular senescence (Pillai etal., 2014), indicating a dual regulatory role for the longevity gene for autophagy and aging with various Akt status.	3	10	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	Akt	Akt	Akt	3	4	7	8
At least three reports indicate that IGF-I and SirT1 can influence the same signaling pathways : 1 ) SIRT1 modulates the IGF-I signaling critical for both growth regulation and mammary gland development in mice ; 126 2 ) in neurons , the inhibition of SIRT1 reduces IGF-I signaling through deacetylation of IRS-2 and thereby protects them ; 85 3 ) SIRT1 reduces IGF-I signaling in fibroblasts by inhibiting Akt activation and cardiomyocytes expressing SIRT1 , but not those lacking it developed hypertrophy after treatment with IGF-I , indicating that SIRT1 is needed for IGF-I-mediated hypertrophy of cardiomyocytes .	At least three reports indicate that IGF-I and SirT1 can influence the same signaling pathways : 1) SIRT1 modulates the IGF-I signaling critical for both growth regulation and mammary gland development in mice; 126 2) in neurons, the inhibition of SIRT1 reduces IGF-I signaling through deacetylation of IRS-2 and thereby protects them; 85 3) SIRT1 reduces IGF-I signaling in fibroblasts by inhibiting Akt activation and cardiomyocytes expressing SIRT1, but not those lacking it developed hypertrophy after treatment with IGF-I, indicating that SIRT1 is needed for IGF-I-mediated hypertrophy of cardiomyocytes.	60	69	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	60	61	68	69
Activation of SIRT1 also seems to be a complex process since we found that SIRT1 activates Akt only in the presence of growth factors .	Activation of SIRT1 also seems to be a complex process since we found that SIRT1 activates Akt only in the presence of growth factors.	14	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	14	15	16	17
For example , in mouse neural cells , SIRT1 silencing and overexpression increased and decreased IGF-I and associated Akt signalling , respectively .	For example, in mouse neural cells, SIRT1 silencing and overexpression increased and decreased IGF-I and associated Akt signalling, respectively.	8	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	8	9	18	19
Expression of SirT1 in chondrocytes leads to activation of the IGF receptor and Akt pathway .	Expression of SirT1 in chondrocytes leads to activation of the IGF receptor and Akt pathway.	0	14	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	SirT1	Expression of SirT1	sirt1	Akt	Akt	akt	2	3	13	14
We also found that SIRT1 can activate Akt directly .	We also found that SIRT1 can activate Akt directly.	4	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	4	5	7	8
While effects on insulin stimulated glucose uptake were not assessed in this study , we and others find that overexpression of SIRT1 in skeletal muscle does not enhance Akt activation ( as measured by pAkt Ser473 and pAkt Thr308 ) or insulin sensitivity .	While effects on insulin stimulated glucose uptake were not assessed in this study, we and others find that overexpression of SIRT1 in skeletal muscle does not enhance Akt activation (as measured by pAkt Ser473 and pAkt Thr308) or insulin sensitivity.	19	29	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	overexpression of SIRT1	sirt1	Akt	Akt	akt	21	22	28	29
Interestingly , the PI3K and Akt pathway , another major effector downstream of IRS-2 was unaffected by SirT1 inhibition , although over-expression of SirT1 was reported to increase Akt activation under insulin resistant conditions but not under normal conditions .	Interestingly, the PI3K and Akt pathway, another major effector downstream of IRS-2 was unaffected by SirT1 inhibition, although over-expression of SirT1 was reported to increase Akt activation under insulin resistant conditions but not under normal conditions.	21	29	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SirT1	over-expression of SirT1	sirt1	Akt	Akt	akt	23	24	28	29
SIRT1 activates Akt , the upstream inhibitory kinase of glycogen synthase kinase 3 ( GSK3 ) , and promotes axonogenesis in cultured hippocampal neurons .	SIRT1 activates Akt, the upstream inhibitory kinase of glycogen synthase kinase 3 (GSK3), and promotes axonogenesis in cultured hippocampal neurons.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	0	1	2	3
These data suggest that EPO induced SIRT1 activation may activate AKT via PPARgamma but not via the mTOR pathway .	These data suggest that EPO induced SIRT1 activation may activate AKT via PPARgamma but not via the mTOR pathway.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	EPO induced SIRT1	sirt1	AKT	AKT	akt	6	7	10	11
We have demonstrated that low dose resveratrol treatment increases phosphorylation of AKT and that knockdown of SirT1 eliminates activation of AKT ( XREF_FIG and XREF_FIG ) .	We have demonstrated that low dose resveratrol treatment increases phosphorylation of AKT and that knockdown of SirT1 eliminates activation of AKT (XREF_FIG and XREF_FIG).	14	24	eliminates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	AKT	AKT	AKT	16	17	20	21
We found that low dose resveratrol stimulated differentiation through SirT1 mediated activation of AKT , whereas high dose resveratrol stimulated differentiation through AMPK mediated inhibition of the mTORC1 pathway , allowing activation of AKT .	We found that low dose resveratrol stimulated differentiation through SirT1 mediated activation of AKT, whereas high dose resveratrol stimulated differentiation through AMPK mediated inhibition of the mTORC1 pathway, allowing activation of AKT.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	AKT	AKT	AKT	9	10	13	14
Our results demonstrated that SIRT1 could promote the AKT activation , but not increased the expression level of AKT in HCC cells , which were consistent with the previous findings .	Our results demonstrated that SIRT1 could promote the AKT activation, but not increased the expression level of AKT in HCC cells, which were consistent with the previous findings.	4	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	AKT	AKT	AKT	4	5	8	9
It has been reported that acetylation blocks binding of AKT and PDK1 to PIP ( 3 ) [ XREF_BIBR ] , thereby preventing its membrane localization and phosphorylation whereas deacetylation by SIRT1 promotes AKT activation .	It has been reported that acetylation blocks binding of AKT and PDK1 to PIP (3) [XREF_BIBR], thereby preventing its membrane localization and phosphorylation whereas deacetylation by SIRT1 promotes AKT activation.	29	34	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	AKT	AKT	AKT	31	32	33	34
We have demonstrated VSMC differentiation at higher dose resveratrol treatment that is independent of SirT1 activation of AKT .	We have demonstrated VSMC differentiation at higher dose resveratrol treatment that is independent of SirT1 activation of AKT.	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	AKT	AKT	AKT	14	15	17	18
Mechanistically , we observed that the antidiabetic effects of E6155 were involved in SIRT1 dependent activation of LKB1 and AMPK and IRS1 and AKT pathways .	Mechanistically, we observed that the antidiabetic effects of E6155 were involved in SIRT1 dependent activation of LKB1 and AMPK and IRS1 and AKT pathways.	13	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	AKT	AKT	AKT	13	14	23	24
We found that SIRT1 activates PI3K and Akt signaling to promote the cardiac hypertrophic response [ XREF_BIBR ] , and Akt inhibitors can prevent SIRT1 mediated cardiac hypertrophy , thus suggesting that many of the cytoprotective and pro growth effects of SIRT1 may be mediated through its ability to activate Akt signaling .	We found that SIRT1 activates PI3K and Akt signaling to promote the cardiac hypertrophic response [XREF_BIBR], and Akt inhibitors can prevent SIRT1 mediated cardiac hypertrophy, thus suggesting that many of the cytoprotective and pro growth effects of SIRT1 may be mediated through its ability to activate Akt signaling.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	3	4	7	8
To confirm that SirT1 mediates the activation of Akt by phosphorylation on Thr308 and Ser473 , the SirT1 inhibitor NAM was added to the cultures following the SirT1transfection .	To confirm that SirT1 mediates the activation of Akt by phosphorylation on Thr308 and Ser473, the SirT1 inhibitor NAM was added to the cultures following the SirT1transfection.	3	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SirT1	SirT1	SirT1	Akt	Akt	Akt	3	4	8	9
SIRT1 is known to deacetylate and activate Akt in cardiomyocytes 46 .	SIRT1 is known to deacetylate and activate Akt in cardiomyocytes 46.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	0	1	7	8
Furthermore , enhanced SIRT1 expression in cells can activate Akt pathway activity through FOXO reporter system ( XREF_SUPPLEMENTARY ) .	Furthermore, enhanced SIRT1 expression in cells can activate Akt pathway activity through FOXO reporter system (XREF_SUPPLEMENTARY).	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1 expression	sirt1	Akt	Akt	akt	3	4	9	10
Sirt1 can deacetylate and thus activate Akt , and inhibition of Akt significantly reversed the axonogenesis induced by Sirt1 overexpression .	Sirt1 can deacetylate and thus activate Akt, and inhibition of Akt significantly reversed the axonogenesis induced by Sirt1 overexpression.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	Akt	Akt	Akt	0	1	6	7
SIRT1 also can function as a positive modulator of insulin signaling in insulin sensitive organs and activate the insulin downstream target Akt through PI3K [ XREF_BIBR ] .	SIRT1 also can function as a positive modulator of insulin signaling in insulin sensitive organs and activate the insulin downstream target Akt through PI3K [XREF_BIBR].	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	0	1	21	22
SIRT1 mediated Akt signaling pathway by CCF-NLs .	SIRT1 mediated Akt signaling pathway by CCF-NLs.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	0	1	2	3
Previous reports have demonstrated that Sirt1 activates Akt and targets endothelial nitric oxide synthase in acute states of induced cardiac angiogenesis17 and that Sirt3 destabilizes hypoxia inducible factor-1alpha to reduce transcription of the proangiogenic gene vascular endothelial growth factor-A ( VEGF-A ) in cancer cell lines during hypoxia ; 18 however , there are no studies reporting the role of Sirt3 in cardiac angiogenesis .	Previous reports have demonstrated that Sirt1 activates Akt and targets endothelial nitric oxide synthase in acute states of induced cardiac angiogenesis17 and that Sirt3 destabilizes hypoxia inducible factor-1alpha to reduce transcription of the proangiogenic gene vascular endothelial growth factor-A (VEGF-A) in cancer cell lines during hypoxia; 18 however, there are no studies reporting the role of Sirt3 in cardiac angiogenesis.	5	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	Akt	Akt	Akt	5	6	7	8
It has been previously shown that loss of Sirt3 results in IDH2-K413-Ac and decreases IDH2 activity .	It has been previously shown that loss of Sirt3 results in IDH2-K413-Ac and decreases IDH2 activity.	6	15	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt3	loss of Sirt3	sirt3	IDH2	IDH2	idh2	8	9	14	15
IDH2 acetylation at K143 results in a 44-fold loss in activity ; deacetylation by SIRT3 restores IDH2 activity and protects cells from oxidative stress [ XREF_BIBR ] .	IDH2 acetylation at K143 results in a 44-fold loss in activity; deacetylation by SIRT3 restores IDH2 activity and protects cells from oxidative stress [XREF_BIBR].	12	17	restores	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	14	15	16	17
In response to CR , Sirt3 stimulates Idh2 activity in mitochondria , leading to increased levels of NADPH and an increased ratio of reduced glutathione and oxidized glutathione , the major redox couple in the cell .	In response to CR, Sirt3 stimulates Idh2 activity in mitochondria, leading to increased levels of NADPH and an increased ratio of reduced glutathione and oxidized glutathione, the major redox couple in the cell.	5	26	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt3	Sirt3	Sirt3	Idh2	Idh2	Idh2	5	6	7	8
SIRT3 deacetylates and activates mitochondrial Idh2 ( isocitrate dehydrogenase 2 ) under CR , and enhances the glutathione antioxidant defence system .	SIRT3 deacetylates and activates mitochondrial Idh2 (isocitrate dehydrogenase 2) under CR, and enhances the glutathione antioxidant defence system.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	Idh2	Idh2	Idh2	0	1	5	6
To establish whether Idh2 activity is stimulated by Sirt3 under CR conditions , we measured Idh2 activity in the mitochondria from the liver , inner ear , and brain of control diet and calorie restricted WT and Sirt3 -/- mice .	To establish whether Idh2 activity is stimulated by Sirt3 under CR conditions, we measured Idh2 activity in the mitochondria from the liver, inner ear, and brain of control diet and calorie restricted WT and Sirt3 -/- mice.	3	9	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Sirt3	Sirt3	Sirt3	Idh2	Idh2	Idh2	8	9	3	4
Moreover , SIRT3 activates glutamate dehydrogenase ( GDH ) and IDH2 in amino acid metabolism through deacetylation , to promote NADPH production , which in turn provides H + for the glutathione reduction reaction , eventually increasing ROS hydrolysis [ XREF_BIBR , XREF_BIBR ] .	Moreover, SIRT3 activates glutamate dehydrogenase (GDH) and IDH2 in amino acid metabolism through deacetylation, to promote NADPH production, which in turn provides H + for the glutathione reduction reaction, eventually increasing ROS hydrolysis [XREF_BIBR, XREF_BIBR].	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	2	3	10	11
Moreover , Sirt3 activates isocitrate dehydrogenase 2 ( IDH2 ) , which drives the tricarboxylic acid ( TCA ) cycle and is a major donor of NADPH , an essential cofactor for both glutathione regeneration and endothelial nitric oxide synthase ( eNOS )-mediated NO formation [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Moreover, Sirt3 activates isocitrate dehydrogenase 2 (IDH2), which drives the tricarboxylic acid (TCA) cycle and is a major donor of NADPH, an essential cofactor for both glutathione regeneration and endothelial nitric oxide synthase (eNOS)-mediated NO formation [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt3	Sirt3	Sirt3	IDH2	IDH2	IDH2	2	3	8	9
SIRT3 deacetylates and thereby activates isocitrate dehydrogenase 2 ( IDH2 ) , an enzyme that catalyzes the TCA cycle redox conversion of isocitrate to alpha-ketoglutarate and serves as a major source of NADPH production [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	SIRT3 deacetylates and thereby activates isocitrate dehydrogenase 2 (IDH2), an enzyme that catalyzes the TCA cycle redox conversion of isocitrate to alpha-ketoglutarate and serves as a major source of NADPH production [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	0	1	9	10
SIRT3 also targets the mitochondrial enzymes IDH2 and MnSOD , which function in part to maintain reactive oxygen species ( ROS ) homeostasis .	SIRT3 also targets the mitochondrial enzymes IDH2 and MnSOD, which function in part to maintain reactive oxygen species (ROS) homeostasis.	0	15	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	0	1	6	7
XREF_BIBR SIRT3 activation also promotes the glutathione antioxidant Idh2 ( isocitrate dehydrogenase 2 ) , which decreases age associated hearing loss in mice .	XREF_BIBR SIRT3 activation also promotes the glutathione antioxidant Idh2 (isocitrate dehydrogenase 2), which decreases age associated hearing loss in mice.	1	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	Idh2	Idh2	Idh2	1	2	8	9
SirT3 deacetylated and activated the TCA cycle enzyme isocitrate dehydrogenase 2 ( IDH2 ) , which produces NADPH in the mitochondria .	SirT3 deacetylated and activated the TCA cycle enzyme isocitrate dehydrogenase 2 (IDH2), which produces NADPH in the mitochondria.	0	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SirT3	SirT3 deacetylated	sirt3	IDH2	IDH2	idh2	0	1	12	13
Interestingly , forward IDH2 activity is increased by the NAD + -dependent deacetylase SIRT3 .	Interestingly, forward IDH2 activity is increased by the NAD + -dependent deacetylase SIRT3.	3	14	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	13	14	3	4
Activation of IDH2 by SIRT3 similarly protects against oxidative stress induced cell death [ XREF_BIBR ] .	Activation of IDH2 by SIRT3 similarly protects against oxidative stress induced cell death [XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	4	5	2	3
In addition , under CR conditions , SIRT3 seems to modulate IDH2 function and protect the cell from oxidative stress induced cell death [ XREF_BIBR ] .	In addition, under CR conditions, SIRT3 seems to modulate IDH2 function and protect the cell from oxidative stress induced cell death [XREF_BIBR].	7	14	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	7	8	11	12
XREF_BIBR SIRT3 deacetylates mitochondrial matrix protein IDH2 to protect cells from oxidative stress ; but in cancer , IDH2 activation by SIRT3 may have a pro survival effect on cancer cells .	XREF_BIBR SIRT3 deacetylates mitochondrial matrix protein IDH2 to protect cells from oxidative stress; but in cancer, IDH2 activation by SIRT3 may have a pro survival effect on cancer cells.	18	22	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	21	22	18	19
Moreover , Sirt3 activated isocitrate dehydrogenase 2 ( Idh2 ) , thereby increasing NADPH levels in mitochondria , leading to suppression of oxidative stress ( Someya etal ., 2010 ) .	Moreover, Sirt3 activated isocitrate dehydrogenase 2 (Idh2), thereby increasing NADPH levels in mitochondria, leading to suppression of oxidative stress (Someya etal., 2010).	2	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt3	Sirt3	Sirt3	Idh2	Idh2	Idh2	2	3	8	9
In summary , we propose that in response to CR , Sirt3 activates Idh2 , thereby increasing NADPH levels in mitochondria .	In summary, we propose that in response to CR, Sirt3 activates Idh2, thereby increasing NADPH levels in mitochondria.	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt3	Sirt3	Sirt3	Idh2	Idh2	Idh2	11	12	13	14
Overexpression of SIRT3 leads to activation of IDH2 and confers protection from oxidative stress .	Overexpression of SIRT3 leads to activation of IDH2 and confers protection from oxidative stress.	0	8	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	SIRT3	Overexpression of SIRT3	sirt3	IDH2	IDH2	idh2	2	3	7	8
The IDH2 activity can be fully restored to maximum by SIRT3 through deacetylation IDH2 at Lys 413 site [ XREF_BIBR ] .	The IDH2 activity can be fully restored to maximum by SIRT3 through deacetylation IDH2 at Lys 413 site [XREF_BIBR].	1	11	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	10	11	1	2
Additionally , SIRT3 can directly target IDH2 , influencing cellular redox status , and SOD2 , activating mitochondrial ROS scavenging .	Additionally, SIRT3 can directly target IDH2, influencing cellular redox status, and SOD2, activating mitochondrial ROS scavenging.	2	19	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	2	3	6	7
XREF_BIBR , XREF_BIBR SIRT3 has been shown to directly regulate IDH2 and SOD2 activities through deacetylation , as hyperacetylation of each is known to be inhibitory .	XREF_BIBR, XREF_BIBR SIRT3 has been shown to directly regulate IDH2 and SOD2 activities through deacetylation, as hyperacetylation of each is known to be inhibitory.	0	13	directly regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	3	4	10	11
In one set of influential experiments , JNK phosphorylates Smad3 outside its COOH-tail phosphorylation site , and enhances activation and nuclear translocation of Smad3 .	In one set of influential experiments, JNK phosphorylates Smad3 outside its COOH-tail phosphorylation site, and enhances activation and nuclear translocation of Smad3.	7	24	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	JNK phosphorylates Smad3	smad3	Smad3	Smad3	smad3	9	10	23	24
RA has been shown to augment phosphorylation of Smad3 allowing translocation of Smad3 to the nucleus [ XREF_BIBR ] , although this was debated [ XREF_BIBR ] .	RA has been shown to augment phosphorylation of Smad3 allowing translocation of Smad3 to the nucleus [XREF_BIBR], although this was debated [XREF_BIBR].	0	13	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	RA has been shown to augment phosphorylation of Smad3	smad3	Smad3	Smad3	smad3	8	9	12	13
Smad3 binding to SBEs in the mouse AMTN gene promoter was induced by overexpression of Smad3 or TGFbeta1 , and this was inhibited by Bax overexpression .	Smad3 binding to SBEs in the mouse AMTN gene promoter was induced by overexpression of Smad3 or TGFbeta1, and this was inhibited by Bax overexpression.	0	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Smad3	overexpression of Smad3	smad3	Smad3	Smad3	smad3	15	16	0	1
Together , our observations support a model for PD-1-mediated blockade of cell cycle progression that is initiated by inhibition of PI3K-Akt and Ras-MEK-ERK signaling , which results in blockade of SKP2 transcription , accumulation of p27 kip1 , suppression of cyclin E-Cdk2 activity , impaired Cdk2 mediated phosphorylation of Rb and Smad3 , and increased Smad3 transactivation .	Together, our observations support a model for PD-1-mediated blockade of cell cycle progression that is initiated by inhibition of PI3K-Akt and Ras-MEK-ERK signaling, which results in blockade of SKP2 transcription, accumulation of p27 kip1, suppression of cyclin E-Cdk2 activity, impaired Cdk2 mediated phosphorylation of Rb and Smad3, and increased Smad3 transactivation.	45	56	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	Cdk2 mediated phosphorylation of Rb and Smad3	smad3	Smad3	Smad3	smad3	51	52	55	56
In pulmonary fibrosis Erk5 also appears to be necessary for the production of ECM by fibroblasts and epithelial cells , however , in this case it is associated with Smad3 acetylation ; acetylation of Lys19 on Smad3 enhances the binding of Smad3 to DNA .	In pulmonary fibrosis Erk5 also appears to be necessary for the production of ECM by fibroblasts and epithelial cells, however, in this case it is associated with Smad3 acetylation; acetylation of Lys19 on Smad3 enhances the binding of Smad3 to DNA.	32	42	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	acetylation of Lys19 on Smad3	smad3	Smad3	Smad3	smad3	36	37	41	42
XREF_BIBR , XREF_BIBR Since CRP has been shown to activate Smad3 signaling in TEC , XREF_BIBR - XREF_BIBR and because phosphorylated Smad3 can translocate into the nucleus and transcriptionally regulate target genes that regulate the cell cycle , 16 we hypothesized that CRP promotion of AKI might involve a Smad3 dependent mechanism .	XREF_BIBR, XREF_BIBR Since CRP has been shown to activate Smad3 signaling in TEC, XREF_BIBR - XREF_BIBR and because phosphorylated Smad3 can translocate into the nucleus and transcriptionally regulate target genes that regulate the cell cycle, 16 we hypothesized that CRP promotion of AKI might involve a Smad3 dependent mechanism.	9	22	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Smad3	phosphorylated Smad3	smad3	Smad3	Smad3	smad3	21	22	10	11
Instead of polyubiquitination and degradation , SMURF2 induced the multiple-site monoubiquitination of SMAD3 in vivo and inhibited the nuclear accumulation of the SMAD3 complex XREF_BIBR .	Instead of polyubiquitination and degradation, SMURF2 induced the multiple-site monoubiquitination of SMAD3 in vivo and inhibited the nuclear accumulation of the SMAD3 complex XREF_BIBR.	6	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMAD3	SMURF2 induced the multiple-site monoubiquitination of SMAD3	smad3	SMAD3	SMAD3	smad3	12	13	22	23
Myostatin signaling specifically induced Smad 3 phosphorylation and increased Smad 3 .	Myostatin signaling specifically induced Smad 3 phosphorylation and increased Smad 3.	0	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad 3	Myostatin signaling specifically induced Smad 3 phosphorylation	smad 3	Smad 3	Smad 3	smad 3	4	6	9	11
Third , JNK can directly phosphorylate residues in the linker regions of SMAD3 which enhances SMAD3 transcriptional activity .	Third, JNK can directly phosphorylate residues in the linker regions of SMAD3 which enhances SMAD3 transcriptional activity.	5	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMAD3	phosphorylate residues in the linker regions of SMAD3	smad3	SMAD3	SMAD3	smad3	12	13	15	16
Our study demonstrates that TGZ can inhibit TGFbeta2 induced early ( 2 h ) Smad2 and 3 and late ( 24 h ) Smad3 phosphorylation in ARPE-19 cells ( XREF_FIG ) .	Our study demonstrates that TGZ can inhibit TGFbeta2 induced early (2 h) Smad2 and 3 and late (24 h) Smad3 phosphorylation in ARPE-19 cells (XREF_FIG).	8	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	Smad3 phosphorylation	smad3	Smad3	Smad3	smad3	23	24	23	24
Meanwhile , the immunofluorescence staining result also showed that TGF-beta1 increased the expression of pSmad3 ; on the contrary , curcumin decreased the expression of pSmad3 and inhibited nuclear translocation of pSmad3 ( XREF_FIG ) .	Meanwhile, the immunofluorescence staining result also showed that TGF-beta1 increased the expression of pSmad3; on the contrary, curcumin decreased the expression of pSmad3 and inhibited nuclear translocation of pSmad3 (XREF_FIG).	20	33	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	pSmad3	curcumin decreased the expression of pSmad3	psmad3	pSmad3	pSmad3	psmad3	25	26	31	32
These results indicate that cyclin E/CDK2 inhibition , in combination with eribulin treatment , represses non canonical Smad3 phosphorylation , restoring canonical Smad3 cell regulatory action .	These results indicate that cyclin E/CDK2 inhibition, in combination with eribulin treatment, represses non canonical Smad3 phosphorylation, restoring canonical Smad3 cell regulatory action.	4	25	restoring	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	cyclin E/CDK2 inhibition, in combination with eribulin treatment, represses non canonical Smad3 phosphorylation	smad3	Smad3	Smad3	smad3	17	18	22	23
Activin induced phosphorylation of Smad3 and the truncated Smad3 isoform was blocked by both follistatin and siRNA mediated knockdown of Smad3 .	Activin induced phosphorylation of Smad3 and the truncated Smad3 isoform was blocked by both follistatin and siRNA mediated knockdown of Smad3.	0	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Activin induced phosphorylation of Smad3	smad3	Smad3	Smad3	smad3	4	5	20	21
Both SIS3 ( Specific inhibitor of p-Smad3 ) and dominant negative Smad3 plasmid ( DN-Smad3 ) attenuated the inhibitory effect of salidroside on C2C12 differentiation .	Both SIS3 (Specific inhibitor of p-Smad3) and dominant negative Smad3 plasmid (DN-Smad3) attenuated the inhibitory effect of salidroside on C2C12 differentiation.	4	12	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Positive_activation	Smad3	Smad3	Smad3	p-Smad3	p-Smad3	p-Smad3	11	12	6	7
Also , phosphorylation of Smad3 mediated by CDK2 and CDK4 inhibits its transcriptional activity , and Smad3-PIAS ( protein inhibitor of activated STAT ) interaction suppresses Smad3 activation by TGFbeta and favors its SUMOilation .	Also, phosphorylation of Smad3 mediated by CDK2 and CDK4 inhibits its transcriptional activity, and Smad3-PIAS (protein inhibitor of activated STAT) interaction suppresses Smad3 activation by TGFbeta and favors its SUMOilation.	2	27	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	phosphorylation of Smad3	smad3	Smad3	Smad3	smad3	4	5	26	27
We performed Samd3 siRNA in BMMCs ' cells , and Smad3 siRNA did not enhance the activities of pSmad3 and NF-kappaB and PAI -1 in CSE treated and activated-BMMCs , but the activities of MAP kinases were enhanced regardless Smad3 siRNA .	We performed Samd3 siRNA in BMMCs ' cells, and Smad3 siRNA did not enhance the activities of pSmad3 and NF-kappaB and PAI -1 in CSE-treated and activated-BMMCs, but the activities of MAP kinases were enhanced regardless Smad3 siRNA.	10	20	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Smad3	Smad3	pSmad3	pSmad3	pSmad3	10	11	18	19
In addition , coexpression of Smad3 with PIASy and SUMO-1 stimulated the nuclear export of Smad3 .	In addition, coexpression of Smad3 with PIASy and SUMO-1 stimulated the nuclear export of Smad3.	3	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	coexpression of Smad3	smad3	Smad3	Smad3	smad3	5	6	15	16
FIEL1 knockdown increased PIAS4 protein , increased SMAD3 sumoylation ( XREF_FIG ) , and further decreased SMAD3 nuclear concentration ( XREF_FIG ) .	FIEL1 knockdown increased PIAS4 protein, increased SMAD3 sumoylation (XREF_FIG), and further decreased SMAD3 nuclear concentration (XREF_FIG).	0	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMAD3	FIEL1 knockdown increased PIAS4 protein, increased SMAD3 sumoylation	smad3	SMAD3	SMAD3	smad3	7	8	16	17
The present study found coexpression of Smad3 with PIASy and SUMO1 stimulated the nuclear export of Smad3 [ XREF_BIBR ] .	The present study found coexpression of Smad3 with PIASy and SUMO1 stimulated the nuclear export of Smad3 [XREF_BIBR].	4	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	coexpression of Smad3	smad3	Smad3	Smad3	smad3	6	7	16	17
We observed that Nodal stimulation led to Smad2 and Smad3 phosphorylation at Serine 423/425 and 465/467 and induced a rapid nuclear translocation of Smad2 and Smad3 in C18-4 cells .	We observed that Nodal stimulation led to Smad2 and Smad3 phosphorylation at Serine 423/425 and 465/467 and induced a rapid nuclear translocation of Smad2 and Smad3 in C18-4 cells.	3	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	Nodal stimulation led to Smad2 and Smad3 phosphorylation at Serine 423/425	smad3	Smad3	Smad3	smad3	9	10	25	26
Furthermore , CD105 overexpression reduced serine phosphorylation of Smad3 and inhibited subsequent nuclear translocation of Smad3 .	Furthermore, CD105 overexpression reduced serine phosphorylation of Smad3 and inhibited subsequent nuclear translocation of Smad3.	2	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	CD105 overexpression reduced serine phosphorylation of Smad3	smad3	Smad3	Smad3	smad3	8	9	15	16
Phospho-SMAD3 ( S423 and S425 ) chromatin immunoprecipitation ( CHIP ) in NHDF treated with PTP4A1 ASO showed significantly reduced TGFbeta induced SMAD3 occupancy on the COL1A2 promoter compared with Cntrl ASO treated cells .	Phospho-SMAD3 (S423 and S425) chromatin immunoprecipitation (CHIP) in NHDF treated with PTP4A1 ASO showed significantly reduced TGFbeta induced SMAD3 occupancy on the COL1A2 promoter compared with Cntrl ASO treated cells.	0	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Phospho-SMAD3	Phospho-SMAD3	Phospho-SMAD3	SMAD3	SMAD3	SMAD3	0	1	22	23
The present study demonstrated that SIS3 not only inhibited AGE induced Smad3 activation and EndoMT in vitro but also abrogated Smad3 activation , decreased EndoMT , and retarded the progression of diabetic nephropathy in vivo .	The present study demonstrated that SIS3 not only inhibited AGE induced Smad3 activation and EndoMT in vitro but also abrogated Smad3 activation, decreased EndoMT, and retarded the progression of diabetic nephropathy in vivo.	5	21	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	SIS3 not only inhibited AGE induced Smad3	smad3	Smad3	Smad3	smad3	11	12	20	21
Noncanonical phosphorylation of Smad3 by CDK4/2 inhibits tumor suppressant actions of Smad3 .	Noncanonical phosphorylation of Smad3 by CDK4/2 inhibits tumor suppressant actions of Smad3.	1	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	phosphorylation of Smad3	smad3	Smad3	Smad3	smad3	3	4	11	12
This may promote Smad3 signaling , including Smad3 phosphorylation , nuclear translocation , promoter activities , and the binding of Smad3 to the collagen I promoter ( COL1A2 ) XREF_BIBR .	This may promote Smad3 signaling, including Smad3 phosphorylation, nuclear translocation, promoter activities, and the binding of Smad3 to the collagen I promoter (COL1A2) XREF_BIBR.	3	9	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Smad3	Smad3 phosphorylation	smad3	Smad3	Smad3	smad3	7	8	3	4
It appears that high RNF125 expression upregulates RNF125 downstream gene TGF-beta1 , SMAD3 and ID1 expression ; on the one hand , upregulated TGF-beta1 , SMAD3 and ID1 strengthens EMT process by activating the TGF-beta1-SMAD3-ID1 signaling pathway , accelerating the invasion , migration and adhesion of GBC cells ; on the other hand , highly expressed TGF-beta1 and ID1 enhances MET process by activating the TGF-beta1-ID1 signaling pathway , stimulating the metastatic colonization of GBC cells ; lastly promoting the metastasis and progression of GBC cells .	It appears that high RNF125 expression upregulates RNF125 downstream gene TGF-beta1, SMAD3 and ID1 expression; on the one hand, upregulated TGF-beta1, SMAD3 and ID1 strengthens EMT process by activating the TGF-beta1-SMAD3-ID1 signaling pathway, accelerating the invasion, migration and adhesion of GBC cells; on the other hand, highly expressed TGF-beta1 and ID1 enhances MET process by activating the TGF-beta1-ID1 signaling pathway, stimulating the metastatic colonization of GBC cells; lastly promoting the metastasis and progression of GBC cells.	12	26	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMAD3	SMAD3 and ID1 expression	smad3	SMAD3	SMAD3	smad3	12	13	25	26
SIS3 is an inhibitor of the phosphorylation of Smad3 XREF_BIBR , which also reduced p-Smad3 and collagen I in C3a treated HRGECs .	SIS3 is an inhibitor of the phosphorylation of Smad3 XREF_BIBR, which also reduced p-Smad3 and collagen I in C3a treated HRGECs.	6	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	phosphorylation of Smad3	smad3	p-Smad3	p-Smad3	p-smad3	8	9	14	15
The existence of Sirt6 in ER provided further supports for the conclusion that Sirt6 regulates TNFalpha secretion through defatty acylation of TNFalpha .	The existence of Sirt6 in ER provided further supports for the conclusion that Sirt6 regulates TNFalpha secretion through defatty acylation of TNFalpha.	1	16	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt6	Sirt6	Sirt6	TNFalpha	TNFalpha	TNFalpha	3	4	15	16
Previously , the only known biological function of the defatty-acylase activity of SIRT6 was to promote TNFalpha secretion .	Previously, the only known biological function of the defatty-acylase activity of SIRT6 was to promote TNFalpha secretion.	10	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNFalpha	TNFalpha	TNFalpha	12	13	16	17
SIRT6 also activates poly [ ADP-ribose ] polymerase 1 ( PARP1 ) via mono-ADP-ribosylation [ XREF_BIBR ] , and promotes secretion of the pro inflammatory cytokine tumor necrosis factor alpha ( TNFalpha ) via deacylation [ XREF_BIBR ] .	SIRT6 also activates poly [ADP-ribose] polymerase 1 (PARP1) via mono-ADP-ribosylation [XREF_BIBR], and promotes secretion of the pro inflammatory cytokine tumor necrosis factor alpha (TNFalpha) via deacylation [XREF_BIBR].	0	29	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	0	1	26	29
SIRT6 promotes TNFalpha secretion by defatty acylation .	SIRT6 promotes TNFalpha secretion by defatty acylation.	0	3	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNFalpha	TNFalpha	TNFalpha	0	1	2	3
Interestingly , SIRT6-KD also significantly increased proinflammatory cytokines , TNFalpha and IL-1beta in diabetic wounds ( P < 0.01 ; XREF_FIG ) .	Interestingly, SIRT6-KD also significantly increased proinflammatory cytokines, TNFalpha and IL-1beta in diabetic wounds (P < 0.01; XREF_FIG).	2	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6-KD	SIRT6-KD	SIRT6-KD	TNFalpha	TNFalpha	TNFalpha	2	3	9	10
Given that SIRT6 promotes TNFalpha secretion by defatty acylation , we wondered whether its defatty-acylase activity regulates the secretion of other proteins .	Given that SIRT6 promotes TNFalpha secretion by defatty acylation, we wondered whether its defatty-acylase activity regulates the secretion of other proteins.	2	5	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNFalpha	TNFalpha	TNFalpha	2	3	4	5
The long-chain deacylase activity for SIRT6 modulates tumor necrosis factor alpha ( TNFalpha ) by controlling its secretion rate .	The long-chain deacylase activity for SIRT6 modulates tumor necrosis factor alpha (TNFalpha) by controlling its secretion rate.	3	10	modulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	5	6	7	10
Thus , hyperexpression of SIRT6 leads to increase in TNF-alpha synthesis through posttranscriptional mechanisms .	Thus, hyperexpression of SIRT6 leads to increase in TNF-alpha synthesis through posttranscriptional mechanisms.	2	10	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	hyperexpression of SIRT6	sirt6	TNF-alpha	TNF-alpha	tnf-alpha	4	5	9	10
However , SIRT6 also appears to positively regulate Tumor necrosis factor ( TNF ) production at a post-transcriptional step in response to an increase in intracellular NAD + concentrations XREF_BIBR , raising the possibility that SIRT6 may play discrete roles in acute and chronic inflammatory responses .	However, SIRT6 also appears to positively regulate Tumor necrosis factor (TNF) production at a post-transcriptional step in response to an increase in intracellular NAD + concentrations XREF_BIBR, raising the possibility that SIRT6 may play discrete roles in acute and chronic inflammatory responses.	2	11	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	Tumor necrosis factor	Tumor necrosis factor	Tumor necrosis factor	2	3	8	11
This assay enabled the robust detection of SIRT6 mediated deacylation of TNF-alpha K20myr peptide fused to the fluorescent probe 7-amino-4-methylcoumarin ( AMC ) .	This assay enabled the robust detection of SIRT6 mediated deacylation of TNF-alpha K20myr peptide fused to the fluorescent probe 7-amino-4-methylcoumarin (AMC).	5	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNF-alpha	TNF-alpha	TNF-alpha	7	8	11	12
21 We further demonstrated that Sirt6 promotes the secretion of tumor necrosis factor alpha ( TNFalpha ) by removing the fatty acyl modification on Lys19 and Lys20 of TNFalpha .	21 We further demonstrated that Sirt6 promotes the secretion of tumor necrosis factor alpha (TNFalpha) by removing the fatty acyl modification on Lys19 and Lys20 of TNFalpha.	5	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt6	Sirt6	Sirt6	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	5	6	10	13
In turn , Sirt6 was previously reported to promote TNF-alpha secretion [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In turn, Sirt6 was previously reported to promote TNF-alpha secretion [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt6	Sirt6	Sirt6	TNF-alpha	TNF-alpha	TNF-alpha	3	4	9	10
To examine the level of TNF-alpha secretion induced by the SIRT6 improved mutants , we co-transfected the SIRT6 KO cells with plasmids encoding for the human TNF-alpha and the different SIRT6 variants .	To examine the level of TNF-alpha secretion induced by the SIRT6 improved mutants, we co-transfected the SIRT6 KO cells with plasmids encoding for the human TNF-alpha and the different SIRT6 variants.	5	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNF-alpha	TNF-alpha	TNF-alpha	10	11	5	6
These data suggested that lysine fatty acylation regulates TNFalpha secretion and Sirt6 promotes TNFalpha secretion by defatty acylation .	These data suggested that lysine fatty acylation regulates TNFalpha secretion and Sirt6 promotes TNFalpha secretion by defatty acylation.	9	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt6	Sirt6	Sirt6	TNFalpha	TNFalpha	TNFalpha	11	12	13	14
Analysis of SIRT6 induced secretion of TNF-alpha from cells .	Analysis of SIRT6 induced secretion of TNF-alpha from cells.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNF-alpha	TNF-alpha	TNF-alpha	2	3	6	7
In the present study , we found that SIRT6 deficiency leads to impaired wound healing in diabetic mice and were associated with reduced wound closure , proliferation and angiogenesis , and increased TNF-alpha , IL-1beta and cellular adhesion molecules in diabetic wound .	In the present study, we found that SIRT6 deficiency leads to impaired wound healing in diabetic mice and were associated with reduced wound closure, proliferation and angiogenesis, and increased TNF-alpha, IL-1beta and cellular adhesion molecules in diabetic wound.	8	34	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNF-alpha	TNF-alpha	TNF-alpha	8	9	32	33
We demonstrate further that Sirt6 promotes the secretion of tumor necrosis factor alpha ( TNFalpha ) by removing the fatty acyl modification on K19 and K20 of TNFalpha .	We demonstrate further that Sirt6 promotes the secretion of tumor necrosis factor alpha (TNFalpha) by removing the fatty acyl modification on K19 and K20 of TNFalpha.	4	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt6	Sirt6	Sirt6	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	4	5	9	12
SIRT6 WT and G60A expression in Sirt6 KO MEFs promoted TNFalpha secretion , while SIRT6 H133Y expression in Sirt6 KO MEFs had no effect on TNFalpha secretion ( XREF_FIG , XREF_SUPPLEMENTARY ) .	SIRT6 WT and G60A expression in Sirt6 KO MEFs promoted TNFalpha secretion, while SIRT6 H133Y expression in Sirt6 KO MEFs had no effect on TNFalpha secretion (XREF_FIG, XREF_SUPPLEMENTARY).	0	11	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNFalpha	TNFalpha	TNFalpha	0	1	10	11
24 By contrast , SIRT6 enhances cytokine IL8 and TNF secretions and cell motility in pancreatic cancer cells by activating Ca 2+ signaling .	24 By contrast, SIRT6 enhances cytokine IL8 and TNF secretions and cell motility in pancreatic cancer cells by activating Ca 2+ signaling.	4	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNF	TNF	TNF	4	5	9	10
Moreover , SIRT6 promotes TNF synthesis by a mechanism that appears to entail the enhancement of the efficiency with which Tnf mRNA is translated [ XREF_BIBR , XREF_BIBR ] .	Moreover, SIRT6 promotes TNF synthesis by a mechanism that appears to entail the enhancement of the efficiency with which Tnf mRNA is translated [XREF_BIBR, XREF_BIBR].	2	5	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNF	TNF	TNF	2	3	4	5
Recent in vitro analyses have demonstrated that SIRT6 stimulates pro inflammatory TNF alpha secretion by removal of long-chain fatty acyl groups .	Recent in vitro analyses have demonstrated that SIRT6 stimulates pro inflammatory TNF alpha secretion by removal of long-chain fatty acyl groups.	7	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNF	TNF	TNF	7	8	11	12
44 SIRT6 promotes the secretion of TNFalpha by defatty acylation of K19 and K20 of TNFalpha .	44 SIRT6 promotes the secretion of TNFalpha by defatty acylation of K19 and K20 of TNFalpha.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT6	SIRT6	SIRT6	TNFalpha	TNFalpha	TNFalpha	1	2	6	7
Taken together , our results demonstrate that Slit2 protein driven activation of endothelial Robo4 receptors can serve to modulate the extent of angiogenesis and subsequent immunopathology that occurs following HSV infection .	Taken together, our results demonstrate that Slit2 protein driven activation of endothelial Robo4 receptors can serve to modulate the extent of angiogenesis and subsequent immunopathology that occurs following HSV infection.	7	14	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Slit2	Slit2	Slit2	Robo4	Robo4	Robo4	7	8	13	14
In the network , Slit2 and Slit3 were redundantly activating Robo1 , Robo2 , Robo4 and ITGA1 receptors in tumor .	In the network, Slit2 and Slit3 were redundantly activating Robo1, Robo2, Robo4 and ITGA1 receptors in tumor.	4	17	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Slit2	Slit2	Slit2	Robo4	Robo4	Robo4	4	5	14	15
Slit2 activates a Robo4 dependent signalling pathway in ECs that represses Vegf signalling by inhibiting the small GTPase , Arf6 XREF_BIBR , XREF_BIBR .	Slit2 activates a Robo4 dependent signalling pathway in ECs that represses Vegf signalling by inhibiting the small GTPase, Arf6 XREF_BIBR, XREF_BIBR.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Slit2	Slit2	Slit2	Robo4	Robo4	Robo4	0	1	3	4
One posits that Slit2 activates Robo4 and initiates a signaling cascade XREF_BIBR , XREF_BIBR .	One posits that Slit2 activates Robo4 and initiates a signaling cascade XREF_BIBR, XREF_BIBR.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Slit2	Slit2	Slit2	Robo4	Robo4	Robo4	3	4	5	6
Again , neither ROBO4 siRNA , nor Robo4DeltaCD affected sprouting induced by Slit2 ( XREF_FIG ) .	Again, neither ROBO4 siRNA, nor Robo4DeltaCD affected sprouting induced by Slit2 (XREF_FIG).	2	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Slit2	Slit2	Slit2	ROBO4	ROBO4	ROBO4	12	13	3	4
As Slit2 activates Robo4 , we asked whether Slit2 stimulation regulates the interaction between Robo4 and paxillin .	As Slit2 activates Robo4, we asked whether Slit2 stimulation regulates the interaction between Robo4 and paxillin.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Slit2	Slit2	Slit2	Robo4	Robo4	Robo4	1	2	3	4
This SLIT2 deficiency triggers the soluble ROBO4 self multimerization and/or ROBO1-ROBO4 heterodimerization [ XREF_BIBR ] which enhances the SLIT2 and ROBO1-ROBO 4 signaling promoting the vascular integrity ( XREF_FIG ) .	This SLIT2 deficiency triggers the soluble ROBO4 self multimerization and/or ROBO1-ROBO4 heterodimerization [XREF_BIBR] which enhances the SLIT2 and ROBO1-ROBO 4 signaling promoting the vascular integrity (XREF_FIG).	1	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SLIT2	SLIT2	SLIT2	ROBO4	ROBO4	ROBO4	1	2	6	7
Accordingly , the balance between the positive signals produced by VEGF may become modulated and perhaps terminated by Slit2 induced Robo4 receptor activation .	Accordingly, the balance between the positive signals produced by VEGF may become modulated and perhaps terminated by Slit2 induced Robo4 receptor activation.	16	22	induced	Positive_early_activation	Positive_activation	Positive_activation	Slit2	Slit2	Slit2	Robo4	Robo4	Robo4	18	19	20	21
To inhibit the Arf6 pathway , we treated HBMECs with Slit2 , a secreted peptide that activates the Robo4 receptor to promote vascular stability via stimulation of the ArfGAP GIT [ XREF_BIBR ] .	To inhibit the Arf6 pathway, we treated HBMECs with Slit2, a secreted peptide that activates the Robo4 receptor to promote vascular stability via stimulation of the ArfGAP GIT [XREF_BIBR].	7	19	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Slit2	Slit2	Slit2	Robo4	Robo4	Robo4	10	11	18	19
[ XREF_BIBR ] Overexpression of miR-24 reduces Smad2 and Smad3 expression and reduces TGF-beta-mediated activation of Smad2 .	[XREF_BIBR] Overexpression of miR-24 reduces Smad2 and Smad3 expression and reduces TGF-beta-mediated activation of Smad2.	3	17	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad2	Overexpression of miR-24 reduces Smad2 and Smad3 expression	smad2	Smad2	Smad2	smad2	7	8	16	17
cav-1 also inhibits the phosphorylation of smad-2 , disrupting its interaction with smad-4 , and prevents nucleus translocation of the smad-2 complex via the scaffolding domain of cav-1 in the mouse fibroblast NIH3T3 .	cav-1 also inhibits the phosphorylation of smad-2, disrupting its interaction with smad-4, and prevents nucleus translocation of the smad-2 complex via the scaffolding domain of cav-1 in the mouse fibroblast NIH3T3.	0	21	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	smad-2	cav-1 also inhibits the phosphorylation of smad-2	smad-2	smad-2	smad-2	smad-2	6	7	20	21
Directed expression of either Smad2 ( Deltaexon3 ) or Smad3 , but not Smad2 ( FL ) , restores the ability of Smad2 deficient embryonic stem ( ES ) cells to contribute descendants to the definitive endoderm in wild-type host embryos .	Directed expression of either Smad2 (Deltaexon3) or Smad3, but not Smad2 (FL), restores the ability of Smad2 deficient embryonic stem (ES) cells to contribute descendants to the definitive endoderm in wild-type host embryos.	1	25	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad2	expression of either Smad2 (Deltaexon3) or Smad3, but not Smad2	smad2	Smad2	Smad2	smad2	13	14	22	23
TGFbeta stimulation has been shown to promote CBP and p300- and PCAF dependent acetylation of active Smad2 , thereby promoting Smad2 nuclear accumulation by decreased nuclear export [ XREF_BIBR ] .	TGFbeta stimulation has been shown to promote CBP and p300- and PCAF dependent acetylation of active Smad2, thereby promoting Smad2 nuclear accumulation by decreased nuclear export [XREF_BIBR].	0	22	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad2	TGFbeta stimulation has been shown to promote CBP and p300- and PCAF dependent acetylation of active Smad2	smad2	Smad2	Smad2	smad2	16	17	20	21
On the other hand , ectopic overexpression of GFP tagged Smurf2 decreased the basal level of p-Smad2 in the absence of TGF-beta ( XREF_FIG , left ) and prevented TGF-beta-induced Smad2 activation .	On the other hand, ectopic overexpression of GFP tagged Smurf2 decreased the basal level of p-Smad2 in the absence of TGF-beta (XREF_FIG, left) and prevented TGF-beta-induced Smad2 activation.	10	31	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p-Smad2	Smurf2 decreased the basal level of p-Smad2	p-smad2	Smad2	Smad2	smad2	16	17	30	31
Both TGF-beta1 and activin A , but not BMP-7 , increased the phosphorylation of Smad2 , induced nuclear translocation of Smad2 , Smad3 , and Smad4 , and inhibited thyrocyte cell growth as well as TSH stimulated cAMP response .	Both TGF-beta1 and activin A, but not BMP-7, increased the phosphorylation of Smad2, induced nuclear translocation of Smad2, Smad3, and Smad4, and inhibited thyrocyte cell growth as well as TSH stimulated cAMP response.	1	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad2	TGF-beta1 and activin A, but not BMP-7, increased the phosphorylation of Smad2	smad2	Smad2	Smad2	smad2	14	15	20	21
XREF_BIBR PTK/ZK at 5 or 10 muM only partially inhibited the expression of TGFbetaRI ; therefore , phospho-Smad2 could still be induced by an incomplete inhibition of the pathway by PTK/ZK and by the possible presence of alternative Smad2 phosphorylation events that are not sensitive to PTK/ZK .	XREF_BIBR PTK/ZK at 5 or 10 muM only partially inhibited the expression of TGFbetaRI; therefore, phospho-Smad2 could still be induced by an incomplete inhibition of the pathway by PTK/ZK and by the possible presence of alternative Smad2 phosphorylation events that are not sensitive to PTK/ZK.	17	40	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Smad2	Smad2 phosphorylation	smad2	phospho-Smad2	phospho-Smad2	phospho-smad2	38	39	17	18
This notion was supported by that knocking down HO-1 level in D3 ESCs with siRNA increased Smad2 whereas re-expression of HO-1 in HO-1 -/- ESCs decreased Smad2 level ( XREF_FIG ) .	This notion was supported by that knocking down HO-1 level in D3 ESCs with siRNA increased Smad2 whereas re-expression of HO-1 in HO-1 -/- ESCs decreased Smad2 level (XREF_FIG).	15	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad2	Smad2 level	smad2	Smad2	Smad2	smad2	26	27	16	17
We show that phosphorylation of Smad2 , a mediator of the activin and transforming growth factor-beta signal , by activated extracellular signal regulated kinase 1 ( ERK1 ) increases the amount of Smad2 protein and leads to enhanced transcriptional activity .	We show that phosphorylation of Smad2, a mediator of the activin and transforming growth factor-beta signal, by activated extracellular signal regulated kinase 1 (ERK1) increases the amount of Smad2 protein and leads to enhanced transcriptional activity.	3	33	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad2	phosphorylation of Smad2	smad2	Smad2	Smad2	smad2	5	6	32	33
This causes phosphorylation of SMAD2 and SMAD3 , two transcription factors that then bind to and activate SMAD4 .	This causes phosphorylation of SMAD2 and SMAD3, two transcription factors that then bind to and activate SMAD4.	2	18	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	SMAD2	phosphorylation of SMAD2	smad2	SMAD4	SMAD4	smad4	4	5	17	18
Smad2 reversed , whereas Smad3 further enhanced , the inhibitory effect of Smad4 on Eomes-luc activity ( XREF_FIG B ) .	Smad2 reversed, whereas Smad3 further enhanced, the inhibitory effect of Smad4 on Eomes-luc activity (XREF_FIG B).	0	15	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad2	Smad2	Smad2	Smad4	Smad4	Smad4	0	1	12	13
Our results revealed that knockdown of Smad2 could inhibit Smad4 and Foxp3 .	Our results revealed that knockdown of Smad2 could inhibit Smad4 and Foxp3.	4	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad2	Smad2	Smad2	Smad4	Smad4	Smad4	6	7	9	10
Overexpression of Smad2 increases endogenous Smad4 and TGF-beta 1 expression while heterozygous loss of Smad2 reduces their expression levels , suggesting a concerted action of Smad2 and -4 in regulating TGF-beta signaling during skin development .	Overexpression of Smad2 increases endogenous Smad4 and TGF-beta 1 expression while heterozygous loss of Smad2 reduces their expression levels, suggesting a concerted action of Smad2 and -4 in regulating TGF-beta signaling during skin development.	0	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad2	Overexpression of Smad2	smad2	Smad4	Smad4	smad4	2	3	5	6
Furthermore , KLF10 overexpression enhanced the TGFbeta induced Smad2 phosphorylation and increased the transcription of Smad2 , but not Smad3 or Smad4 [ XREF_BIBR ] .	Furthermore, KLF10 overexpression enhanced the TGFbeta induced Smad2 phosphorylation and increased the transcription of Smad2, but not Smad3 or Smad4 [XREF_BIBR].	2	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad2	KLF10 overexpression enhanced the TGFbeta induced Smad2 phosphorylation	smad2	Smad4	Smad4	smad4	8	9	21	22
SIRT1 activates Akt1 to control the phosphorylation and subcellular trafficking of the forkhead transcription factor FoxO3a 53 .	SIRT1 activates Akt1 to control the phosphorylation and subcellular trafficking of the forkhead transcription factor FoxO3a 53.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt1	Akt1	Akt1	0	1	2	3
SIRT1 leads to Akt1 Activation and Maintains the Inhibitory Phosphorylation of p-FoxO3a and Relies Upon p-FoxO3a Inhibition for EC Protection .	SIRT1 leads to Akt1 Activation and Maintains the Inhibitory Phosphorylation of p-FoxO3a and Relies Upon p-FoxO3a Inhibition for EC Protection.	0	6	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt1	Akt1	Akt1	0	1	3	4
SIRT1 activates Akt1 to also control the phosphorylation and subcellular trafficking of FoxO3a [ XREF_BIBR ] .	SIRT1 activates Akt1 to also control the phosphorylation and subcellular trafficking of FoxO3a [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Akt1	Akt1	Akt1	0	1	2	3
We describe that AKT1 activity is inhibited by the loss of SIRT1 mediated deacetylation and identify , by mass spectrometry , 11 unique proteins that interact with acetylated AKT1 .	We describe that AKT1 activity is inhibited by the loss of SIRT1 mediated deacetylation and identify, by mass spectrometry, 11 unique proteins that interact with acetylated AKT1.	3	12	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	SIRT1	loss of SIRT1	sirt1	AKT1	AKT1	akt1	11	12	3	4
Smad7 also activates Smurf1 and Smurf2 , members of the E3 ubiquitin ligase family that recognize TGF-beta-activated receptors and target them for polyubiquitinylation and degradation .	Smad7 also activates Smurf1 and Smurf2, members of the E3 ubiquitin ligase family that recognize TGF-beta-activated receptors and target them for polyubiquitinylation and degradation.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad7	Smad7	Smad7	Smurf2	Smurf2	Smurf2	0	1	5	6
However , structural studies have shown that , when compared with the E6-AP HECT domain , the HECT domain of Smurf2 has a suboptimal E2 binding pocket and that Smad-7 stimulates the E3 activity of Smurf2 by recruiting UbcH7 to the HECT domain [ XREF_BIBR , XREF_BIBR ] .	However, structural studies have shown that, when compared with the E6-AP HECT domain, the HECT domain of Smurf2 has a suboptimal E2 binding pocket and that Smad-7 stimulates the E3 activity of Smurf2 by recruiting UbcH7 to the HECT domain [XREF_BIBR, XREF_BIBR].	29	36	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad-7	Smad-7	Smad-7	Smurf2	Smurf2	Smurf2	29	30	35	36
The SMAD7 NTD further enhances the catalytic activity of the SMURF2 ligase by recruiting the E2 UbcH7 to the HECT domain [ XREF_BIBR ] .	The SMAD7 NTD further enhances the catalytic activity of the SMURF2 ligase by recruiting the E2 UbcH7 to the HECT domain [XREF_BIBR].	1	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMAD7	SMAD7	SMAD7	SMURF2	SMURF2	SMURF2	1	2	10	11
In addition , Smad7 is able to stimulate the catalytic activity of Smurf2 by recruiting and positioning the E2 , UbcH7 , in close proximity to the HECT domain of Smurf2 [ XREF_BIBR ] .	In addition, Smad7 is able to stimulate the catalytic activity of Smurf2 by recruiting and positioning the E2, UbcH7, in close proximity to the HECT domain of Smurf2 [XREF_BIBR].	3	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad7	Smad7	Smad7	Smurf2	Smurf2	Smurf2	3	4	12	13
SMURF2 activity is stimulated by the binding of SMAD7 , which abrogates the intramolecular interactions between the C2 and HECT domains permitting SMURF2 autoubiquitination and activation .	SMURF2 activity is stimulated by the binding of SMAD7, which abrogates the intramolecular interactions between the C2 and HECT domains permitting SMURF2 autoubiquitination and activation.	0	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SMAD7	SMAD7	SMAD7	SMURF2	SMURF2	SMURF2	8	9	0	1
We previously showed that Smad7 is required for TGFbeta induced accumulation of beta-catenin and Wnt induced responses in PC-3U cells , as Smad7 , when overexpressed , enhanced transcriptional activity of beta-catenin and TCF-4 .	We previously showed that Smad7 is required for TGFbeta induced accumulation of beta-catenin and Wnt induced responses in PC-3U cells, as Smad7, when overexpressed, enhanced transcriptional activity of beta-catenin and TCF-4.	22	33	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad7	Smad7, when overexpressed	smad7	beta-catenin	beta-catenin	beta-catenin	22	23	31	32
We show that Smad7 is required for oligodendrocyte differentiation and promotes myelination by blocking BMP and Wnt and beta-catenin inhibitory pathways .	We show that Smad7 is required for oligodendrocyte differentiation and promotes myelination by blocking BMP and Wnt and beta-catenin inhibitory pathways.	3	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	3	4	18	19
Smad7 increases the stabilized beta-catenin to form a complex with E-cadherin and stabilizes the E , cadherin , beta , and catenin complex .	Smad7 increases the stabilized beta-catenin to form a complex with E-cadherin and stabilizes the E, cadherin, beta, and catenin complex.	0	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	0	1	4	5
Another mechanistic possibility could be dysregulation of Wnt and beta-catenin signaling , as Smad7 was revealed to antagonize Wnt and beta-catenin signaling by accelerating beta-catenin degradation such that skin differentiation was shifted from forming hair follicles to sebaceous glands [ XREF_BIBR ] .	Another mechanistic possibility could be dysregulation of Wnt and beta-catenin signaling, as Smad7 was revealed to antagonize Wnt and beta-catenin signaling by accelerating beta-catenin degradation such that skin differentiation was shifted from forming hair follicles to sebaceous glands [XREF_BIBR].	13	25	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	13	14	24	25
We observed that Smad7 promotes accumulation of beta-catenin in PC-3U cells , whereas Smad7 was reported to cause degradation of beta-catenin in keratinocytes .	We observed that Smad7 promotes accumulation of beta-catenin in PC-3U cells, whereas Smad7 was reported to cause degradation of beta-catenin in keratinocytes.	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
The Wnt and beta-catenin pathway is required for hf morphogenesis and differentiation , and Smad7 induced beta-catenin degradation disrupts hf development .	The Wnt and beta-catenin pathway is required for hf morphogenesis and differentiation, and Smad7 induced beta-catenin degradation disrupts hf development.	14	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	14	15	16	17
We have found out that HHT can induce phosphorylation of smad3 and subsequently cause translocation of smad4 , but is TGF-beta pathway fully activated to initiate the downstream effects ?	We have found out that HHT can induce phosphorylation of smad3 and subsequently cause translocation of smad4, but is TGF-beta pathway fully activated to initiate the downstream effects?	5	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	smad3	HHT can induce phosphorylation of smad3	smad3	smad4	smad4	smad4	10	11	16	17
SMAD3 deficiency induces the upregulation of SMAD2 , SMAD4 and TGF-beta1 .	SMAD3 deficiency induces the upregulation of SMAD2, SMAD4 and TGF-beta1.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMAD3	SMAD3	SMAD3	SMAD4	SMAD4	SMAD4	0	1	8	9
Smad2 and Smad4 , however , exhibited a strong up-regulation , suggesting that cessation of TGFbeta signaling and pSmad3 activity may enable subsequent Smad2 and Smad4 up-regulation .	Smad2 and Smad4, however, exhibited a strong up-regulation, suggesting that cessation of TGFbeta signaling and pSmad3 activity may enable subsequent Smad2 and Smad4 up-regulation.	18	26	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pSmad3	pSmad3	pSmad3	Smad4	Smad4	Smad4	18	19	25	26
The Smad3 and Smad4 adaptor protein beta2SP modulates Smad4 activation in the early stages of colon cancer to maintain epithelial structure and suppress EMT [ XREF_BIBR ] .	The Smad3 and Smad4 adaptor protein beta2SP modulates Smad4 activation in the early stages of colon cancer to maintain epithelial structure and suppress EMT [XREF_BIBR].	0	22	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	Smad3	Smad3	Smad4	Smad4	Smad4	1	2	8	9
Critically , we found that reduction of SIRT1 abundance by shRNA decreased activity of WT NHLH2 by 57 % .	Critically, we found that reduction of SIRT1 abundance by shRNA decreased activity of WT NHLH2 by 57%.	7	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	NHLH2	NHLH2	NHLH2	7	8	15	16
Control of Nhlh2 by Sirt1 might be less important for gonadal development and onset of puberty since a good nutritional status should lower the activity of Sirt1 and hence also Sirt1 dependent stimulation of Nhlh2 .	Control of Nhlh2 by Sirt1 might be less important for gonadal development and onset of puberty since a good nutritional status should lower the activity of Sirt1 and hence also Sirt1 dependent stimulation of Nhlh2.	24	35	stimulation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	Nhlh2	Nhlh2	Nhlh2	26	27	34	35
It is tempting to speculate that Sirt1 activates Nhlh2 to promote physical activity and exploratory drive , which would nicely fit to the lower voluntary running levels and low sexual behavior phenotype of Nhlh2 mutants .	It is tempting to speculate that Sirt1 activates Nhlh2 to promote physical activity and exploratory drive, which would nicely fit to the lower voluntary running levels and low sexual behavior phenotype of Nhlh2 mutants.	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	Nhlh2	Nhlh2	Nhlh2	6	7	8	9
We show here that Smurf1 targets Smad7 to the plasma membrane through its N-terminal conserved 2 ( C2 ) domain .	We show here that Smurf1 targets Smad7 to the plasma membrane through its N-terminal conserved 2 (C2) domain.	4	14	targets	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Smad7	Smad7	Smad7	Smurf1	Smurf1	Smurf1	6	7	4	5
SIRT1 mediated deacetylation of Smad7 enhances Smad ubiquitination regulatory factor 1 ( Smurf1 )-mediated ubiquitin proteasome degradation , which contributes to the low levels of Smad7 expression in SIRT1 overexpressing mesangial cells .	SIRT1 mediated deacetylation of Smad7 enhances Smad ubiquitination regulatory factor 1 (Smurf1)-mediated ubiquitin proteasome degradation, which contributes to the low levels of Smad7 expression in SIRT1 overexpressing mesangial cells.	0	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	SIRT1 mediated deacetylation of Smad7	smad7	Smad ubiquitination regulatory factor 1	Smad ubiquitination regulatory factor 1	smad ubiquitination regulatory factor 1	4	5	6	11
SMAD6 inhibits the phosphorylation of SMAD1 , 5 , and 8 and additionally inhibits the association of SMAD4 with SMAD1 , both resulting in decreased BMP induced signaling .	SMAD6 inhibits the phosphorylation of SMAD1, 5, and 8 and additionally inhibits the association of SMAD4 with SMAD1, both resulting in decreased BMP induced signaling.	0	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMAD1	SMAD6 inhibits the phosphorylation of SMAD1	smad1	SMAD4	SMAD4	smad4	5	6	17	18
The phosphorylation of Smad1 at the carboxylterminal SSVS motif triggers the release of Smad1 from the receptor , the formation of homo-oligomers of Smad1 and hetero-oligomers of Smad1 and Smad4 , and the subsequent nuclear translocation of both Smad1 and Smad4 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The phosphorylation of Smad1 at the carboxylterminal SSVS motif triggers the release of Smad1 from the receptor, the formation of homo-oligomers of Smad1 and hetero-oligomers of Smad1 and Smad4, and the subsequent nuclear translocation of both Smad1 and Smad4 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	46	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad1	phosphorylation of Smad1	smad1	Smad4	Smad4	smad4	3	4	40	41
While the SLX4-SLX1 interaction is largely responsible for the Holliday junction resolvase activity seen in the complex , SLX4 can also stimulate the activity of ERCC4 and XPF and MUS81 nucleases , both of which have been previously implicated in the processing of interstrand crosslinks ( ICLs ) 8 .	While the SLX4-SLX1 interaction is largely responsible for the Holliday junction resolvase activity seen in the complex, SLX4 can also stimulate the activity of ERCC4 and XPF and MUS81 nucleases, both of which have been previously implicated in the processing of interstrand crosslinks (ICLs) 8.	18	30	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SLX4	SLX4	SLX4	ERCC4	ERCC4	ERCC4	18	19	25	26
In addition to SUMOylating itself , SLX4 also targets the XPF subunit of the repair endonuclease XPF-ERCC1 for SUMO modification .	In addition to SUMOylating itself, SLX4 also targets the XPF subunit of the repair endonuclease XPF-ERCC1 for SUMO modification.	6	11	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SLX4	SLX4	SLX4	XPF	XPF	XPF	6	7	10	11
Hence , SLX4 functions as a scaffold to target XPF , MUS81 , and SLX1 to telomeres via its interaction with TRF2 .	Hence, SLX4 functions as a scaffold to target XPF, MUS81, and SLX1 to telomeres via its interaction with TRF2.	2	14	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SLX4	SLX4	SLX4	XPF	XPF	XPF	2	3	9	10
Mutant huntingtin interacts with SIRT1 and disrupts SIRT1 mediated activation of CRTC1 [ XREF_BIBR ] .	Mutant huntingtin interacts with SIRT1 and disrupts SIRT1 mediated activation of CRTC1 [XREF_BIBR].	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	CRTC1	CRTC1	CRTC1	7	8	11	12
XREF_BIBR found that both Smad3 and Smad4 activated LEF1 transcriptional activity in the systems they analyzed .	XREF_BIBR found that both Smad3 and Smad4 activated LEF1 transcriptional activity in the systems they analyzed.	4	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad4	Smad4	Smad4	LEF1	LEF1	LEF1	6	7	8	9
Previously , SIRT1 had been shown to mediate PPARgamma repression by recruiting its coregulators , NCoR and SMRT , inhibiting adipogenesis 13 .	Previously, SIRT1 had been shown to mediate PPARgamma repression by recruiting its coregulators, NCoR and SMRT, inhibiting adipogenesis 13.	2	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	SMRT	SMRT	SMRT	2	3	17	18
Similarly , WT Runx2 enhanced the induction of colX by Smad1 .	Similarly, WT Runx2 enhanced the induction of colX by Smad1.	2	11	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Smad1	Smad1	Smad1	Runx2	Runx2	Runx2	10	11	3	4
However , overexpression of Smad1 did not induce BSP and Runx2 mRNA .	However, overexpression of Smad1 did not induce BSP and Runx2 mRNA.	2	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad1	overexpression of Smad1	smad1	Runx2	Runx2	runx2	4	5	10	11
This is similar to the mechanism described for Hoxc8 and SMAD6 , whereby SMAD6 increases the repressor function of Hoxc8 and in other circumstances Hoxc8 can repress SMAD6 function [ XREF_BIBR , XREF_BIBR ] .	This is similar to the mechanism described for Hoxc8 and SMAD6, whereby SMAD6 increases the repressor function of Hoxc8 and in other circumstances Hoxc8 can repress SMAD6 function [XREF_BIBR, XREF_BIBR].	13	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMAD6	SMAD6	SMAD6	Hoxc8	Hoxc8	Hoxc8	13	14	19	20
TGFbeta induces phosphorylation of Smad2 , which is known to activate the LEF1 transcription factor .	TGFbeta induces phosphorylation of Smad2, which is known to activate the LEF1 transcription factor.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad2	TGFbeta induces phosphorylation of Smad2	smad2	LEF1	LEF1	lef1	4	5	12	13
Activated Notch1 ( i.e ., ICN1 ) interacts with TGFbeta downstream effector SMAD3 45 .	Activated Notch1 (i.e., ICN1) interacts with TGFbeta downstream effector SMAD3 45.	0	13	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMAD3	SMAD3	SMAD3	Notch1	Notch1	Notch1	12	13	1	2
In the tumor microenvironment , Notch signaling may be modulated by other transcription factors such as HIF1alpha 17 and SMAD3 45 via physical interactions with ICN1 .	In the tumor microenvironment, Notch signaling may be modulated by other transcription factors such as HIF1alpha 17 and SMAD3 45 via physical interactions with ICN1.	5	23	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SMAD3	SMAD3	SMAD3	Notch	Notch	Notch	19	20	5	6
The guanine nucleotide exchange factor ( GEF ) SOS1 mediates KRAS driven proliferation , but little is understood about the role of SOS2 .	The guanine nucleotide exchange factor (GEF) SOS1 mediates KRAS driven proliferation, but little is understood about the role of SOS2.	0	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOS1	SOS1	SOS1	KRAS	KRAS	KRAS	8	9	10	11
XREF_BIBR , XREF_BIBR A synthetic peptide was reported to inhibit the SOS1 mediated nucleotide exchange of K-Ras with an IC 50 of 25 muM and was active in a cell based assay .	XREF_BIBR, XREF_BIBR A synthetic peptide was reported to inhibit the SOS1 mediated nucleotide exchange of K-Ras with an IC 50 of 25 muM and was active in a cell based assay.	9	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOS1	SOS1	SOS1	K-Ras	K-Ras	K-Ras	11	12	16	17
Although both Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras , N-Ras , and Ki-Ras , only Ras-GRF1 also activates the functionally distinct R-Ras GTPase .	Although both Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras, only Ras-GRF1 also activates the functionally distinct R-Ras GTPase.	1	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sos1	Sos1	Sos1	Ki-Ras	Ki-Ras	Ki-Ras	2	3	14	15
In this report , we provide evidence that SOS1 , a p21Ras specific guanine nucleotide exchange factor , directly binds to the SH3 domain of PLC-gamma1 , and that the SH3 domain of PLC-gamma1 is involved in SOS1 mediated p21Ras activation .	In this report, we provide evidence that SOS1, a p21Ras specific guanine nucleotide exchange factor, directly binds to the SH3 domain of PLC-gamma1, and that the SH3 domain of PLC-gamma1 is involved in SOS1 mediated p21Ras activation.	35	40	mediated	Positive_early_activation	Positive_activation	Positive_activation	SOS1	SOS1	SOS1	p21Ras	p21Ras	p21Ras	37	38	39	40
SOS1 activates HRAS and then activates the PI3K and AKT pathway .	SOS1 activates HRAS and then activates the PI3K and AKT pathway.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOS1	SOS1	SOS1	HRAS	HRAS	HRAS	0	1	2	3
As a result of this ligand-receptor interaction SMO gets active and subsequently activate the Serine/Threonine kinase 36 ( STK36 ) in its downstream cytoplasmic region of cell .	As a result of this ligand-receptor interaction SMO gets active and subsequently activate the Serine/Threonine kinase 36 (STK36) in its downstream cytoplasmic region of cell.	7	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMO	SMO	SMO	STK36	STK36	STK36	7	8	18	19
Importantly , SMG1 functions in the nonsense RNA mediated decay ( NMD ) pathway via phosphorylation of the telomere associated eukaryotic helicase up-frameshift 1 ( UPF1 ) .	Importantly, SMG1 functions in the nonsense RNA mediated decay (NMD) pathway via phosphorylation of the telomere associated eukaryotic helicase up-frameshift 1 (UPF1).	2	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMG1	SMG1	SMG1	UPF1	UPF1	UPF1	2	3	25	26
SMG1 phosphorylation leads to the activation of the UPF1 and SMG2 helicase .	SMG1 phosphorylation leads to the activation of the UPF1 and SMG2 helicase.	0	11	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	SMG1	SMG1 phosphorylation	smg1	UPF1	UPF1	upf1	0	1	8	9
In addition , it was found that SMG-1 maintains telomere integrity , protects against tumor necrosis factor-alpha ( TNFalpha )-induced apoptosis , regulates lifespan and oxidative stress resistance in Caenorhabditis elegans , has an essential role in embryogenesis , activates p53 and plays an important role in the DNA damage response network .	In addition, it was found that SMG-1 maintains telomere integrity, protects against tumor necrosis factor-alpha (TNFalpha)-induced apoptosis, regulates lifespan and oxidative stress resistance in Caenorhabditis elegans, has an essential role in embryogenesis, activates p53 and plays an important role in the DNA damage response network.	7	42	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMG-1	SMG-1	SMG-1	p53	p53	p53	7	8	40	41
To determine whether SMG1 dependent activation of p53 was in response to oxidative mRNA damage , mRNA encoding green fluorescence protein ( GFP ) transcribed in vitro was oxidized by Fenton chemistry and transfected into cells .	To determine whether SMG1 dependent activation of p53 was in response to oxidative mRNA damage, mRNA encoding green fluorescence protein (GFP) transcribed in vitro was oxidized by Fenton chemistry and transfected into cells.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SMG1	SMG1	SMG1	p53	p53	p53	3	4	7	8
These findings establish SMG1 activates p53 in response to DNA double-strand breaks independent of the RNA surveillance proteins Upf1 or Upf2 ; however , these proteins can stimulate p53 in response to oxidative stress but not necessarily oxidized RNA .	These findings establish SMG1 activates p53 in response to DNA double-strand breaks independent of the RNA surveillance proteins Upf1 or Upf2; however, these proteins can stimulate p53 in response to oxidative stress but not necessarily oxidized RNA.	3	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMG1	SMG1	SMG1	p53	p53	p53	3	4	5	6
Forced expression of BAF60C enables MyoD to directly activate skeletal myogenesis in hESCs , upon specific culture conditions , with BAF60C and MyoD imposing an epigenetic signature that commits hESCs towards the myogenic lineage 7 .	Forced expression of BAF60C enables MyoD to directly activate skeletal myogenesis in hESCs, upon specific culture conditions, with BAF60C and MyoD imposing an epigenetic signature that commits hESCs towards the myogenic lineage 7.	1	6	enables	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BAF60C	expression of BAF60C	baf60c	MyoD	MyoD	myod	3	4	5	6
Forced expression of BAF60C enables MyoD to directly activate skeletal myogenesis in hESCs , by instructing MyoD positioning and allowing chromatin remodeling at target genes [ XREF_BIBR ] ( XREF_FIG ) .	Forced expression of BAF60C enables MyoD to directly activate skeletal myogenesis in hESCs, by instructing MyoD positioning and allowing chromatin remodeling at target genes [XREF_BIBR] (XREF_FIG).	1	6	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAF60C	expression of BAF60C	baf60c	MyoD	MyoD	myod	3	4	5	6
Forced expression of BAF60C enables MyoD to directly activate skeletal myogenesis in hESCs , by instructing MyoD nuclear positioning and allowing chromatin remodelling at target genes .	Forced expression of BAF60C enables MyoD to directly activate skeletal myogenesis in hESCs, by instructing MyoD nuclear positioning and allowing chromatin remodelling at target genes.	1	6	enables	Positive_activation_token_1_verb	Positive_activation	Positive_activation	BAF60C	expression of BAF60C	baf60c	MyoD	MyoD	myod	3	4	5	6
This complex dissociates upon Smo activation , which in turn allows Tiam1 to activate Rac1 .	This complex dissociates upon Smo activation, which in turn allows Tiam1 to activate Rac1.	4	13	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smo	Smo	Smo	Tiam1	Tiam1	Tiam1	4	5	11	12
Phosphorylation of Smo by GRK2 induces the recruitment of beta-arrestin 2 and the endocytosis of Smo in clathrin coated vesicles [ XREF_BIBR ] .	Phosphorylation of Smo by GRK2 induces the recruitment of beta-arrestin 2 and the endocytosis of Smo in clathrin coated vesicles [XREF_BIBR].	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smo	Phosphorylation of Smo	smo	beta-arrestin 2	beta-arrestin 2	beta-arrestin 2	2	3	9	11
In addition , pretreatment with pertussis toxin ( to inhibit Galpha i ) had no effect on preventing either Smo mediated beta-arrestin2 recruitment to Gpr161 in intermolecular BRET titration assays or Gpr161 loss from cilia ( XREF_FIG ) .	In addition, pretreatment with pertussis toxin (to inhibit Galpha i) had no effect on preventing either Smo mediated beta-arrestin2 recruitment to Gpr161 in intermolecular BRET titration assays or Gpr161 loss from cilia (XREF_FIG).	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Smo	Smo	Smo	beta-arrestin2	beta-arrestin2	beta-arrestin2	19	20	21	22
In addition to SMO function as a GPCR , Yam et al demonstrated that SMO , together with SHH and the BOC co-receptor , can rapidly stimulate Src family kinase activity of Src and Fyn in neurons independent of GLI dependent transcription [ XREF_BIBR ] .	In addition to SMO function as a GPCR, Yam et al demonstrated that SMO, together with SHH and the BOC co-receptor, can rapidly stimulate Src family kinase activity of Src and Fyn in neurons independent of GLI dependent transcription [XREF_BIBR].	14	35	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMO	SMO	SMO	Fyn	Fyn	Fyn	14	15	34	35
44 Therefore , SMARCA4 dependent activation of ZEB1 may play a role in conferring key phenotypic features in SW480Null .	44 Therefore, SMARCA4 dependent activation of ZEB1 may play a role in conferring key phenotypic features in SW480Null.	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SMARCA4	SMARCA4	SMARCA4	ZEB1	ZEB1	ZEB1	3	4	7	8
Additionally , studies in Hela S3 cells showed that human Ini1 ( ySnf5 ) and Baf155 and BAF170 ( ySwi3 ) were targeted to distinct loci not bound by Brg1 ( ySnf2 ) and vice-versa .	Additionally, studies in Hela S3 cells showed that human Ini1 (ySnf5) and Baf155 and BAF170 (ySwi3) were targeted to distinct loci not bound by Brg1 (ySnf2) and vice-versa.	10	34	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Brg1	Brg1	Brg1	Baf155	Baf155	Baf155	29	30	15	16
Smo activation , in turn , causes Kif7 , Sufu and Gli proteins to travel to the tip of the cilium , with Kif7 , in particular , required for efficient Gli2 and Gli3 accumulation .	Smo activation, in turn, causes Kif7, Sufu and Gli proteins to travel to the tip of the cilium, with Kif7, in particular, required for efficient Gli2 and Gli3 accumulation.	0	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smo	Smo	Smo	Kif7	Kif7	Kif7	0	1	7	8
In mouse embryonic fibroblasts ( MEFs ) , SOS2 critically mediated mutant KRAS driven , but not HRAS driven , transformation .	In mouse embryonic fibroblasts (MEFs), SOS2 critically mediated mutant KRAS driven, but not HRAS driven, transformation.	8	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOS2	SOS2	SOS2	HRAS	HRAS	HRAS	8	9	17	18
The disturbance in nNOS , SNTA1 , and PMCA4b complex relieved the inhibition of nNOS by PMCA4b .	The disturbance in nNOS, SNTA1, and PMCA4b complex relieved the inhibition of nNOS by PMCA4b.	1	15	relieved	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SNTA1	SNTA1	SNTA1	nNOS	nNOS	nNOS	5	6	14	15
Other mechanisms that lead to cetuximab resistance include amplification of MET , XREF_BIBR overexpression of IGF1R , XREF_BIBR overexpression of EGFR ligands and receptors , such as ErbB2 XREF_BIBR and amphiregulin , XREF_BIBR modulation of EGFR by Src family kinases , transactivation of alternative pathways that bypass the EGFR pathway , such as MET and IGFR , ubiquitination , expression of EGFR variant III , and induction of EGFR translocation .	Other mechanisms that lead to cetuximab resistance include amplification of MET, XREF_BIBR overexpression of IGF1R, XREF_BIBR overexpression of EGFR ligands and receptors, such as ErbB2 XREF_BIBR and amphiregulin, XREF_BIBR modulation of EGFR by Src family kinases, transactivation of alternative pathways that bypass the EGFR pathway, such as MET and IGFR, ubiquitination, expression of EGFR variant III, and induction of EGFR translocation.	33	39	modulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	37	38	35	36
We also show that MMP independent EGFR activation is essential to the sustained phase of the protease response , and that Src kinases may mediate EGFR transactivation .	We also show that MMP independent EGFR activation is essential to the sustained phase of the protease response, and that Src kinases may mediate EGFR transactivation.	21	26	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	21	22	25	26
It appears that MDA-9 and Syntenin overexpression activates c-Src , which in turn upregulates EGFR by phosphorylation at Tyr 845 with concomitant activation of PI3K and AKT and resulted in increased proliferation .	It appears that MDA-9 and Syntenin overexpression activates c-Src, which in turn upregulates EGFR by phosphorylation at Tyr 845 with concomitant activation of PI3K and AKT and resulted in increased proliferation.	7	28	upregulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	8	9	14	15
Therefore , it appears that a PAR stimulated activation of Src leads via an intracellular route to a ligand independent phosphorylation dependent activation of the EGFR .	Therefore, it appears that a PAR stimulated activation of Src leads via an intracellular route to a ligand independent phosphorylation dependent activation of the EGFR.	8	26	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	10	11	25	26
Regardless how Src is activated by GPCR , it is important to determine how Src activates EGFR , the activation status of Src activated EGFR , and the effects of Src activated EGFR on the downstream signaling cascades and cell functions .	Regardless how Src is activated by GPCR, it is important to determine how Src activates EGFR, the activation status of Src activated EGFR, and the effects of Src activated EGFR on the downstream signaling cascades and cell functions.	28	33	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	30	31	32	33
Because Src can activate EGFR via the direct phosphorylation at Tyr 845 , we evaluated the effects of OVA on the phosphorylation of this residue in EGFR .	Because Src can activate EGFR via the direct phosphorylation at Tyr 845, we evaluated the effects of OVA on the phosphorylation of this residue in EGFR.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	1	2	4	5
G1 induces endothelium dependent vasorelaxation through Src mediated activation of the EGF receptor and the Akt pathway in rat aorta .	G1 induces endothelium dependent vasorelaxation through Src mediated activation of the EGF receptor and the Akt pathway in rat aorta.	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGF receptor	EGF receptor	EGF receptor	6	7	11	13
Transcriptional upregulation of egfr by Src overexpression was confirmed through qRT-PCR from whole midguts ( Fig XREF_FIG H ) .	Transcriptional upregulation of egfr by Src overexpression was confirmed through qRT-PCR from whole midguts (Fig XREF_FIG H).	1	7	upregulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src overexpression	src	egfr	egfr	egfr	5	6	3	4
TGF-beta expression can be regulated by sustained EGFR dependent signaling , which is activated by the ROS dependent phosphorylation of Src due to the Ang II receptor activation [ XREF_BIBR ] .	TGF-beta expression can be regulated by sustained EGFR dependent signaling, which is activated by the ROS dependent phosphorylation of Src due to the Ang II receptor activation [XREF_BIBR].	4	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	phosphorylation of Src	src	EGFR	EGFR	egfr	20	21	7	8
Thus , the Dsg2 dependent EGFR activation may be modulated , in part , by c-Src .	Thus, the Dsg2 dependent EGFR activation may be modulated, in part, by c-Src.	5	16	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	15	16	5	6
In this system , DUOX dependent H 2 O 2 activates Src kinase , which in turn activates EGFR in a ligand independent manner .	In this system, DUOX dependent H 2 O 2 activates Src kinase, which in turn activates EGFR in a ligand independent manner.	11	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	11	12	18	19
Similarly , Src activated Epidermal Growth Factor Receptor ( EGFR ) signals through Ras-MAPK to engender phosphorylation of the E-box binding transcription factor USF and facilitate its interaction with activated Smad2/3 to regulate PAI-1 gene expression [ XREF_BIBR ] .	Similarly, Src activated Epidermal Growth Factor Receptor (EGFR) signals through Ras-MAPK to engender phosphorylation of the E-box binding transcription factor USF and facilitate its interaction with activated Smad2/3 to regulate PAI-1 gene expression [XREF_BIBR].	2	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Epidermal Growth Factor Receptor	Epidermal Growth Factor Receptor	Epidermal Growth Factor Receptor	2	3	4	8
Moreover , Src family kinases , which are frequently activated in HNSCC , can promote EGFR independent STAT3 activation XREF_BIBR .	Moreover, Src family kinases, which are frequently activated in HNSCC, can promote EGFR independent STAT3 activation XREF_BIBR.	2	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	2	3	15	16
Previous studies have shown that Src mediates EGFR transactivation in response to physical stimuli and some active substances such as Ang II.	Previous studies have shown that Src mediates EGFR transactivation in response to physical stimuli and some active substances such as Ang II.	5	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	5	6	7	8
To further complicate matters , active Src may also activate TACE and ADAM17 and lead to ligand dependent EGFR activation [ XREF_BIBR ] .	To further complicate matters, active Src may also activate TACE and ADAM17 and lead to ligand dependent EGFR activation [XREF_BIBR].	5	19	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	6	7	18	19
In contrast , inhibition of Src with PP1 blocked EGF receptor activation and RPTC proliferation after oxidant injury .	In contrast, inhibition of Src with PP1 blocked EGF receptor activation and RPTC proliferation after oxidant injury.	3	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGF receptor	EGF receptor	EGF receptor	5	6	9	11
EGFR dependent STAT activation may be mediated by Src without JAK .	EGFR dependent STAT activation may be mediated by Src without JAK.	0	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	8	9	0	1
Several studies have shown that the Src mediated activation of EGFR plays critical roles not only in cell proliferation but also in the initiation and progression of vascular injury such as atherosclerosis .	Several studies have shown that the Src mediated activation of EGFR plays critical roles not only in cell proliferation but also in the initiation and progression of vascular injury such as atherosclerosis.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	6	7	10	11
Src then causes the activation of the epidermal growth factor receptor , which results in the phosphorylation and activation of the ERK MAPK and the cAMP response element binding protein transcription factor .	Src then causes the activation of the epidermal growth factor receptor, which results in the phosphorylation and activation of the ERK MAPK and the cAMP response element binding protein transcription factor.	0	23	causes	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Src	Src	src	epidermal growth factor receptor	epidermal growth factor receptor, which results in the phosphorylation and activation of the ERK MAPK	epidermal growth factor receptor	0	1	7	11
In summary , the present study provides novel findings that the downstream signaling from Src activated EGFR links to Rho-kinase-mediated MLCP inactivation , thereby regulating smooth muscle contractility .	In summary, the present study provides novel findings that the downstream signaling from Src activated EGFR links to Rho-kinase-mediated MLCP inactivation, thereby regulating smooth muscle contractility.	12	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	14	15	16	17
Together , these studies suggest that either ( i ) the concentration of PP2 did not completely inhibit Src activation , or ( ii ) PP1 may inhibit kinases other than Src and that non Src pathways also trigger EGFR activation .	Together, these studies suggest that either (i) the concentration of PP2 did not completely inhibit Src activation, or (ii) PP1 may inhibit kinases other than Src and that non Src pathways also trigger EGFR activation.	35	40	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	35	36	39	40
Our recent studies indicating a direct association between DUOX1 and Src in response to ATP stimulation suggest a direct role for DUOX1 in oxidative Src activation in EGFR transactivation , and our observation of DUOX1 dependent cysteine oxidation of EGFR may imply a similar direct role for DUOX1 in regulating EGFR activation .	Our recent studies indicating a direct association between DUOX1 and Src in response to ATP stimulation suggest a direct role for DUOX1 in oxidative Src activation in EGFR transactivation, and our observation of DUOX1 dependent cysteine oxidation of EGFR may imply a similar direct role for DUOX1 in regulating EGFR activation.	24	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	24	25	27	28
In a further attempt we investigated whether the above mentioned pathways can be bypassed by GPCR induced Src activation of EGFR .	In a further attempt we investigated whether the above mentioned pathways can be bypassed by GPCR induced Src activation of EGFR.	15	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	GPCR induced Src	src	EGFR	EGFR	egfr	17	18	20	21
Some studies reported that AKI induced fibrosis is mediated by ligand independent activation of EGFR by SRC kinase at Y845 and might involve production of ROS .	Some studies reported that AKI induced fibrosis is mediated by ligand independent activation of EGFR by SRC kinase at Y845 and might involve production of ROS.	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	16	17	14	15
Together , this data indicates that SRC , GRIP1 , and RAB9A normally mediate KIF5B-RET-mediated switching of EGFR from predominantly phospho-Y1068 to predominantly phospho-Y845 , that is , switching from an ERK associated phosphorylation event to a SRC associated event .	Together, this data indicates that SRC, GRIP1, and RAB9A normally mediate KIF5B-RET-mediated switching of EGFR from predominantly phospho-Y1068 to predominantly phospho-Y845, that is, switching from an ERK associated phosphorylation event to a SRC associated event.	6	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	6	7	17	18
It has also been reported that individually or combined inhibition of PLC-gamma and c-Src could block EGFR mediated HNSCC cell invasion .	It has also been reported that individually or combined inhibition of PLC-gamma and c-Src could block EGFR mediated HNSCC cell invasion.	9	17	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	13	14	16	17
Intracellular , Src mediated EGFR transactivation was hypothesized to be one potential mechanism by which trypsin increases TER in SCBNs .	Intracellular, Src mediated EGFR transactivation was hypothesized to be one potential mechanism by which trypsin increases TER in SCBNs.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	2	3	4	5
One of the effects of Src overexpression is to enhance coupling of the EGF receptor to PI3K signalling [ XREF_BIBR ] .	One of the effects of Src overexpression is to enhance coupling of the EGF receptor to PI3K signalling [XREF_BIBR].	5	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src overexpression	src	EGF receptor	EGF receptor	egf receptor	5	6	13	15
The transcription factor Stat5 is activated by phosphorylation after docking to EGFR or indirectly through Src mediated EGFR signaling [ XREF_BIBR , XREF_BIBR ] .	The transcription factor Stat5 is activated by phosphorylation after docking to EGFR or indirectly through Src mediated EGFR signaling [XREF_BIBR, XREF_BIBR].	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	15	16	17	18
Collectively , these results indicated that Src mediates activation of EGFR , which in turn , activates the PI3K and AKT and ERK signaling pathways in cultured mouse RPTC .	Collectively, these results indicated that Src mediates activation of EGFR, which in turn, activates the PI3K and AKT and ERK signaling pathways in cultured mouse RPTC.	6	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	6	7	10	11
Dasatinib , a dual SRC and ABL inhibitor that also targets EGFR and KIT , elicits anti-tumorigenic effects in preclinical studies [ XREF_BIBR , XREF_BIBR ] .	Dasatinib, a dual SRC and ABL inhibitor that also targets EGFR and KIT, elicits anti-tumorigenic effects in preclinical studies [XREF_BIBR, XREF_BIBR].	0	13	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	4	5	11	12
These observations indicate that SRC hyperactivity in TZMB resistant BC cells promotes a positive feedback cycle where SRC activates EGFR , HER2 , and HER3 which , in turn , can activate SRC .	These observations indicate that SRC hyperactivity in TZMB resistant BC cells promotes a positive feedback cycle where SRC activates EGFR, HER2, and HER3 which, in turn, can activate SRC.	17	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	17	18	19	20
Given that c-Src is required for EGFR internalization and signaling , and that active c-Src may induce ligand independent EGFR activation 49 , inhibition of c-Src might also impede EGFR signaling events in NAGLU defective cells as well as in other cells lacking a lysosomal enzyme involved in GAG metabolism .	Given that c-Src is required for EGFR internalization and signaling, and that active c-Src may induce ligand independent EGFR activation 49, inhibition of c-Src might also impede EGFR signaling events in NAGLU defective cells as well as in other cells lacking a lysosomal enzyme involved in GAG metabolism.	23	31	impede	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	25	26	29	30
MBG , NKA , and Src complex activates of epidermal growth factor receptor ( EGFR ) signaling resulting in a degradation of Fli1 ( a negative nuclear regulator of the procollagen-1 gene ) and induction of collagen-1 synthesis ( XREF_FIG ) .	MBG, NKA, and Src complex activates of epidermal growth factor receptor (EGFR) signaling resulting in a degradation of Fli1 (a negative nuclear regulator of the procollagen-1 gene) and induction of collagen-1 synthesis (XREF_FIG).	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	5	6	9	13
EGFR signaling is augmented by Src family kinases , but the mechanism is poorly understood .	EGFR signaling is augmented by Src family kinases, but the mechanism is poorly understood.	0	7	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	5	6	0	1
For example , we show that PI3Kgamma phosphorylates Src , which mediates EGFR transactivation .	For example, we show that PI3Kgamma phosphorylates Src, which mediates EGFR transactivation.	6	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	PI3Kgamma phosphorylates Src	src	EGFR	EGFR	egfr	8	9	12	13
Radiation activated Src kinase initiates EGFR internalization and nuclear transport .	Radiation activated Src kinase initiates EGFR internalization and nuclear transport.	2	6	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	2	3	5	6
These results provide evidence that in human colon cancer cells guggulsterone stimulates cell proliferation through Src mediated activation of EGFR and ERK1/2 .	These results provide evidence that in human colon cancer cells guggulsterone stimulates cell proliferation through Src mediated activation of EGFR and ERK1/2.	15	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	15	16	19	20
On the other hand , SP dependent phosphorylation of HER2 and EGFR decreased substantially in the presence of the MMP inhibitor 1-10 , phenanthroline monohydrate , and the dual inhibition of both c-Src and MMP almost abolished the activation of HER2 and EGFR .	On the other hand, SP dependent phosphorylation of HER2 and EGFR decreased substantially in the presence of the MMP inhibitor 1-10, phenanthroline monohydrate, and the dual inhibition of both c-Src and MMP almost abolished the activation of HER2 and EGFR.	29	43	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	32	33	42	43
Two pathways of LPA mediated transactivation of EGF-R have been described : the first involves activation of matrix metalloproteinases ( MMPs ) , cleavage of pro-HB-EGF , and subsequent ligation and activation of EGF-R [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] , and the second pathway is HB-EGF shedding independent involving the intracellular activation of EGF-R by Src kinases [ XREF_BIBR , XREF_BIBR ] .	Two pathways of LPA mediated transactivation of EGF-R have been described : the first involves activation of matrix metalloproteinases (MMPs), cleavage of pro-HB-EGF, and subsequent ligation and activation of EGF-R [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR], and the second pathway is HB-EGF shedding independent involving the intracellular activation of EGF-R by Src kinases [XREF_BIBR, XREF_BIBR].	55	60	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src	Src	EGF-R	EGF-R	EGF-R	59	60	57	58
Src mediated EGF receptor activation regulates ozone induced interleukin 8 expression in human bronchial epithelial cells .	Src mediated EGF receptor activation regulates ozone induced interleukin 8 expression in human bronchial epithelial cells.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGF receptor	EGF receptor	EGF receptor	0	1	2	4
In this study , we investigated ( 1 ) whether Src mediates epidermal growth factor receptor ( EGFR ) transactivation ; ( 2 ) if ERK1/2 , PI3Kdelta and Akt and NF-kappaB are signaling effectors downstream of Src and EGFR activation ; and ( 3 ) if upstream inhibition of Src and EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways .	In this study, we investigated (1) whether Src mediates epidermal growth factor receptor (EGFR) transactivation; (2) if ERK1/2, PI3Kdelta and Akt and NF-kappaB are signaling effectors downstream of Src and EGFR activation; and (3) if upstream inhibition of Src and EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways.	10	16	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	10	11	12	16
Based on these findings , PAR 4 -mediated EMT is considered to be produced through Src mediated EGFR activation .	Based on these findings, PAR 4 -mediated EMT is considered to be produced through Src mediated EGFR activation.	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	15	16	17	18
In conclusion , by promoting destruction of c-Cbl , c-Src enables EGFR to evade desensitization , which explains Src-EGFR collaboration in oncogenesis .	In conclusion, by promoting destruction of c-Cbl, c-Src enables EGFR to evade desensitization, which explains Src-EGFR collaboration in oncogenesis.	9	12	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	9	10	11	12
Third , Src mediates EGFR transactivation .	Third, Src mediates EGFR transactivation.	0	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	2	3	4	5
Our results show that overexpression of c-Src causes no change in EGFR half-life but does produce an increase in the internalization rate constant of EGF.EGFR complexes when the endocytic apparatus is not stoichiometrically saturated ; this effect of c-Src on EGFR endocytosis is negligible at high receptor occupancy in cells overexpressing the receptor .	Our results show that overexpression of c-Src causes no change in EGFR half-life but does produce an increase in the internalization rate constant of EGF.EGFR complexes when the endocytic apparatus is not stoichiometrically saturated; this effect of c-Src on EGFR endocytosis is negligible at high receptor occupancy in cells overexpressing the receptor.	4	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	overexpression of c-Src	c-src	EGFR	EGFR	egfr	6	7	11	12
Src was constitutively activated ( XREF_FIG ) , and constitutively enhanced yet EGFR kinase activity dependent EGFR-Src interactions ( XREF_FIG ) were observed in mutant EGFR- but not wtEGFR expressing cells .	Src was constitutively activated (XREF_FIG), and constitutively enhanced yet EGFR kinase activity dependent EGFR-Src interactions (XREF_FIG) were observed in mutant EGFR- but not wtEGFR expressing cells.	0	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	12	13
In this context , it has been reported that Src mediated EGFR transactivation is required for Ang II induced production of TGF-beta1 , 36 and sustained EGFR activation can induce arrest of epithelial cells at the G2/M phase , by which they acquire a prominent profibrotic phenotype and produce profibrotic growth factors and cytokines such as TGF-beta1 .	In this context, it has been reported that Src mediated EGFR transactivation is required for Ang II induced production of TGF-beta1, 36 and sustained EGFR activation can induce arrest of epithelial cells at the G2/M phase, by which they acquire a prominent profibrotic phenotype and produce profibrotic growth factors and cytokines such as TGF-beta1.	9	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	9	10	11	12
These data indicate that SRC activation induces trastuzumab resistance by facilitating EGFR , ERBB2 and HER3 activation in TtzmR cells .	These data indicate that SRC activation induces trastuzumab resistance by facilitating EGFR, ERBB2 and HER3 activation in TtzmR cells.	4	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	4	5	11	12
In NSCLC , EGFR transactivation is also mediated by ROS dependent NADPH oxidase activity and c-Src , which results in the downstream activation of the PI3K/AKT/NF-kappaB pathway and cyclooxygenase-2 , which are molecular predictors of the overall survival of patients with NSCLC [ XREF_BIBR ] .	In NSCLC, EGFR transactivation is also mediated by ROS dependent NADPH oxidase activity and c-Src, which results in the downstream activation of the PI3K/AKT/NF-kappaB pathway and cyclooxygenase-2, which are molecular predictors of the overall survival of patients with NSCLC [XREF_BIBR].	3	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	15	16	3	4
Src directly modulates EGFR function through phosphorylation of tyrosine residues on EGFR that allows for coupling to downstream signaling events .	Src directly modulates EGFR function through phosphorylation of tyrosine residues on EGFR that allows for coupling to downstream signaling events.	0	4	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	3	4
Since EGFR transactivation is reportedly promoted by Src ( 18,24 ) , the effects of PP2 ( 300 nM , a Src family tyrosine kinase inhibitor ) were also examined .	Since EGFR transactivation is reportedly promoted by Src (18,24), the effects of PP2 (300 nM, a Src family tyrosine kinase inhibitor) were also examined.	1	9	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	7	8	1	2
Indeed , in murine fibroblasts , overexpression of c-Src has been shown to potentiate the mitogenic and tumorigenic capacity of the overexpressed EGFR .	Indeed, in murine fibroblasts, overexpression of c-Src has been shown to potentiate the mitogenic and tumorigenic capacity of the overexpressed EGFR.	6	23	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	overexpression of c-Src	c-src	EGFR	EGFR	egfr	8	9	22	23
As can be seen in XREF_FIG , under both high and low levels of EGF , the overexpression of Src ( i.e ., mutating Src to be constitutively-active ) leads to the decrease of the activity levels of the node representing EGFR homodimers on the plasma membrane , while increasing the % ON levels of nodes representing the receptor during the internalization process .	As can be seen in XREF_FIG, under both high and low levels of EGF, the overexpression of Src (i.e., mutating Src to be constitutively-active) leads to the decrease of the activity levels of the node representing EGFR homodimers on the plasma membrane, while increasing the% ON levels of nodes representing the receptor during the internalization process.	17	42	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	overexpression of Src	src	EGFR	EGFR	egfr	19	20	41	42
Inhibition of calcium/calmodulin dependent kinase II ( CaMKII ) , phosphatidylinositol 3-kinase ( PI3K ) , and Src , however , did block EGFR transactivation by alpha1A-AR and alpha1D-AR .	Inhibition of calcium/calmodulin dependent kinase II (CaMKII), phosphatidylinositol 3-kinase (PI3K), and Src, however, did block EGFR transactivation by alpha1A-AR and alpha1D-AR.	0	24	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	EGFR	EGFR	EGFR	17	18	23	24
In some cases of NSCLC expressing mutant EGFR , gefitinib does not inhibit cell proliferation , but PP2 does , collectively suggesting that gefitinib resistance of the mutant EGFR is due to the Src dependent modulation of EGFR activity .	In some cases of NSCLC expressing mutant EGFR, gefitinib does not inhibit cell proliferation, but PP2 does, collectively suggesting that gefitinib resistance of the mutant EGFR is due to the Src dependent modulation of EGFR activity.	33	38	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	33	34	37	38
STATs can be activated by interacting directly with EGFR through SH2 domains or indirectly through Src mediated EGFR signaling [ XREF_BIBR ] .	STATs can be activated by interacting directly with EGFR through SH2 domains or indirectly through Src mediated EGFR signaling [XREF_BIBR].	8	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	15	16	17	18
Given that activation of alpha 1 -AR induces Src-Stat3 binding and that Stat3 is a downstream target of EGFR , it is possible that Src may serve as EGFR downstream effector to mediate hepatic cell function , although the possibility of Src induced EGFR activation can not be excluded .	Given that activation of alpha 1 -AR induces Src-Stat3 binding and that Stat3 is a downstream target of EGFR, it is possible that Src may serve as EGFR downstream effector to mediate hepatic cell function, although the possibility of Src induced EGFR activation can not be excluded.	39	44	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	41	42	43	44
Pretreatment with Src or Src family kinase inhibitors ( PP2 and herbimycin A ) abolished ouabain induced Src activation and formation of the active Na/K , ATPase , Src , and EGFR complex .	Pretreatment with Src or Src family kinase inhibitors (PP2 and herbimycin A) abolished ouabain induced Src activation and formation of the active Na/K, ATPase, Src, and EGFR complex.	17	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	17	18	31	32
These findings indicate that , in our MPS IIIB cell model , c-Src phosphorylation might mediate EGFR activation with subsequent signaling leading to the hypertrophic phenotype .	These findings indicate that, in our MPS IIIB cell model, c-Src phosphorylation might mediate EGFR activation with subsequent signaling leading to the hypertrophic phenotype.	12	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src phosphorylation	c-src	EGFR	EGFR	egfr	12	13	16	17
It should be noted that Src can induce activation of EGFR by direct phosphorylation on Tyr 845 .	It should be noted that Src can induce activation of EGFR by direct phosphorylation on Tyr 845.	5	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	5	6	10	11
It has been demonstrated that c-Src , which is nontransforming when overexpressed alone , can potentiate the tumorigenic capacity of overexpressed HER1 .	It has been demonstrated that c-Src, which is nontransforming when overexpressed alone, can potentiate the tumorigenic capacity of overexpressed HER1.	5	22	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	HER1	HER1	HER1	5	6	21	22
In this situation c-Src leads to EGFR activation through the phosphorylation of unspecified tyrosine residues [ XREF_BIBR ] .	In this situation c-Src leads to EGFR activation through the phosphorylation of unspecified tyrosine residues [XREF_BIBR].	3	7	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	3	4	6	7
Arsenic can stimulate c-Src activity , which can then activate EGFR by physical interaction resulting in two unique tyrosine phosphorylation events ( Tyr845 , Tyr1101 ) , leading to ligand independent EGFR phosphorylation and constitutive activation [ XREF_BIBR - XREF_BIBR ] .	Arsenic can stimulate c-Src activity, which can then activate EGFR by physical interaction resulting in two unique tyrosine phosphorylation events (Tyr845, Tyr1101), leading to ligand independent EGFR phosphorylation and constitutive activation [XREF_BIBR - XREF_BIBR].	3	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	3	4	10	11
Transient knockdown of Src in FG cells disrupted EGFR mediated Rap1-GTP loading ( XREF_FIG ) and blocked migration on vitronectin ( XREF_FIG ) , but not on collagen ( data not shown ) suggesting Rap1 activation by EGFR was Src dependent .	Transient knockdown of Src in FG cells disrupted EGFR mediated Rap1-GTP loading (XREF_FIG) and blocked migration on vitronectin (XREF_FIG), but not on collagen (data not shown) suggesting Rap1 activation by EGFR was Src dependent.	1	10	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	3	4	8	9
Src increases EGFR mediated pathway activity in many cancer types and can be activated via FAK binding which initiates a crosstalk between integrin-FAK signaling and other pathways involved in glioma invasion [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Src increases EGFR mediated pathway activity in many cancer types and can be activated via FAK binding which initiates a crosstalk between integrin-FAK signaling and other pathways involved in glioma invasion [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	13	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	2	3
The Src and EgfR module includes Src dependent activation of EgfR ; if either component is missing from the initial state , signaling along this cascade is compromised .	The Src and EgfR module includes Src dependent activation of EgfR; if either component is missing from the initial state, signaling along this cascade is compromised.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EgfR	EgfR	EgfR	6	7	10	11
Interestingly overexpression of either SRC-1 or CBP produced increased occupancy of the EGFR promoter by the other coactivator .	Interestingly overexpression of either SRC-1 or CBP produced increased occupancy of the EGFR promoter by the other coactivator.	1	13	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	overexpression of either SRC-1	src-1	EGFR	EGFR	egfr	4	5	12	13
Similarly , although SRC is sufficient to activate PI3K signaling ( as observed with inducible v-SRC expression , XREF_SUPPLEMENTARY ) , SRC inhibition with dasatinib did not abolish feedback activation of EGFR or PI3K ( XREF_FIG , data not shown ) .	Similarly, although SRC is sufficient to activate PI3K signaling (as observed with inducible v-SRC expression, XREF_SUPPLEMENTARY), SRC inhibition with dasatinib did not abolish feedback activation of EGFR or PI3K (XREF_FIG, data not shown).	21	35	abolish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	21	22	31	32
Interestingly , Src has been shown to induce EGFR transactivation and production of TGF-beta1 in response to stimulation with angiotensin II [ XREF_BIBR ] .	Interestingly, Src has been shown to induce EGFR transactivation and production of TGF-beta1 in response to stimulation with angiotensin II [XREF_BIBR].	2	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	2	3	8	9
Src kinases mediate the EGFR transactivation induced by Bn-analogue and NT in BON cells .	Src kinases mediate the EGFR transactivation induced by Bn-analogue and NT in BON cells.	0	5	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	4	5
Inhibition of Src kinase activity and ROS may inhibit the EGFR activation .	Inhibition of Src kinase activity and ROS may inhibit the EGFR activation.	2	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	2	3	10	11
Besides gene mutation , multiple resistance mechanisms to cetuximab include overexpression of EGFR ligands and receptors , ubiquitylation , translocation of EGFR , EGFR variant III , modulation of EGFR by SRC family kinases , and transactivation of alternative pathways that bypass the EGFR pathway [ XREF_BIBR ] .	Besides gene mutation, multiple resistance mechanisms to cetuximab include overexpression of EGFR ligands and receptors, ubiquitylation, translocation of EGFR, EGFR variant III, modulation of EGFR by SRC family kinases, and transactivation of alternative pathways that bypass the EGFR pathway [XREF_BIBR].	27	33	modulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	31	32	29	30
In the same cell line , however , the Src kinase inhibitor PP1 only slightly reduced LPA induced EGFR transactivation [ XREF_BIBR * ] , and recent data [ XREF_BIBR ] suggest Src as a point of convergence downstream of RTK transactivation and G-protein-mediated focal adhesion complex assembly .	In the same cell line, however, the Src kinase inhibitor PP1 only slightly reduced LPA induced EGFR transactivation [XREF_BIBR *], and recent data [XREF_BIBR] suggest Src as a point of convergence downstream of RTK transactivation and G-protein-mediated focal adhesion complex assembly.	9	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	9	10	18	19
The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC mediated EGFR signaling .	The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC mediated EGFR signaling.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	14	15	16	17
Thus , we tested whether TLR4 and c-Src mediates ox-LDL-induced EGFR activation in macrophages .	Thus, we tested whether TLR4 and c-Src mediates ox-LDL-induced EGFR activation in macrophages.	5	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	7	8	10	11
PP2 inhibition of SRC suppressed the migration ability and activation of EGFR .	PP2 inhibition of SRC suppressed the migration ability and activation of EGFR.	1	12	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	3	4	11	12
9 In addition to ligand dependent mechanisms , EGFR can be directly activated by Src phosporylation on Tyr 845 .	9 In addition to ligand dependent mechanisms, EGFR can be directly activated by Src phosporylation on Tyr 845.	8	15	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	14	15	8	9
EGFR can also be activated in a ligand independent manner by cellular Src ( c-Src ) , a non receptor tyrosine kinase .	EGFR can also be activated in a ligand independent manner by cellular Src (c-Src), a non receptor tyrosine kinase.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	12	13	0	1
In turn , FAK triggered Src activation and Src mediated EGFR transactivation resulting in STAT3 signaling .	In turn, FAK triggered Src activation and Src mediated EGFR transactivation resulting in STAT3 signaling.	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	8	9	10	11
Dsg2 is required for EGFR localization at intercellular junctions as well as for Src mediated EGFR activation .	Dsg2 is required for EGFR localization at intercellular junctions as well as for Src mediated EGFR activation.	13	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	13	14	15	16
Since Src can mediate EGFR transactivation in response to some active substances such as Ang II [ XREF_BIBR , XREF_BIBR ] , we examined the effect of KX2-391 on the phosphorylation of EGFR in the peritoneum after CG injury .	Since Src can mediate EGFR transactivation in response to some active substances such as Ang II [XREF_BIBR, XREF_BIBR], we examined the effect of KX2-391 on the phosphorylation of EGFR in the peritoneum after CG injury.	1	5	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	1	2	4	5
When AKAP121 is transfected , Src dependent activation of the EGF receptor is diminished because PTPD1 is recruited to mitochondria [ XREF_BIBR ] .	When AKAP121 is transfected, Src dependent activation of the EGF receptor is diminished because PTPD1 is recruited to mitochondria [XREF_BIBR].	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGF receptor	EGF receptor	EGF receptor	5	6	10	12
Thus , Src activated EGFR colocalized with integrin clusters at peripheral adhesions only when they were under force .	Thus, Src activated EGFR colocalized with integrin clusters at peripheral adhesions only when they were under force.	2	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	2	3	4	5
The nuclear EGFR might contribute to enhanced DNA repair [ XREF_BIBR ] , and kinase inhibition of Src causes a block of EGFR nuclear transport upon radiation [ XREF_BIBR ] .	The nuclear EGFR might contribute to enhanced DNA repair [XREF_BIBR], and kinase inhibition of Src causes a block of EGFR nuclear transport upon radiation [XREF_BIBR].	15	24	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	17	18	22	23
Speculatively , upregulation of GRP induced Src signalling could enhance EGFR signalling in Basal_3 tumours independently of ADAM17 , which can be repressed locally by stroma secreted ADAM17 inhibitors .	Speculatively, upregulation of GRP induced Src signalling could enhance EGFR signalling in Basal_3 tumours independently of ADAM17, which can be repressed locally by stroma secreted ADAM17 inhibitors.	4	11	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	GRP induced Src	src	EGFR	EGFR	egfr	6	7	10	11
In addition , butaprost stimulation of EP2 led to EP2 , beta , and arrestin1 complex formation with subsequent Src activation and transactivation of EGFR and down stream effectors .	In addition, butaprost stimulation of EP2 led to EP2, beta, and arrestin1 complex formation with subsequent Src activation and transactivation of EGFR and down stream effectors.	19	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	19	20	24	25
These data indicate that c-Src function as an upstream signaler to mediate EGFR transactivation by LPS , which is consistent with these studies that Ang II and TGF-beta activated EGFR signaling pathway via c-Src [ XREF_BIBR , XREF_BIBR ] .	These data indicate that c-Src function as an upstream signaler to mediate EGFR transactivation by LPS, which is consistent with these studies that Ang II and TGF-beta activated EGFR signaling pathway via c-Src [XREF_BIBR, XREF_BIBR].	4	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	4	5	12	13
Mechanistically , inhibition of Src by PP1 appears to disrupt TGFbeta1 and Smad3 and epidermal growth factor receptor ( EGFR ) signaling , 2 key signal pathways that have been implicated in renal fibrogenesis .	Mechanistically, inhibition of Src by PP1 appears to disrupt TGFbeta1 and Smad3 and epidermal growth factor receptor (EGFR) signaling, 2 key signal pathways that have been implicated in renal fibrogenesis.	2	21	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	4	5	19	20
Since EGFR inhibition was effective on stiff but not on soft pillars , and EGFR activation through Src was force dependent , we hypothesized that Src dependent activation of EGFR was required for rigidity sensing .	Since EGFR inhibition was effective on stiff but not on soft pillars, and EGFR activation through Src was force dependent, we hypothesized that Src dependent activation of EGFR was required for rigidity sensing.	25	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	25	26	29	30
We demonstrated previously that EGFR deficient murine embryonic fibroblasts showed decreased activation of c-Src following stimulation with GRP where c-Src was shown to mediate the cleavage of EGFR pro ligand cleavage .	We demonstrated previously that EGFR deficient murine embryonic fibroblasts showed decreased activation of c-Src following stimulation with GRP where c-Src was shown to mediate the cleavage of EGFR pro ligand cleavage.	19	30	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	19	20	27	28
These results together suggested that TLR4 and c-Src signaling mediated PA triggered EGFR activation .	These results together suggested that TLR4 and c-Src signaling mediated PA triggered EGFR activation.	5	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	7	8	12	13
35 In H2228 cells , Src inhibitors alone or in combination with ALKi increased the percentage of apoptotic cells similarly to ALK and gefitinib , suggesting that Src mediates ALK and EGFR signaling in NSCLC .	35 In H2228 cells, Src inhibitors alone or in combination with ALKi increased the percentage of apoptotic cells similarly to ALK and gefitinib, suggesting that Src mediates ALK and EGFR signaling in NSCLC.	27	32	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	27	28	31	32
We have previously demonstrated that both PLCgamma-1 and c-Src mediate HNSCC invasion downstream of EGFR ( Thomas 2003 , Zhang 2004 ) .	We have previously demonstrated that both PLCgamma-1 and c-Src mediate HNSCC invasion downstream of EGFR (Thomas 2003, Zhang 2004).	6	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	8	9	14	15
These data support the concept that Src mediated activation of EGFR might contribute to O 2 -induced DA contraction .	These data support the concept that Src mediated activation of EGFR might contribute to O 2 -induced DA contraction.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	6	7	10	11
Evidence to date supports a model wherein c-Src potentiates the survival , proliferation and tumorigenesis of EGF receptor family members , in part by associating with them .	Evidence to date supports a model wherein c-Src potentiates the survival, proliferation and tumorigenesis of EGF receptor family members, in part by associating with them.	7	19	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGF receptor	EGF receptor	EGF receptor	7	8	16	18
Conclusion : O 3 exposure increased IL-8 expression through Src mediated EGFR transactivation in HBEC .	Conclusion : O 3 exposure increased IL-8 expression through Src mediated EGFR transactivation in HBEC.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	9	10	11	12
Tesevatinib ( KD019 ) is a novel , oral , reversible TKI , which inhibits EGFR , HER2 and neu , and Src family nonreceptor tyrosine kinases .	Tesevatinib (KD019) is a novel, oral, reversible TKI, which inhibits EGFR, HER2 and neu, and Src family nonreceptor tyrosine kinases.	14	24	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	EGFR	EGFR	EGFR	22	23	15	16
This suggests that Src mediates EGF receptor ( EGFR )-dependent regulation of the Hippo pathway , even though we previously reported that the Src inhibitor PP2 did not block the effect of EGF on YAP .	This suggests that Src mediates EGF receptor (EGFR)-dependent regulation of the Hippo pathway, even though we previously reported that the Src inhibitor PP2 did not block the effect of EGF on YAP.	3	7	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGF receptor	EGF receptor	EGF receptor	3	4	5	7
Previous reports demonstrate Src is frequently activated downstream of GPCR activation in cancer cell lines [ XREF_BIBR ] , and evidence suggests that Src can directly activate the intracellular domain of the EGFR [ XREF_BIBR ] as well as play a role in MMP activation [ XREF_BIBR ] .	Previous reports demonstrate Src is frequently activated downstream of GPCR activation in cancer cell lines [XREF_BIBR], and evidence suggests that Src can directly activate the intracellular domain of the EGFR [XREF_BIBR] as well as play a role in MMP activation [XREF_BIBR].	23	39	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	23	24	32	33
Src mediated EGFR transactivation contributes to a survival response following oxidative injury .	Src mediated EGFR transactivation contributes to a survival response following oxidative injury.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	2	3
In addition , beta-arrestin has been shown to recruit Src to some GPCRs and the association of EP4 , beta , arrestin1 , and Src complex has been shown to induce the activation of EGFR and Akt .	In addition, beta-arrestin has been shown to recruit Src to some GPCRs and the association of EP4, beta, arrestin1, and Src complex has been shown to induce the activation of EGFR and Akt.	24	36	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	24	25	34	35
In our previous study , we demonstrated that Src dependent activation of EGFR was required in the sensitization process .	In our previous study, we demonstrated that Src dependent activation of EGFR was required in the sensitization process.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	8	9	12	13
Genetic and pharmacologic inhibition of Src and Fyn block EGFR dependent motility and tumor growth in vitro and in vivo .	Genetic and pharmacologic inhibition of Src and Fyn block EGFR dependent motility and tumor growth in vitro and in vivo.	3	11	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	5	6	9	10
Since STAT activation mediates EGFR and Src synergism and Akt and Erk can also be activated by Src , these findings suggest that mutant EGFRs induce a constitutive activation of the Src signaling pathway .	Since STAT activation mediates EGFR and Src synergism and Akt and Erk can also be activated by Src, these findings suggest that mutant EGFRs induce a constitutive activation of the Src signaling pathway.	4	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	17	18	4	5
We conclude that PAR ( 2 )-triggered PGE ( 2 ) formation in A549 cells involves a coordinated up-regulation of COX-2 and mPGES-1 involving cPLA ( 2 ) , increased cytosolic Ca ( 2+ ) , PKC , Src , MEK-ERK , p38 MAPK , Src mediated EGF receptor trans-activation , and also metabolic products of both COX-1 and COX-2 .	We conclude that PAR (2)-triggered PGE (2) formation in A549 cells involves a coordinated up-regulation of COX-2 and mPGES-1 involving cPLA (2), increased cytosolic Ca (2+), PKC, Src, MEK-ERK, p38 MAPK, Src mediated EGF receptor trans-activation, and also metabolic products of both COX-1 and COX-2.	45	49	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGF receptor	EGF receptor	EGF receptor	45	46	47	49
XREF_BIBR , XREF_BIBR Src can also induce activation of EGFR through direct phosphorylation at Tyr845 .	XREF_BIBR, XREF_BIBR Src can also induce activation of EGFR through direct phosphorylation at Tyr845.	2	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	3	4	9	10
c-Src activates EGFR by phosphorylation on residue Tyr845 XREF_BIBR that is located in the activation loop of the catalytic domain .	c-Src activates EGFR by phosphorylation on residue Tyr845 XREF_BIBR that is located in the activation loop of the catalytic domain.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	0	1	2	3
Our findings suggest that activated forms of Src might stimulate the EGFR and ERK in the Src expressing tumor cells as well as in surrounding non transformed stromal cells by activation of ADAM17 and release of ligands of the EGFR .	Our findings suggest that activated forms of Src might stimulate the EGFR and ERK in the Src expressing tumor cells as well as in surrounding non transformed stromal cells by activation of ADAM17 and release of ligands of the EGFR.	5	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	7	8	11	12
This process is mediated by ligand induced EGFR activation leading to subsequent phosphorylation and activation of protein tyrosine kinases Src and FAK .	This process is mediated by ligand induced EGFR activation leading to subsequent phosphorylation and activation of protein tyrosine kinases Src and FAK.	6	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	19	20	7	8
In particular , Src , as a mediator of receptor transactivation , can uniquely activate EGFR in the absence of EGFR ligand , and a Src inhibitor is synergistic with an EGFR monoclonal antibody in vitro in eliciting growth inhibition .	In particular, Src, as a mediator of receptor transactivation, can uniquely activate EGFR in the absence of EGFR ligand, and a Src inhibitor is synergistic with an EGFR monoclonal antibody in vitro in eliciting growth inhibition.	3	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	3	4	15	16
Src can activate EGFR either directly through the phosphorylation of EGFR at Tyr 845 in the cytoplasm , or indirectly via the metalloproteinase catalyzed release of HB-EGF from pro-HB-EGF .	Src can activate EGFR either directly through the phosphorylation of EGFR at Tyr 845 in the cytoplasm, or indirectly via the metalloproteinase catalyzed release of HB-EGF from pro-HB-EGF.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	3	4
In addition , Src dependent activation of EGFR under oxidative stress has been reported to occur in a ligand independent manner and can not be blocked by inhibitors against EGFR kinase activity .	In addition, Src dependent activation of EGFR under oxidative stress has been reported to occur in a ligand independent manner and can not be blocked by inhibitors against EGFR kinase activity.	3	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	3	4	7	8
On the other hand , Src can also indirectly activate EGFR through promoting release of soluble forms of EGFR ligands via a mechanism involved in the activation of matrix metalloproteinases [ XREF_BIBR ] .	On the other hand, Src can also indirectly activate EGFR through promoting release of soluble forms of EGFR ligands via a mechanism involved in the activation of matrix metalloproteinases [XREF_BIBR].	5	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	5	6	10	11
subsequently , Src promotes the shedding of heparin binding EGF like growth factor and therefore EGFR activation [ XREF_BIBR ] , which in turn activates several signaling cascades , such as the ERK , PI3 kinase and phospholipase C pathways [ XREF_BIBR , XREF_BIBR ] .	subsequently, Src promotes the shedding of heparin binding EGF like growth factor and therefore EGFR activation [XREF_BIBR], which in turn activates several signaling cascades, such as the ERK, PI3 kinase and phospholipase C pathways [XREF_BIBR, XREF_BIBR].	2	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	2	3	15	16
This leads to c-Src activation and stimulation of the epidermal growth factor receptor ( EGFR ) , which evokes phosphatidylinositol 3-kinase-dependent production of phosphatidylinositol ( 3,4,5 )-trisphosphate and , in turn , activates Rac1 subunit of NADPH oxidase .	This leads to c-Src activation and stimulation of the epidermal growth factor receptor (EGFR), which evokes phosphatidylinositol 3-kinase-dependent production of phosphatidylinositol (3,4,5)-trisphosphate and, in turn, activates Rac1 subunit of NADPH oxidase.	3	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	3	4	9	13
The unique pathway elucidated here in which c-Src and PI3K are sequentially activated downstream of the EGF receptor may serve as a prototype of signaling mechanisms by GnRHR and by additional GPCRs in various cell types .	The unique pathway elucidated here in which c-Src and PI3K are sequentially activated downstream of the EGF receptor may serve as a prototype of signaling mechanisms by GnRHR and by additional GPCRs in various cell types.	7	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGF receptor	EGF receptor	EGF receptor	7	8	16	18
Combined inhibition of PLCgamma-1 and c-Src abrogates Epidermal Growth Factor Receptor mediated head and neck squamous cell carcinoma invasion .	Combined inhibition of PLCgamma-1 and c-Src abrogates Epidermal Growth Factor Receptor mediated head and neck squamous cell carcinoma invasion.	1	11	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Epidermal Growth Factor Receptor	Epidermal Growth Factor Receptor	Epidermal Growth Factor Receptor	5	6	7	11
Several observations suggest that the interaction between TACE and Src is of physiological significance and activated forms of Src can stimulate the EGFR and ERK signaling by activation of TACE and release of EGFR ligands .	Several observations suggest that the interaction between TACE and Src is of physiological significance and activated forms of Src can stimulate the EGFR and ERK signaling by activation of TACE and release of EGFR ligands.	16	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	18	19	22	23
Src phosphorylates EGFR in C-terminal ( Y1101 ) and catalytic domains ( Y845 ) , and phosphorylation of Y845 by Src promotes EGFR mediated DNA synthesis [ XREF_BIBR ] .	Src phosphorylates EGFR in C-terminal (Y1101) and catalytic domains (Y845), and phosphorylation of Y845 by Src promotes EGFR mediated DNA synthesis [XREF_BIBR].	16	23	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	phosphorylation of Y845 by Src	src	EGFR	EGFR	egfr	20	21	22	23
PLSCR1 activity affects EGFR related signaling and its downstream effectors , including the adaptor protein Shc , Src , and Erk kinases in fibroblasts and epithelial cells [ XREF_BIBR ] .	PLSCR1 activity affects EGFR related signaling and its downstream effectors, including the adaptor protein Shc, Src, and Erk kinases in fibroblasts and epithelial cells [XREF_BIBR].	3	18	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	17	18	3	4
This pathway involved the receptor mediated activation of a pertussis-toxin sensitive G protein ( presumably G i/o ) , G betagamma -mediated activation of Src and phosphorylation of Shc , resulting in matrix mettaloproteinase mediated release of HB-EGF and transactivation of the EGFR .	This pathway involved the receptor mediated activation of a pertussis-toxin sensitive G protein (presumably G i/o), G betagamma -mediated activation of Src and phosphorylation of Shc, resulting in matrix mettaloproteinase mediated release of HB-EGF and transactivation of the EGFR.	22	43	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src and phosphorylation	src	EGFR	EGFR	egfr	24	25	42	43
Our results present a novel mechanism by which the PI3K and Src signaling cascades cooperate to activate Rac and promote intestinal epithelial cell migration downstream of EGFR .	Our results present a novel mechanism by which the PI3K and Src signaling cascades cooperate to activate Rac and promote intestinal epithelial cell migration downstream of EGFR.	11	27	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	11	12	26	27
XREF_BIBR - XREF_BIBR Src may enable EGFR to evade degradation by promoting the destruction of Cbl , a kinase responsible for the ubiquitination and degradation of multiple receptors , including EGFR .	XREF_BIBR - XREF_BIBR Src may enable EGFR to evade degradation by promoting the destruction of Cbl, a kinase responsible for the ubiquitination and degradation of multiple receptors, including EGFR.	2	7	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	3	4	6	7
We therefore suspected that EGFR activation by heparanase is similarly mediated by Src and examined this possibility by exposing heparanase transfected U87 ( XREF_SUPPLEMENTARY , upper two panels ) and A431 ( XREF_SUPPLEMENTARY , lower two panels ) cells to specific inhibitors of key signaling molecules .	We therefore suspected that EGFR activation by heparanase is similarly mediated by Src and examined this possibility by exposing heparanase transfected U87 (XREF_SUPPLEMENTARY, upper two panels) and A431 (XREF_SUPPLEMENTARY, lower two panels) cells to specific inhibitors of key signaling molecules.	4	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	12	13	4	5
In resistant cell lines , Src silencing moderately inhibited EGFR related transducers , but efficiently reduced Src activation .	In resistant cell lines, Src silencing moderately inhibited EGFR related transducers, but efficiently reduced Src activation.	5	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	5	6	9	10
Using both small-molecule EGFR inhibitors and EGFR shRNA , we investigated the mechanism of EGFR activation in cardiomyocytes and concluded that c-Src mediated the EGFR activation induced by Ang II.	Using both small-molecule EGFR inhibitors and EGFR shRNA, we investigated the mechanism of EGFR activation in cardiomyocytes and concluded that c-Src mediated the EGFR activation induced by Ang II.	21	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	21	22	24	25
XREF_BIBR , XREF_BIBR In line with these observations , our current study showed that Src mediates EGFR transactivation after UUO injury ( see below ) and triggered renal epithelial cells arrest at the G2/M phase of the cell cycle .	XREF_BIBR, XREF_BIBR In line with these observations, our current study showed that Src mediates EGFR transactivation after UUO injury (see below) and triggered renal epithelial cells arrest at the G2/M phase of the cell cycle.	14	26	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	14	15	16	17
Furthermore , combined inhibition of PLCgamma1 and c-Src abrogates EGFR mediated head and neck squamous cell carcinoma invasion [ XREF_BIBR ] .	Furthermore, combined inhibition of PLCgamma1 and c-Src abrogates EGFR mediated head and neck squamous cell carcinoma invasion [XREF_BIBR].	3	10	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	7	8	9	10
Src kinase activation following irradiation triggered caveolin-1 dependent EGFR internalization into caveolae .	Src kinase activation following irradiation triggered caveolin-1 dependent EGFR internalization into caveolae.	0	9	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	8	9
YES also phosphorylates upstream regulators of RAS and MAPK signaling , including EGFR , SHC and SHP2 , which were not targeted by SRC due to the absence of palmitoylation .	YES also phosphorylates upstream regulators of RAS and MAPK signaling, including EGFR, SHC and SHP2, which were not targeted by SRC due to the absence of palmitoylation.	4	24	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	23	24	12	13
These results provided evidence that guggulsterone induced ERK1/2 phosphorylation through Src mediated activation of EGFR .	These results provided evidence that guggulsterone induced ERK1/2 phosphorylation through Src mediated activation of EGFR.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	10	11	14	15
We conclude that CCh stimulated EGFr transactivation and subsequent ERK activation , a pathway that limits CCh induced chloride secretion , is mediated by metalloproteinase dependent extracellular release of TGF-alpha and intracellular Src activation .	We conclude that CCh stimulated EGFr transactivation and subsequent ERK activation, a pathway that limits CCh induced chloride secretion, is mediated by metalloproteinase dependent extracellular release of TGF-alpha and intracellular Src activation.	5	33	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFr	EGFr	EGFr	32	33	5	6
Src kinases mediate EGFR transactivation of Trk receptors .	Src kinases mediate EGFR transactivation of Trk receptors.	0	4	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	3	4
Our results show that the activation of the EGFR increases trans-phosphorylation of integrin beta3 allowing the recruitment of Src , which activates both the EGFR and integrin beta3 , amplifying the signaling cascade leading to the activation of downstream targets regulating migration .	Our results show that the activation of the EGFR increases trans-phosphorylation of integrin beta3 allowing the recruitment of Src, which activates both the EGFR and integrin beta3, amplifying the signaling cascade leading to the activation of downstream targets regulating migration.	16	27	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	18	19	24	25
To our knowledge , this is the first report to demonstrate the combined inhibition of both PLCgamma-1 and c-Src abrogates EGFR mediated tumor cell invasion .	To our knowledge, this is the first report to demonstrate the combined inhibition of both PLCgamma-1 and c-Src abrogates EGFR mediated tumor cell invasion.	13	21	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	18	19	20	21
These results suggest that Src kinase mediates wound induced EGFR transactivation and participates in a pathway to activate the PI3K-AKT pathway downstream of EGFR in HCECs .	These results suggest that Src kinase mediates wound induced EGFR transactivation and participates in a pathway to activate the PI3K-AKT pathway downstream of EGFR in HCECs.	4	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	4	5	9	10
Moreover , enormous reports indicate that Src protein play a crucial role in EGFR transactivation [ XREF_BIBR , XREF_BIBR ] and other study shows that integrin beta3 elicits Src mediated EGFR transactivation [ XREF_BIBR ] .	Moreover, enormous reports indicate that Src protein play a crucial role in EGFR transactivation [XREF_BIBR, XREF_BIBR] and other study shows that integrin beta3 elicits Src mediated EGFR transactivation [XREF_BIBR].	27	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	28	29	30	31
In support of this , inhibition of Src kinase activity by PP1 or siRNA blocked PAR-2-induced EGFR signaling cascade and cell growth .	In support of this, inhibition of Src kinase activity by PP1 or siRNA blocked PAR-2-induced EGFR signaling cascade and cell growth.	7	18	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	7	8	16	17
ROS derived NADPH oxidase activation by tobacco smoke induces metalloproteinase TACE activation in a Src and PKCepsilon dependent manner , which induces the processing and release of amphiregulin and EGFR activation [ XREF_BIBR ] .	ROS derived NADPH oxidase activation by tobacco smoke induces metalloproteinase TACE activation in a Src and PKCepsilon dependent manner, which induces the processing and release of amphiregulin and EGFR activation [XREF_BIBR].	11	32	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	14	15	29	30
At the mechanistic level , we prove that the induction of PGE2 and VEGF by ET-1 involves Src mediated epidermal growth factor receptor transactivation .	At the mechanistic level, we prove that the induction of PGE2 and VEGF by ET-1 involves Src mediated epidermal growth factor receptor transactivation.	17	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	17	18	19	23
Stimulation of cells with EGF revealed that c-Src traffics into the cell with activated EGFR and that c-Src expression and kinase activity prolongs EGFR activation .	Stimulation of cells with EGF revealed that c-Src traffics into the cell with activated EGFR and that c-Src expression and kinase activity prolongs EGFR activation.	17	24	prolongs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src expression	c-src	EGFR	EGFR	egfr	17	18	23	24
Activation of PKC-alpha provokes cooperative signaling that results from Src dependent activation of the EGFR/ERK1/2 pathway and EGFR independent activation of p38-alpha .	Activation of PKC-alpha provokes cooperative signaling that results from Src dependent activation of the EGFR/ERK1/2 pathway and EGFR independent activation of p38-alpha.	9	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	9	10	17	18
We further show that EGFR and HER2 are activated through phosphorylation by Src family kinases ( SFK ) .	We further show that EGFR and HER2 are activated through phosphorylation by Src family kinases (SFK).	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	12	13	4	5
It is remarkable that the model could make an accurate de novo prediction that the elevated Src activity will promote the localization of EGFR in internal compartments of the endocytic pathways even in the absence of added ligand .	It is remarkable that the model could make an accurate de novo prediction that the elevated Src activity will promote the localization of EGFR in internal compartments of the endocytic pathways even in the absence of added ligand.	16	26	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	16	17	23	24
Our results also demonstrate that activation of Src kinases is important in mediating EGFR transactivation in BON cells , because we found that EGFR activation induced by NT or the Bn-analogue , is completely inhibited by the specific Src kinase inhibitor , PP2 , but not by a inactive related compound , PP3 .	Our results also demonstrate that activation of Src kinases is important in mediating EGFR transactivation in BON cells, because we found that EGFR activation induced by NT or the Bn-analogue, is completely inhibited by the specific Src kinase inhibitor, PP2, but not by a inactive related compound, PP3.	23	40	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	38	39	23	24
Src may activate MMP causing the metabolism of EGFR precursor ligands to biologically active TGFalpha .	Src may activate MMP causing the metabolism of EGFR precursor ligands to biologically active TGFalpha.	0	10	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	8	9
To date , G s -, cAMP-, PKA- and ADAM-17-dependent production of EGF like factors and consequent activation of the EGFR/MAPK3/1 pathway have been clearly elucidated in mammalian preovulatory follicles , but an alternative PKA independent pathway involving Src kinase mediated activation of the EGFR has also been described .	To date, G s -, cAMP-, PKA- and ADAM-17-dependent production of EGF like factors and consequent activation of the EGFR/MAPK3/1 pathway have been clearly elucidated in mammalian preovulatory follicles, but an alternative PKA independent pathway involving Src kinase mediated activation of the EGFR has also been described.	38	45	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	38	39	44	45
In conclusion , the present study indicated that SRC mediates EGFR activation through the formation of SRC and EGFR heterodimers , and that activated EGFR stimulates ERK and Akt pathways in CXCL12 and CXCR4 induced gastric cancer cell migration .	In conclusion, the present study indicated that SRC mediates EGFR activation through the formation of SRC and EGFR heterodimers, and that activated EGFR stimulates ERK and Akt pathways in CXCL12 and CXCR4 induced gastric cancer cell migration.	8	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	8	9	10	11
In the absence of ligand , EGFR or HER2 could be activated by Src 25 .	In the absence of ligand, EGFR or HER2 could be activated by Src 25.	6	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	13	14	6	7
In PLC/PRF/6 cell line , complete inhibition of activated Src by dasatinib at the dosage of 0.1 uM , not only induced the inhibition of Akt activity at the same dosage , but also induced the inhibition of p-EGFR at Tyr1068 at higher dosage of 10uM .	In PLC/PRF/6 cell line, complete inhibition of activated Src by dasatinib at the dosage of 0.1 uM, not only induced the inhibition of Akt activity at the same dosage, but also induced the inhibition of p-EGFR at Tyr1068 at higher dosage of 10uM.	6	39	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	p-EGFR	p-EGFR	p-EGFR	9	10	38	39
This might explain previous results showing that Erk1/2 activation induced by antibody cross linking of PrP is mediated by EGFR signaling and that Src kinase activity increases EGFR endocytosis during EGF stimulation .	This might explain previous results showing that Erk1/2 activation induced by antibody cross linking of PrP is mediated by EGFR signaling and that Src kinase activity increases EGFR endocytosis during EGF stimulation.	23	28	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	23	24	27	28
However , in the present study , we showed that guggulsterone caused robust proliferation of two human colon cancer cell lines through Src mediated activation of EGFR and post-EGFR signaling .	However, in the present study, we showed that guggulsterone caused robust proliferation of two human colon cancer cell lines through Src mediated activation of EGFR and post-EGFR signaling.	22	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	22	23	26	27
Transactivation of EGFR by angiotensin II ( AngII ) , ET-1 , or bradykinin involves ROS dependent activation of c-Src , which then activates EGFR and leads to ERK activation and pro growth signaling [ XREF_BIBR - XREF_BIBR ] .	Transactivation of EGFR by angiotensin II (AngII), ET-1, or bradykinin involves ROS dependent activation of c-Src, which then activates EGFR and leads to ERK activation and pro growth signaling [XREF_BIBR - XREF_BIBR].	17	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	EGFR	EGFR	EGFR	19	20	24	25
While Src signaling and function relies heavily on the endosomal system , Src also modulates components of the endocytic pathway by controlling the internalization and trafficking of the very receptors which activate it ( EGFR , FGFR , integrins ) .	While Src signaling and function relies heavily on the endosomal system, Src also modulates components of the endocytic pathway by controlling the internalization and trafficking of the very receptors which activate it (EGFR, FGFR, integrins).	12	38	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	12	13	34	35
Our finding that Src is an important transactivator of EGFR in asthma , therefore leads us to speculate that SFK may be a signaling hub and relay transducing pathways that could lead to airways inflammation , remodeling and AHR .	Our finding that Src is an important transactivator of EGFR in asthma, therefore leads us to speculate that SFK may be a signaling hub and relay transducing pathways that could lead to airways inflammation, remodeling and AHR.	3	11	is an important transactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	3	4	9	10
There are several different mechanisms by which STAT proteins can mediate intracellular EGFR signaling , including direct activation of STATs by EGFR binding and indirect activation of STATs through Src mediated EGFR signaling .	There are several different mechanisms by which STAT proteins can mediate intracellular EGFR signaling, including direct activation of STATs by EGFR binding and indirect activation of STATs through Src mediated EGFR signaling.	29	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	29	30	31	32
Like low EGF concentrations , activated Src triggered EGF-R endocytosis via clathrin coated vesicles and led to its sequestration in perinuclear and recycling endosomes with avoidance of multivesicular bodies and lysosomal degradation .	Like low EGF concentrations, activated Src triggered EGF-R endocytosis via clathrin coated vesicles and led to its sequestration in perinuclear and recycling endosomes with avoidance of multivesicular bodies and lysosomal degradation.	5	15	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGF-R	EGF-R	EGF-R	6	7	8	9
Src signaling induced by T. gondii triggers trans-activation of EGFR that is required to prevent parasite killing within host cells .	Src signaling induced by T. gondii triggers trans-activation of EGFR that is required to prevent parasite killing within host cells.	0	10	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	9	10
Src mediated ligand independent activation of EGFR .	Src mediated ligand independent activation of EGFR.	0	7	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	0	1	6	7
Our and other groups have reported that Src family kinases ( SFKs ) can mediate EGFR activation in response to different stimuli including oxidant injury .	Our and other groups have reported that Src family kinases (SFKs) can mediate EGFR activation in response to different stimuli including oxidant injury.	7	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	7	8	15	16
For example , does Src stimulates the dimerization of EGFR ?	For example, does Src stimulates the dimerization of EGFR?	4	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	4	5	9	10
Activated EGFR associates with multiple signaling adaptor proteins including growth factor receptor bound protein 2 ( GRB2 ) , Src homology 2 domain containing ( SHC ) , and phosphoinositide phospholipase Cgamma ( PLCgamma ) XREF_BIBR - XREF_BIBR .	Activated EGFR associates with multiple signaling adaptor proteins including growth factor receptor bound protein 2 (GRB2), Src homology 2 domain containing (SHC), and phosphoinositide phospholipase Cgamma (PLCgamma) XREF_BIBR - XREF_BIBR.	0	20	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	19	20	1	2
Based on preclinical studies , other strategies to augment EGFR inhibition includes use of bortezomib in combination with EGFR kinase inhibitors due to its growth inhibitory and pro apoptic effects on cancer cell lines [ XREF_BIBR ] and dasatinib in combination with EGFR kinase inhibitor as in vitro data from NSCLC cell lines demonstrates that Src inhibition may enhance the antitumor activity of EGFR inhibition in the presence of EGFR mutations [ XREF_BIBR ] .	Based on preclinical studies, other strategies to augment EGFR inhibition includes use of bortezomib in combination with EGFR kinase inhibitors due to its growth inhibitory and pro apoptic effects on cancer cell lines [XREF_BIBR] and dasatinib in combination with EGFR kinase inhibitor as in vitro data from NSCLC cell lines demonstrates that Src inhibition may enhance the antitumor activity of EGFR inhibition in the presence of EGFR mutations [XREF_BIBR].	55	64	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	55	56	63	64
SRC activation , which was also a prognostically significant finding in our previous study , induces CBL destruction and enables EGFR to evade destruction .	SRC activation, which was also a prognostically significant finding in our previous study, induces CBL destruction and enables EGFR to evade destruction.	0	21	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	EGFR	EGFR	EGFR	0	1	20	21
Surprisingly , even in the absence of EGF addition , c-Src expression induced activation of EGFR and of EGFR mediated downstream signaling targets ERK and Shc .	Surprisingly, even in the absence of EGF addition, c-Src expression induced activation of EGFR and of EGFR mediated downstream signaling targets ERK and Shc.	10	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src expression	c-src	EGFR	EGFR	egfr	10	11	15	16
A high level of Src activates the downstream of the signal pathway of EGFR without combining ligand .	A high level of Src activates the downstream of the signal pathway of EGFR without combining ligand.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	level of Src	src	EGFR	EGFR	egfr	4	5	13	14
In response to PGE 2 stimulation , the EP2 receptor recruits beta-arrestin 1 to phosphorylate tyrosine protein kinase Src , which in turn activates EGFR , leading to activation of PI3K and Akt and Ras and ERK pathways , which together promote tumor cell activities ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	In response to PGE 2 stimulation, the EP2 receptor recruits beta-arrestin 1 to phosphorylate tyrosine protein kinase Src, which in turn activates EGFR, leading to activation of PI3K and Akt and Ras and ERK pathways, which together promote tumor cell activities (XREF_FIG) [XREF_BIBR, XREF_BIBR].	8	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	EP2 receptor recruits beta-arrestin 1 to phosphorylate tyrosine protein kinase Src	src	EGFR	EGFR	egfr	18	19	24	25
Previous studies have linked GPR30 expression to the non receptor tyrosine kinase ( Src )-dependent activation of EGFR signaling in a variety of estrogen responsive cancer cells [ XREF_BIBR ] .	Previous studies have linked GPR30 expression to the non receptor tyrosine kinase (Src)-dependent activation of EGFR signaling in a variety of estrogen responsive cancer cells [XREF_BIBR].	13	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	13	14	17	18
Src kinase was shown to induce activation of Akt , while Lyn kinase seems to inhibit this activation .	Src kinase was shown to induce activation of Akt, while Lyn kinase seems to inhibit this activation.	0	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	8	9
CXCL-12 , by binding to CXCR4 , activates the nonreceptor tyrosine kinase Src , which , in turn , stimulates the AKT cell survival pathway in breast cancer cells residing in the bone marrow [ XREF_BIBR ] .	CXCL-12, by binding to CXCR4, activates the nonreceptor tyrosine kinase Src, which, in turn, stimulates the AKT cell survival pathway in breast cancer cells residing in the bone marrow [XREF_BIBR].	7	24	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	12	13	21	22
Mechanistically , both Src and caveolin-1 are required for ouabain induced activation of Akt and up-regulation of Na/K-ATPase .	Mechanistically, both Src and caveolin-1 are required for ouabain induced activation of Akt and up-regulation of Na/K-ATPase.	2	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	3	4	13	14
Moreover , it has been shown that IL-1beta activates the up-stream kinase c-Src which in turn stimulates the downstream PI-3K and Akt signaling pathway XREF_BIBR .	Moreover, it has been shown that IL-1beta activates the up-stream kinase c-Src which in turn stimulates the downstream PI-3K and Akt signaling pathway XREF_BIBR.	8	24	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	12	13	21	22
We then investigated whether Notch -or SRC -dependent signaling was leading to activation of PI3K-AKT pathway in HCC2429 cells .	We then investigated whether Notch -or SRC -dependent signaling was leading to activation of PI3K-AKT pathway in HCC2429 cells.	4	15	leading to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	PI3K-AKT	PI3K-AKT	PI3K-AKT	6	7	14	15
As Src activation resulted in activation of PI3-K and Akt signals , loss of SRC activation induces anoikis .	As Src activation resulted in activation of PI3-K and Akt signals, loss of SRC activation induces anoikis.	1	10	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	1	2	9	10
These results suggested that t ( 1 ; 19 ) ALL dasatinib sensitivity occurs due to inhibition of pre-BCR-initiated BTK and/or SRC kinases that subsequently activate AKT .	These results suggested that t (1; 19) ALL dasatinib sensitivity occurs due to inhibition of pre-BCR-initiated BTK and/or SRC kinases that subsequently activate AKT.	21	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	AKT	AKT	AKT	21	22	26	27
In agreement with this proposal , the activity of c-Src promotes PTEN degradation and the subsequent activation of the PI3K and Akt pathway [ XREF_BIBR ] .	In agreement with this proposal, the activity of c-Src promotes PTEN degradation and the subsequent activation of the PI3K and Akt pathway [XREF_BIBR].	7	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	9	10	21	22
TRIP6 can further serve as a platform to recruit TRAF6 , c-Src and AKT , which in turn activate the JNK , p38 , ERK and AKT signaling pathways and promote c-Src-dependent tyrosine phosphorylation of TRIP6 .	TRIP6 can further serve as a platform to recruit TRAF6, c-Src and AKT, which in turn activate the JNK, p38, ERK and AKT signaling pathways and promote c-Src-dependent tyrosine phosphorylation of TRIP6.	8	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	AKT	AKT	AKT	11	12	26	27
RanBP9 and TSSC3 complex cooperates to suppress anoikis resistance and metastasis via inhibiting Src mediated Akt signaling in osteosarcoma .	RanBP9 and TSSC3 complex cooperates to suppress anoikis resistance and metastasis via inhibiting Src mediated Akt signaling in osteosarcoma.	13	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	13	14	15	16
Future studies will focus on how Src induces activation of the Akt and JNK pathways in detached pancreatic cancer cells , as well as the importance of the Src and Akt and Src and JNK axes for mediating resistance to anoikis .	Future studies will focus on how Src induces activation of the Akt and JNK pathways in detached pancreatic cancer cells, as well as the importance of the Src and Akt and Src and JNK axes for mediating resistance to anoikis.	6	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	6	7	11	12
Interestingly , ligand dependent ERalpha extranuclear signaling has been shown to cause proliferation of MCF-7 cells via Src kinase activation of PI3-K triggering Akt upregulation of cyclin D1 .	Interestingly, ligand dependent ERalpha extranuclear signaling has been shown to cause proliferation of MCF-7 cells via Src kinase activation of PI3-K triggering Akt upregulation of cyclin D1.	17	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	17	18	23	24
These data suggest that Src potentiates PI3K and AKT signaling downstream of mTOR , however , dasatinib inhibits a number of additional kinases .	These data suggest that Src potentiates PI3K and AKT signaling downstream of mTOR, however, dasatinib inhibits a number of additional kinases.	4	9	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	4	5	8	9
Activation of cellular SRC ( c-SRC ) was previously reported to promote metastasis of NPC by regulating the PI3K and AKT signaling pathway .	Activation of cellular SRC (c-SRC) was previously reported to promote metastasis of NPC by regulating the PI3K and AKT signaling pathway.	0	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	AKT	AKT	AKT	3	4	20	21
c-Src has also been demonstrated to increase AKT activation in HCC progression [ XREF_BIBR ] .	c-Src has also been demonstrated to increase AKT activation in HCC progression [XREF_BIBR].	0	8	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	AKT	AKT	AKT	0	1	7	8
In those previous studies , we have identified p53 as a suppressor of Src induced podosome formation and proposed that p53 acts by upregulating the expression of two anti-invasion regulators : caldesmon , an actin binding protein and a negative regulator of podosome assembly [ XREF_BIBR ] , and PTEN that inhibits the Src mediated PI3K-Akt and Stat3 pro invasion pathways [ XREF_BIBR , XREF_BIBR ] .	In those previous studies, we have identified p53 as a suppressor of Src induced podosome formation and proposed that p53 acts by upregulating the expression of two anti-invasion regulators : caldesmon, an actin binding protein and a negative regulator of podosome assembly [XREF_BIBR], and PTEN that inhibits the Src mediated PI3K-Akt and Stat3 pro invasion pathways [XREF_BIBR, XREF_BIBR].	51	57	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	PI3K-Akt	PI3K-Akt	PI3K-Akt	53	54	55	56
Src and ADP receptor dependent activation of the PI3K-Akt signaling pathway during integrin signaling .	Src and ADP receptor dependent activation of the PI3K-Akt signaling pathway during integrin signaling.	0	10	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Src	Src	Src	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	8	9
Src and PI3K are upstream activators of Akt and the interleukin-8 ( IL-8 ) promoter .	Src and PI3K are upstream activators of Akt and the interleukin-8 (IL-8) promoter.	0	14	are upstream activators	Positive_activation_copula_1	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	7	8
Although Src can activate Akt directly ( Jiang and Qiu , 2003 ) and as well affect Ras-MAPK pathway ( Olayioye et al , 2001 ) , activation of the EphA2 kinase has been shown to stimulate the MAPK pathway ( Pratt and Kinch , 2002 ) and phosphoinositide 3 kinase pathway ( Pandey et al , 1994 ) .	Although Src can activate Akt directly (Jiang and Qiu, 2003) and as well affect Ras-MAPK pathway (Olayioye et al, 2001), activation of the EphA2 kinase has been shown to stimulate the MAPK pathway (Pratt and Kinch, 2002) and phosphoinositide 3 kinase pathway (Pandey et al, 1994).	1	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	1	2	4	5
Our findings demonstrate that leptin protection of gastric mucosa against ethanol cytotoxicity involves Src kinase mediated bifurcated activation of MAPK and ERK and Akt that leads to up-regulation of the respective prostaglandin and nitric oxide synthase pathways .	Our findings demonstrate that leptin protection of gastric mucosa against ethanol cytotoxicity involves Src kinase mediated bifurcated activation of MAPK and ERK and Akt that leads to up-regulation of the respective prostaglandin and nitric oxide synthase pathways.	13	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	13	14	23	24
The importance of FAK for Src mediated Akt activation in detached cells will be examined in future studies .	The importance of FAK for Src mediated Akt activation in detached cells will be examined in future studies.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	5	6	7	8
In addition , our data demonstrated that the inhibition of Src by Dasatinib could also suppress the activation of PI3K-Akt signaling in A549 cells , which was in agreement with previous reports [ XREF_BIBR ] .	In addition, our data demonstrated that the inhibition of Src by Dasatinib could also suppress the activation of PI3K-Akt signaling in A549 cells, which was in agreement with previous reports [XREF_BIBR].	8	20	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	PI3K-Akt	PI3K-Akt	PI3K-Akt	10	11	19	20
As FAK and Src has been shown to activate phosphoinositide 3-kinase ( PI3K ) and Akt to promote cell adhesion and survival [ XREF_BIBR - XREF_BIBR ] , the phosphorylation of Akt at Ser 473 was examined .	As FAK and Src has been shown to activate phosphoinositide 3-kinase (PI3K) and Akt to promote cell adhesion and survival [XREF_BIBR - XREF_BIBR], the phosphorylation of Akt at Ser 473 was examined.	1	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	3	4	15	16
Akt activity was decreased by suppression of c-Src expression .	Akt activity was decreased by suppression of c-Src expression.	0	9	decreased	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src expression	c-src	Akt	Akt	akt	7	8	0	1
Our data showed that inhibition of Src with PP2 attenuated Akt , but not PDK-1 , activity in AGEs- and high glucose treated 3T3-L1 cells , suggesting that Src is upstream of Akt , but not PI3-kinase nor PDK1 .	Our data showed that inhibition of Src with PP2 attenuated Akt, but not PDK-1, activity in AGEs- and high glucose treated 3T3-L1 cells, suggesting that Src is upstream of Akt, but not PI3-kinase nor PDK1.	4	21	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	6	7	10	11
These data demonstrate that Akt activation by the high-affinity CCK A receptor is mediated by both Src and PI3K .	These data demonstrate that Akt activation by the high-affinity CCK A receptor is mediated by both Src and PI3K.	4	18	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	16	17	4	5
Similarly , anoikis resistance is maintained in osteosarcoma cells through Src dependent activation of the PI3K and Akt pathway in a manner independent of FAK activity [ XREF_BIBR ] .	Similarly, anoikis resistance is maintained in osteosarcoma cells through Src dependent activation of the PI3K and Akt pathway in a manner independent of FAK activity [XREF_BIBR].	10	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	10	11	17	18
Moreover , the inhibition of ghrelin induced acinar cell capacity for mucin synthesis , and NO and PGE2 generation by Akt inhibitor , SH-5 , and cNOS inhibitor , L-NAME , and only that of PGE2 and mucin synthesis by COX-1 inhibitor , SC-560 , suggest that up-regulation in NO generation through Src kinase activation of the Akt and cNOS pathway plays an essential role in the regulation of PGE2 production and mucin synthesis in response to ghrelin .	Moreover, the inhibition of ghrelin induced acinar cell capacity for mucin synthesis, and NO and PGE2 generation by Akt inhibitor, SH-5, and cNOS inhibitor, L-NAME, and only that of PGE2 and mucin synthesis by COX-1 inhibitor, SC-560, suggest that up-regulation in NO generation through Src kinase activation of the Akt and cNOS pathway plays an essential role in the regulation of PGE2 production and mucin synthesis in response to ghrelin.	52	60	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	52	53	57	58
22 Additionally , VEGF induced tyrosine phosphatase inhibition promotes Src mediated activation of Akt and mammalian target of rapamycin ( mTOR ) during angiogenesis .	22 Additionally, VEGF induced tyrosine phosphatase inhibition promotes Src mediated activation of Akt and mammalian target of rapamycin (mTOR) during angiogenesis.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	9	10	13	14
Src also activates ERK and MEK , in addition to Akt .	Src also activates ERK and MEK, in addition to Akt.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	10	11
The beta1 activation subsequently results in phosphorylation of non receptor tyrosine kinase FAK and Src and Syk , which in turn activates STAT3 and Akt , leading to the promotion of tumor cell survival .	The beta1 activation subsequently results in phosphorylation of non receptor tyrosine kinase FAK and Src and Syk, which in turn activates STAT3 and Akt, leading to the promotion of tumor cell survival.	1	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	beta1 activation subsequently results in phosphorylation of non receptor tyrosine kinase FAK and Src	src	Akt	Akt	akt	14	15	24	25
Src kinase can also activate the PI3K and Akt and the Ras and MAPK survival pathways independent of FAK signalling and thus stimulate ainoikis resistance [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Src kinase can also activate the PI3K and Akt and the Ras and MAPK survival pathways independent of FAK signalling and thus stimulate ainoikis resistance [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	8	9
These results indicate that FAK and Src dependent activation of the AKT and ERK pathways was involved in 4-HBA-induced migration of HaCaT cells .	These results indicate that FAK and Src dependent activation of the AKT and ERK pathways was involved in 4-HBA-induced migration of HaCaT cells.	4	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	6	7	11	12
Outside-in signalling from integrins can also involve activation of Src , which then activates the PI3K and Akt pathway XREF_BIBR .	Outside-in signalling from integrins can also involve activation of Src, which then activates the PI3K and Akt pathway XREF_BIBR.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	9	10	17	18
The increased phosphorylation of Src on Y529 under these conditions results in impaired Src and Akt activation .	The increased phosphorylation of Src on Y529 under these conditions results in impaired Src and Akt activation.	2	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Src	phosphorylation of Src on Y529	src	Akt	Akt	akt	4	5	15	16
Active ( phosphorylated Y416 ) Src was shown to regulate cancer stemness , since ectopic overexpression of Src strongly activated Akt and subsequently enhanced pluripotency transcription factor SRY ( sex determining region Y )-box 2 ( Sox2 ) mediating CSCs phenotypes , while the ShRNA of Src and Src inhibitor ( Dasatinib ) suppressed Akt , Sox2 , and CSC properties .	Active (phosphorylated Y416) Src was shown to regulate cancer stemness, since ectopic overexpression of Src strongly activated Akt and subsequently enhanced pluripotency transcription factor SRY (sex determining region Y)-box 2 (Sox2) mediating CSCs phenotypes, while the ShRNA of Src and Src inhibitor (Dasatinib) suppressed Akt, Sox2, and CSC properties.	46	60	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Akt	Akt	Akt	46	47	54	55
Moreover , cells expressing c-CblY371H are chemoresistant due to hyperactive Src kinase that promotes AKT signaling via enhanced binding of c-Cbl ( Y371H ) to the PI3K regulatory subunit p85 .	Moreover, cells expressing c-CblY371H are chemoresistant due to hyperactive Src kinase that promotes AKT signaling via enhanced binding of c-Cbl (Y371H) to the PI3K regulatory subunit p85.	10	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	10	11	14	15
Disruption of SRC-1 inhibited Ets-2-mediated HER2 expression and PyMT stimulated Akt activation in the mammary tumors .	Disruption of SRC-1 inhibited Ets-2-mediated HER2 expression and PyMT stimulated Akt activation in the mammary tumors.	0	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	Akt	Akt	Akt	2	3	10	11
Inhibition of Src ( or in SYF-/- cells ) impairs Akt activation .	Inhibition of Src (or in SYF-/- cells) impairs Akt activation.	0	11	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	2	3	10	11
Src activation triggers the PI3K and AKT signaling axis , which is a key regulator of cell proliferation and survival .	Src activation triggers the PI3K and AKT signaling axis, which is a key regulator of cell proliferation and survival.	0	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	0	1	6	7
Phosphorylation of Src and FAK leads to the activation of the PI3K and Akt pathway which initiates cell survival and proliferation pathways via mTOR signaling .	Phosphorylation of Src and FAK leads to the activation of the PI3K and Akt pathway which initiates cell survival and proliferation pathways via mTOR signaling.	0	14	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Src	Phosphorylation of Src	src	Akt	Akt	akt	2	3	13	14
Src also activates Akt and can promote cell proliferation through the Ras-Erk pathway [ XREF_BIBR ] .	Src also activates Akt and can promote cell proliferation through the Ras-Erk pathway [XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	3	4
XREF_BIBR , XREF_BIBR Src phosphorylated PTEN also causes PTEN degradation and PI3K and AKT signaling amplification .	XREF_BIBR, XREF_BIBR Src phosphorylated PTEN also causes PTEN degradation and PI3K and AKT signaling amplification.	0	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	3	4	13	14
Because Src can positively regulate Akt through PI3K , and the tumor suppressor PTEN ( phosphatase and tensin homologue ) negatively regulates the PI3K and Akt signaling pathway , [ XREF_BIBR ] we examined the expression and phosphorylation of Akt in LN18 ( PTEN wild type ) , U373 ( PTEN mutant ) , and U87 and LNZ308 ( PTEN deleted ) cell lines .	Because Src can positively regulate Akt through PI3K, and the tumor suppressor PTEN (phosphatase and tensin homologue) negatively regulates the PI3K and Akt signaling pathway, [XREF_BIBR] we examined the expression and phosphorylation of Akt in LN18 (PTEN wild type), U373 (PTEN mutant), and U87 and LNZ308 (PTEN deleted) cell lines.	1	6	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	1	2	5	6
The ERK activatin was inhibited by the Src inhibitor and the Akt activation was inhibited by inhibitors of EGFR and Src .	The ERK activatin was inhibited by the Src inhibitor and the Akt activation was inhibited by inhibitors of EGFR and Src.	11	21	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	20	21	11	12
These conclusions are consistent with studies showing that Akt activation by angiotensin ( in mesangial cells ) [ XREF_BIBR ] , IGF-1 ( in oligodendrocytes ) [ XREF_BIBR , XREF_BIBR ] , lysophosphatidic acid ( in corneal cells ) [ XREF_BIBR ] adenosine ( in cardiomyocytes ) [ XREF_BIBR ] reactive oxygen species ( in fibroblasts ) [ XREF_BIBR ] and by estrogen ( in endothelial cells ) [ XREF_BIBR ] , are mediated by Src family kinases .	These conclusions are consistent with studies showing that Akt activation by angiotensin (in mesangial cells) [XREF_BIBR], IGF-1 (in oligodendrocytes) [XREF_BIBR, XREF_BIBR], lysophosphatidic acid (in corneal cells) [XREF_BIBR] adenosine (in cardiomyocytes) [XREF_BIBR] reactive oxygen species (in fibroblasts) [XREF_BIBR] and by estrogen (in endothelial cells) [XREF_BIBR], are mediated by Src family kinases.	8	77	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	75	76	8	9
43 As we show here that LMP1 interacts with c-Src via P85 ( XREF_FIG and XREF_FIG ) , we were interested in examining the possibility that c-Src mediates LMP1 activation of Akt .	43 As we show here that LMP1 interacts with c-Src via P85 (XREF_FIG and XREF_FIG), we were interested in examining the possibility that c-Src mediates LMP1 activation of Akt.	26	32	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	26	27	31	32
Dopamine D3 receptor ( Gi ) , known to have a role in addictive behavior , interacts with SH3 ( Src homolog ) domain of growth factor receptor bound protein Grb2 and Src and thus , is likely to signal ERK and Akt activation .	Dopamine D3 receptor (Gi), known to have a role in addictive behavior, interacts with SH3 (Src homolog) domain of growth factor receptor bound protein Grb2 and Src and thus, is likely to signal ERK and Akt activation.	20	43	signal	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	20	21	42	43
The mechanism by which Src regulates the level of TGF-betaI receptor expression has not been explored yet , but may be associated with Src induced activation of AKT .	The mechanism by which Src regulates the level of TGF-betaI receptor expression has not been explored yet, but may be associated with Src induced activation of AKT.	21	28	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	23	24	27	28
Based on the mutual activation of IGF-1R and Src and the Src dependent activation of Akt in high pSrc expressing cells after linsitinib treatment , we speculated that cells with a relatively low level of active Src may display high levels of linsitinib sensitivity .	Based on the mutual activation of IGF-1R and Src and the Src dependent activation of Akt in high pSrc expressing cells after linsitinib treatment, we speculated that cells with a relatively low level of active Src may display high levels of linsitinib sensitivity.	11	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	11	12	15	16
One study revealed that Src dependent activation of the PI3K and Akt pathway , which is independent of FAK phosphorylation , is essential for OS cells to gain anoikis resistance .	One study revealed that Src dependent activation of the PI3K and Akt pathway, which is independent of FAK phosphorylation, is essential for OS cells to gain anoikis resistance.	4	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	4	5	11	12
Activation of SRC by EGFR further activates Akt , which leads to both acquired and de novo trastuzumab resistance in breast cancer .	Activation of SRC by EGFR further activates Akt, which leads to both acquired and de novo trastuzumab resistance in breast cancer.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	Akt	Akt	Akt	2	3	7	8
This protection occurs independently of neurophin signaling but requires Src activation of ERK ( extracellular signal regulated kinase ) and Akt .	This protection occurs independently of neurophin signaling but requires Src activation of ERK (extracellular signal regulated kinase) and Akt.	9	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	9	10	20	21
Src mediates activation of STAT3 and Akt in the peritoneum after CG injury .	Src mediates activation of STAT3 and Akt in the peritoneum after CG injury.	0	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	6	7
In conclusion , fluoxetine at low concentrations stimulates Src which , phosphorylates EGFRs and activates PI3K and AKT signal pathway , but at high concentrations stimulates metalloproteinase and induces shedding of growth factor which stimulates EGFRs and activates MAPK and ERK 1/2 signaling pathway .	In conclusion, fluoxetine at low concentrations stimulates Src which, phosphorylates EGFRs and activates PI3K and AKT signal pathway, but at high concentrations stimulates metalloproteinase and induces shedding of growth factor which stimulates EGFRs and activates MAPK and ERK 1/2 signaling pathway.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src which, phosphorylates EGFRs	src	AKT	AKT	akt	8	9	17	18
PI3-kinase is associated with vascular endothelial growth factor induced PYK2 and Src complex , and inhibition of Src blocked Akt activation .	PI3-kinase is associated with vascular endothelial growth factor induced PYK2 and Src complex, and inhibition of Src blocked Akt activation.	15	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	17	18	19	20
XREF_FIG ) showed there was a distinction between blockage of p - Src and that of p - ERK in the number of DG BrdU labeling cells , indicating that beside Raf and ERK cascade , there might be some other factors triggered by Src getting involved in this event , such as PI3K and Akt pathway which has also been known to be activated by Src kinase following ischemia and reperfusion in various organs , and plays a pivotal role in cell proliferation , differentiation , and survival [ XREF_BIBR - XREF_BIBR ] .	XREF_FIG) showed there was a distinction between blockage of p - Src and that of p - ERK in the number of DG BrdU labeling cells, indicating that beside Raf and ERK cascade, there might be some other factors triggered by Src getting involved in this event, such as PI3K and Akt pathway which has also been known to be activated by Src kinase following ischemia and reperfusion in various organs, and plays a pivotal role in cell proliferation, differentiation, and survival [XREF_BIBR - XREF_BIBR].	53	67	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	66	67	55	56
Akt is a serine/threonine protein kinase that mediates cell survival , proliferation , tumour cell migration and invasion and metastasis and previous studies have shown that c-Src activates the PI3K and Akt signaling pathway .	Akt is a serine/threonine protein kinase that mediates cell survival, proliferation, tumour cell migration and invasion and metastasis and previous studies have shown that c-Src activates the PI3K and Akt signaling pathway.	26	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	26	27	31	32
Notably , in monocytes the interaction between BST1 and the ECM initiates signalling cascade mediated by focal adhesion kinase and Src , leading to activation of the MAP Kinase and PI3K and Akt pathways commonly dysregulated in cancer XREF_BIBR .	Notably, in monocytes the interaction between BST1 and the ECM initiates signalling cascade mediated by focal adhesion kinase and Src, leading to activation of the MAP Kinase and PI3K and Akt pathways commonly dysregulated in cancer XREF_BIBR.	14	33	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	20	21	32	33
FGF induced a transient activation of ERK , but not Akt , which was inhibited by an inhibitor of MEK , the upstream kinase of ERK , but not by inhibitors of PI3K and Akt ( LY294002 ) , epidermal growth factor receptor ( EGFR , AG1478 ) , and Src ( PP2 ) .	FGF induced a transient activation of ERK, but not Akt, which was inhibited by an inhibitor of MEK, the upstream kinase of ERK, but not by inhibitors of PI3K and Akt (LY294002), epidermal growth factor receptor (EGFR, AG1478), and Src (PP2).	1	52	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	50	51	10	11
Thus , we conclude that ADP receptor signaling , particularly P2Y12 signaling , is important in integrin induced and Src dependent activation of the PI3K and Akt signaling pathway .	Thus, we conclude that ADP receptor signaling, particularly P2Y12 signaling, is important in integrin induced and Src dependent activation of the PI3K and Akt signaling pathway.	19	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	19	20	26	27
Src activation independently activated first the MAP-kinase - ERK1/2 pathway , then the PI3-kinase - Akt pathway .	Src activation independently activated first the MAP-kinase - ERK1/2 pathway, then the PI3-kinase - Akt pathway.	0	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	15	16
Src activates AKT via inhibition of PTEN in breast cancer .	Src activates AKT via inhibition of PTEN in breast cancer.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	0	1	2	3
It is interesting to ask whether the regulatory activity of viral RNA unprimed RIG-I on STAT1 activation or on AKT activation by Src ( which is seemingly unrelated to the classic function of RIG-I in sensing viral invasion ) , would contribute to antiviral immunity .	It is interesting to ask whether the regulatory activity of viral RNA unprimed RIG-I on STAT1 activation or on AKT activation by Src (which is seemingly unrelated to the classic function of RIG-I in sensing viral invasion), would contribute to antiviral immunity.	19	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	22	23	19	20
Expression of constitutively active c-Src increased Akt activity to the same extent as with PDGF .	Expression of constitutively active c-Src increased Akt activity to the same extent as with PDGF.	0	7	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	Expression of constitutively active c-Src	c-src	Akt	Akt	akt	4	5	6	7
Src activation triggers the PI3K and Akt signaling axis , which is a key regulator of survival and cell cycle progression .	Src activation triggers the PI3K and Akt signaling axis, which is a key regulator of survival and cell cycle progression.	0	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	6	7
Importantly , inhibition of p38 decreased the phosphorylation of AKT on Ser473 but not Thr308 , suggesting that radiation activated SRC promotes AKT signaling through activation of PI3K and p38 in breast cancer cells .	Importantly, inhibition of p38 decreased the phosphorylation of AKT on Ser473 but not Thr308, suggesting that radiation activated SRC promotes AKT signaling through activation of PI3K and p38 in breast cancer cells.	20	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	AKT	AKT	AKT	20	21	22	23
Moreover , c-Src could activate PI3K and AKT and the MEK and ERK cascades , which indicated that TrkB regulated tumor progression by activation of PI3K and AKT signaling pathway via regulation of c-Src [ XREF_BIBR ] .	Moreover, c-Src could activate PI3K and AKT and the MEK and ERK cascades, which indicated that TrkB regulated tumor progression by activation of PI3K and AKT signaling pathway via regulation of c-Src [XREF_BIBR].	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	AKT	AKT	AKT	2	3	7	8
Further , relevant to diabetic nephropathy , Src activates Akt and ERK and increases ROS generation .	Further, relevant to diabetic nephropathy, Src activates Akt and ERK and increases ROS generation.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	7	8	9	10
Recruitment of TRAF6 to Motif 1 leads to formation of a signaling complex containing c-Src , TAB2 , TAK1 and TAB1 , which subsequently activates Akt , NF-kB , JNK , p38 and ERK pathways [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] ( XREF_FIG ) .	Recruitment of TRAF6 to Motif 1 leads to formation of a signaling complex containing c-Src, TAB2, TAK1 and TAB1, which subsequently activates Akt, NF-kB, JNK, p38 and ERK pathways [XREF_BIBR, XREF_BIBR - XREF_BIBR] (XREF_FIG).	13	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	14	15	25	26
Src inhibition decreased p38 and Akt activation .	Src inhibition decreased p38 and Akt activation.	0	6	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	5	6
Because Src can positively regulate Akt through PI3K , we investigated whether phospho-Akt may also be a marker for dasatinib sensitivity .	Because Src can positively regulate Akt through PI3K, we investigated whether phospho-Akt may also be a marker for dasatinib sensitivity.	1	6	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	1	2	5	6
Incubation of TSU-Pr1 cells with specific kinase inhibitors together with ET-1 or bombesin showed that IGF-IR activation is required for neuropeptide induced Akt phosphorylation , and that neuropeptide induced Akt activation is predominantly mediated by Src and phosphatidylinositol 3-kinase but not by mitogen activated protein kinase or protein kinase C.	Incubation of TSU-Pr1 cells with specific kinase inhibitors together with ET-1 or bombesin showed that IGF-IR activation is required for neuropeptide induced Akt phosphorylation, and that neuropeptide induced Akt activation is predominantly mediated by Src and phosphatidylinositol 3-kinase but not by mitogen activated protein kinase or protein kinase C.	29	38	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	35	36	29	30
XREF_BIBR The suppression of SRC expression has been found to decrease AKT activity and increase gemcitabine chemosensitivity .	XREF_BIBR The suppression of SRC expression has been found to decrease AKT activity and increase gemcitabine chemosensitivity.	4	12	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC expression	src	AKT	AKT	akt	4	5	11	12
The experimental result that constitutive activation of AKT significantly induces the degradation of TSC1 and TSC2 protein complex in a dose dependent manner validates the negative regulation of AKT on TSC2 predicted by our posterior network [ XREF_BIBR ] The positive regulation of SRC on AKT is also consistent with the fact that AKT is transcriptionally up-regulated by SRC ( i = 46 ) through a cascade of molecular interactions [ XREF_BIBR ] .	The experimental result that constitutive activation of AKT significantly induces the degradation of TSC1 and TSC2 protein complex in a dose dependent manner validates the negative regulation of AKT on TSC2 predicted by our posterior network [XREF_BIBR] The positive regulation of SRC on AKT is also consistent with the fact that AKT is transcriptionally up-regulated by SRC (i = 46) through a cascade of molecular interactions [XREF_BIBR].	53	61	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	AKT	AKT	AKT	58	59	53	54
The Src kinase , Lck , as well as mitogen activated protein kinase and Akt were activated , but p21 ( WAF ) , phosphatase and tensin homologue was reduced in K562 BMS-R cells .	The Src kinase, Lck, as well as mitogen activated protein kinase and Akt were activated, but p21 (WAF), phosphatase and tensin homologue was reduced in K562 BMS-R cells.	1	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	1	2	14	15
Thus , it seems that FAK promotes A549 lung cancer cell migration and invasion in concert with Src and subsequent activation of the ERK and PI3K and Akt signalling pathways .	Thus, it seems that FAK promotes A549 lung cancer cell migration and invasion in concert with Src and subsequent activation of the ERK and PI3K and Akt signalling pathways.	17	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	17	18	27	28
Moreover , cells expressing c-CblY371H are chemoresistant due to hyperactive Src kinase that promotes AKT signaling via enhanced binding of c-Cbl ( Y371H ) to the PI3K regulatory subunit p85 [ XREF_BIBR , XREF_BIBR ] .	Moreover, cells expressing c-CblY371H are chemoresistant due to hyperactive Src kinase that promotes AKT signaling via enhanced binding of c-Cbl (Y371H) to the PI3K regulatory subunit p85 [XREF_BIBR, XREF_BIBR].	10	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	10	11	14	15
Another route of PI3K and AKT activation is likely through SRC since SRC kinases have also been shown to stimulate the PI3K and AKT pathway downstream of activated receptor .	Another route of PI3K and AKT activation is likely through SRC since SRC kinases have also been shown to stimulate the PI3K and AKT pathway downstream of activated receptor.	12	24	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	AKT	AKT	AKT	12	13	23	24
Our observation showed that DP2 treatment was able to trigger FAK and Src signaling and activation of PI3K and AKT and MAPKs .	Our observation showed that DP2 treatment was able to trigger FAK and Src signaling and activation of PI3K and AKT and MAPKs.	12	20	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	12	13	19	20
Thus c-Src functions as a switch that initiates the Akt pathway associated to both the G i/o -protein dependent pathway and beta , arrestin , and scaffolded complex .	Thus c-Src functions as a switch that initiates the Akt pathway associated to both the G i/o -protein dependent pathway and beta, arrestin, and scaffolded complex.	1	10	initiates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	1	2	9	10
As some studies have demonstrated that outside-in integrin signalling results in activation of Src , which in turn can activate PI3K and Akt pathway , we also analysed if culture of HSPCs with Postn affected Src phosphorylation .	As some studies have demonstrated that outside-in integrin signalling results in activation of Src, which in turn can activate PI3K and Akt pathway, we also analysed if culture of HSPCs with Postn affected Src phosphorylation.	11	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	13	14	22	23
XREF_BIBR Although we have shown a good correlation between Src induced activation of Akt and podosome formation in smooth muscle cells , how Akt promotes podosome formation is not clear .	XREF_BIBR Although we have shown a good correlation between Src induced activation of Akt and podosome formation in smooth muscle cells, how Akt promotes podosome formation is not clear.	7	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	9	10	13	14
Altogether , these studies indicated a SRC dependent activation of the PI3K and AKT pathway to be a critical component of survival pathways and drug resistances ( Kanda etal ., 2013 ) ( Diaz-Montero etal ., 2006 ) .	Altogether, these studies indicated a SRC dependent activation of the PI3K and AKT pathway to be a critical component of survival pathways and drug resistances (Kanda etal., 2013) (Diaz-Montero etal., 2006).	6	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SRC	SRC	SRC	AKT	AKT	AKT	6	7	13	14
For instance , Src activates AKT and PI3 kinase , which are capable of transporting GLUT4 to the plasma membrane , resulting in glucose influx [ XREF_BIBR , XREF_BIBR ] .	For instance, Src activates AKT and PI3 kinase, which are capable of transporting GLUT4 to the plasma membrane, resulting in glucose influx [XREF_BIBR, XREF_BIBR].	3	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	3	4	5	6
The results suggest that clustered , but not free , opto-Dab1 activates Src family kinases , which then activate PI3K and Akt ( XREF_FIG ) .	The results suggest that clustered, but not free, opto-Dab1 activates Src family kinases, which then activate PI3K and Akt (XREF_FIG).	12	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	12	13	21	22
XREF_BIBR , XREF_BIBR , XREF_BIBR Upon activation , Src can directly activate STAT3 and AKT by phosphosphorylation of their active sites .	XREF_BIBR, XREF_BIBR, XREF_BIBR Upon activation, Src can directly activate STAT3 and AKT by phosphosphorylation of their active sites.	8	15	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	8	9	14	15
The physiological significance of Src mediated AKT activation is further strengthened from the observation that the tumor necrosis family ( TNF ) family member TRANCE and its cognate receptor TRANCE-R , require both c-src and PI3K to activate PKB in dendritic cells and osteoclasts , with TRAF6 acting as a mediator between c-src and TRANCE-R , to promote survival .	The physiological significance of Src mediated AKT activation is further strengthened from the observation that the tumor necrosis family (TNF) family member TRANCE and its cognate receptor TRANCE-R, require both c-src and PI3K to activate PKB in dendritic cells and osteoclasts, with TRAF6 acting as a mediator between c-src and TRANCE-R, to promote survival.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	4	5	6	7
Src kinases are known to play an important role in regulating mitotic events and , like the Bcr-Abl kinase , can activate the STAT5 , PI-3K and Akt and MAPK signaling pathways .	Src kinases are known to play an important role in regulating mitotic events and, like the Bcr-Abl kinase, can activate the STAT5, PI-3K and Akt and MAPK signaling pathways.	0	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	27	28
Src is likely situated between CD44 and Akt since Src indirectly activates PI-3 kinase and Akt during angiogenesis 35 , and also Src maximally activates FAK through FAK-Y 577 phosphorylation .	Src is likely situated between CD44 and Akt since Src indirectly activates PI-3 kinase and Akt during angiogenesis 35, and also Src maximally activates FAK through FAK-Y 577 phosphorylation.	0	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	15	16
A case in point is the specific association of breast cancer bone metastasis with a gene expression signature ( Src response signature , SRS ) that denotes activation of Src and Src dependent enhancement of PI3K-Akt signaling in primary tumors .	A case in point is the specific association of breast cancer bone metastasis with a gene expression signature (Src response signature, SRS) that denotes activation of Src and Src dependent enhancement of PI3K-Akt signaling in primary tumors.	29	36	enhancement	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	PI3K-Akt	PI3K-Akt	PI3K-Akt	29	30	35	36
Because Src kinase can activate Akt via PI3K ( Type I ) XREF_BIBR - XREF_BIBR leading to a decrease in mammalian target of rapamycin ( mTOR )-dependent autophagy XREF_BIBR , XREF_BIBR , we surmised that Nox2 and Src are the critical proteins that link oxidative stress to impaired autophagy in mdx skeletal muscle .	Because Src kinase can activate Akt via PI3K (Type I) XREF_BIBR - XREF_BIBR leading to a decrease in mammalian target of rapamycin (mTOR)-dependent autophagy XREF_BIBR, XREF_BIBR, we surmised that Nox2 and Src are the critical proteins that link oxidative stress to impaired autophagy in mdx skeletal muscle.	1	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	1	2	5	6
SRC can activate the PI3K-AKT , MAPK , and JAK-STAT signaling pathways that are critical for cell cycle progression , survival , and proliferation .	SRC can activate the PI3K-AKT, MAPK, and JAK-STAT signaling pathways that are critical for cell cycle progression, survival, and proliferation.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	4	5
In our previous work , c-Src activation by TrkC was found to induce activation of the PI3K-AKT pathway XREF_BIBR .	In our previous work, c-Src activation by TrkC was found to induce activation of the PI3K-AKT pathway XREF_BIBR.	5	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	PI3K-AKT	PI3K-AKT	PI3K-AKT	5	6	16	17
As reported and illustrated with Figure XREF_FIG F , Src activates PI3K and Akt pathway to negatively regulate Caspase 9 and simultaneously positively regulate NF-kappa B while induces proliferation through MEK/ERK1/2 pathway 19 , 20 , 21 .	As reported and illustrated with Figure XREF_FIG F, Src activates PI3K and Akt pathway to negatively regulate Caspase 9 and simultaneously positively regulate NF-kappa B while induces proliferation through MEK/ERK1/2 pathway 19, 20, 21.	9	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	9	10	13	14
Dedifferentiation was seen in hepatocytes grown on monolayers of dried stiff collagen , caused by a specific signalling network triggered by the ECM , activating focal adhesion kinase ( FAK ) via Src , which in turn activated Akt , causing resistance to TGF-beta-induced apoptosis by antagonizing p38 [ XREF_BIBR ] .	Dedifferentiation was seen in hepatocytes grown on monolayers of dried stiff collagen, caused by a specific signalling network triggered by the ECM, activating focal adhesion kinase (FAK) via Src, which in turn activated Akt, causing resistance to TGF-beta-induced apoptosis by antagonizing p38 [XREF_BIBR].	27	39	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	32	33	38	39
XREF_BIBR AKT activated by active SRC leads to invasiveness of cancer cells via up-regulation of IGF-IR expression .	XREF_BIBR AKT activated by active SRC leads to invasiveness of cancer cells via up-regulation of IGF-IR expression.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	AKT	AKT	AKT	5	6	1	2
RACK1 also induces apoptosis by blocking Src activation of the Akt cell survival pathway .	RACK1 also induces apoptosis by blocking Src activation of the Akt cell survival pathway.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	6	7	10	11
These data demonstrate that , in the context of RV infection , Src and p110beta PI 3-kinase are upstream activators of Akt and the IL-8 promoter and that RV colocalizes with Src , PI 3-kinase , and Akt in lipid rafts .	These data demonstrate that, in the context of RV infection, Src and p110beta PI 3-kinase are upstream activators of Akt and the IL-8 promoter and that RV colocalizes with Src, PI 3-kinase, and Akt in lipid rafts.	12	25	are upstream activators	Positive_activation_copula_1	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	12	13	21	22
Because SRC has been shown to constitutively activate PI3K and AKT signaling , it is likely that overexpression of SRC may also confer resistance to PI3K inhibition in a PI3K and AKT pathway dependent fashion ; however , this remains to be confirmed experimentally .	Because SRC has been shown to constitutively activate PI3K and AKT signaling, it is likely that overexpression of SRC may also confer resistance to PI3K inhibition in a PI3K and AKT pathway dependent fashion; however, this remains to be confirmed experimentally.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	AKT	AKT	AKT	1	2	10	11
It has been reported that Src can induce activation of AKT , and that AKT can directly interact with and phosphorylate ubiquitin specific protease 4 ( USP4 ) , a deubiquitinating enzyme responsible for extending TGF-beta receptor I life on cell membranes by preventing its degradation .	It has been reported that Src can induce activation of AKT, and that AKT can directly interact with and phosphorylate ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme responsible for extending TGF-beta receptor I life on cell membranes by preventing its degradation.	5	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	5	6	10	11
Interaction of the Src homology 2 ( SH2 ) domain of PI3K with MUC1-C activates the PI3K-AKT pathway XREF_BIBR - XREF_BIBR .	Interaction of the Src homology 2 (SH2) domain of PI3K with MUC1-C activates the PI3K-AKT pathway XREF_BIBR - XREF_BIBR.	3	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	16	17
Furthermore , c-Src activated AKT through the formation of a complex with regulatory subunit p85 of PI3K with subsequent activation of the PI3K and Akt pathway .	Furthermore, c-Src activated AKT through the formation of a complex with regulatory subunit p85 of PI3K with subsequent activation of the PI3K and Akt pathway.	2	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	AKT	AKT	AKT	2	3	4	5
Activation of the tyrosine kinase SRC by this complex results in activation of MEK-ERK and PI3K-Akt signaling .	Activation of the tyrosine kinase SRC by this complex results in activation of MEK-ERK and PI3K-Akt signaling.	0	16	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	PI3K-Akt	PI3K-Akt	PI3K-Akt	5	6	15	16
Our findings also show that the Src independent activation of PI3K1A and Akt by ouabain leads to stimulation of proliferative growth in fibroblasts and hypertrophic growth in cardiac myocytes .	Our findings also show that the Src independent activation of PI3K1A and Akt by ouabain leads to stimulation of proliferative growth in fibroblasts and hypertrophic growth in cardiac myocytes.	6	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	6	7	12	13
Src and FAK activate the PI-3 kinase and Akt signaling axis , which in turn recruits Tiam1 and other actin binding proteins leading to increased activation of Rho-GTPases and cell migration .	Src and FAK activate the PI-3 kinase and Akt signaling axis, which in turn recruits Tiam1 and other actin binding proteins leading to increased activation of Rho-GTPases and cell migration.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	8	9
Src promotes the survival of breast cancer cells by amplifying the responsiveness of the PI3K-Akt survival pathway to CXCL12 and IGF1 .	Src promotes the survival of breast cancer cells by amplifying the responsiveness of the PI3K-Akt survival pathway to CXCL12 and IGF1.	0	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	14	15
Interaction of mda-9 and syntenin with the ECM in melanoma cells results in c-Src and FAK activation that subsequently activates the PI3K and AKT pathway resulting in HIF-1-alpha-mediated induction of IGFBP-2 ( XREF_FIG ) .	Interaction of mda-9 and syntenin with the ECM in melanoma cells results in c-Src and FAK activation that subsequently activates the PI3K and AKT pathway resulting in HIF-1-alpha-mediated induction of IGFBP-2 (XREF_FIG).	13	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	AKT	AKT	AKT	13	14	23	24
c-Src is also known to activate PI3K and AKT and the MAP and extracellular signal regulated kinase ( ERK ) kinase ( MEK )/ERK cascades through both focal adhesion kinase ( FAK )-dependent and FAK independent pathways [ XREF_BIBR ] .	c-Src is also known to activate PI3K and AKT and the MAP and extracellular signal regulated kinase (ERK) kinase (MEK)/ERK cascades through both focal adhesion kinase (FAK)-dependent and FAK independent pathways [XREF_BIBR].	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	AKT	AKT	AKT	0	1	8	9
Our results suggest that activated Ras and Src could induce gefitinib resistance by activating either or both of Akt and Erk signaling pathways , thus providing a strategic rationale for assessment of these specific signaling molecules downstream of EGFR to customize treatment .	Our results suggest that activated Ras and Src could induce gefitinib resistance by activating either or both of Akt and Erk signaling pathways, thus providing a strategic rationale for assessment of these specific signaling molecules downstream of EGFR to customize treatment.	5	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	7	8	18	19
In addition , the Src tyrosine kinase inhibitor , PP2 , blocked ISO mediated both Akt and ERK activation and heavily suppressed viability .	In addition, the Src tyrosine kinase inhibitor, PP2, blocked ISO mediated both Akt and ERK activation and heavily suppressed viability.	4	18	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	4	5	15	16
XREF_BIBR Src contributes to bone metastasis and promotes cancer cell survival by amplifying the magnitude of PI3K-Akt signaling induced by CXCL12 and IGF1 , the mesenchymal cytokines from the bone marrow .	XREF_BIBR Src contributes to bone metastasis and promotes cancer cell survival by amplifying the magnitude of PI3K-Akt signaling induced by CXCL12 and IGF1, the mesenchymal cytokines from the bone marrow.	0	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	PI3K-Akt	PI3K-Akt	PI3K-Akt	1	2	16	17
Inhibition of the Src kinase activity abrogates induction of stellate morphology , activation of Akt and mTOR , and the expression of tumor promoting genes by TGF-beta1 and Col-1 .	Inhibition of the Src kinase activity abrogates induction of stellate morphology, activation of Akt and mTOR, and the expression of tumor promoting genes by TGF-beta1 and Col-1.	3	16	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	3	4	14	15
Inhibition of Src kinase activity with PP2 abolished both basal and TGF-beta-induced association of HER2 with FAK and integrin beta1 and the TGF-beta-induced activation of FAK and Akt ( XREF_FIG ) .	Inhibition of Src kinase activity with PP2 abolished both basal and TGF-beta-induced association of HER2 with FAK and integrin beta1 and the TGF-beta-induced activation of FAK and Akt (XREF_FIG).	2	28	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	2	3	27	28
We demonstrated that activation of Src at Tyr416 not only activates AKT ( Ser473 ) but also increased the activity of PI3K in breast cancer cells co-cultured with MSCs .	We demonstrated that activation of Src at Tyr416 not only activates AKT (Ser473) but also increased the activity of PI3K in breast cancer cells co-cultured with MSCs.	3	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	5	6	11	12
c-Src activated the downstream PI3K and Akt pathway to induce migration and invasion in NPC .	c-Src activated the downstream PI3K and Akt pathway to induce migration and invasion in NPC.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	0	1	6	7
The binding of IGF1 to IGF1 receptor ( IGF1R ) leads to the autophosphorylation of the receptor , and subsequently induces insulin receptor substrates ( IRS ) and Src homology and collagen domain protein , which consequently activate the PI3K and Akt and MEK and ERK signaling pathways XREF_BIBR , XREF_BIBR , XREF_BIBR .	The binding of IGF1 to IGF1 receptor (IGF1R) leads to the autophosphorylation of the receptor, and subsequently induces insulin receptor substrates (IRS) and Src homology and collagen domain protein, which consequently activate the PI3K and Akt and MEK and ERK signaling pathways XREF_BIBR, XREF_BIBR, XREF_BIBR.	28	42	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	28	29	41	42
Here , we showed that c-Src activation promoted the EMT process by activating the downstream PI3K and Akt pathway in NPC cells .	Here, we showed that c-Src activation promoted the EMT process by activating the downstream PI3K and Akt pathway in NPC cells.	5	18	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	5	6	17	18
Namely , c-Cbl acts as mediator in Src induced activation of the PI3K-Akt signal transduction pathway through regulating phosphorylation of PI3K ( Figs .	Namely, c-Cbl acts as mediator in Src induced activation of the PI3K-Akt signal transduction pathway through regulating phosphorylation of PI3K (Figs.	5	15	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	PI3K-Akt	PI3K-Akt	PI3K-Akt	7	8	12	13
DAAM1 was shown to interact with SRCfamily tyrosine kinases , and SRC promotes the activation of AKT signaling by growth factors .	DAAM1 was shown to interact with SRCfamily tyrosine kinases, and SRC promotes the activation of AKT signaling by growth factors.	11	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	AKT	AKT	AKT	11	12	16	17
This is supported by a previous study , whereby intracellular Src enhanced PI3K-AKT signalling through stromal CXCL12 , resulting in increased breast cancer metastasis to the bone marrow [ XREF_BIBR ] .	This is supported by a previous study, whereby intracellular Src enhanced PI3K-AKT signalling through stromal CXCL12, resulting in increased breast cancer metastasis to the bone marrow [XREF_BIBR].	9	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	PI3K-AKT	PI3K-AKT	PI3K-AKT	10	11	12	13
In their studies , Src activation in detached cells was transient , resulted in activation of the PI3K and Akt pathway , and produced a delay in the onset of anoikis [ XREF_BIBR ] .	In their studies, Src activation in detached cells was transient, resulted in activation of the PI3K and Akt pathway, and produced a delay in the onset of anoikis [XREF_BIBR].	4	20	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	4	5	19	20
Activation of PI3K-AKT pathway is necessary for prostate cancer progression and IGF-1 stimulated activation of AKT by Src may play a role .	Activation of PI3K-AKT pathway is necessary for prostate cancer progression and IGF-1 stimulated activation of AKT by Src may play a role.	13	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	17	18	15	16
Subsequent mechanistic studies have revealed that Src supports the survival of indolent breast cancer cells in the bone marrow by activating Akt in response to the engagement of the CXCR4 receptor by SDF1 .	Subsequent mechanistic studies have revealed that Src supports the survival of indolent breast cancer cells in the bone marrow by activating Akt in response to the engagement of the CXCR4 receptor by SDF1.	6	23	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	6	7	21	22
c-Cbl acts as a mediator of Src induced activation of the PI3K-Akt signal transduction pathway during TRAIL treatment .	c-Cbl acts as a mediator of Src induced activation of the PI3K-Akt signal transduction pathway during TRAIL treatment.	4	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	PI3K-Akt	PI3K-Akt	PI3K-Akt	6	7	11	12
In general , activation of Src has been shown to mediate invasion , PI3-K and AKT stimulates growth and survival , STATs induce proliferation and survival , PLC-gmediates invasion and MAPK induces growth in HNSCC models ( XREF_FIG ) .	In general, activation of Src has been shown to mediate invasion, PI3-K and AKT stimulates growth and survival, STATs induce proliferation and survival, PLC-gmediates invasion and MAPK induces growth in HNSCC models (XREF_FIG).	3	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	5	6	15	16
SRC and PKC-epsilon exert pro survival effects and contribute to gefitinib resistance by activating AKT and ERK signaling pathways XREF_BIBR , XREF_BIBR .	SRC and PKC-epsilon exert pro survival effects and contribute to gefitinib resistance by activating AKT and ERK signaling pathways XREF_BIBR, XREF_BIBR.	0	18	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	AKT	AKT	AKT	0	1	14	15
Our findings demonstrate that leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase mediated parallel activation of MAPK and ERK and Akt that result in up-regulation of the respective prostaglandin and nitric oxide synthase pathways .	Our findings demonstrate that leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase mediated parallel activation of MAPK and ERK and Akt that result in up-regulation of the respective prostaglandin and nitric oxide synthase pathways.	15	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	15	16	25	26
Src activation triggers the PI3K and Akt signaling axis , which is a key regulator of cell proliferation and survival .	Src activation triggers the PI3K and Akt signaling axis, which is a key regulator of cell proliferation and survival.	0	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	6	7
Our findings demonstrate that ghrelin protection of the acinar cells against ethanol cytotoxicity and the impairment in salivary mucin synthesis involves Src kinase activation of the Akt and cNOS pathway that leads to up-regulation in cNOS activity .	Our findings demonstrate that ghrelin protection of the acinar cells against ethanol cytotoxicity and the impairment in salivary mucin synthesis involves Src kinase activation of the Akt and cNOS pathway that leads to up-regulation in cNOS activity.	21	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	21	22	26	27
Taken together , our data suggest that gallic acid inhibits the activation of EGFR and Src mediated Akt and ERK , leading to reduced levels of p65 and c-Jun-mediated DNA looping and thus inhibiting MMP-9 expression in EGF treated MCF-7cells .	Taken together, our data suggest that gallic acid inhibits the activation of EGFR and Src mediated Akt and ERK, leading to reduced levels of p65 and c-Jun-mediated DNA looping and thus inhibiting MMP-9 expression in EGF treated MCF-7cells.	11	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	15	16	17	18
Altogether , these studies indicated a survival pathway mediated by the Src dependent activation of the PI3-K and Akt pathway in a manner independent of FAK activity .	Altogether, these studies indicated a survival pathway mediated by the Src dependent activation of the PI3-K and Akt pathway in a manner independent of FAK activity.	11	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	11	12	18	19
It remains to be further demonstrated whether Src and/or vinculin mediate PI3K and Akt activation by integrin beta4 in the mesothelial adhesion of ovarian cancer cells .	It remains to be further demonstrated whether Src and/or vinculin mediate PI3K and Akt activation by integrin beta4 in the mesothelial adhesion of ovarian cancer cells.	7	14	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	7	8	13	14
In vitro kinase assays showed that AKT kinases are activated by active Src and inhibited by dominant negative Src or the tumor suppressor PTEN .	In vitro kinase assays showed that AKT kinases are activated by active Src and inhibited by dominant negative Src or the tumor suppressor PTEN.	6	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	12	13	6	7
Furthermore , we recently demonstrated that c-Src activation by TrkC induces activation of the PI3K-AKT pathway XREF_BIBR .	Furthermore, we recently demonstrated that c-Src activation by TrkC induces activation of the PI3K-AKT pathway XREF_BIBR.	6	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	PI3K-AKT	PI3K-AKT	PI3K-AKT	6	7	14	15
These our results are supported by those of a previous study in which the phosphatidylinositol-3-OH kinase and protein kinase B signaling pathways required for EMT , anokis suppression , c-Src activated PI3K and AKT and Ras and MAPK cascades [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	These our results are supported by those of a previous study in which the phosphatidylinositol-3-OH kinase and protein kinase B signaling pathways required for EMT, anokis suppression, c-Src activated PI3K and AKT and Ras and MAPK cascades [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	29	34	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	AKT	AKT	AKT	29	30	33	34
PKA phosphorylates A2aR and shifts its coupling to Gi protein and Src kinase thus activating the surviving mediator phosphatidylinositol-3-kinase ( PI3K ) and its downstream effector Akt [ XREF_BIBR ] .	PKA phosphorylates A2aR and shifts its coupling to Gi protein and Src kinase thus activating the surviving mediator phosphatidylinositol-3-kinase (PI3K) and its downstream effector Akt [XREF_BIBR].	11	28	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	11	12	26	27
Moreover , they showed that activated forms of c-Ha-ras ( v-Ha-ras ) and c-src ( v-src or srcY527F ) , two molecules that transduce growth factor generated signals , also activate Akt in a PI3-K-dependent manner in Sf9 as well as NIH 3T3 cells .	Moreover, they showed that activated forms of c-Ha-ras (v-Ha-ras) and c-src (v-src or srcY527F), two molecules that transduce growth factor generated signals, also activate Akt in a PI3-K-dependent manner in Sf9 as well as NIH 3T3 cells.	6	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-src	c-src	c-src	Akt	Akt	Akt	13	14	31	32
Src activates Akt signaling via promoting the phosphorylation and degradation of the PI3K regulatory unit p85 .	Src activates Akt signaling via promoting the phosphorylation and degradation of the PI3K regulatory unit p85.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	2	3
Application of this method revealed that transient activation of Src induces PI3K and Akt signaling that continues after Src inactivation and stimulates cell spreading independently of Src .	Application of this method revealed that transient activation of Src induces PI3K and Akt signaling that continues after Src inactivation and stimulates cell spreading independently of Src.	7	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	9	10	13	14
c-Src activates PI3-K and Akt in response to GDNF XREF_BIBR , TRANCE XREF_BIBR and VEGF XREF_BIBR , activates JNK pathway under many stimuli , including saturated fatty acids XREF_BIBR and endothelin-1 XREF_BIBR .	c-Src activates PI3-K and Akt in response to GDNF XREF_BIBR, TRANCE XREF_BIBR and VEGF XREF_BIBR, activates JNK pathway under many stimuli, including saturated fatty acids XREF_BIBR and endothelin-1 XREF_BIBR.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	0	1	4	5
Inhibition of c-Src function with PP2 blocked the activation of Akt and ERK1/2 , resulting in the inhibition of RANKL induced migration .	Inhibition of c-Src function with PP2 blocked the activation of Akt and ERK1/2, resulting in the inhibition of RANKL induced migration.	2	12	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	2	3	10	11
Src mediates AKT regulation and cancer cell survival responses to CXCL12 and TRAIL ( tumor necrosis factorrelated apoptosis inducing ligand ) , two factors that are distinctively expressed in the bone metastasis micro- environment [ XREF_BIBR ] .	Src mediates AKT regulation and cancer cell survival responses to CXCL12 and TRAIL (tumor necrosis factorrelated apoptosis inducing ligand), two factors that are distinctively expressed in the bone metastasis micro- environment [XREF_BIBR].	0	3	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AKT	AKT	AKT	0	1	2	3
Src mediates Akt regulation and the survival responses of cancer cells to pro apoptotic signals of CXCL12 and TRAIL in the bone microenvironment .	Src mediates Akt regulation and the survival responses of cancer cells to pro apoptotic signals of CXCL12 and TRAIL in the bone microenvironment.	0	3	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	0	1	2	3
SRC can activate the PI3K-AKT pathway which is important for survival and proliferation .	SRC can activate the PI3K-AKT pathway which is important for survival and proliferation.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	4	5
An EBV infection in HCECs can lead to a mesenchymal fibroblast like morphology , and cause EMT through the activation of PI3K and Akt and Erk by TGF-beta1-mediated Syk and Src signaling .	An EBV infection in HCECs can lead to a mesenchymal fibroblast like morphology, and cause EMT through the activation of PI3K and Akt and Erk by TGF-beta1-mediated Syk and Src signaling.	15	31	cause	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	30	31	23	24
Studies demonstrate that c-Src cooperates with estrogen to activate ERalpha proteolysis , and that increased c-Src activation leads to a reduced ERalpha half-life and increased ERalpha driven transcription .	Studies demonstrate that c-Src cooperates with estrogen to activate ERalpha proteolysis, and that increased c-Src activation leads to a reduced ERalpha half-life and increased ERalpha driven transcription.	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	ERalpha	ERalpha	ERalpha	3	4	9	10
c-Src may drive estrogen dependent ERalpha proteolysis in a subset of ER negative breast cancer .	c-Src may drive estrogen dependent ERalpha proteolysis in a subset of ER negative breast cancer.	0	6	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	ERalpha	ERalpha	ERalpha	0	1	5	6
In HEK-293T cells , expression of AIB1 and SRC1 enhanced ER driven ERE-Luc reporter activity and was blocked by both tamoxifen and ERX-11 in both a ligand dependent ( XREF_FIG ) and ligand independent manner ( XREF_FIG ) .	In HEK-293T cells, expression of AIB1 and SRC1 enhanced ER driven ERE-Luc reporter activity and was blocked by both tamoxifen and ERX-11 in both a ligand dependent (XREF_FIG) and ligand independent manner (XREF_FIG).	4	36	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC1	expression of AIB1 and SRC1	src1	ER	ER	er	8	9	10	11
Src mediates GalNac-T redistribution to the ER by COP-I vesicles .	Src mediates GalNac-T redistribution to the ER by COP-I vesicles.	0	9	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	0	1	6	7
SRC-1 and SRC-3 promote ER dependent breast cancer proliferation , as well as facilitate cancer metastasis by upregulating transcription of invasive gene signature coactivating polyoma enhancer activator 3 ( PEA3 ) .	SRC-1 and SRC-3 promote ER dependent breast cancer proliferation, as well as facilitate cancer metastasis by upregulating transcription of invasive gene signature coactivating polyoma enhancer activator 3 (PEA3).	0	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	0	1	4	5
These findings extend previous in vitro studies indicating that SRC-1 and CBP function together to modulate ER activity .	These findings extend previous in vitro studies indicating that SRC-1 and CBP function together to modulate ER activity.	9	17	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	9	10	16	17
Together , the present data provide neuroanatomical evidence that SRC-1 and SRC-2 potentially contribute to the ER mediated induction of the PR isoforms in brain .	Together, the present data provide neuroanatomical evidence that SRC-1 and SRC-2 potentially contribute to the ER mediated induction of the PR isoforms in brain.	9	17	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	9	10	16	17
We were the first to propose that signalling pathways and in particular , the tyrosine kinase Src regulate the GALNTs sub-cellular localisation and can induce a relocation from the Golgi apparatus to the ER .	We were the first to propose that signalling pathways and in particular, the tyrosine kinase Src regulate the GALNTs sub-cellular localisation and can induce a relocation from the Golgi apparatus to the ER.	13	34	induce	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	16	17	33	34
A variety of in vitro studies indicate that SRC-1 and CBP act synergistically to enhance ER and PR transcriptional activity and function [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	A variety of in vitro studies indicate that SRC-1 and CBP act synergistically to enhance ER and PR transcriptional activity and function [XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR].	8	19	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	8	9	15	16
These findings extend previous in vitro studies indicating that SRC-1 and CBP act together to modulate ER and PR function .	These findings extend previous in vitro studies indicating that SRC-1 and CBP act together to modulate ER and PR function.	9	19	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	9	10	16	17
The higher expression levels of SRC , which activates the regulatory switch for trafficking of GALNTs to the ER , were significantly correlated with resistance to gemcitabine .	The higher expression levels of SRC, which activates the regulatory switch for trafficking of GALNTs to the ER, were significantly correlated with resistance to gemcitabine.	3	19	activates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	SRC	levels of SRC	src	ER	ER	er	5	6	18	19
These findings provide what we believe to be a novel link between Src activation and ER alpha proteolysis and support a model whereby crosstalk between liganded ER alpha and Src drives ER alpha transcriptional activity and targets ER alpha for ubiquitin dependent proteolysis .	These findings provide what we believe to be a novel link between Src activation and ER alpha proteolysis and support a model whereby crosstalk between liganded ER alpha and Src drives ER alpha transcriptional activity and targets ER alpha for ubiquitin dependent proteolysis.	23	32	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	29	30	31	32
Reduction of SRC-1 and CBP protein in brain disrupted ER mediated activation of the behaviorally relevant progestin receptor gene .	Reduction of SRC-1 and CBP protein in brain disrupted ER mediated activation of the behaviorally relevant progestin receptor gene.	2	11	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	2	3	9	10
Since the SRC family coactivators enhance ERalpha transcriptional activity , we compared their expressions in Ncoa6 f/f and Ncoa6 d/d uteri .	Since the SRC family coactivators enhance ERalpha transcriptional activity, we compared their expressions in Ncoa6 f/f and Ncoa6 d/d uteri.	2	8	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	ERalpha	ERalpha	ERalpha	2	3	6	7
SRC-1 and PGC-1alpha enhance ER activity , and increased levels may sensitise cells to oestrogens at lower concentrations ( Lonard et al , 2007 ) .	SRC-1 and PGC-1alpha enhance ER activity, and increased levels may sensitise cells to oestrogens at lower concentrations (Lonard et al, 2007).	0	5	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	0	1	4	5
12 GALNT expression needs to be considered in the context of other components of the O glycosylation pathway , genes encoding the trafficking machinery that shuttles GALNTs from the Golgi apparatus to the ER , and signaling components such as Src which activate the relocation of GALNTs to the ER .	12 GALNT expression needs to be considered in the context of other components of the O glycosylation pathway, genes encoding the trafficking machinery that shuttles GALNTs from the Golgi apparatus to the ER, and signaling components such as Src which activate the relocation of GALNTs to the ER.	37	50	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	40	41	49	50
Similarly , diminished expression of E-cadherin following thapsigargin treatment was restored following PP2 treatment further providing evidence that SRC kinase inhibitor , PP2 can be of potential use to block ER stress and EMT in lung adenocarcinoma cells .	Similarly, diminished expression of E-cadherin following thapsigargin treatment was restored following PP2 treatment further providing evidence that SRC kinase inhibitor, PP2 can be of potential use to block ER stress and EMT in lung adenocarcinoma cells.	18	31	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	ER	ER	ER	18	19	30	31
Thus , we were interested to see whether inhibiting Src kinases , by using well established inhibitor PP2 , could block ER stress and its associated downstream EMT .	Thus, we were interested to see whether inhibiting Src kinases, by using well established inhibitor PP2, could block ER stress and its associated downstream EMT.	9	22	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	9	10	21	22
Enhanced protein synthesis and concomitant ER stress are also observed upon overexpression of oncogenic HRAS ( G12E ) , BRAF ( V600E ) , c-Myc or Src .	Enhanced protein synthesis and concomitant ER stress are also observed upon overexpression of oncogenic HRAS (G12E), BRAF (V600E), c-Myc or Src.	0	27	Enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	26	27	5	6
Coexpression of CBP and SRC-1 stimulated ER and PR transcriptional activity in a synergistic manner and indicated that these two coactivators are not functional homologues .	Coexpression of CBP and SRC-1 stimulated ER and PR transcriptional activity in a synergistic manner and indicated that these two coactivators are not functional homologues.	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	Coexpression of CBP and SRC-1	src-1	ER	ER	er	4	5	6	7
SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen .	SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen.	0	10	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	0	1	9	10
In this study , we report that the Src homology domain containing adaptor protein Nck1 , previously shown to modulate the UPR , is of functional importance in obesity induced ER stress signaling and inhibition of insulin actions .	In this study, we report that the Src homology domain containing adaptor protein Nck1, previously shown to modulate the UPR, is of functional importance in obesity induced ER stress signaling and inhibition of insulin actions.	8	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	8	9	30	31
Thus , these findings suggest that reduction of SRC-1 in brain decreases ER activity , and thus alters brain development and inhibits the defeminizing actions of estrogen during development .	Thus, these findings suggest that reduction of SRC-1 in brain decreases ER activity, and thus alters brain development and inhibits the defeminizing actions of estrogen during development.	6	13	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	8	9	12	13
SRC-1 , the p160 steroid receptor coactivator family member , synergized with XBP-1S or XBP-1U to potentiate ERalpha activity .	SRC-1, the p160 steroid receptor coactivator family member, synergized with XBP-1S or XBP-1U to potentiate ERalpha activity.	0	18	synergized	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ERalpha	ERalpha	ERalpha	0	1	17	18
Recent studies found that inhibition of the Src family tyrosine kinases using inhibitors such as dasatinib can block ERalpha mediated extranuclear actions leading to cell migration and invasion [ XREF_BIBR ] .	Recent studies found that inhibition of the Src family tyrosine kinases using inhibitors such as dasatinib can block ERalpha mediated extranuclear actions leading to cell migration and invasion [XREF_BIBR].	7	19	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ERalpha	ERalpha	ERalpha	7	8	18	19
In this study , overexpression of SRC-1 enhanced 4-hydroxytamoxifen ( 4HT )-stimulated ER activity , whereas overexpression of SMRT strongly suppressed 4HT stimulated ER activity [ XREF_BIBR ] .	In this study, overexpression of SRC-1 enhanced 4-hydroxytamoxifen (4HT)-stimulated ER activity, whereas overexpression of SMRT strongly suppressed 4HT stimulated ER activity [XREF_BIBR].	4	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	overexpression of SRC-1	src-1	ER	ER	er	6	7	12	13
Src is a known co-activator of ERalpha and its increased activity has been attributed to the agonistic effect of tamoxifen and tamoxifen resistance [ XREF_BIBR ] .	Src is a known co-activator of ERalpha and its increased activity has been attributed to the agonistic effect of tamoxifen and tamoxifen resistance [XREF_BIBR].	0	7	is a known co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Src	Src	Src	ERalpha	ERalpha	ERalpha	0	1	6	7
Taken together , these findings suggest that reduction of SRC-1 in brain decreases ER activity , and thus alters brain development and inhibits the defeminizing actions of estrogen during development .	Taken together, these findings suggest that reduction of SRC-1 in brain decreases ER activity, and thus alters brain development and inhibits the defeminizing actions of estrogen during development.	7	14	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	9	10	13	14
Altogether , these results show that Arf ( Q71L ) but not wild-type Arf1 can block or delay the trafficking of GalNAc-Ts to the ER induced by Src .	Altogether, these results show that Arf (Q71L) but not wild-type Arf1 can block or delay the trafficking of GalNAc-Ts to the ER induced by Src.	21	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	27	28	24	25
Src induces up-regulation of ERK activity and its target transcription factors , CREB and ERalpha , through attenuation of PP2A activity .	Src induces up-regulation of ERK activity and its target transcription factors, CREB and ERalpha, through attenuation of PP2A activity.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ERalpha	ERalpha	ERalpha	0	1	14	15
One possible mechanism for the ERalpha Ser305 phosphorylation in tamoxifen resistance is an altered orientation between ERalpha and its coactivator SRC-1 , which elevates the ERalpha transcription activity in the presence of tamoxifen [ XREF_BIBR , XREF_BIBR ] .	One possible mechanism for the ERalpha Ser305 phosphorylation in tamoxifen resistance is an altered orientation between ERalpha and its coactivator SRC-1, which elevates the ERalpha transcription activity in the presence of tamoxifen [XREF_BIBR, XREF_BIBR].	14	27	elevates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ERalpha	ERalpha	ERalpha	20	21	25	26
As has been described previously , both TDG and SRC1 stimulated ERalpha activity in the presence of estrogen ( E2 ) ( XREF_FIG ) .	As has been described previously, both TDG and SRC1 stimulated ERalpha activity in the presence of estrogen (E2) (XREF_FIG).	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC1	SRC1	SRC1	ERalpha	ERalpha	ERalpha	9	10	11	12
These findings are supported by previous in vitro studies indicating that SRC-1 and CBP function together to modulate ER activity .	These findings are supported by previous in vitro studies indicating that SRC-1 and CBP function together to modulate ER activity.	11	19	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	11	12	18	19
A variety of in vitro studies indicate that SRC-1 and CBP act synergistically to enhance ER and PR transcriptional activity and function .	A variety of in vitro studies indicate that SRC-1 and CBP act synergistically to enhance ER and PR transcriptional activity and function.	8	19	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	8	9	15	16
A variety of in vitro studies indicate that SRC-1 and CBP act synergistically to enhance ER and PR transcriptional function and activity .	A variety of in vitro studies indicate that SRC-1 and CBP act synergistically to enhance ER and PR transcriptional function and activity.	8	19	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	8	9	15	16
We demonstrate that inhibition of Src activity attenuates bile acid induced Golgi fragmentation and ER stress ( BiP activation ) .	We demonstrate that inhibition of Src activity attenuates bile acid induced Golgi fragmentation and ER stress (BiP activation).	5	15	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	5	6	14	15
Much of my lab is currently focused on the GALA pathway , the process of relocation of the O glycosylation enzymes GALNTs from the Golgi to the ER that is activated by Src .	Much of my lab is currently focused on the GALA pathway, the process of relocation of the O glycosylation enzymes GALNTs from the Golgi to the ER that is activated by Src.	24	33	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	32	33	27	28
c-Abl ( v-Abl Abelson murine leukemia viral oncogene homolog 1 ) tyrosine kinase directly phosphorylates AIB1 and SRC -3 at Y1357 and modulates the association of AIB1 with c-Abl , ERalpha , the transcriptional cofactor p300 , and the methyltransferase coactivator associated arginine methyltransferase 1 , CARM1 .	c-Abl (v-Abl Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase directly phosphorylates AIB1 and SRC -3 at Y1357 and modulates the association of AIB1 with c-Abl, ERalpha, the transcriptional cofactor p300, and the methyltransferase coactivator associated arginine methyltransferase 1, CARM1.	0	35	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	c-Abl (v-Abl Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase directly phosphorylates AIB1 and SRC -3 at Y1357	src	ERalpha	ERalpha	eralpha	17	18	30	31
Pretreatment with Src increased ER alpha ubiquitylation and degradation in vitro .	Pretreatment with Src increased ER alpha ubiquitylation and degradation in vitro.	0	5	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	2	3	4	5
The effects of these nuclear receptor coactivators on both ER- and PR dependent aspects of female sexual behavior were also specifically investigated and it was confirmed that SRC-1 enhances activity of both ER and PR .	The effects of these nuclear receptor coactivators on both ER- and PR dependent aspects of female sexual behavior were also specifically investigated and it was confirmed that SRC-1 enhances activity of both ER and PR.	27	34	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	27	28	32	33
Src activation at the Golgi induces GalNac-T redistribution to the ER .	Src activation at the Golgi induces GalNac-T redistribution to the ER.	0	11	induces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	0	1	10	11
Our results indicate that Src cooperates with estrogen to activate ER alpha proteolysis .	Our results indicate that Src cooperates with estrogen to activate ER alpha proteolysis.	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	4	5	10	11
Among the numerous co-activators identified to date , one of the best characterized is the p160 family of proteins including SRC-1 , GRIP1 and RAC3 , which enhance ER transactivation by recruiting other transcriptional regulatory factors such as CREB binding protein and p300 .	Among the numerous co-activators identified to date, one of the best characterized is the p160 family of proteins including SRC-1, GRIP1 and RAC3, which enhance ER transactivation by recruiting other transcriptional regulatory factors such as CREB binding protein and p300.	18	29	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	ER	ER	ER	20	21	28	29
For the first time , these results suggested that the relative expression of SRC-1 and SMRT can modulate the 4HT dependent ER activity .	For the first time, these results suggested that the relative expression of SRC-1 and SMRT can modulate the 4HT dependent ER activity.	11	22	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	expression of SRC-1	src-1	ER	ER	er	13	14	21	22
Src activates Abl to augment Robo1 expression and GTPase activity .	Src activates Abl to augment Robo1 expression and GTPase activity.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	0	1	2	3
We recently demonstrated that endogenous Abl kinases ( c-Abl , Arg ) are activated by deregulated ErbB receptors and Src kinases , and drive invasion of aggressive breast cancer cells .	We recently demonstrated that endogenous Abl kinases (c-Abl, Arg) are activated by deregulated ErbB receptors and Src kinases, and drive invasion of aggressive breast cancer cells.	5	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	19	20	5	6
Additionally , c-Src can also activate c-Abl , which plays an important role in regulating cell motility in response to PDGF [ XREF_BIBR ] .	Additionally, c-Src can also activate c-Abl, which plays an important role in regulating cell motility in response to PDGF [XREF_BIBR].	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	c-Abl	c-Abl	c-Abl	2	3	6	7
However , in contrast to previous observations from studies in developing drosophila and mouse embryos [ XREF_BIBR , XREF_BIBR ] , results from our studies demonstrate that Src activates the Abl kinase , which in turn stabilizes Robo1 protein to increase Cdc42 and Rac1 GTPases activity to promote transformed cell migration .	However, in contrast to previous observations from studies in developing drosophila and mouse embryos [XREF_BIBR, XREF_BIBR], results from our studies demonstrate that Src activates the Abl kinase, which in turn stabilizes Robo1 protein to increase Cdc42 and Rac1 GTPases activity to promote transformed cell migration.	27	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	27	28	30	31
Taken together , these data indicate that Src activated Abl to induce Robo1 expression in order to increase migration of transformed cells as illustrated in Figure XREF_FIG .	Taken together, these data indicate that Src activated Abl to induce Robo1 expression in order to increase migration of transformed cells as illustrated in Figure XREF_FIG.	7	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	7	8	9	10
To determine if activated Src promotes invadopodia formation independent of Abl and Arg , WT and DKO cells transfected with activated Src ( 527F ) were assayed for cortactin tyrosine phosphorylation , invadopodia formation and ECM proteolysis .	To determine if activated Src promotes invadopodia formation independent of Abl and Arg, WT and DKO cells transfected with activated Src (527F) were assayed for cortactin tyrosine phosphorylation, invadopodia formation and ECM proteolysis.	3	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	4	5	10	11
Src kinase is known to phosphorylate Tyr245 and stimulate Abl activity XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Src kinase is known to phosphorylate Tyr245 and stimulate Abl activity XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	0	1	9	10
We report here that Src activates Abl to stabilize Robo1 in order to promote cell migration .	We report here that Src activates Abl to stabilize Robo1 in order to promote cell migration.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	4	5	6	7
XREF_BIBR , XREF_BIBR Indeed , Src family tyrosine kinases ( SFKs ) activate Abl and Arg in melanoma cells ( XREF_FIG ) , as we demonstrated in other cell types , XREF_BIBR , XREF_BIBR and SFK inhibition prevented BRAF V600E from inducing Abl or Arg tyrosine phosphorylation , and inhibited binding of BRAF V600E to Abl and Arg ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR Indeed, Src family tyrosine kinases (SFKs) activate Abl and Arg in melanoma cells (XREF_FIG), as we demonstrated in other cell types, XREF_BIBR, XREF_BIBR and SFK inhibition prevented BRAF V600E from inducing Abl or Arg tyrosine phosphorylation, and inhibited binding of BRAF V600E to Abl and Arg (XREF_FIG).	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	5	6	13	14
In addition , we demonstrated that PDGF mediated activation requires Src kinases , which directly phosphorylate and activate Abl kinases , and PLC-gamma1 , which may release negative regulation by hydrolyzing a potential Abl inhibitor , PIP 2 [ XREF_BIBR , XREF_BIBR ] .	In addition, we demonstrated that PDGF mediated activation requires Src kinases, which directly phosphorylate and activate Abl kinases, and PLC-gamma1, which may release negative regulation by hydrolyzing a potential Abl inhibitor, PIP 2 [XREF_BIBR, XREF_BIBR].	10	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	10	11	18	19
The authors have demonstrated that Src activates Abl , and that Abl associates with Robo1 to stabilize its activity and expression in transformed cells .	The authors have demonstrated that Src activates Abl, and that Abl associates with Robo1 to stabilize its activity and expression in transformed cells.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	5	6	7	8
The increased Src activation in HNSCC cells suggested that active Src might directly regulate invadopodia activity independent of Abl and Arg .	The increased Src activation in HNSCC cells suggested that active Src might directly regulate invadopodia activity independent of Abl and Arg.	9	20	directly regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	10	11	18	19
Furthermore , c-Abl activation is mediated by Src and increased by F-actin .	Furthermore, c-Abl activation is mediated by Src and increased by F-actin.	2	8	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	c-Abl	c-Abl	c-Abl	7	8	2	3
Using fibroblastic cells derived from Abl knock-out mice , it was shown that Abl-Crk signaling is implicated in the activation of Rac XREF_BIBR , suggesting that Abl activation by Src may act upstream of RhoGTPases .	Using fibroblastic cells derived from Abl knock-out mice, it was shown that Abl-Crk signaling is implicated in the activation of Rac XREF_BIBR, suggesting that Abl activation by Src may act upstream of RhoGTPases.	26	30	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	29	30	26	27
However , in contrast to this proposed role of Abl as a Robo1 effector , we hypothesized that Src activates Abl to stabilize Robo1 expression in transformed cells .	However, in contrast to this proposed role of Abl as a Robo1 effector, we hypothesized that Src activates Abl to stabilize Robo1 expression in transformed cells.	18	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	18	19	20	21
The activated EGF receptor ( EGFR ) is believed to recruit the tyrosine kinase Src by its SH2 domain , leading to Src mediated activation of the Abl family kinase Arg .	The activated EGF receptor (EGFR) is believed to recruit the tyrosine kinase Src by its SH2 domain, leading to Src mediated activation of the Abl family kinase Arg.	22	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	22	23	27	28
Abl family kinases are activated by FcgammaR engagement and function downstream of Src family kinases during phagocytosis .	Abl family kinases are activated by FcgammaR engagement and function downstream of Src family kinases during phagocytosis.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	12	13	0	1
Our data indicate that Src activates the Abl kinase , which in turn , stabilizes the expression of Robo1 and increases GTPase activity to promote tumor cell migration .	Our data indicate that Src activates the Abl kinase, which in turn, stabilizes the expression of Robo1 and increases GTPase activity to promote tumor cell migration.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	4	5	7	8
Activated Abl also increases the activity of Src members through a positive feedback loop leading to signal amplification .	Activated Abl also increases the activity of Src members through a positive feedback loop leading to signal amplification.	0	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	7	8	1	2
The Abl tyrosine kinase family was recently shown to be required for Shigella invasion and may provide such a link because Abl kinases are activated by Src and have been involved in F-actin dynamics .	The Abl tyrosine kinase family was recently shown to be required for Shigella invasion and may provide such a link because Abl kinases are activated by Src and have been involved in F-actin dynamics.	21	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	26	27	21	22
As seen in Figure XREF_FIG , although Abl protein expression levels were similar in both Src transformed and nontransformed cells , Src increased the activity of Abl in transformed cells by several fold .	As seen in Figure XREF_FIG, although Abl protein expression levels were similar in both Src transformed and nontransformed cells, Src increased the activity of Abl in transformed cells by several fold.	21	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	21	22	26	27
In leukemia , chromosomal translocation activates the Abl kinases , whereas in ER -, PR - breast cancer cells , Abl kinases are activated downstream of deregulated growth factor receptors such as EGFR , ErbB2 and Her-2 , and IGF-1R , as well as by activated Src family kinases [ XREF_BIBR , XREF_BIBR ] .	In leukemia, chromosomal translocation activates the Abl kinases, whereas in ER -, PR - breast cancer cells, Abl kinases are activated downstream of deregulated growth factor receptors such as EGFR, ErbB2/Her-2, and IGF-1R, as well as by activated Src family kinases [XREF_BIBR, XREF_BIBR].	20	48	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	46	47	20	21
The role of Abl and Arg kinase was initially hypothesized in invadopodia formation due to previously known activation of Abl by Src kinases .	The role of Abl and Arg kinase was initially hypothesized in invadopodia formation due to previously known activation of Abl by Src kinases.	17	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	21	22	19	20
Furthermore , overexpression of wild-type Src potentiated c-Abl activation by growth factors , and a kinase-inactive form of Src reduced this activation , showing that Abl activation by growth factors occurs at least in part via activation of Src kinases .	Furthermore, overexpression of wild-type Src potentiated c-Abl activation by growth factors, and a kinase-inactive form of Src reduced this activation, showing that Abl activation by growth factors occurs at least in part via activation of Src kinases.	2	8	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	overexpression of wild-type Src	src	c-Abl	c-Abl	c-abl	5	6	7	8
Src activates Abl to augment Robo1 expression in order to promote tumor cell migration .	Src activates Abl to augment Robo1 expression in order to promote tumor cell migration.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Abl	Abl	Abl	0	1	2	3
Although Sox4 has been demonstrated to directly interact with TCF4 via their respective HMG domain by in vitro protein binding assay , [ XREF_BIBR ] our present data revealed that activation of the Slug promoter by Sox4 , as well as beta-catenin , was not abrogated by dominant negative TCF4 , indicating that the observed activation did not require TCF4 binding sites in the promoter .	Although Sox4 has been demonstrated to directly interact with TCF4 via their respective HMG domain by in vitro protein binding assay, [XREF_BIBR] our present data revealed that activation of the Slug promoter by Sox4, as well as beta-catenin, was not abrogated by dominant negative TCF4, indicating that the observed activation did not require TCF4 binding sites in the promoter.	30	45	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Sox4	Sox4	Sox4	beta-catenin	beta-catenin	beta-catenin	36	37	41	42
We further confirmed that beta-catenin is up-regulated by SOX4 by RT-PCR and western blot in all of the three GBM cell line LN229 , A172 and U87 .	We further confirmed that beta-catenin is up-regulated by SOX4 by RT-PCR and western blot in all of the three GBM cell line LN229, A172 and U87.	4	9	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	8	9	4	5
In vitro studies have proposed that SOX4 and SOX12 may up-regulate canonical WNT and beta-catenin signaling , but in vivo evidence of this action and its consequence and underlying mechanism are lacking .	In vitro studies have proposed that SOX4 and SOX12 may up-regulate canonical WNT and beta-catenin signaling, but in vivo evidence of this action and its consequence and underlying mechanism are lacking.	6	15	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	6	7	14	15
Thus , it is conceivable that SOX4 stimulates beta-catenin activity indirectly via maintenance of active AKT , and that it modulates AR-beta-catenin activity directly via protein protein interactions .	Thus, it is conceivable that SOX4 stimulates beta-catenin activity indirectly via maintenance of active AKT, and that it modulates AR-beta-catenin activity directly via protein protein interactions.	6	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
SOX4 was previously shown to enhance beta-catenin and TCF activities in several cancer types [ XREF_BIBR - XREF_BIBR ] .	SOX4 was previously shown to enhance beta-catenin and TCF activities in several cancer types [XREF_BIBR - XREF_BIBR].	0	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
In fact , SOX4 inhibition reduces AKT and beta-catenin pathways activation and decreases prostate cancer invasiveness through positive feedback loop between SOX4 and PI3K-AKT-mTOR [ XREF_BIBR ] .	In fact, SOX4 inhibition reduces AKT and beta-catenin pathways activation and decreases prostate cancer invasiveness through positive feedback loop between SOX4 and PI3K-AKT-mTOR [XREF_BIBR].	3	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
SOX4 stabilises beta-catenin protein and enhances beta-catenin and TCF activity [ XREF_BIBR ] .	SOX4 stabilises beta-catenin protein and enhances beta-catenin and TCF activity [XREF_BIBR].	0	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
From our microarray data , we also found that beta-catenin is up-regulated by SOX4 ( Additional file 5 : Table S3 ) in GBM cell line LN229 .	From our microarray data, we also found that beta-catenin is up-regulated by SOX4 (Additional file 5 : Table S3) in GBM cell line LN229.	9	23	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	13	14	9	10
Loss of SOX4 Inhibits Activation of AKT and beta-Catenin .	Loss of SOX4 Inhibits Activation of AKT and beta-Catenin.	0	9	Inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SOX4	Loss of SOX4	sox4	beta-Catenin	beta-Catenin	beta-catenin	2	3	8	9
Interestingly , both SOX7 and SOX17 antagonize SOX4 mediated activation of beta-catenin ' s transcriptional activity and inhibit Wnt signaling in endometrial carcinoma cells , likely through competitive binding to beta-catenin .	Interestingly, both SOX7 and SOX17 antagonize SOX4 mediated activation of beta-catenin 's transcriptional activity and inhibit Wnt signaling in endometrial carcinoma cells, likely through competitive binding to beta-catenin.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	7	8	11	12
Finally , we demonstrated that beta-catenin was upregulated by SOX4 , suggesting a role of SOX4 in WNT signaling in GBM cells .	Finally, we demonstrated that beta-catenin was upregulated by SOX4, suggesting a role of SOX4 in WNT signaling in GBM cells.	5	10	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	9	10	5	6
In addition , SOX4 in HepG2 cell can enhance beta-catenin and TCF activity by increasing beta-catenin level .	In addition, SOX4 in HepG2 cell can enhance beta-catenin and TCF activity by increasing beta-catenin level.	3	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	3	4	9	10
SOX4 was previously shown to enhance beta-catenin and TCF activity and the proliferation of colorectal cancer cells [ XREF_BIBR , XREF_BIBR ] .	SOX4 was previously shown to enhance beta-catenin and TCF activity and the proliferation of colorectal cancer cells [XREF_BIBR, XREF_BIBR].	0	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
Here we demonstrate that overexpression of Sox4 enhances beta-catenin and TCF activity by increasing the stability of beta-catenin .	Here we demonstrate that overexpression of Sox4 enhances beta-catenin and TCF activity by increasing the stability of beta-catenin.	4	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sox4	overexpression of Sox4	sox4	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
When HEK293 cells were cotransfected with plasmids encoding SOX4 and beta-catenin , SOX4 increased both the activity of the TOP-Flash reporter and the level of the wild-type form of beta-catenin , as expected ( XREF_FIG ) .	When HEK293 cells were cotransfected with plasmids encoding SOX4 and beta-catenin, SOX4 increased both the activity of the TOP-Flash reporter and the level of the wild-type form of beta-catenin, as expected (XREF_FIG).	12	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SOX4	SOX4	SOX4	beta-catenin	beta-catenin	beta-catenin	12	13	29	30
Sox17 and Sox4 are expressed in mutually exclusive domains in normal and neoplastic gut tissues , and gain- and loss-of-function studies demonstrate that Sox4 enhances beta-catenin and TCF activity and the proliferation of SW480 cells .	Sox17 and Sox4 are expressed in mutually exclusive domains in normal and neoplastic gut tissues, and gain- and loss-of-function studies demonstrate that Sox4 enhances beta-catenin and TCF activity and the proliferation of SW480 cells.	23	28	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sox4	Sox4	Sox4	beta-catenin	beta-catenin	beta-catenin	23	24	25	26
c-Src then activates Cdc42 through FRG , a Cdc42-GDP and GTP exchange factor .	c-Src then activates Cdc42 through FRG, a Cdc42-GDP and GTP exchange factor.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Cdc42	Cdc42	Cdc42	0	1	3	4
Among the Dox-irresponsive group , Grb2 , Src homology 2 domain containing transforming protein 1 ( SHC1 ) , activated Cdc42 associated kinase 1 ( Ack1 ) and Crk fragments were found .	Among the Dox-irresponsive group, Grb2, Src homology 2 domain containing transforming protein 1 (SHC1), activated Cdc42 associated kinase 1 (Ack1) and Crk fragments were found.	7	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Cdc42	Cdc42	Cdc42	7	8	20	21
Src inhibition prevents the activation of Rac , Rho and Cdc42 , impeding actin polymerization and migration .	Src inhibition prevents the activation of Rac, Rho and Cdc42, impeding actin polymerization and migration.	0	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Cdc42	Cdc42	Cdc42	0	1	10	11
With respect to trafficking , Src signaling was recently suggested to activate the small GTPase Cdc42 leading to a facilitation of anterograde transport within the Golgi .	With respect to trafficking, Src signaling was recently suggested to activate the small GTPase Cdc42 leading to a facilitation of anterograde transport within the Golgi.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Cdc42	Cdc42	Cdc42	5	6	15	16
We therefore speculated that the activation of Src may activate Cdc42 and Rac1 through beta-Pix/GIT1/PLCgamma1 complexes and promote actin reorganisation .	We therefore speculated that the activation of Src may activate Cdc42 and Rac1 through beta-Pix/GIT1/PLCgamma1 complexes and promote actin reorganisation.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Cdc42	Cdc42	Cdc42	7	8	10	11
In response to the scratch , Cdc42 is activated by the exchange factor betaPIX downstream of an integrin induced Src dependent signaling cascade , which is activated at the cell wound edge .	In response to the scratch, Cdc42 is activated by the exchange factor betaPIX downstream of an integrin induced Src dependent signaling cascade, which is activated at the cell wound edge.	6	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	integrin induced Src	src	Cdc42	Cdc42	cdc42	19	20	6	7
XREF_BIBR ) Activated c-Src then activates Rap1 , Cdc42 , and Rac small G proteins .	XREF_BIBR) Activated c-Src then activates Rap1, Cdc42, and Rac small G proteins.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Cdc42	Cdc42	Cdc42	3	4	8	9
Therefore , since Cdc42 pathway is mediated by Src kinase , there is a link between cancer and filopodia formation ( Cancer - Src kinase - Cdc42 - Filopodia ) .	Therefore, since Cdc42 pathway is mediated by Src kinase, there is a link between cancer and filopodia formation (Cancer - Src kinase - Cdc42 - Filopodia).	3	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Cdc42	Cdc42	Cdc42	8	9	3	4
Src has been shown to activate cdc42 , a Rho family GTPase required for podosome assembly [ XREF_BIBR ] .	Src has been shown to activate cdc42, a Rho family GTPase required for podosome assembly [XREF_BIBR].	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	cdc42	cdc42	cdc42	0	1	6	7
Moreover , ligation of nectin , which is one of the AJ components , induces Rap1 activation responsible for Src dependent activation of Cdc42 in epithelial cells .	Moreover, ligation of nectin, which is one of the AJ components, induces Rap1 activation responsible for Src dependent activation of Cdc42 in epithelial cells.	19	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Cdc42	Cdc42	Cdc42	19	20	23	24
In this pathway , c-Src phos-phorylates FRG and activates Cdc42 specific GEF catalytic activity .	In this pathway, c-Src phos-phorylates FRG and activates Cdc42 specific GEF catalytic activity.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Cdc42	Cdc42	Cdc42	4	5	9	10
Indeed , FFA stimulated MLK activation could be mediated by a Src pathway that activates Rac and Cdc42 .	Indeed, FFA stimulated MLK activation could be mediated by a Src pathway that activates Rac and Cdc42.	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Cdc42	Cdc42	Cdc42	11	12	17	18
Inhibition of the nectin induced activation of c-Src suppressed the nectin induced activation of FRG and Cdc42 .	Inhibition of the nectin induced activation of c-Src suppressed the nectin induced activation of FRG and Cdc42.	3	17	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	nectin induced activation of c-Src	c-src	Cdc42	Cdc42	cdc42	7	8	16	17
Tuba is a large scaffolding protein with a GEF domain that activates Cdc42 , a Bar domain that interacts with lipids , and a carboxyl-terminal Src Homology 3 ( SH3 ) domain that binds N-WASP .	Tuba is a large scaffolding protein with a GEF domain that activates Cdc42, a Bar domain that interacts with lipids, and a carboxyl-terminal Src Homology 3 (SH3) domain that binds N-WASP.	11	35	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src Homology 3 (SH3) domain that binds N-WASP	src	Cdc42	Cdc42	cdc42	25	26	12	13
SYK and SRC kinases can then activate Btk , which is simultaneously recruited to the plasma membrane by the production of phosphatidylinositol ( 3,4,5 )-trisphosphate ( PIP3 ) by phosphoinositide 3-kinase ( PI3-K ) [ XREF_BIBR ] .	SYK and SRC kinases can then activate Btk, which is simultaneously recruited to the plasma membrane by the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) by phosphoinositide 3-kinase (PI3-K) [XREF_BIBR].	0	31	activate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	SRC	SRC	src	Btk	Btk, which is simultaneously recruited to the plasma membrane by the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) by phosphoinositide 3-kinase	btk	2	3	7	8
The latter is accomplished by Lyn and other Src family kinases ( Fyn , Blk ) , which in turn activate SYK , BTK , and PI3Ks ( XREF_FIG ) .	The latter is accomplished by Lyn and other Src family kinases (Fyn, Blk), which in turn activate SYK, BTK, and PI3Ks (XREF_FIG).	8	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	BTK	BTK	BTK	8	9	23	24
It has been proposed that Src kinases activate Btk through phosphorylation of a tyrosine , Y551 in the activation loop of Btk , leading to increased kinase activity and autophosphorylation of a tyrosine in the SH3 domain .	It has been proposed that Src kinases activate Btk through phosphorylation of a tyrosine, Y551 in the activation loop of Btk, leading to increased kinase activity and autophosphorylation of a tyrosine in the SH3 domain.	5	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Btk	Btk	Btk	5	6	8	9
Activation of Btk by Src family PTKs has been observed .	Activation of Btk by Src family PTKs has been observed.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src	Src	Btk	Btk	Btk	4	5	2	3
This suggests either that Lyn is redundant with other Src family kinases for the activation of Btk in mature B cells or that Btk can be activated by Src family independent mechanisms .	This suggests either that Lyn is redundant with other Src family kinases for the activation of Btk in mature B cells or that Btk can be activated by Src family independent mechanisms.	23	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Btk	Btk	Btk	28	29	23	24
On the other hand , some evidence suggests that Btk can be activated by Src family kinases that lie upstream of both Syk and Btk .	On the other hand, some evidence suggests that Btk can be activated by Src family kinases that lie upstream of both Syk and Btk.	9	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Btk	Btk	Btk	14	15	9	10
In this model , RANK provides the most upstream signal , which results in TRAF6 dependent activation of NF-kappaB and MAPKs , Src dependent activation of Btk and Tec , and transactivation of ITAMs that results in calcium signaling .	In this model, RANK provides the most upstream signal, which results in TRAF6 dependent activation of NF-kappaB and MAPKs, Src dependent activation of Btk and Tec, and transactivation of ITAMs that results in calcium signaling.	22	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Btk	Btk	Btk	22	23	26	27
Using a series of point mutations in Blk ( a representative Src protein kinase ) and Btk , we show that Src kinases activate Btk through an indirect mechanism that requires membrane association of the Src enzymes as well as functional Btk SH3 and SH2 domains .	Using a series of point mutations in Blk (a representative Src protein kinase) and Btk, we show that Src kinases activate Btk through an indirect mechanism that requires membrane association of the Src enzymes as well as functional Btk SH3 and SH2 domains.	21	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Btk	Btk	Btk	21	22	24	25
In this study , we show that coexpression of Glis2 and Src induces nuclear translocation of p120 .	In this study, we show that coexpression of Glis2 and Src induces nuclear translocation of p120.	7	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	coexpression of Glis2 and Src	src	p120	p120	p120	11	12	16	17
To determine the role of Src family kinases in interaction of p120 with M-cadherin , Ric10 cells were treated with the Src kinase inhibitor SU6656 because Src family kinases are major protein kinases that phosphorylate tyrosine residues of p120 [ XREF_BIBR ] .	To determine the role of Src family kinases in interaction of p120 with M-cadherin, Ric10 cells were treated with the Src kinase inhibitor SU6656 because Src family kinases are major protein kinases that phosphorylate tyrosine residues of p120 [XREF_BIBR].	9	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Src	Src	Src	p120	p120	p120	21	22	11	12
Thus , Src family kinases might induce the redistribution of p120 at membrane ruffles through phosphorylation of other substrates .	Thus, Src family kinases might induce the redistribution of p120 at membrane ruffles through phosphorylation of other substrates.	2	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	p120	p120	p120	2	3	10	11
In retinoic acid differentiated HL-60 cells , cross linking of FcgammaRs resulted in a marked increase in the tyrosine phosphorylation of FcgammaRIIa , p58 ( lyn ) , and p120 ( c-cbl ) , which was inhibited by a specific inhibitor of Src family protein tyrosine kinases .	In retinoic acid differentiated HL-60 cells, cross linking of FcgammaRs resulted in a marked increase in the tyrosine phosphorylation of FcgammaRIIa, p58 (lyn), and p120 (c-cbl), which was inhibited by a specific inhibitor of Src family protein tyrosine kinases.	11	46	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	p120	p120	p120	42	43	29	30
Galpha13 mediated Src activation induces endothelial permeability by dissociating p120-catenin from VE-cadherin .	Galpha13 mediated Src activation induces endothelial permeability by dissociating p120-catenin from VE-cadherin.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Galpha13 mediated Src	src	p120-catenin	p120-catenin	p120-catenin	2	3	9	10
Src , a kinase that phosphorylates and subsequently activates NR2A subunits , was also evaluated and no differences were found ( XREF_SUPPLEMENTARY ) .	Src, a kinase that phosphorylates and subsequently activates NR2A subunits, was also evaluated and no differences were found (XREF_SUPPLEMENTARY).	0	14	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Src	Src	Src	NR2A	NR2A	NR2A	0	1	9	10
Recombinant NR1 and NR2A subtype NMDA receptor channels are potentiated by the protein tyrosine kinase Src , an effect which is mediated by a reduction in the high-affinity , voltage independent Zn ( 2+ ) inhibition .	Recombinant NR1 and NR2A subtype NMDA receptor channels are potentiated by the protein tyrosine kinase Src, an effect which is mediated by a reduction in the high-affinity, voltage independent Zn (2+) inhibition.	3	18	potentiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	NR2A	NR2A	NR2A	15	16	3	4
Src potentiation of mouse NR2A and NR1 currents required PSD-95 coexpression .	Src potentiation of mouse NR2A and NR1 currents required PSD-95 coexpression.	0	7	potentiation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	NR2A	NR2A	NR2A	0	1	4	5
The results show opposite effects of PSD-95 coexpression on Src and insulin modulation of NR2A and NR1 receptor currents .	The results show opposite effects of PSD-95 coexpression on Src and insulin modulation of NR2A and NR1 receptor currents.	9	18	modulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	NR2A	NR2A	NR2A	9	10	14	15
Co-transfection of constitutively active Src , such as v-Src , significantly enhanced NMDA NR1-1a and NR2A receptor mediated current density when compared with that recorded in cells without v-Src expression ( XREF_FIG ) .	Co-transfection of constitutively active Src, such as v-Src, significantly enhanced NMDA NR1-1a and NR2A receptor mediated current density when compared with that recorded in cells without v-Src expression (XREF_FIG).	0	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	NR2A	NR2A	NR2A	4	5	15	16
STEP activation by M1 muscarinic receptors limits Src potentiation of GluN2A containing NMDARs .	STEP activation by M1 muscarinic receptors limits Src potentiation of GluN2A containing NMDARs.	7	11	potentiation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	GluN2A	GluN2A	GluN2A	7	8	10	11
Here we demonstrate that PSD-95 eliminates the Src induced potentiation of NR1 and NR2A channels expressed in oocytes and reduces the sensitivity of the channels to Zn ( 2+ ) .	Here we demonstrate that PSD-95 eliminates the Src induced potentiation of NR1 and NR2A channels expressed in oocytes and reduces the sensitivity of the channels to Zn (2+).	6	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	NR2A	NR2A	NR2A	7	8	13	14
Prior work has shown that SRC phosphorylates DDR2 , which , in turn , drives DDR2 autophosphorylation , and that overexpression of SRC increases DDR2 kinase activity .	Prior work has shown that SRC phosphorylates DDR2, which, in turn, drives DDR2 autophosphorylation, and that overexpression of SRC increases DDR2 kinase activity.	5	26	increases	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	SRC	SRC phosphorylates DDR2	src	DDR2	DDR2	ddr2	5	6	24	25
We also observed that SRC GK could partially rescue p-DDR2 , consistent with the results in XREF_FIG ( XREF_FIG A ) .	We also observed that SRC GK could partially rescue p-DDR2, consistent with the results in XREF_FIG (XREF_FIG A).	4	11	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	p-DDR2	p-DDR2	p-DDR2	4	5	9	10
To assess the utility of DDR2 as a therapeutic target , we used dasatinib , an oral multi-BCR and Abl and Src family tyrosine kinase inhibitor that also inhibits DDR2 XREF_BIBR XREF_BIBR .	To assess the utility of DDR2 as a therapeutic target, we used dasatinib, an oral multi-BCR and Abl and Src family tyrosine kinase inhibitor that also inhibits DDR2 XREF_BIBR XREF_BIBR.	21	31	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	DDR2	DDR2	DDR2	21	22	29	30
Cell proliferation assays showed that DDR2 mutated cell lines ( NCI-H2286 and HCC-366 ) were rescued from dasatinib induced cell death by SRC GK mutation to a degree comparable to what we previously observed with DDR2 GK mutation .	Cell proliferation assays showed that DDR2 mutated cell lines (NCI-H2286 and HCC-366) were rescued from dasatinib induced cell death by SRC GK mutation to a degree comparable to what we previously observed with DDR2 GK mutation.	5	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	DDR2	DDR2	DDR2	22	23	5	6
Here we show that DDR2 is also unusual in that it requires Src activity to be maximally tyrosine phosphorylated , and that Src activity also promotes association of DDR2 with Shc .	Here we show that DDR2 is also unusual in that it requires Src activity to be maximally tyrosine phosphorylated, and that Src activity also promotes association of DDR2 with Shc.	22	29	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	DDR2	DDR2	DDR2	22	23	28	29
Further , we show that either selective SRC or DDR2 inhibition is potentiated by inhibition of the other kinase , suggesting a coordinated role of SRC and DDR2 in mediating the survival of cells with DDR2 mutations .	Further, we show that either selective SRC or DDR2 inhibition is potentiated by inhibition of the other kinase, suggesting a coordinated role of SRC and DDR2 in mediating the survival of cells with DDR2 mutations.	5	28	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	DDR2	DDR2	DDR2	7	8	27	28
In addition to normal cytokine activation , Gab1 and Gab2 can also be activated by oncogenic tyrosine kinases , oncoproteins , and Src family kinases ( summarized in XREF_TABLE ) .	In addition to normal cytokine activation, Gab1 and Gab2 can also be activated by oncogenic tyrosine kinases, oncoproteins, and Src family kinases (summarized in XREF_TABLE).	7	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Gab1	Gab1	Gab1	22	23	7	8
Src plays an important role in regulating the endocytosis of PDGFRbeta-G protein coupled receptor complexes , in which Src induces p-Y of Grb-2 associated binder-1 ( Gab1 ) and promotes accumulation of Dyn2 at the plasma membrane .	Src plays an important role in regulating the endocytosis of PDGFRbeta-G protein coupled receptor complexes, in which Src induces p-Y of Grb-2 associated binder-1 (Gab1) and promotes accumulation of Dyn2 at the plasma membrane.	18	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Grb-2 associated binder-1	Grb-2 associated binder-1	Grb-2 associated binder-1	18	19	22	25
These results indicate that Src mediated AREG shedding is involved in DNA synthesis and cyclin D1 promoter activity .	These results indicate that Src mediated AREG shedding is involved in DNA synthesis and cyclin D1 promoter activity.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	AREG	AREG	AREG	4	5	6	7
TGF-alpha and amphiregulin secretion by GRP stimulation also was inhibited by blockade of Src family kinases .	TGF-alpha and amphiregulin secretion by GRP stimulation also was inhibited by blockade of Src family kinases.	0	15	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	amphiregulin	amphiregulin	amphiregulin	13	14	2	3
We next examined the effect of silencing Src or TACE on DCA induced TGF-alpha and AREG shedding and cellular expression .	We next examined the effect of silencing Src or TACE on DCA induced TGF-alpha and AREG shedding and cellular expression.	4	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	AREG	AREG	AREG	7	8	15	16
Together , these observations demonstrate that one or more Src family kinases act upstream as well as downstream of ErbB1 to promote amphiregulin dependent autocrine stimulation of NHKs and suggest that autocrine NHK proliferation is more dependent upon ERK activation than upon Tyr 845 phosphorylation .	Together, these observations demonstrate that one or more Src family kinases act upstream as well as downstream of ErbB1 to promote amphiregulin dependent autocrine stimulation of NHKs and suggest that autocrine NHK proliferation is more dependent upon ERK activation than upon Tyr 845 phosphorylation.	9	25	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	amphiregulin	amphiregulin	amphiregulin	9	10	22	23
Src and TACE are required for DCA induced AREG and TGF-alpha shedding .	Src and TACE are required for DCA induced AREG and TGF-alpha shedding.	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	AREG	AREG	AREG	0	1	8	9
The c-Src and Lck inhibitor modestly decreased the release of AREG in the HARA , and had no impact in the RWGT2 line , raising the possibility that other signaling events may be involved in TACE activation in these lung SCC lines .	The c-Src and Lck inhibitor modestly decreased the release of AREG in the HARA, and had no impact in the RWGT2 line, raising the possibility that other signaling events may be involved in TACE activation in these lung SCC lines.	1	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	AREG	AREG	AREG	1	2	10	11
VEGFR3 can also be activated by integrin mediated activation of SRC , contributing to survival and migration of ECs [ XREF_BIBR ] .	VEGFR3 can also be activated by integrin mediated activation of SRC, contributing to survival and migration of ECs [XREF_BIBR].	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRC	integrin mediated activation of SRC	src	VEGFR3	VEGFR3	vegfr3	10	11	0	1
Phosphorylated IRS-1 will bind with regulatory subunit of phosphatidylinositol 3-kinase ( PI3K ) with Src homology 2 domain and further activate PI3K and protein kinase B ( Akt ) .	Phosphorylated IRS-1 will bind with regulatory subunit of phosphatidylinositol 3-kinase (PI3K) with Src homology 2 domain and further activate PI3K and protein kinase B (Akt).	14	26	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Src	Src	Src	protein kinase B	protein kinase B	protein kinase B	14	15	23	26
Src mediates protein kinase B , also known as Akt , a key factor in the regulation of cancer cell survival in the bone metastasis microenvironment .	Src mediates protein kinase B, also known as Akt, a key factor in the regulation of cancer cell survival in the bone metastasis microenvironment.	0	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	protein kinase B	protein kinase B	protein kinase B	0	1	2	5
For example , the phosphorylation of Y315 AKT1 ( 204 PKA ) , as well as Y326 AKT1 ( 215 PKA ) , is necessary for the activation of AKT1 by Src XREF_BIBR - XREF_BIBR .	For example, the phosphorylation of Y315 AKT1 (204 PKA), as well as Y326 AKT1 (215 PKA), is necessary for the activation of AKT1 by Src XREF_BIBR - XREF_BIBR.	27	32	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src	Src	AKT1	AKT1	AKT1	31	32	29	30
We previously showed that Src mediates growth factors induced activation of Dgk-alpha , whose activity is required for cell motility , proliferation and angiogenesis .	We previously showed that Src mediates growth factors induced activation of Dgk-alpha, whose activity is required for cell motility, proliferation and angiogenesis.	4	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Dgk-alpha	Dgk-alpha	Dgk-alpha	4	5	11	12
PA generated by activation of either DGKs or PLDs mediates cell migration by regulating the function of small GTPases through a variety of mechanisms , and Src dependent activation of DGK-alpha mediates hepatocyte growth factor ( HGF ) - and VEGF induced cell migration by regulating atypical PKCs and Rac .	PA generated by activation of either DGKs or PLDs mediates cell migration by regulating the function of small GTPases through a variety of mechanisms, and Src dependent activation of DGK-alpha mediates hepatocyte growth factor (HGF) - and VEGF induced cell migration by regulating atypical PKCs and Rac.	26	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	DGK-alpha	DGK-alpha	DGK-alpha	26	27	30	31
Thus , there are two mechanisms by which Src can activate DGKalpha .	Thus, there are two mechanisms by which Src can activate DGKalpha.	8	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	DGKalpha	DGKalpha	DGKalpha	8	9	11	12
Both Anxa2 and Stat3 can be activated by Src kinase pathway .	Both Anxa2 and Stat3 can be activated by Src kinase pathway.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Anxa2	Anxa2	Anxa2	8	9	1	2
Certainly in Anxa2 , the key amino residues Tyr 23 , Ser 11 and Ser 25 are targets for phosphorylation by Src family tyrosine kinases and serine kinases XREF_BIBR , XREF_BIBR .	Certainly in Anxa2, the key amino residues Tyr 23, Ser 11 and Ser 25 are targets for phosphorylation by Src family tyrosine kinases and serine kinases XREF_BIBR, XREF_BIBR.	0	24	targets	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	Src	Src	Src	Anxa2	Anxa2	Anxa2	21	22	2	3
Finally , to examine whether the changes in Src signaling and cell morphology observed upon siRNA mediated annexin 2 depletion have consequences for anchorage independent growth , we performed an assay in which proliferation of both control and annexin 2 depleted R1LA29 cells was examined at the nonpermissive and permissive temperatures in soft agar .	Finally, to examine whether the changes in Src signaling and cell morphology observed upon siRNA mediated annexin 2 depletion have consequences for anchorage independent growth, we performed an assay in which proliferation of both control and annexin 2 depleted R1LA29 cells was examined at the nonpermissive and permissive temperatures in soft agar.	8	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	annexin 2	annexin 2	annexin 2	8	9	17	19
Although this second Y may also undergo autophosphorylation , we propose that BMX functions to amplify receptor tyrosine kinase signaling by phosphorylation of the second Y subsequent to the priming phosphorylation of the first Y. Because BMX activity is activated by PI3K and Src , this function of BMX provides the cell with a mechanism to broadly modulate the activity of multiple tyro-sine kinases in response to stimulation by PI3K or Src .	Although this second Y may also undergo autophosphorylation, we propose that BMX functions to amplify receptor tyrosine kinase signaling by phosphorylation of the second Y subsequent to the priming phosphorylation of the first Y. Because BMX activity is activated by PI3K and Src, this function of BMX provides the cell with a mechanism to broadly modulate the activity of multiple tyro-sine kinases in response to stimulation by PI3K or Src.	36	44	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	BMX	BMX	BMX	43	44	36	37
We found that the nonreceptor Tec family tyrosine kinase Bmx and Etk was activated by tyrosine phosphorylation downstream of Src and PI 3-kinase in PTEN deficient LNCaP and PC3 PCa cells and that Bmx down-regulation by short interfering RNA markedly inhibited LNCaP cell growth .	We found that the nonreceptor Tec family tyrosine kinase Bmx and Etk was activated by tyrosine phosphorylation downstream of Src and PI 3-kinase in PTEN deficient LNCaP and PC3 PCa cells and that Bmx down-regulation by short interfering RNA markedly inhibited LNCaP cell growth.	3	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	tyrosine phosphorylation downstream of Src	src	Bmx	Bmx	bmx	19	20	9	10
In response to ligand stimulation , Bmx and Etk is activated by tyrosine phosphorylation downstream of Src and PI3K in PTEN deficient PCa cells .	In response to ligand stimulation, Bmx and Etk is activated by tyrosine phosphorylation downstream of Src and PI3K in PTEN deficient PCa cells.	6	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	tyrosine phosphorylation downstream of Src	src	Bmx	Bmx	bmx	16	17	6	7
Therefore , activated Src may be a direct target of Cbl-c in vivo .	Therefore, activated Src may be a direct target of Cbl-c in vivo.	2	12	be a direct target	Positive_activation_copula_1	Positive_activation	Positive_activation	Src	Src	Src	Cbl-c	Cbl-c	Cbl-c	3	4	10	11
Here we show that Src is a preferential target of Cbl-c for degradation .	Here we show that Src is a preferential target of Cbl-c for degradation.	4	12	is a preferential target	Positive_activation_copula_1	Positive_activation	Positive_activation	Src	Src	Src	Cbl-c	Cbl-c	Cbl-c	4	5	10	11
Binding of Hic-5 to Cbl-c leads to an increase in the ubiquitin ligase activity of Cbl-c once Cbl-c has been activated by Src phosphorylation or through an activating phosphomimetic mutation .	Binding of Hic-5 to Cbl-c leads to an increase in the ubiquitin ligase activity of Cbl-c once Cbl-c has been activated by Src phosphorylation or through an activating phosphomimetic mutation.	17	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src phosphorylation	src	Cbl-c	Cbl-c	cbl-c	22	23	17	18
Somewhat surprisingly , the decrease of SRC-1 expression significantly blocked steroid dependent male sexual behavior and decreased the density of the aromatase immunoreactivity in the POA , but aromatase activity in the POA was not affected by the repeated injection of SRC-1 antisense .	Somewhat surprisingly, the decrease of SRC-1 expression significantly blocked steroid dependent male sexual behavior and decreased the density of the aromatase immunoreactivity in the POA, but aromatase activity in the POA was not affected by the repeated injection of SRC-1 antisense.	6	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1 expression	src-1	aromatase	aromatase	aromatase	6	7	21	22
Similarly , immunoprecipitation of His6 tagged aromatase in MCF-7 cells and investigation of phosphorylated amino acid by immunoblotting revealed that aromatase tyrosine residue is directly targeted by the kinase c-Src .	Similarly, immunoprecipitation of His6 tagged aromatase in MCF-7 cells and investigation of phosphorylated amino acid by immunoblotting revealed that aromatase tyrosine residue is directly targeted by the kinase c-Src.	20	30	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	aromatase	aromatase	aromatase	29	30	20	21
Other post-translational modifications are performed by the tyrosine kinases c-Src XREF_BIBR and PTP1B XREF_BIBR : phosphorylation of Y361 by c-Src increases aromatase activity .	Other post-translational modifications are performed by the tyrosine kinases c-Src XREF_BIBR and PTP1B XREF_BIBR : phosphorylation of Y361 by c-Src increases aromatase activity.	15	22	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	phosphorylation of Y361 by c-Src	c-src	aromatase	aromatase	aromatase	19	20	21	22
In this regard , studies on the inhibitory effects of an ezrin inhibitor , NSC668394 , on the ezrin related signaling such as Src and paxillin and on the migration of cancer cells are underway in our researches .	In this regard, studies on the inhibitory effects of an ezrin inhibitor, NSC668394, on the ezrin related signaling such as Src and paxillin and on the migration of cancer cells are underway in our researches.	18	25	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Src	Src	Src	ezrin	ezrin	ezrin	23	24	18	19
Both Sox9 and Sox10 can activate Mitf , a protein essential for melanogenesis .	Both Sox9 and Sox10 can activate Mitf, a protein essential for melanogenesis.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sox9	Sox9	Sox9	Mitf	Mitf	Mitf	1	2	6	7
To facilitate the detection of Fhit phosphorylation , we raised an anti-phospho-Fhit Tyr 114 antiserum which can detect Src induced Fhit Tyr 114 phosphorylation with high sensitivity ; overexpression of Src was sufficient to induce Fhit phosphorylation in transfected HEK293 cells due to the increase in activated Src ( P-Src in Figure XREF_FIG A ) .	To facilitate the detection of Fhit phosphorylation, we raised an anti-phospho-Fhit Tyr 114 antiserum which can detect Src induced Fhit Tyr 114 phosphorylation with high sensitivity; overexpression of Src was sufficient to induce Fhit phosphorylation in transfected HEK293 cells due to the increase in activated Src (P-Src in Figure XREF_FIG A).	17	21	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Fhit	Fhit	Fhit	18	19	20	21
In this study , we used aromatase inhibitor letrozole in vivo and SRC-1 RNA interference in vitro to investigate whether SRC-1 mediated endogenous estrogen regulation of hippocampal PSD-95 .	In this study, we used aromatase inhibitor letrozole in vivo and SRC-1 RNA interference in vitro to investigate whether SRC-1 mediated endogenous estrogen regulation of hippocampal PSD-95.	20	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC-1	SRC-1	SRC-1	PSD-95	PSD-95	PSD-95	20	21	27	28
The inhibition of c-Src caused a persistent downregulation of P-Stat5 , but only a transient inhibition of P-Stat3 .	The inhibition of c-Src caused a persistent downregulation of P-Stat5, but only a transient inhibition of P-Stat3.	1	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	P-Stat3	P-Stat3	P-Stat3	3	4	17	18
In conclusion , our data provided evidence on the pivotal role of Src mediated STAT3 activation and subsequent p21 Cip1 upregulation in Taxol resistance of ErbB2 overexpressing breast cancer cells .	In conclusion, our data provided evidence on the pivotal role of Src mediated STAT3 activation and subsequent p21 Cip1 upregulation in Taxol resistance of ErbB2 overexpressing breast cancer cells.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	12	13	14	15
Our data provide evidence of activation of Jab1 transcription through IL-6 and Src mediated activation of Stat3 as shown in Figure XREF_FIG .	Our data provide evidence of activation of Jab1 transcription through IL-6 and Src mediated activation of Stat3 as shown in Figure XREF_FIG.	10	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	12	13	16	17
We also noted that Src mediated IL-6-induced focal adhesion kinase ( FAK ) and STAT3 activation in SV-LECs [ XREF_BIBR ] .	We also noted that Src mediated IL-6-induced focal adhesion kinase (FAK) and STAT3 activation in SV-LECs [XREF_BIBR].	4	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	4	5	14	15
Importantly , we found that PKCdelta increased phosphorylation of SRC , which in turn activated STAT3 and , ultimately , NOTCH2 signaling , leading to mesenchymal transformation .	Importantly, we found that PKCdelta increased phosphorylation of SRC, which in turn activated STAT3 and, ultimately, NOTCH2 signaling, leading to mesenchymal transformation.	5	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	PKCdelta increased phosphorylation of SRC	src	STAT3	STAT3	stat3	9	10	15	16
It was previously reported that SRC mediated activation of STAT3 facilitates binding of STAT3 dimmers on the AKT1 promoter , thereby inducing its transcription 29 .	It was previously reported that SRC mediated activation of STAT3 facilitates binding of STAT3 dimmers on the AKT1 promoter, thereby inducing its transcription 29.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT3	STAT3	STAT3	5	6	9	10
Although no direct effector for Galphao has been characterized to date , previous reports have demonstrated that active Galphao ( i.e. constitutively active Q205L mutant ) enhances Src dependent activation of STAT3 to promote neoplastic transformation of NIH3T3 fibroblasts .	Although no direct effector for Galphao has been characterized to date, previous reports have demonstrated that active Galphao (i.e. constitutively active Q205L mutant) enhances Src dependent activation of STAT3 to promote neoplastic transformation of NIH3T3 fibroblasts.	27	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	27	28	31	32
As both JAK and Src activation could induce STAT3 activation , inhibition of JAK2 or Src is another mechanism for CDDO-Me-mediated inhibition of STAT3 phosphorylation and nuclear translocation .	As both JAK and Src activation could induce STAT3 activation, inhibition of JAK2 or Src is another mechanism for CDDO-Me-mediated inhibition of STAT3 phosphorylation and nuclear translocation.	2	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	4	5	8	9
A previous study showed that all Src transformed cell lines have persistently activated STAT3 , and dominant negative STAT3 blocks transformation .	A previous study showed that all Src transformed cell lines have persistently activated STAT3, and dominant negative STAT3 blocks transformation.	5	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	6	7	13	14
Mechanistic studies showed that AR potently suppressed STAT3 and Src phosphorylation , and inhibited STAT3 nuclear localization in cultured CRC cells .	Mechanistic studies showed that AR potently suppressed STAT3 and Src phosphorylation, and inhibited STAT3 nuclear localization in cultured CRC cells.	4	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	AR potently suppressed STAT3 and Src phosphorylation	src	STAT3	STAT3	stat3	9	10	14	15
The HIV protein Nef mediates the proliferation and de-differentiation of podocytes through Src dependent activation of Stat3 and MAPK1 ,2 pathways [ XREF_BIBR ] .	The HIV protein Nef mediates the proliferation and de-differentiation of podocytes through Src dependent activation of Stat3 and MAPK1,2 pathways [XREF_BIBR].	12	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	12	13	16	17
A2058 melanoma cells , like many other tumor cells , sustain mutations , including c-Src , that activate Stat3 .	A2058 melanoma cells, like many other tumor cells, sustain mutations, including c-Src, that activate Stat3.	11	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Stat3	Stat3	Stat3	14	15	18	19
To determine if this Stat3 activation by Src could induce Stat3 mediated gene expression , luciferase reporter constructs based on synthetic and authentic promoters were transfected into NIH 3T3 cells .	To determine if this Stat3 activation by Src could induce Stat3 mediated gene expression, luciferase reporter constructs based on synthetic and authentic promoters were transfected into NIH 3T3 cells.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	7	8	4	5
Notably , STAT3 tyrosine phosphorylation was also inhibited by Src inhibitors , which showed that STAT3 activity was triggered by Src activation .	Notably, STAT3 tyrosine phosphorylation was also inhibited by Src inhibitors, which showed that STAT3 activity was triggered by Src activation.	15	21	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	20	21	15	16
In A549 cells , c-Src knockdown decreased total and activated c-Src levels but increased pSTAT3 Y705 by 6.7 and 7.2 fold at 72 h and 96 h , respectively ( XREF_FIG ) .	In A549 cells, c-Src knockdown decreased total and activated c-Src levels but increased pSTAT3 Y705 by 6.7 and 7.2 fold at 72 h and 96 h, respectively (XREF_FIG).	4	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src knockdown decreased total and activated c-Src levels	c-src	pSTAT3	pSTAT3	pstat3	4	5	14	15
Src and JNK phosphorylation led to activation of the transcription factor Stat3 , resulting in gene expression involved in neurite growth and elongation [ XREF_BIBR - XREF_BIBR ] .	Src and JNK phosphorylation led to activation of the transcription factor Stat3, resulting in gene expression involved in neurite growth and elongation [XREF_BIBR - XREF_BIBR].	0	12	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Src	Src and JNK phosphorylation	src	Stat3	Stat3	stat3	0	1	11	12
Interestingly , it was also observed that icariin treatment induced the inhibition of Src activation as early as 2 h and this suppression of Src activation may act together with JAK kinases to abrogate STAT3 activation .	Interestingly, it was also observed that icariin treatment induced the inhibition of Src activation as early as 2 h and this suppression of Src activation may act together with JAK kinases to abrogate STAT3 activation.	24	35	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	24	25	34	35
When v-Src transformed cells were treated with sunitinib , nuclear Stat3 translocated to the cytoplasm , indicating abrogation of Src induced Stat3 activation ( XREF_FIG ) , which was accompanied by cell apoptosis ( XREF_FIG , lower panels ) .	When v-Src transformed cells were treated with sunitinib, nuclear Stat3 translocated to the cytoplasm, indicating abrogation of Src induced Stat3 activation (XREF_FIG), which was accompanied by cell apoptosis (XREF_FIG, lower panels).	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	19	20	21	22
STAT3 can also can be activated by Src in addition to g protein receptors [ XREF_BIBR ] .	STAT3 can also can be activated by Src in addition to g protein receptors [XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	7	8	0	1
In human immunodeficiency virus associated nephropathy , Src dependent activation of Stat3 , mitogen- activated protein kinase 1,2 , and hypoxia inducible factor 2alpha is an important driver of podocyte proliferation .	In human immunodeficiency virus associated nephropathy, Src dependent activation of Stat3, mitogen- activated protein kinase 1,2, and hypoxia inducible factor 2alpha is an important driver of podocyte proliferation.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	7	8	11	12
XREF_BIBR Src activates STAT3 signaling and promotes STAT3 mediated tumor progression and communication within the tumor microenvironment .	XREF_BIBR Src activates STAT3 signaling and promotes STAT3 mediated tumor progression and communication within the tumor microenvironment.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	1	2	3	4
The oncoprotein Src can also directly activate STAT3 [ XREF_BIBR ] .	The oncoprotein Src can also directly activate STAT3 [XREF_BIBR].	0	9	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	2	3	7	8
Preclinical data have demonstrated that the Vascular Endothelial Growth Factor ( VEGF ) and the proto-oncogene tyrosine protein kinase Src may play a crucial role in the development and progression of prostate cancer [ XREF_BIBR - XREF_BIBR ] , both through a Src related activation of the MAPK , PI3K/AKT/mTOR and STAT3 signaling pathways [ XREF_BIBR , XREF_BIBR ] and direct hormonal control of angiogenesis in the early stages of prostate carcinogenesis [ XREF_BIBR , XREF_BIBR ] .	Preclinical data have demonstrated that the Vascular Endothelial Growth Factor (VEGF) and the proto-oncogene tyrosine protein kinase Src may play a crucial role in the development and progression of prostate cancer [XREF_BIBR - XREF_BIBR], both through a Src related activation of the MAPK, PI3K/AKT/mTOR and STAT3 signaling pathways [XREF_BIBR, XREF_BIBR] and direct hormonal control of angiogenesis in the early stages of prostate carcinogenesis [XREF_BIBR, XREF_BIBR].	42	53	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	42	43	51	52
Furthermore , Stat3 is activated by Src and contributes to oncogenesis by Src XREF_BIBR .	Furthermore, Stat3 is activated by Src and contributes to oncogenesis by Src XREF_BIBR.	2	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	6	7	2	3
The Tyr 705 phosphorylated site is necessary for excitation of STAT3 , which is activated by JAK and Src .	The Tyr 705 phosphorylated site is necessary for excitation of STAT3, which is activated by JAK and Src.	8	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	18	19	10	11
In contrast , it has been shown that both JNKs and p38 are required for STAT3 transcriptional activity induced by the Src oncoprotein [ XREF_BIBR ] .	In contrast, it has been shown that both JNKs and p38 are required for STAT3 transcriptional activity induced by the Src oncoprotein [XREF_BIBR].	15	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	21	22	15	16
Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells .	Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells.	3	16	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	5	6	15	16
Likewise , Stat3 activation was disrupted in AMBN-stable 143B-Luc cells and restored by induction of a constitutively active form of Src ( Src-Y527F ) ( XREF_FIG ) .	Likewise, Stat3 activation was disrupted in AMBN-stable 143B-Luc cells and restored by induction of a constitutively active form of Src (Src-Y527F) (XREF_FIG).	2	25	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	20	21	2	3
Depletion of c-Src by siRNA or sustained inhibition by dasatinib increased pSTAT3 , which could be blocked by inhibition of JAK .	Depletion of c-Src by siRNA or sustained inhibition by dasatinib increased pSTAT3, which could be blocked by inhibition of JAK.	0	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	pSTAT3	pSTAT3	pSTAT3	2	3	11	12
PD180970 , the known Src kinase inhibitor , was able to inhibit STAT3 activity partly in A549 cell line as reported XREF_BIBR ( XREF_FIG ) .	PD180970, the known Src kinase inhibitor, was able to inhibit STAT3 activity partly in A549 cell line as reported XREF_BIBR (XREF_FIG).	4	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	4	5	12	13
Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK , SRC , c-ABL , and JNK kinases .	Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases.	12	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT3	STAT3	STAT3	23	24	12	13
Moreover , inhibition of Src family kinases with the pharmacologic agent , SU6656 , blocks Stat3 activation by PDGF .	Moreover, inhibition of Src family kinases with the pharmacologic agent, SU6656, blocks Stat3 activation by PDGF.	4	16	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	4	5	15	16
Phosphorylation of Tyr985 is essential for phosphorylation of Tyr1138 which promotes Src mediated activation of STAT3 28 .	Phosphorylation of Tyr985 is essential for phosphorylation of Tyr1138 which promotes Src mediated activation of STAT3 28.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	11	12	15	16
Janus activated kinases ( JAK ) , Interleukin-6 ( IL-6 ) , epidermal growth factor receptors and Src kinases activate STAT3 by phosphorylation at important tyrosine residues .	Janus activated kinases (JAK), Interleukin-6 (IL-6), epidermal growth factor receptors and Src kinases activate STAT3 by phosphorylation at important tyrosine residues.	17	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	17	18	20	21
Moreover , TrkB in the absence of c-Src is sufficient to activate JAK2 and STAT3 through blocking of JAK2 degradation by SOCS3 after directly binding to the JAK2 , as well as upregulation of EMT related transcription factors , such as Twist-1 and Twist-2 .	Moreover, TrkB in the absence of c-Src is sufficient to activate JAK2 and STAT3 through blocking of JAK2 degradation by SOCS3 after directly binding to the JAK2, as well as upregulation of EMT related transcription factors, such as Twist-1 and Twist-2.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	7	8	14	15
Inhibition of the tyrosine kinase family Src ( Src ) caused a significant reduction of Stat3 activation , whereas inhibition of phosphatidylinositol 3-kinase ( PI3K ) had no effect .	Inhibition of the tyrosine kinase family Src (Src) caused a significant reduction of Stat3 activation, whereas inhibition of phosphatidylinositol 3-kinase (PI3K) had no effect.	0	16	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	6	7	15	16
Importantly , dehydrocrenatidine does not show significant effect on Src overexpression and epidermal growth factor induced STAT3 activation .	Importantly, dehydrocrenatidine does not show significant effect on Src overexpression and epidermal growth factor induced STAT3 activation.	9	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src overexpression	src	STAT3	STAT3	stat3	9	10	16	17
This supports the fact that Src activated STAT3 signaling has a key role in the survival and growth of melanoma tumor cells .	This supports the fact that Src activated STAT3 signaling has a key role in the survival and growth of melanoma tumor cells.	5	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	5	6	7	8
Although , while it is quite a common knowledge that Src can activate STAT3 26 , the role of Yes-1 as a STAT3 activator has not yet been demonstrated .	Although, while it is quite a common knowledge that Src can activate STAT3 26, the role of Yes-1 as a STAT3 activator has not yet been demonstrated.	10	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	10	11	13	14
We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis .	We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis.	3	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	7	8	3	4
Together , our new findings showed that Src mediated activation of STAT3 upregulated p21 Cip1 and this pathway is involved in Taxol resistance of ErbB2 overexpressing cells .	Together, our new findings showed that Src mediated activation of STAT3 upregulated p21 Cip1 and this pathway is involved in Taxol resistance of ErbB2 overexpressing cells.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	7	8	11	12
JAK as well as Src kinase have been shown to activate STAT3 .	JAK as well as Src kinase have been shown to activate STAT3.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	4	5	11	12
Although the activation of Src was inhibited by IS , Src activator could not reverse IS induced inhibition of pSTAT3 , indicating that Src might not be the upstream modulator of IS mediated STAT3 inhibition .	Although the activation of Src was inhibited by IS, Src activator could not reverse IS induced inhibition of pSTAT3, indicating that Src might not be the upstream modulator of IS mediated STAT3 inhibition.	10	20	reverse	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	pSTAT3	pSTAT3	pSTAT3	10	11	19	20
STAT3 is activated upon VEGF stimulation of EC in vitro and in vivo by a VEGFR2 dependent or Src dependent mechanism .	STAT3 is activated upon VEGF stimulation of EC in vitro and in vivo by a VEGFR2 dependent or Src dependent mechanism.	0	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	18	19	0	1
Src activated Stat3 signaling is necessary for growth and survival of melanoma cells XREF_BIBR .	Src activated Stat3 signaling is necessary for growth and survival of melanoma cells XREF_BIBR.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	0	1	2	3
Src induces STAT3 dimerization and entry into the nucleus , resulting in the activation of the transcription and translation of target genes .	Src induces STAT3 dimerization and entry into the nucleus, resulting in the activation of the transcription and translation of target genes.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	2	3
The potential mechanisms of EET induced angiogenesis include inhibition of the forkhead transcription factor to down-regulate p27Kip1 [ XREF_BIBR ] , crosstalk to growth factors epidermal growth factor receptor [ XREF_BIBR ] , induction of FGF2 [ XREF_BIBR ] , and VEGF [ XREF_BIBR ] , often demonstrated via Akt activation [ XREF_BIBR - XREF_BIBR ] , SRC activation of STAT-3 [ XREF_BIBR ] , the activation of sphingosine kinase-1 [ XREF_BIBR ] , and the induction of endothelial nitric oxide synthase CYP2J2 has been directly implicated as a pro angiogenic EET producer .	The potential mechanisms of EET induced angiogenesis include inhibition of the forkhead transcription factor to down-regulate p27Kip1 [XREF_BIBR], crosstalk to growth factors epidermal growth factor receptor [XREF_BIBR], induction of FGF2 [XREF_BIBR], and VEGF [XREF_BIBR], often demonstrated via Akt activation [XREF_BIBR - XREF_BIBR], SRC activation of STAT-3 [XREF_BIBR], the activation of sphingosine kinase-1 [XREF_BIBR], and the induction of endothelial nitric oxide synthase CYP2J2 has been directly implicated as a pro angiogenic EET producer.	57	61	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT-3	STAT-3	STAT-3	57	58	60	61
JNK , on the other hand , appears to be necessary for Src mediated activation of STAT3 [ XREF_BIBR ] .	JNK, on the other hand, appears to be necessary for Src mediated activation of STAT3 [XREF_BIBR].	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	12	13	16	17
XREF_BIBR Therefore , dual inhibition of Janus and Src family kinases blocks constitutively activated Stat3 in pancreatic cancer cells .	XREF_BIBR Therefore, dual inhibition of Janus and Src family kinases blocks constitutively activated Stat3 in pancreatic cancer cells.	6	18	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	8	9	14	15
20 Src and JAK proteins phosphorylate and activate STAT3 protein in response to various cytokines .	20 Src and JAK proteins phosphorylate and activate STAT3 protein in response to various cytokines.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	1	2	8	9
Of interest , the level of activated Src , which is known to activate Stat3 , was virtually eliminated but the level of the Src protein itself remained the same .	Of interest, the level of activated Src, which is known to activate Stat3, was virtually eliminated but the level of the Src protein itself remained the same.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	level of activated Src	src	Stat3	Stat3	stat3	7	8	14	15
We proceeded to examine whether Src also mediates activation of STAT3 in normally cultured renal fibroblasts .	We proceeded to examine whether Src also mediates activation of STAT3 in normally cultured renal fibroblasts.	5	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	5	6	10	11
Interestingly , c-Src directly activates STAT3 , and NF-kappaB is activated by the PI3K and Akt pathway .	Interestingly, c-Src directly activates STAT3, and NF-kappaB is activated by the PI3K and Akt pathway.	2	6	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	2	3	5	6
c-Src inhibition fails to durably inhibit STAT3 in NSCLC cell lines .	c-Src inhibition fails to durably inhibit STAT3 in NSCLC cell lines.	0	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	0	1	6	7
Also , Src kinase activity can activate STAT3 preassembled with PDGFR receptors , and STAT3 binding to FGFR was shown to be activated by receptor amplification .	Also, Src kinase activity can activate STAT3 preassembled with PDGFR receptors, and STAT3 binding to FGFR was shown to be activated by receptor amplification.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	2	3	7	8
Therefore , decreased miR-204 increases expression of SHP2 , which by activating Src increases Stat3 activation contributing to smooth muscle proliferation and pulmonary vessel wall thickening .	Therefore, decreased miR-204 increases expression of SHP2, which by activating Src increases Stat3 activation contributing to smooth muscle proliferation and pulmonary vessel wall thickening.	12	15	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	12	13	14	15
Furthermore , a later study found that STAT3 activation could be inhibited by Src and JAK inhibitors in human breast cancer cell lines , suggesting a key role for Src in STAT3 activation in breast cancers .	Furthermore, a later study found that STAT3 activation could be inhibited by Src and JAK inhibitors in human breast cancer cell lines, suggesting a key role for Src in STAT3 activation in breast cancers.	7	16	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	13	14	7	8
Sorafenib inhibited p-ERK , but not p-AKT , expression consistent with its ability to block Ras/Raf/MEK/ERK activation , and both ERK and Src and Jak signaling have been shown to activate STAT3 .	Sorafenib inhibited p-ERK, but not p-AKT, expression consistent with its ability to block Ras/Raf/MEK/ERK activation, and both ERK and Src and Jak signaling have been shown to activate STAT3.	22	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	22	23	31	32
It is often stated generally that members of the Src family kinases can activate STAT3 .	It is often stated generally that members of the Src family kinases can activate STAT3.	9	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	9	10	14	15
Prior studies have indicated that Src and JAK kinases activities cooperate to mediate constitutive activation of STAT3 in tumour cells .	Prior studies have indicated that Src and JAK kinases activities cooperate to mediate constitutive activation of STAT3 in tumour cells.	5	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	5	6	16	17
Subsequent studies demonstrated that Src activation enhances the transcriptional activity of HIF-1a and STAT3 that regulate VEGF expression [ XREF_BIBR ] .	Subsequent studies demonstrated that Src activation enhances the transcriptional activity of HIF-1a and STAT3 that regulate VEGF expression [XREF_BIBR].	4	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	4	5	13	14
Assays of electrophoretic mobility , DNA binding specificity , and antigenicity indicated that Stat3 or a closely related STAT family member was constitutively activated by the Src oncoprotein .	Assays of electrophoretic mobility, DNA binding specificity, and antigenicity indicated that Stat3 or a closely related STAT family member was constitutively activated by the Src oncoprotein.	13	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	26	27	13	14
It is reported that the autocrine and/or paracrine system by IL-6 , stimulation of EGF or Src , mutation or overexpression of Stat3 results in constitutive activation of Stat3 in other malignancies .	It is reported that the autocrine and/or paracrine system by IL-6, stimulation of EGF or Src, mutation or overexpression of Stat3 results in constitutive activation of Stat3 in other malignancies.	12	31	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	16	17	28	29
Gallic acid has been suggested to target Src mediated Stat3 signaling , subsequently suppress TKIR cells specifically .	Gallic acid has been suggested to target Src mediated Stat3 signaling, subsequently suppress TKIR cells specifically.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	7	8	9	10
In contrast , Src dependent Y845 phosphorylation of EGFR was critical for parasite induced STAT3 activation but played no significant role in T. gondii induced early Akt signaling .	In contrast, Src dependent Y845 phosphorylation of EGFR was critical for parasite induced STAT3 activation but played no significant role in T. gondii induced early Akt signaling.	3	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	3	4	14	15
Src and JAK family tyrosine kinases cooperate to mediate STAT3 activation .	Src and JAK family tyrosine kinases cooperate to mediate STAT3 activation.	0	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	9	10
As STAT3 can be activated by Janus activated kinases ( JAKs ) and c-Src [ XREF_BIBR ] , we assessed activation of JAK2 and Src in U251 and U87 cells following SFN treatment .	As STAT3 can be activated by Janus activated kinases (JAKs) and c-Src [XREF_BIBR], we assessed activation of JAK2 and Src in U251 and U87 cells following SFN treatment.	1	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	13	14	1	2
More importantly , we unravel the importance of 12/15-LO activity for the PDGF induced and Src mediated STAT3 activation in rat VSMC .	More importantly, we unravel the importance of 12/15-LO activity for the PDGF induced and Src mediated STAT3 activation in rat VSMC.	15	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	15	16	17	18
Members of the Src family of non receptor tyrosine kinases can activate STAT3 by phosphorylating Y705 [ XREF_BIBR ] .	Members of the Src family of non receptor tyrosine kinases can activate STAT3 by phosphorylating Y705 [XREF_BIBR].	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	3	4	12	13
All Src transformed cell lines have persistently activated STAT3 , and dominant negative STAT3 blocks transformation .	All Src transformed cell lines have persistently activated STAT3, and dominant negative STAT3 blocks transformation.	0	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	1	2	8	9
Src has been shown to activate STAT3 , and multiple studies have shown that the gene network regulated by STAT3 mediated transcription is required for v-src-induced cellular transformation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Src has been shown to activate STAT3, and multiple studies have shown that the gene network regulated by STAT3 mediated transcription is required for v-src-induced cellular transformation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	6	7
Phosphorylation of c-Src , which was shown to be activated by AhR ligands , was also increased by I3S and TCDD , and blocking of c-Src activity by 4-amino-5-( 4-chlorophenyl )-7-( t-butyl ) pyrazolo [ 3,4-d ] pyrimidine ( PP2 ) inhibited phosphorylation of both c-Src and STAT3 , raising a possibility that stimulatory activities of I3S and TCDD on Th17 differentiation could be exerted via increased phosphorylation of c-Src , which in turn stimulates STAT3 activation .	Phosphorylation of c-Src, which was shown to be activated by AhR ligands, was also increased by I3S and TCDD, and blocking of c-Src activity by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine (PP2) inhibited phosphorylation of both c-Src and STAT3, raising a possibility that stimulatory activities of I3S and TCDD on Th17 differentiation could be exerted via increased phosphorylation of c-Src, which in turn stimulates STAT3 activation.	25	48	inhibited	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	c-Src	c-Src	c-src	STAT3	phosphorylation of both c-Src and STAT3	stat3	25	26	47	48
Src activation further activated STAT3 that recognizes an SIE binding site on the p21 Cip1 promoter required for ErbB2 mediated p21 Cip1 transcriptional upregulation .	Src activation further activated STAT3 that recognizes an SIE binding site on the p21 Cip1 promoter required for ErbB2 mediated p21 Cip1 transcriptional upregulation.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	4	5
Some Src family tyrosine kinases have also been shown to promote STAT3 activity via phosphorylating Y705 in STAT3 .	Some Src family tyrosine kinases have also been shown to promote STAT3 activity via phosphorylating Y705 in STAT3.	1	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	1	2	11	12
STAT3 is activated by the upstream kinases JAK or Src family [ XREF_BIBR ] and can regulate oncogenesis by targeting various gene products [ XREF_BIBR ] .	STAT3 is activated by the upstream kinases JAK or Src family [XREF_BIBR] and can regulate oncogenesis by targeting various gene products [XREF_BIBR].	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	9	10	0	1
Most Src transformed cell lines have persistently activated STAT3 , and dominant negative STAT3 blocks transformation XREF_BIBR , XREF_BIBR .	Most Src transformed cell lines have persistently activated STAT3, and dominant negative STAT3 blocks transformation XREF_BIBR, XREF_BIBR.	0	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	1	2	8	9
With the cixutumumab induced activation of integrin and Src XREF_BIBR and the capacity of Src to activate STAT3 , STAT3 activation during an IGF-1R blockade could have been mediated by integrin and Src signalling .	With the cixutumumab induced activation of integrin and Src XREF_BIBR and the capacity of Src to activate STAT3, STAT3 activation during an IGF-1R blockade could have been mediated by integrin and Src signalling.	19	33	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	32	33	19	20
Moreover , MTI treatment resulted in a decrease in Src mediated STAT3 tyrosine phosphorylation and activation , an effect that was significantly enhanced by RKIP over expression .	Moreover, MTI treatment resulted in a decrease in Src mediated STAT3 tyrosine phosphorylation and activation, an effect that was significantly enhanced by RKIP over expression.	4	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	9	10	11	12
Inhibition of kinases SRC and JAK can prevent STAT3 activation and induce apoptosis of breast cancer cells .	Inhibition of kinases SRC and JAK can prevent STAT3 activation and induce apoptosis of breast cancer cells.	0	9	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT3	STAT3	STAT3	3	4	8	9
Activation of STAT3 by c-Src promotes tumor progression .	Activation of STAT3 by c-Src promotes tumor progression.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	4	5	2	3
One possible explanation to explain our results is that STAT3 may be activated by non gp130 receptors and possibly Src through receptor tyrosine kinases .	One possible explanation to explain our results is that STAT3 may be activated by non gp130 receptors and possibly Src through receptor tyrosine kinases.	9	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	19	20	9	10
In addition to regulation by c-Src , STAT3 can be activated by the nonreceptor tyrosine kinases Jaks .	In addition to regulation by c-Src, STAT3 can be activated by the nonreceptor tyrosine kinases Jaks.	3	11	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	5	6	7	8
Using tyrosine kinase selective inhibitors , we show here that Src and JAK family tyrosine kinases cooperate to mediate constitutive Stat3 activation in the absence of EGF stimulation in model human breast cancer cell lines .	Using tyrosine kinase selective inhibitors, we show here that Src and JAK family tyrosine kinases cooperate to mediate constitutive Stat3 activation in the absence of EGF stimulation in model human breast cancer cell lines.	10	21	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	10	11	20	21
In addition , combined inhibition of SRC and EGFR with dasatinib , erlotinib and gemcitabine synergistically blocked constitutively activated STAT3 and consequently growth in a mouse model of pancreatic cancer 59 .	In addition, combined inhibition of SRC and EGFR with dasatinib, erlotinib and gemcitabine synergistically blocked constitutively activated STAT3 and consequently growth in a mouse model of pancreatic cancer 59.	4	22	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT3	STAT3	STAT3	6	7	19	20
In another study , the roles of alpha v beta 3 -integrin mediated Src tyrosine kinases for inducing the activation of STAT3 has been well demonstrated in intestinal epithelial cells , while the inhibition of Src prevented the activation of STAT3 XREF_BIBR .	In another study, the roles of alpha v beta 3 -integrin mediated Src tyrosine kinases for inducing the activation of STAT3 has been well demonstrated in intestinal epithelial cells, while the inhibition of Src prevented the activation of STAT3 XREF_BIBR.	33	41	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	35	36	40	41
Here , we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src , resulting in Src dependent activation of STAT3 by tyrosine phosphorylation .	Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Src dependent activation of STAT3 by tyrosine phosphorylation.	16	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	16	17	20	21
Small-molecule inhibitors of upstream kinases JAK , Src , and Bcr-Abl are predicted to inhibit STAT3 activation .	Small-molecule inhibitors of upstream kinases JAK, Src, and Bcr-Abl are predicted to inhibit STAT3 activation.	1	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	7	8	15	16
SRC family kinases are known to activate STAT3 47 , and have also been linked to imatinib resistance in CML cell lines and patient samples XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR .	SRC family kinases are known to activate STAT3 47, and have also been linked to imatinib resistance in CML cell lines and patient samples XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT3	STAT3	STAT3	0	1	7	8
Mechanistic studies showed that AR decreased STAT3 and Src phosphorylation , reduced STAT3 nuclear localization , and downregulated the expression STAT3 target genes .	Mechanistic studies showed that AR decreased STAT3 and Src phosphorylation, reduced STAT3 nuclear localization, and downregulated the expression STAT3 target genes.	4	22	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	AR decreased STAT3 and Src phosphorylation	src	STAT3	STAT3	stat3	8	9	20	21
However , the pro inflammatory properties of mature DC were directed to Th2 phenotype and determined by Src mediated STAT3 activation while Shc was blocked .	However, the pro inflammatory properties of mature DC were directed to Th2 phenotype and determined by Src mediated STAT3 activation while Shc was blocked.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	17	18	19	20
Dephosphorylation of tyrosine 531 can activate Src , which can activate STAT3 to induce transformation [ XREF_BIBR , XREF_BIBR ] .	Dephosphorylation of tyrosine 531 can activate Src, which can activate STAT3 to induce transformation [XREF_BIBR, XREF_BIBR].	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	6	7	11	12
On the other hand , constitutively active Stat3 in carcinoma lines , known to harbor activated Src , was blocked by pharmacological inhibitors of Src as well as JAKs .	On the other hand, constitutively active Stat3 in carcinoma lines, known to harbor activated Src, was blocked by pharmacological inhibitors of Src as well as JAKs.	6	25	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	24	25	7	8
Honokiol has also been shown to inhibit several other proteins that are known to interact with STAT3 including NFkappaB as well as gp130 , a subunit of the IL-6 receptor , and Src , which are both known to directly activate STAT3 in HNSCC .	Honokiol has also been shown to inhibit several other proteins that are known to interact with STAT3 including NFkappaB as well as gp130, a subunit of the IL-6 receptor, and Src, which are both known to directly activate STAT3 in HNSCC.	9	43	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	32	33	41	42
In addition , STAT3 is also activated by soluble tyrosine kinases of the Src kinase families .	In addition, STAT3 is also activated by soluble tyrosine kinases of the Src kinase families.	3	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	13	14	3	4
Specific c-Src knockdown with small interfering RNA ( siRNA ) resulted in STAT3 activation demonstrating specificity , which was inhibited by JAK ( TYK2 and JAK2 ) depletion with siRNA .	Specific c-Src knockdown with small interfering RNA (siRNA) resulted in STAT3 activation demonstrating specificity, which was inhibited by JAK (TYK2 and JAK2) depletion with siRNA.	0	14	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	1	2	12	13
STAT3 activation by activated c-Src led to a significant increase in the levels of phospho-STAT3 and Twist-1 XREF_BIBR .	STAT3 activation by activated c-Src led to a significant increase in the levels of phospho-STAT3 and Twist-1 XREF_BIBR.	0	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	4	5	0	1
While v-Src transformed cells have constitutively active STAT3 , Src also stimulates other STAT3 independent pathways XREF_BIBR - XREF_BIBR .	While v-Src transformed cells have constitutively active STAT3, Src also stimulates other STAT3 independent pathways XREF_BIBR - XREF_BIBR.	9	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	9	10	13	14
Src mediates activation of STAT3 in the obstructed kidney .	Src mediates activation of STAT3 in the obstructed kidney.	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	4	5
Stat3 is activated by various cytokines and growth factors such as OSM , LIF , IL-6 , IL-10 , IL-17 , IL-23 , leptin , EGF , and interferons , as well as the proto-oncogenes and oncogenes c-Src , c-Abl , Met , and ErbB2 XREF_BIBR .	Stat3 is activated by various cytokines and growth factors such as OSM, LIF, IL-6, IL-10, IL-17, IL-23, leptin, EGF, and interferons, as well as the proto-oncogenes and oncogenes c-Src, c-Abl, Met, and ErbB2 XREF_BIBR.	0	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Stat3	Stat3	Stat3	37	38	0	1
Moreover , activated c-Src has been shown to induce STAT3 activation and lead to a significant increase in the levels of Twist-1 and Twist-2 XREF_BIBR .	Moreover, activated c-Src has been shown to induce STAT3 activation and lead to a significant increase in the levels of Twist-1 and Twist-2 XREF_BIBR.	2	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	3	4	9	10
c-Src , a non receptor protein tyrosine kinase , activates NF-kappaB and STAT3 , which in turn triggers the transcription of anti-apoptosis- and cell cycle related genes .	c-Src, a non receptor protein tyrosine kinase, activates NF-kappaB and STAT3, which in turn triggers the transcription of anti-apoptosis- and cell cycle related genes.	0	20	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	c-Src	c-Src	c-src	STAT3	STAT3, which in turn triggers the transcription	stat3	0	1	12	13
Also , Ras- and Rac1 mediated p38 and JNK signals are required for STAT3 transcriptional activity induced by the Src oncoprotein [ XREF_BIBR ] .	Also, Ras- and Rac1 mediated p38 and JNK signals are required for STAT3 transcriptional activity induced by the Src oncoprotein [XREF_BIBR].	13	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	19	20	13	14
In addition , Stat3 activation by Src induces specific gene regulation and is required for cell transformation [ XREF_BIBR , XREF_BIBR ] .	In addition, Stat3 activation by Src induces specific gene regulation and is required for cell transformation [XREF_BIBR, XREF_BIBR].	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	6	7	3	4
In addition to inhibition of Jak2 , sanguinarine can reduce Src phosphorylation , another kinase that activates Stat3 .	In addition to inhibition of Jak2, sanguinarine can reduce Src phosphorylation, another kinase that activates Stat3.	7	18	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Src	sanguinarine can reduce Src phosphorylation	src	Stat3	Stat3	stat3	10	11	17	18
In response to IFNgamma , SRC family kinases are required to activate STAT3 ( but not STAT1 ) through tyrosine phosphorylation , whereas the receptor bound kinases JAK1 and JAK2 are required to activate both STATs .	In response to IFNgamma, SRC family kinases are required to activate STAT3 (but not STAT1) through tyrosine phosphorylation, whereas the receptor bound kinases JAK1 and JAK2 are required to activate both STATs.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT3	STAT3	STAT3	5	6	12	13
Markedly , 2/3 discovered STAT3 mutations have previously been reported as activating XREF_BIBR , XREF_BIBR , and they localized to exons 20 and 21 encoding the Src homology 2 ( SH2 ) domain mediating the dimerization and activation of STAT3 .	Markedly, 2/3 discovered STAT3 mutations have previously been reported as activating XREF_BIBR, XREF_BIBR, and they localized to exons 20 and 21 encoding the Src homology 2 (SH2) domain mediating the dimerization and activation of STAT3.	26	40	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	26	27	39	40
Depending on cell context , STAT3 can be activated directly by Src family kinases or via Jak1 ( in NIH 3T3 cells ) as an intermediate kinase between Src and STAT3 .	Depending on cell context, STAT3 can be activated directly by Src family kinases or via Jak1 (in NIH 3T3 cells) as an intermediate kinase between Src and STAT3.	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	11	12	5	6
Our results demonstrate that Ras- and Rac1 mediated p38 and JNK signals are required for Stat3 transcriptional activity induced by the Src oncoprotein .	Our results demonstrate that Ras- and Rac1 mediated p38 and JNK signals are required for Stat3 transcriptional activity induced by the Src oncoprotein.	15	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	21	22	15	16
Src family kinases have been found to activate STAT3 and linked to drugs resistance in some cell lines and patient samples [ XREF_BIBR ] .	Src family kinases have been found to activate STAT3 and linked to drugs resistance in some cell lines and patient samples [XREF_BIBR].	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	8	9
Constitutive activation of STAT3 induced by Src and JAK tyrosine kinases participates in growth regulation of tumor cells XREF_BIBR .	Constitutive activation of STAT3 induced by Src and JAK tyrosine kinases participates in growth regulation of tumor cells XREF_BIBR.	1	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	6	7	3	4
In addition , members of the Src kinase family such as Src , Lck , Hck , Lyn , Fyn , or Fgr can activate Stat3 either directly or downstream of an RTK or GPCR XREF_BIBR , XREF_BIBR .	In addition, members of the Src kinase family such as Src, Lck, Hck, Lyn, Fyn, or Fgr can activate Stat3 either directly or downstream of an RTK or GPCR XREF_BIBR, XREF_BIBR.	6	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	6	7	25	26
JNK JAK SRC and c-ABL kinases jointly activate STAT3 signaling in fibroblasts in response to TGFbeta .	JNK JAK SRC and c-ABL kinases jointly activate STAT3 signaling in fibroblasts in response to TGFbeta.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT3	STAT3	STAT3	2	3	8	9
Since both NF-kappaB and STAT3 signalling pathways can be activated by Src kinase , we examined its role in the antiapoptotic response .	Since both NF-kappaB and STAT3 signalling pathways can be activated by Src kinase, we examined its role in the antiapoptotic response.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	11	12	4	5
Debio 0617B has a unique profile targeting key kinases upstream of STAT3 and STAT5 signaling such as JAK , SRC , ABL , and class III/V receptor TKs .	Debio 0617B has a unique profile targeting key kinases upstream of STAT3 and STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs.	11	20	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT3	STAT3	STAT3	19	20	11	12
The activation of STAT3 by Src is well characterized 26 while the role of Yes-1 in STAT3 activation is unknown .	The activation of STAT3 by Src is well characterized 26 while the role of Yes-1 in STAT3 activation is unknown.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	5	6	3	4
Our data in this study document the involvement of Src in alpha 1 -AR induced Stat3 activation in hepatic cells .	Our data in this study document the involvement of Src in alpha 1 -AR induced Stat3 activation in hepatic cells.	7	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	9	10	15	16
Previous studies have shown that STAT3 activation by Src is required for Src mediated transformation .	Previous studies have shown that STAT3 activation by Src is required for Src mediated transformation.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	8	9	5	6
Inhibition of Src in these tumors by GA should down-regulate STAT3 activation and suppress growth .	Inhibition of Src in these tumors by GA should down-regulate STAT3 activation and suppress growth.	0	11	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	2	3	10	11
In addition , Src activates Stat-3 , resulting in a subsequent increase in the transcriptional activation of vascular endothelial growth factor , an important regulator of tumor angiogenesis .	In addition, Src activates Stat-3, resulting in a subsequent increase in the transcriptional activation of vascular endothelial growth factor, an important regulator of tumor angiogenesis.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat-3	Stat-3	Stat-3	3	4	5	6
Perhaps one of the best in vitro model of premalignancy for cancer prevention is STAT3 as suggested by the evidence , first that STAT3 plays a major role in oncogenesis and regarded as an oncogene ; second , STAT3 is activated by an oncogenic Src ; third , STAT3 regulates transformation , inflammation , survival , proliferation and angiogenesis of the tumors through expression of c-myc , COX2 , bcl-xl , survivin , cyclin D1 and VEGF respectively .	Perhaps one of the best in vitro model of premalignancy for cancer prevention is STAT3 as suggested by the evidence, first that STAT3 plays a major role in oncogenesis and regarded as an oncogene; second, STAT3 is activated by an oncogenic Src; third, STAT3 regulates transformation, inflammation, survival, proliferation and angiogenesis of the tumors through expression of c-myc, COX2, bcl-xl, survivin, cyclin D1 and VEGF respectively.	38	45	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	44	45	38	39
Moreover , STAT3 activity can be driven by activation of ERK1/2 , SRC , and FAK , all of which are activated by dLEN .	Moreover, STAT3 activity can be driven by activation of ERK1/2, SRC, and FAK, all of which are activated by dLEN.	2	13	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT3	STAT3	STAT3	12	13	2	3
MTIs inhibit STAT3 phosphorylation and in MTI treated MDA breast cancer cells , where c-Src promotes STAT3 activation , we detected the inhibition of c-Src- and IL-6-mediated STAT3 phosphorylation and activation , effects that were greatly enhanced by RKIP over expression .	MTIs inhibit STAT3 phosphorylation and in MTI treated MDA breast cancer cells, where c-Src promotes STAT3 activation, we detected the inhibition of c-Src- and IL-6-mediated STAT3 phosphorylation and activation, effects that were greatly enhanced by RKIP over expression.	14	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	14	15	16	17
We found that Src dependent activation of Stat3 and MAPK1 ,2 pathways is a key driver of podocyte proliferation in HIVAN [ XREF_BIBR ] ( XREF_FIG ) .	We found that Src dependent activation of Stat3 and MAPK1,2 pathways is a key driver of podocyte proliferation in HIVAN [XREF_BIBR] (XREF_FIG).	3	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	3	4	7	8
All Src transformed cell lines have persistently led to the STAT3 activation , and dominant negative STAT3 abrogates transformation [ XREF_BIBR , XREF_BIBR ] .	All Src transformed cell lines have persistently led to the STAT3 activation, and dominant negative STAT3 abrogates transformation [XREF_BIBR, XREF_BIBR].	0	11	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	1	2	10	11
Both the IL-6/GP130/JAK pathway and SRC kinase mediate the activation of STAT3 .	Both the IL-6/GP130/JAK pathway and SRC kinase mediate the activation of STAT3.	5	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	STAT3	STAT3	STAT3	5	6	11	12
Previous studies show that Src can activate STAT3 and myc and mTOR pathway [ XREF_BIBR , XREF_BIBR ] , herein , we showed that YMGKI-2 treatment also reduced the expression of myc and p-mTOR .	Previous studies show that Src can activate STAT3 and myc and mTOR pathway [XREF_BIBR, XREF_BIBR], herein, we showed that YMGKI-2 treatment also reduced the expression of myc and p-mTOR.	4	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	4	5	7	8
Focal adhesion kinase and STAT3 phophorylation were also decreased by diminished Src activity , leading to significantly reduced cell migration and invasion .	Focal adhesion kinase and STAT3 phophorylation were also decreased by diminished Src activity, leading to significantly reduced cell migration and invasion.	4	12	decreased	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	11	12	4	5
Src can activate STAT3 , STAT5 and other downstream targets in melanoma .	Src can activate STAT3, STAT5 and other downstream targets in melanoma.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	3	4
These findings demonstrate that Src activated Stat3 signaling is important for the growth and survival of melanoma tumor cells .	These findings demonstrate that Src activated Stat3 signaling is important for the growth and survival of melanoma tumor cells.	4	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	4	5	6	7
Src activation by miR-204 promotes STAT3 and NFAT activation in PAH-PASMCs .	Src activation by miR-204 promotes STAT3 and NFAT activation in PAH-PASMCs.	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	5	6
However , overexpression of a non constitutively-active SRC ( NCA Src ) failed to enhance STAT3 rescue function in the shmda-9 GSCs ( XREF_SUPPLEMENTARY ) .	However, overexpression of a non constitutively-active SRC (NCA Src) failed to enhance STAT3 rescue function in the shmda-9 GSCs (XREF_SUPPLEMENTARY).	2	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	overexpression of a non constitutively-active SRC	src	STAT3	STAT3	stat3	7	8	15	16
Finally , the cleaved cytoplasmic tail of PC1 was recently shown to integrate signaling inputs from several pathways resulting in Src dependent activation of STAT3 and the proliferative response in tubular cells .	Finally, the cleaved cytoplasmic tail of PC1 was recently shown to integrate signaling inputs from several pathways resulting in Src dependent activation of STAT3 and the proliferative response in tubular cells.	20	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	20	21	24	25
Studies presented here demonstrate that STAT3 is activated upon VEGF stimulation of EC in vitro and in vivo by a VEGFR2 dependent and Src dependent mechanism and that STAT3 activation mediates Bcl-2 induction by VEGF .	Studies presented here demonstrate that STAT3 is activated upon VEGF stimulation of EC in vitro and in vivo by a VEGFR2 dependent and Src dependent mechanism and that STAT3 activation mediates Bcl-2 induction by VEGF.	5	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	23	24	5	6
This latter effect occurs through Src mediated activation of STAT3 [ XREF_BIBR ] , which leads to increased expression of VEGF and interleukin-8 ( IL-8 ) , both of which are crucial for angiogenesis [ XREF_BIBR ] .	This latter effect occurs through Src mediated activation of STAT3 [XREF_BIBR], which leads to increased expression of VEGF and interleukin-8 (IL-8), both of which are crucial for angiogenesis [XREF_BIBR].	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	5	6	9	10
Pharmacological inhibition of JNK blocked Src and CB1R activation of Stat3 , indicating that Rac and JNK are also involved in CB1R mediated neurite outgrowth .	Pharmacological inhibition of JNK blocked Src and CB1R activation of Stat3, indicating that Rac and JNK are also involved in CB1R mediated neurite outgrowth.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	5	6	10	11
Furthermore , Src has been shown to promote STAT3 activation and JNK XREF_BIBR XREF_BIBR XREF_BIBR .	Furthermore, Src has been shown to promote STAT3 activation and JNK XREF_BIBR XREF_BIBR XREF_BIBR.	2	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	2	3	8	9
Src and JAK family tyrosine kinases cooperate to mediate constitutive STAT3 activation in the absence of EGF induced stimulation in model human BC cell lines .	Src and JAK family tyrosine kinases cooperate to mediate constitutive STAT3 activation in the absence of EGF induced stimulation in model human BC cell lines.	0	11	mediate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	10	11
Src kinases channel signals through the conventional Ras/Raf/ERK and PI3K/Akt/mTOR pathways , but also selectively activate Stat3 , c-myc and beta-catenin .	Src kinases channel signals through the conventional Ras/Raf/ERK and PI3K/Akt/mTOR pathways, but also selectively activate Stat3, c-myc and beta-catenin.	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	0	1	16	17
In the absence of PC1-p30 , cAMP dampened EGFR- or IL-6-dependent activation of STAT3 ; in the presence of PC1-p30 , cAMP amplified Src dependent activation of STAT3 .	In the absence of PC1-p30, cAMP dampened EGFR- or IL-6-dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src dependent activation of STAT3.	23	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	23	24	27	28
We also examined other STAT3 activators such as Src , and did not found significant difference of Src expression in MIA PaCa-2 and ASPC-1 cells with ZIP4 overexpression or knockdown ( data not shown ) , indicating that ZIP4 activates STAT3 maybe independent of Src pathway in pancreatic cancer .	We also examined other STAT3 activators such as Src, and did not found significant difference of Src expression in MIA PaCa-2 and ASPC-1 cells with ZIP4 overexpression or knockdown (data not shown), indicating that ZIP4 activates STAT3 maybe independent of Src pathway in pancreatic cancer.	4	9	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	8	9	4	5
Src mediated STAT3 activation is also required for the cardioprotective effect of Ucn , since a Src inhibitor , and a dominant negative form of STAT3 block Ucn mediated cardioprotection .	Src mediated STAT3 activation is also required for the cardioprotective effect of Ucn, since a Src inhibitor, and a dominant negative form of STAT3 block Ucn mediated cardioprotection.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	2	3
These results suggest that PC1 , via its cleaved cytoplasmic tail , integrates signaling inputs from EGFR and cAMP , resulting in Src dependent activation of STAT3 and a proliferative response .	These results suggest that PC1, via its cleaved cytoplasmic tail, integrates signaling inputs from EGFR and cAMP, resulting in Src dependent activation of STAT3 and a proliferative response.	22	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	22	23	26	27
XREF_BIBR Thus , Src mediated STAT3 activation in EC follows a pathway established in other cell types for involving STAT3 signaling during cellular activation .	XREF_BIBR Thus, Src mediated STAT3 activation in EC follows a pathway established in other cell types for involving STAT3 signaling during cellular activation.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	3	4	5	6
Intriguingly , in NIH3T3 cells , Galpha i2 mediates the Src activation of STAT3 , and this may promote the expression of cyclin D1 .	Intriguingly, in NIH3T3 cells, Galpha i2 mediates the Src activation of STAT3, and this may promote the expression of cyclin D1.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	10	11	13	14
STAT3 activation by Src kinases occurred directly at the tyr705 residue and indirectly at the ser727 residue via JNK MAPKs .	STAT3 activation by Src kinases occurred directly at the tyr705 residue and indirectly at the ser727 residue via JNK MAPKs.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	3	4	0	1
They developed the signaling model shown in XREF_FIG where decreased miR-204 increases SHP2 , which by activating Src increases Stat3 activation .	They developed the signaling model shown in XREF_FIG where decreased miR-204 increases SHP2, which by activating Src increases Stat3 activation.	17	20	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat3	Stat3	Stat3	17	18	19	20
CD24 is well known as the regulator of Src activity and Src induced STAT3 and FAK activity [ XREF_BIBR , XREF_BIBR ] .	CD24 is well known as the regulator of Src activity and Src induced STAT3 and FAK activity [XREF_BIBR, XREF_BIBR].	6	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT3	STAT3	STAT3	11	12	13	14
Notably , PKCdelta enhanced Tyr418 phosphorylation of the non receptor tyrosine kinase SRC , which in turn activated STAT3 and subsequent NOTCH2 signaling , ultimately leading to GBM cell invasiveness .	Notably, PKCdelta enhanced Tyr418 phosphorylation of the non receptor tyrosine kinase SRC, which in turn activated STAT3 and subsequent NOTCH2 signaling, ultimately leading to GBM cell invasiveness.	2	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	PKCdelta enhanced Tyr418 phosphorylation of the non receptor tyrosine kinase SRC	src	STAT3	STAT3	stat3	12	13	18	19
Src mediated activation of FAK also enhances BAD phosphorylation by Akt and inhibition of caspases ( 2 , 3 , 8 and 9 ) , thereby suppressing anoikis [ XREF_BIBR ] .	Src mediated activation of FAK also enhances BAD phosphorylation by Akt and inhibition of caspases (2, 3, 8 and 9), thereby suppressing anoikis [XREF_BIBR].	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	0	1	4	5
Treatment with the selective Src family kinase inhibitor pyrazolopyrimidine 2 did not prevent CS induced FAK-Tyr-397 phosphorylation suggesting a Src independent activation of FAK .	Treatment with the selective Src family kinase inhibitor pyrazolopyrimidine 2 did not prevent CS induced FAK-Tyr-397 phosphorylation suggesting a Src independent activation of FAK.	19	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	19	20	23	24
The present studies , demonstrating that HMGB1 diminishes the phagocytic activity of macrophages and other cells through interactions with Src that then affect FAK activation , suggests that therapeutic approaches directed at inhibiting interactions between Src and HMGB1 or at directly activating FAK , and thereby bypassing the ability of HMGB1 to prevent Src mediated activation of FAK , may have beneficial effects in infection and inflammation .	The present studies, demonstrating that HMGB1 diminishes the phagocytic activity of macrophages and other cells through interactions with Src that then affect FAK activation, suggests that therapeutic approaches directed at inhibiting interactions between Src and HMGB1 or at directly activating FAK, and thereby bypassing the ability of HMGB1 to prevent Src mediated activation of FAK, may have beneficial effects in infection and inflammation.	53	58	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	53	54	57	58
Specifically , activation of Src plus JNK or Src plus vav drives oxLDL uptake 33 ; simultaneous activation of Src , ROS and FAK promotes macrophage spreading 12 ; CD36 participates in the activation of NF-kappaB and NLRP3 inflammasome as well as in the production of proinflammatory cytokines 54 .	Specifically, activation of Src plus JNK or Src plus vav drives oxLDL uptake 33; simultaneous activation of Src, ROS and FAK promotes macrophage spreading 12; CD36 participates in the activation of NF-kappaB and NLRP3 inflammasome as well as in the production of proinflammatory cytokines 54.	8	24	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	8	9	23	24
In colon cancer cells , overexpression of constitutively activated Src stimulates integrin and FAK signalling , which results in lamellipodial ruffling through ERK/MLCK/myosin pathways XREF_BIBR .	In colon cancer cells, overexpression of constitutively activated Src stimulates integrin and FAK signalling, which results in lamellipodial ruffling through ERK/MLCK/myosin pathways XREF_BIBR.	5	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	overexpression of constitutively activated Src	src	FAK	FAK	fak	9	10	13	14
We also found that FAK activation is induced by Src in IL-6 and sIL-6R-stimulated SV-LECs [ XREF_BIBR ] .	We also found that FAK activation is induced by Src in IL-6 and sIL-6R-stimulated SV-LECs [XREF_BIBR].	4	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	9	10	4	5
Activated FAK can subsequently phosphorylate other FAK tyrosine residues and associated Src homology 2 domain containing proteins , such as Src and the p85 subunit of phosphatidylinositol 3-kinase ( PI3K ) .	Activated FAK can subsequently phosphorylate other FAK tyrosine residues and associated Src homology 2 domain containing proteins, such as Src and the p85 subunit of phosphatidylinositol 3-kinase (PI3K).	0	15	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	phosphorylate other FAK tyrosine residues and associated Src homology 2 domain	src	FAK	FAK	fak	11	12	1	2
Src family kinases also modulate the activity of other kinases , in particular Tec family members as well as FAK and Pyk2 .	Src family kinases also modulate the activity of other kinases, in particular Tec family members as well as FAK and Pyk2.	0	21	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	0	1	19	20
It was mentioned ( see above ) that , in SCs , Src is directly activated by ALLO through a GABA-A dependent mechanism , involving the modulation of FAK ( Melfi et al ., 2017 ) .	It was mentioned (see above) that, in SCs, Src is directly activated by ALLO through a GABA-A dependent mechanism, involving the modulation of FAK (Melfi et al., 2017).	12	30	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	12	13	28	29
These findings together suggest that Src mediated FAK activation may occur upstream of ERK1/2 and p38MAPK signaling cascades in SV-LECs after IL-6 and sIL-6R exposure .	These findings together suggest that Src mediated FAK activation may occur upstream of ERK1/2 and p38MAPK signaling cascades in SV-LECs after IL-6 and sIL-6R exposure.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	5	6	7	8
The pathway leading from FAK and ERK activation to the stimulation of proliferation involves Src , which modulates FAK , although a Src independent FAK dependent pathway also exists [ XREF_BIBR ] .	The pathway leading from FAK and ERK activation to the stimulation of proliferation involves Src, which modulates FAK, although a Src independent FAK dependent pathway also exists [XREF_BIBR].	13	28	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	14	15	18	19
The activated Src induced FAK pathway facilitates TGF-beta1-mediated EMT by diverse mechanisms required for migration and invasion in different cell types .	The activated Src induced FAK pathway facilitates TGF-beta1-mediated EMT by diverse mechanisms required for migration and invasion in different cell types.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	2	3	4	5
TGFbeta , in fact , induces a Src dependent activation of FAK which has been demonstrated to be necessary for ( i ) transcriptional up-regulation of mesenchymal and invasiveness markers and ( ii ) delocalization of membrane bound E-cadherin .	TGFbeta, in fact, induces a Src dependent activation of FAK which has been demonstrated to be necessary for (i) transcriptional up-regulation of mesenchymal and invasiveness markers and (ii) delocalization of membrane bound E-cadherin.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	7	8	11	12
Moreover , in a model of oxidative stress induced disruption of tight junctions in Caco-2 monolayers , FAK activation is mediated by Src and PI3K .	Moreover, in a model of oxidative stress induced disruption of tight junctions in Caco-2 monolayers, FAK activation is mediated by Src and PI3K.	17	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	22	23	17	18
Furthermore , Src shRNA induced FAK pTyr 925 decrease was not related with an increase in neuronal cell death ( XREF_SUPPLEMENTARY ) .	Furthermore, Src shRNA induced FAK pTyr 925 decrease was not related with an increase in neuronal cell death (XREF_SUPPLEMENTARY).	2	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	2	3	5	6
Src is an important mediator of FAK regulated invasive and migratory activity of bladder cancer cells .	Src is an important mediator of FAK regulated invasive and migratory activity of bladder cancer cells.	0	7	is an important mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	0	1	6	7
Fak activity in ILC cells strongly correlated with c-Src activity , suggesting that c-Src is a main activator of Fak in LBC .	Fak activity in ILC cells strongly correlated with c-Src activity, suggesting that c-Src is a main activator of Fak in LBC.	13	21	is a main activator	Positive_activation_copula_1	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Fak	Fak	Fak	13	14	19	20
Src interacts with and activates FAK [ XREF_BIBR , XREF_BIBR ] .	Src interacts with and activates FAK [XREF_BIBR, XREF_BIBR].	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	0	1	5	6
These data suggest that SRC induced effects may involve FAK and that inhibition of SRC and FAK signaling may be effective in inhibiting tumor growth .	These data suggest that SRC induced effects may involve FAK and that inhibition of SRC and FAK signaling may be effective in inhibiting tumor growth.	4	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	FAK	FAK	FAK	4	5	9	10
Inhibition of Gi/Go proteins , LOX and Src activity prevent FAK activation and cell migration .	Inhibition of Gi/Go proteins, LOX and Src activity prevent FAK activation and cell migration.	7	11	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	7	8	10	11
Through inhibiting Src , AZD0530 prevents the Src specific activation of FAK , AR and possibly Etk and effectively blocks tumor metastasis in our GRP autocrine model .	Through inhibiting Src, AZD0530 prevents the Src specific activation of FAK, AR and possibly Etk and effectively blocks tumor metastasis in our GRP autocrine model.	7	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	7	8	11	12
Upon phosphorylation by integrins , Src associates and activates FAK to regulate several actin related processes , including phosphorylation of key substrates such as paxillin and cortactin XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Upon phosphorylation by integrins, Src associates and activates FAK to regulate several actin related processes, including phosphorylation of key substrates such as paxillin and cortactin XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	5	6	9	10
In addition , Src kinase inhibition also resulted in impaired FAK activation confirming that phosphorylation of FAK in Atgl-/- macrophages occurs in a Src kinase dependent manner .	In addition, Src kinase inhibition also resulted in impaired FAK activation confirming that phosphorylation of FAK in Atgl-/- macrophages occurs in a Src kinase dependent manner.	3	12	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	3	4	10	11
Taken together , our study suggests that Src promotes Tks-5 and ROS dependent invadopodia activity downstream of FAK in melanoma cells .	Taken together, our study suggests that Src promotes Tks-5 and ROS-dependent invadopodia activity downstream of FAK in melanoma cells.	7	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	7	8	17	18
We note that FAK can be activated in vitro by the sole action of PIP 2 and Src , i.e. in the absence of tensile forces acting on membrane bound FAK at FAs in stretched cells .	We note that FAK can be activated in vitro by the sole action of PIP 2 and Src, i.e. in the absence of tensile forces acting on membrane bound FAK at FAs in stretched cells.	3	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	17	18	3	4
Recombinant FAK was treated with recombinant Src in the presence of ATP .	Recombinant FAK was treated with recombinant Src in the presence of ATP.	0	9	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	6	7	1	2
Src is an important mediator of FAK regulated migratory and invasive activity .	Src is an important mediator of FAK regulated migratory and invasive activity.	0	7	is an important mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	0	1	6	7
Src kinase activity has been reported to mediate multiple mechanisms of trastuzumab resistance , and ultimately activates FAK and PI3K and mTOR signaling .	Src kinase activity has been reported to mediate multiple mechanisms of trastuzumab resistance, and ultimately activates FAK and PI3K and mTOR signaling.	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	0	1	17	18
Following this initial event Src further phosphorylates FAK on multiple other sites including Tyr 576 and Tyr 577 in the activation loop , which promotes optimal FAK activity .	Following this initial event Src further phosphorylates FAK on multiple other sites including Tyr 576 and Tyr 577 in the activation loop, which promotes optimal FAK activity.	0	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src further phosphorylates FAK on multiple other sites including Tyr 576 and Tyr 577	src	FAK	FAK	fak	4	5	26	27
It has been shown that Src can also modulate FAK .	It has been shown that Src can also modulate FAK.	5	10	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	5	6	9	10
Fully activated SRC can then further activate FAK by phosphorylation of its C-terminal domain ( Y861 and Y925 ) and catalytic domain ( Y576 and Y577 ) XREF_BIBR .	Fully activated SRC can then further activate FAK by phosphorylation of its C-terminal domain (Y861 and Y925) and catalytic domain (Y576 and Y577) XREF_BIBR.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	FAK	FAK	FAK	2	3	7	8
Therefore , to further characterize the mechanism of the Src mediated FAK and alphavbeta5 interaction , in vitro binding studies were performed using NH 2 - or COOH-terminal domains of FAK and various full-length or truncated fusion proteins of beta5 and beta3 cytoplasmic tails .	Therefore, to further characterize the mechanism of the Src mediated FAK and alphavbeta5 interaction, in vitro binding studies were performed using NH 2 - or COOH-terminal domains of FAK and various full-length or truncated fusion proteins of beta5 and beta3 cytoplasmic tails.	6	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	9	10	11	12
Based on studies in non immune cells , it is also clear that Src family kinases directly modulate the activity of FAK and Pyk2 kinases ( XREF_FIG ) .	Based on studies in non immune cells, it is also clear that Src family kinases directly modulate the activity of FAK and Pyk2 kinases (XREF_FIG).	13	24	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	13	14	21	22
CB 1 -stimulated FAK 397 Tyr P was reduced by Src inhibition in N18TG2 cells which is in accordance with other studies using neuronal cells that demonstrated Src catalyzes FAK phosphorylation [ XREF_BIBR ] .	CB 1 -stimulated FAK 397 Tyr P was reduced by Src inhibition in N18TG2 cells which is in accordance with other studies using neuronal cells that demonstrated Src catalyzes FAK phosphorylation [XREF_BIBR].	3	11	reduced	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	10	11	3	4
Tyr 397 autophosphorylation is an important step for promoting the biological function of FAK , and Tyr 576 and -577 phosphorylation by Src increases FAK activity .	Tyr 397 autophosphorylation is an important step for promoting the biological function of FAK, and Tyr 576 and -577 phosphorylation by Src increases FAK activity.	8	25	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	22	23	24	25
It has been well documented in humans and mice that FAK and Src function mutually in integrin mediated signaling : autophosphorylation of FAK at Tyr 397 , which is stimulated by integrin , enables FAK to bind to the SH2 domain of Src , thereby resulting in the phosphorylation of Src at Tyr 416 .	It has been well documented in humans and mice that FAK and Src function mutually in integrin mediated signaling : autophosphorylation of FAK at Tyr 397, which is stimulated by integrin, enables FAK to bind to the SH2 domain of Src, thereby resulting in the phosphorylation of Src at Tyr 416.	12	36	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	12	13	34	35
Although the total level of Src induced cellular phosphorylation was similar in FAK +/+ and FAK-/- backgrounds , the phosphorylation of some substrates was influenced by FAK depending on adherence state .	Although the total level of Src induced cellular phosphorylation was similar in FAK +/+ and FAK-/- backgrounds, the phosphorylation of some substrates was influenced by FAK depending on adherence state.	3	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	level of Src	src	FAK-/-	FAK-/-	fak-/-	5	6	15	16
In the present study we show that while there is no change in the total levels of Src or FAK phosphorylation in the absence of NEDD9 , phosphorylation of the Src and FAK substrate paxillin is increased at focal adhesions , suggesting small increases in localized Src or FAK activity specifically at focal adhesion in these cells .	In the present study we show that while there is no change in the total levels of Src or FAK phosphorylation in the absence of NEDD9, phosphorylation of the Src and FAK substrate paxillin is increased at focal adhesions, suggesting small increases in localized Src or FAK activity specifically at focal adhesion in these cells.	27	49	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	phosphorylation of the Src	src	FAK	FAK	fak	30	31	48	49
These findings collectively indicate that decidual c-Src may activate signaling pathway ( s ) different from the integrin mediated signaling cascade involving FAK and paxillin .	These findings collectively indicate that decidual c-Src may activate signaling pathway (s) different from the integrin mediated signaling cascade involving FAK and paxillin.	5	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	FAK	FAK	FAK	6	7	22	23
Src mediates FAK Pi-Tyr861 , an indicator of FAK activation [ XREF_BIBR ] .	Src mediates FAK Pi-Tyr861, an indicator of FAK activation [XREF_BIBR].	0	3	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	0	1	2	3
E-cadherin relaxation and beta-catenin translocation require Src activation of FAK .	E-cadherin relaxation and beta-catenin translocation require Src activation of FAK.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	6	7	9	10
We hypothesized that if c-Src is involved in TIMP-2 growth-stimulatory activity , then FAK should be activated by c-Src .	We hypothesized that if c-Src is involved in TIMP-2 growth-stimulatory activity, then FAK should be activated by c-Src.	12	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	FAK	FAK	FAK	18	19	13	14
We have previously demonstrated that chemokine binding to the viral chemokine receptor pUS28 causes SMC migration via a Src mediated activation of FAK and ERK [ XREF_BIBR ] , and the Galpha12 mediated activation of RhoA and ROCK [ XREF_BIBR ] .	We have previously demonstrated that chemokine binding to the viral chemokine receptor pUS28 causes SMC migration via a Src mediated activation of FAK and ERK [XREF_BIBR], and the Galpha12 mediated activation of RhoA and ROCK [XREF_BIBR].	18	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	18	19	22	23
As shown in XREF_FIG , Kp-10 decreased VEGF induced phosphorylation of c-Src at Y416 and inhibited c-Src-mediated phosphoryaltion of FAK at Y576/577 while Kp-10 has little effect on FAK autophosphorylation at Y397 ( XREF_FIG ) .	As shown in XREF_FIG, Kp-10 decreased VEGF induced phosphorylation of c-Src at Y416 and inhibited c-Src-mediated phosphoryaltion of FAK at Y576/577 while Kp-10 has little effect on FAK autophosphorylation at Y397 (XREF_FIG).	5	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	Kp-10 decreased VEGF induced phosphorylation of c-Src at Y416	c-src	FAK	FAK	fak	11	12	19	20
Immunoprecipitation analysis showed lowered signaling of FAK mediated by p130CAS and Src in pMMP-9- and FAKsh treated glioma cells compared to control and pSV cells ( XREF_FIG ) .	Immunoprecipitation analysis showed lowered signaling of FAK mediated by p130CAS and Src in pMMP-9- and FAKsh treated glioma cells compared to control and pSV cells (XREF_FIG).	4	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	11	12	6	7
Src can mediate FAK related migration by further phosphorylation of paxillin or p130Cas , which may result in focal adhesion turnover and/or lamellipodia and filipodia formation via either the RAC , JNK pathway , or the RhoGAP pathway .	Src can mediate FAK related migration by further phosphorylation of paxillin or p130Cas, which may result in focal adhesion turnover and/or lamellipodia and filipodia formation via either the RAC, JNK pathway, or the RhoGAP pathway.	0	5	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	0	1	3	4
Thus , c-Src or FAK inhibitions mutually prevent VEGF initiated adherens junction localization of active c-Src and FAK .	Thus, c-Src or FAK inhibitions mutually prevent VEGF initiated adherens junction localization of active c-Src and FAK.	2	18	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	FAK	FAK	FAK	2	3	17	18
Moreover , SKLB-329 could efficiently restrain the proliferation of HCC cells through down-regulation of Src mediated FAK and Stat3 activity .	Moreover, SKLB-329 could efficiently restrain the proliferation of HCC cells through down-regulation of Src mediated FAK and Stat3 activity.	12	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	14	15	16	17
PDGF mediated migration in SMC is characterized by Src dependent activation of FAK , RhoA mediated activation of ROCK and subsequent phosphorylation and inhibition of myosin light chain phosphatase as well as activation of various other effector molecules via ERK , p38MAPK and JNK MAPK families [ XREF_BIBR ] .	PDGF mediated migration in SMC is characterized by Src dependent activation of FAK, RhoA mediated activation of ROCK and subsequent phosphorylation and inhibition of myosin light chain phosphatase as well as activation of various other effector molecules via ERK, p38MAPK and JNK MAPK families [XREF_BIBR].	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	8	9	12	13
The oncogenic properties of PTPRA are mediated by its direct dephosphorylation of the SRC kinase on Y527 , which increases FAK activity and consequently cell migration XREF_BIBR .	The oncogenic properties of PTPRA are mediated by its direct dephosphorylation of the SRC kinase on Y527, which increases FAK activity and consequently cell migration XREF_BIBR.	10	21	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	dephosphorylation of the SRC kinase on Y527	src	FAK	FAK	fak	13	14	20	21
Also , Src dependent activation of FAK and Pyk2 is affected by CBD wt expression or lack of RhoC .	Also, Src dependent activation of FAK and Pyk2 is affected by CBD wt expression or lack of RhoC.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	2	3	6	7
Src activation leads FAK activation following the initiation of FA assembly .	Src activation leads FAK activation following the initiation of FA assembly.	0	4	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	0	1	3	4
Attenuation of Src suppressed PGN-, polyI : C-, and CpG elicited movement and the level of FAK Pi-Tyr861 , which could be reversed by the reintroduction of siRNA resistant Src .	Attenuation of Src suppressed PGN-, polyI : C-, and CpG elicited movement and the level of FAK Pi-Tyr861, which could be reversed by the reintroduction of siRNA resistant Src.	16	30	reversed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	29	30	16	17
Because FAK was reactivated by RTKs independently of both FAK and SRC activity , we hypothesized that RTKs were directly binding to FAK to promote phosphorylation .	Because FAK was reactivated by RTKs independently of both FAK and SRC activity, we hypothesized that RTKs were directly binding to FAK to promote phosphorylation.	1	12	reactivated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	FAK	FAK	FAK	11	12	1	2
In addition , EGFR1 and Src signaling modulates the FAK and integrin signaling pathway to enhance proliferation , migration , and invasion both in vitro and in vivo [ XREF_BIBR ] by inducing E-Cadherin internalization [ XREF_BIBR ] .	In addition, EGFR1 and Src signaling modulates the FAK and integrin signaling pathway to enhance proliferation, migration, and invasion both in vitro and in vivo [XREF_BIBR] by inducing E-Cadherin internalization [XREF_BIBR].	3	15	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	5	6	9	10
By contrast , mechanisms that limit RhoA activity during rosette formation include Src mediated activation of FAK and ERK5 , and possibly through p190RhoGAP .	By contrast, mechanisms that limit RhoA activity during rosette formation include Src mediated activation of FAK and ERK5, and possibly through p190RhoGAP.	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	12	13	16	17
Therefore , it appears that the spatio-temporal changes in the levels of polyamines regulate the turn over of Src mediated FAK activity and , thereby , migration .	Therefore, it appears that the spatio-temporal changes in the levels of polyamines regulate the turn over of Src mediated FAK activity and, thereby, migration.	13	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	18	19	20	21
Indeed , it was demonstrated that Src is directly activated by allopregnanolone ( ALLO ) through a GABA-A dependent mechanism , involving the modulation of FAK ( XREF_FIG ) .	Indeed, it was demonstrated that Src is directly activated by allopregnanolone (ALLO) through a GABA-A dependent mechanism, involving the modulation of FAK (XREF_FIG).	6	27	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	6	7	25	26
Collectively , our results suggest that mSH3BGRL promotes metastasis through activation of the c-Src activation of FAK and downstream oncogenic Ras and MAPK and AKT pathways .	Collectively, our results suggest that mSH3BGRL promotes metastasis through activation of the c-Src activation of FAK and downstream oncogenic Ras and MAPK and AKT pathways.	13	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	FAK	FAK	FAK	13	14	16	17
Indeed , Src attenuation hampers LPS evoked phagocytosis and FAK Pi-Tyr861 , which can be rescued by ectopic Src .	Indeed, Src attenuation hampers LPS evoked phagocytosis and FAK Pi-Tyr861, which can be rescued by ectopic Src.	7	19	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	18	19	9	10
Upon recruitment at Y397 , Src phosphorylates multiple tyrosine residues and fully activates FAK and thereby , downstream signaling [ XREF_BIBR ] .	Upon recruitment at Y397, Src phosphorylates multiple tyrosine residues and fully activates FAK and thereby, downstream signaling [XREF_BIBR].	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	5	6	13	14
Epidermal growth factor ( EGF ) is another growth factor that activates FAK , as well as Src [ XREF_BIBR ] .	Epidermal growth factor (EGF) is another growth factor that activates FAK, as well as Src [XREF_BIBR].	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	17	18	12	13
Interestingly , attenuation of Eps8 decreases Src Pi-Tyr-416 , Shc Pi-Tyr-317 , and serum induced FAK Pi-Tyr-397 and Pi-Tyr-861 .	Interestingly, attenuation of Eps8 decreases Src Pi-Tyr-416, Shc Pi-Tyr-317, and serum induced FAK Pi-Tyr-397 and Pi-Tyr-861.	6	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	6	7	15	16
Indeed , our results show that radiation induced activation of FAK by phosphorylating tyrosine residue at 397 Src at Y416 and Paxillin at Y118 .	Indeed, our results show that radiation induced activation of FAK by phosphorylating tyrosine residue at 397 Src at Y416 and Paxillin at Y118.	8	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	phosphorylating tyrosine residue at 397 Src	src	FAK	FAK	fak	17	18	10	11
XREF_BIBR Phosphorylation of Y397 results in subsequent recruitment of the tyrosine kinase Src ( and/or Fyn ) , which phosphorylates and further activates FAK ( and phosphorylates certain FAK binding partners ) .	XREF_BIBR Phosphorylation of Y397 results in subsequent recruitment of the tyrosine kinase Src (and/or Fyn), which phosphorylates and further activates FAK (and phosphorylates certain FAK binding partners).	7	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	12	13	23	24
Furthermore , LPS mediated Src induction led to increased FAK Pi-Tyr-397 and Pi-Tyr-861 , which was also iNOS dependent .	Furthermore, LPS mediated Src induction led to increased FAK Pi-Tyr-397 and Pi-Tyr-861, which was also iNOS dependent.	2	12	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Src	LPS mediated Src	src	FAK	FAK	fak	4	5	9	10
In this paper , we show that in hepatocytes TGFbeta induces a Src dependent activation of the focal adhesion protein FAK .	In this paper, we show that in hepatocytes TGFbeta induces a Src dependent activation of the focal adhesion protein FAK.	12	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	12	13	20	21
Inhibition of Src with specific inhibitor ( PP2 , 10 (-8) M ) blocked hypoxia induced FAK activation .	Inhibition of Src with specific inhibitor (PP2, 10 (-8) M) blocked hypoxia induced FAK activation.	0	17	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	2	3	16	17
The stimulatory effect of these protein tyrosine phosphatases on Src activity is opposed by the cytoplasmic protein tyrosine kinase C-terminal Src kinase ( Csk ) that catalyzes the phosphorylation of Src Tyr 527 to inhibit Src mediated FAK Tyr P [ XREF_BIBR ] .	The stimulatory effect of these protein tyrosine phosphatases on Src activity is opposed by the cytoplasmic protein tyrosine kinase C-terminal Src kinase (Csk) that catalyzes the phosphorylation of Src Tyr 527 to inhibit Src mediated FAK Tyr P [XREF_BIBR].	34	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	35	36	37	38
Expression of an activated FAK mutant in the absence of Src family kinases partially restores PKL localization , suggesting that Src activation of FAK is required for PKL phosphorylation and localization .	Expression of an activated FAK mutant in the absence of Src family kinases partially restores PKL localization, suggesting that Src activation of FAK is required for PKL phosphorylation and localization.	20	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	20	21	23	24
For example , Src and PKC can activate FAK , and FAK in turn activates Src and PKC .	For example, Src and PKC can activate FAK, and FAK in turn activates Src and PKC.	3	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	3	4	8	9
Inhibition of Src activity using the Src and Abl inhibitor AZD0530 reduced FAK activity , suppressed cell spreading on matrix coated surfaces and significantly inhibited cell migration .	Inhibition of Src activity using the Src and Abl inhibitor AZD0530 reduced FAK activity, suppressed cell spreading on matrix coated surfaces and significantly inhibited cell migration.	2	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	2	3	12	13
Although the gross level of Src induced tyrosine phosphorylation is similar in the presence or absence of FAK , there are a small number of substrates whose relative phosphorylation level is either increased or decreased by FAK .	Although the gross level of Src induced tyrosine phosphorylation is similar in the presence or absence of FAK, there are a small number of substrates whose relative phosphorylation level is either increased or decreased by FAK.	3	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	level of Src	src	FAK	FAK	fak	5	6	17	18
As such , we propose a regulatory network within individual FA sites where Src activation leads a full-scale FAK activation after both Src and FAK are recruited during FA assembly .	As such, we propose a regulatory network within individual FA sites where Src activation leads a full-scale FAK activation after both Src and FAK are recruited during FA assembly.	13	19	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	13	14	18	19
Inhibition of Src by PP-2 abolished the TUDC induced activation of p38 ( MAPK ) but not of FAK and ERKs .	Inhibition of Src by PP-2 abolished the TUDC induced activation of p38 (MAPK) but not of FAK and ERKs.	0	20	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	2	3	18	19
Src interacts via its SH3 domain with integrin beta 3 to activate FAK signaling to promote tumor growth leading to cytoskeleton driven morphological changes .	Src interacts via its SH3 domain with integrin beta 3 to activate FAK signaling to promote tumor growth leading to cytoskeleton driven morphological changes.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	0	1	12	13
In several cell types , FAK directly recruits Src to the focal adhesion sites where Src potentiates activation of FAK through phosphorylation of additional tyrosine residues .	In several cell types, FAK directly recruits Src to the focal adhesion sites where Src potentiates activation of FAK through phosphorylation of additional tyrosine residues.	15	20	potentiates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	15	16	19	20
XREF_BIBR Src can activate FAK via phosphorylation of Tyr397 leading to autophosphorylation of other tyrosine residues .	XREF_BIBR Src can activate FAK via phosphorylation of Tyr397 leading to autophosphorylation of other tyrosine residues.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	1	2	4	5
Consistent with the in vitro results ( XREF_FIG ) , the expression of wild-type Src ( Src WT ) caused no significant FRET change of the FAK biosensor in FAK -/- cells .	Consistent with the in vitro results (XREF_FIG), the expression of wild-type Src (Src WT) caused no significant FRET change of the FAK biosensor in FAK -/- cells.	16	27	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	16	17	26	27
Activated FAK recruits c-Src at FA sites to form a FAK-Src signaling complex .	Activated FAK recruits c-Src at FA sites to form a FAK-Src signaling complex.	0	6	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	FAK	FAK	FAK	3	4	1	2
In addition to this , we show for the first time that Exo from PrCa cells are enriched in c-Src , Src pY416 , IGF-IR , GRK5 and GRK6 and additionally express FAK and the specific Src target FAK pY861 .	In addition to this, we show for the first time that Exo from PrCa cells are enriched in c-Src, Src pY416, IGF-IR, GRK5 and GRK6 and additionally express FAK and the specific Src target FAK pY861.	36	39	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	36	37	38	39
Although the in vitro findings provide an important insight into the molecular basis of Src mediated FAK and alphavbeta5 interactions in the VEGF pathway , the functional requirement for integrin alphavbeta5 in a VEGF mediated vascular response remained unknown .	Although the in vitro findings provide an important insight into the molecular basis of Src mediated FAK and alphavbeta5 interactions in the VEGF pathway, the functional requirement for integrin alphavbeta5 in a VEGF mediated vascular response remained unknown.	12	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	14	15	16	17
We recently found that FAK is recruited into focal adhesion ( FA ) sites through interactions with XIAP ( X-chromosome linked inhibitor of apoptosis protein ) and activated by Src kinase in response to shear stress .	We recently found that FAK is recruited into focal adhesion (FA) sites through interactions with XIAP (X-chromosome linked inhibitor of apoptosis protein) and activated by Src kinase in response to shear stress.	4	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	29	30	4	5
Src phosphorylation at Y576 and Y577 fully activates FAK .	Src phosphorylation at Y576 and Y577 fully activates FAK.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src phosphorylation at Y576	src	FAK	FAK	fak	0	1	8	9
A recent report also suggests that ribosome protein S6 kinase ( S6K1 ) and its upstream regulator mTOR play a role in stimulating Src dependent activation of Rac1 through association with the Rac1-GEF Tiam1 [ XREF_BIBR ] .	A recent report also suggests that ribosome protein S6 kinase (S6K1) and its upstream regulator mTOR play a role in stimulating Src dependent activation of Rac1 through association with the Rac1-GEF Tiam1 [XREF_BIBR].	23	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	23	24	27	28
Furthermore , the expression of mitochondrial SOD in fibrosarcoma cells increases the levels of MMP-1 and the incidence of experimental pulmonary metastasis [ XREF_BIBR ] , a n d t h e secretion and activation of MMP2 downstream of EGF signaling in pancreatic cancer cells is dependent on NADPH generated ROS mediated by PI3K- and Src dependent activation of Rac1 [ XREF_BIBR ] .	Furthermore, the expression of mitochondrial SOD in fibrosarcoma cells increases the levels of MMP-1 and the incidence of experimental pulmonary metastasis [XREF_BIBR], a n d t h e secretion and activation of MMP2 downstream of EGF signaling in pancreatic cancer cells is dependent on NADPH generated ROS mediated by PI3K- and Src dependent activation of Rac1 [XREF_BIBR].	53	61	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	55	56	59	60
In this study , we examined whether Rac can be directly activated by stress independent of Src .	In this study, we examined whether Rac can be directly activated by stress independent of Src.	7	17	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac	Rac	Rac	16	17	7	8
M-CSF signaling via Src up-regulated Rac1 activity but down-regulated Rho activity .	M-CSF signaling via Src up-regulated Rac1 activity but down-regulated Rho activity.	1	6	up-regulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	3	4	5	6
On the other hand , Rac1 may be activated in adhesion sites through Src and PI3K , which activate Rac1 GEFS .	On the other hand, Rac1 may be activated in adhesion sites through Src and PI3K, which activate Rac1 GEFS.	8	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	13	14	19	20
Importantly , inhibition of Src decreased efferocytosis and Rac1 activation in WT cells .	Importantly, inhibition of Src decreased efferocytosis and Rac1 activation in WT cells.	2	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	4	5	8	9
To explore the mechanisms behind the positive regulation of Rac1 activity , we screened the DOCK180 family of GEFs and identified DOCK8 as a GEF for Rac1 that plays a key role in Src induced activation of Rac during HCC metastasis .	To explore the mechanisms behind the positive regulation of Rac1 activity, we screened the DOCK180 family of GEFs and identified DOCK8 as a GEF for Rac1 that plays a key role in Src induced activation of Rac during HCC metastasis.	31	38	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Rac	Rac	Rac	33	34	37	38
Furthermore , addition NC to cells significantly decreases PDGF induced phosphorylation of c-Src , FAK , MAPKs , activation of RhoA , Rac1 and AP-1 transcriptional activity .	Furthermore, addition NC to cells significantly decreases PDGF induced phosphorylation of c-Src, FAK, MAPKs, activation of RhoA, Rac1 and AP-1 transcriptional activity.	3	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	c-Src	NC to cells significantly decreases PDGF induced phosphorylation of c-Src	c-src	Rac1	Rac1	rac1	12	13	22	23
Further , Src was shown to activate Rac1 through the guanine exchange factor Vav2 and promote E-cadherin adhesion XREF_BIBR .	Further, Src was shown to activate Rac1 through the guanine exchange factor Vav2 and promote E-cadherin adhesion XREF_BIBR.	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	2	3	7	8
One possibility is that the elevated Src activity in C8161.9 cells not only inhibits RhoA , but also increases Rac activity .	One possibility is that the elevated Src activity in C8161.9 cells not only inhibits RhoA, but also increases Rac activity.	6	20	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac	Rac	Rac	6	7	19	20
In support of our data , it was reported that active c-Src can phosphorylate and potentiate Tiam1 , a guanine nucleotide exchange factor ( GEF ) which exhibits the highest specificity for Rac1 , indicating that Rac1 is mainly activated by c-Src via Tiam1 XREF_BIBR .	In support of our data, it was reported that active c-Src can phosphorylate and potentiate Tiam1, a guanine nucleotide exchange factor (GEF) which exhibits the highest specificity for Rac1, indicating that Rac1 is mainly activated by c-Src via Tiam1 XREF_BIBR.	36	44	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Rac1	Rac1	Rac1	41	42	36	37
Single substitution of Y724 to Phe abrogated Rac1 activation triggered by Src .	Single substitution of Y724 to Phe abrogated Rac1 activation triggered by Src.	7	12	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	11	12	7	8
In VEGF stimulated ECs , Src mediates Rac1 activation , leading to VE-cadherin phosphorylation via the serine/threonine kinase PAK , and thereby increasing endothelial permeability XREF_BIBR .	In VEGF stimulated ECs, Src mediates Rac1 activation, leading to VE-cadherin phosphorylation via the serine/threonine kinase PAK, and thereby increasing endothelial permeability XREF_BIBR.	5	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	5	6	7	8
The role of p130cas in migration depends largely on its tyrosine phosphorylation by FAK and Src family kinases ( SFKs ) after growth factor receptor or integrin activation ( by BDNF and collagen , respectively , in our assays ) and assembly of the p130cas-Crk-DOCK180 scaffold , which drives localized Rac1 and MAPK activation XREF_BIBR , XREF_BIBR , XREF_BIBR .	The role of p130cas in migration depends largely on its tyrosine phosphorylation by FAK and Src family kinases (SFKs) after growth factor receptor or integrin activation (by BDNF and collagen, respectively, in our assays) and assembly of the p130cas-Crk-DOCK180 scaffold, which drives localized Rac1 and MAPK activation XREF_BIBR, XREF_BIBR, XREF_BIBR.	13	56	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	15	16	50	51
Integrin alpha2beta1 recruitment triggered the Src kinase independent activation of the small GTPase Rac1 , and activation of Rac1 was not required for PLCgamma2 phosphorylation .	Integrin alpha2beta1 recruitment triggered the Src kinase independent activation of the small GTPase Rac1, and activation of Rac1 was not required for PLCgamma2 phosphorylation.	5	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	5	6	13	14
As an activation of Src leads to an elevation of the complex consisting of p130 Cas / Crk and Dock180 in breast cancer cells [ XREF_BIBR ] , ELMO1 and Dock180 binding must be important for producing Src dependent activation of Rac1 .	As an activation of Src leads to an elevation of the complex consisting of p130 Cas / Crk and Dock180 in breast cancer cells [XREF_BIBR], ELMO1 and Dock180 binding must be important for producing Src dependent activation of Rac1.	37	42	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	37	38	41	42
Inhibition of c-Src by pretreatment with Src family kinase inhibitor PP2 or small interfering RNA targeting of c-Src attenuated radiation induced p38 MAPK and Rac1 activation and enhanced Bax and Bak activation and cell death .	Inhibition of c-Src by pretreatment with Src family kinase inhibitor PP2 or small interfering RNA targeting of c-Src attenuated radiation induced p38 MAPK and Rac1 activation and enhanced Bax and Bak activation and cell death.	0	25	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Rac1	Rac1	Rac1	2	3	24	25
In human pancreatic cancer cells , epidermal growth factor ( EGF ) induces the secretion and activation of MMP-2 through an intracellular signaling pathway that involves PI3K- and Src dependent activation of Rac1 , which , in turn , is responsible for the NOX mediated ROS production [ XREF_BIBR ] .	In human pancreatic cancer cells, epidermal growth factor (EGF) induces the secretion and activation of MMP-2 through an intracellular signaling pathway that involves PI3K- and Src dependent activation of Rac1, which, in turn, is responsible for the NOX mediated ROS production [XREF_BIBR].	26	40	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	28	29	32	33
Previous reports have identified that down-regulation of caveolin-1 increases Src activation , which activates Rac1 through the exchange factors Dock180 XREF_BIBR , Tiam1 , Vav2 XREF_BIBR , and FRG ( through Cdc42 and Vav2 ) XREF_BIBR .	Previous reports have identified that down-regulation of caveolin-1 increases Src activation, which activates Rac1 through the exchange factors Dock180 XREF_BIBR, Tiam1, Vav2 XREF_BIBR, and FRG (through Cdc42 and Vav2) XREF_BIBR.	9	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	9	10	14	15
In vascular smooth muscle cells , activation of the angiotensin AT 1 receptor leads to phosphorylation of p47 phox [ XREF_BIBR ] and Src mediated Rac1 translocation to the membrane which result in Nox1 activation in aortic VSMC [ XREF_BIBR ] .	In vascular smooth muscle cells, activation of the angiotensin AT 1 receptor leads to phosphorylation of p47 phox [XREF_BIBR] and Src mediated Rac1 translocation to the membrane which result in Nox1 activation in aortic VSMC [XREF_BIBR].	23	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	23	24	25	26
Src dependent activation of Rac1 is essential for VEGF induced endothelial cell migration and permeability [ XREF_BIBR , XREF_BIBR ] .	Src dependent activation of Rac1 is essential for VEGF induced endothelial cell migration and permeability [XREF_BIBR, XREF_BIBR].	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	0	1	4	5
Collectively , these data suggest that CiaC contributes to Rac1 membrane recruitment and activation , and that maximal C. jejuni invasion of host cells is dependent Rac1 activity that is induced , in part , by EGFR , FAK , PI3 kinase , and Src activation .	Collectively, these data suggest that CiaC contributes to Rac1 membrane recruitment and activation, and that maximal C. jejuni invasion of host cells is dependent Rac1 activity that is induced, in part, by EGFR, FAK, PI3 kinase, and Src activation.	26	45	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	44	45	26	27
We demonstrate that the PI 3-kinase and Src kinase signaling pathways converge to activate Rac1 and JNK .	We demonstrate that the PI 3-kinase and Src kinase signaling pathways converge to activate Rac1 and JNK.	7	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	7	8	14	15
Additionally , recent reports highlighted the role of mDia1 in v-Src kinase membrane translocation and in c-Src mediated activation of Rac1 upon EGF stimulation .	Additionally, recent reports highlighted the role of mDia1 in v-Src kinase membrane translocation and in c-Src mediated activation of Rac1 upon EGF stimulation.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Rac1	Rac1	Rac1	16	17	20	21
These results suggested that Src promotes the Rac1 signaling pathway but inhibits the RhoA signaling pathway in cytoskeletal rearrangement and cell movement in HCC cells , a role similar to that of CD147 .	These results suggested that Src promotes the Rac1 signaling pathway but inhibits the RhoA signaling pathway in cytoskeletal rearrangement and cell movement in HCC cells, a role similar to that of CD147.	4	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	4	5	7	8
CD147 promotes Src dependent activation of Rac1 signaling through STAT3 and DOCK8 during the motility of hepatocellular carcinoma cells .	CD147 promotes Src dependent activation of Rac1 signaling through STAT3 and DOCK8 during the motility of hepatocellular carcinoma cells.	2	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	2	3	6	7
Inhibition of Src phosphorylation by PP2 also inhibited the activation of Rac1 ( XREF_FIG ) , an event critical for AChR internalization .	Inhibition of Src phosphorylation by PP2 also inhibited the activation of Rac1 (XREF_FIG), an event critical for AChR internalization.	2	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src phosphorylation	src	Rac1	Rac1	rac1	2	3	11	12
found that Rac can be directly activated by a local stress to the integrins , independent of the presence or activity of Src , since Src knockout or inhibition had no effects on stress induced Rac activation .	found that Rac can be directly activated by a local stress to the integrins, independent of the presence or activity of Src, since Src knockout or inhibition had no effects on stress induced Rac activation.	18	36	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac	Rac	Rac	22	23	35	36
As neither CD147 nor Src is a GEF or GAP , Rac1 activity can not be directly regulated by CD147 or Src .	As neither CD147 nor Src is a GEF or GAP, Rac1 activity can not be directly regulated by CD147 or Src.	11	22	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	21	22	11	12
Downstream of CSF-1R , c-Src activates Rac and inhibits Rho , two small GTPases that regulate the cytoskeleton .	Downstream of CSF-1R, c-Src activates Rac and inhibits Rho, two small GTPases that regulate the cytoskeleton.	2	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Rac	Rac	Rac	4	5	6	7
For example , VEGF causes Src dependent activation of the Rac pathway , ultimately resulting in phosphorylation of a serine residue on the cytoplasmic tail of VE-cadherin [ XREF_BIBR ] .	For example, VEGF causes Src dependent activation of the Rac pathway, ultimately resulting in phosphorylation of a serine residue on the cytoplasmic tail of VE-cadherin [XREF_BIBR].	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Rac	Rac	Rac	5	6	10	11
The net effect of the combined action of PKC and Src is to increase the levels of Rac activity relative to RhoA , which inhibits stress fiber formation and reduces focal adhesion and cell attachment favoring a more migratory phenotype required for alphavbeta3 dependent invasion .	The net effect of the combined action of PKC and Src is to increase the levels of Rac activity relative to RhoA, which inhibits stress fiber formation and reduces focal adhesion and cell attachment favoring a more migratory phenotype required for alphavbeta3 dependent invasion.	6	18	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac	Rac	Rac	10	11	17	18
Our observation may provide an additional molecular mechanism underlying the Src mediated local activation of Rac1 .	Our observation may provide an additional molecular mechanism underlying the Src mediated local activation of Rac1.	9	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	10	11	15	16
Src was also shown to increase Rac1 activity through the PI3 kinase pathway and promote E-cadherin adhesion XREF_BIBR , XREF_BIBR ; however , given the fact that CD148 dephosphorylates the p85 regulatory subunit and reduces PI3 kinase activity XREF_BIBR , this mechanism would be less contributory .	Src was also shown to increase Rac1 activity through the PI3 kinase pathway and promote E-cadherin adhesion XREF_BIBR, XREF_BIBR; however, given the fact that CD148 dephosphorylates the p85 regulatory subunit and reduces PI3 kinase activity XREF_BIBR, this mechanism would be less contributory.	0	14	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	0	1	6	7
PG-/- cells also exhibited Src independent activation of the small GTPases Rac1 and RhoA .	PG-/- cells also exhibited Src independent activation of the small GTPases Rac1 and RhoA.	4	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	4	5	11	12
In addition , we found that Src activation could enhance Rac1 activity and F-actin accumulation that typify microglial phagocytic activity .	In addition, we found that Src activation could enhance Rac1 activity and F-actin accumulation that typify microglial phagocytic activity.	6	11	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	6	7	10	11
ROS generation , Rac1 activation , and p67 ( phox ) membrane translocation were also prevented by Src inhibition .	ROS generation, Rac1 activation, and p67 (phox) membrane translocation were also prevented by Src inhibition.	3	18	prevented	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	17	18	3	4
Studies have shown that Src activation induces Rac1 activity and that PI3K activity is important for phagosome formation via the Fcgamma receptor .	Studies have shown that Src activation induces Rac1 activity and that PI3K activity is important for phagosome formation via the Fcgamma receptor.	4	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	4	5	7	8
In addition , inhibition of Src with its selective inhibitor PP2 and shRNA targeted to Src blocked Rac1 signal activation ( p < 0.05 for each ) , but inhibition of the activity of PLCgamma1 did not affect the phosphorylation and activation levels of Rac1 under conditions of periodic mechanical stress .	In addition, inhibition of Src with its selective inhibitor PP2 and shRNA targeted to Src blocked Rac1 signal activation (p < 0.05 for each), but inhibition of the activity of PLCgamma1 did not affect the phosphorylation and activation levels of Rac1 under conditions of periodic mechanical stress.	3	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac1	Rac1	Rac1	5	6	17	18
Src , in turn stimulates Rac via beta-pix and p130Cas-DOCK-ELMO pathways in two spatially distinct , but functionally interrelated signaling complexes involved in cell migration .	Src, in turn stimulates Rac via beta-pix and p130Cas-DOCK-ELMO pathways in two spatially distinct, but functionally interrelated signaling complexes involved in cell migration.	0	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Rac	Rac	Rac	0	1	5	6
Activated Ras binds to Raf-1 and recruits Src kinase that will activate Raf-1 in the membrane proximity resulting in Raf-1 increase in activity ( Baccarini , 2005 ) .	Activated Ras binds to Raf-1 and recruits Src kinase that will activate Raf-1 in the membrane proximity resulting in Raf-1 increase in activity (Baccarini, 2005).	7	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Raf-1	Raf-1	Raf-1	7	8	12	13
Src immunoprecipitates contained equal amounts of Raf-1 , a Src target [ XREF_BIBR ] , in control and Abi3bp knockdown MSC-GFP-Akt1 cells ( XREF_FIG ) indicating that Abi3bp does not control ERK phosphorylation through Src activation of Raf-1 .	Src immunoprecipitates contained equal amounts of Raf-1, a Src target [XREF_BIBR], in control and Abi3bp knockdown MSC-GFP-Akt1 cells (XREF_FIG) indicating that Abi3bp does not control ERK phosphorylation through Src activation of Raf-1.	34	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Raf-1	Raf-1	Raf-1	34	35	37	38
Src together with Ras activates Raf1 which was established by the inability of the Raf1-Tyr ( 340/341 ) mutant to activate AC .	Src together with Ras activates Raf1 which was established by the inability of the Raf1-Tyr (340/341) mutant to activate AC.	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Raf1	Raf1	Raf1	0	1	5	6
By contrast , deletion of this Ras binding site did not diminish activation of Raf-1 kinase by Src , implying that Src and Ras can activate Raf-1 through independent mechanisms .	By contrast, deletion of this Ras binding site did not diminish activation of Raf-1 kinase by Src, implying that Src and Ras can activate Raf-1 through independent mechanisms.	21	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Raf-1	Raf-1	Raf-1	21	22	26	27
PI3K and Src activate HRAS and CRAF , and trans-activate EGFR that results in the paradoxical activation of MEK , during the treatment with vemurafenib .	PI3K and Src activate HRAS and CRAF, and trans-activate EGFR that results in the paradoxical activation of MEK, during the treatment with vemurafenib.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	CRAF	CRAF	CRAF	2	3	6	7
CNK1 interacts with RAF in growth factor stimulated and oncogenic activated cells and mediates SRC dependent activation of CRAF in vascular endothelial growth factor ( VEGF )-stimulated cells XREF_BIBR .	CNK1 interacts with RAF in growth factor stimulated and oncogenic activated cells and mediates SRC dependent activation of CRAF in vascular endothelial growth factor (VEGF)-stimulated cells XREF_BIBR.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SRC	SRC	SRC	CRAF	CRAF	CRAF	14	15	18	19
CNK1 regulates the activation of Raf-1 by Src in a concentration dependent manner typical for a scaffold protein .	CNK1 regulates the activation of Raf-1 by Src in a concentration dependent manner typical for a scaffold protein.	1	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src	Src	Raf-1	Raf-1	Raf-1	7	8	5	6
In baculovirus infected Sf9 insect cells , Tvl-1 potentiates the activation of Raf-1 by Src and Ras while in COS-1 cells it potentiates the activation of Raf-1 by EGF .	In baculovirus infected Sf9 insect cells, Tvl-1 potentiates the activation of Raf-1 by Src and Ras while in COS-1 cells it potentiates the activation of Raf-1 by EGF.	8	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src	Src	Raf-1	Raf-1	Raf-1	14	15	12	13
These signals are specific for Pak1 , because Src activated Raf-1 only stimulates the MAP kinase cascade .	These signals are specific for Pak1, because Src activated Raf-1 only stimulates the MAP kinase cascade.	8	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Raf-1	Raf-1	Raf-1	8	9	10	11
In addition , we show that inclusion of additional Src sequences containing the SH3 domain increased the association of Raf-1 with the Src SH2 domain .	In addition, we show that inclusion of additional Src sequences containing the SH3 domain increased the association of Raf-1 with the Src SH2 domain.	9	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Raf-1	Raf-1	Raf-1	9	10	19	20
Interestingly , Src is known to activate c-Raf to participate in controlling EC tube morphogenesis [ XREF_BIBR ] .	Interestingly, Src is known to activate c-Raf to participate in controlling EC tube morphogenesis [XREF_BIBR].	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	c-Raf	c-Raf	c-Raf	2	3	7	8
Our studies demonstrating that EGFR and Src activities modulate IGF-1R activity supports observations made in both Rat aortic smooth muscle and PCa cells that Src activation leads to IGF-1R phosphorylation on the same autophosphorylation sites as induced by IGF-1 .	Our studies demonstrating that EGFR and Src activities modulate IGF-1R activity supports observations made in both Rat aortic smooth muscle and PCa cells that Src activation leads to IGF-1R phosphorylation on the same autophosphorylation sites as induced by IGF-1.	4	10	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	IGF-1R	IGF-1R	IGF-1R	6	7	9	10
Src mediated activation of IGF-1R , but not GPER1 , is required for E 2 -ERbeta2 induced transcriptional upregulation of TMPRSS2 gene fusions in PC-3 cells .	Src mediated activation of IGF-1R, but not GPER1, is required for E 2 -ERbeta2 induced transcriptional upregulation of TMPRSS2 gene fusions in PC-3 cells.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	IGF-1R	IGF-1R	IGF-1R	0	1	4	5
We demonstrate that integrin associated kinases , Rous sarcoma oncogene ( SRC ) and focal adhesion kinase ( FAK ) , display distinct actions on IGF1 signaling ; FAK regulates IGF1R activation and its downstream effectors , AKT and ERK , whereas SRC controls signaling downstream of IGF1R .	We demonstrate that integrin associated kinases, Rous sarcoma oncogene (SRC) and focal adhesion kinase (FAK), display distinct actions on IGF1 signaling; FAK regulates IGF1R activation and its downstream effectors, AKT and ERK, whereas SRC controls signaling downstream of IGF1R.	42	48	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	IGF1R	IGF1R	IGF1R	42	43	47	48
Src kinase inhibitors pyrazolopyrimidine PP-1 and PP-2 inhibited transactivation of the IGF-IR by EGF .	Src kinase inhibitors pyrazolopyrimidine PP-1 and PP-2 inhibited transactivation of the IGF-IR by EGF.	0	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	IGF-IR	IGF-IR	IGF-IR	0	1	11	12
Although IGF-1R signaling is mediated in part by the Src pathway , other downstream signaling pathways of IGF-1R are Src independent and unaffected by Src inhibition XREF_BIBR ; these additional pathways have been shown recently to play an important role in PCa cell survival XREF_BIBR .	Although IGF-1R signaling is mediated in part by the Src pathway, other downstream signaling pathways of IGF-1R are Src independent and unaffected by Src inhibition XREF_BIBR; these additional pathways have been shown recently to play an important role in PCa cell survival XREF_BIBR.	1	10	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	IGF-1R	IGF-1R	IGF-1R	9	10	1	2
Based on previous findings suggesting that Src can activate IGF-1R in a ligand independent manner [ XREF_BIBR ] , we examined the relationship between IGF-1R and Src in NSCLC .	Based on previous findings suggesting that Src can activate IGF-1R in a ligand independent manner [XREF_BIBR], we examined the relationship between IGF-1R and Src in NSCLC.	6	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	IGF-1R	IGF-1R	IGF-1R	6	7	9	10
We examined if induction of TMPRSS2 by E 2 -ERbeta2 axis is mediated through Src activated IGF-1R or G protein coupled estrogen receptor-1 ( GPER-1 ) , an integral plasma membrane protein with high affinity for E 2 .	We examined if induction of TMPRSS2 by E 2 -ERbeta2 axis is mediated through Src activated IGF-1R or G protein coupled estrogen receptor-1 (GPER-1), an integral plasma membrane protein with high affinity for E 2.	12	19	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	IGF-1R	IGF-1R	IGF-1R	14	15	16	17
Together , the results implicate non canonical Src mediated activation of IGF-1R in the E 2 -induced expression of TMPRSS2 and its ETV gene fusions in PC-3 cells .	Together, the results implicate non canonical Src mediated activation of IGF-1R in the E 2 -induced expression of TMPRSS2 and its ETV gene fusions in PC-3 cells.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	IGF-1R	IGF-1R	IGF-1R	7	8	11	12
As with EGFR , Src can activate IGF-1R by phosphorylating several tyrosine residues enhancing its catalytic activity .	As with EGFR, Src can activate IGF-1R by phosphorylating several tyrosine residues enhancing its catalytic activity.	4	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	IGF-1R	IGF-1R	IGF-1R	4	5	7	8
XL-228 ( Exelixis , San Francisco , CA , US20090232828 ) [ XREF_BIBR ] is a multitarget TKI that inhibits IGF-1R ( IC 50 2 nm ) , Src ( IC 50 5 nm ) , and Bcr-abl kinases ( IC 50 7 nm ) [ XREF_BIBR ] .	XL-228 (Exelixis, San Francisco, CA, US20090232828) [XREF_BIBR] is a multitarget TKI that inhibits IGF-1R (IC 50 2 nm), Src (IC 50 5 nm), and Bcr-abl kinases (IC 50 7 nm) [XREF_BIBR].	0	30	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	IGF-1R	IGF-1R	IGF-1R	28	29	20	21
Src dependent activation of IGF-1R downstream signaling effectors in high-pSrc-expressing NSCLC cells after treatment with IGF-1R TKIs .	Src dependent activation of IGF-1R downstream signaling effectors in high-pSrc-expressing NSCLC cells after treatment with IGF-1R TKIs.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	IGF-1R	IGF-1R	IGF-1R	0	1	4	5
AGEs Activate Akt via the Src mediated IGF-1R Transactivation .	AGEs Activate Akt via the Src mediated IGF-1R Transactivation.	2	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	IGF-1R	IGF-1R	IGF-1R	5	6	7	8
Furthermore , c-Src activation at the IFNgR results in the activation of the calcium dependent kinase Pyk2 , leading to the activation of the Mekk4/MKK6/p38 MAP kinase pathway .	Furthermore, c-Src activation at the IFNgR results in the activation of the calcium dependent kinase Pyk2, leading to the activation of the Mekk4/MKK6/p38 MAP kinase pathway.	2	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Pyk2	Pyk2	Pyk2	2	3	16	17
Pyk2 is a member of the focal adhesion kinase family and can be activated by c-Src , epidermal growth factor receptor ( EGFR ) , Janus kinase 1 , tyrosine kinases , and G-protein-coupled receptor signaling .	Pyk2 is a member of the focal adhesion kinase family and can be activated by c-Src, epidermal growth factor receptor (EGFR), Janus kinase 1, tyrosine kinases, and G-protein-coupled receptor signaling.	0	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Pyk2	Pyk2	Pyk2	15	16	0	1
Pyk2 activation was also suppressed by the Src inhibitor PP2 ( XREF_FIG ) ; Src kinases can activate Pyk2 via ITAM-calcium signaling or by direct interaction and phosphorylation .	Pyk2 activation was also suppressed by the Src inhibitor PP2 (XREF_FIG); Src kinases can activate Pyk2 via ITAM-calcium signaling or by direct interaction and phosphorylation.	14	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Pyk2	Pyk2	Pyk2	14	15	18	19
Pyk2 is a member of the focal adhesion kinase family and can be activated by c-Src .	Pyk2 is a member of the focal adhesion kinase family and can be activated by c-Src.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Pyk2	Pyk2	Pyk2	15	16	0	1
ECs treated with an inhibitor to Src ( PPI ) greatly reduced Src and PYK2 phosphorylation , indicating that Src mediated PYK2 activation .	ECs treated with an inhibitor to Src (PPI) greatly reduced Src and PYK2 phosphorylation, indicating that Src mediated PYK2 activation.	19	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	PYK2	PYK2	PYK2	19	20	21	22
Additionally , Src is known to activate Pyk2 XREF_BIBR , thus completing the bi-directional functional interaction .	Additionally, Src is known to activate Pyk2 XREF_BIBR, thus completing the bi-directional functional interaction.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Pyk2	Pyk2	Pyk2	2	3	7	8
That is , Src may directly phosphorylate Pyk2 on Y402 , or Src may activate Pyk2 , resulting in Pyk2 autophosphorylation .	That is, Src may directly phosphorylate Pyk2 on Y402, or Src may activate Pyk2, resulting in Pyk2 autophosphorylation.	12	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Pyk2	Pyk2	Pyk2	12	13	15	16
Here phloretin appeared to allay estrogen deficiency induced bone resorption through blocking the c-Src downstream signaling of Pyk2 and paxillin .	Here phloretin appeared to allay estrogen deficiency induced bone resorption through blocking the c-Src downstream signaling of Pyk2 and paxillin.	13	19	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Pyk2	Pyk2	Pyk2	13	14	17	18
Furthermore , the Src mediated increase in Pyk2 activity would allow more effective rephosphorylation of Tyr402 should a Tyr402 residue in an oligomeric complex become dephosphorylated .	Furthermore, the Src mediated increase in Pyk2 activity would allow more effective rephosphorylation of Tyr402 should a Tyr402 residue in an oligomeric complex become dephosphorylated.	3	8	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	Pyk2	Pyk2	Pyk2	3	4	7	8
In conclusion , our results showed that Pyk2 promoted cell proliferation and invasiveness by upregulation of the c-Src and ERK and MAPK signaling pathways .	In conclusion, our results showed that Pyk2 promoted cell proliferation and invasiveness by upregulation of the c-Src and ERK and MAPK signaling pathways.	7	23	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Pyk2	Pyk2	Pyk2	17	18	7	8
Neither EGFR kinase nor Pyk2 inhibition prevented Src activation ; however , inhibition of Src kinase activity prevented Pyk2 activation .	Neither EGFR kinase nor Pyk2 inhibition prevented Src activation; however, inhibition of Src kinase activity prevented Pyk2 activation.	14	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Pyk2	Pyk2	Pyk2	14	15	18	19
Studies have demonstrated that the oncogene , Src , can mediate ERK5 signaling which may lead to disruption of the actin cytoskeleton through a loss of actin stress fibers .	Studies have demonstrated that the oncogene, Src, can mediate ERK5 signaling which may lead to disruption of the actin cytoskeleton through a loss of actin stress fibers.	5	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ERK5	ERK5	ERK5	7	8	11	12
The Lad binding motif is encoded within amino acids 228 to 282 in the N terminus of MEKK2 , and expression of this motif blocks Lad-MEKK2 interaction , resulting in inhibition of Src dependent activation of MEKK2 and ERK5 .	The Lad binding motif is encoded within amino acids 228 to 282 in the N terminus of MEKK2, and expression of this motif blocks Lad-MEKK2 interaction, resulting in inhibition of Src dependent activation of MEKK2 and ERK5.	32	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	ERK5	ERK5	ERK5	32	33	38	39
Additionally , in the absence of v-Src expression , neither the ERK5-/- nor the ERK5-FL cells expressed detectable levels of RhoGAP7 and DLC -1 ( XREF_FIG ) , which indicates that its expression is a result of Src activation of ERK5 .	Additionally, in the absence of v-Src expression, neither the ERK5-/- nor the ERK5-FL cells expressed detectable levels of RhoGAP7 and DLC -1 (XREF_FIG), which indicates that its expression is a result of Src activation of ERK5.	37	41	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	ERK5	ERK5	ERK5	37	38	40	41
ERK5 was required for focus formation in v-Src-transformed cells , and activated Src induced ERK5 nuclear translocation and MEF2 dependent gene expression .	ERK5 was required for focus formation in v-Src-transformed cells, and activated Src induced ERK5 nuclear translocation and MEF2 dependent gene expression.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	ERK5	ERK5	ERK5	12	13	14	15
Our studies demonstrate that Src kinase activity is required for ERK5 activation in response to EGF , MEKK2 expression is required for ERK5 activation by Src , Lad and MEKK2 association is required for Src activation of ERK5 , and EGF and Src stimulation of ERK5 regulated MEF2 dependent promoter activity requires a functional Lad-MEKK2 signaling complex .	Our studies demonstrate that Src kinase activity is required for ERK5 activation in response to EGF, MEKK2 expression is required for ERK5 activation by Src, Lad and MEKK2 association is required for Src activation of ERK5, and EGF and Src stimulation of ERK5 regulated MEF2 dependent promoter activity requires a functional Lad-MEKK2 signaling complex.	40	46	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	ERK5	ERK5	ERK5	42	43	45	46
We demonstrate that ERK5 is activated by oncogenic Src as demonstrated by translocation of endogenous ERK5 from the cytoplasm to nucleus and activation of an ERK5 dependent transcriptional reporter and that ERK5 activation is required for Src mediated transformation .	We demonstrate that ERK5 is activated by oncogenic Src as demonstrated by translocation of endogenous ERK5 from the cytoplasm to nucleus and activation of an ERK5 dependent transcriptional reporter and that ERK5 activation is required for Src mediated transformation.	3	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	ERK5	ERK5	ERK5	8	9	3	4
Further kinome-scale siRNA screening demonstrated that SRC \ MEK5 cascade promotes the phospho activation of BMK1 in response to CIBM .	Further kinome-scale siRNA screening demonstrated that SRC \ MEK5 cascade promotes the phospho activation of BMK1 in response to CIBM.	6	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	BMK1	BMK1	BMK1	6	7	15	16
Src has been shown to mediate ERK5 activation in response to a variety of different stimuli , including epidermal growth factor receptor activation , cellular exposure to asbestos , hypoxia inducing conditions , and exposure to reactive oxygen species .	Src has been shown to mediate ERK5 activation in response to a variety of different stimuli, including epidermal growth factor receptor activation, cellular exposure to asbestos, hypoxia inducing conditions, and exposure to reactive oxygen species.	0	7	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ERK5	ERK5	ERK5	0	1	6	7
Second , specific Src family tyrosine kinase inhibitors ( herbimycin A and CP-118 ,556 ) blocked BMK1 activation by H2O2 in a concentration dependent manner .	Second, specific Src family tyrosine kinase inhibitors (herbimycin A and CP-118,556) blocked BMK1 activation by H2O2 in a concentration dependent manner.	3	17	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	BMK1	BMK1	BMK1	3	4	16	17
c-Src has also been shown to mediate activation of ERK5 in response to oxidative stress .	c-Src has also been shown to mediate activation of ERK5 in response to oxidative stress.	0	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	ERK5	ERK5	ERK5	0	1	9	10
These findings suggest that c-Src mediated BMK1 activation by H ( 2 ) O ( 2 ) may counteract ischemic cellular damage probably through the activation of MEF2C transcription factor .	These findings suggest that c-Src mediated BMK1 activation by H (2) O (2) may counteract ischemic cellular damage probably through the activation of MEF2C transcription factor.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	BMK1	BMK1	BMK1	4	5	6	7
This suggests that Src may mediate MLCK kinase activity during cell volume recovery , consistent with our finding that activated Src is recruited to bleb membranes before retraction .	This suggests that Src may mediate MLCK kinase activity during cell volume recovery, consistent with our finding that activated Src is recruited to bleb membranes before retraction.	3	8	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	MLCK	MLCK	MLCK	3	4	6	7
Thus Src activation of MLCK can integrate spatial , signaling , and calcium cues for precise positioning of membrane retrieval .	Thus Src activation of MLCK can integrate spatial, signaling, and calcium cues for precise positioning of membrane retrieval.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	MLCK	MLCK	MLCK	1	2	4	5
In our case , the actomyosin forces that power bleb retraction appear to be regulated by Src activated MLCK and not ROCK .	In our case, the actomyosin forces that power bleb retraction appear to be regulated by Src activated MLCK and not ROCK.	14	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	MLCK	MLCK	MLCK	16	17	18	19
Given that osmotically induced swelling involves contributions from the addition of membrane , a unifying hypothesis would be that Src activated MLCK modulates not only membrane dynamics during bleb retraction but also membrane retrieval at the base of the cell as a compensatory response .	Given that osmotically induced swelling involves contributions from the addition of membrane, a unifying hypothesis would be that Src activated MLCK modulates not only membrane dynamics during bleb retraction but also membrane retrieval at the base of the cell as a compensatory response.	19	22	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	MLCK	MLCK	MLCK	19	20	21	22
We propose that during osmotic cell swelling , Src activated MLCK acts to stabilize and promote repair of the actomyosin cortex and its connections with the plasma membrane .	We propose that during osmotic cell swelling, Src activated MLCK acts to stabilize and promote repair of the actomyosin cortex and its connections with the plasma membrane.	8	15	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	MLCK	MLCK	MLCK	8	9	10	11
Collectively , these observations support the concept that Src activated MLCK ( through myosin II ) , but not ROCK , regulates swelling induced bleb retraction .	Collectively, these observations support the concept that Src activated MLCK (through myosin II), but not ROCK, regulates swelling induced bleb retraction.	8	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	MLCK	MLCK	MLCK	8	9	10	11
Previous findings suggest that NFkappaB activation by H 2 O 2 is cell-type specific and occurs through different mechanisms [ XREF_BIBR , XREF_BIBR ] ; in HeLa cells , H 2 O 2 induced IKKbeta activation , IkappaBalpha phosphorylation , and NFkappaB transcription via protein kinase D , which was activated by two Src mediated signalling pathways [ XREF_BIBR ] .	Previous findings suggest that NFkappaB activation by H 2 O 2 is cell-type specific and occurs through different mechanisms [XREF_BIBR, XREF_BIBR]; in HeLa cells, H 2 O 2 induced IKKbeta activation, IkappaBalpha phosphorylation, and NFkappaB transcription via protein kinase D, which was activated by two Src mediated signalling pathways [XREF_BIBR].	44	54	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	protein kinase D	protein kinase D	protein kinase D	53	54	44	47
Thus , our data indicate that UVB irradiation of keratinocytes induces Src mediated activation of PKD , which protects cells from UVB stimulated apoptosis , providing a possible explanation for the observed up-regulation of PKD in BCC .	Thus, our data indicate that UVB irradiation of keratinocytes induces Src mediated activation of PKD, which protects cells from UVB stimulated apoptosis, providing a possible explanation for the observed up-regulation of PKD in BCC.	11	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	PKD	PKD	PKD	11	12	15	16
Additionally , another Src family kinase inhibitor , Src-1 , was used to verify the role of Src family kinases in AngII elicited PKD activation and aldosterone production .	Additionally, another Src family kinase inhibitor, Src-1, was used to verify the role of Src family kinases in AngII elicited PKD activation and aldosterone production.	17	24	elicited	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	PKD	PKD	PKD	17	18	23	24
Here , we describe for the first time that Src family kinases activate PKD in primary bovine adrenal glomerulosa cells to underlie acute aldosterone production .	Here, we describe for the first time that Src family kinases activate PKD in primary bovine adrenal glomerulosa cells to underlie acute aldosterone production.	9	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	PKD	PKD	PKD	9	10	13	14
Our data and those of others suggest that Src and its substrate FAK , two important mediators of cell invasion and metastasis , are possible downstream targets of MUC1 .	Our data and those of others suggest that Src and its substrate FAK, two important mediators of cell invasion and metastasis, are possible downstream targets of MUC1.	8	29	are possible downstream targets	Positive_activation_copula_1	Positive_activation	Positive_activation	Src	Src	Src	MUC1	MUC1	MUC1	8	9	28	29
We also show that inhibitors of c-Src or HSP90 block HRG induced targeting of MUC1 to mitochondria and integration of MUC1 into the mitochondrial outer membrane .	We also show that inhibitors of c-Src or HSP90 block HRG induced targeting of MUC1 to mitochondria and integration of MUC1 into the mitochondrial outer membrane.	6	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	MUC1	MUC1	MUC1	6	7	14	15
Expression of constitutively active Src in FG cells readily promoted MUC1 cleavage and nuclear localization ( XREF_FIG ) .	Expression of constitutively active Src in FG cells readily promoted MUC1 cleavage and nuclear localization (XREF_FIG).	0	11	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Expression of constitutively active Src	src	MUC1	MUC1	muc1	4	5	10	11
It is possible that Src dependent phosphorylation enhances the recognition of MUC1 by a protease .	It is possible that Src dependent phosphorylation enhances the recognition of MUC1 by a protease.	4	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src dependent phosphorylation	src	MUC1	MUC1	muc1	4	5	11	12
These data are consistent with the hypothesis that Src activity promotes cell migration by regulating cleavage of MUC1 .	These data are consistent with the hypothesis that Src activity promotes cell migration by regulating cleavage of MUC1.	8	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	MUC1	MUC1	MUC1	8	9	17	18
These findings identify a pathway of EGF dependent metastasis that depends on Src mediated MUC1 cleavage leading to the expression of a metastatic gene signature .	These findings identify a pathway of EGF dependent metastasis that depends on Src mediated MUC1 cleavage leading to the expression of a metastatic gene signature.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	MUC1	MUC1	MUC1	12	13	14	15
Importantly , pharmacologic inhibition of Src signaling with bosutinib suppresses MUC1 cleavage , suggesting that targeting the pathways responsible for MUC1 cleavage may represent a promising alternative therapeutic approach .	Importantly, pharmacologic inhibition of Src signaling with bosutinib suppresses MUC1 cleavage, suggesting that targeting the pathways responsible for MUC1 cleavage may represent a promising alternative therapeutic approach.	5	11	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	MUC1	MUC1	MUC1	5	6	10	11
A new series of studies will be required to establish the detailed mechanism by which Src activity enhances MUC1 cleavage .	A new series of studies will be required to establish the detailed mechanism by which Src activity enhances MUC1 cleavage.	15	19	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	MUC1	MUC1	MUC1	15	16	18	19
We next asked whether Src was sufficient to drive cleavage of MUC1 in FG cells .	We next asked whether Src was sufficient to drive cleavage of MUC1 in FG cells.	4	12	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	MUC1	MUC1	MUC1	4	5	11	12
This Src homology domain of Stat1 is also recruited to unrelated phosphotyrosine motifs on the IFN-gammaR , inducing activation of Stat1 in response to IFN-gamma .	This Src homology domain of Stat1 is also recruited to unrelated phosphotyrosine motifs on the IFN-gammaR, inducing activation of Stat1 in response to IFN-gamma.	1	22	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat1	Stat1	Stat1	1	2	20	21
Using a pharmacological inhibitor of Src kinases CGP77675 and cells with knockout c-src , it was shown that Src activated STAT1 upon stimulation by both epidermal growth factor and hypersomatic shock .	Using a pharmacological inhibitor of Src kinases CGP77675 and cells with knockout c-src, it was shown that Src activated STAT1 upon stimulation by both epidermal growth factor and hypersomatic shock.	18	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT1	STAT1	STAT1	18	19	20	21
STAT1 was activated by PC1 and wild-type Src ( Src WT ) , and co-expression of PC1 and Src further increased STAT1 activation levels .	STAT1 was activated by PC1 and wild-type Src (Src WT), and co-expression of PC1 and Src further increased STAT1 activation levels.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT1	STAT1	STAT1	7	8	0	1
These results suggest that PC1 leads to Src independent activation of STAT1 through tyrosine phosphorylation .	These results suggest that PC1 leads to Src independent activation of STAT1 through tyrosine phosphorylation.	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	STAT1	STAT1	STAT1	7	8	11	12
It is conceivable that Src activation leads to AKT activation , resulting in STAT1 upregulation of the CLU gene .	It is conceivable that Src activation leads to AKT activation, resulting in STAT1 upregulation of the CLU gene.	4	14	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT1	STAT1	STAT1	4	5	13	14
Unexpectedly , exogenous overexpression of c-Src did not enhance STAT5b transcriptional activity .	Unexpectedly, exogenous overexpression of c-Src did not enhance STAT5b transcriptional activity.	3	11	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	overexpression of c-Src	c-src	STAT5b	STAT5b	stat5b	5	6	9	10
It was previously shown that Src phosphorylated tyrosine residue Y869 is essential for activation of STAT5b , but does not mediate the interaction itself .	It was previously shown that Src phosphorylated tyrosine residue Y869 is essential for activation of STAT5b, but does not mediate the interaction itself.	5	20	is essential for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	Src	Src phosphorylated	src	STAT5b	STAT5b	stat5b	5	6	15	16
For example , depending on the signal transduction pathway responsible , different effects of Prl and Src on STAT5B tyrosine phosphorylation induced the conformational differences of STAT5B , resulting selective biological responses [ XREF_BIBR ] .	For example, depending on the signal transduction pathway responsible, different effects of Prl and Src on STAT5B tyrosine phosphorylation induced the conformational differences of STAT5B, resulting selective biological responses [XREF_BIBR].	12	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT5B	STAT5B	STAT5B	16	17	26	27
c-Src can activate STAT5B directly by phosphorylation or indirectly by phosphorylating EGFR ( Y845 ) .	c-Src can activate STAT5B directly by phosphorylation or indirectly by phosphorylating EGFR (Y845).	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT5B	STAT5B	STAT5B	0	1	3	4
In addition , Stat5a/b may also be activated by Src kinase or members of the EGF receptor family [ XREF_BIBR - XREF_BIBR ] .	In addition, Stat5a/b may also be activated by Src kinase or members of the EGF receptor family [XREF_BIBR - XREF_BIBR].	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	Stat5a/b	Stat5a/b	Stat5a/b	9	10	3	4
The kinase activity of Brk was necessary for this collaboration as the addition of c-Src to K219M Brk did not enhance STAT5b activity .	The kinase activity of Brk was necessary for this collaboration as the addition of c-Src to K219M Brk did not enhance STAT5b activity.	12	22	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	STAT5b	STAT5b	STAT5b	14	15	21	22
These two isoforms are highly conserved but demonstrate different functions and differential activation in response to certain kinases such as Src , which only activates STAT5b XREF_BIBR - XREF_BIBR .	These two isoforms are highly conserved but demonstrate different functions and differential activation in response to certain kinases such as Src, which only activates STAT5b XREF_BIBR - XREF_BIBR.	17	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT5b	STAT5b	STAT5b	20	21	25	26
Here we show that , in response to Src dependent activation of phospholipase Cgamma1 , the Ras guanine nucleotide exchange factor RasGRP1 translocated to the Golgi where it activated Ras .	Here we show that, in response to Src dependent activation of phospholipase Cgamma1, the Ras guanine nucleotide exchange factor RasGRP1 translocated to the Golgi where it activated Ras.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	phospholipase Cgamma1	phospholipase Cgamma1	phospholipase Cgamma1	8	9	12	14
In T cells , PLCgamma1 is activated downstream of the T cell receptor by a large panoply of SRC , SYK , and TEC kinases .	In T cells, PLCgamma1 is activated downstream of the T cell receptor by a large panoply of SRC, SYK, and TEC kinases.	4	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	PLCgamma1	PLCgamma1	PLCgamma1	18	19	4	5
Inhibition of Src activity with PP2 and shRNA targeted to Src abrogated chondrocyte proliferation and matrix synthesis ( P < 0.05 ) and attenuated PLCgamma1 , MEK1/2 and ERK1/2 activation in chondrocytes subjected to periodic mechanical stress ( P < 0.05 ) .	Inhibition of Src activity with PP2 and shRNA targeted to Src abrogated chondrocyte proliferation and matrix synthesis (P < 0.05) and attenuated PLCgamma1, MEK1/2 and ERK1/2 activation in chondrocytes subjected to periodic mechanical stress (P < 0.05).	2	29	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	PLCgamma1	PLCgamma1	PLCgamma1	2	3	24	25
We show that TG2 , FAK or Src knockdown , or treatment with pharmacologic inhibitors of these activities , reduces PI3K and PDK1 activity in ECS cell cultures , suggesting that FAK and Src signaling triggers PI3K and PDK1 activation .	We show that TG2, FAK or Src knockdown, or treatment with pharmacologic inhibitors of these activities, reduces PI3K and PDK1 activity in ECS cell cultures, suggesting that FAK and Src signaling triggers PI3K and PDK1 activation.	31	39	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	PDK1	PDK1	PDK1	33	34	38	39
Our own work has shown that in Angiotensin II treated cells , ROS regulate the Src dependent activation of PDK1 , which is essential for this process .	Our own work has shown that in Angiotensin II treated cells, ROS regulate the Src dependent activation of PDK1, which is essential for this process.	15	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	PDK1	PDK1	PDK1	15	16	19	20
To corroborate that ADAM17 is critical for the Src stimulated shedding of TGFalpha , we performed rescue experiments in Adam17 -/- mEFs .	To corroborate that ADAM17 is critical for the Src stimulated shedding of TGFalpha, we performed rescue experiments in Adam17 -/- mEFs.	7	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	TGFalpha	TGFalpha	TGFalpha	8	9	12	13
We found no difference in the Src ( E378G )-dependent stimulation of TGFalpha shedding in Adam8-/-, Adam9/12/15-/-, Adam10-/- or Adam19-/- mEF cells compared to wild type controls ( XREF_SUPPLEMENTARY ) , whereas constitutive shedding of TGFalpha was strongly reduced in Adam17-/- cells , with no further stimulation by co-transfection with Src ( E378G ) .	We found no difference in the Src (E378G)-dependent stimulation of TGFalpha shedding in Adam8-/-, Adam9/12/15-/-, Adam10-/- or Adam19-/- mEF cells compared to wild type controls (XREF_SUPPLEMENTARY), whereas constitutive shedding of TGFalpha was strongly reduced in Adam17-/- cells, with no further stimulation by co-transfection with Src (E378G).	6	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	TGFalpha	TGFalpha	TGFalpha	6	7	12	13
Overall , the data suggest that up-regulation of c-Src activity by hypoxia is mediated in part through ROS but that activation of K-Ras by c-Src in hypoxia does not depend upon EGFR .	Overall, the data suggest that up-regulation of c-Src activity by hypoxia is mediated in part through ROS but that activation of K-Ras by c-Src in hypoxia does not depend upon EGFR.	20	26	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	K-Ras	K-Ras	K-Ras	24	25	22	23
Inhibition of c-Src by PP2 treatment or siRNA knockdown blocked the hypoxic activation of K-ras .	Inhibition of c-Src by PP2 treatment or siRNA knockdown blocked the hypoxic activation of K-ras.	0	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	K-ras	K-ras	K-ras	2	3	14	15
Thus , the data suggests that Src accelerates pancreatic tumor progression in a KRas dependent manner and that activation of Src alone is not sufficient to initiate pancreatic cancer .	Thus, the data suggests that Src accelerates pancreatic tumor progression in a KRas dependent manner and that activation of Src alone is not sufficient to initiate pancreatic cancer.	6	15	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	KRas	KRas	KRas	6	7	13	14
Accordingly , we show that the pharmacological inhibitor of Src , PP2 , reduces the ability of LRP1 ligands to extend neurites , but still survive , suggesting that LRP1 dependent cell signaling pathways of differentiation are SFK mediated in embryonic sensory neurons .	Accordingly, we show that the pharmacological inhibitor of Src, PP2, reduces the ability of LRP1 ligands to extend neurites, but still survive, suggesting that LRP1 dependent cell signaling pathways of differentiation are SFK mediated in embryonic sensory neurons.	7	18	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	LRP1	LRP1	LRP1	9	10	17	18
Whether these mechanisms , which are distinct from the Src kinase family mediated activation of the LRP1 and Shc1 signaling cascade , are themselves also modulated by LRP1 tyrosine phosphorylation remains currently unknown , but can now be tested using the knockin mouse model we have reported here .	Whether these mechanisms, which are distinct from the Src kinase family mediated activation of the LRP1 and Shc1 signaling cascade, are themselves also modulated by LRP1 tyrosine phosphorylation remains currently unknown, but can now be tested using the knockin mouse model we have reported here.	9	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	LRP1	LRP1	LRP1	9	10	16	17
Since the tyrosine kinase Src could potentially activate ERK signaling downstream of LRP-1 ( XREF_FIG ) , cell invasion was quantified in the presence of a Src kinase inhibitor .	Since the tyrosine kinase Src could potentially activate ERK signaling downstream of LRP-1 (XREF_FIG), cell invasion was quantified in the presence of a Src kinase inhibitor.	1	14	potentially activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	LRP-1	LRP-1	LRP-1	4	5	12	13
Furthermore , intrahippocampal infusion of SFKs inhibitor PP2 inhibits Src kinase phosphorylation and activation , attenuates the activation of NR2B containing NMDA receptors , and thereby reverses the enhancement of fear extinction induced by novelty exposure .	Furthermore, intrahippocampal infusion of SFKs inhibitor PP2 inhibits Src kinase phosphorylation and activation, attenuates the activation of NR2B containing NMDA receptors, and thereby reverses the enhancement of fear extinction induced by novelty exposure.	7	20	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	PP2 inhibits Src kinase phosphorylation	src	NR2B	NR2B	nr2b	9	10	19	20
We show that beta3 integrin alters TGF-beta signaling in MECs via Src mediated TbetaR-II tyrosine phosphorylation , which significantly enhanced the ability of TGF-beta to induce EMT and invasion .	We show that beta3 integrin alters TGF-beta signaling in MECs via Src mediated TbetaR-II tyrosine phosphorylation, which significantly enhanced the ability of TGF-beta to induce EMT and invasion.	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	TbetaR-II	TbetaR-II	TbetaR-II	11	12	13	14
Phosphorylation by Src enables TbetaRII to recruit Grb2 and Shc , contributing to the TGF-beta-induced activation of p38 MAPK .	Phosphorylation by Src enables TbetaRII to recruit Grb2 and Shc, contributing to the TGF-beta-induced activation of p38 MAPK.	0	5	enables	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Src	Src	TbetaRII	TbetaRII	TbetaRII	2	3	4	5
Activation of Src can stimulate the activity of guanine nucleotide exchange factors ( GEFs ) Vav2 and Tiam1 , leading to Rac1 activation XREF_BIBR .	Activation of Src can stimulate the activity of guanine nucleotide exchange factors (GEFs) Vav2 and Tiam1, leading to Rac1 activation XREF_BIBR.	0	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Tiam1	Tiam1	Tiam1	2	3	17	18
The Src membrane localization domain thus enables C580 Tiam1 and C1199-DeltaPHn to induce membrane ruffling by tethering these proteins to the plasma membrane .	The Src membrane localization domain thus enables C580 Tiam1 and C1199-DeltaPHn to induce membrane ruffling by tethering these proteins to the plasma membrane.	1	10	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Tiam1	Tiam1	Tiam1	1	2	8	9
Secondly , Src can phosphorylate and thereby activate the GEF proteins Vav2 and Tiam1 , although these effects may not require FAK XREF_BIBR .	Secondly, Src can phosphorylate and thereby activate the GEF proteins Vav2 and Tiam1, although these effects may not require FAK XREF_BIBR.	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Tiam1	Tiam1	Tiam1	2	3	13	14
In addition to their roles in cell migration and invasion , FAK and Src phosphorylate and activate the ShcA adaptor , an upstream activator of the Ras pathway .	In addition to their roles in cell migration and invasion, FAK and Src phosphorylate and activate the ShcA adaptor, an upstream activator of the Ras pathway.	11	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ShcA	ShcA	ShcA	13	14	18	19
The BDNF activated Src may directly stimulate the association of ZBP1 to RACK1 , through a direct binding to both proteins , whereas PACAP38 activated Src may indirectly induce the dissociation of ZBP1 and RACK1 complex , through the activation of PKA ( XREF_FIG ) .	The BDNF activated Src may directly stimulate the association of ZBP1 to RACK1, through a direct binding to both proteins, whereas PACAP38 activated Src may indirectly induce the dissociation of ZBP1 and RACK1 complex, through the activation of PKA (XREF_FIG).	3	13	stimulate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Src	Src	Src	RACK1	RACK1	RACK1	3	4	12	13
Furthermore , Src inhibition disrupts the localization of RACK1 at point contacts following BDNF stimulation ( XREF_FIG ) .	Furthermore, Src inhibition disrupts the localization of RACK1 at point contacts following BDNF stimulation (XREF_FIG).	2	9	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	RACK1	RACK1	RACK1	2	3	8	9
Src kinase phosphorylation accelerates activation of HCN2 and HCN4 , whereas there are conflicting data if it also leads to a shift in the HCN4 activation curve [ XREF_BIBR , XREF_BIBR ] .	Src kinase phosphorylation accelerates activation of HCN2 and HCN4, whereas there are conflicting data if it also leads to a shift in the HCN4 activation curve [XREF_BIBR, XREF_BIBR].	0	9	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src kinase phosphorylation	src	HCN4	HCN4	hcn4	0	1	8	9
The diminished stimulation by ISO in the presence of PP2 on I HCN4 , sinus node I f , action potentials , and spontaneous beating rate , respectively , supported the hypothesis that ISO can increase the sinus node pacemaker activity via a cAMP independent , Src mediated stimulation of HCN4 activity by phosphorylation on tentative tyrosine residues in the C-linker of the channel protein .	The diminished stimulation by ISO in the presence of PP2 on I HCN4, sinus node I f, action potentials, and spontaneous beating rate, respectively, supported the hypothesis that ISO can increase the sinus node pacemaker activity via a cAMP independent, Src mediated stimulation of HCN4 activity by phosphorylation on tentative tyrosine residues in the C-linker of the channel protein.	19	51	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	HCN4	HCN4	HCN4	46	47	50	51
These results demonstrate that Src tyrosine kinase enhances HCN4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics .	These results demonstrate that Src tyrosine kinase enhances HCN4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics.	4	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	HCN4	HCN4	HCN4	4	5	8	9
Src family kinases ( SFKs ) mediate IKK2 and STAT3/5 activation .	Src family kinases (SFKs) mediate IKK2 and STAT3/5 activation.	0	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	IKK2	IKK2	IKK2	0	1	7	8
In order to clarify the mechanism underlying the Src kinase mediated cytoplasmic retention of STAT5A , we co-expressed STAT5A-eYFP or STAT5A R618Q -eYFP with the SFK members Hck dsRed and vSrc dsRed .	In order to clarify the mechanism underlying the Src kinase mediated cytoplasmic retention of STAT5A, we co-expressed STAT5A-eYFP or STAT5A R618Q -eYFP with the SFK members Hck dsRed and vSrc dsRed.	8	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	STAT5A	STAT5A	STAT5A	8	9	14	15
Moreover , we were able to rescue Src mediated STAT5A dimerization by using a constitutively active STAT5A variant harboring a serine to phenylalanine mutation in the TA domain at position 710 [ XREF_BIBR ] .	Moreover, we were able to rescue Src mediated STAT5A dimerization by using a constitutively active STAT5A variant harboring a serine to phenylalanine mutation in the TA domain at position 710 [XREF_BIBR].	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	STAT5A	STAT5A	STAT5A	7	8	9	10
Therefore , a CHIP mediated increase in IL-6 and IFN-beta production during TLR response may be caused by Src and PKCzeta dependent activation of IkappaBalpha and IRAK1 and TBK1 , respectively .	Therefore, a CHIP mediated increase in IL-6 and IFN-beta production during TLR response may be caused by Src and PKCzeta dependent activation of IkappaBalpha and IRAK1 and TBK1, respectively.	18	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Src	Src	Src	IkappaBalpha	IkappaBalpha	IkappaBalpha	18	19	24	25
Oxidative stress inactivates NIK and IkappaB kinase gamma subunit and NF-kappaB essential modulator ( IKKgamma and NEMO ) , which might cause activation of NF-kappaB that is independent on IKK and inhibitor of IkappaBalpha degradation , including phosphorylation of Tyr4 ( 2 ) at IkappaBalpha by c-Src and spleen tyrosine kinase ( Syk ) , phosphorylation of the domain rich in proline , glutamic acid , serine and threonine ( PEST ) sequence by casein kinase II and inactivation of protein tyrosine phosphatase 1B ( PTP1B ) .	Oxidative stress inactivates NIK and IkappaB kinase gamma subunit and NF-kappaB essential modulator (IKKgamma and NEMO), which might cause activation of NF-kappaB that is independent on IKK and inhibitor of IkappaBalpha degradation, including phosphorylation of Tyr4 (2) at IkappaBalpha by c-Src and spleen tyrosine kinase (Syk), phosphorylation of the domain rich in proline, glutamic acid, serine and threonine (PEST) sequence by casein kinase II and inactivation of protein tyrosine phosphatase 1B (PTP1B).	21	50	cause	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	IkappaBalpha	IkappaBalpha	IkappaBalpha	46	47	44	45
This further implies that for some genes , Src induced tyrosine phosphorylation converts TFII-I into a transcriptional co-repressor .	This further implies that for some genes, Src induced tyrosine phosphorylation converts TFII-I into a transcriptional co-repressor.	8	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	TFII-I	TFII-I	TFII-I	8	9	13	14
To identify the Tyr residue ( s ) on NoxA1 targeted by Src , we used bioinformatics tools available online ( www.cbs.dtu.dk ) and scanned human NoxA1 protein ( accession number NM_006647 ) for predicted phosphorylation sites .	To identify the Tyr residue (s) on NoxA1 targeted by Src, we used bioinformatics tools available online (www.cbs.dtu.dk) and scanned human NoxA1 protein (accession number NM_006647) for predicted phosphorylation sites.	1	13	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	NoxA1	NoxA1	NoxA1	12	13	9	10
To test whether NoxA1 is targeted by Src under more physiological conditions , HT29 cells were treated with Src inhibitor PP2 or PP3 , endogenous or ectopically expressed NoxA1 was immunoprecipitated and the levels of tyrosine ( Tyr )-phosphorylated NoxA1 were analyzed using p-Tyr antibody .	To test whether NoxA1 is targeted by Src under more physiological conditions, HT29 cells were treated with Src inhibitor PP2 or PP3, endogenous or ectopically expressed NoxA1 was immunoprecipitated and the levels of tyrosine (Tyr)-phosphorylated NoxA1 were analyzed using p-Tyr antibody.	3	8	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	NoxA1	NoxA1	NoxA1	7	8	3	4
Cerebral ischemia induces a Src mediated up-regulation of Spry2 in a NMDA receptor dependent manner , serving as an attenuation signal in the ERK cascade .	Cerebral ischemia induces a Src mediated up-regulation of Spry2 in a NMDA receptor dependent manner, serving as an attenuation signal in the ERK cascade.	3	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Spry2	Spry2	Spry2	4	5	8	9
The NMDA receptor antagonist , ketamine , and the Src family protein kinase inhibitor , PP2 , both potently blocked the ischemia induced up-regulation of Spry2 , indicating that NMDA receptors and Src family tyrosine kinases are essential for Spry2 activity .	The NMDA receptor antagonist, ketamine, and the Src family protein kinase inhibitor, PP2, both potently blocked the ischemia induced up-regulation of Spry2, indicating that NMDA receptors and Src family tyrosine kinases are essential for Spry2 activity.	9	26	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Spry2	Spry2	Spry2	9	10	25	26
Since c-Src is known to activate oxidative stress pathways and iNOS , we measured the expression of phosphorylated c-Src .	Since c-Src is known to activate oxidative stress pathways and iNOS, we measured the expression of phosphorylated c-Src.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	iNOS	iNOS	iNOS	1	2	10	11
We next tested whether SRC activation is sufficient to activate the ERK pathway by comparing the effects of PTPRA and PTPRE ( XREF_FIG ) .	We next tested whether SRC activation is sufficient to activate the ERK pathway by comparing the effects of PTPRA and PTPRE (XREF_FIG).	4	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRC	SRC	SRC	PTPRA	PTPRA	PTPRA	4	5	18	19
Thus , activation of Src by estrogen may enhance RSK2 activity in some tumors .	Thus, activation of Src by estrogen may enhance RSK2 activity in some tumors.	2	10	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	RSK2	RSK2	RSK2	4	5	9	10
E3 ubiquitin ligase NKLAM ubiquitinates STAT1 and positively regulates STAT1 mediated transcriptional activity .	E3 ubiquitin ligase NKLAM ubiquitinates STAT1 and positively regulates STAT1 mediated transcriptional activity.	0	10	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	STAT1	E3 ubiquitin ligase NKLAM ubiquitinates STAT1	stat1	STAT1	STAT1	stat1	5	6	9	10
IFNgamma activates gene expression by stimulating the phosphorylation of the STAT1 transcription factor , which allows STAT1 to translocate to the nucleus and bind DNA .	IFNgamma activates gene expression by stimulating the phosphorylation of the STAT1 transcription factor, which allows STAT1 to translocate to the nucleus and bind DNA.	0	18	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	IFNgamma activates gene expression by stimulating the phosphorylation of the STAT1	stat1	STAT1	STAT1	stat1	10	11	16	17
In XREF_FIG , although the phosphorylation of STAT1 was obviously upregulated in HEK293 cells overexpressing STAT1 WT or its mutant STAT1 Y701F , it did not result in increased levels of SAMHD1 .	In XREF_FIG, although the phosphorylation of STAT1 was obviously upregulated in HEK293 cells overexpressing STAT1 WT or its mutant STAT1 Y701F, it did not result in increased levels of SAMHD1.	5	16	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	phosphorylation of STAT1	stat1	STAT1	STAT1	stat1	7	8	15	16
H5N1 NS1 reduced IFN inducible tyrosine phosphorylation of STAT1 , STAT2 and STAT3 and inhibited the nuclear translocation of phospho-STAT2 and the formation of IFN inducible STAT1 : STAT1-, STAT1 : STAT3- and STAT3 : STAT3-DNA complexes .	H5N1 NS1 reduced IFN inducible tyrosine phosphorylation of STAT1, STAT2 and STAT3 and inhibited the nuclear translocation of phospho-STAT2 and the formation of IFN inducible STAT1 : STAT1-, STAT1 : STAT3- and STAT3 : STAT3-DNA complexes.	1	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	NS1 reduced IFN inducible tyrosine phosphorylation of STAT1	stat1	STAT1	STAT1	stat1	8	9	26	27
Overexpression of SHP-2 in 293T cells inhibited IFNgamma dependent Stat1 phosphorylation and suppressed Stat1 dependent induction of luciferase activity .	Overexpression of SHP-2 in 293T cells inhibited IFNgamma dependent Stat1 phosphorylation and suppressed Stat1 dependent induction of luciferase activity.	0	15	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Stat1	Overexpression of SHP-2 in 293T cells inhibited IFNgamma dependent Stat1 phosphorylation	stat1	Stat1	Stat1	stat1	9	10	13	14
Curcumin ( 50 micromol x L (-1) ) significantly increased phosphorylations of p38 ( T180 and Y182 ) and STAT-1 ( S727 ) in Huh7 and Hep3B cells , and caused relocalization of phosphorylated-STAT-1 ( Y701 ) from cytoplasm to nucleus in Hep3B cells .	Curcumin (50 micromol x L (-1)) significantly increased phosphorylations of p38 (T180 and Y182) and STAT-1 (S727) in Huh7 and Hep3B cells, and caused relocalization of phosphorylated-STAT-1 (Y701) from cytoplasm to nucleus in Hep3B cells.	0	34	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT-1	Curcumin (50 micromol x L (-1)) significantly increased phosphorylations of p38 (T180 and Y182) and STAT-1 (S727	stat-1	phosphorylated-STAT-1	phosphorylated-STAT-1	phosphorylated-stat-1	19	20	33	34
This phenomenon inferred that STAT 701 is not downstream of Ca 2+ signals , but it is indirectly evoked by inhibiting the Ca 2+ pathway via Rho family A PKCalpha- and betaI specific inhibitor ( 5 nM Go6976 ) and non specific inhibitor ( 5 nM staurosporine ) , or all inhibitors of MAP kinases ( 50 muM PD98059 , 10 muM SP600125 , 10 muM SB203580 ) remarkably inhibited the phosphorylation of STAT1 727 , but weakly inhibited STAT1 701 activity .	This phenomenon inferred that STAT 701 is not downstream of Ca 2+ signals, but it is indirectly evoked by inhibiting the Ca 2+ pathway via Rho family A PKCalpha- and betaI specific inhibitor (5 nM Go6976) and non specific inhibitor (5 nM staurosporine), or all inhibitors of MAP kinases (50 muM PD98059, 10 muM SP600125, 10 muM SB203580) remarkably inhibited the phosphorylation of STAT1 727, but weakly inhibited STAT1 701 activity.	22	81	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	Ca 2+ pathway via Rho family A PKCalpha- and betaI specific inhibitor (5 nM Go6976) and non specific inhibitor (5 nM staurosporine), or all inhibitors of MAP kinases (50 muM PD98059, 10 muM SP600125, 10 muM SB203580) remarkably inhibited the phosphorylation of STAT1	stat1	STAT1	STAT1	stat1	73	74	79	80
STAT3 did not suppress STAT1 tyrosine phosphorylation or nuclear translocation but instead sequestered STAT1 and suppressed the formation of DNA binding STAT1 homodimers .	STAT3 did not suppress STAT1 tyrosine phosphorylation or nuclear translocation but instead sequestered STAT1 and suppressed the formation of DNA binding STAT1 homodimers.	0	22	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	STAT3 did not suppress STAT1 tyrosine phosphorylation	stat1	STAT1	STAT1	stat1	4	5	21	22
Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2 .	Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2.	2	15	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	EGFR induces Tyr701 phosphorylation of STAT1	stat1	STAT1	STAT1	stat1	7	8	13	14
In this model , STAT1 tyrosine phosphorylation triggers or stabilizes a conformational change of pre-existing STAT1 dimers from antiparallel to parallel configuration and results in increased abundance of parallel dimers with an exposed nuclear localization sequence and high DNA binding activity .	In this model, STAT1 tyrosine phosphorylation triggers or stabilizes a conformational change of pre-existing STAT1 dimers from antiparallel to parallel configuration and results in increased abundance of parallel dimers with an exposed nuclear localization sequence and high DNA binding activity.	4	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	STAT1 tyrosine phosphorylation	stat1	STAT1	STAT1	stat1	4	5	15	16
JAK mediated phosphorylation of STAT1 induces a change in conformation of STAT1 to its activated form , and the activated STAT1 homodimer translocates to the nucleus to promote transcription of IFNgamma induced genes .	JAK mediated phosphorylation of STAT1 induces a change in conformation of STAT1 to its activated form, and the activated STAT1 homodimer translocates to the nucleus to promote transcription of IFNgamma induced genes.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	JAK mediated phosphorylation of STAT1	stat1	STAT1	STAT1	stat1	4	5	11	12
Overexpression of STAT1 via stable transfection enhances IFN-gamma activation of STAT1 , but surprisingly attenuates IFN-alpha activation of STAT1 , STAT2 and STAT3 without affecting Janus kinase activation .	Overexpression of STAT1 via stable transfection enhances IFN-gamma activation of STAT1, but surprisingly attenuates IFN-alpha activation of STAT1, STAT2 and STAT3 without affecting Janus kinase activation.	0	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	Overexpression of STAT1	stat1	STAT1	STAT1	stat1	2	3	10	11
We concluded from these data that the TgIST repressor effect on STAT1 activity coincided with phosphorylation of STAT1 , a modification that could increase STAT1 ability to associate with chromatin .	We concluded from these data that the TgIST repressor effect on STAT1 activity coincided with phosphorylation of STAT1, a modification that could increase STAT1 ability to associate with chromatin.	15	25	increase	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	STAT1	phosphorylation of STAT1	stat1	STAT1	STAT1	stat1	17	18	24	25
In this study , they showed that IFN-gamma induced activation of STAT1 promoted binding of STAT1 to the DNA binding domain of VDR , preventing VDR from inducing expression of CYP24A1 .	In this study, they showed that IFN-gamma induced activation of STAT1 promoted binding of STAT1 to the DNA binding domain of VDR, preventing VDR from inducing expression of CYP24A1.	7	16	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	IFN-gamma induced activation of STAT1	stat1	STAT1	STAT1	stat1	11	12	15	16
MVP expression in H65 cells also significantly reduced STAT1 phosphorylation at Y701 and decreased the translocation of STAT1 into nuclei .	MVP expression in H65 cells also significantly reduced STAT1 phosphorylation at Y701 and decreased the translocation of STAT1 into nuclei.	0	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	MVP expression in H65 cells also significantly reduced STAT1 phosphorylation at Y701	stat1	STAT1	STAT1	stat1	8	9	17	18
Treatment of c-Jun -/- MEFs with doses as low as 1 IU/mL IFNbeta induced STAT1 mRNA and doses between 5 and 10 IU/mL were sufficient to restore STAT1 mRNA and protein expression to levels seen in wild-type cells ( XREF_SUPPLEMENTARY ) .	Treatment of c-Jun -/- MEFs with doses as low as 1 IU/mL IFNbeta induced STAT1 mRNA and doses between 5 and 10 IU/mL were sufficient to restore STAT1 mRNA and protein expression to levels seen in wild-type cells (XREF_SUPPLEMENTARY).	11	28	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	IU/mL IFNbeta induced STAT1	stat1	STAT1	STAT1	stat1	14	15	27	28
Our data suggest that in addition to degradation , STAT1 ubiquitination may positively regulate STAT1 transcriptional activity ; therefore , we next examined STAT1 nuclear protein expression and translocation .	Our data suggest that in addition to degradation, STAT1 ubiquitination may positively regulate STAT1 transcriptional activity; therefore, we next examined STAT1 nuclear protein expression and translocation.	9	16	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	STAT1	STAT1 ubiquitination	stat1	STAT1	STAT1	stat1	9	10	14	15
Previously we had shown that the loss of Ubp43 in mice resulted in an enhanced and prolonged STAT1 phosphorylation upon IFN-alpha and beta stimulation and increased apoptosis of hematopoietic cells upon polyI : C or LPS administration [ XREF_BIBR ] .	Previously we had shown that the loss of Ubp43 in mice resulted in an enhanced and prolonged STAT1 phosphorylation upon IFN-alpha and beta stimulation and increased apoptosis of hematopoietic cells upon polyI : C or LPS administration [XREF_BIBR].	11	19	prolonged	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	STAT1	STAT1 phosphorylation	stat1	STAT1	STAT1	stat1	17	18	17	18
Alternatively , IE1 may actively induce STAT1 Y701 phosphorylation thereby promoting nuclear import of STAT1 dimers .	Alternatively, IE1 may actively induce STAT1 Y701 phosphorylation thereby promoting nuclear import of STAT1 dimers.	2	15	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	IE1 may actively induce STAT1 Y701 phosphorylation	stat1	STAT1	STAT1	stat1	6	7	14	15
STAT1 and PIAS1 association can be modulated by STAT1 methylation .	STAT1 and PIAS1 association can be modulated by STAT1 methylation.	0	10	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STAT1	STAT1 methylation	stat1	STAT1	STAT1	stat1	8	9	0	1
IFNG binds to the type II IFN receptor and exclusively phosphorylates STAT1 through the receptor associated Janus activated kinases ( JAKs ) , whereas type I IFNs , such as IFNB , recognize the type I IFN receptor , and activate STAT1 and STAT2 .	IFNG binds to the type II IFN receptor and exclusively phosphorylates STAT1 through the receptor associated Janus activated kinases (JAKs), whereas type I IFNs, such as IFNB, recognize the type I IFN receptor, and activate STAT1 and STAT2.	0	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	IFNG binds to the type II IFN receptor and exclusively phosphorylates STAT1	stat1	STAT1	STAT1	stat1	11	12	41	42
De-acetylation of STAT1 that is mediated by HDACs such as HDAC3 thus promotes increased tyrosine phosphorylation and stabilization of the active parallel configuration STAT1 dimer ( XREF_FIG ) .	De-acetylation of STAT1 that is mediated by HDACs such as HDAC3 thus promotes increased tyrosine phosphorylation and stabilization of the active parallel configuration STAT1 dimer (XREF_FIG).	0	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	De-acetylation of STAT1	stat1	STAT1	STAT1	stat1	2	3	23	24
Mechanistically , Dip G activated ERK , which caused phosphorylation of STAT1 at Ser727 and selectively enhanced the interaction of p-STAT1 ( Ser727 ) and p-ERK , further promoting their nuclear translocation .	Mechanistically, Dip G activated ERK, which caused phosphorylation of STAT1 at Ser727 and selectively enhanced the interaction of p-STAT1 (Ser727) and p-ERK, further promoting their nuclear translocation.	2	22	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	Dip G activated ERK, which caused phosphorylation of STAT1 at Ser727	stat1	p-STAT1	p-STAT1	p-stat1	11	12	20	21
IFNgamma induces tyrosine phosphorylation of Stat1 and promotes the formation of Stat1 homodimers ( gamma activated factor , or GAF ) .	IFNgamma induces tyrosine phosphorylation of Stat1 and promotes the formation of Stat1 homodimers (gamma activated factor, or GAF).	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stat1	IFNgamma induces tyrosine phosphorylation of Stat1	stat1	Stat1	Stat1	stat1	5	6	11	12
Our data show that IFNalpha clearly activates phosphorylation of STAT1 and STAT3 but preferentially activates STAT1 over STAT3 in THP1 and A375 cells .	Our data show that IFNalpha clearly activates phosphorylation of STAT1 and STAT3 but preferentially activates STAT1 over STAT3 in THP1 and A375 cells.	4	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	IFNalpha clearly activates phosphorylation of STAT1	stat1	STAT1	STAT1	stat1	9	10	15	16
Western blots demonstrated that doxorubicin not only stimulated the expression of STAT1 but also promoted STAT1 activation through the phosphorylation of Tyr701 and Ser727 residues ( XREF_FIG ) .	Western blots demonstrated that doxorubicin not only stimulated the expression of STAT1 but also promoted STAT1 activation through the phosphorylation of Tyr701 and Ser727 residues (XREF_FIG).	4	16	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	doxorubicin not only stimulated the expression of STAT1	stat1	STAT1	STAT1	stat1	11	12	15	16
When STAT1 expression was restored using a STAT1 expression vector , the cell line showed decreased growth in vivo as well as decreased microvessel density XREF_BIBR .	When STAT1 expression was restored using a STAT1 expression vector, the cell line showed decreased growth in vivo as well as decreased microvessel density XREF_BIBR.	1	9	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	STAT1 expression	stat1	STAT1	STAT1	stat1	1	2	7	8
STAT1 phosphorylation was also increased in infected cells overexpressing STAT1-WT as compared to the control cells ( XREF_FIG ) .	STAT1 phosphorylation was also increased in infected cells overexpressing STAT1-WT as compared to the control cells (XREF_FIG).	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	STAT1 phosphorylation	stat1	STAT1-WT	STAT1-WT	stat1-wt	0	1	9	10
Therefore , JEV NS5 does not block the induction of IFN , but activates a cellular PTP to dephosphorylate STAT1 and Tyk2 , thus preventing the nuclear translocation of STAT1 .	Therefore, JEV NS5 does not block the induction of IFN, but activates a cellular PTP to dephosphorylate STAT1 and Tyk2, thus preventing the nuclear translocation of STAT1.	18	30	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	dephosphorylate STAT1	stat1	STAT1	STAT1	stat1	19	20	29	30
OPN represses inducible nitric oxide synthase ( iNOS ) by increasing Stat1 ubiquitination and proteasome mediated degradation of Stat1 , consequently inhibiting Stat1 mediated iNOS transcription and protein expression .	OPN represses inducible nitric oxide synthase (iNOS) by increasing Stat1 ubiquitination and proteasome mediated degradation of Stat1, consequently inhibiting Stat1 mediated iNOS transcription and protein expression.	0	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Stat1	OPN represses inducible nitric oxide synthase (iNOS) by increasing Stat1 ubiquitination	stat1	Stat1	Stat1	stat1	11	12	18	19
This let us postulate that STAT1 phosphorylation at Y701 might directly enhance the SUMOylatability of STAT1 at K703 .	This let us postulate that STAT1 phosphorylation at Y701 might directly enhance the SUMOylatability of STAT1 at K703.	5	16	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	STAT1 phosphorylation at Y701	stat1	STAT1	STAT1	stat1	5	6	15	16
Moreover , this model does not take into consideration some currently accepted regulatory mechanisms affecting STAT1 : DNA binding activity , such as STAT1 simulation and transcriptional activity of unphosphorylated STAT1 .	Moreover, this model does not take into consideration some currently accepted regulatory mechanisms affecting STAT1 : DNA binding activity, such as STAT1 simulation and transcriptional activity of unphosphorylated STAT1.	11	31	accepted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	unphosphorylated STAT1	stat1	STAT1	STAT1	stat1	30	31	15	16
HDAC4 deacetylates STAT1 , thereby enhancing phosphorylation and nuclear translocation of STAT1 upon cisplatin-treatment in platinum resistant ovarian cancer cells ( exposure to chemotherapy ) [ XREF_BIBR ] .	HDAC4 deacetylates STAT1, thereby enhancing phosphorylation and nuclear translocation of STAT1 upon cisplatin-treatment in platinum resistant ovarian cancer cells (exposure to chemotherapy) [XREF_BIBR].	0	12	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	HDAC4 deacetylates STAT1	stat1	STAT1	STAT1	stat1	2	3	11	12
This STAT1 mediated inhibition does not require STAT1 tyrosine phosphorylation because overexpression of dominant negative STAT1 with a mutation on tyrosine residue 701 also blocks IFN-alpha activation of STAT1 , STAT2 and STAT3 .	This STAT1 mediated inhibition does not require STAT1 tyrosine phosphorylation because overexpression of dominant negative STAT1 with a mutation on tyrosine residue 701 also blocks IFN-alpha activation of STAT1, STAT2 and STAT3.	0	10	mediated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	STAT1	STAT1	stat1	STAT1	STAT1 tyrosine phosphorylation	stat1	1	2	7	8
IFN-gamma induced STAT1 activation 30 min after treatment and increased STAT1 , IRF-1 , and ATF3 proteins with peak effects occurring at 24-120 h post treatment ( XREF_FIG ) .	IFN-gamma induced STAT1 activation 30 min after treatment and increased STAT1, IRF-1, and ATF3 proteins with peak effects occurring at 24-120 h post treatment (XREF_FIG).	0	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	IFN-gamma induced STAT1	stat1	STAT1	STAT1	stat1	2	3	10	11
IFN-gamma stimulation induces phosphorylation of STAT1 and promotes formation of STAT1 homodimers , resulting in many gene transcriptions .	IFN-gamma stimulation induces phosphorylation of STAT1 and promotes formation of STAT1 homodimers, resulting in many gene transcriptions.	0	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	IFN-gamma stimulation induces phosphorylation of STAT1	stat1	STAT1	STAT1	stat1	5	6	10	11
Phosphorylation of STAT1 at Tyr701 increases STAT1 dimerization , nuclear localization , DNA binding and is a key factor in Th1 commitment [ XREF_BIBR ] .	Phosphorylation of STAT1 at Tyr701 increases STAT1 dimerization, nuclear localization, DNA binding and is a key factor in Th1 commitment [XREF_BIBR].	0	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	Phosphorylation of STAT1 at Tyr701	stat1	STAT1	STAT1	stat1	2	3	6	7
STAT1 expression in response to day of pregnancy , estrogen injection , and intrauterine infusion of conceptus secretory proteins in pigs indicated 1 ) estrogen increases STAT1 in luminal epithelial cells , 2 ) conceptus secretory proteins that contain interferons increase STAT1 in stroma , 3 ) STAT1 increases in close proximity to the conceptus , and 4 ) early estrogen results in conceptus death and no STAT1 in stroma .	STAT1 expression in response to day of pregnancy, estrogen injection, and intrauterine infusion of conceptus secretory proteins in pigs indicated 1) estrogen increases STAT1 in luminal epithelial cells, 2) conceptus secretory proteins that contain interferons increase STAT1 in stroma, 3) STAT1 increases in close proximity to the conceptus, and 4) early estrogen results in conceptus death and no STAT1 in stroma.	0	38	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	STAT1 expression	stat1	STAT1	STAT1	stat1	0	1	26	27
Phosphorylation of STAT1 by JAK1 activates STAT1 , which forms a heterodimer with STAT2 and recruits IRF9 to form the IFN stimulated gene factor 3 ( ISGF3 ) transcriptional complex [ XREF_BIBR , XREF_BIBR ] .	Phosphorylation of STAT1 by JAK1 activates STAT1, which forms a heterodimer with STAT2 and recruits IRF9 to form the IFN stimulated gene factor 3 (ISGF3) transcriptional complex [XREF_BIBR, XREF_BIBR].	0	15	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	STAT1	Phosphorylation of STAT1 by JAK1	stat1	STAT1	STAT1, which forms a heterodimer with STAT2	stat1	2	3	6	7
These results demonstrate that the overexpression of p-tyr 701 Stat1 after short times ( 0-48 hours ) does not depend on pyrogenic contaminants but rather from the mechanism of internalization activating JAK and STAT1 signalling pathway .	These results demonstrate that the overexpression of p-tyr 701 Stat1 after short times (0-48 hours) does not depend on pyrogenic contaminants but rather from the mechanism of internalization activating JAK and STAT1 signalling pathway.	5	35	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stat1	overexpression of p-tyr 701 Stat1	stat1	STAT1	STAT1	stat1	9	10	33	34
Consistent with this hypothesis , our recent study indicates that the activation of Stat6 : ER , a conditionally active form of Stat6 , which mimics the IL-4-mediated signaling without ligation of IL-4 and its receptor , did not induce GATA-3 or Th2 cytokines in committed Th1 cells but did so in developing Th1 cells 39 .	Consistent with this hypothesis, our recent study indicates that the activation of Stat6 : ER, a conditionally active form of Stat6, which mimics the IL-4-mediated signaling without ligation of IL-4 and its receptor, did not induce GATA-3 or Th2 cytokines in committed Th1 cells but did so in developing Th1 cells 39.	11	43	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA-3	GATA-3	GATA-3	13	14	40	41
The activation of STAT6 by IL-4 upregulates GATA3 , c-Maf , and Jun B expression as naive CD4 + T cells differentiate into Th2 cells [ XREF_BIBR - XREF_BIBR ] .	The activation of STAT6 by IL-4 upregulates GATA3, c-Maf, and Jun B expression as naive CD4 + T cells differentiate into Th2 cells [XREF_BIBR - XREF_BIBR].	1	12	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	3	4	7	8
STAT1 and STAT4 activate Tbet , the transcription factor which drives Th1cell differentiation , STAT6 induces GATA3 in Th2 differentiation , STAT3 activates RORgammat which activates IL-17 and Th17 differentiation , STAT3 induces Bcl6 transcription factor of Tfh cells , and STAT5 activates Foxp3 which drives Treg differentiation .	STAT1 and STAT4 activate Tbet, the transcription factor which drives Th1cell differentiation, STAT6 induces GATA3 in Th2 differentiation, STAT3 activates RORgammat which activates IL-17 and Th17 differentiation, STAT3 induces Bcl6 transcription factor of Tfh cells, and STAT5 activates Foxp3 which drives Treg differentiation.	14	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	14	15	16	17
However , gene repression may be indirect , through the Stat6 mediated induction of GATA-3 .	However, gene repression may be indirect, through the Stat6 mediated induction of GATA-3.	6	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA-3	GATA-3	GATA-3	10	11	14	15
However , siRNA knockdown of STAT6 attenuated NaB mediated increase in GATA3 and IL-10 mRNAs in PLP primed splenocytes ( XREF_FIG ) .	However, siRNA knockdown of STAT6 attenuated NaB mediated increase in GATA3 and IL-10 mRNAs in PLP primed splenocytes (XREF_FIG).	3	14	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	5	6	11	12
STAT6 stimulates alveolar differentiation and proliferation potentially by transcriptionally inducing GATA3 .	STAT6 stimulates alveolar differentiation and proliferation potentially by transcriptionally inducing GATA3.	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	0	1	10	11
13 Extracellular pathogens or allergens promote Th2 cell lineage development that necessitates the induction of GATA-3 , mediated by IL-4-dependent STAT6 ( signal transducer and activator of transcription 6 ) activation .	13 Extracellular pathogens or allergens promote Th2 cell lineage development that necessitates the induction of GATA-3, mediated by IL-4-dependent STAT6 (signal transducer and activator of transcription 6) activation.	13	30	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA-3	GATA-3	GATA-3	20	21	15	16
During Th2 differentiation , GATA3 can be upregulated by IL-4 and STAT6 and/or TCR mediated signaling .	During Th2 differentiation, GATA3 can be upregulated by IL-4 and STAT6 and/or TCR mediated signaling.	4	12	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	11	12	4	5
The signaling pathway that mediates this response involves STAT6 activation of the GATA3 transcription factor .	The signaling pathway that mediates this response involves STAT6 activation of the GATA3 transcription factor.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	8	9	12	13
XREF_BIBR In T cells , IL-4-activated STAT6 upregulates GATA3 , the master regulator of Th2 cells .	XREF_BIBR In T cells, IL-4-activated STAT6 upregulates GATA3, the master regulator of Th2 cells.	5	12	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	6	7	8	9
For T cells , IL-4 production by Th2 facilitates the polarization of more Th2 through STAT6 induction of GATA3 .	For T cells, IL-4 production by Th2 facilitates the polarization of more Th2 through STAT6 induction of GATA3.	15	19	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	15	16	18	19
IL-4 induces the activation of transcription factors STAT5a and STAT6 via the JAK and STAT pathway which then enables STAT-6 mediated activation of GATA3 , which is the master regulator of Th2 cell differentiation .	IL-4 induces the activation of transcription factors STAT5a and STAT6 via the JAK and STAT pathway which then enables STAT-6 mediated activation of GATA3, which is the master regulator of Th2 cell differentiation.	19	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	STAT-6	STAT-6	STAT-6	GATA3	GATA3	GATA3	19	20	23	24
FOG-1 fully repressed GATA-3-dependent Th2 development and GATA-3 autoactivation , but not Stat6 dependent induction of GATA-3 .	FOG-1 fully repressed GATA-3-dependent Th2 development and GATA-3 autoactivation, but not Stat6 dependent induction of GATA-3.	12	17	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA-3	GATA-3	GATA-3	12	13	16	17
IL-4 and STAT-6 activate the GATA3 gene , which is a main Th2 cell type regulator .	IL-4 and STAT-6 activate the GATA3 gene, which is a main Th2 cell type regulator.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT-6	STAT-6	STAT-6	GATA3	GATA3	GATA3	2	3	5	6
To completely eliminate Stat6 dependent induction of GATA-3 and examine FOG-1 repression of GATA-3 autoactivation in isolation , we repeated the experiment now using Stat6 deficient T cells ( XREF_FIG C ) .	To completely eliminate Stat6 dependent induction of GATA-3 and examine FOG-1 repression of GATA-3 autoactivation in isolation, we repeated the experiment now using Stat6 deficient T cells (XREF_FIG C).	3	8	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA-3	GATA-3	GATA-3	3	4	7	8
In the above experiment , IL-4 induced by the retroviral GATA-3 may not be completely neutralized by antibody , allowing for potential Stat6 dependent induction of GATA-3 in T cells .	In the above experiment, IL-4 induced by the retroviral GATA-3 may not be completely neutralized by antibody, allowing for potential Stat6 dependent induction of GATA-3 in T cells.	22	27	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA-3	GATA-3	GATA-3	22	23	26	27
While activated STAT6 induces GATA3 , the master transcription factor necessary for Th2 development , STAT6 independent mechanisms for GATA3 induction and Th2 differentiation have been identified , including pathways involving Notch , TCF-1 and beta-catenin , and IL-2 and STAT5A signaling .	While activated STAT6 induces GATA3, the master transcription factor necessary for Th2 development, STAT6 independent mechanisms for GATA3 induction and Th2 differentiation have been identified, including pathways involving Notch, TCF-1 and beta-catenin, and IL-2 and STAT5A signaling.	1	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	2	3	4	5
Certainly , signaling through Notch is important for STAT6 independent activation of GATA-3 , and likely plays an important role Th2 cytokine expression [ XREF_BIBR ] .	Certainly, signaling through Notch is important for STAT6 independent activation of GATA-3, and likely plays an important role Th2 cytokine expression [XREF_BIBR].	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA-3	GATA-3	GATA-3	8	9	12	13
Although STAT6 induced GATA3 is thought to mediate the epigenetic changes that result in an open IL-10 locus in T H 2 cells , both proteins are dispensable for IL-10 secretion in mature T H 2 polarized CD4 + T cells .	Although STAT6 induced GATA3 is thought to mediate the epigenetic changes that result in an open IL-10 locus in T H 2 cells, both proteins are dispensable for IL-10 secretion in mature T H 2 polarized CD4 + T cells.	1	7	induced	Positive_early_activation	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	1	2	3	4
IL-4 binding to the IL-4 receptor ( IL-4R ) results in Signal transducer and activator of transcription 6 ( Stat6 ) recruitment , phosphorylation , dimerization and translocation to the nucleus , where Stat6 activates the transcription factor Gata3 , which is considered a Th2 master regulator XREF_BIBR - XREF_BIBR .	IL-4 binding to the IL-4 receptor (IL-4R) results in Signal transducer and activator of transcription 6 (Stat6) recruitment, phosphorylation, dimerization and translocation to the nucleus, where Stat6 activates the transcription factor Gata3, which is considered a Th2 master regulator XREF_BIBR - XREF_BIBR.	33	42	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	Gata3	Gata3	Gata3	33	34	38	39
In peripheral CD4 T cells , the activation of STAT6 induces high-level GATA3 mRNA expression XREF_BIBR .	In peripheral CD4 T cells, the activation of STAT6 induces high-level GATA3 mRNA expression XREF_BIBR.	7	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	9	10	12	13
Interleukin ( IL ) -4 receptor engagement leads to the activation of the transcription factor STAT6 , which then upregulates the transcription factor GATA3 [ XREF_BIBR ] , which in turn augments the production of the Th2 cytokines IL-4 , IL-5 , and IL-13 [ XREF_BIBR ] .	Interleukin (IL) -4 receptor engagement leads to the activation of the transcription factor STAT6, which then upregulates the transcription factor GATA3 [XREF_BIBR], which in turn augments the production of the Th2 cytokines IL-4, IL-5, and IL-13 [XREF_BIBR].	10	25	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	15	16	23	24
Likewise , STAT6 drives Gata3 , Il4 , Il4ra , and other genes necessary for Th2 cells .	Likewise, STAT6 drives Gata3, Il4, Il4ra, and other genes necessary for Th2 cells.	2	8	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	Gata3	Gata3	Gata3	2	3	4	5
Furthermore , STAT6 knockdown inhibited the binding of GATA3 to the NOX1 promoter site , suggesting that GATA3 responds to STAT6 activation upon IL-4 exposure ( XREF_SUPPLEMENTARY ) .	Furthermore, STAT6 knockdown inhibited the binding of GATA3 to the NOX1 promoter site, suggesting that GATA3 responds to STAT6 activation upon IL-4 exposure (XREF_SUPPLEMENTARY).	2	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	2	3	8	9
STAT6 can activate GATA-3 through the Il-4-STAT6 pathway and promote T cell differentiation towards Th2 cells .	STAT6 can activate GATA-3 through the Il-4-STAT6 pathway and promote T cell differentiation towards Th2 cells.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA-3	GATA-3	GATA-3	0	1	3	4
Stat6 activates GATA3 , the master regulator of Th2 cells , which subsequently mediates chromatin remodeling accompanied by an increased level of histone hyperacetylation at the IL-4 locus .	Stat6 activates GATA3, the master regulator of Th2 cells, which subsequently mediates chromatin remodeling accompanied by an increased level of histone hyperacetylation at the IL-4 locus.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA3	GATA3	GATA3	0	1	2	3
Further , IL-13 administration during Th17 polarization downregulated ROR-gammaT , the transcription required for Th17 development ; increased STAT6 phosphorylation , and upregulated GATA3 , the transcription factor activated during the development of Th2 cells .	Further, IL-13 administration during Th17 polarization downregulated ROR-gammaT, the transcription required for Th17 development; increased STAT6 phosphorylation, and upregulated GATA3, the transcription factor activated during the development of Th2 cells.	2	27	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	IL-13 administration during Th17 polarization downregulated ROR-gammaT, the transcription required for Th17 development; increased STAT6 phosphorylation	stat6	GATA3	GATA3	gata3	18	19	23	24
Evidence from retroviral expression studies implied that this pathway involved an autoactivation of GATA-3 expression , since Stat6 deficient T cells induced endogenous GATA-3 when infected with GATA-3-expressing retroviruses .	Evidence from retroviral expression studies implied that this pathway involved an autoactivation of GATA-3 expression, since Stat6 deficient T cells induced endogenous GATA-3 when infected with GATA-3-expressing retroviruses.	17	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA-3	GATA-3	GATA-3	17	18	23	24
Although IL-4 is not an absolute requirement for naive T cell differentiation into Th2 cells , IL-4-induced Stat6 stimulation of GATA3 , the transcription factor required for Th2 differentiation , amplifies Th2 differentiation sufficiently to be required in many instances for the development of a predominant Th2 response ; this requirement has been observed in most , but not all mouse models of asthma .	Although IL-4 is not an absolute requirement for naive T cell differentiation into Th2 cells, IL-4-induced Stat6 stimulation of GATA3, the transcription factor required for Th2 differentiation, amplifies Th2 differentiation sufficiently to be required in many instances for the development of a predominant Th2 response; this requirement has been observed in most, but not all mouse models of asthma.	17	21	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA3	GATA3	GATA3	17	18	20	21
STAT6 activates GATA3 transcription factor , which promotes T cell differentiation into Th2 cells producing IL-4 , IL-5 , and IL-13 .	STAT6 activates GATA3 transcription factor, which promotes T cell differentiation into Th2 cells producing IL-4, IL-5, and IL-13.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	0	1	2	3
Differentiation of naive CD4 + T cells into the Th2 lineage is driven by IL-4-mediated STAT6 activation of the transcription factor Gata3 .	Differentiation of naive CD4 + T cells into the Th2 lineage is driven by IL-4-mediated STAT6 activation of the transcription factor Gata3.	15	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	Gata3	Gata3	Gata3	15	16	21	22
In this way , FOG-1 might regulate GATA-3 activity in naive T cells , but not block the Stat6 dependent IL-4-driven induction of GATA-3 .	In this way, FOG-1 might regulate GATA-3 activity in naive T cells, but not block the Stat6 dependent IL-4-driven induction of GATA-3.	18	24	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA-3	GATA-3	GATA-3	18	19	23	24
IL-4 receptor signals activate STAT6 , which upregulates GATA-3 in activated T cells .	IL-4 receptor signals activate STAT6, which upregulates GATA-3 in activated T cells.	3	12	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA-3	GATA-3	GATA-3	4	5	8	9
In peripheral CD4 T cells , the activation of STAT6 induces high-level expression of GATA3 messenger RNA ( mRNA ) , although the precise mechanisms underlying the STAT6 induced GATA3 transcription remain unclear .	In peripheral CD4 T cells, the activation of STAT6 induces high-level expression of GATA3 messenger RNA (mRNA), although the precise mechanisms underlying the STAT6 induced GATA3 transcription remain unclear.	7	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	GATA3	GATA3	GATA3	9	10	14	15
The differentiation of Th2 cells is induced by the transcription factor GATA3 which is activated by pSTAT6 via IL-4 signalling .	The differentiation of Th2 cells is induced by the transcription factor GATA3 which is activated by pSTAT6 via IL-4 signalling.	6	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	pSTAT6	pSTAT6	pSTAT6	GATA3	GATA3	GATA3	16	17	11	12
IL-4 receptor engagement leads to activation of Stat6 , which in turn upregulates the transcription factor GATA3 .	IL-4 receptor engagement leads to activation of Stat6, which in turn upregulates the transcription factor GATA3.	5	17	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA3	GATA3	GATA3	7	8	16	17
Mechanisms that affect all Th2 responses ( including IL-4 responses ) such as induction of SOCS proteins which hinder Stat6 signaling or inhibition of GATA3 [ XREF_BIBR , XREF_BIBR ] are therefore unlikely to be relevant , as are mechanisms involving immunosuppression which likewise are not IL-13-specific .	Mechanisms that affect all Th2 responses (including IL-4 responses) such as induction of SOCS proteins which hinder Stat6 signaling or inhibition of GATA3 [XREF_BIBR, XREF_BIBR] are therefore unlikely to be relevant, as are mechanisms involving immunosuppression which likewise are not IL-13-specific.	19	28	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Stat6	Stat6	Stat6	GATA3	GATA3	GATA3	19	20	24	25
Sterol regulatory element binding protein-1 ( SREBP-1 ) can activate PPARgamma by inducing its expression and promoting the production of endogenous PPARgamma ligands .	Sterol regulatory element binding protein-1 (SREBP-1) can activate PPARgamma by inducing its expression and promoting the production of endogenous PPARgamma ligands.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SREBP-1	SREBP-1	SREBP-1	PPARgamma	PPARgamma	PPARgamma	6	7	10	11
It is unclear whether mTOR activates SREBP-1 , which in turn induces PPARgamma activity or whether mTOR interacts with each of these transcription factors independently following RCTs .	It is unclear whether mTOR activates SREBP-1, which in turn induces PPARgamma activity or whether mTOR interacts with each of these transcription factors independently following RCTs.	5	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SREBP-1	SREBP-1	SREBP-1	PPARgamma	PPARgamma	PPARgamma	6	7	12	13
SREBP1 can also activate PPARgamma , by both stimulating the production of an endogenous ligand [ XREF_BIBR ] , as well as by inducing PPAR promoter activity [ XREF_BIBR , XREF_BIBR ] .	SREBP1 can also activate PPARgamma, by both stimulating the production of an endogenous ligand [XREF_BIBR], as well as by inducing PPAR promoter activity [XREF_BIBR, XREF_BIBR].	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SREBP1	SREBP1	SREBP1	PPARgamma	PPARgamma	PPARgamma	0	1	4	5
SREBP1 has been found to activate PPARgamma through production of endogenous ligand .	SREBP1 has been found to activate PPARgamma through production of endogenous ligand.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SREBP1	SREBP1	SREBP1	PPARgamma	PPARgamma	PPARgamma	0	1	6	7
We show here that the expression of ADD1 and SREBP1 specifically increases the activity of PPARgamma but not other isoforms , PPARalpha , or PPARdelta .	We show here that the expression of ADD1 and SREBP1 specifically increases the activity of PPARgamma but not other isoforms, PPARalpha, or PPARdelta.	5	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SREBP1	expression of ADD1 and SREBP1	srebp1	PPARgamma	PPARgamma	ppargamma	9	10	15	16
Furthermore , the expression of SREBP1 increases the activity of PPARgamma but not that of PPARalpha or PPARdelta , through production of endogenous ligands [ XREF_BIBR ] .	Furthermore, the expression of SREBP1 increases the activity of PPARgamma but not that of PPARalpha or PPARdelta, through production of endogenous ligands [XREF_BIBR].	3	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SREBP1	expression of SREBP1	srebp1	PPARgamma	PPARgamma	ppargamma	5	6	10	11
SREBP1 is known to critically cross-activate a ligand binding domain of PPAR-gamma and activate the production of an endogenous PPAR-gamma ligand [ XREF_BIBR ] .	SREBP1 is known to critically cross-activate a ligand binding domain of PPAR-gamma and activate the production of an endogenous PPAR-gamma ligand [XREF_BIBR].	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SREBP1	SREBP1	SREBP1	PPAR-gamma	PPAR-gamma	PPAR-gamma	0	1	19	20
XREF_BIBR - XREF_BIBR However , SREBP1 can also activate PPARgamma , by both stimulating the production of an endogenous ligand , 64 as well as by inducing PPARgamma promoter activity via a E-box motif .	XREF_BIBR - XREF_BIBR However, SREBP1 can also activate PPARgamma, by both stimulating the production of an endogenous ligand, 64 as well as by inducing PPARgamma promoter activity via a E-box motif.	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SREBP1	SREBP1	SREBP1	PPARgamma	PPARgamma	PPARgamma	5	6	9	10
In this way , SREBP1 activation potently enhances PPAR-gamma activity , locking the two in a positive feed-forward loop .	In this way, SREBP1 activation potently enhances PPAR-gamma activity, locking the two in a positive feed-forward loop.	4	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SREBP1	SREBP1	SREBP1	PPAR-gamma	PPAR-gamma	PPAR-gamma	4	5	8	9
PPARgamma is presented in adipose and liver tissues and can be stimulated by SREBP-1 .	PPARgamma is presented in adipose and liver tissues and can be stimulated by SREBP-1.	0	14	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SREBP-1	SREBP-1	SREBP-1	PPARgamma	PPARgamma	PPARgamma	13	14	0	1
In contrast , the double deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice ( AG129 ) , indicating that STAT2 is the mediator of the STAT1 independent host defense mechanism .	In contrast, the double deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice (AG129), indicating that STAT2 is the mediator of the STAT1 independent host defense mechanism.	29	39	is the mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	29	30	35	36
DENV NS5 protein induces targeted degradation of STAT2 via the proteasome and NS4B blocks STAT1 activation and thus inhibits IFN-alpha and beta and likely IFN-gamma and IFN-lambda receptor signaling in DENV infected cells .	DENV NS5 protein induces targeted degradation of STAT2 via the proteasome and NS4B blocks STAT1 activation and thus inhibits IFN-alpha and beta and likely IFN-gamma and IFN-lambda receptor signaling in DENV infected cells.	5	15	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	7	8	14	15
In a non infected cell , after IFN binding to its receptor , JAK1 and TYK2 are phosphorylated , then STAT2 binds to one receptor subunit and induces the binding of STAT1 to the phosphotyrosine of the other receptor subunit , allowing its phosphorylation by JAK1 .	In a non infected cell, after IFN binding to its receptor, JAK1 and TYK2 are phosphorylated, then STAT2 binds to one receptor subunit and induces the binding of STAT1 to the phosphotyrosine of the other receptor subunit, allowing its phosphorylation by JAK1.	20	32	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	20	21	31	32
Specifically , Chlamydia trachomatis infection of HeLa 229 cells selectively induces STAT1 , STAT2 , and IFN stimulated transcription factor 3gamma expression and promotes STAT1 activation .	Specifically, Chlamydia trachomatis infection of HeLa 229 cells selectively induces STAT1, STAT2, and IFN stimulated transcription factor 3gamma expression and promotes STAT1 activation.	10	25	promotes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	13	14	24	25
The expression of DUOX2 could not be detected in our WT and STAT2 overexpressing STAT1 KO cells , in response to IFNalpha , which could point to a cell-type-specific mechanism .	The expression of DUOX2 could not be detected in our WT and STAT2 overexpressing STAT1 KO cells, in response to IFNalpha, which could point to a cell-type-specific mechanism.	7	16	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	12	13	14	15
However , STAT2 does not target the activation of STAT1 , but the subsequent step , its nuclear import .	However, STAT2 does not target the activation of STAT1, but the subsequent step, its nuclear import.	2	10	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	2	3	9	10
Although this was the first description of a STAT2 mediated STAT1 independent phenotype , the focus of this work was on an immunosuppressive rather than an antiviral phenotype .	Although this was the first description of a STAT2 mediated STAT1 independent phenotype, the focus of this work was on an immunosuppressive rather than an antiviral phenotype.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	8	9	10	11
To explore how Stat2 signals independently of Stat1 , biochemical studies were carried out in primary Stat1 [-/-] BMMs .	To explore how Stat2 signals independently of Stat1, biochemical studies were carried out in primary Stat1 [-/-] BMMs.	3	8	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Stat2	Stat2	Stat2	Stat1	Stat1	Stat1	3	4	7	8
These studies confirmed that prolonged Stat2 activation in Stat1 [-/-] BMMs was dependent on prolonged and ligand dependent Jak1 activity .	These studies confirmed that prolonged Stat2 activation in Stat1 [-/-] BMMs was dependent on prolonged and ligand dependent Jak1 activity.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Stat2	Stat2	Stat2	Stat1	Stat1	Stat1	5	6	8	9
Strikingly , clear recruitment of both STAT1 and STAT2 to IFNAR2 was observed under these conditions ( XREF_FIG ) , suggesting that STAT2 supports docking of STAT1 to IFNAR2 , probably by STAT1-STAT2 heterodimerization .	Strikingly, clear recruitment of both STAT1 and STAT2 to IFNAR2 was observed under these conditions (XREF_FIG), suggesting that STAT2 supports docking of STAT1 to IFNAR2, probably by STAT1-STAT2 heterodimerization.	22	27	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	22	23	26	27
In STAT2 overexpressing STAT1 deficient human and mouse cells , IFNalpha induced expression of typical ISGs correlated with the kinetics of STAT2 phosphorylation , and the presence of a STAT2 and IRF9 complex .	In STAT2 overexpressing STAT1 deficient human and mouse cells, IFNalpha induced expression of typical ISGs correlated with the kinetics of STAT2 phosphorylation, and the presence of a STAT2 and IRF9 complex.	0	11	overexpressing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	1	2	3	4
STAT2 and IRF9 directs a prolonged ISGF3 like transcriptional response and antiviral activity in the absence of STAT1 .	STAT2 and IRF9 directs a prolonged ISGF3 like transcriptional response and antiviral activity in the absence of STAT1.	0	18	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	0	1	17	18
Although the mechanism by which Stat1 independently signals is well understood ( i.e ., Stat1 homodimers ;) , the mechanism by which Stat2 signals independently of Stat1 has not been fully characterized .	Although the mechanism by which Stat1 independently signals is well understood (i.e., Stat1 homodimers;), the mechanism by which Stat2 signals independently of Stat1 has not been fully characterized.	22	27	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Stat2	Stat2	Stat2	Stat1	Stat1	Stat1	22	23	26	27
The biological importance of these alternative pathways has been demonstrated by studies showing that Stat2 -/- or Irf9 -/- mice were more resistant to certain viral infections than Stat1 -/- mice and that STAT1 independent transcription of some ISGs can be driven by STAT2 or IRF9 .	The biological importance of these alternative pathways has been demonstrated by studies showing that Stat2 -/- or Irf9 -/- mice were more resistant to certain viral infections than Stat1 -/- mice and that STAT1 independent transcription of some ISGs can be driven by STAT2 or IRF9.	33	45	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	43	44	33	34
For instance , STAT2 was reported to mediate STAT1 independent protection against dengue virus infection in mice that were deficient in STAT1 through the formation of non ISGF3 complexes that involved STAT2 homodimers , and did not require STAT1 [ XREF_BIBR ] .	For instance, STAT2 was reported to mediate STAT1 independent protection against dengue virus infection in mice that were deficient in STAT1 through the formation of non ISGF3 complexes that involved STAT2 homodimers, and did not require STAT1 [XREF_BIBR].	3	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	3	4	8	9
STAT2 Balances the Contributions of STAT1 and STAT3 to IL-27 Transcription Output .	STAT2 Balances the Contributions of STAT1 and STAT3 to IL-27 Transcription Output.	0	7	Contributions	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	0	1	5	6
STAT2 mediates STAT1 independent protection against DENV infection in mice .	STAT2 mediates STAT1 independent protection against DENV infection in mice.	0	4	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	0	1	2	3
Remarkably , putative STAT3 binding sites were identified in the caspase3 promoter and a luciferase assay , chromatin immunoprecipitation ( ChIP ) , and an electromobility shift assay ( EMSA ) revealed that STAT3 activated caspase3 .	Remarkably, putative STAT3 binding sites were identified in the caspase3 promoter and a luciferase assay, chromatin immunoprecipitation (ChIP), and an electromobility shift assay (EMSA) revealed that STAT3 activated caspase3.	33	36	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	caspase3	caspase3	caspase3	33	34	35	36
Apoptosis induced by dnStat3 and a JAK and Stat3 small molecular inhibitor through caspase-3 pathway .	Apoptosis induced by dnStat3 and a JAK and Stat3 small molecular inhibitor through caspase-3 pathway.	1	14	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Stat3	Stat3	Stat3	caspase-3	caspase-3	caspase-3	8	9	13	14
However , knockdown of STAT3 in Ad-HO-1-transfected livers downregulated phos-Akt , Bcl-2 , and Bcl-xL , yet upregulated cleaved caspase-3 , compared with NS siRNA-controls .	However, knockdown of STAT3 in Ad-HO-1-transfected livers downregulated phos-Akt, Bcl-2, and Bcl-xL, yet upregulated cleaved caspase-3, compared with NS siRNA-controls.	2	20	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	caspase-3	caspase-3	caspase-3	4	5	19	20
Herein , we show that when present at high levels , pSTAT3 activates caspase3 and induces apoptosis .	Herein, we show that when present at high levels, pSTAT3 activates caspase3 and induces apoptosis.	11	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pSTAT3	pSTAT3	pSTAT3	caspase3	caspase3	caspase3	11	12	13	14
Activation of STAT3 resulted in activation of the effector caspase 7 but not caspase 3 or 6 in EBV infected cells .	Activation of STAT3 resulted in activation of the effector caspase 7 but not caspase 3 or 6 in EBV infected cells.	0	16	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	caspase 3	caspase 3	caspase 3	2	3	13	15
We also observed that the expression of Caspase3 protein was greatly increased in tumors treated with plasmids containing Si-Stat3 , versus the Mock or Scramble controls .	We also observed that the expression of Caspase3 protein was greatly increased in tumors treated with plasmids containing Si-Stat3, versus the Mock or Scramble controls.	7	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Si-Stat3	Si-Stat3	Si-Stat3	Caspase3 protein	Caspase3 protein	Caspase3 protein	18	19	7	9
The primary finding of the current study is that pulmonary exposure to CeO 2 nanoparticles is associated with histological evidence of lung inflammation , the activation of MAPK signaling , the phosphorylation of STAT-3 , increased caspase-3 cleavage , and inflammation .	The primary finding of the current study is that pulmonary exposure to CeO 2 nanoparticles is associated with histological evidence of lung inflammation, the activation of MAPK signaling, the phosphorylation of STAT-3, increased caspase-3 cleavage, and inflammation.	31	37	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT-3	phosphorylation of STAT-3	stat-3	caspase-3	caspase-3	caspase-3	33	34	36	37
However , in cells from patients with high lymphocyte counts , caspase3 levels were significantly high , suggesting that when present at high levels , STAT3 activates caspase3 .	However, in cells from patients with high lymphocyte counts, caspase3 levels were significantly high, suggesting that when present at high levels, STAT3 activates caspase3.	25	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	caspase3	caspase3	caspase3	25	26	27	28
Importantly , the overexpression of dominant negative form of Pim-1 abrogated the endothelial differentiation , indicating that Pim-1 kinase activity is essential for STAT3 mediated endothelial cell differentiation of cardiac Sca-1 + cells .	Importantly, the overexpression of dominant negative form of Pim-1 abrogated the endothelial differentiation, indicating that Pim-1 kinase activity is essential for STAT3 mediated endothelial cell differentiation of cardiac Sca-1 + cells.	23	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	Sca-1	Sca-1	Sca-1	23	24	30	31
[ XREF_BIBR ] STAT3 siRNA complexed with stearate modified PEI reduced the expression level of activated STAT3 in B16 melanoma cells and significantly suppressed tumor growth in vivo , by inducing IL-6 production and Caspase 3 activity , while diminishing VEGF secretion in tumors .	[XREF_BIBR] STAT3 siRNA complexed with stearate modified PEI reduced the expression level of activated STAT3 in B16 melanoma cells and significantly suppressed tumor growth in vivo, by inducing IL-6 production and Caspase 3 activity, while diminishing VEGF secretion in tumors.	9	36	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT3	PEI reduced the expression level of activated STAT3	stat3	Caspase 3	Caspase 3	caspase 3	16	17	34	36
TQ also downregulated the expression of STAT3 regulated genes , such as Bcl-2 , cyclin D , survivin , and vascular endothelial growth factor , and activated caspase-3 ,7,9 .	TQ also downregulated the expression of STAT3 regulated genes, such as Bcl-2, cyclin D, survivin, and vascular endothelial growth factor, and activated caspase-3,7,9.	0	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT3	TQ also downregulated the expression of STAT3	stat3	caspase-3	caspase-3	caspase-3	6	7	27	28
In this study , it was observed that suppression of STAT3 decreased active caspase 3 and lactate dehydrogenase leakage into culture medium compared to hypoxia and when STAT5 is inhibited a reversed trend was visible .	In this study, it was observed that suppression of STAT3 decreased active caspase 3 and lactate dehydrogenase leakage into culture medium compared to hypoxia and when STAT5 is inhibited a reversed trend was visible.	8	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	caspase 3	caspase 3	caspase 3	10	11	13	15
The AMPK related kinases NUAK1 and NUAK2 are activated by the tumor suppressor LKB1 .	The AMPK related kinases NUAK1 and NUAK2 are activated by the tumor suppressor LKB1.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	LKB1	LKB1	LKB1	NUAK1	NUAK1	NUAK1	13	14	4	5
NUAK1 is directly activated by STK11 and indirectly inactivated by PTEN through the AKT pathway [ XREF_BIBR - XREF_BIBR ] .	NUAK1 is directly activated by STK11 and indirectly inactivated by PTEN through the AKT pathway [XREF_BIBR - XREF_BIBR].	0	8	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STK11	STK11	STK11	NUAK1	NUAK1	NUAK1	5	6	0	1
Interplay between Polo kinase , LKB1 activated NUAK1 kinase , PP1beta MYPT1 phosphatase complex and the SCF betaTrCP E3 ubiquitin ligase .	Interplay between Polo kinase, LKB1 activated NUAK1 kinase, PP1beta MYPT1 phosphatase complex and the SCF betaTrCP E3 ubiquitin ligase.	3	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	NUAK1	NUAK1	NUAK1	5	6	7	8
Therefore , LKB1 potentially increases cell detachment by regulating the activity of NUAK1 .	Therefore, LKB1 potentially increases cell detachment by regulating the activity of NUAK1.	2	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	NUAK1	NUAK1	NUAK1	2	3	12	13
The phosphorylation of p53 induced by LKB1 required the kinase activity of NUAK1 and phosphorylation of NUAK1 at Thr211 by LKB1 was essential for its kinase activity , which leads to the conclusion that LKB1 activates NUAK1 and regulates phosphorylation of p53 through the NUAK1 kinase , at least partially .	The phosphorylation of p53 induced by LKB1 required the kinase activity of NUAK1 and phosphorylation of NUAK1 at Thr211 by LKB1 was essential for its kinase activity, which leads to the conclusion that LKB1 activates NUAK1 and regulates phosphorylation of p53 through the NUAK1 kinase, at least partially.	34	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	NUAK1	NUAK1	NUAK1	34	35	36	37
Although , the data suggest that NUAK1 contribution is mediated by LKB1 , these results do not exclude its LKB1 independent effect .	Although, the data suggest that NUAK1 contribution is mediated by LKB1, these results do not exclude its LKB1 independent effect.	6	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	NUAK1	NUAK1	NUAK1	11	12	6	7
This role is surprising , given that NUAK1 is activated by the tumour suppressor LKB1 .	This role is surprising, given that NUAK1 is activated by the tumour suppressor LKB1.	7	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	LKB1	LKB1	LKB1	NUAK1	NUAK1	NUAK1	14	15	7	8
The loss of NUAK1 activation by LKB1 ( by using a NUAK1 NUAK1 mutant unresponsive to LKB1 or by inhibiting LKB1 activity in NUAK1 expressing cells ) results in a failure of NUAK1 to induce senescence , thus demonstrating the major role of LKB1 in NUAK1 induced senescence .	The loss of NUAK1 activation by LKB1 (by using a NUAK1 NUAK1 mutant unresponsive to LKB1 or by inhibiting LKB1 activity in NUAK1 expressing cells) results in a failure of NUAK1 to induce senescence, thus demonstrating the major role of LKB1 in NUAK1 induced senescence.	3	27	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	NUAK1	NUAK1	NUAK1	6	7	3	4
Interestingly , stable expression of wild-type LKB1 in the HeLa cells caused a small but reproducible degree of upregulation of expression of AMPKalpha1 and a marked down-regulation of expression of ACC ( data not shown ) .	Interestingly, stable expression of wild-type LKB1 in the HeLa cells caused a small but reproducible degree of upregulation of expression of AMPKalpha1 and a marked down-regulation of expression of ACC (data not shown).	3	26	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	expression of wild-type LKB1	lkb1	AMPKalpha1	AMPKalpha1	ampkalpha1	6	7	22	23
Fourth , the AMPKK activity in AMPKK1 and AMPKK2 was not a contaminant that co-precipitated with anti-LKB1 antibody , because recombinant complexes of GST-LKB1 , STRAD and MO25 expressed in 293 cells and purified on glutathione-Sepharose also activated the AMPKalpha1 catalytic domain efficiently , and phosphorylated Thr172 .	Fourth, the AMPKK activity in AMPKK1 and AMPKK2 was not a contaminant that co-precipitated with anti-LKB1 antibody, because recombinant complexes of GST-LKB1, STRAD and MO25 expressed in 293 cells and purified on glutathione-Sepharose also activated the AMPKalpha1 catalytic domain efficiently, and phosphorylated Thr172.	21	42	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GST-LKB1	GST-LKB1	GST-LKB1	AMPKalpha1 catalytic domain	AMPKalpha1 catalytic domain	AMPKalpha1 catalytic domain	23	24	39	42
The LKB1 L and LKB1 1-343 complexes activated the bacterially expressed GST fusion of the AMPK-alpha1 kinase domain equally well ( XREF_FIG ) .	The LKB1 L and LKB1 1-343 complexes activated the bacterially expressed GST fusion of the AMPK-alpha1 kinase domain equally well (XREF_FIG).	1	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	AMPK-alpha1	AMPK-alpha1	AMPK-alpha1	1	2	15	16
In silico splicing factor binding analysis predicted SRSF1 to bind predominantly to the cancer associated exon 4B , hence , it was hypothesized that SRPK1 activates SRSF1 through phosphorylation , followed by SRSF1 binding to exon 4B and regulation of SLC39A14 splicing .	In silico splicing factor binding analysis predicted SRSF1 to bind predominantly to the cancer associated exon 4B, hence, it was hypothesized that SRPK1 activates SRSF1 through phosphorylation, followed by SRSF1 binding to exon 4B and regulation of SLC39A14 splicing.	24	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SRSF1	SRSF1	SRSF1	24	25	26	27
We show that SRPK1 restores both mobility and mAB 104 reactivity to a SR protein SF2 and ASF ( splicing factor 2/alternative splicing factor ) produced in bacteria , suggesting that SRPK1 is responsible for the generation of the mAb 104 specific phosphoepitope in vivo .	We show that SRPK1 restores both mobility and mAB 104 reactivity to a SR protein SF2 and ASF (splicing factor 2/alternative splicing factor) produced in bacteria, suggesting that SRPK1 is responsible for the generation of the mAb 104 specific phosphoepitope in vivo.	3	25	restores	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SF2	SF2	SF2	3	4	15	16
SRSF1 is a critical splicing regulator in the cell , and phosphorylation by SRPK1 enables SRSF1 nuclear localisation .	SRSF1 is a critical splicing regulator in the cell, and phosphorylation by SRPK1 enables SRSF1 nuclear localisation.	11	17	enables	Positive_activation_token_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SRSF1	SRSF1	SRSF1	13	14	15	16
Together , these findings suggest that , while SRPK1 induced release generates a form of SRSF1 that binds poorly to RNA in isolation , the released SR protein favors the formation of the ternary complex with U1 and ESE , which likely reflects the active process in 5 ' splice site recognition in the cell .	Together, these findings suggest that, while SRPK1 induced release generates a form of SRSF1 that binds poorly to RNA in isolation, the released SR protein favors the formation of the ternary complex with U1 and ESE, which likely reflects the active process in 5 ' splice site recognition in the cell.	8	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SRSF1	SRSF1	SRSF1	8	9	15	16
SRSF1 activity is activated through phosphorylation by serine-arginine-rich protein kinase SRPK1 .	SRSF1 activity is activated through phosphorylation by serine-arginine-rich protein kinase SRPK1.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SRSF1	SRSF1	SRSF1	10	11	0	1
Our observations that SRPK1 and CLK1 can target the same Arg Ser repeats in the C-terminus of SRSF1 at similar rates raises the possibility that their activities in the nucleus may be differentiated based entirely on Arg Ser versus Ser Pro phosphorylation patterns ( XREF_FIG ) rather than on regiospecific grounds where SRPK1 targets only N-terminal Arg Ser repeats and CLK1 targets all remaining serines in the C-terminal portion ( XREF_FIG ) .	Our observations that SRPK1 and CLK1 can target the same Arg Ser repeats in the C-terminus of SRSF1 at similar rates raises the possibility that their activities in the nucleus may be differentiated based entirely on Arg Ser versus Ser Pro phosphorylation patterns (XREF_FIG) rather than on regiospecific grounds where SRPK1 targets only N-terminal Arg Ser repeats and CLK1 targets all remaining serines in the C-terminal portion (XREF_FIG).	3	18	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SRSF1	SRSF1	SRSF1	3	4	17	18
Likewise , knockdown of NEK2 or SRPK1 similarly reduced the splicing activity of SRSF1 toward the BCL-X minigene .	Likewise, knockdown of NEK2 or SRPK1 similarly reduced the splicing activity of SRSF1 toward the BCL-X minigene.	2	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SRSF1	SRSF1	SRSF1	6	7	13	14
Spinal SRPK1 inhibition attenuated SRSF1 activity , abolished neuropathic pain behaviors and suppressed central sensitization .	Spinal SRPK1 inhibition attenuated SRSF1 activity, abolished neuropathic pain behaviors and suppressed central sensitization.	1	5	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SRSF1	SRSF1	SRSF1	1	2	4	5
4.2 Inhibition of SRPK1 alleviates neuropathic pain and reduces SRSF1 activation .	4.2 Inhibition of SRPK1 alleviates neuropathic pain and reduces SRSF1 activation.	1	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SRSF1	SRSF1	SRSF1	3	4	9	10
A recent study showed that SRPK1 phosphorylation promotes an interaction between the RS domain and RRMs in SRSF1 .	A recent study showed that SRPK1 phosphorylation promotes an interaction between the RS domain and RRMs in SRSF1.	5	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1 phosphorylation	srpk1	SRSF1	SRSF1	srsf1	5	6	17	18
However , the finding that ASF and SF2 , a known splicing factor , requires the presence of a specific short sequence in the polypyrimidine tract upstream of the proximal splice site and that ASF and SF2 is induced to nuclear localization by SRPK1 activation and IGF-1 activation strongly suggest that this is a splicing mechanism rather than a degradation mechanism .	However, the finding that ASF and SF2, a known splicing factor, requires the presence of a specific short sequence in the polypyrimidine tract upstream of the proximal splice site and that ASF and SF2 is induced to nuclear localization by SRPK1 activation and IGF-1 activation strongly suggest that this is a splicing mechanism rather than a degradation mechanism.	34	44	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SF2	SF2	SF2	43	44	36	37
In the case of tau exon 10 splicing , activation of SRPK1 and Clk and Sty could increase the nuclear concentration of active ASF and SF2 that might result in an increase in exon 10 inclusion .	In the case of tau exon 10 splicing, activation of SRPK1 and Clk and Sty could increase the nuclear concentration of active ASF and SF2 that might result in an increase in exon 10 inclusion.	9	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SF2	SF2	SF2	11	12	25	26
During Th17-cell differentiation , STAT3 induces the expression of the master regulatory transcription factor RORc and is , therefore , critical for the differentiation of human and mouse Th17-cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	During Th17-cell differentiation, STAT3 induces the expression of the master regulatory transcription factor RORc and is, therefore, critical for the differentiation of human and mouse Th17-cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	RORc	RORc	RORc	4	5	14	15
While these data suggest probable important involvement of these transcription factors in human Th17 differentiation , there remain numerous open questions , such as i ) what pro inflammatory cytokines phosphorylate Stat3 ; ii ) whether Stat3 induces ROR-c by binding to the ROR-c promoter ; iii ) whether Stat3 and ROR-c bind to the IL-17 promoter to induce IL-17 expression , and iv ) which other transcription factors ( Stat4 , IRF4 , Runx1 etc. ) are involved in IL-17 expression .	While these data suggest probable important involvement of these transcription factors in human Th17 differentiation, there remain numerous open questions, such as i) what pro inflammatory cytokines phosphorylate Stat3; ii) whether Stat3 induces ROR-c by binding to the ROR-c promoter; iii) whether Stat3 and ROR-c bind to the IL-17 promoter to induce IL-17 expression, and iv) which other transcription factors (Stat4, IRF4, Runx1 etc.) are involved in IL-17 expression.	36	39	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stat3	Stat3	Stat3	ROR-c	ROR-c	ROR-c	36	37	38	39
We further found that the levels of RORgammat and RORalpha -- the transcription factors dictating IL-17 expression -- were elevated in DAPK deficient Th17 cells ; even though activation of the Rorc inducer STAT3 was similar between WT and Dapk-/- T cells ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	We further found that the levels of RORgammat and RORalpha -- the transcription factors dictating IL-17 expression -- were elevated in DAPK deficient Th17 cells; even though activation of the Rorc inducer STAT3 was similar between WT and Dapk-/- T cells (XREF_FIG; XREF_SUPPLEMENTARY).	28	34	inducer	Positive_activation_token_1_noun	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	Rorc	Rorc	Rorc	33	34	31	32
Luciferase reporter assays confirmed that p300 further enhanced Smad2 and STAT3 induced activation of the Rorc and Il17 a promoters in 293T cells ( XREF_FIG ) .	Luciferase reporter assays confirmed that p300 further enhanced Smad2 and STAT3 induced activation of the Rorc and Il17 a promoters in 293T cells (XREF_FIG).	8	16	induced	Positive_early_activation	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	Rorc	Rorc	Rorc	10	11	15	16
STAT3 is known to activate the Rorc promoter and promote Th17 cell development XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	STAT3 is known to activate the Rorc promoter and promote Th17 cell development XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	Rorc	Rorc	Rorc	0	1	6	7
Consistently , when co-transfected with PIAS3 in T H 17 cells , Smad3 ( 3S-A ) was able to suppress STAT3 induced activation of the Rorc and Il17a reporters ( XREF_FIG ) .	Consistently, when co-transfected with PIAS3 in T H 17 cells, Smad3 (3S-A) was able to suppress STAT3 induced activation of the Rorc and Il17a reporters (XREF_FIG).	20	26	induced	Positive_early_activation	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	Rorc	Rorc	Rorc	20	21	25	26
The resulting causal network captures known relationships between core TFs , including Rorc activation by STAT3 , IRF4 , and BATF , and further reveals feed-forward loops that reinforce Rorc expression in response to TCR and cytokine signals ( XREF_FIG , box ) .	The resulting causal network captures known relationships between core TFs, including Rorc activation by STAT3, IRF4, and BATF, and further reveals feed-forward loops that reinforce Rorc expression in response to TCR and cytokine signals (XREF_FIG, box).	12	20	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	Rorc	Rorc	Rorc	15	16	12	13
Cytokines like IL-6 and IL-23 activate Stat3 , which induce Rorc , the master regulator for Th17 cells .	Cytokines like IL-6 and IL-23 activate Stat3, which induce Rorc, the master regulator for Th17 cells.	5	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stat3	Stat3	Stat3	Rorc	Rorc	Rorc	6	7	10	11
Luciferase reporter assays showed that Smad2 ( S255A ) failed to enhance STAT3 induced activation of the Rorc and Il17 a promoters ( XREF_FIG ) .	Luciferase reporter assays showed that Smad2 (S255A) failed to enhance STAT3 induced activation of the Rorc and Il17 a promoters (XREF_FIG).	12	18	induced	Positive_early_activation	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	Rorc	Rorc	Rorc	12	13	17	18
IFN-gamma increases levels of STAT1 mRNA through transcriptional regulation and STAT1 can directly activate T-bet in T cells , suggesting that levels of IFN-gamma should correlate with STAT1 signaling and in turn influence levels of T-bet expression .	IFN-gamma increases levels of STAT1 mRNA through transcriptional regulation and STAT1 can directly activate T-bet in T cells, suggesting that levels of IFN-gamma should correlate with STAT1 signaling and in turn influence levels of T-bet expression.	4	17	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	STAT1	STAT1	T-bet	T-bet	T-bet	4	5	14	15
Thus , T-bet is induced by IFN-gamma and STAT1 signaling during T cell activation .	Thus, T-bet is induced by IFN-gamma and STAT1 signaling during T cell activation.	2	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STAT1	STAT1	STAT1	T-bet	T-bet	T-bet	8	9	2	3
IFN-gamma can induce Th1 activation by activating STAT1 , which in turn activates T-bet .	IFN-gamma can induce Th1 activation by activating STAT1, which in turn activates T-bet.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	STAT1	STAT1	T-bet	T-bet	T-bet	7	8	13	14
Furthermore , we found that WGN-26 inhibited the phosphorylation of STAT1 and accelerated the degradation of T-bet protein in allograft recipients .	Furthermore, we found that WGN-26 inhibited the phosphorylation of STAT1 and accelerated the degradation of T-bet protein in allograft recipients.	5	18	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	WGN-26 inhibited the phosphorylation of STAT1	stat1	T-bet protein	T-bet protein	t-bet protein	10	11	16	18
Initial studies demonstrated that T H 2 cells downregulate IL-12R , leaving cells refractory to IL-12 , while T H 1 cells operate positive re-enforcement with IFNgamma mediated STAT-1 activating Tbet and up-regulating IL-12R expression [ XREF_BIBR ] .	Initial studies demonstrated that T H 2 cells downregulate IL-12R, leaving cells refractory to IL-12, while T H 1 cells operate positive re-enforcement with IFNgamma mediated STAT-1 activating Tbet and up-regulating IL-12R expression [XREF_BIBR].	22	32	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	STAT-1	IFNgamma mediated STAT-1	stat-1	Tbet	Tbet	tbet	28	29	30	31
Likewise , type I IFNs may also play dual roles , by both promoting Th1 cell differentiation through STAT1 induction of Tbx21 , as well as suppressing Tfh cell differentiation through upstream ( or indirect ) induction of autocrine IL-2 , subsequently leading to STAT5 activation and direct competition with STAT3 for binding sites in the Bcl6 locus .	Likewise, type I IFNs may also play dual roles, by both promoting Th1 cell differentiation through STAT1 induction of Tbx21, as well as suppressing Tfh cell differentiation through upstream (or indirect) induction of autocrine IL-2, subsequently leading to STAT5 activation and direct competition with STAT3 for binding sites in the Bcl6 locus.	18	22	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	STAT1	STAT1	STAT1	Tbx21	Tbx21	Tbx21	18	19	21	22
Our mutational analysis of Rlk supports a similar mechanism for activation of Rlk by Src family kinases downstream of the TCR .	Our mutational analysis of Rlk supports a similar mechanism for activation of Rlk by Src family kinases downstream of the TCR.	10	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Src	Src	Src	Rlk	Rlk	Rlk	14	15	12	13
We obtained evidence that the reduced replication and dissemination of parental RH parasites compared to DeltaROP16 parasites was due to arginine starvation resulting from ROP16 dependent STAT6 mediated induction of arginase-1 .	We obtained evidence that the reduced replication and dissemination of parental RH parasites compared to DeltaROP16 parasites was due to arginine starvation resulting from ROP16 dependent STAT6 mediated induction of arginase-1.	22	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	arginase-1	arginase-1	arginase-1	26	27	30	31
Recently , it has been shown that cytokine dependent , STAT 6 dependent pathways as well as TLR dependent , STAT-6 independent pathways can induce arginase-1 in macrophages depending on the type of infection XREF_BIBR .	Recently, it has been shown that cytokine dependent, STAT 6 dependent pathways as well as TLR dependent, STAT-6 independent pathways can induce arginase-1 in macrophages depending on the type of infection XREF_BIBR.	20	27	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT-6	STAT-6	STAT-6	arginase-1	arginase-1	arginase-1	20	21	25	26
Phosphorylation of STAT6 by ROP16 mediates induction of arginase-1 , resulting in arginine degradation , depriving the parasite from one important metabolite .	Phosphorylation of STAT6 by ROP16 mediates induction of arginase-1, resulting in arginine degradation, depriving the parasite from one important metabolite.	0	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	Phosphorylation of STAT6	stat6	arginase-1	arginase-1	arginase-1	2	3	8	9
As shown in XREF_FIG , infection of STAT6 - /- MO with all three strains failed to induce arginase-1 protein , in contrast to infection of MO from STAT6 +/+ littermates in which we detected ROP16 dependent arginase-1 induction .	As shown in XREF_FIG, infection of STAT6 - /- MO with all three strains failed to induce arginase-1 protein, in contrast to infection of MO from STAT6 +/+ littermates in which we detected ROP16 dependent arginase-1 induction.	5	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	arginase-1	arginase-1	arginase-1	7	8	18	19
As T gondii has been demonstrated to have a number of TLR-4 ligands such as GPI anchors XREF_BIBR and HSP70 XREF_BIBR , XREF_BIBR this is the likely source of the STAT-6 independent induction of arginase-1 by type-2 strain parasites as demonstrated in the present study .	As T gondii has been demonstrated to have a number of TLR-4 ligands such as GPI anchors XREF_BIBR and HSP70 XREF_BIBR, XREF_BIBR this is the likely source of the STAT-6 independent induction of arginase-1 by type-2 strain parasites as demonstrated in the present study.	30	38	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	STAT-6	STAT-6	STAT-6	arginase-1	arginase-1	arginase-1	30	31	34	35
However , a STAT6 independent pathway also leads to arginase 1 expression during Mycobacterium tuberculosis and Toxoxplasma gondii infections , which in the former is dependent upon TLR signaling [ XREF_BIBR ] .	However, a STAT6 independent pathway also leads to arginase 1 expression during Mycobacterium tuberculosis and Toxoxplasma gondii infections, which in the former is dependent upon TLR signaling [XREF_BIBR].	3	11	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	arginase 1	arginase 1	arginase 1	3	4	9	11
We traced this activity to ROP16 dependent STAT6 mediated induction of arginase-1 , an enzyme that degrades host cell arginine , which is required for both the production of nitric oxide by host cell inducible nitric oxide synthase , as well as being an essential amino acid nutrient the parasite requires for intracellular replication .	We traced this activity to ROP16 dependent STAT6 mediated induction of arginase-1, an enzyme that degrades host cell arginine, which is required for both the production of nitric oxide by host cell inducible nitric oxide synthase, as well as being an essential amino acid nutrient the parasite requires for intracellular replication.	1	47	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	arginase-1	arginase-1	arginase-1	7	8	11	12
The two LKB1 activated kinases AMPK and Par1b have been suggested to play key roles in the development of hepatic polarity .	The two LKB1 activated kinases AMPK and Par1b have been suggested to play key roles in the development of hepatic polarity.	0	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	Par1b	Par1b	Par1b	2	3	7	8
Regulation of beta Cell Polarity by the LKB1 Target Par1b .	Regulation of beta Cell Polarity by the LKB1 Target Par1b.	0	10	Target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	Par1b	Par1b	Par1b	7	8	9	10
This phenotype is , in part , mimicked by the absence of the LKB1 target Par1b .	This phenotype is, in part, mimicked by the absence of the LKB1 target Par1b.	10	16	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	Par1b	Par1b	Par1b	13	14	15	16
Conversely , the precise position of the beta cell nucleus , but not cell size , is controlled by the LKB1 target Par1b .	Conversely, the precise position of the beta cell nucleus, but not cell size, is controlled by the LKB1 target Par1b.	17	23	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	Par1b	Par1b	Par1b	20	21	22	23
XREF_BIBR , XREF_BIBR Hence , Par4 and LKB1 is able to activate Par1 and MARK in the Drosophila oocyte and , in epithelial cells , may have its role through Par1 and MARK activation .	XREF_BIBR, XREF_BIBR Hence, Par4 and LKB1 is able to activate Par1 and MARK in the Drosophila oocyte and, in epithelial cells, may have its role through Par1 and MARK activation.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	MARK	MARK	MARK	7	8	14	15
Apart from AMPK activation , hLKB1 DeltaLB C430A fails to activate two other kinases of the AMPK family , MARK ( XREF_FIG ) and SadA ( XREF_SUPPLEMENTARY ) .	Apart from AMPK activation, hLKB1 DeltaLB C430A fails to activate two other kinases of the AMPK family, MARK (XREF_FIG) and SadA (XREF_SUPPLEMENTARY).	5	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hLKB1	hLKB1	hLKB1	MARK	MARK	MARK	5	6	19	20
Thus its overexpression increased AMPK and acetyl-CoA carboxylase phosphorylation , and conversely , RNA interference mediated SIRT1 knockdown reduced AMPK phosphorylation and that of another LKB1 target MARK1 .	Thus its overexpression increased AMPK and acetyl-CoA carboxylase phosphorylation, and conversely, RNA interference mediated SIRT1 knockdown reduced AMPK phosphorylation and that of another LKB1 target MARK1.	22	28	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	MARK1	MARK1	MARK1	25	26	27	28
MARK protein kinases , which are involved in microtubule stability and share homology with AMPK , are also activated by LKB1 .	MARK protein kinases, which are involved in microtubule stability and share homology with AMPK, are also activated by LKB1.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	MARK	MARK	MARK	20	21	0	1
We conclude that the C/EBP delta gene is activated by APRF and STAT3 , and the expression level is then maintained by an autoregulation mechanism .	We conclude that the C/EBP delta gene is activated by APRF and STAT3, and the expression level is then maintained by an autoregulation mechanism.	4	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	APRF	APRF	APRF	C/EBP delta	C/EBP delta	C/EBP delta	10	11	4	6
A study of STAT3 and STAT5 transcriptional targets in mammary epithelial cells in vitro showed that both c/ebpdelta and c-fos ( a component of Ap-1 ) were upregulated by STAT3 , suggesting a degree of interdependence between these transcription factor pathways in mediating their apoptotic effects .	A study of STAT3 and STAT5 transcriptional targets in mammary epithelial cells in vitro showed that both c/ebpdelta and c-fos (a component of Ap-1) were upregulated by STAT3, suggesting a degree of interdependence between these transcription factor pathways in mediating their apoptotic effects.	16	30	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	c/ebpdelta	c/ebpdelta	c/ebpdelta	29	30	17	18
Furthermore , in the context of this physiological cell death , C/EBPdelta is induced by STAT3 and is necessary for the downregulation of cyclin D1 , upregulation of p53 and IGFBP5 , and proper regulation of several members of the Bcl family XREF_BIBR .	Furthermore, in the context of this physiological cell death, C/EBPdelta is induced by STAT3 and is necessary for the downregulation of cyclin D1, upregulation of p53 and IGFBP5, and proper regulation of several members of the Bcl family XREF_BIBR.	11	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STAT3	STAT3	STAT3	C/EBPdelta	C/EBPdelta	C/EBPdelta	15	16	11	12
XREF_FIG ( A ) shows that , although the LKB1 complex and CaMKKbeta were both able to activate GST-alpha1-KD , only the LKB1 complex was able to activate GST-BRSK1 and GST-BRSK2 .	XREF_FIG (A) shows that, although the LKB1 complex and CaMKKbeta were both able to activate GST-alpha1-KD, only the LKB1 complex was able to activate GST-BRSK1 and GST-BRSK2.	22	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	GST-BRSK2	GST-BRSK2	GST-BRSK2	22	23	30	31
Once activated , LKB1 phosphorylates and thereby activates SAD-A and SAD-B kinases , which are also required for neuronal polarization in the cerebral cortex .	Once activated, LKB1 phosphorylates and thereby activates SAD-A and SAD-B kinases, which are also required for neuronal polarization in the cerebral cortex.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	SAD-A	SAD-A	SAD-A	3	4	8	9
BRSK1 is activated both in vitro and in vivo by serine/threonine protein kinase 11 ( STK11 ) , also known as liver kinase B1 ( LKB1 ) , which plays an important role in the polarization of cortical axons XREF_BIBR - XREF_BIBR .	BRSK1 is activated both in vitro and in vivo by serine/threonine protein kinase 11 (STK11), also known as liver kinase B1 (LKB1), which plays an important role in the polarization of cortical axons XREF_BIBR - XREF_BIBR.	0	41	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STK11	STK11	STK11	BRSK1	BRSK1	BRSK1	15	16	0	1
Mammalian SAD-A and SAD-B , activated by a master kinase LKB1 , regulate microtubule dynamics and polarize neurons .	Mammalian SAD-A and SAD-B, activated by a master kinase LKB1, regulate microtubule dynamics and polarize neurons.	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	SAD-B	SAD-B	SAD-B	10	11	3	4
Presumably the activity of LKB1 and related kinases are sufficient to phosphorylate T175 and T187 and activate SAD-A/B .	Presumably the activity of LKB1 and related kinases are sufficient to phosphorylate T175 and T187 and activate SAD-A/B.	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	SAD-A/B	SAD-A/B	SAD-A/B	4	5	17	18
SNRK and NUAK2 is a member of the AMPK related protein kinases and can be activated by LKB1 through phosphorylation of the Thr 173 residue at its T-loop region , and the LKBI regulatory subunits STRAD and MO25 are necessary for LKBI mediated activation of SNRK and NUAK2 [ XREF_BIBR ] .	SNRK and NUAK2 is a member of the AMPK related protein kinases and can be activated by LKB1 through phosphorylation of the Thr 173 residue at its T-loop region, and the LKBI regulatory subunits STRAD and MO25 are necessary for LKBI mediated activation of SNRK and NUAK2 [XREF_BIBR].	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	NUAK2	NUAK2	NUAK2	17	18	2	3
Contraction stimulated glucose uptake has been shown to be mediated by LKB1 via AMPKalpha2 and/or NUAK2 , an AMPK-RK with the highest homology to NUAK1 .	Contraction stimulated glucose uptake has been shown to be mediated by LKB1 via AMPKalpha2 and/or NUAK2, an AMPK-RK with the highest homology to NUAK1.	1	24	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	NUAK2	NUAK2	NUAK2	11	12	15	16
Consistent with this interpretation , we found that coexpression of SRF , but not TEAD , with YAP synergistically upregulated IL6 and CTGF ( XREF_FIG ) .	Consistent with this interpretation, we found that coexpression of SRF, but not TEAD, with YAP synergistically upregulated IL6 and CTGF (XREF_FIG).	8	24	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRF	coexpression of SRF	srf	IL6	IL6	il6	10	11	20	21
Finally , we found a significant positive correlation between YAP and TAZ and SRF expression and the levels of IL6 , implying that IL6 is induced by SRF and YAP and TAZ in vivo ( XREF_FIG ) .	Finally, we found a significant positive correlation between YAP and TAZ and SRF expression and the levels of IL6, implying that IL6 is induced by SRF and YAP and TAZ in vivo (XREF_FIG).	23	35	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SRF	SRF	SRF	IL6	IL6	IL6	27	28	23	24
Finally , we show that this high SRF expression enables YAP to more efficiently induce IL6 and stemness in BLBC compared with luminal-type breast cancer .	Finally, we show that this high SRF expression enables YAP to more efficiently induce IL6 and stemness in BLBC compared with luminal-type breast cancer.	7	17	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SRF	SRF expression	srf	IL6	IL6	il6	7	8	15	16
Notable in this regard is the finding that KLF4 is induced by IL-4 in a signal transducer and activator of transcription 6 ( STAT6 )-dependent manner and can directly regulate the AAM phenotype in vitro and in vivo .	Notable in this regard is the finding that KLF4 is induced by IL-4 in a signal transducer and activator of transcription 6 (STAT6)-dependent manner and can directly regulate the AAM phenotype in vitro and in vivo.	8	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	KLF4	KLF4	KLF4	23	24	8	9
Importantly , this defect was only apparent following a long-term macrophage exposure to IL4 , that is , conditions under which the KLF4 protein , whose expression is initially activated by STAT6 , accumulates in a cell to further enforce the M ( IL4 ) cell fate commitment .	Importantly, this defect was only apparent following a long-term macrophage exposure to IL4, that is, conditions under which the KLF4 protein, whose expression is initially activated by STAT6, accumulates in a cell to further enforce the M (IL4) cell fate commitment.	22	32	initially activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	KLF4	KLF4	KLF4	31	32	22	23
Moreover , we found that leflunomide , a known JAK and STAT6 inhibitor [ XREF_BIBR ] , prevented CT26 induced KLF4 expression , suggesting that KLF4 was induced by STAT6 under these conditions .	Moreover, we found that leflunomide, a known JAK and STAT6 inhibitor [XREF_BIBR], prevented CT26 induced KLF4 expression, suggesting that KLF4 was induced by STAT6 under these conditions.	25	30	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	STAT6	STAT6	STAT6	KLF4	KLF4	KLF4	29	30	25	26
( v ) cAMP and protein kinase A can activate LIMK1 directly in mouse embryonic fibroblasts [ XREF_BIBR ] ; however elevated cAMP may also lead to cofilin dephosphorylation indirectly [ XREF_BIBR , XREF_BIBR ] ; ( vi ) type I and II coronins have different localizations , but depletion of either one results in increased phospho-cofilin ; phospho-coronin 1B , like cofilin , is activated by SSH1L [ XREF_BIBR ] .	(v) cAMP and protein kinase A can activate LIMK1 directly in mouse embryonic fibroblasts [XREF_BIBR]; however elevated cAMP may also lead to cofilin dephosphorylation indirectly [XREF_BIBR, XREF_BIBR]; (vi) type I and II coronins have different localizations, but depletion of either one results in increased phospho-cofilin; phospho-coronin 1B, like cofilin, is activated by SSH1L [XREF_BIBR].	58	69	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SSH1L	SSH1L	SSH1L	phospho-coronin 1B	phospho-coronin 1B	phospho-coronin 1B	67	68	58	60
This observation opens the exciting possibility that LKB1 may locally activate MARK4 to promote cilia formation .	This observation opens the exciting possibility that LKB1 may locally activate MARK4 to promote cilia formation.	7	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	MARK4	MARK4	MARK4	7	8	11	12
STAG2 is able to enhance the activity of the tumor necrosis factor alpha , the CD69 , and the human immunodeficiency virus long terminal repeat promoters in a NF-kappaB-dependent manner .	STAG2 is able to enhance the activity of the tumor necrosis factor alpha, the CD69, and the human immunodeficiency virus long terminal repeat promoters in a NF-kappaB-dependent manner.	0	16	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAG2	STAG2	STAG2	CD69	CD69	CD69	0	1	15	16
Mechanistic studies showed that inhibition of p-STAT3 within the mouse cancer cachexia model with C188-9 treatment reduced transcript levels of muscle specific ubiquitin ligases MAFbx and Atrogin -1 and MuRF1 and improved protein synthesis in muscles of mice bearing tumors [ XREF_BIBR ] .	Mechanistic studies showed that inhibition of p-STAT3 within the mouse cancer cachexia model with C188-9 treatment reduced transcript levels of muscle specific ubiquitin ligases MAFbx and Atrogin -1 and MuRF1 and improved protein synthesis in muscles of mice bearing tumors [XREF_BIBR].	4	33	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p-STAT3	p-STAT3	p-STAT3	MAFbx	MAFbx	MAFbx	6	7	24	25
Src supports UDP-glucuronosyltransferase-2B7 detoxification of catechol estrogens associated with breast cancer+ .	Src supports UDP-glucuronosyltransferase-2B7 detoxification of catechol estrogens associated with breast cancer+.	0	3	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	UDP-glucuronosyltransferase-2B7	UDP-glucuronosyltransferase-2B7	UDP-glucuronosyltransferase-2B7	0	1	2	3
Furthermore , in the presence of BLNK , SYK directly activates BTK by phosphorylating the Y551 residue in the activation loop of the BTK catalytic domain XREF_BIBR .	Furthermore, in the presence of BLNK, SYK directly activates BTK by phosphorylating the Y551 residue in the activation loop of the BTK catalytic domain XREF_BIBR.	8	12	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SYK	SYK	SYK	BTK	BTK	BTK	8	9	11	12
Syk enhances Btk activity on several downstream proteins , such as phospholipase C gamma 2 ( PLCgamma2 ) [ XREF_BIBR ] and STAT3 [ XREF_BIBR ] .	Syk enhances Btk activity on several downstream proteins, such as phospholipase C gamma 2 (PLCgamma2) [XREF_BIBR] and STAT3 [XREF_BIBR].	0	3	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syk	Syk	Syk	Btk	Btk	Btk	0	1	2	3
Furthermore , SYK directly activates BTK by phosphorylating the Y551 residue in the activation loop of the BTK catalytic domain XREF_BIBR .	Furthermore, SYK directly activates BTK by phosphorylating the Y551 residue in the activation loop of the BTK catalytic domain XREF_BIBR.	2	6	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SYK	SYK	SYK	BTK	BTK	BTK	2	3	5	6
BTK is activated by Syk and sends a signal that stimulates actin polymerization at the cell cortex , leading to a reconfiguration of the actin cytoskeleton [ XREF_BIBR ] .	BTK is activated by Syk and sends a signal that stimulates actin polymerization at the cell cortex, leading to a reconfiguration of the actin cytoskeleton [XREF_BIBR].	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Syk	Syk	Syk	BTK	BTK	BTK	4	5	0	1
This costimulatory pathway is required for RANK mediated osteoclastogenesis , and signals downstream through the protein kinase Syk , which activates phospholipase Cg ( PLCg ) and the BTK and Tec kinases , eventually leading to calcium mediated activation of NFATc1 and NFAT2 .	This costimulatory pathway is required for RANK mediated osteoclastogenesis, and signals downstream through the protein kinase Syk, which activates phospholipase Cg (PLCg) and the BTK and Tec kinases, eventually leading to calcium mediated activation of NFATc1 and NFAT2.	11	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syk	Syk	Syk	BTK	BTK	BTK	17	18	28	29
Syk can also contribute to Btk and Tec activation , further underscoring the tight coupling of RANK and ITAM signaling pathways .	Syk can also contribute to Btk and Tec activation, further underscoring the tight coupling of RANK and ITAM signaling pathways.	0	8	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Syk	Syk	Syk	Btk	Btk	Btk	0	1	5	6
19 SYK is the upstream target of BTK , so SYK phosphorylation could phosphorylate BTK that results in p53 upregulation .	19 SYK is the upstream target of BTK, so SYK phosphorylation could phosphorylate BTK that results in p53 upregulation.	0	8	is the upstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	SYK	SYK	SYK	BTK	BTK	BTK	1	2	7	8
Phosphorylated ITAMs , in turn , lead to the recruitment and activation of the PTK Syk , which activates the Tec family PTK Btk .	Phosphorylated ITAMs, in turn, lead to the recruitment and activation of the PTK Syk, which activates the Tec family PTK Btk.	0	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syk	Syk	Syk	Btk	Btk	Btk	15	16	23	24
In particular , the BTK activator SYK revealed a hypermethylated DMR and the BTK repressor SH3BP5 XREF_BIBR a hypomethylated DMR in their promoter regions ( XREF_FIG ) .	In particular, the BTK activator SYK revealed a hypermethylated DMR and the BTK repressor SH3BP5 XREF_BIBR a hypomethylated DMR in their promoter regions (XREF_FIG).	3	7	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	SYK	SYK	SYK	BTK	BTK	BTK	6	7	4	5
3 Btk is activated by SFK ( src family kinases ) and Syk , and transmits signals to PI3K and PLC-gamma , resulting in a calcium flux and the activation of NF-kB and NFATc transcriptional factors .	3 Btk is activated by SFK (src family kinases) and Syk, and transmits signals to PI3K and PLC-gamma, resulting in a calcium flux and the activation of NF-kB and NFATc transcriptional factors.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Syk	Syk	Syk	Btk	Btk	Btk	12	13	1	2
Syk overexpression resulted in significant upregulation of Syk in all experiments performed .	Syk overexpression resulted in significant upregulation of Syk in all experiments performed.	0	8	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Syk	Syk overexpression	syk	Syk	Syk	syk	0	1	7	8
We report here that CD2 provides a co-stimulus for activation of CD3 mediated syk and ZAP -70 family kinase , p72Syk ( Syk ) , in Jurkat T cells .	We report here that CD2 provides a co-stimulus for activation of CD3 mediated syk and ZAP -70 family kinase, p72Syk (Syk), in Jurkat T cells.	12	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p72Syk	p72Syk	p72Syk	syk	syk	syk	20	21	13	14
In contrast , expression of GFP-Syk in Lyn-KO DT40 B cells was not sufficient to restore spreading and did not allow the effective recruitment of GFP-Syk to antigen microclusters ( XREF_FIG ) .	In contrast, expression of GFP-Syk in Lyn-KO DT40 B cells was not sufficient to restore spreading and did not allow the effective recruitment of GFP-Syk to antigen microclusters (XREF_FIG).	3	26	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GFP-Syk	expression of GFP-Syk	gfp-syk	GFP-Syk	GFP-Syk	gfp-syk	5	6	25	26
First , expression of the ( K395A/3F ) Syk molecule in BCL 1.3 B3 results in constitutive activation of endogenous Syk .	First, expression of the (K395A/3F) Syk molecule in BCL 1.3 B3 results in constitutive activation of endogenous Syk.	2	21	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Syk	expression of the (K395A/3F) Syk	syk	Syk	Syk	syk	8	9	20	21
Mutation of the FG loop sequence of Syk to that of ZAP-70 ( RGMK-to-KKMK ) decreased Syk activation loop autophosphorylation and also decreased the ability of Syk to phosphorylate TCRzeta and LAT ( XREF_FIG and XREF_FIG ) .	Mutation of the FG loop sequence of Syk to that of ZAP-70 (RGMK-to-KKMK) decreased Syk activation loop autophosphorylation and also decreased the ability of Syk to phosphorylate TCRzeta and LAT (XREF_FIG and XREF_FIG).	5	20	decreased	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	Syk	Syk	syk	Syk	Syk activation loop autophosphorylation	syk	7	8	16	17
These results suggest that the Src-PTK associated with BCR phosphorylates the tyrosine residue ( s ) of Syk upon receptor stimulation , enhancing the activity of Syk .	These results suggest that the Src-PTK associated with BCR phosphorylates the tyrosine residue (s) of Syk upon receptor stimulation, enhancing the activity of Syk.	5	27	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syk	Src-PTK associated with BCR phosphorylates the tyrosine residue (s) of Syk	syk	Syk	Syk	syk	17	18	26	27
In conclusion , c-Jun in cooperation with Ets2 increases the expression of Syk and contributes to Syk mediated heightened calcium responses in SLE T cells .	In conclusion, c-Jun in cooperation with Ets2 increases the expression of Syk and contributes to Syk mediated heightened calcium responses in SLE T cells.	3	17	contributes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Syk	c-Jun in cooperation with Ets2 increases the expression of Syk	syk	Syk	Syk	syk	12	13	16	17
Unexpectedly , in vitro kinase assays showed that Fc alpha R aggregation induced tyrosine phosphorylation of Syk did not result in upregulation of Syk activity .	Unexpectedly, in vitro kinase assays showed that Fc alpha R aggregation induced tyrosine phosphorylation of Syk did not result in upregulation of Syk activity.	13	24	result in upregulation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Syk	tyrosine phosphorylation of Syk	syk	Syk	Syk	syk	16	17	23	24
These results indicate that Fgr could directly phosphorylate Syk or stimulate Syk through phosphorylation of the gamma subunit of FcepsilonRI .	These results indicate that Fgr could directly phosphorylate Syk or stimulate Syk through phosphorylation of the gamma subunit of FcepsilonRI.	4	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syk	Fgr could directly phosphorylate Syk	syk	Syk	Syk	syk	8	9	11	12
Thus , our results demonstrated that the initial phosphorylation of Syk allowed a kinase activity that was corroborated by the detection of specific phospho-tyrosine residues , such as Y323 , Y348 and Y525 , in the Syk produced in Sf9 cells ( XREF_FIG ) .	Thus, our results demonstrated that the initial phosphorylation of Syk allowed a kinase activity that was corroborated by the detection of specific phospho-tyrosine residues, such as Y323, Y348 and Y525, in the Syk produced in Sf9 cells (XREF_FIG).	8	37	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syk	phosphorylation of Syk	syk	Syk	Syk	syk	10	11	36	37
Hyper-methylation of the SYK promoter in SYK deficient NK cells suggested that other protein deficiencies , including FcRgamma-deficiency in FcRgamma - NK cells , were due to changes in DNA methylation .	Hyper-methylation of the SYK promoter in SYK deficient NK cells suggested that other protein deficiencies, including FcRgamma-deficiency in FcRgamma - NK cells, were due to changes in DNA methylation.	0	9	promoter	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	SYK	Hyper-methylation of the SYK	syk	SYK	SYK	syk	3	4	6	7
Because AMOTL2 can bind both LATS2 and its activator MST2 , AMOTL2 might act as an adaptor protein to promote MST2 activation of LATS2 .	Because AMOTL2 can bind both LATS2 and its activator MST2, AMOTL2 might act as an adaptor protein to promote MST2 activation of LATS2.	20	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MST2	MST2	MST2	LATS2	LATS2	LATS2	20	21	23	24
MST1 and MST2 kinases activate two downstream kinases , LATS1 and LATS2 .	MST1 and MST2 kinases activate two downstream kinases, LATS1 and LATS2.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST2	MST2	MST2	LATS2	LATS2	LATS2	2	3	11	12
MST2 activates LATS2 , and LATS2 phosphorylates YAP , which inhibits the ability of YAP to promote cell motility and proliferation and maintain stem cell fate .	MST2 activates LATS2, and LATS2 phosphorylates YAP, which inhibits the ability of YAP to promote cell motility and proliferation and maintain stem cell fate.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST2	MST2	MST2	LATS2	LATS2	LATS2	0	1	2	3
The mammalian core Hippo pathway consists of MST1 and MST2 kinases ( Hpo homologs , a.k.a. STK4 and STK3 ) , which activate LATS1 and LATS2 kinases , leading to phosphorylation of effectors YAP1 and TAZ ( WWTR1 ) at multiple sites .	The mammalian core Hippo pathway consists of MST1 and MST2 kinases (Hpo homologs, a.k.a. STK4 and STK3), which activate LATS1 and LATS2 kinases, leading to phosphorylation of effectors YAP1 and TAZ (WWTR1) at multiple sites.	7	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST2	MST2	MST2	LATS2	LATS2	LATS2	9	10	25	26
The heart of the Hippo pathway includes a core of two serine threonine kinase pairs , STK4 ( MST1 ) and STK3 ( MST2 ) , which activate two other kinases , LATS1 and LATS2 .	The heart of the Hippo pathway includes a core of two serine threonine kinase pairs, STK4 (MST1) and STK3 (MST2), which activate two other kinases, LATS1 and LATS2.	21	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST2	MST2	MST2	LATS2	LATS2	LATS2	23	24	34	35
The core of the pathway consists of a short kinase cascade : MST1 and MST2 phosphorylate and activate LATS1 and LATS2 , which in turn phosphorylate and inactivate key transcriptional coactivators , YAP1 and TAZ ( gene WWTR1 ) .	The core of the pathway consists of a short kinase cascade : MST1 and MST2 phosphorylate and activate LATS1 and LATS2, which in turn phosphorylate and inactivate key transcriptional coactivators, YAP1 and TAZ (gene WWTR1).	12	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST2	MST2	MST2	LATS2	LATS2	LATS2	14	15	20	21
Lats1 [ T1079E ] had low basal activity but was activated by Mst2 whereas [ S909D or E ] was entirely inactive [ XREF_BIBR ] .	Lats1 [T1079E] had low basal activity but was activated by Mst2 whereas [S909D or E] was entirely inactive [XREF_BIBR].	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Mst2	Mst2	Mst2	Lats1	Lats1	Lats1	12	13	0	1
Mst1 and Mst2 activate Lats1 and Lats2 by phosphorylation , and in turn phosphorylate Yap and inhibit it from translocating into the nucleus [ XREF_BIBR ] .	Mst1 and Mst2 activate Lats1 and Lats2 by phosphorylation, and in turn phosphorylate Yap and inhibit it from translocating into the nucleus [XREF_BIBR].	0	16	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Mst2	Mst2	Mst2	Lats1	Lats1	Lats1	2	3	4	5
LATS1 is activated by death receptors downstream of RASSF1A and MST2 [ XREF_BIBR ] .	LATS1 is activated by death receptors downstream of RASSF1A and MST2 [XREF_BIBR].	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MST2	MST2	MST2	LATS1	LATS1	LATS1	10	11	0	1
Our study uncovers that BITC concertedly modulates tumor-suppressors- p53 , p73 and LKB1 and not only activates p53 signaling networks in p53-wild-type breast cancer but also functionally restores p53 signaling in p53-mutant breast cancer .	Our study uncovers that BITC concertedly modulates tumor-suppressors- p53, p73 and LKB1 and not only activates p53 signaling networks in p53-wild-type breast cancer but also functionally restores p53 signaling in p53-mutant breast cancer.	8	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	p53	p53	p53	12	13	17	18
Furthermore , a 2001 study indicated that the over-expression of a dominant negative LKB1 K78M mutant in LKB1-wild type HT1080 cells led to paclitaxel and vincristine resistance , and LKB1 was found to mediate p53 dependent apoptosis in this cell line .	Furthermore, a 2001 study indicated that the over-expression of a dominant negative LKB1 K78M mutant in LKB1-wild type HT1080 cells led to paclitaxel and vincristine resistance, and LKB1 was found to mediate p53 dependent apoptosis in this cell line.	29	36	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	p53	p53	p53	29	30	34	35
Furthermore , we observed that wild type LKB1 expression increased p53 activity , while LKB1 A47G mutation had no such effect on p53 activity , indicating that the mis-sense variant of LKB1 influenced the p53 activation function of LKB1 protein .	Furthermore, we observed that wild type LKB1 expression increased p53 activity, while LKB1 A47G mutation had no such effect on p53 activity, indicating that the mis-sense variant of LKB1 influenced the p53 activation function of LKB1 protein.	7	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1 expression	lkb1	p53	p53	p53	7	8	10	11
Furthermore , Stk11 could activate the p53 and p16 pathways to arrest cell cycle progression from the G0/G1 phase to S phase .	Furthermore, Stk11 could activate the p53 and p16 pathways to arrest cell cycle progression from the G0/G1 phase to S phase.	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Stk11	Stk11	Stk11	p53	p53	p53	2	3	6	7
LKB1 leads to induction of p21 and WAF1 expression in a p53 dependent mechanism , which is mediated by cytoplasmic LKB1 initiating negative regulation of cell growth or nuclear LKB1 directly involved in transcriptional regulation of p21 and WAF1 .	LKB1 leads to induction of p21 and WAF1 expression in a p53 dependent mechanism, which is mediated by cytoplasmic LKB1 initiating negative regulation of cell growth or nuclear LKB1 directly involved in transcriptional regulation of p21 and WAF1.	11	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	p53	p53	p53	20	21	11	12
Because the TP53 tumor suppressor gene is frequently mutated in human pancreatic cancer ( 40 %-70% ) XREF_BIBR and LKB1 is down-regulated in around 20 % of PDAC , we hypothesized that loss of Lkb1 mediated p53 and p21 induction might be able to circumvent the need for p53 mutation in human PDAC and thus should not be down-regulated in those tumors with p53 mutation .	Because the TP53 tumor suppressor gene is frequently mutated in human pancreatic cancer (40%-70%) XREF_BIBR and LKB1 is down-regulated in around 20% of PDAC, we hypothesized that loss of Lkb1 mediated p53 and p21 induction might be able to circumvent the need for p53 mutation in human PDAC and thus should not be down-regulated in those tumors with p53 mutation.	32	39	mediated	Positive_early_activation	Positive_activation	Negative_activation	Lkb1	Lkb1	Lkb1	p53	p53	p53	34	35	36	37
In addition , chromatin immunoprecipitation revealed that Stk11 catalyzed p53 serine 15 phosphorylation , and the Stk11 and p53 complex bound to the p21 promoter and stimulated gene transcription .	In addition, chromatin immunoprecipitation revealed that Stk11 catalyzed p53 serine 15 phosphorylation, and the Stk11 and p53 complex bound to the p21 promoter and stimulated gene transcription.	7	26	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Stk11	Stk11	Stk11	p53	p53	p53	7	8	9	10
SIK1 is particularly of interest because SIK1 is able to interact with LKB1 which in turn , enhances p53 dependent anoikis and suppresses cancer metastasis [ XREF_BIBR ] .	SIK1 is particularly of interest because SIK1 is able to interact with LKB1 which in turn, enhances p53 dependent anoikis and suppresses cancer metastasis [XREF_BIBR].	10	22	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	p53	p53	p53	12	13	18	19
Because of the induction of PTEN , p53 , and p21 proteins by LKB1 XREF_BIBR , XREF_BIBR , XREF_BIBR , loss of LKB1 function activates the PI3K/Akt/mTOR pathway to promote proliferation and metastasis XREF_BIBR .	Because of the induction of PTEN, p53, and p21 proteins by LKB1 XREF_BIBR, XREF_BIBR, XREF_BIBR, loss of LKB1 function activates the PI3K/Akt/mTOR pathway to promote proliferation and metastasis XREF_BIBR.	3	14	induction	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	p53	p53	p53	13	14	7	8
Before any direct substrates for LKB1 were identified , LKB1 reconstitution into LKB1 deficient tumor cells was reported to stimulate p53 activity and increase levels of Cdkn1a mRNA , which encodes the cyclin dependent kinase inhibitor p21 XREF_BIBR , XREF_BIBR .	Before any direct substrates for LKB1 were identified, LKB1 reconstitution into LKB1 deficient tumor cells was reported to stimulate p53 activity and increase levels of Cdkn1a mRNA, which encodes the cyclin dependent kinase inhibitor p21 XREF_BIBR, XREF_BIBR.	9	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	p53	p53	p53	9	10	20	21
The affected P53 activity caused by STK11 mutations in PJS patients is significantly associated with protein truncation , while cancer risk in PJS can be elevated through pathways rather than P53 pathway .	The affected P53 activity caused by STK11 mutations in PJS patients is significantly associated with protein truncation, while cancer risk in PJS can be elevated through pathways rather than P53 pathway.	2	10	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PJS	PJS	PJS	P53	P53	P53	9	10	2	3
LKB1 function was previously linked to the tumor suppressor p53 and shown to activate the p53 target gene p21 and WAF1 .	LKB1 function was previously linked to the tumor suppressor p53 and shown to activate the p53 target gene p21 and WAF1.	0	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	p53	p53	p53	0	1	15	16
Overexpression of STK11 could elevate the transcriptional activity of P53 , while its depletion inhibited P53 functions , which has been observed in patients of PJS associated GI carcinomas [ XREF_BIBR , XREF_BIBR ] .	Overexpression of STK11 could elevate the transcriptional activity of P53, while its depletion inhibited P53 functions, which has been observed in patients of PJS associated GI carcinomas [XREF_BIBR, XREF_BIBR].	0	10	elevate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STK11	Overexpression of STK11	stk11	P53	P53	p53	2	3	9	10
XREF_BIBR , XREF_BIBR Interestingly , the protein phosphatase PHLPP , which dephosphorylates Akt [ Ser473 ] 95 and thereby interferes with the ability of Akt to phosphorylate and negatively regulate Foxo , 96 also promotes the dephosphorylation of MST1 [ Thr387 ] , thus enhancing MST1 catalyzed FOXO activation .	XREF_BIBR, XREF_BIBR Interestingly, the protein phosphatase PHLPP, which dephosphorylates Akt [Ser473] 95 and thereby interferes with the ability of Akt to phosphorylate and negatively regulate Foxo, 96 also promotes the dephosphorylation of MST1 [Thr387], thus enhancing MST1 catalyzed FOXO activation.	44	48	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FOXO	FOXO	FOXO	45	46	47	48
This finding is not necessarily inconsistent with the observation that MST1 activates FoxO ; however , it suggests that additional steps , probably involving phosphatase activity in the pathway for MST1 activation of FoxO .	This finding is not necessarily inconsistent with the observation that MST1 activates FoxO; however, it suggests that additional steps, probably involving phosphatase activity in the pathway for MST1 activation of FoxO.	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FoxO	FoxO	FoxO	10	11	12	13
The mammalian MST1 also activates FOXO , but instead stimulates apoptosis in primary neurons in response to oxidative stress , i.e ., decreasing cellular survival [ XREF_BIBR ] .	The mammalian MST1 also activates FOXO, but instead stimulates apoptosis in primary neurons in response to oxidative stress, i.e., decreasing cellular survival [XREF_BIBR].	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FOXO	FOXO	FOXO	2	3	5	6
Here , we demonstrate that the protein kinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors .	Here, we demonstrate that the protein kinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors.	5	23	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FOXO	FOXO	FOXO	8	9	21	22
Furthermore , we performed fractionation assay to define the subcellular localization of FoxO3-GFP and observed that MST1 increased nuclear FoxO3-GFP and BRAF V600E could reverse this MST1 induced FoxO3 nuclear localization ( XREF_SUPPLEMENTARY ) .	Furthermore, we performed fractionation assay to define the subcellular localization of FoxO3-GFP and observed that MST1 increased nuclear FoxO3-GFP and BRAF V600E could reverse this MST1 induced FoxO3 nuclear localization (XREF_SUPPLEMENTARY).	25	30	induced	Positive_early_activation	Positive_activation	Positive_activation	MST1	MST1	MST1	FoxO3	FoxO3	FoxO3	26	27	28	29
Up-regulation of MST1 kinase function following denervation further promoted nuclear accumulation of FOXO3a and thus full development of muscle atrophy .	Up-regulation of MST1 kinase function following denervation further promoted nuclear accumulation of FOXO3a and thus full development of muscle atrophy.	2	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FOXO3a	FOXO3a	FOXO3a	2	3	12	13
Within this context , FOXO3 might be activated by MST1 or inhibited by the AKT kinase [ XREF_BIBR , XREF_BIBR ] .	Within this context, FOXO3 might be activated by MST1 or inhibited by the AKT kinase [XREF_BIBR, XREF_BIBR].	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FOXO3	FOXO3	FOXO3	9	10	4	5
Indeed STK4 is necessary for activation of FOXO1 and FOXO3 , crucial transcription factors for powerful CTL response to chronic viral infection and T cell homeostasis .	Indeed STK4 is necessary for activation of FOXO1 and FOXO3, crucial transcription factors for powerful CTL response to chronic viral infection and T cell homeostasis.	1	10	is necessary for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	STK4	STK4	STK4	FOXO3	FOXO3	FOXO3	1	2	9	10
MST1 activates FOXO3 , which is otherwise maintained in the cytosol in an inactive state by interaction with 14-3-3 proteins [ XREF_BIBR ] .	MST1 activates FOXO3, which is otherwise maintained in the cytosol in an inactive state by interaction with 14-3-3 proteins [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FOXO3	FOXO3	FOXO3	0	1	2	3
Among these atrogenes , we found that activation of FOXO3a by MST1 kinase especially affected the expression of Atrogin-1 and LC3 genes , but not Bnip3 .	Among these atrogenes, we found that activation of FOXO3a by MST1 kinase especially affected the expression of Atrogin-1 and LC3 genes, but not Bnip3.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MST1	MST1	MST1	FOXO3a	FOXO3a	FOXO3a	11	12	9	10
The FoxO3 transactivation is augmented by RASSF1A and the MST1 signaling pathway .	The FoxO3 transactivation is augmented by RASSF1A and the MST1 signaling pathway.	1	11	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FoxO3	FoxO3	FoxO3	9	10	1	2
MST1 phosphorylates and thus activates FOXO3a during neurogenic skeletal muscle atrophy , which provides a new molecular mechanism to precisely determine the subcellular location and activity of FOXO3a in myofibers undergoing atrophy .	MST1 phosphorylates and thus activates FOXO3a during neurogenic skeletal muscle atrophy, which provides a new molecular mechanism to precisely determine the subcellular location and activity of FOXO3a in myofibers undergoing atrophy.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FOXO3a	FOXO3a	FOXO3a	0	1	5	6
Under oxidative stress , JNK and MST1 participate in similar signaling pathways and act in a complementary manner to activate FOXO3a .	Under oxidative stress, JNK and MST1 participate in similar signaling pathways and act in a complementary manner to activate FOXO3a.	4	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FOXO3a	FOXO3a	FOXO3a	6	7	20	21
Based on other studies showing that the stimulation of MST1 may activate the kinases LATs1 and LATs2 , which leads to down-regulation of the anti-apoptotic Bcl-2 , Vos et al ..	Based on other studies showing that the stimulation of MST1 may activate the kinases LATs1 and LATs2, which leads to down-regulation of the anti-apoptotic Bcl-2, Vos et al..	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	LATs2	LATs2	LATs2	9	10	16	17
In the core hippo kinase cassette , MST1 and 2 activate Lats1 by phosphorylating Thr 1079 .	In the core hippo kinase cassette, MST1 and 2 activate Lats1 by phosphorylating Thr 1079.	7	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	Lats1	Lats1	Lats1	7	8	11	12
Cheng and co-authors XREF_BIBR have demonstrated that SIK1 links the tumour suppressor Liver Kinase 1B ( LKB1 ) to p53 dependent suppression of metastasis and that SIK1 activated by LKB1 suppresses metastasis and invasion in a human mammary epithelial cell line XREF_BIBR .	Cheng and co-authors XREF_BIBR have demonstrated that SIK1 links the tumour suppressor Liver Kinase 1B (LKB1) to p53 dependent suppression of metastasis and that SIK1 activated by LKB1 suppresses metastasis and invasion in a human mammary epithelial cell line XREF_BIBR.	26	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	SIK1	SIK1	SIK1	29	30	26	27
Because SIK is activated by the tumor suppressor kinase LKB1 , our study suggests a role of LKB1 in processes of TGFbeta signaling and receptor down-regulation .	Because SIK is activated by the tumor suppressor kinase LKB1, our study suggests a role of LKB1 in processes of TGFbeta signaling and receptor down-regulation.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	LKB1	LKB1	LKB1	SIK	SIK	SIK	9	10	1	2
The SIK1 T182D mutant was used to mimic the activation of SIK1 by LKB1 and was therefore expected to be more active than SIK1-WT [ XREF_BIBR , XREF_BIBR ] .	The SIK1 T182D mutant was used to mimic the activation of SIK1 by LKB1 and was therefore expected to be more active than SIK1-WT [XREF_BIBR, XREF_BIBR].	7	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	SIK1	SIK1	SIK1	13	14	11	12
We next examined the effect of HG-9-91-01 on glucose homeostasis in mouse primary hepatocytes , isolated from a liver specific LKB1 KO mouse , to establish the dependency for LKB1 induced SIK activity .	We next examined the effect of HG-9-91-01 on glucose homeostasis in mouse primary hepatocytes, isolated from a liver specific LKB1 KO mouse, to establish the dependency for LKB1 induced SIK activity.	27	32	induced	Positive_early_activation	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	SIK	SIK	SIK	29	30	31	32
Cheng and co-workers XREF_BIBR have shown that LKB1 mediated activation of SIK1 suppresses metastasis and invasion .	Cheng and co-workers XREF_BIBR have shown that LKB1 mediated activation of SIK1 suppresses metastasis and invasion.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	SIK1	SIK1	SIK1	7	8	11	12
Like other AMPK family members , Sik kinases can be activated by the upstream master kinase Lkb1 64 .	Like other AMPK family members, Sik kinases can be activated by the upstream master kinase Lkb1 64.	6	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Lkb1	Lkb1	Lkb1	Sik	Sik	Sik	16	17	6	7
Furthermore , we demonstrated that MST1 deacetylation promoted the interaction of MST1 with HSC70 in the cells , resulting in a lysosome dependent degradation of MST1 via chaperone mediated autophagy ( CMA ) .	Furthermore, we demonstrated that MST1 deacetylation promoted the interaction of MST1 with HSC70 in the cells, resulting in a lysosome dependent degradation of MST1 via chaperone mediated autophagy (CMA).	5	12	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1 deacetylation	mst1	MST1	MST1	mst1	5	6	11	12
Deacetylation of MST1 promoted the interaction of MST1 with HSC70 in the cells , resulting in a lysosome dependent degradation of MST1 via chaperone mediated autophagy ( CMA ) .	Deacetylation of MST1 promoted the interaction of MST1 with HSC70 in the cells, resulting in a lysosome dependent degradation of MST1 via chaperone mediated autophagy (CMA).	0	8	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	Deacetylation of MST1	mst1	MST1	MST1	mst1	2	3	7	8
Co-expression of RASSF1A , RASSF1C , NORE1A and NORE1B with MST1 markedly suppresses MST1 ( Thr183 ) phosphorylation in vivo and abolishes the ability of MST1 to undergo Mg-ATP-mediated autoactivation in vitro ; direct addition of purified NORE1A in vitro also inhibits MST1 activation .	Co-expression of RASSF1A, RASSF1C, NORE1A and NORE1B with MST1 markedly suppresses MST1 (Thr183) phosphorylation in vivo and abolishes the ability of MST1 to undergo Mg-ATP-mediated autoactivation in vitro; direct addition of purified NORE1A in vitro also inhibits MST1 activation.	0	26	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MST1	Co-expression of RASSF1A, RASSF1C, NORE1A and NORE1B with MST1 markedly suppresses MST1 (Thr183) phosphorylation	mst1	MST1	MST1	mst1	13	14	25	26
Previous study has shown that phosphorylation of MST1 within the kinase domain by JNK kinase enhances MST1 dimerization and kinase activity XREF_BIBR .	Previous study has shown that phosphorylation of MST1 within the kinase domain by JNK kinase enhances MST1 dimerization and kinase activity XREF_BIBR.	5	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	phosphorylation of MST1	mst1	MST1	MST1	mst1	7	8	16	17
Previously , we demonstrated that the protein kinase Hippo and MST1 plays an important role in oxidative stress induced cell death in mammalian primary neurons and that the protein kinase c-Abl phosphorylates MST1 at Y433 , which increases MST1 kinase activity .	Previously, we demonstrated that the protein kinase Hippo and MST1 plays an important role in oxidative stress induced cell death in mammalian primary neurons and that the protein kinase c-Abl phosphorylates MST1 at Y433, which increases MST1 kinase activity.	30	40	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	c-Abl phosphorylates MST1 at Y433	mst1	MST1	MST1	mst1	32	33	38	39
Empirically , it has been reported that deletion of LKB1 will prevent activation of AMPKalpha2 in cardiac and skeletal muscle cells .	Empirically, it has been reported that deletion of LKB1 will prevent activation of AMPKalpha2 in cardiac and skeletal muscle cells.	7	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	AMPKalpha2	AMPKalpha2	AMPKalpha2	9	10	14	15
SIRT1 normally deacetylates and activates both PGC1alpha and LKB1 , the kinase that activates AMPKalpha2 .	SIRT1 normally deacetylates and activates both PGC1alpha and LKB1, the kinase that activates AMPKalpha2.	0	15	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	LKB1	SIRT1 normally deacetylates and activates both PGC1alpha and LKB1	lkb1	AMPKalpha2	AMPKalpha2	ampkalpha2	8	9	14	15
In line with a gastrin induced activation of STK11 , the phosphorylation of the STK11 targeted site in PRKAA2 ( Thr 172 ) was transiently elevated in both AGS-Gr and MKN45 cells .	In line with a gastrin induced activation of STK11, the phosphorylation of the STK11 targeted site in PRKAA2 (Thr 172) was transiently elevated in both AGS-Gr and MKN45 cells.	11	20	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STK11	phosphorylation of the STK11	stk11	PRKAA2	PRKAA2	prkaa2	14	15	18	19
Empirically , it has been reported that deletion of LKB1 will prevent activation of AMPKalpha2 in cardiac and skeletal muscle cells [ XREF_BIBR ] .	Empirically, it has been reported that deletion of LKB1 will prevent activation of AMPKalpha2 in cardiac and skeletal muscle cells [XREF_BIBR].	7	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	AMPKalpha2	AMPKalpha2	AMPKalpha2	9	10	14	15
SLP65 ( also known as BLNK ) , activated by SYK phosphorylation , was a crucial protein for B-cell activation , which promoted apoptosis through the interaction with PLCgamma2 XREF_BIBR and arrested the cell cycle through the inhibition of the JAK3 and STAT5 pathway XREF_BIBR .	SLP65 (also known as BLNK), activated by SYK phosphorylation, was a crucial protein for B-cell activation, which promoted apoptosis through the interaction with PLCgamma2 XREF_BIBR and arrested the cell cycle through the inhibition of the JAK3 and STAT5 pathway XREF_BIBR.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SYK	SYK phosphorylation	syk	SLP65	SLP65	slp65	10	11	0	1
Taken together , these data indicated that the BCR induced activation of HPK1 is largely dependent on binding to the BASH SH2 domain , which is mediated by Tyr 379 after inducible phosphorylation by Syk .	Taken together, these data indicated that the BCR induced activation of HPK1 is largely dependent on binding to the BASH SH2 domain, which is mediated by Tyr 379 after inducible phosphorylation by Syk.	20	35	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Syk	Syk	Syk	BASH	BASH	BASH	34	35	20	21
As expected , only TMD8 and OCILY10 showed strong phosphorylation of these markers , consistent with the presence of activating mutations in CD79 and all inhibitors blocked pSTAT3 , while only SYK inhibition downregulated pBLNK .	As expected, only TMD8 and OCILY10 showed strong phosphorylation of these markers, consistent with the presence of activating mutations in CD79 and all inhibitors blocked pSTAT3, while only SYK inhibition downregulated pBLNK.	31	35	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SYK	SYK	SYK	pBLNK	pBLNK	pBLNK	31	32	34	35
This is consistent with our observation that the target serines are making direct or water mediated contacts to the phosphate backbone ( XREF_FIG ) ; however , this suggests that the proposed mechanism by which MST1 phosphorylation promotes nuclear translocation and transcription of FoxO1 target genes requires an additional step .	This is consistent with our observation that the target serines are making direct or water mediated contacts to the phosphate backbone (XREF_FIG); however, this suggests that the proposed mechanism by which MST1 phosphorylation promotes nuclear translocation and transcription of FoxO1 target genes requires an additional step.	35	45	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1 phosphorylation	mst1	FoxO1	FoxO1	foxo1	35	36	43	44
We also find a requirement for MST1 in cell death of granule neurons upon withdrawal of growth factors and neuronal activity , and MST1 induces cell death in a FOXO1 dependent manner .	We also find a requirement for MST1 in cell death of granule neurons upon withdrawal of growth factors and neuronal activity, and MST1 induces cell death in a FOXO1 dependent manner.	23	31	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FOXO1	FOXO1	FOXO1	23	24	29	30
We propose that dephosphorylation of serines 212 , 218 , 234 and 235 occurs before DNA binding and transcriptional regulation by MST1 restored FoxO1 .	We propose that dephosphorylation of serines 212, 218, 234 and 235 occurs before DNA binding and transcriptional regulation by MST1 restored FoxO1.	16	24	restored	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MST1	MST1	MST1	FoxO1	FoxO1	FoxO1	21	22	23	24
STK4 is necessary for activation of forkhead box protein O1 ( FOXO1 ) , an important transcription factor in T cell homeostasis .	STK4 is necessary for activation of forkhead box protein O1 (FOXO1), an important transcription factor in T cell homeostasis.	0	10	is necessary for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	STK4	STK4	STK4	forkhead box protein O1	forkhead box protein O1	forkhead box protein O1	0	1	6	10
Interestingly , phosphorylation levels of tyrosine 346 ( Y346 ) in SYK , which are elevated in RANKL stimulated Sh3bp2 KI/+ BMMs compared to Sh3bp2 +/+ BMMs , were comparable between TNF-alpha-simulated Sh3bp2 KI/+ and Sh3bp2 +/+ BMMs ( XREF_FIG ) .	Interestingly, phosphorylation levels of tyrosine 346 (Y346) in SYK, which are elevated in RANKL stimulated Sh3bp2 KI/+ BMMs compared to Sh3bp2 +/+ BMMs, were comparable between TNF-alpha-simulated Sh3bp2 KI/+ and Sh3bp2 +/+ BMMs (XREF_FIG).	2	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SYK	phosphorylation levels of tyrosine 346 (Y346) in SYK	syk	Sh3bp2	Sh3bp2	sh3bp2	11	12	19	20
Indeed , SYK ablation in macrophages rescues Sh3bp2 KI/KI mice from inflammation .	Indeed, SYK ablation in macrophages rescues Sh3bp2 KI/KI mice from inflammation.	2	9	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SYK	SYK	SYK	Sh3bp2	Sh3bp2	Sh3bp2	2	3	7	8
Since genetic ablation of spleen tyrosine kinase ( SYK ) in myeloid cells rescues Sh3bp2 KI/KI mice from inflammation , we examined whether SYK inhibitor administration can improve fully developed cherubism symptoms in adult Sh3bp2 KI/KI mice .	Since genetic ablation of spleen tyrosine kinase (SYK) in myeloid cells rescues Sh3bp2 KI/KI mice from inflammation, we examined whether SYK inhibitor administration can improve fully developed cherubism symptoms in adult Sh3bp2 KI/KI mice.	6	16	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SYK	SYK	SYK	Sh3bp2	Sh3bp2	Sh3bp2	8	9	14	15
To investigate the role of WRKY46 in plant defense , we analyzed expression of a luciferase ( LUC ) reporter driven by a routinely used W-box-containing defense related promoter , NDR1 and HIN1 like 10 ( NHL10 ) , in Arabidopsis protoplasts co-expressing either different variants of WRKY46 or CFP ( as a control for expression of a defense unrelated protein ) .	To investigate the role of WRKY46 in plant defense, we analyzed expression of a luciferase (LUC) reporter driven by a routinely used W-box-containing defense related promoter, NDR1 and HIN1 like 10 (NHL10), in Arabidopsis protoplasts co-expressing either different variants of WRKY46 or CFP (as a control for expression of a defense unrelated protein).	11	43	promoter	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	NDR1	NDR1 and HIN1 like 10 (NHL10), in Arabidopsis protoplasts co-expressing	ndr1	NDR1	NDR1	ndr1	30	31	30	31
Similarly , the quantitative inhibition of calcium signaling by PLC-gamma1 SH2 domains suggests that the Syk mediated activation of PLC-gamma1 is the main pathway in RBL cells to generate calcium signals .	Similarly, the quantitative inhibition of calcium signaling by PLC-gamma1 SH2 domains suggests that the Syk mediated activation of PLC-gamma1 is the main pathway in RBL cells to generate calcium signals.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Syk	Syk	Syk	PLC-gamma1	PLC-gamma1	PLC-gamma1	15	16	19	20
In the 293T cells , SIRT1 overexpression diminished lysine acetylation of LKB1 and concurrently increased its activity , cytoplasmic and nuclear ratio , and association with the LKB1 activator STRAD .	In the 293T cells, SIRT1 overexpression diminished lysine acetylation of LKB1 and concurrently increased its activity, cytoplasmic and nuclear ratio, and association with the LKB1 activator STRAD.	14	30	activator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	STRAD	STRAD	STRAD	27	28	29	30
Stk25 has been shown to bind to the LKB1 activator STRAD and regulate neuronal polarization and dendritogenesis in an opposing manner to Reelin-Dab1 signaling .	Stk25 has been shown to bind to the LKB1 activator STRAD and regulate neuronal polarization and dendritogenesis in an opposing manner to Reelin-Dab1 signaling.	5	11	activator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	STRAD	STRAD	STRAD	8	9	10	11
We demonstrate that LKB1 activates SNRK by phosphorylating the T-loop residue ( Thr173 ) , and that the LKB1 regulatory subunits STRAD and MO25 are required for LKB1 to activate SNRK .	We demonstrate that LKB1 activates SNRK by phosphorylating the T-loop residue (Thr173), and that the LKB1 regulatory subunits STRAD and MO25 are required for LKB1 to activate SNRK.	18	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	SNRK	SNRK	SNRK	18	19	30	31
Our data showed that ectopic LKB1 expression induced nuclear translocation of SIK2 , which results in CRTC1 nuclear exportation in human lung cancer cells ( XREF_SUPPLEMENTARY ) .	Our data showed that ectopic LKB1 expression induced nuclear translocation of SIK2, which results in CRTC1 nuclear exportation in human lung cancer cells (XREF_SUPPLEMENTARY).	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1 expression	lkb1	SIK2	SIK2	sik2	5	6	11	12
For example , the LKB1 targets SIK2 and Mark2 were previously shown to phosphorylate and prevent the nuclear translocation of TORC2 , a coactivator of the key transcription factor CREB .	For example, the LKB1 targets SIK2 and Mark2 were previously shown to phosphorylate and prevent the nuclear translocation of TORC2, a coactivator of the key transcription factor CREB.	3	21	targets	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	LKB1	LKB1	lkb1	SIK2	SIK2 and Mark2 were previously shown to phosphorylate and prevent the nuclear translocation of TORC2	sik2	4	5	6	7
LKB1 induces apical brush border formation in intestinal cells by phosphorylating MST4 , which then activates ezrin [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	LKB1 induces apical brush border formation in intestinal cells by phosphorylating MST4, which then activates ezrin [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST4	phosphorylating MST4	mst4	ezrin	ezrin	ezrin	11	12	16	17
Mechanistically , we establish that SYK induced Ikaros activation is essential for its nuclear localization and optimal transcription factor function .	Mechanistically, we establish that SYK induced Ikaros activation is essential for its nuclear localization and optimal transcription factor function.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	SYK	SYK	SYK	Ikaros	Ikaros	Ikaros	5	6	7	8
We demonstrated that LKB1 activated SIK3 regulates the nucleocytoplasmic localization of HDAC4 to control lipolytic gene expression .	We demonstrated that LKB1 activated SIK3 regulates the nucleocytoplasmic localization of HDAC4 to control lipolytic gene expression.	3	6	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	SIK3	SIK3	SIK3	3	4	5	6
Conversely , Abl mediated phosphorylation of Mst2 at Y81 disrupts the c , Raf , and Mst2 heterodimer and enhances Mst2 homodimerization and activity [ XREF_BIBR ] .	Conversely, Abl mediated phosphorylation of Mst2 at Y81 disrupts the c, Raf, and Mst2 heterodimer and enhances Mst2 homodimerization and activity [XREF_BIBR].	2	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mst2	Abl mediated phosphorylation of Mst2 at Y81	mst2	Mst2	Mst2	mst2	6	7	20	21
Thus , mmLDL induced activation of Syk and PLCgamma stimulates PKCalpha activation in macrophages , leading to Nox2 dependent ROS generation .	Thus, mmLDL induced activation of Syk and PLCgamma stimulates PKCalpha activation in macrophages, leading to Nox2 dependent ROS generation.	2	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syk	mmLDL induced activation of Syk	syk	PKCalpha	PKCalpha	pkcalpha	6	7	10	11
Conversely , the release of MST2 from rassf6 causes apoptosis in a WW45 dependent manner ( Drosophila SAV ) .	Conversely, the release of MST2 from rassf6 causes apoptosis in a WW45 dependent manner (Drosophila SAV).	3	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST2	MST2	MST2	WW45	WW45	WW45	5	6	12	13
MST3 ( Thr 178 ) phosphorylation increased MST3 kinase activity , but this activity was independent of MST3 ( Thr 328 ) phosphorylation .	MST3 (Thr 178) phosphorylation increased MST3 kinase activity, but this activity was independent of MST3 (Thr 328) phosphorylation.	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST3	MST3 (Thr 178) phosphorylation	mst3	MST3	MST3	mst3	0	1	7	8
Since phosphorylation of Sufu on S342 and S346 promotes ciliary retention of Sufu ( Chen etal , 2011 ) , these data are in accordance with a model where Sufu dephosphorylation promotes the localization outside the cilium and ubiquitin mediated proteolysis by Fbxl17 .	Since phosphorylation of Sufu on S342 and S346 promotes ciliary retention of Sufu (Chen etal, 2011), these data are in accordance with a model where Sufu dephosphorylation promotes the localization outside the cilium and ubiquitin mediated proteolysis by Fbxl17.	1	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Sufu	phosphorylation of Sufu on S342 and S346	sufu	Sufu	Sufu	sufu	3	4	12	13
Furthermore , as the centrosome recruitment of Nek2 is stimulated through phosphorylation of its C-terminal non catalytic domain by Mst2 , Mst2 might directly regulate the affinity of Nek2 for C-Nap1 .	Furthermore, as the centrosome recruitment of Nek2 is stimulated through phosphorylation of its C-terminal non catalytic domain by Mst2, Mst2 might directly regulate the affinity of Nek2 for C-Nap1.	21	29	directly regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mst2	Mst2	Mst2	Nek2	Nek2	Nek2	21	22	28	29
MST3 has been reported to activate NDR2 protein kinase XREF_BIBR by phosphorylating the Thr of its hydrophobic motif ( sequence FLNYTY ) .	MST3 has been reported to activate NDR2 protein kinase XREF_BIBR by phosphorylating the Thr of its hydrophobic motif (sequence FLNYTY).	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST3	MST3	MST3	NDR2 protein kinase	NDR2 protein kinase	NDR2 protein kinase	0	1	6	9
Since HQ effectively suppressed IRF-3 activity induced by TRIF and TBK1 ( XREF_FIG ) , we next investigated the effect of HQ on IRF-3 activity in macrophages by Western blot analysis .	Since HQ effectively suppressed IRF-3 activity induced by TRIF and TBK1 (XREF_FIG), we next investigated the effect of HQ on IRF-3 activity in macrophages by Western blot analysis.	4	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	10	11	4	5
PLpro-TM antagonizes STING and TBK1 induced IRF3 activation .	PLpro-TM antagonizes STING and TBK1 induced IRF3 activation.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	4	5	6	7
PPM1B inhibits TBK1 induced IRF3 activation and IFNbeta gene expression .	PPM1B inhibits TBK1 induced IRF3 activation and IFNbeta gene expression.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	2	3	4	5
IRF-3 is activated through phosphorylation by the kinases IKK epsilon and/or TBK1 .	IRF-3 is activated through phosphorylation by the kinases IKK epsilon and/or TBK1.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	11	12	0	1
We also tested the effects of STING and c-di-GMP on IRF3 activation by TBK1 using purified proteins .	We also tested the effects of STING and c-di-GMP on IRF3 activation by TBK1 using purified proteins.	10	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	13	14	10	11
In macrophages , IRF3 is activated through its site specific phosphorylation by TANK binding kinase 1 ( TBK1 ) , an important effector kinase of the TRIF pathway .	In macrophages, IRF3 is activated through its site specific phosphorylation by TANK binding kinase 1 (TBK1), an important effector kinase of the TRIF pathway.	3	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	17	18	3	4
Although TBK-1 partially activated IRF3 , inhibition of either PI3K or Akt or mTOR inhibited IFN-beta induction and marks the crucial role of mTOR in the activation of IRF3 to induce IFN-beta in keratinocytes .	Although TBK-1 partially activated IRF3, inhibition of either PI3K or Akt or mTOR inhibited IFN-beta induction and marks the crucial role of mTOR in the activation of IRF3 to induce IFN-beta in keratinocytes.	1	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK-1	TBK-1	TBK-1	IRF3	IRF3	IRF3	1	2	4	5
GST-TBK1 alone did not induce IRF3 activation ; however , in the presence of increasing amounts of His 6 -STING ( 341-379 ) , GST-TBK1 caused IRF3 dimerization ( lanes 3 , 6 and 9 ) .	GST-TBK1 alone did not induce IRF3 activation; however, in the presence of increasing amounts of His 6 -STING (341-379), GST-TBK1 caused IRF3 dimerization (lanes 3, 6 and 9).	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GST-TBK1	GST-TBK1	GST-TBK1	IRF3	IRF3	IRF3	0	1	5	6
Taken together , we identified that PPM1B is the only member in our phosphatase library that can significantly inhibit both TBK1 induced IRF3 activation and IFNbeta gene expression .	Taken together, we identified that PPM1B is the only member in our phosphatase library that can significantly inhibit both TBK1 induced IRF3 activation and IFNbeta gene expression.	19	23	induced	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	20	21	22	23
BIOGF1K also inhibited the phosphorylation of TBK1 ( XREF_FIG C ) , which is a critical event for IRF3 phosphorylation XREF_BIBR , indicating that TBK1 could be targeted in BIOGF1K mediated inhibition of IRF3 activation .	BIOGF1K also inhibited the phosphorylation of TBK1 (XREF_FIG C), which is a critical event for IRF3 phosphorylation XREF_BIBR, indicating that TBK1 could be targeted in BIOGF1K mediated inhibition of IRF3 activation.	4	34	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	phosphorylation of TBK1	tbk1	IRF3	IRF3	irf3	6	7	33	34
From the mitochondrial surface , MAVS activates two cytosolic kinase complexes : TBK1 and IKK , which activate IRF3 and NF-kappaB , respectively .	From the mitochondrial surface, MAVS activates two cytosolic kinase complexes : TBK1 and IKK, which activate IRF3 and NF-kappaB, respectively.	10	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	12	13	18	19
During the induction of IFN , TANK binding kinase 1 ( TBK1 ) or inducible IkappaB kinase ( IKKi ) , two non canonical members of the IKK family , are essential for activation of interferon regulatory factor 3 and 7 ( IRF3 and IRF7 ) which control transcription of type I IFN .	During the induction of IFN, TANK binding kinase 1 (TBK1) or inducible IkappaB kinase (IKKi), two non canonical members of the IKK family, are essential for activation of interferon regulatory factor 3 and 7 (IRF3 and IRF7) which control transcription of type I IFN.	6	39	are essential for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	interferon regulatory factor 3	interferon regulatory factor 3	interferon regulatory factor 3	11	12	35	39
The activation of TRIF dependent pathway also results in the production of type I IFNs triggered by the activation of IRF3 induced by TBK1 kinase through the N-terminal part of TRIF [ XREF_BIBR , XREF_BIBR ] .	The activation of TRIF dependent pathway also results in the production of type I IFNs triggered by the activation of IRF3 induced by TBK1 kinase through the N-terminal part of TRIF [XREF_BIBR, XREF_BIBR].	18	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	23	24	20	21
These results showed that the phosphorylation of Ser386 in IRF-3 is necessary for the activation of IRF-3 by TBK1 .	These results showed that the phosphorylation of Ser386 in IRF-3 is necessary for the activation of IRF-3 by TBK1.	11	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	18	19	16	17
ULD mutated TBK1 ( TBK1 L352A , I353A ) which failed to activate the NF-kappaB , IFN-beta and IRF3 promoter as shown previously [ XREF_BIBR ] , retained its ability to induce ERRalpha expression ( XREF_FIG ) .	ULD mutated TBK1 (TBK1 L352A, I353A) which failed to activate the NF-kappaB, IFN-beta and IRF3 promoter as shown previously [XREF_BIBR], retained its ability to induce ERRalpha expression (XREF_FIG).	1	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	2	3	18	19
XREF_FIG shows that MC159 prevented TBK1 induced IRF3 activation , as measured by a decrease in the intensity of the phospho-IRF3-containing band ( XREF_FIG ) .	XREF_FIG shows that MC159 prevented TBK1 induced IRF3 activation, as measured by a decrease in the intensity of the phospho-IRF3-containing band (XREF_FIG).	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	5	6	7	8
Complementing the phosphorylation status , Triad3A also inhibited DeltaRIG-I and MAVS induced dimerization of endogenous IRF-3 ( XREF_FIG , lanes 4-6 ) , but did not affect TBK1 induced IRF-3 dimer formation ( XREF_FIG , lanes 7-8 ) , indicating that Triad3A targets RLR signaling upstream of TBK1 .	Complementing the phosphorylation status, Triad3A also inhibited DeltaRIG-I and MAVS induced dimerization of endogenous IRF-3 (XREF_FIG, lanes 4-6), but did not affect TBK1 induced IRF-3 dimer formation (XREF_FIG, lanes 7-8), indicating that Triad3A targets RLR signaling upstream of TBK1.	26	31	induced	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	27	28	29	30
Recently , it was found to block TBK1 activity ( IC 50 = 5.2 micromol/L ) and to inhibit TBK1 mediated IRF3 activation and IFN-beta production .	Recently, it was found to block TBK1 activity (IC 50 = 5.2 micromol/L) and to inhibit TBK1 mediated IRF3 activation and IFN-beta production.	18	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	19	20	21	22
This complex recruits TAK1 , a kinase that activates NF-kappaB , or TBK1 and Ikappakappa-epsilon kinases , which in turn stimulate IRF-3 and/or IRF-7 and IFN responses .	This complex recruits TAK1, a kinase that activates NF-kappaB, or TBK1 and Ikappakappa-epsilon kinases, which in turn stimulate IRF-3 and/or IRF-7 and IFN responses.	12	26	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	12	13	21	22
Further investigations should elucidate the mechanism by which the MERS-CoV M protein preferentially modulates IRF3 activators such as TBK1 , while sparing NF-kappaB activators such as CARD9 .	Further investigations should elucidate the mechanism by which the MERS-CoV M protein preferentially modulates IRF3 activators such as TBK1, while sparing NF-kappaB activators such as CARD9.	14	19	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	18	19	14	15
The C6 protein prevents TBK1 driven activation of IRF-3 and IRF-7 .	The C6 protein prevents TBK1 driven activation of IRF-3 and IRF-7.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	4	5	8	9
In this case , TBK1 over-expression was used to stimulate IRF3 , as evidenced by the transcription of isg15 and isg54 ( XREF_FIG ) .	In this case, TBK1 over-expression was used to stimulate IRF3, as evidenced by the transcription of isg15 and isg54 (XREF_FIG).	4	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1 over-expression	tbk1	IRF3	IRF3	irf3	4	5	10	11
Another important question about the function of TBK1 is how TBK1 activates IRF-3 in response to microbial infection .	Another important question about the function of TBK1 is how TBK1 activates IRF-3 in response to microbial infection.	10	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	10	11	12	13
Recognition of lipopolysaccharide by TLR4 triggers the activation of IRF-3 by TBK1 kinase and results in production of IFNbeta [ XREF_BIBR ] .	Recognition of lipopolysaccharide by TLR4 triggers the activation of IRF-3 by TBK1 kinase and results in production of IFNbeta [XREF_BIBR].	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	11	12	9	10
These MAVS aggregates then activate the cytosolic kinases TBK1 and IKK , which in turn activate IRF3 and NF-kappaB , respectively , leading to the induction of type I IFN and other antiviral molecules .	These MAVS aggregates then activate the cytosolic kinases TBK1 and IKK, which in turn activate IRF3 and NF-kappaB, respectively, leading to the induction of type I IFN and other antiviral molecules.	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	8	9	16	17
Similarly , PPM1A completely abolished MAVS or TBK1 stimulated IRF3 activation ( XREF_FIG ) .	Similarly, PPM1A completely abolished MAVS or TBK1 stimulated IRF3 activation (XREF_FIG).	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	7	8	9	10
In response to microbial components , TBK1 activates IFN regulatory factor 3 ( IRF3 ) and cytokine expression .	In response to microbial components, TBK1 activates IFN regulatory factor 3 (IRF3) and cytokine expression.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	6	7	13	14
CYLD mediated deubiquitination of TBK1 has also been shown to inhibit the TBK1 driven IRF3 response .	CYLD mediated deubiquitination of TBK1 has also been shown to inhibit the TBK1 driven IRF3 response.	10	15	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	12	13	14	15
MAVS forms large prion like polymers that activate the cytosolic kinases IKK and TBK1 , which in turn activate NF-kappaB and IRF3 , respectively , to induce interferons .	MAVS forms large prion like polymers that activate the cytosolic kinases IKK and TBK1, which in turn activate NF-kappaB and IRF3, respectively, to induce interferons.	7	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	13	14	21	22
The prototypical transcriptional programme elicited by STING in macrophages or DCs is largely dependent on IRF-3 and NF-kappaB p65 , which are both activated by TBK1 7 .	The prototypical transcriptional programme elicited by STING in macrophages or DCs is largely dependent on IRF-3 and NF-kappaB p65, which are both activated by TBK1 7.	15	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	25	26	15	16
These data suggest that , upon RNA virus infection , SNRNP200 may function between MAVS signal transduction and TBK1 mediated IRF3 licensing .	These data suggest that, upon RNA virus infection, SNRNP200 may function between MAVS signal transduction and TBK1 mediated IRF3 licensing.	18	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	18	19	20	21
Unterstab and coworkers [ XREF_BIBR ] found that the P protein of BDV can inhibit the activity of TBK1 , the principal regulatory kinase that activates IRF3 which is required for RIG-I-dependent induction of IFN genes in virus infected cells .	Unterstab and coworkers [XREF_BIBR] found that the P protein of BDV can inhibit the activity of TBK1, the principal regulatory kinase that activates IRF3 which is required for RIG-I-dependent induction of IFN genes in virus infected cells.	16	29	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	18	19	26	27
It subsequently recruits TBK1 activating IRF-3 .	It subsequently recruits TBK1 activating IRF-3.	2	6	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	3	4	5	6
The CSP is controlled by the host transcription factor interferon regulatory factor 3 ( IRF3 ) , which is activated via phosphorylation by the TBK1 kinase .	The CSP is controlled by the host transcription factor interferon regulatory factor 3 (IRF3), which is activated via phosphorylation by the TBK1 kinase.	11	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	24	25	14	15
The assay to measure the activity of IRF3 regulatory element PRDIII-I regulated reporter induced by the over-expression of different molecules in the cytoplasmic antiviral signal pathway XREF_BIBR , XREF_BIBR ( XREF_FIG ) indicated that MDA5 , MAVS , TBK1 , and IKKepsilon induced approximately only a 2-fold IRF3 reporter activation in HEK293 cells ( XREF_FIG ) .	The assay to measure the activity of IRF3 regulatory element PRDIII-I regulated reporter induced by the over-expression of different molecules in the cytoplasmic antiviral signal pathway XREF_BIBR, XREF_BIBR (XREF_FIG) indicated that MDA5, MAVS, TBK1, and IKKepsilon induced approximately only a 2-fold IRF3 reporter activation in HEK293 cells (XREF_FIG).	34	49	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	38	39	47	48
Recently , the adaptor protein STING was found to play an essential role in the signaling response to cytoplasmic dsDNA , promoting TBK1 specific activation of IRF3 as well as STAT6 .	Recently, the adaptor protein STING was found to play an essential role in the signaling response to cytoplasmic dsDNA, promoting TBK1 specific activation of IRF3 as well as STAT6.	22	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	22	23	26	27
XREF_BIBR In turn , IKKepsilon and TBK1 activates IRF-3 through C-terminal phosphorylation .	XREF_BIBR In turn, IKKepsilon and TBK1 activates IRF-3 through C-terminal phosphorylation.	2	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	6	7	8	9
Cytosolic RNA is detected by the RLRs RIG-I and Mda-5 , which via the adaptor protein IPS-1 ( also known as MAVS , Cardif or VISA ) turn on a signalling pathway similar to TLR3 , in that IFNbeta induction occurs via TBK1 mediated activation of IRF3 2 .	Cytosolic RNA is detected by the RLRs RIG-I and Mda-5, which via the adaptor protein IPS-1 (also known as MAVS, Cardif or VISA) turn on a signalling pathway similar to TLR3, in that IFNbeta induction occurs via TBK1 mediated activation of IRF3 2.	42	47	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	42	43	46	47
In support of this , we observed that cFLIP L inhibited IRF3 activation when TBK1 over-expression stimulated IRF3 activation ( XREF_FIG ) , and this inhibition was greater than that observed with MC159 and this inhibition was shown to be dose dependent ( XREF_FIG ) .	In support of this, we observed that cFLIP L inhibited IRF3 activation when TBK1 over-expression stimulated IRF3 activation (XREF_FIG), and this inhibition was greater than that observed with MC159 and this inhibition was shown to be dose dependent (XREF_FIG).	14	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1 over-expression	tbk1	IRF3	IRF3	irf3	14	15	17	18
In addition , cells transduced with NLRP14 exhibited suppression of IRF3 phosphorylation both in the presence and absence of NDV infection ( which triggers TBK1 mediated IRF3 activation ; XREF_SUPPLEMENTARY ) .	In addition, cells transduced with NLRP14 exhibited suppression of IRF3 phosphorylation both in the presence and absence of NDV infection (which triggers TBK1 mediated IRF3 activation; XREF_SUPPLEMENTARY).	23	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	24	25	26	27
STING then activates the protein kinases IKK and TBK1 , which in turn activate the transcription factors NF-kappaB and IRF3 to induce interferons and other cytokines .	STING then activates the protein kinases IKK and TBK1, which in turn activate the transcription factors NF-kappaB and IRF3 to induce interferons and other cytokines.	2	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	8	9	19	20
Helenalin attenuated ligand independent activation of NF-kappaB induced by MyD88 , IKKbeta , and p65 , and IRF3 induced by TRIF , TBK1 , or IRF3 .	Helenalin attenuated ligand independent activation of NF-kappaB induced by MyD88, IKKbeta, and p65, and IRF3 induced by TRIF, TBK1, or IRF3.	7	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	22	23	17	18
The nucleocapsid of ANDV , but not other hantaviruses , also inhibits autophosphorylation and activation of TBK1 , an enzyme that activates IRF3 and NF-kappaB and induction of type I interferon gene expression [ XREF_BIBR ] .	The nucleocapsid of ANDV, but not other hantaviruses, also inhibits autophosphorylation and activation of TBK1, an enzyme that activates IRF3 and NF-kappaB and induction of type I interferon gene expression [XREF_BIBR].	12	32	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TBK1	autophosphorylation and activation of TBK1	tbk1	IRF3	IRF3	irf3	16	17	22	23
Hence , our work indicated that TBK1 activation not only activated IRF3 but also activated ERRalpha to affect both IFN-I induction and metabolic signaling , indicating the unique status of ERRalpha among the cellular inhibitors of innate immunity .	Hence, our work indicated that TBK1 activation not only activated IRF3 but also activated ERRalpha to affect both IFN-I induction and metabolic signaling, indicating the unique status of ERRalpha among the cellular inhibitors of innate immunity.	6	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	6	7	11	12
Albeit promiscuous in deubiquitinating cellular proteins , PLP2 inactivated TBK1 and IFN-beta response in TNF receptor associated factor 3 ( TRAF3 ) deficient cells , suggesting that targeting TBK1 would be sufficient for PLP2 to inhibit IRF3 activation .	Albeit promiscuous in deubiquitinating cellular proteins, PLP2 inactivated TBK1 and IFN-beta response in TNF receptor associated factor 3 (TRAF3) deficient cells, suggesting that targeting TBK1 would be sufficient for PLP2 to inhibit IRF3 activation.	27	37	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	28	29	36	37
Gambogic acid did not inhibit the activation of Interferon regulatory factor 3 ( IRF3 ) induced by TBK1 overexpression in a luciferase reporter gene assay using IFN-beta-PRD III-I-luc .	Gambogic acid did not inhibit the activation of Interferon regulatory factor 3 (IRF3) induced by TBK1 overexpression in a luciferase reporter gene assay using IFN-beta-PRD III-I-luc.	8	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1 overexpression	tbk1	Interferon regulatory factor 3	Interferon regulatory factor 3	interferon regulatory factor 3	17	18	8	12
KRG-WE , KRG-NSF , and KRG-SF markedly suppressed the luciferase activities of IRF3 induced by TBK1 in HEK293 cells ( XREF_FIG A ) , whereas KRG-WE , KRG-NSF , and KRG-SF failed to significantly modulate the luciferase activities of both NF-kappaB and AP-1 induced by MyD88 ( XREF_FIG B and 4C ) .	KRG-WE, KRG-NSF, and KRG-SF markedly suppressed the luciferase activities of IRF3 induced by TBK1 in HEK293 cells (XREF_FIG A), whereas KRG-WE, KRG-NSF, and KRG-SF failed to significantly modulate the luciferase activities of both NF-kappaB and AP-1 induced by MyD88 (XREF_FIG B and 4C).	10	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	15	16	12	13
TBK1 could activate the transcription factor IRF3 , leading to the production of type I IFNs and other cytokines of the immediate early host defense response XREF_BIBR .	TBK1 could activate the transcription factor IRF3, leading to the production of type I IFNs and other cytokines of the immediate early host defense response XREF_BIBR.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	0	1	6	7
Thus , although TBK1 mediates IRF3 activation and IFNbeta production as well as prompt induction of IFN regulated genes in response to polyI : C , a TBK1 independent pathway exists for these responses during infection of BMMs with an RNA virus .	Thus, although TBK1 mediates IRF3 activation and IFNbeta production as well as prompt induction of IFN regulated genes in response to polyI : C, a TBK1 independent pathway exists for these responses during infection of BMMs with an RNA virus.	3	6	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	3	4	5	6
Downstream signalling involves the kinase TBK1 , which phosphorylates and thereby activates the transcription factor IRF3 XREF_BIBR , XREF_BIBR .	Downstream signalling involves the kinase TBK1, which phosphorylates and thereby activates the transcription factor IRF3 XREF_BIBR, XREF_BIBR.	2	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	5	6	15	16
Examples of nuclear PPIs ( Fos-Jun ) , cytoplasmic membranous PPIs ( MAVS-MAVS , MAVS-TRAF3 ) , inducible PPIs ( e.g ., IRF3 dimerization induced by MAVS and TBK1 ) , and viral protein regulated PPIs ( MAVS-MAVS , MAVS-TRAF3 by HCV NS3/4A ) were studied using the DLR-PD assay .	Examples of nuclear PPIs (Fos-Jun), cytoplasmic membranous PPIs (MAVS-MAVS, MAVS-TRAF3), inducible PPIs (e.g., IRF3 dimerization induced by MAVS and TBK1), and viral protein regulated PPIs (MAVS-MAVS, MAVS-TRAF3 by HCV NS3/4A) were studied using the DLR-PD assay.	22	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	28	29	22	23
The data support a two-step phosphorylation model for IRF-3 activation mediated by TBK1 .	The data support a two-step phosphorylation model for IRF-3 activation mediated by TBK1.	8	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	12	13	8	9
STING recruits and activates the cytosolic kinases IKK and TBK1 , which activate the transcription factors NF-kappaB and IRF3 , respectively .	STING recruits and activates the cytosolic kinases IKK and TBK1, which activate the transcription factors NF-kappaB and IRF3, respectively.	3	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	9	10	18	19
Further , the expression of TBK1 induced nuclear translocation of IRF3 whereas IKKepsilon , IKKbeta KA and Tax failed to do so ( XREF_FIG ) .	Further, the expression of TBK1 induced nuclear translocation of IRF3 whereas IKKepsilon, IKKbeta KA and Tax failed to do so (XREF_FIG).	3	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	expression of TBK1	tbk1	IRF3	IRF3	irf3	5	6	10	11
Mammalian IRF3 is activated by phosphorylation of TBK1 mediated by TLR or RLR signaling XREF_BIBR .	Mammalian IRF3 is activated by phosphorylation of TBK1 mediated by TLR or RLR signaling XREF_BIBR.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	phosphorylation of TBK1	tbk1	IRF3	IRF3	irf3	7	8	1	2
In response to microbial components , TBK1 activates interferon regulatory factor 3 ( IRF3 ) and cytokine expression .	In response to microbial components, TBK1 activates interferon regulatory factor 3 (IRF3) and cytokine expression.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	6	7	13	14
Phosphorylated TBK1 activates IRF3 or IRF7 , and the activated transcriptional factors translocate into the nucleus and bind ISREs ( IFN stimulated response elements ) to induce type I IFN mRNA transcription ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Phosphorylated TBK1 activates IRF3 or IRF7, and the activated transcriptional factors translocate into the nucleus and bind ISREs (IFN stimulated response elements) to induce type I IFN mRNA transcription (XREF_FIG) [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	26	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TBK1	TBK1	tbk1	IRF3	IRF3 or IRF7, and the activated transcriptional factors translocate into the nucleus and bind ISREs	irf3	1	2	3	4
122 TBK1 activates IRF3 and IRF7 , which translocate into the nucleus to stimulate the expression of type I IFNs .	122 TBK1 activates IRF3 and IRF7, which translocate into the nucleus to stimulate the expression of type I IFNs.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	1	2	3	4
MAVS then activates the cytosolic protein kinases IKK and TBK1 , which in turn activate the transcription factors NF-kappaB and IRF3 , respectively .	MAVS then activates the cytosolic protein kinases IKK and TBK1, which in turn activate the transcription factors NF-kappaB and IRF3, respectively.	2	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	9	10	20	21
These findings detail a novel pathway for TBK1 mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs .	These findings detail a novel pathway for TBK1 mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	7	8	9	10
Interfering with PKC-alpha activity did not change the activation of IRF3 in terms of phosphorylation , dimerization , nuclear translocation , or DNA binding but did inhibit IRF-3 transcriptional activity induced by TRIF and TBK1 overexpression .	Interfering with PKC-alpha activity did not change the activation of IRF3 in terms of phosphorylation, dimerization, nuclear translocation, or DNA binding but did inhibit IRF-3 transcriptional activity induced by TRIF and TBK1 overexpression.	27	36	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1 overexpression	tbk1	IRF-3	IRF-3	irf-3	34	35	27	28
TBK1 , an IKK related kinase originally characterized as the kinase responsible for the phosphorylation induced activation of IRF3 in TLR and then RLR signaling is also central for DNA signaling pathways .	TBK1, an IKK related kinase originally characterized as the kinase responsible for the phosphorylation induced activation of IRF3 in TLR and then RLR signaling is also central for DNA signaling pathways.	0	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	0	1	18	19
DUBA deubiquitinates TRAF3 to down-regulate its interaction with TBK1 and consequent activation of IRF-3 .	DUBA deubiquitinates TRAF3 to down-regulate its interaction with TBK1 and consequent activation of IRF-3.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	8	9	13	14
Enhanced ER stress during S. pne infection augmented IRE1 and XBP1 mediated production of Atg9a and subsequent inhibition of STING and TBK1 activation of IRF3 .	Enhanced ER stress during S. pne infection augmented IRE1 and XBP1 mediated production of Atg9a and subsequent inhibition of STING and TBK1 activation of IRF3.	19	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	21	22	24	25
Treatment with TQ ( 12.5 and 25 mM ) significantly decreased TBK1 mediated IRF-3 PRDIII-I luciferase activity in a concentration dependent manner , but not TRIF mediated activity .	Treatment with TQ (12.5 and 25 mM) significantly decreased TBK1 mediated IRF-3 PRDIII-I luciferase activity in a concentration dependent manner, but not TRIF mediated activity.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	11	12	13	14
These data confirm that ubiquitination on K224 is essential for STING trafficking as well as TBK1 mediated IRF3 activation in the presence of cytosolic DNA in human cells .	These data confirm that ubiquitination on K224 is essential for STING trafficking as well as TBK1 mediated IRF3 activation in the presence of cytosolic DNA in human cells.	10	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	15	16	17	18
This TBK1 complex , herein referred to as Flag-TBK1 PD , which contained a small amount of NEMO ( XREF_FIG ) , supported IRF3 dimerization in the presence of His 6 -STING ( 341-379 ) and ATP ( XREF_FIG , lane 3 ) .	This TBK1 complex, herein referred to as Flag-TBK1 PD, which contained a small amount of NEMO (XREF_FIG), supported IRF3 dimerization in the presence of His 6 -STING (341-379) and ATP (XREF_FIG, lane 3).	1	24	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	1	2	23	24
STING is reported to colocalize with TBK1 at these puncta , which represent the proposed platform for TBK1 mediated IRF3 activation .	STING is reported to colocalize with TBK1 at these puncta, which represent the proposed platform for TBK1 mediated IRF3 activation.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	17	18	19	20
The MyD88 independent pathway recruits the TRIF adaptor protein to activate the kinases TBK1 and IKK , which in turn stimulate IRF3 , leading to the production of type 1 interferons .	The MyD88 independent pathway recruits the TRIF adaptor protein to activate the kinases TBK1 and IKK, which in turn stimulate IRF3, leading to the production of type 1 interferons.	11	23	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	13	14	21	22
STING then activates the protein kinases IKK and TBK1 , which in turn activate the transcription factors NF-kappaB and IRF3 to induce interferons and cytokines .	STING then activates the protein kinases IKK and TBK1, which in turn activate the transcription factors NF-kappaB and IRF3 to induce interferons and cytokines.	2	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	8	9	19	20
Both NV proteins strongly inhibit RIG-I- and TBK1 mediated IRF3 dependent IFN and ISRE promoter activities .	Both NV proteins strongly inhibit RIG-I- and TBK1 mediated IRF3 dependent IFN and ISRE promoter activities.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	7	8	9	10
The activated STING then recruits TBK1 , which further activates the downstream transcription factors , IRF3 and NF-kappaB , to initiate the production of type I interferons and other inflammatory cytokines [ XREF_BIBR ] .	The activated STING then recruits TBK1, which further activates the downstream transcription factors, IRF3 and NF-kappaB, to initiate the production of type I interferons and other inflammatory cytokines [XREF_BIBR].	4	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	5	6	15	16
IRF3 activation induced by the overexpression of TBK1 was not suppressed by gambogic acid as determined by an IFNbeta PRDIII-I-luciferase reporter assay ( XREF_FIG A ) .	IRF3 activation induced by the overexpression of TBK1 was not suppressed by gambogic acid as determined by an IFNbeta PRDIII-I-luciferase reporter assay (XREF_FIG A).	0	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	overexpression of TBK1	tbk1	IRF3	IRF3	irf3	7	8	0	1
Here we present evidence that PPM1B and PP2Cbeta functions as a TBK1 phosphatase that dephosphorylates TBK1 at serine172 and terminate TBK1 mediated IRF3 activation and IFNbeta gene expression .	Here we present evidence that PPM1B and PP2Cbeta functions as a TBK1 phosphatase that dephosphorylates TBK1 at serine172 and terminate TBK1 mediated IRF3 activation and IFNbeta gene expression.	19	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	20	21	22	23
Therefore , the authors studied the inhibition of the TLR3 signalling pathway by NS3 , and the reported assays showed that NS3 could inhibit the TRIF- and TBK1 mediated activation of IRF3 , which was achieved via an interaction with TBK1 [ XREF_BIBR ] .	Therefore, the authors studied the inhibition of the TLR3 signalling pathway by NS3, and the reported assays showed that NS3 could inhibit the TRIF- and TBK1 mediated activation of IRF3, which was achieved via an interaction with TBK1 [XREF_BIBR].	25	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	27	28	31	32
Because SARS PLpro-TM inhibited STING- and TBK1 dependent activation of the IRF3 pathway , PLpro-TM might associate with STING , TRAF3 , and TBK1 complex , either directly or as part of the multiprotein complex .	Because SARS PLpro-TM inhibited STING- and TBK1 dependent activation of the IRF3 pathway, PLpro-TM might associate with STING, TRAF3, and TBK1 complex, either directly or as part of the multiprotein complex.	4	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	6	7	11	12
This argument offers a better explanation of why the activation of TBK1 is not efficient to induce IRF3 activation in the absence of STING in response to cytosolic DNA .	This argument offers a better explanation of why the activation of TBK1 is not efficient to induce IRF3 activation in the absence of STING in response to cytosolic DNA.	9	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	11	12	17	18
Results indicated that IRF3 signaling was triggered either by TBK1 or IKKepsilon over-expression and was blocked by HBV Pol in a dose dependent manner ( XREF_FIG ) .	Results indicated that IRF3 signaling was triggered either by TBK1 or IKKepsilon over-expression and was blocked by HBV Pol in a dose dependent manner (XREF_FIG).	3	13	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1 or IKKepsilon over-expression	tbk1	IRF3	IRF3	irf3	9	10	3	4
Activated STING recruits and activates the cytosolic kinases IKK and TBK1 , which in turn activate NF-kappaB and IRF3 , respectively [ XREF_BIBR ] .	Activated STING recruits and activates the cytosolic kinases IKK and TBK1, which in turn activate NF-kappaB and IRF3, respectively [XREF_BIBR].	4	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	10	11	18	19
Two recent studies highlight the importance of IFN-beta in host defense by demonstrating that HSV-1 targets this cytokine by encoding separate virulence factors to interfere with RLRs as well as Tank Binding Kinase 1 ( TBK1 ) , which activates IRF3 , a critical transcription factor for IFN-beta .	Two recent studies highlight the importance of IFN-beta in host defense by demonstrating that HSV-1 targets this cytokine by encoding separate virulence factors to interfere with RLRs as well as Tank Binding Kinase 1 (TBK1), which activates IRF3, a critical transcription factor for IFN-beta.	24	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	35	36	40	41
In addition , although TBK1 and STING are essential for activation of IRF-3 following DNA stimulation , the molecular details of this signalling pathway are poorly understood .	In addition, although TBK1 and STING are essential for activation of IRF-3 following DNA stimulation, the molecular details of this signalling pathway are poorly understood.	4	15	are essential for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	4	5	12	13
STING then activates IkappaB kinase ( IKK kinase ) and TANK binding kinase 1 ( TBK-1 ) that further activate the transcription factors nuclear factor kappaB ( NF-kappaB ) and interferon regulatory factor 3 ( IRF3 ) to induce inflammatory cytokines and interferons ( IFN ) .	STING then activates IkappaB kinase (IKK kinase) and TANK binding kinase 1 (TBK-1) that further activate the transcription factors nuclear factor kappaB (NF-kappaB) and interferon regulatory factor 3 (IRF3) to induce inflammatory cytokines and interferons (IFN).	2	44	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK-1	TBK-1	TBK-1	interferon regulatory factor 3	interferon regulatory factor 3	interferon regulatory factor 3	15	16	30	34
On the other hand , a different pathway governing NKG2DLs expression by chemicals known to induce genotoxic stress has been characterized in murine lymphoma cells : DDR drives to the presence of cytosolic DNA and to STING and TBK1 dependent activation of the transcription factor IRF3 , responsible for the upregulation of RAE1 expression .	On the other hand, a different pathway governing NKG2DLs expression by chemicals known to induce genotoxic stress has been characterized in murine lymphoma cells : DDR drives to the presence of cytosolic DNA and to STING and TBK1 dependent activation of the transcription factor IRF3, responsible for the upregulation of RAE1 expression.	38	46	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	38	39	45	46
These cell biological changes correlate with recruitment of the kinases TBK1 and IKK , which in turn activate IRF3 , STAT6 , and NF-kappaB , resulting in type I IFN induction ( XREF_FIG ) .	These cell biological changes correlate with recruitment of the kinases TBK1 and IKK, which in turn activate IRF3, STAT6, and NF-kappaB, resulting in type I IFN induction (XREF_FIG).	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	10	11	18	19
Interestingly , our mutagenesis analyses show that phosphorylation of residue Ser386 is critical for the activation of IRF-3 by TBK1 .	Interestingly, our mutagenesis analyses show that phosphorylation of residue Ser386 is critical for the activation of IRF-3 by TBK1.	12	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	19	20	17	18
MAVS then activates the cytosolic kinases IKK and TBK1 , which activate the transcription factors NF-kappaB and IRF3 , respectively .	MAVS then activates the cytosolic kinases IKK and TBK1, which activate the transcription factors NF-kappaB and IRF3, respectively.	2	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	8	9	17	18
Q-B contains multiple factors known to be important for virus induced IRF3 activation , such as NEMO , TBK1 , ubiquitin , and E1 ( data not shown ) .	Q-B contains multiple factors known to be important for virus induced IRF3 activation, such as NEMO, TBK1, ubiquitin, and E1 (data not shown).	11	23	activation	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	18	19	11	12
However , the Gn-T from nonpathogenic TULV also inhibits TBK1 directed NF-kappaB and IRF3 activation indicating that IFN regulation is not limited to pathogenic hantaviruses .	However, the Gn-T from nonpathogenic TULV also inhibits TBK1 directed NF-kappaB and IRF3 activation indicating that IFN regulation is not limited to pathogenic hantaviruses.	9	14	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	9	10	13	14
The activated TBK1 in turn causes the activation of IRF3 and subsequent expression of cytokine genes .	The activated TBK1 in turn causes the activation of IRF3 and subsequent expression of cytokine genes.	0	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	2	3	9	10
ILG attenuated ligand independent activation of IRF3 induced by TRIF or TBK1 .	ILG attenuated ligand independent activation of IRF3 induced by TRIF or TBK1.	4	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	11	12	6	7
Activation of the CSP by either L. monocytogenes or cytoplasmic DNA is controlled by the host transcription factor interferon regulatory factor 3 ( IRF3 ) , which is activated via phosphorylation by the kinase TBK1 .	Activation of the CSP by either L. monocytogenes or cytoplasmic DNA is controlled by the host transcription factor interferon regulatory factor 3 (IRF3), which is activated via phosphorylation by the kinase TBK1.	20	35	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	34	35	23	24
Recent studies of monogenic SLE associated with chronic activation of cytoplasmic nucleic acid receptors also demonstrate that IFN-I is induced through TBK1 mediated activation of IRF3 .	Recent studies of monogenic SLE associated with chronic activation of cytoplasmic nucleic acid receptors also demonstrate that IFN-I is induced through TBK1 mediated activation of IRF3.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	21	22	25	26
In both signaling pathways , binding of viral nucleic acids to their respective sensors leads to recruitment and phosphorylation of the kinase TBK1 ( Tank Binding Kinase 1 ) , which in turn activates the IRF3 transcription factor by phosphorylation XREF_BIBR - XREF_BIBR .	In both signaling pathways, binding of viral nucleic acids to their respective sensors leads to recruitment and phosphorylation of the kinase TBK1 (Tank Binding Kinase 1), which in turn activates the IRF3 transcription factor by phosphorylation XREF_BIBR - XREF_BIBR.	16	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	phosphorylation of the kinase TBK1	tbk1	IRF3	IRF3	irf3	22	23	35	36
Specifically , RLRs recruit the signaling adaptor protein IFNbeta-promoter stimulator 1 ( IPS-1 , also known as MAVS , VISA , or Cardif ) , activating the downstream TBK1 and IKKepsilon kinases , which then phosphorylate and activate IRF3 and IRF7 XREF_BIBR .	Specifically, RLRs recruit the signaling adaptor protein IFNbeta-promoter stimulator 1 (IPS-1, also known as MAVS, VISA, or Cardif), activating the downstream TBK1 and IKKepsilon kinases, which then phosphorylate and activate IRF3 and IRF7 XREF_BIBR.	25	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	28	29	38	39
MAVS then activates the cytosolic kinases IKKs and TBK1 , which activate the transcription factors NF-kappaB and IRF-3 .	MAVS then activates the cytosolic kinases IKKs and TBK1, which activate the transcription factors NF-kappaB and IRF-3.	2	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	8	9	17	18
Compound II inhibition of TBK1 impairs AKT signaling and promotes apoptosis of several non-small-cell lung cancer cell lines [ XREF_BIBR ] .	Compound II inhibition of TBK1 impairs AKT signaling and promotes apoptosis of several non-small-cell lung cancer cell lines [XREF_BIBR].	2	7	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	4	5	6	7
Besides being a major protein involved in responsiveness to inflammatory cytokines , it has been demonstrated that TBK1 directly activates Akt by phosphorylation of the hydrophobic motif ( Thr308 ) and the activation loop ( Ser473 ) independently of PDK1 and mTORC2 .	Besides being a major protein involved in responsiveness to inflammatory cytokines, it has been demonstrated that TBK1 directly activates Akt by phosphorylation of the hydrophobic motif (Thr308) and the activation loop (Ser473) independently of PDK1 and mTORC2.	17	21	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	Akt	Akt	Akt	17	18	20	21
The mechanism of TBK1 activation of AKT is believed to be through its recruitment to the exocyst complex and subsequent interaction with AKT1 and AKT2 , which interact with distinct exocyst subunits .	The mechanism of TBK1 activation of AKT is believed to be through its recruitment to the exocyst complex and subsequent interaction with AKT1 and AKT2, which interact with distinct exocyst subunits.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	3	4	6	7
Since our results showed TBK1 and IKKi dual inhibitors reduced AKT activation in both cancer cell lines and tumor tissues , we asked whether TBK1 and IKKi dual inhibitors affect VEGF expression and angiogenesis in tumors .	Since our results showed TBK1 and IKKi dual inhibitors reduced AKT activation in both cancer cell lines and tumor tissues, we asked whether TBK1 and IKKi dual inhibitors affect VEGF expression and angiogenesis in tumors.	4	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	4	5	10	11
Collectively , these observations suggest TBK1 supports AKT pathway activation in multiple regulatory contexts .	Collectively, these observations suggest TBK1 supports AKT pathway activation in multiple regulatory contexts.	5	9	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	5	6	7	8
Here we show that TBK1 directly activates AKT by phosphorylation of the canonical activation loop and hydrophobic motif sites independently of PDK1 and mTORC2 .	Here we show that TBK1 directly activates AKT by phosphorylation of the canonical activation loop and hydrophobic motif sites independently of PDK1 and mTORC2.	4	8	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	4	5	7	8
Consistent with these observations , TBK1 activation of AKT in cells can occur in the absence of the canonical AKT-T308 and AKT-S473 kinases , PDK1 and mTORC2 .	Consistent with these observations, TBK1 activation of AKT in cells can occur in the absence of the canonical AKT-T308 and AKT-S473 kinases, PDK1 and mTORC2.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	5	6	8	9
Complementation of TBK1 -/- MEFs using human wild-type TBK1 rescued AKT activation by EGF and glucose ( XREF_FIG ) .	Complementation of TBK1 -/- MEFs using human wild-type TBK1 rescued AKT activation by EGF and glucose (XREF_FIG).	5	11	rescued	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	8	9	10	11
More recently the association of endogenous TBK1 and Akt was observed in macrophages when stimulated with poly ( I : C ) and LPS , showing that Akt activation mediated by TBK1 contributes to TLR3 and TLR4 mediated immune responses .	More recently the association of endogenous TBK1 and Akt was observed in macrophages when stimulated with poly (I : C) and LPS, showing that Akt activation mediated by TBK1 contributes to TLR3 and TLR4 mediated immune responses.	27	32	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	Akt	Akt	Akt	31	32	27	28
In this pathway , Akt is itself activated by TBK1 and IKKepsilon , which interestingly are also downstream of RIG-I-like receptor ( RLR ) , so it is possible that the rapid induction of glycolysis is a common response to any innate sensing of pathogens by DCs , allowing them to rapidly respond metabolically to these danger signals .	In this pathway, Akt is itself activated by TBK1 and IKKepsilon, which interestingly are also downstream of RIG-I-like receptor (RLR), so it is possible that the rapid induction of glycolysis is a common response to any innate sensing of pathogens by DCs, allowing them to rapidly respond metabolically to these danger signals.	4	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	Akt	Akt	Akt	9	10	4	5
We propose that TBK1 promotes T-cell migration by downregulating AKT and , thereby , maintaining a sufficient level of active Foxo1 for mediating the expression of migration genes .	We propose that TBK1 promotes T-cell migration by downregulating AKT and, thereby, maintaining a sufficient level of active Foxo1 for mediating the expression of migration genes.	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	3	4	9	10
These observations indicate that TBK1 is sufficient to induce AKT activation independently of the canonical PDK1 and mTORC2 collaboration .	These observations indicate that TBK1 is sufficient to induce AKT activation independently of the canonical PDK1 and mTORC2 collaboration.	4	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	4	5	9	10
Co-immunoprecipitation and mutation experiments showed the binding of TRAF3 to TANK binding kinase 1 ( TBK1 ) that results in enhanced TBK1 phosphorylation which further activates Akt via direct phosphorylation at both S473 and T308 .	Co-immunoprecipitation and mutation experiments showed the binding of TRAF3 to TANK binding kinase 1 (TBK1) that results in enhanced TBK1 phosphorylation which further activates Akt via direct phosphorylation at both S473 and T308.	21	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1 phosphorylation	tbk1	Akt	Akt	akt	21	22	26	27
T-cell-specific ablation of TBK1 caused heightened activation of AKT and its downstream targets , mTORC1 and Foxo1 .	T-cell-specific ablation of TBK1 caused heightened activation of AKT and its downstream targets, mTORC1 and Foxo1.	1	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	3	4	8	9
To our knowledge , our results demonstrate a new regulatory mechanism for Akt activation mediated by TBK1 and a novel role of Akt in TLR mediated immune responses .	To our knowledge, our results demonstrate a new regulatory mechanism for Akt activation mediated by TBK1 and a novel role of Akt in TLR mediated immune responses.	12	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	Akt	Akt	Akt	16	17	12	13
TBK1 controls activation of AKT and mTORC1 .	TBK1 controls activation of AKT and mTORC1.	0	6	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	0	1	4	5
TBK1 has been shown to be necessary for the survival of mutant K-Ras-expressing tumour cells , where TBK1 signalling induces c-Rel and BCL-XL XREF_BIBR and activates Akt XREF_BIBR .	TBK1 has been shown to be necessary for the survival of mutant K-Ras-expressing tumour cells, where TBK1 signalling induces c-Rel and BCL-XL XREF_BIBR and activates Akt XREF_BIBR.	17	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	Akt	Akt	Akt	17	18	26	27
Further TBK1 and IKKepsilon have been reported to activate AKT .	Further TBK1 and IKKepsilon have been reported to activate AKT.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	1	2	9	10
This indicates that TBK1 support of pathological AKT activation can likely be pharmacologically targeted in disease .	This indicates that TBK1 support of pathological AKT activation can likely be pharmacologically targeted in disease.	3	8	support	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	3	4	7	8
In cardiac tissue , cardiac hypertrophy reduced SIKE expression levels , but overexpression of SIKE protected against aortic banding induced or agonist induced cardiac hypertrophy by blocking TBK1 mediated activation of Akt 10 .	In cardiac tissue, cardiac hypertrophy reduced SIKE expression levels, but overexpression of SIKE protected against aortic banding induced or agonist induced cardiac hypertrophy by blocking TBK1 mediated activation of Akt 10.	27	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	Akt	Akt	Akt	27	28	31	32
Pharmacological inhibition of PI3K kinase had no affect on TBK1 mediated AKT activation .	Pharmacological inhibition of PI3K kinase had no affect on TBK1 mediated AKT activation.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	9	10	11	12
TBK1 and IKKepsilon also activate AKT and regulate NF-kappaB signaling components such as CYLD .	TBK1 and IKKepsilon also activate AKT and regulate NF-kappaB signaling components such as CYLD.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	0	1	5	6
While TBK1 is demonstrated to be critical for the phosphorylation and activation of interferon response factors , IRF3 and IRF7 , that play key roles in the induction of type I interferon , recent studies indicate that TBK1 can also directly activate AKT by phosphorylation .	While TBK1 is demonstrated to be critical for the phosphorylation and activation of interferon response factors, IRF3 and IRF7, that play key roles in the induction of type I interferon, recent studies indicate that TBK1 can also directly activate AKT by phosphorylation.	37	43	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	37	38	42	43
Both TBK1 and IKKepsilon can activate AKT via a PI3K-indendent pathway and a PI3K dependent pathway .	Both TBK1 and IKKepsilon can activate AKT via a PI3K-indendent pathway and a PI3K dependent pathway.	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	1	2	6	7
TBK1 and IKKepsilon Activate AKT and YAP to Support Survival of the Cell-autonomous Immune Melanoma Subtype .	TBK1 and IKKepsilon Activate AKT and YAP to Support Survival of the Cell-autonomous Immune Melanoma Subtype.	0	6	Activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	0	1	4	5
In contrast , despite equivalent K-RasG12V expression , TBK1 -/- MEFs did not support AKT activation by oncogenic Ras ( XREF_FIG ) .	In contrast, despite equivalent K-RasG12V expression, TBK1 -/- MEFs did not support AKT activation by oncogenic Ras (XREF_FIG).	8	15	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	8	9	14	15
Remarkably , TBK1 expression was sufficient to drive AKT activation in the face of pharmacological inactivation of the PI3K family ( XREF_FIG ) .	Remarkably, TBK1 expression was sufficient to drive AKT activation in the face of pharmacological inactivation of the PI3K family (XREF_FIG).	2	9	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1 expression	tbk1	AKT	AKT	akt	2	3	8	9
Our results show that TBK1 and IKKi dual inhibitors inhibit AKT activation in both cancer cell lines and tumor tissues .	Our results show that TBK1 and IKKi dual inhibitors inhibit AKT activation in both cancer cell lines and tumor tissues.	4	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	4	5	10	11
TBK-1 , a serine/threonine kinase , has been shown to directly activate AKT .	TBK-1, a serine/threonine kinase, has been shown to directly activate AKT.	0	13	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK-1	TBK-1	TBK-1	AKT	AKT	AKT	0	1	12	13
Concordant with mTORC2 independent activation of AKT by TBK1 , the AKT response to host defense signaling in Sin1 -/- and Rictor -/- cells was blocked by Compound II ( XREF_FIG ) .	Concordant with mTORC2 independent activation of AKT by TBK1, the AKT response to host defense signaling in Sin1 -/- and Rictor -/- cells was blocked by Compound II (XREF_FIG).	4	21	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	8	9	6	7
Moreover , TBK1 induced AKT activation loop ( T308 ) and hydrophobic motif ( S473 ) phosphorylation in cells in the absence of PDK1 ( XREF_FIG ) or the mTORC2 subunits Sin1 ( XREF_FIG ) or Rictor ( XREF_FIG ) .	Moreover, TBK1 induced AKT activation loop (T308) and hydrophobic motif (S473) phosphorylation in cells in the absence of PDK1 (XREF_FIG) or the mTORC2 subunits Sin1 (XREF_FIG) or Rictor (XREF_FIG).	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	2	3	4	5
The mechanistic basis of TBK1 support of AKT activation is direct stimulation of AKT catalytic activity as a consequence of TBK1 induced phosphorylation of both the T308 activation loop residue and the S473 hydrophobic domain residue .	The mechanistic basis of TBK1 support of AKT activation is direct stimulation of AKT catalytic activity as a consequence of TBK1 induced phosphorylation of both the T308 activation loop residue and the S473 hydrophobic domain residue.	4	8	support	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	4	5	7	8
TBK1 can directly activate AKT by phosphorylating the activation loop .	TBK1 can directly activate AKT by phosphorylating the activation loop.	0	5	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	0	1	4	5
TBK1 reportedly mediates prosurvival signaling by activating NF-kappaB and AKT .	TBK1 reportedly mediates prosurvival signaling by activating NF-kappaB and AKT.	0	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	0	1	9	10
For example , TBK1 promotes Akt and mTORC1 in response to amino acid addition in starved cells .	For example, TBK1 promotes Akt and mTORC1 in response to amino acid addition in starved cells.	3	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	Akt	Akt	Akt	3	4	5	6
Moreover , a recent report showed that TBK1 and IKKi activated AKT by direct phosphorylation of AKT XREF_BIBR XREF_BIBR .	Moreover, a recent report showed that TBK1 and IKKi activated AKT by direct phosphorylation of AKT XREF_BIBR XREF_BIBR.	7	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	7	8	11	12
These observations indicate that TBK1 is required to support AKT activation in cancer cells , and is required for primary tumor initiation and progression , at least in the context of two different orthotopic xenograft models .	These observations indicate that TBK1 is required to support AKT activation in cancer cells, and is required for primary tumor initiation and progression, at least in the context of two different orthotopic xenograft models.	4	17	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	4	5	9	10
Akt is serine/threonine kinase that acts as a direct effector , TBK1 acts to promote Akt activation through direct stimulation of Akt catalytic activity via TBK1 induced phosphorylation of both the canonical activation loop ( T308 ) and hydrophobic motif ( S473 ) .	Akt is serine/threonine kinase that acts as a direct effector, TBK1 acts to promote Akt activation through direct stimulation of Akt catalytic activity via TBK1 induced phosphorylation of both the canonical activation loop (T308) and hydrophobic motif (S473).	9	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	Akt	Akt	Akt	11	12	15	16
Additionally , Guan and colleagues reported that IKKepsilon and TBK1 can activate Akt by direct phosphorylation on both Thr308 and Ser473 [ XREF_BIBR ] .	Additionally, Guan and colleagues reported that IKKepsilon and TBK1 can activate Akt by direct phosphorylation on both Thr308 and Ser473 [XREF_BIBR].	7	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	Akt	Akt	Akt	9	10	12	13
This approach uncovered evidence that TBK1 supports AKT and mTORC1 pathway activation and function through direct modulation of multiple pathway components acting both upstream and downstream of the mTOR kinase itself .	This approach uncovered evidence that TBK1 supports AKT and mTORC1 pathway activation and function through direct modulation of multiple pathway components acting both upstream and downstream of the mTOR kinase itself.	5	11	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	5	6	7	8
A pathological outcome of TBK1 mediated AKT activation is the oncogenic transformation of cells that could be blocked by a selective TBK1 small molecule inhibitor .	A pathological outcome of TBK1 mediated AKT activation is the oncogenic transformation of cells that could be blocked by a selective TBK1 small molecule inhibitor.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	4	5	6	7
A complementary genetic study also concluded that TBK1 phosphorylated AKT at Ser473 when stably expressed in Ric -/- cells ( which lack mTORC2 and Ser473 kinase activity ) and knockdown of TBK1 by shRNA reduced the residual AKT activation seen in Ric -/- cells .	A complementary genetic study also concluded that TBK1 phosphorylated AKT at Ser473 when stably expressed in Ric -/- cells (which lack mTORC2 and Ser473 kinase activity) and knockdown of TBK1 by shRNA reduced the residual AKT activation seen in Ric -/- cells.	29	38	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	31	32	37	38
TBK1 expression is required to support pathological oncogene dependent AKT signaling , and is required to fully engage AKT in response to EGF , glucose , and host defense signaling .	TBK1 expression is required to support pathological oncogene dependent AKT signaling, and is required to fully engage AKT in response to EGF, glucose, and host defense signaling.	0	10	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1 expression	tbk1	AKT	AKT	akt	0	1	9	10
TAB1 is also required to induce TAK1 catalytic activity , since neither IL-1 nor TNFalpha was able to stimulate detectable TAK1 activity in TAB1 (-/-) MEFs .	TAB1 is also required to induce TAK1 catalytic activity, since neither IL-1 nor TNFalpha was able to stimulate detectable TAK1 activity in TAB1 (-/-) MEFs.	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	0	1	6	7
However , one complication interpreting co-expression data in eukaryotic cells is the fact that TAB1 also promotes the autoactivation of TAK1 , a kinase that lies upstream of p38 16 .	However, one complication interpreting co-expression data in eukaryotic cells is the fact that TAB1 also promotes the autoactivation of TAK1, a kinase that lies upstream of p38 16.	14	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	14	15	20	21
TAB1 is a crucial mediator in TAK1 signalling as Tab1 -/- MEFs do not activate TAK1 in response to IL-1 and TNFalpha .	TAB1 is a crucial mediator in TAK1 signalling as Tab1 -/- MEFs do not activate TAK1 in response to IL-1 and TNFalpha.	9	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tab1	Tab1	Tab1	TAK1	TAK1	TAK1	9	10	15	16
These results demonstrate that TAB1 mediates TAK1 activation only in a subset of TAK1 pathways that are mediated through spontaneous oligomerization of TAB1-TAK1 .	These results demonstrate that TAB1 mediates TAK1 activation only in a subset of TAK1 pathways that are mediated through spontaneous oligomerization of TAB1-TAK1.	4	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	4	5	6	7
Furthermore , we showed that the C-terminal 68 amino acids of TAB1 were sufficient to mediate osmotic stress induced TAK1 activation .	Furthermore, we showed that the C-terminal 68 amino acids of TAB1 were sufficient to mediate osmotic stress induced TAK1 activation.	9	20	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	11	12	19	20
After ligand stimulation , GPR120 couples to beta-arrestin2 which is followed by receptor endocytosis and inhibition of TAB1 mediated activation of TAK1 , providing a mechanism for inhibition of both the TLR and TNF-alpha pro inflammatory signaling pathways .	After ligand stimulation, GPR120 couples to beta-arrestin2 which is followed by receptor endocytosis and inhibition of TAB1 mediated activation of TAK1, providing a mechanism for inhibition of both the TLR and TNF-alpha pro inflammatory signaling pathways.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	17	18	21	22
The MAP3K7IP1 protein interacts with and thus activates MAP3K7 kinase , and may also function as a mediator between TGF-beta receptors and MAP3K7 [ XREF_BIBR - XREF_BIBR ] , suggesting that MAP3K7IP1 can influence the function of the downstream genes of the pathways involving in MAP3K7 .	The MAP3K7IP1 protein interacts with and thus activates MAP3K7 kinase, and may also function as a mediator between TGF-beta receptors and MAP3K7 [XREF_BIBR - XREF_BIBR], suggesting that MAP3K7IP1 can influence the function of the downstream genes of the pathways involving in MAP3K7.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K7IP1	MAP3K7IP1	MAP3K7IP1	MAP3K7	MAP3K7	MAP3K7	1	2	8	9
The C. elegans homolog of TAB1 , TAP-1 , was able to interact with and activate the C. elegans homolog of TAK1 , MOM-4 .	The C. elegans homolog of TAB1, TAP-1, was able to interact with and activate the C. elegans homolog of TAK1, MOM-4.	3	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	5	6	21	22
TAB1 is a TAK1-interactingprotein and induces TAK1 kinase activity through promoting autophosphorylation of key serine/threonine sites of the kinase activation loop .	TAB1 is a TAK1-interactingprotein and induces TAK1 kinase activity through promoting autophosphorylation of key serine/threonine sites of the kinase activation loop.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	0	1	6	7
Here we demonstrate that O GlcNAcylation of a single residue ( Ser395 ) on TAB1 modulates TAK1 activation in response to IL-1 stimulation or osmotic stress .	Here we demonstrate that O GlcNAcylation of a single residue (Ser395) on TAB1 modulates TAK1 activation in response to IL-1 stimulation or osmotic stress.	9	17	modulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	14	15	16	17
Our results indicate that TAB1- or TAB2 dependent activation of TAK1 is required for maintenance of the hematopoietic system through two mechanisms : one is prevention of TNF dependent cell death and the other is TNF independent maintenance of long-term HSC .	Our results indicate that TAB1- or TAB2 dependent activation of TAK1 is required for maintenance of the hematopoietic system through two mechanisms : one is prevention of TNF dependent cell death and the other is TNF independent maintenance of long-term HSC.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TAB1-	TAB1-	TAB1-	TAK1	TAK1	TAK1	4	5	10	11
According to our data , TAB1 glycosylation can be prominently induced by TNF and may represent an interesting stimuli specific regulation mechanism of TAK1 and TABs activity .	According to our data, TAB1 glycosylation can be prominently induced by TNF and may represent an interesting stimuli specific regulation mechanism of TAK1 and TABs activity.	5	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1 glycosylation	tab1	TAK1	TAK1	tak1	5	6	23	24
Tab1 and Tab2 double deficient primary hepatocytes failed to activate TAK1 following LPS stimulation ( XREF_FIG ) , demonstrating that TAB1- and/or TAB2 dependent mechanisms participate in the LPS signaling pathway .	Tab1 and Tab2 double deficient primary hepatocytes failed to activate TAK1 following LPS stimulation (XREF_FIG), demonstrating that TAB1- and/or TAB2 dependent mechanisms participate in the LPS signaling pathway.	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tab1	Tab1	Tab1	TAK1	TAK1	TAK1	0	1	10	11
However , in analogy to TAK1 activation by TAB1 XREF_BIBR ( XREF_FIG ) , it may be speculated that this KD-ULD interaction allosterically potentiates kinase activity .	However, in analogy to TAK1 activation by TAB1 XREF_BIBR (XREF_FIG), it may be speculated that this KD-ULD interaction allosterically potentiates kinase activity.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	8	9	5	6
Overproduction of TAB1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter , which is regulated by TGF-beta , and increased the kinase activity of TAK1 .	Overproduction of TAB1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by TGF-beta, and increased the kinase activity of TAK1.	0	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	2	3	26	27
Although TAB1 is known to augment TAK1 catalytic activity when it is overexpressed , the role of TAB1 under physiological conditions has not yet been identified .	Although TAB1 is known to augment TAK1 catalytic activity when it is overexpressed, the role of TAB1 under physiological conditions has not yet been identified.	1	8	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	1	2	6	7
TAB1 and TAB2 activate the TAK1 ( TGFbeta activated kinase 1 ) multisubunit complex composed of two kinases , IKK1 and alpha and IKK2 and beta , which phosphorylate kappaB inhibitors alpha and beta respectively , as well as a structural component IKKgamma ( NEMO ) .	TAB1 and TAB2 activate the TAK1 (TGFbeta activated kinase 1) multisubunit complex composed of two kinases, IKK1 and alpha and IKK2 and beta, which phosphorylate kappaB inhibitors alpha and beta respectively, as well as a structural component IKKgamma (NEMO).	0	42	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	0	1	5	6
Activated TAK1 was prepared from HEK293 cells overexpressing the catalytic domain of TAK1 ( TAK1DeltaC ) together with TAK1 binding protein 1 ( TAB1 ) , which is an activating subunit of TAK1 .	Activated TAK1 was prepared from HEK293 cells overexpressing the catalytic domain of TAK1 (TAK1DeltaC) together with TAK1 binding protein 1 (TAB1), which is an activating subunit of TAK1.	0	24	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	23	24	1	2
These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser 192 .	These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser 192.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	expression of TAB1	tab1	TAK1	TAK1	tak1	9	10	12	13
Finally , we present a model for the chronological order of events governing TAB1 induced TAK1 autoactivation .	Finally, we present a model for the chronological order of events governing TAB1 induced TAK1 autoactivation.	12	16	induced	Positive_early_activation	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	13	14	15	16
A recent report using reconstituted TAB1 deficient fibroblasts suggested that TAB1 functions specifically in osmotic stress induced TAK1 and subsequent JNK activation providing first evidence for a highly selective function of TAB1 in TAK1 signaling XREF_BIBR .	A recent report using reconstituted TAB1 deficient fibroblasts suggested that TAB1 functions specifically in osmotic stress induced TAK1 and subsequent JNK activation providing first evidence for a highly selective function of TAB1 in TAK1 signaling XREF_BIBR.	10	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	10	11	17	18
Collectively , it is likely that TAB1 and TAB2 and possibly TAB3 redundantly function to activate TAK1 under the basal conditions .	Collectively, it is likely that TAB1 and TAB2 and possibly TAB3 redundantly function to activate TAK1 under the basal conditions.	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	6	7	16	17
The MEKK1 PHD ubiquitinates TAB1 with Lys63 linked Ub to potentiate TAK1 activation , and TAB2 can be recruited to this signalling complex in a manner dependent upon its ZnF motif ( Fig XREF_FIG C ) .	The MEKK1 PHD ubiquitinates TAB1 with Lys63 linked Ub to potentiate TAK1 activation, and TAB2 can be recruited to this signalling complex in a manner dependent upon its ZnF motif (Fig XREF_FIG C).	1	12	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	MEKK1 PHD ubiquitinates TAB1 with Lys63	tab1	TAK1	TAK1	tak1	4	5	11	12
O-GlcNAc modification of TAB1 modulates TAK1 activation .	O-GlcNAc modification of TAB1 modulates TAK1 activation.	1	6	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	3	4	5	6
TAK1 is a proximal kinase in these proinflammatory pathways and in response to inflammatory signals , the adaptor protein TAB1 associates with and activates TAK1 , stimulating both the IKKbeta and NFkappaB and the JNK and AP1 pathways .	TAK1 is a proximal kinase in these proinflammatory pathways and in response to inflammatory signals, the adaptor protein TAB1 associates with and activates TAK1, stimulating both the IKKbeta and NFkappaB and the JNK and AP1 pathways.	16	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	19	20	24	25
Thus , TAB1 and TAB2 redundantly function to activate TAK1 and together play an indispensable role in the reconstitution activity of HSC .	Thus, TAB1 and TAB2 redundantly function to activate TAK1 and together play an indispensable role in the reconstitution activity of HSC.	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	2	3	9	10
Co-immunoprecipitation of differently epitope tagged TAK1 from transfected cells and mutation of hydrophobic alphaG-helix residues in TAK1 point to an intermolecular mechanism of TAB1 induced TAK1 autoactivation , as TAK1 autophosphorylation of the activation segment was impaired in these mutants .	Co-immunoprecipitation of differently epitope tagged TAK1 from transfected cells and mutation of hydrophobic alphaG-helix residues in TAK1 point to an intermolecular mechanism of TAB1 induced TAK1 autoactivation, as TAK1 autophosphorylation of the activation segment was impaired in these mutants.	21	26	induced	Positive_early_activation	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	23	24	25	26
These results collectively suggest that LPS induced activation of TAK1 is mediated by TAB1 and TAB2 , and that either deletion of Tab1 or Tab2 reduces TAK1 activation .	These results collectively suggest that LPS induced activation of TAK1 is mediated by TAB1 and TAB2, and that either deletion of Tab1 or Tab2 reduces TAK1 activation.	20	27	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tab1	Tab1	Tab1	TAK1	TAK1	TAK1	22	23	26	27
For XIAP , BIR1 dimerization has been proposed bring together TAB1 molecules , which in turn activate TAK1 and NFkappa-B signaling [ XREF_BIBR ] .	For XIAP, BIR1 dimerization has been proposed bring together TAB1 molecules, which in turn activate TAK1 and NFkappa-B signaling [XREF_BIBR].	10	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	10	11	17	18
Overall , TAB1 and TAB2 are major activators of TAK1 in several cell types , and contributions of TAB1- and TAB2 dependent mechanisms to TAK1 activity vary depending on cell types .	Overall, TAB1 and TAB2 are major activators of TAK1 in several cell types, and contributions of TAB1- and TAB2 dependent mechanisms to TAK1 activity vary depending on cell types.	2	16	are major activators	Positive_activation_copula_1	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	2	3	9	10
Addition of TAB1 facilitates TAK1 autophosphorylation and reverses the inhibitory effects of TAK1 on MEKK3 phosphorylation and NF-kappaB signal transduction in human 293 cells and TAK1 deficient mouse embryonic fibroblasts .	Addition of TAB1 facilitates TAK1 autophosphorylation and reverses the inhibitory effects of TAK1 on MEKK3 phosphorylation and NF-kappaB signal transduction in human 293 cells and TAK1 deficient mouse embryonic fibroblasts.	0	13	reverses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	2	3	12	13
The MEKK1 PHD , but not MEKK1 mPHD , was able to ubiquitinate TAB1 and Ub modified TAB1 potentiated TAK1 activation ( Supplementary Fig S5B ) .	The MEKK1 PHD, but not MEKK1 mPHD, was able to ubiquitinate TAB1 and Ub modified TAB1 potentiated TAK1 activation (Supplementary Fig S5B).	16	20	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	17	18	19	20
O GlcNAcylation of TAB1 modulates TAK1 mediated cytokine release .	O GlcNAcylation of TAB1 modulates TAK1 mediated cytokine release.	1	8	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	3	4	5	6
According to our MS data , TAK1 can be acetylated at Met18 , which was clearly detectable in samples in which TAK1 stability and activity were supported by TAB1 co-expression ( XREF_SUPPLEMENTARY ) .	According to our MS data, TAK1 can be acetylated at Met18, which was clearly detectable in samples in which TAK1 stability and activity were supported by TAB1 co-expression (XREF_SUPPLEMENTARY).	21	30	supported	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAB1	TAB1 co-expression	tab1	TAK1	TAK1	tak1	28	29	21	22
Finally , we attempted to determine the mechanism by which TAB1 activates TAK1 .	Finally, we attempted to determine the mechanism by which TAB1 activates TAK1.	10	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	10	11	12	13
According to Kishimoto et al ., TAK1 and TAB1 co-expression activates TAK1 kinase activity [ XREF_BIBR ] , which was also observed in AGS cells .	According to Kishimoto et al., TAK1 and TAB1 co-expression activates TAK1 kinase activity [XREF_BIBR], which was also observed in AGS cells.	6	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TAB1	TAB1 co-expression	tab1	TAK1	TAK1	tak1	8	9	11	12
TAB1 can activate TAK1 by overexpression of its C-terminal 68 residues .	TAB1 can activate TAK1 by overexpression of its C-terminal 68 residues.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	0	1	3	4
Furthermore , Sertoli-Sertoli ( i.e. BTB ) and Sertoli-germ cell junction restructuring requires ERK and p38 MAPK activation that results from TGF-beta3-TbetaRI ( a Ser/Thr kinase receptor ) interacting with TGF-beta-activated kinase 1 ( TAK1 )-binding protein 1 ( TAB1 , an adaptor protein that activates TAK1 ) and CD2AP .	Furthermore, Sertoli-Sertoli (i.e. BTB) and Sertoli-germ cell junction restructuring requires ERK and p38 MAPK activation that results from TGF-beta3-TbetaRI (a Ser/Thr kinase receptor) interacting with TGF-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1, an adaptor protein that activates TAK1) and CD2AP.	34	47	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	39	40	46	47
Previous study has reported O GlcNAcylation of TAB1 modulated TAK1 mediated cytokine release [ XREF_BIBR ] .	Previous study has reported O GlcNAcylation of TAB1 modulated TAK1 mediated cytokine release [XREF_BIBR].	5	10	modulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	7	8	9	10
Our results indicate that TAB2 not only activates TAK1 but also plays an essential role in the deactivation of TAK1 by recruiting PP6 through a polyubiquitin chain dependent mechanism .	Our results indicate that TAB2 not only activates TAK1 but also plays an essential role in the deactivation of TAK1 by recruiting PP6 through a polyubiquitin chain dependent mechanism.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	4	5	8	9
As described earlier , Tab2 deletion alone in primary hepatocytes diminished TAK1 activation upon LPS challenge ( XREF_FIG ) .	As described earlier, Tab2 deletion alone in primary hepatocytes diminished TAK1 activation upon LPS challenge (XREF_FIG).	4	12	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tab2	Tab2	Tab2	TAK1	TAK1	TAK1	4	5	11	12
A TRAF6 mediated association of TAB2 and TAB3 with ubiquitin will trigger the activation of TAK1 XREF_BIBR .	A TRAF6 mediated association of TAB2 and TAB3 with ubiquitin will trigger the activation of TAK1 XREF_BIBR.	3	16	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	5	6	15	16
TAB2 and TAB3 redundantly mediate activation of TAK1 .	TAB2 and TAB3 redundantly mediate activation of TAK1.	0	8	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	0	1	7	8
We speculate that that TAB2 dependent activation of TAK1 may be important for prevention of LPS induced liver injury in vivo .	We speculate that that TAB2 dependent activation of TAK1 may be important for prevention of LPS induced liver injury in vivo.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	4	5	8	9
Accordingly , the overexpression of either TAB2 or TAB3 CCD stimulates Beclin 1- and TAK1 dependent autophagy .	Accordingly, the overexpression of either TAB2 or TAB3 CCD stimulates Beclin 1- and TAK1 dependent autophagy.	3	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	overexpression of either TAB2	tab2	TAK1	TAK1	tak1	6	7	14	15
Furthermore , we found that Tab2 single deficient primary hepatocytes failed to activate TAK1 following LPS stimulation ( XREF_FIG ) .	Furthermore, we found that Tab2 single deficient primary hepatocytes failed to activate TAK1 following LPS stimulation (XREF_FIG).	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tab2	Tab2	Tab2	TAK1	TAK1	TAK1	5	6	13	14
Of the proteins encoded by these genes , MAP3K7IP2 activates MAP3K7 by forming a complex with TRAF6 , MAP3K7 and TAB1 [ XREF_BIBR ] .	Of the proteins encoded by these genes, MAP3K7IP2 activates MAP3K7 by forming a complex with TRAF6, MAP3K7 and TAB1 [XREF_BIBR].	8	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K7IP2	MAP3K7IP2	MAP3K7IP2	MAP3K7	MAP3K7	MAP3K7	8	9	10	11
TAB2 is known to mediate polyubiquitin chain dependent TAK1 activation in innate immune signaling pathways , whereas the role of TAB1 is not defined .	TAB2 is known to mediate polyubiquitin chain dependent TAK1 activation in innate immune signaling pathways, whereas the role of TAB1 is not defined.	0	9	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	0	1	8	9
TAB2 stimulates TAK1 kinase activity and binds to K63 linked polyubiquitinated NEMO ( or TRAF6 ) through the Zn-finger domain of TAB2 .	TAB2 stimulates TAK1 kinase activity and binds to K63 linked polyubiquitinated NEMO (or TRAF6) through the Zn-finger domain of TAB2.	0	6	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	0	1	2	3
Consistently , deficiency of TRIM38 resulted in abolished translocation of TAB2 to the lysosome , increased level of TAB2 in cells , and enhanced activation of TAK1 after TNFalpha and IL-1beta stimulation .	Consistently, deficiency of TRIM38 resulted in abolished translocation of TAB2 to the lysosome, increased level of TAB2 in cells, and enhanced activation of TAK1 after TNFalpha and IL-1beta stimulation.	4	27	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TRIM38 resulted in abolished translocation of TAB2 to the lysosome, increased level of TAB2	tab2	TAK1	TAK1	tak1	18	19	26	27
Thus , TAB2- and TAB3 mediated K63 linked polyubiquitin recognition controls B cell activation via MAPKs , but not the TAK1 and NF-kappaB axis .	Thus, TAB2- and TAB3 mediated K63 linked polyubiquitin recognition controls B cell activation via MAPKs, but not the TAK1 and NF-kappaB axis.	2	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2-	TAB2-	TAB2-	TAK1	TAK1	TAK1	2	3	20	21
However , macrophages having deletion of either Tab1 or Tab2 could not withstand LPS activation and Tab1 iKO macrophages underwent necrosis after 3-4 days , while Tab2 iKO die after 1 day , despite showing early LPS induced TAK1 activation at or near WT levels ( XREF_FIG ) .	However, macrophages having deletion of either Tab1 or Tab2 could not withstand LPS activation and Tab1 iKO macrophages underwent necrosis after 3-4 days, while Tab2 iKO die after 1 day, despite showing early LPS induced TAK1 activation at or near WT levels (XREF_FIG).	26	39	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tab2	Tab2	Tab2	TAK1	TAK1	TAK1	26	27	38	39
Interestingly , in the intestinal epithelium , TAK1 activity appears to be regulated through two independent mechanisms , in which TAB1 regulates basal activity of TAK1 , and TAB2 mediates stimulus dependent TAK1 activation XREF_BIBR .	Interestingly, in the intestinal epithelium, TAK1 activity appears to be regulated through two independent mechanisms, in which TAB1 regulates basal activity of TAK1, and TAB2 mediates stimulus dependent TAK1 activation XREF_BIBR.	28	34	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	28	29	32	33
In one hand , this allows BECLIN1 to induce autophagy , and on the other hand TAB2 and TAB3 activates TAK1 that in turn activates IKK [ XREF_BIBR ] .	In one hand, this allows BECLIN1 to induce autophagy, and on the other hand TAB2 and TAB3 activates TAK1 that in turn activates IKK [XREF_BIBR].	16	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	16	17	20	21
Our results suggest that TAB2 dependent activation of TAK1 beyond the basal level is required for hepatocyte survival only when hepatocytes are under stressed conditions .	Our results suggest that TAB2 dependent activation of TAK1 beyond the basal level is required for hepatocyte survival only when hepatocytes are under stressed conditions.	4	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	4	5	8	9
In the current study , we investigated the role of TAB2 in hepatocytes and determined that TAB2 activates TAK1 in response to a TLR ligand lipopolysaccharide ( LPS ) , which is essential for hepatocyte survival .	In the current study, we investigated the role of TAB2 in hepatocytes and determined that TAB2 activates TAK1 in response to a TLR ligand lipopolysaccharide (LPS), which is essential for hepatocyte survival.	16	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	16	17	18	19
Binding of TAB2 and TAB3 to ubiquitin chains made by TRAF6 is required to activate TAK1 [ XREF_BIBR ] .	Binding of TAB2 and TAB3 to ubiquitin chains made by TRAF6 is required to activate TAK1 [XREF_BIBR].	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	Binding of TAB2	tab2	TAK1	TAK1	tak1	2	3	15	16
We have recently discovered that a binding partner of TAK1 , TAK1 binding protein 2 ( TAB2 ) , is essential for TAK1 deactivation by recruiting PP6 to the TAK1 complex , and that ablation of TAB2 causes hyperactivation of TAK1 in fibroblasts .	We have recently discovered that a binding partner of TAK1, TAK1 binding protein 2 (TAB2), is essential for TAK1 deactivation by recruiting PP6 to the TAK1 complex, and that ablation of TAB2 causes hyperactivation of TAK1 in fibroblasts.	34	42	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	36	37	40	41
These ubiquitin chains bind to TAB2 and TAB3 to activate the TAK1 complex and bind to NEMO to activate the IKK complex , both of which are crucial for NF-kappaB activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	These ubiquitin chains bind to TAB2 and TAB3 to activate the TAK1 complex and bind to NEMO to activate the IKK complex, both of which are crucial for NF-kappaB activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	12	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TAB2	bind to TAB2	tab2	TAK1	TAK1	tak1	5	6	11	12
S1 demonstrate that Tab2 deficiency induces hyperactivation of TAK1 , which might be the cause of TNF induced RIPK3 dependent cell death in Tab2 deficient fibroblasts .	S1 demonstrate that Tab2 deficiency induces hyperactivation of TAK1, which might be the cause of TNF induced RIPK3 dependent cell death in Tab2 deficient fibroblasts.	3	19	induces	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Tab2	Tab2	tab2	TAK1	TAK1, which might be the cause of TNF induced RIPK3	tak1	3	4	8	9
K63-ubiquitin chains recruit the homologous zinc-finger proteins TAB2 and TAB3 , which in turn activate the kinase TAK1 ( XREF_FIG ) .	K63-ubiquitin chains recruit the homologous zinc-finger proteins TAB2 and TAB3, which in turn activate the kinase TAK1 (XREF_FIG).	2	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	7	8	17	18
Deletion of either Tab1 or Tab2 impaired LPS induced migration shift of TAK1 , suggesting some impairment of TAK1 activation in response to LPS ( XREF_FIG , top panels ) .	Deletion of either Tab1 or Tab2 impaired LPS induced migration shift of TAK1, suggesting some impairment of TAK1 activation in response to LPS (XREF_FIG, top panels).	5	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tab2	Tab2	Tab2	TAK1	TAK1	TAK1	5	6	12	13
TAB2 modulates TAK1 signalling and interacts with Trbd .	TAB2 modulates TAK1 signalling and interacts with Trbd.	0	5	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	0	1	2	3
However , in contrast to the loss of either MKK3 or MKK6 expression , depletion of TAB1 alone caused a modest but significant decrease in thrombin stimulated p38 activation , whereas loss of TAB2 expression resulted in a marked reduction in p38 activation without affecting MKK3 or MKK6 expression ( XREF_FIG , lanes 1-6 ) .	However, in contrast to the loss of either MKK3 or MKK6 expression, depletion of TAB1 alone caused a modest but significant decrease in thrombin stimulated p38 activation, whereas loss of TAB2 expression resulted in a marked reduction in p38 activation without affecting MKK3 or MKK6 expression (XREF_FIG, lanes 1-6).	14	28	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TAB1	TAB1	TAB1	p38	p38	p38	16	17	27	28
TAB1 promotes a conformational change in p38 , enabling autophosphorylation and activation .	TAB1 promotes a conformational change in p38, enabling autophosphorylation and activation.	0	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	0	1	6	7
In addition , the mechanism by which PAR1 induced TAB1 stimulated p38 MAPK activation promotes endothelial barrier permeability is not clear but may involve direct effects on adherens junction components that lead to disassembly and is an important area for future study .	In addition, the mechanism by which PAR1 induced TAB1 stimulated p38 MAPK activation promotes endothelial barrier permeability is not clear but may involve direct effects on adherens junction components that lead to disassembly and is an important area for future study.	7	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	PAR1 induced TAB1	tab1	p38 MAPK	p38 MAPK	p38 mapk	9	10	11	13
Further , it has been shown that p38 can be activated by TAB1 , independent of TAB2 and MKK3/6 , although TAB1 activated p38 is sequestered in the cytoplasm [ XREF_BIBR ] .	Further, it has been shown that p38 can be activated by TAB1, independent of TAB2 and MKK3/6, although TAB1 activated p38 is sequestered in the cytoplasm [XREF_BIBR].	21	25	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	21	22	23	24
Noncanonical p38 activation is induced by direct binding of TAB1 to the C-terminal domain of p38 and requires a critical proline residue P412 of TAB1 .	Noncanonical p38 activation is induced by direct binding of TAB1 to the C-terminal domain of p38 and requires a critical proline residue P412 of TAB1.	1	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	9	10	1	2
One potential mechanism may be cytokine independent interactions between p38 and the scaffold protein TAB1 , which can activate p38 in PBEos XREF_BIBR .	One potential mechanism may be cytokine independent interactions between p38 and the scaffold protein TAB1, which can activate p38 in PBEos XREF_BIBR.	7	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	14	15	19	20
Further , in cardiac myocytes and perfused mouse hearts , TAB1 activates p38 independent of MAPKK .	Further, in cardiac myocytes and perfused mouse hearts, TAB1 activates p38 independent of MAPKK.	10	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	10	11	12	13
Under other stimulus conditions , such as exposure to ultraviolet light , MKK4 and TAB1 can also activate p38 .	Under other stimulus conditions, such as exposure to ultraviolet light, MKK4 and TAB1 can also activate p38.	12	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	14	15	18	19
TAB1 mediated p38 MAPK autoactivation occurs independent from all three p38 MAPK activating kinases ( MKK3 , MKK6 , MKK4 ) but accounts for only a small portion of overall p38 MAPK activity in a cell-and stimulus dependent manner XREF_BIBR - XREF_BIBR .	TAB1 mediated p38 MAPK autoactivation occurs independent from all three p38 MAPK activating kinases (MKK3, MKK6, MKK4) but accounts for only a small portion of overall p38 MAPK activity in a cell-and stimulus dependent manner XREF_BIBR - XREF_BIBR.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38 MAPK	p38 MAPK	p38 MAPK	0	1	2	4
NO species are known to activate p38 in nonneuronal cells , but this reportedly depends on a TAB1 mediated p38 autophosphorylation mechanism that is not required for glutamate evoked neuronal p38 activation ( unpublished data ) .	NO species are known to activate p38 in nonneuronal cells, but this reportedly depends on a TAB1 mediated p38 autophosphorylation mechanism that is not required for glutamate evoked neuronal p38 activation (unpublished data).	14	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	17	18	19	20
More detailed analysis indicates that MLB does not affect MKK3/6 mediated p38 activation , but specifically inhibits TAB1 mediated p38 activation .	More detailed analysis indicates that MLB does not affect MKK3/6 mediated p38 activation, but specifically inhibits TAB1 mediated p38 activation.	16	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	17	18	19	20
These data suggest that TAB-1 can mediate MKK independent p38 kinase activation while negatively modulating MKK dependent p38 function .	These data suggest that TAB-1 can mediate MKK independent p38 kinase activation while negatively modulating MKK dependent p38 function.	4	11	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB-1	TAB-1	TAB-1	p38	p38	p38	4	5	9	10
p38 activation is triggered by AMPK and mediated by TAB1 .	p38 activation is triggered by AMPK and mediated by TAB1.	0	10	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	9	10	0	1
Based on these data and the fact that the peptide is necessary and sufficient for TAB1 mediated activation of p38 , we hypothesize that this short polypeptide contains the residues required for TAB1 recognition .	Based on these data and the fact that the peptide is necessary and sufficient for TAB1 mediated activation of p38, we hypothesize that this short polypeptide contains the residues required for TAB1 recognition.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	15	16	19	20
An increase in TAB1 expression alone however was not sufficient to initiate p38 activation , but rather required activation of PAR1 .	An increase in TAB1 expression alone however was not sufficient to initiate p38 activation, but rather required activation of PAR1.	3	13	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1 expression	tab1	p38	p38	p38	3	4	12	13
These results imply that TAB1 mediated activation of p38 alpha in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production .	These results imply that TAB1 mediated activation of p38 alpha in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	4	5	8	9
However , although one study showed TAB-1 induced p38 activation in cardiomycoyte caused apoptosis similar to canonically activated p38 activity , another showed TAB-1 interaction with p38 led to its intracellular localization and downstream signaling distinct from the canonical pathway .	However, although one study showed TAB-1 induced p38 activation in cardiomycoyte caused apoptosis similar to canonically activated p38 activity, another showed TAB-1 interaction with p38 led to its intracellular localization and downstream signaling distinct from the canonical pathway.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	TAB-1	TAB-1	TAB-1	p38	p38	p38	6	7	8	9
Thus , there are two ways p38 can be activated by TAB1 : i. through p38alpha-TAB1 interaction and autophosphorylation of p38alpha in a MKK3/6 independent manner ii .	Thus, there are two ways p38 can be activated by TAB1 : i. through p38alpha-TAB1 interaction and autophosphorylation of p38alpha in a MKK3/6 independent manner ii.	6	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	11	12	6	7
TAB1 ( 371-416 ) but not TAB1 ( 371-416A-B ) caused p38 activation ( XREF_FIG ) and at later time points cell death ( see rounded appearance of cells with homogenous distribution of fluorescein label ) .	TAB1 (371-416) but not TAB1 (371-416A-B) caused p38 activation (XREF_FIG) and at later time points cell death (see rounded appearance of cells with homogenous distribution of fluorescein label).	0	12	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	0	1	11	12
Interestingly , Ota et al recently reported that Hsp90 and Cdc37 also plays an inhibitory role in p38 autophosphorylation and selectively modulates TAB1 mediated p38 activation [ XREF_BIBR ] .	Interestingly, Ota et al recently reported that Hsp90 and Cdc37 also plays an inhibitory role in p38 autophosphorylation and selectively modulates TAB1 mediated p38 activation [XREF_BIBR].	21	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	22	23	24	25
Together , the results of this study brought mechanistic insight into the antileishmanial activity of GRA , which is dependent on the TLR2/4-MyD 88 signaling axis , leading to MKK3/6 mediated canonical and TAB1 mediated noncanonical p38 activation .	Together, the results of this study brought mechanistic insight into the antileishmanial activity of GRA, which is dependent on the TLR2/4-MyD 88 signaling axis, leading to MKK3/6 mediated canonical and TAB1 mediated noncanonical p38 activation.	31	37	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	33	34	36	37
Hsp90-Cdc37 specifically regulates TAB1 mediated non canonical activation of p38 , but has no effect on MKK dependent canonical activation of p38 .	Hsp90-Cdc37 specifically regulates TAB1 mediated non canonical activation of p38, but has no effect on MKK dependent canonical activation of p38.	3	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	3	4	9	10
In addition , non Smad ( non canonical ) BMP signaling mediated by Tak1 and Tab1 activates p38 MAPK .	In addition, non Smad (non canonical) BMP signaling mediated by Tak1 and Tab1 activates p38 MAPK.	11	19	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tab1	Tab1	Tab1	p38 MAPK	p38 MAPK	p38 MAPK	15	16	17	19
In addition , we have shown that TAB1 can functionally stimulate p38 , but not IKK , phosphorylation .	In addition, we have shown that TAB1 can functionally stimulate p38, but not IKK, phosphorylation.	7	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	7	8	11	12
TAK1 and TAB1 are required to mediate TGF-beta and BMP dependent activation of p38 MAPK and JNK , and associate with ALK3 through an adaptor protein XIAP .	TAK1 and TAB1 are required to mediate TGF-beta and BMP dependent activation of p38 MAPK and JNK, and associate with ALK3 through an adaptor protein XIAP.	0	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38 MAPK	p38 MAPK	p38 MAPK	2	3	13	15
Two TAB1 splicing-variants ( alpha or beta ) , of 60-kDa and 50-kDa , bind to and activate p38 by an identical mechanism 21 .	Two TAB1 splicing-variants (alpha or beta), of 60-kDa and 50-kDa, bind to and activate p38 by an identical mechanism 21.	1	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	1	2	18	19
TAB1 mediated p38 activation has been pointed out to play important roles in ischemia induced myocardial injury .	TAB1 mediated p38 activation has been pointed out to play important roles in ischemia induced myocardial injury.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	0	1	2	3
Additionally , the binding of TAB1 ( TAK1 binding protein 1 ) induces a conformational rearrangement of p38 in its activation loop enabling autophosphorylation of p38 [ XREF_BIBR , XREF_BIBR ] .	Additionally, the binding of TAB1 (TAK1 binding protein 1) induces a conformational rearrangement of p38 in its activation loop enabling autophosphorylation of p38 [XREF_BIBR, XREF_BIBR].	3	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	5	6	17	18
Next , we examined the role of TAB1 and TAB2 versus MKK3 and MKK6 in thrombin induced p38 activation .	Next, we examined the role of TAB1 and TAB2 versus MKK3 and MKK6 in thrombin induced p38 activation.	5	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38	p38	p38	7	8	17	18
Collectively , the results shown in XREF_FIG suggest that aa 452-457 are engaged in TAB1 dependent activation of p38 MAPK but are also direct targets of p38 MAPK as schematically shown in XREF_FIG .	Collectively, the results shown in XREF_FIG suggest that aa 452-457 are engaged in TAB1 dependent activation of p38 MAPK but are also direct targets of p38 MAPK as schematically shown in XREF_FIG.	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38 MAPK	p38 MAPK	p38 MAPK	14	15	18	20
The present study demonstrates that O GlcNAcylation of a single residue ( Ser408 ) on TAB3 modulates TAK1 activation in response to IL-1beta stimulation .	The present study demonstrates that O GlcNAcylation of a single residue (Ser408) on TAB3 modulates TAK1 activation in response to IL-1beta stimulation.	10	18	modulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TAB3	TAB3	TAB3	TAK1	TAK1	TAK1	15	16	17	18
O-GlcNAc modification of TAB3 modulated TAK1 activation in TNBC cells .	O-GlcNAc modification of TAB3 modulated TAK1 activation in TNBC cells.	1	6	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB3	TAB3	TAB3	TAK1	TAK1	TAK1	3	4	5	6
TAB3 can mediate polyubiquitin dependent activation of TAK1 , but Tab3 deletion alone does not cause any abnormalities during embryogenesis or in adult mice XREF_BIBR .	TAB3 can mediate polyubiquitin dependent activation of TAK1, but Tab3 deletion alone does not cause any abnormalities during embryogenesis or in adult mice XREF_BIBR.	0	8	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB3	TAB3	TAB3	TAK1	TAK1	TAK1	0	1	7	8
Additionally , we showed that overexpression of nuclear TBLR1 leads to selective activation of growth suppression and differentiation AR target genes but not pro proliferative genes ( XREF_FIG ) , however , knockdown of TBLR1 leads to a more global downregulation of both sets of genes ( XREF_SUPPLEMENTARY ) .	Additionally, we showed that overexpression of nuclear TBLR1 leads to selective activation of growth suppression and differentiation AR target genes but not pro proliferative genes (XREF_FIG), however, knockdown of TBLR1 leads to a more global downregulation of both sets of genes (XREF_SUPPLEMENTARY).	5	20	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TBLR1	overexpression of nuclear TBLR1	tblr1	AR	AR	ar	8	9	18	19
In prostatic tissues we showed by luciferase assay that activation of AR by TBLR1 also is indeed dependent on both 19S proteosome activity and phosphorylation ( XREF_FIG ) .	In prostatic tissues we showed by luciferase assay that activation of AR by TBLR1 also is indeed dependent on both 19S proteosome activity and phosphorylation (XREF_FIG).	9	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TBLR1	TBLR1	TBLR1	AR	AR	AR	13	14	11	12
TBLR1 and TBL1XR1 , a core component of the nuclear receptor corepressor ( NCoR ) complex critical for the regulation of multiple nuclear receptors , is a transcriptional coactivator of androgen receptor ( AR ) and functions as a tumor suppressor when expressed in the nucleus in prostate .	TBLR1 and TBL1XR1, a core component of the nuclear receptor corepressor (NCoR) complex critical for the regulation of multiple nuclear receptors, is a transcriptional coactivator of androgen receptor (AR) and functions as a tumor suppressor when expressed in the nucleus in prostate.	0	32	is a transcriptional coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	TBL1XR1	TBL1XR1	TBL1XR1	androgen receptor	androgen receptor	androgen receptor	2	3	30	32
This shows that although increased nuclear TBLR1 does selectively activate a subset of AR target genes , a baseline level may be required for most AR target genes and cell proliferation .	This shows that although increased nuclear TBLR1 does selectively activate a subset of AR target genes, a baseline level may be required for most AR target genes and cell proliferation.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBLR1	TBLR1	TBLR1	AR	AR	AR	6	7	13	14
We show that TBLR1 is a coactivator of AR and acts as a tumor suppressor in prostate cancer , consistent with its decreased nuclear expression in human prostate cancer compared to benign glands in clinical samples by immunohistochemistry .	We show that TBLR1 is a coactivator of AR and acts as a tumor suppressor in prostate cancer, consistent with its decreased nuclear expression in human prostate cancer compared to benign glands in clinical samples by immunohistochemistry.	3	10	is a coactivator	Positive_activation_copula_1	Positive_activation	Positive_activation	TBLR1	TBLR1	TBLR1	AR	AR	AR	3	4	8	9
Our previous study has shown that TBLR1 is a transcriptional activator of AR and its nuclear expression is significantly reduced in PCa compared with benign prostate glands .	Our previous study has shown that TBLR1 is a transcriptional activator of AR and its nuclear expression is significantly reduced in PCa compared with benign prostate glands.	6	13	is a transcriptional activator	Positive_activation_copula_1	Positive_activation	Positive_activation	TBLR1	TBLR1	TBLR1	AR	AR	AR	6	7	12	13
TBLR1 as an AR coactivator selectively activates AR target genes to inhibit prostate cancer growth .	TBLR1 as an AR coactivator selectively activates AR target genes to inhibit prostate cancer growth.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBLR1	TBLR1	TBLR1	AR	AR	AR	0	1	7	8
In the presence of a specific 19S proteosome inhibitor , MG132 , a specific PKC inhibitor , Rottlerin , or mutant TBLR1 constructs , S123A , S199A/T203A/T204A , or the double mutant , TBLR1 activation of AR was diminished up to three fold ( XREF_FIG ) .	In the presence of a specific 19S proteosome inhibitor, MG132, a specific PKC inhibitor, Rottlerin, or mutant TBLR1 constructs, S123A, S199A/T203A/T204A, or the double mutant, TBLR1 activation of AR was diminished up to three fold (XREF_FIG).	33	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBLR1	TBLR1	TBLR1	AR	AR	AR	33	34	36	37
However , after transfection with AR , TBLR1 lead to up to 2.5 fold increase in AR activation in a dose dependent manner ( XREF_FIG ) .	However, after transfection with AR, TBLR1 lead to up to 2.5 fold increase in AR activation in a dose dependent manner (XREF_FIG).	7	17	lead	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TBLR1	TBLR1	TBLR1	AR	AR	AR	7	8	16	17
Once activated , TAB2 and TAK1 likely phosphorylates and activates the IKK complex as well as the JNK pathway through Hemipterous ( MKK7 ) , similar to mammalian NF-kappaB pathways .	Once activated, TAB2 and TAK1 likely phosphorylates and activates the IKK complex as well as the JNK pathway through Hemipterous (MKK7), similar to mammalian NF-kappaB pathways.	3	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	JNK	JNK	JNK	3	4	17	18
Finally , it has been previously shown that the Imd components TAB2 and TAK1 also trigger activation of JNK signaling , whereas negative feedback can occur between the Imd-Relish and Imd-JNK branches of the Drosophila immune system [ XREF_BIBR ] .	Finally, it has been previously shown that the Imd components TAB2 and TAK1 also trigger activation of JNK signaling, whereas negative feedback can occur between the Imd-Relish and Imd-JNK branches of the Drosophila immune system [XREF_BIBR].	8	19	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	JNK	JNK	JNK	11	12	18	19
XREF_BIBR Each ligand can bind and activate each receptor ; however , they all have their preference owing to a graded affinity : SP preferentially activates NK 1 R , NKA preferentially activates NK 2 R , and NKB preferentially activates NK 3 R ( XREF_TABLE ) .	XREF_BIBR Each ligand can bind and activate each receptor; however, they all have their preference owing to a graded affinity : SP preferentially activates NK 1 R, NKA preferentially activates NK 2 R, and NKB preferentially activates NK 3 R (XREF_TABLE).	30	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NKA	NKA	NKA	NK 2 R	NK 2 R	NK 2 R	30	31	33	36
XREF_BIBR The induction of NK2 receptor by NKA is also regulated by autocrine production of TGF-beta in stroma .	XREF_BIBR The induction of NK2 receptor by NKA is also regulated by autocrine production of TGF-beta in stroma.	2	8	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NKA	NKA	NKA	NK2 receptor	NK2 receptor	NK2 receptor	7	8	4	6
It was also observed that Neurokinin A ( NKA ) , which preferentially activates NK-2R , also induced Ca 2+ -responses in a similar number of fura-2 loaded cells , although only at concentrations above 100 nM ( ~ 9 % , 54/605 cells , XREF_FIG ) .	It was also observed that Neurokinin A (NKA), which preferentially activates NK-2R, also induced Ca 2+ -responses in a similar number of fura-2 loaded cells, although only at concentrations above 100 nM (~ 9%, 54/605 cells, XREF_FIG).	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Neurokinin A	Neurokinin A	Neurokinin A	NK-2R	NK-2R	NK-2R	5	7	14	15
SP and NKA preferentially activate NK-1R and NK-2R , respectively .	SP and NKA preferentially activate NK-1R and NK-2R, respectively.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NKA	NKA	NKA	NK-2R	NK-2R	NK-2R	2	3	7	8
In both primary BM cells and progenitor cells , NK2 receptor activation by NKA leads to increased expression of its own mRNA .	In both primary BM cells and progenitor cells, NK2 receptor activation by NKA leads to increased expression of its own mRNA.	9	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	NKA	NKA	NKA	NK2 receptor	NK2 receptor	NK2 receptor	13	14	9	11
IRF5 could be activated by both TBK1 and MyD88 to form homodimers and the activated IRF5 induces the transcription of type I interferon genes and the Prdm1 gene .	IRF5 could be activated by both TBK1 and MyD88 to form homodimers and the activated IRF5 induces the transcription of type I interferon genes and the Prdm1 gene.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IRF5	IRF5	IRF5	6	7	0	1
These findings indicate that WT TAB1 and TAB2 expression are sufficient to restore thrombin dependent p38 activation .	These findings indicate that WT TAB1 and TAB2 expression are sufficient to restore thrombin dependent p38 activation.	7	16	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2 expression	tab2	p38	p38	p38	7	8	15	16
Thus , deletion of TAB2 will abolish IL1 and p38 signaling , resulting in only the basal p38 activity , consistent with our prediction .	Thus, deletion of TAB2 will abolish IL1 and p38 signaling, resulting in only the basal p38 activity, consistent with our prediction.	2	10	abolish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	p38	p38	p38	4	5	9	10
While p38 is activated by MKK3/6 in a TAB2 dependent manner , it is dephosphorylated by a MAP kinase specific phosphatase , MKP1 , and the active p38 increases MKP1 at a post-transcriptional level [ XREF_BIBR ] , creating a negative feedback loop ( XREF_FIG ) .	While p38 is activated by MKK3/6 in a TAB2 dependent manner, it is dephosphorylated by a MAP kinase specific phosphatase, MKP1, and the active p38 increases MKP1 at a post-transcriptional level [XREF_BIBR], creating a negative feedback loop (XREF_FIG).	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TAB2	TAB2	TAB2	p38	p38	p38	8	9	1	2
The tyrosine kinases Syk , Zap70 , and Janus kinase likely phosphorylate and activate Vav1 in vivo , but the kinase ( s ) that stimulate Vav2 in vivo are not known .	The tyrosine kinases Syk, Zap70, and Janus kinase likely phosphorylate and activate Vav1 in vivo, but the kinase (s) that stimulate Vav2 in vivo are not known.	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syk	Syk	Syk	Vav1	Vav1	Vav1	3	4	14	15
Syk can now activate Vav1 and signaling pathways required for the production of cytokines and chemokines including the release of calcium and the activation of the MAPKs , JNK , and p38 .	Syk can now activate Vav1 and signaling pathways required for the production of cytokines and chemokines including the release of calcium and the activation of the MAPKs, JNK, and p38.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syk	Syk	Syk	Vav1	Vav1	Vav1	0	1	4	5
Activation of Syk by alphavbeta3 integrin results in activation of Vav1 and subsequently Rac1 and Pak1 or Rho1 and Fak1 .	Activation of Syk by alphavbeta3 integrin results in activation of Vav1 and subsequently Rac1 and Pak1 or Rho1 and Fak1.	0	11	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Syk	Syk	Syk	Vav1	Vav1	Vav1	2	3	10	11
Furthermore , the Tbk1 deficiency did not promote the activation of p50 or c-Rel and only moderately enhanced the activation of RelA ( XREF_SUPPLEMENTARY ) .	Furthermore, the Tbk1 deficiency did not promote the activation of p50 or c-Rel and only moderately enhanced the activation of RelA (XREF_SUPPLEMENTARY).	3	23	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tbk1	Tbk1	Tbk1	RelA	RelA	RelA	3	4	21	22
LPS and IFNgamma stimulation caused the increase of TBK1 expression , activation of NF-kappaB and induced p50 and p65 movement to nucleus , and TIE repressed luciferase intensity of NF-kappaB promoter in a dose dependent manner ( XREF_FIG ) .	LPS and IFNgamma stimulation caused the increase of TBK1 expression, activation of NF-kappaB and induced p50 and p65 movement to nucleus, and TIE repressed luciferase intensity of NF-kappaB promoter in a dose dependent manner (XREF_FIG).	0	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	LPS and IFNgamma stimulation caused the increase of TBK1 expression	tbk1	p65	p65	p65	8	9	18	19
We previously demonstrated that TAF12 , a component of the TFIID general transcription factor , mediates ATF7 transcriptional activity through direct interactions between the two proteins .	We previously demonstrated that TAF12, a component of the TFIID general transcription factor, mediates ATF7 transcriptional activity through direct interactions between the two proteins.	4	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAF12	TAF12	TAF12	ATF7	ATF7	ATF7	4	5	16	17
Further , TAF12 over-expression was found to potentiate ATF7 induced transcriptional activation through direct interaction in colorectal cancer cells , and this effect was inhibited by TAF4 , which blocks the interaction between TAF12 and ATF7 .	Further, TAF12 over-expression was found to potentiate ATF7 induced transcriptional activation through direct interaction in colorectal cancer cells, and this effect was inhibited by TAF4, which blocks the interaction between TAF12 and ATF7.	2	9	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAF12	TAF12 over-expression	taf12	ATF7	ATF7	atf7	2	3	8	9
[ XREF_BIBR ] In addition , TAF12 was reported to interact with the bZIP activating transcription factor 7 ( ATF7 ) and potentiate ATF7 driven genes .	[XREF_BIBR] In addition, TAF12 was reported to interact with the bZIP activating transcription factor 7 (ATF7) and potentiate ATF7 driven genes.	6	24	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAF12	TAF12	TAF12	ATF7	ATF7	ATF7	6	7	23	24
As previously shown , TAF12 potentiates ATF7 induced transcriptional activation through direct interaction with the N-terminal ATF7 transactivation domain .	As previously shown, TAF12 potentiates ATF7 induced transcriptional activation through direct interaction with the N-terminal ATF7 transactivation domain.	4	7	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAF12	TAF12	TAF12	ATF7	ATF7	ATF7	4	5	6	7
Concurrently , PINK1 also phosphorylates TBK1 at Ser172 , promoting the phosphorylation of three different autophagy adaptor proteins : p62 ( also known as sequestrome 1 ( SQSTM1 ) ) , optineurin ( OPTN ) , and nuclear dot protein ( NDP52 ) [ XREF_BIBR - XREF_BIBR ] .	Concurrently, PINK1 also phosphorylates TBK1 at Ser172, promoting the phosphorylation of three different autophagy adaptor proteins : p62 (also known as sequestrome 1 (SQSTM1)), optineurin (OPTN), and nuclear dot protein (NDP52) [XREF_BIBR - XREF_BIBR].	2	39	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	PINK1 also phosphorylates TBK1 at Ser172	tbk1	p62	p62	p62	5	6	19	20
XREF_BIBR Very recently mutations affecting the gene encoding TBK1 ( TANK binding kinase 1 ) , a kinase which targets both OPTN and SQSTM1 thus linking the proteins in a common pathway , have been identified as a cause of familial ALS-FTLD .	XREF_BIBR Very recently mutations affecting the gene encoding TBK1 (TANK binding kinase 1), a kinase which targets both OPTN and SQSTM1 thus linking the proteins in a common pathway, have been identified as a cause of familial ALS-FTLD.	7	24	targets	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	SQSTM1	SQSTM1	SQSTM1	8	9	23	24
TBK1 ( TANK binding kinase 1 ) promotes mitophagy by enhancing the functions of optineurin and p62 through direct phosphorylation .	TBK1 (TANK binding kinase 1) promotes mitophagy by enhancing the functions of optineurin and p62 through direct phosphorylation.	0	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	p62	p62	p62	0	1	16	17
Furthermore , ubiquitinated proteins accumulated in Tbk1 -/- cells revealed by pull-down assays in cellular extracts using TUBE-2 ( tandem ubiquitin binding entities 2 ) , which recognizes polyubiquitinated proteins and protects them from deubiquitinating enzymes and proteasome during isolation ( XREF_FIG ) Thus , p62 is not being cleared by autophagy when TBK-1 is unavailable and accumulates in the cell , TBK-1 is needed to enable the entry of p62 into autophagic degradative pathway , and several ubiquitinated cargo do not enter degradative pathways in the absence of TBK-1 .	Furthermore, ubiquitinated proteins accumulated in Tbk1 -/- cells revealed by pull-down assays in cellular extracts using TUBE-2 (tandem ubiquitin binding entities 2), which recognizes polyubiquitinated proteins and protects them from deubiquitinating enzymes and proteasome during isolation (XREF_FIG) Thus, p62 is not being cleared by autophagy when TBK-1 is unavailable and accumulates in the cell, TBK-1 is needed to enable the entry of p62 into autophagic degradative pathway, and several ubiquitinated cargo do not enter degradative pathways in the absence of TBK-1.	62	71	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK-1	TBK-1	TBK-1	p62	p62	p62	62	63	70	71
TBK1 enhances the enzymatic activity of IKKbeta by direct phosphorylation , and thus contributes to NF-kappaB activation 12 .	TBK1 enhances the enzymatic activity of IKKbeta by direct phosphorylation, and thus contributes to NF-kappaB activation 12.	0	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IKKbeta	IKKbeta	IKKbeta	0	1	6	7
93 TBK1 activates the NF and kappaB complex by activating IKKbeta .	93 TBK1 activates the NF and kappaB complex by activating IKKbeta.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	IKKbeta	IKKbeta	IKKbeta	1	2	10	11
IKK activation in turn is regulated by its upstream NF-kappaB activating kinase ( NAK ) , which activates IKKbeta through direct phosphorylation .	IKK activation in turn is regulated by its upstream NF-kappaB activating kinase (NAK), which activates IKKbeta through direct phosphorylation.	11	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NAK	NAK	NAK	IKKbeta	IKKbeta	IKKbeta	13	14	18	19
This supports the idea that TFIIS mediates the effect of UBR5 on CDK9 via a physical association of all three proteins in the same genomic regions .	This supports the idea that TFIIS mediates the effect of UBR5 on CDK9 via a physical association of all three proteins in the same genomic regions.	5	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TFIIS	TFIIS	TFIIS	UBR5	UBR5	UBR5	5	6	10	11
Because both TFIIS and P-TEFb stimulate transcriptional elongation by RNAPII , we hypothesized that TFIIS may potentiate the activity of P-TEFb by recruiting the E3 ubiquitin ligase UBR5 to facilitate CDK9 ubiquitination .	Because both TFIIS and P-TEFb stimulate transcriptional elongation by RNAPII, we hypothesized that TFIIS may potentiate the activity of P-TEFb by recruiting the E3 ubiquitin ligase UBR5 to facilitate CDK9 ubiquitination.	14	28	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TFIIS	TFIIS	TFIIS	UBR5	UBR5	UBR5	14	15	27	28
Lower T-bet levels in turn reduced the T-bet : Bcl-6 ratio , favoring the development of memory CD4 T cells at the expense of the terminal effector cells in p27-/- mice .	Lower T-bet levels in turn reduced the T-bet : Bcl-6 ratio, favoring the development of memory CD4 T cells at the expense of the terminal effector cells in p27-/- mice.	1	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	T-bet	T-bet levels	t-bet	T-bet	T-bet	t-bet	1	2	7	8
Conversely , reintroduction of a wild-type TARBP2 increases the Dicer stability , and thereby inhibits tumor growth XREF_BIBR .	Conversely, reintroduction of a wild-type TARBP2 increases the Dicer stability, and thereby inhibits tumor growth XREF_BIBR.	2	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TARBP2	TARBP2	TARBP2	Dicer	Dicer	Dicer	6	7	9	10
At the molecular level , HIF2alpha induces TGF-alpha expression , which in turns activates epidermal growth factor receptor ( EGFR )-dependent cell signaling and proliferation .	At the molecular level, HIF2alpha induces TGF-alpha expression, which in turns activates epidermal growth factor receptor (EGFR)-dependent cell signaling and proliferation.	5	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	HIF2alpha induces TGF-alpha expression	tgf-alpha	EGFR	EGFR	egfr	7	8	19	20
Consistent with this possibility , studies by Fidler and colleagues showed that tumor cell derived transforming growth factor-alpha activates EGFR on endothelial cells , and treatment with an EGFR inhibitor results in apoptosis of tumor associated endothelial cells and thus the surrounding tumor cells .	Consistent with this possibility, studies by Fidler and colleagues showed that tumor cell derived transforming growth factor-alpha activates EGFR on endothelial cells, and treatment with an EGFR inhibitor results in apoptosis of tumor associated endothelial cells and thus the surrounding tumor cells.	14	22	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	transforming growth factor-alpha	transforming growth factor-alpha	transforming growth factor-alpha	EGFR	EGFR	EGFR	15	18	19	20
After 3 days of permanent application , TGFalpha induced a major downregulation of both erbB1 and erbB2 .	After 3 days of permanent application, TGFalpha induced a major downregulation of both erbB1 and erbB2.	7	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	erbB1	erbB1	erbB1	7	8	14	15
This limitation can be overcome by treating cells with TGF-alpha because TGF-alpha stimulates EGFR endocytosis , but not degradation .	This limitation can be overcome by treating cells with TGF-alpha because TGF-alpha stimulates EGFR endocytosis, but not degradation.	11	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	11	12	13	14
The epidermal growth factor receptor ( EGFR ) , a tyrosine kinase receptor , is activated by growth factors of the transforming growth factor alpha ( TGFalpha ) family .	The epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, is activated by growth factors of the transforming growth factor alpha (TGFalpha) family.	1	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	transforming growth factor alpha	transforming growth factor alpha	transforming growth factor alpha	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	21	25	1	5
These results suggest that juxtacrine stimulation takes place in human tumor cells that coexpress both the EGF receptor and membrane anchored TGF-alpha and that TGF-alpha is able to induce its own endoproteolytic cleavage by activating the EGF receptor .	These results suggest that juxtacrine stimulation takes place in human tumor cells that coexpress both the EGF receptor and membrane anchored TGF-alpha and that TGF-alpha is able to induce its own endoproteolytic cleavage by activating the EGF receptor.	24	38	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGF receptor	EGF receptor	EGF receptor	24	25	36	38
Thus , stimulation with TGF-alpha prolongs EGFR signaling compared with EGF .	Thus, stimulation with TGF-alpha prolongs EGFR signaling compared with EGF.	2	7	prolongs	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	4	5	6	7
Briefly , stimulation with TNF alpha leads to a rapid release of TGF alpha ( TGFa in the model ) , which activates the EGF receptor ( EGFR ) .	Briefly, stimulation with TNF alpha leads to a rapid release of TGF alpha (TGFa in the model), which activates the EGF receptor (EGFR).	13	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFa	TGFa	TGFa	EGF receptor	EGF receptor	EGF receptor	15	16	24	26
This is supported by the ability of TGFalpha to rapidly induce COX-2 and the inhibition of the IFN-gamma-mediated COX-2 mRNA induction by an EGFR antibody and EGFR selective kinase inhibitors .	This is supported by the ability of TGFalpha to rapidly induce COX-2 and the inhibition of the IFN-gamma-mediated COX-2 mRNA induction by an EGFR antibody and EGFR selective kinase inhibitors.	2	29	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	7	8	26	27
For example , TGFalpha induced activation of EGFR signaling pathway greatly enhances invasion and motility of tamoxifen resistant cells [ XREF_BIBR ] .	For example, TGFalpha induced activation of EGFR signaling pathway greatly enhances invasion and motility of tamoxifen resistant cells [XREF_BIBR].	3	9	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	3	4	7	8
In a breast cancer mouse model , mucin 1 ( MUC1 for human and Muc1 for nonhuman species ) facilitated TGFalpha induced EGFR activation and breast cancer development XREF_BIBR , XREF_BIBR .	In a breast cancer mouse model, mucin 1 (MUC1 for human and Muc1 for nonhuman species) facilitated TGFalpha induced EGFR activation and breast cancer development XREF_BIBR, XREF_BIBR.	19	23	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	20	21	22	23
Autoradiographic localization of 125I-epidermal growth factor showed a similar pattern of distribution , suggesting that the sites of increased TGF-alpha expression induced epidermal growth factor receptor down-regulation .	Autoradiographic localization of 125I-epidermal growth factor showed a similar pattern of distribution, suggesting that the sites of increased TGF-alpha expression induced epidermal growth factor receptor down-regulation.	19	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha expression	tgf-alpha	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	19	20	22	26
It is well-known that activation of EGFR by TGFalpha or EGF leads to a rapid internalization of these receptors .	It is well-known that activation of EGFR by TGFalpha or EGF leads to a rapid internalization of these receptors.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	8	9	6	7
These findings suggest that fibrin supports the proliferation of keratinocytes in an autocrine fashion via EGF-R ; namely , fibrin stimulates keratinocytes to secrete TGF-alpha , which in turn increases cell proliferation and EGF-R capacity .	These findings suggest that fibrin supports the proliferation of keratinocytes in an autocrine fashion via EGF-R; namely, fibrin stimulates keratinocytes to secrete TGF-alpha, which in turn increases cell proliferation and EGF-R capacity.	23	34	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGF-R	EGF-R	EGF-R	24	25	33	34
In contrast , TGFalpha activates EGFR and is highly expressed in NSCLC [ XREF_BIBR ] .	In contrast, TGFalpha activates EGFR and is highly expressed in NSCLC [XREF_BIBR].	3	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	3	4	5	6
Thus , the increased number of EGF receptors in c-myc expressing hepatocytes , even after prolonged exposure to EGF , or TGF-alpha in vivo , may allow greater triggering of the EGF receptor signaling cascade .	Thus, the increased number of EGF receptors in c-myc expressing hepatocytes, even after prolonged exposure to EGF, or TGF-alpha in vivo, may allow greater triggering of the EGF receptor signaling cascade.	4	34	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	expressing hepatocytes, even after prolonged exposure to EGF, or TGF-alpha	tgf-alpha	EGF receptor	EGF receptor	egf receptor	21	22	31	33
Interestingly , it was recently shown that TGFalpha-null mice exhibited skeletal defects similar to those observed in the Tace-Col2 mice ( shorter long bones and an expansion of the hypertrophic zone ) XREF_BIBR , indicating that lack of EGFR signaling driven by TGFalpha is involved in the defects observed in Tace-col2 mice .	Interestingly, it was recently shown that TGFalpha-null mice exhibited skeletal defects similar to those observed in the Tace-Col2 mice (shorter long bones and an expansion of the hypertrophic zone) XREF_BIBR, indicating that lack of EGFR signaling driven by TGFalpha is involved in the defects observed in Tace-col2 mice.	38	43	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	42	43	38	39
Therefore the overexpression of TGFalpha induces the interaction of EGFR and MET , with subsequent phosphorylation and activation of MET and its effectors .	Therefore the overexpression of TGFalpha induces the interaction of EGFR and MET, with subsequent phosphorylation and activation of MET and its effectors.	2	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	overexpression of TGFalpha	tgfalpha	EGFR	EGFR	egfr	4	5	9	10
In contrast , most TGFalpha is dissociated in MVBs , allowing the EGFR to recycle to the plasma membrane .	In contrast, most TGFalpha is dissociated in MVBs, allowing the EGFR to recycle to the plasma membrane.	3	14	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	4	5	12	13
To examine whether the addition of exogenous TGF-alpha restores the EGFR signaling altered by selumetinib in irradiated A549 cells , the phosphorylation of EGFR and the downstream molecules , ERK1/2 and AKT , and the expression levels of survivin were assessed by immunoblotting ( XREF_FIG ) .	To examine whether the addition of exogenous TGF-alpha restores the EGFR signaling altered by selumetinib in irradiated A549 cells, the phosphorylation of EGFR and the downstream molecules, ERK1/2 and AKT, and the expression levels of survivin were assessed by immunoblotting (XREF_FIG).	4	11	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	7	8	10	11
Taken together , these data argue that TGFalpha and AR stimulate EGFR coupling to tumor cell aggressiveness and chemoresistance , while EGF fails to do so - and may in fact antagonize stimulation of pathogenic signaling by TGFalpha and AR .	Taken together, these data argue that TGFalpha and AR stimulate EGFR coupling to tumor cell aggressiveness and chemoresistance, while EGF fails to do so - and may in fact antagonize stimulation of pathogenic signaling by TGFalpha and AR.	7	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	7	8	11	12
It is apparent from these data that levels of EGFR protein expression are not simply associated with magnitude of ligand response as even cell lines with low levels of EGFR can show a marked stimulation when treated with TGFalpha .	It is apparent from these data that levels of EGFR protein expression are not simply associated with magnitude of ligand response as even cell lines with low levels of EGFR can show a marked stimulation when treated with TGFalpha.	27	39	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	38	39	29	30
While TGFalpha induced ADAM17-promoter activity by 2.2-fold exacerbating TGFalpha and EGFR driven growth , ectopic C/EBPbeta expression completely prevented this vicious synergy .	While TGFalpha induced ADAM17-promoter activity by 2.2-fold exacerbating TGFalpha and EGFR driven growth, ectopic C/EBPbeta expression completely prevented this vicious synergy.	1	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	1	2	10	11
Using the EGFR blocking antibody cetuximab in the absence of an additional EGFR stimulus such as the transforming growth factor-alpha , we found similar effects on the cytokine production of HPV16+ KCs .	Using the EGFR blocking antibody cetuximab in the absence of an additional EGFR stimulus such as the transforming growth factor-alpha, we found similar effects on the cytokine production of HPV16+ KCs.	12	20	stimulus	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	transforming growth factor-alpha	transforming growth factor-alpha	transforming growth factor-alpha	EGFR	EGFR	EGFR	17	20	12	13
Expression of TGFalpha in gliomas is well established and it has been demonstrated that there are no differences between EGF- or TGFalpha stimulated EGFR signaling events thus offering a compelling rationale for its use in our studies .	Expression of TGFalpha in gliomas is well established and it has been demonstrated that there are no differences between EGF- or TGFalpha stimulated EGFR signaling events thus offering a compelling rationale for its use in our studies.	17	25	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	21	22	23	24
In addition , the phosphorylation of EGFR and LOX expression in EGFR wild type NSCLC cell line A549 were both up-regulated when treated with the EGFR agonist TGF-alpha .	In addition, the phosphorylation of EGFR and LOX expression in EGFR wild type NSCLC cell line A549 were both up-regulated when treated with the EGFR agonist TGF-alpha.	9	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	27	28	11	12
We found that both TGF-alpha and TGF-beta1 activate the MAPK and PI3K pathways , yet these two factors activate distinct receptors ( TGF-alpha activates EGFR , while TGF-beta1 activates TGF beta receptor I and II ) .	We found that both TGF-alpha and TGF-beta1 activate the MAPK and PI3K pathways, yet these two factors activate distinct receptors (TGF-alpha activates EGFR, while TGF-beta1 activates TGF beta receptor I and II).	22	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	22	23	24	25
Here we demonstrate that sustained , TGFalpha mediated activation of EGFR is necessary for gliomagenesis in vivo , functionally substantiating the clinical observation that EGFR positive GBMs also express EGFR ligands .	Here we demonstrate that sustained, TGFalpha mediated activation of EGFR is necessary for gliomagenesis in vivo, functionally substantiating the clinical observation that EGFR positive GBMs also express EGFR ligands.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	6	7	10	11
To verify that MAPK was indeed activated as suggested by the multiplex EGFR phosphorylation data , C4-2B cells treated with EGF or TGF-alpha were probed for MAPK and activated MAPK .	To verify that MAPK was indeed activated as suggested by the multiplex EGFR phosphorylation data, C4-2B cells treated with EGF or TGF-alpha were probed for MAPK and activated MAPK.	12	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	22	23	12	13
This concept is based on TGFalpha , which naturally promotes EGFR recycling and is therefore a more potent mitogen than EGF [ XREF_BIBR , XREF_BIBR ] .	This concept is based on TGFalpha, which naturally promotes EGFR recycling and is therefore a more potent mitogen than EGF [XREF_BIBR, XREF_BIBR].	3	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	5	6	10	11
TGF-alpha stimulates the proliferation of HCC cells by activating the epidermal growth factor receptor signaling pathway .	TGF-alpha stimulates the proliferation of HCC cells by activating the epidermal growth factor receptor signaling pathway.	0	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	10	14
STAT3 is likely activated in SCCHN through autocrine activation of EGFR by TGF-alpha [ XREF_BIBR ] .	STAT3 is likely activated in SCCHN through autocrine activation of EGFR by TGF-alpha [XREF_BIBR].	3	14	activated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	12	13	10	11
TGFalpha directly activates the EGFR on these cells in vitro , inducing their proliferation , migration , and transformation to a phenotype that supports robust neurite outgrowth .	TGFalpha directly activates the EGFR on these cells in vitro, inducing their proliferation, migration, and transformation to a phenotype that supports robust neurite outgrowth.	0	5	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	0	1	4	5
Then , TGFalpha activates EGFR and multiple downstream intracellular signaling cascades required for DNA replication [ XREF_BIBR ] .	Then, TGFalpha activates EGFR and multiple downstream intracellular signaling cascades required for DNA replication [XREF_BIBR].	2	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	2	3	4	5
LNCaP and DU145 human PCA cells were treated with silibinin ( 100-200 microM ) for different time points , and the levels of TGFalpha , activated signaling molecules ( EGFR , Erk1/2 and Jnk1/2 ) and Erk1/2 kinase activity were analyzed employing ELISA , immunoprecipitation and/or immunoblotting techniques .	LNCaP and DU145 human PCA cells were treated with silibinin (100-200 microM) for different time points, and the levels of TGFalpha, activated signaling molecules (EGFR, Erk1/2 and Jnk1/2) and Erk1/2 kinase activity were analyzed employing ELISA, immunoprecipitation and/or immunoblotting techniques.	21	33	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	levels of TGFalpha	tgfalpha	EGFR	EGFR	egfr	23	24	29	30
Another pathway associated with alcohol exposure is transforming growth factor alpha ( TGFalpha ) activation of the epidermal growth factor receptor ( EGFR ) and p42 and p44 mitogen kinase ( MAPK ) and PI3K and AKT pathways .	Another pathway associated with alcohol exposure is transforming growth factor alpha (TGFalpha) activation of the epidermal growth factor receptor (EGFR) and p42 and p44 mitogen kinase (MAPK) and PI3K and AKT pathways.	12	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	12	13	17	21
Thus , IL-1beta , IL-6 , TGFalpha and TNFalpha appear to signal upstream of EGFR to induce release of MUC5AC .	Thus, IL-1beta, IL-6, TGFalpha and TNFalpha appear to signal upstream of EGFR to induce release of MUC5AC.	2	15	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	6	7	14	15
In one of these studies , TGFalpha mediated activation of erbB1 receptors in tanycytes of the ME was shown to promote tanycytic outgrowth , and a PGE 2 -dependent production of TGFbeta1 ( XREF_FIG ) , which then elicitedretraction of the tanycytic processes .	In one of these studies, TGFalpha mediated activation of erbB1 receptors in tanycytes of the ME was shown to promote tanycytic outgrowth, and a PGE 2 -dependent production of TGFbeta1 (XREF_FIG), which then elicitedretraction of the tanycytic processes.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	erbB1	erbB1	erbB1	6	7	10	11
We also show that EGFR activation by its potent ligand TGF-alpha induces reactivation of EGFR via binding of endogenously produced CCL20 to its receptor CCR6 in NCI-H292 cells but not in normal human bronchial epithelial ( NHBE ) cells , exaggerating mucin production in the NCI-H292 cells .	We also show that EGFR activation by its potent ligand TGF-alpha induces reactivation of EGFR via binding of endogenously produced CCL20 to its receptor CCR6 in NCI-H292 cells but not in normal human bronchial epithelial (NHBE) cells, exaggerating mucin production in the NCI-H292 cells.	4	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	10	11	4	5
TGF-alpha failed to modulate EGF-R .	TGF-alpha failed to modulate EGF-R.	0	5	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGF-R	EGF-R	EGF-R	0	1	4	5
Both of these steps are critical to TGFA mediated EGFR activation and are dysregulated in a number of diseases .	Both of these steps are critical to TGFA mediated EGFR activation and are dysregulated in a number of diseases.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFA	TGFA	TGFA	EGFR	EGFR	EGFR	7	8	9	10
Interestingly , both ligands initially induced ubiquitination and endocytosis of the EGFR to the same extent , even though TGFalpha very inefficiently induced transport of the EGFR to internal vesicles of MVBs and lysosomal degradation of the EGFR .	Interestingly, both ligands initially induced ubiquitination and endocytosis of the EGFR to the same extent, even though TGFalpha very inefficiently induced transport of the EGFR to internal vesicles of MVBs and lysosomal degradation of the EGFR.	19	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	19	20	26	27
Although transmembrane TGF-alpha potently activates the EGFR , its presentation at the cell surface and its interaction with the EGFR may be regulated by accessory proteins .	Although transmembrane TGF-alpha potently activates the EGFR, its presentation at the cell surface and its interaction with the EGFR may be regulated by accessory proteins.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	2	3	6	7
This result is consistent with the higher level of juxtacrine EGFR stimulation of 32D cells by TGF-alpha and CD9 coexpressing CHO cells , when compared with TGF-alpha-expressing cells ( XREF_FIG A ) .	This result is consistent with the higher level of juxtacrine EGFR stimulation of 32D cells by TGF-alpha and CD9 coexpressing CHO cells, when compared with TGF-alpha-expressing cells (XREF_FIG A).	10	18	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	16	17	10	11
After 786-0 cells have been cultured for 72h in the absence of serum , addition of exogenous TGF-alpha activated EGFR signalling and reinitiated cell proliferation .	After 786-0 cells have been cultured for 72h in the absence of serum, addition of exogenous TGF-alpha activated EGFR signalling and reinitiated cell proliferation.	14	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	17	18	19	20
Physiologically , ligands such as TGFalpha that promote EGFR recycling rather than lysosomal degradation appear to engage the Cbl and ubiquitin machinery more transiently [ XREF_BIBR , XREF_BIBR ] .	Physiologically, ligands such as TGFalpha that promote EGFR recycling rather than lysosomal degradation appear to engage the Cbl and ubiquitin machinery more transiently [XREF_BIBR, XREF_BIBR].	2	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	5	6	8	9
The level of EGFR protein in PC3 treated with TGFalpha was 2.28 0.53 , higher than in the control group ( P < 0.05 ) ; however , the level of EGFR protein in ARCaP treated with TGFalpha was only 1.24 0.22 , not different from the control ( P > 0.05 ) .	The level of EGFR protein in PC3 treated with TGFalpha was 2.28 0.53, higher than in the control group (P < 0.05); however, the level of EGFR protein in ARCaP treated with TGFalpha was only 1.24 0.22, not different from the control (P> 0.05).	31	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	37	38	31	32
U0126 treatment did not affect TGFalpha induced activation of EGFR , Akt , P70S6K , but it blocked ERK1/2 and CREB phosphorylation ( XREF_FIG ) .	U0126 treatment did not affect TGFalpha induced activation of EGFR, Akt, P70S6K, but it blocked ERK1/2 and CREB phosphorylation (XREF_FIG).	5	13	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	5	6	9	10
This was further supported by the observation that membrane anchored TGFA activated EGFR and cell proliferation [ XREF_BIBR ] .	This was further supported by the observation that membrane anchored TGFA activated EGFR and cell proliferation [XREF_BIBR].	9	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFA	TGFA	TGFA	EGFR	EGFR	EGFR	10	11	12	13
Our results indicate that hypoxia causes gefitinib resistance in EGFR-mutant NSCLC through the activation of wild-type EGFR mediated by the upregulation of TGFalpha .	Our results indicate that hypoxia causes gefitinib resistance in EGFR-mutant NSCLC through the activation of wild-type EGFR mediated by the upregulation of TGFalpha.	13	23	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	22	23	16	17
However , when HGC-27 cells were transfected with the EGFR WT plasmid ( XREF_SUPPLEMENTARY ) or treated with EGF or TGF-alpha to up-regulate EGFR expression ( XREF_SUPPLEMENTARY ) , the proportion of cells undergoing early apoptosis in DT-13-TPT combination treatment group was increased and the cleaved PARP protein level was up-regulated .	However, when HGC-27 cells were transfected with the EGFR WT plasmid (XREF_SUPPLEMENTARY) or treated with EGF or TGF-alpha to up-regulate EGFR expression (XREF_SUPPLEMENTARY), the proportion of cells undergoing early apoptosis in DT-13-TPT combination treatment group was increased and the cleaved PARP protein level was up-regulated.	6	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	20	21	9	10
These findings are consistent with other studies which report TGFalpha induced activation of EGFR mediates Bcl-2 induction in NCI-H292 cells and in gastric mucosal cells .	These findings are consistent with other studies which report TGFalpha induced activation of EGFR mediates Bcl-2 induction in NCI-H292 cells and in gastric mucosal cells.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	9	10	13	14
TGF-alpha , similar to EGF , may stimulate prolonged EGFR signaling in the endosome , whereas AREG causes increased receptor localization to cell-cell junctions and does not appear to trigger signaling from the endosomal compartment .	TGF-alpha, similar to EGF, may stimulate prolonged EGFR signaling in the endosome, whereas AREG causes increased receptor localization to cell-cell junctions and does not appear to trigger signaling from the endosomal compartment.	0	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	0	1	9	10
Similar to previous reports in HT-29 cells and mammary epithelial cells , TNFalpha treatment led to transactivation of the EGFR by TGFalpha in the RAS-variant cells .	Similar to previous reports in HT-29 cells and mammary epithelial cells, TNFalpha treatment led to transactivation of the EGFR by TGFalpha in the RAS-variant cells.	14	25	led	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	21	22	19	20
In one pathway , IAV induced TGF-alpha secretion that activated EGFR on AECs .	In one pathway, IAV induced TGF-alpha secretion that activated EGFR on AECs.	6	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	6	7	10	11
XREF_BIBR In addition , overexpression of TGF-alpha , a ligand for EGFR , resulted in activation of the EGFR pathway and subsequent resistance to MET inhibitors .	XREF_BIBR In addition, overexpression of TGF-alpha, a ligand for EGFR, resulted in activation of the EGFR pathway and subsequent resistance to MET inhibitors.	4	19	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	TGF-alpha	overexpression of TGF-alpha	tgf-alpha	EGFR	EGFR	egfr	6	7	18	19
However , subsequently there is a cascade of signals that activate EGFr , both via the soluble tyrosine kinases Pyk2 and Src , and also secondary to the release from epithelial cells of the EGFr ligand , transforming growth factor-alpha ( TGF-alpha ) .	However, subsequently there is a cascade of signals that activate EGFr, both via the soluble tyrosine kinases Pyk2 and Src, and also secondary to the release from epithelial cells of the EGFr ligand, transforming growth factor-alpha (TGF-alpha).	8	42	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFr	EGFr	EGFr	41	42	11	12
Therefore , our data indicate that normal EGFR activation by TGF-alpha contributes to bone metastasis and that over expression of EGFR may facilitate bone metastasis .	Therefore, our data indicate that normal EGFR activation by TGF-alpha contributes to bone metastasis and that over expression of EGFR may facilitate bone metastasis.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	10	11	7	8
41 We therefore investigated whether delayed phosphorylation of Met may be occurring through TGFalpha stimulation of EGFR .	41 We therefore investigated whether delayed phosphorylation of Met may be occurring through TGFalpha stimulation of EGFR.	13	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	13	14	16	17
Increased autocrine EGFR activation by TGF-alpha ligands drives carcinoma progression .	Increased autocrine EGFR activation by TGF-alpha ligands drives carcinoma progression.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	5	6	2	3
One possibility is that within the lower pH in endosomes , EGF-EGFR remains stably bound but TGF-alpha rapidly dissociates , allowing efficient EGFR recycling from endosome-to-plasma membrane .	One possibility is that within the lower pH in endosomes, EGF-EGFR remains stably bound but TGF-alpha rapidly dissociates, allowing efficient EGFR recycling from endosome-to-plasma membrane.	16	23	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	16	17	22	23
Interestingly , in addition to TGFA mRNA upregulation , TGFA autocrine activation of EGFR also induces TGFA cleavage [ XREF_BIBR , XREF_BIBR ] .	Interestingly, in addition to TGFA mRNA upregulation, TGFA autocrine activation of EGFR also induces TGFA cleavage [XREF_BIBR, XREF_BIBR].	9	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFA	TGFA	TGFA	EGFR	EGFR	EGFR	9	10	13	14
Expression of either form of TGFalpha causes constitutive EGFR coupling to cell proliferation , whereas expression of mature EGF does not ( XREF_FIG ) .	Expression of either form of TGFalpha causes constitutive EGFR coupling to cell proliferation, whereas expression of mature EGF does not (XREF_FIG).	3	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	5	6	8	9
Ras-CM and TGF-alpha also increase PI3-K activity downstream of the EGFR and increase postradiation survival , both of which are abrogated by GW572016 .	Ras-CM and TGF-alpha also increase PI3-K activity downstream of the EGFR and increase postradiation survival, both of which are abrogated by GW572016.	0	20	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	2	3	10	11
This releases soluble , active TGF-alpha , which activates the EGFR .	This releases soluble, active TGF-alpha, which activates the EGFR.	1	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	5	6	10	11
Autocrine stimulation of EGF-R by TGF-alpha does not cause malignant transformation of the colonic epithelial cell .	Autocrine stimulation of EGF-R by TGF-alpha does not cause malignant transformation of the colonic epithelial cell.	1	6	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGF-R	EGF-R	EGF-R	5	6	3	4
Then TGF-alpha stimulation was utilized to activate EGFR .	Then TGF-alpha stimulation was utilized to activate EGFR.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	1	2	7	8
The induction of autocrine TGFalpha mediated EGFR activation in the G 1 phase of the cell cycle is an essential event for DNA synthesis in these cells , and the upregulation of EGFR via the autocrine production of TGFalpha is an event lying downstream of the activation of the IGF1R .	The induction of autocrine TGFalpha mediated EGFR activation in the G 1 phase of the cell cycle is an essential event for DNA synthesis in these cells, and the upregulation of EGFR via the autocrine production of TGFalpha is an event lying downstream of the activation of the IGF1R.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	4	5	6	7
Unlike EGF , TGF-alpha upregulated additional EGFR , PDGFR-beta , bFGF , and TGF-beta 1 , suggesting that although they share the same EGFR , TGF-alpha , which is produced by epithelium , is more effective in activating fibroblasts than EGF , which is present in tears .	Unlike EGF, TGF-alpha upregulated additional EGFR, PDGFR-beta, bFGF, and TGF-beta 1, suggesting that although they share the same EGFR, TGF-alpha, which is produced by epithelium, is more effective in activating fibroblasts than EGF, which is present in tears.	3	13	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	3	4	6	7
Mechanistically , high STAT3 activity was suggested to be the result of high EGFR activity , which was triggered by TGF-alpha [ XREF_BIBR ] .	Mechanistically, high STAT3 activity was suggested to be the result of high EGFR activity, which was triggered by TGF-alpha [XREF_BIBR].	13	22	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	20	21	13	14
These data and ours suggest that TGFalpha and AR stimulate EGFR coupling to tumor cell aggressiveness and chemoresistance , whereas EGF does so to a much lesser extent and may antagonize stimulation of pathogenic EGFR signaling by TGFalpha and AR .	These data and ours suggest that TGFalpha and AR stimulate EGFR coupling to tumor cell aggressiveness and chemoresistance, whereas EGF does so to a much lesser extent and may antagonize stimulation of pathogenic EGFR signaling by TGFalpha and AR.	6	11	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	6	7	10	11
In addition to abrogating PDK1 mediated activation of proliferative and motility effectors such as p70S6K and PAK1 , inhibition of TACE mediated release of TGF-alpha mediated by PGE2 and BK may enhance the inhibitory efficacy of EGFR blockade and its consequent autocrine release of EGFR ligands .	In addition to abrogating PDK1 mediated activation of proliferative and motility effectors such as p70S6K and PAK1, inhibition of TACE mediated release of TGF-alpha mediated by PGE2 and BK may enhance the inhibitory efficacy of EGFR blockade and its consequent autocrine release of EGFR ligands.	22	37	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	24	25	36	37
Surprisingly , the ICAM-1 ( 8-22 ) peptide increased EGFR phosphotyrosine and phospho-ERK1/2 in cells treated with TGF-alpha .	Surprisingly, the ICAM-1 (8-22) peptide increased EGFR phosphotyrosine and phospho-ERK1/2 in cells treated with TGF-alpha.	9	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	17	18	9	10
In turn , TGFalpha stimulated EGFR which potentiated SMAD signaling , reinforcing EMT and metastasis .	In turn, TGFalpha stimulated EGFR which potentiated SMAD signaling, reinforcing EMT and metastasis.	3	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	3	4	5	6
TGF-alpha was used as a negative control since we have data indicating that the activation of EGFR by TGF-alpha is independent of CD44v6 ( I. Morath , C. Jung and V. Orian-Rousseau , unpublished data ) .	TGF-alpha was used as a negative control since we have data indicating that the activation of EGFR by TGF-alpha is independent of CD44v6 (I. Morath, C. Jung and V. Orian-Rousseau, unpublished data).	14	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	18	19	16	17
However , high dietary P may not affect parathyroid TACE expression directly , but induce its translocation to the cell surface for the release of TGFalpha required to initiate EGFR driven parathyroid cell growth and TACE stabilization .	However, high dietary P may not affect parathyroid TACE expression directly, but induce its translocation to the cell surface for the release of TGFalpha required to initiate EGFR driven parathyroid cell growth and TACE stabilization.	23	30	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	25	26	29	30
Tyrosine phosphorylation of EGF receptor from cells treated with TGF-alpha decreased more rapidly following removal of TGF-alpha compared to cells treated similarly with EGF .	Tyrosine phosphorylation of EGF receptor from cells treated with TGF-alpha decreased more rapidly following removal of TGF-alpha compared to cells treated similarly with EGF.	3	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGF receptor	EGF receptor	EGF receptor	9	10	3	5
In contrast , neutralizing TGF-alpha in TCDD treated cells significantly enhanced EGFR down-regulation ( 11 +/- 1 % of basal control levels ) , suggesting that TGF-alpha promotes receptor recycling rather than down-regulation .	In contrast, neutralizing TGF-alpha in TCDD treated cells significantly enhanced EGFR down-regulation (11 +/- 1% of basal control levels), suggesting that TGF-alpha promotes receptor recycling rather than down-regulation.	3	12	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	4	5	11	12
In contrast , ERBB1 was activated by TGF-alpha in all lines , indicating the presence of functional receptors ( XREF_FIG ) .	In contrast, ERBB1 was activated by TGF-alpha in all lines, indicating the presence of functional receptors (XREF_FIG).	3	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	ERBB1	ERBB1	ERBB1	7	8	3	4
Western blot data revealed that TGF-alpha activated EGFR , but gefitinib was able to inhibit the activity of EGFR as shown by the decreased pEGFR level ( XREF_FIG a ) .	Western blot data revealed that TGF-alpha activated EGFR, but gefitinib was able to inhibit the activity of EGFR as shown by the decreased pEGFR level (XREF_FIG a).	5	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	5	6	7	8
Here we use isoform specific EGFR and ErbB2 antibodies to show that the duration of EGFR signalling induced by a single TGFalpha exposure is less than that induced by equimolar EGF .	Here we use isoform specific EGFR and ErbB2 antibodies to show that the duration of EGFR signalling induced by a single TGFalpha exposure is less than that induced by equimolar EGF.	15	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	21	22	15	16
Activation of TACE by p38 MAP kinase results in the release of TGF-alpha family ligands , which activate EGF receptor signaling leading to enhanced cell proliferation .	Activation of TACE by p38 MAP kinase results in the release of TGF-alpha family ligands, which activate EGF receptor signaling leading to enhanced cell proliferation.	12	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGF receptor	EGF receptor	EGF receptor	12	13	18	20
Preclinical data indicate that 1 mechanism of neoplastic cell resistance to radiation therapy is through paracrine activation of EGFR by transforming growth factor alpha ( TGF-alpha ) , which is released after radiation exposure .	Preclinical data indicate that 1 mechanism of neoplastic cell resistance to radiation therapy is through paracrine activation of EGFR by transforming growth factor alpha (TGF-alpha), which is released after radiation exposure.	16	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	transforming growth factor alpha	transforming growth factor alpha	transforming growth factor alpha	EGFR	EGFR	EGFR	20	24	18	19
The MMP inhibitors also abolished leptin induced proliferation as well as leptin induced EGFR tyrosine phosphorylation , but did not affect proliferation or EGFR activation induced by TGFalpha .	The MMP inhibitors also abolished leptin induced proliferation as well as leptin induced EGFR tyrosine phosphorylation, but did not affect proliferation or EGFR activation induced by TGFalpha.	21	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	27	28	23	24
Thus , we are putting forth a model where the apex of the vicious cycle is the activation of EGFR by TGF-alpha which results in the release of RANKL ( XREF_FIG ) , suggesting that osteoclast differentiation is directly mediated by the tumor cell in response to TGF-alpha .	Thus, we are putting forth a model where the apex of the vicious cycle is the activation of EGFR by TGF-alpha which results in the release of RANKL (XREF_FIG), suggesting that osteoclast differentiation is directly mediated by the tumor cell in response to TGF-alpha.	17	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	21	22	19	20
High activity of STAT3 during the carcinogenesis of ICC may be the result of high activity of EGFR triggered by TGFalpha .	High activity of STAT3 during the carcinogenesis of ICC may be the result of high activity of EGFR triggered by TGFalpha.	15	21	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	20	21	17	18
Accordingly , TGFalpha will be released in early endosomes , allowing the EGFR to recycle to the plasma membrane .	Accordingly, TGFalpha will be released in early endosomes, allowing the EGFR to recycle to the plasma membrane.	2	14	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	2	3	12	13
Autocrine stimulation of EGFr by TGFa or other unrecognized factors may be present in CaP .	Autocrine stimulation of EGFr by TGFa or other unrecognized factors may be present in CaP.	1	9	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGFa	TGFa	TGFa	EGFr	EGFr	EGFr	5	6	3	4
Increased shedding of TGF-alpha ligands enhances EGFR activation , resulting in epithelial cell proliferation and carcinoma progression .	Increased shedding of TGF-alpha ligands enhances EGFR activation, resulting in epithelial cell proliferation and carcinoma progression.	3	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	3	4	6	7
The relative mRNA level of EGFR in blastocysts treated with TGF-alpha was higher than that of the control .	The relative mRNA level of EGFR in blastocysts treated with TGF-alpha was higher than that of the control.	3	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	10	11	5	6
Introduction of the reported helix disrupting R656 ,657 G mutation impaired EGF- and TGFalpha dependent activation of wild-type EGFR to the same extent ( XREF_FIG ) .	Introduction of the reported helix disrupting R656,657 G mutation impaired EGF- and TGFalpha dependent activation of wild-type EGFR to the same extent (XREF_FIG).	13	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	13	14	18	19
Taken together , the observation of robust ReAsH fluorescence when cells expressing either CC H -9 or CC H -10 are treated with TGF-alpha-provides compelling evidence that the antiparallel helical structures in cluster 1 best represent the JM when EGFR is activated by TGF-alpha .	Taken together, the observation of robust ReAsH fluorescence when cells expressing either CC H -9 or CC H -10 are treated with TGF-alpha-provides compelling evidence that the antiparallel helical structures in cluster 1 best represent the JM when EGFR is activated by TGF-alpha.	39	44	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	43	44	39	40
The authors proposed that in tumour cells , TGFalpha mediated EGFR activation induces EGFR and c-Met interaction , detectable as co-immunoprecipitation and resulting in increased c-Met phosphorylation and signalling [ XREF_BIBR ] .	The authors proposed that in tumour cells, TGFalpha mediated EGFR activation induces EGFR and c-Met interaction, detectable as co-immunoprecipitation and resulting in increased c-Met phosphorylation and signalling [XREF_BIBR].	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	8	9	10	11
Having observed increased TGF-alpha release in response to TNF-alpha and considering the ability of a metalloproteinase inhibitor to attenuate both TGF-alpha release and EGFR phosphorylation , we next asked whether specific blockade of TGF-alpha using a neutralizing antibody could block both EGFR and ERK activations .	Having observed increased TGF-alpha release in response to TNF-alpha and considering the ability of a metalloproteinase inhibitor to attenuate both TGF-alpha release and EGFR phosphorylation, we next asked whether specific blockade of TGF-alpha using a neutralizing antibody could block both EGFR and ERK activations.	31	44	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	33	34	41	42
Here , we show that C. albicans induces hBD-2 through an autocrine IL-1beta loop and that activation of the epidermal growth factor receptor ( EGFR ) by endogenous transforming growth factor-alpha ( TGF-alpha ) is a crucial event in the induction of hBD-3 .	Here, we show that C. albicans induces hBD-2 through an autocrine IL-1beta loop and that activation of the epidermal growth factor receptor (EGFR) by endogenous transforming growth factor-alpha (TGF-alpha) is a crucial event in the induction of hBD-3.	16	31	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	transforming growth factor-alpha	transforming growth factor-alpha	transforming growth factor-alpha	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	28	31	19	23
The LNCaP proliferation data suggest that EGF and TGF-alpha mediated activation of EGFR activate different intra-cellular signals .	The LNCaP proliferation data suggest that EGF and TGF-alpha mediated activation of EGFR activate different intra-cellular signals.	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	8	9	12	13
TGFA mediated activation of EGFR leads to upregulation of TGFA mRNA and protein in normal keratinocytes as well as colorectal carcinoma cell lines [ XREF_BIBR , XREF_BIBR ] .	TGFA mediated activation of EGFR leads to upregulation of TGFA mRNA and protein in normal keratinocytes as well as colorectal carcinoma cell lines [XREF_BIBR, XREF_BIBR].	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFA	TGFA	TGFA	EGFR	EGFR	EGFR	0	1	4	5
There was very little EGFR immunoreactivity in uninjured animals treated with either vehicle or TGF-alpha ( XREF_FIG ) .	There was very little EGFR immunoreactivity in uninjured animals treated with either vehicle or TGF-alpha (XREF_FIG).	4	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	14	15	4	5
Bipartite Tetracysteine Display Reveals the Antiparallel JM Interaction is Not Present when EGFR is Activated by TGFalpha .	Bipartite Tetracysteine Display Reveals the Antiparallel JM Interaction is Not Present when EGFR is Activated by TGFalpha.	12	17	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	16	17	12	13
The authors suggested that the inhibition of TGF-alpha cleavage feeds into enhanced TGF-alpha induced EGFR activation , which can increase cellular proliferation .	The authors suggested that the inhibition of TGF-alpha cleavage feeds into enhanced TGF-alpha induced EGFR activation, which can increase cellular proliferation.	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	12	13	14	15
Consistent with this finding , we first provided evidence that EGCG indeed inhibits EGFR activation in HNSCC cell line that displays autocrine activation of EGFR by TGF-alpha [ XREF_BIBR ] .	Consistent with this finding, we first provided evidence that EGCG indeed inhibits EGFR activation in HNSCC cell line that displays autocrine activation of EGFR by TGF-alpha [XREF_BIBR].	22	28	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	26	27	24	25
TGFalpha dependent activation of EGFR induces resistance .	TGFalpha dependent activation of EGFR induces resistance.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	0	1	4	5
Different upstream signals can induce different phosphorylation patterns on ErbB receptors-for example , in the case of EGF versus TGFalpha stimulation of EGFR .	Different upstream signals can induce different phosphorylation patterns on ErbB receptors-for example, in the case of EGF versus TGFalpha stimulation of EGFR.	19	23	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	19	20	22	23
With the use of an autocrine system of MDCK cells co-expressing CD9 and TGF-alpha , TGF-alpha stimulation promoted EGFR activation .	With the use of an autocrine system of MDCK cells co-expressing CD9 and TGF-alpha, TGF-alpha stimulation promoted EGFR activation.	15	19	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	15	16	18	19
Expression of TGFalpha in 32D/EGFR cells causes greater EGFR coupling to cell proliferation than does expression of EGF .	Expression of TGFalpha in 32D/EGFR cells causes greater EGFR coupling to cell proliferation than does expression of EGF.	0	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	Expression of TGFalpha	tgfalpha	EGFR	EGFR	egfr	2	3	8	9
Consequently , this study indicates , for the first time , that IGF-IR activation up-regulates components of the TGFalpha autocrine loop resulting in TGFalpha mediated EGFr activation which was critical for IGF-IR mediated re-entry into the cell cycle from the growth arrested state .	Consequently, this study indicates, for the first time, that IGF-IR activation up-regulates components of the TGFalpha autocrine loop resulting in TGFalpha mediated EGFr activation which was critical for IGF-IR mediated re-entry into the cell cycle from the growth arrested state.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFr	EGFr	EGFr	23	24	25	26
Soluble TGFalpha binds to and activates the EGFR [ XREF_BIBR ] causing renal parenchymal lesions , including glomerulosclerosis , tubular atrophy and/or dilation with microcyst formation , mild interstitial fibrosis , and multifocal mononuclear cell infiltration accompanied by severe proteinuria .	Soluble TGFalpha binds to and activates the EGFR [XREF_BIBR] causing renal parenchymal lesions, including glomerulosclerosis, tubular atrophy and/or dilation with microcyst formation, mild interstitial fibrosis, and multifocal mononuclear cell infiltration accompanied by severe proteinuria.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	1	2	7	8
TGF-alpha leads to sustained EGFR signaling and , therefore , is more mitogenic than EGF [ Waterman et al ., 1998 ] .	TGF-alpha leads to sustained EGFR signaling and, therefore, is more mitogenic than EGF [Waterman et al., 1998].	0	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	0	1	4	5
More specifically , the IGF1R pathway induces both transforming growth factor alpha ( TGFalpha )-mediated activation of EGFR and stimulation of EGFR independent PI3K and AKT activity .	More specifically, the IGF1R pathway induces both transforming growth factor alpha (TGFalpha)-mediated activation of EGFR and stimulation of EGFR independent PI3K and AKT activity.	13	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	13	14	17	18
In addition , the mutated KRAS also leads to increased TGF-alpha expression , which further stimulates the EGFR [ XREF_BIBR ] .	In addition, the mutated KRAS also leads to increased TGF-alpha expression, which further stimulates the EGFR [XREF_BIBR].	5	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	KRAS also leads to increased TGF-alpha expression	tgf-alpha	EGFR	EGFR	egfr	10	11	17	18
These ligands and receptor changes enhance the activity of the autocrine loop that sustains the monolayer with TGF-alpha promoting EGFR recycling and upregulation as well as sustained levels of ERK activity that promote homeostatic replacement of cells during the culture period .	These ligands and receptor changes enhance the activity of the autocrine loop that sustains the monolayer with TGF-alpha promoting EGFR recycling and upregulation as well as sustained levels of ERK activity that promote homeostatic replacement of cells during the culture period.	13	20	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	17	18	19	20
Here we use both an ErbB2 phosphoantibody ( aPY1222 ) and an activation specific EGFR antibody to show that low concentrations of EGF induce more efficient tyrosine phosphorylation of ErbB2 in A431 cells than does equimolar TGFalpha , while EGFR is more potently activated by TGFalpha .	Here we use both an ErbB2 phosphoantibody (aPY1222) and an activation specific EGFR antibody to show that low concentrations of EGF induce more efficient tyrosine phosphorylation of ErbB2 in A431 cells than does equimolar TGFalpha, while EGFR is more potently activated by TGFalpha.	39	46	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	45	46	39	40
This latter route is followed by TGFalpha driven homodimers of ErbB-1 , and also by E4T bound receptors , whose signaling is further enhanced by repeated cycles of binding and dissociation from the receptors .	This latter route is followed by TGFalpha driven homodimers of ErbB-1, and also by E4T bound receptors, whose signaling is further enhanced by repeated cycles of binding and dissociation from the receptors.	4	11	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	ErbB-1	ErbB-1	ErbB-1	6	7	10	11
The spatial requirements for ReAsH binding also enabled the discovery that this same antiparallel coiled coil does not form when EGFR is activated by the related ligand TGFalpha , and that instead a discrete , alternate ( but still helical and dimeric ) JM interaction occurs .	The spatial requirements for ReAsH binding also enabled the discovery that this same antiparallel coiled coil does not form when EGFR is activated by the related ligand TGFalpha, and that instead a discrete, alternate (but still helical and dimeric) JM interaction occurs.	20	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	27	28	20	21
This property was subsequently found to be dependent on the activation of EGFR by TGF-alpha or EGF XREF_BIBR , XREF_BIBR .	This property was subsequently found to be dependent on the activation of EGFR by TGF-alpha or EGF XREF_BIBR, XREF_BIBR.	10	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	14	15	12	13
Pretreatment of KGN cells with wortmannin blocked the effect of TGFalpha on the activation of Akt and p70S6K , but did not affect TGFalpha activation of EGFR , ERK1/2 , P38 or CREB in the KGN cells ( XREF_FIG ) .	Pretreatment of KGN cells with wortmannin blocked the effect of TGFalpha on the activation of Akt and p70S6K, but did not affect TGFalpha activation of EGFR, ERK1/2, P38 or CREB in the KGN cells (XREF_FIG).	23	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	23	24	26	27
Similarly , in nodular hyperplasia , which is the most severe form of SH and the most resistant to calcitriol therapy , higher TGF-alpha activation of the EGFR was associated with an 80 % reduction in VDR mRNA levels .	Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-alpha activation of the EGFR was associated with an 80% reduction in VDR mRNA levels.	23	28	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	23	24	27	28
Thus there is a node that represents EGFR on the plasma membrane activated by EGF and a node for EGFR activated by TGF-alpha .	Thus there is a node that represents EGFR on the plasma membrane activated by EGF and a node for EGFR activated by TGF-alpha.	12	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	22	23	19	20
TGF-alpha autocrine activation of EGF-R has been suggested as a potential mechanism contributing to abnormal growth control in colon cancer .	TGF-alpha autocrine activation of EGF-R has been suggested as a potential mechanism contributing to abnormal growth control in colon cancer.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGF-R	EGF-R	EGF-R	0	1	4	5
These data indicate that constitutive EGFR activation , potentially driven by autocrine or paracrine TGFalpha signaling , promotes the aggressive invasive behavior characteristic of MPNSTs .	These data indicate that constitutive EGFR activation, potentially driven by autocrine or paracrine TGFalpha signaling, promotes the aggressive invasive behavior characteristic of MPNSTs.	5	15	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	14	15	5	6
Moreover , there are reports of bile acids , including DCA , CDCA and TCDCA , induced cell growth and EGFR activation by the transforming growth factor-alpha ( TGF-alpha ) , ligand dependent mechanism in human CCA KMBC and normal cholangiocyte H69 cell lines .	Moreover, there are reports of bile acids, including DCA, CDCA and TCDCA, induced cell growth and EGFR activation by the transforming growth factor-alpha (TGF-alpha), ligand dependent mechanism in human CCA KMBC and normal cholangiocyte H69 cell lines.	16	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	28	29	20	21
Our previous work demonstrated that EGFR activation by TGFalpha promotes proliferation in cultured chondrocytes .	Our previous work demonstrated that EGFR activation by TGFalpha promotes proliferation in cultured chondrocytes.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	8	9	5	6
We conclude that E-cadherin inhibits growth of HT29 cells by inhibiting either TGF-alpha stimulation of EGFR kinase activity or serum stimulation of an uncharacterized mitogenic pathway .	We conclude that E-cadherin inhibits growth of HT29 cells by inhibiting either TGF-alpha stimulation of EGFR kinase activity or serum stimulation of an uncharacterized mitogenic pathway.	12	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	12	13	15	16
Surprisingly , transforming growth factor-alpha ( TGFalpha ) , which also activates EGFR , did not bring these two cysteine pairs together in the same way - arguing that TGFalpha does not induce formation of the same intracellular antiparallel coiled coil .	Surprisingly, transforming growth factor-alpha (TGFalpha), which also activates EGFR, did not bring these two cysteine pairs together in the same way - arguing that TGFalpha does not induce formation of the same intracellular antiparallel coiled coil.	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	6	7	12	13
In this study , EGFR transactivation and ERK activation could both be blocked by neutralizing TGF-alpha , in contrast to AG1478 which does not block ERK activation to the same degree as it blocks EGFR phosphorylation , suggesting that TGF-alpha may activate another EGFR family receptor leading to the activation of ERK .	In this study, EGFR transactivation and ERK activation could both be blocked by neutralizing TGF-alpha, in contrast to AG1478 which does not block ERK activation to the same degree as it blocks EGFR phosphorylation, suggesting that TGF-alpha may activate another EGFR family receptor leading to the activation of ERK.	39	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	39	40	43	44
The authors suggested that exogenous EGF and TGFalpha may alter the activity of phosphatases that then dephosphorylate certain key EGFR residues differently than CCh regulated , TGFalpha mediated EGFR transactivation .	The authors suggested that exogenous EGF and TGFalpha may alter the activity of phosphatases that then dephosphorylate certain key EGFR residues differently than CCh regulated, TGFalpha mediated EGFR transactivation.	26	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	26	27	28	29
Several ligands from the EGF system such as amphiregulin ( AREG ) , epidermal growth factor ( EGF ) , and transforming growth factor-alpha ( TGF-alpha ) only activate EGFR , whereas some have the ability to activate several combinations of the four EGF receptors like heparin binding epidermal growth factor ( HB-EGF ) , epiregulin ( EPI ) , and betacellulin ( BCL ) .	Several ligands from the EGF system such as amphiregulin (AREG), epidermal growth factor (EGF), and transforming growth factor-alpha (TGF-alpha) only activate EGFR, whereas some have the ability to activate several combinations of the four EGF receptors like heparin binding epidermal growth factor (HB-EGF), epiregulin (EPI), and betacellulin (BCL).	21	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	transforming growth factor-alpha	transforming growth factor-alpha	transforming growth factor-alpha	EGFR	EGFR	EGFR	21	24	29	30
We did not observe evidence of EGFR and Met cross-talk when OSA cells were treated with TGFalpha for 15 min .	We did not observe evidence of EGFR and Met cross-talk when OSA cells were treated with TGFalpha for 15 min.	4	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	16	17	6	7
TGFA is , both structurally and functionally , similar to Epidermal Growth Factor ( EGF ) , and induces a mitogenic response by binding to and stimulating the tyrosine kinase activity of EGF receptor XREF_BIBR , XREF_BIBR .	TGFA is, both structurally and functionally, similar to Epidermal Growth Factor (EGF), and induces a mitogenic response by binding to and stimulating the tyrosine kinase activity of EGF receptor XREF_BIBR, XREF_BIBR.	0	34	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFA	TGFA	TGFA	EGF receptor	EGF receptor	EGF receptor	0	1	32	34
XREF_BIBR Binding of specific ligands such as EGF and transforming growth factor alpha activates EGFR .	XREF_BIBR Binding of specific ligands such as EGF and transforming growth factor alpha activates EGFR.	4	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	transforming growth factor alpha	transforming growth factor alpha	transforming growth factor alpha	EGFR	EGFR	EGFR	9	13	14	15
Our recent studies with human A549 lung adenocarcinoma cells demonstrated that TGF-alpha induced EGFR activation stimulated MUC1-CT tyrosine phosphorylation and increased MUC1-CT and TLR5 interaction , resulting in decreased TLR5 and MyD88 association , diminished TLR5 dependent signaling , and attenuated inflammation .	Our recent studies with human A549 lung adenocarcinoma cells demonstrated that TGF-alpha induced EGFR activation stimulated MUC1-CT tyrosine phosphorylation and increased MUC1-CT and TLR5 interaction, resulting in decreased TLR5 and MyD88 association, diminished TLR5 dependent signaling, and attenuated inflammation.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	11	12	13	14
These observations , coupled with the distinct and separable phenotypes observed in the Tgf-alpha and Hb-egf mutants , implicate two parallel Egfr intercellular signaling circuits in these PNET tumors : one circuit involves membrane tethered Tgf-alpha that signals in autocrine and juxtacrine fashion to Egfr expressed as well on cancer cells , thereby enhancing cancer cell survival , while the second circuit involves Hb-egf expressed in multiple cell types , which signals to Egfr expressed on pericytes of the tumor vasculature .	These observations, coupled with the distinct and separable phenotypes observed in the Tgf-alpha and Hb-egf mutants, implicate two parallel Egfr intercellular signaling circuits in these PNET tumors : one circuit involves membrane tethered Tgf-alpha that signals in autocrine and juxtacrine fashion to Egfr expressed as well on cancer cells, thereby enhancing cancer cell survival, while the second circuit involves Hb-egf expressed in multiple cell types, which signals to Egfr expressed on pericytes of the tumor vasculature.	33	45	signals	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Tgf-alpha	Tgf-alpha	Tgf-alpha	Egfr	Egfr	Egfr	35	36	44	45
Therefore , we investigated activation of c-Cbl in Hep2 cells upon EGF- and TGFalpha induced activation of EGFR .	Therefore, we investigated activation of c-Cbl in Hep2 cells upon EGF- and TGFalpha induced activation of EGFR.	9	18	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	13	14	17	18
Previous studies in our lab have shown TGFalpha mediated activation of epidermal growth factor receptor ( EGFR ) induces cartilage degeneration in vitro , and inhibition of EGFR in vivo partially protects against surgically induced osteoarthritis in rats [ XREF_BIBR , XREF_BIBR ] .	Previous studies in our lab have shown TGFalpha mediated activation of epidermal growth factor receptor (EGFR) induces cartilage degeneration in vitro, and inhibition of EGFR in vivo partially protects against surgically induced osteoarthritis in rats [XREF_BIBR, XREF_BIBR].	7	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	7	8	11	15
TGF-alpha stimulation of EGFR is associated with constitutive signal transducer and activator of transcription 3 ( Stat3 ) activation in SCCHN .	TGF-alpha stimulation of EGFR is associated with constitutive signal transducer and activator of transcription 3 (Stat3) activation in SCCHN.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	0	1	3	4
Autocrine stimulation of EGF-R by TGF-alpha is therefore required for growth of the adenoma cell line .	Autocrine stimulation of EGF-R by TGF-alpha is therefore required for growth of the adenoma cell line.	1	6	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGF-R	EGF-R	EGF-R	5	6	3	4
This is likely due to the fact that EGFR expression is low in the tarsal muscle but extremely high in the CPF of mutant mice ; implicating that TGFalpha activates EGFR signaling in the tenocytes but not in the tarsal muscle cells .	This is likely due to the fact that EGFR expression is low in the tarsal muscle but extremely high in the CPF of mutant mice; implicating that TGFalpha activates EGFR signaling in the tenocytes but not in the tarsal muscle cells.	28	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	28	29	30	31
Having validated the utility of RosettaDock to refine our understanding of the EGF induced structure within the EGFR JM-A dimer , we next sought to identify the most likely structure formed when EGFR is instead activated by TGF-alpha .	Having validated the utility of RosettaDock to refine our understanding of the EGF induced structure within the EGFR JM-A dimer, we next sought to identify the most likely structure formed when EGFR is instead activated by TGF-alpha.	32	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	37	38	32	33
Indeed , administration of highly specific EGFR-tyrosine kinase inhibitors ( TKI ) , which block downstream signaling from TGFalpha activated EGFR , completely prevented high P- and low Ca induced parathyroid hyperplasia in early KD , as well as the severe progression of high P induced parathyroid growth in established secondary hyperparathyroidism , the latter characterized by marked TGFalpha and EGFR overexpression in the parathyroid glands .	Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGFalpha activated EGFR, completely prevented high P- and low Ca induced parathyroid hyperplasia in early KD, as well as the severe progression of high P induced parathyroid growth in established secondary hyperparathyroidism, the latter characterized by marked TGFalpha and EGFR overexpression in the parathyroid glands.	16	21	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	18	19	20	21
The active form of TGF-alpha in turn induces EGFR signaling activation to induce inflammatory gene expression such as IL8 .	The active form of TGF-alpha in turn induces EGFR signaling activation to induce inflammatory gene expression such as IL8.	2	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	4	5	8	9
We found that LPS induced TGF-alpha secretion activated EGFR and thus increased MUC5AC expression in HIBECs .	We found that LPS induced TGF-alpha secretion activated EGFR and thus increased MUC5AC expression in HIBECs.	3	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	LPS induced TGF-alpha	tgf-alpha	EGFR	EGFR	egfr	5	6	8	9
Further , EGFR activation by its ligand TGF-alpha was sufficient to induce activation of the Src-FAK pathway as well as receptor clustering .	Further, EGFR activation by its ligand TGF-alpha was sufficient to induce activation of the Src-FAK pathway as well as receptor clustering.	2	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	7	8	2	3
Oncogenic activation of the MAPK pathway has been shown to trigger the overexpression of Egfr and autocrine activation of Egfr by transforming growth factor alpha ( TGF-alpha ) family of Egfr ligands in cancer cells XREF_BIBR XREF_BIBR .	Oncogenic activation of the MAPK pathway has been shown to trigger the overexpression of Egfr and autocrine activation of Egfr by transforming growth factor alpha (TGF-alpha) family of Egfr ligands in cancer cells XREF_BIBR XREF_BIBR.	10	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	transforming growth factor alpha	transforming growth factor alpha	transforming growth factor alpha	Egfr	Egfr	Egfr	21	25	19	20
An Alternate and Discrete JM Interaction is Present when EGFR is Activated by TGFalpha .	An Alternate and Discrete JM Interaction is Present when EGFR is Activated by TGFalpha.	9	14	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	13	14	9	10
The Gurken , a TGF-alpha homolog , is produced by the oocyte and activates EGFR in follicle cells to specify the dorsal cell fates , followed by attenuation of EGFR signaling via negative regulators , such as sprouty , and kekkon , which together determine the area of the follicle epithelium where the dorsal appendages ( DAs ) form XREF_BIBR , XREF_BIBR .	The Gurken, a TGF-alpha homolog, is produced by the oocyte and activates EGFR in follicle cells to specify the dorsal cell fates, followed by attenuation of EGFR signaling via negative regulators, such as sprouty, and kekkon, which together determine the area of the follicle epithelium where the dorsal appendages (DAs) form XREF_BIBR, XREF_BIBR.	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	4	5	14	15
With this hypothesis , we have delineated the pathogenesis of Camurati-Engelmann disease ( CED ) , in which mutations in the LAP cause conformational dissociation , 223 resulting in increased release of activated TGF-beta1 and distortion of the resorption induced TGF-beta1 gradients .	With this hypothesis, we have delineated the pathogenesis of Camurati-Engelmann disease (CED), in which mutations in the LAP cause conformational dissociation, 223 resulting in increased release of activated TGF-beta1 and distortion of the resorption induced TGF-beta1 gradients.	21	41	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAP	LAP	LAP	TGF-beta1	TGF-beta1	TGF-beta1	21	22	40	41
Increased level of TGF-beta1 in CM activates TGF-beta1 signaling in macrophages .	Increased level of TGF-beta1 in CM activates TGF-beta1 signaling in macrophages.	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	level of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	3	4	7	8
Treatment of RPTC-D 2 R-SNPs with miR-217 mimic increased miR-217 expression ( XREF_SUPPLEMENTARY ) and decreased the expression of TGFbeta1 and EMT markers MMP3 , FN1 , and Col1a and decreased TGFbeta1 immunofluorescence signal ( XREF_FIG ) .	Treatment of RPTC-D 2 R-SNPs with miR-217 mimic increased miR-217 expression (XREF_SUPPLEMENTARY) and decreased the expression of TGFbeta1 and EMT markers MMP3, FN1, and Col1a and decreased TGFbeta1 immunofluorescence signal (XREF_FIG).	2	33	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFbeta1	RPTC-D 2 R-SNPs with miR-217 mimic increased miR-217 expression (XREF_SUPPLEMENTARY) and decreased the expression of TGFbeta1	tgfbeta1	TGFbeta1	TGFbeta1	tgfbeta1	19	20	31	32
LAP + Treg overexpress TGF-beta ( resulting in detectable latency associated peptide ( LAP ) on the cell surface , suppress via a TGF-beta dependent mechanism , and may be more immune suppressive than FoxP3 + Treg [ XREF_BIBR , XREF_BIBR ] .	LAP + Treg overexpress TGF-beta (resulting in detectable latency associated peptide (LAP) on the cell surface, suppress via a TGF-beta dependent mechanism, and may be more immune suppressive than FoxP3 + Treg [XREF_BIBR, XREF_BIBR].	0	12	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAP	LAP	LAP	latency associated peptide	latency associated peptide	latency associated peptide	0	1	9	12
XREF_BIBR Therefore , we hypothesized that dysregulation of TGF-beta1 signaling induced by T869C polymorphism of TGFB1 gene might contribute to a poor prognosis in patients with NSCLC .	XREF_BIBR Therefore, we hypothesized that dysregulation of TGF-beta1 signaling induced by T869C polymorphism of TGFB1 gene might contribute to a poor prognosis in patients with NSCLC.	8	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFB1	TGFB1	TGFB1	TGF-beta1	TGF-beta1	TGF-beta1	15	16	8	9
Additionally , NF-kappaB can also promote the expression of TGF-beta1 and activate TGF-beta1 and Smad2 signaling by binding with NF-kappaB combining site locating in TGF-beta1 activating factor-tissue transglutaminase ( tTG ) gene promoter [ XREF_BIBR ] .	Additionally, NF-kappaB can also promote the expression of TGF-beta1 and activate TGF-beta1 and Smad2 signaling by binding with NF-kappaB combining site locating in TGF-beta1 activating factor-tissue transglutaminase (tTG) gene promoter [XREF_BIBR].	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	NF-kappaB can also promote the expression of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	9	10	12	13
Consistently high incidence of TGFbeta1 expression in the invasive components of each subgroup further supports TGFbeta1 up-regulation as an early event in the invasive process .	Consistently high incidence of TGFbeta1 expression in the invasive components of each subgroup further supports TGFbeta1 up-regulation as an early event in the invasive process.	4	16	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta1	TGFbeta1 expression	tgfbeta1	TGFbeta1	TGFbeta1	tgfbeta1	4	5	15	16
Respiratory epithelial cells were isolated and divided into four groups : control ( untreated ) , treated with 0.05 % OE ( OE group ) , EMT induced with 5ng/ml of transforming growth factor beta-1 ( TGFbeta1 group ) and treated with 5ng/ml TGFbeta1 +0.05 % OE ( TGFbeta1+ OE group ) .	Respiratory epithelial cells were isolated and divided into four groups : control (untreated), treated with 0.05% OE (OE group), EMT induced with 5ng/ml of transforming growth factor beta-1 (TGFbeta1 group) and treated with 5ng/ml TGFbeta1 +0.05% OE (TGFbeta1+ OE group).	29	44	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta1	TGFbeta1	TGFbeta1	transforming growth factor beta-1	transforming growth factor beta-1	transforming growth factor beta-1	43	44	31	35
The most possible reason of TXL inhibiting EMT may be that TXL represses TGF-beta1 expression and blocks downstream signaling cascades of TGF-beta1 in HKCs .	The most possible reason of TXL inhibiting EMT may be that TXL represses TGF-beta1 expression and blocks downstream signaling cascades of TGF-beta1 in HKCs.	11	22	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	TXL represses TGF-beta1 expression	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	13	14	21	22
However , surface expression of latency associated peptide ( binds TGF-beta ) in activated FoxP3+ cells and in vitro production of TGF-beta1 were decreased in PAPS patients with high titers of aPL IgG .	However, surface expression of latency associated peptide (binds TGF-beta) in activated FoxP3+ cells and in vitro production of TGF-beta1 were decreased in PAPS patients with high titers of aPL IgG.	3	22	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	latency associated peptide	expression of latency associated peptide	latency associated peptide	TGF-beta1	TGF-beta1	tgf-beta1	5	8	21	22
The findings in this study demonstrate that during bleomycin induced injury , alveolar macrophages not only secrete large quantities of active TGF-beta 1 , but are a predominant source of the enhanced TGF-beta response seen in this model .	The findings in this study demonstrate that during bleomycin induced injury, alveolar macrophages not only secrete large quantities of active TGF-beta 1, but are a predominant source of the enhanced TGF-beta response seen in this model.	9	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta 1	quantities of active TGF-beta 1	tgf-beta 1	TGF-beta 1	TGF-beta 1	tgf-beta 1	21	23	21	23
[ XREF_BIBR ] However , in CED , mutations in the LAP cause premature dissociation of TGF-beta1 causing distortion of the resorption induced TGF-beta1 gradients .	[XREF_BIBR] However, in CED, mutations in the LAP cause premature dissociation of TGF-beta1 causing distortion of the resorption induced TGF-beta1 gradients.	11	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAP	LAP	LAP	TGF-beta1	TGF-beta1	TGF-beta1	11	12	23	24
However there is a re-expression of TGF-beta1 as progressive CKD develops with longer recovery XREF_BIBR , XREF_BIBR .	However there is a re-expression of TGF-beta1 as progressive CKD develops with longer recovery XREF_BIBR, XREF_BIBR.	2	7	is a re-expression	Positive_activation_copula_1	Positive_activation	Positive_activation	TGF-beta1	re-expression of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	6	7	6	7
Granular corneal dystrophy type 2 ( GCD2 ) is caused by a point mutation in the Transforming Growth Factor Beta 1 ( TGFbeta1 ) gene resulting in age dependent accumulation of aggregated proteins in the corneal epithelia and stroma , which interferes with corneal transparency .	Granular corneal dystrophy type 2 (GCD2) is caused by a point mutation in the Transforming Growth Factor Beta 1 (TGFbeta1) gene resulting in age dependent accumulation of aggregated proteins in the corneal epithelia and stroma, which interferes with corneal transparency.	9	24	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Transforming Growth Factor Beta 1	Transforming Growth Factor Beta 1	Transforming Growth Factor Beta 1	TGFbeta1	TGFbeta1	TGFbeta1	16	21	22	23
In summary , our data demonstrate that TGF-beta 1 -induced miR-21 over-expression enhances TGF-beta 1 -induced collagens expression by directly down-regulating Smad7 .	In summary, our data demonstrate that TGF-beta 1 -induced miR-21 over-expression enhances TGF-beta 1 -induced collagens expression by directly down-regulating Smad7.	7	17	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGF-beta 1	TGF-beta 1 -induced miR-21 over-expression	tgf-beta 1	TGF-beta 1	TGF-beta 1	tgf-beta 1	7	9	13	15
ROS can augment the expression and secretion of TGF-beta1 and activate the latent TGF-beta1 to become active and functional .	ROS can augment the expression and secretion of TGF-beta1 and activate the latent TGF-beta1 to become active and functional.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	ROS can augment the expression and secretion of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	8	9	13	14
Ang II stimulates TGFbeta1 expression , promotes its conversion to bioactive TGFbeta1 and upregulates TGFbeta receptors .	Ang II stimulates TGFbeta1 expression, promotes its conversion to bioactive TGFbeta1 and upregulates TGFbeta receptors.	0	12	promotes	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TGFbeta1	Ang II stimulates TGFbeta1 expression	tgfbeta1	TGFbeta1	TGFbeta1	tgfbeta1	3	4	11	12
LAP is cleaved to allow the activation of TGF-beta1 which is able to bind its receptors TGF-betaR1 ( transforming growth factor receptor-beta1 ) and TGF-betaR2 .	LAP is cleaved to allow the activation of TGF-beta1 which is able to bind its receptors TGF-betaR1 (transforming growth factor receptor-beta1) and TGF-betaR2.	0	24	allow	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	LAP	LAP	lap	TGF-beta1	TGF-beta1 which is able to bind its receptors TGF-betaR1	tgf-beta1	0	1	8	9
In an earlier study , we demonstrated that deletion of TGFbeta1 from CD4 + Foxp3 + regulatory T cells was insufficient to inhibit primary tumor growth in Tgfb1 f/n Foxp3cre-TRAMP mice .	In an earlier study, we demonstrated that deletion of TGFbeta1 from CD4 + Foxp3 + regulatory T cells was insufficient to inhibit primary tumor growth in Tgfb1 f/n Foxp3cre-TRAMP mice.	8	30	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta1	TGFbeta1	TGFbeta1	Tgfb1	Tgfb1	Tgfb1	10	11	27	28
Further , transgenic TGFbeta1 overexpression in the heart and plasma of atherosclerotic mice led to reduction of atherosclerosis and thus also supported the atheroprotective function of TGFbeta1 XREF_BIBR .	Further, transgenic TGFbeta1 overexpression in the heart and plasma of atherosclerotic mice led to reduction of atherosclerosis and thus also supported the atheroprotective function of TGFbeta1 XREF_BIBR.	3	27	supported	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta1	TGFbeta1 overexpression	tgfbeta1	TGFbeta1	TGFbeta1	tgfbeta1	3	4	26	27
We found that exogenous , as well as endogenous ( overexpressed ) bFGF increased TGFbeta1 mRNA expression in the cells and enhanced the secretion of TGFbeta1 into culture medium .	We found that exogenous, as well as endogenous (overexpressed) bFGF increased TGFbeta1 mRNA expression in the cells and enhanced the secretion of TGFbeta1 into culture medium.	12	26	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta1	bFGF increased TGFbeta1 mRNA expression	tgfbeta1	TGFbeta1	TGFbeta1	tgfbeta1	14	15	25	26
Especially molecular features linked to transforming growth factor beta 1 ( TGFB1 ) signaling were upregulated by tacrolimus , namely TGFB1 itself as well as COL4A1 , NADPH oxidase 4 ( NOX4 ) , or thrombospondin 1 ( THBS1 ) .	Especially molecular features linked to transforming growth factor beta 1 (TGFB1) signaling were upregulated by tacrolimus, namely TGFB1 itself as well as COL4A1, NADPH oxidase 4 (NOX4), or thrombospondin 1 (THBS1).	3	21	upregulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	TGFB1	TGFB1	TGFB1	transforming growth factor beta 1	transforming growth factor beta 1	transforming growth factor beta 1	20	21	5	10
Importantly , JWH133 reduced serum profibrotic cytokines levels of TGF-beta1 and inhibited TGF-beta1 and Smad2 pathway in vitro and in vivo .	Importantly, JWH133 reduced serum profibrotic cytokines levels of TGF-beta1 and inhibited TGF-beta1 and Smad2 pathway in vitro and in vivo.	2	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	JWH133 reduced serum profibrotic cytokines levels of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	9	10	12	13
Although Ad-TGFbeta1 vector no longer produces TGFbeta1 at the time of cell injections into mice , we wished to determine whether TGFbeta1 might be capable of initiating the dormant-to-proliferative switch .	Although Ad-TGFbeta1 vector no longer produces TGFbeta1 at the time of cell injections into mice, we wished to determine whether TGFbeta1 might be capable of initiating the dormant-to-proliferative switch.	1	7	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ad-TGFbeta1	Ad-TGFbeta1	Ad-TGFbeta1	TGFbeta1	TGFbeta1	TGFbeta1	1	2	6	7
We also found that TGF-beta1 signaling had no effect on prion incubation times , using three different mouse models : Tg ( Tgfb1 ) mice overexpressing TGF-beta1 , heterozygous Tg ( Tgfb1 +/-) mice , and double-transgenic Tg ( TbetaRIIDeltak ) +/- x Tg ( tTA ) +/- Prnp +/- mice expressing a transdominant negative mutant of TGF-beta receptor II that disrupts TGF-beta signaling ( XREF_SUPPLEMENTARY ) .	We also found that TGF-beta1 signaling had no effect on prion incubation times, using three different mouse models : Tg (Tgfb1) mice overexpressing TGF-beta1, heterozygous Tg (Tgfb1 +/-) mice, and double-transgenic Tg (TbetaRIIDeltak) +/- x Tg (tTA) +/- Prnp +/- mice expressing a transdominant negative mutant of TGF-beta receptor II that disrupts TGF-beta signaling (XREF_SUPPLEMENTARY).	22	37	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tgfb1	Tgfb1	Tgfb1	TGF-beta1	TGF-beta1	TGF-beta1	22	23	26	27
Importantly , the amounts of TGF-beta1 present in the protein preparations consistently triggered the canonical TGF-beta1 signaling pathway in fibroblasts through Smad2 phosphorylation , whereas conventional methods did not detect TGF-beta1 in the protein preparations .	Importantly, the amounts of TGF-beta1 present in the protein preparations consistently triggered the canonical TGF-beta1 signaling pathway in fibroblasts through Smad2 phosphorylation, whereas conventional methods did not detect TGF-beta1 in the protein preparations.	3	17	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	amounts of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	5	6	15	16
Cannabinoid receptor type 2 agonist JWH133 reduced serum profibrotic cytokines levels of TGF-beta1 and inhibited TGF-beta1 and Smad2 pathway in vitro and in vivo .	Cannabinoid receptor type 2 agonist JWH133 reduced serum profibrotic cytokines levels of TGF-beta1 and inhibited TGF-beta1 and Smad2 pathway in vitro and in vivo.	0	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	Cannabinoid receptor type 2 agonist JWH133 reduced serum profibrotic cytokines levels of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	12	13	15	16
The mRNA expression levels of TGF-beta1 , alpha-SMA , and collagen type I of fibroblasts in P311 over-expression group , and the protein expression levels of pro-TGF-beta1 , activated TGF-beta1 , alpha-SMA , and collagen type I of fibroblasts in P311 over-expression group were significantly higher than those in blank control group ( with t values from 8.192 to 49.090 , P values below 0.01 ) .	The mRNA expression levels of TGF-beta1, alpha-SMA, and collagen type I of fibroblasts in P311 over-expression group, and the protein expression levels of pro-TGF-beta1, activated TGF-beta1, alpha-SMA, and collagen type I of fibroblasts in P311 over-expression group were significantly higher than those in blank control group (with t values from 8.192 to 49.090, P values below 0.01).	24	45	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pro-TGF-beta1	levels of pro-TGF-beta1	pro-tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	26	27	29	30
Transgenic expression of TGF-beta1 in murine osteoblasts induces OA and inhibition of TGF-beta1 by antibodies or by deletion of TGF-beta type II receptor , in nestin positive MSCs , leads to less pronounced cartilage degradation after surgery induced OA XREF_BIBR .	Transgenic expression of TGF-beta1 in murine osteoblasts induces OA and inhibition of TGF-beta1 by antibodies or by deletion of TGF-beta type II receptor, in nestin positive MSCs, leads to less pronounced cartilage degradation after surgery induced OA XREF_BIBR.	1	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	expression of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	3	4	12	13
To determine whether CSE promoted the activation of the TGF-beta1 pathway , A549 cells were treated with 1.0 % CSE for 48 h , and the expression of TGF-beta1 and Smad2 , which mediates TGF-beta1 signaling , was assessed .	To determine whether CSE promoted the activation of the TGF-beta1 pathway, A549 cells were treated with 1.0% CSE for 48 h, and the expression of TGF-beta1 and Smad2, which mediates TGF-beta1 signaling, was assessed.	26	35	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	expression of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	28	29	34	35
It was found that high TGF-beta1 expression levels promoted the growth of tumour cells by affecting molecules in the TGF-beta1 signalling pathway during the occurrence and progression of tumours , resulting in the abnormal proliferation of tumour cells ; however , the proliferation of tumour cells also promoted TGF-beta1 secretion and accelerated the invasion of tumour cells into normal tissues 42 .	It was found that high TGF-beta1 expression levels promoted the growth of tumour cells by affecting molecules in the TGF-beta1 signalling pathway during the occurrence and progression of tumours, resulting in the abnormal proliferation of tumour cells; however, the proliferation of tumour cells also promoted TGF-beta1 secretion and accelerated the invasion of tumour cells into normal tissues 42.	5	21	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1 expression levels	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	5	6	19	20
The prostaglandin E2 receptor , EP2 ( E-prostanoid 2 ) , plays an important role in mice glomerular MCs ( mesangial cells ) damage induced by TGFbeta1 ( transforming growth factor-beta1 ) ; however , the molecular mechanisms for this remain unknown .	The prostaglandin E2 receptor, EP2 (E-prostanoid 2), plays an important role in mice glomerular MCs (mesangial cells) damage induced by TGFbeta1 (transforming growth factor-beta1); however, the molecular mechanisms for this remain unknown.	18	31	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFbeta1	TGFbeta1	TGFbeta1	transforming growth factor-beta1	transforming growth factor-beta1	transforming growth factor-beta1	26	27	28	31
Consistently , the present results suggest that the decrease in TbetaRIII mRNA and protein expression in human TSCC cancer cells might be possibly due to TGF-beta1 overexpression , which are resistant to the negative growth effects of TGF-beta1 due to the loss of TbetaRIII , thereby restoring TGF-beta1 sensitivity .	Consistently, the present results suggest that the decrease in TbetaRIII mRNA and protein expression in human TSCC cancer cells might be possibly due to TGF-beta1 overexpression, which are resistant to the negative growth effects of TGF-beta1 due to the loss of TbetaRIII, thereby restoring TGF-beta1 sensitivity.	25	48	restoring	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1 overexpression	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	25	26	47	48
LAP + Treg overexpress latency associated peptide ( LAP ) and are known to potently suppress via a TGF-beta-dependent mechanism .	LAP + Treg overexpress latency associated peptide (LAP) and are known to potently suppress via a TGF-beta-dependent mechanism.	0	15	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAP	LAP	LAP	latency associated peptide	latency associated peptide	latency associated peptide	0	1	4	7
A TGFB1 point mutation ( H222D ) , derived from published cases of Camurati-Engelmann disease ( CED ) , has been shown to constitutively activate TGF-beta1 , leading to excess bone matrix production .	A TGFB1 point mutation (H222D), derived from published cases of Camurati-Engelmann disease (CED), has been shown to constitutively activate TGF-beta1, leading to excess bone matrix production.	1	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFB1	TGFB1	TGFB1	TGF-beta1	TGF-beta1	TGF-beta1	1	2	25	26
Furthermore , P311 enhanced the methylation of TGFbeta1 promoter and increased activities of TGFbeta1 5 '/3 ' untranslated regions ( UTRs ) to stimulate TGFbeta1 expression .	Furthermore, P311 enhanced the methylation of TGFbeta1 promoter and increased activities of TGFbeta1 5 '/3 ' untranslated regions (UTRs) to stimulate TGFbeta1 expression.	2	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta1	P311 enhanced the methylation of TGFbeta1	tgfbeta1	TGFbeta1	TGFbeta1	tgfbeta1	7	8	13	14
Collectively , the results demonstrated that upregulation of NNMT in gastric cancer cells may increase the expression of TGF-beta1 , therefore activating TGF-beta1 and Smad signaling , which in turn promotes EMT .	Collectively, the results demonstrated that upregulation of NNMT in gastric cancer cells may increase the expression of TGF-beta1, therefore activating TGF-beta1 and Smad signaling, which in turn promotes EMT.	8	25	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	NNMT in gastric cancer cells may increase the expression of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	18	19	22	23
That Itgb6 is able to activate TGF-beta1 in oral epithelia tissue is supported by the Itgb6 mediated activation of TGF-beta1 in gingival epithelium .	That Itgb6 is able to activate TGF-beta1 in oral epithelia tissue is supported by the Itgb6 mediated activation of TGF-beta1 in gingival epithelium.	6	20	supported	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta1	Itgb6 mediated activation of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	19	20	6	7
Our data show that TGF-beta1 stimulates the production of FN mRNA ( XREF_FIG , XREF_FIG ) , and the growth factors TGFB1 and CCN2 in the de-tensioned tissue ( XREF_FIG , XREF_FIG ) .	Our data show that TGF-beta1 stimulates the production of FN mRNA (XREF_FIG, XREF_FIG), and the growth factors TGFB1 and CCN2 in the de-tensioned tissue (XREF_FIG, XREF_FIG).	4	23	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TGFB1	TGFB1	TGFB1	4	5	21	22
TGF-beta1 signaling of both pathways in the AAC stenotic area in WT , but not Tgfb1 flox mice .	TGF-beta1 signaling of both pathways in the AAC stenotic area in WT, but not Tgfb1 flox mice.	0	17	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	Tgfb1	Tgfb1	Tgfb1	0	1	15	16
The results showed that E-cadherin and SnoN expression in NRK52Es decreased significantly , but poly-ubiquitination of SnoN , TGF-beta1 , alpha-SMA , FN , Arkadia , p-Smad2 and p-Smad3 expression significantly increased due to high glucose stimulation , which could be almost completely reversed by OM , suggesting that OM may alleviate EMT induced by high glucose via upregulating SnoN expression and inhibiting TGF-beta1 and Smad signaling pathway activation .	The results showed that E-cadherin and SnoN expression in NRK52Es decreased significantly, but poly-ubiquitination of SnoN, TGF-beta1, alpha-SMA, FN, Arkadia, p-Smad2 and p-Smad3 expression significantly increased due to high glucose stimulation, which could be almost completely reversed by OM, suggesting that OM may alleviate EMT induced by high glucose via upregulating SnoN expression and inhibiting TGF-beta1 and Smad signaling pathway activation.	14	68	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	poly-ubiquitination of SnoN, TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	18	19	63	64
The results suggest that light-to-moderate alcohol drinking reduces LAP level in patients with hypertension and attenuates the relation of LAP to hypertension .	The results suggest that light-to-moderate alcohol drinking reduces LAP level in patients with hypertension and attenuates the relation of LAP to hypertension.	5	20	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LAP	alcohol drinking reduces LAP level	lap	LAP	LAP	lap	8	9	19	20
Taurine can promote apoptosis in HSCs by inhibiting the expression of TGF-beta1 , thereby blocking the TGF-beta1 and Smad pathway , a canonical pathway that can potently regulate hepatic fibrogenesis .	Taurine can promote apoptosis in HSCs by inhibiting the expression of TGF-beta1, thereby blocking the TGF-beta1 and Smad pathway, a canonical pathway that can potently regulate hepatic fibrogenesis.	0	19	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	Taurine can promote apoptosis in HSCs by inhibiting the expression of TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	11	12	16	17
TGFbeta1 increased Tgfb1 and Myc in rat but decreased them in mouse .	TGFbeta1 increased Tgfb1 and Myc in rat but decreased them in mouse.	0	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta1	TGFbeta1	TGFbeta1	Tgfb1	Tgfb1	Tgfb1	0	1	2	3
There was a marked overexpression of TGF-beta 1 , TGF-beta 3 and T beta R-II in 94 % of the Crohn ' s disease tissue samples .	There was a marked overexpression of TGF-beta 1, TGF-beta 3 and T beta R-II in 94% of the Crohn 's disease tissue samples.	1	14	was a marked overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	TGF-beta 1	overexpression of TGF-beta 1	tgf-beta 1	TGF-beta 1	TGF-beta 1	tgf-beta 1	6	8	6	8
Release of LAP activates circulating TGFbeta1 and presumably also TGFbeta1 within bone .	Release of LAP activates circulating TGFbeta1 and presumably also TGFbeta1 within bone.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LAP	LAP	LAP	TGFbeta1	TGFbeta1	TGFbeta1	2	3	5	6
Tcl1 is an oncogene cloned from a translocation in T cell leukemia ; XREF_BIBR , XREF_BIBR Tcl1 is an important activator of Akt , a key kinase required for cell survival .	Tcl1 is an oncogene cloned from a translocation in T cell leukemia; XREF_BIBR, XREF_BIBR Tcl1 is an important activator of Akt, a key kinase required for cell survival.	13	26	is an important activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Tcl1	Tcl1	Tcl1	Akt	Akt	Akt	16	17	22	23
Taken together , these data indicate that KLF4 induced TCL1 activates the AKT pathway , which in turn promotes reprogramming toward pluripotency .	Taken together, these data indicate that KLF4 induced TCL1 activates the AKT pathway, which in turn promotes reprogramming toward pluripotency.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	KLF4 induced TCL1	tcl1	AKT	AKT	akt	9	10	12	13
In addition , the T cell leukemia/lymphoma 1 ( TCL1 ) protein binds to the PH domain of Akt to increase Akt activity ( XREF_FIG ) .	In addition, the T cell leukemia/lymphoma 1 (TCL1) protein binds to the PH domain of Akt to increase Akt activity (XREF_FIG).	3	22	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	Akt	Akt	Akt	9	10	21	22
TCL1 induced by KLF4 activates AKT to enhance glycolysis and inhibits mitochondrial polynucleotide phosphorylase ( PnPase ) to suppress oxidative phosphorylation .	TCL1 induced by KLF4 activates AKT to enhance glycolysis and inhibits mitochondrial polynucleotide phosphorylase (PnPase) to suppress oxidative phosphorylation.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	AKT	AKT	AKT	0	1	5	6
The observations together supported the notion that TCL1b , which activates Akt , possibly underlies various human cancer types of non lymphoid lineages .	The observations together supported the notion that TCL1b, which activates Akt, possibly underlies various human cancer types of non lymphoid lineages.	7	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1b	TCL1b	TCL1b	Akt	Akt	Akt	7	8	11	12
TCL1 enhances AKT kinase activity , and therefore functions as an AKT kinase co-activator [ XREF_BIBR ] .	TCL1 enhances AKT kinase activity, and therefore functions as an AKT kinase co-activator [XREF_BIBR].	0	8	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	AKT	AKT	AKT	0	1	2	3
TCL1 and MTCP1 proteins directly interact with AKT and modulate the AKT signal-transduction pathway , but the relevance of this mechanism in leukemogenesis remains unclear .	TCL1 and MTCP1 proteins directly interact with AKT and modulate the AKT signal-transduction pathway, but the relevance of this mechanism in leukemogenesis remains unclear.	0	13	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	AKT	AKT	AKT	0	1	11	12
As predicted by the highly homologous amino-acid sequences among the TCL1 family proteins ( see XREF_FIG ) , TCL1b also forms dimers in co-immunoprecipitation assays , suggesting that TCL1b enhances Akt kinase activity via dimerization mediated transphosphorylation analogous to the mechanisms of TCL1 to enhance Akt kinase activity .	As predicted by the highly homologous amino-acid sequences among the TCL1 family proteins (see XREF_FIG), TCL1b also forms dimers in co-immunoprecipitation assays, suggesting that TCL1b enhances Akt kinase activity via dimerization mediated transphosphorylation analogous to the mechanisms of TCL1 to enhance Akt kinase activity.	28	32	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1b	TCL1b	TCL1b	Akt	Akt	Akt	28	29	30	31
However , TCL1 overexpression restores AKT signaling and B-cells production , which were abrogated in parental Pkcbeta -/- mice , suggesting hierarchical order with TCL1 and AKT acting downstream to PKCbeta .	However, TCL1 overexpression restores AKT signaling and B-cells production, which were abrogated in parental Pkcbeta -/- mice, suggesting hierarchical order with TCL1 and AKT acting downstream to PKCbeta.	2	6	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1 overexpression	tcl1	AKT	AKT	akt	2	3	5	6
TCL1 interacts with the Akt kinase to promote Akt signaling , which via the PI3K - Akt signaling axis plays broad roles in cell activation , survival , and proliferation .	TCL1 interacts with the Akt kinase to promote Akt signaling, which via the PI3K - Akt signaling axis plays broad roles in cell activation, survival, and proliferation.	0	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	Akt	Akt	Akt	0	1	8	9
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR TCL1 physically binds to Akt and activates Akt via a transphosphorylation reaction .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR TCL1 physically binds to Akt and activates Akt via a transphosphorylation reaction.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	Akt	Akt	Akt	7	8	14	15
For example , the TCL1 activated target kinase AKT increases ROS by a fueled oxidative metabolism .	For example, the TCL1 activated target kinase AKT increases ROS by a fueled oxidative metabolism.	3	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	AKT	AKT	AKT	4	5	8	9
Located opposite the phospholipid binding pocket and distal from known protein protein interaction sites on PH domains , the binding of dimeric TCL1 proteins to this site would allow the crosslinking of two PKB molecules at the cellular membrane in a preactivated conformation without disrupting certain PH-ligand interactions .	Located opposite the phospholipid binding pocket and distal from known protein protein interaction sites on PH domains, the binding of dimeric TCL1 proteins to this site would allow the crosslinking of two PKB molecules at the cellular membrane in a preactivated conformation without disrupting certain PH-ligand interactions.	22	34	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	PKB	PKB	PKB	22	23	33	34
However , it remains perplexing how a subcortical complex would affect nuclear events , although disruption of TCL1 ( T cell leukemia/lymphoma 1 ) mediated shuttling of Akt ( protein kinase B ) into the nucleus inhibits embryonic progression .	However, it remains perplexing how a subcortical complex would affect nuclear events, although disruption of TCL1 (T cell leukemia/lymphoma 1) mediated shuttling of Akt (protein kinase B) into the nucleus inhibits embryonic progression.	15	35	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TCL1	TCL1	TCL1	Akt	Akt	Akt	17	18	27	28
Although TCL1 is a positive regulator of AKT activation , it seems unlikely that this is due to a direct regulation of TCL1 by RhoH , because the mechanism by which TCL1 activates AKT does not depend on AKT phosphorylation at Ser473 and seems to occur at the level of nuclear translocation of AKT .	Although TCL1 is a positive regulator of AKT activation, it seems unlikely that this is due to a direct regulation of TCL1 by RhoH, because the mechanism by which TCL1 activates AKT does not depend on AKT phosphorylation at Ser473 and seems to occur at the level of nuclear translocation of AKT.	31	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	AKT	AKT	AKT	31	32	33	34
58 Furthermore , transgenic expression of the AKT enhancer TCL1 in immature and mature murine B cells induces a CLL like phenotype that presents with an expansion of CD5 + B cells in the PC , and later on the accumulation of leukemic cells in the BM , spleen and PB .	58 Furthermore, transgenic expression of the AKT enhancer TCL1 in immature and mature murine B cells induces a CLL like phenotype that presents with an expansion of CD5 + B cells in the PC, and later on the accumulation of leukemic cells in the BM, spleen and PB.	4	16	enhancer	Positive_activation_token_1_noun	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	AKT	AKT	AKT	9	10	7	8
As shown in XREF_FIG A and 5B , we found that an active form of AKT , phosphorylated at Ser473 , is increased in iPSCs ( High-K ) or when exogenous TCL1 was expressed in iPSCs ( Low-K ) , suggesting that KLF4 induced TCL1 enhances the AKT activity .	As shown in XREF_FIG A and 5B, we found that an active form of AKT, phosphorylated at Ser473, is increased in iPSCs (High-K) or when exogenous TCL1 was expressed in iPSCs (Low-K), suggesting that KLF4 induced TCL1 enhances the AKT activity.	42	48	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	KLF4 induced TCL1	tcl1	AKT	AKT	akt	44	45	47	48
KLF4 induced TCL1 employs a two pronged mechanism , whereby TCL1 activates AKT to enhance glycolysis and counteracts PnPase to diminish oxidative phosphorylation .	KLF4 induced TCL1 employs a two pronged mechanism, whereby TCL1 activates AKT to enhance glycolysis and counteracts PnPase to diminish oxidative phosphorylation.	10	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	AKT	AKT	AKT	10	11	12	13
In contrast , the T cell leukemia/lymphoma 1 ( TCL1 ) protein binds to the PH domain of Akt to enhance Akt activity .	In contrast, the T cell leukemia/lymphoma 1 (TCL1) protein binds to the PH domain of Akt to enhance Akt activity.	3	22	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	Akt	Akt	Akt	9	10	21	22
In vitro , TCL1 can modulate the activity of the serine threonine kinase AKT , a downstream effector of T-cell receptor ( TCR ) signaling .	In vitro, TCL1 can modulate the activity of the serine threonine kinase AKT, a downstream effector of T-cell receptor (TCR) signaling.	1	14	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	AKT	AKT	AKT	3	4	13	14
In T-cells , Tcl1 activates Akt , this leads to increased proliferation , inhibition of apoptosis and T-cell transformation [ XREF_BIBR ] .	In T-cells, Tcl1 activates Akt, this leads to increased proliferation, inhibition of apoptosis and T-cell transformation [XREF_BIBR].	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tcl1	Tcl1	Tcl1	Akt	Akt	Akt	3	4	5	6
Tcl1 is known to augment Akt function through direct interaction XREF_BIBR .	Tcl1 is known to augment Akt function through direct interaction XREF_BIBR.	0	6	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tcl1	Tcl1	Tcl1	Akt	Akt	Akt	0	1	5	6
A heat map of the cluster analysis indicated that gene-induction signature from the cells transfected with TCL1 , TCL1b or Myr-Akt resembled each other ( XREF_FIG ) , supporting the notion that TCL1b indeed enhanced Akt kinase activity to mediate similar down-stream intracellular signals as Myr-Akt or TCL1 .	A heat map of the cluster analysis indicated that gene-induction signature from the cells transfected with TCL1, TCL1b or Myr-Akt resembled each other (XREF_FIG), supporting the notion that TCL1b indeed enhanced Akt kinase activity to mediate similar down-stream intracellular signals as Myr-Akt or TCL1.	32	37	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1b	TCL1b	TCL1b	Akt	Akt	Akt	32	33	35	36
The results demonstrate the structural basis of TCL1 induced activation of Akt , which causes human T-PLL .	The results demonstrate the structural basis of TCL1 induced activation of Akt, which causes human T-PLL.	5	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	Akt	Akt	Akt	7	8	11	12
TCL1 increases Akt activation by binding the PH domain of Akt and causing a conformational change to promote Ser473 phosphorylation 44 .	TCL1 increases Akt activation by binding the PH domain of Akt and causing a conformational change to promote Ser473 phosphorylation 44.	0	3	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	Akt	Akt	Akt	0	1	2	3
KLF4 Induced TCL1 Activates the AKT Pathway to Enhance Glycolysis during Reprogramming .	KLF4 Induced TCL1 Activates the AKT Pathway to Enhance Glycolysis during Reprogramming.	0	6	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	KLF4 Induced TCL1	tcl1	AKT	AKT	akt	2	3	5	6
TCL1B is known to enhance the AKT kinase activity and induce naive pluripotency XREF_BIBR .	TCL1B is known to enhance the AKT kinase activity and induce naive pluripotency XREF_BIBR.	0	10	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1B	TCL1B	TCL1B	AKT	AKT	AKT	0	1	6	7
In in vitro Akt kinase assays , TCL1b enhanced Akt kinase activity in dose- and time dependent manners .	In in vitro Akt kinase assays, TCL1b enhanced Akt kinase activity in dose- and time dependent manners.	0	11	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TCL1b	TCL1b	TCL1b	Akt	Akt	Akt	7	8	9	10
The observation supported that TCL1b mediated activation of Akt may underlie the malignant transformation of generation of angiosarcoma .	The observation supported that TCL1b mediated activation of Akt may underlie the malignant transformation of generation of angiosarcoma.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	TCL1b	TCL1b	TCL1b	Akt	Akt	Akt	4	5	8	9
The TGFBR1 protein level was significantly elevated in C2C12 cells treated with TGF-beta1 .	The TGFBR1 protein level was significantly elevated in C2C12 cells treated with TGF-beta1.	1	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TGFBR1	TGFBR1	TGFBR1	12	13	1	2
Femoral head cartilage isolated from Alk5 Col2ERT2 and Cre negative mice was treated with 4-OH TM to delete Alk5 , followed by treated with TGF-beta1 to dissect the role of ALK5 in TGF-beta1- induced Prg4 expression .	Femoral head cartilage isolated from Alk5 Col2ERT2 and Cre negative mice was treated with 4-OH TM to delete Alk5, followed by treated with TGF-beta1 to dissect the role of ALK5 in TGF-beta1- induced Prg4 expression.	17	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	Alk5	Alk5	Alk5	24	25	18	19
However , TGF-beta1 and 3 can also activate the ALK5 and SMAD2 and 3 pathway ( the canonical most studied pathway ) , leading to an anti-angiogenic effect XREF_BIBR , XREF_BIBR , XREF_BIBR .	However, TGF-beta1 and 3 can also activate the ALK5 and SMAD2 and 3 pathway (the canonical most studied pathway), leading to an anti-angiogenic effect XREF_BIBR, XREF_BIBR, XREF_BIBR.	2	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	2	3	9	10
Although TGF-beta1 can activate angiogenesis indirectly through VEGF synthesis , and can support endothelial cell survival and proliferation by activating the endothelium specific ALK1/Smad1/5/8 pathway , persistently high concentrations of TGF-beta1 activate ALK5 and Smad3 in endothelial cells , which results in VEGF receptor downregulation and the induction of endothelial cell apoptosis .	Although TGF-beta1 can activate angiogenesis indirectly through VEGF synthesis, and can support endothelial cell survival and proliferation by activating the endothelium specific ALK1/Smad1/5/8 pathway, persistently high concentrations of TGF-beta1 activate ALK5 and Smad3 in endothelial cells, which results in VEGF receptor downregulation and the induction of endothelial cell apoptosis.	28	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	30	31	32	33
Interestingly , administration of exogenous TGF-beta1 before CIP activated the TGF-beta and ALK5 pathway and reduced BBB permeability to 14 C-sucrose .	Interestingly, administration of exogenous TGF-beta1 before CIP activated the TGF-beta and ALK5 pathway and reduced BBB permeability to 14 C-sucrose.	2	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	5	6	12	13
Further , PAI-1 , which is induced by TGF-beta1 activation of the Alk5 and SMAD2/3 pathway , contributes to vessel stabilization by preventing degradation of the provisional matrix deposited around new vessels and favoring the establishment of new basal lamina , again consistently with our finding that PAI-1 was specifically and robustly induced in the low VEGF conditions , leading to the fastest stabilization .	Further, PAI-1, which is induced by TGF-beta1 activation of the Alk5 and SMAD2/3 pathway, contributes to vessel stabilization by preventing degradation of the provisional matrix deposited around new vessels and favoring the establishment of new basal lamina, again consistently with our finding that PAI-1 was specifically and robustly induced in the low VEGF conditions, leading to the fastest stabilization.	8	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	Alk5	Alk5	Alk5	8	9	12	13
These findings establish that TGF-beta1 activates TbetaR-I and its downstream p38 MAPK and PI3K-Akt signaling pathways in microglia to protect against DAergic neuronal loss that characterizes in PD .	These findings establish that TGF-beta1 activates TbetaR-I and its downstream p38 MAPK and PI3K-Akt signaling pathways in microglia to protect against DAergic neuronal loss that characterizes in PD.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaR-I	TbetaR-I	TbetaR-I	4	5	6	7
Our data suggest that binding of TGF-beta1 activates ALK5 and leads to phosphorylation of SMAD2 .	Our data suggest that binding of TGF-beta1 activates ALK5 and leads to phosphorylation of SMAD2.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	6	7	8	9
Effect of Ac-SDKP on TGF-beta Receptor Type I and II in Cultured Rat Pulmonary Fibroblasts Induced by TGF-beta1 .	Effect of Ac-SDKP on TGF-beta Receptor Type I and II in Cultured Rat Pulmonary Fibroblasts Induced by TGF-beta1.	4	18	Induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TGF-beta Receptor Type I	TGF-beta Receptor Type I	TGF-beta Receptor Type I	17	18	4	8
As TGFbeta1 induced SVZ derived gliospheres to produce more astrocytes and the signal transduction studies indicated that TGFbeta1 was stimulating the ALK5 receptor , we hypothesized that inhibiting the ALK5 receptor would inhibit astrocyte generation .	As TGFbeta1 induced SVZ derived gliospheres to produce more astrocytes and the signal transduction studies indicated that TGFbeta1 was stimulating the ALK5 receptor, we hypothesized that inhibiting the ALK5 receptor would inhibit astrocyte generation.	17	22	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta1	TGFbeta1	TGFbeta1	ALK5	ALK5	ALK5	17	18	21	22
TGF-beta1 induces stable myofibroblast differentiation independent of autocrine ALK5 signaling .	TGF-beta1 induces stable myofibroblast differentiation independent of autocrine ALK5 signaling.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	0	1	8	9
TGF-beta1 also induced ALK5 dependent downregulation of Notch1 but not of its ligand delta like ligand 4 .	TGF-beta1 also induced ALK5 dependent downregulation of Notch1 but not of its ligand delta like ligand 4.	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	0	1	3	4
As shown in XREF_FIG , Western blot analysis revealed that TGF-beta1 treatment of cultured rat pulmonary fibroblasts resulted in up-regulation of the TGF-beta receptor type I and II by 1.7 and 1.8 fold , respectively , as compared to non induced cells .	As shown in XREF_FIG, Western blot analysis revealed that TGF-beta1 treatment of cultured rat pulmonary fibroblasts resulted in up-regulation of the TGF-beta receptor type I and II by 1.7 and 1.8 fold, respectively, as compared to non induced cells.	10	26	up-regulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TGF-beta receptor type I	TGF-beta receptor type I	TGF-beta receptor type I	10	11	22	26
Small round chondrocytes showed widely distributed immunoreactivity of TGF-beta1 , TbetaR-I and TbetaR-II in the 42-day explants treated with TGF-beta1 .	Small round chondrocytes showed widely distributed immunoreactivity of TGF-beta1, TbetaR-I and TbetaR-II in the 42-day explants treated with TGF-beta1.	6	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaR-I	TbetaR-I	TbetaR-I	19	20	10	11
XREF_BIBR In general , TGF-beta1 stimulates ALK-5 and phosphorylates second messenger proteins termed Smads .	XREF_BIBR In general, TGF-beta1 stimulates ALK-5 and phosphorylates second messenger proteins termed Smads.	4	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK-5	ALK-5	ALK-5	4	5	6	7
Stimulation with IGF-1 resulted in an enhanced expression of IGF1R and TGFBR2 whereas TGF-beta1 stimulated TGFBR1 in the monolayer and pellet cultures .	Stimulation with IGF-1 resulted in an enhanced expression of IGF1R and TGFBR2 whereas TGF-beta1 stimulated TGFBR1 in the monolayer and pellet cultures.	13	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TGFBR1	TGFBR1	TGFBR1	13	14	15	16
In both species , TGFbeta1 decreased Pparg and increased Tgfbr1 ; both were unaffected by IL-10 .	In both species, TGFbeta1 decreased Pparg and increased Tgfbr1; both were unaffected by IL-10.	4	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta1	TGFbeta1	TGFbeta1	Tgfbr1	Tgfbr1	Tgfbr1	4	5	9	10
This indicated a possible mechanism by which TGF-beta1 triggered the down-regulation of ALK5 mRNA and protein , leading to the desensitization of grass carp leukocytes toward TGF-beta1 .	This indicated a possible mechanism by which TGF-beta1 triggered the down-regulation of ALK5 mRNA and protein, leading to the desensitization of grass carp leukocytes toward TGF-beta1.	7	13	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	7	8	12	13
Notably , we found that these cellular responses described above did not require persistent TGF-beta1 stimulation ( XREF_FIG ) , indicating that one possible mechanism by which TGF-beta1 triggered down-regulation of ALK5 protein and mRNA expression , leads to the desensitization of the leukocytes toward TGF-beta1 stimulation .	Notably, we found that these cellular responses described above did not require persistent TGF-beta1 stimulation (XREF_FIG), indicating that one possible mechanism by which TGF-beta1 triggered down-regulation of ALK5 protein and mRNA expression, leads to the desensitization of the leukocytes toward TGF-beta1 stimulation.	27	32	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	27	28	31	32
In ECs , TGF-beta1 activation of ALK5 is growth inhibitory and is thought to mediate vessel stability XREF_BIBR .	In ECs, TGF-beta1 activation of ALK5 is growth inhibitory and is thought to mediate vessel stability XREF_BIBR.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	3	4	6	7
The microscopy pictures showed that TGF-beta1 activates TGFBR1 , which is indicated by the foci of p-TGFBR 1 ; and the downregulation of IDH1 increased the foci number of p-TGFBR 1 .	The microscopy pictures showed that TGF-beta1 activates TGFBR1, which is indicated by the foci of p-TGFBR 1; and the downregulation of IDH1 increased the foci number of p-TGFBR 1.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TGFBR1	TGFBR1	TGFBR1	5	6	7	8
Additionally , to address the issue that whether Akt and USP4 regulate the interaction between Smurf2 and Smad7 , and Smurf2 and TbetaRI induced by TGF-beta1 , immunoprecipitation and Western blot assays were carried out .	Additionally, to address the issue that whether Akt and USP4 regulate the interaction between Smurf2 and Smad7, and Smurf2 and TbetaRI induced by TGF-beta1, immunoprecipitation and Western blot assays were carried out.	5	31	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaRI	TbetaRI	TbetaRI	25	26	22	23
TGF-beta1 induces assembly of TbetaRI and TbetaRII into a complex at the cell surface followed by phosphorylation of Smad transcription factors , nuclear translocation of activated Smads , and transcriptional responses XREF_BIBR .	TGF-beta1 induces assembly of TbetaRI and TbetaRII into a complex at the cell surface followed by phosphorylation of Smad transcription factors, nuclear translocation of activated Smads, and transcriptional responses XREF_BIBR.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaRI	TbetaRI	TbetaRI	0	1	4	5
After stroke , TGFbeta1 expression is rapidly increased and activates its cell surface receptor ALK5 in astrocyte , which then enhances RGMa expression .	After stroke, TGFbeta1 expression is rapidly increased and activates its cell surface receptor ALK5 in astrocyte, which then enhances RGMa expression.	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta1	TGFbeta1 expression	tgfbeta1	ALK5	ALK5	alk5	3	4	14	15
Thus , our findings are in complete agreement with the signalling imbalance model XREF_BIBR , XREF_BIBR of tilting the ALK1 and ALK5 signalling balance towards a non endoglin modulated TGF-beta1 activated ALK5 and TbetaRII pathway .	Thus, our findings are in complete agreement with the signalling imbalance model XREF_BIBR, XREF_BIBR of tilting the ALK1 and ALK5 signalling balance towards a non endoglin modulated TGF-beta1 activated ALK5 and TbetaRII pathway.	28	34	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	29	30	31	32
Therefore TbetaRI and TGF-beta-mediated activation of MAPK are indispensable for Linker specific phosphorylation of Smad3 [ XREF_BIBR ] .	Therefore TbetaRI and TGF-beta-mediated activation of MAPK are indispensable for Linker specific phosphorylation of Smad3 [XREF_BIBR].	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TbetaRI	TbetaRI	TbetaRI	MAPK	MAPK	MAPK	1	2	6	7
TGF-beta receptor type I has dual specificity kinase activities that phosphorylate R-SMAD proteins including SMAD3 [ XREF_BIBR , XREF_BIBR ] , activate the ERK MAPK pathway .	TGF-beta receptor type I has dual specificity kinase activities that phosphorylate R-SMAD proteins including SMAD3 [XREF_BIBR, XREF_BIBR], activate the ERK MAPK pathway.	0	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta receptor type I	TGF-beta receptor type I has dual specificity kinase activities that phosphorylate R-SMAD proteins	tgf-beta receptor type i	ERK MAPK	ERK MAPK	erk mapk	0	4	23	25
A previous study suggested that inhibition of TbetaRI activity blocked TGF-beta-induced MAPK activation .	A previous study suggested that inhibition of TbetaRI activity blocked TGF-beta-induced MAPK activation.	7	12	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRI	TbetaRI	TbetaRI	MAPK	MAPK	MAPK	7	8	11	12
However , it is also possible that ERK activation is initiated by the tyrosine kinase domain of ALK5 and that PAR2 promotes ERK activation in an indirect fashion by sustaining the expression of ALK5 [ XREF_BIBR ] .	However, it is also possible that ERK activation is initiated by the tyrosine kinase domain of ALK5 and that PAR2 promotes ERK activation in an indirect fashion by sustaining the expression of ALK5 [XREF_BIBR].	7	18	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	ERK	ERK	ERK	17	18	7	8
We also determined that Lewis y antigen , an important component of the transmembrane glycoproteins TbetaRI and TbetaRII , can up-regulate TGF-beta1-dependent ERK and PI3K signaling pathways to promote ovarian cancer cell proliferation ( unpublished data ) .	We also determined that Lewis y antigen, an important component of the transmembrane glycoproteins TbetaRI and TbetaRII, can up-regulate TGF-beta1-dependent ERK and PI3K signaling pathways to promote ovarian cancer cell proliferation (unpublished data).	10	26	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRI	TbetaRI	TbetaRI	ERK	ERK	ERK	15	16	22	23
However , ALK5 may also be able to activate ERK by transactivation of other receptors that stimulate ERK1/2 , such as epidermal growth factor receptor ( EGFR ) [ XREF_BIBR ] or PAR2 .	However, ALK5 may also be able to activate ERK by transactivation of other receptors that stimulate ERK1/2, such as epidermal growth factor receptor (EGFR) [XREF_BIBR] or PAR2.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	ERK	ERK	ERK	2	3	9	10
The failure of SB431542 to decrease the MMP9 mRNA levels in Rac1b depleted and TGF-beta1-treated cells is likely due to the fact that ERK activation by TGF-beta is mediated by the tyrosine kinase rather than the serine/threonine kinase function of ALK5 21 .	The failure of SB431542 to decrease the MMP9 mRNA levels in Rac1b depleted and TGF-beta1-treated cells is likely due to the fact that ERK activation by TGF-beta is mediated by the tyrosine kinase rather than the serine/threonine kinase function of ALK5 21.	23	41	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	ERK	ERK	ERK	40	41	23	24
The ERK pathway is stimulated by activated ALK5 through tyrosine phosphorylation of the adaptor protein Shc , allowing docking of the Grb2 and Sos1 complex which subsequently leads to downstream activation of the Ras-Raf-MEK-ERK pathway 21 .	The ERK pathway is stimulated by activated ALK5 through tyrosine phosphorylation of the adaptor protein Shc, allowing docking of the Grb2 and Sos1 complex which subsequently leads to downstream activation of the Ras-Raf-MEK-ERK pathway 21.	1	8	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	ERK	ERK	ERK	7	8	1	2
Moreover , PAR2 and TGF-beta and ALK5 activate the same intracellular signaling pathways ( ERK1/2 and p38 mitogen activated protein kinase ( MAPK ) , protein kinase C , Rac and PAK , c-Src , NFkappaB ) and intermediates ( reactive oxygen species , Ca 2+ ) [ XREF_BIBR ] , while others are receptor ( class )-specific such as phosphatidylinositol ( 3-5 )-trisphosphate and beta-arrestin-2 signaling for PAR2 [ XREF_BIBR , XREF_BIBR ] and signaling through Smad proteins for TGF-beta and ALK5 [ XREF_BIBR ] .	Moreover, PAR2 and TGF-beta and ALK5 activate the same intracellular signaling pathways (ERK1/2 and p38 mitogen activated protein kinase (MAPK), protein kinase C, Rac and PAK, c-Src, NFkappaB) and intermediates (reactive oxygen species, Ca 2+) [XREF_BIBR], while others are receptor (class)-specific such as phosphatidylinositol (3-5)-trisphosphate and beta-arrestin-2 signaling for PAR2 [XREF_BIBR, XREF_BIBR] and signaling through Smad proteins for TGF-beta and ALK5 [XREF_BIBR].	2	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	ERK1/2	ERK1/2	ERK1/2	6	7	14	15
Erk activation by TGF-b and ALK5 has also been shown to be mediated by the tyrosine kinase function of ALK5 [ XREF_BIBR ] .	Erk activation by TGF-b and ALK5 has also been shown to be mediated by the tyrosine kinase function of ALK5 [XREF_BIBR].	0	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Erk	Erk	Erk	19	20	0	1
Rac1b depletion also strongly increased basal ERK activation - independent of the kinase function of the TGF-beta type I receptor ALK5 - and sensitised cells towards further upregulation of phospho-ERK levels by TGF-beta1 , while ectopic overexpression of Rac1b had the reverse effect .	Rac1b depletion also strongly increased basal ERK activation - independent of the kinase function of the TGF-beta type I receptor ALK5 - and sensitised cells towards further upregulation of phospho-ERK levels by TGF-beta1, while ectopic overexpression of Rac1b had the reverse effect.	4	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	ERK	ERK	ERK	16	20	6	7
XREF_BIBR reported that activated TbetaRI binds and phosphorylates ShcA proteins on tyrosine and serine residues , which induces the recruitment of Grb2 and Sos to TbetaRI , and hence activation of Ras , Raf and ERK .	XREF_BIBR reported that activated TbetaRI binds and phosphorylates ShcA proteins on tyrosine and serine residues, which induces the recruitment of Grb2 and Sos to TbetaRI, and hence activation of Ras, Raf and ERK.	17	36	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	TbetaRI	TbetaRI	TbetaRI	ERK	ERK	ERK	25	26	35	36
It was observed an enrichment of MAPK related genes , represented in our results by upregulation , in the tumor samples , of TGB1 , TGFB2 and TGFBR1 that were shown to activate the MAPK pathway 46 .	It was observed an enrichment of MAPK related genes, represented in our results by upregulation, in the tumor samples, of TGB1, TGFB2 and TGFBR1 that were shown to activate the MAPK pathway 46.	8	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFBR1	TGFBR1	TGFBR1	MAPK	MAPK	MAPK	27	28	34	35
In summary , these results present convincing evidence to support our emerging view that SLC35F2 contributes to the progression of PTC through the TGFBR1 mediated MAPK pathway activation .	In summary, these results present convincing evidence to support our emerging view that SLC35F2 contributes to the progression of PTC through the TGFBR1 mediated MAPK pathway activation.	15	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFBR1	TGFBR1	TGFBR1	MAPK	MAPK	MAPK	23	24	25	26
Ox-LDL ( 50 microg/mL ) induced an acute increase in ERK activity within 15 min , which decreased to control value at 2 h. Incubation with anti-TGF-beta or SB-431542 , an inhibitor of the TGF-beta type I receptor , along with Ox-LDL , inhibited the expected increase in ERK phosphorylation .	Ox-LDL (50 microg/mL) induced an acute increase in ERK activity within 15 min, which decreased to control value at 2 h. Incubation with anti-TGF-beta or SB-431542, an inhibitor of the TGF-beta type I receptor, along with Ox-LDL, inhibited the expected increase in ERK phosphorylation.	10	44	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	ERK	ERK	ERK	34	38	10	11
Shedding of CRIPTO by PGAP6 modulates Nodal signaling : Shed CRIPTO acted on other cells as a Nodal coreceptor , whereas cell associated CRIPTO activity was decreased by coexpression of PGAP6 .	Shedding of CRIPTO by PGAP6 modulates Nodal signaling : Shed CRIPTO acted on other cells as a Nodal coreceptor, whereas cell associated CRIPTO activity was decreased by coexpression of PGAP6.	0	7	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CRIPTO	CRIPTO	CRIPTO	Nodal	Nodal	Nodal	2	3	6	7
Thus , we propose that Cripto stimulates Nodal activity by localizing it at the interface of endosomes with cytoplasmic effectors .	Thus, we propose that Cripto stimulates Nodal activity by localizing it at the interface of endosomes with cytoplasmic effectors.	5	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	5	6	7	8
According to this model , Cripto and GRP78 cooperatively attenuate cytostatic Smad2/3 signaling in response to activin and TGF-beta and cause activin , Nodal and TGF-beta to promote stemness and oncogenesis through coordination of restricted Smad2/3 signaling and activation of Src , MAPK and PI3K pathways .	According to this model, Cripto and GRP78 cooperatively attenuate cytostatic Smad2/3 signaling in response to activin and TGF-beta and cause activin, Nodal and TGF-beta to promote stemness and oncogenesis through coordination of restricted Smad2/3 signaling and activation of Src, MAPK and PI3K pathways.	5	24	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	5	6	23	24
Knockdown of GRP78 alone appeared to cause a modest inhibition of Nodal signaling whereas knockdown of Cripto and GRP78 together inhibited Nodal signaling to a greater extent than knockdown of either Cripto or GRP78 alone ( XREF_FIG ) .	Knockdown of GRP78 alone appeared to cause a modest inhibition of Nodal signaling whereas knockdown of Cripto and GRP78 together inhibited Nodal signaling to a greater extent than knockdown of either Cripto or GRP78 alone (XREF_FIG).	14	22	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	16	17	21	22
Although transfection of wild-type cripto potently stimulated the activity of Nodal , Cripto F78A was completely inactive in this assay ( XREF_FIG ) .	Although transfection of wild-type cripto potently stimulated the activity of Nodal, Cripto F78A was completely inactive in this assay (XREF_FIG).	1	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cripto	cripto	cripto	Nodal	Nodal	Nodal	4	5	10	11
Mosaic lineage tracing studies revealed that Nodal and Cripto and caAlk4 induced cardiac markers cell non autonomously , thus supporting the idea that Cerberus or another diffusible factor is an essential mediator of Nodal induced cardiogenesis .	Mosaic lineage tracing studies revealed that Nodal and Cripto and caAlk4 induced cardiac markers cell non autonomously, thus supporting the idea that Cerberus or another diffusible factor is an essential mediator of Nodal induced cardiogenesis.	6	34	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	8	9	33	34
Thus , our results indicate that Cripto and GRP78 can cooperate to promote tumor growth in part by facilitating mitogenic effects of Nodal and causing activin-A and TGF-beta1 to switch from being cytostatic to pro proliferative in nature .	Thus, our results indicate that Cripto and GRP78 can cooperate to promote tumor growth in part by facilitating mitogenic effects of Nodal and causing activin-A and TGF-beta1 to switch from being cytostatic to pro proliferative in nature.	6	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	6	7	22	23
Foxh1 and Cripto mediate the Nodal signaling pathway [ XREF_BIBR , XREF_BIBR ] .	Foxh1 and Cripto mediate the Nodal signaling pathway [XREF_BIBR, XREF_BIBR].	0	7	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	2	3	5	6
Notably , knockdown of Cripto and GRP78 together caused activin-A , activin-B and TGF-beta1 signaling to be enhanced to a greater extent than knockdown of either protein alone and reduced Nodal signaling to undetectable levels ( XREF_FIG ) .	Notably, knockdown of Cripto and GRP78 together caused activin-A, activin-B and TGF-beta1 signaling to be enhanced to a greater extent than knockdown of either protein alone and reduced Nodal signaling to undetectable levels (XREF_FIG).	2	31	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	4	5	30	31
Loss of the Cripto gene in mice dramatically reduces , but does not completely abolish , Nodal activity leading to the absence of a morphological primitive streak .	Loss of the Cripto gene in mice dramatically reduces, but does not completely abolish, Nodal activity leading to the absence of a morphological primitive streak.	3	17	abolish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	3	4	16	17
Interestingly , Cripto and GRP78 signaling inhibited cytostatic effects of activin and TGF-beta and promoted pro proliferative responses to activin , TGF-beta and Nodal in both MCF10A cells and in NCCIT cells [ XREF_BIBR , XREF_BIBR ] .	Interestingly, Cripto and GRP78 signaling inhibited cytostatic effects of activin and TGF-beta and promoted pro proliferative responses to activin, TGF-beta and Nodal in both MCF10A cells and in NCCIT cells [XREF_BIBR, XREF_BIBR].	2	24	promoted	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	2	3	23	24
By contrast , shRNA knockdown of Cripto significantly decreased Nodal signaling ( XREF_FIG ) .	By contrast, shRNA knockdown of Cripto significantly decreased Nodal signaling (XREF_FIG).	4	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	6	7	9	10
According to this model , Cripto and GRP78 cooperatively inhibit cytostatic Smad2/3 signaling in response to activin and TGF-beta and cause activin , Nodal and TGF-beta to adopt pro proliferative effects .	According to this model, Cripto and GRP78 cooperatively inhibit cytostatic Smad2/3 signaling in response to activin and TGF-beta and cause activin, Nodal and TGF-beta to adopt pro proliferative effects.	5	24	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	5	6	23	24
A soluble form of Cripto lacking the COOH-terminal region interacted with Nodal but failed to mediate Nodal signalling , indicating that the native Cripto protein functions as a membrane bound co-receptor for Nodal .	A soluble form of Cripto lacking the COOH-terminal region interacted with Nodal but failed to mediate Nodal signalling, indicating that the native Cripto protein functions as a membrane bound co-receptor for Nodal.	2	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	4	5	16	17
Understanding how Cripto stimulates Nodal dependent cell movements in the visceral endoderm and epiblast is fundamental to our understanding of how the A-P body axis is established in mammalian embryos .	Understanding how Cripto stimulates Nodal dependent cell movements in the visceral endoderm and epiblast is fundamental to our understanding of how the A-P body axis is established in mammalian embryos.	2	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	2	3	4	5
Another possibility for the mechanism by which Panda may antagonize Nodal is that Panda may work like the Nodal antagonist Lefty , by sequestering a factor essential for Nodal signaling such as the co-receptor Cripto , ACVRII , or Alk4/5/7 [ XREF_BIBR ] .	Another possibility for the mechanism by which Panda may antagonize Nodal is that Panda may work like the Nodal antagonist Lefty, by sequestering a factor essential for Nodal signaling such as the co-receptor Cripto, ACVRII, or Alk4/5/7 [XREF_BIBR].	28	41	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Cripto	Cripto	Cripto	Nodal	Nodal	Nodal	34	35	28	29
In contrast , 1.0 ng/mL of TGF-beta1 significantly increased TGFBR2 , which was inhibited by 100nM BAF treatment .	In contrast, 1.0 ng/mL of TGF-beta1 significantly increased TGFBR2, which was inhibited by 100nM BAF treatment.	4	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TGFBR2	TGFBR2	TGFBR2	6	7	9	10
TGF-beta1 mainly stimulates TGF-beta receptor type II ( TGFBR2 ) , which recruits TGF-beta receptor type I ( TGFBR1 ) to form a complex ( TGF-beta1+ TGFBR2+ TGFBR1 ) that activates the Smad pathway .	TGF-beta1 mainly stimulates TGF-beta receptor type II (TGFBR2), which recruits TGF-beta receptor type I (TGFBR1) to form a complex (TGF-beta1+ TGFBR2+ TGFBR1) that activates the Smad pathway.	0	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TGF-beta receptor type II	TGF-beta receptor type II	TGF-beta receptor type II	0	1	3	7
As shown in XREF_FIG ( Upper panel ) , TGF-beta1 alone induced down-regulation of TbetaRII at 24 hours , whereas in the presence of PMA , TbetaRII levels were sustained for at least 48 hours .	As shown in XREF_FIG (Upper panel), TGF-beta1 alone induced down-regulation of TbetaRII at 24 hours, whereas in the presence of PMA, TbetaRII levels were sustained for at least 48 hours.	9	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaRII	TbetaRII	TbetaRII	9	10	14	15
VASP knockdown inhibits TGF-beta1 downregulation of TbetaRII in HSCs .	VASP knockdown inhibits TGF-beta1 downregulation of TbetaRII in HSCs.	3	8	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaRII	TbetaRII	TbetaRII	3	4	6	7
11 Interestingly , TGF-beta1 induces TIAF1 self aggregation in a TbetaRII independent manner , and this may be related with binding of TGF-beta1 to membrane hyaluronidase Hyal-2 .	11 Interestingly, TGF-beta1 induces TIAF1 self aggregation in a TbetaRII independent manner, and this may be related with binding of TGF-beta1 to membrane hyaluronidase Hyal-2.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaRII	TbetaRII	TbetaRII	3	4	10	11
Given that TGF-beta1 signaling functions in the hypothalamic-pituitary-gonadal axis as well as intratesticular testosterone synthesis , the dysregulation of intratesticular testosterone synthesis due to Leydig cell specific deficiency of TGF-beta1 signaling in Tgfbr2 flox and flox Cyp17iCre testes might be partially restored by TGF-beta1 signaling in the brain .	Given that TGF-beta1 signaling functions in the hypothalamic-pituitary-gonadal axis as well as intratesticular testosterone synthesis, the dysregulation of intratesticular testosterone synthesis due to Leydig cell specific deficiency of TGF-beta1 signaling in Tgfbr2 flox and flox Cyp17iCre testes might be partially restored by TGF-beta1 signaling in the brain.	29	33	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	Tgfbr2	Tgfbr2	Tgfbr2	29	30	32	33
hENT1 is down-regulated by activation of TbetaRII by TGF-beta1 in HUVECs , a phenomenon where NO and Sp1 play key roles .	hENT1 is down-regulated by activation of TbetaRII by TGF-beta1 in HUVECs, a phenomenon where NO and Sp1 play key roles.	2	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaRII	TbetaRII	TbetaRII	8	9	6	7
TGFBR2 expression was significantly higher in cells treated with TGFbeta1 ( XREF_SUPPLEMENTARY ) .	TGFBR2 expression was significantly higher in cells treated with TGFbeta1 (XREF_SUPPLEMENTARY).	0	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta1	TGFbeta1	TGFbeta1	TGFBR2	TGFBR2	TGFBR2	9	10	0	1
The GlcNAcylation does not affect the hydroxylation activity of Tet2 and Tet3 , rather Tet2 and Tet3 were shown to promote Ogt activity by enhancing the localization of Ogt to chromatin .	The GlcNAcylation does not affect the hydroxylation activity of Tet2 and Tet3, rather Tet2 and Tet3 were shown to promote Ogt activity by enhancing the localization of Ogt to chromatin.	13	22	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tet2	Tet2	Tet2	Ogt	Ogt	Ogt	14	15	21	22
Since TET2 targets OGT to chromatin , we wondered whether TET2 regulates OGT dependent H2B GlcNAcylation .	Since TET2 targets OGT to chromatin, we wondered whether TET2 regulates OGT dependent H2B GlcNAcylation.	0	8	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TET2	TET2	TET2	OGT	OGT	OGT	1	2	3	4
Interestingly , knockdown of TET2 by shRNA in ES cells abolished the chromatin associated OGT , suggesting that TET2 may target OGT to chromatin ( XREF_SUPPLEMENTARY ) .	Interestingly, knockdown of TET2 by shRNA in ES cells abolished the chromatin associated OGT, suggesting that TET2 may target OGT to chromatin (XREF_SUPPLEMENTARY).	18	22	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TET2	TET2	TET2	OGT	OGT	OGT	18	19	21	22
TET2 promotes OGT activity and facilitates OGT dependent histone modification .	TET2 promotes OGT activity and facilitates OGT dependent histone modification.	0	5	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TET2	TET2	TET2	OGT	OGT	OGT	0	1	2	3
Loss of TET2 in ESCs prevents the association of OGT with chromatin , and overexpression of TET2 increases the level of chromatin bound OGT .	Loss of TET2 in ESCs prevents the association of OGT with chromatin, and overexpression of TET2 increases the level of chromatin bound OGT.	0	10	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TET2	Loss of TET2	tet2	OGT	OGT	ogt	2	3	9	10
Furthermore , TET2 and TET3 promote OGT activity , which in turn stabilizes the Set1 and COMPASS complex , responsible for bulk deposition of H3K4me3 ( XREF_FIG ) [ XREF_BIBR ] .	Furthermore, TET2 and TET3 promote OGT activity, which in turn stabilizes the Set1 and COMPASS complex, responsible for bulk deposition of H3K4me3 (XREF_FIG) [XREF_BIBR].	2	7	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TET2	TET2	TET2	OGT	OGT	OGT	2	3	6	7
It was reported that TET2 mediates OGT modification on H2B Ser112 and is associated with highly transcribed genes [ XREF_BIBR ] ; and that TET2 and TET3 recruit OGT to modify HCF1 ( Host cell factor 1 ) , an essential transcriptional regulator in the SET1 and COMPASS complex , which contains the MLL methyltransferase that deposits H3K4me3 [ XREF_BIBR ] .	It was reported that TET2 mediates OGT modification on H2B Ser112 and is associated with highly transcribed genes [XREF_BIBR]; and that TET2 and TET3 recruit OGT to modify HCF1 (Host cell factor 1), an essential transcriptional regulator in the SET1 and COMPASS complex, which contains the MLL methyltransferase that deposits H3K4me3 [XREF_BIBR].	4	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TET2	TET2	TET2	OGT	OGT	OGT	4	5	6	7
Depletion of Tet2 reduces O GlcNAcylation of H2B at Ser112 suggesting that Tet2 targets OGT to the nucleosome for H2B O GlcNAcylation supporting the link between DNA methylation and the histone code through OGT and O GlcNAcylation .	Depletion of Tet2 reduces O GlcNAcylation of H2B at Ser112 suggesting that Tet2 targets OGT to the nucleosome for H2B O GlcNAcylation supporting the link between DNA methylation and the histone code through OGT and O GlcNAcylation.	10	15	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tet2	Tet2	Tet2	OGT	OGT	OGT	12	13	14	15
Due to the different tissue distribution XREF_BIBR , XREF_BIBR - XREF_BIBR , it is TET2 that targets OGT to the chromatin and regulates H2B GlcNAcylation in ES cells .	Due to the different tissue distribution XREF_BIBR, XREF_BIBR - XREF_BIBR, it is TET2 that targets OGT to the chromatin and regulates H2B GlcNAcylation in ES cells.	10	22	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TET2	TET2	TET2	OGT	OGT	OGT	14	15	17	18
However , when mono-nucleosomes were used as the substrates , supplementation of recombinant TET2 significantly increased the enzymatic activity of wild type OGT but not the D2 mutant ( XREF_FIG , XREF_SUPPLEMENTARY ) , suggesting that the interaction with TET2 facilitates OGT to recognize the substrate .	However, when mono-nucleosomes were used as the substrates, supplementation of recombinant TET2 significantly increased the enzymatic activity of wild type OGT but not the D2 mutant (XREF_FIG, XREF_SUPPLEMENTARY), suggesting that the interaction with TET2 facilitates OGT to recognize the substrate.	10	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TET2	TET2	TET2	OGT	OGT	OGT	13	14	22	23
Concurrent with TET2 overexpression inducing OGT association with chromatin , H2B S112 GlcNAcylation was increased ( XREF_FIG ) .	Concurrent with TET2 overexpression inducing OGT association with chromatin, H2B S112 GlcNAcylation was increased (XREF_FIG).	2	6	inducing	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TET2	TET2 overexpression	tet2	OGT	OGT	ogt	2	3	5	6
To investigate whether Tcl1 also activates Akt1 in ES cells , Western blot analysis was performed .	To investigate whether Tcl1 also activates Akt1 in ES cells, Western blot analysis was performed.	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tcl1	Tcl1	Tcl1	Akt1	Akt1	Akt1	3	4	6	7
Interestingly , Akt1 was also found in the nucleus when AKT1 was cotransfected with TCL1 , suggesting that Tcl1 promotes the transport of Akt1 to the nucleus .	Interestingly, Akt1 was also found in the nucleus when AKT1 was cotransfected with TCL1, suggesting that Tcl1 promotes the transport of Akt1 to the nucleus.	18	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tcl1	Tcl1	Tcl1	Akt1	Akt1	Akt1	18	19	23	24
TCL1 enhanced hetero-oligomerization of Akt1 with Akt3 and as a consequence facilitated transphosphorylation of Akt molecules , which may contribute to Akt activation and TCL1 induced leukemogenesis in vivo .	TCL1 enhanced hetero-oligomerization of Akt1 with Akt3 and as a consequence facilitated transphosphorylation of Akt molecules, which may contribute to Akt activation and TCL1 induced leukemogenesis in vivo.	0	5	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	Akt1	Akt1	Akt1	0	1	4	5
It has been shown that Tcl1 enhances the kinase activity of Akt1 XREF_BIBR .	It has been shown that Tcl1 enhances the kinase activity of Akt1 XREF_BIBR.	5	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tcl1	Tcl1	Tcl1	Akt1	Akt1	Akt1	5	6	11	12
The only known function of Tcl1 protein is to enhance the kinase activity of Akt1 ( thymoma viral proto-oncogene 1 ) in leukemia cells XREF_BIBR .	The only known function of Tcl1 protein is to enhance the kinase activity of Akt1 (thymoma viral proto-oncogene 1) in leukemia cells XREF_BIBR.	5	18	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tcl1	Tcl1	Tcl1	Akt1	Akt1	Akt1	5	6	14	15
Mechanistically , Tcl1 increases Akt1 activity and may support an increased glycolysis , while Tcl1b1 suppresses the mitochondrial polynucleotide phosphorylase , thus impairing mitochondrial biogenesis and contributing to the switch from oxidative metabolism to glycolysis during reprogramming [ XREF_BIBR ] .	Mechanistically, Tcl1 increases Akt1 activity and may support an increased glycolysis, while Tcl1b1 suppresses the mitochondrial polynucleotide phosphorylase, thus impairing mitochondrial biogenesis and contributing to the switch from oxidative metabolism to glycolysis during reprogramming [XREF_BIBR].	2	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tcl1	Tcl1	Tcl1	Akt1	Akt1	Akt1	2	3	4	5
TCL1 is transcriptionally controlled by OCT4 and enhances the kinase activity of AKT1 , whose activation could promote cell proliferation XREF_BIBR .	TCL1 is transcriptionally controlled by OCT4 and enhances the kinase activity of AKT1, whose activation could promote cell proliferation XREF_BIBR.	0	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1	TCL1	TCL1	AKT1	AKT1	AKT1	0	1	12	13
However , it was shown that Ogt drives Tet3 out of the nucleus further affecting its activity on DNA .	However, it was shown that Ogt drives Tet3 out of the nucleus further affecting its activity on DNA.	6	14	drives	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tet3	Tet3	Tet3	Ogt	Ogt	Ogt	8	9	6	7
Besides TET2 , TET3 also interacts with OGT , indicating that TET3 might also target OGT to chromatin for gene transcription regulation .	Besides TET2, TET3 also interacts with OGT, indicating that TET3 might also target OGT to chromatin for gene transcription regulation.	11	16	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TET3	TET3	TET3	OGT	OGT	OGT	11	12	15	16
Interaction between Tet3 and OGT drives Tet3 out of the nucleus , concomitant with decreased 5hmC on DNA .	Interaction between Tet3 and OGT drives Tet3 out of the nucleus, concomitant with decreased 5hmC on DNA.	1	10	drives	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tet3	Tet3	Tet3	OGT	OGT	OGT	6	7	4	5
Like TET2 , TET3 might also target OGT to chromatin for gene transcription regulation .	Like TET2, TET3 might also target OGT to chromatin for gene transcription regulation.	3	8	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TET3	TET3	TET3	OGT	OGT	OGT	3	4	7	8
At gene specific loci , Tet3 targets OGT to GlcNAc transferase 9 ( GnT-XI ) promoters and the complex acts as a dock for the recruitment of NeuroD1 , required for the expression of GnT-XI in a brain specific manner [ XREF_BIBR ] .	At gene specific loci, Tet3 targets OGT to GlcNAc transferase 9 (GnT-XI) promoters and the complex acts as a dock for the recruitment of NeuroD1, required for the expression of GnT-XI in a brain specific manner [XREF_BIBR].	5	8	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tet3	Tet3	Tet3	OGT	OGT	OGT	5	6	7	8
TET2 and TET3 promote OGT mediated GlcNAcylation .	TET2 and TET3 promote OGT mediated GlcNAcylation.	0	5	promote	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TET3	TET3	TET3	OGT	OGT	OGT	2	3	4	5
TCL1A expression is associated with CD4 + and CD8 + T-cell activation through the phosphoinositide 3-kinase/Akt signaling pathway [ XREF_BIBR ] , and TCL1A enhances Akt kinase activity [ XREF_BIBR ] .	TCL1A expression is associated with CD4 + and CD8 + T-cell activation through the phosphoinositide 3-kinase/Akt signaling pathway [XREF_BIBR], and TCL1A enhances Akt kinase activity [XREF_BIBR].	23	27	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1A	TCL1A	TCL1A	Akt	Akt	Akt	23	24	25	26
In contrast , decreasing Tcl1a levels by small interfering RNA reduced Akt activation in the fludarabine-insensitive CLL cell line MEC-2 and sensitized the malignant cells to fludarabine treatment .	In contrast, decreasing Tcl1a levels by small interfering RNA reduced Akt activation in the fludarabine-insensitive CLL cell line MEC-2 and sensitized the malignant cells to fludarabine treatment.	4	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tcl1a	Tcl1a levels	tcl1a	Akt	Akt	akt	4	5	11	12
TCL1A expression enhances Akt serine threonine kinase activity , functioning as an Akt co- activator , and is usually associated with hematopoietic malignancies .	TCL1A expression enhances Akt serine threonine kinase activity, functioning as an Akt co- activator, and is usually associated with hematopoietic malignancies.	0	7	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1A	TCL1A expression	tcl1a	Akt	Akt	akt	0	1	3	4
We can safely to conclude that , PILRLS specific binding with and stabilized TCL1A which activating MDM2 and AKT , suppressing P53 , leading to promote proliferation in RLS .	We can safely to conclude that, PILRLS specific binding with and stabilized TCL1A which activating MDM2 and AKT, suppressing P53, leading to promote proliferation in RLS.	12	19	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1A	TCL1A	TCL1A	AKT	AKT	AKT	13	14	18	19
TCL1A is a co-activator of AKT , a serine/threonine protein kinase that regulates many cellular processes , including proliferation and survival XREF_BIBR , XREF_BIBR .	TCL1A is a co-activator of AKT, a serine/threonine protein kinase that regulates many cellular processes, including proliferation and survival XREF_BIBR, XREF_BIBR.	0	10	is a co-activator	Positive_activation_copula_1	Positive_activation	Positive_activation	TCL1A	TCL1A	TCL1A	AKT	AKT	AKT	0	1	5	6
Importantly , TCL1A also needs co-stimulatory signals to induce AKT activation , and the requirement of co-activators may constitute an additional control mechanism for TCL1A .	Importantly, TCL1A also needs co-stimulatory signals to induce AKT activation, and the requirement of co-activators may constitute an additional control mechanism for TCL1A.	2	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TCL1A	TCL1A	TCL1A	AKT	AKT	AKT	2	3	9	10
TET2 activates WT1 target genes .	TET2 activates WT1 target genes.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TET2	TET2	TET2	WT1	WT1	WT1	0	1	2	3
TGF-beta2 enhanced SOCE and potently stimulated the production of FGF23 , an effect significantly attenuated by SB431542 , an inhibitor of the transforming growth factor-beta ( TGF-beta ) type I receptor activin receptor like kinases ALK5 , ALK4 , and ALK7 .	TGF-beta2 enhanced SOCE and potently stimulated the production of FGF23, an effect significantly attenuated by SB431542, an inhibitor of the transforming growth factor-beta (TGF-beta) type I receptor activin receptor like kinases ALK5, ALK4, and ALK7.	0	40	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta2	TGF-beta2	TGF-beta2	ALK5	ALK5	ALK5	0	1	35	36
Overexpression of TGF-beta2 in severe asthmatics ' fibroblasts induced enhanced TGF-beta2 in exosomes leading to a reduced proliferation of epithelial cells , whereas knockdown of TGF-beta2 enhanced epithelial cell proliferation .	Overexpression of TGF-beta2 in severe asthmatics ' fibroblasts induced enhanced TGF-beta2 in exosomes leading to a reduced proliferation of epithelial cells, whereas knockdown of TGF-beta2 enhanced epithelial cell proliferation.	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta2	Overexpression of TGF-beta2	tgf-beta2	TGF-beta2	TGF-beta2	tgf-beta2	2	3	10	11
PRP upregulates expression of TGF-beta 2 in the retina , and increased TGF-beta 2 concentrations are found in the retina and the vitreous humor .	PRP upregulates expression of TGF-beta 2 in the retina, and increased TGF-beta 2 concentrations are found in the retina and the vitreous humor.	0	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta 2	PRP upregulates expression of TGF-beta 2	tgf-beta 2	TGF-beta 2	TGF-beta 2	tgf-beta 2	4	6	12	14
Loss of Tgfb3 or tissue specific inactivation of Tgfbr2 or Tgfbr1 in the palatal epithelium results in cleft palate with complete phenotype penetrance .	Loss of Tgfb3 or tissue specific inactivation of Tgfbr2 or Tgfbr1 in the palatal epithelium results in cleft palate with complete phenotype penetrance.	2	14	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Tgfb3	Tgfb3	Tgfb3	Tgfbr2	Tgfbr2	Tgfbr2	2	3	8	9
To verify if TFDP1 knockdown could inhibit the activating effect of E2F1 , luciferase experiments were performed with selected regions of the PITX1 promoter .	To verify if TFDP1 knockdown could inhibit the activating effect of E2F1, luciferase experiments were performed with selected regions of the PITX1 promoter.	3	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TFDP1	TFDP1	TFDP1	E2F1	E2F1	E2F1	3	4	11	12
To understand the possible role of the unique pleckstrin homology and Tec homology ( PHTH ) module of Btk , we have compared the enzymatic properties of full-length Btk and a Btk mutant lacking the PHTH module ( BtkDeltaPHTH ) .	To understand the possible role of the unique pleckstrin homology and Tec homology (PHTH) module of Btk, we have compared the enzymatic properties of full-length Btk and a Btk mutant lacking the PHTH module (BtkDeltaPHTH).	11	19	module	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tec	Tec	Tec	Btk	Btk	Btk	11	12	18	19
Taken together , these results show that loss of BRCA1 or reduced BRCA1 expression significantly modulated TGF-beta induced activation of Smad3 and Smad4 in breast cancer cells .	Taken together, these results show that loss of BRCA1 or reduced BRCA1 expression significantly modulated TGF-beta induced activation of Smad3 and Smad4 in breast cancer cells.	16	22	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	16	17	20	21
In addition , TGFbeta induces the binding of a Smad3 and Smad4 containing nuclear complex to CAGA boxes .	In addition, TGFbeta induces the binding of a Smad3 and Smad4 containing nuclear complex to CAGA boxes.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	3	4	9	10
TGFbeta induced Smad3 downregulation in myofibroblast .	TGFbeta induced Smad3 downregulation in myofibroblast.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	0	1	2	3
TGFbeta and activin signals activate the R-SMADs : SMAD2 and SMAD3 , while BMP signals activate SMAD1 , SMAD5 , and SMAD8 XREF_BIBR XREF_BIBR .	TGFbeta and activin signals activate the R-SMADs : SMAD2 and SMAD3, while BMP signals activate SMAD1, SMAD5, and SMAD8 XREF_BIBR XREF_BIBR.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	0	1	10	11
The binding of Smad3 or Smad4 to E1 and E4 was further confirmed in vivo by chromatin immunoprecipitation ( CHIP ) assays , which revealed that TGFbeta increased the binding of Smad3 or Smad4 to E1 and E4 of PRL-3 promoter in FET cells ( XREF_FIG ) .	The binding of Smad3 or Smad4 to E1 and E4 was further confirmed in vivo by chromatin immunoprecipitation (CHIP) assays, which revealed that TGFbeta increased the binding of Smad3 or Smad4 to E1 and E4 of PRL-3 promoter in FET cells (XREF_FIG).	26	33	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	26	27	31	32
OTUB1 was identified as a novel interactor of GFP-SMAD3 only when cells were treated with TGFbeta ( XREF_FIG ) .	OTUB1 was identified as a novel interactor of GFP-SMAD3 only when cells were treated with TGFbeta (XREF_FIG).	6	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	GFP-SMAD3	GFP-SMAD3	GFP-SMAD3	15	16	8	9
Interference with TGF-beta signaling in Smad3 deficient mice limits diabetic glomerulosclerosis without affecting albuminuria 37 .	Interference with TGF-beta signaling in Smad3 deficient mice limits diabetic glomerulosclerosis without affecting albuminuria 37.	2	6	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	2	3	5	6
Furthermore , co-treatment of the cells with GnRH + TGF-beta , or pretreatment with TGF-beta type II receptor antisense to block TGF-beta autocrine and paracrine action , in part inhibited TGF-beta activated Smad3 .	Furthermore, co-treatment of the cells with GnRH + TGF-beta, or pretreatment with TGF-beta type II receptor antisense to block TGF-beta autocrine and paracrine action, in part inhibited TGF-beta activated Smad3.	29	33	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	30	31	32	33
Hif1alpha has been shown to regulate collagen I ( alpha2 ) expression by TGFbeta stimulated Smad 3 XREF_BIBR .	Hif1alpha has been shown to regulate collagen I (alpha2) expression by TGFbeta stimulated Smad 3 XREF_BIBR.	11	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad 3	Smad 3	Smad 3	13	14	15	17
Smad3 variants exhibit quantitative differences in the TGF-beta inducibilty of six Smad3 regulated genes in C2C12 cells .	Smad3 variants exhibit quantitative differences in the TGF-beta inducibilty of six Smad3 regulated genes in C2C12 cells.	7	13	inducibilty	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	7	8	11	12
Upon activation , TGF-beta activates Smad3 , which subsequently translocates into the nucleus and initiates transcription of target genes .	Upon activation, TGF-beta activates Smad3, which subsequently translocates into the nucleus and initiates transcription of target genes.	3	16	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TGF-beta	TGF-beta	tgf-beta	Smad3	Smad3, which subsequently translocates into the nucleus and initiates transcription	smad3	3	4	5	6
It is well-known that TGF-beta activates downstream mediators SMAD2 and SMAD3 , and the TGF-beta and SMAD pathway is negatively regulated by SMAD7 .	It is well-known that TGF-beta activates downstream mediators SMAD2 and SMAD3, and the TGF-beta and SMAD pathway is negatively regulated by SMAD7.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	4	5	10	11
ChIP indicates that TGF-beta treatment stimulates the binding of SMAD3 to the promoter region of S1PR3 .	ChIP indicates that TGF-beta treatment stimulates the binding of SMAD3 to the promoter region of S1PR3.	3	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	3	4	9	10
ChIP-qPCR of SMAD3 at HIF-1alpha binding sites near COL1A1 and SERPINE1 indicated that HIF-1alpha promotes the bindings of SMAD3 , which is induced by TGF-beta .	ChIP-qPCR of SMAD3 at HIF-1alpha binding sites near COL1A1 and SERPINE1 indicated that HIF-1alpha promotes the bindings of SMAD3, which is induced by TGF-beta.	16	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	24	25	18	19
TGF-beta and IL-2 treatment enhanced co-immunoprecipitation of Smad3 and Stat5 with Tet1 and Tet2 in T cells while TGF-beta and IL-2 neutralizing antibody attenuated the co-immunoprecipitation of Smad3 and Stat5 with Tet1 and Tet2 in Treg cells ( XREF_FIG ) .	TGF-beta and IL-2 treatment enhanced co-immunoprecipitation of Smad3 and Stat5 with Tet1 and Tet2 in T cells while TGF-beta and IL-2 neutralizing antibody attenuated the co-immunoprecipitation of Smad3 and Stat5 with Tet1 and Tet2 in Treg cells (XREF_FIG).	0	9	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	7	8
Our findings suggest that increased cardiac ACE activity can increase cardiac collagen content by degradation of AcSDKP , an inhibitor of the phosphorylation of transforming growth factor-beta signaling molecules Smad2 and Smad3 .	Our findings suggest that increased cardiac ACE activity can increase cardiac collagen content by degradation of AcSDKP, an inhibitor of the phosphorylation of transforming growth factor-beta signaling molecules Smad2 and Smad3.	22	32	signaling	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	transforming growth factor-beta	phosphorylation of transforming growth factor-beta	transforming growth factor-beta	Smad3	Smad3	smad3	24	27	31	32
We also determined whether TGF-beta regulates the expression Smads and activates Smad3 in these cells and endometrial surface epithelial cell line ( HES ) .	We also determined whether TGF-beta regulates the expression Smads and activates Smad3 in these cells and endometrial surface epithelial cell line (HES).	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	4	5	11	12
While TGFbeta stimulated the association of SNX9 and pSmad3 with the nuclear membrane , only pSmad3 entered the nucleus and bound chromatin ( XREF_FIG ) .	While TGFbeta stimulated the association of SNX9 and pSmad3 with the nuclear membrane, only pSmad3 entered the nucleus and bound chromatin (XREF_FIG).	1	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	pSmad3	pSmad3	pSmad3	1	2	8	9
TGF-beta induced the enrichment of Smad3 on the PAI-1 promoter , and this enrichment was abolished by STAT3C ( XREF_FIG ) .	TGF-beta induced the enrichment of Smad3 on the PAI-1 promoter, and this enrichment was abolished by STAT3C (XREF_FIG).	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	5	6
TGF-beta induced the expression of fibrosis markers by mediating Smad3 .	TGF-beta induced the expression of fibrosis markers by mediating Smad3.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	9	10
TGFbeta has also been shown to activate Smad3 , leading to glial scar formation after a cortical stab injury .	TGFbeta has also been shown to activate Smad3, leading to glial scar formation after a cortical stab injury.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	0	1	7	8
An E3 ubiquitin ligase complex RBX1 and SCFbeta -TrCP is responsible for the ubiquitination of TGFbeta activated Smad3 .	An E3 ubiquitin ligase complex RBX1 and SCFbeta -TrCP is responsible for the ubiquitination of TGFbeta activated Smad3.	13	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	ubiquitination of TGFbeta	tgfbeta	Smad3	Smad3	smad3	15	16	17	18
Western blot results also showed that silencing TRAF6 expression can inhibit the activation of SMAD2 , SMAD3 , ERK , p38 , and JNK induced by TGF-beta in SACC cells .	Western blot results also showed that silencing TRAF6 expression can inhibit the activation of SMAD2, SMAD3, ERK, p38, and JNK induced by TGF-beta in SACC cells.	12	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	26	27	16	17
These findings suggest that the Sox9 dependent chondrogenesis might be strictly controlled by TGF-beta signal Smad3 and chromatin remodeling factor p300 .	These findings suggest that the Sox9 dependent chondrogenesis might be strictly controlled by TGF-beta signal Smad3 and chromatin remodeling factor p300.	11	20	signal	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	13	14	15	16
However , increased cAMP levels are able to inhibit TGF-beta induced interaction of Smad3 with its transcriptional co-activator cAMP response element binding protein ( CREB )-binding protein ( CBP )/p300 XREF_BIBR , XREF_BIBR .	However, increased cAMP levels are able to inhibit TGF-beta induced interaction of Smad3 with its transcriptional co-activator cAMP response element binding protein (CREB)-binding protein (CBP)/p300 XREF_BIBR, XREF_BIBR.	8	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	9	10	13	14
Nucleus pulposus cells were co-transfected with DN-Smad3 ( XREF_FIG ) or siRNA against Smad3 ( XREF_SUPPLEMENTARY ) and then treated with TGFbeta .	Nucleus pulposus cells were co-transfected with DN-Smad3 (XREF_FIG) or siRNA against Smad3 (XREF_SUPPLEMENTARY) and then treated with TGFbeta.	11	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	21	22	13	14
However , SMAD3 , which is principally activated by activin and TGFbeta rather than BMP4 , also increases .	However, SMAD3, which is principally activated by activin and TGFbeta rather than BMP4, also increases.	2	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	11	12	2	3
XREF_BIBR , XREF_BIBR , XREF_BIBR TGFbeta , a key bone matrix and tumor cell derived factor , significantly contributes to osteolytic bone metastasis by regulating Smad2 and Smad3 .	XREF_BIBR, XREF_BIBR, XREF_BIBR TGFbeta, a key bone matrix and tumor cell derived factor, significantly contributes to osteolytic bone metastasis by regulating Smad2 and Smad3.	2	28	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	5	6	27	28
Here we find that not all MDA-MB-231 cancer cells have similar TGF-beta mediated Smad3 transcription activity and display at least two distinct migratory populations .	Here we find that not all MDA-MB-231 cancer cells have similar TGF-beta mediated Smad3 transcription activity and display at least two distinct migratory populations.	9	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	11	12	13	14
Specifically , Smad3 signaling initiated by TGF-beta is a potent inhibitory signal that leads to deceleration of chondrocyte maturation in vitro [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] and delayed endochondral ossification in vivo [ XREF_BIBR ] .	Specifically, Smad3 signaling initiated by TGF-beta is a potent inhibitory signal that leads to deceleration of chondrocyte maturation in vitro [XREF_BIBR; XREF_BIBR; XREF_BIBR] and delayed endochondral ossification in vivo [XREF_BIBR].	2	7	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	6	7	2	3
In contrast to the physiological role of TGF-beta that regulates cell growth and differentiation , the authors find that circulating , pathological levels of TGF-beta activate a SMAD3 signaling pathway in both proximal and distal skeletal muscles that leads to the oxidation and nitrosylation of the ryanodine receptor 5 ( RyR1 ) .	In contrast to the physiological role of TGF-beta that regulates cell growth and differentiation, the authors find that circulating, pathological levels of TGF-beta activate a SMAD3 signaling pathway in both proximal and distal skeletal muscles that leads to the oxidation and nitrosylation of the ryanodine receptor 5 (RyR1).	22	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	levels of TGF-beta	tgf-beta	SMAD3	SMAD3	smad3	24	25	27	28
Smad3 and NFAT , activated by TGF-beta and TCR mediated signaling , respectively , cooperate in Foxp3 gene remodeling and expression .	Smad3 and NFAT, activated by TGF-beta and TCR mediated signaling, respectively, cooperate in Foxp3 gene remodeling and expression.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	6	7	0	1
Smad signaling is demonstrated as a major pathway of TGF-beta signaling in DN and Smad3 is highly activated during fibrogenesis .	Smad signaling is demonstrated as a major pathway of TGF-beta signaling in DN and Smad3 is highly activated during fibrogenesis.	9	15	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	9	10	14	15
Here , we show that Smad3 activated by TGF-beta is degraded by the ubiquitin-proteasome pathway .	Here, we show that Smad3 activated by TGF-beta is degraded by the ubiquitin-proteasome pathway.	5	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	5	6
TGFbeta treatment equally induced the nuclear accumulation of Smad2 and Smad3 in wild-type and IRAK-1 -/- cells ( XREF_FIG ) .	TGFbeta treatment equally induced the nuclear accumulation of Smad2 and Smad3 in wild-type and IRAK-1 -/- cells (XREF_FIG).	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	0	1	10	11
The development of pTregs is particularly dependent on TGFbeta activation of pSmad3 through its action on CNS1 of Foxp3 .	The development of pTregs is particularly dependent on TGFbeta activation of pSmad3 through its action on CNS1 of Foxp3.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	pSmad3	pSmad3	pSmad3	8	9	11	12
Using ChIP-QPCR , we confirmed that TGF-beta induced Smad3 occupancy at the EFNA1 promoter to a much greater extent in M3 than M4 cells , reflecting a more active state of the chromatin at the EFNA1 promoter in M3 than M4 cells under basal conditions .	Using ChIP-QPCR, we confirmed that TGF-beta induced Smad3 occupancy at the EFNA1 promoter to a much greater extent in M3 than M4 cells, reflecting a more active state of the chromatin at the EFNA1 promoter in M3 than M4 cells under basal conditions.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	6	7	8	9
In human breast cancer cells TGF-beta induces rapid entry of Smad3 into the nucleus where it binds to the TERT gene promoter and represses TERT gene transcription .	In human breast cancer cells TGF-beta induces rapid entry of Smad3 into the nucleus where it binds to the TERT gene promoter and represses TERT gene transcription.	5	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	5	6	10	11
Moreover , we detected a TGF-beta time-course-dependent increase of Smad3 and N-CoR occupancy at the REGgamma promoter in control cells .	Moreover, we detected a TGF-beta time-course-dependent increase of Smad3 and N-CoR occupancy at the REGgamma promoter in control cells.	5	12	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	5	6	9	10
The EOB phenotype was observed in mice lacking the type I BMP receptor genes , Acvr1 and Bmpr1a , the R-Smad genes , Smad 1 and Smad5 , and the Co-Smad gene , Smad 4 , but not in mice lacking the type II TGFbeta receptor gene Tgfbr2 and the activin and TGFbeta activated R-Smad genes , Smad2 and Smad3 .	The EOB phenotype was observed in mice lacking the type I BMP receptor genes, Acvr1 and Bmpr1a, the R-Smad genes, Smad 1 and Smad5, and the Co-Smad gene, Smad 4, but not in mice lacking the type II TGFbeta receptor gene Tgfbr2 and the activin and TGFbeta activated R-Smad genes, Smad2 and Smad3.	44	60	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	44	45	59	60
In contrast , Smad3 is activated by the TGF-beta and ALK -5 signaling pathway , also known as the canonical TGF-beta signaling pathway , and acts to increase invasion .	In contrast, Smad3 is activated by the TGF-beta and ALK -5 signaling pathway, also known as the canonical TGF-beta signaling pathway, and acts to increase invasion.	3	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	3	4
In contrast , at S2 , TGFbeta increased the association of Smad3 , but had no effect on Smad2 binding .	In contrast, at S2, TGFbeta increased the association of Smad3, but had no effect on Smad2 binding.	6	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	6	7	11	12
Smad3 belongs to receptor regulated Smads ( R-Smads ) and can be activated by TGF-beta and activin receptors .	Smad3 belongs to receptor regulated Smads (R-Smads) and can be activated by TGF-beta and activin receptors.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	14	15	0	1
EM-A and EM703 inhibited the augmentation of Smad3 mRNA induced by TGF-beta .	EM-A and EM703 inhibited the augmentation of Smad3 mRNA induced by TGF-beta.	7	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	11	12	7	8
Consistent with these data , reduced TGF-beta signaling in Smad3 +/- mice or DNTbetaRII mice also relieves the suppression of osteoblast differentiation by TGF-beta , which is exerted by Smad3 and histone deacetylases XREF_BIBR XREF_BIBR , thereby contributing to increased BMD XREF_BIBR XREF_BIBR .	Consistent with these data, reduced TGF-beta signaling in Smad3 +/- mice or DNTbetaRII mice also relieves the suppression of osteoblast differentiation by TGF-beta, which is exerted by Smad3 and histone deacetylases XREF_BIBR XREF_BIBR, thereby contributing to increased BMD XREF_BIBR XREF_BIBR.	6	14	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	6	7	9	10
Our previous study demonstrated that activin treatment of pituitary gonadotrope ( LbetaT2 ) cells positively regulated the production of furin mRNA through a pathway that involved the TGFbeta receptor activated transcription factors Smad2 and Smad3 XREF_BIBR .	Our previous study demonstrated that activin treatment of pituitary gonadotrope (LbetaT2) cells positively regulated the production of furin mRNA through a pathway that involved the TGFbeta receptor activated transcription factors Smad2 and Smad3 XREF_BIBR.	27	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	27	28	34	35
TGF-beta typeIreceptor activates Smad3 to create COOH-terminally phosphorylated Smad3 ( pSmad3C ) , while pro inflammatory cytokine activated kinases phosphorylates Smad3 to create the linker phosphorylated Smad3 ( pSmad3L ) .	TGF-beta typeIreceptor activates Smad3 to create COOH-terminally phosphorylated Smad3 (pSmad3C), while pro inflammatory cytokine activated kinases phosphorylates Smad3 to create the linker phosphorylated Smad3 (pSmad3L).	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	3	4
Activation of Smad3 by TGF-beta stimulates IH and enhances adaptive remodeling .	Activation of Smad3 by TGF-beta stimulates IH and enhances adaptive remodeling.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	4	5	2	3
Knockdown of Smad3 , but not Smad2 increased C/EBP-beta promoter activity in cells treated with TGF-beta , compared to control siRNA expressing cells ( XREF_FIG ) .	Knockdown of Smad3, but not Smad2 increased C/EBP-beta promoter activity in cells treated with TGF-beta, compared to control siRNA expressing cells (XREF_FIG).	0	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	15	16	2	3
Transfection of an activated Ras with a mutation enabling the activation of the PI3-kinase pathway alone mimicked the EGF and TGF-beta potentiation of Smad3 transactivation , and TAM-67 abolished this effect , suggesting that the PI3-kinase pathway stimulates Smad3 via AP-1 stimulation .	Transfection of an activated Ras with a mutation enabling the activation of the PI3-kinase pathway alone mimicked the EGF and TGF-beta potentiation of Smad3 transactivation, and TAM-67 abolished this effect, suggesting that the PI3-kinase pathway stimulates Smad3 via AP-1 stimulation.	18	24	potentiation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	20	21	23	24
It is now understood that TGF-beta activates Smad2 and Smad3 to control the process of angiogenesis by diversely regulating expression of vascular endothelial growth factor ( VEGF ) , a proangiogenic factor , and thrombospondin-1 ( TSP-1 ) , an antiangiogenic factor XREF_BIBR .	It is now understood that TGF-beta activates Smad2 and Smad3 to control the process of angiogenesis by diversely regulating expression of vascular endothelial growth factor (VEGF), a proangiogenic factor, and thrombospondin-1 (TSP-1), an antiangiogenic factor XREF_BIBR.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	5	6	9	10
Ligation of TGF-beta to its cell surface receptor complex TbetaRII and TbetaRI initiates a signal transduction path-way by activating the proteins Smad2 and Smad3 ( R-Smads ) , which in conjunction with the co-activator Smad4 ( also known as DPC4 deleted in pancreatic carcinoma 4 ) co-operate with other transcription factors for the transcription of target genes .	Ligation of TGF-beta to its cell surface receptor complex TbetaRII and TbetaRI initiates a signal transduction path-way by activating the proteins Smad2 and Smad3 (R-Smads), which in conjunction with the co-activator Smad4 (also known as DPC4 deleted in pancreatic carcinoma 4) co-operate with other transcription factors for the transcription of target genes.	0	46	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	2	3	23	24
Moreover , normal chondrocytes were treated with TGF-beta and Smad3 activity was assessed by luciferase activity ( GACA ) 12-luc plasmid showing that TGF-beta induces Smad3 activation ( XREF_FIG ) .	Moreover, normal chondrocytes were treated with TGF-beta and Smad3 activity was assessed by luciferase activity (GACA) 12-luc plasmid showing that TGF-beta induces Smad3 activation (XREF_FIG).	23	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	23	24	25	26
BMP7 induced Snail expression via Smad1 , Smad5 and Smad4 , independently of the TGFbeta receptor activated Smads , Smad2 and Smad3 , even though BMP7 could promote Smad2 C-terminal phosphorylation ( XREF_FIG and XREF_FIG ) .	BMP7 induced Snail expression via Smad1, Smad5 and Smad4, independently of the TGFbeta receptor activated Smads, Smad2 and Smad3, even though BMP7 could promote Smad2 C-terminal phosphorylation (XREF_FIG and XREF_FIG).	3	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	expression via Smad1, Smad5 and Smad4, independently of the TGFbeta	tgfbeta	Smad3	Smad3	smad3	14	15	21	22
TGF-beta and EGF respectively induce SMAD3 and PCBP1 to interact and accumulate in the nucleus .	TGF-beta and EGF respectively induce SMAD3 and PCBP1 to interact and accumulate in the nucleus.	0	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	0	1	5	6
Within the nucleus , TGFbeta stimulation potentiates Smad3 to bind SnoN and promote its subsequent degradation by the anaphase promoting complex ( APC ) or Smurf2 .	Within the nucleus, TGFbeta stimulation potentiates Smad3 to bind SnoN and promote its subsequent degradation by the anaphase promoting complex (APC) or Smurf2.	4	8	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	4	5	7	8
Smad4 acts as a cofactor that binds transforming growth factor-beta ( TGF-beta ) receptor activated Smad2 and Smad3 generating transcriptional complexes .	Smad4 acts as a cofactor that binds transforming growth factor-beta (TGF-beta) receptor activated Smad2 and Smad3 generating transcriptional complexes.	9	18	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	11	12	17	18
In contrast , induction of protein inhibitor of activated Stat3 ( PIAS3 ) , a factor induced by Stat3 activation , significantly increased TGFbeta mediated Smad3 activation suggesting that TGFbeta-Smad signaling could be a negative feedback loop to inhibit Stat3 mediated proliferative signals .	In contrast, induction of protein inhibitor of activated Stat3 (PIAS3), a factor induced by Stat3 activation, significantly increased TGFbeta mediated Smad3 activation suggesting that TGFbeta-Smad signaling could be a negative feedback loop to inhibit Stat3 mediated proliferative signals.	22	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	23	24	25	26
TGFbeta activated SMAD3 co-occupies the genome with the myogenic identity facto r myoblast determination protein 1 ( MYOD1 ) in mesenchymal progenitors and with the lymphoid identity factor PU.1 ( also known as SPI1 ) in pro B cells 4 .	TGFbeta activated SMAD3 co-occupies the genome with the myogenic identity facto r myoblast determination protein 1 (MYOD1) in mesenchymal progenitors and with the lymphoid identity factor PU.1 (also known as SPI1) in pro B cells 4.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	0	1	2	3
Our results show that these inhibitors delay the onset of TGFbeta induced nuclear accumulation of Smad3 and reduces its amplitude .	Our results show that these inhibitors delay the onset of TGFbeta induced nuclear accumulation of Smad3 and reduces its amplitude.	8	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	10	11	15	16
Moreover , a TGFbeta and BMP regulated protein PRAJA is expressed in hepatoblasts and modulates beta2SP and Smad3 , adding to the complexity of TGFbeta signaling in the liver .	Moreover, a TGFbeta and BMP regulated protein PRAJA is expressed in hepatoblasts and modulates beta2SP and Smad3, adding to the complexity of TGFbeta signaling in the liver.	2	18	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta and BMP regulated protein PRAJA is expressed	tgfbeta	Smad3	Smad3	smad3	3	4	17	18
TGFbeta activated SMAD3 or BMP activated SMAD1 are recruited to the Drosha miRNA processing complex by the RNA helicase DDX5 ( DEAD box protein 5 ) , which is a component of the Drosha complex .	TGFbeta activated SMAD3 or BMP activated SMAD1 are recruited to the Drosha miRNA processing complex by the RNA helicase DDX5 (DEAD box protein 5), which is a component of the Drosha complex.	0	5	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	0	1	2	3
Poly ( ADP-ribose ) Polymerase 1 Is Indispensable for Transforming Growth Factor-beta Induced Smad3 Activation in Vascular Smooth Muscle Cell .	Poly (ADP-ribose) Polymerase 1 Is Indispensable for Transforming Growth Factor-beta Induced Smad3 Activation in Vascular Smooth Muscle Cell.	7	14	Induced	Positive_early_activation	Positive_activation	Positive_activation	Transforming Growth Factor-beta	Transforming Growth Factor-beta	Transforming Growth Factor-beta	Smad3	Smad3	Smad3	9	12	13	14
In the study , TGFbeta resistance of H460 cell was first confirmed by analyses of PPARgamma expression , its interaction with TGFbeta induced Smad3 and phospho-Smad3 ( p-Smad3 ) and survival of H460 .	In the study, TGFbeta resistance of H460 cell was first confirmed by analyses of PPARgamma expression, its interaction with TGFbeta induced Smad3 and phospho-Smad3 (p-Smad3) and survival of H460.	19	30	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	21	22	23	24
Apparently , TGF-beta and EGF respectively induce SMAD3 and PCBP1 to accumulate in the nucleus and to interact with each other .	Apparently, TGF-beta and EGF respectively induce SMAD3 and PCBP1 to accumulate in the nucleus and to interact with each other.	2	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	2	3	7	8
In TGFbeta signaling , Axin assists in TGFbeta mediated activation of Smad3 [ XREF_BIBR ] .	In TGFbeta signaling, Axin assists in TGFbeta mediated activation of Smad3 [XREF_BIBR].	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	7	8	11	12
TGFbeta activated Smad3 had already been shown to induce the mRNA expression of the tenocyte lineage specific transcription factor Scx in avian mesenchymal cultures .	TGFbeta activated Smad3 had already been shown to induce the mRNA expression of the tenocyte lineage specific transcription factor Scx in avian mesenchymal cultures.	0	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	0	1	2	3
As shown in XREF_FIG , a and b , TGF-beta specifically induced binding of both Smad3 and Smad4 to a region of the RPTP-kappa promoter located between nucleotides 522 and 706 .	As shown in XREF_FIG, a and b, TGF-beta specifically induced binding of both Smad3 and Smad4 to a region of the RPTP-kappa promoter located between nucleotides 522 and 706.	9	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	9	10	15	16
Indeed , TGFbeta signaling in the presence of IL-2 is a well established stimulus that can induce FoxP3 expression in mouse naive T cells , by means of direct binding of TGFbeta activated SMAD2 and SMAD3 to the FOXP3 locus .	Indeed, TGFbeta signaling in the presence of IL-2 is a well established stimulus that can induce FoxP3 expression in mouse naive T cells, by means of direct binding of TGFbeta activated SMAD2 and SMAD3 to the FOXP3 locus.	29	36	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	31	32	35	36
In this cell model , TGFbeta stimulates and activates Smad2 and Smad3 properly ; however , the transcriptional responses of TGFbeta are severely crippled because of the lack of Smad4 .	In this cell model, TGFbeta stimulates and activates Smad2 and Smad3 properly; however, the transcriptional responses of TGFbeta are severely crippled because of the lack of Smad4.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	5	6	11	12
Our data demonstrate that IRAK-1 is preferentially involved in modulating TCR induced NFATc2 levels , instead of TGFbeta induced Smad3 .	Our data demonstrate that IRAK-1 is preferentially involved in modulating TCR induced NFATc2 levels, instead of TGFbeta induced Smad3.	13	20	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	17	18	19	20
TGF-beta could clearly accelerate the overall movement of MDA-MB-231 cells into the wound area and significantly enhanced Smad3 activity in cells within and outside the wound area compared to unstimulated cells .	TGF-beta could clearly accelerate the overall movement of MDA-MB-231 cells into the wound area and significantly enhanced Smad3 activity in cells within and outside the wound area compared to unstimulated cells.	0	18	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	17	18
Previous studies showed cross-talk between the TGF-beta and vitamin D signaling pathways and VDR binds to the MH1 domain of Smad3 , enhancing Smad3 ligand induced transactivation .	Previous studies showed cross-talk between the TGF-beta and vitamin D signaling pathways and VDR binds to the MH1 domain of Smad3, enhancing Smad3 ligand induced transactivation.	6	24	enhancing	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	6	7	23	24
We also observed a similar increase in the phosphorylation and activation of Smad2 and Smad3 in KLE cells treated with each TGF-beta isoforms ( data not shown ) .	We also observed a similar increase in the phosphorylation and activation of Smad2 and Smad3 in KLE cells treated with each TGF-beta isoforms (data not shown).	8	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	21	22	14	15
However , Smad3 (-/-) cells transfected with WT-Smad3 and treated with TGFbeta demonstrated increased transcriptional activity , the MPT , and TGFbeta induced apoptosis .	However, Smad3 (-/-) cells transfected with WT-Smad3 and treated with TGFbeta demonstrated increased transcriptional activity, the MPT, and TGFbeta induced apoptosis.	5	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	WT-Smad3	WT-Smad3	WT-Smad3	11	12	7	8
We demonstrate that treatment of invasive MDA-MB-231 breast cancer cells with SB-202190 and SB-203580 interferes with TGFbeta induced Smad3 nuclear accumulation and that this is paralleled by a differential transcriptional response of TGFbeta target genes .	We demonstrate that treatment of invasive MDA-MB-231 breast cancer cells with SB-202190 and SB-203580 interferes with TGFbeta induced Smad3 nuclear accumulation and that this is paralleled by a differential transcriptional response of TGFbeta target genes.	16	20	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	16	17	18	19
Future work should determine the exact mechanisms whereby TGF-beta reduces Smad3 mRNA and LCM promotes Smad3 degradation .	Future work should determine the exact mechanisms whereby TGF-beta reduces Smad3 mRNA and LCM promotes Smad3 degradation.	8	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	15	16
And , TGF-beta production and activations of Smad3 and MAP kinases are induced by more cells than by just mast cells .	And, TGF-beta production and activations of Smad3 and MAP kinases are induced by more cells than by just mast cells.	2	10	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	2	3	7	8
Smad2 and Smad3 can be activated by other TGF-beta superfamily members such as the activins [ XREF_BIBR ] , as well as by the unrelated kinases Mps1 [ XREF_BIBR ] , WNK1 [ XREF_BIBR ] and MPK38 [ XREF_BIBR ] , and by advanced glycation end products [ XREF_BIBR ] .	Smad2 and Smad3 can be activated by other TGF-beta superfamily members such as the activins [XREF_BIBR], as well as by the unrelated kinases Mps1 [XREF_BIBR], WNK1 [XREF_BIBR] and MPK38 [XREF_BIBR], and by advanced glycation end products [XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	2	3
These results clearly indicate that Smad2 , but not Smad3 , activation is induced by TGF-beta in SM10 cells during the process of differentiation .	These results clearly indicate that Smad2, but not Smad3, activation is induced by TGF-beta in SM10 cells during the process of differentiation.	5	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	15	16	9	10
These data suggest that reduced TGFbeta induced SMAD3 occupancy of target loci in PTP4A1 silenced fibroblasts is due to a combination of decreased expression of SMAD3 and diminished TGFbeta induced nuclear translocation or retention .	These data suggest that reduced TGFbeta induced SMAD3 occupancy of target loci in PTP4A1 silenced fibroblasts is due to a combination of decreased expression of SMAD3 and diminished TGFbeta induced nuclear translocation or retention.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	5	6	7	8
While TGFbeta upregulates its receptors and Smad3 for short incubation ( at least at mRNA level ) , it downregulates them in the long term .	While TGFbeta upregulates its receptors and Smad3 for short incubation (at least at mRNA level), it downregulates them in the long term.	1	7	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	1	2	6	7
In Smad dependent pathways , TGF-beta induces activation of the receptor complex and activates Smad2 and Smad3 .	In Smad dependent pathways, TGF-beta induces activation of the receptor complex and activates Smad2 and Smad3.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	5	6	16	17
Smad3 activation induced by TGF-beta apparently counteracts the negative influence exerted on Foxp3 by active mTORC1 , leading to strong Treg induction even at high antigen dose .	Smad3 activation induced by TGF-beta apparently counteracts the negative influence exerted on Foxp3 by active mTORC1, leading to strong Treg induction even at high antigen dose.	0	5	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	4	5	0	1
Upon phosphorylation , activated TGFR-I phosphorylates the TGF-beta pathway signaling molecules SMAD2 and SMAD3 ( SMAD2/3 ) 10 , which act as transcription factors in the nucleus .	Upon phosphorylation, activated TGFR-I phosphorylates the TGF-beta pathway signaling molecules SMAD2 and SMAD3 (SMAD2/3) 10, which act as transcription factors in the nucleus.	4	20	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGFR-I phosphorylates the TGF-beta	tgf-beta	SMAD3	SMAD3	smad3	7	8	13	14
This effect was likely mediated by suppression of beta 1 transcription by the transcription factors HIF-1alpha and/or Smad3 that are known to be induced by TGF-beta .	This effect was likely mediated by suppression of beta 1 transcription by the transcription factors HIF-1alpha and/or Smad3 that are known to be induced by TGF-beta.	4	26	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	25	26	17	18
Inhibition of TGF-beta Signaling Disrupts the Association of Smad3 With the Ink4a and Arf Locus to Promote Proliferation in P9 MEFs .	Inhibition of TGF-beta Signaling Disrupts the Association of Smad3 With the Ink4a and Arf Locus to Promote Proliferation in P9 MEFs.	2	9	Disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	2	3	8	9
This observation was consistent with a previous report that demonstrated that TGF-beta could induce nuclear localization of SMAD2 and SMAD3 in SMAD4-null cancer cell lines [ XREF_BIBR ] .	This observation was consistent with a previous report that demonstrated that TGF-beta could induce nuclear localization of SMAD2 and SMAD3 in SMAD4-null cancer cell lines [XREF_BIBR].	11	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	11	12	19	20
vIRF1 interacts with Smad3 and Smad4 and inhibits TGF-beta mediated Smad3 and Smad4 DNA binding , as well as formation of the Smad3 and Smad4 complex .	vIRF1 interacts with Smad3 and Smad4 and inhibits TGF-beta mediated Smad3 and Smad4 DNA binding, as well as formation of the Smad3 and Smad4 complex.	7	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	10	11
Whereas Smad3 is typically localized in the cytoplasm , activation of the TGFbeta pathway causes Smad3 to be phosphorylated and migrate to the nucleus .	Whereas Smad3 is typically localized in the cytoplasm, activation of the TGFbeta pathway causes Smad3 to be phosphorylated and migrate to the nucleus.	12	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	12	13	15	16
In these ChIP experiments , we included the c-myc TIE as positive controls and confirmed the binding of Smad3 and E2F4 to the c-myc TIE in SKOV-3 cells treated with TGFbeta .	In these ChIP experiments, we included the c-myc TIE as positive controls and confirmed the binding of Smad3 and E2F4 to the c-myc TIE in SKOV-3 cells treated with TGFbeta.	16	31	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	30	31	18	19
Very intriguing , HCC-M and HCC-T display strong and prolonged TGF-beta induced Smad3 activation , however very low if any CAGA reporter activation .	Very intriguing, HCC-M and HCC-T display strong and prolonged TGF-beta induced Smad3 activation, however very low if any CAGA reporter activation.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	10	11	12	13
Activated SMAD2 or SMAD3 demonstrates activation of TGF-beta signaling .	Activated SMAD2 or SMAD3 demonstrates activation of TGF-beta signaling.	0	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	7	8	3	4
Interrupted TGFbeta mediated signaling in Smad3 null mice delays ulcer healing , whereas human ulcers are associated with distinct patterns of TGFbeta immunoreactivity that colocalize with similar patterns of immunoreactivity for FAK and phosphorylated FAK .	Interrupted TGFbeta mediated signaling in Smad3 null mice delays ulcer healing, whereas human ulcers are associated with distinct patterns of TGFbeta immunoreactivity that colocalize with similar patterns of immunoreactivity for FAK and phosphorylated FAK.	1	7	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	1	2	5	6
Canonical TGFbeta stimulated Smad 3 signaling has been shown to regulate fibrotic gene expression XREF_BIBR .	Canonical TGFbeta stimulated Smad 3 signaling has been shown to regulate fibrotic gene expression XREF_BIBR.	0	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad 3	Smad 3	Smad 3	1	2	3	5
Recently , it has been revealed that the TGF-beta and Smad system can stimulate de-differentiation of SMCs in high Smad3 and Smad2 ratio circumstances [ XREF_BIBR - XREF_BIBR ] .	Recently, it has been revealed that the TGF-beta and Smad system can stimulate de-differentiation of SMCs in high Smad3 and Smad2 ratio circumstances [XREF_BIBR - XREF_BIBR].	8	23	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	19	20
TGF-beta activates the Smad3 signaling pathway to promote the occurrence of cataracts .	TGF-beta activates the Smad3 signaling pathway to promote the occurrence of cataracts.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	3	4
The current study is limited in this regard with respect to understanding the cell specific effects of a loss of Smad3 throughout the regenerative response though it is clear that TGFbeta mediated Smad3 activation provides both pro proliferative and potentially inhibitor signals during liver regeneration .	The current study is limited in this regard with respect to understanding the cell specific effects of a loss of Smad3 throughout the regenerative response though it is clear that TGFbeta mediated Smad3 activation provides both pro proliferative and potentially inhibitor signals during liver regeneration.	30	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	30	31	32	33
TGFbeta activates Smad3 , which is necessary for the two-hit-induced cilium loss .	TGFbeta activates Smad3, which is necessary for the two-hit-induced cilium loss.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	0	1	2	3
Our results support that TGFbeta stimulated Smad 3 acts as a key node to instill a feedback loop between deptor down-regulation and TORC1/2 activation in driving mesangial cell hypertrophy .	Our results support that TGFbeta stimulated Smad 3 acts as a key node to instill a feedback loop between deptor down-regulation and TORC1/2 activation in driving mesangial cell hypertrophy.	4	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad 3	Smad 3	Smad 3	4	5	6	8
Atf3 is activated by inflammation and by the TGF-beta mediator Smad3 XREF_BIBR , suggesting a functional connection with Gdf15 .	Atf3 is activated by inflammation and by the TGF-beta mediator Smad3 XREF_BIBR, suggesting a functional connection with Gdf15.	8	11	mediator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	10	11
Interestingly , we also observed that different natural core variants isolated from tumor or non tumor nodules could differently bind Smad3 , and consequently inhibit TGF-beta induced Smad3 transcriptional activity suggesting that the HCV core protein may modulate TGF-beta signaling and its downstream biological responses XREF_BIBR .	Interestingly, we also observed that different natural core variants isolated from tumor or non tumor nodules could differently bind Smad3, and consequently inhibit TGF-beta induced Smad3 transcriptional activity suggesting that the HCV core protein may modulate TGF-beta signaling and its downstream biological responses XREF_BIBR.	25	28	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	25	26	27	28
Arsenic up regulated TGF-beta and Smad3 [ XREF_BIBR ] , which both indicate apoptosis ( TGF-beta triggers Smad3 activation ) .	Arsenic up regulated TGF-beta and Smad3 [XREF_BIBR], which both indicate apoptosis (TGF-beta triggers Smad3 activation).	15	18	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	15	16	17	18
SB-202190 and SB-203580 deregulate TGFbeta induced Smad3 nuclear accumulation .	SB-202190 and SB-203580 deregulate TGFbeta induced Smad3 nuclear accumulation.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	4	5	6	7
In this way , TGFbeta activated Smad3 is a major regulator of cell differentiation in tissues of the musculoskeletal system including bone , cartilage , and muscle .	In this way, TGFbeta activated Smad3 is a major regulator of cell differentiation in tissues of the musculoskeletal system including bone, cartilage, and muscle.	4	10	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	4	5	6	7
Massague and colleagues have demonstrated that Id1 is transiently induced by TGFbeta activated SMAD3 but long-term TGFbeta stimulation results in Id1 transcriptional repression , which is dependent on induction of the ATF3 transcriptional repressor [ XREF_BIBR ] .	Massague and colleagues have demonstrated that Id1 is transiently induced by TGFbeta activated SMAD3 but long-term TGFbeta stimulation results in Id1 transcriptional repression, which is dependent on induction of the ATF3 transcriptional repressor [XREF_BIBR].	9	18	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	11	12	13	14
The changes in oxidant and antioxidant enzymes and IL-6 release were reversed by the antioxidants N-acetyl-cysteine ( NAC ) and ebselen through inhibition of Smad3 phosphorylation , indicating redox dependent activation of Smad3 by TGF-beta .	The changes in oxidant and antioxidant enzymes and IL-6 release were reversed by the antioxidants N-acetyl-cysteine (NAC) and ebselen through inhibition of Smad3 phosphorylation, indicating redox dependent activation of Smad3 by TGF-beta.	27	35	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	34	35	32	33
Conversely , reduced TGF-beta signaling in DNTbetaRII or Smad3-/- mice led to increased mineral concentration .	Conversely, reduced TGF-beta signaling in DNTbetaRII or Smad3-/- mice led to increased mineral concentration.	3	9	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3-/-	Smad3-/-	Smad3-/-	3	4	8	9
In the present study , we showed that p38 MAPK and PI3K signaling are important for SPARC induction by TGF-beta rather than the SMAD3 pathway using pharmacological inhibitors and siRNA experiments .	In the present study, we showed that p38 MAPK and PI3K signaling are important for SPARC induction by TGF-beta rather than the SMAD3 pathway using pharmacological inhibitors and siRNA experiments.	17	24	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	19	20	23	24
XREF_BIBR , XREF_BIBR As a result , TGF-beta activates R-Smads ( Smad2 and Smad3 ) via phosphorylation at their C-terminal serine residues .	XREF_BIBR, XREF_BIBR As a result, TGF-beta activates R-Smads (Smad2 and Smad3) via phosphorylation at their C-terminal serine residues.	7	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	7	8	13	14
TGFbeta stimulated SMAD3 contributes to DEPTOR suppression and mTORC1 activation [ XREF_BIBR ] .	TGFbeta stimulated SMAD3 contributes to DEPTOR suppression and mTORC1 activation [XREF_BIBR].	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	0	1	2	3
Treg differentiation is dependent on TGFbeta , which activates SMAD3 .	Treg differentiation is dependent on TGFbeta, which activates SMAD3.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	5	6	9	10
This suggests that in SMAD4-null SW480 cells , TGFbeta induces a predominant SMAD2 specific transcriptional response and no SMAD3 specific response , even without the presence of SMAD4 .	This suggests that in SMAD4-null SW480 cells, TGFbeta induces a predominant SMAD2 specific transcriptional response and no SMAD3 specific response, even without the presence of SMAD4.	8	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	8	9	18	19
Recent study demonstrate that TGFbeta activate smad3 in medial smooth muscle cells , causing them to secret CTGF , which in turn stimulate adventitial fibroblasts to migrate , proliferate , produce collagen , and transform into myofibroblast [ XREF_BIBR ] .	Recent study demonstrate that TGFbeta activate smad3 in medial smooth muscle cells, causing them to secret CTGF, which in turn stimulate adventitial fibroblasts to migrate, proliferate, produce collagen, and transform into myofibroblast [XREF_BIBR].	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	smad3	smad3	smad3	4	5	6	7
This downstream signaling of AKT and GSK3beta was also suggested to contribute to TGFbeta stimulated SMAD3 stability in a variety of cell lines XREF_BIBR , emphasizing the importance of GSK3beta in collagen accumulation .	This downstream signaling of AKT and GSK3beta was also suggested to contribute to TGFbeta stimulated SMAD3 stability in a variety of cell lines XREF_BIBR, emphasizing the importance of GSK3beta in collagen accumulation.	11	16	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	13	14	15	16
Inhibition of autocrine TGF-beta signaling by either SB431542 or anti-TGF-beta antibody reduced Smad3 activation and strongly increased the number of Ki67 positive cells .	Inhibition of autocrine TGF-beta signaling by either SB431542 or anti-TGF-beta antibody reduced Smad3 activation and strongly increased the number of Ki67 positive cells.	3	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	3	4	12	13
Consistent with the findings in HaCaT and 1205Lu cells , efficient SMAD3 nuclear translocation was also observed in fibroblasts treated with TGF-beta , whether at low or high cell density ( XREF_SUPPLEMENTARY ) .	Consistent with the findings in HaCaT and 1205Lu cells, efficient SMAD3 nuclear translocation was also observed in fibroblasts treated with TGF-beta, whether at low or high cell density (XREF_SUPPLEMENTARY).	11	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	21	22	11	12
In both A549 and PC9 after 24hours of treatment , pSmad2 and pSmad3 levels seem elevated in cells treated with TGFbeta , and the effect was diminished in cells treated with SB-431542 or the combination of SB- 431542 and TGFbeta .	In both A549 and PC9 after 24hours of treatment, pSmad2 and pSmad3 levels seem elevated in cells treated with TGFbeta, and the effect was diminished in cells treated with SB-431542 or the combination of SB- 431542 and TGFbeta.	10	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	pSmad3	pSmad3	pSmad3	20	21	12	13
This TGFbeta isoform induced phosphorylation of AKT is both TGFbetaRI and Smad3 dependent .	This TGFbeta isoform induced phosphorylation of AKT is both TGFbetaRI and Smad3 dependent.	1	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	1	2	11	12
Both S1P and TGFbeta activate ERK1/2 , but only TGFbeta activates Smad3 .	Both S1P and TGFbeta activate ERK1/2, but only TGFbeta activates Smad3.	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	9	10	11	12
Other kinase inhibitors fail to inhibit TGFbeta mediated Smad3 nuclear entry .	Other kinase inhibitors fail to inhibit TGFbeta mediated Smad3 nuclear entry.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	6	7	8	9
These experiments led us to conclude that TGFbeta and antipsychotics differentially activate SMAD3 and SMAD2 , and there must be distinct pathways by which antipsychotics and TGFbeta promote phosphorylation of R-SMADs .	These experiments led us to conclude that TGFbeta and antipsychotics differentially activate SMAD3 and SMAD2, and there must be distinct pathways by which antipsychotics and TGFbeta promote phosphorylation of R-SMADs.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	7	8	12	13
Smad2 and Smad3 are activated by TGF-beta proteins , while Smad1 , 5 and 8 are activated by BMP ligands .	Smad2 and Smad3 are activated by TGF-beta proteins, while Smad1, 5 and 8 are activated by BMP ligands.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	6	7	2	3
Activation of the TGF-beta receptor by TGF-beta , Activin or Nodal leads to phosphorylation of the transcription factors Smad2 and Smad3 ( Smad2/3 ) .	Activation of the TGF-beta receptor by TGF-beta, Activin or Nodal leads to phosphorylation of the transcription factors Smad2 and Smad3 (Smad2/3).	0	22	Activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	6	7	20	21
These results suggest that TGFbeta mediated activation of Smad3 inhibits insulin production and secretion , whereas inactivation of Smad3 increases insulin secretion in response to glucose [ XREF_BIBR ] .	These results suggest that TGFbeta mediated activation of Smad3 inhibits insulin production and secretion, whereas inactivation of Smad3 increases insulin secretion in response to glucose [XREF_BIBR].	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	4	5	8	9
Next , we studied the time-course of TGFbeta induced Smad3 nuclear entry in the presence or absence of SB-203580 .	Next, we studied the time-course of TGFbeta induced Smad3 nuclear entry in the presence or absence of SB-203580.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	7	8	9	10
We then asked whether TGF-beta induced binding of Smad3 to these target gene loci was affected by Smad3 gene dosage .	We then asked whether TGF-beta induced binding of Smad3 to these target gene loci was affected by Smad3 gene dosage.	4	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	4	5	8	9
Interestingly , neither the addition of 1,25 ( OH ) 2 D 3 nor TGFbeta enhanced the VDR and RXR or SMAD3 and SMAD4 mediated effects .	Interestingly, neither the addition of 1,25 (OH) 2 D 3 nor TGFbeta enhanced the VDR and RXR or SMAD3 and SMAD4 mediated effects.	0	25	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	14	15	21	22
Here , we report that in a concerted action with inputs from receptor-tyrosine kinase ( RTK ) pathways , TGF-beta induces SMAD3 to form a complex with RNA binding protein poly-( rC ) binding protein 1 ( PCBP1 , also known as hnRNPE1 ) .	Here, we report that in a concerted action with inputs from receptor-tyrosine kinase (RTK) pathways, TGF-beta induces SMAD3 to form a complex with RNA binding protein poly-(rC) binding protein 1 (PCBP1, also known as hnRNPE1).	19	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	19	20	21	22
Physical interaction required activation of Smad3 by TGF-beta but not dexamethasone binding to GR .	Physical interaction required activation of Smad3 by TGF-beta but not dexamethasone binding to GR.	2	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	7	8	5	6
Two signaling components of the pro fibrotic cytokine TGF-beta were upregulated , SMAD3 and TGFBR3 ( TGF-beta receptor 3 ) , although TGFBR1 ( TGF-beta receptor 1 ) was downregulated and the inhibitory SMAD7 was upregulated .	Two signaling components of the pro fibrotic cytokine TGF-beta were upregulated, SMAD3 and TGFBR3 (TGF-beta receptor 3), although TGFBR1 (TGF-beta receptor 1) was downregulated and the inhibitory SMAD7 was upregulated.	2	35	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	8	9	12	13
In addition , TGF-beta stimulation of Smad3 results in upregulated Mdm2 expression , which destabilizes p53 during the initiation of breast cancer EMT and metastasis .	In addition, TGF-beta stimulation of Smad3 results in upregulated Mdm2 expression, which destabilizes p53 during the initiation of breast cancer EMT and metastasis.	3	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	3	4	6	7
Also , exogenous TGF-beta was shown to induce further SMAD3 and SMAD4 dependent transcription , demonstrating the functionality of the entire TGF-beta signaling cascade .	Also, exogenous TGF-beta was shown to induce further SMAD3 and SMAD4 dependent transcription, demonstrating the functionality of the entire TGF-beta signaling cascade.	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	3	4	9	10
However , neurons could be induced from P19 cells stably over-expressing Dll1IC without RA stimulation and this induction was strongly inhibited by SB431542 , a specific inhibitor of TGF-beta type1 receptor that activates Smad2 and Smad3 ( XREF_FIG a and b ) .	However, neurons could be induced from P19 cells stably over-expressing Dll1IC without RA stimulation and this induction was strongly inhibited by SB431542, a specific inhibitor of TGF-beta type1 receptor that activates Smad2 and Smad3 (XREF_FIG a and b).	28	36	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	28	29	35	36
Gene Set Enrichment Analysis ( GSEA ) and GSEA Leading Edge analysis of these gene sets identified TGFbeta induced SMAD3 direct target genes ( XREF_SUPPLEMENTARY ) as enriched in SOX4 target genes .	Gene Set Enrichment Analysis (GSEA) and GSEA Leading Edge analysis of these gene sets identified TGFbeta induced SMAD3 direct target genes (XREF_SUPPLEMENTARY) as enriched in SOX4 target genes.	16	20	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	17	18	19	20
TGF-beta activates SMAD3 , SMAD4 and/or RUNX proteins to promote transcription proceeding through Sgamma2b and Salpha for CSR to IgG2b and IgA , respectively .	TGF-beta activates SMAD3, SMAD4 and/or RUNX proteins to promote transcription proceeding through Sgamma2b and Salpha for CSR to IgG2b and IgA, respectively.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	0	1	2	3
XREF_BIBR - XREF_BIBR GDF15 is a TGF-beta superfamily ligand that activates SMAD2 and SMAD3 , and TWSG1 can function as a BMP agonist or antagonist .	XREF_BIBR - XREF_BIBR GDF15 is a TGF-beta superfamily ligand that activates SMAD2 and SMAD3, and TWSG1 can function as a BMP agonist or antagonist.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	6	7	13	14
Our data suggest that NAC prevents the activation of Smad3 by TGF-beta , thus attenuating the resulting imbalance in oxidant and antioxidant enzyme expression and elevated IL-6 release .	Our data suggest that NAC prevents the activation of Smad3 by TGF-beta, thus attenuating the resulting imbalance in oxidant and antioxidant enzyme expression and elevated IL-6 release.	5	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	11	12	9	10
Overexpression of nuclear factor ( NF-kappaB ) or activation of Smad3 by transforming growth factor beta ( TGF-beta1 ) induced by oncogenes results in overexpression of fibrotic processes and hence cell death .	Overexpression of nuclear factor (NF-kappaB) or activation of Smad3 by transforming growth factor beta (TGF-beta1) induced by oncogenes results in overexpression of fibrotic processes and hence cell death.	8	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	transforming growth factor beta	transforming growth factor beta	transforming growth factor beta	Smad3	Smad3	Smad3	12	16	10	11
It is also interesting to note that SMAD3 , which is activated by TGF-beta and has an inhibitory effect on cMYC expression , was significantly up-regulated after DON treatment , suggesting that the treatment might also favor inhibition of proliferation via SMAD3 and cMYC axis .	It is also interesting to note that SMAD3, which is activated by TGF-beta and has an inhibitory effect on cMYC expression, was significantly up-regulated after DON treatment, suggesting that the treatment might also favor inhibition of proliferation via SMAD3 and cMYC axis.	7	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	13	14	7	8
Our preliminary data have shown that SIS3 , a specific inhibitor of Smad3 phosphorylation , blocked TGFbeta induced activation of Smad3 , but had no effect on the TGFbeta-GM-CSF-ERK pathway , as TGFbeta still significantly inhibited GM-CSF-induced phosphorylation of ERK in the presence of SIS3 ( unpublished data ) .	Our preliminary data have shown that SIS3, a specific inhibitor of Smad3 phosphorylation, blocked TGFbeta induced activation of Smad3, but had no effect on the TGFbeta-GM-CSF-ERK pathway, as TGFbeta still significantly inhibited GM-CSF-induced phosphorylation of ERK in the presence of SIS3 (unpublished data).	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	16	17	20	21
CHIP assays with antibody to Smad3 revealed that TGF-beta induced Smad3 accumulation at the lnc-Smad3 promoter region ( XREF_FIG ) .	CHIP assays with antibody to Smad3 revealed that TGF-beta induced Smad3 accumulation at the lnc-Smad3 promoter region (XREF_FIG).	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	10	11
Induction of Smad3 and/or Smad4 transcription factors by the interaction of TGF-beta and receptors also leads to release of tissue factors ( TFs ) involved in the transcription of Cdc25A cyclin proteins as well as p15INK4 that in turn transcribe CDK4 and CDK6 cyclins responsible for the stimulation of Rb and E2F transcription factors .	Induction of Smad3 and/or Smad4 transcription factors by the interaction of TGF-beta and receptors also leads to release of tissue factors (TFs) involved in the transcription of Cdc25A cyclin proteins as well as p15INK4 that in turn transcribe CDK4 and CDK6 cyclins responsible for the stimulation of Rb and E2F transcription factors.	0	13	Induction	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	11	12	2	3
Surprisingly , SMAD3 transcriptional activity , as determined by the CAGA 12 -luciferase reporter construct , was enhanced by co-stimulation of TGFbeta and IL1beta compared to TGFbeta alone .	Surprisingly, SMAD3 transcriptional activity, as determined by the CAGA 12 -luciferase reporter construct, was enhanced by co-stimulation of TGFbeta and IL1beta compared to TGFbeta alone.	2	23	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	21	22	2	3
In EpH4 cells , however , while TAZ was efficiently excluded from the cell nucleus at high density , SMAD3 nuclear accumulation only occurred in sparse cell cultures treated with TGF-beta , not in confluent cells ( XREF_FIG and XREF_SUPPLEMENTARY ) .	In EpH4 cells, however, while TAZ was efficiently excluded from the cell nucleus at high density, SMAD3 nuclear accumulation only occurred in sparse cell cultures treated with TGF-beta, not in confluent cells (XREF_FIG and XREF_SUPPLEMENTARY).	19	35	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	30	31	19	20
After activation , the TGFbeta receptor ( comprised of two transmembrane serine/threonine kinases - TbetaRI and TbetaRII ) phosphorylates and activates Smad2 and Smad3 proteins which complex with co-Smad ( Smad4 ) , translocate to the nucleus and transcribe genes whose products regulate scarring ( reviewed by ( Finnson et al ., 2013 ) .	After activation, the TGFbeta receptor (comprised of two transmembrane serine/threonine kinases - TbetaRI and TbetaRII) phosphorylates and activates Smad2 and Smad3 proteins which complex with co-Smad (Smad4), translocate to the nucleus and transcribe genes whose products regulate scarring (reviewed by (Finnson et al., 2013).	4	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	4	5	23	24
OTUB1 was isolated from a proteomic screen as an interactor of GFP-SMAD3 only when cells were treated with TGFbeta .	OTUB1 was isolated from a proteomic screen as an interactor of GFP-SMAD3 only when cells were treated with TGFbeta.	9	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	GFP-SMAD3	GFP-SMAD3	GFP-SMAD3	18	19	11	12
Furthermore , TGF-beta induced the activation of pSMAD2 , pSMAD3 , pSTAT3 , pAKT and dpERK1/2 , while addition of metformin decreased expression levels of those phosphorylated proteins .	Furthermore, TGF-beta induced the activation of pSMAD2, pSMAD3, pSTAT3, pAKT and dpERK1/2, while addition of metformin decreased expression levels of those phosphorylated proteins.	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	pSMAD3	pSMAD3	pSMAD3	2	3	9	10
Given our new findings , we propose that transcription factors Smad3 ( CNS1 ) , Stat5 ( CNS2 ) and c-Rel ( CNS3 ) function as initiators for Foxp3 induction by opening up the three regulatory regions , each CNS being initiated by distinct signaling processes ( Smad3 activated by TGF-beta signaling in CNS1 , Stat5 activated by Il-2rgamma , TCR and TGF-beta signaling in CNS2 and c-Rel activated by TCR signaling in CNS3 ) .	Given our new findings, we propose that transcription factors Smad3 (CNS1), Stat5 (CNS2) and c-Rel (CNS3) function as initiators for Foxp3 induction by opening up the three regulatory regions, each CNS being initiated by distinct signaling processes (Smad3 activated by TGF-beta signaling in CNS1, Stat5 activated by Il-2rgamma, TCR and TGF-beta signaling in CNS2 and c-Rel activated by TCR signaling in CNS3).	45	51	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	50	51	47	48
Results presented here showed that EGF induces a small but significant increase in Smad3 activation and nuclear accumulation and amplified TGFbeta induced nuclear accumulation of Smad3 ( XREF_FIG ) .	Results presented here showed that EGF induces a small but significant increase in Smad3 activation and nuclear accumulation and amplified TGFbeta induced nuclear accumulation of Smad3 (XREF_FIG).	20	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	20	21	25	26
Here we report that two small molecules , SB-202190 and SB-203580 , diminished TGFbeta induced expression of TGFbeta target genes which was accompanied by a perturbation of TGFbeta mediated Smad3 nuclear accumulation , a crucial step in TGFbeta signal transduction .	Here we report that two small molecules, SB-202190 and SB-203580, diminished TGFbeta induced expression of TGFbeta target genes which was accompanied by a perturbation of TGFbeta mediated Smad3 nuclear accumulation, a crucial step in TGFbeta signal transduction.	25	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	27	28	29	30
In addition , TGFbeta induced a rapid interaction of Smad3 with DIC in km23-2-transfected cells ( lanes 3-6 , 2nd panel ) .	In addition, TGFbeta induced a rapid interaction of Smad3 with DIC in km23-2-transfected cells (lanes 3-6, 2nd panel).	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	3	4	9	10
Smad2 and Smad 3 are activated by TGF-beta and Activin , whereas Smad1 , Smad5 , and Smad8 are activated by BMP signaling .	Smad2 and Smad 3 are activated by TGF-beta and Activin, whereas Smad1, Smad5, and Smad8 are activated by BMP signaling.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad 3	Smad 3	Smad 3	7	8	2	4
At S1 , TGFbeta increased binding of Smad2 but not Smad3 ( XREF_FIG ) .	At S1, TGFbeta increased binding of Smad2 but not Smad3 (XREF_FIG).	3	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	3	4	10	11
Ligation of TGFbeta to its cell surface receptors TbetaRI and TbetaRII activates proteins Smad2 and Smad3 which form dimers with Smad4 and act as transcription factors [ XREF_BIBR ] .	Ligation of TGFbeta to its cell surface receptors TbetaRI and TbetaRII activates proteins Smad2 and Smad3 which form dimers with Smad4 and act as transcription factors [XREF_BIBR].	0	21	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TGFbeta	TGFbeta	tgfbeta	Smad3	Smad3 which form dimers with Smad4	smad3	2	3	15	16
We then determine whether GnRH alters the activation of Smad3 , either alone , or Smad3 induced by TGF-beta .	We then determine whether GnRH alters the activation of Smad3, either alone, or Smad3 induced by TGF-beta.	7	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	18	19	9	10
Transforming growth factor-beta ( TGF-beta ) activates not only TGF-beta type I receptor ( Tbeta RI ) but also c-Jun N-terminal kinase ( JNK ) , converting the mediator Smad3 to two distinct phosphoisoforms : C-terminally phosphorylated Smad3 ( pSmad3C ) and linker phosphorylated Smad3 ( pSmad3L ) .	Transforming growth factor-beta (TGF-beta) activates not only TGF-beta type I receptor (Tbeta RI) but also c-Jun N-terminal kinase (JNK), converting the mediator Smad3 to two distinct phosphoisoforms : C-terminally phosphorylated Smad3 (pSmad3C) and linker phosphorylated Smad3 (pSmad3L).	2	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	4	5	29	30
Instead , TbetaRIII specifically increased Smad3 phosphorylation , both basal and TGFbeta stimulated Smad3 nuclear localization and Smad3 dependent activation of reporter genes independent of its cytoplasmic domain .	Instead, TbetaRIII specifically increased Smad3 phosphorylation, both basal and TGFbeta stimulated Smad3 nuclear localization and Smad3 dependent activation of reporter genes independent of its cytoplasmic domain.	6	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	phosphorylation, both basal and TGFbeta	tgfbeta	Smad3	Smad3	smad3	11	12	13	14
To confirm the specificity of TGFbeta and PKA pathway in this response , FET Smad3 KD cells were treated with TGFbeta for the specified times and XIAP protein expression was determined ( XREF_FIG ) .	To confirm the specificity of TGFbeta and PKA pathway in this response, FET Smad3 KD cells were treated with TGFbeta for the specified times and XIAP protein expression was determined (XREF_FIG).	14	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	20	21	14	15
TGFbeta recombinant protein treatment successfully restored TGFbeta , p-TbetaRII , p-Smad2 , p-Smad3 and expression of the three TGFbeta responsive genes which were suppressed by high glucose ( XREF_FIG ) .	TGFbeta recombinant protein treatment successfully restored TGFbeta, p-TbetaRII, p-Smad2, p-Smad3 and expression of the three TGFbeta responsive genes which were suppressed by high glucose (XREF_FIG).	0	13	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	p-Smad3	p-Smad3	p-Smad3	0	1	12	13
Upon binding to its ligands , TGFbeta receptor transduces signals to activate smad3 or smad2 , which subsequently bind to smad4 and regulate gene expression [ XREF_BIBR ] .	Upon binding to its ligands, TGFbeta receptor transduces signals to activate smad3 or smad2, which subsequently bind to smad4 and regulate gene expression [XREF_BIBR].	6	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	smad3	smad3	smad3	6	7	12	13
Moreover , ATRA reversed the translocation of Smad3 and Smad7 induced by TGF-beta .	Moreover, ATRA reversed the translocation of Smad3 and Smad7 induced by TGF-beta.	5	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	12	13	7	8
TGFbeta activated kinase ( TAK1 )-p38 MAPK 90 and Smad3 XREF_BIBR , XREF_BIBR signaling axes have been implicated in mediating TGFbeta induced pathologic responses .	TGFbeta activated kinase (TAK1)-p38 MAPK 90 and Smad3 XREF_BIBR, XREF_BIBR signaling axes have been implicated in mediating TGFbeta induced pathologic responses.	0	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	0	1	9	10
The results expose a new role for SNX9 downstream of its canonical plasma membrane action and define a mechanism by which specificity in profibrotic TGFbeta signaling can be controlled through SNX9 promoting Smad3 nuclear import following ligand induced phosphorylation .	The results expose a new role for SNX9 downstream of its canonical plasma membrane action and define a mechanism by which specificity in profibrotic TGFbeta signaling can be controlled through SNX9 promoting Smad3 nuclear import following ligand induced phosphorylation.	24	34	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	24	25	32	33
Indeed , flavopiridol extended the half-life of BMP activated Smad1/5 as much as MG132 ( XREF_FIG ) , and a similar effect was observed with TGFbeta activated Smad3 ( data not shown ) .	Indeed, flavopiridol extended the half-life of BMP activated Smad1/5 as much as MG132 (XREF_FIG), and a similar effect was observed with TGFbeta activated Smad3 (data not shown).	23	29	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	25	26	27	28
Interestingly , although TGF-beta readily stimulated Smad2 and Smad3 in 4T1 cells , we only detected the activation of Smad2 in CST-Abl-expressing 4T1 cells treated with TGF-beta .	Interestingly, although TGF-beta readily stimulated Smad2 and Smad3 in 4T1 cells, we only detected the activation of Smad2 in CST-Abl-expressing 4T1 cells treated with TGF-beta.	3	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	3	4	8	9
Oncogenically activated Ras inhibits the TGFbeta induced nuclear accumulation of Smad2 and Smad3 and Smad dependent transcription .	Oncogenically activated Ras inhibits the TGFbeta induced nuclear accumulation of Smad2 and Smad3 and Smad dependent transcription.	4	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	5	6	12	13
A low concentration ( 0.5 ng/mL ) of TGFbeta was sufficient to significantly induce pSmad3 nuclear accumulation , whereas a higher concentration ( 5 ng/mL ) led to a further increase in pSmad3 nuclear accumulation ( XREF_FIG ) .	A low concentration (0.5 ng/mL) of TGFbeta was sufficient to significantly induce pSmad3 nuclear accumulation, whereas a higher concentration (5 ng/mL) led to a further increase in pSmad3 nuclear accumulation (XREF_FIG).	2	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	pSmad3	pSmad3	pSmad3	8	9	14	15
Interestingly , TGFbeta stimulation failed to activate pSMAD3 on softer matrices ( < 3kPa ) but TGFbeta mediated pSMAD3 induction was found to occur with matrix stiffness at 9 kPa ( XREF_FIG ) , suggesting that matrix stiffness influences TGFbeta signaling and myofibroblast activation .	Interestingly, TGFbeta stimulation failed to activate pSMAD3 on softer matrices (< 3kPa) but TGFbeta mediated pSMAD3 induction was found to occur with matrix stiffness at 9 kPa (XREF_FIG), suggesting that matrix stiffness influences TGFbeta signaling and myofibroblast activation.	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	pSMAD3	pSMAD3	pSMAD3	2	3	7	8
To examine phosphorylation levels of Smad2 and Smad3 ; SM10 cells were treated with TGF-beta for 72 hours and analyzed by Western blot using phospho specific antibodies .	To examine phosphorylation levels of Smad2 and Smad3; SM10 cells were treated with TGF-beta for 72 hours and analyzed by Western blot using phospho specific antibodies.	3	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	14	15	7	8
Of note , SMAD2 , SMAD3 and STAT5 are strongly induced by TGF-beta and IL-2 , which are required for the induction of Foxp3 .	Of note, SMAD2, SMAD3 and STAT5 are strongly induced by TGF-beta and IL-2, which are required for the induction of Foxp3.	3	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	12	13	5	6
In conclusion , we demonstrate a mechanism in VSMCs by which TGF-beta activates Smad3 , which in turn activates ERK MAPK leading to VSMC proliferation .	In conclusion, we demonstrate a mechanism in VSMCs by which TGF-beta activates Smad3, which in turn activates ERK MAPK leading to VSMC proliferation.	11	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	11	12	13	14
In addition , high levels of pSmad3 in the non lens ectoderm may depend on a Wnt2b mediated feed-forward loop : canonical Wnt signalling not only stabilizes beta-catenin but also Smad3 through inhibition of GSK3beta XREF_BIBR XREF_BIBR XREF_BIBR , suggesting that sustained TGF-beta signalling is required to activate Smad3 .	In addition, high levels of pSmad3 in the non lens ectoderm may depend on a Wnt2b mediated feed-forward loop : canonical Wnt signalling not only stabilizes beta-catenin but also Smad3 through inhibition of GSK3beta XREF_BIBR XREF_BIBR XREF_BIBR, suggesting that sustained TGF-beta signalling is required to activate Smad3.	42	49	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	42	43	48	49
To test whether TGFbeta stimulated CXCR4 expression depends on Smad3 , we incubated SMCs with Smad3 siRNA and then treated with TGFbeta for 6 hour .	To test whether TGFbeta stimulated CXCR4 expression depends on Smad3, we incubated SMCs with Smad3 siRNA and then treated with TGFbeta for 6 hour.	15	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	21	22	15	16
However , the depletion of RBX1 or beta-TrCP , the components of the E3 ubiquitin ligase complex which is responsible for the ubiquitination of TGFbeta activated Smad3 , could not lead to an accumulation of Smad3 in MDA-MB-231 cells whether TGFbeta stimulation or not , maybe other E3 ubiquitin ligase participate in this process .	However, the depletion of RBX1 or beta-TrCP, the components of the E3 ubiquitin ligase complex which is responsible for the ubiquitination of TGFbeta activated Smad3, could not lead to an accumulation of Smad3 in MDA-MB-231 cells whether TGFbeta stimulation or not, maybe other E3 ubiquitin ligase participate in this process.	22	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	ubiquitination of TGFbeta	tgfbeta	Smad3	Smad3	smad3	24	25	26	27
Further analysis proved that Smad3 , activated by the TGF-beta signaling pathway , transcriptionally regulated Six2 and rescued the proliferation phenotype caused by the knockdown of TbetaRII .	Further analysis proved that Smad3, activated by the TGF-beta signaling pathway, transcriptionally regulated Six2 and rescued the proliferation phenotype caused by the knockdown of TbetaRII.	4	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	9	10	4	5
ChIP analyses revealed that stimulation with TGF-beta increased Smad3 occupancy on both Smad3 sites identified , within 1 h and was sustained up to 24 h ( XREF_FIG ) .	ChIP analyses revealed that stimulation with TGF-beta increased Smad3 occupancy on both Smad3 sites identified, within 1 h and was sustained up to 24 h (XREF_FIG).	4	9	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	6	7	8	9
Both TGF-beta and PDGF activate SMAD2 and SMAD3 through JNK , resulting in HSC migration 94 .	Both TGF-beta and PDGF activate SMAD2 and SMAD3 through JNK, resulting in HSC migration 94.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	1	2	7	8
Smad2 and Smad3 are activated by TGF-beta and activin , while Smad1 and Smad5 are major components that are activated by bone morphogenic proteins ( BMPs ) .	Smad2 and Smad3 are activated by TGF-beta and activin, while Smad1 and Smad5 are major components that are activated by bone morphogenic proteins (BMPs).	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	6	7	2	3
These results indicate that TGFbeta treatment induces changes in Smad2 and Smad3 gene and protein expression patterns in both fibroblasts and myofibroblasts .	These results indicate that TGFbeta treatment induces changes in Smad2 and Smad3 gene and protein expression patterns in both fibroblasts and myofibroblasts.	4	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	4	5	11	12
BMP4 stimulates SMAD-1 and -5 , while TGF-beta stimulates SMAD-3 , to bind to the RNA helicase p68 , which is part of the Drosha complex .	BMP4 stimulates SMAD-1 and -5, while TGF-beta stimulates SMAD-3, to bind to the RNA helicase p68, which is part of the Drosha complex.	7	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD-3	SMAD-3	SMAD-3	7	8	9	10
We show that TGF-beta and EGF respectively induce SMAD3 and PCBP1 to colocalize in SC35 positive nuclear speckles , and the two proteins interact in the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly in favor of expressing the mesenchymal isoform CD44s over the epithelial isoform CD44E .	We show that TGF-beta and EGF respectively induce SMAD3 and PCBP1 to colocalize in SC35 positive nuclear speckles, and the two proteins interact in the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly in favor of expressing the mesenchymal isoform CD44s over the epithelial isoform CD44E.	3	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	3	4	8	9
The loss or reduction of BRCA1 expression , moreover , significantly reduces the TGF-beta induced activation of SMAD3 in breast cancer cells [ XREF_BIBR ] .	The loss or reduction of BRCA1 expression, moreover, significantly reduces the TGF-beta induced activation of SMAD3 in breast cancer cells [XREF_BIBR].	12	18	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	13	14	17	18
Smad2 and Smad3 can be activated as well by non TGFbeta growth factors , which are capable of activating mitogen activated protein kinases .	Smad2 and Smad3 can be activated as well by non TGFbeta growth factors, which are capable of activating mitogen activated protein kinases.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	10	11	2	3
The influence of Smad3 activation on hepatic KC responses has not been thoroughly investigated though it is thought that TGFbeta mediated activation of Smad3 likely suppresses their function .	The influence of Smad3 activation on hepatic KC responses has not been thoroughly investigated though it is thought that TGFbeta mediated activation of Smad3 likely suppresses their function.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	19	20	23	24
Although many of the mutations in these genes are predicted to cause loss of function , there is evidence of increased TGFbeta signaling in the cells in the diseased aortic tissues of the patients with syndromic TAAD , including those with mutations in either FBN1 , TGFBR1 , TGFBR2 , or SMAD3 [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	Although many of the mutations in these genes are predicted to cause loss of function, there is evidence of increased TGFbeta signaling in the cells in the diseased aortic tissues of the patients with syndromic TAAD, including those with mutations in either FBN1, TGFBR1, TGFBR2, or SMAD3 [XREF_BIBR; XREF_BIBR; XREF_BIBR].	21	52	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	21	22	51	52
To ask whether the 38 Smad3 target genes that were uniquely upregulated by TGF-beta in M3 cells in vitro were also regulated by TGF-beta in vivo , we next analyzed gene expression in M3 tumors with and without TGF-beta pathway ablation using a dnTbetaRII [ XREF_BIBR ] .	To ask whether the 38 Smad3 target genes that were uniquely upregulated by TGF-beta in M3 cells in vitro were also regulated by TGF-beta in vivo, we next analyzed gene expression in M3 tumors with and without TGF-beta pathway ablation using a dnTbetaRII [XREF_BIBR].	5	16	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	13	14	5	6
First , a subset of enhancer like regions occupied by Smad3 in cells treated with TGFbeta were occupied by p65 in cells treated with KLA .	First, a subset of enhancer like regions occupied by Smad3 in cells treated with TGFbeta were occupied by p65 in cells treated with KLA.	8	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	15	16	10	11
To test whether miR-20a has any effect on TGF-beta and Smad signaling , we first analyzed the levels of phosphorylation of Smad2 and Smad3 in Beas2B and HPL1A lung epithelial cells treated with TGF-beta .	To test whether miR-20a has any effect on TGF-beta and Smad signaling, we first analyzed the levels of phosphorylation of Smad2 and Smad3 in Beas2B and HPL1A lung epithelial cells treated with TGF-beta.	19	34	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	33	34	23	24
Regardless of sensitivity to TGF-beta-induced growth arrest , TGF-beta enhanced the ability of Smad3 protein complexes to bind c-myc regulatory elements .	Regardless of sensitivity to TGF-beta-induced growth arrest, TGF-beta enhanced the ability of Smad3 protein complexes to bind c-myc regulatory elements.	8	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	13	14
TGF-beta stimulation resulted in prolonged activation of Smad3 in wild-type T cells ( XREF_SUPPLEMENTARY ) .	TGF-beta stimulation resulted in prolonged activation of Smad3 in wild-type T cells (XREF_SUPPLEMENTARY).	0	8	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	7	8
These data reveal an unexpected link between ASC and the TGF-beta pathway whereby ASC deficient cerebella exhibit altered TGF-beta pathway gene expression and increased nuclear Smad3 in a mouse model of medulloblastoma .	These data reveal an unexpected link between ASC and the TGF-beta pathway whereby ASC deficient cerebella exhibit altered TGF-beta pathway gene expression and increased nuclear Smad3 in a mouse model of medulloblastoma.	10	26	increased	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	10	11	25	26
Using RNA immunoprecipitation ( RIP ) assay , we found that SMAD3 presented in the same complex of CD44 pre-mRNA and the association was augmented by TGF-beta , and additively by simultaneous treatment with both TGF-beta and EGF ( XREF_FIG ) .	Using RNA immunoprecipitation (RIP) assay, we found that SMAD3 presented in the same complex of CD44 pre-mRNA and the association was augmented by TGF-beta, and additively by simultaneous treatment with both TGF-beta and EGF (XREF_FIG).	11	27	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	26	27	11	12
We previously showed that TGF-beta activates Smad3 to repress Runx2 inducible Runx2 and osteocalcin expression in osteoblasts .	We previously showed that TGF-beta activates Smad3 to repress Runx2 inducible Runx2 and osteocalcin expression in osteoblasts.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	4	5	6	7
Screening of an E3 ubiquitin ligase small interfering RNA library , using TGF-beta induction of a Smad3 and Smad4 dependent luciferase reporter as a readout , revealed that Arkadia is an E3 ubiquitin ligase that is absolutely required for this TGF-beta response .	Screening of an E3 ubiquitin ligase small interfering RNA library, using TGF-beta induction of a Smad3 and Smad4 dependent luciferase reporter as a readout, revealed that Arkadia is an E3 ubiquitin ligase that is absolutely required for this TGF-beta response.	12	21	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	12	13	16	17
Inhibition of TGF-beta or Smad3 has been shown to suppresses the growth and metastasis of AI tumours in Nude mice ( but not tumour incidence ) and , as for GLI , Smad3 is expressed at considerably higher levels in DU145 cells compared to LNCaP cells XREF_BIBR , XREF_BIBR .	Inhibition of TGF-beta or Smad3 has been shown to suppresses the growth and metastasis of AI tumours in Nude mice (but not tumour incidence) and, as for GLI, Smad3 is expressed at considerably higher levels in DU145 cells compared to LNCaP cells XREF_BIBR, XREF_BIBR.	0	33	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	2	3	32	33
Second , both Smad2 and Smad3 were properly activated by shortterm TGF-beta treatment ( 30-60 min ) regardless of CKIgamma2 overexpression , suggesting that CKIgamma2 does not interfere with TGF-beta receptor activity ( XREF_FIG ) .	Second, both Smad2 and Smad3 were properly activated by shortterm TGF-beta treatment (30-60 min) regardless of CKIgamma2 overexpression, suggesting that CKIgamma2 does not interfere with TGF-beta receptor activity (XREF_FIG).	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	11	12	5	6
TGFbeta induces Smad2-and Smad3 independent activation of the TK c-Abl in fibroblasts XREF_BIBR , XREF_BIBR ; thus , TGFbeta signaling could potentially be dampened with a TK inhibitor that targets c-Abl .	TGFbeta induces Smad2-and Smad3 independent activation of the TK c-Abl in fibroblasts XREF_BIBR, XREF_BIBR; thus, TGFbeta signaling could potentially be dampened with a TK inhibitor that targets c-Abl.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	0	1	3	4
Binding of TGFbeta to its receptor activates specific SMAD family members , and TGFbeta activated phosphor-SMAD3 directly binds to the Il9 locus , the Notch intracellular domain ( NICD ) , and RBP-Jk ( recombination signal binding protein for immunoglobulin kappa J region ) [ XREF_BIBR , XREF_BIBR ] .	Binding of TGFbeta to its receptor activates specific SMAD family members, and TGFbeta activated phosphor-SMAD3 directly binds to the Il9 locus, the Notch intracellular domain (NICD), and RBP-Jk (recombination signal binding protein for immunoglobulin kappa J region) [XREF_BIBR, XREF_BIBR].	13	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	phosphor-SMAD3	phosphor-SMAD3	phosphor-SMAD3	13	14	15	16
In resident satellite cells of aged animals , excessive levels of TGF-beta induce high pSmad3 , which antagonizes Notch signaling by activating the expression of cyclin dependent kinase inhibitors ( cdks ) .	In resident satellite cells of aged animals, excessive levels of TGF-beta induce high pSmad3, which antagonizes Notch signaling by activating the expression of cyclin dependent kinase inhibitors (cdks).	9	29	induce	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TGF-beta	levels of TGF-beta	tgf-beta	pSmad3	pSmad3, which antagonizes Notch signaling by activating the expression of cyclin dependent kinase inhibitors	psmad3	11	12	14	15
EMT has been described in the collecting duct where TGF-beta induced activation of Smad3 and ERK1/2 leading to a mesenchymal morphology , increased vimentin and alpha-SMA , and a decrease in E-cadherin and beta-catenin [ XREF_BIBR ] .	EMT has been described in the collecting duct where TGF-beta induced activation of Smad3 and ERK1/2 leading to a mesenchymal morphology, increased vimentin and alpha-SMA, and a decrease in E-cadherin and beta-catenin [XREF_BIBR].	9	15	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	9	10	13	14
A key signaling pathway for early cell fate decisions is initiated by the extracellular TGF-beta like factors Nodal and Activin , which activate the downstream nuclear effectors Smad2 and Smad3 ( Smad2/3 ) .	A key signaling pathway for early cell fate decisions is initiated by the extracellular TGF-beta like factors Nodal and Activin, which activate the downstream nuclear effectors Smad2 and Smad3 (Smad2/3).	10	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	14	15	29	30
DEAR1 Represses TGFbeta induced SMAD3 dependent Signaling .	DEAR1 Represses TGFbeta induced SMAD3 dependent Signaling.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	2	3	4	5
Examination of the signaling pathways involved revealed that TGF-beta activation of Smad2 and Smad3 appear to be essential for the observed differentiation .	Examination of the signaling pathways involved revealed that TGF-beta activation of Smad2 and Smad3 appear to be essential for the observed differentiation.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	13	14
Importantly , gp130 mediated lung fibrosis occurred independently of canonical TGF-beta signalling in Smad3 deficient mice , but required mature B lymphocytes and correlated with parenchymal accumulation of B-cell containing foci .	Importantly, gp130 mediated lung fibrosis occurred independently of canonical TGF-beta signalling in Smad3 deficient mice, but required mature B lymphocytes and correlated with parenchymal accumulation of B-cell containing foci.	10	15	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	10	11	13	14
293T cells were co-transfected with TBRI , Smad3 and CEA , treated with TGF-beta for 1 h ., and total cell lysates were subjected to coimmunoprecipitation assays .	293T cells were co-transfected with TBRI, Smad3 and CEA, treated with TGF-beta for 1 h., and total cell lysates were subjected to coimmunoprecipitation assays.	3	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	13	14	7	8
Smad1 , Smad2 , Smad3 , Smad5 and Smad8 are activated via serine/threonine phosphorylation by the TGF-beta class of receptors and were thus termed receptor regulated Smads ( R-Smads ) .	Smad1, Smad2, Smad3, Smad5 and Smad8 are activated via serine/threonine phosphorylation by the TGF-beta class of receptors and were thus termed receptor regulated Smads (R-Smads).	0	25	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	16	17	4	5
TGF-beta ( Transforming Growth Factor-beta ) mediates its biological effects through members of activin receptor like kinase ( ALK ) family and TGF-beta and Smad3 signaling link inflammation to pulmonary fibrosis .	TGF-beta (Transforming Growth Factor-beta) mediates its biological effects through members of activin receptor like kinase (ALK) family and TGF-beta and Smad3 signaling link inflammation to pulmonary fibrosis.	0	27	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	24	25
BMPs , as members of the TGF-beta superfamily , bind to typeIand typeII BMP receptors ( BMPR-I or BMPR-II ) , and then primarily phosphorylate Smad1 , Smad5 and Smad8 , whereas both TGF-beta and activin receptors activate Smad2 and Smad3 [ XREF_BIBR - XREF_BIBR ] .	BMPs, as members of the TGF-beta superfamily, bind to typeIand typeII BMP receptors (BMPR-I or BMPR-II), and then primarily phosphorylate Smad1, Smad5 and Smad8, whereas both TGF-beta and activin receptors activate Smad2 and Smad3 [XREF_BIBR - XREF_BIBR].	33	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	33	34	40	41
In the pro motility pathway , the TGFbeta ligand binds to the RII-RI receptor complex composed of TGFbetaRII-ALK5 , activates Smad3 , and thereby stimulates invasion .	In the pro motility pathway, the TGFbeta ligand binds to the RII-RI receptor complex composed of TGFbetaRII-ALK5, activates Smad3, and thereby stimulates invasion.	7	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	7	8	20	21
This study also reported that hydrogen sulfide ( H2S ) was required for Treg cell differentiation and function by promoting the expression of Tet1 and Tet2 , which were recruited to the Foxp3 locus by TGFbeta activated Smad3 and IL2 activated Stat5 to maintain Foxp3 CNS2 demethylation and Treg-cell-associated immune homeostasis .	This study also reported that hydrogen sulfide (H2S) was required for Treg cell differentiation and function by promoting the expression of Tet1 and Tet2, which were recruited to the Foxp3 locus by TGFbeta activated Smad3 and IL2 activated Stat5 to maintain Foxp3 CNS2 demethylation and Treg-cell-associated immune homeostasis.	29	40	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	35	36	37	38
Western blot analyses showed enhanced levels of phosphorylated Smad2 and Smad3 in both the cell lines when they were treated with TGF-beta , which again indicated signaling activity of TGF-beta in both the cell lines ( XREF_FIG ) .	Western blot analyses showed enhanced levels of phosphorylated Smad2 and Smad3 in both the cell lines when they were treated with TGF-beta, which again indicated signaling activity of TGF-beta in both the cell lines (XREF_FIG).	7	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	21	22	10	11
XREF_FIG showed that pSmad3 is activated by TGFbeta within 4 h , and alpha-SM actin expression is significantly increased .	XREF_FIG showed that pSmad3 is activated by TGFbeta within 4 h, and alpha-SM actin expression is significantly increased.	3	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	pSmad3	pSmad3	pSmad3	7	8	3	4
Besides NF-kappaB , the Smad3 transcription factor activated by TGFbeta has been shown to be partially involved with the GR in the synergistic upregulation of plasmogen activator inhibitor ( PAI ) -1 gene by Dex and TGFbeta .	Besides NF-kappaB, the Smad3 transcription factor activated by TGFbeta has been shown to be partially involved with the GR in the synergistic upregulation of plasmogen activator inhibitor (PAI) -1 gene by Dex and TGFbeta.	4	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	9	10	4	5
Further evidence supporting a Smad independent mechanism is provided by transient transfections in Smad3 knockout ( KO ) fibroblasts completely lacking Smad3 compared with WT fibroblasts treated with and without TGF-beta ( Supplementary Data , Figure 1A ) .	Further evidence supporting a Smad independent mechanism is provided by transient transfections in Smad3 knockout (KO) fibroblasts completely lacking Smad3 compared with WT fibroblasts treated with and without TGF-beta (Supplementary Data, Figure 1A).	20	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	30	31	21	22
Correspondingly , it was recently shown that CDK2 inhibition promotes induction of T regulatory cells by enhancing the TGFbeta mediated Smad3 signaling pathway [ XREF_BIBR ] .	Correspondingly, it was recently shown that CDK2 inhibition promotes induction of T regulatory cells by enhancing the TGFbeta mediated Smad3 signaling pathway [XREF_BIBR].	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	18	19	20	21
In the current report , we have also demonstrated that Smad2- versus Smad3 specific responses are differentially regulated by km23-1 versus km23-2 in that blockade of endogenous km23-2 expression reduced TGFbeta stimulation of the Smad3 dependent transcriptional reporter SBE2-Luc , while km23-1 knockdown did not .	In the current report, we have also demonstrated that Smad2- versus Smad3 specific responses are differentially regulated by km23-1 versus km23-2 in that blockade of endogenous km23-2 expression reduced TGFbeta stimulation of the Smad3 dependent transcriptional reporter SBE2-Luc, while km23-1 knockdown did not.	30	38	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	30	31	34	35
As well as its role in canonical TGFbeta signaling SMAD3 can also be involved in the non canonical pathway .	As well as its role in canonical TGFbeta signaling SMAD3 can also be involved in the non canonical pathway.	4	10	signaling	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	7	8	9	10
We also observed that miR-2909 over-expression attenuated TGFbeta mediated SMAD3 activation , cell growth inhibition and apoptosis .	We also observed that miR-2909 over-expression attenuated TGFbeta mediated SMAD3 activation, cell growth inhibition and apoptosis.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	7	8	9	10
To gain further insights into how serine and tyrosine deficient mutants affect TGF-beta/Alk5/Smad3 pathway downstream of Smad3 , we have performed RT-PCR to determine mRNA levels of the two target genes of Smad3 , namely PAI-1 and Col-1 in control and treated with TGF-beta ( 1 ng/ml ; 48 h ) pBABE , WT-Cav-2 , S23/36A-Cav-2 , and Y19/27F-Cav -2 MLECs .	To gain further insights into how serine and tyrosine deficient mutants affect TGF-beta/Alk5/Smad3 pathway downstream of Smad3, we have performed RT-PCR to determine mRNA levels of the two target genes of Smad3, namely PAI-1 and Col-1 in control and treated with TGF-beta (1 ng/ml; 48 h) pBABE, WT-Cav-2, S23/36A-Cav-2, and Y19/27F-Cav -2 MLECs.	30	58	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	43	44	32	33
For this , scr shRNA , COX-2 shRNA and Smad3 shRNA transfected SUM159 were treated with TGFbeta for 4 days , after which the proportion of CD24 low CD44 high and ALDH+ populations were examined by flow cytometry analysis .	For this, scr shRNA, COX-2 shRNA and Smad3 shRNA transfected SUM159 were treated with TGFbeta for 4 days, after which the proportion of CD24 low CD44 high and ALDH+ populations were examined by flow cytometry analysis.	9	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	16	17	9	10
The transcription factors SMAD2 and SMAD3 are activated by TGF-beta signaling to mediate the transcriptional effects of the canonical TGF-beta signaling pathway [ XREF_BIBR ] and SMAD3 appears to play the dominant role in HSC myofibroblast activation [ XREF_BIBR ] .	The transcription factors SMAD2 and SMAD3 are activated by TGF-beta signaling to mediate the transcriptional effects of the canonical TGF-beta signaling pathway [XREF_BIBR] and SMAD3 appears to play the dominant role in HSC myofibroblast activation [XREF_BIBR].	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	9	10	5	6
Concomitantly , TGFbeta activates the transcription factors Smad2 and Smad3 , inhibits proliferation , and blocks Cdk2 activity ; all these events are blocked by an inhibitor of TbetaRI serine kinase activity ( SD208 ) .	Concomitantly, TGFbeta activates the transcription factors Smad2 and Smad3, inhibits proliferation, and blocks Cdk2 activity; all these events are blocked by an inhibitor of TbetaRI serine kinase activity (SD208).	2	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	2	3	9	10
Subsequently , we observed significant induction of both Smad2 and Smad3 phosphorylation in MS-1 cells treated with TGF-beta .	Subsequently, we observed significant induction of both Smad2 and Smad3 phosphorylation in MS-1 cells treated with TGF-beta.	10	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	17	18	10	11
Additionally , activation of LXR obviously repressed IFNgamma induced STAT1 activation and TGFbeta induced SMAD3 activation .	Additionally, activation of LXR obviously repressed IFNgamma induced STAT1 activation and TGFbeta induced SMAD3 activation.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	12	13	14	15
Further analysis of 5 '-UTR ( untranslated region ) of GLI2 gene revealed TGFbeta signaling mediated localization of SMAD3 and beta-catenin , suggesting novel role for WNT and beta-catenin signaling in regulation of GLI2 [ XREF_BIBR ] .	Further analysis of 5 '-UTR (untranslated region) of GLI2 gene revealed TGFbeta signaling mediated localization of SMAD3 and beta-catenin, suggesting novel role for WNT and beta-catenin signaling in regulation of GLI2 [XREF_BIBR].	13	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	13	14	18	19
The SMAD proteins are transcription factors , and TGF-beta signaling has been shown to robustly activate SMAD2 and SMAD3 ( receptor associated SMAD family members ; R-Smads ) through phosphorylation of C-terminal regulatory residues [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The SMAD proteins are transcription factors, and TGF-beta signaling has been shown to robustly activate SMAD2 and SMAD3 (receptor associated SMAD family members; R-Smads) through phosphorylation of C-terminal regulatory residues [XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	8	9	18	19
In isolated heart tissue and in cultured NIH-3T3 fibroblasts , ATRA increases TGF-beta stimulated pSMAD2 and pSMAD3 , but decreases nuclear accumulation of these transcription factors and decreases pSMAD mediated transcriptional activity 5 .	In isolated heart tissue and in cultured NIH-3T3 fibroblasts, ATRA increases TGF-beta stimulated pSMAD2 and pSMAD3, but decreases nuclear accumulation of these transcription factors and decreases pSMAD mediated transcriptional activity 5.	11	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	pSMAD3	pSMAD3	pSMAD3	12	13	16	17
To assess the role of SMADs in ERBB ligand induction and receptor activation , AKR-2B cells stably expressing shRNA targeting Smad2 , Smad3 , or a nontargeting control were treated with TGF-beta for different time periods .	To assess the role of SMADs in ERBB ligand induction and receptor activation, AKR-2B cells stably expressing shRNA targeting Smad2, Smad3, or a nontargeting control were treated with TGF-beta for different time periods.	17	35	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	31	32	22	23
Like other signal dependent transcription factors , ligation of TGFbeta receptors causes the localization of Smad3 to genomic loci containing lineage determining transcription factors .	Like other signal dependent transcription factors, ligation of TGFbeta receptors causes the localization of Smad3 to genomic loci containing lineage determining transcription factors.	9	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	9	10	15	16
Upon ligand binding , TGFbeta type II receptor ( RII ) recruits and activates TGFbeta type I receptor ( RI ) , which then activates Smad2 and Smad3 .	Upon ligand binding, TGFbeta type II receptor (RII) recruits and activates TGFbeta type I receptor (RI), which then activates Smad2 and Smad3.	14	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	14	15	27	28
How TTK downregulates KLF5 remains unknown , but could be related to TGF-beta signaling , as TGF-beta downregulates KLF5 28 and TTK inhibition reduced the activation of SMAD3 by TGF-beta , potentially impacting the assembly of the transcriptional complex for KLF5 or altering the cellular localization and function of KLF5 .	How TTK downregulates KLF5 remains unknown, but could be related to TGF-beta signaling, as TGF-beta downregulates KLF5 28 and TTK inhibition reduced the activation of SMAD3 by TGF-beta, potentially impacting the assembly of the transcriptional complex for KLF5 or altering the cellular localization and function of KLF5.	23	30	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	29	30	27	28
The mechanism by which HF reduces fibrosis was recently elucidated in a mouse model for scleroderma ( dermal fibrosis ) , where a low dose of halo blocked TGF-beta mediated SMAD3 activation in fibroblasts [ XREF_BIBR ] .	The mechanism by which HF reduces fibrosis was recently elucidated in a mouse model for scleroderma (dermal fibrosis), where a low dose of halo blocked TGF-beta mediated SMAD3 activation in fibroblasts [XREF_BIBR].	28	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	28	29	30	31
TGF-beta mediated SMAD3 signalling was also seen to be suppressed by miR-2909 through induction of SMAD7 via enhanced STAT1 expression .	TGF-beta mediated SMAD3 signalling was also seen to be suppressed by miR-2909 through induction of SMAD7 via enhanced STAT1 expression.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	0	1	2	3
An additional regulator of HSC activity missing in Prep1 i/i cells might be the TGFbeta dependent activation of Smad2 and Smad3 , in agreement with the Pbx1 -/- phenotype XREF_BIBR .	An additional regulator of HSC activity missing in Prep1 i/i cells might be the TGFbeta dependent activation of Smad2 and Smad3, in agreement with the Pbx1 -/- phenotype XREF_BIBR.	14	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	14	15	20	21
Furthermore , TGF-beta blockade by means of either a neutralizing pan-TGF-beta antibody XREF_BIBR , SMAD7 overexpression XREF_BIBR , or treatment of cells with a TbetaRI small molecule inhibitor XREF_BIBR , inhibited basal SMAD3 and SMAD4 dependent transcriptional activity in melanoma cells .	Furthermore, TGF-beta blockade by means of either a neutralizing pan-TGF-beta antibody XREF_BIBR, SMAD7 overexpression XREF_BIBR, or treatment of cells with a TbetaRI small molecule inhibitor XREF_BIBR, inhibited basal SMAD3 and SMAD4 dependent transcriptional activity in melanoma cells.	2	37	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	2	3	32	33
The possible mechanism identified indicated that CaeA obstructed IFN-gamma-induced STAT1 signaling by enhancing the display of SOCS1 and increased TGF-beta mediated Smad3 function .	The possible mechanism identified indicated that CaeA obstructed IFN-gamma-induced STAT1 signaling by enhancing the display of SOCS1 and increased TGF-beta mediated Smad3 function.	18	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	19	20	21	22
TGFbeta also promotes endogenous Smad3 oligo ( ADP-ribosyl ) ation , while in vitro ADP ribosylation experiments demonstrated that recombinant Smad3 or Smad4 could co-precipitate activated poly ( ADP-ribosyl ) ated PARP-1 and PARP-2 .	TGFbeta also promotes endogenous Smad3 oligo (ADP-ribosyl) ation, while in vitro ADP ribosylation experiments demonstrated that recombinant Smad3 or Smad4 could co-precipitate activated poly (ADP-ribosyl) ated PARP-1 and PARP-2.	0	30	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	0	1	4	5
In human primary fibroblasts , we show that PTP4A1 sustains extracellular regulated kinase ( ERK )-dependent expression of the important TGFbeta mediator mothers against decapentaplegic homolog 3 ( SMAD3 ) .	In human primary fibroblasts, we show that PTP4A1 sustains extracellular regulated kinase (ERK)-dependent expression of the important TGFbeta mediator mothers against decapentaplegic homolog 3 (SMAD3).	9	27	mediator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	mothers against decapentaplegic homolog 3	mothers against decapentaplegic homolog 3	mothers against decapentaplegic homolog 3	20	21	22	27
Smad1 , Smad5 , and Smad8 are specific substrates of the BMP receptors , whereas Smad2 and Smad3 are activated by both TGF-beta and activin receptors [ XREF_BIBR , XREF_BIBR ] .	Smad1, Smad5, and Smad8 are specific substrates of the BMP receptors, whereas Smad2 and Smad3 are activated by both TGF-beta and activin receptors [XREF_BIBR, XREF_BIBR].	15	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	22	23	17	18
In contrast , more complete inhibition of TGF-beta signaling in Smad3-/- and TGF-beta1-/- mice is associated with low bone mass and poor bone quality , which may result , in part , from the significant systemic effects of Smad3 and TGF-beta1 deletion XREF_BIBR , XREF_BIBR , XREF_BIBR .	In contrast, more complete inhibition of TGF-beta signaling in Smad3-/- and TGF-beta1-/- mice is associated with low bone mass and poor bone quality, which may result, in part, from the significant systemic effects of Smad3 and TGF-beta1 deletion XREF_BIBR, XREF_BIBR, XREF_BIBR.	7	13	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3-/-	Smad3-/-	Smad3-/-	7	8	10	11
These findings suggest that TGF-beta signal Smad3 plays a key role for chromatin remodeling to induce chondrogenesis via its association with Sox9 .	These findings suggest that TGF-beta signal Smad3 plays a key role for chromatin remodeling to induce chondrogenesis via its association with Sox9.	4	7	signal	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	4	5	6	7
For example , TGF-beta can activate its downstream molecule Smad3 , which forms a complex with Smad4 and enters the nucleus to enhance VEGF transcription by interacting with its promoter 41 .	For example, TGF-beta can activate its downstream molecule Smad3, which forms a complex with Smad4 and enters the nucleus to enhance VEGF transcription by interacting with its promoter 41.	3	18	activate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TGF-beta	TGF-beta	tgf-beta	Smad3	Smad3, which forms a complex with Smad4	smad3	3	4	9	10
In part , this occurs through TGF-beta activation of Smad 3 , resulting in Smad 3binding to Runx2 , which inhibits Runx2 dependent transcription of osteoblast genes and of Runx2 itself [ XREF_BIBR ] .	In part, this occurs through TGF-beta activation of Smad 3, resulting in Smad 3binding to Runx2, which inhibits Runx2 dependent transcription of osteoblast genes and of Runx2 itself [XREF_BIBR].	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad 3	Smad 3	Smad 3	6	7	9	11
Because several studies by Sorrentino et al and Yamashita et al have shown that TGF-beta activates JNK by mediating Smad independent signaling [ XREF_BIBR , XREF_BIBR ] and our previous study showed that MUC1 expression induces TGF-beta1 secretion ( data not shown ) in HCC cells , we sought to investigate whether MUC1 induced TGF-beta secretion could activate JNK and mediate Smad3 signaling .	Because several studies by Sorrentino et al and Yamashita et al have shown that TGF-beta activates JNK by mediating Smad independent signaling [XREF_BIBR, XREF_BIBR] and our previous study showed that MUC1 expression induces TGF-beta1 secretion (data not shown) in HCC cells, we sought to investigate whether MUC1 induced TGF-beta secretion could activate JNK and mediate Smad3 signaling.	52	62	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	MUC1 induced TGF-beta	tgf-beta	Smad3	Smad3	smad3	54	55	61	62
Neutralizing TGF-beta expression either by blocking TGF-beta signaling in the Smad-3 pathway or administering anti activin-A significantly reduces peribronchial fibrosis , ASM proliferation , and mucus production [ XREF_BIBR ] .	Neutralizing TGF-beta expression either by blocking TGF-beta signaling in the Smad-3 pathway or administering anti activin-A significantly reduces peribronchial fibrosis, ASM proliferation, and mucus production [XREF_BIBR].	6	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad-3	Smad-3	Smad-3	6	7	10	11
Both SMAD3 and STAT5 signalling pathways were active in cells treated with IL-15 plus TGF-beta and the IL-15 dependent exclusion of FOXO3 from the nucleus was also unaffected by TGF-beta treatment .	Both SMAD3 and STAT5 signalling pathways were active in cells treated with IL-15 plus TGF-beta and the IL-15 dependent exclusion of FOXO3 from the nucleus was also unaffected by TGF-beta treatment.	0	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	14	15	1	2
However , TGF-beta only induced Smad3 occupancy at SBRs in regions of chromatin that were activated prior to TGF-beta treatment , as assessed by ChIP for the presence of H3AcK9/14 at the SBR in the untreated state .	However, TGF-beta only induced Smad3 occupancy at SBRs in regions of chromatin that were activated prior to TGF-beta treatment, as assessed by ChIP for the presence of H3AcK9/14 at the SBR in the untreated state.	2	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	2	3	5	6
Here we show that TGF-beta induces association of SMAD3 with both SMAD4 , needed for translocation of the complex into the nucleus , and the essential context sensitive corepressors E2F4 and p107 .	Here we show that TGF-beta induces association of SMAD3 with both SMAD4, needed for translocation of the complex into the nucleus, and the essential context sensitive corepressors E2F4 and p107.	4	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	4	5	8	9
TGF-beta activation of Smad3 also inhibits Runx2 via epigenetic regulation .	TGF-beta activation of Smad3 also inhibits Runx2 via epigenetic regulation.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	3	4
Interfering with TGFbeta induced Smad3 nuclear accumulation differentially affects TGFbeta dependent gene expression .	Interfering with TGFbeta induced Smad3 nuclear accumulation differentially affects TGFbeta dependent gene expression.	0	6	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	2	3	4	5
Type-I collagen , a major component of fibrotic tissue , is expressed by many renal cells in response to TGF-beta activation of Smad3 .	Type-I collagen, a major component of fibrotic tissue, is expressed by many renal cells in response to TGF-beta activation of Smad3.	19	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	19	20	22	23
Furthermore , FOXM1 has been shown to sustain TGFbeta induced formation of a SMAD3 and SMAD4 nuclear transcription complex that up-regulates the downstream EMT target SLUG to promote breast cancer metastasis [ XREF_BIBR , XREF_BIBR ] .	Furthermore, FOXM1 has been shown to sustain TGFbeta induced formation of a SMAD3 and SMAD4 nuclear transcription complex that up-regulates the downstream EMT target SLUG to promote breast cancer metastasis [XREF_BIBR, XREF_BIBR].	7	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	8	9	13	14
The delayed TGFbeta mediated entry of Smad3 into the nucleus in the presence of SB-203580 prompted us to examine the effect of SB-203580 on TGFbeta induced gene expression in a time-course experiment .	The delayed TGFbeta mediated entry of Smad3 into the nucleus in the presence of SB-203580 prompted us to examine the effect of SB-203580 on TGFbeta induced gene expression in a time-course experiment.	0	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	2	3	6	7
As shown in Figure XREF_FIG , the results clearly indicate that p/CAF is required for TGFbeta induced Smad3 transcriptional activity .	As shown in Figure XREF_FIG, the results clearly indicate that p/CAF is required for TGFbeta induced Smad3 transcriptional activity.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	15	16	17	18
Further , TGF-beta has previously been shown to trigger intracellular ROS release via redox- and Smad3 dependent upregulation of NADPH oxidase 4 while inhibiting the expression of MnSOD and catalase in asthmatic and obstructive airway smooth muscle .	Further, TGF-beta has previously been shown to trigger intracellular ROS release via redox- and Smad3 dependent upregulation of NADPH oxidase 4 while inhibiting the expression of MnSOD and catalase in asthmatic and obstructive airway smooth muscle.	2	17	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	2	3	15	16
An important delineator of Smad signaling pathways is the difference between outcomes after TGF-beta stimulation of Smad2 and Smad3 versus BMP-7 stimulation of Smad1 and Smad5 .	An important delineator of Smad signaling pathways is the difference between outcomes after TGF-beta stimulation of Smad2 and Smad3 versus BMP-7 stimulation of Smad1 and Smad5.	13	19	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	13	14	18	19
To test whether a similar mechanism is present in the near-wound areas and whether nuclear Smad3 levels follow a biphasic pattern , we compared TGFbeta induced Smad3 translocation at the wound edge and in the intact area after 6 h of stimulation ( XREF_FIG ) .	To test whether a similar mechanism is present in the near-wound areas and whether nuclear Smad3 levels follow a biphasic pattern, we compared TGFbeta induced Smad3 translocation at the wound edge and in the intact area after 6 h of stimulation (XREF_FIG).	24	27	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	24	25	26	27
Similarly , TGFbeta mediated inhibition of telomerase expression and cell immortalization is Smad3 specific XREF_BIBR .	Similarly, TGFbeta mediated inhibition of telomerase expression and cell immortalization is Smad3 specific XREF_BIBR.	2	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	2	3	12	13
Taken together , these findings indicate that TGF-beta and IL-2 activated Smad3 and Stat5 , recruiting Tet1 and Tet2 binding to Foxp3 locus to regulate Foxp3 demethyaltion and Treg cell differentiation and function .	Taken together, these findings indicate that TGF-beta and IL-2 activated Smad3 and Stat5, recruiting Tet1 and Tet2 binding to Foxp3 locus to regulate Foxp3 demethyaltion and Treg cell differentiation and function.	7	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	7	8	11	12
Internalization of TGFbeta receptors via clathrin coated pits into the early endosome promotes TGFbeta and Smad3 signaling while lipid-raft and caveolar internalization promotes Smad7-Smurf dependent receptor degradation , thus inhibiting the canonical TGFbeta signaling [ XREF_BIBR ] .	Internalization of TGFbeta receptors via clathrin coated pits into the early endosome promotes TGFbeta and Smad3 signaling while lipid-raft and caveolar internalization promotes Smad7-Smurf dependent receptor degradation, thus inhibiting the canonical TGFbeta signaling [XREF_BIBR].	2	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	2	3	15	16
We now demonstrate that TGF-beta treatment activates Smad3 but not Smad2 in SBOT3.1 and MPSC1 cells .	We now demonstrate that TGF-beta treatment activates Smad3 but not Smad2 in SBOT3.1 and MPSC1 cells.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	4	5	7	8
Interestingly , the Dll1 ICD has been reported to enhance TGFbeta induced Smad3 transcriptional activation , reminiscent of Smad enhanced NICD transcriptional activation .	Interestingly, the Dll1 ICD has been reported to enhance TGFbeta induced Smad3 transcriptional activation, reminiscent of Smad enhanced NICD transcriptional activation.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	10	11	12	13
To investigate whether FLCN supplementation in UOK257-FS cells had any effect on the regulation of TGF-beta signaling , we performed Western analysis against TGF-beta mediator SMAD3 .	To investigate whether FLCN supplementation in UOK257-FS cells had any effect on the regulation of TGF-beta signaling, we performed Western analysis against TGF-beta mediator SMAD3.	19	26	mediator	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	23	24	25	26
Figure XREF_FIG B shows that TGFbeta treatment significantly enhanced nuclear fluorescence intensity of P-smad3 but pretreatment with cGMP significantly limits nuclear translocation of P-smad3 in fibroblasts of wt-kidneys in the presence of TGFbeta .	Figure XREF_FIG B shows that TGFbeta treatment significantly enhanced nuclear fluorescence intensity of P-smad3 but pretreatment with cGMP significantly limits nuclear translocation of P-smad3 in fibroblasts of wt-kidneys in the presence of TGFbeta.	5	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	P-smad3	P-smad3	P-smad3	5	6	13	14
To assess the impact of the p21 and Smad3 interaction on TGFbeta signaling , we then examined the effect of p21 on TGFbeta induced Smad3 activity .	To assess the impact of the p21 and Smad3 interaction on TGFbeta signaling, we then examined the effect of p21 on TGFbeta induced Smad3 activity.	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	22	23	24	25
XREF_BIBR ] demonstrated that RA enhances TGF-beta driven SMAD3 signaling and inhibits IL-6 and IL-23 receptor expression .	XREF_BIBR] demonstrated that RA enhances TGF-beta driven SMAD3 signaling and inhibits IL-6 and IL-23 receptor expression.	5	9	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	6	7	8	9
As reported , TGF-beta induced the interaction of Smad3 with Smad4 and with p300 .	As reported, TGF-beta induced the interaction of Smad3 with Smad4 and with p300.	3	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	3	4	8	9
TGF-beta stimulation in T cells can induce Smad3 activation by phosphorylation , however , the epigenetic mechanisms governing TGF-beta-dependent Smad3 expression is still unclear .	TGF-beta stimulation in T cells can induce Smad3 activation by phosphorylation, however, the epigenetic mechanisms governing TGF-beta-dependent Smad3 expression is still unclear.	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	7	8
PAPSS2 mRNA levels were also higher in cells that expressed the exogenous SMAD3 and were treated with TGF-beta when compared to cells infected with SMAD3 ( XREF_FIG , XREF_SUPPLEMENTARY ) .	PAPSS2 mRNA levels were also higher in cells that expressed the exogenous SMAD3 and were treated with TGF-beta when compared to cells infected with SMAD3 (XREF_FIG, XREF_SUPPLEMENTARY).	9	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	17	18	12	13
These data suggest that TGFbeta increases the fraction of active Smad3 complexed with BRD4 and that BRD4 interacts with CDK9 .	These data suggest that TGFbeta increases the fraction of active Smad3 complexed with BRD4 and that BRD4 interacts with CDK9.	4	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	4	5	10	11
We previously described that TGF-beta signal Smad3 promotes the early chondrogenesis through the activation of Sox9 .	We previously described that TGF-beta signal Smad3 promotes the early chondrogenesis through the activation of Sox9.	4	7	signal	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	4	5	6	7
SMAD2 and SMAD3 are specifically activated by TGFbeta like cytokines , whereas SMAD1 , SMAD5 and SMAD8 are exclusively phosphorylated by BMPs ; ( ii ) a co-SMAD , SMAD4 heteropolymerises with activated ra-SMADs .	SMAD2 and SMAD3 are specifically activated by TGFbeta like cytokines, whereas SMAD1, SMAD5 and SMAD8 are exclusively phosphorylated by BMPs; (ii) a co-SMAD, SMAD4 heteropolymerises with activated ra-SMADs.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	7	8	2	3
Although necessary , MRTF is insufficient ; Nox4 expression also requires TGFbeta activated Smad3 and TAZ and YAP , two contact- and cytoskeleton regulated Smad3 interacting coactivators .	Although necessary, MRTF is insufficient; Nox4 expression also requires TGFbeta activated Smad3 and TAZ and YAP, two contact- and cytoskeleton regulated Smad3 interacting coactivators.	10	17	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	11	12	13	14
TGF-beta has been so far shown to induce smooth muscle differentiation via Notch or SMAD2 and SMAD3 signaling in ES cells or in a neural crest stem cell line .	TGF-beta has been so far shown to induce smooth muscle differentiation via Notch or SMAD2 and SMAD3 signaling in ES cells or in a neural crest stem cell line.	0	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	0	1	16	17
A direct cross talk between the Notch and TGF-beta signaling pathways comes from a recent study in which a direct interaction between Notch intracellular domain and Smad-3 was demonstrated , and activation of Smad-3 by TGF-beta led to an enhancement of Notch induced Hes1 gene transcription .	A direct cross talk between the Notch and TGF-beta signaling pathways comes from a recent study in which a direct interaction between Notch intracellular domain and Smad-3 was demonstrated, and activation of Smad-3 by TGF-beta led to an enhancement of Notch induced Hes1 gene transcription.	31	36	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad-3	Smad-3	Smad-3	35	36	33	34
TGF-beta activates Smad3 signaling , induces TERT gene repression and results in G1/S phase cell cycle arrest and apoptosis .	TGF-beta activates Smad3 signaling, induces TERT gene repression and results in G1/S phase cell cycle arrest and apoptosis.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	2	3
Not only that TGF-beta influences collagen production directly through Smad signaling but also induces Smad 3 to transcribe proteins that activate the Wnt pathway that induces scarring .	Not only that TGF-beta influences collagen production directly through Smad signaling but also induces Smad 3 to transcribe proteins that activate the Wnt pathway that induces scarring.	3	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad 3	Smad 3	Smad 3	3	4	14	16
However , we also demonstrate that blockade of endogenous km23-2 attenuated TGFbeta stimulation of the Smad3 specific target genes PAI-1 and p21 , while blockade of km23-1 had no effect on either of these TGFbeta responses .	However, we also demonstrate that blockade of endogenous km23-2 attenuated TGFbeta stimulation of the Smad3 specific target genes PAI-1 and p21, while blockade of km23-1 had no effect on either of these TGFbeta responses.	11	16	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	11	12	15	16
We believe that TGF-beta receptor is an especially important target since TGF-beta might activate Smad3 and Smad2 .	We believe that TGF-beta receptor is an especially important target since TGF-beta might activate Smad3 and Smad2.	11	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	11	12	14	15
Smad 3 , on the contrary , is not activated by TGFbeta , as it is expressed in a very low amount in both treated and untreated cells in the cytoplasm and showed no expression in the nucleus .	Smad 3, on the contrary, is not activated by TGFbeta, as it is expressed in a very low amount in both treated and untreated cells in the cytoplasm and showed no expression in the nucleus.	0	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad 3	Smad 3	Smad 3	11	12	0	2
The high TGF-beta expression induced by haemodynamic abnormalities during hyperfiltration may increase production of downstream molecular pathways and further production of Smad3 .	The high TGF-beta expression induced by haemodynamic abnormalities during hyperfiltration may increase production of downstream molecular pathways and further production of Smad3.	2	22	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta expression	tgf-beta	Smad3	Smad3	smad3	2	3	21	22
Remarkably , the effects of the loss of TRIP-1 are not abrogated by blockage of TGFbeta ligand activation of the Smad3 pathway or by Smad3 knockdown .	Remarkably, the effects of the loss of TRIP-1 are not abrogated by blockage of TGFbeta ligand activation of the Smad3 pathway or by Smad3 knockdown.	15	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	15	16	20	21
We found that , in nonstimulated cells , phosphorylated Smad3 was not present or was below detection level ; however , 5 ng/ml of TGF-beta caused a significant up-regulation of phospho-Smad3 that localized primarily in the nucleus of the TK173 cells .	We found that, in nonstimulated cells, phosphorylated Smad3 was not present or was below detection level; however, 5 ng/ml of TGF-beta caused a significant up-regulation of phospho-Smad3 that localized primarily in the nucleus of the TK173 cells.	22	31	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	phospho-Smad3	phospho-Smad3	phospho-Smad3	24	25	30	31
As expected , TGF-beta treatment ( 10ng/ml , 1h ) significantly increased nuclear content of total SMAD-3 in MEFs and cardiac fibroblasts .	As expected, TGF-beta treatment (10ng/ml, 1h) significantly increased nuclear content of total SMAD-3 in MEFs and cardiac fibroblasts.	3	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD-3	SMAD-3	SMAD-3	3	4	16	17
The results showed that in PPAR-gamma control MEFs , TGF-beta enhanced the accumulation of phospho-Smad3 on its cognate binding site ( XREF_FIG ) as shown previously in normal fibroblasts [ XREF_BIBR , XREF_BIBR ] .	The results showed that in PPAR-gamma control MEFs, TGF-beta enhanced the accumulation of phospho-Smad3 on its cognate binding site (XREF_FIG) as shown previously in normal fibroblasts [XREF_BIBR, XREF_BIBR].	9	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	phospho-Smad3	phospho-Smad3	phospho-Smad3	9	10	14	15
Taken together , these results suggest that TGF-beta induced Smad-3 and amino acid uptake through a PI3-kinase independent pathway .	Taken together, these results suggest that TGF-beta induced Smad-3 and amino acid uptake through a PI3-kinase independent pathway.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad-3	Smad-3	Smad-3	7	8	9	10
TGF-beta could activate the Smad path ( Smad2 and Smad3 ) through the Serine/threonine kinase receptors I and II [ XREF_BIBR ] .	TGF-beta could activate the Smad path (Smad2 and Smad3) through the Serine/threonine kinase receptors I and II [XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	9	10
For example , it has also been reported that TGF-beta activates Wnt signaling in a Smad3 independent manner ( through p38 ) in human dermal fibroblasts by down-regulating Dkk-1 , a Wnt signaling inhibitor protein [ XREF_BIBR ] .	For example, it has also been reported that TGF-beta activates Wnt signaling in a Smad3 independent manner (through p38) in human dermal fibroblasts by down-regulating Dkk-1, a Wnt signaling inhibitor protein [XREF_BIBR].	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	9	10	15	16
In mammals , it is known that members of the two subfamilies activate distinct classes of Smad proteins : TGF-beta subfamily members activate Smad2 and Smad3 homologues while BMP subfamily members activate Smad1 , Smad5 and Smad8 homologues .	In mammals, it is known that members of the two subfamilies activate distinct classes of Smad proteins : TGF-beta subfamily members activate Smad2 and Smad3 homologues while BMP subfamily members activate Smad1, Smad5 and Smad8 homologues.	19	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	19	20	25	26
TGF-beta-increased beta-catenin induction was reproduced by overexpression of SMAD3 and was absent in Smad3 (-/-) chondrocytes treated with TGF-beta .	TGF-beta-increased beta-catenin induction was reproduced by overexpression of SMAD3 and was absent in Smad3 (-/-) chondrocytes treated with TGF-beta.	6	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	18	19	8	9
Moreover , a TGF-beta and BMP regulated protein PRAJA ( Proliferation Regeneration Architecture Juxtaposition Apoptosis ) is expressed in hepatoblasts and modulates ELF and Smad3 , adding to the complexity of TGF-beta signaling in the gut .	Moreover, a TGF-beta and BMP regulated protein PRAJA (Proliferation Regeneration Architecture Juxtaposition Apoptosis) is expressed in hepatoblasts and modulates ELF and Smad3, adding to the complexity of TGF-beta signaling in the gut.	2	25	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta and BMP regulated protein PRAJA (Proliferation Regeneration Architecture Juxtaposition Apoptosis) is expressed	tgf-beta	Smad3	Smad3	smad3	3	4	24	25
Thus , TGF-beta induces the type I receptor TbetaRI to activate Smad2 and/or Smad3 , which then dissociate from the receptor complexes and form trimers of two receptor activated Smads and one Smad4 .	Thus, TGF-beta induces the type I receptor TbetaRI to activate Smad2 and/or Smad3, which then dissociate from the receptor complexes and form trimers of two receptor activated Smads and one Smad4.	2	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	2	3	13	14
In response to TGFbeta stimulation Smad3 and Smad2 translocate into the nucleus and induce degradation of the transcriptional corepressor SnoN leading to activation of TGFbeta target genes and growth inhibition in cultured cells .	In response to TGFbeta stimulation Smad3 and Smad2 translocate into the nucleus and induce degradation of the transcriptional corepressor SnoN leading to activation of TGFbeta target genes and growth inhibition in cultured cells.	3	13	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	3	4	5	6
In conjunction with p300 and CBP , the PIAS3 protein , from the Protein Inhibitor of Activated Stat family , may also modulate TGFbeta mediated Smad3 transcriptional activity .	In conjunction with p300 and CBP, the PIAS3 protein, from the Protein Inhibitor of Activated Stat family, may also modulate TGFbeta mediated Smad3 transcriptional activity.	22	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	23	24	25	26
OTUB1 was identified as an interactor of SMAD3 only under conditions where cells were treated with TGFbeta XREF_BIBR .	OTUB1 was identified as an interactor of SMAD3 only under conditions where cells were treated with TGFbeta XREF_BIBR.	5	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	16	17	7	8
Indeed , we found that in SMCs HF inhibited TGFbeta activated Smad3 signaling but did not affect pSmad3 in ECs .	Indeed, we found that in SMCs HF inhibited TGFbeta activated Smad3 signaling but did not affect pSmad3 in ECs.	8	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	9	10	11	12
Then TGF-beta signalling activates R-Smads ( SMAD2 and SMAD3 localised in the cytoplasm ) , through phosphorylation and after that allows the assembly of complexes with SMAD4 .	Then TGF-beta signalling activates R-Smads (SMAD2 and SMAD3 localised in the cytoplasm), through phosphorylation and after that allows the assembly of complexes with SMAD4.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	1	2	8	9
TGF-beta leads to the intracellular activation of Smad2 , Smad3 and Smad4 , which can be counteracted by the inhibitory proteins , Smad6 and Smad7 [ XREF_BIBR ] .	TGF-beta leads to the intracellular activation of Smad2, Smad3 and Smad4, which can be counteracted by the inhibitory proteins, Smad6 and Smad7 [XREF_BIBR].	0	10	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	9	10
Tiam1 ( T lymphoma invasion and metastasis 1 ) , a guanine nucleotide exchange factor that activates Rac , was recently identified as a novel colorectal cancer metastasis related gene .	Tiam1 (T lymphoma invasion and metastasis 1), a guanine nucleotide exchange factor that activates Rac, was recently identified as a novel colorectal cancer metastasis related gene.	0	21	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	17	18
XREF_BIBR Additionally , Tiam1 mediated activation of Rac1 is also associated with reduced HGF- and epidermal growth factor ( EGF )-induced cell scattering , further demonstrating the importance of Tiam1-Rac1 signaling in stabilizing cell-cell contacts .	XREF_BIBR Additionally, Tiam1 mediated activation of Rac1 is also associated with reduced HGF- and epidermal growth factor (EGF)-induced cell scattering, further demonstrating the importance of Tiam1-Rac1 signaling in stabilizing cell-cell contacts.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	3	4	7	8
In fibroblasts , Tiam1 mediated Rac activation also resulted in strong inhibition of migration , by increasing cell-cell and cell-matrix adhesions .	In fibroblasts, Tiam1 mediated Rac activation also resulted in strong inhibition of migration, by increasing cell-cell and cell-matrix adhesions.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	5	6
Tiam1 mediated Rac Activation on Fibronectin and Collagen I Is Similar .	Tiam1 mediated Rac Activation on Fibronectin and Collagen I Is Similar.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	2	3
Similarly , T cells deficient in the Rac activator Tiam1 are deficient in polarization and locomotion on endothelium and tend to migrate transcellularly .	Similarly, T cells deficient in the Rac activator Tiam1 are deficient in polarization and locomotion on endothelium and tend to migrate transcellularly.	4	10	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	9	10	7	8
This indicates that activation of Rac by Tiam1 stimulates the formation or stabilization of functional E-cadherin complexes at the cell surface leading to phenotypic reversion towards an epithelioid phenotype and inhibition of motile and invasive behavior .	This indicates that activation of Rac by Tiam1 stimulates the formation or stabilization of functional E-cadherin complexes at the cell surface leading to phenotypic reversion towards an epithelioid phenotype and inhibition of motile and invasive behavior.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	5	6
Interestingly , it has been demonstrated that Tiam1 and Tiam2 enhance Rac1 activity and are involved in the suppression of RhoA activity in N1E-115 cells [ XREF_BIBR ] .	Interestingly, it has been demonstrated that Tiam1 and Tiam2 enhance Rac1 activity and are involved in the suppression of RhoA activity in N1E-115 cells [XREF_BIBR].	7	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	11	12
In support of this notion , Tiam1 , Vav2 and Asef , Rac GEFs that contain a PIP3 binding PH domain , have been shown to activate Rac1 in response to EGF XREF_BIBR XREF_BIBR .	In support of this notion, Tiam1, Vav2 and Asef, Rac GEFs that contain a PIP3 binding PH domain, have been shown to activate Rac1 in response to EGF XREF_BIBR XREF_BIBR.	6	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	27	28
However , and consistent with recent studies , we find that the formation of the signaling complex Tiam1 and Rac1 is not abrogated by inhibition of PI3K using Ly294002 , indicating that Tiam1 mediates Rac1 activation by a PI3K independent mechanism XREF_BIBR , XREF_BIBR ( XREF_SUPPLEMENTARY ) .	However, and consistent with recent studies, we find that the formation of the signaling complex Tiam1 and Rac1 is not abrogated by inhibition of PI3K using Ly294002, indicating that Tiam1 mediates Rac1 activation by a PI3K independent mechanism XREF_BIBR, XREF_BIBR (XREF_SUPPLEMENTARY).	32	35	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	32	33	34	35
This result suggests that Rac1 activation by Tiam1 largely counteracted the extraction of Rac1 from the liposomes by RhoGDI and shifts Rac1 towards a signaling-competent state .	This result suggests that Rac1 activation by Tiam1 largely counteracted the extraction of Rac1 from the liposomes by RhoGDI and shifts Rac1 towards a signaling-competent state.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	4	5
First , it is likely that Tiam1 , by itself , or Tiam1 activated Rac1 might control activities of putative transcriptional factors that might play negative modulatory roles in GSIS ; regulation of cellular function by such factors [ e.g ., STAT and c-myc ] has been described in other cell types [ XREF_BIBR , XREF_BIBR ] .	First, it is likely that Tiam1, by itself, or Tiam1 activated Rac1 might control activities of putative transcriptional factors that might play negative modulatory roles in GSIS; regulation of cellular function by such factors [e.g., STAT and c-myc] has been described in other cell types [XREF_BIBR, XREF_BIBR].	6	16	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	12	13	14	15
Down-regulation of Par3 in MDCK cells , as studied by XREF_BIBR , might prevent the recruitment of Tiam1 to cell-cell contacts and , thereby , promote Tiam1 mediated Rac activation at the cell periphery , leading to the destabilization of cell-cell adhesions and the inhibition of TJ formation .	Down-regulation of Par3 in MDCK cells, as studied by XREF_BIBR, might prevent the recruitment of Tiam1 to cell-cell contacts and, thereby, promote Tiam1 mediated Rac activation at the cell periphery, leading to the destabilization of cell-cell adhesions and the inhibition of TJ formation.	26	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	26	27	28	29
The Tiam1- but not V12Rac mediated migration was reduced three- to fourfold upon inhibition of PI3-kinase , consistent with the effects of PI3-kinase inhibition on the Tiam1 mediated activation of Rac determined in the Rac activity assay .	The Tiam1- but not V12Rac mediated migration was reduced three- to fourfold upon inhibition of PI3-kinase, consistent with the effects of PI3-kinase inhibition on the Tiam1 mediated activation of Rac determined in the Rac activity assay.	23	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	26	27	30	31
It is documented that RhoA activity is relatively high in cultured fibroblasts such as NIH3T3 , and activation of Rac by Tiam1 in NIH3T3 cells induces an epithelial like morphology with functional cadherin based adhesions .	It is documented that RhoA activity is relatively high in cultured fibroblasts such as NIH3T3, and activation of Rac by Tiam1 in NIH3T3 cells induces an epithelial like morphology with functional cadherin based adhesions.	17	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	21	22	19	20
This phenotype is mediated by the guanine nucleotide exchange factor TIAM1 , which activates the small GTPase Rac1 .	This phenotype is mediated by the guanine nucleotide exchange factor TIAM1, which activates the small GTPase Rac1.	3	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	Rac1	Rac1	Rac1	10	11	17	18
In fibroblasts , however , Tiam1 mediated activation of Rac is associated with an increase in cell-cell interactions and loss of cell motility .	In fibroblasts, however, Tiam1 mediated activation of Rac is associated with an increase in cell-cell interactions and loss of cell motility.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	5	6	9	10
The Rac activator Tiam1 is required for polarized protrusional outgrowth of primary astrocytes by affecting the organization of the microtubule network .	The Rac activator Tiam1 is required for polarized protrusional outgrowth of primary astrocytes by affecting the organization of the microtubule network.	0	5	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	1	2
Cells overexpressing Tiam1 no longer respond to lysophosphatidic acid- induced neurite retraction and cell rounding , processes mediated by Rho , suggesting that Tiam1 induced activation of Rac antagonizes Rho signaling .	Cells overexpressing Tiam1 no longer respond to lysophosphatidic acid- induced neurite retraction and cell rounding, processes mediated by Rho, suggesting that Tiam1 induced activation of Rac antagonizes Rho signaling.	23	28	induced	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	23	24	27	28
Tiam1 ( T-cell lymphoma invasion and metastasis inducing protein 1 ) , a guanine nucleotide exchange factor that activates Rac , is a colorectal cancer metastasis related gene .	Tiam1 (T-cell lymphoma invasion and metastasis inducing protein 1), a guanine nucleotide exchange factor that activates Rac, is a colorectal cancer metastasis related gene.	0	27	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	19	20
For the OR gate , FKBP , GID1 , and YFP were fused to Tiam1 , a guanine nucleotide exchange factor that activates Rac1 and results in membrane ruffling when it is recruited to the plasma membrane .	For the OR gate, FKBP, GID1, and YFP were fused to Tiam1, a guanine nucleotide exchange factor that activates Rac1 and results in membrane ruffling when it is recruited to the plasma membrane.	12	24	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	14	15	23	24
In this study , we show that Tiam1 mediated Rac activation controls TJ biogenesis and cell polarity by association with and activation of the Par polarity complex in keratinocytes .	In this study, we show that Tiam1 mediated Rac activation controls TJ biogenesis and cell polarity by association with and activation of the Par polarity complex in keratinocytes.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	9	10
Tiam1 has previously been shown to direct Rac signalling by binding to other proteins XREF_BIBR XREF_BIBR .	Tiam1 has previously been shown to direct Rac signalling by binding to other proteins XREF_BIBR XREF_BIBR.	0	8	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	7	8
Kalirin-7 and Tiam1 are also translocated into the postsynaptic region by interacting with the EphB receptor after ephrinB ligand stimulation and enhance Rac activity in the spines .	Kalirin-7 and Tiam1 are also translocated into the postsynaptic region by interacting with the EphB receptor after ephrinB ligand stimulation and enhance Rac activity in the spines.	0	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	2	3	22	23
Our results indicate that the Rac activator Tiam1 controls the intracellular redox balance by Nox mediated ROS production , which regulates ERK phosphorylation and the susceptibility of keratinocytes to apoptotic signaling .	Our results indicate that the Rac activator Tiam1 controls the intracellular redox balance by Nox mediated ROS production, which regulates ERK phosphorylation and the susceptibility of keratinocytes to apoptotic signaling.	4	8	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	5	6
Therefore it is likely that moverastin might inhibit cell migration not only by inhibiting protein farnesylation , but also by inhibiting Tiam1 mediated Rac1 activation .	Therefore it is likely that moverastin might inhibit cell migration not only by inhibiting protein farnesylation, but also by inhibiting Tiam1 mediated Rac1 activation.	21	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	21	22	23	24
22 Ablation of the Rac1-GEF , Tiam1 , reduces metastasis in an ErbB2 mouse model of breast cancer , 23 and loss of Par3 in ErbB2 mouse mammary tumors also promotes invasion and metastasis through Tiam1 mediated Rac1 activation .	22 Ablation of the Rac1-GEF, Tiam1, reduces metastasis in an ErbB2 mouse model of breast cancer, 23 and loss of Par3 in ErbB2 mouse mammary tumors also promotes invasion and metastasis through Tiam1 mediated Rac1 activation.	31	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	35	36	37	38
Previously , we identified the Rac activator Tiam1 ( T-lymphoma invasion and metastasis 1 ) , which plays an important role in Rac mediated E-cadherin-based cell-cell adhesions .	Previously, we identified the Rac activator Tiam1 (T-lymphoma invasion and metastasis 1), which plays an important role in Rac mediated E-cadherin-based cell-cell adhesions.	3	17	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	5	6
The NSC23766 inhibitor that was used , however , specifically blocks Rac1 signaling mediated by the GEFs Tiam1 or Trio .	The NSC23766 inhibitor that was used, however, specifically blocks Rac1 signaling mediated by the GEFs Tiam1 or Trio.	11	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	17	18	11	12
Previous studies demonstrated that endocytosis is needed for activation of Rac by Tiam1 , a signaling pathway critical for migration .	Previous studies demonstrated that endocytosis is needed for activation of Rac by Tiam1, a signaling pathway critical for migration.	6	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	12	13	10	11
Rac activation by Tiam1 , however , leads to signaling events that are not necessary for macrophage force generation .	Rac activation by Tiam1, however, leads to signaling events that are not necessary for macrophage force generation.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	0	1
Tiam1 can then promote Rac1 dependent actin cytoskeletal remodeling required for dendritic spine morphogenesis .	Tiam1 can then promote Rac1 dependent actin cytoskeletal remodeling required for dendritic spine morphogenesis.	0	6	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	0	1	4	5
This suggests that actin accumulation in lamellae as well as in adherens junctions is linked to PI3-kinase-induced , Tiam1 mediated Rac activation .	This suggests that actin accumulation in lamellae as well as in adherens junctions is linked to PI3-kinase-induced, Tiam1 mediated Rac activation.	18	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	18	19	20	21
Adherens junction maintenance requires the Rac activator Tiam1 .	Adherens junction maintenance requires the Rac activator Tiam1.	3	8	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	5	6
XREF_BIBR Interestingly , Tiam1 mediated Rac1 activation has been linked to increased transcriptional and post-transcriptional upregulation of Tissue Inhibitor of Metalloproteinase-1 ( TIMP-1 ) and TIMP-2 , respectively , while not affecting the secreted levels or activity of Matrix Metalloproteinase-9 ( MMP-9 ) or MMP-2 .	XREF_BIBR Interestingly, Tiam1 mediated Rac1 activation has been linked to increased transcriptional and post-transcriptional upregulation of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and TIMP-2, respectively, while not affecting the secreted levels or activity of Matrix Metalloproteinase-9 (MMP-9) or MMP-2.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	3	4	5	6
Overexpression of TIAM1 GTP-exchange factor that activates Rac1 and is required for junctional assembly has been found in human HCC samples .	Overexpression of TIAM1 GTP-exchange factor that activates Rac1 and is required for junctional assembly has been found in human HCC samples.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIAM1	Overexpression of TIAM1	tiam1	Rac1	Rac1	rac1	2	3	7	8
ROCK1 indirectly diminishes the activity of upstream RhoA by stimulating Tiam1 induced Rac1 activity .	ROCK1 indirectly diminishes the activity of upstream RhoA by stimulating Tiam1 induced Rac1 activity.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	10	11	12	13
To further investigate the mechanistic details underlying Tiam1 mediated Rac1 activation by NGF , we analyzed whether H-Ras was required for both Tiam1-Rac1 interaction and Rac1 activity in response to NGF .	To further investigate the mechanistic details underlying Tiam1 mediated Rac1 activation by NGF, we analyzed whether H-Ras was required for both Tiam1-Rac1 interaction and Rac1 activity in response to NGF.	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	9	10
The contribution of Tiam1 mediated activation of Rac1 to the upregulation of such tumour promoting genes may represent one mechanism by which the Tiam1 and Rac1 signalling module contributes to tumour development in the colon .	The contribution of Tiam1 mediated activation of Rac1 to the upregulation of such tumour promoting genes may represent one mechanism by which the Tiam1 and Rac1 signalling module contributes to tumour development in the colon.	3	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	3	4	7	8
Tiam1 specifically activates Rac , and earlier studies have demonstrated that Tiam1-Rac signaling affects migration and invasion in a cell type- and cell substrate specific manner .	Tiam1 specifically activates Rac, and earlier studies have demonstrated that Tiam1-Rac signaling affects migration and invasion in a cell type- and cell substrate specific manner.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	3	4
Most importantly , we have found that the binding of ankyrin ( e.g ., erythrocyte ankyrin [ ANK1 ] , XREF_FIG A , or ANK3 ' s ARD , XREF_FIG B ) to Tiam1 significantly increases the GDP/GTP exchange activity of Rac1 GTPase as compared with untreated Tiam1 mediated Rac1 activation ( XREF_FIG C ) .	Most importantly, we have found that the binding of ankyrin (e.g., erythrocyte ankyrin [ANK1], XREF_FIG A, or ANK3 's ARD, XREF_FIG B) to Tiam1 significantly increases the GDP/GTP exchange activity of Rac1 GTPase as compared with untreated Tiam1 mediated Rac1 activation (XREF_FIG C).	46	50	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	47	48	49	50
It seems that the particular function of Tiam1 mediated Rac activity identified in this study involves the microtubule cytoskeleton rather than the actin cytoskeleton .	It seems that the particular function of Tiam1 mediated Rac activity identified in this study involves the microtubule cytoskeleton rather than the actin cytoskeleton.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	9	10
Employing data base screening we identified a recently cloned cDNA , KIAA0424 , showing substantial sequence homology with Rac activators such as Tiam1 , Sos , Vav , and PIX within the catalytic domain .	Employing data base screening we identified a recently cloned cDNA, KIAA0424, showing substantial sequence homology with Rac activators such as Tiam1, Sos, Vav, and PIX within the catalytic domain.	18	33	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	22	23	18	19
We also discuss additional modes by which Tiam1 and P-Rex1 might induce Rac1 anti- versus pro migratory phenotypes in light of the newly highlighted Rac1 interactors .	We also discuss additional modes by which Tiam1 and P-Rex1 might induce Rac1 anti- versus pro migratory phenotypes in light of the newly highlighted Rac1 interactors.	7	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	12	13
We found that MECs expressing the ANDV N protein had dramatically reduced levels of the RhoA inhibitor p190RhoGAP and the Rac1 activator TIAM1 , while levels of IQGAP remained unchanged in N-protein-expressing cells ( XREF_FIG ) .	We found that MECs expressing the ANDV N protein had dramatically reduced levels of the RhoA inhibitor p190RhoGAP and the Rac1 activator TIAM1, while levels of IQGAP remained unchanged in N-protein-expressing cells (XREF_FIG).	12	23	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	Rac1	Rac1	Rac1	22	23	20	21
IOS production by NOX-1 in response to growth factors , and possibly alpha3beta1 integrin stimulation too , requires Tiam1 mediated Rac1 activation in keratinocytes [ XREF_BIBR ] .	IOS production by NOX-1 in response to growth factors, and possibly alpha3beta1 integrin stimulation too, requires Tiam1 mediated Rac1 activation in keratinocytes [XREF_BIBR].	17	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	18	19	20	21
It has been shown that Tiam1 dependent localized activation of Rac1 contributes to the rapid elongation of the nascent axon XREF_BIBR .	It has been shown that Tiam1 dependent localized activation of Rac1 contributes to the rapid elongation of the nascent axon XREF_BIBR.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	10	11
FL-Tiam1 , but not Tiam1DeltaDH ( XREF_FIG B ) , could fully restore TJ protein levels in Tiam1KO cells ( XREF_FIG A ) , indicating that the Tiam1 mediated activation of Rac controls the amount of TJ molecules even under conditions in which no TJs are formed .	FL-Tiam1, but not Tiam1DeltaDH (XREF_FIG B), could fully restore TJ protein levels in Tiam1KO cells (XREF_FIG A), indicating that the Tiam1 mediated activation of Rac controls the amount of TJ molecules even under conditions in which no TJs are formed.	27	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	27	28	31	32
This was not altogether surprising , as Tiam1 directs Rac signaling to specific downstream effector pathways , leading to precise defects in Rac signaling , rather than the global Rac defect imposed by Rac silencing .	This was not altogether surprising, as Tiam1 directs Rac signaling to specific downstream effector pathways, leading to precise defects in Rac signaling, rather than the global Rac defect imposed by Rac silencing.	7	10	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	9	10
Rac activation by Tiam1 requires PI3-kinase activity .	Rac activation by Tiam1 requires PI3-kinase activity.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	0	1
The cells were modified so that diffusion driven linear gradients XREF_BIBR of a small molecule would induce translocation of the Rac activator Tiam1 to the plasma membrane ; this resulted in graded Rac activation across the cell length independent of upstream effectors .	The cells were modified so that diffusion driven linear gradients XREF_BIBR of a small molecule would induce translocation of the Rac activator Tiam1 to the plasma membrane; this resulted in graded Rac activation across the cell length independent of upstream effectors.	17	23	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	22	23	20	21
TIAM1 driven Rac1 activation at the leading edge underpins lamellipodial protrusion XREF_BIBR , XREF_BIBR .	TIAM1 driven Rac1 activation at the leading edge underpins lamellipodial protrusion XREF_BIBR, XREF_BIBR.	0	8	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	Rac1	Rac1	Rac1	0	1	2	3
Our data thus reveal a prominent role of the alpha ( 1A )-AR/G ( i ) betagamma and Tiam1 mediated activation of Rac1 and its effector PAK2 in the induction of hypertrophy in NRCM .	Our data thus reveal a prominent role of the alpha (1A)-AR/G (i) betagamma and Tiam1 mediated activation of Rac1 and its effector PAK2 in the induction of hypertrophy in NRCM.	18	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	18	19	22	23
Based on these data , Zheng and coworkers concluded that NSC23766 represents a specific inhibitor of Tiam1 mediated activation of Rac1 [ XREF_BIBR , XREF_BIBR ] .	Based on these data, Zheng and coworkers concluded that NSC23766 represents a specific inhibitor of Tiam1 mediated activation of Rac1 [XREF_BIBR, XREF_BIBR].	16	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	16	17	20	21
Indeed , Tiam1 mediated Rac activation induced transcriptional up-regulation of tissue inhibitor of metalloproteinases-1 ( TIMP-1 ) and post-transcriptional up-regulation of TIMP-2 , whereas secretion and activity levels of their counterparts , matrix metalloproteinase-9 and matrix metalloproteinase-2 , respectively , were not affected .	Indeed, Tiam1 mediated Rac activation induced transcriptional up-regulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) and post-transcriptional up-regulation of TIMP-2, whereas secretion and activity levels of their counterparts, matrix metalloproteinase-9 and matrix metalloproteinase-2, respectively, were not affected.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	2	3	4	5
TIAM1 can activate Rac by phosphatidyl-inositol-3-kinase-dependent or independent mechanisms .	TIAM1 can activate Rac by phosphatidyl-inositol-3-kinase-dependent or independent mechanisms.	0	4	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	Rac	Rac	Rac	0	1	3	4
NSC23766 , a specific inhibitor of Tiam1 mediated activation of Rac1 , markedly attenuated glucose-, but not KCl induced insulin secretion in INS 832/13 cells and normal rat islets .	NSC23766, a specific inhibitor of Tiam1 mediated activation of Rac1, markedly attenuated glucose-, but not KCl induced insulin secretion in INS 832/13 cells and normal rat islets.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	10	11
Together , based on the data depicted in XREF_FIG and XREF_FIG , we conclude that Tiam1 mediated activation is necessary for glucose to promote trafficking and membrane association of Rac1 and activation of Rac1 in isolated beta-cells .	Together, based on the data depicted in XREF_FIG and XREF_FIG, we conclude that Tiam1 mediated activation is necessary for glucose to promote trafficking and membrane association of Rac1 and activation of Rac1 in isolated beta-cells.	15	31	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	15	16	29	30
Tiam1 , a typical member of the Dbl like family of GEFs , activates the Rho family GTPase Rac1 [ XREF_BIBR ] .	Tiam1, a typical member of the Dbl like family of GEFs, activates the Rho family GTPase Rac1 [XREF_BIBR].	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	0	1	18	19
Bcr inhibits Tiam1 induced Rac1 signaling .	Bcr inhibits Tiam1 induced Rac1 signaling.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	2	3	4	5
These results suggest that Tiam1 mediates the stimulatory effects of Rac1 on canonical Wnt signalling , and this is supported by the reduction in beta-catenin and TCF dependent transcription in response to Tiam1 knock-down .	These results suggest that Tiam1 mediates the stimulatory effects of Rac1 on canonical Wnt signalling, and this is supported by the reduction in beta-catenin and TCF-dependent transcription in response to Tiam1 knock-down.	4	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	4	5	10	11
This association led to Tiam1 activation , which in turn increased Rac1 activity and facilitated Eph and ephrin endocytosis .	This association led to Tiam1 activation, which in turn increased Rac1 activity and facilitated Eph and ephrin endocytosis.	4	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	4	5	11	12
Tightly balanced activation of Tiam1 with concurrent deactivation of BCR results in activation of Rac1 and its subsequent downstream effectors .	Tightly balanced activation of Tiam1 with concurrent deactivation of BCR results in activation of Rac1 and its subsequent downstream effectors.	2	19	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	4	5	14	15
Furthermore , Tiam1 is required to activate Rac downstream of the Par complex , presumably to regulate actin remodeling required for T cell polarization .	Furthermore, Tiam1 is required to activate Rac downstream of the Par complex, presumably to regulate actin remodeling required for T cell polarization.	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	2	3	7	8
From the endosomal membrane , Tiam1 activates Rac1 and thereafter Rac1 is targeted to the plasma membrane in an Arf6 dependent manner to ensure actin dynamics and thus promote cell migration .	From the endosomal membrane, Tiam1 activates Rac1 and thereafter Rac1 is targeted to the plasma membrane in an Arf6 dependent manner to ensure actin dynamics and thus promote cell migration.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	7	8
The RhoA effector ROCK phosphorylates Par3 , thereby inducing disruption of the Par complex , deregulation of Rac activator Tiam1 and impaired Rac activation [ XREF_BIBR ] .	The RhoA effector ROCK phosphorylates Par3, thereby inducing disruption of the Par complex, deregulation of Rac activator Tiam1 and impaired Rac activation [XREF_BIBR].	15	20	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	19	20	17	18
Tiam1 and P-Rex1 induce differential Rac1 downstream effects .	Tiam1 and P-Rex1 induce differential Rac1 downstream effects.	0	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	0	1	5	6
In addition , NMDAR downstream pathways of Rac1 activator Tiam1 , phosphorylated p21 activated kinase 1 , and actin were upregulated in response to the EF .	In addition, NMDAR downstream pathways of Rac1 activator Tiam1, phosphorylated p21 activated kinase 1, and actin were upregulated in response to the EF.	5	11	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	9	10	7	8
Thus , decreased migration in polyamine depleted cells may be due to the inhibition of Tiam1 activation of Rac1 and the subsequent decreased expression of beta-catenin and E-cadherin leading to reduced cell-cell contacts .	Thus, decreased migration in polyamine depleted cells may be due to the inhibition of Tiam1 activation of Rac1 and the subsequent decreased expression of beta-catenin and E-cadherin leading to reduced cell-cell contacts.	15	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	15	16	18	19
The Rac subfamily GTPases act downstream of the GEFs ; CED-10 and Rac1 is activated by TIAM-1 , whereas CED-10 and MIG-2 and RhoG act redundantly downstream of UNC-73 .	The Rac subfamily GTPases act downstream of the GEFs; CED-10 and Rac1 is activated by TIAM-1, whereas CED-10 and MIG-2 and RhoG act redundantly downstream of UNC-73.	10	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TIAM-1	TIAM-1	TIAM-1	Rac1	Rac1	Rac1	16	17	12	13
The PI3-kinase-dependent Rac activation by Tiam1 , and the subsequent decrease in cell-cell adhesion upon inhibition of PI3-kinase activity , also suggests a role for PI3-kinase in the establishment of E-cadherin-mediated cell-cell adhesion .	The PI3-kinase-dependent Rac activation by Tiam1, and the subsequent decrease in cell-cell adhesion upon inhibition of PI3-kinase activity, also suggests a role for PI3-kinase in the establishment of E-cadherin-mediated cell-cell adhesion.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	5	6	2	3
XREF_BIBR Functional validation of Tiam1 enriched Rac1 interactors identified from our proteomic screen indicated that Tiam1 mediated activation of Rac1 enhances Rac1-IQGAP1 binding .	XREF_BIBR Functional validation of Tiam1 enriched Rac1 interactors identified from our proteomic screen indicated that Tiam1 mediated activation of Rac1 enhances Rac1-IQGAP1 binding.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	15	16	19	20
This phenotypic transformation of NIH3T3 fibroblasts is due to Tiam1 mediated activation of Rac and Rac mediated downregulation of Rho activity .	This phenotypic transformation of NIH3T3 fibroblasts is due to Tiam1 mediated activation of Rac and Rac mediated downregulation of Rho activity.	7	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	9	10	13	14
XREF_BIBR Interestingly , in a recent proteomic study , both Tiam1 and Rac1 were shown to interact with IQGAP1 , XREF_BIBR further supporting the notion that Tiam1 modulates the Rac1 interactome via its scaffolding function .	XREF_BIBR Interestingly, in a recent proteomic study, both Tiam1 and Rac1 were shown to interact with IQGAP1, XREF_BIBR further supporting the notion that Tiam1 modulates the Rac1 interactome via its scaffolding function.	26	30	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	26	27	29	30
However , a possible role for this C-PH domain is to promote protein protein contacts with Tiam1 ligands that stimulate Rac1 activity .	However, a possible role for this C-PH domain is to promote protein protein contacts with Tiam1 ligands that stimulate Rac1 activity.	16	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	16	17	20	21
Further , using in vitro experimental approaches , these researchers have also demonstrated specific inhibition of Tiam1 mediated activation of Rac1 by NSC23766 , without significantly affecting the activation of Cdc42 or Rho by their respective GEFs [ XREF_BIBR , XREF_BIBR ] .	Further, using in vitro experimental approaches, these researchers have also demonstrated specific inhibition of Tiam1 mediated activation of Rac1 by NSC23766, without significantly affecting the activation of Cdc42 or Rho by their respective GEFs [XREF_BIBR, XREF_BIBR].	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	16	17	20	21
XREF_BIBR Given the importance of the P-Rex1 scaffolding function in stimulating P-Rex1-specific Rac1 interactions , together with the previously reported scaffolding role of Tiam1 , it is likely that the observed Tiam1 mediated modulation of the Rac1 interactome is also a consequence of Tiam1 serving as a scaffolding protein .	XREF_BIBR Given the importance of the P-Rex1 scaffolding function in stimulating P-Rex1-specific Rac1 interactions, together with the previously reported scaffolding role of Tiam1, it is likely that the observed Tiam1 mediated modulation of the Rac1 interactome is also a consequence of Tiam1 serving as a scaffolding protein.	29	41	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	31	32	36	37
It was previously demonstrated that Tiam1 can activate Rac1 and Cdc42 in in vitro exchange assays , and Rac1 in cell based assays [ XREF_BIBR ] .	It was previously demonstrated that Tiam1 can activate Rac1 and Cdc42 in in vitro exchange assays, and Rac1 in cell based assays [XREF_BIBR].	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	8	9
Expression of V12Rac1 produced a phenotype very similar to that of Tiam1 , which is consistent with earlier observations that Tiam1 activates Rac1 .	Expression of V12Rac1 produced a phenotype very similar to that of Tiam1, which is consistent with earlier observations that Tiam1 activates Rac1.	20	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	20	21	22	23
Since the inhibition of TJ assembly by over-expressed Tiam1 requires its Rac-GEF activity ( XREF_FIG ) , we hypothesised that beta2-syntrophin promotes Tiam1 mediated Rac activation during TJ assembly .	Since the inhibition of TJ assembly by over-expressed Tiam1 requires its Rac-GEF activity (XREF_FIG), we hypothesised that beta2-syntrophin promotes Tiam1 mediated Rac activation during TJ assembly.	21	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	22	23	24	25
The Rac activator Tiam1 is required for alpha3beta1 mediated laminin-5 deposition , cell spreading , and cell migration .	The Rac activator Tiam1 is required for alpha3beta1 mediated laminin-5 deposition, cell spreading, and cell migration.	0	5	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	1	2
Because Tiam1 mediated Rac1 activation is a key output of PAR complex signaling , BAI1 could affect this phenomenon .	Because Tiam1 mediated Rac1 activation is a key output of PAR complex signaling, BAI1 could affect this phenomenon.	1	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	1	2	3	4
Apparently , various responses by Tiam1 catalyzed Rac1 signaling may be controlled by selective upstream activators ( e.g ., availability of certain cytoskeletal proteins [ e.g ., ankyrin ] , cell adhesion receptors [ e.g ., CD44 , integrin or E-cadherin ] , growth activators [ e.g ., serum , S1P , or LPA ] or extracellular matrix components [ hyaluronic acid , collagen , or fibronectin , etc. ] ) .	Apparently, various responses by Tiam1 catalyzed Rac1 signaling may be controlled by selective upstream activators (e.g., availability of certain cytoskeletal proteins [e.g., ankyrin], cell adhesion receptors [e.g., CD44, integrin or E-cadherin], growth activators [e.g., serum, S1P, or LPA] or extracellular matrix components [hyaluronic acid, collagen, or fibronectin, etc.]).	3	8	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	7	8
In conclusion , the ability of R-Ras-GTP to convert RIN2 from a GEF to an adaptor that preferentially binds Rab5-GTP allows the triggering of the endocytosis of ECM bound and active beta1 integrins and the ensuing funneling of R-Ras-GTP toward early endosomes to elicit the pro adhesive and TIAM1 mediated activation of Rac1 .	In conclusion, the ability of R-Ras-GTP to convert RIN2 from a GEF to an adaptor that preferentially binds Rab5-GTP allows the triggering of the endocytosis of ECM-bound and active beta1 integrins and the ensuing funneling of R-Ras-GTP toward early endosomes to elicit the pro adhesive and TIAM1 mediated activation of Rac1.	46	53	mediated	Positive_early_activation	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	Rac1	Rac1	Rac1	48	49	52	53
Taken together , it is evident that GSIS involves transient activation of Rac1 , which is mediated by Tiam1 and Vav2 .	Taken together, it is evident that GSIS involves transient activation of Rac1, which is mediated by Tiam1 and Vav2.	10	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	18	19	12	13
Insight into Tiam1 mediated Rac1 anti-migratory effects through modulating Rac1-effector binding .	Insight into Tiam1 mediated Rac1 anti-migratory effects through modulating Rac1-effector binding.	0	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	2	3	4	5
Tiam1 mediated Rac Activation Is Regulated by PI3-Kinase .	Tiam1 mediated Rac Activation Is Regulated by PI3-Kinase.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	2	3
HA ( mixed sizes ) also promotes the interaction between CD44 and several Rac1 specific guanine nucleotide exchange factors [ e.g ., Tiam1 and Vav2 ] , thereby up-regulating Rac1 ( another member of the Rho subclass of the Ras superfamily ) , leading to altered cytoskeleton mediated cell functions .	HA (mixed sizes) also promotes the interaction between CD44 and several Rac1 specific guanine nucleotide exchange factors [e.g., Tiam1 and Vav2], thereby up-regulating Rac1 (another member of the Rho subclass of the Ras superfamily), leading to altered cytoskeleton mediated cell functions.	8	32	up-regulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	interaction between CD44 and several Rac1 specific guanine nucleotide exchange factors [e.g., Tiam1 and Vav2	tiam1	Rac1	Rac1	rac1	22	23	29	30
Furthermore , Par3 recruits the Rac-GEF T-lymphoma invasion and metastasis 1 ( Tiam1 ) to specialized sites , where Tiam1 activates Rac1 , resulting in local actin polymerization and microtubule stabilization .	Furthermore, Par3 recruits the Rac-GEF T-lymphoma invasion and metastasis 1 (Tiam1) to specialized sites, where Tiam1 activates Rac1, resulting in local actin polymerization and microtubule stabilization.	19	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	19	20	21	22
In the absence of Par3 , TIAM1 becomes mislocalized causing aberrant activation of Rac , which disrupts normal spine morphogenesis [ XREF_BIBR ] .	In the absence of Par3, TIAM1 becomes mislocalized causing aberrant activation of Rac, which disrupts normal spine morphogenesis [XREF_BIBR].	6	16	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	Rac	Rac	Rac	6	7	13	14
Together , these data demonstrate that pharmacological inhibition of Tiam1 mediated activation of Rac1 results in inhibition of GSIS in normal rat islets and clonal beta-cells .	Together, these data demonstrate that pharmacological inhibition of Tiam1 mediated activation of Rac1 results in inhibition of GSIS in normal rat islets and clonal beta-cells.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	9	10	13	14
The Rac1 activator Tiam1 is inhibited by internal interactions .	The Rac1 activator Tiam1 is inhibited by internal interactions.	0	5	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	3	4	1	2
To confirm that Bcr regulates PKCzeta degradation in astrocytes in a Rac dependent manner , we treated WT and Bcr -/- astrocytes with NSC23766 to inhibit Tiam1 mediated Rac1 activation , which is elevated in Bcr deficient astrocytes ( XREF_FIG ) .	To confirm that Bcr regulates PKCzeta degradation in astrocytes in a Rac dependent manner, we treated WT and Bcr -/- astrocytes with NSC23766 to inhibit Tiam1 mediated Rac1 activation, which is elevated in Bcr deficient astrocytes (XREF_FIG).	25	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	26	27	28	29
Indeed , Tiam1 associates with activated Ras , and these two oncogenes cooperate to activate Rac .	Indeed, Tiam1 associates with activated Ras, and these two oncogenes cooperate to activate Rac.	2	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	2	3	15	16
In RasV12 transformed cells , persistent Ras signaling results in a Raf and MAP kinase mediated downregulation of the Rac specific exchange factor Tiam1 , leading to decreased Rac activity ( XREF_FIG ) .	In RasV12 transformed cells, persistent Ras signaling results in a Raf and MAP kinase mediated downregulation of the Rac specific exchange factor Tiam1, leading to decreased Rac activity (XREF_FIG).	15	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	23	24	19	20
Together , these data indicate that upon the formation of PAs , Tiam1 mediated Rac activation is required for activation of the polarity complex , leading to TJ maturation .	Together, these data indicate that upon the formation of PAs, Tiam1 mediated Rac activation is required for activation of the polarity complex, leading to TJ maturation.	12	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	12	13	14	15
Association of p110alpha via p85 with VE-cadherin might thereby provide a mechanism by which Tiam-1 is recruited and activates Rac1 .	Association of p110alpha via p85 with VE-cadherin might thereby provide a mechanism by which Tiam-1 is recruited and activates Rac1.	14	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam-1	Tiam-1	Tiam-1	Rac1	Rac1	Rac1	14	15	19	20
To measure the effect of Bcr on Tiam1 mediated Rac1 signaling in neurons , we utilized the Forster resonance energy transfer ( FRET ) Rac1 activation biosensor RaichuEV-Rac1 .	To measure the effect of Bcr on Tiam1 mediated Rac1 signaling in neurons, we utilized the Forster resonance energy transfer (FRET) Rac1 activation biosensor RaichuEV-Rac1.	1	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	9	10
In contrast to P-Rex1 , Tiam1 mediated activation of Rac1 was associated with reduced cell migration .	In contrast to P-Rex1, Tiam1 mediated activation of Rac1 was associated with reduced cell migration.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	9	10
To study the effect of Tiam1 mediated Rac activation on migration , we quantified the migratory behavior of control and C1199Tiam1 expressing fibroblast cells using a transwell invasion assay .	To study the effect of Tiam1 mediated Rac activation on migration, we quantified the migratory behavior of control and C1199Tiam1 expressing fibroblast cells using a transwell invasion assay.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	5	6	7	8
The GTP exchange factor , Tiam1 , when presents at cell membranes , activates Rac1 to initiate a signaling pathway that leads to cytoskeletal remodeling and forms filopodia and lemelopodia .	The GTP exchange factor, Tiam1, when presents at cell membranes, activates Rac1 to initiate a signaling pathway that leads to cytoskeletal remodeling and forms filopodia and lemelopodia.	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	14	15
These results demonstrate that Tiam1 induced activation of Rac prevents Rho dependent neurite retraction and cell rounding .	These results demonstrate that Tiam1 induced activation of Rac prevents Rho dependent neurite retraction and cell rounding.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	4	5	8	9
We also found that expression of betaPIX could not rescue the deficiencies in Rac1 activation and cell spreading caused by Tiam1 depletion ( unpublished data ) .	We also found that expression of betaPIX could not rescue the deficiencies in Rac1 activation and cell spreading caused by Tiam1 depletion (unpublished data).	13	21	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	20	21	13	14
Given our findings that Tiam1 mediates the stimulatory effects of Rac1 on Wnt target gene transcription , we sought to determine whether Tiam1 could influence the interaction between Rac1 and beta-catenin .	Given our findings that Tiam1 mediates the stimulatory effects of Rac1 on Wnt target gene transcription, we sought to determine whether Tiam1 could influence the interaction between Rac1 and beta-catenin.	4	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	4	5	10	11
These results suggest that Tiam1 mediated Rac activity is required for full activation of Pak1/2 on centrosomes in prophase , and that this change in Pak activity does not influence Aurora A activation .	These results suggest that Tiam1 mediated Rac activity is required for full activation of Pak1/2 on centrosomes in prophase, and that this change in Pak activity does not influence Aurora A activation.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	4	5	6	7
Our findings indicate that inhibition of Tiam1 mediated activation of Rac1 results in attenuation of glucose-, but not KCl induced insulin secretion from pancreatic beta-cells .	Our findings indicate that inhibition of Tiam1 mediated activation of Rac1 results in attenuation of glucose-, but not KCl induced insulin secretion from pancreatic beta-cells.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	10	11
We found that Tiam1 mediated Rac signaling functions in various aspects of tumorigenicity including the formation and progression of Ras induced skin tumors and Wnt induced intestinal tumors .	We found that Tiam1 mediated Rac signaling functions in various aspects of tumorigenicity including the formation and progression of Ras induced skin tumors and Wnt induced intestinal tumors.	3	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	5	6
XREF_BIBR In this model , loss of Par3 activates the GTPase Rac1 by delocalizing the Rac activator Tiam1 , XREF_BIBR and Tiam1 itself is necessary for ErbB2 mediated mammary tumor growth and metastasis ( XREF_FIG ) .	XREF_BIBR In this model, loss of Par3 activates the GTPase Rac1 by delocalizing the Rac activator Tiam1, XREF_BIBR and Tiam1 itself is necessary for ErbB2 mediated mammary tumor growth and metastasis (XREF_FIG).	13	24	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	17	18	15	16
EphBs promote spinogenesis in hippocampal pyramidal neurons via Tiam1 mediated Rac1 activation [ XREF_BIBR ] .	EphBs promote spinogenesis in hippocampal pyramidal neurons via Tiam1 mediated Rac1 activation [XREF_BIBR].	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	8	9	10	11
Our data indicate that Tiam1 mediated activation of Rac in PAs controls TJ biogenesis and polarity in epithelial cells by association with and activation of the Par3-Par6-aPKC polarity complex .	Our data indicate that Tiam1 mediated activation of Rac in PAs controls TJ biogenesis and polarity in epithelial cells by association with and activation of the Par3-Par6-aPKC polarity complex.	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	4	5	8	9
Tiam1 and Tiam2 activate Rac1 [ XREF_BIBR , XREF_BIBR ] by stimulating GDP-GTP exchange activity that leads to activated Rac1 .	Tiam1 and Tiam2 activate Rac1 [XREF_BIBR, XREF_BIBR] by stimulating GDP-GTP exchange activity that leads to activated Rac1.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	0	1	4	5
XREF_BIBR , XREF_BIBR For example , Ras binds to and activates T-lymphoma invasion and metastasis inducing protein 1 ( TIAM1 ) , a GEF for Rac1 that may activate Rac1 to contribute to Ras transformation .	XREF_BIBR, XREF_BIBR For example, Ras binds to and activates T-lymphoma invasion and metastasis inducing protein 1 (TIAM1), a GEF for Rac1 that may activate Rac1 to contribute to Ras transformation.	16	30	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	Rac1	Rac1	Rac1	19	20	29	30
From the data obtained in this study we conclude that FAK and Src are rapidly activated upon fibronectin mediated signaling leading to Tiam1 mediated Rac1 activation and that intracellular polyamines influence the signaling strength by modulating interaction of Src with Tiam1 using focal adhesion kinase as a scaffolding site .	From the data obtained in this study we conclude that FAK and Src are rapidly activated upon fibronectin mediated signaling leading to Tiam1 mediated Rac1 activation and that intracellular polyamines influence the signaling strength by modulating interaction of Src with Tiam1 using focal adhesion kinase as a scaffolding site.	19	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	22	23	24	25
We have previously identified the Rac activator Tiam1 ( T-lymphoma invasion and metastasis ) , which stimulates the strength of intercellular adhesion .	We have previously identified the Rac activator Tiam1 (T-lymphoma invasion and metastasis), which stimulates the strength of intercellular adhesion.	3	16	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	5	6
We examined the involvement of Tiam1 and talin in adhesion induced Rac1 activation and cell spreading .	We examined the involvement of Tiam1 and talin in adhesion induced Rac1 activation and cell spreading.	3	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	11	12
First , the interaction of LC1 and cytoskeleton elements at subcortical domains may recruit Tiam1 promoting Rac1 activation .	First, the interaction of LC1 and cytoskeleton elements at subcortical domains may recruit Tiam1 promoting Rac1 activation.	13	17	promoting	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	14	15	16	17
Similarly , using an RNA interference based approach , BDNF regulated migration of cerebellar granule cell precursors was shown to require Tiam1 dependent activation of Rac .	Similarly, using an RNA interference based approach, BDNF regulated migration of cerebellar granule cell precursors was shown to require Tiam1 dependent activation of Rac.	21	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	21	22	25	26
Silencing Tiam1 impaired both ephrinA1 dependent activation of Rac1 and EphA2 endocytosis , definitely establishing Tiam1 as an important modulator of EphA2 signalling .	Silencing Tiam1 impaired both ephrinA1 dependent activation of Rac1 and EphA2 endocytosis, definitely establishing Tiam1 as an important modulator of EphA2 signalling.	0	11	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	1	2	8	9
These findings suggest that signaling steps involving Tiam1 mediated activation of Rac1 is relevant for glucose- [ XREF_FIG ] , but not KCl induced insulin secretion from beta-cells .	These findings suggest that signaling steps involving Tiam1 mediated activation of Rac1 is relevant for glucose- [XREF_FIG], but not KCl induced insulin secretion from beta-cells.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	11	12
This Rac1 activation was mediated by G i/o -betagamma and PI3K signaling and by the widely expressed RacGEF Tiam1 ( Vettel etal , 2012 ) .	This Rac1 activation was mediated by G i/o -betagamma and PI3K signaling and by the widely expressed RacGEF Tiam1 (Vettel etal, 2012).	1	21	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	18	19	1	2
We studied therefore , whether the Tiam1 mediated activation of Rac is dependent on PI3-kinase activity .	We studied therefore, whether the Tiam1 mediated activation of Rac is dependent on PI3-kinase activity.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	6	7	10	11
Expression of GFP-Dvl2 did not restore Rac1 activity or polarity in Tiam1 depleted cells , whereas expression of Myc-Tiam1 rescued Rac1 activity and partially restored polarity in Dvls depleted cells ( XREF_FIG and Supplemental Figures S2 , F and H , and S5B ) .	Expression of GFP-Dvl2 did not restore Rac1 activity or polarity in Tiam1 depleted cells, whereas expression of Myc-Tiam1 rescued Rac1 activity and partially restored polarity in Dvls depleted cells (XREF_FIG and Supplemental Figures S2, F and H, and S5B).	16	21	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Myc-Tiam1	expression of Myc-Tiam1	myc-tiam1	Rac1	Rac1	rac1	18	19	20	21
In contrast to the other liposomes , on which Rac1 Ic was modestly activated by Tiam1 , Folch III did not bind Rac1 Ic at all ( XREF_FIG ) .	In contrast to the other liposomes, on which Rac1 Ic was modestly activated by Tiam1, Folch III did not bind Rac1 Ic at all (XREF_FIG).	9	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	15	16	9	10
So we propose that the dynamics of junction assembly and TER development result at least in part from a balance between Tiam1 mediated Rac1 activation and MgcRacGAP mediated Rac1 inhibition .	So we propose that the dynamics of junction assembly and TER development result at least in part from a balance between Tiam1 mediated Rac1 activation and MgcRacGAP mediated Rac1 inhibition.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	21	22	23	24
From these data , we conclude that Tiam1 mediated Rac activation controls , to a large extent , the chemokine induced polarization of T cells .	From these data, we conclude that Tiam1 mediated Rac activation controls, to a large extent, the chemokine induced polarization of T cells.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	9	10
Furthermore , we provide evidence that Tiam1 mediates the stimulatory effects of Rac1 on the Wnt responsive transcription factor complex in a Wnt dependent manner .	Furthermore, we provide evidence that Tiam1 mediates the stimulatory effects of Rac1 on the Wnt responsive transcription factor complex in a Wnt dependent manner.	6	13	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	12	13
As our results suggest , Tiam1 mediated Rac1 activation may feed back to augment nuclear Wnt signalling , leading to sustained Tiam1 and Rac1 signalling and as a consequence , the enhanced transcription of target genes that may be important for tumour initiation and/or progression .	As our results suggest, Tiam1 mediated Rac1 activation may feed back to augment nuclear Wnt signalling, leading to sustained Tiam1 and Rac1 signalling and as a consequence, the enhanced transcription of target genes that may be important for tumour initiation and/or progression.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	7	8
Tiam1 , a Rac1 guanine nucleotide exchange factor , is phosphorylated by EphBs and promotes Rac1 dependent actin cytoskeletal remodeling for dendritic spine morphogenesis .	Tiam1, a Rac1 guanine nucleotide exchange factor, is phosphorylated by EphBs and promotes Rac1 dependent actin cytoskeletal remodeling for dendritic spine morphogenesis.	0	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1, a Rac1 guanine nucleotide exchange factor, is phosphorylated	tiam1	Rac1	Rac1	rac1	0	1	15	16
TIAM1 activates Rac1 and stimulates neuronal migration by regulating actin cytoskeleton dynamics , and JNK regulates microtubule dynamics by stimulating MAP1B phosphorylation to control neuronal migration [ XREF_BIBR ] .	TIAM1 activates Rac1 and stimulates neuronal migration by regulating actin cytoskeleton dynamics, and JNK regulates microtubule dynamics by stimulating MAP1B phosphorylation to control neuronal migration [XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	Rac1	Rac1	Rac1	0	1	2	3
Another more probable mechanism is that Tiam1 activates Rac1 directly at the plasma membrane .	Another more probable mechanism is that Tiam1 activates Rac1 directly at the plasma membrane.	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	8	9
This indicates that Tiam1 mediated Rac activation does not activate aPKCzeta in protruding astrocytes , as has been shown previously during tight junction formation in keratinocytes .	This indicates that Tiam1 mediated Rac activation does not activate aPKCzeta in protruding astrocytes, as has been shown previously during tight junction formation in keratinocytes.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	5	6
For instance NSC23766 inhibits only Tiam-1 and and Trio activation of Rac , while EHop-016 is a specific inhibitor of the Vav and Rac interaction .	For instance NSC23766 inhibits only Tiam-1 and and Trio activation of Rac, while EHop-016 is a specific inhibitor of the Vav and Rac interaction.	5	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam-1	Tiam-1	Tiam-1	Rac	Rac	Rac	5	6	11	12
A further MALDI-TOF study targeted T Lymphoma invasion and metastasis 1 ( Tiam 1 ) , a guanine nucleotide exchange factor that activates Rac ( a GTPase responsible for stimulating cell spreading and migration ) .	A further MALDI-TOF study targeted T Lymphoma invasion and metastasis 1 (Tiam 1), a guanine nucleotide exchange factor that activates Rac (a GTPase responsible for stimulating cell spreading and migration).	9	24	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Tiam 1	Tiam 1	Tiam 1	Rac	Rac	Rac	12	14	23	24
With this in mind , and as a logical extension to our ongoing studies , which provided a compelling evidence for key regulatory roles for Rac1 in GSIS , we undertook the current investigation to determine potential role of Tiam1 mediated Rac1 signaling steps in GSIS in INS 832/13 cells [ referred to as beta-cells throughout the manuscript ] .	With this in mind, and as a logical extension to our ongoing studies, which provided a compelling evidence for key regulatory roles for Rac1 in GSIS, we undertook the current investigation to determine potential role of Tiam1 mediated Rac1 signaling steps in GSIS in INS 832/13 cells [referred to as beta-cells throughout the manuscript].	37	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	39	40	41	42
Taken together , these observations indicate that both Tiam1 and talin mediate and are required for the propagation of outside-in signals from integrins to activate Rac1 .	Taken together, these observations indicate that both Tiam1 and talin mediate and are required for the propagation of outside-in signals from integrins to activate Rac1.	7	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	8	9	25	26
The clustering of VE-cadherin and beta-catenin at adherens junctions recruits additional proteins that stabilize the junctions including Rac1 along with regulators that increase or maintain Rac1 activity ( Tiam1 , Vav , IQGAP1 ) , and P190RhoGAP , which inhibits RhoA .	The clustering of VE-cadherin and beta-catenin at adherens junctions recruits additional proteins that stabilize the junctions including Rac1 along with regulators that increase or maintain Rac1 activity (Tiam1, Vav, IQGAP1), and P190RhoGAP, which inhibits RhoA.	22	32	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	28	29	25	26
77 HGF protects against thrombin induced EC dysfunction by Tiam1 mediated activation of Rac and inhibition of Rho pathways .	77 HGF protects against thrombin induced EC dysfunction by Tiam1 mediated activation of Rac and inhibition of Rho pathways.	5	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	9	10	13	14
In epidermal keratinocytes , the Rac1 activator Tiam1 has been shown to prevent keratinocyte apoptosis after growth factor starvation and heat shock treatment .	In epidermal keratinocytes, the Rac1 activator Tiam1 has been shown to prevent keratinocyte apoptosis after growth factor starvation and heat shock treatment.	4	12	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	5	6
Through our work , we confirm that Tiam1 activation of Rac1 stimulates cell-cell adhesion and reduces cell migration .	Through our work, we confirm that Tiam1 activation of Rac1 stimulates cell-cell adhesion and reduces cell migration.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	10	11
Based on these data , these researchers have concluded that Tiam1 mediated activation of Rac1 is necessary for LPA ' s effects in these cells .	Based on these data, these researchers have concluded that Tiam1 mediated activation of Rac1 is necessary for LPA 's effects in these cells.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	10	11	14	15
XREF_BIBR Focusing on Tiam1 and P-Rex1 , which have been associated with contrasting migratory phenotypes , XREF_BIBR we first demonstrated that activation of Rac1 by Tiam1 or P-Rex1 , irrespective of cell type or upstream signaling , promotes Rac1 anti- vs. pro migratory effects , respectively .	XREF_BIBR Focusing on Tiam1 and P-Rex1, which have been associated with contrasting migratory phenotypes, XREF_BIBR we first demonstrated that activation of Rac1 by Tiam1 or P-Rex1, irrespective of cell type or upstream signaling, promotes Rac1 anti- vs. pro migratory effects, respectively.	21	27	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	25	26	23	24
Therefore , we determined in more detail the effect of Tiam1 mediated Rac activation on the activity state of endogenous Rho protein .	Therefore, we determined in more detail the effect of Tiam1 mediated Rac activation on the activity state of endogenous Rho protein.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	10	11	12	13
Reduction in expression of either SIP 1 or Tiam1 ( via siRNA techniques ) or inhibition of PI3 kinase by LY294002 inhibits S1P induced Rac1 activation , cortical actin rearrangement and endothelial barrier enhancement .	Reduction in expression of either SIP 1 or Tiam1 (via siRNA techniques) or inhibition of PI3 kinase by LY294002 inhibits S1P induced Rac1 activation, cortical actin rearrangement and endothelial barrier enhancement.	2	25	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	expression of either SIP 1 or Tiam1	tiam1	Rac1	Rac1	rac1	8	9	24	25
Through conducting a comparative analysis of Rac1 driven cellular functions upon activation by 2 Rac specific GEFs , Tiam1 and P-Rex1 , we provide clear evidence highlighting their role in dictating differential Rac1 dependent cellular processes .	Through conducting a comparative analysis of Rac1 driven cellular functions upon activation by 2 Rac specific GEFs, Tiam1 and P-Rex1, we provide clear evidence highlighting their role in dictating differential Rac1 dependent cellular processes.	4	19	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	18	19	6	7
Tiam1 and talin are required for adhesion induced Rac1 activation and cell spreading .	Tiam1 and talin are required for adhesion induced Rac1 activation and cell spreading.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	0	1	8	9
NSC23766 , a specific inhibitor of Tiam1 mediated activation of Rac1 , but not Cdc42 or Rho , markedly attenuated glucose induced , but not KCl induced , insulin secretion in INS 832/13 cells and normal rat islets [ XREF_BIBR ] .	NSC23766, a specific inhibitor of Tiam1 mediated activation of Rac1, but not Cdc42 or Rho, markedly attenuated glucose induced, but not KCl induced, insulin secretion in INS 832/13 cells and normal rat islets [XREF_BIBR].	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	10	11
In addition , the Rac1 specific exchange factor , Tiam1 , potentiated the stimulatory effects of Rac1 on the canonical Wnt pathway .	In addition, the Rac1 specific exchange factor, Tiam1, potentiated the stimulatory effects of Rac1 on the canonical Wnt pathway.	7	17	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	9	10	16	17
TIAM1 links activated RAC1 to its effector WASF2 ( WAVE2 ) in lamellipodia through mutual interactions with the adaptor protein BAIAP2 .	TIAM1 links activated RAC1 to its effector WASF2 (WAVE2) in lamellipodia through mutual interactions with the adaptor protein BAIAP2.	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	RAC1	RAC1	RAC1	0	1	3	4
XREF_BIBR This is mainly due to the fact that Tiam1 mediated activation of Rac1 regulates both actin cytoskeleton rearrangements as well as cell-cell and cell-matrix adhesions .	XREF_BIBR This is mainly due to the fact that Tiam1 mediated activation of Rac1 regulates both actin cytoskeleton rearrangements as well as cell-cell and cell-matrix adhesions.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	9	10	13	14
The involvement of the Rac1 activator Tiam1 , a guanine nucleotide exchange factor , as well as the Rac1 effector IQGAP1 has been documented [ XREF_BIBR , XREF_BIBR ] .	The involvement of the Rac1 activator Tiam1, a guanine nucleotide exchange factor, as well as the Rac1 effector IQGAP1 has been documented [XREF_BIBR, XREF_BIBR].	1	12	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	4	5
Also , a recent report indicates that the cell migration promoted by syndecan-2 occurs through Tiam1 mediated activation of Rac [ XREF_BIBR ] .	Also, a recent report indicates that the cell migration promoted by syndecan-2 occurs through Tiam1 mediated activation of Rac [XREF_BIBR].	15	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	15	16	19	20
One study implicated Tiam1 mediated Rac activation in neuronal cell polarization , whereas another study reported that a Par3 mediated inactivation of Tiam1 and Rac is required for the polarization of epithelial MDCK cells .	One study implicated Tiam1 mediated Rac activation in neuronal cell polarization, whereas another study reported that a Par3 mediated inactivation of Tiam1 and Rac is required for the polarization of epithelial MDCK cells.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	5	6
Consistent with previously described Tiam1 driven formation of Rac1 dependent cell-cell contacts XREF_BIBR , XREF_BIBR , we observe loss of refractile morphology of Tiam1 expressing fibroblasts under brightfield microscopy at high cell densities which hints at altered cell to cell adhesion ( XREF_FIG ) .	Consistent with previously described Tiam1 driven formation of Rac1 dependent cell-cell contacts XREF_BIBR, XREF_BIBR, we observe loss of refractile morphology of Tiam1 expressing fibroblasts under brightfield microscopy at high cell densities which hints at altered cell to cell adhesion (XREF_FIG).	3	12	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	4	5	8	9
Since Tiam1 [ XREF_BIBR ] and Rac1 are active in the majority of pancreatic cancer cells , Tiam1 might mediate the activation of Rac1 .	Since Tiam1 [XREF_BIBR] and Rac1 are active in the majority of pancreatic cancer cells, Tiam1 might mediate the activation of Rac1.	17	24	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	17	18	23	24
Furthermore , Tiam1 cooperated with Src to induce activation of Rac1 in vivo and the formation of membrane ruffles .	Furthermore, Tiam1 cooperated with Src to induce activation of Rac1 in vivo and the formation of membrane ruffles.	2	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	2	3	10	11
We demonstrate that Tiam1 specifically activates Rac but not Cdc42 or Rho in NIH3T3 fibroblasts .	We demonstrate that Tiam1 specifically activates Rac but not Cdc42 or Rho in NIH3T3 fibroblasts.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	6	7
To determine whether Bcr inhibits Tiam1 induced Rac1 signaling , we expressed Flag tagged Tiam1 in 293T cells with or without Myc tagged Bcr constructs and assessed the effects on Rac1 activation and signaling .	To determine whether Bcr inhibits Tiam1 induced Rac1 signaling, we expressed Flag tagged Tiam1 in 293T cells with or without Myc tagged Bcr constructs and assessed the effects on Rac1 activation and signaling.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	7	8
From these data we conclude that PI3-kinase activity is required for Tiam1 mediated activation of endogenous Rac .	From these data we conclude that PI3-kinase activity is required for Tiam1 mediated activation of endogenous Rac.	11	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	11	12	16	17
One of these pathways involves DOCK2 through an unknown mechanism and the other pathway involves Rap1 and the Par polarity complex in conjunction with Rac activators such as Tiam1 or possibly Vav1-3 .	One of these pathways involves DOCK2 through an unknown mechanism and the other pathway involves Rap1 and the Par polarity complex in conjunction with Rac activators such as Tiam1 or possibly Vav1-3.	24	31	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	28	29	24	25
After LPA or serum stimulation , wild-type fibroblasts are characterized by relatively high Rho activity , whereas Tiam1 expressing cells show decreased levels of Rho activity , as a result of Tiam1 mediated Rac activation ( XREF_FIG C , lane 4 ) .	After LPA or serum stimulation, wild-type fibroblasts are characterized by relatively high Rho activity, whereas Tiam1 expressing cells show decreased levels of Rho activity, as a result of Tiam1 mediated Rac activation (XREF_FIG C, lane 4).	29	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	31	32	33	34
Taken together , these results suggest that EphB receptors regulate spine development in part by recruiting , phosphorylating and activating Tiam1 , which leads to Rac dependent actin remodeling required for spine formation .	Taken together, these results suggest that EphB receptors regulate spine development in part by recruiting, phosphorylating and activating Tiam1, which leads to Rac dependent actin remodeling required for spine formation.	9	26	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	20	21	25	26
In addition , we provide mechanistic evidence of how the RIN2 assisted targeting of R-Ras-GTP onto the Rab5 positive endosomal compartment causes the TIAM1 mediated activation of Rac1 , finally promoting EC attachment to the ECM .	In addition, we provide mechanistic evidence of how the RIN2 assisted targeting of R-Ras-GTP onto the Rab5 positive endosomal compartment causes the TIAM1 mediated activation of Rac1, finally promoting EC attachment to the ECM.	23	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	Rac1	Rac1	Rac1	23	24	27	28
Activation of Tiam1 most likely involves binding to lipid products of PI3-kinase , since Tiam1 mediated Rac activation is dependent on PI3-kinase activity .	Activation of Tiam1 most likely involves binding to lipid products of PI3-kinase, since Tiam1 mediated Rac activation is dependent on PI3-kinase activity.	14	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	14	15	16	17
Because Tiam1 activates Rac XREF_BIBR , we wanted to determine if binding of PB1 to S4D elicited this response .	Because Tiam1 activates Rac XREF_BIBR, we wanted to determine if binding of PB1 to S4D elicited this response.	1	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	1	2	3	4
Finally , we have shown that Rac signaling is critical for force generation when Rac is activated by Vav1 but not when Rac is activated by Tiam1 ; these results illustrate the complexity of signaling that occurs upstream of force generation .	Finally, we have shown that Rac signaling is critical for force generation when Rac is activated by Vav1 but not when Rac is activated by Tiam1; these results illustrate the complexity of signaling that occurs upstream of force generation.	22	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	26	27	22	23
In conclusion , our data indicate that the Tiam1 mediated activation of Rac ( and not the inactivation of Rac ) is required for TJ formation in epithelial keratinocytes .	In conclusion, our data indicate that the Tiam1 mediated activation of Rac (and not the inactivation of Rac) is required for TJ formation in epithelial keratinocytes.	8	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	8	9	12	13
These results demonstrate that depletion of Par3 acts through Tiam1 mediated Rac1 activation to induce JNK mediated proliferation in mammary tumors .	These results demonstrate that depletion of Par3 acts through Tiam1 mediated Rac1 activation to induce JNK mediated proliferation in mammary tumors.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	9	10	11	12
The above findings have immediate relevance to our current findings for potential involvement of Tiam1 mediated Rac1 activation in GSIS .	The above findings have immediate relevance to our current findings for potential involvement of Tiam1 mediated Rac1 activation in GSIS.	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	14	15	16	17
Cdc42 functionalized MNPs concentrated with a magnetic field localized actin polymerization while membrane bound Rac1 signaling was dynamically modulated by bringing MNPs functionalised with the Rac1 activator TIAM1 into and out of membrane proximity .	Cdc42 functionalized MNPs concentrated with a magnetic field localized actin polymerization while membrane bound Rac1 signaling was dynamically modulated by bringing MNPs functionalised with the Rac1 activator TIAM1 into and out of membrane proximity.	22	28	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	Rac1	Rac1	Rac1	27	28	25	26
As it has been shown previously that the dissociation of BCR from Tiam1 augments Rac1 activation , we investigated the impact of OGD on BCR-Tiam1 interactions in co-IP experiments .	As it has been shown previously that the dissociation of BCR from Tiam1 augments Rac1 activation, we investigated the impact of OGD on BCR-Tiam1 interactions in co-IP experiments.	10	15	augments	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	12	13	14	15
The Par polarity complex consisting of Par3 , Par6 , and PKCzeta , in conjunction with Tiam1 mediated Rac signaling , controls apical-basal cell polarity in contacting epithelial cells .	The Par polarity complex consisting of Par3, Par6, and PKCzeta, in conjunction with Tiam1 mediated Rac signaling, controls apical-basal cell polarity in contacting epithelial cells.	4	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	16	17	18	19
These findings indicate that Tiam1 not only activates Rac but also contributes to Rac signaling specificity through binding to IRSp53 .	These findings indicate that Tiam1 not only activates Rac but also contributes to Rac signaling specificity through binding to IRSp53.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	4	5	8	9
Tiam1 localization at the PM should activate Rac and its downstream signaling circuits that lead to formation of ruffling and lamellipodia .	Tiam1 localization at the PM should activate Rac and its downstream signaling circuits that lead to formation of ruffling and lamellipodia.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	7	8
These data support our hypothesis that inhibition of Tiam1 mediated activation of Rac1 leads to inhibition of glucose induced membrane association of Rac1 [ XREF_FIG ] culminating in inhibition of GSIS under these conditions [ XREF_FIG ] .	These data support our hypothesis that inhibition of Tiam1 mediated activation of Rac1 leads to inhibition of glucose induced membrane association of Rac1 [XREF_FIG] culminating in inhibition of GSIS under these conditions [XREF_FIG].	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	8	9	12	13
In particular , we report that knockdown of Tiam1 causes a significant reduction in Rac1 activity and neurite outgrowth induced by NGF .	In particular, we report that knockdown of Tiam1 causes a significant reduction in Rac1 activity and neurite outgrowth induced by NGF.	6	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	8	9	14	15
We also quantitated the metabolic cell viability in beta-cells treated with NSC23766 to rule out the possibility that it might exert cytotoxic effects following inhibition of Tiam1 mediated activation of Rac1 in these cells .	We also quantitated the metabolic cell viability in beta-cells treated with NSC23766 to rule out the possibility that it might exert cytotoxic effects following inhibition of Tiam1 mediated activation of Rac1 in these cells.	26	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	26	27	30	31
Rac activation was completely inhibited by double knockdown of Asef and Tiam1 ( XREF_FIG , left panel ) .	Rac activation was completely inhibited by double knockdown of Asef and Tiam1 (XREF_FIG, left panel).	0	12	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	11	12	0	1
Our studies identify the Rac activator Tiam1 as a critical regulator of different aspects of Ras induced tumour formation .	Our studies identify the Rac activator Tiam1 as a critical regulator of different aspects of Ras induced tumour formation.	2	7	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	6	7	4	5
For instance , the GEFs Vav , Sos1 , and Tiam1 induce Rac1 signaling in spatially restricted membrane regions enriched in PtdIns ( 3,4,5 ) P 3 .	For instance, the GEFs Vav, Sos1, and Tiam1 induce Rac1 signaling in spatially restricted membrane regions enriched in PtdIns (3,4,5) P 3.	5	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	10	11	12	13
As shown in XREF_FIG ( lane 1 vs 2-4 ) , knockdown of Tiam1 significantly inhibited the activation of Rac1 compared to cells co-expressing FLT3ITD and scrambled shRNA .	As shown in XREF_FIG (lane 1 vs 2-4), knockdown of Tiam1 significantly inhibited the activation of Rac1 compared to cells co-expressing FLT3ITD and scrambled shRNA.	11	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	13	14	19	20
The Tiam1 mediated Rac activation regulates the further production , secretion , and organized deposition of LN5 , which is essential for the spreading and migration of keratinocytes .	The Tiam1 mediated Rac activation regulates the further production, secretion, and organized deposition of LN5, which is essential for the spreading and migration of keratinocytes.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	1	2	3	4
Since the Tiam1 mediated Rac activation on each substrate is similar , we suggest that the different intracellular localization of the Rac signaling complex determines whether Rac stimulates E-cadherin-mediated cell-cell adhesion or cell migration .	Since the Tiam1 mediated Rac activation on each substrate is similar, we suggest that the different intracellular localization of the Rac signaling complex determines whether Rac stimulates E-cadherin-mediated cell-cell adhesion or cell migration.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	2	3	4	5
Together , these findings provide conclusive evidence to suggest that Tiam1 mediated Rac1 activation is not necessary for KCl induced insulin secretion .	Together, these findings provide conclusive evidence to suggest that Tiam1 mediated Rac1 activation is not necessary for KCl induced insulin secretion.	10	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	10	11	12	13
We have shown that dbcAMP induced Rac1 activation was principally mediated by PKA and Sif- and Tiam1 like exchange factor ( STEF )/Tiam2 .	We have shown that dbcAMP induced Rac1 activation was principally mediated by PKA and Sif- and Tiam1 like exchange factor (STEF)/Tiam2.	6	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	16	17	6	7
We conclude that motility triggered by collagen I is stimulated by Tiam1 mediated Rac activation , but only under conditions which prevent E-cadherin-mediated adhesions .	We conclude that motility triggered by collagen I is stimulated by Tiam1 mediated Rac activation, but only under conditions which prevent E-cadherin-mediated adhesions.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	11	12	13	14
We have shown previously that full-length Tiam1 ( FL1591 ) or a large COOH-terminal fragment of the Tiam1 protein ( C1199 ) causes Rac1 dependent induction of membrane ruffling in NIH3T3 fibroblast cells .	We have shown previously that full-length Tiam1 (FL1591) or a large COOH-terminal fragment of the Tiam1 protein (C1199) causes Rac1 dependent induction of membrane ruffling in NIH3T3 fibroblast cells.	5	25	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	23	24
For this study we utilized the Rac1 specific inhibitor NSC23766 which blocks a subset of Rac1 signaling mediated by the GEFs Tiam1 and Trio XREF_BIBR .	For this study we utilized the Rac1 specific inhibitor NSC23766 which blocks a subset of Rac1 signaling mediated by the GEFs Tiam1 and Trio XREF_BIBR.	15	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	21	22	15	16
The level of Tiam1 mediated Rac activation was thus not dependent on the cell substrate , suggesting that rather the different substrate dependent intracellular localization of the Rac activity caused the opposite cellular effects on cell-cell adhesion and motility .	The level of Tiam1 mediated Rac activation was thus not dependent on the cell substrate, suggesting that rather the different substrate dependent intracellular localization of the Rac activity caused the opposite cellular effects on cell-cell adhesion and motility.	1	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	5	6
During the preparation of this manuscript , another group reported that VE-cadherin and Tiam1 mediate shear induced Rac1 GTP loading and barrier enhancement in brain microvascular ECs .	During the preparation of this manuscript, another group reported that VE-cadherin and Tiam1 mediate shear induced Rac1 GTP loading and barrier enhancement in brain microvascular ECs.	11	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	13	14	17	18
3 ) PI3-kinase activity has been implicated in the control of Tiam1 driven activation of Rac1 , probably through its effect on the membrane translocation of Tiam1 via the binding of PIP 3 to the TSS domain , including the N-terminal pleckstrin homology domain .	3) PI3-kinase activity has been implicated in the control of Tiam1 driven activation of Rac1, probably through its effect on the membrane translocation of Tiam1 via the binding of PIP 3 to the TSS domain, including the N-terminal pleckstrin homology domain.	11	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	11	12	15	16
Thus , an alternative mechanism likely explains the role of Tiam1 and Tiam2 in the ROCK1 induced regulation of Rac1 and RhoA activity .	Thus, an alternative mechanism likely explains the role of Tiam1 and Tiam2 in the ROCK1 induced regulation of Rac1 and RhoA activity.	8	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	10	11	19	20
To analyze the functional relevance of Tiam1 and Rac1 physical interaction with RORgammat in Th17 cells , we investigated the ability of Tiam1 mediated Rac1 activation to induce the Il17 promoter in reporter assays using 293T cells .	To analyze the functional relevance of Tiam1 and Rac1 physical interaction with RORgammat in Th17 cells, we investigated the ability of Tiam1 mediated Rac1 activation to induce the Il17 promoter in reporter assays using 293T cells.	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	22	23	24	25
Recently , Zheng et al have developed NSC23766 , which is a soluble first generation small molecule inhibitor of Tiam1 mediated activation of Rac1 [ XREF_BIBR ] .	Recently, Zheng et al have developed NSC23766, which is a soluble first generation small molecule inhibitor of Tiam1 mediated activation of Rac1 [XREF_BIBR].	19	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	19	20	23	24
These findings suggest potential off-target effects of NSC23766 on cell function since effects of NSC23766 are known to be mediated primarily through inactivation of Tiam1 mediated activation of Rac1 .	These findings suggest potential off-target effects of NSC23766 on cell function since effects of NSC23766 are known to be mediated primarily through inactivation of Tiam1 mediated activation of Rac1.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	24	25	28	29
We demonstrate that Tiam1 mediated Rac activation plays a key role at an early stage of intercellular adhesion to trigger the formation of TJs and , as a consequence , to trigger the polarization of epidermal keratinocytes .	We demonstrate that Tiam1 mediated Rac activation plays a key role at an early stage of intercellular adhesion to trigger the formation of TJs and, as a consequence, to trigger the polarization of epidermal keratinocytes.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	5	6
The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex .	The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex.	0	4	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	1	2
Transient PDGF induced as well as sustained Rac activation by Tiam1 or V12Rac downregulate Rho activity .	Transient PDGF induced as well as sustained Rac activation by Tiam1 or V12Rac downregulate Rho activity.	7	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	10	11	7	8
Bcr therefore serves to restrict Tiam1 induced Rac1 activation to an optimal range that promotes excitatory synapse formation and growth while preventing receptor endocytosis and synapse loss .	Bcr therefore serves to restrict Tiam1 induced Rac1 activation to an optimal range that promotes excitatory synapse formation and growth while preventing receptor endocytosis and synapse loss.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	7	8
These defects are accompanied by an impaired targeting of the Rac1 activator Tiam1 at synaptic compartments .	These defects are accompanied by an impaired targeting of the Rac1 activator Tiam1 at synaptic compartments.	7	13	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	12	13	10	11
While Tiam1 appear to mediate NT-3 and BDNF induced Rac1 activation , it is not clear whether activation of Rac1 by Tiam1 is critical for biological responses induced by NGF and TrkA .	While Tiam1 appear to mediate NT-3 and BDNF induced Rac1 activation, it is not clear whether activation of Rac1 by Tiam1 is critical for biological responses induced by NGF and TrkA.	17	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	21	22	19	20
The results show that simultaneous down-regulation of Tiam-1 and DOCK180 led to a profound block of C. jejuni induced Rac1 activity .	The results show that simultaneous down-regulation of Tiam-1 and DOCK180 led to a profound block of C. jejuni induced Rac1 activity.	5	20	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam-1	Tiam-1	Tiam-1	Rac1	Rac1	Rac1	7	8	19	20
Furthermore , an N-terminal truncation of mammalian Tiam1 , which does not affect the DHPH domains , activates Rac more strongly than full length Tiam1 XREF_BIBR , XREF_BIBR , suggesting that a deleted portion of Tiam1 might normally inhibit GEF activity of the molecule .	Furthermore, an N-terminal truncation of mammalian Tiam1, which does not affect the DHPH domains, activates Rac more strongly than full length Tiam1 XREF_BIBR, XREF_BIBR, suggesting that a deleted portion of Tiam1 might normally inhibit GEF activity of the molecule.	4	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	18	19
Together these results suggest that Tiam1 activation of Rac1 is associated with reduced cell migration potentially through its ability to increase actin and cadherin deposition at cell-cell contacts , as previously suggested XREF_BIBR XREF_BIBR .	Together these results suggest that Tiam1 activation of Rac1 is associated with reduced cell migration potentially through its ability to increase actin and cadherin deposition at cell-cell contacts, as previously suggested XREF_BIBR XREF_BIBR.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	8	9
These findings confirm our earlier conclusion that Tiam1 activates Rac downstream of PKCzeta and the Par polarity complex .	These findings confirm our earlier conclusion that Tiam1 activates Rac downstream of PKCzeta and the Par polarity complex.	7	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	9	10
Tiam1 , which is a Rho-GEF for Rac , was shown to activate Rac by a PI3K independent mechanism XREF_BIBR .	Tiam1, which is a Rho-GEF for Rac, was shown to activate Rac by a PI3K independent mechanism XREF_BIBR.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	13	14
In fibroblasts , Tiam1 induces Rac mediated membrane ruffling , which requires the N-terminal pleckstrin homology ( PHn ) domain .	In fibroblasts, Tiam1 induces Rac mediated membrane ruffling, which requires the N-terminal pleckstrin homology (PHn) domain.	3	6	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	5	6
The level of Rac activation by Tiam1 , as determined by binding to a glutathione-S-transferase- PAK protein , is similar on fibronectin or collagen I , suggesting that rather the localization of the Tiam1 and Rac signaling complex determines the substrate dependent cellular responses .	The level of Rac activation by Tiam1, as determined by binding to a glutathione-S-transferase- PAK protein, is similar on fibronectin or collagen I, suggesting that rather the localization of the Tiam1 and Rac signaling complex determines the substrate dependent cellular responses.	3	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	6	7	3	4
Tiam1 ( T lymphoma invasion and metastasis-1 ) , a guanine nucleotide exchange factor that activates Rac , was recently identified as a novel colorectal cancer metastasis related gene .	Tiam1 (T lymphoma invasion and metastasis-1), a guanine nucleotide exchange factor that activates Rac, was recently identified as a novel colorectal cancer metastasis related gene.	0	20	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	16	17
To investigate whether the substrate dependent phenotypes were due to differences in the degree of Rac activation , we analyzed the level of Tiam1 mediated Rac activation in cells seeded on a fibronectin or collagen I substrate .	To investigate whether the substrate dependent phenotypes were due to differences in the degree of Rac activation, we analyzed the level of Tiam1 mediated Rac activation in cells seeded on a fibronectin or collagen I substrate.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	23	24	25	26
Tiam1 can activate Rac1 , but not Cdc42 [ XREF_BIBR , XREF_BIBR ] and it is involved in T cell trafficking [ XREF_BIBR ] .	Tiam1 can activate Rac1, but not Cdc42 [XREF_BIBR, XREF_BIBR] and it is involved in T cell trafficking [XREF_BIBR].	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	0	1	3	4
P-Rex1 , Tiam1 and TrioN activated Rac1 Ic to a lower extent ( XREF_FIG ) , particularly TrioN , corresponding to their liposome binding capabilities ( XREF_FIG ) .	P-Rex1, Tiam1 and TrioN activated Rac1 Ic to a lower extent (XREF_FIG), particularly TrioN, corresponding to their liposome binding capabilities (XREF_FIG).	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	2	3	6	7
Activation of Rac by Tiam1 induces an epithelial like morphology with functional cadherin based adhesions and inhibits migration of fibroblasts .	Activation of Rac by Tiam1 induces an epithelial like morphology with functional cadherin based adhesions and inhibits migration of fibroblasts.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	4	5	2	3
In particular , Tiam1 activation has been recently linked to the ERBB2 oncogene XREF_BIBR , where Tiam1 mediated Rac activation leads to uncontrolled actin dynamics that may compromise E-cadherin junctions , promoting metastasis XREF_BIBR XREF_BIBR XREF_BIBR .	In particular, Tiam1 activation has been recently linked to the ERBB2 oncogene XREF_BIBR, where Tiam1 mediated Rac activation leads to uncontrolled actin dynamics that may compromise E-cadherin junctions, promoting metastasis XREF_BIBR XREF_BIBR XREF_BIBR.	16	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	16	17	18	19
Our results indicate that they act in a linear pathway , with CDC-42 controlling Rac activity mediated by TIAM-1 .	Our results indicate that they act in a linear pathway, with CDC-42 controlling Rac activity mediated by TIAM-1.	14	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TIAM-1	TIAM-1	TIAM-1	Rac	Rac	Rac	18	19	14	15
Recent studies from the laboratory of Zheng et al suggested that NSC23766 specifically inhibits Tiam1 induced activation of Rac1 , but not Cdc42 or Rho .	Recent studies from the laboratory of Zheng et al suggested that NSC23766 specifically inhibits Tiam1 induced activation of Rac1, but not Cdc42 or Rho.	14	19	induced	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	14	15	18	19
These data clearly indicate that Tiam1 DHPH was able to activate Rac1 Ic on the liposomes .	These data clearly indicate that Tiam1 DHPH was able to activate Rac1 Ic on the liposomes.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	11	12
PTHrP ( parathyroid hormone related peptide )-stimulated cell migration and invasion in colorectal adenocarcinomas is dependent on RAC1 activity , which is augmented by the increased expression of alpha6beta4 integrin and TIAM1 these cells exhibit .	PTHrP (parathyroid hormone related peptide)-stimulated cell migration and invasion in colorectal adenocarcinomas is dependent on RAC1 activity, which is augmented by the increased expression of alpha6beta4 integrin and TIAM1 these cells exhibit.	17	32	augmented	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TIAM1	expression of alpha6beta4 integrin and TIAM1	tiam1	RAC1	RAC1	rac1	31	32	17	18
Furthermore , experiments using a dominant negative form demonstrate that STEF and Tiam1 mediate extracellular laminin signals to activate Rac1 , promoting neurite growth in N1E-115 neuroblastoma cells .	Furthermore, experiments using a dominant negative form demonstrate that STEF and Tiam1 mediate extracellular laminin signals to activate Rac1, promoting neurite growth in N1E-115 neuroblastoma cells.	10	20	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	12	13	19	20
In support of this possibility , both Trio and Tiam1 are expressed in the hippocampus CA1 , and interestingly Tiam1 has been shown to mediate NMDA receptor activation of Rac1 in neurons .	In support of this possibility, both Trio and Tiam1 are expressed in the hippocampus CA1, and interestingly Tiam1 has been shown to mediate NMDA receptor activation of Rac1 in neurons.	19	30	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	19	20	29	30
Thus , consistent with previous reports , our data strongly suggests that Tiam1 mediated Rac1 anti-migratory effects might be a consequence of stronger cell-cell contacts .	Thus, consistent with previous reports, our data strongly suggests that Tiam1 mediated Rac1 anti-migratory effects might be a consequence of stronger cell-cell contacts.	12	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	12	13	14	15
In both cases , the effects were due to the TIAM1 mediated activation of RAC1 , which , actually , has different effects in the two cell types .	In both cases, the effects were due to the TIAM1 mediated activation of RAC1, which, actually, has different effects in the two cell types.	10	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	RAC1	RAC1	RAC1	10	11	14	15
We also showed that prior incubation of INS-1 832/13 cells with GGTI-2147 , an inhibitor of geranylgeranylation of Rac1 or NSC23766 , a known inhibitor of Rac1 mediated by Tiam1 , a guanine nucleotide exchange factor for Rac1 markedly attenuated cytomix induced ROS generation [ XREF_BIBR ] .	We also showed that prior incubation of INS-1 832/13 cells with GGTI-2147, an inhibitor of geranylgeranylation of Rac1 or NSC23766, a known inhibitor of Rac1 mediated by Tiam1, a guanine nucleotide exchange factor for Rac1 markedly attenuated cytomix induced ROS generation [XREF_BIBR].	24	30	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	29	30	26	27
To confirm that the increase in LN5 mRNA levels was because of Tiam1 mediated Rac activation , we analyzed Tiam1-/- keratinocytes that were reconstituted with Tiam1 and constitutive active V12Rac1 ( XREF_FIG ) .	To confirm that the increase in LN5 mRNA levels was because of Tiam1 mediated Rac activation, we analyzed Tiam1-/- keratinocytes that were reconstituted with Tiam1 and constitutive active V12Rac1 (XREF_FIG).	11	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	12	13	14	15
Oncogenic RAS stimulates MP by engaging TIAM1 , which activates RAC1 and thereby enhances PM ruffling .	Oncogenic RAS stimulates MP by engaging TIAM1, which activates RAC1 and thereby enhances PM ruffling.	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	RAC1	RAC1	RAC1	6	7	10	11
We next determined potential regulatory effects of Tiam1 mediated Rac1 activation on KCl induced insulin secretion from beta-cells .	We next determined potential regulatory effects of Tiam1 mediated Rac1 activation on KCl induced insulin secretion from beta-cells.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	9	10
As stated above , NSC23766 has been used to specifically inhibit Tiam1 mediated activation of Rac1 in multiple cell types .	As stated above, NSC23766 has been used to specifically inhibit Tiam1 mediated activation of Rac1 in multiple cell types.	11	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	11	12	15	16
Tiam1 mediated Rac1 activation is not necessary for insulin secretion elicited by a membrane depolarizing concentration of KCl .	Tiam1 mediated Rac1 activation is not necessary for insulin secretion elicited by a membrane depolarizing concentration of KCl.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	0	1	2	3
Membrane trafficking between compartments has also been suggested , for example , activation of Rac by Tiam1 on endosomes resulted in protrusive activity on the plasma membrane and cell migration .	Membrane trafficking between compartments has also been suggested, for example, activation of Rac by Tiam1 on endosomes resulted in protrusive activity on the plasma membrane and cell migration.	12	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	16	17	14	15
These studies indicate that the Rac activator Tiam1 is essential for the formation as well as the maintenance of cadherin based adhesions .	These studies indicate that the Rac activator Tiam1 is essential for the formation as well as the maintenance of cadherin based adhesions.	4	9	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	5	6
Following EphB activation , Tiam1 induces Rac1 dependent spine formation , whereas Bcr prevents Rac1 mediated receptor internalization , promoting spine growth over retraction .	Following EphB activation, Tiam1 induces Rac1 dependent spine formation, whereas Bcr prevents Rac1 mediated receptor internalization, promoting spine growth over retraction.	2	7	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	4	5	6	7
Transfection of dominant negative N17 Cdc42 did not affect the Tiam1 phenotype , consistent with Tiam1 activating Rac rather than Cdc42 .	Transfection of dominant negative N17 Cdc42 did not affect the Tiam1 phenotype, consistent with Tiam1 activating Rac rather than Cdc42.	13	20	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	15	16	17	18
This mutant lacks the catalytic DH domain , still contains the Par3 interaction domain , and inhibits Tiam1 mediated Rac activation .	This mutant lacks the catalytic DH domain, still contains the Par3 interaction domain, and inhibits Tiam1 mediated Rac activation.	16	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	17	18	19	20
Recent work has established that Tiam1 can activate Rac downstream of LFA-1 in T cells , although it remains unclear whether PIP 3 is involved .	Recent work has established that Tiam1 can activate Rac downstream of LFA-1 in T cells, although it remains unclear whether PIP 3 is involved.	5	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	5	6	8	9
Rac1 activation is mediated by Tiam1 XREF_BIBR , whereas Cdc42 activation is mediated by Dbs XREF_BIBR .	Rac1 activation is mediated by Tiam1 XREF_BIBR, whereas Cdc42 activation is mediated by Dbs XREF_BIBR.	0	6	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	0	1
Here , we have analyzed the function of the Rac activator Tiam1 in the control of T-cell trafficking and transendothelial migration .	Here, we have analyzed the function of the Rac activator Tiam1 in the control of T-cell trafficking and transendothelial migration.	6	12	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	11	12	9	10
As Pak1/2 are direct effectors of Rac1 , we hypothesized that Tiam1 dependent Pak1/2 centrosomal activation was due to Tiam1 activation of Rac1 .	As Pak1/2 are direct effectors of Rac1, we hypothesized that Tiam1 dependent Pak1/2 centrosomal activation was due to Tiam1 activation of Rac1.	19	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	19	20	22	23
Based on these findings , these authors concluded that both Vav2 and Tiam1 mediate regulation of Rac1 by linking components of the polarity complex to NADPH oxidase .	Based on these findings, these authors concluded that both Vav2 and Tiam1 mediate regulation of Rac1 by linking components of the polarity complex to NADPH oxidase.	10	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	12	13	16	17
We show that knockdown of Tiam1 expression with siRNA causes a significant reduction in both Rac1 and neurite outgrowth activity induced by NGF stimulation .	We show that knockdown of Tiam1 expression with siRNA causes a significant reduction in both Rac1 and neurite outgrowth activity induced by NGF stimulation.	5	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1 expression	tiam1	Rac1	Rac1	rac1	5	6	15	16
Tiam1 is an activator of the small GTPase Rac1 , which directs the actin cytoskeletal remodeling that drives spine and synapse development [ XREF_BIBR ] .	Tiam1 is an activator of the small GTPase Rac1, which directs the actin cytoskeletal remodeling that drives spine and synapse development [XREF_BIBR].	0	11	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	0	1	8	9
Another interesting hit that reduced EphB trans-endocytosis was Abr , a protein that antagonizes Tiam1 stimulated Rac activity downstream ephrinB induced EphB2 forward signaling .	Another interesting hit that reduced EphB trans-endocytosis was Abr, a protein that antagonizes Tiam1 stimulated Rac activity downstream ephrinB induced EphB2 forward signaling.	13	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	14	15	16	17
Moreover , Tiam1 with a mutation in the Rac activation domain ( GEF * ) , which renders it inactive , was unable to rescue the decrease in P * Pak seen on Tiam1 depletion ( XREF_FIG , XREF_SUPPLEMENTARY ) , strongly suggesting that regulation of centrosomal Pak1/2 activity requires Tiam1 mediated Rac activation .	Moreover, Tiam1 with a mutation in the Rac activation domain (GEF *), which renders it inactive, was unable to rescue the decrease in P * Pak seen on Tiam1 depletion (XREF_FIG, XREF_SUPPLEMENTARY), strongly suggesting that regulation of centrosomal Pak1/2 activity requires Tiam1 mediated Rac activation.	50	53	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	50	51	52	53
Based on these data , Zheng et al concluded that NSC23766 represents a specific inhibitor of Tiam1 mediated activation of Rac1 .	Based on these data, Zheng et al concluded that NSC23766 represents a specific inhibitor of Tiam1 mediated activation of Rac1.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	16	17	20	21
Similarly , NME1 has been demonstrated to inhibit RAC1 activity by interacting with the RAC1 activator TIAM1 , an effect which is independent of its nucleoside disphosphate kinase activity XREF_BIBR .	Similarly, NME1 has been demonstrated to inhibit RAC1 activity by interacting with the RAC1 activator TIAM1, an effect which is independent of its nucleoside disphosphate kinase activity XREF_BIBR.	11	19	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	TIAM1	TIAM1	TIAM1	RAC1	RAC1	RAC1	16	17	14	15
Tiam-1 and DOCK180 act cooperatively to trigger Rac1 activation and C. jejuni invasion downstream of FAK .	Tiam-1 and DOCK180 act cooperatively to trigger Rac1 activation and C. jejuni invasion downstream of FAK.	0	8	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam-1	Tiam-1	Tiam-1	Rac1	Rac1	Rac1	0	1	7	8
Furthermore , we observed that PA induced generation of lipid peroxides [ Panel B ] and reactive oxygen species [ Panel C ] in INS 832/13 cells were also reduced [ ~ 20 to 30 % ] following inhibition of Tiam1 mediated activation of Rac1 .	Furthermore, we observed that PA induced generation of lipid peroxides [Panel B] and reactive oxygen species [Panel C] in INS 832/13 cells were also reduced [~ 20 to 30%] following inhibition of Tiam1 mediated activation of Rac1.	40	45	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	40	41	44	45
Tiam1 dependent activation of Rac in WT keratinocytes followed the same kinetics as the formation of PAs ( XREF_FIG ) , suggesting that Tiam1 is a downstream target of cadherins and nectins to activate Rac and , thereby , to activate the polarity complex .	Tiam1 dependent activation of Rac in WT keratinocytes followed the same kinetics as the formation of PAs (XREF_FIG), suggesting that Tiam1 is a downstream target of cadherins and nectins to activate Rac and, thereby, to activate the polarity complex.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	4	5
Importantly , although additional data we obtained indicated that FLII binds preferentially to active Rac1 , Tiam1 mediated Rac1 activation did not enhance Rac1-FLII association , highlighting an additional level of regulation beyond Rac1 activation .	Importantly, although additional data we obtained indicated that FLII binds preferentially to active Rac1, Tiam1 mediated Rac1 activation did not enhance Rac1-FLII association, highlighting an additional level of regulation beyond Rac1 activation.	16	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	16	17	18	19
Conversely , stimulation of the Epac1-Rap1 pathway by cAMP promotes Tiam1 mediated Rac1 activation , stabilizing cortical actin and junctions between endothelial cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Conversely, stimulation of the Epac1-Rap1 pathway by cAMP promotes Tiam1 mediated Rac1 activation, stabilizing cortical actin and junctions between endothelial cells [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	10	11	12	13
Tiam1 mediated Rac Activation Increases Cell-Surface E-cadherin .	Tiam1 mediated Rac Activation Increases Cell-Surface E-cadherin.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	2	3
Tiam1 mediated Rac activation was decreased by dominant negative Deltap85 as well as by PI3-kinase inhibitors on a fibronectin as well as on a collagen I substrate , which argues that Tiam1 activity on both substrates is dependent on lipid products produced by PI3-kinase .	Tiam1 mediated Rac activation was decreased by dominant negative Deltap85 as well as by PI3-kinase inhibitors on a fibronectin as well as on a collagen I substrate, which argues that Tiam1 activity on both substrates is dependent on lipid products produced by PI3-kinase.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	2	3
Functional relevance of GEF [ Tiam1 and Vav2 ] induced Rac1 activation in the generation of oxidative stress , stress kinase activation and mitochondrial dysfunction need to be validated further in islets from animal models and human donors with diabetes .	Functional relevance of GEF [Tiam1 and Vav2] induced Rac1 activation in the generation of oxidative stress, stress kinase activation and mitochondrial dysfunction need to be validated further in islets from animal models and human donors with diabetes.	1	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	5	6	10	11
Surprisingly , Tiam1 induced activation of Rac produces the opposite phenotype : cell spreading and the formation of neurites .	Surprisingly, Tiam1 induced activation of Rac produces the opposite phenotype : cell spreading and the formation of neurites.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	2	3	6	7
This suggests , that sustained activation of Rac by Tiam1 resulted in downmodulation of Rho activity .	This suggests, that sustained activation of Rac by Tiam1 resulted in downmodulation of Rho activity.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	9	10	7	8
Tiam1 activates Rac1 at synapses , and loss of Tiam1 function in neurons uncouples Rac1 activation and spinogenesis from glutamate and NMDA receptor signaling and ephrinB and EphB receptor signaling .	Tiam1 activates Rac1 at synapses, and loss of Tiam1 function in neurons uncouples Rac1 activation and spinogenesis from glutamate and NMDA receptor signaling and ephrinB and EphB receptor signaling.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	0	1	2	3
To confirm that the observed defect in adhesion and spreading was because of the absence of Tiam1 mediated Rac activation , we introduced full-length Tiam1 and constitutively active Rac1 ( V12 or L61 mutants ) into Tiam1-/- keratinocytes .	To confirm that the observed defect in adhesion and spreading was because of the absence of Tiam1 mediated Rac activation, we introduced full-length Tiam1 and constitutively active Rac1 (V12 or L61 mutants) into Tiam1-/- keratinocytes.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	16	17	18	19
Although Tiam1 can act directly as an exchange factor , it can also interact with different membrane and intracellular proteins , which control its GEF activity and determine the outcome signalling of Tiam1 mediated Rac1 activation .	Although Tiam1 can act directly as an exchange factor, it can also interact with different membrane and intracellular proteins, which control its GEF activity and determine the outcome signalling of Tiam1 mediated Rac1 activation.	30	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	32	33	34	35
Tiam1 mediated Rac activity is responsible for polarized outgrowth of protrusions .	Tiam1 mediated Rac activity is responsible for polarized outgrowth of protrusions.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	2	3
Evidence now implicates the Rac activator Tiam1 as a crucial component of the Par complex in regulating neuronal ( axonal ) and epithelial ( apical-basal ) polarity .	Evidence now implicates the Rac activator Tiam1 as a crucial component of the Par complex in regulating neuronal (axonal) and epithelial (apical-basal) polarity.	2	7	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	6	7	4	5
Studies in neuroblastoma lines demonstrated that over-expression of Tiam1 increases Rac1 dependent neurite outgrowth and insensitivity to RhoA induced neurite retraction .	Studies in neuroblastoma lines demonstrated that over-expression of Tiam1 increases Rac1 dependent neurite outgrowth and insensitivity to RhoA induced neurite retraction.	6	18	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	over-expression of Tiam1	tiam1	Rac1	Rac1	rac1	8	9	10	11
Rac activation by Tiam1 requires PI3-kinase activity on all substrates .	Rac activation by Tiam1 requires PI3-kinase activity on all substrates.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	0	1
MAP1B is found to interact with Tiam1 thereby activating Rac1 and cdc42 and further inhibiting RhoA activity which leads to actin polymerization and axonal elongation XREF_BIBR , XREF_BIBR .	MAP1B is found to interact with Tiam1 thereby activating Rac1 and cdc42 and further inhibiting RhoA activity which leads to actin polymerization and axonal elongation XREF_BIBR, XREF_BIBR.	4	16	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	9	10
Together , these data demonstrate that while Tiam1 mediated activation of Rac1 is necessary for GSIS [ e.g ., data from NSC23766 studies ] ; data from knock-down experiments indicate that Tiam1 might play additional modulatory role [ s ] in the events leading to GSIS [ see below ] .	Together, these data demonstrate that while Tiam1 mediated activation of Rac1 is necessary for GSIS [e.g., data from NSC23766 studies]; data from knock-down experiments indicate that Tiam1 might play additional modulatory role [s] in the events leading to GSIS [see below].	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	11	12
Tiam1 ( T lymphoma invasion and metastasis 1 ) , a guanine nucleotide exchange factor that activates Rac , is an important regulator of cell shape and invasiveness in epithelial cells and fibroblasts .	Tiam1 (T lymphoma invasion and metastasis 1), a guanine nucleotide exchange factor that activates Rac, is an important regulator of cell shape and invasiveness in epithelial cells and fibroblasts.	0	22	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	17	18
Altogether , these results indicate that LC1 of MAP1B interacts with both PH domains of Tiam1 , increasing Rac1 activity .	Altogether, these results indicate that LC1 of MAP1B interacts with both PH domains of Tiam1, increasing Rac1 activity.	13	19	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	15	16	18	19
Tiam1 specifically activates Rac , and Rac has been shown to affect several signaling pathways in a partly cell-type-specific manner .	Tiam1 specifically activates Rac, and Rac has been shown to affect several signaling pathways in a partly cell-type-specific manner.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	3	4
Similarly , T cells deficient in the Rac activator Tiam1 are deficient in polarization and locomotion on endothelium , and tend to migrate transcellularly .	Similarly, T cells deficient in the Rac activator Tiam1 are deficient in polarization and locomotion on endothelium, and tend to migrate transcellularly.	4	10	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	9	10	7	8
To investigate whether Tiam1 mediated Rac activation is essential for V12Rap1 induced T cell polarization , we used a dominant negative mutant of Tiam1 , corresponding to the PHnCCex domain of Tiam1 .	To investigate whether Tiam1 mediated Rac activation is essential for V12Rap1 induced T cell polarization, we used a dominant negative mutant of Tiam1, corresponding to the PHnCCex domain of Tiam1.	3	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	3	4	5	6
Similarly , the Par3/6 polarity complex , in conjunction with Tiam1 mediated Rac1 signaling , controls apical-basal cell polarity in contacting epithelial cells .	Similarly, the Par3/6 polarity complex, in conjunction with Tiam1 mediated Rac1 signaling, controls apical-basal cell polarity in contacting epithelial cells.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	10	11	12	13
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Keratinocytes deficient for the Rac1 activator Tiam1 show increased apoptosis upon growth factor deprivation or heat shock treatment , supporting an anti-apoptotic role of Rac1 in keratinocytes .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Keratinocytes deficient for the Rac1 activator Tiam1 show increased apoptosis upon growth factor deprivation or heat shock treatment, supporting an anti-apoptotic role of Rac1 in keratinocytes.	8	14	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	13	14	11	12
Rac is endocytosed by Rab5 and activated by RacGEF Tiam1 at the early endosome and recycled back to the plasma membrane through Arf6 dependent pathway XREF_BIBR .	Rac is endocytosed by Rab5 and activated by RacGEF Tiam1 at the early endosome and recycled back to the plasma membrane through Arf6 dependent pathway XREF_BIBR.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	9	10	0	1
For example in the Rho subfamily , Tiam1 is a specific activator of Rac1 while Vav promiscuously bind RhoA , RhoG , Rac1 , and Cdc42 .	For example in the Rho subfamily, Tiam1 is a specific activator of Rac1 while Vav promiscuously bind RhoA, RhoG, Rac1, and Cdc42.	7	14	is a specific activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	13	14
34 The NSC 23766 treatment lead to decreases in the percentage of cells showing ruffling in both cases of ABA and ABA-HP plus H 2 O 2 addition ( XREF_FIG ) , which indicated that the Tiam1 activated Rac1 signaling was indeed involved in the observed H 2 O 2 -induced ruffling .	34 The NSC 23766 treatment lead to decreases in the percentage of cells showing ruffling in both cases of ABA and ABA-HP plus H 2 O 2 addition (XREF_FIG), which indicated that the Tiam1 activated Rac1 signaling was indeed involved in the observed H 2 O 2 -induced ruffling.	35	39	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	36	37	38	39
Tiam1 mediated Rac activation was dependent on PI3-kinase activity both on a collagen I and fibronectin substrate , suggesting that PI3-kinase is required for Tiam1 and Rac induced cell migration as well as E-cadherin- mediated cell-cell adhesion .	Tiam1 mediated Rac activation was dependent on PI3-kinase activity both on a collagen I and fibronectin substrate, suggesting that PI3-kinase is required for Tiam1 and Rac induced cell migration as well as E-cadherin- mediated cell-cell adhesion.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	2	3
Tiam1 mediated activation of Rac was dependent on PI3-kinase , suggesting that PI3-kinase might also play a role in the Tiam1 induced increase of E-cadherin-mediated cell-cell adhesion .	Tiam1 mediated activation of Rac was dependent on PI3-kinase, suggesting that PI3-kinase might also play a role in the Tiam1 induced increase of E-cadherin-mediated cell-cell adhesion.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	4	5
Tiam1 mediated Rac activation is required for Rap1 induced polarization of T cells .	Tiam1 mediated Rac activation is required for Rap1 induced polarization of T cells.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	2	3
Previously , it has been shown that the Rac1 activator Tiam1 regulates the Par3 polarity complex in keratinocytes [ XREF_BIBR ] .	Previously, it has been shown that the Rac1 activator Tiam1 regulates the Par3 polarity complex in keratinocytes [XREF_BIBR].	7	11	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	10	11	8	9
Fgd1 , Tiam1 , and SGEF were used to specifically activate Cdc42 , Rac1 , and RhoG , respectively , and broad-spectrum Vav2 was used for simultaneous activation of Cdc42 , Rac1 , and RhoG .	Fgd1, Tiam1, and SGEF were used to specifically activate Cdc42, Rac1, and RhoG, respectively, and broad-spectrum Vav2 was used for simultaneous activation of Cdc42, Rac1, and RhoG.	0	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	2	3	13	14
The signaling mechanism involved recruitment of sphingosine 1-phosphate receptor-1 ( S1P-R1 ) to the caveolin enriched microdomains ( CEMs , also known as lipid rafts or caveoli ) and activation of serine/threonine kinases mammalian target of rapamycin ( mTOR ) and phosphoinositide 3-kinase ( PI3K ) and Rac specific nucleotide exchange factors Tiam1 and Vav2 , which stimulated Rac1 GTPase signaling to cytoskeleton and cell junctions .	The signaling mechanism involved recruitment of sphingosine 1-phosphate receptor-1 (S1P-R1) to the caveolin enriched microdomains (CEMs, also known as lipid rafts or caveoli) and activation of serine/threonine kinases mammalian target of rapamycin (mTOR) and phosphoinositide 3-kinase (PI3K) and Rac specific nucleotide exchange factors Tiam1 and Vav2, which stimulated Rac1 GTPase signaling to cytoskeleton and cell junctions.	2	60	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	52	53	58	59
Moreover , the FRET analysis of Rac1 in U251 cells showed that the region of higher Rac1 activation sometimes , but not always , overlapped with large adhesions , suggesting that Tiam1 at large adhesion activates Rac1 to control adhesion dynamics for cell migration ( see following paragraph ) .	Moreover, the FRET analysis of Rac1 in U251 cells showed that the region of higher Rac1 activation sometimes, but not always, overlapped with large adhesions, suggesting that Tiam1 at large adhesion activates Rac1 to control adhesion dynamics for cell migration (see following paragraph).	31	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	31	32	36	37
XREF_BIBR During angiogenic sprouting elicited by angiopoitin-1 , which induces collective and directional migration of endothelial cells , a signaling complex that includes beta-catenin and Par3/Par6/PKCzeta is recruited to the cell front to coordinate localized activation of Rac by Tiam1 , a Rac specific GEF .	XREF_BIBR During angiogenic sprouting elicited by angiopoitin-1, which induces collective and directional migration of endothelial cells, a signaling complex that includes beta-catenin and Par3/Par6/PKCzeta is recruited to the cell front to coordinate localized activation of Rac by Tiam1, a Rac specific GEF.	33	44	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	39	40	37	38
Dock2 promotes T cell homing to lymph nodes , whereas Tiam1 mediated Rac activation is associated with T cell adhesion and transendothelial migration .	Dock2 promotes T cell homing to lymph nodes, whereas Tiam1 mediated Rac activation is associated with T cell adhesion and transendothelial migration.	10	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	10	11	12	13
Since Bcr interacts with Tiam1 and limits Tiam1 induced Rac1 signaling , we hypothesized that Bcr specifically opposes Tiam1 ' s function at synapses , and that together Tiam1 and Bcr precisely regulate Rac1 activity during spinogenesis .	Since Bcr interacts with Tiam1 and limits Tiam1 induced Rac1 signaling, we hypothesized that Bcr specifically opposes Tiam1 's function at synapses, and that together Tiam1 and Bcr precisely regulate Rac1 activity during spinogenesis.	2	10	induced	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	7	8	9	10
Most importantly , the binding of HA to CD44v3 of SP1 cells stimulates Tiam1 catalyzed Rac1 signaling and cytoskeleton mediated tumor cell migration .	Most importantly, the binding of HA to CD44v3 of SP1 cells stimulates Tiam1 catalyzed Rac1 signaling and cytoskeleton mediated tumor cell migration.	13	19	catalyzed	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	13	14	15	16
This is a good example that the Rac1 activity is driven by Tiam1 mostly and is regulated dynamically by outside-in signals .	This is a good example that the Rac1 activity is driven by Tiam1 mostly and is regulated dynamically by outside-in signals.	7	13	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	12	13	7	8
Since translocation of Tiam1 to the plasma membrane promotes the local activation of Rac1 to result in membrane ruffling , we employed a semi-quantitative method to score membrane ruffling activity ( see Methods and XREF_SUPPLEMENTARY for quantification method ) .	Since translocation of Tiam1 to the plasma membrane promotes the local activation of Rac1 to result in membrane ruffling, we employed a semi-quantitative method to score membrane ruffling activity (see Methods and XREF_SUPPLEMENTARY for quantification method).	1	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	translocation of Tiam1 to the plasma membrane	tiam1	Rac1	Rac1	rac1	3	4	13	14
We accomplished the above objective by two independent approaches ; first through the use of NSC23766 to impede the functional activation of Rac1 mediated by Tiam1 , and second via the siRNA mediated knock-down of endogenous Tiam1 .	We accomplished the above objective by two independent approaches; first through the use of NSC23766 to impede the functional activation of Rac1 mediated by Tiam1, and second via the siRNA mediated knock-down of endogenous Tiam1.	20	26	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	25	26	22	23
Tiam1 mediated Rac1 signaling promotes protrusion formation at the leading edge by stimulating actin polymerization and microtubule stabilization , whereas Par6-PKCzeta signaling controls the reorientation of protrusions and centrosomes toward the direction of migration by regulating GSK-3beta signaling .	Tiam1 mediated Rac1 signaling promotes protrusion formation at the leading edge by stimulating actin polymerization and microtubule stabilization, whereas Par6-PKCzeta signaling controls the reorientation of protrusions and centrosomes toward the direction of migration by regulating GSK-3beta signaling.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	0	1	2	3
This suggested that inhibition of sirtuin activity with the same doses and duration that induced TIAM1 acetylation and decreased Rac1 activation also decreased the GEF activity of TIAM1 .	This suggested that inhibition of sirtuin activity with the same doses and duration that induced TIAM1 acetylation and decreased Rac1 activation also decreased the GEF activity of TIAM1.	5	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TIAM1	sirtuin activity with the same doses and duration that induced TIAM1 acetylation	tiam1	Rac1	Rac1	rac1	15	16	19	20
The concept that the Tiam1 controlled activation of Rac is required for proper cell polarization holds true for both epithelial and neuronal cells .	The concept that the Tiam1 controlled activation of Rac is required for proper cell polarization holds true for both epithelial and neuronal cells.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	4	5	8	9
Although our findings provide evidence showing that Tiam1 cooperates with Ras to mediate NGF induced Rac1 activation , the residual activity of Rac1 observed in cells treated with Tiam1 RNAi in the presence of NGF , suggests the existence of alternative Tiam1 independent mechanisms through which NGF can activate Rac1 .	Although our findings provide evidence showing that Tiam1 cooperates with Ras to mediate NGF induced Rac1 activation, the residual activity of Rac1 observed in cells treated with Tiam1 RNAi in the presence of NGF, suggests the existence of alternative Tiam1 independent mechanisms through which NGF can activate Rac1.	20	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	28	29	22	23
However , the activity of Rac1 was significantly reduced after knocking down Tiam1 expression , indicating that Tiam1 mediates Rac1 activation triggered by NGF ( XREF_FIG ) .	However, the activity of Rac1 was significantly reduced after knocking down Tiam1 expression, indicating that Tiam1 mediates Rac1 activation triggered by NGF (XREF_FIG).	17	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	17	18	19	20
Having demonstrated that Tiam1 and P-Rex1 elicit distinct Rac1 driven phenotypes , we were interested in deciphering the mechanism by which these contrasting phenotypes are manifested .	Having demonstrated that Tiam1 and P-Rex1 elicit distinct Rac1 driven phenotypes, we were interested in deciphering the mechanism by which these contrasting phenotypes are manifested.	3	9	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	3	4	8	9
Expression of truncated , constitutively active variants of DH-PH-CRD VAV2 or C1199 Tiam1 increased Rac1 GTP content even when endogenous Rap1 was inactivated by Rap1GAP .	Expression of truncated, constitutively active variants of DH-PH-CRD VAV2 or C1199 Tiam1 increased Rac1 GTP content even when endogenous Rap1 was inactivated by Rap1GAP.	6	16	increased	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	12	13	14	15
Our data indicate that the Rac activator Tiam1 contributes to tumorigenicity induced by specific oncogenic signaling pathways only .	Our data indicate that the Rac activator Tiam1 contributes to tumorigenicity induced by specific oncogenic signaling pathways only.	4	8	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	7	8	5	6
V12Rac or Tiam1 mediated Rac activation resulted in a substantial reduction of Rho activity , leading to an epithelial like morphology .	V12Rac or Tiam1 mediated Rac activation resulted in a substantial reduction of Rho activity, leading to an epithelial like morphology.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	2	3	4	5
Tiam1 activates RAC1 , a subunit of the NADPH oxidase complex ( Nox1 , Nox2 , and Nox3 isoforms ) , and in turn mediates ROS generation .	Tiam1 activates RAC1, a subunit of the NADPH oxidase complex (Nox1, Nox2, and Nox3 isoforms), and in turn mediates ROS generation.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	RAC1	RAC1	RAC1	0	1	2	3
Together these findings indicate that Tiam1 mediated Rac activation is required for the increase in levels of LN5 mRNA and protein upon adhesion of keratinocytes to an exogenous substrate .	Together these findings indicate that Tiam1 mediated Rac activation is required for the increase in levels of LN5 mRNA and protein upon adhesion of keratinocytes to an exogenous substrate.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	5	6	7	8
Although most TLR responses depend on the second messenger molecule myd88 ( myeloid differentiation factor 88 ) as the primary adapter , including microbial stimulated signaling , TLR3 and TLR4 can activate myd88 independent responses via interferon response factor 3 ( IRF3 ) .	Although most TLR responses depend on the second messenger molecule myd88 (myeloid differentiation factor 88) as the primary adapter, including microbial stimulated signaling, TLR3 and TLR4 can activate myd88 independent responses via interferon response factor 3 (IRF3).	27	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	myd88	myd88	myd88	29	30	32	33
TLR4 does not induce the simultaneous activation of both MYD88- and TRIF dependent pathways ; instead , TLR4 induces its signalling pathways sequentially 54 .	TLR4 does not induce the simultaneous activation of both MYD88- and TRIF dependent pathways; instead, TLR4 induces its signalling pathways sequentially 54.	0	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MYD88-	MYD88-	MYD88-	0	1	9	10
Acr1 activates the tyrosine phosphorylation of TLR-4 , thus enhancing the MyD88 and TRIF mediated signaling cascade .	Acr1 activates the tyrosine phosphorylation of TLR-4, thus enhancing the MyD88 and TRIF mediated signaling cascade.	0	16	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR-4	Acr1 activates the tyrosine phosphorylation of TLR-4	tlr-4	MyD88	MyD88	myd88	6	7	11	12
Ligation of TLR4 by LPS at the plasma membrane activates the adaptor proteins TIRAP and MYD88 , which enable pro inflammatory gene transcription .	Ligation of TLR4 by LPS at the plasma membrane activates the adaptor proteins TIRAP and MYD88, which enable pro inflammatory gene transcription.	0	23	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TLR4	TLR4	tlr4	MYD88	MYD88, which enable pro inflammatory gene transcription	myd88	2	3	15	16
Thus , after delivery of LPS to TLR4 , it is thought that the function of CD14 is complete and TLR4 can then act independently of any extracellular factors to promote MyD88 and TRIF signaling .	Thus, after delivery of LPS to TLR4, it is thought that the function of CD14 is complete and TLR4 can then act independently of any extracellular factors to promote MyD88 and TRIF signaling.	20	34	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	20	21	31	32
These results further shed light on an action model in which SFA or LPS activates TLR4 , in vivo and in vitro , which initiates the TLR4 and MyD88 signaling and finally the production of proinflammatory cytokines .	These results further shed light on an action model in which SFA or LPS activates TLR4, in vivo and in vitro, which initiates the TLR4 and MyD88 signaling and finally the production of proinflammatory cytokines.	14	29	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	15	16	28	29
Activation of TLR4 induces two signaling pathways : MyD88 and TRIF dependent signaling pathways which induces NF-kappaB and IRF3 activation and finally results in the release of inflammatory cytokines .	Activation of TLR4 induces two signaling pathways : MyD88 and TRIF dependent signaling pathways which induces NF-kappaB and IRF3 activation and finally results in the release of inflammatory cytokines.	0	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	8	9
TLR4 , however , activates both MyD88 and TRIF , but induces type I IFNs only through TRIF dependent signaling .	TLR4, however, activates both MyD88 and TRIF, but induces type I IFNs only through TRIF dependent signaling.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	6	7
We conducted a comprehensive analysis of the effect of multiple in vitro alcohol pre-exposure timepoints on expression of TLR4 induced MyD88 dependent pro inflammatory cytokines TNFalpha , IL-6 and IL-1beta in primary human monocytes .	We conducted a comprehensive analysis of the effect of multiple in vitro alcohol pre-exposure timepoints on expression of TLR4 induced MyD88 dependent pro inflammatory cytokines TNFalpha, IL-6 and IL-1beta in primary human monocytes.	16	21	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	18	19	20	21
TLR2 and TLR4 activate MyD88 dependant signaling and induce NFkappaB transactivation , leading to the production of pro inflammatory cytokines .	TLR2 and TLR4 activate MyD88 dependant signaling and induce NFkappaB transactivation, leading to the production of pro inflammatory cytokines.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	4	5
Interestingly , TLR4 utilizes all four adapters and activates both the MyD88- and TRIF dependent pathways .	Interestingly, TLR4 utilizes all four adapters and activates both the MyD88- and TRIF dependent pathways.	2	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	2	3	11	12
Once being activated , TLR4 mainly initiates two different downstream pathways : MyD88 dependent and MyD88 independent signaling pathway .	Once being activated, TLR4 mainly initiates two different downstream pathways : MyD88 dependent and MyD88 independent signaling pathway.	4	18	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	12	13
In response to LPS , TLR4 activates the MyD88 independent pathway to produce tumor necrosis factor alpha ( TNFalpha ) [ XREF_BIBR ] , whereas 8-Br activates cyclic AMP response element binding protein ( CREB ) , which binds to cAMP responsive element ( CRE ) sequences , 5 '-TGACGTCA-3 ' , and is also a substrate for various cellular kinases [ XREF_BIBR - XREF_BIBR ] .	In response to LPS, TLR4 activates the MyD88 independent pathway to produce tumor necrosis factor alpha (TNFalpha) [XREF_BIBR], whereas 8-Br activates cyclic AMP response element binding protein (CREB), which binds to cAMP responsive element (CRE) sequences, 5 '-TGACGTCA-3 ', and is also a substrate for various cellular kinases [XREF_BIBR - XREF_BIBR].	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	8	9
TLR4 induced MyD88 dependent and independent pathways lead to IKK kinase activation resulting in proinflammatory cytokine production [ XREF_BIBR ] .	TLR4 induced MyD88 dependent and independent pathways lead to IKK kinase activation resulting in proinflammatory cytokine production [XREF_BIBR].	0	7	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	2	3
In the present study , we found that the total alkaloids of D.crepidatum ( TAD ) can inhibit the production of nitric oxide ( NO ) in lipopolysaccharide ( LPS )-activated macrophages and showed protective effects against LPS induced acute lung injury ( ALI ) in mice through downregulating the TLR4 mediated MyD88 and MAPK signaling pathway .	In the present study, we found that the total alkaloids of D.crepidatum (TAD) can inhibit the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated macrophages and showed protective effects against LPS induced acute lung injury (ALI) in mice through downregulating the TLR4 mediated MyD88 and MAPK signaling pathway.	49	56	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	50	51	52	53
The major steps in the MyD88 dependent signalling cascade initiated by TLR4 are depicted in XREF_FIG .	The major steps in the MyD88 dependent signalling cascade initiated by TLR4 are depicted in XREF_FIG.	5	12	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	11	12	5	6
Interestingly , TLR4 activates both MyD88 dependent and TRIF dependent pathways XREF_BIBR ; XREF_BIBR ; XREF_BIBR .	Interestingly, TLR4 activates both MyD88 dependent and TRIF dependent pathways XREF_BIBR; XREF_BIBR; XREF_BIBR.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	5	6
TLR4 serves as the main LPS binding component and initiates signal transduction by recruiting the intracellular adapter molecules TIRAP and MyD88 .	TLR4 serves as the main LPS binding component and initiates signal transduction by recruiting the intracellular adapter molecules TIRAP and MyD88.	0	21	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	20	21
By using macrophages from TLR2-/- mice , we observed that the two strains differed in their ability to activate the TLR4 induced MyD88 independent pathway , but not the MyD88 dependent pathway .	By using macrophages from TLR2-/- mice, we observed that the two strains differed in their ability to activate the TLR4 induced MyD88 independent pathway, but not the MyD88 dependent pathway.	19	24	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	20	21	22	23
In conclusion , we hypothesise that GAS sub-acute chronic colonisation of tonsils may contribute to tonsillar hyperplasia via a SLO dependent TLR4 mediated , TRIF and MyD88 dependent p 38MAPK pathway which activates CysLTs production , and that this mechanism could be associated with paediatric OSAS disease .	In conclusion, we hypothesise that GAS sub-acute chronic colonisation of tonsils may contribute to tonsillar hyperplasia via a SLO dependent TLR4 mediated, TRIF and MyD88 dependent p 38MAPK pathway which activates CysLTs production, and that this mechanism could be associated with paediatric OSAS disease.	16	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	21	22	26	27
Since TLR4 can activate both MyD88 and TRIF , we also measured TRIF mRNA in TLR4-/- mice .	Since TLR4 can activate both MyD88 and TRIF, we also measured TRIF mRNA in TLR4-/- mice.	1	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	1	2	5	6
TLR-4 signaling activates MyD88 dependent pathways to subsequent activation of interleukin-1R-associated kinase ( IRAK ) , tumor necrosis factor receptor associated factor-6 ( TRAF6 ) and ultimately nuclear factor kappa B ( NF-kappaB ) required for cytokine induction .	TLR-4 signaling activates MyD88 dependent pathways to subsequent activation of interleukin-1R-associated kinase (IRAK), tumor necrosis factor receptor associated factor-6 (TRAF6) and ultimately nuclear factor kappa B (NF-kappaB) required for cytokine induction.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR-4	TLR-4	TLR-4	MyD88	MyD88	MyD88	0	1	3	4
TRIF is the only adaptor used by TLR3 , and TRIF-mutant mice display an impaired TLR3 mediated response being defective in the TLR4 mediated activation of the MyD88 independent pathway [ XREF_BIBR ] .	TRIF is the only adaptor used by TLR3, and TRIF-mutant mice display an impaired TLR3 mediated response being defective in the TLR4 mediated activation of the MyD88 independent pathway [XREF_BIBR].	22	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	22	23	27	28
MyD88 independent pathway can be stimulated by TLR3 and TLR4 , which associate with TIR domain containing adaptor protein inducing IFN-beta ( TRIF ) leading to IRF-3 or NF-kappaB activation [ XREF_BIBR ] .	MyD88 independent pathway can be stimulated by TLR3 and TLR4, which associate with TIR domain containing adaptor protein inducing IFN-beta (TRIF) leading to IRF-3 or NF-kappaB activation [XREF_BIBR].	0	12	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	0	1
TLR4 triggers MyD88 dependent and TRIF dependent signaling .	TLR4 triggers MyD88 dependent and TRIF dependent signaling.	0	3	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	2	3
In monocytes , it has been observed that TLR4 activation initiates zinc mediated signaling in a MyD88 ( Myeloid differentiation primary response gene 88 ) and TRIF independent manner .	In monocytes, it has been observed that TLR4 activation initiates zinc mediated signaling in a MyD88 (Myeloid differentiation primary response gene 88) and TRIF independent manner.	8	28	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	16	17
TLR4 mediated myeloid differential protein-88 ( MyD88 ) expression activating the nuclear factor kappa-light-chain-enhancer of activated B cells ( NF-kappaB ) and inhabiting kappa B kinase-beta ( IKK-beta ) .	TLR4 mediated myeloid differential protein-88 (MyD88) expression activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and inhabiting kappa B kinase-beta (IKK-beta).	0	7	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	6	7
TLR4 can trigger both MyD88 dependent and MyD88 independent signaling , which may help to explain the somewhat contradictory findings concerning the effects of TLR4 agonists in modulating EAE .	TLR4 can trigger both MyD88 dependent and MyD88 independent signaling, which may help to explain the somewhat contradictory findings concerning the effects of TLR4 agonists in modulating EAE.	0	5	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	4	5
MyD88 signaling activation by TLR4 involves recruitment and binding to this adaptor molecule .	MyD88 signaling activation by TLR4 involves recruitment and binding to this adaptor molecule.	0	5	signaling activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	0	1
Stimulation of Myd88 -/- or Trif -/- BMDCs with LPS , a TLR4 agonist that activates both MYD88- and TRIF dependent pathways , resulted in impaired CD155 induction when compared to WT BMDCs ( XREF_FIG and S2 ) .	Stimulation of Myd88 -/- or Trif -/- BMDCs with LPS, a TLR4 agonist that activates both MYD88- and TRIF dependent pathways, resulted in impaired CD155 induction when compared to WT BMDCs (XREF_FIG and S2).	12	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MYD88-	MYD88-	MYD88-	12	13	17	18
TLR4 levels were upregulated to induce proinflammatory cytokines , activating both MyD88 dependent and -independent pathways , in the retina of streptozotocin induced diabetic rats [ XREF_BIBR ] .	TLR4 levels were upregulated to induce proinflammatory cytokines, activating both MyD88 dependent and -independent pathways, in the retina of streptozotocin induced diabetic rats [XREF_BIBR].	0	12	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4 levels	tlr4	MyD88	MyD88	myd88	0	1	11	12
Since both TLR2 and TLR4 activate MyD88 signaling and TLR3 activates Toll-IL-1 receptor domain containing adaptor inducing interferon-beta ( TRIF ) signaling [ XREF_BIBR ] , these data suggest that Galpha i protein may only regulate MyD88 dependent signaling and have no effect on TRIF dependent signaling in macrophage and splenocytes .	Since both TLR2 and TLR4 activate MyD88 signaling and TLR3 activates Toll-IL-1 receptor domain containing adaptor inducing interferon-beta (TRIF) signaling [XREF_BIBR], these data suggest that Galpha i protein may only regulate MyD88 dependent signaling and have no effect on TRIF dependent signaling in macrophage and splenocytes.	2	7	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	6	7
These findings suggest that , in LPS induced inflammation , the TLR4 mediated MyD88- and TRIF dependent MAPK pathways result in cPLA ( 2 ) activation and production of pro inflammatory lipid mediators .	These findings suggest that, in LPS induced inflammation, the TLR4 mediated MyD88- and TRIF dependent MAPK pathways result in cPLA (2) activation and production of pro inflammatory lipid mediators.	8	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	11	12	13	14
It is well known that stimulation of TLR4 induces signaling cascades through MyD88 ( myeloid differentiation factor 88 ) dependent and/or MyD88 independent ( TRIF dependent ) pathways , leading eventually to the activation of NF-kB , AP-1 , and IRF-3 transcription factors , but which one of the three may play a more important role in inducing the up-regulation of CD274 expression in MPS is still unknown .	It is well known that stimulation of TLR4 induces signaling cascades through MyD88 (myeloid differentiation factor 88) dependent and/or MyD88 independent (TRIF dependent) pathways, leading eventually to the activation of NF-kB, AP-1, and IRF-3 transcription factors, but which one of the three may play a more important role in inducing the up-regulation of CD274 expression in MPS is still unknown.	5	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	21	22
The discovery that TLR4 must be delivered to PIP2 rich regions of the plasma membrane to activate MyD88 signaling XREF_BIBR , XREF_BIBR , and then endocytosed to activate TRIF signaling 30 , suggests that the initial site of receptor-ligand interaction does not determine where signal transduction occurs .	The discovery that TLR4 must be delivered to PIP2 rich regions of the plasma membrane to activate MyD88 signaling XREF_BIBR, XREF_BIBR, and then endocytosed to activate TRIF signaling 30, suggests that the initial site of receptor-ligand interaction does not determine where signal transduction occurs.	3	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	17	18
TLR2 or TLR4 agonists stimulate the MyD88 signaling pathway in APCs such as macrophages and DC , which leads to subsequent downstream activation of the major transcription factors , the nuclear factor of kappa light polypeptide gene enhancer in B-cells ( NF-kappaB ) and mitogen associated protein ( MAP ) kinase signaling pathways ( such as the ERK-CREB pathway , the JNK-AP1 pathway , and the p38 pathways ) [ XREF_BIBR ] .	TLR2 or TLR4 agonists stimulate the MyD88 signaling pathway in APCs such as macrophages and DC, which leads to subsequent downstream activation of the major transcription factors, the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kappaB) and mitogen associated protein (MAP) kinase signaling pathways (such as the ERK-CREB pathway, the JNK-AP1 pathway, and the p38 pathways) [XREF_BIBR].	0	8	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	6	7
Two single nucleotide polymorphisms of human TLR4 , D299G , and T399I lead to hyporesponsiveness to LPS by interfering with recruitment of TLR adapter molecules , such as myeloid differentiation primary response 88 ( MYD88 ) and TIR domain containing adaptor inducing interferon beta ( TRIF ) .	Two single nucleotide polymorphisms of human TLR4, D299G, and T399I lead to hyporesponsiveness to LPS by interfering with recruitment of TLR adapter molecules, such as myeloid differentiation primary response 88 (MYD88) and TIR domain containing adaptor inducing interferon beta (TRIF).	3	38	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MYD88	MYD88	MYD88	6	7	34	35
TLR4 activates two distinct signaling pathways : the MyD88 dependent and TRIF dependent pathway .	TLR4 activates two distinct signaling pathways : the MyD88 dependent and TRIF dependent pathway.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	8	9
When LPS recognition occurs , the cytoplasmic TIR ( Toll-interleukin-1 receptor ) domain of TLR4 initiates two distinct signaling cascades : MyD88 dependent and MyD88 independent cascades .	When LPS recognition occurs, the cytoplasmic TIR (Toll-interleukin-1 receptor) domain of TLR4 initiates two distinct signaling cascades : MyD88 dependent and MyD88 independent cascades.	12	26	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	14	15	21	22
Western blot analysis and immunofluorescence indicated that dose-dependently HSYA down-regulated TLR4 induced downstream effectors myeloid differentiation factor 88 ( MyD88 ) , nuclear factor kappa b ( NF-kappaB ) , and the mitogen activated protein kinases ( MAPK )-regulated proteins c-Jun NH2-terminal protein kinase ( JNK ) , protein kinase ( ERK ) 1/2 ( ERK1/2 ) , p38 MAPK ( p38 ) , as well as the LPS induced inflammatory cytokine release .	Western blot analysis and immunofluorescence indicated that dose-dependently HSYA down-regulated TLR4 induced downstream effectors myeloid differentiation factor 88 (MyD88), nuclear factor kappa b (NF-kappaB), and the mitogen activated protein kinases (MAPK)-regulated proteins c-Jun NH2-terminal protein kinase (JNK), protein kinase (ERK) 1/2 (ERK1/2), p38 MAPK (p38), as well as the LPS induced inflammatory cytokine release.	10	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	10	11	19	20
In contrast , TLR4 activation in adult neural progenitor cells results in the activation of both MyD88 dependent and -independent pathways , similar to the pathways activated in the immune system .	In contrast, TLR4 activation in adult neural progenitor cells results in the activation of both MyD88 dependent and -independent pathways, similar to the pathways activated in the immune system.	3	20	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	16	17
We further show that TLR2 and TLR4 knockdown also prevented the induction of their downstream signaling molecules MyD88 , IRAK1 , and NFkappaB p65 as well as the pro inflammatory cytokines IL-1beta , IL-6 , and TNFalpha .	We further show that TLR2 and TLR4 knockdown also prevented the induction of their downstream signaling molecules MyD88, IRAK1, and NFkappaB p65 as well as the pro inflammatory cytokines IL-1beta, IL-6, and TNFalpha.	4	23	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	17	18
This signaling by galatrox was mediated via its carbohydrate recognition domain by activation of the TLR4 mediated MyD88 dependent signaling pathway .	This signaling by galatrox was mediated via its carbohydrate recognition domain by activation of the TLR4 mediated MyD88 dependent signaling pathway.	12	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	15	16	17	18
Meanwhile , stimulation of TLR3 and TLR4 may also activate MyD88 independent pathway that induces IFNbeta secretion .	Meanwhile, stimulation of TLR3 and TLR4 may also activate MyD88 independent pathway that induces IFNbeta secretion.	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	10	11
MyD88 is common to all TLRs , whereas TRIF is essential for TLR4 mediated activation of the MyD88 independent signaling pathway [ XREF_BIBR ] .	MyD88 is common to all TLRs, whereas TRIF is essential for TLR4 mediated activation of the MyD88 independent signaling pathway [XREF_BIBR].	12	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	17	18
These findings suggest that the inability of intestinal macrophages to release IFN-alpha and TNF-alpha through TLR3- and TLR4 mediated MyD88 independent TRIF signaling may be dysregulated transcriptionally and through the expression of the SARM inhibitor .	These findings suggest that the inability of intestinal macrophages to release IFN-alpha and TNF-alpha through TLR3- and TLR4 mediated MyD88 independent TRIF signaling may be dysregulated transcriptionally and through the expression of the SARM inhibitor.	10	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	17	18	19	20
The differential healing responses we observed in knockout mouse models suggest that the CD11c + cells expressing TLR4 mediated MyD88 signaling pathway might be detrimental for calvarial defect healing .	The differential healing responses we observed in knockout mouse models suggest that the CD11c + cells expressing TLR4 mediated MyD88 signaling pathway might be detrimental for calvarial defect healing.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	17	18	19	20
TLR4 activates both the MyD88 dependent and TRIF dependent pathways .	TLR4 activates both the MyD88 dependent and TRIF dependent pathways.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	4	5
We next examined the effects of TIRAP-antisense treatments on TLR4 induced MyD88 independent TRIF and IFN-beta expression in THP-1 cells incubated with HCMV .	We next examined the effects of TIRAP-antisense treatments on TLR4 induced MyD88 independent TRIF and IFN-beta expression in THP-1 cells incubated with HCMV.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	11	12
We take our data to indicate that TBI is one of the stresses that up-regulates gene expression in TLR mediated signaling pathways and that TLR2 and TLR4 mediated MyD88 dependent pathways are the most closely implicated in the unfolding pathophysiological processes following TBI .	We take our data to indicate that TBI is one of the stresses that up-regulates gene expression in TLR mediated signaling pathways and that TLR2 and TLR4 mediated MyD88 dependent pathways are the most closely implicated in the unfolding pathophysiological processes following TBI.	24	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	26	27	28	29
These results were rather surprising because TLR4 activates the classical MyD88 dependent NF-kappaB activation , in addition to the TRIF dependent NF-kappaB and IRF3 activation pathway .	These results were rather surprising because TLR4 activates the classical MyD88 dependent NF-kappaB activation, in addition to the TRIF dependent NF-kappaB and IRF3 activation pathway.	6	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	10	11
Thus , we speculated that TLR4 mediated MyD88 signal might be crucial for development of LPS specific B cell responses following oral vaccination with attenuated Salmonella vaccine .	Thus, we speculated that TLR4 mediated MyD88 signal might be crucial for development of LPS specific B cell responses following oral vaccination with attenuated Salmonella vaccine.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	7	8
The stimulation of TLR4 by LPS can activate the MyD88 independent pathway resulting in the activation of NF-kappaB and MAPK cascades [ XREF_BIBR ] .	The stimulation of TLR4 by LPS can activate the MyD88 independent pathway resulting in the activation of NF-kappaB and MAPK cascades [XREF_BIBR].	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	9	10
TLR4 initiates the MyD88 dependent and -independent pathway that involves TRAF6 to activate the MAPK signaling pathway , resulting in phosphorylation of the extracellular signal regulated kinase ( ERK ) , p38 and c-Jun N-terminal kinase ( JNK ) , with subsequent nuclear translocation to regulate proinflammatory cytokine transcription .	TLR4 initiates the MyD88 dependent and -independent pathway that involves TRAF6 to activate the MAPK signaling pathway, resulting in phosphorylation of the extracellular signal regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK), with subsequent nuclear translocation to regulate proinflammatory cytokine transcription.	0	45	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	3	4
TRIF related adaptor molecule ( TRAM ) was identified as an adopter specifically involved in the TLR4 mediated MyD88 independent signaling pathway .	TRIF related adaptor molecule (TRAM) was identified as an adopter specifically involved in the TLR4 mediated MyD88 independent signaling pathway.	13	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	16	17	18	19
Activation of the TLR-4 pathway stimulates the MyD88 and ERK pathway leading to release of the proinflammatory cytokines such as IL-8 , CXCL2 and TNF-alpha .	Activation of the TLR-4 pathway stimulates the MyD88 and ERK pathway leading to release of the proinflammatory cytokines such as IL-8, CXCL2 and TNF-alpha.	3	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR-4	TLR-4	TLR-4	MyD88	MyD88	MyD88	3	4	7	8
When cells are stimulated with lower doses of bacteria the difference in induction of the MyD88 dependent pathway becomes apparent , because LPS is by far the most active component of the bacterium and the other non TLR4 ligands that can activate the MyD88 dependent pathway are diluted too far to be still active .	When cells are stimulated with lower doses of bacteria the difference in induction of the MyD88 dependent pathway becomes apparent, because LPS is by far the most active component of the bacterium and the other non TLR4 ligands that can activate the MyD88 dependent pathway are diluted too far to be still active.	37	47	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	37	38	43	44
TLR3 and TLR4 mediated MyD88 independent ( TRIF dependent ) signaling induces the expression of type I IFN and IRGs [ XREF_BIBR ] .	TLR3 and TLR4 mediated MyD88 independent (TRIF dependent) signaling induces the expression of type I IFN and IRGs [XREF_BIBR].	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	4	5
Additional subtlety exists as TLR2 signals exclusively via the adaptor myeloid differentiation primary response gene-88 ( MyD88 ) , whereas TLR4 activates both MyD88 and TRIF [ Toll and interleukin -1 ( IL-1 ) receptor ( TIR ) domain containing adapter protein inducing interferon-beta ( IFN-beta ) ] pathways , resulting in more complex , pathogen specific inflammatory responses .	Additional subtlety exists as TLR2 signals exclusively via the adaptor myeloid differentiation primary response gene-88 (MyD88), whereas TLR4 activates both MyD88 and TRIF [Toll and interleukin -1 (IL-1) receptor (TIR) domain containing adapter protein inducing interferon-beta (IFN-beta)] pathways, resulting in more complex, pathogen specific inflammatory responses.	20	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	20	21	23	24
To elucidate if TLR4 mediated MyD88 and TRIF signalling by the clinically applicable Lipopolysaccharide ( LPS )-derivative monophosphoryl lipid A ( MPLA ) in primary human dendritic cells requires LPS cofactors LPS binding protein ( LBP ) and CD14 .	To elucidate if TLR4 mediated MyD88 and TRIF signalling by the clinically applicable Lipopolysaccharide (LPS)-derivative monophosphoryl lipid A (MPLA) in primary human dendritic cells requires LPS cofactors LPS binding protein (LBP) and CD14.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	5	6
A MyD88 independent pathway is triggered by TLR3 and TLR4 ( in addition to the TLR4 and MyD88 dependent signaling pathway ) and , potentially , by TLR2 .	A MyD88 independent pathway is triggered by TLR3 and TLR4 (in addition to the TLR4 and MyD88 dependent signaling pathway) and, potentially, by TLR2.	1	20	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	15	16	1	2
TLR2 and TLR4 receptors signal in a MyD88 and TIR-domain-containing adapter inducing interferon-beta ( TRIF ) dependent manner , while TLR3 signals via a MyD88 independent pathway .	TLR2 and TLR4 receptors signal in a MyD88 and TIR-domain-containing adapter inducing interferon-beta (TRIF) dependent manner, while TLR3 signals via a MyD88 independent pathway.	0	10	signal	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	7	8
Previous studies indicate that the expression of TLR4 in gastric epithelial cells activates myeloid differentiation protein 88 ( MyD88 ) leading to NF-kappaB activity and the production of cytokines and chemokines , which causes chemotaxis of monocytes and macrophages and polymorphonuclear leukocyte infiltration XREF_BIBR , XREF_BIBR .	Previous studies indicate that the expression of TLR4 in gastric epithelial cells activates myeloid differentiation protein 88 (MyD88) leading to NF-kappaB activity and the production of cytokines and chemokines, which causes chemotaxis of monocytes and macrophages and polymorphonuclear leukocyte infiltration XREF_BIBR, XREF_BIBR.	5	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	expression of TLR4	tlr4	MyD88	MyD88	myd88	7	8	18	19
TLR4 activates both MyD88 dependent and -independent pathways .	TLR4 activates both MyD88 dependent and -independent pathways.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	3	4
Downstream of TLR4 , LPS activates both MyD88 dependent and independent ( TRIF dependent ) pathways XREF_BIBR .	Downstream of TLR4, LPS activates both MyD88 dependent and independent (TRIF dependent) pathways XREF_BIBR.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	7	8
It has been postulated that the sequential activation of MyD88 and TRIF pathways is preserved across multiple cells ; however , endothelial TLR4 primarily stimulates the MyD88 pathway with very little TRIF activation [ XREF_BIBR , XREF_BIBR ] .	It has been postulated that the sequential activation of MyD88 and TRIF pathways is preserved across multiple cells; however, endothelial TLR4 primarily stimulates the MyD88 pathway with very little TRIF activation [XREF_BIBR, XREF_BIBR].	21	27	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	22	23	26	27
The TLR4 triggered MyD88 pathway was found to be crucial to hepatic fibrosis by potentiating pro fibrotic TGF-beta1 signalling 44 .	The TLR4 triggered MyD88 pathway was found to be crucial to hepatic fibrosis by potentiating pro fibrotic TGF-beta1 signalling 44.	0	4	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	1	2	3	4
Lipopolysaccharide regulation of intestinal tight junction permeability is mediated by TLR-4 signal transduction pathway activation of FAK and MyD88 .	Lipopolysaccharide regulation of intestinal tight junction permeability is mediated by TLR-4 signal transduction pathway activation of FAK and MyD88.	10	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR-4	TLR-4	TLR-4	MyD88	MyD88	MyD88	10	11	18	19
Upon recognition of lipopolysaccharide ( LPS ) derived from the cell wall of Gram negative bacteria , TLR4 dimerizes and can stimulate two different signaling pathways , the proinflammatory , MyD88 dependent pathway and the antiviral , MyD88 independent pathway .	Upon recognition of lipopolysaccharide (LPS) derived from the cell wall of Gram negative bacteria, TLR4 dimerizes and can stimulate two different signaling pathways, the proinflammatory, MyD88 dependent pathway and the antiviral, MyD88 independent pathway.	17	32	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	17	18	30	31
Activation of TLR4 by bacteria derived LPS can induce both TRIF and MyD88 dependent pathways [ XREF_BIBR ] .	Activation of TLR4 by bacteria derived LPS can induce both TRIF and MyD88 dependent pathways [XREF_BIBR].	0	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	12	13
TLR4 can also initiate a Mal and MyD88 independent signalling pathway through the recruitment of TRAM and TRIF .	TLR4 can also initiate a Mal and MyD88 independent signalling pathway through the recruitment of TRAM and TRIF.	0	10	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	7	8
Together with TLR4 , this complex induces the TLR4 mediated MyD88 dependent signal transduction pathway , which leads to the rapid activation of transcription factors , mainly NF-kappaB , and cytokines such as TNF-alpha , IL-1beta , IL-6 , and IL-12 .	Together with TLR4, this complex induces the TLR4 mediated MyD88 dependent signal transduction pathway, which leads to the rapid activation of transcription factors, mainly NF-kappaB, and cytokines such as TNF-alpha, IL-1beta, IL-6, and IL-12.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	10	11
The MyD88 independent signaling pathway is activated by TLR4 after recruitment of the TRIF adapter , TRAF6 and TBK and IKKepsilon phosphorylation leading to phosphorylation of the interleukin regulatory factor 3 ( IRF3 ) .	The MyD88 independent signaling pathway is activated by TLR4 after recruitment of the TRIF adapter, TRAF6 and TBK and IKKepsilon phosphorylation leading to phosphorylation of the interleukin regulatory factor 3 (IRF3).	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	1	2
However , predominant levels of LPS specific IgG and IgA antibodies in systemic and mucosal compartments were elicited in TLR4 -/- and MyD88 -/- mice following oral vaccination with RASV strain , indicating that TLR4 mediated MyD88 signaling is not essential for induction of LPS specific antibody response .	However, predominant levels of LPS specific IgG and IgA antibodies in systemic and mucosal compartments were elicited in TLR4 -/- and MyD88 -/- mice following oral vaccination with RASV strain, indicating that TLR4 mediated MyD88 signaling is not essential for induction of LPS specific antibody response.	34	37	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	34	35	36	37
Upon LPS activation , TLR4 rapidly induces the assembly of the adaptor proteins MyD88 ( myeloid differentiation primary response gene 88 ) and TIRAP , as well as several serine threonine kinases of the interleukin-1 receptor associated kinase ( IRAK ) family .	Upon LPS activation, TLR4 rapidly induces the assembly of the adaptor proteins MyD88 (myeloid differentiation primary response gene 88) and TIRAP, as well as several serine threonine kinases of the interleukin-1 receptor associated kinase (IRAK) family.	4	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	13	14
In addition , TIRAP ( also known as MAL ) , another MyD88 adaptor like protein that acts as a bridging adaptor for TLR2- and TLR4 mediated MyD88 dependent signalling pathways , has been identified as a target of miR-145 in hematopoietic stem and progenitor cells [ XREF_BIBR ] .	In addition, TIRAP (also known as MAL), another MyD88 adaptor like protein that acts as a bridging adaptor for TLR2- and TLR4 mediated MyD88 dependent signalling pathways, has been identified as a target of miR-145 in hematopoietic stem and progenitor cells [XREF_BIBR].	21	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	25	26	27	28
The effects of mel therapy and/or EtOH intake on the TLR2- and TLR4 induced MyD88 mediated signaling pathways are presented in Figure XREF_FIG Q.	The effects of mel therapy and/or EtOH intake on the TLR2- and TLR4 induced MyD88 mediated signaling pathways are presented in Figure XREF_FIG Q.	7	19	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	14	15
Therefore , APS may modulate immunity of host organism through activation of TLR4 mediated MyD88 dependent signaling pathway .	Therefore, APS may modulate immunity of host organism through activation of TLR4 mediated MyD88 dependent signaling pathway.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	14	15
TLR4 recognizes LPS and activates two signaling pathways by utilizing the adaptor molecules MyD88 or TRIF , respectively .	TLR4 recognizes LPS and activates two signaling pathways by utilizing the adaptor molecules MyD88 or TRIF, respectively.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	13	14
Although , activation of TLR2 & TLR4 leads to similar mechanisms in terms of the involvement of MyD88 XREF_BIBR , whether down-regulation of COX-1 in response to TLR2 activation by BLP also involves MyD88 pathway needs to be examined .	Although, activation of TLR2 & TLR4 leads to similar mechanisms in terms of the involvement of MyD88 XREF_BIBR, whether down-regulation of COX-1 in response to TLR2 activation by BLP also involves MyD88 pathway needs to be examined.	2	34	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	33	34
In addition to MyD88 pathway , stimulation of TLR4 also activates MyD88 independent TIR-domain containing adapter inducing interferon-beta ( TRIF ) pathway where TRIF links to interferon regulatory factor-3 ( IRF3 ) which induces interferon-beta secretion , and this cytokine subsequently activates a series of genes that regulate host protection [ XREF_BIBR , XREF_BIBR ] .	In addition to MyD88 pathway, stimulation of TLR4 also activates MyD88 independent TIR-domain containing adapter inducing interferon-beta (TRIF) pathway where TRIF links to interferon regulatory factor-3 (IRF3) which induces interferon-beta secretion, and this cytokine subsequently activates a series of genes that regulate host protection [XREF_BIBR, XREF_BIBR].	6	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	11	12
In our study , Corilagin showed capability of inhibiting the expression of TLR4 signaling molecules in both MyD88 and TRIF signaling pathways , which demonstrated that Corilagin might be a potential agent to rescue the patients from extreme inflammatory status in sepsis .	In our study, Corilagin showed capability of inhibiting the expression of TLR4 signaling molecules in both MyD88 and TRIF signaling pathways, which demonstrated that Corilagin might be a potential agent to rescue the patients from extreme inflammatory status in sepsis.	10	21	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	expression of TLR4	tlr4	MyD88	MyD88	myd88	12	13	17	18
The formation of TLR4 , MD2 , and LPS complex activates the adaptor of myeloid differentiation factor 88 ( MyD88 ) and drives pro inflammatory signalling cascades , resulting in the activation of phosphatidylinositol-3-kinase ( PI3K ) and protein kinase B ( Akt or PKB ) 5 .	The formation of TLR4, MD2, and LPS complex activates the adaptor of myeloid differentiation factor 88 (MyD88) and drives pro inflammatory signalling cascades, resulting in the activation of phosphatidylinositol-3-kinase (PI3K) and protein kinase B (Akt or PKB) 5.	3	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	19	20
TLR4 activation leads to cell signaling through both myeloid differentiation primary response gene 88 ( MyD88 ) - and Trif dependent pathways .	TLR4 activation leads to cell signaling through both myeloid differentiation primary response gene 88 (MyD88) - and Trif dependent pathways.	0	21	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	15	16
Thus , TIRAP was expected to participate specifically in the TLR4 mediated MyD88 independent pathway .	Thus, TIRAP was expected to participate specifically in the TLR4 mediated MyD88 independent pathway.	9	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	10	11	12	13
Using a cell culture model we demonstrated that Cryptosporidium parvum and the TLR4 agonist , LPS , induced TLR and Myd88 dependent activation of NFkB [ XREF_BIBR ] .	Using a cell culture model we demonstrated that Cryptosporidium parvum and the TLR4 agonist, LPS, induced TLR and Myd88 dependent activation of NFkB [XREF_BIBR].	12	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Myd88	Myd88	Myd88	12	13	20	21
Upon stimulation with LPS or free fatty acids , TLR4 activates MyD88 dependent signaling and induces NF-kappaB activation , leading to the production of the pro inflammatory cytokine TNFalpha and the pro inflammatory factor IL6 [ XREF_BIBR ] .	Upon stimulation with LPS or free fatty acids, TLR4 activates MyD88 dependent signaling and induces NF-kappaB activation, leading to the production of the pro inflammatory cytokine TNFalpha and the pro inflammatory factor IL6 [XREF_BIBR].	9	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	11	12
These data demonstrate dysregulation of TLR4 triggered MyD88- and TRIF dependent signaling pathways and increased expression of negative regulators of TLR signaling in endotoxin-tolerant human monocytes .	These data demonstrate dysregulation of TLR4 triggered MyD88- and TRIF dependent signaling pathways and increased expression of negative regulators of TLR signaling in endotoxin-tolerant human monocytes.	3	15	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	5	6	7	8
LPS mediated TLR4 signaling elicits two parallel signaling pathways : the MyD88 pathway , which triggers NF-kappaB and AP-1 activation , TLR stimulated genes ( TSGs ) and related inflammatory cytokine production , and the TRIF pathway , which activates the interferon regulatory factor-3 ( IRF3 ) transcription factor that mediates the subsequent up-regulation of genes encoding type I IFNs and co-stimulatory molecules .	LPS mediated TLR4 signaling elicits two parallel signaling pathways : the MyD88 pathway, which triggers NF-kappaB and AP-1 activation, TLR stimulated genes (TSGs) and related inflammatory cytokine production, and the TRIF pathway, which activates the interferon regulatory factor-3 (IRF3) transcription factor that mediates the subsequent up-regulation of genes encoding type I IFNs and co-stimulatory molecules.	0	12	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	LPS mediated TLR4	tlr4	MyD88	MyD88	myd88	2	3	11	12
The internalized TLR4 is relocated to early endosomes and associated with TRAM and TRIF , activating the MyD88 independent pathway XREF_BIBR .	The internalized TLR4 is relocated to early endosomes and associated with TRAM and TRIF, activating the MyD88 independent pathway XREF_BIBR.	0	20	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	17	18
We have previously reported that MyD88 deficiency failed to prevent alcohol induced liver damage and inflammation suggesting that TLR4 mediated MyD88 independent pathways are important in induction of ALD .	We have previously reported that MyD88 deficiency failed to prevent alcohol induced liver damage and inflammation suggesting that TLR4 mediated MyD88 independent pathways are important in induction of ALD.	18	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	18	19	20	21
Engagement of TLR4 activates intracellular signaling via the adapter protein myeloid differentiation factor 88 ( MyD88 ) ultimately leading to intracellular activation of mitogen activated protein kinase and nuclear factor-kappaB that activate transcription of cytokine and chemokine genes .	Engagement of TLR4 activates intracellular signaling via the adapter protein myeloid differentiation factor 88 (MyD88) ultimately leading to intracellular activation of mitogen activated protein kinase and nuclear factor-kappaB that activate transcription of cytokine and chemokine genes.	0	33	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TLR4	TLR4	tlr4	MyD88	MyD88) ultimately leading to intracellular activation of mitogen activated protein kinase and nuclear factor-kappaB that activate transcription	myd88	2	3	15	16
132 In another study , miR-145 is known to target MAL ( bridging adaptor for TLR2- and TLR4 mediated MyD88 dependent signaling ) , 133 although it remains to be determined whether the expression of miR-145 is also regulated during TLR2 or TLR4 signaling .	132 In another study, miR-145 is known to target MAL (bridging adaptor for TLR2- and TLR4 mediated MyD88 dependent signaling), 133 although it remains to be determined whether the expression of miR-145 is also regulated during TLR2 or TLR4 signaling.	13	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	17	18	19	20
Engagement of TLR4 by LPS triggers dimerization and association of myD88 with the intracellular TIR ( toll/IL -1 receptor ) domain of TLR4 , followed by additional signal transduction events [ XREF_BIBR , XREF_BIBR ] .	Engagement of TLR4 by LPS triggers dimerization and association of myD88 with the intracellular TIR (toll/IL -1 receptor) domain of TLR4, followed by additional signal transduction events [XREF_BIBR, XREF_BIBR].	0	15	triggers	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TLR4	TLR4	tlr4	myD88	dimerization and association of myD88 with the intracellular TIR	myd88	2	3	10	11
MyD88 is essential for inflammatory cytokine production via all TLRs , whereas TRIF is involved in TLR3- and TLR4 mediated MyD88 independent induction of IFN-beta .	MyD88 is essential for inflammatory cytokine production via all TLRs, whereas TRIF is involved in TLR3- and TLR4 mediated MyD88 independent induction of IFN-beta.	14	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	18	19	20	21
The TLR4 induced MyD88 independent , TRIF mediated pathway activation results in Type I IFN induction .	The TLR4 induced MyD88 independent, TRIF mediated pathway activation results in Type I IFN induction.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	1	2	3	4
Stimulation of the TLR4 extracellular domain by LPS or endotoxins sequentially triggers the intracellular association of MyD88 with its cytosolic domain .	Stimulation of the TLR4 extracellular domain by LPS or endotoxins sequentially triggers the intracellular association of MyD88 with its cytosolic domain.	3	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	16	17
indicated that TLR4 signaling activates Myeloid Differentiation Primary Response gene 88 ( MYD88 ) dependent pathways to subsequent activation of Interleukin-1 Receptor Associated Kinase ( IRAK ) , TNF Receptor Associated Factor 6 ( TRAF6 ) , and , ultimately NF-kappaB , which is required for cytokine induction .	indicated that TLR4 signaling activates Myeloid Differentiation Primary Response gene 88 (MYD88) dependent pathways to subsequent activation of Interleukin-1 Receptor Associated Kinase (IRAK), TNF Receptor Associated Factor 6 (TRAF6), and, ultimately NF-kappaB, which is required for cytokine induction.	2	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MYD88	MYD88	MYD88	2	3	12	13
However , TLR4 can signal through both MyD88 dependent and -independent pathways , and the MyD88 independent signaling for TLR4 results in the production of type I IFNs XREF_BIBR .	However, TLR4 can signal through both MyD88 dependent and -independent pathways, and the MyD88 independent signaling for TLR4 results in the production of type I IFNs XREF_BIBR.	2	17	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	15	16
TLR4 induced MyD88 independent signaling leads to activation of IKKepsilon and interferon regulatory factor 3 ( IRF3 ) and downstream Type I IFN activation [ XREF_BIBR , XREF_BIBR ] .	TLR4 induced MyD88 independent signaling leads to activation of IKKepsilon and interferon regulatory factor 3 (IRF3) and downstream Type I IFN activation [XREF_BIBR, XREF_BIBR].	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	2	3
Upon sequential coordinated activation of both the MyD88 dependent and MyD88 independent pathways , it has been proposed that adapter protein pair TIRAP and MyD88 signaling is primarily induced by cell surface TLR4 complexes and that a delay in TRAM and TRIF activation occurs at the endosomal level after endocytosis of the TLR4 complexes .	Upon sequential coordinated activation of both the MyD88 dependent and MyD88 independent pathways, it has been proposed that adapter protein pair TIRAP and MyD88 signaling is primarily induced by cell surface TLR4 complexes and that a delay in TRAM and TRIF activation occurs at the endosomal level after endocytosis of the TLR4 complexes.	24	33	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	32	33	24	25
Loss of TLR4 in mouse Muller cells inhibits both MyD88 dependent and -independent signaling .	Loss of TLR4 in mouse Muller cells inhibits both MyD88 dependent and -independent signaling.	0	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	Loss of TLR4	tlr4	MyD88	MyD88	myd88	2	3	9	10
Upon ligand recognition , TLR4 activates both the MyD88 dependent and -independent pathways , whereas TLR2 activates only the MyD88 dependent pathway .	Upon ligand recognition, TLR4 activates both the MyD88 dependent and -independent pathways, whereas TLR2 activates only the MyD88 dependent pathway.	4	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	8	9
Furthermore , it can be speculated that the general more pronounced effect of LPS as compared to both the ligands that activate TLR2 , which also mediated their effects through the MyD88 pathway , and poly ( I : C ) , is because TLR4 stimulation activates both MyD88 dependent and independent signalling pathways XREF_BIBR .	Furthermore, it can be speculated that the general more pronounced effect of LPS as compared to both the ligands that activate TLR2, which also mediated their effects through the MyD88 pathway, and poly (I : C), is because TLR4 stimulation activates both MyD88 dependent and independent signalling pathways XREF_BIBR.	44	53	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	44	45	48	49
Both , TLR4 and TLR9 stimulation , induce a MyD88 dependent signaling pathway leading to production of pro inflammatory cytokines and chemokines .	Both, TLR4 and TLR9 stimulation, induce a MyD88 dependent signaling pathway leading to production of pro inflammatory cytokines and chemokines.	2	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	9	10
In contrast , TLR4 can also activate the MyD88 independent pathway , leading to IRF3 activation [ XREF_BIBR ] .	In contrast, TLR4 can also activate the MyD88 independent pathway, leading to IRF3 activation [XREF_BIBR].	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	8	9
TLR4 stimulation by lipopolysaccharide can cause both MAL and MyD88- and TRAM and TRIF ( Toll IL-1 receptor domain containing adaptor inducing IFNbeta )-dependent signaling events .	TLR4 stimulation by lipopolysaccharide can cause both MAL and MyD88- and TRAM and TRIF (Toll IL-1 receptor domain containing adaptor inducing IFNbeta)-dependent signaling events.	0	10	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	0	1	9	10
Thus , TRADD appears to be involved in TLR3 and TLR4 mediated MyD88 independent activation of NF-kappaB and MAP kinases in MEFs .	Thus, TRADD appears to be involved in TLR3 and TLR4 mediated MyD88 independent activation of NF-kappaB and MAP kinases in MEFs.	10	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	10	11	12	13
There is a TLR4 mediated MyD88 dependent pathway in hippocampal neurons .	There is a TLR4 mediated MyD88 dependent pathway in hippocampal neurons.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	5	6
Internalization of TLR-4 , governed by the small GTPase , Rab11a , is necessary to induce MyD88 independent signaling [ XREF_BIBR ] while internalization of TLR-2 is not necessary for signaling [ XREF_BIBR ] .	Internalization of TLR-4, governed by the small GTPase, Rab11a, is necessary to induce MyD88 independent signaling [XREF_BIBR] while internalization of TLR-2 is not necessary for signaling [XREF_BIBR].	0	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR-4	TLR-4	TLR-4	MyD88	MyD88	MyD88	2	3	16	17
TLR4 signaling triggers both MyD88- and TRIF dependent pathways .	TLR4 signaling triggers both MyD88- and TRIF dependent pathways.	0	8	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	0	1	4	5
Activation of a TLR4 mediated MyD88 independent ( TRIF and IRF-3 ) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis , whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis .	Activation of a TLR4 mediated MyD88 independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis.	0	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	5	6
TRIF plays a critical role in the TLR3- and TLR4 mediated MyD88 independent pathways [ XREF_BIBR ] .	TRIF plays a critical role in the TLR3- and TLR4 mediated MyD88 independent pathways [XREF_BIBR].	4	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	11	12
IL-12 secreted by macrophages and dendritic cells is a well known inflammatory Th1 inducing cytokine whose synthesis is contributed by TLR3 and TLR4 using MyD88 as a common adaptor molecule for down-stream signaling XREF_BIBR .	IL-12 secreted by macrophages and dendritic cells is a well known inflammatory Th1 inducing cytokine whose synthesis is contributed by TLR3 and TLR4 using MyD88 as a common adaptor molecule for down-stream signaling XREF_BIBR.	18	25	contributed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	22	23	24	25
Together with TLR4 , this complex induces the TLR4 mediated MyD88 dependent signal transduction pathway , which leads to the activation of transcription factors , mainly NF-kappaB , and cytokines such as TNF-alpha , IL-1beta , IL-6 and IL-12 XREF_BIBR .	Together with TLR4, this complex induces the TLR4 mediated MyD88 dependent signal transduction pathway, which leads to the activation of transcription factors, mainly NF-kappaB, and cytokines such as TNF-alpha, IL-1beta, IL-6 and IL-12 XREF_BIBR.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	10	11
It was suggested that TLR4 dependent signaling could lead to MyD88 dependent activation of NF-kappaB and generation of downstream proinflammatory factors leading to AHR .	It was suggested that TLR4 dependent signaling could lead to MyD88 dependent activation of NF-kappaB and generation of downstream proinflammatory factors leading to AHR.	4	12	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	10	11
Triptolide inhibited the expression of COX-2 and iNOS induced by MyD88- specific ligand - Zymosan ( TLR2 ) , TRIF- specific ligand , Poly I : C ( TLR3 ) and LPS ( TLR4 ) which activates both MyD88 and TRIF pathways .	Triptolide inhibited the expression of COX-2 and iNOS induced by MyD88- specific ligand - Zymosan (TLR2), TRIF- specific ligand, Poly I : C (TLR3) and LPS (TLR4) which activates both MyD88 and TRIF pathways.	31	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	33	34	38	39
TRIF is implicated in the TLR4 mediated MyD88 independent pathway .	TRIF is implicated in the TLR4 mediated MyD88 independent pathway.	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	7	8
Cytokine secretion was the result of TLR4 stimulation of the MyD88 dependent signaling cascade and resulted in activation and translocation of NFkappaB .	Cytokine secretion was the result of TLR4 stimulation of the MyD88 dependent signaling cascade and resulted in activation and translocation of NFkappaB.	6	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	10	11
Previous studies have established that LPS treatment of cells such as macrophages and synovial fibroblasts induce TLR4 mediated MyD88- and TRIF dependent ERK activation leading cytosolic PLA 2 activation and AA-COX-2-PGE 2 synthesis .	Previous studies have established that LPS treatment of cells such as macrophages and synovial fibroblasts induce TLR4 mediated MyD88- and TRIF dependent ERK activation leading cytosolic PLA 2 activation and AA-COX-2-PGE 2 synthesis.	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	16	17	18	19
Upon LPS binding , TLR4 activates a MyD88 dependent pathway leading to the transcriptional activation of proinflammatory genes , as well as a MyD88 independent and TRIF dependent pathway , responsible for the transcriptional induction of IFN-beta .	Upon LPS binding, TLR4 activates a MyD88 dependent pathway leading to the transcriptional activation of proinflammatory genes, as well as a MyD88-independent and TRIF-dependent pathway, responsible for the transcriptional induction of IFN-beta.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	7	8
TLR4 mediated MyD88 dependent signaling requires proper localization of the sorting adaptor TIRAP , which is targeted to regions enriched with PI P2 ( PIP 2 ) , such as membrane ruffles and lipid rafts .	TLR4 mediated MyD88 dependent signaling requires proper localization of the sorting adaptor TIRAP, which is targeted to regions enriched with PI P2 (PIP 2), such as membrane ruffles and lipid rafts.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	2	3
TLR4 can mediate MyD88 dependent pathways through the interaction with a series of cytokines to promote tumorigenesis .	TLR4 can mediate MyD88 dependent pathways through the interaction with a series of cytokines to promote tumorigenesis.	0	5	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	3	4
For example , TLR4 can activate both myeloid differentiation factor 88 ( MyD88 )-dependent signaling pathways , which induce genes encoding pro inflammatory molecules , and the expression of type I IFNs through the TIR ( Toll/IL -1 receptor ) -domain containing adaptor inducing IFN ( TIRF ) signaling pathway [ XREF_BIBR ] .	For example, TLR4 can activate both myeloid differentiation factor 88 (MyD88)-dependent signaling pathways, which induce genes encoding pro inflammatory molecules, and the expression of type I IFNs through the TIR (Toll/IL -1 receptor) -domain containing adaptor inducing IFN (TIRF) signaling pathway [XREF_BIBR].	3	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	12	13
For example , TLR4 a ligand of F protein of RSV can activate MyD88 dependent signaling pathways resulting in the production of Th1 cytokines such as TNF-alpha , IL-6 , IL-8 , IL-12 , and IL-18 .	For example, TLR4 a ligand of F protein of RSV can activate MyD88 dependent signaling pathways resulting in the production of Th1 cytokines such as TNF-alpha, IL-6, IL-8, IL-12, and IL-18.	3	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	13	14
The results of the present study showed that TLR4 signalling activated the MyD88 and NF-kappaB and the TRIF and IRF3 pathway to elicit lung inflammation and lipidosis in the ApoE -/- WD mice .	The results of the present study showed that TLR4 signalling activated the MyD88 and NF-kappaB and the TRIF and IRF3 pathway to elicit lung inflammation and lipidosis in the ApoE -/- WD mice.	8	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	12	13
Activation of TLR4 by LPS can induce both TRIF and MyD88 dependent pathways .	Activation of TLR4 by LPS can induce both TRIF and MyD88 dependent pathways.	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	10	11
TLR4 activates two signal transduction pathways : one dependent on the adaptor molecule MyD88 and one independent of MyD88 , and these pathways induce distinct patterns of gene expression in response to TLR4 ligands .	TLR4 activates two signal transduction pathways : one dependent on the adaptor molecule MyD88 and one independent of MyD88, and these pathways induce distinct patterns of gene expression in response to TLR4 ligands.	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	18	19
Consequently , TLR2 and TLR4 mediate the activation of the same signaling pathways downstream of MyD88 , including NF-kappaB , MAPK , and PI-3k and Akt pathways .	Consequently, TLR2 and TLR4 mediate the activation of the same signaling pathways downstream of MyD88, including NF-kappaB, MAPK, and PI-3k and Akt pathways.	2	16	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	15	16
TLR4 sharing with TRL2 downstream molecules TIRAP , and then the signal activated MyD88 .	TLR4 sharing with TRL2 downstream molecules TIRAP, and then the signal activated MyD88.	0	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	13	14
In conclusion , the TLR4 mediated MyD88 dependent signaling pathway is probably one of the APS induced signal pathways underlying the immunoregulation and anti-tumor effects of APS both in vitro and in vivo .	In conclusion, the TLR4 mediated MyD88 dependent signaling pathway is probably one of the APS induced signal pathways underlying the immunoregulation and anti-tumor effects of APS both in vitro and in vivo.	3	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	6	7
It has been reported that TLR4 mediated suppression of HBV replication in nonparenchymal liver cells is MyD88 independent , which can also be initiated by TLR4 activation leading to the production of IFN-beta .	It has been reported that TLR4 mediated suppression of HBV replication in nonparenchymal liver cells is MyD88 independent, which can also be initiated by TLR4 activation leading to the production of IFN-beta.	5	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	16	17
The studies from last decade suggest that activation of a TLR4 mediated MyD88 independent ( TRIF and IRF-3-dependent ) signaling pathway and complement system in the liver play an important role in the initiation and progression of AH ( Gao et al ..	The studies from last decade suggest that activation of a TLR4 mediated MyD88 independent (TRIF and IRF-3-dependent) signaling pathway and complement system in the liver play an important role in the initiation and progression of AH (Gao et al..	7	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	10	11	12	13
TLR4 mediated MyD88 dependent pathway in hippocampal neurons participate in neuroinflammation , that means neurons are not passive in inflammation .	TLR4 mediated MyD88 dependent pathway in hippocampal neurons participate in neuroinflammation, that means neurons are not passive in inflammation.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	2	3
IRF3 is involved in the MyD88 independent signaling pathway activated by TLR4 , which may explain the lack of effect detected in IRF3 between LTA alone and controls .	IRF3 is involved in the MyD88 independent signaling pathway activated by TLR4, which may explain the lack of effect detected in IRF3 between LTA alone and controls.	5	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	11	12	5	6
Mitogen activated protein kinases ( MAPK ) were also involved in TLR4 signaling in a MyD88 independent fashion .	Mitogen activated protein kinases (MAPK) were also involved in TLR4 signaling in a MyD88 independent fashion.	11	17	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	11	12	15	16
TLR4 mediated MyD88 independent activities are abolished in mice lacking TRAM , another adaptor in this pathway .	TLR4 mediated MyD88 independent activities are abolished in mice lacking TRAM, another adaptor in this pathway.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	2	3
In addition , since TLR4 activates both MyD88- and TRIF dependent pathways , an important question still remains as to whether GRK5 selectively regulates one of these pathways .	In addition, since TLR4 activates both MyD88- and TRIF dependent pathways, an important question still remains as to whether GRK5 selectively regulates one of these pathways.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	4	5	7	8
It has been shown that TLR4 mediated liver injury in ALD is MyD88 independent and involves the role of IRF-3-mediated type I interferon production , whereas fructose induced NAFLD is likely MyD88 dependent .	It has been shown that TLR4 mediated liver injury in ALD is MyD88 independent and involves the role of IRF-3-mediated type I interferon production, whereas fructose induced NAFLD is likely MyD88 dependent.	5	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	12	13
The results demonstrated that TLR4 mediated MyD88 dependent signaling pathway activated by ischemia-reperfusion may be involved in the mechanism of ischemia-reperfusion through upregulation of NF-kappaB , IL-1beta .	The results demonstrated that TLR4 mediated MyD88 dependent signaling pathway activated by ischemia-reperfusion may be involved in the mechanism of ischemia-reperfusion through upregulation of NF-kappaB, IL-1beta.	4	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	6	7
These studies suggest that pertussis toxin could be stimulating the TLR4 signaling of both the MyD88 dependent and the MyD88 independent pathways , and/or that pertussis toxin modulation of EAE is only partly dependent on TLR4 .	These studies suggest that pertussis toxin could be stimulating the TLR4 signaling of both the MyD88 dependent and the MyD88 independent pathways, and/or that pertussis toxin modulation of EAE is only partly dependent on TLR4.	10	21	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	10	11	15	16
Of note , the TLR3- and TLR4 triggered TRIF pathway is preserved in Myd88 -/- mice , hence , their activation would lead to type I IFN secretion and consequent DC maturation , resulting in the normal CD8 + T-cell response observed in these mice .	Of note, the TLR3- and TLR4 triggered TRIF pathway is preserved in Myd88 -/- mice, hence, their activation would lead to type I IFN secretion and consequent DC maturation, resulting in the normal CD8 + T-cell response observed in these mice.	4	15	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Myd88	Myd88	Myd88	6	7	13	14
The TLR4 mediated MyD88 dependent pathway plays a significant role in the mechanism of tissue injury after ICH in human tissues .	The TLR4 mediated MyD88 dependent pathway plays a significant role in the mechanism of tissue injury after ICH in human tissues.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	1	2	3	4
After LPS binding , TLR4 initially triggers MyD88 dependent pathway on the plasma membrane and subsequently undergoes dynamin- and clathrin dependent endocytosis and translocates to the endosome [ XREF_BIBR , XREF_BIBR ] .	After LPS binding, TLR4 initially triggers MyD88 dependent pathway on the plasma membrane and subsequently undergoes dynamin- and clathrin dependent endocytosis and translocates to the endosome [XREF_BIBR, XREF_BIBR].	4	23	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	7	8
Astragalus polysaccharides exerts immunomodulatory effects via TLR4 mediated MyD88 dependent signaling pathway in vitro and in vivo .	Astragalus polysaccharides exerts immunomodulatory effects via TLR4 mediated MyD88 dependent signaling pathway in vitro and in vivo.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	8	9
TLR4 mediates both MyD88- and TRIF dependent signaling pathways to produce inflammatory cytokines and type I IFNs ( XREF_FIG ) .	TLR4 mediates both MyD88- and TRIF dependent signaling pathways to produce inflammatory cytokines and type I IFNs (XREF_FIG).	0	10	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	0	1	3	4
These data demonstrate that mTOR influences both MyD88 dependent and -independent TLR4 mediated signaling , but mTOR inhibition selectively restores TLR4 induced MyD88 dependent TNFalpha release in HIV+ human macrophages mTOR inhibition promotes MAP kinase phosphorylation and reduces MKP-1 phosphorylation in HIV+ macrophages .	These data demonstrate that mTOR influences both MyD88 dependent and -independent TLR4 mediated signaling, but mTOR inhibition selectively restores TLR4 induced MyD88 dependent TNFalpha release in HIV+ human macrophages mTOR inhibition promotes MAP kinase phosphorylation and reduces MKP-1 phosphorylation in HIV+ macrophages.	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	20	21	22	23
We previously demonstrated that TNF-alpha induced photoreceptor death after TLR4 mediated MyD88 signaling in primary retina dissociated cultures .	We previously demonstrated that TNF-alpha induced photoreceptor death after TLR4 mediated MyD88 signaling in primary retina dissociated cultures.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	11	12
TLR4 requires the accessory molecule MD2 and activates two distinct signaling pathways mediated by the adapter proteins , myeloid differentiation primary response 88 ( MyD88 ) and TIR domain containing adaptor inducing interferon-beta ( TRIF ) , while most other TLR family members do not associate with accessory molecules and signal through one main pathway [ XREF_BIBR ] .	TLR4 requires the accessory molecule MD2 and activates two distinct signaling pathways mediated by the adapter proteins, myeloid differentiation primary response 88 (MyD88) and TIR domain containing adaptor inducing interferon-beta (TRIF), while most other TLR family members do not associate with accessory molecules and signal through one main pathway [XREF_BIBR].	0	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	24	25
In order to determine the role of the TLR4 signalling pathways in the HS induced inflammatory response , TLR4 -/- as well as the adaptor protein , MyD88 -/- and the transcription factor , IRF3 -/- were used .	In order to determine the role of the TLR4 signalling pathways in the HS induced inflammatory response, TLR4 -/- as well as the adaptor protein, MyD88 -/- and the transcription factor, IRF3 -/- were used.	5	28	induced	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	27	28
Distinctively , TLR4 recruits additional adaptors and triggers both MyD88 and TRIF signals .	Distinctively, TLR4 recruits additional adaptors and triggers both MyD88 and TRIF signals.	2	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	9	10
TLR4 is known to activate two distinct signaling pathways : the MyD88 dependent and TRIF dependent signaling pathways .	TLR4 is known to activate two distinct signaling pathways : the MyD88 dependent and TRIF dependent signaling pathways.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	11	12
As MyD88 is crucial for nuclear factor ( NF )-kappaB activation of all TLRs except TLR3 , and as TIR mediates TLR3 induced RANTES and interferon-beta production ( as well as TLR4 mediated MyD88 independent signaling ) , the downregulated MyD88 and TIR predictably result in NF-kappaB inactivation .	As MyD88 is crucial for nuclear factor (NF)-kappaB activation of all TLRs except TLR3, and as TIR mediates TLR3 induced RANTES and interferon-beta production (as well as TLR4 mediated MyD88 independent signaling), the downregulated MyD88 and TIR predictably result in NF-kappaB inactivation.	31	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	31	32	33	34
Complete TLR4 mediated induction of TRIF and MyD88 adaptor proteins are represented by the induction of IFN-beta ( ) and NFkappaB ( ) , respectively .	Complete TLR4 mediated induction of TRIF and MyD88 adaptor proteins are represented by the induction of IFN-beta () and NFkappaB (), respectively.	0	11	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	1	2	7	8
Importantly , besides inducing MyD88 mediated signalling like other TLRs , the stimulation of TLR4 can also activate the MyD88 independent TIR-domain containing the adapter inducing interferon-beta ( TRIF ) pathway , inducing IFN-beta secretion [ XREF_BIBR ] .	Importantly, besides inducing MyD88 mediated signalling like other TLRs, the stimulation of TLR4 can also activate the MyD88 independent TIR-domain containing the adapter inducing interferon-beta (TRIF) pathway, inducing IFN-beta secretion [XREF_BIBR].	12	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	14	15	19	20
TLR4 can activate the myeloid differentiation primary response gene 88 ( MyD88 ) , leading to translocation of NF-kappaB into the nucleus , subsequently activating the expression of genes related to the inflammatory process .	TLR4 can activate the myeloid differentiation primary response gene 88 (MyD88), leading to translocation of NF-kappaB into the nucleus, subsequently activating the expression of genes related to the inflammatory process.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	11	12
LPS mediated activation of TLR4 induces the MYD88 dependent activation of both p38 and NF-kB , through phosphorylation of IKKbeta .	LPS mediated activation of TLR4 induces the MYD88 dependent activation of both p38 and NF-kB, through phosphorylation of IKKbeta.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	LPS mediated activation of TLR4	tlr4	MYD88	MYD88	myd88	4	5	7	8
Bacterial lipopolysaccharide ( LPS ) , the major structural component of the outer wall of all Gram negative bacteria , is recognized by TLR4 and myeloid differentiation factor 2 ( MD-2 ) and CD14 complex to initiate myeloid differentiation factor ( MyD88 )-dependent and MyD88 independent signaling pathways to activate inflammatory gene expression .	Bacterial lipopolysaccharide (LPS), the major structural component of the outer wall of all Gram negative bacteria, is recognized by TLR4 and myeloid differentiation factor 2 (MD-2) and CD14 complex to initiate myeloid differentiation factor (MyD88)-dependent and MyD88 independent signaling pathways to activate inflammatory gene expression.	21	49	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	23	24	41	42
From the plasma membrane , TLR4 mediates MyD88 dependent signaling , leading to rapid NF-kappaB activation and production of proinflammatory cytokines .	From the plasma membrane, TLR4 mediates MyD88 dependent signaling, leading to rapid NF-kappaB activation and production of proinflammatory cytokines.	5	9	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	7	8
Very little activity was seen downstream of TLR4 , which can also activate an MyD88 independent pathway .	Very little activity was seen downstream of TLR4, which can also activate an MyD88 independent pathway.	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	14	15
MyD88 is a critical element in the NF-kappaB activation pathway of all TLRs except TLR3 , and TRIF mediates TLR3 induced RANTES and IFN-beta production , as well as TLR4 mediated MyD88 independent signaling .	MyD88 is a critical element in the NF-kappaB activation pathway of all TLRs except TLR3, and TRIF mediates TLR3 induced RANTES and IFN-beta production, as well as TLR4 mediated MyD88 independent signaling.	24	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	29	30	31	32
TLR4 can activate both the MyD88 dependent signaling pathway and the MyD88 independent pathway .	TLR4 can activate both the MyD88 dependent signaling pathway and the MyD88 independent pathway.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	11	12
Of note , TLR4 reportedly activates both MyD88- and Trif dependent pathways .	Of note, TLR4 reportedly activates both MyD88- and Trif dependent pathways.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	3	4	7	8
TIRAP specifically participates in the MyD88 dependent pathways shared by TLR2 and TLR4 , and TRAM is essential for the TLR4 mediated MyD88 independent pathway .	TIRAP specifically participates in the MyD88 dependent pathways shared by TLR2 and TLR4, and TRAM is essential for the TLR4 mediated MyD88 independent pathway.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	20	21	22	23
The activation of TLR4 triggers two distinct signalling pathways : MyD88 dependent signalling and MyD88 independent signalling ( also known as TRIF dependent signalling ) .	The activation of TLR4 triggers two distinct signalling pathways : MyD88 dependent signalling and MyD88 independent signalling (also known as TRIF dependent signalling).	1	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	10	11
It is known that activation of TLR4 triggers both the myeloid differentiation primary response 88 ( MYD88 )-dependent pathway and the TLR adaptor molecule 1 ( TICAM1 )-dependent pathway , leading to the activation of the NFKB , IRF , and MAPK pathways 31 .	It is known that activation of TLR4 triggers both the myeloid differentiation primary response 88 (MYD88)-dependent pathway and the TLR adaptor molecule 1 (TICAM1)-dependent pathway, leading to the activation of the NFKB, IRF, and MAPK pathways 31.	4	18	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MYD88	MYD88	MYD88	6	7	16	17
XREF_FIG shows that loss of TLR4 in the TLR4-PDGFRalpha-Cre mice led to reduced TRIF and IRF3 levels in Muller cells , demonstrating that loss of TLR4 repressed MyD88 independent signaling .	XREF_FIG shows that loss of TLR4 in the TLR4-PDGFRalpha-Cre mice led to reduced TRIF and IRF3 levels in Muller cells, demonstrating that loss of TLR4 repressed MyD88 independent signaling.	23	29	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	loss of TLR4	tlr4	MyD88	MyD88	myd88	25	26	27	28
Following association with LPS , TLR4 is activated at the cell surface and recruits myeloid differentiation primary response gene 88 ( MyD88 ) to its cytosolic Toll and IL-1R ( TIR ) domain via the adaptor protein MyD88 adaptor like ( Mal ) XREF_BIBR - XREF_BIBR .	Following association with LPS, TLR4 is activated at the cell surface and recruits myeloid differentiation primary response gene 88 (MyD88) to its cytosolic Toll and IL-1R (TIR) domain via the adaptor protein MyD88 adaptor like (Mal) XREF_BIBR - XREF_BIBR.	5	45	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	21	22
Although most TLRs ( except for TLR3 ) signal through the key adaptor molecule MyD88 , TLR3 and TLR4 can activate MyD88 independent signaling which is mediated by the TRIF adaptor ( TIR-domain-containing adapter inducing IFN-beta ) .	Although most TLRs (except for TLR3) signal through the key adaptor molecule MyD88, TLR3 and TLR4 can activate MyD88 independent signaling which is mediated by the TRIF adaptor (TIR-domain-containing adapter inducing IFN-beta).	16	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	18	19	21	22
Chlamydia abortus Pmp18.1 Induces IL-1beta Secretion by TLR4 Activation through the MyD88 , NF-kappaB , and Caspase-1 Signaling Pathways .	Chlamydia abortus Pmp18.1 Induces IL-1beta Secretion by TLR4 Activation through the MyD88, NF-kappaB, and Caspase-1 Signaling Pathways.	3	18	Induces	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	11	12
TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88 independent DC maturation .	TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88 independent DC maturation.	4	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	16	17
TLR2 signaling relies solely on the MyD88 dependent pathway , whereas TLR4 can signal through both the MyD88 dependent and the TRIF-IRF-3 , MyD88 independent pathway .	TLR2 signaling relies solely on the MyD88 dependent pathway, whereas TLR4 can signal through both the MyD88 dependent and the TRIF-IRF-3, MyD88 independent pathway.	11	21	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	11	12	17	18
We showed that MyD88 , NF-kappaB1 , NF-kappaB2 , IRF1 , and IRF3 were all significantly stimulated by activation of TLR2 , TLR3 , and TLR4 in melanoma cells .	We showed that MyD88, NF-kappaB1, NF-kappaB2, IRF1, and IRF3 were all significantly stimulated by activation of TLR2, TLR3, and TLR4 in melanoma cells.	3	26	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	25	26	3	4
We previously reported that IL-27 is mainly produced by macrophages through TLR4 signaling in a MyD88 dependent manner XREF_BIBR , XREF_BIBR .	We previously reported that IL-27 is mainly produced by macrophages through TLR4 signaling in a MyD88 dependent manner XREF_BIBR, XREF_BIBR.	11	18	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	11	12	15	16
TLR4 also activates MyD88 independent signalling pathway .	TLR4 also activates MyD88 independent signalling pathway.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	3	4
There is growing evidence showing that LPS induced NF-kappaB activation is related to TLR4 mediated MyD88 dependent signaling pathway .	There is growing evidence showing that LPS induced NF-kappaB activation is related to TLR4 mediated MyD88 dependent signaling pathway.	11	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	13	14	15	16
In conclusion , we hypothesise that GAS sub-acute chronic colonisation of tonsils may contribute to tonsillar hyperplasia via a SLO dependent TLR4 mediated , TRIF and MyD88 dependent p 38MAPK pathway which activates CysLTs production , and that this mechanism , although still requiring evidence of cause-effect relationship , could possibly be associated with paediatric OSAS disease .	In conclusion, we hypothesise that GAS sub-acute chronic colonisation of tonsils may contribute to tonsillar hyperplasia via a SLO dependent TLR4 mediated, TRIF and MyD88 dependent p 38MAPK pathway which activates CysLTs production, and that this mechanism, although still requiring evidence of cause-effect relationship, could possibly be associated with paediatric OSAS disease.	16	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	21	22	26	27
Ligand binding to TRIF mediates TLR3 induced RANTES production as well as TLR4 mediated MyD88 independent TNF-alpha synthesis 19 .	Ligand binding to TRIF mediates TLR3 induced RANTES production as well as TLR4 mediated MyD88 independent TNF-alpha synthesis 19.	6	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	14	15
Taken together , these data suggest that the immune response of Chinese Holstein cattle with mastitis may occur by a MyD88 dependent channel that is mediated by TLR4 / NF-kappaB .	Taken together, these data suggest that the immune response of Chinese Holstein cattle with mastitis may occur by a MyD88 dependent channel that is mediated by TLR4 / NF-kappaB.	20	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	27	28	20	21
TRIF is now known to control the TLR4 induced MyD88 independent pathway , and also to be the exclusive adaptor used by TLR3 XREF_BIBR - XREF_BIBR .	TRIF is now known to control the TLR4 induced MyD88 independent pathway, and also to be the exclusive adaptor used by TLR3 XREF_BIBR - XREF_BIBR.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	9	10
Importantly , TLR3 deficiency prevented CLP sepsis activation of both TLR4 mediated MyD88 dependent NF-kappaB activation and TRIF dependent IFN-beta signaling pathways .	Importantly, TLR3 deficiency prevented CLP sepsis activation of both TLR4 mediated MyD88 dependent NF-kappaB activation and TRIF dependent IFN-beta signaling pathways.	7	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	10	11	12	13
TLR4 , which recognizes LPS and initiates a series of intracellular responses , invokes a vigorous cytokine response among immune cells against Gram negative bacteria XREF_BIBR , TLR4 activates the MyD88- and TRIF dependent pathways through nuclear factor-kappaB ( NF-kappaB )-associated signaling events XREF_BIBR - XREF_BIBR .	TLR4, which recognizes LPS and initiates a series of intracellular responses, invokes a vigorous cytokine response among immune cells against Gram negative bacteria XREF_BIBR, TLR4 activates the MyD88- and TRIF dependent pathways through nuclear factor-kappaB (NF-kappaB)-associated signaling events XREF_BIBR - XREF_BIBR.	27	43	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	27	28	30	31
LPS is a unique adjuvant in that TLR4 stimulation results in activation of both MyD88 and TRIF signaling pathways .	LPS is a unique adjuvant in that TLR4 stimulation results in activation of both MyD88 and TRIF signaling pathways.	7	18	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	14	15
TRIF is essential for the TLR3- and TLR4 mediated MyD88 independent pathway , which involves the activation of IRF-3 , leading to expression of IFN-beta [ XREF_BIBR , XREF_BIBR ] .	TRIF is essential for the TLR3- and TLR4 mediated MyD88 independent pathway, which involves the activation of IRF-3, leading to expression of IFN-beta [XREF_BIBR, XREF_BIBR].	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	9	10
TLR-3 signals through the TIR-domain-containing adaptor inducing interferon-beta ( Trif ) , while TLR-4 can activate both Trif and MyD88 .	TLR-3 signals through the TIR-domain-containing adaptor inducing interferon-beta (Trif), while TLR-4 can activate both Trif and MyD88.	13	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR-4	TLR-4	TLR-4	MyD88	MyD88	MyD88	13	14	19	20
TRIF plays a critical role in the TLR3- and TLR4 mediated MyD88 independent pathways [ XREF_BIBR , XREF_BIBR ] .	TRIF plays a critical role in the TLR3- and TLR4 mediated MyD88 independent pathways [XREF_BIBR, XREF_BIBR].	4	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	11	12
TRAM is a particular bridging adapter protein in the TLR4 mediated MyD88 independent pathway , which is localized to the cytosolic surface of the plasma membrane .	TRAM is a particular bridging adapter protein in the TLR4 mediated MyD88 independent pathway, which is localized to the cytosolic surface of the plasma membrane.	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	11	12
TLR2 and TLR4 both activate MyD88 and NF-kappaB , common downstream signaling components for all TLRs except TLR3 .	TLR2 and TLR4 both activate MyD88 and NF-kappaB, common downstream signaling components for all TLRs except TLR3.	0	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	5	6
TAK-242 is a specific inhibitor of TLR4 , which could selectively suppress TLR4 mediated myeloid differentiation factor 88 ( MyD88 )-dependent pathway as well as TIR domain containing adapter inducing IFN-beta ( TRIF ) dependent pathway by binding to Cys747 in the intracellular domain of TLR4 and its inhibitory effect is largely unaffected by LPS concentration and types of TLR4 ligands , and finally inhibit the expression of NO , TNF-alpha , IL-6 , and IL-1beta [ XREF_BIBR , XREF_BIBR ] .	TAK-242 is a specific inhibitor of TLR4, which could selectively suppress TLR4 mediated myeloid differentiation factor 88 (MyD88)-dependent pathway as well as TIR domain containing adapter inducing IFN-beta (TRIF) dependent pathway by binding to Cys747 in the intracellular domain of TLR4 and its inhibitory effect is largely unaffected by LPS concentration and types of TLR4 ligands, and finally inhibit the expression of NO, TNF-alpha, IL-6, and IL-1beta [XREF_BIBR, XREF_BIBR].	11	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	19	20
Although TLR-2 signaling is mediated mainly through the MyD88 , TLR-4 activates MyD88 dependent and TIR-domain-containing adapter inducing interferon beta ( TRIF )-dependent pathways .	Although TLR-2 signaling is mediated mainly through the MyD88, TLR-4 activates MyD88 dependent and TIR-domain-containing adapter inducing interferon beta (TRIF)-dependent pathways.	10	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR-4	TLR-4	TLR-4	MyD88	MyD88	MyD88	10	11	12	13
XREF_BIBR mCD14 then transfers LPS to TLR-4 , which activates both myeloid differentiation markers ( MyD ) 88 dependent and MyD88 independent intracellular signaling cascades .	XREF_BIBR mCD14 then transfers LPS to TLR-4, which activates both myeloid differentiation markers (MyD) 88 dependent and MyD88 independent intracellular signaling cascades.	3	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR-4	TLR-4	TLR-4	MyD88	MyD88	MyD88	6	7	20	21
TLR4 triggers the downstream signaling pathway by recruiting the MyD88 adaptor protein to its receptor .	TLR4 triggers the downstream signaling pathway by recruiting the MyD88 adaptor protein to its receptor.	0	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	9	10
For instance , upon recognition of LPS on the cell surface , TLR4 first induces the TIRAP and MyD88 signaling on the plasma membrane and is thereafter endocytosed .	For instance, upon recognition of LPS on the cell surface, TLR4 first induces the TIRAP and MyD88 signaling on the plasma membrane and is thereafter endocytosed.	12	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	18	19
TLR2 and TLR4 trigger MyD88 dependent intracellular signaling cascades involving the activation of nuclear factor-kappaB ( NF-kappaB ) , mitogen activated protein kinase ( MAPK ) p38 , extracellular signal regulated kinase ( ERK ) , and c-Jun NH ( 2 )-terminal kinase .	TLR2 and TLR4 trigger MyD88 dependent intracellular signaling cascades involving the activation of nuclear factor-kappaB (NF-kappaB), mitogen activated protein kinase (MAPK) p38, extracellular signal regulated kinase (ERK), and c-Jun NH (2)-terminal kinase.	0	5	trigger	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	4	5
Following the activation of MyD88 dependent signaling at the cell surface , TLR4 subsequently activates MyD88 independent signaling in the early endosomes through the recruitment of another adaptor protein , TIR domain containing adaptor inducing interferon-beta ( TRIF ) , which is responsible for the production of type I IFN through the activation of TRAF3- and IRF3 dependent signaling XREF_BIBR .	Following the activation of MyD88 dependent signaling at the cell surface, TLR4 subsequently activates MyD88 independent signaling in the early endosomes through the recruitment of another adaptor protein, TIR domain containing adaptor inducing interferon-beta (TRIF), which is responsible for the production of type I IFN through the activation of TRAF3- and IRF3 dependent signaling XREF_BIBR.	12	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	15	16
Activation of the TLR4 initiated MyD88 dependent pathway as well as the MEK-1 and ERK pathway may both be involved in the outside-in signalling events that lead to cellular activation .	Activation of the TLR4 initiated MyD88 dependent pathway as well as the MEK-1 and ERK pathway may both be involved in the outside-in signalling events that lead to cellular activation.	0	7	initiated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	5	6
TLR4 dimerization leads to downstream signaling of two pathways : the MyD88 dependent and MyD88 independent pathways .	TLR4 dimerization leads to downstream signaling of two pathways : the MyD88 dependent and MyD88 independent pathways.	0	16	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	14	15
In this study , we discovered that the endogenous TLR2 and TLR4 ligands LMW-HA and HMGB1 are able to stimulate cartilage matrix catabolism in a manner dependent on TLR2 and TLR4 and their signaling adaptor MyD88 .	In this study, we discovered that the endogenous TLR2 and TLR4 ligands LMW-HA and HMGB1 are able to stimulate cartilage matrix catabolism in a manner dependent on TLR2 and TLR4 and their signaling adaptor MyD88.	11	36	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	11	12	35	36
Earlier studies have shown that activation of TLR4 usually triggers two classic signaling cascades : MyD88 dependent and/or MyD88 independent pathway , which involves initial recruitment of MyD88 and/or TRIF .	Earlier studies have shown that activation of TLR4 usually triggers two classic signaling cascades : MyD88 dependent and/or MyD88 independent pathway, which involves initial recruitment of MyD88 and/or TRIF.	5	20	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	15	16
TLR4 also mediates to induce nitric-oxide synthase ( iNOS ) , and soluble guanylate cyclase ( sGC ) trough MyD88 and Trif activation pathways .	TLR4 also mediates to induce nitric-oxide synthase (iNOS), and soluble guanylate cyclase (sGC) trough MyD88 and Trif activation pathways.	0	23	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	19	20
TLR4 regulation of LPS activates the MyD88 dependent pathway ( mediated by TLR-IL-1 receptor domain containing adapter protein and TIRAP ) , leading to the rapid activation of NF-kappaB , which induces the production of various pro inflammatory cytokines [ XREF_BIBR ] .	TLR4 regulation of LPS activates the MyD88 dependent pathway (mediated by TLR-IL-1 receptor domain containing adapter protein and TIRAP), leading to the rapid activation of NF-kappaB, which induces the production of various pro inflammatory cytokines [XREF_BIBR].	0	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	6	7
MyD88 is essential for the induction of inflammatory cytokines whereas TRIF is mainly implicated in the TLR3- and TLR4 mediated MyD88 independent pathway [ XREF_BIBR , XREF_BIBR ] .	MyD88 is essential for the induction of inflammatory cytokines whereas TRIF is mainly implicated in the TLR3- and TLR4 mediated MyD88 independent pathway [XREF_BIBR, XREF_BIBR].	13	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	18	19	20	21
TLR4- but not TLR3 mediated MyD88 independent interferon-beta production and activation of signaling cascades were abolished in TRAM deficient cells .	TLR4- but not TLR3 mediated MyD88 independent interferon-beta production and activation of signaling cascades were abolished in TRAM deficient cells.	0	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4-	TLR4-	TLR4-	MyD88	MyD88	MyD88	0	1	5	6
It has been demonstrated that SlaA , which is involved in the generation of pro inflammatory lipid mediators such as leukotrienes , is regulated by TLR4 signaling in LPS activated macrophages and that the regulation occurs through TLR4 mediated MyD88- and TRIF dependent MAPK signaling pathways .	It has been demonstrated that SlaA, which is involved in the generation of pro inflammatory lipid mediators such as leukotrienes, is regulated by TLR4 signaling in LPS activated macrophages and that the regulation occurs through TLR4 mediated MyD88- and TRIF dependent MAPK signaling pathways.	35	45	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	37	38	39	40
TLR4 activation induces nitric oxide production in a MyD88 dependent manner .	TLR4 activation induces nitric oxide production in a MyD88 dependent manner.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	8	9
For example , TLR4 induced MyD88 dependent signaling originates from the cell surface , whereas TRIF mediated signaling occurs from endosomes .	For example, TLR4 induced MyD88 dependent signaling originates from the cell surface, whereas TRIF mediated signaling occurs from endosomes.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	5	6
In this study we show that TLR4 mediates MyD88 dependent activation of TNF receptor associated factor 2 , apoptosis signal regulating kinase 1 ( ASK1 ) , and Jun N-terminal kinase ( JNK ) and p38 MAP kinases in ischemic reperfused kidneys and posthypoxic renal tubule epithelial cells ( RTECs ) .	In this study we show that TLR4 mediates MyD88 dependent activation of TNF receptor associated factor 2, apoptosis signal regulating kinase 1 (ASK1), and Jun N-terminal kinase (JNK) and p38 MAP kinases in ischemic reperfused kidneys and posthypoxic renal tubule epithelial cells (RTECs).	6	10	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	8	9
They showed that TLR4 and MyD88 were expressed in tumor cells of OEC both at the mRNA and protein level , and that the TLR4 induces NF-kappaB activation in MyD88 positive OEC cells .	They showed that TLR4 and MyD88 were expressed in tumor cells of OEC both at the mRNA and protein level, and that the TLR4 induces NF-kappaB activation in MyD88 positive OEC cells.	23	32	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	24	25	29	30
Our findings show that LPS specific IgG and IgA antibodies were induced after oral administration of RASV strain through a PP dependent , CD4 + T cell dependent , and TLR4 mediated MyD88 signaling independent pathway .	Our findings show that LPS specific IgG and IgA antibodies were induced after oral administration of RASV strain through a PP dependent, CD4 + T cell dependent, and TLR4 mediated MyD88 signaling independent pathway.	30	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	30	31	32	33
Similarly , TLR2 and TLR4 activation led to upregulation of miR-125a and miR-146a primary transcripts in WT BMDMs , while induction of pri-miR-125a was MyD88 dependent ( XREF_FIG ) .	Similarly, TLR2 and TLR4 activation led to upregulation of miR-125a and miR-146a primary transcripts in WT BMDMs, while induction of pri-miR-125a was MyD88 dependent (XREF_FIG).	2	27	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	24	25
TLR4 leads to activation of both MYD88 and TRIF dependent pathways .	TLR4 leads to activation of both MYD88 and TRIF dependent pathways.	0	10	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MYD88	MYD88	MYD88	0	1	6	7
TLR4 can activate both MyD88 and TICAM-1 , but requires the adaptor molecule TRAM ( TRIF related adaptor molecule ) to recruit the TICAM-1 complex , the other members of the TLR family signaling only through MyD88 .	TLR4 can activate both MyD88 and TICAM-1, but requires the adaptor molecule TRAM (TRIF related adaptor molecule) to recruit the TICAM-1 complex, the other members of the TLR family signaling only through MyD88.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	4	5
After noting that TIRAP antisense treatments increased TRAM expression and resultant IFN-beta induction ( XREF_FIG ) , we sought to determine whether TRAM antisense treatment affected HCMV induction of TLR4 mediated MyD88 dependent signaling in THP-1 cells .	After noting that TIRAP antisense treatments increased TRAM expression and resultant IFN-beta induction (XREF_FIG), we sought to determine whether TRAM antisense treatment affected HCMV induction of TLR4 mediated MyD88 dependent signaling in THP-1 cells.	27	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	29	30	31	32
It is known that TLR2 and TLR4 ligands activate Akt S473 in a MyD88 dependent manner .	It is known that TLR2 and TLR4 ligands activate Akt S473 in a MyD88 dependent manner.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	13	14
Ligation of TLR4 activates both MyD88 dependent and MyD88 independent adaptor driven signaling pathways , which leads to the activation of canonical NF-kappaB and IRF3 transcription factors .	Ligation of TLR4 activates both MyD88 dependent and MyD88 independent adaptor driven signaling pathways, which leads to the activation of canonical NF-kappaB and IRF3 transcription factors.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	5	6
LPS binding protein and CD14 bind LPS and facilitate its ligation to TLR4 , which initiates MyD88 mediated signaling , ultimately causing nuclear factor ( NF )-kappaB activation and production of a variety of proinflammatory cytokines , including interleukin ( IL )-1beta and tumor necrosis factor ( TNF )-alpha .	LPS binding protein and CD14 bind LPS and facilitate its ligation to TLR4, which initiates MyD88 mediated signaling, ultimately causing nuclear factor (NF)-kappaB activation and production of a variety of proinflammatory cytokines, including interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha.	8	18	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	16	17
Surprisingly , the TLR4 driven activation of a MyD88- and TIRAP independent cytokine , RANTES , was sensitive to 2R9 in iBMDM ( XREF_FIG ) and in peritoneal macrophages ( XREF_FIG ) , albeit less sensitive than the genes that are completely MyD88- and TIRAP dependent ( XREF_FIG ) .	Surprisingly, the TLR4 driven activation of a MyD88- and TIRAP independent cytokine, RANTES, was sensitive to 2R9 in iBMDM (XREF_FIG) and in peritoneal macrophages (XREF_FIG), albeit less sensitive than the genes that are completely MyD88- and TIRAP dependent (XREF_FIG).	3	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	3	4	8	9
RG-II-mediated activation of TLR4 stimulates the MyD88 and TRIF signaling pathways .	RG-II-mediated activation of TLR4 stimulates the MyD88 and TRIF signaling pathways.	1	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	6	7
Only TLR4 is known to activate both the TIRAP and MyD88 and the TRAM and TRIF signaling pathways XREF_BIBR , XREF_BIBR , unlike all other known TLRs that use either MyD88 or TRIF as a downstream adaptor molecule XREF_BIBR , XREF_BIBR .	Only TLR4 is known to activate both the TIRAP and MyD88 and the TRAM and TRIF signaling pathways XREF_BIBR, XREF_BIBR, unlike all other known TLRs that use either MyD88 or TRIF as a downstream adaptor molecule XREF_BIBR, XREF_BIBR.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	1	2	10	11
LPS engagement of TLR4 promotes receptor dimerization and engagement of two adapter proteins , MyD88 and TRIF , to initiate downstream signaling events .	LPS engagement of TLR4 promotes receptor dimerization and engagement of two adapter proteins, MyD88 and TRIF, to initiate downstream signaling events.	1	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	14	15
XREF_BIBR , XREF_BIBR , XREF_BIBR The activation of TLR3 induced pathway and TLR4 induced MyD88 independent pathway relies on TRIF as an adapter .	XREF_BIBR, XREF_BIBR, XREF_BIBR The activation of TLR3 induced pathway and TLR4 induced MyD88 independent pathway relies on TRIF as an adapter.	9	16	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	14	15
The observation that the TLR4 -/- mouse appears to be more protected in models of ischemic AKI than the MyD88-/- mouse XREF_BIBR , XREF_BIBR suggests that both MyD88 dependent and MyD88 independent pathways are activated by TLR4 activation .	The observation that the TLR4 -/- mouse appears to be more protected in models of ischemic AKI than the MyD88-/- mouse XREF_BIBR, XREF_BIBR suggests that both MyD88 dependent and MyD88 independent pathways are activated by TLR4 activation.	26	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	36	37	27	28
TLR4 can activate downstream pathways of MyD88 and IRAK and TRIF/IKKepsilon/TBK1 that are involved in the innate immune response [ XREF_BIBR ] .	TLR4 can activate downstream pathways of MyD88 and IRAK and TRIF/IKKepsilon/TBK1 that are involved in the innate immune response [XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	6	7
LPS is a major ligand for TLR4 , which activates both MyD88 and TRIF signaling pathways that leads to activation of NF-kB .	LPS is a major ligand for TLR4, which activates both MyD88 and TRIF signaling pathways that leads to activation of NF-kB.	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	11	12
TLR4 mediated pathway may involve both MyD88 dependent and -independent pathways .	TLR4 mediated pathway may involve both MyD88 dependent and -independent pathways.	0	7	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	6	7
TLR4 is also endocytosed after ligand binding ; endolysosomal TLR4 signals in a MyD88 independent manner via the cytoplasmic adaptor TRIF ( TIR domain containing adaptor inducing interferon [ IFN ]-beta ) and the bridging adaptor TRAM ( TRIF related adaptor molecule ) .	TLR4 is also endocytosed after ligand binding; endolysosomal TLR4 signals in a MyD88 independent manner via the cytoplasmic adaptor TRIF (TIR domain containing adaptor inducing interferon [IFN]-beta) and the bridging adaptor TRAM (TRIF related adaptor molecule).	9	15	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	13	14
Interestingly , TLR4 induced TRIF dependent pathway was positively regulated by FcgammaIIA , whereas TLR4 triggered MyD88 dependent signaling pathway was suppressed by FcgammaIIA in human monocytes [ XREF_BIBR ] .	Interestingly, TLR4 induced TRIF dependent pathway was positively regulated by FcgammaIIA, whereas TLR4 triggered MyD88 dependent signaling pathway was suppressed by FcgammaIIA in human monocytes [XREF_BIBR].	14	21	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	14	15	16	17
TLR4 activates a MyD88 independent pathway via TRIF , which complexes with TRAM and leads to NF-kappaB activation [ XREF_BIBR ] .	TLR4 activates a MyD88 independent pathway via TRIF, which complexes with TRAM and leads to NF-kappaB activation [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	3	4
The TLR4 triggered TRIF pathway is also preserved in Myd88 -/- mice and its activation would lead to type I IFN secretion and DC maturation , with the consequent normal adaptive responses against T. cruzi in these mice .	The TLR4 triggered TRIF pathway is also preserved in Myd88 -/- mice and its activation would lead to type I IFN secretion and DC maturation, with the consequent normal adaptive responses against T. cruzi in these mice.	0	11	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Myd88	Myd88	Myd88	1	2	9	10
Activation of TLR4 by LPS induces the MyD88 independent pathway that promotes the internalization of the antigen-receptor LPS and TLR4 complex and activates interferon regulatory factor 3 ( IRF3 ) [ XREF_BIBR ] .	Activation of TLR4 by LPS induces the MyD88 independent pathway that promotes the internalization of the antigen-receptor LPS and TLR4 complex and activates interferon regulatory factor 3 (IRF3) [XREF_BIBR].	0	21	induces	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TLR4	TLR4	tlr4	MyD88	MyD88 independent pathway that promotes the internalization of the antigen-receptor LPS and TLR4 complex	myd88	2	3	7	8
XREF_BIBR Of note , mice lacking TICAM2 ( a TICAM1 related protein also known as TRAM ) , exhibit defective cytokine production in response to TLR4 ( but not TLR3 ) ligands , indicating that TICAM1 is required -- but not sufficient -- to transduce MYD88 independent signals elicited by TLR4 ( but not by TLR3 ) .	XREF_BIBR Of note, mice lacking TICAM2 (a TICAM1 related protein also known as TRAM), exhibit defective cytokine production in response to TLR4 (but not TLR3) ligands, indicating that TICAM1 is required -- but not sufficient -- to transduce MYD88 independent signals elicited by TLR4 (but not by TLR3).	45	51	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MYD88	MYD88	MYD88	50	51	45	46
The TRIF related adapter molecule is important in the MyD88 independent signaling mediated by TLR4 [ XREF_BIBR ] .	The TRIF related adapter molecule is important in the MyD88 independent signaling mediated by TLR4 [XREF_BIBR].	9	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	14	15	9	10
When associated with LPS , the TLR4 complex can trigger cascade activation of intracellular adaptor myeloid differentiation factor 88 ( MyD88 ) and mitogen activated protein kinase ( MAPK ) kinases ( MEK ) 1/2 [ XREF_BIBR , XREF_BIBR ] .	When associated with LPS, the TLR4 complex can trigger cascade activation of intracellular adaptor myeloid differentiation factor 88 (MyD88) and mitogen activated protein kinase (MAPK) kinases (MEK) 1/2 [XREF_BIBR, XREF_BIBR].	6	21	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	20	21
The engagement of TLR4 by LPS activates the MyD88 dependent pathway through TIR domain containing adaptor protein ( TIRAP ) , and then recruits the downstream IRAK family and TRAF6 XREF_BIBR , XREF_BIBR .	The engagement of TLR4 by LPS activates the MyD88 dependent pathway through TIR domain containing adaptor protein (TIRAP), and then recruits the downstream IRAK family and TRAF6 XREF_BIBR, XREF_BIBR.	1	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	8	9
TLR3 and TLR4 activate a MyD88 independent signaling pathway .	TLR3 and TLR4 activate a MyD88 independent signaling pathway.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	5	6
It is generally thought that TLR4 signaling is more complex than TLR2 signaling , since TLR4 activation initiates two divergent signaling cascades : The TIRAP and MyD88 pathway which activates NF-kappaB , and the TRAM and TRIF ( TIR-domain-containing adapter inducing interferon-beta ) pathway , which additionally triggers activation of the interferon regulatory factor-3 .	It is generally thought that TLR4 signaling is more complex than TLR2 signaling, since TLR4 activation initiates two divergent signaling cascades : The TIRAP and MyD88 pathway which activates NF-kappaB, and the TRAM and TRIF (TIR-domain-containing adapter inducing interferon-beta) pathway, which additionally triggers activation of the interferon regulatory factor-3.	15	27	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	15	16	26	27
As shown in XREF_FIG , all the protein mentioned above in the TLR4 signaling pathway were upregulated when stimulated by LPS , and in the MTDH knockdown cells the TLR4 and TRIF were slightly upregulated meanwhile MyD88 , IRAK4 expression changes were not obvious .	As shown in XREF_FIG, all the protein mentioned above in the TLR4 signaling pathway were upregulated when stimulated by LPS, and in the MTDH knockdown cells the TLR4 and TRIF were slightly upregulated meanwhile MyD88, IRAK4 expression changes were not obvious.	28	37	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	29	30	36	37
TIRAP and Mal is implicated in the TLR2- and TLR4 mediated MyD88 dependent signaling pathway .	TIRAP and Mal is implicated in the TLR2- and TLR4 mediated MyD88 dependent signaling pathway.	9	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	11	12
TLR4 recognises mycobacterial lipopolysaccharides ( LPS ) and can trigger one of two innate immune response pathways , the MyD88 dependant or independent pathway .	TLR4 recognises mycobacterial lipopolysaccharides (LPS) and can trigger one of two innate immune response pathways, the MyD88 dependant or independent pathway.	0	20	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	19	20
TRIF , one of the TIR domain containing adaptors , is a MyD88 homologous protein , which is specifically implicated in the TLR3- and TLR4 mediated MyD88 independent pathway [ XREF_BIBR ] .	TRIF, one of the TIR domain containing adaptors, is a MyD88 homologous protein, which is specifically implicated in the TLR3- and TLR4 mediated MyD88 independent pathway [XREF_BIBR].	19	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	24	25	26	27
Other molecules involved in down-regulating the TLR4 induced MyD88 dependent signaling pathway would be worth investigating .	Other molecules involved in down-regulating the TLR4 induced MyD88 dependent signaling pathway would be worth investigating.	4	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	8	9
To determine whether MSP inhibits the MyD88 independent signaling pathway induced by TLR4 , we treated primary peritoneal macrophages with MSP followed by stimulation with LPS , and the phosphorylation of IRF3 and upregulation of IFN-beta were assessed .	To determine whether MSP inhibits the MyD88 independent signaling pathway induced by TLR4, we treated primary peritoneal macrophages with MSP followed by stimulation with LPS, and the phosphorylation of IRF3 and upregulation of IFN-beta were assessed.	6	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	6	7
In addition , there exists a TLR4 mediated MyD88 independent pathway that recruits toll and interleukin -1 receptor ( TIR ) domain containing adaptor inducing interferon-beta ( TRIF ) instead of recruitment of MyD88 to TLR4 in response to LPS , thereby activating the expression of interferon ( IFN )-beta and IFN inducible genes like chemokine ( C-X-C motif ) ligand 10 ( CXCL10 ) XREF_BIBR - XREF_BIBR .	In addition, there exists a TLR4 mediated MyD88 independent pathway that recruits toll and interleukin -1 receptor (TIR) domain containing adaptor inducing interferon-beta (TRIF) instead of recruitment of MyD88 to TLR4 in response to LPS, thereby activating the expression of interferon (IFN)-beta and IFN inducible genes like chemokine (C-X-C motif) ligand 10 (CXCL10) XREF_BIBR - XREF_BIBR.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	6	7	8	9
The canonical TLR4 agonist LPS induces activation of TLR4 resulting in stimulation of MyD88 dependent and MyD88 independent pathways , both of which contribute to activation of inflammatory and stress response signaling .	The canonical TLR4 agonist LPS induces activation of TLR4 resulting in stimulation of MyD88 dependent and MyD88 independent pathways, both of which contribute to activation of inflammatory and stress response signaling.	2	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	13	14
We have previously reported that I/R significantly increased the levels of TLR4 mediated MyD88 dependent NF-kappaB activation in the myocardium [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	We have previously reported that I/R significantly increased the levels of TLR4 mediated MyD88 dependent NF-kappaB activation in the myocardium [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	11	12	13	14
Our results suggested that TLR4 mediated MyD88 dependent signaling pathway contributed to neuroprotection of PACAP to microglia against OGD and reoxygenation .	Our results suggested that TLR4 mediated MyD88 dependent signaling pathway contributed to neuroprotection of PACAP to microglia against OGD and reoxygenation.	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	6	7
In order to ascertain more directly the effect of TRIF signaling , we used the OVA model to compare the effect of Poly I : C , a TLR3 synthetic agonist analog of dsRNA , which signals solely thorough TRIF ; with LPS , a TLR4 agonist that signals thorough MyD88 and TRIF pathways .	In order to ascertain more directly the effect of TRIF signaling, we used the OVA model to compare the effect of Poly I : C, a TLR3 synthetic agonist analog of dsRNA, which signals solely thorough TRIF; with LPS, a TLR4 agonist that signals thorough MyD88 and TRIF pathways.	45	53	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	45	46	50	51
In response to LPS , CXCL10 is induced in a TLR4 mediated MyD88 independent pathway XREF_BIBR , XREF_BIBR , XREF_BIBR .	In response to LPS, CXCL10 is induced in a TLR4 mediated MyD88 independent pathway XREF_BIBR, XREF_BIBR, XREF_BIBR.	7	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	10	11	12	13
In animal models of endotoxin shock , a TLR4 mediated event , both MyD88 and Trif deficiency lead to a survival benefit XREF_BIBR , XREF_BIBR .	In animal models of endotoxin shock, a TLR4 mediated event, both MyD88 and Trif deficiency lead to a survival benefit XREF_BIBR, XREF_BIBR.	7	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	13	14
In addition to the MyD88 dependent signaling pathway , the TLR4 signaling also activates a MyD88 independent signaling cascade via another TIR domain containing adaptor protein inducing IFN-beta , TRIF .	In addition to the MyD88 dependent signaling pathway, the TLR4 signaling also activates a MyD88 independent signaling cascade via another TIR domain containing adaptor protein inducing IFN-beta, TRIF.	10	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	10	11	15	16
TIRAP interacts with MyD88 through the TIR domain and selectively participates in TLR2- and TLR4 mediated MyD88 dependent signaling pathways [ XREF_BIBR , XREF_BIBR ] .	TIRAP interacts with MyD88 through the TIR domain and selectively participates in TLR2- and TLR4 mediated MyD88 dependent signaling pathways [XREF_BIBR, XREF_BIBR].	10	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	14	15	16	17
Like TLR2 , TLR4 also induces MyD88 mediated signaling pathway upon recognition of selected PAMPs and regulates the production of proinflammatory cytokines [ XREF_BIBR ] ( XREF_FIG ) .	Like TLR2, TLR4 also induces MyD88 mediated signaling pathway upon recognition of selected PAMPs and regulates the production of proinflammatory cytokines [XREF_BIBR] (XREF_FIG).	3	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	6	7
TLR3 activates primarily the TRIF pathway , whereas TLR4 activates both MyD88- and TRIF dependent pathways -- Both IKKepsilon and TBK1 are key regulators of the IRF3 and IRF7 activation pathways in cells that have been exposed to viruses and/or activated by dsRNA via TLR3 .	TLR3 activates primarily the TRIF pathway, whereas TLR4 activates both MyD88- and TRIF dependent pathways -- Both IKKepsilon and TBK1 are key regulators of the IRF3 and IRF7 activation pathways in cells that have been exposed to viruses and/or activated by dsRNA via TLR3.	8	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	8	9	11	12
In the canonical TLR4-MyD88 pathway , binding of TLR4 by LPS activates MyD88 through its cytosolic domain , which further triggers a cascade of intracellular signaling events leading to activation of NF-kB and inflammation .	In the canonical TLR4-MyD88 pathway, binding of TLR4 by LPS activates MyD88 through its cytosolic domain, which further triggers a cascade of intracellular signaling events leading to activation of NF-kB and inflammation.	6	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	12	13
Interestingly , Gorina et al [ XREF_BIBR ] reported a similar signaling interplay in astrocyte inflammation , i.e ., TLR4 activation leads to MyD88 dependent NF-kappaB activation in early phase and MyD88-indepdnent MAPK and JNK pathway in late phase .	Interestingly, Gorina et al [XREF_BIBR] reported a similar signaling interplay in astrocyte inflammation, i.e., TLR4 activation leads to MyD88 dependent NF-kappaB activation in early phase and MyD88-indepdnent MAPK and JNK pathway in late phase.	19	24	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	19	20	23	24
DHA also suppressed NFkappaB activation induced by TLR4 ( CA ) , but not MyD88 ( CA ) or AKT ( CA ) , suggesting that the molecular targets of DHA are signaling components upstream of MyD88 and AKT .	DHA also suppressed NFkappaB activation induced by TLR4 (CA), but not MyD88 (CA) or AKT (CA), suggesting that the molecular targets of DHA are signaling components upstream of MyD88 and AKT.	2	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	14	15
In our previous study , TLR4 mediated MyD88 dependent pathway was studied , with a particular focus on the role of Bruton ' s tyrosine kinase and MAL in the production of hyperinflammatory responses especially in the case of cerebral malaria XREF_BIBR .	In our previous study, TLR4 mediated MyD88 dependent pathway was studied, with a particular focus on the role of Bruton 's tyrosine kinase and MAL in the production of hyperinflammatory responses especially in the case of cerebral malaria XREF_BIBR.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	7	8
By silencing individual genes in the signaling pathway , we further unveiled that the GO induced autophagy was modulated by TLR4 , TLR9 and was dependent on downstream adaptor proteins MyD88 , TRIF and TRAF6 .	By silencing individual genes in the signaling pathway, we further unveiled that the GO induced autophagy was modulated by TLR4, TLR9 and was dependent on downstream adaptor proteins MyD88, TRIF and TRAF6.	18	34	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	20	21	30	31
One potential implication of this difference is that TLR4 , in addition to utilizing MyD88 for activation of signaling pathways , can also activate MyD88 independent pathways through the use of TRIF adaptor pathway .	One potential implication of this difference is that TLR4, in addition to utilizing MyD88 for activation of signaling pathways, can also activate MyD88 independent pathways through the use of TRIF adaptor pathway.	8	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	24	25
Similarly , TRIF was confirmed to have a key role in the induction of inflammatory mediators contributing to antiviral innate immune responses via MyD88 independent signaling that is mediated by both TLR3 and TLR4 [ XREF_BIBR ] .	Similarly, TRIF was confirmed to have a key role in the induction of inflammatory mediators contributing to antiviral innate immune responses via MyD88 independent signaling that is mediated by both TLR3 and TLR4 [XREF_BIBR].	23	35	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	33	34	23	24
Whilst TRAM is required for TLR4 mediated anti-viral signaling , TLR4 mediated MyD88 dependent signaling remains intact in TRAM deficient cells .	Whilst TRAM is required for TLR4 mediated anti-viral signaling, TLR4 mediated MyD88 dependent signaling remains intact in TRAM deficient cells.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	10	11	12	13
As mentioned above , TLR4 homodimers initiate two distinct adapter protein complexes , TRAM and TRIF and MAL and MyD88 [ XREF_BIBR ] .	As mentioned above, TLR4 homodimers initiate two distinct adapter protein complexes, TRAM and TRIF and MAL and MyD88 [XREF_BIBR].	4	20	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	19	20
Upon LPS stimulation , TLR4 initiates the first MyD88 dependent signaling pathway at the plasma membrane , and is subsequently internalized along with LPS into the early and sorting endosome network , where the second signaling pathway is triggered through TRIF and TRIF related adaptor molecule .	Upon LPS stimulation, TLR4 initiates the first MyD88 dependent signaling pathway at the plasma membrane, and is subsequently internalized along with LPS into the early and sorting endosome network, where the second signaling pathway is triggered through TRIF and TRIF related adaptor molecule.	4	20	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	8	9
In fact , stimulation of TLR3 and TLR4 induces the activation of a MyD88 independent , TRIF dependent signaling pathway , which has been pointed out as a negative regulator of immunity .	In fact, stimulation of TLR3 and TLR4 induces the activation of a MyD88 independent, TRIF dependent signaling pathway, which has been pointed out as a negative regulator of immunity.	3	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	13	14
TLR-4 subsequently activates the MyD88 dependent pathway with Mal and TIRAP and the TRIF dependent pathway with TRAM .	TLR-4 subsequently activates the MyD88 dependent pathway with Mal and TIRAP and the TRIF dependent pathway with TRAM.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR-4	TLR-4	TLR-4	MyD88	MyD88	MyD88	0	1	4	5
Because TLR4 activation can initiate one of two non redundant pathways , the MyD88 dependent and MyD88 independent pathways , both pathways were evaluated ( XREF_FIG ) .	Because TLR4 activation can initiate one of two non redundant pathways, the MyD88 dependent and MyD88 independent pathways, both pathways were evaluated (XREF_FIG).	1	14	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	1	2	13	14
While plasma membrane bound TLR4 induces cytokine expression in a MyD88 dependent manner , endocytosis of TLR4 induces type I IFN induction in a TRIF dependent manner .	While plasma membrane bound TLR4 induces cytokine expression in a MyD88 dependent manner, endocytosis of TLR4 induces type I IFN induction in a TRIF dependent manner.	4	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	10	11
Then , the formation of TLR4 , MD2 , CD14 , and LPS complex activates MyD88 and drives pro inflammatory signalling cascades , resulting in the activation of PI3K and Akt 5 .	Then, the formation of TLR4, MD2, CD14, and LPS complex activates MyD88 and drives pro inflammatory signalling cascades, resulting in the activation of PI3K and Akt 5.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	15	16
TLR4 induced MyD88 dependent and -independent pathways led to the IKK kinase activation crucial in proinflammatory gene expression [ XREF_BIBR ] .	TLR4 induced MyD88 dependent and -independent pathways led to the IKK kinase activation crucial in proinflammatory gene expression [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	2	3
Besides MyD88 and Trif , two other adaptor proteins have been described : TIR-domain-containing adaptor protein ( TIRAP , required for MyD88 dependent signaling by TLR2 and TLR4 ) , and Trif related adaptor molecule .	Besides MyD88 and Trif, two other adaptor proteins have been described : TIR-domain-containing adaptor protein (TIRAP, required for MyD88 dependent signaling by TLR2 and TLR4), and Trif related adaptor molecule.	21	28	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	27	28	21	22
We demonstrated that activation of TLR4 by nickel and cobalt ions can trigger both the MyD88 dependent and the -independent pathway .	We demonstrated that activation of TLR4 by nickel and cobalt ions can trigger both the MyD88 dependent and the -independent pathway.	3	20	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	15	16
In response to LPS stimulation , NF-kappaB is translocated into a nucleus through IkappaB degradation by activating TLR4 mediated MyD88 dependent signaling pathway and in turn induces pro inflammatory mediators .	In response to LPS stimulation, NF-kappaB is translocated into a nucleus through IkappaB degradation by activating TLR4 mediated MyD88 dependent signaling pathway and in turn induces pro inflammatory mediators.	17	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	17	18	19	20
Induction of TLR4 mediated MyD88 and TRIF dependent signalling produced different responses .	Induction of TLR4 mediated MyD88 and TRIF dependent signalling produced different responses.	0	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	4	5
These data suggest that mTOR plays a dominant role in regulating innate immune responses since mTOR can influence both TLR4 mediated MyD88 dependent and MyD88 independent signaling pathways .	These data suggest that mTOR plays a dominant role in regulating innate immune responses since mTOR can influence both TLR4 mediated MyD88 dependent and MyD88 independent signaling pathways.	18	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	19	20	21	22
Stimulation of TLR4 led to the activation of NF-kappaB via the myeloid differentiation primary response protein 88 ( MyD88 )-dependent pathway , which induced pro inflammatory cytokine production .	Stimulation of TLR4 led to the activation of NF-kappaB via the myeloid differentiation primary response protein 88 (MyD88)-dependent pathway, which induced pro inflammatory cytokine production.	0	20	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	18	19
In the present study , we observed that CLP sepsis markedly increased TLR4 mediated MyD88 dependent NF-kappaB activation and TRIF dependent IRF3 mediated IFN-beta signaling pathways .	In the present study, we observed that CLP sepsis markedly increased TLR4 mediated MyD88 dependent NF-kappaB activation and TRIF dependent IRF3 mediated IFN-beta signaling pathways.	11	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	12	13	14	15
TLR4 induced MyD88 independent signalling leads to activation of IKKepsilon , NFkappaB as well as interferon regulatory factor 3 ( IRF3 ) and downstream Type I IFN activation .	TLR4 induced MyD88 independent signalling leads to activation of IKKepsilon, NFkappaB as well as interferon regulatory factor 3 (IRF3) and downstream Type I IFN activation.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	2	3
Strikingly , the MyD88 independent pathway which leads to IFN production is not induced by TLR4 activation , which may be due to a lack of cell surface CD14 .	Strikingly, the MyD88 independent pathway which leads to IFN production is not induced by TLR4 activation, which may be due to a lack of cell surface CD14.	3	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	15	16	3	4
Activation of TLR4 stimulated both a myeloid differentiation factor 88 ( Myd88 )-dependent and a Myd88 independent pathway .	Activation of TLR4 stimulated both a myeloid differentiation factor 88 (Myd88)-dependent and a Myd88 independent pathway.	0	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Myd88	Myd88	Myd88	2	3	11	12
The cell membrane bound TLR4 can initiate both the MyD88 pathway and the TRAF3 pathway .	The cell membrane bound TLR4 can initiate both the MyD88 pathway and the TRAF3 pathway.	4	10	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	9	10
Clearly , TLR4 activates both a common MyD88 dependent pathway and a MyD88 independent TRIF dependent pathway .	Clearly, TLR4 activates both a common MyD88 dependent pathway and a MyD88 independent TRIF dependent pathway.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	2	3	12	13
Endosomal TLR4 has been shown to activate the MyD88 independent interferon pathway .	Endosomal TLR4 has been shown to activate the MyD88 independent interferon pathway.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	1	2	8	9
ES-62 subverted TLR4 signaling to block TLR2- and TLR4 driven inflammatory responses via autophagosome mediated downregulation of the TLR adaptor-transducer MyD88 .	ES-62 subverted TLR4 signaling to block TLR2- and TLR4 driven inflammatory responses via autophagosome mediated downregulation of the TLR adaptor-transducer MyD88.	5	21	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	8	9	20	21
MAL acts as a partner for MyD88 in the TLR4 initiated MyD88 dependent pathway .	MAL acts as a partner for MyD88 in the TLR4 initiated MyD88 dependent pathway.	6	13	initiated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	11	12
TRIF is the TIR domain containing adaptor for TLR3 and is required for the TLR4 induced MyD88 independent pathway .	TRIF is the TIR domain containing adaptor for TLR3 and is required for the TLR4 induced MyD88 independent pathway.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	14	15	16	17
These results not only shed new light on the action mechanisms of 3-MA to differentially regulate inflammatory outcomes derived from TLR4 mediated MyD88 and Toll and IL-1R domain containing adapter inducing IFN-beta pathways , but also highlight the necessity to check autophagy status upon taking 3-MA as a general autophagy inhibitor .	These results not only shed new light on the action mechanisms of 3-MA to differentially regulate inflammatory outcomes derived from TLR4 mediated MyD88 and Toll and IL-1R domain containing adapter inducing IFN-beta pathways, but also highlight the necessity to check autophagy status upon taking 3-MA as a general autophagy inhibitor.	18	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	20	21	22	23
Collectively , our results suggest that mel attenuates the TLR4 induced MyD88- and TRIF dependent signaling pathways in ethanol preferring rats with OC .	Collectively, our results suggest that mel attenuates the TLR4 induced MyD88- and TRIF dependent signaling pathways in ethanol preferring rats with OC.	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	9	10	11	12
Results from our recent study showed that PAR 2 and TLR4 synergized in vitro to augment a MyD88 mediated , NF-kappaB-dependent inflammatory response .	Results from our recent study showed that PAR 2 and TLR4 synergized in vitro to augment a MyD88 mediated, NF-kappaB-dependent inflammatory response.	7	18	synergized	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	10	11	17	18
In astrocytes , however , TLR4 activates the MyD88- but not the TRIF dependent pathway .	In astrocytes, however, TLR4 activates the MyD88- but not the TRIF dependent pathway.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	5	6	8	9
As depicted in Figure XREF_FIG , upon TLR4 stimulation MyD88 binds to the cytoplasmic portion of the TLRs through interactions between individual TIR domains .	As depicted in Figure XREF_FIG, upon TLR4 stimulation MyD88 binds to the cytoplasmic portion of the TLRs through interactions between individual TIR domains.	1	10	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	9	10
The knockout of TRIF in mice triggers defective expression of IFN-beta production and IFN related genes that are mediated by TLR3 and TLR4 , although early-phase activation of NF-kappaB and TLR4 mediated activation of MyD88 pathway were observed [ XREF_BIBR ] .	The knockout of TRIF in mice triggers defective expression of IFN-beta production and IFN related genes that are mediated by TLR3 and TLR4, although early-phase activation of NF-kappaB and TLR4 mediated activation of MyD88 pathway were observed [XREF_BIBR].	28	35	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	30	31	34	35
This pathway is called the TLR4 mediated MyD88 dependent pathway , which is common to most TLRs ( except TLR3 ) and shared by both TLR2 and TLR4 .	This pathway is called the TLR4 mediated MyD88 dependent pathway, which is common to most TLRs (except TLR3) and shared by both TLR2 and TLR4.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	5	6	7	8
TLR4 signaling activates the MyD88 ( myeloid differentiation primary response protein 88 ) - and TRIF ( TIR domain containing adaptor protein inducing interferon-beta )-dependent pathways to induce the production of proinflammatory cytokines and interferons ( IFNs ) , respectively XREF_BIBR - XREF_BIBR .	TLR4 signaling activates the MyD88 (myeloid differentiation primary response protein 88) - and TRIF (TIR domain containing adaptor protein inducing interferon-beta)-dependent pathways to induce the production of proinflammatory cytokines and interferons (IFNs), respectively XREF_BIBR - XREF_BIBR.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	4	5
TAG is therefore an example of a specific inhibitor of the adaptor MyD88 independent pathway activated by TLR4 .	TAG is therefore an example of a specific inhibitor of the adaptor MyD88 independent pathway activated by TLR4.	12	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	17	18	12	13
However , the effect of LPS was significantly decreased by the use of TAK-242 , which could selectively suppress TLR4 mediated MyD88 dependent pathway as well as TRIF dependent pathway by binding to Cys747 in the intracellular domain of TLR4 and its inhibitory effect is largely unaffected by LPS concentration and types of TLR4 ligands [ XREF_BIBR , XREF_BIBR ] .	However, the effect of LPS was significantly decreased by the use of TAK-242, which could selectively suppress TLR4 mediated MyD88 dependent pathway as well as TRIF dependent pathway by binding to Cys747 in the intracellular domain of TLR4 and its inhibitory effect is largely unaffected by LPS concentration and types of TLR4 ligands [XREF_BIBR, XREF_BIBR].	18	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	19	20	21	22
As TLR4 mediated TRIF signaling requires dynamin dependent endocytosis of TLR4 , we next analyzed LPS induced TLR4 endocytosis .	As TLR4 mediated TRIF signaling requires dynamin dependent endocytosis of TLR4, we next analyzed LPS induced TLR4 endocytosis.	1	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	1	2	3	4
Thus , although TLR4 and LPS moves to the endosome to be subjected to degradation , TLR4 and LPS activates the TRAM and TRIF pathway to produce type 1 IFN before degradation .	Thus, although TLR4 and LPS moves to the endosome to be subjected to degradation, TLR4 and LPS activates the TRAM and TRIF pathway to produce type 1 IFN before degradation.	16	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	16	17	23	24
Furthermore , novel synthetic TLR4 adjuvants preferentially trigger the TRIF pathway XREF_BIBR .	Furthermore, novel synthetic TLR4 adjuvants preferentially trigger the TRIF pathway XREF_BIBR.	4	11	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	4	5	9	10
In addition to the TLR3 mediated TRIF pathway , TRIF can be induced by TLR4 activation .	In addition to the TLR3 mediated TRIF pathway, TRIF can be induced by TLR4 activation.	9	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	14	15	9	10
Furthermore , we show that TRIF dependent type I IFN is a central underlying mechanism for TLR4 mediated adjuvant effects on T cell priming by TLR4 agonists .	Furthermore, we show that TRIF dependent type I IFN is a central underlying mechanism for TLR4 mediated adjuvant effects on T cell priming by TLR4 agonists.	5	26	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	25	26	5	6
The TRIF dependent pathway is initiated by the endocytosis of TLR4 with LPS XREF_BIBR .	The TRIF dependent pathway is initiated by the endocytosis of TLR4 with LPS XREF_BIBR.	1	11	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	10	11	1	2
In addition to suppressing iNOS production , PGLs decreased the TLR4 induced production of TRIF dependent cytokines and chemokines .	In addition to suppressing iNOS production, PGLs decreased the TLR4 induced production of TRIF dependent cytokines and chemokines.	9	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	10	11	14	15
Recent studies suggest that TLR4 activates the TRAM and TRIF pathway by signaling from early endosomes XREF_BIBR , XREF_BIBR .	Recent studies suggest that TLR4 activates the TRAM and TRIF pathway by signaling from early endosomes XREF_BIBR, XREF_BIBR.	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	4	5	9	10
TRIF activation by LPS and TLR4 signaling led to the activation of IRF-3 and IRF-7 and NF-kappaB-dependent signaling pathways .	TRIF activation by LPS and TLR4 signaling led to the activation of IRF-3 and IRF-7 and NF-kappaB-dependent signaling pathways.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	5	6	0	1
In contrast , we found no evidence of IRF3 phosphorylation after LPS or MPLA exposure , suggesting that TLR4 does not significantly activate TRIF dependent mechanisms in endothelial cells .	In contrast, we found no evidence of IRF3 phosphorylation after LPS or MPLA exposure, suggesting that TLR4 does not significantly activate TRIF dependent mechanisms in endothelial cells.	18	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	18	19	23	24
We also compared induction of IFN-beta in wild-type and tlr4 -/- PEM infected with EGDe or DeltapgdA strains , as TLR4 can mediate TRIF dependent synthesis of IFN-beta .	We also compared induction of IFN-beta in wild-type and tlr4 -/- PEM infected with EGDe or DeltapgdA strains, as TLR4 can mediate TRIF dependent synthesis of IFN-beta.	20	25	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	20	21	23	24
TLR4 also activates TRIF signaling in endosome after relocation from the plasma membrane .	TLR4 also activates TRIF signaling in endosome after relocation from the plasma membrane.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	0	1	3	4
In the TRIF dependent pathway TLR4 may signal via TRIF related adaptor molecule ( TRAM ) and TRIF which activates TBK1 ( TANK Binding Kinase-1 ) eventually activating interferon-regulatory factor-3 ( IRF3 ) .	In the TRIF dependent pathway TLR4 may signal via TRIF related adaptor molecule (TRAM) and TRIF which activates TBK1 (TANK Binding Kinase-1) eventually activating interferon-regulatory factor-3 (IRF3).	3	19	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	5	6	17	18
XREF_BIBR , XREF_BIBR - XREF_BIBR In contrast , the TRIF dependent pathway is activated by TLR3 and TLR4 , and leads to production of type I interferons associated with viral infection .	XREF_BIBR, XREF_BIBR - XREF_BIBR In contrast, the TRIF dependent pathway is activated by TLR3 and TLR4, and leads to production of type I interferons associated with viral infection.	9	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	17	18	9	10
It is unclear whether the actions of YopJ or any other Yersinia effector influences the TRIF pathway induced by TLR4 .	It is unclear whether the actions of YopJ or any other Yersinia effector influences the TRIF pathway induced by TLR4.	15	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	19	20	15	16
TLR3 and TLR4 induce the TRIF dependent pathway XREF_BIBR , XREF_BIBR .	TLR3 and TLR4 induce the TRIF dependent pathway XREF_BIBR, XREF_BIBR.	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	2	3	5	6
The TRIF dependent pathway is activated by TLR3 and TLR4 .	The TRIF dependent pathway is activated by TLR3 and TLR4.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	9	10	1	2
As mentioned above , TLR3 and TLR4 are able to activate the signaling adaptor TRIF , inducing IRF3 phosphorylation , translocation and the transcription of type I IFN genes .	As mentioned above, TLR3 and TLR4 are able to activate the signaling adaptor TRIF, inducing IRF3 phosphorylation, translocation and the transcription of type I IFN genes.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	6	7	14	15
Alternatively , TLR4 signaling can activate the TRIF pathway that acts through interferon ( IFN ) regulatory factor 3 to promote the production of type I IFN ( IFN alpha/beta ) , IFN inducible gene products and an immune regulatory response [ XREF_BIBR ] .	Alternatively, TLR4 signaling can activate the TRIF pathway that acts through interferon (IFN) regulatory factor 3 to promote the production of type I IFN (IFN alpha/beta), IFN inducible gene products and an immune regulatory response [XREF_BIBR].	2	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	2	3	7	8
For the adjuvant component , they compared monophosphoryl lipid A ( MPL ) , a TLR4 ligand that has been reported to stimulate the Trif pathway well but the MyD88 pathway poorly , either alone or together with a synthetic TLR7 ligand ( R837 ) .	For the adjuvant component, they compared monophosphoryl lipid A (MPL), a TLR4 ligand that has been reported to stimulate the Trif pathway well but the MyD88 pathway poorly, either alone or together with a synthetic TLR7 ligand (R837).	15	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Trif	Trif	Trif	15	16	24	25
Thus , TLR mediated type I IFN production is mediated by the TLR3 and TLR4 mediated TRIF dependent or the TLR7 and TLR9 mediated MyD88 dependent pathways [ XREF_BIBR ] .	Thus, TLR mediated type I IFN production is mediated by the TLR3 and TLR4 mediated TRIF dependent or the TLR7 and TLR9 mediated MyD88 dependent pathways [XREF_BIBR].	9	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	14	15	16	17
Endocytosis of plasma membrane localized TLRs downregulates the MyD88 signaling pathway whereas TLR4 delivery to endosomes upregulates the TRIF signaling pathway .	Endocytosis of plasma membrane localized TLRs downregulates the MyD88 signaling pathway whereas TLR4 delivery to endosomes upregulates the TRIF signaling pathway.	12	20	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	12	13	18	19
The central dogma in the field is that TLR4 activates both the MyD88 and non MyD88 ( TRIF ) pathways and TLR3 activates only the TRIF pathway .	The central dogma in the field is that TLR4 activates both the MyD88 and non MyD88 (TRIF) pathways and TLR3 activates only the TRIF pathway.	8	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	8	9	25	26
In comparison , TRIF transcription was unaltered by LPS exposure , reaffirming a diminished role of TLR4 mediated TRIF activation in endothelial cells .	In comparison, TRIF transcription was unaltered by LPS exposure, reaffirming a diminished role of TLR4 mediated TRIF activation in endothelial cells.	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	16	17	18	19
Since TLR3 activation stimulates TRIF and TICAM-1 , but not Myd88 , these results were consistent with the notion that TLR4 does not activate TRIF and TICAM in HDMECs , but mediates a modest effect on ICAM-1 expression likely through MyD88 .	Since TLR3 activation stimulates TRIF/TICAM-1, but not Myd88, these results were consistent with the notion that TLR4 does not activate TRIF and TICAM in HDMECs, but mediates a modest effect on ICAM-1 expression likely through MyD88.	20	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	20	21	24	25
Downstream of TLR3 and TLR4 signaling , TRIM38 also targets TRIF and NAP1 for degradation [ XREF_BIBR , XREF_BIBR ] .	Downstream of TLR3 and TLR4 signaling, TRIM38 also targets TRIF and NAP1 for degradation [XREF_BIBR, XREF_BIBR].	2	18	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	4	5	10	11
However , it could very well be that MyD88 independent , yet TLR dependent , pathways , such as TLR4 mediated TRIF signaling , are involved in recognition of the polysaccharides and these issues are currently under study .	However, it could very well be that MyD88 independent, yet TLR dependent, pathways, such as TLR4 mediated TRIF signaling, are involved in recognition of the polysaccharides and these issues are currently under study.	15	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	19	20	21	22
XREF_BIBR , XREF_BIBR In the absence of these proinflammatory signals , TLR4 induced TRIF and other proapoptotic pathways cause the macrophage to die via caspase-3-dependent apoptosis without initiating an appropriate immune response .	XREF_BIBR, XREF_BIBR In the absence of these proinflammatory signals, TLR4 induced TRIF and other proapoptotic pathways cause the macrophage to die via caspase-3-dependent apoptosis without initiating an appropriate immune response.	11	18	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	11	12	13	14
Vascular endothelial cells lack expression of TRAM and therefore , LPS stimulation of TLR4 does not activate TICAM-1 [ XREF_BIBR ] .	Vascular endothelial cells lack expression of TRAM and therefore, LPS stimulation of TLR4 does not activate TICAM-1 [XREF_BIBR].	11	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TICAM-1	TICAM-1	TICAM-1	13	14	17	18
Because we found that TLR3 deletion did not reduce lesion burden , we conclude that TRIF signaling through another receptor , most likely TLR4 mediates TRIF ' s atherogenic activity in hyperlipidemic LDLr-/- mice .	Because we found that TLR3 deletion did not reduce lesion burden, we conclude that TRIF signaling through another receptor, most likely TLR4 mediates TRIF 's atherogenic activity in hyperlipidemic LDLr-/- mice.	19	26	mediates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	23	24	25	26
Studies suggest that TLR4 activates TRIF signaling from the endosome rather than the cell membrane .	Studies suggest that TLR4 activates TRIF signaling from the endosome rather than the cell membrane.	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	3	4	5	6
These results suggest that LPS-liposomes activate the TLR4 mediated TRIF dependent pathway independent of CD14 .	These results suggest that LPS-liposomes activate the TLR4 mediated TRIF dependent pathway independent of CD14.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	7	8	9	10
In contrast , TLR4 stimulation in TRIF lps and lps mice caused only weak upregulation of CD86 in the first 6 h that dropped to levels comparable to unstimulated DCs thereafter .	In contrast, TLR4 stimulation in TRIF lps and lps mice caused only weak upregulation of CD86 in the first 6 h that dropped to levels comparable to unstimulated DCs thereafter.	3	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	3	4	6	7
The MyD88 dependent pathway , typically activated via TLR1 ,2,4,5 or 6 ligands is required for IL-12p40 gene expression , whereas TRIF dependent signaling , typically activated by TLR4 ligands appears critical for IRF-3-dependent IL-12p35 gene expression [ XREF_BIBR ] and also for the activation of an autocrine loop in which type I IFN production facilitates the generation of IL-12p35 [ XREF_BIBR ] .	The MyD88 dependent pathway, typically activated via TLR1,2,4,5 or 6 ligands is required for IL-12p40 gene expression, whereas TRIF dependent signaling, typically activated by TLR4 ligands appears critical for IRF-3-dependent IL-12p35 gene expression [XREF_BIBR] and also for the activation of an autocrine loop in which type I IFN production facilitates the generation of IL-12p35 [XREF_BIBR].	21	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	28	29	21	22
For this induction , TLR3 and TLR4 activate the signaling adaptor TRIF , inducing phosphorylation and translocation of IRF3 , while TLR7 and TLR9 use a pathway that involves the transcription factor IRF7 and takes place downstream of the MyD88 signaling pathway XREF_BIBR , XREF_BIBR .	For this induction, TLR3 and TLR4 activate the signaling adaptor TRIF, inducing phosphorylation and translocation of IRF3, while TLR7 and TLR9 use a pathway that involves the transcription factor IRF7 and takes place downstream of the MyD88 signaling pathway XREF_BIBR, XREF_BIBR.	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	6	7	11	12
TLR4 has also been shown to activate only the TRIF and TRAM dependent pathway downstream of the vesicular stomatitis virus glycoprotein G.	TLR4 has also been shown to activate only the TRIF and TRAM dependent pathway downstream of the vesicular stomatitis virus glycoprotein G.	0	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	0	1	9	10
Thus , TLR4 mediated TRIF signaling modulates synergistic cell death through an IRF3 independent mechanism .	Thus, TLR4 mediated TRIF signaling modulates synergistic cell death through an IRF3 independent mechanism.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	2	3	4	5
TLR4 engages two distinct adaptor proteins : MyD88 which is recruited by TIRAP and elicits the production of proinflammatory cytokinesand TRIF which is recruited by the adaptor TRAM and activates the production of type 1 interferon as well as proinflammatory cytokines .	TLR4 engages two distinct adaptor proteins : MyD88 which is recruited by TIRAP and elicits the production of proinflammatory cytokinesand TRIF which is recruited by the adaptor TRAM and activates the production of type 1 interferon as well as proinflammatory cytokines.	0	21	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	0	1	20	21
To discern whether p120 expression regulates the TLR4 triggered TRIF pathway , we examined LPS induced recruitment of TRIF to TLR4 and subsequent activation of the TRIF-IRF3-IFN-beta signaling axis .	To discern whether p120 expression regulates the TLR4 triggered TRIF pathway, we examined LPS induced recruitment of TRIF to TLR4 and subsequent activation of the TRIF-IRF3-IFN-beta signaling axis.	6	10	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	7	8	9	10
These results indicate that dLOS induced TLR4 activation triggers MyD88- and TRIF dependent signaling pathways , though much lower in activity when compared with LPS .	These results indicate that dLOS induced TLR4 activation triggers MyD88- and TRIF dependent signaling pathways, though much lower in activity when compared with LPS.	6	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	6	7	11	12
Since major toxicity caused by TLR4 stimulation involves MyD88 dependent induction of multiple pro inflammatory cytokines , the TLR4 agonist has been specifically designed to induce TRIF signaling ( CRX-675 and CRX-547 , and monohosphoryl lipid A : MPL ) , which has shown to induce strong resistance against viral and bacterial infections .	Since major toxicity caused by TLR4 stimulation involves MyD88 dependent induction of multiple pro inflammatory cytokines, the TLR4 agonist has been specifically designed to induce TRIF signaling (CRX-675 and CRX-547, and monohosphoryl lipid A : MPL), which has shown to induce strong resistance against viral and bacterial infections.	18	27	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	18	19	26	27
These data therefore provide definitive proof that the receptor itself ( TLR4 ) must be delivered to endosomes in order to initiate TRIF signaling .	These data therefore provide definitive proof that the receptor itself (TLR4) must be delivered to endosomes in order to initiate TRIF signaling.	8	23	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	11	12	22	23
It has been demonstrated that TLR4 activation by TRIF dependent signaling pathway is delayed in comparison to the MyD88 dependent signaling , which has been proposed to be restricted to the plasma membrane while the internalized TLR4 activates TRIF dependent signaling from early endosomes [ XREF_BIBR ] .	It has been demonstrated that TLR4 activation by TRIF dependent signaling pathway is delayed in comparison to the MyD88 dependent signaling, which has been proposed to be restricted to the plasma membrane while the internalized TLR4 activates TRIF dependent signaling from early endosomes [XREF_BIBR].	34	40	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	36	37	38	39
Studies are underway to determine whether TRIF and TRAM activation by TLR4 required for increased IL-1beta-induced transcription of COX-2 involves post-translational modifications of NF-kappaB , or is required for sustained NF-kappaB activation XREF_BIBR or recruitment of other DNA binding proteins such as CREB binding protein ( CBP ) co-activator that has been shown to associate with IRF3 and play a critical role in transcription of COX-2 XREF_BIBR .	Studies are underway to determine whether TRIF and TRAM activation by TLR4 required for increased IL-1beta-induced transcription of COX-2 involves post-translational modifications of NF-kappaB, or is required for sustained NF-kappaB activation XREF_BIBR or recruitment of other DNA binding proteins such as CREB binding protein (CBP) co-activator that has been shown to associate with IRF3 and play a critical role in transcription of COX-2 XREF_BIBR.	6	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	11	12	6	7
An unexpected finding was the exaggerated effect of IT TLR4 ligand signaling in the Trif lps2 and Ifnar1 -/- mice .	An unexpected finding was the exaggerated effect of IT TLR4 ligand signaling in the Trif lps2 and Ifnar1 -/- mice.	9	15	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Trif	Trif	Trif	9	10	14	15
Our results highlight an immunological model in which TLR4 mediated TRIF activation leads to the rapid induction of IFN-beta by macrophages , and IFN-beta in turn promotes IFN-gamma production by NK cells that then feed back on the macrophages , enhancing their bactericidal activity .	Our results highlight an immunological model in which TLR4 mediated TRIF activation leads to the rapid induction of IFN-beta by macrophages, and IFN-beta in turn promotes IFN-gamma production by NK cells that then feed back on the macrophages, enhancing their bactericidal activity.	8	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	8	9	10	11
In PTX sensitive , MyD88 neg A2780 cells , TLR4 stimulation upregulated TRIF , and TLR4 silencing eliminated this effect .	In PTX sensitive, MyD88 neg A2780 cells, TLR4 stimulation upregulated TRIF, and TLR4 silencing eliminated this effect.	9	13	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	9	10	12	13
TLR4 activation of the TRIF / IRF3 pathway leads to STAT1 phosphorylation and subsequent inflammatory gene expression such as expression of IP-10 .	TLR4 activation of the TRIF / IRF3 pathway leads to STAT1 phosphorylation and subsequent inflammatory gene expression such as expression of IP-10.	0	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	0	1	4	5
TLR4 activates not only TRIF but also TRAM ( also called TICAM2 ) , its closest protein homologue , and an adapter protein that exists only to serve TLR4 signaling .	TLR4 activates not only TRIF but also TRAM (also called TICAM2), its closest protein homologue, and an adapter protein that exists only to serve TLR4 signaling.	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	0	1	4	5
These results highlight an important role of IFN-beta induction by TLR4 mediated TRIF activation to elicit macrophage bactericidal activity during Y. enterocolitica infection .	These results highlight an important role of IFN-beta induction by TLR4 mediated TRIF activation to elicit macrophage bactericidal activity during Y. enterocolitica infection.	2	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	10	11	12	13
In addition to activating NF-kappaB signaling , TLR3- and TLR4 induced activation of TRIF also causes IRF3 phosphorylation , which in turn leads to its dimerization , nuclear translocation , and stimulation of IFN-alpha and beta gene transcription .	In addition to activating NF-kappaB signaling, TLR3- and TLR4 induced activation of TRIF also causes IRF3 phosphorylation, which in turn leads to its dimerization, nuclear translocation, and stimulation of IFN-alpha and beta gene transcription.	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	9	10	13	14
Moreover , melatonin significantly attenuated the elevation of interferon ( IFN )-regulated factor-3 ( IRF3 ) , which was involved in TLR4 mediated TRIF dependent signaling pathway , in LPS stimulated macrophages .	Moreover, melatonin significantly attenuated the elevation of interferon (IFN)-regulated factor-3 (IRF3), which was involved in TLR4 mediated TRIF dependent signaling pathway, in LPS stimulated macrophages.	19	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	21	22	23	24
In addition , TLR3 and TLR4 activate TRIF ( toll/IL -1 receptor homology domain containing adaptor inducing interferon beta ) signaling , inducing interferon regulatory factors ( IRFs ) .	In addition, TLR3 and TLR4 activate TRIF (toll/IL -1 receptor homology domain containing adaptor inducing interferon beta) signaling, inducing interferon regulatory factors (IRFs).	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	5	6	7	8
In the non Myd88 dependent pathway , TLR4 triggers the activation of the TRIF related adaptor molecule ( TRAM ) , followed by the activation of interferon regulatory factor 3 , which induces the production of IFN-gamma .	In the non Myd88 dependent pathway, TLR4 triggers the activation of the TRIF related adaptor molecule (TRAM), followed by the activation of interferon regulatory factor 3, which induces the production of IFN-gamma.	7	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	7	8	13	14
Activation of TLR4 triggers two different signaling pathways controlled respectively by MyD88 and MAL , which is critical for regulating proinflammatory cytokines production , and TRIF and TRAM , which is responsible for mediating the induction of Type I interferons [ XREF_BIBR , XREF_BIBR ] .	Activation of TLR4 triggers two different signaling pathways controlled respectively by MyD88 and MAL, which is critical for regulating proinflammatory cytokines production, and TRIF and TRAM, which is responsible for mediating the induction of Type I interferons [XREF_BIBR, XREF_BIBR].	0	31	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	2	3	25	26
Recent data from overexpression studies have suggested that TLR4 mediated TRIF and IRF3 signaling occurs at early endosomes , whereas our study ' s use of macrophages and dendritic cells points to a later endosomal/lysosomal compartment .	Recent data from overexpression studies have suggested that TLR4 mediated TRIF and IRF3 signaling occurs at early endosomes, whereas our study 's use of macrophages and dendritic cells points to a later endosomal/lysosomal compartment.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	8	9	10	11
Additionally , our data highlights the relative insignificance of TLR4 mediated TRIF activation previously suggested in endothelial cells [ XREF_BIBR ] .	Additionally, our data highlights the relative insignificance of TLR4 mediated TRIF activation previously suggested in endothelial cells [XREF_BIBR].	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	9	10	11	12
TLR4 signals through MyD88 at the cell surface and , after internalization to the early endosome , activates Trif dependent pathways that are linked to the type I interferons ( IFNs ) 48 .	TLR4 signals through MyD88 at the cell surface and, after internalization to the early endosome, activates Trif dependent pathways that are linked to the type I interferons (IFNs) 48.	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Trif	Trif	Trif	0	1	18	19
Isoacteoside blocked TLR4 dimerization , which activates the MyD88-TAK1-NF-kappaB and MAPK signalling cascades and TRIF pathway .	Isoacteoside blocked TLR4 dimerization, which activates the MyD88-TAK1-NF-kappaB and MAPK signalling cascades and TRIF pathway.	2	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	2	3	14	15
Activation of TLR4 signalling triggers two divergent inflammatory cascades , the MyD88 pathway , which leads to NF-kappaB activation , and the TRIF pathway [ XREF_BIBR ] .	Activation of TLR4 signalling triggers two divergent inflammatory cascades, the MyD88 pathway, which leads to NF-kappaB activation, and the TRIF pathway [XREF_BIBR].	2	23	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	2	3	22	23
In the TRIF dependent pathway triggered by TLR3 and TLR4 , TRIF recruits TRAF3 , TAB1 , and IKK and activates the type I IFN .	In the TRIF dependent pathway triggered by TLR3 and TLR4, TRIF recruits TRAF3, TAB1, and IKK and activates the type I IFN.	2	10	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	9	10	2	3
TLR4 also activates the TRIF and TRAM pathway in response to selected ligands .	TLR4 also activates the TRIF and TRAM pathway in response to selected ligands.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	0	1	4	5
TLR3 and TLR4 can activate the TRIF dependent pathway , which leads to the production of type I interferons ( IFNs ) against viral infection .	TLR3 and TLR4 can activate the TRIF dependent pathway, which leads to the production of type I interferons (IFNs) against viral infection.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	2	3	6	7
Although the mechanism has not yet been elucidated , the difference in cardiac function and survival/HF between TLR3- and TRIF deficient mice suggests that TLR4 mediated TRIF may be responsible for reducing the negative cardiac effects of IL-33 in the heart during acute CVB3 myocarditis .	Although the mechanism has not yet been elucidated, the difference in cardiac function and survival/HF between TLR3- and TRIF deficient mice suggests that TLR4 mediated TRIF may be responsible for reducing the negative cardiac effects of IL-33 in the heart during acute CVB3 myocarditis.	24	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	24	25	26	27
XREF_BIBR , XREF_BIBR TLR4 can also signal through a MyD88 independent pathway by recruiting the adaptor proteins TRAM ( TRIF related adaptor molecule ) and TRIF ( TIR-domain-containing adaptor inducing interferon-beta ) to the receptor complex ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR TLR4 can also signal through a MyD88 independent pathway by recruiting the adaptor proteins TRAM (TRIF related adaptor molecule) and TRIF (TIR-domain-containing adaptor inducing interferon-beta) to the receptor complex (XREF_FIG).	0	28	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	3	4	25	26
On the other hand , TLR3 and TLR4 initiate a TRIF dependent pathway to induce inflammatory cytokines and type I IFN signaling .	On the other hand, TLR3 and TLR4 initiate a TRIF dependent pathway to induce inflammatory cytokines and type I IFN signaling.	5	12	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	7	8	10	11
These results suggest that TLR4 activates TRIF signaling in endosome and lysosome after relocation from the cell surface .	These results suggest that TLR4 activates TRIF signaling in endosome and lysosome after relocation from the cell surface.	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	4	5	6	7
Although deficiency in TRAF3 has resulted in severe abnormalities in TRIF mediated type I IFN production as well as IL-10 production , it is largely normal in TRAF6 deficient cells , suggesting that TRAF3 rather than TRAF6 plays the critical role in the TLR3 and TLR4 mediated TRIF dependent pathway [ XREF_BIBR , XREF_BIBR ] .	Although deficiency in TRAF3 has resulted in severe abnormalities in TRIF mediated type I IFN production as well as IL-10 production, it is largely normal in TRAF6 deficient cells, suggesting that TRAF3 rather than TRAF6 plays the critical role in the TLR3 and TLR4 mediated TRIF dependent pathway [XREF_BIBR, XREF_BIBR].	40	48	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	45	46	47	48
The D299G polymorphism inhibits TLR4 mediated activation of the TRIF pathway .	The D299G polymorphism inhibits TLR4 mediated activation of the TRIF pathway.	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	4	5	9	10
TLR4 can also activate the TRIF dependent pathway from late endosomes following phagocytosis .	TLR4 can also activate the TRIF dependent pathway from late endosomes following phagocytosis.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	0	1	5	6
Surprisingly , deficiencies in Toll/IL -1 receptor domain containing adapter inducing interferon beta ( TRIF , the intracellular adaptor molecule for TLR4 ) and in TLR4 itself also resulted in significantly less intraocular inflammation during experimental B. cereus endophthalmitis , suggesting that MyD88 independent pathways were involved in the intraocular response to B. cereus and that B. cereus may harbor ligands for TLR4 which instigate intraocular inflammation .	Surprisingly, deficiencies in Toll/IL -1 receptor domain containing adapter inducing interferon beta (TRIF, the intracellular adaptor molecule for TLR4) and in TLR4 itself also resulted in significantly less intraocular inflammation during experimental B. cereus endophthalmitis, suggesting that MyD88 independent pathways were involved in the intraocular response to B. cereus and that B. cereus may harbor ligands for TLR4 which instigate intraocular inflammation.	10	28	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	25	26	14	15
As described above , TLR4 initiates a TRIF dependent pathway from endosomes through the sorting adaptor TRAM .	As described above, TLR4 initiates a TRIF dependent pathway from endosomes through the sorting adaptor TRAM.	4	9	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	4	5	7	8
We also studied mRNA expression of the key molecules in two additional pathways : 1 ) the TLR4 mediated TRIF dependent pathway focusing on TRIF , TRAM , IRF-3 , and IFN-beta ; and 2 ) the MyD88 dependent pathway focusing on MyD88 , NF-kappaB and IL-1beta .	We also studied mRNA expression of the key molecules in two additional pathways : 1) the TLR4 mediated TRIF dependent pathway focusing on TRIF, TRAM, IRF-3, and IFN-beta; and 2) the MyD88 dependent pathway focusing on MyD88, NF-kappaB and IL-1beta.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	17	18	19	20
TLR4 mediated downregulation of Bambi expression requires the activation of NF-kappaB and partially JNK through MyD88 , but not TRIF , in HSCs .	TLR4 mediated downregulation of Bambi expression requires the activation of NF-kappaB and partially JNK through MyD88, but not TRIF, in HSCs.	0	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	0	1	19	20
In contrast , our results indicate that TLR4 mediated TRIF signaling is critical in papain induced T H 2 responses .	In contrast, our results indicate that TLR4 mediated TRIF signaling is critical in papain induced T H 2 responses.	7	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	7	8	9	10
Our previous study demonstrated that maltose binding protein ( MBP ) activated Th1 through the TLR2 mediated MyD88 dependent pathway and the TLR4 mediated TRIF dependent pathway .	Our previous study demonstrated that maltose binding protein (MBP) activated Th1 through the TLR2 mediated MyD88 dependent pathway and the TLR4 mediated TRIF dependent pathway.	19	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	22	23	24	25
The Trif dependent pathway can be activated by TLR3 and TLR4 .	The Trif dependent pathway can be activated by TLR3 and TLR4.	1	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Trif	Trif	Trif	10	11	1	2
On the other hand , TLR3- and TLR4 mediated TRIF dependent pathways control IRF3 mediated IFNbeta production .	On the other hand, TLR3- and TLR4 mediated TRIF dependent pathways control IRF3 mediated IFNbeta production.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	7	8	9	10
In this case , IFN-beta was likely not induced to sufficient levels during in vivo infection , perhaps because B. thailandensis LPS is a somewhat weak TLR4 agonist , or because B. thailandensis escapes the vacuole before vacuolar TLR4 can activate TRIF .	In this case, IFN-beta was likely not induced to sufficient levels during in vivo infection, perhaps because B. thailandensis LPS is a somewhat weak TLR4 agonist, or because B. thailandensis escapes the vacuole before vacuolar TLR4 can activate TRIF.	37	42	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	38	39	41	42
The Trif dependent pathway can be activated by TLR3 and TLR4 , which activates interferon regulatory factor ( IRF ) 3 and NF-kappaB , and consequently induces the production of type I interferon and inflammatory cytokines 2 .	The Trif dependent pathway can be activated by TLR3 and TLR4, which activates interferon regulatory factor (IRF) 3 and NF-kappaB, and consequently induces the production of type I interferon and inflammatory cytokines 2.	1	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Trif	Trif	Trif	10	11	1	2
These results indicate that DGLHD appears to exert its anti-inflammatory and antidiabetic actions at least in part by inhibiting the JAK2-STAT3 pathway , but not by affecting either TLR4 mediated TRIF dependent or MyD88 dependent pathways .	These results indicate that DGLHD appears to exert its anti-inflammatory and antidiabetic actions at least in part by inhibiting the JAK2-STAT3 pathway, but not by affecting either TLR4 mediated TRIF dependent or MyD88 dependent pathways.	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	28	29	30	31
In addition to triggering MyD88 dependent signaling , TLR4 elicits TRIF dependent signaling .	In addition to triggering MyD88 dependent signaling, TLR4 elicits TRIF dependent signaling.	8	12	elicits	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	8	9	10	11
It is noteworthy that TLR4 also signals through the TRIF dependent pathway and is highly microglial , so perhaps TLR3 signaling is predominant in astrocytes , while TLR4 induced TRIF dependent signaling dominates in microglia , leading to the increased Ifnb , Ccl5 , and Cxcl10 seen in the CD11b+ fraction .	It is noteworthy that TLR4 also signals through the TRIF dependent pathway and is highly microglial, so perhaps TLR3 signaling is predominant in astrocytes, while TLR4 induced TRIF dependent signaling dominates in microglia, leading to the increased Ifnb, Ccl5, and Cxcl10 seen in the CD11b+ fraction.	27	32	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	27	28	29	30
TRIF deficient mice also develop a Th2 biased response with high production of IL-33 [ XREF_BIBR ] , which is nonetheless different from the response in TLR3 deficient mice , indicating that TLR3 acts together with TLR4 , the other TLR that activates TRIF signaling , in the impairment of CVB3 induced disease .	TRIF deficient mice also develop a Th2 biased response with high production of IL-33 [XREF_BIBR], which is nonetheless different from the response in TLR3 deficient mice, indicating that TLR3 acts together with TLR4, the other TLR that activates TRIF signaling, in the impairment of CVB3 induced disease.	33	44	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	36	37	43	44
Together , our data suggest that Lyst is specifically involved in TLR3- and TLR4 induced production of proinflammatory cytokines by regulating the endosomal TRIF and IRF3 signaling pathway .	Together, our data suggest that Lyst is specifically involved in TLR3- and TLR4 induced production of proinflammatory cytokines by regulating the endosomal TRIF and IRF3 signaling pathway.	13	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	13	14	23	24
TLR4 can activate TRIF dependent pathways without MyD88 association , leading to activation of the transcription factor IRF3 , in turn producing interferon and costimulatory molecules .	TLR4 can activate TRIF dependent pathways without MyD88 association, leading to activation of the transcription factor IRF3, in turn producing interferon and costimulatory molecules.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	0	1	3	4
Shortly , following endocytosis of the ligand-receptor complexes TLR4 initiates the second signal pathway TRIF --> IRF .	Shortly, following endocytosis of the ligand-receptor complexes TLR4 initiates the second signal pathway TRIF --> IRF.	3	16	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	8	9	14	15
Our mechanistic analysis of the stages of TLR4 signaling revealed that YopJ does not interfere with any TLR4 dependent activities that specifically promote TRIF signaling , such as TLR4 endocytosis , TBK1 phosphorylation , or IRF3 activation .	Our mechanistic analysis of the stages of TLR4 signaling revealed that YopJ does not interfere with any TLR4 dependent activities that specifically promote TRIF signaling, such as TLR4 endocytosis, TBK1 phosphorylation, or IRF3 activation.	23	33	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	TLR4	TLR4 endocytosis, TBK1 phosphorylation	tlr4	TRIF	TRIF	trif	28	29	23	24
Consistent with this idea , it was shown that TRIF signaling by TLR4 in endosomes requires CD14 mediated internalization of TLR4 from the cell surface , whereas TRIF signaling from E. coli containing phagosomes is CD14 independent .	Consistent with this idea, it was shown that TRIF signaling by TLR4 in endosomes requires CD14 mediated internalization of TLR4 from the cell surface, whereas TRIF signaling from E. coli containing phagosomes is CD14 independent.	9	14	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	12	13	9	10
In conclusion , the data described in this study demonstrate that TLR3 and TLR4 stimulation induces a TRIF dependent signaling pathway that leads to the caspase-1-independent maturation of pro-IL-1beta .	In conclusion, the data described in this study demonstrate that TLR3 and TLR4 stimulation induces a TRIF dependent signaling pathway that leads to the caspase-1-independent maturation of pro-IL-1beta.	11	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	13	14	17	18
All TLRs , except for TLR3 , activate the MyD88 dependent pathway , whereas TLR3 and TLR4 activate the TRIF dependent pathway .	All TLRs, except for TLR3, activate the MyD88 dependent pathway, whereas TLR3 and TLR4 activate the TRIF dependent pathway.	14	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	16	17	19	20
TRAM was shown to be involved in the TLR4 mediated TRIF signaling pathway in the innate immune response to LPS .	TRAM was shown to be involved in the TLR4 mediated TRIF signaling pathway in the innate immune response to LPS.	5	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	8	9	10	11
TRAM is specifically involved in the TLR4 mediated TRIF dependent pathway .	TRAM is specifically involved in the TLR4 mediated TRIF dependent pathway.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	6	7	8	9
The other pathway is activated only by TLR3 and TLR4 and is referred to as the MyD88 independent or TRIF dependent pathway .	The other pathway is activated only by TLR3 and TLR4 and is referred to as the MyD88 independent or TRIF dependent pathway.	4	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	9	10	19	20
As TLR4 activates autophagy by using the TRIF dependent pathway , and TLR3 also activates the TRIF pathway , this supports the possibility that a TLR3 ligand induces autophagy on TLR3 activation .	As TLR4 activates autophagy by using the TRIF dependent pathway, and TLR3 also activates the TRIF pathway, this supports the possibility that a TLR3 ligand induces autophagy on TLR3 activation.	1	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	1	2	7	8
Collectively , the identification of Lyst as a specific regulator of TLR3- and TLR4 mediated TRIF signaling pathways reveals how the regulation of the intracellular membrane trafficking network is functionally linked to specific TLR signaling pathways .	Collectively, the identification of Lyst as a specific regulator of TLR3- and TLR4 mediated TRIF signaling pathways reveals how the regulation of the intracellular membrane trafficking network is functionally linked to specific TLR signaling pathways.	9	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	13	14	15	16
Moreover , LPS induced signaling pathways activated by TLR4 , Myeloid differentiation factor 88 , ( MyD88 ) and primarily TIR-domain-containing adapter inducing interferon-beta ( TRIF and TRAM ) were altered in LMP7 and LMP10 subunit deficient macrophages ( obtained from knockout mice ) such that TNF-alpha was not affected , but NO , IL-1 , IL-12 and IL-6 ( TRIF and TRAM pathway ) were not induced robustly with LPS ; but IFN-gamma treatment prior to LPS reversed this defect and these cells behaved normally with respect to NO induction .	Moreover, LPS induced signaling pathways activated by TLR4, Myeloid differentiation factor 88, (MyD88) and primarily TIR-domain-containing adapter inducing interferon-beta (TRIF and TRAM) were altered in LMP7 and LMP10 subunit deficient macrophages (obtained from knockout mice) such that TNF-alpha was not affected, but NO, IL-1, IL-12 and IL-6 (TRIF and TRAM pathway) were not induced robustly with LPS; but IFN-gamma treatment prior to LPS reversed this defect and these cells behaved normally with respect to NO induction.	6	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	8	9	25	26
It has been shown that dendritic cell apoptosis is controlled by the TLR4 mediated TRIF dependent signaling pathway [ XREF_BIBR ] and that Type-1 interferons are necessary and sufficient for the induction of apoptosis for dendritic cells [ XREF_BIBR ] .	It has been shown that dendritic cell apoptosis is controlled by the TLR4 mediated TRIF dependent signaling pathway [XREF_BIBR] and that Type-1 interferons are necessary and sufficient for the induction of apoptosis for dendritic cells [XREF_BIBR].	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	12	13	14	15
In contrast , the TRIF dependent pathway is activated by the formation of a complex between TRIF , TRIF related adaptor molecule ( TRAM or TICAM2 ) and TLR4 XREF_BIBR .	In contrast, the TRIF dependent pathway is activated by the formation of a complex between TRIF, TRIF related adaptor molecule (TRAM or TICAM2) and TLR4 XREF_BIBR.	4	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	28	29	4	5
Upon activation by LPS , TLR4 undergoes CD14 dependent endocytosis to initiate the TRIF signaling pathway .	Upon activation by LPS, TLR4 undergoes CD14 dependent endocytosis to initiate the TRIF signaling pathway.	5	15	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	5	6	13	14
For example , TLR3 and TLR4 induce macrophage necrosis requires the action of RIPK3 and TRIF .	For example, TLR3 and TLR4 induce macrophage necrosis requires the action of RIPK3 and TRIF.	3	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	5	6	15	16
TLR4 also initiates TRIF dependent immune signaling from the endosomal membrane .	TLR4 also initiates TRIF dependent immune signaling from the endosomal membrane.	0	6	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	0	1	3	4
The TRIF dependent pathway is triggered by the endosomal TLR3 and TLR4 , which culminate in the activation of both NF-kappaB and IRFs ( XREF_FIG ) .	The TRIF dependent pathway is triggered by the endosomal TLR3 and TLR4, which culminate in the activation of both NF-kappaB and IRFs (XREF_FIG).	1	14	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	11	12	1	2
Activation of TLR4 also triggers signal transduction for the induction of type I interferon by recruiting TRAM and TRIF , which leads to the activation of IRF-3 and NF-kappaB [ XREF_BIBR , XREF_BIBR ] .	Activation of TLR4 also triggers signal transduction for the induction of type I interferon by recruiting TRAM and TRIF, which leads to the activation of IRF-3 and NF-kappaB [XREF_BIBR, XREF_BIBR].	0	21	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	2	3	18	19
Instead , the data revealed a regulatory function of Lyst that was restricted to only a specific subset of TLR pathways , namely endolysosomal TLR3- and TLR4 induced TRIF and IRF3 signaling pathways .	Instead, the data revealed a regulatory function of Lyst that was restricted to only a specific subset of TLR pathways, namely endolysosomal TLR3- and TLR4 induced TRIF and IRF3 signaling pathways.	24	32	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	26	27	28	29
We found that TLR3 agonist poly ( I : C ) and TLR4 agonist LPS induced secretion of several pro inflammatory cytokines in a TLR dependent manner which required the TLR signaling adaptor molecule TRIF .	We found that TLR3 agonist poly (I : C) and TLR4 agonist LPS induced secretion of several pro inflammatory cytokines in a TLR dependent manner which required the TLR signaling adaptor molecule TRIF.	12	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	12	13	34	35
TLR4 induction may be caused by an influx of macrophages as well as TLR4 expressing intrinsic renal cells .	TLR4 induction may be caused by an influx of macrophages as well as TLR4 expressing intrinsic renal cells.	0	15	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4 expressing	tlr4	TLR4	TLR4	tlr4	13	14	0	1
Prx1 could increase the expression of TLR4 and activate TLR4 and NF-kappaB signaling pathway [ XREF_BIBR ] .	Prx1 could increase the expression of TLR4 and activate TLR4 and NF-kappaB signaling pathway [XREF_BIBR].	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	Prx1 could increase the expression of TLR4	tlr4	TLR4	TLR4	tlr4	6	7	9	10
Consistent with other studies XREF_BIBR , XREF_BIBR , XREF_BIBR , our study showed that Rab26 silencing with siRab26-DYM in LPS stimulated cells increased the surface levels of TLR4 and subsequently activated TLR4 signal pathway in primary HPMVECs .	Consistent with other studies XREF_BIBR, XREF_BIBR, XREF_BIBR, our study showed that Rab26 silencing with siRab26-DYM in LPS stimulated cells increased the surface levels of TLR4 and subsequently activated TLR4 signal pathway in primary HPMVECs.	14	33	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	Rab26 silencing with siRab26-DYM in LPS stimulated cells increased the surface levels of TLR4	tlr4	TLR4	TLR4	tlr4	27	28	31	32
In vitro experiments reveal that OA-NO2 suppresses LPS induced TLR4 signalling , inhibitor of kappaB ( IkappaBalpha ) phosphorylation and ubiquitination , phosphorylation of the IkappaB kinase ( IKK ) , impairing the recruitment of the TLR4 and TNF receptor associated factor 6 ( TRAF6 ) to the lipid rafts compartments .	In vitro experiments reveal that OA-NO2 suppresses LPS induced TLR4 signalling, inhibitor of kappaB (IkappaBalpha) phosphorylation and ubiquitination, phosphorylation of the IkappaB kinase (IKK), impairing the recruitment of the TLR4 and TNF receptor associated factor 6 (TRAF6) to the lipid rafts compartments.	5	39	impairing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	OA-NO2 suppresses LPS induced TLR4 signalling, inhibitor of kappaB (IkappaBalpha) phosphorylation	tlr4	TLR4	TLR4	tlr4	9	10	36	37
Expression of TLR4 on marrow derived cells then serves to enhance parenchymal TLR4 driven plasma cytokine levels as this process proceeds .	Expression of TLR4 on marrow derived cells then serves to enhance parenchymal TLR4 driven plasma cytokine levels as this process proceeds.	0	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	Expression of TLR4	tlr4	TLR4	TLR4	tlr4	2	3	12	13
Ang II , via AT1 , has been shown to increase TLR4 expression and Ang II mediated ROS production and Ang II induced microglial activation was blunted in TLR4 deficient mice .	Ang II, via AT1, has been shown to increase TLR4 expression and Ang II mediated ROS production and Ang II induced microglial activation was blunted in TLR4 deficient mice.	10	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	increase TLR4 expression and Ang II mediated ROS	tlr4	TLR4	TLR4	tlr4	11	12	28	29
In contrast , Rab26 overexpression reduced the TLR4 levels on cell surface , inactivated the TLR4 signaling pathway , resulting in inhibition of cell apoptosis and attenuated the LPS stimulated hyperpermeability of HPMVECs .	In contrast, Rab26 overexpression reduced the TLR4 levels on cell surface, inactivated the TLR4 signaling pathway, resulting in inhibition of cell apoptosis and attenuated the LPS stimulated hyperpermeability of HPMVECs.	3	17	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	Rab26 overexpression reduced the TLR4 levels	tlr4	TLR4	TLR4	tlr4	7	8	15	16
These findings suggest that the higher expression of TLR4 and CD14 by MIC ECs when compared to MAC ECs may lead to the stronger inflammatory response to TLR4 activation in MIC ECs .	These findings suggest that the higher expression of TLR4 and CD14 by MIC ECs when compared to MAC ECs may lead to the stronger inflammatory response to TLR4 activation in MIC ECs.	6	28	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TLR4	expression of TLR4	tlr4	TLR4	TLR4	tlr4	8	9	27	28
The level of TLR4 was not reduced by TAK-242 ( an inhibitor of TLR4 ) , which indicated that TLR4 was not depended on MyD88 .	The level of TLR4 was not reduced by TAK-242 (an inhibitor of TLR4), which indicated that TLR4 was not depended on MyD88.	1	14	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	TLR4	level of TLR4 was not reduced by TAK-242	tlr4	TLR4	TLR4	tlr4	3	4	13	14
These authors hypothesized that conceptus expression of TLR4 endogenous ligands , fibrinogen and fibronectin , which are up-regulated at the time of implantation , could activate endometrial TLR4 and subsequently trigger the downstream signalling that leads to NF-kappaB activation XREF_BIBR .	These authors hypothesized that conceptus expression of TLR4 endogenous ligands, fibrinogen and fibronectin, which are up-regulated at the time of implantation, could activate endometrial TLR4 and subsequently trigger the downstream signalling that leads to NF-kappaB activation XREF_BIBR.	5	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	expression of TLR4	tlr4	TLR4	TLR4	tlr4	7	8	27	28
DAMPs and PAMPs from infection related inflammatory , tumor associated inflammatory , or antitumor therapy induced inflammatory could upregulate the TLR4 expression and activate TLR4 signaling in tumor cells and contribute tumor pathogenesis and progression in a direct or indirect way .	DAMPs and PAMPs from infection related inflammatory, tumor associated inflammatory, or antitumor therapy induced inflammatory could upregulate the TLR4 expression and activate TLR4 signaling in tumor cells and contribute tumor pathogenesis and progression in a direct or indirect way.	0	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	DAMPs and PAMPs from infection related inflammatory, tumor associated inflammatory, or antitumor therapy induced inflammatory could upregulate the TLR4 expression	tlr4	TLR4	TLR4	tlr4	20	21	24	25
The expression of fluorescent TLR4 in cell lines allowed us to map TLR4 subcellular location , demonstrating its presence on the cellular surface and in the Golgi , similar to the TLR4 distribution observed in human monocytes XREF_BIBR .	The expression of fluorescent TLR4 in cell lines allowed us to map TLR4 subcellular location, demonstrating its presence on the cellular surface and in the Golgi, similar to the TLR4 distribution observed in human monocytes XREF_BIBR.	1	14	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	expression of fluorescent TLR4	tlr4	TLR4	TLR4	tlr4	4	5	12	13
We also performed co-immunoprecipitation in tumor tissues and found that paeoniflorin treatment promoted TLR4 ubiquitination and enhanced conjunction of TLR4 and Triad3A in the intracranial xenograft mouse model ( XREF_FIG ) .	We also performed co-immunoprecipitation in tumor tissues and found that paeoniflorin treatment promoted TLR4 ubiquitination and enhanced conjunction of TLR4 and Triad3A in the intracranial xenograft mouse model (XREF_FIG).	10	21	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	paeoniflorin treatment promoted TLR4 ubiquitination	tlr4	TLR4	TLR4	tlr4	13	14	19	20
TLR4 mRNA expression was inhibited by IL-4 as early as 6 h but the effect was lost by 24 h. Surface expression of TLR4 was inhibited by IL-4 at 12 and 24 h , but returned to baseline at 48 h. IL-4 inhibited activity of the TLR4 promoter as early as 6 h , but , like the mRNA , these effects were transient .	TLR4 mRNA expression was inhibited by IL-4 as early as 6 h but the effect was lost by 24 h. Surface expression of TLR4 was inhibited by IL-4 at 12 and 24 h, but returned to baseline at 48 h. IL-4 inhibited activity of the TLR4 promoter as early as 6 h, but, like the mRNA, these effects were transient.	0	47	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4 mRNA expression	tlr4	TLR4	TLR4	tlr4	0	1	46	47
This NS5A induced TLR4 is activated by endotoxemia associated with alcohol intake , leading to accentuated TLR4 signaling which in turn upregulates the stem cell marker Nanog required for TLR4 dependent liver oncogenesis .	This NS5A induced TLR4 is activated by endotoxemia associated with alcohol intake, leading to accentuated TLR4 signaling which in turn upregulates the stem cell marker Nanog required for TLR4 dependent liver oncogenesis.	1	17	leading	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	NS5A induced TLR4	tlr4	TLR4	TLR4	tlr4	3	4	16	17
Recent studies have shown that there is an overexpression of TLR2 and TLR4 in intestinal epithelial cells which is correlated with the severity of mucosal damage , together with an increase of apoptotic cells and markedly impaired proliferation [ XREF_BIBR ] .	Recent studies have shown that there is an overexpression of TLR2 and TLR4 in intestinal epithelial cells which is correlated with the severity of mucosal damage, together with an increase of apoptotic cells and markedly impaired proliferation [XREF_BIBR].	6	13	is an overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	TLR4	overexpression of TLR2 and TLR4	tlr4	TLR4	TLR4	tlr4	12	13	12	13
3.1 Palmitate exposure up-regulates TLR4 expression and activates TLR4 signalling pathway .	3.1 Palmitate exposure up-regulates TLR4 expression and activates TLR4 signalling pathway.	1	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	Palmitate exposure up-regulates TLR4 expression	tlr4	TLR4	TLR4	tlr4	4	5	8	9
In the mouse model of clonorchiasis , the expressions of TLR2 and TLR4 were upregulated during the infestation of C. sinensis , indicating probable participation of TLR2 and TLR4 in the stimulation of innate immune response during C. sinensis infestation .	In the mouse model of clonorchiasis, the expressions of TLR2 and TLR4 were upregulated during the infestation of C. sinensis, indicating probable participation of TLR2 and TLR4 in the stimulation of innate immune response during C. sinensis infestation.	8	29	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	expressions of TLR2 and TLR4	tlr4	TLR4	TLR4	tlr4	12	13	28	29
The siRab26-DYM nanoparticles enhanced normal and LPS induced TLR4 accumulation on the cell membrane , promoted the nuclear translocation of Foxo1 , subsequently activated the TLR4 signaling pathway , and induced the apoptosis and hyperpermeability of HPMVECs .	The siRab26-DYM nanoparticles enhanced normal and LPS induced TLR4 accumulation on the cell membrane, promoted the nuclear translocation of Foxo1, subsequently activated the TLR4 signaling pathway, and induced the apoptosis and hyperpermeability of HPMVECs.	6	27	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	LPS induced TLR4	tlr4	TLR4	TLR4	tlr4	8	9	25	26
The reduced cellular binding of Stx upon siRNA-transfection was solely due to TLR4 depletion , because reconstitution of TLR4 expression by the introduction of an siRNA resistant TLR4 gene completely abolished the TLR4 targeting siRNA mediated effect .	The reduced cellular binding of Stx upon siRNA-transfection was solely due to TLR4 depletion, because reconstitution of TLR4 expression by the introduction of an siRNA resistant TLR4 gene completely abolished the TLR4 targeting siRNA mediated effect.	18	33	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4 expression	tlr4	TLR4	TLR4	tlr4	18	19	32	33
The two studies showed that TLR2 deficiency does not decrease MCD diet induced NASH , but increases the sensitivity to TLR4 ligand by increasing expression of TLR4 and CD14 .	The two studies showed that TLR2 deficiency does not decrease MCD diet induced NASH, but increases the sensitivity to TLR4 ligand by increasing expression of TLR4 and CD14.	16	28	increases	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TLR4	expression of TLR4	tlr4	TLR4	TLR4	tlr4	26	27	20	21
The results may be consistent with that DEP activates Toll like receptor 4 ( TLR4 ) signalling because the Tnf response occurs late in this pathway .	The results may be consistent with that DEP activates Toll like receptor 4 (TLR4) signalling because the Tnf response occurs late in this pathway.	8	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Toll like receptor 4	Toll like receptor 4	Toll like receptor 4	14	15	9	13
TLR4 expression induced by combined treatment with 5-aza-dC and LPS activates TLR4 and NF-kappaB signaling .	TLR4 expression induced by combined treatment with 5-aza-dC and LPS activates TLR4 and NF-kappaB signaling.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4 expression	tlr4	TLR4	TLR4	tlr4	0	1	11	12
In the present study , confocal analysis show that pretreatment of primary AM with SP-A prior to LPS almost completely abolishes the LPS induced TLR4 and EEA1 positioning and promotes the co-localization of TLR4 with the post-Golgi compartment .	In the present study, confocal analysis show that pretreatment of primary AM with SP-A prior to LPS almost completely abolishes the LPS induced TLR4 and EEA1 positioning and promotes the co-localization of TLR4 with the post-Golgi compartment.	14	34	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	SP-A prior to LPS almost completely abolishes the LPS induced TLR4	tlr4	TLR4	TLR4	tlr4	24	25	33	34
Thus CS increased TLR4 expression and up-regulated TLR4 mediated signaling in the lungs .	Thus CS increased TLR4 expression and up-regulated TLR4 mediated signaling in the lungs.	1	9	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	CS increased TLR4 expression	tlr4	TLR4	TLR4	tlr4	3	4	7	8
We show that human apo A-I gene transfer decreases TLR4 expression in vivo in the absence of LPS and attenuates TLR4 signalling following LPS administration .	We show that human apo A-I gene transfer decreases TLR4 expression in vivo in the absence of LPS and attenuates TLR4 signalling following LPS administration.	4	21	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	apo A-I gene transfer decreases TLR4 expression	tlr4	TLR4	TLR4	tlr4	9	10	20	21
TbetaRII activates TbetaRI through phosphorylation of the Gly-Ser-rich ( GS ) domain of TbetaRI , which in turn phosphorylates and activates Smad2 and Smad3 , receptor regulated Smads ( R-Smads ) specific for TGF-beta and activin signaling ( XREF_FIG ) .	TbetaRII activates TbetaRI through phosphorylation of the Gly-Ser-rich (GS) domain of TbetaRI, which in turn phosphorylates and activates Smad2 and Smad3, receptor regulated Smads (R-Smads) specific for TGF-beta and activin signaling (XREF_FIG).	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	0	1	2	3
In the canonical TGF-beta and Smad pathway , active TGF-beta1 binds to the cell surface receptor kinases TGF-beta1 type I ( TbetaRI ) and type II receptors ( TbetaRII ) , then the TbetaRII activates TbetaRI , which further phosphorylates the receptor associated Smads ( R-Smads ) , Smad2 and Smad3 , to regulate gene expression .	In the canonical TGF-beta and Smad pathway, active TGF-beta1 binds to the cell surface receptor kinases TGF-beta1 type I (TbetaRI) and type II receptors (TbetaRII), then the TbetaRII activates TbetaRI, which further phosphorylates the receptor associated Smads (R-Smads), Smad2 and Smad3, to regulate gene expression.	32	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	33	34	35	36
Within this complex , TbetaRI is activated by TbetaRII through phosphorylation , and the activated TbetaRI phosphorylates receptor regulated Smad2 and Smad3 ( R-Smads ) at two serine residues in the C-terminus [ XREF_BIBR , XREF_BIBR ] .	Within this complex, TbetaRI is activated by TbetaRII through phosphorylation, and the activated TbetaRI phosphorylates receptor regulated Smad2 and Smad3 (R-Smads) at two serine residues in the C-terminus [XREF_BIBR, XREF_BIBR].	4	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	8	9	4	5
In the canonical pathway , activation of TGFbeta type 2 receptor ( TGFBR2 ) activates TGF-beta type I receptor ( TBRI ; also known as TGFBRI1 or ALK5 ) and then the TBRI phosphorylates the transcription factors SMAD-2 and SMAD-3 ( Receptor SMADs ; R-SMAD ) .	In the canonical pathway, activation of TGFbeta type 2 receptor (TGFBR2) activates TGF-beta type I receptor (TBRI; also known as TGFBRI1 or ALK5) and then the TBRI phosphorylates the transcription factors SMAD-2 and SMAD-3 (Receptor SMADs; R-SMAD).	10	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFBR2	TGFBR2	TGFBR2	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	12	13	15	19
TGF-beta initiates intracellular signaling by binding with TGF-beta type II receptor ( TbetaRII ) , which activates TGF-beta type I receptor ( TbetaRI ) , resulting in activation of downstream signaling pathways , including both SMAD dependent and SMAD independent pathways XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	TGF-beta initiates intracellular signaling by binding with TGF-beta type II receptor (TbetaRII), which activates TGF-beta type I receptor (TbetaRI), resulting in activation of downstream signaling pathways, including both SMAD dependent and SMAD independent pathways XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	10	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	12	13	17	21
Upon ligand binding , TbetaR-II recruits and activates TbetaRI by phosphorylating the GS domain .	Upon ligand binding, TbetaR-II recruits and activates TbetaRI by phosphorylating the GS domain.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaR-II	TbetaR-II	TbetaR-II	TbetaRI	TbetaRI	TbetaRI	4	5	8	9
Upon ligand binding , the type II TGF-beta receptor ( TbetaRII ) heterodimerizes with and activates TGF-beta receptor type I ( TbetaRI ) .	Upon ligand binding, the type II TGF-beta receptor (TbetaRII) heterodimerizes with and activates TGF-beta receptor type I (TbetaRI).	8	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TGF-beta receptor type I	TGF-beta receptor type I	TGF-beta receptor type I	10	11	16	20
Upon ligand binding , the TbetaRII activates the kinase catalytic domain of the TbetaRI ( Alk5 or Alk1 ) , leading to phosphorylation of Smad proteins .	Upon ligand binding, the TbetaRII activates the kinase catalytic domain of the TbetaRI (Alk5 or Alk1), leading to phosphorylation of Smad proteins.	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	Alk5	Alk5	Alk5	5	6	15	16
In response to TGF-beta binding , TbetaRII recruits and activates TbetaRI through phosphorylation of the regulatory GS-domain .	In response to TGF-beta binding, TbetaRII recruits and activates TbetaRI through phosphorylation of the regulatory GS-domain.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	6	7	10	11
Restoration of TbetaRII rescued the insulin induced increased cell surface abundance of TbetaRI and TbetaRII ( XREF_FIG ) .	Restoration of TbetaRII rescued the insulin induced increased cell surface abundance of TbetaRI and TbetaRII (XREF_FIG).	0	16	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	2	3	12	13
TbetaRII firstly phosphorylates and activates TbetaRI , then forms a complex with TbetaRI .	TbetaRII firstly phosphorylates and activates TbetaRI, then forms a complex with TbetaRI.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	0	1	5	6
Transforming growth factor , beta 1 ( TGFB1 ) signaling occurs by binding of the growth factor to transforming growth factor , beta receptor II ( TGFBR2 ) , which activates and binds to the structurally-similar TGFBR1 .	Transforming growth factor, beta 1 (TGFB1) signaling occurs by binding of the growth factor to transforming growth factor, beta receptor II (TGFBR2), which activates and binds to the structurally-similar TGFBR1.	24	37	activates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TGFBR2	TGFBR2	TGFBR2	TGFBR1	TGFBR1	TGFBR1	26	27	36	37
However , since TbetaRII can become activated in a homocomplex , whereas TbetaRI can only be activated by TbetaRII , an alternative explanation is that TRAF6 interacts with an activated receptor complex consisting of either a homodimer of TbetaRII or a heterocomplex of two types of receptors [ XREF_BIBR ] .	However, since TbetaRII can become activated in a homocomplex, whereas TbetaRI can only be activated by TbetaRII, an alternative explanation is that TRAF6 interacts with an activated receptor complex consisting of either a homodimer of TbetaRII or a heterocomplex of two types of receptors [XREF_BIBR].	12	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	18	19	12	13
These results indicate that downstream of TbetaRII , Src family kinase-RhoA-ROCK-JNK signaling pathway mediates TbetaRI independent ATF2 activation .	These results indicate that downstream of TbetaRII, Src family kinase-RhoA-ROCK-JNK signaling pathway mediates TbetaRI independent ATF2 activation.	4	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	6	7	14	15
Upon ligand binding , TGF-beta type I receptor activated by TbetaRII propagates signals to Smad proteins , which mediate the activation of TGF-beta target genes .	Upon ligand binding, TGF-beta type I receptor activated by TbetaRII propagates signals to Smad proteins, which mediate the activation of TGF-beta target genes.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	10	11	4	8
TbetaRII augments the association of ALK5 with endoglin .	TbetaRII augments the association of ALK5 with endoglin.	0	6	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	ALK5	ALK5	ALK5	0	1	5	6
As TbetaRI is activated by TbetaRII upon ligand binding and forms a tetrameric receptor heterocomplex with TbetaRII , it is not clear whether the tyrosine phosphorylation of TbetaRI stems from TbetaRI autophosphorylation or from transphosphorylation by TbetaRII .	As TbetaRI is activated by TbetaRII upon ligand binding and forms a tetrameric receptor heterocomplex with TbetaRII, it is not clear whether the tyrosine phosphorylation of TbetaRI stems from TbetaRI autophosphorylation or from transphosphorylation by TbetaRII.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	5	6	1	2
The general pathway of TGF-beta signalling involves the binding of mature TGF-beta1 to the TGF-beta type II receptor , which in turn activates the TGF-beta type I receptor ( TGFbetaRI ) .	The general pathway of TGF-beta signalling involves the binding of mature TGF-beta1 to the TGF-beta type II receptor, which in turn activates the TGF-beta type I receptor (TGFbetaRI).	14	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta type II receptor	TGF-beta type II receptor	TGF-beta type II receptor	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	14	18	24	28
In MEFs , silencing TbetaRII enhanced the cell surface amount of TbetaRI , yet still allowed for insulin to induce enhanced cell surface TbetaRI abundance ( XREF_FIG ) , whereas in NMuMG cells , the decrease in TbetaRII impaired the increase of cell surface TbetaRI in response to insulin ( XREF_FIG ) .	In MEFs, silencing TbetaRII enhanced the cell surface amount of TbetaRI, yet still allowed for insulin to induce enhanced cell surface TbetaRI abundance (XREF_FIG), whereas in NMuMG cells, the decrease in TbetaRII impaired the increase of cell surface TbetaRI in response to insulin (XREF_FIG).	35	46	impaired	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	37	38	44	45
After ligand binding to TbetaRII , TbetaRI is recruited into the complex and activated by TbetaRII dependent phosphorylation , thereby enabling it to transduce signals through downstream mediators such as the Smad family of proteins .	After ligand binding to TbetaRII, TbetaRI is recruited into the complex and activated by TbetaRII dependent phosphorylation, thereby enabling it to transduce signals through downstream mediators such as the Smad family of proteins.	6	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII dependent phosphorylation	tbetarii	TbetaRI	TbetaRI	tbetari	15	16	6	7
Ligand binding leads to formation of the receptor heterocomplex , in which TbetaRII phosphorylates threonine and serine residues in the TTSGSGSG motif of TbetaRI and thus activates TbetaRI [ XREF_BIBR , XREF_BIBR ] .	Ligand binding leads to formation of the receptor heterocomplex, in which TbetaRII phosphorylates threonine and serine residues in the TTSGSGSG motif of TbetaRI and thus activates TbetaRI [XREF_BIBR, XREF_BIBR].	12	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	12	13	27	28
We next investigated how TbetaRII mediates ATF2 activation independent of TbetaRI in VSMCs .	We next investigated how TbetaRII mediates ATF2 activation independent of TbetaRI in VSMCs.	4	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	4	5	10	11
Treating AVICs with TGF-beta1 leads to increased levels of pSrc in a manner that is abrogated by treatment with an Alk5 inhibitor , indicating that pSrc induction is downstream of Alk5 activation by TbetaRII after TGF-beta1 ligand binding ( XREF_FIG ) .	Treating AVICs with TGF-beta1 leads to increased levels of pSrc in a manner that is abrogated by treatment with an Alk5 inhibitor, indicating that pSrc induction is downstream of Alk5 activation by TbetaRII after TGF-beta1 ligand binding (XREF_FIG).	30	37	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	Alk5	Alk5	Alk5	33	34	30	31
Taken together , we concluded that TbetaRI activation by a higher level of TbetaRII in HDFs is both necessary and sufficient for transmitting anti-motility signal of TGFbeta3 .	Taken together, we concluded that TbetaRI activation by a higher level of TbetaRII in HDFs is both necessary and sufficient for transmitting anti-motility signal of TGFbeta3.	6	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TbetaRII	level of TbetaRII	tbetarii	TbetaRI	TbetaRI	tbetari	13	14	6	7
Upon ligand binding , TGF-beta type II receptor dimers recruit , phosphorylate , and activate TGF-beta type I receptor dimers .	Upon ligand binding, TGF-beta type II receptor dimers recruit, phosphorylate, and activate TGF-beta type I receptor dimers.	4	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta type II receptor	TGF-beta type II receptor	TGF-beta type II receptor	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	4	8	15	19
The fact that TbetaRII can become activated in a homocomplex , whereas TbetaRI can only be activated by TbetaRII is consistent with the higher affinity of TRAF6 to TbetaRII ( XREF_FIG ) and the role of the kinase activity of TbetaRI in binding ( XREF_FIG ) .	The fact that TbetaRII can become activated in a homocomplex, whereas TbetaRI can only be activated by TbetaRII is consistent with the higher affinity of TRAF6 to TbetaRII (XREF_FIG) and the role of the kinase activity of TbetaRI in binding (XREF_FIG).	12	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TbetaRII	TbetaRII	TbetaRII	TbetaRI	TbetaRI	TbetaRI	18	19	12	13
Since overexpression of ectopic ALK5 , as demonstrated exemplarily for the wild-type protein , was also seen in the membrane fraction of transfected cells ( XREF_SUPPLEMENTARY ) , we conclude that both wild-type ALK5 and its kinase active mutant can rescue TGF-beta / Smad3 signalling , TGF-beta / Smad dependent transcriptional activity and cell motility .	Since overexpression of ectopic ALK5, as demonstrated exemplarily for the wild-type protein, was also seen in the membrane fraction of transfected cells (XREF_SUPPLEMENTARY), we conclude that both wild-type ALK5 and its kinase active mutant can rescue TGF-beta / Smad3 signalling, TGF-beta / Smad dependent transcriptional activity and cell motility.	31	44	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	33	34	43	44
The L45 loops of TbetaR-I and activin type IB receptor and ALK -4 interact with and activate Smad2 and Smad3 , whereas the BMPR-I L45 loops bind to Smad1 and Smad5 .	The L45 loops of TbetaR-I and activin type IB receptor and ALK -4 interact with and activate Smad2 and Smad3, whereas the BMPR-I L45 loops bind to Smad1 and Smad5.	2	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaR-I	TbetaR-I	TbetaR-I	Smad3	Smad3	Smad3	4	5	19	20
Notably , adenovirus mediated overexpression of TGFBR1 enhanced TGFBR1 , Smad2 , and Smad3 activation in VSMCs and partially blocked the inhibitory effect of luteolin on TGFBR1 , Smad2 , and Smad3 .	Notably, adenovirus mediated overexpression of TGFBR1 enhanced TGFBR1, Smad2, and Smad3 activation in VSMCs and partially blocked the inhibitory effect of luteolin on TGFBR1, Smad2, and Smad3.	4	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFBR1	overexpression of TGFBR1	tgfbr1	Smad3	Smad3	smad3	6	7	13	14
Following ligand binding , TbetaRII phosphorylates TbetaRI , which activates Smad2 and Smad3 .	Following ligand binding, TbetaRII phosphorylates TbetaRI, which activates Smad2 and Smad3.	4	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRI	TbetaRII phosphorylates TbetaRI	tbetari	Smad3	Smad3	smad3	6	7	12	13
In the first one , the activation of TGFBR1 leads to phosphorylation of receptor specific Smad ( R-Smad ) proteins , Smad2 and Smad3 .	In the first one, the activation of TGFBR1 leads to phosphorylation of receptor specific Smad (R-Smad) proteins, Smad2 and Smad3.	6	24	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFBR1	TGFBR1	TGFBR1	Smad3	Smad3	Smad3	8	9	23	24
ALK5 activates Smad2 and Smad3 as downstream effectors of TGF-beta1 signaling XREF_BIBR .	ALK5 activates Smad2 and Smad3 as downstream effectors of TGF-beta1 signaling XREF_BIBR.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	0	1	4	5
Activation of Smad2 and Smad3 proceeds primarily by the ALK5 kinase through phosphorylation of the two C-terminal Ser residues in the Ser-Xaa-Ser motif of the MH2 domain ( Smad2/3C ) .	Activation of Smad2 and Smad3 proceeds primarily by the ALK5 kinase through phosphorylation of the two C-terminal Ser residues in the Ser-Xaa-Ser motif of the MH2 domain (Smad2/3C).	0	10	Activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	9	10	4	5
ALK5 activates Smad2 and Smad3 through phosphorylation [ XREF_BIBR - XREF_BIBR ] .	ALK5 activates Smad2 and Smad3 through phosphorylation [XREF_BIBR - XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	0	1	4	5
In human embryonic kidney 293 cells , the expression of constitutively active TGF-beta type I receptor was able to induce the formation of a Smad3- and Smad4 containing nuclear protein complex that bound the SBE .	In human embryonic kidney 293 cells, the expression of constitutively active TGF-beta type I receptor was able to induce the formation of a Smad3- and Smad4 containing nuclear protein complex that bound the SBE.	8	27	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta type I receptor	expression of constitutively active TGF-beta type I receptor	tgf-beta type i receptor	Smad3-	Smad3-	smad3-	12	16	24	25
Ligand binding to TbetaRII causes the phosphorylation of TbetaRI , which activates Smad2 and Smad3 .	Ligand binding to TbetaRII causes the phosphorylation of TbetaRI, which activates Smad2 and Smad3.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRI	phosphorylation of TbetaRI	tbetari	Smad3	Smad3	smad3	8	9	14	15
SB431542 , a small molecular inhibitor of TGF-beta type I receptor , is known to inhibit TGF-beta and Smad3 signaling pathway .	SB431542, a small molecular inhibitor of TGF-beta type I receptor, is known to inhibit TGF-beta and Smad3 signaling pathway.	7	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	Smad3	Smad3	Smad3	7	11	18	19
In addition , our results show that ALK1 inhibits , whereas ALK5 potentiates , TGF-beta-induced Smad3 driven transcriptional activity and the expression of PAI-1 , fibronectin , and type II collagen in chondrocytes .	In addition, our results show that ALK1 inhibits, whereas ALK5 potentiates, TGF-beta-induced Smad3 driven transcriptional activity and the expression of PAI-1, fibronectin, and type II collagen in chondrocytes.	11	16	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	11	12	15	16
Interference with Smad3 activation by TbetaRI results from association of activated IRF3 , but not inactive IRF3 , with non activated Smad3 , thus preventing Smad3 recruitment to TbetaRI , and decreasing Smad3 activation .	Interference with Smad3 activation by TbetaRI results from association of activated IRF3, but not inactive IRF3, with non activated Smad3, thus preventing Smad3 recruitment to TbetaRI, and decreasing Smad3 activation.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TbetaRI	TbetaRI	TbetaRI	Smad3	Smad3	Smad3	5	6	2	3
Binding of TGF-beta allows TbetaRII to activate TbetaRI , which in turn activates transcription factors , Smad2 and Smad3 .	Binding of TGF-beta allows TbetaRII to activate TbetaRI, which in turn activates transcription factors, Smad2 and Smad3.	6	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRI	TbetaRI	TbetaRI	Smad3	Smad3	Smad3	7	8	18	19
It has been reported that Chka , Kit , and Pik3ca function in PI3K and AKT signaling [ XREF_BIBR - XREF_BIBR ] and that Smad3 , a transcription factor , is activated by Tgfbr1 and Trib3 [ XREF_BIBR , XREF_BIBR ] .	It has been reported that Chka, Kit, and Pik3ca function in PI3K and AKT signaling [XREF_BIBR - XREF_BIBR] and that Smad3, a transcription factor, is activated by Tgfbr1 and Trib3 [XREF_BIBR, XREF_BIBR].	24	37	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tgfbr1	Tgfbr1	Tgfbr1	Smad3	Smad3	Smad3	33	34	24	25
TbetaRI activation propagates downstream intracellular signals through the Smad proteins [ XREF_BIBR ] ; Smad2 and Smad3 are activated through phosphorylation by ALK5 , whereas Smad1 , Smad5 and Smad8 are activated by ALK1 as well as the Bone Morphogenetic Protein ( BMP ) receptors [ XREF_BIBR ] .	TbetaRI activation propagates downstream intracellular signals through the Smad proteins [XREF_BIBR]; Smad2 and Smad3 are activated through phosphorylation by ALK5, whereas Smad1, Smad5 and Smad8 are activated by ALK1 as well as the Bone Morphogenetic Protein (BMP) receptors [XREF_BIBR].	14	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	22	23	16	17
TGF-beta signaling is initiated by ligand binding to TbetaR-II , which leads to the activated type II receptor ; then , protease TbetaR-I is phosphorylated , and the TbetaR-I kinase activates Smad2 and Smad3 .	TGF-beta signaling is initiated by ligand binding to TbetaR-II, which leads to the activated type II receptor; then, protease TbetaR-I is phosphorylated, and the TbetaR-I kinase activates Smad2 and Smad3.	28	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaR-I	TbetaR-I	TbetaR-I	Smad3	Smad3	Smad3	28	29	33	34
The constitutively active serine/threonine kinase of TbetaRII phosphorylates TbetaRI , which activates Smad2 and Smad3 via phosphorylation .	The constitutively active serine/threonine kinase of TbetaRII phosphorylates TbetaRI, which activates Smad2 and Smad3 via phosphorylation.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRI	phosphorylates TbetaRI	tbetari	Smad3	Smad3	smad3	8	9	14	15
Upon ligand binding by TGF-beta1 , type II TGF-beta receptors ( TbetaRII ) activate type I TGF-beta receptors ( TbetaRI ) , recruiting and activating the intracellular mediators Smad2 and Smad3 , which subsequently complex with Smad4 before translocating to the nucleus where the complex regulate gene transcription [ XREF_BIBR ] .	Upon ligand binding by TGF-beta1, type II TGF-beta receptors (TbetaRII) activate type I TGF-beta receptors (TbetaRI), recruiting and activating the intracellular mediators Smad2 and Smad3, which subsequently complex with Smad4 before translocating to the nucleus where the complex regulate gene transcription [XREF_BIBR].	17	42	activating	Positive_regulation_syntax_5_verb	Positive_activation	Positive_regulation	TbetaRI	TbetaRI	tbetari	Smad3	Smad3, which subsequently complex with Smad4 before translocating to the nucleus	smad3	19	20	30	31
TbetaRI activates Smad3 to create COOH-terminally phosphorylated Smad3 ( pSmad3C ) , while pro inflammatory cytokine activated JNK phosphorylates Smad3 to create the linker phosphorylated Smad3 ( pSmad3L ) [ XREF_BIBR ] .	TbetaRI activates Smad3 to create COOH-terminally phosphorylated Smad3 (pSmad3C), while pro inflammatory cytokine activated JNK phosphorylates Smad3 to create the linker phosphorylated Smad3 (pSmad3L) [XREF_BIBR].	0	3	activates	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	TbetaRI	TbetaRI	TbetaRI	Smad3	Smad3	Smad3	0	1	2	3
The binding of TGF-beta to TbetaR-II enables this polypeptide to transphosphorylate and activate TbetaR-I , which subsequently binds , phosphorylates , and stimulates the latent transcription factors , Smad2 and Smad3 .	The binding of TGF-beta to TbetaR-II enables this polypeptide to transphosphorylate and activate TbetaR-I, which subsequently binds, phosphorylates, and stimulates the latent transcription factors, Smad2 and Smad3.	10	31	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaR-I	transphosphorylate and activate TbetaR-I	tbetar-i	Smad3	Smad3	smad3	13	14	30	31
20 During TGF-beta pathway mediated hypertrophic scar formation , there is an up-regulation of SMAD-2 and SMAD-3 , as well as increased expression of TGF-beta1 , TbetaRI and TbetaRII , which lead to positive feedback loop .	20 During TGF-beta pathway mediated hypertrophic scar formation, there is an up-regulation of SMAD-2 and SMAD-3, as well as increased expression of TGF-beta1, TbetaRI and TbetaRII, which lead to positive feedback loop.	10	27	is an up-regulation	Positive_activation_copula_1	Positive_activation	Positive_activation	TbetaRI	expression of TGF-beta1, TbetaRI	tbetari	SMAD-3	SMAD-3	smad-3	26	27	16	17
The ALK5 receptor is known to activate SMAD2 and SMAD3 ; however , pro fibrotic effects TGF-beta1 and ALK5 signaling have been largely attributed to SMAD3 signaling XREF_BIBR .	The ALK5 receptor is known to activate SMAD2 and SMAD3; however, pro fibrotic effects TGF-beta1 and ALK5 signaling have been largely attributed to SMAD3 signaling XREF_BIBR.	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	SMAD3	SMAD3	SMAD3	1	2	9	10
Smad2 and Smad3 , the principal receptor activated proteins involved in activin / TGF-beta signaling , are activated directly by TGF-beta type I receptor kinase then translocate to the nucleus in complex with a common co-Smad , Smad4 , to regulate transcription of target genes [ XREF_BIBR - XREF_BIBR ] .	Smad2 and Smad3, the principal receptor activated proteins involved in activin / TGF-beta signaling, are activated directly by TGF-beta type I receptor kinase then translocate to the nucleus in complex with a common co-Smad, Smad4, to regulate transcription of target genes [XREF_BIBR - XREF_BIBR].	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	Smad3	Smad3	Smad3	20	24	2	3
We report that induction of the Erk MAP kinase pathway decreases the TbetaRI mediated Smad3 activation , due to a decrease in cell surface level of TbetaRI , but not TbetaRII .	We report that induction of the Erk MAP kinase pathway decreases the TbetaRI mediated Smad3 activation, due to a decrease in cell surface level of TbetaRI, but not TbetaRII.	11	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TbetaRI	TbetaRI	TbetaRI	Smad3	Smad3	Smad3	12	13	14	15
SMAD2 , but not SMAD1/5 activation could be blocked by an inhibitor of the TGFbeta 1 receptor ALK5 , thereby indicating specificity of this inhibitor for TGFbeta-SMAD2 signaling .	SMAD2, but not SMAD1/5 activation could be blocked by an inhibitor of the TGFbeta 1 receptor ALK5, thereby indicating specificity of this inhibitor for TGFbeta-SMAD2 signaling.	0	20	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	SMAD2	SMAD2	SMAD2	17	18	0	1
In pericytes and ECs , TGFRbeta2 and Alk5 initiates mothers against decapentaplegic homolog 2 ( Smad2 )/3/4 signaling that inhibits proliferation and promotes differentiation [ XREF_BIBR , XREF_BIBR ] .	In pericytes and ECs, TGFRbeta2 and Alk5 initiates mothers against decapentaplegic homolog 2 (Smad2)/3/4 signaling that inhibits proliferation and promotes differentiation [XREF_BIBR, XREF_BIBR].	5	17	initiates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Alk5	Alk5	Alk5	mothers against decapentaplegic homolog 2	mothers against decapentaplegic homolog 2	mothers against decapentaplegic homolog 2	7	8	9	14
Also , TGF-beta1 activated SMAD2 and SMAD1/5 , an effect that was abolished by ALK5 inhibition .	Also, TGF-beta1 activated SMAD2 and SMAD1/5, an effect that was abolished by ALK5 inhibition.	3	15	abolished	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	SMAD2	SMAD2	SMAD2	14	15	4	5
The activated ALK5 subsequently induces Smad2 and/or Smad3 phosphorylation at C-terminal serines .	The activated ALK5 subsequently induces Smad2 and/or Smad3 phosphorylation at C-terminal serines.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Smad2	Smad2	Smad2	2	3	5	6
Interestingly , while inhibition of ALK5 and TGFbetaR I blocked the activation of SMAD2 by hypoxia , SMAD2 activation was not affected by the inhibition of ROCK and RhoA under the same conditions .	Interestingly, while inhibition of ALK5 and TGFbetaR I blocked the activation of SMAD2 by hypoxia, SMAD2 activation was not affected by the inhibition of ROCK and RhoA under the same conditions.	3	14	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	SMAD2	SMAD2	SMAD2	5	6	13	14
The TBRI , Alk5 activates its specific intracellular substrates , smad2 and -3 which undergo nuclear translocation and form transcriptional complexes at specific regulatory gene elements with smad4 and other co-regulators .	The TBRI, Alk5 activates its specific intracellular substrates, smad2 and -3 which undergo nuclear translocation and form transcriptional complexes at specific regulatory gene elements with smad4 and other co-regulators.	1	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Alk5	Alk5	Alk5	smad2	smad2	smad2	3	4	10	11
Activation of ALK1 induces SMAD1 or -5 phosphorylation and mediates endothelial cell proliferation and migration , whereas ALK5 induces SMAD2 and -3 activation leading to vascular quiescence XREF_BIBR , XREF_BIBR .	Activation of ALK1 induces SMAD1 or -5 phosphorylation and mediates endothelial cell proliferation and migration, whereas ALK5 induces SMAD2 and -3 activation leading to vascular quiescence XREF_BIBR, XREF_BIBR.	17	23	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	SMAD2	SMAD2	SMAD2	17	18	19	20
Activation of ALK5 induces Smad2 and/or Smad3 phosphorylation at C-terminal serines , and the activated Smad2 and/or Smad3 forms a heterotrimeric complex with Smad4 , which translocates to the nucleus for transcription regulation .	Activation of ALK5 induces Smad2 and/or Smad3 phosphorylation at C-terminal serines, and the activated Smad2 and/or Smad3 forms a heterotrimeric complex with Smad4, which translocates to the nucleus for transcription regulation.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Smad2	Smad2	Smad2	2	3	4	5
Last , Arf induction by oncogenic Ras depends on p38 MAPK but is independent of TbetarI activation of Smad 2 .	Last, Arf induction by oncogenic Ras depends on p38 MAPK but is independent of TbetarI activation of Smad 2.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TbetarI	TbetarI	TbetarI	Smad 2	Smad 2	Smad 2	15	16	18	20
Pharmacologic inhibition of TBRI ( alk5 ) kinase by a small molecule inhibitor , SD-208 , inhibits smad2 activation in hematopoietic progenitors , suppresses TGF-beta-mediated gene activation in BM stromal cells , and reverses TGF-beta-mediated cell-cycle arrest in BM CD34 ( + ) cells .	Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-beta-mediated gene activation in BM stromal cells, and reverses TGF-beta-mediated cell-cycle arrest in BM CD34 (+) cells.	1	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	alk5	alk5	alk5	smad2	smad2	smad2	5	6	17	18
Ligand engagement of TbetaRII leads to recruitment , phosphorylation , and activation of TbetaRI , which subsequently binds , phosphorylates , and stimulates Smad-2 and Smad-3 , XREF_BIBR , XREF_BIBR and imbalances in Smad-2/3 signaling contribute to oncogenic TGF-beta signaling .	Ligand engagement of TbetaRII leads to recruitment, phosphorylation, and activation of TbetaRI, which subsequently binds, phosphorylates, and stimulates Smad-2 and Smad-3, XREF_BIBR, XREF_BIBR and imbalances in Smad-2/3 signaling contribute to oncogenic TGF-beta signaling.	6	24	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRI	phosphorylation, and activation of TbetaRI	tbetari	Smad-2	Smad-2	smad-2	13	14	23	24
In endothelial cells , ALK1 antagonizes ALK5 mediated Smad2 and Smad3 signaling , and the ratio of ALK5 to ALK1 determines the responsiveness to TGF-betas [ XREF_BIBR , XREF_BIBR ] .	In endothelial cells, ALK1 antagonizes ALK5 mediated Smad2 and Smad3 signaling, and the ratio of ALK5 to ALK1 determines the responsiveness to TGF-betas [XREF_BIBR, XREF_BIBR].	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Smad2	Smad2	Smad2	6	7	8	9
The activation of ALK1/2/3/6 induces the phosphorylation of Smad1 , Smad5 and Smad8 , while ALK5 induces Smad2 and Smad3 [ XREF_BIBR , XREF_BIBR ] .	The activation of ALK1/2/3/6 induces the phosphorylation of Smad1, Smad5 and Smad8, while ALK5 induces Smad2 and Smad3 [XREF_BIBR, XREF_BIBR].	15	21	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	Smad2	Smad2	Smad2	15	16	17	18
These data suggested that the activation of RIG-I , IPS-1 , or STING signaling , but not TICAM-1 signaling , induced p-TBK1 mitochondrial localization in HeLa cells .	These data suggested that the activation of RIG-I, IPS-1, or STING signaling, but not TICAM-1 signaling, induced p-TBK1 mitochondrial localization in HeLa cells.	17	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TICAM-1	TICAM-1	TICAM-1	p-TBK1	p-TBK1	p-TBK1	17	18	21	22
The TRIF dependent TLR3 signaling pathway activates IKKepsilon and TBK1 , which mediate activation of IRF3 and IFN responsive genes .	The TRIF dependent TLR3 signaling pathway activates IKKepsilon and TBK1, which mediate activation of IRF3 and IFN responsive genes.	1	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	1	2	9	10
Although TRIF dependent TLR signaling can activate TBK1 41 and IRF3 activation 42 , we showed that in macrophages LPS stimulation induced primarily NF-kappaB activation .	Although TRIF dependent TLR signaling can activate TBK1 41 and IRF3 activation 42, we showed that in macrophages LPS stimulation induced primarily NF-kappaB activation.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	1	2	7	8
Signaling through TLR3 is dependent on TRIF mediated activation of TBK1 and IRFs resulting strong induction of type I IFN .	Signaling through TLR3 is dependent on TRIF mediated activation of TBK1 and IRFs resulting strong induction of type I IFN.	6	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	6	7	10	11
TBK1 can be activated in a TLR3 dependent MyD88 independent way by the adaptor TRIF XREF_BIBR .	TBK1 can be activated in a TLR3 dependent MyD88 independent way by the adaptor TRIF XREF_BIBR.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	14	15	0	1
Interestingly , although both the TRIF and MyD88 signalling pathways lead to activation of IKKepsilon and TBK1 , only activation of the TRIF pathway is capable of inducing the phosphorylation of IRF3 illustrating that biological consequences of TBK1 and IKKepsilon activation depends on whether these enzymes are activated by the MyD88 or TRIF pathways XREF_BIBR .	Interestingly, although both the TRIF and MyD88 signalling pathways lead to activation of IKKepsilon and TBK1, only activation of the TRIF pathway is capable of inducing the phosphorylation of IRF3 illustrating that biological consequences of TBK1 and IKKepsilon activation depends on whether these enzymes are activated by the MyD88 or TRIF pathways XREF_BIBR.	3	17	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	5	6	16	17
On the one hand , it promotes TRIF dependent activation of TBK1 and IRF3 by mediating K63 linked ubiquitination of TBK1 ; on the other hand , it catalyzes K48 linked ubiquitination of MyD88 and negatively regulates MyD88 dependent activation of NF-kappaB and AP1 84 .	On the one hand, it promotes TRIF dependent activation of TBK1 and IRF3 by mediating K63 linked ubiquitination of TBK1; on the other hand, it catalyzes K48 linked ubiquitination of MyD88 and negatively regulates MyD88 dependent activation of NF-kappaB and AP1 84.	7	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	7	8	11	12
Toll like receptor3 recruits the adaptor molecule TRIF , which also interacts with TRAF3 and 6 , activates TBK1 and IKK , stimulating NF-kappaB and IRF3 , and cytokine secretion .	Toll like receptor3 recruits the adaptor molecule TRIF, which also interacts with TRAF3 and 6, activates TBK1 and IKK, stimulating NF-kappaB and IRF3, and cytokine secretion.	4	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF, which also interacts with TRAF3	trif	TBK1	TBK1	tbk1	7	8	18	19
This could be explained if the MyD88 and TRIF pathways activate distinct pools of TBK1 and IKKepsilon , which are targeted to specific subsets of substrates .	This could be explained if the MyD88 and TRIF pathways activate distinct pools of TBK1 and IKKepsilon, which are targeted to specific subsets of substrates.	6	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	8	9	14	15
In TLR signaling the adaptor protein for TLR7/8 is MyD88 , which interacts with TLR7 , while the adaptor protein for TLR3 is TRIF , which activates TRAF3 and TBK1 .	In TLR signaling the adaptor protein for TLR7/8 is MyD88, which interacts with TLR7, while the adaptor protein for TLR3 is TRIF, which activates TRAF3 and TBK1.	12	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	23	24	29	30
The activation of TRIF dependent pathway by TLR3 and TLR4 leads to the activation of IKK complex consisting of TBK1 , IKKepsilon and IKKi further leading to the activation of NF-kappaB and IRF3 [ XREF_BIBR ] .	The activation of TRIF dependent pathway by TLR3 and TLR4 leads to the activation of IKK complex consisting of TBK1, IKKepsilon and IKKi further leading to the activation of NF-kappaB and IRF3 [XREF_BIBR].	3	23	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	3	4	19	20
In addition to targeting the TAK/IKK/MAPK signaling axis , TRIF activates the IKK related kinases TBK1 and IKKepsilon , resulting in the activation of transcription factor IRF3 and induction of type I IFNs .	In addition to targeting the TAK/IKK/MAPK signaling axis, TRIF activates the IKK related kinases TBK1 and IKKepsilon, resulting in the activation of transcription factor IRF3 and induction of type I IFNs.	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	9	10	15	16
TRIF dependent signaling utilizes TRAF3 , which couples TRIF and MyD88 , to activate TBK1 , a kinase that regulates the activation of IFN regulatory factor ( IRF ) 3 and IRF7 .	TRIF dependent signaling utilizes TRAF3, which couples TRIF and MyD88, to activate TBK1, a kinase that regulates the activation of IFN regulatory factor (IRF) 3 and IRF7.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	0	1	14	15
TRIF signals the downstream kinases TBK1 and IKK , leading to phosphorylation of IRF3 and the consequent production of IFNs and IFN inducible genes [ XREF_BIBR ] .	TRIF signals the downstream kinases TBK1 and IKK, leading to phosphorylation of IRF3 and the consequent production of IFNs and IFN inducible genes [XREF_BIBR].	0	7	signals	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	0	1	5	6
IE86 protein had no effect on both the level of TRIF protein and TRIF induced TBK1 activation .	IE86 protein had no effect on both the level of TRIF protein and TRIF induced TBK1 activation.	4	16	induced	Positive_early_activation	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	13	14	15	16
IRF3 can be phosphorylated and nuclear translocated by IKK , TBK1 , and IKKi ( IKKepsilon ) that can be activated by TRIF requiring TRAF3 ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	IRF3 can be phosphorylated and nuclear translocated by IKK, TBK1, and IKKi (IKKepsilon) that can be activated by TRIF requiring TRAF3 (XREF_FIG) [XREF_BIBR, XREF_BIBR].	6	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	22	23	10	11
In the case of TLR3 , the adaptor , TRIF , is used to activate TBK1 ( TANK binding kinase 1 ) and IKK-alpha ( IkappaB kinase-alpha , which phosphorylate and activate the transcription factor , IRF3 .	In the case of TLR3, the adaptor, TRIF, is used to activate TBK1 (TANK binding kinase 1) and IKK-alpha (IkappaB kinase-alpha, which phosphorylate and activate the transcription factor, IRF3.	7	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	9	10	15	16
TLR3 stimulation in macrophages and conventional DCs , for instance , recruits the adaptor protein TRIF ( TIR domain containing adaptor inducing IFN-beta ) , which leads to the TBK1 ( Tank binding kinase 1 )-IRF3-dependent induction of type I IFNs as well as to the TRAF6 dependent induction of NF-kappaB .	TLR3 stimulation in macrophages and conventional DCs, for instance, recruits the adaptor protein TRIF (TIR domain containing adaptor inducing IFN-beta), which leads to the TBK1 (Tank binding kinase 1)-IRF3-dependent induction of type I IFNs as well as to the TRAF6 dependent induction of NF-kappaB.	11	36	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	TBK1	TBK1	TBK1	15	16	29	30
In polarized NMuMG cells , TGFbeta induces EMT by recruiting TbetaRII to TJs which results in TJ dissolution .	In polarized NMuMG cells, TGFbeta induces EMT by recruiting TbetaRII to TJs which results in TJ dissolution.	5	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	TbetaRII	TbetaRII	TbetaRII	5	6	10	11
TGFbeta initiates its signaling by the binding of extracellular TGFbeta to TbetaRII , followed by transphosphorylation of TGFbeta receptor I ( TbetaRI ) .	TGFbeta initiates its signaling by the binding of extracellular TGFbeta to TbetaRII, followed by transphosphorylation of TGFbeta receptor I (TbetaRI).	0	12	initiates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	TbetaRII	TbetaRII	TbetaRII	0	1	11	12
TGF-beta isoforms initiate signaling by organizing their cell surface receptors TbetaRI and TbetaRII .	TGF-beta isoforms initiate signaling by organizing their cell surface receptors TbetaRI and TbetaRII.	0	13	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaRII	TbetaRII	TbetaRII	0	1	12	13
Abrogation of TGFbeta signaling in TbetaRII ocy-/- bone was validated by reduced TbetaRII and Serpine1 gene expression ( XREF_FIG ) .	Abrogation of TGFbeta signaling in TbetaRII ocy-/- bone was validated by reduced TbetaRII and Serpine1 gene expression (XREF_FIG).	2	7	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	TbetaRII	TbetaRII	TbetaRII	2	3	5	6
Upon binding to the type 2 TGF-beta receptor ( TGFBR2 ) , TGF-beta causes TGFBR2 and TGFBR1 to heterodimerize with two TGFBR1 and TGFBR2 complexes .	Upon binding to the type 2 TGF-beta receptor (TGFBR2), TGF-beta causes TGFBR2 and TGFBR1 to heterodimerize with two TGFBR1 and TGFBR2 complexes.	12	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TGFBR2	TGFBR2	TGFBR2	12	13	14	15
Therefore , these results suggest that reestablishment of TGF-beta signalling in TbetaRII null cells by stable expression of TbetaRII can reverse malignant behaviour of cells and loss of TbetaRII expression may be involved in lung tumour progression .	Therefore, these results suggest that reestablishment of TGF-beta signalling in TbetaRII null cells by stable expression of TbetaRII can reverse malignant behaviour of cells and loss of TbetaRII expression may be involved in lung tumour progression.	8	13	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaRII	TbetaRII	TbetaRII	8	9	11	12
The TGF-beta type II receptor can be modulated by the TGFbeta receptor interacting protein-1 ( TRIP-1 ) , which has a high affinity for the secreted osteoclast enzyme , tartrate resistant acid phosphatase 5b ( TRAP ) controlling osteoblast activity when coupled during bone remodeling at sites of resorption [ XREF_BIBR , XREF_BIBR ] .	The TGF-beta type II receptor can be modulated by the TGFbeta receptor interacting protein-1 (TRIP-1), which has a high affinity for the secreted osteoclast enzyme, tartrate resistant acid phosphatase 5b (TRAP) controlling osteoblast activity when coupled during bone remodeling at sites of resorption [XREF_BIBR, XREF_BIBR].	1	11	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	TGF-beta type II receptor	TGF-beta type II receptor	TGF-beta type II receptor	10	11	1	5
On binding to its receptors , TGFbeta enables TbetaRII to transphosphorylate TbetaRI , which in turn activates the canonical SMAD pathway ( phosphorylation of SMAD2 and SMAD3 that further interact with SMAD4 to accumulate inside the nucleus ) and other signaling pathways ( MAPK , RHOA , and PI3K and AKT ) .	On binding to its receptors, TGFbeta enables TbetaRII to transphosphorylate TbetaRI, which in turn activates the canonical SMAD pathway (phosphorylation of SMAD2 and SMAD3 that further interact with SMAD4 to accumulate inside the nucleus) and other signaling pathways (MAPK, RHOA, and PI3K and AKT).	6	9	enables	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	TbetaRII	TbetaRII	TbetaRII	6	7	8	9
Treatment of TGFB receptor II overexpressing LNCaP TGFBR2 cells with TGFB in the presence of DHT , both cell cycle arrest and apoptosis induction are significantly enhanced over TGFB alone , through caspase-1 activation and targeting of BCL-2 .	Treatment of TGFB receptor II overexpressing LNCaP TGFBR2 cells with TGFB in the presence of DHT, both cell cycle arrest and apoptosis induction are significantly enhanced over TGFB alone, through caspase-1 activation and targeting of BCL-2.	2	8	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFB	TGFB	TGFB	TGFBR2	TGFBR2	TGFBR2	2	3	7	8
Moreover , reduction of altered noncanonical TGFbeta signaling rescues microglossia in Wnt1-Cre ; Tgfbr2 fl/fl mice by restoring proliferation of the myogenic progenitors .	Moreover, reduction of altered noncanonical TGFbeta signaling rescues microglossia in Wnt1-Cre; Tgfbr2 fl/fl mice by restoring proliferation of the myogenic progenitors.	6	15	rescues	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Tgfbr2	Tgfbr2	Tgfbr2	6	7	13	14
The transforming growth factor beta ( TGFbeta ) cytokine stimulates type I and II Ser/Thr kinase receptors ( TbetaRI and TbetaRII ) [ XREF_BIBR , XREF_BIBR ] , which initiates a Ubc13 dependent non SMAD signaling pathway [ XREF_BIBR ] .	The transforming growth factor beta (TGFbeta) cytokine stimulates type I and II Ser/Thr kinase receptors (TbetaRI and TbetaRII) [XREF_BIBR, XREF_BIBR], which initiates a Ubc13 dependent non SMAD signaling pathway [XREF_BIBR].	1	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	transforming growth factor beta	transforming growth factor beta	transforming growth factor beta	TbetaRII	TbetaRII	TbetaRII	1	5	20	21
This results in disappearance of co-localization of TbetaR-II-HA and caveolin-1 at the plasma membrane in cells treated with TGF-beta in either the presence or absence of ethanol ( XREF_FIG , panels g , h , and i ) .	This results in disappearance of co-localization of TbetaR-II-HA and caveolin-1 at the plasma membrane in cells treated with TGF-beta in either the presence or absence of ethanol (XREF_FIG, panels g, h, and i).	5	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaR-II-HA	TbetaR-II-HA	TbetaR-II-HA	18	19	7	8
Although TGF-beta treatment caused down regulation of TbetaRII in RL cells in a time dependent manner , the levels of TbetaRII were unaffected in TGF-beta sensitive cell lines HaCaT and BJAB ( XREF_SUPPLEMENTARY , & data not shown ) .	Although TGF-beta treatment caused down regulation of TbetaRII in RL cells in a time dependent manner, the levels of TbetaRII were unaffected in TGF-beta sensitive cell lines HaCaT and BJAB (XREF_SUPPLEMENTARY, & data not shown).	1	8	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaRII	TbetaRII	TbetaRII	1	2	7	8
We observed EMT induced by TGF-beta to not only downregulate E-cadherin expression , but also to prevent its interaction with EGFR , allowing for the formation of EGFR : TbetaR-II complexes that stabilized EGFR at the cell surface of post-EMT MECs .	We observed EMT induced by TGF-beta to not only downregulate E-cadherin expression, but also to prevent its interaction with EGFR, allowing for the formation of EGFR : TbetaR-II complexes that stabilized EGFR at the cell surface of post-EMT MECs.	3	30	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaR-II	TbetaR-II	TbetaR-II	5	6	29	30
Active TGF-beta dimers mediate signaling through the TGF-beta type I and type II receptors ( TbetaRI and TbetaRII , respectively ) , which are active serine/threonine kinases .	Active TGF-beta dimers mediate signaling through the TGF-beta type I and type II receptors (TbetaRI and TbetaRII, respectively), which are active serine/threonine kinases.	1	18	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaRII	TbetaRII	TbetaRII	1	2	17	18
The ACVR2/TGFBR2/SMAD4 wild type microsatellite stable colon cancer cell line FET and ACVR2 and TGFBR2 wild type and SMAD4-null SW480 colon cancer cells were treated with either activin or TGFbeta and cellular growth was assessed .	The ACVR2/TGFBR2/SMAD4 wild type microsatellite stable colon cancer cell line FET and ACVR2 and TGFBR2 wild type and SMAD4-null SW480 colon cancer cells were treated with either activin or TGFbeta and cellular growth was assessed.	14	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	TGFBR2	TGFBR2	TGFBR2	29	30	14	15
Knocking out the TGF-beta signaling in Cre + Tgfbr2 KO cultures resulted in the abrogation of TGF-beta effects on Noggin expression and Smad-1 , -5 , and -8 phosphorylation ( XREF_FIG ) .	Knocking out the TGF-beta signaling in Cre + Tgfbr2 KO cultures resulted in the abrogation of TGF-beta effects on Noggin expression and Smad-1, -5, and -8 phosphorylation (XREF_FIG).	3	10	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Tgfbr2	Tgfbr2	Tgfbr2	3	4	8	9
This finding implies that TbetaRI as well as TbetaRII activation by TGF-beta is critical mechanism for the induction of TRAF6 and TbetaRIII complex formation .	This finding implies that TbetaRI as well as TbetaRII activation by TGF-beta is critical mechanism for the induction of TRAF6 and TbetaRIII complex formation.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaRII	TbetaRII	TbetaRII	11	12	8	9
XREF_BIBR , XREF_BIBR TGF-beta signal transduction is initiated by the ligand binding and activating the TGF-beta type II receptor .	XREF_BIBR, XREF_BIBR TGF-beta signal transduction is initiated by the ligand binding and activating the TGF-beta type II receptor.	3	19	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TGF-beta type II receptor	TGF-beta type II receptor	TGF-beta type II receptor	3	4	15	19
TGFbeta initiates its signaling by activating two pairs of structurally similar , single-pass transmembrane receptors , TGFbeta receptor type II ( TbetaRII ) and type I ( TbetaRI ) .	TGFbeta initiates its signaling by activating two pairs of structurally similar, single-pass transmembrane receptors, TGFbeta receptor type II (TbetaRII) and type I (TbetaRI).	0	22	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	TbetaRII	TbetaRII	TbetaRII	0	1	21	22
TGF-beta activates TbetaRI and TbetaRII , which results in the phosphorylation of receptor regulated SMAD2/3 proteins , which are associated with the common mediator , SMAD4 .	TGF-beta activates TbetaRI and TbetaRII, which results in the phosphorylation of receptor regulated SMAD2/3 proteins, which are associated with the common mediator, SMAD4.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaRII	TbetaRII	TbetaRII	0	1	4	5
Blockade of TGFbeta signaling in CAFs , either through application of a chemical inhibitor or shRNA induced knockdown of TGFBR2 , resulted in increased cell growth and survival of breast cancer cells .	Blockade of TGFbeta signaling in CAFs, either through application of a chemical inhibitor or shRNA induced knockdown of TGFBR2, resulted in increased cell growth and survival of breast cancer cells.	2	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	TGFBR2	TGFBR2	TGFBR2	2	3	19	20
Binding of TGF-beta induces the association of TbetaR-I and TbetaR-II , allowing TbetaR-II to phosphorylate the GS domain of TbetaR-I .	Binding of TGF-beta induces the association of TbetaR-I and TbetaR-II, allowing TbetaR-II to phosphorylate the GS domain of TbetaR-I.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaR-II	TbetaR-II	TbetaR-II	2	3	9	10
Parental cells , two vector control clones , and three TbetaRII clones were treated with TGF-beta for 90min and cell lysates were subjected to Western blot analyses by antiphospho-Smad2 and antiphospho-Smad3 antibodies .	Parental cells, two vector control clones, and three TbetaRII clones were treated with TGF-beta for 90min and cell lysates were subjected to Western blot analyses by antiphospho-Smad2 and antiphospho-Smad3 antibodies.	10	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaRII	TbetaRII	TbetaRII	15	16	10	11
These data suggest that TGFbeta stimulates SMAD2 and p38 signalling through lumican increased TGFBR2 .	These data suggest that TGFbeta stimulates SMAD2 and p38 signalling through lumican increased TGFBR2.	4	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	TGFBR2	TGFBR2	TGFBR2	4	5	13	14
In most types of cells , the formation of the heteromeric complex TbetaRII , TGFbeta , and TbetaRI allows the constitutively active kinase in the cytoplasmic tail of TbetaRII to phosphorylate and activate the cytoplasmic tail of TbetaRI and ALK5 , which in turn activates the Smad2/3 cascades .	In most types of cells, the formation of the heteromeric complex TbetaRII, TGFbeta, and TbetaRI allows the constitutively active kinase in the cytoplasmic tail of TbetaRII to phosphorylate and activate the cytoplasmic tail of TbetaRI and ALK5, which in turn activates the Smad2/3 cascades.	7	29	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	TbetaRII	TbetaRII	TbetaRII	14	15	28	29
TLR signalling is mediated via a family of five adaptor proteins : MyD88 , MyD88-adaptor-like ( MAL ) , toll and interleukin -1 receptor-domain-containing adaptor protein inducing interferon-beta ( TRIF ) , TRIF related adaptor molecule ( TRAM ) and sterile alpha- and armadillo-motif-containing protein ( SARM ) .	TLR signalling is mediated via a family of five adaptor proteins : MyD88, MyD88-adaptor-like (MAL), toll and interleukin -1 receptor-domain-containing adaptor protein inducing interferon-beta (TRIF), TRIF related adaptor molecule (TRAM) and sterile alpha- and armadillo-motif-containing protein (SARM).	0	37	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	0	1	32	33
Although the relevance of TLR mediated TRIF pathways for protective immunity is well demonstrated for many infectious diseases , the specific subcellular localization of endosomal TRIF signaling is still not very well defined .	Although the relevance of TLR mediated TRIF pathways for protective immunity is well demonstrated for many infectious diseases, the specific subcellular localization of endosomal TRIF signaling is still not very well defined.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	4	5	6	7
As we discussed earlier , TLR mediated TRIF signaling may contribute to the organ pathology in several infectious diseases , blocking upstream TLR signaling may be useful to control the organ symptoms if we can simultaneously control the pathogen load .	As we discussed earlier, TLR mediated TRIF signaling may contribute to the organ pathology in several infectious diseases, blocking upstream TLR signaling may be useful to control the organ symptoms if we can simultaneously control the pathogen load.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	5	6	7	8
TLR4 is therefore the only TLR that activates both the MyD88 and TRIF signaling pathways XREF_BIBR .	TLR4 is therefore the only TLR that activates both the MyD88 and TRIF signaling pathways XREF_BIBR.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	5	6	12	13
NLRP3 activation is profoundly integrated with RIP3 dependent cell death : RIP3 and RIP1 driven caspase-8 activation downstream of TNFR1 or TLR mediated TRIF activation , as well as RIP3 driven MLKL activation , triggers NLRP3 in the event of caspase-8 inhibition .	NLRP3 activation is profoundly integrated with RIP3 dependent cell death : RIP3 and RIP1 driven caspase-8 activation downstream of TNFR1 or TLR mediated TRIF activation, as well as RIP3 driven MLKL activation, triggers NLRP3 in the event of caspase-8 inhibition.	16	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	21	22	23	24
Dual TLR stimulation results in the activation of both the MyD88- and TRIF dependent signal transduction cascades .	Dual TLR stimulation results in the activation of both the MyD88- and TRIF dependent signal transduction cascades.	1	13	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	1	2	12	13
At the same time , generation of mILFs from iILFs in the SI , but not in the colon , is blocked in mice with perturbed TLR signaling due to absence of the adapter proteins MyD88 or TRIF , 4 suggesting that different bacterial signals are required for this step .	At the same time, generation of mILFs from iILFs in the SI, but not in the colon, is blocked in mice with perturbed TLR signaling due to absence of the adapter proteins MyD88 or TRIF, 4 suggesting that different bacterial signals are required for this step.	26	39	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	26	27	37	38
These results suggest TLR agonists that activate TRIF , and consequently induce IFN-beta , but not those that exclusively signal through MyD88 , abrogate the immunosuppressive properties of Mphis , and thus promote T cell expansion and elimination of invading microorganisms .	These results suggest TLR agonists that activate TRIF, and consequently induce IFN-beta, but not those that exclusively signal through MyD88, abrogate the immunosuppressive properties of Mphis, and thus promote T cell expansion and elimination of invading microorganisms.	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	3	4	7	8
The impact of this synergy on adaptive immunity is beginning to be understood ; a recent study demonstrates a synergistic enhancement of the T cell response in mice immunized with TLR ligands that activate the MyD99 and TRIF dependent pathways [ XREF_BIBR ] .	The impact of this synergy on adaptive immunity is beginning to be understood; a recent study demonstrates a synergistic enhancement of the T cell response in mice immunized with TLR ligands that activate the MyD99 and TRIF dependent pathways [XREF_BIBR].	30	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	30	31	37	38
These results indicate that higher expression of TLR signaling activation of both MyD88 dependent and TRIF dependent pathways are more beneficial to avian heterophil mediated innate immunity and a complicated regulation of downstream adaptors is involved in stronger induction of a TLR mediated innate response in the resistant line A.	These results indicate that higher expression of TLR signaling activation of both MyD88 dependent and TRIF dependent pathways are more beneficial to avian heterophil mediated innate immunity and a complicated regulation of downstream adaptors is involved in stronger induction of a TLR mediated innate response in the resistant line A.	7	17	signaling activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	7	8	15	16
In addition , defects in genes for the TLR signaling molecules MyD88 and TRIF , as well as the important downstream target molecule TNF , result in abnormal OM recovery .	In addition, defects in genes for the TLR signaling molecules MyD88 and TRIF, as well as the important downstream target molecule TNF, result in abnormal OM recovery.	5	14	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	8	9	13	14
TLR4 is the only TLR that activates both MyD88- and TRIF dependent signaling pathways .	TLR4 is the only TLR that activates both MyD88- and TRIF dependent signaling pathways.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	4	5	10	11
However , in contrast to pathogen induced TLR triggering and subsequent activation of the MyD88 and TRIF dependent signaling pathways by invading pathogens XREF_BIBR , DC activation caused by contact sensitizers is incomplete .	However, in contrast to pathogen induced TLR triggering and subsequent activation of the MyD88 and TRIF dependent signaling pathways by invading pathogens XREF_BIBR, DC activation caused by contact sensitizers is incomplete.	7	19	triggering	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	7	8	16	17
TLR triggered TRIF and MyD88 signaling pathways depend on ubiquitination processes mediated by a number of E3 ubiquitin ligases , including tumor necrosis factor receptor associated factor 3 ( TRAF3 ) , TRAF6 , and cellular inhibitor of apoptosis 1 ( cIAP1 ) and cIAP2 ( collectively known as cIAP1/2 ) .	TLR triggered TRIF and MyD88 signaling pathways depend on ubiquitination processes mediated by a number of E3 ubiquitin ligases, including tumor necrosis factor receptor associated factor 3 (TRAF3), TRAF6, and cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2 (collectively known as cIAP1/2).	0	6	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	0	1	2	3
HO-1 protects liver against I/R injury by inhibiting TLR2 and TLR4 triggered MyD88- and TRIF dependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats .	HO-1 protects liver against I/R injury by inhibiting TLR2 and TLR4 triggered MyD88- and TRIF dependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats.	11	26	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	25	26	14	15
TLR Mediated Dual Activation of MyD88 Dependent and TRIF dependent Signaling Pathways .	TLR Mediated Dual Activation of MyD88 Dependent and TRIF dependent Signaling Pathways.	0	11	Mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	0	1	8	9
The relatively late timing of IRF3 activation , when TLR4 containing endosomal vesicles have already progressed to Rab7 + stages , further supports the idea of TLR induced TRIF signaling originating from later endosomal/lysosomal compartments .	The relatively late timing of IRF3 activation, when TLR4 containing endosomal vesicles have already progressed to Rab7 + stages, further supports the idea of TLR induced TRIF signaling originating from later endosomal/lysosomal compartments.	24	29	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	26	27	28	29
However , we have demonstrated that ESP and a somatic extract impair the DC activation induced by TLR ligands that involve both adaptor molecules ( TRIF and MyD88 ) as well as non TLR signaling XREF_BIBR , XREF_BIBR , suggesting that other molecules distinct from FhCL1 but present in F hepatica antigens modulate DC maturation .	However, we have demonstrated that ESP and a somatic extract impair the DC activation induced by TLR ligands that involve both adaptor molecules (TRIF and MyD88) as well as non TLR signaling XREF_BIBR, XREF_BIBR, suggesting that other molecules distinct from FhCL1 but present in F hepatica antigens modulate DC maturation.	14	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	17	18	25	26
The TLR mediated signaling pathways consist of the MyD88 dependent pathway and TRIF dependent pathway , both of which induce gene expression .	The TLR mediated signaling pathways consist of the MyD88 dependent pathway and TRIF dependent pathway, both of which induce gene expression.	0	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	1	2	12	13
Whereas TLR stimulation induces MyD88 and TRIF and TRAM dependent pathways that elicit a Th1 polarizing immune response , Alum ' s mode of action is distinct and still under investigation .	Whereas TLR stimulation induces MyD88 and TRIF and TRAM dependent pathways that elicit a Th1 polarizing immune response, Alum 's mode of action is distinct and still under investigation.	1	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	1	2	6	7
TLR mediated signaling involves at least four crucial adaptors , MyD88 , TRIF , TIRAP and Mal , and TRAM , having a Toll IL-1 receptor domain , which has the capability to bind an appropriate Toll IL-1 receptor domain in the cytoplasmic region of TLR ( s ) .	TLR mediated signaling involves at least four crucial adaptors, MyD88, TRIF, TIRAP and Mal, and TRAM, having a Toll IL-1 receptor domain, which has the capability to bind an appropriate Toll IL-1 receptor domain in the cytoplasmic region of TLR (s).	0	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	0	1	12	13
Using TLR ligands or drugs that selectively induce TRIF or type I IFN in the intestinal mucosa could have compelling potential to prevent or treat acute inflammatory flares in IBD patients with lack of IL-10 signaling .	Using TLR ligands or drugs that selectively induce TRIF or type I IFN in the intestinal mucosa could have compelling potential to prevent or treat acute inflammatory flares in IBD patients with lack of IL-10 signaling.	1	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	1	2	8	9
IRF-3 , a member of the interferon regulatory transcription factor ( IRF ) family , is an important transcription factor mediated through the TLR mediated TRIF dependent pathway .	IRF-3, a member of the interferon regulatory transcription factor (IRF) family, is an important transcription factor mediated through the TLR mediated TRIF dependent pathway.	22	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	23	24	25	26
Using TLR4 as a prototypical TLR that elicits both MyD88- and TRIF dependent responses , we now show that differential TRAF3 ubiquitination is the key to selective production of type I IFNs versus proinflammatory cytokines .	Using TLR4 as a prototypical TLR that elicits both MyD88- and TRIF dependent responses, we now show that differential TRAF3 ubiquitination is the key to selective production of type I IFNs versus proinflammatory cytokines.	0	13	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	5	6	11	12
The TLR 4 , in particular , recognizes lipopolysaccharide ( LPS ) and triggers the MyD88- and TRIF dependent pathways .	The TLR 4, in particular, recognizes lipopolysaccharide (LPS) and triggers the MyD88- and TRIF dependent pathways.	0	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	1	2	17	18
Shi and Kehrl [ XREF_BIBR ] demonstrated that TLR family members induce autophagy in macrophages , and MyD88 and TRIF co-immunoprecipitate with Beclin-1 .	Shi and Kehrl [XREF_BIBR] demonstrated that TLR family members induce autophagy in macrophages, and MyD88 and TRIF co-immunoprecipitate with Beclin-1.	8	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	8	9	19	20
To advance these observations , Hmox1 and IL-10 expression was evaluated in colonic CD11b + lamina propria mononuclear cells ( LPMC ) from WT mice and mice deficient in the downstream TLR signaling molecules MyD88 and TRIF .	To advance these observations, Hmox1 and IL-10 expression was evaluated in colonic CD11b + lamina propria mononuclear cells (LPMC) from WT mice and mice deficient in the downstream TLR signaling molecules MyD88 and TRIF.	27	37	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	31	32	36	37
This inhibited TLR4 induced activation of both NF-kappaB and Jun kinase .	This inhibited TLR4 induced activation of both NF-kappaB and Jun kinase.	2	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Jun	Jun	Jun	2	3	9	10
In addition , the MAPK pathway and thereby the transcription factor AP-1 , which also controls the expression of proinflammatory cytokines , is activated by TLR4 stimulation [ XREF_BIBR ] .	In addition, the MAPK pathway and thereby the transcription factor AP-1, which also controls the expression of proinflammatory cytokines, is activated by TLR4 stimulation [XREF_BIBR].	9	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	25	26	9	12
TLR4 signaling activates the pro inflammatory transcription factor AP-1 through ERK dependent phosphorylation XREF_BIBR .	TLR4 signaling activates the pro inflammatory transcription factor AP-1 through ERK dependent phosphorylation XREF_BIBR.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	0	1	6	9
TLR4 , TLR1 and TLR2 and TLR5 engage a common adaptor protein , myeloid differentiation primary response gene 88 ( MYD88 ) , to initiate mitogen activated protein ( MAP ) kinase signal transduction pathways that induce expression of pro inflammatory genes by activating two transcription factors , activator protein 1 ( AP-1 ) and nuclear factor kappa-light-chain-enhancer of activated B cells ( NF-kappaB ) ( XREF_FIG ) .	TLR4, TLR1 and TLR2 and TLR5 engage a common adaptor protein, myeloid differentiation primary response gene 88 (MYD88), to initiate mitogen activated protein (MAP) kinase signal transduction pathways that induce expression of pro inflammatory genes by activating two transcription factors, activator protein 1 (AP-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) (XREF_FIG).	0	51	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	activator protein 1	activator protein 1	activator protein 1	0	1	48	51
Regardless , MyD88 appears to represent the most upstream mediator of the hToll mediated signaling cascade , which ultimately activates NF-kappaB and c-Jun , thus driving transcriptional activation of several cytokines and costimulatory molecules .	Regardless, MyD88 appears to represent the most upstream mediator of the hToll mediated signaling cascade, which ultimately activates NF-kappaB and c-Jun, thus driving transcriptional activation of several cytokines and costimulatory molecules.	12	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	hToll	hToll	hToll	c-Jun	c-Jun	c-Jun	12	13	22	23
Upon ligand binding , TLR4 signalling activates transcription factors NF-kappaB ( p50 and p65 heterodimer ) , AP-1 ( c , Fos/c , and Jun heterodimer ) and IRF3 XREF_BIBR XREF_BIBR .	Upon ligand binding, TLR4 signalling activates transcription factors NF-kappaB (p50 and p65 heterodimer), AP-1 (c, Fos/c, and Jun heterodimer) and IRF3 XREF_BIBR XREF_BIBR.	4	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Jun	Jun	Jun	4	5	24	25
Activation of TLR4 also stimulates mitogen activated protein ( MAP ) and stress kinases including extracellular regulated kinase ( ERK ) 1/2 , p38 , and Jun kinase ( JNK ) 1/2 , which in turn activates transcription regulators of inflammation .	Activation of TLR4 also stimulates mitogen activated protein (MAP) and stress kinases including extracellular regulated kinase (ERK) 1/2, p38, and Jun kinase (JNK) 1/2, which in turn activates transcription regulators of inflammation.	0	27	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Jun	Jun	Jun	2	3	26	27
IL-27 upregulated TLR4 expression in lung fibroblasts through activation of Janus activated kinase ( JAK ) and Jun NH2-terminal kinase ( JNK ) signaling pathways , and inhibition of the JAK pathway could partially decrease IL-27-induced TLR4 expression , while inhibition of JNK pathway could completely suppress IL-27-induced TLR4 expression .	IL-27 upregulated TLR4 expression in lung fibroblasts through activation of Janus activated kinase (JAK) and Jun NH2-terminal kinase (JNK) signaling pathways, and inhibition of the JAK pathway could partially decrease IL-27-induced TLR4 expression, while inhibition of JNK pathway could completely suppress IL-27-induced TLR4 expression.	0	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	IL-27 upregulated TLR4 expression	tlr4	Jun	Jun	jun	2	3	17	18
TLR4 signaling activates pro inflammatory transcription factor AP-1 through ERK1/2 dependent phosphorylation XREF_BIBR .	TLR4 signaling activates pro inflammatory transcription factor AP-1 through ERK1/2 dependent phosphorylation XREF_BIBR.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	0	1	5	8
However , there was little decrease in TLR4 activated c-Jun nuclear localization .	However, there was little decrease in TLR4 activated c-Jun nuclear localization.	7	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	c-Jun	c-Jun	c-Jun	7	8	9	10
TLR2 activation can mediate signaling cascades through myeloid differentiation factor-88 ( MyD-88 ) and NF-kappaB , and TLR4 activation can activate NF-kappaB as well as activator protein 1 ( AP-1 ) , triggering cerebral inflammation by the upregulation of proinflammatory cytokines .	TLR2 activation can mediate signaling cascades through myeloid differentiation factor-88 (MyD-88) and NF-kappaB, and TLR4 activation can activate NF-kappaB as well as activator protein 1 (AP-1), triggering cerebral inflammation by the upregulation of proinflammatory cytokines.	17	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	activator protein 1	activator protein 1	activator protein 1	17	18	25	28
Taken together , these results indicate that TIRAP is unlikely to mediate the MyD88 independent pathway ; rather , it participates in the MyD88 dependent pathway downstream of TLR2 and TLR4 .	Taken together, these results indicate that TIRAP is unlikely to mediate the MyD88 independent pathway; rather, it participates in the MyD88 dependent pathway downstream of TLR2 and TLR4.	7	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	7	8	13	14
The saturation BRET results suggest that a threshold amount of TIRAP is needed to allow MyD88 to interact with TLR1/2 .	The saturation BRET results suggest that a threshold amount of TIRAP is needed to allow MyD88 to interact with TLR1/2.	8	17	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIRAP	amount of TIRAP	tirap	MyD88	MyD88	myd88	10	11	15	16
The TIRAP independent pathway rescued by LTA specific Abs is therefore also TLR2- and MyD88 dependent .	The TIRAP independent pathway rescued by LTA specific Abs is therefore also TLR2- and MyD88 dependent.	1	15	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	1	2	14	15
We do note however , that not all MyD88 dependent responses are mediated by TIRAP .	We do note however, that not all MyD88 dependent responses are mediated by TIRAP.	8	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	14	15	8	9
TIRAP mediates the activation of the MyD88 dependent pathway downstream of TLR2 and TLR4 [ XREF_BIBR , XREF_BIBR ] .	TIRAP mediates the activation of the MyD88 dependent pathway downstream of TLR2 and TLR4 [XREF_BIBR, XREF_BIBR].	0	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	0	1	6	7
As TIRAP construct concentrations increased , the linear relationship changed to a saturation curve , indicating that a minimum expression level of TIRAP was required to allow constitutive interaction of MyD88 with TLR1/2 ( XREF_FIG ) .	As TIRAP construct concentrations increased, the linear relationship changed to a saturation curve, indicating that a minimum expression level of TIRAP was required to allow constitutive interaction of MyD88 with TLR1/2 (XREF_FIG).	20	31	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIRAP	level of TIRAP	tirap	MyD88	MyD88	myd88	22	23	30	31
TRAM and TIRAP function to recruit MyD88 and TRIF to their respective TLRs and all TLRs , except for TLR3 , activate the MyD88 dependent pathway ( as reviewed by Kawai ) .	TRAM and TIRAP function to recruit MyD88 and TRIF to their respective TLRs and all TLRs, except for TLR3, activate the MyD88 dependent pathway (as reviewed by Kawai).	0	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	2	3	23	24
In addition , MyD88 independent pathway is triggered by TIRAP and Mal signals through RNA dependent protein kinase ( PKR ) and interferon regulatory factor -- 3 ( IRF -- 3 ) .	In addition, MyD88 independent pathway is triggered by TIRAP and Mal signals through RNA dependent protein kinase (PKR) and interferon regulatory factor -- 3 (IRF -- 3).	3	12	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	9	10	3	4
The MyD88 dependent pathway is mediated by the adaptors MyD88 and TIRAP , leading to activation of NFkappaB and MAPK family members and induction of inflammatory cytokines .	The MyD88 dependent pathway is mediated by the adaptors MyD88 and TIRAP, leading to activation of NFkappaB and MAPK family members and induction of inflammatory cytokines.	1	12	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	11	12	1	2
MyD88 and TIRAP mediate rapid activation of NF-kappaB and mitogen activated protein kinases ( MAPKs ) and induce MyD88 dependent cytokines , such as TNF-alpha and IL-1beta .	MyD88 and TIRAP mediate rapid activation of NF-kappaB and mitogen activated protein kinases (MAPKs) and induce MyD88 dependent cytokines, such as TNF-alpha and IL-1beta.	0	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	2	3	18	19
TIRAP mediates the activation of the MyD88 dependent pathway downstream of TLR2 and TLR4 [ XREF_BIBR ] .	TIRAP mediates the activation of the MyD88 dependent pathway downstream of TLR2 and TLR4 [XREF_BIBR].	0	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	0	1	6	7
TIRAP mediates the activation of a MyD88 dependent pathway downstream of TLR2 and TLR4 .	TIRAP mediates the activation of a MyD88 dependent pathway downstream of TLR2 and TLR4.	0	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	0	1	6	7
This observation adds evidence for a potential dual role of CD14 molecule in TLR2- or TLR4 induced TIRAP mediated activation of IL-8 , possibly even TLR9 induced TRAF6 mediated IFN-beta activation .	This observation adds evidence for a potential dual role of CD14 molecule in TLR2- or TLR4 induced TIRAP mediated activation of IL-8, possibly even TLR9 induced TRAF6 mediated IFN-beta activation.	11	19	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TIRAP	TIRAP	TIRAP	15	16	17	18
In contrast , the TLR4 mediated maturation of DCs and the activation of IRF3 were intact in TIRAP deficient mice .	In contrast, the TLR4 mediated maturation of DCs and the activation of IRF3 were intact in TIRAP deficient mice.	3	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TIRAP	TIRAP	TIRAP	4	5	17	18
Consistent with coupling of TLR2 and TLR4 , but not TLR3 , through TIRAP , IT TLR2 and TLR4 agonists initiated TA was absent in Tirap -/- mice , while TLR3-L effects were unaltered .	Consistent with coupling of TLR2 and TLR4, but not TLR3, through TIRAP, IT TLR2 and TLR4 agonists initiated TA was absent in Tirap -/- mice, while TLR3-L effects were unaltered.	18	27	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	Tirap	Tirap	Tirap	18	19	25	26
TRIF activates TANK binding kinase 1 ( TBK1 ) and receptor interacting serine/threonine kinase 1 ( RIPK1 ) , respectively , which creates a branch in the signaling pathway .	TRIF activates TANK binding kinase 1 (TBK1) and receptor interacting serine/threonine kinase 1 (RIPK1), respectively, which creates a branch in the signaling pathway.	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	RIPK1	RIPK1	RIPK1	0	1	16	17
Therefore , oligomerization of TRIF , and thus RIPK3 , can promote the activation of the latter independently of RIPK1 .	Therefore, oligomerization of TRIF, and thus RIPK3, can promote the activation of the latter independently of RIPK1.	2	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	RIPK1	RIPK1	RIPK1	4	5	19	20
TRAM recruits the Toll and interleukin -1 receptor ( TIR )-domain-containing adaptor protein inducing interferon-beta ( TRIF ) which activates the tumor-necrosis factor-receptor-associated factor 3 ( TRAF3 ) , TRAF6 and receptor interacting protein 1 ( RIP1 ) .	TRAM recruits the Toll and interleukin -1 receptor (TIR)-domain-containing adaptor protein inducing interferon-beta (TRIF) which activates the tumor-necrosis factor-receptor-associated factor 3 (TRAF3), TRAF6 and receptor interacting protein 1 (RIP1).	14	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	RIP1	RIP1	RIP1	16	17	36	37
Analogously to TNFR1 , signaling through either of these TLRs normally leads to pro inflammatory and pro survival responses in the cell due to NF-kappaB and IRF-3 activation , but when cells are sensitized to necroptosis by inhibition of capase-8 and cFLIP , TRIF can activate RIPK1 and/or RIPK3 .	Analogously to TNFR1, signaling through either of these TLRs normally leads to pro inflammatory and pro survival responses in the cell due to NF-kappaB and IRF-3 activation, but when cells are sensitized to necroptosis by inhibition of capase-8 and cFLIP, TRIF can activate RIPK1 and/or RIPK3.	43	48	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIF	TRIF	TRIF	RIPK1	RIPK1	RIPK1	43	44	46	47
The activation of TPOR by thrombopoietin ( TPO ) ( a glycoprotein hormone ) triggers an intracellular cascade of megakaryocytopoiesis for the formation of platelets .	The activation of TPOR by thrombopoietin (TPO) (a glycoprotein hormone) triggers an intracellular cascade of megakaryocytopoiesis for the formation of platelets.	1	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	thrombopoietin	thrombopoietin	thrombopoietin	TPOR	TPOR	TPOR	5	6	3	4
These thrombopoietin mimetics bind to and activate the thrombopoietin receptor , c-Mpl , and cause proliferation and differentiation of megakaryocyte progenitor cells [ XREF_BIBR ] .	These thrombopoietin mimetics bind to and activate the thrombopoietin receptor, c-Mpl, and cause proliferation and differentiation of megakaryocyte progenitor cells [XREF_BIBR].	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombopoietin	thrombopoietin	thrombopoietin	thrombopoietin receptor	thrombopoietin receptor	thrombopoietin receptor	1	2	8	10
We also demonstrate that upon MGDF stimulation Mpl receptor activates the classical transduction pathways described for hematopoietic cell lines in FRE cells .	We also demonstrate that upon MGDF stimulation Mpl receptor activates the classical transduction pathways described for hematopoietic cell lines in FRE cells.	5	8	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MGDF	MGDF	MGDF	Mpl	Mpl	Mpl	5	6	7	8
Importantly , CALR exon 9 mutations were suggested to be early initiating events in MPN , and more recently mutant CALR ( mCALR ) has been shown to mediate thrombopoietin independent activation of the thrombopoietin receptor MPL [ XREF_BIBR , XREF_BIBR ] .	Importantly, CALR exon 9 mutations were suggested to be early initiating events in MPN, and more recently mutant CALR (mCALR) has been shown to mediate thrombopoietin independent activation of the thrombopoietin receptor MPL [XREF_BIBR, XREF_BIBR].	29	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	thrombopoietin	thrombopoietin	thrombopoietin	MPL	MPL	MPL	29	30	36	37
These thrombocytopenic mice had low Thpo levels and could be rescued by the application of Thpo , indicating a competition of the ectopic and endogenous Mpl for Thpo binding and subsequent internalization .	These thrombocytopenic mice had low Thpo levels and could be rescued by the application of Thpo, indicating a competition of the ectopic and endogenous Mpl for Thpo binding and subsequent internalization.	10	31	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Thpo	Thpo	Thpo	Mpl	Mpl	Mpl	15	16	25	26
Romiplostim , a thrombopoietin mimetic peptibody that stimulates the thrombopoietin receptor , has been used as a treatment for primary immune thrombocytopenia .	Romiplostim, a thrombopoietin mimetic peptibody that stimulates the thrombopoietin receptor, has been used as a treatment for primary immune thrombocytopenia.	3	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombopoietin	thrombopoietin	thrombopoietin	thrombopoietin receptor	thrombopoietin receptor	thrombopoietin receptor	3	4	9	11
Thrombocytosis can be due to genetic alterations that affect either the intrinsic MPL signaling through gain-of-function ( GOF ) activity ( MPL , JAK2 , CALR ) and loss-of-function ( LOF ) activity of negative regulators ( CBL , LNK ) or the extrinsic MPL signaling by THPO GOF mutations leading to increased TPO synthesis .	Thrombocytosis can be due to genetic alterations that affect either the intrinsic MPL signaling through gain-of-function (GOF) activity (MPL, JAK2, CALR) and loss-of-function (LOF) activity of negative regulators (CBL, LNK) or the extrinsic MPL signaling by THPO GOF mutations leading to increased TPO synthesis.	44	49	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	THPO	THPO	THPO	MPL	MPL	MPL	47	48	44	45
Alternatively , Lyp may serve to dephosphorylate an inhibitor of TLR signaling , thereby promoting TLR responses , and Lyp620W may be more effective at turning off this inhibitory pathway .	Alternatively, Lyp may serve to dephosphorylate an inhibitor of TLR signaling, thereby promoting TLR responses, and Lyp620W may be more effective at turning off this inhibitory pathway.	2	16	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	Lyp may serve to dephosphorylate an inhibitor of TLR	tlr	TLR	TLR	tlr	10	11	15	16
Briefly , they are poly-C , poly-AC repeat based or degenerate oligonucleotides containing , or not , the following modifications : phosphorothioation ( PS ) increasing stability and amphipathicity , 2 ' O-methyl ribose modification ( 2 ' O-Me ) increasing stability and reducing TLR reactivity and methylation of cytosine bases ( 5-MeC ) reducing TLR reactivity .	Briefly, they are poly-C, poly-AC repeat based or degenerate oligonucleotides containing, or not, the following modifications : phosphorothioation (PS) increasing stability and amphipathicity, 2 ' O-methyl ribose modification (2 ' O-Me) increasing stability and reducing TLR reactivity and methylation of cytosine bases (5-MeC) reducing TLR reactivity.	23	56	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR	PS) increasing stability and amphipathicity, 2 ' O-methyl ribose modification (2 ' O-Me) increasing stability and reducing TLR reactivity and methylation	tlr	TLR	TLR	tlr	44	45	55	56
These observations , taken with our finding that NKG2D ligand expression increases NK cell sensitivity to LPS induced TLR stimulation ( as assessed by intracellular IFN-gamma ) led us to postulate that NKG2D and TLR co-stimulation creates an amplification loop following recognition of pathogen .	These observations, taken with our finding that NKG2D ligand expression increases NK cell sensitivity to LPS induced TLR stimulation (as assessed by intracellular IFN-gamma) led us to postulate that NKG2D and TLR co-stimulation creates an amplification loop following recognition of pathogen.	8	35	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	NKG2D ligand expression increases NK cell sensitivity to LPS induced TLR	tlr	TLR	TLR	tlr	18	19	34	35
The ANKRD1 gene is associated with the actin cytoskeleton signalling network [ XREF_BIBR ] , in our model thrombin mediated transactivation of the TGFBR1 activates Rho and ROCK signalling via cytoskeletal rearrangement leading to the activation of cell surface integrins [ XREF_BIBR ] .	The ANKRD1 gene is associated with the actin cytoskeleton signalling network [XREF_BIBR], in our model thrombin mediated transactivation of the TGFBR1 activates Rho and ROCK signalling via cytoskeletal rearrangement leading to the activation of cell surface integrins [XREF_BIBR].	20	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFBR1	TGFBR1	TGFBR1	Rho	Rho	Rho	23	24	25	26
Furthermore , we show that ALK5 mediated activation of RhoA is required for efficient ( V12 ) HaRas , V-Raf and ( V600E ) BRAF transformation and ( V12 ) HaRas mediated anchorage independent growth .	Furthermore, we show that ALK5 mediated activation of RhoA is required for efficient (V12) HaRas, V-Raf and (V600E) BRAF transformation and (V12) HaRas mediated anchorage independent growth.	5	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	RhoA	RhoA	RhoA	5	6	9	10
Although most of the previous studies showed a TbetaRI and Smad dependent mechanism for TGFbeta activated RhoA signalling XREF_BIBR XREF_BIBR , a recent study reported a TbetaRII-Src signalling mediated but TbetaRI and Smad independent mechanism for TGFbeta stimulated early RhoA and RhoB activation XREF_BIBR .	Although most of the previous studies showed a TbetaRI and Smad dependent mechanism for TGFbeta activated RhoA signalling XREF_BIBR XREF_BIBR, a recent study reported a TbetaRII-Src signalling mediated but TbetaRI and Smad independent mechanism for TGFbeta stimulated early RhoA and RhoB activation XREF_BIBR.	7	19	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TbetaRI	TbetaRI	TbetaRI	RhoA	RhoA	RhoA	8	9	16	17
Although the SMAD dependent induction of RHO GEFs has been described in other studies , [ XREF_BIBR , XREF_BIBR ] how TGFBR1 directly activates RHOA in melanoma cells in a SMAD independent manner is unclear at present .	Although the SMAD dependent induction of RHO GEFs has been described in other studies, [XREF_BIBR, XREF_BIBR] how TGFBR1 directly activates RHOA in melanoma cells in a SMAD independent manner is unclear at present.	21	25	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFBR1	TGFBR1	TGFBR1	RHOA	RHOA	RHOA	21	22	24	25
Moreover , our data suggest that TLR4 activation of the TPL-2 pathway negatively regulates the production of IFN-beta , in contrast to its positive effects on IL-10 production .	Moreover, our data suggest that TLR4 activation of the TPL-2 pathway negatively regulates the production of IFN-beta, in contrast to its positive effects on IL-10 production.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TPL-2	TPL-2	TPL-2	6	7	10	11
TLR activation causes TIRAP to oligomerize with MyD88 and IRAK kinases , thus creating a SMOC called the myddosome that promotes the expression of inflammatory cytokines and IFNs .	TLR activation causes TIRAP to oligomerize with MyD88 and IRAK kinases, thus creating a SMOC called the myddosome that promotes the expression of inflammatory cytokines and IFNs.	0	4	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TIRAP	TIRAP	TIRAP	0	1	3	4
We and others have shown that RAC1 can be activated by TGF-beta and ALK5 and is itself involved in intracellular signal transduction by promoting the C-terminal phosphorylation and activation of SMAD2 [ XREF_BIBR ] and p38 MAPK [ XREF_BIBR ] .	We and others have shown that RAC1 can be activated by TGF-beta and ALK5 and is itself involved in intracellular signal transduction by promoting the C-terminal phosphorylation and activation of SMAD2 [XREF_BIBR] and p38 MAPK [XREF_BIBR].	6	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ALK5	ALK5	ALK5	RAC1	RAC1	RAC1	13	14	6	7
Likewise , overexpression of TGIF also diminished GLalpha promoter activity and further strengthened the inhibitory effect of Tiul1 , suggesting that Tiul1 and TGIF can down-regulate TGFbeta1 induced GLalpha expression .	Likewise, overexpression of TGIF also diminished GLalpha promoter activity and further strengthened the inhibitory effect of Tiul1, suggesting that Tiul1 and TGIF can down-regulate TGFbeta1 induced GLalpha expression.	2	18	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TGIF	overexpression of TGIF	tgif	Tiul1	Tiul1	tiul1	4	5	17	18
In this study , we found that TNF-alpha induces c-Src-mediated signal activation in HCFs via TNFR1 , in turn initiates the activation of EGFR , PI3K and Akt , and NF-kappaB .	In this study, we found that TNF-alpha induces c-Src-mediated signal activation in HCFs via TNFR1, in turn initiates the activation of EGFR, PI3K and Akt, and NF-kappaB.	7	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	7	8	27	28
One unique property of Sulindac and analogs is their ability to inhibit TNFalpha induced AKT activation .	One unique property of Sulindac and analogs is their ability to inhibit TNFalpha induced AKT activation.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	12	13	14	15
Whereas TNFalpha activated Akt , ERK and P38 MAPK simultaneously in hMEC , inhibitors of Akt and P38 MAPK , but not ERK blunted TNFalpha induced TSP-1 expression .	Whereas TNFalpha activated Akt, ERK and P38 MAPK simultaneously in hMEC, inhibitors of Akt and P38 MAPK, but not ERK blunted TNFalpha induced TSP-1 expression.	1	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	1	2	3	4
Celecoxib has also recently been shown to decrease the activation of the transcription factor NFkappaB in lung cancer cell lines ; celecoxib was found to interfere with the tumour necrosis factor-alpha ( TNF-alpha ) induced interaction of AKT with IKK ( the protein kinase required for NFkappaB activation ) .	Celecoxib has also recently been shown to decrease the activation of the transcription factor NFkappaB in lung cancer cell lines; celecoxib was found to interfere with the tumour necrosis factor-alpha (TNF-alpha) induced interaction of AKT with IKK (the protein kinase required for NFkappaB activation).	30	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	32	33	37	38
The molecular link between the NF-kappaB and PDK1 and AKT signaling remains to be determined , but both IL-1 and TNF have been shown to trigger AKT activation in a PI3K dependent manner [ XREF_BIBR , XREF_BIBR ] .	The molecular link between the NF-kappaB and PDK1 and AKT signaling remains to be determined, but both IL-1 and TNF have been shown to trigger AKT activation in a PI3K dependent manner [XREF_BIBR, XREF_BIBR].	18	27	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	20	21	26	27
FOXO1 siRNA blocked TNF-alpha induced upregulation of apoptosis pathway and Akt pathway gene sets , but had no effect on the p53 pathway gene set .	FOXO1 siRNA blocked TNF-alpha induced upregulation of apoptosis pathway and Akt pathway gene sets, but had no effect on the p53 pathway gene set.	3	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	3	4	10	11
When the effect of 23 on the PI3K and AKT signaling was examined , we found that it could suppress basal and TNFalpha induced AKT activation and induce apoptosis in cancer cells in a RXRalpha dependent manner .	When the effect of 23 on the PI3K and AKT signaling was examined, we found that it could suppress basal and TNFalpha induced AKT activation and induce apoptosis in cancer cells in a RXRalpha dependent manner.	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	22	23	24	25
Here , we report that TNF-alpha activates other antiapoptotic factors , such as sphingosine kinase ( SphK ) , phosphatidylinositol 3-kinase ( PI3K ) , and Akt kinase .	Here, we report that TNF-alpha activates other antiapoptotic factors, such as sphingosine kinase (SphK), phosphatidylinositol 3-kinase (PI3K), and Akt kinase.	5	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	5	6	26	27
These data indicate that the observed increase in TNF production from human skin mast cells pre-treated with 10 microM Resveratrol ( XREF_FIG ) was not due to an increase in FcepsilonRI induced activation of Akt , p38 or p42/44 .	These data indicate that the observed increase in TNF production from human skin mast cells pre-treated with 10 microM Resveratrol (XREF_FIG) was not due to an increase in FcepsilonRI induced activation of Akt, p38 or p42/44.	8	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	8	9	34	35
Both TNF knockout and overexpression attenuate HF neogenesis in wounds , suggesting dose dependent induction of HF neogenesis by TNF , which is consistent with TNF induced AKT signalling in epidermal stem cells in vitro .	Both TNF knockout and overexpression attenuate HF neogenesis in wounds, suggesting dose dependent induction of HF neogenesis by TNF, which is consistent with TNF induced AKT signalling in epidermal stem cells in vitro.	23	28	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	25	26	27	28
The detailed mechanisms of how Cr ( VI ) impacts the activation of the Akt , NF-kappaB and MAPK pathways , expression of TNF-alpha and IL-1alpha mRNA and release of IL-1alpha are complicated .	The detailed mechanisms of how Cr (VI) impacts the activation of the Akt, NF-kappaB and MAPK pathways, expression of TNF-alpha and IL-1alpha mRNA and release of IL-1alpha are complicated.	11	26	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	TNF-alpha	expression of TNF-alpha	tnf-alpha	Akt	Akt	akt	23	24	14	15
Pharmacological inhibition of PI 3-kinase blocked TNF induced NF-kappa B DNA binding in the 293 line of embryonic kidney cells , partially affected binding in MCF-7 breast cancer cells , HeLa and ME-180 cervical carcinoma cells , and NIH 3T3 cells but was without significant effect in H1299 and human umbilical vein endothelial cells , cell types in which TNF activated Akt .	Pharmacological inhibition of PI 3-kinase blocked TNF induced NF-kappa B DNA binding in the 293 line of embryonic kidney cells, partially affected binding in MCF-7 breast cancer cells, HeLa and ME-180 cervical carcinoma cells, and NIH 3T3 cells but was without significant effect in H1299 and human umbilical vein endothelial cells, cell types in which TNF activated Akt.	59	62	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	59	60	61	62
The TNF induced activation of AKT and S6K1 could be blocked by Torin-1 and PP242 ( XREF_FIG B ) , two specific inhibitors of both mTORC1 and mTORC2 functions , indicating that TNF specifically activates AKT and S6K1 via mTOR .	The TNF induced activation of AKT and S6K1 could be blocked by Torin-1 and PP242 (XREF_FIG B), two specific inhibitors of both mTORC1 and mTORC2 functions, indicating that TNF specifically activates AKT and S6K1 via mTOR.	32	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	32	33	35	36
In MCF7 cells , TNF does not activate Akt and requires IKKbeta to activate mTOR .	In MCF7 cells, TNF does not activate Akt and requires IKKbeta to activate mTOR.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	4	5	8	9
Here we report that both TNF and IL-1 activate the anti-apoptotic protein kinase Akt in growth factor and serum deprived EC , assessed by Western blotting for phospho-Akt .	Here we report that both TNF and IL-1 activate the anti-apoptotic protein kinase Akt in growth factor and serum deprived EC, assessed by Western blotting for phospho-Akt.	4	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	5	6	13	14
Of note , Neither IL-17 or TNF-alpha activates AKT signaling in LNCaP cells .	Of note, Neither IL-17 or TNF-alpha activates AKT signaling in LNCaP cells.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	6	7	8	9
In HeLa cells , TNFalpha treatment enhanced AKT activation , while CF31 and K-80003 showed comparable effect on inhibiting AKT activation .	In HeLa cells, TNFalpha treatment enhanced AKT activation, while CF31 and K-80003 showed comparable effect on inhibiting AKT activation.	4	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	4	5	7	8
Sulindac Inhibits RXRalpha dependent AKT Activation by TNFalpha .	Sulindac Inhibits RXRalpha dependent AKT Activation by TNFalpha.	4	8	Activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	7	8	4	5
To gain insight into the mechanisms underlying TNF induced AKT signalling , we performed an in vitro analysis of Epi-SCs .	To gain insight into the mechanisms underlying TNF induced AKT signalling, we performed an in vitro analysis of Epi-SCs.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	7	8	9	10
Whereas inhibition of CAM and CAMKII both completely prevented TNFalpha dependent activation of AKT , neither W7 nor KN62 affected the basal phosphorylation level of AKT ; such constitutive AKT activity , which is not a rare finding in macrophages from different sources and species [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] , might explain the constitutive phosphorylation of GSK3beta which was not modified by TNFalpha treatment but completely suppressed by inhibition of PI3K , an obligatory upstream regulator of AKT .	Whereas inhibition of CAM and CAMKII both completely prevented TNFalpha dependent activation of AKT, neither W7 nor KN62 affected the basal phosphorylation level of AKT; such constitutive AKT activity, which is not a rare finding in macrophages from different sources and species [XREF_BIBR; XREF_BIBR; XREF_BIBR], might explain the constitutive phosphorylation of GSK3beta which was not modified by TNFalpha treatment but completely suppressed by inhibition of PI3K, an obligatory upstream regulator of AKT.	9	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	9	10	13	14
PJ also abolished TNFalpha induced AKT activation , needed for NFkappaB activity .	PJ also abolished TNFalpha induced AKT activation, needed for NFkappaB activity.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	3	4	5	6
Based on different responses to EGF or TNF in ovarian cancer cells , we compared those signaling components previously related with EGF- or TNF activated Akt , Erk and IkappaB in ovarian cancer cells .	Based on different responses to EGF or TNF in ovarian cancer cells, we compared those signaling components previously related with EGF- or TNF activated Akt, Erk and IkappaB in ovarian cancer cells.	16	29	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	23	24	25	26
Thus , NGF and NGF induced TNF-alpha cooperate to activate Akt , promoting survival of normal neural cells .	Thus, NGF and NGF induced TNF-alpha cooperate to activate Akt, promoting survival of normal neural cells.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	NGF induced TNF-alpha	tnf-alpha	Akt	Akt	akt	6	7	10	11
Consistent with this result , ErbB4 overexpression enhanced both basal and TNF stimulated Akt activation ( XREF_FIG and XREF_SUPPLEMENTARY ) without affecting other downstream signaling cascades tested .	Consistent with this result, ErbB4 overexpression enhanced both basal and TNF stimulated Akt activation (XREF_FIG and XREF_SUPPLEMENTARY) without affecting other downstream signaling cascades tested.	9	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	11	12	13	14
We then determined whether the ability of triptolide to inhibit TNFalpha activation of AKT could result in TNFalpha activation of caspase 8 dependent apoptotic pathway XREF_BIBR .	We then determined whether the ability of triptolide to inhibit TNFalpha activation of AKT could result in TNFalpha activation of caspase 8 dependent apoptotic pathway XREF_BIBR.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	10	11	13	14
Akt , also activated by TNF-alpha , has been shown to associate with and subsequently activate IKK as shown previously in cells other than HUVECs XREF_BIBR , XREF_BIBR .	Akt, also activated by TNF-alpha, has been shown to associate with and subsequently activate IKK as shown previously in cells other than HUVECs XREF_BIBR, XREF_BIBR.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	5	6	0	1
Although leptin protection might be limited in extreme models of obesity , benefit could be preserved in obesity with insulin-sensitivity , and absence of elevations in TNF-alpha could further promote Akt dependent protection .	Although leptin protection might be limited in extreme models of obesity, benefit could be preserved in obesity with insulin-sensitivity, and absence of elevations in TNF-alpha could further promote Akt dependent protection.	24	32	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	26	27	30	31
CNPs , significantly inhibit proinflammatory cytokines TNF-alpha and IL-8 through blockade of mitogen activated protein kinase ( MAPK ) and phosphoinistol kinase ( PI3K and Akt ) signaling pathways and suppressing the activation of NFkappaB [ XREF_BIBR ] .	CNPs, significantly inhibit proinflammatory cytokines TNF-alpha and IL-8 through blockade of mitogen activated protein kinase (MAPK) and phosphoinistol kinase (PI3K and Akt) signaling pathways and suppressing the activation of NFkappaB [XREF_BIBR].	6	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	6	7	25	26
PKD2 binds to PI3K subunits to stimulate TNF-alpha induced activation of AKT and GSK-3beta .	PKD2 binds to PI3K subunits to stimulate TNF-alpha induced activation of AKT and GSK-3beta.	7	13	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	7	8	11	12
Moreover , the TNF superfamily members APRIL and B-cell-activating factor ( BAFF ) , upon engagement with their receptors , have recently been shown to activate the PI3K and Akt pathway in malignant B cells XREF_BIBR , XREF_BIBR .	Moreover, the TNF superfamily members APRIL and B-cell-activating factor (BAFF), upon engagement with their receptors, have recently been shown to activate the PI3K and Akt pathway in malignant B cells XREF_BIBR, XREF_BIBR.	2	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	3	4	29	30
We previously demonstrated that inhibition of AKT activation by the Sulindac and TNFalpha combination was closely associated with its apoptotic effect [ XREF_BIBR ] .	We previously demonstrated that inhibition of AKT activation by the Sulindac and TNFalpha combination was closely associated with its apoptotic effect [XREF_BIBR].	6	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	12	13	6	7
The PI3K and Akt signaling pathway was activated by TNF-alpha in NP cells .	The PI3K and Akt signaling pathway was activated by TNF-alpha in NP cells.	3	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	9	10	3	4
We then examined whether CF31 could inhibit TNFalpha activation of AKT .	We then examined whether CF31 could inhibit TNFalpha activation of AKT.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	7	8	10	11
Treatment with two pharmacological inhibitors of NF-kappa B , SN50 and N-tosyl-l-phenylalanine chloromethyl ketone ( TPCK ) , blocks TNF induced Akt activation .	Treatment with two pharmacological inhibitors of NF-kappa B, SN50 and N-tosyl-l-phenylalanine chloromethyl ketone (TPCK), blocks TNF induced Akt activation.	19	22	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	19	20	21	22
The present study shows that PTEN , a tumor suppressor that inhibits PI 3-kinase function , impairs TNF activation of Akt and the IKK complex in 293 cells .	The present study shows that PTEN, a tumor suppressor that inhibits PI 3-kinase function, impairs TNF activation of Akt and the IKK complex in 293 cells.	17	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	17	18	20	21
Though PI3 and Akt signalling pathway can be activated by TNF-alpha in human smooth muscle cells [ XREF_BIBR ] or IL-1beta in rat brain astrocytes [ XREF_BIBR ] , our results are consistent with BDNF induced migration in human chondrosarcoma [ XREF_BIBR ] through a transducing signal involving TrkB .	Though PI3 and Akt signalling pathway can be activated by TNF-alpha in human smooth muscle cells [XREF_BIBR] or IL-1beta in rat brain astrocytes [XREF_BIBR], our results are consistent with BDNF induced migration in human chondrosarcoma [XREF_BIBR] through a transducing signal involving TrkB.	3	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	10	11	3	4
XREF_BIBR , XREF_BIBR Here , TNF induced activation of the Akt and ERK signaling , on both transient and sustained time scales , was dependent on autocrine TGF-alpha ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR Here, TNF induced activation of the Akt and ERK signaling, on both transient and sustained time scales, was dependent on autocrine TGF-alpha (XREF_FIG).	5	13	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	5	6	10	11
XREF_BIBR It is known that TNF-alpha signaling activates AKT for NF-kappaB activation , XREF_BIBR and PAK1 might be another player in the activation of NF-kappaB pathway .	XREF_BIBR It is known that TNF-alpha signaling activates AKT for NF-kappaB activation, XREF_BIBR and PAK1 might be another player in the activation of NF-kappaB pathway.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	5	6	8	9
In this study , we showed that TNF-alpha stimulation resulted in increased Akt activation and time dependent association of Akt to IKK-beta .	In this study, we showed that TNF-alpha stimulation resulted in increased Akt activation and time dependent association of Akt to IKK-beta.	7	14	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	7	8	12	13
To investigate whether triptolide could inhibit TNFalpha induced AKT activation , MCF-7 cells were treated with vehicle or 10 nM TNFalpha in the presence or absence of triptolide .	To investigate whether triptolide could inhibit TNFalpha induced AKT activation, MCF-7 cells were treated with vehicle or 10 nM TNFalpha in the presence or absence of triptolide.	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	6	7	8	9
In agreement with previous results XREF_BIBR , immunoblotting assays showed that TNFalpha strongly induced AKT activation in these cells , which was inhibited by triptolide in a dose dependent manner ( XREF_FIG ) .	In agreement with previous results XREF_BIBR, immunoblotting assays showed that TNFalpha strongly induced AKT activation in these cells, which was inhibited by triptolide in a dose dependent manner (XREF_FIG).	11	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	11	12	14	15
Pretreatment with ' classic ' ( ERalpha and ERbeta ) or ' non classic ' ( GPR30 ) oestrogen receptor ( ER ) inhibitors ( ICI182 ,780 and PTX , respectively ) counteracted the ability of Apigenin to decrease the TNFalpha triggered activation of the Akt pathway .	Pretreatment with ' classic ' (ERalpha and ERbeta) or ' non classic ' (GPR30) oestrogen receptor (ER) inhibitors (ICI182,780 and PTX, respectively) counteracted the ability of Apigenin to decrease the TNFalpha triggered activation of the Akt pathway.	39	46	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	40	41	45	46
Activated Akt is a downstream effector of PI3K , which can inhibit apoptosis by regulating multiple targets such as mitochondrial permeability transition pore ( MPTP ) , ATPase , tumour necrosis factor alpha ( TNF-alpha ) , endothelial nitric oxide synthase ( eNOS ) , the Bcl-2 family proteins , and NF-kappaB XREF_BIBR .	Activated Akt is a downstream effector of PI3K, which can inhibit apoptosis by regulating multiple targets such as mitochondrial permeability transition pore (MPTP), ATPase, tumour necrosis factor alpha (TNF-alpha), endothelial nitric oxide synthase (eNOS), the Bcl-2 family proteins, and NF-kappaB XREF_BIBR.	0	35	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	34	35	1	2
The use of inhibitors that block individual PI3K isoforms , including the novel selective PI3Kdelta inhibitor INK007 , showed that PI3Kdelta is required for PDGF- and TNF induced Akt activation .	The use of inhibitors that block individual PI3K isoforms, including the novel selective PI3Kdelta inhibitor INK007, showed that PI3Kdelta is required for PDGF- and TNF induced Akt activation.	22	29	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	26	27	28	29
The inhibition of TNFalpha induced tRXRalpha and p85alpha complex formation by N-6 implies that N-6 targets tRXRalpha to inhibit TNFalpha induced AKT activation and to induce cancer cell apoptosis .	The inhibition of TNFalpha induced tRXRalpha and p85alpha complex formation by N-6 implies that N-6 targets tRXRalpha to inhibit TNFalpha induced AKT activation and to induce cancer cell apoptosis.	18	22	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	19	20	21	22
We hypothesized at the time 1 ) that TNF acting through one of its receptors led to activation of PI3K and Akt and 2 ) that PKA phosphorylation of GluA1ser845 and trafficking into the membrane was downstream not only of the spinal TNF release , but also of the PI3K and Akt activation .	We hypothesized at the time 1) that TNF acting through one of its receptors led to activation of PI3K and Akt and 2) that PKA phosphorylation of GluA1ser845 and trafficking into the membrane was downstream not only of the spinal TNF release, but also of the PI3K and Akt activation.	8	22	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	8	9	21	22
Furthermore , flavopiridol suppressed TNF induced activation of Akt .	Furthermore, flavopiridol suppressed TNF induced activation of Akt.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	4	5	8	9
TNF-alpha induced marked activation of PI3-kinase and Akt and PKB , and the activation of PI3-kinase and Akt and PKB was rapid ( maximal at 10 and 15 min , respectively ) and concentration dependent .	TNF-alpha induced marked activation of PI3-kinase and Akt and PKB, and the activation of PI3-kinase and Akt and PKB was rapid (maximal at 10 and 15 min, respectively) and concentration dependent.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	PKB	PKB	PKB	0	1	9	10
In this work , we demonstrate that in the premalignant keratinocyte cell line HaCaT , TNF-alpha activates Akt , ERK1/2 and p38 .	In this work, we demonstrate that in the premalignant keratinocyte cell line HaCaT, TNF-alpha activates Akt, ERK1/2 and p38.	15	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	15	16	17	18
We then investigated whether compound 30 could inhibit TNFalpha induced AKT activation .	We then investigated whether compound 30 could inhibit TNFalpha induced AKT activation.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	8	9	10	11
Figure XREF_FIG A showed that N-6 significantly inhibited TNFalpha induced AKT activation in HCT116 cells , revealed by its suppression of the expression of phosphor-AKT but not total AKT .	Figure XREF_FIG A showed that N-6 significantly inhibited TNFalpha induced AKT activation in HCT116 cells, revealed by its suppression of the expression of phosphor-AKT but not total AKT.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	8	9	10	11
We reported previously that K-80003 , a Sulindac derivative , could inhibit TNFalpha induced Akt activation by preventing the interaction of tRXRalpha and p85alpha .	We reported previously that K-80003, a Sulindac derivative, could inhibit TNFalpha induced Akt activation by preventing the interaction of tRXRalpha and p85alpha.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	12	13	14	15
TNF targets the quiescent and slow cycling stem cells and promotes PI3K and AKT driven expansion in melanoma by preventing their asymmetrical self-renewal [ XREF_BIBR ] .	TNF targets the quiescent and slow cycling stem cells and promotes PI3K and AKT driven expansion in melanoma by preventing their asymmetrical self-renewal [XREF_BIBR].	0	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	0	1	13	14
On the other hand , TNF clearly activated IkappaB ( and gradually Akt and Erk ) in preadipocytes whereas it had no or less effect in adipocytes ( XREF_FIG ) .	On the other hand, TNF clearly activated IkappaB (and gradually Akt and Erk) in preadipocytes whereas it had no or less effect in adipocytes (XREF_FIG).	5	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	5	6	12	13
In contrast , AKT and ERK1/2 signaling pathways were not activated by IL-17 or TNF-alpha in LNCaP cells .	In contrast, AKT and ERK1/2 signaling pathways were not activated by IL-17 or TNF-alpha in LNCaP cells.	3	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	14	15	3	4
TNFalpha can act independently of TGF-beta to induce EMT by repressing GSK-3beta , activating the AKT pathway , and stabilizing Snail .	TNFalpha can act independently of TGF-beta to induce EMT by repressing GSK-3beta, activating the AKT pathway, and stabilizing Snail.	0	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	0	1	15	16
Consistently , LY294002 suppressed the TNF induced upregulation of GFP high ABCB5 high melanoma SCs , strongly supporting AKT involvement in the TNF mediated regulation of melanoma SC fate determination and functionality .	Consistently, LY294002 suppressed the TNF induced upregulation of GFP high ABCB5 high melanoma SCs, strongly supporting AKT involvement in the TNF mediated regulation of melanoma SC fate determination and functionality.	4	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	5	6	18	19
Curcumin also inhibits TNF induced Akt activation and its association with IKK .	Curcumin also inhibits TNF induced Akt activation and its association with IKK.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	3	4	5	6
Although this apoptosis was associated with a loss of Bcl-2 and Bcl-X ( L ) expression , allogeneic recipients of donor BM deficient in Fas-, tumor necrosis factor related apoptosis inducing ligand ( TRAIL ) - or Bax-, or BM overexpressing Bcl-2 or Akt showed no decrease in apoptosis of peripheral donor derived T cells .	Although this apoptosis was associated with a loss of Bcl-2 and Bcl-X (L) expression, allogeneic recipients of donor BM deficient in Fas-, tumor necrosis factor related apoptosis inducing ligand (TRAIL) - or Bax-, or BM overexpressing Bcl-2 or Akt showed no decrease in apoptosis of peripheral donor derived T cells.	25	44	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	Akt	Akt	Akt	25	28	43	44
XREF_BIBR The other enzymes , such as PDK1 and PTEN , were not affected by TNF-alpha ; this suggested that TNF-alpha activates Akt via an unknown pathway other than the PI3K pathway .	XREF_BIBR The other enzymes, such as PDK1 and PTEN, were not affected by TNF-alpha; this suggested that TNF-alpha activates Akt via an unknown pathway other than the PI3K pathway.	20	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	20	21	22	23
TNFalpha , a multifunctional cytokine , can activate AKT in a tRXRalpha dependent manner in certain cancer cells .	TNFalpha, a multifunctional cytokine, can activate AKT in a tRXRalpha dependent manner in certain cancer cells.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	0	1	8	9
TNF-alpha also increased mRNA levels of Akt and p53 apoptotic genes .	TNF-alpha also increased mRNA levels of Akt and p53 apoptotic genes.	0	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	0	1	6	7
In our studies , basal ErbB4 expression was required for acute TNF induced Akt signaling ( XREF_FIG ) .	In our studies, basal ErbB4 expression was required for acute TNF induced Akt signaling (XREF_FIG).	8	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	11	12	13	14
Knocking down RXRalpha expression by RXRalpha siRNA transfection significantly diminished the effect of K-8008 on inducing PARP cleavage ( XREF_FIG ) and inhibiting TNFalpha induced AKT activation ( XREF_FIG ) .	Knocking down RXRalpha expression by RXRalpha siRNA transfection significantly diminished the effect of K-8008 on inducing PARP cleavage (XREF_FIG) and inhibiting TNFalpha induced AKT activation (XREF_FIG).	22	26	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	23	24	25	26
TNF-alpha alone caused a modest activation of Akt in homogenates of all groups compared to pyrazole alone treated mice ( XREF_FIG ) .	TNF-alpha alone caused a modest activation of Akt in homogenates of all groups compared to pyrazole alone treated mice (XREF_FIG).	0	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	0	1	7	8
TNF-alpha activated NFkappaB p-P65 ( p = 0.002 ) , SAPK and JNK ( p = 0.005 ) , MAPK and ERK ( p = 0.01 ) , but not Akt or STAT2 pathways , whereas Abeta did not alter any of these pathways in hCMEC/D3 ( Additional file 7 ) .	TNF-alpha activated NFkappaB p-P65 (p = 0.002), SAPK and JNK (p = 0.005), MAPK and ERK (p = 0.01), but not Akt or STAT2 pathways, whereas Abeta did not alter any of these pathways in hCMEC/D3 (Additional file 7).	0	33	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	0	1	30	31
XREF_BIBR Recent studies also indicated that TNF-alpha could activate the PI3K and Akt pathway in synovial cells .	XREF_BIBR Recent studies also indicated that TNF-alpha could activate the PI3K and Akt pathway in synovial cells.	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	6	7	12	13
Our results suggested that TNF-alpha promoted ERK and Akt activation in HaCaT cells .	Our results suggested that TNF-alpha promoted ERK and Akt activation in HaCaT cells.	4	9	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	4	5	8	9
Since silencing of S6K1 caused a modest inhibition of TNF- and TRAIL induced apoptosis ( XREF_FIG ) , and S6K1 was shown to negatively regulate Akt via a feedback loop , we examined if knockdown of S6K1 enhances TNF induced activation of Akt in MCF-7 cells .	Since silencing of S6K1 caused a modest inhibition of TNF- and TRAIL induced apoptosis (XREF_FIG), and S6K1 was shown to negatively regulate Akt via a feedback loop, we examined if knockdown of S6K1 enhances TNF induced activation of Akt in MCF-7 cells.	38	45	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	38	39	42	43
AR was necessary for TNF-alpha activation of ERK1/2 and Akt signaling in hepatocytes .	AR was necessary for TNF-alpha activation of ERK1/2 and Akt signaling in hepatocytes.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	4	5	9	10
Therefore , AKT activation by IFN-gamma and TNF-alpha in human keratinocytes executes anti-apoptotic functions by activating the pro survival NF-kappaB cascade and , in parallel , by inducing BAD phosphorylation and inactivation and dissociation from the anti-apoptotic BCL-X L molecule .	Therefore, AKT activation by IFN-gamma and TNF-alpha in human keratinocytes executes anti-apoptotic functions by activating the pro survival NF-kappaB cascade and, in parallel, by inducing BAD phosphorylation and inactivation and dissociation from the anti-apoptotic BCL-X L molecule.	2	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	7	8	2	3
TNF can also activate PI3K and PKB .	TNF can also activate PI3K and PKB.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	PKB	PKB	PKB	0	1	6	7
Our result show that TNF-alpha is able to induce Akt activation in MDA-MB-231 cells .	Our result show that TNF-alpha is able to induce Akt activation in MDA-MB-231 cells.	4	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	4	5	9	10
TNF-alpha also caused PI3-kinase and Akt activation , which was further increased by PDTC and prevented by the PI3-kinase inhibitor , LY294002 .	TNF-alpha also caused PI3-kinase and Akt activation, which was further increased by PDTC and prevented by the PI3-kinase inhibitor, LY294002.	0	6	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	0	1	5	6
Interestingly , the detachment of PC-3 results in the upregulation of TNFalpha XREF_BIBR , which activates AKT signaling and cell survival in PC3 cells XREF_BIBR .	Interestingly, the detachment of PC-3 results in the upregulation of TNFalpha XREF_BIBR, which activates AKT signaling and cell survival in PC3 cells XREF_BIBR.	11	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	11	12	16	17
To examine the effect of MPTAG on activation of Akt by TNF-alpha , we pretreated cells with MPTAG followed by induction with TNF-alpha and performed western blot analysis to determine the levels of Akt phosphorylation at both Thr308 and Ser473 residues .	To examine the effect of MPTAG on activation of Akt by TNF-alpha, we pretreated cells with MPTAG followed by induction with TNF-alpha and performed western blot analysis to determine the levels of Akt phosphorylation at both Thr308 and Ser473 residues.	1	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	11	12	9	10
In BMDMs , TNFalpha induced rapid activation of the survival pathways NFkB , AKT and p38MAPK .	In BMDMs, TNFalpha induced rapid activation of the survival pathways NFkB, AKT and p38MAPK.	3	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	3	4	13	14
N-terminally Truncated RXRalpha Mediates TNFalpha Activation of the PI3K and AKT Pathway and Promotes Cancer Cell Growth and Survival .	N-terminally Truncated RXRalpha Mediates TNFalpha Activation of the PI3K and AKT Pathway and Promotes Cancer Cell Growth and Survival.	4	11	Activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	4	5	10	11
EGF and TNFalpha ligands stimulate ERK , JNK and p38 MAPK cascades , the PI3K and AKT pathways , and the NFkB cascade .	EGF and TNFalpha ligands stimulate ERK, JNK and p38 MAPK cascades, the PI3K and AKT pathways, and the NFkB cascade.	0	17	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	2	3	16	17
TNF-alpha ( 5 ng/mL ) caused activation of JNK , p38 MAPK , PI3K and Akt , whereas pretreatment with JNK inhibitor ( SP600125 ) , p38 MAPK inhibitor ( SB202190 ) or PI-3K inhibitor ( LY294002 ) significantly suppressed TNF-alpha-induced CXCL1 release from the cells .	TNF-alpha (5 ng/mL) caused activation of JNK, p38 MAPK, PI3K and Akt, whereas pretreatment with JNK inhibitor (SP600125), p38 MAPK inhibitor (SB202190) or PI-3K inhibitor (LY294002) significantly suppressed TNF-alpha-induced CXCL1 release from the cells.	0	16	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	0	1	15	16
XREF_BIBR , XREF_BIBR Our studies demonstrate no effect of ropivacaine on Src activation induced by Ca 2+ ionophore , a non-Akt-dependent activator of eNOS , but inhibited TNFalpha induced Akt activation suggesting the site of ropivacaine action may be upstream of Akt , for example via inhibition of PI3K .	XREF_BIBR, XREF_BIBR Our studies demonstrate no effect of ropivacaine on Src activation induced by Ca 2+ ionophore, a non-Akt-dependent activator of eNOS, but inhibited TNFalpha induced Akt activation suggesting the site of ropivacaine action may be upstream of Akt, for example via inhibition of PI3K.	27	30	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	27	28	29	30
These results suggested that TNFalpha induced both cell survival and apoptosis pathways in ameloblastoma and potential of TNFalpha in inducing apoptosis can be improved by inhibiting TNFalpha induced Akt and p44/42 mitogen activated protein kinase ( MAPK ) cell survival pathways .	These results suggested that TNFalpha induced both cell survival and apoptosis pathways in ameloblastoma and potential of TNFalpha in inducing apoptosis can be improved by inhibiting TNFalpha induced Akt and p44/42 mitogen activated protein kinase (MAPK) cell survival pathways.	26	31	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	26	27	28	29
In BAE cells , TNF activates MAP kinase in a MAP kinase kinase 1 ( MEK1 ) manner and Akt in PI3-kinase-dependent manner .	In BAE cells, TNF activates MAP kinase in a MAP kinase kinase 1 (MEK1) manner and Akt in PI3-kinase-dependent manner.	4	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	4	5	19	20
Moreover , TNF-alpha stimulated Akt activation via a Jak2 and PDGFR pathway in HPAEpiCs .	Moreover, TNF-alpha stimulated Akt activation via a Jak2 and PDGFR pathway in HPAEpiCs.	2	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	2	3	4	5
TNF , in most cells examined , activates Akt to use IKKalpha to control mTOR activation .	TNF, in most cells examined, activates Akt to use IKKalpha to control mTOR activation.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	0	1	8	9
CF31 could also inhibit basal and TNFalpha induced AKT activation in other cancer cell lines , including A549 lung cancer and HepG2 liver cancer cells ( XREF_FIG ) .	CF31 could also inhibit basal and TNFalpha induced AKT activation in other cancer cell lines, including A549 lung cancer and HepG2 liver cancer cells (XREF_FIG).	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	6	7	8	9
TNF-alpha caused activation of NF-kappaB , MAP kinases , and PI3K-Akt in podocytes , whereas blockade of these molecules did not affect inhibition of RAR by TNF-alpha .	TNF-alpha caused activation of NF-kappaB, MAP kinases, and PI3K-Akt in podocytes, whereas blockade of these molecules did not affect inhibition of RAR by TNF-alpha.	0	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	10	11
Crude N-terminal fragment of NRG1 ( NTF ) activates Akt in a similar fashion .	Crude N-terminal fragment of NRG1 (NTF) activates Akt in a similar fashion.	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	N-terminal fragment	N-terminal fragment	N-terminal fragment	Akt	Akt	Akt	1	3	9	10
Although it is well known that Akt induces the inactivation of GSK-3beta via PI3K pathway , XREF_BIBR there are only a few reports concerning the TNF-alpha activation of Akt through its phosphorylation .	Although it is well known that Akt induces the inactivation of GSK-3beta via PI3K pathway, XREF_BIBR there are only a few reports concerning the TNF-alpha activation of Akt through its phosphorylation.	25	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	25	26	28	29
Consistent with its ability to induce apoptosis , alpha-tomatine reduced TNF-alpha induced activation of the pro survival mediator Akt and its inhibition of NF-kappaB activation was accompanied by significant reduction in the expression of NF-kappaB-dependent anti-apoptotic ( c-IAP1 , c-IAP2 , Bcl-2 , Bcl-xL , XIAP and survivin ) proteins .	Consistent with its ability to induce apoptosis, alpha-tomatine reduced TNF-alpha induced activation of the pro survival mediator Akt and its inhibition of NF-kappaB activation was accompanied by significant reduction in the expression of NF-kappaB-dependent anti-apoptotic (c-IAP1, c-IAP2, Bcl-2, Bcl-xL, XIAP and survivin) proteins.	10	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	10	11	18	19
Our observation that tRXRalpha mediates AKT activation by TNFalpha suggests a possibility of using Sulindac or analogs to suppress TNFalpha induced AKT mediated survival function , thereby shifting its function from survival to death .	Our observation that tRXRalpha mediates AKT activation by TNFalpha suggests a possibility of using Sulindac or analogs to suppress TNFalpha induced AKT mediated survival function, thereby shifting its function from survival to death.	18	22	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	19	20	21	22
On the one hand , TNFalpha activates AKT signaling and subsequently represses GSK-3beta activity .	On the one hand, TNFalpha activates AKT signaling and subsequently represses GSK-3beta activity.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	5	6	7	8
Previous data shows that the PI3K and Akt signaling pathway is activated by TNF-alpha XREF_BIBR XREF_BIBR XREF_BIBR .	Previous data shows that the PI3K and Akt signaling pathway is activated by TNF-alpha XREF_BIBR XREF_BIBR XREF_BIBR.	7	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	13	14	7	8
Although ERK and AKT inactivation was also noted in the presence of SHH inhibitors , these kinases were not significantly activated upon TNF-alpha stimulation of IEC-6 cells ( in colon cancer cells HCT-116 , ERK and AKT were significantly activated by TNF-alpha and significantly inactivated by SHH inhibitors ; data not shown ) .	Although ERK and AKT inactivation was also noted in the presence of SHH inhibitors, these kinases were not significantly activated upon TNF-alpha stimulation of IEC-6 cells (in colon cancer cells HCT-116, ERK and AKT were significantly activated by TNF-alpha and significantly inactivated by SHH inhibitors; data not shown).	23	42	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	41	42	36	37
We also show that TNFalpha activates both the PI3K and Akt and MAPK and ERK pathways , which act upstream of AP-1 .	We also show that TNFalpha activates both the PI3K and Akt and MAPK and ERK pathways, which act upstream of AP-1.	4	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	4	5	10	11
In CRC , Akt activation triggered by TNF-alpha could induce EMT , promoting CRC progression .	In CRC, Akt activation triggered by TNF-alpha could induce EMT, promoting CRC progression.	3	8	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	7	8	3	4
In addition , triptolide strongly inhibits basal and TNFalpha induced AKT activity through disrupting the interaction between tRXRalpha and p85alpha ( XREF_FIG ) .	In addition, triptolide strongly inhibits basal and TNFalpha induced AKT activity through disrupting the interaction between tRXRalpha and p85alpha (XREF_FIG).	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	8	9	10	11
TNF-alpha stimulated production of the inflammatory mediators and reactive oxygen species in keratinocytes , and activation of the Akt , mTOR and NF-kappaB pathways in HaCaT cells and primary keratinocytes .	TNF-alpha stimulated production of the inflammatory mediators and reactive oxygen species in keratinocytes, and activation of the Akt, mTOR and NF-kappaB pathways in HaCaT cells and primary keratinocytes.	0	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	0	1	18	19
Akt and PKB activation by TNF-alpha was inhibited by a PI3-kinase-specific inhibitor LY-294002 and adenovirus mediated expression of a dominant negative mutant of PI3-kinase , indicating that TNF-alpha activates Akt and PKB through PI3-kinase activation .	Akt and PKB activation by TNF-alpha was inhibited by a PI3-kinase-specific inhibitor LY-294002 and adenovirus mediated expression of a dominant negative mutant of PI3-kinase, indicating that TNF-alpha activates Akt and PKB through PI3-kinase activation.	0	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	5	6	0	1
Endogenous PKD2 could directly interact with the p110alpha and p85 subunits of PI3K to activate PI3K and AKT , which could be enhanced by TNF-alpha stimulation .	Endogenous PKD2 could directly interact with the p110alpha and p85 subunits of PI3K to activate PI3K and AKT, which could be enhanced by TNF-alpha stimulation.	14	25	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	24	25	17	18
Phosphorylation of VEGFR2 at Tyr 801 and Tyr 1175 , the critical sites for VEGF induced PI3K-Akt signaling , was not involved in TNF mediated Akt activation .	Phosphorylation of VEGFR2 at Tyr 801 and Tyr 1175, the critical sites for VEGF induced PI3K-Akt signaling, was not involved in TNF mediated Akt activation.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	23	24	25	26
IL-17 and/or TNF-alpha activated AKT , nuclear factor-kappaB ( NF-kappaB ) , and extracellular signal regulated kinases 1/2 ( ERK1/2 ) signaling pathways in HCT116 cells , whereas only NF-kappaB signaling was activated in LNCaP cells .	IL-17 and/or TNF-alpha activated AKT, nuclear factor-kappaB (NF-kappaB), and extracellular signal regulated kinases 1/2 (ERK1/2) signaling pathways in HCT116 cells, whereas only NF-kappaB signaling was activated in LNCaP cells.	0	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	2	3	4	5
EGF activated IkappaB , Akt and Erk whereas TNF activated only IkappaB and reduced EGF activated Akt and Erk in these cells .	EGF activated IkappaB, Akt and Erk whereas TNF activated only IkappaB and reduced EGF activated Akt and Erk in these cells.	8	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	8	9	16	17
In vitro the Zybody inhibits both NF-kappaB and AKT pathways that are activated by TNF-alpha and Ang-2 , respectively .	In vitro the Zybody inhibits both NF-kappaB and AKT pathways that are activated by TNF-alpha and Ang-2, respectively.	6	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	14	15	8	9
The levels of TNF-alpha production at T. vaginalis MOI 2 for 2 hr were 11-fold higher than that of the control ( 610 +/-55 pg/ml at 4 hr vs. 52 +/-8 pg/ml at control ; P < 0.001 ) T. vaginalis infection induced activation of AKT , ERK1/2 , p38 MAPK , and JNK1/2 in SiHa cells .	The levels of TNF-alpha production at T. vaginalis MOI 2 for 2 hr were 11-fold higher than that of the control (610 +/-55 pg/ml at 4 hr vs. 52 +/-8 pg/ml at control; P < 0.001) T. vaginalis infection induced activation of AKT, ERK1/2, p38 MAPK, and JNK1/2 in SiHa cells.	3	53	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	3	4	45	46
Indeed , TNF-alpha stimulated the Akt pathway in PC-3 cells , as demonstrated by elevations of ph-GSK3beta , ph-p70S6K , and ph-4EBP1 ( XREF_FIG ) .	Indeed, TNF-alpha stimulated the Akt pathway in PC-3 cells, as demonstrated by elevations of ph-GSK3beta, ph-p70S6K, and ph-4EBP1 (XREF_FIG).	2	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	2	3	5	6
The effect of an increased TNF-alpha level upon podocytes is to induce robust MCP-1 production , which proceeds via TNFR2 to the NF-kappaB system and also the PI3K and Akt pathway .	The effect of an increased TNF-alpha level upon podocytes is to induce robust MCP-1 production, which proceeds via TNFR2 to the NF-kappaB system and also the PI3K and Akt pathway.	5	30	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha level	tnf-alpha	Akt	Akt	akt	5	6	29	30
BBR but not LOVA treatment abolished the TNFalpha induced cytotoxicity and restored the activation of Akt signaling .	BBR but not LOVA treatment abolished the TNFalpha induced cytotoxicity and restored the activation of Akt signaling.	6	16	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	7	8	15	16
Our analysis revealed that TNFalpha did not show significant variation with time but TNF soluble receptors , known to initiate the PI3K-AKT signalling pathway , showed a significant increase at 48h ( XREF_FIG A ) in co-cultured adipocytes .	Our analysis revealed that TNFalpha did not show significant variation with time but TNF soluble receptors, known to initiate the PI3K-AKT signalling pathway, showed a significant increase at 48h (XREF_FIG A) in co-cultured adipocytes.	13	23	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	PI3K-AKT	PI3K-AKT	PI3K-AKT	13	14	21	22
MK2206 prevented the TNF induced activation of mTOR and S6K1 ( XREF_FIG B ) , demonstrating that TNF activates AKT to subsequently control mTOR activity in RA-FLSs .	MK2206 prevented the TNF induced activation of mTOR and S6K1 (XREF_FIG B), demonstrating that TNF activates AKT to subsequently control mTOR activity in RA-FLSs.	17	20	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	17	18	19	20
Although our study does not address how TNF and TNFR1 actually activates AKT signalling ( p-AKT ) , it will be interesting to obtain further insight into how TNF induces p-AKT signalling in a dose dependent manner and how negative feedback is regulated .	Although our study does not address how TNF and TNFR1 actually activates AKT signalling (p-AKT), it will be interesting to obtain further insight into how TNF induces p-AKT signalling in a dose dependent manner and how negative feedback is regulated.	7	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	7	8	12	13
Celecoxib also inhibited the TNF induced interaction of Akt with I kappa B alpha kinase ( IKK ) .	Celecoxib also inhibited the TNF induced interaction of Akt with I kappa B alpha kinase (IKK).	3	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	4	5	8	9
tRXRalpha is able to bind to p85alpha to enhance TNFalpha stimulated Akt activation and cancer growth .	tRXRalpha is able to bind to p85alpha to enhance TNFalpha stimulated Akt activation and cancer growth.	8	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	9	10	11	12
TNF activates phosphatidylinositol-3-OH kinase ( PI ( 3 ) K ) and its downstream target Akt ( protein kinase B ) .	TNF activates phosphatidylinositol-3-OH kinase (PI (3) K) and its downstream target Akt (protein kinase B).	0	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	0	1	15	16
Because Pik3r1 was significantly downregulated by Rela deletion , we examined activation of Akt by TNF in Rela knockout chondrocytes .	Because Pik3r1 was significantly downregulated by Rela deletion, we examined activation of Akt by TNF in Rela knockout chondrocytes.	10	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	15	16	13	14
TNF-alpha triggered up to approximately 80 % increase ( depending on the method used ) in CB2 receptor mRNA and/or protein expression in HCASMCs , and induced Ras , p38 MAPK , ERK 1/2 , SAPK and JNK and Akt activation , while increasing proliferation and migration .	TNF-alpha triggered up to approximately 80% increase (depending on the method used) in CB2 receptor mRNA and/or protein expression in HCASMCs, and induced Ras, p38 MAPK, ERK 1/2, SAPK and JNK and Akt activation, while increasing proliferation and migration.	0	40	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	0	1	39	40
Triptolide inhibits TNFalpha induced AKT activation .	Triptolide inhibits TNFalpha induced AKT activation.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	2	3	4	5
Tnfrsf9 encodes a TNF family receptor whose ligation in T cells activates the PI3K and Akt pathway , which subsequently results in highly concentrated depots of PI3K and Akt in close proximity to TCR signaling units [ XREF_BIBR ] and stimulates their proliferation [ XREF_BIBR ] .	Tnfrsf9 encodes a TNF family receptor whose ligation in T cells activates the PI3K and Akt pathway, which subsequently results in highly concentrated depots of PI3K and Akt in close proximity to TCR signaling units [XREF_BIBR] and stimulates their proliferation [XREF_BIBR].	3	16	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	3	4	15	16
In these studies , TNF-alpha was shown to induce NF-kappaB , Akt , ERK and p38 MAPK and activated Akt and inhibited GSK-3beta activity which resulted in elevated Snail activity [ XREF_BIBR ] .	In these studies, TNF-alpha was shown to induce NF-kappaB, Akt, ERK and p38 MAPK and activated Akt and inhibited GSK-3beta activity which resulted in elevated Snail activity [XREF_BIBR].	4	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	4	5	11	12
Our results demonstrate that IFN-gamma and TNF-alpha up-regulate pro apoptotic protein-Par-4 with a concomitant decrease in the expression of pro survival protein-Bcl-2 , and activation of NF-kappaB and Akt .	Our results demonstrate that IFN-gamma and TNF-alpha up-regulate pro apoptotic protein-Par-4 with a concomitant decrease in the expression of pro survival protein-Bcl-2, and activation of NF-kappaB and Akt.	4	29	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	6	7	28	29
It has been reported that RXRalpha antagonist K-80003 inhibits TNFalpha induced AKT activation in a tRXRalpha dependent pathway .	It has been reported that RXRalpha antagonist K-80003 inhibits TNFalpha induced AKT activation in a tRXRalpha dependent pathway.	9	12	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	9	10	11	12
ErbB4 mediates TNF induced Akt activation in intestinal epithelial cells .	ErbB4 mediates TNF induced Akt activation in intestinal epithelial cells.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	2	3	4	5
TNF induced Akt activation needed for IKK activation was also abolished by deletion of PKR .	TNF induced Akt activation needed for IKK activation was also abolished by deletion of PKR.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	0	1	2	3
However , stable expression of GFP-RXRalpha and Delta80 enhanced not only their basal AKT activation but also their response to TNFalpha induction of AKT activation ( XREF_FIG ) .	However, stable expression of GFP-RXRalpha and Delta80 enhanced not only their basal AKT activation but also their response to TNFalpha induction of AKT activation (XREF_FIG).	20	24	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	20	21	23	24
Most surprisingly , TNF induced Akt activation also required the presence of GSK-3beta .	Most surprisingly, TNF induced Akt activation also required the presence of GSK-3beta.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	3	4	5	6
It has been reported that TNF causes activation of Akt through phosphorylation at Ser473 .	It has been reported that TNF causes activation of Akt through phosphorylation at Ser473.	5	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	5	6	9	10
PJ also abolished TNFalpha induced AKT activation , needed for NF-kappaB activity .	PJ also abolished TNFalpha induced AKT activation, needed for NF-kappaB activity.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	3	4	5	6
Strikingly , the activation of p42 ( mapk and erk2 ) and Akt by TNF-alpha was also inhibited in the presence of NaCl .	Strikingly, the activation of p42 (mapk and erk2) and Akt by TNF-alpha was also inhibited in the presence of NaCl.	3	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	14	15	12	13
Treatment of cells with TNFalpha enhanced AKT activation as revealed by Western blotting ( XREF_FIG ) .	Treatment of cells with TNFalpha enhanced AKT activation as revealed by Western blotting (XREF_FIG).	2	7	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	4	5	6	7
In addition , APC significantly downregulated tumor necrosis factor ( TNF ) alpha stimulated cell proliferation and activation of p38 , c-Jun NH2-terminal kinase ( JNK ) and Akt in RSFs .	In addition, APC significantly downregulated tumor necrosis factor (TNF) alpha stimulated cell proliferation and activation of p38, c-Jun NH2-terminal kinase (JNK) and Akt in RSFs.	8	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	10	11	28	29
We conclude that pro inflammatory TNF targets the quiescent and slow cycling melanoma SC compartment and promotes PI3K and AKT driven expansion of melanoma SCs most likely by preventing their asymmetrical self-renewal .	We conclude that pro inflammatory TNF targets the quiescent and slow cycling melanoma SC compartment and promotes PI3K and AKT driven expansion of melanoma SCs most likely by preventing their asymmetrical self-renewal.	3	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	5	6	19	20
Since TNFalpha could induce RXRalpha dependent AKT activation , 24 cells were also treated with TNFalpha , and its activation of AKT in the absence or presence of 23 was examined .	Since TNFalpha could induce RXRalpha dependent AKT activation, 24 cells were also treated with TNFalpha, and its activation of AKT in the absence or presence of 23 was examined.	1	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	1	2	6	7
Ropivacaine Blocks TNFalpha induced Activation of Akt Upstream of eNOS but Does Not Directly Inhibit PI3K Activity Upstream of Akt .	Ropivacaine Blocks TNFalpha induced Activation of Akt Upstream of eNOS but Does Not Directly Inhibit PI3K Activity Upstream of Akt.	0	14	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	2	3	6	7
First , N-6 strongly inhibited TNFalpha induced AKT activation in cancer cells .	First, N-6 strongly inhibited TNFalpha induced AKT activation in cancer cells.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	5	6	7	8
Partial cleavage of p120 RasGAP by caspase-3 in stressed cells generates an N-terminal fragment , called fragment N , which activates an anti-apoptotic Akt dependent survival response .	Partial cleavage of p120 RasGAP by caspase-3 in stressed cells generates an N-terminal fragment, called fragment N, which activates an anti-apoptotic Akt dependent survival response.	12	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	N-terminal fragment	N-terminal fragment	N-terminal fragment	Akt	Akt	Akt	12	14	23	24
Downstream of the fibroblast growth factor inducible 14 receptor ( Fn14 ) , the Rac1 protein is important in promoting the TNF like weak inducer of apoptosis ( TWEAK ) ligand induced activation of the Akt and NF-kappaB-pathways , and Fn14 signaling through Rac1 promoted increased cell invasion and resistance to cytotoxic therapy induced apoptosis .	Downstream of the fibroblast growth factor inducible 14 receptor (Fn14), the Rac1 protein is important in promoting the TNF like weak inducer of apoptosis (TWEAK) ligand induced activation of the Akt and NF-kappaB-pathways, and Fn14 signaling through Rac1 promoted increased cell invasion and resistance to cytotoxic therapy induced apoptosis.	21	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	21	22	35	36
The interaction of TNFalpha with TNFR2 also activates the reciprocal PI3K and Akt pathway .	The interaction of TNFalpha with TNFR2 also activates the reciprocal PI3K and Akt pathway.	1	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	3	4	12	13
CPPD crystals were observed to induce a robust and transient activation of ERK1 , ERK2 , and Akt , whereas TNF-alpha produced only a modest and delayed activation of Akt .	CPPD crystals were observed to induce a robust and transient activation of ERK1, ERK2, and Akt, whereas TNF-alpha produced only a modest and delayed activation of Akt.	20	30	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	20	21	29	30
These results suggest that TNF-alpha promotes the survival of osteoclasts by engaging the phosphatidylinositol 3-kinase Akt and MEK and ERK signaling pathways .	These results suggest that TNF-alpha promotes the survival of osteoclasts by engaging the phosphatidylinositol 3-kinase Akt and MEK and ERK signaling pathways.	4	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	4	5	15	16
These findings suggest that the PI3K and Akt signaling pathway was activated by TNF-alpha in NP cells .	These findings suggest that the PI3K and Akt signaling pathway was activated by TNF-alpha in NP cells.	7	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	13	14	7	8
TNF-alpha activated two signaling cascades : 1 ) ERK1/2 and its target eIF4E and 2 ) Akt and its downstream effectors GSK-3 , p70 ( S6K ) , and 4E-BP1 .	TNF-alpha activated two signaling cascades : 1) ERK1/2 and its target eIF4E and 2) Akt and its downstream effectors GSK-3, p70 (S6K), and 4E-BP1.	0	29	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	0	1	16	17
The results revealed that TNF-alpha induction caused a time dependent association of Akt with IKK-beta ( XREF_FIG ) , and MPTAG significantly prevented this association in a dose dependent ( XREF_FIG ) and time dependent manner ( XREF_FIG ) with no increase in the expression levels of IKK-beta in these cells .	The results revealed that TNF-alpha induction caused a time dependent association of Akt with IKK-beta (XREF_FIG), and MPTAG significantly prevented this association in a dose dependent (XREF_FIG) and time dependent manner (XREF_FIG) with no increase in the expression levels of IKK-beta in these cells.	4	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	4	5	12	13
We also showed that TNF-alpha induced Akt translocation and the formation of an Akt , p65 , and p300 complex .	We also showed that TNF-alpha induced Akt translocation and the formation of an Akt, p65, and p300 complex.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	4	5	6	7
N-6 inhibits TNFalpha induced AKT activation in an RXRalpha and tRXRalpha dependent manner .	N-6 inhibits TNFalpha induced AKT activation in an RXRalpha and tRXRalpha dependent manner.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	2	3	4	5
Thus , the TNF induced AKT and beta-catenin signalling axis in Lgr5 + HF stem cells plays a dominant role in both WIHN and WIH-A .	Thus, the TNF induced AKT and beta-catenin signalling axis in Lgr5 + HF stem cells plays a dominant role in both WIHN and WIH-A.	2	9	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	3	4	5	6
We demonstrate that in addition to the well described action of Na + channel blockade , local anesthetics also blocked TNFalpha induced TNF-R1-dependent PI3K , Akt , and eNOS activation resulting in the inhibition of nitric oxide driven Src signaling .	We demonstrate that in addition to the well described action of Na + channel blockade, local anesthetics also blocked TNFalpha induced TNF-R1-dependent PI3K, Akt, and eNOS activation resulting in the inhibition of nitric oxide driven Src signaling.	20	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	20	21	25	26
Characteristics of components related with differential EGF- or TNF activated Akt , Erk and IkappaB in ovarian cancer cells .	Characteristics of components related with differential EGF- or TNF activated Akt, Erk and IkappaB in ovarian cancer cells.	3	14	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	8	9	10	11
Mechanistic studies indicate that TNFalpha induced binding of PI3K subunit p85alpha to N-terminal truncated nuclear receptor RXRalpha ( tRXRalpha ) proteins , and activated AKT .	Mechanistic studies indicate that TNFalpha induced binding of PI3K subunit p85alpha to N-terminal truncated nuclear receptor RXRalpha (tRXRalpha) proteins, and activated AKT.	4	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	4	5	24	25
It is noteworthy that this flavone also suppressed TNF induced activation of Akt , a cell survival kinase , and expression of various antiapoptotic proteins , such as IAP-1 , IAP-2 , XIAP , Bcl-2 , Bcl-xL , and TRAF-1 .	It is noteworthy that this flavone also suppressed TNF induced activation of Akt, a cell survival kinase, and expression of various antiapoptotic proteins, such as IAP-1, IAP-2, XIAP, Bcl-2, Bcl-xL, and TRAF-1.	8	20	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	8	9	12	13
Immunofluorescence staining showed that TNF-alpha alone increased the production of P-Akt , whereas LY294002 and 50muM resveratrol suppressed the TNF-alpha-stimulated expression of P-Akt .	Immunofluorescence staining showed that TNF-alpha alone increased the production of P-Akt, whereas LY294002 and 50muM resveratrol suppressed the TNF-alpha-stimulated expression of P-Akt.	4	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	P-Akt	P-Akt	P-Akt	4	5	10	11
On the other hand , TNFalpha stimulation induced AKT activation but did not affect MEK1/2 or ERK1/2 , implying that the PI3K to MEK1/2 reaction was not active .	On the other hand, TNFalpha stimulation induced AKT activation but did not affect MEK1/2 or ERK1/2, implying that the PI3K to MEK1/2 reaction was not active.	5	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	5	6	8	9
Thus , in the present study , we showed that TNF-alpha significantly enhanced permeability in endothelial cells via a signaling pathway involving Src and PI3K and Akt , which led to the disruption of TJ proteins , such as ZO-1 , and barrier dysfunction in the endothelial cells .	Thus, in the present study, we showed that TNF-alpha significantly enhanced permeability in endothelial cells via a signaling pathway involving Src and PI3K and Akt, which led to the disruption of TJ proteins, such as ZO-1, and barrier dysfunction in the endothelial cells.	10	29	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	10	11	26	27
DPP23 inhibits TNFalpha induced Akt activation .	DPP23 inhibits TNFalpha induced Akt activation.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	2	3	4	5
This effect was dependent on atypical protein kinase C species ( aPKC ) since a specific peptide blocking the activity of the PKCxi and iota and lambda abrogated the activation of Akt by TNF-alpha .	This effect was dependent on atypical protein kinase C species (aPKC) since a specific peptide blocking the activity of the PKCxi and iota and lambda abrogated the activation of Akt by TNF-alpha.	27	34	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	33	34	31	32
We conclude that TNF increases atrogin mRNA independent of AKT via Foxo4 .	We conclude that TNF increases atrogin mRNA independent of AKT via Foxo4.	3	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	3	4	9	10
In addition to promoting cytokine production , PKR has been reported to mediate activation of NF-kappaB , MAPK and Akt in cells treated with IFN-gamma , TNF-alpha and/or the combination of these cytokines XREF_BIBR , XREF_BIBR , XREF_BIBR .	In addition to promoting cytokine production, PKR has been reported to mediate activation of NF-kappaB, MAPK and Akt in cells treated with IFN-gamma, TNF-alpha and/or the combination of these cytokines XREF_BIBR, XREF_BIBR, XREF_BIBR.	13	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	26	27	19	20
TNFalpha could also activate PI3K and AKT signaling .	TNFalpha could also activate PI3K and AKT signaling.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	0	1	6	7
Since TNFalpha was able to activate Akt , ERK and P38 MAPK simultaneously , we next sought to determine which of these pathways are responsible for the regulation of synthesis and secretion of TSP-1 by the hMEC .	Since TNFalpha was able to activate Akt, ERK and P38 MAPK simultaneously, we next sought to determine which of these pathways are responsible for the regulation of synthesis and secretion of TSP-1 by the hMEC.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	1	2	6	7
As shown in XREF_FIG , we confirmed that TNF-alpha induced activation of the Akt and NF-kappaB pathway , while NAC ( 10 mM ) pretreatment blocked TNF-alpha-induced Akt and NF-kappaB activation .	As shown in XREF_FIG, we confirmed that TNF-alpha induced activation of the Akt and NF-kappaB pathway, while NAC (10 mM) pretreatment blocked TNF-alpha-induced Akt and NF-kappaB activation.	8	16	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	8	9	13	14
The fact that TNFalpha induced c-FLIP expression is completely prevented by Sulindac places c-FLIP in a central position for integrating TNFalpha induced AKT activation and its inhibition by Sulindac and induction of apoptosis by Sulindac and TNFalpha combination .	The fact that TNFalpha induced c-FLIP expression is completely prevented by Sulindac places c-FLIP in a central position for integrating TNFalpha induced AKT activation and its inhibition by Sulindac and induction of apoptosis by Sulindac and TNFalpha combination.	19	23	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	20	21	22	23
Transduction with specific siRNAs targeting SLAMF7 in the UnS plaque derived CD14+ cells for 24 hours resulted in a significant reduction of proinflammatory cytokines interleukin-6 ( IL-6 ) , IL-8 , IL-12 and tumor necrosis factor alpha ( TNF-alpha ) ( p < 0.05 ) , mediated by the SLAMF7 downstream protein kinase B ( PKB , also known as AKT ) and phosphoinositide phospholipase C ( PLCgamma1 ) signalings ( XREF_FIG ) .	Transduction with specific siRNAs targeting SLAMF7 in the UnS plaque derived CD14+ cells for 24 hours resulted in a significant reduction of proinflammatory cytokines interleukin-6 (IL-6), IL-8, IL-12 and tumor necrosis factor alpha (TNF-alpha) (p < 0.05), mediated by the SLAMF7 downstream protein kinase B (PKB, also known as AKT) and phosphoinositide phospholipase C (PLCgamma1) signalings (XREF_FIG).	29	58	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	PKB	PKB	PKB	33	36	55	56
Importantly , both the 1 and 2 h Western blot peaks were blocked by spinal Etanercept pretreatment indicating that Akt activation in both laminae I and V neurons was triggered directly or indirectly by TNF .	Importantly, both the 1 and 2 h Western blot peaks were blocked by spinal Etanercept pretreatment indicating that Akt activation in both laminae I and V neurons was triggered directly or indirectly by TNF.	19	35	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	34	35	19	20
TNFalpha , angiotensin II , and free fatty acid produced from perivas- cular adipose tissue activate Akt pathway , but not ERK1/2 pathway .	TNFalpha, angiotensin II, and free fatty acid produced from perivas- cular adipose tissue activate Akt pathway, but not ERK1/2 pathway.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	0	1	16	17
Akt is activated by TNF-alpha through the phosphoinositide-3-kinase ( PI-3K ) pathway in various cells including HUVECs .	Akt is activated by TNF-alpha through the phosphoinositide-3-kinase (PI-3K) pathway in various cells including HUVECs.	0	5	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	4	5	0	1
These molecular targets of MNK1 are shared with those of PI3K in neutrophils , and accordingly , MNK1 inhibition partially impaired the belated PI3K and Akt activation elicited by LPS or TNF in these cells .	These molecular targets of MNK1 are shared with those of PI3K in neutrophils, and accordingly, MNK1 inhibition partially impaired the belated PI3K and Akt activation elicited by LPS or TNF in these cells.	25	32	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	31	32	25	26
TNF-alpha ( tumor necrosis factor-alpha ) and IL-6 ( interleukin-6 ) activate the PI3K and AKT pathway to induce cell growth and maintain cell survival , whereas adiponectin inhibits TNF-alpha and IL-6 to regulate the PI3K and AKT pathway XREF_BIBR .	TNF-alpha (tumor necrosis factor-alpha) and IL-6 (interleukin-6) activate the PI3K and AKT pathway to induce cell growth and maintain cell survival, whereas adiponectin inhibits TNF-alpha and IL-6 to regulate the PI3K and AKT pathway XREF_BIBR.	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	0	1	15	16
TNFalpha and zVAD activates Akt and mTOR signaling pathways in HT22 cells .	TNFalpha and zVAD activates Akt and mTOR signaling pathways in HT22 cells.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	0	1	4	5
Diosgenin [ ( 25R )-5-spirosten-3beta-ol ] , a steroid sapogenin constituent of fenugreek seeds suppresses proliferation , osteoclastogenesis and inhibits invasion through inhibition of necrosis factor NF-kappaB-regulated gene expression and Tumor Necrotic Factor ( TNF )-induced activation of AKT .	Diosgenin [(25R)-5-spirosten-3beta-ol], a steroid sapogenin constituent of fenugreek seeds suppresses proliferation, osteoclastogenesis and inhibits invasion through inhibition of necrosis factor NF-kappaB-regulated gene expression and Tumor Necrotic Factor (TNF)-induced activation of AKT.	34	39	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	34	35	38	39
These results suggest that NF-kappa B is required for TNF mediated Akt activation and that it lies upstream of the stimulation of Akt .	These results suggest that NF-kappa B is required for TNF mediated Akt activation and that it lies upstream of the stimulation of Akt.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	9	10	11	12
TNF activates the AKT and beta-catenin signalling in HF stem cells .	TNF activates the AKT and beta-catenin signalling in HF stem cells.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	0	1	3	4
Treatment of cells with TNFalpha enhanced AKT activation , which was also suppressed by 23 .	Treatment of cells with TNFalpha enhanced AKT activation, which was also suppressed by 23.	2	7	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	4	5	6	7
Moreover , the sensitivity of SW480 cells to CF31 was restored , as it could effectively inhibit TNFalpha induced AKT activation in SW480/RXRalpha/Delta80 cells .	Moreover, the sensitivity of SW480 cells to CF31 was restored, as it could effectively inhibit TNFalpha induced AKT activation in SW480/RXRalpha/Delta80 cells.	16	20	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	17	18	19	20
Moreover , a novel PI3Kdelta inhibitor , INK007 , blocks TNF induced AKT activation 185 ( XREF_TABLE ) .	Moreover, a novel PI3Kdelta inhibitor, INK007, blocks TNF induced AKT activation 185 (XREF_TABLE).	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	10	11	12	13
More recently , however , van Wijk and colleagues demonstrated that TNFalpha signaling activated Akt in Tcon cells from JIA patients , allowing them to resist Treg suppression , as was seen with IL-6 .	More recently, however, van Wijk and colleagues demonstrated that TNFalpha signaling activated Akt in Tcon cells from JIA patients, allowing them to resist Treg suppression, as was seen with IL-6.	11	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	11	12	14	15
Different from full-length RXRalpha , tRXRalpha is able to reside in the cytoplasm and interact with p85alpha , the subunit of phophoinositide 3-kinase ( PI3K ) , which leads to the enhanced TNFalpha induced AKT activation .	Different from full-length RXRalpha, tRXRalpha is able to reside in the cytoplasm and interact with p85alpha, the subunit of phophoinositide 3-kinase (PI3K), which leads to the enhanced TNFalpha induced AKT activation.	28	35	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	32	33	34	35
Since TNFalpha was able to activate Akt , ERK and P38 MAPK simultaneously , we determined what the net effect of these signaling pathways will be on hMEC survival , apoptosis and proliferation .	Since TNFalpha was able to activate Akt, ERK and P38 MAPK simultaneously, we determined what the net effect of these signaling pathways will be on hMEC survival, apoptosis and proliferation.	1	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	1	2	6	7
4-HPR also inhibited TNF induced Akt activation linked with IKK activation .	4-HPR also inhibited TNF induced Akt activation linked with IKK activation.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	3	4	5	6
Interestingly , this regulatory pathway is iTreg cell specific as TNF-alpha does not activate Akt in naturally occurring regulatory T cells , therefore conferring a selective effect of TNF-alpha and its antagonism on iTreg cells .	Interestingly, this regulatory pathway is iTreg cell specific as TNF-alpha does not activate Akt in naturally occurring regulatory T cells, therefore conferring a selective effect of TNF-alpha and its antagonism on iTreg cells.	10	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	10	11	14	15
In addition , TNF-alpha activates the PI3K and AKT signaling pathway [ XREF_BIBR ] .	In addition, TNF-alpha activates the PI3K and AKT signaling pathway [XREF_BIBR].	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	3	4	8	9
TNF activated Akt in PC-3 cells , but not in DU145 cells , and the ability of TNF to activate NF-kappaB was blocked by pharmacological inhibition of PI 3-kinase activity in PC-3 cells , but not in DU145 cells .	TNF activated Akt in PC-3 cells, but not in DU145 cells, and the ability of TNF to activate NF-kappaB was blocked by pharmacological inhibition of PI 3-kinase activity in PC-3 cells, but not in DU145 cells.	0	3	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt	Akt	Akt	0	1	2	3
Pomegranate juice almost downregulated the TNFalpha induced Akt ( protein kinase B ) activation required for NF-kappaB activity [ XREF_BIBR ] .	Pomegranate juice almost downregulated the TNFalpha induced Akt (protein kinase B) activation required for NF-kappaB activity [XREF_BIBR].	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	5	6	7	8
In fact , our data show that Akt signaling is activated by the TNFalpha induced stimulation of NFkappaB signaling ( XREF_FIG ) .	In fact, our data show that Akt signaling is activated by the TNFalpha induced stimulation of NFkappaB signaling (XREF_FIG).	7	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	13	14	7	8
In addition to causing a TNF dependent increase in P-Akt and P-GluR1 ser 845 , intraplantar carrageenan also elicited a TNF dependent increase in total GluR1 ( p < = 0.05 ; N = 3-4 ) in membrane fractions of dorsal spinal cord homogenates ipsilateral to the paw injection ( XREF_FIG ) .	In addition to causing a TNF dependent increase in P-Akt and P-GluR1 ser 845, intraplantar carrageenan also elicited a TNF dependent increase in total GluR1 (p < = 0.05; N = 3-4) in membrane fractions of dorsal spinal cord homogenates ipsilateral to the paw injection (XREF_FIG).	5	12	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	P-Akt	P-Akt	P-Akt	5	6	9	10
The conjunct of RANKL and RANK recruits TNF receptor associated factors ( TRAFs ) , typically TRAF6 , which activates multiple downstream signaling pathways , mainly NF-kappaB , MAPKs , and AKT , and thereby initiates osteoclast differentiation and bone resorption by inducing transcription and expression of osteoclast specific genes , such as tartrate resistant acid phosphatase ( TRAP ) , cathepsin K , matrix metalloproteinase 9 ( MMP-9 ) , and C-Src .	The conjunct of RANKL and RANK recruits TNF receptor associated factors (TRAFs), typically TRAF6, which activates multiple downstream signaling pathways, mainly NF-kappaB, MAPKs, and AKT, and thereby initiates osteoclast differentiation and bone resorption by inducing transcription and expression of osteoclast specific genes, such as tartrate resistant acid phosphatase (TRAP), cathepsin K, matrix metalloproteinase 9 (MMP-9), and C-Src.	7	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	7	8	31	32
Similarly , TNFalpha impairs vasorelaxation by inhibiting the P13K and Akt signaling [ XREF_BIBR , XREF_BIBR ] .	Similarly, TNFalpha impairs vasorelaxation by inhibiting the P13K and Akt signaling [XREF_BIBR, XREF_BIBR].	2	15	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	2	3	10	11
To establish the mechanism by which ropivacaine blocks TNFalpha induced eNOS and Src activation , we determined whether ropivacaine blocks TNFalpha induced activation of Akt , an upstream kinase known to activate eNOS 11 via phosphorylation of serine 1177 .	To establish the mechanism by which ropivacaine blocks TNFalpha induced eNOS and Src activation, we determined whether ropivacaine blocks TNFalpha induced activation of Akt, an upstream kinase known to activate eNOS 11 via phosphorylation of serine 1177.	20	28	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	20	21	24	25
We do not present direct evidence to determine whether TNF-alpha activates MAPKs and PI3K and Akt through TNFR1 and/or TNFR2 in pericytes .	We do not present direct evidence to determine whether TNF-alpha activates MAPKs and PI3K and Akt through TNFR1 and/or TNFR2 in pericytes.	9	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	9	10	15	16
Marmelosin thus displayed potential multi-potent antioxidant , anti-inflammatory and anticancer properties via TNF-alpha mediated Akt signaling pathway .	Marmelosin thus displayed potential multi-potent antioxidant, anti-inflammatory and anticancer properties via TNF-alpha mediated Akt signaling pathway.	10	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	12	13	14	15
Notably , together TNF-alpha and RANKL induced upregulation of RANK .	Notably, together TNF-alpha and RANKL induced upregulation of RANK.	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	9	10
The release of active nuclear factor-kappa-B ( NF-kappaB ) secondary to the stimulation of RANK by RANK-L is associated with the phosphorylation of the inhibitory I-kappaB-alpha protein .	The release of active nuclear factor-kappa-B (NF-kappaB) secondary to the stimulation of RANK by RANK-L is associated with the phosphorylation of the inhibitory I-kappaB-alpha protein.	9	17	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANK-L	RANK-L	RANK-L	RANK	RANK	RANK	16	17	14	15
However , 8-bromo-cGMP , a membrane-permeable derivative of cGMP , did not have an effect on either RANKL induced osteoclast differentiation or expression of the RANK gene .	However, 8-bromo-cGMP, a membrane-permeable derivative of cGMP, did not have an effect on either RANKL induced osteoclast differentiation or expression of the RANK gene.	14	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	17	18	25	26
Catabolic effects of RANKL are inhibited by OPG , thereby preventing the activation of its receptor RANK .	Catabolic effects of RANKL are inhibited by OPG, thereby preventing the activation of its receptor RANK.	1	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	3	4	16	17
Activation of RANK by RANKL during osteoclastogenesis results in the generation of ROS which reinforces activation of the RANKL mediated signaling XREF_BIBR - XREF_BIBR .	Activation of RANK by RANKL during osteoclastogenesis results in the generation of ROS which reinforces activation of the RANKL mediated signaling XREF_BIBR - XREF_BIBR.	0	6	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	2	3
Research interest has focused on the RANK and RANKL ( receptor activator of NF-kappabeta and RANK ligand ) pathway and TNF-alpha .	Research interest has focused on the RANK and RANKL (receptor activator of NF-kappabeta and RANK ligand) pathway and TNF-alpha.	3	20	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	8	9	15	16
Purified RANK-N was assayed for its inhibitory effect on RANK activated signaling in Raw264.7 cells because RANKL can lead to RANK mediated processing of NF-kappaB2 p100 into NF-kappaB2 p52 , activating a noncanonical NF-kappaB signaling pathway [ XREF_BIBR ] .	Purified RANK-N was assayed for its inhibitory effect on RANK activated signaling in Raw264.7 cells because RANKL can lead to RANK mediated processing of NF-kappaB2 p100 into NF-kappaB2 p52, activating a noncanonical NF-kappaB signaling pathway [XREF_BIBR].	16	21	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	16	17	20	21
RANK , a cell surface receptor on osteoclast precursors , is stimulated by RANKL , resulting in osteoclastogenesis and activation of mature osteoclasts .	RANK, a cell surface receptor on osteoclast precursors, is stimulated by RANKL, resulting in osteoclastogenesis and activation of mature osteoclasts.	0	14	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	13	14	0	1
XREF_BIBR , XREF_BIBR There was a consistent finding of complete or near complete elimination of RANKL producing stromal cells and disappearance of original RANK positive multinuclear giant cells , along with the concomitant production of osteoid and new woven bone .	XREF_BIBR, XREF_BIBR There was a consistent finding of complete or near complete elimination of RANKL producing stromal cells and disappearance of original RANK positive multinuclear giant cells, along with the concomitant production of osteoid and new woven bone.	13	39	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	15	16	23	24
RANKL may also trigger tumour cell proliferation [ XREF_BIBR ] and promote migration of RANK expressing tumour cells to bone [ XREF_BIBR ] .	RANKL may also trigger tumour cell proliferation [XREF_BIBR] and promote migration of RANK expressing tumour cells to bone [XREF_BIBR].	0	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	14	15
Zoledronic acid ( 10 and 30 muM ) strongly inhibited TNF-alpha- and RANKL induced upregulation of RANK in a dose dependent manner .	Zoledronic acid (10 and 30 muM) strongly inhibited TNF-alpha- and RANKL induced upregulation of RANK in a dose dependent manner.	10	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	12	13	16	17
OPG regulates TRAP and RANK mRNA expression in osteoclasts treated with M-CSF and RANKL .	OPG regulates TRAP and RANK mRNA expression in osteoclasts treated with M-CSF and RANKL.	2	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	13	14	4	5
Upon stimulation of RANK by RANKL under costimulatory signals such as M-CSF , the process of osteoclast differentiation and maturation begins [ XREF_BIBR ] .	Upon stimulation of RANK by RANKL under costimulatory signals such as M-CSF, the process of osteoclast differentiation and maturation begins [XREF_BIBR].	1	8	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	3	4
The receptor RANK , which is present on the plasma membrane of osteoclasts , can be activated by binding of its cognate ligand RANKL that is predominantly expressed by osteoblasts .	The receptor RANK, which is present on the plasma membrane of osteoclasts, can be activated by binding of its cognate ligand RANKL that is predominantly expressed by osteoblasts.	0	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	23	24	2	3
Indeed , RANKL stimulate RANK signaling promoting maturation of immature CD80 - AIRE - cells to mature CD80 + AIRE + mTECs .	Indeed, RANKL stimulate RANK signaling promoting maturation of immature CD80 - AIRE - cells to mature CD80 + AIRE + mTECs.	2	5	stimulate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	2	3	4	5
The RANK and RANKL ( receptor activator of nuclear factor-kappaB and RANK ligand ) pathway has been shown to be essential for osteoclast differentiation in inflammatory arthritis .	The RANK and RANKL (receptor activator of nuclear factor-kappaB and RANK ligand) pathway has been shown to be essential for osteoclast differentiation in inflammatory arthritis.	1	14	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	3	4	11	12
In giant cell tumour of bone ( GCT ) RANKL is secreted by neoplastic ovoid cells as well as monocytoid cells and drives the formation of RANK positive non neoplastic osteoclast like cells , which mediate bone destruction in GCT .	In giant cell tumour of bone (GCT) RANKL is secreted by neoplastic ovoid cells as well as monocytoid cells and drives the formation of RANK positive non neoplastic osteoclast like cells, which mediate bone destruction in GCT.	9	30	drives	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	9	10	26	27
Stimulation of RANK by RANKL has been reported to activate several signaling pathways , including phosphatidylinositol 3-kinase ( PI3K )/AKT and mitogen activated protein kinases ( MAPKs ) , and subsequently activating a series of transcription factors , including nuclear factor kappa B ( NF-kappaB ) and NFATc1 [ XREF_BIBR ] .	Stimulation of RANK by RANKL has been reported to activate several signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinases (MAPKs), and subsequently activating a series of transcription factors, including nuclear factor kappa B (NF-kappaB) and NFATc1 [XREF_BIBR].	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	2	3
After RANKL induced RANK stimulation , several key regulatory transcription factors and enzymes are enhanced to promote the differentiation , proliferation , multinucleation , activation , and survival of osteoclasts .	After RANKL induced RANK stimulation, several key regulatory transcription factors and enzymes are enhanced to promote the differentiation, proliferation, multinucleation, activation, and survival of osteoclasts.	1	4	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	1	2	3	4
RANKL is expressed on the membrane of osteoblasts and stromal cells and binds to and activates RANK on osteoclast precursor cells .	RANKL is expressed on the membrane of osteoblasts and stromal cells and binds to and activates RANK on osteoclast precursor cells.	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL is expressed	rankl	RANK	RANK	rank	0	1	16	17
Activation of RANK by RANKL initiates a RANK/RANKL/OPG signaling cascade , resulting in osteoclast differentiation and increased bone resorption .	Activation of RANK by RANKL initiates a RANK/RANKL/OPG signaling cascade, resulting in osteoclast differentiation and increased bone resorption.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	2	3
OPG binding to RANKL prevents RANKL activation of RANK and thus activation of the osteoclastogenesis [ XREF_BIBR , XREF_BIBR ] .	OPG binding to RANKL prevents RANKL activation of RANK and thus activation of the osteoclastogenesis [XREF_BIBR, XREF_BIBR].	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	8	9
Receptor activator of nuclear factor kappaB ligand ( RANKL ) activates RANK , which in turn activates osteoclasts .	Receptor activator of nuclear factor kappaB ligand (RANKL) activates RANK, which in turn activates osteoclasts.	1	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	8	9	11	12
Furthermore , defective mTEC maturation is recovered by supplying agonist anti-RANK antibodies for 4days to both WT and mutant alymphoid FTOCs , demonstrating that the RANK stimulation mediated by RANKL expressing cells can be substituted by direct stimulation of the receptor in the presence of reduced lymphoid cells .	Furthermore, defective mTEC maturation is recovered by supplying agonist anti-RANK antibodies for 4days to both WT and mutant alymphoid FTOCs, demonstrating that the RANK stimulation mediated by RANKL expressing cells can be substituted by direct stimulation of the receptor in the presence of reduced lymphoid cells.	25	31	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	29	30	25	26
Deficiency of Traf6 in mice exhibits bone phenotypes similar to Rankl -/- and Rank-/- in which osteocalstogenesis is largely blocked and the downstream signaling pathways , including NF-kappaB , MAPKs and Ca 2+ oscillation , can not be stimulated by RANKL XREF_BIBR .	Deficiency of Traf6 in mice exhibits bone phenotypes similar to Rankl -/- and Rank-/- in which osteocalstogenesis is largely blocked and the downstream signaling pathways, including NF-kappaB, MAPKs and Ca 2+ oscillation, can not be stimulated by RANKL XREF_BIBR.	8	41	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	Rank-/-	Rank-/-	Rank-/-	40	41	13	14
As shown in Figure XREF_FIG A , serum RANK and RANKL levels in rats with steroid induced ONFH were significantly higher than levels in control rats ( RANK : 60.32 +/-19.52 U/L vs. 23.33 +/-4.26 U/L , P < 0.01 ; RANKL : 63.33 +/-13.24 U/L vs. 35.74 +/-9.41 U/L , P < 0.01 ) .	As shown in Figure XREF_FIG A, serum RANK and RANKL levels in rats with steroid induced ONFH were significantly higher than levels in control rats (RANK : 60.32 +/-19.52 U/L vs. 23.33 +/-4.26 U/L, P < 0.01; RANKL : 63.33 +/-13.24 U/L vs. 35.74 +/-9.41 U/L, P < 0.01).	10	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL levels	rankl	RANK	RANK	rank	10	11	27	28
WP9QY , but not the altered control peptide , inhibited the RANKL induced activation of RANK dependent signaling in RAW 264.7 cells but had no effect on M-CSF-induced activation of some of the same signaling events .	WP9QY, but not the altered control peptide, inhibited the RANKL induced activation of RANK dependent signaling in RAW 264.7 cells but had no effect on M-CSF-induced activation of some of the same signaling events.	10	23	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	11	12	15	16
It is possible that the GM-0111 may prevent oligomerization of RANKL or inhibit RANKL induced oligomerization of RANK [ XREF_BIBR ] .	It is possible that the GM-0111 may prevent oligomerization of RANKL or inhibit RANKL induced oligomerization of RANK [XREF_BIBR].	13	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	13	14	17	18
Purified monocytes were precultured with 25 ng/ml M-CSF for 3 days to enhance RANK expression , and were then treated with RANKL .	Purified monocytes were precultured with 25 ng/ml M-CSF for 3 days to enhance RANK expression, and were then treated with RANKL.	13	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	21	22	13	14
[ XREF_BIBR ] Activation of RANK by RANKL not only induces osteoclast differentiation and survival , but also leads to activation of bone resorption by mature osteoclasts .	[XREF_BIBR] Activation of RANK by RANKL not only induces osteoclast differentiation and survival, but also leads to activation of bone resorption by mature osteoclasts.	3	8	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	7	8	5	6
Myeloid precursors from wild-type ( WT ) mice , or mice with either germline or conditional deletion of Rank , Nfatc1 , Dap12 or Fcrg , were treated with either RANKL , or TNFalpha plus IL-6 .	Myeloid precursors from wild-type (WT) mice, or mice with either germline or conditional deletion of Rank, Nfatc1, Dap12 or Fcrg, were treated with either RANKL, or TNFalpha plus IL-6.	10	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	Rank	Rank	Rank	30	31	18	19
TNF-alpha and RANKL promote osteoclastogenesis by upregulating RANK via the NF-kappaB pathway .	TNF-alpha and RANKL promote osteoclastogenesis by upregulating RANK via the NF-kappaB pathway.	0	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	2	3	7	8
RANK is activated by RANKL , which is produced by osteoblasts .	RANK is activated by RANKL, which is produced by osteoblasts.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	0	1
Kim et al ., have also shown that RANK activation by RANKL is crucial to control proliferation of mammary epithelial cells .	Kim et al., have also shown that RANK activation by RANKL is crucial to control proliferation of mammary epithelial cells.	8	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	11	12	8	9
The important role of RANKL activation of RANK in SF induced bone resorption is also indicated by the finding that the stimulatory effect on 45 Ca release was abolished by the decoy receptor antagonist OPG .	The important role of RANKL activation of RANK in SF induced bone resorption is also indicated by the finding that the stimulatory effect on 45 Ca release was abolished by the decoy receptor antagonist OPG.	4	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	7	8
RANKL plays an important role in bone reconstruction by binding and activating its receptor RANK , a 616-amino acid peptide XREF_BIBR , XREF_BIBR .	RANKL plays an important role in bone reconstruction by binding and activating its receptor RANK, a 616-amino acid peptide XREF_BIBR, XREF_BIBR.	0	20	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	14	15
These results provide clear evidence for rapidly induced RANK mediated calcium dependent signaling , and provide support for a model whereby tonic ITAM signaling and an additional RANKL induced signal that is also dependent on ITAM containing adaptors are integrated downstream of RANK .	These results provide clear evidence for rapidly induced RANK mediated calcium dependent signaling, and provide support for a model whereby tonic ITAM signaling and an additional RANKL induced signal that is also dependent on ITAM containing adaptors are integrated downstream of RANK.	23	43	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	27	28	42	43
In conclusion , we revealed that while PU.1 and C/EBPalpha are critical for osteoclastogenesis , they respond differently to RANKL induced activation of RANK IVVY motif .	In conclusion, we revealed that while PU.1 and C/EBPalpha are critical for osteoclastogenesis, they respond differently to RANKL induced activation of RANK IVVY motif.	17	25	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	19	20	23	24
The chimeric RANKL protein expressed by huRANKL-KI mice activates murine RANK and is thus capable of inducing bone resorption in mice , while being fully inhibited by human specific RANKL antibodies 43 .	The chimeric RANKL protein expressed by huRANKL-KI mice activates murine RANK and is thus capable of inducing bone resorption in mice, while being fully inhibited by human specific RANKL antibodies 43.	2	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	2	3	10	11
In the absence of osteoprotegerin , RANKL activates the RANK receptor , which is found on osteoclasts and preosteoclast precursors .	In the absence of osteoprotegerin, RANKL activates the RANK receptor, which is found on osteoclasts and preosteoclast precursors.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	6	7	9	10
Normally , osteoblasts induce osteoclast differentiation when RANK ( receptor for the activation of the NFkappabeta ) on the cell surface of osteoclast progenitors is activated by RANKL ( RANK ligand ) , a cell surface ligand expressed on the surface of osteoblasts .	Normally, osteoblasts induce osteoclast differentiation when RANK (receptor for the activation of the NFkappabeta) on the cell surface of osteoclast progenitors is activated by RANKL (RANK ligand), a cell surface ligand expressed on the surface of osteoblasts.	7	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	27	28	7	8
To address this issue , RANK DeltaIEC mice were treated with RANKL and orally exposed to a 1 % dose of ME7 scrapie prions as in the previous experiment .	To address this issue, RANK DeltaIEC mice were treated with RANKL and orally exposed to a 1% dose of ME7 scrapie prions as in the previous experiment.	5	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	11	12	5	6
To begin with , RANKL and RANK are expressed in cells of the immune system , including activated T lymphocytes , B cells , and dendritic cells , XREF_BIBR , XREF_BIBR and RANK activation by RANKL is also essential for the growth of T cells and function of dendritic cells , XREF_BIBR , XREF_BIBR and is considered to play a key role in the development of lymph nodes .	To begin with, RANKL and RANK are expressed in cells of the immune system, including activated T lymphocytes, B cells, and dendritic cells, XREF_BIBR, XREF_BIBR and RANK activation by RANKL is also essential for the growth of T cells and function of dendritic cells, XREF_BIBR, XREF_BIBR and is considered to play a key role in the development of lymph nodes.	28	36	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	35	36	32	33
To further confirm the role of the RANKL and RANK pathway in sensitivity to cetuximab , we downregulated RANK by siRNA and then treated with cetuximab , RANKL , or a combination of them .	To further confirm the role of the RANKL and RANK pathway in sensitivity to cetuximab, we downregulated RANK by siRNA and then treated with cetuximab, RANKL, or a combination of them.	17	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	27	28	18	19
Additionally , it has also shown that RANKL did not substantially contribute to RANK induced bone resorption XREF_BIBR .	Additionally, it has also shown that RANKL did not substantially contribute to RANK induced bone resorption XREF_BIBR.	7	14	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	7	8	13	14
Additionally , osteoclasts with R450W mutation could have a RANKL independent activation of RANK , leading to a more favorable bone niche for BC relapse .	Additionally, osteoclasts with R450W mutation could have a RANKL independent activation of RANK, leading to a more favorable bone niche for BC relapse.	9	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	9	10	13	14
In our previous study of metastatic breast cancer , we found that HER2 overexpression was not due to gene amplification but was mediated by receptor activation of RANK by RANKL ( an abundant ligand in the bone microenvironment ) .	In our previous study of metastatic breast cancer, we found that HER2 overexpression was not due to gene amplification but was mediated by receptor activation of RANK by RANKL (an abundant ligand in the bone microenvironment).	22	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	29	30	27	28
Studies have shown that osteoclast activity is enhanced in MM patients through increased expression of receptor activator of nuclear factor kappaB ligand ( RANKL ) , triggering RANK signaling on osteoclast precursors , which results in aggressive bone resorption .	Studies have shown that osteoclast activity is enhanced in MM patients through increased expression of receptor activator of nuclear factor kappaB ligand (RANKL), triggering RANK signaling on osteoclast precursors, which results in aggressive bone resorption.	21	28	triggering	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	23	24	27	28
Osteoclasts promote bone resorption , and RANKL expressed on bone marrow stromal cells stimulates RANK on osteoclast precursors to promote their differentiation .	Osteoclasts promote bone resorption, and RANKL expressed on bone marrow stromal cells stimulates RANK on osteoclast precursors to promote their differentiation.	6	15	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL expressed	rankl	RANK	RANK	rank	6	7	14	15
Since FAM19A5 induced inhibitory effect on osteoclastogenesis was mediated by FPR2 , these results suggested that there might be cross-talks between FAM19A5 stimulated FPR2 signaling and RANKL induced RANK signaling in macrophages .	Since FAM19A5 induced inhibitory effect on osteoclastogenesis was mediated by FPR2, these results suggested that there might be cross-talks between FAM19A5 stimulated FPR2 signaling and RANKL induced RANK signaling in macrophages.	24	29	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	26	27	28	29
Activation of RANK by RANKL promotes the maturation of preosteoclasts into osteoclasts .	Activation of RANK by RANKL promotes the maturation of preosteoclasts into osteoclasts.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	2	3
Our results showed that exogenous RANKL stimulated the RANKL and RANK pathway and then activated the EGFR pathway in GC cells .	Our results showed that exogenous RANKL stimulated the RANKL and RANK pathway and then activated the EGFR pathway in GC cells.	4	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	10	11
The activation of RANK by RANKL leads to distinct signaling cascades mediated by c-Jun N-terminal Kinase 1/2 ( JNK1/2 ) , p38 and extracellular signal regulated kinase 1/2 ( ERK1/2 ) MAP kinases regulated by the activation of MEK1 in osteoclast precursors , which are critical for RANKL induced osteoclast differentiation .	The activation of RANK by RANKL leads to distinct signaling cascades mediated by c-Jun N-terminal Kinase 1/2 (JNK1/2), p38 and extracellular signal regulated kinase 1/2 (ERK1/2) MAP kinases regulated by the activation of MEK1 in osteoclast precursors, which are critical for RANKL induced osteoclast differentiation.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	3	4
The giant cells overexpress a key mediator in osteoclastogenesis : the RANK receptor , which is stimulated in turn by the cytokine RANKL , which is secreted by the stromal cells .	The giant cells overexpress a key mediator in osteoclastogenesis : the RANK receptor, which is stimulated in turn by the cytokine RANKL, which is secreted by the stromal cells.	11	26	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	22	23	11	12
Activation of RANK by RANKL induces mitogen activated protein kinase and nuclear factor-kappaB ( NF-kappaB ) signaling .	Activation of RANK by RANKL induces mitogen activated protein kinase and nuclear factor-kappaB (NF-kappaB) signaling.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	2	3
When RANK is activated by the RANKL , a signaling cascade is initiated , causing osteoclast differentiation is triggered and bone resorption is increased .	When RANK is activated by the RANKL, a signaling cascade is initiated, causing osteoclast differentiation is triggered and bone resorption is increased.	1	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	6	7	1	2
The stimulation of RANK by OPGL appears to enhance cytoskeletal rearrangements beyond those induced by OC attachment and integrin engagement , and leads to marked stimulation of bone resorption .	The stimulation of RANK by OPGL appears to enhance cytoskeletal rearrangements beyond those induced by OC attachment and integrin engagement, and leads to marked stimulation of bone resorption.	1	6	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	OPGL	OPGL	OPGL	RANK	RANK	RANK	5	6	3	4
RANKL activates its specific receptor , RANK located on osteoclasts and dendritic cells , and its signaling cascade involves stimulation of the c-jun , NF-kappaB , and serine/threonine kinase PKB and Akt pathways .	RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells, and its signaling cascade involves stimulation of the c-jun, NF-kappaB, and serine/threonine kinase PKB and Akt pathways.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	6	7
When the macrophage stimulating factor is present , RANKL activates its receptor RANK [ XREF_BIBR ] , leading to formation and activation of osteoclasts [ XREF_BIBR ] .	When the macrophage stimulating factor is present, RANKL activates its receptor RANK [XREF_BIBR], leading to formation and activation of osteoclasts [XREF_BIBR].	8	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	8	9	12	13
Receptor activator of nuclear factor kappa B ( RANK ) ligand ( RANKL ) stimulates bone resorption by activating RANK signaling .	Receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) stimulates bone resorption by activating RANK signaling.	10	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	12	13	19	20
Furthermore , Rg3 dose-dependently reduced the mRNA expression levels of osteoclast specific markers such as RANK , TRAP , and Cat-K induced by RANKL through the down regulation of p38 , extracellular signal regulated kinase , and c-Jun N-terminal kinase ( JNK ) pathways .	Furthermore, Rg3 dose-dependently reduced the mRNA expression levels of osteoclast specific markers such as RANK, TRAP, and Cat-K induced by RANKL through the down regulation of p38, extracellular signal regulated kinase, and c-Jun N-terminal kinase (JNK) pathways.	12	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	23	24	15	16
RANKL induced activation of RANK on osteoclast progenitor cells leads to the recruitment of tumor necrosis factor ( TNF ) receptor associated factor 6 ( TRAF6 ) , consequently activating several downstream signaling molecules such as NF-kappaB and mitogen activated protein kinases ( MAPKs ) in early-stage osteoclast differentiation 7 .	RANKL induced activation of RANK on osteoclast progenitor cells leads to the recruitment of tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6), consequently activating several downstream signaling molecules such as NF-kappaB and mitogen activated protein kinases (MAPKs) in early-stage osteoclast differentiation 7.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	4	5
These data demonstrate that although GM-0111 does bind to RANKL with high affinity , it does not interfere with RANKL-RANK binding or RANKL induced RANK signaling .	These data demonstrate that although GM-0111 does bind to RANKL with high affinity, it does not interfere with RANKL-RANK binding or RANKL induced RANK signaling.	17	25	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	22	23	24	25
RANK stimulation by RANKL results in the differentiation of preosteoclasts into active osteoclasts , which resorb the mineralized bone matrix , thus releasing factors to promote further colonization and growth of tumor cells .	RANK stimulation by RANKL results in the differentiation of preosteoclasts into active osteoclasts, which resorb the mineralized bone matrix, thus releasing factors to promote further colonization and growth of tumor cells.	0	4	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	3	4	0	1
It is noteworthy that T Reg cells in a primary mammary tumour secrete RANKL , which activates its receptor RANK on cancer cells and promotes lung metastasis without affecting primary tumour growth .	It is noteworthy that T Reg cells in a primary mammary tumour secrete RANKL, which activates its receptor RANK on cancer cells and promotes lung metastasis without affecting primary tumour growth.	12	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	13	14	19	20
Acting in an autocrine manner , RANKL may stimulate tumor cell migration and invasion of RANK expressing cancer cells , as reported for prostate cancer C42b cells in vitro for instance .	Acting in an autocrine manner, RANKL may stimulate tumor cell migration and invasion of RANK expressing cancer cells, as reported for prostate cancer C42b cells in vitro for instance.	4	16	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	6	7	15	16
In precursors of osteoclasts , RANKL induced activation of RANK stimulates ROS production , which is essential for osteoclastogenesis .	In precursors of osteoclasts, RANKL induced activation of RANK stimulates ROS production, which is essential for osteoclastogenesis.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	9	10
XREF_FIG , RANK-N disrupted the processing of NF-kappaB2 p100 into NF-kappaB2 p52 that is induced by RANKL in Raw264.7 cells in a dose dependent manner , proving that RANK-N could disrupt RANKL activated RANK signaling .	XREF_FIG, RANK-N disrupted the processing of NF-kappaB2 p100 into NF-kappaB2 p52 that is induced by RANKL in Raw264.7 cells in a dose dependent manner, proving that RANK-N could disrupt RANKL activated RANK signaling.	30	34	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	31	32	33	34
As summarized in XREF_FIG , the underlying mechanism of PCA in the suppression of bone loss in OVX mice may be associated with the following effects : ( 1 ) reduction of serum level of RANKL and increase in OPG ; ( 2 ) blocking the RANK signaling pathway via downregulation of TRAF6 and NFATc1 expression ; and ( 3 ) attenuation of cathepsin K and calcitonin receptor expression .	As summarized in XREF_FIG, the underlying mechanism of PCA in the suppression of bone loss in OVX mice may be associated with the following effects : (1) reduction of serum level of RANKL and increase in OPG; (2) blocking the RANK signaling pathway via downregulation of TRAF6 and NFATc1 expression; and (3) attenuation of cathepsin K and calcitonin receptor expression.	33	48	blocking	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	level of RANKL	rankl	RANK	RANK	rank	35	36	46	47
However , in a series of experiments it was conclusively shown that RANKL expressing T cells can also activate RANK expressing osteoclasts , and thereby in principal mimicking RANKL expressing osteoblasts .	However, in a series of experiments it was conclusively shown that RANKL expressing T cells can also activate RANK expressing osteoclasts, and thereby in principal mimicking RANKL expressing osteoblasts.	12	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL expressing	rankl	RANK	RANK	rank	12	13	19	20
RANKL activation of RANK also induces a rise in intracellular calcium in osteoclastogenesis .	RANKL activation of RANK also induces a rise in intracellular calcium in osteoclastogenesis.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	3	4
The RANKL expression on the osteoblast surface increases in response to inflammatory cytokines , thereby stimulating RANK osteoclast receptors and bone resorption .	The RANKL expression on the osteoblast surface increases in response to inflammatory cytokines, thereby stimulating RANK osteoclast receptors and bone resorption.	1	18	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL expression	rankl	RANK	RANK	rank	1	2	16	17
To determine whether the Aire expression in TECs in the presence of SEB was preferentially dependent on RANKL mediated RANK signaling , blocking antibody against RANKL was added to FTOC with SEB .	To determine whether the Aire expression in TECs in the presence of SEB was preferentially dependent on RANKL mediated RANK signaling, blocking antibody against RANKL was added to FTOC with SEB.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	17	18	19	20
RANK activation by RANKL regulates osteoclast differentiation , activity and survival .	RANK activation by RANKL regulates osteoclast differentiation, activity and survival.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	3	4	0	1
RANKL activates RANK mediated signaling , including MAP kinases , nuclear factor kappaB ( NF-kappaB ) , c-Fos , and nuclear factor of activated T-cells , cytoplasmic 1 ( NFATc1 ) .	RANKL activates RANK mediated signaling, including MAP kinases, nuclear factor kappaB (NF-kappaB), c-Fos, and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1).	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	2	3
For example , in osteoclasts RANKL activation of RANK increases intracellular Ca 2+ which initiates downstream signaling processes that result in osteoclast differentiation .	For example, in osteoclasts RANKL activation of RANK increases intracellular Ca 2+ which initiates downstream signaling processes that result in osteoclast differentiation.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	8	9
Here we showed that RANKL directly promoted migration , invasion , and EMT of RANK positive HCC cells via the NF-kappaB pathway .	Here we showed that RANKL directly promoted migration, invasion, and EMT of RANK positive HCC cells via the NF-kappaB pathway.	4	17	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	14	15
Next , we further analyzed the expression of osteoclast markers [ cathepsin K ( CathK ) and RANK ] induced by IL-7 , M-CSF , and RANKL .	Next, we further analyzed the expression of osteoclast markers [cathepsin K (CathK) and RANK] induced by IL-7, M-CSF, and RANKL.	6	27	induced	Positive_regulation_syntax_2_verb	Positive_activation	Positive_regulation	RANKL	RANKL	rankl	RANK	expression of osteoclast markers [cathepsin K (CathK) and RANK	rank	26	27	17	18
Furthermore , high concentration RANKL might overly activate both the RANK-RANKL pathway and the RANK intracellular domain ( ivvy535-538 ) to counteract the inhibitory effect .	Furthermore, high concentration RANKL might overly activate both the RANK-RANKL pathway and the RANK intracellular domain (ivvy535-538) to counteract the inhibitory effect.	2	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	14	15
The time course was similar to that of RANKL induced RANK translocation to the Golgi apparatus as well as termination of RANK signaling in Raw264.7 cells ( XREF_FIG and XREF_FIG ) .	The time course was similar to that of RANKL induced RANK translocation to the Golgi apparatus as well as termination of RANK signaling in Raw264.7 cells (XREF_FIG and XREF_FIG).	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	8	9	10	11
In adult thymus , RANK signaling is mediated by RANKL expressing positively selected CD4 + thymocytes but during embryonic development , when there are no SP thymocytes , RORgammat + lymphoid tissue inducing cells and canonical Vgamma5 + T cells are involved .	In adult thymus, RANK signaling is mediated by RANKL expressing positively selected CD4 + thymocytes but during embryonic development, when there are no SP thymocytes, RORgammat + lymphoid tissue inducing cells and canonical Vgamma5 + T cells are involved.	4	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	9	10	4	5
Osteoblasts produce membrane associated RANKL that activates RANK on osteoclasts and their hematopoietic precursors .	Osteoblasts produce membrane associated RANKL that activates RANK on osteoclasts and their hematopoietic precursors.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	7	8
Membrane bound RANKL activates RANK to generate osteoclasts through cell-cell contact .	Membrane bound RANKL activates RANK to generate osteoclasts through cell-cell contact.	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	2	3	4	5
40 In the presence of M-CSF , RANKL drives RANK + and CD14 + osteoclast precursors in healthy controls to osteoclasts , i.e ., to fuse to multinuclear cells , XREF_BIBR , XREF_BIBR if a soluble decoy receptor osteoprotegerin does not neutralize it .	40 In the presence of M-CSF, RANKL drives RANK + and CD14 + osteoclast precursors in healthy controls to osteoclasts, i.e., to fuse to multinuclear cells, XREF_BIBR, XREF_BIBR if a soluble decoy receptor osteoprotegerin does not neutralize it.	7	12	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	7	8	9	10
However , seminal studies demonstrated that arthritic mice lacking RANKL or the RANK receptor do not form osteoclasts , and humans treated with denosumab , a RANKL specific blocking antibody , are protected from inflammatory bone erosion .	However, seminal studies demonstrated that arthritic mice lacking RANKL or the RANK receptor do not form osteoclasts, and humans treated with denosumab, a RANKL specific blocking antibody, are protected from inflammatory bone erosion.	12	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	26	27	12	13
MCSF promotes the survival and expansion of precursors , while stimulation of RANK by RANKL initiates canonical and non canonical NF-kappaB pathways , as well as the mitogen activated kinase ( MAPK ) pathway .	MCSF promotes the survival and expansion of precursors, while stimulation of RANK by RANKL initiates canonical and non canonical NF-kappaB pathways, as well as the mitogen activated kinase (MAPK) pathway.	10	15	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	14	15	12	13
RANKL mediates the process of osteoclastogenesis by binding to its RANK , which is expressed on mononuclear osteoclast precursors .	RANKL mediates the process of osteoclastogenesis by binding to its RANK, which is expressed on mononuclear osteoclast precursors.	0	15	mediates	Positive_regulation_syntax_7_verb	Positive_activation	Positive_regulation	RANKL	RANKL	rankl	RANK	RANK, which is expressed	rank	0	1	10	11
None of the other osteoclast signalling genes tested - RANK , TRAF6 , p38 , NF-kappaB , c-Fos , c-jun , FcgammaRIIB , DAP12 , Gab2 , and Pim1 - were upregulated as strongly as NFATc1 by RANKL , and none of them were downregulated by IL-10 ( data not shown ) .	None of the other osteoclast signalling genes tested - RANK, TRAF6, p38, NF-kappaB, c-Fos, c-jun, FcgammaRIIB, DAP12, Gab2, and Pim1 - were upregulated as strongly as NFATc1 by RANKL, and none of them were downregulated by IL-10 (data not shown).	0	38	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	37	38	9	10
Another target of TNF is the RANKL receptor RANK , whose expression in OC precursors is synergistically upregulated by TNF and RANKL .	Another target of TNF is the RANKL receptor RANK, whose expression in OC precursors is synergistically upregulated by TNF and RANKL.	1	22	upregulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	21	22	8	9
Since dasatinib is a Src family kinase inhibitor and could have been exerting its effect on the MCSF receptor ( cfms-1 ) , MCSF and RANKL were added to the cells and allowed to activate their receptors , cfms-1 and RANK , respectively .	Since dasatinib is a Src family kinase inhibitor and could have been exerting its effect on the MCSF receptor (cfms-1), MCSF and RANKL were added to the cells and allowed to activate their receptors, cfms-1 and RANK, respectively.	23	41	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	25	26	40	41
We next conducted a population analysis of RANK positive cells induced by M-CSF and RANKL stimulation .	We next conducted a population analysis of RANK positive cells induced by M-CSF and RANKL stimulation.	7	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	14	15	7	8
Flavonoids may also inhibit RANKL induced formation of multinucleated osteoclasts and expression of osteoclastic differentiation markers ; RANK and osteocalcin receptor [ XREF_BIBR ] .	Flavonoids may also inhibit RANKL induced formation of multinucleated osteoclasts and expression of osteoclastic differentiation markers; RANK and osteocalcin receptor [XREF_BIBR].	3	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	17	18
Furthermore compared with controls , RANKL induces enhanced association of TRAF6 and RANK in both RAW264.7 cells expressing SHP-1 ( C453S ) and bone marrow macrophages from Me ( v )/Me ( v ) mice .	Furthermore compared with controls, RANKL induces enhanced association of TRAF6 and RANK in both RAW264.7 cells expressing SHP-1 (C453S) and bone marrow macrophages from Me (v)/Me (v) mice.	5	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	12	13
After RANK is activated by RANKL , p105 is processed to P50 constitutively and forms dimers usually with RelA .	After RANK is activated by RANKL, p105 is processed to P50 constitutively and forms dimers usually with RelA.	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	1	2
RANKL can activate TNF receptor associated factors ( TRAFs ) and the cognate receptor RANK on osteoclast progenitor cells , leading to osteoclast progenitor cell differentiation [ XREF_BIBR - XREF_BIBR ] .	RANKL can activate TNF receptor associated factors (TRAFs) and the cognate receptor RANK on osteoclast progenitor cells, leading to osteoclast progenitor cell differentiation [XREF_BIBR - XREF_BIBR].	0	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	14	15
They indicated that UV irradiation induces expression of RANKL in keratinocytes , and then RANKL activates its receptor RANK in epidermal Langerhans cells , leading to induction of Treg cell proliferation .	They indicated that UV irradiation induces expression of RANKL in keratinocytes, and then RANKL activates its receptor RANK in epidermal Langerhans cells, leading to induction of Treg cell proliferation.	14	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	14	15	18	19
RANKL activates RANK , which is expressed by osteoclasts and dendritic cells ( DC ) , whereas OPG acts as its decoy receptor .	RANKL activates RANK, which is expressed by osteoclasts and dendritic cells (DC), whereas OPG acts as its decoy receptor.	0	7	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	RANKL	RANKL	rankl	RANK	RANK, which is expressed	rank	0	1	2	3
These cytokines can induce production of RANKL , decrease production of osteoprotegerin ( OPG ) , upregulate RANK on osteoclast precursors , and increase RANKL to affect RANK/RANKL/OPG signaling pathway .	These cytokines can induce production of RANKL, decrease production of osteoprotegerin (OPG), upregulate RANK on osteoclast precursors, and increase RANKL to affect RANK/RANKL/OPG signaling pathway.	4	18	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	6	7	17	18
The primary mechanism by which osteoclasto-genesis occurs is through activation of RANK by RANKL on the surface of osteoclast precursors , a process controlled by OPG binding to RANKL as a decoy receptor .	The primary mechanism by which osteoclasto-genesis occurs is through activation of RANK by RANKL on the surface of osteoclast precursors, a process controlled by OPG binding to RANKL as a decoy receptor.	9	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	13	14	11	12
RANKL pretreatment made cells refractory to phagocytosis mediated downregulation of RANK , consistent with the ability of RANKL pretreatment to reverse the antiosteoclastogenic effects of particle phagocytosis .	RANKL pretreatment made cells refractory to phagocytosis mediated downregulation of RANK, consistent with the ability of RANKL pretreatment to reverse the antiosteoclastogenic effects of particle phagocytosis.	0	11	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	10	11
Only CD4 + regulatory T cells in the stroma of mammary tumors produced RANKL , which stimulated RANK expressing ERBB2 driven mammary tumors to metastasize .	Only CD4 + regulatory T cells in the stroma of mammary tumors produced RANKL, which stimulated RANK expressing ERBB2 driven mammary tumors to metastasize.	12	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	13	14	17	18
There , RANKL presented by mature T cells stimulates RANK on osteoclast precursors , resulting in their proliferation and simultaneous production of IFNbeta .	There, RANKL presented by mature T cells stimulates RANK on osteoclast precursors, resulting in their proliferation and simultaneous production of IFNbeta.	2	10	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	2	3	9	10
RANKL induced activation of RANK causes TNF receptor associated factor 6 ( TRAF6 ) recruitment in osteoclast precursor cells [ XREF_BIBR ] and the sequential activation of mitogen activated protein kinases ( MAPKs ) involving extracellular signaling related kinase ( ERK ) , p38 , and Jun N-terminal kinase ( JNK ) , and transcription factors such as nuclear factor-kappa B ( NF-kappaB ) , activating protein 1 ( AP-1 ) , nuclear factor of activated T cells ( NFATc1 ) , and c-Fos [ XREF_BIBR ] .	RANKL induced activation of RANK causes TNF receptor associated factor 6 (TRAF6) recruitment in osteoclast precursor cells [XREF_BIBR] and the sequential activation of mitogen activated protein kinases (MAPKs) involving extracellular signaling related kinase (ERK), p38, and Jun N-terminal kinase (JNK), and transcription factors such as nuclear factor-kappa B (NF-kappaB), activating protein 1 (AP-1), nuclear factor of activated T cells (NFATc1), and c-Fos [XREF_BIBR].	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	4	5
The RANK receptor ( receptor activator of NF-kappaB ) located on hematopoietic osteoclast progenitor cells and mature osteoclasts is activated by the RANK ligand RANKL .	The RANK receptor (receptor activator of NF-kappaB) located on hematopoietic osteoclast progenitor cells and mature osteoclasts is activated by the RANK ligand RANKL.	1	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	24	25	1	2
We found that RANKL treatment induced drug resistance in RANK expressing but not RANK negative cell lines .	We found that RANKL treatment induced drug resistance in RANK expressing but not RANK negative cell lines.	3	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	3	4	13	14
XREF_BIBR When RANK is activated by the RANKL , a signaling cascade is initiated , causing osteoclast differentiation and increased bone resorption .	XREF_BIBR When RANK is activated by the RANKL, a signaling cascade is initiated, causing osteoclast differentiation and increased bone resorption.	2	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	7	8	2	3
Thus , we evaluated the effect of IL-6 and sIL-6R on RANKL triggered RANK-TRAF6 interaction in murine BMMs and found that IL-6 and sIL-6R did not change the association of RANK and TRAF6 induced by either low- or high level RANKL .	Thus, we evaluated the effect of IL-6 and sIL-6R on RANKL triggered RANK-TRAF6 interaction in murine BMMs and found that IL-6 and sIL-6R did not change the association of RANK and TRAF6 induced by either low- or high level RANKL.	28	41	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	40	41	30	31
Regarding bone remodelling ( reabsorption ) , activation of RANK by RANKL transforms preosteoclasts into their mature form .	Regarding bone remodelling (reabsorption), activation of RANK by RANKL transforms preosteoclasts into their mature form.	7	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	11	12	9	10
Receptor activator of nuclear factor-kappaB ligand ( RANKL ) , a member of tumor necrosis factor ( TNF )-alpha , is produced by osteoblasts ( Obs ) and stimulates its receptor RANK on osteoclast ( Oc ) progenitors to differentiate them to osteoclasts .	Receptor activator of nuclear factor-kappaB ligand (RANKL), a member of tumor necrosis factor (TNF)-alpha, is produced by osteoblasts (Obs) and stimulates its receptor RANK on osteoclast (Oc) progenitors to differentiate them to osteoclasts.	5	37	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	7	8	31	32
The activation of RANK is antagonized when soluble OPG binds to RANKL , thereby preventing RANKL activation of RANK .	The activation of RANK is antagonized when soluble OPG binds to RANKL, thereby preventing RANKL activation of RANK.	15	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	15	16	18	19
RANKL activates osteoclasts through binding to RANK on the osteoclast surface .	RANKL activates osteoclasts through binding to RANK on the osteoclast surface.	0	10	activates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	6	7
Osteoprotegerin ( OPG ) is a soluble protein in the TNF receptor family that can hinder RANKL activation of the RANK receptor protein by binding RANKL and acting as a decoy receptor for RANKL .	Osteoprotegerin (OPG) is a soluble protein in the TNF receptor family that can hinder RANKL activation of the RANK receptor protein by binding RANKL and acting as a decoy receptor for RANKL.	16	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	16	17	20	21
Cell biological experiments suggest that VPS35 may inactivate RANK signaling by promoting RANKL induced RANK endosome to Golgi translocation .	Cell biological experiments suggest that VPS35 may inactivate RANK signaling by promoting RANKL induced RANK endosome to Golgi translocation.	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	12	13	14	15
The osteoblast secreted receptor of activated NF-kappaB ( RANK ) ligand ( RANKL ) activates RANK receptors on osteoclasts to promote their differentiation , maturation and survival , and bone resorption [ XREF_BIBR ] .	The osteoblast secreted receptor of activated NF-kappaB (RANK) ligand (RANKL) activates RANK receptors on osteoclasts to promote their differentiation, maturation and survival, and bone resorption [XREF_BIBR].	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	12	13	15	16
The close proximity of cells , along with RANKL mediated activation of the RANK receptor , is believed to induce fusion competency via transcription and surface expression of fusion receptors .	The close proximity of cells, along with RANKL mediated activation of the RANK receptor, is believed to induce fusion competency via transcription and surface expression of fusion receptors.	6	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	8	9	13	14
In nondifferentiating conditions , we observed a greater proportion of multipotent self renewing cells , and RANKL treatment activated the RANK pathway in these cultures .	In nondifferentiating conditions, we observed a greater proportion of multipotent self renewing cells, and RANKL treatment activated the RANK pathway in these cultures.	16	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	16	17	20	21
The key event in subsequent osteoclastogenesis is activation of RANK by RANKL , which is expressed on osteoblast lineage cells under physiological conditions .	The key event in subsequent osteoclastogenesis is activation of RANK by RANKL, which is expressed on osteoblast lineage cells under physiological conditions.	7	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL, which is expressed	rankl	RANK	RANK	rank	11	12	9	10
The increased expression of RANK mRNA substantiated matching trends in the intensity of immunofluorescent staining of RANK in BMMs treated with TNF-alpha and RANKL individually or in combination .	The increased expression of RANK mRNA substantiated matching trends in the intensity of immunofluorescent staining of RANK in BMMs treated with TNF-alpha and RANKL individually or in combination.	14	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	23	24	16	17
RANK signaling triggered by RANKL modulates the activation of various signal pathways including NF-kappaB and mitogen activated protein kinases ( MAPKs ) via TRAF6 , an essential mediator of RANK signaling .	RANK signaling triggered by RANKL modulates the activation of various signal pathways including NF-kappaB and mitogen activated protein kinases (MAPKs) via TRAF6, an essential mediator of RANK signaling.	0	5	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	4	5	0	1
TNF receptor associated factor 6 ( TRAF6 ) is recruited upon the activation of RANK by RANKL , which also leads to a complex of c-Src and TRAF6 and ultimately the activation of phosphoinositide 3-kinase ( PI3K ) and AKT XREF_BIBR , XREF_BIBR .	TNF receptor associated factor 6 (TRAF6) is recruited upon the activation of RANK by RANKL, which also leads to a complex of c-Src and TRAF6 and ultimately the activation of phosphoinositide 3-kinase (PI3K) and AKT XREF_BIBR, XREF_BIBR.	9	20	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	16	17	14	15
When RANK is activated by RANKL , it sends signals into TNF receptor associated factor molecules ( TRAFs ) , leading to up-regulation of the downstream molecules such as c-Fos and down-regulation of MafB and IFR-8 which regulate NFATc1 activity and its auto-amplification , resulting in the activation , survival and differentiation of osteoclasts .	When RANK is activated by RANKL, it sends signals into TNF receptor associated factor molecules (TRAFs), leading to up-regulation of the downstream molecules such as c-Fos and down-regulation of MafB and IFR-8 which regulate NFATc1 activity and its auto-amplification, resulting in the activation, survival and differentiation of osteoclasts.	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	1	2
In vitro studies have found that RANKL is expressed on immature osteoblasts in the presence of macrophage colony stimulating factor , activates RANK , induces the formation of osteoclasts through recruitment of osteoclast precursors in the marrow , and promotes their differentiation and fusion into multinucleated osteoclasts , which are responsible for resorption .	In vitro studies have found that RANKL is expressed on immature osteoblasts in the presence of macrophage colony stimulating factor, activates RANK, induces the formation of osteoclasts through recruitment of osteoclast precursors in the marrow, and promotes their differentiation and fusion into multinucleated osteoclasts, which are responsible for resorption.	6	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL is expressed	rankl	RANK	RANK	rank	6	7	22	23
Furthermore , the activation of RANK by RANKL attracts osteoclastic precursors [ XREF_BIBR ] and its upregulation contributes to an enhanced RANKL induced monocyte migration to the affected foot .	Furthermore, the activation of RANK by RANKL attracts osteoclastic precursors [XREF_BIBR] and its upregulation contributes to an enhanced RANKL induced monocyte migration to the affected foot.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	7	8	5	6
Importantly , it was demonstrated that progesterone induced RANKL signaling in luminal mammary epithelial cells not only activates RANK downstream pathway in an autocrine way but also activates RANK signaling in the RANKL negative basal mammary epithelial cells in a paracrine manner [ XREF_BIBR ] .	Importantly, it was demonstrated that progesterone induced RANKL signaling in luminal mammary epithelial cells not only activates RANK downstream pathway in an autocrine way but also activates RANK signaling in the RANKL negative basal mammary epithelial cells in a paracrine manner [XREF_BIBR].	6	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	progesterone induced RANKL	rankl	RANK	RANK	rank	8	9	18	19
The mutated RANKL protein fails to form bioactive trimers , activate the RANK receptor , or induce osteoclastogenesis .	The mutated RANKL protein fails to form bioactive trimers, activate the RANK receptor, or induce osteoclastogenesis.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	2	3	12	13
96 Like other TNFR family members , RANKL activation of RANK signals via TRAF induced nuclear factor kappa-B ( NF-kB ) and Jun-N-terminal kinase ( JNK ) activation .	96 Like other TNFR family members, RANKL activation of RANK signals via TRAF induced nuclear factor kappa-B (NF-kB) and Jun-N-terminal kinase (JNK) activation.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	7	8	10	11
RANK , TRAF6 , Fra1 , c-src and c-fos ( at 15-30 nmol/L ) expression were enhanced ( 30-70 % ) by cadmium in the presence of RANKL , but cadmium had little influence on them in the absence of RANKL .	RANK, TRAF6, Fra1, c-src and c-fos (at 15-30 nmol/L) expression were enhanced (30-70%) by cadmium in the presence of RANKL, but cadmium had little influence on them in the absence of RANKL.	0	28	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	27	28	0	1
However , the effects of GM-0111 on RANKL induced RANK activation were weak , with reduced activation only observable at very high concentrations ( 3000 mug/mL , XREF_FIG ) .	However, the effects of GM-0111 on RANKL induced RANK activation were weak, with reduced activation only observable at very high concentrations (3000 mug/mL, XREF_FIG).	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	7	8	9	10
Whether the expression of a3 in the brain was the result of RANKL stimulation of RANK is not clear .	Whether the expression of a3 in the brain was the result of RANKL stimulation of RANK is not clear.	12	16	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	12	13	15	16
However , RANKL increased RANK distribution in fractions enriched with Golgi apparatus in Vps35 +/+ , but not Vps35 +/m , BMMs ( XREF_FIG ) .	However, RANKL increased RANK distribution in fractions enriched with Golgi apparatus in Vps35 +/+, but not Vps35 +/m, BMMs (XREF_FIG).	2	5	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	2	3	4	5
Furthermore , we show that RANKL treatment induces lymphotoxin alpha ( LTalpha ) upregulation specifically in LTi cells , which express its cognate receptor , RANK .	Furthermore, we show that RANKL treatment induces lymphotoxin alpha (LTalpha) upregulation specifically in LTi cells, which express its cognate receptor, RANK.	5	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	25	26
B ligand , also known as TRANCE , TNF related activation induced cytokine , or ODF , osteoclast differentiation factor ) and its receptor RANK ( receptor activator of nuclear factor ?	B ligand, also known as TRANCE, TNF related activation induced cytokine, or ODF, osteoclast differentiation factor) and its receptor RANK (receptor activator of nuclear factor?	0	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	B ligand	B ligand	B ligand	RANK	RANK	RANK	0	2	24	25
In RANK positive cells , RANKL ( RANK ligand ) induces the activation of RANK dependent pathway , increases migration and invasion , and induces epithelia-mesenchymal transition , favoring an invasive phenotype XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	In RANK positive cells, RANKL (RANK ligand) induces the activation of RANK dependent pathway, increases migration and invasion, and induces epithelia-mesenchymal transition, favoring an invasive phenotype XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	5	6	14	15
RANKL released by osteoblasts and bone marrow stromal cells creates a cytokine gradient between bone site and extraosseous sites and triggers the migration of RANK positive tumours cells .	RANKL released by osteoblasts and bone marrow stromal cells creates a cytokine gradient between bone site and extraosseous sites and triggers the migration of RANK positive tumours cells.	0	25	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	24	25
RANKL induces RANK proximal signals consisting of key transcription factors that converge to promote expression of OC specific genes [ XREF_BIBR , XREF_BIBR ] .	RANKL induces RANK proximal signals consisting of key transcription factors that converge to promote expression of OC specific genes [XREF_BIBR, XREF_BIBR].	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	2	3
RANKL could potentiate migration and invasion ability of RANK positive HCC cells through NF-kappaB pathway mediated epithelial-mesenchymal transition , which means that RANKL-RANK axis could be a potential target for HCC therapy .	RANKL could potentiate migration and invasion ability of RANK positive HCC cells through NF-kappaB pathway mediated epithelial-mesenchymal transition, which means that RANKL-RANK axis could be a potential target for HCC therapy.	0	11	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	8	9
Induction of RANK signalling by RANK-L , a cytokine that is highly expressed in the bone marrow environment , can potentially lead to the activation of AP-1 , NFATc1 and NF-kappaB transcription factors , all of which are important for osteoclastogenesis and/or activity [ XREF_BIBR ] .	Induction of RANK signalling by RANK-L, a cytokine that is highly expressed in the bone marrow environment, can potentially lead to the activation of AP-1, NFATc1 and NF-kappaB transcription factors, all of which are important for osteoclastogenesis and/or activity [XREF_BIBR].	2	6	signalling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	RANK-L	RANK-L	RANK-L	RANK	RANK	RANK	5	6	2	3
Previously , we and others have shown that upon binding to the respective target antigen , scFv : TRAIL fusion proteins can efficiently activate TRAIL-R2 , whereas untargeted sTRAIL preparations have a markedly reduced capacity to activate TRAIL-R2 signaling .	Previously, we and others have shown that upon binding to the respective target antigen, scFv : TRAIL fusion proteins can efficiently activate TRAIL-R2, whereas untargeted sTRAIL preparations have a markedly reduced capacity to activate TRAIL-R2 signaling.	18	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	18	19	24	25
Furthermore , resistance to TRAIL and tumor cell restricted loss of TRAIL-receptor 2 were observed in 16 of 16 SzS PBLs .	Furthermore, resistance to TRAIL and tumor cell restricted loss of TRAIL-receptor 2 were observed in 16 of 16 SzS PBLs.	4	13	loss	Negative_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-receptor 2	TRAIL-receptor 2	TRAIL-receptor 2	4	5	11	13
TRAIL mediates apoptosis via the binding two death receptors , TRAIL-R1 ( DR4 ) and/or TRAIL-R2 ( DR5 ) .	TRAIL mediates apoptosis via the binding two death receptors, TRAIL-R1 (DR4) and/or TRAIL-R2 (DR5).	0	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	0	1	15	16
Cleavage of pro-caspase-8 into a mature and active product [ XREF_BIBR ] is one of the earliest steps of TRAIL stimulated DR5 signaling .	Cleavage of pro-caspase-8 into a mature and active product [XREF_BIBR] is one of the earliest steps of TRAIL stimulated DR5 signaling.	17	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	19	20	21	22
In this regard , our western blotting showed that combination of Tanshinone I and TRAIL attenuated the anti-apoptotic proteins such as Bcl-2 , Bcl- X L and also activated caspase 8 , 9 and DR5 in PC-3 and DU145 cells .	In this regard, our western blotting showed that combination of Tanshinone I and TRAIL attenuated the anti-apoptotic proteins such as Bcl-2, Bcl- X L and also activated caspase 8, 9 and DR5 in PC-3 and DU145 cells.	9	35	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	14	15	34	35
As expected , combined TRAIL and SAHA treatments significantly induced Bax , DR5 and CDKN1A , and they also significantly inhibited Bcl-2 , Bcl-x and Phospho P53 ( s46 ) expression in both of the cell lines .	As expected, combined TRAIL and SAHA treatments significantly induced Bax, DR5 and CDKN1A, and they also significantly inhibited Bcl-2, Bcl-x and Phospho P53 (s46) expression in both of the cell lines.	3	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	4	5	12	13
In addition to the CHOP dependent pathway , CHOP independent DR5 upregulation has been observed in certain cancer cells treated with TRAIL and other chemicals , such as Orlistat ( Xenical TM ) [ XREF_BIBR ] and curcumin [ XREF_BIBR ] , although the key mediators of DR5 upregulation have not been identified .	In addition to the CHOP dependent pathway, CHOP independent DR5 upregulation has been observed in certain cancer cells treated with TRAIL and other chemicals, such as Orlistat (Xenical TM) [XREF_BIBR] and curcumin [XREF_BIBR], although the key mediators of DR5 upregulation have not been identified.	10	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	21	22	10	11
With the discovery of TRAIL ( Apo2L ) [ XREF_BIBR , XREF_BIBR ] and its two apoptosis inducing receptors TRAIL-R1 [ XREF_BIBR ] and TRAIL-R2 [ XREF_BIBR - XREF_BIBR ] a new potential opportunity for death receptor targeting arose .	With the discovery of TRAIL (Apo2L) [XREF_BIBR, XREF_BIBR] and its two apoptosis inducing receptors TRAIL-R1 [XREF_BIBR] and TRAIL-R2 [XREF_BIBR - XREF_BIBR] a new potential opportunity for death receptor targeting arose.	2	26	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	4	5	24	25
For instance , retinyl acetate was recently shown to increase TNF related apoptosis inducing ligand ( TRAIL ) dependent cell death in mouse adenomatous polyposis coli ( Apc )-mutant intestinal cells , without affecting normal cells , by up-regulating TRAIL activated death receptors TNFRSF10A and B ( DR4 and DR5 ) transcripts and by reducing decoy receptor TNFRSF10C and D ( DcR1 and DcR2 ) transcripts .	For instance, retinyl acetate was recently shown to increase TNF related apoptosis inducing ligand (TRAIL) dependent cell death in mouse adenomatous polyposis coli (Apc)-mutant intestinal cells, without affecting normal cells, by up-regulating TRAIL activated death receptors TNFRSF10A and B (DR4 and DR5) transcripts and by reducing decoy receptor TNFRSF10C and D (DcR1 and DcR2) transcripts.	39	51	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	39	40	49	50
TRAIL induced clustering and oligomerization of DR4 and DR5 results in conformational changes of the death domains within their cytoplasmic tails , facilitating recruitment and activation of caspases 8 and 10 within a death inducing signaling complex ( DISC ) XREF_BIBR , XREF_BIBR , XREF_BIBR .	TRAIL induced clustering and oligomerization of DR4 and DR5 results in conformational changes of the death domains within their cytoplasmic tails, facilitating recruitment and activation of caspases 8 and 10 within a death inducing signaling complex (DISC) XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	8	9
Trying to ascertain the molecular mechanism by which LUV-TRAIL exhibited improved cytotoxicity , we demonstrated that TRAIL coated lipid nanoparticles were able to activate DR5 more efficiently than sTRAIL , and this relied on LUV-TRAIL ability to promote DR5 clustering on the cell surface .	Trying to ascertain the molecular mechanism by which LUV-TRAIL exhibited improved cytotoxicity, we demonstrated that TRAIL coated lipid nanoparticles were able to activate DR5 more efficiently than sTRAIL, and this relied on LUV-TRAIL ability to promote DR5 clustering on the cell surface.	16	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	16	17	24	25
Pretreatment of A549 cells with NAC and GSH markedly reduced silibinin and TRAIL induced upregulation of DR5 at the transcription ( top ) and translation ( bottom ) levels .	Pretreatment of A549 cells with NAC and GSH markedly reduced silibinin and TRAIL induced upregulation of DR5 at the transcription (top) and translation (bottom) levels.	10	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	12	13	16	17
Apo2L and TRAIL induced a transient upregulation of DR5 mRNA , while CPT-11 increased both death and decoy receptor expression .	Apo2L and TRAIL induced a transient upregulation of DR5 mRNA, while CPT-11 increased both death and decoy receptor expression.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Apo2L	Apo2L	Apo2L	DR5	DR5	DR5	0	1	8	9
Normal human articular chondrocytes were known to express the TRAIL receptors modulating apoptosis ( DR4 and DR5 ) , and cartilage obtained from experimentally induced OA rats showed an increased expression of TRAIL and DR4 , implicating a role for TRAIL induced chondrocyte apoptosis in the pathogenesis of OA [ XREF_BIBR ] .	Normal human articular chondrocytes were known to express the TRAIL receptors modulating apoptosis (DR4 and DR5), and cartilage obtained from experimentally induced OA rats showed an increased expression of TRAIL and DR4, implicating a role for TRAIL induced chondrocyte apoptosis in the pathogenesis of OA [XREF_BIBR].	9	17	modulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	9	10	16	17
Previously , we showed that the combined addition of recombinant TRAIL and anti-DR5 antibody ( MD5 ) enhanced the ability of TRAIL to cluster and activate DR5 resulting in significant increases in apoptosis in the GC2spd ( ts ) germ cell line , thereby implicating a likely role for TRAIL in the modulation of germ cell apoptosis in the testes in vivo XREF_BIBR .	Previously, we showed that the combined addition of recombinant TRAIL and anti-DR5 antibody (MD5) enhanced the ability of TRAIL to cluster and activate DR5 resulting in significant increases in apoptosis in the GC2spd (ts) germ cell line, thereby implicating a likely role for TRAIL in the modulation of germ cell apoptosis in the testes in vivo XREF_BIBR.	7	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	10	11	26	27
Hence , we set out to develop MSCs that express and secrete TRAIL variants that specifically target TRAIL-R2 to achieve greater apoptosis induction in 5-FU-treated tumor cells .	Hence, we set out to develop MSCs that express and secrete TRAIL variants that specifically target TRAIL-R2 to achieve greater apoptosis induction in 5-FU-treated tumor cells.	12	18	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	12	13	17	18
TRAIL induced down-regulation of DNA-PKcs/Akt/GSK-3beta pathway and c-FLIP and up-regulation of DR4 and DR5 cell surface expression are associated with the susceptibility to TRAIL of MDR cells .	TRAIL induced down-regulation of DNA-PKcs/Akt/GSK-3beta pathway and c-FLIP and up-regulation of DR4 and DR5 cell surface expression are associated with the susceptibility to TRAIL of MDR cells.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	13	14
Olaparib elicits a nuclear stress response with up-regulation of CHOP in a time dependent manner in GBM cells , and siRNA mediated suppression of CHOP attenuates TRAIL and Olaparib mediated increase of DR5 .	Olaparib elicits a nuclear stress response with up-regulation of CHOP in a time dependent manner in GBM cells, and siRNA mediated suppression of CHOP attenuates TRAIL and Olaparib mediated increase of DR5.	26	33	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	26	27	32	33
TRAIL triggers the extrinsic pathway of apoptosis by binding to cognate DR4 or DR5 , which results in the formation of receptor homotrimers and the propagation of a proapoptotic signal through caspase-8 , which then self-activates and initiates downstream caspase events .	TRAIL triggers the extrinsic pathway of apoptosis by binding to cognate DR4 or DR5, which results in the formation of receptor homotrimers and the propagation of a proapoptotic signal through caspase-8, which then self-activates and initiates downstream caspase events.	0	16	triggers	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	13	14
On the contrary , TRAIL triggers the extrinsic apoptotic pathway by binding to and stimulating fully functional DR4 and DR5 , which subsequently aggregate and recruit signaling proteins at the membrane through their DD .	On the contrary, TRAIL triggers the extrinsic apoptotic pathway by binding to and stimulating fully functional DR4 and DR5, which subsequently aggregate and recruit signaling proteins at the membrane through their DD.	4	25	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	4	5	19	20
We discovered that cells that have high nuclear BNIP3 and low DR5 expression contain less DNA fragmentation than parental controls when treated with TRAIL .	We discovered that cells that have high nuclear BNIP3 and low DR5 expression contain less DNA fragmentation than parental controls when treated with TRAIL.	11	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	23	24	11	12
27 To detect whether salubrinal affected DR5 expression , HepG2 cells were treated with salubrinal , TRAIL or both for 24h .	27 To detect whether salubrinal affected DR5 expression, HepG2 cells were treated with salubrinal, TRAIL or both for 24h.	6	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	16	17	6	7
Indeed , TRAIL-R2 activation by TRAIL is reminiscent of Fas activation by sFasL in that it requires oligomerization to be effectuated .	Indeed, TRAIL-R2 activation by TRAIL is reminiscent of Fas activation by sFasL in that it requires oligomerization to be effectuated.	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	5	6	2	3
Furthermore , we have recently shown that TRAIL-R1 is activated by the soluble as well as the membrane bound form of the ligand , whereas TRAIL-R2 is preferentially activated by membrane TRAIL or oligomerized soluble trimeric TRAIL .	Furthermore, we have recently shown that TRAIL-R1 is activated by the soluble as well as the membrane bound form of the ligand, whereas TRAIL-R2 is preferentially activated by membrane TRAIL or oligomerized soluble trimeric TRAIL.	25	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	31	32	25	26
TRAIL ( tumor necrosis factor related apoptosis inducing ligand ) mediates apoptosis in cancer cells through death receptors DR4 and DR5 preferring often one receptor over another in the cells expressing both receptors .	TRAIL (tumor necrosis factor related apoptosis inducing ligand) mediates apoptosis in cancer cells through death receptors DR4 and DR5 preferring often one receptor over another in the cells expressing both receptors.	0	21	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	20	21
Recombinant human TRAIL activates both DR4 and DR5 , but has limited clinical utility because it is rapidly hydrolyzed in blood , resulting in a very short half-life of less than an hour .	Recombinant human TRAIL activates both DR4 and DR5, but has limited clinical utility because it is rapidly hydrolyzed in blood, resulting in a very short half-life of less than an hour.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	2	3	7	8
TRAIL containing EVs activate DR5 on the surface of macrophages , leading to increased expression of the anti-inflammatory cytokines interleukin ( IL )-1beta and IL-6 [ XREF_BIBR ] .	TRAIL containing EVs activate DR5 on the surface of macrophages, leading to increased expression of the anti-inflammatory cytokines interleukin (IL)-1beta and IL-6 [XREF_BIBR].	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	4	5
To determine whether upregulation of DR5 plays a critical role in sensitization of PC-3 cells to TRAIL , control or DR5 siRNA plasmids transfected PC-3 cells were treated with Tanshinone I and/or TRAIL .	To determine whether upregulation of DR5 plays a critical role in sensitization of PC-3 cells to TRAIL, control or DR5 siRNA plasmids transfected PC-3 cells were treated with Tanshinone I and/or TRAIL.	16	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	32	33	20	21
However , TRAIL and 100 muM kaempferol caused slight up-regulation of DR5 .	However, TRAIL and 100 muM kaempferol caused slight up-regulation of DR5.	2	12	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	2	3	11	12
Moreover , TRAIL and agonistic monoclonal antibodies ( mAbs ) targeting TRAIL-R1 or TRAIL-R2 inhibit primary tumor growth and metastatic tumor burden in preclinical models of diverse tumor types including breast cancer .	Moreover, TRAIL and agonistic monoclonal antibodies (mAbs) targeting TRAIL-R1 or TRAIL-R2 inhibit primary tumor growth and metastatic tumor burden in preclinical models of diverse tumor types including breast cancer.	2	14	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	2	3	13	14
In this study , we found the upregulation of DR4 and DR5 mediated HBX was associated with apoptosis of hepatoma cells treated with TRAIL .	In this study, we found the upregulation of DR4 and DR5 mediated HBX was associated with apoptosis of hepatoma cells treated with TRAIL.	7	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	23	24	11	12
TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non apoptotic signaling pathways , but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far .	TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non apoptotic signaling pathways, but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	4	5
5 TRAIL induces apoptosis by binding to TRAIL-R1 and death receptor 4 ( DR4 ) and TRAIL-R2 and death receptor 5 ( DR5 ) , which are widely expressed in cancer cells .	5 TRAIL induces apoptosis by binding to TRAIL-R1 and death receptor 4 (DR4) and TRAIL-R2 and death receptor 5 (DR5), which are widely expressed in cancer cells.	0	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	1	2	16	17
It was previously shown that the TRAIL activation of DR5 induces cholesterol dependent caspase-8 activation and concomitant migration of DR5 to cholesterol rich , detergent resistant membrane ( DRM ) fractions [ XREF_BIBR ] .	It was previously shown that the TRAIL activation of DR5 induces cholesterol dependent caspase-8 activation and concomitant migration of DR5 to cholesterol rich, detergent resistant membrane (DRM) fractions [XREF_BIBR].	6	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	6	7	19	20
TRAIL ( 100 ng/ml ) induced only light lipid raft aggregation and DR4 and DR5 clustering .	TRAIL (100 ng/ml) induced only light lipid raft aggregation and DR4 and DR5 clustering.	0	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	14	15
Since the TRAIL , a trimer , activates the homotrimerization or heterotrimerization of DR4 and DR5 , the real time activation of DR4 or DR5 in live cells can be monitored once a molecule of DR4 or DR5 is conjugated with a donor fluorophore and another DR4 or DR5 with an acceptor fluorophore .	Since the TRAIL, a trimer, activates the homotrimerization or heterotrimerization of DR4 and DR5, the real time activation of DR4 or DR5 in live cells can be monitored once a molecule of DR4 or DR5 is conjugated with a donor fluorophore and another DR4 or DR5 with an acceptor fluorophore.	1	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	2	3	15	16
Receptor associated complexes were further analyzed after stimulating cells with the endogenous ligand TRAIL that activates both TRAIL-R1 and TRAIL-R2 .	Receptor associated complexes were further analyzed after stimulating cells with the endogenous ligand TRAIL that activates both TRAIL-R1 and TRAIL-R2.	7	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	13	14	19	20
The ratio of caspase-8 and DR5 was higher in GST-TRAIL activated DR5 pulldowns from cells in which Axl was knocked down ( XREF_SUPPLEMENTARY , see numbers below lanes 5 and 7 ) .	The ratio of caspase-8 and DR5 was higher in GST-TRAIL activated DR5 pulldowns from cells in which Axl was knocked down (XREF_SUPPLEMENTARY, see numbers below lanes 5 and 7).	9	12	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	GST-TRAIL	GST-TRAIL	GST-TRAIL	DR5	DR5	DR5	9	10	11	12
Once DR5 is activated by TRAIL , the death receptor trimerizes and recruits Fas associated death domain ( FADD ) protein and procaspase-8 , both of which rapidly form a death inducing signalling complex ( DISC ) [ XREF_BIBR , XREF_BIBR ] .	Once DR5 is activated by TRAIL, the death receptor trimerizes and recruits Fas associated death domain (FADD) protein and procaspase-8, both of which rapidly form a death inducing signalling complex (DISC) [XREF_BIBR, XREF_BIBR].	1	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	1	2
The combined use of apigenin and TRAIL caused Bcl-2-interacting domain cleavage , activation of caspases , and increased expression of TRAIL-R2 [ XREF_BIBR ] .	The combined use of apigenin and TRAIL caused Bcl-2-interacting domain cleavage, activation of caspases, and increased expression of TRAIL-R2 [XREF_BIBR].	2	22	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	6	7	20	21
These data are in agreement with immunohistochemistry and western blot data where the proapoptotic DR4 and DR5 proteins were upregulated by resveratrol and TRAIL .	These data are in agreement with immunohistochemistry and western blot data where the proapoptotic DR4 and DR5 proteins were upregulated by resveratrol and TRAIL.	16	24	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	23	24	16	17
IFN-alpha triggers the up-regulation of the TRAIL apoptotic ligand , thus turning pDCs into Interferon producing Killer pDCs ( IKpDCs ) , capable of killing HIV infected and uninfected CD4 + T cells through TRAIL activation of the Death receptor 5 ( DR5 ) pathway [ XREF_BIBR ] [ XREF_BIBR ] .	IFN-alpha triggers the up-regulation of the TRAIL apoptotic ligand, thus turning pDCs into Interferon producing Killer pDCs (IKpDCs), capable of killing HIV infected and uninfected CD4 + T cells through TRAIL activation of the Death receptor 5 (DR5) pathway [XREF_BIBR] [XREF_BIBR].	34	44	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	Death receptor 5	Death receptor 5	Death receptor 5	34	35	38	41
Interestingly , the Ca 2+ signal inhibitors also decreased silibinin and TRAIL induced upregulation of DR5 .	Interestingly, the Ca 2+ signal inhibitors also decreased silibinin and TRAIL induced upregulation of DR5.	9	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	11	12	15	16
Pan etal.545 developed a conjugate of MMAE and the TRAIL with the purpose of overcoming TRAIL resistance in cell lines expressing the TRAIL targeted DR4 and DR5 death receptors .	Pan etal.545 developed a conjugate of MMAE and the TRAIL with the purpose of overcoming TRAIL resistance in cell lines expressing the TRAIL targeted DR4 and DR5 death receptors.	20	28	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	22	23	26	27
The unique characteristic of TRAIL encouraged the development of TRAIL-R agonists , including recombinant TRAIL protein and monoclonal antibodies targeting specifically DR4 or DR5 , which have demonstrated efficient anticancer activities in a number of preclinical studies [ XREF_BIBR ] .	The unique characteristic of TRAIL encouraged the development of TRAIL-R agonists, including recombinant TRAIL protein and monoclonal antibodies targeting specifically DR4 or DR5, which have demonstrated efficient anticancer activities in a number of preclinical studies [XREF_BIBR].	14	27	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	14	15	23	24
TRAIL induces apoptosis through its specific receptors , death receptor 5 ( DR5 , also called TRAIL-R2 , Apo2 , TRICK2 , or KILLER ) and death receptor 4 ( DR4 ) , which are expressed on the cell surface XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	TRAIL induces apoptosis through its specific receptors, death receptor 5 (DR5, also called TRAIL-R2, Apo2, TRICK2, or KILLER) and death receptor 4 (DR4), which are expressed on the cell surface XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	0	1	16	17
To determine whether DR5 co-localizes with lysosomes , Huh-7 cells transfected with DR5-EGFP were treated with TRAIL for 60 min and then observed by confocal microscopy .	To determine whether DR5 co-localizes with lysosomes, Huh-7 cells transfected with DR5-EGFP were treated with TRAIL for 60 min and then observed by confocal microscopy.	10	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5-EGFP	DR5-EGFP	DR5-EGFP	16	17	12	13
Furthermore , bortezomib and TRAIL synergistically induced reactive oxygen species ( ROS ) generation and caused DR5 upregulation through activation of ERK-CHOP signaling cascade .	Furthermore, bortezomib and TRAIL synergistically induced reactive oxygen species (ROS) generation and caused DR5 upregulation through activation of ERK-CHOP signaling cascade.	2	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	4	5	16	17
26 Therefore , we next assessed the impact of antagonistic antibodies directed against DR4 or DR5 on the viability of myeloid leukemia cells treated with the Med+ TRAIL combination .	26 Therefore, we next assessed the impact of antagonistic antibodies directed against DR4 or DR5 on the viability of myeloid leukemia cells treated with the Med+ TRAIL combination.	11	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	27	28	15	16
Consequently , TRAIL based therapies aim to trigger apoptosis in cancer cells by providing the soluble TRAIL or monoclonal antibodies targeting the death receptors TRAIL-R1 or TRAIL-R2 .	Consequently, TRAIL based therapies aim to trigger apoptosis in cancer cells by providing the soluble TRAIL or monoclonal antibodies targeting the death receptors TRAIL-R1 or TRAIL-R2.	14	27	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	16	17	26	27
Combination of TRAIL and Tanshinone I increased DR5 promoter activity compared to untreated control or TRAIL alone ( Fig XREF_FIG ) .	Combination of TRAIL and Tanshinone I increased DR5 promoter activity compared to untreated control or TRAIL alone (Fig XREF_FIG).	0	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	2	3	7	8
TRAIL initiates cytotoxic signals by ligating one of two cognate receptors , DR4 and DR5 .	TRAIL initiates cytotoxic signals by ligating one of two cognate receptors, DR4 and DR5.	0	15	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	14	15
TRAIL-R1 and death receptor ( DR ) 4 and TRAIL-R2 and DR5 are members of the tumor necrosis factor ( TNF ) receptor family , and can be activated by the TRAIL .	TRAIL-R1 and death receptor (DR) 4 and TRAIL-R2 and DR5 are members of the tumor necrosis factor (TNF) receptor family, and can be activated by the TRAIL.	0	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	31	32	9	10
Combination of Tanshinone I and TRAIL upregulated DR5 in PC-3 cells .	Combination of Tanshinone I and TRAIL upregulated DR5 in PC-3 cells.	0	8	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	7	8
We next investigated whether lapatinib sensitizes colon cancer cells to mapatumumab and lexatumumab , two agonistic TRAIL receptor antibodies that selectively target DR4 and DR5 , respectively .	We next investigated whether lapatinib sensitizes colon cancer cells to mapatumumab and lexatumumab, two agonistic TRAIL receptor antibodies that selectively target DR4 and DR5, respectively.	16	25	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	16	17	24	25
We showed that DR5 , upregulated by TRAIL , could be the mediator of TRAIL induced OC apoptosis , since the addition of anti-DR5 neutralizing antibodies restores the OC viability previously reduced by TRAIL .	We showed that DR5, upregulated by TRAIL, could be the mediator of TRAIL induced OC apoptosis, since the addition of anti-DR5 neutralizing antibodies restores the OC viability previously reduced by TRAIL.	3	12	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	7	8	3	4
More recently , TRAIL was found to induce apoptosis in a variety of tumor cells and leukemia [ XREF_BIBR ] upon binding with its death inducing receptors , DR4 and DR5 .	More recently, TRAIL was found to induce apoptosis in a variety of tumor cells and leukemia [XREF_BIBR] upon binding with its death inducing receptors, DR4 and DR5.	3	31	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	3	4	30	31
Thus , to confirm the findings that the basal B TNBC are most sensitive to TRAIL receptor agonists that activate DR5 , we evaluated the ability of drozitumab to kill breast cancer cells .	Thus, to confirm the findings that the basal B TNBC are most sensitive to TRAIL receptor agonists that activate DR5, we evaluated the ability of drozitumab to kill breast cancer cells.	15	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	15	16	20	21
Apo2L and TRAIL directly induces apoptosis through the cell surface death receptors DR4 and DR5 4 and we have previously shown that some patient tumors grown subcutaneously in SCID mice are sensitive to treatment with Apo2L and TRAIL while others are quite resistant .	Apo2L and TRAIL directly induces apoptosis through the cell surface death receptors DR4 and DR5 4 and we have previously shown that some patient tumors grown subcutaneously in SCID mice are sensitive to treatment with Apo2L and TRAIL while others are quite resistant.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	2	3	14	15
XREF_BIBR , XREF_BIBR TNFRSF10A ( known as DR4 or TRAILR1 ) and TNFRSF10B ( known as DR5 or TRAILR2 ) , both highlighted by the red box in XREF_FIG , are characteristically activated by TRAIL and TNFSF10 .	XREF_BIBR, XREF_BIBR TNFRSF10A (known as DR4 or TRAILR1) and TNFRSF10B (known as DR5 or TRAILR2), both highlighted by the red box in XREF_FIG, are characteristically activated by TRAIL and TNFSF10.	0	36	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TNFRSF10B	TNFRSF10B	TNFRSF10B	34	35	12	13
Another prediction of the model suggests that preventing binding to the decoy receptors should increase the kinetics of receptor activation and thus induction of apoptosis by WT TRAIL but not of the DR5 specific mutant .	Another prediction of the model suggests that preventing binding to the decoy receptors should increase the kinetics of receptor activation and thus induction of apoptosis by WT TRAIL but not of the DR5 specific mutant.	14	34	increase	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	27	28	32	33
XREF_FIG C , the expression levels of DR4 and DR5 in HepG2 cells that were only treated with TRAIL were not significantly different from that of the control cells .	XREF_FIG C, the expression levels of DR4 and DR5 in HepG2 cells that were only treated with TRAIL were not significantly different from that of the control cells.	5	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	18	19	9	10
This was associated with enhanced formation of TRAIL death inducing signaling complex and up-regulation of TRAIL-R2 , and was blocked by a recombinant TRAIL-R2/Fc chimeric protein or siRNA knockdown of TRAIL-R2 .	This was associated with enhanced formation of TRAIL death inducing signaling complex and up-regulation of TRAIL-R2, and was blocked by a recombinant TRAIL-R2/Fc chimeric protein or siRNA knockdown of TRAIL-R2.	7	16	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	7	8	15	16
On the other hand , treatment of mice with a combination of resveratrol plus TRAIL significantly showed enhanced expressions of DR4 and DR5 proteins than that of mice treated with resveratrol alone or TRAIL alone .	On the other hand, treatment of mice with a combination of resveratrol plus TRAIL significantly showed enhanced expressions of DR4 and DR5 proteins than that of mice treated with resveratrol alone or TRAIL alone.	20	34	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	33	34	22	23
The potential utility of TRAIL or death receptor antibodies is limited by intrinsic resistance of many tumor cell lines and tumors to these agents [ XREF_BIBR ] , and clinical development of TRAIL or antibodies targeting DR4 or DR5 would be facilitated by the identification of patients most likely to respond to these agents [ XREF_BIBR ] .	The potential utility of TRAIL or death receptor antibodies is limited by intrinsic resistance of many tumor cell lines and tumors to these agents [XREF_BIBR], and clinical development of TRAIL or antibodies targeting DR4 or DR5 would be facilitated by the identification of patients most likely to respond to these agents [XREF_BIBR].	30	39	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	32	33	38	39
Furthermore , PL potentiates TRAIL induced cytotoxicity in breast cancer cells by upregulating DR5 , as DR5 knockdown abolished the sensitizing effect of PL on TRAIL responses .	Furthermore, PL potentiates TRAIL induced cytotoxicity in breast cancer cells by upregulating DR5, as DR5 knockdown abolished the sensitizing effect of PL on TRAIL responses.	4	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	4	5	13	14
It has been reported that simultaneous administration of SAHA and TRAIL significantly upregulated the TRAIL death receptors DR4 and DR5 and downregulated the anti-apoptotic members of the BCL-2 family in several tumor cell lines XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	It has been reported that simultaneous administration of SAHA and TRAIL significantly upregulated the TRAIL death receptors DR4 and DR5 and downregulated the anti-apoptotic members of the BCL-2 family in several tumor cell lines XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	6	20	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	10	11	19	20
48 A recombinant version of its cognate ligand TRAIL has been shown to selectively activate DR5 in tumors inducing synergistic cytotoxicity with other chemotherapeutic agents .	48 A recombinant version of its cognate ligand TRAIL has been shown to selectively activate DR5 in tumors inducing synergistic cytotoxicity with other chemotherapeutic agents.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	8	9	15	16
XREF_BIBR , XREF_BIBR TRAIL induces extrinsic apoptotic pathway by interacting with its receptors TRAIL-R1 and TRAIL-R2 , also known as ' death receptors ' .	XREF_BIBR, XREF_BIBR TRAIL induces extrinsic apoptotic pathway by interacting with its receptors TRAIL-R1 and TRAIL-R2, also known as ' death receptors '.	2	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	3	4	15	16
To confirm whether activation of transcription factor FOXO3a plays a crucial role in TRAIL induced DR5 and DR4 up-regulation as well as apoptosis , we next ablated FOXO3a in HT-29 cells using specific siRNA .	To confirm whether activation of transcription factor FOXO3a plays a crucial role in TRAIL induced DR5 and DR4 up-regulation as well as apoptosis, we next ablated FOXO3a in HT-29 cells using specific siRNA.	11	18	induced	Positive_early_activation	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	13	14	15	16
46 TRAIL triggers the extrinsic apoptosis pathway upon binding of the TRAIL trimer to TRAIL-R1 and/or TRAIL-R2 , resulting in receptor trimerization , which in turn leads to recruitment of the adaptor protein Fas associated DD ( FADD ) via homotypic DD-DD interaction between the DDs of the ligand cross linked receptors and FADD , respectively .	46 TRAIL triggers the extrinsic apoptosis pathway upon binding of the TRAIL trimer to TRAIL-R1 and/or TRAIL-R2, resulting in receptor trimerization, which in turn leads to recruitment of the adaptor protein Fas associated DD (FADD) via homotypic DD-DD interaction between the DDs of the ligand cross linked receptors and FADD, respectively.	0	17	triggers	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	1	2	16	17
The targeting of DR5 by TRAIL or anti-DR5 monoclonal antibodies has been the focus of various clinical trials in clinical cancers .	The targeting of DR5 by TRAIL or anti-DR5 monoclonal antibodies has been the focus of various clinical trials in clinical cancers.	1	9	targeting	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	3	4
Several TRAIL based therapies , including the human recombinant TRAIL ligand ( dulanermin ) , which targets both DR4 and DR5 , and agonistic antibodies against DR4 ( mapatumumab ) and DR5 ( drozitumab , lexatumumab , tigatuzumab , LBY-135 , and conatumumab ) have been assessed within clinical trials [ XREF_BIBR , XREF_BIBR ] .	Several TRAIL based therapies, including the human recombinant TRAIL ligand (dulanermin), which targets both DR4 and DR5, and agonistic antibodies against DR4 (mapatumumab) and DR5 (drozitumab, lexatumumab, tigatuzumab, LBY-135, and conatumumab) have been assessed within clinical trials [XREF_BIBR, XREF_BIBR].	9	21	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	9	10	20	21
It suggested that the TRAIL induced redistribution of DR4 and DR5 in lipid rafts contributed to the sensitivity to TRAIL in TRAIL sensitive NSCLC H460 cell line , which was also confirmed by intervention tests of the cholesterol sequestering agent nystatin .	It suggested that the TRAIL induced redistribution of DR4 and DR5 in lipid rafts contributed to the sensitivity to TRAIL in TRAIL sensitive NSCLC H460 cell line, which was also confirmed by intervention tests of the cholesterol sequestering agent nystatin.	3	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	4	5	10	11
In contrast , pretreatment with native or CaP@LDL-enveloped STAT3-decoy ODNs induced a significant increase in DR4 and DR5 expression levels as compared to the corresponding group treated with TRAIL alone ( p < 0.01 ) .	In contrast, pretreatment with native or CaP@LDL-enveloped STAT3-decoy ODNs induced a significant increase in DR4 and DR5 expression levels as compared to the corresponding group treated with TRAIL alone (p < 0.01).	15	31	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	28	29	17	18
In our experiment , we demonstrated that siRNA mediated depletion of c-Myc in metastatic cancer cells suppressed TRAIL induced up-regulation of DR5 and activation of caspase , and these phenomena could be associated with decreased cytotoxic effect of TRAIL on PC3-MM2 and KM12L4A cells .	In our experiment, we demonstrated that siRNA mediated depletion of c-Myc in metastatic cancer cells suppressed TRAIL induced up-regulation of DR5 and activation of caspase, and these phenomena could be associated with decreased cytotoxic effect of TRAIL on PC3-MM2 and KM12L4A cells.	17	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	17	18	21	22
Our RT-PCR and RT-qPCR analyses confirmed that combination of Tanshinone I and TRAIL up-regulated miR135a-3p and DR5 at mRNA level or activity of DR5 promoter in PC-3 cells , indicating the possible involvement of miR135a-3p along with DR5 upregulation in antitumor activity of Tanshinone I and TRAIL in PC-3 cells .	Our RT-PCR and RT-qPCR analyses confirmed that combination of Tanshinone I and TRAIL up-regulated miR135a-3p and DR5 at mRNA level or activity of DR5 promoter in PC-3 cells, indicating the possible involvement of miR135a-3p along with DR5 upregulation in antitumor activity of Tanshinone I and TRAIL in PC-3 cells.	7	17	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	12	13	16	17
DR5 receptor was upregulated by TRAIL variants in HCT116 p53 +/+ but not in HCT116 p53 -/- cells at low concentration of ligands ( 1 ng/ml ) .	DR5 receptor was upregulated by TRAIL variants in HCT116 p53 +/+ but not in HCT116 p53 -/- cells at low concentration of ligands (1 ng/ml).	0	6	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	0	1
Taken together , our results indicate that apigenin can enhance the apoptotic effect of TRAIL via ERK induced up-regulation of DR5 .	Taken together, our results indicate that apigenin can enhance the apoptotic effect of TRAIL via ERK induced up-regulation of DR5.	12	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	14	15	20	21
Interestingly , miR135a-3p mimic enhanced DR5 at mRNA , increased PARP cleavage , Bax and the number of TUNEL positive cells in Tanshinone I and TRAIL cotreated PC-3 .	Interestingly, miR135a-3p mimic enhanced DR5 at mRNA, increased PARP cleavage, Bax and the number of TUNEL positive cells in Tanshinone I and TRAIL cotreated PC-3.	3	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	25	26	5	6
Tumor necrosis factor superfamily cytokine TRAIL ( tumor necrosis factor related apoptosis inducing ligand ) induces apoptosis in tumor cells by binding to death receptors DR4 and DR5 without affecting normal cells .	Tumor necrosis factor superfamily cytokine TRAIL (tumor necrosis factor related apoptosis inducing ligand) induces apoptosis in tumor cells by binding to death receptors DR4 and DR5 without affecting normal cells.	0	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	27	28
Importantly , we and others have previously shown that tumor directed scFv : TRAIL fusion proteins effectively activate TRAIL-R2 on targeted cancer cells only .	Importantly, we and others have previously shown that tumor directed scFv : TRAIL fusion proteins effectively activate TRAIL-R2 on targeted cancer cells only.	13	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	13	14	18	19
TRAIL producing natural killer ( NK ) cells actively promote a pro inflammatory environment in the early stages of fatty liver disease , which suggests that this cell compartment may contribute to the progression of NASH [ XREF_BIBR ] .	TRAIL producing natural killer (NK) cells actively promote a pro inflammatory environment in the early stages of fatty liver disease, which suggests that this cell compartment may contribute to the progression of NASH [XREF_BIBR].	0	9	producing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	killer	killer	killer	0	1	3	4
As shown in XREF_FIG , TRAIL treatment of LS-LiM6 caused internalization and uptake of both DR4 and DR5 .	As shown in XREF_FIG, TRAIL treatment of LS-LiM6 caused internalization and uptake of both DR4 and DR5.	5	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	17	18
We found that either TRAIL or antibody agonist induces disulfide mediated dimerization of DR5 ( XREF_FIG , lanes 1-3 ) .	We found that either TRAIL or antibody agonist induces disulfide mediated dimerization of DR5 (XREF_FIG, lanes 1-3).	3	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	4	5	13	14
The DR4 and DR5 upregulation induced by ActD liposomes and subsequent enhancement of TRAIL mediated cytotoxicity in A-549 cells may correlate with p53 status .	The DR4 and DR5 upregulation induced by ActD liposomes and subsequent enhancement of TRAIL mediated cytotoxicity in A-549 cells may correlate with p53 status.	1	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	13	14	3	4
Binding of TRAIL to cognate apoptosis inducing TRAIL-R1 ( DR4 ) 8 and/or TRAIL-R2 ( DR5 ) 9 results in receptor trimerization .	Binding of TRAIL to cognate apoptosis inducing TRAIL-R1 (DR4) 8 and/or TRAIL-R2 (DR5) 9 results in receptor trimerization.	0	18	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	2	3	13	14
Casticin initially promotes ROS generation and triggers ER stress then induces DR5 upregulation through activation of CHOP which consequently enhances TRAIL induced activation of DR5 induced and mitochondria mediated apoptosis pathways .	Casticin initially promotes ROS generation and triggers ER stress then induces DR5 upregulation through activation of CHOP which consequently enhances TRAIL induced activation of DR5 induced and mitochondria mediated apoptosis pathways.	20	25	induced	Positive_early_activation	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	20	21	24	25
We also demonstrated that the death receptor DR5 , upregulated by TRAIL , could be the mediator of TRAIL induced OC apoptosis .	We also demonstrated that the death receptor DR5, upregulated by TRAIL, could be the mediator of TRAIL induced OC apoptosis.	4	16	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	11	12	7	8
TRAIL ( TNF related apoptosis inducing ligand ) induces apoptosis in susceptible cells by binding to death receptors 4 ( DR4 ) and 5 ( DR5 ) .	TRAIL (TNF related apoptosis inducing ligand) induces apoptosis in susceptible cells by binding to death receptors 4 (DR4) and 5 (DR5).	0	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	25	26
TRAIL activates the TNF receptor family members death receptor 4 and death receptor 5 ( DR4 and DR5 ) , which initiate the extrinsic apoptosis pathway and caspase-8 activation 26 .	TRAIL activates the TNF receptor family members death receptor 4 and death receptor 5 (DR4 and DR5), which initiate the extrinsic apoptosis pathway and caspase-8 activation 26.	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	17	18
Alternatively , the combination of LMB and TRAIL induced the upregulation of DR5 in A2780CP cells , but not in ECC-1 ; on the other hand , the same treatment produced a strong downregulation of DcR1 in ECC-1 cells , an effect that we did not observe in A2780CP cells .	Alternatively, the combination of LMB and TRAIL induced the upregulation of DR5 in A2780CP cells, but not in ECC-1; on the other hand, the same treatment produced a strong downregulation of DcR1 in ECC-1 cells, an effect that we did not observe in A2780CP cells.	3	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	7	8	12	13
TRAIL initiates the extrinsic pathway of apoptosis by ligating the signaling competent TRAILreceptors , TRAIL-R1 and TRAIL-R2 , triggering formation of a multiprotein death inducing signaling complex ( DISC ) whichisalso formed after CD95 ligation .	TRAIL initiates the extrinsic pathway of apoptosis by ligating the signaling competent TRAILreceptors, TRAIL-R1 and TRAIL-R2, triggering formation of a multiprotein death inducing signaling complex (DISC) whichisalso formed after CD95 ligation.	0	17	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	0	1	16	17
Concordantly , our studies demonstrated increased DR4 and DR5 expression in STS specimens treated with combined doxorubicin and TRAIL .	Concordantly, our studies demonstrated increased DR4 and DR5 expression in STS specimens treated with combined doxorubicin and TRAIL.	8	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	18	19	8	9
TRAIL triggers apoptosis through binding of the trans-membrane death receptors TRAIL receptor 1 ( TRAIL-R1 ) also death receptor 4 ( DR4 ) and TRAIL receptor 2 ( TRAIL-R2 ) also death receptor 5 ( DR5 ) thereby inducing the formation of the death inducing signaling complex ( DISC ) and activation of the apoptotic cascade .	TRAIL triggers apoptosis through binding of the trans-membrane death receptors TRAIL receptor 1 (TRAIL-R1) also death receptor 4 (DR4) and TRAIL receptor 2 (TRAIL-R2) also death receptor 5 (DR5) thereby inducing the formation of the death inducing signaling complex (DISC) and activation of the apoptotic cascade.	0	35	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	death receptor 5	death receptor 5	death receptor 5	0	1	31	34
Most natural TRAIL sensitizers induce transcriptional up-regulation of DR5 in p53- dependent or -independent manners , the latter of which often involves the ROS-( JNK )-CHOP pathway , whereas the proteasome inhibitor bortezomib up-regulates DR5 by facilitating DR5 protein stabilization .	Most natural TRAIL sensitizers induce transcriptional up-regulation of DR5 in p53- dependent or -independent manners, the latter of which often involves the ROS-(JNK)-CHOP pathway, whereas the proteasome inhibitor bortezomib up-regulates DR5 by facilitating DR5 protein stabilization.	2	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	2	3	8	9
GST-TRAIL can activate both DR4 and DR5 .	GST-TRAIL can activate both DR4 and DR5.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GST-TRAIL	GST-TRAIL	GST-TRAIL	DR5	DR5	DR5	0	1	6	7
TNF related apoptosis inducing ligand ( TRAIL ) , which also activates the DR4 ( TRAIL-R1 ) and DR5 ( TRAIL-R2 ) death receptors , is a more promising biologic because it preferentially targets malignant cells [ XREF_BIBR , XREF_BIBR ] .	TNF related apoptosis inducing ligand (TRAIL), which also activates the DR4 (TRAIL-R1) and DR5 (TRAIL-R2) death receptors, is a more promising biologic because it preferentially targets malignant cells [XREF_BIBR, XREF_BIBR].	2	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	6	7	18	19
TNF related apoptosis ligand ( TRAIL ) induces apoptosis of HIV-1-exposed CD4 T cells expressing the death receptor 5 ( DR5 ) in vitro and has been associated with reduced CD4 T cell number in viremic HIV-1-infected patients .	TNF related apoptosis ligand (TRAIL) induces apoptosis of HIV-1-exposed CD4 T cells expressing the death receptor 5 (DR5) in vitro and has been associated with reduced CD4 T cell number in viremic HIV-1-infected patients.	0	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	death receptor 5	death receptor 5	death receptor 5	5	6	16	19
TRAIL induces apoptosis via activation of its death receptors , DR4 ( TRAIL-R1 ) and DR5 ( TRAIL-R2 ) [ XREF_BIBR ] .	TRAIL induces apoptosis via activation of its death receptors, DR4 (TRAIL-R1) and DR5 (TRAIL-R2) [XREF_BIBR].	0	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	15	16
DU-145 cells transfected with the control plasmid ( pcDNA ) or Myc-DR5 were treated with TRAIL ( 5-100 ng/ml ) for 4 h and then subjected to immunoblot analysis .	DU-145 cells transfected with the control plasmid (pcDNA) or Myc-DR5 were treated with TRAIL (5-100 ng/ml) for 4 h and then subjected to immunoblot analysis.	2	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	Myc-DR5	Myc-DR5	Myc-DR5	15	16	11	12
The ability of TRAIL to initiate apoptosis selectively in cancer cells has led to clinical trials with novel agents that engage the TRAIL pathway , which includes recombinant TRAIL and TRAIL agonist antibodies that target DR4 or DR5 [ XREF_BIBR - XREF_BIBR ] .	The ability of TRAIL to initiate apoptosis selectively in cancer cells has led to clinical trials with novel agents that engage the TRAIL pathway, which includes recombinant TRAIL and TRAIL agonist antibodies that target DR4 or DR5 [XREF_BIBR - XREF_BIBR].	26	38	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	28	29	37	38
Unexpectedly , knockdown of DR5 , but not DR4 , abrogated GGTI-298 plus TRAIL induced reduction of both IkappaBalpha and p-Akt , indicating that the combination of GGTII-298 and TRAIL induces DR5 dependent IkappaBalpha degradation and Akt inhibition .	Unexpectedly, knockdown of DR5, but not DR4, abrogated GGTI-298 plus TRAIL induced reduction of both IkappaBalpha and p-Akt, indicating that the combination of GGTII-298 and TRAIL induces DR5 dependent IkappaBalpha degradation and Akt inhibition.	25	32	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	29	30	31	32
Several proapoptotic receptor agonists ( PARAs ) , including the recombinant human TRAIL ligand ( dulanermin ) , which targets both DR4 and DR5 , and agonistic antibodies against the functional receptors DR4 ( mapatumumab ) and DR5 ( lexatumumab , drozitumab , conatumumab , tigatuzumab and LBY-135 ) have been assessed within clinical trials for cancer treatment .	Several proapoptotic receptor agonists (PARAs), including the recombinant human TRAIL ligand (dulanermin), which targets both DR4 and DR5, and agonistic antibodies against the functional receptors DR4 (mapatumumab) and DR5 (lexatumumab, drozitumab, conatumumab, tigatuzumab and LBY-135) have been assessed within clinical trials for cancer treatment.	12	24	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	12	13	23	24
In addition , we reveal that co-treatment with delphinidin and TRAIL induces DR5 up-regulation and downstream cleavage of HDAC3 by effector caspases .	In addition, we reveal that co-treatment with delphinidin and TRAIL induces DR5 up-regulation and downstream cleavage of HDAC3 by effector caspases.	6	13	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	10	11	12	13
In short , liposome bound TRAIL induced superior DR5 clustering , enhancing DISC recruitment and , consequently , triggering caspase activation more efficiently than the sTRAIL [ XREF_BIBR , XREF_BIBR ] .	In short, liposome bound TRAIL induced superior DR5 clustering, enhancing DISC recruitment and, consequently, triggering caspase activation more efficiently than the sTRAIL [XREF_BIBR, XREF_BIBR].	5	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	8	9
Slight reduction of cell surface DR5 receptor induced by combined action of TRAIL and bortezomib could be the result of some heterotrimeric DR4 and DR5 complexes internalization ( XREF_FIG ) .	Slight reduction of cell surface DR5 receptor induced by combined action of TRAIL and bortezomib could be the result of some heterotrimeric DR4 and DR5 complexes internalization (XREF_FIG).	5	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	12	13	5	6
In addition , SiDcR3 and TRAIL caused a greater increase of DR5 than SiDcR3 or TRAIL alone .	In addition, SiDcR3 and TRAIL caused a greater increase of DR5 than SiDcR3 or TRAIL alone.	3	12	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	11	12
TRAIL can induce extrinsic and intrinsic death pathways by binding its specific receptors with death domain TRAIL receptor ( TRAIL-R ) 1/death receptor ( DR ) 4 and TRAIL-R2 and DR5 .	TRAIL can induce extrinsic and intrinsic death pathways by binding its specific receptors with death domain TRAIL receptor (TRAIL-R) 1/death receptor (DR) 4 and TRAIL-R2 and DR5.	0	30	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	0	1	28	29
TRAIL triggers apoptosis through binding to its receptors DR4 and KILLER and DR5 .	TRAIL triggers apoptosis through binding to its receptors DR4 and KILLER and DR5.	0	12	triggers	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	KILLER	KILLER	KILLER	0	1	10	11
TRAIL death inducing receptors DR4 and DR5 are considered tumor suppressors because their loss is expected to provide a survival advantage to the tumor cells .	TRAIL death inducing receptors DR4 and DR5 are considered tumor suppressors because their loss is expected to provide a survival advantage to the tumor cells.	0	7	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	6	7
As a member of the TNF superfamily , TRAIL could induce human tumor cell apoptosis through its cognate death receptors DR4 or DR5 , which can induce formation of the death inducing signaling complex ( DISC ) and activation of the membrane proximal caspases ( caspase-8 or caspase-10 ) and mitochondrial pathway .	As a member of the TNF superfamily, TRAIL could induce human tumor cell apoptosis through its cognate death receptors DR4 or DR5, which can induce formation of the death inducing signaling complex (DISC) and activation of the membrane proximal caspases (caspase-8 or caspase-10) and mitochondrial pathway.	8	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	8	9	22	23
In particular , TRAIL seems to mediate the ability of natural killer ( NK ) cells and cytotoxic T lymphocytes to block tumor growth and metastasis development [ XREF_BIBR , XREF_BIBR ] .	In particular, TRAIL seems to mediate the ability of natural killer (NK) cells and cytotoxic T lymphocytes to block tumor growth and metastasis development [XREF_BIBR, XREF_BIBR].	3	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	killer	killer	killer	3	4	11	12
Tumor necrosis factor related apoptosis inducing ligand ( TRAIL ) , a member of the tumor necrosis factor family , can induce apoptotic cell death in a variety of tumor cells by engaging specific death receptors , DR4 and DR5 [ ref .	Tumor necrosis factor related apoptosis inducing ligand (TRAIL), a member of the tumor necrosis factor family, can induce apoptotic cell death in a variety of tumor cells by engaging specific death receptors, DR4 and DR5 [ref.	4	41	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	8	9	39	40
TRAIL signaling mediates T-cell- and natural killer ( NK ) cell dependent metastasis suppression in xenografts XREF_BIBR - XREF_BIBR .	TRAIL signaling mediates T-cell- and natural killer (NK) cell dependent metastasis suppression in xenografts XREF_BIBR - XREF_BIBR.	0	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	killer	killer	killer	0	1	6	7
However , TRAIL stimulation significantly decreased the expression of DR4 whereas the expression of DR5 was increased albeit not to a significant degree ( DR4 : 1908 +/-296.6 for non stimulated cell cultures versus 722.4 +/-86.0 for TRAIL stimulated cell cultures , n = 6 , p = 0.0009 ; DR5 : 866.2 +/-77.6 versus 1018 +/-22.0 , p = 0.08 ) .	However, TRAIL stimulation significantly decreased the expression of DR4 whereas the expression of DR5 was increased albeit not to a significant degree (DR4 : 1908 +/-296.6 for non stimulated cell cultures versus 722.4 +/-86.0 for TRAIL stimulated cell cultures, n = 6, p = 0.0009; DR5 : 866.2 +/-77.6 versus 1018 +/-22.0, p = 0.08).	30	59	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	37	38	50	51
It is known that TRAIL triggers the extrinsic pathway by engaging the death receptors DR4 or DR5 and requires FADD recruitment and DISC formation to initiate caspase-8-, and caspase-3-mediated signaling [ XREF_BIBR , XREF_BIBR ] .	It is known that TRAIL triggers the extrinsic pathway by engaging the death receptors DR4 or DR5 and requires FADD recruitment and DISC formation to initiate caspase-8-, and caspase-3-mediated signaling [XREF_BIBR, XREF_BIBR].	4	18	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	4	5	16	17
Since both membrane and soluble forms of TRAIL can induce apoptosis of DR4 and DR5 expressing cells via recruiting FADD and caspase 8 , elevated TRAIL and its receptors may participate in renal graft rejection .	Since both membrane and soluble forms of TRAIL can induce apoptosis of DR4 and DR5 expressing cells via recruiting FADD and caspase 8, elevated TRAIL and its receptors may participate in renal graft rejection.	5	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	7	8	14	15
TRAIL mediates its effect via death receptors 4 ( DR4 ) and DR5 and appears to selectively induce apoptosis in cancer cells .	TRAIL mediates its effect via death receptors 4 (DR4) and DR5 and appears to selectively induce apoptosis in cancer cells.	0	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	0	1	12	13
Cervical neoplasia specimens have been shown to express the death receptors DR4 and DR5 , both of which are activated by TRAIL , and the expression of these receptors are up-regulated upon re-instatement of the p53 pathway [ XREF_BIBR , XREF_BIBR ] .	Cervical neoplasia specimens have been shown to express the death receptors DR4 and DR5, both of which are activated by TRAIL, and the expression of these receptors are up-regulated upon re-instatement of the p53 pathway [XREF_BIBR, XREF_BIBR].	7	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	21	22	13	14
Many reports have confirmed that TRAIL-R1 or TRAIL-R2 mediated by TRAIL or agonistic antibodies triggered cell apoptosis via activation of extrinsic and intrinsic apoptosis pathways XREF_BIBR - XREF_BIBR .	Many reports have confirmed that TRAIL-R1 or TRAIL-R2 mediated by TRAIL or agonistic antibodies triggered cell apoptosis via activation of extrinsic and intrinsic apoptosis pathways XREF_BIBR - XREF_BIBR.	5	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R2	TRAIL-R2	TRAIL-R2	10	11	7	8
With virtually no toxicity toward normal cells , recombinant human TRAIL or agonistic antibodies specifically targeting DR5 are currently being tested in several clinical trials .	With virtually no toxicity toward normal cells, recombinant human TRAIL or agonistic antibodies specifically targeting DR5 are currently being tested in several clinical trials.	8	20	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	10	11	16	17
The results using drozitumab , a specific DR5 agonist , are consistent with our previous observation that TRAIL receptor agonists which activate DR5 induce apoptosis in the basal B TNBC cells .	The results using drozitumab, a specific DR5 agonist, are consistent with our previous observation that TRAIL receptor agonists which activate DR5 induce apoptosis in the basal B TNBC cells.	17	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	17	18	22	23
Thus , it is possible that knockdown of DR4 abolishes NF-kappaB activation , leading to sensitization of DR5 dependent apoptosis induced by the combination of GGTI298 and TRAIL .	Thus, it is possible that knockdown of DR4 abolishes NF-kappaB activation, leading to sensitization of DR5 dependent apoptosis induced by the combination of GGTI298 and TRAIL.	17	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	27	28	17	18
Collectively , our results demonstrate that combination of Tanshinone I and TRAIL synergistically induce apoptosis via upregulation of miR135a-3p and DR5 in prostate cancer cells and overexpression of miR135a-3p enhances upregulation of DR5 leading to cell death by combined treatment of TRAIL and Tanshinone I. Thus , our findings suggest that Tanshinone I can be used as a potent sensitizer for TRAIL based combination therapy in prostate cancer cells .	Collectively, our results demonstrate that combination of Tanshinone I and TRAIL synergistically induce apoptosis via upregulation of miR135a-3p and DR5 in prostate cancer cells and overexpression of miR135a-3p enhances upregulation of DR5 leading to cell death by combined treatment of TRAIL and Tanshinone I. Thus, our findings suggest that Tanshinone I can be used as a potent sensitizer for TRAIL based combination therapy in prostate cancer cells.	6	33	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	11	12	32	33
The TNF family factors include Fas ligand , TNF-alpha , Apo3L , Apo2L , and TRAIL ( TNF related apoptosis inducing ligand ) that can activate their corresponding receptors FasR , TNFR1 , DR3 , and DR4 and DR5 .	The TNF family factors include Fas ligand, TNF-alpha, Apo3L, Apo2L, and TRAIL (TNF related apoptosis inducing ligand) that can activate their corresponding receptors FasR, TNFR1, DR3, and DR4 and DR5.	6	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	15	16	38	39
The super-aggregation , or capping , of death receptors has been considered to play a pivotal role to induce cellular apoptosis ; the importance of Fas capping for apoptosis induction was validated , and it was also demonstrated that DR5 aggregation triggered by TRAIL ( tumor necrosis factor related apoptosis inducing ligand ) was essential to drive intracellular signals for death .	The super-aggregation, or capping, of death receptors has been considered to play a pivotal role to induce cellular apoptosis; the importance of Fas capping for apoptosis induction was validated, and it was also demonstrated that DR5 aggregation triggered by TRAIL (tumor necrosis factor related apoptosis inducing ligand) was essential to drive intracellular signals for death.	39	44	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	43	44	39	40
Altogether , these results strongly suggest that besides acting as a main apoptotic inducer ( XREF_FIG and XREF_SUPPLEMENTARY ) DR5 mediates also the TRAIL dependent activation of non apoptotic signaling , independently of DR4 or DcR2 .	Altogether, these results strongly suggest that besides acting as a main apoptotic inducer (XREF_FIG and XREF_SUPPLEMENTARY) DR5 mediates also the TRAIL dependent activation of non apoptotic signaling, independently of DR4 or DcR2.	23	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	23	24	33	34
PC3 cells were treated with different concentrations of Andro and TRAIL for 12 h. Results of the western blot analysis showed that the expressions of DR4 , p53 , and p-p53 in the PC3 cells treated with TRAIL were significantly different than the expressions of those in the untreated control group ; the combined Andro and TRAIL treatment of PC3 cells significantly increased the expressions of DR4 and p53 in the cells ( XREF_FIG ) .	PC3 cells were treated with different concentrations of Andro and TRAIL for 12 h. Results of the western blot analysis showed that the expressions of DR4, p53, and p-p53 in the PC3 cells treated with TRAIL were significantly different than the expressions of those in the untreated control group; the combined Andro and TRAIL treatment of PC3 cells significantly increased the expressions of DR4 and p53 in the cells (XREF_FIG).	23	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	37	38	25	26
The binding of TRAIL and/or agonist antibodies to TRAIL-R1 or R2 causes a conformational change in the TRAIL-R1 or R2 ectodomain and the formation of a death inducing signaling complex ( DISC ) , which triggers activation of apoptosis signaling pathways XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR .	The binding of TRAIL and/or agonist antibodies to TRAIL-R1 or R2 causes a conformational change in the TRAIL-R1 or R2 ectodomain and the formation of a death inducing signaling complex (DISC), which triggers activation of apoptosis signaling pathways XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR.	3	20	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R1	TRAIL-R1	TRAIL-R1	3	4	17	18
DR4 is a cell surface protein restricted to glioma cells and is targeted by TRAIL .	DR4 is a cell surface protein restricted to glioma cells and is targeted by TRAIL.	0	15	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	14	15	0	1
These results indicate that rhTRAIL-C3 is an agonistic TRAIL variant that preferentially activates DR4 .	These results indicate that rhTRAIL-C3 is an agonistic TRAIL variant that preferentially activates DR4.	8	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	8	9	13	14
Collectively , these results indicate that the pathway used by aNK cells to kill iDCs involves the death ligand TRAIL , whose release by NK cells induces DR4 receptor on iDCs , followed by their killing .	Collectively, these results indicate that the pathway used by aNK cells to kill iDCs involves the death ligand TRAIL, whose release by NK cells induces DR4 receptor on iDCs, followed by their killing.	16	32	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	19	20	27	28
In similar experiments TRAIL activation of both TRAIL-R1 and -R2 were shown to be involved in trophoblast induced VSMC apoptosis XREF_BIBR .	In similar experiments TRAIL activation of both TRAIL-R1 and -R2 were shown to be involved in trophoblast induced VSMC apoptosis XREF_BIBR.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R1	TRAIL-R1	TRAIL-R1	3	4	7	8
Death receptor DR4 was also slightly upregulated by TRAIL or bortezomib in both HCT116 p53 +/+ and HCT116 p53 -/- cells when these drugs were used separately .	Death receptor DR4 was also slightly upregulated by TRAIL or bortezomib in both HCT116 p53 +/+ and HCT116 p53 -/- cells when these drugs were used separately.	0	10	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	8	9	2	3
TRAIL , a death ligand with high homology to FasL , triggers extensive apoptosis via the binding to TRAIL receptors , Death receptor 4 ( DR4 ) and DR5 , recruiting Fas associated protein with death domain ( FADD ) , and cleaving caspase-8 .	TRAIL, a death ligand with high homology to FasL, triggers extensive apoptosis via the binding to TRAIL receptors, Death receptor 4 (DR4) and DR5, recruiting Fas associated protein with death domain (FADD), and cleaving caspase-8.	0	24	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	Death receptor 4	Death receptor 4	Death receptor 4	0	1	21	24
TNFRSF10A , also known as DR4 or TRAIL-R1 , is activated by TRAIL and transduces cell death signals and induces apoptosis [ XREF_BIBR ] .	TNFRSF10A, also known as DR4 or TRAIL-R1, is activated by TRAIL and transduces cell death signals and induces apoptosis [XREF_BIBR].	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TNFRSF10A	TNFRSF10A	TNFRSF10A	12	13	0	1
TRAIL-R1 ( DR4 ) is activated by TRAIL and functions in transducing cell death signals and inducing apoptosis [ XREF_BIBR ] .	TRAIL-R1 (DR4) is activated by TRAIL and functions in transducing cell death signals and inducing apoptosis [XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R1	TRAIL-R1	TRAIL-R1	7	8	0	1
They found that stromal DcRs profoundly reduced TRAIL induced DR4 and DR5 activation and protected tumour cells against TRAIL .	They found that stromal DcRs profoundly reduced TRAIL induced DR4 and DR5 activation and protected tumour cells against TRAIL.	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	7	8	9	10
Despite the presence of both TRAIL receptors DR4 and DR5 in MR microdomains in non endothelial cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , the present study only found DR4 , but not DR5 , in MR clusters after TRAIL stimulation implicating that DR4 is activated by TRAIL and involved in consequent MR clustering in CAECs .	Despite the presence of both TRAIL receptors DR4 and DR5 in MR microdomains in non endothelial cells [XREF_BIBR, XREF_BIBR, XREF_BIBR], the present study only found DR4, but not DR5, in MR clusters after TRAIL stimulation implicating that DR4 is activated by TRAIL and involved in consequent MR clustering in CAECs.	44	50	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	48	49	44	45
In both pathways , TRAIL induces apoptosis by binding to TRAIL receptor 1 [ death receptor 4 ( DR4 ) ] and TRAIL receptor 2 [ death receptor 5 ( DR5 ) ] , which are widely expressed in cancer cells .	In both pathways, TRAIL induces apoptosis by binding to TRAIL receptor 1 [death receptor 4 (DR4)] and TRAIL receptor 2 [death receptor 5 (DR5)], which are widely expressed in cancer cells.	4	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	death receptor 4	death receptor 4	death receptor 4	4	5	14	17
The development and clinical application of TRAIL based anti-cancer therapeutics targeting DR4 ( e.g ., mapatumumab ) , DR5 ( e.g ., lexatumumab ) , or a recombinant form of TRAIL targeting both receptors ( i.e ., dulanermin ) have recently undergone widespread clinical investigation for PDA and other solid tumors .	The development and clinical application of TRAIL based anti-cancer therapeutics targeting DR4 (e.g., mapatumumab), DR5 (e.g., lexatumumab), or a recombinant form of TRAIL targeting both receptors (i.e., dulanermin) have recently undergone widespread clinical investigation for PDA and other solid tumors.	4	12	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	6	7	11	12
Preincubation with E-17-beta completely prevented both TRAIL induced DR4 and DR5 upregulation and apoptosis .	Preincubation with E-17-beta completely prevented both TRAIL induced DR4 and DR5 upregulation and apoptosis.	4	11	induced	Positive_early_activation	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	6	7	8	9
We observed no change in the steady-state levels of DR4 mRNA following HuR knockdown , but found a rapid increase in TRAIL induced DR4 mRNA in the absence of HuR ( XREF_FIG ) .	We observed no change in the steady-state levels of DR4 mRNA following HuR knockdown, but found a rapid increase in TRAIL induced DR4 mRNA in the absence of HuR (XREF_FIG).	19	24	induced	Positive_early_activation	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	21	22	23	24
Next , we have investigated the molecular mechanisms of bortezomib and TRAIL induced DR4 internalization and degradation by inhibition of lysosomal activity with highly selective inhibitor to lysosomal cathepsins B , H , and L E-64 and specific inhibitor of the vacuolar H ( + )-ATPase bafilomycin A1 ( Baf-A1 ) which blocks the endosome acidification .	Next, we have investigated the molecular mechanisms of bortezomib and TRAIL induced DR4 internalization and degradation by inhibition of lysosomal activity with highly selective inhibitor to lysosomal cathepsins B, H, and L E-64 and specific inhibitor of the vacuolar H (+)-ATPase bafilomycin A1 (Baf-A1) which blocks the endosome acidification.	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	11	12	13	14
TRAIL induces apoptosis via ligand binding to the death receptors , DR4 and 5 ( a.k.a. TRAIL receptor 1 and TRAIL receptor 2 , respectively ) , which results in the formation of the death inducing signaling complex ( DISC ) and recruitment and activation of caspase-8 [ XREF_BIBR ] .	TRAIL induces apoptosis via ligand binding to the death receptors, DR4 and 5 (a.k.a. TRAIL receptor 1 and TRAIL receptor 2, respectively), which results in the formation of the death inducing signaling complex (DISC) and recruitment and activation of caspase-8 [XREF_BIBR].	0	12	induces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	0	1	11	12
TRAIL ( 100 microg/L ) did not induce obvious lipid rafts aggregation and death receptor 4 ( DR4 ) clustering , while cisplatin ( 8.49 mg/L ) significantly promoted the localization of DR4 in aggregated lipid rafts .	TRAIL (100 microg/L) did not induce obvious lipid rafts aggregation and death receptor 4 (DR4) clustering, while cisplatin (8.49 mg/L) significantly promoted the localization of DR4 in aggregated lipid rafts.	0	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	death receptor 4	death receptor 4	death receptor 4	0	1	13	16
Similarly , monoclonal TRAIL receptor antibodies targeting the proapoptotic TRAIL receptors TRAIL-R1 or -R2 resulted in suppression of tumor growth .	Similarly, monoclonal TRAIL receptor antibodies targeting the proapoptotic TRAIL receptors TRAIL-R1 or -R2 resulted in suppression of tumor growth.	3	13	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R1	TRAIL-R1	TRAIL-R1	3	4	11	12
Rather in one of the cell lines , TRAIL induced the downregulation of DR4 .	Rather in one of the cell lines, TRAIL induced the downregulation of DR4.	8	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	8	9	13	14
Here we show that TRAIL increases vascular smooth muscle cell ( VSMC ) proliferation in vitro , effects that can be blocked with neutralizing antibodies to TRAIL receptors DR4 and DcR1 .	Here we show that TRAIL increases vascular smooth muscle cell (VSMC) proliferation in vitro, effects that can be blocked with neutralizing antibodies to TRAIL receptors DR4 and DcR1.	4	30	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	4	5	28	29
However , no significant difference in the number of DR4 positive events were observed in the cells treated with TRAIL or triptolide or a combination of both .	However, no significant difference in the number of DR4 positive events were observed in the cells treated with TRAIL or triptolide or a combination of both.	9	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	19	20	9	10
General caspase inhibitor z-VAD-FMK inhibited cell death and abrogated bortezomib and TRAIL induced disappearance of DR4 receptor from the cell surface indicating the essential role of caspases activation in DR4 internalization ( XREF_FIG ) .	General caspase inhibitor z-VAD-FMK inhibited cell death and abrogated bortezomib and TRAIL induced disappearance of DR4 receptor from the cell surface indicating the essential role of caspases activation in DR4 internalization (XREF_FIG).	9	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	11	12	15	16
For example , one resistance mechanism that has been found in human tumors ( somatic mutation in DR5 ) was not overcome with the proteasome inhibitors , however we previously showed that the inhibitory effect of the DR5 mutation could be bypassed through the use of a TRAIL receptor agonist ( Mapatumumab ) that is targeted only to DR4 .	For example, one resistance mechanism that has been found in human tumors (somatic mutation in DR5) was not overcome with the proteasome inhibitors, however we previously showed that the inhibitory effect of the DR5 mutation could be bypassed through the use of a TRAIL receptor agonist (Mapatumumab) that is targeted only to DR4.	47	59	targeted	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	47	48	58	59
Our findings suggest that the rational design of TRAIL variants that target DR4 potentiate the death inducing activity of TRAIL and offer a novel therapeutic strategy for the treatment of AML .	Our findings suggest that the rational design of TRAIL variants that target DR4 potentiate the death inducing activity of TRAIL and offer a novel therapeutic strategy for the treatment of AML.	8	13	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	8	9	12	13
In our study , the combination of TRAIL and LA activated DR4 in A549 and H1299 cells , implying the potent role of a death-receptor-dependent pathway by combination of TRAIL and LA ..	In our study, the combination of TRAIL and LA activated DR4 in A549 and H1299 cells, implying the potent role of a death-receptor-dependent pathway by combination of TRAIL and LA..	5	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	7	8	11	12
13 In tumour cells , TRAIL induces apoptosis by ligating functional DR4 and/or DR5 TRAIL receptors that recruit FADD and initiator caspase-8 ( or -10 ) to the death inducing complex DISC .	13 In tumour cells, TRAIL induces apoptosis by ligating functional DR4 and/or DR5 TRAIL receptors that recruit FADD and initiator caspase-8 (or -10) to the death inducing complex DISC.	5	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	5	6	11	12
TNFalpha activates TNF receptor 1 ( TNFR1 ) XREF_BIBR and TNF receptor 2 ( TNFR2 ) XREF_BIBR , while TRAIL activates DR4 ( TRAIL-R1 ) , DR5 ( TRAIL-R2 ) and three other decoy receptors XREF_BIBR .	TNFalpha activates TNF receptor 1 (TNFR1) XREF_BIBR and TNF receptor 2 (TNFR2) XREF_BIBR, while TRAIL activates DR4 (TRAIL-R1), DR5 (TRAIL-R2) and three other decoy receptors XREF_BIBR.	19	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	19	20	21	22
XREF_BIBR , XREF_BIBR However , recently it was shown that oligomerized TRAIL versions can also activate TRAIL-R1 more efficiently than sTRAIL .	XREF_BIBR, XREF_BIBR However, recently it was shown that oligomerized TRAIL versions can also activate TRAIL-R1 more efficiently than sTRAIL.	11	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	TRAIL-R1	TRAIL-R1	TRAIL-R1	11	12	16	17
Thus , the positive effect of amino bisphosphonates in the treatment of PDB may be due to either direct or indirect suppression of RANKL induced bone resorption through decreased RANKL and increased OPG production .	Thus, the positive effect of amino bisphosphonates in the treatment of PDB may be due to either direct or indirect suppression of RANKL induced bone resorption through decreased RANKL and increased OPG production.	4	33	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	23	24	32	33
IL-1beta treatment induced RANKL expression and increased the RANKL and OPG ratio in human cementoblasts .	IL-1beta treatment induced RANKL expression and increased the RANKL and OPG ratio in human cementoblasts.	0	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	IL-1beta treatment induced RANKL expression	rankl	OPG	OPG	opg	3	4	10	11
In a human synovite cell line , vitamin D was also found to decrease IL-1beta-mediated l-6 and TNFbeta gene expression , and increased the ratio of osteoprotegerin ( OPG ) to receptor activator of nuclear factor kappaB ligand ( RANKL ) ; with enhancement of this ratio thought to limit osteoclast formation [ XREF_BIBR ] .	In a human synovite cell line, vitamin D was also found to decrease IL-1beta-mediated l-6 and TNFbeta gene expression, and increased the ratio of osteoprotegerin (OPG) to receptor activator of nuclear factor kappaB ligand (RANKL); with enhancement of this ratio thought to limit osteoclast formation [XREF_BIBR].	22	40	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	osteoprotegerin	osteoprotegerin	osteoprotegerin	39	40	26	27
RT-PCR analysis showed that 1.0 mug/ml Zol inhibited mRNA expression of oteocalcin ( OCN ) and RANKL , and down-regulated ratio of RANKL and OPG in jaw BMSCs after 14 days of osteogenic induction ( P < 0.05 ) ( XREF_FIG ) .	RT-PCR analysis showed that 1.0 mug/ml Zol inhibited mRNA expression of oteocalcin (OCN) and RANKL, and down-regulated ratio of RANKL and OPG in jaw BMSCs after 14 days of osteogenic induction (P < 0.05) (XREF_FIG).	6	25	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	Zol inhibited mRNA expression of oteocalcin (OCN) and RANKL	rankl	OPG	OPG	opg	16	17	24	25
The ratio of cytokines RANKL and OPG ( receptor activator of nuclear factor kappaB ligand and osteoprotegerin ) was significantly higher in children with allergy compared with their healthy counterparts ( p < 0.05 ) .	The ratio of cytokines RANKL and OPG (receptor activator of nuclear factor kappaB ligand and osteoprotegerin) was significantly higher in children with allergy compared with their healthy counterparts (p < 0.05).	1	17	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	osteoprotegerin	osteoprotegerin	osteoprotegerin	4	5	16	17
To establish whether our observed enhancement of OCL differentiation by BMP2 is mediated indirectly through contaminating bone marrow stromal cells or osteoblasts , we compared expression of RANKL and OPG in bone marrow derived cultures treated with suboptimal RANKL or suboptimal RANKL plus BMP2 for three days ( XREF_FIG ) .	To establish whether our observed enhancement of OCL differentiation by BMP2 is mediated indirectly through contaminating bone marrow stromal cells or osteoblasts, we compared expression of RANKL and OPG in bone marrow derived cultures treated with suboptimal RANKL or suboptimal RANKL plus BMP2 for three days (XREF_FIG).	25	43	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	38	39	29	30
Furthermore , the activated antigen specific T cells provide B cell co-stimulatory signals through CD40 and CD40L ligation , which also is considered to upregulate RANKL expression from B cells , as well as promote the production of OPG .	Furthermore, the activated antigen specific T cells provide B cell co-stimulatory signals through CD40 and CD40L ligation, which also is considered to upregulate RANKL expression from B cells, as well as promote the production of OPG.	14	39	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	CD40 and CD40L ligation, which also is considered to upregulate RANKL expression	rankl	OPG	OPG	opg	25	26	38	39
IL-17 not only enhanced RANKL expression but also strongly upregulated the RANKL and OPG ratio in the synovium , while systemic OPG treatment prevented joint damage induced by local IL-17 overexpression .	IL-17 not only enhanced RANKL expression but also strongly upregulated the RANKL and OPG ratio in the synovium, while systemic OPG treatment prevented joint damage induced by local IL-17 overexpression.	0	14	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	IL-17 not only enhanced RANKL expression	rankl	OPG	OPG	opg	4	5	13	14
This increased bone resorption associated with local bone erosion is likely to be mediated by changes in the balance of the OPG and RANK-L system ( receptor activator of nuclear factor kappaB-ligand and osteoprotegerin ) as suggested by the significant association of this ratio in serum and long-term radiologic progression .	This increased bone resorption associated with local bone erosion is likely to be mediated by changes in the balance of the OPG and RANK-L system (receptor activator of nuclear factor kappaB-ligand and osteoprotegerin) as suggested by the significant association of this ratio in serum and long-term radiologic progression.	23	34	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	RANK-L	RANK-L	RANK-L	osteoprotegerin	osteoprotegerin	osteoprotegerin	23	24	33	34
A positive effect of Sr ranelate was observed on the OPG and RANKL ratio , causing an increased secretion of OPG and a simultaneous reduction of RANKL expression , leading to the suppression of osteoclastogenesis [ XREF_BIBR ] .	A positive effect of Sr ranelate was observed on the OPG and RANKL ratio, causing an increased secretion of OPG and a simultaneous reduction of RANKL expression, leading to the suppression of osteoclastogenesis [XREF_BIBR].	15	28	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL expression	rankl	OPG	OPG	opg	26	27	20	21
Recently , it has been shown that RANKL is upregulated whereas OPG is downregulated in periodontitis compared to periodontal health , resulting in an increased RANKL and OPG ratio .	Recently, it has been shown that RANKL is upregulated whereas OPG is downregulated in periodontitis compared to periodontal health, resulting in an increased RANKL and OPG ratio.	7	28	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	7	8	27	28
Proinflammatory cytokines , matrix proteins and bone regulating cytokines of the RANKL and OPG ( receptor activator of nuclear factor kappa B ligand and osteoprotegerin ) and Wnt and beta-catenin pathways are mandatory for normal bone repair but their spatial and temporal role in the healing of primary total hip arthroplasties ( THA ) has not been previously shown .	Proinflammatory cytokines, matrix proteins and bone regulating cytokines of the RANKL and OPG (receptor activator of nuclear factor kappa B ligand and osteoprotegerin) and Wnt and beta-catenin pathways are mandatory for normal bone repair but their spatial and temporal role in the healing of primary total hip arthroplasties (THA) has not been previously shown.	8	25	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	osteoprotegerin	osteoprotegerin	osteoprotegerin	11	12	24	25
RANKL strongly induced Tnfrsf11b in enterocytes , which may be part of an inhibitory feedback loop that regulates the enterocyte response to RANKL .	RANKL strongly induced Tnfrsf11b in enterocytes, which may be part of an inhibitory feedback loop that regulates the enterocyte response to RANKL.	0	4	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	Tnfrsf11b	Tnfrsf11b	Tnfrsf11b	0	1	3	4
Induction of Tnfrsf11b by RANKL was previously demonstrated in thymic medullary epithelial cells .	Induction of Tnfrsf11b by RANKL was previously demonstrated in thymic medullary epithelial cells.	0	5	Induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	Tnfrsf11b	Tnfrsf11b	Tnfrsf11b	4	5	2	3
Confocal microscopy demonstrated via the clathrin pathway an internalization of OPG mediated by RANKL .	Confocal microscopy demonstrated via the clathrin pathway an internalization of OPG mediated by RANKL.	8	14	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	13	14	10	11
Multiple lines of evidence in models of PD clearly indicate that increases in RANKL mRNA expression and protein production increase the RANKL and OPG ratio and stimulate the differentiation of macrophage precursor cells into osteoclasts .	Multiple lines of evidence in models of PD clearly indicate that increases in RANKL mRNA expression and protein production increase the RANKL and OPG ratio and stimulate the differentiation of macrophage precursor cells into osteoclasts.	13	24	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL mRNA expression	rankl	OPG	OPG	opg	13	14	23	24
The latter was upregulated robustly by E 2 , and there was a slight upregulation of RANKL , increasing the OPG and RANKL ratio fivefold .	The latter was upregulated robustly by E 2, and there was a slight upregulation of RANKL, increasing the OPG and RANKL ratio fivefold.	14	23	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	16	17	20	21
The mRNA levels for receptor activator of nuclear factor ( kappa ) B ligand ( RANKL ) in Ctsk-/- bones were increased resulting in increased RANKL and OPG ratio favoring osteoclastogenesis .	The mRNA levels for receptor activator of nuclear factor (kappa) B ligand (RANKL) in Ctsk-/- bones were increased resulting in increased RANKL and OPG ratio favoring osteoclastogenesis.	13	28	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	15	16	27	28
In contrast , in-miR-124-CM reduced the expression of OPG , enhanced the expression of RANKL , thus decreasing the ration of OPG and RANKL .	In contrast, in-miR-124-CM reduced the expression of OPG, enhanced the expression of RANKL, thus decreasing the ration of OPG and RANKL.	6	23	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	expression of OPG, enhanced the expression of RANKL	rankl	OPG	OPG	opg	14	15	21	22
In a few years , OPG and RANKL couple became the principal system regulating osteoclastogenesis and bone resorption and has impressively stimulated the development of OPG and RANKL targeting agents for the treatment of osteolytic disorders in oncologic contexts or not competing with bisphosphonates , a well admitted drug class for the treatment of bone loss XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	In a few years, OPG and RANKL couple became the principal system regulating osteoclastogenesis and bone resorption and has impressively stimulated the development of OPG and RANKL targeting agents for the treatment of osteolytic disorders in oncologic contexts or not competing with bisphosphonates, a well admitted drug class for the treatment of bone loss XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	7	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	7	8	25	26
Several studies have examined the effect of vitamin D3 on osteoprotegerin synthesis [ XREF_BIBR ] and it has been shown that active 1alpha , 25-hydroxyvitamin D3 upregulates the level of RANKL , but downregulates osteoprotegerin expression in human periodontal ligament cells by accelerating degradation of osteoprotegerin mRNA and transrepressing the osteoprotegerin gene [ XREF_BIBR , XREF_BIBR ] .	Several studies have examined the effect of vitamin D3 on osteoprotegerin synthesis [XREF_BIBR] and it has been shown that active 1alpha, 25-hydroxyvitamin D3 upregulates the level of RANKL, but downregulates osteoprotegerin expression in human periodontal ligament cells by accelerating degradation of osteoprotegerin mRNA and transrepressing the osteoprotegerin gene [XREF_BIBR, XREF_BIBR].	24	36	downregulates	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	RANKL	25-hydroxyvitamin D3 upregulates the level of RANKL	rankl	osteoprotegerin	osteoprotegerin expression	osteoprotegerin	30	31	34	35
It has been demonstrated that RANKL is up-regulated , whereas OPG is down-regulated in periodontitis , compared to periodontal health , resulting in an increased RANKL and OPG ratio [ XREF_BIBR ] .	It has been demonstrated that RANKL is up-regulated, whereas OPG is down-regulated in periodontitis, compared to periodontal health, resulting in an increased RANKL and OPG ratio [XREF_BIBR].	5	30	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	5	6	27	28
Our in vitro data suggest that hepatocytes produce RANKL and OPG and Kupffer cells produce OPG .	Our in vitro data suggest that hepatocytes produce RANKL and OPG and Kupffer cells produce OPG.	8	16	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	8	9	15	16
Hence the effect we see on RANKL and the RANKL and OPG ratio in women who get clinical manifest breast cancer close to serum collection may be triggered by an effect of epithelial and tumor cells altering RANKL and OPG in the bone marrow .	Hence the effect we see on RANKL and the RANKL and OPG ratio in women who get clinical manifest breast cancer close to serum collection may be triggered by an effect of epithelial and tumor cells altering RANKL and OPG in the bone marrow.	2	40	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	9	10	39	40
XREF_BIBR Metastasis changes the skeletal microenvironment , because tumor cells express factors that act on osteoblasts to increase production of RANKL and decrease production of osteoprotegerin , thereby increasing the RANKL to osteoprotegerin ratio to accelerate osteoclast formation and bone resorption .	XREF_BIBR Metastasis changes the skeletal microenvironment, because tumor cells express factors that act on osteoblasts to increase production of RANKL and decrease production of osteoprotegerin, thereby increasing the RANKL to osteoprotegerin ratio to accelerate osteoclast formation and bone resorption.	20	26	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	osteoprotegerin	osteoprotegerin	osteoprotegerin	20	21	25	26
T reg depletion reduced the RANKL and OPG ratio and IL-17 blockade increased the RANKL and OPG ratio , indicating that T reg depletion favours a more resorptive state , whereas IL-17 blockade reverses the effect of T reg depletion on bone erosion ( XREF_FIG F ) .	T reg depletion reduced the RANKL and OPG ratio and IL-17 blockade increased the RANKL and OPG ratio, indicating that T reg depletion favours a more resorptive state, whereas IL-17 blockade reverses the effect of T reg depletion on bone erosion (XREF_FIG F).	4	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	5	6	16	17
Our study preliminarily demonstrated expression of RANKL was higher in OBs from AIS patients with low BMD as compared with controls , suggesting the unbalanced RANKL and OPG ratio caused by an over-expression of RANKL in OBs may be responsible for the low BMD in AIS patients .	Our study preliminarily demonstrated expression of RANKL was higher in OBs from AIS patients with low BMD as compared with controls, suggesting the unbalanced RANKL and OPG ratio caused by an over-expression of RANKL in OBs may be responsible for the low BMD in AIS patients.	27	35	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	over-expression of RANKL	rankl	OPG	OPG	opg	34	35	27	28
In conclusion , the combination of isomeric flavonoids ( CIT/IT ) and OPG and RANKL targets attenuated the excitation effects of OPG or RANKL on RANKL .	In conclusion, the combination of isomeric flavonoids (CIT/IT) and OPG and RANKL targets attenuated the excitation effects of OPG or RANKL on RANKL.	12	22	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	14	15	21	22
The MC3T3-E1 murine pre-osteoblastic cell line was treated with PIO and processed for reverse transcription-quantitative polymerase chain reaction ( RT-qPCR ) analysis of OPG , RANKL , peroxisome proliferator activated receptorgamma ( PPARgamma ) , Runt related transcription factor2 ( RUNX2 ) , alkaline phosphatase ( ALP ) and osteocalcin ( OCN ) , and western blotting analysis of OPG and RANKL .	The MC3T3-E1 murine pre-osteoblastic cell line was treated with PIO and processed for reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis of OPG, RANKL, peroxisome proliferator activated receptorgamma (PPARgamma), Runt related transcription factor2 (RUNX2), alkaline phosphatase (ALP) and osteocalcin (OCN), and western blotting analysis of OPG and RANKL.	21	30	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	25	26	23	24
Papers fulfilling the inclusion criteria demonstrate that RANKL is up-regulated , whereas OPG is down-regulated in periodontitis , compared to periodontal health , resulting in an increased RANKL and OPG ratio .	Papers fulfilling the inclusion criteria demonstrate that RANKL is up-regulated, whereas OPG is down-regulated in periodontitis, compared to periodontal health, resulting in an increased RANKL and OPG ratio.	7	30	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	7	8	29	30
We initially confirmed that three recombinant human TGF-betas ( rhTGF-beta1 , rhTGF-beta2 , and rhTGF-beta3 ) evenly induced RANKL mediated osteoclast differentiation ( XREF_FIG A ) , and the addition of OPG suppressed it ( XREF_FIG : Effect of OPG against RANKL stimulated RAW264 cells ) .	We initially confirmed that three recombinant human TGF-betas (rhTGF-beta1, rhTGF-beta2, and rhTGF-beta3) evenly induced RANKL mediated osteoclast differentiation (XREF_FIG A), and the addition of OPG suppressed it (XREF_FIG : Effect of OPG against RANKL stimulated RAW264 cells).	18	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	18	19	31	32
Mesenchymal stem cell ( MSC ) lineage cells control osteoclastogenesis via expression of RANKL and OPG ( receptor activator of nuclear factor kappaB ligand and osteoprotegerin ) , which promote and inhibit bone resorption , respectively .	Mesenchymal stem cell (MSC) lineage cells control osteoclastogenesis via expression of RANKL and OPG (receptor activator of nuclear factor kappaB ligand and osteoprotegerin), which promote and inhibit bone resorption, respectively.	11	31	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	RANKL	expression of RANKL	rankl	osteoprotegerin	osteoprotegerin	osteoprotegerin	13	14	25	26
Furthermore , OPG was upregulated by TNF superfamily members TNF-alpha , anti-CD40 , and RANKL , and by ligands of the Toll-like/IL -1 receptor family including IL-1beta , double stranded RNA ( poly I : C ) , or lipopolysaccharide ( LPS ) , all of which induce maturation of DC .	Furthermore, OPG was upregulated by TNF superfamily members TNF-alpha, anti-CD40, and RANKL, and by ligands of the Toll-like/IL -1 receptor family including IL-1beta, double stranded RNA (poly I : C), or lipopolysaccharide (LPS), all of which induce maturation of DC.	2	15	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	14	15	2	3
PGE2 and RANKL , but not OPG , were increased in groups V , C , and VC , thus increasing the RANKL and OPG ratio .	PGE2 and RANKL, but not OPG, were increased in groups V, C, and VC, thus increasing the RANKL and OPG ratio.	0	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	2	3	24	25
We found that a decrease in the RANKL and OPG ratio by 20 % strongly inhibited osteoclastogenesis , which suggests that the PFF induced inhibition of osteoclastogenesis can be attributed to a loading induced decrease in RANKL and OPG ratio .	We found that a decrease in the RANKL and OPG ratio by 20% strongly inhibited osteoclastogenesis, which suggests that the PFF induced inhibition of osteoclastogenesis can be attributed to a loading induced decrease in RANKL and OPG ratio.	4	39	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	7	8	38	39
In previous studies , OPG may have partly prevented bone metastasis by inhibition of TRAIL activity , even if RANKL was the major target of OPG .	In previous studies, OPG may have partly prevented bone metastasis by inhibition of TRAIL activity, even if RANKL was the major target of OPG.	19	26	was the major target	Positive_activation_copula_1	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	19	20	25	26
RANKL was elevated 3.5-fold in comparison to OPG at post-burn day 7 and 14 and 1.5 fold at post-burn day 21 in lumbar vertebrae ( XREF_FIG ) .	RANKL was elevated 3.5-fold in comparison to OPG at post-burn day 7 and 14 and 1.5 fold at post-burn day 21 in lumbar vertebrae (XREF_FIG).	0	8	elevated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	0	1	7	8
Estrogen also modulates osteoclasts by suppressing production of RANKL and increasing production of osteoprotegerin .	Estrogen also modulates osteoclasts by suppressing production of RANKL and increasing production of osteoprotegerin.	8	14	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	osteoprotegerin	osteoprotegerin	osteoprotegerin	8	9	13	14
On the contrary , this concentration of Zol promoted mRNA expression of OCN and RANKL , and up-regulated ratio of RANKL and OPG in iliac and tibial BMSCs ( P < 0.05 ) ( XREF_FIG ) .	On the contrary, this concentration of Zol promoted mRNA expression of OCN and RANKL, and up-regulated ratio of RANKL and OPG in iliac and tibial BMSCs (P < 0.05) (XREF_FIG).	7	23	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	Zol promoted mRNA expression of OCN and RANKL	rankl	OPG	OPG	opg	14	15	22	23
We speculate that the decrease in RANKL production and up-regulation of OPG provide a plausible explanation for the loss of osteoclast inducing activity .	We speculate that the decrease in RANKL production and up-regulation of OPG provide a plausible explanation for the loss of osteoclast inducing activity.	6	12	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	6	7	11	12
The present study demonstrates , for the first time , that T-614 could decrease the RANKL expression and downregulate the ratio of RANKL and OPG in RASFs via blocking ERK1/2 phosphorylation ; we also confirmed that T-614 could suppress IL-17 and MMP-3 expression in IL-6-induced RASFs .	The present study demonstrates, for the first time, that T-614 could decrease the RANKL expression and downregulate the ratio of RANKL and OPG in RASFs via blocking ERK1/2 phosphorylation; we also confirmed that T-614 could suppress IL-17 and MMP-3 expression in IL-6-induced RASFs.	11	25	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	T-614 could decrease the RANKL expression	rankl	OPG	OPG	opg	15	16	24	25
In cell culture , IL-6 decreased the expression of Osteocalcin in osteoblasts , but more importantly , increased the expression of Rankl , a cytokine that favors osteoclast differentiation , and decreased the one of Osteoprotegerin ( Opg ) , a decoy receptor for Rankl and an inhibitor of bone resorption ( XREF_FIG ) .	In cell culture, IL-6 decreased the expression of Osteocalcin in osteoblasts, but more importantly, increased the expression of Rankl, a cytokine that favors osteoclast differentiation, and decreased the one of Osteoprotegerin (Opg), a decoy receptor for Rankl and an inhibitor of bone resorption (XREF_FIG).	4	37	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rankl	IL-6 decreased the expression of Osteocalcin in osteoblasts, but more importantly, increased the expression of Rankl	rankl	Osteoprotegerin	Osteoprotegerin	osteoprotegerin	21	22	35	36
Up-regulation of the RANKL gene increases the RANKL and OPG ratio and enhances bone loss XREF_BIBR .	Up-regulation of the RANKL gene increases the RANKL and OPG ratio and enhances bone loss XREF_BIBR.	3	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	3	4	9	10
However , it appeared to prevent RANKL induced increases in cellular OPG protein ( when baseline effects of 5 ng/mL TRAIL are taken into account ) ( XREF_FIG ) .	However, it appeared to prevent RANKL induced increases in cellular OPG protein (when baseline effects of 5 ng/mL TRAIL are taken into account) (XREF_FIG).	5	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	6	7	11	12
Osteoclasts apoptosis can be prevented by 1,25 ( OH ) 2 vitamin D3 and parathyroid hormone ( PTH ) probably through RANKL stimulation or reduction in osteoprotegerin ( OPG ) expression .	Osteoclasts apoptosis can be prevented by 1,25 (OH) 2 vitamin D3 and parathyroid hormone (PTH) probably through RANKL stimulation or reduction in osteoprotegerin (OPG) expression.	21	28	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	osteoprotegerin	osteoprotegerin	osteoprotegerin	21	22	26	27
Osteocytes also are a source of osteoprotegerin ( OPG ) , the potent inhibitor of RANKL , XREF_BIBR and differential production of OPG and RANKL by osteocytes provides a unique mechanism by which osteocytes can regulate osteoclast mediated bone resorption ( XREF_FIG ) .	Osteocytes also are a source of osteoprotegerin (OPG), the potent inhibitor of RANKL, XREF_BIBR and differential production of OPG and RANKL by osteocytes provides a unique mechanism by which osteocytes can regulate osteoclast mediated bone resorption (XREF_FIG).	15	23	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	15	16	22	23
Interestingly , AdIL-17 not only enhanced RANKL expression but also strongly up-regulated the RANKL and OPG ratio in the synovium .	Interestingly, AdIL-17 not only enhanced RANKL expression but also strongly up-regulated the RANKL and OPG ratio in the synovium.	2	16	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	AdIL-17 not only enhanced RANKL expression	rankl	OPG	OPG	opg	6	7	15	16
In the collagen arthritis model , overexpression of IL-17 not only enhanced RANK-L expression , but also strongly upregulated the RANK-L and OPG ratio in the synovium [ XREF_BIBR ] .	In the collagen arthritis model, overexpression of IL-17 not only enhanced RANK-L expression, but also strongly upregulated the RANK-L and OPG ratio in the synovium [XREF_BIBR].	6	23	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANK-L	overexpression of IL-17 not only enhanced RANK-L expression	rank-l	OPG	OPG	opg	12	13	22	23
Moreover , TNF-alpha ( tumour necrosis factor-alpha ) levels and RANKL and OPG ( receptor activator of NF-kappaB ligand and osteoprotegerin ) ratio were increased in the maxilla after OVX , and these responses were also reversed by E2 .	Moreover, TNF-alpha (tumour necrosis factor-alpha) levels and RANKL and OPG (receptor activator of NF-kappaB ligand and osteoprotegerin) ratio were increased in the maxilla after OVX, and these responses were also reversed by E2.	2	24	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	osteoprotegerin	osteoprotegerin	osteoprotegerin	10	11	20	21
These results suggest that DHMEQ suppresses osteoclastogenesis in vivo , through downregulation of NFATc1 expression , without significantly affecting expression of upstream molecules of the RANKL and receptor activator of NF-kappaB and osteoprotegerin cascade , at least in our experimental condition .	These results suggest that DHMEQ suppresses osteoclastogenesis in vivo, through downregulation of NFATc1 expression, without significantly affecting expression of upstream molecules of the RANKL and receptor activator of NF-kappaB and osteoprotegerin cascade, at least in our experimental condition.	25	33	activator	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	osteoprotegerin	osteoprotegerin	osteoprotegerin	25	26	32	33
In addition , multiple myeloma cells induce RANKL expression in stromal and osteoblastic cells inducing an imbalance of RANKL and OPG ratio in favor of RANKL [ XREF_BIBR ] , and multiple myeloma cells also upregulate RANKL in T lymphocytes [ XREF_BIBR ] .	In addition, multiple myeloma cells induce RANKL expression in stromal and osteoblastic cells inducing an imbalance of RANKL and OPG ratio in favor of RANKL [XREF_BIBR], and multiple myeloma cells also upregulate RANKL in T lymphocytes [XREF_BIBR].	7	21	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL expression	rankl	OPG	OPG	opg	7	8	20	21
Increased production of RANKL causes an increase in the relative RANKL and OPG ratio resulting into more periodontal destruction .	Increased production of RANKL causes an increase in the relative RANKL and OPG ratio resulting into more periodontal destruction.	1	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	3	4	12	13
PKA stimulators such as IBMX , forskolin and Sp-cAMP , which stimulated the expression of PPARgamma2 , inhibited the expression of RANKL ( day 7 versus 14 ) , stimulated the expression of OPG ( day 7 versus 14 ) , and thus decreased the RANKL and OPG ratio ( XREF_FIG ) .	PKA stimulators such as IBMX, forskolin and Sp-cAMP, which stimulated the expression of PPARgamma2, inhibited the expression of RANKL (day 7 versus 14), stimulated the expression of OPG (day 7 versus 14), and thus decreased the RANKL and OPG ratio (XREF_FIG).	0	38	stimulated	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	RANKL	PKA stimulators such as IBMX, forskolin and Sp-cAMP, which stimulated the expression of PPARgamma2, inhibited the expression of RANKL	rankl	OPG	expression of OPG	opg	21	22	33	34
Although HVEM mediates both positive and negative immune signals XREF_BIBR , our observations are most consistent with the hypothesis that early in infection , gD interferes with a positive signal through HVEM initiated by LIGHT .	Although HVEM mediates both positive and negative immune signals XREF_BIBR, our observations are most consistent with the hypothesis that early in infection, gD interferes with a positive signal through HVEM initiated by LIGHT.	25	35	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	34	35	31	32
HVEM and LIGHTare each expressed on a variety of cell types including T cells , DC , macrophages , and NK cells , and activation of HVEM by LIGHT or BTLA leads to NF-kappaB-driven gene activation and inflammatory signaling .	HVEM and LIGHTare each expressed on a variety of cell types including T cells, DC, macrophages, and NK cells, and activation of HVEM by LIGHT or BTLA leads to NF-kappaB-driven gene activation and inflammatory signaling.	24	30	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	28	29	26	27
Although the interaction stoichiometry and the relative positions of HVEM and BTLA or CD160 on opposing membranes are not clear , the trimeric TNF related ligands LIGHT and LTalpha are thought to induce HVEM trimerization , whereas HVEM and BTLA bind as heterodimers in solution XREF_BIBR - XREF_BIBR .	Although the interaction stoichiometry and the relative positions of HVEM and BTLA or CD160 on opposing membranes are not clear, the trimeric TNF related ligands LIGHT and LTalpha are thought to induce HVEM trimerization, whereas HVEM and BTLA bind as heterodimers in solution XREF_BIBR - XREF_BIBR.	21	34	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	26	27	33	34
XREF_BIBR proposed that increased production of both IL-13 by eosinophils ( via TNFSF14 stimulation of eosinophil TNFRSF14 ) and TGF-beta by macrophages ( via TNFSF14 stimulation of macrophage TNFRSF3 ) might represent important TNFSF14 mediated mechanisms which contribute to airway remodelling .	XREF_BIBR proposed that increased production of both IL-13 by eosinophils (via TNFSF14 stimulation of eosinophil TNFRSF14) and TGF-beta by macrophages (via TNFSF14 stimulation of macrophage TNFRSF3) might represent important TNFSF14 mediated mechanisms which contribute to airway remodelling.	12	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFSF14	TNFSF14	TNFSF14	TNFRSF14	TNFRSF14	TNFRSF14	12	13	16	17
The soluble forms of LIGHT and LTalpha were also unable to initiate HVEM signaling in cells expressing the cis-complex ; indeed , the soluble ligands enhanced binding between HVEM and BTLA .	The soluble forms of LIGHT and LTalpha were also unable to initiate HVEM signaling in cells expressing the cis-complex; indeed, the soluble ligands enhanced binding between HVEM and BTLA.	2	13	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	4	5	12	13
HVEM stimulation by LIGHT leads to costimulation T cells and DC activation .	HVEM stimulation by LIGHT leads to costimulation T cells and DC activation.	0	4	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	3	4	0	1
To further investigate LIGHT effect on OC formation in the presence or absence of RANKL , we analyzed both the intracellular signal and the expression of HVEM and LTbetaR in pre-osteoclasts treated with RANKL and/or LIGHT .	To further investigate LIGHT effect on OC formation in the presence or absence of RANKL, we analyzed both the intracellular signal and the expression of HVEM and LTbetaR in pre-osteoclasts treated with RANKL and/or LIGHT.	24	36	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	35	36	26	27
It has been reported that LIGHT associated pathways inhibit proliferation and trigger the apoptosis of HT-29 tumor cells , possibly through engagement of HVEM and LTbetaR .	It has been reported that LIGHT associated pathways inhibit proliferation and trigger the apoptosis of HT-29 tumor cells, possibly through engagement of HVEM and LTbetaR.	5	25	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	5	6	23	24
In addition , TNF receptor superfamily member 14 ( TNFRSF14 ) activation by its ligand cytokine TNFSF14 ( LIGHT ) has been reported to enhance FcepsilonR1 signaling and result in enhanced degranulation in both human mast cells and mouse BMMCs .	In addition, TNF receptor superfamily member 14 (TNFRSF14) activation by its ligand cytokine TNFSF14 (LIGHT) has been reported to enhance FcepsilonR1 signaling and result in enhanced degranulation in both human mast cells and mouse BMMCs.	9	17	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNFSF14	TNFSF14	TNFSF14	TNFRSF14	TNFRSF14	TNFRSF14	16	17	9	10
However , this activation is reduced compared to membrane LIGHT activation of HVEM in the absence of BTLA .	However, this activation is reduced compared to membrane LIGHT activation of HVEM in the absence of BTLA.	9	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	9	10	12	13
HVEM signals stimulated by LIGHT more strongly induce the activation of CD8+ T cells than CD4+ T cells [ XREF_BIBR ] .	HVEM signals stimulated by LIGHT more strongly induce the activation of CD8+ T cells than CD4+ T cells [XREF_BIBR].	0	5	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	4	5	0	1
HVEM activation by LIGHT could also be involved in different contexts , however , in promoting the survival of activated T lymphocytes during microbial infections .	HVEM activation by LIGHT could also be involved in different contexts, however, in promoting the survival of activated T lymphocytes during microbial infections.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	3	4	0	1
HVEM-BTLA cis-complex modulates LIGHT mediated HVEM signaling .	HVEM-BTLA cis-complex modulates LIGHT mediated HVEM signaling.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	3	4	5	6
As there is a significant difference in the binding avidity of LIGHT and BTLA , the much higher avidity of LIGHT for HVEM may drive the uncompetitive dissociation of HVEM from BTLA .	As there is a significant difference in the binding avidity of LIGHT and BTLA, the much higher avidity of LIGHT for HVEM may drive the uncompetitive dissociation of HVEM from BTLA.	18	30	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	20	21	29	30
It is postulated that LIGHT expression on DC and T cells causes HVEM engagement on naive B cells , which costimulates B cell proliferation and Ig secretion , as a result , enhancing humoral immune responses [ XREF_BIBR ] .	It is postulated that LIGHT expression on DC and T cells causes HVEM engagement on naive B cells, which costimulates B cell proliferation and Ig secretion, as a result, enhancing humoral immune responses [XREF_BIBR].	4	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIGHT	LIGHT expression	light	HVEM	HVEM	hvem	4	5	12	13
Thus HVEM signaling mediated by LIGHT plays a critical role in regulating ILC3 derived IFN-gamma production for protection following infection .	Thus HVEM signaling mediated by LIGHT plays a critical role in regulating ILC3 derived IFN-gamma production for protection following infection.	1	6	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	5	6	1	2
Upon activation of CD4 + T cells , CD160 is upregulated , and engagement of CD160 by HVEM ( expressed by APCs ) blocks LIGHT activating HVEM signaling that promotes cytokine release .	Upon activation of CD4 + T cells, CD160 is upregulated, and engagement of CD160 by HVEM (expressed by APCs) blocks LIGHT activating HVEM signaling that promotes cytokine release.	17	27	activating	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	24	25	26	27
Recombinant soluble LIGHT can bind to HVEM on vascular smooth muscle cells enhancing cell proliferation , and it is therefore possible that LIGHT induces hyperplasia by engaging HVEM on vascular smooth muscle cells .	Recombinant soluble LIGHT can bind to HVEM on vascular smooth muscle cells enhancing cell proliferation, and it is therefore possible that LIGHT induces hyperplasia by engaging HVEM on vascular smooth muscle cells.	22	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	22	23	27	28
We have examined the role of inflammatory cytokines in an experimental model of hypertension in mice.9 Specifically we have recently shown that TNF superfamily member 14 , LIGHT ( an acronym for homologous to lymphotoxins , exhibits inducible expression , and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator [ HVEM ] , a receptor expressed by T lymphocytes , also known as TNFSF14 ) is elevated in women with preeclampsia ( a serious hypertensive condition of pregnancy ) and induces hypertension when injected into pregnant or nonpregnant mice.9 LIGHT is produced by cells of the innate and adaptive immune system , including granulocytes , monocytes , macrophages , dendritic cells , and T cells.10 , 11 It is initially present on the cell membrane as a homotrimer but can be released from the cell membrane via proteolytic cleavage and exist in a soluble form.12 Whether membrane bound or free , LIGHT can bind to two receptors , HVEM , which is present on T cells , and lymphotoxin beta receptor , present on nonlymphoid hematopoietic cells including natural killer cells.13 LIGHT mediated activation of HVEM receptors on T cells results in a costimulatory response leading to T-cell activation , cell proliferation , and cytokine production.11 LIGHT deficient mice have reduced T-cell immunity associated with impaired allograph rejection.14 Thus , considerable evidence supports a role for LIGHT in adaptive T-cell immunity and cytokine production .	We have examined the role of inflammatory cytokines in an experimental model of hypertension in mice.9 Specifically we have recently shown that TNF superfamily member 14, LIGHT (an acronym for homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes, also known as TNFSF14) is elevated in women with preeclampsia (a serious hypertensive condition of pregnancy) and induces hypertension when injected into pregnant or nonpregnant mice.9 LIGHT is produced by cells of the innate and adaptive immune system, including granulocytes, monocytes, macrophages, dendritic cells, and T cells.10, 11 It is initially present on the cell membrane as a homotrimer but can be released from the cell membrane via proteolytic cleavage and exist in a soluble form.12 Whether membrane bound or free, LIGHT can bind to two receptors, HVEM, which is present on T cells, and lymphotoxin beta receptor, present on nonlymphoid hematopoietic cells including natural killer cells.13 LIGHT mediated activation of HVEM receptors on T cells results in a costimulatory response leading to T-cell activation, cell proliferation, and cytokine production.11 LIGHT deficient mice have reduced T-cell immunity associated with impaired allograph rejection.14 Thus, considerable evidence supports a role for LIGHT in adaptive T-cell immunity and cytokine production.	185	237	mediated	Positive_early_activation	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	185	186	189	190
Activation of HVEM by LIGHT leads to co-stimulation of several cell types , including T cells and antigen presenting cells , whereas ligation of T-cell-expressed BTLA or CD160 by HVEM results in inhibition of T-cell proliferation and effector function XREF_BIBR - XREF_BIBR .	Activation of HVEM by LIGHT leads to co-stimulation of several cell types, including T cells and antigen presenting cells, whereas ligation of T-cell-expressed BTLA or CD160 by HVEM results in inhibition of T-cell proliferation and effector function XREF_BIBR - XREF_BIBR.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	4	5	2	3
Importantly , the addition of soluble LIGHT or LTalpha failed to activate HVEM as detected by induction of NFkappaB , although binding of LIGHT was detectable as expected , and in cells expressing HVEM alone , these ligands were fully functional .	Importantly, the addition of soluble LIGHT or LTalpha failed to activate HVEM as detected by induction of NFkappaB, although binding of LIGHT was detectable as expected, and in cells expressing HVEM alone, these ligands were fully functional.	3	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	6	7	12	13
Our findings reveal that Tnfsf14 functions as a pro survival factor during myogenic differentiation , an effect mediated by its receptors HVEM and LTbetaR in an Akt dependent manner .	Our findings reveal that Tnfsf14 functions as a pro survival factor during myogenic differentiation, an effect mediated by its receptors HVEM and LTbetaR in an Akt dependent manner.	4	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tnfsf14	Tnfsf14	Tnfsf14	HVEM	HVEM	HVEM	4	5	21	22
It has been shown that HVEM has a stronger binding avidity to LIGHT than LTalpha [ XREF_BIBR ] , and LIGHT induced HVEM signaling results in the recruitment of the TNF receptor associated factor 2 ( TRAF2 ) to the cytoplasmic tail of HVEM .	It has been shown that HVEM has a stronger binding avidity to LIGHT than LTalpha [XREF_BIBR], and LIGHT induced HVEM signaling results in the recruitment of the TNF receptor associated factor 2 (TRAF2) to the cytoplasmic tail of HVEM.	20	23	induced	Positive_early_activation	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	20	21	22	23
LIGHT mediated HVEM signaling provides prosurvival signals and proliferative responses to T cells through the activation of NF-kB transcriptional programs .	LIGHT mediated HVEM signaling provides prosurvival signals and proliferative responses to T cells through the activation of NF-kB transcriptional programs.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	0	1	2	3
Activation of HVEM signaling by LIGHT , BTLA , or CD160 enhances antigen induced T cell proliferation and cytokine production , and epithelial cell expression of host defense genes in response to bacterial infection .	Activation of HVEM signaling by LIGHT, BTLA, or CD160 enhances antigen induced T cell proliferation and cytokine production, and epithelial cell expression of host defense genes in response to bacterial infection.	2	10	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	5	6	2	3
TNFSF14 is known to bind to its receptors herpes virus entry mediator ( HVEM ) and lymphotoxin beta receptor ( LTbetaR ) for signal transduction , but TNFSF14 induced hypopigmentation was independent of HVEM and LTbetaR in melanocytes .	TNFSF14 is known to bind to its receptors herpes virus entry mediator (HVEM) and lymphotoxin beta receptor (LTbetaR) for signal transduction, but TNFSF14 induced hypopigmentation was independent of HVEM and LTbetaR in melanocytes.	27	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFSF14	TNFSF14	TNFSF14	HVEM	HVEM	HVEM	27	28	33	34
Transfer of T cells expressing constitutive LIGHT promoted HVEM dependent T cell proliferation as well as LTbetaR dependent intestinal inflammation , elevated serum IgA levels and renal IgA deposition .	Transfer of T cells expressing constitutive LIGHT promoted HVEM dependent T cell proliferation as well as LTbetaR dependent intestinal inflammation, elevated serum IgA levels and renal IgA deposition.	4	28	promoted	Positive_activation_token_1_verb	Positive_activation	Positive_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	6	7	8	9
In contrast , BAFFR can also be stimulated by BAFF 3-mer and , in that respect , resembles TNFR1 activated by soluble TNF .	In contrast, BAFFR can also be stimulated by BAFF 3-mer and, in that respect, resembles TNFR1 activated by soluble TNF.	3	17	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFFR	BAFFR	BAFFR	9	10	3	4
Similarly , mice with mutations in the gene encoding BAFFR XREF_BIBR or a deficiency of BAFF , or mice treated with BAFF antagonists , have a marked decrease in B cell number , despite a normal BCR repertoire .	Similarly, mice with mutations in the gene encoding BAFFR XREF_BIBR or a deficiency of BAFF, or mice treated with BAFF antagonists, have a marked decrease in B cell number, despite a normal BCR repertoire.	9	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFFR	BAFFR	BAFFR	21	22	9	10
In contrast , activation of BAFFR by BAFF is thought to be influenced by B cell access to niches with high local BAFF concentrations .	In contrast, activation of BAFFR by BAFF is thought to be influenced by B cell access to niches with high local BAFF concentrations.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFFR	BAFFR	BAFFR	7	8	5	6
Together with MEK5 inhibitor experiments , these results suggested that BAFF stimulation of BAFF-R activated the MEK5-ERK5 signaling pathway and that this was required for optimal mature B cell survival in vitro .	Together with MEK5 inhibitor experiments, these results suggested that BAFF stimulation of BAFF-R activated the MEK5-ERK5 signaling pathway and that this was required for optimal mature B cell survival in vitro.	10	14	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	10	11	13	14
By contrast , decreased BAFF-R expression might be due to potent receptor internalization in the presence of high BAFF levels as suggested during malaria infection or to enhanced BAFF mediated BAFF-R processing .	By contrast, decreased BAFF-R expression might be due to potent receptor internalization in the presence of high BAFF levels as suggested during malaria infection or to enhanced BAFF mediated BAFF-R processing.	21	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	28	29	30	31
Disease in MRL and Lpr was accompanied by high levels of BAFF in vivo , low BAFFR surface expression on B cells , increased peripheral antibody secreting cells , and elevated activation of alternative NF-kappaB2 ; which indicated in vivo BAFF activation of BAFFR .	Disease in MRL and Lpr was accompanied by high levels of BAFF in vivo, low BAFFR surface expression on B cells, increased peripheral antibody secreting cells, and elevated activation of alternative NF-kappaB2; which indicated in vivo BAFF activation of BAFFR.	40	44	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFFR	BAFFR	BAFFR	40	41	43	44
As HKI and Vkappa10 mice have lower numbers of B cells in the periphery than wild type mice ( unpublished ) , more available BLyS per B cell may cause down regulation of surface BR3 .	As HKI and Vkappa10 mice have lower numbers of B cells in the periphery than wild type mice (unpublished), more available BLyS per B cell may cause down regulation of surface BR3.	22	35	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BLyS	BLyS	BLyS	BR3	BR3	BR3	24	25	34	35
BAFF Stimulates PI3K Activity in Malignant B Cells Expressing BAFF-R .	BAFF Stimulates PI3K Activity in Malignant B Cells Expressing BAFF-R.	0	10	Stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	0	1	9	10
The homotrimeric soluble form of BAFF activates BAFF-R .	The homotrimeric soluble form of BAFF activates BAFF-R.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	5	6	7	8
To address the question of how BAFF activates BAFFR , and therefore promotes B cell survival , mutations were designed to inhibit interactions between adjacent flaps .	To address the question of how BAFF activates BAFFR, and therefore promotes B cell survival, mutations were designed to inhibit interactions between adjacent flaps.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFFR	BAFFR	BAFFR	6	7	8	9
BAFF can additionally activate BAFF receptor , an alternate receptor expressed on immature B cells .	BAFF can additionally activate BAFF receptor, an alternate receptor expressed on immature B cells.	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF receptor	BAFF receptor	BAFF receptor	0	1	4	6
Whether TACI-short is released and whether it differently modulates BAFF mediated BAFF-R cleavage on RM B-cells should be examined .	Whether TACI-short is released and whether it differently modulates BAFF mediated BAFF-R cleavage on RM B-cells should be examined.	8	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	9	10	11	12
BAFF can signal through three different receptors on B cells : BAFF receptor 3 ( BR3 ; also known as BAFF-R ) , B-cell maturation antigen ( BCMA ) , and transmembrane activator and calcium-modulator and cytophilin ligand interactor ( TACI ) XREF_BIBR - XREF_BIBR .	BAFF can signal through three different receptors on B cells : BAFF receptor 3 (BR3; also known as BAFF-R), B-cell maturation antigen (BCMA), and transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI) XREF_BIBR - XREF_BIBR.	0	20	signal	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BR3	BR3	BR3	0	1	15	16
Our results suggested that excess BAFF promoted autoreactive B cell survival by binding to BAFF-R in ITP .	Our results suggested that excess BAFF promoted autoreactive B cell survival by binding to BAFF-R in ITP.	4	15	promoted	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	5	6	14	15
Alternatively , BAFF excess in GC might enhance BAFF mediated BAFF-R cleavage on TACI + GC B-cells ( centrocytes ) .	Alternatively, BAFF excess in GC might enhance BAFF mediated BAFF-R cleavage on TACI + GC B-cells (centrocytes).	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	8	9	10	11
While BAFF-R is activated by BAFF trimers , signaling through TACI requires multimerized ligands [ XREF_BIBR ] such as membrane BAFF , circulating BAFF 60-mer , or multimerized APRIL .	While BAFF-R is activated by BAFF trimers, signaling through TACI requires multimerized ligands [XREF_BIBR] such as membrane BAFF, circulating BAFF 60-mer, or multimerized APRIL.	1	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	5	6	1	2
While both NF-kappaB and PI3K pathways are activated downstream of BAFF-R engagement by BAFF , and loss of either Baff or Baff-r expression results in a block at the transitional stage of B cell maturation , it is unclear whether mature B cells still require IKK1 and/or PI3K for maintenance and survival .	While both NF-kappaB and PI3K pathways are activated downstream of BAFF-R engagement by BAFF, and loss of either Baff or Baff-r expression results in a block at the transitional stage of B cell maturation, it is unclear whether mature B cells still require IKK1 and/or PI3K for maintenance and survival.	7	14	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	13	14	10	11
Thus , the survival and maturation pathways normally activated by physiologic triggering of BAFF-R by BAFF are constitutively activated when the expression of TRAF2 , TRAF3 , or cIAP1 and cIAP2 is absent from B cells [ XREF_BIBR ] .	Thus, the survival and maturation pathways normally activated by physiologic triggering of BAFF-R by BAFF are constitutively activated when the expression of TRAF2, TRAF3, or cIAP1 and cIAP2 is absent from B cells [XREF_BIBR].	8	16	triggering	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	15	16	13	14
BAFF and APRIL molecules on DCs activate surface BAFFR and TACI molecules on B cells , and stimulate NFkappaB through a pathway involving NIK ( NFkappaB inducing kinase ) and p52 activation .	BAFF and APRIL molecules on DCs activate surface BAFFR and TACI molecules on B cells, and stimulate NFkappaB through a pathway involving NIK (NFkappaB inducing kinase) and p52 activation.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFFR	BAFFR	BAFFR	0	1	8	9
Although BAFF mediated activation of BAFF-R and/or BCMA might also impact atherosclerosis progression in this model , these findings demonstrate that TACI is required for the BAFF mediated decrease in hypercholesterolemia and attenuation of atherosclerosis in BAFF-Tg mice .	Although BAFF mediated activation of BAFF-R and/or BCMA might also impact atherosclerosis progression in this model, these findings demonstrate that TACI is required for the BAFF mediated decrease in hypercholesterolemia and attenuation of atherosclerosis in BAFF-Tg mice.	1	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	1	2	5	6
However , levels of its immediate downstream target IKKalpha were elevated and p100 accumulated already before BAFF mediated BAFFR ligation ( XREF_FIG ) , possibly reflecting pre-activation of the NF-kappaB pathway in B-LCL by viral proteins XREF_BIBR .	However, levels of its immediate downstream target IKKalpha were elevated and p100 accumulated already before BAFF mediated BAFFR ligation (XREF_FIG), possibly reflecting pre-activation of the NF-kappaB pathway in B-LCL by viral proteins XREF_BIBR.	13	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFFR	BAFFR	BAFFR	16	17	18	19
The TNF superfamily ligands , B-cell-activating factor ( BAFF ) and a proliferation inducing ligand ( APRIL ) , activate anti-apoptotic pathways , including phosphatidylinositol-3 kinase ( PI3K )/Akt , through binding to TACI , BAFF receptor , and B cell maturation protein A ( BCMA ) and are major B cell survival factors , some of which play an important role in multiple myeloma .	The TNF superfamily ligands, B-cell-activating factor (BAFF) and a proliferation inducing ligand (APRIL), activate anti-apoptotic pathways, including phosphatidylinositol-3 kinase (PI3K)/Akt, through binding to TACI, BAFF receptor, and B cell maturation protein A (BCMA) and are major B cell survival factors, some of which play an important role in multiple myeloma.	5	37	activate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	B-cell-activating factor	B-cell-activating factor	B-cell-activating factor	BAFF receptor	BAFF receptor	BAFF receptor	5	7	35	37
Since BAFFR is critical for the selection and survival of mature B cells , the elevated serum BAFF observed in SLE is likely promoting the survival of mature autoreactive B cells by inducing chronic BAFFR signaling [ XREF_BIBR - XREF_BIBR ] .	Since BAFFR is critical for the selection and survival of mature B cells, the elevated serum BAFF observed in SLE is likely promoting the survival of mature autoreactive B cells by inducing chronic BAFFR signaling [XREF_BIBR - XREF_BIBR].	14	35	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFFR	BAFFR	BAFFR	17	18	34	35
In summary , binding and activation of BAFFR by BAFF are distinct steps .	In summary, binding and activation of BAFFR by BAFF are distinct steps.	3	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	BAFFR	BAFFR	BAFFR	9	10	7	8
GA was also shown to reduce BAFF mRNA expression in the brain , and decrease the number of BAFF-R + B cells , but not the TACI + B cells in the spleen of EAE mice .	GA was also shown to reduce BAFF mRNA expression in the brain, and decrease the number of BAFF-R + B cells, but not the TACI + B cells in the spleen of EAE mice.	0	21	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAFF	GA was also shown to reduce BAFF mRNA expression	baff	BAFF-R	BAFF-R	baff-r	6	7	18	19
As described here , dual BCR and TLR signalling is crucial for the generation of short lived , extrafollicular plasmablasts in a process that is markedly facilitated by BAFF driven TACI signalling .	As described here, dual BCR and TLR signalling is crucial for the generation of short lived, extrafollicular plasmablasts in a process that is markedly facilitated by BAFF driven TACI signalling.	26	31	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	TACI	TACI	TACI	28	29	30	31
BAFF 60-mer , or membrane bound BAFF , might be required to activate TACI and possibly BCMA 20 .	BAFF 60-mer, or membrane bound BAFF, might be required to activate TACI and possibly BCMA 20.	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	TACI	TACI	TACI	0	1	13	14
In contrast to the mouse system , we find that BAFF trimer activates the human TACI receptor .	In contrast to the mouse system, we find that BAFF trimer activates the human TACI receptor.	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	TACI	TACI	TACI	10	11	15	16
Triggered by the finding that TACI and c-maf expressions correlate in TACI+ HMCL , we demonstrated that TACI activation influences c-maf expression : ( i ) activation of TACI by BAFF or APRIL increases c-maf , cyclin D2 , and integrin beta7 gene expressions in TACI+ HMCL , ( ii ) blocking of autocrine BAFF and APRIL stimulation in some TACI+ HMCL by the TACI-Fc fusion protein reduces c-maf , cyclin D2 , and integrin beta7 gene expression , ( iii ) nucleofection of siRNA to c-maf decreases c-maf mRNA levels and reduces the expression of cyclin D2 and integrin beta7 gene expressions , without affecting TACI expression We conclude that TACI activation can upregulate c-maf expression which , in turn , controls cyclin D2 , and integrin beta7 gene expression .	Triggered by the finding that TACI and c-maf expressions correlate in TACI+ HMCL, we demonstrated that TACI activation influences c-maf expression : (i) activation of TACI by BAFF or APRIL increases c-maf, cyclin D2, and integrin beta7 gene expressions in TACI+ HMCL, (ii) blocking of autocrine BAFF and APRIL stimulation in some TACI+ HMCL by the TACI-Fc fusion protein reduces c-maf, cyclin D2, and integrin beta7 gene expression, (iii) nucleofection of siRNA to c-maf decreases c-maf mRNA levels and reduces the expression of cyclin D2 and integrin beta7 gene expressions, without affecting TACI expression We conclude that TACI activation can upregulate c-maf expression which, in turn, controls cyclin D2, and integrin beta7 gene expression.	26	130	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	TACI	TACI	TACI	30	31	28	29
By showing increased BAFF production in TACI deficient mice , our data suggest that the conserved mTORC1 signaling observed in MZ B cells from TACI deficient mice stems from enhanced BAFF-R activity .	By showing increased BAFF production in TACI deficient mice, our data suggest that the conserved mTORC1 signaling observed in MZ B cells from TACI deficient mice stems from enhanced BAFF-R activity.	3	8	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	TACI	TACI	TACI	3	4	6	7
BCMA and TACI are also targeted by the ligand APRIL , but not BAFF R. All three receptors have been shown to lead to activation of NF-kappaB activity , but among them , only the BAFF R is known to activate the alternative pathway .	BCMA and TACI are also targeted by the ligand APRIL, but not BAFF R. All three receptors have been shown to lead to activation of NF-kappaB activity, but among them, only the BAFF R is known to activate the alternative pathway.	0	15	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	TACI	TACI	TACI	13	14	2	3
BAFF levels are increased in many patients with autoimmune disease ( including those with SLE , RA and systemic sclerosis ) , which suggests that BAFF driven TACI signalling may promote pathogenic plasmablast formation 40 , although this possibility has not yet been examined in humans .	BAFF levels are increased in many patients with autoimmune disease (including those with SLE, RA and systemic sclerosis), which suggests that BAFF driven TACI signalling may promote pathogenic plasmablast formation 40, although this possibility has not yet been examined in humans.	25	30	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	TACI	TACI	TACI	25	26	27	28
Additionally Pin1 plays an indispensable role in the ability of toll like receptors to mount an interferon dependent response in mice , a pathway also regulated by BAFF dependent activation of TACI [ XREF_BIBR - XREF_BIBR ] .	Additionally Pin1 plays an indispensable role in the ability of toll like receptors to mount an interferon dependent response in mice, a pathway also regulated by BAFF dependent activation of TACI [XREF_BIBR - XREF_BIBR].	27	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	TACI	TACI	TACI	27	28	31	32
Whereas TACI is known to activate the canonical NFkappaB pathway , recent studies have also implicated BAFF-R and shown that BAFF stimulation of Taci -/- B cells also leads to IkappaBalpha degradation and canonical pathway activation .	Whereas TACI is known to activate the canonical NFkappaB pathway, recent studies have also implicated BAFF-R and shown that BAFF stimulation of Taci -/- B cells also leads to IkappaBalpha degradation and canonical pathway activation.	20	24	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	Taci	Taci	Taci	20	21	23	24
Candidate signaling molecules on B cells that may be involved in MZ B cell development are the TNF receptor family members , transmembrane activator and calcium modulator and cyclophilin ligand interactor ( TACI ) and B cell maturation antigen ( BCMA ) 27 , which are triggered by B lymphocyte stimulator ( BlyS )/B cell activator belonging to the TNF family ( BAFF ) 2829 .	Candidate signaling molecules on B cells that may be involved in MZ B cell development are the TNF receptor family members, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) 27, which are triggered by B lymphocyte stimulator (BlyS)/B cell activator belonging to the TNF family (BAFF) 2829.	30	55	triggered	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	B lymphocyte stimulator	B lymphocyte stimulator	B lymphocyte stimulator	TACI	TACI	TACI	48	51	32	33
Therefore , signaling through TACI by BAFF and/or APRIL may lead to increased expansion , differentiation , and survival of B cells .	Therefore, signaling through TACI by BAFF and/or APRIL may lead to increased expansion, differentiation, and survival of B cells.	2	8	signaling	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	BAFF	BAFF	BAFF	TACI	TACI	TACI	6	7	4	5
Our results show that NF-kB activation only occurs when TNFR2 is unable to induce TRAF2 depletion ( Fig XREF_FIG ) .	Our results show that NF-kB activation only occurs when TNFR2 is unable to induce TRAF2 depletion (Fig XREF_FIG).	9	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	9	10	14	15
Then , TRAF2 degradation induced by TNFR2 contributes to inhibition of NF-kappaB and TRAF2 dependent JNK signaling , but TNFR2 is still able to activate a TRAF2 independent JNK pathway , which is responsible for TNFR2 dependent cell death in some cell types .	Then, TRAF2 degradation induced by TNFR2 contributes to inhibition of NF-kappaB and TRAF2 dependent JNK signaling, but TNFR2 is still able to activate a TRAF2 independent JNK pathway, which is responsible for TNFR2 dependent cell death in some cell types.	19	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	19	20	26	27
Collectively , these results provide evidence that the TNFR2 signaling pathway is involved in regulating AICD and that TRAF2 depletion induced by TNFR2 is critical to this process .	Collectively, these results provide evidence that the TNFR2 signaling pathway is involved in regulating AICD and that TRAF2 depletion induced by TNFR2 is critical to this process.	18	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	22	23	18	19
Taken together , these results show that TNFR2 induced TRAF2 depletion has a negative regulatory role on TNFR1 signalling and that the primary action of this regulatory role is the inhibition of NF-kB .	Taken together, these results show that TNFR2 induced TRAF2 depletion has a negative regulatory role on TNFR1 signalling and that the primary action of this regulatory role is the inhibition of NF-kB.	7	10	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	7	8	9	10
TNFR2 induced TRAF2 depletion may lead to cell death because survival and proliferative signals triggered by both TNFR1 and TNFR2 depend on TRAF2 .	TNFR2 induced TRAF2 depletion may lead to cell death because survival and proliferative signals triggered by both TNFR1 and TNFR2 depend on TRAF2.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	0	1	2	3
We next addressed the question of whether TNFR2 induced TRAF2 depletion affects the activation of NF-kB by TNFR1 .	We next addressed the question of whether TNFR2 induced TRAF2 depletion affects the activation of NF-kB by TNFR1.	7	10	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	7	8	9	10
To further confirm that the cytotoxicity observed after the combined treatment with RANKL and sTNF was due to TRAF2 depletion induced by TNFR2 we generated the L929 derived cell line named L929-RANK-TNFR2-Delta343 .	To further confirm that the cytotoxicity observed after the combined treatment with RANKL and sTNF was due to TRAF2 depletion induced by TNFR2 we generated the L929 derived cell line named L929-RANK-TNFR2-Delta343.	18	23	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	22	23	18	19
TNFR2 activates the transcription factor NF-kappaB presumably by recruiting TRAF1 and TRAF2 proteins to the receptor .	TNFR2 activates the transcription factor NF-kappaB presumably by recruiting TRAF1 and TRAF2 proteins to the receptor.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	0	1	11	12
All these results show once again that TRAF2 binding ( and hence activation of NF-kB ) and TRAF2 depletion are independent features of TNFR2 and also strongly suggest that TRAF2 depletion induced by TNFR2 is a key event in TNFR1-TNFR2 functional crosstalk .	All these results show once again that TRAF2 binding (and hence activation of NF-kB) and TRAF2 depletion are independent features of TNFR2 and also strongly suggest that TRAF2 depletion induced by TNFR2 is a key event in TNFR1-TNFR2 functional crosstalk.	29	34	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	33	34	29	30
Upon TNFR2 stimulation TRAF2 translocates to a new compartment [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] where the adaptor protein is K48 linked , ubiquitinated and finally degraded by the proteasome [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] although it has been also proposed that TRAF2 degradation takes place in the lysosome [ XREF_BIBR ] , being cIAP1 identified in both cases as the E3 ligase responsible for TRAF2 degradation .	Upon TNFR2 stimulation TRAF2 translocates to a new compartment [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] where the adaptor protein is K48 linked, ubiquitinated and finally degraded by the proteasome [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] although it has been also proposed that TRAF2 degradation takes place in the lysosome [XREF_BIBR], being cIAP1 identified in both cases as the E3 ligase responsible for TRAF2 degradation.	0	4	stimulation	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	1	2	3	4
TRAF2 , also stimulated by the TNFR2 agonist , is also required for TNF mediated activation of NFkB and the MAPK8 and JNK pathway which associates with cIAP2 .	TRAF2, also stimulated by the TNFR2 agonist, is also required for TNF mediated activation of NFkB and the MAPK8 and JNK pathway which associates with cIAP2.	0	11	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	6	7	0	1
We show that cells treated with both RANKL and sTNF are killed more efficiently than those treated with sTNF alone ( Fig XREF_FIG ) , indicating again that the activation of TNFR2 causing TRAF2 depletion is a biological mechanism to enhance TNFR1 cytotoxicity .	We show that cells treated with both RANKL and sTNF are killed more efficiently than those treated with sTNF alone (Fig XREF_FIG), indicating again that the activation of TNFR2 causing TRAF2 depletion is a biological mechanism to enhance TNFR1 cytotoxicity.	29	34	causing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	31	32	33	34
For all three aldehydes the increased expression of TNFR2 does not result in TRAF1 and TRAF2 activation , revealing the absence of these survival pathways .	For all three aldehydes the increased expression of TNFR2 does not result in TRAF1 and TRAF2 activation, revealing the absence of these survival pathways.	6	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	TNFR2	expression of TNFR2	tnfr2	TRAF2	TRAF2	traf2	8	9	15	16
Moreover , TNFR2 signaling was reported to lead to the degradation of TNF receptor associated factor 2 ( TRAF2 ) , which were important in the regulation of the receptor signaling .	Moreover, TNFR2 signaling was reported to lead to the degradation of TNF receptor associated factor 2 (TRAF2), which were important in the regulation of the receptor signaling.	2	23	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	2	3	18	19
Attempts to measure TNFalpha induced movement of the alternative pathway proteins c-Rel , RelB , and p52 were unsuccessful due to low abundance and poor antibody detection .	Attempts to measure TNFalpha induced movement of the alternative pathway proteins c-Rel, RelB, and p52 were unsuccessful due to low abundance and poor antibody detection.	2	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	c-Rel	c-Rel	c-Rel	3	4	11	12
Since TNFalpha is one of the activators of NF-kappaB including c-Rel and its expression was compromised upon GSI treatment in LPS and IFNgamma stimulated macrophages , we asked whether addition of exogenous TNFalpha would rescue the defective c-Rel activation in activated BMM treated with GSI .	Since TNFalpha is one of the activators of NF-kappaB including c-Rel and its expression was compromised upon GSI treatment in LPS and IFNgamma stimulated macrophages, we asked whether addition of exogenous TNFalpha would rescue the defective c-Rel activation in activated BMM treated with GSI.	29	38	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	c-Rel	c-Rel	c-Rel	32	33	37	38
For instance , TNF alpha induces five mammalian NF-kappaB and Rel proteins , c-Rel , NF-kappaB1 ( p50 and p105 ) , NF-kappaB2 ( p52 and p100 ) , RelA and p65 and RelB .	For instance, TNF alpha induces five mammalian NF-kappaB and Rel proteins, c-Rel, NF-kappaB1 (p50 and p105), NF-kappaB2 (p52 and p100), RelA and p65 and RelB.	3	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Rel	Rel	Rel	3	4	10	11
The subunits of NF-kappaB activated by TNF and WNV differed , WNV activated a p65 and p50 NF and kappaB complex while TNF activated NF-kappaB was composed of p65 , p50 , and c-Rel .	The subunits of NF-kappaB activated by TNF and WNV differed, WNV activated a p65 and p50 NF and kappaB complex while TNF activated NF-kappaB was composed of p65, p50, and c-Rel.	22	34	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	c-Rel	c-Rel	c-Rel	22	23	33	34
These observations suggest that TNF might stimulate the transactivation of c-Rel independently of its O GlcNAcylation status .	These observations suggest that TNF might stimulate the transactivation of c-Rel independently of its O GlcNAcylation status.	4	16	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	c-Rel	c-Rel	c-Rel	4	5	10	11
In contrast to the TNFalpha mechanism , which strongly induces Rel A x NF-kappaB1 binding , Sar1 AII selectively activates a heterogenous pattern of NF-kappaB1 binding .	In contrast to the TNFalpha mechanism, which strongly induces Rel A x NF-kappaB1 binding, Sar1 AII selectively activates a heterogenous pattern of NF-kappaB1 binding.	4	11	induces	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Rel	Rel	Rel	4	5	10	11
Immunohistochemical staining of HMEC-1 and A549 cells revealed TNFalpha stimulated nuclear localization of Rel A , whereas no translocation of Rel A was detected in either cell type stimulated by H2O2 .	Immunohistochemical staining of HMEC-1 and A549 cells revealed TNFalpha stimulated nuclear localization of Rel A, whereas no translocation of Rel A was detected in either cell type stimulated by H2O2.	7	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Rel	Rel	Rel	8	9	13	14
TNF-alpha , which is able to activate the NF-kappaB pathway , is nonetheless unable to activate c-Rel particularly ( XREF_FIG C ) , thus explaining to some extent its inability to substitute for LPS in the transcriptional regulation of IL-12 p35 ( XREF_FIG B ) .	TNF-alpha, which is able to activate the NF-kappaB pathway, is nonetheless unable to activate c-Rel particularly (XREF_FIG C), thus explaining to some extent its inability to substitute for LPS in the transcriptional regulation of IL-12 p35 (XREF_FIG B).	0	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	c-Rel	c-Rel	c-Rel	0	1	16	17
Moreover , TNF-alpha has been shown to activate NF-kappaB and Rel through the activation of Akt XREF_BIBR , XREF_BIBR .	Moreover, TNF-alpha has been shown to activate NF-kappaB and Rel through the activation of Akt XREF_BIBR, XREF_BIBR.	2	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Rel	Rel	Rel	2	3	10	11
Electrophoretic mobility shift assays revealed that tumor necrosis factor or phorbol 12-myristate 13-acetate induced nuclear factor-kappaB binding complexes of Rel A and p50 in E1A and control transfectants , whereas LPS was effective only in E1A transfectants .	Electrophoretic mobility shift assays revealed that tumor necrosis factor or phorbol 12-myristate 13-acetate induced nuclear factor-kappaB binding complexes of Rel A and p50 in E1A and control transfectants, whereas LPS was effective only in E1A transfectants.	6	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	Rel	Rel	Rel	6	9	19	20
Consistent with the expression studies , RSV but not TNFalpha induction of Rel A and p50 were markedly inhibited by NAC , providing a mechanism by which TNFalpha and RSV can differentially activate chemokine gene expression via NF-kappaB .	Consistent with the expression studies, RSV but not TNFalpha induction of Rel A and p50 were markedly inhibited by NAC, providing a mechanism by which TNFalpha and RSV can differentially activate chemokine gene expression via NF-kappaB.	9	13	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Rel	Rel	Rel	9	10	12	13
Both NAC and DEX were unable to inhibit TNFalpha induction of either Rel A or p50 .	Both NAC and DEX were unable to inhibit TNFalpha induction of either Rel A or p50.	8	13	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Rel	Rel	Rel	8	9	12	13
Transient reconstitution of c-Rel in TNF treated cells restored transcriptional activation of a c-Rel and AP-1-dependent reporter to untreated control cell levels but not to those of control cells also over-expressing c-Rel .	Transient reconstitution of c-Rel in TNF treated cells restored transcriptional activation of a c-Rel and AP-1-dependent reporter to untreated control cell levels but not to those of control cells also over-expressing c-Rel.	3	16	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	c-Rel	c-Rel	c-Rel	5	6	13	14
However , while IL-1beta and TNF-alpha both induced nuclear binding of the Rel proteins p50 and p65 to an NF-kappaB consensus oligonucleotide in gel shift assays and caused transient degradation of inhibitor of NF-kappaB-alpha ( IkappaB-alpha ) in the cytoplasm of myofibroblasts , only IL-1beta upregulated PDGF-Ralpha .	However, while IL-1beta and TNF-alpha both induced nuclear binding of the Rel proteins p50 and p65 to an NF-kappaB consensus oligonucleotide in gel shift assays and caused transient degradation of inhibitor of NF-kappaB-alpha (IkappaB-alpha) in the cytoplasm of myofibroblasts, only IL-1beta upregulated PDGF-Ralpha.	3	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Rel	Rel	Rel	5	6	12	13
APRIL induces TACI dependent proliferation and production of IgG1 in murine splenic B cells .	APRIL induces TACI dependent proliferation and production of IgG1 in murine splenic B cells.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APRIL	APRIL	APRIL	TACI	TACI	TACI	0	1	2	3
APRIL binds to two of three B-cell activating factor ( BAFF ) receptors ( B-cell maturation antigen and transmembrane activator and CAML interactor [ TACI ] ) and is supposed to have a regulatory role in B-cell proliferation .	APRIL binds to two of three B-cell activating factor (BAFF) receptors (B-cell maturation antigen and transmembrane activator and CAML interactor [TACI]) and is supposed to have a regulatory role in B-cell proliferation.	0	31	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APRIL	APRIL	APRIL	TACI	TACI	TACI	0	1	24	25
In support of murine studies , we find that APRIL induces proliferation of human patient follicular lymphoma ( FL ) B cells in a TACI dependent manner .	In support of murine studies, we find that APRIL induces proliferation of human patient follicular lymphoma (FL) B cells in a TACI dependent manner.	9	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APRIL	APRIL	APRIL	TACI	TACI	TACI	9	10	24	25
APRIL drives TACI mediated switching from IgA1 to IgA2 through the Toll like receptor ( TLR ) [ XREF_BIBR ] .	APRIL drives TACI mediated switching from IgA1 to IgA2 through the Toll like receptor (TLR) [XREF_BIBR].	0	3	drives	Positive_activation_token_1_verb	Positive_activation	Positive_activation	APRIL	APRIL	APRIL	TACI	TACI	TACI	0	1	2	3
Given the observation that BAFF-R engagement can activate CSR , it was important to rule out the possibility that APRIL mediated switching involved , in addition to TACI , engagement of BAFF-R by BAFF which may be endogenously made by B cells .	Given the observation that BAFF-R engagement can activate CSR, it was important to rule out the possibility that APRIL mediated switching involved, in addition to TACI, engagement of BAFF-R by BAFF which may be endogenously made by B cells.	19	38	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APRIL	APRIL	APRIL	TACI	TACI	TACI	19	20	27	28
APRIL stimulation caused naive B cells from TACI +/+ mice , but not TACI -/- mice , to secrete IgG1 ( XREF_FIG ) .	APRIL stimulation caused naive B cells from TACI +/+ mice, but not TACI -/- mice, to secrete IgG1 (XREF_FIG).	0	15	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APRIL	APRIL	APRIL	TACI	TACI	TACI	0	1	13	14
TACI activation by APRIL requires ligand multimerization , suggesting a requirement for receptor clustering or for a certain signaling threshold to be reached [ XREF_BIBR ] .	TACI activation by APRIL requires ligand multimerization, suggesting a requirement for receptor clustering or for a certain signaling threshold to be reached [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	APRIL	APRIL	APRIL	TACI	TACI	TACI	3	4	0	1
Rapamycin induced a similar effect in mice expressing a human APRIL encoding TNFSF13 transgene ( TNFSF13-Tg ) that strongly activates TACI 42 .	Rapamycin induced a similar effect in mice expressing a human APRIL encoding TNFSF13 transgene (TNFSF13-Tg) that strongly activates TACI 42.	12	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFSF13	TNFSF13	TNFSF13	TACI	TACI	TACI	12	13	20	21
Collectively , our results show that TNFR1 induced TRADD- and FADD dependent apoptosis of Sharpin deficient keratinocytes triggers the chronic proliferative dermatitis phenotype in Sharpin cpdm and cpdm mice .	Collectively, our results show that TNFR1 induced TRADD- and FADD dependent apoptosis of Sharpin deficient keratinocytes triggers the chronic proliferative dermatitis phenotype in Sharpin cpdm and cpdm mice.	6	12	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFR1	TNFR1	TNFR1	TRADD-	TRADD-	TRADD-	6	7	8	9
TNFR1 stimulation leads to the rapid assembly of a complex ( complex I ) comprising TNFR1 , TRADD , RIPK1 , and TRAF2 .	TNFR1 stimulation leads to the rapid assembly of a complex (complex I) comprising TNFR1, TRADD, RIPK1, and TRAF2.	0	18	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFR1	TNFR1	TNFR1	TRADD	TRADD	TRADD	0	1	17	18
TNFR1 activates canonical NFkappaB1 by recruiting and activating TRADD , leading to the formation of a complex consisting of RIP1 , TRAF2 or 5 , and cIAP1 or 2 .	TNFR1 activates canonical NFkappaB1 by recruiting and activating TRADD, leading to the formation of a complex consisting of RIP1, TRAF2 or 5, and cIAP1 or 2.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFR1	TNFR1	TNFR1	TRADD	TRADD	TRADD	0	1	8	9
TNFR1 internalization activates caspase-8 and -3 by engaging TRADD , RIP-1 and FADD , thereby forming a signalosome engaged in the extrinsic pathway [ XREF_BIBR ] .	TNFR1 internalization activates caspase-8 and -3 by engaging TRADD, RIP-1 and FADD, thereby forming a signalosome engaged in the extrinsic pathway [XREF_BIBR].	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFR1	TNFR1	TNFR1	TRADD	TRADD	TRADD	0	1	8	9
Genetic and biochemical studies , using fibroblasts from gene targeted mice , have shown that TNF-R1 triggers apoptosis by binding the adaptor proteins TRADD and FADD , which facilitate recruitment and activation of the aspartate specific cysteine protease , caspase-8 .	Genetic and biochemical studies, using fibroblasts from gene targeted mice, have shown that TNF-R1 triggers apoptosis by binding the adaptor proteins TRADD and FADD, which facilitate recruitment and activation of the aspartate specific cysteine protease, caspase-8.	15	28	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-R1	TNF-R1	TNF-R1	TRADD	TRADD	TRADD	15	16	23	24
Here we show that the skin inflammation in Sharpin cpdm and cpdm mice is triggered by TNFR1 mediated TRADD- and FADD dependent apoptosis of keratinocytes .	Here we show that the skin inflammation in Sharpin cpdm and cpdm mice is triggered by TNFR1 mediated TRADD- and FADD dependent apoptosis of keratinocytes.	14	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	TNFR1	TNFR1	TNFR1	TRADD-	TRADD-	TRADD-	16	17	18	19
Although TNFR1 deficiency did not prevent liver damage in NEMO LPC-KO mice , it remains unclear whether TNFR1 signaling might contribute to TRADD dependent hepatocyte death in mice lacking both NEMO and RIPK1 in LPCs .	Although TNFR1 deficiency did not prevent liver damage in NEMO LPC-KO mice, it remains unclear whether TNFR1 signaling might contribute to TRADD dependent hepatocyte death in mice lacking both NEMO and RIPK1 in LPCs.	17	23	contribute	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TNFR1	TNFR1	TNFR1	TRADD	TRADD	TRADD	17	18	22	23
Under some conditions , the intracellular tails of TNFR1 also induce apoptosis through cytosolic complex IIA ( TRADD , Fas associated protein with death domain ( FADD ) , and caspase-8 ) and IIB ( RIPK1 , RIPK3 , FADD , caspase-8 , and cellular FLICE-inhibitory protein-L ( cFLIP L ) ) , and in particular conditions or cells , necroptosis can be executed by necrosomes including RIPK1 , RIPK3 , and MLKL [ XREF_BIBR ] .	Under some conditions, the intracellular tails of TNFR1 also induce apoptosis through cytosolic complex IIA (TRADD, Fas associated protein with death domain (FADD), and caspase-8) and IIB (RIPK1, RIPK3, FADD, caspase-8, and cellular FLICE-inhibitory protein-L (cFLIP L)), and in particular conditions or cells, necroptosis can be executed by necrosomes including RIPK1, RIPK3, and MLKL [XREF_BIBR].	6	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFR1	TNFR1	TNFR1	TRADD	TRADD	TRADD	8	9	17	18
In summary , PIK3CD transcripts with 5 '-UTRs containing exons -2 c , -2 d or -2 e are detectable at low levels in unstimulated cells and are further induced by TNFalpha stimulation in ECs and synovial fibroblasts , but not in leucocytes .	In summary, PIK3CD transcripts with 5 '-UTRs containing exons -2 c, -2 d or -2 e are detectable at low levels in unstimulated cells and are further induced by TNFalpha stimulation in ECs and synovial fibroblasts, but not in leucocytes.	3	32	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	PIK3CD	PIK3CD	PIK3CD	31	32	3	4
Indeed , TNFalpha stimulation of HUVECs and the human endothelium derived cell line EA.hy926 increased the levels of p110delta protein ( XREF_FIG A ) and mRNA ( XREF_FIG B ) .	Indeed, TNFalpha stimulation of HUVECs and the human endothelium derived cell line EA.hy926 increased the levels of p110delta protein (XREF_FIG A) and mRNA (XREF_FIG B).	2	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	p110delta	p110delta	p110delta	2	3	18	19
It is possible , however , that activity from the TNFalpha induced p110delta might be required to synergize with other PI3K isoforms as is the case in HepG2 cells where insulin stimulated PKB phosphorylation is dependent on both p110alpha and p110delta activity [ XREF_BIBR ] .	It is possible, however, that activity from the TNFalpha induced p110delta might be required to synergize with other PI3K isoforms as is the case in HepG2 cells where insulin stimulated PKB phosphorylation is dependent on both p110alpha and p110delta activity [XREF_BIBR].	7	17	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	p110delta	p110delta	p110delta	10	11	12	13
We next used 5 ' RACE to identify the structure of the 5 '-UTR of PIK3CD mRNA transcripts induced by TNFalpha stimulation of HUVECs and EA.hy926 cells ( XREF_FIG A ) .	We next used 5 ' RACE to identify the structure of the 5 '-UTR of PIK3CD mRNA transcripts induced by TNFalpha stimulation of HUVECs and EA.hy926 cells (XREF_FIG A).	15	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	PIK3CD	PIK3CD	PIK3CD	20	21	15	16
Unfortunately , the lack of specific and high-affinity antibodies against p110delta , together with the low expression of p110delta in ECs , prevented our attempts to examine the subcellular localization of TNFalpha induced p110delta .	Unfortunately, the lack of specific and high-affinity antibodies against p110delta, together with the low expression of p110delta in ECs, prevented our attempts to examine the subcellular localization of TNFalpha induced p110delta.	29	34	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	p110delta	p110delta	p110delta	31	32	33	34
Activation of JNK pathway contributes to the induction of tissue degrading enzymes , whereas the induction of PI3Kdelta by TNFalpha results in the activation of Akt , which in turn leads to increased growth and survival of FLS .	Activation of JNK pathway contributes to the induction of tissue degrading enzymes, whereas the induction of PI3Kdelta by TNFalpha results in the activation of Akt, which in turn leads to increased growth and survival of FLS.	15	20	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	PI3Kdelta	PI3Kdelta	PI3Kdelta	19	20	17	18
Our attempts to uncover a function for TNFalpha induced p110delta in ECs or synovial fibroblasts were not successful , as p110delta inhibition did not affect survival , migration or production of IL-6 or IL-8 in TNFalpha stimulated HUVECs , or production of IL-6 , IL-8 or CCL2 [ chemokine ( C-C motif ) ligand 2 ] in TNFalpha stimulated synovial fibroblasts ( results not shown ) .	Our attempts to uncover a function for TNFalpha induced p110delta in ECs or synovial fibroblasts were not successful, as p110delta inhibition did not affect survival, migration or production of IL-6 or IL-8 in TNFalpha stimulated HUVECs, or production of IL-6, IL-8 or CCL2 [chemokine (C-C motif) ligand 2] in TNFalpha stimulated synovial fibroblasts (results not shown).	5	17	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	p110delta	p110delta	p110delta	7	8	9	10
In NIH-3T3 fibroblasts , which contain very low levels of endogenous p110delta compared to leukocytes , p110delta could not be induced by TNF , the proteasome inhibitor PS-341 , UV irradiation , osmotic stress or the glucocorticoid dexamethasone ( data not shown ) .	In NIH-3T3 fibroblasts, which contain very low levels of endogenous p110delta compared to leukocytes, p110delta could not be induced by TNF, the proteasome inhibitor PS-341, UV irradiation, osmotic stress or the glucocorticoid dexamethasone (data not shown).	16	39	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	p110delta	p110delta	p110delta	22	23	16	17
Alternatively , TNFalpha induced p110delta activity could be functionally important in a subcellularly localized manner and thus would not require expression levels similar to p110alpha or p110beta .	Alternatively, TNFalpha induced p110delta activity could be functionally important in a subcellularly localized manner and thus would not require expression levels similar to p110alpha or p110beta.	2	19	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	p110delta	p110delta	p110delta	2	3	4	5
Here we report that integrin ligation acts permissive for TNF induced protein kinase B ( PKB and Akt ) but not nuclear factor ( NF )-kappaB activation .	Here we report that integrin ligation acts permissive for TNF induced protein kinase B (PKB and Akt) but not nuclear factor (NF)-kappaB activation.	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	protein kinase B	protein kinase B	protein kinase B	9	10	11	14
Moreover , the TNF derived TIP peptide , which upregulates sodium uptake in H441 cells both in the presence and in the absence of LLO , is able to restore the activation status of Sgk-1 , but not Akt-1 , and then only at a much later time point than its effects on PKC-alpha activation and sodium uptake .	Moreover, the TNF derived TIP peptide, which upregulates sodium uptake in H441 cells both in the presence and in the absence of LLO, is able to restore the activation status of Sgk-1, but not Akt-1, and then only at a much later time point than its effects on PKC-alpha activation and sodium uptake.	2	48	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Akt-1	Akt-1	Akt-1	3	4	38	39
The activation of phosphatidylinositol ( PI ) 3-kinase and Akt and protein kinase B ( PKB ) by tumor necrosis factor ( TNF )-alpha and their roles on stimulation of protein synthesis were investigated in cultured neonatal rat cardiac myocytes .	The activation of phosphatidylinositol (PI) 3-kinase and Akt and protein kinase B (PKB) by tumor necrosis factor (TNF)-alpha and their roles on stimulation of protein synthesis were investigated in cultured neonatal rat cardiac myocytes.	1	21	activation	Positive_activation_syntax_1_noun	Positive_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	protein kinase B	protein kinase B	protein kinase B	18	21	11	14
TNFalpha activates PI3Kgamma in endothelial cells leading to oxidant generation and NF-kappaB activation .	TNFalpha activates PI3Kgamma in endothelial cells leading to oxidant generation and NF-kappaB activation.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	PI3Kgamma	PI3Kgamma	PI3Kgamma	0	1	2	3
How TNFalpha receptor signals to increase PI3Kgamma , NF-kappaB , and ICAM-1 expression remains unknown .	How TNFalpha receptor signals to increase PI3Kgamma, NF-kappaB, and ICAM-1 expression remains unknown.	1	11	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	PI3Kgamma	PI3Kgamma	PI3Kgamma	1	2	6	7
Tumour necrosis factor ( TNF ) has been shown to activate PI3Kgamma leading to events that subsequently cause decreased cardiac function , associated with superoxide radical production .	Tumour necrosis factor (TNF) has been shown to activate PI3Kgamma leading to events that subsequently cause decreased cardiac function, associated with superoxide radical production.	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	PI3Kgamma	PI3Kgamma	PI3Kgamma	4	5	11	12
Since PI3K inhibition reduces GRK2 recruitment and beta 2 AR phosphorylation , we assessed whether PI3Kgamma is activated in Myo-Tg mice and in cells treated with TNFalpha .	Since PI3K inhibition reduces GRK2 recruitment and beta 2 AR phosphorylation, we assessed whether PI3Kgamma is activated in Myo-Tg mice and in cells treated with TNFalpha.	15	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	PI3Kgamma	PI3Kgamma	PI3Kgamma	26	27	15	16
Adhesion dependent , TNF stimulated ROS generation by neutrophils requires SFKs but is independent of PI3Kgamma .	Adhesion dependent, TNF stimulated ROS generation by neutrophils requires SFKs but is independent of PI3Kgamma.	3	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	PI3Kgamma	PI3Kgamma	PI3Kgamma	3	4	15	16
This would suggest that BAFF and APRIL mediated survival of plasma cells is controlled by BAFF-R or TACI in the absence of BCMA .	This would suggest that BAFF and APRIL mediated survival of plasma cells is controlled by BAFF-R or TACI in the absence of BCMA.	4	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APRIL	APRIL	APRIL	BCMA	BCMA	BCMA	6	7	22	23
This suggestion is supported by data from experiments in mice showing that BCMA activation by BLyS and APRIL is mandatory for plasma cell differentiation ( O'Connor et al , 2004 ) , and that atacicept treatment can reduce the numbers of both mature B cells and plasma cells ( Ramanujam et al , 2006 ; Benson et al , 2008 ) .	This suggestion is supported by data from experiments in mice showing that BCMA activation by BLyS and APRIL is mandatory for plasma cell differentiation (O'Connor et al, 2004), and that atacicept treatment can reduce the numbers of both mature B cells and plasma cells (Ramanujam et al, 2006; Benson et al, 2008).	12	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	APRIL	APRIL	APRIL	BCMA	BCMA	BCMA	17	18	12	13
However , the immunocytochemical demonstration of APRIL in pyramidal cells raised the possibility that these cells secrete APRIL in culture which could activate BCMA .	However, the immunocytochemical demonstration of APRIL in pyramidal cells raised the possibility that these cells secrete APRIL in culture which could activate BCMA.	16	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	APRIL	APRIL	APRIL	BCMA	BCMA	BCMA	17	18	23	24
TNFR1 stimulation causes activation of NF-kappaB , p38alpha , and its downstream effector kinase MK2 , thereby promoting transcription , mRNA stabilization , and translation of target genes .	TNFR1 stimulation causes activation of NF-kappaB, p38alpha, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes.	0	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFR1	TNFR1	TNFR1	p38alpha	p38alpha	p38alpha	0	1	7	8
Activation of TNFR1 but not TNFR2 robustly upregulated A20 and TRAF1 in TNF-knockout macrophages .	Activation of TNFR1 but not TNFR2 robustly upregulated A20 and TRAF1 in TNF-knockout macrophages.	0	11	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFR2	TNFR2	TNFR2	TRAF1	TRAF1	TRAF1	5	6	10	11
Neopterin precursors are formed when IFN-gamma , endotoxins , TNF and IFN-alpha activate GTP-CH-I within macrophages .	Neopterin precursors are formed when IFN-gamma, endotoxins, TNF and IFN-alpha activate GTP-CH-I within macrophages.	5	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	GTP-CH-I	GTP-CH-I	GTP-CH-I	9	10	13	14
In addition , TNF-alpha elicits GTP cyclohydrolase 1 that furnishes tetrahydrobiopterin ( BH 4 ) as an essential cofactor for NOS2 catalysis and induces argininosuccinate synthetase 1 and cationic amino acid transporter 2 ( CAT-2 ) to regenerate and import the NOS2 substrate , L-arginine , respectively .	In addition, TNF-alpha elicits GTP cyclohydrolase 1 that furnishes tetrahydrobiopterin (BH 4) as an essential cofactor for NOS2 catalysis and induces argininosuccinate synthetase 1 and cationic amino acid transporter 2 (CAT-2) to regenerate and import the NOS2 substrate, L-arginine, respectively.	3	8	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	GTP cyclohydrolase 1	GTP cyclohydrolase 1	GTP cyclohydrolase 1	3	4	5	8
Among them , only TNFalpha augmented PIK3CA promoter activity in SP but not in NSP cells , indicating NF-kappaB as distinct activator of PIK3CA in SP cells .	Among them, only TNFalpha augmented PIK3CA promoter activity in SP but not in NSP cells, indicating NF-kappaB as distinct activator of PIK3CA in SP cells.	3	8	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	PIK3CA	PIK3CA	PIK3CA	4	5	6	7
Alternatively , if one assumes that TNF is the major effecter in carrageenan induced inflammation , 15 this may represent a multi phased response as TNF induced PI3Kalpha mediated activity in endothelial cells in vitro has an early peak , 10 to 30 minutes after injection and then falls off before a second phase of Akt phosphorylation and junctional changes .	Alternatively, if one assumes that TNF is the major effecter in carrageenan induced inflammation, 15 this may represent a multi phased response as TNF induced PI3Kalpha mediated activity in endothelial cells in vitro has an early peak, 10 to 30 minutes after injection and then falls off before a second phase of Akt phosphorylation and junctional changes.	19	29	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	PI3Kalpha	PI3Kalpha	PI3Kalpha	25	26	27	28
Our preliminary result suggested that TNF-alpha induced up regulation of wild type PIK3CA promoter was lost in MPFT-4 construct ( data not shown ) and further experiments are ongoing .	Our preliminary result suggested that TNF-alpha induced up regulation of wild type PIK3CA promoter was lost in MPFT-4 construct (data not shown) and further experiments are ongoing.	5	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	PIK3CA	PIK3CA	PIK3CA	5	6	12	13
TRAIL-R1 and TRAIL-R2 induce FADD dependent apoptosis and activate the NF-kappaB pathway XREF_BIBR .	TRAIL-R1 and TRAIL-R2 induce FADD dependent apoptosis and activate the NF-kappaB pathway XREF_BIBR.	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAIL-R2	TRAIL-R2	TRAIL-R2	FADD	FADD	FADD	2	3	4	5
Secondly , simultaneous knockdown of Akt isoforms Akt1 and Akt2 using siRNAs protected cells from necroptosis induced by both zVAD.fmk and TNFalpha ( XREF_FIG ) .	Secondly, simultaneous knockdown of Akt isoforms Akt1 and Akt2 using siRNAs protected cells from necroptosis induced by both zVAD.fmk and TNFalpha (XREF_FIG).	3	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt2	Akt2	Akt2	21	22	9	10
In this study , we show that AKT2 in epithelial cells is activated by UV-C irradiation , heat shock , and hyperosmolarity as well as by tumor necrosis factor alpha ( TNFalpha ) through a phosphatidylinositol 3-kinase-dependent pathway .	In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor alpha (TNFalpha) through a phosphatidylinositol 3-kinase-dependent pathway.	7	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	AKT2	AKT2	AKT2	26	29	7	8
Activation of DR3 induces the formation of a signaling complex containing TRADD , TRAF2 , and RIP and activates the NF-kappaB pathway .	Activation of DR3 induces the formation of a signaling complex containing TRADD, TRAF2, and RIP and activates the NF-kappaB pathway.	0	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DR3	DR3	DR3	TRADD	TRADD	TRADD	2	3	11	12
Finally , TNFSF4 expressed on endothelial cells was reported to mediate the adhesion of TNFRSF4 expressing T-cells to vascular endothelial cells and the subsequent migration to distant inflammatory sites XREF_BIBR , suggesting an involvement of TNFSF4 in lymphocyte recruitment as well .	Finally, TNFSF4 expressed on endothelial cells was reported to mediate the adhesion of TNFRSF4 expressing T-cells to vascular endothelial cells and the subsequent migration to distant inflammatory sites XREF_BIBR, suggesting an involvement of TNFSF4 in lymphocyte recruitment as well.	2	15	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFSF4	TNFSF4 expressed	tnfsf4	TNFRSF4	TNFRSF4	tnfrsf4	2	3	14	15
We also show that overexpression of BCMA in 293 cells activates NF-kappa B , Elk-1 , the c-Jun N-terminal kinase , and the p38 mitogen activated protein kinase .	We also show that overexpression of BCMA in 293 cells activates NF-kappa B, Elk-1, the c-Jun N-terminal kinase, and the p38 mitogen activated protein kinase.	4	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BCMA	overexpression of BCMA	bcma	Elk-1	Elk-1	elk-1	6	7	14	15
The release of mitochondrial Cyt-c can be triggered through p53 induced activation of Bax in a caspase dependent Manner [ XREF_BIBR ] .	The release of mitochondrial Cyt-c can be triggered through p53 induced activation of Bax in a caspase dependent Manner [XREF_BIBR].	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	9	10	13	14
These observations are consistent with recent studies , which indicated that p53 elicits nontranscriptional Bax dependent prodeath activities either in the cytosol or directly at the mitochondria .	These observations are consistent with recent studies, which indicated that p53 elicits nontranscriptional Bax dependent prodeath activities either in the cytosol or directly at the mitochondria.	11	17	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	14	15
Furthermore , CP-31398 treatment increased expression of the p53 targets p21 and BAX .	Furthermore, CP-31398 treatment increased expression of the p53 targets p21 and BAX.	5	13	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	expression of the p53	p53	BAX	BAX	bax	8	9	12	13
The relationship between cell cycle and apoptosis was evident in the role of p53 , which is a well-known tumor suppressor gene that induces the target genes p21 WAF1 and CIP1 and BAX for cell cycle arrest and cell death [ XREF_BIBR ] .	The relationship between cell cycle and apoptosis was evident in the role of p53, which is a well-known tumor suppressor gene that induces the target genes p21 WAF1 and CIP1 and BAX for cell cycle arrest and cell death [XREF_BIBR].	11	33	induces	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	13	14	32	33
Similar to p53 , another apoptosis related protein , Bax , belonged to Bcl2 family , is known as the main effecter of apoptosis and the activity of Bax is enhanced in p53 induced tumor cell apoptosis , thus , Bax is activated by p53 to take part in multiple processes such as apoptotic program .	Similar to p53, another apoptosis related protein, Bax, belonged to Bcl2 family, is known as the main effecter of apoptosis and the activity of Bax is enhanced in p53 induced tumor cell apoptosis, thus, Bax is activated by p53 to take part in multiple processes such as apoptotic program.	40	46	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	44	45	40	41
Moreover , the pro apoptotic and pro autophagic effect of FK-16 required p53 dependent upregulation of Bax and downregulation of Bcl-2 .	Moreover, the pro apoptotic and pro autophagic effect of FK-16 required p53 dependent upregulation of Bax and downregulation of Bcl-2.	12	18	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	12	13	16	17
The increased stabilization of p53 upregulated the level of Bax and mitochondrial depolarization .	The increased stabilization of p53 upregulated the level of Bax and mitochondrial depolarization.	2	12	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	9	10
Paradoxically , the S100P induced p53 is unable to activate its transcriptional targets hdm2 , p21 WAF , and bax following the DNA damage .	Paradoxically, the S100P induced p53 is unable to activate its transcriptional targets hdm2, p21 WAF, and bax following the DNA damage.	5	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	5	6	19	20
p53 initiates apoptosis by down-regulating Bcl-2 XREF_BIBR and up-regulating Bax , Bid , PUMA , and NOXA XREF_BIBR - XREF_BIBR .	p53 initiates apoptosis by down-regulating Bcl-2 XREF_BIBR and up-regulating Bax, Bid, PUMA, and NOXA XREF_BIBR - XREF_BIBR.	0	19	up-regulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	9	10
In addition to mildly facilitating the ability of compounds to derepress BAX from BCL-xL , p53 also provides a death signal downstream of anti-apoptotic proteins inhibition that is independent from PUMA , as enhanced p53 can substitute for PUMA to promote BAX activation in response to BH3 mimetics [ XREF_BIBR ] .	In addition to mildly facilitating the ability of compounds to derepress BAX from BCL-xL, p53 also provides a death signal downstream of anti-apoptotic proteins inhibition that is independent from PUMA, as enhanced p53 can substitute for PUMA to promote BAX activation in response to BH3 mimetics [XREF_BIBR].	33	42	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	34	35	41	42
We also found that whereas Nutlin-3a , a compound that induces p53 expression XREF_BIBR , induced the expression of a pro apoptotic p53 target BAX but not of an anti-apoptotic p53 target TIGAR in mast cells , IgE mediated stimulation induced the expression of TIGAR but not of BAX in mast cells ( XREF_FIG ) .	We also found that whereas Nutlin-3a, a compound that induces p53 expression XREF_BIBR, induced the expression of a pro apoptotic p53 target BAX but not of an anti-apoptotic p53 target TIGAR in mast cells, IgE mediated stimulation induced the expression of TIGAR but not of BAX in mast cells (XREF_FIG).	15	25	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	22	23	24	25
Interestingly , p53 independent upregulation of Puma and Bax has been shown previously in other cancer types .	Interestingly, p53 independent upregulation of Puma and Bax has been shown previously in other cancer types.	2	9	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	8	9
It is noteworthy that AVN944 mediated induction of p53 mediators Bax , XREF_BIBR Bok and Noxa XREF_BIBR in LNCaP and 22Rv1 cells .	It is noteworthy that AVN944 mediated induction of p53 mediators Bax, XREF_BIBR Bok and Noxa XREF_BIBR in LNCaP and 22Rv1 cells.	6	16	mediators	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	10	11
Tumor suppressor activities of p53 have also been attributed to its capacity to target Bax at the mitochondria , thereby directly regulating pro apoptotic functions in a transcription independent fashion .	Tumor suppressor activities of p53 have also been attributed to its capacity to target Bax at the mitochondria, thereby directly regulating pro apoptotic functions in a transcription independent fashion.	2	15	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	14	15
Consistent with its p53 independent tumor suppressive function , the levels of p73 targets including BAX , PUMA , and Caspase 3 are significantly increased in Pot1b increment and increment ; p53 -/- spleens Pot1b deficient telomeres induce p73 to activate BAX and PUMA , as the expression of both of these pro apoptotic genes is abrogated in p53 -/-; p73 -/- MEFs .	Consistent with its p53 independent tumor suppressive function, the levels of p73 targets including BAX, PUMA, and Caspase 3 are significantly increased in Pot1b increment and increment; p53 -/- spleens Pot1b deficient telomeres induce p73 to activate BAX and PUMA, as the expression of both of these pro apoptotic genes is abrogated in p53 -/-; p73 -/- MEFs.	31	43	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	31	32	41	42
Cytoplasmic p53 is then released from the p53.Bcl-xL complex by PUMA to activate Bax directly .	Cytoplasmic p53 is then released from the p53.Bcl-xL complex by PUMA to activate Bax directly.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	13	14
During apoptosis , Bax is translocated from the cytosol to mitochondria where it triggers mitochondrial outer membrane permeabilization , and wild-type p53 was reported to activate Bax directly and induce a conformational change in Bax .	During apoptosis, Bax is translocated from the cytosol to mitochondria where it triggers mitochondrial outer membrane permeabilization, and wild-type p53 was reported to activate Bax directly and induce a conformational change in Bax.	20	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	21	22	26	27
However , while the pro apoptotic p53 target Bax was reduced following suppression of ERp57 , another pro apoptotic p53 target , PUMA , was strongly induced .	However, while the pro apoptotic p53 target Bax was reduced following suppression of ERp57, another pro apoptotic p53 target, PUMA, was strongly induced.	3	10	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	8	9
However , ectopic expression of the p53 point mutation L22Q and W23S , but not the proline rich domain deletion mutants 83-393 and DeltaProAE , could also sensitize p53 knockout HCT116 cells to MDA induced Bax activation and apoptosis , although all mutants failed to restore PUMA expression .	However, ectopic expression of the p53 point mutation L22Q and W23S, but not the proline rich domain deletion mutants 83-393 and DeltaProAE, could also sensitize p53 knockout HCT116 cells to MDA induced Bax activation and apoptosis, although all mutants failed to restore PUMA expression.	3	36	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	expression of the p53	p53	Bax	Bax	bax	6	7	35	36
This p53 segment may activate BAX directly or favor a suitable spatial organization of neighboring domains to trigger BAX activation via a transient interaction [ XREF_BIBR ] .	This p53 segment may activate BAX directly or favor a suitable spatial organization of neighboring domains to trigger BAX activation via a transient interaction [XREF_BIBR].	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	1	2	5	6
This RA induced apoptosis was accompanied by p53 independent up-regulation of endogenous p21 ( CIPI and Waf1 ) and Bax proteins , as well as activation of p34 ( cdc2 ) kinase , and increase of Rb2 protein level and phosphorylation pattern .	This RA induced apoptosis was accompanied by p53 independent up-regulation of endogenous p21 (CIPI and Waf1) and Bax proteins, as well as activation of p34 (cdc2) kinase, and increase of Rb2 protein level and phosphorylation pattern.	7	20	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	19	20
Similarly , p53 also failed to activate the Bax promoter in the absence of p73 ( lane 7 ) .	Similarly, p53 also failed to activate the Bax promoter in the absence of p73 (lane 7).	2	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	8	9
p53 can transcriptionally activate bax , a bcl-2 family member that promotes apoptosis .	p53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	0	1	4	5
While , p53 mediated transcriptional activation of BAX , PUMA , NOXA and/or p53AIP1 participates in the proper cell death response .	While, p53 mediated transcriptional activation of BAX, PUMA, NOXA and/or p53AIP1 participates in the proper cell death response.	2	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	2	3	7	8
Bax , a Bcl-2 family protein that resides in the cytosol and translocates to mitochondria after activation of apoptosis signaling , can be upregulated and transcriptionally activated by the p53 protein XREF_BIBR , XREF_BIBR .	Bax, a Bcl-2 family protein that resides in the cytosol and translocates to mitochondria after activation of apoptosis signaling, can be upregulated and transcriptionally activated by the p53 protein XREF_BIBR, XREF_BIBR.	0	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	29	30	0	1
p53 initiates apoptosis by transactivating Bax , Bid , Noxa , and Puma and antagonizes the function of Bcl2 and Bcl-xL .	p53 initiates apoptosis by transactivating Bax, Bid, Noxa, and Puma and antagonizes the function of Bcl2 and Bcl-xL.	0	14	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	5	6
Increased phosphorylation of p53 , in turn , led to induction of Bax protein , a key regulator of p53 dependent apoptotic cell death , as well as of caspase-7 cleavage in MCF7 cells .	Increased phosphorylation of p53, in turn, led to induction of Bax protein, a key regulator of p53 dependent apoptotic cell death, as well as of caspase-7 cleavage in MCF7 cells.	1	13	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	p53	phosphorylation of p53	p53	Bax	Bax	bax	3	4	12	13
Although the role of KLF5 in DNA damage repair has not been investigated , there is evidence that KLF4 , which is of the same family as KLF5 , is required for p53 mediated induction of p21 in response to DNA damage and inhibits p53 activation of the Bax promoter after gamma radiation XREF_BIBR - XREF_BIBR .	Although the role of KLF5 in DNA damage repair has not been investigated, there is evidence that KLF4, which is of the same family as KLF5, is required for p53 mediated induction of p21 in response to DNA damage and inhibits p53 activation of the Bax promoter after gamma radiation XREF_BIBR - XREF_BIBR.	44	49	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	44	45	48	49
p53 can induce Bax activation , leading to changes in the mitochondrial membrane permeabilization ; however , in the absence of mortalin , there is nuclear accumulation of p53 , concomitant with increased levels of Bax , suggesting that the low levels ( or absence ) of mortalin cause activation of the p53-Bax apoptosis pathway [ XREF_BIBR ] .	p53 can induce Bax activation, leading to changes in the mitochondrial membrane permeabilization; however, in the absence of mortalin, there is nuclear accumulation of p53, concomitant with increased levels of Bax, suggesting that the low levels (or absence) of mortalin cause activation of the p53-Bax apoptosis pathway [XREF_BIBR].	0	4	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	3	4
If the damage can not be repaired and is poised to create a deranged cell potentially harmful to the organism , p53 induces apoptosis , through activation of the proapoptotic genes Puma , Noxa , and Bax , or promotes senescence through induction of p21 .	If the damage can not be repaired and is poised to create a deranged cell potentially harmful to the organism, p53 induces apoptosis, through activation of the proapoptotic genes Puma, Noxa, and Bax, or promotes senescence through induction of p21.	21	39	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	21	22	36	37
Over-expression of sigmaC resulted in the upregulation of p53 , p53 serine 46 phosphorylation , p53 driven reporter activity and accumulation of bax .	Over-expression of sigmaC resulted in the upregulation of p53, p53 serine 46 phosphorylation, p53 driven reporter activity and accumulation of bax.	13	23	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	15	16	22	23
It was demonstrated that the human BAX gene promoter contains typical p53 binding sites and is transcriptionally upregulated by p53 XREF_BIBR .	It was demonstrated that the human BAX gene promoter contains typical p53 binding sites and is transcriptionally upregulated by p53 XREF_BIBR.	6	20	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	19	20	6	7
Indeed , in these conditions the pro apototic Bax , Noxa and PUMA genes and the anti-apoptotic BCL-2 gene which are not known as direct target genes of HIC1 but as direct P53 target genes are activated or repressed , respectively by P53 [ XREF_BIBR ] .	Indeed, in these conditions the pro apototic Bax, Noxa and PUMA genes and the anti-apoptotic BCL-2 gene which are not known as direct target genes of HIC1 but as direct P53 target genes are activated or repressed, respectively by P53 [XREF_BIBR].	5	44	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	P53	P53	P53	Bax	Bax	Bax	42	43	8	9
In addition , p53 is a transcriptional regulator of the proapoptotic gene product Bax and antiapoptotic gene product Bcl-2 , the activation of p53 may upregulate Bax and downregulate Bcl-2 in myocytes .	In addition, p53 is a transcriptional regulator of the proapoptotic gene product Bax and antiapoptotic gene product Bcl-2, the activation of p53 may upregulate Bax and downregulate Bcl-2 in myocytes.	21	27	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	23	24	26	27
Meanwhile , when entering the cytoplasm and targeted the mitochondria , p53 directly activates the primed Bax and Bak for their oligomerization , inducing mitochondrial outer membrane permeabilization ( MOMP ) .	Meanwhile, when entering the cytoplasm and targeted the mitochondria, p53 directly activates the primed Bax and Bak for their oligomerization, inducing mitochondrial outer membrane permeabilization (MOMP).	11	21	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	16	17
In response to DNA damage , cytoplasmic p53 induces the oligomerization of Bax , Bak , VDAC and cyclophilin D , which triggers the permeabilisation of the mitochondrial membrane , resulting in the release of the pro apoptotic molecules cytochrome c , smac and AIF [ XREF_BIBR , XREF_BIBR ] .	In response to DNA damage, cytoplasmic p53 induces the oligomerization of Bax, Bak, VDAC and cyclophilin D, which triggers the permeabilisation of the mitochondrial membrane, resulting in the release of the pro apoptotic molecules cytochrome c, smac and AIF [XREF_BIBR, XREF_BIBR].	6	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	12	13
In the mitochondrion , p53 induces Bax and Bak oligomerization and physically interacts with Bcl-xL and Bcl-2 , antagonizing their anti-apoptotic effects [ XREF_BIBR ] .	In the mitochondrion, p53 induces Bax and Bak oligomerization and physically interacts with Bcl-xL and Bcl-2, antagonizing their anti-apoptotic effects [XREF_BIBR].	4	12	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	6	7
Our simulations show that the strength of p53 transcriptional activity and its coupling ( or timing with respect ) to mitochondrial pore opening are major determinants of cell fate : for systems where apoptosis is elicited via a p53-transcription-independent mechanism , direct activation of Bax by p53 becomes critical to IR-induced-damage initiation .	Our simulations show that the strength of p53 transcriptional activity and its coupling (or timing with respect) to mitochondrial pore opening are major determinants of cell fate : for systems where apoptosis is elicited via a p53-transcription-independent mechanism, direct activation of Bax by p53 becomes critical to IR-induced-damage initiation.	42	47	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	46	47	44	45
p53 has been reported to activate proapoptotic protein Bax and suppress antiapoptotic protein Bcl-2 [ XREF_BIBR - XREF_BIBR ] .	p53 has been reported to activate proapoptotic protein Bax and suppress antiapoptotic protein Bcl-2 [XREF_BIBR - XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	8	9
p53 can increase Bax and Bcl -2 ( or Bcl-X L ) pro apoptotic ratio through transcriptional Bax upregulation and/or Bax oligomerization .	p53 can increase Bax and Bcl -2 (or Bcl-X L) pro apoptotic ratio through transcriptional Bax upregulation and/or Bax oligomerization.	0	5	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	3	4
Although a stable p53-Bax interaction was not observed , p53 is able to directly activate Bax in the absence of other proteins [ XREF_BIBR ] .	Although a stable p53-Bax interaction was not observed, p53 is able to directly activate Bax in the absence of other proteins [XREF_BIBR].	9	18	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	9	10	15	16
This implies that enhanced p53 can substitute for PUMA to promote BAX activation and subsequent cell death ( as shown in XREF_FIG ) .	This implies that enhanced p53 can substitute for PUMA to promote BAX activation and subsequent cell death (as shown in XREF_FIG).	3	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	4	5	11	12
These apoptosis induction was accompanied with increased NAD + / NADH ratio , thus , antioxidant effect of anthocyanin could play a role in inducing apoptosis , suggesting that anthocyanin induced apoptosis of DU-145 cells by up-regulating p53 , which modulated the Bax and Bcl -2 ratio .	These apoptosis induction was accompanied with increased NAD + / NADH ratio, thus, antioxidant effect of anthocyanin could play a role in inducing apoptosis, suggesting that anthocyanin induced apoptosis of DU-145 cells by up-regulating p53, which modulated the Bax and Bcl -2 ratio.	36	46	modulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	37	38	42	43
p53 initiated apoptosis may involve the mitochondrial protein Bax .	p53 initiated apoptosis may involve the mitochondrial protein Bax.	0	9	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	8	9
The present study demonstrated that Dio significantly upregulates p53 expression and increases the ratio of Bax and Bcl -2 proteins in cells treated with Dio , which suggests p53 and Bax and Bcl -2 proteins are key in Dio induced cell apoptosis .	The present study demonstrated that Dio significantly upregulates p53 expression and increases the ratio of Bax and Bcl -2 proteins in cells treated with Dio, which suggests p53 and Bax and Bcl -2 proteins are key in Dio induced cell apoptosis.	5	17	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	Dio significantly upregulates p53 expression	p53	Bax	Bax	bax	8	9	15	16
Interestingly , the levels of p53 were increased at 12 h after stretch although we observed that Bax upregulation and apoptosis occurred as early as 1 h. Adenovirus delivered dominant negative p53 blocked Bax upregulation in cardiomyocytes but showed partial effect on preventing stretch induced apoptosis , suggesting that p53 was only partially involved in mediating stretch induced apoptosis .	Interestingly, the levels of p53 were increased at 12 h after stretch although we observed that Bax upregulation and apoptosis occurred as early as 1 h. Adenovirus delivered dominant negative p53 blocked Bax upregulation in cardiomyocytes but showed partial effect on preventing stretch induced apoptosis, suggesting that p53 was only partially involved in mediating stretch induced apoptosis.	29	38	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	31	32	33	34
This action was associated with p53 induced oligomerization of Bax , Bak and VDAC , and the formation of stress induced endogenous p53-cyclophilin D complex located at the inner membrane .	This action was associated with p53 induced oligomerization of Bax, Bak and VDAC, and the formation of stress induced endogenous p53-cyclophilin D complex located at the inner membrane.	3	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	9	10
The ( 1068 ) LKK ( 1070 ) and ( 1125 ) SHP ( 1127 ) substitutions did not reduce LANA ' s inhibition of RB1 induced growth arrest , transactivation of the CDK2 promoter , or C-terminal LANA ' s inhibition of p53 activation of the BAX promoter .	The (1068) LKK (1070) and (1125) SHP (1127) substitutions did not reduce LANA 's inhibition of RB1 induced growth arrest, transactivation of the CDK2 promoter, or C-terminal LANA 's inhibition of p53 activation of the BAX promoter.	43	48	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	43	44	47	48
Unexpectedly , expression of transactivation deficient p53 variants sensitized p53-null cells to HDACi mediated BAX dependent apoptosis , whereas knockdown of endogenous mutant p53 in cancer cells reduced HDACi mediated cytotoxicity .	Unexpectedly, expression of transactivation deficient p53 variants sensitized p53-null cells to HDACi mediated BAX dependent apoptosis, whereas knockdown of endogenous mutant p53 in cancer cells reduced HDACi mediated cytotoxicity.	2	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	expression of transactivation deficient p53	p53	BAX	BAX	bax	6	7	14	15
In accordance , p53 depleted UKF-NB-3 p53shRNA cells displayed lower BAX activation than control vector transduced UKF-NB-3 scr cells ( XREF_FIG ) .	In accordance, p53 depleted UKF-NB-3 p53shRNA cells displayed lower BAX activation than control vector transduced UKF-NB-3 scr cells (XREF_FIG).	3	11	depleted	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	3	4	10	11
Apoptotic signals in this pathway may come in the form of members of the Bcl-2 family of proteins such as pro apoptotic Bax , which can be upregulated by tumor suppressor protein p53 in response to DNA damage [ XREF_BIBR ] .	Apoptotic signals in this pathway may come in the form of members of the Bcl-2 family of proteins such as pro apoptotic Bax, which can be upregulated by tumor suppressor protein p53 in response to DNA damage [XREF_BIBR].	17	34	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	32	33	22	23
Also , p53 could activate Bax and Bad and caspase cascade , which leading to cell apoptosis .	Also, p53 could activate Bax and Bad and caspase cascade, which leading to cell apoptosis.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	5	6
As seen above for the neuronal protection of APC , 3K3A-APC inhibited p53 expression , decreased favorably the Bax : Bcl-2 ratio ( XREF_FIG ) ( one-way ANOVA followed by Tukey ' s post-hoc test , P < 0.05 ; n = 4 different blots per group ; XREF_FIG ) and blocked the activation of caspase-9 and -3 ( one-way ANOVA followed by Tukey ' s post-hoc test , P < 0.05 ; n = 5 independent cultures per treatment ; XREF_FIG ) ; its effects were more pronounced than those obtained with wt-APC .	As seen above for the neuronal protection of APC, 3K3A-APC inhibited p53 expression, decreased favorably the Bax : Bcl-2 ratio (XREF_FIG) (one-way ANOVA followed by Tukey 's post-hoc test, P < 0.05; n = 4 different blots per group; XREF_FIG) and blocked the activation of caspase-9 and -3 (one-way ANOVA followed by Tukey 's post-hoc test, P < 0.05; n = 5 independent cultures per treatment; XREF_FIG); its effects were more pronounced than those obtained with wt-APC.	10	27	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	3K3A-APC inhibited p53 expression	p53	Bax	Bax	bax	12	13	18	19
Analysis of isolated patient leukemic cells by FACS revealed induction of p53 targets Bax and Puma upon APR-246 treatment , and microarray analysis showed substantial alterations in gene expression , including genes associated with cell cycle regulation and cell death , consistent with the proposed mechanism of action .	Analysis of isolated patient leukemic cells by FACS revealed induction of p53 targets Bax and Puma upon APR-246 treatment, and microarray analysis showed substantial alterations in gene expression, including genes associated with cell cycle regulation and cell death, consistent with the proposed mechanism of action.	8	18	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	13	14
In summary , our findings reveal a novel mechanism of how TFIIS.h could exert its tumor suppressive functions in facilitating p53 induction of bax .	In summary, our findings reveal a novel mechanism of how TFIIS.h could exert its tumor suppressive functions in facilitating p53 induction of bax.	20	24	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	20	21	23	24
The tumor suppressor gene p53 induces cell cycle arrest and apoptosis by increasing the expressions of its two transcriptional targets p21 Waf1 and Cip1 and Bax , respectively XREF_BIBR .	The tumor suppressor gene p53 induces cell cycle arrest and apoptosis by increasing the expressions of its two transcriptional targets p21 Waf1 and Cip1 and Bax, respectively XREF_BIBR.	0	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	4	5	25	26
These results demonstrate that BCL-xL mutations that disrupted binding to p53 N-D-T also impaired the ability of BCL-xL to inhibit p53 stimulated BAX activation .	These results demonstrate that BCL-xL mutations that disrupted binding to p53 N-D-T also impaired the ability of BCL-xL to inhibit p53 stimulated BAX activation.	19	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	20	21	22	23
An important regulator of apoptosis following DNA damage is p53 , which can induce Bax and Bak , regulating the release of cytochrome C from mitochondria and thereby initiating the cascade leading to apoptosis [ XREF_BIBR ] .	An important regulator of apoptosis following DNA damage is p53, which can induce Bax and Bak, regulating the release of cytochrome C from mitochondria and thereby initiating the cascade leading to apoptosis [XREF_BIBR].	2	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	9	10	14	15
Of the bcl-2 family members , IFN-gamma directly induced bak but notably not bax , which is activated by p53 .	Of the bcl-2 family members, IFN-gamma directly induced bak but notably not bax, which is activated by p53.	9	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	19	20	13	14
p53 knockdown inhibited up-regulation of p21 and BAX .	p53 knockdown inhibited up-regulation of p21 and BAX.	0	8	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	0	1	7	8
The reasons why IgE mediated stimulation induces an anti-apoptotic p53 target TIGRR while p53 activation by Nutlin-3a induces a pro apoptotic p53 target BAX in mast cells are still unclear .	The reasons why IgE mediated stimulation induces an anti-apoptotic p53 target TIGRR while p53 activation by Nutlin-3a induces a pro apoptotic p53 target BAX in mast cells are still unclear.	13	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	13	14	23	24
Under apoptotic conditions , p53 upregulates Bax and concomitantly downregulates the antiapoptotic factors resulting in the release of cytochrome c and apoptosis inducing factor and subsequent downstream caspase activation .	Under apoptotic conditions, p53 upregulates Bax and concomitantly downregulates the antiapoptotic factors resulting in the release of cytochrome c and apoptosis inducing factor and subsequent downstream caspase activation.	4	9	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	6	7
Upregulation of P53 also activated or repressed apoptosis associated genes , including BIRC5 , Bax , and Bcl-2 , and then increased the Bax and Bcl -2 ratio , and subsequently activated caspase cascade , resulting in the initiation of the apoptotic machinery .	Upregulation of P53 also activated or repressed apoptosis associated genes, including BIRC5, Bax, and Bcl-2, and then increased the Bax and Bcl -2 ratio, and subsequently activated caspase cascade, resulting in the initiation of the apoptotic machinery.	0	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	Bax	Bax	Bax	2	3	23	24
Our study showed that TSA treatment not only led to an NQO1 dependent and p53 independent loss of MMP and the subsequent release of cytochrome c from mitochondria ( XREF_FIG and XREF_FIG ) , but also cause a p53 independent increased ratio of pro apoptotic protein Bax to pro survival protein Bcl-xl ( XREF_FIG ) , which were considered to initiate apoptotic cell death XREF_BIBR .	Our study showed that TSA treatment not only led to an NQO1 dependent and p53 independent loss of MMP and the subsequent release of cytochrome c from mitochondria (XREF_FIG and XREF_FIG), but also cause a p53 independent increased ratio of pro apoptotic protein Bax to pro survival protein Bcl-xl (XREF_FIG), which were considered to initiate apoptotic cell death XREF_BIBR.	37	47	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	38	39	46	47
We demonstrated that bortezomib induced p53 , and activated its downstream genes p21 , PUMA and Bax in a p53 dependent fashion .	We demonstrated that bortezomib induced p53, and activated its downstream genes p21, PUMA and Bax in a p53 dependent fashion.	3	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	bortezomib induced p53	p53	Bax	Bax	bax	5	6	16	17
Indeed , we found that p53 activation and expression of p53 targets p21 and BAX was much more robust after combined MLN8237 and (-)-Nutlin-3 treatment in comparison with single agent therapies ( XREF_FIG ) .	Indeed, we found that p53 activation and expression of p53 targets p21 and BAX was much more robust after combined MLN8237 and (-)-Nutlin-3 treatment in comparison with single agent therapies (XREF_FIG).	5	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	5	6	14	15
Parallel treatment of 4HNE to HepG2 cells also induces apoptosis by the p53 pathway through activation of Bax , p21 , JNK , and caspase-3 .	Parallel treatment of 4HNE to HepG2 cells also induces apoptosis by the p53 pathway through activation of Bax, p21, JNK, and caspase-3.	8	24	induces	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	12	13	17	18
Alpha lipoic acid suppressed proliferating cell nuclear antigen ( PCNA ) and p53 expression , induced apoptosis , upregulated proapoptotic protein Bax .	Alpha lipoic acid suppressed proliferating cell nuclear antigen (PCNA) and p53 expression, induced apoptosis, upregulated proapoptotic protein Bax.	0	22	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	Alpha lipoic acid suppressed proliferating cell nuclear antigen (PCNA) and p53 expression	p53	Bax	Bax	bax	12	13	21	22
For severe damage , p53 is driven to high levels , inducing Bax , PTEN and DDB2 .	For severe damage, p53 is driven to high levels, inducing Bax, PTEN and DDB2.	4	16	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	12	13
These are mediated by multiple factors including p21 , 14-3-3sigma , Cdc25C , Bax , PUMA and Noxa , whose expression is induced or repressed by p53 .	These are mediated by multiple factors including p21, 14-3-3sigma, Cdc25C, Bax, PUMA and Noxa, whose expression is induced or repressed by p53.	5	27	induced	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	26	27	13	14
Under our experimental conditions , p53 dependent endogenous transcriptional induction of p21 , Bax and MDM2 was detectable .	Under our experimental conditions, p53 dependent endogenous transcriptional induction of p21, Bax and MDM2 was detectable.	5	14	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	13	14
Besides its obvious effects on transcription of numerous proapoptotic factors , p53 is also known to directly activate Bax , which leads to mitochondrial permeabilization and subsequent apoptosis XREF_BIBR .	Besides its obvious effects on transcription of numerous proapoptotic factors, p53 is also known to directly activate Bax, which leads to mitochondrial permeabilization and subsequent apoptosis XREF_BIBR.	11	21	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	18	19
Mechanistically , CCN1 induces fibroblast apoptosis through binding to alpha 6 beta 1 and syndecan-4 , leading to the p53 dependent activation of Bax and cytochrome c release .	Mechanistically, CCN1 induces fibroblast apoptosis through binding to alpha 6 beta 1 and syndecan-4, leading to the p53 dependent activation of Bax and cytochrome c release.	19	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	19	20	23	24
p53 is a known modulator of the cellular response following stress and is known to induce Bax activation XREF_BIBR , while the polymorphism detected has been shown to affect transcription XREF_BIBR .	p53 is a known modulator of the cellular response following stress and is known to induce Bax activation XREF_BIBR, while the polymorphism detected has been shown to affect transcription XREF_BIBR.	0	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	16	17
In MI hearts , where TIP60 is overexpressed , p53 is acetylated at the Lys 118 residue and binds to the BAX promoter and induces upregulation of BAX protein .	In MI hearts, where TIP60 is overexpressed, p53 is acetylated at the Lys 118 residue and binds to the BAX promoter and induces upregulation of BAX protein.	9	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 is acetylated	p53	BAX	BAX	bax	9	10	27	28
Bax is directly activated by p53 and is a direct target of p53 .	Bax is directly activated by p53 and is a direct target of p53.	0	6	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	0	1
Additional studies have suggested that p53 itself may translocate to the mitochondria and activate Bax after select stimuli .	Additional studies have suggested that p53 itself may translocate to the mitochondria and activate Bax after select stimuli.	5	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 itself may translocate to the mitochondria	p53	Bax	Bax	bax	5	6	14	15
p53 induction by H 2 O 2 may have resulted in activation of BAX , a proapoptotic factor , in the present study ( XREF_FIG ) further confirming that H 2 O 2 tended to push cells into apoptotic death .	p53 induction by H 2 O 2 may have resulted in activation of BAX, a proapoptotic factor, in the present study (XREF_FIG) further confirming that H 2 O 2 tended to push cells into apoptotic death.	0	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	0	1	13	14
To clarify the roles p53 and the p53 targets p21 and Bax , we exposed the colorectal cancer cell line HCT116 to the individual therapeutic modalities employed in clinical rectal carcinoma therapy : IR , 5-FU and heat shock .	To clarify the roles p53 and the p53 targets p21 and Bax, we exposed the colorectal cancer cell line HCT116 to the individual therapeutic modalities employed in clinical rectal carcinoma therapy : IR, 5-FU and heat shock.	2	12	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	11	12
P53 targeted proteins , Puma and Bax , were up-regulated and activated .	P53 targeted proteins, Puma and Bax, were up-regulated and activated.	0	11	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	Bax	Bax	Bax	0	1	6	7
Dehy , CD and VOSL treatment all can up-regulate the expression of p53 , and increase the ratio of BAX to BCL-2 .	Dehy, CD and VOSL treatment all can up-regulate the expression of p53, and increase the ratio of BAX to BCL-2.	2	20	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	CD and VOSL treatment all can up-regulate the expression of p53	p53	BAX	BAX	bax	12	13	19	20
The localization of p53 to the mitochondria in response to stress is carried out by mitochondrial-import peptides to promote the oligomerization of Bax and Bak , which then counteracts the effect of Bcl-2 and Bcl-xL .	The localization of p53 to the mitochondria in response to stress is carried out by mitochondrial-import peptides to promote the oligomerization of Bax and Bak, which then counteracts the effect of Bcl-2 and Bcl-xL.	1	28	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	22	23
Besides differences in experimental models which are relevant to steer MNs toward one or other cell death program , it should be taken also into consideration that pleiotropic effect of p53 promote both apoptotic programs ( BAX dependent ) and inhibition of anti-anoikis programs mediated by AKT XREF_BIBR ( see below ) .	Besides differences in experimental models which are relevant to steer MNs toward one or other cell death program, it should be taken also into consideration that pleiotropic effect of p53 promote both apoptotic programs (BAX dependent) and inhibition of anti-anoikis programs mediated by AKT XREF_BIBR (see below).	28	37	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	30	31	36	37
As was expected in HCT116 WT cells , LSSE dose-dependently increased p53 levels and increased the levels of the p53 targeted genes p21 ( XREF_FIG ) as well as NOXA , PUMA , and Bax ( XREF_FIG ) .	As was expected in HCT116 WT cells, LSSE dose-dependently increased p53 levels and increased the levels of the p53 targeted genes p21 (XREF_FIG) as well as NOXA, PUMA, and Bax (XREF_FIG).	8	36	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	LSSE dose-dependently increased p53 levels and increased the levels of the p53	p53	Bax	Bax	bax	19	20	34	35
Together , these data indicate that mitochondrial p53 promotes oligomerization and activation of endogenous Bax and Bak in the mitochondria and that this activity does not require Puma .	Together, these data indicate that mitochondrial p53 promotes oligomerization and activation of endogenous Bax and Bak in the mitochondria and that this activity does not require Puma.	6	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	14	15
Upon stress activation , Puma rescues p53 from Bcl-xL , and p53 activates cytosolic Bax .	Upon stress activation, Puma rescues p53 from Bcl-xL, and p53 activates cytosolic Bax.	11	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	14	15
* Both p53 and p21 were up-regulated in treated cells with P. harmala ' s seed extract , hence p53 as transcription regulator up-regulated Bax , Puma and TRAIL .	* Both p53 and p21 were up-regulated in treated cells with P. harmala 's seed extract, hence p53 as transcription regulator up-regulated Bax, Puma and TRAIL.	18	28	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	19	20	24	25
This includes an increase in p53 ( wild-type ) , a decrease in BCL2 , a p53 dependent increase in the BCL2 family member BAX , and increases in Growth Arrest and DNA Damage inducible ( GADD ) genes such as GADD45 ; these changes occur as early events in a sequence that culminates in DNA damage induced apoptosis .	This includes an increase in p53 (wild-type), a decrease in BCL2, a p53 dependent increase in the BCL2 family member BAX, and increases in Growth Arrest and DNA Damage inducible (GADD) genes such as GADD45; these changes occur as early events in a sequence that culminates in DNA damage induced apoptosis.	16	25	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	16	17	24	25
Additionally , p53 transcriptionally represses Bcl-2 and also upregulates BAX [ XREF_BIBR , XREF_BIBR ] , which could contribute to p53 mediated CIA .	Additionally, p53 transcriptionally represses Bcl-2 and also upregulates BAX [XREF_BIBR, XREF_BIBR], which could contribute to p53 mediated CIA.	2	11	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	2	3	9	10
This p53 independent PUMA expression activated Bax and the mitochondrial apoptotic pathway .	This p53 independent PUMA expression activated Bax and the mitochondrial apoptotic pathway.	0	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 independent PUMA expression	p53	Bax	Bax	bax	1	2	6	7
In addition , p53 can enhance Bax activity through transcription or combine with Bcl-2 to promote cell apoptosis .	In addition, p53 can enhance Bax activity through transcription or combine with Bcl-2 to promote cell apoptosis.	3	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	6	7
In addition , both the response to oxidative stress and the response to ER stress converge at the mitochondrion ; p53 activated by oxidative stress stimulates the oligomerization of BAX XREF_BIBR , and BiP responding to ER stress releases IRE-1 to which BAX is bound .	In addition, both the response to oxidative stress and the response to ER stress converge at the mitochondrion; p53 activated by oxidative stress stimulates the oligomerization of BAX XREF_BIBR, and BiP responding to ER stress releases IRE-1 to which BAX is bound.	20	30	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	20	21	29	30
Furthermore , co-treatment with lidocaine and hyaluronan significantly decreased the levels of p53 and its transcription targets Bax and p21 in SW1353 cells , although treatment with lidocaine alone did not significantly change these proteins .	Furthermore, co-treatment with lidocaine and hyaluronan significantly decreased the levels of p53 and its transcription targets Bax and p21 in SW1353 cells, although treatment with lidocaine alone did not significantly change these proteins.	10	22	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	levels of p53	p53	Bax	Bax	bax	12	13	17	18
XREF_BIBR , XREF_BIBR Cellular stress mediates p53 stabilization directing cell cycle arrest ( controlled by p21 and 14-3-3sigma ) or apoptosis ( requiring PUMA , Bax , Noxa or BID ) .	XREF_BIBR, XREF_BIBR Cellular stress mediates p53 stabilization directing cell cycle arrest (controlled by p21 and 14-3-3sigma) or apoptosis (requiring PUMA, Bax, Noxa or BID).	6	26	directing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	25	26
Germline deletion of p53 from BdkrB2-/- mice prevented Bax activation and normalized the apoptosis index .	Germline deletion of p53 from BdkrB2-/- mice prevented Bax activation and normalized the apoptosis index.	1	9	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	8	9
p53 directly activates the proapoptotic Bcl-2 protein BAX to permeabilize mitochondria , which results in the release of mitochondrial factors , such as cytochrome c , that signal apoptotic cell death .	p53 directly activates the proapoptotic Bcl-2 protein BAX to permeabilize mitochondria, which results in the release of mitochondrial factors, such as cytochrome c, that signal apoptotic cell death.	0	9	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	0	1	7	8
Indeed , both p53 and tBid are able to induce Bax containing oligomers in mitochondria from HCT116 WT cells , but not from their Bax-/- counterparts , indicating the specificity of the oligomeric bands ( XREF_FIG ) .	Indeed, both p53 and tBid are able to induce Bax containing oligomers in mitochondria from HCT116 WT cells, but not from their Bax-/- counterparts, indicating the specificity of the oligomeric bands (XREF_FIG).	2	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	10	11
Ligation of CCN1 to the adhesion receptors in fibroblasts , neither of which has previously been implicated in apoptosis , results in the transcription independent p53 activation of Bax and cytochrome c release , triggering the activation of caspase-9 and -3 .	Ligation of CCN1 to the adhesion receptors in fibroblasts, neither of which has previously been implicated in apoptosis, results in the transcription independent p53 activation of Bax and cytochrome c release, triggering the activation of caspase-9 and -3.	25	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	25	26	28	29
To evaluate changes in p53 dependent transcription , we next compared the protein levels of p53 transcription targets PUMA , NOXA , p21 and Waf1 , FasR , and BAX in 5-FU treated and untreated control cells ( XREF_FIG ) .	To evaluate changes in p53 dependent transcription, we next compared the protein levels of p53 transcription targets PUMA, NOXA, p21 and Waf1, FasR, and BAX in 5-FU treated and untreated control cells (XREF_FIG).	15	30	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 transcription	p53	BAX	BAX	bax	15	16	29	30
Finally , p53 may act through a combined protein interaction and transactivation mechanism : The product of the p53 target gene PUMA resolves an inactive cytosolic p53 and BclXL complex by binding to a distinct site on BclXL and allows the activation of Bax by free p53 [ XREF_BIBR ] .	Finally, p53 may act through a combined protein interaction and transactivation mechanism : The product of the p53 target gene PUMA resolves an inactive cytosolic p53 and BclXL complex by binding to a distinct site on BclXL and allows the activation of Bax by free p53 [XREF_BIBR].	18	44	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	18	19	43	44
Furthermore wildtype p53 upregulation of Bax and downregulation of Bcl-2 that results in apoptosis was categorized as the principle process involved [ XREF_BIBR , XREF_BIBR ] .	Furthermore wildtype p53 upregulation of Bax and downregulation of Bcl-2 that results in apoptosis was categorized as the principle process involved [XREF_BIBR, XREF_BIBR].	2	11	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	5	6
Src mediated apoptosis is also linked to p53 upregulation and induction of the pro apoptotic protein Bax [ XREF_BIBR ] , leading one to believe that p53 status of neuroblastoma may be important to our findings .	Src mediated apoptosis is also linked to p53 upregulation and induction of the pro apoptotic protein Bax [XREF_BIBR], leading one to believe that p53 status of neuroblastoma may be important to our findings.	7	18	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	16	17
We assessed ROS driven DNA damage and p53 mediated activation of Bax in vitro in ARPE-19 cells .	We assessed ROS driven DNA damage and p53 mediated activation of Bax in vitro in ARPE-19 cells.	5	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	11	12
In response to a variety of stresses such as DNA damage , hypoxia , and chemotherapeutic drugs , p53 protein , a key regulator of cell cycle progression and mediator of apoptosis , activates and leads to cell cycle arrest , DNA repair , and apoptosis by activation of its downstream effectors p21 , GADD45 , and Bax .	In response to a variety of stresses such as DNA damage, hypoxia, and chemotherapeutic drugs, p53 protein, a key regulator of cell cycle progression and mediator of apoptosis, activates and leads to cell cycle arrest, DNA repair, and apoptosis by activation of its downstream effectors p21, GADD45, and Bax.	18	58	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	18	19	57	58
Wild type p53 binds to gene promoters with different affinity ; for example , p53 activates p21 promoter with a higher affinity than the Bax promoter p53 function .	Wild type p53 binds to gene promoters with different affinity; for example, p53 activates p21 promoter with a higher affinity than the Bax promoter p53 function.	24	27	promoter	Positive_activation_token_1_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	26	27	24	25
Besides the control of p53 activity , Sirt1 regulates the proapoptotic function of the proapoptotic p53 target Bax by retaining it in the cytoplasm in complex with the hypoacetylated form of Ku70 and preventing it from translocating to the outer mitochondrial membrane to induce apoptosis [ XREF_BIBR , XREF_BIBR ] .	Besides the control of p53 activity, Sirt1 regulates the proapoptotic function of the proapoptotic p53 target Bax by retaining it in the cytoplasm in complex with the hypoacetylated form of Ku70 and preventing it from translocating to the outer mitochondrial membrane to induce apoptosis [XREF_BIBR, XREF_BIBR].	11	18	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	15	16	17	18
Therefore , apoptosis in the S phase population of MM.1 r cells was likely a consequence of p53 dependent up-regulation of Bax after loss of MAGE-A , since disproportionate S phase apoptosis was not observed in p53-null ARP-1 or Pt # 1 cells .	Therefore, apoptosis in the S phase population of MM.1 r cells was likely a consequence of p53 dependent up-regulation of Bax after loss of MAGE-A, since disproportionate S phase apoptosis was not observed in p53-null ARP-1 or Pt # 1 cells.	17	23	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	17	18	21	22
Whereas Western immunoblotting demonstrated that E2F-1 antagonized p53 induction of p21Waf1 and BAX , Northern blotting revealed that this interference was pretranslationally regulated and p53 dependent .	Whereas Western immunoblotting demonstrated that E2F-1 antagonized p53 induction of p21Waf1 and BAX, Northern blotting revealed that this interference was pretranslationally regulated and p53 dependent.	7	13	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	7	8	12	13
[ XREF_BIBR ] The first category includes members that promote apoptosis such as bax , bak , bcl-xs , which are also upregulated by p53 .	[XREF_BIBR] The first category includes members that promote apoptosis such as bax, bak, bcl-xs, which are also upregulated by p53.	10	25	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	24	25	13	14
Adp14 and p53 treatment leads to an elevated bax : bcl2 ratio and induction of apoptosis in vitro and in vivo , coupled with a failure of the tumor cells to induce neovascularization in vivo .	Adp14 and p53 treatment leads to an elevated bax : bcl2 ratio and induction of apoptosis in vitro and in vivo, coupled with a failure of the tumor cells to induce neovascularization in vivo.	0	13	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	2	3	8	9
In addition to mitochondrial p53 , cytosolic p53 induces the activation of Bax , subsequently resulting in mitochondrial membrane permeabilization and cytochrome c release [ XREF_BIBR ] .	In addition to mitochondrial p53, cytosolic p53 induces the activation of Bax, subsequently resulting in mitochondrial membrane permeabilization and cytochrome c release [XREF_BIBR].	6	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	12	13
It is currently accepted that the BAX promoter contains the binding site for typical p53 tumor suppressor , as a result , the roll of p53 in the induction of apoptosis is due in part to increased BAX protein expression , since p53 induces apoptosis by activating the BAX gene .	It is currently accepted that the BAX promoter contains the binding site for typical p53 tumor suppressor, as a result, the roll of p53 in the induction of apoptosis is due in part to increased BAX protein expression, since p53 induces apoptosis by activating the BAX gene.	42	49	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	42	43	48	49
59 Phosphorylation of p53 by Chk2 may lead to upregulation of Bax , an event also promoting apoptosis .	59 Phosphorylation of p53 by Chk2 may lead to upregulation of Bax, an event also promoting apoptosis.	1	14	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	p53	Phosphorylation of p53	p53	Bax	Bax	bax	3	4	11	12
This was demonstrated by the ability of wild-type p53 to down-regulate Bcl-2 and up-regulate Bax and proceed to programmed cell death [ XREF_BIBR - XREF_BIBR ] .	This was demonstrated by the ability of wild-type p53 to down-regulate Bcl-2 and up-regulate Bax and proceed to programmed cell death [XREF_BIBR - XREF_BIBR].	5	15	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	14	15
XREF_BIBR , XREF_BIBR , XREF_BIBR It is well established that Bax can be up-regulated by the tumor suppressor p53 protein .	XREF_BIBR, XREF_BIBR, XREF_BIBR It is well established that Bax can be up-regulated by the tumor suppressor p53 protein.	10	19	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	Bax	Bax	Bax	16	19	10	11
ODQ prolonged p53 half-life , induced phosphorylation of p53 on Ser15 , and upregulated the p53 dependent gene products p21 , murine double minute-2 , and the proapoptotic , p53 responsive gene product Bax .	ODQ prolonged p53 half-life, induced phosphorylation of p53 on Ser15, and upregulated the p53 dependent gene products p21, murine double minute-2, and the proapoptotic, p53 responsive gene product Bax.	0	34	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	ODQ prolonged p53 half-life, induced phosphorylation of p53 on Ser15	p53	Bax	Bax	bax	8	9	33	34
These events appear to occur in parallel in contrast to the findings of Chipuk et al in which p53 and PUMA ` flip-flop ' their association with Bcl-X L so that p53 can then activate pro apoptotoic Bax .	These events appear to occur in parallel in contrast to the findings of Chipuk et al in which p53 and PUMA ` flip-flop ' their association with Bcl-X L so that p53 can then activate pro apoptotoic Bax.	31	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	31	32	37	38
To better understand the cellular events involved in p73 mediated apoptosis in combination treatments , mRNA and protein expression of p53 mediated pro apoptotic mediators DR5 , Fas , Bax , and Noxa , and anti-apoptotic mediator Bcl-2 were examined .	To better understand the cellular events involved in p73 mediated apoptosis in combination treatments, mRNA and protein expression of p53 mediated pro apoptotic mediators DR5, Fas, Bax, and Noxa, and anti-apoptotic mediator Bcl-2 were examined.	18	30	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	expression of p53	p53	Bax	Bax	bax	20	21	29	30
For example , the upstream kinase , JNK , has also been shown to phosphorylate p53 , which can up-regulate BAX .	For example, the upstream kinase, JNK, has also been shown to phosphorylate p53, which can up-regulate BAX.	7	21	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	JNK, has also been shown to phosphorylate p53	p53	BAX	BAX	bax	15	16	20	21
The resultant increased p53 levels in the nucleus induce Bax activation and Bcl-2 inhibition , followed by a release of cytochrome c into the cytosol that truncates procaspase-9 .	The resultant increased p53 levels in the nucleus induce Bax activation and Bcl-2 inhibition, followed by a release of cytochrome c into the cytosol that truncates procaspase-9.	3	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 levels	p53	Bax	Bax	bax	3	4	9	10
In this study , we found that structurally unrelated Hsp90 inhibitors induce DNA damage and apoptosis via p53 dependent induction of PUMA , which indirectly triggers Bax activation and mitochondrial dysfunction in colon cancer cells .	In this study, we found that structurally unrelated Hsp90 inhibitors induce DNA damage and apoptosis via p53 dependent induction of PUMA, which indirectly triggers Bax activation and mitochondrial dysfunction in colon cancer cells.	17	27	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	17	18	26	27
Still , in JHAD1 cells , C-PAC induced cell death may be partially p53 mediated as the p53 target BAX is also up-regulated ( 1.4 fold , 48 hours ) .	Still, in JHAD1 cells, C-PAC induced cell death may be partially p53 mediated as the p53 target BAX is also up-regulated (1.4 fold, 48 hours).	16	22	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	17	18	19	20
Moreover , accordingly to IPA MAP tool , p53 can directly activate pro apoptotic factor Bax 43 and trigger a cascade of activation of other pro apoptotic factors such as HTRA2 and DIABLO 44 , Cytochrome C release and apoptosome formation 45 , activation of AIF and ENDO G that couple to DNA fragmentation 46 .	Moreover, accordingly to IPA MAP tool, p53 can directly activate pro apoptotic factor Bax 43 and trigger a cascade of activation of other pro apoptotic factors such as HTRA2 and DIABLO 44, Cytochrome C release and apoptosome formation 45, activation of AIF and ENDO G that couple to DNA fragmentation 46.	8	18	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	15	16
PUMA , p53 inducible gene , is closely related to strong apoptosis and modulates anti-apoptotic Bcl-2 and pro apoptotic Bax , thereby activating caspase-3 and -9 [ XREF_BIBR ] .	PUMA, p53 inducible gene, is closely related to strong apoptosis and modulates anti-apoptotic Bcl-2 and pro apoptotic Bax, thereby activating caspase-3 and -9 [XREF_BIBR].	2	20	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	19	20
Activation of p53 increases Bax , PUMA , and NOXA expression .	Activation of p53 increases Bax, PUMA, and NOXA expression.	0	10	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	4	5
DNA damage or intra and extra-cellular stress initiates signaling cascades in the cytoplasm , eventually leading to the phosphorylation of p53 which , in turn , increases Bax concentration while lowering Bcl-2 [ XREF_BIBR ] .	DNA damage or intra and extra-cellular stress initiates signaling cascades in the cytoplasm, eventually leading to the phosphorylation of p53 which, in turn, increases Bax concentration while lowering Bcl-2 [XREF_BIBR].	18	28	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	phosphorylation of p53	p53	Bax	Bax	bax	20	21	27	28
Other studies have suggested that p53 can directly activate Bax and thereby induce apoptosis XREF_BIBR XREF_BIBR .	Other studies have suggested that p53 can directly activate Bax and thereby induce apoptosis XREF_BIBR XREF_BIBR.	5	12	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	9	10
Upon release from BCL-xL , cytosolic p53 can directly activate BAX or BAK , thereby triggering the apoptotic signaling cascade via mitochondrial outer membrane permeabilization ( MOMP ) XREF_BIBR , XREF_BIBR .	Upon release from BCL-xL, cytosolic p53 can directly activate BAX or BAK, thereby triggering the apoptotic signaling cascade via mitochondrial outer membrane permeabilization (MOMP) XREF_BIBR, XREF_BIBR.	5	12	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	6	7	10	11
Previous report showed that the requirement of p53 mediated transcriptional activation of Bax XREF_BIBR , XREF_BIBR .	Previous report showed that the requirement of p53 mediated transcriptional activation of Bax XREF_BIBR, XREF_BIBR.	5	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	12	13
Bax is a pro apoptosis protein and is activated by the tumor suppressor p53 .	Bax is a pro apoptosis protein and is activated by the tumor suppressor p53.	0	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	Bax	Bax	Bax	11	14	0	1
Wild type Pin1 , but not its inactive mutant , enhanced p53 dependent BAX activation in LUV assays , suggesting that Pin1 dependent p53 Pro 47 cis-trans isomerization directly promotes BAX activation by p53 ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	Wild type Pin1, but not its inactive mutant, enhanced p53 dependent BAX activation in LUV assays, suggesting that Pin1 dependent p53 Pro 47 cis-trans isomerization directly promotes BAX activation by p53 (XREF_FIG; XREF_SUPPLEMENTARY).	23	31	promotes	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	23	24	30	31
As MDM2 can not recognize phosphorylated p53 , the nuclear p53 is stabilized and induce pro apoptotic proteins ( Bax , Puma and Noxa etc. ) .	As MDM2 can not recognize phosphorylated p53, the nuclear p53 is stabilized and induce pro apoptotic proteins (Bax, Puma and Noxa etc.).	8	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	10	11	19	20
We demonstrate that repression of p53 mediated activation of the Bax promoter involves a complex upstream sequence in which two Brn-3a response elements flank the p53 response element .	We demonstrate that repression of p53 mediated activation of the Bax promoter involves a complex upstream sequence in which two Brn-3a response elements flank the p53 response element.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	10	11
In HT1080 cells , both Ad-p53 14/19 and Ad-wt p53 induced p53 target proteins Mdm2 and Bax .	In HT1080 cells, both Ad-p53 14/19 and Ad-wt p53 induced p53 target proteins Mdm2 and Bax.	5	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	9	10	16	17
The activation of Bax is mediated by an increase in p53 and knockdown of p53 abolished oxLDL induced activation of Bax and apoptosis .	The activation of Bax is mediated by an increase in p53 and knockdown of p53 abolished oxLDL induced activation of Bax and apoptosis.	12	22	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	14	15	20	21
Taken together , these results show the requirement for a novel intronic element in the p53 dependent transcriptional activation of bax , and demonstrate that bax is indeed a direct and evolutionarily conserved transcriptional target of p53 .	Taken together, these results show the requirement for a novel intronic element in the p53 dependent transcriptional activation of bax, and demonstrate that bax is indeed a direct and evolutionarily conserved transcriptional target of p53.	15	21	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	15	16	20	21
This increased intracellular reactive oxygen species ( ROS ) generation and activated p53 mediated Bax promoter and endoplasmic reticulum ( ER ) stress signaling .	This increased intracellular reactive oxygen species (ROS) generation and activated p53 mediated Bax promoter and endoplasmic reticulum (ER) stress signaling.	1	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	12	13	14	15
Alternatively , cytosolic p53 can directly trigger Bax activation and apoptosis XREF_BIBR .	Alternatively, cytosolic p53 can directly trigger Bax activation and apoptosis XREF_BIBR.	2	8	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	7	8
Because p53 activation led to increase in p21 and Bax , we investigated whether these two proteins are important in this process .	Because p53 activation led to increase in p21 and Bax, we investigated whether these two proteins are important in this process.	1	10	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	9	10
The increased p53 levels led to an increased Bax and Bcl -2 ratio , resulting in apoptosis .	The increased p53 levels led to an increased Bax and Bcl -2 ratio, resulting in apoptosis.	2	12	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	p53	p53 levels	p53	Bax	Bax	bax	2	3	8	9
XREF_BIBR , XREF_BIBR p53 might initiate apoptosis by directly altering the transcriptional activity of the Bax gene .	XREF_BIBR, XREF_BIBR p53 might initiate apoptosis by directly altering the transcriptional activity of the Bax gene.	0	16	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	15	16
In addition , A34 ( a small peptide derived from p53 linker ) binds directly to iASPP and competitively inhibits the iASPP-p53 interaction in human tumor cells [ XREF_BIBR ] , causing WT p53 mediated transcriptional activation of Bax and PUMA and tumor cell apoptosis in vitro and in vivo [ XREF_BIBR ] .	In addition, A34 (a small peptide derived from p53 linker) binds directly to iASPP and competitively inhibits the iASPP-p53 interaction in human tumor cells [XREF_BIBR], causing WT p53 mediated transcriptional activation of Bax and PUMA and tumor cell apoptosis in vitro and in vivo [XREF_BIBR].	31	40	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	33	34	38	39
Telocinobufagin can decrease the viability of CRC cells by inducing cell apoptosis , which involves p53 mediated Bax activation and inhibition of the IAP pathway .	Telocinobufagin can decrease the viability of CRC cells by inducing cell apoptosis, which involves p53 mediated Bax activation and inhibition of the IAP pathway.	14	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	15	16	17	18
In fact , Brn-3b appears to be required for maximal induction of Bax by p53 because sensory neurons from Brn-3b KO-mutant mice are highly resistant to apoptotic stimuli and express reduced Bax despite p53 expression being intact .	In fact, Brn-3b appears to be required for maximal induction of Bax by p53 because sensory neurons from Brn-3b KO-mutant mice are highly resistant to apoptotic stimuli and express reduced Bax despite p53 expression being intact.	7	15	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	14	15	12	13
As a master regulator of cell apoptosis , p53 dependent apoptosis also contributes to chemotherapy induced cell death by transcriptionally activating pro apoptotic Bcl-2 family members ( e.g ., Bax , Bak , PUMA , and Noxa ) and repressing anti-apoptotic Bcl-2 proteins ( Bcl-2 , Bcl-XL ) and IAPs ( survivin ) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	As a master regulator of cell apoptosis, p53 dependent apoptosis also contributes to chemotherapy induced cell death by transcriptionally activating pro apoptotic Bcl-2 family members (e.g., Bax, Bak, PUMA, and Noxa) and repressing anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL) and IAPs (survivin) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	8	36	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	29	30
In contrast to p53 mediated induction of PUMA and Bax , induction of p21 protected against 17AAG induced apoptosis , consistent with the known antiapoptotic function of p21 in p53 dependent apoptosis .	In contrast to p53 mediated induction of PUMA and Bax, induction of p21 protected against 17AAG induced apoptosis, consistent with the known antiapoptotic function of p21 in p53 dependent apoptosis.	1	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	9	10
In addition , Bax , which is transcriptionally induced by activated p53 , has been reported to be partially localized in lysosomes and to activate a lysosome dependent apoptosis pathway [ XREF_BIBR ] .	In addition, Bax, which is transcriptionally induced by activated p53, has been reported to be partially localized in lysosomes and to activate a lysosome dependent apoptosis pathway [XREF_BIBR].	3	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	3	4
Toshiyuki and Reed [ XREF_BIBR ] showed that the human BAX gene is directly regulated by TP53 ( TP53 ) , whereas BAX is participating in the regulation of endoplasmatic reticulum Ca 2+ [ XREF_BIBR ] as well .	Toshiyuki and Reed [XREF_BIBR] showed that the human BAX gene is directly regulated by TP53 (TP53), whereas BAX is participating in the regulation of endoplasmatic reticulum Ca 2+ [XREF_BIBR] as well.	10	18	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TP53	TP53	TP53	BAX	BAX	BAX	16	17	10	11
Wild-type p53 induces Bax synthesis to mediate apoptosis , while mutant p53 can inhibit apoptosis leading to uncontrolled proliferation XREF_BIBR .	Wild-type p53 induces Bax synthesis to mediate apoptosis, while mutant p53 can inhibit apoptosis leading to uncontrolled proliferation XREF_BIBR.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	3	4
The variation in the extent of BAX activation by p53 40-59 peptides that contained non natural analogs of Pro 47 with different cis-trans isomerization properties suggests that the process of cis-trans Pro 47 isomerization is directly involved in BAX activation and that Pin1 may enhance BAX activation by accelerating this process .	The variation in the extent of BAX activation by p53 40-59 peptides that contained non natural analogs of Pro 47 with different cis-trans isomerization properties suggests that the process of cis-trans Pro 47 isomerization is directly involved in BAX activation and that Pin1 may enhance BAX activation by accelerating this process.	6	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	9	10	6	7
It has been demonstrated that p53 can up-regulate the proapoptotic gene Bax [ XREF_BIBR ] , and possibly , transcriptionally repress the antiapoptotic gene Bcl-2 [ XREF_BIBR ] .	It has been demonstrated that p53 can up-regulate the proapoptotic gene Bax [XREF_BIBR], and possibly, transcriptionally repress the antiapoptotic gene Bcl-2 [XREF_BIBR].	5	13	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	11	12
Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors , apoptosis inducing factor ( AIF ) and endonuclease G ( EndoG ) , through p53 dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin sensitive G-protein-coupled receptor ( GPCR ) pathway .	Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis inducing factor (AIF) and endonuclease G (EndoG), through p53 dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin sensitive G-protein-coupled receptor (GPCR) pathway.	26	32	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	26	27	30	31
It has been suggested that bax is up-regulated by p53 XREF_BIBR .	It has been suggested that bax is up-regulated by p53 XREF_BIBR.	5	10	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	9	10	5	6
Pin1 catalyzed isomerization of p53 Pro 47 enhances BAX activation .	Pin1 catalyzed isomerization of p53 Pro 47 enhances BAX activation.	4	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	4	5	8	9
This increase in cell death was not seen in other tissues such as liver or muscle as shown by low levels of cleaved caspase 3 and no difference in expression of pro apoptotic genes p53 upregulated modulator of apoptosis ( PUMA ) ( Bbc3 ) and Bax ( Bax ) ( XREF_SUPPLEMENTARY ) .	This increase in cell death was not seen in other tissues such as liver or muscle as shown by low levels of cleaved caspase 3 and no difference in expression of pro apoptotic genes p53 upregulated modulator of apoptosis (PUMA) (Bbc3) and Bax (Bax) (XREF_SUPPLEMENTARY).	34	51	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	34	35	46	47
In addition , ABCG5 , ENOX1 , INSR , MCC , NFAT5 together with p21 and BAX were induced in MCF7 cells treated with nutlin-3 , a p53 stabilizing agent ( XREF_FIG ) .	In addition, ABCG5, ENOX1, INSR, MCC, NFAT5 together with p21 and BAX were induced in MCF7 cells treated with nutlin-3, a p53 stabilizing agent (XREF_FIG).	11	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	27	28	16	17
Proapoptotic Bax , directly induced by p53 , can overcome the antiapoptotic effect of Bcl-2 , whereas p53 can directly inhibit Bcl-2 .	Proapoptotic Bax, directly induced by p53, can overcome the antiapoptotic effect of Bcl-2, whereas p53 can directly inhibit Bcl-2.	0	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	1	2
We demonstrated that inactivation of p53 by p53 specific siRNA significantly inhibits the expression of p53 targeted genes ( i.e. p21 and Bax ) and alleviated alcohol induced cell cycle arrest ( XREF_FIG ) .	We demonstrated that inactivation of p53 by p53 specific siRNA significantly inhibits the expression of p53 targeted genes (i.e. p21 and Bax) and alleviated alcohol induced cell cycle arrest (XREF_FIG).	3	23	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 by p53 specific siRNA significantly inhibits the expression of p53	p53	Bax	Bax	bax	5	6	22	23
The increased expression of the apoptotic proteins p53 and p53 upregulated modulator of apoptosis ( PUMA ) , as well as Bax , activated caspase-3 and caspase-9 together with significantly lower expression of Bcl-2 in preeclamptic placentas are consistent with the increased apoptosis .	The increased expression of the apoptotic proteins p53 and p53 upregulated modulator of apoptosis (PUMA), as well as Bax, activated caspase-3 and caspase-9 together with significantly lower expression of Bcl-2 in preeclamptic placentas are consistent with the increased apoptosis.	2	26	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	expression of the apoptotic proteins p53 and p53	p53	Bax	Bax	bax	9	10	21	22
Likewise , phosphorylation of p53 by Chk2 may lead to upregulation of Bax , an event promoting apoptosis .	Likewise, phosphorylation of p53 by Chk2 may lead to upregulation of Bax, an event promoting apoptosis.	2	15	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	p53	phosphorylation of p53	p53	Bax	Bax	bax	4	5	12	13
The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis .	The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	BAX	BAX	BAX	5	8	13	14
Intratumor injection of PEPD siRNA once every 2-3 days strongly downregulated PEPD in both types of tumors , strongly inhibited HCT116-p53 +/+ tumors , which was accompanied by p53 activation ( Bcl-2 downregulation , upregulation of p21 and Bax , and caspase 3 activation ) in the tumors , but had no effect on HCT116-p53 -/- tumor growth or the p53 targets in these tumors .	Intratumor injection of PEPD siRNA once every 2-3 days strongly downregulated PEPD in both types of tumors, strongly inhibited HCT116-p53 +/+ tumors, which was accompanied by p53 activation (Bcl-2 downregulation, upregulation of p21 and Bax, and caspase 3 activation) in the tumors, but had no effect on HCT116-p53 -/- tumor growth or the p53 targets in these tumors.	28	39	upregulation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	28	29	38	39
As shown in XREF_FIG , ABT-737 treatment did not increase p53 levels or induce p53 related genes BAX , PUMA , CDKN1A ( p21 ) , FAS or MDM2 .	As shown in XREF_FIG, ABT-737 treatment did not increase p53 levels or induce p53 related genes BAX, PUMA, CDKN1A (p21), FAS or MDM2.	5	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	ABT-737 treatment did not increase p53 levels	p53	BAX	BAX	bax	10	11	17	18
In fact cytosolic and mitochondrial p53 could activate Bax and Bak without direct regulation of gene expression XREF_BIBR .	In fact cytosolic and mitochondrial p53 could activate Bax and Bak without direct regulation of gene expression XREF_BIBR.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	8	9
One of the p53 transcription independent mechanisms that promote apoptosis involves wild-type p53 protein interacting with the antiapoptotic Bcl-XL protein in the cytoplasm to augment Bax and Bak induced outer mitochondrial membrane permeabilization .	One of the p53 transcription independent mechanisms that promote apoptosis involves wild-type p53 protein interacting with the antiapoptotic Bcl-XL protein in the cytoplasm to augment Bax and Bak induced outer mitochondrial membrane permeabilization.	12	27	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	12	13	25	26
Because ionizing radiation may activate the p53 mediated Bax pathway earlier than 24 h , we hypothesized that 17-DMAG also inhibited p53 activation in samples collected at 1 and 4 h postirradiation .	Because ionizing radiation may activate the p53 mediated Bax pathway earlier than 24 h, we hypothesized that 17-DMAG also inhibited p53 activation in samples collected at 1 and 4 h postirradiation.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	8	9
The activation of p53 activates the intrinsic apoptotic pathway by triggering the permeability of the outer mitochondrial membrane and coordinating pro apoptotic Bax and anti-apoptotic Bcl-2 .	The activation of p53 activates the intrinsic apoptotic pathway by triggering the permeability of the outer mitochondrial membrane and coordinating pro apoptotic Bax and anti-apoptotic Bcl-2.	1	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	22	23
Interestingly , p53 could also activate BAX ( and BAK ) in a transcription independent manner in response to DNA damage and metabolic changes [ XREF_BIBR - XREF_BIBR ] .	Interestingly, p53 could also activate BAX (and BAK) in a transcription independent manner in response to DNA damage and metabolic changes [XREF_BIBR - XREF_BIBR].	2	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	2	3	6	7
These include p53 upregulated modulator of apoptosis ( PUMA ) , NADPH oxidase activator ( NOXA ) , XREF_BIBR , XREF_BIBR , XREF_BIBR Bcl-2 family members Bax and Bid , XREF_BIBR , XREF_BIBR and apoptotic peptidase activating factor 1 ( Apaf-1 ) .	These include p53 upregulated modulator of apoptosis (PUMA), NADPH oxidase activator (NOXA), XREF_BIBR, XREF_BIBR, XREF_BIBR Bcl-2 family members Bax and Bid, XREF_BIBR, XREF_BIBR and apoptotic peptidase activating factor 1 (Apaf-1).	2	27	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	26	27
We have shown previously that p53 mediated neuronal cell death involves a Bax dependent activation of caspase 3 ; however , the transcriptional targets involved in the regulation of this process have not been identified .	We have shown previously that p53 mediated neuronal cell death involves a Bax dependent activation of caspase 3; however, the transcriptional targets involved in the regulation of this process have not been identified.	5	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	12	13
Yet another model proposed that stress induced cytosolic p53 is sequestered by soluble anti-apoptotic BCL-X L and transcriptional activation of PUMA displaces p53 , which then activates monomeric cytosolic BAX to induce apoptosis [ XREF_BIBR ] .	Yet another model proposed that stress induced cytosolic p53 is sequestered by soluble anti-apoptotic BCL-X L and transcriptional activation of PUMA displaces p53, which then activates monomeric cytosolic BAX to induce apoptosis [XREF_BIBR].	21	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	22	23	29	30
Furthermore , we find that p53 dependent activation of PUMA in response to EGCG directly leads to apoptosis with out requiring Bax as is the case in response to agents that induce DNA damage .	Furthermore, we find that p53 dependent activation of PUMA in response to EGCG directly leads to apoptosis with out requiring Bax as is the case in response to agents that induce DNA damage.	5	22	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	21	22
The mechanism of action of apigenin seems to involve p53 , as it increased the levels of p53 and the p53 induced gene products p21WAF1 and CIP1 and Bax .	The mechanism of action of apigenin seems to involve p53, as it increased the levels of p53 and the p53 induced gene products p21WAF1 and CIP1 and Bax.	15	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	levels of p53	p53	Bax	Bax	bax	17	18	28	29
We found that RO-3306 enhanced Nutlin induced p53 mediated Bax conformational changes and apoptosis in AML cells independently of cell cycle phases .	We found that RO-3306 enhanced Nutlin induced p53 mediated Bax conformational changes and apoptosis in AML cells independently of cell cycle phases.	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	9	10
Accordingly , we noted decreased apoptosis and down regulation of the p53 targeted pro apoptotic gene BAX and the DNA repair genes ERCC1 and XPC after UVB plus heat treatments .	Accordingly, we noted decreased apoptosis and down regulation of the p53 targeted pro apoptotic gene BAX and the DNA repair genes ERCC1 and XPC after UVB plus heat treatments.	8	20	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	11	12	16	17
Collectively , these data demonstrate that TSWU-BR23 leads to HT-29 cell apoptosis by inducing p53 mediated mitochondrial oligomerization of BAX and BAK and the localization of CD95 and FADD with lipid rafts at the cell surface .	Collectively, these data demonstrate that TSWU-BR23 leads to HT-29 cell apoptosis by inducing p53 mediated mitochondrial oligomerization of BAX and BAK and the localization of CD95 and FADD with lipid rafts at the cell surface.	14	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	14	15	19	20
An important regulator of apoptosis is p53 , which can induce Bax and Bak , which regulate the release of cytochrome C from mitochondria , thereby initiating the cascade that leads to apoptosis .	An important regulator of apoptosis is p53, which can induce Bax and Bak, which regulate the release of cytochrome C from mitochondria, thereby initiating the cascade that leads to apoptosis.	2	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	11	12
Interestingly , p53 mediated Bax induction is much greater in APE-1-suppressed AGS .	Interestingly, p53 mediated Bax induction is much greater in APE-1-suppressed AGS.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	4	5
Ser phosphorylation is implicated in stimulating transcriptional activation of p53 targeted genes ( p21 , BAX , and BAK ) and adopting in a wild-type conformation of p53 .	Ser phosphorylation is implicated in stimulating transcriptional activation of p53 targeted genes (p21, BAX, and BAK) and adopting in a wild-type conformation of p53.	7	16	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	9	10	15	16
It was speculated that the decreased phospho-Bad resulted from the reduced phospho-PKB and the up regulation of p53 caused the elevated activity of Bax .	It was speculated that the decreased phospho-Bad resulted from the reduced phospho-PKB and the up regulation of p53 caused the elevated activity of Bax.	15	24	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	17	18	23	24
Bax is directly activated by the p53 tumor suppressor proteins following stress induction or indirectly through the p53 activation of the Bcl-2 pro apoptotic member Noxa and PUMA , or throught the p53-independant mechanisms .	Bax is directly activated by the p53 tumor suppressor proteins following stress induction or indirectly through the p53 activation of the Bcl-2 pro apoptotic member Noxa and PUMA, or throught the p53-independant mechanisms.	0	9	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	0	1
As a result , p53 , a known activator of pro apoptotic genes , activates Bax , Bad and Bak proteins , which are known to cause mitochondrial membrane leakage and release Cyt-C , thereby activating caspase-3 during the cascade reaction .	As a result, p53, a known activator of pro apoptotic genes, activates Bax, Bad and Bak proteins, which are known to cause mitochondrial membrane leakage and release Cyt-C, thereby activating caspase-3 during the cascade reaction.	4	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	15	16
As a result of the high DNA damage , the dynamic behavior of p53 caused sequential activation of the Bax , Cyt C and Caspase3 synthesis process , which qualitatively supports the intrinsic apoptosis induction system mechanism XREF_BIBR .	As a result of the high DNA damage, the dynamic behavior of p53 caused sequential activation of the Bax, Cyt C and Caspase3 synthesis process, which qualitatively supports the intrinsic apoptosis induction system mechanism XREF_BIBR.	11	26	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	13	14	19	20
These data indicate that adiponectin induces apoptosis through p53 mediated Bax induction that results in caspase 3 activation .	These data indicate that adiponectin induces apoptosis through p53 mediated Bax induction that results in caspase 3 activation.	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	10	11
P53 promotes apoptosis by inducing bax , so increasing the ratio of pro- to anti-apoptotic proteins ( Haupt et al , 2003 ) .	P53 promotes apoptosis by inducing bax, so increasing the ratio of pro- to anti-apoptotic proteins (Haupt et al, 2003).	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	bax	bax	bax	0	1	5	6
BAX is transcriptionally upregulated by the tumor suppressor p53 and upon death stimuli it dimerizes and inserts into the mitochondrial membrane to induce the mitochondrial pathway of apoptosis by mitochondrial outer membrane permeabilization .	BAX is transcriptionally upregulated by the tumor suppressor p53 and upon death stimuli it dimerizes and inserts into the mitochondrial membrane to induce the mitochondrial pathway of apoptosis by mitochondrial outer membrane permeabilization.	0	9	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	BAX	BAX	BAX	6	9	0	1
Interestingly , Bax and Noxa can be transcriptionally upregulated by p53 , a tumor suppressor that is upregulated in response to IR .	Interestingly, Bax and Noxa can be transcriptionally upregulated by p53, a tumor suppressor that is upregulated in response to IR.	2	14	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	10	11	2	3
An accumulation of p53 in the cytosol can act in a similar way to BH3-only proteins , thus inducing the oligomerization of Bax [ XREF_BIBR ] .	An accumulation of p53 in the cytosol can act in a similar way to BH3-only proteins, thus inducing the oligomerization of Bax [XREF_BIBR].	1	24	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	22	23
However , the overexpression of miR-214 reduced the anticancer effect of cantharidin on the proliferation and apoptosis of TSCC Tca8113 cells , inhibited p53 protein expression , and increased the Bcl-2 and Bax signaling pathway .	However, the overexpression of miR-214 reduced the anticancer effect of cantharidin on the proliferation and apoptosis of TSCC Tca8113 cells, inhibited p53 protein expression, and increased the Bcl-2 and Bax signaling pathway.	3	34	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	overexpression of miR-214 reduced the anticancer effect of cantharidin on the proliferation and apoptosis of TSCC Tca8113 cells, inhibited p53 protein expression	p53	Bax	Bax	bax	23	24	32	33
A p53 transcriptional independent activation of Bax has been described following the activation of caspase 8 and the up-regulation of Puma XREF_BIBR , consistently with our data from bDHC treated cells ( XREF_FIG and XREF_FIG ) .	A p53 transcriptional independent activation of Bax has been described following the activation of caspase 8 and the up-regulation of Puma XREF_BIBR, consistently with our data from bDHC treated cells (XREF_FIG and XREF_FIG).	1	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	6	7
Inhibition of p53 with pifthrin-alpha or Bax with siRNAs significantly reduced rotenone induced Bax induction and apoptotic cell death .	Inhibition of p53 with pifthrin-alpha or Bax with siRNAs significantly reduced rotenone induced Bax induction and apoptotic cell death.	0	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	13	14
The cytosolic p53 induces homo-oligomerization of Bax ( XREF_FIG ) , followed by Bax activation and mitochondrial translocation [ XREF_BIBR ] .	The cytosolic p53 induces homo-oligomerization of Bax (XREF_FIG), followed by Bax activation and mitochondrial translocation [XREF_BIBR].	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	6	7
Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins ( BIM and BID ) .	Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins (BIM and BID).	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	4	5	6	7
Cytosolic accumulation of p53 has been reported to directly activate Bax to insert and oligomerize into the mitochondrial membrane , thus leading to the cascade of mitochondria mediated apoptosis and caspase-3 activation [ XREF_BIBR ] .	Cytosolic accumulation of p53 has been reported to directly activate Bax to insert and oligomerize into the mitochondrial membrane, thus leading to the cascade of mitochondria mediated apoptosis and caspase-3 activation [XREF_BIBR].	1	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	10	11
Nutlin-3 rapidly accumulates p53 ( ~ 1 hour ) that can directly activate Bax , and our results suggest that CDK1 inhibition actively enhances the p53 mediated mitochondrial apoptotic pathway .	Nutlin-3 rapidly accumulates p53 (~ 1 hour) that can directly activate Bax, and our results suggest that CDK1 inhibition actively enhances the p53 mediated mitochondrial apoptotic pathway.	2	14	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	13	14
Pin1 induced proline isomerization in cytosolic p53 mediates BAX activation and apoptosis .	Pin1 induced proline isomerization in cytosolic p53 mediates BAX activation and apoptosis.	3	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	6	7	8	9
Moreover , the induction of PUMA and other p53 targets Bax and p21 paralleled that of p53 , p53S15 phosphorylation and gamma-H2AX , a marker of DNA double-strand breaks ( XREF_FIG ) .	Moreover, the induction of PUMA and other p53 targets Bax and p21 paralleled that of p53, p53S15 phosphorylation and gamma-H2AX, a marker of DNA double-strand breaks (XREF_FIG).	8	12	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	10	11
Our results also revealed curcumin induced G2/M arrest and apoptosis of mammary epithelial carcinoma cells via p53 mediated Bax activation [ XREF_BIBR , XREF_BIBR ] .	Our results also revealed curcumin induced G2/M arrest and apoptosis of mammary epithelial carcinoma cells via p53 mediated Bax activation [XREF_BIBR, XREF_BIBR].	14	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	16	17	18	19
While p53 alone weakly activates BAX , activation is dramatically enhanced through catalysis of Pro47 cis-trans isomerization by Pin1 .	While p53 alone weakly activates BAX, activation is dramatically enhanced through catalysis of Pro47 cis-trans isomerization by Pin1.	1	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	1	2	5	6
In contrast to the nuclear and mitochondrial p53 functions that are mediated by the p53 DNA binding domain , here the N-terminus of p53 , comprising the first 102 amino acids , and in particular the polyproline rich domain spanning aa 62-91 , is sufficient to mediate Bax activation and apoptosis [ XREF_BIBR ] .	In contrast to the nuclear and mitochondrial p53 functions that are mediated by the p53 DNA binding domain, here the N-terminus of p53, comprising the first 102 amino acids, and in particular the polyproline rich domain spanning aa 62-91, is sufficient to mediate Bax activation and apoptosis [XREF_BIBR].	21	48	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	23	24	47	48
A second client is p53 since Hsp60 depletion disrupts Hsp60 and p53 complex and induces p53 stabilization that subsequently stimulates Bax dependent apoptosis .	A second client is p53 since Hsp60 depletion disrupts Hsp60 and p53 complex and induces p53 stabilization that subsequently stimulates Bax dependent apoptosis.	15	22	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	15	16	20	21
Induction of p53 has been reported to downregulate BCL-2 in breast cancer , 19 and upregulate BAX in lung cancer .	Induction of p53 has been reported to downregulate BCL-2 in breast cancer, 19 and upregulate BAX in lung cancer.	0	19	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	2	3	16	17
Interestingly , p53 increases after HIE injury and induces the increase of Bax .	Interestingly, p53 increases after HIE injury and induces the increase of Bax.	2	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	12	13
BAX activation is further enhanced by phosphorylation of p53 on Ser46 .	BAX activation is further enhanced by phosphorylation of p53 on Ser46.	0	11	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	phosphorylation of p53 on Ser46	p53	BAX	BAX	bax	8	9	0	1
However , activating p53 by actinomycin D did not promote ENOX1 , INSR , MCC expression , in contrast to BAX , p21 and ABCG5 ( XREF_FIG ) .	However, activating p53 by actinomycin D did not promote ENOX1, INSR, MCC expression, in contrast to BAX, p21 and ABCG5 (XREF_FIG).	2	24	promote	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	3	4	20	21
It has been suggested that bax is up-regulated by p53 gene XREF_BIBR .	It has been suggested that bax is up-regulated by p53 gene XREF_BIBR.	5	11	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	9	10	5	6
Expression of p53 shown in this study is able to activate proapoptotic factors ( Bax , Bak , Bcl- Xs , and Bad ) and antiapoptotic ( Bcl-2 , BclXL , and Bcl-W ) .	Expression of p53 shown in this study is able to activate proapoptotic factors (Bax, Bak, Bcl- Xs, and Bad) and antiapoptotic (Bcl-2, BclXL, and Bcl-W).	0	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	Expression of p53	p53	Bax	Bax	bax	2	3	14	15
p53 also activates proapoptotic members of the Bcl2 family : Bax , Noxa , and Puma involved in the permeabilization of the outer mitochondrial membrane [ XREF_BIBR ] .	p53 also activates proapoptotic members of the Bcl2 family : Bax, Noxa, and Puma involved in the permeabilization of the outer mitochondrial membrane [XREF_BIBR].	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	10	11
In conclusion , the trophoblast and decidual cells of patients with recurrent abortion were obviously apoptotic , which was probably related to abnormal expression of the CDKN1A and Bax genes mediated by TP53 protein through cellular pathways .	In conclusion, the trophoblast and decidual cells of patients with recurrent abortion were obviously apoptotic, which was probably related to abnormal expression of the CDKN1A and Bax genes mediated by TP53 protein through cellular pathways.	26	33	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TP53	TP53	TP53	Bax	Bax	Bax	32	33	28	29
p53 also has cytoplasmic actions at the mitochondrial level and can promote BAX dependent mitochondrial permeabilization .	p53 also has cytoplasmic actions at the mitochondrial level and can promote BAX dependent mitochondrial permeabilization.	0	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	0	1	12	13
p53 overexpression did not induce p21 , bax , or mdm2 in neurons .	p53 overexpression did not induce p21, bax, or mdm2 in neurons.	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 overexpression	p53	bax	bax	bax	0	1	7	8
In contrast with these observations , it was shown in human colorectal cancer cells that pharmacologic inhibition of GSK-3 elicited p53 dependent conformational activation of Bax , resulting in apoptosis induction .	In contrast with these observations, it was shown in human colorectal cancer cells that pharmacologic inhibition of GSK-3 elicited p53 dependent conformational activation of Bax, resulting in apoptosis induction.	20	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	20	21	25	26
Thus , AurA restrains p53 function in undifferentiated ESCs , and its downregulation during differentiation allows p53 mediated upregulation of Fas and initiation of Bax and Bak dependent apoptosis .	Thus, AurA restrains p53 function in undifferentiated ESCs, and its downregulation during differentiation allows p53 mediated upregulation of Fas and initiation of Bax and Bak dependent apoptosis.	16	28	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	16	17	24	25
Cytosolic p53 can be sequestered by antiapoptotic BCL-2 proteins , and directly activates BAK and BAX .	Cytosolic p53 can be sequestered by antiapoptotic BCL-2 proteins, and directly activates BAK and BAX.	0	16	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	1	2	15	16
Furthermore , dietary agent induced activation of p53 ( activator of bax ) can also mediate apoptosis in response to DNA damage [ XREF_BIBR ] .	Furthermore, dietary agent induced activation of p53 (activator of bax) can also mediate apoptosis in response to DNA damage [XREF_BIBR].	5	12	activator	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	7	8	11	12
Bax can be upregulated by p53 and is involved in p53 mediated apoptosis XREF_BIBR .	Bax can be upregulated by p53 and is involved in p53 mediated apoptosis XREF_BIBR.	0	8	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	0	1
p53 is then free to activate monomeric Bax in the cytosol [ XREF_BIBR ] .	p53 is then free to activate monomeric Bax in the cytosol [XREF_BIBR].	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	7	8
The proapoptotic protein Bax is up-regulated by p53 in response to DNA strand breaks that occur during ischemia and mediates p53 induced neuronal apoptosis .	The proapoptotic protein Bax is up-regulated by p53 in response to DNA strand breaks that occur during ischemia and mediates p53 induced neuronal apoptosis.	0	9	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	3	4
Inhibition of p53 expression with p53 antisense oligonucleotides inhibits apoptosis and prevents the increase in Bax and decrease in Bcl-2 .	Inhibition of p53 expression with p53 antisense oligonucleotides inhibits apoptosis and prevents the increase in Bax and decrease in Bcl-2.	2	16	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 expression	p53	Bax	Bax	bax	2	3	15	16
However , proapoptotic Bcl-2 family proteins such as Bax which is upregulated by p53 can activate apoptosis by releasing cytochrome c ( cyt-c ) from mitochondria , where Apaf-1 activation takes place [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	However, proapoptotic Bcl-2 family proteins such as Bax which is upregulated by p53 can activate apoptosis by releasing cytochrome c (cyt-c) from mitochondria, where Apaf-1 activation takes place [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	14	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	13	14	8	9
Once activated , p53 induces up-regulation of p21 and Bax , which mediate different aspects of p53 function on proliferation arrest and apoptosis [ XREF_BIBR , XREF_BIBR ] .	Once activated, p53 induces up-regulation of p21 and Bax, which mediate different aspects of p53 function on proliferation arrest and apoptosis [XREF_BIBR, XREF_BIBR].	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	9	10
Increased p53 levels and its phosphorylation increased Bax protein , caspase-9 , -3 activation and apoptosis .	Increased p53 levels and its phosphorylation increased Bax protein, caspase-9, -3 activation and apoptosis.	1	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 levels	p53	Bax	Bax	bax	1	2	7	8
These results not only indicated the requirement of p53 mediated transcriptional activation of Bax but also its role as down-stream effecter in theaflavin induced apoptosis .	These results not only indicated the requirement of p53 mediated transcriptional activation of Bax but also its role as down-stream effecter in theaflavin induced apoptosis.	6	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	13	14
Western blotting and real time PCR results showed that several p53 downstream genes responded strongly and synergistically to BTZ function and p53 restored expression ( accumulation of p21 and bax , activation of caspase 3 , down-regulation of Bcl-2 , etc. ) .	Western blotting and real time PCR results showed that several p53 downstream genes responded strongly and synergistically to BTZ function and p53 restored expression (accumulation of p21 and bax, activation of caspase 3, down-regulation of Bcl-2, etc.).	10	30	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	10	11	29	30
Activation of p53 promoted the intrinsic apoptosis pathway by triggering permeabilization of the outer mitochondrial membrane and coordinating pro apoptotic Bax and anti-apoptotic Bcl-2 .	Activation of p53 promoted the intrinsic apoptosis pathway by triggering permeabilization of the outer mitochondrial membrane and coordinating pro apoptotic Bax and anti-apoptotic Bcl-2.	0	23	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	20	21
These observations indicate that phosphorylation of p53 can induce Bax activation resulting in attenuation of cell viability .	These observations indicate that phosphorylation of p53 can induce Bax activation resulting in attenuation of cell viability.	4	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	phosphorylation of p53	p53	Bax	Bax	bax	6	7	9	10
However , RT-PCR analysis did not reveal increased steady-state mRNA levels of the p53 targets p21 and WAF1 , bax or the zebrafish ortholog of mdm2 in PS-341-treated embryos whereas ionizing radiation led , as expected , to elevated transcript levels for these genes ( XREF_SUPPLEMENTARY ) .	However, RT-PCR analysis did not reveal increased steady-state mRNA levels of the p53 targets p21 and WAF1, bax or the zebrafish ortholog of mdm2 in PS-341-treated embryos whereas ionizing radiation led, as expected, to elevated transcript levels for these genes (XREF_SUPPLEMENTARY).	10	20	targets	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p53	levels of the p53	p53	bax	bax	bax	13	14	19	20
Interestingly , even the targeted expression of p53 to mitochondria was insufficient to launch apoptosis , whereas overexpression of wild-type p53 induced Bax activation and apoptotic alterations .	Interestingly, even the targeted expression of p53 to mitochondria was insufficient to launch apoptosis, whereas overexpression of wild-type p53 induced Bax activation and apoptotic alterations.	17	23	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	20	21	22	23
Additionally , p53 promotes Bax mediated mitochondrial membrane permeabilization through transcriptional upregulation of the BH3-only-domain proteins Puma and Noxa [ XREF_BIBR - XREF_BIBR ] .	Additionally, p53 promotes Bax mediated mitochondrial membrane permeabilization through transcriptional upregulation of the BH3-only-domain proteins Puma and Noxa [XREF_BIBR - XREF_BIBR].	2	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	4	5
p53 , despite its lack of a canonical BH3 domain , is a direct activator of BAX and BAK .	p53, despite its lack of a canonical BH3 domain, is a direct activator of BAX and BAK.	0	18	is a direct activator	Positive_activation_copula_1	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	0	1	16	17
DDA3 dose-dependently inhibited ASPP2 in stimulating the p53 mediated BAX promoter activation without interfering the binding of ASPP2 to p53 .	DDA3 dose-dependently inhibited ASPP2 in stimulating the p53 mediated BAX promoter activation without interfering the binding of ASPP2 to p53.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	7	8	9	10
The CDK1 inhibitor RO-3306 enhances p53 mediated Bax activation and mitochondrial apoptosis in AML .	The CDK1 inhibitor RO-3306 enhances p53 mediated Bax activation and mitochondrial apoptosis in AML.	4	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	7	8
During apoptosis , the Bax gene is directly induced by the p53 protein .	During apoptosis, the Bax gene is directly induced by the p53 protein.	4	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	4	5
The activation of BAX mediated by cytosolic p53 occurs through a single step mechanism whereby cis-trans isomerization of p53 Pro47 triggers the simultaneous release of alpha6-alpha9 from the globular core of BAX .	The activation of BAX mediated by cytosolic p53 occurs through a single step mechanism whereby cis-trans isomerization of p53 Pro47 triggers the simultaneous release of alpha6-alpha9 from the globular core of BAX.	1	8	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	7	8	3	4
The apoptotic death of putaminal neurons and glia in a patient with hereditary ferritinopathy is studied immunohistochemically with antibodies to p53 , activated caspase-3 , PUMA , BAX , cytochrome c , and inducible nitric oxide synthase .	The apoptotic death of putaminal neurons and glia in a patient with hereditary ferritinopathy is studied immunohistochemically with antibodies to p53, activated caspase-3, PUMA, BAX, cytochrome c, and inducible nitric oxide synthase.	15	28	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	20	21	27	28
The stabilization and accumulation of p53 can induce up-regulation of the apoptotic Bax gene , which can induce apoptosis [ XREF_BIBR ] .	The stabilization and accumulation of p53 can induce up-regulation of the apoptotic Bax gene, which can induce apoptosis [XREF_BIBR].	1	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	12	13
In agreement , p53 has been shown to transcriptionally activate BAX and repress BCL2 .	In agreement, p53 has been shown to transcriptionally activate BAX and repress BCL2.	3	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	3	4	10	11
Gopinath et al XREF_BIBR have reported that bax is upregulated by p53 .	Gopinath et al XREF_BIBR have reported that bax is upregulated by p53.	7	12	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	11	12	7	8
Mitochondrial p53 inhibits the anti-apoptotic protein Bcl-2 , and activates Bax to promote the formation of mitochondrial outer membrane permeability pores for the release of cytochrome c ( cyt c ) , which leads to caspase activation .	Mitochondrial p53 inhibits the anti-apoptotic protein Bcl-2, and activates Bax to promote the formation of mitochondrial outer membrane permeability pores for the release of cytochrome c (cyt c), which leads to caspase activation.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	10	11
p53 is an upstream mediator of Bax , and as expected , increased p53 levels were detected after ARHGAP10 reconstitution ( XREF_FIG H ) .	p53 is an upstream mediator of Bax, and as expected, increased p53 levels were detected after ARHGAP10 reconstitution (XREF_FIG H).	0	7	is an upstream mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	6	7
Though p53 induces Bax activation and apoptosis , relocating the p53 protein to mitochondria does not trigger tumor cell death , conversely grants apoptotic resistance to ionizing radiation [ XREF_BIBR ] .	Though p53 induces Bax activation and apoptosis, relocating the p53 protein to mitochondria does not trigger tumor cell death, conversely grants apoptotic resistance to ionizing radiation [XREF_BIBR].	1	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	3	4
Moreover , p53 but not tBid was able to induce swelling ( another classical hallmark of PTP opening ) of Bax and Bak DKO and WT mitochondria in a CsA dependent ( XREF_FIG ) and CypD dependent ( XREF_FIG ) manner .	Moreover, p53 but not tBid was able to induce swelling (another classical hallmark of PTP opening) of Bax and Bak DKO and WT mitochondria in a CsA dependent (XREF_FIG) and CypD dependent (XREF_FIG) manner.	2	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	20	21
These results suggested that ARHGAP10 promotes apoptosis by inducing p53 mediated Bax trans-activation and were further validated in ANTI-NC- and ANTI-3174-transfected BGC823 cells with or without ARHGAP10 repression ( XREF_FIG I ) .	These results suggested that ARHGAP10 promotes apoptosis by inducing p53 mediated Bax trans-activation and were further validated in ANTI-NC- and ANTI-3174-transfected BGC823 cells with or without ARHGAP10 repression (XREF_FIG I).	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	9	10	11	12
MI drugs also directly suppress Ku70 mRNA and protein expression ( XREF_FIG ) which in turn allows p53 induced free Bax to mediate apoptotic events .	MI drugs also directly suppress Ku70 mRNA and protein expression (XREF_FIG) which in turn allows p53 induced free Bax to mediate apoptotic events.	17	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	17	18	20	21
To show the induction of p21 promoter activity by Calcein AM was dependent on p53 , we used a pair of isogenic cell lines 27 p53 +/+ and p53 -/- HCT116 and showed that the induction of p21 and another p53 target Bax was observed on in p53 +/+ , but not in p53 -/- HCT116 cells ( XREF_SUPPLEMENTARY ) .	To show the induction of p21 promoter activity by Calcein AM was dependent on p53, we used a pair of isogenic cell lines 27 p53 +/+ and p53 -/- HCT116 and showed that the induction of p21 and another p53 target Bax was observed on in p53 +/+, but not in p53 -/- HCT116 cells (XREF_SUPPLEMENTARY).	35	43	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	40	41	42	43
This was in agreement with the fact that p53 activation did not induce Bax upregulation nor did EGFR inhibition promote Bad dephosphorylation .	This was in agreement with the fact that p53 activation did not induce Bax upregulation nor did EGFR inhibition promote Bad dephosphorylation.	8	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	13	14
In addition , p53 was found to directly activate BAX in the cytoplasm .	In addition, p53 was found to directly activate BAX in the cytoplasm.	3	12	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	3	4	9	10
RhoA-ROCK pathway also induces p53 mediated upregulation of Bax to activate a mitochondrial apoptosis in cardiomyocytes XREF_BIBR .	RhoA-ROCK pathway also induces p53 mediated upregulation of Bax to activate a mitochondrial apoptosis in cardiomyocytes XREF_BIBR.	4	9	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	8	9
The responses to infection included : ( 1 ) > 30 % decrease at 72 h after infection in overall host-cell production of monitored mRNA synthesis , with the replacement of host-cell mRNA by viral mRNA , ( 2 ) suppression of the expression of selected mitochondrial and DNA repair gene transcripts , ( 3 ) increased expression of the proapoptotic gene and its gene p53 induced product Bax , and ( 4 ) activation of caspases 2 , 3 , and 9 .	The responses to infection included : (1)> 30% decrease at 72 h after infection in overall host-cell production of monitored mRNA synthesis, with the replacement of host-cell mRNA by viral mRNA, (2) suppression of the expression of selected mitochondrial and DNA repair gene transcripts, (3) increased expression of the proapoptotic gene and its gene p53 induced product Bax, and (4) activation of caspases 2, 3, and 9.	57	69	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	expression of the proapoptotic gene and its gene p53	p53	Bax	Bax	bax	65	66	68	69
Thus , Pin1 and p53 may cooperate to trigger the displacement of BAX alpha6-9 .	Thus, Pin1 and p53 may cooperate to trigger the displacement of BAX alpha6-9.	2	13	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	4	5	12	13
p53 can induce intrinsic apoptosis by increasing the gene expression of proapoptotic stimuli ( e.g ., BAX , NOXA , and PUMA ) while inhibiting the expression of antiapoptotic Bcl-2 family members .	p53 can induce intrinsic apoptosis by increasing the gene expression of proapoptotic stimuli (e.g., BAX, NOXA, and PUMA) while inhibiting the expression of antiapoptotic Bcl-2 family members.	0	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	0	1	16	17
Full-length or near full-length p53 ( p53 1-360 ) activated BAX with modest potency compared to cleaved BID , a BH3-only BAX activator ( n/c-BID ; XREF_FIG ; XREF_SUPPLEMENTARY ) .	Full-length or near full-length p53 (p53 1-360) activated BAX with modest potency compared to cleaved BID, a BH3-only BAX activator (n/c-BID; XREF_FIG; XREF_SUPPLEMENTARY).	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	4	5	10	11
p53 also can directly activate Bax to permeabilize mitochondria , cause mitochondrial CytC release , caspase activation , which triggers apoptosis [ XREF_BIBR ] .	p53 also can directly activate Bax to permeabilize mitochondria, cause mitochondrial CytC release, caspase activation, which triggers apoptosis [XREF_BIBR].	0	6	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	5	6
However , cell death was associated with p53 induction and concomitant upregulation of PUMAalpha and Bax and downregulation of Bcl-2 and Hsp70 protein expression .	However, cell death was associated with p53 induction and concomitant upregulation of PUMAalpha and Bax and downregulation of Bcl-2 and Hsp70 protein expression.	7	16	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	15	16
p53 has been postulated to up-regulate Bax [ XREF_BIBR ] .	p53 has been postulated to up-regulate Bax [XREF_BIBR].	0	8	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	6	7
The tumor suppressor protein , p53 , targets both Bcl-2 and Bax and promotes growth arrest and cell death in response to cell damage .	The tumor suppressor protein, p53, targets both Bcl-2 and Bax and promotes growth arrest and cell death in response to cell damage.	3	12	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	11	12
In this context , p53 can up-regulate the proapoptotic Bcl-2 family member Bax and possibly transcriptionally repress the antiapoptotic protein Bcl-2 XREF_BIBR .	In this context, p53 can up-regulate the proapoptotic Bcl-2 family member Bax and possibly transcriptionally repress the antiapoptotic protein Bcl-2 XREF_BIBR.	4	16	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	12	13
Further , TUDCA protected PC12 cells against p53- and Bax dependent apoptosis induced by E2F-1 and p53 overexpression , respectively .	Further, TUDCA protected PC12 cells against p53- and Bax dependent apoptosis induced by E2F-1 and p53 overexpression, respectively.	7	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53 overexpression	p53	Bax	Bax	bax	16	17	9	10
A Western blot analysis showed that imperatorin significantly enhanced the p53 protein level , which subsequently down-regulated Mcl-1 protein and up-regulated Bax , while it had a minimal effect on Bcl-2 expression .	A Western blot analysis showed that imperatorin significantly enhanced the p53 protein level, which subsequently down-regulated Mcl-1 protein and up-regulated Bax, while it had a minimal effect on Bcl-2 expression.	6	22	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	imperatorin significantly enhanced the p53 protein level	p53	Bax	Bax	bax	10	11	21	22
BAX , a member of the Bcl-2 gene family , may be activated by p53 to induce apoptosis .	BAX, a member of the Bcl-2 gene family, may be activated by p53 to induce apoptosis.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	14	15	0	1
Two patients ( P3 and P8 ) were selected for ex vivo treatment experiments and determination of protein expression of the p53 targeted genes BAX and BCL-2 , and showed an appropriate induction of these p53 regulated gene products in concordance with mRNA expression .	Two patients (P3 and P8) were selected for ex vivo treatment experiments and determination of protein expression of the p53 targeted genes BAX and BCL-2, and showed an appropriate induction of these p53 regulated gene products in concordance with mRNA expression.	18	26	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	expression of the p53	p53	BAX	BAX	bax	21	22	24	25
However , the expression of P53 target genes involved in apoptosis was generally much lower in melanoma cell lines compared to that in normal cells ( for example BAX is normally increased by P53 , but showed decreased expression in melanoma ) and suggests that P53 signalling is aberrant in melanoma .	However, the expression of P53 target genes involved in apoptosis was generally much lower in melanoma cell lines compared to that in normal cells (for example BAX is normally increased by P53, but showed decreased expression in melanoma) and suggests that P53 signalling is aberrant in melanoma.	27	36	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	P53	P53	P53	BAX	BAX	BAX	33	34	28	29
The isomerization of p53 Pro 47 directly mediates BAX activation .	The isomerization of p53 Pro 47 directly mediates BAX activation.	3	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	3	4	8	9
P53 dependent up-regulation of Bax and down-regulation of Bcl X L is suggested as the possible pathway of apoptosis followed by MCF7 cells on exposure to the bioactive fraction .	P53 dependent up-regulation of Bax and down-regulation of Bcl X L is suggested as the possible pathway of apoptosis followed by MCF7 cells on exposure to the bioactive fraction.	0	10	up-regulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	P53	P53	P53	Bax	Bax	Bax	0	1	4	5
In particular , by using gene targeted mice , we have shown that while p53 mediates Bax transcriptional induction following complex I blockade with MPTP , it does not participate in Bax mitochondrial translocation in this model , neither by a transcription independent mechanism nor through induction of the BH3-only proteins Puma or Noxa [ XREF_BIBR ] .	In particular, by using gene targeted mice, we have shown that while p53 mediates Bax transcriptional induction following complex I blockade with MPTP, it does not participate in Bax mitochondrial translocation in this model, neither by a transcription independent mechanism nor through induction of the BH3-only proteins Puma or Noxa [XREF_BIBR].	14	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	14	15	16	17
The transcription independent activation of Bax by p53 occurred with similar kinetics and concentrations to those produced by activated Bid .	The transcription independent activation of Bax by p53 occurred with similar kinetics and concentrations to those produced by activated Bid.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	5	6
And expressions of p21 and Bax were significantly down-regulated after p53 knockdown ( XREF_FIG ) , demonstrating that p21 and Bax were directly regulated by p53 , which is consistent with the reported results XREF_BIBR .	And expressions of p21 and Bax were significantly down-regulated after p53 knockdown (XREF_FIG), demonstrating that p21 and Bax were directly regulated by p53, which is consistent with the reported results XREF_BIBR.	18	26	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	25	26	20	21
Thus , Myc induced apoptotic signals through Bim and p53 must bifurcate to activate Bax , suggesting that the activation of Bim and p53 significantly contribute to apoptosis .	Thus, Myc induced apoptotic signals through Bim and p53 must bifurcate to activate Bax, suggesting that the activation of Bim and p53 significantly contribute to apoptosis.	9	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	9	10	14	15
Thus , Bax , Noxa , Puma , Bik and Nbk and Bid are upregulated by p53 [ XREF_BIBR - XREF_BIBR ] .	Thus, Bax, Noxa, Puma, Bik and Nbk and Bid are upregulated by p53 [XREF_BIBR - XREF_BIBR].	2	18	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	16	17	2	3
In transcription independent apoptosis , p53 translocates to the mitochondria , where it directly activates BAX and induces MOMP , leading to the release of cytochrome c and subsequent activation of caspases 9 and 3 [ XREF_BIBR ] .	In transcription independent apoptosis, p53 translocates to the mitochondria, where it directly activates BAX and induces MOMP, leading to the release of cytochrome c and subsequent activation of caspases 9 and 3 [XREF_BIBR].	5	16	directly activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p53	p53 translocates to the mitochondria	p53	BAX	BAX	bax	5	6	15	16
For example , cytosolic and mitochondrial forms of p53 have been shown to directly activate the pro apoptotic effectors BAK and BAX as well as bind and inhibit the anti-apoptotic proteins BCL-xL and BCL-2 [ XREF_BIBR - XREF_BIBR ] .	For example, cytosolic and mitochondrial forms of p53 have been shown to directly activate the pro apoptotic effectors BAK and BAX as well as bind and inhibit the anti-apoptotic proteins BCL-xL and BCL-2 [XREF_BIBR - XREF_BIBR].	6	22	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	8	9	21	22
Others also implicated that p53 upregulated proapoptotic Bax and downregulated prosurvival Bcl-2 to mediate apoptosis [ XREF_BIBR , XREF_BIBR ] .	Others also implicated that p53 upregulated proapoptotic Bax and downregulated prosurvival Bcl-2 to mediate apoptosis [XREF_BIBR, XREF_BIBR].	4	9	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	7	8
Such an example was recently reported by us [ XREF_BIBR ] in a patient of the present cohort and involved the deletion of the full BAX gene , which is directly activated by the TP53 protein .	Such an example was recently reported by us [XREF_BIBR] in a patient of the present cohort and involved the deletion of the full BAX gene, which is directly activated by the TP53 protein.	25	35	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TP53	TP53	TP53	BAX	BAX	BAX	34	35	25	26
BAX , a homologue of BCL-2 , is induced by p53 and is a promoter of apoptosis .	BAX, a homologue of BCL-2, is induced by p53 and is a promoter of apoptosis.	0	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	10	11	0	1
A subgroup of the Bcl-2 family , BH3 ( Bcl-2 homology 3 )-only proteins , such as PUMA were also activated primarily by p53 and act indirectly on the Bcl-2 family members Bax and/or Bak by relieving the inhibition imposed by antiapoptotic members such as Bcl-2 .	A subgroup of the Bcl-2 family, BH3 (Bcl-2 homology 3)-only proteins, such as PUMA were also activated primarily by p53 and act indirectly on the Bcl-2 family members Bax and/or Bak by relieving the inhibition imposed by antiapoptotic members such as Bcl-2.	20	33	activated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	23	24	32	33
Increased expression of p53 induces an increase in the Bax : Bcl-2 ratio , resulting in cytochrome-c , caspase activation , and , ultimately , apoptosis .	Increased expression of p53 induces an increase in the Bax : Bcl-2 ratio, resulting in cytochrome-c, caspase activation, and, ultimately, apoptosis.	1	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	expression of p53	p53	Bax	Bax	bax	3	4	9	10
Syncytia arising from the fusion of cells expressing the HIV-1-encoded Env gene with cells expressing the CD4 and CXCR4 complex undergo apoptosis following the nuclear translocation of mammalian target of rapamycin ( mTOR ) , mTOR mediated phosphorylation of p53 on Ser15 ( p53 ( S15 ) ) , p53 dependent upregulation of Bax and activation of the mitochondrial death pathway .	Syncytia arising from the fusion of cells expressing the HIV-1-encoded Env gene with cells expressing the CD4 and CXCR4 complex undergo apoptosis following the nuclear translocation of mammalian target of rapamycin (mTOR), mTOR mediated phosphorylation of p53 on Ser15 (p53 (S15)), p53 dependent upregulation of Bax and activation of the mitochondrial death pathway.	49	55	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	49	50	53	54
P53 directly activated Bax and released pro apoptotic molecules , activating multidomain protein complexes in the cytoplasm .	P53 directly activated Bax and released pro apoptotic molecules, activating multidomain protein complexes in the cytoplasm.	0	5	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	Bax	Bax	Bax	0	1	3	4
Aim of this study was to investigate the p53 and to define the impact of individual gene defects in p53 and the transcriptional p53 targets Bax and p21 CIP and WAF -1 .	Aim of this study was to investigate the p53 and to define the impact of individual gene defects in p53 and the transcriptional p53 targets Bax and p21 CIP and WAF -1.	11	26	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	23	24	25	26
This resulted in increased levels of the p53 target Bax , and was further increased following cisplatin treatment [ XREF_BIBR ] .	This resulted in increased levels of the p53 target Bax, and was further increased following cisplatin treatment [XREF_BIBR].	4	10	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	9	10
In mammals , the release of mitochondrial cytochrome C can be triggered through p53 induced activation of BAX in a caspase independent manner , and cells from mice deficient in caspase 9 or Apaf-1 were resistant to DNA damage induced apoptosis and to p53 dependent death stimuli .	In mammals, the release of mitochondrial cytochrome C can be triggered through p53 induced activation of BAX in a caspase independent manner, and cells from mice deficient in caspase 9 or Apaf-1 were resistant to DNA damage induced apoptosis and to p53 dependent death stimuli.	11	18	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	13	14	17	18
These findings , when taken together , suggest that the lack of fortilin TCTP allowed p53 to transcriptionally activate BAX and to induce the loss of MPhis through apoptosis , leading to the amelioration of atherosclerosis [ XREF_BIBR ] .	These findings, when taken together, suggest that the lack of fortilin TCTP allowed p53 to transcriptionally activate BAX and to induce the loss of MPhis through apoptosis, leading to the amelioration of atherosclerosis [XREF_BIBR].	15	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	15	16	19	20
In functional p53 expressing cancer cells , crocetin targets p53 mediated BAX activation in one hand and PIDD and caspase-2-mediated BID activation on the other which together converge to mitochondria to cause transmembrane permeability loss and caspase cascade activation .	In functional p53 expressing cancer cells, crocetin targets p53 mediated BAX activation in one hand and PIDD and caspase-2-mediated BID activation on the other which together converge to mitochondria to cause transmembrane permeability loss and caspase cascade activation.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	9	10	11	12
Additionally , the combination of FK228 and Ad-p53 induced Bax translocation to the mitochondria .	Additionally, the combination of FK228 and Ad-p53 induced Bax translocation to the mitochondria.	3	10	induced	Positive_early_activation	Positive_activation	Positive_activation	Ad-p53	Ad-p53	Ad-p53	Bax	Bax	Bax	7	8	9	10
Thus , p53 induces upregulation of the pro apoptotic regulator Bax leading to mitochondrial permeabilization and release of pro apoptotic mitochondrial proteins .	Thus, p53 induces upregulation of the pro apoptotic regulator Bax leading to mitochondrial permeabilization and release of pro apoptotic mitochondrial proteins.	2	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	10	11
In the nucleus , p53 activates p21 and Bax genes ; p21 arrest cycling cells at the G 1 -S checkpoint , whereas free Bax localize to mitochondria and trigger apoptosis .	In the nucleus, p53 activates p21 and Bax genes; p21 arrest cycling cells at the G 1 -S checkpoint, whereas free Bax localize to mitochondria and trigger apoptosis.	4	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	8	9
Cytoplasmic p53 directly activates the proapoptotic protein Bax through direct interaction .	Cytoplasmic p53 directly activates the proapoptotic protein Bax through direct interaction.	0	8	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	7	8
For example , enhanced p53 may activate bax , an antagonist of Bcl-2 [ XREF_BIBR ] , or enhance the synthesis of insulin like growth factor-I ( IGF-I ) receptor and one of its binding proteins , IGF-BP3 [ XREF_BIBR ] .	For example, enhanced p53 may activate bax, an antagonist of Bcl-2 [XREF_BIBR], or enhance the synthesis of insulin like growth factor-I (IGF-I) receptor and one of its binding proteins, IGF-BP3 [XREF_BIBR].	3	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	4	5	7	8
We found that the treatment of iPSCs with phthalate esters activated the transcriptional activity of p53 ( XREF_FIG ) , which is known to upregulate BAX and p21 Cip1 .	We found that the treatment of iPSCs with phthalate esters activated the transcriptional activity of p53 (XREF_FIG), which is known to upregulate BAX and p21 Cip1.	13	28	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	15	16	25	26
Overexpression of the anti-apoptotic protein Bcl-2 in MCF-7 cells inhibited SST induced apoptosis upstream of acidification by inhibiting p53 dependent induction of Bax as well as by raising the resting pH ( i ) and attenuating SST induced decrease in pH ( i ) .	Overexpression of the anti-apoptotic protein Bcl-2 in MCF-7 cells inhibited SST induced apoptosis upstream of acidification by inhibiting p53 dependent induction of Bax as well as by raising the resting pH (i) and attenuating SST induced decrease in pH (i).	18	23	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	18	19	22	23
Furthermore , upregulation of p53 may further elevate the Bax and Bcl -2 ratio , thus inducing cellular apoptosis .	Furthermore, upregulation of p53 may further elevate the Bax and Bcl -2 ratio, thus inducing cellular apoptosis.	2	13	elevate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	9	10
Following high-dose UV irradiation , p53 accumulated in the cytoplasm and led to activation of the pro apoptotic protein Bax .	Following high-dose UV irradiation, p53 accumulated in the cytoplasm and led to activation of the pro apoptotic protein Bax.	5	20	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	19	20
Under conditions of genotoxic stress , human p53 activates the apoptotic effectors BAX or BAK , resulting in mitochondrial outer membrane permeabilization and apoptosis .	Under conditions of genotoxic stress, human p53 activates the apoptotic effectors BAX or BAK, resulting in mitochondrial outer membrane permeabilization and apoptosis.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	7	8	12	13
In parallel treatment of 4-HNE to HepG2 cells also induces apoptosis by p53 pathway through activation of Bax , p21 , JNK , and caspase-3 .	In parallel treatment of 4-HNE to HepG2 cells also induces apoptosis by p53 pathway through activation of Bax, p21, JNK, and caspase-3.	9	24	induces	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	12	13	17	18
Network analysis using Ingenuity Pathway Analysis revealed that SNEB was associated with NRF2 mediated oxidative stress , mitochondrial dysfunction , endoplasmic reticulum stress , natural killer cell signaling , p53 signaling , downregulation of IL-15 , BCL-2 , and IFN-gamma ; upregulation of BAX and CHOP and increased apoptosis with a potential negative impact on innate and adaptive immunity .	Network analysis using Ingenuity Pathway Analysis revealed that SNEB was associated with NRF2 mediated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, natural killer cell signaling, p53 signaling, downregulation of IL-15, BCL-2, and IFN-gamma; upregulation of BAX and CHOP and increased apoptosis with a potential negative impact on innate and adaptive immunity.	29	45	upregulation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	29	30	43	44
This study also found increased expression of proapoptotic genes such as p53 induced Bax and activation of caspase-2 , -3 , and -9 [ XREF_BIBR ] .	This study also found increased expression of proapoptotic genes such as p53 induced Bax and activation of caspase-2, -3, and -9 [XREF_BIBR].	8	22	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	13	14
Bax is induced both by p53 and by TGF-beta1 .	Bax is induced both by p53 and by TGF-beta1.	0	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	0	1
The pro apoptotic functions of p53 are largely promoted by effectors that include p53 upregulated modulator of apoptosis ( PUMA ) and Bax , both proapoptotic members of the Bcl-2 family .	The pro apoptotic functions of p53 are largely promoted by effectors that include p53 upregulated modulator of apoptosis (PUMA) and Bax, both proapoptotic members of the Bcl-2 family.	13	23	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	13	14	22	23
As tumor suppressor p53 has been shown to engage and activate Bax and Bak in vitro , XREF_BIBR , XREF_BIBR it is possible that p53 directly activates Bax and Bak in the TKO cells following Bcl-xL and Mcl -1 inactivation .	As tumor suppressor p53 has been shown to engage and activate Bax and Bak in vitro, XREF_BIBR, XREF_BIBR it is possible that p53 directly activates Bax and Bak in the TKO cells following Bcl-xL and Mcl -1 inactivation.	24	29	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	24	25	27	28
Bcl-2 and Bax modify this pathway or directly regulated by p53 .	Bcl-2 and Bax modify this pathway or directly regulated by p53.	0	11	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	10	11	2	3
p53 functions as a transcription factor inducing MDM2 , Bax or IGF-BP3 , and represses myc , fos or Bcl2 .	p53 functions as a transcription factor inducing MDM2, Bax or IGF-BP3, and represses myc, fos or Bcl2.	0	10	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	9	10
WithaD robustly enhanced p53 expression and also induced p53 dependent Bax and independent Bak upregulation .	WithaD robustly enhanced p53 expression and also induced p53 dependent Bax and independent Bak upregulation.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	WithaD robustly enhanced p53 expression	p53	Bax	Bax	bax	3	4	10	11
In the endogenous network we constructed , BAX is activated by c-Myc and p53 while it is inhibited by Bcl-2 and Bcl-xL .	In the endogenous network we constructed, BAX is activated by c-Myc and p53 while it is inhibited by Bcl-2 and Bcl-xL.	7	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	13	14	7	8
In bone marrow cells of FLV + total body irradiation ( TBI )-treated C3H mice , the p53 protein was prominently activated to overexpress p21 and bax suggesting that apoptosis enhancing mechanisms lay upstream of p53 protein in the signaling pathway .	In bone marrow cells of FLV + total body irradiation (TBI)-treated C3H mice, the p53 protein was prominently activated to overexpress p21 and bax suggesting that apoptosis enhancing mechanisms lay upstream of p53 protein in the signaling pathway.	17	27	overexpress	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	17	18	26	27
Our results show that JP-1 upregulates p53 protein level to increase those of p21 and BAX , resulting in growth arrest and apoptosis of A549 cells .	Our results show that JP-1 upregulates p53 protein level to increase those of p21 and BAX, resulting in growth arrest and apoptosis of A549 cells.	4	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	JP-1 upregulates p53 protein level	p53	BAX	BAX	bax	6	7	15	16
Our data show that MLL-AF9 , MLL-AF10 , MLL-ENL , and MLL-ELL substantially down-regulate p53 mediated induction of p21 , MDM2 , and Bax in response to DNA damage .	Our data show that MLL-AF9, MLL-AF10, MLL-ENL, and MLL-ELL substantially down-regulate p53 mediated induction of p21, MDM2, and Bax in response to DNA damage.	14	24	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	14	15	23	24
BAX activation by p53 was abrogated upon ablation of the proline rich region between the transcriptional activation and DNA binding domains of p53 [ XREF_BIBR ] .	BAX activation by p53 was abrogated upon ablation of the proline rich region between the transcriptional activation and DNA binding domains of p53 [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	3	4	0	1
Moreover , AE up-regulated p53 , increased intracellular reactive oxygen species levels , depleted intracellular reduced GSH , up-regulated cytochrome c and Bax , down-regulated Bcl-2 , and activated caspase-9 and -3 .	Moreover, AE up-regulated p53, increased intracellular reactive oxygen species levels, depleted intracellular reduced GSH, up-regulated cytochrome c and Bax, down-regulated Bcl-2, and activated caspase-9 and -3.	4	28	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	22	23
The representative member , Bcl-2 , is a protein of the outer mitochondrial membrane with anti-apoptotic activity.The Bcl-2 homologue , Bax , a monomeric cytosolic protein , displays a pro apoptotic function.The Bax gene is transcriptionally activated by p53 , a tumour suppressor , now firmly established as a key inhibitory regulator of cell proliferation .	The representative member, Bcl-2, is a protein of the outer mitochondrial membrane with anti-apoptotic activity.The Bcl-2 homologue, Bax, a monomeric cytosolic protein, displays a pro apoptotic function.The Bax gene is transcriptionally activated by p53, a tumour suppressor, now firmly established as a key inhibitory regulator of cell proliferation.	32	54	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	38	39	32	33
Mitochondrial localization of p53 allows it to induce the release of mitochondrial Cyt c by triggering the membrane permeabilization activity of BAX .	Mitochondrial localization of p53 allows it to induce the release of mitochondrial Cyt c by triggering the membrane permeabilization activity of BAX.	1	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	3	4	21	22
In ( 7 ) , the first term represents Bax induced by p53 and the second one , self degradation of Bax .	In (7), the first term represents Bax induced by p53 and the second one, self degradation of Bax.	8	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	12	13	9	10
Recently , p53 has been shown to directly activate the pro apoptotic Bcl-2 protein Bax allowing for mitochondrial membrane permeabilization and apoptosis .	Recently, p53 has been shown to directly activate the pro apoptotic Bcl-2 protein Bax allowing for mitochondrial membrane permeabilization and apoptosis.	2	15	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	14	15
After DNA damage , PDCD5 is required for p53 mediated induction of Bax , thus promoting Tip60 dependent apoptosis [ XREF_BIBR ] .	After DNA damage, PDCD5 is required for p53 mediated induction of Bax, thus promoting Tip60 dependent apoptosis [XREF_BIBR].	8	13	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	12	13
p53 can also induce Bax to commence apoptosis which suppresses irregular cell growth such as cancer [ XREF_BIBR , XREF_BIBR ] .	p53 can also induce Bax to commence apoptosis which suppresses irregular cell growth such as cancer [XREF_BIBR, XREF_BIBR].	0	5	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	4	5
Irradiation induced thymocyte apoptosis is regulated in part through p53 dependent induction of the pro apoptotic genes NOXA , PUMA , and BAX .	Irradiation induced thymocyte apoptosis is regulated in part through p53 dependent induction of the pro apoptotic genes NOXA, PUMA, and BAX.	9	23	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	9	10	22	23
Various mechanisms of action have been proposed , including p53 mediated signaling XREF_BIBR , XREF_BIBR , XREF_BIBR , increased Bax expression XREF_BIBR , and decreased Bcl-2 XREF_BIBR .	Various mechanisms of action have been proposed, including p53 mediated signaling XREF_BIBR, XREF_BIBR, XREF_BIBR, increased Bax expression XREF_BIBR, and decreased Bcl-2 XREF_BIBR.	6	24	increased	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	9	10	19	20
BID interacts with BCl2 associated X protein ( BAX ) which in turn is up-regulated by wild type p53 to regulate cell cycle arrest and apoptosis in response to DNA damage .	BID interacts with BCl2 associated X protein (BAX) which in turn is up-regulated by wild type p53 to regulate cell cycle arrest and apoptosis in response to DNA damage.	6	19	up-regulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	18	19	8	9
If the DNA can not be repaired , p53 can induce Bax activation and downregulation of Bcl-2 , causing apoptosis [ XREF_BIBR , XREF_BIBR ] .	If the DNA can not be repaired, p53 can induce Bax activation and downregulation of Bcl-2, causing apoptosis [XREF_BIBR, XREF_BIBR].	8	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	11	12
Together , these results suggest a model in which p53 requires the cooperation of Sp1 or a Sp1 like factor to mediate transcriptional activation of the human BAX promoter .	Together, these results suggest a model in which p53 requires the cooperation of Sp1 or a Sp1 like factor to mediate transcriptional activation of the human BAX promoter.	9	28	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	9	10	27	28
Expression of mRNA for p53 , which induces Cdkn1a , did not change significantly , but the level of mRNA for Bax , which is induced by p53 , increased and that for Mdm2 , which promotes degradation of p53 , decreased with allergy .	Expression of mRNA for p53, which induces Cdkn1a, did not change significantly, but the level of mRNA for Bax, which is induced by p53, increased and that for Mdm2, which promotes degradation of p53, decreased with allergy.	21	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	27	28	21	22
Although 8226 cells contain mutated p53 ( 15 ) , a previous study [ XREF_BIBR ] indicated that p53 could activate BAX and induce apoptosis in the absence of transcriptional activity .	Although 8226 cells contain mutated p53 (15), a previous study [XREF_BIBR] indicated that p53 could activate BAX and induce apoptosis in the absence of transcriptional activity.	18	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	18	19	21	22
p53 phosphorylation mediated by doxorubicin may enhance Bax ( XREF_FIG ) and p21 WAF-1 ( data not shown ) induction in SJSA cells .	p53 phosphorylation mediated by doxorubicin may enhance Bax (XREF_FIG) and p21 WAF-1 (data not shown) induction in SJSA cells.	0	19	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 phosphorylation	p53	Bax	Bax	bax	0	1	7	8
In addition , DNA damage induced by Jaridonin activates p53 , which in turn up-regulates p21 and Bax , leading to cycle arrest and the loss of mitochondrial membrane potential for induction of apoptosis .	In addition, DNA damage induced by Jaridonin activates p53, which in turn up-regulates p21 and Bax, leading to cycle arrest and the loss of mitochondrial membrane potential for induction of apoptosis.	8	18	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	9	10	17	18
p53 Mediated Induction of Bax and p21 in Response to DNA Damage .	p53 Mediated Induction of Bax and p21 in Response to DNA Damage.	0	6	Mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	4	5
Other protein involved in the regulation of apoptosis is the tumour suppressor p53 that transcriptionally activates the proapoptotic genes Bax , Noxa , PUMA , and Bid and transcriptionally represses Bcl-2 and IAPs [ XREF_BIBR ] .	Other protein involved in the regulation of apoptosis is the tumour suppressor p53 that transcriptionally activates the proapoptotic genes Bax, Noxa, PUMA, and Bid and transcriptionally represses Bcl-2 and IAPs [XREF_BIBR].	1	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	12	13	19	20
It was also shown that cytosolic p53 can induce the mitochondrial apoptosis pathway by activating Bax and that Puma is required to release cytosolic p53 from Bcl-xL [ XREF_BIBR , XREF_BIBR ] .	It was also shown that cytosolic p53 can induce the mitochondrial apoptosis pathway by activating Bax and that Puma is required to release cytosolic p53 from Bcl-xL [XREF_BIBR, XREF_BIBR].	5	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	15	16
In addition to its transcriptional role , p53 can function directly at the mitochondrial level and activate Bax , via a specific interaction with Bcl-x L.	In addition to its transcriptional role, p53 can function directly at the mitochondrial level and activate Bax, via a specific interaction with Bcl-x L.	7	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	17	18
p53 mainly induced Bax and restrain the Bcl-2 , which can lead to the release of ATP and Cyt C in the cytoplasm .	p53 mainly induced Bax and restrain the Bcl-2, which can lead to the release of ATP and Cyt C in the cytoplasm.	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	3	4
Kohn and Pommier showed that p53 activates the synthesis of Bax while suppressing Bcl-2 synthesis , which is associated with the Bax degradation process XREF_BIBR .	Kohn and Pommier showed that p53 activates the synthesis of Bax while suppressing Bcl-2 synthesis, which is associated with the Bax degradation process XREF_BIBR.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	10	11
P53 can activate BAX , which lacks a clearly identifiable BH3 domain [ XREF_BIBR ] .	P53 can activate BAX, which lacks a clearly identifiable BH3 domain [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	BAX	BAX	BAX	0	1	3	4
Testing of other p53 constructs spanning individual or multiple domains showed that the N-terminal transcriptional activation region of p53 ( NTD ) was necessary and sufficient to activate BAX , consistent with studies reporting that p53-NTD triggers apoptosis upon expression in cells .	Testing of other p53 constructs spanning individual or multiple domains showed that the N-terminal transcriptional activation region of p53 (NTD) was necessary and sufficient to activate BAX, consistent with studies reporting that p53-NTD triggers apoptosis upon expression in cells.	16	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	18	19	28	29
Similarly , p53 ( M ) in the p53-transcription-independent pathway also activates Bax either directly or indirectly via binding Bcl-2 .	Similarly, p53 (M) in the p53-transcription-independent pathway also activates Bax either directly or indirectly via binding Bcl-2.	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	12	13
Ankrd2 enhanced the p53 mediated activation of both the BAX and MDM2 promoters , while ZASP6 acted as a negative regulator of p53 transcriptional activation both in the presence and absence of Ankrd2 .	Ankrd2 enhanced the p53 mediated activation of both the BAX and MDM2 promoters, while ZASP6 acted as a negative regulator of p53 transcriptional activation both in the presence and absence of Ankrd2.	3	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	3	4	9	10
PUMA inhibits the interaction of p53 with Bcl-XL , which releases p53 that subsequently activate Bax XREF_BIBR .	PUMA inhibits the interaction of p53 with Bcl-XL, which releases p53 that subsequently activate Bax XREF_BIBR.	10	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	15	16
Second , a site distal to the hydrophobic groove in Bcl-xL binds cytosolic p53 , inhibiting p53 dependent activation of BAX and apoptosis 8 .	Second, a site distal to the hydrophobic groove in Bcl-xL binds cytosolic p53, inhibiting p53 dependent activation of BAX and apoptosis 8.	16	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	16	17	20	21
Mechanistic studies reveal that inhibition of ATM and MET does not affect p53 dependent activation of p21 , 14-3-3sigma , PUMA or BAX .	Mechanistic studies reveal that inhibition of ATM and MET does not affect p53 dependent activation of p21, 14-3-3sigma, PUMA or BAX.	12	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	12	13	22	23
Apoptotic signals may come in the form of members of the Bcl-2 family of proteins , such as pro apoptotic Bax that can be up-regulated by tumor suppressor protein p53 in response to sensing DNA damage .	Apoptotic signals may come in the form of members of the Bcl-2 family of proteins, such as pro apoptotic Bax that can be up-regulated by tumor suppressor protein p53 in response to sensing DNA damage.	6	31	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	29	30	20	21
p53 activates transcriptionally target genes , such as p21waf1 and gadd45 , which can lead to cell cycle arrest , or bax , which can lead to cell death .	p53 activates transcriptionally target genes, such as p21waf1 and gadd45, which can lead to cell cycle arrest, or bax, which can lead to cell death.	0	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	0	1	21	22
In the transcription independent pathway , p53 directly activates BAX , which undergoes a conformational switch , oligomerizes , and inserts into OMM leading to apoptosis .	In the transcription independent pathway, p53 directly activates BAX, which undergoes a conformational switch, oligomerizes, and inserts into OMM leading to apoptosis.	6	12	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	6	7	9	10
p53 can directly activate the pro apoptotic protein Bax , a p53 primary response gene that leads to permeabilizitation mitochondria that induces the apoptotic program .	p53 can directly activate the pro apoptotic protein Bax, a p53 primary response gene that leads to permeabilizitation mitochondria that induces the apoptotic program.	0	14	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	8	9
Loss of a single p53 allele attenuated the increase of Bax ( XREF_FIG ) and reduced the number of apoptotic cardiomyocytes in mActin-Tg mice ( XREF_FIG ) .	Loss of a single p53 allele attenuated the increase of Bax (XREF_FIG) and reduced the number of apoptotic cardiomyocytes in mActin-Tg mice (XREF_FIG).	4	12	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	10	11
It has been shown previously that wild-type p53 activity can simultaneously up-regulate Bax , a protein which predisposes cells to programmed cell death ( PCD ) , and down-regulate Bcl-2 , a protein which antagonizes PCD .	It has been shown previously that wild-type p53 activity can simultaneously up-regulate Bax, a protein which predisposes cells to programmed cell death (PCD), and down-regulate Bcl-2, a protein which antagonizes PCD.	7	15	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	12	13
The accumulated p53 activated Bax and caspase-3 7 days after hydronephrosis induction and the resulting high levels of p53 dependent apoptotic proteins and gamma-H2AX tended to decrease APE .	The accumulated p53 activated Bax and caspase-3 7 days after hydronephrosis induction and the resulting high levels of p53 dependent apoptotic proteins and gamma-H2AX tended to decrease APE.	0	6	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	4	5
In contrast to promoter activation , we find that the 223 amino acids of the LANA C terminus are sufficient to inhibit p53 mediated activation of the human BAX promoter , indicating that the CBM is not required for all transcription related functions .	In contrast to promoter activation, we find that the 223 amino acids of the LANA C terminus are sufficient to inhibit p53 mediated activation of the human BAX promoter, indicating that the CBM is not required for all transcription related functions.	22	29	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	22	23	28	29
The activation of p53 increases Bax synthesis .	The activation of p53 increases Bax synthesis.	3	6	increases	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	5	6
( e ) p53 mediated caspase 11 activation , aside from p53 mediated Bax gene induction , may be an important pathway for cellular apoptosis after benzene exposure .	(e) p53 mediated caspase 11 activation, aside from p53 mediated Bax gene induction, may be an important pathway for cellular apoptosis after benzene exposure.	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	13	14
Furthermore , p53 protein , an important regulator of apoptosis can induce the Bax and Bak proteins thereby initiating the cascade leading to apoptosis through cytochrome C [ XREF_BIBR ] .	Furthermore, p53 protein, an important regulator of apoptosis can induce the Bax and Bak proteins thereby initiating the cascade leading to apoptosis through cytochrome C [XREF_BIBR].	2	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	13	14
p53 interacts with antiapoptotic members of the Bcl family such as Bcl-XL and Bcl-2 at the outer mitochondrial membrane to promote the oligomerization of the proapoptotic factors Bak and Bax .	p53 interacts with antiapoptotic members of the Bcl family such as Bcl-XL and Bcl-2 at the outer mitochondrial membrane to promote the oligomerization of the proapoptotic factors Bak and Bax.	0	30	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	29	30
Bax , the apoptosis inducing factor , has a p53 responsive element in its promoter region and is induced by p53 .	Bax, the apoptosis inducing factor, has a p53 responsive element in its promoter region and is induced by p53.	0	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	20	21	0	1
They also suggest that p53 induces Bax activation and this may be an initiation step of DRB induced apoptosis .	They also suggest that p53 induces Bax activation and this may be an initiation step of DRB induced apoptosis.	4	7	induces	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	6	7
Our results showing the transcription independent , p53 mediated activation of Bax in CCN1 mediated apoptosis ( XREF_FIG ) are consistent with recent findings that direct interaction of p53 with Bax and Bak , or with Bcl family members to displace BH3-only proteins , can lead to Bax activation and apoptosis independent of de novo protein synthesis .	Our results showing the transcription independent, p53 mediated activation of Bax in CCN1 mediated apoptosis (XREF_FIG) are consistent with recent findings that direct interaction of p53 with Bax and Bak, or with Bcl family members to displace BH3-only proteins, can lead to Bax activation and apoptosis independent of de novo protein synthesis.	7	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	11	12
The BAX and GTSE1 genes are transcriptionally upregulated by TP53 protein .	The BAX and GTSE1 genes are transcriptionally upregulated by TP53 protein.	1	10	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TP53	TP53	TP53	BAX	BAX	BAX	9	10	1	2
In fibroblasts , CCN1 triggers apoptosis by binding alpha 6 beta 1 and syndecan-4 , leading to the p53 dependent activation of Bax and cytochrome c release , resulting in apoptosis [ XREF_BIBR ] .	In fibroblasts, CCN1 triggers apoptosis by binding alpha 6 beta 1 and syndecan-4, leading to the p53 dependent activation of Bax and cytochrome c release, resulting in apoptosis [XREF_BIBR].	18	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	18	19	22	23
Furthermore , p53 can directly activate Bax and Bak to initiate apoptosis via the mitochondrial mediated pathway [ XREF_BIBR , XREF_BIBR ] .	Furthermore, p53 can directly activate Bax and Bak to initiate apoptosis via the mitochondrial mediated pathway [XREF_BIBR, XREF_BIBR].	2	8	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	6	7
XREF_BIBR At the mitochondria , p53 activates the main apoptotic effector proteins BAK and BAX , inducing their oligomerization and thereby initiating the apoptotic program .	XREF_BIBR At the mitochondria, p53 activates the main apoptotic effector proteins BAK and BAX, inducing their oligomerization and thereby initiating the apoptotic program.	5	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	5	6	14	15
For example , p53 was also reported to directly activate Bax at the mitochondria XREF_BIBR or contribute to cell death caused by necrosis , triggered by reactive oxygen species XREF_BIBR .	For example, p53 was also reported to directly activate Bax at the mitochondria XREF_BIBR or contribute to cell death caused by necrosis, triggered by reactive oxygen species XREF_BIBR.	3	16	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	10	11
A likely candidate is p53 , which activates BAX- and BAK dependent MOMP .	A likely candidate is p53, which activates BAX- and BAK dependent MOMP.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX-	BAX-	BAX-	4	5	8	9
This p53 protein activation causes an alteration of the Bax and Bcl -2 ratio , leading to caspase dependent apoptosis mediated by a mitochondrial Cyt-c release [ XREF_BIBR ] .	This p53 protein activation causes an alteration of the Bax and Bcl -2 ratio, leading to caspase dependent apoptosis mediated by a mitochondrial Cyt-c release [XREF_BIBR].	1	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	9	10
We also found that the activation of p53 induced Bax accumulation similarly in all cell lines and that this pro apoptotic member of the Bcl-2 family was involved in the apoptotic pathway in EBV (-) cell lines .	We also found that the activation of p53 induced Bax accumulation similarly in all cell lines and that this pro apoptotic member of the Bcl-2 family was involved in the apoptotic pathway in EBV (-) cell lines.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	9	10
In addition , p53 also has cytoplasmic actions at the mitochondrial level and can promote Bax dependent MOMP [ XREF_BIBR , XREF_BIBR ] .	In addition, p53 also has cytoplasmic actions at the mitochondrial level and can promote Bax dependent MOMP [XREF_BIBR, XREF_BIBR].	3	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	15	16
Previous studies have shown that Bax induction by p53 is necessary to inhibit tumour growth ( Yin et al , 1997 ) , but that the contribution of Bax to p53 mediated apoptosis is cell-type dependent ( Knudson et al , 1995 ; McCurrach et al , 1997 ) .	Previous studies have shown that Bax induction by p53 is necessary to inhibit tumour growth (Yin et al, 1997), but that the contribution of Bax to p53 mediated apoptosis is cell-type dependent (Knudson et al, 1995; McCurrach et al, 1997).	5	9	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	5	6
Bcl-2 and Bax is directly regulated by the tumor suppressor P53 and has been shown to be involved in P53 mediated apoptosis .	Bcl-2 and Bax is directly regulated by the tumor suppressor P53 and has been shown to be involved in P53 mediated apoptosis.	0	11	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	tumor suppressor P53	tumor suppressor P53	tumor suppressor P53	Bax	Bax	Bax	8	11	2	3
p53 can also up-regulate Bax and Bad and activate caspase cascade , which ultimately leads to apoptosis .	p53 can also up-regulate Bax and Bad and activate caspase cascade, which ultimately leads to apoptosis.	0	8	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	4	5
Mitochondria mediated apoptosis proceeds primarily through activation of the transcription factor p53 which further activates its downstream targets Bax , PUMA ( p53 upregulated modulator of apoptosis ) and represses Bcl-2 XREF_BIBR .	Mitochondria mediated apoptosis proceeds primarily through activation of the transcription factor p53 which further activates its downstream targets Bax, PUMA (p53 upregulated modulator of apoptosis) and represses Bcl-2 XREF_BIBR.	6	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	11	12	18	19
Exactly how p21 promotes apoptosis is not clear , but might depend on both p53 dependent and p53 independent upregulation of the pro apoptotic protein BAX , activation of members of the tumour necrosis factor family of death receptors or effects on DNA repair XREF_BIBR .	Exactly how p21 promotes apoptosis is not clear, but might depend on both p53 dependent and p53 independent upregulation of the pro apoptotic protein BAX, activation of members of the tumour necrosis factor family of death receptors or effects on DNA repair XREF_BIBR.	17	27	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	17	18	25	26
The increased wild-type p53 protein levels were fundamental to NO induced apoptosis and the up-regulation of BAX .	The increased wild-type p53 protein levels were fundamental to NO induced apoptosis and the up-regulation of BAX.	3	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	3	4	16	17
In osteosarcoma U2-OS cells , sCLU depletion induced Bax activation by suppressing Bcl-2 protein and stabilizing p53 , which leads to the activation of p21 and Bax genes [ XREF_BIBR ] .	In osteosarcoma U2-OS cells, sCLU depletion induced Bax activation by suppressing Bcl-2 protein and stabilizing p53, which leads to the activation of p21 and Bax genes [XREF_BIBR].	7	27	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	16	17	26	27
Bax is also activated by p53 ( M ) 3 and by PUMA XREF_BIBR .	Bax is also activated by p53 (M) 3 and by PUMA XREF_BIBR.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	0	1
These results suggested that p53 mediated Bax activation might contribute to apoptosis induction by patulin .	These results suggested that p53 mediated Bax activation might contribute to apoptosis induction by patulin.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	6	7
p53 can mediate Bcl-2 inhibition , thereby modulating Bax activity to facilitate the release of cytochrome c XREF_BIBR and p53 can also activate Bax directly XREF_BIBR .	p53 can mediate Bcl-2 inhibition, thereby modulating Bax activity to facilitate the release of cytochrome c XREF_BIBR and p53 can also activate Bax directly XREF_BIBR.	19	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	19	20	23	24
Interestingly , while Bax , Noxa , and Puma are induced by p53 to similar levels in the contexts of apoptosis and cell cycle arrest and therefore do not specify the apoptotic cell fate [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , the p53 target gene Perp is upregulated to high levels during p53 mediated apoptosis compared to cell cycle arrest .	Interestingly, while Bax, Noxa, and Puma are induced by p53 to similar levels in the contexts of apoptosis and cell cycle arrest and therefore do not specify the apoptotic cell fate [XREF_BIBR, XREF_BIBR, XREF_BIBR], the p53 target gene Perp is upregulated to high levels during p53 mediated apoptosis compared to cell cycle arrest.	3	29	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	12	13	3	4
Among them , Bax , caspase-3 , caspase-9 , DR5 , PUMA and Apaf-1 would be up-regulated by expression of p53 and while Bcl-2 , survivin would be down-regulated .	Among them, Bax, caspase-3, caspase-9, DR5, PUMA and Apaf-1 would be up-regulated by expression of p53 and while Bcl-2, survivin would be down-regulated.	3	21	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	expression of p53	p53	Bax	Bax	bax	20	21	3	4
These results demonstrated that MAGE-A inhibited apoptosis in proliferating MM cells through at least two novel mechanisms : inhibition of p53 dependent upregulation of Bax and maintenance of survivin expression by p53 dependent and independent mechanisms .	These results demonstrated that MAGE-A inhibited apoptosis in proliferating MM cells through at least two novel mechanisms : inhibition of p53 dependent upregulation of Bax and maintenance of survivin expression by p53 dependent and independent mechanisms.	20	26	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	20	21	24	25
p53 dependent direct activation of BAX [ XREF_BIBR ] and BAK [ XREF_BIBR ] is not mediated by a BH3 region in p53 , because p53 does not contain such region , and may therefore be achieved through non canonical mechanisms .	p53 dependent direct activation of BAX [XREF_BIBR] and BAK [XREF_BIBR] is not mediated by a BH3 region in p53, because p53 does not contain such region, and may therefore be achieved through non canonical mechanisms.	0	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	0	1	5	6
Mitochondrial p53 mediates oligomerization of Bax and Bak independently of Puma .	Mitochondrial p53 mediates oligomerization of Bax and Bak independently of Puma.	0	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	5	6
According to recent studies , PABPC1 depletion of cells by siRNA results to enhance serine 46 phosphorylation of p53 , and eventually trigger Bax apoptosis pathway .	According to recent studies, PABPC1 depletion of cells by siRNA results to enhance serine 46 phosphorylation of p53, and eventually trigger Bax apoptosis pathway.	5	25	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	PABPC1 depletion of cells by siRNA results to enhance serine 46 phosphorylation of p53	p53	Bax	Bax	bax	18	19	23	24
Considering the tetramer of p53 as a transcription factor , p53 induced Bax is characterized by a Hill function .	Considering the tetramer of p53 as a transcription factor, p53 induced Bax is characterized by a Hill function.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	10	11	12	13
P53 protein inhibits anti-apoptotic Bcl-2 and activates pro apoptotic Bax , thereby promoting apoptosis .	P53 protein inhibits anti-apoptotic Bcl-2 and activates pro apoptotic Bax, thereby promoting apoptosis.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	Bax	Bax	Bax	0	1	9	10
In this study , we demonstrated that the Giant seaperch iridovirus ( GSIV ) genome encoded a serine/threonine kinase ( ST kinase ) protein , and induced apoptotic cell death via a p53 mediated Bax upregulation approach and a downregulation of Bcl-2 in fish cells .	In this study, we demonstrated that the Giant seaperch iridovirus (GSIV) genome encoded a serine/threonine kinase (ST kinase) protein, and induced apoptotic cell death via a p53 mediated Bax upregulation approach and a downregulation of Bcl-2 in fish cells.	29	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	32	33	34	35
The stabilized p53 activates Bax protein that in turn mediates apoptosis [ XREF_BIBR ] .	The stabilized p53 activates Bax protein that in turn mediates apoptosis [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	4	5
P53 directly activates Bax to permeabilize mitochondria and engage the apoptotic program XREF_BIBR .	P53 directly activates Bax to permeabilize mitochondria and engage the apoptotic program XREF_BIBR.	0	4	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	Bax	Bax	Bax	0	1	3	4
The reporter gene assays suggest that the introduction of p53 activated p21 and Bax promoter activities but suppressed MMP-2 promoter activity .	The reporter gene assays suggest that the introduction of p53 activated p21 and Bax promoter activities but suppressed MMP-2 promoter activity.	7	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	9	10	13	14
Moreover , recent research demonstrates that p53 , as a transcriptional factor , mediates the upregulation of Bax after its activation .	Moreover, recent research demonstrates that p53, as a transcriptional factor, mediates the upregulation of Bax after its activation.	6	18	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	17	18
Wild-type p53 upregulates and activates BAX , and it downregulates and inactivates BCL-2 .	Wild-type p53 upregulates and activates BAX, and it downregulates and inactivates BCL-2.	0	6	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	1	2	5	6
XREF_BIBR , XREF_BIBR Cis-trans interconversion of Pro47 in this domain by the prolyl isomerase Pin1 was shown recently to enhance p53 induced BAX activation .	XREF_BIBR, XREF_BIBR Cis-trans interconversion of Pro47 in this domain by the prolyl isomerase Pin1 was shown recently to enhance p53 induced BAX activation.	19	23	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	20	21	22	23
p53 dependent PUMA expression directly activates Bax and the mitochondrial apoptotic pathway .	p53 dependent PUMA expression directly activates Bax and the mitochondrial apoptotic pathway.	0	11	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 dependent PUMA expression	p53	Bax	Bax	bax	0	1	6	7
The interaction of fortilin with p53 blocks p53 induced transcriptional activation of Bax .	The interaction of fortilin with p53 blocks p53 induced transcriptional activation of Bax.	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	7	8	12	13
In UV irradiated B-cell lines , further , p53 dependent increase of Bax resulted in a greater caspase-3 activation compared to its absence .	In UV irradiated B-cell lines, further, p53 dependent increase of Bax resulted in a greater caspase-3 activation compared to its absence.	8	13	increase	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	12	13
Since we could not observe obvious induction of Bid and Bim ( data not shown ) , it is possible that Bax was activated by cytosolic p53 with APTM treatment .	Since we could not observe obvious induction of Bid and Bim (data not shown), it is possible that Bax was activated by cytosolic p53 with APTM treatment.	21	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	26	27	21	22
After occurring a severe damage in the DNA of cells in a way that can not be repaired , it will undergo the apoptosis in which activation of p53 causes Bax ( BCL-2 associated x protein ) .	After occurring a severe damage in the DNA of cells in a way that can not be repaired, it will undergo the apoptosis in which activation of p53 causes Bax (BCL-2 associated x protein).	26	32	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	28	29	30	31
In the original Ribba model , for example , P53 activated BAX and BAX , in turn , activated apoptosis .	In the original Ribba model, for example, P53 activated BAX and BAX, in turn, activated apoptosis.	9	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	BAX	BAX	BAX	9	10	11	12
P53 dependent upregulation of Bax has been reported during retinal ganglion cell degeneration , UV irradiated melanocytes , and in adult mice exposed to hyperoxia [ XREF_BIBR - XREF_BIBR ] .	P53 dependent upregulation of Bax has been reported during retinal ganglion cell degeneration, UV irradiated melanocytes, and in adult mice exposed to hyperoxia [XREF_BIBR - XREF_BIBR].	0	5	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	P53	P53	P53	Bax	Bax	Bax	0	1	4	5
In the eukaryotic system , the ROS activate JNK and p53 proteins which induce Bax proteins to migrate to the mitochondrial surface resulting in cytochrome C release from mitochondria which subsequently results in PARP cleavage .	In the eukaryotic system, the ROS activate JNK and p53 proteins which induce Bax proteins to migrate to the mitochondrial surface resulting in cytochrome C release from mitochondria which subsequently results in PARP cleavage.	8	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	10	11	14	15
Apigenin treatment resulted in increased expression of PUMA ( via p53 transcriptional activation ) and coimmunoprecipitation demonstrated dissociation of stable complexes between both p53 and Bcl-X L and PUMA and Bcl-X L , indicating that p53 and PUMA may act in parallel to activate Bax following dissociation from Bcl- X L.	Apigenin treatment resulted in increased expression of PUMA (via p53 transcriptional activation) and coimmunoprecipitation demonstrated dissociation of stable complexes between both p53 and Bcl-X L and PUMA and Bcl-X L, indicating that p53 and PUMA may act in parallel to activate Bax following dissociation from Bcl- X L.	35	46	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	35	36	44	45
p53 induces transcriptional upregulation of Bax , while JNK participates in Bax mitochondrial translocation through transcriptional activation of the BH3-only protein Bim .	p53 induces transcriptional upregulation of Bax, while JNK participates in Bax mitochondrial translocation through transcriptional activation of the BH3-only protein Bim.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	5	6
Finally , we sought to determine if the addition of a BH3 mimetic could enhance the activity of an MDM2 inhibitor , in part with the rationale that the p53 mediated activation of Bax could be potentiated by blocking its interaction with Bcl-2 .	Finally, we sought to determine if the addition of a BH3 mimetic could enhance the activity of an MDM2 inhibitor, in part with the rationale that the p53 mediated activation of Bax could be potentiated by blocking its interaction with Bcl-2.	29	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	29	30	33	34
P53 directly activated Bax and released pro apoptotic molecules , activating multidomain proteins in the cytoplasm .	P53 directly activated Bax and released pro apoptotic molecules, activating multidomain proteins in the cytoplasm.	0	5	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	Bax	Bax	Bax	0	1	3	4
We found that p53 mediated induction of PUMA and Bax is required for the apoptotic responses to Hsp90 inhibitors via the mitochondrial pathway in vitro and in vivo .	We found that p53 mediated induction of PUMA and Bax is required for the apoptotic responses to Hsp90 inhibitors via the mitochondrial pathway in vitro and in vivo.	3	10	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	9	10
On the other hand , upregulation of P53 also activated Bax gene and repressed Bcl-2 and BIRC5 genes , resulting in an increase of the Bax and Bcl -2 ratio and subsequently activating caspase cascade , ultimately led to an initiation of the apoptotic machinery .	On the other hand, upregulation of P53 also activated Bax gene and repressed Bcl-2 and BIRC5 genes, resulting in an increase of the Bax and Bcl -2 ratio and subsequently activating caspase cascade, ultimately led to an initiation of the apoptotic machinery.	5	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	Bax	Bax	Bax	7	8	10	11
As shown in XREF_FIG , both bax and TFIIS.h were induced in HCT116 cells treated with doxorubicin , a p53 activating agent .	As shown in XREF_FIG, both bax and TFIIS.h were induced in HCT116 cells treated with doxorubicin, a p53 activating agent.	5	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	19	20	6	7
XREF_BIBR , XREF_BIBR , XREF_BIBR p53 might also directly activate BAX and or BAK by a similar , yet to be fully characterized , type of interaction .	XREF_BIBR, XREF_BIBR, XREF_BIBR p53 might also directly activate BAX and or BAK by a similar, yet to be fully characterized, type of interaction.	0	11	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	5	6	10	11
Injection of the apoptosis inhibitors Pifithrin-mu or MDL28170 found no rescue of phenotypes or embryonic lethality , suggesting MeHg induced apoptosis does not solely involve p53 or calpain induction of Bax , respectively .	Injection of the apoptosis inhibitors Pifithrin-mu or MDL28170 found no rescue of phenotypes or embryonic lethality, suggesting MeHg induced apoptosis does not solely involve p53 or calpain induction of Bax, respectively.	25	31	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	25	26	30	31
In our animal model , the p53 gene also could induce the up-regulation of the pro apoptotic Bax gene at 24 h pi and simultaneously it could repress the transcription of the anti-apoptotic genes Bcl 2 and BI-1 .	In our animal model, the p53 gene also could induce the up-regulation of the pro apoptotic Bax gene at 24 h pi and simultaneously it could repress the transcription of the anti-apoptotic genes Bcl 2 and BI-1.	6	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	17	18
Indeed , transient silencing of p53 in cancer cells with p53 targeted siRNA nullified both DCN mediated regulation of BAX and activation of the caspase-3 signaling pathway .	Indeed, transient silencing of p53 in cancer cells with p53 targeted siRNA nullified both DCN mediated regulation of BAX and activation of the caspase-3 signaling pathway.	3	20	nullified	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	5	6	19	20
We further confirmed that GLP-1R knockdown by glp-1r-specific small interfering ( si ) RNA resulted in increased ROS generation , p53 mediated Bax promoter activity , and apoptotic cell number , in addition to activation of signaling molecules involved in ER stress .	We further confirmed that GLP-1R knockdown by glp-1r-specific small interfering (si) RNA resulted in increased ROS generation, p53 mediated Bax promoter activity, and apoptotic cell number, in addition to activation of signaling molecules involved in ER stress.	20	24	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	20	21	22	23
In this study , melatonin reduced the expression of caspase 3 , p53 upregulated modulator of apoptosis , and BAX , while inducing the expression of basic fibroblast growth factor , TGFbeta , vascular endothelial growth factor , ( BCL-2 ) , and platelet derived growth factor [ XREF_BIBR ] .	In this study, melatonin reduced the expression of caspase 3, p53 upregulated modulator of apoptosis, and BAX, while inducing the expression of basic fibroblast growth factor, TGFbeta, vascular endothelial growth factor, (BCL-2), and platelet derived growth factor [XREF_BIBR].	12	20	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	12	13	19	20
10 Among many other roles , p53 causes Bax to translocate to the mitochondrion to elicit cytochrome c release and trigger caspase mediated apoptosis .	10 Among many other roles, p53 causes Bax to translocate to the mitochondrion to elicit cytochrome c release and trigger caspase mediated apoptosis.	6	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	8	9
The increasing of p53 levels further increased p21 , bax , cytochrome c , caspase-8 , -7 and -3 activities , except caspase-9 .	The increasing of p53 levels further increased p21, bax, cytochrome c, caspase-8, -7 and -3 activities, except caspase-9.	3	10	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 levels	p53	bax	bax	bax	3	4	9	10
In accordance with these results , silencing of p53 significantly decreased p21 and Bax promoter driven luciferase expression but enhanced MMP-2 activity ( XREF_FIG ) .	In accordance with these results, silencing of p53 significantly decreased p21 and Bax promoter driven luciferase expression but enhanced MMP-2 activity (XREF_FIG).	6	14	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	13	14
Under these circumstances , the extent of Bax activation by p53 ( M ) ( k 10 , k 29 ) or PUMA ( k 30 ) may become critical .	Under these circumstances, the extent of Bax activation by p53 (M) (k 10, k 29) or PUMA (k 30) may become critical.	7	15	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	10	11	7	8
Consistent with the potential role of Tp53 and BAX in neuronal cell body apoptosis , in a previous study using the same dopaminergic neuron specific Tp53 conditional knockout mouse , we have demonstrated that dopaminergic neuron specific deletion of Tp53 gene attenuates DA neuronal death in the MPTP mouse model of Parkinson ' s disease and attenuates MPTP induced Bax upregulation ( Qi et al ., 2016 ) .	Consistent with the potential role of Tp53 and BAX in neuronal cell body apoptosis, in a previous study using the same dopaminergic neuron specific Tp53 conditional knockout mouse, we have demonstrated that dopaminergic neuron specific deletion of Tp53 gene attenuates DA neuronal death in the MPTP mouse model of Parkinson 's disease and attenuates MPTP induced Bax upregulation (Qi et al., 2016).	39	60	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tp53	Tp53	Tp53	Bax	Bax	Bax	39	40	59	60
The p53 protein directly activates the proapoptotic Bcl-2 family member Bax , which results in cytochrome c release , loss of mitochondrial membrane potential , and caspase-9 and caspase-3 processing .	The p53 protein directly activates the proapoptotic Bcl-2 family member Bax, which results in cytochrome c release, loss of mitochondrial membrane potential, and caspase-9 and caspase-3 processing.	1	13	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	10	11
p53 may also induce Bax , leading to cell apoptosis before the viral life cycle has been completed ( Miyashita and Reed , 1995 ) .	p53 may also induce Bax, leading to cell apoptosis before the viral life cycle has been completed (Miyashita and Reed, 1995).	0	5	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	4	5
To support this hypothesis , we examined whether DNA damage induced p53 phosphorylation , known to activate Bax , occurs in atRAL induced cell death .	To support this hypothesis, we examined whether DNA damage induced p53 phosphorylation, known to activate Bax, occurs in atRAL induced cell death.	11	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 phosphorylation	p53	Bax	Bax	bax	11	12	17	18
The expression of p53 is directly linked to a blockage of cell cycle progression at G0/G1 phase and upregulates Bax , cytochrome c , and caspase 3 while Bcl2 was deregulated .	The expression of p53 is directly linked to a blockage of cell cycle progression at G0/G1 phase and upregulates Bax, cytochrome c, and caspase 3 while Bcl2 was deregulated.	1	25	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	expression of p53	p53	Bax	Bax	bax	3	4	19	20
As p53 positively regulates Bax XREF_BIBR , it is possible that SIRT1 may partly exert its protective effects by deacetylating and inhibiting p53 .	As p53 positively regulates Bax XREF_BIBR, it is possible that SIRT1 may partly exert its protective effects by deacetylating and inhibiting p53.	1	5	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	1	2	4	5
When incubated with mitochondria isolated from BAX and BAK null mouse embryonic fibroblasts , this recombinant p53 did not trigger cytochrome c release by itself , did not activate recombinant BAX , did not enhance the effects of tBID on BAX , and did not derepress the inhibitory effects of BCL-xL ( XREF_SUPPLEMENTARY ) .	When incubated with mitochondria isolated from BAX and BAK null mouse embryonic fibroblasts, this recombinant p53 did not trigger cytochrome c release by itself, did not activate recombinant BAX, did not enhance the effects of tBID on BAX, and did not derepress the inhibitory effects of BCL-xL (XREF_SUPPLEMENTARY).	14	45	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	16	17	30	31
Although the p53 signal increases the level of Bax , still Bax tot < Bcl-xL tot-Bad u , and thus all Bax remains sequestered by Bcl-x L.	Although the p53 signal increases the level of Bax, still Bax tot < Bcl-xL tot-Bad u, and thus all Bax remains sequestered by Bcl-x L.	2	12	increases	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	p53	p53	p53	Bax	level of Bax	bax	2	3	8	9
XREF_BIBR Gopinath et al XREF_BIBR also showed that bax is upregulated by p53 .	XREF_BIBR Gopinath et al XREF_BIBR also showed that bax is upregulated by p53.	8	13	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	bax	bax	bax	12	13	8	9
The molecular mechanism of direct BAX activation by p53 follows a different path leading to the structural rearrangement of BAX .	The molecular mechanism of direct BAX activation by p53 follows a different path leading to the structural rearrangement of BAX.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	8	9	5	6
EGCG induced p53 stabilization causes up-regulation of its downstream targets WAF1 and p21 and Bax ; consequently , EGCG produces a change in the Bax and Bcl2 ratio , shifting the balance between pro / antiapoptotic proteins in favor of apoptosis .	EGCG induced p53 stabilization causes up-regulation of its downstream targets WAF1 and p21 and Bax; consequently, EGCG produces a change in the Bax and Bcl2 ratio, shifting the balance between pro /antiapoptotic proteins in favor of apoptosis.	0	15	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	EGCG induced p53	p53	Bax	Bax	bax	2	3	14	15
p53 directly activated the proapoptotic Bcl-2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program .	p53 directly activated the proapoptotic Bcl-2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program.	0	8	directly activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	7	8
Interestingly , the level of Bax transcription in tetraploid TS cells was consistently maintained at very low levels , indicating that p53 could not activate the Bax gene ; thus the p53 dependent tetraploidy checkpoint will not function in the trophoblast lineage due to very low expression of the p53 effector , Bax .	Interestingly, the level of Bax transcription in tetraploid TS cells was consistently maintained at very low levels, indicating that p53 could not activate the Bax gene; thus the p53 dependent tetraploidy checkpoint will not function in the trophoblast lineage due to very low expression of the p53 effector, Bax.	21	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	21	22	26	27
In turn the accumulated p53 induces p21 and Bax ( and other pro apoptotic proteins ) .	In turn the accumulated p53 induces p21 and Bax (and other pro apoptotic proteins).	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	8	9
p53 can activate the transcription of the proapoptotic genes PUMA , PMAIP , Bax , Fas , and others , with repression of the transcription of the survival genes Bcl-2 , MAP4 , BIRC5 ( survivin ) , Mcl-1 , IGF-1R , MYC , EIF4E , and PIK3CA [ XREF_BIBR ] .	p53 can activate the transcription of the proapoptotic genes PUMA, PMAIP, Bax, Fas, and others, with repression of the transcription of the survival genes Bcl-2, MAP4, BIRC5 (survivin), Mcl-1, IGF-1R, MYC, EIF4E, and PIK3CA [XREF_BIBR].	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	13	14
14 Wild-type p53 , but not mutant p53 , upregulates and activates BAX , and downregulates and inactivates BCL-2 .	14 Wild-type p53, but not mutant p53, upregulates and activates BAX, and downregulates and inactivates BCL-2.	0	15	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	2	3	12	13
These findings demonstrate that 17AAG treatment leads to p53 dependent induction of PUMA and Bax , besides modulation of survival pathways .	These findings demonstrate that 17AAG treatment leads to p53 dependent induction of PUMA and Bax, besides modulation of survival pathways.	8	15	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	14	15
No significant differences were observed when PATZ1 was transfected alone , whereas co-transfection of PATZ1 and p53 significantly enhances BAX promoter activity compared with that obtained by p53 alone , but had no significant effect on the other two promoters ( XREF_SUPPLEMENTARY ) .	No significant differences were observed when PATZ1 was transfected alone, whereas co-transfection of PATZ1 and p53 significantly enhances BAX promoter activity compared with that obtained by p53 alone, but had no significant effect on the other two promoters (XREF_SUPPLEMENTARY).	12	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	16	17	19	20
We chose to use the p53 R273H dominant negative ( p53 DN ) mutant because it effectively inhibits p53 transcriptional activation of Bax .	We chose to use the p53 R273H dominant negative (p53 DN) mutant because it effectively inhibits p53 transcriptional activation of Bax.	18	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	18	19	22	23
One of the functions of Akt is inhibiting a pre-apoptotic protein , BAX , which is triggered by p53 and induces apoptosis .	One of the functions of Akt is inhibiting a pre-apoptotic protein, BAX, which is triggered by p53 and induces apoptosis.	10	19	triggered	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	18	19	12	13
p53 can up-regulate Bax and down-regulatie Bcl-2 or Bcl-xL , affecting the apoptosis of cancer cells , and changing the permeability of mitochondria , thus affecting the function of downstream pro apoptotic genes [ XREF_BIBR ] .	p53 can up-regulate Bax and down-regulatie Bcl-2 or Bcl-xL, affecting the apoptosis of cancer cells, and changing the permeability of mitochondria, thus affecting the function of downstream pro apoptotic genes [XREF_BIBR].	0	6	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	3	4
p53 induces Bax , which leads to activation of the intrinsic apoptotic pathway .	p53 induces Bax, which leads to activation of the intrinsic apoptotic pathway.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	2	3
A BAX construct lacking the C-terminal alpha9 ( BAX DeltaC ) was not activated by p53 , and another in which packing of alpha9 within the globular core was stabilized ( through introduction of a salt bridge via mutation of Val 180 to Asp , BAX V180D ) was only weakly activated by p53 , with little enhancement by Pin1 ; furthermore , p53-NTD did not bind to BAX DeltaC ( XREF_SUPPLEMENTARY ) .	A BAX construct lacking the C-terminal alpha9 (BAX DeltaC) was not activated by p53, and another in which packing of alpha9 within the globular core was stabilized (through introduction of a salt bridge via mutation of Val 180 to Asp, BAX V180D) was only weakly activated by p53, with little enhancement by Pin1; furthermore, p53-NTD did not bind to BAX DeltaC (XREF_SUPPLEMENTARY).	1	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	15	16	1	2
DNA damage by radiation in proliferative cells activates p53 protein via ATM signals , and then the p53 activates the growth-arrest protein CDKN1A and proapoptotic proteins BAX and BBC3 [ XREF_BIBR ] .	DNA damage by radiation in proliferative cells activates p53 protein via ATM signals, and then the p53 activates the growth-arrest protein CDKN1A and proapoptotic proteins BAX and BBC3 [XREF_BIBR].	16	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	17	18	26	27
XREF_BIBR , XREF_BIBR , XREF_BIBR In addition , p53 activates , directly binds to , and induces oligomerization of Bak and Bax .	XREF_BIBR, XREF_BIBR, XREF_BIBR In addition, p53 activates, directly binds to, and induces oligomerization of Bak and Bax.	8	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	8	9	21	22
Activation of p53 could mediate the up-regulation of Bax ( B-cell associated X protein ) , down-regulation of Bcl-2 , and PARP cleavage [ XREF_BIBR ] .	Activation of p53 could mediate the up-regulation of Bax (B-cell associated X protein), down-regulation of Bcl-2, and PARP cleavage [XREF_BIBR].	0	9	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	8	9
P53 mediated BAX activation and induction of caspases , and apoptosis execution has been identified in multiple diseases including cancer [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	P53 mediated BAX activation and induction of caspases, and apoptosis execution has been identified in multiple diseases including cancer [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	P53	P53	P53	BAX	BAX	BAX	0	1	2	3
In the current study , PEGylated liposomal Epi , used separately or together with ASOs significantly inhibited non pump resistance by raising the mRNA expression levels of p53 , which subsequently activated BAX and repressed BCL-2 .	In the current study, PEGylated liposomal Epi, used separately or together with ASOs significantly inhibited non pump resistance by raising the mRNA expression levels of p53, which subsequently activated BAX and repressed BCL-2.	25	33	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	levels of p53	p53	BAX	BAX	bax	27	28	32	33
We conclude that p53 is a downstream effector of Bruce , and , in response to loss of Bruce function , p53 activates Pidd and caspase -2 and Bax and Bak , leading to mitochondrial apoptosis .	We conclude that p53 is a downstream effector of Bruce, and, in response to loss of Bruce function, p53 activates Pidd and caspase -2 and Bax and Bak, leading to mitochondrial apoptosis.	21	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	21	22	28	29
It is assumed that p53 may transcriptionally activate the pro apoptotic Bax gene and/or repress anti-apoptotic Bcl-2 gene [ XREF_BIBR , XREF_BIBR ] .	It is assumed that p53 may transcriptionally activate the pro apoptotic Bax gene and/or repress anti-apoptotic Bcl-2 gene [XREF_BIBR, XREF_BIBR].	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	4	5	11	12
In glaucoma , the transcription factor p53 activates the proapoptotic Bax protein , which leads to RGCs apoptosis via a caspase-3-dependent pathway [ XREF_BIBR ] .	In glaucoma, the transcription factor p53 activates the proapoptotic Bax protein, which leads to RGCs apoptosis via a caspase-3-dependent pathway [XREF_BIBR].	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	6	7	10	11
Interestingly , the S100P expressing , drug treated RKO cells differed from the mock transfected cells by the reduced expression of several important pro apoptotic proteins , including the p53 target Bax , thus indicating a down-regulation of the death related signaling .	Interestingly, the S100P expressing, drug treated RKO cells differed from the mock transfected cells by the reduced expression of several important pro apoptotic proteins, including the p53 target Bax, thus indicating a down-regulation of the death related signaling.	27	34	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	29	30	31	32
CCN1 induces fibroblast apoptosis through its adhesion receptors , integrin alpha 6 beta 1 and the heparan sulfate proteoglycan ( HSPG ) syndecan-4 , triggering the transcription independent p53 activation of Bax to render cytochrome c release and activation of caspase-9 and -3 .	CCN1 induces fibroblast apoptosis through its adhesion receptors, integrin alpha 6 beta 1 and the heparan sulfate proteoglycan (HSPG) syndecan-4, triggering the transcription independent p53 activation of Bax to render cytochrome c release and activation of caspase-9 and -3.	28	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	28	29	31	32
Both membrane and soluble TNF-alpha activate TNFR1 ; TNFR2 , mostly by mTNF-alpha .	Both membrane and soluble TNF-alpha activate TNFR1; TNFR2, mostly by mTNF-alpha.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	4	5	6	7
In vitro , TNF activated TNFR1 deficient macrophages to produce nitric oxide ( NO ) .	In vitro, TNF activated TNFR1 deficient macrophages to produce nitric oxide (NO).	1	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	3	4	5	6
Accordingly , TNF receptor 1 ( TNFR1 ) resides in ~ 40 % of mouse TRPV1 positive DRGs XREF_BIBR ; also , the proportion of TRPV1 expressing DRG neurons is increased by a TNFalpha induced TNFR1 response , which involves extracellular signal regulated kinases XREF_BIBR .	Accordingly, TNF receptor 1 (TNFR1) resides in ~ 40% of mouse TRPV1 positive DRGs XREF_BIBR; also, the proportion of TRPV1 expressing DRG neurons is increased by a TNFalpha induced TNFR1 response, which involves extracellular signal regulated kinases XREF_BIBR.	30	36	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	33	34	35	36
TNF-alpha treatment stimulates TNFR1 accumulation and , 1 muM of SIM could significantly suppress the expression of TNFR1 ( XREF_FIG ) .	TNF-alpha treatment stimulates TNFR1 accumulation and, 1 muM of SIM could significantly suppress the expression of TNFR1 (XREF_FIG).	0	4	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	0	1	3	4
Activation of TNFR1 by TNF-alpha transactivated c-Src-dependent EGF receptor ( EGFR ) linking to PI3K and Akt cascade , and then led to transcriptional activity of NF-kappaB .	Activation of TNFR1 by TNF-alpha transactivated c-Src-dependent EGF receptor (EGFR) linking to PI3K and Akt cascade, and then led to transcriptional activity of NF-kappaB.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	4	5	2	3
In particular , TNFalpha mediates either pro- or anti-convulsive effects by differential activation of receptor type 1 ( TNFR1 ) and type 2 ( TNFR2 ) , respectively [ XREF_BIBR - XREF_BIBR ] .	In particular, TNFalpha mediates either pro- or anti-convulsive effects by differential activation of receptor type 1 (TNFR1) and type 2 (TNFR2), respectively [XREF_BIBR - XREF_BIBR].	3	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	3	4	18	19
Here , we show that local increase of TNFalpha in the hippocampal dentate gyrus activates astrocyte TNF receptor type 1 ( TNFR1 ) , which in turn triggers an astrocyte-neuron signaling cascade that results in persistent functional modification of hippocampal excitatory synapses .	Here, we show that local increase of TNFalpha in the hippocampal dentate gyrus activates astrocyte TNF receptor type 1 (TNFR1), which in turn triggers an astrocyte-neuron signaling cascade that results in persistent functional modification of hippocampal excitatory synapses.	6	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	8	9	21	22
Activation of TNFR1 by TNFalpha leads to the rapid recruitment of RIPK1 , TNF receptor associated death domain ( TRADD ) , TNF receptor associated factor 2 ( TRAF2 ) and E3 ubiquitin ligases , cellular inhibitor of apoptosis protein 1/2 ( cIAP1/2 ) , to form complex I , also called TNFR1-signaling-complex ( TNF-RSC ) , associated with the intracellular domain of TNFR1 .	Activation of TNFR1 by TNFalpha leads to the rapid recruitment of RIPK1, TNF receptor associated death domain (TRADD), TNF receptor associated factor 2 (TRAF2) and E3 ubiquitin ligases, cellular inhibitor of apoptosis protein 1/2 (cIAP1/2), to form complex I, also called TNFR1-signaling-complex (TNF-RSC), associated with the intracellular domain of TNFR1.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	4	5	2	3
The previous study in our lab indicated TNF-alpha promoted the up-regulation of TRAF2 and expression of TNFR1 on dendritic cells .	The previous study in our lab indicated TNF-alpha promoted the up-regulation of TRAF2 and expression of TNFR1 on dendritic cells.	7	17	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	7	8	16	17
As monocytes showed cell surface expression of membrane TNF and TNFR1 ( XREF_FIG ) , we evaluated whether TNFR1 activation by endogenous TNF is involved in SMAC mimetic induced killing of monocytes .	As monocytes showed cell surface expression of membrane TNF and TNFR1 (XREF_FIG), we evaluated whether TNFR1 activation by endogenous TNF is involved in SMAC mimetic induced killing of monocytes.	18	23	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	22	23	18	19
The biological responses of TNF-alpha are mediated by its two receptors TNFR1 and TNFR2 , both of which can be released as soluble molecules .	The biological responses of TNF-alpha are mediated by its two receptors TNFR1 and TNFR2, both of which can be released as soluble molecules.	2	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	4	5	11	12
XREF_BIBR These results differ from those of a previous report , which found that TNF-alpha upregulates only TNFR1 in rat astrocytes and human epithelial cells .	XREF_BIBR These results differ from those of a previous report, which found that TNF-alpha upregulates only TNFR1 in rat astrocytes and human epithelial cells.	14	24	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	14	15	17	18
TNF-R1 activation by TNF-alpha induces both NF-kappaB activation and apoptosis .	TNF-R1 activation by TNF-alpha induces both NF-kappaB activation and apoptosis.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	3	4	0	1
Importantly , it has been shown that local increase of TNFalpha in the hippocampal dentate gyrus activates astrocytic TNFR1 , which in turn triggers an astrocyte-neuron signaling cascade that results in the persistent functional decline of hippocampal excitatory synapses [ XREF_BIBR ] .	Importantly, it has been shown that local increase of TNFalpha in the hippocampal dentate gyrus activates astrocytic TNFR1, which in turn triggers an astrocyte-neuron signaling cascade that results in the persistent functional decline of hippocampal excitatory synapses [XREF_BIBR].	8	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	10	11	18	19
Necroptosis can be induced through ligation of tumor necrosis factor ( TNF ) members ( through TNFR1 , TNFR2 , TRAILR1 , and TRAILR2 ) , Fas ligand , toll like receptors , lipopolysaccharides ( LPS ) , and genotoxic stress [ XREF_BIBR - XREF_BIBR ] As described earlier , ligation of TNFalpha activates TNFR1 and in turn induces the recruitment of RIP1 kinase via adaptor protein TRADD [ XREF_BIBR , XREF_BIBR ] , to the membrane .	Necroptosis can be induced through ligation of tumor necrosis factor (TNF) members (through TNFR1, TNFR2, TRAILR1, and TRAILR2), Fas ligand, toll like receptors, lipopolysaccharides (LPS), and genotoxic stress [XREF_BIBR - XREF_BIBR] As described earlier, ligation of TNFalpha activates TNFR1 and in turn induces the recruitment of RIP1 kinase via adaptor protein TRADD [XREF_BIBR, XREF_BIBR], to the membrane.	50	55	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	52	53	54	55
These results demonstrated that TNF-alpha induces TNFR1 and PKCalpha dependent Nox/ROS/MAPKs cascade in HCFs .	These results demonstrated that TNF-alpha induces TNFR1 and PKCalpha dependent Nox/ROS/MAPKs cascade in HCFs.	4	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	4	5	6	7
Double deficient Sharpin cpdm and cpdm ; Tnfrsf1a -/- mice did not develop skin inflammation , demonstrating that TNF induced TNFR1 signaling is essential for the pathogenesis of inflammatory skin lesions in Sharpin cpdm and cpdm mice ( XREF_FIG ) .	Double deficient Sharpin cpdm and cpdm; Tnfrsf1a -/- mice did not develop skin inflammation, demonstrating that TNF induced TNFR1 signaling is essential for the pathogenesis of inflammatory skin lesions in Sharpin cpdm and cpdm mice (XREF_FIG).	18	21	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	18	19	20	21
Importantly , there was no increase in TAEC apoptosis in TNFR1 ,2-/- animals treated with Ad.Egr- TNF alone compared with untreated control ( P = 0.26 ) or Ad.Egr-TNF +20 Gy compared with 20 Gy alone ( P = 0.42 ) .	Importantly, there was no increase in TAEC apoptosis in TNFR1,2-/- animals treated with Ad.Egr- TNF alone compared with untreated control (P = 0.26) or Ad.Egr-TNF +20 Gy compared with 20 Gy alone (P = 0.42).	10	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	16	17	10	11
Soluble TNF ( sTNF ) only activates TNFR1 , while membrane bound TNF ( mTNF ) activates both receptors [ XREF_BIBR , XREF_BIBR ] .	Soluble TNF (sTNF) only activates TNFR1, while membrane bound TNF (mTNF) activates both receptors [XREF_BIBR, XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	1	2	7	8
The IPA results confirmed that miR-17 overexpression may significantly influence canonical pathways with high pathological relevance , including protein ubiquitin pathway , TNF-alpha related weak inducer of apoptosis ( TWAEK ) and TNF-R1 signaling ( XREF_SUPPLEMENTARY ) .	The IPA results confirmed that miR-17 overexpression may significantly influence canonical pathways with high pathological relevance, including protein ubiquitin pathway, TNF-alpha related weak inducer of apoptosis (TWAEK) and TNF-R1 signaling (XREF_SUPPLEMENTARY).	22	33	inducer	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	22	23	32	33
TNF caused upregulation of TNFR2 in CM and in VEC , but not TNFR1 in WT C57BL/6 cultures ( XREF_SUPPLEMENTARY ) .	TNF caused upregulation of TNFR2 in CM and in VEC, but not TNFR1 in WT C57BL/6 cultures (XREF_SUPPLEMENTARY).	0	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	0	1	13	14
Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFalpha dependent manner , A172 glioblastoma cells undergo BV6 induced apoptosis largely independently of TNFalpha and TNFR1 , as the TNFalpha blocking antibody Enbrel or TNFR1 knockdown provide little protection .	Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFalpha dependent manner, A172 glioblastoma cells undergo BV6 induced apoptosis largely independently of TNFalpha and TNFR1, as the TNFalpha blocking antibody Enbrel or TNFR1 knockdown provide little protection.	34	42	blocking	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	35	36	40	41
TNFalpha stimulation of TNF-R1 induces the formation of a cell membrane complex with the adaptor TRADD , TNFR associated factor 2 ( TRAF2 ) and receptor interacting protein 1 ( RIP1 ) that leads to the activation of NF-kappaB and cell survival .	TNFalpha stimulation of TNF-R1 induces the formation of a cell membrane complex with the adaptor TRADD, TNFR associated factor 2 (TRAF2) and receptor interacting protein 1 (RIP1) that leads to the activation of NF-kappaB and cell survival.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-R1	TNF-R1	TNF-R1	0	1	3	4
The use of agonistic antibodies or recombinant proteins of TNF-alpha that specifically activate either TNFR1 or TNFR2 receptor led us to conclude that TNF-alpha mediates most of its cellular effects by activating the TNFR1 receptor [ XREF_BIBR ] .	The use of agonistic antibodies or recombinant proteins of TNF-alpha that specifically activate either TNFR1 or TNFR2 receptor led us to conclude that TNF-alpha mediates most of its cellular effects by activating the TNFR1 receptor [XREF_BIBR].	23	34	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	23	24	33	34
Finally , TNFR1 signaling and cell death were reduced by PKF-242-484 , a dual matrix metaloproteinase and TNFalpha converting enzyme inhibitor .	Finally, TNFR1 signaling and cell death were reduced by PKF-242-484, a dual matrix metaloproteinase and TNFalpha converting enzyme inhibitor.	2	20	reduced	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	17	18	2	3
Given that in endothelial cells TNF-alpha activates TNFR1 to promote a COX-1 dependent increase in prostanoid production [ XREF_BIBR ] , activation of vascular p38 in these cells may be a link between TNF-alpha , COX-1 activation and the sensitization of meningeal nociceptors .	Given that in endothelial cells TNF-alpha activates TNFR1 to promote a COX-1 dependent increase in prostanoid production [XREF_BIBR], activation of vascular p38 in these cells may be a link between TNF-alpha, COX-1 activation and the sensitization of meningeal nociceptors.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	5	6	7	8
For example , tumor necrosis factor-alpha ( TNFalpha ) , a key proinflammatory cytokine , was shown to increase the frequency of excitatory postsynaptic currents ( EPSCs ) and N-methyl-D-aspartate ( NMDA ) currents in lamina II neurons by stimulating TNF receptor subtype-1 and 2 ( TNFR1 and TNFR2 ) in an inflammatory pain model [ XREF_BIBR ] .	For example, tumor necrosis factor-alpha (TNFalpha), a key proinflammatory cytokine, was shown to increase the frequency of excitatory postsynaptic currents (EPSCs) and N-methyl-D-aspartate (NMDA) currents in lamina II neurons by stimulating TNF receptor subtype-1 and 2 (TNFR1 and TNFR2) in an inflammatory pain model [XREF_BIBR].	5	48	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	7	8	46	47
Prompting to the significance of TNF receptor crosstalk discussed above , the TNFR2 also takes part in inducing macrophage death by necroptosis upon TNF induced TNFR1 activation upon contact with pathogen .	Prompting to the significance of TNF receptor crosstalk discussed above, the TNFR2 also takes part in inducing macrophage death by necroptosis upon TNF induced TNFR1 activation upon contact with pathogen.	17	26	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	23	24	25	26
In vivo , TNF induced glomerular leukocyte infiltration was abrogated in Tnfr1 deficient mice , whereas Tnfr2-deficiency decreased mononuclear phagocytes infiltrates , but not neutrophils .	In vivo, TNF induced glomerular leukocyte infiltration was abrogated in Tnfr1 deficient mice, whereas Tnfr2-deficiency decreased mononuclear phagocytes infiltrates, but not neutrophils.	1	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Tnfr1	Tnfr1	Tnfr1	3	4	11	12
Two different problems needed to be solved for this approach : a ) although TNFR1 is ubiquitously expressed , TNFR2 expression is much more restricted in terms of cell type , b ) TNFR2 is efficiently activated only by mTNF which also activates TNFR1 ; TNFR1 can be activated by soluble TNF as well .	Two different problems needed to be solved for this approach : a) although TNFR1 is ubiquitously expressed, TNFR2 expression is much more restricted in terms of cell type, b) TNFR2 is efficiently activated only by mTNF which also activates TNFR1; TNFR1 can be activated by soluble TNF as well.	45	52	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	51	52	45	46
This paradoxical effect is associated with NF-kappaB-dependent pronounced secretion of tumour necrosis factor-alpha ( TNF ) which activates TNF-R1 in an autocrine fashion to enhance UVB induced apoptosis .	This paradoxical effect is associated with NF-kappaB-dependent pronounced secretion of tumour necrosis factor-alpha (TNF) which activates TNF-R1 in an autocrine fashion to enhance UVB induced apoptosis.	12	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNF-R1	TNF-R1	TNF-R1	14	15	18	19
Low levels of TNF-alpha stimulate mainly neuroprotective TNFR2 and high levels stimulate the neurodestructive TNFR1 .	Low levels of TNF-alpha stimulate mainly neuroprotective TNFR2 and high levels stimulate the neurodestructive TNFR1.	1	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	levels of TNF-alpha	tnf-alpha	TNFR1	TNFR1	tnfr1	3	4	14	15
To determine if altered TNF and TNFR1 interactions contribute to key brain aging biomarkers , aged rats received chronic ( 4-6 week ) intracranial infusions of XPro1595 : a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling .	To determine if altered TNF and TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4-6 week) intracranial infusions of XPro1595 : a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling.	17	37	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	32	33	36	37
Soluble TNF-alpha activates TNFR1 , whereas mTNF-alpha initiates TNFR2 signalling , resulting in a pro inflammatory and less apoptosis inducing response XREF_BIBR , XREF_BIBR .	Soluble TNF-alpha activates TNFR1, whereas mTNF-alpha initiates TNFR2 signalling, resulting in a pro inflammatory and less apoptosis inducing response XREF_BIBR, XREF_BIBR.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	1	2	3	4
Triggering of TNF-R1 by TNF leads to clustering of pre-assembled TNF-R complexes , and the recruitment of TRADD to TNF-R via a homotypic DD-DD interaction .	Triggering of TNF-R1 by TNF leads to clustering of pre-assembled TNF-R complexes, and the recruitment of TRADD to TNF-R via a homotypic DD-DD interaction.	0	5	Triggering	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	TNF-R1	TNF-R1	TNF-R1	4	5	2	3
The finding that the TNFalpha activation of TNF-R1 signaling of apoptosis or survival is determined , at least in part , by integrin signaling is consistent with the report by other investigators that the matricellular protein known as CCN1 and CYR61 can cooperate with integrins alphavbeta5 and alpha6beta1 and the heparin sulfate proteoglycan-syndecan-4 on fibroblasts to promote TNFalpha pro apoptotic signaling .	The finding that the TNFalpha activation of TNF-R1 signaling of apoptosis or survival is determined, at least in part, by integrin signaling is consistent with the report by other investigators that the matricellular protein known as CCN1 and CYR61 can cooperate with integrins alphavbeta5 and alpha6beta1 and the heparin sulfate proteoglycan-syndecan-4 on fibroblasts to promote TNFalpha pro apoptotic signaling.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-R1	TNF-R1	TNF-R1	4	5	7	8
Both C33Y TNFR1- and WT TNFR1 transfected SK-Hep-1 cells were treated with TNF-alpha under three different conditions : time course of response to constant exposure to 10 ng/mL TNF-alpha ; pulse-chase response to 2 min exposure to 10 ng/mL TNF-alpha ; dose response of exposure to various concentrations of TNF-alpha for 30 min .	Both C33Y TNFR1- and WT TNFR1 transfected SK-Hep-1 cells were treated with TNF-alpha under three different conditions : time course of response to constant exposure to 10 ng/mL TNF-alpha; pulse-chase response to 2 min exposure to 10 ng/mL TNF-alpha; dose response of exposure to various concentrations of TNF-alpha for 30 min.	2	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	12	13	5	6
TNFalpha can stimulate its receptor TNFR1 , and the TNFR associated death protein TRADD signals to RIPK1 - which recruits RIPK3 , to form the necrosome through the interaction of RIP-homology interaction motif ( RHIM ) .	TNFalpha can stimulate its receptor TNFR1, and the TNFR associated death protein TRADD signals to RIPK1 - which recruits RIPK3, to form the necrosome through the interaction of RIP-homology interaction motif (RHIM).	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	0	1	5	6
We demonstrated that a long acting TNF antagonist ( soluble TNF receptor : IgG Fc [ sTNFR : IgG-Fc ] ) prevented and reduced development of acute liver failure by blocking the TNF and TNFR1 ( TNFRp55 ) pathway .	We demonstrated that a long acting TNF antagonist (soluble TNF receptor : IgG Fc [sTNFR : IgG-Fc]) prevented and reduced development of acute liver failure by blocking the TNF and TNFR1 (TNFRp55) pathway.	6	38	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	6	7	34	35
1 Whereas membrane bound TNF activates TNFR1 and TNFR2 efficiently , soluble TNF is sufficient for TNFR1 activation but largely inactive upon binding to TNFR2 .	1 Whereas membrane bound TNF activates TNFR1 and TNFR2 efficiently, soluble TNF is sufficient for TNFR1 activation but largely inactive upon binding to TNFR2.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	6	7
TNF-alpha activated the TNFRI on the intestinal epithelial cells and promoted gut permeability , facilitating bacterial translocation .	TNF-alpha activated the TNFRI on the intestinal epithelial cells and promoted gut permeability, facilitating bacterial translocation.	0	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFRI	TNFRI	TNFRI	0	1	3	4
9 It is worth mentioning that both TNF receptors are robustly activated by membrane TNF while soluble TNF predominantly stimulates TNFR1 despite binding to TNFR2 .	9 It is worth mentioning that both TNF receptors are robustly activated by membrane TNF while soluble TNF predominantly stimulates TNFR1 despite binding to TNFR2.	16	21	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	17	18	20	21
Probably , the observation that the TFM-C treatment had no effect on demyelination in organotypic culture model could be explained by increased astrocytic TNF-alpha , that in turn induces TNFR1 activation .	Probably, the observation that the TFM-C treatment had no effect on demyelination in organotypic culture model could be explained by increased astrocytic TNF-alpha, that in turn induces TNFR1 activation.	19	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	23	24	29	30
For example , one of the best characterized pathways that results in NF-kappaB activation is the Tumor Necrosis Factor Receptor 1 ( TNFR1 ) signaling pathway , which is activated by TNFalpha XREF_BIBR , XREF_BIBR .	For example, one of the best characterized pathways that results in NF-kappaB activation is the Tumor Necrosis Factor Receptor 1 (TNFR1) signaling pathway, which is activated by TNFalpha XREF_BIBR, XREF_BIBR.	1	32	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	31	32	22	23
TNF-alpha initiates shedding of the membrane receptors TNFR-I and II which are cleaved from the membrane and are detectable in serum , plasma and urine .	TNF-alpha initiates shedding of the membrane receptors TNFR-I and II which are cleaved from the membrane and are detectable in serum, plasma and urine.	0	18	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR-I	TNFR-I	TNFR-I	0	1	7	8
Animals deficient in TNF-alpha receptor 1 ( TNFR1 ) [ XREF_BIBR ] or treated with TNF-alpha neutralizing antibody are protected from ethanol induced lipid peroxidation and liver injury [ XREF_BIBR ] .	Animals deficient in TNF-alpha receptor 1 (TNFR1) [XREF_BIBR] or treated with TNF-alpha neutralizing antibody are protected from ethanol induced lipid peroxidation and liver injury [XREF_BIBR].	7	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	15	16	7	8
TNF-alpha exposure activates TNFR1 and induces release of big- endothlin-1 ( ET-1 ) , which is converted to ET-1 by extracellular ET converting enzyme .	TNF-alpha exposure activates TNFR1 and induces release of big- endothlin-1 (ET-1), which is converted to ET-1 by extracellular ET converting enzyme.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	0	1	3	4
Despite lack of TNFR1 induction by nPM in the OE , experimental blocking of TNFR1 by TNFalpha receptor blockers restored total neurite length .	Despite lack of TNFR1 induction by nPM in the OE, experimental blocking of TNFR1 by TNFalpha receptor blockers restored total neurite length.	12	18	blocking	Negative_activation_token_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	16	17	14	15
Based on its inhibitory effects on both TNFR1 mediated IkappaBalpha and NF-kappaB and pro apoptotic signaling pathways , we assumed that AST could act through preventing the initiation of TNFalpha induced TNFR1 mediated signaling .	Based on its inhibitory effects on both TNFR1 mediated IkappaBalpha and NF-kappaB and pro apoptotic signaling pathways, we assumed that AST could act through preventing the initiation of TNFalpha induced TNFR1 mediated signaling.	27	33	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	29	30	31	32
Two TNFalpha receptors are activated by TNFalpha , being TNF-R1 the most common since it is expressed in the majority of cells and TNF-R2 is only limited to the immune cells [ XREF_BIBR ] .	Two TNFalpha receptors are activated by TNFalpha, being TNF-R1 the most common since it is expressed in the majority of cells and TNF-R2 is only limited to the immune cells [XREF_BIBR].	1	26	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-R1	TNF-R1	TNF-R1	1	2	9	10
TNF-alpha initiates apoptosis in many cell types by the recruitment of the DED containing protein caspase-8 to the receptor complex following association of TRADD and FADD to TNFR-1 .	TNF-alpha initiates apoptosis in many cell types by the recruitment of the DED containing protein caspase-8 to the receptor complex following association of TRADD and FADD to TNFR-1.	0	28	initiates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR-1	TNFR-1	TNFR-1	0	1	27	28
TNF activate TNF receptor 1 ( TNFR1 ) through the pre-ligand assembly domain in the extracellular portion of TNFR1 and then triggers the trimerization of TNFR1 .	TNF activate TNF receptor 1 (TNFR1) through the pre-ligand assembly domain in the extracellular portion of TNFR1 and then triggers the trimerization of TNFR1.	0	26	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	0	1	25	26
Here , we demonstrated that TNF-alpha induced TNFR1 , TRAF2 , and p47 phox complex formation which was blocked by pretreatment with TNF-alpha neutralizing antibody , and leading to cPLA 2 expression in HPAEpiCs .	Here, we demonstrated that TNF-alpha induced TNFR1, TRAF2, and p47 phox complex formation which was blocked by pretreatment with TNF-alpha neutralizing antibody, and leading to cPLA 2 expression in HPAEpiCs.	5	12	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	5	6	7	8
Mechanistically , TNF-alpha activates TNFR1 forming a positive feedback loop of TNFR1 and NF-kappaB ( and/or p38 )/p-STAT3/HBXIP/TNFR1 [ XREF_BIBR ] .	Mechanistically, TNF-alpha activates TNFR1 forming a positive feedback loop of TNFR1 and NF-kappaB (and/or p38)/p-STAT3/HBXIP/TNFR1 [XREF_BIBR].	2	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	2	3	4	5
Notably , TNF-alpha was able to up-regulate TNFR1 through driving the loop .	Notably, TNF-alpha was able to up-regulate TNFR1 through driving the loop.	2	8	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	2	3	7	8
Transmembrane TNF-alpha ( mTNF ) and soluble TNF-alpha activate TNFR1 , whereas TNFR2 is effectively activated mainly by combining with mTNF [ XREF_BIBR ] .	Transmembrane TNF-alpha (mTNF) and soluble TNF-alpha activate TNFR1, whereas TNFR2 is effectively activated mainly by combining with mTNF [XREF_BIBR].	0	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	1	2	9	10
In some cell types , exposure to IAP antagonists results in stimulation of non canonical NF-kappaB pathways that promote induction of TNFalpha expression , which stimulates autocrine TNF-R1 signaling of apoptotic and/or necroptotic cell death [ XREF_BIBR ] .	In some cell types, exposure to IAP antagonists results in stimulation of non canonical NF-kappaB pathways that promote induction of TNFalpha expression, which stimulates autocrine TNF-R1 signaling of apoptotic and/or necroptotic cell death [XREF_BIBR].	15	28	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	NF-kappaB pathways that promote induction of TNFalpha expression	tnfalpha	TNF-R1	TNF-R1	tnf-r1	21	22	27	28
The alpha2-6 sialylation of TNFR1 was found to inhibit TNF induced TNFR1 internalization .	The alpha2-6 sialylation of TNFR1 was found to inhibit TNF induced TNFR1 internalization.	8	12	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	9	10	11	12
It is known that binding of the TNF homotrimer to TNF-receptor 1 ( TNF-R1 ) initiates the formation of a TNF-R1 signaling complex by recruiting several adaptor and effector proteins .	It is known that binding of the TNF homotrimer to TNF-receptor 1 (TNF-R1) initiates the formation of a TNF-R1 signaling complex by recruiting several adaptor and effector proteins.	7	22	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNF-R1	TNF-R1	TNF-R1	7	8	20	21
The EBV protein BZLF1 inhibits the expression of TNF induced genes and decreases TNFR1 promoter activity , which results in decreased TNFR1 transcription during lytic reactivation of the virus XREF_BIBR .	The EBV protein BZLF1 inhibits the expression of TNF induced genes and decreases TNFR1 promoter activity, which results in decreased TNFR1 transcription during lytic reactivation of the virus XREF_BIBR.	1	15	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	EBV protein BZLF1 inhibits the expression of TNF	tnf	TNFR1	TNFR1	tnfr1	8	9	13	14
TNFalpha activates TNFR1 signals to form complex II consisting of RIP1 , FADD and caspase-8 15 .	TNFalpha activates TNFR1 signals to form complex II consisting of RIP1, FADD and caspase-8 15.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	0	1	2	3
Notably , prolonged TNF-alpha or IL-1beta treatment induced TNFR1 mRNA .	Notably, prolonged TNF-alpha or IL-1beta treatment induced TNFR1 mRNA.	2	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	3	4	8	9
The TNF-R1 pathway was not activated by TNF or IL-1beta in mutant cells , nor was it even inhibited by IL-1beta in the T50M mutant .	The TNF-R1 pathway was not activated by TNF or IL-1beta in mutant cells, nor was it even inhibited by IL-1beta in the T50M mutant.	1	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNF-R1	TNF-R1	TNF-R1	7	8	1	2
TNFRSF1A is preferentially activated by the shed form of TNF ligand , whereas the membrane bound form of TNF serves to activate TNFRSF1A and TNFRSF1B equally .	TNFRSF1A is preferentially activated by the shed form of TNF ligand, whereas the membrane bound form of TNF serves to activate TNFRSF1A and TNFRSF1B equally.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFRSF1A	TNFRSF1A	TNFRSF1A	9	10	0	1
Morin also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF , TNF receptor ( TNFR ) 1 , TNFR1 associated death domain , TNFR associated factor 2 , NF-kappaB-inducing kinase , IkappaB kinase , and the p65 subunit of NF-kappaB .	Morin also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR1 associated death domain, TNFR associated factor 2, NF-kappaB-inducing kinase, IkappaB kinase, and the p65 subunit of NF-kappaB.	2	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	10	11	19	20
Once activated , the expression of TNFalpha by NK cells induced lysis of 55 % +/- 2 % of bile duct epithelial cells , which was completely prevented by blocking TNFalpha or TNFR2 , but not TNFR1 .	Once activated, the expression of TNFalpha by NK cells induced lysis of 55% +/- 2% of bile duct epithelial cells, which was completely prevented by blocking TNFalpha or TNFR2, but not TNFR1.	4	37	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	expression of TNFalpha	tnfalpha	TNFR1	TNFR1	tnfr1	6	7	36	37
The role of tumor necrosis factor ( TNF )-alpha and its receptors in the pathogenesis of experimental autoimmune neuritis ( EAN ) induced by P0 peptide 180-199 in TNFR1 ( p55 ) deficient ( TNFR1-/-) mice was investigated .	The role of tumor necrosis factor (TNF)-alpha and its receptors in the pathogenesis of experimental autoimmune neuritis (EAN) induced by P0 peptide 180-199 in TNFR1 (p55) deficient (TNFR1-/-) mice was investigated.	3	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	TNFR1	TNFR1	TNFR1	3	6	28	29
TNF-alpha markedly induced both caveolin-1 and TNFR-1 , the events which were further induced when cells were first enriched with linoleic acid .	TNF-alpha markedly induced both caveolin-1 and TNFR-1, the events which were further induced when cells were first enriched with linoleic acid.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR-1	TNFR-1	TNFR-1	0	1	6	7
In addition to the effects of TNF-alpha on agonist evoked calcium signals , we also reported that activation of TNFR1 by TNF-alpha regulates the expression of functional ICAM-1 on human ASM cells [ XREF_BIBR ] .	In addition to the effects of TNF-alpha on agonist evoked calcium signals, we also reported that activation of TNFR1 by TNF-alpha regulates the expression of functional ICAM-1 on human ASM cells [XREF_BIBR].	17	22	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	21	22	19	20
Necroptosis is sometimes induced by TNF mediated TNFR1 ligation through activation of the RIP family kinases and dependent on activation of RIP1 , RIP3 , or mixed lineage kinase domain like [ XREF_BIBR ] , which is inhibited by the RIP1 targeting necrostatin [ XREF_BIBR ] .	Necroptosis is sometimes induced by TNF mediated TNFR1 ligation through activation of the RIP family kinases and dependent on activation of RIP1, RIP3, or mixed lineage kinase domain like [XREF_BIBR], which is inhibited by the RIP1 targeting necrostatin [XREF_BIBR].	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	5	6	7	8
Furthermore , TNF-alpha mediates its effect by two surface receptors , TNF-alpha receptor 1 ( TNFR1 ) , or p55 , and TNFR2 , or p75 , and both receptors are expressed in the pancreas [ XREF_BIBR , XREF_BIBR ] .	Furthermore, TNF-alpha mediates its effect by two surface receptors, TNF-alpha receptor 1 (TNFR1), or p55, and TNFR2, or p75, and both receptors are expressed in the pancreas [XREF_BIBR, XREF_BIBR].	2	16	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	2	3	15	16
In these cells TNFR1 is selectively activated by soluble TNF ( sTNF ) while RANK-TNFR2 is selectively activated by RANKL .	In these cells TNFR1 is selectively activated by soluble TNF (sTNF) while RANK-TNFR2 is selectively activated by RANKL.	3	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	9	10	3	4
The kinase activity of RIPK1 may be activated upon stimulation of TNFR1 by TNFalpha under selective conditions , which leads to multiple deleterious consequences including cell death and inflammation .	The kinase activity of RIPK1 may be activated upon stimulation of TNFR1 by TNFalpha under selective conditions, which leads to multiple deleterious consequences including cell death and inflammation.	7	16	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	13	14	11	12
TNFR1 , predominantly activated by soluble TNF XREF_BIBR , exerts proinflammatory effects XREF_BIBR , XREF_BIBR , whereas TNFR2 , preferentially activated by membrane bound TNF XREF_BIBR promotes both neuroprotection and remyelination XREF_BIBR , XREF_BIBR .	TNFR1, predominantly activated by soluble TNF XREF_BIBR, exerts proinflammatory effects XREF_BIBR, XREF_BIBR, whereas TNFR2, preferentially activated by membrane bound TNF XREF_BIBR promotes both neuroprotection and remyelination XREF_BIBR, XREF_BIBR.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	6	7	0	1
Murine TNF-alpha ( mTNF-alpha ) activates both TNF-R1 and TNF-R2 on murine macrophages , while human TNF-alpha ( hTNF-alpha ) activates TNF-R1 only , thereby providing a means to distinguish effects that are mediated through different receptors [ XREF_BIBR ] .	Murine TNF-alpha (mTNF-alpha) activates both TNF-R1 and TNF-R2 on murine macrophages, while human TNF-alpha (hTNF-alpha) activates TNF-R1 only, thereby providing a means to distinguish effects that are mediated through different receptors [XREF_BIBR].	15	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	16	17	21	22
Activation of the TNFR1 pathway occurs when trimeric TNF crosslinks three TNFR1 monomers to initiate formation of the TNFR1 signaling complex ( TNF-RSC ) .	Activation of the TNFR1 pathway occurs when trimeric TNF crosslinks three TNFR1 monomers to initiate formation of the TNFR1 signaling complex (TNF-RSC).	8	20	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	8	9	18	19
Together , these data support a working model in which locally produced TNFalpha activates epidermal cell TNFR1 , which then alters CDK4 protein levels in a NF-kappaB and JNK regulated manner to control cell cycle progression in epidermis .	Together, these data support a working model in which locally produced TNFalpha activates epidermal cell TNFR1, which then alters CDK4 protein levels in a NF-kappaB and JNK regulated manner to control cell cycle progression in epidermis.	12	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	12	13	16	17
We infected primary human monocytes and monocyte derived macrophages with the virulent Mycobacterium tuberculosis strain H37Rv and followed the rate of cell death in the absence or presence of a wide concentration range of four different TNF targeted biologicals : infliximab and adalimumab ( both monoclonal antibodies to human TNF ) and etanercept and polyethylene-glycols TNFR1 ( fusion constructs of human TNFR2 and TNFR1 , respectively ) .	We infected primary human monocytes and monocyte derived macrophages with the virulent Mycobacterium tuberculosis strain H37Rv and followed the rate of cell death in the absence or presence of a wide concentration range of four different TNF targeted biologicals : infliximab and adalimumab (both monoclonal antibodies to human TNF) and etanercept and polyethylene-glycols TNFR1 (fusion constructs of human TNFR2 and TNFR1, respectively).	32	58	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	36	37	55	56
Chemokine secretion was absent in TNF stimulated Tnfr1 deficient glomeruli , but also significantly decreased in glomeruli lacking TNFR2 .	Chemokine secretion was absent in TNF stimulated Tnfr1 deficient glomeruli, but also significantly decreased in glomeruli lacking TNFR2.	3	14	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Tnfr1	Tnfr1	Tnfr1	5	6	7	8
TNF-R1 mRNA was upregulated by TNF-alpha in normal NP cells but downregulated in degenerate samples .	TNF-R1 mRNA was upregulated by TNF-alpha in normal NP cells but downregulated in degenerate samples.	0	9	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	5	6	0	1
However , TNF-R1 is expressed in all studied cell lines and it was shown previously that TNF-R2 can induce apoptosis by strongly enhancing the activation of TNF-R1 by TNF-alpha and also by inhibiting nuclear factor kappa B mediated protection , indicating that TNF-R2 overexpression may sensitizes cells to TNF-a-mediated apoptotic signal after gamma irradiation .	However, TNF-R1 is expressed in all studied cell lines and it was shown previously that TNF-R2 can induce apoptosis by strongly enhancing the activation of TNF-R1 by TNF-alpha and also by inhibiting nuclear factor kappa B mediated protection, indicating that TNF-R2 overexpression may sensitizes cells to TNF-a-mediated apoptotic signal after gamma irradiation.	22	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	28	29	26	27
Membrane TNF can trigger TNFR1 and TNFR2 signaling , whereas soluble TNF has preferential effects on TNFR1 over TNFR2 [ XREF_BIBR , XREF_BIBR ] .	Membrane TNF can trigger TNFR1 and TNFR2 signaling, whereas soluble TNF has preferential effects on TNFR1 over TNFR2 [XREF_BIBR, XREF_BIBR].	0	7	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	1	2	4	5
Under conditions that are insufficient to trigger apoptosis , TNFalpha activates TNFR1 and in turn induces the recruitment of receptor interacting protein 1 ( RIP1 ) kinase and other proteins to form complex I. Subsequently , these proteins dissociate from TNFR1 and RIP1 can be found in the cytosol in complex IIb , which includes RIP1 , receptor interacting protein 3 ( RIP3 ) kinase , caspase-8 and FADD .	Under conditions that are insufficient to trigger apoptosis, TNFalpha activates TNFR1 and in turn induces the recruitment of receptor interacting protein 1 (RIP1) kinase and other proteins to form complex I. Subsequently, these proteins dissociate from TNFR1 and RIP1 can be found in the cytosol in complex IIb, which includes RIP1, receptor interacting protein 3 (RIP3) kinase, caspase-8 and FADD.	9	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	9	10	11	12
However , our study highlights the fact that TNFalpha and TNFR1 is not the only death receptor ligand and receptor system that can mediate Smac mimetic induced apoptosis , as the TNFalpha blocking antibody Enbrel or TNFR1 knockdown largely fail to rescue BV6 induced apoptosis in A172 glioblastoma cells .	However, our study highlights the fact that TNFalpha and TNFR1 is not the only death receptor ligand and receptor system that can mediate Smac mimetic induced apoptosis, as the TNFalpha blocking antibody Enbrel or TNFR1 knockdown largely fail to rescue BV6 induced apoptosis in A172 glioblastoma cells.	30	43	blocking	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	31	32	36	37
XREF_BIBR Lastly , the infection studies in double TNF tm/tm x TNFR1 or R2 -/- transgenic mice rescued protection in TNF tm/tm x TNFR2 -/- mice and comparable protection in TNF tm/tm x TNFR1 -/- mice as in TNF tm/tm mice suggest that membrane signalling though TNFR2 likely provides host protection .	XREF_BIBR Lastly, the infection studies in double TNF tm/tm x TNFR1 or R2 -/- transgenic mice rescued protection in TNF tm/tm x TNFR2 -/- mice and comparable protection in TNF tm/tm x TNFR1 -/- mice as in TNF tm/tm mice suggest that membrane signalling though TNFR2 likely provides host protection.	8	35	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	8	9	33	34
TNF activates two receptors , TNFR1 and TNFR2 .	TNF activates two receptors, TNFR1 and TNFR2.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	0	1	5	6
In VSMCs , TNF-alpha stimulates TNFR1 and leads to activation of MAPK , which is required for VSMC migration .	In VSMCs, TNF-alpha stimulates TNFR1 and leads to activation of MAPK, which is required for VSMC migration.	3	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	3	4	5	6
Excessive activation of TNFR1 by TNF leads to the apoptosis of hepatocytes , and thus leads to organ damage ; however , membrane bound TNFR1 can be cleaved through proteolytic shedding of its ectodomain , which is dependent on activation of TNF converting enzyme ( TACE , also known as ADAM17 ) .	Excessive activation of TNFR1 by TNF leads to the apoptosis of hepatocytes, and thus leads to organ damage; however, membrane bound TNFR1 can be cleaved through proteolytic shedding of its ectodomain, which is dependent on activation of TNF converting enzyme (TACE, also known as ADAM17).	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	5	6	3	4
These findings indicate that low TNF-alpha concentrations may stimulate TNFR1 , whereas TNFR2 stimulation may require high TNF-alpha concentrations .	These findings indicate that low TNF-alpha concentrations may stimulate TNFR1, whereas TNFR2 stimulation may require high TNF-alpha concentrations.	5	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	5	6	9	10
TNFalpha stimulation induces the trimerization of TNFR1 to promote the formation of a transient intracellular multi protein complex , the TNFR1 signaling complex - TNF-RSC ( also called complex I ) , which recruits RIPK1 via homotypic interactions of their death domains 14 .	TNFalpha stimulation induces the trimerization of TNFR1 to promote the formation of a transient intracellular multi protein complex, the TNFR1 signaling complex - TNF-RSC (also called complex I), which recruits RIPK1 via homotypic interactions of their death domains 14.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	0	1	6	7
TNF-alpha induced by HCV could activate its own receptor TNFR1 on hepatocytes to suppress HCV replication .	TNF-alpha induced by HCV could activate its own receptor TNFR1 on hepatocytes to suppress HCV replication.	0	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	0	1	9	10
Our lab has recently shown that TNF causes TNFR1 dependent , developmental stage dependent changes in intestinal goblet cell secretion of mucus [ XREF_BIBR ] .	Our lab has recently shown that TNF causes TNFR1 dependent, developmental stage dependent changes in intestinal goblet cell secretion of mucus [XREF_BIBR].	6	9	causes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	6	7	8	9
The pleotropic biological functions of TNF-alpha are mediated through its cognate receptors TNFR1 and TNFR2 , which activate various signalling pathways predominantly through TNFR1 XREF_BIBR .	The pleotropic biological functions of TNF-alpha are mediated through its cognate receptors TNFR1 and TNFR2, which activate various signalling pathways predominantly through TNFR1 XREF_BIBR.	3	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	5	6	12	13
However , NF-kappaB activation by interleukin-1 leads to NF-kappaB-dependent secretion of TNF-alpha , which activates TNF-R1 in an autocrine fashion to enhance UVB induced apoptosis .	However, NF-kappaB activation by interleukin-1 leads to NF-kappaB-dependent secretion of TNF-alpha, which activates TNF-R1 in an autocrine fashion to enhance UVB induced apoptosis.	9	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	11	12	15	16
Tumour necrosis factor ( TNF ) receptor associated periodic syndrome ( TRAPS ) is caused by TNFRSF1A mutations , known to induce intracellular retention of the TNFalpha receptor 1 ( TNFR1 ) protein , defective TNFalpha induced apoptosis , and production of reactive oxygen species .	Tumour necrosis factor (TNF) receptor associated periodic syndrome (TRAPS) is caused by TNFRSF1A mutations, known to induce intracellular retention of the TNFalpha receptor 1 (TNFR1) protein, defective TNFalpha induced apoptosis, and production of reactive oxygen species.	2	32	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	30	31
Additionally , by activating TNFR1 in airway smooth muscle , TNF-alpha triggers extracellular signal regulated kinase ( ERK ) and p38 mitogen activated protein kinases ( MAPKs ) signaling pathway and transcription factors to turn on a variety of genes ( interleukins ) that mediate inflammatory and immune responses [ XREF_BIBR ] .	Additionally, by activating TNFR1 in airway smooth muscle, TNF-alpha triggers extracellular signal regulated kinase (ERK) and p38 mitogen activated protein kinases (MAPKs) signaling pathway and transcription factors to turn on a variety of genes (interleukins) that mediate inflammatory and immune responses [XREF_BIBR].	3	12	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	10	11	4	5
It is known that TNF triggers the formation of a TNF receptor 1 ( TNFR1 ) signaling complex by recruiting several effectors such as TNFR1 associated death domain protein ( TRADD ) , receptor interacting protein kinase 1 ( RIP1 ) and TNFR associated factor 2 ( TRAF2 ) to mediate the activation of the transcription factor nuclear factor-kappaB ( NF-kappaB ) and mitogen activaed protein ( MAP ) kinases XREF_BIBR , XREF_BIBR .	It is known that TNF triggers the formation of a TNF receptor 1 (TNFR1) signaling complex by recruiting several effectors such as TNFR1 associated death domain protein (TRADD), receptor interacting protein kinase 1 (RIP1) and TNFR associated factor 2 (TRAF2) to mediate the activation of the transcription factor nuclear factor-kappaB (NF-kappaB) and mitogen activaed protein (MAP) kinases XREF_BIBR, XREF_BIBR.	4	43	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	14	15
Notably , whereas TNFRI can be activated by both soluble and membrane TNF , TNFRII is activated efficiently only by mTNF .	Notably, whereas TNFRI can be activated by both soluble and membrane TNF, TNFRII is activated efficiently only by mTNF.	3	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFRI	TNFRI	TNFRI	12	13	3	4
They function similarly to endogenous SMAC by antagonizing the inhibition of caspases mediated by XIAP and by inducing the auto-ubiquitination of cIAP1 or cIAP2 ; subsequent NF-kappaB-induced expression of TNFalpha further activates pro apoptotic TNFR1 ( TNFalpha receptor ) signaling [ XREF_BIBR - XREF_BIBR ] .	They function similarly to endogenous SMAC by antagonizing the inhibition of caspases mediated by XIAP and by inducing the auto-ubiquitination of cIAP1 or cIAP2; subsequent NF-kappaB-induced expression of TNFalpha further activates pro apoptotic TNFR1 (TNFalpha receptor) signaling [XREF_BIBR - XREF_BIBR].	27	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	expression of TNFalpha	tnfalpha	TNFR1	TNFR1	tnfr1	29	30	34	35
Tumor necrosis factor ( TNF ) is structurally homologous to LTa and similarly activates TNFR1 , but notably lacks methionine residues .	Tumor necrosis factor (TNF) is structurally homologous to LTa and similarly activates TNFR1, but notably lacks methionine residues.	2	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	14	15
Although , in principle , transmembrane TNF can activate both TNFR1 and TNFR2 , our finding that anti-TNFR1 has similar effects to XPro1595 , therefore may support the notion that blocking of TNFR1 is neuroprotective in EAE .	Although, in principle, transmembrane TNF can activate both TNFR1 and TNFR2, our finding that anti-TNFR1 has similar effects to XPro1595, therefore may support the notion that blocking of TNFR1 is neuroprotective in EAE.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	6	7	10	11
Activation of TNFR1 by TNF can result in both RIPK1 independent apoptosis and RIPK1 kinase dependent apoptosis or necroptosis .	Activation of TNFR1 by TNF can result in both RIPK1 independent apoptosis and RIPK1 kinase dependent apoptosis or necroptosis.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	2	3
Taken together , these reports point to a signaling pathway by which activation of TNF-R1 by TNF-alpha or UVB triggers K + channel activation .	Taken together, these reports point to a signaling pathway by which activation of TNF-R1 by TNF-alpha or UVB triggers K + channel activation.	9	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	16	17	14	15
Typically , necroptosis ensues following TNF mediated TNFR1 ligation , which follows activation of RIP1 , RIP3 , or MLKL ( that is , mixed lineage kinase domain like kinase ) .	Typically, necroptosis ensues following TNF mediated TNFR1 ligation, which follows activation of RIP1, RIP3, or MLKL (that is, mixed lineage kinase domain like kinase).	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	5	6	7	8
However , castration or flutamide treatment did not affect TNF production and myocardial expression of TNFR1 and TNFR2 .	However, castration or flutamide treatment did not affect TNF production and myocardial expression of TNFR1 and TNFR2.	9	17	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	9	10	15	16
Although specific to the model of autoimmune diabetes , TNFalpha secretion from CD4 + T cells can activate TNFR1 on beta-cells and cause apoptosis [ XREF_BIBR ] , while CD8 + T cells can kill NOD beta-cells by a Fas dependent mechanism [ XREF_BIBR ] or by perforin release [ XREF_BIBR ] .	Although specific to the model of autoimmune diabetes, TNFalpha secretion from CD4 + T cells can activate TNFR1 on beta-cells and cause apoptosis [XREF_BIBR], while CD8 + T cells can kill NOD beta-cells by a Fas dependent mechanism [XREF_BIBR] or by perforin release [XREF_BIBR].	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	9	10	18	19
The biological activity of TNF-alpha is mediated by two membrane receptors TNFR1 and TNFR2 that have different effects .	The biological activity of TNF-alpha is mediated by two membrane receptors TNFR1 and TNFR2 that have different effects.	2	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	4	5	11	12
In contrast , LPS and TNFalpha mediated apoptosis is dependent on soluble TNFalpha , which can only activate TNF-R1 .	In contrast, LPS and TNFalpha mediated apoptosis is dependent on soluble TNFalpha, which can only activate TNF-R1.	9	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-R1	TNF-R1	TNF-R1	12	13	18	19
Activation of several death receptors ( Fas and CD95 , TNFR1 , and TRAIL receptor ) is promoted by ligands of TNF family , including FASL , TNF , LT-alpha , LT-beta , CD40L , LIGHT , RANKL , and TRAIL , many of which are released as part of the inflammatory response to ischemia [ XREF_BIBR ] .	Activation of several death receptors (Fas and CD95, TNFR1, and TRAIL receptor) is promoted by ligands of TNF family, including FASL, TNF, LT-alpha, LT-beta, CD40L, LIGHT, RANKL, and TRAIL, many of which are released as part of the inflammatory response to ischemia [XREF_BIBR].	0	22	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	21	22	10	11
TNF-alpha can activate TNFR1 and induce neuronal apoptosis to aggregate brain tissue damage .	TNF-alpha can activate TNFR1 and induce neuronal apoptosis to aggregate brain tissue damage.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	0	1	3	4
Also , the addition of 100 ng/ml TNFalpha plus Abeta42 to middle-age neurons increased TNFR1 : TNFR2 ratio both for the soma and the processes more than 10 ng/ml TNFalpha plus Abeta42 .	Also, the addition of 100 ng/ml TNFalpha plus Abeta42 to middle-age neurons increased TNFR1 : TNFR2 ratio both for the soma and the processes more than 10 ng/ml TNFalpha plus Abeta42.	3	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	7	8	14	15
Zheng and colleagues 30 show that cIAP2 is part of the TNF induced TNFR1 signaling complex , which is vital in the regulation of the nuclear factor-kappabeta proinflammatory transcription pathway .	Zheng and colleagues 30 show that cIAP2 is part of the TNF induced TNFR1 signaling complex, which is vital in the regulation of the nuclear factor-kappabeta proinflammatory transcription pathway.	8	15	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	11	12	13	14
In most cell types , TNF-alpha activates NF-kappaB through binding to tumor necrosis factor receptor1 ( TNFR1 ) [ XREF_BIBR ] .	In most cell types, TNF-alpha activates NF-kappaB through binding to tumor necrosis factor receptor1 (TNFR1) [XREF_BIBR].	5	15	activates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	tumor necrosis factor receptor1	tumor necrosis factor receptor1	tumor necrosis factor receptor1	5	6	11	15
Furthermore , CD40 stimulation mediated TNFalpha production and upregulation of TNFalpha receptors TNFR1 and TNFR2 .	Furthermore, CD40 stimulation mediated TNFalpha production and upregulation of TNFalpha receptors TNFR1 and TNFR2.	5	14	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	5	6	12	13
Tumor necrosis factor ( TNF ) triggers distinct pathways in liver cells through TNF receptor 1 ( TNF-R1 ) via adapter molecules , including the intracellular cascades leading to apoptosis , nuclear factor-kappa B ( NF-kappa B ) , and Jun kinase ( JNK ) activation .	Tumor necrosis factor (TNF) triggers distinct pathways in liver cells through TNF receptor 1 (TNF-R1) via adapter molecules, including the intracellular cascades leading to apoptosis, nuclear factor-kappa B (NF-kappa B), and Jun kinase (JNK) activation.	2	45	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNF-R1	TNF-R1	TNF-R1	4	5	17	18
Soluble TNF and tmTNF preferentially trigger TNFR1 and TNFR2 signaling pathways , respectively .	Soluble TNF and tmTNF preferentially trigger TNFR1 and TNFR2 signaling pathways, respectively.	0	10	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	1	2	6	7
TNF-alpha failed to activate JNK1 in these TNFR1 deficient astrocytes , supporting an essential role of TNFR1 for JNK1 activation by TNF-alpha in astrocytes ( XREF_FIG ) .	TNF-alpha failed to activate JNK1 in these TNFR1 deficient astrocytes, supporting an essential role of TNFR1 for JNK1 activation by TNF-alpha in astrocytes (XREF_FIG).	0	19	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	0	1	16	17
Several studies have suggested a link between increased TNF-alpha levels and cognitive alteration , and a recent study showed that local increase of TNF-alpha in the hippocampal dentate gyrus activated astrocyte TNF receptor type 1 ( TNFR1 ) , which in turn triggered an astrocyte-neuron signaling cascade that resulted in persistent functional modification of hippocampal excitatory synapses .	Several studies have suggested a link between increased TNF-alpha levels and cognitive alteration, and a recent study showed that local increase of TNF-alpha in the hippocampal dentate gyrus activated astrocyte TNF receptor type 1 (TNFR1), which in turn triggered an astrocyte-neuron signaling cascade that resulted in persistent functional modification of hippocampal excitatory synapses.	21	42	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	23	24	36	37
The study revealed , that long-term , but not short-term TNF-alpha treatment leads to TNF-receptor 1 ( TNFR1 ) mediated downregulation of ABCB1 resulting in sensitization towards drug treatment .	The study revealed, that long-term, but not short-term TNF-alpha treatment leads to TNF-receptor 1 (TNFR1) mediated downregulation of ABCB1 resulting in sensitization towards drug treatment.	10	18	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	10	11	17	18
In contrast to a local secretion of TNFalpha by activated monocytes and macrophages in the intestinal lamina propria , it is also conceivable that systemic TNFalpha is elevated during alcoholic liver disease and activates TNFRI on intestinal epithelial cells to induce tight junction disruption .	In contrast to a local secretion of TNFalpha by activated monocytes and macrophages in the intestinal lamina propria, it is also conceivable that systemic TNFalpha is elevated during alcoholic liver disease and activates TNFRI on intestinal epithelial cells to induce tight junction disruption.	24	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFRI	TNFRI	TNFRI	25	26	34	35
Moreover , CPS-A attenuated both the normal expression and overexpression of TNF-alpha receptor 1 ( TNFR1 ) induced by TNF-alpha administration .	Moreover, CPS-A attenuated both the normal expression and overexpression of TNF-alpha receptor 1 (TNFR1) induced by TNF-alpha administration.	3	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	19	20	15	16
Stimulation of TNFR1 by TNFalpha can promote three distinct alternative mechanisms of cell death : necroptosis , RIPK1 independent and -dependent apoptosis .	Stimulation of TNFR1 by TNFalpha can promote three distinct alternative mechanisms of cell death : necroptosis, RIPK1 independent and -dependent apoptosis.	0	5	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	4	5	2	3
Protein A is taken up by epithelial cells ( inhibitable by cytochalasin D ) as it is abundantly shed by organisms during growth and can activate signaling through TNFR1 and IRF1 , which can be activated by TNF .	Protein A is taken up by epithelial cells (inhibitable by cytochalasin D) as it is abundantly shed by organisms during growth and can activate signaling through TNFR1 and IRF1, which can be activated by TNF.	25	38	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	37	38	28	29
Research suggests that TNFalpha activates the TNF receptor type 1 ( TNFR1 ) to induce caspase dependent apoptosis in acute phases of CNS insults XREF_BIBR .	Research suggests that TNFalpha activates the TNF receptor type 1 (TNFR1) to induce caspase dependent apoptosis in acute phases of CNS insults XREF_BIBR.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	3	4	11	12
In conclusion we assume that TNF-alpha induces an increase in PTV and CBF by binding to TNF-R1 on tracheal mast cells which then release serotonin that stimulates the 5-HT 2 serotonin receptor on cilia bearing cells .	In conclusion we assume that TNF-alpha induces an increase in PTV and CBF by binding to TNF-R1 on tracheal mast cells which then release serotonin that stimulates the 5-HT 2 serotonin receptor on cilia bearing cells.	5	23	induces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	5	6	16	17
However , other studies have shown that high astrocytic expression of human TNFalpha , which preferentially activates TNFR1 , can be proconvulsive , pointing to a context dependence of the disease modifying potential of TNFalpha .	However, other studies have shown that high astrocytic expression of human TNFalpha, which preferentially activates TNFR1, can be proconvulsive, pointing to a context dependence of the disease modifying potential of TNFalpha.	9	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	expression of human TNFalpha	tnfalpha	TNFR1	TNFR1	tnfr1	12	13	17	18
TNFR1 activation by TNF-alpha leads to formation of two distinct TNF signaling complexes : Complex 1 has anti-apoptotic functions , while Complex II/death inducing signaling complex ( DISC ) induces apoptosis after receptor internalization .	TNFR1 activation by TNF-alpha leads to formation of two distinct TNF signaling complexes : Complex 1 has anti-apoptotic functions, while Complex II/death inducing signaling complex (DISC) induces apoptosis after receptor internalization.	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	3	4	0	1
When TNF-R1 and/or -R2 are stimulated by TNF-alpha , the extracellular portions of transmembrane proteins are cleaved , soluble ectodomains are released from the cell surface by a sheddase known as TNF converting enzyme ( TACE ) XREF_BIBR , and sTNF is neutralized by the sTNF-Rs XREF_BIBR .	When TNF-R1 and/or -R2 are stimulated by TNF-alpha, the extracellular portions of transmembrane proteins are cleaved, soluble ectodomains are released from the cell surface by a sheddase known as TNF converting enzyme (TACE) XREF_BIBR, and sTNF is neutralized by the sTNF-Rs XREF_BIBR.	1	8	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	7	8	1	2
TNFalpha binds to and activates two distinct receptors TNF-receptor 1 ( TNF-R1 ) and TNF-R2 ; both are expressed on EC and VSMC XREF_BIBR .	TNFalpha binds to and activates two distinct receptors TNF-receptor 1 (TNF-R1) and TNF-R2; both are expressed on EC and VSMC XREF_BIBR.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-R1	TNF-R1	TNF-R1	0	1	11	12
Specifically , our data showed exposure of A549 cells to IFN-gamma inhibited the TNF-alpha induced downregulation of TNFR1 mRNA without altering total cellular or cell surface TNFR1 protein compared to TNF treated cells alone .	Specifically, our data showed exposure of A549 cells to IFN-gamma inhibited the TNF-alpha induced downregulation of TNFR1 mRNA without altering total cellular or cell surface TNFR1 protein compared to TNF treated cells alone.	12	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	13	14	17	18
The TNFalpha dependent activation of TNFR1 leads to formation of a signaling complex that contains several important molecules , including TRADD , RIP and TRAF2 .	The TNFalpha dependent activation of TNFR1 leads to formation of a signaling complex that contains several important molecules, including TRADD, RIP and TRAF2.	1	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	1	2	5	6
TNF-alpha is used to stimulate TNFR1 activation .	TNF-alpha is used to stimulate TNFR1 activation.	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	0	1	5	6
TNFR1 can be activated by both mTNF and TNF , whereas TNFR2 preferentially binds to mTNF to initiate the activation of the receptor .	TNFR1 can be activated by both mTNF and TNF, whereas TNFR2 preferentially binds to mTNF to initiate the activation of the receptor.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	8	9	0	1
To investigate TNFR1 mediated signaling , HPMCs were treated with PDF or TNF , and expression patterns of proteins involved in the TNFR1 signaling pathway were assessed by western blot .	To investigate TNFR1 mediated signaling, HPMCs were treated with PDF or TNF, and expression patterns of proteins involved in the TNFR1 signaling pathway were assessed by western blot.	2	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	12	13	2	3
TNFR1 may also be activated at a later time point after UV exposure by TNF-alpha released by keratinocytes , since it was shown that UV induced apoptosis can be partially reduced by blocking TNF-alpha .	TNFR1 may also be activated at a later time point after UV exposure by TNF-alpha released by keratinocytes, since it was shown that UV induced apoptosis can be partially reduced by blocking TNF-alpha.	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	14	15	0	1
In contrast , TNFR1 (-Fas ) is strongly activated by TNF spaced within up to 200 nm distances , whereas larger spacings of 290 nm fails completely .	In contrast, TNFR1 (-Fas) is strongly activated by TNF spaced within up to 200 nm distances, whereas larger spacings of 290 nm fails completely.	3	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	10	11	3	4
XREF_BIBR , XREF_BIBR In contrast to the critical role of IFNbeta for BV6 and TMZ induced apoptosis that we discovered in the current study , we previously reported that TNFalpha , another prototypic NF-kappaB target gene , is largely dispensable for BV6 and TMZ induced apoptosis , as addition of the TNFalpha blocking antibody Enbrel or TNFR1 knockdown failed to rescue apoptosis upon combination treatment .	XREF_BIBR, XREF_BIBR In contrast to the critical role of IFNbeta for BV6 and TMZ induced apoptosis that we discovered in the current study, we previously reported that TNFalpha, another prototypic NF-kappaB target gene, is largely dispensable for BV6 and TMZ induced apoptosis, as addition of the TNFalpha blocking antibody Enbrel or TNFR1 knockdown failed to rescue apoptosis upon combination treatment.	48	57	blocking	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	51	52	56	57
Collectively , these results suggest that HUHS1015 upregulates expression of the TNFalpha mRNA and protein in MKN45 cells , thereby causing activation of TNFR1 and caspase-8 .	Collectively, these results suggest that HUHS1015 upregulates expression of the TNFalpha mRNA and protein in MKN45 cells, thereby causing activation of TNFR1 and caspase-8.	6	25	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	HUHS1015 upregulates expression of the TNFalpha	tnfalpha	TNFR1	TNFR1	tnfr1	11	12	23	24
Consistent with a previous study , 29 autocrine TNFalpha signaling is not involved in BV6 and Drozitumab mediated apoptosis , as pharmacological or genetic inhibition of TNFalpha and TNFR1 signaling by the TNFalpha blocking antibody Enbrel or by RNA interference mediated silencing of TNFR1 failed to prevent BV6 and Drozitumab induced apoptosis .	Consistent with a previous study, 29 autocrine TNFalpha signaling is not involved in BV6 and Drozitumab mediated apoptosis, as pharmacological or genetic inhibition of TNFalpha and TNFR1 signaling by the TNFalpha blocking antibody Enbrel or by RNA interference mediated silencing of TNFR1 failed to prevent BV6 and Drozitumab induced apoptosis.	26	33	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	32	33	28	29
First , we showed that IFN-gamma and TNF-alpha treatment could not induce up-regulation of TNFR1 , TRAIL , and Fas L proteins ( XREF_SUPPLEMENTARY ) .	First, we showed that IFN-gamma and TNF-alpha treatment could not induce up-regulation of TNFR1, TRAIL, and Fas L proteins (XREF_SUPPLEMENTARY).	5	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	7	8	14	15
TNFalpha binds to and activates two receptors -- TNF-R1 and TNF-R2 -- and the outcome of their activation hinges on the relative levels of stimulation of three main pathways : a pro apoptotic pathway , a pro necroptotic pathway , and a cell-survival pathway .	TNFalpha binds to and activates two receptors -- TNF-R1 and TNF-R2 -- and the outcome of their activation hinges on the relative levels of stimulation of three main pathways : a pro apoptotic pathway, a pro necroptotic pathway, and a cell-survival pathway.	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-R1	TNF-R1	TNF-R1	0	1	8	9
We hypothesized that TNFalpha induced sickness behavior requires TNF-R1 and that FAN is a necessary component for this response .	We hypothesized that TNFalpha induced sickness behavior requires TNF-R1 and that FAN is a necessary component for this response.	3	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-R1	TNF-R1	TNF-R1	3	4	8	9
As shown in Figure XREF_FIG B , TNF-alpha stimulated association of TNFR1 , TRAF2 , and c-Src in a time dependent manner .	As shown in Figure XREF_FIG B, TNF-alpha stimulated association of TNFR1, TRAF2, and c-Src in a time dependent manner.	7	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	7	8	11	12
TNFR1 can be activated by TNF through the pre-ligand assembly domain of the Cys rich domain 1 in the extracellular portion of TNFR1 .	TNFR1 can be activated by TNF through the pre-ligand assembly domain of the Cys rich domain 1 in the extracellular portion of TNFR1.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	5	6	0	1
For example , TNF-alpha mediated activation of TNF-RI enhances tetrodotoxin-insensitive Na + channel currents at the plasma membrane in dorsal root ganglia ( DRG ) neurons [ XREF_BIBR ] .	For example, TNF-alpha mediated activation of TNF-RI enhances tetrodotoxin-insensitive Na + channel currents at the plasma membrane in dorsal root ganglia (DRG) neurons [XREF_BIBR].	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-RI	TNF-RI	TNF-RI	3	4	7	8
Taken together , these data indicate that TNF activates TNFR1 by DD- and p38 dependent mechanisms to promote EGFR internalization , with potential impact on EGF induced proliferation and migration key processes that promote healing in inflammatory intestinal diseases .	Taken together, these data indicate that TNF activates TNFR1 by DD- and p38 dependent mechanisms to promote EGFR internalization, with potential impact on EGF induced proliferation and migration key processes that promote healing in inflammatory intestinal diseases.	7	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	7	8	9	10
TNFalpha is known to initiate apoptosis in diverse cell types by activating its cognate receptor , TNF-RI , a cell surface receptor and member of the tumor necrosis receptor super family ( TNFRSF ) .	TNFalpha is known to initiate apoptosis in diverse cell types by activating its cognate receptor, TNF-RI, a cell surface receptor and member of the tumor necrosis receptor super family (TNFRSF).	0	17	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-RI	TNF-RI	TNF-RI	0	1	16	17
Necroptosis is an early cell death pathway which is triggered by inflammatory mediators led by TNF-alpha and TNF family death receptor ( TNFR ) : TNFR-1 , FAS , and TLR , namely TLR-3 and TLR-4 .	Necroptosis is an early cell death pathway which is triggered by inflammatory mediators led by TNF-alpha and TNF family death receptor (TNFR) : TNFR-1, FAS, and TLR, namely TLR-3 and TLR-4.	12	35	led	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR-1	TNFR-1	TNFR-1	15	16	25	26
NF-kappaB is one of the major mediators of TNFalpha activated TNFR1 signaling .	NF-kappaB is one of the major mediators of TNFalpha activated TNFR1 signaling.	6	11	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	8	9	10	11
We found that TRADD is essential for induction of the four most studied consequences of TNF induced TNFR1 signaling in mouse embryonic fibroblasts ( MEFs ) , namely the activation of NF-kappaB , the activation of MAP kinases , the induction of necrotic cell death , and the initiation of apoptosis .	We found that TRADD is essential for induction of the four most studied consequences of TNF induced TNFR1 signaling in mouse embryonic fibroblasts (MEFs), namely the activation of NF-kappaB, the activation of MAP kinases, the induction of necrotic cell death, and the initiation of apoptosis.	13	18	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	15	16	17	18
In sum , our data suggest a model in which TNFR2 sensitizes macrophages for endogenous TNF induced TNFR1 mediated necroptosis by the known ability of TNFR2 to interfere with the survival activity of TRAF2-cIAP1/2 complexes .	In sum, our data suggest a model in which TNFR2 sensitizes macrophages for endogenous TNF induced TNFR1 mediated necroptosis by the known ability of TNFR2 to interfere with the survival activity of TRAF2-cIAP1/2 complexes.	12	19	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	15	16	17	18
TNFalpha at high concentration may activate both TNFR1 and TNFR2 , with effects of TNFR1 concealed by that of TNFR2 , rending increased BAT thermogenic activity and obesity .	TNFalpha at high concentration may activate both TNFR1 and TNFR2, with effects of TNFR1 concealed by that of TNFR2, rending increased BAT thermogenic activity and obesity.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	0	1	7	8
110 The increased expression of CD47 in cells made apoptotic by proatherosclerotic oxidized phospholipids was found to be related to TNF-alpha signaling of TNFR1 , leading to enhanced transcription via activation of NF-kappaB .	110 The increased expression of CD47 in cells made apoptotic by proatherosclerotic oxidized phospholipids was found to be related to TNF-alpha signaling of TNFR1, leading to enhanced transcription via activation of NF-kappaB.	20	24	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	20	21	23	24
Recruitment of neutrophils and activation by cytokines leads to increased TNFalpha expression which then activates TNFR1 on the OSCC cells , completing a positive-feedback loop .	Recruitment of neutrophils and activation by cytokines leads to increased TNFalpha expression which then activates TNFR1 on the OSCC cells, completing a positive-feedback loop.	10	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha expression	tnfalpha	TNFR1	TNFR1	tnfr1	10	11	15	16
Here we found that TNFR1 could directly regulate BACE1 transcription through NF-kappaB , which is one of the major mediators of TNFalpha activated TNFR1 signaling .	Here we found that TNFR1 could directly regulate BACE1 transcription through NF-kappaB, which is one of the major mediators of TNFalpha activated TNFR1 signaling.	19	24	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	21	22	23	24
In rat brain capillaries , a long-term ( > 6h ) TNF-alpha exposure activates TNF-R1 and induces a series of cascade events that culminate in the activation of the transcription factor NF-kappaB , and subsequent increase of the expression and activity of P-gp [ XREF_BIBR , XREF_BIBR ] .	In rat brain capillaries, a long-term (> 6h) TNF-alpha exposure activates TNF-R1 and induces a series of cascade events that culminate in the activation of the transcription factor NF-kappaB, and subsequent increase of the expression and activity of P-gp [XREF_BIBR, XREF_BIBR].	11	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	11	12	14	15
Further studies are now required to better understand the respective protective and deleterious effects mediated by TNFalpha on immune and nonimmune cells through TNF-RI and TNF-RII in order to develop more specific inhibitors with potentially an increased efficacy and/or safety .	Further studies are now required to better understand the respective protective and deleterious effects mediated by TNFalpha on immune and nonimmune cells through TNF-RI and TNF-RII in order to develop more specific inhibitors with potentially an increased efficacy and/or safety.	14	25	mediated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-RI	TNF-RI	TNF-RI	16	17	23	24
Tumor necrosis factor ( TNF ) binding to TNF receptor 1 ( TNFR1 ) triggers formation of the TNFR1 signaling complex ( TNFR1-SC ) .	Tumor necrosis factor (TNF) binding to TNF receptor 1 (TNFR1) triggers formation of the TNFR1 signaling complex (TNFR1-SC).	2	20	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	18	19
TNFR1 deficient mice , and mice treated with polyclonal anti-mouse TNFalpha rabbit serum intravenously , do not exhibit signs of ethanol induced liver damage .	TNFR1 deficient mice, and mice treated with polyclonal anti-mouse TNFalpha rabbit serum intravenously, do not exhibit signs of ethanol induced liver damage.	0	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	10	11	0	1
TNFR-1 activation by TNF-alpha upregulated after myocardial or hindlimb ischemia impairs angiogenesis and contributes to tissue apoptosis and the consequent progression of ischemic diseases [ XREF_BIBR , XREF_BIBR ] .	TNFR-1 activation by TNF-alpha upregulated after myocardial or hindlimb ischemia impairs angiogenesis and contributes to tissue apoptosis and the consequent progression of ischemic diseases [XREF_BIBR, XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR-1	TNFR-1	TNFR-1	3	4	0	1
Moreover , neither TNFalpha alone nor SMC alone was able to promote formation of TNFR1 Complex IIb ; only cotreatment with both agents resulted in formation of this potentially cell death inducing complex .	Moreover, neither TNFalpha alone nor SMC alone was able to promote formation of TNFR1 Complex IIb; only cotreatment with both agents resulted in formation of this potentially cell death inducing complex.	2	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	3	4	14	15
This might explain why TNF-alpha is a better activator of TNFR1 , which uses TRADD as an adaptor , than TNFR2 , which does not interact with TRADD .	This might explain why TNF-alpha is a better activator of TNFR1, which uses TRADD as an adaptor, than TNFR2, which does not interact with TRADD.	4	13	is a better activator	Positive_activation_copula_1	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	4	5	10	11
Binding of trimeric TNF complexes induces trimerization of TNFR1 molecules and enables the DD to recruit downstream signaling molecules .	Binding of trimeric TNF complexes induces trimerization of TNFR1 molecules and enables the DD to recruit downstream signaling molecules.	3	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	3	4	8	9
Although attenuation of TNF-alpha actions on TNFR1 would reduce the pro seizure influence of TNFR1 , simultaneous reduction of TNF-alpha actions on TNFR2 would reduce the anti-seizure actions mediated through the TNFR2 receptor .	Although attenuation of TNF-alpha actions on TNFR1 would reduce the pro seizure influence of TNFR1, simultaneous reduction of TNF-alpha actions on TNFR2 would reduce the anti-seizure actions mediated through the TNFR2 receptor.	3	15	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	3	4	14	15
Tumor necrosis factor-alpha ( TNF-alpha ) is a key factor for the pathogenesis of inflammatory bowel diseases ( IBD ) , whose function is known to be mediated by TNF receptor 1 ( TNFR1 ) or 2 .	Tumor necrosis factor-alpha (TNF-alpha) is a key factor for the pathogenesis of inflammatory bowel diseases (IBD), whose function is known to be mediated by TNF receptor 1 (TNFR1) or 2.	27	36	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	29	30	33	34
We used human TNF-alpha , which has been shown to activate TNF-RI but not TNF-RII in rat neuronal cultures [ XREF_BIBR , XREF_BIBR ] .	We used human TNF-alpha, which has been shown to activate TNF-RI but not TNF-RII in rat neuronal cultures [XREF_BIBR, XREF_BIBR].	1	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-RI	TNF-RI	TNF-RI	3	4	11	12
Recent studies demonstrated that a mixture of TNFalpha , IL-1beta and IFNgamma , which are all known to be present in the lungs of the patients with ARDS , stimulated the release of soluble TNF-R 1 but not TNF-R 2 from cell surfaces .	Recent studies demonstrated that a mixture of TNFalpha, IL-1beta and IFNgamma, which are all known to be present in the lungs of the patients with ARDS, stimulated the release of soluble TNF-R 1 but not TNF-R 2 from cell surfaces.	5	38	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-R 1	TNF-R 1	TNF-R 1	7	8	34	36
The activated NF-kappaB signaling stimulates the expression of a wide spectrum of NF-kB responsive genes , including TNFalpha , which activate TNFR1 signaling in an autocrine and paracrine manner [ XREF_BIBR , XREF_BIBR ] .	The activated NF-kappaB signaling stimulates the expression of a wide spectrum of NF-kB responsive genes, including TNFalpha, which activate TNFR1 signaling in an autocrine and paracrine manner [XREF_BIBR, XREF_BIBR].	6	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	17	18	21	22
On the other hand , TNF-alpha induced TNFR1 , TRAF2 , ASK1 , and p47 phox complex formation in HPAEpiCs , which were attenuated by a TNF-alpha neutralizing antibody .	On the other hand, TNF-alpha induced TNFR1, TRAF2, ASK1, and p47 phox complex formation in HPAEpiCs, which were attenuated by a TNF-alpha neutralizing antibody.	5	17	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	5	6	7	8
The effects of LPS on the glomerular endothelial surface layer , endothelial cell fenestrae , GFR , and albuminuria were diminished in TNF receptor 1 ( TNFR1 ) knockout mice , suggesting that these LPS effects are mediated by TNF-alpha activation of TNFR1 .	The effects of LPS on the glomerular endothelial surface layer, endothelial cell fenestrae, GFR, and albuminuria were diminished in TNF receptor 1 (TNFR1) knockout mice, suggesting that these LPS effects are mediated by TNF-alpha activation of TNFR1.	39	43	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	39	40	42	43
Further , soluble TNF ( sTNF ) is practically incapable of triggering TNFR2 signaling and can only efficiently activate TNFR1 , whereas TNFR2 signaling positively affects the efficacy of TNFR1 apoptotic signaling .	Further, soluble TNF (sTNF) is practically incapable of triggering TNFR2 signaling and can only efficiently activate TNFR1, whereas TNFR2 signaling positively affects the efficacy of TNFR1 apoptotic signaling.	2	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	3	4	19	20
TNF induces its effects by binding two distinct receptors , TNFR1 and p55 and TNFR2 and p75 XREF_BIBR , XREF_BIBR .	TNF induces its effects by binding two distinct receptors, TNFR1 and p55 and TNFR2 and p75 XREF_BIBR, XREF_BIBR.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	0	1	10	11
Although activation of TNFR1 by TNF-alpha plays a critical role in host defense , pathogenic bacteria that have the capacity to bind to this receptor can subvert the pathway to heighten the host inflammatory responses .	Although activation of TNFR1 by TNF-alpha plays a critical role in host defense, pathogenic bacteria that have the capacity to bind to this receptor can subvert the pathway to heighten the host inflammatory responses.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	5	6	3	4
Therefore , we further studied whether TNF-alpha promoted the association of TNFR1 , TRAF2 , ASK1 , and p47 phox in HPAEpiCs .	Therefore, we further studied whether TNF-alpha promoted the association of TNFR1, TRAF2, ASK1, and p47 phox in HPAEpiCs.	6	15	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	6	7	11	12
One possibility is that astrocytes promote TNF mediated preOL death by upregulating TNFR1 in preOLs since oligodendroglial TNFR1 is required for the toxicity ( XREF_FIG ) .	One possibility is that astrocytes promote TNF mediated preOL death by upregulating TNFR1 in preOLs since oligodendroglial TNFR1 is required for the toxicity (XREF_FIG).	6	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	6	7	12	13
The vast majority of TNF related biological processes are initiated by the death-domain ( DD ) containing TNFR1 , which is also called TNFRSF1A .	The vast majority of TNF related biological processes are initiated by the death-domain (DD) containing TNFR1, which is also called TNFRSF1A.	2	22	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	17	18
The formation of inactive heteromeric TNF molecules was shown for processed , soluble TNF and supports the notion that TNF signaling via TNFR1 mediates neuroinflammation in EAE , since soluble TNF predominantly activates TNFR1 XREF_BIBR .	The formation of inactive heteromeric TNF molecules was shown for processed, soluble TNF and supports the notion that TNF signaling via TNFR1 mediates neuroinflammation in EAE, since soluble TNF predominantly activates TNFR1 XREF_BIBR.	29	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	30	31	33	34
XREF_BIBR , XREF_BIBR Irrespective of zVAD-fmk , human TNF mediated TNFR1 activation had no cytotoxic effects , neither in HoxB8 immortalized MPCs , nor in macrophages ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR Irrespective of zVAD-fmk, human TNF mediated TNFR1 activation had no cytotoxic effects, neither in HoxB8 immortalized MPCs, nor in macrophages (XREF_FIG).	5	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	8	9	10	11
In these cells , this weak and late signal seemed to be strong enough to induce endogenous expression and secretion of TNF , which in an autocrine manner activated TNFR1 and subsequently the apoptotic signaling-cascade leading to Kym-1 cell death ( XREF_FIG ) , as shown previously XREF_BIBR , XREF_BIBR .	In these cells, this weak and late signal seemed to be strong enough to induce endogenous expression and secretion of TNF, which in an autocrine manner activated TNFR1 and subsequently the apoptotic signaling-cascade leading to Kym-1 cell death (XREF_FIG), as shown previously XREF_BIBR, XREF_BIBR.	17	34	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	expression and secretion of TNF	tnf	TNFR1	TNFR1	tnfr1	21	22	29	30
Another category of molecules involved in cell communication that have been demonstrated to be essential to the ACAID mechanism comprises the secreted molecules and their receptors , including CXCR2 , DR5 , TNF related apoptosis inducing ligands ( TRAIL ) , IFNgamma , IFNgammaR , IL-4 , IL-13 , IL-6 , IL-10 , TGFbetaRII , TNFRI , TNFRII , uPA , uPAR , plasminogen , substance P , and neurokinin A.	Another category of molecules involved in cell communication that have been demonstrated to be essential to the ACAID mechanism comprises the secreted molecules and their receptors, including CXCR2, DR5, TNF related apoptosis inducing ligands (TRAIL), IFNgamma, IFNgammaR, IL-4, IL-13, IL-6, IL-10, TGFbetaRII, TNFRI, TNFRII, uPA, uPAR, plasminogen, substance P, and neurokinin A.	32	66	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFRI	TNFRI	TNFRI	32	33	55	56
In AD , excessive TNF-alpha activated TNFR1 through high affinity binding [ XREF_BIBR ] and signaling accordingly suppresses Abeta degradation by reducing the expression of insulin degrading enzyme [ XREF_BIBR ] and affects Abeta production through upregulation of BACE expression [ XREF_BIBR ] and gamma-secretase activity [ XREF_BIBR ] .	In AD, excessive TNF-alpha activated TNFR1 through high affinity binding [XREF_BIBR] and signaling accordingly suppresses Abeta degradation by reducing the expression of insulin degrading enzyme [XREF_BIBR] and affects Abeta production through upregulation of BACE expression [XREF_BIBR] and gamma-secretase activity [XREF_BIBR].	3	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	4	5	6	7
Another report showed that BBB P-gp is regulated by the inflammatory mediators LPS , TNF-alpha , and ET-1 , which activated TLR4 , TNFR1 , ETB receptor , NOS , and PKC , leading to reduced P-gp activity [ XREF_BIBR ] .	Another report showed that BBB P-gp is regulated by the inflammatory mediators LPS, TNF-alpha, and ET-1, which activated TLR4, TNFR1, ETB receptor, NOS, and PKC, leading to reduced P-gp activity [XREF_BIBR].	11	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	14	15	23	24
It has long been recognized that membrane bound and soluble TNF differentially activate TNFRSF1A ( TNFR1 ) and TNFRSF1B ( TNFR2 ) and fulfill different functions in inflammation and immunity to mycobacteria XREF_BIBR - XREF_BIBR .	It has long been recognized that membrane bound and soluble TNF differentially activate TNFRSF1A (TNFR1) and TNFRSF1B (TNFR2) and fulfill different functions in inflammation and immunity to mycobacteria XREF_BIBR - XREF_BIBR.	9	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFRSF1A	TNFRSF1A	TNFRSF1A	10	11	13	14
TLR4 ligation induces TNF expression that then activates TNFR1 .	TLR4 ligation induces TNF expression that then activates TNFR1.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TLR4 ligation induces TNF expression	tnf	TNFR1	TNFR1	tnfr1	3	4	8	9
In the Results , APG-1387 induces apoptotic cell death through engagement of TNFR1 by TNF-alpha signaling pathway section there was an error : ' We have investigated the expression of NF-kappaB1 and p50 and NF-kappaB2 and p52 by western blot after cells were incubated with various concentrations of APG-1387 ' .	In the Results, APG-1387 induces apoptotic cell death through engagement of TNFR1 by TNF-alpha signaling pathway section there was an error : ' We have investigated the expression of NF-kappaB1 and p50 and NF-kappaB2 and p52 by western blot after cells were incubated with various concentrations of APG-1387 '.	5	17	induces	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	14	15	12	13
Human TNF , which only activates mouse TNFR1 but not TNFR2 , inhibited the bone morphogenetic protein 2 ( BMP2 )-induced production of alkaline phosphatase ( ALP ) in mouse preosteoblastic C2C12 cells , whereas STAR2 failed to do so ( XREF_FIG ) .	Human TNF, which only activates mouse TNFR1 but not TNFR2, inhibited the bone morphogenetic protein 2 (BMP2)-induced production of alkaline phosphatase (ALP) in mouse preosteoblastic C2C12 cells, whereas STAR2 failed to do so (XREF_FIG).	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	1	2	7	8
Previous studies have shown that mouse TNF-alpha activated both mouse TNFR1 and TNFR2 while human TNF-alpha ( hTNF-alpha ) only activated mouse TNFR1 .	Previous studies have shown that mouse TNF-alpha activated both mouse TNFR1 and TNFR2 while human TNF-alpha (hTNF-alpha) only activated mouse TNFR1.	14	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	15	16	22	23
Under osteogenic induction , IFN-gamma and TNF-alpha treatment in combination was able to dramatically upregulate IFN-gamma receptor IFNGRalpha and TNF-alpha receptor TNFR1 , but not TNFR2 , when compared with IFN-gamma and TNF-alpha treatment alone ( XREF_FIG ) .	Under osteogenic induction, IFN-gamma and TNF-alpha treatment in combination was able to dramatically upregulate IFN-gamma receptor IFNGRalpha and TNF-alpha receptor TNFR1, but not TNFR2, when compared with IFN-gamma and TNF-alpha treatment alone (XREF_FIG).	4	22	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	6	7	21	22
For example , HCV induced TNF-alpha activates TNFR1 to regulate viral replication 32 .	For example, HCV induced TNF-alpha activates TNFR1 to regulate viral replication 32.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	5	6	7	8
TNF-R1 and -R2 on the monocyte surface are stimulated by transmembrane TNF-alpha on glutaraldehyde fixed pre-stimulated human CD4 + T cells to produce TNF-alpha .	TNF-R1 and -R2 on the monocyte surface are stimulated by transmembrane TNF-alpha on glutaraldehyde fixed pre-stimulated human CD4 + T cells to produce TNF-alpha.	0	13	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	11	12	0	1
TNF induced cytoplasmic accumulation of TNF-R1 in all mutant cells .	TNF induced cytoplasmic accumulation of TNF-R1 in all mutant cells.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNF-R1	TNF-R1	TNF-R1	0	1	5	6
Depletion of cIAPs enables accumulation of NF-kappaB-inducing kinase ( NIK ) , resulting in non canonical activation of NF-kappaB and NF-kappaB target gene expression , including TNFA , which stimulates TNFR1 in an autocrine loop .	Depletion of cIAPs enables accumulation of NF-kappaB-inducing kinase (NIK), resulting in non canonical activation of NF-kappaB and NF-kappaB target gene expression, including TNFA, which stimulates TNFR1 in an autocrine loop.	23	34	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFA	TNFA	TNFA	TNFR1	TNFR1	TNFR1	26	27	30	31
Instead , TNF induced TNFR1 signaling typically activates classical nuclear factor kappa B ( NFkappaB ) proinflammatory signaling [ XREF_BIBR ] .	Instead, TNF induced TNFR1 signaling typically activates classical nuclear factor kappa B (NFkappaB) proinflammatory signaling [XREF_BIBR].	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	2	3	4	5
We also excluded a role of TNF autocrine 29 in Ppm1b depletion induced spontaneous necroptosis by using TNFR1 KO L929 .	We also excluded a role of TNF autocrine 29 in Ppm1b depletion induced spontaneous necroptosis by using TNFR1 KO L929.	6	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	6	7	17	18
TNF-alpha can activate TNFR1 and TNFR2 receptor subtypes , both of which trigger cell death through similar signaling cascades .	TNF-alpha can activate TNFR1 and TNFR2 receptor subtypes, both of which trigger cell death through similar signaling cascades.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	0	1	3	4
Adenoviruses encode RID proteins that promote the internalization of death receptors for Fas , tumor necrosis factor related apoptosis inducing ligand ( TRAIL ) , and tumor necrosis factor receptor 1 ( TNFR1 ) , thereby allowing infected cells to withstand these apoptotic stimuli [ XREF_BIBR - XREF_BIBR ] .	Adenoviruses encode RID proteins that promote the internalization of death receptors for Fas, tumor necrosis factor related apoptosis inducing ligand (TRAIL), and tumor necrosis factor receptor 1 (TNFR1), thereby allowing infected cells to withstand these apoptotic stimuli [XREF_BIBR - XREF_BIBR].	14	33	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	TNFR1	TNFR1	TNFR1	14	17	32	33
Bauer et al showed that long-term exposure ( > 6 h ) of rat brain capillaries to TNF-alpha activates TNF-R1 and induces release of ET-1 , which binds to endothelin receptor ( ETR ) ( XREF_FIG ) .	Bauer et al showed that long-term exposure (> 6 h) of rat brain capillaries to TNF-alpha activates TNF-R1 and induces release of ET-1, which binds to endothelin receptor (ETR) (XREF_FIG).	15	20	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	17	18	19	20
If the conditions are not sufficient to induce apoptotic cell death , pro inflammatory mediator TNF alphainitially activates TNFR1 and in turn recruits RIP1 to form complex I. Subsequently , these proteins combine with other components , and can be located in the cytosol in with complex IIb , which includes RIP1 , RIP3 , caspase-8 and FADD , further leading to necroptosis XREF_BIBR .	If the conditions are not sufficient to induce apoptotic cell death, pro inflammatory mediator TNF alphainitially activates TNFR1 and in turn recruits RIP1 to form complex I. Subsequently, these proteins combine with other components, and can be located in the cytosol in with complex IIb, which includes RIP1, RIP3, caspase-8 and FADD, further leading to necroptosis XREF_BIBR.	13	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	15	16	18	19
In this model , the activation of TNFR1 by TNFalpha is known to play an important role in mediating the degeneration of oligodendrocytes in the EAE model .	In this model, the activation of TNFR1 by TNFalpha is known to play an important role in mediating the degeneration of oligodendrocytes in the EAE model.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	9	10	7	8
TNFR1 can be activated by both the soluble TNF-alpha and membrane TNF-alpha , but TNFR2 only responds to membrane TNF-alpha .	TNFR1 can be activated by both the soluble TNF-alpha and membrane TNF-alpha, but TNFR2 only responds to membrane TNF-alpha.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	8	9	0	1
Mutations in the TNFRSF1A gene encoding the TNF cell surface receptor , TNFR1 , cause TNFR associated periodic syndrome ( TRAPS ) and polymorphisms in TNFRSF1A , including rs4149570 , rs767455 and rs1800692 , are associated with inflammatory diseases .	Mutations in the TNFRSF1A gene encoding the TNF cell surface receptor, TNFR1, cause TNFR associated periodic syndrome (TRAPS) and polymorphisms in TNFRSF1A, including rs4149570, rs767455 and rs1800692, are associated with inflammatory diseases.	7	32	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFRSF1A	TNFRSF1A	TNFRSF1A	7	8	25	26
APG-1387 induces apoptotic cell death through engagement of TNFR1 by TNF-alpha signaling pathway .	APG-1387 induces apoptotic cell death through engagement of TNFR1 by TNF-alpha signaling pathway.	1	12	induces	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	10	11	8	9
XREF_BIBR TNF can lead to the induction of either necrotic or apoptotic pathways via binding to the TNF-receptor 1 ( TNFR1 ) that leads on to a cascade of events , the final outcome of which depends on the activation or inhibition of caspases .	XREF_BIBR TNF can lead to the induction of either necrotic or apoptotic pathways via binding to the TNF-receptor 1 (TNFR1) that leads on to a cascade of events, the final outcome of which depends on the activation or inhibition of caspases.	0	23	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	1	2	20	21
TNFR1 is activated by both membrane bound and soluable forms of TNF-alpha .	TNFR1 is activated by both membrane bound and soluable forms of TNF-alpha.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	11	12	0	1
Although TNFR1 signaling is mainly initiated by TNFalpha , which is suggested to promote HCC development in mdr2 -/- mouse [ XREF_BIBR ] , deletion of TNFalpha accelerated rather than inhibited hepatocarcinogenesis in DDB1 F/F , Alb-Cre +/- mouse .	Although TNFR1 signaling is mainly initiated by TNFalpha, which is suggested to promote HCC development in mdr2 -/- mouse [XREF_BIBR], deletion of TNFalpha accelerated rather than inhibited hepatocarcinogenesis in DDB1 F/F, Alb-Cre +/- mouse.	1	13	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	7	8	1	2
Shedding occurs through proteolytic cleavage of plasma membrane expressed TNFR1 catalysed by TNF-alpha converting enzyme ( TACE ) .	Shedding occurs through proteolytic cleavage of plasma membrane expressed TNFR1 catalysed by TNF-alpha converting enzyme (TACE).	8	13	catalysed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	12	13	9	10
In contrast , no TRAP positive cells were observed in TNFR1 (-/-) M-BMMphi cultures treated with mouse TNF-alpha ( XREF_FIG B ) .	In contrast, no TRAP positive cells were observed in TNFR1 (-/-) M-BMMphi cultures treated with mouse TNF-alpha (XREF_FIG B).	10	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	17	18	10	11
Mentioned earlier , the ability of the cell to respond to femtomolar TNFalpha concentrations suggests that NF-kappaB regulatory module may be turned on by the single TNFalpha trimer activating one TNFR1 receptor ( receptor trimer ) .	Mentioned earlier, the ability of the cell to respond to femtomolar TNFalpha concentrations suggests that NF-kappaB regulatory module may be turned on by the single TNFalpha trimer activating one TNFR1 receptor (receptor trimer).	26	31	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	26	27	30	31
Comparing TNF stimulated wildtype and Tnfr1-/- glomeruli , we identified 219 unique genes being differentially expressed between the two genotypes ( XREF_FIG , XREF_FIG , XREF_SUPPLEMENTARY ) .	Comparing TNF stimulated wildtype and Tnfr1-/- glomeruli, we identified 219 unique genes being differentially expressed between the two genotypes (XREF_FIG, XREF_FIG, XREF_SUPPLEMENTARY).	0	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Tnfr1-/-	Tnfr1-/-	Tnfr1-/-	1	2	5	6
TNFalpha activates TNF receptor 1 ( TNFR1 ) , which forms a complex of TNFR1 associated death domain protein ( TRADD )/FADD/procaspase-8 , to activate caspase-8 followed by the effector caspase-3 [ XREF_BIBR ] .	TNFalpha activates TNF receptor 1 (TNFR1), which forms a complex of TNFR1 associated death domain protein (TRADD)/FADD/procaspase-8, to activate caspase-8 followed by the effector caspase-3 [XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	0	1	6	7
TNFalpha activates the membrane bound TNF receptors TNFR1 and TNFR2 .	TNFalpha activates the membrane bound TNF receptors TNFR1 and TNFR2.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	0	1	7	8
Pro apoptotic effects of TNFR1 activation by TNFalpha are two-fold .	Pro apoptotic effects of TNFR1 activation by TNFalpha are two-fold.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	7	8	4	5
TNFR-1 activation by TNF-alpha also inhibits EC proliferation by VEGF signaling [ XREF_BIBR ] .	TNFR-1 activation by TNF-alpha also inhibits EC proliferation by VEGF signaling [XREF_BIBR].	0	4	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR-1	TNFR-1	TNFR-1	3	4	0	1
1 In context of TNFR1 activation by soluble TNF , subsequent induction of membrane bound TNF results in costimulation of TNFR2 , thereby converting the initially transient activation into sustained autocrine signaling .	1 In context of TNFR1 activation by soluble TNF, subsequent induction of membrane bound TNF results in costimulation of TNFR2, thereby converting the initially transient activation into sustained autocrine signaling.	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	8	9	4	5
In contrast , membrane TNF activates TNFR1 and TNFR2 with high efficiency .	In contrast, membrane TNF activates TNFR1 and TNFR2 with high efficiency.	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	6	7
Tumor necrosis factor elicits its activities by stimulating two structurally related types of receptors , TNF receptor 1 ( TNFR1 ) and tumor necrosis factor receptor 2 ( TNFR2 ) .	Tumor necrosis factor elicits its activities by stimulating two structurally related types of receptors, TNF receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2).	0	20	elicits	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tumor necrosis factor	Tumor necrosis factor	Tumor necrosis factor	TNFR1	TNFR1	TNFR1	0	3	19	20
On the other hand , it coincided with long term transcriptional up-regulation followed by pronounced release of tumor necrosis factor alpha ( TNFalpha ) , which activates the death receptor TNF-R1 in an autocrine fashion , thereby enhancing UVB induced apoptosis [ XREF_BIBR ] .	On the other hand, it coincided with long term transcriptional up-regulation followed by pronounced release of tumor necrosis factor alpha (TNFalpha), which activates the death receptor TNF-R1 in an autocrine fashion, thereby enhancing UVB induced apoptosis [XREF_BIBR].	17	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	TNF-R1	TNF-R1	TNF-R1	17	20	30	31
These data show that the pathological changes of the glomerular endothelium and glomerular ESL are likely mediated by TNF-alpha released during endotoxemia and acting through TNFR1 , since the LPS induced pathological changes were abolished in Tnfr1 -/- mice and administration of TNF alone induced similar pathological changes .	These data show that the pathological changes of the glomerular endothelium and glomerular ESL are likely mediated by TNF-alpha released during endotoxemia and acting through TNFR1, since the LPS induced pathological changes were abolished in Tnfr1 -/- mice and administration of TNF alone induced similar pathological changes.	16	26	mediated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	18	19	25	26
Released TNF triggered TNF-R1 in an autocrine manner to additively promote apoptosis .	Released TNF triggered TNF-R1 in an autocrine manner to additively promote apoptosis.	0	4	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNF-R1	TNF-R1	TNF-R1	1	2	3	4
Further supporting TNFalpha ' s involvement in the inflammatory component of AKI , TNFR1 ( TNFalpha receptor ) KO mice or rats treated with etanercept ( TNFalpha neutralizing antibody ) show less tubular injury , inflammation , and neutrophil ingress after ischemic AKI .	Further supporting TNFalpha 's involvement in the inflammatory component of AKI, TNFR1 (TNFalpha receptor) KO mice or rats treated with etanercept (TNFalpha neutralizing antibody) show less tubular injury, inflammation, and neutrophil ingress after ischemic AKI.	11	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	26	27	13	14
TNF-alpha activates TNF-R1 , which leads to the activation of the Fas associated death domain protein and downstream caspase pathways .	TNF-alpha activates TNF-R1, which leads to the activation of the Fas associated death domain protein and downstream caspase pathways.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	0	1	2	3
To verify the predictions of TNFR1 model simulations , we prepared corresponding MEF and BALB/3T3 cells treated with TNF in wildtype and in RIP1 suppression .	To verify the predictions of TNFR1 model simulations, we prepared corresponding MEF and BALB/3T3 cells treated with TNF in wildtype and in RIP1 suppression.	5	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	18	19	5	6
Previously , we reported that TNF induced lethal inflammation is strictly TNFR1 ( P55 )-dependent .	Previously, we reported that TNF induced lethal inflammation is strictly TNFR1 (P55)-dependent.	5	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	5	6	11	12
The excessive glutamate concentrations resulting from TNF-alpha stimulation of astroglial and microglial TNFR1 could be diminished by the glutamate uptake system [ XREF_BIBR , XREF_BIBR ] ; however , TNF-alpha has a detrimental effect on astroglial glutamate uptake ( XREF_FIG ) .	The excessive glutamate concentrations resulting from TNF-alpha stimulation of astroglial and microglial TNFR1 could be diminished by the glutamate uptake system [XREF_BIBR, XREF_BIBR]; however, TNF-alpha has a detrimental effect on astroglial glutamate uptake (XREF_FIG).	6	13	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	6	7	12	13
In the present study , we specifically blocked TNFR1 mediated TNF responses using the monoclonal antibody H398 in an acute PD-mouse model to investigate a pathogenic role of TNFR1 during PD induced inflammation and potential therapeutic activity of a TNFR1 antagonistic antibody .	In the present study, we specifically blocked TNFR1 mediated TNF responses using the monoclonal antibody H398 in an acute PD-mouse model to investigate a pathogenic role of TNFR1 during PD induced inflammation and potential therapeutic activity of a TNFR1 antagonistic antibody.	8	41	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNFR1 mediated TNF	tnf	TNFR1	TNFR1	tnfr1	10	11	39	40
Using elegant genetic models , the authors demonstrated that TNFalpha activates TNFR1 at astrocytes , which then signal to the neurons via glutamate and NMDAR to increase presynaptic activity .	Using elegant genetic models, the authors demonstrated that TNFalpha activates TNFR1 at astrocytes, which then signal to the neurons via glutamate and NMDAR to increase presynaptic activity.	9	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	9	10	11	12
In both cell types , co-treatment with zVAD-fmk and TNC-sc ( mu ) TNF80 showed no significant cytotoxic effect ( XREF_FIG ) indicating that TNFR2 induced necroptosis in macrophages is due to sensitization for endogenous TNF induced TNFR1 mediated necroptosis .	In both cell types, co-treatment with zVAD-fmk and TNC-sc (mu) TNF80 showed no significant cytotoxic effect (XREF_FIG) indicating that TNFR2 induced necroptosis in macrophages is due to sensitization for endogenous TNF induced TNFR1 mediated necroptosis.	32	39	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	35	36	37	38
For instance , TNF-alpha induces TNFR1 internalization and activation of certain signaling events , or internalization and subsequent degradation while increasing solubilization of TNFR2 .	For instance, TNF-alpha induces TNFR1 internalization and activation of certain signaling events, or internalization and subsequent degradation while increasing solubilization of TNFR2.	3	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	3	4	5	6
Activation of TNFR1 by TNF induces an intracellular signaling cascade with pleiotropic effects involving apoptosis , cell proliferation or cytokine secretion .	Activation of TNFR1 by TNF induces an intracellular signaling cascade with pleiotropic effects involving apoptosis, cell proliferation or cytokine secretion.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	2	3
Given that PMA mediated apoptosis is thought to result from up-regulation of TNFalpha , which then activates TNFR1 , we next evaluated the alpha2-6 sialylation of TNFR1 .	Given that PMA mediated apoptosis is thought to result from up-regulation of TNFalpha, which then activates TNFR1, we next evaluated the alpha2-6 sialylation of TNFR1.	10	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	12	13	17	18
Moreover , we used immunoprecipitation to determine the interaction among TNFR1 , TRAF2 , and c-Src to confirm that TNF-alpha induced TNFR1 , TRAF2 and c-Src association .	Moreover, we used immunoprecipitation to determine the interaction among TNFR1, TRAF2, and c-Src to confirm that TNF-alpha induced TNFR1, TRAF2 and c-Src association.	19	26	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	19	20	21	22
Chemokine secretion was absent and glomerular leukocyte infiltration was abrogated in TNF stimulated TNFR1 deficient glomeruli .	Chemokine secretion was absent and glomerular leukocyte infiltration was abrogated in TNF stimulated TNFR1 deficient glomeruli.	9	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	11	12	13	14
TNF triggers the formation of TNFR1 signaling complex .	TNF triggers the formation of TNFR1 signaling complex.	0	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	0	1	5	6
IFN-gamma and TNF-alpha up-regulated TNFR1 , TNFR2 , Fas and membrane FasL on SMC .	IFN-gamma and TNF-alpha up-regulated TNFR1, TNFR2, Fas and membrane FasL on SMC.	0	11	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	2	3	4	5
Moreover , in contrast to soluble TNF which efficiently activates TNFR1 in vitro XREF_BIBR , membrane bound TNF has been suggested to preferentially activate TNFR2 XREF_BIBR .	Moreover, in contrast to soluble TNF which efficiently activates TNFR1 in vitro XREF_BIBR, membrane bound TNF has been suggested to preferentially activate TNFR2 XREF_BIBR.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	6	7	10	11
This response appeared to be mediated by differential TNF-alpha receptor expression : TNFR1 basolaterally and TNFR1 and TNFR2 apically .	This response appeared to be mediated by differential TNF-alpha receptor expression : TNFR1 basolaterally and TNFR1 and TNFR2 apically.	2	13	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha receptor expression	tnf-alpha	TNFR1	TNFR1	tnfr1	8	9	12	13
Bone marrow ( BM ) transplantation experiments showed that TNF-alpha expressed by BM derived cells ( BMDCs ) stimulates the TNFR1 on BMDCs by an autocrine or paracrine manner , which is important for gastric tumor promotion .	Bone marrow (BM) transplantation experiments showed that TNF-alpha expressed by BM derived cells (BMDCs) stimulates the TNFR1 on BMDCs by an autocrine or paracrine manner, which is important for gastric tumor promotion.	9	22	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha expressed	tnf-alpha	TNFR1	TNFR1	tnfr1	9	10	20	21
XREF_BIBR reported earlier that TNFR2 is a marker associated with increased suppression by human peripheral blood T reg cells , and recently , it was demonstrated that both an agonistic antibody for TNFR2 and a cross linked TNF multimer , which would also activate TNFR1 , efficiently expanded T reg cells from healthy donors in vitro .	XREF_BIBR reported earlier that TNFR2 is a marker associated with increased suppression by human peripheral blood T reg cells, and recently, it was demonstrated that both an agonistic antibody for TNFR2 and a cross linked TNF multimer, which would also activate TNFR1, efficiently expanded T reg cells from healthy donors in vitro.	37	50	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	37	38	44	45
TNFalpha activates TNFR1 , which forms a complex with TRADD , FADD , and procaspase-8 , to activate caspase-8 [ XREF_BIBR ] .	TNFalpha activates TNFR1, which forms a complex with TRADD, FADD, and procaspase-8, to activate caspase-8 [XREF_BIBR].	0	15	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TNFalpha	TNFalpha	tnfalpha	TNFR1	TNFR1, which forms a complex with TRADD, FADD, and procaspase-8	tnfr1	0	1	2	3
These results imply that presence of TNF may induce both up-regulations of TNFR1 and TNFR2 in inflamed epithelial cells as reported by Mizoguchi et al XREF_BIBR , XREF_BIBR , suggesting that NF-kappaB activation in the epithelial cells we observed may be caused by both signaling .	These results imply that presence of TNF may induce both up-regulations of TNFR1 and TNFR2 in inflamed epithelial cells as reported by Mizoguchi et al XREF_BIBR, XREF_BIBR, suggesting that NF-kappaB activation in the epithelial cells we observed may be caused by both signaling.	4	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	6	7	12	13
ASK1 is a mitogen activated protein kinase kinase kinase ( MAPK3K ) stress responsive kinase , that can be activated by multiple stimuli including reactive oxygen species ( ROS ) and TNFalpha activation of TNFR1 XREF_BIBR , XREF_BIBR .	ASK1 is a mitogen activated protein kinase kinase kinase (MAPK3K) stress responsive kinase, that can be activated by multiple stimuli including reactive oxygen species (ROS) and TNFalpha activation of TNFR1 XREF_BIBR, XREF_BIBR.	31	35	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	31	32	34	35
In line with the clinical experience , administration of Enbrel , a TNF neutralizing protein , induced however only a partial protection in B6 mice , with no improvement of clinical settings , suggesting that future TNF immunomodulatory strategies should target TNFR1 and R2 .	In line with the clinical experience, administration of Enbrel, a TNF neutralizing protein, induced however only a partial protection in B6 mice, with no improvement of clinical settings, suggesting that future TNF immunomodulatory strategies should target TNFR1 and R2.	36	43	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	36	37	41	42
In short , the action of regulatory pathway may be summarized as follows : Binding of TNFalpha trimer initiates receptor TNFR1 trimerization and formation of an active receptor complex in a multistep process involving binding of RIP and TRAF2 .	In short, the action of regulatory pathway may be summarized as follows : Binding of TNFalpha trimer initiates receptor TNFR1 trimerization and formation of an active receptor complex in a multistep process involving binding of RIP and TRAF2.	16	21	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	16	17	20	21
TNF-alpha can induce biological reactions via two cell-surface receptors : TNF receptor type 1 ( TNFR1 ) and TNF receptor type 2 ( TNFR2 ) .	TNF-alpha can induce biological reactions via two cell-surface receptors : TNF receptor type 1 (TNFR1) and TNF receptor type 2 (TNFR2).	0	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	0	1	15	16
Twelve hours after transduction , NMCMs with TNFR1 knocked down ( NMCMs-TNFR1-KD ) were treated with TNFalpha ( 0.5 ng/mL ) for different time periods and then harvested for transmission electron microscopic examination to analyze the mitochondrial morphology .	Twelve hours after transduction, NMCMs with TNFR1 knocked down (NMCMs-TNFR1-KD) were treated with TNFalpha (0.5 ng/mL) for different time periods and then harvested for transmission electron microscopic examination to analyze the mitochondrial morphology.	5	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	16	17	7	8
Human TNF , irrespective of the presence of ZVAD , as well as TNFR2 stimulation in the presence of ZVAD resulted in TNFR1 dependent upregulation of A20 and TRAF1 .	Human TNF, irrespective of the presence of ZVAD, as well as TNFR2 stimulation in the presence of ZVAD resulted in TNFR1 dependent upregulation of A20 and TRAF1.	0	25	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	1	2	22	23
Based on the findings in this study , as well as previous reports , we propose a model for summarizing the protective role of PGRN and its regulation in Ti particle induced inflammatory osteolysis ( XREF_FIG ) : Ti particles lead to the release of TNFalpha , a master regulator of proinflammatory cytokine cascades , that activates classical TNFR1 and NF-kappaB pathways and in turn the release of downstream inflammatory mediators , such as IL-1beta and NOS-2 .	Based on the findings in this study, as well as previous reports, we propose a model for summarizing the protective role of PGRN and its regulation in Ti particle induced inflammatory osteolysis (XREF_FIG) : Ti particles lead to the release of TNFalpha, a master regulator of proinflammatory cytokine cascades, that activates classical TNFR1 and NF-kappaB pathways and in turn the release of downstream inflammatory mediators, such as IL-1beta and NOS-2.	43	66	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	45	46	58	59
Representative genes differentially expressed in TNF stimulated Tnfr1 ,2-/-, Tnfr1-/- and Tnfr2-/- glomeruli compared to wildtype are listed in XREF_SUPPLEMENTARY .	Representative genes differentially expressed in TNF stimulated Tnfr1,2-/-, Tnfr1-/- and Tnfr2-/- glomeruli compared to wildtype are listed in XREF_SUPPLEMENTARY.	3	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Tnfr1	Tnfr1	Tnfr1	5	6	7	8
Diverse biological effects of TNF are mediated by two functionally distinct receptors , namely , TNFR1 ( p55 ) and TNFR2 ( p75 ) XREF_BIBR .	Diverse biological effects of TNF are mediated by two functionally distinct receptors, namely, TNFR1 (p55) and TNFR2 (p75) XREF_BIBR.	2	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	15	16
TNF-R1 is present almost in all nuclear cells of the human body and stimulated by free and transmembrane forms of TNF-alpha .	TNF-R1 is present almost in all nuclear cells of the human body and stimulated by free and transmembrane forms of TNF-alpha.	0	21	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R1	TNF-R1	TNF-R1	20	21	0	1
Finally , a recent study shows that increased levels of hippocampal TNF and depressive behavior could be prevented by the treatment with Xpro1595 , supporting the role of sTNF and TNFR1 signaling in the development of depression .	Finally, a recent study shows that increased levels of hippocampal TNF and depressive behavior could be prevented by the treatment with Xpro1595, supporting the role of sTNF and TNFR1 signaling in the development of depression.	8	31	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	levels of hippocampal TNF	tnf	TNFR1	TNFR1	tnfr1	11	12	30	31
Hypoxia and/or TNF Induce Up-regulation of TNF and TNFR2 in CMs in Murine Heart Organ Cultures .	Hypoxia and/or TNF Induce Up-regulation of TNF and TNFR2 in CMs in Murine Heart Organ Cultures.	0	9	Induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	2	3	8	9
For example , in the TNFR2 experiment described here the introduction of human TNF labelled with a spectrally-distinct fluorophore may have allowed us to identify TNFR2 + / TNF - memory B cells presumably producing antibodies that can block TNF binding to the receptor .	For example, in the TNFR2 experiment described here the introduction of human TNF labelled with a spectrally-distinct fluorophore may have allowed us to identify TNFR2 + / TNF - memory B cells presumably producing antibodies that can block TNF binding to the receptor.	10	38	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	13	14	25	26
TNF-alpha induces Tnfrsf1b .	TNF-alpha induces Tnfrsf1b.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Tnfrsf1b	Tnfrsf1b	Tnfrsf1b	0	1	2	3
TNF-alpha activates at least two cell-surface receptors -TNFR1 ( 55kDa ) and TNFR2 ( 75kDa ) - that are expressed in most cell types .	TNF-alpha activates at least two cell-surface receptors -TNFR1 (55kDa) and TNFR2 (75kDa) - that are expressed in most cell types.	0	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	0	1	12	13
XREF_BIBR found that acute , selective activation of TNFR1 by human TNF-alpha exerted no influence on hippocampal seizure sensitivity , but activation of both TNFR1 and TNFR2 by mouse TNF-alpha strongly inhibited seizure activity .	XREF_BIBR found that acute, selective activation of TNFR1 by human TNF-alpha exerted no influence on hippocampal seizure sensitivity, but activation of both TNFR1 and TNFR2 by mouse TNF-alpha strongly inhibited seizure activity.	21	30	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	29	30	26	27
We show that the mere mechanical fixation of TNF is insufficient to efficiently activate TNFR2 that is responsive to only the membrane bound form of TNF but not its soluble form .	We show that the mere mechanical fixation of TNF is insufficient to efficiently activate TNFR2 that is responsive to only the membrane bound form of TNF but not its soluble form.	6	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	8	9	14	15
We provide several independent pieces of evidence to indicate that STAT3 , rather than NFkappaB , is the predominant mediator of TNFR2 induction by IL-6 and TNFalpha .	We provide several independent pieces of evidence to indicate that STAT3, rather than NFkappaB, is the predominant mediator of TNFR2 induction by IL-6 and TNFalpha.	21	27	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	26	27	21	22
The precise significance of the upregulation of TNF-R2 by TNF-alpha in NP cells remains to be elucidated .	The precise significance of the upregulation of TNF-R2 by TNF-alpha in NP cells remains to be elucidated.	5	12	upregulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R2	TNF-R2	TNF-R2	9	10	7	8
Conversely , when TNF-alpha activates TNF-R2 , recruitment of the TNF receptor associated factors ( TRAF2 ) occurs , resulting in stimulation of NF-kappa B , which possesses anti-apoptotic properties [ XREF_BIBR , XREF_BIBR ] .	Conversely, when TNF-alpha activates TNF-R2, recruitment of the TNF receptor associated factors (TRAF2) occurs, resulting in stimulation of NF-kappa B, which possesses anti-apoptotic properties [XREF_BIBR, XREF_BIBR].	3	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R2	TNF-R2	TNF-R2	3	4	5	6
TNFalpha activation of TNFR2 enhances NK cell cytotoxicity , but its effects on the other essential function of NK cells - cytokine production , for which IFNgamma is paramount - are poorly defined .	TNFalpha activation of TNFR2 enhances NK cell cytotoxicity, but its effects on the other essential function of NK cells - cytokine production, for which IFNgamma is paramount - are poorly defined.	0	4	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	0	1	3	4
Furthermore , the finding that STAT3 is a mediator of TNFR2 induction by combined TNFalpha and IL-6 adds to the growing evidence for STAT3 as a key mediator of colitis associated cancer and supports further investigation of STAT3 inhibitors as potential cancer therapies .	Furthermore, the finding that STAT3 is a mediator of TNFR2 induction by combined TNFalpha and IL-6 adds to the growing evidence for STAT3 as a key mediator of colitis associated cancer and supports further investigation of STAT3 inhibitors as potential cancer therapies.	10	16	induction	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	14	15	10	11
It was , therefore , possible that , even if we could not detect direct effects for TNF , TNF would still potentiate TNFR2 induction by IL-6 .	It was, therefore, possible that, even if we could not detect direct effects for TNF, TNF would still potentiate TNFR2 induction by IL-6.	19	24	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	19	20	23	24
To explore the contribution of TNFR2 to TNF mediated responses , MHEC from wild-type and Tnfrsf1b -/- mice were treated with TNF for 4hrs and their transcription profile was assessed via genome-wide microarrays .	To explore the contribution of TNFR2 to TNF mediated responses, MHEC from wild-type and Tnfrsf1b -/- mice were treated with TNF for 4hrs and their transcription profile was assessed via genome-wide microarrays.	13	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNF	TNF	TNF	Tnfrsf1b	Tnfrsf1b	Tnfrsf1b	21	22	15	16
The enhancing effect of TNF-alpha on carbachol induced isometric force generation was completely abrogated in the tracheal rings obtained from TNF-alpha receptor ( TNFR ) 1 deficient mice and in control rings treated with a TNF alpha mutant that solely activates TNFR2 .	The enhancing effect of TNF-alpha on carbachol induced isometric force generation was completely abrogated in the tracheal rings obtained from TNF-alpha receptor (TNFR) 1 deficient mice and in control rings treated with a TNF alpha mutant that solely activates TNFR2.	32	42	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	35	36	41	42
Both soluble and transmembrane TNF bind to the TNFRI whereas the TNFRII can only be fully activated by transmembrane TNF .	Both soluble and transmembrane TNF bind to the TNFRI whereas the TNFRII can only be fully activated by transmembrane TNF.	10	20	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFRII	TNFRII	TNFRII	19	20	11	12
Interestingly , both TNFR2 mRNA and protein were significantly increased by the combination of IFN-gamma and TNF-alpha , once again demonstrating synergy between the two cytokines in modulating expression of alveolar epithelial cell derived proteins .	Interestingly, both TNFR2 mRNA and protein were significantly increased by the combination of IFN-gamma and TNF-alpha, once again demonstrating synergy between the two cytokines in modulating expression of alveolar epithelial cell derived proteins.	3	17	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	16	17	3	4
In line with this , additional data indicate that mere mechanical fixation of TNF to an immobilized surface is insufficient to efficiently activate TNFR2 .	In line with this, additional data indicate that mere mechanical fixation of TNF to an immobilized surface is insufficient to efficiently activate TNFR2.	11	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	13	14	23	24
There was a significant overexpression of TNF-alpha ( P = 0.002 ) , TNFR2 ( P = 0.0001 ) , RELA ( P = 0.0117 ) , and IL6 ( P = 0.0007 ) in the KC corneal tissues as compared to the control .	There was a significant overexpression of TNF-alpha (P = 0.002), TNFR2 (P = 0.0001), RELA (P = 0.0117), and IL6 (P = 0.0007) in the KC corneal tissues as compared to the control.	1	28	was a significant overexpression	Positive_activation_copula_1	Positive_activation	Positive_activation	TNF-alpha	overexpression of TNF-alpha	tnf-alpha	TNFR2	TNFR2	tnfr2	6	7	13	14
Consequently , at low concentration TNF-alpha activates TNFR2 mediated neuroprotection , whereas at high concentration TNFR1 contributes to cell injury [ XREF_BIBR ] .	Consequently, at low concentration TNF-alpha activates TNFR2 mediated neuroprotection, whereas at high concentration TNFR1 contributes to cell injury [XREF_BIBR].	2	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	5	6	7	8
The effects on T lymphocytes are mainly mediated by interaction of TNFalpha with TNF-RII inducing a costimulatory signal to TCR mediated T cell activation , thereby increasing T cell proliferation , expression of T cell activation markers ( CD25 , human leukocyte antigen-DR , and TNF-RII ) , and secretion of inflammatory cytokines including IFNgamma and TNFalpha [ XREF_BIBR ] .	The effects on T lymphocytes are mainly mediated by interaction of TNFalpha with TNF-RII inducing a costimulatory signal to TCR mediated T cell activation, thereby increasing T cell proliferation, expression of T cell activation markers (CD25, human leukocyte antigen-DR, and TNF-RII), and secretion of inflammatory cytokines including IFNgamma and TNFalpha [XREF_BIBR].	9	46	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-RII	TNF-RII	TNF-RII	11	12	45	46
We propose a novel mechanism in which TNF activates TNFR2 on Treg cells and thereby expands this immunosuppressive immune cell population .	We propose a novel mechanism in which TNF activates TNFR2 on Treg cells and thereby expands this immunosuppressive immune cell population.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	7	8	9	10
By contrast , as the local inflammatory response including TNF expression evolves , thereby inducing TNFR2 expression , TNF blockade also abrogates protective TNFR2 signaling events that both induce remyelination and immunosuppressive action [ XREF_BIBR , XREF_BIBR ] .	By contrast, as the local inflammatory response including TNF expression evolves, thereby inducing TNFR2 expression, TNF blockade also abrogates protective TNFR2 signaling events that both induce remyelination and immunosuppressive action [XREF_BIBR, XREF_BIBR].	18	25	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	18	19	23	24
Upon cell activation , the extracellular domain of tmTNF is cleaved by ADAM17 metalloproteinase whereupon the soluble TNFalpha ( sTNFalpha ) is released to the extracellular milieu and activates TNF receptor ( TNFR ) 1 and TNFR2 .	Upon cell activation, the extracellular domain of tmTNF is cleaved by ADAM17 metalloproteinase whereupon the soluble TNFalpha (sTNFalpha) is released to the extracellular milieu and activates TNF receptor (TNFR) 1 and TNFR2.	15	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	17	18	36	37
The increased TNF-alpha production was thought to contribute to the resistant phenotype by activating TNFR2 dependent survival pathways , although TNFR2 blockade accounted for only a small restoration of drug sensitivity relative to that achieved by inhibiting NF-kappaB [ XREF_BIBR ] .	The increased TNF-alpha production was thought to contribute to the resistant phenotype by activating TNFR2 dependent survival pathways, although TNFR2 blockade accounted for only a small restoration of drug sensitivity relative to that achieved by inhibiting NF-kappaB [XREF_BIBR].	2	17	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	2	3	14	15
Analyses of the effects of cucurbitacin and Bay 11-7082 on TNFR2 mRNA in cells treated with TNFalpha alone revealed that either the NFkappaB inhibitor or the STAT3 inhibitor significantly attenuated TNFalpha-induction of TNFR2 , but combined inhibitors did not have a more dramatic effect than either inhibitor alone .	Analyses of the effects of cucurbitacin and Bay 11-7082 on TNFR2 mRNA in cells treated with TNFalpha alone revealed that either the NFkappaB inhibitor or the STAT3 inhibitor significantly attenuated TNFalpha-induction of TNFR2, but combined inhibitors did not have a more dramatic effect than either inhibitor alone.	10	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	16	17	10	11
Second , in wild type mouse heart organ culture , TNF upregulates TNFR2 , activates both ASK1 and Etk , and causes apoptosis and cell cycle entry .	Second, in wild type mouse heart organ culture, TNF upregulates TNFR2, activates both ASK1 and Etk, and causes apoptosis and cell cycle entry.	10	21	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	10	11	12	13
Addition of exogenous TNF , but not IL-6 or IL-1beta , have been found to upregulate TNFR2 on murine Treg cells in vitro .	Addition of exogenous TNF, but not IL-6 or IL-1beta, have been found to upregulate TNFR2 on murine Treg cells in vitro.	0	17	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	3	4	16	17
Our data demonstrate that TNF-alpha also upregulates IL-1beta and IL-1Ra genes , but not IL-1alpha or IL-1R1 , whereas IL-1beta upregulates TNF-alpha and TNF-R2 .	Our data demonstrate that TNF-alpha also upregulates IL-1beta and IL-1Ra genes, but not IL-1alpha or IL-1R1, whereas IL-1beta upregulates TNF-alpha and TNF-R2.	4	24	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-R2	TNF-R2	TNF-R2	4	5	23	24
TNFR2 is upregulated in IBD and in models of inflammation associated cancer , regarded to be in response to increased inflammatory cytokines in the mucosa , as TNF-alpha and IL-6 induce TNFR2 in colon cancer cells .	TNFR2 is upregulated in IBD and in models of inflammation associated cancer, regarded to be in response to increased inflammatory cytokines in the mucosa, as TNF-alpha and IL-6 induce TNFR2 in colon cancer cells.	27	35	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	27	28	31	32
Noteworthy , TNFR1 mediated apoptosis occurs during high TNFalpha levels whereas small amounts of TNFalpha in the low ng/ml range activate the TNFR2 mediated signaling cascade [ XREF_BIBR , XREF_BIBR ] .	Noteworthy, TNFR1 mediated apoptosis occurs during high TNFalpha levels whereas small amounts of TNFalpha in the low ng/ml range activate the TNFR2 mediated signaling cascade [XREF_BIBR, XREF_BIBR].	12	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	amounts of TNFalpha	tnfalpha	TNFR2	TNFR2	tnfr2	14	15	22	23
XREF_BIBR However , our results are consistent with the finding that TNF-alpha upregulates only TNFR2 in rat primary astrocytes .	XREF_BIBR However, our results are consistent with the finding that TNF-alpha upregulates only TNFR2 in rat primary astrocytes.	11	18	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	11	12	14	15
Only membrane bound TNF triggers TNFR2 mediated NF-kappaB-inducing kinase ( NIK )/IKKalpha-dependent noncanonical pathway 25 .	Only membrane bound TNF triggers TNFR2 mediated NF-kappaB-inducing kinase (NIK)/IKKalpha-dependent noncanonical pathway 25.	3	9	triggers	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TNF	TNF	tnf	TNFR2	TNFR2 mediated NF-kappaB-inducing kinase	tnfr2	3	4	5	6
Together , our results define a pathway for macrophage induced bystander effects in which TNF-alpha triggers TNFRSF1b receptor signaling leading to increased production of Netrin-1 , crypt hyperplasia and decreased epithelial cell apoptosis .	Together, our results define a pathway for macrophage induced bystander effects in which TNF-alpha triggers TNFRSF1b receptor signaling leading to increased production of Netrin-1, crypt hyperplasia and decreased epithelial cell apoptosis.	14	18	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFRSF1b	TNFRSF1b	TNFRSF1b	14	15	16	17
IL-6 and TNFalpha induce TNFR2 in COLO205 and SW480 cells .	IL-6 and TNFalpha induce TNFR2 in COLO205 and SW480 cells.	0	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	2	3	4	5
In our current study , we observed that IFN-gamma and TNF induced up-regulation of TNFR2 , and possibly MLCK , in the epithelial cells were specifically suppressed by ML-7 treatment ( XREF_FIG ) .	In our current study, we observed that IFN-gamma and TNF induced up-regulation of TNFR2, and possibly MLCK, in the epithelial cells were specifically suppressed by ML-7 treatment (XREF_FIG).	8	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	10	11	14	15
Third , PGRN enhances TNF induced TNFR2 mediated proliferation and suppressive activity of regulatory T cells and PGRN induced Akt signaling has found to be inhibited by neutralizing TNFR2 antibodies .	Third, PGRN enhances TNF induced TNFR2 mediated proliferation and suppressive activity of regulatory T cells and PGRN induced Akt signaling has found to be inhibited by neutralizing TNFR2 antibodies.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	4	5	6	7
The extrinsic pathway of apoptosis is induced by cytokines of the TNF superfamily acting on death receptors tumor necrosis factor receptor ( TNFR ) 1 , TNFR2 , TNF related apoptosis inducing ligand receptor ( TRAILR ) 1 , and TRAILR2 XREF_BIBR .	The extrinsic pathway of apoptosis is induced by cytokines of the TNF superfamily acting on death receptors tumor necrosis factor receptor (TNFR) 1, TNFR2, TNF related apoptosis inducing ligand receptor (TRAILR) 1, and TRAILR2 XREF_BIBR.	6	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	11	12	26	27
TNFR2 expression became significantly elevated , however , when podocytes were treated with TNF-alpha , a case in which the ligand upregulates its receptor .	TNFR2 expression became significantly elevated, however, when podocytes were treated with TNF-alpha, a case in which the ligand upregulates its receptor.	0	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	13	14	0	1
Blockade of IL-6 , but not TNF , within ascites decreased TNFR2 + Treg frequency .	Blockade of IL-6, but not TNF, within ascites decreased TNFR2 + Treg frequency.	0	14	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	6	7	11	12
Emerging evidence indicates that activation of TNFR2 by TNFalpha exerts opposite biologic effects as activation of TNFR1 .	Emerging evidence indicates that activation of TNFR2 by TNFalpha exerts opposite biologic effects as activation of TNFR1.	4	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	8	9	6	7
Further studies applying engineered TNFalpha that can specifically activate TNFR2 may be helpful in elucidating the exact roles of TNFR1 vs. TNFR2 signaling intrinsic to the neural stem and progenitor cells as well as the more complex signaling that occurs in an injury context in vivo .	Further studies applying engineered TNFalpha that can specifically activate TNFR2 may be helpful in elucidating the exact roles of TNFR1 vs. TNFR2 signaling intrinsic to the neural stem and progenitor cells as well as the more complex signaling that occurs in an injury context in vivo.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	4	5	9	10
TNF and/or hypoxia resulted in a similar induction of TNF expression in WT and TNFR2 -/- mice ( XREF_SUPPLEMENTARY ) .	TNF and/or hypoxia resulted in a similar induction of TNF expression in WT and TNFR2 -/- mice (XREF_SUPPLEMENTARY).	0	16	induction	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	0	1	14	15
An intriguing second possibility is that neutralizing TNFR1 may indirectly promote stimulation of TNFR2 by TNF present in the EAE lesions .	An intriguing second possibility is that neutralizing TNFR1 may indirectly promote stimulation of TNFR2 by TNF present in the EAE lesions.	10	16	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	15	16	13	14
TNF alone has no effect on TNFR2 expression on human colon cancer cell lines in vitro ; however , the combination of IL-6 and TNF can upregulate TNFR2 on such cells .	TNF alone has no effect on TNFR2 expression on human colon cancer cell lines in vitro; however, the combination of IL-6 and TNF can upregulate TNFR2 on such cells.	20	28	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	24	25	27	28
Thus , our data clearly show that TNF activation of TNFR2 is able to stabilize FoxP3 expression by Tregs upon potent TCR stimulation .	Thus, our data clearly show that TNF activation of TNFR2 is able to stabilize FoxP3 expression by Tregs upon potent TCR stimulation.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	7	8	10	11
Accordingly , TNF variants selectively activating TNFR2 could be a useful therapeutic regimen in a variety of diseases , including heart failure , autoimmune and neurodegenerative diseases .	Accordingly, TNF variants selectively activating TNFR2 could be a useful therapeutic regimen in a variety of diseases, including heart failure, autoimmune and neurodegenerative diseases.	2	7	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	2	3	6	7
These results clearly demonstrate that the mere mechanical fixation of TNF is not sufficient to allow strong TNFR2 activation .	These results clearly demonstrate that the mere mechanical fixation of TNF is not sufficient to allow strong TNFR2 activation.	8	18	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	10	11	17	18
TNF activates two cell surface receptors , TNFR1 ( CD120a ) and TNFR2 ( CD120b ) XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	TNF activates two cell surface receptors, TNFR1 (CD120a) and TNFR2 (CD120b) XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	0	1	12	13
At later stages , the TNF induction of Tnfrsf1b , specifically in SCMECs , may allow a full TNF response .	At later stages, the TNF induction of Tnfrsf1b, specifically in SCMECs, may allow a full TNF response.	5	9	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	Tnfrsf1b	Tnfrsf1b	Tnfrsf1b	5	6	8	9
Signaling through TNF receptor type II ( TNFRII ) , which is constitutively expressed by Tregs and is upregulated by TNF-alpha , can mediate this inhibition [ XREF_BIBR ] .	Signaling through TNF receptor type II (TNFRII), which is constitutively expressed by Tregs and is upregulated by TNF-alpha, can mediate this inhibition [XREF_BIBR].	0	21	upregulated	Positive_regulation_syntax_2_verb	Positive_activation	Positive_regulation	TNF-alpha	TNF-alpha	tnf-alpha	TNFRII	TNFRII), which is constitutively expressed	tnfrii	20	21	7	8
XREF_BIBR - XREF_BIBR TNF is synthesized and in initially bound to the membrane requiring proteolytic cleavage to yield a soluble form which can then bind to the TNF receptor I ( TNFRI ) and/or TNFRII .	XREF_BIBR - XREF_BIBR TNF is synthesized and in initially bound to the membrane requiring proteolytic cleavage to yield a soluble form which can then bind to the TNF receptor I (TNFRI) and/or TNFRII.	2	35	synthesized	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFRII	TNFRII	TNFRII	3	4	34	35
Overall , these data indicate that production of Tnfa from primitive neutrophils activates Tnfr2 , upregulating the expression of Jag1a on the surface of endothelial cells .	Overall, these data indicate that production of Tnfa from primitive neutrophils activates Tnfr2, upregulating the expression of Jag1a on the surface of endothelial cells.	6	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tnfa	Tnfa	Tnfa	Tnfr2	Tnfr2	Tnfr2	8	9	13	14
TNFR2 , on the other hand , is preferentially activated by transmural TNF .	TNFR2, on the other hand, is preferentially activated by transmural TNF.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	12	13	0	1
In the present study , we have shown that TNFR2 is selectively upregulated by IL-1beta , TNF-alpha , or IFN-gamma treatment in astrocytes , while LPS does not affect TNFR2 mRNA expression .	In the present study, we have shown that TNFR2 is selectively upregulated by IL-1beta, TNF-alpha, or IFN-gamma treatment in astrocytes, while LPS does not affect TNFR2 mRNA expression.	9	20	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	16	17	9	10
Our studies reveal a novel pathway where IL-6 and TNFalpha cooperatively induce TNFR2 in colon cancer cells by interactions at multiple levels .	Our studies reveal a novel pathway where IL-6 and TNFalpha cooperatively induce TNFR2 in colon cancer cells by interactions at multiple levels.	7	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	9	10	12	13
TNF activates TNFR2 in cortical inhibitory interneurons .	TNF activates TNFR2 in cortical inhibitory interneurons.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	0	1	2	3
Furthermore , murine TNF was able to induce necroptosis in Tnfr2 +/+ but not Tnfr2 -/- BMDMs ( XREF_FIG ) , confirming the requirement for TNFR2 .	Furthermore, murine TNF was able to induce necroptosis in Tnfr2 +/+ but not Tnfr2 -/- BMDMs (XREF_FIG), confirming the requirement for TNFR2.	2	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	Tnfr2	Tnfr2	Tnfr2	3	4	10	11
In a biological model for TNFalpha activation of TNFR2 , three of the four peptides induced cytotoxic response in the target cell line suggesting that at least one of these domains induced a unique TNFR2 specific biological response .	In a biological model for TNFalpha activation of TNFR2, three of the four peptides induced cytotoxic response in the target cell line suggesting that at least one of these domains induced a unique TNFR2 specific biological response.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	5	6	8	9
Membrane bound TNF ( mTNF ) mainly binds to and activates TNFR2 XREF_BIBR .	Membrane bound TNF (mTNF) mainly binds to and activates TNFR2 XREF_BIBR.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	2	3	11	12
Interestingly , the transmembrane form of tumor necrosis factor ( tmTNF ) is necessary to robustly activate TNFR2 .	Interestingly, the transmembrane form of tumor necrosis factor (tmTNF) is necessary to robustly activate TNFR2.	6	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	TNFR2	TNFR2	TNFR2	6	9	17	18
Human TNF , known not to activate the mouse TNFR2 , did not affect T cell proliferation .	Human TNF, known not to activate the mouse TNFR2, did not affect T cell proliferation.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	1	2	9	10
Interestingly , IFN-gamma significantly augmented TNF induced TNFR2 mRNA and protein although this did not translate into a functional effect on TF activity as TNFR2 inhibition had no significant effect on TNF-alpha + IFN-gamma synergy .	Interestingly, IFN-gamma significantly augmented TNF induced TNFR2 mRNA and protein although this did not translate into a functional effect on TF activity as TNFR2 inhibition had no significant effect on TNF-alpha + IFN-gamma synergy.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	5	6	7	8
Consequently , target cell bound scFv : TNF can efficiently activate TNFR2 and thereby sensitize cancer cells to induction of TNFR1 apoptotic signaling .	Consequently, target cell bound scFv : TNF can efficiently activate TNFR2 and thereby sensitize cancer cells to induction of TNFR1 apoptotic signaling.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	7	8	11	12
To determine whether TNF-alpha binding to epithelial cells was involved in increased netrin-1 production , we initially assayed YAMC cells for Tnfrsf1a and Tnfrsf1b and noted strong induction of Tnfrsf1b by TNF-alpha ( XREF_FIG and XREF_SUPPLEMENTARY ) .	To determine whether TNF-alpha binding to epithelial cells was involved in increased netrin-1 production, we initially assayed YAMC cells for Tnfrsf1a and Tnfrsf1b and noted strong induction of Tnfrsf1b by TNF-alpha (XREF_FIG and XREF_SUPPLEMENTARY).	25	35	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Tnfrsf1b	Tnfrsf1b	Tnfrsf1b	31	32	29	30
We have , however , recently demonstrated TNF mediated induction of TNFR2 in tumor stem cells in ccRCC organ cultures in association with increased cell cycle entry ( RSL ; unpublished observations ) .	We have, however, recently demonstrated TNF mediated induction of TNFR2 in tumor stem cells in ccRCC organ cultures in association with increased cell cycle entry (RSL; unpublished observations).	7	12	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	7	8	11	12
Furthermore , in the presence of IL-7 , TNF increased the proportion of TNFR2 + cells in the FoxP3 + subset , but not in FoxP3 - cells ( XREF_FIG ) , indicating that IL-7 could also promulgate the Treg activating effect of TNF .	Furthermore, in the presence of IL-7, TNF increased the proportion of TNFR2 + cells in the FoxP3 + subset, but not in FoxP3 - cells (XREF_FIG), indicating that IL-7 could also promulgate the Treg activating effect of TNF.	8	25	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	8	9	13	14
Thus , the modest effects of NFkappaB inhibitor versus STAT3 inhibitor on TNFR2 expression in cells treated with IL-6 and TNFalpha were not due to a lack of effective Bay 11-7082 dosing .	Thus, the modest effects of NFkappaB inhibitor versus STAT3 inhibitor on TNFR2 expression in cells treated with IL-6 and TNFalpha were not due to a lack of effective Bay 11-7082 dosing.	12	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	20	21	12	13
In vitro studies have shown that TNFR2 is induced in colon cancer cells by TNFalpha and IL-6 combined , but neither cytokine alone .	In vitro studies have shown that TNFR2 is induced in colon cancer cells by TNFalpha and IL-6 combined, but neither cytokine alone.	6	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	14	15	6	7
Our studies also reveal that TNFalpha acts through NFkappaB to induce endogenous IL-6 and promote TNFR2 induction via autocrine effects of IL-6 ( XREF_FIG ) .	Our studies also reveal that TNFalpha acts through NFkappaB to induce endogenous IL-6 and promote TNFR2 induction via autocrine effects of IL-6 (XREF_FIG).	5	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	5	6	15	16
As shown in XREF_FIG following treatment with TNF-alpha , the percentage of apoptotic cells significantly increased for Tnfrsf1b silenced cells compared to cells transfected with non targeting siRNA ( 31.9 +/- 2.0 vs. 8.2 +/- 0.7 , P < 0.01 ) , supporting induction of netrin-1 by TNF-alpha through the action of Tnfrsf1b .	As shown in XREF_FIG following treatment with TNF-alpha, the percentage of apoptotic cells significantly increased for Tnfrsf1b silenced cells compared to cells transfected with non targeting siRNA (31.9 +/- 2.0 vs. 8.2 +/- 0.7, P < 0.01), supporting induction of netrin-1 by TNF-alpha through the action of Tnfrsf1b.	42	53	supporting	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Tnfrsf1b	Tnfrsf1b	Tnfrsf1b	47	48	52	53
Wild-type TNF induces TNFR2 and Etk and activates both ASK1 and Etk but does not down-regulate TNFR1 .	Wild-type TNF induces TNFR2 and Etk and activates both ASK1 and Etk but does not down-regulate TNFR1.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	1	2	3	4
In contrast , TNFR2 is preferentially activated by transmembrane TNFalpha and protects neurons against excitotoxicity XREF_BIBR .	In contrast, TNFR2 is preferentially activated by transmembrane TNFalpha and protects neurons against excitotoxicity XREF_BIBR.	3	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	9	10	3	4
Our findings that TNFalpha cooperates with IL-6 to induce TNFR2 , an inducer of colon cancer cell growth , suggests that TNFR2 may prove useful as a biomarker of the potential effects of anti-TNFalpha on colitis associated cancer risk , or could represent a specific target to decrease colon cancer risk in IBD .	Our findings that TNFalpha cooperates with IL-6 to induce TNFR2, an inducer of colon cancer cell growth, suggests that TNFR2 may prove useful as a biomarker of the potential effects of anti-TNFalpha on colitis associated cancer risk, or could represent a specific target to decrease colon cancer risk in IBD.	3	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	3	4	9	10
In accord with earlier findings demonstrating that only membrane TNF , but not soluble TNF , properly activates TNFR2 , we further show by use of TNFR1- and TNFR2 specific mutants of soluble TNF and membrane TNF that soluble ligand trimers fail to activate the alternative NFkappaB pathway .	In accord with earlier findings demonstrating that only membrane TNF, but not soluble TNF, properly activates TNFR2, we further show by use of TNFR1- and TNFR2 specific mutants of soluble TNF and membrane TNF that soluble ligand trimers fail to activate the alternative NFkappaB pathway.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	9	10	18	19
TNFR2-Fc was known to block the soluble form but not membrane bound form of TNF [ XREF_BIBR ] , while the membrane bound TNF preferentially activates TNFR2 [ XREF_BIBR ] .	TNFR2-Fc was known to block the soluble form but not membrane bound form of TNF [XREF_BIBR], while the membrane bound TNF preferentially activates TNFR2 [XREF_BIBR].	23	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	23	24	26	27
Mice producing human TNFR2 that can be activated by mouse TNF , in addition to mouse TNFR2 , did not demonstrate enhanced susceptibility to the lethal effects of glomerulonephritis , indicating that pro inflammatory signalling via TNFR2 does not account for a sensitizing effect .	Mice producing human TNFR2 that can be activated by mouse TNF, in addition to mouse TNFR2, did not demonstrate enhanced susceptibility to the lethal effects of glomerulonephritis, indicating that pro inflammatory signalling via TNFR2 does not account for a sensitizing effect.	1	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	10	11	3	4
XREF_BIBR TNFR2 can only be fully activated by membrane TNF-alpha and not by soluble TNF-alpha , even though it can bind both forms .	XREF_BIBR TNFR2 can only be fully activated by membrane TNF-alpha and not by soluble TNF-alpha, even though it can bind both forms.	0	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	9	10	1	2
In contrast Bay 11-7082 had no significant effect on basal or IL-6 + TNFalpha induced TNFR2 mRNA .	In contrast Bay 11-7082 had no significant effect on basal or IL-6 + TNFalpha induced TNFR2 mRNA.	4	16	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	13	14	15	16
Given this and the fact that soluble TNF can not induce full activation of TNFR2 , it appears likely that this receptor plays a lesser or secondary role in the cytokine induced permeabilization observed in this work .	Given this and the fact that soluble TNF can not induce full activation of TNFR2, it appears likely that this receptor plays a lesser or secondary role in the cytokine induced permeabilization observed in this work.	6	15	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	7	8	14	15
It is known that TNFalpha induces a TNFR2 and NFkappaB dependent pathway in human Treg , and that an increase in NFkappaB activity promotes FOXP3 expression [ XREF_BIBR ] .	It is known that TNFalpha induces a TNFR2 and NFkappaB dependent pathway in human Treg, and that an increase in NFkappaB activity promotes FOXP3 expression [XREF_BIBR].	4	14	induces	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	4	5	7	8
In terms of mouse TNFR2 , it is difficult to confirm its function using mouse or a mouse derived cell line , because human TNF can not selectively stimulate mouse TNFR2 .	In terms of mouse TNFR2, it is difficult to confirm its function using mouse or a mouse derived cell line, because human TNF can not selectively stimulate mouse TNFR2.	23	31	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	24	25	30	31
It has been previously reported that TNFalpha induced a TNFR2 specific proliferation of the neuroblastoma cell line SK-N-BE [ XREF_BIBR ] .	It has been previously reported that TNFalpha induced a TNFR2 specific proliferation of the neuroblastoma cell line SK-N-BE [XREF_BIBR].	6	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	6	7	9	10
Interestingly , TNFalpha can induce TNFR2 receptors which imply that these receptors could be involved in the dual effects reported here [ XREF_BIBR ] .	Interestingly, TNFalpha can induce TNFR2 receptors which imply that these receptors could be involved in the dual effects reported here [XREF_BIBR].	2	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	2	3	5	6
TNFR2 is more efficiently triggered by transmembrane TNF than by soluble TNF .	TNFR2 is more efficiently triggered by transmembrane TNF than by soluble TNF.	0	8	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	7	8	0	1
Therefore , inflammatory injury stimulated by TNF-alpha induced TNFR2 activation .	Therefore, inflammatory injury stimulated by TNF-alpha induced TNFR2 activation.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR2	TNFR2	TNFR2	6	7	8	9
NFkappaB inhibition had little effect on IL-6 + TNFalpha induced TNFR2 , but did inhibit induction of endogenous IL-6 and TNFR2 in cells treated with TNFalpha alone .	NFkappaB inhibition had little effect on IL-6 + TNFalpha induced TNFR2, but did inhibit induction of endogenous IL-6 and TNFR2 in cells treated with TNFalpha alone.	2	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	8	9	10	11
This study used colon cancer cell lines to test the hypothesis that IL-6 and TNFalpha induce TNFR2 via STAT3 and/or NFkappaB .	This study used colon cancer cell lines to test the hypothesis that IL-6 and TNFalpha induce TNFR2 via STAT3 and/or NFkappaB.	12	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	14	15	16	17
Taken together , our novel data indicate that TNF preferentially up-regulates TNFR2 on Tregs , and this is amplified by the stimulation of 4-1BB and OX40 , resulting in the optimal activation of Tregs and augmented attenuation of excessive inflammatory responses .	Taken together, our novel data indicate that TNF preferentially up-regulates TNFR2 on Tregs, and this is amplified by the stimulation of 4-1BB and OX40, resulting in the optimal activation of Tregs and augmented attenuation of excessive inflammatory responses.	8	13	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	8	9	11	12
Novel strategies to mimic transmembrane tumor necrosis factor dependent activation of tumor necrosis factor receptor 2 .	Novel strategies to mimic transmembrane tumor necrosis factor dependent activation of tumor necrosis factor receptor 2.	5	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor receptor 2	tumor necrosis factor receptor 2	tumor necrosis factor receptor 2	5	8	11	16
Moreover , we noted increased cleaved caspase-3 compared to cells transfected with non targeting siRNA and additional increases when Tnfrsf1b silenced cells were treated with TNF-alpha ( XREF_FIG ) .	Moreover, we noted increased cleaved caspase-3 compared to cells transfected with non targeting siRNA and additional increases when Tnfrsf1b silenced cells were treated with TNF-alpha (XREF_FIG).	19	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Tnfrsf1b	Tnfrsf1b	Tnfrsf1b	25	26	19	20
Our data demonstrate that excessive TNF-alpha stimulates TNF-RII and enhances migration of ESCs in vitro .	Our data demonstrate that excessive TNF-alpha stimulates TNF-RII and enhances migration of ESCs in vitro.	4	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-RII	TNF-RII	TNF-RII	5	6	7	8
The fact that membrane bound TNFalpha can activate JNK not only through TNF-R1 but also TNF-R2 may therefore explain why Bim is more important than Bid in ConA induced hepatocyte killing ( XREF_SUPPLEMENTARY ) .	The fact that membrane bound TNFalpha can activate JNK not only through TNF-R1 but also TNF-R2 may therefore explain why Bim is more important than Bid in ConA induced hepatocyte killing (XREF_SUPPLEMENTARY).	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNF-R2	TNF-R2	TNF-R2	5	6	15	16
XREF_BIBR NFkappaB activation can also be induced by TNFR2 that can be activated by TNFalpha to further activate NFkappaB .	XREF_BIBR NFkappaB activation can also be induced by TNFR2 that can be activated by TNFalpha to further activate NFkappaB.	6	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	14	15	8	9
TNFRII , activated optimally by membranous TNF-alpha , lowers the threshold of activation on T-effector cells , while contributing to the suppressive function of T-regulatory cells , in part from TNFRII shedding .	TNFRII, activated optimally by membranous TNF-alpha, lowers the threshold of activation on T-effector cells, while contributing to the suppressive function of T-regulatory cells, in part from TNFRII shedding.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFRII	TNFRII	TNFRII	6	7	0	1
Emerging evidence indicates that TNFR2 activation by TNFalpha exerts opposite biologic effects as TNFR1 activation .	Emerging evidence indicates that TNFR2 activation by TNFalpha exerts opposite biologic effects as TNFR1 activation.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	7	8	4	5
Finally , since high concentrations of TNF-alpha have been reported to impair Treg activity , and the functional impairment of Tregs observed in rheumatoid arthritis patients can be reversed by anti-TNF-alpha antibodies XREF_BIBR , we considered the hypothesis that the high levels of TNF-alpha seen in severe malaria patients XREF_BIBR , XREF_BIBR , might upregulate TNFR2 and impair Treg function .	Finally, since high concentrations of TNF-alpha have been reported to impair Treg activity, and the functional impairment of Tregs observed in rheumatoid arthritis patients can be reversed by anti-TNF-alpha antibodies XREF_BIBR, we considered the hypothesis that the high levels of TNF-alpha seen in severe malaria patients XREF_BIBR, XREF_BIBR, might upregulate TNFR2 and impair Treg function.	41	56	upregulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	levels of TNF-alpha	tnf-alpha	TNFR2	TNFR2	tnfr2	43	44	55	56
Although binding of soluble TNF by TNFR1 is fully sufficient for receptor activation , soluble TNF poorly stimulates TNFR2 signaling despite high-affinity binding 16 .	Although binding of soluble TNF by TNFR1 is fully sufficient for receptor activation, soluble TNF poorly stimulates TNFR2 signaling despite high-affinity binding 16.	14	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	15	16	18	19
Since TNFR2 is only fully activated by membrane bound TNF ( memTNF ) but not by soluble TNF trimers XREF_BIBR , the trimerization domain of tenascin C ( TNC ) was fused to the N-terminus of the TNFR2 selective scTNF .	Since TNFR2 is only fully activated by membrane bound TNF (memTNF) but not by soluble TNF trimers XREF_BIBR, the trimerization domain of tenascin C (TNC) was fused to the N-terminus of the TNFR2 selective scTNF.	1	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	17	18	1	2
E6 ' s ability to degrade Bak is independent of its p53 degradation function , although p53 activation is known to activate Bak .	E6 's ability to degrade Bak is independent of its p53 degradation function, although p53 activation is known to activate Bak.	16	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	16	17	22	23
Furthermore , we demonstrate that Akt negatively regulates p53 mediated Bak activation , independent of caspases ( XREF_SUPPLEMENTARY ) .	Furthermore, we demonstrate that Akt negatively regulates p53 mediated Bak activation, independent of caspases (XREF_SUPPLEMENTARY).	7	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	8	9	10	11
In addition to the upregulation of death receptors , p53 induced the pro apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein .	In addition to the upregulation of death receptors, p53 induced the pro apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein.	9	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	9	10	19	20
p53 mediates bak activation in cell death .	p53 mediates bak activation in cell death.	0	3	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	bak	bak	bak	0	1	2	3
P53 also promotes mitochondrial apoptosis by activating BAK protein XREF_BIBR .	P53 also promotes mitochondrial apoptosis by activating BAK protein XREF_BIBR.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	BAK	BAK	BAK	0	1	7	8
According to previous reports , p53 mediates apoptosis by activating proapoptotic genes ( Bak , Bax ) and repressing antiapoptotic B-cell leukemia/lymphoma 2 ( Bcl2 ) family genes [ XREF_BIBR , XREF_BIBR ] .	According to previous reports, p53 mediates apoptosis by activating proapoptotic genes (Bak, Bax) and repressing antiapoptotic B-cell leukemia/lymphoma 2 (Bcl2) family genes [XREF_BIBR, XREF_BIBR].	5	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	5	6	13	14
TRAF6 triggers K63 linked ubiquitination of p53 at K24 in the cytoplasm , which reduces the interaction between p53 and MCL-1 and BAK , thus keeping p53 away from mitochondria and preventing p53 mediated activation of BAK .	TRAF6 triggers K63 linked ubiquitination of p53 at K24 in the cytoplasm, which reduces the interaction between p53 and MCL-1 and BAK, thus keeping p53 away from mitochondria and preventing p53 mediated activation of BAK.	32	37	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	BAK	BAK	BAK	32	33	36	37
Further , the BAK S117E mutant , that we showed undergoes N-terminal conformational change , associated with p53 following DNA damage to levels equivalent to the wild-type protein ( XREF_FIG ) , supporting the idea that p53 can activate BAK by a mechanism separate from that used by BH3 proteins interacting with the hydrophobic groove .	Further, the BAK S117E mutant, that we showed undergoes N-terminal conformational change, associated with p53 following DNA damage to levels equivalent to the wild-type protein (XREF_FIG), supporting the idea that p53 can activate BAK by a mechanism separate from that used by BH3 proteins interacting with the hydrophobic groove.	36	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAK	BAK	BAK	36	37	39	40
In the present work , we reveal that mitochondrial p53 can induce Bak activation .	In the present work, we reveal that mitochondrial p53 can induce Bak activation.	8	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	9	10	12	13
Recently , p53 dependent upregulation of intra-cellular molecule Bak as in the case of Bax has been reported ( LeBlanc et al , 2002 ) .	Recently, p53 dependent upregulation of intra-cellular molecule Bak as in the case of Bax has been reported (LeBlanc et al, 2002).	2	12	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	2	3	8	9
We have previously shown that p53 can induce this activated conformation of BAK .	We have previously shown that p53 can induce this activated conformation of BAK.	5	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAK	BAK	BAK	5	6	12	13
Further experimentation demonstrated that p53 Ser15 phosphorylation and mitochondrial translocation mediated Bak activation and subsequent cell death .	Further experimentation demonstrated that p53 Ser15 phosphorylation and mitochondrial translocation mediated Bak activation and subsequent cell death.	4	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 Ser15 phosphorylation	p53	Bak	Bak	bak	4	5	11	12
Mitochondrial p53 induces conformational activation of proapoptotic Bak without disrupting the Bak-Bcl-xL interaction .	Mitochondrial p53 induces conformational activation of proapoptotic Bak without disrupting the Bak-Bcl-xL interaction.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	1	2	7	8
These data lead us to speculate that one mechanism whereby p53 activates BAK is by relieving the negative regulation normally exhibited by acidic residues in the N terminal alpha helix of BAK , and in the zinc dependent dimerization domain .	These data lead us to speculate that one mechanism whereby p53 activates BAK is by relieving the negative regulation normally exhibited by acidic residues in the N terminal alpha helix of BAK, and in the zinc dependent dimerization domain.	10	15	activates	Positive_activation_token_1_verb	Positive_activation	Negative_activation	p53	p53	p53	BAK	BAK	BAK	10	11	12	13
Mitochondrial p53 phosphorylation induces Bak mediated and caspase independent cell death .	Mitochondrial p53 phosphorylation induces Bak mediated and caspase independent cell death.	1	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 phosphorylation	p53	Bak	Bak	bak	1	2	4	5
A number of studies report that binding of p53 can trigger BAK activation , and BAK residues required for p53 interaction have been identified to the N-terminal region of the protein XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	A number of studies report that binding of p53 can trigger BAK activation, and BAK residues required for p53 interaction have been identified to the N-terminal region of the protein XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	6	12	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAK	BAK	BAK	8	9	11	12
As telomere attrition has the ability to trigger the activation of p53 , and p53 can further lead to Bak mediated mitochondrial apoptosis which may participate in the progression of ARHI , further studies are warranted to verify whether telomere attrition participates in the pathophysiology of ARHI through activating p53 pathway .	As telomere attrition has the ability to trigger the activation of p53, and p53 can further lead to Bak mediated mitochondrial apoptosis which may participate in the progression of ARHI, further studies are warranted to verify whether telomere attrition participates in the pathophysiology of ARHI through activating p53 pathway.	14	20	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	14	15	19	20
SR-A deficiency attenuated I/R induced myocardial apoptosis by preventing p53 mediated Bak-1 apoptotic signaling .	SR-A deficiency attenuated I/R induced myocardial apoptosis by preventing p53 mediated Bak-1 apoptotic signaling.	9	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bak-1	Bak-1	Bak-1	9	10	11	12
Consistent with our model , we find that indeed p53 can trigger BAK conformational change and this can occur independent of the phosphorylation or charge status of S117 .	Consistent with our model, we find that indeed p53 can trigger BAK conformational change and this can occur independent of the phosphorylation or charge status of S117.	9	14	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAK	BAK	BAK	9	10	12	13
Mitochondrial p53 phosphorylation mediates bak activation .	Mitochondrial p53 phosphorylation mediates bak activation.	1	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 phosphorylation	p53	bak	bak	bak	1	2	4	5
For example , SemRep extracts the predication in ( 2 ) from the sentence in ( 1 ) : In addition to the upregulation of death receptors , p53 induced the pro apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein .	For example, SemRep extracts the predication in (2) from the sentence in (1) : In addition to the upregulation of death receptors, p53 induced the pro apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein.	28	40	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	28	29	38	39
Over-expression of p53 stimulates recruitment of BAK to the ER , and both its recruitment and assembly into higher order structures is inhibited by BIK small interfering RNA .	Over-expression of p53 stimulates recruitment of BAK to the ER, and both its recruitment and assembly into higher order structures is inhibited by BIK small interfering RNA.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	Over-expression of p53	p53	BAK	BAK	bak	2	3	6	7
On the other hand , p53 independent induction of Bak has been reported during butyrate [ XREF_BIBR ] or tumor suppressor WT1 induced apoptosis [ XREF_BIBR ] , and in HCT116 cells exposed to hyperoxia [ XREF_BIBR ] .	On the other hand, p53 independent induction of Bak has been reported during butyrate [XREF_BIBR] or tumor suppressor WT1 induced apoptosis [XREF_BIBR], and in HCT116 cells exposed to hyperoxia [XREF_BIBR].	5	10	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	5	6	9	10
Activated p53 triggers Bak dependent and Bax and caspase independent cell death .	Activated p53 triggers Bak dependent and Bax and caspase independent cell death.	0	8	triggers	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	1	2	3	4
These results suggest that glial proliferation and the repair of damaged DNA may be regulated by p53 induced p21WAF1 and CIP1 and GADD45 , and that glial apoptosis caused by oxidative stress may be mediated by p53 induced Bak .	These results suggest that glial proliferation and the repair of damaged DNA may be regulated by p53 induced p21WAF1 and CIP1 and GADD45, and that glial apoptosis caused by oxidative stress may be mediated by p53 induced Bak.	34	39	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	36	37	38	39
It was hypothesized that these ROS induce DNA damage , which results in the upregulation of P53 causing chronic activation of the mitochondrial BAK pathway , ultimately resulting in the triggering of apoptotic cell death .	It was hypothesized that these ROS induce DNA damage, which results in the upregulation of P53 causing chronic activation of the mitochondrial BAK pathway, ultimately resulting in the triggering of apoptotic cell death.	14	24	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	P53	P53	P53	BAK	BAK	BAK	16	17	23	24
We recently reported that p53 directly induces oligomerization of the BH1 ,2,3 effector protein Bak , leading to outer mitochondrial membrane permeabilization ( OMMP ) with release of apoptotic activator proteins .	We recently reported that p53 directly induces oligomerization of the BH1,2,3 effector protein Bak, leading to outer mitochondrial membrane permeabilization (OMMP) with release of apoptotic activator proteins.	4	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	4	5	14	15
Thus , there is no cell cycle arrest , and Bak is directly activated by mitochondrial p53 .	Thus, there is no cell cycle arrest, and Bak is directly activated by mitochondrial p53.	10	17	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	16	17	10	11
Likewise , and as predicted from its MOMP action in Bax-/- cells , p53 also induces oligomerization of Bak in WT , Bax-/- and PUMA-/- mitochondria ( XREF_FIG ) .	Likewise, and as predicted from its MOMP action in Bax-/- cells, p53 also induces oligomerization of Bak in WT, Bax-/- and PUMA-/- mitochondria (XREF_FIG).	13	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	13	14	18	19
Interaction of p53 with Bak causes oligomerization of Bak and release of cytochrome c from mitochondria .	Interaction of p53 with Bak causes oligomerization of Bak and release of cytochrome c from mitochondria.	0	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	2	3	8	9
BAK conformational change induced by p53 does not depend on S117 dephosphorylation .	BAK conformational change induced by p53 does not depend on S117 dephosphorylation.	0	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	BAK	BAK	BAK	5	6	0	1
It is also well established that oxidative DNA damage can initiate an apoptosis program and that p53 promotes Bak mediated mitochondrial apoptosis in response to DNA damage .	It is also well established that oxidative DNA damage can initiate an apoptosis program and that p53 promotes Bak mediated mitochondrial apoptosis in response to DNA damage.	16	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	16	17	18	19
As expected , p53 caused release of cytochrome c from HEK293 and MCF7 mitochondria ( XREF_FIG ) , whereas the presence of HMGA1 greatly reduced such release resulting in the depletion of cytochrome c from the supernatant fraction .	As expected, p53 caused release of cytochrome c from HEK293 and MCF7 mitochondria (XREF_FIG), whereas the presence of HMGA1 greatly reduced such release resulting in the depletion of cytochrome c from the supernatant fraction.	3	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	3	4	7	9
To identify whether mitochondrial p53 accumulation is associated with heat stress induced early cells apoptosis , we found that knockdown of p53 by P53 siRNA , reduced DeltaPsim loss , release of cytochrome c and caspase-9 and -3 activation , as well as early wave of apoptosis ( XREF_FIG ) .	To identify whether mitochondrial p53 accumulation is associated with heat stress induced early cells apoptosis, we found that knockdown of p53 by P53 siRNA, reduced DeltaPsim loss, release of cytochrome c and caspase-9 and -3 activation, as well as early wave of apoptosis (XREF_FIG).	19	34	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	21	22	32	34
Taken together , these results demonstrate that Bax and Bcl-2 regulate both the p53 induced release of cytochrome-c and AIF from mitochondria as well as the caspase dependent and -independent cell death pathways .	Taken together, these results demonstrate that Bax and Bcl-2 regulate both the p53 induced release of cytochrome-c and AIF from mitochondria as well as the caspase dependent and -independent cell death pathways.	12	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome-c	cytochrome-c	cytochrome-c	13	14	17	18
Recently , Wang and colleagues [ XREF_BIBR ] found that overexpression of human tau , in vivo in transgenic mice and in vitro in N2a cells , decreased p53 levels , decreased mitochondrial cytochrome c release , and decreased caspase-9 and caspase-3 activation .	Recently, Wang and colleagues [XREF_BIBR] found that overexpression of human tau, in vivo in transgenic mice and in vitro in N2a cells, decreased p53 levels, decreased mitochondrial cytochrome c release, and decreased caspase-9 and caspase-3 activation.	10	35	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	overexpression of human tau, in vivo in transgenic mice and in vitro in N2a cells, decreased p53 levels	p53	cytochrome c	cytochrome c	cytochrome c	28	29	33	35
The death effector Bax is a transcriptional target of p53 and plays an essential role on the p53 dependent apoptosis , which triggers mitochondrial cytochrome c release and caspase signaling activation [ XREF_BIBR - XREF_BIBR ] .	The death effector Bax is a transcriptional target of p53 and plays an essential role on the p53 dependent apoptosis, which triggers mitochondrial cytochrome c release and caspase signaling activation [XREF_BIBR - XREF_BIBR].	17	26	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	17	18	24	26
Thereby , p53 induces mitochondrial outer membrane permeabilization and cytochrome c release , finally triggering apoptosis .	Thereby, p53 induces mitochondrial outer membrane permeabilization and cytochrome c release, finally triggering apoptosis.	2	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	2	3	9	11
At a single-cell level , enforced expression of p53 is sufficient to induce Bax translocation and Cytochrome c release .	At a single-cell level, enforced expression of p53 is sufficient to induce Bax translocation and Cytochrome c release.	6	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	expression of p53	p53	Cytochrome c	Cytochrome c	cytochrome c	8	9	16	18
SNAP , an NO donor , induces apoptosis in these cells because it 1 ) increases the p53 and 2 ) induces cytochrome c release and activation of caspase-9 and caspase-3 .	SNAP, an NO donor, induces apoptosis in these cells because it 1) increases the p53 and 2) induces cytochrome c release and activation of caspase-9 and caspase-3.	16	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	17	18	22	24
Because modifications in the p53 DBD ( represented by the p53 R175H and p53 R273H naturally occurring mutants ) were strictly unable to promote cytochrome c release and the fact that p53 L194F , R280K , G245S , R248W , R249S , and R282W missense mutants destroyed any attempt to mediate OMM permeabilization , the integrity of the p53 DBD was declared essential for SST independent apoptosis as well as for transcription independent cell death .	Because modifications in the p53 DBD (represented by the p53 R175H and p53 R273H naturally occurring mutants) were strictly unable to promote cytochrome c release and the fact that p53 L194F, R280K, G245S, R248W, R249S, and R282W missense mutants destroyed any attempt to mediate OMM permeabilization, the integrity of the p53 DBD was declared essential for SST independent apoptosis as well as for transcription independent cell death.	4	26	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	4	5	24	26
Moreover , p53 knockdown blocked cytochrome c release in response to CCN1 and TNFalpha treatment ( XREF_FIG ) .	Moreover, p53 knockdown blocked cytochrome c release in response to CCN1 and TNFalpha treatment (XREF_FIG).	2	7	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	2	3	5	7
Inhibition of p53 blocked cytochrome C release from mitochondria to cytosol and prevented caspase-3 activation .	Inhibition of p53 blocked cytochrome C release from mitochondria to cytosol and prevented caspase-3 activation.	0	6	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome C	cytochrome C	cytochrome C	2	3	4	6
Indeed , we observed that increased mitochondrial Lon rescued Deltapsim and the release of cytochrome C induced by p53 .	Indeed, we observed that increased mitochondrial Lon rescued Deltapsim and the release of cytochrome C induced by p53.	14	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome C	cytochrome C	cytochrome C	18	19	14	16
Furthermore , we found that p53 ( XREF_FIG , lanes 2-5 ) and OKL38 ( XREF_FIG , lanes 6-8 ) induced cytochrome c release in a dose dependent manner .	Furthermore, we found that p53 (XREF_FIG, lanes 2-5) and OKL38 (XREF_FIG, lanes 6-8) induced cytochrome c release in a dose dependent manner.	5	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	5	6	21	23
In addition , p53 may induce cytochrome c release XREF_BIBR .	In addition, p53 may induce cytochrome c release XREF_BIBR.	3	9	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	3	4	6	8
To verify whether the mitochondrial localization of HMGA1 has functional effects , HEK293 and MCF7 cells were transfected with HMGA1b expressing vector and treated with a lethal dose of UV ( 40J/m 2 ) to induce cytochrome c release mediated by p53 activity .	To verify whether the mitochondrial localization of HMGA1 has functional effects, HEK293 and MCF7 cells were transfected with HMGA1b expressing vector and treated with a lethal dose of UV (40J/m 2) to induce cytochrome c release mediated by p53 activity.	36	42	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	41	42	36	38
Additionally , p53 may directly activate the apoptotic machinery by initiating the release of cytochrome c from mitochondria XREF_BIBR .	Additionally, p53 may directly activate the apoptotic machinery by initiating the release of cytochrome c from mitochondria XREF_BIBR.	2	16	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	2	3	14	16
Here , p53 can lead to the release of the effectors Bak and Bax and elicit cytochrome C release [ XREF_BIBR ] .	Here, p53 can lead to the release of the effectors Bak and Bax and elicit cytochrome C release [XREF_BIBR].	2	18	elicit	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome C	cytochrome C	cytochrome C	2	3	16	18
Notably , p53 readily translocates from cytosol to mitochondria to trigger cytochrome C release and subsequent apoptosis in response to genotoxic stresses .	Notably, p53 readily translocates from cytosol to mitochondria to trigger cytochrome C release and subsequent apoptosis in response to genotoxic stresses.	2	13	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 readily translocates from cytosol to mitochondria	p53	cytochrome C	cytochrome C	cytochrome c	2	3	11	13
Apoptotic induction by TPT-CuCl ( 2 ) was shown to mediate in a p53-depedent manner ; loss of p53 impairs the release of cytochrome c and Smac/DIABLO from mitochondria to cytosol .	Apoptotic induction by TPT-CuCl (2) was shown to mediate in a p53-depedent manner; loss of p53 impairs the release of cytochrome c and Smac/DIABLO from mitochondria to cytosol.	16	25	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	loss of p53	p53	cytochrome c	cytochrome c	cytochrome c	18	19	23	25
Furthermore , CCN1 promotes the activation of p53 and p38 MAPK , which mediate enhanced cytochrome c release to amplify the cytotoxicity of TNFalpha .	Furthermore, CCN1 promotes the activation of p53 and p38 MAPK, which mediate enhanced cytochrome c release to amplify the cytotoxicity of TNFalpha.	7	17	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	7	8	15	17
p66Shc-/- MEFs were unable to trigger cytochrome c release , while p53 is activated upon H2O2 treatment , whereas the deficit was restored upon re-expression of p66Shc in these cells , suggesting the involvement of p66Shc in the regulation of p53 induced cytochrome c release .	p66Shc-/- MEFs were unable to trigger cytochrome c release, while p53 is activated upon H2O2 treatment, whereas the deficit was restored upon re-expression of p66Shc in these cells, suggesting the involvement of p66Shc in the regulation of p53 induced cytochrome c release.	38	44	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	40	41	42	44
Several p53 regulated genes , such as Bax , enhance the release of cytochrome c , which interacts with APAF-1 to initiate a protease cascade resulting in the activation of caspase-9 and caspase-3 , from the mitochondria into the cytoplasm .	Several p53 regulated genes, such as Bax, enhance the release of cytochrome c, which interacts with APAF-1 to initiate a protease cascade resulting in the activation of caspase-9 and caspase-3, from the mitochondria into the cytoplasm.	0	20	enhance	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	p53	p53	p53	cytochrome c	cytochrome c, which interacts with APAF-1	cytochrome c	1	2	13	15
It is known that the cytochrome c release mediated by p53 depends on its ability to bind members of the anti-apoptotic Bcl-2 family ( i.e. Bcl-2 and Bcl-xL ) and to inactivate their inhibitory effect exerted on the proapoptotic proteins Bax and Bak .	It is known that the cytochrome c release mediated by p53 depends on its ability to bind members of the anti-apoptotic Bcl-2 family (i.e. Bcl-2 and Bcl-xL) and to inactivate their inhibitory effect exerted on the proapoptotic proteins Bax and Bak.	5	11	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	10	11	5	7
When a combination of p53 and OKL38 was incubated with mitochondria , we found that lower concentrations of p53 and OKL38 together ( XREF_FIG , lanes 10-11 ) induced more efficient cytochrome c release than single protein used at the same concentration , suggesting p53 and OKL38 might cooperate to induce cytochrome c release .	When a combination of p53 and OKL38 was incubated with mitochondria, we found that lower concentrations of p53 and OKL38 together (XREF_FIG, lanes 10-11) induced more efficient cytochrome c release than single protein used at the same concentration, suggesting p53 and OKL38 might cooperate to induce cytochrome c release.	16	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	18	19	31	33
Phosphorylation of p53 mediates the release of cytochrome c by mitochondria and the subsequent activation of caspase 9/3 , inducing the apoptosis [ XREF_BIBR ] .	Phosphorylation of p53 mediates the release of cytochrome c by mitochondria and the subsequent activation of caspase 9/3, inducing the apoptosis [XREF_BIBR].	0	9	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	Phosphorylation of p53	p53	cytochrome c	cytochrome c	cytochrome c	2	3	7	9
The interaction of p53 with anti-apoptotic protein and enhancement of pro apoptotic protein can cause mitochondrial pore opening and cytochrome c release from mitochondria .	The interaction of p53 with anti-apoptotic protein and enhancement of pro apoptotic protein can cause mitochondrial pore opening and cytochrome c release from mitochondria.	1	21	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	3	4	19	21
10 Translocation of p53 to the mitochondrial outer membrane triggers the release of cytochrome c and procaspase-3 activation .	10 Translocation of p53 to the mitochondrial outer membrane triggers the release of cytochrome c and procaspase-3 activation.	1	15	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	Translocation of p53 to the mitochondrial outer membrane	p53	cytochrome c	cytochrome c	cytochrome c	3	4	13	15
Gyp increased the levels of p53 and promoted the release of cytochrome c and the activation of caspase-3 before leading to apoptosis .	Gyp increased the levels of p53 and promoted the release of cytochrome c and the activation of caspase-3 before leading to apoptosis.	0	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	Gyp increased the levels of p53	p53	cytochrome c	cytochrome c	cytochrome c	5	6	11	13
Emerging publications suggest that following stress , a fraction of p53 translocates to mitochondria to induce cytochrome c release and apoptosis .	Emerging publications suggest that following stress, a fraction of p53 translocates to mitochondria to induce cytochrome c release and apoptosis.	8	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	10	11	16	18
The p21-22 bands have been determined to be p53 cleavage products that have affinity for mitochondria and aid initiating cytochrome c release .	The p21-22 bands have been determined to be p53 cleavage products that have affinity for mitochondria and aid initiating cytochrome c release.	8	21	initiating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	8	9	19	21
Cytosolic p53 can in turn inhibit anti-apoptotic Bcl-xL and promote cytochrome c release .	Cytosolic p53 can in turn inhibit anti-apoptotic Bcl-xL and promote cytochrome c release.	0	12	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	1	2	10	12
OKL38 and p53 Induce Cytochrome c Release from Purified Mitochondria in vitro .	OKL38 and p53 Induce Cytochrome c Release from Purified Mitochondria in vitro.	0	6	Induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Cytochrome c	Cytochrome c	Cytochrome c	2	3	4	6
This particular function of p53 can trigger the release of cytochrome c from the mitochondria , the activation of caspases , and death through a classical apoptotic mechanism .	This particular function of p53 can trigger the release of cytochrome c from the mitochondria, the activation of caspases, and death through a classical apoptotic mechanism.	2	12	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	4	5	10	12
This mechanism involves the downstream TP53 target genes TP53 induced glycolysis and apoptosis regulator ( TIGAR ) and synthesis of cytochrome c oxidase-2 ( SCO2 ) .	This mechanism involves the downstream TP53 target genes TP53 induced glycolysis and apoptosis regulator (TIGAR) and synthesis of cytochrome c oxidase-2 (SCO2).	5	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TP53	TP53	TP53	cytochrome c	cytochrome c	cytochrome c	5	6	20	22
Importantly , recombinant p53 induces MOMP and release of cytochrome c from isolated healthy mitochondria within minutes , confirming the direct effect of p53 on MOMP XREF_BIBR ( XREF_FIG ) .	Importantly, recombinant p53 induces MOMP and release of cytochrome c from isolated healthy mitochondria within minutes, confirming the direct effect of p53 on MOMP XREF_BIBR (XREF_FIG).	2	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	3	4	9	11
p53 induced cytochrome c release occurs through a mechanism involving Bax ' s integral insertion into the outer mitochondrial membrane .	p53 induced cytochrome c release occurs through a mechanism involving Bax 's integral insertion into the outer mitochondrial membrane.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	0	1	2	4
It has recently been shown that , when activated , a fraction of p53 translocates to mitochondria , causing cytochrome c release .	It has recently been shown that, when activated, a fraction of p53 translocates to mitochondria, causing cytochrome c release.	11	21	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	13	14	19	21
OGDR induced p53 translocation to mitochondria and association with Cyp-D , causing mitochondrial depolarization , cytochrome C release and reactive oxygen species production .	OGDR induced p53 translocation to mitochondria and association with Cyp-D, causing mitochondrial depolarization, cytochrome C release and reactive oxygen species production.	0	17	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	OGDR induced p53	p53	cytochrome C	cytochrome C	cytochrome c	2	3	15	17
61 Although p53 is capable of interacting directly or indirectly with these Bcl2 family members and induce cytochrome c release , it is yet unknown whether ubiquitinated p53 is required for these events to occur in vivo .	61 Although p53 is capable of interacting directly or indirectly with these Bcl2 family members and induce cytochrome c release, it is yet unknown whether ubiquitinated p53 is required for these events to occur in vivo.	2	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	2	3	17	19
Bcl-x ( L ) significantly decreased the p53 induced cytochrome c release , but not the apoptin triggered one .	Bcl-x (L) significantly decreased the p53 induced cytochrome c release, but not the apoptin triggered one.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	7	8	9	11
p53 translocates from cytosol to mitochondria to trigger cytochrome C release and subsequent apoptosis in response to genotoxic stresses .	p53 translocates from cytosol to mitochondria to trigger cytochrome C release and subsequent apoptosis in response to genotoxic stresses.	0	10	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 translocates from cytosol to mitochondria	p53	cytochrome C	cytochrome C	cytochrome c	0	1	8	10
GSK-3beta is involved in multiple cellular processes ; GSK-3beta inhibition reduces infarct size in adult stroke models and further interacted with pro apoptotic transcription factors , such as p53 , which upregulates cytochrome C release and Caspase-3 activity , providing more evidence of GSK-3beta ' s pro apoptotic role following brain injury .	GSK-3beta is involved in multiple cellular processes; GSK-3beta inhibition reduces infarct size in adult stroke models and further interacted with pro apoptotic transcription factors, such as p53, which upregulates cytochrome C release and Caspase-3 activity, providing more evidence of GSK-3beta 's pro apoptotic role following brain injury.	24	34	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome C	cytochrome C	cytochrome C	28	29	32	34
Therefore , downregulation or upregulation of Bcl-2 or p53 , respectively , in ETBO treated cancer cells could promote the release of mitochondrial cytochrome c and activate the caspase cascade ; p53 activation can trigger cytochrome c release into the cytoplasm via the Bcl-2-mediated pathway , and the released cytochrome c activates caspase-3 .	Therefore, downregulation or upregulation of Bcl-2 or p53, respectively, in ETBO treated cancer cells could promote the release of mitochondrial cytochrome c and activate the caspase cascade; p53 activation can trigger cytochrome c release into the cytoplasm via the Bcl-2-mediated pathway, and the released cytochrome c activates caspase-3.	31	37	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	31	32	35	37
Intrinsic apoptosis is triggered by cytotoxic stress resulting in the activation of p53 , which promotes mitochondrial cytochrome c release into the cytosol .	Intrinsic apoptosis is triggered by cytotoxic stress resulting in the activation of p53, which promotes mitochondrial cytochrome c release into the cytosol.	10	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	12	13	17	19
Thus , activated p66Shc is necessary for the stress activated , p53 mediated release of cytochrome c from the mitochondrial membrane that triggers apoptosis XREF_BIBR , XREF_BIBR , XREF_BIBR .	Thus, activated p66Shc is necessary for the stress activated, p53 mediated release of cytochrome c from the mitochondrial membrane that triggers apoptosis XREF_BIBR, XREF_BIBR, XREF_BIBR.	11	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	11	12	15	17
In transcription independent p53 apoptosis pathways , p53 can be translocated to mitochondria and interacted with Bcl-XL to induce the release of cytochrome c [ XREF_BIBR ] .	In transcription independent p53 apoptosis pathways, p53 can be translocated to mitochondria and interacted with Bcl-XL to induce the release of cytochrome c [XREF_BIBR].	7	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 can be translocated to mitochondria	p53	cytochrome c	cytochrome c	cytochrome c	7	8	22	24
Both pin1 (-/-) and pin1 (-/-) p53 (-/-) MEFs were enhanced the release of cytochrome c from the mitochondria , which might induce apoptosis .	Both pin1 (-/-) and pin1 (-/-) p53 (-/-) MEFs were enhanced the release of cytochrome c from the mitochondria, which might induce apoptosis.	1	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	6	7	14	16
Apoptosis stimulating of p53 protein 2 ( ASPP2 ) can promote cell apoptosis by enhancing binding of p53 to the promoters of the pro apoptotic genes BAX and PIG-3 , upregulating their expression [ XREF_BIBR ] .	Apoptosis stimulating of p53 protein 2 (ASPP2) can promote cell apoptosis by enhancing binding of p53 to the promoters of the pro apoptotic genes BAX and PIG-3, upregulating their expression [XREF_BIBR].	1	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	7	8	17	18
p63 activity is regulated by proteins such as ASPP1 and ASPP2 , which also modulate p53 activity .	p63 activity is regulated by proteins such as ASPP1 and ASPP2, which also modulate p53 activity.	5	16	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	10	11	15	16
ASPP2 selectively stimulates the p53 ( and p73 and p63 ) transactivation of target genes , in addition to mediating p53 independent functions and inhibiting cell growth .	ASPP2 selectively stimulates the p53 (and p73 and p63) transactivation of target genes, in addition to mediating p53 independent functions and inhibiting cell growth.	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	0	1	4	5
ASPP2 inhibition causes enhanced degradation of p53 , in a way similar to DNA tumor viruses , thereby decreasing apoptotic activity , which may explain the increased risk of GC associated with cagA + H. pylori infection .	ASPP2 inhibition causes enhanced degradation of p53, in a way similar to DNA tumor viruses, thereby decreasing apoptotic activity, which may explain the increased risk of GC associated with cagA + H. pylori infection.	0	7	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	0	1	6	7
An increase in nucleostemin expression and a reduction in ASPP2 caused the inhibition of the cell apoptotic function of p53 .	An increase in nucleostemin expression and a reduction in ASPP2 caused the inhibition of the cell apoptotic function of p53.	7	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	9	10	19	20
One explanatory mechanism in this aspect may be the interaction of CagA with the protein ASPP2 , which normally activates p53 to induce apoptosis .	One explanatory mechanism in this aspect may be the interaction of CagA with the protein ASPP2, which normally activates p53 to induce apoptosis.	11	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	15	16	20	21
A study suggested that ASPP is a crucial regulatory protein for p53 in vivo and that ASPP1 and ASPP2 may enhance p53 dependent apoptosis through increasing the vitality of the original apoptosis gene .	A study suggested that ASPP is a crucial regulatory protein for p53 in vivo and that ASPP1 and ASPP2 may enhance p53 dependent apoptosis through increasing the vitality of the original apoptosis gene.	16	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	18	19	21	22
ASPP2 overexpression induces CHOP in a p53- or p73 independent manner ; however , CHOP is still involved in ASPP2 overexpression induced apoptosis in hepatoma cells .	ASPP2 overexpression induces CHOP in a p53- or p73 independent manner; however, CHOP is still involved in ASPP2 overexpression induced apoptosis in hepatoma cells.	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2 overexpression	aspp2	p53-	p53-	p53-	0	1	6	7
ASPP2 can specifically stimulate the apoptotic function of p53 but not cell cycle arrest , but the mechanism of enhancing the activation of pro apoptotic genes over cell cycle arrest genes remains unknown .	ASPP2 can specifically stimulate the apoptotic function of p53 but not cell cycle arrest, but the mechanism of enhancing the activation of pro apoptotic genes over cell cycle arrest genes remains unknown.	0	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	0	1	8	9
We show here that ASPP1 and ASPP2 also induce apoptosis independently of p53 .	We show here that ASPP1 and ASPP2 also induce apoptosis independently of p53.	4	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	6	7	12	13
We have previously shown that ASPP1 and ASPP2 are specific activators of p53 ; one mechanism by which wild-type p53 is tolerated in human breast carcinomas is through loss of ASPP activity .	We have previously shown that ASPP1 and ASPP2 are specific activators of p53; one mechanism by which wild-type p53 is tolerated in human breast carcinomas is through loss of ASPP activity.	5	13	are specific activators	Positive_activation_copula_1	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	7	8	12	13
53BP2 , a p53 interacting protein , enhances p53 transactivation , impedes cell cycle progression , and promotes apoptosis through unknown mechanisms .	53BP2, a p53 interacting protein, enhances p53 transactivation, impedes cell cycle progression, and promotes apoptosis through unknown mechanisms.	0	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	53BP2	53BP2	53BP2	p53	p53	p53	0	1	8	9
Similarly , the coexpression of ASPP2 and HRASV12 or KRASV12 stimulated the transcriptional activity of p53 by around 30-35-fold .	Similarly, the coexpression of ASPP2 and HRASV12 or KRASV12 stimulated the transcriptional activity of p53 by around 30-35-fold.	3	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	coexpression of ASPP2	aspp2	p53	p53	p53	5	6	15	16
Furthermore , ASPP2 is known to promote the apoptotic function of p53 , p63 and p73 XREF_BIBR , XREF_BIBR .	Furthermore, ASPP2 is known to promote the apoptotic function of p53, p63 and p73 XREF_BIBR, XREF_BIBR.	2	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	2	3	11	12
Additionally , we demonstrate that ASPP1 and ASPP2 cooperate with oncogenic RAS to enhance the transcription and apoptotic function of p53 in cancer cells .	Additionally, we demonstrate that ASPP1 and ASPP2 cooperate with oncogenic RAS to enhance the transcription and apoptotic function of p53 in cancer cells.	5	21	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	7	8	20	21
By binding p53 , ASPP2 mediates the transactivation action of p53 on pro apoptotic genes XREF_BIBR .	By binding p53, ASPP2 mediates the transactivation action of p53 on pro apoptotic genes XREF_BIBR.	4	11	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	4	5	10	11
In contrast , Mdm and mdmX were shown to block the p53 apoptotic effect that was induced by ASPP1 and ASPP2 .	In contrast, Mdm and mdmX were shown to block the p53 apoptotic effect that was induced by ASPP1 and ASPP2.	11	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	20	21	11	12
The ankyin-repeat and SH3 domains of ASPP2 bind the p53 core domain [ XREF_BIBR ] and modulate p53 function [ XREF_BIBR - XREF_BIBR ] .	The ankyin-repeat and SH3 domains of ASPP2 bind the p53 core domain [XREF_BIBR] and modulate p53 function [XREF_BIBR - XREF_BIBR].	3	18	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	SH3 domains of ASPP2 bind the p53	aspp2	p53	p53	p53	6	7	17	18
16 We thus tested whether ASPP1 and ASPP2 cooperate with RAS to stimulate the apoptotic function of p53 .	16 We thus tested whether ASPP1 and ASPP2 cooperate with RAS to stimulate the apoptotic function of p53.	5	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	7	8	17	18
Additional evidence suggests that p53 independent pathway may also be modulated by ASPP2 .	Additional evidence suggests that p53 independent pathway may also be modulated by ASPP2.	4	13	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	12	13	4	5
Thus , ASPP2 overexpression for 24 hours transiently induces apoptosis by enhancing the transactivation activation of p53 .	Thus, ASPP2 overexpression for 24 hours transiently induces apoptosis by enhancing the transactivation activation of p53.	2	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2 overexpression	aspp2	p53	p53	p53	2	3	16	17
ASPP1 and ASPP2 enhance the proapoptotic function of p53 by selectively promoting the binding of p53 to proapoptotic gene targets such as BAX , PUMA , and PIG3 .	ASPP1 and ASPP2 enhance the proapoptotic function of p53 by selectively promoting the binding of p53 to proapoptotic gene targets such as BAX, PUMA, and PIG3.	0	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	2	3	8	9
ASPP1 and ASPP2 enhance the ability of p53 to induce apoptosis [ XREF_BIBR , XREF_BIBR ] , iASPP is an inhibitory member of ASPP , which inhibits p53 dependent apoptosis [ XREF_BIBR ] .	ASPP1 and ASPP2 enhance the ability of p53 to induce apoptosis [XREF_BIBR, XREF_BIBR], iASPP is an inhibitory member of ASPP, which inhibits p53 dependent apoptosis [XREF_BIBR].	0	8	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	2	3	7	8
Here , ASPP2 overexpression for 24 hours transiently induced apoptosis in hepatoma cells by enhancing the transactivation of p53 on pro apoptotic gene promoters .	Here, ASPP2 overexpression for 24 hours transiently induced apoptosis in hepatoma cells by enhancing the transactivation of p53 on pro apoptotic gene promoters.	2	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2 overexpression	aspp2	p53	p53	p53	2	3	18	19
ASPP1 and ASPP2 activate P53 through induction of pro apoptotic genes such as BAX and PIG3 but iASPP acts as an activator of P53 .	ASPP1 and ASPP2 activate P53 through induction of pro apoptotic genes such as BAX and PIG3 but iASPP acts as an activator of P53.	0	5	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	P53	P53	P53	2	3	4	5
We recently showed that ASPP1 and ASPP2 stimulate the apoptotic function of p53 .	We recently showed that ASPP1 and ASPP2 stimulate the apoptotic function of p53.	4	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	6	7	12	13
Thus , although ASPP2 overexpression induces CHOP expression in a p53- or p73 independent manner , CHOP is still involved in ASPP2 induced p53- or p73 mediated apoptosis .	Thus, although ASPP2 overexpression induces CHOP expression in a p53- or p73 independent manner, CHOP is still involved in ASPP2 induced p53- or p73 mediated apoptosis.	19	27	induced	Positive_early_activation	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53-	p53-	p53-	21	22	23	24
ASPP1 and ASPP2 cooperate with RAS to enhance the transcriptional activity of p53 .	ASPP1 and ASPP2 cooperate with RAS to enhance the transcriptional activity of p53.	0	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	2	3	12	13
The apoptosis stimulating p53 proteins , ASPP1 and ASPP2 , are the first two common activators of the p53 protein family that selectively enable the latter to regulate specific apoptotic target genes , which facilitates yes yet unknown mechanisms for discrimination between cell cycle arrest and apoptosis .	The apoptosis stimulating p53 proteins, ASPP1 and ASPP2, are the first two common activators of the p53 protein family that selectively enable the latter to regulate specific apoptotic target genes, which facilitates yes yet unknown mechanisms for discrimination between cell cycle arrest and apoptosis.	1	9	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	8	9	3	4
TP53BP2 promotes transcription of pro apoptotic molecules via enhances the DNA binding and trans activation function of TP53 on the promoter region of the related genes .	TP53BP2 promotes transcription of pro apoptotic molecules via enhances the DNA binding and trans activation function of TP53 on the promoter region of the related genes.	0	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TP53BP2	TP53BP2	TP53BP2	TP53	TP53	TP53	0	1	17	18
As expected , coexpression of ASPP1 or ASPP2 with p53 enhanced the transcriptional activity of p53 on the Bax promoter-luciferase reporter by 3 and 10 times , respectively .	As expected, coexpression of ASPP1 or ASPP2 with p53 enhanced the transcriptional activity of p53 on the Bax promoter-luciferase reporter by 3 and 10 times, respectively.	3	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	coexpression of ASPP1 or ASPP2	aspp2	p53	p53	p53	7	8	15	16
Expression of either ASPP1 or ASPP2 stimulates the proapoptotic function of wild-type p53 by increasing p53 dependent induction of apoptotic effectors such as Bax and PIG3 , whereas expression of nonapoptotic proteins such as p21 Waf1 was much less affected .	Expression of either ASPP1 or ASPP2 stimulates the proapoptotic function of wild-type p53 by increasing p53 dependent induction of apoptotic effectors such as Bax and PIG3, whereas expression of nonapoptotic proteins such as p21 Waf1 was much less affected.	0	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	Expression of either ASPP1 or ASPP2	aspp2	p53	p53	p53	5	6	12	13
Biochemical and genetic evidences have shown that ASPP1 and ASPP2 activate the apoptotic but not the cell-cycle arrest function of p53 [ XREF_BIBR ] .	Biochemical and genetic evidences have shown that ASPP1 and ASPP2 activate the apoptotic but not the cell-cycle arrest function of p53 [XREF_BIBR].	7	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	9	10	20	21
These results suggest that MAPK phosphorylation of ASPP2 Ser827 is necessary for Raf CAAX to stimulate the full transcriptional activity of p53 via ASPP2 .	These results suggest that MAPK phosphorylation of ASPP2 Ser827 is necessary for Raf CAAX to stimulate the full transcriptional activity of p53 via ASPP2.	4	23	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	MAPK phosphorylation of ASPP2 Ser827	aspp2	p53	p53	p53	7	8	21	22
ASPP1 and ASPP2 enhance the apoptotic function of p53 , whereas iASPP inhibits p53 dependent apoptosis [ XREF_BIBR - XREF_BIBR ] .	ASPP1 and ASPP2 enhance the apoptotic function of p53, whereas iASPP inhibits p53 dependent apoptosis [XREF_BIBR - XREF_BIBR].	0	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	2	3	8	9
Among other cellular factors , ASPP2 protein ( apoptosis stimulating protein of p53 ) , which normally activates p53 , was identified to regulate p53 in H. pylori infected cells [ XREF_BIBR ] .	Among other cellular factors, ASPP2 protein (apoptosis stimulating protein of p53), which normally activates p53, was identified to regulate p53 in H. pylori infected cells [XREF_BIBR].	5	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	5	6	18	19
ASPP1 and ASPP2 enhance the ability of p53 to stimulate specifically the expression of pro apoptotic target genes but not genes involved in cell-cycle arrest ( Samuels-Lev et al , 2001 ; Bergamaschi et al , 2004 ) , whereas iASPP inhibits p53 mediated apoptosis ( Bergamaschi et al , 2003b ) .	ASPP1 and ASPP2 enhance the ability of p53 to stimulate specifically the expression of pro apoptotic target genes but not genes involved in cell-cycle arrest (Samuels-Lev et al, 2001; Bergamaschi et al, 2004), whereas iASPP inhibits p53 mediated apoptosis (Bergamaschi et al, 2003b).	0	8	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	2	3	7	8
TP53BP2 enhances TP53 mediated transcriptional activation and has been proposed to play a key role in the response to DNA damage and checkpoint signaling during mitosis [ XREF_BIBR ] .	TP53BP2 enhances TP53 mediated transcriptional activation and has been proposed to play a key role in the response to DNA damage and checkpoint signaling during mitosis [XREF_BIBR].	0	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TP53BP2	TP53BP2	TP53BP2	TP53	TP53	TP53	0	1	2	3
Interestingly , mounting evidence is also accumulating showing that ASPP2 promotes p53 independent cell death and growth inhibition XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Interestingly, mounting evidence is also accumulating showing that ASPP2 promotes p53 independent cell death and growth inhibition XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	9	12	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	9	10	11	12
Our study confirms that ASPP2 overexpression induces apoptotic cell death in HepG2 and PHCs by enhancing p53 activity .	Our study confirms that ASPP2 overexpression induces apoptotic cell death in HepG2 and PHCs by enhancing p53 activity.	4	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2 overexpression	aspp2	p53	p53	p53	4	5	16	17
In cancer cells , ASPP1 and ASPP2 cooperate with oncogenic RAS to enhance the transcription and apoptotic function of p53 .	In cancer cells, ASPP1 and ASPP2 cooperate with oncogenic RAS to enhance the transcription and apoptotic function of p53.	4	20	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	6	7	19	20
From a functional point of view , ASPP1 and ASPP2 significantly enhance p53 mediated transactivation of pro apoptotic target genes such as BAX and PIG-3 ( p53 inducible gene 3 ) , whereas ASPP1 and ASPP2 enhance p53 dependent transactivation of p53-target genes implicated in cell cycle arrest to a lesser degree .	From a functional point of view, ASPP1 and ASPP2 significantly enhance p53 mediated transactivation of pro apoptotic target genes such as BAX and PIG-3 (p53 inducible gene 3), whereas ASPP1 and ASPP2 enhance p53 dependent transactivation of p53-target genes implicated in cell cycle arrest to a lesser degree.	7	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	9	10	12	13
Neither ASPP2 , a p53 interacting protein reported to specifically stimulate p53 transcriptional activity on apoptosis related promoters , nor DNA damage resulted in p53 utilization of isolated DBS of apoptosis related genes .	Neither ASPP2, a p53 interacting protein reported to specifically stimulate p53 transcriptional activity on apoptosis related promoters, nor DNA damage resulted in p53 utilization of isolated DBS of apoptosis related genes.	0	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	1	2	11	12
A central function of TP53BP2 is to impede cell cycle progression at G2/M and stimulate apoptosis by enhancing the DNA binding and transactivation function of p53 on the promoters of genes involved in these processes .	A central function of TP53BP2 is to impede cell cycle progression at G2/M and stimulate apoptosis by enhancing the DNA binding and transactivation function of p53 on the promoters of genes involved in these processes.	2	26	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TP53BP2	TP53BP2	TP53BP2	p53	p53	p53	4	5	25	26
Alternatively , ectopic expression of either ASPP1 or ASPP2 enhances p53 dependent apoptosis , and depletion of ASPP1 and/or ASPP2 suppresses the ability of p53 to induce apoptosis .	Alternatively, ectopic expression of either ASPP1 or ASPP2 enhances p53 dependent apoptosis, and depletion of ASPP1 and/or ASPP2 suppresses the ability of p53 to induce apoptosis.	15	25	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	19	20	24	25
ASPP2 proteins promote the apoptotic function of p53 ; however , Bcl-2 anti-apoptotic proteins can combine with Ank-SH3 amino acids ( the structural region of ASPP2 that is mainly responsible for regulating apoptosis ) [ XREF_BIBR ] .	ASPP2 proteins promote the apoptotic function of p53; however, Bcl-2 anti-apoptotic proteins can combine with Ank-SH3 amino acids (the structural region of ASPP2 that is mainly responsible for regulating apoptosis) [XREF_BIBR].	0	8	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	0	1	7	8
The altered expression of p53 activators such as ASPP1 and ASPP2 and inhibitors of p53 such as iASPP during tumour development in different tissue and cell types may explain the variation in p53 mutation rates in different tumour types .	The altered expression of p53 activators such as ASPP1 and ASPP2 and inhibitors of p53 such as iASPP during tumour development in different tissue and cell types may explain the variation in p53 mutation rates in different tumour types.	4	11	activators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	10	11	4	5
ASPP2 triggers apoptosis in a p53 independent manner .	ASPP2 triggers apoptosis in a p53 independent manner.	0	7	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	0	1	5	6
53BP2 was initially identified as a protein interacting with p53 in a yeast two-hybrid screen and subsequently shown to enhance p53 transcriptional transactivation and induce apoptosis when transiently overexpressed in cell lines .	53BP2 was initially identified as a protein interacting with p53 in a yeast two-hybrid screen and subsequently shown to enhance p53 transcriptional transactivation and induce apoptosis when transiently overexpressed in cell lines.	0	22	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	53BP2	53BP2	53BP2	p53	p53	p53	0	1	20	21
Furthermore , it was shown that both ASPP1 and ASPP2 can stimulate the apoptotic function not only of p53 but also that of the p53 homologous proteins p63 and p73 .	Furthermore, it was shown that both ASPP1 and ASPP2 can stimulate the apoptotic function not only of p53 but also that of the p53 homologous proteins p63 and p73.	7	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	9	10	18	19
iASPP is one of the most evolutionarily conserved inhibitors of p53 , whereas ASPP1 and ASPP2 are activators of p53 .	iASPP is one of the most evolutionarily conserved inhibitors of p53, whereas ASPP1 and ASPP2 are activators of p53.	13	20	are activators	Positive_activation_copula_1	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	15	16	19	20
In contrast to iASPP , ASPP1 and ASPP2 activate p53 to stimulate specifically the expression of pro apoptotic target genes .	In contrast to iASPP, ASPP1 and ASPP2 activate p53 to stimulate specifically the expression of pro apoptotic target genes.	5	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	7	8	9	10
ASPP2 selectively stimulates p53 transactivation of target genes [ XREF_BIBR ] but also mediates p53 independent functions [ XREF_BIBR , XREF_BIBR ] .	ASPP2 selectively stimulates p53 transactivation of target genes [XREF_BIBR] but also mediates p53 independent functions [XREF_BIBR, XREF_BIBR].	0	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	0	1	3	4
Last but not least , ERS associated apoptotic programme is set off by c-Jun N-terminal kinase ( JNK ) as the effect of IRE1alpha complexed with TNF-receptor-associated factor 2 ( TRAF2 ) activation of apoptosis-signal-regulating kinase 1 ( ASK1 ) [ XREF_BIBR , XREF_BIBR ] .	Last but not least, ERS associated apoptotic programme is set off by c-Jun N-terminal kinase (JNK) as the effect of IRE1alpha complexed with TNF-receptor-associated factor 2 (TRAF2) activation of apoptosis-signal-regulating kinase 1 (ASK1) [XREF_BIBR, XREF_BIBR].	30	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	apoptosis-signal-regulating kinase 1	apoptosis-signal-regulating kinase 1	apoptosis-signal-regulating kinase 1	30	31	34	37
On the other hand , TRAF-2 can activate ASK-1 and JNK pathway via an ROS dependent manner and induce apoptotic signaling cascades [ XREF_BIBR ] .	On the other hand, TRAF-2 can activate ASK-1 and JNK pathway via an ROS dependent manner and induce apoptotic signaling cascades [XREF_BIBR].	5	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF-2	TRAF-2	TRAF-2	ASK-1	ASK-1	ASK-1	5	6	8	9
Taken together , our data suggest that AIP1 is a novel transducer in TNF induced TRAF2 dependent activation of ASK1 that mediates a balance between JNK versus NF-kappaB signaling .	Taken together, our data suggest that AIP1 is a novel transducer in TNF induced TRAF2 dependent activation of ASK1 that mediates a balance between JNK versus NF-kappaB signaling.	13	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAF2	TNF induced TRAF2	traf2	ASK1	ASK1	ask1	15	16	19	20
A PERIOD like domain ( amino acids 591-719 ) of AIP1 binds to the intact RING finger of TRAF2 , and specifically enhances TRAF2 induced ASK1 activation .	A PERIOD like domain (amino acids 591-719) of AIP1 binds to the intact RING finger of TRAF2, and specifically enhances TRAF2 induced ASK1 activation.	23	26	induced	Positive_early_activation	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	23	24	25	26
However , the precise mechanisms by which Trx inhibits and TRAF2 and TRAF6 activate ASK1 have not been elucidated fully .	However, the precise mechanisms by which Trx inhibits and TRAF2 and TRAF6 activate ASK1 have not been elucidated fully.	10	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	10	11	14	15
TNF-alpha receptor associated factor 2 ( TRAF2 ) and TRAF6 positively regulate ASK1 activity , promoting cell death , whereas protein phosphatase 5 can negatively regulate ASK1 activity , resulting in ASK1 dephosphorylation [ XREF_BIBR ] .	TNF-alpha receptor associated factor 2 (TRAF2) and TRAF6 positively regulate ASK1 activity, promoting cell death, whereas protein phosphatase 5 can negatively regulate ASK1 activity, resulting in ASK1 dephosphorylation [XREF_BIBR].	4	13	positively regulate	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	6	7	12	13
ROS oxidation of thioredoxin ( TRX ) causes dissociation from the MAP3K apoptosis signaling kinase 1 ( ASK1 ) , which allows for TNF receptor associated factor 2 ( TRAF2 ) activation of ASK1 and leads to JNK and p38 signaling .	ROS oxidation of thioredoxin (TRX) causes dissociation from the MAP3K apoptosis signaling kinase 1 (ASK1), which allows for TNF receptor associated factor 2 (TRAF2) activation of ASK1 and leads to JNK and p38 signaling.	29	34	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	29	30	33	34
In response to ER stress , IRE1 is activated by autophosphorylation , and then recruits TRAF2 ( tumor necrosis factor receptor associated factor 2 ) , which subsequently activates ASK1 leading to JNK activation .	In response to ER stress, IRE1 is activated by autophosphorylation, and then recruits TRAF2 (tumor necrosis factor receptor associated factor 2), which subsequently activates ASK1 leading to JNK activation.	14	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	15	16	29	30
IRE1alpha and TRAF2 activates ASK1 ( apoptosis signal regulating kinase 1 ) , which subsequently promotes activation and phosphorylation of c-Jun-N terminal kinase ( JNK ) [ XREF_BIBR ] .	IRE1alpha and TRAF2 activates ASK1 (apoptosis signal regulating kinase 1), which subsequently promotes activation and phosphorylation of c-Jun-N terminal kinase (JNK) [XREF_BIBR].	0	23	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TRAF2	TRAF2	traf2	ASK1	ASK1 (apoptosis signal regulating kinase 1), which subsequently promotes activation and phosphorylation of c-Jun-N terminal kinase	ask1	2	3	4	5
Expression of CIIA suppressed UV-, H 2 O 2 -, and TRAF2 stimulated ASK1 activities in the cells .	Expression of CIIA suppressed UV-, H 2 O 2 -, and TRAF2 stimulated ASK1 activities in the cells.	11	14	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	11	12	13	14
Aggregation with its ligand recruits TRAF2 , which can activate ASK1 , resulting in activation of the JNK and SAPK and p38 MAPK pathways XREF_BIBR .	Aggregation with its ligand recruits TRAF2, which can activate ASK1, resulting in activation of the JNK and SAPK and p38 MAPK pathways XREF_BIBR.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	5	6	10	11
TRAF2 and TRAF6 promote ASK1 dependent cell death and inflammatory cytokine production downstream of the TNF-alpha receptor and Toll like receptor 4 ( TLR4 ; a receptor for LPS ) , respectively .	TRAF2 and TRAF6 promote ASK1 dependent cell death and inflammatory cytokine production downstream of the TNF-alpha receptor and Toll like receptor 4 (TLR4; a receptor for LPS), respectively.	0	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	0	1	4	5
During TNF-a mediated apoptotic signaling , it appears that ROS dependent activation of ASK1 by TNF-receptor-associated factor 2 ( TRAF-2 ) leads to the subsequent stimulation of JNK-module and apoptosis .	During TNF-a mediated apoptotic signaling, it appears that ROS dependent activation of ASK1 by TNF-receptor-associated factor 2 (TRAF-2) leads to the subsequent stimulation of JNK-module and apoptosis.	11	18	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TNF-receptor-associated factor 2	TNF-receptor-associated factor 2	TNF-receptor-associated factor 2	ASK1	ASK1	ASK1	15	18	13	14
Consistent with our previous findings that TRAF2 and TRAF6 activate ASK1 , H ( 2 ) O ( 2 )-induced ASK1 activation and cell death were strongly reduced in the cells derived from Traf2-/- and Traf6-/- mice .	Consistent with our previous findings that TRAF2 and TRAF6 activate ASK1, H (2) O (2)-induced ASK1 activation and cell death were strongly reduced in the cells derived from Traf2-/- and Traf6-/- mice.	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	6	7	10	11
Likewise , in tumor necrosis factor TNFalpha signaling , ROS generation is needed for the activation of ASK1 by TRAF2 and sustained JNK and p38 activation for the induction of apoptosis [ XREF_BIBR ] .	Likewise, in tumor necrosis factor TNFalpha signaling, ROS generation is needed for the activation of ASK1 by TRAF2 and sustained JNK and p38 activation for the induction of apoptosis [XREF_BIBR].	12	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	19	20	17	18
TRAF2 activates the apoptosis signaling kinase 1 ( ASK1 ) , a mitogen activated protein kinase kinase kinase ( MAPKKK ) .	TRAF2 activates the apoptosis signaling kinase 1 (ASK1), a mitogen activated protein kinase kinase kinase (MAPKKK).	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	0	1	8	9
Players involved in the cell death response include ( i ) PERK and eIF2alpha dependent induction of the pro apoptotic transcriptional factor CHOP ; ( ii ) IRE1 mediated activation of TRAF2 ( tumor necrosis factor receptor associated factor 2 ) , which stimulates the ASK1 ( apoptosis signal regulating kinase 1 )/JNK ( c-Jun amino terminal kinase ) kinase cascade , and ( iii ) Bax and Bcl2 regulated Ca 2+ release from the ER .	Players involved in the cell death response include (i) PERK and eIF2alpha dependent induction of the pro apoptotic transcriptional factor CHOP; (ii) IRE1 mediated activation of TRAF2 (tumor necrosis factor receptor associated factor 2), which stimulates the ASK1 (apoptosis signal regulating kinase 1)/JNK (c-Jun amino terminal kinase) kinase cascade, and (iii) Bax and Bcl2 regulated Ca 2+ release from the ER.	27	60	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	IRE1 mediated activation of TRAF2	traf2	ASK1	ASK1	ask1	31	32	45	46
Ectopic ASK1 was stimulated by an exposure of the transfected cells to UV light or H 2 O 2 or by coexpression of TRAF2 ( XREF_FIG A ) .	Ectopic ASK1 was stimulated by an exposure of the transfected cells to UV light or H 2 O 2 or by coexpression of TRAF2 (XREF_FIG A).	0	24	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF2	coexpression of TRAF2	traf2	ASK1	ASK1	ask1	23	24	1	2
Activation of PARP1 can stimulate JNK via receptor interacting protein 1 ( RIP1 ) and TNF receptor associated factor 2 ( TRAF2 ) activation of ASK1 .	Activation of PARP1 can stimulate JNK via receptor interacting protein 1 (RIP1) and TNF receptor associated factor 2 (TRAF2) activation of ASK1.	21	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	21	22	25	26
Previous studies have shown that TRAF2 stimulates TNFalpha induced JNK activation through TRAF2 interaction with ASK1 and TRAF2 mediated ASK1 activation .	Previous studies have shown that TRAF2 stimulates TNFalpha induced JNK activation through TRAF2 interaction with ASK1 and TRAF2 mediated ASK1 activation.	13	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	17	18	19	20
Formation of PINs indicates that Ack1 mediated AKT activation could be an earlier event in this neoplastic progression as an alternative to PTEN loss observed in mouse models of prostate cancer .	Formation of PINs indicates that Ack1 mediated AKT activation could be an earlier event in this neoplastic progression as an alternative to PTEN loss observed in mouse models of prostate cancer.	5	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	5	6	7	8
Another example relates to a non membrane tyrosine kinase called Acetate Kinase ( Ack1 ) that is recruited by the upstream receptors and activates AKT through Tyr 176 phosphorylation , favoring the development of PCa [ XREF_BIBR ] .	Another example relates to a non membrane tyrosine kinase called Acetate Kinase (Ack1) that is recruited by the upstream receptors and activates AKT through Tyr 176 phosphorylation, favoring the development of PCa [XREF_BIBR].	11	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	13	14	24	25
Neoplasia observed in PB-Ack1 mice could be due to the combined effect of Ack1 mediated AKT , AR and Wwox Tyr phosphorylations .	Neoplasia observed in PB-Ack1 mice could be due to the combined effect of Ack1 mediated AKT, AR and Wwox Tyr phosphorylations.	11	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	13	14	15	16
ACK1 activation results in tyrosine phosphorylation and apparent activation of AKT in a PI3K independent mechanism XREF_BIBR .	ACK1 activation results in tyrosine phosphorylation and apparent activation of AKT in a PI3K independent mechanism XREF_BIBR.	0	11	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	ACK1	ACK1	ACK1	AKT	AKT	AKT	0	1	10	11
ACK1 not only activates survival kinase AKT and up-regulates the activity of hormone receptor androgen receptor but also induces tumor suppressor WWOX degradation in hormone driven breast and prostate cancers [ XREF_BIBR , XREF_BIBR ] .	ACK1 not only activates survival kinase AKT and up-regulates the activity of hormone receptor androgen receptor but also induces tumor suppressor WWOX degradation in hormone driven breast and prostate cancers [XREF_BIBR, XREF_BIBR].	0	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACK1	ACK1	ACK1	AKT	AKT	AKT	0	1	6	7
30 Conversely , pancreatic cancer cell lines treated with ACK1 inhibitors , displayed inhibition of cell growth and apoptosis , indicating that AKT activation in the absence of PTEN mutations may be driven by RTK and ACK1 signaling axis .	30 Conversely, pancreatic cancer cell lines treated with ACK1 inhibitors, displayed inhibition of cell growth and apoptosis, indicating that AKT activation in the absence of PTEN mutations may be driven by RTK and ACK1 signaling axis.	22	38	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACK1	ACK1	ACK1	AKT	AKT	AKT	36	37	22	23
AKT Activation by Ack1 .	AKT Activation by Ack1.	0	4	Activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	3	4	0	1
Moreover , ACK1 activated AKT and Src enhanced nuclear factor-kB ( NF-kB ) activity , suggesting a correlation between NF-kB signaling and TNF-alpha-mediated apoptosis in Caco-2 cells .	Moreover, ACK1 activated AKT and Src enhanced nuclear factor-kB (NF-kB) activity, suggesting a correlation between NF-kB signaling and TNF-alpha-mediated apoptosis in Caco-2 cells.	2	7	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ACK1	ACK1	ACK1	AKT	AKT	AKT	2	3	4	5
Recently , we have demonstrated a new signaling mechanism wherein RTK and Ack1 signaling directly regulates AKT function .	Recently, we have demonstrated a new signaling mechanism wherein RTK and Ack1 signaling directly regulates AKT function.	12	17	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	12	13	16	17
We found that Ack1 was overexpressed in HCC and Ack1 promoted HCC metastasis through EMT by activating AKT signaling pathway .	We found that Ack1 was overexpressed in HCC and Ack1 promoted HCC metastasis through EMT by activating AKT signaling pathway.	9	19	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	9	10	17	18
ACK1 has been reported to regulate the receptor tyrosine kinase AXL , to promote activation of AKT , androgen receptor , and negatively regulate the tumor suppressor WWOX .	ACK1 has been reported to regulate the receptor tyrosine kinase AXL, to promote activation of AKT, androgen receptor, and negatively regulate the tumor suppressor WWOX.	0	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACK1	ACK1	ACK1	AKT	AKT	AKT	0	1	16	17
While in normal cells Ack1 mediated AKT activation is regulated by growth factors , growth factor independent AKT activation can be mediated by the somatic mutants of Ack1 kinase .	While in normal cells Ack1 mediated AKT activation is regulated by growth factors, growth factor independent AKT activation can be mediated by the somatic mutants of Ack1 kinase.	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	4	5	6	7
[ XREF_BIBR ] Cell adhesion assays further tested the view and suggested that Ack1 could mediate activation of AKT by phosphorylation on Ser473 .	[XREF_BIBR] Cell adhesion assays further tested the view and suggested that Ack1 could mediate activation of AKT by phosphorylation on Ser473.	13	19	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	13	14	18	19
In this report , we have identified a novel mechanism of Ack1 mediated AKT activation wherein phosphorylation of Tyrosine 176 in the AKT kinase domain results in its translocation to the plasma membrane and subsequent kinase activation .	In this report, we have identified a novel mechanism of Ack1 mediated AKT activation wherein phosphorylation of Tyrosine 176 in the AKT kinase domain results in its translocation to the plasma membrane and subsequent kinase activation.	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	11	12	13	14
Taken together , these data suggest that Ack1 can promote EMT by mediating activation of AKT signaling pathway in HCC .	Taken together, these data suggest that Ack1 can promote EMT by mediating activation of AKT signaling pathway in HCC.	7	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	7	8	15	16
These results demonstrate that the somatic autoactivating mutations in Ack1 are sufficient to activate AKT .	These results demonstrate that the somatic autoactivating mutations in Ack1 are sufficient to activate AKT.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	9	10	14	15
To substantiate AKT activation mediated by Ack1 , we tested the results by cell adhesion assays .	To substantiate AKT activation mediated by Ack1, we tested the results by cell adhesion assays.	2	7	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	6	7	2	3
ACK1 has recently been reported to activate AKT in hepatocellular and pancreatic cancer .	ACK1 has recently been reported to activate AKT in hepatocellular and pancreatic cancer.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACK1	ACK1	ACK1	AKT	AKT	AKT	0	1	7	8
Somatic Autoactivating Mutation ( E346K ) in Ack1 Activates AKT .	Somatic Autoactivating Mutation (E346K) in Ack1 Activates AKT.	2	10	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	7	8	9	10
It was reported that the kinase activation of Ack1 could activate AKT pathway in other disease , [ XREF_BIBR , XREF_BIBR ] which is important for epithelial-mesenchymal transition ( EMT ) .	It was reported that the kinase activation of Ack1 could activate AKT pathway in other disease, [XREF_BIBR, XREF_BIBR] which is important for epithelial-mesenchymal transition (EMT).	6	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ack1	Ack1	Ack1	AKT	AKT	AKT	8	9	11	12
Once the ligated TNFR1 receptor is internalized , a second complex is formed upon deubiquitinated RIP1 recruitment to TRADD , Fas associated protein with death domain ( FADD ) , and pro-caspase-8 ( forming complex II or DISC ) , which further activates caspase-8 and starts the cell death cascade .	Once the ligated TNFR1 receptor is internalized, a second complex is formed upon deubiquitinated RIP1 recruitment to TRADD, Fas associated protein with death domain (FADD), and pro-caspase-8 (forming complex II or DISC), which further activates caspase-8 and starts the cell death cascade.	18	44	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	caspase-8	caspase-8	caspase-8	18	19	43	44
The apoptotic signaling pathway is mediated by TNF receptor I ( TNFR1 ) via the intermediate adapter TNF receptor associated death domain protein ( TRADD ) , which activates caspase 8 and triggers the downstream caspase cascade via mitochondria dependent and independent mechanisms .	The apoptotic signaling pathway is mediated by TNF receptor I (TNFR1) via the intermediate adapter TNF receptor associated death domain protein (TRADD), which activates caspase 8 and triggers the downstream caspase cascade via mitochondria dependent and independent mechanisms.	22	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	caspase 8	caspase 8	caspase 8	24	25	29	31
Receptor stimulation allows FADD , and thereby FLICE , to interact with the adaptor molecule TRADD that is recruited to the cytoplasmic region of TNFR-1 causing FLICE activation and apoptosis .	Receptor stimulation allows FADD, and thereby FLICE, to interact with the adaptor molecule TRADD that is recruited to the cytoplasmic region of TNFR-1 causing FLICE activation and apoptosis.	10	27	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	FLICE	FLICE	FLICE	15	16	26	27
Although activated TRADD triggers apoptotic signaling by recruiting FADD and caspase-8 and prolonging JNK activation , NF-kappaB activation leads to the expression of anti-apoptotic proteins such as cFLIP ( cellular FLICE ( caspase-8 )-like inhibitory protein ) and cIAP ( cellular inhibitors of apoptosis ) , which block caspase-8 activation [ XREF_BIBR , XREF_BIBR ] .	Although activated TRADD triggers apoptotic signaling by recruiting FADD and caspase-8 and prolonging JNK activation, NF-kappaB activation leads to the expression of anti-apoptotic proteins such as cFLIP (cellular FLICE (caspase-8)-like inhibitory protein) and cIAP (cellular inhibitors of apoptosis), which block caspase-8 activation [XREF_BIBR, XREF_BIBR].	1	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	caspase-8	caspase-8	caspase-8	2	3	10	11
Mechanistically , in the absence of NFkappaB signalling , inhibitor-of-apoptosis proteins ( IAPs ) fail to suppress assembly of the death inducing complex II , which allows for the TRADD mediated activation of caspase-8 and subsequent apoptosis [ XREF_BIBR , XREF_BIBR ] .	Mechanistically, in the absence of NFkappaB signalling, inhibitor-of-apoptosis proteins (IAPs) fail to suppress assembly of the death inducing complex II, which allows for the TRADD mediated activation of caspase-8 and subsequent apoptosis [XREF_BIBR, XREF_BIBR].	29	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	caspase-8	caspase-8	caspase-8	29	30	33	34
For instance , TRADD can recruit FADD and promote caspase-8 activation and apoptosis through the extrinsic pathway [ XREF_BIBR ] .	For instance, TRADD can recruit FADD and promote caspase-8 activation and apoptosis through the extrinsic pathway [XREF_BIBR].	3	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	caspase-8	caspase-8	caspase-8	3	4	9	10
Although silencing TRADD did not totally eliminate caspase 8 activation and apoptosis during treatments , the silencing of TRADD resulted in lowering the active caspase 8 levels and in increasing cell survival ( XREF_FIG ) .	Although silencing TRADD did not totally eliminate caspase 8 activation and apoptosis during treatments, the silencing of TRADD resulted in lowering the active caspase 8 levels and in increasing cell survival (XREF_FIG).	1	9	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	caspase 8	caspase 8	caspase 8	2	3	7	9
Interestingly , TNF receptor 1 ( TNFR1 ) and its signaling complex of TRADD , RIPK1 , TRAF2 , and cIAP not only activate NF-kappaB but also activate caspase-8 through the adaptor FADD .	Interestingly, TNF receptor 1 (TNFR1) and its signaling complex of TRADD, RIPK1, TRAF2, and cIAP not only activate NF-kappaB but also activate caspase-8 through the adaptor FADD.	11	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	caspase-8	caspase-8	caspase-8	13	14	28	29
We subsequently determined the role of TRADD in TNFalpha induced caspase 8 activation in RIP3 knockdown L929 cells and found that TRADD knockdown significantly suppressed the TNFalpha induced increase in caspase 8 activity , further confirming the critical role of TRADD in activating the caspase pathway during RIP3 independent apoptosis .	We subsequently determined the role of TRADD in TNFalpha induced caspase 8 activation in RIP3 knockdown L929 cells and found that TRADD knockdown significantly suppressed the TNFalpha induced increase in caspase 8 activity, further confirming the critical role of TRADD in activating the caspase pathway during RIP3 independent apoptosis.	21	32	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	caspase 8	caspase 8	caspase 8	21	22	30	32
Our findings in this study reveal how GBM derived gangliosides induce T cell apoptosis ( XREF_FIG ) by directly interacting with the TNFRI , thereby recruiting individual components of the death inducing signaling complex ( DISC ) , namely Fas associated death domain ( FADD ) and TNF receptor associated death domain ( TRADD ) , which in turn activates initiator caspase-8 , thereby , activating the receptor dependent pathway of caspase activation .	Our findings in this study reveal how GBM derived gangliosides induce T cell apoptosis (XREF_FIG) by directly interacting with the TNFRI, thereby recruiting individual components of the death inducing signaling complex (DISC), namely Fas associated death domain (FADD) and TNF receptor associated death domain (TRADD), which in turn activates initiator caspase-8, thereby, activating the receptor dependent pathway of caspase activation.	51	62	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	caspase-8	caspase-8	caspase-8	53	54	61	62
TRAF1 Modulates TRAF2 Signaling .	TRAF1 Modulates TRAF2 Signaling.	0	3	Modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	0	1	2	3
Whereas TRAF1 can mediate solubilization of TRAF2 , an equivalent amount of TRAF5 does not ( XREF_FIG E ) , suggesting a unique role for TRAF1 .	Whereas TRAF1 can mediate solubilization of TRAF2, an equivalent amount of TRAF5 does not (XREF_FIG E), suggesting a unique role for TRAF1.	1	7	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	1	2	6	7
TRAF1 Promotes Sustained TRAF2 mediated Signaling .	TRAF1 Promotes Sustained TRAF2 mediated Signaling.	0	4	Promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	0	1	3	4
To determine if TRAF1 can indeed modulate TRAF2 dependent signaling in a physiologically relevant situation consistent with our biochemical findings from overexpression experiments , we examined the role of TRAF1 in DCs .	To determine if TRAF1 can indeed modulate TRAF2 dependent signaling in a physiologically relevant situation consistent with our biochemical findings from overexpression experiments, we examined the role of TRAF1 in DCs.	3	9	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	3	4	7	8
The favored formation of TRAF1 1 -TRAF2 2 -cIAP complexes along with their weak affinity for CD40 might result in reduced recruitment of cIAP containing TRAF complexes to CD40 and could further enhance the effect of Fn14 mediated depletion of TRAF2 containing complexes .	The favored formation of TRAF1 1 -TRAF2 2 -cIAP complexes along with their weak affinity for CD40 might result in reduced recruitment of cIAP containing TRAF complexes to CD40 and could further enhance the effect of Fn14 mediated depletion of TRAF2 containing complexes.	4	41	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	4	5	40	41
This suggests that TRAF1 can either potentiate or inhibit sustained TRAF2 mediated signaling depending on the ratio of TRAF1 and TRAF2 .	This suggests that TRAF1 can either potentiate or inhibit sustained TRAF2 mediated signaling depending on the ratio of TRAF1 and TRAF2.	3	11	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	3	4	10	11
Collectively , our results suggest that LMP1 and TRAF1 stimulate K63-pUb attachment to TRAF2 , likely in the context of a TRAF1 : TRAF2 heterotrimer .	Collectively, our results suggest that LMP1 and TRAF1 stimulate K63-pUb attachment to TRAF2, likely in the context of a TRAF1 : TRAF2 heterotrimer.	6	14	stimulate	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	8	9	13	14
By preventing TRAF2 from interacting with Filamin , most likely due to a greater affinity for Filamin , TRAF1 may therefore prolong and enhance TRAF2 mediated signaling .	By preventing TRAF2 from interacting with Filamin, most likely due to a greater affinity for Filamin, TRAF1 may therefore prolong and enhance TRAF2 mediated signaling.	1	23	prolong	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	18	19	2	3
TRAF1 Rescues TRAF2 from Insolubility and Degradation .	TRAF1 Rescues TRAF2 from Insolubility and Degradation.	0	3	Rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	0	1	2	3
TRAF1 , when it is up-regulated in response to TRAF2 mediated signals , regulates the removal of CD40 and TRAF2 from insoluble complexes and modulates the ability of TRAF2 to mediate sustained activation of NF-kappaB and JNK .	TRAF1, when it is up-regulated in response to TRAF2 mediated signals, regulates the removal of CD40 and TRAF2 from insoluble complexes and modulates the ability of TRAF2 to mediate sustained activation of NF-kappaB and JNK.	0	24	up-regulated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	0	1	9	10
In support of this , in transient transfection assays where TNF-alpha stimulation or overexpression of CD40 and TRAF2 simulates prolonged stimulation , TRAF1 increases the solubility of TRAF2 , which increases JNK and NF-kappaB activation at lower levels of TRAF1 .	In support of this, in transient transfection assays where TNF-alpha stimulation or overexpression of CD40 and TRAF2 simulates prolonged stimulation, TRAF1 increases the solubility of TRAF2, which increases JNK and NF-kappaB activation at lower levels of TRAF1.	22	30	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	22	23	27	28
These results suggest that the increased susceptibility of HL-60 cells to mTNF-alpha may be due to the failure of TRAF2 membrane translocation caused by the upregulation of TRAF1 expression and formation of a TRAF1 and TRAF2 complex in the cytoplasm , thereby inhibiting NF-kappaB activation and inducing apoptosis .	These results suggest that the increased susceptibility of HL-60 cells to mTNF-alpha may be due to the failure of TRAF2 membrane translocation caused by the upregulation of TRAF1 expression and formation of a TRAF1 and TRAF2 complex in the cytoplasm, thereby inhibiting NF-kappaB activation and inducing apoptosis.	19	29	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF1	TRAF1 expression	traf1	TRAF2	TRAF2	traf2	27	28	19	20
TRAF1 can displace TRAF2 from rafts and promote sustained TRAF2 mediated signaling in response to a single stimulus or multiple stimuli over time .	TRAF1 can displace TRAF2 from rafts and promote sustained TRAF2 mediated signaling in response to a single stimulus or multiple stimuli over time.	0	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	0	1	9	10
Thus , the absence of Traf2 , similar to the loss of cIAP1/2 during SM treatment , activates RIP1- and EDD dependent TNFalpha production .	Thus, the absence of Traf2, similar to the loss of cIAP1/2 during SM treatment, activates RIP1- and EDD dependent TNFalpha production.	3	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Traf2	Traf2	Traf2	RIP1-	RIP1-	RIP1-	5	6	18	19
S1P in turn is an essential cofactor for TRAF2 mediated RIP1 K63 linked polyubiquitylation , which is necessary for NF-kappaB activation and the anti-apoptotic programme initiated by TNF 76 .	S1P in turn is an essential cofactor for TRAF2 mediated RIP1 K63 linked polyubiquitylation, which is necessary for NF-kappaB activation and the anti-apoptotic programme initiated by TNF 76.	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	RIP1	RIP1	RIP1	8	9	10	11
Both cIAP1/2 and Traf2 have been implicated as E3 ubiquitin ligases targeting RIP1 .	Both cIAP1/2 and Traf2 have been implicated as E3 ubiquitin ligases targeting RIP1.	1	13	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Traf2	Traf2	Traf2	RIP1	RIP1	RIP1	3	4	12	13
NFkappaB activation occurred as a consequence of oncogene-inhibitor induced ubiquitination of TRAF2 , which in turn activates RIP1 .	NFkappaB activation occurred as a consequence of oncogene-inhibitor induced ubiquitination of TRAF2, which in turn activates RIP1.	9	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	ubiquitination of TRAF2	traf2	RIP1	RIP1	rip1	11	12	17	18
During this process , TRAF2 , an E3 ubiquitin ligase , becomes polyubiquitinated and activates RIP1 kinase activity .	During this process, TRAF2, an E3 ubiquitin ligase, becomes polyubiquitinated and activates RIP1 kinase activity.	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	RIP1	RIP1	RIP1	4	5	15	16
Reduction of cIAP interacting TRAF2 decreases the ubiquitinated form of RIP1 within the TRAF2 complex , resulting in the inhibition of NF-kappaB signaling activity stimulated by TNFalpha .	Reduction of cIAP interacting TRAF2 decreases the ubiquitinated form of RIP1 within the TRAF2 complex, resulting in the inhibition of NF-kappaB signaling activity stimulated by TNFalpha.	0	11	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	RIP1	RIP1	RIP1	4	5	10	11
The Atr activating domain ( AAD ) of TopBP1 is comprised of a region between the sixth and seventh BRCA1 C terminal ( BRCT ) repeats and is sufficient to activate Atr in the presence of ATP and Atrip in vitro .	The Atr activating domain (AAD) of TopBP1 is comprised of a region between the sixth and seventh BRCA1 C terminal (BRCT) repeats and is sufficient to activate Atr in the presence of ATP and Atrip in vitro.	3	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TopBP1	TopBP1	TopBP1	Atrip	Atrip	Atrip	8	9	38	39
TRAF3 in turn activates downstream TBK1 and IKKepsilon kinases and TRAF2 and TRAF6 activate TAK1 and IKKalphabetagamma kinases , leading to activation of the transcription factors IFN regulatory factor ( IRF ) 3/7 and NF-kappaB , respectively .	TRAF3 in turn activates downstream TBK1 and IKKepsilon kinases and TRAF2 and TRAF6 activate TAK1 and IKKalphabetagamma kinases, leading to activation of the transcription factors IFN regulatory factor (IRF) 3/7 and NF-kappaB, respectively.	5	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	TAK1	TAK1	TAK1	10	11	14	15
In response to IL-1beta and TNF-alpha , ubiquitylation dependent activation of TNF associated factor ( TRAF ) 6 and TRAF2 complexes leads to activation of TGF-beta-activated kinase 1 ( TAK1 ) which activates nuclear factor kappa B ( NF-kappaB ) and c-Jun NH 2 -terminus kinase ( JNK ) pathways XREF_BIBR , XREF_BIBR .	In response to IL-1beta and TNF-alpha, ubiquitylation dependent activation of TNF associated factor (TRAF) 6 and TRAF2 complexes leads to activation of TGF-beta-activated kinase 1 (TAK1) which activates nuclear factor kappa B (NF-kappaB) and c-Jun NH 2 -terminus kinase (JNK) pathways XREF_BIBR, XREF_BIBR.	19	28	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	19	20	25	28
Stimulus dependent autoubiquitination of TRAF2 and TRAF6 activates the TAK1 , which is critical in the activation of NF-kappaB and MAPK ( mitogen activated protein kinase ) .	Stimulus dependent autoubiquitination of TRAF2 and TRAF6 activates the TAK1, which is critical in the activation of NF-kappaB and MAPK (mitogen activated protein kinase).	2	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	autoubiquitination of TRAF2	traf2	TAK1	TAK1	tak1	4	5	9	10
Activation of JNK and IKK by these cytokines requires the kinase activity of TAK1 , which is activated by TRAF2 or TRAF6 , two RING domain ubiquitin ligases that catalyze the synthesis of polyubiquitin chains linked via a lysine at position 63 ( K63 ) .	Activation of JNK and IKK by these cytokines requires the kinase activity of TAK1, which is activated by TRAF2 or TRAF6, two RING domain ubiquitin ligases that catalyze the synthesis of polyubiquitin chains linked via a lysine at position 63 (K63).	11	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	TAK1	TAK1	TAK1	19	20	13	14
However , other reports have shown that TRAF2 can activate MAP3K7 under certain conditions [ XREF_BIBR , XREF_BIBR ] and that MAP3K7 still contributes to IkappaB phosphorylation under TNF stimulation [ XREF_BIBR ] , suggesting that signaling through each branch is not exclusive .	However, other reports have shown that TRAF2 can activate MAP3K7 under certain conditions [XREF_BIBR, XREF_BIBR] and that MAP3K7 still contributes to IkappaB phosphorylation under TNF stimulation [XREF_BIBR], suggesting that signaling through each branch is not exclusive.	7	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	MAP3K7	MAP3K7	MAP3K7	7	8	10	11
The final outcome results from the modulation , integration and cross-talk of distinct signaling cascades that are initiated by TRADD ( TNFR1 associated DEATH domain protein ) and TRAF2 ( TNF receptor associated factor 2 ) [ XREF_BIBR , XREF_BIBR ] .	The final outcome results from the modulation, integration and cross-talk of distinct signaling cascades that are initiated by TRADD (TNFR1 associated DEATH domain protein) and TRAF2 (TNF receptor associated factor 2) [XREF_BIBR, XREF_BIBR].	3	37	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	TRAF2	TRAF2	TRAF2	19	20	28	29
The signal is initiated through binding of either TNF ( tumor necrosis factor ) or FASL ( Fas ligand ) to their receptors on the cell surface resulting in the formation of a complex that includes several mediators such as TRADD ( TNFRSF1A associated via death domain ) , FADD ( Fas associated via death domain ) , DAXX ( death-domain associated protein ) , and TRAF2 ( TNF receptor associated factor 2 ) .	The signal is initiated through binding of either TNF (tumor necrosis factor) or FASL (Fas ligand) to their receptors on the cell surface resulting in the formation of a complex that includes several mediators such as TRADD (TNFRSF1A associated via death domain), FADD (Fas associated via death domain), DAXX (death-domain associated protein), and TRAF2 (TNF receptor associated factor 2).	35	69	mediators	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	TRAF2	TRAF2	TRAF2	40	41	66	67
Activated IRAK-1 then dissociates from the TLR4 complex and subsequently binds and activates TNF receptor associated factor-6 ( TRAF-6 ) , which in turn activates TGFbeta activated kinase-1 ( TAK1 ) and nuclear factor of kappaB inducing kinase ( NIK ) .	Activated IRAK-1 then dissociates from the TLR4 complex and subsequently binds and activates TNF receptor associated factor-6 (TRAF-6), which in turn activates TGFbeta activated kinase-1 (TAK1) and nuclear factor of kappaB inducing kinase (NIK).	0	17	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF receptor associated factor-6	TNF receptor associated factor-6	TNF receptor associated factor-6	IRAK-1	IRAK-1	IRAK-1	13	17	1	2
Although IRAK-Inh partially suppresses NF-kappaB in TRAF6 overexpressing cells ( XREF_FIG ) , forced expression of TRAF6 in MDSL cells can overcome the inhibitory effects of IRAK-Inh and restore cell viability and progenitor function in IRAK Inh treated cells ( XREF_SUPPLEMENTARY ) .	Although IRAK-Inh partially suppresses NF-kappaB in TRAF6 overexpressing cells (XREF_FIG), forced expression of TRAF6 in MDSL cells can overcome the inhibitory effects of IRAK-Inh and restore cell viability and progenitor function in IRAK Inh treated cells (XREF_SUPPLEMENTARY).	14	36	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	expression of TRAF6	traf6	IRAK	IRAK	irak	16	17	35	36
Except for TLR3 , TLR activation recruits the adapter MyD88 into the receptor complex through TIR-TIR interactions followed by the recruitment of IRAK kinases mediated by DD-DD interactions and activation of TRAF6 .	Except for TLR3, TLR activation recruits the adapter MyD88 into the receptor complex through TIR-TIR interactions followed by the recruitment of IRAK kinases mediated by DD-DD interactions and activation of TRAF6.	22	32	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	IRAK	IRAK	IRAK	31	32	22	23
MED inhibited not only polyubiquitination of TRAF6 but also polyubiquitination mediated degradation of IRAK1 and IkappaBalpha induced by LPS , implicating that MED may serve as an ubiquitination inhibitor to inhibit the ubiquitination of proteins involved in TLR4 pathway .	MED inhibited not only polyubiquitination of TRAF6 but also polyubiquitination mediated degradation of IRAK1 and IkappaBalpha induced by LPS, implicating that MED may serve as an ubiquitination inhibitor to inhibit the ubiquitination of proteins involved in TLR4 pathway.	0	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF6	MED inhibited not only polyubiquitination of TRAF6 but also polyubiquitination	traf6	IRAK1	IRAK1	irak1	6	7	13	14
We obtained genetic and biochemical evidence that TRAF2 mediates proteasome dependent degradation of the proinflammatory transcription factors IRF5 and c-Rel in a mechanism that also requires TRAF3 and the E3 ubiquitin ligase cIAP ( cIAP1 or cIAP2 ) .	We obtained genetic and biochemical evidence that TRAF2 mediates proteasome dependent degradation of the proinflammatory transcription factors IRF5 and c-Rel in a mechanism that also requires TRAF3 and the E3 ubiquitin ligase cIAP (cIAP1 or cIAP2).	7	36	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	cIAP1	cIAP1	cIAP1	7	8	34	35
In addition , dual phosphorylation of TRAF2 also appears to suppress cell death under conditions of oxidative stress by preventing the degradation of Bcl-2 and cIAP1 .	In addition, dual phosphorylation of TRAF2 also appears to suppress cell death under conditions of oxidative stress by preventing the degradation of Bcl-2 and cIAP1.	4	26	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	phosphorylation of TRAF2	traf2	cIAP1	cIAP1	ciap1	6	7	25	26
When increasing amounts of TRAF2 were added to the reaction , TRAF2 did not change cIAP1 mediated auto-ubiquitylation ( XREF_FIG ) , indicating that TRAF2 does not enhance the intrinsic E3 ligase activity of cIAP1 under these conditions .	When increasing amounts of TRAF2 were added to the reaction, TRAF2 did not change cIAP1 mediated auto-ubiquitylation (XREF_FIG), indicating that TRAF2 does not enhance the intrinsic E3 ligase activity of cIAP1 under these conditions.	24	35	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	cIAP1	cIAP1	cIAP1	24	25	34	35
TANK also inhibited TRAF2 mediated cIAP1 inactivation .	TANK also inhibited TRAF2 mediated cIAP1 inactivation.	2	6	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	cIAP1	cIAP1	cIAP1	3	4	5	6
Interestingly , overexpression of TRADD restored RIP1 K63-Ub ( XREF_FIG ) .	Interestingly, overexpression of TRADD restored RIP1 K63-Ub (XREF_FIG).	2	7	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	overexpression of TRADD	tradd	RIP1	RIP1	rip1	4	5	6	7
To assess whether TRADD triggers apoptosis in NEMO and RIPK1 deficient hepatocytes , we generated NEMO LPC-KO ; RIPK1 LPC-KO ; TRADD LPC-KO mice ( XREF_FIG A ) .	To assess whether TRADD triggers apoptosis in NEMO and RIPK1 deficient hepatocytes, we generated NEMO LPC-KO; RIPK1 LPC-KO; TRADD LPC-KO mice (XREF_FIG A).	3	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	RIPK1	RIPK1	RIPK1	3	4	9	10
Since TRADD was shown to induce RIPK1 independent apoptosis , we examined the role of TRADD in NEMO LPC-KO mice by generating mice lacking both NEMO and TRADD in LPCs ( XREF_SUPPLEMENTARY A ) .	Since TRADD was shown to induce RIPK1 independent apoptosis, we examined the role of TRADD in NEMO LPC-KO mice by generating mice lacking both NEMO and TRADD in LPCs (XREF_SUPPLEMENTARY A).	1	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	RIPK1	RIPK1	RIPK1	1	2	6	7
In turn , TRADD activates FAS associated with death domain ( FADD ) and RIP1 , which cleaves procaspase 8 to its active form .	In turn, TRADD activates FAS associated with death domain (FADD) and RIP1, which cleaves procaspase 8 to its active form.	3	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	RIP1	RIP1	RIP1	3	4	14	15
Moreover , activation of Ack1 by overexpression of Ack1 produced several epithelial-to-mesenchymal transition ( EMT ) phenotypes in the human breast cancer cell line MDA-MB-231 .	Moreover, activation of Ack1 by overexpression of Ack1 produced several epithelial-to-mesenchymal transition (EMT) phenotypes in the human breast cancer cell line MDA-MB-231.	2	9	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Ack1	overexpression of Ack1	ack1	Ack1	Ack1	ack1	8	9	4	5
It has been shown that Ack1 is activated by overexpression of the Ack1 gene and cell adhesion .	It has been shown that Ack1 is activated by overexpression of the Ack1 gene and cell adhesion.	5	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Ack1	overexpression of the Ack1	ack1	Ack1	Ack1	ack1	12	13	5	6
So far the DR family comprises TNF-R1 , CD95/Fas/APO-1 , DR3 , TNF related apoptosis inducing ligand-receptor ( TRAIL-R1 ) , TRAIL-R2 and DR6 .	So far the DR family comprises TNF-R1, CD95/Fas/APO-1, DR3, TNF related apoptosis inducing ligand-receptor (TRAIL-R1), TRAIL-R2 and DR6.	12	24	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	DR6	DR6	DR6	12	13	23	24
DR6 is upregulated by TNF-alpha , which has ability to elevate NF-kappaB and its target gene interleukin-6 ( IL-6 ) 23 .	DR6 is upregulated by TNF-alpha, which has ability to elevate NF-kappaB and its target gene interleukin-6 (IL-6) 23.	0	7	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	DR6	DR6	DR6	4	5	0	1
As a member of the superfamily of TNF receptor , DR6 is upregulated by TNF-alpha via NF-kappaB activation in prostate tumor cell lines 10 .	As a member of the superfamily of TNF receptor, DR6 is upregulated by TNF-alpha via NF-kappaB activation in prostate tumor cell lines 10.	10	17	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	DR6	DR6	DR6	14	15	10	11
Neurotrophic factor depletion increases sAPPbeta production and further induces proteolytic cleavage of sAPPbeta , releasing a cleaved N-terminal fragment , N-APP , which triggers axon degeneration and neuronal cell death through binding to death receptor 6 .	Neurotrophic factor depletion increases sAPPbeta production and further induces proteolytic cleavage of sAPPbeta, releasing a cleaved N-terminal fragment, N-APP, which triggers axon degeneration and neuronal cell death through binding to death receptor 6.	17	36	triggers	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	N-terminal fragment	N-terminal fragment	N-terminal fragment	death receptor 6	death receptor 6	death receptor 6	17	19	33	36
The death receptors ( DR ) are a family of six members containing a conserved death domain ( DD ) : Fas/CD95/APO-1 , tumor necrosis factor receptor 1 ( TNFR1 ) , DR 3 , TNF apoptosis inducing ligand ( TRAIL ) R1/DR4 , TRAIL R2/DR5 , and DR6 .	The death receptors (DR) are a family of six members containing a conserved death domain (DD) : Fas/CD95/APO-1, tumor necrosis factor receptor 1 (TNFR1), DR 3, TNF apoptosis inducing ligand (TRAIL) R1/DR4, TRAIL R2/DR5, and DR6.	35	49	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	DR6	DR6	DR6	35	36	48	49
In addition , we have developed an in vitro assay system with which we demonstrate that purified , active GCK and TRAF2 activate MEKK1 .	In addition, we have developed an in vitro assay system with which we demonstrate that purified, active GCK and TRAF2 activate MEKK1.	19	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	MEKK1	MEKK1	MEKK1	21	22	23	24
Thus , TRAF1 up-regulation by TRAF2 independent signals ( e.g ., lymphocyte receptor stimulation ) may in fact result in the inhibition of TRAF2 mediated signaling , such as that observed by Tsitsikov et al ..	Thus, TRAF1 up-regulation by TRAF2 independent signals (e.g., lymphocyte receptor stimulation) may in fact result in the inhibition of TRAF2 mediated signaling, such as that observed by Tsitsikov et al..	2	7	up-regulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	TRAF1	TRAF1	TRAF1	5	6	2	3
We showed consistently that indeed TRAF1 enhanced the pulldown of cIAP2 by TRAF2 significantly ( XREF_FIG ) .	We showed consistently that indeed TRAF1 enhanced the pulldown of cIAP2 by TRAF2 significantly (XREF_FIG).	4	15	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	TRAF1	TRAF1	TRAF1	12	13	5	6
PRPK was first cloned from an interleukin-2-activated cytotoxic T-cell subtraction library and was shown to up-regulate the transcriptional activity of p53 when transfected into COS-7 cells .	PRPK was first cloned from an interleukin-2-activated cytotoxic T-cell subtraction library and was shown to up-regulate the transcriptional activity of p53 when transfected into COS-7 cells.	0	21	up-regulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PRPK	PRPK	PRPK	p53	p53	p53	0	1	20	21
In this communication we report that p53 mediated NF-kappaB2 up-regulation significantly contributes to the aggressive oncogenic behavior of cancer cells .	In this communication we report that p53 mediated NF-kappaB2 up-regulation significantly contributes to the aggressive oncogenic behavior of cancer cells.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	NF-kappaB2	NF-kappaB2	NF-kappaB2	6	7	8	9
We conclude that the proteolytic degradation of Mad2 caused by Tpr depletion is the leading cause of reduced Mad2 levels at unattached KTs and , consequently , of the weaker SAC response .	We conclude that the proteolytic degradation of Mad2 caused by Tpr depletion is the leading cause of reduced Mad2 levels at unattached KTs and, consequently, of the weaker SAC response.	5	11	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Tpr	Tpr	Tpr	Mad2	Mad2	Mad2	10	11	7	8
The average level of TNF produced by LPS induced PBL was Med = 962 pg/ml , in 75 % of cases TNF level was higher than Q1 = 572 pg/ml , and 25 % of cases were higher than Q3 = 1618 pg/ml .	The average level of TNF produced by LPS induced PBL was Med = 962 pg/ml, in 75% of cases TNF level was higher than Q1 = 572 pg/ml, and 25% of cases were higher than Q3 = 1618 pg/ml.	2	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	level of TNF	tnf	Med	Med	med	4	5	11	12
The canonical pathway of RSK1 activation is through ERK1/2 XREF_BIBR , and it has been reported that RSK1 dependent NF-kappaB activation may be induced by p53 or IL-1beta XREF_BIBR , XREF_BIBR .	The canonical pathway of RSK1 activation is through ERK1/2 XREF_BIBR, and it has been reported that RSK1 dependent NF-kappaB activation may be induced by p53 or IL-1beta XREF_BIBR, XREF_BIBR.	17	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p53	p53	p53	RSK1	RSK1	RSK1	25	26	17	18
40 Our biochemical data demonstrate that Ack1 signaling regulates the MAPK and Akt pathways ; in line with this premise , overexpression of Ack1 promoted a higher activation of ERK 1/2 and Akt1 whereas endogenous Ack1 knock-down partially counteracted NGF induced activation .	40 Our biochemical data demonstrate that Ack1 signaling regulates the MAPK and Akt pathways; in line with this premise, overexpression of Ack1 promoted a higher activation of ERK 1/2 and Akt1 whereas endogenous Ack1 knock-down partially counteracted NGF induced activation.	21	33	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ack1	overexpression of Ack1	ack1	Akt1	Akt1	akt1	23	24	32	33
In classical NF-kappaB pathways , TRAF6 activates TGF-beta activating kinase 1 ( TAK1 ) , which in turn activates the IKK complex composed of IKKalpha , IKKbeta , and NEMO .	In classical NF-kappaB pathways, TRAF6 activates TGF-beta activating kinase 1 (TAK1), which in turn activates the IKK complex composed of IKKalpha, IKKbeta, and NEMO.	5	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	5	6	12	13
Combined with the previous studies , we may infer that reducing intracellular free copper will inhibit O2- production , and elicit TRAF6 mediated activation of TAK1 .	Combined with the previous studies, we may infer that reducing intracellular free copper will inhibit O2- production, and elicit TRAF6 mediated activation of TAK1.	21	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	21	22	25	26
MyD88 subsequently binds to and activates IRAK1 , and activated IRAK1 phosphorylates TRAF6 thereby inducing Lys 63 -linked auto ubiquitination and activation of TAK1 .	MyD88 subsequently binds to and activates IRAK1, and activated IRAK1 phosphorylates TRAF6 thereby inducing Lys 63 -linked auto ubiquitination and activation of TAK1.	0	24	inducing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	MyD88 subsequently binds to and activates IRAK1, and activated IRAK1 phosphorylates TRAF6	traf6	TAK1	TAK1	tak1	12	13	23	24
These results demonstrate that TRAF6 catalyzed K63 polyubiquitination is both necessary and sufficient to activate TAK1 in vitro .	These results demonstrate that TRAF6 catalyzed K63 polyubiquitination is both necessary and sufficient to activate TAK1 in vitro.	4	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	4	5	15	16
The plasmid pcDNA3-Traf6-M , which encodes a Tak1-binding-defective Traf6 ( referred to as ' Traf6-M ' ) lacking the Tak1 binding domain , was then generated to determine whether the interaction between Traf6 and Tak1 is a factor underlying the activation of Tak1 by Traf6 during the hypertrophic response .	The plasmid pcDNA3-Traf6-M, which encodes a Tak1-binding-defective Traf6 (referred to as ' Traf6-M ') lacking the Tak1 binding domain, was then generated to determine whether the interaction between Traf6 and Tak1 is a factor underlying the activation of Tak1 by Traf6 during the hypertrophic response.	38	45	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Traf6	Traf6	Traf6	Tak1	Tak1	Tak1	44	45	42	43
This event leads to recruitment of TRAF6 ( TNFR associated factor 6 ) , which activates the TAK1 ( transforming growth factor beta activated kinase 1 ) , MAPK and ultimately NF-kappaB .	This event leads to recruitment of TRAF6 (TNFR associated factor 6), which activates the TAK1 (transforming growth factor beta activated kinase 1), MAPK and ultimately NF-kappaB.	4	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	6	7	17	18
The activation of TRAF6 causes activation of transforming-growth-factor-beta-activated kinase 1 ( TAK1 ) that leads to activation of activator protein1 ( AP-1 ) and NF-kappaB through the mitogen activated protein kinases ( MAPK ) and NF-kappaB kinase ( IKK ) complex , respectively [ XREF_BIBR ] .	The activation of TRAF6 causes activation of transforming-growth-factor-beta-activated kinase 1 (TAK1) that leads to activation of activator protein1 (AP-1) and NF-kappaB through the mitogen activated protein kinases (MAPK) and NF-kappaB kinase (IKK) complex, respectively [XREF_BIBR].	1	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	transforming-growth-factor-beta-activated kinase 1	transforming-growth-factor-beta-activated kinase 1	transforming-growth-factor-beta-activated kinase 1	3	4	7	10
The evidence in support of this model includes : 1 ) in vitro reconstitution of TAK1 and IKK activation by TRAF6 catalyzed K63 polyubiquitination ; 2 ) discovery of ubiquitin binding domains in TAB2 and NEMO , which are important for the activation TAK1 and IKK , respectively ; 3 ) discovery of deubiquitination enzymes such as CYLD and A20 that remove K63 polyubiquitin chains to inhibit IKK .	The evidence in support of this model includes : 1) in vitro reconstitution of TAK1 and IKK activation by TRAF6 catalyzed K63 polyubiquitination; 2) discovery of ubiquitin binding domains in TAB2 and NEMO, which are important for the activation TAK1 and IKK, respectively; 3) discovery of deubiquitination enzymes such as CYLD and A20 that remove K63 polyubiquitin chains to inhibit IKK.	15	21	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	20	21	15	16
TLR3 , on the other hand , uses TRIF as an adaptor molecule instead of MyD88 , but this pathway also leads to TRAF6 mediated activation of TAK1 and the same downstream inflammatory pathways .	TLR3, on the other hand, uses TRIF as an adaptor molecule instead of MyD88, but this pathway also leads to TRAF6 mediated activation of TAK1 and the same downstream inflammatory pathways.	23	33	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	23	24	27	28
Since ubiquitination of TRAF6 is necessary for activation of TAK1 , which leads to activation of NF-kappaB and MAPK pathways in both MyD88 dependent and TRIF dependent pathways , and PKD1 is required for MyD88 dependent ubiquitination of TRAF6 , effects of PKD1 on TLR ligand mediated activation of MAPKs and NF-kappaB might be indirect due to its contribution on ubiquitination of TRAF6 and subsequent TAK1 activation .	Since ubiquitination of TRAF6 is necessary for activation of TAK1, which leads to activation of NF-kappaB and MAPK pathways in both MyD88 dependent and TRIF dependent pathways, and PKD1 is required for MyD88 dependent ubiquitination of TRAF6, effects of PKD1 on TLR ligand mediated activation of MAPKs and NF-kappaB might be indirect due to its contribution on ubiquitination of TRAF6 and subsequent TAK1 activation.	1	12	is necessary for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	TRAF6	ubiquitination of TRAF6	traf6	TAK1	TAK1	tak1	3	4	9	10
TRAF6 effectively activates its downstream protein TAK1 with the assistance of TAB1/2 .	TRAF6 effectively activates its downstream protein TAK1 with the assistance of TAB1/2.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	6	7
TRAF6 activates the ubiquitin dependent kinase TAK1 , which in turn activates IKK and the MAPKs JNK and p38 .	TRAF6 activates the ubiquitin dependent kinase TAK1, which in turn activates IKK and the MAPKs JNK and p38.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	6	7
IRAK activation results in an interaction with tumor necrosis factor ( TNF ) receptor associated factor 6 ( TRAF6 ) to activate TAK1 downstream XREF_BIBR .	IRAK activation results in an interaction with tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) to activate TAK1 downstream XREF_BIBR.	16	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	18	19	22	23
Because TRAF6 is a critical activator of TAK1 that functions upstream as the MAP3K of p38 and JNK , our finding connects a missing link between the ligand activated receptors and the MAP kinase branch of Smad independent TGF-beta signaling .	Because TRAF6 is a critical activator of TAK1 that functions upstream as the MAP3K of p38 and JNK, our finding connects a missing link between the ligand activated receptors and the MAP kinase branch of Smad independent TGF-beta signaling.	1	8	is a critical activator	Positive_activation_copula_1	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	1	2	7	8
17 The adaptor proteins TRAF2 and TRAF6 activate TAK1 , which is known to act upstream of the IKK complex .	17 The adaptor proteins TRAF2 and TRAF6 activate TAK1, which is known to act upstream of the IKK complex.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	6	7	8	9
In mammalian cells , TAK1 associates with TAB1/TAB2/TAB3 and is activated by TRAF6 in a Lys63 linked polyubiquitin chain dependent manner XREF_BIBR , XREF_BIBR .	In mammalian cells, TAK1 associates with TAB1/TAB2/TAB3 and is activated by TRAF6 in a Lys63 linked polyubiquitin chain dependent manner XREF_BIBR, XREF_BIBR.	4	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	12	13	4	5
Association of TRAF6 with TGF-betaRI causes activation of TGF-beta-activated kinase 1 ( TAK1 ) , which is involved in EMT of mammary epithelial cells in a SMAD independent manner .	Association of TRAF6 with TGF-betaRI causes activation of TGF-beta-activated kinase 1 (TAK1), which is involved in EMT of mammary epithelial cells in a SMAD independent manner.	0	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	2	3	8	11
TGFbeta induced oligomerization of TGFbeta receptors leads to autoubiquitination of TRAF6 , which in turn activates the MAPK kinase kinase TAK1 and the MKK3/6-p 38 pathway .	TGFbeta induced oligomerization of TGFbeta receptors leads to autoubiquitination of TRAF6, which in turn activates the MAPK kinase kinase TAK1 and the MKK3/6-p 38 pathway.	8	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	autoubiquitination of TRAF6	traf6	TAK1	TAK1	tak1	10	11	20	21
TIFA overexpression promotes oligomerization and poly-ubiquitinylation of TRAF6 , which in turn activates TAK1 and IKK .	TIFA overexpression promotes oligomerization and poly-ubiquitinylation of TRAF6, which in turn activates TAK1 and IKK.	3	15	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	7	8	13	14
Subsequent polyubiquitination of TRAF6 induces the activation of TAK1 which activates the IKK complex or MAP kinases leading to NF-kappaB or AP-1 induction and inflammatory cytokine transcription [ XREF_BIBR ] .	Subsequent polyubiquitination of TRAF6 induces the activation of TAK1 which activates the IKK complex or MAP kinases leading to NF-kappaB or AP-1 induction and inflammatory cytokine transcription [XREF_BIBR].	1	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	polyubiquitination of TRAF6	traf6	TAK1	TAK1	tak1	3	4	8	9
Notably , only TRAF6 but not Tax treatment led to detectable phosphorylation and thus activation of TAK1 ( XREF_SUPPLEMENTARY ) .	Notably, only TRAF6 but not Tax treatment led to detectable phosphorylation and thus activation of TAK1 (XREF_SUPPLEMENTARY).	2	18	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	3	4	16	17
TRAF6 then re-localizes to the TLR signaling complex to activate TAK1 , inducing NF-kappaB [ XREF_BIBR , XREF_BIBR ] similar to the pathway described in the aforementioned RLR section .	TRAF6 then re-localizes to the TLR signaling complex to activate TAK1, inducing NF-kappaB [XREF_BIBR, XREF_BIBR] similar to the pathway described in the aforementioned RLR section.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	10	11
This mechanism depends on TRAF6 mediated TGF-beta-activated kinase 1 ( MAP3K7 and TAK1 ) activation , which in turn phosphorylates and activates the I-kappa-B kinase complex ( IKK ) [ XREF_BIBR ] .	This mechanism depends on TRAF6 mediated TGF-beta-activated kinase 1 (MAP3K7 and TAK1) activation, which in turn phosphorylates and activates the I-kappa-B kinase complex (IKK) [XREF_BIBR].	2	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	4	5	6	9
TRAF6 then activates TAK1 in a manner similar to that of the MyD88 dependent pathway for NF-kappaB activation .	TRAF6 then activates TAK1 in a manner similar to that of the MyD88 dependent pathway for NF-kappaB activation.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	3	4
Current concepts of TAK1 and IKKbeta activation by TRAF6 have been reviewed XREF_BIBR - XREF_BIBR .	Current concepts of TAK1 and IKKbeta activation by TRAF6 have been reviewed XREF_BIBR - XREF_BIBR.	3	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	8	9	3	4
The activation of TRAF6 in turn activates TAK1 .	The activation of TRAF6 in turn activates TAK1.	1	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	3	4	7	8
TGF-beta also induces p38 and JNK MAPK signaling through activation of TAK1 by the ubiquitin ligase TRAF6 that interacts with the TGF-beta receptor complex [ XREF_BIBR , XREF_BIBR ] .	TGF-beta also induces p38 and JNK MAPK signaling through activation of TAK1 by the ubiquitin ligase TRAF6 that interacts with the TGF-beta receptor complex [XREF_BIBR, XREF_BIBR].	2	18	induces	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	16	17	11	12
TRIF then recruits TRAF6 which , in turn , activates TAK1 , initiating the late-phase activation of NF-kappaB and AP-1 .	TRIF then recruits TRAF6 which, in turn, activates TAK1, initiating the late-phase activation of NF-kappaB and AP-1.	2	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	3	4	10	11
Moreover , SOCS 3 inhibit ubiquitination of TRAF6 , preventing association and activation of TAK1 in the TLR pathway [ XREF_BIBR ] .	Moreover, SOCS 3 inhibit ubiquitination of TRAF6, preventing association and activation of TAK1 in the TLR pathway [XREF_BIBR].	2	15	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF6	SOCS 3 inhibit ubiquitination of TRAF6	traf6	TAK1	TAK1	tak1	7	8	14	15
TRAF6 next activates TAK1 which can activate IKK complexes , thus leading to the MYD88 independent activation of NF-kappaB .	TRAF6 next activates TAK1 which can activate IKK complexes, thus leading to the MYD88 independent activation of NF-kappaB.	0	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	3	4
For example , ubiquitination of TRAF6 allows the activation of downstream kinase TGF-beta-activated kinase 1 ( TAK1 ) , which is required for activation of NF-kappaB in response to various stimuli including IL-1 , TNF , and Toll like receptor agonists .	For example, ubiquitination of TRAF6 allows the activation of downstream kinase TGF-beta-activated kinase 1 (TAK1), which is required for activation of NF-kappaB in response to various stimuli including IL-1, TNF, and Toll like receptor agonists.	3	15	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	ubiquitination of TRAF6	traf6	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	tgf-beta-activated kinase 1	5	6	12	15
TRAF2 and TRAF6 mediated TAK1 Lys63 linked TAK1 polyubiquitination have been suggested to be essential for TNFalpha- and IL-1beta-induced NF-kappaB activation .	TRAF2 and TRAF6 mediated TAK1 Lys63 linked TAK1 polyubiquitination have been suggested to be essential for TNFalpha- and IL-1beta-induced NF-kappaB activation.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	2	3	4	5
The activated TRAF6 in turn activates MAP3K7 , which subsequently coordinates the assembly of the IKK complex [ XREF_BIBR , XREF_BIBR ] .	The activated TRAF6 in turn activates MAP3K7, which subsequently coordinates the assembly of the IKK complex [XREF_BIBR, XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MAP3K7	MAP3K7	MAP3K7	2	3	6	7
The mechanism of IKK activation by Tax is very similar to that employed by the TCR pathway , in which polyubiquitination of BCL10 , MALT1 and/or TRAF6 leads to the activation of TAK1 and IKK .	The mechanism of IKK activation by Tax is very similar to that employed by the TCR pathway, in which polyubiquitination of BCL10, MALT1 and/or TRAF6 leads to the activation of TAK1 and IKK.	20	34	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	polyubiquitination of BCL10, MALT1 and/or TRAF6	traf6	TAK1	TAK1	tak1	26	27	32	33
TRAF6 induces the activation of TAK1 through K63 linked polyubiquitination .	TRAF6 induces the activation of TAK1 through K63 linked polyubiquitination.	0	6	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	5	6
Subsequently , TRAF6 activates growth factor-beta- activated protein kinase 1 ( TAK1 ) in a ubiquitin dependent manner .	Subsequently, TRAF6 activates growth factor-beta- activated protein kinase 1 (TAK1) in a ubiquitin dependent manner.	2	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	2	3	11	12
Shortly , TLR4 homodimerization recruits MYD88 and the IRAK complex including TRAF6 that activates TAK1 .	Shortly, TLR4 homodimerization recruits MYD88 and the IRAK complex including TRAF6 that activates TAK1.	9	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	11	12	14	15
XREF_BIBR Ubiquitinated TRAF6 recruits transforming-growth-factor-beta-activated protein kinase 1 ( TAK1 )-binding protein 2 , and activates TAK1 , which then phosphorylates and activates the inhibitor of NF-kappaB kinase ( IKK ) complex , composed of two catalytic subunits ( IKKalpha and IKKbeta ) and a regulatory subunit ( NEMO , also known as IKKgamma ) .	XREF_BIBR Ubiquitinated TRAF6 recruits transforming-growth-factor-beta-activated protein kinase 1 (TAK1)-binding protein 2, and activates TAK1, which then phosphorylates and activates the inhibitor of NF-kappaB kinase (IKK) complex, composed of two catalytic subunits (IKKalpha and IKKbeta) and a regulatory subunit (NEMO, also known as IKKgamma).	0	46	activates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	TRAF6	TRAF6	traf6	TAK1	TAK1, which then phosphorylates and activates the inhibitor of NF-kappaB	tak1	2	3	16	17
However , data from Sorrentino and colleagues suggest a kinase independent role for the type I receptor in TRAF6 mediated TAK1 and p38 activation [ XREF_BIBR ] .	However, data from Sorrentino and colleagues suggest a kinase independent role for the type I receptor in TRAF6 mediated TAK1 and p38 activation [XREF_BIBR].	16	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	18	19	20	21
While its activation by CpG DNA is dependent on MyD88 , IRAK4 , and IRAK1 , PKD1 is required for ubiquitination of TRAF6 and subsequent activation of TAK1 , MAPKs , and NF-kappaB , as well as expression of proinflammatory genes XREF_BIBR .	While its activation by CpG DNA is dependent on MyD88, IRAK4, and IRAK1, PKD1 is required for ubiquitination of TRAF6 and subsequent activation of TAK1, MAPKs, and NF-kappaB, as well as expression of proinflammatory genes XREF_BIBR.	20	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAF6	ubiquitination of TRAF6	traf6	TAK1	TAK1	tak1	22	23	27	28
Analysis of the upstream kinases revealed that Tak1 activation was selectively augmented by Traf6 overexpression but suppressed by Traf6 ablation ( XREF_FIG ) , whereas negligible effects were observed on the phosphorylation levels of Tbk1 , Ask1 , Pi3k , Ilk and Fak in response to hypertrophic stresses ( XREF_SUPPLEMENTARY ) .	Analysis of the upstream kinases revealed that Tak1 activation was selectively augmented by Traf6 overexpression but suppressed by Traf6 ablation (XREF_FIG), whereas negligible effects were observed on the phosphorylation levels of Tbk1, Ask1, Pi3k, Ilk and Fak in response to hypertrophic stresses (XREF_SUPPLEMENTARY).	7	19	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Traf6	Traf6	Traf6	Tak1	Tak1	Tak1	18	19	7	8
In contrast , TRIF dependent signaling leads to NF-kappaB activation through TRAF6 which activates TAK1 in a manner similar to that of the MyD88 dependent pathway via receptor interacting protein-1 ( RIP1 ) .	In contrast, TRIF dependent signaling leads to NF-kappaB activation through TRAF6 which activates TAK1 in a manner similar to that of the MyD88 dependent pathway via receptor interacting protein-1 (RIP1).	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	11	12	14	15
TRAF6 , along with Ubc13 and Uev1A , which are ubiquitin conjugating proteins , activates the TAK1 complex [ XREF_BIBR ] .	TRAF6, along with Ubc13 and Uev1A, which are ubiquitin conjugating proteins, activates the TAK1 complex [XREF_BIBR].	0	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	16	17
TIFA induces the oligomerization and polyubiquitination of TRAF6 , and then activates TAK1 and IKK XREF_BIBR .	TIFA induces the oligomerization and polyubiquitination of TRAF6, and then activates TAK1 and IKK XREF_BIBR.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TIFA induces the oligomerization and polyubiquitination of TRAF6	traf6	TAK1	TAK1	tak1	7	8	12	13
This ubiquitination event is required for TRAF6 mediated activation of TAK1 and the IKK complex , resulting in activation of transcription factor NFkB and subsequent NFkB dependent transcription of pro inflammatory and neutrophil mobilizing cytokines and chemokines .	This ubiquitination event is required for TRAF6 mediated activation of TAK1 and the IKK complex, resulting in activation of transcription factor NFkB and subsequent NFkB dependent transcription of pro inflammatory and neutrophil mobilizing cytokines and chemokines.	6	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	6	7	10	11
TRAF6 then activates TAK1 , causing the activation of NF-kappaB and MAPK pathways , both of which control the expression of pro inflammatory cytokines .	TRAF6 then activates TAK1, causing the activation of NF-kappaB and MAPK pathways, both of which control the expression of pro inflammatory cytokines.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	3	4
TRAF6 activates TAK1 , and in turn , phospho-TAK1 activates downstream signaling that leads to the activation of JNK , p38 MAPK , and NF-kappaB .	TRAF6 activates TAK1, and in turn, phospho-TAK1 activates downstream signaling that leads to the activation of JNK, p38 MAPK, and NF-kappaB.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	2	3
TRAF6 further activates the TAK1 complex , which mediates NF-kappaB and MAP kinase activation [ XREF_BIBR ] .	TRAF6 further activates the TAK1 complex, which mediates NF-kappaB and MAP kinase activation [XREF_BIBR].	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	4	5
While the exact signaling cascade which leads to the activation of these factors has yet to be clearly defined , it is believed that following TRAF6 induced activation , TAK1 associates with apoptosis signal regulating kinase 1 ( ASK1 and MAPKKK5 ) under certain circumstances instead of IKK as mentioned above [ XREF_BIBR ] .	While the exact signaling cascade which leads to the activation of these factors has yet to be clearly defined, it is believed that following TRAF6 induced activation, TAK1 associates with apoptosis signal regulating kinase 1 (ASK1 and MAPKKK5) under certain circumstances instead of IKK as mentioned above [XREF_BIBR].	24	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	25	26	29	30
While this study reports that K124 is essential for TRAF6 mediated activation of TAK1 and IKK , a separate study showed that while the TRAF6 RING finger domain is essential for IL-1R- and RANK mediated TRAF6 dependent signaling , ubiquitination of TRAF6 itself is dispensable .	While this study reports that K124 is essential for TRAF6 mediated activation of TAK1 and IKK, a separate study showed that while the TRAF6 RING finger domain is essential for IL-1R- and RANK mediated TRAF6 dependent signaling, ubiquitination of TRAF6 itself is dispensable.	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	9	10	13	14
The IRAKs subsequently recruits TRAF6 , which activates TAK1 , resulting in activation of downstream signalings of NF-kappaB and MAPKs ( Erk1/2 , JNK , and p38 ) .	The IRAKs subsequently recruits TRAF6, which activates TAK1, resulting in activation of downstream signalings of NF-kappaB and MAPKs (Erk1/2, JNK, and p38).	3	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	4	5	8	9
The activated IRAK family proteins associate with TRAF6 ( TNF receptor associated factor 6 ) , and TRAF6 activates TAK1 , which in turn activates the IKK complex composed of NEMO , IKKalpha and IKKbeta .	The activated IRAK family proteins associate with TRAF6 (TNF receptor associated factor 6), and TRAF6 activates TAK1, which in turn activates the IKK complex composed of NEMO, IKKalpha and IKKbeta.	17	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	17	18	19	20
As TRAF6 knockdown abolished activation of TAK1 , but not ATM in damaged cells , the function of TRAF6 in acute signaling network of the ASAP was further substantiated .	As TRAF6 knockdown abolished activation of TAK1, but not ATM in damaged cells, the function of TRAF6 in acute signaling network of the ASAP was further substantiated.	1	7	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	1	2	6	7
We have previously shown that Act1 utilizes Ubc13-Uev1A E2 complex to exert K63 linked polyubiquitination of TRAF6 , which is required for TRAF6 mediated activation of TAK1 and the IKK complex , resulting in activation of transcription factor NFkappaB21 .	We have previously shown that Act1 utilizes Ubc13-Uev1A E2 complex to exert K63 linked polyubiquitination of TRAF6, which is required for TRAF6 mediated activation of TAK1 and the IKK complex, resulting in activation of transcription factor NFkappaB21.	22	30	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	22	23	26	27
TRAF6 , in particular , is a critical activator of TAK1 and has been highlighted as a potential target in cardiac hypertrophy and fibrosis [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	TRAF6, in particular, is a critical activator of TAK1 and has been highlighted as a potential target in cardiac hypertrophy and fibrosis [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	14	is a critical activator	Positive_activation_copula_1	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	10	11
9 TRAF6 activates tumor growth factor-beta-activated protein kinase 1 ( TAK1 ) 10 that activates IkappaB kinase complex ( IkappaK ) , which leads to the activation of nuclear factor ( NF )-kappaB .	9 TRAF6 activates tumor growth factor-beta-activated protein kinase 1 (TAK1) 10 that activates IkappaB kinase complex (IkappaK), which leads to the activation of nuclear factor (NF)-kappaB.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	1	2	10	11
In one study , deletion of the RING domain of TRAF6 was found to block the activation of TAK1 and JNK but not IKK by IL-1beta 23 .	In one study, deletion of the RING domain of TRAF6 was found to block the activation of TAK1 and JNK but not IKK by IL-1beta 23.	8	20	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	10	11	18	19
Collectively , our results suggest that even though TRAF6 is an upstream activator of TAK1 in many signaling cascades , inactivation of TAK1 , but not TRAF6 , regulates adipocyte survival , energy expenditure , and HFD induced obesity in mice .	Collectively, our results suggest that even though TRAF6 is an upstream activator of TAK1 in many signaling cascades, inactivation of TAK1, but not TRAF6, regulates adipocyte survival, energy expenditure, and HFD induced obesity in mice.	8	18	is an upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	8	9	14	15
TRAF6 in turn activates activated kinase 1 ( TAK1 ) which can activate the IkappaB kinase ( IKK ) complex and mitogen activated protein kinase kinase kinase ( MAPKKKs ) .	TRAF6 in turn activates activated kinase 1 (TAK1) which can activate the IkappaB kinase (IKK) complex and mitogen activated protein kinase kinase kinase (MAPKKKs).	0	28	activates activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	8	9
TRAF6 further activates downstream TRAF6 dependent TAK1 for NF-kappaB activation .	TRAF6 further activates downstream TRAF6 dependent TAK1 for NF-kappaB activation.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	6	7
In the current study , utilizing cardiac specific genetic manipulation , we provided robust evidence suggesting that TRAF6 promotes the activation of TAK1 , a MAPK kinase kinase ( MAPKKK ) that controls the downstream JNK1/2 and p38 MAPK cascades , during cardiac hypertrophy .	In the current study, utilizing cardiac specific genetic manipulation, we provided robust evidence suggesting that TRAF6 promotes the activation of TAK1, a MAPK kinase kinase (MAPKKK) that controls the downstream JNK1/2 and p38 MAPK cascades, during cardiac hypertrophy.	17	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	17	18	22	23
TRAF6 is then able to activate TAK1 .	TRAF6 is then able to activate TAK1.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	6	7
TRAF6 causes activation of TAK1 , which results in activation of NF-kappaB and AP-1 through the IKK complex and MAP kinases , respectively .	TRAF6 causes activation of TAK1, which results in activation of NF-kappaB and AP-1 through the IKK complex and MAP kinases, respectively.	0	7	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	4	5
TRAF6 , together with UBC13 and UEV1A , in turn activates TAK1 and IKK .	TRAF6, together with UBC13 and UEV1A, in turn activates TAK1 and IKK.	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	11	12
We showed here that TRAF6 promotes myogenic differentiation mainly by activating the TAK1 and p38 MAPK pathway and the Akt pathway , as knockdown of TRAF6 reduced the levels of active p38 MAPK and Akt in myoblasts ( XREF_FIG ) .	We showed here that TRAF6 promotes myogenic differentiation mainly by activating the TAK1 and p38 MAPK pathway and the Akt pathway, as knockdown of TRAF6 reduced the levels of active p38 MAPK and Akt in myoblasts (XREF_FIG).	4	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	4	5	12	13
Downstream of innate receptors , TRAF6 activates TAK1 , which results in the activation of the classical NF-kappaB pathway .	Downstream of innate receptors, TRAF6 activates TAK1, which results in the activation of the classical NF-kappaB pathway.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	5	6	7	8
TRAF6 in turn activates TAK1 which itself activates the IKK complex and MAPKKs .	TRAF6 in turn activates TAK1 which itself activates the IKK complex and MAPKKs.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	4	5
TAK1 can be activated by TRAF6 and TRIM8 through K63 linked ubiquitination XREF_BIBR XREF_BIBR .	TAK1 can be activated by TRAF6 and TRIM8 through K63 linked ubiquitination XREF_BIBR XREF_BIBR.	0	7	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	5	6	0	1
Interleukin-1 and TRAF6 dependent activation of TAK1 in the absence of TAB2 and TAB3 .	Interleukin-1 and TRAF6 dependent activation of TAK1 in the absence of TAB2 and TAB3.	0	9	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	2	3	6	7
Our in vitro and in vivo analyses suggest that TAK1 lysine 158 is TRAF6 mediated TAK1 K63 linked polyubiqutination acceptor site in IL-1beta-mediated signal transduction pathway .	Our in vitro and in vivo analyses suggest that TAK1 lysine 158 is TRAF6 mediated TAK1 K63 linked polyubiqutination acceptor site in IL-1beta-mediated signal transduction pathway.	6	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	13	14	15	16
Recruitment of TAK1 to K63 polyubiquitinated TRAF6 leads to activation of TAK1 that in turn phosphorylates IKKbeta .	Recruitment of TAK1 to K63 polyubiquitinated TRAF6 leads to activation of TAK1 that in turn phosphorylates IKKbeta.	5	12	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	polyubiquitinated TRAF6	traf6	TAK1	TAK1	tak1	6	7	11	12
Further , while we have focused here on TRAF6 mediated activation of the TAK1 pathway , it should be noted that the kinase MEKK3 governs an alternate TRAF6 dependent signaling pathway , for which the role of TRAF6 autoubiquitination remains unclear XREF_BIBR .	Further, while we have focused here on TRAF6 mediated activation of the TAK1 pathway, it should be noted that the kinase MEKK3 governs an alternate TRAF6 dependent signaling pathway, for which the role of TRAF6 autoubiquitination remains unclear XREF_BIBR.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	8	9	13	14
Another intriguing mechanism of TRAF6 function is to activate TAK1 via synthesizing free or unanchored polyubiquitin chains 103 .	Another intriguing mechanism of TRAF6 function is to activate TAK1 via synthesizing free or unanchored polyubiquitin chains 103.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	4	5	9	10
In addition to activation of ( canonical ) signaling via the SMADs , the TGF-beta receptor complex can also recruit TNF receptor associated factor ( TRAF ) 4 and TRAF6 , which then by K63 polyubiquitination activates the effector kinase TGF-beta-activated kinase 1 ( TAK1 ) ; TAK1 subsequently phosphorylates MAPK kinases , leading to activation of p38 or JNK .	In addition to activation of (canonical) signaling via the SMADs, the TGF-beta receptor complex can also recruit TNF receptor associated factor (TRAF) 4 and TRAF6, which then by K63 polyubiquitination activates the effector kinase TGF-beta-activated kinase 1 (TAK1); TAK1 subsequently phosphorylates MAPK kinases, leading to activation of p38 or JNK.	22	43	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	TGF-beta-activated kinase 1	29	30	40	43
We show that ( i ) MUC1-C induces TAK1 expression by promoting NF-kappaB-mediated activation of the TAK1 promoter , and ( ii ) MUC1-C binds directly to TAK1 and confers the formation of a TAK1 complex with TRAF6 , which in turn activates TAK1 --> NF-kappaB signaling .	We show that (i) MUC1-C induces TAK1 expression by promoting NF-kappaB-mediated activation of the TAK1 promoter, and (ii) MUC1-C binds directly to TAK1 and confers the formation of a TAK1 complex with TRAF6, which in turn activates TAK1 --> NF-kappaB signaling.	35	46	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	37	38	43	44
The disassociation of TRAF6 and TAK1 failed to induce the activation of TAK1 and its downstream effectors JNK1/2 and p38 .	The disassociation of TRAF6 and TAK1 failed to induce the activation of TAK1 and its downstream effectors JNK1/2 and p38.	1	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	3	4	12	13
TRAF6 functions to produce a poly-ubiquitin scaffold on itself , which recruits a complex of transforming growth factor beta ( TGF-beta ) activated kinase 1 ( TAK1 ) and TAK1 associated binding proteins 1 and 2 ( TAB1 , TAB2 ) .	TRAF6 functions to produce a poly-ubiquitin scaffold on itself, which recruits a complex of transforming growth factor beta (TGF-beta) activated kinase 1 (TAK1) and TAK1 associated binding proteins 1 and 2 (TAB1, TAB2).	0	37	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	29	30
We found that the TAK1 kinase complex is activated by TRAF6 catalyzed K63 polyubiquitination .	We found that the TAK1 kinase complex is activated by TRAF6 catalyzed K63 polyubiquitination.	4	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	10	11	4	5
In the non canonical pathway , upon TGF-beta ligand stimulation , receptors recruit TRAF6 , which leads to lysine-63-linked autoubiquitylation , which in turn recruits and activates TAK1 [ XREF_BIBR ] .	In the non canonical pathway, upon TGF-beta ligand stimulation, receptors recruit TRAF6, which leads to lysine-63-linked autoubiquitylation, which in turn recruits and activates TAK1 [XREF_BIBR].	12	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	13	14	27	28
To rule out the possibility that different stimuli may induce TRAF6 mediated TAK1 K63 linked polyubiquitination at different sites , we have examined the effect of TAK1 K158R and K34R mutation on TGF-beta-induced TAK1 polyubiquitination and IKK , JNK as well as p38 activation .	To rule out the possibility that different stimuli may induce TRAF6 mediated TAK1 K63 linked polyubiquitination at different sites, we have examined the effect of TAK1 K158R and K34R mutation on TGF-beta-induced TAK1 polyubiquitination and IKK, JNK as well as p38 activation.	9	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	10	11	12	13
TRAF6 activates TAK1 to promote NF-kappaB signaling via the canonical pathway ( XREF_FIG ) .	TRAF6 activates TAK1 to promote NF-kappaB signaling via the canonical pathway (XREF_FIG).	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	2	3
Ubiquinated TRAF6 activates TAK1 a kinase phosphorylating IKKs and MKKs , resulting in gene expression which is thereby blocked [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Ubiquinated TRAF6 activates TAK1 a kinase phosphorylating IKKs and MKKs, resulting in gene expression which is thereby blocked [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	4	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	1	2	3	4
TRAF6 subsequently activates TGF-beta-activated kinase 1 ( TAK1 ) , which in turn activates MAPK / AP-1 and the IkappaB kinase ( IKK ) / NF-kappaB signaling pathways , resulting in a rapid innate immune response [ XREF_BIBR , XREF_BIBR ] .	TRAF6 subsequently activates TGF-beta-activated kinase 1 (TAK1), which in turn activates MAPK / AP-1 and the IkappaB kinase (IKK) / NF-kappaB signaling pathways, resulting in a rapid innate immune response [XREF_BIBR, XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	7	8
However , autoubiquitylation of TRAF6 is unlikely to play a role in recruiting TAK1 , as lysine free TRAF6 has been demonstrated to restore IL-1-stimulated TAK1 activation to TRAF6 -/- cells [ XREF_BIBR ] .	However, autoubiquitylation of TRAF6 is unlikely to play a role in recruiting TAK1, as lysine free TRAF6 has been demonstrated to restore IL-1-stimulated TAK1 activation to TRAF6 -/- cells [XREF_BIBR].	16	26	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	18	19	25	26
TRAF6 also activates TAK1 in an ubiquitin dependent manner .	TRAF6 also activates TAK1 in an ubiquitin dependent manner.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	0	1	3	4
The activation of TAK1 was reported to require the interaction of the ubiquitin ligase TRAF6 with the TGF-beta receptor complex followed by a consequent direct activation of TAK1 by TRAF6 [ XREF_BIBR , XREF_BIBR ] .	The activation of TAK1 was reported to require the interaction of the ubiquitin ligase TRAF6 with the TGF-beta receptor complex followed by a consequent direct activation of TAK1 by TRAF6 [XREF_BIBR, XREF_BIBR].	25	33	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	29	30	27	28
Although the exact mechanisms are unclear , GIDE mediated TAK1 activation may be similar to how TAK1 is activated by TRAF6 .	Although the exact mechanisms are unclear, GIDE mediated TAK1 activation may be similar to how TAK1 is activated by TRAF6.	16	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	20	21	16	17
In these pathways , TRAF6 signals through TAK1 and the auto-ubiquitination of TRAF6 is sufficient to trigger the activation of TAK1 .	In these pathways, TRAF6 signals through TAK1 and the auto-ubiquitination of TRAF6 is sufficient to trigger the activation of TAK1.	10	21	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	auto-ubiquitination of TRAF6	traf6	TAK1	TAK1	tak1	12	13	20	21
Since human CRLF2 can not be activated by mouse TSLP , conventional mouse xenograft models are not suitable to test the efficacy of ruxolitinib and other JAK inhibitors on JAK2 mutated cells .	Since human CRLF2 can not be activated by mouse TSLP, conventional mouse xenograft models are not suitable to test the efficacy of ruxolitinib and other JAK inhibitors on JAK2 mutated cells.	1	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	CRLF2	CRLF2	CRLF2	9	10	2	3
TSLP activates multiple immune cell subsets expressing the TSLPR complex and plays a role in several models of disease .	TSLP activates multiple immune cell subsets expressing the TSLPR complex and plays a role in several models of disease.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	0	1	8	9
Human platelets express functional TSLPR , which can be activated by TSLP to promote platelet activation .	Human platelets express functional TSLPR, which can be activated by TSLP to promote platelet activation.	2	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	11	12	4	5
TSLP induced preferential proliferation of CRLF2 wild-type and IL7RA mutant cells in comparison to CRLF2 wild-type and IL7RA wild-type cells .	TSLP induced preferential proliferation of CRLF2 wild-type and IL7RA mutant cells in comparison to CRLF2 wild-type and IL7RA wild-type cells.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	CRLF2	CRLF2	CRLF2	0	1	5	6
Interestingly , TSLP induces down-modulation of TSLPR and slightly IL-7Ralpha ( XREF_FIG ) though expression of TSLPR mRNA in TSLP treated Th2 cells was not affected ( unpublished observation ) , suggesting the loss of cell surface expression reflected receptor internalization .	Interestingly, TSLP induces down-modulation of TSLPR and slightly IL-7Ralpha (XREF_FIG) though expression of TSLPR mRNA in TSLP treated Th2 cells was not affected (unpublished observation), suggesting the loss of cell surface expression reflected receptor internalization.	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	2	3	6	7
The absence of TSLP upregulation in TSLPR -/- mice suggests an autocrine loop of TSLP production in the lung ( XREF_FIG ) .	The absence of TSLP upregulation in TSLPR -/- mice suggests an autocrine loop of TSLP production in the lung (XREF_FIG).	3	8	upregulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	3	4	6	7
However , mouse TSLP is species specific and does not activate human CRLF2 .	However, mouse TSLP is species specific and does not activate human CRLF2.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	CRLF2	CRLF2	CRLF2	3	4	12	13
In fact , TSLP activates TSLPR + DCs and plasmacytoid DCs to induce functional Th2 and regulatory T ( Treg ) cells and human T follicular helper ( Tfh ) cells .	In fact, TSLP activates TSLPR + DCs and plasmacytoid DCs to induce functional Th2 and regulatory T (Treg) cells and human T follicular helper (Tfh) cells.	3	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	3	4	5	6
Induction of GATA-3 by TSLP upregulates TSLPR and ST2 , resulting in the ability of ILC2 to respond to TSLP and IL-33 for further enhancement of GATA-3 .	Induction of GATA-3 by TSLP upregulates TSLPR and ST2, resulting in the ability of ILC2 to respond to TSLP and IL-33 for further enhancement of GATA-3.	2	8	upregulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	4	5	6	7
CRLF2 is a receptor for the TSLP cytokine and thus TSLP induced CRLF2 signaling likely contributes to oncogenesis and progression of CRLF2+ B-ALL .	CRLF2 is a receptor for the TSLP cytokine and thus TSLP induced CRLF2 signaling likely contributes to oncogenesis and progression of CRLF2+ B-ALL.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	CRLF2	CRLF2	CRLF2	10	11	12	13
24 Thus , classic PDX mice do not model the TSLP induced CRLF2 signaling present in vivo in patients .	24 Thus, classic PDX mice do not model the TSLP induced CRLF2 signaling present in vivo in patients.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	CRLF2	CRLF2	CRLF2	10	11	12	13
TSLP alone had no effect on TSLPr expression , while co-priming with TSLP reduced TSLPr expression at 24 hours but enhanced TSLPr upregulation at later time points ; however , this effect was not observed in all atopic subjects ( XREF_FIG & data not shown ) .	TSLP alone had no effect on TSLPr expression, while co-priming with TSLP reduced TSLPr expression at 24 hours but enhanced TSLPr upregulation at later time points; however, this effect was not observed in all atopic subjects (XREF_FIG & data not shown).	0	22	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLPr	TSLPr	TSLPr	0	1	21	22
Our current study demonstrates that TSLP can modulate Eo/B lineage commitment , by inducing PB CD34 + cells to actively secrete chemokines and cytokines ( key among which is TNFalpha ) , which , together with IL-3 , induce the upregulation of TSLPR , leading to the subsequent amplification of Eo/B CFU .	Our current study demonstrates that TSLP can modulate Eo/B lineage commitment, by inducing PB CD34 + cells to actively secrete chemokines and cytokines (key among which is TNFalpha), which, together with IL-3, induce the upregulation of TSLPR, leading to the subsequent amplification of Eo/B CFU.	5	43	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	5	6	42	43
The marginal sensitivity for both inhibitors and the low levels of phosphorylated STAT5 in JAK2 mutated cells may be explained by lack of human TSLP ligand to activate the CRLF2 pathway in our culture conditions .	The marginal sensitivity for both inhibitors and the low levels of phosphorylated STAT5 in JAK2 mutated cells may be explained by lack of human TSLP ligand to activate the CRLF2 pathway in our culture conditions.	24	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	CRLF2	CRLF2	CRLF2	24	25	29	30
We have found that truncation between residues 130 and 131 does not diminish , but rather enhances the functional activity , although TSLP ( M29-124 ) did not activate the TSLPR complex ( XREF_FIG and XREF_FIG ) .	We have found that truncation between residues 130 and 131 does not diminish, but rather enhances the functional activity, although TSLP (M29-124) did not activate the TSLPR complex (XREF_FIG and XREF_FIG).	22	31	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	22	23	30	31
While Tslpr +/+ mice treated with control antibody that were sensitized to OVA on tape stripped skin exhibited esophageal eosinophilia following oral antigen challenge , Tslpr +/+ mice treated with a TSLP specific mAb and Tslpr -/- mice did not develop esophageal eosinophilia ( XREF_SUPPLEMENTARY ) .	While Tslpr +/+ mice treated with control antibody that were sensitized to OVA on tape stripped skin exhibited esophageal eosinophilia following oral antigen challenge, Tslpr +/+ mice treated with a TSLP specific mAb and Tslpr -/- mice did not develop esophageal eosinophilia (XREF_SUPPLEMENTARY).	25	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	Tslpr	Tslpr	Tslpr	31	32	25	26
TSLP signals through a heterodimer of TSLP receptor chain and IL7 receptor alpha chain [ XREF_BIBR ] .	TSLP signals through a heterodimer of TSLP receptor chain and IL7 receptor alpha chain [XREF_BIBR].	0	8	signals	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLP receptor	TSLP receptor	TSLP receptor	0	1	6	8
For example , thymic stromal lymphopoietin ( TSLP ) , which is released by keratinocytes in response to histaminergic signaling , activates neuronal TRPA1 downstream of the TSLP receptor [ XREF_BIBR ] .	For example, thymic stromal lymphopoietin (TSLP), which is released by keratinocytes in response to histaminergic signaling, activates neuronal TRPA1 downstream of the TSLP receptor [XREF_BIBR].	5	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLP receptor	TSLP receptor	TSLP receptor	7	8	27	29
12 In response to IL13 stimulation and binding IL4Ra and IL13Ra1 , TYK2 activates STAT1 and STAT6 , while JAK2 signaling is upstream of STAT3 activation .	12 In response to IL13 stimulation and binding IL4Ra and IL13Ra1, TYK2 activates STAT1 and STAT6, while JAK2 signaling is upstream of STAT3 activation.	12	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TYK2	TYK2	TYK2	STAT1	STAT1	STAT1	12	13	14	15
On the one hand , phosphorylation of TSC2 and raptor by AMPK is known to elevate TSC2 and TSC1 activity and reduce mTOR ' s kinase function , respectively [ XREF_BIBR , XREF_BIBR ] .	On the one hand, phosphorylation of TSC2 and raptor by AMPK is known to elevate TSC2 and TSC1 activity and reduce mTOR 's kinase function, respectively [XREF_BIBR, XREF_BIBR].	5	19	elevate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	phosphorylation of TSC2	tsc2	TSC1	TSC1	tsc1	7	8	18	19
Akt induced phosphorylation of the tumour suppressor TSC2 ( also known as tuberin ) causes the dissociation of TSC2 and TSC1 ( also known as hamartin ) , relieving their inhibition of mTOR kinase .	Akt induced phosphorylation of the tumour suppressor TSC2 (also known as tuberin) causes the dissociation of TSC2 and TSC1 (also known as hamartin), relieving their inhibition of mTOR kinase.	0	21	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	Akt induced phosphorylation of the tumour suppressor TSC2	tsc2	TSC1	TSC1	tsc1	7	8	20	21
PI3K stimulates mTORC1 by increasing Akt activity , which in turn phosphorylates TSC2 and relieves TSC1 and TSC2 inhibition of the mTORC1 activating GTPase Rheb .	PI3K stimulates mTORC1 by increasing Akt activity, which in turn phosphorylates TSC2 and relieves TSC1 and TSC2 inhibition of the mTORC1 activating GTPase Rheb.	5	18	relieves	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	Akt activity, which in turn phosphorylates TSC2	tsc2	TSC1	TSC1	tsc1	12	13	15	16
Hamartin and tuberin are products of the tumor suppressor genes , TSC1 and TSC2 , respectively .	Hamartin and tuberin are products of the tumor suppressor genes, TSC1 and TSC2, respectively.	0	12	are products	Positive_activation_copula_1	Positive_activation	Positive_activation	tuberin	tuberin	tuberin	TSC1	TSC1	TSC1	2	3	11	12
The complex consists of two proteins , hamartin or TSC1 ( the protein product of gene tsc1 ) and tuberin or TSC2 ( the protein product of gene tsc2 ) .	The complex consists of two proteins, hamartin or TSC1 (the protein product of gene tsc1) and tuberin or TSC2 (the protein product of gene tsc2).	7	22	product	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	TSC2	TSC2	TSC2	tsc1	tsc1	tsc1	21	22	16	17
Increased S6K activity is observed in TSC mutations in D. melanogaster , cells derived from TSC1 or TSC2 knockout mice , or cells treated with TSC1 or TSC2 small interfering RNA .	Increased S6K activity is observed in TSC mutations in D. melanogaster, cells derived from TSC1 or TSC2 knockout mice, or cells treated with TSC1 or TSC2 small interfering RNA.	15	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TSC2	TSC2	TSC2	TSC1	TSC1	TSC1	27	28	15	16
Phosphorylation of raptor and TSC2 , as downstream effectors of the ROS-AMPK axis , reduced mTORC1 activity since i ) raptor phosphorylation at Ser 722 and Ser 792 can promote its binding to 14-3-3 , which would attenuate the Ser Thr kinase function of mTOR [ XREF_BIBR ] ; and ii ) stimulatory phosphorylation of TSC2 at Ser 1387 can enhance the TSC2 and TSC1 tuberous sclerosis complex activity , which is a negative regulator of mTORC1 [ XREF_BIBR ] .	Phosphorylation of raptor and TSC2, as downstream effectors of the ROS-AMPK axis, reduced mTORC1 activity since i) raptor phosphorylation at Ser-722 and Ser-792 can promote its binding to 14-3-3, which would attenuate the Ser Thr kinase function of mTOR [XREF_BIBR]; and ii) stimulatory phosphorylation of TSC2 at Ser 1387 can enhance the TSC2 and TSC1 tuberous sclerosis complex activity, which is a negative regulator of mTORC1 [XREF_BIBR].	0	68	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSC2	Phosphorylation of raptor and TSC2	tsc2	TSC1	TSC1	tsc1	4	5	64	65
16 Hamartin and tuberin are the gene products of TSC1 and TSC2 , respectively .	16 Hamartin and tuberin are the gene products of TSC1 and TSC2, respectively.	1	11	are the gene products	Positive_activation_copula_1	Positive_activation	Positive_activation	tuberin	tuberin	tuberin	TSC1	TSC1	TSC1	3	4	9	10
TSC occurs due to the deletion , rearrangement and inactivating mutation of tumor suppressor genes TSC1 or TSC2 , that lead to abnormal proteins hamartin and tuberin , codified in the loci 9p34 and 16p13 , respectively .	TSC occurs due to the deletion, rearrangement and inactivating mutation of tumor suppressor genes TSC1 or TSC2, that lead to abnormal proteins hamartin and tuberin, codified in the loci 9p34 and 16p13, respectively.	15	28	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TSC2	TSC2	TSC2	hamartin	hamartin	hamartin	17	18	24	25
Hamartin and tuberin are products of the tumor suppressor genes TSC1 and TSC2 , respectively .	Hamartin and tuberin are products of the tumor suppressor genes TSC1 and TSC2, respectively.	0	12	are products	Positive_activation_copula_1	Positive_activation	Negative_activation	tuberin	tuberin	tuberin	TSC1	TSC1	TSC1	2	3	10	11
Similarly , expression of TSC2 in Tsc2 -/- MEFs induced upregulation of TSC1 ( XREF_FIG ) .	Similarly, expression of TSC2 in Tsc2 -/- MEFs induced upregulation of TSC1 (XREF_FIG).	2	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	expression of TSC2	tsc2	TSC1	TSC1	tsc1	4	5	12	13
Many of these , however , converge on the tuberous sclerosis genes TSC1 and TSC2 , which produce the proteins hamartin and tuberin , respectively , and act as regulators of mTORC1 .	Many of these, however, converge on the tuberous sclerosis genes TSC1 and TSC2, which produce the proteins hamartin and tuberin, respectively, and act as regulators of mTORC1.	11	22	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	TSC2	TSC2	hamartin	hamartin	hamartin	14	15	20	21
We also reported that TSC1 and TSC2 regulate the activity of RhoA and Rac1 GTPases in a reciprocal manner : TSC2 loss induces TSC1 dependent inhibition of Rac1 associated with RhoA activation XREF_BIBR .	We also reported that TSC1 and TSC2 regulate the activity of RhoA and Rac1 GTPases in a reciprocal manner : TSC2 loss induces TSC1 dependent inhibition of Rac1 associated with RhoA activation XREF_BIBR.	20	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	TSC2	TSC2	TSC1	TSC1	TSC1	20	21	23	24
41 Fisetin caused inhibition of the phosphorylation of TSC2 and increase in the protein expression of TSC2 consistent with the fact that Akt phosphorylates TSC2 and disrupts the TSC1 and TSC2complex , leading to activation of mTOR .	41 Fisetin caused inhibition of the phosphorylation of TSC2 and increase in the protein expression of TSC2 consistent with the fact that Akt phosphorylates TSC2 and disrupts the TSC1 and TSC2complex, leading to activation of mTOR.	1	30	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSC2	Fisetin caused inhibition of the phosphorylation of TSC2 and increase in the protein expression of TSC2 consistent with the fact that Akt phosphorylates TSC2	tsc2	TSC1	TSC1	tsc1	24	25	28	29
Phosphorylation of tuberin by PKB through a PI3K dependent pathway abrogates the inhibitory hamartin and tuberin activity towards mTOR .	Phosphorylation of tuberin by PKB through a PI3K dependent pathway abrogates the inhibitory hamartin and tuberin activity towards mTOR.	0	18	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	tuberin	Phosphorylation of tuberin	tuberin	hamartin	hamartin	hamartin	2	3	13	14
Firstly , AMPK may directly phosphorylate tuberous sclerosis complex 2 ( TSC2 ) on T1227 and S1345 , and activate the TSC1 and TSC2 compounds , which inhibit the activity of Ras homolog enriched in brain and mTOR .	Firstly, AMPK may directly phosphorylate tuberous sclerosis complex 2 (TSC2) on T1227 and S1345, and activate the TSC1 and TSC2 compounds, which inhibit the activity of Ras homolog enriched in brain and mTOR.	2	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	AMPK may directly phosphorylate tuberous sclerosis complex 2 (TSC2) on T1227 and S1345	tsc2	TSC1	TSC1	tsc1	11	12	21	22
TSC2 phosphorylation at serine 1387 by AMPK stimulates TSC2 and TSC1 activity , thus inhibiting mTORC1 .	TSC2 phosphorylation at serine 1387 by AMPK stimulates TSC2 and TSC1 activity, thus inhibiting mTORC1.	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	TSC2 phosphorylation at serine 1387	tsc2	TSC1	TSC1	tsc1	0	1	10	11
Energy stress , through activation of AMPK is also upstream of TSC1 and TSC2 , where AMPK dependent phosphorylation of TSC2 on Thr1227 and Ser1345 activates the TSC1 and TSC2 tumour suppressor , leading to mTORC1 inhibition [ XREF_BIBR ] .	Energy stress, through activation of AMPK is also upstream of TSC1 and TSC2, where AMPK dependent phosphorylation of TSC2 on Thr1227 and Ser1345 activates the TSC1 and TSC2 tumour suppressor, leading to mTORC1 inhibition [XREF_BIBR].	16	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	AMPK dependent phosphorylation of TSC2 on Thr1227 and Ser1345	tsc2	TSC1	TSC1	tsc1	20	21	27	28
Phosphorylation of TSC2 at S939 by AKT causes partitioning of TSC2 away from the membrane , its GAP target Rheb , and its activating partner TSC1 to the cytosol via 14-3-3 protein binding .	Phosphorylation of TSC2 at S939 by AKT causes partitioning of TSC2 away from the membrane, its GAP target Rheb, and its activating partner TSC1 to the cytosol via 14-3-3 protein binding.	0	28	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	Phosphorylation of TSC2 at S939	tsc2	TSC1	TSC1	tsc1	2	3	25	26
TSC1 and TSC2 produce the proteins hamartin and tuberin , respectively .	TSC1 and TSC2 produce the proteins hamartin and tuberin, respectively.	0	8	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	TSC2	TSC2	hamartin	hamartin	hamartin	2	3	6	7
The Rho activating domain of TSC1 overlaps with the region that binds TSC2 , indicating that TSC2 may modulate TSC1 dependent activation of Rho .	The Rho activating domain of TSC1 overlaps with the region that binds TSC2, indicating that TSC2 may modulate TSC1 dependent activation of Rho.	16	21	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	TSC2	TSC2	TSC1	TSC1	TSC1	16	17	19	20
Phosphorylation of TSC2 and raptor by AMPK is known to elevate TSC2 and TSC1 activity and reduce mTOR ' s kinase function , respectively [ XREF_BIBR , XREF_BIBR ] .	Phosphorylation of TSC2 and raptor by AMPK is known to elevate TSC2 and TSC1 activity and reduce mTOR 's kinase function, respectively [XREF_BIBR, XREF_BIBR].	0	14	elevate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	TSC1	TSC1	tsc1	2	3	13	14
Phosphorylation of TSC2 is thought to allow TSC1 and TSC2 to disassociate and stimulate mTOR activity .	Phosphorylation of TSC2 is thought to allow TSC1 and TSC2 to disassociate and stimulate mTOR activity.	0	13	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	TSC1	TSC1	tsc1	2	3	7	8
Importantly , however , only enhanced Stat3 activation by Tyk2 -- and to a certain extent hyperactive Erk1/2 signalling -- were essential for EMT induced by loss of AnxA1 ( XREF_FIG and S5B ) .	Importantly, however, only enhanced Stat3 activation by Tyk2 -- and to a certain extent hyperactive Erk1/2 signalling -- were essential for EMT induced by loss of AnxA1 (XREF_FIG and S5B).	6	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Tyk2	Tyk2	Tyk2	Stat3	Stat3	Stat3	9	10	6	7
Moreover , we show that SIAH2 reduces TYK2 and the TYK2 dependent activation of STAT3 in lung cancer cells .	Moreover, we show that SIAH2 reduces TYK2 and the TYK2 dependent activation of STAT3 in lung cancer cells.	10	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TYK2	TYK2	TYK2	STAT3	STAT3	STAT3	10	11	14	15
Using pSTAT3 levels as a readout of IL-22 signaling , HT-29 cells treated with siRNA against TYK2 , JAK1 , or both , were stimulated by IL-22 ( 10 ng/mL for 15 minutes ) , then pSTAT3 was evaluated by flow cytometry .	Using pSTAT3 levels as a readout of IL-22 signaling, HT-29 cells treated with siRNA against TYK2, JAK1, or both, were stimulated by IL-22 (10 ng/mL for 15 minutes), then pSTAT3 was evaluated by flow cytometry.	1	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	TYK2	TYK2	TYK2	pSTAT3	pSTAT3	pSTAT3	16	17	1	2
JAK1 together with JAK2 or TYK2 activates STAT3 [ XREF_BIBR ] .	JAK1 together with JAK2 or TYK2 activates STAT3 [XREF_BIBR].	3	9	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TYK2	TYK2	TYK2	STAT3	STAT3	STAT3	5	6	7	8
Here , we reveal that TYK2 induces STAT3 activation and that TYK2 is a SIAH2 target .	Here, we reveal that TYK2 induces STAT3 activation and that TYK2 is a SIAH2 target.	5	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TYK2	TYK2	TYK2	STAT3	STAT3	STAT3	5	6	7	8
The disruption of TRAF6 polyubiquitination suppresses the diacylglycerol-CBM ( CARD , BCL10 , and MALT1 complex ) , TRAF6-NF , and kappa B signaling pathway and significantly reduces the host inflammatory responses .	The disruption of TRAF6 polyubiquitination suppresses the diacylglycerol-CBM (CARD, BCL10, and MALT1 complex), TRAF6-NF, and kappa B signaling pathway and significantly reduces the host inflammatory responses.	3	15	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6 polyubiquitination	traf6	MALT1	MALT1	malt1	3	4	14	15
On the other hand , our data suggest that TRAF6 is able to accelerate the turnover of MALT1 in a MALT1-protease dependent manner ( XREF_FIG ) .	On the other hand, our data suggest that TRAF6 is able to accelerate the turnover of MALT1 in a MALT1-protease dependent manner (XREF_FIG).	9	18	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	9	10	17	18
This further indicated that proteolytic competency is required for TRAF6 mediated MALT1 down-regulation .	This further indicated that proteolytic competency is required for TRAF6 mediated MALT1 down-regulation.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	9	10	11	12
Therefore , the hypothesis of CBM-independency of TRAF6 mediated activation of MALT1 would need to be thoroughly tested in a complete CARD deficient background .	Therefore, the hypothesis of CBM-independency of TRAF6 mediated activation of MALT1 would need to be thoroughly tested in a complete CARD deficient background.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	7	8	11	12
By using MALT1 isoforms and cleaved fragments thereof , as well as TRAF6 WT and mutant forms , this work shows that TRAF6 induces N-terminal auto-proteolytic cleavage of MALT1 at R149 and accelerates MALT1 protein turnover .	By using MALT1 isoforms and cleaved fragments thereof, as well as TRAF6 WT and mutant forms, this work shows that TRAF6 induces N-terminal auto-proteolytic cleavage of MALT1 at R149 and accelerates MALT1 protein turnover.	22	32	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	22	23	28	29
TRAF6 can directly activate MALT1 , promoting self-cleavage at R149 .	TRAF6 can directly activate MALT1, promoting self-cleavage at R149.	0	5	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	0	1	4	5
To determine if TRAF6 ligase function is involved in TRAF6 dependent activation of MALT1 , co-transfections were carried out with the TRAF6 C70A mutant protein which is unable to interact with the Ubc13/E2 ubiquitin ligase complex resulting in loss of TRAF6 E3 ubiquitin ligase activity [ XREF_BIBR , XREF_BIBR ] .	To determine if TRAF6 ligase function is involved in TRAF6 dependent activation of MALT1, co-transfections were carried out with the TRAF6 C70A mutant protein which is unable to interact with the Ubc13/E2 ubiquitin ligase complex resulting in loss of TRAF6 E3 ubiquitin ligase activity [XREF_BIBR, XREF_BIBR].	9	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	9	10	13	14
TRAF6 triggers auto-proteolysis-dependent MALT1 down-regulation .	TRAF6 triggers auto-proteolysis-dependent MALT1 down-regulation.	0	4	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	0	1	3	4
These differences in activity became more prominent in the TM assay , indicating that C-terminal self-cleavage does hamper proteolytic function of MALT1 triggered by TRAF6 ( XREF_FIG ) .	These differences in activity became more prominent in the TM assay, indicating that C-terminal self-cleavage does hamper proteolytic function of MALT1 triggered by TRAF6 (XREF_FIG).	19	26	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	24	25	21	22
Inclusion of exon7 in MALT1A facilitates the recruitment of TRAF6 , which augments MALT1 scaffolding function , but not protease activity .	Inclusion of exon7 in MALT1A facilitates the recruitment of TRAF6, which augments MALT1 scaffolding function, but not protease activity.	7	15	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	9	10	13	14
The disruption of TRAF6 polyubiquitination suppresses the diacylglycerol-CBM ( CARD , BCL10 , and MALT1 complex ) , TRAF6-NF , and kappaB signaling pathway and dampens the host inflammatory responses XREF_BIBR .	The disruption of TRAF6 polyubiquitination suppresses the diacylglycerol-CBM (CARD, BCL10, and MALT1 complex), TRAF6-NF, and kappaB signaling pathway and dampens the host inflammatory responses XREF_BIBR.	3	15	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6 polyubiquitination	traf6	MALT1	MALT1	malt1	3	4	14	15
TRAF6-C70A failed to induce auto-cleavage of MALT1 ( XREF_FIG ) , implying that interaction of TRAF6 with the Ubc13/E2 ubiquitin ligase complex is required to activate MALT1 .	TRAF6-C70A failed to induce auto-cleavage of MALT1 (XREF_FIG), implying that interaction of TRAF6 with the Ubc13/E2 ubiquitin ligase complex is required to activate MALT1.	13	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	15	16	26	27
In the context of the current work , one might speculate that absence of TRAF6 , by preventing or limiting self-cleavage of MALT1 at R149 , led to stabilization of the CBM complex after T cell activation , resulting in signaling capabilities not adequately controlled by regulatory cells .	In the context of the current work, one might speculate that absence of TRAF6, by preventing or limiting self-cleavage of MALT1 at R149, led to stabilization of the CBM complex after T cell activation, resulting in signaling capabilities not adequately controlled by regulatory cells.	12	27	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	14	15	22	23
This work identified a prominent self-cleavage site of MALT1 isoform A ( MALT1A ) at R781 ( R770 in MALT1B ) and revealed that TRAF6 can activate MALT1 independently of the CBM .	This work identified a prominent self-cleavage site of MALT1 isoform A (MALT1A) at R781 (R770 in MALT1B) and revealed that TRAF6 can activate MALT1 independently of the CBM.	24	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	24	25	27	28
Dominant negative TRAF6 blocks MALT1 self-cleavage at R149 without interfering with CBM induced MALT1 activation .	Dominant negative TRAF6 blocks MALT1 self-cleavage at R149 without interfering with CBM induced MALT1 activation.	0	5	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	MALT1	MALT1	MALT1	2	3	4	5
The NDP independent component of signaling induced by forced FZD4 and LRP5 heterodimerization was not enhanced by TSPAN12 ( XREF_SUPPLEMENTARY ) .	The NDP independent component of signaling induced by forced FZD4 and LRP5 heterodimerization was not enhanced by TSPAN12 (XREF_SUPPLEMENTARY).	1	19	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	NDP	NDP	NDP	17	18	1	2
TSPAN12 enhances the Norrin signaling by augmentation of FZD4 multimerization [ XREF_BIBR ] .	TSPAN12 enhances the Norrin signaling by augmentation of FZD4 multimerization [XREF_BIBR].	0	4	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	Norrin	Norrin	Norrin	0	1	3	4
The finding that the TSPAN12 11-LEL chimera localizes to the plasma membrane at high levels , but does not enhance NDP and FZD4 signaling , suggests that essential protein protein interactions are disrupted .	The finding that the TSPAN12 11-LEL chimera localizes to the plasma membrane at high levels, but does not enhance NDP and FZD4 signaling, suggests that essential protein protein interactions are disrupted.	4	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	NDP	NDP	NDP	4	5	20	21
Current evidence indicates that Tspan12 is an integral part of the Norrin/Fz4/Lrp5 signaling complex , and that Tspan12 enhances Norrin induced but not Wnt induced canonical signaling through Fz4 ( Junge et al ., 2012 ) .	Current evidence indicates that Tspan12 is an integral part of the Norrin/Fz4/Lrp5 signaling complex, and that Tspan12 enhances Norrin induced but not Wnt induced canonical signaling through Fz4 (Junge et al., 2012).	17	23	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tspan12	Tspan12	Tspan12	Norrin	Norrin	Norrin	17	18	19	20
In cell culture , Tspan12 acts in conjunction with Fz4 and Lrp5 to specifically enhance Norrin signaling .	In cell culture, Tspan12 acts in conjunction with Fz4 and Lrp5 to specifically enhance Norrin signaling.	4	16	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tspan12	Tspan12	Tspan12	Norrin	Norrin	Norrin	4	5	15	16
This might be caused by a regulate protein TSPAN12 , which could specifically enhance Norrin and Frizzled 4 pathway , but not Wnt and Frizzled 4 18 in those brain regions .	This might be caused by a regulate protein TSPAN12, which could specifically enhance Norrin and Frizzled 4 pathway, but not Wnt and Frizzled 4 18 in those brain regions.	6	18	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	Norrin	Norrin	Norrin	8	9	14	15
Previous work has shown that in mouse , TSPAN12 promotes Norrin and beta-catenin signaling by enhancing clustering of the Norrin receptor FZD4 [ XREF_BIBR , XREF_BIBR ] .	Previous work has shown that in mouse, TSPAN12 promotes Norrin and beta-catenin signaling by enhancing clustering of the Norrin receptor FZD4 [XREF_BIBR, XREF_BIBR].	8	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	Norrin	Norrin	Norrin	8	9	10	11
Our data support a model in which TSPAN12 functions in the NDP receptor complex as a co-receptor for NDP , facilitates selective ligand recognition , and enhances NDP and FZD4 signaling strength to a level that is required for normal retinal angiogenesis and blood-retina barrier function .	Our data support a model in which TSPAN12 functions in the NDP receptor complex as a co-receptor for NDP, facilitates selective ligand recognition, and enhances NDP and FZD4 signaling strength to a level that is required for normal retinal angiogenesis and blood-retina barrier function.	7	31	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	NDP	NDP	NDP	7	8	27	28
We also observed that TSPAN12 promotes binding of wild type NDP to FZD4 ( XREF_FIG and XREF_FIG ) .	We also observed that TSPAN12 promotes binding of wild type NDP to FZD4 (XREF_FIG and XREF_FIG).	4	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	NDP	NDP	NDP	4	5	10	11
TSPAN12 enhances NDP induced axis duplication in frog embryos .	TSPAN12 enhances NDP induced axis duplication in frog embryos.	0	3	enhances	Positive_activation_token_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	NDP	NDP	NDP	0	1	2	3
These in vivo findings are in good agreement with the observation that TSPAN12 restores binding and signaling of NDP and FZD4 M105V .	These in vivo findings are in good agreement with the observation that TSPAN12 restores binding and signaling of NDP and FZD4 M105V.	12	21	restores	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	NDP	NDP	NDP	12	13	18	19
TSPAN12 participation in Norrin receptor complex significantly increases Norrin signaling through nuclear beta-catenin , but does not change Wnt ligand dependent signaling XREF_BIBR .	TSPAN12 participation in Norrin receptor complex significantly increases Norrin signaling through nuclear beta-catenin, but does not change Wnt ligand dependent signaling XREF_BIBR.	0	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	Norrin	Norrin	Norrin	0	1	8	9
Because TSPAN12 enhances NDP- but not WNT7A/B induced signaling , whereas GPR124 enhances WNT7A/B- but not NDP signaling , the accessory proteins are candidates for mediating ligand selectivity of receptor complexes containing FZD .	Because TSPAN12 enhances NDP- but not WNT7A/B induced signaling, whereas GPR124 enhances WNT7A/B- but not NDP signaling, the accessory proteins are candidates for mediating ligand selectivity of receptor complexes containing FZD.	1	6	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	NDP-	NDP-	NDP-	1	2	3	4
An increase of TSPAN12 in CNS could prominently enhance the protective effects of Norrin but not Wnt 18 .	An increase of TSPAN12 in CNS could prominently enhance the protective effects of Norrin but not Wnt 18.	1	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	Norrin	Norrin	Norrin	3	4	13	14
These experiments show that Gpr124 enhances Wnt7a but not Norrin signaling , and that Tspan12 enhances Norrin but not Wnt7a signaling .	These experiments show that Gpr124 enhances Wnt7a but not Norrin signaling, and that Tspan12 enhances Norrin but not Wnt7a signaling.	14	20	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tspan12	Tspan12	Tspan12	Norrin	Norrin	Norrin	14	15	16	17
A striking example is TSPAN12 , a TM protein that potentiates Norrin mediated , but not Wnt mediated , signaling of FZD4 via the induction of intramembrane receptor multimerization .	A striking example is TSPAN12, a TM protein that potentiates Norrin mediated, but not Wnt mediated, signaling of FZD4 via the induction of intramembrane receptor multimerization.	2	16	potentiates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TSPAN12	TSPAN12	TSPAN12	Norrin	Norrin	Norrin	4	5	11	12
Additionally , TTK activity at the kinetochore stimulates MAD1 dependent conformational changes in MAD2L1 from an open to a closed form [ XREF_BIBR , XREF_BIBR ] , which is crucial for inhibition of anaphase promoting complex and cyclosome ( APC/C ) [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] , the ubiquitin ligase that controls anaphase onset .	Additionally, TTK activity at the kinetochore stimulates MAD1 dependent conformational changes in MAD2L1 from an open to a closed form [XREF_BIBR, XREF_BIBR], which is crucial for inhibition of anaphase promoting complex and cyclosome (APC/C) [XREF_BIBR, XREF_BIBR - XREF_BIBR], the ubiquitin ligase that controls anaphase onset.	2	14	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TTK	TTK	TTK	MAD2L1	MAD2L1	MAD2L1	2	3	13	14
Furthermore , artificial recruitment of Mps1 to kinetochores before mitosis by inducible expression of Mis12-Mps1 Delta200 caused Mad2 accumulation at kinetochores of G2-phase cells ( XREF_SUPPLEMENTARY ) .	Furthermore, artificial recruitment of Mps1 to kinetochores before mitosis by inducible expression of Mis12-Mps1 Delta200 caused Mad2 accumulation at kinetochores of G2-phase cells (XREF_SUPPLEMENTARY).	3	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	recruitment of Mps1 to kinetochores	mps1	Mad2	Mad2	mad2	5	6	17	18
By using a chemical inhibitor AZ3146 to inhibit Mps1 during different cell cycle stages , they have shown that inhibition of the Mps1 kinase activity before mitotic entry disrupts the kinetochore localization of both Mad1 and Mad2 .	By using a chemical inhibitor AZ3146 to inhibit Mps1 during different cell cycle stages, they have shown that inhibition of the Mps1 kinase activity before mitotic entry disrupts the kinetochore localization of both Mad1 and Mad2.	22	37	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1	Mps1	Mad2	Mad2	Mad2	22	23	36	37
Mps1 kinase activity promotes localization of Mad1 , Mad2 , Cdc20 and Bub1 to unattached kinetochores .	Mps1 kinase activity promotes localization of Mad1, Mad2, Cdc20 and Bub1 to unattached kinetochores.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1	Mps1	Mad2	Mad2	Mad2	0	1	8	9
In the absence of endogenous Mps1 , both Mps1 2A and Mps1 2D localized to kinetochore and restored the kinetochore localization of Mad1 and Mad2 ( XREF_FIG ) .	In the absence of endogenous Mps1, both Mps1 2A and Mps1 2D localized to kinetochore and restored the kinetochore localization of Mad1 and Mad2 (XREF_FIG).	8	25	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1	Mps1	Mad2	Mad2	Mad2	8	9	24	25
In addition , Mps1 catalytic activity enhances the production of closed Mad2 in human cells , underlining the importance of Mps1 in maintaining a SAC response .	In addition, Mps1 catalytic activity enhances the production of closed Mad2 in human cells, underlining the importance of Mps1 in maintaining a SAC response.	3	14	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1	Mps1	Mad2	Mad2	Mad2	3	4	11	12
Moreover , Mps1 activity at the kinetochore has been proposed to stimulate Mad1 dependent conformational change of Mad2 from an open to a closed form that is crucial for inhibition of the Cdc20 , anaphase , and promoting complex and cyclosome , the ubiquitin ligase that controls anaphase onset .	Moreover, Mps1 activity at the kinetochore has been proposed to stimulate Mad1 dependent conformational change of Mad2 from an open to a closed form that is crucial for inhibition of the Cdc20-anaphase-promoting complex and cyclosome, the ubiquitin ligase that controls anaphase onset.	2	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1	Mps1	Mad2	Mad2	Mad2	2	3	17	18
However , Mad2 and Bub3 localization is lost in cells treated with Mps1 morpholinos .	However, Mad2 and Bub3 localization is lost in cells treated with Mps1 morpholinos.	2	13	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Mps1	Mps1	Mps1	Mad2	Mad2	Mad2	12	13	2	3
Mps1 activity directs checkpoint proteins to unattached kinetochores , allows Mad2 conformational activation , and stabilizes the cytoplasmic APC/C inhibitory complexes .	Mps1 activity directs checkpoint proteins to unattached kinetochores, allows Mad2 conformational activation, and stabilizes the cytoplasmic APC/C inhibitory complexes.	0	12	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1	Mps1	Mad2	Mad2	Mad2	0	1	10	11
In cells lacking Mps1 , expression of Mps1 WT restored the kinetochore localization of Mad2 .	In cells lacking Mps1, expression of Mps1 WT restored the kinetochore localization of Mad2.	5	15	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	expression of Mps1	mps1	Mad2	Mad2	mad2	7	8	14	15
As described above ( see section Mps1 targets Mad1 and Mad2 to kinetochores ) , repression of Mps1 reduced kinetochore bound Mad1 to ~ 30 % ( unpublished data ) .	As described above (see section Mps1 targets Mad1 and Mad2 to kinetochores), repression of Mps1 reduced kinetochore bound Mad1 to ~ 30% (unpublished data).	5	11	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1	Mps1	Mad2	Mad2	Mad2	6	7	10	11
These observations suggest that Mps1 overexpression might result in transient detachment of one or two occasional kinetochores , causing SAC activation and metaphase delay in mad2 + embryos .	These observations suggest that Mps1 overexpression might result in transient detachment of one or two occasional kinetochores, causing SAC activation and metaphase delay in mad2 + embryos.	4	27	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1 overexpression	mps1	mad2	mad2	mad2	4	5	25	26
In agreement with these observations , in vivo treatment with ASA led to TRAF2 and TRAF6 polyubiquitylation and degradation that could be prevented by pretreatment with PR11 ( XREF_FIG ) .	In agreement with these observations, in vivo treatment with ASA led to TRAF2 and TRAF6 polyubiquitylation and degradation that could be prevented by pretreatment with PR11 (XREF_FIG).	11	17	led	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	TRAF6	TRAF6 polyubiquitylation	traf6	TRAF6	TRAF6	traf6	15	16	15	16
Finally , we revealed that A20 was required to inhibit CVB3 induced NF-kappaB signaling by restricting TNF receptor associated factor 6 ( TRAF6 ) ubiquitylation .	Finally, we revealed that A20 was required to inhibit CVB3 induced NF-kappaB signaling by restricting TNF receptor associated factor 6 (TRAF6) ubiquitylation.	11	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF receptor associated factor 6	TNF receptor associated factor 6 (TRAF6) ubiquitylation	tnf receptor associated factor 6	TNF receptor associated factor 6	TNF receptor associated factor 6	tnf receptor associated factor 6	16	21	16	21
Exogenous TRAF6 expression was thus able to rescue the interaction between TNIK and LMP1 in TRAF6 deficient cells .	Exogenous TRAF6 expression was thus able to rescue the interaction between TNIK and LMP1 in TRAF6 deficient cells.	1	17	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6 expression	traf6	TRAF6	TRAF6	traf6	1	2	15	16
p62 induces polyubiquitination and oligomerization of TRAF6 , thereby enhancing the ubiquitin ligase activity of TRAF6 .	p62 induces polyubiquitination and oligomerization of TRAF6, thereby enhancing the ubiquitin ligase activity of TRAF6.	0	16	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	p62 induces polyubiquitination and oligomerization of TRAF6	traf6	TRAF6	TRAF6	traf6	6	7	15	16
Like TRAF2 , TRAF6 overexpression induces malignant transformation and TRAF6 depletion inhibits lung cancer cell proliferation and tumorigenesis .	Like TRAF2, TRAF6 overexpression induces malignant transformation and TRAF6 depletion inhibits lung cancer cell proliferation and tumorigenesis.	3	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF6	TRAF6 overexpression	traf6	TRAF6	TRAF6	traf6	3	4	9	10
If a similar relation holds for the TRAF6-Lyn interaction , Lyn would phosphorylate TRAF6 and stimulate the downstream TRAF6 signaling in LPS treated cells while TRAF6 would catalyze Lys 63 -mediated ubiquitination of Lyn .	If a similar relation holds for the TRAF6-Lyn interaction, Lyn would phosphorylate TRAF6 and stimulate the downstream TRAF6 signaling in LPS treated cells while TRAF6 would catalyze Lys 63 -mediated ubiquitination of Lyn.	10	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	Lyn would phosphorylate TRAF6	traf6	TRAF6	TRAF6	traf6	13	14	18	19
It has been demonstrated that TRAF6 mediated RANK signaling in pre-OCs is negatively regulated de-ubiquitinase CYLD , and that CYLD deficient mice exhibit osteoporosis due to increased OC activity .	It has been demonstrated that TRAF6 mediated RANK signaling in pre-OCs is negatively regulated de-ubiquitinase CYLD, and that CYLD deficient mice exhibit osteoporosis due to increased OC activity.	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	RANK	RANK	RANK	5	6	7	8
The RANKL and RANK Pathway Mediated by TRAF6 Is Critical to Osteoclastogenesis in MM .	The RANKL and RANK Pathway Mediated by TRAF6 Is Critical to Osteoclastogenesis in MM.	1	8	Mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	RANK	RANK	RANK	7	8	3	4
In the former category , TRAF6 in DCs is a critical mediator of the TNFRSF members CD40 and RANK .	In the former category, TRAF6 in DCs is a critical mediator of the TNFRSF members CD40 and RANK.	5	19	is a critical mediator	Positive_activation_copula_1	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	RANK	RANK	RANK	5	6	18	19
Considering the well documented role of TRAF6 signaling in RANK mediated osteoclastogenesis [ XREF_BIBR ] , it may , therefore , be hypothesized that TRAF6 is involved in differentiation of osteoclasts in RA .	Considering the well documented role of TRAF6 signaling in RANK mediated osteoclastogenesis [XREF_BIBR], it may, therefore, be hypothesized that TRAF6 is involved in differentiation of osteoclasts in RA.	6	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	RANK	RANK	RANK	6	7	9	10
TRAF6 mediated RANK signaling is also required for expression of the osteoclast master regulatory transcription factor NFATc1 .	TRAF6 mediated RANK signaling is also required for expression of the osteoclast master regulatory transcription factor NFATc1.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	RANK	RANK	RANK	0	1	2	3
Further studies show that within its role as a regulator of osteoclast differentiation and function , TRAF6 mediates RANK dependent NF-kappaB , MAPK , and Akt and PBK signaling , osteoclast maturation and cytoskeletal rearrangement , as well as induction of reactive oxygen species ( ROS ) pathways necessary for optimal osteoclastogenesis .	Further studies show that within its role as a regulator of osteoclast differentiation and function, TRAF6 mediates RANK dependent NF-kappaB, MAPK, and Akt and PBK signaling, osteoclast maturation and cytoskeletal rearrangement, as well as induction of reactive oxygen species (ROS) pathways necessary for optimal osteoclastogenesis.	16	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	RANK	RANK	RANK	16	17	18	19
Several studies indicated that TRAF6 mediates RANK signaling and CD40 signaling but not LtbetaR signaling .	Several studies indicated that TRAF6 mediates RANK signaling and CD40 signaling but not LtbetaR signaling.	4	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	RANK	RANK	RANK	4	5	6	7
In human cells , Mps1 promotes biorientation by regulating Aurora B activity through phosphorylation of the chromosomal passenger complex ( CPC ) member Borealin XREF_BIBR , XREF_BIBR .	In human cells, Mps1 promotes biorientation by regulating Aurora B activity through phosphorylation of the chromosomal passenger complex (CPC) member Borealin XREF_BIBR, XREF_BIBR.	4	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1	Mps1	Borealin	Borealin	Borealin	4	5	23	24
TRIM24 augments AR signaling , and AR and TRIM24 co-activated genes are significantly up-regulated in CRPC .	TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly up-regulated in CRPC.	0	3	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIM24	TRIM24	TRIM24	AR	AR	AR	0	1	2	3
TRIM24 has been shown to mediate ligand dependent activation of the androgen receptor -- a key prostate cancer driver-and to degrade TP53 through its E3 ligase activity .	TRIM24 has been shown to mediate ligand dependent activation of the androgen receptor -- a key prostate cancer driver-and to degrade TP53 through its E3 ligase activity.	0	13	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIM24	TRIM24	TRIM24	androgen receptor	androgen receptor	androgen receptor	0	1	11	13
More specifically , genes within the signature were defined as those in a 100kb interval around overlapping AR and TRIM24 sites , which were also down-regulated by siRNA targeting AR and TRIM24 ( LIMMA , p < 0.05 , fold-change > 1.5 ) .	More specifically, genes within the signature were defined as those in a 100kb interval around overlapping AR and TRIM24 sites, which were also down-regulated by siRNA targeting AR and TRIM24 (LIMMA, p < 0.05, fold-change> 1.5).	19	31	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIM24	TRIM24	TRIM24	AR	AR	AR	19	20	29	30
In line with these observations , TRIM24 was shown to enhance AR mediated gene activation in reporter assays .	In line with these observations, TRIM24 was shown to enhance AR mediated gene activation in reporter assays.	6	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRIM24	TRIM24	TRIM24	AR	AR	AR	6	7	11	12
Conversely , the protein showed strong interaction with TAB2 , which was enhanced even further by the co-expression TRAF6 ( XREF_FIG ) .	Conversely, the protein showed strong interaction with TAB2, which was enhanced even further by the co-expression TRAF6 (XREF_FIG).	4	20	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAB2	TAB2	TAB2	18	19	8	9
17 TRAF6 ultimately recruits TAB2 and activates TAB2 associated TGF-beta-activated kinase 1 ( TAK1 ) eventually promoting cell survival through activation of NF-kappaB .	17 TRAF6 ultimately recruits TAB2 and activates TAB2 associated TGF-beta-activated kinase 1 (TAK1) eventually promoting cell survival through activation of NF-kappaB.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAB2	TAB2	TAB2	1	2	7	8
Importantly , we demonstrate that Tyk2 slows down IFNAR1 degradation and that this is due , at least in part , to inhibition of IFNAR1 endocytosis .	Importantly, we demonstrate that Tyk2 slows down IFNAR1 degradation and that this is due, at least in part, to inhibition of IFNAR1 endocytosis.	5	9	slows	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tyk2	Tyk2	Tyk2	IFNAR1	IFNAR1	IFNAR1	5	6	8	9
These defects could not be explained by total STAT1 content , surface expression of IFN-AR components ( XREF_FIG E-G ) , failure to phosphorylate Tyk2 or Jak1 or IFN-alpha induced downregulation of IFN-AR from the cell surface of gamma-H2AX+ CD8+ T lymphocytes ( XREF_FIG H ) .	These defects could not be explained by total STAT1 content, surface expression of IFN-AR components (XREF_FIG E-G), failure to phosphorylate Tyk2 or Jak1 or IFN-alpha induced downregulation of IFN-AR from the cell surface of gamma-H2AX+ CD8+ T lymphocytes (XREF_FIG H).	23	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tyk2	phosphorylate Tyk2	tyk2	IFN-AR	IFN-AR	ifn-ar	24	25	32	33
Studies have demonstrated that tyk2 stabilizes the expression and increases the half-life of IFNAR1 , and that this in turn has lead to increased interferon alpha receptor engagement .	Studies have demonstrated that tyk2 stabilizes the expression and increases the half-life of IFNAR1, and that this in turn has lead to increased interferon alpha receptor engagement.	4	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tyk2	tyk2	tyk2	IFNAR1	IFNAR1	IFNAR1	4	5	13	14
TRAF6 activates IKK in a K63-ubiquitin chain dependent manner that requires the dimeric E2 enzyme complex Ubc13 and Uev1a as well as the transforming growth factor receptor-beta-activated kinase 1 ( TAK1 ) and its regulatory subunits TAB1 and TAB2 [ XREF_BIBR ] .	TRAF6 activates IKK in a K63-ubiquitin chain dependent manner that requires the dimeric E2 enzyme complex Ubc13 and Uev1a as well as the transforming growth factor receptor-beta-activated kinase 1 (TAK1) and its regulatory subunits TAB1 and TAB2 [XREF_BIBR].	0	40	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAB1	TAB1	TAB1	0	1	36	37
Activated Chk2 stabilizes Mps1 protein levels , possibly through phosphorylating Mps1-T288 and inhibits Cdk1-Y15 phosphorylation through an Mps1 dependent mechanism to prevent mitotic exit after prolonged checkpoint activation .	Activated Chk2 stabilizes Mps1 protein levels, possibly through phosphorylating Mps1-T288 and inhibits Cdk1-Y15 phosphorylation through an Mps1 dependent mechanism to prevent mitotic exit after prolonged checkpoint activation.	0	6	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1 protein levels	mps1	Chk2	Chk2	chk2	3	4	1	2
Tpl2 is probably also activated by the TRAF6 complex and seems to be essential for the production of TNF , IL-6 , and in some cells type I IFNs .	Tpl2 is probably also activated by the TRAF6 complex and seems to be essential for the production of TNF, IL-6, and in some cells type I IFNs.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	Tpl2	Tpl2	Tpl2	7	8	0	1
However , UBC9 overexpression was also found to inhibit osteoblast differentiation by suppressing BMP and SMAD4 signaling 8 .	However, UBC9 overexpression was also found to inhibit osteoblast differentiation by suppressing BMP and SMAD4 signaling 8.	2	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	UBC9	UBC9 overexpression	ubc9	SMAD4	SMAD4	smad4	2	3	15	16
Thus , the phosphorylation of Rlk appears to cause an increase in Rlk kinase activity .	Thus, the phosphorylation of Rlk appears to cause an increase in Rlk kinase activity.	3	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rlk	phosphorylation of Rlk	rlk	Rlk	Rlk	rlk	5	6	12	13
Furthermore , we have observed that the phosphorylation of Rlk by Fyn increases Rlk turnover , consistent with the increased turnover observed with other TCR signaling molecules following activation .	Furthermore, we have observed that the phosphorylation of Rlk by Fyn increases Rlk turnover, consistent with the increased turnover observed with other TCR signaling molecules following activation.	7	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Rlk	phosphorylation of Rlk	rlk	Rlk	Rlk	rlk	9	10	13	14
An alternative spice variant of Tshb ( Tshb-sv ) that includes a 27 nucleotide portion of intron 4 adjoining the coding region of exon 5 has been previously identified in mouse ( XREF_FIG B ) but not human bone marrow and has also been shown to stimulate a cAMP response in TSHR expressing cells in vitro .	An alternative spice variant of Tshb (Tshb-sv) that includes a 27 nucleotide portion of intron 4 adjoining the coding region of exon 5 has been previously identified in mouse (XREF_FIG B) but not human bone marrow and has also been shown to stimulate a cAMP response in TSHR expressing cells in vitro.	3	53	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Tshb	Tshb	Tshb	TSHR	TSHR	TSHR	5	6	51	52
TRPM7 is ubiquitous and appears to activate both myosin IIA heavy chain and annexin 1 , which suggests a role in cell growth , survival and cytoskeleton function .	TRPM7 is ubiquitous and appears to activate both myosin IIA heavy chain and annexin 1, which suggests a role in cell growth, survival and cytoskeleton function.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TRPM7	TRPM7	TRPM7	annexin 1	annexin 1	annexin 1	0	1	13	15
These results demonstrate that TTK stimulates the malignance of HCC cells via Akt and mTOR and MDM2 and p53 activation in a p53 dependent mechanism .	These results demonstrate that TTK stimulates the malignance of HCC cells via Akt and mTOR and MDM2 and p53 activation in a p53 dependent mechanism.	4	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TTK	TTK	TTK	p53	p53	p53	4	5	18	19
VEGF-A is defined to increase micro-vascular growth and permeability via specific receptors such as fms like tyrosine kinase 1 ( FLT-1 ) , VEGFR1 and fetal liver kinase 1 ( FLK-1 ) .	VEGF-A is defined to increase micro-vascular growth and permeability via specific receptors such as fms like tyrosine kinase 1 (FLT-1), VEGFR1 and fetal liver kinase 1 (FLK-1).	0	30	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	fetal liver kinase 1	fetal liver kinase 1	fetal liver kinase 1	0	1	25	29
Activation of VEGFR2 by VEGF-A is necessary for many critical processes of physiologic and pathologic angiogenesis .	Activation of VEGFR2 by VEGF-A is necessary for many critical processes of physiologic and pathologic angiogenesis.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	4	5	2	3
VEGF-A activates VEGFR-1 and VEGFR-2 , whereas VEGF-B and PlGF bind to only VEFGR-1 .	VEGF-A activates VEGFR-1 and VEGFR-2, whereas VEGF-B and PlGF bind to only VEFGR-1.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	0	1	4	5
The mechanism of VEGFA activation of VEGFR2 has been well studied and through mutational analysis , the second and third Ig domain were identified [ XREF_BIBR ] .	The mechanism of VEGFA activation of VEGFR2 has been well studied and through mutational analysis, the second and third Ig domain were identified [XREF_BIBR].	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	3	4	6	7
Collectively , these data indicated that Myocardin nitrosylation by nitric oxide after VEGF-A induced VEGFR2 activation provides a critical checkpoint for STAT3 activation and subsequent VSMC proliferation .	Collectively, these data indicated that Myocardin nitrosylation by nitric oxide after VEGF-A induced VEGFR2 activation provides a critical checkpoint for STAT3 activation and subsequent VSMC proliferation.	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	12	13	14	15
These three TR3 transcript variant mRNAs are differentially regulated in endothelial cells by VEGF-A through a novel signaling pathway , in which VEGF-A and VEGF-E , but neither VEGF-B , nor PlGF , induce the interaction of VEGFR2 and KDR with insulin like growth factor-1 receptor ( IGF-1R ) , resulting in IGF-1R transactivation [ XREF_BIBR ] .	These three TR3 transcript variant mRNAs are differentially regulated in endothelial cells by VEGF-A through a novel signaling pathway, in which VEGF-A and VEGF-E, but neither VEGF-B, nor PlGF, induce the interaction of VEGFR2 and KDR with insulin like growth factor-1 receptor (IGF-1R), resulting in IGF-1R transactivation [XREF_BIBR].	22	39	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	22	23	37	38
In conclusion , this study demonstrates that CA by suppressing VEGFA mediated activation of VEGFR-2 inhibits the pro angiogenic actions of this cytokine on endothelial cells .	In conclusion, this study demonstrates that CA by suppressing VEGFA mediated activation of VEGFR-2 inhibits the pro angiogenic actions of this cytokine on endothelial cells.	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR-2	VEGFR-2	VEGFR-2	10	11	14	15
We conclude that VEGF-A stimulation of VEGFR2 + vascular progenitor cells specifically induces Ras-Erk activation around 6-9 h after stimulation , which in turn specifies endothelial differentiation .	We conclude that VEGF-A stimulation of VEGFR2 + vascular progenitor cells specifically induces Ras-Erk activation around 6-9 h after stimulation, which in turn specifies endothelial differentiation.	3	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	3	4	6	7
Vascular endothelial growth factor , which is expressed by podocytes both during development and in the adult , activates VEGFR-2 on glomerular capillary endothelial cells .	Vascular endothelial growth factor, which is expressed by podocytes both during development and in the adult, activates VEGFR-2 on glomerular capillary endothelial cells.	0	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vascular endothelial growth factor	Vascular endothelial growth factor, which is expressed	vascular endothelial growth factor	VEGFR-2	VEGFR-2	vegfr-2	0	4	19	20
As VEGFA induces VEGFR2 homodimers and VEGFR2/-3 heterodimers but not VEGFR3 homodimers ( XREF_FIG ) , these data indicate that the effect of the VEGFR3 neutralizing antibodies is to block formation of VEGFR2/-3 heterodimers .	As VEGFA induces VEGFR2 homodimers and VEGFR2/-3 heterodimers but not VEGFR3 homodimers (XREF_FIG), these data indicate that the effect of the VEGFR3 neutralizing antibodies is to block formation of VEGFR2/-3 heterodimers.	1	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	1	2	3	4
The lack of effect of Y297A NRP1 on KDR phosphorylation probably reflects the fact that KDR activation by VEGF-A 165 is mainly independent of NRP1 .	The lack of effect of Y297A NRP1 on KDR phosphorylation probably reflects the fact that KDR activation by VEGF-A 165 is mainly independent of NRP1.	15	19	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	18	19	15	16
VEGF-A stimulates many actions of endothelial cells including proliferation , migration , and nitric oxide release via binding to and activation of the two primarily endothelial specific receptor-tyrosine kinases KDR and Flt-1 .	VEGF-A stimulates many actions of endothelial cells including proliferation, migration, and nitric oxide release via binding to and activation of the two primarily endothelial specific receptor-tyrosine kinases KDR and Flt-1.	0	31	stimulates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	0	1	29	30
While previous studies showed that OPCs express VEGFR2 and that VEGF-A promotes OPC migration by activating VEGFR2 [ XREF_BIBR , XREF_BIBR ] , there is no evidence that the VEGF-A and VEGFR2 signaling influences differentiated oligodendroglia under normal or disease conditions .	While previous studies showed that OPCs express VEGFR2 and that VEGF-A promotes OPC migration by activating VEGFR2 [XREF_BIBR, XREF_BIBR], there is no evidence that the VEGF-A and VEGFR2 signaling influences differentiated oligodendroglia under normal or disease conditions.	10	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	10	11	16	17
Compared with VEGF-A 165 , VEGF-A 165 b does not fully activate VEGFR-2 and thus could act as a much weaker agonist for VEGFR-2 than VEGF-A 165 [ XREF_BIBR ] .	Compared with VEGF-A 165, VEGF-A 165 b does not fully activate VEGFR-2 and thus could act as a much weaker agonist for VEGFR-2 than VEGF-A 165 [XREF_BIBR].	5	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	5	6	12	13
Moreover , we found that LG1/2 blocked the rapid VEGFA activation of VEGFR2 at Tyr1175 in endothelial cells .	Moreover, we found that LG1/2 blocked the rapid VEGFA activation of VEGFR2 at Tyr1175 in endothelial cells.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	9	10	12	13
Through these signaling pathways each of the VEGF family provides different actions , with VEGF-A activation of VEGFR2 representing the major mediator of angiogenesis induction [ XREF_BIBR - XREF_BIBR ] .	Through these signaling pathways each of the VEGF family provides different actions, with VEGF-A activation of VEGFR2 representing the major mediator of angiogenesis induction [XREF_BIBR - XREF_BIBR].	14	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	14	15	17	18
To determine the role VEGF-A activation of VEGFR2 serves in lymphangiogenesis we used the monoclonal anti-VEGF-A antibody r84 which specifically blocks mouse and human VEGF-A activation of VEGFR2 , but not VEGFR1 .	To determine the role VEGF-A activation of VEGFR2 serves in lymphangiogenesis we used the monoclonal anti-VEGF-A antibody r84 which specifically blocks mouse and human VEGF-A activation of VEGFR2, but not VEGFR1.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	4	5	7	8
In acute inflammation , B cells express VEGFA , which activates VEGFR2 and lymph node lymphangiogenesis [ XREF_BIBR ] .	In acute inflammation, B cells express VEGFA, which activates VEGFR2 and lymph node lymphangiogenesis [XREF_BIBR].	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	7	8	11	12
Thus , stimulation of VEGFR2 by VEGF-A activates shedding of VEGFR and several other substrates of ADAM17 .	Thus, stimulation of VEGFR2 by VEGF-A activates shedding of VEGFR and several other substrates of ADAM17.	2	7	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	6	7	4	5
VEGF-A induces these VEGFR2 containing endothelial precursors to form clusters of blood islands : the first site of vascular development in the embryo , located in the yolk sac and comprising primitive erythroblasts surrounded by a layer of endothelial cells .	VEGF-A induces these VEGFR2 containing endothelial precursors to form clusters of blood islands : the first site of vascular development in the embryo, located in the yolk sac and comprising primitive erythroblasts surrounded by a layer of endothelial cells.	0	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	3	4
The data demonstrates that basal cell derived VEGFA activates VEGFR2 mediated signaling cascades within the endothelium , confirming that basal cell secreted VEGFA functions in a paracrine manner .	The data demonstrates that basal cell derived VEGFA activates VEGFR2 mediated signaling cascades within the endothelium, confirming that basal cell secreted VEGFA functions in a paracrine manner.	6	12	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	7	8	9	10
Unlike VEGF-A , it is not thought to play a prominent role in angiogenesis [ XREF_BIBR ] , and operates primarily via interaction with VEGFR-1 , rather than the angiogenesis associated VEGFR-2 targeted primarily by VEGF-A [ XREF_BIBR ] .	Unlike VEGF-A, it is not thought to play a prominent role in angiogenesis [XREF_BIBR], and operates primarily via interaction with VEGFR-1, rather than the angiogenesis associated VEGFR-2 targeted primarily by VEGF-A [XREF_BIBR].	30	37	targeted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	35	36	31	32
This activity was attributed to myocardial derived Vegf-A , which signals to Vegfr2 in endocardial cells .	This activity was attributed to myocardial derived Vegf-A, which signals to Vegfr2 in endocardial cells.	6	15	signals	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Vegf-A	Vegf-A	Vegf-A	Vegfr2	Vegfr2	Vegfr2	7	8	12	13
The finding that differential KDR activation by VEGF-A and VEGF-D has distinct consequences for endothelial signaling and function has important implications for understanding how multiple ligands for the same VEGF receptors can generate ligand specific biological responses .	The finding that differential KDR activation by VEGF-A and VEGF-D has distinct consequences for endothelial signaling and function has important implications for understanding how multiple ligands for the same VEGF receptors can generate ligand specific biological responses.	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	7	8	4	5
In conclusion , we demonstrate that ENG knockdown has no effect on VEGFR2 activation , but alters VEGFA induced VEGFR2 kinetics .	In conclusion, we demonstrate that ENG knockdown has no effect on VEGFR2 activation, but alters VEGFA induced VEGFR2 kinetics.	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	17	18	19	20
Whilst the signalling of VEGFR2 stimulated by VEGF-A 165 a and VEGF-A 165 b has been investigated in human microvascular endothelial cells ( HMVECs ) , it has not been conducted in HemECs , an endothelial cell with progenitor like gene expression and properties 22 , nor in HemSCs .	Whilst the signalling of VEGFR2 stimulated by VEGF-A 165 a and VEGF-A 165 b has been investigated in human microvascular endothelial cells (HMVECs), it has not been conducted in HemECs, an endothelial cell with progenitor like gene expression and properties 22, nor in HemSCs.	2	8	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	7	8	4	5
Mechanistically , we demonstrate that Bmx differentially regulates VEGFR-2 and VEGFR-3 signaling pathways ( XREF_FIG , A model for Bmx function in VEGF-A/C signaling ) : VEGF-A activates VEGFR-2 whereas VEGF-C activates both VEGFR-2 and VEGFR-3 .	Mechanistically, we demonstrate that Bmx differentially regulates VEGFR-2 and VEGFR-3 signaling pathways (XREF_FIG, A model for Bmx function in VEGF-A/C signaling) : VEGF-A activates VEGFR-2 whereas VEGF-C activates both VEGFR-2 and VEGFR-3.	26	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	26	27	28	29
For example , in melanoma ( Liu et al , 1995 ) and mesothelioma ( Strizzi et al , 2001 ) cells , exogenous VEGF-A stimulates cell proliferation by activating VEGFR-2 .	For example, in melanoma (Liu et al, 1995) and mesothelioma (Strizzi et al, 2001) cells, exogenous VEGF-A stimulates cell proliferation by activating VEGFR-2.	23	31	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	24	25	30	31
VEGF-A isoforms cause differential VEGFR2 activation and signal transduction .	VEGF-A isoforms cause differential VEGFR2 activation and signal transduction.	0	5	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	4	5
The inhibition of hypoxic induction of autocrine VEGF-A would be expected to reduce hypoxic activation of the Flk-1 ( VEGFR2 ) receptor by phosphorylation , and this is indeed seen in iNOS nullprimary endothelial cells ( XREF_FIG E , left , and phosphor imaging quantification , right ) .	The inhibition of hypoxic induction of autocrine VEGF-A would be expected to reduce hypoxic activation of the Flk-1 (VEGFR2) receptor by phosphorylation, and this is indeed seen in iNOS nullprimary endothelial cells (XREF_FIG E, left, and phosphor imaging quantification, right).	4	21	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	Flk-1	Flk-1	Flk-1	7	8	17	18
In contrast , VEGF-A 121 stimulation did not cause a significant increase in VEGFR2 co-distribution with EEA1 ( XREF_FIG E ) .	In contrast, VEGF-A 121 stimulation did not cause a significant increase in VEGFR2 co-distribution with EEA1 (XREF_FIG E).	3	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	3	4	13	14
VEGFR-2 is activated primarily by VEGF-A , but cleaved forms of VEGF-C and VEGF-D can also activate VEGFR-2 .	VEGFR-2 is activated primarily by VEGF-A, but cleaved forms of VEGF-C and VEGF-D can also activate VEGFR-2.	0	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	5	6	0	1
These results suggested that autocrine VEGF-A induced cancer proliferation , but did not mediate the VEGFR1 or VEGFR2 signaling pathway .	These results suggested that autocrine VEGF-A induced cancer proliferation, but did not mediate the VEGFR1 or VEGFR2 signaling pathway.	4	19	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	5	6	17	18
Taking together , we demonstrate that TR3-TVs are differentially regulated by VEGF-A and identify a novel signaling pathway by which VEGF-A and VEGF-E , but neither VEGF-B , nor PlGF , induce the interaction of VEGFR2 and KDR with IGF-1R , resulting in IGF-1R transactivation to induce the high level expression of TR3-TV2 .	Taking together, we demonstrate that TR3-TVs are differentially regulated by VEGF-A and identify a novel signaling pathway by which VEGF-A and VEGF-E, but neither VEGF-B, nor PlGF, induce the interaction of VEGFR2 and KDR with IGF-1R, resulting in IGF-1R transactivation to induce the high level expression of TR3-TV2.	20	37	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	20	21	35	36
Mechanistically , we demonstrated that circRNA-MYLK could directly bind to miR-29a and relieve suppression for target VEGFA , which activated VEGFA and VEGFR2 signaling pathway .	Mechanistically, we demonstrated that circRNA-MYLK could directly bind to miR-29a and relieve suppression for target VEGFA, which activated VEGFA and VEGFR2 signaling pathway.	12	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	16	17	22	23
In contrast , VEGFA did not induce co-immunoprecipitation of VEGFR2 and VEGFR3 from monocultures of HSaVECs .	In contrast, VEGFA did not induce co-immunoprecipitation of VEGFR2 and VEGFR3 from monocultures of HSaVECs.	3	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	3	4	9	10
VEGF-A can activate both VEGFR-1 and VEGFR-2 .	VEGF-A can activate both VEGFR-1 and VEGFR-2.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	0	1	6	7
A future challenge will be to identify specific cytoplasmic factors that regulate the differences in VEGF-A isoform mediated VEGFR2 trafficking and turnover .	A future challenge will be to identify specific cytoplasmic factors that regulate the differences in VEGF-A isoform mediated VEGFR2 trafficking and turnover.	15	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	15	16	18	19
Our finding that VEGF-A induced down-regulation of EphB4 is VEGFR2 dependent ( XREF_FIG ) is not surprising , since VEGFR2 is the primary signaling receptor of VEGF-A in EC .	Our finding that VEGF-A induced down-regulation of EphB4 is VEGFR2 dependent (XREF_FIG) is not surprising, since VEGFR2 is the primary signaling receptor of VEGF-A in EC.	3	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	3	4	9	10
VEGF-A treatment activated VEGFR-2 , as indicated by autophosphorylation , and activated the Akt pathway , with a peak in phospho-Akt ( Ser 473 ) at 5 min after addition of the VEGF-A ligand ( XREF_FIG ) .	VEGF-A treatment activated VEGFR-2, as indicated by autophosphorylation, and activated the Akt pathway, with a peak in phospho-Akt (Ser 473) at 5 min after addition of the VEGF-A ligand (XREF_FIG).	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	0	1	3	4
ENG knock-down altered VEGFA mediated VEGFR2 kinetics and promoted AKT signalling .	ENG knock-down altered VEGFA mediated VEGFR2 kinetics and promoted AKT signalling.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	3	4	5	6
The signalling cascade stimulated by VEGF-A activates VEGFR-2 followed by c-Src tyrosine kinase and MAP kinases the Erk subfamily activation .	The signalling cascade stimulated by VEGF-A activates VEGFR-2 followed by c-Src tyrosine kinase and MAP kinases the Erk subfamily activation.	3	8	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	5	6	7	8
By building on these concepts , our study shows for the first time that three different VEGF-A isoforms ( VEGF-A 165 , VEGF-A 121 and VEGF-A 145 ) promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes .	By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A 165, VEGF-A 121 and VEGF-A 145) promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes.	16	33	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	16	17	32	33
A previous in vitro study shows that oligodendrocyte progenitor cells ( OPCs ) express VEGFR2 and that VEGF-A enhances OPC migration by activating VEGFR2 .	A previous in vitro study shows that oligodendrocyte progenitor cells (OPCs) express VEGFR2 and that VEGF-A enhances OPC migration by activating VEGFR2.	17	24	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	17	18	23	24
Moreover , we have recently shown that VEGF-A , could also directly induce Treg proliferation in tumor bearing mice and metastatic colorectal patients in a VEGFR2 dependent manner .	Moreover, we have recently shown that VEGF-A, could also directly induce Treg proliferation in tumor bearing mice and metastatic colorectal patients in a VEGFR2 dependent manner.	7	27	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	7	8	25	26
Ramucirumab binds VEGFR-2 and inhibits responses resulting from the activation of VEGFR-2 by VEGF-A and VEGF-C .	Ramucirumab binds VEGFR-2 and inhibits responses resulting from the activation of VEGFR-2 by VEGF-A and VEGF-C.	6	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	13	14	11	12
VEGF-A ( 165 ) , which stimulates both Flt-1 and KDR , induced the formation of both fenestrae and VVOs at a similar rate , while VEGF-F , a KDR specific VEGF vammin , predominantly induced the formation of fenestrae with an approximately 5-fold more potent vascular permeability response than VEGF-A ( 165 ) .	VEGF-A (165), which stimulates both Flt-1 and KDR, induced the formation of both fenestrae and VVOs at a similar rate, while VEGF-F, a KDR specific VEGF vammin, predominantly induced the formation of fenestrae with an approximately 5-fold more potent vascular permeability response than VEGF-A (165).	0	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	0	1	10	11
However , we found no evidence for a role of NRP-1 in regulating VEGF dependent activation of ADAM10 or 17 , at least under the conditions tested here ( XREF_SUPPLEMENTARY ) To extend our analysis to endothelial cells , porcine aortic endothelial cells expressing human VEGFR2 and KDR ( PAE-KDR cells ) were treated with PMA or VEGF-A , both of which stimulated shedding of VEGFR2 ( XREF_FIG ) .	However, we found no evidence for a role of NRP-1 in regulating VEGF dependent activation of ADAM10 or 17, at least under the conditions tested here (XREF_SUPPLEMENTARY) To extend our analysis to endothelial cells, porcine aortic endothelial cells expressing human VEGFR2 and KDR (PAE-KDR cells) were treated with PMA or VEGF-A, both of which stimulated shedding of VEGFR2 (XREF_FIG).	43	62	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	57	58	47	48
EGCG ( 0.5-10 muM ) disrupted VEGFA induced VEGFR2 dimerization in human umbilical vein endothelial cells [ XREF_BIBR ] , and inhibited growth and activation of VEGF and VEGFR axis in human colorectal cancer cells [ XREF_BIBR ] .	EGCG (0.5-10 muM) disrupted VEGFA induced VEGFR2 dimerization in human umbilical vein endothelial cells [XREF_BIBR], and inhibited growth and activation of VEGF and VEGFR axis in human colorectal cancer cells [XREF_BIBR].	6	21	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	6	7	8	9
Human clinical trials aimed at inducing VEGF-A mediated VEGFR2 signaling in PAD via VEGF-A delivery to ischemic muscle were not successful .	Human clinical trials aimed at inducing VEGF-A mediated VEGFR2 signaling in PAD via VEGF-A delivery to ischemic muscle were not successful.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	6	7	8	9
For example , activation of VEGFR-2 by VEGF-A leads to activation of Raf and the mitogen activated protein kinase ( MAPK ) pathway via phospholipase C-gamma ( PLC-gamma ) in the endothelial cell .	For example, activation of VEGFR-2 by VEGF-A leads to activation of Raf and the mitogen activated protein kinase (MAPK) pathway via phospholipase C-gamma (PLC-gamma) in the endothelial cell.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	7	8	5	6
While serum does typically contain VEGF-C in the single digit ng/ml-range , serum supplemented LEC culture medium would still contain only small amounts of VEGF-C compared to VEGF-A , which stimulates VEGFR-2 , but not VEGFR-3 .	While serum does typically contain VEGF-C in the single digit ng/ml-range, serum supplemented LEC culture medium would still contain only small amounts of VEGF-C compared to VEGF-A, which stimulates VEGFR-2, but not VEGFR-3.	19	35	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	27	28	31	32
These data indicate that VEGF-A or VEGF-C activation of the VEGFR-2 , and not of VEGFR-1 , is involved in the formation of capillary like tubular structures of hMVEC in 3D fibrin matrices used as a model of repair associated or pathological angiogenesis in vitro .	These data indicate that VEGF-A or VEGF-C activation of the VEGFR-2, and not of VEGFR-1, is involved in the formation of capillary like tubular structures of hMVEC in 3D fibrin matrices used as a model of repair associated or pathological angiogenesis in vitro.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	4	5	10	11
VEGFR2 homodimers were induced only by VEGFA and not by VEGFC ( XREF_FIG ) .	VEGFR2 homodimers were induced only by VEGFA and not by VEGFC (XREF_FIG).	0	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	6	7	0	1
We found that the amount of pVEGFR2 in cells first treated with sunitinib followed by VEGFA was higher than that in cells treated with sunitinib alone .	We found that the amount of pVEGFR2 in cells first treated with sunitinib followed by VEGFA was higher than that in cells treated with sunitinib alone.	4	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	pVEGFR2	pVEGFR2	pVEGFR2	15	16	6	7
Stimulation of the VEGFR2 activates signaling pathways such as the p42/44 and p38 MAP kinases , which also activate ADAM17 XREF_BIBR , so we tested whether VEGF-A could stimulate VEGFR2 shedding .	Stimulation of the VEGFR2 activates signaling pathways such as the p42/44 and p38 MAP kinases, which also activate ADAM17 XREF_BIBR, so we tested whether VEGF-A could stimulate VEGFR2 shedding.	26	30	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	26	27	29	30
The best characterized VEGF ligand is VEGFA that activates intracellular signaling via high affinity binding to cognate receptors VEGFR1 and VEGFR2 .	The best characterized VEGF ligand is VEGFA that activates intracellular signaling via high affinity binding to cognate receptors VEGFR1 and VEGFR2.	1	21	activates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	6	7	20	21
These results support that sVegfr1 inhibits the Vegfa induced Vegfr2 signaling in the endocardial cells for the onset of coronary angiogenesis XREF_BIBR ; removal of Vegfr1 results in the premature coronary angiogenesis by these cells .	These results support that sVegfr1 inhibits the Vegfa induced Vegfr2 signaling in the endocardial cells for the onset of coronary angiogenesis XREF_BIBR; removal of Vegfr1 results in the premature coronary angiogenesis by these cells.	6	10	induced	Positive_early_activation	Positive_activation	Positive_activation	Vegfa	Vegfa	Vegfa	Vegfr2	Vegfr2	Vegfr2	7	8	9	10
Some data suggest that VEGFR2 activation by VEGFA upregulates DLL4 in tip cells .	Some data suggest that VEGFR2 activation by VEGFA upregulates DLL4 in tip cells.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	7	8	4	5
In contrast , induction of VEGFR-2 by VEGF-A in HUVEC was unaffected by the Notch1 decoy .	In contrast, induction of VEGFR-2 by VEGF-A in HUVEC was unaffected by the Notch1 decoy.	3	9	induction	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	7	8	5	6
In agreement with studies showing that VEGF-A triggers PDGFR-beta , VEGFR-2 and ErbB2 signalling that can modulate the MAPK pathway , excess miR-378-a-5p resulted in elevated phosphorylation of ERK1/2 and , surprisingly , depletion of Aurora B kinase .	In agreement with studies showing that VEGF-A triggers PDGFR-beta, VEGFR-2 and ErbB2 signalling that can modulate the MAPK pathway, excess miR-378-a-5p resulted in elevated phosphorylation of ERK1/2 and, surprisingly, depletion of Aurora B kinase.	6	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	6	7	10	11
This result was corroborated by FACS analysis , which showed that VEGF-A treatment markedly increased the frequency of KDR + / VE-cadherin + endothelial cells ( 68 % vs. 14 % ; XREF_SUPPLEMENTARY ) , and by immunofluorescence imaging , which demonstrated co-expression of VE-cadherin and GFP ( expressed from Wt1 GFPCre ) in cultures stimulated by VEGF-A ( XREF_SUPPLEMENTARY ) .	This result was corroborated by FACS analysis, which showed that VEGF-A treatment markedly increased the frequency of KDR + / VE-cadherin + endothelial cells (68% vs. 14%; XREF_SUPPLEMENTARY), and by immunofluorescence imaging, which demonstrated co-expression of VE-cadherin and GFP (expressed from Wt1 GFPCre) in cultures stimulated by VEGF-A (XREF_SUPPLEMENTARY).	11	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	11	12	18	19
These data reveal that VEGF-A activation of VEGFR2 , not VEGFR1 , directly promotes cellular processes required for lymphangiogenesis .	These data reveal that VEGF-A activation of VEGFR2, not VEGFR1, directly promotes cellular processes required for lymphangiogenesis.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	4	5	7	8
VEGF-A 165 promotes the formation of a complex of NRP1 and KDR in endothelial cells , which is thought to be important for optimal VEGF signaling and function .	VEGF-A 165 promotes the formation of a complex of NRP1 and KDR in endothelial cells, which is thought to be important for optimal VEGF signaling and function.	0	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	0	1	11	12
A series of detailed experiments examining how calcium was involved in the VEGF response have indicated that VEGFR2 activation by VEGF-A stimulates phospholipase C activation and production of DAG and IP3 .	A series of detailed experiments examining how calcium was involved in the VEGF response have indicated that VEGFR2 activation by VEGF-A stimulates phospholipase C activation and production of DAG and IP3.	17	21	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	20	21	17	18
Taken together , VEGFA provides proangiogenic stimulus and induces Flk-1 expressing cells to sprout and form new vessels , while simultaneously activating Dll4-Notch pathway signaling to maintain the necessary balance between tip and stalk cell specification .	Taken together, VEGFA provides proangiogenic stimulus and induces Flk-1 expressing cells to sprout and form new vessels, while simultaneously activating Dll4-Notch pathway signaling to maintain the necessary balance between tip and stalk cell specification.	3	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	Flk-1	Flk-1	Flk-1	3	4	9	10
VEGF-A and VEGF-B exclusively promote vascular neogenesis via their tyrosinkinase-receptors VEGFR1 and Flt -1 and VEGFR2 and KDR , while VEGF-C and VEGF-D additionally promote lymphangiogenesis via VEGFR4 and Flt-4 .	VEGF-A and VEGF-B exclusively promote vascular neogenesis via their tyrosinkinase-receptors VEGFR1 and Flt -1 and VEGFR2 and KDR, while VEGF-C and VEGF-D additionally promote lymphangiogenesis via VEGFR4/Flt-4.	0	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	15	16
VEGF-A is the most potent and primary endothelial cell specific angiogenic growth factor and stimulates vascular permeability , endothelial cell proliferation , migration and tube formation , primarily through the VEGF-A receptor 2 ( VEGFR-2 ) .	VEGF-A is the most potent and primary endothelial cell specific angiogenic growth factor and stimulates vascular permeability, endothelial cell proliferation, migration and tube formation, primarily through the VEGF-A receptor 2 (VEGFR-2).	0	35	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	0	1	34	35
In conclusion , we show for the first time that VEGF-A activation of VEGFR2 , not VEGFR1 , directly drives LEC proliferation and migration via the PI3-K and ERK1/2 signaling pathways .	In conclusion, we show for the first time that VEGF-A activation of VEGFR2, not VEGFR1, directly drives LEC proliferation and migration via the PI3-K and ERK1/2 signaling pathways.	10	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	10	11	13	14
Aflibercept also inhibited activation of VEGFR2 activation induced by VEGF-A 165 or VEGF-A 121 , which may suggest some clinical benefits since binding kinetics and affinity are important determinants of the biological activity of antibody like drugs [ XREF_BIBR ] .	Aflibercept also inhibited activation of VEGFR2 activation induced by VEGF-A 165 or VEGF-A 121, which may suggest some clinical benefits since binding kinetics and affinity are important determinants of the biological activity of antibody like drugs [XREF_BIBR].	5	12	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	9	10	5	6
It thus appeared possible that VEGF-A induced by signaling from H-Ras [ G12V ] directed differentiation of VEGFR2 + progenitor cells to PECAM1 + cells in the present experimental system .	It thus appeared possible that VEGF-A induced by signaling from H-Ras [G12V] directed differentiation of VEGFR2 + progenitor cells to PECAM1 + cells in the present experimental system.	5	20	directed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	5	6	17	18
Pericytes ( paracrine signaling ) and endothelial cells ( autocrine signaling ) secrete VEGF-A that activates the VEGFR2 pathway to increase expression of anti-apoptotic Bcl-2 , survivin , and X linked inhibitor of apoptosis protein ( XIAP ) , as shown by in vitro studies of human brain pericyte and endothelial cell co-cultures 119 ( XREF_FIG , right ) .	Pericytes (paracrine signaling) and endothelial cells (autocrine signaling) secrete VEGF-A that activates the VEGFR2 pathway to increase expression of anti-apoptotic Bcl-2, survivin, and X linked inhibitor of apoptosis protein (XIAP), as shown by in vitro studies of human brain pericyte and endothelial cell co-cultures 119 (XREF_FIG, right).	12	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	13	14	17	18
First , VEGF-A 165 a , an isoform capable of binding both VEGFR2 and Nrp1 , directs VEGFR2 to the Rab5/Rab4/Rab11 recycling pathway ( presumably via EEA1 ) , whereas non-Nrp1-binding isoform VEGF-A 165 b directs it toward degradation via the Rab7 pathway .	First, VEGF-A 165 a, an isoform capable of binding both VEGFR2 and Nrp1, directs VEGFR2 to the Rab5/Rab4/Rab11 recycling pathway (presumably via EEA1), whereas non-Nrp1-binding isoform VEGF-A 165 b directs it toward degradation via the Rab7 pathway.	2	18	directs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	2	3	17	18
Taken together , our results highlight the ability of tumor derived VEGFA to stimulate the proliferation of VEGFR2 + Tregs , and that this phenomenon is efficiently inhibited by VEGFA and VEGFR targeted therapies in preclinical models of CRC as well as in CRC patients .	Taken together, our results highlight the ability of tumor derived VEGFA to stimulate the proliferation of VEGFR2 + Tregs, and that this phenomenon is efficiently inhibited by VEGFA and VEGFR targeted therapies in preclinical models of CRC as well as in CRC patients.	11	19	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	11	12	17	18
VEGF-A stimulates VEGFR2 , which is autophosphorylated and activates various downstream signaling pathways [ XREF_BIBR ] .	VEGF-A stimulates VEGFR2, which is autophosphorylated and activates various downstream signaling pathways [XREF_BIBR].	0	8	stimulates	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	VEGF-A	VEGF-A	vegf-a	VEGFR2	VEGFR2, which is autophosphorylated	vegfr2	0	1	2	3
As shown in Figure XREF_FIG , VEGF-A rapidly induced complex formation of NRP-1 and VEGFR2 in HUVECs .	As shown in Figure XREF_FIG, VEGF-A rapidly induced complex formation of NRP-1 and VEGFR2 in HUVECs.	6	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	6	7	14	15
In comparison , minor to moderate increases in Ang2 and FOXO1 , but not in Tie2 , were detected in retinas of DTA iDeltaPC mice treated with BSA , whereas increases in VEGFR2 and vascular leakage were observed in retinas of WT mice treated with VEGF-A ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	In comparison, minor to moderate increases in Ang2 and FOXO1, but not in Tie2, were detected in retinas of DTA iDeltaPC mice treated with BSA, whereas increases in VEGFR2 and vascular leakage were observed in retinas of WT mice treated with VEGF-A (XREF_FIG; XREF_SUPPLEMENTARY).	32	47	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	45	46	32	33
VEGF-A- mediated activation of VEGFR2 recruits Src and facilitates phosphorylation of the beta3 cytoplasmic tail [ XREF_BIBR ] .	VEGF-A- mediated activation of VEGFR2 recruits Src and facilitates phosphorylation of the beta3 cytoplasmic tail [XREF_BIBR].	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A-	VEGF-A-	VEGF-A-	VEGFR2	VEGFR2	VEGFR2	0	1	4	5
Vascular endothelial growth factor A has a greater binding affinity for VEGFR1 than VEGFR2 , and thus , VEGFA stimulation of VEGFR2 requires a decrease in available VEGFR1 .	Vascular endothelial growth factor A has a greater binding affinity for VEGFR1 than VEGFR2, and thus, VEGFA stimulation of VEGFR2 requires a decrease in available VEGFR1.	18	22	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	18	19	21	22
These data show that VEGFA does not activate classical VEGFR2 mediated signaling cascades in basal cells .	These data show that VEGFA does not activate classical VEGFR2 mediated signaling cascades in basal cells.	4	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	4	5	9	10
Since VEGFA induced Flk-1 activation is the key regulator of endothelial cell survival and growth , VEGFA haplodeficient mouse shows a lethal phenotype in embryonic days 11-12 due to impairment of blood vessel development and deficiency of red blood cell in blood island of york sac .	Since VEGFA induced Flk-1 activation is the key regulator of endothelial cell survival and growth, VEGFA haplodeficient mouse shows a lethal phenotype in embryonic days 11-12 due to impairment of blood vessel development and deficiency of red blood cell in blood island of york sac.	1	4	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	Flk-1	Flk-1	Flk-1	1	2	3	4
VEGF-A stimulates the activation of preformed VEGFR2 dimers by the auto-phosphorylation of activation segment tyrosines followed by the phosphorylation of additional protein-tyrosines that recruit phosphotyrosine binding proteins thereby leading to signalling by the ERK1/2 , AKT , Src , and p38 MAP kinase pathways .	VEGF-A stimulates the activation of preformed VEGFR2 dimers by the auto-phosphorylation of activation segment tyrosines followed by the phosphorylation of additional protein-tyrosines that recruit phosphotyrosine binding proteins thereby leading to signalling by the ERK1/2, AKT, Src, and p38 MAP kinase pathways.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	6	7
In agreement with previous findings , XREF_BIBR this observation indicates that VEGF-A 165 induced clathrin dependent endocytosis of VEGFR2 .	In agreement with previous findings, XREF_BIBR this observation indicates that VEGF-A 165 induced clathrin dependent endocytosis of VEGFR2.	11	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	11	12	18	19
VEGF-A 165 b competitively binds to VEGFR2 , in line with the partial activation of VEGFR2 by VEGF-A 165 b , this ligand only partially activates DAG and therefore partially activates typical PKC isoforms ; therefore , there is little or no phosphorylation of TJs .	VEGF-A 165 b competitively binds to VEGFR2, in line with the partial activation of VEGFR2 by VEGF-A 165 b, this ligand only partially activates DAG and therefore partially activates typical PKC isoforms; therefore, there is little or no phosphorylation of TJs.	13	19	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	17	18	15	16
Consistent with previous results XREF_BIBR , XREF_BIBR , VEGF-A activates VEGFR-2 whereas VEGF-C activates VEGFR-2 and VEGFR-3 .	Consistent with previous results XREF_BIBR, XREF_BIBR, VEGF-A activates VEGFR-2 whereas VEGF-C activates VEGFR-2 and VEGFR-3.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	8	9	10	11
The influence of neuropilins on this loop was not investigated , but since the ability of NRPs to enhance the activation of VEGF-R2 by VEGFA is well documented XREF_BIBR , such an influence appears to be likely .	The influence of neuropilins on this loop was not investigated, but since the ability of NRPs to enhance the activation of VEGF-R2 by VEGFA is well documented XREF_BIBR, such an influence appears to be likely.	18	25	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGF-R2	VEGF-R2	VEGF-R2	24	25	22	23
In tumors , vascular endothelial growth factor-A ( VEGF-A ) stimulates angiogenesis and vascular permeability by activating the tyrosine kinase receptor-2 ( VEGFR-2 or KDR and Flk-1 ) and-1 ( VEGFR-1 or Flt-1 ) .	In tumors, vascular endothelial growth factor-A (VEGF-A) stimulates angiogenesis and vascular permeability by activating the tyrosine kinase receptor-2 (VEGFR-2 or KDR/Flk-1) and-1 (VEGFR-1 or Flt-1).	6	26	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	8	9	22	23
Vegfa upregulates Bmp4 and Sftpc and induces proliferation of Vegfr2 positive cells [ XREF_BIBR , XREF_BIBR ] .	Vegfa upregulates Bmp4 and Sftpc and induces proliferation of Vegfr2 positive cells [XREF_BIBR, XREF_BIBR].	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vegfa	Vegfa	Vegfa	Vegfr2	Vegfr2	Vegfr2	0	1	9	10
VEGF-A 165 b inhibits canonical VEGF-A signaling by competitive interference with the interaction of pro angiogenic isoforms with the VEGFR2 and NRP1 receptor complex thereby preventing full downstream signaling of VEGFR2 .	VEGF-A 165 b inhibits canonical VEGF-A signaling by competitive interference with the interaction of pro angiogenic isoforms with the VEGFR2 and NRP1 receptor complex thereby preventing full downstream signaling of VEGFR2.	0	31	preventing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	30	31
VEGF-A stimulates ADAM17 dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling .	VEGF-A stimulates ADAM17 dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling.	0	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	6	7
Activation of VEGFR-2 by VEGF-A increases intracellular calcium leading to calcineurin activation and nuclear translocation of NFATc1 in human pulmonary valve endothelial cells in culture .	Activation of VEGFR-2 by VEGF-A increases intracellular calcium leading to calcineurin activation and nuclear translocation of NFATc1 in human pulmonary valve endothelial cells in culture.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	4	5	2	3
3 VEGF-A induces blood endothelial cell ( EC ) proliferation and increases vascular permeability by stimulating two tyrosine kinase receptors , VEGFR-1 and VEGFR-2 on EC surface .	3 VEGF-A induces blood endothelial cell (EC) proliferation and increases vascular permeability by stimulating two tyrosine kinase receptors, VEGFR-1 and VEGFR-2 on EC surface.	0	24	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	1	2	23	24
Activation of VEGFR-2 by VEGF-A depends on the phosphorylation status of several tyrosine residues ( such as 951 , 1059 , 1175 , and 1214 ) in VEGFR-2 .	Activation of VEGFR-2 by VEGF-A depends on the phosphorylation status of several tyrosine residues (such as 951, 1059, 1175, and 1214) in VEGFR-2.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	4	5	2	3
Furthermore , electron microscopy has confirmed that VEGFA induces VEGFR2 dimerization through the membrane proximal Ig domain 7 [ XREF_BIBR ] .	Furthermore, electron microscopy has confirmed that VEGFA induces VEGFR2 dimerization through the membrane proximal Ig domain 7 [XREF_BIBR].	7	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	7	8	9	10
Furthermore , as a positive , upstream regulator of VEGF- and shear stress induced VEGFR2 activation and signaling , Rap1 signaling may be exploited in pathologies associated with abnormal VEGF signaling , such as retinopathies , diabetes , and tumor angiogenesis .	Furthermore, as a positive, upstream regulator of VEGF- and shear stress induced VEGFR2 activation and signaling, Rap1 signaling may be exploited in pathologies associated with abnormal VEGF signaling, such as retinopathies, diabetes, and tumor angiogenesis.	9	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-	VEGF-	VEGF-	VEGFR2	VEGFR2	VEGFR2	9	10	14	15
For comparison we also looked at the ability of E7080 to inhibit VEGF-A induced activation of VEGFR-2 in HUVECs .	For comparison we also looked at the ability of E7080 to inhibit VEGF-A induced activation of VEGFR-2 in HUVECs.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	12	13	16	17
Analysis of marker genes by qRT-PCR revealed that VEGF-A stimulation strongly upregulated endothelial markers VE-Cadherin , Pecam1 , and Kdr ( XREF_SUPPLEMENTARY ) .	Analysis of marker genes by qRT-PCR revealed that VEGF-A stimulation strongly upregulated endothelial markers VE-Cadherin, Pecam1, and Kdr (XREF_SUPPLEMENTARY).	8	20	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	Kdr	Kdr	Kdr	8	9	19	20
The mechanism for the decrease in sVEGFR2 has not been established , but preclinical studies suggest that VEGF-A stimulates shedding of VEGFR2 from endothelium by VEGFR2 dependent activation of the metalloproteinase ADAM-17 .	The mechanism for the decrease in sVEGFR2 has not been established, but preclinical studies suggest that VEGF-A stimulates shedding of VEGFR2 from endothelium by VEGFR2 dependent activation of the metalloproteinase ADAM-17.	17	23	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	17	18	21	22
Generally speaking , VEGFR3 activation by VEGF-C regulates the lymphatic vasculature , whereas VEGF-A activation of VEGFR2 is the main regulator of blood endothelial cell function [ XREF_BIBR , XREF_BIBR ] .	Generally speaking, VEGFR3 activation by VEGF-C regulates the lymphatic vasculature, whereas VEGF-A activation of VEGFR2 is the main regulator of blood endothelial cell function [XREF_BIBR, XREF_BIBR].	13	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	13	14	16	17
To identify the mechanisms by which VEGF-A activation of VEGFR2 stimulated LEC proliferation and migration , we analyzed VEGF-A-induced signaling pathways in LECs .	To identify the mechanisms by which VEGF-A activation of VEGFR2 stimulated LEC proliferation and migration, we analyzed VEGF-A-induced signaling pathways in LECs.	6	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	6	7	9	10
However , 1 muM of CA had no such significant effects on VEGFA mediated activation of VEGFR-2 ( XREF_FIG and XREF_FIG ) .	However, 1 muM of CA had no such significant effects on VEGFA mediated activation of VEGFR-2 (XREF_FIG and XREF_FIG).	10	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR-2	VEGFR-2	VEGFR-2	12	13	16	17
Specifically , Myocardin-an interation with STAT3 nuclear transcription factors-can be nitrosylated and inhibited by nitric oxide after VEGFR2 activation induced by VEGF-A .	Specifically, Myocardin-an interation with STAT3 nuclear transcription factors-can be nitrosylated and inhibited by nitric oxide after VEGFR2 activation induced by VEGF-A.	17	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	21	22	17	18
23 VEGFR-2 signaling induced by VEGF-A can suppress cell apoptosis and promote angiogenesis in recovery and regeneration after ischemia-reperfusion .	23 VEGFR-2 signaling induced by VEGF-A can suppress cell apoptosis and promote angiogenesis in recovery and regeneration after ischemia-reperfusion.	1	6	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	5	6	1	2
In vitro experiments with primary human dermal lymphatic endothelial cells ( LECs ) demonstrate that blocking VEGF-A activation of VEGFR2 , not VEGFR1 , significantly inhibits VEGF-A-induced proliferation and migration of LECs .	In vitro experiments with primary human dermal lymphatic endothelial cells (LECs) demonstrate that blocking VEGF-A activation of VEGFR2, not VEGFR1, significantly inhibits VEGF-A-induced proliferation and migration of LECs.	16	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	16	17	19	20
One question left unanswered is what is the mechanism ( s ) behind how these two VEGF-A isoforms with similar binding affinities , promote such diverse activation of VEGFR2 and downstream signalling enzymes .	One question left unanswered is what is the mechanism (s) behind how these two VEGF-A isoforms with similar binding affinities, promote such diverse activation of VEGFR2 and downstream signalling enzymes.	16	32	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	16	17	28	29
Activation of VEGFR-2 by VEGFA 165 was shown to enhance migration of PC3 cells .	Activation of VEGFR-2 by VEGFA 165 was shown to enhance migration of PC3 cells.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR-2	VEGFR-2	VEGFR-2	4	5	2	3
VEGF-A stimulates the activation of VEGFR-2 in LECs and promotes tissue repair associated lymphatic vessel formation and lymphangiogenesis 31 , 34 .	VEGF-A stimulates the activation of VEGFR-2 in LECs and promotes tissue repair associated lymphatic vessel formation and lymphangiogenesis 31, 34.	0	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	0	1	5	6
After VEGF-A mediated VEGFR-2 activation , Shb stimulates PI3kinase activity , and interacts with Src and FAK , to promote focal adhesion formation and cell migration .	After VEGF-A mediated VEGFR-2 activation, Shb stimulates PI3kinase activity, and interacts with Src and FAK, to promote focal adhesion formation and cell migration.	0	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	1	2	3	4
The activation of VEGFR2 by VEGF-A results in the activation of PI3K and Akt , leading to EC survival and activation of the MAPK pathway , which leads to EC proliferation .	The activation of VEGFR2 by VEGF-A results in the activation of PI3K and Akt, leading to EC survival and activation of the MAPK pathway, which leads to EC proliferation.	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	5	6	3	4
To determine whether the response to VEGFA was time dependent , we examined the levels of VEGFR1 and VEGFR2 on the surface of HUVEC , which were treated with VEGFA for 10 minutes , 4 hours ( XREF_FIG ) , or 24 hours ( XREF_FIG ) .	To determine whether the response to VEGFA was time dependent, we examined the levels of VEGFR1 and VEGFR2 on the surface of HUVEC, which were treated with VEGFA for 10 minutes, 4 hours (XREF_FIG), or 24 hours (XREF_FIG).	14	32	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	29	30	18	19
VEGF-A enhances VEGFR2 shedding by ADAM17 , but not shedding of NRP-1 by ADAM10 .	VEGF-A enhances VEGFR2 shedding by ADAM17, but not shedding of NRP-1 by ADAM10.	0	3	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	2	3
Based on alternative splicing , there are five pro angiogenic variants of vascular endothelial growth factor ( VEGF-A ) that target and activate VEGFR1 and VEGFR2 .	Based on alternative splicing, there are five pro angiogenic variants of vascular endothelial growth factor (VEGF-A) that target and activate VEGFR1 and VEGFR2.	15	26	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	17	18	25	26
VEGFR-2 homodimers , however , can be induced by VEGF-A [ XREF_BIBR ] .	VEGFR-2 homodimers, however, can be induced by VEGF-A [XREF_BIBR].	0	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	9	10	0	1
VEGFR-2 and VEGFR-3 are known to exist in hLECs and are activated by VEGF-A and VEGF-C , respectively [ XREF_BIBR , XREF_BIBR ] .	VEGFR-2 and VEGFR-3 are known to exist in hLECs and are activated by VEGF-A and VEGF-C, respectively [XREF_BIBR, XREF_BIBR].	0	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	13	14	0	1
VEGF-A receptor-1 ( fms like tyrosine kinase-1 , FLT-1 ) and VEGF-A receptor -2 ( fetal liver kinase-1 , FLK-1 ) are activated by VEGF-A .	VEGF-A receptor-1 (fms like tyrosine kinase-1, FLT-1) and VEGF-A receptor -2 (fetal liver kinase-1, FLK-1) are activated by VEGF-A.	15	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	fetal liver kinase-1	fetal liver kinase-1	fetal liver kinase-1	24	25	15	18
In fact , due to its ability of not interfering with ligand binding to the extracellular domain of the receptors , D16F7 would not increase the amount of VEGF-A available to interact with and activate VEGFR-2 .	In fact, due to its ability of not interfering with ligand binding to the extracellular domain of the receptors, D16F7 would not increase the amount of VEGF-A available to interact with and activate VEGFR-2.	26	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	amount of VEGF-A	vegf-a	VEGFR-2	VEGFR-2	vegfr-2	28	29	35	36
The new variants of the biparatopic Affibody bound to VEGFR2 expressing cells , blocked VEGFA binding , and inhibited VEGFA induced signaling of VEGFR2 over expressing cells .	The new variants of the biparatopic Affibody bound to VEGFR2 expressing cells, blocked VEGFA binding, and inhibited VEGFA induced signaling of VEGFR2 over expressing cells.	19	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	19	20	23	24
Our data show that RLYE blocked the angiogenic signals , angiogenesis , and VEGFR-2 internalization induced by VEGF-A .	Our data show that RLYE blocked the angiogenic signals, angiogenesis, and VEGFR-2 internalization induced by VEGF-A.	13	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	17	18	13	14
As a major mediator , VEGF-A induced VEGFR-2 activation modulated the mitogenic , angiogenic , and permeability increasing effects in ECs [ XREF_BIBR , XREF_BIBR ] .	As a major mediator, VEGF-A induced VEGFR-2 activation modulated the mitogenic, angiogenic, and permeability increasing effects in ECs [XREF_BIBR, XREF_BIBR].	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	5	6	7	8
Therefore , it is possible that constant VEGF-A expression may also activate intrinsic VEGFR2 activity in migratory cells in an autocrine manner .	Therefore, it is possible that constant VEGF-A expression may also activate intrinsic VEGFR2 activity in migratory cells in an autocrine manner.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A expression	vegf-a	VEGFR2	VEGFR2	vegfr2	7	8	13	14
VEGF-A activates VEGFR-2 whereas VEGF-C activates both VEGFR-2 and VEGFR-3 .	VEGF-A activates VEGFR-2 whereas VEGF-C activates both VEGFR-2 and VEGFR-3.	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	0	1	2	3
However , previous study reported that VEGFA induced p-VEGFR2 to enhance EC proliferation by exacerbating STAT3 activation , leading to pathological angiogenesis 15 .	However, previous study reported that VEGFA induced p-VEGFR2 to enhance EC proliferation by exacerbating STAT3 activation, leading to pathological angiogenesis 15.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	p-VEGFR2	p-VEGFR2	p-VEGFR2	6	7	8	9
It has been reported that increased expression of VEGFA could induce up-regulation of VEGFR2 in podocytes in vitro [ XREF_BIBR ] .	It has been reported that increased expression of VEGFA could induce up-regulation of VEGFR2 in podocytes in vitro [XREF_BIBR].	6	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	expression of VEGFA	vegfa	VEGFR2	VEGFR2	vegfr2	8	9	13	14
VEGF-A isoforms cause differential plasma membrane-to-endosome trafficking of VEGFR2 .	VEGF-A isoforms cause differential plasma membrane-to-endosome trafficking of VEGFR2.	0	9	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	8	9
In contrast , VEGF-A induced strong VEGFR2 but only marginal VEGFR3 internalization and a much lesser extent of co-localization of the two receptors was observed ( XREF_FIG ) .	In contrast, VEGF-A induced strong VEGFR2 but only marginal VEGFR3 internalization and a much lesser extent of co-localization of the two receptors was observed (XREF_FIG).	3	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	3	4	6	7
Under normal conditions , VEGF-A stimulation causes VEGFR2 localization to Rab11 positive endosomes and subsequent receptor recycling to the plasma membrane .	Under normal conditions, VEGF-A stimulation causes VEGFR2 localization to Rab11 positive endosomes and subsequent receptor recycling to the plasma membrane.	4	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	4	5	7	8
To determine the potency of C-furSema function in cellular context , we examined its ability to inhibit VEGF-A mediated activation of VEGFR-2 .	To determine the potency of C-furSema function in cellular context, we examined its ability to inhibit VEGF-A mediated activation of VEGFR-2.	17	22	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	17	18	21	22
Our results show that VEGFA induced p-VEGFR2 activates EPOR and causes an interaction between p-EPOR and p-VEGFR2 to enhance VEGFA induced EC proliferation by exacerbating STAT3 activation , leading to pathological angiogenesis .	Our results show that VEGFA induced p-VEGFR2 activates EPOR and causes an interaction between p-EPOR and p-VEGFR2 to enhance VEGFA induced EC proliferation by exacerbating STAT3 activation, leading to pathological angiogenesis.	4	10	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	p-VEGFR2	p-VEGFR2	p-VEGFR2	4	5	6	7
VEGF-A induces signaling in VEGFR-2 and -3 , which are expressed in the tip cells leading to up-regulation of Dll4 and subsequent activation of Notch signaling in adjacent endothelial stalk cells .	VEGF-A induces signaling in VEGFR-2 and -3, which are expressed in the tip cells leading to up-regulation of Dll4 and subsequent activation of Notch signaling in adjacent endothelial stalk cells.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	0	1	4	5
VEGFA ligand activates VEGFR2 and critical downstream signals including MEK and ERK , SRC , and AKT , which can be detected with phosphospecific antibodies that report the activated forms of these proteins 5 .	VEGFA ligand activates VEGFR2 and critical downstream signals including MEK and ERK, SRC, and AKT, which can be detected with phosphospecific antibodies that report the activated forms of these proteins 5.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	0	1	3	4
r84 significantly suppressed lymphangiogenesis in vivo , suggesting that blockade of VEGF-A activation of VEGFR2 is sufficient to inhibit lymphangiogenesis .	r84 significantly suppressed lymphangiogenesis in vivo, suggesting that blockade of VEGF-A activation of VEGFR2 is sufficient to inhibit lymphangiogenesis.	11	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	11	12	14	15
To verify that the increased surface VEGFR2 after sunitinib treatment were indeed active , we measured pVEGFR2 in b-End3 that were treated with sunitinib or treated with VEGFA after first treating with sunitinib using immunoblots ( XREF_FIG ) .	To verify that the increased surface VEGFR2 after sunitinib treatment were indeed active, we measured pVEGFR2 in b-End3 that were treated with sunitinib or treated with VEGFA after first treating with sunitinib using immunoblots (XREF_FIG).	15	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	pVEGFR2	pVEGFR2	pVEGFR2	27	28	16	17
XREF_BIBR - XREF_BIBR VEGFA activates VEGFR1 and VEGFR2 , which , in turn , induces endothelial cell proliferation , sprouting , migration and tube formation , thereby promoting the generation of blood vessels .	XREF_BIBR - XREF_BIBR VEGFA activates VEGFR1 and VEGFR2, which, in turn, induces endothelial cell proliferation, sprouting, migration and tube formation, thereby promoting the generation of blood vessels.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	3	4	7	8
Using targeted KO mice , release of VEGF-A from GFAP positive cells stimulates VEGFR1 and VEGFR2 to regulate proliferation and migration of SVZ neuroblasts , and ultimately alters rates of surviving cells in vivo .	Using targeted KO mice, release of VEGF-A from GFAP positive cells stimulates VEGFR1 and VEGFR2 to regulate proliferation and migration of SVZ neuroblasts, and ultimately alters rates of surviving cells in vivo.	5	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	7	8	15	16
VEGFR-2 binds to , and is activated by the ligands VEGF-A , VEGF-E , and a number of processed forms of VEGF-C and VEGF-D .	VEGFR-2 binds to, and is activated by the ligands VEGF-A, VEGF-E, and a number of processed forms of VEGF-C and VEGF-D.	0	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	10	11	0	1
In contrast , VEGFR-2 , activated by VEGF-A , VEGF-C and VEGF-D , is a mediator of angiogenesis and drives primary tumor growth .	In contrast, VEGFR-2, activated by VEGF-A, VEGF-C and VEGF-D, is a mediator of angiogenesis and drives primary tumor growth.	3	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	7	8	3	4
Since VEGF-R2 is activated only indirectly by endogenously available VEGF-A , even significant VEGF-B overexpression does not cause excessive stimulation of R2 signaling 54 .	Since VEGF-R2 is activated only indirectly by endogenously available VEGF-A, even significant VEGF-B overexpression does not cause excessive stimulation of R2 signaling 54.	1	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A, even significant VEGF-B overexpression	vegf-a	VEGF-R2	VEGF-R2	vegf-r2	9	10	1	2
These data indicate that VEGF-A activation of VEGFR2 , not VEGFR1 , directly drives LEC proliferation and migration .	These data indicate that VEGF-A activation of VEGFR2, not VEGFR1, directly drives LEC proliferation and migration.	4	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	4	5	7	8
VEGFR2 plays the most important role in angiogenesis , and is activated by different isoforms of VEGF-A , -C , and -D .	VEGFR2 plays the most important role in angiogenesis, and is activated by different isoforms of VEGF-A, -C, and -D.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	16	17	0	1
In addition , EGCG ( 0.5-10 muM ) disrupted VEGFA induced VEGFR2 dimerization and decreased the downstream PI3K activity in human umbilical vein endothelial cells XREF_BIBR .	In addition, EGCG (0.5-10 muM) disrupted VEGFA induced VEGFR2 dimerization and decreased the downstream PI3K activity in human umbilical vein endothelial cells XREF_BIBR.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	9	10	11	12
Here we show for the first time that VEGF-A activation of VEGFR2 directly stimulates LEC proliferation and migration through the PI3-K and ERK1/2 signaling pathways .	Here we show for the first time that VEGF-A activation of VEGFR2 directly stimulates LEC proliferation and migration through the PI3-K and ERK1/2 signaling pathways.	8	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	8	9	11	12
VEGF-A 165 b , the most extensively studied isoform , binds to and activates VEGF-R2 , but is quantitatively and qualitatively different from VEGF-A 165 a [ XREF_BIBR ] , stimulating cyto-protective signalling , but not angiogenic pathways [ XREF_BIBR , XREF_BIBR ] .	VEGF-A 165 b, the most extensively studied isoform, binds to and activates VEGF-R2, but is quantitatively and qualitatively different from VEGF-A 165 a [XREF_BIBR], stimulating cyto-protective signalling, but not angiogenic pathways [XREF_BIBR, XREF_BIBR].	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGF-R2	VEGF-R2	VEGF-R2	0	1	14	15
Interestingly , VEGF-A 121 stimulation also caused significant VEGFR2 proteolysis , which was higher than that observed upon VEGF-A 145 stimulation ( XREF_FIG D ) .	Interestingly, VEGF-A 121 stimulation also caused significant VEGFR2 proteolysis, which was higher than that observed upon VEGF-A 145 stimulation (XREF_FIG D).	2	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	2	3	8	9
VEGF-A stimulates the activation of preformed VEGFR2 dimers by the autophosphorylation of activation segment tyrosines followed by the phosphorylation of additional protein-tyrosines that recruit phosphotyrosine binding proteins thereby leading to signaling by the ERK1/2 , AKT , Src , and p38 MAP kinase pathways [ XREF_BIBR ] .	VEGF-A stimulates the activation of preformed VEGFR2 dimers by the autophosphorylation of activation segment tyrosines followed by the phosphorylation of additional protein-tyrosines that recruit phosphotyrosine binding proteins thereby leading to signaling by the ERK1/2, AKT, Src, and p38 MAP kinase pathways [XREF_BIBR].	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	6	7
VEGFA treatment induced a gradual clearance of VEGFR2 from the membrane in control and shENG ECs but the latter displayed a slightly altered VEGFR2 internalisation kinetics .	VEGFA treatment induced a gradual clearance of VEGFR2 from the membrane in control and shENG ECs but the latter displayed a slightly altered VEGFR2 internalisation kinetics.	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	0	1	7	8
VEGF-A was identified as an essential factor for endothelial differentiation from such KDR + mesodermal precursors ; however , VEGF-A alone also promoted EP ( VEC + KDR high CD34 + ) differentiation into mature ECs ( VEC + KDR low CD34 - ) , or KDR + precursor differentiation into non endothelial lineage cells , e.g ., smooth muscle cells ( SMCs ) , which was enhanced especially in cultures with active delta like 4 ( Dll4 )/Notch signaling .	VEGF-A was identified as an essential factor for endothelial differentiation from such KDR + mesodermal precursors; however, VEGF-A alone also promoted EP (VEC + KDR high CD34 +) differentiation into mature ECs (VEC + KDR low CD34 -), or KDR + precursor differentiation into non endothelial lineage cells, e.g., smooth muscle cells (SMCs), which was enhanced especially in cultures with active delta like 4 (Dll4)/Notch signaling.	19	47	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	19	20	46	47
Podocyte Vegf 164 overexpression in diabetic mice induces semaphorin3a and VEGFR2 production .	Podocyte Vegf 164 overexpression in diabetic mice induces semaphorin3a and VEGFR2 production.	0	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vegf	Vegf 164 overexpression	vegf	VEGFR2	VEGFR2	vegfr2	1	2	10	11
The effects mediated by VEGF-A ( 165 ) and VEGF-A ( 121 ) ( VEGFR-1 and VEGFR-2 agonists ) were blocked by a selective VEGFR-2 inhibitor , SU1498 .	The effects mediated by VEGF-A (165) and VEGF-A (121) (VEGFR-1 and VEGFR-2 agonists) were blocked by a selective VEGFR-2 inhibitor, SU1498.	2	17	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	4	5	16	17
Both VEGF-A 165 and VEGF-A 145 produced similar kinetics of VEGFR2 endocytosis at the plasma membrane ; however , VEGF-A 121 -stimulated internalization of VEGFR2 was clearly slower ( XREF_FIG C ) .	Both VEGF-A 165 and VEGF-A 145 produced similar kinetics of VEGFR2 endocytosis at the plasma membrane; however, VEGF-A 121 -stimulated internalization of VEGFR2 was clearly slower (XREF_FIG C).	0	11	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	1	2	10	11
These findings expand our knowledge on the endocytic pathways of VEGFR2 and suggest that VEGFA driven internalisation of VEGFR2 through macropinocytosis is essential for endothelial cell signalling and angiogenesis .	These findings expand our knowledge on the endocytic pathways of VEGFR2 and suggest that VEGFA driven internalisation of VEGFR2 through macropinocytosis is essential for endothelial cell signalling and angiogenesis.	14	22	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	14	15	18	19
Together , these observations demonstrate that in the developing retina tip cell migration and stalk cell proliferation are independently controlled phenomena that depend on VEGF-A stimulation of VEGFR2 .	Together, these observations demonstrate that in the developing retina tip cell migration and stalk cell proliferation are independently controlled phenomena that depend on VEGF-A stimulation of VEGFR2.	24	28	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	24	25	27	28
Effects of VEGF Trap , ranibizumab and bevacizumab on VEGF-A induced activation of VEGFR2 .	Effects of VEGF Trap, ranibizumab and bevacizumab on VEGF-A induced activation of VEGFR2.	5	14	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	9	10	13	14
Quantification of these data showed that all three VEGF-A isoforms significantly promoted VEGFR2 proteolysis , with a peak at ~ 30min post-stimulation ( XREF_FIG D ) .	Quantification of these data showed that all three VEGF-A isoforms significantly promoted VEGFR2 proteolysis, with a peak at ~ 30min post-stimulation (XREF_FIG D).	8	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	8	9	12	13
Vascular endothelial growth factor-A ( VEGF-A ) is the primary activator of tumour angiogenesis and functions by binding to VEGF-Receptor 2 ( VEGF-R2 ) and is often required for tumour growth beyond 2-3 mm .	Vascular endothelial growth factor-A (VEGF-A) is the primary activator of tumour angiogenesis and functions by binding to VEGF-Receptor 2 (VEGF-R2) and is often required for tumour growth beyond 2-3 mm.	0	23	activator	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Vascular endothelial growth factor-A	Vascular endothelial growth factor-A	Vascular endothelial growth factor-A	VEGF-R2	VEGF-R2	VEGF-R2	0	4	22	23
As for VEGFR1 , VEGF Trap efficiently blocked VEGFR2 signaling induced by 20pM of human VEGF-A 121 or VEGF-A 165 ( IC 50 of 16 and 26pM , respectively ) .	As for VEGFR1, VEGF Trap efficiently blocked VEGFR2 signaling induced by 20pM of human VEGF-A 121 or VEGF-A 165 (IC 50 of 16 and 26pM, respectively).	8	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	15	16	8	9
Functional comparisons of the extent to which VEGF-A isoforms can drive distinct VEGFR2 signalling responses has largely come from phenotypic observations , such as changes in endothelial cell proliferation , or relative levels of phosphorylated VEGFR2 and downstream signalling proteins in endothelial cells using Western blots .	Functional comparisons of the extent to which VEGF-A isoforms can drive distinct VEGFR2 signalling responses has largely come from phenotypic observations, such as changes in endothelial cell proliferation, or relative levels of phosphorylated VEGFR2 and downstream signalling proteins in endothelial cells using Western blots.	7	14	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	7	8	12	13
XREF_BIBR , XREF_BIBR , XREF_BIBR VEGF and Notch regulation of angiogenic sprouting is therefore clearly complex ; VEGF-A provides a pro angiogenic stimulus and induces Flk-1 expressing cells to sprout and form new vessels , whilst simultaneously activating Dll4-Notch pathway signaling to maintain the necessary balance between tip and stalk cell specification .	XREF_BIBR, XREF_BIBR, XREF_BIBR VEGF and Notch regulation of angiogenic sprouting is therefore clearly complex; VEGF-A provides a pro angiogenic stimulus and induces Flk-1 expressing cells to sprout and form new vessels, whilst simultaneously activating Dll4-Notch pathway signaling to maintain the necessary balance between tip and stalk cell specification.	17	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	Flk-1	Flk-1	Flk-1	17	18	25	26
XREF_FIG concludes on these results ; VEGFA induces VEGFR2 homodimers and VEGFR2/-3 heterodimers .	XREF_FIG concludes on these results; VEGFA induces VEGFR2 homodimers and VEGFR2/-3 heterodimers.	6	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	6	7	8	9
XREF_BIBR Since ERK1/2 activation is tightly related to VEGFR2 trafficking , it is reasonable to infer that VEGF-A 165 induces more efficient VEGFR2 trafficking than VEGF-A 121 , probably because of the engagement of NRP1 in the process .	XREF_BIBR Since ERK1/2 activation is tightly related to VEGFR2 trafficking, it is reasonable to infer that VEGF-A 165 induces more efficient VEGFR2 trafficking than VEGF-A 121, probably because of the engagement of NRP1 in the process.	17	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	17	18	22	23
Transgenic ( TG ) overexpression of VEGFB revealed an interesting mechanism in which excess VEGFB can occupy VEGFR1 , allowing more VEGFA activation of VEGFR2 ( XREF_FIG ) .	Transgenic (TG) overexpression of VEGFB revealed an interesting mechanism in which excess VEGFB can occupy VEGFR1, allowing more VEGFA activation of VEGFR2 (XREF_FIG).	21	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	21	22	24	25
XREF_BIBR When the ability to inhibit VEGF-A-induced activation of VEGFR-2 was examined in this study , aflibercept also inhibited activation of VEGFR-2 induced by VEGF-A 165 and was 51-fold more potent than bevacizumab ( XREF_TABLE ) .	XREF_BIBR When the ability to inhibit VEGF-A-induced activation of VEGFR-2 was examined in this study, aflibercept also inhibited activation of VEGFR-2 induced by VEGF-A 165 and was 51-fold more potent than bevacizumab (XREF_TABLE).	19	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	24	25	21	22
However , the reduction caused by VEGF-A 165 b stimulation was more prominent than that induced byVEGF-A 165 a with prolonged stimulations , suggesting that VEGF-A 165 b may preferentially direct VEGFR2 for degradation , as opposed to recycling .	However, the reduction caused by VEGF-A 165 b stimulation was more prominent than that induced byVEGF-A 165 a with prolonged stimulations, suggesting that VEGF-A 165 b may preferentially direct VEGFR2 for degradation, as opposed to recycling.	25	32	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	25	26	31	32
We have recently shown in HLEC that VEGF-A activates VEGFR-2 whereas VEGF-C activates VEGFR-3 strongly and VEGFR-2 weakly .	We have recently shown in HLEC that VEGF-A activates VEGFR-2 whereas VEGF-C activates VEGFR-3 strongly and VEGFR-2 weakly.	7	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	7	8	9	10
VEGFA 165 induces association of Nrp1 , VEGFR2 , and synectin to form a protein complex and drive intracellular trafficking of Nrp1 and VEGFR2 through specific endosomal compartments .	VEGFA 165 induces association of Nrp1, VEGFR2, and synectin to form a protein complex and drive intracellular trafficking of Nrp1 and VEGFR2 through specific endosomal compartments.	0	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	0	1	7	8
VEGF-A mediated VEGFR2 signaling activation is largely viewed as the dominant receptor tyrosine kinase signaling to induce angiogenesis .	VEGF-A mediated VEGFR2 signaling activation is largely viewed as the dominant receptor tyrosine kinase signaling to induce angiogenesis.	0	4	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	2	3
VEGFR2 Is Activated by VEGF-A and Is Required for VSMC Phenotypic Switch .	VEGFR2 Is Activated by VEGF-A and Is Required for VSMC Phenotypic Switch.	0	7	Activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	4	5	0	1
Further , VEGFA promoted VEGFR2 + eTreg cell proliferation , and this effect could be inhibited by RAM .	Further, VEGFA promoted VEGFR2 + eTreg cell proliferation, and this effect could be inhibited by RAM.	2	8	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	2	3	4	5
Increased VEGFR2 endocytosis triggered by VEGF-A could be linked to VEGFR2 exit from plasma membrane caveolae or lipid rafts to facilitate receptor mediated endocytosis .	Increased VEGFR2 endocytosis triggered by VEGF-A could be linked to VEGFR2 exit from plasma membrane caveolae or lipid rafts to facilitate receptor mediated endocytosis.	1	6	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	5	6	1	2
Various studies have shown that VEGF-A isoforms promote differential VEGFR2 activation and downstream signal transduction .	Various studies have shown that VEGF-A isoforms promote differential VEGFR2 activation and downstream signal transduction.	5	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	5	6	9	10
To test the idea that VEGF-A isoforms trigger differential VEGFR2 activation , we monitored the presence of such VEGFR2 phosphotyrosine-epitopes in human umbilical vein endothelial cells ( HUVECs ) in response to stimulation with different VEGF-A isoforms ( 1.25 nM ; 0-20min ) using immunoblot analysis ( XREF_FIG A ) .	To test the idea that VEGF-A isoforms trigger differential VEGFR2 activation, we monitored the presence of such VEGFR2 phosphotyrosine-epitopes in human umbilical vein endothelial cells (HUVECs) in response to stimulation with different VEGF-A isoforms (1.25 nM; 0-20min) using immunoblot analysis (XREF_FIG A).	5	10	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	5	6	9	10
These findings taken together suggest that the effect on the ureteric epithelium is direct , as VEGF-A could directly signal to VEGFR2 on the ureteric epithelium .	These findings taken together suggest that the effect on the ureteric epithelium is direct, as VEGF-A could directly signal to VEGFR2 on the ureteric epithelium.	16	22	signal	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	16	17	21	22
The activation of VEGFR2 by VEGFA can initiate multiple signaling pathways that orchestrate a variety of complex biological effects , such as endothelial cells maturation , vessel lumen formation , vascular permeability , vasodilation , angiogenesis and arteriogenesis [ XREF_BIBR - XREF_BIBR ] .	The activation of VEGFR2 by VEGFA can initiate multiple signaling pathways that orchestrate a variety of complex biological effects, such as endothelial cells maturation, vessel lumen formation, vascular permeability, vasodilation, angiogenesis and arteriogenesis [XREF_BIBR - XREF_BIBR].	1	6	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	5	6	3	4
Key lines of evidence support our conclusion that VEGF-A isoforms differentially stimulate VEGFR2 endocytosis and delivery to early endosomes ( XREF_FIG ) .	Key lines of evidence support our conclusion that VEGF-A isoforms differentially stimulate VEGFR2 endocytosis and delivery to early endosomes (XREF_FIG).	8	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	8	9	12	13
Vascular endothelial growth factor receptor-2 ( VEGFR-2 ) activation by VEGF-A is essential in vasculogenesis and angiogenesis .	Vascular endothelial growth factor receptor-2 (VEGFR-2) activation by VEGF-A is essential in vasculogenesis and angiogenesis.	0	11	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	Vascular endothelial growth factor receptor-2	Vascular endothelial growth factor receptor-2	Vascular endothelial growth factor receptor-2	10	11	0	5
The targeting of VEGFR-1 by Vasotide may play a greater role in the angiogenic mechanism than the targeting of VEGFR-2 by VEGF-A if the onset of angiogenesis is indeed a consequence of a hypoxic state .	The targeting of VEGFR-1 by Vasotide may play a greater role in the angiogenic mechanism than the targeting of VEGFR-2 by VEGF-A if the onset of angiogenesis is indeed a consequence of a hypoxic state.	7	22	targeting	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	21	22	19	20
Further results showed that SP600125 and JNK and SAPK siRNA decreased VEGFA induced VEGFR2 ( Flk-1 and KDR ) sustained phosphorylation in HUVECs .	Further results showed that SP600125 and JNK and SAPK siRNA decreased VEGFA induced VEGFR2 (Flk-1 and KDR) sustained phosphorylation in HUVECs.	11	17	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	11	12	13	14
Besides being the most important survival system for nascent vessels by regulating cell adhesion to matrix , alphavbeta3 integrin participates in the full activation of VEGFR-2 triggered by VEGF-A , which is an important angiogenic inducer in tumors , inflammation and tissue regeneration .	Besides being the most important survival system for nascent vessels by regulating cell adhesion to matrix, alphavbeta3 integrin participates in the full activation of VEGFR-2 triggered by VEGF-A, which is an important angiogenic inducer in tumors, inflammation and tissue regeneration.	23	35	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	28	29	25	26
Also , gremlin and VEGF-A stimulate the formation of VEGFR2 and alpha ( v ) beta ( 3 ) integrin complexes as shown by co-immunoprecipitation experiments and fluorescence resonance energy transfer analysis of beta ( 3 )-ECFP/VEGFR2-EYFP co-transfected ECs .	Also, gremlin and VEGF-A stimulate the formation of VEGFR2 and alpha (v) beta (3) integrin complexes as shown by co-immunoprecipitation experiments and fluorescence resonance energy transfer analysis of beta (3)-ECFP/VEGFR2-EYFP co-transfected ECs.	2	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	4	5	9	10
In conclusion , the presence of NRP-1 on EC preferentially increases KDR activation by VEGF-A as well as KDR mediated biological activities , and may elicit novel intracellular events .	In conclusion, the presence of NRP-1 on EC preferentially increases KDR activation by VEGF-A as well as KDR mediated biological activities, and may elicit novel intracellular events.	11	18	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	14	15	11	12
Conversely , blockade of VEGF-A activation of VEGFR2 with r84 significantly ( P < 0.05 ) inhibited VEGF-A-induced proliferation of LECs ( XREF_FIG ) .	Conversely, blockade of VEGF-A activation of VEGFR2 with r84 significantly (P < 0.05) inhibited VEGF-A-induced proliferation of LECs (XREF_FIG).	4	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	4	5	7	8
VEGFR-2 was equally activated by VEGF-A in VEC-WT-, -Y658F-, -Y685F-, and -Y733F expressing ECs , and VEGF-A-initiated paracellular permeability at 15 min was increased to the same extent in VEC-WT-, -Y685F-, and -Y733F expressing ECs ( XREF_FIG ) .	VEGFR-2 was equally activated by VEGF-A in VEC-WT-, -Y658F-, -Y685F-, and -Y733F expressing ECs, and VEGF-A-initiated paracellular permeability at 15 min was increased to the same extent in VEC-WT-, -Y685F-, and -Y733F expressing ECs (XREF_FIG).	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	5	6	0	1
Several studies have shown that VEGF-A 165 b poorly activates the VEGFR-2 kinase domain , resulting in weak , transient phosphorylation of downstream targets including Akt and ERK1/2 [ XREF_BIBR , XREF_BIBR ] .	Several studies have shown that VEGF-A 165 b poorly activates the VEGFR-2 kinase domain, resulting in weak, transient phosphorylation of downstream targets including Akt and ERK1/2 [XREF_BIBR, XREF_BIBR].	5	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	5	6	11	12
Upon ligation by VEGFA , VEGFR2 can be activated through receptor dimerization and autophosphorylation , thus resulting in activation of various downstream signal cascades .	Upon ligation by VEGFA, VEGFR2 can be activated through receptor dimerization and autophosphorylation, thus resulting in activation of various downstream signal cascades.	1	9	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	3	4	5	6
VEGFR-2 , also known as kinase insert domain receptor , is the main regulator of angiogenesis and is activated by VEGF-A .	VEGFR-2, also known as kinase insert domain receptor, is the main regulator of angiogenesis and is activated by VEGF-A.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	20	21	0	1
Recent evidence indicates that the VEGFR2 signalling output elicited by matrix associated VEGFA is also distinct to that induced by soluble isoforms 30 .	Recent evidence indicates that the VEGFR2 signalling output elicited by matrix associated VEGFA is also distinct to that induced by soluble isoforms 30.	5	13	elicited	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	12	13	5	6
NRP1 makes a co and receptor complex with VEGFR2 , promoting VEGFA induced VEGFR2 signalling in BECs .	NRP1 makes a co and receptor complex with VEGFR2, promoting VEGFA induced VEGFR2 signalling in BECs.	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	11	12	13	14
Compared to VEGF-A activation of VEGFR2 , VEGF-C-induced VEGFR3 activation led to a more extensive AKT activation while activation of ERK1/2 displayed a distinctly different kinetics .	Compared to VEGF-A activation of VEGFR2, VEGF-C-induced VEGFR3 activation led to a more extensive AKT activation while activation of ERK1/2 displayed a distinctly different kinetics.	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	2	3	5	6
In contrast , VEGFR-2 is induced in neuronal and endothelial cells by infused VEGF-A or injury [ XREF_BIBR ] .	In contrast, VEGFR-2 is induced in neuronal and endothelial cells by infused VEGF-A or injury [XREF_BIBR].	3	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	13	14	3	4
Bevacizumab-Fab , but not bevacizumab-Fc , inhibited VEGFA induced Vegfr2 phosphoryla-tion , consistent with the location of the VEGFA binding residues on the Fab fragment and indicating that the VEGFA neutralizing properties of bevacizumab were not affected by enzymatic digestion ( XREF_SUPPLEMENTARY ) .	Bevacizumab-Fab, but not bevacizumab-Fc, inhibited VEGFA induced Vegfr2 phosphoryla-tion, consistent with the location of the VEGFA binding residues on the Fab fragment and indicating that the VEGFA neutralizing properties of bevacizumab were not affected by enzymatic digestion (XREF_SUPPLEMENTARY).	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	Vegfr2	Vegfr2	Vegfr2	7	8	9	10
These data reveal that specifically blocking VEGF-A activation of VEGFR2 with r84 is sufficient to suppress lymphangiogenesis in vivo .	These data reveal that specifically blocking VEGF-A activation of VEGFR2 with r84 is sufficient to suppress lymphangiogenesis in vivo.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	6	7	9	10
VEGFA is released from tissues in response to hypoxia , inflammation , or wound healing and activates VEGFR2 receptor tyrosine kinase activity in endothelial cells .	VEGFA is released from tissues in response to hypoxia, inflammation, or wound healing and activates VEGFR2 receptor tyrosine kinase activity in endothelial cells.	0	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	0	1	17	18
Endorepellin attenuated VEGFA mediated activation of VEGFR2 in endothelial cells , and this attenuation is required for alpha2beta1 integrin .	Endorepellin attenuated VEGFA mediated activation of VEGFR2 in endothelial cells, and this attenuation is required for alpha2beta1 integrin.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	2	3	6	7
Activation of VEGFR-3 signaling by VEGF-C is essential for normal development of the lymphatic vascular system 17 and can promote growth of lymphatics in the adult XREF_BIBR - XREF_BIBR .	Activation of VEGFR-3 signaling by VEGF-C is essential for normal development of the lymphatic vascular system 17 and can promote growth of lymphatics in the adult XREF_BIBR - XREF_BIBR.	2	6	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	5	6	2	3
NSCs contain Vegf-c transcripts , suggesting that , besides paracrine VEGF-C from DG cells , autocrine VEGF-C may activate VEGFR3 at the cell membrane .	NSCs contain Vegf-c transcripts, suggesting that, besides paracrine VEGF-C from DG cells, autocrine VEGF-C may activate VEGFR3 at the cell membrane.	15	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	16	17	19	20
It has been suggested that VEGF-C could promote the VEGFR3 positive tumor cells invade to lymphatic vessels through autocrine and CCR-7 dependent paracrine mechanism [ XREF_BIBR ] .	It has been suggested that VEGF-C could promote the VEGFR3 positive tumor cells invade to lymphatic vessels through autocrine and CCR-7 dependent paracrine mechanism [XREF_BIBR].	5	13	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	5	6	9	10
We have found that VEGF-C activated VEGFR-3 was translocated into the nucleus of both lung adenocarcinoma cells and primary lymphatic endothelial cells ( our unpublished data ) .	We have found that VEGF-C activated VEGFR-3 was translocated into the nucleus of both lung adenocarcinoma cells and primary lymphatic endothelial cells (our unpublished data).	4	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	6	7
It is possible that flt4 mutant is not a complete null , and high level of Vegfc overexpression is sufficient to stimulate the remaining Flt4 activity .	It is possible that flt4 mutant is not a complete null, and high level of Vegfc overexpression is sufficient to stimulate the remaining Flt4 activity.	16	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vegfc	Vegfc overexpression	vegfc	Flt4	Flt4	flt4	16	17	24	25
VEGF-C induced VEGFR-3 endocytosis in HLEC , and the surface VEGFR-3 level was reduced by 50 % at 5 min and 75 % at 10 min after VEGF-C stimulation ( XREF_SUPPLEMENTARY ) .	VEGF-C induced VEGFR-3 endocytosis in HLEC, and the surface VEGFR-3 level was reduced by 50% at 5 min and 75% at 10 min after VEGF-C stimulation (XREF_SUPPLEMENTARY).	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	0	1	2	3
The receptor tyrosine kinase ( RTK ) VEGFR-3 , one of the first discovered lymphatic endothelial markers [ XREF_BIBR ] , is activated by VEGF-C and VEGF-D of the VEGF family of growth factors [ XREF_BIBR ] .	The receptor tyrosine kinase (RTK) VEGFR-3, one of the first discovered lymphatic endothelial markers [XREF_BIBR], is activated by VEGF-C and VEGF-D of the VEGF family of growth factors [XREF_BIBR].	0	30	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	24	25	7	8
In contrast , more limited exposure to plasmin generated VEGF-C able to activate VEGFR-3 , although the cleavage site involved has not been reported .	In contrast, more limited exposure to plasmin generated VEGF-C able to activate VEGFR-3, although the cleavage site involved has not been reported.	9	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	9	10	13	14
However , VEGF-C is thought to primarily induce lymphangiogenesis by activating VEGFR3 .	However, VEGF-C is thought to primarily induce lymphangiogenesis by activating VEGFR3.	2	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	2	3	11	12
From the first report of isolated LECs , VEGF-C stimulation of VEGFR3 was shown to lead to the downstream phosphorylation of both MAPK and AKT ( XREF_FIG ) .	From the first report of isolated LECs, VEGF-C stimulation of VEGFR3 was shown to lead to the downstream phosphorylation of both MAPK and AKT (XREF_FIG).	8	12	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	8	9	11	12
XREF_BIBR , XREF_BIBR The following has been proposed as possible induction mechanisms : a direct pathway via Phospatidylinositol 3-kinase/Akt XREF_BIBR , XREF_BIBR and an indirect pathway associated with VEGF-C and VEGF-D that activates VEGFR-3 .	XREF_BIBR, XREF_BIBR The following has been proposed as possible induction mechanisms : a direct pathway via Phospatidylinositol 3-kinase/Akt XREF_BIBR, XREF_BIBR and an indirect pathway associated with VEGF-C and VEGF-D that activates VEGFR-3.	26	34	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	28	29	33	34
VEGFB ( VEGFB , P49765 ) and placental growth factor ( PGF , P49763 ) activate VEGFR1 homodimers , while VEGFC ( VEGFC , P49767 ) and VEGFD ( VEGFD , O43915 ) activate VEGFR2/3 heterodimers and VEGFR3 homodimers , and , following proteolysis , VEGFR2 homodimers .	VEGFB (VEGFB, P49765) and placental growth factor (PGF, P49763) activate VEGFR1 homodimers, while VEGFC (VEGFC, P49767) and VEGFD (VEGFD, O43915) activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers.	20	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR3	VEGFR3	VEGFR3	20	21	37	38
VEGF-C and VEGF-D specifically activate VEGFR3 on lymphatic endothelium to induce lymphatic capillary proliferation and growth [ XREF_BIBR , XREF_BIBR ] .	VEGF-C and VEGF-D specifically activate VEGFR3 on lymphatic endothelium to induce lymphatic capillary proliferation and growth [XREF_BIBR, XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	0	1	5	6
A significant increase in VEGFR-3 and phosphoPI3K interactions was detected in LECs treated with VEGF-C when compared to vehicle control ( XREF_FIG ) .	A significant increase in VEGFR-3 and phosphoPI3K interactions was detected in LECs treated with VEGF-C when compared to vehicle control (XREF_FIG).	4	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	14	15	4	5
Together , these findings demonstrate the dual action of VEGFR-3 in angiogenesis , i.e ., on the one hand , passive , ubiquitous and anti-angiogenic through interactions with the extracellular matrix and , on the other hand , active , local and pro angiogenic following VEGFR-3 stimulation by its ligands VEGF-C and VEGF-D .	Together, these findings demonstrate the dual action of VEGFR-3 in angiogenesis, i.e., on the one hand, passive, ubiquitous and anti-angiogenic through interactions with the extracellular matrix and, on the other hand, active, local and pro angiogenic following VEGFR-3 stimulation by its ligands VEGF-C and VEGF-D.	45	52	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	50	51	45	46
Similarly , we found that culturing isolated LECs with SA and either recombinant VEGF-C ( direct activation of VEGFR-3 downstream pathways ) or recombinant insulin ( indirect activation of PIP3 pathway via tyrosine kinase activation ) restored the viability of LECs cultured with SA ( XREF_SUPPLEMENTARY ) .	Similarly, we found that culturing isolated LECs with SA and either recombinant VEGF-C (direct activation of VEGFR-3 downstream pathways) or recombinant insulin (indirect activation of PIP3 pathway via tyrosine kinase activation) restored the viability of LECs cultured with SA (XREF_SUPPLEMENTARY).	5	24	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	13	14	18	19
To determine whether activation of VEGFR-3 induces NFATc1 nuclear translocation , factor starved HMVEC- L were cultured for 3 hours with VEGF-C , VEGF-D or VEGF-C C156S , a mutant of VEGF-C that activates VEGFR-3 , but not VEGFR-2 , at concentrations up to 500ng/ml .	To determine whether activation of VEGFR-3 induces NFATc1 nuclear translocation, factor starved HMVEC- L were cultured for 3 hours with VEGF-C, VEGF-D or VEGF-C C156S, a mutant of VEGF-C that activates VEGFR-3, but not VEGFR-2, at concentrations up to 500ng/ml.	21	41	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	21	22	34	35
VEGF , VEGF-B , and PlGF can bind and activate VEGFR-1 , whereas VEGFR-2 is primarily activated by VEGF , and VEGFR-3 activation is only triggered by VEGF-C and VEGF-D [ XREF_BIBR ] .	VEGF, VEGF-B, and PlGF can bind and activate VEGFR-1, whereas VEGFR-2 is primarily activated by VEGF, and VEGFR-3 activation is only triggered by VEGF-C and VEGF-D [XREF_BIBR].	21	31	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	27	28	21	22
Interestingly , in this experiment , inhibition of VEGF-C mediated activation of VEGFR-3 was associated with a decrease in eNOS expression .	Interestingly, in this experiment, inhibition of VEGF-C mediated activation of VEGFR-3 was associated with a decrease in eNOS expression.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	8	9	12	13
Previously , the authors had shown that signaling via VEGFR-3 was sufficient to induce hyperplasia of cutaneous lymphatic vessels because transgenic mice with skin specific overexpression of a mutated VEGF-C ( K14-VEGF-C156S ) that selectively activates VEGFR-3 developed lymphatic vessel enlargement in the skin .	Previously, the authors had shown that signaling via VEGFR-3 was sufficient to induce hyperplasia of cutaneous lymphatic vessels because transgenic mice with skin specific overexpression of a mutated VEGF-C (K14-VEGF-C156S) that selectively activates VEGFR-3 developed lymphatic vessel enlargement in the skin.	25	37	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	overexpression of a mutated VEGF-C	vegf-c	VEGFR-3	VEGFR-3	vegfr-3	29	30	36	37
Using various mouse models , we also determined that Vegfr3 regulates Prox1 by establishing a feedback loop necessary to maintain the identity of LEC progenitors and that Vegfc mediated activation of Vegfr3 signaling is necessary to maintain Prox1 expression in LEC progenitors .	Using various mouse models, we also determined that Vegfr3 regulates Prox1 by establishing a feedback loop necessary to maintain the identity of LEC progenitors and that Vegfc mediated activation of Vegfr3 signaling is necessary to maintain Prox1 expression in LEC progenitors.	27	32	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vegfc	Vegfc	Vegfc	Vegfr3	Vegfr3	Vegfr3	27	28	31	32
In the presence of VEGFR-2 , VEGF-C and -D induced heterodimerization of VEGFR-3 with VEGFR-2 .	In the presence of VEGFR-2, VEGF-C and -D induced heterodimerization of VEGFR-3 with VEGFR-2.	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	6	7	12	13
Interestingly , double Vegfc -/- / Vegfd -/- mutants survive until E16.5 and do not recapitulate the phenotype of Vegfr3 -/- mutants , suggesting VEGF-C and VEGF-D-independent activation of VEGFR-3 .	Interestingly, double Vegfc -/- / Vegfd -/- mutants survive until E16.5 and do not recapitulate the phenotype of Vegfr3 -/- mutants, suggesting VEGF-C and VEGF-D-independent activation of VEGFR-3.	24	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	24	25	29	30
For example , the release of VEGFC by macrophages can activate FLT4 in endothelial tip cells to promote the rapid conversion of tip cells to stalks cells at vessel fusion points 98 .	For example, the release of VEGFC by macrophages can activate FLT4 in endothelial tip cells to promote the rapid conversion of tip cells to stalks cells at vessel fusion points 98.	4	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	FLT4	FLT4	FLT4	6	7	11	12
However , VEGF-C activation of LEC specific VEGFR3 receptors blocked ANDV- and VEGF-A-induced LEC permeability .	However, VEGF-C activation of LEC specific VEGFR3 receptors blocked ANDV- and VEGF-A-induced LEC permeability.	2	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	2	3	7	8
Activation of VEGFR3 by VEGF-C increases the diameter of meningeal LVs , and blocking VEGFR3 signaling completely abrogates meningeal LVs , indicating that these vessels , like peripheral LVs , are regulated by VEGFR3 .	Activation of VEGFR3 by VEGF-C increases the diameter of meningeal LVs, and blocking VEGFR3 signaling completely abrogates meningeal LVs, indicating that these vessels, like peripheral LVs, are regulated by VEGFR3.	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	4	5	2	3
Lymphangiogenesis and sprouting of the first Prox1 positive LECs during embryogenesis are driven by VEGF-C and VEGF-D-mediated activation of VEGFR-2 and VEGFR-3 .	Lymphangiogenesis and sprouting of the first Prox1 positive LECs during embryogenesis are driven by VEGF-C and VEGF-D-mediated activation of VEGFR-2 and VEGFR-3.	14	22	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	14	15	21	22
Recent evidence [ XREF_BIBR ] shows that macrophage derived VEGF-C activates VEGFR-3 in endothelial tip cells during lymphangiogenesis .	Recent evidence [XREF_BIBR] shows that macrophage derived VEGF-C activates VEGFR-3 in endothelial tip cells during lymphangiogenesis.	8	15	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	9	10	11	12
VEGF activates VEGF receptor-1 ( VEGFR-1 ) and VEGFR-2 , whereas VEGF-C activates VEGFR-2 and VEGFR-3 .	VEGF activates VEGF receptor-1 (VEGFR-1) and VEGFR-2, whereas VEGF-C activates VEGFR-2 and VEGFR-3.	11	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	11	12	15	16
Therefore , VEGF-C does not induce VEGFR-3 release via exosomes or the release of fragmented VEGFR-3 into the media .	Therefore, VEGF-C does not induce VEGFR-3 release via exosomes or the release of fragmented VEGFR-3 into the media.	2	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	2	3	6	7
To determine whether VEGF-C activation of VEGFR2 or VEGFR3 was required for the formation of bone lymphatics , we treated 21-day-old Osx-tTA ; TetO-Vegfc mice with vehicle , DC101 ( VEGFR2 function blocking antibody ) , or mF4-31C1 ( VEGFR3 function blocking antibody ) for 2 weeks .	To determine whether VEGF-C activation of VEGFR2 or VEGFR3 was required for the formation of bone lymphatics, we treated 21-day-old Osx-tTA; TetO-Vegfc mice with vehicle, DC101 (VEGFR2 function blocking antibody), or mF4-31C1 (VEGFR3 function blocking antibody) for 2 weeks.	3	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	3	4	8	9
Administration of VEGF-C into naive ears did not increase HS expression above baseline ( not shown ) , suggesting that VEGFR-3 stimulated by homeostatic VEGF-C was already maximal to establish and maintain the HS scaffold .	Administration of VEGF-C into naive ears did not increase HS expression above baseline (not shown), suggesting that VEGFR-3 stimulated by homeostatic VEGF-C was already maximal to establish and maintain the HS scaffold.	20	31	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	24	25	20	21
Important primary tumor derived signals may stem from the VEGF-C and VEGF-D activation of lymphatic endothelial VEGFR-3 , which stimulates lymphangiogenesis toward the primary tumor and allows for cellular dissemination [ XREF_BIBR ] .	Important primary tumor derived signals may stem from the VEGF-C and VEGF-D activation of lymphatic endothelial VEGFR-3, which stimulates lymphangiogenesis toward the primary tumor and allows for cellular dissemination [XREF_BIBR].	9	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	9	10	16	17
VEGF-C and VEGFR -3 signalling pathway mediates differentiation of CD34 + VEGFR-3 + EPCs towards lymphatic endothelial cells and lymphangiogenesis .	VEGF-C and VEGFR -3 signalling pathway mediates differentiation of CD34 + VEGFR-3 + EPCs towards lymphatic endothelial cells and lymphangiogenesis.	0	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	0	1	11	12
Since literatures have showed that tumor induced lymphangiogenesis driven by VEGF-C and VEGF-D-induced activation of VEGFR-3 could promote regional lymph node metastasis in multiple solid tumors [ XREF_BIBR - XREF_BIBR ] .	Since literatures have showed that tumor induced lymphangiogenesis driven by VEGF-C and VEGF-D-induced activation of VEGFR-3 could promote regional lymph node metastasis in multiple solid tumors [XREF_BIBR - XREF_BIBR].	10	16	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	10	11	15	16
VEGFR- 3 , a receptor tyrosine kinase , is restricted to lymphatic endothelium in adults and is activated by VEGF-C and VEGF-D .	VEGFR- 3, a receptor tyrosine kinase, is restricted to lymphatic endothelium in adults and is activated by VEGF-C and VEGF-D.	0	21	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR- 3	VEGFR- 3	VEGFR- 3	19	20	0	2
VEGFC is able to stimulate VEGFR3 expressing neural stem cells in mice .	VEGFC is able to stimulate VEGFR3 expressing neural stem cells in mice.	0	6	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR3	VEGFR3	VEGFR3	0	1	5	6
To support this hypothesis , dermal administration of VEGF-C that specifically activates VEGFR-3 but not VEGFR-2 reduces inflammation induced skin edema .	To support this hypothesis, dermal administration of VEGF-C that specifically activates VEGFR-3 but not VEGFR-2 reduces inflammation induced skin edema.	6	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	8	9	12	13
In order to determine whether activation of VEGFR-3 by VEGF-C and the following downstream signaling events can lead to activation of eNOS in LECs , we studied the activation of eNOS in response to angiogenic and lymphangiogenic stimuli in LECs .	In order to determine whether activation of VEGFR-3 by VEGF-C and the following downstream signaling events can lead to activation of eNOS in LECs, we studied the activation of eNOS in response to angiogenic and lymphangiogenic stimuli in LECs.	5	15	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	9	10	7	8
Our results could be explained by differences in the levels of sFlt-1 ( the soluble version of VEGFR1 acting as a specific antagonist of VEGFA ) or VEGFC , which activates VEGFR3 and VEGFR2 .	Our results could be explained by differences in the levels of sFlt-1 (the soluble version of VEGFR1 acting as a specific antagonist of VEGFA) or VEGFC, which activates VEGFR3 and VEGFR2.	4	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR3	VEGFR3	VEGFR3	27	28	31	32
Lymphangiogenesis requires activation of VEGFR-3 by VEGF-C or VEGF-D .	Lymphangiogenesis requires activation of VEGFR-3 by VEGF-C or VEGF-D.	1	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	6	7	4	5
It has been shown that secretion of VEGF-C and VEGF-D by some tumors induces VEGFR-3 activation in the vascular endothelium , thereby promoting the formation of new lymphatic vessels .	It has been shown that secretion of VEGF-C and VEGF-D by some tumors induces VEGFR-3 activation in the vascular endothelium, thereby promoting the formation of new lymphatic vessels.	5	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	7	8	14	15
The propagation of lymphatic endothelial cells is mediated by VEGFR3 signalling , driven by VEGF-C from the surrounding mesenchyme .	The propagation of lymphatic endothelial cells is mediated by VEGFR3 signalling, driven by VEGF-C from the surrounding mesenchyme.	9	15	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	14	15	9	10
SDF-1 and VEGF-C both induced the differentiation of CD34 + / VEGFR-3 + EPCs towards LECs and enhanced the LECs migration .	SDF-1 and VEGF-C both induced the differentiation of CD34 + / VEGFR-3 + EPCs towards LECs and enhanced the LECs migration.	0	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	2	3	11	12
Previously , it has been reported that VEGFC activates VEGFR3 in tip cells to activate NOTCH signaling in the neighboring ECs leading to their phenotypic conversion to stalk cells .	Previously, it has been reported that VEGFC activates VEGFR3 in tip cells to activate NOTCH signaling in the neighboring ECs leading to their phenotypic conversion to stalk cells.	7	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR3	VEGFR3	VEGFR3	7	8	9	10
VEGF-C mediates its signals by binding to and activating the vascular endothelial growth factor receptors VEGFR-3 and VEGFR-2 4 .	VEGF-C mediates its signals by binding to and activating the vascular endothelial growth factor receptors VEGFR-3 and VEGFR-2 4.	0	17	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	0	1	15	16
In the present study , VEGF-C-treated mice also had a significant increase in blood vessel density and dilation of blood vessels compared to control mice , suggesting that VEGF-C specifically stimulated the VEGFR-3 signaling pathway to induce angiogenesis during acute colitis .	In the present study, VEGF-C-treated mice also had a significant increase in blood vessel density and dilation of blood vessels compared to control mice, suggesting that VEGF-C specifically stimulated the VEGFR-3 signaling pathway to induce angiogenesis during acute colitis.	28	34	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	28	29	32	33
Lymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 ( VEGFR-3 ) , which is activated by its ligands VEGF-C and VEGF-D .	Lymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by its ligands VEGF-C and VEGF-D.	10	23	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	21	22	12	13
These results indicate that macrophage derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling , which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts .	These results indicate that macrophage derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.	5	13	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	6	7	8	9
This is supported by our observation that a mutant of mature VEGF-C , in which residues 113-121 were deleted , is able to activate VEGFR-2 and VEGFR-3 .	This is supported by our observation that a mutant of mature VEGF-C, in which residues 113-121 were deleted, is able to activate VEGFR-2 and VEGFR-3.	8	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	11	12	26	27
VEGF-C has been shown to activate the VEGFR-3 and Notch signalling pathways [ XREF_BIBR ] .	VEGF-C has been shown to activate the VEGFR-3 and Notch signalling pathways [XREF_BIBR].	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	0	1	7	8
VEGFR-3 is activated by VEGF-C and -D , and proteolytic processing of these ligands gives rise to variants also interacting with VEGFR-2 , although with lower affinity than with VEGFR-3 .	VEGFR-3 is activated by VEGF-C and -D, and proteolytic processing of these ligands gives rise to variants also interacting with VEGFR-2, although with lower affinity than with VEGFR-3.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	0	1
Finally , VEGFR-3 is activated by VEGF-C and VEGF-D [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Finally, VEGFR-3 is activated by VEGF-C and VEGF-D [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	8	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	6	7	2	3
The long-term VEGF-C treatment caused the downregulation of VEGFR2 and VEGFR3 in HUVECs and LECs .	The long-term VEGF-C treatment caused the downregulation of VEGFR2 and VEGFR3 in HUVECs and LECs.	2	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	2	3	10	11
VEGFC and VEGFD activate KDR and Flt-4 .	VEGFC and VEGFD activate KDR and Flt-4.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	Flt-4	Flt-4	Flt-4	0	1	6	7
We hypothesized that VEGFR3 activated by VEGF-C or VEGF-D also undergoes similar epsin mediated internalization and degradation to decrease VEGFR3 signaling .	We hypothesized that VEGFR3 activated by VEGF-C or VEGF-D also undergoes similar epsin mediated internalization and degradation to decrease VEGFR3 signaling.	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	6	7	3	4
VEGFR3 homodimers were induced by VEGFC ( XREF_FIG ) .	VEGFR3 homodimers were induced by VEGFC (XREF_FIG).	0	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR3	VEGFR3	VEGFR3	5	6	0	1
VEGF-C can activate the VEGFR-3 signaling pathway to induce the lymphatic enlargement and lymphangiogenesis [ XREF_BIBR ] .	VEGF-C can activate the VEGFR-3 signaling pathway to induce the lymphatic enlargement and lymphangiogenesis [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	0	1	4	5
VEGFR-3 is activated by its ligand VEGF-C , which results in the phosphorylation of tyrosine residues .	VEGFR-3 is activated by its ligand VEGF-C, which results in the phosphorylation of tyrosine residues.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	6	7	0	1
VEGFC and VEGFD activate VEGFR3 ( FLT4 ) , which is mainly expressed on lymphatic endothelial cells .	VEGFC and VEGFD activate VEGFR3 (FLT4), which is mainly expressed on lymphatic endothelial cells.	0	13	activate	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	VEGFC	VEGFC	vegfc	VEGFR3	VEGFR3 (FLT4), which is mainly expressed	vegfr3	0	1	4	5
VEGF-C activates VEGFR2 and VEGFR3 .	VEGF-C activates VEGFR2 and VEGFR3.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	0	1	4	5
These findings suggest that NRP2 has a role in VEGFC mediated VEGFR3 signaling and lymphangiogenesis .	These findings suggest that NRP2 has a role in VEGFC mediated VEGFR3 signaling and lymphangiogenesis.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR3	VEGFR3	VEGFR3	9	10	11	12
These data confirm that VEGF-C induces VEGFR-3 down-regulation , at least in part , through activation of VEGFR-3 and lysosomal protease degradation .	These data confirm that VEGF-C induces VEGFR-3 down-regulation, at least in part, through activation of VEGFR-3 and lysosomal protease degradation.	4	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	6	7
Our data show that VEGF-C and VEGFR -3 signalling pathway mediates differentiation of CD34 + VEGFR-3 + EPCs into lymphatic endothelial cells .	Our data show that VEGF-C and VEGFR -3 signalling pathway mediates differentiation of CD34 + VEGFR-3 + EPCs into lymphatic endothelial cells.	4	21	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	15	16
In particular , VEGFR3 is mainly activated by VEGF-C and -D related cascades , whereas VEGFR1 is mainly activated by VEGF-A , as well as VEGF-C and -D ; thus , the branching point at days7 to 14 appears to be represented by decreased activation of VEGF-A .	In particular, VEGFR3 is mainly activated by VEGF-C and -D related cascades, whereas VEGFR1 is mainly activated by VEGF-A, as well as VEGF-C and -D; thus, the branching point at days7 to 14 appears to be represented by decreased activation of VEGF-A.	3	10	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	8	9	3	4
VEGFC expressed by macrophages activates VEGFR3 in tip cells .	VEGFC expressed by macrophages activates VEGFR3 in tip cells.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC expressed	vegfc	VEGFR3	VEGFR3	vegfr3	0	1	5	6
Stimulation of VEGFR-3 by VEGF-C or VEGF-D results in selective association between VEGFR-3 and integrin alpha 5 beta 1 in lymphatic endothelial cells and this interaction appears to be involved in the regulation of lymphangiogenesis [ XREF_BIBR , XREF_BIBR ] .	Stimulation of VEGFR-3 by VEGF-C or VEGF-D results in selective association between VEGFR-3 and integrin alpha 5 beta 1 in lymphatic endothelial cells and this interaction appears to be involved in the regulation of lymphangiogenesis [XREF_BIBR, XREF_BIBR].	0	7	Stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	2	3
VEGFR3 is activated by the VEGF homologues , VEGF-C and VEGF-D , which , when fully proteolytically processed , also stimulate VEGFR2 and induce the formation and activation of VEGFR2-VEGFR3 heterodimers .	VEGFR3 is activated by the VEGF homologues, VEGF-C and VEGF-D, which, when fully proteolytically processed, also stimulate VEGFR2 and induce the formation and activation of VEGFR2-VEGFR3 heterodimers.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	8	9	0	1
Mutation of the conserved residues mediating the D5 interaction ( Thr446 and Lys516 ) and the D7 interaction ( Arg737 ) compromised VEGF-C induced VEGFR-3 activation .	Mutation of the conserved residues mediating the D5 interaction (Thr446 and Lys516) and the D7 interaction (Arg737) compromised VEGF-C induced VEGFR-3 activation.	21	25	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	22	23	24	25
Furthermore , Marchio et al ( 1999 ) reported that tyrosine phosphorylation of VEGFR-3 was increased in Kaposi sarcoma cells treated with VEGF-C recombinant protein as well as C156S mutant VEGF-C recombinant protein , a selective ligand and an activator of VEGFR-3 , although devoid of any Flt-1 activation property .	Furthermore, Marchio et al (1999) reported that tyrosine phosphorylation of VEGFR-3 was increased in Kaposi sarcoma cells treated with VEGF-C recombinant protein as well as C156S mutant VEGF-C recombinant protein, a selective ligand and an activator of VEGFR-3, although devoid of any Flt-1 activation property.	11	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	22	23	13	14
The activation of VEGF receptor-2 ( VEGFR-2 ) and VEGFR-3 by VEGF-C and -D was reported to initiate lymphangiogenesis by promoting lymphatic proliferation and migration and by organizing new lymphatic endothelial cells into functional capillaries .	The activation of VEGF receptor-2 (VEGFR-2) and VEGFR-3 by VEGF-C and -D was reported to initiate lymphangiogenesis by promoting lymphatic proliferation and migration and by organizing new lymphatic endothelial cells into functional capillaries.	1	13	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	11	12	9	10
In addition to direct activation of VEGFR-3-bound pro-VEGF-C 16 , a significant proportion of pro-VEGF-C could first interact with CCBE1 and ADAMTS3 independently of VEGFR-3 on cell surface sites containing syndecan-4 18 , and after cleavage , the mature VEGF-C would activate adjacent VEGFR-3 .	In addition to direct activation of VEGFR-3-bound pro-VEGF-C 16, a significant proportion of pro-VEGF-C could first interact with CCBE1 and ADAMTS3 independently of VEGFR-3 on cell surface sites containing syndecan-4 18, and after cleavage, the mature VEGF-C would activate adjacent VEGFR-3.	37	44	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	39	40	43	44
Overexpression of VEGF-C stimulates VEGFR-3 expressing NSCs as well as neurogenesis in the SVZ , but not affecting angiogenesis .	Overexpression of VEGF-C stimulates VEGFR-3 expressing NSCs as well as neurogenesis in the SVZ, but not affecting angiogenesis.	0	5	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	Overexpression of VEGF-C	vegf-c	VEGFR-3	VEGFR-3	vegfr-3	2	3	4	5
VEGF-C induced VEGFR-3 activation in both groups of transfectants .	VEGF-C induced VEGFR-3 activation in both groups of transfectants.	0	3	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	0	1	2	3
In contrast , wild-type VEGF-C activates both VEGFR-3 and , after proteolytic processing , VEGFR-2 .	In contrast, wild-type VEGF-C activates both VEGFR-3 and, after proteolytic processing, VEGFR-2.	3	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	7	8
As mentioned previously , this more stable dimeric form of VEGF-C can bind to and activate the VEGFR-3 and VEGFR-2 receptors more efficiently and the corresponding change in VEGF-D has a similar effect XREF_BIBR .	As mentioned previously, this more stable dimeric form of VEGF-C can bind to and activate the VEGFR-3 and VEGFR-2 receptors more efficiently and the corresponding change in VEGF-D has a similar effect XREF_BIBR.	8	20	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	10	11	17	18
VEGFC induces VEGFR3 homodimers and VEGFR2/-3 heterodimers .	VEGFC induces VEGFR3 homodimers and VEGFR2/-3 heterodimers.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR3	VEGFR3	VEGFR3	0	1	2	3
Compared with the controls , the recombinant VEGF-C promoted the proliferation of NB4 cells ( VEGFR-3 ( + ) ) ( P ( 24h ) = 0.006 , P ( 48h ) = 0.018 ) , but had no effect on K562 cells ( VEGFR-3 (-) ) ; it inhibited the chemotherapy induced apoptosis of NB4 cells ( P ( VP-16 ) = 0.019 , P ( DNR ) = 0.013 , P ( As2O3 ) = 0.042 ) .	Compared with the controls, the recombinant VEGF-C promoted the proliferation of NB4 cells (VEGFR-3 (+)) (P (24h) = 0.006, P (48h) = 0.018), but had no effect on K562 cells (VEGFR-3 (-)); it inhibited the chemotherapy induced apoptosis of NB4 cells (P (VP-16) = 0.019, P (DNR) = 0.013, P (As2O3) = 0.042).	5	37	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	7	8	15	16
In developmental lymphangiogenesis , VEGF-C stimulation of VEGFR3 is essential for the proliferation , growth , and survival of lymphatic endothelial cells ( LECs ) , while a role for VEGF-D appears to be to linked to pathological lymphangiogenesis .	In developmental lymphangiogenesis, VEGF-C stimulation of VEGFR3 is essential for the proliferation, growth, and survival of lymphatic endothelial cells (LECs), while a role for VEGF-D appears to be to linked to pathological lymphangiogenesis.	4	8	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	4	5	7	8
Recombinant Flt4-L activated Flt4 as judged by induction of tyrosyl phosphorylation , and induced mitogenesis in vitro of lymphatic endothelial cells .	Recombinant Flt4-L activated Flt4 as judged by induction of tyrosyl phosphorylation, and induced mitogenesis in vitro of lymphatic endothelial cells.	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Flt4-L	Flt4-L	Flt4-L	Flt4	Flt4	Flt4	1	2	3	4
VEGFR-3 is activated by the VEGF homologues VEGF-C and VEGF-D , which , when fully proteolytically processed , also stimulate VEGFR-2 and induce the formation and activation of VEGFR-2-VEGFR-3 heterodimers XREF_BIBR , XREF_BIBR .	VEGFR-3 is activated by the VEGF homologues VEGF-C and VEGF-D, which, when fully proteolytically processed, also stimulate VEGFR-2 and induce the formation and activation of VEGFR-2-VEGFR-3 heterodimers XREF_BIBR, XREF_BIBR.	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	7	8	0	1
However , a recent study in zebrafish proposes that Dll4 suppresses Vegfc induced Vegfr3 function but does not influence the expression of Vegfr3 ' s encoding gene , flt4 , suggesting additional roles for other Notch ligands in the transcriptional control of flt4 .	However, a recent study in zebrafish proposes that Dll4 suppresses Vegfc induced Vegfr3 function but does not influence the expression of Vegfr3 's encoding gene, flt4, suggesting additional roles for other Notch ligands in the transcriptional control of flt4.	11	18	induced	Positive_early_activation	Positive_activation	Positive_activation	Vegfc	Vegfc	Vegfc	Vegfr3	Vegfr3	Vegfr3	11	12	13	14
A third VEGF receptor VEGFR-3 , is important for lymphangiogenesis and is activated by two different ligands , VEGF-C and VEGF-D [ XREF_BIBR ] .	A third VEGF receptor VEGFR-3, is important for lymphangiogenesis and is activated by two different ligands, VEGF-C and VEGF-D [XREF_BIBR].	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	18	19	4	5
Taken together , these data demonstrate that dll4 functions to suppress the ability of developing intersegmental arteries to respond to Vegfc driven Flt4 signalling in zebrafish .	Taken together, these data demonstrate that dll4 functions to suppress the ability of developing intersegmental arteries to respond to Vegfc driven Flt4 signalling in zebrafish.	18	23	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vegfc	Vegfc	Vegfc	Flt4	Flt4	Flt4	20	21	22	23
Mosaic Vegfc over-expression following heat shock at 15 somite state caused ectopic branching of ISVs along the horizontal myoseptum in control embryos at 33 hpf ( XREF_FIG ) , but not in flt4 deficient embryos ( XREF_FIG ) indicating that this effect is dependent on the Flt4 receptor .	Mosaic Vegfc over-expression following heat shock at 15 somite state caused ectopic branching of ISVs along the horizontal myoseptum in control embryos at 33 hpf (XREF_FIG), but not in flt4 deficient embryos (XREF_FIG) indicating that this effect is dependent on the Flt4 receptor.	1	33	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vegfc	Vegfc over-expression	vegfc	flt4	flt4	flt4	1	2	32	33
VEGF-C may also directly activate VEGF-R3 in tumor cells to promote tumor growth and increase tumor invasiveness .	VEGF-C may also directly activate VEGF-R3 in tumor cells to promote tumor growth and increase tumor invasiveness.	0	8	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGF-R3	VEGF-R3	VEGF-R3	0	1	5	6
The key protein that induces lymphangiogenesis is vascular endothelial growth factor receptor-3 ( VEGFR-3 ) , which is activated by vascular endothelial growth factor-C and -D ( VEGF-C and VEGF-D ) .	The key protein that induces lymphangiogenesis is vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by vascular endothelial growth factor-C and -D (VEGF-C and VEGF-D).	11	24	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	vascular endothelial growth factor-C	vascular endothelial growth factor-C	vascular endothelial growth factor-C	VEGFR-3	VEGFR-3	VEGFR-3	20	24	13	14
Lymphangiogenic growth factors , in particular vascular endothelial growth factor C ( VEGF-C ) , are derived from tumor cells and promote tumor lymphangiogenesis by activating the endothelial receptor tyrosine kinases VEGFR2 and VEGFR3 .	Lymphangiogenic growth factors, in particular vascular endothelial growth factor C (VEGF-C), are derived from tumor cells and promote tumor lymphangiogenesis by activating the endothelial receptor tyrosine kinases VEGFR2 and VEGFR3.	6	34	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	vascular endothelial growth factor C	vascular endothelial growth factor C	vascular endothelial growth factor C	VEGFR3	VEGFR3	VEGFR3	6	11	33	34
Jessie Z. Yu , MD , Matthew D. Nitti , BA , Gabriela D. Garcia Nores , MD , Geoffrey E. Hespe , BS , Jung-Ju Huang , MD , Raghu P. Kataru , PhD , Babak J. Mehrara , MD From the Memorial Sloan Kettering Cancer Center , New York , N.Y. PURPOSE : Lymphatic endothelial cell ( LEC ) function is regulated by the activation of VEGFR-3 by VEGF-C , and recent studies suggest that this signaling pathway is disturbed in obesity .	Jessie Z. Yu, MD, Matthew D. Nitti, BA, Gabriela D. Garcia Nores, MD, Geoffrey E. Hespe, BS, Jung-Ju Huang, MD, Raghu P. Kataru, PhD, Babak J. Mehrara, MD From the Memorial Sloan Kettering Cancer Center, New York, N.Y. PURPOSE : Lymphatic endothelial cell (LEC) function is regulated by the activation of VEGFR-3 by VEGF-C, and recent studies suggest that this signaling pathway is disturbed in obesity.	63	71	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	70	71	68	69
VEGFR-3 is a transmemberane receptor tyrosine kinase in LECs and activated by binding of the ligands , VEGF-C and D.	VEGFR-3 is a transmemberane receptor tyrosine kinase in LECs and activated by binding of the ligands, VEGF-C and D.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	17	18	0	1
The authors suggested that VEGF-C and VEGF-D secreted by cancer cells might activate VEGFR-3 in the endothelial cells of adjacent lymphatic vessels via a paracrine mechanism to induce lymphatic invasion , possibly by modifying vessel permeability .	The authors suggested that VEGF-C and VEGF-D secreted by cancer cells might activate VEGFR-3 in the endothelial cells of adjacent lymphatic vessels via a paracrine mechanism to induce lymphatic invasion, possibly by modifying vessel permeability.	4	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	13	14
Lymphangiogenesis is generally thought to be driven by activation of VEGFR-2 and/or VEGFR-3 signaling by VEGF-C , VEGF-D , or in some cases VEGF-A .	Lymphangiogenesis is generally thought to be driven by activation of VEGFR-2 and/or VEGFR-3 signaling by VEGF-C, VEGF-D, or in some cases VEGF-A.	12	17	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	15	16	12	13
These data suggest that VEGF-C does not induce the recycling of VEGFR-3 to the cell surface ; rather , they suggest that VEGF-C may target VEGFR-3 to the lysosomes for degradation .	These data suggest that VEGF-C does not induce the recycling of VEGFR-3 to the cell surface; rather, they suggest that VEGF-C may target VEGFR-3 to the lysosomes for degradation.	4	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	11	12
We observed similar effects of AIP1 siRNA on VEGFR-3 signaling induced by wild-type VEGF-C ( XREF_FIG ) .	We observed similar effects of AIP1 siRNA on VEGFR-3 signaling induced by wild-type VEGF-C (XREF_FIG).	8	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	13	14	8	9
VEGFR-3 is activated by VEGF-C and VEGF-D .	VEGFR-3 is activated by VEGF-C and VEGF-D.	0	6	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	0	1
Proteolytic processing can remove the propeptides to generate mature VEGF-C and VEGF-D , which activate VEGFR-2 and VEGFR-3 , thus driving the growth of blood vessels and lymphatics .	Proteolytic processing can remove the propeptides to generate mature VEGF-C and VEGF-D, which activate VEGFR-2 and VEGFR-3, thus driving the growth of blood vessels and lymphatics.	7	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	9	10	17	18
The effects of VEGF-C and VEGF-D are mediated by VEGF receptor ( VEGFR ) 2 and VEGFR-3 , cell surface receptor tyrosine kinases predominantly expressed on endothelial cells ( for review see reference 14 ) .	The effects of VEGF-C and VEGF-D are mediated by VEGF receptor (VEGFR) 2 and VEGFR-3, cell surface receptor tyrosine kinases predominantly expressed on endothelial cells (for review see reference 14).	1	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	3	4	16	17
In addition , our data showed that IGFIR high expression was positively correlated with VEGF-C high expression , and the expression of VEGF-C in mRNA and protein level also could be effectively induced by IGF-I in human colorectal cancer cells expressing IGFIR molecules , implying VEGF-C receptor VEGFR-3 could also be stimulated to promote lymphangiogenesis .	In addition, our data showed that IGFIR high expression was positively correlated with VEGF-C high expression, and the expression of VEGF-C in mRNA and protein level also could be effectively induced by IGF-I in human colorectal cancer cells expressing IGFIR molecules, implying VEGF-C receptor VEGFR-3 could also be stimulated to promote lymphangiogenesis.	20	51	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	expression of VEGF-C	vegf-c	VEGFR-3	VEGFR-3	vegfr-3	22	23	47	48
The binding of extracellular VEGF ligands , in particular VEGF-C and VEGF-D , activates VEGFR-3 .	The binding of extracellular VEGF ligands, in particular VEGF-C and VEGF-D, activates VEGFR-3.	1	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	9	10	14	15
OCT4 promotes VEGF-C expression and activates the VEGFR-3 phosphokinase activity and the downstream signaling pathways , thus inducing EMT in cancer cells and ultimately enhancing tumor invasion and metastasis , promoting tumor progression , and severely affecting patient prognosis .	OCT4 promotes VEGF-C expression and activates the VEGFR-3 phosphokinase activity and the downstream signaling pathways, thus inducing EMT in cancer cells and ultimately enhancing tumor invasion and metastasis, promoting tumor progression, and severely affecting patient prognosis.	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	OCT4 promotes VEGF-C expression	vegf-c	VEGFR-3	VEGFR-3	vegfr-3	2	3	7	8
Although both Slit2N and VEGF-C alone induced the internalization of VEGFR-3 , only VEGF-C decreased total VEGFR-3 levels , and Slit2N pretreatment did not alter these VEGF-C-induced effects on VEGFR-3 .	Although both Slit2N and VEGF-C alone induced the internalization of VEGFR-3, only VEGF-C decreased total VEGFR-3 levels, and Slit2N pretreatment did not alter these VEGF-C-induced effects on VEGFR-3.	2	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	10	11
Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C .	Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C.	5	14	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	13	14	5	6
VEGFB ( VEGFB , P49765 ) and placental growth factor ( PGF , P49763 ) activate VEGFR1 homodimers , while VEGFC ( VEGFC , P49767 ) and VEGFD ( FIGF , O43915 ) activate VEGFR2/3 heterodimers and VEGFR3 homodimers , and , following proteolysis , VEGFR2 homodimers .	VEGFB (VEGFB, P49765) and placental growth factor (PGF, P49763) activate VEGFR1 homodimers, while VEGFC (VEGFC, P49767) and VEGFD (FIGF, O43915) activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers.	20	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR3	VEGFR3	VEGFR3	20	21	37	38
VEGF activates the endothelial VEGF receptors ( VEGFR ) 1 and 2 , and VEGF-C activates VEGFR-3 and VEGFR-2 .	VEGF activates the endothelial VEGF receptors (VEGFR) 1 and 2, and VEGF-C activates VEGFR-3 and VEGFR-2.	14	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	14	15	16	17
Activation of VEGFR-3 by VEGF-C leads to phosphorylation of protein kinase B ( AKT ) and extracellular signal regulated kinase ( ERK ) , which in turn leads to lymphatic endothelial cell proliferation and lymphatic tube formation [ XREF_BIBR , XREF_BIBR ] .	Activation of VEGFR-3 by VEGF-C leads to phosphorylation of protein kinase B (AKT) and extracellular signal regulated kinase (ERK), which in turn leads to lymphatic endothelial cell proliferation and lymphatic tube formation [XREF_BIBR, XREF_BIBR].	0	5	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	2	3
First , VEGFC was able to induce formation of VEGFR3 homodimers and VEGFR2/-3 heterodimers , but not VEGFR2 homodimers .	First, VEGFC was able to induce formation of VEGFR3 homodimers and VEGFR2/-3 heterodimers, but not VEGFR2 homodimers.	2	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR3	VEGFR3	VEGFR3	2	3	9	10
Overexpression of constitutively active Vav2 activated Rac1 and Cdc42 and reorganized junctional actin cytoskeleton ; these effects were suppressed by WT Cbl and enhanced by a ubiquitin ligase deficient Cbl mutant .	Overexpression of constitutively active Vav2 activated Rac1 and Cdc42 and reorganized junctional actin cytoskeleton; these effects were suppressed by WT Cbl and enhanced by a ubiquitin ligase deficient Cbl mutant.	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Overexpression of constitutively active Vav2	vav2	Rac1	Rac1	rac1	4	5	6	7
Instead , it is more likely that Vav2 positively regulates Rac , and while amplification of this pathway by wild-type Gab2 is not detectable by the pull-down assay , the further enhancement of signaling that occurs when Gab2 2xA is expressed leads to a demonstrable elevation of Rac-GTP .	Instead, it is more likely that Vav2 positively regulates Rac, and while amplification of this pathway by wild-type Gab2 is not detectable by the pull-down assay, the further enhancement of signaling that occurs when Gab2 2xA is expressed leads to a demonstrable elevation of Rac-GTP.	7	11	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	7	8	10	11
Together , these results suggest that Vav2 activates Rac1 to inhibit RhoA signaling downstream of LPA .	Together, these results suggest that Vav2 activates Rac1 to inhibit RhoA signaling downstream of LPA.	6	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	6	7	8	9
In addition , our assays also indicated that Dbl , Vav2 and Sos1 could activate Rac1 ; and Dbl , Vav2 worked on RhoA .	In addition, our assays also indicated that Dbl, Vav2 and Sos1 could activate Rac1; and Dbl, Vav2 worked on RhoA.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	10	11	15	16
Since overexpression of wild-type Vav2 alone activated Rac1 , we wanted to be certain that the T7 epitope tag did not stimulate Vav2 .	Since overexpression of wild-type Vav2 alone activated Rac1, we wanted to be certain that the T7 epitope tag did not stimulate Vav2.	1	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	overexpression of wild-type Vav2	vav2	Rac1	Rac1	rac1	4	5	7	8
XREF_BIBR found that Vav2 expressed in CHO cells activates Rac1 , RhoA , and Cdc42 in vivo .	XREF_BIBR found that Vav2 expressed in CHO cells activates Rac1, RhoA, and Cdc42 in vivo.	3	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2 expressed	vav2	Rac1	Rac1	rac1	3	4	9	10
Taken together , our results provide evidence that Vav2 acts downstream of VEGF to activate Rac1 .	Taken together, our results provide evidence that Vav2 acts downstream of VEGF to activate Rac1.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	8	9	15	16
Conversely , loss of Vav2 and Vav3 GEFs inhibits Rac1 activation and ephrin-A1-induced angiogenic responses both in vitro and in vivo .	Conversely, loss of Vav2 and Vav3 GEFs inhibits Rac1 activation and ephrin-A1-induced angiogenic responses both in vitro and in vivo.	4	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	4	5	9	10
Localization of VAV2 by Rap1 is required to induce Rac1 dependent protrusive activity ( XREF_FIG and XREF_FIG ) .	Localization of VAV2 by Rap1 is required to induce Rac1 dependent protrusive activity (XREF_FIG and XREF_FIG).	0	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	2	3	9	10
Via activation of Rac specific guanine nucleotide exchange factors Tiam1 and Vav2 , Rap1 may activate Rac GTPase and trigger additional Rac mediated mechanisms of EC barrier enhancement .	Via activation of Rac specific guanine nucleotide exchange factors Tiam1 and Vav2, Rap1 may activate Rac GTPase and trigger additional Rac mediated mechanisms of EC barrier enhancement.	1	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	11	12	16	17
The expression level of VIMENTIN , an EMT marker regulates VAV2 mediated Rac1 activation , reduced by 36 % ( P = 0.0002 , Fig .	The expression level of VIMENTIN, an EMT marker regulates VAV2 mediated Rac1 activation, reduced by 36% (P = 0.0002, Fig.	9	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	10	11	12	13
Vav2 mediates flow induced Rac1 activation , whereas Tiam1 regulates spatial organization of activated Rac1 .	Vav2 mediates flow induced Rac1 activation, whereas Tiam1 regulates spatial organization of activated Rac1.	0	5	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	0	1	4	5
wt Rac1 GDP dissociation was significantly enhanced by a combination of Vav2 DPC and O 2 *-.	wt Rac1 GDP dissociation was significantly enhanced by a combination of Vav2 DPC and O 2 *-.	1	12	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	11	12	1	2
Phosphorylation of residues in the N-terminal tyrosine rich tandem repeats of Tarp by host Src and Abl kinases recruit the guanine nucleotide exchange factors ( GEFs ) , Sos1 and Vav2 , which activate Rac1 .	Phosphorylation of residues in the N-terminal tyrosine rich tandem repeats of Tarp by host Src and Abl kinases recruit the guanine nucleotide exchange factors (GEFs), Sos1 and Vav2, which activate Rac1.	23	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	30	31	34	35
Down-regulation of Vav2 could disturb leukocyte migration , for knockdown of Vav2 prevents Rac activation in some cells XREF_BIBR .	Down-regulation of Vav2 could disturb leukocyte migration, for knockdown of Vav2 prevents Rac activation in some cells XREF_BIBR.	9	14	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	11	12	13	14
Therefore , we conclude that Vav2 and Vav3 jointly mediate the rapid activation of both RhoG and Rac1 through their direct phosphorylation by the EGFR kinase .	Therefore, we conclude that Vav2 and Vav3 jointly mediate the rapid activation of both RhoG and Rac1 through their direct phosphorylation by the EGFR kinase.	5	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	5	6	17	18
We next targeted another protein family , GEFs , beginning with the Rac1 activator Vav2 .	We next targeted another protein family, GEFs, beginning with the Rac1 activator Vav2.	2	15	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	14	15	12	13
Assuming that Vav2 over-expression increases active Rac1 and/or Cdc42 in growth cones , this result is consistent with the notion that balanced levels of Rho GTPase activity is necessary for optimal promotion of neurite outgrowth .	Assuming that Vav2 over-expression increases active Rac1 and/or Cdc42 in growth cones, this result is consistent with the notion that balanced levels of Rho GTPase activity is necessary for optimal promotion of neurite outgrowth.	2	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2 over-expression	vav2	Rac1	Rac1	rac1	2	3	6	7
These data support a role for VAV2 induced Rac1 activation in actin depolymerisation in beta cells , consistent with its role in facilitating insulin secretion .	These data support a role for VAV2 induced Rac1 activation in actin depolymerisation in beta cells, consistent with its role in facilitating insulin secretion.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	6	7	8	9
Vimentin regulates VAV2 mediated Rac1 activation .	Vimentin regulates VAV2 mediated Rac1 activation.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	2	3	4	5
The activity of FAK is found to be associated with VAV2 mediated RAC1 activation 18 and RAC1 has been demonstrated in the decidualization associated signaling XREF_BIBR , XREF_BIBR .	The activity of FAK is found to be associated with VAV2 mediated RAC1 activation 18 and RAC1 has been demonstrated in the decidualization associated signaling XREF_BIBR, XREF_BIBR.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	RAC1	RAC1	RAC1	10	11	12	13
Further , our observation that CA Rac1 most closely phenocopies Vav2 over-expression ( XREF_FIG , XREF_SUPPLEMENTARY ) , also supports previous studies showing that Vav2 specifically activates Rac1 over Cdc42 .	Further, our observation that CA Rac1 most closely phenocopies Vav2 over-expression (XREF_FIG, XREF_SUPPLEMENTARY), also supports previous studies showing that Vav2 specifically activates Rac1 over Cdc42.	24	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	24	25	27	28
Furthermore , Ehop-016 , a small molecule inhibitor of Vav2 mediated activation of Rac1 , significantly attenuated GSIS in INS-1 832/13 cells and primary rat islets [ XREF_BIBR ] .	Furthermore, Ehop-016, a small molecule inhibitor of Vav2 mediated activation of Rac1, significantly attenuated GSIS in INS-1 832/13 cells and primary rat islets [XREF_BIBR].	9	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	9	10	13	14
The formation of early cell-cell contacts correlates with the activation of Cdc42 and Rac1 and the inhibition of RhoA , and these changes in activities of the small GTPases are at least in part regulated by p120 ctn which interacts with the Rac activator Vav2 and the RhoA inhibitor p190RhoGAP .	The formation of early cell-cell contacts correlates with the activation of Cdc42 and Rac1 and the inhibition of RhoA, and these changes in activities of the small GTPases are at least in part regulated by p120 ctn which interacts with the Rac activator Vav2 and the RhoA inhibitor p190RhoGAP.	39	49	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	44	45	42	43
Vav2 is an activator of Cdc42 and Rac1 .	Vav2 is an activator of Cdc42 and Rac1.	0	8	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	0	1	7	8
Loss of Vav2 and Vav3 inhibits Rac1 activity and ephrin-A1-induced angiogenic responses both in vitro and in vivo [ XREF_BIBR ] .	Loss of Vav2 and Vav3 inhibits Rac1 activity and ephrin-A1-induced angiogenic responses both in vitro and in vivo [XREF_BIBR].	0	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Vav2	Loss of Vav2	vav2	Rac1	Rac1	rac1	2	3	6	7
Because phospho-Vav2 is responsible for activation of Rac1 and Cdc42 , disruption of adherens junctions ( this study ) , and disruption of mammary epithelial acini in three-dimensional matrix culture as we have shown previously , our finding of Cbl dependent phospho-Vav2 ubiquitinylation highlights the role of Cbl in the maintenance of epithelial homeostasis during EGFR mediated cellular remodeling processes .	Because phospho-Vav2 is responsible for activation of Rac1 and Cdc42, disruption of adherens junctions (this study), and disruption of mammary epithelial acini in three-dimensional matrix culture as we have shown previously, our finding of Cbl dependent phospho-Vav2 ubiquitinylation highlights the role of Cbl in the maintenance of epithelial homeostasis during EGFR mediated cellular remodeling processes.	1	9	is responsible for activation	Positive_activation_copula_1	Positive_activation	Positive_activation	phospho-Vav2	phospho-Vav2	phospho-Vav2	Rac1	Rac1	Rac1	1	2	7	8
In the present study , we found that activation of Rac1 by overexpression of Rac1 or Vav2 induced extracellular O 2 .	In the present study, we found that activation of Rac1 by overexpression of Rac1 or Vav2 induced extracellular O 2.	8	17	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Vav2	overexpression of Rac1 or Vav2	vav2	Rac1	Rac1	rac1	16	17	10	11
By studying a hypertensive knockout mouse lacking the Rho and Rac activator Vav2 , we have discovered a new signaling pathway involving Vav2 , the GTPase Rac1 , and the serine/threonine kinase Pak that contributes to nitric oxide triggered blood vessel relaxation and normotensia .	By studying a hypertensive knockout mouse lacking the Rho and Rac activator Vav2, we have discovered a new signaling pathway involving Vav2, the GTPase Rac1, and the serine/threonine kinase Pak that contributes to nitric oxide triggered blood vessel relaxation and normotensia.	6	13	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	12	13	10	11
XREF_BIBR Other labs subsequently confirmed that VEGFR-2 promotes Src dependent phosphorylation of Vav-2 and activates Rac1 .	XREF_BIBR Other labs subsequently confirmed that VEGFR-2 promotes Src dependent phosphorylation of Vav-2 and activates Rac1.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav-2	VEGFR-2 promotes Src dependent phosphorylation of Vav-2	vav-2	Rac1	Rac1	rac1	12	13	15	16
PECAM-1 induces activation of Src , which in turn promotes phosphorylation of Vav2 and hence Vav2 mediated activation of Rac1 signaling at AJs 174 .	PECAM-1 induces activation of Src, which in turn promotes phosphorylation of Vav2 and hence Vav2 mediated activation of Rac1 signaling at AJs 174.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	15	16	19	20
Here , we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2 .	Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2.	10	18	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	15	16	13	14
During Chlamydia trachomatis invasion , Rac1 is activated by Sos2 and Vav2 [ XREF_BIBR , XREF_BIBR ] , Rac1 guanine nucleotide exchange factors ( GEFs ) , and results in the recruitment of the actin regulators WAVE2 and Abi-1 and Arp2/3 dependent actin remodeling and transient pedestal formation [ XREF_BIBR ] .	During Chlamydia trachomatis invasion, Rac1 is activated by Sos2 and Vav2 [XREF_BIBR, XREF_BIBR], Rac1 guanine nucleotide exchange factors (GEFs), and results in the recruitment of the actin regulators WAVE2 and Abi-1 and Arp2/3 dependent actin remodeling and transient pedestal formation [XREF_BIBR].	5	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	11	12	5	6
GEFs can be promiscuous in terms of small G protein activation ( for example Vav2 activates Rho , Cdc42 and Rac ) or display selectivity , such as Tiam1 or P-Rex1 for Rac [ XREF_BIBR , XREF_BIBR ] .	GEFs can be promiscuous in terms of small G protein activation (for example Vav2 activates Rho, Cdc42 and Rac) or display selectivity, such as Tiam1 or P-Rex1 for Rac [XREF_BIBR, XREF_BIBR].	13	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	14	15	20	21
Based upon this data , we propose a model whereby vimentin promotes FAK stabilization through VAV2 mediated Rac1 activation .	Based upon this data, we propose a model whereby vimentin promotes FAK stabilization through VAV2 mediated Rac1 activation.	11	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	15	16	17	18
Lastly , real-time imaging in live beta-cells indicated a marked reduction in glucose induced cortical actin remodeling following inhibition of Vav2 mediated activation of Rac1 by Ehop-016 .	Lastly, real-time imaging in live beta-cells indicated a marked reduction in glucose induced cortical actin remodeling following inhibition of Vav2 mediated activation of Rac1 by Ehop-016.	20	25	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	20	21	24	25
Tiam1 serves as the scaffold for Rac1 at AJs 335 whereas Vav2 , a common GEF for RhoA , Rac1 , and Cdc42 336 promotes Rac1 GTP loading and hence facilitates activation of Rac1 signaling XREF_BIBR , XREF_BIBR .	Tiam1 serves as the scaffold for Rac1 at AJs 335 whereas Vav2, a common GEF for RhoA, Rac1, and Cdc42 336 promotes Rac1 GTP loading and hence facilitates activation of Rac1 signaling XREF_BIBR, XREF_BIBR.	11	26	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	11	12	25	26
Based on the induction of lamellipodia in cells overexpressing Vav2 , assays of GTPase activation in vivo and the ability of a dominant negative Vav2 to block lamellipodia formation in cells plated on fibronectin , we conclude that Vav2 activates Rac in vivo and is necessary for cell spreading .	Based on the induction of lamellipodia in cells overexpressing Vav2, assays of GTPase activation in vivo and the ability of a dominant negative Vav2 to block lamellipodia formation in cells plated on fibronectin, we conclude that Vav2 activates Rac in vivo and is necessary for cell spreading.	38	45	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	38	39	40	41
To accomplish this , the investigators utilized Ehop-016 , a specific inhibitor of Vav2 mediated activation of Rac1 .	To accomplish this, the investigators utilized Ehop-016, a specific inhibitor of Vav2 mediated activation of Rac1.	13	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	13	14	17	18
One question that our study raises is why activation of Rac1 by Vav2 over-expression inhibits neurite outgrowth .	One question that our study raises is why activation of Rac1 by Vav2 over-expression inhibits neurite outgrowth.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	12	13	10	11
We use this information to test a vimentin based model of lung cancer cell adhesion and motility , whereby vimentin promotes VAV2 mediated Rac1 activation at focal adhesions , leading to stabilization of FAK positive FAs through a potential feedback loop .	We use this information to test a vimentin based model of lung cancer cell adhesion and motility, whereby vimentin promotes VAV2 mediated Rac1 activation at focal adhesions, leading to stabilization of FAK positive FAs through a potential feedback loop.	21	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	21	22	23	24
In addition , we have observed that the binding of HA to CD44v3 activates Vav2 mediated Rac1 signaling leading to ovarian tumor cell migration .	In addition, we have observed that the binding of HA to CD44v3 activates Vav2 mediated Rac1 signaling leading to ovarian tumor cell migration.	13	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	14	15	16	17
Given our results that Cbl and Vav2 form a complex , together with our previous studies that Cbl-Vav1 interaction promotes Vav1 ubiquitinylation , we reasoned that association with Cbl may promote Vav2 ubiquitinylation , resulting in attenuation of EGF induced and Vav2 dependent activation of Rac1 and Cdc42 .	Given our results that Cbl and Vav2 form a complex, together with our previous studies that Cbl-Vav1 interaction promotes Vav1 ubiquitinylation, we reasoned that association with Cbl may promote Vav2 ubiquitinylation, resulting in attenuation of EGF induced and Vav2 dependent activation of Rac1 and Cdc42.	41	47	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	41	42	45	46
Overexpression of Vav2 activates Rac as assessed by both direct measurement of Rac-GTP and cell morphology .	Overexpression of Vav2 activates Rac as assessed by both direct measurement of Rac-GTP and cell morphology.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Overexpression of Vav2	vav2	Rac	Rac	rac	2	3	4	5
Vav2 mediates Rac activation in ECs in response to VEGF and is activated downstream of multiple receptor tyrosine kinases .	Vav2 mediates Rac activation in ECs in response to VEGF and is activated downstream of multiple receptor tyrosine kinases.	0	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	0	1	2	3
Activation of VAV-2 activates RhoA and Rac1 [ XREF_BIBR ] .	Activation of VAV-2 activates RhoA and Rac1 [XREF_BIBR].	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VAV-2	VAV-2	VAV-2	Rac1	Rac1	Rac1	2	3	6	7
We found that Vav2 activates Rac1 and , to a lesser extent , RhoA , but has a minimal effect on Cdc42 in HEK293T or NIH3T3 cells .	We found that Vav2 activates Rac1 and, to a lesser extent, RhoA, but has a minimal effect on Cdc42 in HEK293T or NIH3T3 cells.	3	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	3	4	5	6
Consistent with the major roles for the Sos/Abi1/Eps8 and Vav2 guanine nucleotide exchange factors ( GEFs ) in the activation of the small GTPase Rac1 during C. trachomatis entry [ XREF_BIBR ] , the EHop inhibitor that specifically prevents Vav2 mediated Rac1 activation [ XREF_BIBR ] induced a clear and significant dose dependent decrease in the number of inclusion containing cells , whereas NSC that alternatively targets Rac1 specific GEFs TrioN and Tiam1 had a lesser effect [ XREF_BIBR ] ( compare EHop and NSC in XREF_SUPPLEMENTARY ) .	Consistent with the major roles for the Sos/Abi1/Eps8 and Vav2 guanine nucleotide exchange factors (GEFs) in the activation of the small GTPase Rac1 during C. trachomatis entry [XREF_BIBR], the EHop inhibitor that specifically prevents Vav2 mediated Rac1 activation [XREF_BIBR] induced a clear and significant dose dependent decrease in the number of inclusion containing cells, whereas NSC that alternatively targets Rac1 specific GEFs TrioN and Tiam1 had a lesser effect [XREF_BIBR] (compare EHop and NSC in XREF_SUPPLEMENTARY).	38	46	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	39	40	41	42
Taken together , our data suggest that VAV2 mediated activation of Rac1 represents one of the key signalling steps involved in actin cytoskeleton remodelling and facilitation of GSIS from pancreatic beta cell .	Taken together, our data suggest that VAV2 mediated activation of Rac1 represents one of the key signalling steps involved in actin cytoskeleton remodelling and facilitation of GSIS from pancreatic beta cell.	7	12	mediated	Positive_early_activation	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	7	8	11	12
Our current findings also suggest that VAV2 mediated Rac1 activation is important for actin cytoskeletal reorganisation and mobilisation of insulin granules towards the plasma membrane for their fusion and release .	Our current findings also suggest that VAV2 mediated Rac1 activation is important for actin cytoskeletal reorganisation and mobilisation of insulin granules towards the plasma membrane for their fusion and release.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	6	7	8	9
Importantly , CA VAV2 , but not dominant negative or wild-type VAV2 , could rescue Rac1 activity defects in vimentin depleted cells ( XREF_FIG ) , indicating that activating VAV2 can bypass vimentin function .	Importantly, CA VAV2, but not dominant negative or wild-type VAV2, could rescue Rac1 activity defects in vimentin depleted cells (XREF_FIG), indicating that activating VAV2 can bypass vimentin function.	2	17	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	3	4	15	16
Not only Cdc42 but also Rac1 can be activated by Vav2 downstream of EGFR , representing one possible mechanism to compensate for Cdc42 depletion .	Not only Cdc42 but also Rac1 can be activated by Vav2 downstream of EGFR, representing one possible mechanism to compensate for Cdc42 depletion.	1	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	10	11	5	6
Vav2 has been shown to activate Cdc42 , Rac and RhoA downstream of growth factor receptors .	Vav2 has been shown to activate Cdc42, Rac and RhoA downstream of growth factor receptors.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	0	1	8	9
As shown in XREF_FIG , shear stress induced Rac1 GTP loading was compromised in Vav2 depleted ECs , whereas nonspecific siRNA had no effect , suggesting that Vav2 mediates flow induced GTP loading of Rac .	As shown in XREF_FIG, shear stress induced Rac1 GTP loading was compromised in Vav2 depleted ECs, whereas nonspecific siRNA had no effect, suggesting that Vav2 mediates flow induced GTP loading of Rac.	27	35	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	27	28	34	35
Vav2 over-expression protected neurons from RhoA mediated growth cone collapse , similar to constitutively active Rac1 , suggesting Vav2 activates Rac1 in spinal neurons .	Vav2 over-expression protected neurons from RhoA mediated growth cone collapse, similar to constitutively active Rac1, suggesting Vav2 activates Rac1 in spinal neurons.	17	23	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	18	19	20	21
These data strongly suggest that Src or an Src family member is necessary for Vav2 activation of Rac in vivo .	These data strongly suggest that Src or an Src family member is necessary for Vav2 activation of Rac in vivo.	14	19	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	14	15	17	18
Based on a hypertensive knockout mouse lacking the Rho and Rac activator Vav2 , a new signaling pathway involving Vav2 , the GTPase Rac1 and the serine/threonine kinase Pak , has been discovered to contribute to nitric oxide - triggered blood vessel relaxation and normotensia [ XREF_BIBR ] .	Based on a hypertensive knockout mouse lacking the Rho and Rac activator Vav2, a new signaling pathway involving Vav2, the GTPase Rac1 and the serine/threonine kinase Pak, has been discovered to contribute to nitric oxide - triggered blood vessel relaxation and normotensia [XREF_BIBR].	6	13	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	12	13	10	11
However , more recent studies have shown that Vav2 activates Cdc42 and Rac1 .	However, more recent studies have shown that Vav2 activates Cdc42 and Rac1.	8	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	8	9	12	13
Interestingly , although Cbl family ubiquitin ligases appear to prominently control the biological output of EGFR activation in MECs in terms of Vav2 mediated Rac1 and Cdc42 activation , cell-cell junctions , and cell migration , we did not see substantial changes in EGF dependent cell proliferation .	Interestingly, although Cbl family ubiquitin ligases appear to prominently control the biological output of EGFR activation in MECs in terms of Vav2 mediated Rac1 and Cdc42 activation, cell-cell junctions, and cell migration, we did not see substantial changes in EGF dependent cell proliferation.	20	27	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	22	23	24	25
Vav2 was found to activate Rac1 in response to stimulation with Nef , a human immunodeficiency virus , type 1 ( HIV-1 ) accessory protein associated with HIV-1-associated nephropathy ( HIVAN ) , severe proteinuria , and FSGS .	Vav2 was found to activate Rac1 in response to stimulation with Nef, a human immunodeficiency virus, type 1 (HIV-1) accessory protein associated with HIV-1-associated nephropathy (HIVAN), severe proteinuria, and FSGS.	0	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	0	1	5	6
Since Vav2 also activates Rac1 XREF_BIBR , we also tested the relevance of Rac1 for P + GC internalization .	Since Vav2 also activates Rac1 XREF_BIBR, we also tested the relevance of Rac1 for P + GC internalization.	1	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	1	2	4	5
Since activation of Jnk in COS7 cells is dependent on Rac or Cdc42 but not Rho , and we detect minimal activation of Cdc42 by Vav2 , stimulation of Jnk by Vav2 in COS7 cells indicates that Vav2 activates Rac in vivo .	Since activation of Jnk in COS7 cells is dependent on Rac or Cdc42 but not Rho, and we detect minimal activation of Cdc42 by Vav2, stimulation of Jnk by Vav2 in COS7 cells indicates that Vav2 activates Rac in vivo.	37	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	37	38	39	40
Moreover , blockade of Vav2 attenuated enhancement of Rac activity and O 2 .	Moreover, blockade of Vav2 attenuated enhancement of Rac activity and O 2.	2	9	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	4	5	8	9
As LPA is known to strongly activate RhoA and that Rho GTPases can exhibit signal cross-talk , our results suggest that Vav2 activation of Rac1 and Cdc42 likely inhibits RhoA signaling in growth cones .	As LPA is known to strongly activate RhoA and that Rho GTPases can exhibit signal cross-talk, our results suggest that Vav2 activation of Rac1 and Cdc42 likely inhibits RhoA signaling in growth cones.	21	26	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	21	22	24	25
L342R and L343SVav2 should be recruited to sites where Rac would be activated by Vav2 and thereby block recruitment of endogenous Vav2 and thus Rac activation by endogenous Vav2 .	L342R and L343SVav2 should be recruited to sites where Rac would be activated by Vav2 and thereby block recruitment of endogenous Vav2 and thus Rac activation by endogenous Vav2.	24	29	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	28	29	24	25
To explore the possible cooperation between the two GEF activities in chlamydial invasion , Sos1 depleted cells were also treated with wortmannin , which is implicated in the Vav2 dependent activation of Rac .	To explore the possible cooperation between the two GEF activities in chlamydial invasion, Sos1 depleted cells were also treated with wortmannin, which is implicated in the Vav2 dependent activation of Rac.	28	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	28	29	32	33
Previous studies by us and others have demonstrated that Vav2 activation caused constitutive upregulation of Rac1 resulting in enhancement of ROS production in vitro and in vivo XREF_BIBR , XREF_BIBR .	Previous studies by us and others have demonstrated that Vav2 activation caused constitutive upregulation of Rac1 resulting in enhancement of ROS production in vitro and in vivo XREF_BIBR, XREF_BIBR.	9	27	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	9	10	15	16
Filamin has been demonstrated to be a scaffold protein for Vav2 mediated Rac1 activation and Rac1 downstream signaling .	Filamin has been demonstrated to be a scaffold protein for Vav2 mediated Rac1 activation and Rac1 downstream signaling.	10	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	10	11	12	13
VAV2 depletion resulted in a 40-60 % reduction in activity of Rac1 ( XREF_FIG ) , supporting the notion that VAV2 is a critical downstream effector of NEDD9 dependent Rac1 activation .	VAV2 depletion resulted in a 40-60% reduction in activity of Rac1 (XREF_FIG), supporting the notion that VAV2 is a critical downstream effector of NEDD9 dependent Rac1 activation.	0	30	supporting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	0	1	29	30
Optimal Rac activation by Vav2 in vitro also required the presence of the phospholipids PI 3,4,5-P 3 , which is generated at the site of chlamydial attachment by virtue of the interaction of the p85 subunit of PI3-kinase with the TARP phosphodomain .	Optimal Rac activation by Vav2 in vitro also required the presence of the phospholipids PI 3,4,5-P 3, which is generated at the site of chlamydial attachment by virtue of the interaction of the p85 subunit of PI3-kinase with the TARP phosphodomain.	1	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac	Rac	Rac	4	5	1	2
Treatment with SU6656 abolished glucose induced VAV2 phosphorylation ( XREF_FIG ) , suggesting that upstream SFK activation by glucose is important for the VAV2 mediated Rac1 activation signalling step .	Treatment with SU6656 abolished glucose induced VAV2 phosphorylation (XREF_FIG), suggesting that upstream SFK activation by glucose is important for the VAV2 mediated Rac1 activation signalling step.	22	28	mediated	Positive_early_activation	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	23	24	25	26
From our findings , we confirmed that expression of constitutively active Vav2 , can itself drive the activation of the Rac-1 protein ( XREF_FIG ) and the aggregation of a functional NOX complex , which produces O 2 .	From our findings, we confirmed that expression of constitutively active Vav2, can itself drive the activation of the Rac-1 protein (XREF_FIG) and the aggregation of a functional NOX complex, which produces O 2.	7	22	drive	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	expression of constitutively active Vav2	vav2	Rac-1 protein	Rac-1 protein	rac-1 protein	11	12	20	22
Vav2 activated Rac1 ( XREF_FIG A ) and to a lesser extent RhoA ( XREF_FIG D ) , but we detected minimal activation of Cdc42 , although Dbl did activate Cdc42 as expected ( XREF_FIG C ) .	Vav2 activated Rac1 (XREF_FIG A) and to a lesser extent RhoA (XREF_FIG D), but we detected minimal activation of Cdc42, although Dbl did activate Cdc42 as expected (XREF_FIG C).	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	0	1	2	3
Our studies suggest that Vav2 activates Rac1 in spinal neurons to promote neurite outgrowth , process formation and axon branching .	Our studies suggest that Vav2 activates Rac1 in spinal neurons to promote neurite outgrowth, process formation and axon branching.	4	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	4	5	6	7
Expression of a carboxy-terminal fragment of Vav2 decreased the elevation of Rac1 activity induced by epidermal growth factor , consistent with Vav2 mediating activation of Rac1 downstream from growth factor receptors .	Expression of a carboxy-terminal fragment of Vav2 decreased the elevation of Rac1 activity induced by epidermal growth factor, consistent with Vav2 mediating activation of Rac1 downstream from growth factor receptors.	4	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	6	7	11	12
Using baculovirus derived recombinant protein , XREF_BIBR found that Vav2 activates RhoA , RhoB , and RhoG , but not Rac1 or Cdc42 , as determined by exchange assays in vitro .	Using baculovirus derived recombinant protein, XREF_BIBR found that Vav2 activates RhoA, RhoB, and RhoG, but not Rac1 or Cdc42, as determined by exchange assays in vitro.	9	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	9	10	20	21
VAV2 is a widely expressed GEF that reportedly acts on Rac1 , RhoA , and Cdc42 in vitro , although overexpression of VAV2 leads to a predominantly Rac1 like morphology .	VAV2 is a widely expressed GEF that reportedly acts on Rac1, RhoA, and Cdc42 in vitro, although overexpression of VAV2 leads to a predominantly Rac1 like morphology.	20	29	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	VAV2	overexpression of VAV2	vav2	Rac1	Rac1	rac1	22	23	27	28
Consistent with Vav2 activating Rac1 over Cdc42 , constitutively active ( CA )-Rac1 had similar effects on neurite formation and branching , while CA Cdc42 had little effect on branching ( XREF_SUPPLEMENTARY ) .	Consistent with Vav2 activating Rac1 over Cdc42, constitutively active (CA)-Rac1 had similar effects on neurite formation and branching, while CA Cdc42 had little effect on branching (XREF_SUPPLEMENTARY).	0	6	activating	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	2	3	4	5
In this study , VEGF-A 165 promoted significant trafficking of VEGFR1 to the plasma membrane whereas VEGF-A 121 was largely ineffective in this context ; again this could be explained by signal transduction effects on cytosolic calcium ion levels .	In this study, VEGF-A 165 promoted significant trafficking of VEGFR1 to the plasma membrane whereas VEGF-A 121 was largely ineffective in this context; again this could be explained by signal transduction effects on cytosolic calcium ion levels.	4	11	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	4	5	10	11
VEGF-A stimulated ADAM17 shedding of VEGFR-1 , suggesting that processing of the receptor is important for angiogenesis [ XREF_BIBR ] .	VEGF-A stimulated ADAM17 shedding of VEGFR-1, suggesting that processing of the receptor is important for angiogenesis [XREF_BIBR].	0	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	0	1	5	6
VEGF-A stimulation of endothelial cells causes transient redistribution of VEGFR1 to the plasma membrane via a trans-Golgi network-to-plasma membrane route that is regulated by cytosolic calcium flux [ XREF_BIBR ] ( XREF_FIG ) .	VEGF-A stimulation of endothelial cells causes transient redistribution of VEGFR1 to the plasma membrane via a trans-Golgi network-to-plasma membrane route that is regulated by cytosolic calcium flux [XREF_BIBR] (XREF_FIG).	0	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	0	1	9	10
VEGFA ( VEGFA , P15692 ) is able to activate VEGFR1 homodimers , VEGFR1/2 heterodimers and VEGFR2/3 heterodimers .	VEGFA (VEGFA, P15692) is able to activate VEGFR1 homodimers, VEGFR1/2 heterodimers and VEGFR2/3 heterodimers.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR1	VEGFR1	VEGFR1	0	1	10	11
Ex vivo studies have also shown that VEGFR-1 activation by VEGF-A or VEGF-B induces increased cell invasion and migration , as well as phenotypic changes associated with activation of the MAPK pathway in tumor cells [ XREF_BIBR ] .	Ex vivo studies have also shown that VEGFR-1 activation by VEGF-A or VEGF-B induces increased cell invasion and migration, as well as phenotypic changes associated with activation of the MAPK pathway in tumor cells [XREF_BIBR].	7	12	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	10	11	7	8
VEGF-A elicits cellular responses through binding to the receptor tyrosine kinases , VEGFR1 and VEGFR2 XREF_BIBR .	VEGF-A elicits cellular responses through binding to the receptor tyrosine kinases, VEGFR1 and VEGFR2 XREF_BIBR.	0	13	elicits	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	0	1	12	13
Conversely , the absence of VEGF-B in RIP1-Tag2 ; Vegfb -/- mice may enhance the specific signaling by VEGF-A and PlGF through VEGFR-1 in endothelial cells .	Conversely, the absence of VEGF-B in RIP1-Tag2; Vegfb -/- mice may enhance the specific signaling by VEGF-A and PlGF through VEGFR-1 in endothelial cells.	13	25	enhance	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	18	19	22	23
Matrix metalloproteinase-9 ( MMP-9 ) secreted by BMDCs degrades the basement membrane and liberates the matrix sequestered VEGFR1 ligand , the VEGFA , promoting the homing of more VEGFR1 + cells into the niche [ XREF_BIBR ] .	Matrix metalloproteinase-9 (MMP-9) secreted by BMDCs degrades the basement membrane and liberates the matrix sequestered VEGFR1 ligand, the VEGFA, promoting the homing of more VEGFR1 + cells into the niche [XREF_BIBR].	18	30	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR1	VEGFR1	VEGFR1	21	22	28	29
In retinal and choroidal vascular diseases in which VEGF-A levels are high , it is unlikely that specific neutralization of PlGF would have much effect because VEGF-A also activates VEGFR1 .	In retinal and choroidal vascular diseases in which VEGF-A levels are high, it is unlikely that specific neutralization of PlGF would have much effect because VEGF-A also activates VEGFR1.	26	30	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	26	27	29	30
Accordingly , VEGFR1 signal activated by PlGF or VEGF-A is involved in pathological angiogenesis with a large hemorrhagic phenotype in retinopathy of N-PRbeta-KO mice .	Accordingly, VEGFR1 signal activated by PlGF or VEGF-A is involved in pathological angiogenesis with a large hemorrhagic phenotype in retinopathy of N-PRbeta-KO mice.	2	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	8	9	2	3
VEGFR1 activation by VEGF-A , VEGF-B , and placental growth factor attracts mononuclear leukocytes and promotes development of myocardial arterioles .	VEGFR1 activation by VEGF-A, VEGF-B, and placental growth factor attracts mononuclear leukocytes and promotes development of myocardial arterioles.	0	10	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	3	4	0	1
Likewise , neurons expressed no VEGFR1 mRNA when the cells were treated with VEGF-A 165 , indicating VEGFR1 is unimportant for neurogenesis XREF_BIBR .	Likewise, neurons expressed no VEGFR1 mRNA when the cells were treated with VEGF-A 165, indicating VEGFR1 is unimportant for neurogenesis XREF_BIBR.	5	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	13	14	5	6
Vascular endothelial grow factor ( VEGF ) promotes angiogenesis by activating the specific receptors KDR and Flt-1 .	Vascular endothelial grow factor (VEGF) promotes angiogenesis by activating the specific receptors KDR and Flt-1.	0	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vascular endothelial grow factor	Vascular endothelial grow factor	Vascular endothelial grow factor	Flt-1	Flt-1	Flt-1	0	4	16	17
Luminal VEGFA activates VEGFR1 homodimers and AKT , leading to a cytoprotective response , whilst abluminal VEGFA induces vascular leakage via VEGFR2 homodimers and p38 .	Luminal VEGFA activates VEGFR1 homodimers and AKT, leading to a cytoprotective response, whilst abluminal VEGFA induces vascular leakage via VEGFR2 homodimers and p38.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR1	VEGFR1	VEGFR1	1	2	3	4
XREF_BIBR VEGFA has been shown to activate both FLT1 and KDR , XREF_BIBR and activation of this signaling pathway has led to vascularization and angiogenesis in malignant tissue to support its growth and survival .	XREF_BIBR VEGFA has been shown to activate both FLT1 and KDR, XREF_BIBR and activation of this signaling pathway has led to vascularization and angiogenesis in malignant tissue to support its growth and survival.	0	9	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	FLT1	FLT1	FLT1	1	2	8	9
In addition , the frequency of lymphatic vessels was lower in tumor tissue compared with benign tissue , suggesting that in carcinoma cells activation of VEGFR-1 by VEGF-A , and activation of lymphatic endothelial cell VEGFR-3 by VEGF-D within the adjacent benign stroma may be important for the progression and subsequent metastatic spread of prostate cancer [ XREF_BIBR ] .	In addition, the frequency of lymphatic vessels was lower in tumor tissue compared with benign tissue, suggesting that in carcinoma cells activation of VEGFR-1 by VEGF-A, and activation of lymphatic endothelial cell VEGFR-3 by VEGF-D within the adjacent benign stroma may be important for the progression and subsequent metastatic spread of prostate cancer [XREF_BIBR].	23	30	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	27	28	25	26
These results suggest that activation of VEGFR-1 by VEGF-A within the carcinoma , and activation of lymphatic endothelial cell VEGFR-3 by VEGF-D within the adjacent benign stroma may be important signaling mechanisms involved in the progression and subsequent metastatic spread of prostate cancer .	These results suggest that activation of VEGFR-1 by VEGF-A within the carcinoma, and activation of lymphatic endothelial cell VEGFR-3 by VEGF-D within the adjacent benign stroma may be important signaling mechanisms involved in the progression and subsequent metastatic spread of prostate cancer.	4	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	8	9	6	7
Cytosolic calcium ions play a key role in VEGFR1 trafficking as treatment with either VEGF-A , histamine , thrombin , thapsigargin or A23187 ionophore caused VEGFR1 redistribution from the Golgi apparatus to small punctate vesicles and plasma membrane .	Cytosolic calcium ions play a key role in VEGFR1 trafficking as treatment with either VEGF-A, histamine, thrombin, thapsigargin or A23187 ionophore caused VEGFR1 redistribution from the Golgi apparatus to small punctate vesicles and plasma membrane.	14	26	caused	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	14	15	25	26
However , VEGFA seems to induce much weaker tyrosine kinase activity in VEGFR1 possibly because of an inhibitory sequence in the juxtamembrane domain that represses VEGFR1 activity [ XREF_BIBR ] .	However, VEGFA seems to induce much weaker tyrosine kinase activity in VEGFR1 possibly because of an inhibitory sequence in the juxtamembrane domain that represses VEGFR1 activity [XREF_BIBR].	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR1	VEGFR1	VEGFR1	2	3	12	13
XREF_BIBR Similarly , aflibercept inhibited VEGF-A induced activation of VEGFR-1 and VEGFR-2 more potently than bevacizumab or ranibizumab in cell based assays .	XREF_BIBR Similarly, aflibercept inhibited VEGF-A induced activation of VEGFR-1 and VEGFR-2 more potently than bevacizumab or ranibizumab in cell based assays.	5	11	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	5	6	9	10
VEGFR-1 stimulation by VEGF-A or VEGF-B was found to promote migration in both cell lines .	VEGFR-1 stimulation by VEGF-A or VEGF-B was found to promote migration in both cell lines.	0	5	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	3	4	0	1
In a study of VEGF-A-induced activation of VEGFR1 , aflibercept demonstrated 92-fold greater potency than bevacizumab in an assay in which VEGFR1 activation was induced by VEGF-A 165 or VEGF-A 121 [ XREF_BIBR ] .	In a study of VEGF-A-induced activation of VEGFR1, aflibercept demonstrated 92-fold greater potency than bevacizumab in an assay in which VEGFR1 activation was induced by VEGF-A 165 or VEGF-A 121 [XREF_BIBR].	21	27	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	26	27	21	22
VEGFR-1 , but not VEGFR-2 , is expressed in motor neurons of the facial nerve , leading to the assumption that VEGF-A induces the formation of a complex of VEGFR-1 and Nrp-1 that then transmits the VEGF-A signal [ XREF_BIBR ] .	VEGFR-1, but not VEGFR-2, is expressed in motor neurons of the facial nerve, leading to the assumption that VEGF-A induces the formation of a complex of VEGFR-1 and Nrp-1 that then transmits the VEGF-A signal [XREF_BIBR].	21	31	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	21	22	29	30
In terms of their biological activity as assessed via inhibition of VEGF-A or PlGF-2-induced activation of VEGFR-1 , both bevacizumab and aflibercept inhibited VEGFR-1 activation induced by VEGF-A 165 or VEGF-A 121 .	In terms of their biological activity as assessed via inhibition of VEGF-A or PlGF-2-induced activation of VEGFR-1, both bevacizumab and aflibercept inhibited VEGFR-1 activation induced by VEGF-A 165 or VEGF-A 121.	23	30	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	27	28	23	24
Since VEGFR1 signal blockade significantly ameliorated the vascular phenotype in N-PRbeta-KO mice , the augmented VEGFR1 signal by PlGF and VEGF-A was indicated to mediate vascular lesions .	Since VEGFR1 signal blockade significantly ameliorated the vascular phenotype in N-PRbeta-KO mice, the augmented VEGFR1 signal by PlGF and VEGF-A was indicated to mediate vascular lesions.	15	21	signal	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	20	21	15	16
Consistent with its higher affinity for VEGF-A and faster association rate , VEGF Trap demonstrates increased potency relative to ranibizumab and bevacizumab in blocking VEGF-A induced activation of VEGFR1 and VEGFR2 in cell based assays , and also in blocking VEGF mediated calcium mobilization and migration in human endothelial cells .	Consistent with its higher affinity for VEGF-A and faster association rate, VEGF Trap demonstrates increased potency relative to ranibizumab and bevacizumab in blocking VEGF-A induced activation of VEGFR1 and VEGFR2 in cell based assays, and also in blocking VEGF mediated calcium mobilization and migration in human endothelial cells.	24	30	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	24	25	28	29
However , no significant difference in VEGFR2 activation was observed between VEGF 165 a and VEGF 165 b treatments at any concentration or time points ( XREF_FIG ) indicating that VEGF 165 b can decrease VEGF-A mediated VEGFR1 activation .	However, no significant difference in VEGFR2 activation was observed between VEGF 165 a and VEGF 165 b treatments at any concentration or time points (XREF_FIG) indicating that VEGF 165 b can decrease VEGF-A mediated VEGFR1 activation.	34	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR1	VEGFR1	VEGFR1	35	36	37	38
As shown in XREF_FIG , VEGFR-1 is activated by FBS and VEGF-A in both SW480 and Hep1 cell lines .	As shown in XREF_FIG, VEGFR-1 is activated by FBS and VEGF-A in both SW480 and Hep1 cell lines.	5	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	11	12	5	6
This is an important finding because VEGFC also activates VEGFR-2 .	This is an important finding because VEGFC also activates VEGFR-2.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR-2	VEGFR-2	VEGFR-2	6	7	9	10
In order to investigate whether VEGF-C induced Hsp90 expression via VEGFR-2 ( KDR ) , MAPK and PI3K pathways , HeLa cells were treated with VEGF-C , VEGF-C + KDR-Ab , VEGF-C + LY294002 , VEGF-C + PD98059 and VEGF-C + GA ..	In order to investigate whether VEGF-C induced Hsp90 expression via VEGFR-2 (KDR), MAPK and PI3K pathways, HeLa cells were treated with VEGF-C, VEGF-C + KDR-Ab, VEGF-C + LY294002, VEGF-C + PD98059 and VEGF-C + GA..	10	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	KDR	KDR	KDR	27	28	12	13
Mature VEGF-C induced p42/44 MAPK activation in the KDR - / FLT4 + cell line OCI-AML1 verifying the model character of this cell line for VEGF-C signal transduction studies .	Mature VEGF-C induced p42/44 MAPK activation in the KDR - / FLT4 + cell line OCI-AML1 verifying the model character of this cell line for VEGF-C signal transduction studies.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	KDR	KDR	KDR	1	2	8	9
Alternatively , in some cases VEGFC has been reported to stimulate VEGFR2 expressing endothelial cells .	Alternatively, in some cases VEGFC has been reported to stimulate VEGFR2 expressing endothelial cells.	5	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	VEGFR2	VEGFR2	VEGFR2	5	6	11	12
VEGF-C and VEGF-D , when fully proteolytically processed , can also activate VEGFR-2 , but whether VEGFR-2 plays a direct role in lymphangiogenesis is less clear .	VEGF-C and VEGF-D, when fully proteolytically processed, can also activate VEGFR-2, but whether VEGFR-2 plays a direct role in lymphangiogenesis is less clear.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	0	1	12	13
VEGF-C is the ligand for the receptor tyrosine kinase VEGFR-3 ( also known as Flt4 ) , which is expressed predominantly in lymphatic endothelium of adult tissues , but a proteolytically processed form of VEGF-C can also activate VEGFR-2 of blood vessels .	VEGF-C is the ligand for the receptor tyrosine kinase VEGFR-3 (also known as Flt4), which is expressed predominantly in lymphatic endothelium of adult tissues, but a proteolytically processed form of VEGF-C can also activate VEGFR-2 of blood vessels.	32	41	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	34	35	38	39
To investigate whether VEGF-C induced Hsp90 expression via the VEGFR-2 ( KDR ) , MAPK and PI3K pathways , HeLa cells were treated with VEGF-C ( 50 ng/mul ) , VEGF-C ( 50 ng/mul ) + KDR-Ab ( 20 mug/ml ) , VEGF-C ( 50 ng/mul ) + LY294002 ( 3 mumol/l ) , VEGF-C ( 50 ng/mul ) + PD98059 ( 30 mumol/l ) or VEGF-C ( 50 ng/mul ) + GA ( 10 mumol/l ) .	To investigate whether VEGF-C induced Hsp90 expression via the VEGFR-2 (KDR), MAPK and PI3K pathways, HeLa cells were treated with VEGF-C (50 ng/mul), VEGF-C (50 ng/mul) + KDR-Ab (20 mug/ml), VEGF-C (50 ng/mul) + LY294002 (3 mumol/l), VEGF-C (50 ng/mul) + PD98059 (30 mumol/l) or VEGF-C (50 ng/mul) + GA (10 mumol/l).	9	72	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	KDR	KDR	KDR	24	25	11	12
The mature forms of VEGF-C and VEGF-D can activate VEGFR-2 , although with binding affinities three-fold lower than for VEGFR-3 .	The mature forms of VEGF-C and VEGF-D can activate VEGFR-2, although with binding affinities three-fold lower than for VEGFR-3.	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	4	5	9	10
Similarly , VEGF-C activated VEGFR-2 ; however , Slit2N did not significantly inhibit VEGF-C-induced VEGFR-2 activation .	Similarly, VEGF-C activated VEGFR-2; however, Slit2N did not significantly inhibit VEGF-C-induced VEGFR-2 activation.	2	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	2	3	4	5
After proteolytic processing to the mature protein , VEGF-C can also activate VEGFR-2 21 , which drives lymphangiogenesis under some conditions XREF_BIBR , XREF_BIBR .	After proteolytic processing to the mature protein, VEGF-C can also activate VEGFR-2 21, which drives lymphangiogenesis under some conditions XREF_BIBR, XREF_BIBR.	8	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	8	9	12	13
VEGF-C and -D are members of the vascular endothelial growth factor family and promote lymphaniogenesis via binding and activating their cognate tyrosine kinase receptors VEGFR2 and 3 XREF_BIBR .	VEGF-C and -D are members of the vascular endothelial growth factor family and promote lymphaniogenesis via binding and activating their cognate tyrosine kinase receptors VEGFR2 and 3 XREF_BIBR.	0	27	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR2	VEGFR2	VEGFR2	0	1	24	25
Processed forms of VEGF-C and VEGF-D can also activate VEGFR-2 , a key player in the regulation of angiogenesis .	Processed forms of VEGF-C and VEGF-D can also activate VEGFR-2, a key player in the regulation of angiogenesis.	1	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	3	4	9	10
EGCG also suppressed VEGFC expression and reduced VEGFR2 and ERK activation in endothelial cells .	EGCG also suppressed VEGFC expression and reduced VEGFR2 and ERK activation in endothelial cells.	0	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFC	EGCG also suppressed VEGFC expression	vegfc	VEGFR2	VEGFR2	vegfr2	3	4	7	8
However , proteolytically processed VEGF-C also stimulates VEGFR-2 , the predominant transducer of signals required for physiological and pathological angiogenesis .	However, proteolytically processed VEGF-C also stimulates VEGFR-2, the predominant transducer of signals required for physiological and pathological angiogenesis.	3	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	4	5	7	8
When processed through proteolysis in the ECM to mature forms , VEGF-C has been reported to also activate VEGFR-2 on the surface of the BECs , thereby inducing angiogenesis ( Joukov et al , 1996 ) .	When processed through proteolysis in the ECM to mature forms, VEGF-C has been reported to also activate VEGFR-2 on the surface of the BECs, thereby inducing angiogenesis (Joukov et al, 1996).	11	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	11	12	18	19
However VEGF-A may be replaced as an angiogenic factor by other growth factors as disease progresses , including VEGF-C and -D , which can activate VEGFR-2 after proteolytic cleavage [ XREF_BIBR ] , placental growth factor which specifically targets VEGFR-1 [ XREF_BIBR ] , bFGF and PDGF [ XREF_BIBR ] .	However VEGF-A may be replaced as an angiogenic factor by other growth factors as disease progresses, including VEGF-C and -D, which can activate VEGFR-2 after proteolytic cleavage [XREF_BIBR], placental growth factor which specifically targets VEGFR-1 [XREF_BIBR], bFGF and PDGF [XREF_BIBR].	15	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	18	19	25	26
VEGF-C activated autocrine VEGFR2 signaling to promote cell survival , whereas targeting VEGF-C expression reprogrammed cellular transcription to attenuate survival and cell cycle progression .	VEGF-C activated autocrine VEGFR2 signaling to promote cell survival, whereas targeting VEGF-C expression reprogrammed cellular transcription to attenuate survival and cell cycle progression.	0	4	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR2	VEGFR2	VEGFR2	0	1	3	4
VEGF-A or VEGF-C activation of KDR is involved in the formation of capillary like tubular structures [ XREF_BIBR ] .	VEGF-A or VEGF-C activation of KDR is involved in the formation of capillary like tubular structures [XREF_BIBR].	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	KDR	KDR	KDR	2	3	5	6
XREF_BIBR , XREF_BIBR For example , PlGF only binds and activates VEGFR1 whereas VEGF-C specifically activates VEGFR2 .	XREF_BIBR, XREF_BIBR For example, PlGF only binds and activates VEGFR1 whereas VEGF-C specifically activates VEGFR2.	13	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR2	VEGFR2	VEGFR2	13	14	16	17
Delineating VEGF-C activation is not only important in order to understand the development of the lymphatic system , but also to understand tumor angiogenesis , because mature VEGF-C is also able to activate the VEGFR-2 signaling pathway and because some tumors might escape antiangiogenic therapy by employing VEGF-C instead of VEGF-A 32 .	Delineating VEGF-C activation is not only important in order to understand the development of the lymphatic system, but also to understand tumor angiogenesis, because mature VEGF-C is also able to activate the VEGFR-2 signaling pathway and because some tumors might escape antiangiogenic therapy by employing VEGF-C instead of VEGF-A 32.	26	36	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	27	28	34	35
VEGF-C , a member of the VEGF family , also induces angiogenesis by activating VEGFR-2 XREF_BIBR .	VEGF-C, a member of the VEGF family, also induces angiogenesis by activating VEGFR-2 XREF_BIBR.	0	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	0	1	14	15
Whereas addition of exogenous VEGF-A induced EC dispersion , VEGF-C , which can also stimulate VEGFR-2 , promoted EC growth without disturbing the EC clusters .	Whereas addition of exogenous VEGF-A induced EC dispersion, VEGF-C, which can also stimulate VEGFR-2, promoted EC growth without disturbing the EC clusters.	9	17	stimulate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	9	10	15	16
Using a modified Miles assay , intradermal injection in mice ears of VEGF-A ( 165 ) , VEGF-A ( 121 ) , and VEGF-C ( 1 microM ) which activate VEGFR-2 ( Flk-1 ) receptor increased vascular permeability , whereas a treatment with VEGFR-1 ( Flt-1 ) analogs ; PlGF and VEGF-B ( 1 microM ) had no such effect .	Using a modified Miles assay, intradermal injection in mice ears of VEGF-A (165), VEGF-A (121), and VEGF-C (1 microM) which activate VEGFR-2 (Flk-1) receptor increased vascular permeability, whereas a treatment with VEGFR-1 (Flt-1) analogs; PlGF and VEGF-B (1 microM) had no such effect.	0	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	23	24	30	31
The more-than-additive effect of blocking VEGFR-2 and VEGFR-3 together suggests that VEGF-C is not just simply saturating VEGFR-3 and then activating VEGFR-2 .	The more-than-additive effect of blocking VEGFR-2 and VEGFR-3 together suggests that VEGF-C is not just simply saturating VEGFR-3 and then activating VEGFR-2.	11	22	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	11	12	21	22
As human VEGF-D activates VEGFR-2 and VEGFR-3 8 , we also analysed these receptors .	As human VEGF-D activates VEGFR-2 and VEGFR-3 8, we also analysed these receptors.	1	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	2	3	6	7
VEGFD is known to activate the VEGFR3 receptor .	VEGFD is known to activate the VEGFR3 receptor.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFD	VEGFD	VEGFD	VEGFR3	VEGFR3	VEGFR3	0	1	6	7
Enhancing the Capacity of VEGF-D to Activate VEGFR-3 Promotes Lymphatic Sprouting .	Enhancing the Capacity of VEGF-D to Activate VEGFR-3 Promotes Lymphatic Sprouting.	2	8	Activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	4	5	7	8
Human VEGF-D activates the endothelial cell surface receptors VEGFR-2 and VEGFR-3 8 ; mouse Vegf-d activates Vegfr-3 but is a poor ligand for Vegfr-2 17 .	Human VEGF-D activates the endothelial cell surface receptors VEGFR-2 and VEGFR-3 8; mouse Vegf-d activates Vegfr-3 but is a poor ligand for Vegfr-2 17.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	1	2	10	11
Our results suggest that these two derivatives exhibit different receptor binding specificities ; VEGF-D ( 89-205 ) would activate both VEGFR-2 and VEGFR-3 , whereas VEGF-D ( 100-205 ) would not activate VEGFR-3 .	Our results suggest that these two derivatives exhibit different receptor binding specificities; VEGF-D (89-205) would activate both VEGFR-2 and VEGFR-3, whereas VEGF-D (100-205) would not activate VEGFR-3.	25	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	25	26	32	33
VEGF-D activates both VEGFR-2 and VEGFR-3 , is a mitogen for blood vascular and lymphatic endothelial cells and is closely related to VEGF-C ( another member of VEGF family of ligands ) from a structural perspective [ XREF_BIBR , XREF_BIBR ] .	VEGF-D activates both VEGFR-2 and VEGFR-3, is a mitogen for blood vascular and lymphatic endothelial cells and is closely related to VEGF-C (another member of VEGF family of ligands) from a structural perspective [XREF_BIBR, XREF_BIBR].	0	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	0	1	5	6
Specifically , Vegfd is a ligand for the Vegf receptor tyrosine kinases and activates the structurally similar type III receptor tyrosine kinase Vegfr3 XREF_BIBR .	Specifically, Vegfd is a ligand for the Vegf receptor tyrosine kinases and activates the structurally similar type III receptor tyrosine kinase Vegfr3 XREF_BIBR.	2	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vegfd	Vegfd	Vegfd	Vegfr3	Vegfr3	Vegfr3	2	3	22	23
In contrast to murine VEGF-C , murine VEGF-D only activates VEGFR3 .	In contrast to murine VEGF-C, murine VEGF-D only activates VEGFR3.	6	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR3	VEGFR3	VEGFR3	7	8	10	11
Using a recombinant adenovirus encoding a soluble form of their receptor VEGFR-3 ( AdVEGFR-3-Ig ) , we studied lymphatic vessel dependency on VEGF-C and VEGF-D induced VEGFR-3 signaling in postnatal and adult mice .	Using a recombinant adenovirus encoding a soluble form of their receptor VEGFR-3 (AdVEGFR-3-Ig), we studied lymphatic vessel dependency on VEGF-C and VEGF-D induced VEGFR-3 signaling in postnatal and adult mice.	20	27	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	24	25	26	27
This is likely due to the activation of VEGFR-3 by VEGF-D on the lymphatic endothelium in tumors .	This is likely due to the activation of VEGFR-3 by VEGF-D on the lymphatic endothelium in tumors.	3	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	10	11	8	9
VEGF-C or VEGF-D activation of VEGFR-3 plays a critical role in lymphangiogenesis ; in lymphatic endothelial cells , SHC and growth factor receptor bound protein 2 ( GRB2 ) adaptor proteins are recruited to activated VEGFR-3 and promote ERK1/2 and PI3K and Akt pathway , which is critical for lymphatic endothelial cell migration [ XREF_BIBR , XREF_BIBR ] .	VEGF-C or VEGF-D activation of VEGFR-3 plays a critical role in lymphangiogenesis; in lymphatic endothelial cells, SHC and growth factor receptor bound protein 2 (GRB2) adaptor proteins are recruited to activated VEGFR-3 and promote ERK1/2 and PI3K and Akt pathway, which is critical for lymphatic endothelial cell migration [XREF_BIBR, XREF_BIBR].	2	6	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	2	3	5	6
The secreted glycoproteins VEGF-C or VEGF-D activate VEGFR-3 , a cell surface receptor tyrosine kinase on lymphatic endothelium , leading to growth of lymphatic vessels .	The secreted glycoproteins VEGF-C or VEGF-D activate VEGFR-3, a cell surface receptor tyrosine kinase on lymphatic endothelium, leading to growth of lymphatic vessels.	3	19	activate	Positive_activation_token_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	5	6	7	8
Vascular endothelial growth factor ( VEGF ) C and VEGF-D stimulate lymphangiogenesis and angiogenesis in tissues and tumors by activating the endothelial cell surface receptor tyrosine kinases VEGF receptor ( VEGFR ) 2 and VEGFR-3 .	Vascular endothelial growth factor (VEGF) C and VEGF-D stimulate lymphangiogenesis and angiogenesis in tissues and tumors by activating the endothelial cell surface receptor tyrosine kinases VEGF receptor (VEGFR) 2 and VEGFR-3.	7	35	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	9	10	34	35
FIGF is an activator of KDR and FLT4 ( VEGFR-3 ) and induces angiogenesis and lymphangiogenesis XREF_BIBR .	FIGF is an activator of KDR and FLT4 (VEGFR-3) and induces angiogenesis and lymphangiogenesis XREF_BIBR.	0	12	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	FIGF	FIGF	FIGF	FLT4	FLT4	FLT4	0	1	7	8
These predictions are broadly consistent with a previous study showing that a variant of VEGF-D ( 89-195 ) , with a C117A mutation , could activate both VEGFR-2 and VEGFR-3 .	These predictions are broadly consistent with a previous study showing that a variant of VEGF-D (89-195), with a C117A mutation, could activate both VEGFR-2 and VEGFR-3.	12	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-3	VEGFR-3	VEGFR-3	14	15	29	30
These results further substantiated that USP7 modulates steady-state SUV39H1 levels independent of p53 .	These results further substantiated that USP7 modulates steady-state SUV39H1 levels independent of p53.	5	13	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	5	6	12	13
There also seems to be a delicate balance between these proteins , as a modest reduction of HAUSP levels prevents p53 deubiquitination but complete ablation of HAUSP causes robust p53 stabilization .	There also seems to be a delicate balance between these proteins, as a modest reduction of HAUSP levels prevents p53 deubiquitination but complete ablation of HAUSP causes robust p53 stabilization.	24	30	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	26	27	29	30
Overexpression of USP7 induces p53 activation , leading to growth suppression and apoptosis .	Overexpression of USP7 induces p53 activation, leading to growth suppression and apoptosis.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	Overexpression of USP7	usp7	p53	p53	p53	2	3	4	5
First , we tested whether USP7 could stimulate p53 function in a ubiquitin independent manner during conditions of cellular stress such as DNA damage .	First, we tested whether USP7 could stimulate p53 function in a ubiquitin independent manner during conditions of cellular stress such as DNA damage.	5	9	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	5	6	8	9
Taken together , these findings indicate that TSPY1 can regulate the cell cycle and apoptosis by suppressing Usp7 mediated p53 function , promoting the proliferation of mouse spermatogonia .	Taken together, these findings indicate that TSPY1 can regulate the cell cycle and apoptosis by suppressing Usp7 mediated p53 function, promoting the proliferation of mouse spermatogonia.	16	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	Usp7	Usp7	Usp7	p53	p53	p53	17	18	19	20
Inhibiting USP7 with the small-molecule inhibitor P22077 attenuates the p53 dependent apoptotic pathway by destabilizing Tip60 .	Inhibiting USP7 with the small-molecule inhibitor P22077 attenuates the p53 dependent apoptotic pathway by destabilizing Tip60.	0	12	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	1	2	9	10
25 USP7 deficiency in mouse embryonic fibroblasts ( MEFs ) greatly reduces the half-life of MDM2 and activates p53 .	25 USP7 deficiency in mouse embryonic fibroblasts (MEFs) greatly reduces the half-life of MDM2 and activates p53.	1	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	1	2	18	19
Hdm2 is preferentially targeted by USP7 over p53 under normal unstressed conditions ; however , USP7 targets p53 in response to DNA damage .	Hdm2 is preferentially targeted by USP7 over p53 under normal unstressed conditions; however, USP7 targets p53 in response to DNA damage.	11	19	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	15	16	17	18
It is also possible that HAUSP mediated p53 effects could be tissue specific , and more recently it was shown that neural cell specific inactivation of HAUSP in mice caused p53 dependent hypoplasia and brain development deficiencies [ XREF_BIBR ] .	It is also possible that HAUSP mediated p53 effects could be tissue specific, and more recently it was shown that neural cell specific inactivation of HAUSP in mice caused p53 dependent hypoplasia and brain development deficiencies [XREF_BIBR].	5	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	5	6	7	8
Indeed , USP7 overexpression increases the steady-state levels of the Mdm2 and p53 protein .	Indeed, USP7 overexpression increases the steady-state levels of the Mdm2 and p53 protein.	2	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7 overexpression	usp7	p53	p53	p53	2	3	12	13
The USP7 deubiquitinase is known to modulate the p53 pathway both by protecting p53 from MDM2 mediated degradation and MDM2 from auto-ubiquitination .	The USP7 deubiquitinase is known to modulate the p53 pathway both by protecting p53 from MDM2 mediated degradation and MDM2 from auto-ubiquitination.	1	9	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	1	2	8	9
TSPY1 suppresses USP7 mediated p53 function and promotes spermatogonial proliferation .	TSPY1 suppresses USP7 mediated p53 function and promotes spermatogonial proliferation.	1	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	2	3	4	5
These results uncover a new layer of the p53 transcriptional program mediated by USP7 , which restrains relaxation of local chromatin conformation at p53 target promoters .	These results uncover a new layer of the p53 transcriptional program mediated by USP7, which restrains relaxation of local chromatin conformation at p53 target promoters.	8	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	13	14	8	9
However , USP7 deficiency paradoxically promotes p53 stabilization .	However, USP7 deficiency paradoxically promotes p53 stabilization.	2	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	2	3	6	7
These results indicate that HAUSP mediated p53 regulation is crucial for brain development , and also suggest that both the p53 dependent and the p53 independent functions of HAUSP contribute to the neonatal lethality of hausp-mutant mice .	These results indicate that HAUSP mediated p53 regulation is crucial for brain development, and also suggest that both the p53 dependent and the p53 independent functions of HAUSP contribute to the neonatal lethality of hausp-mutant mice.	4	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	4	5	6	7
Under conditions of genotoxic stress , however , the expression of ABRO1 is rapidly induced by DNA damage , and ABRO1 translocates into the nucleus , thereby promoting USP7 targeting of p53 and antagonizing the ubiquitination modification of MDM2 and p53 .	Under conditions of genotoxic stress, however, the expression of ABRO1 is rapidly induced by DNA damage, and ABRO1 translocates into the nucleus, thereby promoting USP7 targeting of p53 and antagonizing the ubiquitination modification of MDM2 and p53.	28	32	targeting	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	28	29	31	32
The role of HAUSP in the p53 pathway appears to be unique : on the one hand , overexpression of HAUSP stabilizes both p53 and MDM2 and , more importantly , activates p53 ; on the other hand , HAUSP ablation destabilizes MDM2 and activates p53 XREF_BIBR , XREF_BIBR .	The role of HAUSP in the p53 pathway appears to be unique : on the one hand, overexpression of HAUSP stabilizes both p53 and MDM2 and, more importantly, activates p53; on the other hand, HAUSP ablation destabilizes MDM2 and activates p53 XREF_BIBR, XREF_BIBR.	18	33	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	overexpression of HAUSP	hausp	p53	p53	p53	20	21	32	33
These findings provide the first evidence that TSPY1 , in addition to TSPYL5 , can promote the ubiquitin mediated degradation of USP7 , suggesting TSPYL5 independent regulation of USP7 mediated p53 function by TSPY1 .	These findings provide the first evidence that TSPY1, in addition to TSPYL5, can promote the ubiquitin mediated degradation of USP7, suggesting TSPYL5 independent regulation of USP7 mediated p53 function by TSPY1.	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	28	29	30	31
ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage .	ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage.	2	11	Activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	6	7	10	11
The findings suggest an additional mechanism underlying the regulation of spermatogonial p53 function , indicating the significance of TSPY1 in germline homeostasis maintenance and the potential of TSPY1 in regulating human spermatogonial proliferation via the USP7 mediated p53 signaling pathway .	The findings suggest an additional mechanism underlying the regulation of spermatogonial p53 function, indicating the significance of TSPY1 in germline homeostasis maintenance and the potential of TSPY1 in regulating human spermatogonial proliferation via the USP7 mediated p53 signaling pathway.	32	39	mediated	Positive_early_activation	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	35	36	37	38
In contrast , a more modest reduction in HAUSP causes a decrease in both MDM2 and p53 stability , suggesting that , under these conditions , sufficient MDM2 remains to degrade p53 .	In contrast, a more modest reduction in HAUSP causes a decrease in both MDM2 and p53 stability, suggesting that, under these conditions, sufficient MDM2 remains to degrade p53.	6	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	8	9	16	17
Expression of the apoptosis regulator p53 is governed by minute double minute 2 ( MDM2 ) , an E3 enzyme that targets p53 for ubiquitination and proteasomal processing , and by the deubiquitinating enzyme , herpesvirus associated ubiquitin specific protease ( HAUSP ) , which rescues p53 by removing ubiquitin chains from it .	Expression of the apoptosis regulator p53 is governed by minute double minute 2 (MDM2), an E3 enzyme that targets p53 for ubiquitination and proteasomal processing, and by the deubiquitinating enzyme, herpesvirus associated ubiquitin specific protease (HAUSP), which rescues p53 by removing ubiquitin chains from it.	39	47	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	41	42	46	47
Here , we show that guanosine 5 '-monophosphate synthase ( GMPS ) is required for USP7 mediated stabilization of p53 .	Here, we show that guanosine 5 '-monophosphate synthase (GMPS) is required for USP7 mediated stabilization of p53.	15	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	15	16	19	20
Impact of TSPY1 on mouse spermatogonia by regulating Usp7 mediated p53 function .	Impact of TSPY1 on mouse spermatogonia by regulating Usp7 mediated p53 function.	7	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	Usp7	Usp7	Usp7	p53	p53	p53	8	9	10	11
HAUSP strongly stabilizes p53 even in the presence of excess Mdm2 , and also induces p53 dependent cell growth repression and apoptosis .	HAUSP strongly stabilizes p53 even in the presence of excess Mdm2, and also induces p53 dependent cell growth repression and apoptosis.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	0	1	15	16
Although future investigations are required to identify the key substrates for HAUSP mediated p53 independent function , our study provides strong evidence that the HAUSP/Mdm2/p53 interplay represents the major role for HAUSP in vivo .	Although future investigations are required to identify the key substrates for HAUSP mediated p53 independent function, our study provides strong evidence that the HAUSP/Mdm2/p53 interplay represents the major role for HAUSP in vivo.	6	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	11	12	13	14
This is underscored by recent findings showing that HAUSP can be used to therapeutically target p53 independent apoptosis responses in certain tumors .	This is underscored by recent findings showing that HAUSP can be used to therapeutically target p53 independent apoptosis responses in certain tumors.	8	18	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	8	9	15	16
HAUSP , a nuclear ubiquitin specific protease , targets p53 and Mdm2 as substrates and , in concert with Mdm2 , plays a dynamic role in p53 functionality .	HAUSP, a nuclear ubiquitin specific protease, targets p53 and Mdm2 as substrates and, in concert with Mdm2, plays a dynamic role in p53 functionality.	0	21	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	0	1	9	10
USP7 stabilizes the E3 ligase MDM2 due to its deubiquitinating activity , and hence indirectly leads to enhanced p53 proteasomal degradation .	USP7 stabilizes the E3 ligase MDM2 due to its deubiquitinating activity, and hence indirectly leads to enhanced p53 proteasomal degradation.	0	20	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	0	1	18	19
Taken together , our results show that USP7 can promote p53 function in a manner that is independent of the interaction through the USP7-NTD and deubiquitylation by the catalytic domain .	Taken together, our results show that USP7 can promote p53 function in a manner that is independent of the interaction through the USP7-NTD and deubiquitylation by the catalytic domain.	7	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	7	8	10	11
From a functional perspective , we speculate that , WDR79 , a scaffold protein with multiple WD-repeat domains , may form a platform to actively recruit or tether USP7 and its targets Mdm2 and/or p53 from the nucleoplasm , which facilitates the USP7 mediated stabilization of Mdm2 and p53 .	From a functional perspective, we speculate that, WDR79, a scaffold protein with multiple WD-repeat domains, may form a platform to actively recruit or tether USP7 and its targets Mdm2 and/or p53 from the nucleoplasm, which facilitates the USP7 mediated stabilization of Mdm2 and p53.	41	49	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	42	43	48	49
Roles of HAUSP mediated p53 regulation in central nervous system development .	Roles of HAUSP mediated p53 regulation in central nervous system development.	0	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	2	3	4	5
Inactivation of HAUSP in vivo modulates p53 function .	Inactivation of HAUSP in vivo modulates p53 function.	0	7	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	2	3	6	7
The fact that STIP is involved in two different ternary complexes raises the possibility that this interaction may facilitate the USP7 mediated the stabilization of Mdm2 and p53 .	The fact that STIP is involved in two different ternary complexes raises the possibility that this interaction may facilitate the USP7 mediated the stabilization of Mdm2 and p53.	19	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	20	21	27	28
However coexpression of USP7-CTD with p53 resulted in a 5-fold increase in luciferase activity , indicating that the USP7-CTD can stimulate p53 transactivation from the p21 promoter .	However coexpression of USP7-CTD with p53 resulted in a 5-fold increase in luciferase activity, indicating that the USP7-CTD can stimulate p53 transactivation from the p21 promoter.	17	22	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7-CTD	USP7-CTD	USP7-CTD	p53	p53	p53	18	19	21	22
Initially , USP7 was believed to primarily deubiquitinate p53 , increasing the level of p53 [ XREF_BIBR ] .	Initially, USP7 was believed to primarily deubiquitinate p53, increasing the level of p53 [XREF_BIBR].	2	16	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7 was believed to primarily deubiquitinate p53	usp7	p53	p53	p53	2	3	14	15
This has been described for deubiquitinating enzymes such as HAUSP , which rescues the tumor suppressor p53 by removing ubiquitin moieties that would otherwise target it for degradation by the proteasome .	This has been described for deubiquitinating enzymes such as HAUSP, which rescues the tumor suppressor p53 by removing ubiquitin moieties that would otherwise target it for degradation by the proteasome.	6	17	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	9	10	14	17
USP7 promotes the deubiquitination of : i ) p53 , increasing its stability via MDM2 ; ii ) PTEN , favoring its shuttling from the nucleus into the cytoplasm ; iii ) FOXOs , favoring changes in cellular compartmentalization .	USP7 promotes the deubiquitination of : i) p53, increasing its stability via MDM2; ii) PTEN, favoring its shuttling from the nucleus into the cytoplasm; iii) FOXOs, favoring changes in cellular compartmentalization.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	0	1	8	9
These findings strongly support the potential of TSPY1 function in the regulation of human spermatogonial proliferation by suppressing USP7 mediated p53 function .	These findings strongly support the potential of TSPY1 function in the regulation of human spermatogonial proliferation by suppressing USP7 mediated p53 function.	17	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	18	19	20	21
The data obtained from the present study did not demonstrate whether p53 upregulation is directly regulated by HAUSP activity or is dependent on the more complex BCR , ABL , HAUSP , MDM2 , and p53 network , but the upregulation in p53 levels supports the assessment of HAUSP inhibitors in the clinical setting .	The data obtained from the present study did not demonstrate whether p53 upregulation is directly regulated by HAUSP activity or is dependent on the more complex BCR, ABL, HAUSP, MDM2, and p53 network, but the upregulation in p53 levels supports the assessment of HAUSP inhibitors in the clinical setting.	11	18	directly regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	17	18	11	12
Furthermore , the effect of USP7 on Mdm2 and p53 was significantly diminished when STIP was knocked down by shRNA , indicating that STIP plays a significant facilitating role in USP7 mediated stabilization of Mdm2 and P53 .	Furthermore, the effect of USP7 on Mdm2 and p53 was significantly diminished when STIP was knocked down by shRNA, indicating that STIP plays a significant facilitating role in USP7 mediated stabilization of Mdm2 and P53.	28	37	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	P53	P53	P53	30	31	36	37
We also find that ING1 physically interacts with herpesvirus associated ubiquitin specific protease ( HAUSP ) , a p53 and MDM2 deubiquitinase ( DUB ) , and knockdown of HAUSP blocks the ability of ING1 to stabilize p53 .	We also find that ING1 physically interacts with herpesvirus associated ubiquitin specific protease (HAUSP), a p53 and MDM2 deubiquitinase (DUB), and knockdown of HAUSP blocks the ability of ING1 to stabilize p53.	27	38	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	29	30	37	38
HAUSP also modulates p53 stability indirectly by deubiquitination and stabilization of Hdm2 .	HAUSP also modulates p53 stability indirectly by deubiquitination and stabilization of Hdm2.	0	4	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	0	1	3	4
Although both TSPY1 and TSPYL5 regulate USP7 mediated p53 activity , the influence of TSPY1 , compared to TSPYL5 , on p53 function may be more dynamic .	Although both TSPY1 and TSPYL5 regulate USP7 mediated p53 activity, the influence of TSPY1, compared to TSPYL5, on p53 function may be more dynamic.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	6	7	8	9
As previously shown , a modest reduction in Hausp by RNA interference decreased p53 stability .	As previously shown, a modest reduction in Hausp by RNA interference decreased p53 stability.	6	14	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Hausp	Hausp	Hausp	p53	p53	p53	8	9	13	14
Furthermore , this feedback regulation is specific to Mdm2 ; in HeLa cells , where p53 is preferentially degraded by viral E6 dependent ubiquitination , depletion of HAUSP fails to activate p53 .	Furthermore, this feedback regulation is specific to Mdm2; in HeLa cells, where p53 is preferentially degraded by viral E6 dependent ubiquitination, depletion of HAUSP fails to activate p53.	25	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	27	28	31	32
In addition to the ability of HAUSP to deubiquitinate PTEN and the relevance of the BCR-ABL/HAUSP/PTEN network in CML , HAUSP is also able to target p53 .	In addition to the ability of HAUSP to deubiquitinate PTEN and the relevance of the BCR-ABL/HAUSP/PTEN network in CML, HAUSP is also able to target p53.	20	27	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	20	21	26	27
Notably , when simulating TSPY1 function in Tspy1 deficient spermatogonia cells derived from mouse testes , we observed the promotion of spermatogonial proliferation by TSPY1 along with signaling changes in the Usp7 mediated p53 pathway .	Notably, when simulating TSPY1 function in Tspy1 deficient spermatogonia cells derived from mouse testes, we observed the promotion of spermatogonial proliferation by TSPY1 along with signaling changes in the Usp7 mediated p53 pathway.	28	34	mediated	Positive_early_activation	Positive_activation	Positive_activation	Usp7	Usp7	Usp7	p53	p53	p53	31	32	33	34
Correspondingly , it is highly possible that the regulation of USP7 mediated p53 function by TSPY1 is an important molecular mechanism underlying its function in human spermatogenesis .	Correspondingly, it is highly possible that the regulation of USP7 mediated p53 function by TSPY1 is an important molecular mechanism underlying its function in human spermatogenesis.	8	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	10	11	12	13
Next we tested whether USP7 enhanced p53 function by examining the induction of p21 in H1299 cells after transfection of a p53 expressing plasmid alone or in combination with a plasmid expressing either WT USP7 or a USP7 mutant ( XREF_FIG ) .	Next we tested whether USP7 enhanced p53 function by examining the induction of p21 in H1299 cells after transfection of a p53 expressing plasmid alone or in combination with a plasmid expressing either WT USP7 or a USP7 mutant (XREF_FIG).	4	7	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	4	5	6	7
HAUSP was originally reported as an MDM2 antagonist because overexpression of HAUSP promotes stability of p53 .	HAUSP was originally reported as an MDM2 antagonist because overexpression of HAUSP promotes stability of p53.	9	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	overexpression of HAUSP	hausp	p53	p53	p53	11	12	15	16
Taken together , the observations reveal the significance of TSPY1 as a suppressor of USP7 mediated p53 function in inhibiting p53 dependent cell proliferation arrest .	Taken together, the observations reveal the significance of TSPY1 as a suppressor of USP7 mediated p53 function in inhibiting p53 dependent cell proliferation arrest.	12	17	mediated	Positive_early_activation	Positive_activation	Negative_activation	USP7	USP7	USP7	p53	p53	p53	14	15	16	17
USP7 can Stimulate p53 Function Independent of its Catalytic Activity .	USP7 can Stimulate p53 Function Independent of its Catalytic Activity.	0	5	Stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	0	1	3	4
Mechanisms of action underlying the regulation of USP7 mediated p53 function by TSPY1 .	Mechanisms of action underlying the regulation of USP7 mediated p53 function by TSPY1.	0	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	7	8	9	10
Another contrasting possibility is that HAUSP can target both p53 and MDM2 for deubiquitylation and thus may play a dynamic role in the p53-MDM2 pathway [ XREF_BIBR ] .	Another contrasting possibility is that HAUSP can target both p53 and MDM2 for deubiquitylation and thus may play a dynamic role in the p53-MDM2 pathway [XREF_BIBR].	5	11	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	5	6	9	10
XREF_BIBR , XREF_BIBR , XREF_BIBR Although VEGF-D does not activate mouse VEGFR-2 , XREF_BIBR , XREF_BIBR it is possible that VEGFR-3 is involved in the angiogenic response .	XREF_BIBR, XREF_BIBR, XREF_BIBR Although VEGF-D does not activate mouse VEGFR-2, XREF_BIBR, XREF_BIBR it is possible that VEGFR-3 is involved in the angiogenic response.	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR-2	VEGFR-2	VEGFR-2	6	7	11	12
Importantly , this study demonstrated that VEGFR2 is associated with an active conformer of alpha v beta 3 , which is detected using an engineered Fab fragment of WOW-1 antibody [ XREF_BIBR ] and this association is enhanced upon treatment with VEGF-A or VEGF-DDeltaNDeltaC ( a truncated variant of VEGF-D that preferentially activated VEGFR2 ) [ XREF_BIBR ] .	Importantly, this study demonstrated that VEGFR2 is associated with an active conformer of alpha v beta 3, which is detected using an engineered Fab fragment of WOW-1 antibody [XREF_BIBR] and this association is enhanced upon treatment with VEGF-A or VEGF-DDeltaNDeltaC (a truncated variant of VEGF-D that preferentially activated VEGFR2) [XREF_BIBR].	47	54	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-D	VEGF-D	VEGF-D	VEGFR2	VEGFR2	VEGFR2	49	50	53	54
In a more recent study , a vasoactive intestinal peptide ( VIP ) analogue ( TP3939 ) targeting VPAC1 receptor , radiolabeled with 64 Cu was evaluated in mice carrying PC3 xenografts .	In a more recent study, a vasoactive intestinal peptide (VIP) analogue (TP3939) targeting VPAC1 receptor, radiolabeled with 64 Cu was evaluated in mice carrying PC3 xenografts.	11	19	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	11	12	18	19
Collectively , we showed that neurally released VIP can activate neurons expressing VPAC1 and/or VPAC2 receptors to modulate purine-release onto glia .	Collectively, we showed that neurally released VIP can activate neurons expressing VPAC1 and/or VPAC2 receptors to modulate purine-release onto glia.	6	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	7	8	12	13
SKNSH and VPAC1 cells treated with VIP were observed to express a more differentiated phenotype compared to wild type cells as characterized by an increase in tissue transglutaminase II and a decrease in bcl-2 immunostaining .	SKNSH and VPAC1 cells treated with VIP were observed to express a more differentiated phenotype compared to wild type cells as characterized by an increase in tissue transglutaminase II and a decrease in bcl-2 immunostaining.	2	7	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	6	7	2	3
VIP effectively activates VPAC1 and VPAC2 receptors , but is much less effective in activating the PACAP selective PAC1 receptor .	VIP effectively activates VPAC1 and VPAC2 receptors, but is much less effective in activating the PACAP selective PAC1 receptor.	0	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	0	1	3	4
VIP induced activation of VPAC1 in bone marrow derived DCs induces a tolerogenic phenotype with low levels of costimulatory molecules CD80 , CD86 , and CD40 , and high levels of the anti-inflammatory cytokine IL-10 .	VIP induced activation of VPAC1 in bone marrow derived DCs induces a tolerogenic phenotype with low levels of costimulatory molecules CD80, CD86, and CD40, and high levels of the anti-inflammatory cytokine IL-10.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	0	1	4	5
Even VIP which can stimulate both VPAC1 and VPAC2 may preferentially stimulate VPAC2 due to its increased expression on activated T-cells ; and thus , could provide some protection at this time .	Even VIP which can stimulate both VPAC1 and VPAC2 may preferentially stimulate VPAC2 due to its increased expression on activated T-cells; and thus, could provide some protection at this time.	0	26	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	1	2	6	7
We had previously reported that VIP stimulates the VPAC1 receptor , PKCepsilon signaling cascade , and increases CFTR stability and function at the apical membrane of airway epithelial cells by reducing its internalization rate .	We had previously reported that VIP stimulates the VPAC1 receptor, PKCepsilon signaling cascade, and increases CFTR stability and function at the apical membrane of airway epithelial cells by reducing its internalization rate.	5	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	5	6	8	9
So the nuclear translocation of VPAC1 induced by VIP , to our opinion , is involved in the formation of the anti-apoptotic activity of VPAC1 maybe by contributing to the significant up-regulation of intracellular Bcl-2 .	So the nuclear translocation of VPAC1 induced by VIP, to our opinion, is involved in the formation of the anti-apoptotic activity of VPAC1 maybe by contributing to the significant up-regulation of intracellular Bcl-2.	3	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	8	9	5	6
In cells that were not transfected with Galpha16 and expressed a similar density of receptors , the VIP induced [ Ca2+ ] i ncrease was higher in VPAC1 than in VPAC2 receptor expressing cells .	In cells that were not transfected with Galpha16 and expressed a similar density of receptors, the VIP induced [Ca2+] i ncrease was higher in VPAC1 than in VPAC2 receptor expressing cells.	16	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	17	18	27	28
These data provide evidence showing that the loss of the VPAC2 receptor does not appear to significantly alter the dynamics of thymocyte maturation and suggests that any VIP effects on thymocyte development are mediated though VPAC1 .	These data provide evidence showing that the loss of the VPAC2 receptor does not appear to significantly alter the dynamics of thymocyte maturation and suggests that any VIP effects on thymocyte development are mediated though VPAC1.	27	36	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	27	28	35	36
The very similar immune effects seen in VIPhyb treated mice ( in which VPAC1 , VPAC2 and PAC1 receptors are blocked ) compared with VIP-KO mice ( lacking VIP and PHI ) suggests that VIP ( or PHI ) signaling to VPAC1 and/or VPAC2 is most relevant to regulating immune responses in the mCMV infection models .	The very similar immune effects seen in VIPhyb treated mice (in which VPAC1, VPAC2 and PAC1 receptors are blocked) compared with VIP-KO mice (lacking VIP and PHI) suggests that VIP (or PHI) signaling to VPAC1 and/or VPAC2 is most relevant to regulating immune responses in the mCMV infection models.	34	43	signaling	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	34	35	41	42
Vasoactive intestinal peptide can activate VPAC1 , VPAC2 and the NPR-C receptor .	Vasoactive intestinal peptide can activate VPAC1, VPAC2 and the NPR-C receptor.	0	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vasoactive intestinal peptide	Vasoactive intestinal peptide	Vasoactive intestinal peptide	VPAC1	VPAC1	VPAC1	0	3	5	6
VIP 28 , a VIP analog radiolabeled with 64 Cu , specifically targets VPAC1 receptors for visualization of PCa by PET .	VIP 28, a VIP analog radiolabeled with 64 Cu, specifically targets VPAC1 receptors for visualization of PCa by PET.	0	14	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	0	1	13	14
A low concentration of VIP ( 1 nM ) likely activates both VPAC1 and VPAC2-Rs as an increase is also observed using either the VPAC1 selective agonist [ Ala 11,22,28 ] VIP or the VPAC2 selective agonist Bay55-9837 .	A low concentration of VIP (1 nM) likely activates both VPAC1 and VPAC2-Rs as an increase is also observed using either the VPAC1 selective agonist [Ala 11,22,28] VIP or the VPAC2 selective agonist Bay55-9837.	2	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	4	5	12	13
However , it was later shown that depletion of HAUSP promotes MDM2 destabilization and leads to p53 activation .	However, it was later shown that depletion of HAUSP promotes MDM2 destabilization and leads to p53 activation.	7	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HAUSP	HAUSP	HAUSP	MDM2	MDM2	MDM2	9	10	11	12
Supporting evidence suggests that an inhibitor of USP7 would act to abrogate the action of Hdm2 , and thereby elevate levels of the p53 protein , with associated therapeutic benefits in cancer and potentially other diseases .	Supporting evidence suggests that an inhibitor of USP7 would act to abrogate the action of Hdm2, and thereby elevate levels of the p53 protein, with associated therapeutic benefits in cancer and potentially other diseases.	5	16	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	Hdm2	Hdm2	Hdm2	7	8	15	16
As Hdm2 induced autoubiquitylation leads to its destruction , inhibitors of Usp7 promote the degradation of Hdm2 , which in turn stabilizes Hdm2 substrates , particularly p53 .	As Hdm2 induced autoubiquitylation leads to its destruction, inhibitors of Usp7 promote the degradation of Hdm2, which in turn stabilizes Hdm2 substrates, particularly p53.	9	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Usp7	Usp7	Usp7	Hdm2	Hdm2	Hdm2	11	12	16	17
This study provides an example of an ubiquitin ligase ( Mdm2 ) that is directly regulated by a deubiquitinase ( HAUSP ) and also reveals a dynamic role of HAUSP in the p53-Mdm2 pathway .	This study provides an example of an ubiquitin ligase (Mdm2) that is directly regulated by a deubiquitinase (HAUSP) and also reveals a dynamic role of HAUSP in the p53-Mdm2 pathway.	4	21	directly regulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	Mdm2	Mdm2	Mdm2	20	21	10	11
This interference is first evidenced by the response to oxidative DNA damage and modulation of DNA accessibility to base excision repair ( BER ) machinery , which is an indirect effect due to HAUSP mediated MDM2 regulation .	This interference is first evidenced by the response to oxidative DNA damage and modulation of DNA accessibility to base excision repair (BER) machinery, which is an indirect effect due to HAUSP mediated MDM2 regulation.	31	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	MDM2	MDM2	MDM2	33	34	35	36
This can be explained in part by the fact that USP7 also binds to polyubiquitinated Mdm2 and promotes Mdm2 stability .	This can be explained in part by the fact that USP7 also binds to polyubiquitinated Mdm2 and promotes Mdm2 stability.	10	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7 also binds to polyubiquitinated Mdm2	usp7	Mdm2	Mdm2	mdm2	10	11	18	19
Both USP2 and USP7 and HAUSP target MDM2 and lead to its degradation XREF_BIBR .	Both USP2 and USP7 and HAUSP target MDM2 and lead to its degradation XREF_BIBR.	1	9	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	MDM2	MDM2	MDM2	5	6	7	8
In unstressed cells , SUV39H1 is deubiquitinated and protected from MDM2 mediated degradation by HAUSP , promoting the repression of p53 responsive gene transcription .	In unstressed cells, SUV39H1 is deubiquitinated and protected from MDM2 mediated degradation by HAUSP, promoting the repression of p53 responsive gene transcription.	6	15	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	MDM2	MDM2	MDM2	14	15	10	11
This observation indicates that Mdm2 may recruit nucleolin to HAUSP , and that HAUSP then increases the stability of both Mdm2 and nucleolin via its deubiquitinating enzyme activity .	This observation indicates that Mdm2 may recruit nucleolin to HAUSP, and that HAUSP then increases the stability of both Mdm2 and nucleolin via its deubiquitinating enzyme activity.	13	22	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	Mdm2	Mdm2	Mdm2	13	14	20	21
Examples of MDM2 regulators are : ARF4 that may dampen the p53 pathway by releasing MDM2 ; HAUSP that targets MDM2 resulting in its stabilization and negative regulation of the p53 pathway ; and WIP1 , a phosphatase that dephosphorylates MDM2 preventing prolonged p53-pathway activation [ XREF_BIBR ] .	Examples of MDM2 regulators are : ARF4 that may dampen the p53 pathway by releasing MDM2; HAUSP that targets MDM2 resulting in its stabilization and negative regulation of the p53 pathway; and WIP1, a phosphatase that dephosphorylates MDM2 preventing prolonged p53-pathway activation [XREF_BIBR].	6	21	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	HAUSP	HAUSP	MDM2	MDM2	MDM2	17	18	20	21
It has also been shown that the inhibition USP7 and USP2a which are de-ubiquitinases of Hdm2 , increases Hdm2 proteolysis and stabilizes p53 levels in multiple myeloma cells enabling the initiation of apoptosis .	It has also been shown that the inhibition USP7 and USP2a which are de-ubiquitinases of Hdm2, increases Hdm2 proteolysis and stabilizes p53 levels in multiple myeloma cells enabling the initiation of apoptosis.	6	21	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	Hdm2	Hdm2	Hdm2	8	9	18	19
However , coexpression of USP10 or HAUSP , but not USP10 CA or USP10Delta1-100 , significantly reversed the inhibitory effect of Mdm2 on p53 mediated apoptosis .	However, coexpression of USP10 or HAUSP, but not USP10 CA or USP10Delta1-100, significantly reversed the inhibitory effect of Mdm2 on p53 mediated apoptosis.	2	22	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	coexpression of USP10 or HAUSP	hausp	Mdm2	Mdm2	mdm2	6	7	21	22
Hence , inhibition of Usp7 is thought to inactivate Mdm2 and thereby activate p53 , resulting in inhibition of cell cycle progression and tumor cell apoptosis .	Hence, inhibition of Usp7 is thought to inactivate Mdm2 and thereby activate p53, resulting in inhibition of cell cycle progression and tumor cell apoptosis.	2	10	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Usp7	Usp7	Usp7	Mdm2	Mdm2	Mdm2	4	5	9	10
In this light , it is interesting that HAUSP ( USP7 ) , a DUB originally proposed to counteract MDM2 dependent p53 ubiquination , has since been found to target MDM2 as its prime substrate , reconciling contradictory observations that p53 was stabilized in cells of diminished HAUSP .	In this light, it is interesting that HAUSP (USP7), a DUB originally proposed to counteract MDM2 dependent p53 ubiquination, has since been found to target MDM2 as its prime substrate, reconciling contradictory observations that p53 was stabilized in cells of diminished HAUSP.	8	31	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	MDM2	MDM2	MDM2	10	11	30	31
Interestingly , beclin-1 and UVRAG also increases the association of hVps34 with hVps15 .	Interestingly, beclin-1 and UVRAG also increases the association of hVps34 with hVps15.	2	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	hVps34	hVps34	hVps34	4	5	10	11
However , beclin-1 and UVRAG caused a 2-fold activation of hVps34 in cells co-expressing hVps15 .	However, beclin-1 and UVRAG caused a 2-fold activation of hVps34 in cells co-expressing hVps15.	2	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	hVps34	hVps34	hVps34	4	5	10	11
Taken together with the in vitro data , this suggests that mTOR mediated UVRAG phosphorylation at S550 and S571 enhances VPS34 activity .	Taken together with the in vitro data, this suggests that mTOR mediated UVRAG phosphorylation at S550 and S571 enhances VPS34 activity.	11	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	mTOR mediated UVRAG phosphorylation at S550	uvrag	VPS34	VPS34	vps34	13	14	20	21
Upon phosphorylation by MTORC1 , UVRAG activates PIK3C3 ; mutant versions of UVRAG result in reduced PIK3C3 activity , which in turn reduces the lysosomal pool of phosphatidylinositol 3-phopshate ( PtdIns3P ) causing increased lysosomal tubulation and failure to generate normal lysosomes during starvation .	Upon phosphorylation by MTORC1, UVRAG activates PIK3C3; mutant versions of UVRAG result in reduced PIK3C3 activity, which in turn reduces the lysosomal pool of phosphatidylinositol 3-phopshate (PtdIns3P) causing increased lysosomal tubulation and failure to generate normal lysosomes during starvation.	5	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	PIK3C3	PIK3C3	PIK3C3	5	6	7	8
The UVRAG associated PI3K and III complex component BIF-1 ( endophilin B1/BAX interacting factor 1 ) supports membrane trafficking events by enhancing VPS34 kinase activity and PtdIns3P-production [ XREF_BIBR ] in addition to its membrane sculpturing abilities [ XREF_BIBR , XREF_BIBR ] .	The UVRAG associated PI3K and III complex component BIF-1 (endophilin B1/BAX interacting factor 1) supports membrane trafficking events by enhancing VPS34 kinase activity and PtdIns3P-production [XREF_BIBR] in addition to its membrane sculpturing abilities [XREF_BIBR, XREF_BIBR].	0	24	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	VPS34	VPS34	VPS34	1	2	22	23
UVRAG phosphorylation enhances VPS34 lipid kinase activity .	UVRAG phosphorylation enhances VPS34 lipid kinase activity.	0	6	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG phosphorylation	uvrag	VPS34	VPS34	vps34	0	1	3	4
Another function of UVRAG is to stimulate the activity of vacuolar protein sorting 34kDa ( Vps34 , also known as phosphatidylinositol 3-kinase class III ) , a critical component for autophagy .	Another function of UVRAG is to stimulate the activity of vacuolar protein sorting 34kDa (Vps34, also known as phosphatidylinositol 3-kinase class III), a critical component for autophagy.	1	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	Vps34	Vps34	Vps34	3	4	15	16
UVRAG has been shown to enhance VPS34 activity .	UVRAG has been shown to enhance VPS34 activity.	0	7	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	VPS34	VPS34	VPS34	0	1	6	7
Indeed , it has recently been shown that UVRAG , together with Beclin1 , promotes the activation of PI3KC3 in a Vps15 dependent manner .	Indeed, it has recently been shown that UVRAG, together with Beclin1, promotes the activation of PI3KC3 in a Vps15 dependent manner.	8	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	PI3KC3	PI3KC3	PI3KC3	8	9	18	19
When phosphorylated by mTORC1 , UVRAG enhances Vps34 lipid kinase activity which appears to be critical for tubule scission [ XREF_BIBR ] .	When phosphorylated by mTORC1, UVRAG enhances Vps34 lipid kinase activity which appears to be critical for tubule scission [XREF_BIBR].	5	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	Vps34	Vps34	Vps34	5	6	7	8
Interaction of Beclin1 with Atg14 or with UVRAG with Bif1 via UVRAG promotes PIK3C3 kinase activity [ XREF_BIBR - XREF_BIBR , XREF_BIBR ] .	Interaction of Beclin1 with Atg14 or with UVRAG with Bif1 via UVRAG promotes PIK3C3 kinase activity [XREF_BIBR - XREF_BIBR, XREF_BIBR].	9	15	promotes	Positive_activation_token_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	PIK3C3	PIK3C3	PIK3C3	11	12	13	14
Furthermore , UVRAG was originally found to interact with Beclin1 and enhance the interaction of Beclin1 with PI3KC3 to promote the activation of PI3KC3 and the formation of autophagosomes .	Furthermore, UVRAG was originally found to interact with Beclin1 and enhance the interaction of Beclin1 with PI3KC3 to promote the activation of PI3KC3 and the formation of autophagosomes.	2	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	Beclin1	Beclin1	Beclin1	2	3	15	16
Atg14L and UVRAG promote the transition of metastable homodimeric Beclin 1 to heterodimeric Beclin1-Atg14L and UVRAG assembly .	Atg14L and UVRAG promote the transition of metastable homodimeric Beclin 1 to heterodimeric Beclin1-Atg14L and UVRAG assembly.	0	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	Beclin 1	Beclin 1	Beclin 1	2	3	9	11
Complex II of VPS34 is similar to complex I , except ATG14 is replaced by UV radiation resistance associated gene protein ( UVRAG ) , which targets Beclin1 to the endosomes , and functions in vacuolar protein sorting and autophagy induction in mammalian cells .	Complex II of VPS34 is similar to complex I, except ATG14 is replaced by UV radiation resistance associated gene protein (UVRAG), which targets Beclin1 to the endosomes, and functions in vacuolar protein sorting and autophagy induction in mammalian cells.	20	28	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	Beclin1	Beclin1	Beclin1	22	23	27	28
The intimate coordination between the autophagic and endocytic pathways is further strengthened by the observation that UVRAG , which activates Beclin1 , also cooperates with the HOPS ( homotypic vacuole fusion and protein sorting ) tethering complex and the endosome associated PI3KC3 complex to facilitate autophagosomal maturation and membrane trafficking of multiple growth factor receptors , including the epidermal growth factor ( EGF ) receptor , probably via distinctly different mechanisms [ XREF_BIBR , XREF_BIBR ] .	The intimate coordination between the autophagic and endocytic pathways is further strengthened by the observation that UVRAG, which activates Beclin1, also cooperates with the HOPS (homotypic vacuole fusion and protein sorting) tethering complex and the endosome associated PI3KC3 complex to facilitate autophagosomal maturation and membrane trafficking of multiple growth factor receptors, including the epidermal growth factor (EGF) receptor, probably via distinctly different mechanisms [XREF_BIBR, XREF_BIBR].	16	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	Beclin1	Beclin1	Beclin1	16	17	20	21
Furthermore , UVRAG interacts not only with Beclin 1 but also with Bcl-xL , and overexpression of UVRAG partially rescued the internalization defect of Beclin 1 knockout cells during GAS infection .	Furthermore, UVRAG interacts not only with Beclin 1 but also with Bcl-xL, and overexpression of UVRAG partially rescued the internalization defect of Beclin 1 knockout cells during GAS infection.	15	27	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	overexpression of UVRAG	uvrag	Beclin 1	Beclin 1	beclin 1	17	18	24	26
Nucleation is dependent on a group of proteins including : class III phosphotidylinositol-3 kinase ( PI3K ) vacuolar protein sorting ( VPS ) 15 , Beclin-1 , activating molecule in BECN1 regulated autophagy protein 1 ( AMBRA1 ) , ultraviolet irradiation resistance associated gene ( UVRAG ) , ATG14L , and bax interacting factor 1 ( BIF-1 ) .	Nucleation is dependent on a group of proteins including : class III phosphotidylinositol-3 kinase (PI3K) vacuolar protein sorting (VPS) 15, Beclin-1, activating molecule in BECN1 regulated autophagy protein 1 (AMBRA1), ultraviolet irradiation resistance associated gene (UVRAG), ATG14L, and bax interacting factor 1 (BIF-1).	27	46	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	BECN1	BECN1	BECN1	45	46	30	31
Indeed , UVRAG has been proposed to induce Beclin1 conformational changes , thus activating Vps34 complex .	Indeed, UVRAG has been proposed to induce Beclin1 conformational changes, thus activating Vps34 complex.	2	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	Beclin1	Beclin1	Beclin1	2	3	8	9
UVRAG positively regulates BECN1 , suggesting that the interaction with BECN1 is necessary for the tumor suppressor function of UVRAG .	UVRAG positively regulates BECN1, suggesting that the interaction with BECN1 is necessary for the tumor suppressor function of UVRAG.	0	4	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	UVRAG	UVRAG	UVRAG	BECN1	BECN1	BECN1	0	1	3	4
RAP80 targets BRCA1 and Abraxas to ubiquitinated chromatin extending for a distance away from DSBs , whereas BRCA1 complexes containing BRCA2 and PALB2 or BRIP1 are thought to directly interact with DNA intermediates during homologous recombination dependent DNA repair .	RAP80 targets BRCA1 and Abraxas to ubiquitinated chromatin extending for a distance away from DSBs, whereas BRCA1 complexes containing BRCA2 and PALB2 or BRIP1 are thought to directly interact with DNA intermediates during homologous recombination dependent DNA repair.	0	8	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	0	1	2	3
The upstream regulator RAP80 is required to initially target BRCA1 and BARD1 and associated proteins to DNA double-strand breaks ; however , recent findings indicate that RAP80 does not remain as a fixed anchor of the BRCA1-A complex at foci , as generally presumed in the literature , but its interactions with BRCA1 and associated factors are transient and change after the complex forms ( XREF_FIG ) .	The upstream regulator RAP80 is required to initially target BRCA1 and BARD1 and associated proteins to DNA double-strand breaks; however, recent findings indicate that RAP80 does not remain as a fixed anchor of the BRCA1-A complex at foci, as generally presumed in the literature, but its interactions with BRCA1 and associated factors are transient and change after the complex forms (XREF_FIG).	0	13	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	3	4	9	10
Although the loss of RAP80 did not prevent the formation of BRCA1 IRIF , a significant decrease in foci intensity and the percentage of cells containing nuclei with > 5 BRCA1 + foci was observed in RAP80 -/- MEFs compared to WT MEFs 8 h after IR ( XREF_FIG ) .	Although the loss of RAP80 did not prevent the formation of BRCA1 IRIF, a significant decrease in foci intensity and the percentage of cells containing nuclei with> 5 BRCA1 + foci was observed in RAP80 -/- MEFs compared to WT MEFs 8 h after IR (XREF_FIG).	2	12	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RAP80	loss of RAP80	rap80	BRCA1	BRCA1	brca1	4	5	11	12
The DNA repair function of the breast cancer susceptibility protein BRCA1 depends in part on its interaction with RAP80 , which targets BRCA1 to DNA double strand breaks ( DSBs ) through recognition of K63 linked polyubiquitin chains .	The DNA repair function of the breast cancer susceptibility protein BRCA1 depends in part on its interaction with RAP80, which targets BRCA1 to DNA double strand breaks (DSBs) through recognition of K63 linked polyubiquitin chains.	11	29	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	18	19	22	23
However , deletion of RAP80 does not completely abolish the IR induced foci formation of BRCA1 , suggesting that alternative mechanism of recruitment of BRCA1 to DNA damage sites exists .	However, deletion of RAP80 does not completely abolish the IR induced foci formation of BRCA1, suggesting that alternative mechanism of recruitment of BRCA1 to DNA damage sites exists.	2	16	abolish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	4	5	15	16
This observation is consistent with a recent study showing that knockdown of RAP80 expression by siRNAs in U2OS cells did not prevent the formation of BRCA1 IRIF , but diminished the intensity of the foci and particularly reduced the retention of the foci at later time points .	This observation is consistent with a recent study showing that knockdown of RAP80 expression by siRNAs in U2OS cells did not prevent the formation of BRCA1 IRIF, but diminished the intensity of the foci and particularly reduced the retention of the foci at later time points.	12	26	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RAP80	RAP80 expression	rap80	BRCA1	BRCA1	brca1	12	13	25	26
Rap80 targets the breast cancer suppressor protein BRCA1 along with Abraxas and the BRCC36 deubiquitinating enzyme ( DUB ) to polyubiquitin structures at DNA double-strand breaks ( DSBs ) .	Rap80 targets the breast cancer suppressor protein BRCA1 along with Abraxas and the BRCC36 deubiquitinating enzyme (DUB) to polyubiquitin structures at DNA double-strand breaks (DSBs).	0	8	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Rap80	Rap80	Rap80	BRCA1	BRCA1	BRCA1	0	1	7	8
RAP80 targets BRCA1 to DNA breaks through its ability to act as a molecular bridge between poly-ubiquitylated histones and CCDC98 , the latter directly binds and recruits BRCA1 [ XREF_BIBR - XREF_BIBR ] .	RAP80 targets BRCA1 to DNA breaks through its ability to act as a molecular bridge between poly-ubiquitylated histones and CCDC98, the latter directly binds and recruits BRCA1 [XREF_BIBR - XREF_BIBR].	0	26	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	0	1	2	3
RAP80 prevents hyper-recombination by limiting the access of BRCA1 to end resected DSBs .	RAP80 prevents hyper-recombination by limiting the access of BRCA1 to end resected DSBs.	0	9	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	0	1	8	9
Loss of RAP80 impairs the IRIF of the BRCA1-A complex and BRCA1 dependent DNA damage response , which could be a molecular mechanism contributing to ovarian tumorigenesis .	Loss of RAP80 impairs the IRIF of the BRCA1-A complex and BRCA1 dependent DNA damage response, which could be a molecular mechanism contributing to ovarian tumorigenesis.	0	12	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RAP80	Loss of RAP80	rap80	BRCA1	BRCA1	brca1	2	3	11	12
USP9x has been reported to increase SMAD4 activity by removing an inhibitory ubiquitin moiety [ XREF_BIBR ] .	USP9x has been reported to increase SMAD4 activity by removing an inhibitory ubiquitin moiety [XREF_BIBR].	0	7	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP9x	USP9x	USP9x	SMAD4	SMAD4	SMAD4	0	1	6	7
3.5 USP9X targets SMAD4 for deubiquitylation in the TGFbeta pathway .	3.5 USP9X targets SMAD4 for deubiquitylation in the TGFbeta pathway.	1	5	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	USP9X	USP9X	USP9X	SMAD4	SMAD4	SMAD4	1	2	3	4
Removal of the mono-ubiquitin by the de-ubiquitinase FAM and USP9x restores Smad4 function [ XREF_BIBR ] .	Removal of the mono-ubiquitin by the de-ubiquitinase FAM and USP9x restores Smad4 function [XREF_BIBR].	3	12	restores	Positive_activation_token_1_verb	Positive_activation	Positive_activation	USP9x	USP9x	USP9x	Smad4	Smad4	Smad4	9	10	11	12
Thus , the de-ubiquitylase FAM and USP9 can remove K519 mono-ubiquitylation of Smad4 imposed by TIF1gamma , and thus restore Smad4 function .	Thus, the de-ubiquitylase FAM and USP9 can remove K519 mono-ubiquitylation of Smad4 imposed by TIF1gamma, and thus restore Smad4 function.	2	21	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAM	FAM	FAM	Smad4	Smad4	Smad4	4	5	20	21
USP9X was previously reported to regulate Smad4 transcriptional activity positively , thus we hypothesized that decreased USP9X expression would attenuate Smad4 function and TGF-beta responsiveness in HCC cell lines [ XREF_BIBR ] .	USP9X was previously reported to regulate Smad4 transcriptional activity positively, thus we hypothesized that decreased USP9X expression would attenuate Smad4 function and TGF-beta responsiveness in HCC cell lines [XREF_BIBR].	16	21	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	USP9X	USP9X expression	usp9x	Smad4	Smad4	smad4	16	17	20	21
Since USP9X was previously reported to positively regulate SMAD4 transcriptional activity 17 and SMAD4 is commonly mutated in PDA 4 , we hypothesized that Usp9x loss would attenuate Smad4 function or TGFbeta responsiveness in PDA cell lines .	Since USP9X was previously reported to positively regulate SMAD4 transcriptional activity 17 and SMAD4 is commonly mutated in PDA 4, we hypothesized that Usp9x loss would attenuate Smad4 function or TGFbeta responsiveness in PDA cell lines.	24	29	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Usp9x	Usp9x	Usp9x	Smad4	Smad4	Smad4	24	25	28	29
A recent study reported that USP9X activates SMAD4 by deubiquitination at K519 , resulting in the activation of SMAD2/3 , and promotion of TGFbeta pathway , which will induce cell apoptosis .	A recent study reported that USP9X activates SMAD4 by deubiquitination at K519, resulting in the activation of SMAD2/3, and promotion of TGFbeta pathway, which will induce cell apoptosis.	5	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP9X	USP9X	USP9X	SMAD4	SMAD4	SMAD4	5	6	7	8
Sall4 shows an interaction with Usp9x ( XREF_FIG B ) , an essential component of the TGF-beta and BMP signaling pathway , which activates Smad4 by removing a monoubiquitin group .	Sall4 shows an interaction with Usp9x (XREF_FIG B), an essential component of the TGF-beta and BMP signaling pathway, which activates Smad4 by removing a monoubiquitin group.	1	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Usp9x	Usp9x	Usp9x	Smad4	Smad4	Smad4	5	6	24	25
Data presented here suggest that Vav1 can also activate ERK in MCF-10A cells through an indirect pathway involving secretion of an EGF receptor ligand .	Data presented here suggest that Vav1 can also activate ERK in MCF-10A cells through an indirect pathway involving secretion of an EGF receptor ligand.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav1	Vav1	Vav1	ERK	ERK	ERK	5	6	9	10
Activation of Vav1 also stimulates MAPK signaling cascades , which may contribute to cancer by enhancing cell mitogenic properties .	Activation of Vav1 also stimulates MAPK signaling cascades, which may contribute to cancer by enhancing cell mitogenic properties.	0	7	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav1	Vav1	Vav1	MAPK	MAPK	MAPK	2	3	5	6
Once recruited , Vav1 may trigger the Rac1 --> PAK1 --> MEK --> ERK cascade that elicits cytotoxicity in human NK cells .	Once recruited, Vav1 may trigger the Rac1 --> PAK1 --> MEK --> ERK cascade that elicits cytotoxicity in human NK cells.	3	14	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav1	Vav1	Vav1	ERK	ERK	ERK	3	4	13	14
In subsequent studies , they showed that Vav1 appears to activate ERK downstream of TCR activation through a pathway involving LAT phosphorylation and Sos activation as well as phospholipase C activation and membrane recruitment of RasGRP1 [ XREF_BIBR ] .	In subsequent studies, they showed that Vav1 appears to activate ERK downstream of TCR activation through a pathway involving LAT phosphorylation and Sos activation as well as phospholipase C activation and membrane recruitment of RasGRP1 [XREF_BIBR].	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav1	Vav1	Vav1	ERK	ERK	ERK	7	8	11	12
Thus , in MCF-10A cells , Vav1 activates migration and the ERK pathway indirectly through secretion of an EGF receptor ligand .	Thus, in MCF-10A cells, Vav1 activates migration and the ERK pathway indirectly through secretion of an EGF receptor ligand.	6	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav1	Vav1	Vav1	ERK	ERK	ERK	6	7	11	12
However , the Vav1 induced increase in migration and ERK activation , but not activation of Rac1 and Pak , are dependent on the secretion of an epidermal growth factor ( EGF ) receptor ligand stimulated by Vav1Y3F .	However, the Vav1 induced increase in migration and ERK activation, but not activation of Rac1 and Pak, are dependent on the secretion of an epidermal growth factor (EGF) receptor ligand stimulated by Vav1Y3F.	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav1	Vav1	Vav1	ERK	ERK	ERK	3	4	9	10
These results indicate that Vav1Y3F activates the ERK pathway indirectly through autocrine stimulation of the EGF receptor and that ERK activation downstream of EGF receptor stimulation is required for the increased MCF10A migration resulting from Vav1Y3F expression .	These results indicate that Vav1Y3F activates the ERK pathway indirectly through autocrine stimulation of the EGF receptor and that ERK activation downstream of EGF receptor stimulation is required for the increased MCF10A migration resulting from Vav1Y3F expression.	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav1Y3F	Vav1Y3F	Vav1Y3F	ERK	ERK	ERK	4	5	7	8
Besides , knockdown of USP28 blocked the effect of c-Myc on activation of ataxia telangiectasia mutated and ataxia telangiectasia and Rad3 related DNA damage checkpoint after irradiation .	Besides, knockdown of USP28 blocked the effect of c-Myc on activation of ataxia telangiectasia-mutated and ataxia telangiectasia and Rad3 related DNA damage checkpoint after irradiation.	2	10	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	USP28	USP28	USP28	c-Myc	c-Myc	c-Myc	4	5	9	10
Additionally , a deubiquitinase , USP28 , has been reported to antagonize ubiquitin dependent proteasomal degradation of c-Myc .	Additionally, a deubiquitinase, USP28, has been reported to antagonize ubiquitin dependent proteasomal degradation of c-Myc.	3	18	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	USP28	USP28	USP28	c-Myc	c-Myc	c-Myc	5	6	17	18
Independently , USP28 has been reported to modulate the activity of the Myc proto-oncogene [ XREF_BIBR ] .	Independently, USP28 has been reported to modulate the activity of the Myc proto-oncogene [XREF_BIBR].	2	15	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP28	USP28	USP28	Myc	Myc	Myc	2	3	12	13
FBXW7-185aa reduced the half-life of c-Myc by antagonizing USP28 induced c-Myc stabilization .	FBXW7-185aa reduced the half-life of c-Myc by antagonizing USP28 induced c-Myc stabilization.	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	USP28	USP28	USP28	c-Myc	c-Myc	c-Myc	8	9	10	11
Here , using murine genetic models , we determined that USP28 antagonizes the ubiquitin dependent degradation of c-MYC , a known USP28 substrate , as well as 2 additional oncogenic factors , c-JUN and NOTCH1 , in the intestine .	Here, using murine genetic models, we determined that USP28 antagonizes the ubiquitin dependent degradation of c-MYC, a known USP28 substrate, as well as 2 additional oncogenic factors, c-JUN and NOTCH1, in the intestine.	10	30	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	USP28	USP28	USP28	c-MYC	c-MYC	c-MYC	10	11	17	18
USP28 can counteract the activity of FBW7 and promote c-MYC stability in cancer cells .	USP28 can counteract the activity of FBW7 and promote c-MYC stability in cancer cells.	0	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP28	USP28	USP28	c-MYC	c-MYC	c-MYC	0	1	9	10
Since FBW7gamma lacks the USP28 interaction motif of FBW7alpha , Usp28 selectively antagonize nucleoplasmic MYC degradation while not affecting nucleolar degradation .	Since FBW7gamma lacks the USP28 interaction motif of FBW7alpha, Usp28 selectively antagonize nucleoplasmic MYC degradation while not affecting nucleolar degradation.	10	15	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Usp28	Usp28	Usp28	MYC	MYC	MYC	10	11	14	15
As a consequence , the affinity of Atg1 for both Atg13 and Atg17 increases , promoting the formation of a trimeric , Atg1 , Atg13 , and Atg17 complex .	As a consequence, the affinity of Atg1 for both Atg13 and Atg17 increases, promoting the formation of a trimeric, Atg1, Atg13, and Atg17 complex.	5	28	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg1	Atg1	Atg1	Atg13	Atg13	Atg13	7	8	24	25
In contrast to the prevailing view that Ulk1 and Atg13 function as a complex , our data indicate that Ulk1 kinase activity promotes the release of Atg13 from Ulk1 , and that released Atg13 then localizes to ring like structures around damaged mitochondria , and thereby contributes to their degradation .	In contrast to the prevailing view that Ulk1 and Atg13 function as a complex, our data indicate that Ulk1 kinase activity promotes the release of Atg13 from Ulk1, and that released Atg13 then localizes to ring like structures around damaged mitochondria, and thereby contributes to their degradation.	19	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ulk1	Ulk1	Ulk1	Atg13	Atg13	Atg13	19	20	26	27
Strikingly , Ulk1 activation promotes the release of Atg13 from the Hsp90 , Cdc37 , and Ulk1 complex and the localization of Atg13 to depolarized mitochondria , where it plays an essential role in Parkin dependent mitophagy .	Strikingly, Ulk1 activation promotes the release of Atg13 from the Hsp90, Cdc37, and Ulk1 complex and the localization of Atg13 to depolarized mitochondria, where it plays an essential role in Parkin dependent mitophagy.	2	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ulk1	Ulk1	Ulk1	Atg13	Atg13	Atg13	2	3	8	9
Collectively , these observations suggest that though the interaction of Ulk1 with Hsp90-Cdc37 is necessary for Atg13 phosphorylation , the activation of Ulk1 kinase by Hsp90-Cdc37 promotes release of Atg13 from the Ulk1 , Hsp90 , and Cdc37 complex .	Collectively, these observations suggest that though the interaction of Ulk1 with Hsp90-Cdc37 is necessary for Atg13 phosphorylation, the activation of Ulk1 kinase by Hsp90-Cdc37 promotes release of Atg13 from the Ulk1, Hsp90, and Cdc37 complex.	22	30	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ulk1	Ulk1	Ulk1	Atg13	Atg13	Atg13	22	23	29	30
Indeed , ULK1 co-transfection enabled Atg13 and FIP200 to interact with Sestrin2 ( XREF_FIG ) , indicating that Sestrin2 can bind to the ULK1 , Atg13 , and FIP200 complex as a whole .	Indeed, ULK1 co-transfection enabled Atg13 and FIP200 to interact with Sestrin2 (XREF_FIG), indicating that Sestrin2 can bind to the ULK1, Atg13, and FIP200 complex as a whole.	2	7	enabled	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ULK1	ULK1	ULK1	Atg13	Atg13	Atg13	2	3	5	6
To this regard , we have reported that phosphorylation of the ubiquitin ligase c-Cbl , a negative regulator of NKG2D signaling , and the activation of the ubiquitin pathway is indispensable for MICA- but not ULBP2 induced NKG2D internalization and degradation .	To this regard, we have reported that phosphorylation of the ubiquitin ligase c-Cbl, a negative regulator of NKG2D signaling, and the activation of the ubiquitin pathway is indispensable for MICA- but not ULBP2 induced NKG2D internalization and degradation.	34	38	induced	Positive_early_activation	Positive_activation	Positive_activation	ULBP2	ULBP2	ULBP2	NKG2D	NKG2D	NKG2D	35	36	37	38
Here , we report that Vpr from most HIV-1 primary isolates can upregulate ULBP2 expression and induce NKG2D dependent NK cell killing .	Here, we report that Vpr from most HIV-1 primary isolates can upregulate ULBP2 expression and induce NKG2D dependent NK cell killing.	5	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ULBP2	Vpr from most HIV-1 primary isolates can upregulate ULBP2 expression	ulbp2	NKG2D	NKG2D	nkg2d	13	14	17	18
MICA and ULBP2 vary in their potential to induce NKG2D down-modulation , with MICA being the most potent ligand leading to a severe impairment of NKG2D dependent NK cell cytotoxicity .	MICA and ULBP2 vary in their potential to induce NKG2D down-modulation, with MICA being the most potent ligand leading to a severe impairment of NKG2D dependent NK cell cytotoxicity.	0	10	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ULBP2	ULBP2	ULBP2	NKG2D	NKG2D	NKG2D	2	3	9	10
Indeed , the ubiquitin ligase c-Cbl is required for MICA- but not ULBP2 induced NKG2D endocytosis [ XREF_BIBR ] .	Indeed, the ubiquitin ligase c-Cbl is required for MICA- but not ULBP2 induced NKG2D endocytosis [XREF_BIBR].	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	ULBP2	ULBP2	ULBP2	NKG2D	NKG2D	NKG2D	12	13	14	15
In particular it was hard to predict whether expression of ULBP2 in HCMV infected DC increases the CD8+ T cell response by engaging the costimulatory NKG2D receptor [ XREF_BIBR , XREF_BIBR ] , or whether it would perhaps lead to T cell exhaustion [ XREF_BIBR ] .	In particular it was hard to predict whether expression of ULBP2 in HCMV infected DC increases the CD8+ T cell response by engaging the costimulatory NKG2D receptor [XREF_BIBR, XREF_BIBR], or whether it would perhaps lead to T cell exhaustion [XREF_BIBR].	8	26	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ULBP2	expression of ULBP2	ulbp2	NKG2D	NKG2D	nkg2d	10	11	25	26
In this study , we show that both VEGF-A and VEGF-C induce the interaction of NRP2 with VEGFR-2 .	In this study, we show that both VEGF-A and VEGF-C induce the interaction of NRP2 with VEGFR-2.	8	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	NRP2	NRP2	NRP2	10	11	15	16
In a model of colorectal cancer , TALA was stimulated by upregulation of Nrp-2 in LECs , and LVD correlated with the level of Nrp-2 expression ; this Nrp-2 induction was mediated by integrin-alpha9beta1 signaling in a VEGF-C and VEGFR -3 pathway independent manner [ XREF_BIBR ] .	In a model of colorectal cancer, TALA was stimulated by upregulation of Nrp-2 in LECs, and LVD correlated with the level of Nrp-2 expression; this Nrp-2 induction was mediated by integrin-alpha9beta1 signaling in a VEGF-C and VEGFR -3 pathway independent manner [XREF_BIBR].	28	45	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VEGF-C	VEGF-C	VEGF-C	Nrp-2	Nrp-2	Nrp-2	37	38	28	29
Nrp2 plays a role in tumourigenesis ; VEGFC supplementation can not rescue the biological function of Nrp2 in Nrp2 depleted cell lines .	Nrp2 plays a role in tumourigenesis; VEGFC supplementation can not rescue the biological function of Nrp2 in Nrp2 depleted cell lines.	7	17	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFC	VEGFC	VEGFC	Nrp2	Nrp2	Nrp2	7	8	16	17
As ULK1 has been shown to activate AMBRA1 by phosphorylation , the proposed pathway may act as a positive regulation loop , which may be targeted in human disorders linked to impaired autophagy .	As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ULK1	ULK1	ULK1	AMBRA1	AMBRA1	AMBRA1	1	2	7	8
The ULK1 mediated release of AMBRA1 from DYNLL1 ( dynein light chain LC8-type 1 ) and its subsequent binding to BECN1 is also required for the complex to localize to omegasomes in the ER [ XREF_BIBR , XREF_BIBR ] .	The ULK1 mediated release of AMBRA1 from DYNLL1 (dynein light chain LC8-type 1) and its subsequent binding to BECN1 is also required for the complex to localize to omegasomes in the ER [XREF_BIBR, XREF_BIBR].	0	6	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ULK1	ULK1	ULK1	AMBRA1	AMBRA1	AMBRA1	1	2	5	6
Whether Bim and Beclin1 interaction XREF_BIBR is part of a pathway distinct from the Ulk1 activated Ambra1 , XREF_BIBR or whether the complexes may differ depending on cell type , needs to be explored further .	Whether Bim and Beclin1 interaction XREF_BIBR is part of a pathway distinct from the Ulk1 activated Ambra1, XREF_BIBR or whether the complexes may differ depending on cell type, needs to be explored further.	11	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ulk1	Ulk1	Ulk1	Ambra1	Ambra1	Ambra1	14	15	16	17
VAV2 has been reported to regulate EGFR , and knockdown of VAV2 enhanced EGFR degradation and further reduced cell proliferation [ XREF_BIBR ] .	VAV2 has been reported to regulate EGFR, and knockdown of VAV2 enhanced EGFR degradation and further reduced cell proliferation [XREF_BIBR].	9	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	EGFR	EGFR	EGFR	11	12	13	14
Simultaneous knockdown of Vav2 and Vav3 also decreases EGFR endocytosis .	Simultaneous knockdown of Vav2 and Vav3 also decreases EGFR endocytosis.	1	9	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	EGFR	EGFR	EGFR	3	4	8	9
Both Vav2 Y172 phosphorylation and RhoA activation were blocked by the EGFR inhibitor AG1478 and prevented in MC overexpressing kinase inactive EGFR .	Both Vav2 Y172 phosphorylation and RhoA activation were blocked by the EGFR inhibitor AG1478 and prevented in MC overexpressing kinase inactive EGFR.	1	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Vav2	Vav2 Y172 phosphorylation	vav2	EGFR	EGFR	egfr	1	2	21	22
USP24 targeting DDB2 and p53 .	USP24 targeting DDB2 and p53.	0	4	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP24	USP24	USP24	DDB2	DDB2	DDB2	0	1	2	3
Knockdown of USP24 resulted in a decreased level of DDB2 , suggesting that USP24 stabilizes DDB2 by removing the ubiquitin moiety from modified DDB2 , thereby preventing DDB2 degradation .	Knockdown of USP24 resulted in a decreased level of DDB2, suggesting that USP24 stabilizes DDB2 by removing the ubiquitin moiety from modified DDB2, thereby preventing DDB2 degradation.	0	28	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	USP24	USP24	USP24	DDB2	DDB2	DDB2	2	3	27	28
Thus , in primary T cell blasts , Duox1 appears to promote proximal TCR signaling , especially the phosphorylation of ZAP-70 , PLC-gamma1 , Vav1 , and ADAP , as well as the activation of ERK1 and ERK2 .	Thus, in primary T cell blasts, Duox1 appears to promote proximal TCR signaling, especially the phosphorylation of ZAP-70, PLC-gamma1, Vav1, and ADAP, as well as the activation of ERK1 and ERK2.	8	38	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	Vav1	Duox1 appears to promote proximal TCR signaling, especially the phosphorylation of ZAP-70, PLC-gamma1, Vav1	vav1	ERK2	ERK2	erk2	24	25	37	38
We also found that Mesd suppressed Wnt and beta-catenin signaling induced by Wnt1 in prostate cancer PC-3 cells , and inhibited tumor growth in PC-3 xenograft model .	We also found that Mesd suppressed Wnt and beta-catenin signaling induced by Wnt1 in prostate cancer PC-3 cells, and inhibited tumor growth in PC-3 xenograft model.	6	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	12	13	8	9
Chimeric reporter vectors that use the hAR gene promoter to drive luciferase expression confirmed that these LEF-1 and TCF binding elements are able to confer robust upregulation of luciferase expression when stimulated by Wnt-1 or by transfection with beta-catenin and that dominant negative TCF or mutations within the dominant TCF binding element abrogated the response .	Chimeric reporter vectors that use the hAR gene promoter to drive luciferase expression confirmed that these LEF-1 and TCF binding elements are able to confer robust upregulation of luciferase expression when stimulated by Wnt-1 or by transfection with beta-catenin and that dominant negative TCF or mutations within the dominant TCF binding element abrogated the response.	31	39	stimulated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	33	34	38	39
Collectively , our findings suggested that Wnt1 stimulates osteogenic differentiation and mineralization of hPLFs , mainly by activating the canonical Wnt and beta-catenin pathway , in which Runx2 is a key downstream regulator .	Collectively, our findings suggested that Wnt1 stimulates osteogenic differentiation and mineralization of hPLFs, mainly by activating the canonical Wnt and beta-catenin pathway, in which Runx2 is a key downstream regulator.	6	23	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	6	7	22	23
Mesd , a general Wnt inhibitor , suppressed Wnt and beta-catenin signaling induced by Wnt1 in PC-3 cells , and inhibited PC-3 cells tumorigenicity in vivo [ XREF_BIBR ] .	Mesd, a general Wnt inhibitor, suppressed Wnt and beta-catenin signaling induced by Wnt1 in PC-3 cells, and inhibited PC-3 cells tumorigenicity in vivo [XREF_BIBR].	8	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	14	15	10	11
Reporter studies indicate that Wnt1 activates beta-catenin signaling in a paracrine manner , increasing basally located multipotent stem cells at the expense of differentiated myoepithelial cells [ XREF_BIBR ] .	Reporter studies indicate that Wnt1 activates beta-catenin signaling in a paracrine manner, increasing basally located multipotent stem cells at the expense of differentiated myoepithelial cells [XREF_BIBR].	4	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	4	5	6	7
In conclusion , the data suggest that Wnt-1 is necessary but insufficient to activate Wnt and beta-catenin signaling in hepatoma cells and the enhanced stabilization of beta-catenin by HBx , in addition to Wnt-1 , is essential for the activation of Wnt and beta-catenin signaling in hepatoma cells .	In conclusion, the data suggest that Wnt-1 is necessary but insufficient to activate Wnt and beta-catenin signaling in hepatoma cells and the enhanced stabilization of beta-catenin by HBx, in addition to Wnt-1, is essential for the activation of Wnt and beta-catenin signaling in hepatoma cells.	7	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	7	8	16	17
Transient expression of Wnt1 in basal epithelia significantly activated Wnt and beta-catenin pathway in submandibular glands of male mice but not in those of females .	Transient expression of Wnt1 in basal epithelia significantly activated Wnt and beta-catenin pathway in submandibular glands of male mice but not in those of females.	1	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	expression of Wnt1	wnt1	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
Aberrant expression of Wnt-1 leads to activation of the Wnt-1 and beta-catenin signaling pathway , which is essential for MCF-7 breast cancer cell survival and metastasis [ XREF_BIBR ] .	Aberrant expression of Wnt-1 leads to activation of the Wnt-1 and beta-catenin signaling pathway, which is essential for MCF-7 breast cancer cell survival and metastasis [XREF_BIBR].	1	13	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Wnt-1	expression of Wnt-1	wnt-1	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
Mesd Suppresses Wnt and beta-catenin Signaling Induced by Wnt1 , Wnt3 and Wnt10b in HEK293 Cells .	Mesd Suppresses Wnt and beta-catenin Signaling Induced by Wnt1, Wnt3 and Wnt10b in HEK293 Cells.	2	12	Induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	8	9	4	5
In addition , gene silencing of TIPE1 in AGS cells increased Wnt1 mediated the activity of Wnt and beta-catenin signalling .	In addition, gene silencing of TIPE1 in AGS cells increased Wnt1 mediated the activity of Wnt and beta-catenin signalling.	11	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	11	12	18	19
Furthermore , the activation of beta-catenin signaling induced by Wnt1 obviously prevented retinal neuron like differentiation .	Furthermore, the activation of beta-catenin signaling induced by Wnt1 obviously prevented retinal neuron like differentiation.	5	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	9	10	5	6
Furthermore , we found that among the major isoforms of Wnts , Wnt1 was regulated by beta-arrestin-1 and gene silencing of Wnt1 inhibited the activation of beta-catenin and suppressed beta-arrestin-1-mediated renal fibrosis .	Furthermore, we found that among the major isoforms of Wnts, Wnt1 was regulated by beta-arrestin-1 and gene silencing of Wnt1 inhibited the activation of beta-catenin and suppressed beta-arrestin-1-mediated renal fibrosis.	19	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	21	22	26	27
APC has the capacity to oppose this Wnt-1 effect in experiments in which overexpression of the central region of APC significantly reduced the size of the monomeric pool of beta-catenin induced by Wnt-1 .	APC has the capacity to oppose this Wnt-1 effect in experiments in which overexpression of the central region of APC significantly reduced the size of the monomeric pool of beta-catenin induced by Wnt-1.	27	33	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	32	33	29	30
Thus , at least in MEFs , Wnt-1 can activate both the canonical beta-catenin pathway and the non canonical PCP pathway at the same time , as shown by the simultaneous activation of RhoU and TOPFlash in our system .	Thus, at least in MEFs, Wnt-1 can activate both the canonical beta-catenin pathway and the non canonical PCP pathway at the same time, as shown by the simultaneous activation of RhoU and TOPFlash in our system.	7	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	7	8	13	14
Our data indicate that inhibition of Wnt-1 by siRNA significantly reduced phospho-beta-catenin , cyclin D1 levels ( XREF_FIG ) compared to random siRNA treated CSCs .	Our data indicate that inhibition of Wnt-1 by siRNA significantly reduced phospho-beta-catenin, cyclin D1 levels (XREF_FIG) compared to random siRNA treated CSCs.	4	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	phospho-beta-catenin	phospho-beta-catenin	phospho-beta-catenin	6	7	11	12
While Wnt1 expression induces the activation of both beta-catenin and mammalian Target of Rapamcyin ( mTOR ) , stem cell exhaustion was uniquely associated with mTOR activation [ XREF_BIBR ] .	While Wnt1 expression induces the activation of both beta-catenin and mammalian Target of Rapamcyin (mTOR), stem cell exhaustion was uniquely associated with mTOR activation [XREF_BIBR].	1	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 expression	wnt1	beta-catenin	beta-catenin	beta-catenin	1	2	8	9
Nevertheless , it is clear that Wnt1 transgene expression induces a profound beta-catenin and TCF signaling response in mammary myoepithelial cells , which mirrors the Pea3 NLSlacZ staining pattern in MMTV and Wnt1 mammary glands ( compare XREF_FIG and XREF_FIG with 2C ) .	Nevertheless, it is clear that Wnt1 transgene expression induces a profound beta-catenin and TCF signaling response in mammary myoepithelial cells, which mirrors the Pea3 NLSlacZ staining pattern in MMTV and Wnt1 mammary glands (compare XREF_FIG and XREF_FIG with 2C).	6	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 transgene expression	wnt1	beta-catenin	beta-catenin	beta-catenin	6	7	12	13
We only examined effects of Wnt activation on radiation induced hyposalivation in male mice since Wnt1 over-expression failed to activate Wnt and beta-catenin pathway in SMG of female mice .	We only examined effects of Wnt activation on radiation induced hyposalivation in male mice since Wnt1 over-expression failed to activate Wnt and beta-catenin pathway in SMG of female mice.	15	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 over-expression	wnt1	beta-catenin	beta-catenin	beta-catenin	15	16	22	23
XREF_BIBR Notably , the Dvl1 PDZ bound peptide attenuates the Wnt and beta-catenin signaling induced by Wnt1 .	XREF_BIBR Notably, the Dvl1 PDZ bound peptide attenuates the Wnt and beta-catenin signaling induced by Wnt1.	10	17	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	16	17	12	13
In addition , Wnt4 and Wnt1 have been shown to direct beta-catenin to the membrane by noncanonical mechanisms .	In addition, Wnt4 and Wnt1 have been shown to direct beta-catenin to the membrane by noncanonical mechanisms.	3	12	direct	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	5	6	11	12
Interestingly , we observed that Wnt1 mediated beta-catenin stabilization resulted in increased hepatocyte survival and strong hepatic resistance to oxidative injury .	Interestingly, we observed that Wnt1 mediated beta-catenin stabilization resulted in increased hepatocyte survival and strong hepatic resistance to oxidative injury.	5	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	5	6	7	8
Moreover , we show that Wnt1 driven beta-catenin signaling did not lead to increased GL261 and C6 tumor growth .	Moreover, we show that Wnt1 driven beta-catenin signaling did not lead to increased GL261 and C6 tumor growth.	5	11	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	5	6	7	8
Wnt and beta-catenin signaling is activated in ductal cells by transient Wnt1 expression in male but not female SMG .	Wnt and beta-catenin signaling is activated in ductal cells by transient Wnt1 expression in male but not female SMG.	0	13	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 expression	wnt1	beta-catenin	beta-catenin	beta-catenin	11	12	2	3
Taken together , these results indicate that ectopic Wnt1 expressed from the Wnt1-Cre transgene activates canonical Wnt and beta-catenin signaling , possibly leading to the midbrain phenotypes that we observe .	Taken together, these results indicate that ectopic Wnt1 expressed from the Wnt1-Cre transgene activates canonical Wnt and beta-catenin signaling, possibly leading to the midbrain phenotypes that we observe.	7	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 expressed	wnt1	beta-catenin	beta-catenin	beta-catenin	8	9	18	19
Wnt1 transgenic mice have increased beta-catenin activity , suppressed epithelial differentiation and preneoplastic lesions , while the generation of tumors in these mice requires the cooperative activation of both Wnt and COX-2 and PGE 2 pathways .	Wnt1 transgenic mice have increased beta-catenin activity, suppressed epithelial differentiation and preneoplastic lesions, while the generation of tumors in these mice requires the cooperative activation of both Wnt and COX-2 and PGE 2 pathways.	0	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	0	1	5	6
Luciferase assays indicated that GABARAPL1 represses Wnt and beta-catenin signaling stimulated by Wnt1 , Dvl2 and beta-catenin .	Luciferase assays indicated that GABARAPL1 represses Wnt and beta-catenin signaling stimulated by Wnt1, Dvl2 and beta-catenin.	6	16	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	12	13	8	9
Thus , in HC11 cells , both WNT1 and WNT5A activate the classic beta-catenin and TCF pathway .	Thus, in HC11 cells, both WNT1 and WNT5A activate the classic beta-catenin and TCF pathway.	6	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT1	WNT1	WNT1	beta-catenin	beta-catenin	beta-catenin	7	8	13	14
Our findings suggested that the therapeutic mechanisms of WPX in treating GPL might be related with its inhibitory effects on the expressions of Lgr5 , MMP-7 , Wnt1 , beta-catenin and the aberrant activation of Wnt and beta-catenin pathway .	Our findings suggested that the therapeutic mechanisms of WPX in treating GPL might be related with its inhibitory effects on the expressions of Lgr5, MMP-7, Wnt1, beta-catenin and the aberrant activation of Wnt and beta-catenin pathway.	21	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt1	expressions of Lgr5, MMP-7, Wnt1	wnt1	beta-catenin	beta-catenin	beta-catenin	27	28	37	38
Mesd Suppresses Wnt and beta-catenin Signaling Induced by Wnt1 , Wnt3 and Wnt10b in LRP5 or LRP6 Expressing HEK293 Cells .	Mesd Suppresses Wnt and beta-catenin Signaling Induced by Wnt1, Wnt3 and Wnt10b in LRP5 or LRP6 Expressing HEK293 Cells.	2	12	Induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	8	9	4	5
63 Recent studies also illustrate that in vitro activation of beta-catenin by Wnt1 protects tubular epithelial cells from apoptosis , activates Akt , induces survivin , and represses p53 and Bax expression .	63 Recent studies also illustrate that in vitro activation of beta-catenin by Wnt1 protects tubular epithelial cells from apoptosis, activates Akt, induces survivin, and represses p53 and Bax expression.	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	12	13	10	11
Mesd Suppresses Wnt and beta-catenin Signaling Induced by Wnt1 in Prostate Cancer PC-3 Cells .	Mesd Suppresses Wnt and beta-catenin Signaling Induced by Wnt1 in Prostate Cancer PC-3 Cells.	2	13	Induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	8	9	4	5
Wnt1 activates the beta-catenin pathway in HF : prolonged exposure to Wnt1 leads to hair loss .	Wnt1 activates the beta-catenin pathway in HF : prolonged exposure to Wnt1 leads to hair loss.	0	4	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	0	1	3	4
There are several Wnt ligands that activate Wnt and beta-catenin signaling , such as Wnt1 , Wnt3a and Wnt8 .	There are several Wnt ligands that activate Wnt and beta-catenin signaling, such as Wnt1, Wnt3a and Wnt8.	7	18	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	14	15	9	10
Reduced Wnt-1 expression by MCF-7-PKC-alpha cells may promote beta-catenin degradation by enhancing GSK-3 activity .	Reduced Wnt-1 expression by MCF-7-PKC-alpha cells may promote beta-catenin degradation by enhancing GSK-3 activity.	1	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1 expression	wnt-1	beta-catenin	beta-catenin	beta-catenin	1	2	8	9
Our findings that Wnt-1 overexpression results in activation of beta-catenin and TCF signaling and relevant downstream target genes is also supported by previous experimental observations in other tissues XREF_BIBR , XREF_BIBR .	Our findings that Wnt-1 overexpression results in activation of beta-catenin and TCF signaling and relevant downstream target genes is also supported by previous experimental observations in other tissues XREF_BIBR, XREF_BIBR.	3	12	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1 overexpression	wnt-1	beta-catenin	beta-catenin	beta-catenin	3	4	9	10
In the present study , following the successful knockdown of miR-19b , which normally acts on the 3 '-UTR of Wnt1 , the levels of Wnt1 protein expression significantly increased , thereby activating Wnt and beta-catenin signaling and inhibiting myocardial cell development .	In the present study, following the successful knockdown of miR-19b, which normally acts on the 3 '-UTR of Wnt1, the levels of Wnt1 protein expression significantly increased, thereby activating Wnt and beta-catenin signaling and inhibiting myocardial cell development.	25	36	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 protein expression	wnt1	beta-catenin	beta-catenin	beta-catenin	25	26	35	36
Overexpression of PTEN inhibits Wnt-1 induced beta-catenin stabilization and mammary tumorigenesis in mice XREF_BIBR .	Overexpression of PTEN inhibits Wnt-1 induced beta-catenin stabilization and mammary tumorigenesis in mice XREF_BIBR.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	4	5	6	7
Work from our laboratory obtained in vivo in rodent models of PD , as well as in vitro , in primary mesencephalic neuron-astrocyte and astrocyte-microglia coculture systems , indicates that during MPTP injury , in the inflammed midbrain , microglial derived chemokines induce Wnt1 in astrocytes , and this Wnt1 up-regulation activates canonical Wnt and beta-catenin signaling in mDA neurons , as an intrinsic neurorescue response , in turn responsible for mDA neuroprotection against a variety of insults , such as oxidative stress and PD neuroxins ( i.e ., MPP+ or 6-OHDA ) .	Work from our laboratory obtained in vivo in rodent models of PD, as well as in vitro, in primary mesencephalic neuron-astrocyte and astrocyte-microglia coculture systems, indicates that during MPTP injury, in the inflammed midbrain, microglial derived chemokines induce Wnt1 in astrocytes, and this Wnt1 up-regulation activates canonical Wnt and beta-catenin signaling in mDA neurons, as an intrinsic neurorescue response, in turn responsible for mDA neuroprotection against a variety of insults, such as oxidative stress and PD neuroxins (i.e., MPP+ or 6-OHDA).	49	56	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	49	50	55	56
Development of an ovary in mammals instead involves expression of respondin-1 and wnt1 , which enhance the beta-catenin pathway and , in concert with foxl2 , repress the sox9 and fgf9 amplifying loop .	Development of an ovary in mammals instead involves expression of respondin-1 and wnt1, which enhance the beta-catenin pathway and, in concert with foxl2, repress the sox9 and fgf9 amplifying loop.	8	18	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	wnt1	expression of respondin-1 and wnt1	wnt1	beta-catenin	beta-catenin	beta-catenin	12	13	17	18
Both Wnt1 and Wnt3A signal to activate beta-catenin .	Both Wnt1 and Wnt3A signal to activate beta-catenin.	1	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	1	2	7	8
Activation of Wnt and beta-catenin signaling by over-expression of Wnt1 or Wnt10b prevents the induction of PPARgamma and C/EBPalpha but not C/EBPbeta , which works upstream of PPARgamma and C/EBPalpha [ XREF_BIBR ] .	Activation of Wnt and beta-catenin signaling by over-expression of Wnt1 or Wnt10b prevents the induction of PPARgamma and C/EBPalpha but not C/EBPbeta, which works upstream of PPARgamma and C/EBPalpha [XREF_BIBR].	2	11	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Wnt1	over-expression of Wnt1	wnt1	beta-catenin	beta-catenin	beta-catenin	9	10	4	5
In vivo , overexpression of Wnt1 at 5 days after IRI induced beta-catenin activation and accelerated AKI to CKD progression .	In vivo, overexpression of Wnt1 at 5 days after IRI induced beta-catenin activation and accelerated AKI to CKD progression.	3	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	overexpression of Wnt1	wnt1	beta-catenin	beta-catenin	beta-catenin	5	6	12	13
Results showed that WNT1 knockdown blocked WNT and beta-catenin signaling , while miR-148b downregualtion activated WNT and beta-catenin pathway in ox-LDL-stimulated HA-VSMCs .	Results showed that WNT1 knockdown blocked WNT and beta-catenin signaling, while miR-148b downregualtion activated WNT and beta-catenin pathway in ox-LDL-stimulated HA-VSMCs.	3	9	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT1	WNT1	WNT1	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
Interestingly , though coexpression of DN-Tcf also blocked Wnt mediated survival , overexpression of Wnt-1 by the transient transfection more potently inhibited VCR- or VBL mediated killing than that of beta-catenin , indicating that Wnt-1 may activate other signaling pathways or molecules to enhance beta-catenin and Tcf mediated anti-apoptotic function ( XREF_FIG D ) .	Interestingly, though coexpression of DN-Tcf also blocked Wnt mediated survival, overexpression of Wnt-1 by the transient transfection more potently inhibited VCR- or VBL mediated killing than that of beta-catenin, indicating that Wnt-1 may activate other signaling pathways or molecules to enhance beta-catenin and Tcf-mediated anti-apoptotic function (XREF_FIG D).	34	46	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	34	35	44	45
To show the predictive power of our approach , we experimentally validated the so far unknown Wnt1 target gene Dkk3 as a direct target gene of the Lef1 and Tcf mediated Wnt1 and beta-catenin signaling cascade invitro .	To show the predictive power of our approach, we experimentally validated the so far unknown Wnt1 target gene Dkk3 as a direct target gene of the Lef1 and Tcf mediated Wnt1 and beta-catenin signaling cascade invitro.	16	36	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	16	17	33	34
These results suggest that Wnt-1 induction of cytosolic beta-catenin may have functions in addition to Tcf/Lef transcriptional activation .	These results suggest that Wnt-1 induction of cytosolic beta-catenin may have functions in addition to Tcf/Lef transcriptional activation.	4	9	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	4	5	8	9
On the other hand , the specific antagonism of canonical Wnt pathway with Dkk1 efficiently reversed Wnt1 induced TH + neuroprotection and Caspase3 like activity inhibition , supporting Wnt1 activation of a canonical Wnt and beta-catenin signaling pathway associated to inhibition of the pro apoptotic GSK-3beta pathway [ XREF_BIBR - XREF_BIBR ] .	On the other hand, the specific antagonism of canonical Wnt pathway with Dkk1 efficiently reversed Wnt1 induced TH + neuroprotection and Caspase3 like activity inhibition, supporting Wnt1 activation of a canonical Wnt and beta-catenin signaling pathway associated to inhibition of the pro apoptotic GSK-3beta pathway [XREF_BIBR - XREF_BIBR].	28	37	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	28	29	35	36
We found that knockdown of DDAH1 in the GC cells increased the levels of Wnt1 , enhanced phosphorylation of GSK-3beta at Ser9 , and reduced the phosphorylated forms of beta-catenin ( Ser33/37/Thr41 ) .	We found that knockdown of DDAH1 in the GC cells increased the levels of Wnt1, enhanced phosphorylation of GSK-3beta at Ser9, and reduced the phosphorylated forms of beta-catenin (Ser33/37/Thr41).	5	31	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	DDAH1 in the GC cells increased the levels of Wnt1	wnt1	beta-catenin	beta-catenin	beta-catenin	14	15	29	30
Transient overexpression of Wnt-1 or beta-catenin in FRTL-5 cells increased active beta-catenin ( ABC ) , decreased thyroperoxidase ( TPO ) mRNA , and suppressed TPO-promoter activity .	Transient overexpression of Wnt-1 or beta-catenin in FRTL-5 cells increased active beta-catenin (ABC), decreased thyroperoxidase (TPO) mRNA, and suppressed TPO-promoter activity.	1	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-1	overexpression of Wnt-1	wnt-1	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
Furthermore , in HEK293 cells , TMEM88 attenuated the Wnt and beta-catenin signaling induced by Wnt-1 ligand in a dose dependent manner , and TMEM88 knockdown by RNAi increased Wnt activity .	Furthermore, in HEK293 cells, TMEM88 attenuated the Wnt and beta-catenin signaling induced by Wnt-1 ligand in a dose dependent manner, and TMEM88 knockdown by RNAi increased Wnt activity.	9	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	15	16	11	12
Unlike Wnt1 and Wnt3a which activate the beta-catenin pathway , Wnt5a has been frequently shown to activate the beta-catenin-independent and non canonical Wnt signaling pathways via binding to its receptors , frizzled and Ror2 , as well as inhibiting the beta-catenin pathway .	Unlike Wnt1 and Wnt3a which activate the beta-catenin pathway, Wnt5a has been frequently shown to activate the beta-catenin-independent and non canonical Wnt signaling pathways via binding to its receptors, frizzled and Ror2, as well as inhibiting the beta-catenin pathway.	0	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	1	2	7	8
Classical Wnt and beta-catenin signaling pathway , also named the canonical pathway , is usually activated by Wnt1 protein and inactivated by Wnt5a protein .	Classical Wnt and beta-catenin signaling pathway, also named the canonical pathway, is usually activated by Wnt1 protein and inactivated by Wnt5a protein.	3	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	17	18	3	4
Interestingly , while Wnt1 expression led to activation of both beta-catenin and the mTOR pathway , hair follicle hyperproliferation and stem cell loss could be largely reversed using rapamycin , suggesting that mTOR plays a dominant role in this process ( XREF_FIG ) .	Interestingly, while Wnt1 expression led to activation of both beta-catenin and the mTOR pathway, hair follicle hyperproliferation and stem cell loss could be largely reversed using rapamycin, suggesting that mTOR plays a dominant role in this process (XREF_FIG).	3	14	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 expression	wnt1	beta-catenin	beta-catenin	beta-catenin	3	4	10	11
Here we report that Frzb-1 blocks Wnt-1 induced cytosolic accumulation of beta-catenin , a key component of the Wnt signaling pathway , in human embryonic kidney cells .	Here we report that Frzb-1 blocks Wnt-1 induced cytosolic accumulation of beta-catenin, a key component of the Wnt signaling pathway, in human embryonic kidney cells.	6	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	6	7	11	12
Wnt1 , Wnt2 , Wnt3a , Wnt8 , Wnt8b are members of the Wnt1 class , which induce a secondary body axis in Xenopus embryos and activate the Wnt and beta-catenin signaling cascade [ XREF_BIBR ] .	Wnt1, Wnt2, Wnt3a, Wnt8, Wnt8b are members of the Wnt1 class, which induce a secondary body axis in Xenopus embryos and activate the Wnt and beta-catenin signaling cascade [XREF_BIBR].	13	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	13	14	30	31
To demonstrate Wnt1 expression activated the WNT and beta-catenin pathway , we initially looked at the expression of the pathway target Axin2 by RT-PCR .	To demonstrate Wnt1 expression activated the WNT and beta-catenin pathway, we initially looked at the expression of the pathway target Axin2 by RT-PCR.	2	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 expression	wnt1	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
Hydrodynamic injection of Wnt-1 naked DNA induces beta-catenin activation and regeneration in wild-type mice .	Hydrodynamic injection of Wnt-1 naked DNA induces beta-catenin activation and regeneration in wild-type mice.	3	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
While Wnt1 expression induced the activation of both beta-catenin and mTOR in the epithelial compartment of the skin , both HF growth and stem cell exhaustion were uniquely associated with mTOR activation .	While Wnt1 expression induced the activation of both beta-catenin and mTOR in the epithelial compartment of the skin, both HF growth and stem cell exhaustion were uniquely associated with mTOR activation.	1	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 expression	wnt1	beta-catenin	beta-catenin	beta-catenin	1	2	8	9
Furthermore , while SIIA cells do not respond to Wnt-1-conditioned medium , inhibition of Hh signaling by smoothened ( SMO ) antagonist KAAD-cyclopamine ( keto-N-aminoethylaminocaproyldihydrocinnamoylcyclopamine ) leads to Wnt1 mediated beta-catenin accumulation in the cytosol .	Furthermore, while SIIA cells do not respond to Wnt-1-conditioned medium, inhibition of Hh signaling by smoothened (SMO) antagonist KAAD-cyclopamine (keto-N-aminoethylaminocaproyldihydrocinnamoylcyclopamine) leads to Wnt1 mediated beta-catenin accumulation in the cytosol.	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	28	29	30	31
These studies highlight a disconnect between the cell surface localization and secretion of WNT1 and the activation of beta-catenin dependent signaling by WNT1 .	These studies highlight a disconnect between the cell surface localization and secretion of WNT1 and the activation of beta-catenin dependent signaling by WNT1.	18	23	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	WNT1	WNT1	WNT1	beta-catenin	beta-catenin	beta-catenin	22	23	18	19
In contrast , Wnt1 challenge in human sarcoma cells stimulated the tyrosine kinase domain of Ror2 and subsequent beta-catenin reporter activity .	In contrast, Wnt1 challenge in human sarcoma cells stimulated the tyrosine kinase domain of Ror2 and subsequent beta-catenin reporter activity.	3	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	3	4	18	19
We found that Wnt and beta-catenin signaling could be activated by ectopic expression of Wnt-1 in some hepatoma cells , such as Hep3B and PLC/PRF/5 cells , but not in others , such as Huh7 and Chang cells .	We found that Wnt and beta-catenin signaling could be activated by ectopic expression of Wnt-1 in some hepatoma cells, such as Hep3B and PLC/PRF/5 cells, but not in others, such as Huh7 and Chang cells.	3	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt-1	expression of Wnt-1	wnt-1	beta-catenin	beta-catenin	beta-catenin	14	15	5	6
We have previously demonstrated that Wnt-1 induction of cytosolic beta-catenin and Tcf/Lef transcriptional activation correlate with enhanced proliferation , survival , and post-confluent growth in Rat-1 fibroblasts .	We have previously demonstrated that Wnt-1 induction of cytosolic beta-catenin and Tcf/Lef transcriptional activation correlate with enhanced proliferation, survival, and post-confluent growth in Rat-1 fibroblasts.	5	13	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
These results suggested that Wnt1 could elevate Wnt and beta-catenin signaling of NOD-MSCs .	These results suggested that Wnt1 could elevate Wnt and beta-catenin signaling of NOD-MSCs.	4	10	elevate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	4	5	9	10
So , the immunofluorescence results supported the previous Western blotting data , indicating that the activation of beta-catenin signaling induced by Wnt1 obviously prevented retinal neuron like differentiation in NOD-MSCs .	So, the immunofluorescence results supported the previous Western blotting data, indicating that the activation of beta-catenin signaling induced by Wnt1 obviously prevented retinal neuron like differentiation in NOD-MSCs.	17	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	21	22	17	18
Notably , a study has shown that angiotensin II induces Wnt1 expression and activates beta-catenin in podocytes and that DKK1 protects against proteinuria initiated by angiotensin II infusion .	Notably, a study has shown that angiotensin II induces Wnt1 expression and activates beta-catenin in podocytes and that DKK1 protects against proteinuria initiated by angiotensin II infusion.	7	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	angiotensin II induces Wnt1 expression	wnt1	beta-catenin	beta-catenin	beta-catenin	10	11	14	15
WNT3 ligand , but not WNT1 and WNT3A augmented the endogenous beta-catenin activity of MCF7 cells in a DKK1-insensitive manner .	WNT3 ligand, but not WNT1 and WNT3A augmented the endogenous beta-catenin activity of MCF7 cells in a DKK1-insensitive manner.	1	12	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT1	WNT1	WNT1	beta-catenin	beta-catenin	beta-catenin	5	6	11	12
Wnt1 , Xwnt5 , Wnt8 and other Wnts activate Wnt and beta-catenin canonical pathway and induce duplication of the axis in Xenopus and Zebrafish .	Wnt1, Xwnt5, Wnt8 and other Wnts activate Wnt and beta-catenin canonical pathway and induce duplication of the axis in Xenopus and Zebrafish.	0	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	0	1	11	12
Similar to mMesd ( 155-191 ) , hMesd ( 160-197 ) displayed inhibitory effects on Wnt and beta-catenin signaling induced by LRP6 , Wnt3A , Rspo1 , Wnt1 and Wnt10b ( XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY ) .	Similar to mMesd (155-191), hMesd (160-197) displayed inhibitory effects on Wnt and beta-catenin signaling induced by LRP6, Wnt3A, Rspo1, Wnt1 and Wnt10b (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).	15	28	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	27	28	17	18
While Wnt1 induced the activation of beta-catenin and the mTOR pathway , both hair follicle hyperproliferation and stem cell exhaustion were strictly dependent on mTOR function .	While Wnt1 induced the activation of beta-catenin and the mTOR pathway, both hair follicle hyperproliferation and stem cell exhaustion were strictly dependent on mTOR function.	1	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
In mammalian cells , Axin inhibits Wnt-1 stimulation of beta-catenin and lymphoid enhancer factor 1 dependent transcription .	In mammalian cells, Axin inhibits Wnt-1 stimulation of beta-catenin and lymphoid enhancer factor 1 dependent transcription.	6	16	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	6	7	9	10
Gleevec has been shown to effectively inhibit the constitutive activity of beta-catenin signaling in human colon cancer cells ( HCT-116 and SW480 ) as well as in Wnt1 induced activation of beta-catenin signaling in different cell lines [ XREF_BIBR ] .	Gleevec has been shown to effectively inhibit the constitutive activity of beta-catenin signaling in human colon cancer cells (HCT-116 and SW480) as well as in Wnt1 induced activation of beta-catenin signaling in different cell lines [XREF_BIBR].	26	32	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	27	28	31	32
Previous studies have shown that ectopic expression of Wnt1 causes endogenous beta-catenin activation in HKC-8 cells .	Previous studies have shown that ectopic expression of Wnt1 causes endogenous beta-catenin activation in HKC-8 cells.	6	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	expression of Wnt1	wnt1	beta-catenin	beta-catenin	beta-catenin	8	9	11	12
At a molecular level , VPA enhanced Wnt1 expression and activated the GSK-3beta and beta-catenin pathway .	At a molecular level, VPA enhanced Wnt1 expression and activated the GSK-3beta and beta-catenin pathway.	5	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	VPA enhanced Wnt1 expression	wnt1	beta-catenin	beta-catenin	beta-catenin	7	8	14	15
Quantitative RT-PCR results showed that the main genes of Wnt and beta-catenin signaling Wnt1 , CyclinD1 , c-Myc , TCF4 , LEF1 expressed markedly higher in tumors derived from SP compared with those from non SP .	Quantitative RT-PCR results showed that the main genes of Wnt and beta-catenin signaling Wnt1, CyclinD1, c-Myc, TCF4, LEF1 expressed markedly higher in tumors derived from SP compared with those from non SP.	11	21	signaling	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	13	14	11	12
Here , we confirmed WNT-1 , WNT-2 , WNT-3 and WNT-7A expression , all of which can activate WNT and beta-catenin signaling , in adult mouse brain ( XREF_FIG ) .	Here, we confirmed WNT-1, WNT-2, WNT-3 and WNT-7A expression, all of which can activate WNT and beta-catenin signaling, in adult mouse brain (XREF_FIG).	4	21	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT-1	WNT-1, WNT-2, WNT-3 and WNT-7A expression	wnt-1	beta-catenin	beta-catenin	beta-catenin	4	5	20	21
Wnt1 class ligands ( e.g ., Wnt1 , Wnt3a and Wnt8 ) activate the canonical Wnt and beta-catenin pathway , which stabilizes beta-catenin as a transcriptional regulator in the nucleus XREF_BIBR , XREF_BIBR .	Wnt1 class ligands (e.g., Wnt1, Wnt3a and Wnt8) activate the canonical Wnt and beta-catenin pathway, which stabilizes beta-catenin as a transcriptional regulator in the nucleus XREF_BIBR, XREF_BIBR.	0	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	0	1	17	18
After Dox induction , expression of Axin2 mRNA in SMG was significantly elevated in male KRT5-rtTA and tetO-Wnt 1 mice , but not in females ( XREF_FIG ) , indicating that transient Wnt1 expression in basal epithelia only efficiently activated Wnt and beta-catenin pathway in SMGs of male mice .	After Dox induction, expression of Axin2 mRNA in SMG was significantly elevated in male KRT5-rtTA and tetO-Wnt 1 mice, but not in females (XREF_FIG), indicating that transient Wnt1 expression in basal epithelia only efficiently activated Wnt and beta-catenin pathway in SMGs of male mice.	32	43	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 expression	wnt1	beta-catenin	beta-catenin	beta-catenin	32	33	42	43
Moreover , exogenous expression of the Wnt1 ligand induced betaCatenin nuclear accumulation and TRIB2 up-regulation in Huh7 cells ( XREF_FIG ) .	Moreover, exogenous expression of the Wnt1 ligand induced betaCatenin nuclear accumulation and TRIB2 up-regulation in Huh7 cells (XREF_FIG).	6	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	betaCatenin	betaCatenin	betaCatenin	6	7	9	10
Our previous study hasdemonstrated that Wnt and beta-catenin signal is inhibited in SH-SY5Y cells treated with 6-OHDA , a cellular model of PD , while activation of Wnt and beta-catenin signal by exogenous Wnt1 could protect cells by restoring mitochondria and endoplasmic reticulum function [ XREF_BIBR ] .	Our previous study hasdemonstrated that Wnt and beta-catenin signal is inhibited in SH-SY5Y cells treated with 6-OHDA, a cellular model of PD, while activation of Wnt and beta-catenin signal by exogenous Wnt1 could protect cells by restoring mitochondria and endoplasmic reticulum function [XREF_BIBR].	27	34	signal	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	33	34	29	30
Both Wnt1 and Wnt3 ligands activate the Wnt and beta-catenin pathways , however , their expression patterns during liver regeneration exhibited differentially ( XREF_FIG ) .	Both Wnt1 and Wnt3 ligands activate the Wnt and beta-catenin pathways, however, their expression patterns during liver regeneration exhibited differentially (XREF_FIG).	1	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	1	2	9	10
Howe et al reported that WNT1 induces overexpression of downstream target genes by activating the WNT and beta-catenin signaling pathway , resulting in excessive cell growth .	Howe et al reported that WNT1 induces overexpression of downstream target genes by activating the WNT and beta-catenin signaling pathway, resulting in excessive cell growth.	5	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT1	WNT1	WNT1	beta-catenin	beta-catenin	beta-catenin	5	6	17	18
Thus , Wnt1 expression may cause the paracrine activation of beta-catenin in the adjacent HF epithelial layers .	Thus, Wnt1 expression may cause the paracrine activation of beta-catenin in the adjacent HF epithelial layers.	2	11	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 expression	wnt1	beta-catenin	beta-catenin	beta-catenin	2	3	10	11
Transfection of Wnt-1 plasmid was previously shown to induce nuclear localization of beta-catenin in NIH3T3 and mammary epithelial cells .	Transfection of Wnt-1 plasmid was previously shown to induce nuclear localization of beta-catenin in NIH3T3 and mammary epithelial cells.	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	2	3	12	13
Intriguingly , Wnt1 induced beta-catenin accumulation does not seem to affect AChR clustering in C2C12 myotubes and AChR cluster sizes are increased in betacatenin loss-of-function mutation in muscles .	Intriguingly, Wnt1 induced beta-catenin accumulation does not seem to affect AChR clustering in C2C12 myotubes and AChR cluster sizes are increased in betacatenin loss-of-function mutation in muscles.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
Wnt-1 induces morphological transformation of C57MG mammary epithelial cells and accumulation of cytosolic beta-catenin whereas Wnt-5a has no effect .	Wnt-1 induces morphological transformation of C57MG mammary epithelial cells and accumulation of cytosolic beta-catenin whereas Wnt-5a has no effect.	0	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	0	1	13	14
Members of the Wnt1 class include Wnt1 , Wnt2 , Wnt3 , Wnt3A , Wnt8 , Wnt8B , and Wnt10B ( Wnt1 shares 96 % identity in amino acid sequence to Wnt10B and overlap in function ) and induce secondary body axis in Xenopus and activates the canonical Wnt and beta-catenin pathway .	Members of the Wnt1 class include Wnt1, Wnt2, Wnt3, Wnt3A, Wnt8, Wnt8B, and Wnt10B (Wnt1 shares 96% identity in amino acid sequence to Wnt10B and overlap in function) and induce secondary body axis in Xenopus and activates the canonical Wnt and beta-catenin pathway.	3	51	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	3	4	50	51
Our in vitro and in vivo data further support the use of an anti-Wnt-1 antibody as a new treatment option for HCC , since it blocks Wnt-1 mediated beta-catenin and Tcf4 transcription , which in turn leads to reduced proliferation , enhanced apoptosis , and down-regulation of important downstream target oncoproteins in HCC .	Our in vitro and in vivo data further support the use of an anti-Wnt-1 antibody as a new treatment option for HCC, since it blocks Wnt-1 mediated beta-catenin and Tcf4 transcription, which in turn leads to reduced proliferation, enhanced apoptosis, and down-regulation of important downstream target oncoproteins in HCC.	25	41	mediated	Positive_early_activation	Positive_activation	Positive_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	26	27	28	29
In addition , hypotonic stress was shown to activate SPAK and OSR1 and induce phosphorylation of the conserved OSR1 serine residue , suggesting that WNK1 may be an activator of the SPAK and OSR1 kinases .	In addition, hypotonic stress was shown to activate SPAK and OSR1 and induce phosphorylation of the conserved OSR1 serine residue, suggesting that WNK1 may be an activator of the SPAK and OSR1 kinases.	24	34	be an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	SPAK	SPAK	SPAK	24	25	31	32
However , WNK1 also activates the SPAK and OSR1 pathway during hypotonic Cl - -depleted or K + -depleted conditions [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	However, WNK1 also activates the SPAK and OSR1 pathway during hypotonic Cl - -depleted or K + -depleted conditions [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	SPAK	SPAK	SPAK	2	3	6	7
In the present study , we first describe the generation of double-knockin ES ( embryonic stem ) cells , where SPAK and OSR1 can not be activated by WNK1 .	In the present study, we first describe the generation of double-knockin ES (embryonic stem) cells, where SPAK and OSR1 can not be activated by WNK1.	20	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	SPAK	SPAK	SPAK	28	29	20	21
This is in contrast to WNK1 and WNK3 , which typically stimulate SPAK and NCC activity in the same model conditions .	This is in contrast to WNK1 and WNK3, which typically stimulate SPAK and NCC activity in the same model conditions.	3	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	SPAK	SPAK	SPAK	5	6	12	13
If WNK1 can activate SPAK and NCC , independent of WNK4 , as suggested by biochemical studies , the phenotype of WNK1 +/FHHt might persist when WNK4 is inactivated .	If WNK1 can activate SPAK and NCC, independent of WNK4, as suggested by biochemical studies, the phenotype of WNK1 +/FHHt might persist when WNK4 is inactivated.	1	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	SPAK	SPAK	SPAK	1	2	4	5
WNK1 may also activate STK39 [ XREF_BIBR ] .	WNK1 may also activate STK39 [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	STK39	STK39	STK39	0	1	4	5
In cell based models , low intracellular chloride concentrations ( [ Cl - ] i ) result in WNK1 mediated SPAK activation that strongly increases CFTR HCO 3 - permeability in CFTR transfected HEK 293T , PANC1 , and guinea pig pancreatic duct cells , making CFTR primarily an HCO 3 - channel XREF_BIBR .	In cell based models, low intracellular chloride concentrations ([Cl -] i) result in WNK1 mediated SPAK activation that strongly increases CFTR HCO 3 - permeability in CFTR transfected HEK 293T, PANC1, and guinea pig pancreatic duct cells, making CFTR primarily an HCO 3 - channel XREF_BIBR.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	SPAK	SPAK	SPAK	18	19	20	21
These data support the existence of a WNK1/SPAK/NCC cascade , but do not indicate whether SPAK and NCC is stimulated directly by WNK1 , or whether the effects result from relief of WNK4 inhibition .	These data support the existence of a WNK1/SPAK/NCC cascade, but do not indicate whether SPAK and NCC is stimulated directly by WNK1, or whether the effects result from relief of WNK4 inhibition.	15	23	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	SPAK	SPAK	SPAK	22	23	15	16
Phosphorylation of WNK1 at Ser 1261 , which is located next to a CCT domain binding RFXV motif ( see the Introduction ) , is thought to promote dissociation of SPAK and OSR1 from WNK1 after these enzymes are activated by osmotic stress [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Phosphorylation of WNK1 at Ser 1261, which is located next to a CCT domain binding RFXV motif (see the Introduction), is thought to promote dissociation of SPAK and OSR1 from WNK1 after these enzymes are activated by osmotic stress [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	31	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	Phosphorylation of WNK1 at Ser 1261	wnk1	SPAK	SPAK	spak	2	3	30	31
To reconcile with those early reports that WNK4 is inhibitory to NCC and in keeping with the notion that WNK1 activates NCC , a more recent report by Hadchouel , Gamba , and coworkers proposed a revised model that WNK1 activates SPAK to activate NCC in DCT , and that WNK4 working upstream to antagonize WNK1 activation of NCC .	To reconcile with those early reports that WNK4 is inhibitory to NCC and in keeping with the notion that WNK1 activates NCC, a more recent report by Hadchouel, Gamba, and coworkers proposed a revised model that WNK1 activates SPAK to activate NCC in DCT, and that WNK4 working upstream to antagonize WNK1 activation of NCC.	39	43	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	SPAK	SPAK	SPAK	39	40	41	42
Regarding the results of the study by Hadchouel , Gamba , and coworkers , because both WNK1 and 4 activate NCC through the same OSR1 and SPAK signaling cascade , increased function of WNK1 may activate OSR1 and SPAK to an ( maximal ) extent such that loss-of-function of WNK4 does not affect the total activation of NCC .	Regarding the results of the study by Hadchouel, Gamba, and coworkers, because both WNK1 and 4 activate NCC through the same OSR1 and SPAK signaling cascade, increased function of WNK1 may activate OSR1 and SPAK to an (maximal) extent such that loss-of-function of WNK4 does not affect the total activation of NCC.	31	39	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	SPAK	SPAK	SPAK	33	34	38	39
Our results further showed that beta-catenin and pGSK3beta levels were increased compared to the MSCs treated with siRNA Wnt10b .	Our results further showed that beta-catenin and pGSK3beta levels were increased compared to the MSCs treated with siRNA Wnt10b.	5	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Wnt10b	Wnt10b	Wnt10b	beta-catenin	beta-catenin	beta-catenin	18	19	5	6
Mechanistically , ChIP analysis uncovered that WNT10B activates canonical beta-catenin signalling leading to up-regulation of HMGA2 .	Mechanistically, ChIP analysis uncovered that WNT10B activates canonical beta-catenin signalling leading to up-regulation of HMGA2.	6	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT10B	WNT10B	WNT10B	beta-catenin	beta-catenin	beta-catenin	6	7	9	10
Although the 19 different Wnt ligands found in both human and mouse can activate several branches of the Wnt pathway , WNT10B specifically activates canonical Wnt and beta-catenin signalling and thus triggers beta-catenin/LEF/TCF-mediated transcriptional programs .	Although the 19 different Wnt ligands found in both human and mouse can activate several branches of the Wnt pathway, WNT10B specifically activates canonical Wnt and beta-catenin signalling and thus triggers beta-catenin/LEF/TCF-mediated transcriptional programs.	21	31	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT10B	WNT10B	WNT10B	beta-catenin	beta-catenin	beta-catenin	21	22	27	28
Wnt10b and BIO activate the Wnt and beta-catenin pathway through inactivation of GSK-3beta Y216 both in insulin sensitive and insulin resistant myotubes ( XREF_FIG ) , which resulted in nuclear translocation of active beta-catenin , stimulation of myogenic genes transcription ( e.g myoD , myogenin ) and inhibition of Srebp-1c transcription ( XREF_FIG ) .	Wnt10b and BIO activate the Wnt and beta-catenin pathway through inactivation of GSK-3beta Y216 both in insulin sensitive and insulin resistant myotubes (XREF_FIG), which resulted in nuclear translocation of active beta-catenin, stimulation of myogenic genes transcription (e.g myoD, myogenin) and inhibition of Srebp-1c transcription (XREF_FIG).	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10b	Wnt10b	Wnt10b	beta-catenin	beta-catenin	beta-catenin	0	1	7	8
We previously reported the differentiation of cultured primary skin epithelial cells toward hair shaft and inner root sheath ( IRS ) of the hair follicle via beta-catenin stabilization caused by Wnt-10b , however , the effects of Wnt-10b on cultured hair follicles have not been reported .	We previously reported the differentiation of cultured primary skin epithelial cells toward hair shaft and inner root sheath (IRS) of the hair follicle via beta-catenin stabilization caused by Wnt-10b, however, the effects of Wnt-10b on cultured hair follicles have not been reported.	26	31	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt-10b	Wnt-10b	Wnt-10b	beta-catenin	beta-catenin	beta-catenin	30	31	26	27
For instance , the WNT ligands WNT-3A and WNT-10B activate beta-catenin signaling in NIH 3T3 fibroblasts resulting in an increased mRNA expression of connective tissue growth factor ( CTGF , CCN2 ) , endothelin-1 and TGF-beta XREF_BIBR .	For instance, the WNT ligands WNT-3A and WNT-10B activate beta-catenin signaling in NIH 3T3 fibroblasts resulting in an increased mRNA expression of connective tissue growth factor (CTGF, CCN2), endothelin-1 and TGF-beta XREF_BIBR.	6	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT-10B	WNT-10B	WNT-10B	beta-catenin	beta-catenin	beta-catenin	8	9	10	11
Although high levels of WNT2 , WNT7B and WNT10B are reported to activate WNT and beta-catenin signalling , several studies report a reduction in nuclear beta-catenin staining in high-risk melanoma patients .	Although high levels of WNT2, WNT7B and WNT10B are reported to activate WNT and beta-catenin signalling, several studies report a reduction in nuclear beta-catenin staining in high-risk melanoma patients.	2	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT10B	levels of WNT2, WNT7B and WNT10B	wnt10b	beta-catenin	beta-catenin	beta-catenin	8	9	15	16
Moreover , recent data indicate that WNT10B induces transcriptionally active beta-catenin in human triple negative breast cancers and predicts survival-outcome of patients with these two types of tumors [ XREF_BIBR ] .	Moreover, recent data indicate that WNT10B induces transcriptionally active beta-catenin in human triple negative breast cancers and predicts survival-outcome of patients with these two types of tumors [XREF_BIBR].	6	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT10B	WNT10B	WNT10B	beta-catenin	beta-catenin	beta-catenin	6	7	10	11
We illustrate that WNT10B induces transcriptionally active beta-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal like tumours .	We illustrate that WNT10B induces transcriptionally active beta-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal like tumours.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT10B	WNT10B	WNT10B	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
As expected , Wnt10b over-expression decreased GSK-3beta activity by dephosphorylating Y 216 and induced the nuclear translocation of active beta-catenin , which led to the up-regulation of MyoD in the nucleus .	As expected, Wnt10b over-expression decreased GSK-3beta activity by dephosphorylating Y 216 and induced the nuclear translocation of active beta-catenin, which led to the up-regulation of MyoD in the nucleus.	3	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10b	Wnt10b over-expression	wnt10b	beta-catenin	beta-catenin	beta-catenin	3	4	19	20
We found that WNT10B up-regulated beta-catenin and Tcf activity .	We found that WNT10B up-regulated beta-catenin and Tcf activity.	3	8	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT10B	WNT10B	WNT10B	beta-catenin	beta-catenin	beta-catenin	3	4	5	6
Here , we show that in response to prolonged ectopic Wnt10b mediated beta-catenin activation , regenerating anagen hair follicles grow larger in size .	Here, we show that in response to prolonged ectopic Wnt10b mediated beta-catenin activation, regenerating anagen hair follicles grow larger in size.	6	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Wnt10b	Wnt10b	Wnt10b	beta-catenin	beta-catenin	beta-catenin	10	11	12	13
Our data suggest an additional mechanism in which activation of beta-catenin by WNT10B in cDC1 can contribute to insulin sensitivity in FABP4-WNT10B mice .	Our data suggest an additional mechanism in which activation of beta-catenin by WNT10B in cDC1 can contribute to insulin sensitivity in FABP4-WNT10B mice.	8	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	WNT10B	WNT10B	WNT10B	beta-catenin	beta-catenin	beta-catenin	12	13	10	11
Through expression assays and observations under phase-contrast microscopy , prolonged expression of Wnt10b activated Wnt and beta-catenin pathway and induced morphological changes of cells showing longer protrusions and multilayer growth , indicating early-stage cell transformation .	Through expression assays and observations under phase-contrast microscopy, prolonged expression of Wnt10b activated Wnt and beta-catenin pathway and induced morphological changes of cells showing longer protrusions and multilayer growth, indicating early-stage cell transformation.	10	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10b	expression of Wnt10b	wnt10b	beta-catenin	beta-catenin	beta-catenin	12	13	16	17
These observations suggest that ectopic Wnt10b expression via autocrine or paracrine pathways induces beta-catenin signaling in cutaneous mesenchymal cells , leading to their activation and the induction of sustained fibrotic responses .	These observations suggest that ectopic Wnt10b expression via autocrine or paracrine pathways induces beta-catenin signaling in cutaneous mesenchymal cells, leading to their activation and the induction of sustained fibrotic responses.	5	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10b	Wnt10b expression	wnt10b	beta-catenin	beta-catenin	beta-catenin	5	6	13	14
Furthermore , ectopic expression of Wnt10b activates Wnt and beta-catenin signaling and potently inhibits adipogenesis .	Furthermore, ectopic expression of Wnt10b activates Wnt and beta-catenin signaling and potently inhibits adipogenesis.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10b	expression of Wnt10b	wnt10b	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
A previous study revealed that Wnt10B activates canonical beta-catenin signaling to promote development of breast cancer .	A previous study revealed that Wnt10B activates canonical beta-catenin signaling to promote development of breast cancer.	5	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10B	Wnt10B	Wnt10B	beta-catenin	beta-catenin	beta-catenin	5	6	8	9
Transient activation of Wnt and beta-catenin signaling by Wnt10b rapidly suppresses the master adipogenic regulators C/EBPalpha and PPARgamma in bipotential ST2 cells and this suppression precedes the Wnt induced increase in osteogenic transcription factors [ XREF_BIBR ] .	Transient activation of Wnt and beta-catenin signaling by Wnt10b rapidly suppresses the master adipogenic regulators C/EBPalpha and PPARgamma in bipotential ST2 cells and this suppression precedes the Wnt induced increase in osteogenic transcription factors [XREF_BIBR].	3	9	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Wnt10b	Wnt10b	Wnt10b	beta-catenin	beta-catenin	beta-catenin	8	9	5	6
It was reported that in hair follicles , Wnt10b could specifically activate the Wnt and beta-catenin signaling pathway .	It was reported that in hair follicles, Wnt10b could specifically activate the Wnt and beta-catenin signaling pathway.	8	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10b	Wnt10b	Wnt10b	beta-catenin	beta-catenin	beta-catenin	8	9	15	16
Further studies have shown that the inactivation of miR-148a has led to the overproduction of oncogenic ROCK1 , a kinase that promotes cell migration and invasion in gastric cancer [ XREF_BIBR ] ; Bcl-2 , an antiapoptotic protein that increases cell survival in colorectal cancer [ XREF_BIBR ] ; and WNT10B , a signaling protein that stimulates beta-catenin activation and cancer associated fibroblast cell motility [ XREF_BIBR ] .	Further studies have shown that the inactivation of miR-148a has led to the overproduction of oncogenic ROCK1, a kinase that promotes cell migration and invasion in gastric cancer [XREF_BIBR]; Bcl-2, an antiapoptotic protein that increases cell survival in colorectal cancer [XREF_BIBR]; and WNT10B, a signaling protein that stimulates beta-catenin activation and cancer associated fibroblast cell motility [XREF_BIBR].	10	58	stimulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	WNT10B	WNT10B	WNT10B	beta-catenin	beta-catenin	beta-catenin	50	51	57	58
Western blot analysis showed the nuclear shift of beta-catenin stimulated by Wnt10b was stimulated in osteoblasts ( XREF_FIG ) .	Western blot analysis showed the nuclear shift of beta-catenin stimulated by Wnt10b was stimulated in osteoblasts (XREF_FIG).	6	12	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt10b	Wnt10b	Wnt10b	beta-catenin	beta-catenin	beta-catenin	11	12	8	9
Mechanistically , our data now provide evidence that WNT10B activates canonical beta-catenin signalling leading to proliferation and up-regulation of HMGA2 in TNBC directly by components of the Wnt canonical signalling pathway .	Mechanistically, our data now provide evidence that WNT10B activates canonical beta-catenin signalling leading to proliferation and up-regulation of HMGA2 in TNBC directly by components of the Wnt canonical signalling pathway.	8	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT10B	WNT10B	WNT10B	beta-catenin	beta-catenin	beta-catenin	8	9	11	12
Preclinical studies have shown that Wnt10b driven activation of beta-catenin stimulates the proliferation of metastatic breast cancer cells 8 .	Preclinical studies have shown that Wnt10b driven activation of beta-catenin stimulates the proliferation of metastatic breast cancer cells 8.	5	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt10b	Wnt10b	Wnt10b	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
Knockdown of Xenopus Ryk results in gastrulation defects with compromised Wnt11 induced Fz7 and Dishevelled ( Dvl ) endocytosis .	Knockdown of Xenopus Ryk results in gastrulation defects with compromised Wnt11 induced Fz7 and Dishevelled (Dvl) endocytosis.	9	18	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	10	11	12	13
Importantly , Wnt11 induced Fz7 accumulations at host-host and donor-donor cell contact sites ( XREF_FIG ; and not depicted ) , confirming our previous observation ( XREF_FIG ) that Wnt11 acts both cell-autonomously and nonautonomously .	Importantly, Wnt11 induced Fz7 accumulations at host-host and donor-donor cell contact sites (XREF_FIG; and not depicted), confirming our previous observation (XREF_FIG) that Wnt11 acts both cell-autonomously and nonautonomously.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	2	3	4	5
Furthermore , we found that Wnt11 and Dsh puncta at cell contact sites display properties similar to Wnt11 induced Fz7 accumulations in the animal pole assay .	Furthermore, we found that Wnt11 and Dsh puncta at cell contact sites display properties similar to Wnt11 induced Fz7 accumulations in the animal pole assay.	17	20	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	17	18	19	20
As Dsh puncta at the plasma membrane are only partially reduced in slb and wnt11 mutants ( XREF_FIG ) , it is unlikely that all Dsh puncta correspond to endogenous Wnt11 induced Fz7 accumulations .	As Dsh puncta at the plasma membrane are only partially reduced in slb and wnt11 mutants (XREF_FIG), it is unlikely that all Dsh puncta correspond to endogenous Wnt11 induced Fz7 accumulations.	27	33	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	30	31	32	33
Overall , our observations suggest that Wnt11 induced Fz7 accumulations increase the persistence of cell contacts in the immediate area .	Overall, our observations suggest that Wnt11 induced Fz7 accumulations increase the persistence of cell contacts in the immediate area.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	6	7	8	9
These Wnt11 induced Fz7 accumulations increase cell contact persistence in a manner that is dependent on the activity of Flamingo ( Fmi ) , which is an atypical cadherin , but independent of further downstream signaling by RhoA and Rok2 .	These Wnt11 induced Fz7 accumulations increase cell contact persistence in a manner that is dependent on the activity of Flamingo (Fmi), which is an atypical cadherin, but independent of further downstream signaling by RhoA and Rok2.	0	4	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	1	2	3	4
This suggests that Wnt11 downstream signaling through RhoA and Rok is not directly involved in mediating enhancement of contact persistence by Wnt11 induced Fz7 accumulation .	This suggests that Wnt11 downstream signaling through RhoA and Rok is not directly involved in mediating enhancement of contact persistence by Wnt11 induced Fz7 accumulation.	15	24	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	21	22	23	24
To compare the effect of Wnt11 puncta on contact persistence with that of Wnt11 induced Fz7 accumulations , we also expressed Wnt11-YFP and mem-RFP in the animal pole assay .	To compare the effect of Wnt11 puncta on contact persistence with that of Wnt11 induced Fz7 accumulations, we also expressed Wnt11-YFP and mem-RFP in the animal pole assay.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	13	14	15	16
To analyze the influence of Wnt11 induced Fz7 accumulation on cell contact persistence , we determined the rate of cell contact shrinkage during separation and the time of cell separation in the presence and absence of Fz7 accumulation ( XREF_FIG ) .	To analyze the influence of Wnt11 induced Fz7 accumulation on cell contact persistence, we determined the rate of cell contact shrinkage during separation and the time of cell separation in the presence and absence of Fz7 accumulation (XREF_FIG).	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	5	6	7	8
To test whether Wnt11 induced Fz7 accumulations influence cell morphology or adhesion , we recorded 3D time-lapse videos of cells in the animal pole assay .	To test whether Wnt11 induced Fz7 accumulations influence cell morphology or adhesion, we recorded 3D time-lapse videos of cells in the animal pole assay.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	3	4	5	6
In sum , Wnt11 induced Fz7 accumulations are associated with a local increase in cell contact persistence , most likely reflecting stronger cell adhesion at these contact sites .	In sum, Wnt11 induced Fz7 accumulations are associated with a local increase in cell contact persistence, most likely reflecting stronger cell adhesion at these contact sites.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	3	4	5	6
Moreover , Wnt11 induced Fz7-YFP accumulations in a concentration dependent manner , with increased amounts of Wnt11 enhancing both the number and size of Fz7-YFP accumulations ( XREF_FIG ) .	Moreover, Wnt11 induced Fz7-YFP accumulations in a concentration dependent manner, with increased amounts of Wnt11 enhancing both the number and size of Fz7-YFP accumulations (XREF_FIG).	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7-YFP	Fz7-YFP	Fz7-YFP	2	3	4	5
As we observed cell sorting by Fz7 or PAPC supported by Wnt-11 ( XREF_FIG ) but no degradation or internalization of C-cadherin ( XREF_FIG , XREF_FIG , and S2 ) , we speculated that the hindrance of lateral clustering or cis dimerization of C-cadherin might cause reduction in cell adhesion .	As we observed cell sorting by Fz7 or PAPC supported by Wnt-11 (XREF_FIG) but no degradation or internalization of C-cadherin (XREF_FIG, XREF_FIG, and S2), we speculated that the hindrance of lateral clustering or cis dimerization of C-cadherin might cause reduction in cell adhesion.	2	19	supported	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt-11	Wnt-11	Wnt-11	Fz7	Fz7	Fz7	11	12	6	7
Collectively , our data strongly suggests that Fmi plays a key role in controlling cell adhesion at sites of Wnt11 induced Fz7 accumulation .	Collectively, our data strongly suggests that Fmi plays a key role in controlling cell adhesion at sites of Wnt11 induced Fz7 accumulation.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	19	20	21	22
Consistent with the analysis in Drosophila , the local accumulation of Fz7 induced by Wnt11 at cell-cell contacts is dependent on Celsr and Fmi proteins in zebrafish [ XREF_BIBR ] .	Consistent with the analysis in Drosophila, the local accumulation of Fz7 induced by Wnt11 at cell-cell contacts is dependent on Celsr and Fmi proteins in zebrafish [XREF_BIBR].	9	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	14	15	11	12
Consistent with Wnt11 induced Fz7 accumulations causing increased contact persistence , we found that Fz7 accumulations shrink slower than the cell contacts ( XREF_FIG ) .	Consistent with Wnt11 induced Fz7 accumulations causing increased contact persistence, we found that Fz7 accumulations shrink slower than the cell contacts (XREF_FIG).	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	2	3	4	5
In contrast , high amounts of the slb mutant allele of wnt11 ( 40 pg mRNA ; wnt11 tx226 ) , which encodes an inactive C-terminal truncated version of Wnt11 , did not induce Fz7 accumulations ( unpublished data ) .	In contrast, high amounts of the slb mutant allele of wnt11 (40 pg mRNA; wnt11 tx226), which encodes an inactive C-terminal truncated version of Wnt11, did not induce Fz7 accumulations (unpublished data).	9	35	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	wnt11	wnt11	wnt11	Fz7	Fz7	Fz7	11	12	34	35
It is possible that these subcellular sites of endogenous Wnt11 and Fz7 activity modulate contact persistence of gastrulating cells , similar to the Wnt11 induced Fz7 accumulations in the animal pole assay .	It is possible that these subcellular sites of endogenous Wnt11 and Fz7 activity modulate contact persistence of gastrulating cells, similar to the Wnt11 induced Fz7 accumulations in the animal pole assay.	23	26	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	23	24	25	26
This Wnt11 enhancement of contact persistence was considerably smaller than that of Wnt11 induced Fz7 accumulation , an expected result given the small size of Wnt11 puncta ( XREF_FIG ) .	This Wnt11 enhancement of contact persistence was considerably smaller than that of Wnt11 induced Fz7 accumulation, an expected result given the small size of Wnt11 puncta (XREF_FIG).	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	12	13	14	15
Taken together , our results suggest that PLD1 acts as a new positive mediator of Wnt and PCP signaling by promoting Wnt11 induced Fz7 endocytosis for precise regulation of Xenopus CE movements .	Taken together, our results suggest that PLD1 acts as a new positive mediator of Wnt and PCP signaling by promoting Wnt11 induced Fz7 endocytosis for precise regulation of Xenopus CE movements.	20	24	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	21	22	23	24
In zebrafish , Wnt11 does not induce Fz7 and Dvl endocytosis , but rather stimulates Fz7 and Dvl accumulation on the plasma membrane , raising the possibility that Wnt-Ryk and Wnt-Fz signaling pathways are distinct .	In zebrafish, Wnt11 does not induce Fz7 and Dvl endocytosis, but rather stimulates Fz7 and Dvl accumulation on the plasma membrane, raising the possibility that Wnt-Ryk and Wnt-Fz signaling pathways are distinct.	3	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	3	4	7	8
This suggests that Wnt11 induced Fz7 accumulations are sites of Wnt11 activity .	This suggests that Wnt11 induced Fz7 accumulations are sites of Wnt11 activity.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	3	4	5	6
To test if Wnt11 induced Fz7 accumulations are sites of local Wnt11 activity , we looked for changes in Dsh localization .	To test if Wnt11 induced Fz7 accumulations are sites of local Wnt11 activity, we looked for changes in Dsh localization.	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	3	4	5	6
To distinguish between these possibilities , we monitored the effects of Wnt11 induced Fz7 accumulations on cell contact behavior within the animal pole assay when RhoA and Rok activity is decreased .	To distinguish between these possibilities, we monitored the effects of Wnt11 induced Fz7 accumulations on cell contact behavior within the animal pole assay when RhoA and Rok activity is decreased.	9	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	11	12	13	14
The notion that WNK1 and 4 both stimulates NCC and NKCC1/2 via phosphorylation and activation of intermediate kinases OSR1 and/or SPAK in vivo were supported by studies showing that Wnk4-null mice have hypotension and decreased NCC abundance in the kidney and diminished urinary excretion of Na + in response to hydrochlorothiazide .	The notion that WNK1 and 4 both stimulates NCC and NKCC1/2 via phosphorylation and activation of intermediate kinases OSR1 and/or SPAK in vivo were supported by studies showing that Wnk4-null mice have hypotension and decreased NCC abundance in the kidney and diminished urinary excretion of Na + in response to hydrochlorothiazide.	3	19	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	OSR1	OSR1	OSR1	3	4	18	19
Mutation of Thr185 to alanine prevented the activation of OSR1 by WNK1 , whereas mutation of Thr185 to glutamic acid ( to mimic phosphorylation ) increased the basal activity of OSR1 over 20-fold and prevented further activation by WNK1 .	Mutation of Thr185 to alanine prevented the activation of OSR1 by WNK1, whereas mutation of Thr185 to glutamic acid (to mimic phosphorylation) increased the basal activity of OSR1 over 20-fold and prevented further activation by WNK1.	5	12	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	OSR1	OSR1	OSR1	11	12	9	10
These results indicate that WNK1 activation of the OSR1 signaling cascade is an essential pathway that regulates angiogenesis and cardiac formation during mouse embryo development .	These results indicate that WNK1 activation of the OSR1 signaling cascade is an essential pathway that regulates angiogenesis and cardiac formation during mouse embryo development.	4	10	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	OSR1	OSR1	OSR1	4	5	8	9
These characteristics are reminiscent of phenotypes caused by inhibiting Wnt and beta-catenin signaling in mouse embryonic ectoderm , suggesting that WNT10A activates the beta-catenin pathway in the development of these epithelial organs .	These characteristics are reminiscent of phenotypes caused by inhibiting Wnt and beta-catenin signaling in mouse embryonic ectoderm, suggesting that WNT10A activates the beta-catenin pathway in the development of these epithelial organs.	20	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT10A	WNT10A	WNT10A	beta-catenin	beta-catenin	beta-catenin	20	21	23	24
Interestingly , genes involved in the regulation of HF-SC behavior were found to be the most upregulated ones in macrophages before the onset of HF-SC activation , among them Wnt7b and Wnt10a ligands that can activate canonical beta-catenin and Wnt signaling .	Interestingly, genes involved in the regulation of HF-SC behavior were found to be the most upregulated ones in macrophages before the onset of HF-SC activation, among them Wnt7b and Wnt10a ligands that can activate canonical beta-catenin and Wnt signaling.	31	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10a	Wnt10a	Wnt10a	beta-catenin	beta-catenin	beta-catenin	31	32	37	38
These results indicate that WNT10A promotes renal cell proliferation by activating WNT and beta-catenin pathway .	These results indicate that WNT10A promotes renal cell proliferation by activating WNT and beta-catenin pathway.	4	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT10A	WNT10A	WNT10A	beta-catenin	beta-catenin	beta-catenin	4	5	13	14
Furthermore , Wnt10a was revealed to promote invasion in esophageal squamous cell carcinoma and function as an oncogene in renal cell carcinoma , by activating the Wnt and beta-catenin signaling pathway .	Furthermore, Wnt10a was revealed to promote invasion in esophageal squamous cell carcinoma and function as an oncogene in renal cell carcinoma, by activating the Wnt and beta-catenin signaling pathway.	2	30	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10a	Wnt10a	Wnt10a	beta-catenin	beta-catenin	beta-catenin	2	3	28	29
Moreover , the regeneration of the zebrafish tail fin is also associated with Wnt and beta-catenin signalling , mediated by the Wnt10a and Wnt5a ligands XREF_BIBR .	Moreover, the regeneration of the zebrafish tail fin is also associated with Wnt and beta-catenin signalling, mediated by the Wnt10a and Wnt5a ligands XREF_BIBR.	13	25	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt10a	Wnt10a	Wnt10a	beta-catenin	beta-catenin	beta-catenin	21	22	15	16
However , there were no synergistic effects observed between Wnt10a siRNA3 and LGK-974 , which indicated that Wnt10a activated the Wnt and beta-catenin signaling pathway in SKOV3 cells .	However, there were no synergistic effects observed between Wnt10a siRNA3 and LGK-974, which indicated that Wnt10a activated the Wnt and beta-catenin signaling pathway in SKOV3 cells.	17	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10a	Wnt10a	Wnt10a	beta-catenin	beta-catenin	beta-catenin	17	18	22	23
Wnt10a was identified to function in an autocrine manner in renal cell carcinoma , and so we hypothesize that Wnt10a may also activate the Wnt and beta-catenin signaling pathway in an autocrine manner in ovarian cancer cells .	Wnt10a was identified to function in an autocrine manner in renal cell carcinoma, and so we hypothesize that Wnt10a may also activate the Wnt and beta-catenin signaling pathway in an autocrine manner in ovarian cancer cells.	19	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10a	Wnt10a	Wnt10a	beta-catenin	beta-catenin	beta-catenin	19	20	26	27
Wnt10a activates the Wnt and beta-catenin signaling pathway .	Wnt10a activates the Wnt and beta-catenin signaling pathway.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10a	Wnt10a	Wnt10a	beta-catenin	beta-catenin	beta-catenin	0	1	5	6
The results showed that WNT10A , nuclear beta-catenin , and nuclear cyclin D1 were independent risk factors for renal carcinogenesis even after adjustment of age and gender and increased the incidence risk of renal carcinogenesis by 2-4 fold ( WNT10A , 2.20 fold ; nuclear beta-catenin , 2.65 fold ; and nuclear cyclin D1 , 3.95 fold ( XREF_TABLE ) ) .	The results showed that WNT10A, nuclear beta-catenin, and nuclear cyclin D1 were independent risk factors for renal carcinogenesis even after adjustment of age and gender and increased the incidence risk of renal carcinogenesis by 2-4 fold (WNT10A, 2.20 fold; nuclear beta-catenin, 2.65 fold; and nuclear cyclin D1, 3.95 fold (XREF_TABLE)).	4	58	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	WNT10A	WNT10A	WNT10A	beta-catenin	beta-catenin	beta-catenin	39	40	7	8
Therefore , we hypothesized that the knockdown of Wnt10a in SKOV3 cells may disrupt the Wnt and beta-catenin signaling pathway .	Therefore, we hypothesized that the knockdown of Wnt10a in SKOV3 cells may disrupt the Wnt and beta-catenin signaling pathway.	6	19	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10a	Wnt10a	Wnt10a	beta-catenin	beta-catenin	beta-catenin	8	9	17	18
A previous study reported that Wnt10a activates the Wnt and beta-catenin signaling pathway in renal carcinoma cells .	A previous study reported that Wnt10a activates the Wnt and beta-catenin signaling pathway in renal carcinoma cells.	5	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10a	Wnt10a	Wnt10a	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
Human VRK1 induces a stabilization and accumulation of p53 by specific phosphorylation in Thr18 .	Human VRK1 induces a stabilization and accumulation of p53 by specific phosphorylation in Thr18.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VRK1	VRK1	VRK1	p53	p53	p53	1	2	8	9
Activated p53 induces the downregulation of VRK1 .	Activated p53 induces the downregulation of VRK1.	0	7	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VRK1	VRK1	VRK1	p53	p53	p53	6	7	1	2
VRK1 mediates p53 accumulation by increasing its stability through phosphorylation of Thr 18 within its mdm-2 binding site [ XREF_BIBR , XREF_BIBR ] .	VRK1 mediates p53 accumulation by increasing its stability through phosphorylation of Thr 18 within its mdm-2 binding site [XREF_BIBR, XREF_BIBR].	0	3	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VRK1	VRK1	VRK1	p53	p53	p53	0	1	2	3
In conclusion , the pharmacological targeting of VRK1 will impair p53 mediated responses , prevent cell cycle progression and proliferation , and sensitize cells to treatments based on DNA damage , such as ionizing radiation and some chemotherapeutic drugs .	In conclusion, the pharmacological targeting of VRK1 will impair p53 mediated responses, prevent cell cycle progression and proliferation, and sensitize cells to treatments based on DNA damage, such as ionizing radiation and some chemotherapeutic drugs.	5	12	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VRK1	VRK1	VRK1	p53	p53	p53	7	8	10	11
Control cells accumulated p53 in response to UV , but the knockdown of VRK1 prevented the accumulation of p53 , and its Thr18 phosphorylation induced by UV light with respect to the siControl and non transfected control cells ( XREF_FIG ) .	Control cells accumulated p53 in response to UV, but the knockdown of VRK1 prevented the accumulation of p53, and its Thr18 phosphorylation induced by UV light with respect to the siControl and non transfected control cells (XREF_FIG).	11	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	VRK1	VRK1	VRK1	p53	p53	p53	13	14	18	19
Overexpression of VRK1 increases the stability of p53 by a posttranslational mechanism leading to its accumulation by a mechanism independent of the Chk2 kinase .	Overexpression of VRK1 increases the stability of p53 by a posttranslational mechanism leading to its accumulation by a mechanism independent of the Chk2 kinase.	0	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VRK1	Overexpression of VRK1	vrk1	p53	p53	p53	2	3	7	8
Catalytically inactive VRK1 protein ( a K179E mutant ) does not induce p53 accumulation .	Catalytically inactive VRK1 protein (a K179E mutant) does not induce p53 accumulation.	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VRK1	VRK1	VRK1	p53	p53	p53	2	3	12	13
VRK1 activates p53 by phosphorylation of the N-terminus [ XREF_BIBR ] , while AURB phosphorylates the C-terminus of p53 to facilitate its degradation by ubiquitination [ XREF_BIBR ] .	VRK1 activates p53 by phosphorylation of the N-terminus [XREF_BIBR], while AURB phosphorylates the C-terminus of p53 to facilitate its degradation by ubiquitination [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VRK1	VRK1	VRK1	p53	p53	p53	0	1	2	3
VRK1 mediated p53 stabilization was also detected in Mdm2 (-/-) cells .	VRK1 mediated p53 stabilization was also detected in Mdm2 (-/-) cells.	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	VRK1	VRK1	VRK1	p53	p53	p53	0	1	2	3
Gigantol treatment inhibited Wnt signaling activated by Wnt1 , LRP6 and Wnt1 and LRP6 in a dose dependent manner .	Gigantol treatment inhibited Wnt signaling activated by Wnt1, LRP6 and Wnt1 and LRP6 in a dose dependent manner.	2	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	LRP6	LRP6	LRP6	7	8	13	14
This was confirmed in further experiments which demonstrated that selectively blocking Wnt1 induced LRP6 signaling reduced bone density gains in mice with both Sost and Lrp5 mutations .	This was confirmed in further experiments which demonstrated that selectively blocking Wnt1 induced LRP6 signaling reduced bone density gains in mice with both Sost and Lrp5 mutations.	10	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	LRP6	LRP6	LRP6	11	12	13	14
Thus , whereas Sost deficiency induced bone anabolism partially requires Lrp5 , it fully depends on Wnt1 class induced Lrp6 activity .	Thus, whereas Sost deficiency induced bone anabolism partially requires Lrp5, it fully depends on Wnt1 class induced Lrp6 activity.	16	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	Lrp6	Lrp6	Lrp6	16	17	19	20
We found that transgenic expression of Wnt1 partially rescued the Lrp6 -/- ductal phenotype at E18.5 and induced sprout elongation and side branching ( XREF_FIG ) .	We found that transgenic expression of Wnt1 partially rescued the Lrp6 -/- ductal phenotype at E18.5 and induced sprout elongation and side branching (XREF_FIG).	4	13	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	expression of Wnt1	wnt1	Lrp6	Lrp6	lrp6	6	7	10	11
WNT1- and WNT7B mediated synergistic Wnt signaling requires FZD5 , FZD8 and LRP6 , as well as the WNT7B co-receptors GPR124 ( also known as ADGRA2 ) and RECK .	WNT1- and WNT7B mediated synergistic Wnt signaling requires FZD5, FZD8 and LRP6, as well as the WNT7B co-receptors GPR124 (also known as ADGRA2) and RECK.	0	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT1-	WNT1-	WNT1-	LRP6	LRP6	LRP6	0	1	12	13
For example , Wnt1 expression preferentially activates Myf5 , while Wnt7a expressing cells activate MyoD , and Wnt4 , Wnt5a and Wnt6 can activate both Myf5 and MyoD [ XREF_BIBR ] .	For example, Wnt1 expression preferentially activates Myf5, while Wnt7a expressing cells activate MyoD, and Wnt4, Wnt5a and Wnt6 can activate both Myf5 and MyoD [XREF_BIBR].	3	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 expression	wnt1	Myf5	Myf5	myf5	3	4	7	8
The expression of Myf5 and MyoD has been shown to be activated by Wnts differentially : Wnt1 and Wnt7a preferentially activate Myf5 and MyoD respectively , whereas Wnt4 , Wnt5 and Wnt6 activate both MRFs at an intermediate level ; the expression of MyoD was also found to be enhanced by Wnt3a during directed myogenic differentiation of P19 cells [ XREF_BIBR - XREF_BIBR ] .	The expression of Myf5 and MyoD has been shown to be activated by Wnts differentially : Wnt1 and Wnt7a preferentially activate Myf5 and MyoD respectively, whereas Wnt4, Wnt5 and Wnt6 activate both MRFs at an intermediate level; the expression of MyoD was also found to be enhanced by Wnt3a during directed myogenic differentiation of P19 cells [XREF_BIBR - XREF_BIBR].	16	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	Myf5	Myf5	Myf5	16	17	21	22
Further , Wnt1 preferentially activates Myf5 , and Wnt7a preferentially activates MyoD in the presomitic mesoderm ; however , Wnt4 , Wnt5a , and Wnt6 can moderately activate both MyoD and Myf5 expression [ XREF_BIBR ] .	Further, Wnt1 preferentially activates Myf5, and Wnt7a preferentially activates MyoD in the presomitic mesoderm; however, Wnt4, Wnt5a, and Wnt6 can moderately activate both MyoD and Myf5 expression [XREF_BIBR].	2	6	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	Myf5	Myf5	Myf5	2	3	5	6
In the somites , Wnt1 ligands preferentially activate Myf5 , whereas Wnt7a ligands activate MyoD in myogenic progenitors .	In the somites, Wnt1 ligands preferentially activate Myf5, whereas Wnt7a ligands activate MyoD in myogenic progenitors.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	Myf5	Myf5	Myf5	4	5	8	9
It is currently unclear whether MuSK activation by Wnt11 is Lrp4 dependent and what role Lrp4 plays during AChR pre-patterning .	It is currently unclear whether MuSK activation by Wnt11 is Lrp4 dependent and what role Lrp4 plays during AChR pre-patterning.	5	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	MuSK	MuSK	MuSK	8	9	5	6
It has been postulated that Wnt11 induced MuSK endocytosis localizes MuSK to Rab11 positive recycling endosomes , thereby inducing a signalling cascade via planar cell polarity components XREF_BIBR .	It has been postulated that Wnt11 induced MuSK endocytosis localizes MuSK to Rab11 positive recycling endosomes, thereby inducing a signalling cascade via planar cell polarity components XREF_BIBR.	5	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	MuSK	MuSK	MuSK	5	6	7	8
These results argue that PI3K dependent activation of Akt by IGF1 leads to phosphorylation of WNK1 and enhances the ability of WNK1 to synergistically regulate PLC-beta signaling by promoting PIP 2 synthesis .	These results argue that PI3K dependent activation of Akt by IGF1 leads to phosphorylation of WNK1 and enhances the ability of WNK1 to synergistically regulate PLC-beta signaling by promoting PIP 2 synthesis.	4	22	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	PI3K dependent activation of Akt by IGF1 leads to phosphorylation of WNK1	wnk1	WNK1	WNK1	wnk1	15	16	21	22
Phosphorylation of WNK1 by the PI3K-Akt kinase cascade enhances the ability of WNK1 to synergistically regulate PLC-beta signaling via synthesis of PIP 2 .	Phosphorylation of WNK1 by the PI3K-Akt kinase cascade enhances the ability of WNK1 to synergistically regulate PLC-beta signaling via synthesis of PIP 2.	0	13	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	Phosphorylation of WNK1	wnk1	WNK1	WNK1	wnk1	2	3	12	13
Endothelium specific expression of WNK1 was sufficient to rescue the WNK1 knockout cardiovascular development phenotype .	Endothelium specific expression of WNK1 was sufficient to rescue the WNK1 knockout cardiovascular development phenotype.	2	14	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	expression of WNK1	wnk1	WNK1	WNK1	wnk1	4	5	10	11
We speculate that under our experimental conditions of LRP5 or LRP5 * over-expression , only a portion , but not all , of LRP5 or * LRP5 is activated by Wnt1 , possibly due to availability of specific Fz proteins ( and/or other factors such as LRP chaperones ) .	We speculate that under our experimental conditions of LRP5 or LRP5 * over-expression, only a portion, but not all, of LRP5 or * LRP5 is activated by Wnt1, possibly due to availability of specific Fz proteins (and/or other factors such as LRP chaperones).	26	31	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	LRP5	LRP5	LRP5	30	31	26	27
This might be due to the molecular mechanism underlying this phenomenon ; thus Wnt1 expression induces the cell surface presentation of Lrp5 ( at low but functionally significant amounts ) from an mRNA not usually translated in luminal cells .	This might be due to the molecular mechanism underlying this phenomenon; thus Wnt1 expression induces the cell surface presentation of Lrp5 (at low but functionally significant amounts) from an mRNA not usually translated in luminal cells.	13	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt1	Wnt1 expression	wnt1	Lrp5	Lrp5	lrp5	13	14	21	22
To determine whether activation of Ryk by Wnt1 affected excitatory neurotransmission within the spinal dorsal horn , we performed whole-cell patch-clamp recordings of sEPSCs in SG neurons in spinal cord slices of control and SNL rats .	To determine whether activation of Ryk by Wnt1 affected excitatory neurotransmission within the spinal dorsal horn, we performed whole-cell patch-clamp recordings of sEPSCs in SG neurons in spinal cord slices of control and SNL rats.	3	8	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	Ryk	Ryk	Ryk	7	8	5	6
These results indicated that acute local activation of Ryk by Wnt1 enhances excitatory neurotransmission in SG neurons of SNL rats .	These results indicated that acute local activation of Ryk by Wnt1 enhances excitatory neurotransmission in SG neurons of SNL rats.	6	11	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	Ryk	Ryk	Ryk	10	11	8	9
The disease is caused by deficiency or dysfunction of von Willebrand factor ( VWF ) , a plasma protein that mediates platelet hemostatic function and stabilizes blood coagulation factor VIII .	The disease is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet hemostatic function and stabilizes blood coagulation factor VIII.	9	30	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	von Willebrand factor	von Willebrand factor	von Willebrand factor	coagulation factor VIII	coagulation factor VIII	coagulation factor VIII	9	12	27	30
VWD is caused by deficiency or dysfunction of von Willebrand factor ( VWF ) , a plasma protein that mediates platelet haemostatic function and stabilizes blood coagulation factor VIII .	VWD is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet haemostatic function and stabilizes blood coagulation factor VIII.	10	29	mediates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	VWF	VWF	VWF	coagulation factor VIII	coagulation factor VIII	coagulation factor VIII	12	13	26	29
Collectively , we conclude that VRK1 promotes CDDP resistance through c-MYC by activating c-Jun and potentiating a malignant phenotype in ESCC .	Collectively, we conclude that VRK1 promotes CDDP resistance through c-MYC by activating c-Jun and potentiating a malignant phenotype in ESCC.	5	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VRK1	VRK1	VRK1	c-Jun	c-Jun	c-Jun	5	6	13	14
Semantics : semantic relations capture meaning ; for instance , example 3 ( above ) ' c-Jun is activated by VRK1 ' can be represented as an operator ( the verb ' activate ) operating on two arguments - ' activate ( VRK1 , c-Jun ) ' - in the same way that a logical operator operates on its arguments .	Semantics : semantic relations capture meaning; for instance, example 3 (above) ' c-Jun is activated by VRK1 ' can be represented as an operator (the verb ' activate) operating on two arguments - ' activate (VRK1, c-Jun) ' - in the same way that a logical operator operates on its arguments.	16	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	VRK1	VRK1	VRK1	c-Jun	c-Jun	c-Jun	20	21	16	17
VRK1 depletion causes a defective formation of 53BP1 foci induced by ionizing radiation or doxorubicin , both in number and size , which requires a kinase-active VRK1 protein for their rescue [ XREF_BIBR ] .	VRK1 depletion causes a defective formation of 53BP1 foci induced by ionizing radiation or doxorubicin, both in number and size, which requires a kinase-active VRK1 protein for their rescue [XREF_BIBR].	0	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VRK1	VRK1	VRK1	53BP1	53BP1	53BP1	0	1	7	8
In contrast , Wnt1 treatment of MDA-MB-231 and sFRP1-P1 cells did not significantly stimulate migration , reflecting the ability of sFRP1 to block Wnt1 mediated FZD activation .	In contrast, Wnt1 treatment of MDA-MB-231 and sFRP1-P1 cells did not significantly stimulate migration, reflecting the ability of sFRP1 to block Wnt1 mediated FZD activation.	22	26	mediated	Positive_early_activation	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	FZD	FZD	FZD	23	24	25	26
Additionally , WNT-11 induces the formation of a FZD 7 / DVL/AP -2 complex that translocates to Ras related gene from brain5 or RAB5 positive endosomes in the Xenopus dorsal marginal zone in a beta-arrestin-dependent manner , and this process is critical for planar cell polarity signaling [ XREF_BIBR ] .	Additionally, WNT-11 induces the formation of a FZD 7 / DVL/AP -2 complex that translocates to Ras related gene from brain5 or RAB5 positive endosomes in the Xenopus dorsal marginal zone in a beta-arrestin-dependent manner, and this process is critical for planar cell polarity signaling [XREF_BIBR].	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT-11	WNT-11	WNT-11	FZD	FZD	FZD	2	3	8	9
The secreted Wnt5a protein then activated the orphan tyrosine kinase , ROR2 , or an uncharacterized Fzd receptor in an autocrine manner to increase the mRNA and protein expression levels of the E-ubiquitin ligase , SIAH2 .	The secreted Wnt5a protein then activated the orphan tyrosine kinase, ROR2, or an uncharacterized Fzd receptor in an autocrine manner to increase the mRNA and protein expression levels of the E-ubiquitin ligase, SIAH2.	2	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR2	ROR2	ROR2	2	3	11	12
Moreover , the increased WNT5a signaling and expression of ROR2 are associated with metastases and increased resistance to BRAF inhibition [ XREF_BIBR ] .	Moreover, the increased WNT5a signaling and expression of ROR2 are associated with metastases and increased resistance to BRAF inhibition [XREF_BIBR].	4	10	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	WNT5a	WNT5a	WNT5a	ROR2	ROR2	ROR2	4	5	9	10
When Ror1 and Ror2 deficient MEF cells were treated with 30 ng/ml of Wnt-5a and 500 ng/ml of Noggin simultaneously , no shift of Dvl2 mobility ( upper panels ) or effects on non phospho Dvl2 ( middle panel ) was observed , in contrast to wt MEF where Dvl2 was activated by the combination of Wnt-5a ( 30 ng/ml ) and Noggin ( 500 ng/ml ) .	When Ror1 and Ror2 deficient MEF cells were treated with 30 ng/ml of Wnt-5a and 500 ng/ml of Noggin simultaneously, no shift of Dvl2 mobility (upper panels) or effects on non phospho Dvl2 (middle panel) was observed, in contrast to wt MEF where Dvl2 was activated by the combination of Wnt-5a (30 ng/ml) and Noggin (500 ng/ml).	1	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Wnt-5a	Wnt-5a	Wnt-5a	Ror2	Ror2	Ror2	13	14	3	4
Our current results showing 5YF Ror2 prevented pERK1/2 stimulation and villin protein increases , while BDB Ror2 had no effect , suggest to us that recruitment of Src and phosphorylation of the five tyrosines in the BDB region were a necessary and sufficient event for Wnt5a activation of Ror2 to generate transient pERK1/2 stimulation leading to villin production .	Our current results showing 5YF Ror2 prevented pERK1/2 stimulation and villin protein increases, while BDB Ror2 had no effect, suggest to us that recruitment of Src and phosphorylation of the five tyrosines in the BDB region were a necessary and sufficient event for Wnt5a activation of Ror2 to generate transient pERK1/2 stimulation leading to villin production.	45	49	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	45	46	48	49
Indeed , WNT5A mediated Ror-2 signalling results in enhanced Src kinase activity in melanoma cells , which is essential for WNT5A mediated cell migration .	Indeed, WNT5A mediated Ror-2 signalling results in enhanced Src kinase activity in melanoma cells, which is essential for WNT5A mediated cell migration.	2	5	mediated	Positive_early_activation	Positive_activation	Positive_activation	WNT5A	WNT5A	WNT5A	Ror-2	Ror-2	Ror-2	2	3	4	5
MG-63 and U2OS cells transfected with ROR2-Flag or ROR2-siRNA and stable ROR2 knockdown MG-63 cells were seeded into 6-well plates and treated with 100ng/mL Wnt5a .	MG-63 and U2OS cells transfected with ROR2-Flag or ROR2-siRNA and stable ROR2 knockdown MG-63 cells were seeded into 6-well plates and treated with 100ng/mL Wnt5a.	11	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR2	ROR2	ROR2	24	25	11	12
WNT-5A also induces clathrin mediated internalization of FZD 4 [ XREF_BIBR ] in a PKC- and beta-arrestin-dependent process and that of ROR2 in a PKC dependent manner [ XREF_BIBR ] .	WNT-5A also induces clathrin mediated internalization of FZD 4 [XREF_BIBR] in a PKC- and beta-arrestin-dependent process and that of ROR2 in a PKC dependent manner [XREF_BIBR].	0	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT-5A	WNT-5A	WNT-5A	ROR2	ROR2	ROR2	0	1	21	22
Also , Wnt5a induced the intrnalization of Ror2 .	Also, Wnt5a induced the intrnalization of Ror2.	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	2	3	7	8
Moreover , another study showed that Wnt5a induced gastric cancer migration and invasion through binding to Fzd2 and Ror2 , leading to their internalization in a clathrin dependent manner .	Moreover, another study showed that Wnt5a induced gastric cancer migration and invasion through binding to Fzd2 and Ror2, leading to their internalization in a clathrin dependent manner.	6	19	induced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	6	7	18	19
Ror2 is a receptor for Wnt5a , a ligand that is also required for germ cell migration , though not as a chemoattractant , suggesting that Wnt5a mediated Ror2 activation may permit robust SCF mediated c-Kit activation [ XREF_BIBR , XREF_BIBR ] .	Ror2 is a receptor for Wnt5a, a ligand that is also required for germ cell migration, though not as a chemoattractant, suggesting that Wnt5a mediated Ror2 activation may permit robust SCF mediated c-Kit activation [XREF_BIBR, XREF_BIBR].	26	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	26	27	28	29
Several studies have shown that though Wnt5a addition induced activation of wild-type Ror2 kinase .	Several studies have shown that though Wnt5a addition induced activation of wild-type Ror2 kinase.	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	6	7	12	13
Evidence that Wnt5a stimulated Ror2 to induce ERK1/2 activation was demonstrated by different experimental approaches .	Evidence that Wnt5a stimulated Ror2 to induce ERK1/2 activation was demonstrated by different experimental approaches.	2	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	2	3	4	5
Since WNT5A induces noncanonical Wnt activity in the presence of the receptor ROR2 , we analyzed the expression of ROR2 in the two CC cell lines .	Since WNT5A induces noncanonical Wnt activity in the presence of the receptor ROR2, we analyzed the expression of ROR2 in the two CC cell lines.	1	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT5A	WNT5A	WNT5A	ROR2	ROR2	ROR2	1	2	12	13
Finally , to determine whether Wnt5a activates the tyrosine kinase activity Ror2 in a cell based assay , HEK293 cells , which express endogenous Ror2 protein , were treated with vehicle or Wnt5a for 10 min .	Finally, to determine whether Wnt5a activates the tyrosine kinase activity Ror2 in a cell based assay, HEK293 cells, which express endogenous Ror2 protein, were treated with vehicle or Wnt5a for 10 min.	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	5	6	11	12
Wnt5a induces heterooligermization of ROR1 and ROR2 , which activates RhoA and Rac1 and then enhances leukemia-cell chemotaxis and proliferation [ XREF_BIBR ] .	Wnt5a induces heterooligermization of ROR1 and ROR2, which activates RhoA and Rac1 and then enhances leukemia-cell chemotaxis and proliferation [XREF_BIBR].	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR2	ROR2	ROR2	0	1	6	7
A cell surface biotinylation assay revealed that Wnt5a induced the internalization of endogenous Ror2 in a time dependent manner , and mAb5A16 inhibited Wnt5a induced Ror2 internalization ( XREF_FIG ) .	A cell surface biotinylation assay revealed that Wnt5a induced the internalization of endogenous Ror2 in a time dependent manner, and mAb5A16 inhibited Wnt5a induced Ror2 internalization (XREF_FIG).	23	26	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	23	24	25	26
54 It has been demonstrated that Wnt5a and Wnt3a bind to ROR2 ; however , only Wnt5a is able to initiate the activation of the ROR2 signaling cascade .	54 It has been demonstrated that Wnt5a and Wnt3a bind to ROR2; however, only Wnt5a is able to initiate the activation of the ROR2 signaling cascade.	15	27	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR2	ROR2	ROR2	16	17	25	26
It was reported that Wnt5a can stimulate the ability of full-length Ror2 to phosphorylate a GST-Ror2 kinase domain fusion protein on tyrosine residue ( s ) in vitro , and that mutagenesis of conserved tyrosine residues within the tyrosine kinase regulatory loop of Ror2 impairs the protein ' s ability to repress canonical Wnt and beta-catenin signaling .	It was reported that Wnt5a can stimulate the ability of full-length Ror2 to phosphorylate a GST-Ror2 kinase domain fusion protein on tyrosine residue (s) in vitro, and that mutagenesis of conserved tyrosine residues within the tyrosine kinase regulatory loop of Ror2 impairs the protein 's ability to repress canonical Wnt and beta-catenin signaling.	4	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	4	5	11	12
In CLL cells , Wnt5a induces oligomerization of Ror1 and Ror2 , which in turn recruits guanine exchange factors ( GEFs ) , thereby activating Rac1 , which is associated with enhanced leukemia cell proliferation [ XREF_BIBR ] .	In CLL cells, Wnt5a induces oligomerization of Ror1 and Ror2, which in turn recruits guanine exchange factors (GEFs), thereby activating Rac1, which is associated with enhanced leukemia cell proliferation [XREF_BIBR].	4	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	4	5	10	11
To determine if Wnt5A causes clathrin mediated internalization of ROR2 , cells were treated with rWnt5A .	To determine if Wnt5A causes clathrin mediated internalization of ROR2, cells were treated with rWnt5A.	3	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5A	Wnt5A	Wnt5A	ROR2	ROR2	ROR2	3	4	9	10
This is the first demonstration that Wnt5a activating the BDB Ror2 signals differently than when Wnt5a interacts with 5YF Ror2 .	This is the first demonstration that Wnt5a activating the BDB Ror2 signals differently than when Wnt5a interacts with 5YF Ror2.	4	11	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	6	7	10	11
Wnt5a stimulates GPCRs of the frizzled ( Fzd ) family , the tyrosine kinase receptors Ror2 and Ryk and receptor complexes between Fzd and Ror2 or LRP5-LRP6 , while IL-1beta and TNF-alpha , act through receptors of the Toll-IL-1R ( TIR ) domain and death domain families respectively .	Wnt5a stimulates GPCRs of the frizzled (Fzd) family, the tyrosine kinase receptors Ror2 and Ryk and receptor complexes between Fzd and Ror2 or LRP5-LRP6, while IL-1beta and TNF-alpha, act through receptors of the Toll-IL-1R (TIR) domain and death domain families respectively.	0	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	0	1	15	16
Although others have shown that Wnt5a is able to induce Ror2 signaling through tyrosine kinase activation , it has not been shown that tyrosine kinase activity is required for the inhibitory effects of Wnt5a on Wnt and beta-catenin signaling , leading us to investigate this using several approaches .	Although others have shown that Wnt5a is able to induce Ror2 signaling through tyrosine kinase activation, it has not been shown that tyrosine kinase activity is required for the inhibitory effects of Wnt5a on Wnt and beta-catenin signaling, leading us to investigate this using several approaches.	5	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	5	6	10	11
ROR1 and ROR2 belong to the receptor tyrosine kinases ( RTK ) and are activated by the binding of WNT5a [ XREF_BIBR , XREF_BIBR ] .	ROR1 and ROR2 belong to the receptor tyrosine kinases (RTK) and are activated by the binding of WNT5a [XREF_BIBR, XREF_BIBR].	0	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	WNT5a	WNT5a	WNT5a	ROR2	ROR2	ROR2	19	20	2	3
Moreover , we uncovered a regulatory process where induction of Wnt5a causes downregulation of its receptor Ror2 .	Moreover, we uncovered a regulatory process where induction of Wnt5a causes downregulation of its receptor Ror2.	8	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	10	11	16	17
The results suggested that Wnt5a might activate Wnt and Ror2 signaling pathway in melan-a cells .	The results suggested that Wnt5a might activate Wnt and Ror2 signaling pathway in melan-a cells.	4	11	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	4	5	9	10
Thus , to test whether Wnt5a protein directly activates Ror2 tyrosine activity , we performed IP kinase assays .	Thus, to test whether Wnt5a protein directly activates Ror2 tyrosine activity, we performed IP kinase assays.	5	11	directly activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	5	6	9	10
One potential explanation is that WNT5A preferentially interacts with RYK ; in the absence of RYK , WNT5A activates JNK1/2 ( XREF_FIG ) in a ROR2 dependent manner .	One potential explanation is that WNT5A preferentially interacts with RYK; in the absence of RYK, WNT5A activates JNK1/2 (XREF_FIG) in a ROR2 dependent manner.	17	27	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT5A	WNT5A	WNT5A	ROR2	ROR2	ROR2	17	18	25	26
Important to this point is the fact that Wnt5a activates Ror2 , which is a Tyrosine Kinase ( TK ) receptor containing a CRD in its extracellular region that presumably serves as the Wnt binding domain .	Important to this point is the fact that Wnt5a activates Ror2, which is a Tyrosine Kinase (TK) receptor containing a CRD in its extracellular region that presumably serves as the Wnt binding domain.	8	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	8	9	10	11
Interestingly , Wnt5a mediated activation of Ror2 also requires Dsh ( and Fz ) causing Ror2 phosphorylation of Ser864 ( by GSK3 ) , suggesting an analogous mechanism to Fz/Dsh dependent canonical Wnt3a induced phosphorylation of LRP6 110 .	Interestingly, Wnt5a mediated activation of Ror2 also requires Dsh (and Fz) causing Ror2 phosphorylation of Ser864 (by GSK3), suggesting an analogous mechanism to Fz/Dsh dependent canonical Wnt3a induced phosphorylation of LRP6 110.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	2	3	6	7
In summary , we demonstrate that Wnt5a can activate Wnt and Ror2 signaling and suppress canonical Wnt signaling and thereby inhibit the proliferation and melanin synthesis of melan-a cells .	In summary, we demonstrate that Wnt5a can activate Wnt and Ror2 signaling and suppress canonical Wnt signaling and thereby inhibit the proliferation and melanin synthesis of melan-a cells.	6	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	6	7	11	12
While we have shown that Wnt5a stimulation of Ror2 will increase CDX2 , we do not know if this precedes or is in parallel with pERK1/2 activation .	While we have shown that Wnt5a stimulation of Ror2 will increase CDX2, we do not know if this precedes or is in parallel with pERK1/2 activation.	5	9	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	5	6	8	9
3.3 Wnt5a activated the Wnt and Ror2 signaling pathway in melan-a cells .	3.3 Wnt5a activated the Wnt and Ror2 signaling pathway in melan-a cells.	0	8	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	1	2	6	7
Wnt5a can modulate ROR2 receptor function via tyrosine kinase activity and ROR2 autophosphorylation .	Wnt5a can modulate ROR2 receptor function via tyrosine kinase activity and ROR2 autophosphorylation.	0	5	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR2	ROR2	ROR2	0	1	3	4
Wnt5a stimulation has been shown to enhance the tyrosine kinase activity of ROR2 .	Wnt5a stimulation has been shown to enhance the tyrosine kinase activity of ROR2.	0	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR2	ROR2	ROR2	0	1	12	13
Another candidate signal transducer is Src protein-tyrosine kinase , which is activated when Ror2 expressing T/C28a2 human chondrocytes are treated with Wnt5a [ XREF_BIBR ] .	Another candidate signal transducer is Src protein-tyrosine kinase, which is activated when Ror2 expressing T/C28a2 human chondrocytes are treated with Wnt5a [XREF_BIBR].	13	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	21	22	13	14
Wnt3a treatment increased P-LRP6 , P-Akt ( S473 ) , and P-S6K ( > 10-, 1.6-, 9.2-fold , respectively ) and increased P-IGF-IR/IR relative to total IR ( 1.4-fold ) but did not change P-IGF-IR/IR relative to total IGF-IR .	Wnt3a treatment increased P-LRP6, P-Akt (S473), and P-S6K (> 10-, 1.6-, 9.2-fold, respectively) and increased P-IGF-IR/IR relative to total IR (1.4-fold) but did not change P-IGF-IR/IR relative to total IGF-IR.	0	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	P-LRP6	P-LRP6	P-LRP6	0	1	3	4
Using this strategy , we found that the levels of internalized LRP6-WT increased by 1hr of Wnt3a treatment while S1317P mutant expressing cells showed no detectable increase in internalized LRP6 levels under the same conditions .	Using this strategy, we found that the levels of internalized LRP6-WT increased by 1hr of Wnt3a treatment while S1317P mutant expressing cells showed no detectable increase in internalized LRP6 levels under the same conditions.	10	17	increased	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	LRP6-WT	LRP6-WT	LRP6-WT	16	17	11	12
Of interest , adiponectin efficiently inhibited Wnt3a mediated Lrp6 phospho activation in both wild-type and AdipoR1 and R2 knock-out MEFs ( XREF_FIG ) .	Of interest, adiponectin efficiently inhibited Wnt3a mediated Lrp6 phospho activation in both wild-type and AdipoR1 and R2 knock-out MEFs (XREF_FIG).	6	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	Lrp6	Lrp6	Lrp6	6	7	8	9
DKK1 or Wnt3A also fails to induce internalization of endogenous LRP6 XREF_BIBR , XREF_BIBR .	DKK1 or Wnt3A also fails to induce internalization of endogenous LRP6 XREF_BIBR, XREF_BIBR.	0	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	2	3	10	11
In our current studies , we found that Dkk1 is able to stabilize LRP6 while antagonizing Wnt and LRP6 signaling and blocks Wnt3A induced LRP6 down-regulation .	In our current studies, we found that Dkk1 is able to stabilize LRP6 while antagonizing Wnt and LRP6 signaling and blocks Wnt3A induced LRP6 down-regulation.	22	25	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	22	23	24	25
Dkk1 blocks Wnt3A induced LRP6 down-regulation .	Dkk1 blocks Wnt3A induced LRP6 down-regulation.	2	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	2	3	4	5
Wnt3A induces LRP6 down-regulation .	Wnt3A induces LRP6 down-regulation.	0	3	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	0	1	2	3
Furthermore , super-resolution fluorescence microscopic studies indicated that LRP6 internalization , if exists in HEK293 , MEF and BS-C-1 cells , only occurs at very low levels , whereas WNT3A induced LRP6 signalosomes are primarily localized to large clathrin coated plaques ( > 200 nm ) at plasma membrane .	Furthermore, super-resolution fluorescence microscopic studies indicated that LRP6 internalization, if exists in HEK293, MEF and BS-C-1 cells, only occurs at very low levels, whereas WNT3A induced LRP6 signalosomes are primarily localized to large clathrin coated plaques (> 200 nm) at plasma membrane.	29	32	induced	Positive_early_activation	Positive_activation	Positive_activation	WNT3A	WNT3A	WNT3A	LRP6	LRP6	LRP6	29	30	31	32
Furthermore , we found that Wnt3A treatment induces LRP6 down-regulation , an effect paralleled with a Wnt and LRP6 signaling decay , and that Dkk1 treatment blocked Wnt3A induced LRP6 down-regulation .	Furthermore, we found that Wnt3A treatment induces LRP6 down-regulation, an effect paralleled with a Wnt and LRP6 signaling decay, and that Dkk1 treatment blocked Wnt3A induced LRP6 down-regulation.	27	30	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	27	28	29	30
Further , apigenin inhibits , in a dose dependent manner , Wnt3A induced interaction of WT-LRP6 with Dab2 and clathrin .	Further, apigenin inhibits, in a dose dependent manner, Wnt3A induced interaction of WT-LRP6 with Dab2 and clathrin.	11	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	WT-LRP6	WT-LRP6	WT-LRP6	11	12	15	16
Confirming that endogenous Dab2 inhibits Wnt and beta-catenin signalling , Wnt3A induced phospho-LRP6 , Axin2 and beta-catenin accumulation are shown to be attenuated in RA treated F9 cells but not in RA treated siDab2 F9 cells ( XREF_SUPPLEMENTARY ) .	Confirming that endogenous Dab2 inhibits Wnt and beta-catenin signalling, Wnt3A induced phospho-LRP6, Axin2 and beta-catenin accumulation are shown to be attenuated in RA treated F9 cells but not in RA treated siDab2 F9 cells (XREF_SUPPLEMENTARY).	10	17	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	phospho-LRP6	phospho-LRP6	phospho-LRP6	10	11	12	13
HEK293T cells stably expressing LRP6-GFP were transfected with control or PS1 siRNAs , treated with high concentrations of Wnt3a overnight , and activation of LRP6 detected with a phospho specific anti p-LRP6 antibody ( XREF_FIG ) .	HEK293T cells stably expressing LRP6-GFP were transfected with control or PS1 siRNAs, treated with high concentrations of Wnt3a overnight, and activation of LRP6 detected with a phospho specific anti p-LRP6 antibody (XREF_FIG).	3	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Wnt3a	Wnt3a	Wnt3a	LRP6-GFP	LRP6-GFP	LRP6-GFP	18	19	4	5
Therefore , we performed Wnt and beta-catenin signaling reporter assay to test whether the Mesd C-terminal region peptide mimics Mesd protein to act as an inhibitor of Wnt and beta-catenin signaling induced by Wnt3A and Rspo1 in LRP5- or LRP6 expressing cells .	Therefore, we performed Wnt and beta-catenin signaling reporter assay to test whether the Mesd C-terminal region peptide mimics Mesd protein to act as an inhibitor of Wnt and beta-catenin signaling induced by Wnt3A and Rspo1 in LRP5- or LRP6 expressing cells.	31	41	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	33	34	39	40
Our results showed that Wnt3A CM , but not Wnt5A CM , reduced LRP6 levels after 24 h treatment ( XREF_FIG ) , and that Wnt3A induced LRP6 down-regulation was dose dependent ( XREF_FIG ) .	Our results showed that Wnt3A CM, but not Wnt5A CM, reduced LRP6 levels after 24 h treatment (XREF_FIG), and that Wnt3A induced LRP6 down-regulation was dose dependent (XREF_FIG).	25	28	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	25	26	27	28
Third , Wnt3a induced LRP6 internalization depended on caveolin , and LRP6 endocytotic and recycling trafficking processes required general Rab small GTPases including Rab5 and Rab11 .	Third, Wnt3a induced LRP6 internalization depended on caveolin, and LRP6 endocytotic and recycling trafficking processes required general Rab small GTPases including Rab5 and Rab11.	0	5	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	LRP6	LRP6	LRP6	2	3	4	5
In addition , Wnt3A treatment greatly enhanced the effect of LRP6 on TOPFlash luciferase activity in HMECs ( XREF_FIG ) .	In addition, Wnt3A treatment greatly enhanced the effect of LRP6 on TOPFlash luciferase activity in HMECs (XREF_FIG).	3	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	3	4	10	11
Having established that there is a Wnt3A induced LRP6 down-regulation and Wnt and LRP6 signaling decay after Wnt3A treatment , we then investigated the effects of Dkk1 on Wnt3A induced LRP6 down-regulation .	Having established that there is a Wnt3A induced LRP6 down-regulation and Wnt and LRP6 signaling decay after Wnt3A treatment, we then investigated the effects of Dkk1 on Wnt3A induced LRP6 down-regulation.	26	31	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	28	29	30	31
It was found that Wnt3A induced LRP6 down-regulation was time dependent and was roughly parallel to the decrease of free beta-catenin ( XREF_FIG ) .	It was found that Wnt3A induced LRP6 down-regulation was time dependent and was roughly parallel to the decrease of free beta-catenin (XREF_FIG).	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	4	5	6	7
Perhaps consistent with this general role , the Wnt3a induced LRP6 aggregates appear to contain PIP 2 and are dependent on cellular PIP 2 levels for their formation .	Perhaps consistent with this general role, the Wnt3a induced LRP6 aggregates appear to contain PIP 2 and are dependent on cellular PIP 2 levels for their formation.	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	LRP6	LRP6	LRP6	8	9	10	11
However , while both DKK1 and Dab2 inhibit Wnt and beta-catenin signalling by promoting LRP6 internalization through the clathrin pathway , their inhibitory actions differ in several important aspects : ( 1 ) whereas Dab2 interacts with LRP6 ' s intracellular domain , DKK1 interacts with the extracellular domain of LRP6 ; ( 2 ) mere expression of DKK1 in cells induces internalization of LRP6 , whereas Dab2 expression has no effect on basal or Wnt3A induced LRP6 internalization .	However, while both DKK1 and Dab2 inhibit Wnt and beta-catenin signalling by promoting LRP6 internalization through the clathrin pathway, their inhibitory actions differ in several important aspects : (1) whereas Dab2 interacts with LRP6 's intracellular domain, DKK1 interacts with the extracellular domain of LRP6; (2) mere expression of DKK1 in cells induces internalization of LRP6, whereas Dab2 expression has no effect on basal or Wnt3A induced LRP6 internalization.	75	78	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	75	76	77	78
Next , we assessed the importance of clathrin and AP2 in WNT3A induced formation of the LRP6 signalosome .	Next, we assessed the importance of clathrin and AP2 in WNT3A induced formation of the LRP6 signalosome.	7	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT3A	WNT3A	WNT3A	LRP6	LRP6	LRP6	11	12	16	17
First , Wnt3a triggered the interaction of LRP6 with caveolin , causing not only Axin recruitment but also dissociation of beta-catenin from Axin , supporting that LRP6 localized in caveolin enriched rafts promotes signaling ( XREF_FIG ) .	First, Wnt3a triggered the interaction of LRP6 with caveolin, causing not only Axin recruitment but also dissociation of beta-catenin from Axin, supporting that LRP6 localized in caveolin enriched rafts promotes signaling (XREF_FIG).	2	8	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	LRP6	LRP6	LRP6	2	3	7	8
In addition , these results support the conclusion that WNT3A may induce the aggregation of LRP6 and clathrin at the cell surface .	In addition, these results support the conclusion that WNT3A may induce the aggregation of LRP6 and clathrin at the cell surface.	9	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT3A	WNT3A	WNT3A	LRP6	LRP6	LRP6	9	10	15	16
We found that treatment with Filipin III , an inhibitor of caveolae mediated endocytosis , induced LRP6 accumulation , enhanced Dkk1 induced LRP6 stabilization , and blocked Wnt3A induced LRP6 down-regulation in HT1080 LRP6 cells ( XREF_FIG ) .	We found that treatment with Filipin III, an inhibitor of caveolae mediated endocytosis, induced LRP6 accumulation, enhanced Dkk1 induced LRP6 stabilization, and blocked Wnt3A induced LRP6 down-regulation in HT1080 LRP6 cells (XREF_FIG).	27	30	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	27	28	29	30
We used sucrose density gradient centrifugation to detect LRP6 aggregates in cells treated with Wnt3a ( XREF_FIG ) .	We used sucrose density gradient centrifugation to detect LRP6 aggregates in cells treated with Wnt3a (XREF_FIG).	8	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	LRP6	LRP6	LRP6	14	15	8	9
All together , these results suggest that LRP6 down-regulation and Wnt and LRP6 signaling decay occur after activation of Wnt and LRP6 signaling when the cells were treated with Wnt3A .	All together, these results suggest that LRP6 down-regulation and Wnt and LRP6 signaling decay occur after activation of Wnt and LRP6 signaling when the cells were treated with Wnt3A.	19	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	29	30	21	22
WNT3A induced appreciable clustering of LRP6 ( XREF_FIG ) and significant cluster size distribution shift toward larger size clusters upon Wnt treatment .	WNT3A induced appreciable clustering of LRP6 (XREF_FIG) and significant cluster size distribution shift toward larger size clusters upon Wnt treatment.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT3A	WNT3A	WNT3A	LRP6	LRP6	LRP6	0	1	5	6
Importantly , we also demonstrated that there is a Wnt3A induced LRP6 down-regulation , an effect that is blocked by Dkk1 .	Importantly, we also demonstrated that there is a Wnt3A induced LRP6 down-regulation, an effect that is blocked by Dkk1.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	9	10	11	12
To test whether there is also a change of LRP6 levels in endosomes after Dkk1 and/or Wnt3A treatment , we carried out endosome isolation after the cells were treated for 24 h. Similar to the changes of cell surface LRP6 levels , we found that Dkk1 treatment also induces LRP6 accumulation and blocks Wnt3A induced LRP6 down-regulation in endosomes ( XREF_FIG ) , suggesting that Dkk1 treatment induces LRP6 accumulation ; not only on the cell surface , but also in endosomes .	To test whether there is also a change of LRP6 levels in endosomes after Dkk1 and/or Wnt3A treatment, we carried out endosome isolation after the cells were treated for 24 h. Similar to the changes of cell surface LRP6 levels, we found that Dkk1 treatment also induces LRP6 accumulation and blocks Wnt3A induced LRP6 down-regulation in endosomes (XREF_FIG), suggesting that Dkk1 treatment induces LRP6 accumulation; not only on the cell surface, but also in endosomes.	53	56	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	53	54	55	56
In HEK293 cells , MEF cells , and BS-C-1 cells , the LRP6 signalosomes seem to be primarily localized at cell surfaces , and WNT3A does not strongly induce LRP6 internalization in contrast to observations made in some tumor cell lines ( F9 and Hela cells ) or in cells overexpressing LRP6 .	In HEK293 cells, MEF cells, and BS-C-1 cells, the LRP6 signalosomes seem to be primarily localized at cell surfaces, and WNT3A does not strongly induce LRP6 internalization in contrast to observations made in some tumor cell lines (F9 and Hela cells) or in cells overexpressing LRP6.	24	30	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT3A	WNT3A	WNT3A	LRP6	LRP6	LRP6	24	25	29	30
Dkk1 induces LRP6 accumulation , and blocks Wnt3A induced LRP6 down-regulation on the cell surface and in endosomes .	Dkk1 induces LRP6 accumulation, and blocks Wnt3A induced LRP6 down-regulation on the cell surface and in endosomes.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	7	8	9	10
As expected , we found that co-incubation of recombinant Dkk1 protein with Wnt3A CM blocks Wnt3A induced LRP6 down-regulation ( XREF_FIG ) .	As expected, we found that co-incubation of recombinant Dkk1 protein with Wnt3A CM blocks Wnt3A induced LRP6 down-regulation (XREF_FIG).	15	18	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	15	16	17	18
Consistent with the biochemical evidence that WNT3A does not induce marked LRP6 internalization , WNT3A did not visibly reduce LRP6 staining at the surfaces of MEF cells examined by confocal fluorescence microscopy ( XREF_FIG ) .	Consistent with the biochemical evidence that WNT3A does not induce marked LRP6 internalization, WNT3A did not visibly reduce LRP6 staining at the surfaces of MEF cells examined by confocal fluorescence microscopy (XREF_FIG).	14	20	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	WNT3A	WNT3A	WNT3A	LRP6	LRP6	LRP6	14	15	19	20
Here we show that Wnt3a induced transcriptional responses and induction of alkaline phosphatase activity , an early marker of osteoblast differentiation , require the Wnt co-receptors LRP5 and LRP6 .	Here we show that Wnt3a induced transcriptional responses and induction of alkaline phosphatase activity, an early marker of osteoblast differentiation, require the Wnt co-receptors LRP5 and LRP6.	4	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	LRP6	LRP6	LRP6	4	5	28	29
Wnt3a , via the Dvl proteins , induces the production of phosphatidylinositol ( 4,5 ) bisphosphate ( PtdIns ( 4,5 ) P 2 ) , which is required for Wnt3a induced LRP6 aggregation and Axin membrane translocation .	Wnt3a, via the Dvl proteins, induces the production of phosphatidylinositol (4,5) bisphosphate (PtdIns (4,5) P 2), which is required for Wnt3a induced LRP6 aggregation and Axin membrane translocation.	29	32	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	LRP6	LRP6	LRP6	29	30	31	32
Thus , these data collectively indicate that LRP6 signalosomes are primarily localized at cell surfaces and that WNT3A does not induce significant LRP6 internalization in HEK293 and MEF cells .	Thus, these data collectively indicate that LRP6 signalosomes are primarily localized at cell surfaces and that WNT3A does not induce significant LRP6 internalization in HEK293 and MEF cells.	17	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT3A	WNT3A	WNT3A	LRP6	LRP6	LRP6	17	18	22	23
Furthermore , co-incubation of recombinant Dkk1 protein with Wnt3A CM blocked Wnt3A induced LRP6 down-regulation on the cell surface ( XREF_FIG ) .	Furthermore, co-incubation of recombinant Dkk1 protein with Wnt3A CM blocked Wnt3A induced LRP6 down-regulation on the cell surface (XREF_FIG).	11	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt3A	Wnt3A	Wnt3A	LRP6	LRP6	LRP6	11	12	13	14
Wnt3a treatment of HEK293 or HeLa cells induced intracellular localization of LRP6 in Rab5 positive early endosomes around 10 min to 2 hr after stimulation .	Wnt3a treatment of HEK293 or HeLa cells induced intracellular localization of LRP6 in Rab5 positive early endosomes around 10 min to 2 hr after stimulation.	0	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	LRP6	LRP6	LRP6	0	1	11	12
To understand how Wnt3a signaling regulates gene expression and to identify the roles of Lrp5 and Lrp6 in mediating Wnt3a signaling in osteoblasts , neonatal calvarial osteoblasts isolated from C57Bl6 ( WT ) and osteoblasts lacking either Lrp5 , Lrp6 or , both Lrp5 and 6 were treated with Wnt3a for 24 hours ( h ) and gene expression changes were quantified by RNA sequencing ( RNA-seq ) .	To understand how Wnt3a signaling regulates gene expression and to identify the roles of Lrp5 and Lrp6 in mediating Wnt3a signaling in osteoblasts, neonatal calvarial osteoblasts isolated from C57Bl6 (WT) and osteoblasts lacking either Lrp5, Lrp6 or, both Lrp5 and 6 were treated with Wnt3a for 24 hours (h) and gene expression changes were quantified by RNA sequencing (RNA-seq).	37	52	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	Lrp6	Lrp6	Lrp6	49	50	39	40
Further , we demonstrate using quantitative mass spectrometry that Wnt5a activation of ROR1 is not associated with kinase activation of the receptors in mammalian cells .	Further, we demonstrate using quantitative mass spectrometry that Wnt5a activation of ROR1 is not associated with kinase activation of the receptors in mammalian cells.	9	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	9	10	12	13
WNT5A INDUCES ROR1 TO COMPLEX WITH HS1 TO ENHANCE MIGRATION OF CHRONIC LYMPHOCYTIC LEUKEMIA CELLS .	WNT5A INDUCES ROR1 TO COMPLEX WITH HS1 TO ENHANCE MIGRATION OF CHRONIC LYMPHOCYTIC LEUKEMIA CELLS.	0	3	INDUCES	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT5A	WNT5A	WNT5A	ROR1	ROR1	ROR1	0	1	2	3
Taken together , these data suggest that Wnt5A targets ROR1 to proteasomes for degradation in a PKC dependent manner .	Taken together, these data suggest that Wnt5A targets ROR1 to proteasomes for degradation in a PKC dependent manner.	5	10	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Wnt5A	Wnt5A	Wnt5A	ROR1	ROR1	ROR1	7	8	9	10
ROR1 , when stimulated by recombinant Wnt5a , interacts with casein kinase1epsilon ( CK1epsilon ) , whose subsequent interaction with phosphoinositide 3-kinase ( PI3K ) results in the phosphorylation of AKT and CREB .	ROR1, when stimulated by recombinant Wnt5a, interacts with casein kinase1epsilon (CK1epsilon), whose subsequent interaction with phosphoinositide 3-kinase (PI3K) results in the phosphorylation of AKT and CREB.	0	8	stimulated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	6	7	0	1
Mass spectrometry on immune-precipitates of Wnt5a activated ROR1 identified 14-3-3zeta , which was confirmed by co-immunoprecipitation .	Mass spectrometry on immune-precipitates of Wnt5a activated ROR1 identified 14-3-3zeta, which was confirmed by co-immunoprecipitation.	3	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	5	6	7	8
Wnt5a increased the survival of ROR1 expressing breast cancer cells , confirming the hypothesis of Wnt5a as a ligand for ROR1 .	Wnt5a increased the survival of ROR1 expressing breast cancer cells, confirming the hypothesis of Wnt5a as a ligand for ROR1.	0	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	0	1	5	6
Studies indicated that Wnt5a induced ROR1 dependent activation of RhoGTPases , RhoA and Rac1 , by recruiting guanine-exchange factors ( GEFs ) , such as ARFGEF2 .	Studies indicated that Wnt5a induced ROR1 dependent activation of RhoGTPases, RhoA and Rac1, by recruiting guanine-exchange factors (GEFs), such as ARFGEF2.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	3	4	5	6
WNT5A induces ROR1 dependent signaling and enhances cell growth .	WNT5A induces ROR1 dependent signaling and enhances cell growth.	0	6	induces	Positive_activation_token_1_verb	Positive_activation	Positive_activation	WNT5A	WNT5A	WNT5A	ROR1	ROR1	ROR1	0	1	2	3
We found Wnt5a could induce ROR1 to complex with DOCK2 and induce activation of Rac1/2 ; these effects could be blocked by cirmtuzumab , a humanized anti-ROR1 mAb .	We found Wnt5a could induce ROR1 to complex with DOCK2 and induce activation of Rac1/2; these effects could be blocked by cirmtuzumab, a humanized anti-ROR1 mAb.	2	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	2	3	5	6
First , we validated the Wnt5a induced interaction of ROR1 with 14-3-3zeta in primary CLL cells using co-immunoprecipitation studies and immunoblot analyses .	First, we validated the Wnt5a induced interaction of ROR1 with 14-3-3zeta in primary CLL cells using co-immunoprecipitation studies and immunoblot analyses.	4	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	5	6	9	10
Inhibition of lysosomal function with either of those inhibitors did not increase the accumulation of ROR1 , suggesting that lysosomal degradation is not the primary mechanism for Wnt5A mediated ROR1 degradation ( XREF_SUPPLEMENTARY ) .	Inhibition of lysosomal function with either of those inhibitors did not increase the accumulation of ROR1, suggesting that lysosomal degradation is not the primary mechanism for Wnt5A mediated ROR1 degradation (XREF_SUPPLEMENTARY).	25	30	mediated	Positive_early_activation	Positive_activation	Negative_activation	Wnt5A	Wnt5A	Wnt5A	ROR1	ROR1	ROR1	27	28	29	30
However , Wnt5a induced activation of ROR1 tyrosine kinase activity can be ruled out by our quantitative mass spectrometry experiments using full length ROR1 expressed in HEK293 cells and activated with Wnt5a .	However, Wnt5a induced activation of ROR1 tyrosine kinase activity can be ruled out by our quantitative mass spectrometry experiments using full length ROR1 expressed in HEK293 cells and activated with Wnt5a.	2	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	2	3	6	7
On the other hand , anti-ROR1 immune-precipitates made from lysates of serum starved CLL cells that were treated for 30 minutes with or without exogenous Wnt5a showed that Wnt5a could induce ROR1 to associate with HS1 ( XREF_FIG ) .	On the other hand, anti-ROR1 immune-precipitates made from lysates of serum starved CLL cells that were treated for 30 minutes with or without exogenous Wnt5a showed that Wnt5a could induce ROR1 to associate with HS1 (XREF_FIG).	28	32	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	28	29	31	32
Treatment of CLL cells with Wnt5a induced ROR1 to oligomerize with ROR2 and recruit guanine exchange factors ( GEFs ) , which activated Rac1 and RhoA ; siRNA mediated silencing of either ROR1 or ROR2 or treatment with UC-961 inhibited these effects .	Treatment of CLL cells with Wnt5a induced ROR1 to oligomerize with ROR2 and recruit guanine exchange factors (GEFs), which activated Rac1 and RhoA; siRNA mediated silencing of either ROR1 or ROR2 or treatment with UC-961 inhibited these effects.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	5	6	7	8
In contrast to its effect on ROR1 Pos CLL , Wnt5a did not enhance the proliferation , chemotaxis , or survival of ROR1 Neg CLL .	In contrast to its effect on ROR1 Pos CLL, Wnt5a did not enhance the proliferation, chemotaxis, or survival of ROR1 Neg CLL.	10	24	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	10	11	22	23
11 More recent studies on CLL cells found Wnt5a could induce ROR1 to form hetero-oligomers with ROR2 and recruit and activate guanine exchange factors ( GEFs ) , resulting in activation of Rho GTPases and enhanced leukemia-cell migration and proliferation .	11 More recent studies on CLL cells found Wnt5a could induce ROR1 to form hetero-oligomers with ROR2 and recruit and activate guanine exchange factors (GEFs), resulting in activation of Rho GTPases and enhanced leukemia-cell migration and proliferation.	8	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	8	9	11	12
In summary , this study demonstrates that Wnt5a can induce ROR1 dependent activation of Rac1 in MCL and that such signaling could be inhibited by cirmtuzumab .	In summary, this study demonstrates that Wnt5a can induce ROR1 dependent activation of Rac1 in MCL and that such signaling could be inhibited by cirmtuzumab.	7	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	7	8	10	11
XREF_BIBR , XREF_BIBR These results imply that the correlation of HS1 phosphorylation with adverse clinical outcome may reflect differences in Wnt5a induced ROR1 dependent signaling .	XREF_BIBR, XREF_BIBR These results imply that the correlation of HS1 phosphorylation with adverse clinical outcome may reflect differences in Wnt5a induced ROR1 dependent signaling.	17	24	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	20	21	22	23
To determine whether PKC activation plays a role in the Wnt5A mediated down-regulation of ROR1 , we manipulated the activity of PKC in cells using the PKC inhibitor GO6983 ( targeted to the conventional PKC isoforms ) .	To determine whether PKC activation plays a role in the Wnt5A mediated down-regulation of ROR1, we manipulated the activity of PKC in cells using the PKC inhibitor GO6983 (targeted to the conventional PKC isoforms).	7	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5A	Wnt5A	Wnt5A	ROR1	ROR1	ROR1	10	11	14	15
XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR Here we report the finding that Wnt5a induces ROR1 to associate with HS1 , which undergoes tyrosine phosphorylation and recruits and activates ARHGEF1 to promote F-actin polymerization and leukemia-cell migration .	XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR Here we report the finding that Wnt5a induces ROR1 to associate with HS1, which undergoes tyrosine phosphorylation and recruits and activates ARHGEF1 to promote F-actin polymerization and leukemia-cell migration.	13	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	13	14	15	16
Wnt5a Induces ROR1 To Associate With HS1 In Primary CLL Cells .	Wnt5a Induces ROR1 To Associate With HS1 In Primary CLL Cells.	0	3	Induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	0	1	2	3
Cirmtuzumab ( UC-961 ) is a humanized anti-ROR1 mAb that inhibits WNT5A induced ROR1 signaling through ROR1 dephosphorylation and represses in vivo growth of ROR1 expressing CLL cells .	Cirmtuzumab (UC-961) is a humanized anti-ROR1 mAb that inhibits WNT5A induced ROR1 signaling through ROR1 dephosphorylation and represses in vivo growth of ROR1 expressing CLL cells.	11	19	induced	Positive_early_activation	Positive_activation	Positive_activation	WNT5A	WNT5A	WNT5A	ROR1	ROR1	ROR1	11	12	13	14
Wnt5a Induces ROR1 To Associate With 14-3-3zeta For Enhanced Chemotaxis and Proliferation of Chronic Lymphocytic Leukemia Cells .	Wnt5a Induces ROR1 To Associate With 14-3-3zeta For Enhanced Chemotaxis and Proliferation of Chronic Lymphocytic Leukemia Cells.	0	3	Induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	0	1	2	3
N-cadherin down-modulation did not prevent Wnt5a induced Fz interactions with Dvl2 , p120-catenin , or CK1epsilon , ruling out that the p120-catenin and CK1epsilon interactions with Ror2 are mediated by N-cadherin .	N-cadherin down-modulation did not prevent Wnt5a induced Fz interactions with Dvl2, p120-catenin, or CK1epsilon, ruling out that the p120-catenin and CK1epsilon interactions with Ror2 are mediated by N-cadherin.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Fz	Fz	Fz	5	6	7	8
Wnt5a promotes clathrin dependent Fz and receptor complex internalization ( Sato etal ., 2010 ; Shojima etal ., 2015 ) .	Wnt5a promotes clathrin dependent Fz and receptor complex internalization (Sato etal., 2010; Shojima etal., 2015).	0	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Fz	Fz	Fz	0	1	4	5
Fz , which localized to integrin closely , is activated by Wnt5a , and Fz and integrin recruit the Dvl and FAK complex .	Fz, which localized to integrin closely, is activated by Wnt5a, and Fz and integrin recruit the Dvl and FAK complex.	0	12	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Fz	Fz	Fz	11	12	0	1
Thus , in both short term ( 1 hour ) and long term ( 3 day ) experiments , Wnt5a promoted axon outgrowth does not required Fz receptors .	Thus, in both short term (1 hour) and long term (3 day) experiments, Wnt5a promoted axon outgrowth does not required Fz receptors.	19	27	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Fz	Fz	Fz	19	20	26	27
This process was clearly demonstrated for Fzd 4 in HEK293 cells , where Wnt5A stimulated Fzd 4 endocytosis via sequential recruitments of Dvl 2 and beta-Arrestin 2 , resulting in enhanced signaling .	This process was clearly demonstrated for Fzd 4 in HEK293 cells, where Wnt5A stimulated Fzd 4 endocytosis via sequential recruitments of Dvl 2 and beta-Arrestin 2, resulting in enhanced signaling.	13	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5A	Wnt5A	Wnt5A	Fzd	Fzd	Fzd	13	14	15	16
Wnt5a was shown to activate several different Fzd members , i.e. Fzd2 , Fzd3 , Fzd4 , Fzd5 and Fzd8 in a canonical or non canonical fashion , of which Fzd5 is the most abundant receptor in first trimester CTBs XREF_BIBR .	Wnt5a was shown to activate several different Fzd members, i.e. Fzd2, Fzd3, Fzd4, Fzd5 and Fzd8 in a canonical or non canonical fashion, of which Fzd5 is the most abundant receptor in first trimester CTBs XREF_BIBR.	0	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Fzd	Fzd	Fzd	0	1	7	8
At the onset of embryonic myogenesis , MyoD is activated in the presomitic mesoderm by Wnt7a signaling through a beta-catenin independent pathway [ XREF_BIBR ] .	At the onset of embryonic myogenesis, MyoD is activated in the presomitic mesoderm by Wnt7a signaling through a beta-catenin independent pathway [XREF_BIBR].	7	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt7a	Wnt7a	Wnt7a	MyoD	MyoD	MyoD	15	16	7	8
Wnt1 is expressed in the dorsal neural tube and Wnt7a in dorsal ectoderm in the early embryo , therefore both can potentially act in vivo to activate Myf5 and MyoD , respectively .	Wnt1 is expressed in the dorsal neural tube and Wnt7a in dorsal ectoderm in the early embryo, therefore both can potentially act in vivo to activate Myf5 and MyoD, respectively.	7	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt7a	Wnt7a	Wnt7a	MyoD	MyoD	MyoD	9	10	29	30
Wnt7a , which is expressed in the dorsal ectoderm activates MyoD in presomitic mesoderm through a PKC dependent beta-catenin-independent non canonical pathway [ XREF_BIBR ] .	Wnt7a, which is expressed in the dorsal ectoderm activates MyoD in presomitic mesoderm through a PKC dependent beta-catenin-independent non canonical pathway [XREF_BIBR].	0	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt7a	Wnt7a, which is expressed	wnt7a	MyoD	MyoD	myod	0	1	10	11
FZD5 was down-regulated in response to differentiation of NT2/D1 cells and in human melanoma cells FZD5 activation by WNT5A had been associated with elevated metastatic potential [ XREF_BIBR ] .	FZD5 was down-regulated in response to differentiation of NT2/D1 cells and in human melanoma cells FZD5 activation by WNT5A had been associated with elevated metastatic potential [XREF_BIBR].	15	19	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	WNT5A	WNT5A	WNT5A	FZD5	FZD5	FZD5	18	19	15	16
Wnt5a induces its effects via several known receptors and co-receptors including Frizzled2 ( FZD2 ) , Frizzled5 ( FZD5 ) , and receptor tyrosine kinase like orphan receptor 2 ( ROR2 ) , activating intracellular release of calcium , thereby activating PLC , PKC , CaMKII and calcineurin .	Wnt5a induces its effects via several known receptors and co-receptors including Frizzled2 (FZD2), Frizzled5 (FZD5), and receptor tyrosine kinase like orphan receptor 2 (ROR2), activating intracellular release of calcium, thereby activating PLC, PKC, CaMKII and calcineurin.	0	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Frizzled5	Frizzled5	Frizzled5	0	1	16	17
Monocyte secreted Wnt5a activates FZD5 in mECs , which signals to induce the release of intracellular Ca ( 2+ ) and increase NFkappaB transcription activity and TF gene expression .	Monocyte secreted Wnt5a activates FZD5 in mECs, which signals to induce the release of intracellular Ca (2+) and increase NFkappaB transcription activity and TF gene expression.	1	5	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	FZD5	FZD5	FZD5	2	3	4	5
Recent studies demonstrated that in cultured cells , Wnt5a triggers the internalization of Fz4 and Fz5 , and Wnt3a also induces Fz5 internalization .	Recent studies demonstrated that in cultured cells, Wnt5a triggers the internalization of Fz4 and Fz5, and Wnt3a also induces Fz5 internalization.	8	16	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Fz5	Fz5	Fz5	8	9	15	16
Thus , this study shows for the first time how a single Wnt5a ligand can activate the neural differentiation pathway through the activation of Wnt5a and JNK pathway by binding Fzd3 and Fzd5 and directing Axin and GSK-3beta in hADSCs .	Thus, this study shows for the first time how a single Wnt5a ligand can activate the neural differentiation pathway through the activation of Wnt5a and JNK pathway by binding Fzd3 and Fzd5 and directing Axin and GSK-3beta in hADSCs.	12	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Fzd5	Fzd5	Fzd5	12	13	32	33
For example , Wnt5a can engage Ror2 to inhibit the canonical Wnt signaling pathway , while paradoxically Wnt5a can also activate the canonical pathway by directly engaging Fz4 [ XREF_BIBR ] and Fz5 [ XREF_BIBR ] .	For example, Wnt5a can engage Ror2 to inhibit the canonical Wnt signaling pathway, while paradoxically Wnt5a can also activate the canonical pathway by directly engaging Fz4 [XREF_BIBR] and Fz5 [XREF_BIBR].	16	33	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Fz5	Fz5	Fz5	17	18	32	33
The classical transforming Wnt3a is also capable of stabilizing beta-catenin via non canonical Rho [ XREF_BIBR ] , while the notorious non canonical Wnt5a is able to activate the beta-catenin-driven canonical Wnt pathway in the presence of Fzd5 in Xenopus laevis overexpression studies [ XREF_BIBR ] .	The classical transforming Wnt3a is also capable of stabilizing beta-catenin via non canonical Rho [XREF_BIBR], while the notorious non canonical Wnt5a is able to activate the beta-catenin-driven canonical Wnt pathway in the presence of Fzd5 in Xenopus laevis overexpression studies [XREF_BIBR].	19	38	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Fzd5	Fzd5	Fzd5	23	24	37	38
Meanwhile , Wnt6 activated the beta-catenin signaling pathway as indicated by the dual luciferase assay result , and blockade of the WNT and beta-catenin pathway reduced the cytoactivity of Wnt6 in MEPM cells ( P < 0.01 ) .	Meanwhile, Wnt6 activated the beta-catenin signaling pathway as indicated by the dual luciferase assay result, and blockade of the WNT and beta-catenin pathway reduced the cytoactivity of Wnt6 in MEPM cells (P < 0.01).	2	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt6	Wnt6	Wnt6	beta-catenin	beta-catenin	beta-catenin	2	3	5	6
Experiments utilizing a dominant negative form of beta-Catenin show that Paraxis is a mediator of beta-Catenin signaling initiated by Wnt6 .	Experiments utilizing a dominant negative form of beta-Catenin show that Paraxis is a mediator of beta-Catenin signaling initiated by Wnt6.	15	20	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt6	Wnt6	Wnt6	beta-Catenin	beta-Catenin	beta-Catenin	19	20	15	16
To confirm that WNT6 activates the canonical WNT and beta-catenin signaling pathway , TCF/LEF reporter assays were performed in both U373 shCtrl and shWNT6 cells and in U87 Ctrl and WNT6 cells .	To confirm that WNT6 activates the canonical WNT and beta-catenin signaling pathway, TCF/LEF reporter assays were performed in both U373 shCtrl and shWNT6 cells and in U87 Ctrl and WNT6 cells.	3	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT6	WNT6	WNT6	beta-catenin	beta-catenin	beta-catenin	3	4	9	10
Co-incubation of CPCs with 1 nM of Wnt6 with increasing concentrations of Sfrp2 achieved neutralization of both the Wnt6 induced beta-Catenin activation ( XREF_SUPPLEMENTARY ) and the Wnt6 induced proliferative effects ( XREF_FIG ) , suggesting a functional importance between the interaction of Sfrp2 and Wnt6 in modulating CPC proliferation .	Co-incubation of CPCs with 1 nM of Wnt6 with increasing concentrations of Sfrp2 achieved neutralization of both the Wnt6 induced beta-Catenin activation (XREF_SUPPLEMENTARY) and the Wnt6 induced proliferative effects (XREF_FIG), suggesting a functional importance between the interaction of Sfrp2 and Wnt6 in modulating CPC proliferation.	14	23	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt6	Wnt6	Wnt6	beta-Catenin	beta-Catenin	beta-Catenin	18	19	20	21
After 24 hours , Wnt6 activated canonical beta-Catenin and TCF signaling at 1 nM but did not affect JNK-AP1 or NFAT signaling at greater than 10 nM ( XREF_SUPPLEMENTARY ) , suggesting in CPCs , Wnt6 acts as a canonical Wnt .	After 24 hours, Wnt6 activated canonical beta-Catenin and TCF signaling at 1 nM but did not affect JNK-AP1 or NFAT signaling at greater than 10 nM (XREF_SUPPLEMENTARY), suggesting in CPCs, Wnt6 acts as a canonical Wnt.	4	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt6	Wnt6	Wnt6	beta-Catenin	beta-Catenin	beta-Catenin	4	5	7	8
Similarly , human MSCs transduced with activated LRP5 and treated with Wnt3a in vitro were found to have increased ALP expression and activity with decreased lipid droplet formation , as well as the formation of ectopic mineralized bone when implanted in a scaffold subcutaneously in mice ; the opposite phenotype was observed in hMSCs transduced with inactivated LRP5 and treated with Wnt3a [ XREF_BIBR ] .	Similarly, human MSCs transduced with activated LRP5 and treated with Wnt3a in vitro were found to have increased ALP expression and activity with decreased lipid droplet formation, as well as the formation of ectopic mineralized bone when implanted in a scaffold subcutaneously in mice; the opposite phenotype was observed in hMSCs transduced with inactivated LRP5 and treated with Wnt3a [XREF_BIBR].	4	12	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	LRP5	LRP5	LRP5	11	12	7	8
Finally , both Wnt-3a and Wnt-5a were able to stimulate insulin secretion in wild-type but not LRP-5 -/- mice [ XREF_BIBR ] .	Finally, both Wnt-3a and Wnt-5a were able to stimulate insulin secretion in wild-type but not LRP-5 -/- mice [XREF_BIBR].	2	18	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-3a	Wnt-3a	Wnt-3a	LRP-5	LRP-5	LRP-5	3	4	16	17
LRP6 phosphorylation , a primary response to the binding of a WNT ligand to the FZD and LRP5/6 complex , was amplified in HEK293 cells treated with WNT3A , as expected , but was not affected by SOX11 overexpression , whether cells were treated or not with WNT3A ( XREF_FIG ) .	LRP6 phosphorylation, a primary response to the binding of a WNT ligand to the FZD and LRP5/6 complex, was amplified in HEK293 cells treated with WNT3A, as expected, but was not affected by SOX11 overexpression, whether cells were treated or not with WNT3A (XREF_FIG).	15	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	WNT3A	WNT3A	WNT3A	FZD	FZD	FZD	27	28	15	16
Importantly , however , a compensatory induction of other Fzd genes in Fzd8 deficient mice was not observed in vivo ( XREF_FIG ) , thus implying that the failure to demonstrate a cell-autonomous defect of Fzd8 deficient osteoclasts is potentially explained by a Wnt3a dependent induction of other Fzd genes in Fzd8 deficient cultures specifically ex vivo .	Importantly, however, a compensatory induction of other Fzd genes in Fzd8 deficient mice was not observed in vivo (XREF_FIG), thus implying that the failure to demonstrate a cell-autonomous defect of Fzd8 deficient osteoclasts is potentially explained by a Wnt3a dependent induction of other Fzd genes in Fzd8 deficient cultures specifically ex vivo.	43	49	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	Fzd	Fzd	Fzd	43	44	48	49
Consistently , a combined injection of equimolar mRNAs encoding for the two Wnt3a domains also did not induce in vivo activity , indicating that the individual Wnt3a domains are not able to activate Fz receptor signaling effectively in an independent manner .	Consistently, a combined injection of equimolar mRNAs encoding for the two Wnt3a domains also did not induce in vivo activity, indicating that the individual Wnt3a domains are not able to activate Fz receptor signaling effectively in an independent manner.	26	35	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	Fz	Fz	Fz	26	27	33	34
In HEK293 cells , Wnt3a induces rapid Fzd 5 internalization ( as quickly as 30 min ) through EEA1- and Rab5 positive endosomes in a clathrin dependent manner ; internalized Fzd 5 receptors are then returned through Rab11 positive vesicles back to plasma membrane after 3 ~ 4 hours of stimulation .	In HEK293 cells, Wnt3a induces rapid Fzd 5 internalization (as quickly as 30 min) through EEA1- and Rab5 positive endosomes in a clathrin dependent manner; internalized Fzd 5 receptors are then returned through Rab11 positive vesicles back to plasma membrane after 3 ~ 4 hours of stimulation.	4	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	Fzd	Fzd	Fzd	4	5	7	8
Wnt7a stimulation of Fzd7 leads to cellular polarization and selectively increases symmetric stem cell expansion .	Wnt7a stimulation of Fzd7 leads to cellular polarization and selectively increases symmetric stem cell expansion.	0	4	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt7a	Wnt7a	Wnt7a	Fzd7	Fzd7	Fzd7	0	1	3	4
In fact , expression of WNT7A , which targets FZD7 , has been shown to be downregulated in lung cancer [ XREF_BIBR ] .	In fact, expression of WNT7A, which targets FZD7, has been shown to be downregulated in lung cancer [XREF_BIBR].	3	10	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT7A	expression of WNT7A	wnt7a	FZD7	FZD7	fzd7	5	6	9	10
The change in IP 5 and IP 6 levels in PC12 cells after differentiation with NGF represents one of very few instances known -- the others being during cell cycle progression , hematopoietic cell differentiation , and activation of Frizzled-1 by Wnt3a -- in which a physiological stimulus regulates intracellular IP 5 and IP 6 concentrations in mammalian cells .	The change in IP 5 and IP 6 levels in PC12 cells after differentiation with NGF represents one of very few instances known -- the others being during cell cycle progression, hematopoietic cell differentiation, and activation of Frizzled-1 by Wnt3a -- in which a physiological stimulus regulates intracellular IP 5 and IP 6 concentrations in mammalian cells.	30	42	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	Frizzled-1	Frizzled-1	Frizzled-1	41	42	39	40
Wnt5a increases Frizzled3 endocytosis , which correlates with filopodia elongation .	Wnt5a increases Frizzled3 endocytosis, which correlates with filopodia elongation.	0	3	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Frizzled3	Frizzled3	Frizzled3	0	1	2	3
Consequently , Wnt-5a activates a Frizzled-3 and Galpha ( s )/cAMP/PKA signaling pathway that triggers a DARPP-32- and CREB dependent antimigratory response in breast cancer cells , representing a novel mechanism whereby Wnt-5a can inhibit breast cancer cell migration .	Consequently, Wnt-5a activates a Frizzled-3 and Galpha (s)/cAMP/PKA signaling pathway that triggers a DARPP-32- and CREB dependent antimigratory response in breast cancer cells, representing a novel mechanism whereby Wnt-5a can inhibit breast cancer cell migration.	2	12	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt-5a	Wnt-5a	Wnt-5a	Frizzled-3	Frizzled-3	Frizzled-3	2	3	5	6
In particular , Wnt5a can activate both myf5 and MyoD [ XREF_BIBR ] .	In particular, Wnt5a can activate both myf5 and MyoD [XREF_BIBR].	3	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	MyoD	MyoD	MyoD	3	4	9	10
Notably , Wnt5a over-expression markedly increased the levels of Myf5 and MyoD mRNA following RA exposure as compared to control cells ( XREF_FIG ) , indicating that Wnt5a antagonizes the suppressive effects RA on Myf5 and MyoD expression .	Notably, Wnt5a over-expression markedly increased the levels of Myf5 and MyoD mRNA following RA exposure as compared to control cells (XREF_FIG), indicating that Wnt5a antagonizes the suppressive effects RA on Myf5 and MyoD expression.	2	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a over-expression	wnt5a	MyoD	MyoD	myod	2	3	11	12
In addition , the beta-catenin pathway can be negatively regulated by Wnt5a signaling in a GSK3beta independent manner .	In addition, the beta-catenin pathway can be negatively regulated by Wnt5a signaling in a GSK3beta independent manner.	11	17	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	GSK3beta	GSK3beta	GSK3beta	11	12	15	16
Previous studies using Ror2 in heterologous cell lines have shown that Wnt5a stimulates JNK and GSK-3beta , while the receptors which mediate p38 , PKC , or CK1/2 following Wnt5a stimulation have not yet been identified .	Previous studies using Ror2 in heterologous cell lines have shown that Wnt5a stimulates JNK and GSK-3beta, while the receptors which mediate p38, PKC, or CK1/2 following Wnt5a stimulation have not yet been identified.	11	16	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	GSK-3beta	GSK-3beta	GSK-3beta	11	12	15	16
To rationalize DVL1 ' s apparent distribution throughout the rDNA repeat , we hypothesized that Wnt5a signaling may induce DVL1 to associate with either UBF or Pol I. Consistent with this model , immunoprecipitation assays performed on total nuclear lysates showed that DVL1 co-precipitated with UBF more efficiently in Wnt5a expressing cells ( XREF_FIG , compare lanes 4 and 8 ) .	To rationalize DVL1 's apparent distribution throughout the rDNA repeat, we hypothesized that Wnt5a signaling may induce DVL1 to associate with either UBF or Pol I. Consistent with this model, immunoprecipitation assays performed on total nuclear lysates showed that DVL1 co-precipitated with UBF more efficiently in Wnt5a expressing cells (XREF_FIG, compare lanes 4 and 8).	15	20	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	DVL1	DVL1	DVL1	15	16	19	20
XREF_BIBR Wnt5a was found to trigger nucleolar accumulation of Dishevelled 1 ( DVL1 ) , a tumor suppressor that binds to rDNA .	XREF_BIBR Wnt5a was found to trigger nucleolar accumulation of Dishevelled 1 (DVL1), a tumor suppressor that binds to rDNA.	0	11	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	Dishevelled 1	Dishevelled 1	Dishevelled 1	1	2	9	11
Wnt5a signaling promotes DVL1 localization to nucleoli and rDNA chromatin .	Wnt5a signaling promotes DVL1 localization to nucleoli and rDNA chromatin.	0	4	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt5a	Wnt5a	Wnt5a	DVL1	DVL1	DVL1	0	1	3	4
Wnt3a stimulation further enhanced the co-IP of axin1 and FL DVL1 and the DVL1 ( 1-502 ) variant but not that of the DeltaLPDSG mutant .	Wnt3a stimulation further enhanced the co-IP of axin1 and FL DVL1 and the DVL1 (1-502) variant but not that of the DeltaLPDSG mutant.	0	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	DVL1	DVL1	DVL1	0	1	10	11
The abundance of Dvl3 and Dvl1 following stimulation by Wnt3a , in contrast to that of Dvl2 , were increased .	The abundance of Dvl3 and Dvl1 following stimulation by Wnt3a, in contrast to that of Dvl2, were increased.	3	10	stimulation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	Dvl1	Dvl1	Dvl1	9	10	5	6
Wnt4 overexpression induces muscle satellite cell markers Pax7 and MyoD , and increases skeletal muscle mass in chick embryos [ XREF_BIBR ] .	Wnt4 overexpression induces muscle satellite cell markers Pax7 and MyoD, and increases skeletal muscle mass in chick embryos [XREF_BIBR].	0	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt4	Wnt4 overexpression	wnt4	MyoD	MyoD	myod	0	1	9	10
Our study shows that WNT-5A attenuates canonical WNT-beta-catenin signaling by reducing LRP6 activation and accumulation of transcriptionally ABC in alveolar epithelial cells .	Our study shows that WNT-5A attenuates canonical WNT-beta-catenin signaling by reducing LRP6 activation and accumulation of transcriptionally ABC in alveolar epithelial cells.	4	12	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	WNT-5A	WNT-5A	WNT-5A	LRP6	LRP6	LRP6	4	5	11	12
We demonstrate that stimulation of FZD2 by Wnt3a and Wnt5a regulates beta-catenin-dependent and -independent Wnt signaling factors .	We demonstrate that stimulation of FZD2 by Wnt3a and Wnt5a regulates beta-catenin-dependent and -independent Wnt signaling factors.	3	9	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	Wnt3a	Wnt3a	Wnt3a	FZD2	FZD2	FZD2	7	8	5	6
Co-expression of either Wnt7b or Wnt5a enhanced Fzd10 activation , while Wnt11 and Wnt4 did not .	Co-expression of either Wnt7b or Wnt5a enhanced Fzd10 activation, while Wnt11 and Wnt4 did not.	0	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt7b	Co-expression of either Wnt7b	wnt7b	Fzd10	Fzd10	fzd10	3	4	7	8
The Xbp1 embryonic lethality can be rescued by the expression of Xbp1 in the liver whereas IRE1alpha is essential for placental development XREF_BIBR , XREF_BIBR .	The Xbp1 embryonic lethality can be rescued by the expression of Xbp1 in the liver whereas IRE1alpha is essential for placental development XREF_BIBR, XREF_BIBR.	1	14	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Xbp1	expression of Xbp1	xbp1	Xbp1	Xbp1	xbp1	11	12	1	2
Coexpression of pXBP1 ( U ) significantly accelerated pXBP1 ( S ) degradation ( XREF_FIG , left and middle ) , whereas that of pXBP1 ( U )-[ 1-185 ] hardly effected pXBP1 ( S ) stability ( XREF_FIG , right ) .	Coexpression of pXBP1 (U) significantly accelerated pXBP1 (S) degradation (XREF_FIG, left and middle), whereas that of pXBP1 (U)-[1-185] hardly effected pXBP1 (S) stability (XREF_FIG, right).	0	31	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pXBP1	Coexpression of pXBP1	pxbp1	pXBP1	pXBP1	pxbp1	2	3	8	9
XBP1 ( S ) expression is associated with acquired endocrine resistance ; overexpression of the XBP1 cDNA in breast cancer cells produces primarily XBP1 ( S ) and is sufficient to confer both E2-independence and antiestrogen crossresistance .	XBP1 (S) expression is associated with acquired endocrine resistance; overexpression of the XBP1 cDNA in breast cancer cells produces primarily XBP1 (S) and is sufficient to confer both E2-independence and antiestrogen crossresistance.	0	31	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	XBP1	XBP1 (S) expression is associated with acquired endocrine resistance; overexpression	xbp1	XBP1	XBP1	xbp1	0	1	23	24
As the amount of unfolded protein decreased , so did IRE1 activity , and the amount of XBP1 ( U ) increased relative to XBP1 ( S ) .	As the amount of unfolded protein decreased, so did IRE1 activity, and the amount of XBP1 (U) increased relative to XBP1 (S).	15	26	increased	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	XBP1	amount of XBP1	xbp1	XBP1	XBP1	xbp1	17	18	24	25
We previously demonstrated that overexpression of XBP1 ( S ) , the active form of XBP1 generated by UPR mediated splicing of Xbp1 mRNA , augments the activity of the cytidine diphosphocholine ( CDP-choline ) pathway for biosynthesis of phosphatidylcholine ( PtdCho ) and induces ER biogenesis .	We previously demonstrated that overexpression of XBP1 (S), the active form of XBP1 generated by UPR mediated splicing of Xbp1 mRNA, augments the activity of the cytidine diphosphocholine (CDP-choline) pathway for biosynthesis of phosphatidylcholine (PtdCho) and induces ER biogenesis.	4	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	XBP1	overexpression of XBP1	xbp1	Xbp1	Xbp1	xbp1	6	7	22	23
Silencing XBP1 expression under MG132 induced ER stress block the XBP1 survival pathway and synergism with MG132 to promote Tca8113 cell apoptosis .	Silencing XBP1 expression under MG132 induced ER stress block the XBP1 survival pathway and synergism with MG132 to promote Tca8113 cell apoptosis.	1	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	XBP1	XBP1 expression	xbp1	XBP1	XBP1	xbp1	1	2	10	11
Therefore , the increased expression of p-IRE1alpha-spliced XBP1 in our samples supports the activation of the IRE1 and XBP1 pathway in all of these three different types of cataract lenses .	Therefore, the increased expression of p-IRE1alpha-spliced XBP1 in our samples supports the activation of the IRE1 and XBP1 pathway in all of these three different types of cataract lenses.	4	19	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	XBP1	expression of p-IRE1alpha-spliced XBP1	xbp1	XBP1	XBP1	xbp1	7	8	18	19
Ectopic expression of UL41 decreased the expression of XBP1 and blocked XBP1 splicing activation induced by the ER stress inducer thapsigargin .	Ectopic expression of UL41 decreased the expression of XBP1 and blocked XBP1 splicing activation induced by the ER stress inducer thapsigargin.	1	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	XBP1	expression of UL41 decreased the expression of XBP1	xbp1	XBP1	XBP1	xbp1	8	9	11	12
IRE1a activates splicing of various mRNAs in the cytoplasm , including the mRNA of X-box binding protein 1 ( XBP1 ) , which is thereby activated to XBP1 ( S ) .	IRE1a activates splicing of various mRNAs in the cytoplasm, including the mRNA of X-box binding protein 1 (XBP1), which is thereby activated to XBP1 (S).	14	29	activated	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	X-box binding protein 1	X-box binding protein 1	X-box binding protein 1	XBP1	XBP1	XBP1	14	18	27	28
Hepatocyte specific transgenic expression of XBP-1 rescues the embryonic lethality of XBP-1 -/- mice , but these animals display abnormalities in other secretory organs such as the pancreas , leading to neonatal death .	Hepatocyte specific transgenic expression of XBP-1 rescues the embryonic lethality of XBP-1 -/- mice, but these animals display abnormalities in other secretory organs such as the pancreas, leading to neonatal death.	3	13	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	XBP-1	expression of XBP-1	xbp-1	XBP-1	XBP-1	xbp-1	5	6	11	12
A small fragment of the X-box binding protein 1 ( XBP1 ) mRNA is spliced out by the active form of IRE1 to produce the active form of XBP1 .	A small fragment of the X-box binding protein 1 (XBP1) mRNA is spliced out by the active form of IRE1 to produce the active form of XBP1.	5	29	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	X-box binding protein 1	X-box binding protein 1	X-box binding protein 1	XBP1	XBP1	XBP1	5	9	28	29
The expression of XBP1 in Drosophila where the AD associated Abeta peptide was expressed in neurons , led to reduced neurotoxicity , supporting the cytoprotective role of XBP1 .	The expression of XBP1 in Drosophila where the AD associated Abeta peptide was expressed in neurons, led to reduced neurotoxicity, supporting the cytoprotective role of XBP1.	1	28	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	XBP1	expression of XBP1	xbp1	XBP1	XBP1	xbp1	3	4	27	28
The downstream phosporylation of ZAP70 results in activation of LAT , that in turn , recruits Grb2 , phospholipase C-1 ( PLC-1 ) , and the p85 subunit of phosphatidylinositol 3-kinase and indirectly , Vav , Cb1 , and SLP76 .	The downstream phosporylation of ZAP70 results in activation of LAT, that in turn, recruits Grb2, phospholipase C-1 (PLC-1), and the p85 subunit of phosphatidylinositol 3-kinase and indirectly, Vav, Cb1, and SLP76.	2	15	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Positive_activation	ZAP70	ZAP70	ZAP70	LAT	LAT	LAT	4	5	9	10
ZAP70 remains associated with TCR and induces activation of LAT , which binds to the adaptor growth factor receptor-IL-2 inducible T-cell kinase ( ITK ) .	ZAP70 remains associated with TCR and induces activation of LAT, which binds to the adaptor growth factor receptor-IL-2 inducible T-cell kinase (ITK).	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ZAP70	ZAP70	ZAP70	LAT	LAT	LAT	0	1	9	10
Using mutant mice lacking a Y chromosome ( XO ) and transgenic approaches , researchers have demonstrated that overexpression by the gonadal promoter WT1 driven Y related ( Sry and Eif2s3y ) or non-Y-related ( Sox9 and Eif2s3x ) genes is necessary to develop and maintain male germline cells .	Using mutant mice lacking a Y chromosome (XO) and transgenic approaches, researchers have demonstrated that overexpression by the gonadal promoter WT1 driven Y related (Sry and Eif2s3y) or non-Y-related (Sox9 and Eif2s3x) genes is necessary to develop and maintain male germline cells.	18	30	driven	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WT1	WT1	WT1	Sry	Sry	Sry	23	24	28	29
Interestingly , the -340 bp Sry promoter construct ( containing an intact proximal WT1 site and no consensus GATA sites ) was synergistically activated by GATA4 and WT1 to the same extent as the full-length ( -1090 bp ) Sry construct .	Interestingly, the -340 bp Sry promoter construct (containing an intact proximal WT1 site and no consensus GATA sites) was synergistically activated by GATA4 and WT1 to the same extent as the full-length (-1090 bp) Sry construct.	2	28	synergistically activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	WT1	WT1	WT1	Sry	Sry	Sry	27	28	5	6
In contrast to the mouse and pig , the human SRY promoter was strongly activated by WT1 (-KTS ) alone and synergism with GATA4 only occurred with the WT1 ( + KTS ) isoform .	In contrast to the mouse and pig, the human SRY promoter was strongly activated by WT1 (-KTS) alone and synergism with GATA4 only occurred with the WT1 (+ KTS) isoform.	10	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	WT1	WT1	WT1	SRY	SRY	SRY	16	17	10	11
Transfection studies carried out in this cell line clearly showed that the deletion or mutation of the proximal WT1 element reduced Sry promoter activity to the same level as the minimal promoter ( approximately 33 % of the intact construct ; Fig .	Transfection studies carried out in this cell line clearly showed that the deletion or mutation of the proximal WT1 element reduced Sry promoter activity to the same level as the minimal promoter (approximately 33% of the intact construct; Fig.	18	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	WT1	WT1	WT1	Sry	Sry	Sry	18	19	21	22
Immediately 5 ' to this is a somewhat conserved sequence that has previously been investigated in vitro in the context of WT1 binding , where it has been found essential for WT1 dependent activation of the mouse Sry promoter [ XREF_BIBR ] .	Immediately 5 ' to this is a somewhat conserved sequence that has previously been investigated in vitro in the context of WT1 binding, where it has been found essential for WT1 dependent activation of the mouse Sry promoter [XREF_BIBR].	31	38	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	WT1	WT1	WT1	Sry	Sry	Sry	31	32	37	38
Our results showed that WT1 up-regulates the SRY gene through the proximal early growth response gene-1-like DNA binding sequences in the core promoter .	Our results showed that WT1 up-regulates the SRY gene through the proximal early growth response gene-1-like DNA binding sequences in the core promoter.	4	8	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WT1	WT1	WT1	SRY	SRY	SRY	4	5	7	8
The presence of Ku70 , Ku80 , or DNA causes DNA-PKcs dimerization that promotes trans-autophosphorylation , resulting in a sufficiently large opening in the ring structure that potentially promotes either the entry or the release of DNA ends .	The presence of Ku70, Ku80, or DNA causes DNA-PKcs dimerization that promotes trans-autophosphorylation, resulting in a sufficiently large opening in the ring structure that potentially promotes either the entry or the release of DNA ends.	1	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ku70	Ku70	Ku70	DNA-PKcs	DNA-PKcs	DNA-PKcs	3	4	10	11
Deacetylation of Ku70 by SIRT1 and autophosphorylation of DNA-PKcs at position S2056 are critical to activate DNA-PKcs .	Deacetylation of Ku70 by SIRT1 and autophosphorylation of DNA-PKcs at position S2056 are critical to activate DNA-PKcs.	0	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ku70	Deacetylation of Ku70	ku70	DNA-PKcs	DNA-PKcs	dna-pkcs	2	3	16	17
Inactivation of Ku70 gene rescues perinatal lethality of XLF -/- DNA-PKcs -/- mice .	Inactivation of Ku70 gene rescues perinatal lethality of XLF -/- DNA-PKcs -/- mice.	2	12	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ku70	Ku70	Ku70	DNA-PKcs	DNA-PKcs	DNA-PKcs	2	3	10	11
Ku70 and Ku80 have been shown to form a heterodimeric complex that can bind tightly to free DNA ends and activate the protein kinase DNA-PKcs .	Ku70 and Ku80 have been shown to form a heterodimeric complex that can bind tightly to free DNA ends and activate the protein kinase DNA-PKcs.	0	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ku70	Ku70	Ku70	DNA-PKcs	DNA-PKcs	DNA-PKcs	0	1	24	25
This embryonic lethality is however rescued by combined inactivation of Ku80 or Ku70 , leading to alive Ku80 -/- DNA-PKcs KD/KD and Ku70 -/- DNA-PKcs KD/KD mice .	This embryonic lethality is however rescued by combined inactivation of Ku80 or Ku70, leading to alive Ku80 -/- DNA-PKcs KD/KD and Ku70 -/- DNA-PKcs KD/KD mice.	5	26	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ku70	Ku70	Ku70	DNA-PKcs	DNA-PKcs	DNA-PKcs	12	13	24	25
Moreover , YAP1 overexpression activated Wnt and beta-catenin signaling pathway .	Moreover, YAP1 overexpression activated Wnt and beta-catenin signaling pathway.	2	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	YAP1	YAP1 overexpression	yap1	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
Inhibition of YAP1 resulted in a modest decrease in the proliferation of CRC cells , perhaps because antagonism of YAP1 function in Hippo signaling was offset in part by further activation of beta-catenin signaling in the cells , due to loss of YAP1 dependent degradation of beta-catenin ( XREF_FIG ) .	Inhibition of YAP1 resulted in a modest decrease in the proliferation of CRC cells, perhaps because antagonism of YAP1 function in Hippo signaling was offset in part by further activation of beta-catenin signaling in the cells, due to loss of YAP1 dependent degradation of beta-catenin (XREF_FIG).	42	48	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	YAP1	YAP1	YAP1	beta-catenin	beta-catenin	beta-catenin	42	43	46	47
On the contrary , several studies show that the cytoplasmic YAP1 and TAZ inactivates the canonical Wnt signaling pathway by inhibiting nuclear localization of beta-catenin .	On the contrary, several studies show that the cytoplasmic YAP1 and TAZ inactivates the canonical Wnt signaling pathway by inhibiting nuclear localization of beta-catenin.	8	25	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	YAP1	YAP1	YAP1	beta-catenin	beta-catenin	beta-catenin	10	11	24	25
Results now demonstrate how the LUST transcript targets and modulates the chromatin context surrounding specific beta-catenin targets such as CMYC , CCND1 , YAP1 and SGK1 ( XREF_FIG ) .	Results now demonstrate how the LUST transcript targets and modulates the chromatin context surrounding specific beta-catenin targets such as CMYC, CCND1, YAP1 and SGK1 (XREF_FIG).	15	24	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	YAP1	YAP1	YAP1	beta-catenin	beta-catenin	beta-catenin	23	24	15	16
YAP1 overexpression in mice causes an increase in cytoplasmic YAP1 levels and downregulates intestinal beta-catenin target gene expression 104 .	YAP1 overexpression in mice causes an increase in cytoplasmic YAP1 levels and downregulates intestinal beta-catenin target gene expression 104.	0	15	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	YAP1	YAP1 overexpression	yap1	beta-catenin	beta-catenin	beta-catenin	0	1	14	15
Similarly , these observations suggest that YAP1 interferes with beta-catenin functions in homeostasis and promotes beta-catenin activity in tumor pathogenesis .	Similarly, these observations suggest that YAP1 interferes with beta-catenin functions in homeostasis and promotes beta-catenin activity in tumor pathogenesis.	6	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	YAP1	YAP1	YAP1	beta-catenin	beta-catenin	beta-catenin	6	7	15	16
The addition of lymphotactin ( XCL1 and XCL2 ) stimulated migration and proliferation of XCR1 positive cells .	The addition of lymphotactin (XCL1 and XCL2) stimulated migration and proliferation of XCR1 positive cells.	1	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	lymphotactin	lymphotactin	lymphotactin	XCR1	XCR1	XCR1	3	4	14	15
Surprisingly , XCL1 could not activate the murine lymphotactin receptor although the sequences of mXCL1 and XCL1 are very similar ( 60 % identity and 84 % similarity using BLASTP 2.2.17 at the NCBI website ) .	Surprisingly, XCL1 could not activate the murine lymphotactin receptor although the sequences of mXCL1 and XCL1 are very similar (60% identity and 84% similarity using BLASTP 2.2.17 at the NCBI website).	2	10	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	XCL1	XCL1	XCL1	lymphotactin receptor	lymphotactin receptor	lymphotactin receptor	2	3	8	10
As expected , XCL1 , mXCL1 and vCCL3 activated the human lymphotactin receptor in a dose responsive manner .	As expected, XCL1, mXCL1 and vCCL3 activated the human lymphotactin receptor in a dose responsive manner.	3	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	XCL1	XCL1	XCL1	lymphotactin receptor	lymphotactin receptor	lymphotactin receptor	3	4	11	13
On the other hand , in certain cancers , YAP1 up-regulates p73 dependent gene transcription and behaves as a tumor suppressor .	On the other hand, in certain cancers, YAP1 up-regulates p73 dependent gene transcription and behaves as a tumor suppressor.	9	16	up-regulates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	YAP1	YAP1	YAP1	p73	p73	p73	9	10	11	12
c-Abl also phosphorylates YAP1 at Y357 site following DNA damage , which in turn enhanced YAP1 bind to p73 and activates p73 regulated pro apoptotic target genes expression 16 .	c-Abl also phosphorylates YAP1 at Y357 site following DNA damage, which in turn enhanced YAP1 bind to p73 and activates p73 regulated pro apoptotic target genes expression 16.	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	YAP1	c-Abl also phosphorylates YAP1 at Y357	yap1	p73	p73	p73	3	4	21	22
YAP1 can transactivate growth promoting genes and enhance p73 dependent apoptosis in response to DNA damage by binding to specific domains XREF_BIBR , XREF_BIBR , XREF_BIBR .	YAP1 can transactivate growth promoting genes and enhance p73 dependent apoptosis in response to DNA damage by binding to specific domains XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	9	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	YAP1	YAP1	YAP1	p73	p73	p73	0	1	8	9
By bioinformatics analysis ( www.microrna.org and www.targetscan.org ) , miR-375 was found to have several putative targets including YAP1 ( two binding sites for miR-375 in its 3 ' UTR ) , TEAD4 , and CTGF which belong to key oncogenic downstream mediators of Hippo signaling pathway .	By bioinformatics analysis (www.microrna.org and www.targetscan.org), miR-375 was found to have several putative targets including YAP1 (two binding sites for miR-375 in its 3 ' UTR), TEAD4, and CTGF which belong to key oncogenic downstream mediators of Hippo signaling pathway.	13	33	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	YAP1	YAP1	YAP1	TEAD4	TEAD4	TEAD4	18	19	32	33
For example , WNT8B upregulates phospho-LRP6 , but can not stabilize beta-catenin in HEK293 cells , suggesting that LRP6 phosphorylation may not always be sufficient to inactivate the destruction complex .	For example, WNT8B upregulates phospho-LRP6, but can not stabilize beta-catenin in HEK293 cells, suggesting that LRP6 phosphorylation may not always be sufficient to inactivate the destruction complex.	3	10	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	WNT8B	WNT8B	WNT8B	phospho-LRP6	phospho-LRP6	phospho-LRP6	3	4	5	6
Moreover , this mutant form of Yap65 was also able to increase the nuclear fraction of Tead1 .	Moreover, this mutant form of Yap65 was also able to increase the nuclear fraction of Tead1.	4	17	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Yap65	Yap65	Yap65	Tead1	Tead1	Tead1	6	7	16	17
Secondly , mutating the O-glucose sites of EGF16-20 fully suppresses the Notch loss-of-function phenotypes caused by GXYLT1 and XXYLT1 overexpression , strongly suggesting that these phenotypes result from the addition of xylose by these enzymes to O-glucose on these EGF repeats .	Secondly, mutating the O-glucose sites of EGF16-20 fully suppresses the Notch loss-of-function phenotypes caused by GXYLT1 and XXYLT1 overexpression, strongly suggesting that these phenotypes result from the addition of xylose by these enzymes to O-glucose on these EGF repeats.	11	20	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	XXYLT1	XXYLT1 overexpression	xxylt1	Notch	Notch	notch	18	19	11	12
ADAMTS13 downregulates the multimeric size of VWF in order to prevent unwanted platelet thrombus formation .	ADAMTS13 downregulates the multimeric size of VWF in order to prevent unwanted platelet thrombus formation.	0	7	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	0	1	6	7
Recent studies report that , in patients with DKD , the observed high risk of cardiovascular complications might be associated with increased plasma levels of vWF and reduced ADAMTS13 levels [ XREF_BIBR XREF_BIBR ] ; these decreased ADAMTS13 levels might cause the increased vWF levels [ XREF_BIBR XREF_BIBR XREF_BIBR ] .	Recent studies report that, in patients with DKD, the observed high risk of cardiovascular complications might be associated with increased plasma levels of vWF and reduced ADAMTS13 levels [XREF_BIBR XREF_BIBR]; these decreased ADAMTS13 levels might cause the increased vWF levels [XREF_BIBR XREF_BIBR XREF_BIBR].	37	45	cause	Positive_regulation_syntax_1_verb	Negative_activation	Negative_regulation	ADAMTS13	ADAMTS13 levels	adamts13	vWF	vWF levels	vwf	37	38	43	44
It is possible that the repeated increase in vWF and constant degradation by ADAMTS-13 results in lower overall levels of both proteins in smokers ( at rest ) compared to nonsmokers who do not experience a similar ( repeated ) injury to the endothelium .	It is possible that the repeated increase in vWF and constant degradation by ADAMTS-13 results in lower overall levels of both proteins in smokers (at rest) compared to nonsmokers who do not experience a similar (repeated) injury to the endothelium.	8	14	degradation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	vWF	vWF	vWF	13	14	8	9
Next , we showed that addition of ADAMTS-13 diminished VWF mediated platelet capture on collagen under flow ; surprisingly , this was more pronounced with the S1486A , Cluster 2 and DC variants than with wild-type VWF , indicating that these are proteolyzed more rapidly under shear flow .	Next, we showed that addition of ADAMTS-13 diminished VWF mediated platelet capture on collagen under flow; surprisingly, this was more pronounced with the S1486A, Cluster 2 and DC variants than with wild-type VWF, indicating that these are proteolyzed more rapidly under shear flow.	5	10	diminished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	7	8	9	10
This evidence suggests that ADAMTS-13 prevents thrombus propagation and thrombotic occlusion by regulating the size of VWF multimers under high shear rate conditions .	This evidence suggests that ADAMTS-13 prevents thrombus propagation and thrombotic occlusion by regulating the size of VWF multimers under high shear rate conditions.	4	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	4	5	16	17
ADAMTS13 , a von Willebrand factor ( VWF ) cleaving protease , has a protective effect against ischemic brain injury and may reduce bleeding risk by cleaving VWF .	ADAMTS13, a von Willebrand factor (VWF) cleaving protease, has a protective effect against ischemic brain injury and may reduce bleeding risk by cleaving VWF.	0	28	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	0	1	27	28
ADAMTS-13 reduced shear induced disulfide bonds in VWF .	ADAMTS-13 reduced shear induced disulfide bonds in VWF.	0	8	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	0	1	7	8
ADAMTS13 prevents the normal processing of large VWF multimers that are secreted from endothelial cells [ XREF_BIBR ] , which is due to the microthrombi from massive platelet aggregation rather than the plaque rupture-thrombosis cascade [ XREF_BIBR ] .	ADAMTS13 prevents the normal processing of large VWF multimers that are secreted from endothelial cells [XREF_BIBR], which is due to the microthrombi from massive platelet aggregation rather than the plaque rupture-thrombosis cascade [XREF_BIBR].	0	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	0	1	7	8
ADAMTS13 , a 190-kD plasma protease originating primarily in hepatic stellate cells , prevents microvascular thrombosis by cleaving von Willebrand factor when the substrate is conformationally unfolded by high levels of shear stress in the circulation .	ADAMTS13, a 190-kD plasma protease originating primarily in hepatic stellate cells, prevents microvascular thrombosis by cleaving von Willebrand factor when the substrate is conformationally unfolded by high levels of shear stress in the circulation.	0	21	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	0	1	18	21
ADAMTS13 proteolysis of the VWF A2 domain reduces the multimeric size of VWF .	ADAMTS13 proteolysis of the VWF A2 domain reduces the multimeric size of VWF.	0	13	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	0	1	12	13
For instance , certain mutations in the vwf gene may result in increased proteolysis of vWF by ADAMTS13 and significant reduction of vWF multimer sizes , leading to compromised hemostatic function as seen in patients with von Willebrand disease XREF_BIBR .	For instance, certain mutations in the vwf gene may result in increased proteolysis of vWF by ADAMTS13 and significant reduction of vWF multimer sizes, leading to compromised hemostatic function as seen in patients with von Willebrand disease XREF_BIBR.	17	24	reduction	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	vWF	vWF	vWF	17	18	22	23
During this pathology , the reduction of ADAMTS13 activity in blood enhances VWF multimer size in circulation , and this causes the formation of platelet rich microthrombi in the small vessels of multiple organs .	During this pathology, the reduction of ADAMTS13 activity in blood enhances VWF multimer size in circulation, and this causes the formation of platelet rich microthrombi in the small vessels of multiple organs.	7	14	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	7	8	12	13
It remains to be determined , however , whether ADAMTS13 has a direct effect against atherosclerosis or merely functions to reduce the adhesiveness of ultra large VWF multimers , thereby an anti-athero effect is indirect .	It remains to be determined, however, whether ADAMTS13 has a direct effect against atherosclerosis or merely functions to reduce the adhesiveness of ultra large VWF multimers, thereby an anti-athero effect is indirect.	9	27	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	9	10	26	27
In the presence of supraphysiologic shear stress , ADAMTS-13 completely eliminated large von Willebrand factor multimers and generated statistically significant amounts of 11/11 von Willebrand factor degradation fragments ( P < .05 ) .	In the presence of supraphysiologic shear stress, ADAMTS-13 completely eliminated large von Willebrand factor multimers and generated statistically significant amounts of 11/11 von Willebrand factor degradation fragments (P <.05).	8	17	eliminated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	von Willebrand factor	von Willebrand factor	von Willebrand factor	8	9	12	15
This demonstrated that proteolyzed ADAMTS-13 could block the proteolysis of VWF by uncleaved ADAMTS-13 , and suggests that ADAMTS-13 retains some VWF binding function after thrombin cleavage .	This demonstrated that proteolyzed ADAMTS-13 could block the proteolysis of VWF by uncleaved ADAMTS-13, and suggests that ADAMTS-13 retains some VWF binding function after thrombin cleavage.	3	11	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	4	5	10	11
The supplementation of ADAMTS13 by prophylactic FFP infusion may suppress the increase in VWF : AG that is extensively released from damaged SEC .	The supplementation of ADAMTS13 by prophylactic FFP infusion may suppress the increase in VWF : AG that is extensively released from damaged SEC.	1	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	3	4	13	14
A severe deficiency of ADAMTS-13 activity prevents the physiological processing of large vWF multimers which can lead to a strong platelet aggregation , and leads to the formation of microthrombosis in terminal arterioles and capillaries .	A severe deficiency of ADAMTS-13 activity prevents the physiological processing of large vWF multimers which can lead to a strong platelet aggregation, and leads to the formation of microthrombosis in terminal arterioles and capillaries.	4	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	vWF	vWF	vWF	4	5	12	13
ADAMTS13 , as a specific von Willebrand factor ( VWF )-cleaving protease , prevents microvascular thrombosis of VWF and platelet thrombi .	ADAMTS13, as a specific von Willebrand factor (VWF)-cleaving protease, prevents microvascular thrombosis of VWF and platelet thrombi.	0	20	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	0	1	17	18
XREF_BIBR However , the most dominant regulator seems to be ADAMTS13 , which is able to proteolytically degrade VWF via cleavages in the A2 domain between residues Tyr1605 and Met1606 .	XREF_BIBR However, the most dominant regulator seems to be ADAMTS13, which is able to proteolytically degrade VWF via cleavages in the A2 domain between residues Tyr1605 and Met1606.	6	20	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	10	11	18	19
[ XREF_BIBR ] In most cases of idiopathic TTP , severe deficiency of ADAMTS13 prevents processing of unusually large vWF multimers released from endothelial cells .	[XREF_BIBR] In most cases of idiopathic TTP, severe deficiency of ADAMTS13 prevents processing of unusually large vWF multimers released from endothelial cells.	11	20	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	vWF	vWF	vWF	13	14	19	20
This study seems to confirm the correlation between immunological abnormalities and decreased ADAMTS13 serum levels suggesting that reduced activity of ADAMTS13 is contributing to enhance the prothrombotic function of VWF and may play a role in microangiopathy and secondary fibrosis .	This study seems to confirm the correlation between immunological abnormalities and decreased ADAMTS13 serum levels suggesting that reduced activity of ADAMTS13 is contributing to enhance the prothrombotic function of VWF and may play a role in microangiopathy and secondary fibrosis.	18	30	contributing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	20	21	29	30
Enzymatic desialylation of VWF by alpha2-3 ,6,8,9 neuraminidase ( Neu-VWF ) markedly impaired ADAMTS13 mediated VWF proteolysis .	Enzymatic desialylation of VWF by alpha2-3,6,8,9 neuraminidase (Neu-VWF) markedly impaired ADAMTS13 mediated VWF proteolysis.	12	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	13	14	15	16
Antibody mAb508 is specific to the D4 domain of VWF , and has been observed to interfere with ADAMTS13 mediated degradation of VWF in a vortex based degradation assay [ XREF_BIBR ] .	Antibody mAb508 is specific to the D4 domain of VWF, and has been observed to interfere with ADAMTS13 mediated degradation of VWF in a vortex based degradation assay [XREF_BIBR].	18	25	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	18	19	22	23
XREF_BIBR - XREF_BIBR The ADAMTS13 specifically cleaves unusually large VWF multimer ( UL-VWFM ) with hyperaggregability of platelets , 5 and down-regulates VWF function .	XREF_BIBR - XREF_BIBR The ADAMTS13 specifically cleaves unusually large VWF multimer (UL-VWFM) with hyperaggregability of platelets, 5 and down-regulates VWF function.	3	23	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	4	5	22	23
In the normal state , circulating proteases , notably ADAMTS13 , degrade vWF into smaller multimers thereby reducing the thrombogenic propensity of vWF ; however , in sepsis this homeostatic function may go awry .	In the normal state, circulating proteases, notably ADAMTS13, degrade vWF into smaller multimers thereby reducing the thrombogenic propensity of vWF; however, in sepsis this homeostatic function may go awry.	6	13	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	vWF	vWF	vWF	9	10	12	13
In the acquired immune mediated form of TTP ( iTTP ) , patients develop antibodies ( Abs ) against ADAMTS13 that enhance its clearance or inhibit its VWF processing activity .	In the acquired immune mediated form of TTP (iTTP), patients develop antibodies (Abs) against ADAMTS13 that enhance its clearance or inhibit its VWF processing activity.	14	29	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	19	20	27	28
Expression of the truncated ADAMTS13 variant eliminated circulating ultralarge von Willebrand factor multimers , prevented severe thrombocytopenia , and reduced mortality in Adamts13 (-/-) disease-prone mice triggered by shigatoxin-2 .	Expression of the truncated ADAMTS13 variant eliminated circulating ultralarge von Willebrand factor multimers, prevented severe thrombocytopenia, and reduced mortality in Adamts13 (-/-) disease-prone mice triggered by shigatoxin-2.	0	12	eliminated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	Expression of the truncated ADAMTS13	adamts13	von Willebrand factor	von Willebrand factor	von willebrand factor	4	5	9	12
ADAMTS13 promptly degrades highly multimerized vWF , which , by being more sensitive to shear , exposes its cleavage sites to the protease under flow XREF_BIBR XREF_BIBR .	ADAMTS13 promptly degrades highly multimerized vWF, which, by being more sensitive to shear, exposes its cleavage sites to the protease under flow XREF_BIBR XREF_BIBR.	0	16	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	vWF	vWF	vWF	0	1	5	6
The ADAMTS13 dependent degradation of VWF to its proteolytic fragments can be visualized as a characteristic so called triplet structure of individual VWF oligomers by multimer analysis .	The ADAMTS13 dependent degradation of VWF to its proteolytic fragments can be visualized as a characteristic so called triplet structure of individual VWF oligomers by multimer analysis.	1	9	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	1	2	5	6
Decrease of ADAMTS13 and deficient VWF cleavage allows ultralarge VWF ( ULVWF ) to accumulate in the circulation and contribute to thrombus formation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Decrease of ADAMTS13 and deficient VWF cleavage allows ultralarge VWF (ULVWF) to accumulate in the circulation and contribute to thrombus formation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	14	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	2	3	9	10
ADAMTS-13 prevents inappropriate microvascular platelet aggregation by cleaving VWF between Tyr1605 and Met1606 thereby producing dimers of 176 kd and 140 kd and smaller multimers .	ADAMTS-13 prevents inappropriate microvascular platelet aggregation by cleaving VWF between Tyr1605 and Met1606 thereby producing dimers of 176 kd and 140 kd and smaller multimers.	0	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	0	1	8	9
Using molecular imaging , we have also demonstrated for the first time that exogenous ADAMTS13 enzyme therapy reduces both VWF and platelet adhesion on the vascular endothelium .	Using molecular imaging, we have also demonstrated for the first time that exogenous ADAMTS13 enzyme therapy reduces both VWF and platelet adhesion on the vascular endothelium.	14	22	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	14	15	19	20
33 TTP and HUS , either typical or atypical , are not characterized by elevated liver enzymes and , in addition , TTP is associated with deficiency in the enzyme ADAMTS13 , a metalloproteinase that degrades von Willebrand factor multimers .	33 TTP and HUS, either typical or atypical, are not characterized by elevated liver enzymes and, in addition, TTP is associated with deficiency in the enzyme ADAMTS13, a metalloproteinase that degrades von Willebrand factor multimers.	24	39	degrades	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	30	31	36	39
Recombinant ADAMTS-13 given either before or after TBI reduced the VWF reactivity with minimal influence on VWF secretion .	Recombinant ADAMTS-13 given either before or after TBI reduced the VWF reactivity with minimal influence on VWF secretion.	0	11	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	1	2	10	11
A disintegrin like and metalloproteinase with thrombospondin type-1 motifs 13 ( ADAMTS13 ) specifically cleaves unusually-large von Willebrand factor ( VWF ) multimers under high shear stress , and down-regulates VWF function to form platelet thrombi .	A disintegrin like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) specifically cleaves unusually-large von Willebrand factor (VWF) multimers under high shear stress, and down-regulates VWF function to form platelet thrombi.	1	31	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	11	12	30	31
ADAMTS-13 prevented shear induced thiol-disulfide exchange of VWF .	ADAMTS-13 prevented shear induced thiol-disulfide exchange of VWF.	0	8	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	0	1	7	8
XREF_BIBR , XREF_BIBR - XREF_BIBR Apparently , proteolytic degradation of VWF by ADAMTS13 downregulates the inflammatory potential of VWF .	XREF_BIBR, XREF_BIBR - XREF_BIBR Apparently, proteolytic degradation of VWF by ADAMTS13 downregulates the inflammatory potential of VWF.	8	13	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	12	13	10	11
Our results suggest that high vWF activity is accompanied by an increase in ADAMTS-13 activity as a natural physiological mechanism to degrade the elevated vWF molecules .	Our results suggest that high vWF activity is accompanied by an increase in ADAMTS-13 activity as a natural physiological mechanism to degrade the elevated vWF molecules.	13	25	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	vWF	vWF	vWF	13	14	24	25
Hemodynamic activation of vWF and increased plasma ADAMTS-13 activity may have reduced high-molecular-weight vWF multimers and thereby impaired the vWF-platelet aggregation pathway .	Hemodynamic activation of vWF and increased plasma ADAMTS-13 activity may have reduced high-molecular-weight vWF multimers and thereby impaired the vWF-platelet aggregation pathway.	7	14	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	vWF	vWF	vWF	7	8	13	14
Increasing levels of VWF and decreasing levels of ADAMTS13 were associated with the risk of IS and MI in a dose dependent manner .	Increasing levels of VWF and decreasing levels of ADAMTS13 were associated with the risk of IS and MI in a dose dependent manner.	3	9	decreasing	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	ADAMTS13	levels of ADAMTS13	adamts13	VWF	VWF	vwf	8	9	3	4
Inhibition of ADAMTS-13 by doxycycline decreased vWF degradation and improved vWF function during supraphysiological shear stress without hyperactivating platelets .	Inhibition of ADAMTS-13 by doxycycline decreased vWF degradation and improved vWF function during supraphysiological shear stress without hyperactivating platelets.	0	7	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	vWF	vWF	vWF	2	3	6	7
The levels of plasma ADAMTS13 were sufficient to eliminate the ultralarge VWF multimers and offered systemic protection against ferric chloride induced arterial thrombosis .	The levels of plasma ADAMTS13 were sufficient to eliminate the ultralarge VWF multimers and offered systemic protection against ferric chloride induced arterial thrombosis.	1	12	eliminate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	levels of plasma ADAMTS13	adamts13	VWF	VWF	vwf	4	5	11	12
A possible relative insufficiency of ADAMTS13 could be present in children who develop silent infarcts : in a situation of chronic endothelial activation the activity of ADAMTS13 may not always suffice to prevent an abnormal increase of VWF : Ag in the already hypercoagulable blood and therefore lead to increased infarcts in the cerebral microvasculature .	A possible relative insufficiency of ADAMTS13 could be present in children who develop silent infarcts : in a situation of chronic endothelial activation the activity of ADAMTS13 may not always suffice to prevent an abnormal increase of VWF : Ag in the already hypercoagulable blood and therefore lead to increased infarcts in the cerebral microvasculature.	24	38	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	26	27	37	38
Furthermore , recombinant ADAMTS13 mediated degradation of VWF multimers was entirely inhibited in the presence of plasma from a patient with acquired TTP .	Furthermore, recombinant ADAMTS13 mediated degradation of VWF multimers was entirely inhibited in the presence of plasma from a patient with acquired TTP.	2	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	3	4	7	8
In that study , increasing concentrations of ADAMTS13 reduced VWF multimer size , resulting in a significant loss of VWF hemostatic function and a rapid clearance of VWF from the circulation .	In that study, increasing concentrations of ADAMTS13 reduced VWF multimer size, resulting in a significant loss of VWF hemostatic function and a rapid clearance of VWF from the circulation.	5	11	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	7	8	9	10
VWF multimer size is reduced in the circulation by ADAMTS13 cleavage of the A2 domain Tyr 1605 -Met 1606 peptide bond .	VWF multimer size is reduced in the circulation by ADAMTS13 cleavage of the A2 domain Tyr 1605 -Met 1606 peptide bond.	0	10	reduced	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	9	10	0	1
For example , absence or malfunction of ADAMTS13 causes the disruption of the downregulation mechanism of VWF .	For example, absence or malfunction of ADAMTS13 causes the disruption of the downregulation mechanism of VWF.	3	17	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	7	8	16	17
vWF ' s contribution to pro thrombotic conditions is dramatically demonstrated by thrombotic thrombocytopenic purpura ( TTP ) , a condition in which the ultra-large vWF multimers released by endothelial cells are not reduced in size by the circulating metalloprotease ADAMTS13 .	vWF 's contribution to pro thrombotic conditions is dramatically demonstrated by thrombotic thrombocytopenic purpura (TTP), a condition in which the ultra-large vWF multimers released by endothelial cells are not reduced in size by the circulating metalloprotease ADAMTS13.	25	41	reduced	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	vWF	vWF	vWF	40	41	25	26
ADAMTS13 ( A Disintegrin And Metalloprotease with Thrombospondin type I repeats-13 ) prevents microvascular thrombosis by cleaving prothrombogenic ultra-large von Willebrand factor ( ULVWF ) multimers .	ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type I repeats-13) prevents microvascular thrombosis by cleaving prothrombogenic ultra-large von Willebrand factor (ULVWF) multimers.	0	25	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	0	1	19	22
It remains to be demonstrated whether ADAMTS-13 may limit the potential role of VWF in mediating the occlusion of stenotic arteries where pathologically elevated shear rates develop .	It remains to be demonstrated whether ADAMTS-13 may limit the potential role of VWF in mediating the occlusion of stenotic arteries where pathologically elevated shear rates develop.	6	14	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	6	7	13	14
35 ADAMTS13 , a metalloproteinase , prevents spontaneous microvascular thrombosis by cleaving large , hyperactive von Willebrand factor ( VWF ) multimers into smaller , less active ones .	35 ADAMTS13, a metalloproteinase, prevents spontaneous microvascular thrombosis by cleaving large, hyperactive von Willebrand factor (VWF) multimers into smaller, less active ones.	0	21	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	1	2	15	18
Besides the fact that removal of the C-terminal of ADAMTS13 domains or antibodies against the CUB1-2 domains enhance the cleavage of the peptide substrate FRETS-VWF73 , removal of the C-terminal of ADAMTS13 abrogate the capacity of ADAMTS13 to bind and cleave VWF under flow conditions ex vivo and in vivo .	Besides the fact that removal of the C-terminal of ADAMTS13 domains or antibodies against the CUB1-2 domains enhance the cleavage of the peptide substrate FRETS-VWF73, removal of the C-terminal of ADAMTS13 abrogate the capacity of ADAMTS13 to bind and cleave VWF under flow conditions ex vivo and in vivo.	29	42	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	31	32	41	42
Proteolysis might represent a mechanism by which ADAMTS-13 function is locally modulated at sites of vascular injury , thereby limiting VWF proteolysis and reducing platelet embolization .	Proteolysis might represent a mechanism by which ADAMTS-13 function is locally modulated at sites of vascular injury, thereby limiting VWF proteolysis and reducing platelet embolization.	7	21	modulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	7	8	20	21
Because early platelet deposition in arterioles is VWF dependent , it means that either plasma ADAMTS13 reduces VWF incorporation into the basement membrane when it is exposed to blood or that it digests VWF already present in the extracellular matrix .	Because early platelet deposition in arterioles is VWF dependent, it means that either plasma ADAMTS13 reduces VWF incorporation into the basement membrane when it is exposed to blood or that it digests VWF already present in the extracellular matrix.	14	18	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	15	16	17	18
ADAMTS13 reduces the adhesiveness of hyperactive ultra-large von Willebrand factor ( ULVWF ) multimers by cleaving them into smaller , less active multimers .	ADAMTS13 reduces the adhesiveness of hyperactive ultra-large von Willebrand factor (ULVWF) multimers by cleaving them into smaller, less active multimers.	0	13	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	0	1	7	10
The ultra-large von Willebrand factor ( vWF ) multimers are very active and must be degraded by ADAMTS13 for optimal activity .	The ultra-large von Willebrand factor (vWF) multimers are very active and must be degraded by ADAMTS13 for optimal activity.	2	20	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	17	18	2	5
This indicates that ADAMTS-13 reduces disulfide bonds formed between laterally associated VWF multimers under the influence of fluid shear stress ( XREF_FIG ) .	This indicates that ADAMTS-13 reduces disulfide bonds formed between laterally associated VWF multimers under the influence of fluid shear stress (XREF_FIG).	3	12	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	3	4	11	12
Interestingly , inhibition of ADAMTS-13 significantly decreased VWF degradation during supraphysiological shear stress without affecting platelet activity in an ex vivo setting [ XREF_BIBR ] .	Interestingly, inhibition of ADAMTS-13 significantly decreased VWF degradation during supraphysiological shear stress without affecting platelet activity in an ex vivo setting [XREF_BIBR].	2	8	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	4	5	7	8
During the acute phase , her plasma levels of von Willebrand factor ( VWF ) were remarkably elevated , whereas those of ADAMTS13 were reduced without its inhibitors , generating a markedly high ratio of VWF to ADAMTS13 in circulation .	During the acute phase, her plasma levels of von Willebrand factor (VWF) were remarkably elevated, whereas those of ADAMTS13 were reduced without its inhibitors, generating a markedly high ratio of VWF to ADAMTS13 in circulation.	20	36	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	22	23	35	36
Thus we next determined whether cleavage of the TSP6-8 and the two C-terminal CUB domains of ADAMTS13 by FXIa or the cleavage of the CUB 1-2 domains of ADAMTS13 alone by alpha-thrombin might abrogate ADAMTS13 activity under flow by assessing the length of VWF that had been released by activated endothelial cells under shear .	Thus we next determined whether cleavage of the TSP6-8 and the two C-terminal CUB domains of ADAMTS13 by FXIa or the cleavage of the CUB 1-2 domains of ADAMTS13 alone by alpha-thrombin might abrogate ADAMTS13 activity under flow by assessing the length of VWF that had been released by activated endothelial cells under shear.	14	44	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	16	17	43	44
Consistent with a similar mechanism of decreased ADAMTS13 mediated VWF cleavage in our patient , proteolytic subbands accounting for the typical multimeric triplet structure were absent at presentation , but appeared following remission induction .	Consistent with a similar mechanism of decreased ADAMTS13 mediated VWF cleavage in our patient, proteolytic subbands accounting for the typical multimeric triplet structure were absent at presentation, but appeared following remission induction.	4	10	mediated	Positive_early_activation	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	7	8	9	10
The more distal portion of ADAMTS13 ( TSP1 2-8 repeats and CUB domains ) may function as a disulphide bond reductase to prevent an elongation of ultra large VWF strings on activated endothelial cells and inhibit platelet adhesion and aggregation on collagen surface under flow .	The more distal portion of ADAMTS13 (TSP1 2-8 repeats and CUB domains) may function as a disulphide bond reductase to prevent an elongation of ultra large VWF strings on activated endothelial cells and inhibit platelet adhesion and aggregation on collagen surface under flow.	3	29	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	5	6	28	29
Liver sinusoids contain Kupffer cells which endocytose chilled platelets and stellate cells expressing ADAMTS-13 which degrades vWF , so sequestration out of the sinusoids may protect platelets from clearance by the liver .	Liver sinusoids contain Kupffer cells which endocytose chilled platelets and stellate cells expressing ADAMTS-13 which degrades vWF, so sequestration out of the sinusoids may protect platelets from clearance by the liver.	12	19	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	vWF	vWF	vWF	13	14	16	17
We tested the hypothesis that inhibition of ADAMTS-13 with doxycycline , an inexpensive , clinically approved drug , reduces vWF degradation during shear stress .	We tested the hypothesis that inhibition of ADAMTS-13 with doxycycline, an inexpensive, clinically approved drug, reduces vWF degradation during shear stress.	5	20	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	vWF	vWF	vWF	7	8	19	20
In familial TTP , mutations in the ADAMTS13 gene cause absent or severely reduced plasma VWF cleaving metalloprotease activity .	In familial TTP, mutations in the ADAMTS13 gene cause absent or severely reduced plasma VWF cleaving metalloprotease activity.	7	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	7	8	15	16
Loss of VWF multimer size regulation caused by severe ADAMTS13 deficiency ( either inherited or acquired ) is associated with the microvascular thrombotic disorder thrombotic thrombocytopenic purpura ( TTP ) .	Loss of VWF multimer size regulation caused by severe ADAMTS13 deficiency (either inherited or acquired) is associated with the microvascular thrombotic disorder thrombotic thrombocytopenic purpura (TTP).	2	10	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	9	10	2	3
Conversely , blockade of MC4R by AgRP results in robust increases in feeding as well as decreases in energy expenditure .	Conversely, blockade of MC4R by AgRP results in robust increases in feeding as well as decreases in energy expenditure.	2	7	blockade	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	6	7	4	5
ARC POMC neurons release the MC4R agonist alpha-MSH and promote negative energy balance , whereas ARC AgRP neurons release the MC4R antagonist AgRP , as well as the inhibitory transmitters GABA and NPY , to do the opposite .	ARC POMC neurons release the MC4R agonist alpha-MSH and promote negative energy balance, whereas ARC AgRP neurons release the MC4R antagonist AgRP, as well as the inhibitory transmitters GABA and NPY, to do the opposite.	18	35	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	22	23	20	21
The AgRP inhibition of the MC4R prevents appetite inhibition in response to LPS and well after LPS inhibition of feed intake , both AgRP and a-melanocyte-stimulating hormone may change in a pattern that favors appetite increases .	The AgRP inhibition of the MC4R prevents appetite inhibition in response to LPS and well after LPS inhibition of feed intake, both AgRP and a-melanocyte-stimulating hormone may change in a pattern that favors appetite increases.	1	6	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	1	2	5	6
This finding substantiated the commonly held Yin-Yang view of feeding regulation , with POMC neurons and alpha-MSH inhibiting food intake and energy storage , and NPY and AgRP neurons stimulating it in part , through AgRP antagonism of MC4R signaling ( XREF_FIG ) .	This finding substantiated the commonly held Yin-Yang view of feeding regulation, with POMC neurons and alpha-MSH inhibiting food intake and energy storage, and NPY and AgRP neurons stimulating it in part, through AgRP antagonism of MC4R signaling (XREF_FIG).	35	39	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	35	36	38	39
To confirm these effects of central DNP were mediated via the melanocortin system , we tested the effects of the endogenous MC4R antagonist AgRP on DNP induced changes in body weight , food intake , and BAT thermogenesis .	To confirm these effects of central DNP were mediated via the melanocortin system, we tested the effects of the endogenous MC4R antagonist AgRP on DNP induced changes in body weight, food intake, and BAT thermogenesis.	17	25	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	23	24	21	22
4.12 Blockade of MC4R by AgRP .	4.12 Blockade of MC4R by AgRP.	1	6	Blockade	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	5	6	3	4
alphaMSH modulates its downstream homeostatic signalling via their action at melanocortin receptors MC3R and MC4R , which are antagonized by AgRP [ XREF_BIBR ] .	alphaMSH modulates its downstream homeostatic signalling via their action at melanocortin receptors MC3R and MC4R, which are antagonized by AgRP [XREF_BIBR].	11	22	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	20	21	14	15
MC4R can be directly activated via ACTH or alpha-MSH , or inhibited by AgRP , via release from terminals of POMC or AgRP and NPY axonal projections from the ARC [ XREF_BIBR ] .	MC4R can be directly activated via ACTH or alpha-MSH, or inhibited by AgRP, via release from terminals of POMC or AgRP and NPY axonal projections from the ARC [XREF_BIBR].	0	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	13	14	0	1
In contrast to AgRP related blockade of MC4R activation , stimulates alpha-MSH binding MC4R activation toward steering food intake via BDNF signaling to higher cerebral centers .	In contrast to AgRP related blockade of MC4R activation, stimulates alpha-MSH binding MC4R activation toward steering food intake via BDNF signaling to higher cerebral centers.	3	8	blockade	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	3	4	7	8
These data imply that MC4R suppression by agrp is required for the maximal rate of growth during this period , allowing rapid maturation and thus perhaps reducing predation .	These data imply that MC4R suppression by agrp is required for the maximal rate of growth during this period, allowing rapid maturation and thus perhaps reducing predation.	4	8	suppression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	agrp	agrp	agrp	MC4R	MC4R	MC4R	7	8	4	5
It is notable that AgRP also inhibits the residual N terminal independent constitutive activity of MC4R Delta1-24 ( XREF_SUPPLEMENTARY ) .	It is notable that AgRP also inhibits the residual N terminal independent constitutive activity of MC4R Delta1-24 (XREF_SUPPLEMENTARY).	4	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	4	5	15	16
The AgRP peptide directly antagonizes the MC3R and MC4R melanocortin receptors , critical components of the melanocortin system that promotes satiety and decreases feeding .	The AgRP peptide directly antagonizes the MC3R and MC4R melanocortin receptors, critical components of the melanocortin system that promotes satiety and decreases feeding.	1	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	1	2	8	9
AgRP - more than an antagonist of MC4R and MC3R ?	AgRP - more than an antagonist of MC4R and MC3R?	0	9	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	0	1	7	8
Importantly , ARC AgRP neurons selectively , monosynaptically engage and consequently inhibit PVH MC4R neurons 23 and optogenetic stimulation of ARC AgRP terminals in the PVH stimulates intense feeding within minutes XREF_BIBR , XREF_BIBR .	Importantly, ARC AgRP neurons selectively, monosynaptically engage and consequently inhibit PVH MC4R neurons 23 and optogenetic stimulation of ARC AgRP terminals in the PVH stimulates intense feeding within minutes XREF_BIBR, XREF_BIBR.	2	14	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	ARC AgRP	ARC AgRP	ARC AgRP	MC4R	MC4R	MC4R	2	4	13	14
MC4R desensitization and increased AgRP expression are thought to decrease the effectiveness of MC4R agonists as an antiobesity treatment .	MC4R desensitization and increased AgRP expression are thought to decrease the effectiveness of MC4R agonists as an antiobesity treatment.	1	14	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP expression	agrp	MC4R	MC4R	mc4r	4	5	13	14
XREF_BIBR Another critical component of the central melanocortin system within the ARC is the neurons expressing neuropeptide Y ( NPY ) and the potent MC3R and MC4R antagonist AgRP ( XREF_FIG ) .	XREF_BIBR Another critical component of the central melanocortin system within the ARC is the neurons expressing neuropeptide Y (NPY) and the potent MC3R and MC4R antagonist AgRP (XREF_FIG).	17	29	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	28	29	26	27
The present studies were designed to determine the specific contribution of MC4R exoloops and transmembrane domains to AGRP binding by using chimeric receptor constructs of the human melanocortin-1 receptor ( hMC1R ) , a receptor that is not inhibited by AGRP , and the human MC4R ( hMC4R ) , a receptor that is potently inhibited by AGRP .	The present studies were designed to determine the specific contribution of MC4R exoloops and transmembrane domains to AGRP binding by using chimeric receptor constructs of the human melanocortin-1 receptor (hMC1R), a receptor that is not inhibited by AGRP, and the human MC4R (hMC4R), a receptor that is potently inhibited by AGRP.	20	58	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	AGRP	AGRP	AGRP	MC4R	MC4R	MC4R	57	58	45	46
AgRP inhibits the activation of MC4R Delta1-24 by MC4R 2-26 with similar potency as its inverse agonism of the wild-type receptor ( XREF_FIG ) .	AgRP inhibits the activation of MC4R Delta1-24 by MC4R 2-26 with similar potency as its inverse agonism of the wild-type receptor (XREF_FIG).	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	0	1	5	6
Three MC4R antagonists , including the endogenous AgRP and two small molecule synthetic antagonists , ML00253764 and Ipsen 5i , were shown to be inverse agonists for these two mutant receptors as well as the WT MC4R [ XREF_BIBR ] .	Three MC4R antagonists, including the endogenous AgRP and two small molecule synthetic antagonists, ML00253764 and Ipsen 5i, were shown to be inverse agonists for these two mutant receptors as well as the WT MC4R [XREF_BIBR].	1	13	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	7	8	1	2
XREF_BIBR alpha-MSH , beta-MSH , and ACTH are the known agonists and AgRP is the known antagonist of the MC4R ( XREF_FIG ) .	XREF_BIBR alpha-MSH, beta-MSH, and ACTH are the known agonists and AgRP is the known antagonist of the MC4R (XREF_FIG).	12	21	is the known antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	12	13	19	20
However , a key difference between these receptors is that MC4R is inhibited by both ASIP and AgRP , whereas MC1R responds only to ASIP .	However, a key difference between these receptors is that MC4R is inhibited by both ASIP and AgRP, whereas MC1R responds only to ASIP.	10	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	17	18	10	11
Indeed , the peptide alpha-melanocyte stimulating hormone ( alpha-MSH ) secreted from POMC neurons activates whereas AgRP inhibits melanocortin 3 and 4 receptors ( MC3R and MC4R ) .	Indeed, the peptide alpha-melanocyte stimulating hormone (alpha-MSH) secreted from POMC neurons activates whereas AgRP inhibits melanocortin 3 and 4 receptors (MC3R and MC4R).	16	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	16	17	26	27
When MC4R antagonists such as AgRP are injected directly into the PVN , feeding is stimulated .	When MC4R antagonists such as AgRP are injected directly into the PVN, feeding is stimulated.	1	6	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	5	6	1	2
AgRP suppresses MC4R , increases feeding , and diminishes the response to leptin .	AgRP suppresses MC4R, increases feeding, and diminishes the response to leptin.	0	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	0	1	2	3
AgRP is an endogenous antagonist of MC4R and NPY is an agonist at Y1 and Y5 receptors , and both peptides cause increased food intake and body fat and weight [ XREF_BIBR ] .	AgRP is an endogenous antagonist of MC4R and NPY is an agonist at Y1 and Y5 receptors, and both peptides cause increased food intake and body fat and weight [XREF_BIBR].	0	8	is an endogenous antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	0	1	6	7
As MC4R PVH neurons lie downstream of and are inhibited by AgRP neurons , their activation ( owing in part to silencing of AgRP neurons as a meal progresses ) may contribute to positive affect associated with food consumption .	As MC4R PVH neurons lie downstream of and are inhibited by AgRP neurons, their activation (owing in part to silencing of AgRP neurons as a meal progresses) may contribute to positive affect associated with food consumption.	1	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	11	12	1	2
Leptin binding suppresses AgRP synthesis and triggers the production of POMC , which is the precursor for alpha-, beta-, and gamma-MSH : AgRP is the main antagonist of MC4R .	Leptin binding suppresses AgRP synthesis and triggers the production of POMC, which is the precursor for alpha-, beta-, and gamma-MSH : AgRP is the main antagonist of MC4R.	22	29	is the main antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	22	23	28	29
Given the fact that MC1R , MC4R , and MC5R are expressed in the explants ( XREF_FIG ) , ASIP should block all the 3 subtypes , and AGRP only block MC4R in these cultures .	Given the fact that MC1R, MC4R, and MC5R are expressed in the explants (XREF_FIG), ASIP should block all the 3 subtypes, and AGRP only block MC4R in these cultures.	28	34	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AGRP	AGRP	AGRP	MC4R	MC4R	MC4R	28	29	31	32
AgRP antagonizes alpha-MSH and MC4R signaling and inhibits endogenous MC4R activity [ XREF_BIBR ; XREF_BIBR ] , and NPY effectively increases appetite and reduces energy expenditure [ XREF_BIBR ; XREF_BIBR ] .	AgRP antagonizes alpha-MSH and MC4R signaling and inhibits endogenous MC4R activity [XREF_BIBR; XREF_BIBR], and NPY effectively increases appetite and reduces energy expenditure [XREF_BIBR; XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	0	1	9	10
Central administration of MC4R antagonists such as AgRP have the opposite effect to alpha-MSH ; they increase food intake , decrease energy expenditure , alter metabolism to promote deposition of adipose mass and suppress systemic thermogenesis resulting in weight gain [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Central administration of MC4R antagonists such as AgRP have the opposite effect to alpha-MSH; they increase food intake, decrease energy expenditure, alter metabolism to promote deposition of adipose mass and suppress systemic thermogenesis resulting in weight gain [XREF_BIBR, XREF_BIBR - XREF_BIBR].	3	8	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	7	8	3	4
AgRP suppresses MC4R and MC3R activity by competing with alpha-MSH for these receptors ( XREF_FIG ) .	AgRP suppresses MC4R and MC3R activity by competing with alpha-MSH for these receptors (XREF_FIG).	0	5	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	0	1	2	3
Mice null for MC4R , or treated with MC4R antagonists , including AgRP , have reduced thermogenesis and fail to upregulate UCP1 in the intercapsular BAT when fed high fat diet or when exposed to cold .	Mice null for MC4R, or treated with MC4R antagonists, including AgRP, have reduced thermogenesis and fail to upregulate UCP1 in the intercapsular BAT when fed high fat diet or when exposed to cold.	8	13	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	12	13	8	9
Contrary to alpha-MSH , AGRP inhibits the MC4R and the consequent reduction in appetite ; thus , a decrease in its secretion results in an increase in the activity of the MC4R positive cells in the PVN .	Contrary to alpha-MSH, AGRP inhibits the MC4R and the consequent reduction in appetite; thus, a decrease in its secretion results in an increase in the activity of the MC4R positive cells in the PVN.	4	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AGRP	AGRP	AGRP	MC4R	MC4R	MC4R	4	5	7	8
Orexigenic neuro-peptide Y/agouti related peptide ( NPY and AgRP ) neurons increase appetite and food intake by releasing the endogenous MC4R antagonist AgRP , and they suppress POMC neurons by releasing GABA .	Orexigenic neuro-peptide Y/agouti related peptide (NPY and AgRP) neurons increase appetite and food intake by releasing the endogenous MC4R antagonist AgRP, and they suppress POMC neurons by releasing GABA.	17	23	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	22	23	20	21
Critical to mediating the response to fasting and starvation is an increase in the endogenous MC4R antagonist AgRP , which potently stimulates food intake XREF_BIBR , increases fat preference and reduces carbohydrate intake when administered centrally XREF_BIBR .	Critical to mediating the response to fasting and starvation is an increase in the endogenous MC4R antagonist AgRP, which potently stimulates food intake XREF_BIBR, increases fat preference and reduces carbohydrate intake when administered centrally XREF_BIBR.	11	30	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	17	18	15	16
alphaMSH modulate its downstream homeostatic signaling via their action at melanocortin receptors MC3R and MC4R , which are antagonized by AGRP XREF_BIBR .	alphaMSH modulate its downstream homeostatic signaling via their action at melanocortin receptors MC3R and MC4R, which are antagonized by AGRP XREF_BIBR.	11	21	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AGRP	AGRP	AGRP	MC4R	MC4R	MC4R	20	21	14	15
Another population of neurons located in the hypothalamic arcuate nucleus synthesize the MC4R antagonist AgRP XREF_BIBR , XREF_BIBR , XREF_BIBR .	Another population of neurons located in the hypothalamic arcuate nucleus synthesize the MC4R antagonist AgRP XREF_BIBR, XREF_BIBR, XREF_BIBR.	12	15	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	14	15	12	13
By contrast , NPY and AgRP are orexigenic peptides and AgRP antagonizes the actions of MC3R and MC4R .	By contrast, NPY and AgRP are orexigenic peptides and AgRP antagonizes the actions of MC3R and MC4R.	8	18	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	10	11	17	18
AgRP antagonizes MC3R and MC4R , and causes marked hyperphagia and obesity when it is transgenically overexpressed or centrally injected .	AgRP antagonizes MC3R and MC4R, and causes marked hyperphagia and obesity when it is transgenically overexpressed or centrally injected.	0	7	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	0	1	4	5
a-MSH binds to and activates MC4R , whereas AgRP inhibits MC4R activity .	a-MSH binds to and activates MC4R, whereas AgRP inhibits MC4R activity.	8	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	8	9	10	11
Conversely , the orexigenic neuropeptides AGRP and NPY inhibit MC4R activation and promote food intake .	Conversely, the orexigenic neuropeptides AGRP and NPY inhibit MC4R activation and promote food intake.	2	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AGRP	AGRP	AGRP	MC4R	MC4R	MC4R	5	6	9	10
As previously mentioned , AgRP is an antagonist of MC4R .	As previously mentioned, AgRP is an antagonist of MC4R.	4	10	is an antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	4	5	9	10
The SFK would then bind and phosphorylate ZAP70 and Syk on tyrosine enabling ZAP70 and Syk to bind the SH2 domain of phosphatidylinositide 3-kinase ( PI3K ) .	The SFK would then bind and phosphorylate ZAP70 and Syk on tyrosine enabling ZAP70 and Syk to bind the SH2 domain of phosphatidylinositide 3-kinase (PI3K).	4	15	enabling	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	ZAP70	phosphorylate ZAP70	zap70	ZAP70	ZAP70	zap70	7	8	13	14
Expression of CA-Lck , ZAP-70 and RhoH together enhanced the interaction of ZAP-70 with RhoH and the phosphorylation of RhoH ( XREF_FIG , upper panel , lane 4 and lower panel and C ) .	Expression of CA-Lck, ZAP-70 and RhoH together enhanced the interaction of ZAP-70 with RhoH and the phosphorylation of RhoH (XREF_FIG, upper panel, lane 4 and lower panel and C).	0	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ZAP-70	Expression of CA-Lck, ZAP-70	zap-70	ZAP-70	ZAP-70	zap-70	4	5	12	13
Lack of ZAP-70 T293 phosphorylation increased association of ZAP-70 with the TCR and prolonged the existence of TCR signaling microclusters .	Lack of ZAP-70 T293 phosphorylation increased association of ZAP-70 with the TCR and prolonged the existence of TCR signaling microclusters.	2	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ZAP-70	ZAP-70 T293 phosphorylation	zap-70	ZAP-70	ZAP-70	zap-70	2	3	8	9
In support of this hypothesis , CA-Lck is required for the activation of ZAP-70 and co-expression of CA-Lck and ZAP-70 enhanced the phosphorylation and binding affinity of RhoH to ZAP-70 .	In support of this hypothesis, CA-Lck is required for the activation of ZAP-70 and co-expression of CA-Lck and ZAP-70 enhanced the phosphorylation and binding affinity of RhoH to ZAP-70.	15	30	enhanced	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ZAP-70	co-expression of CA-Lck and ZAP-70	zap-70	ZAP-70	ZAP-70	zap-70	19	20	29	30
Zap70 phosphorylation enables ZAP70 kinase activity , resulting in phosphorylation of the adaptor molecules SLP-76 and Linker of Activated T cells ( LAT ) .	Zap70 phosphorylation enables ZAP70 kinase activity, resulting in phosphorylation of the adaptor molecules SLP-76 and Linker of Activated T cells (LAT).	0	5	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Zap70	Zap70 phosphorylation	zap70	ZAP70	ZAP70	zap70	0	1	3	4
Interestingly , under transient transfection conditions , Nrdp1 induces Zap70 ubiquitination at six different K residues , and mutation of K538 blocks Nrdp1 induced Zap70 ubiquitination and promotes the signaling function of Zap70 .	Interestingly, under transient transfection conditions, Nrdp1 induces Zap70 ubiquitination at six different K residues, and mutation of K538 blocks Nrdp1 induced Zap70 ubiquitination and promotes the signaling function of Zap70.	22	33	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Zap70	Nrdp1 induced Zap70 ubiquitination	zap70	Zap70	Zap70	zap70	24	25	32	33
However , expression of CA-Lck and functional ZAP-70 together enhanced the interaction of ZAP-70 with RhoH and the phosphorylation of RhoH .	However, expression of CA-Lck and functional ZAP-70 together enhanced the interaction of ZAP-70 with RhoH and the phosphorylation of RhoH.	2	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ZAP-70	expression of CA-Lck and functional ZAP-70	zap-70	ZAP-70	ZAP-70	zap-70	7	8	13	14
Inducing transgenic WT Zap70 expression following dox administration restored thymic development of Zap70 YYAA expressing F5 thymocytes ( XREF_FIG ) .	Inducing transgenic WT Zap70 expression following dox administration restored thymic development of Zap70 YYAA expressing F5 thymocytes (XREF_FIG).	3	13	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Zap70	Zap70 expression	zap70	Zap70	Zap70	zap70	3	4	12	13
The high specificity and fast kinetics of the biosensor response enabled us to evaluate both TCR induced ZAP-70 activation and basal level of active ZAP-70 in resting cells .	The high specificity and fast kinetics of the biosensor response enabled us to evaluate both TCR induced ZAP-70 activation and basal level of active ZAP-70 in resting cells.	15	25	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ZAP-70	TCR induced ZAP-70	zap-70	ZAP-70	ZAP-70	zap-70	17	18	24	25
No changes were detected in LC3-I levels compared to MAP-2 in Tg-APP mice ( XREF_FIG ) , but LC3-II , which indicates the amount of autophagosomes , was detected and Bosutinib significantly decreased LC3-II relative to both LC3-I ( 16 +/-2.4 , mean +/-sd , p = 0.0001 ) and MAP-2 ( 29 +/-8, mean +/-sd , p = 0.0001 ) levels ( XREF_FIG , N = 9 ) , suggesting that Abl inhibition increases parkin and facilitates autophagic clearance .	No changes were detected in LC3-I levels compared to MAP-2 in Tg-APP mice (XREF_FIG), but LC3-II, which indicates the amount of autophagosomes, was detected and Bosutinib significantly decreased LC3-II relative to both LC3-I (16 +/-2.4, mean +/-sd, p = 0.0001) and MAP-2 (29 +/-8, mean +/-sd, p = 0.0001) levels (XREF_FIG, N = 9), suggesting that Abl inhibition increases parkin and facilitates autophagic clearance.	72	76	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Abl	Abl	Abl	parkin	parkin	parkin	72	73	75	76
Abl activation also inhibits parkin activity , and Abl inhibition activates parkin in PD models XREF_BIBR .	Abl activation also inhibits parkin activity, and Abl inhibition activates parkin in PD models XREF_BIBR.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Abl	Abl	Abl	parkin	parkin	parkin	0	1	4	5
c-Abl phosphorylation of parkin and alpha-synuclein could proceed along parallel pathways where each pathway contributes to loss of SN DA neurons or since aggregation of alpha-synuclein seems to be driver of PD pathogenesis , parkin inactivation by c-Abl phosphorylation could be downstream of c-Abl phosphorylation of Y39 alpha-synuclein .	c-Abl phosphorylation of parkin and alpha-synuclein could proceed along parallel pathways where each pathway contributes to loss of SN DA neurons or since aggregation of alpha-synuclein seems to be driver of PD pathogenesis, parkin inactivation by c-Abl phosphorylation could be downstream of c-Abl phosphorylation of Y39 alpha-synuclein.	34	39	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	c-Abl	c-Abl phosphorylation	c-abl	parkin	parkin	parkin	37	38	34	35
Moreover , it is important to further elucidate how different parkin substrates each can contribute to c-Abl driven neurodegeneration , and whether c-Abl inactivation of parkin compromises other reported aspects of parkin mediated mitochondrial quality control such as transport , fission and fusion dynamics , or mitophagy [ XREF_BIBR ] .	Moreover, it is important to further elucidate how different parkin substrates each can contribute to c-Abl driven neurodegeneration, and whether c-Abl inactivation of parkin compromises other reported aspects of parkin mediated mitochondrial quality control such as transport, fission and fusion dynamics, or mitophagy [XREF_BIBR].	22	26	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	c-Abl	c-Abl	c-Abl	parkin	parkin	parkin	22	23	25	26
Since oxidative stress is intimately involved in sporadic PD , we propose a novel stress induced cell signaling mechanism featuring activated c-Abl , which inhibits parkin function and consequently increases cell death due to accumulation of cytotoxic parkin substrates , such as AIMP2 ( XREF_FIG ) .	Since oxidative stress is intimately involved in sporadic PD, we propose a novel stress induced cell signaling mechanism featuring activated c-Abl, which inhibits parkin function and consequently increases cell death due to accumulation of cytotoxic parkin substrates, such as AIMP2 (XREF_FIG).	19	42	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Abl	c-Abl	c-Abl	parkin	parkin	parkin	21	22	25	26
Abl activation inhibits the E3 ubiquitin ligase activity of parkin , and Abl inhibition induces parkin protective function in Parkinson ' s disease ( PD ) models .	Abl activation inhibits the E3 ubiquitin ligase activity of parkin, and Abl inhibition induces parkin protective function in Parkinson 's disease (PD) models.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Abl	Abl	Abl	parkin	parkin	parkin	0	1	9	10
The identification of c-Abl tyrosine phosphorylation mediated inhibition of parkin activity and its pathological relevance as demonstrated in PD will pave the way for better understanding of the pathophysiology of this disease .	The identification of c-Abl tyrosine phosphorylation mediated inhibition of parkin activity and its pathological relevance as demonstrated in PD will pave the way for better understanding of the pathophysiology of this disease.	3	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Abl	c-Abl tyrosine phosphorylation	c-abl	parkin	parkin	parkin	3	4	9	10
Since oxidative stress is intricately involved in the activation of c-Abl and in sporadic PD , we propose that a novel , stress induced cell signaling mechanism involving activated c-Abl that inhibits parkin function and consequently increases the cell ' s susceptibility to death due to accumulation of cytotoxic parkin substrates , such as AIMP2 is involved in this process .	Since oxidative stress is intricately involved in the activation of c-Abl and in sporadic PD, we propose that a novel, stress induced cell signaling mechanism involving activated c-Abl that inhibits parkin function and consequently increases the cell 's susceptibility to death due to accumulation of cytotoxic parkin substrates, such as AIMP2 is involved in this process.	26	54	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Abl	c-Abl	c-Abl	parkin	parkin	parkin	29	30	32	33
It was previously reported that Abl inhibition may activate parkin and improve dopaminergic neuron survival in PD models [ XREF_BIBR ] .	It was previously reported that Abl inhibition may activate parkin and improve dopaminergic neuron survival in PD models [XREF_BIBR].	5	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Abl	Abl	Abl	parkin	parkin	parkin	5	6	9	10
Compelling evidence indicates that pharmacological inhibition of c-Abl with STI-571 enhances E3 ligase activity of Parkin .	Compelling evidence indicates that pharmacological inhibition of c-Abl with STI-571 enhances E3 ligase activity of Parkin.	5	16	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Abl	c-Abl	c-Abl	Parkin	Parkin	Parkin	7	8	15	16
EphA2 tyrosine phosphorylation level was dramatically decreased by overexpression of LMW-PTP , and increased by expression of dnLMW-PTP , suggesting tyrosine phosphorylated EphA2 is a substrate of LMW-PTP .	EphA2 tyrosine phosphorylation level was dramatically decreased by overexpression of LMW-PTP, and increased by expression of dnLMW-PTP, suggesting tyrosine phosphorylated EphA2 is a substrate of LMW-PTP.	0	11	decreased	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	LMW-PTP	overexpression of LMW-PTP	lmw-ptp	EphA2	EphA2	epha2	10	11	0	1
Recently , AIP was shown to inhibit ERalpha transcriptional activity and AIP mutations lead to enhanced ERalpha transcriptional activity .	Recently, AIP was shown to inhibit ERalpha transcriptional activity and AIP mutations lead to enhanced ERalpha transcriptional activity.	11	18	lead	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	AIP	AIP	AIP	ERalpha	ERalpha	ERalpha	11	12	16	17
Taken together , this study shows that XAP2 exerts a negative effect on ERalpha transcriptional activity and may thus prevent ERalpha dependent events .	Taken together, this study shows that XAP2 exerts a negative effect on ERalpha transcriptional activity and may thus prevent ERalpha dependent events.	7	22	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAP2	XAP2	XAP2	ERalpha	ERalpha	ERalpha	7	8	20	21
Because AHR binds ERalpha and inhibits its function , it is likely that AIP inhibition of ERalpha is mediated by AHR .	Because AHR binds ERalpha and inhibits its function, it is likely that AIP inhibition of ERalpha is mediated by AHR.	13	17	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AIP	AIP	AIP	ERalpha	ERalpha	ERalpha	13	14	16	17
SARA activates TGF-beta and Smad3 signaling by recruiting non phosphorylated Smad2/3 to the activated receptors for phosphorylation .	SARA activates TGF-beta and Smad3 signaling by recruiting non phosphorylated Smad2/3 to the activated receptors for phosphorylation.	0	5	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SARA	SARA	SARA	Smad3	Smad3	Smad3	0	1	4	5
Likewise , depletion of Kindlin-1 reduced P-Smad3 ( S423/425 ) and this effect could be rescued by SARA overexpression .	Likewise, depletion of Kindlin-1 reduced P-Smad3 (S423/425) and this effect could be rescued by SARA overexpression.	6	19	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	SARA	SARA overexpression	sara	P-Smad3	P-Smad3	p-smad3	17	18	6	7
ATM and c-Abl inhibit Mdm2 activity via the phosphorylation of Ser395 ( S395 ) and Tyr394 , respectively , whereas phosphorylation of Ser166 and Ser186 promote its E3-ligase activity .	ATM and c-Abl inhibit Mdm2 activity via the phosphorylation of Ser395 (S395) and Tyr394, respectively, whereas phosphorylation of Ser166 and Ser186 promote its E3-ligase activity.	0	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Abl	c-Abl	c-Abl	Mdm2	Mdm2	Mdm2	2	3	4	5
As part of this mechanism ATM itself , and the ATM activated protein tyrosine kinase , c-Abl , inhibit Hdm2 function through phosphorylation of serine 395 and tyrosine 394 ( Y394 ) , respectively .	As part of this mechanism ATM itself, and the ATM activated protein tyrosine kinase, c-Abl, inhibit Hdm2 function through phosphorylation of serine 395 and tyrosine 394 (Y394), respectively.	14	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Abl	c-Abl	c-Abl	Hdm2	Hdm2	Hdm2	16	17	19	20
In our previous work to identify the Crk SH3 binding partners essential for transformation of NIH3T3 cells by CrkI , we found that the activity of Abl family kinases antagonized the transforming activity of Crk .	In our previous work to identify the Crk SH3 binding partners essential for transformation of NIH3T3 cells by CrkI, we found that the activity of Abl family kinases antagonized the transforming activity of Crk.	26	35	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Abl	Abl	Abl	Crk	Crk	Crk	26	27	34	35
We further show that Fc-ephrin-A1 activates Abl kinase and causes Abl dependent disruption of the CrkII and C3G complex and the down-regulation of Rap1-GTP in PC3 prostate cancer cells ( XREF_FIG ) .	We further show that Fc-ephrin-A1 activates Abl kinase and causes Abl dependent disruption of the CrkII and C3G complex and the down-regulation of Rap1-GTP in PC3 prostate cancer cells (XREF_FIG).	10	18	disruption	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Abl	Abl	Abl	CrkII	CrkII	CrkII	10	11	15	16
During ephrin-A1-induced retraction of PC3 prostate cancer cells , we show that endogenous Abl is activated and disrupts the CrkII and C3G complex to reduce Rap1-GTP .	During ephrin-A1-induced retraction of PC3 prostate cancer cells, we show that endogenous Abl is activated and disrupts the CrkII and C3G complex to reduce Rap1-GTP.	12	22	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Abl	Abl	Abl	CrkII	CrkII	CrkII	13	14	19	20
Akt1 overexpression significantly reduced A/R injury in cardiomyocytes , and this could be related to its effects on various targets of the PI3K and Akt signalling pathway , such as Bcl-2 , Bax , HIF-1alpha and VEGF .	Akt1 overexpression significantly reduced A/R injury in cardiomyocytes, and this could be related to its effects on various targets of the PI3K and Akt signalling pathway, such as Bcl-2, Bax, HIF-1alpha and VEGF.	0	5	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1 overexpression	akt1	A/R	A/R	a/r	0	1	4	5
Moreover , ZIC was reported to associate with GLI and enhance the nuclear accumulation and transcriptional activity of GLI proteins .	Moreover, ZIC was reported to associate with GLI and enhance the nuclear accumulation and transcriptional activity of GLI proteins.	2	19	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ZIC	ZIC	ZIC	GLI	GLI	GLI	2	3	18	19
The overexpression of miR-29b in K562 cells lowers ABL-1 protein levels , and induces G1 phase cell arrest by activating p21 and p27 .	The overexpression of miR-29b in K562 cells lowers ABL-1 protein levels, and induces G1 phase cell arrest by activating p21 and p27.	1	23	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ABL-1 protein	overexpression of miR-29b in K562 cells lowers ABL-1 protein levels	abl-1 protein	p27	p27	p27	8	10	22	23
Interestingly , the overexpression of SARA prolonged the activity period of Smad2 and shortened that of Smad3 , which seemed consistent with the change of EMT phenotype and ECM changes in HK-2 cell induced by HG .	Interestingly, the overexpression of SARA prolonged the activity period of Smad2 and shortened that of Smad3, which seemed consistent with the change of EMT phenotype and ECM changes in HK-2 cell induced by HG.	3	12	prolonged	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SARA	overexpression of SARA	sara	Smad2	Smad2	smad2	5	6	11	12
Supporting the idea that ABL2 can help convey VEGF164 induced VEGFR2 mediated permeability signaling , we show here that ABL1 knockdown or NRP1 does not completely abolish pCRKL induction , whereas the pharmacological VEGFR2 blockade with PTK/ZK or dual ABL1 and ABL2 blockade with Imatinib abrogated pCRKL and pSFK induction in response to VEGF164 in vitro .	Supporting the idea that ABL2 can help convey VEGF164 induced VEGFR2 mediated permeability signaling, we show here that ABL1 knockdown or NRP1 does not completely abolish pCRKL induction, whereas the pharmacological VEGFR2 blockade with PTK/ZK or dual ABL1 and ABL2 blockade with Imatinib abrogated pCRKL and pSFK induction in response to VEGF164 in vitro.	34	49	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ABL1	ABL1	ABL1	pCRKL	pCRKL	pCRKL	39	40	46	47
This leads to abrogation of AKT-1 inhibition of FOXO .	This leads to abrogation of AKT-1 inhibition of FOXO.	5	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT-1	AKT-1	AKT-1	FOXO	FOXO	FOXO	5	6	8	9
Parallel signaling of AKT-1 and EAK proteins could occur either at the organismal level , whereby AKT-1 signaling in non XXX cells would converge with EAK signals in XXX to inhibit DAF-16 and FoxO cell nonautonomously , or at the intracellular level , whereby AKT-1 signaling would converge with EAK signals in XXX to inhibit DAF-16 and FoxO cell autonomously .	Parallel signaling of AKT-1 and EAK proteins could occur either at the organismal level, whereby AKT-1 signaling in non XXX cells would converge with EAK signals in XXX to inhibit DAF-16 and FoxO cell nonautonomously, or at the intracellular level, whereby AKT-1 signaling would converge with EAK signals in XXX to inhibit DAF-16 and FoxO cell autonomously.	44	58	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT-1	AKT-1	AKT-1	FoxO	FoxO	FoxO	44	45	57	58
Thus , EAK-7 and AKT-1 inhibit DAF-16 and FoxO activity via distinct mechanisms .	Thus, EAK-7 and AKT-1 inhibit DAF-16 and FoxO activity via distinct mechanisms.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT-1	AKT-1	AKT-1	FoxO	FoxO	FoxO	4	5	8	9
AKT1 and the SGK1-3 kinases inhibit the activity of the Forkhead transcription factors FOXO by retaining them in the cytoplasm .	AKT1 and the SGK1-3 kinases inhibit the activity of the Forkhead transcription factors FOXO by retaining them in the cytoplasm.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT1	AKT1	AKT1	FOXO	FOXO	FOXO	0	1	13	14
Transcriptional activity of FoxO factors is controlled through the actions of multiple growth factors signaling through protein kinase B , whereby phosphorylation of FoxO factors inhibits FoxO mediated transactivation by promoting nuclear export .	Transcriptional activity of FoxO factors is controlled through the actions of multiple growth factors signaling through protein kinase B, whereby phosphorylation of FoxO factors inhibits FoxO mediated transactivation by promoting nuclear export.	16	28	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	protein kinase B	protein kinase B	protein kinase B	FoxO	FoxO	FoxO	16	19	26	27
Protein kinase B can phoshorylate and thereby inactivate the FOXO ( forkhead box O ) family of transcription factors .	Protein kinase B can phoshorylate and thereby inactivate the FOXO (forkhead box O) family of transcription factors.	0	15	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Protein kinase B	Protein kinase B	Protein kinase B	FOXO	FOXO	FOXO	0	3	9	10
This is consistent with the increased nuclear localization of DAF-16 and FoxO caused by reduction of AKT-1 activity .	This is consistent with the increased nuclear localization of DAF-16 and FoxO caused by reduction of AKT-1 activity.	7	17	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT-1	AKT-1	AKT-1	FoxO	FoxO	FoxO	16	17	11	12
Foxo activity is down-regulated by protein kinase B ( PKB )-mediated phosphorylation at three conserved sites that triggers nuclear export of Foxo proteins in complex with the 14-3-3 protein .	Foxo activity is down-regulated by protein kinase B (PKB)-mediated phosphorylation at three conserved sites that triggers nuclear export of Foxo proteins in complex with the 14-3-3 protein.	0	12	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	protein kinase B	protein kinase B (PKB)-mediated phosphorylation	protein kinase b	Foxo	Foxo	foxo	5	8	0	1
Although Akt2 was the major isoform expressed in the liver , the deletion of Akt1 in the livers of Akt2 -/- mice significantly and markedly induced many FoxO target genes ( XREF_SUPPLEMENTARY ) .	Although Akt2 was the major isoform expressed in the liver, the deletion of Akt1 in the livers of Akt2 -/- mice significantly and markedly induced many FoxO target genes (XREF_SUPPLEMENTARY).	12	29	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	FoxO	FoxO	FoxO	14	15	27	28
Akt1 signaling inactivates the transcription factor FOXO which regulates the expression of Thor XREF_BIBR , XREF_BIBR .	Akt1 signaling inactivates the transcription factor FOXO which regulates the expression of Thor XREF_BIBR, XREF_BIBR.	0	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	FOXO	FOXO	FOXO	0	1	6	7
Glycogen synthesis occurs by activation of the insulin signaling pathway in which PI3K phosphorylates protein kinase B ( Akt ) that in turn inhibits GSK3beta activity .	Glycogen synthesis occurs by activation of the insulin signaling pathway in which PI3K phosphorylates protein kinase B (Akt) that in turn inhibits GSK3beta activity.	7	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	protein kinase B	insulin signaling pathway in which PI3K phosphorylates protein kinase B	protein kinase b	GSK3beta	GSK3beta	gsk3beta	14	17	24	25
In addition , puerarin is shown to activate protein kinase B ( PKB )/Akt , an important upstream kinase of GSK-3beta , possibly promoting subsequent GSK-3beta inhibition .	In addition, puerarin is shown to activate protein kinase B (PKB)/Akt, an important upstream kinase of GSK-3beta, possibly promoting subsequent GSK-3beta inhibition.	8	26	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	protein kinase B	protein kinase B	protein kinase B	GSK-3beta	GSK-3beta	GSK-3beta	8	11	25	26
GSK3beta , an important pathogenic protein kinase for PD , is activated by phosphorylation of Try216 residue located in the kinase domain and inactivated by protein kinase B- ( Akt-) mediated phosphorylation of Ser9 residue [ XREF_BIBR , XREF_BIBR ] .	GSK3beta, an important pathogenic protein kinase for PD, is activated by phosphorylation of Try216 residue located in the kinase domain and inactivated by protein kinase B- (Akt-) mediated phosphorylation of Ser9 residue [XREF_BIBR, XREF_BIBR].	0	28	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	protein kinase B-	phosphorylation of Try216 residue located in the kinase domain and inactivated by protein kinase B-	protein kinase b-	GSK3beta	GSK3beta	gsk3beta	25	28	0	1
Moreover , protein kinase B lies on the downstream of GDNF and RET signaling module to inhibit the GSK3beta , resulting in activation of HH signaling .	Moreover, protein kinase B lies on the downstream of GDNF and RET signaling module to inhibit the GSK3beta, resulting in activation of HH signaling.	2	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	protein kinase B	protein kinase B	protein kinase B	GSK3beta	GSK3beta	GSK3beta	2	5	18	19
Furthermore , overexpression of AKT1 or an AKT chimera including the PH domain and hinge region of AKT2 and the catalytic domain and C-tail of AKT1 prevented strain activation of GSK-3beta , but overexpression of AKT2 or a chimera including the PH domain and hinge region of AKT1 and the catalytic domain and C-tail of AKT2 did not .	Furthermore, overexpression of AKT1 or an AKT chimera including the PH domain and hinge region of AKT2 and the catalytic domain and C-tail of AKT1 prevented strain activation of GSK-3beta, but overexpression of AKT2 or a chimera including the PH domain and hinge region of AKT1 and the catalytic domain and C-tail of AKT2 did not.	2	31	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT1	overexpression of AKT1	akt1	GSK-3beta	GSK-3beta	gsk-3beta	4	5	30	31
Although it was also reported that GSK-3beta is inactivated by protein kinase B at the spindle poles , functions and targets of GSK-3beta in the mitotic phase are unknown .	Although it was also reported that GSK-3beta is inactivated by protein kinase B at the spindle poles, functions and targets of GSK-3beta in the mitotic phase are unknown.	6	13	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	protein kinase B	protein kinase B	protein kinase B	GSK-3beta	GSK-3beta	GSK-3beta	10	13	6	7
Here , we show that PI3K and AKT1 signaling promotes self-renewal by suppressing GSK3beta activity and restricting its access to nuclear substrates such as c-myc .	Here, we show that PI3K and AKT1 signaling promotes self-renewal by suppressing GSK3beta activity and restricting its access to nuclear substrates such as c-myc.	5	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT1	AKT1	AKT1	GSK3beta	GSK3beta	GSK3beta	7	8	13	14
Regulatory inhibition of GSK-3beta by Akt-1 in hypertrophied hearts is impaired , leading to activation during ischemia .	Regulatory inhibition of GSK-3beta by Akt-1 in hypertrophied hearts is impaired, leading to activation during ischemia.	1	8	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt-1	Akt-1	Akt-1	GSK-3beta	GSK-3beta	GSK-3beta	5	6	3	4
Functional experiments on Apoe isoforms showed that Apoe4 , but not wild-type Apoe , inhibits glycogen synthase kinase ( GSK )-3beta and increases the amount of active protein kinase B ( PKB ) , which further inactivates GSK-3beta , leading to enhancement of beta-catenin translocation into nuclei [ XREF_BIBR ] .	Functional experiments on Apoe isoforms showed that Apoe4, but not wild-type Apoe, inhibits glycogen synthase kinase (GSK)-3beta and increases the amount of active protein kinase B (PKB), which further inactivates GSK-3beta, leading to enhancement of beta-catenin translocation into nuclei [XREF_BIBR].	7	38	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	protein kinase B	Apoe4, but not wild-type Apoe, inhibits glycogen synthase kinase (GSK)-3beta and increases the amount of active protein kinase B	protein kinase b	GSK-3beta	GSK-3beta	gsk-3beta	27	30	37	38
In fact , Akt kinase ( also called protein kinase B , PKB ) directly phosphorylates and thereby inhibits GSK-3beta , leading to impaired phosphorylation and stabilization of the beta-catenin protein [ XREF_BIBR ] .	In fact, Akt kinase (also called protein kinase B, PKB) directly phosphorylates and thereby inhibits GSK-3beta, leading to impaired phosphorylation and stabilization of the beta-catenin protein [XREF_BIBR].	3	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	kinase	kinase	kinase	GSK-3beta	GSK-3beta	GSK-3beta	4	5	19	20
Constitutive protein kinase B ( also known as AKT ) activation in prostate cancer due to loss of PTEN can inhibit GSK-3beta activity leading to stabilization and nuclear accumulation of beta-catenin [ XREF_BIBR ] .	Constitutive protein kinase B (also known as AKT) activation in prostate cancer due to loss of PTEN can inhibit GSK-3beta activity leading to stabilization and nuclear accumulation of beta-catenin [XREF_BIBR].	1	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	protein kinase B	protein kinase B	protein kinase B	GSK-3beta	GSK-3beta	GSK-3beta	1	4	21	22
Overexpression of GSK3beta , which is functionally similar to activation of GSK3beta by Akt1 deletion , shifts Per2 transcription later , similar to the effect on Per2 expression in the present experiments in aortae .	Overexpression of GSK3beta, which is functionally similar to activation of GSK3beta by Akt1 deletion, shifts Per2 transcription later, similar to the effect on Per2 expression in the present experiments in aortae.	9	14	activation	Positive_activation_token_2_noun	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	GSK3beta	GSK3beta	GSK3beta	13	14	11	12
Insulin or adenovirus mediated expression of constitutively active AKT1 inhibited FoxO1 and Smad3 synergy .	Insulin or adenovirus mediated expression of constitutively active AKT1 inhibited FoxO1 and Smad3 synergy.	0	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT1	Insulin or adenovirus mediated expression of constitutively active AKT1	akt1	FoxO1	FoxO1	foxo1	8	9	10	11
Blocking protein kinase A ( PKA ) , phosphatidylinositol-3 kinase ( PI3K ) or protein kinase B ( AKT ) restored the upregulation of FoxO1 and apoptotic signals , which was suppressed by FSH .	Blocking protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K) or protein kinase B (AKT) restored the upregulation of FoxO1 and apoptotic signals, which was suppressed by FSH.	14	27	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	FoxO1	FoxO1	FoxO1	14	17	24	25
To this end , our data support a previous report by Zhang and colleagues [ XREF_BIBR ] , which proposed that Akt1 signalling promotes cell cycle progression of arrested pre-adipocytes by inhibiting FoxO1 and restricting the expression of its target genes including the cell cycle inhibitor p27 kip1 [ XREF_BIBR ] .	To this end, our data support a previous report by Zhang and colleagues [XREF_BIBR], which proposed that Akt1 signalling promotes cell cycle progression of arrested pre-adipocytes by inhibiting FoxO1 and restricting the expression of its target genes including the cell cycle inhibitor p27 kip1 [XREF_BIBR].	21	33	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	FoxO1	FoxO1	FoxO1	21	22	32	33
For example , the chemotherapeutic drugs paclitaxel and Akt and protein kinase B signaling inhibitor-2 ( API-2 )/Triciribine , which are clinically used for the treatment of breast carcinoma and acute myeloid leukemia , can activate FOXO3a by reducing AKT activity .	For example, the chemotherapeutic drugs paclitaxel and Akt and protein kinase B signaling inhibitor-2 (API-2)/Triciribine, which are clinically used for the treatment of breast carcinoma and acute myeloid leukemia, can activate FOXO3a by reducing AKT activity.	8	37	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	protein kinase B	protein kinase B	protein kinase B	FOXO3a	FOXO3a	FOXO3a	10	13	36	37
In serum starved cells , wild-type AKT1 repressed FOXO3a less strongly ( XREF_FIG C , D ) .	In serum starved cells, wild-type AKT1 repressed FOXO3a less strongly (XREF_FIG C, D).	5	9	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT1	AKT1	AKT1	FOXO3a	FOXO3a	FOXO3a	6	7	8	9
Specifically , AKT1 induces SKP2 transcription in an E2F1 dependent manner and antagonizes the transcriptional repressor function of FOXO3 that binds the SKP2 promoter ; AKT1/2 reportedly enhance the translation of SKP2 mRNA through activation of the translation initiation protein eIF4E ;, and AKT1 promotes Skp2 protein stability in part through direct phosphorylation of Skp2 at Ser 72 .	Specifically, AKT1 induces SKP2 transcription in an E2F1 dependent manner and antagonizes the transcriptional repressor function of FOXO3 that binds the SKP2 promoter; AKT1/2 reportedly enhance the translation of SKP2 mRNA through activation of the translation initiation protein eIF4E;, and AKT1 promotes Skp2 protein stability in part through direct phosphorylation of Skp2 at Ser 72.	2	23	antagonizes	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	AKT1	AKT1 induces SKP2 transcription	akt1	FOXO3	FOXO3 that binds the SKP2	foxo3	2	3	18	19
This finding is supported by a previously published study that showed that inhibition of protein kinase B ( Akt ) promoted FOXO3a dependent apoptosis in prostate cancer [ XREF_BIBR ] .	This finding is supported by a previously published study that showed that inhibition of protein kinase B (Akt) promoted FOXO3a dependent apoptosis in prostate cancer [XREF_BIBR].	14	23	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	protein kinase B	protein kinase B	protein kinase B	FOXO3a	FOXO3a	FOXO3a	14	17	21	22
Akt1 is known to phosphorylate FoxO3a [ XREF_BIBR ] and block the activity of this transcription factor [ XREF_BIBR ] , but loss of Akt1 activity allows FoxO3a to translocate to the cell nucleus and initiate apoptosis [ XREF_BIBR , XREF_BIBR ] .	Akt1 is known to phosphorylate FoxO3a [XREF_BIBR] and block the activity of this transcription factor [XREF_BIBR], but loss of Akt1 activity allows FoxO3a to translocate to the cell nucleus and initiate apoptosis [XREF_BIBR, XREF_BIBR].	24	35	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	FoxO3a	FoxO3a	FoxO3a	24	25	27	28
Reportedly , Akt1 inactivates Caspase 9 by phosphorylation on ser196 .	Reportedly, Akt1 inactivates Caspase 9 by phosphorylation on ser196.	2	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	Caspase 9	Caspase 9	Caspase 9	2	3	4	6
XREF_BIBR , XREF_BIBR Whether this constitutes an off-target mechanism of resistance or rather reflects the inhibition of caspase-9 by AKT1 transduced signals 196 ( hence representing a post-target effect ) remains to be clarified .	XREF_BIBR, XREF_BIBR Whether this constitutes an off-target mechanism of resistance or rather reflects the inhibition of caspase-9 by AKT1 transduced signals 196 (hence representing a post-target effect) remains to be clarified.	15	20	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT1	AKT1	AKT1	caspase-9	caspase-9	caspase-9	19	20	17	18
Caspase-9 was possibly inhibited in part by AKT1 activation and blocked a positive feedback loop for sustained caspase-3 activation as well as sustaining loss of mitochondrial membrane potential .	Caspase-9 was possibly inhibited in part by AKT1 activation and blocked a positive feedback loop for sustained caspase-3 activation as well as sustaining loss of mitochondrial membrane potential.	0	22	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT1	AKT1	AKT1	Caspase-9	Caspase-9	Caspase-9	7	8	0	1
Here we show that activation of protein kinase B ( PKB )/Akt , contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27 .	Here we show that activation of protein kinase B (PKB)/Akt, contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27.	6	34	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	p27	p27	p27	6	9	33	34
That study showed that the down-regulation of Akt2 or Akt3 , but not Akt1 , reduced the phosphorylated form of Bad , resulting in induction of caspase dependent apoptosis .	That study showed that the down-regulation of Akt2 or Akt3, but not Akt1, reduced the phosphorylated form of Bad, resulting in induction of caspase dependent apoptosis.	5	21	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	Bad	Bad	Bad	13	14	20	21
Moreover , knockdown of Akt1 induces MST2 activation and enhances doxorubicin activated MST2 and apoptosis in PTEN mutated MDA-MB-468 cells ( XREF_FIG ) .	Moreover, knockdown of Akt1 induces MST2 activation and enhances doxorubicin activated MST2 and apoptosis in PTEN mutated MDA-MB-468 cells (XREF_FIG).	2	7	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	MST2	MST2	MST2	4	5	6	7
The modular map shows that the AKT1 module inhibits RAF1 and consequently MAPK1/3-module pathways .	The modular map shows that the AKT1 module inhibits RAF1 and consequently MAPK1/3-module pathways.	6	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT1	AKT1	AKT1	RAF1	RAF1	RAF1	6	7	9	10
As seen in XREF_FIG , absence of Akt1 significantly reduces Rac1 activity ( assayed as Rac1-GTP ) after PDGF stimulation .	As seen in XREF_FIG, absence of Akt1 significantly reduces Rac1 activity (assayed as Rac1-GTP) after PDGF stimulation.	5	11	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	Rac1	Rac1	Rac1	7	8	10	11
RHOB loss was found to induce AKT1 activation , which in turn activates RAC1 through its GEF TRIO .	RHOB loss was found to induce AKT1 activation, which in turn activates RAC1 through its GEF TRIO.	6	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT1	AKT1	AKT1	RAC1	RAC1	RAC1	6	7	13	14
Of note , PIK3CA mutation activates AKT1 , which in turn inhibits MAP2K4 , thereby providing an additional pathway to attenuate JNK signaling even in wt MAP2K4 and MAP3K1 tumors .	Of note, PIK3CA mutation activates AKT1, which in turn inhibits MAP2K4, thereby providing an additional pathway to attenuate JNK signaling even in wt MAP2K4 and MAP3K1 tumors.	5	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT1	AKT1	AKT1	MAP2K4	MAP2K4	MAP2K4	6	7	12	13
The involvement of AKT in the regulation of MST1 induced apoptosis was confirmed by co-overexpression of MST1 and Myr-AKT1 , which reduced BIM induction and caspase-3 cleavage ( XREF_FIG ) , indicating that AKT negatively regulates the downstream target of MST1 .	The involvement of AKT in the regulation of MST1 induced apoptosis was confirmed by co-overexpression of MST1 and Myr-AKT1, which reduced BIM induction and caspase-3 cleavage (XREF_FIG), indicating that AKT negatively regulates the downstream target of MST1.	14	23	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myr-AKT1	co-overexpression of MST1 and Myr-AKT1	myr-akt1	BIM	BIM	bim	18	19	22	23
Gain-of-function of Akt1 by Akt1 CA transfection abrogated the stimulation of the Bim promoter activity by FoxO3a ( XREF_FIG ) .	Gain-of-function of Akt1 by Akt1 CA transfection abrogated the stimulation of the Bim promoter activity by FoxO3a (XREF_FIG).	0	14	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	Bim	Bim	Bim	2	3	12	13
Furthermore , inhibition of cell migration by DN-Akt1-expressing PC3 cells on vitronectin , osteonectin and osteopontin were significantly rescued by co-treatment with AP7.4 ( XREF_FIG ) , thus demonstrating that Akt1 mediated affinity modulation of integrin beta 3 is necessary for prostate cancer cell migration .	Furthermore, inhibition of cell migration by DN-Akt1-expressing PC3 cells on vitronectin, osteonectin and osteopontin were significantly rescued by co-treatment with AP7.4 (XREF_FIG), thus demonstrating that Akt1 mediated affinity modulation of integrin beta 3 is necessary for prostate cancer cell migration.	30	38	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	integrin beta 3	integrin beta 3	integrin beta 3	30	31	35	38
Transcriptionally , MYR-AKT1 impaired the capacity of NR3C1 to activate a luciferase reporter construct under the control of a synthetic glucocorticoid response element ( XREF_FIG ) .	Transcriptionally, MYR-AKT1 impaired the capacity of NR3C1 to activate a luciferase reporter construct under the control of a synthetic glucocorticoid response element (XREF_FIG).	2	8	impaired	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MYR-AKT1	MYR-AKT1	MYR-AKT1	NR3C1	NR3C1	NR3C1	2	3	7	8
To test if AKT1 can interact with and inhibit the glucocorticoid receptor protein , we transfected 293T cells with plasmid constructs driving the expression of Flag tagged AKT1 and HA tagged NR3C1 and isolated glucocorticoid receptor containing protein complexes via immunoprecipitation using an anti-HA antibody .	To test if AKT1 can interact with and inhibit the glucocorticoid receptor protein, we transfected 293T cells with plasmid constructs driving the expression of Flag tagged AKT1 and HA tagged NR3C1 and isolated glucocorticoid receptor containing protein complexes via immunoprecipitation using an anti-HA antibody.	3	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT1	AKT1	AKT1	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	3	4	10	12
Protein Kinase B ( PKB and AKT ) mediates the MLK3 inhibition by Estrogen .	Protein Kinase B (PKB and AKT) mediates the MLK3 inhibition by Estrogen.	0	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Protein Kinase B	Protein Kinase B	Protein Kinase B	MLK3	MLK3	MLK3	0	3	10	11
Initially , parallels were drawn to the inactivation of GSK3 in the insulin signalling pathway whereby GSK3alpha and beta is inactivated through inhibitory phosphorylation at residues S21/S9 by Protein Kinase B ( PKB ) [ XREF_BIBR ] .	Initially, parallels were drawn to the inactivation of GSK3 in the insulin signalling pathway whereby GSK3alpha and beta is inactivated through inhibitory phosphorylation at residues S21/S9 by Protein Kinase B (PKB) [XREF_BIBR].	16	31	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Protein Kinase B	Protein Kinase B	Protein Kinase B	GSK3alpha	GSK3alpha	GSK3alpha	28	31	16	17
Overexpression of constitutively active Akt1 , as well as PTEN loss , was found to abrogate G2 cell cycle checkpoint and Chk1 activation upon genotoxic stress [ XREF_BIBR , XREF_BIBR ] .	Overexpression of constitutively active Akt1, as well as PTEN loss, was found to abrogate G2 cell cycle checkpoint and Chk1 activation upon genotoxic stress [XREF_BIBR, XREF_BIBR].	0	22	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Overexpression of constitutively active Akt1	akt1	Chk1	Chk1	chk1	4	5	21	22
Suppression of Akt can directly activate Bad .	Suppression of Akt can directly activate Bad.	0	7	directly activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	2	3	6	7
For instance , both AKT and ERK phosphorylate and inactivate the proapoptotic protein BAD and the translational repressor 4E-BP1 .	For instance, both AKT and ERK phosphorylate and inactivate the proapoptotic protein BAD and the translational repressor 4E-BP1.	3	18	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	4	5	13	14
Whereas AKT is well known to phosphorylate and inhibit the proteins BAD and glycogen synthase kinase 3beta ( GSK3beta ) , it is not always recognized for its role in inducing upregulation of Hif-1alpha [ XREF_BIBR , XREF_BIBR ] .	Whereas AKT is well known to phosphorylate and inhibit the proteins BAD and glycogen synthase kinase 3beta (GSK3beta), it is not always recognized for its role in inducing upregulation of Hif-1alpha [XREF_BIBR, XREF_BIBR].	1	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	1	2	11	12
For example , both AKT and PIM-1 both directly phosphorylate and inactivate BAD , a proapoptotic BCL-2 family member .	For example, both AKT and PIM-1 both directly phosphorylate and inactivate BAD, a proapoptotic BCL-2 family member.	3	18	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	4	5	12	13
Reduced Akt activity allows Bad to translocate to the mitochondria in kaempferol treated cells , thereby leading to the stimulation of mitochondrial membrane depolarization .	Reduced Akt activity allows Bad to translocate to the mitochondria in kaempferol treated cells, thereby leading to the stimulation of mitochondrial membrane depolarization.	1	6	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	1	2	4	5
In CML cells , Bcr-Abl tyrosine kinase activity results in the phosphorylation and activation of Akt , which inactivates Bad , caspase-9 and FOXO3 , and in the phosphorylation and DNA binding activity of STAT5 , which results in increased expression of the anti-apoptotic protein Bcl-xL .	In CML cells, Bcr-Abl tyrosine kinase activity results in the phosphorylation and activation of Akt, which inactivates Bad, caspase-9 and FOXO3, and in the phosphorylation and DNA binding activity of STAT5, which results in increased expression of the anti-apoptotic protein Bcl-xL.	11	23	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	phosphorylation and activation of Akt	akt	Bad	Bad	bad	15	16	19	20
The survival PI3K and Akt pathway was also activated but could not prevent the activation of the apoptotic calcineurin and BAD pathway .	The survival PI3K and Akt pathway was also activated but could not prevent the activation of the apoptotic calcineurin and BAD pathway.	4	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	BAD	BAD	BAD	4	5	20	21
We identify that this effect stems from suppression of AKT , as inducible expression of constitutively active AKT prevented accumulation of BAD and BIM and abolished the synergy .	We identify that this effect stems from suppression of AKT, as inducible expression of constitutively active AKT prevented accumulation of BAD and BIM and abolished the synergy.	13	23	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	expression of constitutively active AKT	akt	BAD	BAD	bad	17	18	21	22
AKT inactivates through phosphorylation proapoptotic factors BAD , procaspase-9 , and FOXO transcription factor , all involved in the expression of proapoptotic genes .	AKT inactivates through phosphorylation proapoptotic factors BAD, procaspase-9, and FOXO transcription factor, all involved in the expression of proapoptotic genes.	0	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	0	1	6	7
Once activated , Akt inhibits the pro apoptotic proteins Bad and caspase-9 .	Once activated, Akt inhibits the pro apoptotic proteins Bad and caspase-9.	3	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	3	4	9	10
AKT ( protein kinase B ) promotes cell growth and survival by inhibiting the pro apoptotic function of the BAD protein and inducing the NF-kappabeta pro survival pathway .	AKT (protein kinase B) promotes cell growth and survival by inhibiting the pro apoptotic function of the BAD protein and inducing the NF-kappabeta pro survival pathway.	0	21	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	BAD protein	BAD protein	BAD protein	0	1	19	21
Furthermore , Akt prevented release of cytochrome c and cleavage of Bad in DDN treated HL-60 cells .	Furthermore, Akt prevented release of cytochrome c and cleavage of Bad in DDN treated HL-60 cells.	2	12	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	2	3	11	12
Taken together , our data suggest that cytokine induced signaling can inhibit cells from apoptosis through activation of PKB ( or possibly SGK ) , which inhibits FKHR-L1 and Bad through phosphorylation and transcriptionally upregulates Mcl-1 .	Taken together, our data suggest that cytokine induced signaling can inhibit cells from apoptosis through activation of PKB (or possibly SGK), which inhibits FKHR-L1 and Bad through phosphorylation and transcriptionally upregulates Mcl-1.	16	34	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	Bad	Bad	Bad	18	19	29	30
Akt may also inhibit apoptosis and autophagy via phosphorylation of mTOR complex 1 ( mTORC1 ) , Bad , and Bax ( not shown ) .	Akt may also inhibit apoptosis and autophagy via phosphorylation of mTOR complex 1 (mTORC1), Bad, and Bax (not shown).	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	0	1	17	18
In addition , Akt completely abolishes the activity of Bad at an early stage ( 3 hrs ) of PA-BSA treatment .	In addition, Akt completely abolishes the activity of Bad at an early stage (3 hrs) of PA-BSA treatment.	3	10	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	3	4	9	10
Akt can inhibit pro apoptotic Bad , activate the pro survival nuclear factor-kappaB ( NF-kappaB ) , and also inhibit the pro apoptotic transcription factor Forkhead [ XREF_BIBR ] .	Akt can inhibit pro apoptotic Bad, activate the pro survival nuclear factor-kappaB (NF-kappaB), and also inhibit the pro apoptotic transcription factor Forkhead [XREF_BIBR].	0	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	0	1	5	6
It is known that phosphorylation of Akt suppresses caspases [ XREF_BIBR ] and inactivates Bad that causes release of Bcl-xL thus promoting cell survival [ XREF_BIBR ] .	It is known that phosphorylation of Akt suppresses caspases [XREF_BIBR] and inactivates Bad that causes release of Bcl-xL thus promoting cell survival [XREF_BIBR].	4	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	phosphorylation of Akt	akt	Bad	Bad	bad	6	7	14	15
One of the Akt substrates turned out to be the pro apoptotic protein BAD , which is inhibited in its apoptotic function upon phosphorylation by Akt .	One of the Akt substrates turned out to be the pro apoptotic protein BAD, which is inhibited in its apoptotic function upon phosphorylation by Akt.	0	26	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	BAD	BAD	BAD	25	26	13	14
To validate the inhibition of AKT and ERK1/2 signaling in these cells , we analyzed their common downstream target BAD , a pro apoptotic protein whose stability is normally inhibited by the AKT and ERK1/2 pathways .	To validate the inhibition of AKT and ERK1/2 signaling in these cells, we analyzed their common downstream target BAD, a pro apoptotic protein whose stability is normally inhibited by the AKT and ERK1/2 pathways.	14	35	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	32	33	19	20
Thus , PKB activity is hypothesized to antagonize BAD mediated repression of Bcl-2 and Bcl-X L.	Thus, PKB activity is hypothesized to antagonize BAD mediated repression of Bcl-2 and Bcl-X L.	2	9	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	BAD	BAD	BAD	2	3	8	9
The authors showed that SC51089 induced Akt activation and attenuated the mitochondrial translocation of the pro apoptotic protein BAD .	The authors showed that SC51089 induced Akt activation and attenuated the mitochondrial translocation of the pro apoptotic protein BAD.	4	19	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	SC51089 induced Akt	akt	BAD	BAD	bad	6	7	18	19
Akt can also inactivate Bad , a member of pro apoptotic Bcl-2 family , through phosphorylation of its serine residues [ XREF_BIBR ] .	Akt can also inactivate Bad, a member of pro apoptotic Bcl-2 family, through phosphorylation of its serine residues [XREF_BIBR].	0	7	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	0	1	4	5
Beclin-1 plays a key role in autophagy , and Akt directly downregulates the anti-apoptotic protein Bad .	Beclin-1 plays a key role in autophagy, and Akt directly downregulates the anti-apoptotic protein Bad.	9	16	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	9	10	15	16
Akt pathway promotes cell survival and proliferation by inhibiting the pro apoptotic activity of Bad ( pBad-S112 ) and hence activation of caspase9 .	Akt pathway promotes cell survival and proliferation by inhibiting the pro apoptotic activity of Bad (pBad-S112) and hence activation of caspase9.	0	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bad	Bad	Bad	0	1	14	15
After phosphorylation , activated Akt inactivates BAD or caspase-9 or other apoptogenic components , thereby inhibiting cell death .	After phosphorylation, activated Akt inactivates BAD or caspase-9 or other apoptogenic components, thereby inhibiting cell death.	3	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	BAD	BAD	BAD	4	5	6	7
Activated Akt , in turn , can modulate the expression of apoptosis inhibitors ( i.e ., Bcl-2 and Bcl-x ) or inducers ( i.e ., Bax and Bad ) , thus influencing cell death .	Activated Akt, in turn, can modulate the expression of apoptosis inhibitors (i.e., Bcl-2 and Bcl-x) or inducers (i.e., Bax and Bad), thus influencing cell death.	1	28	modulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	1	2	27	28
XREF_BIBR , XREF_BIBR Interestingly , nicotine activation of the PI3K-Akt pathway inactivates Bad and phosphorylates Bax ( of the Bcl-2 protein family ) leading to increases in cell survival .	XREF_BIBR, XREF_BIBR Interestingly, nicotine activation of the PI3K-Akt pathway inactivates Bad and phosphorylates Bax (of the Bcl-2 protein family) leading to increases in cell survival.	9	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	Bad	Bad	Bad	9	10	12	13
Thus , inactivation of the PI3K and Akt pathway following CTLA-4 blockade may block the inactivation of BAD and promote , in consequence , the apoptosis of cells .	Thus, inactivation of the PI3K and Akt pathway following CTLA-4 blockade may block the inactivation of BAD and promote, in consequence, the apoptosis of cells.	5	18	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	BAD	BAD	BAD	7	8	17	18
Activation of Akt downregulates Bad , a proapoptotic mediator , and increases the anti-apoptotic protein B-cell lymphoma 2 ( Bcl-2 ) by an NF-kappaB-dependent mechanism [ XREF_BIBR ] .	Activation of Akt downregulates Bad, a proapoptotic mediator, and increases the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) by an NF-kappaB-dependent mechanism [XREF_BIBR].	0	8	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	2	3	4	5
In addition , studies have also revealed that the activation of AKT can suppress the pro apoptotic factor Bad to inhibit apoptosis and counteract the function of p21 to promote cell cycle progression [ XREF_BIBR - XREF_BIBR ] .	In addition, studies have also revealed that the activation of AKT can suppress the pro apoptotic factor Bad to inhibit apoptosis and counteract the function of p21 to promote cell cycle progression [XREF_BIBR - XREF_BIBR].	9	19	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Bad	Bad	Bad	11	12	18	19
Previous studies have demonstrated that AKT inhibits BAD via direct phosphorylation , thereby preventing Bim expression by phosphorylating and inhibiting the Forkhead family of transcription factors ( FoxO ) XREF_BIBR .	Previous studies have demonstrated that AKT inhibits BAD via direct phosphorylation, thereby preventing Bim expression by phosphorylating and inhibiting the Forkhead family of transcription factors (FoxO) XREF_BIBR.	5	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	5	6	7	8
The pro apoptotic BAD gene is also downregulated by Akt ( serine/threonine kinase 1 ) .	The pro apoptotic BAD gene is also downregulated by Akt (serine/threonine kinase 1).	3	12	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	BAD	BAD	BAD	9	10	3	4
AKT also suppresses the pro apoptotic function of BCL2 family member BAD and BAX .	AKT also suppresses the pro apoptotic function of BCL2 family member BAD and BAX.	0	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	0	1	11	12
An important function of PI3-kinase and Akt is to inactivate the proapoptotic peptide Bad and , thus , promote cell survival XREF_BIBR .	An important function of PI3-kinase and Akt is to inactivate the proapoptotic peptide Bad and, thus, promote cell survival XREF_BIBR.	2	14	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	6	7	13	14
Furthermore , AKT inhibits the pro apoptotic protein BAD , further contributing to cell survival [ XREF_BIBR ] .	Furthermore, AKT inhibits the pro apoptotic protein BAD, further contributing to cell survival [XREF_BIBR].	2	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	2	3	8	9
Akt is a potent inhibitor of Bad and Caspase 9 XREF_BIBR and therefore mediates cell survival and inhibition of apoptosis .	Akt is a potent inhibitor of Bad and Caspase 9 XREF_BIBR and therefore mediates cell survival and inhibition of apoptosis.	0	13	is a potent inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	0	1	6	7
IRS-1 also phosphorylates phosphatidylinositol 3 '-kinase ( PI3K ) and the Akt complex , which blocks Bad and Caspase 9 , which are key pro apoptotic proteins [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	IRS-1 also phosphorylates phosphatidylinositol 3 '-kinase (PI3K) and the Akt complex, which blocks Bad and Caspase 9, which are key pro apoptotic proteins [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	26	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	IRS-1 also phosphorylates phosphatidylinositol 3 '-kinase (PI3K) and the Akt	akt	Bad	Bad	bad	11	12	16	17
AKT inhibits the pro apoptotic genes ( BAD and BIM ) thus promoting cell survival XREF_BIBR - XREF_BIBR .	AKT inhibits the pro apoptotic genes (BAD and BIM) thus promoting cell survival XREF_BIBR - XREF_BIBR.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	0	1	7	8
AKT can inhibit the proapoptotic gene Bad via phosphorylation to activate the prosurvival gene Bcl-2 indirectly , and phosphorylate CREB to increase the expression of Bcl-2 .	AKT can inhibit the proapoptotic gene Bad via phosphorylation to activate the prosurvival gene Bcl-2 indirectly, and phosphorylate CREB to increase the expression of Bcl-2.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Bad	Bad	Bad	0	1	6	7
Furthermore , since elevated Akt also inactivates the Bad , Caspase-9 and FOXO proteins to allow tumor cells to evade the apoptosis pathway , cancer cells with cytoplasmic Skp2 localization tend to be more advanced .	Furthermore, since elevated Akt also inactivates the Bad, Caspase-9 and FOXO proteins to allow tumor cells to evade the apoptosis pathway, cancer cells with cytoplasmic Skp2 localization tend to be more advanced.	3	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	4	5	8	9
According to a study in which the same hepatic cell line was treated for 3 h with 0.3 mM H 2 O 2 , the PJ34 inhibitor increases Akt activation , which in turn inhibits the proapototic molecule BAD [ XREF_BIBR ] .	According to a study in which the same hepatic cell line was treated for 3 h with 0.3 mM H 2 O 2, the PJ34 inhibitor increases Akt activation, which in turn inhibits the proapototic molecule BAD [XREF_BIBR].	28	40	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	BAD	BAD	BAD	28	29	38	39
Downstream substrates of Akt include mammalian target of rapamycin ( mTOR ) , which stimulates ribosome production and protein synthesis , and Bad , a pro apoptopic protein that is inhibited by Akt phosphorylation .	Downstream substrates of Akt include mammalian target of rapamycin (mTOR), which stimulates ribosome production and protein synthesis, and Bad, a pro apoptopic protein that is inhibited by Akt phosphorylation.	4	34	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	Bad	Bad	bad	32	33	22	23
Moreover , Akt phosphorylates and thus inactivates the pro apoptotic proteins BAD and Forkhead transcription factors ( FKHR , FKHRL1 ) .	Moreover, Akt phosphorylates and thus inactivates the pro apoptotic proteins BAD and Forkhead transcription factors (FKHR, FKHRL1).	2	15	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	BAD	BAD	BAD	2	3	11	12
For example , adhesion of melanoma cells to fibroblast monolayers through N-cadherin activates AKT , which blocks BAD and significantly reduces the cytotoxic effects of the chemotherapy drug , cisplatin [ XREF_BIBR ] .	For example, adhesion of melanoma cells to fibroblast monolayers through N-cadherin activates AKT, which blocks BAD and significantly reduces the cytotoxic effects of the chemotherapy drug, cisplatin [XREF_BIBR].	12	20	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	13	14	17	18
The activation of PI3K and Akt pathway leads to increase in Bcl-2 , Bcl-xL expression , and decrease in Bad , Bax expression [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The activation of PI3K and Akt pathway leads to increase in Bcl-2, Bcl-xL expression, and decrease in Bad, Bax expression [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	22	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	5	6	19	20
Akt suppresses functionality of the pro apoptotic proteins Bad and Bax , rendering them unable to permeabilize mitochondrial membrane .	Akt suppresses functionality of the pro apoptotic proteins Bad and Bax, rendering them unable to permeabilize mitochondrial membrane.	0	10	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	0	1	8	9
However , unlike other tumor cell contexts , where suppression of mTORC1 has been shown to reduce MCL-1 expression [ XREF_BIBR - XREF_BIBR ] , our analysis of GCB-DLBCL cells reveals an unpredicted mechanism of synergy wherein suppression of AKT induces mitochondrial accumulation of BAD and BIM .	However, unlike other tumor cell contexts, where suppression of mTORC1 has been shown to reduce MCL-1 expression [XREF_BIBR - XREF_BIBR], our analysis of GCB-DLBCL cells reveals an unpredicted mechanism of synergy wherein suppression of AKT induces mitochondrial accumulation of BAD and BIM.	37	46	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	39	40	44	45
Akt mediated inhibition of pro apoptotic genes ( BAD and BIM ) and degradation of the tumor suppressor protein p53 limits programmed cell death and enhances cell survival [ XREF_BIBR ] .	Akt mediated inhibition of pro apoptotic genes (BAD and BIM) and degradation of the tumor suppressor protein p53 limits programmed cell death and enhances cell survival [XREF_BIBR].	0	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	BAD	BAD	BAD	0	1	8	9
Instead , we show that suppression of AKT activation by BEZ235 can induce the mitochondrial accumulation of pro apoptotic BAD and BIM , and that expression of a constitutively active form of AKT prevents sensitization to BCL-2 antagonism .	Instead, we show that suppression of AKT activation by BEZ235 can induce the mitochondrial accumulation of pro apoptotic BAD and BIM, and that expression of a constitutively active form of AKT prevents sensitization to BCL-2 antagonism.	7	21	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	7	8	19	20
If Akt does not inactivate forkheads and BAD in this manner , the forkheads translocate to the nucleus and initiate transcription of pro apoptotic proteins [ XREF_BIBR ] , while BAD translocates to the mitochondria with subsequent heterodimerization with Bcl-xl or Bcl-2 to promote cell death [ XREF_BIBR , XREF_BIBR ] .	If Akt does not inactivate forkheads and BAD in this manner, the forkheads translocate to the nucleus and initiate transcription of pro apoptotic proteins [XREF_BIBR], while BAD translocates to the mitochondria with subsequent heterodimerization with Bcl-xl or Bcl-2 to promote cell death [XREF_BIBR, XREF_BIBR].	1	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	BAD	BAD	BAD	1	2	7	8
In the context of PTEN loss , BRAF inhibition led to an increase in AKT signaling that suppressed the pro apoptotic protein BAD .	In the context of PTEN loss, BRAF inhibition led to an increase in AKT signaling that suppressed the pro apoptotic protein BAD.	14	23	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	14	15	22	23
It is reported that reduced Akt activity increases mitochondrial Bad , thereby leading to the mitochondria dependent apoptosis [ XREF_BIBR ] .	It is reported that reduced Akt activity increases mitochondrial Bad, thereby leading to the mitochondria dependent apoptosis [XREF_BIBR].	5	10	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	5	6	9	10
AKT inactivates BAD via phosphorylation at Ser99 , which prevents it ' s binding to Bax and relieves the antagonism of Bax on Bcl-2 and Bcl-XL .	AKT inactivates BAD via phosphorylation at Ser99, which prevents it 's binding to Bax and relieves the antagonism of Bax on Bcl-2 and Bcl-XL.	0	17	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BAD	BAD	BAD	0	1	2	3
Taken together , these data suggest that Akt inhibits activation of caspase-9 and -3 by posttranslational modification of a cytosolic factor downstream of cytochrome c and before activation of caspase-9 .	Taken together, these data suggest that Akt inhibits activation of caspase-9 and -3 by posttranslational modification of a cytosolic factor downstream of cytochrome c and before activation of caspase-9.	7	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	7	8	11	12
The inhibition of PI3K and Akt pathway triggers caspase-9 and caspase-3 activation , which is an execution phase of apoptosis [ XREF_BIBR ] .	The inhibition of PI3K and Akt pathway triggers caspase-9 and caspase-3 activation, which is an execution phase of apoptosis [XREF_BIBR].	3	11	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	5	6	8	9
Akt might also directly inhibit the activation of caspase-9 .	Akt might also directly inhibit the activation of caspase-9.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	0	1	8	9
The resultant increase in Akt expression and activation , compared with the heat stress group , inhibited caspase-3 and caspase-9 activities and reduced the myocardial cells apoptosis rate ( by 2.14 ~ 2.56 times ) .	The resultant increase in Akt expression and activation, compared with the heat stress group, inhibited caspase-3 and caspase-9 activities and reduced the myocardial cells apoptosis rate (by 2.14 ~ 2.56 times).	4	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt expression	akt	caspase-9	caspase-9	caspase-9	4	5	19	20
Chemerin induces apoptosis , reduces AKT phosphorylation and increases the cleavage of caspase-9 in murine cardiomyocytes .	Chemerin induces apoptosis, reduces AKT phosphorylation and increases the cleavage of caspase-9 in murine cardiomyocytes.	0	13	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	Chemerin induces apoptosis, reduces AKT phosphorylation	akt	caspase-9	caspase-9	caspase-9	5	6	12	13
Akt activation may also prevent activation of caspase-9 to prevent apoptosis in the cerebral vasculature .	Akt activation may also prevent activation of caspase-9 to prevent apoptosis in the cerebral vasculature.	0	8	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	0	1	7	8
Wortmannin or LY294002 , two structurally dissimilar inhibitors of phosphatidylinositol 3 '-kinase ( PI-3 kinase ) , abolished both cisplatin induced Akt phosphorylation and Bad phosphorylation , and promoted cisplatin induced early and accelerated activation of caspase-3 and caspase-9 , but not of caspase-8 and caspase-1 , indicating that inhibition of the Akt and PKB phosphorylation pathway enhances the mitochondrial dependent activation of caspases .	Wortmannin or LY294002, two structurally dissimilar inhibitors of phosphatidylinositol 3 '-kinase (PI-3 kinase), abolished both cisplatin induced Akt phosphorylation and Bad phosphorylation, and promoted cisplatin induced early and accelerated activation of caspase-3 and caspase-9, but not of caspase-8 and caspase-1, indicating that inhibition of the Akt and PKB phosphorylation pathway enhances the mitochondrial dependent activation of caspases.	2	39	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	LY294002, two structurally dissimilar inhibitors of phosphatidylinositol 3 '-kinase (PI-3 kinase), abolished both cisplatin induced Akt phosphorylation	akt	caspase-9	caspase-9	caspase-9	21	22	38	39
We demonstrated that parthenolide inhibits Akt phosphorylation , upregulates Bak and Bax , and activates caspase-3 and caspase-9 .	We demonstrated that parthenolide inhibits Akt phosphorylation, upregulates Bak and Bax, and activates caspase-3 and caspase-9.	3	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	parthenolide inhibits Akt phosphorylation	akt	caspase-9	caspase-9	caspase-9	5	6	17	18
For example , activated PI3K and Akt pathway inactivates caspase-9 and offers resistance against Dexamethasone induced apoptosis XREF_BIBR .	For example, activated PI3K and Akt pathway inactivates caspase-9 and offers resistance against Dexamethasone induced apoptosis XREF_BIBR.	6	10	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	6	7	9	10
Akt suppresses the release of cytochrome c and inactivation of caspase-9 , thereby promoting cell survival [ XREF_BIBR ] .	Akt suppresses the release of cytochrome c and inactivation of caspase-9, thereby promoting cell survival [XREF_BIBR].	0	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	0	1	10	11
Caspase 9 , another pro apoptotic protein , is also inhibited by Akt in human tissues .	Caspase 9, another pro apoptotic protein, is also inhibited by Akt in human tissues.	0	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Caspase 9	Caspase 9	Caspase 9	12	13	0	2
In addition , it was reported that Akt can directly inhibit caspase9 and caspase3 to avoid apoptosis and cleaved caspase3 level was activated and increased by decreased p-Akt level [ XREF_BIBR ] .	In addition, it was reported that Akt can directly inhibit caspase9 and caspase3 to avoid apoptosis and cleaved caspase3 level was activated and increased by decreased p-Akt level [XREF_BIBR].	7	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase9	caspase9	caspase9	7	8	11	12
However , IL-11 stimulation resulted in a dose dependent tyrosine phosphorylation of Akt , a decreased activation of caspase-9 , and a reduced induction of apoptosis in cultured CEC .	However, IL-11 stimulation resulted in a dose dependent tyrosine phosphorylation of Akt, a decreased activation of caspase-9, and a reduced induction of apoptosis in cultured CEC.	2	19	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	Akt	IL-11 stimulation resulted in a dose dependent tyrosine phosphorylation of Akt	akt	caspase-9	caspase-9	caspase-9	12	13	18	19
Associations between HER2 positive tumours and caspase-3 expression have not been reported previously ; however , activation of HER2 can trigger downstream signalling via the phosphatidylinositol kinase 3 ( PI3K and AKT ) pathways , and AKT signalling has been shown to reduce the activity of caspase-9 , the downstream effector of caspase-3 [ XREF_BIBR , XREF_BIBR ] .	Associations between HER2 positive tumours and caspase-3 expression have not been reported previously; however, activation of HER2 can trigger downstream signalling via the phosphatidylinositol kinase 3 (PI3K and AKT) pathways, and AKT signalling has been shown to reduce the activity of caspase-9, the downstream effector of caspase-3 [XREF_BIBR, XREF_BIBR].	36	50	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	caspase-9	caspase-9	caspase-9	36	37	46	47
XREF_BIBR Akt has been shown to inactivate caspase-9 by phosphorylation , XREF_BIBR which in turn inhibits downstream effector caspase-3 .	XREF_BIBR Akt has been shown to inactivate caspase-9 by phosphorylation, XREF_BIBR which in turn inhibits downstream effector caspase-3.	0	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	1	2	7	8
XREF_BIBR Akt ( acting via phosphorylation ) has been shown to inhibit the initiator caspase-9 , which in turn blocks the effector caspase-3 , suppressing apoptosis .	XREF_BIBR Akt (acting via phosphorylation) has been shown to inhibit the initiator caspase-9, which in turn blocks the effector caspase-3, suppressing apoptosis.	0	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	1	2	14	15
PKB has been shown to antagonize the proapoptotic functions of the Bcl-2-related molecule BAD 1920 and caspase 9 21 through direct phosphorylation .	PKB has been shown to antagonize the proapoptotic functions of the Bcl-2-related molecule BAD 1920 and caspase 9 21 through direct phosphorylation.	0	18	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	caspase 9	caspase 9	caspase 9	0	1	16	18
Moreover , we also found that HC inhibited the phosphorylation of Akt and ERK1/2 which usually activated by IPoC in normal heart , induced excessive apoptosis by down-regulating Bcl-2 and up-regulating Bax , cytochrome c , caspase 9 and caspase 3 when compared with that in normal heart .	Moreover, we also found that HC inhibited the phosphorylation of Akt and ERK1/2 which usually activated by IPoC in normal heart, induced excessive apoptosis by down-regulating Bcl-2 and up-regulating Bax, cytochrome c, caspase 9 and caspase 3 when compared with that in normal heart.	6	38	up-regulating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	HC inhibited the phosphorylation of Akt	akt	caspase 9	caspase 9	caspase 9	11	12	36	38
Akt inhibits activation of caspase-9 and caspase-3 by posttranslational modification of a cytosolic factor downstream of cytochrome-c and before activation of caspase-9 [ XREF_BIBR ] .	Akt inhibits activation of caspase-9 and caspase-3 by posttranslational modification of a cytosolic factor downstream of cytochrome-c and before activation of caspase-9 [XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	0	1	4	5
It is therefore , possible that Pls mediated activation of AKT and ERK can inhibit caspase-9 probably by targeting Bad protein .	It is therefore, possible that Pls mediated activation of AKT and ERK can inhibit caspase-9 probably by targeting Bad protein.	6	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Pls mediated activation of AKT	akt	caspase-9	caspase-9	caspase-9	10	11	15	16
The activated Akt could directly suppress proteolytic activity of caspase-9 via phosphorylating the protein 44 .	The activated Akt could directly suppress proteolytic activity of caspase-9 via phosphorylating the protein 44.	0	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	2	3	9	10
Moreover , it has been demonstrated that Akt directly inhibits caspase-9 activity by phosphorylation and , intriguingly , we demonstrated that in our experimental model ZOL induced apoptosis is caspase-9-dependent ( Fujita et al , 1999 ; Zhou et al , 2000 ) .	Moreover, it has been demonstrated that Akt directly inhibits caspase-9 activity by phosphorylation and, intriguingly, we demonstrated that in our experimental model ZOL induced apoptosis is caspase-9-dependent (Fujita et al, 1999; Zhou et al, 2000).	7	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	7	8	10	11
Akt inhibits the catalytic function of caspase-9 by phosphorylation and reduces its proapoptotic activity .	Akt inhibits the catalytic function of caspase-9 by phosphorylation and reduces its proapoptotic activity.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	0	1	6	7
In addition , FKBP5 overexpression inhibited the phosphorylation of Akt at Ser743 , decreased the level of Bcl-2 , increased the level of Bax , and enhanced the cleavage of caspase-9 and caspase-3 ( p < 0.05 compared to control ) .	In addition, FKBP5 overexpression inhibited the phosphorylation of Akt at Ser743, decreased the level of Bcl-2, increased the level of Bax, and enhanced the cleavage of caspase-9 and caspase-3 (p < 0.05 compared to control).	3	32	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	FKBP5 overexpression inhibited the phosphorylation of Akt at Ser743	akt	caspase-9	caspase-9	caspase-9	9	10	30	31
Ang1 induced Akt phosphorylation , increased the Bcl-2 and Bax ratio , and decreased the activation of caspase-9 and -3 .	Ang1 induced Akt phosphorylation, increased the Bcl-2 and Bax ratio, and decreased the activation of caspase-9 and -3.	0	19	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Ang1 induced Akt phosphorylation	akt	caspase-9	caspase-9	caspase-9	2	3	17	18
AKT also inhibits the catalytic activity of caspase-9 by phosphorylation at S196 [ XREF_BIBR ] , as well as the activity of FOXO1 by phosphorylation at T32 and S253 [ XREF_BIBR ] .	AKT also inhibits the catalytic activity of caspase-9 by phosphorylation at S196 [XREF_BIBR], as well as the activity of FOXO1 by phosphorylation at T32 and S253 [XREF_BIBR].	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	caspase-9	caspase-9	caspase-9	0	1	7	8
Thus , it is possible that inhibition of AKT phosphorylation and activation by OSU-03012 may allow cleavage and generation of an active caspase 9 , ultimately leading to apoptosis .	Thus, it is possible that inhibition of AKT phosphorylation and activation by OSU-03012 may allow cleavage and generation of an active caspase 9, ultimately leading to apoptosis.	6	26	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	inhibition of AKT phosphorylation and activation by OSU-03012	akt	caspase 9	caspase 9	caspase 9	8	9	22	24
Deactivation of Akt may increase the activity of caspase-9 , leading to apoptosis through intrinsic caspase pathway .	Deactivation of Akt may increase the activity of caspase-9, leading to apoptosis through intrinsic caspase pathway.	0	9	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	2	3	8	9
Akt was reported to be activated during viral replication in order to prevent premature apoptosis [ XREF_BIBR - XREF_BIBR ] ; the viral Non Structural Protein 1 ( NS1 ) activates the Akt pathway in the late stages of infection which inhibits Caspase-9 and results in anti-apoptotic signaling .	Akt was reported to be activated during viral replication in order to prevent premature apoptosis [XREF_BIBR - XREF_BIBR]; the viral Non Structural Protein 1 (NS1) activates the Akt pathway in the late stages of infection which inhibits Caspase-9 and results in anti-apoptotic signaling.	32	43	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Caspase-9	Caspase-9	Caspase-9	32	33	42	43
In addition , AKT decreases caspase 9 activity by phosphorylation on Ser196 [ XREF_BIBR ] , thus promoting cell survival .	In addition, AKT decreases caspase 9 activity by phosphorylation on Ser196 [XREF_BIBR], thus promoting cell survival.	3	7	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	caspase 9	caspase 9	caspase 9	3	4	5	7
Another important substrate of Akt that initiates the mitochondrial apoptotic pathway is caspase-9 , which is inactivated by Akt through the phosphorylation at Ser196 [ XREF_BIBR ] .	Another important substrate of Akt that initiates the mitochondrial apoptotic pathway is caspase-9, which is inactivated by Akt through the phosphorylation at Ser196 [XREF_BIBR].	2	19	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	18	19	12	13
Caspase-9 may also be inactivated by Akt , which results in inhibition of the apoptotic pathway [ XREF_BIBR ] .	Caspase-9 may also be inactivated by Akt, which results in inhibition of the apoptotic pathway [XREF_BIBR].	0	9	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Caspase-9	Caspase-9	Caspase-9	6	7	0	1
Moreover , Cardone et al ( 1998 ) reported that AKT directly phosphorylated and inactivated caspase-9 .	Moreover, Cardone et al (1998) reported that AKT directly phosphorylated and inactivated caspase-9.	10	16	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	caspase-9	caspase-9	caspase-9	10	11	15	16
Activation of Akt or MEK in cell culture can prevent proteolytic cleavage of pro-caspase-9 thereby inhibiting classical caspase dependent apoptosis .	Activation of Akt or MEK in cell culture can prevent proteolytic cleavage of pro-caspase-9 thereby inhibiting classical caspase dependent apoptosis.	0	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	pro-caspase-9	pro-caspase-9	pro-caspase-9	2	3	13	14
Akt phosphorylation also inhibits the catalytic activity of caspase-9 , an initiator caspase that cleaves and activates downstream effector caspases .	Akt phosphorylation also inhibits the catalytic activity of caspase-9, an initiator caspase that cleaves and activates downstream effector caspases.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	caspase-9	caspase-9	caspase-9	0	1	8	9
Second , active Akt was demonstrated to phosphorylate and impair the processing of human procaspase-9 and also to phosphorylate ( Ser 196 ) and inactivate human caspase-9 in different transfected cell lines .	Second, active Akt was demonstrated to phosphorylate and impair the processing of human procaspase-9 and also to phosphorylate (Ser 196) and inactivate human caspase-9 in different transfected cell lines.	2	27	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	3	4	26	27
XREF_BIBR Akt also inhibits caspase-9 activity through phosphorylation of Ser 196 .	XREF_BIBR Akt also inhibits caspase-9 activity through phosphorylation of Ser 196.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	1	2	4	5
Caspase 9 is an initiator caspase which leads to cleavage ( activation ) of caspase 3/7 XREF_BIBR and blockade of Akt activated caspase 9 XREF_BIBR - XREF_BIBR .	Caspase 9 is an initiator caspase which leads to cleavage (activation) of caspase 3/7 XREF_BIBR and blockade of Akt activated caspase 9 XREF_BIBR - XREF_BIBR.	18	24	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase 9	caspase 9	caspase 9	20	21	22	24
Since Akt has been suggested to inhibit the activation of caspase 9 XREF_BIBR - XREF_BIBR , we investigated the involvement of intrinsic caspase cascade activation in GPE induced apoptosis .	Since Akt has been suggested to inhibit the activation of caspase 9 XREF_BIBR - XREF_BIBR, we investigated the involvement of intrinsic caspase cascade activation in GPE induced apoptosis.	1	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase 9	caspase 9	caspase 9	1	2	10	12
Another signalling pathway which is activated by VEGF binding inherits PKB which negatively regulates caspase-9 , resulting in cell survival .	Another signalling pathway which is activated by VEGF binding inherits PKB which negatively regulates caspase-9, resulting in cell survival.	9	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	caspase-9	caspase-9	caspase-9	10	11	14	15
It was also reported that the activation of PI3K and AKT pathway can suppress the AR activity in low passage LNCaP and enhance AR activity in high passage , hence suggesting modulation as cells evolve towards less responsive status [ XREF_BIBR ] .	It was also reported that the activation of PI3K and AKT pathway can suppress the AR activity in low passage LNCaP and enhance AR activity in high passage, hence suggesting modulation as cells evolve towards less responsive status [XREF_BIBR].	8	24	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	10	11	23	24
For instance , it was reported that the PI3K and Akt pathway can suppress AR activity in androgen dependent LNCaP cells with low passage numbers , but enhances AR activity in LNCaP cells with high passage numbers .	For instance, it was reported that the PI3K and Akt pathway can suppress AR activity in androgen dependent LNCaP cells with low passage numbers, but enhances AR activity in LNCaP cells with high passage numbers.	8	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	10	11	14	15
Akt repressed AR transactivation in a reporter assay in AR negative castration resistant prostate cancer DU145 cells when the AR was exogenously expressed .	Akt repressed AR transactivation in a reporter assay in AR negative castration resistant prostate cancer DU145 cells when the AR was exogenously expressed.	0	3	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	0	1	2	3
AR may be inactivated by an overactive AKT pathway XREF_BIBR , XREF_BIBR .	AR may be inactivated by an overactive AKT pathway XREF_BIBR, XREF_BIBR.	0	9	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	AR	AR	AR	7	8	0	1
Further , it is also hypothesized that Akt activation may inhibit HER-2-mediated AR activation [ XREF_BIBR ] .	Further, it is also hypothesized that Akt activation may inhibit HER-2-mediated AR activation [XREF_BIBR].	7	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	7	8	12	13
Because of the reciprocal activation mechanism between PI3K and AKT and AR signaling pathways [ XREF_BIBR ] , we originally hypothesized that PI3K and AKT inhibition would increase AR function in PTEN deficient cells , thereby stabilizing REST expression to prevent neuroendocrine differentiation .	Because of the reciprocal activation mechanism between PI3K and AKT and AR signaling pathways [XREF_BIBR], we originally hypothesized that PI3K and AKT inhibition would increase AR function in PTEN deficient cells, thereby stabilizing REST expression to prevent neuroendocrine differentiation.	22	29	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	AR	AR	AR	24	25	28	29
While proposing somewhat different mechanisms , the significant contribution of these studies is evidence that AKT activation combined with PTEN loss is sufficient for prostate tumor growth in the absence of robust AR signaling , and may actively repress the AR program .	While proposing somewhat different mechanisms, the significant contribution of these studies is evidence that AKT activation combined with PTEN loss is sufficient for prostate tumor growth in the absence of robust AR signaling, and may actively repress the AR program.	15	41	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	AR	AR	AR	15	16	40	41
We also observed that APPL could further enhance the Akt mediated suppression of AR transactivation and AR target gene using the reporter gene and Northern blot assay .	We also observed that APPL could further enhance the Akt mediated suppression of AR transactivation and AR target gene using the reporter gene and Northern blot assay.	8	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	9	10	13	14
The PI3K inhibitor LY294002 completely blocked the basal and EGF stimulated Akt phosphorylation in LNCaP cells but did not prevent the marked decrease in AR protein in response to EGF ( XREF_FIG , left and middle ) .	The PI3K inhibitor LY294002 completely blocked the basal and EGF stimulated Akt phosphorylation in LNCaP cells but did not prevent the marked decrease in AR protein in response to EGF (XREF_FIG, left and middle).	1	25	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	PI3K inhibitor LY294002 completely blocked the basal and EGF stimulated Akt phosphorylation	akt	AR	AR	ar	11	12	24	25
While some research suggests Akt inhibition and activation of AR is not critical for progression of prostate cancer XREF_BIBR , XREF_BIBR , clinical studies indicate that high phosphorylation of Ser790 is associated to a longer time to death from recurrence in castration resistant prostate cancer 26 .	While some research suggests Akt inhibition and activation of AR is not critical for progression of prostate cancer XREF_BIBR, XREF_BIBR, clinical studies indicate that high phosphorylation of Ser790 is associated to a longer time to death from recurrence in castration resistant prostate cancer 26.	4	10	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	4	5	9	10
Unfortunately , negative feedback loops exist between the AR and PI3K and AKT pathways such that targeting AR leads to activation of PI3K and AKT signaling , while PI3K and AKT pathway inhibition leads to increased AR transcriptional activity .	Unfortunately, negative feedback loops exist between the AR and PI3K and AKT pathways such that targeting AR leads to activation of PI3K and AKT signaling, while PI3K and AKT pathway inhibition leads to increased AR transcriptional activity.	30	38	leads	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	AR	AR	AR	30	31	36	37
Specifically , PI3K and Akt pathway can suppress AR activity in androgen dependent LNCaP cells with low passage numbers .	Specifically, PI3K and Akt pathway can suppress AR activity in androgen dependent LNCaP cells with low passage numbers.	2	9	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	4	5	8	9
Because we have found that IGF-1 and Akt signaling reduces polyglutamine AR aggregation in cultured cells ( XREF_FIG ) , we asked whether mIGF-1 decreases the accumulation of AR positive aggregates in vivo .	Because we have found that IGF-1 and Akt signaling reduces polyglutamine AR aggregation in cultured cells (XREF_FIG), we asked whether mIGF-1 decreases the accumulation of AR positive aggregates in vivo.	5	12	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	7	8	11	12
To determine whether AR may be downregulated acutely by activated AKT , we next examined AR expression in prostates after 2-7 days of doxycycline mediated myrAKT induction .	To determine whether AR may be downregulated acutely by activated AKT, we next examined AR expression in prostates after 2-7 days of doxycycline mediated myrAKT induction.	3	11	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	AR	AR	AR	10	11	3	4
Furthermore , the PI3K and Akt signaling pathway has been shown to inhibit AR signaling , and by reciprocal negative feedback , AR inhibition activates Akt signaling by inducing the Akt phosphatase PHLPP .	Furthermore, the PI3K and Akt signaling pathway has been shown to inhibit AR signaling, and by reciprocal negative feedback, AR inhibition activates Akt signaling by inducing the Akt phosphatase PHLPP.	5	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	5	6	13	14
Palazzolo et al found that substituting alanines for both of the sites also prevented AKT mediated inhibition of AR transcriptional activity .	Palazzolo et al found that substituting alanines for both of the sites also prevented AKT mediated inhibition of AR transcriptional activity.	14	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	AR	AR	AR	14	15	18	19
Moreover , AR degradation by Akt has been reported to require the E3 ligase activity of MDM2 [ XREF_BIBR ] .	Moreover, AR degradation by Akt has been reported to require the E3 ligase activity of MDM2 [XREF_BIBR].	2	6	degradation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	5	6	2	3
Additionally , depleting Usp12 sensitises PC cells to Akt inhibition irrespectively of their AR status .	Additionally, depleting Usp12 sensitises PC cells to Akt inhibition irrespectively of their AR status.	8	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	8	9	13	14
We have previously shown that phosphorylation by Akt induces AR degradation through the proteasome .	We have previously shown that phosphorylation by Akt induces AR degradation through the proteasome.	5	10	induces	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	7	8	9	10
Whereas the AR transactivation can be suppressed by the PI3K and AKT pathway .	Whereas the AR transactivation can be suppressed by the PI3K and AKT pathway.	2	12	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	AR	AR	AR	11	12	2	3
Overexpression of active AKT triggers AR degradation .	Overexpression of active AKT triggers AR degradation.	0	6	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Overexpression of active AKT	akt	AR	AR	ar	3	4	5	6
We found that depleting Usp12 protein resulted in the sensitisation of prostate cancer cells to Akt inhibition irrespectively of their androgen sensitivity and AR status .	We found that depleting Usp12 protein resulted in the sensitisation of prostate cancer cells to Akt inhibition irrespectively of their androgen sensitivity and AR status.	15	24	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	15	16	23	24
We report that depleting Usp12 significantly sensitised PC cells to Akt inhibition irrespectively of their castration sensitivity or AR status .	We report that depleting Usp12 significantly sensitised PC cells to Akt inhibition irrespectively of their castration sensitivity or AR status.	10	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	10	11	18	19
Although we have previously proven that the PI3K and Akt pathway can suppress androgen receptor ( AR ) transactivation , the potential linkage from APPL to the AR remains unclear .	Although we have previously proven that the PI3K and Akt pathway can suppress androgen receptor (AR) transactivation, the potential linkage from APPL to the AR remains unclear.	7	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	androgen receptor	androgen receptor	androgen receptor	9	10	13	15
Implication of Akt and Mdm2 phosphorylations in gal and VNPT55 induced AR degradation .	Implication of Akt and Mdm2 phosphorylations in gal and VNPT55 induced AR degradation.	2	12	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt and Mdm2 phosphorylations	akt	AR	AR	ar	2	3	11	12
In Pten negative tumors , active Akt would degrade AR resulting in AR loss .	In Pten negative tumors, active Akt would degrade AR resulting in AR loss.	5	10	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	6	7	9	10
Our qPCR analysis revealed that AKT overexepression could downregulate AR at mRNA levels regardless of culture conditions ( XREF_FIG ) .	Our qPCR analysis revealed that AKT overexepression could downregulate AR at mRNA levels regardless of culture conditions (XREF_FIG).	5	10	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	AR	AR	AR	5	6	9	10
Castrate resistant prostate cancer most often progress with an activated AR despite potent AR pathway suppression , supported by a vast network of pro survival genes and growth factor pathways , including the PI3K and AKT pathway .	Castrate resistant prostate cancer most often progress with an activated AR despite potent AR pathway suppression, supported by a vast network of pro survival genes and growth factor pathways, including the PI3K and AKT pathway.	13	36	suppression	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	AKT	AKT	AKT	AR	AR	AR	35	36	13	14
In prostate cancer cells , Appl1 potentiated Akt activity has also been shown to suppress androgen receptor transactivation .	In prostate cancer cells, Appl1 potentiated Akt activity has also been shown to suppress androgen receptor transactivation.	7	17	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	androgen receptor	androgen receptor	androgen receptor	7	8	15	17
In some cases , Akt has been shown to suppress AR activity , while in other reports , it is also shown to potentiate AR action .	In some cases, Akt has been shown to suppress AR activity, while in other reports, it is also shown to potentiate AR action.	4	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	4	5	10	11
71 The results in both reports are consistent with earlier studies XREF_BIBR , XREF_BIBR and clearly demonstrate that the PI3K and Akt pathway can inhibit AR transcriptional activity and lead to castrate-resistance .	71 The results in both reports are consistent with earlier studies XREF_BIBR, XREF_BIBR and clearly demonstrate that the PI3K and Akt pathway can inhibit AR transcriptional activity and lead to castrate-resistance.	19	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	21	22	25	26
For instance , the PI3K and Akt signaling pathway has been shown to inhibit AR signaling , and by reciprocal negative feedback , AR inhibition activates Akt signaling .	For instance, the PI3K and Akt signaling pathway has been shown to inhibit AR signaling, and by reciprocal negative feedback, AR inhibition activates Akt signaling.	6	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	6	7	14	15
In addition , overexpression of constitutively active Akt ( cAkt ) in LNCaP cells at low passage numbers ( less than 38 ) suppressed AR activity as assessed by MMTV-luciferase and AR protein expression when compared to high passage numbers ( greater than 60 ) , at which point MMTV-luciferase and AR expression was enhanced in response to overexpression of cAkt .	In addition, overexpression of constitutively active Akt (cAkt) in LNCaP cells at low passage numbers (less than 38) suppressed AR activity as assessed by MMTV-luciferase and AR protein expression when compared to high passage numbers (greater than 60), at which point MMTV-luciferase and AR expression was enhanced in response to overexpression of cAkt.	3	25	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	overexpression of constitutively active Akt	akt	AR	AR	ar	7	8	24	25
Indeed , the authors suggest that the inhibition of PI3K and AKT signaling activates AR transactivation potential .	Indeed, the authors suggest that the inhibition of PI3K and AKT signaling activates AR transactivation potential.	9	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	AR	AR	AR	11	12	14	15
Inhibition of the PI3K and Akt pathway by NVP-BEZ235 activates androgen receptor signaling by relieving feedback inhibition of Her2 kinases [ XREF_BIBR , XREF_BIBR ] , thus maintaining tumor cell growth in PTEN deficient murine prostate cancer models .	Inhibition of the PI3K and Akt pathway by NVP-BEZ235 activates androgen receptor signaling by relieving feedback inhibition of Her2 kinases [XREF_BIBR, XREF_BIBR], thus maintaining tumor cell growth in PTEN deficient murine prostate cancer models.	3	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	androgen receptor	androgen receptor	androgen receptor	5	6	10	12
Overexpression of Akt in low-passage LNCaP inhibited AR transcriptional activity , as measured by a MMTV-luciferase assay and PSA immunoblot , but activated AR transcriptional activity in high-passage LNCaP [ XREF_BIBR ] .	Overexpression of Akt in low-passage LNCaP inhibited AR transcriptional activity, as measured by a MMTV-luciferase assay and PSA immunoblot, but activated AR transcriptional activity in high-passage LNCaP [XREF_BIBR].	0	25	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Overexpression of Akt	akt	AR	AR	ar	2	3	23	24
We demonstrated that expression of constitutively active Akt decreased Galphas protein content and inhibited basal and beta 1 AR stimulated cAMP production , and Akt knockdown inhibited Galphaq induced reduction of Galphas protein .	We demonstrated that expression of constitutively active Akt decreased Galphas protein content and inhibited basal and beta 1 AR stimulated cAMP production, and Akt knockdown inhibited Galphaq induced reduction of Galphas protein.	3	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	expression of constitutively active Akt	akt	AR	AR	ar	7	8	18	19
In view of the above , two not mutually exclusive scenarios can be considered to tentatively explain the molecular mechanisms underlying UCM 1037 antiproliferative and cytotoxic effects in androgen sensitive prostate cancer cell lines : UCM 1037 may directly down-regulate AR and p-Akt levels , or AR down-regulation may be triggered by inhibition of Akt activation .	In view of the above, two not mutually exclusive scenarios can be considered to tentatively explain the molecular mechanisms underlying UCM 1037 antiproliferative and cytotoxic effects in androgen sensitive prostate cancer cell lines : UCM 1037 may directly down-regulate AR and p-Akt levels, or AR down-regulation may be triggered by inhibition of Akt activation.	46	55	triggered	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	54	55	46	47
Additionally , AKT inactivates PRAS40 , which alleviates the PRAS40 mediated inhibition of mTORC1 .	Additionally, AKT inactivates PRAS40, which alleviates the PRAS40 mediated inhibition of mTORC1.	2	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	PRAS40	PRAS40	PRAS40	2	3	4	5
By contrast , AKT inhibition greatly enhanced P-AKT , as predicted by this agent ' s mechanism of action , reduced P-PRAS40 , and had little or no effect on P-p70 S6K or P-4E-BP1 .	By contrast, AKT inhibition greatly enhanced P-AKT, as predicted by this agent 's mechanism of action, reduced P-PRAS40, and had little or no effect on P-p70 S6K or P-4E-BP1.	7	24	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P-AKT	P-AKT	P-AKT	P-PRAS40	P-PRAS40	P-PRAS40	7	8	21	22
In addition to its effect on TSC2 , Akt also inactivates PRAS40 preventing it from blocking mTORC1 activity [ XREF_BIBR ] .	In addition to its effect on TSC2, Akt also inactivates PRAS40 preventing it from blocking mTORC1 activity [XREF_BIBR].	8	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	8	9	11	12
Akt can also inhibit PRAS40 , which then activates mTORC1 and induces autophagy [ XREF_BIBR ] .	Akt can also inhibit PRAS40, which then activates mTORC1 and induces autophagy [XREF_BIBR].	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	0	1	4	5
AKT is known to inactivate PRAS40 via phosphorylation , thereby disrupting PRAS40-mTORC1 binding and removing PRAS40 inhibition of mTORC1 [ XREF_BIBR , XREF_BIBR ] .	AKT is known to inactivate PRAS40 via phosphorylation, thereby disrupting PRAS40-mTORC1 binding and removing PRAS40 inhibition of mTORC1 [XREF_BIBR, XREF_BIBR].	0	7	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	PRAS40	PRAS40	PRAS40	0	1	5	6
AKT can also activate mTOR , a second key regulator of cell growth , by inhibiting TSC2 or blocking PRAS40 35 .	AKT can also activate mTOR, a second key regulator of cell growth, by inhibiting TSC2 or blocking PRAS40 35.	0	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	PRAS40	PRAS40	PRAS40	0	1	19	20
An interesting study recently showed that mTORC1 is activated during pressure overload through Akt dependent inactivation of PRAS40 .	An interesting study recently showed that mTORC1 is activated during pressure overload through Akt dependent inactivation of PRAS40.	13	18	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	13	14	17	18
Independent of TSC2 , AKT also stimulates mTOR activity directly by inhibiting PRAS40 .	Independent of TSC2, AKT also stimulates mTOR activity directly by inhibiting PRAS40.	2	13	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	PRAS40	PRAS40	PRAS40	4	5	12	13
Akt activates mTORC1 by releasing the inhibitory effects of PRAS40 and TSC2 .	Akt activates mTORC1 by releasing the inhibitory effects of PRAS40 and TSC2.	0	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	0	1	9	10
In return , activated AKT inhibited the activities of TSC2 and PRAS40 through phosphorylating them at Thr1462 and Thr246 respectively , thus initiating the activation of mTORC1 .	In return, activated AKT inhibited the activities of TSC2 and PRAS40 through phosphorylating them at Thr1462 and Thr246 respectively, thus initiating the activation of mTORC1.	3	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	PRAS40	PRAS40	PRAS40	4	5	11	12
The latter subsequently phosphorylate AKT at Th308 , thereby enabling it to directly activate mTORC1 by promoting the dissociation of inhibitory PRAS40 protein from raptor or indirectly via the degradation of the tuberous sclerosis ( TSC ) 1/2 complex .	The latter subsequently phosphorylate AKT at Th308, thereby enabling it to directly activate mTORC1 by promoting the dissociation of inhibitory PRAS40 protein from raptor or indirectly via the degradation of the tuberous sclerosis (TSC) 1/2 complex.	3	22	directly activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	phosphorylate AKT	akt	PRAS40	PRAS40	pras40	4	5	21	22
Another recently reported intermediary for Akt activation of mTORC1 is PRAS40 which normally inhibits mTORC1 but is inhibited by Akt through phosphorylation to promote mTORC1 activity .	Another recently reported intermediary for Akt activation of mTORC1 is PRAS40 which normally inhibits mTORC1 but is inhibited by Akt through phosphorylation to promote mTORC1 activity.	6	23	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	19	20	10	11
Furthermore , we demonstrate that DJ-1-stimulated Akt kinase phosphorylates and hence inactivates PRAS40 .	Furthermore, we demonstrate that DJ-1-stimulated Akt kinase phosphorylates and hence inactivates PRAS40.	6	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	6	7	12	13
In addition , Akt can suppress PRAS40 by phosphorylation to eliminate its inhibition on mTORC1 .	In addition, Akt can suppress PRAS40 by phosphorylation to eliminate its inhibition on mTORC1.	3	7	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	3	4	6	7
In summary , Akt stimulates mTORC1 signalling by inhibiting the function of tuberin and PRAS40 .	In summary, Akt stimulates mTORC1 signalling by inhibiting the function of tuberin and PRAS40.	3	15	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	3	4	14	15
mTOR can be regulated by its upstream effector AKT , which can suppress PRAS40 so as to eliminate the inhibition it exerts on mTORC1 [ XREF_BIBR ] .	mTOR can be regulated by its upstream effector AKT, which can suppress PRAS40 so as to eliminate the inhibition it exerts on mTORC1 [XREF_BIBR].	3	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	PRAS40	PRAS40	PRAS40	8	9	13	14
Second , Akt inhibits Pras40 , another negative regulator of mTORC1 [ XREF_BIBR ] .	Second, Akt inhibits Pras40, another negative regulator of mTORC1 [XREF_BIBR].	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Pras40	Pras40	Pras40	2	3	4	5
These effects were due to increased levels of pS473 -Akt ( P < 0.0001 ) and pS473 -Akt and total Akt ( both P < 0.0001 ) in ethanol exposed livers , increased pT246 -PRAS40 and Total PRAS40 in ethanol exposed livers ( P < 0.05 ) , and decreased pT246 -PRAS40 and pT246 -PRAS40 and Total PRAS40 in control livers ( both P < 0.0001 ) .	These effects were due to increased levels of pS473 -Akt (P < 0.0001) and pS473 -Akt and total Akt (both P < 0.0001) in ethanol exposed livers, increased pT246 -PRAS40 and Total PRAS40 in ethanol exposed livers (P < 0.05), and decreased pT246 -PRAS40 and pT246 -PRAS40 and Total PRAS40 in control livers (both P < 0.0001).	17	38	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	20	21	37	38
To test whether direct AKT inhibition induces BIM upregulation , we transfected the human T-ALL cell line CCRF-CEM with control or anti-AKT siRNA .	To test whether direct AKT inhibition induces BIM upregulation, we transfected the human T-ALL cell line CCRF-CEM with control or anti-AKT siRNA.	4	8	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BIM	BIM	BIM	4	5	7	8
XREF_BIBR , XREF_BIBR Both AKT and MAPK survival pathways are known to negatively regulate BIM stability .	XREF_BIBR, XREF_BIBR Both AKT and MAPK survival pathways are known to negatively regulate BIM stability.	0	15	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BIM	BIM	BIM	4	5	14	15
Inhibition of PI3K and Akt signaling by LY294002 resulted in reduced FoxO3A phosphorylation and its accumulation in the nucleus , and increased p27 KIP1 and Bim mRNA in vitro .	Inhibition of PI3K and Akt signaling by LY294002 resulted in reduced FoxO3A phosphorylation and its accumulation in the nucleus, and increased p27 KIP1 and Bim mRNA in vitro.	2	26	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bim	Bim	Bim	4	5	25	26
In this context , the activation of the AKT pathway has been reported to negatively regulate BIM activity and expression .	In this context, the activation of the AKT pathway has been reported to negatively regulate BIM activity and expression.	8	17	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BIM	BIM	BIM	8	9	16	17
Pro apoptotic protein Bim , which is negatively regulated by AKT through FOXO proteins was up-regulated in the tumors of the BITC treated mice .	Pro apoptotic protein Bim, which is negatively regulated by AKT through FOXO proteins was up-regulated in the tumors of the BITC treated mice.	2	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Bim	Bim	Bim	10	11	3	4
58 Interestingly , tonic AKT and PI3K signalling has been reported to suppress induction of PUMA and BIM , by both transcriptional and post-translational mechanisms , and consequently suppress apoptosis in leukaemia cells following growth factor withdrawal .	58 Interestingly, tonic AKT and PI3K signalling has been reported to suppress induction of PUMA and BIM, by both transcriptional and post-translational mechanisms, and consequently suppress apoptosis in leukaemia cells following growth factor withdrawal.	3	28	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BIM	BIM	BIM	4	5	17	18
Protection may arise through the inhibition of the pro apoptotic protein Bim , which is normally repressed by a PKB dependent mechanism .	Protection may arise through the inhibition of the pro apoptotic protein Bim, which is normally repressed by a PKB dependent mechanism.	2	21	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	Bim	Bim	Bim	19	20	11	12
In addition , N-Br and N-I compounds induced Akt inactivation and expression of pro apoptotic BH3 protein BIM .	In addition, N-Br and N-I compounds induced Akt inactivation and expression of pro apoptotic BH3 protein BIM.	8	18	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	BIM	BIM	BIM	8	9	17	18
Treatment of KOSR cultured cells with the PH-domain inhibitor MK2206 blocked AKT phosphorylation , abrogated the formation of BIM resistant mitochondria and stimulated cell death .	Treatment of KOSR cultured cells with the PH-domain inhibitor MK2206 blocked AKT phosphorylation, abrogated the formation of BIM resistant mitochondria and stimulated cell death.	2	20	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	KOSR cultured cells with the PH-domain inhibitor MK2206 blocked AKT phosphorylation	akt	BIM	BIM	bim	11	12	18	19
To test whether MYC and AKT repress BIM in primary treatment resistant T-ALL , we took advantage of the panel of primary T-ALL samples that we have collected from children with relapsed or refractory T-ALL ( samples collected at diagnosis from patients in whom initial induction chemotherapy failed to achieve a remission , or samples collected at the time of relapse ) that have been engrafted and expanded in immunodeficient mice , without exposure to in vitro selection .	To test whether MYC and AKT repress BIM in primary treatment resistant T-ALL, we took advantage of the panel of primary T-ALL samples that we have collected from children with relapsed or refractory T-ALL (samples collected at diagnosis from patients in whom initial induction chemotherapy failed to achieve a remission, or samples collected at the time of relapse) that have been engrafted and expanded in immunodeficient mice, without exposure to in vitro selection.	3	12	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BIM	BIM	BIM	5	6	7	8
Inhibition of Akt increased the FKHR and Bim response and DNA fragmentation within the normally resistant cortex .	Inhibition of Akt increased the FKHR and Bim response and DNA fragmentation within the normally resistant cortex.	0	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bim	Bim	Bim	2	3	7	8
Furthermore , through direct inhibition and exclusion of proapoptotic transcription factor FOXO3a ( Forkhead box O3 ) , AKT also suppresses the expressions of the pro apoptotic factors Bim and Noxa .	Furthermore, through direct inhibition and exclusion of proapoptotic transcription factor FOXO3a (Forkhead box O3), AKT also suppresses the expressions of the pro apoptotic factors Bim and Noxa.	18	30	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Bim	Bim	Bim	18	19	28	29
XREF_BIBR - XREF_BIBR Thus , cooperative repression of BIM by PI3K-AKT and MYC provides a molecular mechanism for the association between activation of both of these oncogenic pathways and treatment resistance in human T-ALL .	XREF_BIBR - XREF_BIBR Thus, cooperative repression of BIM by PI3K-AKT and MYC provides a molecular mechanism for the association between activation of both of these oncogenic pathways and treatment resistance in human T-ALL.	6	13	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	BIM	BIM	BIM	10	11	8	9
AKT has also been shown to suppress Bim , another BH3-only pro apoptotic protein [ XREF_BIBR ] .	AKT has also been shown to suppress Bim, another BH3-only pro apoptotic protein [XREF_BIBR].	0	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Bim	Bim	Bim	0	1	7	8
Similar to our results with Puma , it has been reported that AKT upregulation by IGF-1 can suppress the transcriptional induction of Bim in potassium deprived CGNs XREF_BIBR .	Similar to our results with Puma, it has been reported that AKT upregulation by IGF-1 can suppress the transcriptional induction of Bim in potassium deprived CGNs XREF_BIBR.	12	23	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Bim	Bim	Bim	12	13	22	23
BIM is downregulated by AKT and MYC in high-risk T-ALL .	BIM is downregulated by AKT and MYC in high-risk T-ALL.	0	6	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BIM	BIM	BIM	4	5	0	1
Furthermore , the inhibition of these activities must be coordinated over relatively long periods of time , with duration of AKT inhibition having enough overlap with that of ERK to cause both the accumulation and activation of BIM .	Furthermore, the inhibition of these activities must be coordinated over relatively long periods of time, with duration of AKT inhibition having enough overlap with that of ERK to cause both the accumulation and activation of BIM.	20	38	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BIM	BIM	BIM	20	21	37	38
Downregulation of MCL-1 by BEZ235 further contributed to the modulation of dexamethasone resistance by increasing the amount of BIM available to induce apoptosis , especially in PTEN-null T-ALL where inhibition of AKT only partially overcame AKT induced BIM suppression .	Downregulation of MCL-1 by BEZ235 further contributed to the modulation of dexamethasone resistance by increasing the amount of BIM available to induce apoptosis, especially in PTEN-null T-ALL where inhibition of AKT only partially overcame AKT induced BIM suppression.	35	38	induced	Positive_early_activation	Negative_activation	Negative_activation	AKT	AKT	AKT	BIM	BIM	BIM	35	36	37	38
We propose that Ser ( 87 ) of Bim ( EL ) is an important regulatory site that is targeted by Akt to attenuate the pro apoptotic function of Bim ( EL ) , thereby promoting cell survival .	We propose that Ser (87) of Bim (EL) is an important regulatory site that is targeted by Akt to attenuate the pro apoptotic function of Bim (EL), thereby promoting cell survival.	19	31	targeted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bim	Bim	Bim	21	22	29	30
Expression of AKT inhibited Bim upregulation induced by GF removal in NIH 3T3 fibroblasts , which may involve forkhead transcription factors XREF_BIBR .	Expression of AKT inhibited Bim upregulation induced by GF removal in NIH 3T3 fibroblasts, which may involve forkhead transcription factors XREF_BIBR.	0	5	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Expression of AKT	akt	Bim	Bim	bim	2	3	4	5
Inhibition of AKT or PI3-K also allowed cAMP dependent activation of B-Raf and ERK at normal Ca 2+ levels .	Inhibition of AKT or PI3-K also allowed cAMP dependent activation of B-Raf and ERK at normal Ca 2+ levels.	0	13	allowed	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	B-Raf	B-Raf	B-Raf	2	3	11	12
We added a reaction to the original model in which Akt downregulated B-Raf with Akt ' s normal K m and a k cat of one-hundredth of the strength by which Akt influences Raf-1 .	We added a reaction to the original model in which Akt downregulated B-Raf with Akt 's normal K m and a k cat of one-hundredth of the strength by which Akt influences Raf-1.	10	23	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	B-Raf	B-Raf	B-Raf	10	11	12	13
In PKD cells , disruption of intracellular Ca 2+ homeostasis due to mutations in the PKD genes relieves Akt inhibition of B-Raf , allowing cAMP stimulation of B-Raf , ERK and cell proliferation .	In PKD cells, disruption of intracellular Ca 2+ homeostasis due to mutations in the PKD genes relieves Akt inhibition of B-Raf, allowing cAMP stimulation of B-Raf, ERK and cell proliferation.	18	22	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	B-Raf	B-Raf	B-Raf	18	19	21	22
Along the same line , early reports showing that both AKT and SGK1 could phosphorylate and negatively regulate BRAF and MEKK3 have never been conclusively validated .	Along the same line, early reports showing that both AKT and SGK1 could phosphorylate and negatively regulate BRAF and MEKK3 have never been conclusively validated.	9	20	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	BRAF	BRAF	BRAF	10	11	18	19
Akt is known to also downregulate B-Raf , a reaction that is not described in this model .	Akt is known to also downregulate B-Raf, a reaction that is not described in this model.	0	9	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	B-Raf	B-Raf	B-Raf	0	1	6	7
Our results demonstrate that B-Raf activity can be negatively regulated by Akt through phosphorylation in the amino-terminal regulatory domain of B-Raf .	Our results demonstrate that B-Raf activity can be negatively regulated by Akt through phosphorylation in the amino-terminal regulatory domain of B-Raf.	4	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	B-Raf	B-Raf	B-Raf	11	12	4	5
This switch is associated with upregulation of B-RAF and ERK , due in part to removal of inhibition of B-RAF by AKT , a kinase dependent on sufficient Ca 2+ levels [ XREF_BIBR , XREF_BIBR ] .	This switch is associated with upregulation of B-RAF and ERK, due in part to removal of inhibition of B-RAF by AKT, a kinase dependent on sufficient Ca 2+ levels [XREF_BIBR, XREF_BIBR].	11	22	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	B-RAF	B-RAF	B-RAF	21	22	19	20
Taken together , these studies support the hypothesis that a reduction in intracellular Ca 2+ , secondary to mutations in the PKD genes ( PKD1 , PKD1 or PKHD1 ) , decreases Akt activity , relieving Akt inhibition of B-Raf , and allowing cAMP activation of the B-Raf/MEK/ERK signaling and cell proliferation ( XREF_FIG ) .	Taken together, these studies support the hypothesis that a reduction in intracellular Ca 2+, secondary to mutations in the PKD genes (PKD1, PKD1 or PKHD1), decreases Akt activity, relieving Akt inhibition of B-Raf, and allowing cAMP activation of the B-Raf/MEK/ERK signaling and cell proliferation (XREF_FIG).	36	40	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	B-Raf	B-Raf	B-Raf	36	37	39	40
In normal cells , B-Raf is suppressed by AKT in a calcium dependent manner , but in ADPKD and calcium restricted cells , AKT activity is decreased , allowing for activation of B-Raf by cAMP [ XREF_BIBR ] .	In normal cells, B-Raf is suppressed by AKT in a calcium dependent manner, but in ADPKD and calcium restricted cells, AKT activity is decreased, allowing for activation of B-Raf by cAMP [XREF_BIBR].	4	9	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	B-Raf	B-Raf	B-Raf	8	9	4	5
Inhibition of Akt or phosphatidylinositol 3-kinase also allowed cAMP dependent activation of B-Raf and ERK in normal calcium .	Inhibition of Akt or phosphatidylinositol 3-kinase also allowed cAMP dependent activation of B-Raf and ERK in normal calcium.	2	14	allowed	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	B-Raf	B-Raf	B-Raf	2	3	12	13
Reduced AKT signalling after Sorafenib treatment in KRAS and BRAF wildtype cells also extends to downstream target levels , as shown with reduced FOXO3a activity after Sorafenib treatment .	Reduced AKT signalling after Sorafenib treatment in KRAS and BRAF wildtype cells also extends to downstream target levels, as shown with reduced FOXO3a activity after Sorafenib treatment.	1	11	signalling	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	BRAF	BRAF	BRAF	1	2	9	10
Furthermore , WT-AKT2 prevented WT-FOXO1 from binding to the MMP-9 promoter , whereasWT-AKT2 failed to prevent CA-FOXO1 from binding to the MMP-9 promoter , indicating that the inhibition of FOXO1 by AKT2 is FOXO1 phosphorylation dependent .	Furthermore, WT-AKT2 prevented WT-FOXO1 from binding to the MMP-9 promoter, whereasWT-AKT2 failed to prevent CA-FOXO1 from binding to the MMP-9 promoter, indicating that the inhibition of FOXO1 by AKT2 is FOXO1 phosphorylation dependent.	27	32	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT2	AKT2	AKT2	FOXO1	FOXO1	FOXO1	31	32	29	30
Silencing AKT2 expression with AKT2 siRNA or inhibiting AKT activation with Wortmannin promoted the nuclear translocation of FOXO1 ( XREF_FIG ) .	Silencing AKT2 expression with AKT2 siRNA or inhibiting AKT activation with Wortmannin promoted the nuclear translocation of FOXO1 (XREF_FIG).	1	19	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT2	AKT2 expression	akt2	FOXO1	FOXO1	foxo1	1	2	17	18
The inability of WT-AKT2 to prevent CA-FOXO1 from binding to the TIMP-1 promoter indicates that the inhibition of FOXO1 by AKT2 is FOXO1 phosphorylation dependent .	The inability of WT-AKT2 to prevent CA-FOXO1 from binding to the TIMP-1 promoter indicates that the inhibition of FOXO1 by AKT2 is FOXO1 phosphorylation dependent.	16	21	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT2	AKT2	AKT2	FOXO1	FOXO1	FOXO1	20	21	18	19
ChIP analysis showed that WT-AKT2 reduced the binding of FOXO1 to the MMP-9 promoter , whereas AKT2 shRNA increased the binding of FOXO1 to the MMP-9 promoter ( XREF_FIG ) .	ChIP analysis showed that WT-AKT2 reduced the binding of FOXO1 to the MMP-9 promoter, whereas AKT2 shRNA increased the binding of FOXO1 to the MMP-9 promoter (XREF_FIG).	4	10	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WT-AKT2	WT-AKT2	WT-AKT2	FOXO1	FOXO1	FOXO1	4	5	9	10
Interestingly , concomitant deletion of Akt2 and FoxO1 led to livers that accumulated TG levels comparable to those in AFP > Cre ; Akt2 ( loxP and loxP ) rather than AFP > Cre ; FoxO1 ( loxP and loxP ) mice ( XREF_FIG ) .	Interestingly, concomitant deletion of Akt2 and FoxO1 led to livers that accumulated TG levels comparable to those in AFP> Cre; Akt2 (loxP and loxP) rather than AFP> Cre; FoxO1 (loxP and loxP) mice (XREF_FIG).	3	41	led	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt2	Akt2	Akt2	FoxO1	FoxO1	FoxO1	5	6	35	36
WT-AKT2 also reduced the binding of FOXO1 to the TIMP-1 promoter , whereas AKT2 shRNA increased the binding of FOXO1 to the TIMP-1 promoter ( XREF_FIG ) .	WT-AKT2 also reduced the binding of FOXO1 to the TIMP-1 promoter, whereas AKT2 shRNA increased the binding of FOXO1 to the TIMP-1 promoter (XREF_FIG).	0	7	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WT-AKT2	WT-AKT2	WT-AKT2	FOXO1	FOXO1	FOXO1	0	1	6	7
It also includes aakg-4 , which encodes an atypical AMP kinase gamma subunit that participates in a positive feedback loop to promote DAF-16 and FoxO activity , akt-2 , which acts together with akt-1 to inhibit DAF-16 and FoxO , and ins-7 , which encodes an insulin like peptide that is repressed by DAF-16 and FoxO as part of a feedback loop that coordinates organism-wide DAF-16 and FoxO activation .	It also includes aakg-4, which encodes an atypical AMP kinase gamma subunit that participates in a positive feedback loop to promote DAF-16 and FoxO activity, akt-2, which acts together with akt-1 to inhibit DAF-16 and FoxO, and ins-7, which encodes an insulin like peptide that is repressed by DAF-16 and FoxO as part of a feedback loop that coordinates organism-wide DAF-16 and FoxO activation.	25	39	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	akt-2	akt-2	akt-2	FoxO	FoxO	FoxO	27	28	38	39
These findings revealed that knockdown of Akt2 antagonized TGF-beta1-induced EMT by inhibiting GSK3beta and Snail signaling pathway .	These findings revealed that knockdown of Akt2 antagonized TGF-beta1-induced EMT by inhibiting GSK3beta and Snail signaling pathway.	4	16	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt2	Akt2	Akt2	GSK3beta	GSK3beta	GSK3beta	6	7	12	13
Moreover , Akt2 is able to inactivate GSK3beta , limiting the activation of NFkappaB .	Moreover, Akt2 is able to inactivate GSK3beta, limiting the activation of NFkappaB.	2	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt2	Akt2	Akt2	GSK3beta	GSK3beta	GSK3beta	2	3	7	8
AKT2 downregulated GSK3b , which modulates cell migration [ XREF_BIBR ] .	AKT2 downregulated GSK3b, which modulates cell migration [XREF_BIBR].	0	5	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT2	AKT2	AKT2	GSK3b	GSK3b	GSK3b	0	1	2	3
The Glycogen synthase kinase 3-beta ( GSK-3beta ) may inhibit the translation of beta-catenin in Wnt and beta-catenin pathway by phosphorylation and degradation of beta-catenin XREF_BIBR , and the GSK-3beta is negatively regulated by AKT2 XREF_BIBR .	The Glycogen synthase kinase 3-beta (GSK-3beta) may inhibit the translation of beta-catenin in Wnt and beta-catenin pathway by phosphorylation and degradation of beta-catenin XREF_BIBR, and the GSK-3beta is negatively regulated by AKT2 XREF_BIBR.	28	35	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT2	AKT2	AKT2	GSK-3beta	GSK-3beta	GSK-3beta	34	35	29	30
Akt-2 inhibition of FoxO4 is required for adiponectin induced differentiation .	Akt-2 inhibition of FoxO4 is required for adiponectin induced differentiation.	0	4	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt-2	Akt-2	Akt-2	FoxO4	FoxO4	FoxO4	0	1	3	4
We report the novel findings that 1 ) HMW or trimeric adiponectin induces VSMC differentiation via mTORC1 inhibition ; 2 ) Adiponectin transduces this signal via AMPKalpha2 , and Akt2 suppression of FoxO4 ; 3 ) While adiponectin and rapamycin similarly promoteVSMC differentiation , only adiponectin promotes protective signaling in EC .	We report the novel findings that 1) HMW or trimeric adiponectin induces VSMC differentiation via mTORC1 inhibition; 2) Adiponectin transduces this signal via AMPKalpha2, and Akt2 suppression of FoxO4; 3) While adiponectin and rapamycin similarly promoteVSMC differentiation, only adiponectin promotes protective signaling in EC.	29	33	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt2	Akt2	Akt2	FoxO4	FoxO4	FoxO4	29	30	32	33
Akt1 has been found to inhibit cell migration via phosphorylation of the actin binding factor paladin , as well as via the regulation of the nuclear factors of activated T-cells , ERK and TSC2 [ XREF_BIBR ] .	Akt1 has been found to inhibit cell migration via phosphorylation of the actin binding factor paladin, as well as via the regulation of the nuclear factors of activated T-cells, ERK and TSC2 [XREF_BIBR].	0	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	TSC2	TSC2	TSC2	0	1	33	34
Akt1 dependent phosphorylation negatively regulates the functioning of TSC1 and TSC2 , 2 other factors involved in insulin signaling .	Akt1 dependent phosphorylation negatively regulates the functioning of TSC1 and TSC2, 2 other factors involved in insulin signaling.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1 dependent phosphorylation	akt1	TSC2	TSC2	tsc2	0	1	10	11
Insulin and growth factors result in protein kinase B ( PKB or Akt ) phosphorylation , which inhibits tuberin ( tuberous sclerosis 2 or TSC2 ) .	Insulin and growth factors result in protein kinase B (PKB or Akt) phosphorylation, which inhibits tuberin (tuberous sclerosis 2 or TSC2).	6	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	protein kinase B	protein kinase B (PKB or Akt) phosphorylation	protein kinase b	tuberin	tuberin	tuberin	6	9	18	19
AKT3 inhibits B-RAF activity , which , counterintuitively , promotes cell proliferation .	AKT3 inhibits B-RAF activity, which, counterintuitively, promotes cell proliferation.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT3	AKT3	AKT3	B-RAF	B-RAF	B-RAF	0	1	2	3
Inhibition of B-RAF by AKT3 regulates B-RAF to levels high enough to promote proliferation , survival , and metastasis but low enough to prevent activation of cellular defense mechanisms and cell senescence .	Inhibition of B-RAF by AKT3 regulates B-RAF to levels high enough to promote proliferation, survival, and metastasis but low enough to prevent activation of cellular defense mechanisms and cell senescence.	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT3	AKT3	AKT3	B-RAF	B-RAF	B-RAF	4	5	2	3
Being consistent with our observations , downregulation of AKT3 expression by RNA interference reduces the expression of the phosphorylated form of Bad , resulting in induction of the caspase dependent apoptosis of glioma cells [ XREF_BIBR ] .	Being consistent with our observations, downregulation of AKT3 expression by RNA interference reduces the expression of the phosphorylated form of Bad, resulting in induction of the caspase dependent apoptosis of glioma cells [XREF_BIBR].	8	22	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT3	AKT3 expression	akt3	Bad	Bad	bad	8	9	21	22
In U87MG , T98G , and TGB cells , the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad , resulting in the induction of caspase dependent apoptosis .	In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad, resulting in the induction of caspase dependent apoptosis.	10	27	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt3	Akt3	Akt3	Bad	Bad	Bad	14	15	26	27
Overexpression of either Halo-Akt2 or -Akt3 suppressed FOXO mediated transcriptional activation using luciferase reporter assays ( XREF_SUPPLEMENTARY ) , further substantiating that HaloTagged-Akt2 and -Akt3 are functional and that elevated Akt activity can be detected in this assay .	Overexpression of either Halo-Akt2 or -Akt3 suppressed FOXO mediated transcriptional activation using luciferase reporter assays (XREF_SUPPLEMENTARY), further substantiating that HaloTagged-Akt2 and -Akt3 are functional and that elevated Akt activity can be detected in this assay.	0	8	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	-Akt3	Overexpression of either Halo-Akt2 or -Akt3	-akt3	FOXO	FOXO	foxo	5	6	7	8
The glutamatergic pathway interferes with the dopaminergic signals : the upregulation of AMPA 1 and 2 ( Gria1 , Gria2 ) receptors are linked with the upregulation of the Akt and Gsk3 pathway : kinesin family members Kif5c , Kif5b , and Kif5 indirectly , whereas Akt3 , from the dopaminergic side , directly inhibits Gsk3a and Gsk3b .	The glutamatergic pathway interferes with the dopaminergic signals : the upregulation of AMPA 1 and 2 (Gria1, Gria2) receptors are linked with the upregulation of the Akt and Gsk3 pathway : kinesin family members Kif5c, Kif5b, and Kif5 indirectly, whereas Akt3, from the dopaminergic side, directly inhibits Gsk3a and Gsk3b.	46	58	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt3	Akt3	Akt3	Gsk3b	Gsk3b	Gsk3b	46	47	57	58
Surprisingly , whereas the mRNA levels of two targets of p53 , p21 and Bax , are not affected by Akt1 depletion , knockdown of Akt2 significantly enhances p21 and Bax message .	Surprisingly, whereas the mRNA levels of two targets of p53, p21 and Bax, are not affected by Akt1 depletion, knockdown of Akt2 significantly enhances p21 and Bax message.	23	31	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt2	Akt2	Akt2	p21	p21	p21	25	26	28	29
Mechanistically , we show that Akt2 silencing up-regulates p21 and the pro apoptotic protein Bax and downregulates the insulin like growth factor receptor-1 .	Mechanistically, we show that Akt2 silencing up-regulates p21 and the pro apoptotic protein Bax and downregulates the insulin like growth factor receptor-1.	5	14	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt2	Akt2	Akt2	p21	p21	p21	5	6	8	9
One possible explanation for it was that the MST1 kinase activity might be inactivated in LNCaP xenografts , possibly due to the expression of the constitutively active AKT1 , which is known to inactivate MST1 via phosphorylation 59 .	One possible explanation for it was that the MST1 kinase activity might be inactivated in LNCaP xenografts, possibly due to the expression of the constitutively active AKT1, which is known to inactivate MST1 via phosphorylation 59.	22	36	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT1	expression of the constitutively active AKT1	akt1	MST1	MST1	mst1	27	28	34	35
Accordingly , activated AKT2 blocked signaling down-stream of ASK1 , including activation of JNK and p38 and the conversion of Bax to its active conformation .	Accordingly, activated AKT2 blocked signaling down-stream of ASK1, including activation of JNK and p38 and the conversion of Bax to its active conformation.	2	9	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT2	AKT2	AKT2	ASK1	ASK1	ASK1	3	4	8	9
As GSK-3beta is inhibited by AKT phosphorylation it follows that therapies/diets/conditions that activate PI3K ( upstream of AKT ) may be as effective as inhibitors of GSK-3beta .	As GSK-3beta is inhibited by AKT phosphorylation it follows that therapies/diets/conditions that activate PI3K (upstream of AKT) may be as effective as inhibitors of GSK-3beta.	1	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	5	6	1	2
Akt inactivates GSK-3beta by phosphorylation at serine 9 , preventing GSK-3beta induced mitochondrial permeability transition and cell death XREF_BIBR .	Akt inactivates GSK-3beta by phosphorylation at serine 9, preventing GSK-3beta induced mitochondrial permeability transition and cell death XREF_BIBR.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	2	3
It has been reported DNA-PKcs regulates c-Myc stability via phosphorylation of Akt on Ser473 , which in turn inactivates GSK-3beta by the phosphorylation of GSK-3b on Ser9 , resulting in stabilization of c-Myc [ XREF_BIBR ] .	It has been reported DNA-PKcs regulates c-Myc stability via phosphorylation of Akt on Ser473, which in turn inactivates GSK-3beta by the phosphorylation of GSK-3b on Ser9, resulting in stabilization of c-Myc [XREF_BIBR].	9	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	phosphorylation of Akt on Ser473	akt	GSK-3beta	GSK-3beta	gsk-3beta	11	12	19	20
However , active AKT phosphorylates and inhibits GSK-3beta , releasing its repression .	However, active AKT phosphorylates and inhibits GSK-3beta, releasing its repression.	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	3	4	7	8
Proximal signaling causes mechanical activation of mTORC2 , which phosphorylates Akt on serine 473 , leading to an Akt dependent inhibition of GSK3beta ( see XREF_FIG ) .	Proximal signaling causes mechanical activation of mTORC2, which phosphorylates Akt on serine 473, leading to an Akt dependent inhibition of GSK3beta (see XREF_FIG).	18	23	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	18	19	22	23
Both Akt and PI3K dependent mTOR activation modulate IL-12p40 and IL-10 production by suppressing GSK-3beta activity .	Both Akt and PI3K dependent mTOR activation modulate IL-12p40 and IL-10 production by suppressing GSK-3beta activity.	0	15	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	1	2	14	15
Activation of EphB2 receptor dephosphorylates tau through phosphatidylinositol-3 -- kinase ( PI3K ) and Akt mediated GSK-3beta inhibition .	Activation of EphB2 receptor dephosphorylates tau through phosphatidylinositol-3 -- kinase (PI3K) and Akt mediated GSK-3beta inhibition.	9	17	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	14	15	16	17
Both Protein kinase C activation and GSK3beta inhibition can be triggered by an increase in PI3K-Akt signalling , and rapamycin is able to produce this effect by means of a negative feedback loop in TORC1 regulation [ XREF_BIBR , XREF_BIBR ] ( XREF_SUPPLEMENTARY ) .	Both Protein kinase C activation and GSK3beta inhibition can be triggered by an increase in PI3K-Akt signalling, and rapamycin is able to produce this effect by means of a negative feedback loop in TORC1 regulation [XREF_BIBR, XREF_BIBR] (XREF_SUPPLEMENTARY).	6	16	triggered	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	GSK3beta	GSK3beta	GSK3beta	15	16	6	7
Once phosphorylated , activated Akt inactivate GSK-3beta through phosphorylation at Ser9 , resulting in stabilization and activation of beta-catenin that enhanced P-gp expression [ XREF_BIBR ] .	Once phosphorylated, activated Akt inactivate GSK-3beta through phosphorylation at Ser9, resulting in stabilization and activation of beta-catenin that enhanced P-gp expression [XREF_BIBR].	3	7	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	4	5	6	7
The proapoptotic role of GSK-3beta is shown to be negatively regulated by Akt [ XREF_BIBR ] and inactivation of GSK-3beta by Akt phosphorylation [ XREF_BIBR ] .	The proapoptotic role of GSK-3beta is shown to be negatively regulated by Akt [XREF_BIBR] and inactivation of GSK-3beta by Akt phosphorylation [XREF_BIBR].	14	24	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	21	22	19	20
GSK3beta activation is attenuated by phosphorylation following insulin stimulated Akt phosphorylation XREF_BIBR .	GSK3beta activation is attenuated by phosphorylation following insulin stimulated Akt phosphorylation XREF_BIBR.	0	11	attenuated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	insulin stimulated Akt phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	9	10	0	1
GSK3beta inhibition by Akt signaling stabilizes Pdx1 to prevent proteosomal degradation [ XREF_BIBR ] .	GSK3beta inhibition by Akt signaling stabilizes Pdx1 to prevent proteosomal degradation [XREF_BIBR].	0	4	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	0	1
In the present work , we found that activation of upstream AKT signaling represses GSK-3beta activity .	In the present work, we found that activation of upstream AKT signaling represses GSK-3beta activity.	11	15	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	11	12	14	15
The negative effect of GSK3beta on Nrf2 mediated transcription was also corroborated by that Akt inhibition reduced ARE mediated transcription , as Akt inactivates GSK3beta .	The negative effect of GSK3beta on Nrf2 mediated transcription was also corroborated by that Akt inhibition reduced ARE mediated transcription, as Akt inactivates GSK3beta.	22	25	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	22	23	24	25
Meanwhile , PI3K inhibitor and AKT agonist could suppress or elevate p-AKT , p-GSK3beta and Cyclin D1 activities respectively .	Meanwhile, PI3K inhibitor and AKT agonist could suppress or elevate p-AKT, p-GSK3beta and Cyclin D1 activities respectively.	5	17	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p-GSK3beta	p-GSK3beta	p-GSK3beta	5	6	13	14
Several studies have demonstrated that AKT inhibits GSK3beta by S9 phosphorylation .	Several studies have demonstrated that AKT inhibits GSK3beta by S9 phosphorylation.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	5	6	7	8
In response to insulin , therefore , activated Akt inhibits the activity of GSK-3alpha or GSK-3beta isoforms by phosphorylating their NH 2 -terminal serine residues ( Ser21 in GSK-3alpha and Ser9 in GSK-3beta ) , releasing their inhibitory effects on glycogen synthase .	In response to insulin, therefore, activated Akt inhibits the activity of GSK-3alpha or GSK-3beta isoforms by phosphorylating their NH 2 -terminal serine residues (Ser21 in GSK-3alpha and Ser9 in GSK-3beta), releasing their inhibitory effects on glycogen synthase.	7	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	8	9	32	33
Pharmacological inhibitors of PI3K , Akt , and GSK3beta induce inactivation of GSK3beta .	Pharmacological inhibitors of PI3K, Akt, and GSK3beta induce inactivation of GSK3beta.	1	13	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	12	13
AKT inhibits GSK-3beta , which suppresses Snail , a well established EMT inducer .	AKT inhibits GSK-3beta, which suppresses Snail, a well established EMT inducer.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	0	1	2	3
Therefore , given that Akt phoshorylates and inactivates GSK3beta [ XREF_BIBR ] , we hypothesised that Akt dependent inactivation of GSK3beta might be responsible for Notch potentiation .	Therefore, given that Akt phoshorylates and inactivates GSK3beta [XREF_BIBR], we hypothesised that Akt dependent inactivation of GSK3beta might be responsible for Notch potentiation.	16	21	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	16	17	20	21
Under this signal transduction pathway , GSK-3beta , which was required for Slug instability , was repressed via phosphorylation at Ser 9 by Akt 56 .	Under this signal transduction pathway, GSK-3beta, which was required for Slug instability, was repressed via phosphorylation at Ser 9 by Akt 56.	6	24	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	23	24	6	7
Akt activation ( its phosphorylation at Ser473 in particular ) is known to inhibit GSK3beta by phosphorylating Ser9 residue .	Akt activation (its phosphorylation at Ser473 in particular) is known to inhibit GSK3beta by phosphorylating Ser9 residue.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	14	15
AKT inhibits GSK-3beta , which promotes cellular metabolism , proliferation and cell survival .	AKT inhibits GSK-3beta, which promotes cellular metabolism, proliferation and cell survival.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	0	1	2	3
Aurora A inhibition enhances Akt mediated GSK3beta inactivation .	Aurora A inhibition enhances Akt mediated GSK3beta inactivation.	3	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	6	7
The role of the PI 3 K/AKT pathway in EMT is well established ; after activation of the pathway , AKT inhibits GSK3beta by phosphorylating serine 9 .	The role of the PI 3 K/AKT pathway in EMT is well established; after activation of the pathway, AKT inhibits GSK3beta by phosphorylating serine 9.	20	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	20	21	22	23
In this pathway , activated AKT phosphorylates and inhibits GSK-3beta , resulting in rescues of Snail , which is inhibited by GSK-3beta .	In this pathway, activated AKT phosphorylates and inhibits GSK-3beta, resulting in rescues of Snail, which is inhibited by GSK-3beta.	4	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	5	6	9	10
Deactivation of Gsk3beta by Akt phosphorylation is one of those modulations .	Deactivation of Gsk3beta by Akt phosphorylation is one of those modulations.	0	6	Deactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	Gsk3beta	Gsk3beta	gsk3beta	4	5	2	3
AKT inhibits GSK3beta by phosphorylation at serine 9 ( S9 ) , and we therefore speculated that IGF-1R and AKT inhibition by OSI-906 might increase p53 apoptotic function by increasing K120 acetylation of p53 .	AKT inhibits GSK3beta by phosphorylation at serine 9 (S9), and we therefore speculated that IGF-1R and AKT inhibition by OSI-906 might increase p53 apoptotic function by increasing K120 acetylation of p53.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	0	1	2	3
In C. rodentium infections of CEC , Akt inhibits GSK3beta by phosphorylation at Ser9 [ XREF_BIBR ] with no phenotypic consequence reported so far .	In C. rodentium infections of CEC, Akt inhibits GSK3beta by phosphorylation at Ser9 [XREF_BIBR] with no phenotypic consequence reported so far.	7	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	7	8	9	10
The western blot results showed that TAC treatment markedly increased the phosphorylation of IRS , PI3K , and Akt , and inhibited the overactivation of GSK3beta in the brain of type 2 diabetic rats .	The western blot results showed that TAC treatment markedly increased the phosphorylation of IRS, PI3K, and Akt, and inhibited the overactivation of GSK3beta in the brain of type 2 diabetic rats.	6	26	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	TAC treatment markedly increased the phosphorylation of IRS, PI3K, and Akt	akt	GSK3beta	GSK3beta	gsk3beta	18	19	25	26
The phosphorylation of GSK3beta is controlled by Akt , which inhibits GSK3beta by phosphorylation .	The phosphorylation of GSK3beta is controlled by Akt, which inhibits GSK3beta by phosphorylation.	5	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	7	8	11	12
As a consequence of the activation of PI3K signaling , GSK-3beta activity is attenuated by activated AKT .	As a consequence of the activation of PI3K signaling, GSK-3beta activity is attenuated by activated AKT.	10	17	attenuated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	16	17	10	11
72 Because GSK3beta is inactivated by AKT and ERK through phosphorylation , XREF_BIBR , XREF_BIBR both AKT and ERK can inhibit GSK3beta mediated Mcl-1 degradation .	72 Because GSK3beta is inactivated by AKT and ERK through phosphorylation, XREF_BIBR, XREF_BIBR both AKT and ERK can inhibit GSK3beta mediated Mcl-1 degradation.	2	8	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	6	7	2	3
However , linagliptin could reduce GSK3beta activity by increasing Akt mediated GSK3beta Ser 9 phosphorylation during Abeta treatment .	However, linagliptin could reduce GSK3beta activity by increasing Akt mediated GSK3beta Ser 9 phosphorylation during Abeta treatment.	4	12	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	9	10	11	12
They also found reduced levels of Akt and PKB , increased GSK3beta activity in AD neurons , and the colocalization of GSK3beta and tau , suggesting a possible interaction between Akt and GSK3beta and tau in vivo in AD .	They also found reduced levels of Akt and PKB, increased GSK3beta activity in AD neurons, and the colocalization of GSK3beta and tau, suggesting a possible interaction between Akt and GSK3beta and tau in vivo in AD.	4	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	levels of Akt and PKB	pkb	GSK3beta	GSK3beta	gsk3beta	8	9	21	22
PDK1 phosphorylates and activates AKT , that inhibits GSK3beta , blocking beta-catenin degradation and promoting cell proliferation .	PDK1 phosphorylates and activates AKT, that inhibits GSK3beta, blocking beta-catenin degradation and promoting cell proliferation.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	PDK1 phosphorylates and activates AKT	akt	GSK3beta	GSK3beta	gsk3beta	4	5	8	9
As expected , suppression of AKT after 16 h of arsenic exposure was also accompanied by down-regulation of protein expression levels of beta-catenin ( XREF_FIG ) that could be protected from degradation via AKT mediated inactivation of GSK3beta [ XREF_BIBR ] .	As expected, suppression of AKT after 16 h of arsenic exposure was also accompanied by down-regulation of protein expression levels of beta-catenin (XREF_FIG) that could be protected from degradation via AKT mediated inactivation of GSK3beta [XREF_BIBR].	3	39	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	5	6	37	38
Akt , a serine threonine kinase , has been well characterized as an antiapoptotic kinase and directly inactivates endogenous GSK-3beta via Ser9 phosphorylation [ XREF_BIBR ] .	Akt, a serine threonine kinase, has been well characterized as an antiapoptotic kinase and directly inactivates endogenous GSK-3beta via Ser9 phosphorylation [XREF_BIBR].	0	24	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	19	20
Based on this , the activation of PI3K-Akt by R-LA was postulated to mediate the inhibition of GSK-3beta , which will be followed by suppression of NF-kappabeta p65 translocation .	Based on this, the activation of PI3K-Akt by R-LA was postulated to mediate the inhibition of GSK-3beta, which will be followed by suppression of NF-kappabeta p65 translocation.	5	22	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	GSK-3beta	GSK-3beta	GSK-3beta	7	8	17	18
Given that we found distinct higher expressions of c-kit and AKT , we presumed that c-kit-activated AKT could inhibit Math1 degradation by inactivating GSK3beta and subsequently promote MUC2 secretion as well as CRMAC tumorigenesis [ XREF_BIBR , XREF_BIBR ] .	Given that we found distinct higher expressions of c-kit and AKT, we presumed that c-kit-activated AKT could inhibit Math1 degradation by inactivating GSK3beta and subsequently promote MUC2 secretion as well as CRMAC tumorigenesis [XREF_BIBR, XREF_BIBR].	15	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	16	17	23	24
Akt and PKB inactivates GSK-3beta by phosphorylating serine 9 in GSK-3beta [ XREF_BIBR ] .	Akt and PKB inactivates GSK-3beta by phosphorylating serine 9 in GSK-3beta [XREF_BIBR].	0	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	GSK-3beta	GSK-3beta	GSK-3beta	2	3	4	5
In the PI3K and AKT signaling pathway , AKT phosphorylates Ser 9 of GSK3beta and inhibits GSK3beta activity for cell proliferation [ XREF_BIBR ] .	In the PI3K and AKT signaling pathway, AKT phosphorylates Ser 9 of GSK3beta and inhibits GSK3beta activity for cell proliferation [XREF_BIBR].	4	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT signaling pathway, AKT phosphorylates	akt	GSK3beta	GSK3beta	gsk3beta	4	5	16	17
The recently reported feedback inhibition of PHLPP degradation by Akt mediated GSK-3beta inactivation adds complexity to the evolving paradigm .	The recently reported feedback inhibition of PHLPP degradation by Akt mediated GSK-3beta inactivation adds complexity to the evolving paradigm.	4	12	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	9	10	11	12
It is also known that GSK3beta can be deactivated by AKT , a serine threonine kinase that is mutated and overexpressed in many cancers [ XREF_BIBR , XREF_BIBR ] .	It is also known that GSK3beta can be deactivated by AKT, a serine threonine kinase that is mutated and overexpressed in many cancers [XREF_BIBR, XREF_BIBR].	5	15	deactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	10	11	5	6
As described above , DRD2 stimulation by DA inhibits AKT , which suppresses GSK-3beta activity and thus makes GSK-3beta more active [ XREF_BIBR , XREF_BIBR ] .	As described above, DRD2 stimulation by DA inhibits AKT, which suppresses GSK-3beta activity and thus makes GSK-3beta more active [XREF_BIBR, XREF_BIBR].	8	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	9	10	13	14
PI3-kinase and AKT cause an upregulation of p21 by suppressing GSK-3beta activity and activating mTOR in both cultured human urothelial carcinoma cells and mouse urothelial cells in vivo .	PI3-kinase and AKT cause an upregulation of p21 by suppressing GSK-3beta activity and activating mTOR in both cultured human urothelial carcinoma cells and mouse urothelial cells in vivo.	0	11	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	2	3	10	11
As GYS is an enzyme that catalyzes the final step of glycogen synthesis [ XREF_BIBR ] , the inactivation of GSK3beta by AKT promotes glucose storage as glycogen .	As GYS is an enzyme that catalyzes the final step of glycogen synthesis [XREF_BIBR], the inactivation of GSK3beta by AKT promotes glucose storage as glycogen.	18	23	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	22	23	20	21
One mechanism by which insulin and IGF maintain neuronal survival is to stimulate the PI3K and AKT pathway , which results in GSK3beta phosphorylation at Ser9 and subsequently represses GSK3beta activity .	One mechanism by which insulin and IGF maintain neuronal survival is to stimulate the PI3K and AKT pathway, which results in GSK3beta phosphorylation at Ser9 and subsequently represses GSK3beta activity.	14	30	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	16	17	29	30
The beta-catenin level is regulated by GSK3beta , which is inhibited by PI3K and Akt .	The beta-catenin level is regulated by GSK3beta, which is inhibited by PI3K and Akt.	4	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	14	15	6	7
In the present study we show for the first time that the concordant inhibition of the PI3K and Akt signaling pathway by the clinically used BCR-ABL TKI imatinib or nilotinib , Akt inhibitor MK2206 or the immunosuppressive cytokine IL-10 activates the downstream serine/threonine protein kinase GSK3beta , and subsequently the transcription factor MITF that is translocated into the cell nucleus .	In the present study we show for the first time that the concordant inhibition of the PI3K and Akt signaling pathway by the clinically used BCR-ABL TKI imatinib or nilotinib, Akt inhibitor MK2206 or the immunosuppressive cytokine IL-10 activates the downstream serine/threonine protein kinase GSK3beta, and subsequently the transcription factor MITF that is translocated into the cell nucleus.	18	55	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	18	19	45	46
Akt phosphorylates and deactivates GSK3beta , releasing Nrf2 from inhibition .	Akt phosphorylates and deactivates GSK3beta, releasing Nrf2 from inhibition.	0	5	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	4	5
Interestingly and in agreement with our studies , Akt also inactivates GSK-3beta by phosphorylation , a fact that has been used in favor of the association of HKII to the OMM , and therefore to the inhibition of mPTP opening .	Interestingly and in agreement with our studies, Akt also inactivates GSK-3beta by phosphorylation, a fact that has been used in favor of the association of HKII to the OMM, and therefore to the inhibition of mPTP opening.	8	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	8	9	11	12
The active form of Akt is known to inactivate GSK3beta via phosphorylation .	The active form of Akt is known to inactivate GSK3beta via phosphorylation.	2	11	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	9	10
GSK-3beta induces apoptosis and is inhibited by Akt phosphorylation [ XREF_BIBR ] .	GSK-3beta induces apoptosis and is inhibited by Akt phosphorylation [XREF_BIBR].	0	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	7	8	0	1
Akt down-regulates the activities of GSK-3beta by phosphorylating serine residue 9 ( Ser9 ) XREF_BIBR .	Akt down-regulates the activities of GSK-3beta by phosphorylating serine residue 9 (Ser9) XREF_BIBR.	0	6	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	5	6
Akt is a downstream target of PI3K , and can inactivate GSK-3beta by phosphorylation on serine 9 .	Akt is a downstream target of PI3K, and can inactivate GSK-3beta by phosphorylation on serine 9.	0	12	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	11	12
Increased Akt phosphorylation inactivates GSK-3beta and prevents mitochondrial permeability transition pore ( mPTP ) opening [ XREF_BIBR ] .	Increased Akt phosphorylation inactivates GSK-3beta and prevents mitochondrial permeability transition pore (mPTP) opening [XREF_BIBR].	1	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	1	2	4	5
Similarly , activation of PI3K by insulin removes the AKT dependent inhibition of GSK-3beta consistent with the role of PI3K and AKT signaling in alcohol induced fatty liver disease .	Similarly, activation of PI3K by insulin removes the AKT dependent inhibition of GSK-3beta consistent with the role of PI3K and AKT signaling in alcohol induced fatty liver disease.	9	24	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	9	10	13	14
Neuronal polarization is controlled by 473 Ser AKT phosphorylation , which in turn inhibits GSK3beta thus activating microtubule polymerization and allowing axonal specification [ XREF_BIBR , XREF_BIBR ] .	Neuronal polarization is controlled by 473 Ser AKT phosphorylation, which in turn inhibits GSK3beta thus activating microtubule polymerization and allowing axonal specification [XREF_BIBR, XREF_BIBR].	6	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Ser AKT phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	7	8	14	15
Glycogen synthase kinase-3 beta ( GSK-3 beta ) , which is inhibited upon phosphorylation by Akt , was recently shown to function during cell death induced by PI 3-kinase inhibitors .	Glycogen synthase kinase-3 beta (GSK-3 beta), which is inhibited upon phosphorylation by Akt, was recently shown to function during cell death induced by PI 3-kinase inhibitors.	0	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Glycogen synthase kinase-3 beta	Glycogen synthase kinase-3 beta	Glycogen synthase kinase-3 beta	15	16	0	4
The WNT- and PI3K and Akt signaling pathways negatively regulate GSK3beta activity .	The WNT- and PI3K and Akt signaling pathways negatively regulate GSK3beta activity.	5	11	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	10	11
The GSK3alpha and GSK3beta isoforms are inactivated after phosphorylation by Akt ; inactivation of GSK3 stimulates glucose uptake and also allows activation of glycogen synthase , and hence synthesis of glycogen [ XREF_BIBR , XREF_BIBR ] .	The GSK3alpha and GSK3beta isoforms are inactivated after phosphorylation by Akt; inactivation of GSK3 stimulates glucose uptake and also allows activation of glycogen synthase, and hence synthesis of glycogen [XREF_BIBR, XREF_BIBR].	1	11	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	10	11	3	4
Akt dependent phosphorylation of mitochondrial HK II inhibits Ca 2+ -induced cytochrome c release [ XREF_BIBR ] , and association of HK II to the OMM is favoured when GSK3beta is inactivated by Akt phosphorylation [ XREF_BIBR , XREF_BIBR ] .	Akt dependent phosphorylation of mitochondrial HK II inhibits Ca 2+ -induced cytochrome c release [XREF_BIBR], and association of HK II to the OMM is favoured when GSK3beta is inactivated by Akt phosphorylation [XREF_BIBR, XREF_BIBR].	29	35	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	33	34	29	30
We focused on GSK-3beta , which is a kinase within the beta-catenin destruction complex , because Akt inactivates GSK-3beta by phosphorylation of Ser 9 .	We focused on GSK-3beta, which is a kinase within the beta-catenin destruction complex, because Akt inactivates GSK-3beta by phosphorylation of Ser 9.	16	19	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	16	17	18	19
GSK3beta is negatively regulated by the serine/threonine kinase AKT through its phosphorylation at Ser9 .	GSK3beta is negatively regulated by the serine/threonine kinase AKT through its phosphorylation at Ser9.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	8	9	0	1
73 Importantly , it has been shown that compromised inactivation of GSK-3beta by Akt may be involved in tau hyperphosphoryation .	73 Importantly, it has been shown that compromised inactivation of GSK-3beta by Akt may be involved in tau hyperphosphoryation.	9	14	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	13	14	11	12
Inhibition of GSK3beta by Akt is responsible for the increased stability of Snail .	Inhibition of GSK3beta by Akt is responsible for the increased stability of Snail.	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	2	3
Importantly , administration of Akt and mTOR inhibitors together ( but not of either alone ) improved postinjury motor ( P = 0.02 ) and cognitive deficits ( hidden platform trials , P = 0.001 ; probe trials , P < 0.05 ) , decreased propidium iodide positive cells in CA1 and CA3 ( P < 0.005 ) , and unexpectedly increased p-GSK3beta in hippocampus .	Importantly, administration of Akt and mTOR inhibitors together (but not of either alone) improved postinjury motor (P = 0.02) and cognitive deficits (hidden platform trials, P = 0.001; probe trials, P < 0.05), decreased propidium iodide positive cells in CA1 and CA3 (P < 0.005), and unexpectedly increased p-GSK3beta in hippocampus.	4	63	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p-GSK3beta	p-GSK3beta	p-GSK3beta	4	5	62	63
This occurs through a GSK3beta control node , where the inhibition of GSK3beta by Akt results in increases in , and activation of , beta-catenin .	This occurs through a GSK3beta control node, where the inhibition of GSK3beta by Akt results in increases in, and activation of, beta-catenin.	10	15	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	14	15	12	13
Glycogen synthase kinase 3 ( GSK-3 ) has two isoforms , GSK-3alpha and GSK-3beta , that are inactivated by Akt phosphorylation on Ser21 and Ser9 , respectively .	Glycogen synthase kinase 3 (GSK-3) has two isoforms, GSK-3alpha and GSK-3beta, that are inactivated by Akt phosphorylation on Ser21 and Ser9, respectively.	9	23	inactivated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation on Ser21	akt	GSK-3beta	GSK-3beta	gsk-3beta	19	20	13	14
Active phosphatidylinositol 3 kinase and Akt signaling sequestered GSK3-beta in the cytoplasm by constitutively phosphorylating serine 9 .	Active phosphatidylinositol 3 kinase and Akt signaling sequestered GSK3-beta in the cytoplasm by constitutively phosphorylating serine 9.	5	9	sequestered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3-beta	GSK3-beta	GSK3-beta	5	6	8	9
Inhibitors of RTKs ( Alk and Trk ) , PI3K and Akt should activate Gsk3beta ( which is negatively regulated by phosphorylation ) , whereas inhibitors of mTOR kinase activity should inhibit the de-activation of PP2A by mTORC1 , enabling PP2A to dephosphorylate S62 , collectively driving degradation of Mycn in neuroblastoma ( XREF_FIG ) .	Inhibitors of RTKs (Alk and Trk), PI3K and Akt should activate Gsk3beta (which is negatively regulated by phosphorylation), whereas inhibitors of mTOR kinase activity should inhibit the de-activation of PP2A by mTORC1, enabling PP2A to dephosphorylate S62, collectively driving degradation of Mycn in neuroblastoma (XREF_FIG).	0	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Gsk3beta	Gsk3beta	Gsk3beta	11	12	14	15
In this experiment , we found D-gal up-regulated the expression of p-AKT in the hippocampus , the active form of AKT , leading to decrease the activity of GSK-3beta .	In this experiment, we found D-gal up-regulated the expression of p-AKT in the hippocampus, the active form of AKT, leading to decrease the activity of GSK-3beta.	18	29	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	20	21	28	29
The PI3K-AKT pathway inactivates GSK-3beta by phosphorylation of the S9 residue 6 , which should interfere with GSK-3beta dependent phosphorylation , ubiquitination , and proteasomal degradation of cyclin D2 .	The PI3K-AKT pathway inactivates GSK-3beta by phosphorylation of the S9 residue 6, which should interfere with GSK-3beta dependent phosphorylation, ubiquitination, and proteasomal degradation of cyclin D2.	1	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	GSK-3beta	GSK-3beta	GSK-3beta	1	2	4	5
Moreover , since Abeta down-regulates trophic signaling , particularly the PI3K and AKT pathway which promotes survival and is important for synaptic function XREF_BIBR , the promotion of AKT activation by ligand binding to p75 NTR XREF_BIBR , XREF_BIBR may reduce the effects of Abeta In addition , AKT down-regulates JNK XREF_BIBR and GSK3beta XREF_BIBR .	Moreover, since Abeta down-regulates trophic signaling, particularly the PI3K and AKT pathway which promotes survival and is important for synaptic function XREF_BIBR, the promotion of AKT activation by ligand binding to p75 NTR XREF_BIBR, XREF_BIBR may reduce the effects of Abeta In addition, AKT down-regulates JNK XREF_BIBR and GSK3beta XREF_BIBR.	48	54	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	48	49	53	54
Activation of AKT downstream of RTKs such as EGFR may similarly inhibit GSK3beta and stabilize beta-catenin ( XREF_FIG ) .	Activation of AKT downstream of RTKs such as EGFR may similarly inhibit GSK3beta and stabilize beta-catenin (XREF_FIG).	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	2	3	12	13
Furthermore , AKT inhibition has been shown to activate GSK3beta and ERK1/2 to decrease cellular proliferation and induce cell senescence via CYCLIN D1 down regulation and p21 as well as p27 up-regulation .	Furthermore, AKT inhibition has been shown to activate GSK3beta and ERK1/2 to decrease cellular proliferation and induce cell senescence via CYCLIN D1 down regulation and p21 as well as p27 up-regulation.	2	11	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	2	3	9	10
Since AKT inactivates GSK- 3beta by phosphorylation of its S9 residue , we examined whether GSK-3beta regulates AKT activity in osteosarcoma and osteoblast cells .	Since AKT inactivates GSK- 3beta by phosphorylation of its S9 residue, we examined whether GSK-3beta regulates AKT activity in osteosarcoma and osteoblast cells.	1	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK- 3beta	GSK- 3beta	GSK- 3beta	1	2	3	5
Our results indicate that AKT phosphorylates and thus inactivates GSK3beta , leading to improved axon regeneration , but not RGC survival .	Our results indicate that AKT phosphorylates and thus inactivates GSK3beta, leading to improved axon regeneration, but not RGC survival.	4	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	4	5	9	10
The kinase Akt inactivates GSK-3beta by phosphorylation of Ser9 .	The kinase Akt inactivates GSK-3beta by phosphorylation of Ser9.	0	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	4	5
PI3K and Akt pathway decreases the activity of GSK-3beta in adipocyte differentiation [ XREF_BIBR , XREF_BIBR ] .	PI3K and Akt pathway decreases the activity of GSK-3beta in adipocyte differentiation [XREF_BIBR, XREF_BIBR].	0	9	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	8	9
Reduced GSK3beta activity in nontransgenic mice may be induced by the activation of its upstream PI3K and Akt signaling pathway .	Reduced GSK3beta activity in nontransgenic mice may be induced by the activation of its upstream PI3K and Akt signaling pathway.	1	19	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	17	18	1	2
Of note , the PI3K and Akt pathway , which suppresses GSK3beta , can concurrently activate the Wnt and beta-catenin and Hh pathways [ XREF_BIBR ] .	Of note, the PI3K and Akt pathway, which suppresses GSK3beta, can concurrently activate the Wnt and beta-catenin and Hh pathways [XREF_BIBR].	4	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	6	7	11	12
AKT also phosphorylates and inactivates GSK-3beta a cellular kinase that localizes to the mitochondria under certain circumstances .	AKT also phosphorylates and inactivates GSK-3beta a cellular kinase that localizes to the mitochondria under certain circumstances.	0	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	0	1	5	6
Also in osteoblasts , S1P has been shown to interact with WNT signaling pathway by activating AKT , which inhibits GSK3beta and lead to the nuclear traslocation of beta-Catenin , downstream effector of WNT signaling .	Also in osteoblasts, S1P has been shown to interact with WNT signaling pathway by activating AKT, which inhibits GSK3beta and lead to the nuclear traslocation of beta-Catenin, downstream effector of WNT signaling.	15	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	16	17	20	21
Akt activity inhibits GSK3beta , which normally phosphorylates and promotes degradation of N-Myc [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Akt activity inhibits GSK3beta, which normally phosphorylates and promotes degradation of N-Myc [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	13	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Akt	Akt	akt	GSK3beta	GSK3beta, which normally phosphorylates and promotes degradation of N-Myc	gsk3beta	0	1	3	4
PI3K and Akt mediated inhibition of GSK3beta has been demonstrated to be responsible for Snail expression by ROS such as H 2 O 2 XREF_BIBR .	PI3K and Akt mediated inhibition of GSK3beta has been demonstrated to be responsible for Snail expression by ROS such as H 2 O 2 XREF_BIBR.	0	7	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	6	7
GSK-3beta can be inactivated through the phosphorylation at S9 by Akt XREF_BIBR or by cAMP XREF_BIBR ( XREF_FIG ) .	GSK-3beta can be inactivated through the phosphorylation at S9 by Akt XREF_BIBR or by cAMP XREF_BIBR (XREF_FIG).	0	11	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	10	11	0	1
In addition , GSK-3beta is also an intermediator for PI3K/AKT/mTOR signaling pathway by enhancing phosphorylation of AKT , which inactivates GSK-3beta and accumulates beta-catenin [ XREF_BIBR ] .	In addition, GSK-3beta is also an intermediator for PI3K/AKT/mTOR signaling pathway by enhancing phosphorylation of AKT, which inactivates GSK-3beta and accumulates beta-catenin [XREF_BIBR].	14	22	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	phosphorylation of AKT	akt	GSK-3beta	GSK-3beta	gsk-3beta	16	17	20	21
Phosphorylation of serine 9 residue in NH 2 -terminal region of GSK-3beta by AKT inhibits GSK-3beta , thereby leading to diverse effects including improved cell survival and hypertrophy , and improves contractile function in pressure overloaded hearts , implying the activity of AKT as a cardio-protective mechanism .	Phosphorylation of serine 9 residue in NH 2 -terminal region of GSK-3beta by AKT inhibits GSK-3beta, thereby leading to diverse effects including improved cell survival and hypertrophy, and improves contractile function in pressure overloaded hearts, implying the activity of AKT as a cardio-protective mechanism.	0	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Phosphorylation of serine 9 residue in NH 2 -terminal region of GSK-3beta by AKT	akt	GSK-3beta	GSK-3beta	gsk-3beta	13	14	15	16
This increase may be due to the suppression of GSK-3beta by Akt increasing CREB activation .	This increase may be due to the suppression of GSK-3beta by Akt increasing CREB activation.	4	12	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	11	12	9	10
Moreover , in adipocyte differentiation , activated PI3K and Akt pathway inhibits GSK-3beta [ XREF_BIBR , XREF_BIBR ] .	Moreover, in adipocyte differentiation, activated PI3K and Akt pathway inhibits GSK-3beta [XREF_BIBR, XREF_BIBR].	9	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	9	10	12	13
Furthermore , Akt stimulates glycogen synthesis by inhibiting GSK-3beta and promotes glycolysis by increasing the expression of glycolytic enzymes .	Furthermore, Akt stimulates glycogen synthesis by inhibiting GSK-3beta and promotes glycolysis by increasing the expression of glycolytic enzymes.	2	10	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	8	9
Phospho-Akt ( p-Akt ) in turn activates beta-catenin by blocking its inhibitor GSK-3beta through phosphorylation .	Phospho-Akt (p-Akt) in turn activates beta-catenin by blocking its inhibitor GSK-3beta through phosphorylation.	0	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Phospho-Akt	Phospho-Akt	Phospho-Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	12	13
Moreover the inhibition of PI3K and AKT with Wortamannin significantly increases the activation of GSK-3beta ( decreases GSK-3beta phosphorylation ) , even in presence of EE whereas on blocking ERK pathway with U0216 , no significant change in activation of GSK-3beta was observed .	Moreover the inhibition of PI3K and AKT with Wortamannin significantly increases the activation of GSK-3beta (decreases GSK-3beta phosphorylation), even in presence of EE whereas on blocking ERK pathway with U0216, no significant change in activation of GSK-3beta was observed.	2	16	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	6	7	14	15
Moreover , in adipocyte differentiation , the activated PI3K and Akt pathway inhibits GSK-3beta [ XREF_BIBR , XREF_BIBR ] .	Moreover, in adipocyte differentiation, the activated PI3K and Akt pathway inhibits GSK-3beta [XREF_BIBR, XREF_BIBR].	10	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	10	11	13	14
XREF_BIBR Akt inactivates GSK-3beta by phosphorylation at Ser9 .	XREF_BIBR Akt inactivates GSK-3beta by phosphorylation at Ser9.	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	1	2	3	4
It is of note that mTOR activity is negatively regulated by GSK-3 , implying that Wnt or PI3K and Akt induced GSK-3beta inhibition may enhance mTOR activity ( Ka et al ., 2014 ) .	It is of note that mTOR activity is negatively regulated by GSK-3, implying that Wnt or PI3K and Akt induced GSK-3beta inhibition may enhance mTOR activity (Ka et al., 2014).	15	22	induced	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	19	20	21	22
As a constitutively active kinase , Gsk3beta is inactivated upon innate immune stimulation in macrophages by Akt , and Gsk3 inhibition results in diminished NF-kB-driven pro inflammatory , but increased IL-10 , gene expression .	As a constitutively active kinase, Gsk3beta is inactivated upon innate immune stimulation in macrophages by Akt, and Gsk3 inhibition results in diminished NF-kB-driven pro inflammatory, but increased IL-10, gene expression.	6	17	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Gsk3beta	Gsk3beta	Gsk3beta	16	17	6	7
Upon activation , AKT can effectively suppress the role of GSK3beta , thus leading to a decrease in the degradation of beta-catenin that , in turn , elicits a decreased transcription of its target genes resulting in proliferation , inhibition and apoptosis .	Upon activation, AKT can effectively suppress the role of GSK3beta, thus leading to a decrease in the degradation of beta-catenin that, in turn, elicits a decreased transcription of its target genes resulting in proliferation, inhibition and apoptosis.	3	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	3	4	10	11
XREF_BIBR Furthermore , GSK-3beta activity is inhibited by AKT phosphorylation at Ser9 .	XREF_BIBR Furthermore, GSK-3beta activity is inhibited by AKT phosphorylation at Ser9.	3	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	8	9	3	4
We then used a genetic rescue approach to provide a causal demonstration that the inactivation of GSK-3beta by Akt and PKB is responsible for the inhibition of cell migration .	We then used a genetic rescue approach to provide a causal demonstration that the inactivation of GSK-3beta by Akt and PKB is responsible for the inhibition of cell migration.	14	20	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	18	19	16	17
It is known that [ Ca 2+ ] cyt signaling could stimulate AKT activity that inactivates GSK3beta , resulting in the nuclear accumulation of beta-catenin , which produces tumorigenesis 41 .	It is known that [Ca 2+] cyt signaling could stimulate AKT activity that inactivates GSK3beta, resulting in the nuclear accumulation of beta-catenin, which produces tumorigenesis 41.	12	17	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	12	13	16	17
Further studies suggested that formononetin induced Akt activation and GSK-3beta ( Ser9 ) phosphorylation , thereby reducing GSK-3beta activity towards mPTP opening .	Further studies suggested that formononetin induced Akt activation and GSK-3beta (Ser9) phosphorylation, thereby reducing GSK-3beta activity towards mPTP opening.	4	18	reducing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	formononetin induced Akt	akt	GSK-3beta	GSK-3beta	gsk-3beta	6	7	17	18
However , both Wnt and AKT inhibit the action of GSK-3beta and thus stabilize Snail1 .	However, both Wnt and AKT inhibit the action of GSK-3beta and thus stabilize Snail1.	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	5	6	10	11
XREF_FIG shows that treatment of the cells with CIP significantly increased the level of activated Akt level , inactivated GSK3beta , and beta-catenin .	XREF_FIG shows that treatment of the cells with CIP significantly increased the level of activated Akt level, inactivated GSK3beta, and beta-catenin.	15	22	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt level	akt	GSK3beta	GSK3beta	gsk3beta	15	16	19	20
Another major substrate of AKT is glycogen synthesis kinase 3beta ( GSK3beta ) , which is inactivated by AKT phosphorylation leading to increased glycogen synthesis during glucose metabolism following insulin stimulation .	Another major substrate of AKT is glycogen synthesis kinase 3beta (GSK3beta), which is inactivated by AKT phosphorylation leading to increased glycogen synthesis during glucose metabolism following insulin stimulation.	9	20	inactivated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	18	19	11	12
GSK3b interfaces between these pathways XREF_BIBR , XREF_BIBR , inhibited by MEK and mGLUR signaling XREF_BIBR and increased by PTEN inhibition of PI3K and AKT .	GSK3b interfaces between these pathways XREF_BIBR, XREF_BIBR, inhibited by MEK and mGLUR signaling XREF_BIBR and increased by PTEN inhibition of PI3K and AKT.	0	25	increased	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3b	GSK3b	GSK3b	24	25	0	1
Resveratrol can activate the PI3K and Akt signaling pathway , and the activated Akt then inactivates GSK-3beta and stabilizes beta-catenin .	Resveratrol can activate the PI3K and Akt signaling pathway, and the activated Akt then inactivates GSK-3beta and stabilizes beta-catenin.	11	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	13	14	16	17
Akt and PKB inhibits GSK-3beta activity by phosphorylating serine 9 in GSK-3beta [ XREF_BIBR ] .	Akt and PKB inhibits GSK-3beta activity by phosphorylating serine 9 in GSK-3beta [XREF_BIBR].	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	GSK-3beta	GSK-3beta	GSK-3beta	2	3	4	5
Induction of NMDA dependent LTP triggers the PI3K-Akt pathway , which in turn inhibits GSK-3beta .	Induction of NMDA dependent LTP triggers the PI3K-Akt pathway, which in turn inhibits GSK-3beta.	7	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	GSK-3beta	GSK-3beta	GSK-3beta	7	8	14	15
Mechanically , CHIP probably activated the MAPK and AKT signaling , which inactivated GSK-3beta .	Mechanically, CHIP probably activated the MAPK and AKT signaling, which inactivated GSK-3beta.	6	14	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	8	9	13	14
Here , activation of AKT downstream of ER inhibits GSK3beta , which is essential for cell cycle progression 21 .	Here, activation of AKT downstream of ER inhibits GSK3beta, which is essential for cell cycle progression 21.	2	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	4	5	9	10
Because Akt reduces GSK3beta kinase activity through the phosphorylation of Ser9 ( Manning and Cantley , 2007 ) and increases mRNA translation and protein synthesis ( Proud and Denton , 1997 ) , we analyzed phosphorylated GSK3beta levels in Dex treated C2C12 myotubes , with and without heat stress .	Because Akt reduces GSK3beta kinase activity through the phosphorylation of Ser9 (Manning and Cantley, 2007) and increases mRNA translation and protein synthesis (Proud and Denton, 1997), we analyzed phosphorylated GSK3beta levels in Dex treated C2C12 myotubes, with and without heat stress.	1	19	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	1	2	3	4
Simultaneously , active Akt inhibits GSK3beta which itself is a potent suppressor of myogenesis XREF_BIBR , XREF_BIBR .	Simultaneously, active Akt inhibits GSK3beta which itself is a potent suppressor of myogenesis XREF_BIBR, XREF_BIBR.	2	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	5	6
The activation of Akt inhibits the activity of GSK3beta , potentiating Wnt and Hh signaling pathways as described above .	The activation of Akt inhibits the activity of GSK3beta, potentiating Wnt and Hh signaling pathways as described above.	1	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	8	9
In accordance with this evidence , we believe that TRPV1 activation by CBD in GMSCs may trigger PI3K and Akt signalling , which in turn inactivates GSK3beta through the phosphorylation at serine 9 , thereby attenuating tau phosphorylation and Abeta production .	In accordance with this evidence, we believe that TRPV1 activation by CBD in GMSCs may trigger PI3K and Akt signalling, which in turn inactivates GSK3beta through the phosphorylation at serine 9, thereby attenuating tau phosphorylation and Abeta production.	17	27	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	19	20	26	27
Interestingly , despite the inhibition of GSK-3beta , we observed a decrease in the total levels of beta-catenin in stable Dsc2 knockdown cells , suggesting that Akt mediated GSK-3beta inhibition may promote the nuclear redistribution of beta-catenin and enhance beta-catenin-dependent transcription without inducing stabilization of total beta-catenin protein levels .	Interestingly, despite the inhibition of GSK-3beta, we observed a decrease in the total levels of beta-catenin in stable Dsc2 knockdown cells, suggesting that Akt mediated GSK-3beta inhibition may promote the nuclear redistribution of beta-catenin and enhance beta-catenin-dependent transcription without inducing stabilization of total beta-catenin protein levels.	26	38	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	26	27	28	29
Consistent with this idea , we have observed that insulin increases Myc stability in Drosophila tissue culture , via PKB dependent inactivation of GSK3beta ( PB , unpublished data ) .	Consistent with this idea, we have observed that insulin increases Myc stability in Drosophila tissue culture, via PKB dependent inactivation of GSK3beta (PB, unpublished data).	19	25	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKB	PKB	PKB	GSK3beta	GSK3beta	GSK3beta	19	20	23	24
Phosphorylation of GSK3beta on Ser9 is a well described mechanism by which Akt inhibits GSK3beta activity .	Phosphorylation of GSK3beta on Ser9 is a well described mechanism by which Akt inhibits GSK3beta activity.	12	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	12	13	14	15
The results suggest that phosphorylation of Akt and subsequent inactivation of GSK3beta signaling is critical in mediating Post C beneficial effects upon mitochondrial integrity , function and neuroprotection following GCI injury .	The results suggest that phosphorylation of Akt and subsequent inactivation of GSK3beta signaling is critical in mediating Post C beneficial effects upon mitochondrial integrity, function and neuroprotection following GCI injury.	4	12	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	phosphorylation of Akt	akt	GSK3beta	GSK3beta	gsk3beta	6	7	11	12
Moreover , AKT activation also inhibits GSK3beta through phosphorylation , thereby blocking c-Myc and beta-catenin degradation , which in turn facilitates tumor cell proliferation and invasion [ XREF_BIBR , XREF_BIBR ] .	Moreover, AKT activation also inhibits GSK3beta through phosphorylation, thereby blocking c-Myc and beta-catenin degradation, which in turn facilitates tumor cell proliferation and invasion [XREF_BIBR, XREF_BIBR].	2	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	2	3	6	7
Once activated via phosphorylation at Serine 473 , Akt then inactivates GSK3beta , which leads to the subsequent stabilization and nuclear retention of cytosolic beta-Catenin .	Once activated via phosphorylation at Serine 473, Akt then inactivates GSK3beta, which leads to the subsequent stabilization and nuclear retention of cytosolic beta-Catenin.	8	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	8	9	11	12
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR In contrast to hESCs , the primary function of PI3K and Akt in naive mESCs is to suppress Gsk3beta activity through Gsk3beta hyperphosphorylation , which allows Nanog and c-Myc to maintain pluripotency .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR In contrast to hESCs, the primary function of PI3K and Akt in naive mESCs is to suppress Gsk3beta activity through Gsk3beta hyperphosphorylation, which allows Nanog and c-Myc to maintain pluripotency.	14	26	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Gsk3beta	Gsk3beta	Gsk3beta	18	19	25	26
Previous work showed that Akt inhibits GSK-3beta activity through the phosphorylation of serine 9 on GSK-3beta [ XREF_BIBR ] .	Previous work showed that Akt inhibits GSK-3beta activity through the phosphorylation of serine 9 on GSK-3beta [XREF_BIBR].	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	4	5	6	7
On the other hand Akt inhibits GSK3beta activity and so GSK3beta may become more active even if actual protein levels are reduced .	On the other hand Akt inhibits GSK3beta activity and so GSK3beta may become more active even if actual protein levels are reduced.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	6	7
It is known that GSK3beta activity is inhibited by AKT phosphorylation , resulting in increased protein synthesis and proliferation in cells .	It is known that GSK3beta activity is inhibited by AKT phosphorylation, resulting in increased protein synthesis and proliferation in cells.	4	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	9	10	4	5
Therefore , our data indicate that reduction of PTEN activates PI3K and Akt signaling , which in turn inhibits GSK-3beta by its phosphorylation , leading to axonal outgrowth of cortical neurons after OGD .	Therefore, our data indicate that reduction of PTEN activates PI3K and Akt signaling, which in turn inhibits GSK-3beta by its phosphorylation, leading to axonal outgrowth of cortical neurons after OGD.	10	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	12	13	19	20
PI3K activates Akt , which inactivates GSK3beta by phosphorylation of Ser9 or dephosphrylation of Tyr216 .	PI3K activates Akt, which inactivates GSK3beta by phosphorylation of Ser9 or dephosphrylation of Tyr216.	1	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	6	7
It has been shown that activated Akt can effectively suppress the role of GSK-3beta in regulating the degradation of beta-catenin XREF_BIBR .	It has been shown that activated Akt can effectively suppress the role of GSK-3beta in regulating the degradation of beta-catenin XREF_BIBR.	5	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	6	7	13	14
Activation of AKT by IGF-I exposure suppressed GSK3beta activity , stabilized beta-catenin , increased Ser552 phosphorylation and cyclin D1 levels , yet pretreatment with 4HPR abolished the effects of IGF-I stimulation .	Activation of AKT by IGF-I exposure suppressed GSK3beta activity, stabilized beta-catenin, increased Ser552 phosphorylation and cyclin D1 levels, yet pretreatment with 4HPR abolished the effects of IGF-I stimulation.	0	8	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	2	3	7	8
In this study , we showed that INSM1 possesses extra-nuclear activity to activate the PI3K and AKT signaling pathway that blocks GSK3beta activity .	In this study, we showed that INSM1 possesses extra-nuclear activity to activate the PI3K and AKT signaling pathway that blocks GSK3beta activity.	16	22	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	16	17	21	22
AKT inactivated GSK3beta via Ser9 phosphorylation in bystander cells that was followed by notable up-regulation of beta-catenin protein levels , due to beta-catenin stabilization ( XREF_FIG ) [ XREF_BIBR ] .	AKT inactivated GSK3beta via Ser9 phosphorylation in bystander cells that was followed by notable up-regulation of beta-catenin protein levels, due to beta-catenin stabilization (XREF_FIG) [XREF_BIBR].	0	5	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	0	1	2	3
XREF_BIBR Luteolin attenuates GSK3beta inactivation in the Wnt and beta-catenin pathway , XREF_BIBR and because Akt is known to inactivate GSK3beta , XREF_BIBR it is plausible to suspect that luteolin induced NICD decrease may be the result of Akt inhibition and increased GSK3beta activity .	XREF_BIBR Luteolin attenuates GSK3beta inactivation in the Wnt and beta-catenin pathway, XREF_BIBR and because Akt is known to inactivate GSK3beta, XREF_BIBR it is plausible to suspect that luteolin induced NICD decrease may be the result of Akt inhibition and increased GSK3beta activity.	15	21	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	15	16	20	21
Akt signaling negatively regulates GSK-3beta activity by phosphorylating Ser 9 , and GSK-3beta was shown to regulate the cell cycles through cyclin D1 proteasome mediated degradation XREF_BIBR .	Akt signaling negatively regulates GSK-3beta activity by phosphorylating Ser 9, and GSK-3beta was shown to regulate the cell cycles through cyclin D1 proteasome mediated degradation XREF_BIBR.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	4	5
In AKT and GSK-3beta signalling pathway , AKT could inhibit GSK-3beta activity and promote Snail protein stability [ XREF_BIBR ] and participate in metastasis of prostate cancer .	In AKT and GSK-3beta signalling pathway, AKT could inhibit GSK-3beta activity and promote Snail protein stability [XREF_BIBR] and participate in metastasis of prostate cancer.	7	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	7	8	10	11
With regard to PI3K and AKT signaling , activation of beta-catenin by strain requires AKT mediated inhibition of GSK3beta , which also occurs in osteocytes .	With regard to PI3K and AKT signaling, activation of beta-catenin by strain requires AKT mediated inhibition of GSK3beta, which also occurs in osteocytes.	13	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	14	15	18	19
The signaling proteins related to Wnt and beta-catenin including activated Akt ( phosphorylated Akt at Ser 473 ) , total Akt , inactivated glycogen synthase kinase3beta ( phosphorylated GSK3beta at Ser 9 ) , parental GSK3beta , and beta-catenin were determined by western blot analysis .	The signaling proteins related to Wnt and beta-catenin including activated Akt (phosphorylated Akt at Ser 473), total Akt, inactivated glycogen synthase kinase3beta (phosphorylated GSK3beta at Ser 9), parental GSK3beta, and beta-catenin were determined by western blot analysis.	2	29	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	20	21	28	29
Finally , Akt can inhibit GSK3beta activity .	Finally, Akt can inhibit GSK3beta activity.	2	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	5	6
Morin was also found to prevent the Akt mediated suppression of GSK-3beta possibly causing cell cycle arrest at the G1/S phase .	Morin was also found to prevent the Akt mediated suppression of GSK-3beta possibly causing cell cycle arrest at the G1/S phase.	6	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	7	8	11	12
Deactivation of Akt stimulates GSK-3beta and increases cell activity .	Deactivation of Akt stimulates GSK-3beta and increases cell activity.	0	5	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	4	5
During tumorigenesis , EMT is associated with aberrant activation of canonical Wnt or the PI3K and AKT pathway , which inactivates GSK-3beta and stabilizes beta-catenin or Snail , respectively [ XREF_BIBR , XREF_BIBR ] .	During tumorigenesis, EMT is associated with aberrant activation of canonical Wnt or the PI3K and AKT pathway, which inactivates GSK-3beta and stabilizes beta-catenin or Snail, respectively [XREF_BIBR, XREF_BIBR].	14	22	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	16	17	21	22
Increased Akt expression inhibits the catalytic activity of GSK-3beta , thereby increasing the nuclear translocation of beta-catenin and expression of its target angiogenic and anti-apoptotic genes XREF_BIBR .	Increased Akt expression inhibits the catalytic activity of GSK-3beta, thereby increasing the nuclear translocation of beta-catenin and expression of its target angiogenic and anti-apoptotic genes XREF_BIBR.	1	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt expression	akt	GSK-3beta	GSK-3beta	gsk-3beta	1	2	8	9
Thus , Akt activity leads to beta-catenin stabilization by suppressing the GSK3beta kinase , thereby preventing the proteosomal degradation of beta-catenin , consequently results increased expression of beta-catenin target genes XREF_BIBR .	Thus, Akt activity leads to beta-catenin stabilization by suppressing the GSK3beta kinase, thereby preventing the proteosomal degradation of beta-catenin, consequently results increased expression of beta-catenin target genes XREF_BIBR.	2	12	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	11	12
Considering that syntaxin-4 led to inactivation of Akt , which negatively regulates GSK3beta , a potent regulator of E-cadherin expression XREF_BIBR XREF_BIBR , GSK3beta might mediate syntaxin-4 signaling to induce the morphogenic effect but not differentiation .	Considering that syntaxin-4 led to inactivation of Akt, which negatively regulates GSK3beta, a potent regulator of E-cadherin expression XREF_BIBR XREF_BIBR, GSK3beta might mediate syntaxin-4 signaling to induce the morphogenic effect but not differentiation.	5	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	7	8	12	13
AKT is a negative regulator of GSK-3beta and thus blocking GSK-3beta function using a chemical inhibitor ( SB216763 ) significantly reduced caspase-3 activity upon co-treatment .	AKT is a negative regulator of GSK-3beta and thus blocking GSK-3beta function using a chemical inhibitor (SB216763) significantly reduced caspase-3 activity upon co-treatment.	0	11	blocking	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	0	1	10	11
AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase ( GSK-3beta ) but reduced GSK-3beta and caspase-3 activities in the heart .	AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3beta) but reduced GSK-3beta and caspase-3 activities in the heart.	0	19	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	AM gene transfer increased phosphorylation of Akt	akt	GSK-3beta	GSK-3beta	gsk-3beta	6	7	16	17
The activation of Akt by HER-2 and neu inhibits GSK-3beta activity and increases the formation of the cyclin D1 and Cdk4 complex , which may sequester p27 Kip1 in the cytoplasm to enhance its turnover [ XREF_BIBR ] .	The activation of Akt by HER-2 and neu inhibits GSK-3beta activity and increases the formation of the cyclin D1 and Cdk4 complex, which may sequester p27 Kip1 in the cytoplasm to enhance its turnover [XREF_BIBR].	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	9	10
In parallel , the Gbetagamma component of the initial heterotrimeric Gs protein activates PI3K and AKT , which in turn inhibits GSK3beta by phosphorylation .	In parallel, the Gbetagamma component of the initial heterotrimeric Gs protein activates PI3K and AKT, which in turn inhibits GSK3beta by phosphorylation.	12	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	15	16	21	22
Because AKT inhibits GSK3beta as described above , AKT increases Mcl-1 stability , at least in part , by inhibiting GSK3beta .	Because AKT inhibits GSK3beta as described above, AKT increases Mcl-1 stability, at least in part, by inhibiting GSK3beta.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	1	2	3	4
Leishmania infection triggered membrane-raft reorientation dependent Lyn-PI3K and Akt pathway activation which in turn deactivated GSK3beta to stabilize nuclear SREBP2 .	Leishmania infection triggered membrane-raft reorientation dependent Lyn-PI3K and Akt pathway activation which in turn deactivated GSK3beta to stabilize nuclear SREBP2.	8	16	deactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	8	9	15	16
Both reelin and DHA increase phosphoinositide 3-kinase ( PI3K ) activity , which activates AkT , which in turn inhibits GSK3beta .	Both reelin and DHA increase phosphoinositide 3-kinase (PI3K) activity, which activates AkT, which in turn inhibits GSK3beta.	13	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AkT	AkT	AkT	GSK3beta	GSK3beta	GSK3beta	14	15	20	21
The inhibition of GSK3beta by Akt kinases activity is counteracted by protein overexpression raising doubt on the effective role of GSK3beta in DS/AD as solely responsible for tau hyperphosphorylation occurring in DS .	The inhibition of GSK3beta by Akt kinases activity is counteracted by protein overexpression raising doubt on the effective role of GSK3beta in DS/AD as solely responsible for tau hyperphosphorylation occurring in DS.	1	7	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	3	4
In macrophages , microglia and fibroblasts PGN induces the expression of pro inflammatory molecules by activation of the PI3K and Akt signaling pathway in a TLR2 dependent manner [ XREF_BIBR - XREF_BIBR ] , and Akt dependent inhibition of GSK3beta by phosphorylation at Ser9 [ XREF_BIBR ] .	In macrophages, microglia and fibroblasts PGN induces the expression of pro inflammatory molecules by activation of the PI3K and Akt signaling pathway in a TLR2 dependent manner [XREF_BIBR - XREF_BIBR], and Akt dependent inhibition of GSK3beta by phosphorylation at Ser9 [XREF_BIBR].	35	40	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	35	36	39	40
mGluR5 is known to activate the PI3K and Akt and MEK and ERK pathways , both of which can inhibit GSK3beta .	mGluR5 is known to activate the PI3K and Akt and MEK and ERK pathways, both of which can inhibit GSK3beta.	4	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	8	9	20	21
In addition , PIs induced Akt dependent inactivation of GSK-3beta .	In addition, PIs induced Akt dependent inactivation of GSK-3beta.	3	10	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	PIs induced Akt	akt	GSK-3beta	GSK-3beta	gsk-3beta	5	6	9	10
GSK3beta , inhibited by Akt , inhibits adipogenesis .	GSK3beta, inhibited by Akt, inhibits adipogenesis.	0	6	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	0	1
These data imply that the ERK pathway may act as a regulator for PI-3K and Akt inhibition of GSK-3beta activity and provides support for our hypothesis that GSK-3beta is the key downstream target that mediates the anti-apoptotic effects of activating the PI-3K and Akt and ERK pathways .	These data imply that the ERK pathway may act as a regulator for PI-3K and Akt inhibition of GSK-3beta activity and provides support for our hypothesis that GSK-3beta is the key downstream target that mediates the anti-apoptotic effects of activating the PI-3K and Akt and ERK pathways.	13	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	15	16	18	19
Instead , PI3K and Akt serves to inactivate GSK3beta , a downstream repressor of NF-kappaB .	Instead, PI3K and Akt serves to inactivate GSK3beta, a downstream repressor of NF-kappaB.	2	12	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	8	9
AKT inhibits the kinase activity of GSK3beta via phosphorylation , thereby promoting cell proliferation [ XREF_BIBR ] .	AKT inhibits the kinase activity of GSK3beta via phosphorylation, thereby promoting cell proliferation [XREF_BIBR].	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	0	1	6	7
XREF_BIBR Activation of Akt by PI3K negatively regulates GSK3beta and consequently increases progression of the cell cycle from G0 to G1 and the promotion of cyclin D1 stability .	XREF_BIBR Activation of Akt by PI3K negatively regulates GSK3beta and consequently increases progression of the cell cycle from G0 to G1 and the promotion of cyclin D1 stability.	1	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	8	9
GSK3beta suppression is mediated by activation of phosphoinositide 3-kinase and Akt .	GSK3beta suppression is mediated by activation of phosphoinositide 3-kinase and Akt.	0	11	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	10	11	0	1
For example , inactivation of GSK-3beta by Akt and PKB was shown to regulate the recycling of integrins thus promoting cell migration in fibroblasts .	For example, inactivation of GSK-3beta by Akt and PKB was shown to regulate the recycling of integrins thus promoting cell migration in fibroblasts.	3	9	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	7	8	5	6
As noted above , GSK-3beta is negatively regulated by Akt phosphorylation , and XREF_BIBR demonstrated that GSK-3beta inactivation by Akt enhanced myelin gene expression in Schwann cells .	As noted above, GSK-3beta is negatively regulated by Akt phosphorylation, and XREF_BIBR demonstrated that GSK-3beta inactivation by Akt enhanced myelin gene expression in Schwann cells.	4	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	9	10	4	5
Notably , GSK-3beta is inhibited through phosphorylation by Akt , which is activated by DNA-PK following DNA damage .	Notably, GSK-3beta is inhibited through phosphorylation by Akt, which is activated by DNA-PK following DNA damage.	2	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	8	9	2	3
Akt also promotes sequestration of Bad and suppresses the pro apoptotic activity of GSK-3beta .	Akt also promotes sequestration of Bad and suppresses the pro apoptotic activity of GSK-3beta.	0	14	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	13	14
Inhibition of either the AKT or STAT3 pathway potentiated H2O2 induced cell death and increased GSK-3beta activity by dephosphorylation at serine 9 .	Inhibition of either the AKT or STAT3 pathway potentiated H2O2 induced cell death and increased GSK-3beta activity by dephosphorylation at serine 9.	0	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	4	5	15	16
Sakuranetin was also found to inhibit the phosphorylation of AKT at threonine 308 and serine 473 and leads to activation of GSK3beta via decreased phosphorylation at serine 9 .	Sakuranetin was also found to inhibit the phosphorylation of AKT at threonine 308 and serine 473 and leads to activation of GSK3beta via decreased phosphorylation at serine 9.	0	24	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	AKT	Sakuranetin was also found to inhibit the phosphorylation of AKT at threonine 308 and serine 473	akt	GSK3beta	GSK3beta	gsk3beta	9	10	21	22
In summary , this study indicates that early GLP-1 analog intervention prevented the age dependent tau hyperphosphorylation in T2D mice brain , probably by facilitating sequential activation in an insulin signaling pathway reflected in increased basal activation of Akt and basal suppression of glycogen synthase kinase-3 beta .	In summary, this study indicates that early GLP-1 analog intervention prevented the age dependent tau hyperphosphorylation in T2D mice brain, probably by facilitating sequential activation in an insulin signaling pathway reflected in increased basal activation of Akt and basal suppression of glycogen synthase kinase-3 beta.	38	47	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta	38	39	43	47
PI3K and Akt mediated GSK-3beta inhibition is required for the EphB2 stimulation induced tau dephosphorylation .	PI3K and Akt mediated GSK-3beta inhibition is required for the EphB2 stimulation induced tau dephosphorylation.	0	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	4	5
Akt can inhibit the kinase GSK3-beta through phosphorylation , which should result in the accumulation of beta-catenin protein .	Akt can inhibit the kinase GSK3-beta through phosphorylation, which should result in the accumulation of beta-catenin protein.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3-beta	GSK3-beta	GSK3-beta	0	1	5	6
Akt inactivates GSK-3beta by phosphorylation at Ser9 [ XREF_BIBR ] .	Akt inactivates GSK-3beta by phosphorylation at Ser9 [XREF_BIBR].	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	2	3
It is well known that AKT negatively regulates GSK3beta through phosphorylation in mammals , and this mechanism is conserved in Drosophila [ XREF_BIBR ] ( XREF_FIG ) .	It is well known that AKT negatively regulates GSK3beta through phosphorylation in mammals, and this mechanism is conserved in Drosophila [XREF_BIBR] (XREF_FIG).	5	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	5	6	8	9
GSK-3beta negatively regulates beta-catenin by phosphorylation of Ser33/37/Thr41 - leading to its degradation - while AKT , a critical upstream negative regulator of GSK3beta , inactivates GSK-3beta by phosphorylation of its Ser9 residue XREF_BIBR .	GSK-3beta negatively regulates beta-catenin by phosphorylation of Ser33/37/Thr41 - leading to its degradation - while AKT, a critical upstream negative regulator of GSK3beta, inactivates GSK-3beta by phosphorylation of its Ser9 residue XREF_BIBR.	15	27	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	15	16	26	27
To further verify the role of PI3K and Akt mediated GSK-3beta inhibition in EphB2 stimulation induced tau dephosphorylation , we first used wortmannin , a PI3K inhibitor , in SK-N-SH cells .	To further verify the role of PI3K and Akt mediated GSK-3beta inhibition in EphB2 stimulation induced tau dephosphorylation, we first used wortmannin, a PI3K inhibitor, in SK-N-SH cells.	4	11	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	8	9	10	11
For example , Akt inhibits GSK3beta activation , and its protein levels have been shown to be reduced in the brains of schizophrenia patients .	For example, Akt inhibits GSK3beta activation, and its protein levels have been shown to be reduced in the brains of schizophrenia patients.	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	5	6
To confirm our observation , we targeted the Akt downstream molecule GSK3beta , which is negatively regulated by greater Akt activity ( increased level of p-Akt ) .	To confirm our observation, we targeted the Akt downstream molecule GSK3beta, which is negatively regulated by greater Akt activity (increased level of p-Akt).	6	20	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	19	20	11	12
GSK-3beta is an active kinase under basal conditions and Akt phosphorylation at Ser9 inhibits the kinase activity of GSK-3beta .	GSK-3beta is an active kinase under basal conditions and Akt phosphorylation at Ser9 inhibits the kinase activity of GSK-3beta.	9	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation at Ser9	akt	GSK-3beta	GSK-3beta	gsk-3beta	9	10	18	19
Normally , activated Akt suppresses GSK3beta ; however , GSK3beta can be activated by I/R induced injury , which contributes the mitochondrial dysfunction and subsequently induces neuronal apoptosis ( Hanumanthappa et al ., 2014 ) .	Normally, activated Akt suppresses GSK3beta; however, GSK3beta can be activated by I/R induced injury, which contributes the mitochondrial dysfunction and subsequently induces neuronal apoptosis (Hanumanthappa et al., 2014).	2	6	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	5	6
Since activation of AKT by EGFR suppresses GSK3beta activity through Ser9 phosphorylation XREF_BIBR , inhibition of EGF signalling in BLBC cells creates a therapeutic benefit by reducing cancer cell immune escape via PD-L1 destabilization .	Since activation of AKT by EGFR suppresses GSK3beta activity through Ser9 phosphorylation XREF_BIBR, inhibition of EGF signalling in BLBC cells creates a therapeutic benefit by reducing cancer cell immune escape via PD-L1 destabilization.	1	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	3	4	7	8
PI3K and Akt pathway is involved in testosterone induced GSK-3beta inhibition in cardiac myocytes .	PI3K and Akt pathway is involved in testosterone induced GSK-3beta inhibition in cardiac myocytes.	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	9	10
GSK3beta is reported to regulate cell cycle analysis and apoptosis , Akt prevents the apoptotic activity of GSK3beta by phosphorylation [ XREF_BIBR ] .	GSK3beta is reported to regulate cell cycle analysis and apoptosis, Akt prevents the apoptotic activity of GSK3beta by phosphorylation [XREF_BIBR].	11	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	11	12	17	18
Several studies have concluded that Akt inactivation of GSK3beta is cytoprotective by blocking apoptosis .	Several studies have concluded that Akt inactivation of GSK3beta is cytoprotective by blocking apoptosis.	5	9	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	8	9
Akt inhibits GSK3beta , a major candidate kinase involved in tau hyperphosphorylation [ XREF_BIBR , XREF_BIBR ] .	Akt inhibits GSK3beta, a major candidate kinase involved in tau hyperphosphorylation [XREF_BIBR, XREF_BIBR].	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	2	3
Akt , PKC , and PKA phosphorylate and inactivate GSK3beta .	Akt, PKC, and PKA phosphorylate and inactivate GSK3beta.	0	10	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	9	10
We demonstrated that both Akt and ERK signaling pathways , which are known to be critical for angiogenesis , became activated in response to 5muM of resveratrol and functioned to inactivate GSK3beta .	We demonstrated that both Akt and ERK signaling pathways, which are known to be critical for angiogenesis, became activated in response to 5muM of resveratrol and functioned to inactivate GSK3beta.	3	32	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	31	32
In an alternative model , lithium dissociates a beta-arrestin-protein phosphatase and Akt complex , which leads to augmented Akt activity , which in turn inhibits GSK3beta .	In an alternative model, lithium dissociates a beta-arrestin-protein phosphatase and Akt complex, which leads to augmented Akt activity, which in turn inhibits GSK3beta.	18	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	18	19	25	26
GSK3beta in turn is inactivated by AKT and ERK1/2 .	GSK3beta in turn is inactivated by AKT and ERK1/2.	0	8	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	6	7	0	1
It has been reported that activated Akt ( p-Akt ) can inactivate GSK-3beta and reduce the amount of GSK-3beta available for phosphorylation ( through the tyrosine 216 form ) [ XREF_BIBR , XREF_BIBR ] .	It has been reported that activated Akt (p-Akt) can inactivate GSK-3beta and reduce the amount of GSK-3beta available for phosphorylation (through the tyrosine 216 form) [XREF_BIBR, XREF_BIBR].	5	14	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	6	7	12	13
Although the protein kinase Akt inhibits GSK3beta by phosphorylation at the N terminus , preventing Akt mediated phosphorylation does not affect the cell-survival pathway activated through the GSK3beta substrate beta-catenin .	Although the protein kinase Akt inhibits GSK3beta by phosphorylation at the N terminus, preventing Akt mediated phosphorylation does not affect the cell-survival pathway activated through the GSK3beta substrate beta-catenin.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	6	7
Abnormally high Akt activity suppresses GSK-3beta function , thereby accumulating the nuclear factor of activated T-cells c1 ( NFATc1 ) in the nucleus , increasing DcR3 expression in IPF fibroblasts .	Abnormally high Akt activity suppresses GSK-3beta function, thereby accumulating the nuclear factor of activated T-cells c1 (NFATc1) in the nucleus, increasing DcR3 expression in IPF fibroblasts.	2	6	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	5	6
Although the detailed mechanism how Wnt pathway inactivates GSK3beta is still unclear , PI3K and AKT inhibits GSK3beta via increasing its Ser 9 phosphorylation [ XREF_BIBR ] .	Although the detailed mechanism how Wnt pathway inactivates GSK3beta is still unclear, PI3K and AKT inhibits GSK3beta via increasing its Ser 9 phosphorylation [XREF_BIBR].	13	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	15	16	17	18
P4 inhibits this pathway by blocking AKT phosphorylation and , thus , the inactivation of GSK3beta with the resultant loss of nuclear cyclin D1 [ XREF_BIBR ] .	P4 inhibits this pathway by blocking AKT phosphorylation and, thus, the inactivation of GSK3beta with the resultant loss of nuclear cyclin D1 [XREF_BIBR].	0	16	inactivation	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	AKT	P4 inhibits this pathway by blocking AKT phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	6	7	15	16
GSK3beta is inhibited by AKT downstream of PI3K .	GSK3beta is inhibited by AKT downstream of PI3K.	0	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	4	5	0	1
By inhibiting GSK3beta , AKT effectively activates glycogen synthase , and allows for improved intracellular glucose utilization and glycogen synthesis .	By inhibiting GSK3beta, AKT effectively activates glycogen synthase, and allows for improved intracellular glucose utilization and glycogen synthesis.	1	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	4	5	2	3
Since AKT inhibits GSK-3beta , we investigated if exposure of DCs to the SB216763 GSK-3beta inhibitor influences CD40 expression on DCs .	Since AKT inhibits GSK-3beta, we investigated if exposure of DCs to the SB216763 GSK-3beta inhibitor influences CD40 expression on DCs.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	1	2	3	4
Akt stabilizes C-myc via phosphorylation and inhibits the activation of GSK-3beta , which promotes the transcriptional activation of C-myc XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Akt stabilizes C-myc via phosphorylation and inhibits the activation of GSK-3beta, which promotes the transcriptional activation of C-myc XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	10	11
On the other hand , Akt inhibits GSK3beta by phosphorylation at residue Serine9 [ XREF_BIBR ] and Akt phosphorylation and activation in a phosphatidylinositol 3-kinase ( PI3K ) - and lipid raft formation dependent manner as a response to viral infections with cytoplasmic RNA viruses has been demonstrated ( e.g ., the DENV and the JEV ) [ XREF_BIBR ] .	On the other hand, Akt inhibits GSK3beta by phosphorylation at residue Serine9 [XREF_BIBR] and Akt phosphorylation and activation in a phosphatidylinositol 3-kinase (PI3K) - and lipid raft formation dependent manner as a response to viral infections with cytoplasmic RNA viruses has been demonstrated (e.g., the DENV and the JEV) [XREF_BIBR].	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	7	8
In addition , Akt was previously shown to suppress GSK3beta activation , leading to impaired NF-kappaB activation XREF_BIBR .	In addition, Akt was previously shown to suppress GSK3beta activation, leading to impaired NF-kappaB activation XREF_BIBR.	3	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	9	10
Akt downregulates the activities of GSK-3alpha and GSK-3beta by phosphorylating the former at Ser21 and the latter at Ser9 [ XREF_BIBR ] .	Akt downregulates the activities of GSK-3alpha and GSK-3beta by phosphorylating the former at Ser21 and the latter at Ser9 [XREF_BIBR].	0	8	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	7	8
Zhang et al propose an elaborate signaling network in confluent endothelial cells whereby Angiopoietin-1 and Tie-2 induction of PI3K and Akt inhibits GSK3B and stabilizes B-catenin , which forms a complex with NICD and RBPJk to enhance expression of DLL4 , resulting in vascular quiescence [ XREF_BIBR ] .	Zhang et al propose an elaborate signaling network in confluent endothelial cells whereby Angiopoietin-1 and Tie-2 induction of PI3K and Akt inhibits GSK3B and stabilizes B-catenin, which forms a complex with NICD and RBPJk to enhance expression of DLL4, resulting in vascular quiescence [XREF_BIBR].	16	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3B	GSK3B	GSK3B	20	21	22	23
Akt is known to inactivate GSK3beta , thereby relieving inhibition of cyclins , translation initiator eIF2B and other cell cycle regulators .	Akt is known to inactivate GSK3beta, thereby relieving inhibition of cyclins, translation initiator eIF2B and other cell cycle regulators.	0	6	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	5	6
The PI3K and AKT pathway , which also inhibits GSK3beta , can , for this reason , be considered a central component in NHR and Wnt pathway crosstalk , and these interactions are nicely reviewed by Mulholland et al [ XREF_BIBR ] .	The PI3K and AKT pathway, which also inhibits GSK3beta, can, for this reason, be considered a central component in NHR and Wnt pathway crosstalk, and these interactions are nicely reviewed by Mulholland et al [XREF_BIBR].	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	3	4	9	10
Activation of Akt inhibits Gsk-3beta and causing accumulation of cyclin D1 leading to loss of cell cycle regulation XREF_BIBR - XREF_BIBR .	Activation of Akt inhibits Gsk-3beta and causing accumulation of cyclin D1 leading to loss of cell cycle regulation XREF_BIBR - XREF_BIBR.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Gsk-3beta	Gsk-3beta	Gsk-3beta	2	3	4	5
PI3K and AKT activates wnt signalling by blocking Gsk3-beta , which was confirmed by beta-catenin up-regulation and nuclear localization .	PI3K and AKT activates wnt signalling by blocking Gsk3-beta, which was confirmed by beta-catenin up-regulation and nuclear localization.	0	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	Gsk3-beta	Gsk3-beta	Gsk3-beta	2	3	8	9
Since GSK3beta is negatively regulated by AKT phosphorylation [ XREF_BIBR ] , activation of the phosphatidylinositol-3-kinase ( PI3K )/AKT pathway , for instance through RAS signaling can lead to stabilization of Ser-62-phosphorylated MYC by preventing GSK3beta mediated Thr 58 phosphorylation [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Since GSK3beta is negatively regulated by AKT phosphorylation [XREF_BIBR], activation of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, for instance through RAS signaling can lead to stabilization of Ser-62-phosphorylated MYC by preventing GSK3beta mediated Thr 58 phosphorylation [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	6	7	1	2
For example , RTK signaling can potentiate the SHH pathway through PI3K and AKT mediated GSK-3beta suppression or RAS and STIL1 mediated SUFU inhibition .	For example, RTK signaling can potentiate the SHH pathway through PI3K and AKT mediated GSK-3beta suppression or RAS and STIL1 mediated SUFU inhibition.	13	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	13	14	15	16
In this model , Akt activates anti-apoptotic proteins and inactivates glycogen synthase kinase-3beta ( GSK3beta ) activity by increasing the phosphorylation level of Ser9 and Ser21 .	In this model, Akt activates anti-apoptotic proteins and inactivates glycogen synthase kinase-3beta (GSK3beta) activity by increasing the phosphorylation level of Ser9 and Ser21.	4	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	14	15
Given that AKT inactivates GSK3beta signaling , the potentially oncogenic role of GSK3beta in melanoma has been little considered .	Given that AKT inactivates GSK3beta signaling, the potentially oncogenic role of GSK3beta in melanoma has been little considered.	2	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	2	3	4	5
SDF1 activation of AKT would be expected to decrease GSK3beta activity through phosphorylation of Ser9 .	SDF1 activation of AKT would be expected to decrease GSK3beta activity through phosphorylation of Ser9.	1	10	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	3	4	9	10
Consequently , the decreased expression of AKT may further target GSK3beta and activate its expression , which would result in increased expression of gluconeogenic genes ( such as FOXO1 ) , accompanied by the promotion of gluconeogenesis and the impairment of glycogen synthesis .	Consequently, the decreased expression of AKT may further target GSK3beta and activate its expression, which would result in increased expression of gluconeogenic genes (such as FOXO1), accompanied by the promotion of gluconeogenesis and the impairment of glycogen synthesis.	4	11	target	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	expression of AKT	akt	GSK3beta	GSK3beta	gsk3beta	6	7	10	11
Akt decreases GSK-3beta activity through phosphorylation and leads to increased expression of mRNA derived from eIF2B ( Eukaryotic Translation Initiation Factor 2B ) increased activity because of decreased inhibition of eIF2Bepsilon through GSK-3beta .	Akt decreases GSK-3beta activity through phosphorylation and leads to increased expression of mRNA derived from eIF2B (Eukaryotic Translation Initiation Factor 2B) increased activity because of decreased inhibition of eIF2Bepsilon through GSK-3beta.	0	23	decreases	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	2	3
In contrast to p70S6K and 4E-BP1 , GSK-3beta is negatively regulated by the PI3K and AKT signaling .	In contrast to p70S6K and 4E-BP1, GSK-3beta is negatively regulated by the PI3K and AKT signaling.	7	16	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	15	16	7	8
In mESCs , Gsk3beta is directly inactivated by LIF activating PI3K and Akt phosphorylation .	In mESCs, Gsk3beta is directly inactivated by LIF activating PI3K and Akt phosphorylation.	3	14	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	Gsk3beta	Gsk3beta	gsk3beta	12	13	3	4
As such , Akt inhibits GSK-3beta with the end result being activation of these transcription factors .	As such, Akt inhibits GSK-3beta with the end result being activation of these transcription factors.	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	5	6
Thus , one consequence of the action of Akt in mitochondria is to inhibit GSK-3beta .	Thus, one consequence of the action of Akt in mitochondria is to inhibit GSK-3beta.	6	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	8	9	14	15
Furthermore , activation of PKA but not Akt mediated the inhibition of GSK-3beta by I2PP2A silencing .	Furthermore, activation of PKA but not Akt mediated the inhibition of GSK-3beta by I2PP2A silencing.	2	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	7	8	12	13
PI3K and Akt also inhibits GSK-3beta .	PI3K and Akt also inhibits GSK-3beta.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	5	6
AKT inhibits GSK3beta by phosphorylation at serine 9 .	AKT inhibits GSK3beta by phosphorylation at serine 9.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	0	1	2	3
Compared with the BSA control , palmitate significantly reduced the phosphorylation of Akt ( Ser473 ) and increased GSK3B activation as demonstrated by the impairment of phosphorylated-Ser9-GSK3B expression , which led to a dramatically decreased stability of b-catenin as demonstrated by reduced expression of active b-catenin ( non phosphorylated at Ser33/37/Thr41 ) ( XREF_FIG ) .	Compared with the BSA control, palmitate significantly reduced the phosphorylation of Akt (Ser473) and increased GSK3B activation as demonstrated by the impairment of phosphorylated-Ser9-GSK3B expression, which led to a dramatically decreased stability of b-catenin as demonstrated by reduced expression of active b-catenin (non phosphorylated at Ser33/37/Thr41) (XREF_FIG).	6	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	palmitate significantly reduced the phosphorylation of Akt (Ser473	akt	GSK3B	GSK3B	gsk3b	12	13	18	19
GSK3beta is also negatively regulated by phosphatidylinositol 3-kinase-mediated Akt activation .	GSK3beta is also negatively regulated by phosphatidylinositol 3-kinase-mediated Akt activation.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	8	9	0	1
Akt inhibits GSK-3beta resulting in release of beta-catenin from the APC-GSK-3beta-axincomplex .	Akt inhibits GSK-3beta resulting in release of beta-catenin from the APC-GSK-3beta-axincomplex.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	2	3
Because GSK-3beta is inhibited by AKT phosphorylation , which is part of the WNT signalling pathway , we explored whether the activation of PI3K , AKT and inactivation of GSK3beta are required for SDF-1-enhanced TOPflash activity .	Because GSK-3beta is inhibited by AKT phosphorylation, which is part of the WNT signalling pathway, we explored whether the activation of PI3K, AKT and inactivation of GSK3beta are required for SDF-1-enhanced TOPflash activity.	1	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	5	6	1	2
Moreover , these two signaling pathways converge downstream to GSK3beta , which is inhibited by Akt ( Woodgett , 1990 ) .	Moreover, these two signaling pathways converge downstream to GSK3beta, which is inhibited by Akt (Woodgett, 1990).	7	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	15	16	9	10
Activation of Akt promotes cell survival pathways , including phosphorylation and thus inhibition of GSK-3beta and decreases in caspase activity .	Activation of Akt promotes cell survival pathways, including phosphorylation and thus inhibition of GSK-3beta and decreases in caspase activity.	0	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	14	15
Simultaneously , activated Akt inhibits GSK3beta by phosphorylation at serine 9 .	Simultaneously, activated Akt inhibits GSK3beta by phosphorylation at serine 9.	2	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	5	6
Both ILK and Akt phosphorylate and inhibit the activity of GSK-3beta , which results in activation of beta-catenin and LEF -1 and AP-1 transcription factors .	Both ILK and Akt phosphorylate and inhibit the activity of GSK-3beta, which results in activation of beta-catenin and LEF -1 and AP-1 transcription factors.	1	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	10	11
In conclusion , Akt protein activity was decreased in newborn rats in the 24 h following HI brain damage , thereby triggering the activity of its downstream effector GSK-3beta , which may be one of the signaling pathways underlying neuronal apoptosis .	In conclusion, Akt protein activity was decreased in newborn rats in the 24 h following HI brain damage, thereby triggering the activity of its downstream effector GSK-3beta, which may be one of the signaling pathways underlying neuronal apoptosis.	3	37	triggering	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	28	29
Akt can also inhibit GSK-3beta , which is an inhibitor of cyclin D1 , a protein critical for early cell cycle progression [ XREF_BIBR ] .	Akt can also inhibit GSK-3beta, which is an inhibitor of cyclin D1, a protein critical for early cell cycle progression [XREF_BIBR].	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	4	5
Serotonin signaling through the 5-HT1A receptor increases the velocity of mitochondrial transport in hippocampal neurons through a signaling pathway that may involve Akt inhibition of GSK3beta .	Serotonin signaling through the 5-HT1A receptor increases the velocity of mitochondrial transport in hippocampal neurons through a signaling pathway that may involve Akt inhibition of GSK3beta.	22	26	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	22	23	25	26
Interestingly , despite the Akt mediated inhibition of GSK-3beta , total levels of beta-catenin were decreased in the stable Dsc2 knockdown cells compared with controls ( Supplemental Figure 5D ) .	Interestingly, despite the Akt mediated inhibition of GSK-3beta, total levels of beta-catenin were decreased in the stable Dsc2 knockdown cells compared with controls (Supplemental Figure 5D).	2	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	4	5	8	9
The present study is the first to show , in breast cancer cells , that an IL-1beta/IL-1RI/beta-catenin signaling pathway induces beta-catenin accumulation due to GSK3beta inactivation by Akt phosphorylation .	The present study is the first to show, in breast cancer cells, that an IL-1beta/IL-1RI/beta-catenin signaling pathway induces beta-catenin accumulation due to GSK3beta inactivation by Akt phosphorylation.	24	29	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	27	28	24	25
Following the canonical pathway which establishes that Akt inactivates GSK-3beta by an N-terminal phosphorylation ( Ser 9 ) in neurons exposed to Abeta , the increased levels of active caspase-3 correlated with a decrease in the levels of p-GSK-3beta ( Ser 9 ) .	Following the canonical pathway which establishes that Akt inactivates GSK-3beta by an N-terminal phosphorylation (Ser 9) in neurons exposed to Abeta, the increased levels of active caspase-3 correlated with a decrease in the levels of p-GSK-3beta (Ser 9).	7	10	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	7	8	9	10
SDF1 has been shown to stabilize beta-catenin levels in pancreatic islet cells that was proposed to occur via AKT dependent inhibition of GSK3beta activity 20 .	SDF1 has been shown to stabilize beta-catenin levels in pancreatic islet cells that was proposed to occur via AKT dependent inhibition of GSK3beta activity 20.	18	23	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	18	19	22	23
Activation of PI3K and Akt , such as that induced by insulin and IGF -1 during glycogen metabolism , can phosphorylate Ser9 and inhibit GSK-3beta activity .	Activation of PI3K and Akt, such as that induced by insulin and IGF -1 during glycogen metabolism, can phosphorylate Ser9 and inhibit GSK-3beta activity.	0	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	4	5	24	25
Furthermore , enhanced Akt inhibits GSK-3beta activity by phosphorylating the Ser 9 residue [ XREF_BIBR - XREF_BIBR ] .	Furthermore, enhanced Akt inhibits GSK-3beta activity by phosphorylating the Ser 9 residue [XREF_BIBR - XREF_BIBR].	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	5	6
AKT phosphorylates and thus inactivates GSK3beta on Ser 9 leading to increased levels of hypophosphorylated beta-catenin XREF_BIBR .	AKT phosphorylates and thus inactivates GSK3beta on Ser 9 leading to increased levels of hypophosphorylated beta-catenin XREF_BIBR.	0	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	0	1	5	6
PI3K and Akt inactivates GSK3beta ( phosphorylation ) to benefit cell survival and suppress inflammation [ XREF_BIBR , XREF_BIBR ] .	PI3K and Akt inactivates GSK3beta (phosphorylation) to benefit cell survival and suppress inflammation [XREF_BIBR, XREF_BIBR].	0	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	4	5
However , functional redundancy of AKT suppression of GSK3beta has been shown in HCT116 cells by knockout studies .	However, functional redundancy of AKT suppression of GSK3beta has been shown in HCT116 cells by knockout studies.	5	9	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	5	6	8	9
Both proteins display kinase activity , and Akt reduces GSK3beta activity by phosphorylating S9 .	Both proteins display kinase activity, and Akt reduces GSK3beta activity by phosphorylating S9.	7	10	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	7	8	9	10
WM also inhibited the phosphorylation of the Akt targets GSK3alpha and GSK3beta and the activation of MEKs .	WM also inhibited the phosphorylation of the Akt targets GSK3alpha and GSK3beta and the activation of MEKs.	4	12	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	phosphorylation of the Akt	akt	GSK3beta	GSK3beta	gsk3beta	7	8	11	12
AKT is known to negatively regulate GSK3beta in cancer cells .	AKT is known to negatively regulate GSK3beta in cancer cells.	0	9	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	0	1	6	7
Upon M-CSF stimulation , Akt is activated by CSF-1R-PI3K and then inactivates GSK3beta , leading to the stabilization of CKIP-1 and beta-catenin proteins .	Upon M-CSF stimulation, Akt is activated by CSF-1R-PI3K and then inactivates GSK3beta, leading to the stabilization of CKIP-1 and beta-catenin proteins.	4	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	12	13
In addition , since Akt is one of the upstream GSK3 regulating protein kinases that inactivates GSK3 , the GSK3 dependent activation of Akt by 5-HT1B receptors could function as a feedback regulation to prevent prolonged effect of GSK3beta on 5-HT1B receptors , but this postulation remains to be examined .	In addition, since Akt is one of the upstream GSK3 regulating protein kinases that inactivates GSK3, the GSK3 dependent activation of Akt by 5-HT1B receptors could function as a feedback regulation to prevent prolonged effect of GSK3beta on 5-HT1B receptors, but this postulation remains to be examined.	21	39	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	23	24	38	39
GSK-3beta is a key molecule in the PI3K and Akt signaling pathway , and activated Akt has been shown to effectively suppress the role of GSK-3beta in regulating the degradation of beta-catenin XREF_BIBR .	GSK-3beta is a key molecule in the PI3K and Akt signaling pathway, and activated Akt has been shown to effectively suppress the role of GSK-3beta in regulating the degradation of beta-catenin XREF_BIBR.	14	26	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	15	16	25	26
Because the Wnt pathway also uses protein kinase B ( Akt ) to promote cell survival , and since Akt inhibits the activity of GSK-3beta through phosphorylation of this protein to promote cell survival [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] , the participation of Akt in the observed effects is likely to occur and deserves further investigations .	Because the Wnt pathway also uses protein kinase B (Akt) to promote cell survival, and since Akt inhibits the activity of GSK-3beta through phosphorylation of this protein to promote cell survival [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR], the participation of Akt in the observed effects is likely to occur and deserves further investigations.	19	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	19	20	24	25
VDAC1 is a target of GSK3beta , which in turn is negatively regulated by Akt , i.e. inhibition of Akt activates GSK3beta and GSK3beta mediated phosphorylation of VDAC1 is associated with increased cytotoxicity XREF_BIBR .	VDAC1 is a target of GSK3beta, which in turn is negatively regulated by Akt, i.e. inhibition of Akt activates GSK3beta and GSK3beta mediated phosphorylation of VDAC1 is associated with increased cytotoxicity XREF_BIBR.	3	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	14	15	5	6
Akt is a major upstream modulator of GSK-3beta and directly inhibits GSK-3beta by phosphorylation of GSK-3beta , thereby inactivates its kinase activity .	Akt is a major upstream modulator of GSK-3beta and directly inhibits GSK-3beta by phosphorylation of GSK-3beta, thereby inactivates its kinase activity.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	11	12
GSK-3beta can be pharmacologically inhibited by lithium ( Li ) as a mood stabilizer through direct binding to the ATP dependent magnesium ( Mg 2+ )-sensitive catalytic enzyme , or indirectly through enhanced phosphorylation of GSK-3beta by activation of PKA , PI3K and Akt signaling pathways ( PKB ) and phosphorylation of PKC at Ser 9 .	GSK-3beta can be pharmacologically inhibited by lithium (Li) as a mood stabilizer through direct binding to the ATP dependent magnesium (Mg 2+)-sensitive catalytic enzyme, or indirectly through enhanced phosphorylation of GSK-3beta by activation of PKA, PI3K and Akt signaling pathways (PKB) and phosphorylation of PKC at Ser 9.	0	45	inhibited	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	Akt	phosphorylation of GSK-3beta by activation of PKA, PI3K and Akt	akt	GSK-3beta	GSK-3beta	gsk-3beta	43	44	0	1
Akt reduces GSK3beta kinase activity by Ser9 phosphorylation , enhancing mRNA translation by increased eukaryotic translation initiation factor ( eIF ) 2B activity ( Proud and Denton , 1997 ) .	Akt reduces GSK3beta kinase activity by Ser9 phosphorylation, enhancing mRNA translation by increased eukaryotic translation initiation factor (eIF) 2B activity (Proud and Denton, 1997).	0	4	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	2	3
In turn , the PI-3K and Akt and ERK pathways may act cooperatively to suppress GSK-3beta activity .	In turn, the PI-3K and Akt and ERK pathways may act cooperatively to suppress GSK-3beta activity.	6	16	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	6	7	15	16
Furthermore , AKT may phosphorylate and thereby inactivate GSK3beta , a member of the CTNNB1 destruction complex , resulting in CTNNB1 accumulation and nuclear shuttling .	Furthermore, AKT may phosphorylate and thereby inactivate GSK3beta, a member of the CTNNB1 destruction complex, resulting in CTNNB1 accumulation and nuclear shuttling.	2	18	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	2	3	8	9
Akt has been shown to inhibit GSK-3alpha and GSK-3beta in response to insulin , insulin related peptides such as insulin like growth factor ( IGF ) , and neurotrophins such as nerve growth factor ( NGF ) , brain derived neurotrophic factor ( BDNF ) , and neurotrophin 3 ( Cross et al 1995 ; Chen et al 2005 ) .	Akt has been shown to inhibit GSK-3alpha and GSK-3beta in response to insulin, insulin related peptides such as insulin like growth factor (IGF), and neurotrophins such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin 3 (Cross et al 1995; Chen et al 2005).	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	8	9
GSK3beta mediates apoptosis in response to various stimuli and is inhibited by Akt which phosphorylates the kinase on serine residue 9 .	GSK3beta mediates apoptosis in response to various stimuli and is inhibited by Akt which phosphorylates the kinase on serine residue 9.	0	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	12	13	0	1
GSK3beta , which is directly inhibited by Akt phosphorylation , has also been implicated as part of the Akt and Foxo3a pathway in promoting Puma expression in cerebellar neurons .	GSK3beta, which is directly inhibited by Akt phosphorylation, has also been implicated as part of the Akt and Foxo3a pathway in promoting Puma expression in cerebellar neurons.	0	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	7	8	0	1
In contrast , AKT is known to directly inhibit GSK3beta through inhibitory phosphorylation on serine 9 .	In contrast, AKT is known to directly inhibit GSK3beta through inhibitory phosphorylation on serine 9.	3	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	3	4	9	10
Inhibition of PI3K and Akt signaling pathway increases GSK-3beta activity , resulting in tau protein hyperphosphorylation [ XREF_BIBR ] .	Inhibition of PI3K and Akt signaling pathway increases GSK-3beta activity, resulting in tau protein hyperphosphorylation [XREF_BIBR].	2	9	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	4	5	8	9
In contrast , Akt , the upstream kinase of GSK3beta , has been shown to be activated by the exposure of nickel compounds in our previous study in mouse epidermal Cl41 cells , which may in turn phosphorylate and inactivate GSK3beta .	In contrast, Akt, the upstream kinase of GSK3beta, has been shown to be activated by the exposure of nickel compounds in our previous study in mouse epidermal Cl41 cells, which may in turn phosphorylate and inactivate GSK3beta.	3	41	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	40	41
AKT dependent suppression of GSK3beta activity that resulted in stabilization of protein levels of beta-catenin was one of the essential events in regulation of proliferation and survival of human NSC [ XREF_BIBR ] .	AKT dependent suppression of GSK3beta activity that resulted in stabilization of protein levels of beta-catenin was one of the essential events in regulation of proliferation and survival of human NSC [XREF_BIBR].	0	5	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	0	1	4	5
Furthermore , our results also suggest that inhibition of GSK-3beta by Akt may enhance beta-catenin signaling in a more distinct manner than Wnt mediated GSK-3beta inactivation , even though this component is shared by both Wnt and beta-catenin and Akt and beta-catenin pathways ( see XREF_FIG ) .	Furthermore, our results also suggest that inhibition of GSK-3beta by Akt may enhance beta-catenin signaling in a more distinct manner than Wnt mediated GSK-3beta inactivation, even though this component is shared by both Wnt and beta-catenin and Akt and beta-catenin pathways (see XREF_FIG).	7	12	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	11	12	9	10
BAFF controls Mcl1 protein levels in part by the Akt dependent inactivation of Gsk-3beta , which constitutively phosphorylates and induces the proteolysis of Mcl1 in unstimulated cells .	BAFF controls Mcl1 protein levels in part by the Akt dependent inactivation of Gsk-3beta, which constitutively phosphorylates and induces the proteolysis of Mcl1 in unstimulated cells.	9	14	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Gsk-3beta	Gsk-3beta	Gsk-3beta	9	10	13	14
Together , these observations describe a regulatory axis wherein VEGF triggers increased Snail1 mRNA expression in an NF-kappaB-dependent manner while stabilizing Snail1 protein via the ERK and Akt dependent phosphorylation / inactivation of GSK3beta ( XREF_FIG ) .	Together, these observations describe a regulatory axis wherein VEGF triggers increased Snail1 mRNA expression in an NF-kappaB-dependent manner while stabilizing Snail1 protein via the ERK and Akt dependent phosphorylation / inactivation of GSK3beta (XREF_FIG).	27	34	inactivation	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	27	28	33	34
Akt can inhibit GSK-3beta , therefore preventing the degradation of beta-catenin .	Akt can inhibit GSK-3beta, therefore preventing the degradation of beta-catenin.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	3	4
On the other hand Akt inhibits GSK3beta activity and so the effect of Hsp90 inhibition on GSK3beta is not entirely clear and requires further investigation .	On the other hand Akt inhibits GSK3beta activity and so the effect of Hsp90 inhibition on GSK3beta is not entirely clear and requires further investigation.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	6	7
As a result , it is possible that Aurora-A activates Akt followed by Akt inactivation of Gsk3beta resulting in the increase of Aurora-A levels .	As a result, it is possible that Aurora-A activates Akt followed by Akt inactivation of Gsk3beta resulting in the increase of Aurora-A levels.	13	17	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Gsk3beta	Gsk3beta	Gsk3beta	13	14	16	17
Activation of AKT in tamoxifen resistant cells could thus rescue proteasomal degradation of these proteins by inhibiting GSK3beta .	Activation of AKT in tamoxifen resistant cells could thus rescue proteasomal degradation of these proteins by inhibiting GSK3beta.	0	18	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	2	3	17	18
For example , inhibition of Akt activates GSK3beta through reducing GSK3beta phosphorylation at serine 9 , whereas activation of Akt inhibits GSK3beta through enhancing phosphorylation .	For example, inhibition of Akt activates GSK3beta through reducing GSK3beta phosphorylation at serine 9, whereas activation of Akt inhibits GSK3beta through enhancing phosphorylation.	3	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	7	8
rFGF21 treatment rescued Akt activation level but reversed GSK-3beta activation status ( XREF_FIG ) , demonstrating a potent role of rFGF21 in modulating Akt and GSK-3beta signaling in the hippocampus of the HFD obese mouse model .	rFGF21 treatment rescued Akt activation level but reversed GSK-3beta activation status (XREF_FIG), demonstrating a potent role of rFGF21 in modulating Akt and GSK-3beta signaling in the hippocampus of the HFD obese mouse model.	0	10	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	rFGF21 treatment rescued Akt activation level	akt	GSK-3beta	GSK-3beta	gsk-3beta	3	4	8	9
Additionally , PAT exposure caused enhanced Akt expression , which in turn inhibits GSK-3beta and stabilizes beta-catenin .	Additionally, PAT exposure caused enhanced Akt expression, which in turn inhibits GSK-3beta and stabilizes beta-catenin.	2	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	PAT exposure caused enhanced Akt expression	akt	GSK-3beta	GSK-3beta	gsk-3beta	6	7	13	14
In PC12 cells , it was found that puerarin triggers Akt activation , which in turn inhibits GSK-3beta activation resulting in more Nrf2 nuclear translocation .	In PC12 cells, it was found that puerarin triggers Akt activation, which in turn inhibits GSK-3beta activation resulting in more Nrf2 nuclear translocation.	10	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	10	11	17	18
In our present work , we found that activation of upstream AKT signalling represses GSK-3beta activity .	In our present work, we found that activation of upstream AKT signalling represses GSK-3beta activity.	11	15	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	11	12	14	15
Thus , GSK3beta is negatively regulated by Akt via Ser9 phosphorylation , with ELL priming evoking less GSK3beta activity than FL priming .	Thus, GSK3beta is negatively regulated by Akt via Ser9 phosphorylation, with ELL priming evoking less GSK3beta activity than FL priming.	2	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	7	8	2	3
PI3K and Akt dependent inhibition of GSK3beta activity in monocytes regulates TLR dependent activation of inflammatory responses [ XREF_BIBR , XREF_BIBR ] .	PI3K and Akt dependent inhibition of GSK3beta activity in monocytes regulates TLR dependent activation of inflammatory responses [XREF_BIBR, XREF_BIBR].	0	7	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	6	7
Thus , as Akt inactivates GSK-3beta , we investigated whether GSK-3beta has a role in the CSE induced increase in IL-17R .	Thus, as Akt inactivates GSK-3beta, we investigated whether GSK-3beta has a role in the CSE induced increase in IL-17R.	3	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	5	6
MUC1-C binds directly to PI3K , promotes activation of AKT and thereby AKT mediated suppression of GSK3beta XREF_BIBR XREF_BIBR .	MUC1-C binds directly to PI3K, promotes activation of AKT and thereby AKT mediated suppression of GSK3beta XREF_BIBR XREF_BIBR.	12	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	12	13	16	17
To test if glycogen synthase kinase-3beta ( GSK3beta ) , a pro apoptotic kinase that is inhibited by Akt , is involved in regulating MPP induced apoptosis , overexpression of GSK3beta and lithium , a selective inhibitor of GSK3beta , were used to directly alter GSK3beta activity .	To test if glycogen synthase kinase-3beta (GSK3beta), a pro apoptotic kinase that is inhibited by Akt, is involved in regulating MPP induced apoptosis, overexpression of GSK3beta and lithium, a selective inhibitor of GSK3beta, were used to directly alter GSK3beta activity.	5	19	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	18	19	7	8
Akt , a serine/threonine kinase and an upstream regulator of GSK-3beta , prevents GSK-3beta activity via the phosphorylation of GSK-3beta at Ser 9 XREF_BIBR .	Akt, a serine/threonine kinase and an upstream regulator of GSK-3beta, prevents GSK-3beta activity via the phosphorylation of GSK-3beta at Ser 9 XREF_BIBR.	0	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	13	14
GSK-3beta can be negatively regulated through phosphorylation on S9 by active Akt .	GSK-3beta can be negatively regulated through phosphorylation on S9 by active Akt.	0	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	11	12	0	1
Once activated , AKT inhibits the more downstream molecule GSK3beta , preventing it from phosphorylating the cell survival molecule Mcl-1 .	Once activated, AKT inhibits the more downstream molecule GSK3beta, preventing it from phosphorylating the cell survival molecule Mcl-1.	3	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	3	4	9	10
The intracellular infection of monocytes and macrophages with Burkholderia cenocepacia , a Gram negative bacterium associated with exacerbated inflammation [ XREF_BIBR ] , caused the activation of PI3K-Akt signaling that in turn inactivated GSK3beta and enhanced NF-kappaB activity , with the subsequent production of pro inflammatory cytokines such as , TNFalpha , IL-6 and IL-8 .	The intracellular infection of monocytes and macrophages with Burkholderia cenocepacia, a Gram negative bacterium associated with exacerbated inflammation [XREF_BIBR], caused the activation of PI3K-Akt signaling that in turn inactivated GSK3beta and enhanced NF-kappaB activity, with the subsequent production of pro inflammatory cytokines such as, TNFalpha, IL-6 and IL-8.	27	34	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	GSK3beta	GSK3beta	GSK3beta	27	28	33	34
We further elucidated that enhanced Akt suppresses GSK-3beta activity , facilitating the translocation of NFATc1 ( a key transcription factor of DcR3 ) , to the nucleus , enhancing DcR3 mRNA levels .	We further elucidated that enhanced Akt suppresses GSK-3beta activity, facilitating the translocation of NFATc1 (a key transcription factor of DcR3), to the nucleus, enhancing DcR3 mRNA levels.	4	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	5	6	7	8
Akt inactivates GSK-3beta and FKHR through phosphorylation .	Akt inactivates GSK-3beta and FKHR through phosphorylation.	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	2	3
Nevertheless , most literature suggests that GSK-3beta inactivation by IGF-I and Akt signaling is not sufficient to stabilize beta-catenin or induce beta-catenin-dependent transcription [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Nevertheless, most literature suggests that GSK-3beta inactivation by IGF-I and Akt signaling is not sufficient to stabilize beta-catenin or induce beta-catenin-dependent transcription [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	12	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	11	12	6	7
Constitutive activation of PI3K and AKT signaling may inhibit GSK3beta and stabilize beta-catenin , thereby contributing to tumorigenesis [ XREF_BIBR ] .	Constitutive activation of PI3K and AKT signaling may inhibit GSK3beta and stabilize beta-catenin, thereby contributing to tumorigenesis [XREF_BIBR].	3	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	5	6	9	10
Akt can inactivate GSK3beta through Ser9 phosphorylation .	Akt can inactivate GSK3beta through Ser9 phosphorylation.	0	4	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	3	4
Interestingly , EMT is importantly regulated by GSK3beta inhibition of beta-catenin and GSK3beta is negatively regulated by AKT .	Interestingly, EMT is importantly regulated by GSK3beta inhibition of beta-catenin and GSK3beta is negatively regulated by AKT.	12	18	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	17	18	12	13
Reintroduction of PRL-1 in Huh7 and SK-hep1 HCC cell lines caused phosphorylation of AKT at ser 474 , which subsequently inactivated GSK-3beta at ser 9 and elevated transcriptional factor Snail expression .	Reintroduction of PRL-1 in Huh7 and SK-hep1 HCC cell lines caused phosphorylation of AKT at ser 474, which subsequently inactivated GSK-3beta at ser 9 and elevated transcriptional factor Snail expression.	2	22	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	PRL-1 in Huh7 and SK-hep1 HCC cell lines caused phosphorylation of AKT at ser 474	akt	GSK-3beta	GSK-3beta	gsk-3beta	13	14	21	22
The results showed that wortmannin and Akt shRNA treatment significantly reduced ( Ser473 ) p-Akt , ( Ser9 ) p-GSK-3beta , beta-catenin , c-Myc , Cyclin D1 , TCF1 , TCF4 and MMP-7 expression .	The results showed that wortmannin and Akt shRNA treatment significantly reduced (Ser473) p-Akt, (Ser9) p-GSK-3beta, beta-catenin, c-Myc, Cyclin D1, TCF1, TCF4 and MMP-7 expression.	6	33	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p-GSK-3beta	p-GSK-3beta	p-GSK-3beta	6	7	19	20
In the macrophage study , sTREM2 did not detectably increase pAKT , while in microglia , the anti-apoptotic effect was blocked with PI3K inhibitors and was mediated by AKT inhibition of GSK3-beta to increasebeta-catenin .	In the macrophage study, sTREM2 did not detectably increase pAKT, while in microglia, the anti-apoptotic effect was blocked with PI3K inhibitors and was mediated by AKT inhibition of GSK3-beta to increasebeta-catenin.	28	32	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3-beta	GSK3-beta	GSK3-beta	28	29	31	32
GSK3beta , which is in its active state under basal conditions , is inhibited through phosphorylation by Akt on S9 .	GSK3beta, which is in its active state under basal conditions, is inhibited through phosphorylation by Akt on S9.	0	19	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	17	18	0	1
Many members of the apoptotic signaling cascade are targets of AKT mediated phosphorylation and inactivation [ XREF_BIBR ] , and GSK3beta inhibition by AKT has been shown to protect both neurons [ XREF_BIBR ] and neural precursor cells from apoptosis [ XREF_BIBR ] .	Many members of the apoptotic signaling cascade are targets of AKT mediated phosphorylation and inactivation [XREF_BIBR], and GSK3beta inhibition by AKT has been shown to protect both neurons [XREF_BIBR] and neural precursor cells from apoptosis [XREF_BIBR].	20	24	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	23	24	20	21
GSK3beta activity is inhibited by AKT .	GSK3beta activity is inhibited by AKT.	0	6	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	5	6	0	1
FAK promotes the phosphorylation and activation of AKT , which in turn phosphorylates GSK-3beta on the serine 9 residue and inactivates GSK-3beta ; the latter phosphorylates beta-Catenin , driving its degradation [ XREF_BIBR ] .	FAK promotes the phosphorylation and activation of AKT, which in turn phosphorylates GSK-3beta on the serine 9 residue and inactivates GSK-3beta; the latter phosphorylates beta-Catenin, driving its degradation [XREF_BIBR].	0	22	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	FAK promotes the phosphorylation and activation of AKT	akt	GSK-3beta	GSK-3beta	gsk-3beta	7	8	21	22
Moreover , the active form of AKT deactivates GSK-3beta , which by phosphorylation of VDAC displaces HKII , promoting permanent opening of the MPTP under stressing conditions .	Moreover, the active form of AKT deactivates GSK-3beta, which by phosphorylation of VDAC displaces HKII, promoting permanent opening of the MPTP under stressing conditions.	4	15	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	6	7	8	9
ZNF281-S638A abrogated the inhibitory effect of GSK-3beta on the activity of ZNF281 whereas Akt-DD ( mutations with D ( 308 ) T and D ( 473 ) S ) , a constitutively active Akt which inactivates GSK3beta by phosphorylating GSK3beta , significantly enhanced the activity of ZNF281 .	ZNF281-S638A abrogated the inhibitory effect of GSK-3beta on the activity of ZNF281 whereas Akt-DD (mutations with D (308) T and D (473) S), a constitutively active Akt which inactivates GSK3beta by phosphorylating GSK3beta, significantly enhanced the activity of ZNF281.	13	40	inactivates	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Akt	Akt	akt	GSK3beta	phosphorylating GSK3beta	gsk3beta	33	34	39	40
Our data further suggest that GSK-3beta is inactivated by Akt , known as protein kinase B ( PKB ) , a serine/threonine kinase that is fully activated following its phosphorylation XREF_BIBR .	Our data further suggest that GSK-3beta is inactivated by Akt, known as protein kinase B (PKB), a serine/threonine kinase that is fully activated following its phosphorylation XREF_BIBR.	5	11	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	9	10	5	6
Consistent with previous studies XREF_BIBR - XREF_BIBR , we observed that DENV induced synergistic activation of PKA and PKB inhibited GSK-3beta , leading to CREB mediated IL-10 production .	Consistent with previous studies XREF_BIBR - XREF_BIBR, we observed that DENV induced synergistic activation of PKA and PKB inhibited GSK-3beta, leading to CREB mediated IL-10 production.	14	21	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	GSK-3beta	GSK-3beta	GSK-3beta	18	19	20	21
We have found that PI3K and Akt signaling inactivates GSK3beta to permit enhanced NF-kappaB activity and production of pro inflammatory cytokines following B. cenocepacia infection .	We have found that PI3K and Akt signaling inactivates GSK3beta to permit enhanced NF-kappaB activity and production of pro inflammatory cytokines following B. cenocepacia infection.	4	10	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	6	7	9	10
The data are consistent with other study in which Akt mediated GSK3beta inhibition showed an abrogate effect on cell migration in intestinal epithelium cells XREF_BIBR .	The data are consistent with other study in which Akt mediated GSK3beta inhibition showed an abrogate effect on cell migration in intestinal epithelium cells XREF_BIBR.	9	12	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	9	10	11	12
Akt deactivates GSK3beta by phosphorylation at S9 ; reduced Akt activity ( XREF_FIG ) is thus predicted to lead to decreased pGSK3beta-S9 , which would correspond to increased GSK3beta activity .	Akt deactivates GSK3beta by phosphorylation at S9; reduced Akt activity (XREF_FIG) is thus predicted to lead to decreased pGSK3beta-S9, which would correspond to increased GSK3beta activity.	0	3	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	2	3
GSK-3beta activity is inhibited by the AKT and Wnt and Hedgehog pathways , whilst GSK-3beta in turn has been found to phosphorylate several key oncogenic transcription factors as well as serine residues in the EMT marker Snai1 [ XREF_BIBR ] .	GSK-3beta activity is inhibited by the AKT and Wnt and Hedgehog pathways, whilst GSK-3beta in turn has been found to phosphorylate several key oncogenic transcription factors as well as serine residues in the EMT marker Snai1 [XREF_BIBR].	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	6	7	0	1
Importantly , GSK3beta is inactivated by AKT in response to mTORC2 signaling triggered by glucose limitation .	Importantly, GSK3beta is inactivated by AKT in response to mTORC2 signaling triggered by glucose limitation.	2	8	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	6	7	2	3
Alternatively , cyclin D1 can be regulated by promoting nuclear accumulation and stabilization through Akt phosphorylation induced inhibition of GSK-3beta .	Alternatively, cyclin D1 can be regulated by promoting nuclear accumulation and stabilization through Akt phosphorylation induced inhibition of GSK-3beta.	14	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	14	15	19	20
The activation of Akt phosphorylated and suppressed GSK-3beta , which is the major kinase for the phosphorylation of beta-catenin and Snail [ XREF_BIBR , XREF_BIBR ] .	The activation of Akt phosphorylated and suppressed GSK-3beta, which is the major kinase for the phosphorylation of beta-catenin and Snail [XREF_BIBR, XREF_BIBR].	1	13	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylated	akt	GSK-3beta	GSK-3beta	gsk-3beta	3	4	7	8
Furthermore , GSK-3beta activity is inhibited by Akt phosphorylation at Ser9 .	Furthermore, GSK-3beta activity is inhibited by Akt phosphorylation at Ser9.	2	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	7	8	2	3
Since blocking AKT-S473 phosphorylation increased GSK3beta-S9 phosphorylation and inactivation ( XREF_FIG ) , we speculated that WT AKT alone only partially inhibits GSK3beta and that AKT3 activation together with Gsk3b deletion would further increase axon regeneration .	Since blocking AKT-S473 phosphorylation increased GSK3beta-S9 phosphorylation and inactivation (XREF_FIG), we speculated that WT AKT alone only partially inhibits GSK3beta and that AKT3 activation together with Gsk3b deletion would further increase axon regeneration.	16	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	17	18	22	23
Once activated , Akt promotes the inhibition of GSK-3beta through phosphorylation on ser 9 .	Once activated, Akt promotes the inhibition of GSK-3beta through phosphorylation on ser 9.	3	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	8	9
Crosstalk between the WNT signaling pathway and other signaling pathways such as EGFR is now well established and recent data suggests that inhibition of both EGRF and beta-catenin may show some synergy for inhibition of brain cancer In addition , beta-catenin can be stabilized by inhibition of GSK3beta by AKT , downstream of CXCR4 .	Crosstalk between the WNT signaling pathway and other signaling pathways such as EGFR is now well established and recent data suggests that inhibition of both EGRF and beta-catenin may show some synergy for inhibition of brain cancer In addition, beta-catenin can be stabilized by inhibition of GSK3beta by AKT, downstream of CXCR4.	43	51	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	49	50	47	48
Akt inactivates GSK-3beta .	Akt inactivates GSK-3beta.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	2	3
Akt negatively regulates GSK3beta activity as an upstream inhibitor , thereby blocking LTD induction .	Akt negatively regulates GSK3beta activity as an upstream inhibitor, thereby blocking LTD induction.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	3	4
Hesperidin , indeed , promotes the phosphorylation of Akt , which once activated , reduces GSK-3beta activity .	Hesperidin, indeed, promotes the phosphorylation of Akt, which once activated, reduces GSK-3beta activity.	6	16	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	phosphorylation of Akt	akt	GSK-3beta	GSK-3beta	gsk-3beta	8	9	15	16
Akt negatively regulates GSK-3alpha and GSK3beta via phosphorylation at Ser 21 and Ser 9 respectively , so an increase in p-GSK levels at these sites would lead to an inhibition of its activity .	Akt negatively regulates GSK-3alpha and GSK3beta via phosphorylation at Ser 21 and Ser 9 respectively, so an increase in p-GSK levels at these sites would lead to an inhibition of its activity.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	5	6
GSK3beta is negatively regulated by Akt at serine 9 residue .	GSK3beta is negatively regulated by Akt at serine 9 residue.	0	6	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	0	1
It was therefore logical that activation of insulin and IGF -1 signaling networks through PI3K-Akt could have long-term effects on AAH ' s mRNA , and short-term effects on AAH ' s protein due to PI3K-Akt inhibition of GSK-3beta ( XREF_FIG ) .	It was therefore logical that activation of insulin and IGF -1 signaling networks through PI3K-Akt could have long-term effects on AAH 's mRNA, and short-term effects on AAH 's protein due to PI3K-Akt inhibition of GSK-3beta (XREF_FIG).	35	40	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	GSK-3beta	GSK-3beta	GSK-3beta	35	36	38	39
Thus , PI3K and Akt suppresses ERK activity but activates GSK3beta .	Thus, PI3K and Akt suppresses ERK activity but activates GSK3beta.	2	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	10	11
Because GSK-3beta activity is inhibited by Akt , Akt can upregulate PHLPP levels by suppressing GSK-3beta-dependent degradation .	Because GSK-3beta activity is inhibited by Akt, Akt can upregulate PHLPP levels by suppressing GSK-3beta-dependent degradation.	1	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	6	7	1	2
Akt directly inactivates GSK3beta , increasing Cyclin D1 which then inhibits Forkhead family transcription factors and the tumor suppressor tuberin ( TSC2 ) , reducing p27Kip levels [ XREF_BIBR ] .	Akt directly inactivates GSK3beta, increasing Cyclin D1 which then inhibits Forkhead family transcription factors and the tumor suppressor tuberin (TSC2), reducing p27Kip levels [XREF_BIBR].	0	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	3	4
Activation of Akt promotes protein synthesis by activating the mTOR complex and inhibiting GSK3beta .	Activation of Akt promotes protein synthesis by activating the mTOR complex and inhibiting GSK3beta.	0	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	13	14
In the present study , we found that silencing I2PP2A could improve tau pathologies with improvement of memory deficits through activation of PP2A and inhibition of GSK-3beta in htau mice , further studies in HEK293 and tau and N2a and tau cells demonstrate that activation of protein kinase A ( PKA ) but not Akt mediates the GSK-3beta inhibition induced by silencing I2PP2A .	In the present study, we found that silencing I2PP2A could improve tau pathologies with improvement of memory deficits through activation of PP2A and inhibition of GSK-3beta in htau mice, further studies in HEK293 and tau and N2a and tau cells demonstrate that activation of protein kinase A (PKA) but not Akt mediates the GSK-3beta inhibition induced by silencing I2PP2A.	44	58	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	54	55	57	58
Taken together , our results reveal a novel outside-in signaling pathway involving sequential activation of Src , ADP secretion , P2Y12 and P2Y1 dependent activation of PI3K and Akt , and Akt mediated inhibition of GSK-3beta , leading to stimulation of platelet spreading ( XREF_FIG ) .	Taken together, our results reveal a novel outside-in signaling pathway involving sequential activation of Src, ADP secretion, P2Y12 and P2Y1 dependent activation of PI3K and Akt, and Akt mediated inhibition of GSK-3beta, leading to stimulation of platelet spreading (XREF_FIG).	31	36	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	31	32	35	36
Increased Akt expression inhibits the catalytic activity of GSK-3 beta , which impedes cytoplasmic beta-catenin degradation [ XREF_BIBR ] .	Increased Akt expression inhibits the catalytic activity of GSK-3 beta, which impedes cytoplasmic beta-catenin degradation [XREF_BIBR].	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt expression	akt	GSK-3 beta	GSK-3 beta	gsk-3 beta	1	2	8	10
Keeping in mind that UVB and UVA , both , potently activate AKT , which downstream inhibits GSK3beta [ XREF_BIBR ] , plus the fact that AKT inhibits autophagy by mTOR activation and possibly by down-regulation of UVRAG , the data appear to be disparate .	Keeping in mind that UVB and UVA, both, potently activate AKT, which downstream inhibits GSK3beta [XREF_BIBR], plus the fact that AKT inhibits autophagy by mTOR activation and possibly by down-regulation of UVRAG, the data appear to be disparate.	11	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	12	13	17	18
Our data indicate that this effect is mediated at least in part via inhibition of GSK-3beta by Akt but not via mTORC1 activation .	Our data indicate that this effect is mediated at least in part via inhibition of GSK-3beta by Akt but not via mTORC1 activation.	7	18	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	17	18	15	16
Active Akt inhibits GSK-3beta activity via phosphorylation [ XREF_BIBR ] .	Active Akt inhibits GSK-3beta activity via phosphorylation [XREF_BIBR].	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	1	2	3	4
GSK-3beta inactivated by Akt does not inhibit the nuclear beta-catenin signaling , resulting in cell proliferation in several cancers .	GSK-3beta inactivated by Akt does not inhibit the nuclear beta-catenin signaling, resulting in cell proliferation in several cancers.	0	6	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	0	1
Inhibition of Akt signaling and activation of GSK-3beta partially contributes to the pro apoptotic effect of embelin .	Inhibition of Akt signaling and activation of GSK-3beta partially contributes to the pro apoptotic effect of embelin.	2	8	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	7	8
This effect may be exacerbated by additional secretion of Dkk1 from non epithelial cells , such as infiltrating leukocytes and platelets ( XREF_SUPPLEMENTARY ) , and the inhibition of GSK-3beta by AKT .	This effect may be exacerbated by additional secretion of Dkk1 from non epithelial cells, such as infiltrating leukocytes and platelets (XREF_SUPPLEMENTARY), and the inhibition of GSK-3beta by AKT.	17	32	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	31	32	29	30
It is noteworthy that GSK-3beta is also inhibited through phosphorylation by Akt , while Wnt7a is able to activate the Akt and mTOR pathway .	It is noteworthy that GSK-3beta is also inhibited through phosphorylation by Akt, while Wnt7a is able to activate the Akt and mTOR pathway.	4	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	11	12	4	5
This effect can be readily attributed to reductions in Akt signaling , which normally inhibits GSK-3beta via S9 phosphorylation .	This effect can be readily attributed to reductions in Akt signaling, which normally inhibits GSK-3beta via S9 phosphorylation.	9	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	9	10	15	16
Akt phosphorylation and activation is known to inhibit the function of GSK3beta , thereby inducing Snail expression [ XREF_BIBR ] .	Akt phosphorylation and activation is known to inhibit the function of GSK3beta, thereby inducing Snail expression [XREF_BIBR].	0	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	0	1	11	12
PI3K-AKT inhibits GSK3beta leading to beta-catenin stability and this potentiates Notch signal mediated D114 expression .	PI3K-AKT inhibits GSK3beta leading to beta-catenin stability and this potentiates Notch signal mediated D114 expression.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	GSK3beta	GSK3beta	GSK3beta	0	1	2	3
Importantly , Akt inhibits GSK3beta and hence plays a critical role in maintaining the balance between the activities of GSK3beta and PP2A [ XREF_BIBR ] .	Importantly, Akt inhibits GSK3beta and hence plays a critical role in maintaining the balance between the activities of GSK3beta and PP2A [XREF_BIBR].	2	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	4	5
PI3K and AKT may also mediate cardiomyocyte differentiation by canonical WNT by suppressing GSK-3beta activity .	PI3K and AKT may also mediate cardiomyocyte differentiation by canonical WNT by suppressing GSK-3beta activity.	0	14	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	2	3	13	14
Using a chemical inhibitor and genetic manipulation targeting Akt function and activity , we found that the Akt regulated suppression of GSK-3beta activity was reversed , similar to those observations in cypripedin treatment .	Using a chemical inhibitor and genetic manipulation targeting Akt function and activity, we found that the Akt regulated suppression of GSK-3beta activity was reversed, similar to those observations in cypripedin treatment.	17	22	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	17	18	21	22
As mentioned before , activated Akt not only affects mTOR , but also inhibits GSK3beta .	As mentioned before, activated Akt not only affects mTOR, but also inhibits GSK3beta.	4	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	14	15
As feedback , Akt can inhibit GSK3beta , thereby reducing the negative regulation of GSK3beta in cellular processes .	As feedback, Akt can inhibit GSK3beta, thereby reducing the negative regulation of GSK3beta in cellular processes.	3	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	6	7
However , aside from Rap1b and GSK3beta , a kinase the activity of which is negatively regulated by Akt , little is known about Akt dependent signaling pathways in platelets .	However, aside from Rap1b and GSK3beta, a kinase the activity of which is negatively regulated by Akt, little is known about Akt dependent signaling pathways in platelets.	4	22	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	18	19	6	7
Interestingly , Shimura and colleagues proposed that fractionated irradiation of HeLa or HepG2 cells evokes an Akt1 dependent DNA damage response-loop : Akt dependent inhibition of GSK3beta led to nuclear accumulation of Cyclin D1 and Cyclin D1 triggered S phase progression of cells with an enhanced amount of DNA DSBs that in turn trigger activation of DNA-PKcs , the key enzyme of cNHEJ , and finally DNA-PKcs-dependent Akt1 activation [ XREF_BIBR ] .	Interestingly, Shimura and colleagues proposed that fractionated irradiation of HeLa or HepG2 cells evokes an Akt1 dependent DNA damage response-loop : Akt dependent inhibition of GSK3beta led to nuclear accumulation of Cyclin D1 and Cyclin D1 triggered S phase progression of cells with an enhanced amount of DNA DSBs that in turn trigger activation of DNA-PKcs, the key enzyme of cNHEJ, and finally DNA-PKcs-dependent Akt1 activation [XREF_BIBR].	22	27	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	22	23	26	27
Phosphorylation of GSK3beta at Ser9 ( an AKT site that suppresses GSK3beta activity ) was strikingly elevated in KPiP compared to KP cells and substantially reduced by GDC-0941 , BYL719 , or their combinations with PD901 , while these agents had little to no effect on pGSK3beta in KP cells ( XREF_FIG ) .	Phosphorylation of GSK3beta at Ser9 (an AKT site that suppresses GSK3beta activity) was strikingly elevated in KPiP compared to KP cells and substantially reduced by GDC-0941, BYL719, or their combinations with PD901, while these agents had little to no effect on pGSK3beta in KP cells (XREF_FIG).	0	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Phosphorylation of GSK3beta at Ser9 (an AKT	akt	GSK3beta	GSK3beta	gsk3beta	7	8	11	12
Moreover , this factor activates Akt which inhibits GSK3beta , preventing Tau hyperphosporilation .	Moreover, this factor activates Akt which inhibits GSK3beta, preventing Tau hyperphosporilation.	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	8	9
GSK-3beta activity can be inhibited by AKT phosphorylation at Ser9 and beta-catenin transfers into the nucleus to activate the transcription of downstream target oncogenes such as cyclin D1 , c-Myc , MMP-2 and MMP- 7 .	GSK-3beta activity can be inhibited by AKT phosphorylation at Ser9 and beta-catenin transfers into the nucleus to activate the transcription of downstream target oncogenes such as cyclin D1, c-Myc, MMP-2 and MMP- 7.	0	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	6	7	0	1
The transcriptional activity of Snail is regulated by GSK-3beta , which is negatively regulated by PI3K and Akt .	The transcriptional activity of Snail is regulated by GSK-3beta, which is negatively regulated by PI3K and Akt.	6	18	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	17	18	8	9
Insulin induced insertion of GABA A receptors to the cell surface requires activation of AKT or PI3K , which in turn inhibits GSK-3beta ; BDNF facilitates endocytosis of GABA A receptors to reduce surface expression by PP2A mediated dephosphorylation of GABA A receptors ; in contrast , Wnt-5a , which is involved in the inhibition of GSK3beta , increases clustering of GABA A receptors on membrane surfaces .	Insulin induced insertion of GABA A receptors to the cell surface requires activation of AKT or PI3K, which in turn inhibits GSK-3beta; BDNF facilitates endocytosis of GABA A receptors to reduce surface expression by PP2A mediated dephosphorylation of GABA A receptors; in contrast, Wnt-5a, which is involved in the inhibition of GSK3beta, increases clustering of GABA A receptors on membrane surfaces.	12	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	14	15	22	23
Snail1 is phosphorylated by GSK3beta , leading to its ubiquitylation and degradation , and inhibition of GSK3beta by Akt stabilizes Snail1 , thus enhancing EMT [ XREF_BIBR , XREF_BIBR ] .	Snail1 is phosphorylated by GSK3beta, leading to its ubiquitylation and degradation, and inhibition of GSK3beta by Akt stabilizes Snail1, thus enhancing EMT [XREF_BIBR, XREF_BIBR].	14	19	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	18	19	16	17
Thus inactivation of GSK-3beta by Akt may contribute to improved survival of female ACMs .	Thus inactivation of GSK-3beta by Akt may contribute to improved survival of female ACMs.	1	6	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	5	6	3	4
These strands of evidence all support the inference that there is a strain responsive Wnt and LRP5 independent pathway in which beta-catenin is activated by PI3K and AKT mediated GSK-3beta suppression .	These strands of evidence all support the inference that there is a strain responsive Wnt and LRP5 independent pathway in which beta-catenin is activated by PI3K and AKT mediated GSK-3beta suppression.	23	30	mediated	Positive_early_activation	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	27	28	29	30
GSK3beta can also be inhibited by ERK or Akt [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	GSK3beta can also be inhibited by ERK or Akt [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	8	9	0	1
While Galphas binds to axin , leading to the release of GSK-3beta , the betagamma subunits activate AKT which inactivates GSK-3beta by phosphorylation [ XREF_BIBR ] .	While Galphas binds to axin, leading to the release of GSK-3beta, the betagamma subunits activate AKT which inactivates GSK-3beta by phosphorylation [XREF_BIBR].	16	21	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	17	18	20	21
A typical downstream effect of the AKT signaling pathway , inactivation of GSK3beta by AKT dependent phosphorylation and the subsequent stabilization of beta-catenin protein levels [ XREF_BIBR ] , was also observed in bystander cells and appeared to be important for the development of bystander response , for example via further activation of COX2 gene expression by beta-catenin-LEF1 [ XREF_BIBR ] .	A typical downstream effect of the AKT signaling pathway, inactivation of GSK3beta by AKT dependent phosphorylation and the subsequent stabilization of beta-catenin protein levels [XREF_BIBR], was also observed in bystander cells and appeared to be important for the development of bystander response, for example via further activation of COX2 gene expression by beta-catenin-LEF1 [XREF_BIBR].	10	20	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT dependent phosphorylation	akt	GSK3beta	GSK3beta	gsk3beta	14	15	12	13
The finding that DISC1 directly inhibits GSK3beta is interesting given that the common mood stabilizer drug lithium , and the schizophrenia risk gene Akt , also inhibit GSK3beta which results in activation of canonical Wnt signaling , suggesting it may be an important target in psychiatric disease .	The finding that DISC1 directly inhibits GSK3beta is interesting given that the common mood stabilizer drug lithium, and the schizophrenia risk gene Akt, also inhibit GSK3beta which results in activation of canonical Wnt signaling, suggesting it may be an important target in psychiatric disease.	16	29	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	23	24	27	28
We showed that IL-1 or STAT1 deficient THP1 macrophages failed to phosphorylate AKT or activate PDK1 in tumor cells , confirming that IL-1 mediates AKT dependent inactivation of GSK3beta in tumor cells.Finally , we showed that IL-1 , THP1 macrophages and peripheral blood monocytes failed to phosphorylate AKT and PDK1 in tumor cells expressing dnIkappaB , demonstrating that they activate AKT signaling in a NF-kappaB dependent manner .	We showed that IL-1 or STAT1 deficient THP1 macrophages failed to phosphorylate AKT or activate PDK1 in tumor cells, confirming that IL-1 mediates AKT dependent inactivation of GSK3beta in tumor cells.Finally, we showed that IL-1, THP1 macrophages and peripheral blood monocytes failed to phosphorylate AKT and PDK1 in tumor cells expressing dnIkappaB, demonstrating that they activate AKT signaling in a NF-kappaB dependent manner.	24	30	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	24	25	28	29
Expectedly , NDRG2 overexpression diminished the AKT phosphorylation at Ser473 site , and further increased GSK-3beta activity via the reduction of GSK-3beta phosphorylation at Ser9 site .	Expectedly, NDRG2 overexpression diminished the AKT phosphorylation at Ser473 site, and further increased GSK-3beta activity via the reduction of GSK-3beta phosphorylation at Ser9 site.	2	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	NDRG2 overexpression diminished the AKT phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	6	7	15	16
Akt inhibits GSK3beta activity and enhances nuclear accumulation of GATA4 .	Akt inhibits GSK3beta activity and enhances nuclear accumulation of GATA4.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	2	3
Phosphorylated AKT inactivates GSK-3beta by increasing its phosphorylation , leading to the stabilization of beta-catenin , which in turn is required for Yap mediated proliferation .	Phosphorylated AKT inactivates GSK-3beta by increasing its phosphorylation, leading to the stabilization of beta-catenin, which in turn is required for Yap mediated proliferation.	0	4	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	AKT	Phosphorylated AKT	akt	GSK-3beta	GSK-3beta	gsk-3beta	1	2	3	4
BDNF binds to tyrosine kinase receptor B to activate PI3K and Akt , which subsequently phosphorylates the N-terminal serine of GSK-3beta and thus inhibits GSK-3beta activity .	BDNF binds to tyrosine kinase receptor B to activate PI3K and Akt, which subsequently phosphorylates the N-terminal serine of GSK-3beta and thus inhibits GSK-3beta activity.	0	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	BDNF binds to tyrosine kinase receptor B to activate PI3K and Akt, which subsequently phosphorylates the N-terminal serine of GSK-3beta	akt	GSK-3beta	GSK-3beta	gsk-3beta	11	12	24	25
For example , EGFR activated PI3K and AKT leads to phosphorylation and subsequently inhibition of the beta-catenin suppressor GSK3beta , resulting in nuclear accumulation of beta-catenin [ XREF_BIBR ] .	For example, EGFR activated PI3K and AKT leads to phosphorylation and subsequently inhibition of the beta-catenin suppressor GSK3beta, resulting in nuclear accumulation of beta-catenin [XREF_BIBR].	5	19	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	7	8	18	19
Oxidative stress induces PI3K and Akt dependent inhibition of GSK3beta activity in monocytes .	Oxidative stress induces PI3K and Akt dependent inhibition of GSK3beta activity in monocytes.	3	10	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	9	10
Activation of Akt also inhibits GSK-3beta and pro apoptosis members of the Bcl-2 protein family such as Bad and Bim , thereby inhibiting mPTP opening .	Activation of Akt also inhibits GSK-3beta and pro apoptosis members of the Bcl-2 protein family such as Bad and Bim, thereby inhibiting mPTP opening.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	5	6
The enzyme Akt inactivates GSK3beta through the phosphorylation of serine 9 [ XREF_BIBR ] and thereby regulates p105 processing to generate the p50 subunit .	The enzyme Akt inactivates GSK3beta through the phosphorylation of serine 9 [XREF_BIBR] and thereby regulates p105 processing to generate the p50 subunit.	0	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	4	5
It is known that activation of the FGF and EGF receptors , FGFR and EGFR , respectively , could both lead to the activation of the PI3K and Akt pathway that negatively regulates GSK3beta XREF_BIBR .	It is known that activation of the FGF and EGF receptors, FGFR and EGFR, respectively, could both lead to the activation of the PI3K and Akt pathway that negatively regulates GSK3beta XREF_BIBR.	26	34	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	28	29	33	34
Constitutive expression of active PKB can prolong the half-life of cyclin D , while pharmacological inhibition of PI3K speeds up cyclin D1 degradation , indicating that PKB mediated GSK-3beta inhibition can stabilize cyclin D1 [ XREF_BIBR ] .	Constitutive expression of active PKB can prolong the half-life of cyclin D, while pharmacological inhibition of PI3K speeds up cyclin D1 degradation, indicating that PKB mediated GSK-3beta inhibition can stabilize cyclin D1 [XREF_BIBR].	26	29	mediated	Positive_early_activation	Negative_activation	Negative_activation	PKB	PKB	PKB	GSK-3beta	GSK-3beta	GSK-3beta	26	27	28	29
Hence , we focused our attention to Akt , which is known to inactivate GSK3beta through its S9 phosphorylation .	Hence, we focused our attention to Akt, which is known to inactivate GSK3beta through its S9 phosphorylation.	3	15	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	7	8	14	15
Some GPCRs act through Gq and/or Gi proteins activating PKB ( protein kinase B )/Akt which inhibits GSK-3beta via phosphorylation .	Some GPCRs act through Gq and/or Gi proteins activating PKB (protein kinase B)/Akt which inhibits GSK-3beta via phosphorylation.	8	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	GSK-3beta	GSK-3beta	GSK-3beta	9	10	17	18
We have previously shown that strain prevents adipogenesis in marrow derived stem cells in a signaling process that culminates in increased nuclear beta-catenin , whereby GSK3beta is inactivated through phosphorylation by Akt .	We have previously shown that strain prevents adipogenesis in marrow derived stem cells in a signaling process that culminates in increased nuclear beta-catenin, whereby GSK3beta is inactivated through phosphorylation by Akt.	25	32	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	31	32	25	26
c-MYC stability is afforded by IKKepsilon mediated Akt activation , which leads to phosphorylation mediated inhibition of GSK3beta , and , in turn , promotes nuclear-retention and increase in overall transcriptional activity ( XREF_FIG ) .	c-MYC stability is afforded by IKKepsilon mediated Akt activation, which leads to phosphorylation mediated inhibition of GSK3beta, and, in turn, promotes nuclear-retention and increase in overall transcriptional activity (XREF_FIG).	5	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	IKKepsilon mediated Akt	akt	GSK3beta	GSK3beta	gsk3beta	7	8	17	18
27 Activation of Akt and subsequent phosphorylatory inhibition of GSK-3beta increases axonal outgrowth of dorsal root ganglial neurons .	27 Activation of Akt and subsequent phosphorylatory inhibition of GSK-3beta increases axonal outgrowth of dorsal root ganglial neurons.	3	10	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	9	10
Addition of ubiquitin to the media of cardiomyocytes undergoing beta-adrenergic receptor inhibited apoptosis , JNK activation , and cytochrome c release ; further PI3K activation was required [ XREF_BIBR ] , since PI3K activates Akt , which directly inhibits GSK3beta .	Addition of ubiquitin to the media of cardiomyocytes undergoing beta-adrenergic receptor inhibited apoptosis, JNK activation, and cytochrome c release; further PI3K activation was required [XREF_BIBR], since PI3K activates Akt, which directly inhibits GSK3beta.	33	40	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	34	35	39	40
In addition , IR downregulates PTEN to activate the PI3K and Akt pathway , which then inactivates GSK3beta to increase Snail expression and induce EMT [ XREF_BIBR ] .	In addition, IR downregulates PTEN to activate the PI3K and Akt pathway, which then inactivates GSK3beta to increase Snail expression and induce EMT [XREF_BIBR].	9	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	11	12	17	18
Considering that SREBP is also regulated by the Fbw7 and GSK3beta pathway and that AKT associated phosphorylation suppresses GSK3beta , we thus tested whether BI2536 also affects the activation of GSK3beta .	Considering that SREBP is also regulated by the Fbw7 and GSK3beta pathway and that AKT associated phosphorylation suppresses GSK3beta, we thus tested whether BI2536 also affects the activation of GSK3beta.	14	19	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	14	15	18	19
Inactivation of GSK-3beta by phosphorylation at serine 9 and activation of PI3K and Akt , MAPK and ERK and beta-catenin was associated with increased cell proliferation and apoptosis evasion during stepwise evolution of HBP carcinomas .	Inactivation of GSK-3beta by phosphorylation at serine 9 and activation of PI3K and Akt, MAPK and ERK and beta-catenin was associated with increased cell proliferation and apoptosis evasion during stepwise evolution of HBP carcinomas.	0	14	Inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	phosphorylation at serine 9 and activation of PI3K and Akt	akt	GSK-3beta	GSK-3beta	gsk-3beta	13	14	2	3
GSK3beta is constitutively active , but can be inactivated through the phosphorylation of a single residue at serine 9 by AKT .	GSK3beta is constitutively active, but can be inactivated through the phosphorylation of a single residue at serine 9 by AKT.	0	21	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	20	21	0	1
The increased mitochondrial respiratory function correlated with the inhibition of GSK3beta by AKT .	The increased mitochondrial respiratory function correlated with the inhibition of GSK3beta by AKT.	5	13	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	12	13	10	11
16 Activation of AKT results in GSK3beta phosphorylation , thereby inhibiting the normal function of GSK3beta in destabilizing c-MYC via phosphorylation at Thr58 .	16 Activation of AKT results in GSK3beta phosphorylation, thereby inhibiting the normal function of GSK3beta in destabilizing c-MYC via phosphorylation at Thr58.	1	16	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	3	4	15	16
ECT , as a marked inducer of stress , induces increased hippocampal Glu concentration , while Glu excites the ionotropic receptor GluR , therefore , inhibiting the Akt signaling pathway , decreasing the activity of Akt , weakening the inhibition of GSK-3beta by Akt , increasing the activity of GSK-3beta , increasing hippocampal protein Tau phosphorylation , decreasing axonal transport efficiency , impairing neural signal transmission and causing neuron apoptosis or death , leading to the learning and memory impairment .	ECT, as a marked inducer of stress, induces increased hippocampal Glu concentration, while Glu excites the ionotropic receptor GluR, therefore, inhibiting the Akt signaling pathway, decreasing the activity of Akt, weakening the inhibition of GSK-3beta by Akt, increasing the activity of GSK-3beta, increasing hippocampal protein Tau phosphorylation, decreasing axonal transport efficiency, impairing neural signal transmission and causing neuron apoptosis or death, leading to the learning and memory impairment.	37	44	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	43	44	41	42
Akt also phosphorylates Ser9 in GSK3beta to inhibit GSK3beta .	Akt also phosphorylates Ser9 in GSK3beta to inhibit GSK3beta.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	8	9
Akt over-expression would be predicted to repress Gsk3beta resulting in increased beta-catenin and NFAT activity while over-expression of c-Myc would be expected to have less effect as many parallel pathways would still down-regulated in response to increased Gsk3beta activity .	Akt over-expression would be predicted to repress Gsk3beta resulting in increased beta-catenin and NFAT activity while over-expression of c-Myc would be expected to have less effect as many parallel pathways would still down-regulated in response to increased Gsk3beta activity.	0	8	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt over-expression	akt	Gsk3beta	Gsk3beta	gsk3beta	0	1	7	8
We hypothesized that PI3K and Akt signaling after G-CSFR stimulation inhibits GSK-3beta activity , conferring neuroprotection via anti-apoptotic signaling .	We hypothesized that PI3K and Akt signaling after G-CSFR stimulation inhibits GSK-3beta activity, conferring neuroprotection via anti-apoptotic signaling.	3	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	5	6	11	12
We previously showed the upstream role of GSK-3beta in SHP2 inhibition [ XREF_BIBR ] , and , in gastric AGS cells , PI3K and AKT induced GSK-3beta inactivation might trigger SHP2 activation for IFN-gamma resistance [ XREF_BIBR ] .	We previously showed the upstream role of GSK-3beta in SHP2 inhibition [XREF_BIBR], and, in gastric AGS cells, PI3K and AKT induced GSK-3beta inactivation might trigger SHP2 activation for IFN-gamma resistance [XREF_BIBR].	22	27	induced	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	24	25	26	27
The enhanced GSK3beta activities were supported by the concurrently decreased AKT and mTOR activities .	The enhanced GSK3beta activities were supported by the concurrently decreased AKT and mTOR activities.	2	13	supported	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	10	11	2	3
GSK-3beta is involved in tau phosphorylation and is inhibited by Akt .	GSK-3beta is involved in tau phosphorylation and is inhibited by Akt.	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	10	11	0	1
However , it remains to be tested whether the mechanism of GSK3beta inhibition by PI3K and Akt is also similar , as the nature of B. cenocepacia versus B. pseudomallei infection is quite different .	However, it remains to be tested whether the mechanism of GSK3beta inhibition by PI3K and Akt is also similar, as the nature of B. cenocepacia versus B. pseudomallei infection is quite different.	11	17	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	16	17	11	12
The RAS-RAF-MEK pathway activates ERK-p90RSK , which phosphorylates CREB at Ser133 and MITF at Ser73 and Ser409 XREF_BIBR and promotes melanogenesis , whereas AKT inhibits the MITF activating kinase GSK-3 beta and downregulates melanogenesis XREF_BIBR .	The RAS-RAF-MEK pathway activates ERK-p90RSK, which phosphorylates CREB at Ser133 and MITF at Ser73 and Ser409 XREF_BIBR and promotes melanogenesis, whereas AKT inhibits the MITF activating kinase GSK-3 beta and downregulates melanogenesis XREF_BIBR.	23	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK-3 beta	GSK-3 beta	GSK-3 beta	23	24	29	31
As several studies have reported an association between GSK-3beta and NF-kappaB activity [ XREF_BIBR ] , we might speculate that PPAR-delta activation phosphorylates , and hence , activates the Akt pathway , which in turn phosphorylates , and hence , inhibits GSK-3beta , presumably resulting in the inhibition of NF-kappaB and , in turn , NF-kappaB-dependent proinflammatory gene transcription .	As several studies have reported an association between GSK-3beta and NF-kappaB activity [XREF_BIBR], we might speculate that PPAR-delta activation phosphorylates, and hence, activates the Akt pathway, which in turn phosphorylates, and hence, inhibits GSK-3beta, presumably resulting in the inhibition of NF-kappaB and, in turn, NF-kappaB-dependent proinflammatory gene transcription.	29	42	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	29	30	41	42
The above data suggested that AKT inhibition mediates GSK3beta activation , leading to p65 translocation and PUMA induction by idelalisib .	The above data suggested that AKT inhibition mediates GSK3beta activation, leading to p65 translocation and PUMA induction by idelalisib.	5	9	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	5	6	8	9
FOXO proteins are inactivated by the PI3k-Akt and PKB pathway in response to hormonal signaling .	FOXO proteins are inactivated by the PI3k-Akt and PKB pathway in response to hormonal signaling.	0	9	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3k-Akt	PI3k-Akt	PI3k-Akt	FOXO	FOXO	FOXO	6	7	0	1
Other major branches include the GSK3 ( glycogen synthase kinase 3 ) pathway , which promotes cell proliferation via Myc and Cyclin-D ( CCND ) activation ; and the FoxO ( forkhead box O ) pathway , which promotes apoptosis and is negatively regulated by AKT .	Other major branches include the GSK3 (glycogen synthase kinase 3) pathway, which promotes cell proliferation via Myc and Cyclin-D (CCND) activation; and the FoxO (forkhead box O) pathway, which promotes apoptosis and is negatively regulated by AKT.	29	46	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	45	46	29	30
This genetic alteration increases the catalytic activity of PI3K , activating the downstream oncokinase AKT that in turn inactivates FOXO supporting the hypothesis that LOM612 mediates part of its cytotoxic effect through FOXO .	This genetic alteration increases the catalytic activity of PI3K, activating the downstream oncokinase AKT that in turn inactivates FOXO supporting the hypothesis that LOM612 mediates part of its cytotoxic effect through FOXO.	10	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	14	15	19	20
Moreover , the mechanism for this prevention involves Akt mediated inhibition of the FoxO family of transcription factors [ XREF_BIBR , XREF_BIBR ] .	Moreover, the mechanism for this prevention involves Akt mediated inhibition of the FoxO family of transcription factors [XREF_BIBR, XREF_BIBR].	8	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	8	9	13	14
Studies have suggested that PI3K mediated Akt activation in mammals negatively regulates the Forkhead box class O ( FoxO ) subfamily of Forkhead transcription factors XREF_BIBR , XREF_BIBR .	Studies have suggested that PI3K mediated Akt activation in mammals negatively regulates the Forkhead box class O (FoxO) subfamily of Forkhead transcription factors XREF_BIBR, XREF_BIBR.	4	20	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	PI3K mediated Akt	akt	FoxO	FoxO	foxo	6	7	18	19
However , as discussed previously , constitutive levels of Akt also repress the activity of FoxO family members .	However, as discussed previously, constitutive levels of Akt also repress the activity of FoxO family members.	7	17	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	levels of Akt	akt	FoxO	FoxO	foxo	9	10	15	16
In addition , we demonstrate that the positive effect of V1aR overexpression in muscle homeostasis involves Akt mediated inhibition of FoxO transcription factors .	In addition, we demonstrate that the positive effect of V1aR overexpression in muscle homeostasis involves Akt mediated inhibition of FoxO transcription factors.	16	22	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	16	17	20	21
The molecular mechanism for cell cycle arrest was shown to be dependent on increased Akt activation via overexpression of PRL-3 , followed by negative feedback regulation of the PI3K and Akt pathway and subsequent transcription of growth arresting genes ( specifically Foxo , p21 , and p27 ) ( XREF_FIG ) .	The molecular mechanism for cell cycle arrest was shown to be dependent on increased Akt activation via overexpression of PRL-3, followed by negative feedback regulation of the PI3K and Akt pathway and subsequent transcription of growth arresting genes (specifically Foxo, p21, and p27) (XREF_FIG).	14	46	arresting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	14	15	41	42
Akt phosphorylated at S473 inhibits FoxO in non proliferative senescent cells and there appears to be waves of activation and inactivation cycles between Akt , mTOR complexes , autophagy , and FoxO in such cells to keep the survival of the cells intact .	Akt phosphorylated at S473 inhibits FoxO in non proliferative senescent cells and there appears to be waves of activation and inactivation cycles between Akt, mTOR complexes, autophagy, and FoxO in such cells to keep the survival of the cells intact.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylated at S473	akt	FoxO	FoxO	foxo	0	1	5	6
Active AKT complex phosphorylates and thereby inactivates the DAF-16 and FOXO transcription factor .	Active AKT complex phosphorylates and thereby inactivates the DAF-16 and FOXO transcription factor.	1	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	1	2	10	11
Roy et al demonstrated that inhibition of the PI3K and AKT and MAPK and ERK pathways in PC induces the activation of FOXO transcription factor , leading to cell cycle arrest and apoptosis .	Roy et al demonstrated that inhibition of the PI3K and AKT and MAPK and ERK pathways in PC induces the activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis.	5	24	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	10	11	22	23
This regulation is conserved , because mammalian AKT and SGK also directly phosphorylate and negatively regulate FOXO proteins [ XREF_BIBR ] .	This regulation is conserved, because mammalian AKT and SGK also directly phosphorylate and negatively regulate FOXO proteins [XREF_BIBR].	6	17	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	7	8	16	17
Consistent with a role for FOXO factors in opposing cell cycle progression , Akt dependent inactivation of FOXO transcription factors is important for optimal B cell proliferation in response to lipopolysaccharide .	Consistent with a role for FOXO factors in opposing cell cycle progression, Akt dependent inactivation of FOXO transcription factors is important for optimal B cell proliferation in response to lipopolysaccharide.	13	19	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	13	14	17	18
AKT inhibitor ( AKT Inh-IV ) and MEK1/2 inhibitor ( PD98059 ) synergistically induced FOXO transcriptional activity in AsPC-1 and PANC-1 cells ( XREF_FIG ) .	AKT inhibitor (AKT Inh-IV) and MEK1/2 inhibitor (PD98059) synergistically induced FOXO transcriptional activity in AsPC-1 and PANC-1 cells (XREF_FIG).	3	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	3	4	14	15
16 Then , mTORC2 phosphorylates Akt on Ser473 , which inactivates the FoxO proteins that positively regulate Foxp3 expression .	16 Then, mTORC2 phosphorylates Akt on Ser473, which inactivates the FoxO proteins that positively regulate Foxp3 expression.	3	19	inactivates	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Akt	mTORC2 phosphorylates Akt on Ser473	akt	FoxO	FoxO proteins that positively regulate Foxp3 expression	foxo	5	6	12	13
The FOXO transcription factor family ( FOXO1 , 3 , 4 and 6 ) is negatively regulated by the insulin pathway in an AKT dependent manner .	The FOXO transcription factor family (FOXO1, 3, 4 and 6) is negatively regulated by the insulin pathway in an AKT dependent manner.	1	25	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	23	24	1	2
Moreover , the transient inhibition of Akt activity could activate a FoxO related feedback , resulting in upregulation of receptor tyrosine kinase ( RTK ) expression and further sensitizing the malignant cells to multiple growth factors [ XREF_BIBR ] .	Moreover, the transient inhibition of Akt activity could activate a FoxO related feedback, resulting in upregulation of receptor tyrosine kinase (RTK) expression and further sensitizing the malignant cells to multiple growth factors [XREF_BIBR].	6	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	6	7	11	12
According to these findings , AKT inhibits FOXO which in turn activates HER3 that leads to an activation of the mTOR pathway .	According to these findings, AKT inhibits FOXO which in turn activates HER3 that leads to an activation of the mTOR pathway.	5	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	5	6	7	8
Hence , inducible overexpression of active Akt soon after blood ingestion would be available to repress FOXO dependent antioxidants , including mitochondrial MnSOD , allowing a rise in damaging mitochondrial RNOS XREF_BIBR , XREF_BIBR .	Hence, inducible overexpression of active Akt soon after blood ingestion would be available to repress FOXO dependent antioxidants, including mitochondrial MnSOD, allowing a rise in damaging mitochondrial RNOS XREF_BIBR, XREF_BIBR.	3	18	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	overexpression of active Akt	akt	FOXO	FOXO	foxo	6	7	16	17
45 Akt also inhibits the evolutionarily conserved Forkhead family of transcription factors FoxO , which induces very diverse responses , including apoptosis initiated by activation of the Bcl-2 family member Bim .	45 Akt also inhibits the evolutionarily conserved Forkhead family of transcription factors FoxO, which induces very diverse responses, including apoptosis initiated by activation of the Bcl-2 family member Bim.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	1	2	12	13
In this way , Akt prevents FOXO induced target gene transcription that promotes apoptosis , cell-cycle arrest , and metabolic processes .	In this way, Akt prevents FOXO induced target gene transcription that promotes apoptosis, cell-cycle arrest, and metabolic processes.	4	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	4	5	6	7
It is known that myostatin can inhibit Akt phosphorylation and induce FoxO transcriptional activity in skeletal muscle and that myostatin is able to decrease protein synthesis via P70S6K in C2C12 cells .	It is known that myostatin can inhibit Akt phosphorylation and induce FoxO transcriptional activity in skeletal muscle and that myostatin is able to decrease protein synthesis via P70S6K in C2C12 cells.	4	13	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	myostatin can inhibit Akt phosphorylation	akt	FoxO	FoxO	foxo	7	8	11	12
This is not surprising as part of the normal function of activated AKT is to inhibit FOXO family members ( including FOXO1 and FOXO3a ) by direct phosphorylation , which facilitates their export from the nucleus and ubiquitination and proteosome mediated degradation in the cytoplasm .	This is not surprising as part of the normal function of activated AKT is to inhibit FOXO family members (including FOXO1 and FOXO3a) by direct phosphorylation, which facilitates their export from the nucleus and ubiquitination and proteosome mediated degradation in the cytoplasm.	9	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	12	13	16	17
The role of PI3Kdelta signaling in these cell fate decisions is not known , although it has been proposed that FOXO transcription factors , which are inhibited by PI3K-Akt signaling , may oppose the effects of Notch signaling .	The role of PI3Kdelta signaling in these cell fate decisions is not known, although it has been proposed that FOXO transcription factors, which are inhibited by PI3K-Akt signaling, may oppose the effects of Notch signaling.	20	29	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FOXO	FOXO	FOXO	28	29	20	21
Thus , our studies suggest that inhibition of ERK and AKT pathways act together to activate FOXO transcription factors which are involved in resveratrol mediated pancreatic tumor growth suppression .	Thus, our studies suggest that inhibition of ERK and AKT pathways act together to activate FOXO transcription factors which are involved in resveratrol mediated pancreatic tumor growth suppression.	8	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	10	11	16	17
Consistent with the FOXO downregulation by AKT activation , the expression level of the FOXO target gene TRAIL was lower in ST1-N6 than in ST1 cells .	Consistent with the FOXO downregulation by AKT activation, the expression level of the FOXO target gene TRAIL was lower in ST1-N6 than in ST1 cells.	3	7	downregulation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	6	7	3	4
Thus , AKT inhibition will result in activation of FOXO dependent transcription of receptors and inhibition of S6K dependent inhibition of signaling with resultant activation of multiple receptors .	Thus, AKT inhibition will result in activation of FOXO dependent transcription of receptors and inhibition of S6K dependent inhibition of signaling with resultant activation of multiple receptors.	2	11	result in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	2	3	9	10
It has been shown that activation of the PI3-kinase pathway leads to an Akt dependent inactivation of FoxO transcription factors resulting in a reduced DNA binding such as to the eNOS promoter XREF_BIBR , XREF_BIBR , XREF_BIBR .	It has been shown that activation of the PI3-kinase pathway leads to an Akt dependent inactivation of FoxO transcription factors resulting in a reduced DNA binding such as to the eNOS promoter XREF_BIBR, XREF_BIBR, XREF_BIBR.	13	19	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	13	14	17	18
XREF_BIBR , XREF_BIBR Furthermore , Akt family members phosphorylate and inhibit the transcriptional activity of FoxO proteins .	XREF_BIBR, XREF_BIBR Furthermore, Akt family members phosphorylate and inhibit the transcriptional activity of FoxO proteins.	5	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	5	6	15	16
This observation led to the discovery that FoxO transcriptional activity is inhibited by PI3K-Akt signaling whereby PI3K phosphorylation causes Akt to translocate to the nucleus , where it phosphorylates FoxO ( Thr24 , Ser256 , Ser319 of FoxO1 ; Thr32 , Ser253 , Ser315 of FoxO3 ) .	This observation led to the discovery that FoxO transcriptional activity is inhibited by PI3K-Akt signaling whereby PI3K phosphorylation causes Akt to translocate to the nucleus, where it phosphorylates FoxO (Thr24, Ser256, Ser319 of FoxO1; Thr32, Ser253, Ser315 of FoxO3).	7	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FoxO	FoxO	FoxO	13	14	7	8
Akt and PKB inhibits FoxO transcription factors via a well established and evolutionarily conserved mechanism involving phosphorylation of FoxO at three sites that lie within conserved RxRxxS/T motifs .	Akt and PKB inhibits FoxO transcription factors via a well established and evolutionarily conserved mechanism involving phosphorylation of FoxO at three sites that lie within conserved RxRxxS/T motifs.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	0	1	4	5
While FoxO is blocked by Akt , the other mediators are activated in response to pro inflammatory molecules .	While FoxO is blocked by Akt, the other mediators are activated in response to pro inflammatory molecules.	1	6	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	5	6	1	2
Inhibition of PI3K and AKT and MEK and ERK pathways synergistically and additively induces FOXO transcriptional activity and apoptosis in the presence or absence of sulforaphane .	Inhibition of PI3K and AKT and MEK and ERK pathways synergistically and additively induces FOXO transcriptional activity and apoptosis in the presence or absence of sulforaphane.	0	16	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	4	5	14	15
Specifically , mTOR and Akt activation inhibits the Foxo family of transcription factors leading to decreased expression of kruppel like factor 2 ( KLF2 ) , which in turn leads to the reduced expression of CD62L , the IL-7 receptor , and CCR7 .	Specifically, mTOR and Akt activation inhibits the Foxo family of transcription factors leading to decreased expression of kruppel like factor 2 (KLF2), which in turn leads to the reduced expression of CD62L, the IL-7 receptor, and CCR7.	2	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	4	5	8	9
In conclusion , we have demonstrated that inhibition of PI3K and AKT and Ras/MEK/ERK pathways interact synergistically to activate FOXO transcription factors which , in turn , inhibit angiogenesis .	In conclusion, we have demonstrated that inhibition of PI3K and AKT and Ras/MEK/ERK pathways interact synergistically to activate FOXO transcription factors which, in turn, inhibit angiogenesis.	7	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	11	12	19	20
However , when Akt inhibition in aged muscle allows FOXO to translocate , the expression of atrophy related genes such as atrogin-1 and MuRF-1 is enhanced [ XREF_BIBR ] .	However, when Akt inhibition in aged muscle allows FOXO to translocate, the expression of atrophy related genes such as atrogin-1 and MuRF-1 is enhanced [XREF_BIBR].	3	11	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	3	4	9	10
Moreover , the mechanism for this inhibition involves Akt mediated inhibition of the FoxO family of transcription factors ; a mutant form of FOXO1 , which prevents Akt phosphorylation , thereby prevents Akt mediated inhibition of MuRF1 and MAFbx upregulation .	Moreover, the mechanism for this inhibition involves Akt mediated inhibition of the FoxO family of transcription factors; a mutant form of FOXO1, which prevents Akt phosphorylation, thereby prevents Akt mediated inhibition of MuRF1 and MAFbx upregulation.	8	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	8	9	13	14
Activation of Akt suppresses FOXO transcription factor mediated growth arrest and apoptosis in various cancers .	Activation of Akt suppresses FOXO transcription factor mediated growth arrest and apoptosis in various cancers.	0	6	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	2	3	4	5
Akt phosphorylates and inhibits the transcriptional activity of FoxO at least in part by promoting its exclusion from the nucleus .	Akt phosphorylates and inhibits the transcriptional activity of FoxO at least in part by promoting its exclusion from the nucleus.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	0	1	8	9
These data suggest that inhibition of AKT activity by overexpression of PTEN enhances FOXO transcriptional activity .	These data suggest that inhibition of AKT activity by overexpression of PTEN enhances FOXO transcriptional activity.	6	15	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	6	7	13	14
To the best of our knowledge , this is the first study to demonstrate that inhibition of PI3K and AKT and MEK and ERK pathways acted synergistically to induce activation of FOXO transcription factors and enhanced the anti-angiogenic effects of resveratrol in HUVEC cells .	To the best of our knowledge, this is the first study to demonstrate that inhibition of PI3K and AKT and MEK and ERK pathways acted synergistically to induce activation of FOXO transcription factors and enhanced the anti-angiogenic effects of resveratrol in HUVEC cells.	15	33	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	19	20	31	32
AKT negatively regulates the FoxO proteins , which target expression of several anti-oxidant enzymes , including the GPx , catalase ( CAT ) and SODs .	AKT negatively regulates the FoxO proteins, which target expression of several anti-oxidant enzymes, including the GPx, catalase (CAT) and SODs.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	0	1	4	5
Under normal conditions of growth factor signalling , FoxO transcription factors are inactivated through phosphorylation by activated AKT .	Under normal conditions of growth factor signalling, FoxO transcription factors are inactivated through phosphorylation by activated AKT.	8	18	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	17	18	8	9
Bim is a known transcriptional target of FOXO transcription factors , which are negatively regulated by AKT .	Bim is a known transcriptional target of FOXO transcription factors, which are negatively regulated by AKT.	7	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	16	17	7	8
Because Akt inhibits the transcriptional activity of FoxO proteins , we investigated the possible roles of FoxO proteins in maternal diabetes induced apoptosis .	Because Akt inhibits the transcriptional activity of FoxO proteins, we investigated the possible roles of FoxO proteins in maternal diabetes induced apoptosis.	1	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	1	2	7	8
Akt activation promotes FOXO protein degradation .	Akt activation promotes FOXO protein degradation.	0	5	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	0	1	3	4
For example , inhibition of RTKs , PI3K or Akt induces the expression and activation of multiple RTKs by relieving mTORC1 feedback suppression of RTKs and stimulating FOXO dependent activation of RTK expression [ XREF_BIBR - XREF_BIBR ] .	For example, inhibition of RTKs, PI3K or Akt induces the expression and activation of multiple RTKs by relieving mTORC1 feedback suppression of RTKs and stimulating FOXO dependent activation of RTK expression [XREF_BIBR - XREF_BIBR].	3	29	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	9	10	27	28
Akt negatively regulates FOXO transcription factors by promoting proteosomal degradation and the nuclear exclusion of FOXO proteins .	Akt negatively regulates FOXO transcription factors by promoting proteosomal degradation and the nuclear exclusion of FOXO proteins.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	0	1	3	4
FoxO proteins are inactivated through the phosphorylation by Akt .	FoxO proteins are inactivated through the phosphorylation by Akt.	0	9	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	8	9	0	1
In the presence of growth factors , AKT negatively regulates FOXO proteins by phosphorylating them XREF_BIBR , XREF_BIBR , which results in their binding to 14-3-3 proteins and is followed by their nuclear export XREF_BIBR .	In the presence of growth factors, AKT negatively regulates FOXO proteins by phosphorylating them XREF_BIBR, XREF_BIBR, which results in their binding to 14-3-3 proteins and is followed by their nuclear export XREF_BIBR.	7	29	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	7	8	10	11
reported that the suppression of the PI3K and AKT and MEK and ERK pathways activated foxo transcription factors , leading to cell cycle arrest and apoptosis in pancreatic cancer .	reported that the suppression of the PI3K and AKT and MEK and ERK pathways activated foxo transcription factors, leading to cell cycle arrest and apoptosis in pancreatic cancer.	3	17	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	foxo	foxo	foxo	8	9	15	16
Notably , Akt and mTOR activation combined with PKD/CAMKII/AMPK inactivation by the obestatin signalling is required to inhibit FoxO dependent atrogenes and autophagy in human muscle cells .	Notably, Akt and mTOR activation combined with PKD/CAMKII/AMPK inactivation by the obestatin signalling is required to inhibit FoxO dependent atrogenes and autophagy in human muscle cells.	2	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	2	3	18	19
In fact , it has been shown that AKT can inhibit FOXO activity , potentially acting as an anti-atrophic agent per se [ XREF_BIBR ] .	In fact, it has been shown that AKT can inhibit FOXO activity, potentially acting as an anti-atrophic agent per se [XREF_BIBR].	8	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	8	9	11	12
Thus , Akt accelerates cell senescence by inhibiting FoxO activity , resulting in increased ROS production .	Thus, Akt accelerates cell senescence by inhibiting FoxO activity, resulting in increased ROS production.	2	9	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	2	3	8	9
FoxO proteins are inactivated through the phosphorylation of Thr24 , S256 , and S319 in FoxO1 and that of Thr32 , S253 , and S315 in FoxO3 by Akt , and are activated through the phosphorylation of S212 in FoxO1 and S207 in FoxO3a by Mst1 , and Akt and Mst1 are activated by phosphorylation [ XREF_BIBR ] ( XREF_FIG ) .	FoxO proteins are inactivated through the phosphorylation of Thr24, S256, and S319 in FoxO1 and that of Thr32, S253, and S315 in FoxO3 by Akt, and are activated through the phosphorylation of S212 in FoxO1 and S207 in FoxO3a by Mst1, and Akt and Mst1 are activated by phosphorylation [XREF_BIBR] (XREF_FIG).	0	29	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	28	29	0	1
Akt dependent phosphorylation negatively regulates the ability of FoxO by inducing nuclear exclusion .	Akt dependent phosphorylation negatively regulates the ability of FoxO by inducing nuclear exclusion.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	FoxO	FoxO	foxo	0	1	8	9
The inhibition of PI3K and AKT pathway induced FOXO transcriptional activity resulting in induction of Bim , TRAIL , p27 and KIP1 , DR4 and DR5 , and inhibition of cyclin D1 [ XREF_BIBR ] .	The inhibition of PI3K and AKT pathway induced FOXO transcriptional activity resulting in induction of Bim, TRAIL, p27 and KIP1, DR4 and DR5, and inhibition of cyclin D1 [XREF_BIBR].	3	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	5	6	8	9
Furthermore , FOXO dependent apoptosis , which is inhibited by Akt , was augmented in the rictor-null background , indicating that rictor is essential for the Akt-FOXO signaling module .	Furthermore, FOXO dependent apoptosis, which is inhibited by Akt, was augmented in the rictor-null background, indicating that rictor is essential for the Akt-FOXO signaling module.	2	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	10	11	2	3
In mammals , the Akt and SGK kinases can phosphorylate and negatively regulate FOXO .	In mammals, the Akt and SGK kinases can phosphorylate and negatively regulate FOXO.	4	14	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	4	5	13	14
Akt inhibits FOXO transcriptional activity by mediating cytoplasmic FOXO sequestration by 14-3-3 proteins , which ultimately promotes its proteosomal degradation [ XREF_BIBR ] .	Akt inhibits FOXO transcriptional activity by mediating cytoplasmic FOXO sequestration by 14-3-3 proteins, which ultimately promotes its proteosomal degradation [XREF_BIBR].	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	0	1	2	3
In the network , we only included the inhibition of FoxO by Akt .	In the network, we only included the inhibition of FoxO by Akt.	6	13	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	12	13	10	11
As FOXO transcriptional activity is inhibited by PI3K-Akt signaling [ XREF_BIBR ] , whereby PI3K phosphorylation causes Akt to translocate to the nucleus [ XREF_BIBR ] , where it phosphorylates FOXO ( Thr24 , Ser256 , and Ser319 of FoxO1 ; Thr32 , Ser253 , and Ser315 of FoxO3 ) , the SIRT1 specific inhibitor EX527 ( 25muM ) and PI3K inhibitor LY294002 ( 20muM ) were used in the in vitro H/R cell model to clarify the role of CD38 in SIRT1 and FOXO antistress signaling pathway .	As FOXO transcriptional activity is inhibited by PI3K-Akt signaling [XREF_BIBR], whereby PI3K phosphorylation causes Akt to translocate to the nucleus [XREF_BIBR], where it phosphorylates FOXO (Thr24, Ser256, and Ser319 of FoxO1; Thr32, Ser253, and Ser315 of FoxO3), the SIRT1 specific inhibitor EX527 (25muM) and PI3K inhibitor LY294002 (20muM) were used in the in vitro H/R cell model to clarify the role of CD38 in SIRT1 and FOXO antistress signaling pathway.	1	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FOXO	FOXO	FOXO	7	8	1	2
As Lapatinib mediated inhibition of HER2 represses a cascade of downstream protein kinases including PI3K and AKT , which phosphorylates and thus inhibits FOXO transcription factors by excluding their nuclear distribution , we examined whether IBET has an impact on expression of FOXO1 and its cellular distribution in BT474 cells .	As Lapatinib mediated inhibition of HER2 represses a cascade of downstream protein kinases including PI3K and AKT, which phosphorylates and thus inhibits FOXO transcription factors by excluding their nuclear distribution, we examined whether IBET has an impact on expression of FOXO1 and its cellular distribution in BT474 cells.	12	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	16	17	23	24
The inhibition of PI3K and AKT and MEK and ERK pathways induced FOXO transcriptional activity and apoptosis .	The inhibition of PI3K and AKT and MEK and ERK pathways induced FOXO transcriptional activity and apoptosis.	1	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	5	6	12	13
AKT promotes metabolic activity in the mitochondria and inhibits FOXO transcriptional activity , leading to high level of ROS .	AKT promotes metabolic activity in the mitochondria and inhibits FOXO transcriptional activity, leading to high level of ROS.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	0	1	9	10
FoxO proteins are inhibited by Akt phosphorylation , which leads to FoxO nuclear exclusion and ubiquitin mediated degradation .	FoxO proteins are inhibited by Akt phosphorylation, which leads to FoxO nuclear exclusion and ubiquitin mediated degradation.	0	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	FoxO	FoxO	foxo	5	6	0	1
Foxo activity is controlled by AKT dependent phosphorylation , which sequesters Foxo molecules in the cytoplasm , preventing them from promoting Bim transcription .	Foxo activity is controlled by AKT dependent phosphorylation, which sequesters Foxo molecules in the cytoplasm, preventing them from promoting Bim transcription.	5	12	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT dependent phosphorylation	akt	Foxo	Foxo	foxo	5	6	11	12
Specifically , increased signaling through this pathway is marked by increased levels of expression of PI3K , PDK1 , and Akt , which inactivate the pathway antagonist FOXO XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Specifically, increased signaling through this pathway is marked by increased levels of expression of PI3K, PDK1, and Akt, which inactivate the pathway antagonist FOXO XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	13	28	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	expression of PI3K, PDK1, and Akt	akt	FOXO	FOXO	foxo	20	21	27	28
In addition , rhein inhibits Akt phosphorylation and stimulates FOXO transactivation activity .	In addition, rhein inhibits Akt phosphorylation and stimulates FOXO transactivation activity.	3	11	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	rhein inhibits Akt phosphorylation	akt	FOXO	FOXO	foxo	5	6	9	10
FoxO transcription factors , which are negatively regulated by AKT , were identified as potent activators of CCN2 gene expression .	FoxO transcription factors, which are negatively regulated by AKT, were identified as potent activators of CCN2 gene expression.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	9	10	0	1
AKT is reported to promote the degradation of FoxO proteins by the proteasome through increasing their phosphorylation , which will induce the nuclear exportation XREF_BIBR .	AKT is reported to promote the degradation of FoxO proteins by the proteasome through increasing their phosphorylation, which will induce the nuclear exportation XREF_BIBR.	0	9	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	0	1	8	9
FOXO transcription factors are important negative regulators of B-cell survival in CLL and are inhibited by AKT .	FOXO transcription factors are important negative regulators of B-cell survival in CLL and are inhibited by AKT.	0	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	16	17	0	1
It is noteworthy that , with PP2A low and without JNK , a lower level of Akt activation ( in E compared to D ) is sufficient to drive FOXO to the cytoplasm , but also a lower level of JNK activity suffices to retain it in the nucleus even at a high level of Akt activation ( compare the response to JNK = 10 3 ) .	It is noteworthy that, with PP2A low and without JNK, a lower level of Akt activation (in E compared to D) is sufficient to drive FOXO to the cytoplasm, but also a lower level of JNK activity suffices to retain it in the nucleus even at a high level of Akt activation (compare the response to JNK = 10 3).	16	30	drive	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	16	17	29	30
Phosphorylation of Akt prevents the nuclear trafficking of Foxo transcription factors , which are important for T reg cell stability and function .	Phosphorylation of Akt prevents the nuclear trafficking of Foxo transcription factors, which are important for T reg cell stability and function.	0	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Phosphorylation of Akt	akt	Foxo	Foxo	foxo	2	3	8	9
As a result of this disruption by Cbl-b , Foxo proteins are not inactivated by AKT and freely translocate to the nucleus to enhance Foxp3 expression [ XREF_BIBR ] .	As a result of this disruption by Cbl-b, Foxo proteins are not inactivated by AKT and freely translocate to the nucleus to enhance Foxp3 expression [XREF_BIBR].	9	16	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Foxo	Foxo	Foxo	15	16	9	10
As reported , transgenic expression of AKT suppressed FoxO mediated developmental defects in the eye .	As reported, transgenic expression of AKT suppressed FoxO mediated developmental defects in the eye.	4	11	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	expression of AKT	akt	FoxO	FoxO	foxo	6	7	8	9
Inhibition of AKT and MEK kinases synergistically induced FOXO transcriptional activity , which was further enhanced in the presence of EGCG .	Inhibition of AKT and MEK kinases synergistically induced FOXO transcriptional activity, which was further enhanced in the presence of EGCG.	2	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	2	3	8	9
In recent years , the Foxo factors , which are negatively regulated by Akt phosphorylation , have emerged as critical downstream regulators controlling diverse physiological processes such as cell cycle progression , metabolism , apoptosis , and oxidative defense .	In recent years, the Foxo factors, which are negatively regulated by Akt phosphorylation, have emerged as critical downstream regulators controlling diverse physiological processes such as cell cycle progression, metabolism, apoptosis, and oxidative defense.	5	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	Foxo	Foxo	foxo	13	14	5	6
Akt dependent phosphorylation inactivates FOXO through 14-3-3 binding and subsequent cytoplasmic sequestration .	Akt dependent phosphorylation inactivates FOXO through 14-3-3 binding and subsequent cytoplasmic sequestration.	0	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	FOXO	FOXO	foxo	0	1	4	5
FOXO is normally inactivated by Akt dependent phosphorylation , which restricts nuclear entry of FOXO and leads to its ubiquitin dependent destruction .	FOXO is normally inactivated by Akt dependent phosphorylation, which restricts nuclear entry of FOXO and leads to its ubiquitin dependent destruction.	0	8	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	FOXO	FOXO	foxo	5	6	0	1
Interestingly , mTORC1 has a role in inhibiting the mTORC2 pathway in T reg cells , and mTORC2 activity is required for Akt mediated inhibition of Foxo transcription factors .	Interestingly, mTORC1 has a role in inhibiting the mTORC2 pathway in T reg cells, and mTORC2 activity is required for Akt mediated inhibition of Foxo transcription factors.	22	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	22	23	26	27
In different types of endothelial cells , FoxO transcription factors , which are negatively regulated by AKT , were identified as potent activators of CCN2 gene expression .	In different types of endothelial cells, FoxO transcription factors, which are negatively regulated by AKT, were identified as potent activators of CCN2 gene expression.	7	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	16	17	7	8
Akt suppresses FoxO protein function by phosphorylating the transcription factor at critical sites required for export from the nucleus and degradation XREF_BIBR .	Akt suppresses FoxO protein function by phosphorylating the transcription factor at critical sites required for export from the nucleus and degradation XREF_BIBR.	0	4	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	0	1	2	3
The expression of MAFbx and Atrogin -1 and MuRF1 is positively regulated by the transcription factor FoxO3A in the heart , and is negatively regulated through Akt which suppresses FoxO .	The expression of MAFbx and Atrogin -1 and MuRF1 is positively regulated by the transcription factor FoxO3A in the heart, and is negatively regulated through Akt which suppresses FoxO.	24	30	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	26	27	29	30
Inhibition of PI3K and AKT and MEK and ERK pathways activates FOXO transcription factors .	Inhibition of PI3K and AKT and MEK and ERK pathways activates FOXO transcription factors.	0	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	4	5	11	12
In Ph + ALL cells , FoxO factors are inactivated by PI3K and AKT XREF_BIBR signaling , which is reversed by Pten ( XREF_SUPPLEMENTARY ) .	In Ph + ALL cells, FoxO factors are inactivated by PI3K and AKT XREF_BIBR signaling, which is reversed by Pten (XREF_SUPPLEMENTARY).	6	15	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	13	14	6	7
To examine Trbl effects on FoxO directly , we used specific antisera to detect Akt phosphorylation inactivation of FoxO , which occurs at Ser 256 .	To examine Trbl effects on FoxO directly, we used specific antisera to detect Akt phosphorylation inactivation of FoxO, which occurs at Ser 256.	14	21	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	FoxO	FoxO	foxo	14	15	18	19
Akt also inhibits FOXO transcription factors , which consist of FOXO1 , 3 and 4 in skeletal muscle .	Akt also inhibits FOXO transcription factors, which consist of FOXO1, 3 and 4 in skeletal muscle.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	0	1	3	4
Since Akt signaling inhibits the activity of FoxO family of transcription factors , which are required for the expression of MuRF1 and MAFBx , it is likely that the inhibition of Akt signaling is another mechanism by which TWEAK augments the gene expression of MuRF1 and MAFBx in cultured myotubes .	Since Akt signaling inhibits the activity of FoxO family of transcription factors, which are required for the expression of MuRF1 and MAFBx, it is likely that the inhibition of Akt signaling is another mechanism by which TWEAK augments the gene expression of MuRF1 and MAFBx in cultured myotubes.	1	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	1	2	7	8
As Akt phosphorylates and inhibits FOXO1 , blockade of the PI3K and Akt pathway would increase FOXO activity .	As Akt phosphorylates and inhibits FOXO1, blockade of the PI3K and Akt pathway would increase FOXO activity.	10	17	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	12	13	16	17
The inhibition of PI3K and AKT and MEK and ERK pathways activated FOXO transcription factors .	The inhibition of PI3K and AKT and MEK and ERK pathways activated FOXO transcription factors.	1	14	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	5	6	12	13
Lack of nutrients and growth factors activates FoxO transcription factors in pancreatic beta-cells , whereas PI3K and Akt dependent inactivation of FoxO favors proliferation .	Lack of nutrients and growth factors activates FoxO transcription factors in pancreatic beta-cells, whereas PI3K and Akt dependent inactivation of FoxO favors proliferation.	15	22	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	17	18	21	22
Inhibition of PI3K and AKT and MAPK and ERK pathways causes activation of FOXO transcription factor , leading to cell cycle arrest and apoptosis in pancreatic cancer .	Inhibition of PI3K and AKT and MAPK and ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer.	0	15	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	4	5	13	14
Our data suggest that the continued , inflammatory activation of T cells in cancer promotes a defect in mitochondrial biogenesis , mediated in part by Akt controlled inhibition of Foxo programmed PGC1alpha transcription .	Our data suggest that the continued, inflammatory activation of T cells in cancer promotes a defect in mitochondrial biogenesis, mediated in part by Akt controlled inhibition of Foxo programmed PGC1alpha transcription.	25	30	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	25	26	29	30
FOXO transcription factors are negatively regulated by the PI3K-PKB and AKT signaling pathway and have been mainly considered to be tumor suppressors due to their inhibitory effect on cancer cell growth and survival .	FOXO transcription factors are negatively regulated by the PI3K-PKB and AKT signaling pathway and have been mainly considered to be tumor suppressors due to their inhibitory effect on cancer cell growth and survival.	0	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	10	11	0	1
Thus , FoxO is essentially inactivated by Akt .	Thus, FoxO is essentially inactivated by Akt.	2	8	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	7	8	2	3
High PI3K and Akt activity suppresses FOXO function to promote rapid production of plasma cells secreting mainly IgM .	High PI3K and Akt activity suppresses FOXO function to promote rapid production of plasma cells secreting mainly IgM.	3	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	3	4	6	7
This occurs , in part , because AKT phosphorylation inhibits the nuclear activity of FoxO transcription factors , namely FoxO1 , which positively regulates several genes involved in naive and memory T cell survival and trafficking including Il7ra , Ccr7 , Klf2 , Sell ( CD62L ) , Tcf7 , Eomes and Bcl2 .	This occurs, in part, because AKT phosphorylation inhibits the nuclear activity of FoxO transcription factors, namely FoxO1, which positively regulates several genes involved in naive and memory T cell survival and trafficking including Il7ra, Ccr7, Klf2, Sell (CD62L), Tcf7, Eomes and Bcl2.	7	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	FoxO	FoxO	foxo	7	8	14	15
At the early stage of cancer development , FOXO activity is inhibited by the activation of the PI3K-AKT pathway , which causes accumulation of ROS and drives cancer progression [ XREF_BIBR ] .	At the early stage of cancer development, FOXO activity is inhibited by the activation of the PI3K-AKT pathway, which causes accumulation of ROS and drives cancer progression [XREF_BIBR].	8	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO	FOXO	FOXO	17	18	8	9
FOXO transcription factors are inactivated by the PI3K-AKT pathway .	FOXO transcription factors are inactivated by the PI3K-AKT pathway.	0	8	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO	FOXO	FOXO	7	8	0	1
Overall , acetylation is enhancing and interacting with AKT phosphorylation induced inhibition of FOXO , while sirt1 deacetylation enhances FOXO activity .	Overall, acetylation is enhancing and interacting with AKT phosphorylation induced inhibition of FOXO, while sirt1 deacetylation enhances FOXO activity.	8	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	FOXO	FOXO	foxo	8	9	13	14
In these lines , inhibition of AKT phosphorylation relieves inhibition of FOXO proteins thereby facilitating their nuclear retention .	In these lines, inhibition of AKT phosphorylation relieves inhibition of FOXO proteins thereby facilitating their nuclear retention.	6	12	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	FOXO	FOXO	foxo	6	7	11	12
Among other substrates , Akt inhibits the activities of the transcription factor FoxO XREF_BIBR and the Rheb specific GTPase activating protein ( GAP ) Tsc2 .	Among other substrates, Akt inhibits the activities of the transcription factor FoxO XREF_BIBR and the Rheb specific GTPase activating protein (GAP) Tsc2.	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	4	5	12	13
Akt activation , which occurs commonly in cancer as a result of mutations in upstream signaling components , is also associated with higher mitochondrial oxygen consumption and ROS generation , coupled with reduced ROS scavenging , due to Akt dependent inhibition of FoxO transcription factors .	Akt activation, which occurs commonly in cancer as a result of mutations in upstream signaling components, is also associated with higher mitochondrial oxygen consumption and ROS generation, coupled with reduced ROS scavenging, due to Akt dependent inhibition of FoxO transcription factors.	38	43	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	38	39	42	43
Furthermore , Akt dependent inhibition of the FoxO transcription factor results in reduced transcription of the inR gene .	Furthermore, Akt dependent inhibition of the FoxO transcription factor results in reduced transcription of the inR gene.	2	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	2	3	7	8
This AKT activation ( and subsequent inactivation of FOXO and p53 ) may also be highly relevant for other therapeutics that target the upstream PI3K and AKT network such as trastuzumab approved for the treatment of breast and gastric cancers and cetuximab for the treatment of colon cancer XREF_BIBR .	This AKT activation (and subsequent inactivation of FOXO and p53) may also be highly relevant for other therapeutics that target the upstream PI3K and AKT network such as trastuzumab approved for the treatment of breast and gastric cancers and cetuximab for the treatment of colon cancer XREF_BIBR.	1	10	inactivation	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	1	2	8	9
XREF_BIBR , XREF_BIBR , XREF_BIBR Inhibition of FOXO by Akt is also known to lead to a downregulation of pro apoptotic BH3-only proteins .	XREF_BIBR, XREF_BIBR, XREF_BIBR Inhibition of FOXO by Akt is also known to lead to a downregulation of pro apoptotic BH3-only proteins.	5	10	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	9	10	7	8
XREF_BIBR Akt inhibits the FoxO family of transcription factors , FoxO1 and FoxO3a , which direct both Foxp3 dependent and independent suppressive programs in Treg cells .	XREF_BIBR Akt inhibits the FoxO family of transcription factors, FoxO1 and FoxO3a, which direct both Foxp3 dependent and independent suppressive programs in Treg cells.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	1	2	4	5
Akt represses the transcription factors of the FoxO family XREF_BIBR and then block the upregulation of the ubiquitin-ligases MuRF1 and MAFbx , which are the key mediators of skeletal muscle atrophy XREF_BIBR , XREF_BIBR .	Akt represses the transcription factors of the FoxO family XREF_BIBR and then block the upregulation of the ubiquitin-ligases MuRF1 and MAFbx, which are the key mediators of skeletal muscle atrophy XREF_BIBR, XREF_BIBR.	0	12	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	0	1	7	8
The kinase AKT negatively regulates transcription factors of the FoxO family , which are active in their dephosphorylated form .	The kinase AKT negatively regulates transcription factors of the FoxO family, which are active in their dephosphorylated form.	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	2	3	9	10
Activation of the PI3K and AKT signaling pathway , leads to decreased activity of FOXO and decreased levels of FOXO target genes like catalase and MnSOD XREF_BIBR .	Activation of the PI3K and AKT signaling pathway, leads to decreased activity of FOXO and decreased levels of FOXO target genes like catalase and MnSOD XREF_BIBR.	5	21	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	5	6	19	20
In this manner , Akt promotes cell survival by blocking the FoxO induced expression of pro apoptotic gene targets such as FasL , TRAIL , and Bim [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	In this manner, Akt promotes cell survival by blocking the FoxO induced expression of pro apoptotic gene targets such as FasL, TRAIL, and Bim [XREF_BIBR; XREF_BIBR; XREF_BIBR].	4	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	4	5	11	12
The exact mechanism by which the FOXO transcription factors are activated is unclear since the FOXO transcription factors are not always activated by a decrease in Akt and PKB activity , and Akt and PKB activity is not always decreased in response to unloading .	The exact mechanism by which the FOXO transcription factors are activated is unclear since the FOXO transcription factors are not always activated by a decrease in Akt and PKB activity, and Akt and PKB activity is not always decreased in response to unloading.	15	29	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	FOXO	FOXO	FOXO	28	29	15	16
Akt phosphorylation inhibits the transcription factors of the FoxO family .	Akt phosphorylation inhibits the transcription factors of the FoxO family.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	FoxO	FoxO	foxo	0	1	8	9
Normally , AKT negatively regulates all FOXO protein activity by direct phosphorylation , causing their nuclear exclusion [ XREF_BIBR ] .	Normally, AKT negatively regulates all FOXO protein activity by direct phosphorylation, causing their nuclear exclusion [XREF_BIBR].	2	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	2	3	6	7
Our western blotting data do show that AKT1 phosphorylation and phosphorylation of AKT targets FOXO 1/3 and PRAS40 are less inhibited at equivalent drug exposure compared to PIK3CA E545K cells .	Our western blotting data do show that AKT1 phosphorylation and phosphorylation of AKT targets FOXO 1/3 and PRAS40 are less inhibited at equivalent drug exposure compared to PIK3CA E545K cells.	7	20	targets	Positive_activation_token_1_verb	Negative_activation	Negative_activation	AKT	AKT1 phosphorylation and phosphorylation of AKT	akt	FOXO	FOXO	foxo	12	13	14	15
For instance , Akt inhibits FOXO , which in muscle promotes protein degradation via the ubiquitin-proteasome system and autophagy .	For instance, Akt inhibits FOXO, which in muscle promotes protein degradation via the ubiquitin-proteasome system and autophagy.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	3	4	5	6
These data suggest that inhibition of PI3K and AKT and ERK pathways acts together to activate FOXO transcription factor and enhances SFN induced FOXO transcriptional activity , leading to cell cycle arrest and apoptosis .	These data suggest that inhibition of PI3K and AKT and ERK pathways acts together to activate FOXO transcription factor and enhances SFN induced FOXO transcriptional activity, leading to cell cycle arrest and apoptosis.	4	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	8	9	16	17
To the best of our knowledge , this is the first study to demonstrate that inhibition of PI3K and AKT and MEK and ERK pathways acted synergistically to induce activation of FOXO transcription factors and enhanced the antiangiogenic effects of EGCG in HUVEC cells .	To the best of our knowledge, this is the first study to demonstrate that inhibition of PI3K and AKT and MEK and ERK pathways acted synergistically to induce activation of FOXO transcription factors and enhanced the antiangiogenic effects of EGCG in HUVEC cells.	15	33	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	19	20	31	32
Akt and Mst1 exhibit mutually antagonistic functions , and FoxO proteins can be inactivated by Akt XREF_BIBR - XREF_BIBR .	Akt and Mst1 exhibit mutually antagonistic functions, and FoxO proteins can be inactivated by Akt XREF_BIBR - XREF_BIBR.	9	16	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	15	16	9	10
RANKL activates Akt and Erk , which , in turn , decrease FoxO activity by increasing FoxO phosphorylation XREF_BIBR XREF_BIBR .	RANKL activates Akt and Erk, which, in turn, decrease FoxO activity by increasing FoxO phosphorylation XREF_BIBR XREF_BIBR.	2	13	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	2	3	12	13
Akt , otherwise known as protein kinase B ( PKB ) , has been shown to block the function of all three Foxo proteins through phosphorylation , leading to their containment in the cytoplasm .	Akt, otherwise known as protein kinase B (PKB), has been shown to block the function of all three Foxo proteins through phosphorylation, leading to their containment in the cytoplasm.	0	23	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	0	1	22	23
A conclusion of these studies was that a higher level of regulation , upstream of FOXP3 , determines the T Reg cell lineage 108 , and one possibility is that FOXO transcription factors , which are inhibited by AKT , constitute an essential aspect of this higher level of control .	A conclusion of these studies was that a higher level of regulation, upstream of FOXP3, determines the T Reg cell lineage 108, and one possibility is that FOXO transcription factors, which are inhibited by AKT, constitute an essential aspect of this higher level of control.	30	39	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	38	39	30	31
Akt also inhibits FOXO , a virus induced transcription factor downstream of Toll , which upregulates antimicrobial peptides and possibly RNAi pathway components [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Akt also inhibits FOXO, a virus induced transcription factor downstream of Toll, which upregulates antimicrobial peptides and possibly RNAi pathway components [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	0	1	3	4
PKB activation via the stimulation of the T cell receptor , CD28 , and cytokine signaling pathways inactivates Foxo proteins , which is associated with the induction of T cell proliferation .	PKB activation via the stimulation of the T cell receptor, CD28, and cytokine signaling pathways inactivates Foxo proteins, which is associated with the induction of T cell proliferation.	0	19	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	Foxo	Foxo	Foxo	0	1	18	19
FOXO is negatively regulated through phosphorylation by PI3K and AKT and ERK signaling pathway , which leads to its nuclear exclusion [ XREF_BIBR , XREF_BIBR ] .	FOXO is negatively regulated through phosphorylation by PI3K and AKT and ERK signaling pathway, which leads to its nuclear exclusion [XREF_BIBR, XREF_BIBR].	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	9	10	0	1
Overexpression of AKT by transient transfection significantly blocked the modulation of FOXO proteins and protected the cells from BITC mediated apoptosis and growth suppression .	Overexpression of AKT by transient transfection significantly blocked the modulation of FOXO proteins and protected the cells from BITC mediated apoptosis and growth suppression.	0	12	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Overexpression of AKT	akt	FOXO	FOXO	foxo	2	3	11	12
AKT is also known to activate CREB ( see discussion in section 4.1 ) and inactivate FoxO family ( see discussion in section 4.2 ) transcription factors [ XREF_BIBR , XREF_BIBR ] .	AKT is also known to activate CREB (see discussion in section 4.1) and inactivate FoxO family (see discussion in section 4.2) transcription factors [XREF_BIBR, XREF_BIBR].	0	17	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	0	1	16	17
It has been well documented that the Foxo family can be negatively regulated by the signaling pathways of phosphatidylinositol-3-OH kinase ( PI ( 3 ) K ) and the kinase Akt in response to insulin , growth factors or the engagement of costimulatory receptors ( CD28 and ICOS ) XREF_BIBR , XREF_BIBR .	It has been well documented that the Foxo family can be negatively regulated by the signaling pathways of phosphatidylinositol-3-OH kinase (PI (3) K) and the kinase Akt in response to insulin, growth factors or the engagement of costimulatory receptors (CD28 and ICOS) XREF_BIBR, XREF_BIBR.	7	32	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	30	31	7	8
Activation of WNT signaling activates the AKT and PKB pathway ; PKB then phosphorylates and sequesters FOXO in the cytoplasm , and prevents it from competing with beta-catenin .	Activation of WNT signaling activates the AKT and PKB pathway; PKB then phosphorylates and sequesters FOXO in the cytoplasm, and prevents it from competing with beta-catenin.	11	22	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	FOXO	FOXO	FOXO	11	12	16	17
Inhibition of AKT activates FOXO , a transcription factor which up-regulates several ' longevity pathways ' controlling DNA repair , autophagy , antioxidant activity , and stress resistance , and cell proliferation .	Inhibition of AKT activates FOXO, a transcription factor which up-regulates several ' longevity pathways ' controlling DNA repair, autophagy, antioxidant activity, and stress resistance, and cell proliferation.	0	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	2	3	4	5
SFN inhibited phosphorylation of AKT and ERK , and activated FOXO transcription factors , leading to cell cycle arrest and apoptosis .	SFN inhibited phosphorylation of AKT and ERK, and activated FOXO transcription factors, leading to cell cycle arrest and apoptosis.	0	12	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	SFN inhibited phosphorylation of AKT	akt	FOXO	FOXO	foxo	4	5	10	11
Our results demonstrate that inhibition of PI3K and AKT and ERK pathways activates FOXO transcription factors .	Our results demonstrate that inhibition of PI3K and AKT and ERK pathways activates FOXO transcription factors.	4	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	8	9	13	14
Among 41 genes , FOXO4 was one of the candidate genes identified because FOXO transcription factors , which are directly inhibited by Akt dependent phosphorylation , have been implicated in stem cell maintenance of several cell lineages [ XREF_BIBR ] .	Among 41 genes, FOXO4 was one of the candidate genes identified because FOXO transcription factors, which are directly inhibited by Akt dependent phosphorylation, have been implicated in stem cell maintenance of several cell lineages [XREF_BIBR].	13	25	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	FOXO	FOXO	foxo	22	23	13	14
Interestingly , IGF-1 signaling and localized PI3K activity at the nascent axon promote axon specification in hippocampal neurons , raising a potential paradox of how the FOXO transcription factors , which are inhibited by the PI3K-Akt signaling pathway , promote neuronal polarization .	Interestingly, IGF-1 signaling and localized PI3K activity at the nascent axon promote axon specification in hippocampal neurons, raising a potential paradox of how the FOXO transcription factors, which are inhibited by the PI3K-Akt signaling pathway, promote neuronal polarization.	26	37	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FOXO	FOXO	FOXO	35	36	26	27
FOXO transcription factors are negatively regulated by PI3K-AKT , and hence , their loss mimics some of the effects of hyperactive PI3K-AKT signalling .	FOXO transcription factors are negatively regulated by PI3K-AKT, and hence, their loss mimics some of the effects of hyperactive PI3K-AKT signalling.	0	8	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO	FOXO	FOXO	7	8	0	1
The inhibition of PI3K and AKT pathway induced FOXO transcriptional activity resulting in induction of Bim , TRAIL , p27 / KIP1 , DR4 and DR5 , and inhibition of cyclin D1 .	The inhibition of PI3K and AKT pathway induced FOXO transcriptional activity resulting in induction of Bim, TRAIL, p27 / KIP1, DR4 and DR5, and inhibition of cyclin D1.	3	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	5	6	8	9
Based on evidence that the Akt pathway induces hypertrophy and inhibits activation of FoxO transcription factors MuRF1 and MAFbx , an intramuscular injection of IGF-1 has been used to activate Akt and prevent glucocorticoid and denervation induced muscle atrophy .	Based on evidence that the Akt pathway induces hypertrophy and inhibits activation of FoxO transcription factors MuRF1 and MAFbx, an intramuscular injection of IGF-1 has been used to activate Akt and prevent glucocorticoid and denervation induced muscle atrophy.	5	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	5	6	13	14
The FoxO transcription factors , which are suppressed by Akt during cell proliferation , are essential for HSC self-renewal XREF_BIBR .	The FoxO transcription factors, which are suppressed by Akt during cell proliferation, are essential for HSC self-renewal XREF_BIBR.	1	10	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	9	10	1	2
FOXO activity is inhibited by the insulin effector kinase Akt ; we show that Akt activation is systemically reduced as a result of M. marinum infection .	FOXO activity is inhibited by the insulin effector kinase Akt; we show that Akt activation is systemically reduced as a result of M. marinum infection.	0	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	9	10	0	1
FOXO nuclear localization and transcriptional activity are directly inhibited by insulin signaling , through phosphorylation of FOXO by the insulin-effector kinase Akt ; conversely , c-Jun-catalyzed phosphorylation of other sites induces FOXO nuclear localization and activation .	FOXO nuclear localization and transcriptional activity are directly inhibited by insulin signaling, through phosphorylation of FOXO by the insulin-effector kinase Akt; conversely, c-Jun-catalyzed phosphorylation of other sites induces FOXO nuclear localization and activation.	0	22	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	21	22	0	1
Akt misexpression led to a significant increase in phospho-FoxO , indicating that the antisera can reliably detect Akt dependent phosphorylation dependent inactivation of FoxO ( XREF_FIG ) .	Akt misexpression led to a significant increase in phospho-FoxO, indicating that the antisera can reliably detect Akt dependent phosphorylation dependent inactivation of FoxO (XREF_FIG).	17	25	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	FoxO	FoxO	foxo	17	18	23	24
We have demonstrated that inhibition of PI3K and AKT and Ras/MEK/ERK pathways interact synergistically to activate FOXO transcription factors which , in turn , inhibit angiogenesis .	We have demonstrated that inhibition of PI3K and AKT and Ras/MEK/ERK pathways interact synergistically to activate FOXO transcription factors which, in turn, inhibit angiogenesis.	4	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	8	9	16	17
Recently , the siRNA mediated depletion of RRM2B was reported to result in the upregulation of AKT phosphorylation , which inactivates FOXO activity [ XREF_BIBR ] .	Recently, the siRNA mediated depletion of RRM2B was reported to result in the upregulation of AKT phosphorylation, which inactivates FOXO activity [XREF_BIBR].	16	22	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	FOXO	FOXO	foxo	16	17	21	22
Because the target genes for FOXO proteins are E3 ubiquitin ligases such as atrogin-1 and muscle upregulated RING finger-1 ( MURF-1 ) in the skeletal muscle , Akt mediated FOXO inactivation inhibits the ubiquitin-proteasome system ( UPS ) , which is essential for the degradation of myofibrillar , metabolic , and transcriptional proteins XREF_BIBR , XREF_BIBR , XREF_BIBR .	Because the target genes for FOXO proteins are E3 ubiquitin ligases such as atrogin-1 and muscle upregulated RING finger-1 (MURF-1) in the skeletal muscle, Akt mediated FOXO inactivation inhibits the ubiquitin-proteasome system (UPS), which is essential for the degradation of myofibrillar, metabolic, and transcriptional proteins XREF_BIBR, XREF_BIBR, XREF_BIBR.	25	30	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	27	28	29	30
CD4+ CD25+ Treg cells displayed a consistent defect in phosphorylation of AKT at serine 473 and reduced phosphorylation of the AKT substrates FOXO and S6 .	CD4+ CD25+ Treg cells displayed a consistent defect in phosphorylation of AKT at serine 473 and reduced phosphorylation of the AKT substrates FOXO and S6.	0	24	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	CD4+ CD25+ Treg cells displayed a consistent defect in phosphorylation of AKT at serine 473	akt	FOXO	FOXO	foxo	11	12	22	23
AKT phosphorylation inactivates FOXO , making a cell more likely to proliferate , but also more vulnerable to oxidative stress .	AKT phosphorylation inactivates FOXO, making a cell more likely to proliferate, but also more vulnerable to oxidative stress.	0	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	FOXO	FOXO	foxo	0	1	3	4
FoxO proteins are negatively regulated by the PI3K and Akt pathway and , similar to Pten inactivation , Akt activation results in FoxO phosphorylation and inhibition .	FoxO proteins are negatively regulated by the PI3K and Akt pathway and, similar to Pten inactivation, Akt activation results in FoxO phosphorylation and inhibition.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	9	10	0	1
It was subsequently shown that attenuation of the PI3K and Akt pathway is required to allow transcriptional activation of FOXO in G2 [ XREF_BIBR ] .	It was subsequently shown that attenuation of the PI3K and Akt pathway is required to allow transcriptional activation of FOXO in G2 [XREF_BIBR].	8	20	allow	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	10	11	19	20
AKT and SGK-1 further phosphorylate and inactivate the transcription factor DAF-16 and FOXO , thereby blocking the transcription of target genes such as the sod-3 gene XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	AKT and SGK-1 further phosphorylate and inactivate the transcription factor DAF-16 and FOXO, thereby blocking the transcription of target genes such as the sod-3 gene XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	0	13	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	0	1	12	13
Indeed , FOXO factors are negatively regulated by AKT in response to a series of growth factors and other signals .	Indeed, FOXO factors are negatively regulated by AKT in response to a series of growth factors and other signals.	2	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	8	9	2	3
FoxO factors are negatively regulated by Akt ; dephosphorylated FoxO1 localizes to the nucleus and exhibits transcriptional activity , whereas Akt dependent phosphorylation of FoxO1 induces nuclear export and allows proteasomal degradation .	FoxO factors are negatively regulated by Akt; dephosphorylated FoxO1 localizes to the nucleus and exhibits transcriptional activity, whereas Akt dependent phosphorylation of FoxO1 induces nuclear export and allows proteasomal degradation.	0	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	6	7	0	1
FoxO family proteins are inhibited by exclusion from the nucleus as a result of phosphorylation by AKT , downstream of the PI3K-AKT phosphorylation cascade [ XREF_BIBR ] .	FoxO family proteins are inhibited by exclusion from the nucleus as a result of phosphorylation by AKT, downstream of the PI3K-AKT phosphorylation cascade [XREF_BIBR].	0	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	16	17	0	1
Therefore , in response to TOR pathway hyperactivation , we predicted that reduced Akt activity would cause FOXO protein to accumulate .	Therefore, in response to TOR pathway hyperactivation, we predicted that reduced Akt activity would cause FOXO protein to accumulate.	13	18	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	13	14	17	18
Our results further reveal that TMSB10 promotes the proliferation , invasion and migration of breast cancer cells via AKT and FOXO signaling , which is antagonized by the AKT kinase inhibitor perifosine .	Our results further reveal that TMSB10 promotes the proliferation, invasion and migration of breast cancer cells via AKT and FOXO signaling, which is antagonized by the AKT kinase inhibitor perifosine.	20	31	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	28	29	20	21
Recent evidence suggests that this effect of IGF-I at least in part reflects PI3K and Akt mediated inhibition of Foxo transcription factors .	Recent evidence suggests that this effect of IGF-I at least in part reflects PI3K and Akt mediated inhibition of Foxo transcription factors.	13	21	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	15	16	19	20
In endothelial cells , activation of PI3K-AKT suppresses CCN2 expression , whereas inhibition of AKT activates FoxO transcription factors , which serve as potent inducers of CCN2 gene expression .	In endothelial cells, activation of PI3K-AKT suppresses CCN2 expression, whereas inhibition of AKT activates FoxO transcription factors, which serve as potent inducers of CCN2 gene expression.	12	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	14	15	16	17
XREF_BIBR AKT kinase negatively regulates the activity of FOXO ( forkhead box O ) transcription factors by phosphorylation , and decreased levels of phosphorylated AKT represent a permissive condition for FOXO activation .	XREF_BIBR AKT kinase negatively regulates the activity of FOXO (forkhead box O) transcription factors by phosphorylation, and decreased levels of phosphorylated AKT represent a permissive condition for FOXO activation.	1	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	1	2	8	9
We have recently demonstrated that inhibition of the MEK and ERK and PI3K and AKT pathways synergistically induced FOXO transcriptional activity and inhibited cancer cell growth and angiogenesis ; these events were further enhanced in the presence of sulforaphane , resveratrol and EGCG .	We have recently demonstrated that inhibition of the MEK and ERK and PI3K and AKT pathways synergistically induced FOXO transcriptional activity and inhibited cancer cell growth and angiogenesis; these events were further enhanced in the presence of sulforaphane, resveratrol and EGCG.	14	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	14	15	18	19
mTORC1 is a downstream effector of Akt , whereas mTORC2 is an upstream regulator of Akt phosphorylation at Ser473 , a crucial modification for Akt inactivation of Foxo proteins [ XREF_BIBR ] .	mTORC1 is a downstream effector of Akt, whereas mTORC2 is an upstream regulator of Akt phosphorylation at Ser473, a crucial modification for Akt inactivation of Foxo proteins [XREF_BIBR].	24	28	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	24	25	27	28
Cellular apoptosis can be prevented during the phosphorylation of FoxO proteins by Akt to sequester FoxO transcription factors in the cytoplasm by association with 14-3-3 proteins and prevent the transcription of pro apoptotic target genes [ XREF_BIBR , XREF_BIBR ] .	Cellular apoptosis can be prevented during the phosphorylation of FoxO proteins by Akt to sequester FoxO transcription factors in the cytoplasm by association with 14-3-3 proteins and prevent the transcription of pro apoptotic target genes [XREF_BIBR, XREF_BIBR].	4	17	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	12	13	15	16
This outcome is reproducible and suggests that Akt and Trbl act synergistically to direct FoxO degradation ( model , XREF_FIG ) .	This outcome is reproducible and suggests that Akt and Trbl act synergistically to direct FoxO degradation (model, XREF_FIG).	7	15	direct	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	7	8	14	15
These data suggest that inhibition of ERK and AKT pathways act together to activate FOXO transcription factors which are involved in resveratrol mediated pancreatic tumor growth suppression .	These data suggest that inhibition of ERK and AKT pathways act together to activate FOXO transcription factors which are involved in resveratrol mediated pancreatic tumor growth suppression.	6	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	8	9	14	15
Among predicted targets were components of IR signaling , including the PDK and AKT kinase cascade which inhibits DAF-16 and FOXO .	Among predicted targets were components of IR signaling, including the PDK and AKT kinase cascade which inhibits DAF-16 and FOXO.	13	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	13	14	20	21
Indeed , AKT dependent inhibition of FOXO and , the concurrently stimulated JNK and c-JUN signaling , markedly decreased leukemic cell growth and leukemia initiating cell function in acute myeloid leukemia .	Indeed, AKT dependent inhibition of FOXO and, the concurrently stimulated JNK and c-JUN signaling, markedly decreased leukemic cell growth and leukemia initiating cell function in acute myeloid leukemia.	2	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	2	3	6	7
FoxO factors are inhibited by the PI3K-Akt pathway and activated by the PTEN phosphatase .	FoxO factors are inhibited by the PI3K-Akt pathway and activated by the PTEN phosphatase.	0	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FoxO	FoxO	FoxO	6	7	0	1
Further studies revealed that the hyperactive Akt induced by JC inhibited Foxo transcription factors , impaired ROS scavenging , and eventually resulted in the apoptosis of HCC cells .	Further studies revealed that the hyperactive Akt induced by JC inhibited Foxo transcription factors, impaired ROS scavenging, and eventually resulted in the apoptosis of HCC cells.	4	21	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	6	7	11	12
Two other mediators of atrophy , Atrogin-1 and MuRF1 , were not induced , likely due to the suppression of FOXO by AKT , thus resulting in a dampened atrophic response .	Two other mediators of atrophy, Atrogin-1 and MuRF1, were not induced, likely due to the suppression of FOXO by AKT, thus resulting in a dampened atrophic response.	18	23	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	22	23	20	21
AKT kinase negatively regulates , by phosphorylation , the activity of FOXO transcriptional factors .	AKT kinase negatively regulates, by phosphorylation, the activity of FOXO transcriptional factors.	0	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	0	1	11	12
EGCG inhibited phosphorylation of AKT and ERK , and activated FOXO transcription factors , leading to cell cycle arrest and apoptosis and further enhanced FOXO activity and apoptosis [ XREF_BIBR ] .	EGCG inhibited phosphorylation of AKT and ERK, and activated FOXO transcription factors, leading to cell cycle arrest and apoptosis and further enhanced FOXO activity and apoptosis [XREF_BIBR].	0	12	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	EGCG inhibited phosphorylation of AKT	akt	FOXO	FOXO	foxo	4	5	10	11
[ XREF_BIBR ] In addition , inhibition of Ras/MEK/ERK and PI3K and AKT pathways was shown to activate FOXO transcription factors .	[XREF_BIBR] In addition, inhibition of Ras/MEK/ERK and PI3K and AKT pathways was shown to activate FOXO transcription factors.	12	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	12	13	18	19
The effects of AMPK on FoxO transcription factors and on subsequent regulation of ubiquitin ligase expression are complex , since although AMPK can phosphorylate FoxO on multiple residues that are activating , AMPK also activates Akt which can inhibit FoxO activity .	The effects of AMPK on FoxO transcription factors and on subsequent regulation of ubiquitin ligase expression are complex, since although AMPK can phosphorylate FoxO on multiple residues that are activating, AMPK also activates Akt which can inhibit FoxO activity.	34	40	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	35	36	39	40
AKT inhibitor ( AKT Inh-IV ) and MEK1/2 inhibitor ( PD98059 ) synergistically induced FOXO transcriptional activity in AsPC-1 and PANC-1 cells .	AKT inhibitor (AKT Inh-IV) and MEK1/2 inhibitor (PD98059) synergistically induced FOXO transcriptional activity in AsPC-1 and PANC-1 cells.	3	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	3	4	14	15
Thus , FOXO inactivation by the PI3K-Akt pathway may contribute to down-regulation of p27 kip1 by IL-7 .	Thus, FOXO inactivation by the PI3K-Akt pathway may contribute to down-regulation of p27 kip1 by IL-7.	2	7	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FOXO	FOXO	FOXO	6	7	2	3
Akt inactivates FOXO transcription factors , thereby allowing increased cellular metabolism and concomitant entry into cell cycle .	Akt inactivates FOXO transcription factors, thereby allowing increased cellular metabolism and concomitant entry into cell cycle.	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	0	1	2	3
These data indicate that inhibition of PI3K and AKT and MEK and ERK pathways act synergistically to activate FOXO transcription factors , and activation of FOXO transcription factors further enhances the anti-angiogenic effects of resveratrol .	These data indicate that inhibition of PI3K and AKT and MEK and ERK pathways act synergistically to activate FOXO transcription factors, and activation of FOXO transcription factors further enhances the anti-angiogenic effects of resveratrol.	4	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	8	9	18	19
Examination of simulated perturbation effects with our AGS logical model revealed that FOXO , representing pro apoptotic transcription factors inactivated by phosphorylation [ XREF_BIBR ] , was synergistically activated by combined MEK and PI3K or MEK and AKT inhibition ( see XREF_SUPPLEMENTARY ) .	Examination of simulated perturbation effects with our AGS logical model revealed that FOXO, representing pro apoptotic transcription factors inactivated by phosphorylation [XREF_BIBR], was synergistically activated by combined MEK and PI3K or MEK and AKT inhibition (see XREF_SUPPLEMENTARY).	12	38	synergistically activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	37	38	12	13
Further , PI3K and AKT inhibits mammalian FOXO , which when active antagonizes MYC through several mechanisms .	Further, PI3K and AKT inhibits mammalian FOXO, which when active antagonizes MYC through several mechanisms.	2	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	4	5	7	8
It has been shown that FoxO transcription factors could modulate HER3 expression XREF_BIBR , XREF_BIBR , indeed , we found that induction of PI3K and AKT signaling resulted in substantially increased phospho-FoxO proteins , and attenuated nuclear localization of FoxO proteins in NIC + PIK3CA H1047R tumors when compared to NIC + tumors ( XREF_FIG ) .	It has been shown that FoxO transcription factors could modulate HER3 expression XREF_BIBR, XREF_BIBR, indeed, we found that induction of PI3K and AKT signaling resulted in substantially increased phospho-FoxO proteins, and attenuated nuclear localization of FoxO proteins in NIC + PIK3CA H1047R tumors when compared to NIC + tumors (XREF_FIG).	23	40	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	25	26	39	40
Secondly , AKT inhibits FOXO mediated RTK expression .	Secondly, AKT inhibits FOXO mediated RTK expression.	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	2	3	4	5
FoxO transcription factors , whose activities are negatively regulated through the phosphorylation by Akt , play important roles in multiple cell events , including proliferation , death , differentiation , longevity , and stress response .	FoxO transcription factors, whose activities are negatively regulated through the phosphorylation by Akt, play important roles in multiple cell events, including proliferation, death, differentiation, longevity, and stress response.	0	14	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	13	14	0	1
In contrast to AMPK , FOXO is negatively regulated by AKT signaling .	In contrast to AMPK, FOXO is negatively regulated by AKT signaling.	5	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	10	11	5	6
AKT inhibits Foxo proteins , which normally facilitate Foxp3 induction .	AKT inhibits Foxo proteins, which normally facilitate Foxp3 induction.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Foxo	Foxo	Foxo	0	1	2	3
Hence , it could be postulated that the expressions of mTOR complex and AKT are sufficiently high to downregulate FOXO , which in turn may negatively control PCK1 expression .	Hence, it could be postulated that the expressions of mTOR complex and AKT are sufficiently high to downregulate FOXO, which in turn may negatively control PCK1 expression.	8	26	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	expressions of mTOR complex and AKT	akt	FOXO	FOXO	foxo	13	14	19	20
Inhibition of AKT resulted in upregulation of ER- and FoxO dependent IGF-IR , IGF-I , and IGF-II .	Inhibition of AKT resulted in upregulation of ER- and FoxO dependent IGF-IR, IGF-I, and IGF-II.	0	11	resulted in upregulation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	2	3	9	10
Additionally , activated Akt is known to inhibit the pro apoptotic Bad protein , as well as the FoxO and Myc family of proteins .	Additionally, activated Akt is known to inhibit the pro apoptotic Bad protein, as well as the FoxO and Myc family of proteins.	2	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	3	4	18	19
Moreover , Smad2/3 downregulates the Akt pathway , which otherwise reduces FoxO family activity XREF_BIBR .	Moreover, Smad2/3 downregulates the Akt pathway, which otherwise reduces FoxO family activity XREF_BIBR.	5	14	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	5	6	11	12
Rapamycin- or everolimus mediated inhibition of mTORC1 , mTORC2 and thereby Akt should support the maintenance of active Foxo factors within the nucleus in order to promote Foxp3 expression .	Rapamycin- or everolimus mediated inhibition of mTORC1, mTORC2 and thereby Akt should support the maintenance of active Foxo factors within the nucleus in order to promote Foxp3 expression.	4	19	support	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	11	12	18	19
The activation of Akt has been shown to downregulate FOXO , a protein that is over-expressed in type I SMA that contributes to muscle atrophy .	The activation of Akt has been shown to downregulate FOXO, a protein that is over-expressed in type I SMA that contributes to muscle atrophy.	1	12	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	3	4	9	10
These growth factors have in common that they can target keratinocytes , as opposed to PDGF XREF_BIBR , and that they , like insulin and PDGF , all increase Akt signaling which in turn will decrease FOXO activity and FOXO expression XREF_BIBR .	These growth factors have in common that they can target keratinocytes, as opposed to PDGF XREF_BIBR, and that they, like insulin and PDGF, all increase Akt signaling which in turn will decrease FOXO activity and FOXO expression XREF_BIBR.	29	37	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	29	30	36	37
Akt antagonizes nuclear localization of FoxO and is itself activated via phosphorylation .	Akt antagonizes nuclear localization of FoxO and is itself activated via phosphorylation.	0	9	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	0	1	5	6
In the next example , Akt inhibits Foxo by phosphorylation , hence the interaction sign is negative .	In the next example, Akt inhibits Foxo by phosphorylation, hence the interaction sign is negative.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	5	6	7	8
Similarly , Akt is known to block the functional activity of the FOXO transcription factors , including FOXO1 [ XREF_BIBR ] .	Similarly, Akt is known to block the functional activity of the FOXO transcription factors, including FOXO1 [XREF_BIBR].	2	14	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	2	3	12	13
AKT blocks the function of FOXO3a by phosphorylation leading to its sequestration in the cytoplasm away from the target genes .	AKT blocks the function of FOXO3a by phosphorylation leading to its sequestration in the cytoplasm away from the target genes.	0	6	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	0	1	5	6
Akt and PKB activation blocks FoxO3 activation and autophagy , and this effect is not prevented by rapamycin .	Akt and PKB activation blocks FoxO3 activation and autophagy, and this effect is not prevented by rapamycin.	0	6	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	0	1	5	6
In TRAMP mice , FoxO3a activity is negatively regulated by Akt and PKB through posttranslational modification .	In TRAMP mice, FoxO3a activity is negatively regulated by Akt and PKB through posttranslational modification.	4	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	10	11	4	5
Following 6 h and 18 h of MV , diaphragmatic Akt activation decreased in parallel with increased nuclear localization and transcriptional activation of FoxO1 and decreased nuclear localization of FoxO3 and FoxO4 , culminating in increased expression of the muscle specific ubiquitin ligases , muscle atrophy factor ( MAFbx ) and muscle ring finger-1 ( MuRF-1 ) .	Following 6 h and 18 h of MV, diaphragmatic Akt activation decreased in parallel with increased nuclear localization and transcriptional activation of FoxO1 and decreased nuclear localization of FoxO3 and FoxO4, culminating in increased expression of the muscle specific ubiquitin ligases, muscle atrophy factor (MAFbx) and muscle ring finger-1 (MuRF-1).	10	31	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	10	11	29	30
AKT inhibition can increase transcriptional activity of FOXO1A and FOXO3A .	AKT inhibition can increase transcriptional activity of FOXO1A and FOXO3A.	0	10	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3A	FOXO3A	FOXO3A	0	1	9	10
Alcohol inhibits Akt phosphorylation and increases the nuclear retention of FOXO3 .	Alcohol inhibits Akt phosphorylation and increases the nuclear retention of FOXO3.	0	11	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Alcohol inhibits Akt phosphorylation	akt	FOXO3	FOXO3	foxo3	2	3	10	11
In the PTEN-mutant LNCaP with a constitutively active Akt which is expected to phosphorylate FOXO3A [ XREF_BIBR ] , p53 activation can further hyperphosphorylate FOXO3A [ XREF_BIBR ] , thus preventing the proapoptotic FOXO3A transcription .	In the PTEN-mutant LNCaP with a constitutively active Akt which is expected to phosphorylate FOXO3A [XREF_BIBR], p53 activation can further hyperphosphorylate FOXO3A [XREF_BIBR], thus preventing the proapoptotic FOXO3A transcription.	3	34	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt which is expected to phosphorylate FOXO3A [XREF_BIBR], p53 activation can further hyperphosphorylate	akt	FOXO3A	FOXO3A	foxo3a	8	9	33	34
Besides , FoxO3 is inactivated by Akt XREF_BIBR , XREF_BIBR .	Besides, FoxO3 is inactivated by Akt XREF_BIBR, XREF_BIBR.	2	7	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	6	7	2	3
In addition , Akt inactivates Foxo3a by phosphorylation at serine 253 ( S253 ) and threonine 32 .	In addition, Akt inactivates Foxo3a by phosphorylation at serine 253 (S253) and threonine 32.	3	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	3	4	5	6
In the Pten deleted mice , constant Akt activation causes the suppression of Foxo3a .	In the Pten deleted mice, constant Akt activation causes the suppression of Foxo3a.	7	14	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	7	8	13	14
A recent study reported that inhibition of Akt promotes FOXO3a dependent apoptosis via inducing pro apoptotic response-4 ( Par-4 ) in prostate cancer [ XREF_BIBR ] .	A recent study reported that inhibition of Akt promotes FOXO3a dependent apoptosis via inducing pro apoptotic response-4 (Par-4) in prostate cancer [XREF_BIBR].	5	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	7	8	9	10
Furthermore , inhibition of AKT does not enhance nuclear localization of FOXO1 nor FOXO3 .	Furthermore, inhibition of AKT does not enhance nuclear localization of FOXO1 nor FOXO3.	2	14	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	4	5	13	14
Akt can inactivate FOXO3a via phosphorylation and subsequent translocation to cytosol , but in CTet treated cells , there was no evidence of variation in FOXO3a localization , suggesting that this transcription factor was not involved in the overexpression of p21 and CDKN1A .	Akt can inactivate FOXO3a via phosphorylation and subsequent translocation to cytosol, but in CTet treated cells, there was no evidence of variation in FOXO3a localization, suggesting that this transcription factor was not involved in the overexpression of p21 and CDKN1A.	0	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	0	1	3	4
When FOXO3A is activated by inhibition of PI3K and AKT pathway , FOXO3A can promote a wide range of cellular effects including cell cycle arrest , induction of autophagy , sensitization to chemotherapeutics , inhibition of metastasis and cell differentiation , and apoptotic cell death [ XREF_BIBR , XREF_BIBR ] .	When FOXO3A is activated by inhibition of PI3K and AKT pathway, FOXO3A can promote a wide range of cellular effects including cell cycle arrest, induction of autophagy, sensitization to chemotherapeutics, inhibition of metastasis and cell differentiation, and apoptotic cell death [XREF_BIBR, XREF_BIBR].	1	10	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3A	FOXO3A	FOXO3A	9	10	1	2
Active AKT inhibits the transcriptional activity of FOXO3a and thereby downregulates MnSOD , leading to an increased level of ROS that induces activation of the p53 and p21 WAF1 pathway and senescence .	Active AKT inhibits the transcriptional activity of FOXO3a and thereby downregulates MnSOD, leading to an increased level of ROS that induces activation of the p53 and p21 WAF1 pathway and senescence.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	1	2	7	8
Moreover , PI3K and AKT can suppress FoxO3a , which is a critical promoter of the apoptosis in fibroblasts 31 .	Moreover, PI3K and AKT can suppress FoxO3a, which is a critical promoter of the apoptosis in fibroblasts 31.	2	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO3a	FoxO3a	FoxO3a	4	5	7	8
Pharmacological blockade or genetic loss of PTEN leads to Akt dependent inhibition of Foxo3a and subsequent loss of Foxp3 and tumor regression .	Pharmacological blockade or genetic loss of PTEN leads to Akt dependent inhibition of Foxo3a and subsequent loss of Foxp3 and tumor regression.	9	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	9	10	13	14
Akt represses the function of FoXO3 , and since FoXO3 acts as an oncogene in AML , 46 we determined the FoXO3 protein level .	Akt represses the function of FoXO3, and since FoXO3 acts as an oncogene in AML, 46 we determined the FoXO3 protein level.	0	6	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoXO3	FoXO3	FoXO3	0	1	5	6
The transcription factor FOXO3a is induced by nutrient restriction and oxidative stress , is inhibited by Akt signaling , and mediates the protective upregulation of antioxidant proteins such as MnSOD and later the proapoptotic regulation of FasL , Bim , and Bcl-6 [ XREF_BIBR ] .	The transcription factor FOXO3a is induced by nutrient restriction and oxidative stress, is inhibited by Akt signaling, and mediates the protective upregulation of antioxidant proteins such as MnSOD and later the proapoptotic regulation of FasL, Bim, and Bcl-6 [XREF_BIBR].	0	20	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	16	17	3	4
A decrease in AKT signaling activates FOXO3A and induces apoptosis XREF_BIBR ; therefore , it is possible that a reduction in EPS8 levels decreases AKT , triggering phosphorylation of FOXO3A and cancer cells to undergo apoptosis instead of continued proliferation .	A decrease in AKT signaling activates FOXO3A and induces apoptosis XREF_BIBR; therefore, it is possible that a reduction in EPS8 levels decreases AKT, triggering phosphorylation of FOXO3A and cancer cells to undergo apoptosis instead of continued proliferation.	3	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3A	FOXO3A	FOXO3A	3	4	6	7
AKT , IKKh , and ERK phosphorylate and down-regulate the tumor suppressors FOXO3a and TSC .	AKT, IKKh, and ERK phosphorylate and down-regulate the tumor suppressors FOXO3a and TSC.	0	14	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	0	1	12	13
FOXO3 is the central mediator of the pro proliferative PI3K and AKT signaling pathway in which AKT phosphorylation causes inactivation , nuclear exclusion , and subsequent degradation of FOXO3 .	FOXO3 is the central mediator of the pro proliferative PI3K and AKT signaling pathway in which AKT phosphorylation causes inactivation, nuclear exclusion, and subsequent degradation of FOXO3.	16	29	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	FOXO3	FOXO3	foxo3	16	17	28	29
XREF_BIBR , XREF_BIBR Xu et al XREF_BIBR reported that active AKT inhibits the transcriptional activity of FOXO3a and thereby downregulates MnSOD , leading to an increased level of ROS that induced activation of the p53 and p21 pathway and senescence .	XREF_BIBR, XREF_BIBR Xu et al XREF_BIBR reported that active AKT inhibits the transcriptional activity of FOXO3a and thereby downregulates MnSOD, leading to an increased level of ROS that induced activation of the p53 and p21 pathway and senescence.	9	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	10	11	16	17
Cisplatin treatment leads to a decrease in PTEN levels , resulting in the increased phosphorylation of AKT and enhanced FOXO3a extra-nucleation followed by an increase inthe multiple , simultaneous , activation of primordial follicles .	Cisplatin treatment leads to a decrease in PTEN levels, resulting in the increased phosphorylation of AKT and enhanced FOXO3a extra-nucleation followed by an increase inthe multiple, simultaneous, activation of primordial follicles.	0	20	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	Cisplatin treatment leads to a decrease in PTEN levels, resulting in the increased phosphorylation of AKT	akt	FOXO3a	FOXO3a	foxo3a	16	17	19	20
AKT , IKK and ERK phosphorylate and downregulate the tumor suppressor FOXO3a ( XREF_FIG ) .	AKT, IKK and ERK phosphorylate and downregulate the tumor suppressor FOXO3a (XREF_FIG).	0	13	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	0	1	11	12
Other studies have shown that activated AKT can negatively regulate FOXO3a through direct phosphorylation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Other studies have shown that activated AKT can negatively regulate FOXO3a through direct phosphorylation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	11	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	6	7	10	11
Moreover , simultaneous Wnt-beta-catenin pathway hyperactivation and PI3K-AKT signaling inhibition promote nuclear accumulation of beta-catenin and FOXO3a , and eventual metastasis [ XREF_BIBR ] .	Moreover, simultaneous Wnt-beta-catenin pathway hyperactivation and PI3K-AKT signaling inhibition promote nuclear accumulation of beta-catenin and FOXO3a, and eventual metastasis [XREF_BIBR].	7	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO3a	FOXO3a	FOXO3a	7	8	16	17
14 Stress conditions , such as chemotherapy , override growth-factor-mediated phosphorylation and inactivation of FOXO3 by PKB , which results in the relocation of FOXO3 to the nucleus .	14 Stress conditions, such as chemotherapy, override growth-factor-mediated phosphorylation and inactivation of FOXO3 by PKB, which results in the relocation of FOXO3 to the nucleus.	12	17	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PKB	PKB	PKB	FOXO3	FOXO3	FOXO3	16	17	14	15
However , PI3K and AKT can inhibit the activity of FoxO3a , and hinder the atrophy process , thereby regulating the muscle atrophy [ XREF_BIBR , XREF_BIBR ] .	However, PI3K and AKT can inhibit the activity of FoxO3a, and hinder the atrophy process, thereby regulating the muscle atrophy [XREF_BIBR, XREF_BIBR].	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO3a	FoxO3a	FoxO3a	4	5	10	11
We recently demonstrated that AKT activation plays a role in prostate cancer progression and inhibits the pro apoptotic function of FOXO3a and Par-4 .	We recently demonstrated that AKT activation plays a role in prostate cancer progression and inhibits the pro apoptotic function of FOXO3a and Par-4.	4	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	4	5	20	21
Additionally , we have demonstrated FOXO3A activity is negatively regulated by Akt and PKB through post translational modifications .	Additionally, we have demonstrated FOXO3A activity is negatively regulated by Akt and PKB through post translational modifications.	5	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3A	FOXO3A	FOXO3A	11	12	5	6
Literature has shown that FOXO3a is negatively regulated by Akt dependent phosphorylation at three specific sites ( Thr32 , Ser253 , and Ser315 ) , and phosphorylated FOXO3a will bind to 14-3-3 protein and be exported from the nucleus to the cytoplasm , thereby losing its transcriptional function [ XREF_BIBR , XREF_BIBR ] .	Literature has shown that FOXO3a is negatively regulated by Akt dependent phosphorylation at three specific sites (Thr32, Ser253, and Ser315), and phosphorylated FOXO3a will bind to 14-3-3 protein and be exported from the nucleus to the cytoplasm, thereby losing its transcriptional function [XREF_BIBR, XREF_BIBR].	4	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	FOXO3a	FOXO3a	foxo3a	9	10	4	5
There are evidences showing that FOXO3a is inactivated by over-activation of PI3K and Akt cascade [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	There are evidences showing that FOXO3a is inactivated by over-activation of PI3K and Akt cascade [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	14	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	13	14	5	6
It acts by reestablishing the Akt mediated inhibition of FoxO3 , thereby suppressing atrogene expression and limiting induction of autophagy .	It acts by reestablishing the Akt mediated inhibition of FoxO3, thereby suppressing atrogene expression and limiting induction of autophagy.	4	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	5	6	9	10
In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm , and nuclear targeted FOXO3a does not induce cell death or cell cycle arrest .	In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm, and nuclear targeted FOXO3a does not induce cell death or cell cycle arrest.	5	12	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	5	6	11	12
Expression trends in key apoptosis genes along the AKT and p53 signaling axis ( upregulation of transcriptional targets of FOXO3A : TNFRSF10B , GADD45A , GADD45B and FAS ) and cytokine and chemokine receptors ( downregulation of IL1R1 , CCR2 , CCR6 , CD58 and CXCR3 ) mimic those observed in T regs from T1D subjects , at one or more time-points .	Expression trends in key apoptosis genes along the AKT and p53 signaling axis (upregulation of transcriptional targets of FOXO3A : TNFRSF10B, GADD45A, GADD45B and FAS) and cytokine and chemokine receptors (downregulation of IL1R1, CCR2, CCR6, CD58 and CXCR3) mimic those observed in T regs from T1D subjects, at one or more time-points.	5	20	upregulation	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3A	FOXO3A	FOXO3A	8	9	19	20
Inhibition of AKT promotes FOXO3a dependent apoptosis in prostate cancer .	Inhibition of AKT promotes FOXO3a dependent apoptosis in prostate cancer.	0	6	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	2	3	4	5
In the current study , we found that the upregulation of miR-182-5p decreased AKT phosphorylation and significantly increased the transactivation activity of FOXO3a , suggesting that this pathway might represent a new mechanism underlying the development of RCC .	In the current study, we found that the upregulation of miR-182-5p decreased AKT phosphorylation and significantly increased the transactivation activity of FOXO3a, suggesting that this pathway might represent a new mechanism underlying the development of RCC.	11	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	miR-182-5p decreased AKT phosphorylation	akt	FOXO3a	FOXO3a	foxo3a	13	14	22	23
New studies show that the Foxo proteins Foxo1 and Foxo3a , which are inactivated by Akt , drive Foxp3 expression .	New studies show that the Foxo proteins Foxo1 and Foxo3a, which are inactivated by Akt, drive Foxp3 expression.	2	16	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	15	16	9	10
Upon activation following mitogenic stimulation , Akt translocates to the nucleus and phosphorylates FoxO3A , decreasing FoxO3A activity .	Upon activation following mitogenic stimulation, Akt translocates to the nucleus and phosphorylates FoxO3A, decreasing FoxO3A activity.	6	17	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt translocates to the nucleus	akt	FoxO3A	FoxO3A	foxo3a	6	7	16	17
Upon type I IFN stimulation , the transcription of IRF7 is induced and the PI3K and Akt pathway is also activated , which in turn induces FOXO3 degradation .	Upon type I IFN stimulation, the transcription of IRF7 is induced and the PI3K and Akt pathway is also activated, which in turn induces FOXO3 degradation.	14	27	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3	FOXO3	FOXO3	16	17	26	27
Previous studies have shown that IKBKE directly activates Akt and that Akt inhibits FOXO3a by phosphorylation of Ser32 , Ser253 and Ser315 .	Previous studies have shown that IKBKE directly activates Akt and that Akt inhibits FOXO3a by phosphorylation of Ser32, Ser253 and Ser315.	11	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	11	12	13	14
Inhibition of Akt Ser473 resulted in upregulation of FOXO3A in the nucleus along with reductions in the endogenous levels of FOXO3A , which predominantly resides in the cytosol .	Inhibition of Akt Ser473 resulted in upregulation of FOXO3A in the nucleus along with reductions in the endogenous levels of FOXO3A, which predominantly resides in the cytosol.	2	9	resulted in upregulation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3A	FOXO3A	FOXO3A	2	3	8	9
As the FOXO3A transcription factor can be deactivated by AKT , which is activated by phosphorylation , PML-NB deficiency or its functional deletion activates the phosphorylation of AKT , which results in deficient FOXO3A transcription activity .	As the FOXO3A transcription factor can be deactivated by AKT, which is activated by phosphorylation, PML-NB deficiency or its functional deletion activates the phosphorylation of AKT, which results in deficient FOXO3A transcription activity.	2	13	deactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3A	FOXO3A	FOXO3A	9	10	2	3
In the present study , it was demonstrated that MTZ significantly inhibits pS473 Akt phosphorylation and causes nuclear localization and activation of FOXO3 in osteosarcoma cells ( XREF_FIG ) .	In the present study, it was demonstrated that MTZ significantly inhibits pS473 Akt phosphorylation and causes nuclear localization and activation of FOXO3 in osteosarcoma cells (XREF_FIG).	9	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	MTZ significantly inhibits pS473 Akt phosphorylation	akt	FOXO3	FOXO3	foxo3	13	14	22	23
Since FOXO3A is negatively regulated by AKT , the negative association between phospho-GSK3 and the forkhead protein is likely an indicator of AKT activity in the individual patients .	Since FOXO3A is negatively regulated by AKT, the negative association between phospho-GSK3 and the forkhead protein is likely an indicator of AKT activity in the individual patients.	1	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3A	FOXO3A	FOXO3A	6	7	1	2
Because apoptosis is abnormally reduced in bim-/- mast cells , these data provide evidence that Akt mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells .	Because apoptosis is abnormally reduced in bim-/- mast cells, these data provide evidence that Akt mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells.	15	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	15	16	19	20
Akt inhibition resulting from growth factor depletion also causes FOXO3 activation , although via a different mechanism .	Akt inhibition resulting from growth factor depletion also causes FOXO3 activation, although via a different mechanism.	0	10	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3	FOXO3	FOXO3	0	1	9	10
Akt inactivates Foxo3a through an extracellular signaling pathway such as insulin signaling , so the effect of insulin for follicular activation is by the inhibition of FOXO3 [ XREF_BIBR , XREF_BIBR ] .	Akt inactivates Foxo3a through an extracellular signaling pathway such as insulin signaling, so the effect of insulin for follicular activation is by the inhibition of FOXO3 [XREF_BIBR, XREF_BIBR].	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	0	1	2	3
Taken together , these data support that the TRIB2 COP1 domain promotes AKT activation repressing FOXO3a and p53 activity , thereby fuelling cellular resistance to PI3K inhibitor regimes .	Taken together, these data support that the TRIB2 COP1 domain promotes AKT activation repressing FOXO3a and p53 activity, thereby fuelling cellular resistance to PI3K inhibitor regimes.	12	18	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	12	13	15	16
15 In addition , FOXO3 is also the central mediator of the pro proliferative phosphoinositide 3-kinase/AKT signalling pathway in which AKT phosphorylation causes the inactivation , nuclear exclusion and subsequently degradation of FOXO3 .	15 In addition, FOXO3 is also the central mediator of the pro proliferative phosphoinositide 3-kinase/AKT signalling pathway in which AKT phosphorylation causes the inactivation, nuclear exclusion and subsequently degradation of FOXO3.	20	33	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	FOXO3	FOXO3	foxo3	20	21	32	33
Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival .	Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival.	0	5	Inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	4	5	2	3
To address this question in more detail , we examined gene expression , subcellular localization , and response to AKT inhibition of FOXO1 and FOXO3 , the main FOXO expressed in HSPCs ( haematopoietic stem and progenitor cells ) .	To address this question in more detail, we examined gene expression, subcellular localization, and response to AKT inhibition of FOXO1 and FOXO3, the main FOXO expressed in HSPCs (haematopoietic stem and progenitor cells).	19	25	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	19	20	24	25
ROS overproduction activated Akt and PKB kinase , which phosphorylated and inactivated FOXO3a protein ( XREF_FIG ) .	ROS overproduction activated Akt and PKB kinase, which phosphorylated and inactivated FOXO3a protein (XREF_FIG).	0	13	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	ROS overproduction activated Akt and PKB kinase, which phosphorylated	akt	FOXO3a	FOXO3a	foxo3a	3	4	12	13
Importantly , PI3K and autophagy pathways are tightly related , as mTORC1 suppress autophagy by inhibiting ULK1 , and the transcription factor FoxO3 , which is inhibited by active Akt , regulates a number of autophagy related genes , including LC3 , GABARAPL1 , BNIP3 , PIK3C3 , and ULK1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Importantly, PI3K and autophagy pathways are tightly related, as mTORC1 suppress autophagy by inhibiting ULK1, and the transcription factor FoxO3, which is inhibited by active Akt, regulates a number of autophagy related genes, including LC3, GABARAPL1, BNIP3, PIK3C3, and ULK1 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	19	31	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	29	30	22	23
Therefore , in high-stage-derived NB cells FOXO3 inactivation by PKB is disrupted by an unknown mechanism , possibly via stress induced kinases [ XREF_BIBR , XREF_BIBR ] .	Therefore, in high-stage-derived NB cells FOXO3 inactivation by PKB is disrupted by an unknown mechanism, possibly via stress induced kinases [XREF_BIBR, XREF_BIBR].	6	10	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	PKB	PKB	PKB	FOXO3	FOXO3	FOXO3	9	10	6	7
Here we report that FL induces AKT and PKB activation , which in turn phosphorylates and thereby inactivates the Forkhead protein FoxO3 in the progenitor cell line FDC-P1 stably expressing murine FLT3 receptor .	Here we report that FL induces AKT and PKB activation, which in turn phosphorylates and thereby inactivates the Forkhead protein FoxO3 in the progenitor cell line FDC-P1 stably expressing murine FLT3 receptor.	8	22	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	FoxO3	FoxO3	FoxO3	8	9	21	22
Indeed , it is known that mTOR inhibition by rapamycin induces autophagy without affecting gene expression , while Akt can repress the transcription factor FoxO3 .	Indeed, it is known that mTOR inhibition by rapamycin induces autophagy without affecting gene expression, while Akt can repress the transcription factor FoxO3.	18	25	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	18	19	24	25
In breast cancer stem like cells , FoxO3 activation by Akt inhibition reduced stemness and triggered cell death ; overexpression of dominant negative FoxO3 retained stem cell marker expression and viability [ XREF_BIBR ] .	In breast cancer stem like cells, FoxO3 activation by Akt inhibition reduced stemness and triggered cell death; overexpression of dominant negative FoxO3 retained stem cell marker expression and viability [XREF_BIBR].	7	11	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	10	11	7	8
Furthermore , the proapoptotic gene FOXO3A , which is negatively regulated by AKT , was up-regulated 7- and 25-fold in lapatinib responsive SKBr3 and BT474 cells , respectively .	Furthermore, the proapoptotic gene FOXO3A, which is negatively regulated by AKT, was up-regulated 7- and 25-fold in lapatinib responsive SKBr3 and BT474 cells, respectively.	2	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3A	FOXO3A	FOXO3A	12	13	5	6
Given the fact that FOXO proteins are direct targets of Akt signaling , the authors assessed the role of FOXO3 and demonstrated that constitutive activation of Akt inhibits the transcriptional activity of FOXO3 leading to a decrease in the expression of ROS detoxifying enzymes and therefore increase in intra-cellular ROS level .	Given the fact that FOXO proteins are direct targets of Akt signaling, the authors assessed the role of FOXO3 and demonstrated that constitutive activation of Akt inhibits the transcriptional activity of FOXO3 leading to a decrease in the expression of ROS detoxifying enzymes and therefore increase in intra-cellular ROS level.	24	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3	FOXO3	FOXO3	26	27	32	33
We have previously shown that Akt and ERK inhibition results in Foxo3a activation , translocation to the nucleus and TRAIL-induction [ XREF_BIBR ] .	We have previously shown that Akt and ERK inhibition results in Foxo3a activation, translocation to the nucleus and TRAIL-induction [XREF_BIBR].	5	13	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	5	6	11	12
There are also reports that FOXO3A is negatively regulated by AKT , and in the absence of AKT mediated phosphorylation , FOXO3A translocates to nucleus .	There are also reports that FOXO3A is negatively regulated by AKT, and in the absence of AKT mediated phosphorylation, FOXO3A translocates to nucleus.	5	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3A	FOXO3A	FOXO3A	10	11	5	6
XREF_BIBR In addition , AKT activation suppresses FOXO3 activation and autophagy independently of MTOR .	XREF_BIBR In addition, AKT activation suppresses FOXO3 activation and autophagy independently of MTOR.	4	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	4	5	7	8
Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupled of the Akt-FOXO3a signaling axis , as in these breast cancers active Akt fails to inactivate and re-localize FOXO3a to the cytoplasm and that nuclear targeted FOXO3a does not induce cell death or cell cycle arrest .	Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupled of the Akt-FOXO3a signaling axis, as in these breast cancers active Akt fails to inactivate and re-localize FOXO3a to the cytoplasm and that nuclear targeted FOXO3a does not induce cell death or cell cycle arrest.	32	40	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	33	34	39	40
54 Thus , it is conceivable that reduced activity of the mTORC and AKT axis supports FOXO3 transcriptional activity in our model system .	54 Thus, it is conceivable that reduced activity of the mTORC and AKT axis supports FOXO3 transcriptional activity in our model system.	11	18	supports	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	13	14	16	17
Previously , it has been reported that transcription factor FOXO3a ( formerly known as FKHRL-1 ) is a regulator of ER-alpha gene transcription and the FOXO3a mediated regulation of ER-alpha can be repressed by PI3K and Akt signaling pathway .	Previously, it has been reported that transcription factor FOXO3a (formerly known as FKHRL-1) is a regulator of ER-alpha gene transcription and the FOXO3a mediated regulation of ER-alpha can be repressed by PI3K and Akt signaling pathway.	25	38	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	36	37	25	26
Akt is known to inhibit Foxo3a from translocating to the nucleus and regulating the transcription of genes by phosphorylating Foxo3a at T32 .	Akt is known to inhibit Foxo3a from translocating to the nucleus and regulating the transcription of genes by phosphorylating Foxo3a at T32.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	0	1	5	6
FoxO3 , blocked by Akt and PKB , controls the expression of autophagy related genes , including LC3 and Bnip3 , to regulate autophagy XREF_BIBR .	FoxO3, blocked by Akt and PKB, controls the expression of autophagy related genes, including LC3 and Bnip3, to regulate autophagy XREF_BIBR.	0	8	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	FoxO3	FoxO3	FoxO3	6	7	0	1
It is known that FOXO3a is inactivated through its phosphorylation by AKT and subsequently becomes sequestered in the cytoplasm 45 .	It is known that FOXO3a is inactivated through its phosphorylation by AKT and subsequently becomes sequestered in the cytoplasm 45.	4	14	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	11	12	4	5
In this way , activation of the PIK3 and AKT signaling pathway inhibits FOXO3 and indirectly induces FOXM1 activity [ XREF_BIBR ] .	In this way, activation of the PIK3 and AKT signaling pathway inhibits FOXO3 and indirectly induces FOXM1 activity [XREF_BIBR].	9	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	9	10	13	14
This is indicated by XREF_FIG and XREF_FIG wherein Akt is deactivated by Abeta expression and constitutively active ( CA ) Akt ( myrAkt ) reverses nuclear Foxo3A localization .	This is indicated by XREF_FIG and XREF_FIG wherein Akt is deactivated by Abeta expression and constitutively active (CA) Akt (myrAkt) reverses nuclear Foxo3A localization.	16	27	reverses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3A	Foxo3A	Foxo3A	20	21	26	27
Downregulation of FOXO3A gene and protein expression by siRNA [ XREF_BIBR ] and inhibition of FOXO3A by overexpression of Akt [ XREF_BIBR ] have been shown to accelerate senescence in HDFs .	Downregulation of FOXO3A gene and protein expression by siRNA [XREF_BIBR] and inhibition of FOXO3A by overexpression of Akt [XREF_BIBR] have been shown to accelerate senescence in HDFs.	10	21	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	overexpression of Akt	akt	FOXO3A	FOXO3A	foxo3a	19	20	15	16
We also found that ATG suppressed PDGF-BB-induced phosphorylation of Akt and its downstream transcription factor Forkhead box O 3a ( FOXO3a ) , decreased binding of FOXO3a to 14-3-3 protein , and stimulated nuclear translocation of FOXO3a in activated HSCs .	We also found that ATG suppressed PDGF-BB-induced phosphorylation of Akt and its downstream transcription factor Forkhead box O 3a (FOXO3a), decreased binding of FOXO3a to 14-3-3 protein, and stimulated nuclear translocation of FOXO3a in activated HSCs.	4	30	decreased	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Akt	ATG suppressed PDGF-BB-induced phosphorylation of Akt	akt	FOXO3a	binding of FOXO3a to 14-3-3 protein	foxo3a	9	10	26	27
Immunoblotting data showed reduced phosphorylation of Akt , mTOR , GSK3beta and Foxo3a , upregulated Foxo3a and PTEN , as well as dampened SERCA2a , PGC1alpha and UCP-2 following alcohol intake .	Immunoblotting data showed reduced phosphorylation of Akt, mTOR, GSK3beta and Foxo3a, upregulated Foxo3a and PTEN, as well as dampened SERCA2a, PGC1alpha and UCP-2 following alcohol intake.	4	30	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	phosphorylation of Akt	akt	Foxo3a	Foxo3a	foxo3a	6	7	15	16
Upon phosphorylation by Akt , FoxO3a is inactivated and accentuated in cytoplasm .	Upon phosphorylation by Akt, FoxO3a is inactivated and accentuated in cytoplasm.	1	9	inactivated	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	3	4	5	6
The inhibition of PI3K-Akt by LY294002 enhanced the binding of FOXO3a to the PRNP promoter , which then down-regulated the expression of PRNP by inducing the nuclear retention of FOXO3a .	The inhibition of PI3K-Akt by LY294002 enhanced the binding of FOXO3a to the PRNP promoter, which then down-regulated the expression of PRNP by inducing the nuclear retention of FOXO3a.	1	11	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FOXO3a	FOXO3a	FOXO3a	3	4	10	11
FoxO3a is inhibited by Akt , IkappaB kinase beta ( IKKbeta ) , and extracellular-signal-regulated kinase ( Erk ) , which promote FoxO3a sequestration in the cytosol , and accumulates in the nucleus upon phosphorylation by c-Jun N-terminal kinase ( JNK ) and p38 mitogen activated kinase ( p38 MAPK ) .	FoxO3a is inhibited by Akt, IkappaB kinase beta (IKKbeta), and extracellular-signal-regulated kinase (Erk), which promote FoxO3a sequestration in the cytosol, and accumulates in the nucleus upon phosphorylation by c-Jun N-terminal kinase (JNK) and p38 mitogen activated kinase (p38 MAPK).	0	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	4	5	0	1
Inhibition of Akt and ERK pathways caused nuclear accumulation and activation of FoxO3a more effectively than blockade of either alone , and promoted differentiation of GSCs in a FoxO3a expression dependent fashion .	Inhibition of Akt and ERK pathways caused nuclear accumulation and activation of FoxO3a more effectively than blockade of either alone, and promoted differentiation of GSCs in a FoxO3a expression dependent fashion.	2	13	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	2	3	12	13
To further confirm that FOXO3a is a downstream target of AKT phosphorylation in RCC cells , we found that a small molecule inhibitor of AKT ( LY294002 ) could significantly activate FOXO3a ( Additional file XREF_SUPPLEMENTARY : Figure S4 ) .	To further confirm that FOXO3a is a downstream target of AKT phosphorylation in RCC cells, we found that a small molecule inhibitor of AKT (LY294002) could significantly activate FOXO3a (Additional file XREF_SUPPLEMENTARY : Figure S4).	22	35	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	24	25	31	32
Akt inhibits FoxO3a function by phosphorylating FoxO3a on Thr 32 , Ser 253 and Ser 315 , which results in cytoplasmic retention of FoxO3a .	Akt inhibits FoxO3a function by phosphorylating FoxO3a on Thr 32, Ser 253 and Ser 315, which results in cytoplasmic retention of FoxO3a.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	0	1	2	3
Specifically , Akt activation by CD31 signals prevents the localization of the forkhead transcription factor FoxO3 to the nucleus , thus inhibiting transcription of the proapoptotic genes CD95 and Fas and caspase 7 and de-repressing the expression of the antiapoptotic gene cFlar .	Specifically, Akt activation by CD31 signals prevents the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting transcription of the proapoptotic genes CD95 and Fas and caspase 7 and de-repressing the expression of the antiapoptotic gene cFlar.	2	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	2	3	15	16
To date , protein kinases AKT , ERK1/2 , and IkappaB Kinase beta ( IKKbeta ) have been shown to down-regulate FoxO3 stability through phosphorylation [ XREF_BIBR ] leading to FoxO3 ubiquitination and degradation [ XREF_BIBR ] .	To date, protein kinases AKT, ERK1/2, and IkappaB Kinase beta (IKKbeta) have been shown to down-regulate FoxO3 stability through phosphorylation [XREF_BIBR] leading to FoxO3 ubiquitination and degradation [XREF_BIBR].	3	22	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO3	FoxO3	FoxO3	5	6	21	22
Akt activation after Pten deletion activates mTORC1 but does not inactivate FoxO3a .	Akt activation after Pten deletion activates mTORC1 but does not inactivate FoxO3a.	0	12	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	0	1	11	12
Akt phosphorylated at Ser473 phosphorylates FOXO3a at multiple sites , including Ser253 and Thr32 , and prevents nuclear translocation of FOXO3a , inhibiting its function as a transcription factor of pro apoptotic genes [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Akt phosphorylated at Ser473 phosphorylates FOXO3a at multiple sites, including Ser253 and Thr32, and prevents nuclear translocation of FOXO3a, inhibiting its function as a transcription factor of pro apoptotic genes [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	21	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylated at Ser473 phosphorylates FOXO3a	akt	FOXO3a	FOXO3a	foxo3a	0	1	20	21
AKT negatively regulates the pro apoptotic protein FOXO3a through the shuttling and degradation of FOXO3a XREF_BIBR .	AKT negatively regulates the pro apoptotic protein FOXO3a through the shuttling and degradation of FOXO3a XREF_BIBR.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	0	1	7	8
Collectively , the results suggest that cisplatin enhances EGFR and AKT kinase activity and that the activated EGFR and AKT further inactivates FOXO3a via phosphorylation .	Collectively, the results suggest that cisplatin enhances EGFR and AKT kinase activity and that the activated EGFR and AKT further inactivates FOXO3a via phosphorylation.	17	24	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	19	20	22	23
Thus , our studies suggest that inhibition of ERK and AKT pathways by EGCG act together to activate FOXO3a which can regulate pancreatic cancer growth .	Thus, our studies suggest that inhibition of ERK and AKT pathways by EGCG act together to activate FOXO3a which can regulate pancreatic cancer growth.	8	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	10	11	18	19
We identify for the first time the Forkhead box protein FOXO3a ( formerly termed FKHRL-1 ) , which is inactivated by Akt , as a key regulator of ERalpha gene transcription .	We identify for the first time the Forkhead box protein FOXO3a (formerly termed FKHRL-1), which is inactivated by Akt, as a key regulator of ERalpha gene transcription.	1	22	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	21	22	10	11
Constitutive activation of Akt phosphorylated and inhibited the transcription factor Foxo3a .	Constitutive activation of Akt phosphorylated and inhibited the transcription factor Foxo3a.	1	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylated	akt	Foxo3a	Foxo3a	foxo3a	3	4	10	11
However , the exact roles of YWHAZ and miR-22 in degradation of FOXO3a by AKT phosphorylation remains need to be clarified in future studies .	However, the exact roles of YWHAZ and miR-22 in degradation of FOXO3a by AKT phosphorylation remains need to be clarified in future studies.	10	16	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	FOXO3a	FOXO3a	foxo3a	14	15	12	13
The expression of a constitutively active form of Akt enhances the differentiation of all Th subsets including Th17 cells , and T-cell-specific deletion of Foxo1 and Foxo3a results in the autoimmunity with an increased Th17 differentiation in vivo .	The expression of a constitutively active form of Akt enhances the differentiation of all Th subsets including Th17 cells, and T-cell-specific deletion of Foxo1 and Foxo3a results in the autoimmunity with an increased Th17 differentiation in vivo.	6	27	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	8	9	26	27
Curiously , within RA patient populations , PKB dependent inactivation of FoxO1 , FoxO3a and FoxO4 correlates inversely with patient parameters of inflammatory disease activity ( erythrocyte sedimentation rate and serum C-reactive protein concentrations ) [ XREF_BIBR ] .	Curiously, within RA patient populations, PKB dependent inactivation of FoxO1, FoxO3a and FoxO4 correlates inversely with patient parameters of inflammatory disease activity (erythrocyte sedimentation rate and serum C-reactive protein concentrations) [XREF_BIBR].	7	14	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKB	PKB	PKB	FoxO3a	FoxO3a	FoxO3a	7	8	13	14
For example , Akt inactivates the Forkhead box protein FOXO3a that represents a key regulator of ER gene transcription .	For example, Akt inactivates the Forkhead box protein FOXO3a that represents a key regulator of ER gene transcription.	3	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	3	4	9	10
These data suggest that autocrine TGF-beta signaling , through an unknown mechanism , may suppress AKT inhibition of FOXO3a in CML LSCs .	These data suggest that autocrine TGF-beta signaling, through an unknown mechanism, may suppress AKT inhibition of FOXO3a in CML LSCs.	15	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	15	16	18	19
Thus , activated Akt inhibits FoxO1 , FoxO3 and FoxO4 through direct phosphorylation and indirectly activates mTORC1 , which in turn increases protein and lipid synthesis and induces insulin resistance XREF_BIBR .	Thus, activated Akt inhibits FoxO1, FoxO3 and FoxO4 through direct phosphorylation and indirectly activates mTORC1, which in turn increases protein and lipid synthesis and induces insulin resistance XREF_BIBR.	2	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	3	4	7	8
The fact that CD28 signals dampen suppression by Treg cells XREF_BIBR and , as a correlate , that CD28 blockade amplifies Treg suppression , as shown here , finds an explanation in that CD28 induces activation of AKT , which in turn inhibits Foxo1 and Foxo3 transcription factors that are required for the suppressive function of Tregs XREF_BIBR , XREF_BIBR , XREF_BIBR .	The fact that CD28 signals dampen suppression by Treg cells XREF_BIBR and, as a correlate, that CD28 blockade amplifies Treg suppression, as shown here, finds an explanation in that CD28 induces activation of AKT, which in turn inhibits Foxo1 and Foxo3 transcription factors that are required for the suppressive function of Tregs XREF_BIBR, XREF_BIBR, XREF_BIBR.	35	47	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Foxo3	Foxo3	Foxo3	37	38	45	46
The over-expressed AKT genes also inactivate FOXO3 and therefore disrupt the cell efforts toward apoptosis .	The over-expressed AKT genes also inactivate FOXO3 and therefore disrupt the cell efforts toward apoptosis.	2	7	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	2	3	6	7
Their data suggest that TGF-beta signaling ( predominantly TGF-beta1 ) , through an unknown mechanism , may suppress AKT inhibition of FOXO3a in CML LSCs , which may be critical for LSC maintenance .	Their data suggest that TGF-beta signaling (predominantly TGF-beta1), through an unknown mechanism, may suppress AKT inhibition of FOXO3a in CML LSCs, which may be critical for LSC maintenance.	18	22	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	18	19	21	22
These steps include physical interaction with BCL2 and attenuation of AKT dependent inhibition of FOXO3a functions , such as transcriptional induction of BIM and phosphorylation of ataxia telangiectasia mutated ( ATM ) after DNA damage .	These steps include physical interaction with BCL2 and attenuation of AKT dependent inhibition of FOXO3a functions, such as transcriptional induction of BIM and phosphorylation of ataxia telangiectasia mutated (ATM) after DNA damage.	10	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	10	11	14	15
Nonetheless AKT inhibition in the context of loss of NAD dependent SIRT1 deacetylase modulates FOXO3 localization in HSPCs .	Nonetheless AKT inhibition in the context of loss of NAD dependent SIRT1 deacetylase modulates FOXO3 localization in HSPCs.	1	15	modulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	1	2	14	15
Furthermore , it is known that activated Akt can suppress FoxO3a function .	Furthermore, it is known that activated Akt can suppress FoxO3a function.	6	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	7	8	10	11
Consequently , inhibition of Akt , for example by treatment with S-equol , a secondary metabolite of the natural anticancer isoflavone daidzein , prevents the degradation of FOXO3a and decreased prostate tumor growth [ XREF_BIBR ] .	Consequently, inhibition of Akt, for example by treatment with S-equol, a secondary metabolite of the natural anticancer isoflavone daidzein, prevents the degradation of FOXO3a and decreased prostate tumor growth [XREF_BIBR].	2	28	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	4	5	27	28
We demonstrated that AKT inhibition directly activated FoxO3a in response to selenite , an event crucial for selenite induced apoptosis .	We demonstrated that AKT inhibition directly activated FoxO3a in response to selenite, an event crucial for selenite induced apoptosis.	3	8	directly activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO3a	FoxO3a	FoxO3a	3	4	7	8
Akt inactivates FOXO3a through post-translational modification .	Akt inactivates FOXO3a through post-translational modification.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	0	1	2	3
Thus , it is important that the activation of Akt was repressed in order to promote up-regulation of Foxo3 and to facilitate its localization to nucleus in HepG2 cells after ergosterol peroxide treatment .	Thus, it is important that the activation of Akt was repressed in order to promote up-regulation of Foxo3 and to facilitate its localization to nucleus in HepG2 cells after ergosterol peroxide treatment.	7	19	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3	Foxo3	Foxo3	9	10	18	19
Because AKT inhibition activates transcriptional activity of FOXO3 by relieving the suppression pathway [ XREF_BIBR - XREF_BIBR ] , we also observed enhanced inhibition of AKT phosphorylation with combination treatment ( XREF_SUPPLEMENTARY ) .	Because AKT inhibition activates transcriptional activity of FOXO3 by relieving the suppression pathway [XREF_BIBR - XREF_BIBR], we also observed enhanced inhibition of AKT phosphorylation with combination treatment (XREF_SUPPLEMENTARY).	1	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	1	2	7	8
PKB has been demonstrated to negatively regulate members of a subfamily of forkhead transcription factors : AFX , FKHR , and FKHR-L1 .	PKB has been demonstrated to negatively regulate members of a subfamily of forkhead transcription factors : AFX, FKHR, and FKHR-L1.	0	22	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	FKHR-L1	FKHR-L1	FKHR-L1	0	1	21	22
FOXO3 action is inhibited by phosphorylation of AKT in the PI3K signaling pathway ( XREF_FIG ) .	FOXO3 action is inhibited by phosphorylation of AKT in the PI3K signaling pathway (XREF_FIG).	0	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	phosphorylation of AKT	akt	FOXO3	FOXO3	foxo3	7	8	0	1
Akt has been shown to relieve FoxO3a mediated suppression of the transcription factor FoxM1 [ XREF_BIBR ] , which regulates expression of numerous genes including NEDD4 [ XREF_BIBR ] .	Akt has been shown to relieve FoxO3a mediated suppression of the transcription factor FoxM1 [XREF_BIBR], which regulates expression of numerous genes including NEDD4 [XREF_BIBR].	0	8	relieve	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	0	1	6	7
p66Shc linked alpha 1 -AR to an Akt signaling pathway that selectively inactivated FOXO3a and downregulated mitochondrial MnSOD .	p66Shc linked alpha 1 -AR to an Akt signaling pathway that selectively inactivated FOXO3a and downregulated mitochondrial MnSOD.	7	14	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	7	8	13	14
It has recently been reported that deletion of the gene encoding PTEN , a negative regulator of PI3K-Akt signaling , was associated with exhaustion of 12-week CRU in mice 35 ; in addition , deletion of Foxo3a , a transcription factor that negatively regulates HSC cycling and is inhibited by Akt , has been associated with depletion of LT-HSCs in mice 36 .	It has recently been reported that deletion of the gene encoding PTEN, a negative regulator of PI3K-Akt signaling, was associated with exhaustion of 12-week CRU in mice 35; in addition, deletion of Foxo3a, a transcription factor that negatively regulates HSC cycling and is inhibited by Akt, has been associated with depletion of LT-HSCs in mice 36.	34	51	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	50	51	36	37
Deregulation of FOXO3A by hyperphosphorylated Akt in human prostate cancer cells .	Deregulation of FOXO3A by hyperphosphorylated Akt in human prostate cancer cells.	0	10	Deregulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	hyperphosphorylated Akt	akt	FOXO3A	FOXO3A	foxo3a	5	6	2	3
Based on these results , we conclude that the ERK5 signaling pathway promotes cell survival by downregulating FasL expression via a mechanism that implicates PKB dependent inhibition of Foxo3a downstream of phosphoinositide 3 kinase .	Based on these results, we conclude that the ERK5 signaling pathway promotes cell survival by downregulating FasL expression via a mechanism that implicates PKB dependent inhibition of Foxo3a downstream of phosphoinositide 3 kinase.	24	33	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKB	PKB	PKB	Foxo3a	Foxo3a	Foxo3a	24	25	28	29
In addition , Akt has been reported to inactivate FoxO3a and FoxO1 , two transcription factors which differentially impact on gene regulation .	In addition, Akt has been reported to inactivate FoxO3a and FoxO1, two transcription factors which differentially impact on gene regulation.	3	11	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	3	4	9	10
In our model of heart failure , both JNK and AKT were activated ; however , AKT failed to inhibit FOXO3a .	In our model of heart failure, both JNK and AKT were activated; however, AKT failed to inhibit FOXO3a.	16	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	16	17	20	21
Augmentation of Akt phosphorylation has been found to inactivate the FoxO3 pathway in EPCs [ XREF_BIBR ] .	Augmentation of Akt phosphorylation has been found to inactivate the FoxO3 pathway in EPCs [XREF_BIBR].	2	11	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	FoxO3	FoxO3	foxo3	2	3	10	11
Our studies demonstrate that FOXO3A activity is negatively regulated by Akt and PKB through posttranslational modifications .	Our studies demonstrate that FOXO3A activity is negatively regulated by Akt and PKB through posttranslational modifications.	4	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3A	FOXO3A	FOXO3A	10	11	4	5
Foxo3a can be inactivated and sequestered in the cytoplasm by AKT activation .	Foxo3a can be inactivated and sequestered in the cytoplasm by AKT activation.	0	11	inactivated	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Foxo3a	Foxo3a	Foxo3a	10	11	0	1
Since Akt is known to downregulate Foxo3a activity , this result suggests that the effect of Akt on Skp2 expression is likely though its effect on Foxo3a inhibition .	Since Akt is known to downregulate Foxo3a activity, this result suggests that the effect of Akt on Skp2 expression is likely though its effect on Foxo3a inhibition.	1	7	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	1	2	6	7
FOXO1 , FOXO3 and FOXO4 mRNAs are expressed ubiquitously in varying levels in mammals and negatively regulated by the PI3K and Akt pathway [ XREF_BIBR ] [ XREF_BIBR ] .	FOXO1, FOXO3 and FOXO4 mRNAs are expressed ubiquitously in varying levels in mammals and negatively regulated by the PI3K and Akt pathway [XREF_BIBR] [XREF_BIBR].	0	22	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3	FOXO3	FOXO3	21	22	2	3
We illustrate that the pathways of PI 3-K and Akt are critical for WISP1 to govern inhibitory post-translational phosphorylation of the forkhead transcription factor FoxO3a and sequester FoxO3a in the cytoplasm of neurons , since FoxO3a activation leads to caspase 1 and caspase 3 mediated apoptotic cell death .	We illustrate that the pathways of PI 3-K and Akt are critical for WISP1 to govern inhibitory post-translational phosphorylation of the forkhead transcription factor FoxO3a and sequester FoxO3a in the cytoplasm of neurons, since FoxO3a activation leads to caspase 1 and caspase 3 mediated apoptotic cell death.	4	28	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	9	10	27	28
In contrast , oxidative stress induced by Abeta can be antagonized by active Akt that , in turn , inhibits Foxo3a , a pro apoptotic transcription factor activated by reactive oxygen species generation .	In contrast, oxidative stress induced by Abeta can be antagonized by active Akt that, in turn, inhibits Foxo3a, a pro apoptotic transcription factor activated by reactive oxygen species generation.	10	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	13	14	20	21
It is known that an activity of FOXO3 is inhibited by Akt activation in a variety of cells XREF_BIBR XREF_BIBR , and Akt is kept activated in the HRG stimulated cells until 6hrs ( XREF_FIG ) , which suggests that a FOSL dependent expression and Akt dependent suppression of FOXO3 might shape the transient expression profiles of the genes belonging to Cluster 8 .	It is known that an activity of FOXO3 is inhibited by Akt activation in a variety of cells XREF_BIBR XREF_BIBR, and Akt is kept activated in the HRG stimulated cells until 6hrs (XREF_FIG), which suggests that a FOSL dependent expression and Akt dependent suppression of FOXO3 might shape the transient expression profiles of the genes belonging to Cluster 8.	45	50	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3	FOXO3	FOXO3	45	46	49	50
Stimulation of IIS activates the Akt kinase , which in turn inactivates Foxo3A through phosphorylation resulting in nuclear exclusion .	Stimulation of IIS activates the Akt kinase, which in turn inactivates Foxo3A through phosphorylation resulting in nuclear exclusion.	5	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3A	Foxo3A	Foxo3A	5	6	12	13
Akt not only promotes protein synthesis but also suppresses catabolism partly by phosphorylating and thereby inactivating FoxO3 .	Akt not only promotes protein synthesis but also suppresses catabolism partly by phosphorylating and thereby inactivating FoxO3.	0	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	0	1	16	17
Recently , we demonstrated that AKT negatively regulates the pro apoptotic function of prostate apoptosis response-4 ( Par-4 ) by inactivating FOXO3a .	Recently, we demonstrated that AKT negatively regulates the pro apoptotic function of prostate apoptosis response-4 (Par-4) by inactivating FOXO3a.	5	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	5	6	21	22
According to our results , total AKT levels were not reduced in Hdh 109/109 cells compared with WT cells , and no significant differences in pAKT1/2/3 ( S473 ) or pFOXO3a ( S253 ) levels were detected in Hdh cells with different genotypes .	According to our results, total AKT levels were not reduced in Hdh 109/109 cells compared with WT cells, and no significant differences in pAKT1/2/3 (S473) or pFOXO3a (S253) levels were detected in Hdh cells with different genotypes.	6	31	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT levels	akt	pFOXO3a	pFOXO3a	pfoxo3a	6	7	30	31
Unlike Akt , which only inhibited FOXO3a , IKBKE abrogated both FOXO3a- and FOXO3a-A3-induced p27 promoter activities ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Unlike Akt, which only inhibited FOXO3a, IKBKE abrogated both FOXO3a- and FOXO3a-A3-induced p27 promoter activities (XREF_FIG and XREF_SUPPLEMENTARY).	0	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	1	2	6	7
Since FOXO3a is negatively regulated by Akt signaling , 36 the ability of CCN5 to regulate Akt phosphorylation was determined using western blotting as well as in-cell-western blotting .	Since FOXO3a is negatively regulated by Akt signaling, 36 the ability of CCN5 to regulate Akt phosphorylation was determined using western blotting as well as in-cell-western blotting.	1	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	6	7	1	2
Taken together , these data revealed that high glucose impaired Akt activation , whereas , increased the FoxO3a activation in CMECs .	Taken together, these data revealed that high glucose impaired Akt activation, whereas, increased the FoxO3a activation in CMECs.	10	18	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	10	11	17	18
To test this idea , we examined whether the JNK mediated phosphorylation of 14-3-3 releases FOXO3a from 14-3-3 , as Akt inactivates the proapoptotic protein FOXO3a by direct phosphorylation , inducing its association with 14-3-3 .	To test this idea, we examined whether the JNK mediated phosphorylation of 14-3-3 releases FOXO3a from 14-3-3, as Akt inactivates the proapoptotic protein FOXO3a by direct phosphorylation, inducing its association with 14-3-3.	20	26	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	20	21	25	26
Akt also inhibits Foxo1 and Foxo3 transcription factors which are important for Foxp3 gene expression .	Akt also inhibits Foxo1 and Foxo3 transcription factors which are important for Foxp3 gene expression.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3	Foxo3	Foxo3	0	1	5	6
Interestingly , a number of these up-regulated and down-regulated genes are commonly regulated by the transcription factor FOXO3a ( XREF_SUPPLEMENTARY ) , which is negatively regulated by PDK1 substrates AKT or SGK .	Interestingly, a number of these up-regulated and down-regulated genes are commonly regulated by the transcription factor FOXO3a (XREF_SUPPLEMENTARY), which is negatively regulated by PDK1 substrates AKT or SGK.	12	31	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	29	30	17	18
These results suggested that EnSCs inhibited AKT mediated degradation of FoxO3a in vivo and in vitro , which would contribute to the anti-tumor properties of EnSCs on epithelial ovarian cancer .	These results suggested that EnSCs inhibited AKT mediated degradation of FoxO3a in vivo and in vitro, which would contribute to the anti-tumor properties of EnSCs on epithelial ovarian cancer.	5	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO3a	FoxO3a	FoxO3a	6	7	10	11
The guanine nucleotide exchange factor betaPix and the adaptor protein p66 ( Shc ) are important players in Akt independent inactivation of FOXO3a transcription factor .	The guanine nucleotide exchange factor betaPix and the adaptor protein p66 (Shc) are important players in Akt independent inactivation of FOXO3a transcription factor.	18	24	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	18	19	22	23
53 AKT , in turn , negatively regulates FOXO3a by phosphorylation , preventing its nuclear translocation .	53 AKT, in turn, negatively regulates FOXO3a by phosphorylation, preventing its nuclear translocation.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	1	2	8	9
By inducing FOXO3a nuclear to cytoplasmic export and subsequent degradation , AKT negatively regulates the pro death protein FOXO3a .	By inducing FOXO3a nuclear to cytoplasmic export and subsequent degradation, AKT negatively regulates the pro death protein FOXO3a.	1	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	11	12	2	3
Similarly , AKT and SGK1 have several of the same phosphorylation sites on FOXO3a , and inhibit the activity of FOXO3a .	Similarly, AKT and SGK1 have several of the same phosphorylation sites on FOXO3a, and inhibit the activity of FOXO3a.	2	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	2	3	20	21
AKT activation was further increased by two-fold in TRbeta PV/PV Pten +/- mice thyroids , leading to increased activity of the downstream mammalian target of rapamycin ( mTOR )-p70S6K signalling and decreased activity of the forkhead family member FOXO3a .	AKT activation was further increased by two-fold in TRbeta PV/PV Pten +/- mice thyroids, leading to increased activity of the downstream mammalian target of rapamycin (mTOR)-p70S6K signalling and decreased activity of the forkhead family member FOXO3a.	0	39	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	0	1	38	39
Previous studies have suggested that activating Akt negatively regulates FoxO transcription factors , and that the direct phosphorylation of Akt inhibits FoxO3a transcriptional activation .	Previous studies have suggested that activating Akt negatively regulates FoxO transcription factors, and that the direct phosphorylation of Akt inhibits FoxO3a transcriptional activation.	17	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	phosphorylation of Akt	akt	FoxO3a	FoxO3a	foxo3a	19	20	21	22
As a final mechanism , AKT was shown to inhibit the activity of forkhead box protein O3 ( FOXO3 ) , which results in reduced general protein turnover and catabolism mediated by the ubiquitin ligases atrogin 1 ( also known as FBXO32 ) and muscle specific RING finger protein 1 ( MURF1 ; also known as TRIM63 ) , and hence favours the net protein accumulation needed for hypertrophy 93 .	As a final mechanism, AKT was shown to inhibit the activity of forkhead box protein O3 (FOXO3), which results in reduced general protein turnover and catabolism mediated by the ubiquitin ligases atrogin 1 (also known as FBXO32) and muscle specific RING finger protein 1 (MURF1; also known as TRIM63), and hence favours the net protein accumulation needed for hypertrophy 93.	5	61	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	forkhead box protein O3	forkhead box protein O3	forkhead box protein O3	5	6	13	17
FOXO3a cytoplasmic staining ( p < 0.0001 , Chi-Square test ) was also significantly associated with P-Akt staining , which is supportive that the activated P-Akt can negatively regulate FOXO3a and relocate it from the nuclear to cytoplasm in most breast cancer samples .	FOXO3a cytoplasmic staining (p < 0.0001, Chi-Square test) was also significantly associated with P-Akt staining, which is supportive that the activated P-Akt can negatively regulate FOXO3a and relocate it from the nuclear to cytoplasm in most breast cancer samples.	23	31	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P-Akt	P-Akt	P-Akt	FOXO3a	FOXO3a	FOXO3a	25	26	29	30
In addition , AKT is known to suppress FOXO3 transcriptional activity , although data presented here do not show alterations in pAKT protein levels after SRT2104 treatment .	In addition, AKT is known to suppress FOXO3 transcriptional activity, although data presented here do not show alterations in pAKT protein levels after SRT2104 treatment.	3	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	3	4	8	9
We then used an AKT inhibitor ( LY294002 ) to verify whether the inhibition of AKT phosphorylation could induce the activation of FOXO3a in BCa cells .	We then used an AKT inhibitor (LY294002) to verify whether the inhibition of AKT phosphorylation could induce the activation of FOXO3a in BCa cells.	15	23	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	FOXO3a	FOXO3a	foxo3a	15	16	22	23
This was accompanied with a downregulation of p27 Kip1 ( Fig XREF_FIG G ) and upregulation of PIK3R3 ( encoding the PI3K regulatory subunit p55gamma ) and CCND1 ( Cyclin D1 ) ( Fig XREF_FIG D ) , known to be mediated through inactivation of FOXO3a by P-Akt ( Biggs etal , 1999 ; Brunet etal , 1999 ) .	This was accompanied with a downregulation of p27 Kip1 (Fig XREF_FIG G) and upregulation of PIK3R3 (encoding the PI3K regulatory subunit p55gamma) and CCND1 (Cyclin D1) (Fig XREF_FIG D), known to be mediated through inactivation of FOXO3a by P-Akt (Biggs etal, 1999; Brunet etal, 1999).	41	49	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	P-Akt	P-Akt	P-Akt	FOXO3a	FOXO3a	FOXO3a	47	48	45	46
Moreover , Akt , which inhibits FOXO3a , allows a final proliferative and anti-apoptotic response in high competence follicles .	Moreover, Akt, which inhibits FOXO3a, allows a final proliferative and anti-apoptotic response in high competence follicles.	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	2	3	6	7
Taken together our data strongly suggest that high expression of Id1 , through PKB mediated inhibition of FOXO3a , is critical for maintenance of the leukemic phenotype .	Taken together our data strongly suggest that high expression of Id1, through PKB mediated inhibition of FOXO3a, is critical for maintenance of the leukemic phenotype.	12	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	FOXO3a	FOXO3a	FOXO3a	13	14	17	18
Phosphorylation dependent inhibition of FOXO3a mediated by activated AKT promotes cell survival , and deregulation of this pathway strongly associates with poor prognosis of NB .	Phosphorylation dependent inhibition of FOXO3a mediated by activated AKT promotes cell survival, and deregulation of this pathway strongly associates with poor prognosis of NB.	2	9	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	8	9	4	5
In addition , FOXO3a and the TGFbeta signaling component SMAD3 , two transcription factors promoting FOXP3 expression , are negatively regulated by AKT downstream of TORC2 .	In addition, FOXO3a and the TGFbeta signaling component SMAD3, two transcription factors promoting FOXP3 expression, are negatively regulated by AKT downstream of TORC2.	3	25	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	22	23	3	4
Also , AKT CA expressions sequestered FOXO3a in the cytoplasm , while AKT DN expression kept it in the nuclei of PC3 cells ( XREF_FIG ) .	Also, AKT CA expressions sequestered FOXO3a in the cytoplasm, while AKT DN expression kept it in the nuclei of PC3 cells (XREF_FIG).	2	7	sequestered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT CA expressions	akt	FOXO3a	FOXO3a	foxo3a	2	3	6	7
Our present findings suggest that ghrelin reduced the apoptosis of thymic murine T cells upon in vivo ( XREF_FIG ) and in vitro ( XREF_FIG ) ghrelin administration , which is mediated by phosphorylation and inactivation of FoxO3a by Akt and Erk ( XREF_FIG ) .	Our present findings suggest that ghrelin reduced the apoptosis of thymic murine T cells upon in vivo (XREF_FIG) and in vitro (XREF_FIG) ghrelin administration, which is mediated by phosphorylation and inactivation of FoxO3a by Akt and Erk (XREF_FIG).	31	43	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	39	40	37	38
We demonstrated that AKT activation inactivated FoxO3 , an essential occurrence in apoptosis resistance when cells were treated with chemotherapeutic drugs .	We demonstrated that AKT activation inactivated FoxO3, an essential occurrence in apoptosis resistance when cells were treated with chemotherapeutic drugs.	3	10	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO3	FoxO3	FoxO3	3	4	6	7
The transcription factors FoxO consist of three members ; FoxO1 , FoxO3A , and FoxO4 , which are all inactivated by Akt XREF_BIBR .	The transcription factors FoxO consist of three members; FoxO1, FoxO3A, and FoxO4, which are all inactivated by Akt XREF_BIBR.	7	22	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3A	FoxO3A	FoxO3A	21	22	11	12
Two recent studies connect these observations to direct transcriptional regulation of Foxp3 by demonstrating that Foxo1 and Foxo3a , which are inactivated by Akt , bind to the Foxp3 promoter and to CNS2 and drive Foxp3 expression .	Two recent studies connect these observations to direct transcriptional regulation of Foxp3 by demonstrating that Foxo1 and Foxo3a, which are inactivated by Akt, bind to the Foxp3 promoter and to CNS2 and drive Foxp3 expression.	15	25	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	23	24	17	18
Taken together , our work strongly suggests that during IPF fibroblast interaction with polymerized collagen , inappropriately low PTEN function aberrantly activates Akt , which suppresses FoxO3a activity .	Taken together, our work strongly suggests that during IPF fibroblast interaction with polymerized collagen, inappropriately low PTEN function aberrantly activates Akt, which suppresses FoxO3a activity.	21	27	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	22	23	26	27
The PTEN-mutant LNCaP possess a constitutively active Akt which negatively regulates the forkhead transcription factor FOXO3A and FKHRL1 .	The PTEN-mutant LNCaP possess a constitutively active Akt which negatively regulates the forkhead transcription factor FOXO3A and FKHRL1.	3	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FKHRL1	FKHRL1	FKHRL1	7	8	17	18
Here , we report that Akt inactivation and activation of FOXO3a as observed in the skeletal muscle of ALS animals are responsible for ferritin up-regulation and iron accumulation .	Here, we report that Akt inactivation and activation of FOXO3a as observed in the skeletal muscle of ALS animals are responsible for ferritin up-regulation and iron accumulation.	5	12	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	5	6	10	11
Loss of Akt phosphorylation ( due to increased expression of miR-1 ) enhances the activation of FoxO3 which upregulates the transcription of MuRF1 and MAFBx [ XREF_BIBR ] .	Loss of Akt phosphorylation (due to increased expression of miR-1) enhances the activation of FoxO3 which upregulates the transcription of MuRF1 and MAFBx [XREF_BIBR].	2	25	enhances	Positive_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Akt	Akt phosphorylation	akt	FoxO3	FoxO3 which upregulates the transcription of MuRF1 and MAFBx	foxo3	2	3	16	17
Activation of the PI3K and Akt pathway is known to inhibit the FOXO3 family .	Activation of the PI3K and Akt pathway is known to inhibit the FOXO3 family.	3	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3	FOXO3	FOXO3	5	6	12	13
Akt can suppress FoxO3a function via direct phosphorylation of three target sites on the molecule , including the Thr 32 of FoxO3a , which has a consensus Akt target sequence ( RPRSCpT ) .	Akt can suppress FoxO3a function via direct phosphorylation of three target sites on the molecule, including the Thr 32 of FoxO3a, which has a consensus Akt target sequence (RPRSCpT).	0	4	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	0	1	3	4
Our data are consistent with the model proposed by Garrett , in which lapatinib increases ErbB3 mRNA levels by blocking AKT suppression of FoxO3a dependent ERBB3 transcription .	Our data are consistent with the model proposed by Garrett, in which lapatinib increases ErbB3 mRNA levels by blocking AKT suppression of FoxO3a dependent ERBB3 transcription.	20	26	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO3a	FoxO3a	FoxO3a	20	21	23	24
A first , rapid arm attenuated AKT inhibition of FOXO3 through p38 MAPK mediated blockade of IGF-I stimulation of AKT .	A first, rapid arm attenuated AKT inhibition of FOXO3 through p38 MAPK mediated blockade of IGF-I stimulation of AKT.	6	12	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	6	7	9	10
In our current study , we showed that inhibition of both RAS/MEK/ERK and PI3K and AKT pathways enhances FOXO3a activity ( XREF_FIG ) .	In our current study, we showed that inhibition of both RAS/MEK/ERK and PI3K and AKT pathways enhances FOXO3a activity (XREF_FIG).	13	19	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	15	16	18	19
Together with recent evidence that the phophorylation of PKB at Ser473 is required for PKB to phosphorylate Foxo3a , this study indicates that ERK5 down-regulates Bim expression by promoting PKB dependent inhibition of Foxo3a ( XREF_FIG ) .	Together with recent evidence that the phophorylation of PKB at Ser473 is required for PKB to phosphorylate Foxo3a, this study indicates that ERK5 down-regulates Bim expression by promoting PKB dependent inhibition of Foxo3a (XREF_FIG).	29	35	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKB	PKB	PKB	Foxo3a	Foxo3a	Foxo3a	29	30	33	34
XREF_BIBR In support , recent evidence suggests that Akt inhibition can promote FOXO3a dependent apoptosis .	XREF_BIBR In support, recent evidence suggests that Akt inhibition can promote FOXO3a dependent apoptosis.	8	14	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	8	9	12	13
FoxM1 transcriptional activity is normally suppressed by FoxO3a , which itself is negatively regulated by Akt .	FoxM1 transcriptional activity is normally suppressed by FoxO3a, which itself is negatively regulated by Akt.	5	16	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	15	16	7	8
These pathways involve a variety of atrophy related genes or atrogenes , which are controlled by specific transcription factors , such as FoxO3 , which is negatively regulated by Akt , and NF-kappaB , which is activated by inflammatory cytokines .	These pathways involve a variety of atrophy related genes or atrogenes, which are controlled by specific transcription factors, such as FoxO3, which is negatively regulated by Akt, and NF-kappaB, which is activated by inflammatory cytokines.	4	30	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	29	30	22	23
The inhibition of Akt phosphory lation at Thr 308 and Ser 473 by DN-Akt impaired FoxO3a phosphorylation at Ser 318 and Ser 321 and Ser 253 and increased FoxO3a dependent transactivation ( XREF_FIG ) .	The inhibition of Akt phosphory lation at Thr-308 and Ser-473 by DN-Akt impaired FoxO3a phosphorylation at Ser-318 and Ser-321 and Ser 253 and increased FoxO3a dependent transactivation (XREF_FIG).	3	30	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	3	4	28	29
The transcription factor FoxO3a is a key target of PI3K and AKT pathway , in which AKT inactivates FoxO3a by phosphorylation 15 .	The transcription factor FoxO3a is a key target of PI3K and AKT pathway, in which AKT inactivates FoxO3a by phosphorylation 15.	9	19	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO3a	FoxO3a	FoxO3a	11	12	18	19
Dominant negative Akt approach in PC-3 cells increased FOXO3A accumulation in the nucleus , causing upregulation of the downstream target , MnSOD .	Dominant negative Akt approach in PC-3 cells increased FOXO3A accumulation in the nucleus, causing upregulation of the downstream target, MnSOD.	2	9	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3A	FOXO3A	FOXO3A	2	3	8	9
The hyper-activation of Akt caused by loss of Cbl-b significantly suppresses Foxo1 and Foxo3a , thus inhibiting Foxp3 expression upon suboptimal stimulation of WT T cells with anti-CD3 .	The hyper-activation of Akt caused by loss of Cbl-b significantly suppresses Foxo1 and Foxo3a, thus inhibiting Foxp3 expression upon suboptimal stimulation of WT T cells with anti-CD3.	1	14	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	3	4	13	14
mTORC2 , on the other hand , phosphorylates and activates Akt , which not only stimulates mTORC1 , but also inhibits FOXO3 , which promotes the expression of autophagy related genes .	mTORC2, on the other hand, phosphorylates and activates Akt, which not only stimulates mTORC1, but also inhibits FOXO3, which promotes the expression of autophagy related genes.	0	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	mTORC2, on the other hand, phosphorylates and activates Akt	akt	FOXO3	FOXO3	foxo3	10	11	21	22
It was reported that Akt is the kinase responsible for phosphorylation of FoxO3a protein , which mediates FoxO3a nuclear exportation and inhibition ; therefore FoxO3a is negatively regulated by Akt .	It was reported that Akt is the kinase responsible for phosphorylation of FoxO3a protein, which mediates FoxO3a nuclear exportation and inhibition; therefore FoxO3a is negatively regulated by Akt.	24	30	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	29	30	24	25
FOXO3a is inhibited at the protein level by AKT signaling , and has been shown to regulate its own expression through a positive feed-back mechanism further indicating an anti-apoptotic role for ic-MPL through AKT signaling .	FOXO3a is inhibited at the protein level by AKT signaling, and has been shown to regulate its own expression through a positive feed-back mechanism further indicating an anti-apoptotic role for ic-MPL through AKT signaling.	0	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	8	9	0	1
XREF_BIBR A decrease in Akt phosphorylation induces the nuclear translocation of the transcription factor FoxO3 and , thus , the transcription of genes involved in the ubiquitin-proteasome-dependent proteolysis ( UPS ) .	XREF_BIBR A decrease in Akt phosphorylation induces the nuclear translocation of the transcription factor FoxO3 and, thus, the transcription of genes involved in the ubiquitin-proteasome-dependent proteolysis (UPS).	4	20	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	FoxO3	FoxO3	foxo3	4	5	14	15
46 We further confirmed that inhibition of AKT triggers FOXO3a mediated Par-4-induced cell death in xenograft models .	46 We further confirmed that inhibition of AKT triggers FOXO3a mediated Par-4-induced cell death in xenograft models.	5	13	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	7	8	9	10
XREF_BIBR showed that active nuclear PTEN can downregulate nuclear P-AKT , which was previously known to inactivate FOXO3a and accelerate tumor progression .	XREF_BIBR showed that active nuclear PTEN can downregulate nuclear P-AKT, which was previously known to inactivate FOXO3a and accelerate tumor progression.	7	19	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P-AKT	P-AKT	P-AKT	FOXO3a	FOXO3a	FOXO3a	9	10	17	18
It is well established that activation of the PI3K-Akt pathway suppresses Foxo1 activity , which is critical for IL-7Ralpha expression and B cell development .	It is well established that activation of the PI3K-Akt pathway suppresses Foxo1 activity, which is critical for IL-7Ralpha expression and B cell development.	8	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	Foxo1	Foxo1	Foxo1	8	9	11	12
Active Akt in reverse inhibits Foxo1a activity .	Active Akt in reverse inhibits Foxo1a activity.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1a	Foxo1a	Foxo1a	1	2	5	6
Inactivation of FoXO1 by Akt then follows , resulting in upregulation of POMC and downregulation of NPY expression , leading to loss of appetite [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Inactivation of FoXO1 by Akt then follows, resulting in upregulation of POMC and downregulation of NPY expression, leading to loss of appetite [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	5	Inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoXO1	FoXO1	FoXO1	4	5	2	3
Activation of the latter pathway was supported via decreased activities of the PI3K and Akt pathway inhibitor , Pten and Foxo1 , which are negatively regulated by Akt .	Activation of the latter pathway was supported via decreased activities of the PI3K and Akt pathway inhibitor, Pten and Foxo1, which are negatively regulated by Akt.	12	28	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	27	28	20	21
Our data suggested that the AKT signaling inhibits FOXO1 directly , and by feeding into NF-kappaB pathway , since simultaneous inhibition of the AKT and the NF-kappaB pathways resulted in increased levels of nuclear FOXO1 and a synergistic increase in Rag activity ( XREF_FIG ) .	Our data suggested that the AKT signaling inhibits FOXO1 directly, and by feeding into NF-kappaB pathway, since simultaneous inhibition of the AKT and the NF-kappaB pathways resulted in increased levels of nuclear FOXO1 and a synergistic increase in Rag activity (XREF_FIG).	5	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	5	6	8	9
In contrast Akt limited FOXO1 nuclear localization , consistent with our previous report that Akt attenuates FOXO1 activation induced by LPS .	In contrast Akt limited FOXO1 nuclear localization, consistent with our previous report that Akt attenuates FOXO1 activation induced by LPS.	14	17	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	14	15	16	17
However , considering that Akt activation did not induce FoxO1 degradation in LMP1 transgenic B cells , Akt may not be the sole regulator of FoxO1 , and it may be that progression to lymphoma requires modulation of multiple pathways .	However, considering that Akt activation did not induce FoxO1 degradation in LMP1 transgenic B cells, Akt may not be the sole regulator of FoxO1, and it may be that progression to lymphoma requires modulation of multiple pathways.	4	10	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	4	5	9	10
The expression of KLF2 is known to be mediated by Foxo1 , a transcription factor that is negatively regulated by AKT XREF_BIBR .	The expression of KLF2 is known to be mediated by Foxo1, a transcription factor that is negatively regulated by AKT XREF_BIBR.	1	21	negatively regulated	Negative_regulation_syntax_6_verb	Negative_activation	Negative_regulation	AKT	AKT	akt	Foxo1	expression of KLF2 is known to be mediated by Foxo1	foxo1	20	21	10	11
In fact , inhibition of AKT by APN has been shown to promote activation of FoxO1 indirectly , via suppressing its AKT induced nuclear exclusion XREF_BIBR .	In fact, inhibition of AKT by APN has been shown to promote activation of FoxO1 indirectly, via suppressing its AKT induced nuclear exclusion XREF_BIBR.	3	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	5	6	15	16
Besides demonstrating that multiple fibrogenic receptors converge upon GIV , we demonstrate that subsequent activation of Galphai by GIV modulates two functionally antagonistic signaling events ( see XREF_FIG ) -- ( a ) Activation of the profibrotic PI3K-Akt signals that potentiate TGFbeta-SMAD signals and inhibit FoxO1 , and ( b ) inhibition of cAMP production , which suppresses the PKA-pCREB pathway ; thereby generating an overall profibrotic signaling program that favors fibrosis .	Besides demonstrating that multiple fibrogenic receptors converge upon GIV, we demonstrate that subsequent activation of Galphai by GIV modulates two functionally antagonistic signaling events (see XREF_FIG) -- (a) Activation of the profibrotic PI3K-Akt signals that potentiate TGFbeta-SMAD signals and inhibit FoxO1, and (b) inhibition of cAMP production, which suppresses the PKA-pCREB pathway; thereby generating an overall profibrotic signaling program that favors fibrosis.	37	46	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FoxO1	FoxO1	FoxO1	37	38	45	46
However , we also made several unexpected observations that can not be explained by the prevalent , long-held model in which insulin regulates glycemia via Akt dependent suppression of Foxo1 driven metabolic gene expression .	However, we also made several unexpected observations that can not be explained by the prevalent, long-held model in which insulin regulates glycemia via Akt dependent suppression of Foxo1 driven metabolic gene expression.	25	30	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	25	26	29	30
Similarly , targeted disruption of Foxo1 , a key transcription factor that is negatively regulated by AKT phosphorylation , also results in an early B cell developmental block due to the requirement of Foxo1 to activate transcription of critical pre-B cell genes including Rag1 , Rag2 .	Similarly, targeted disruption of Foxo1, a key transcription factor that is negatively regulated by AKT phosphorylation, also results in an early B cell developmental block due to the requirement of Foxo1 to activate transcription of critical pre-B cell genes including Rag1, Rag2.	3	18	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Positive_activation	AKT	AKT phosphorylation	akt	Foxo1	Foxo1	foxo1	16	17	5	6
Foxo1 is negatively regulated by Akt , as its phosphorylation by active Akt leads to its exclusion from the nucleus .	Foxo1 is negatively regulated by Akt, as its phosphorylation by active Akt leads to its exclusion from the nucleus.	0	6	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	5	6	0	1
The established mechanism by which Akt directly inhibits Foxo1 involves its phosphorylation at T24 , S253 and S316 of the mouse protein by Akt .	The established mechanism by which Akt directly inhibits Foxo1 involves its phosphorylation at T24, S253 and S316 of the mouse protein by Akt.	5	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	5	6	8	9
It is well documented that inhibition of the PI3K and AKT pathway results in activation of FOXO1 and restores its transcriptional activity which acts as transcription factor for many genes involved in apoptotic pathway XREF_BIBR .	It is well documented that inhibition of the PI3K and AKT pathway results in activation of FOXO1 and restores its transcriptional activity which acts as transcription factor for many genes involved in apoptotic pathway XREF_BIBR.	8	17	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	10	11	16	17
We found that MHY908 fed old rats suppressed phosphorylation of IRS and Akt and induced FoxO1 activation , leading to increased expression of MnSOD and catalase .	We found that MHY908 fed old rats suppressed phosphorylation of IRS and Akt and induced FoxO1 activation, leading to increased expression of MnSOD and catalase.	3	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	MHY908 fed old rats suppressed phosphorylation of IRS and Akt	akt	FoxO1	FoxO1	foxo1	12	13	15	16
Besides activating NF-kappaB and NFAT , the TCR signal activates Akt , which in turn suppresses Foxo1 .	Besides activating NF-kappaB and NFAT, the TCR signal activates Akt, which in turn suppresses Foxo1.	9	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	10	11	16	17
In the liver , insulin suppresses hepatic gluconeogenesis by activating Akt , which inactivates the key gluconeogenic transcription factor FoxO1 ( Forkhead Box O1 ) .	In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1).	9	22	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	10	11	19	20
Active Akt makes FoxO1 phosphorylative and , in turn , represses the transcriptional activation of FoxO1 .	Active Akt makes FoxO1 phosphorylative and, in turn, represses the transcriptional activation of FoxO1.	0	16	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	1	2	15	16
FoxO1 is inactivated by Akt , whereas activation of FoxO1 promotes food intake by reducing POMC expression and inducing NPY expression .	FoxO1 is inactivated by Akt, whereas activation of FoxO1 promotes food intake by reducing POMC expression and inducing NPY expression.	0	5	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	4	5	0	1
PI3K and AKT inhibits FoxO1 via phosphorylation and subsequent nuclear exclusion that in turn releases the expression of targeted genes [ XREF_BIBR ] .	PI3K and AKT inhibits FoxO1 via phosphorylation and subsequent nuclear exclusion that in turn releases the expression of targeted genes [XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	2	3	4	5
The FOXO class of proteins consists of four members , FOXO1 , FOXO3a , FOXO4 , and FOXO6 , which are negatively regulated by the PI3K signaling cascade effector protein AKT .	The FOXO class of proteins consists of four members, FOXO1, FOXO3a, FOXO4, and FOXO6, which are negatively regulated by the PI3K signaling cascade effector protein AKT.	10	31	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	30	31	10	11
Akt activation induced phosphorylation inhibits GSK3 and Foxo1 which , in turn , reverses the toxic effects of glucose and fatty acids on beta-cells [ XREF_BIBR , XREF_BIBR ] .	Akt activation induced phosphorylation inhibits GSK3 and Foxo1 which, in turn, reverses the toxic effects of glucose and fatty acids on beta-cells [XREF_BIBR, XREF_BIBR].	0	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	0	1	7	8
Retroviral gene transfer studies have shown that constitutively active AKT in B cells can inactivate Forkhead transcription factor FOXO1 resulting in concomitant decreases in AID and suppression of CSR ; in addition , phosphorylation of AKT at Ser473 is required for phosphorylation of FOXO1/3a .	Retroviral gene transfer studies have shown that constitutively active AKT in B cells can inactivate Forkhead transcription factor FOXO1 resulting in concomitant decreases in AID and suppression of CSR; in addition, phosphorylation of AKT at Ser473 is required for phosphorylation of FOXO1/3a.	8	19	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	9	10	18	19
Akt mediated FoxO1 inhibition is required for liver regeneration .	Akt mediated FoxO1 inhibition is required for liver regeneration.	0	3	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	0	1	2	3
We further tested this hypothesis by assessing Foxo1 localization because AKT inhibits Foxo1 activity by sequestering it in the cytoplasm .	We further tested this hypothesis by assessing Foxo1 localization because AKT inhibits Foxo1 activity by sequestering it in the cytoplasm.	10	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Foxo1	Foxo1	Foxo1	10	11	12	13
In addition to the nuclear and cytoplasmic translocation , activation of Akt also promotes Skp2 E3 ligase mediated proteasome degradation of FOXO1 .	In addition to the nuclear and cytoplasmic translocation, activation of Akt also promotes Skp2 E3 ligase mediated proteasome degradation of FOXO1.	9	22	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	11	12	21	22
Constitutively active Akt stimulated activity of the ABCA1 promoter , and a dominant negative mutant of Akt or mutagenesis of the FoxO1 response element in the ABCA1 promoter abolished the ability of IGF-1 to stimulate promoter activity .	Constitutively active Akt stimulated activity of the ABCA1 promoter, and a dominant negative mutant of Akt or mutagenesis of the FoxO1 response element in the ABCA1 promoter abolished the ability of IGF-1 to stimulate promoter activity.	1	28	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	2	3	21	22
AKT also inactivates the forkhead box class O 1 ( FOXO1 ) transcription factor that targets cell cycle arrest genes such as cyclin G2 and Rbl2 .	AKT also inactivates the forkhead box class O 1 (FOXO1) transcription factor that targets cell cycle arrest genes such as cyclin G2 and Rbl2.	0	15	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	0	1	10	11
This process requires suppression of the recombination activating gene ( RAG ) loci Rag1 and Rag2 , which is mediated through AKT dependent inhibition of FoxO1 , a transcriptional activator of these genes .	This process requires suppression of the recombination activating gene (RAG) loci Rag1 and Rag2, which is mediated through AKT dependent inhibition of FoxO1, a transcriptional activator of these genes.	21	29	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	21	22	25	26
In contrast , high PI3K and Akt signaling activity inactivates Foxo1 proteins by excluding them from the nucleus .	In contrast, high PI3K and Akt signaling activity inactivates Foxo1 proteins by excluding them from the nucleus.	6	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	6	7	10	11
Inhibition of AKT activity caused nuclear retention of FoxO1-GFP at all times and in the absence or presence of either growth factors or miR-22 ( XREF_SUPPLEMENTARY ) .	Inhibition of AKT activity caused nuclear retention of FoxO1-GFP at all times and in the absence or presence of either growth factors or miR-22 (XREF_SUPPLEMENTARY).	2	9	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1-GFP	FoxO1-GFP	FoxO1-GFP	2	3	8	9
CCR7 downregulation was attenuated in CA expressing Treg cells as well ( XREF_FIG ) , revealing that relief of Akt triggered Foxo1 inhibition is sufficient to maintain high expression of molecules involved in lymph node homing and intranodal T cell migration .	CCR7 downregulation was attenuated in CA expressing Treg cells as well (XREF_FIG), revealing that relief of Akt triggered Foxo1 inhibition is sufficient to maintain high expression of molecules involved in lymph node homing and intranodal T cell migration.	17	22	triggered	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	19	20	21	22
Akt also inactivates FKHR through phosphorylation , which leads to anti-apoptotic events or cell survival .	Akt also inactivates FKHR through phosphorylation, which leads to anti-apoptotic events or cell survival.	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FKHR	FKHR	FKHR	0	1	3	4
FoxO1 is sequestered in the cytoplasm for degradation upon phosphorylation by Akt .	FoxO1 is sequestered in the cytoplasm for degradation upon phosphorylation by Akt.	0	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	11	12	0	1
However , FSH can also activate the PI3K pathway ( likely via a SRC tyrosine kinase ) leading to the phosphorylation and activation of AKT , which phosphorylates and thereby inactivates FOXO1 .	However, FSH can also activate the PI3K pathway (likely via a SRC tyrosine kinase) leading to the phosphorylation and activation of AKT, which phosphorylates and thereby inactivates FOXO1.	20	32	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	phosphorylation and activation of AKT	akt	FOXO1	FOXO1	foxo1	24	25	31	32
We reasoned that if AKT negatively regulates Foxo1 in these cells , inhibiting this pathway will lead to activation of Foxo1 , and thus up-regulation of Rag expression .	We reasoned that if AKT negatively regulates Foxo1 in these cells, inhibiting this pathway will lead to activation of Foxo1, and thus up-regulation of Rag expression.	4	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Foxo1	Foxo1	Foxo1	4	5	7	8
Hence , Akt and PKB reduces the transcriptional activity of FoxO1 .	Hence, Akt and PKB reduces the transcriptional activity of FoxO1.	2	11	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	FoxO1	FoxO1	FoxO1	4	5	10	11
Insulin signals in hepatocytes to activate Akt , which inhibits Foxo1 suppressing hepatic glucose production ( HGP ) and allowing the transition to the postprandial state .	Insulin signals in hepatocytes to activate Akt, which inhibits Foxo1 suppressing hepatic glucose production (HGP) and allowing the transition to the postprandial state.	5	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	6	7	10	11
It is known that FOXO1 is inhibited by Akt upon phosphorylation [ XREF_BIBR ] .	It is known that FOXO1 is inhibited by Akt upon phosphorylation [XREF_BIBR].	4	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	8	9	4	5
These findings showed that FOXO1 was activated by the ROS depended activation of p38 and JNK and inactivated by Akt kinase .	These findings showed that FOXO1 was activated by the ROS depended activation of p38 and JNK and inactivated by Akt kinase.	4	20	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	19	20	4	5
Akt also inactivates FoxO1 to inhibit muscle atrophy [ XREF_BIBR ] .	Akt also inactivates FoxO1 to inhibit muscle atrophy [XREF_BIBR].	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	0	1	3	4
Furthermore , knockdown or overexpression of the Akt targets Foxo1 and Foxo3a inhibited or promoted the iTreg differentiation of Prkcq -/- T cells , respectively .	Furthermore, knockdown or overexpression of the Akt targets Foxo1 and Foxo3a inhibited or promoted the iTreg differentiation of Prkcq -/- T cells, respectively.	2	14	targets	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	7	8	9	10
Because both FoxO1 and p27 are negatively regulated by AKT , and both serve as critical cell cycle inhibitors for pancreatic beta-cells , the increased amount of these proteins in the betaRicKO mice would be expected to cause a reduction in beta-cell proliferation , and thus mass .	Because both FoxO1 and p27 are negatively regulated by AKT, and both serve as critical cell cycle inhibitors for pancreatic beta-cells, the increased amount of these proteins in the betaRicKO mice would be expected to cause a reduction in beta-cell proliferation, and thus mass.	1	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	9	10	2	3
Rather , in order for Akt to stimulate DNL , Akt must both suppress Foxo1 and activate mTorc1 .	Rather, in order for Akt to stimulate DNL, Akt must both suppress Foxo1 and activate mTorc1.	10	16	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	10	11	14	15
Astragaloside IV promoted phosphorylated Akt binding to FoxO1 , providing support to the suppression of FoxO1 by Akt .	Astragaloside IV promoted phosphorylated Akt binding to FoxO1, providing support to the suppression of FoxO1 by Akt.	9	18	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	17	18	15	16
These data further support the permissive role for Akt dependent inhibition of Foxo1 , as normal regulation persists in the absence of both proteins .	These data further support the permissive role for Akt dependent inhibition of Foxo1, as normal regulation persists in the absence of both proteins.	8	13	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	8	9	12	13
According to previous reports , FOXO1 activity was negatively regulated by PI3-K and Akt .	According to previous reports, FOXO1 activity was negatively regulated by PI3-K and Akt.	5	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	13	14	5	6
Because AKT is known to negatively regulate Foxo1 activity in primary B cells , we asked whether Foxo1 is similarly regulated by AKT in AMuLV transformed cells .	Because AKT is known to negatively regulate Foxo1 activity in primary B cells, we asked whether Foxo1 is similarly regulated by AKT in AMuLV transformed cells.	1	8	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Foxo1	Foxo1	Foxo1	1	2	7	8
However , significant tumor heterogeneity in the response of ovarian tumors to progestins may relate in part to PR isoform expression as well as FOXO1 expression and activity ( i.e. as influenced by AKT and other kinases that inactivate FOXO1 via phosphorylation events ; see discussion ) .	However, significant tumor heterogeneity in the response of ovarian tumors to progestins may relate in part to PR isoform expression as well as FOXO1 expression and activity (i.e. as influenced by AKT and other kinases that inactivate FOXO1 via phosphorylation events; see discussion).	33	42	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	33	34	39	40
Thus , when studied ex vivo , liver cells behaved as if insulin signals through the canonical linear pathway of Akt dependent inhibition of Foxo1 driven gluconeogenic gene expression ( XREF_FIG ) .	Thus, when studied ex vivo, liver cells behaved as if insulin signals through the canonical linear pathway of Akt dependent inhibition of Foxo1 driven gluconeogenic gene expression (XREF_FIG).	20	25	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	20	21	24	25
In contrast , Akt which is known to negatively regulate FOXO1 did not have a significant effect on RANKL induced FOXO1 nuclear localization two days after stimulation .	In contrast, Akt which is known to negatively regulate FOXO1 did not have a significant effect on RANKL induced FOXO1 nuclear localization two days after stimulation.	3	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	3	4	20	21
MiR-27a synergizes with Akt by targeting transcription factors FoxO1 ( miR-27 ) that is repressed by Akt phosphorylation [ XREF_BIBR , XREF_BIBR ] .	MiR-27a synergizes with Akt by targeting transcription factors FoxO1 (miR-27) that is repressed by Akt phosphorylation [XREF_BIBR, XREF_BIBR].	5	18	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	FoxO1	FoxO1	foxo1	16	17	8	9
Given the inactivation of FoxO1 by Akt , it is reasonable to hypothesize that pharmacological activation of Akt could restrain hepatic glucagon response via suppressing FoxO1 activation .	Given the inactivation of FoxO1 by Akt, it is reasonable to hypothesize that pharmacological activation of Akt could restrain hepatic glucagon response via suppressing FoxO1 activation.	2	7	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	6	7	4	5
Mechanistically , the gate keeping role of intact pericyte-Tie2 and Akt signalling , which suppresses FOXO1 mediated transcriptional activation of vascular destabilizing factors including Ang2 in ECs , seems central for the maintenance and protection of BRB integrity against injuries ( XREF_FIG ) .	Mechanistically, the gate keeping role of intact pericyte-Tie2 and Akt signalling, which suppresses FOXO1 mediated transcriptional activation of vascular destabilizing factors including Ang2 in ECs, seems central for the maintenance and protection of BRB integrity against injuries (XREF_FIG).	10	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	10	11	15	16
Second , Akt negatively regulates the transcriptional activity of FOXO1 , which is known to upregulate p27kip1 [ XREF_BIBR ] .	Second, Akt negatively regulates the transcriptional activity of FOXO1, which is known to upregulate p27kip1 [XREF_BIBR].	2	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	2	3	9	10
Impaired Akt and mTOR signaling due to chronic viral infection enhances Foxo1 activity , thereby increasing the expression of PD-1 on T cells .	Impaired Akt and mTOR signaling due to chronic viral infection enhances Foxo1 activity, thereby increasing the expression of PD-1 on T cells.	0	12	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	1	2	11	12
Activation of Akt , on the other hand , inhibits Foxo1 , a process leading to increased cell survival , control of glucose homeostasis , and maintenance of stem cell differentiation .	Activation of Akt, on the other hand, inhibits Foxo1, a process leading to increased cell survival, control of glucose homeostasis, and maintenance of stem cell differentiation.	0	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	2	3	10	11
Here we show that Akt , but not inactive Akt , represses the transcriptional activity of FKHR , another member of the forkhead family .	Here we show that Akt, but not inactive Akt, represses the transcriptional activity of FKHR, another member of the forkhead family.	4	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FKHR	FKHR	FKHR	4	5	16	17
In summary , PI3K and AKT and SKP2 and SCF pathways potentially cooperate to downregulate FoxO1 in delta-cells of regenerating younglings .	In summary, PI3K and AKT and SKP2 and SCF pathways potentially cooperate to downregulate FoxO1 in delta-cells of regenerating younglings.	3	16	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	5	6	15	16
Specifically , AKT mediated serine/threonine phospho regulation of FOXO1 is well defined and prevents FOXO1 nuclear accumulation , thus impairing target gene regulation .	Specifically, AKT mediated serine/threonine phospho regulation of FOXO1 is well defined and prevents FOXO1 nuclear accumulation, thus impairing target gene regulation.	2	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	2	3	14	15
Akt inactivates FoxO1 by phosphorylation and nuclear exclusion .	Akt inactivates FoxO1 by phosphorylation and nuclear exclusion.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	0	1	2	3
Akt then inhibits FoxO1 thus suppressing gluconeogenic gene transcription and gluconeogenesis [ XREF_BIBR , XREF_BIBR ] while simultaneously acting to stimulate net glycogen synthesis through inactivation of Gsk3alpha [ XREF_BIBR ] - with the combined effect of these actions being a decrease in hepatic glucose production .	Akt then inhibits FoxO1 thus suppressing gluconeogenic gene transcription and gluconeogenesis [XREF_BIBR, XREF_BIBR] while simultaneously acting to stimulate net glycogen synthesis through inactivation of Gsk3alpha [XREF_BIBR] - with the combined effect of these actions being a decrease in hepatic glucose production.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	0	1	3	4
AKT activation also inhibits forkhead transcription factor FKHR ( FOXO1 ) which protects endothelial cells from apoptosis [ XREF_BIBR ] .	AKT activation also inhibits forkhead transcription factor FKHR (FOXO1) which protects endothelial cells from apoptosis [XREF_BIBR].	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FKHR	FKHR	FKHR	0	1	7	8
These results were further supported by our in vitro studies in which inhibition of PI3K in PTEN siRNA transfected BMMs decreased phosphorylation of Akt , Foxo1 and beta-catenin but increased nuclear Foxo1 , leading to enhanced TLR4 mediated proinflammatory response after LPS stimulation .	These results were further supported by our in vitro studies in which inhibition of PI3K in PTEN siRNA transfected BMMs decreased phosphorylation of Akt, Foxo1 and beta-catenin but increased nuclear Foxo1, leading to enhanced TLR4 mediated proinflammatory response after LPS stimulation.	14	32	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	PI3K in PTEN siRNA transfected BMMs decreased phosphorylation of Akt	akt	Foxo1	Foxo1	foxo1	23	24	31	32
It is worth mentioning that SLP65 was suggested to inhibit the phosphorylation of AKT at S473 and promote FOXO1 stability XREF_BIBR .	It is worth mentioning that SLP65 was suggested to inhibit the phosphorylation of AKT at S473 and promote FOXO1 stability XREF_BIBR.	5	20	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	SLP65 was suggested to inhibit the phosphorylation of AKT at S473	akt	FOXO1	FOXO1	foxo1	13	14	18	19
On the other hand , activated Akt also inhibits the transcriptional activity or expression of FOXO1 or KLF2 , respectively .	On the other hand, activated Akt also inhibits the transcriptional activity or expression of FOXO1 or KLF2, respectively.	5	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	6	7	15	16
Mechanistically , the forkhead transcription factor FoxO1 can function as a barrier to the iPSC induction , and the inactivation of FoxO1 by Akt dependent phosphorylation largely accounts for the enhancing effect of ERas-Akt signaling on reprogramming .	Mechanistically, the forkhead transcription factor FoxO1 can function as a barrier to the iPSC induction, and the inactivation of FoxO1 by Akt dependent phosphorylation largely accounts for the enhancing effect of ERas-Akt signaling on reprogramming.	19	26	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	FoxO1	FoxO1	foxo1	23	24	21	22
However , insulin and Akt inactivate FoxO1 and inhibit the FoxO1 increased PGC1alpha promoter activity directly through phosphorylation of putative Akt sites in FoxO1 , further suppressing the combining capacity of FoxO1 to PGC1alpha promoter in liver .	However, insulin and Akt inactivate FoxO1 and inhibit the FoxO1 increased PGC1alpha promoter activity directly through phosphorylation of putative Akt sites in FoxO1, further suppressing the combining capacity of FoxO1 to PGC1alpha promoter in liver.	17	32	suppressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	phosphorylation of putative Akt	akt	FoxO1	FoxO1	foxo1	20	21	31	32
We have previously shown that activation of PI3K and Akt pathway inhibited the transcription factor FOXO1A , resulting in nuclear export of p27 kip1 and reduced the inhibitory properties of trastuzumab .	We have previously shown that activation of PI3K and Akt pathway inhibited the transcription factor FOXO1A, resulting in nuclear export of p27 kip1 and reduced the inhibitory properties of trastuzumab.	7	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1A	FOXO1A	FOXO1A	9	10	15	16
Mechanistically , AKT functions in precursor cells to suppress Foxo1 activity XREF_BIBR , XREF_BIBR .	Mechanistically, AKT functions in precursor cells to suppress Foxo1 activity XREF_BIBR, XREF_BIBR.	2	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Foxo1	Foxo1	Foxo1	2	3	9	10
Another possible downstream effector of Akt signaling is Foxo1 , which is negatively regulated by Akt phosphorylation .	Another possible downstream effector of Akt signaling is Foxo1, which is negatively regulated by Akt phosphorylation.	3	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	Foxo1	Foxo1	foxo1	15	16	8	9
In mature T cells , an active form of Akt has been shown to inactivate Foxo1 , and this correlates with enhanced cell cycle progression XREF_BIBR .	In mature T cells, an active form of Akt has been shown to inactivate Foxo1, and this correlates with enhanced cell cycle progression XREF_BIBR.	7	16	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	9	10	15	16
In performing numerous additional experiments , including genome wide association screening of the DLKO and TLKO mice , the authors came to the stunning conclusion -- which sharply challenges the prevailing paradigm -- that Akt dependent inhibition of FoxO1 was not the only arbiter of hepatic glucose homeostasis .	In performing numerous additional experiments, including genome wide association screening of the DLKO and TLKO mice, the authors came to the stunning conclusion -- which sharply challenges the prevailing paradigm -- that Akt dependent inhibition of FoxO1 was not the only arbiter of hepatic glucose homeostasis.	34	39	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	34	35	38	39
Expression of IL-7R in conventional T cells is controlled in large part by the transcription factor , Foxo1 , which in T cells is inactivated and removed from the nucleus after phosphorylation by activated Akt following TCR stimulation .	Expression of IL-7R in conventional T cells is controlled in large part by the transcription factor, Foxo1, which in T cells is inactivated and removed from the nucleus after phosphorylation by activated Akt following TCR stimulation.	15	37	inactivated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	34	35	17	18
Myostatin also inhibits phosphorylation of Akt , thus increasing FoxO-1 but not NF-kappaB [ XREF_BIBR ] .	Myostatin also inhibits phosphorylation of Akt, thus increasing FoxO-1 but not NF-kappaB [XREF_BIBR].	0	14	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Myostatin also inhibits phosphorylation of Akt	akt	FoxO-1	FoxO-1	foxo-1	5	6	9	10
Consistently , miR-181b overexpression increased Akt phosphorylation at Ser473 and reduced nuclear accumulation of FoxO1 at 10 min after insulin stimulation in ECs ( XREF_FIG ) .	Consistently, miR-181b overexpression increased Akt phosphorylation at Ser473 and reduced nuclear accumulation of FoxO1 at 10 min after insulin stimulation in ECs (XREF_FIG).	2	15	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	miR-181b overexpression increased Akt phosphorylation at Ser473	akt	FoxO1	FoxO1	foxo1	5	6	14	15
This finding is significant because Akt blocks FOXO1 activation .	This finding is significant because Akt blocks FOXO1 activation.	5	8	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	5	6	7	8
The results indicated that 10 -4 M H 2 O 2 promoted osteoclast formation via the AKT mediating inhibition of FoxO1 transcriptional activity .	The results indicated that 10 -4 M H 2 O 2 promoted osteoclast formation via the AKT mediating inhibition of FoxO1 transcriptional activity.	16	22	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	16	17	20	21
It is generally accepted that Foxo1 is active during fasting , inactivated by Akt mediated phosphorylation after feeding , and that the antagonism of Foxo1 by Akt is the predominant mechanism by which insulin suppresses hepatic glucose output after a meal XREF_BIBR , XREF_BIBR - XREF_BIBR .	It is generally accepted that Foxo1 is active during fasting, inactivated by Akt mediated phosphorylation after feeding, and that the antagonism of Foxo1 by Akt is the predominant mechanism by which insulin suppresses hepatic glucose output after a meal XREF_BIBR, XREF_BIBR - XREF_BIBR.	22	27	antagonism	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	26	27	24	25
XREF_BIBR Therefore , inhibition of PLCgamma or silencing of the ATF6 and PERK genes , which lead to mTORC2 inactivation and deficient phosphorylation on Ser473 of AKT , apparently insufficiently suppresses FOXO1 target genes and results in inhibition of angiogenesis .	XREF_BIBR Therefore, inhibition of PLCgamma or silencing of the ATF6 and PERK genes, which lead to mTORC2 inactivation and deficient phosphorylation on Ser473 of AKT, apparently insufficiently suppresses FOXO1 target genes and results in inhibition of angiogenesis.	5	33	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	PLCgamma or silencing of the ATF6 and PERK genes, which lead to mTORC2 inactivation and deficient phosphorylation on Ser473 of AKT	akt	FOXO1	FOXO1	foxo1	26	27	31	32
Thus , the inhibition of hepatic Akt activity induces liver injury and inflammation in a FoxO1 dependent manner , which in turn induces compensatory proliferation via STAT3 activation .	Thus, the inhibition of hepatic Akt activity induces liver injury and inflammation in a FoxO1 dependent manner, which in turn induces compensatory proliferation via STAT3 activation.	6	17	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	6	7	15	16
The major PI3K and AKT downstream substrate is FoxO1 , the activity of which is inhibited through its phosphorylation by PI3K and AKT , resulting in its nuclear exclusion and attenuation of the inhibition of targeted gene expression XREF_BIBR .	The major PI3K and AKT downstream substrate is FoxO1, the activity of which is inhibited through its phosphorylation by PI3K and AKT, resulting in its nuclear exclusion and attenuation of the inhibition of targeted gene expression XREF_BIBR.	2	23	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	22	23	8	9
As a result , forkhead box O1 ( FoxO1 ) , a transcription factor that is negatively regulated by Akt , was activated , translocated to the nucleus , and induced the pro apoptotic gene BCL2 like 11 ( Bim ) .	As a result, forkhead box O1 (FoxO1), a transcription factor that is negatively regulated by Akt, was activated, translocated to the nucleus, and induced the pro apoptotic gene BCL2 like 11 (Bim).	6	20	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	19	20	8	9
In a fed state , insulin levels are high , and AKT is activated and inactivates FoxO1 by excluding it from the nucleus .	In a fed state, insulin levels are high, and AKT is activated and inactivates FoxO1 by excluding it from the nucleus.	11	17	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	11	12	16	17
FOXO1 is negatively regulated by Akt , such that dephosphorylated FOXO1 localizes to the nucleus and shows transcriptional activity , whereas Akt dependent phosphorylation of FOXO1 protein causes its nuclear exportation and proteasomal degradation.18 , 19 Mutagenesis studies showed that this AMPK mediated phosphorylation of FOXO1 is critical for FOXO1 stability and nuclear localization , establishing the molecular basis for the induction of FOXO1 transcriptional activity .	FOXO1 is negatively regulated by Akt, such that dephosphorylated FOXO1 localizes to the nucleus and shows transcriptional activity, whereas Akt dependent phosphorylation of FOXO1 protein causes its nuclear exportation and proteasomal degradation.18, 19 Mutagenesis studies showed that this AMPK mediated phosphorylation of FOXO1 is critical for FOXO1 stability and nuclear localization, establishing the molecular basis for the induction of FOXO1 transcriptional activity.	0	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	5	6	0	1
Consistent with the ability of CoPP to upregulate Nrf2 protein in human liver cells by post-transcriptional site of action , we found that Nrf2 activation following CoPP conditioning in vivo , increased Stat3 and Akt phosphorylation but inhibited Foxo1 , consistent with diminished Stat3 and Akt yet enhanced Foxo1 protein levels in Nrf2 deficient livers .	Consistent with the ability of CoPP to upregulate Nrf2 protein in human liver cells by post-transcriptional site of action, we found that Nrf2 activation following CoPP conditioning in vivo, increased Stat3 and Akt phosphorylation but inhibited Foxo1, consistent with diminished Stat3 and Akt yet enhanced Foxo1 protein levels in Nrf2 deficient livers.	40	51	enhanced	Positive_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Akt	Akt	akt	Foxo1	Foxo1 protein levels	foxo1	45	46	48	49
Cell-extrinsic stimuli of the PI3K-AKT pathway , including TCR ligands , costimulatory B7 molecules that bind to CD28 , and pro survival cytokines such as IL-7 , can downregulate molecules of T cell homeostasis by inactivating FOXO1 [ XREF_BIBR , XREF_BIBR ] .	Cell-extrinsic stimuli of the PI3K-AKT pathway, including TCR ligands, costimulatory B7 molecules that bind to CD28, and pro survival cytokines such as IL-7, can downregulate molecules of T cell homeostasis by inactivating FOXO1 [XREF_BIBR, XREF_BIBR].	4	40	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO1	FOXO1	FOXO1	4	5	36	37
Expression of PIPP also interferes with oncogenic transformation induced by the four isoforms of class I PI3K , reduces the levels of AKT phosphorylation and attenuates the degradation of FOXO1 .	Expression of PIPP also interferes with oncogenic transformation induced by the four isoforms of class I PI3K, reduces the levels of AKT phosphorylation and attenuates the degradation of FOXO1.	0	30	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	Expression of PIPP also interferes with oncogenic transformation induced by the four isoforms of class I PI3K, reduces the levels of AKT phosphorylation	akt	FOXO1	FOXO1	foxo1	22	23	29	30
Insulin action required PI3K and Akt , which suppress FoxO1 .	Insulin action required PI3K and Akt, which suppress FoxO1.	2	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	5	6	9	10
ProF binds to the transcription factor Foxo1 ( Forkhead box O1 ) , a negative regulator of insulin action and adipogenesis , and facilitates the phosphorylation and thus inactivation of Foxo1 by Akt .	ProF binds to the transcription factor Foxo1 (Forkhead box O1), a negative regulator of insulin action and adipogenesis, and facilitates the phosphorylation and thus inactivation of Foxo1 by Akt.	23	33	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	32	33	30	31
Inhibition of Akt enhanced nuclear localization of FOXO1 by approximately 49-56 % ( P < 0.05 ) ( XREF_FIG ) .	Inhibition of Akt enhanced nuclear localization of FOXO1 by approximately 49-56% (P < 0.05) (XREF_FIG).	0	8	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	2	3	7	8
Physiologically , activation of Akt suppresses gluconeogenic gene expression and gluconeogenesis by promoting the nuclear exclusion of FOXO1 , a key transcriptor controlling the transcription of crucial gluconeogenic genes such as PEPCK [ XREF_BIBR ] .	Physiologically, activation of Akt suppresses gluconeogenic gene expression and gluconeogenesis by promoting the nuclear exclusion of FOXO1, a key transcriptor controlling the transcription of crucial gluconeogenic genes such as PEPCK [XREF_BIBR].	2	21	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	4	5	17	18
Androgen mediated stimulation of mTORC2 and consecutive mTORC2 mediated activation of Akt inhibit FoxO1 activity XREF_BIBR and stimulate androgen receptor transcriptional activity XREF_BIBR .	Androgen mediated stimulation of mTORC2 and consecutive mTORC2 mediated activation of Akt inhibit FoxO1 activity XREF_BIBR and stimulate androgen receptor transcriptional activity XREF_BIBR.	7	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	mTORC2 mediated activation of Akt	akt	FoxO1	FoxO1	foxo1	11	12	13	14
SirT1 interacts with an anti-aging transcription factor , FoxO1 , which is negatively regulated by Akt .	SirT1 interacts with an anti-aging transcription factor, FoxO1, which is negatively regulated by Akt.	6	16	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	15	16	8	9
Fatty acids induced nuclear localization of Foxo1 at 4 h when Akt activity was increased , indicating that FoxO1 activation was not mediated by JNK inhibition of Akt .	Fatty acids induced nuclear localization of Foxo1 at 4 h when Akt activity was increased, indicating that FoxO1 activation was not mediated by JNK inhibition of Akt.	18	28	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	27	28	18	19
Mechanistically , disruption of AKT signaling preserved MAPK activation and promoted the intranuclear localization of FOXO1 , a transcriptional regulator of T cell memory .	Mechanistically, disruption of AKT signaling preserved MAPK activation and promoted the intranuclear localization of FOXO1, a transcriptional regulator of T cell memory.	4	19	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	4	5	15	16
A constitutively active mutant of the insulin responsive protein kinase Akt , but not the kinase negative mutant , effectively blocked FOXO1 activity in cell based assays .	A constitutively active mutant of the insulin responsive protein kinase Akt, but not the kinase negative mutant, effectively blocked FOXO1 activity in cell based assays.	3	22	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	10	11	21	22
Since Akt suppresses Foxo1 activity , if activation of Foxo1 were responsible for the glucose intolerance and altered gene expression in DLKO mice , deletion of Foxo1 should largely reverse the abnormal metabolism .	Since Akt suppresses Foxo1 activity, if activation of Foxo1 were responsible for the glucose intolerance and altered gene expression in DLKO mice, deletion of Foxo1 should largely reverse the abnormal metabolism.	1	4	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	1	2	3	4
29 Therefore , FOXO1 promotes induction of inflammatory cytokines in DCs ; in contrast , activation of mTOR and AKT deactivate FOXO1 to prevent a hyperinflammatory response .	29 Therefore, FOXO1 promotes induction of inflammatory cytokines in DCs; in contrast, activation of mTOR and AKT deactivate FOXO1 to prevent a hyperinflammatory response.	15	22	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	19	20	21	22
Activation of Akt increases cell survival by phosphorylating and inhibiting Foxo1 , leading to reducing cell apoptosis [ XREF_BIBR ] .	Activation of Akt increases cell survival by phosphorylating and inhibiting Foxo1, leading to reducing cell apoptosis [XREF_BIBR].	0	11	increases	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Akt	Akt	akt	Foxo1	phosphorylating and inhibiting Foxo1	foxo1	2	3	10	11
Since the basis for PI3K regulation of cell growth and differentiation largely emanates through AKT mediated inhibition of FOXO1 transcriptional activity , we wished to test the idea that Foxo1 is epistatic to Icos in the elaboration of one or more of these Tfh characteristics .	Since the basis for PI3K regulation of cell growth and differentiation largely emanates through AKT mediated inhibition of FOXO1 transcriptional activity, we wished to test the idea that Foxo1 is epistatic to Icos in the elaboration of one or more of these Tfh characteristics.	14	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	14	15	18	19
Both feeding and insulin injection into the fasted mice induced Foxo1 phosphorylation at these sites , indicating that the majority of Foxo1 is not phosphorylated during fasting and therefore can not be used to explain the Akt dependent repression of Foxo1 .	Both feeding and insulin injection into the fasted mice induced Foxo1 phosphorylation at these sites, indicating that the majority of Foxo1 is not phosphorylated during fasting and therefore can not be used to explain the Akt dependent repression of Foxo1.	36	41	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	36	37	40	41
Accordingly , a major role of Akt is to inhibit FoxO1 activity which appears to be dispensable for other insulin actions .	Accordingly, a major role of Akt is to inhibit FoxO1 activity which appears to be dispensable for other insulin actions.	4	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	6	7	10	11
Akt inhibits FoxO1 by direct phosphorylation on the residues T 24 , S 253 and S 316 ( mouse sequence ) .	Akt inhibits FoxO1 by direct phosphorylation on the residues T 24, S 253 and S 316 (mouse sequence).	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	0	1	2	3
Whereas previous studies showed that Akt reduced transactivation of Foxo1 through the phosphorylation of Foxo1 at Ser 256 , our data demonstrated that the phosphorylation of Foxo1 at Ser 256 was augmented by reduction of ROS independently of the insulin signal at Akt phosphorylation level .	Whereas previous studies showed that Akt reduced transactivation of Foxo1 through the phosphorylation of Foxo1 at Ser 256, our data demonstrated that the phosphorylation of Foxo1 at Ser 256 was augmented by reduction of ROS independently of the insulin signal at Akt phosphorylation level.	5	10	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	5	6	9	10
Insulin inhibits hepatic glucose production by AKT phosphorylation promoting the inactivation of transcription factor Forkhead box protein O1 ( FOXO1 ) , which in turn inhibits target genes transcription , such as PEPCK and glucose-6-phosphatase ( G6Pase ) gene ( Barthel etal .	Insulin inhibits hepatic glucose production by AKT phosphorylation promoting the inactivation of transcription factor Forkhead box protein O1 (FOXO1), which in turn inhibits target genes transcription, such as PEPCK and glucose-6-phosphatase (G6Pase) gene (Barthel etal.	6	29	promoting	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	AKT	AKT phosphorylation	akt	Forkhead box protein O1	Forkhead box protein O1 (FOXO1), which in turn inhibits target genes transcription	forkhead box protein o1	6	7	14	18
In the luciferase reporter assay , HER2 overexpression inhibited the activity of FOXO1 , but subsequent AKT inhibition effectively restored the activity of FOXO1 ( XREF_FIG , right ) .	In the luciferase reporter assay, HER2 overexpression inhibited the activity of FOXO1, but subsequent AKT inhibition effectively restored the activity of FOXO1 (XREF_FIG, right).	16	25	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	16	17	23	24
Furthermore , MHY-449 reduced the phosphorylation of Akt and FoxO1 and induced the translocation of FoxO1 from cytoplasm to nucleus as shown by western blot analysis .	Furthermore, MHY-449 reduced the phosphorylation of Akt and FoxO1 and induced the translocation of FoxO1 from cytoplasm to nucleus as shown by western blot analysis.	2	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	MHY-449 reduced the phosphorylation of Akt	akt	FoxO1	FoxO1	foxo1	7	8	15	16
Studies from our group and other laboratories suggest that Sin1 and mTORC2 mediates PI3K signals to activate Akt which in turn suppresses FoxO1 activity .	Studies from our group and other laboratories suggest that Sin1 and mTORC2 mediates PI3K signals to activate Akt which in turn suppresses FoxO1 activity.	16	23	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	17	18	22	23
Expression of active but not inactive Akt can suppress FKHR mediated transcriptional activation .	Expression of active but not inactive Akt can suppress FKHR mediated transcriptional activation.	0	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Expression of active but not inactive Akt	akt	FKHR	FKHR	fkhr	6	7	9	10
Akt can directly suppress hepatic gluconeogenesis by negatively regulating the gluconeogenic transcriptional regulators : Foxo1 , PGC-1alpha and CRTC2 ( also known as TORC2 ) .	Akt can directly suppress hepatic gluconeogenesis by negatively regulating the gluconeogenic transcriptional regulators : Foxo1, PGC-1alpha and CRTC2 (also known as TORC2).	0	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	0	1	14	15
Akt directly up-regulates cell glucose uptake and increases glycolysis , in part , by suppressing FoxO1 .	Akt directly up-regulates cell glucose uptake and increases glycolysis, in part, by suppressing FoxO1.	0	16	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	0	1	15	16
Hepatic insulin resistance , which is characterized by impaired IRS and Akt inactivation of FOXO1 , also could lead to hepatic GH resistance , since FOXO1 has been shown to decrease hepatic GHR expression .	Hepatic insulin resistance, which is characterized by impaired IRS and Akt inactivation of FOXO1, also could lead to hepatic GH resistance, since FOXO1 has been shown to decrease hepatic GHR expression.	11	15	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	11	12	14	15
Akt activation sequesters FOXO1a away from its target genes and serves as an endpoint of a complex signaling network .	Akt activation sequesters FOXO1a away from its target genes and serves as an endpoint of a complex signaling network.	0	4	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1a	FOXO1a	FOXO1a	0	1	3	4
Consistently , phosphorylation of the Akt targets FOXO1 and PRAS40 was diminished ( XREF_SUPPLEMENTARY ) .	Consistently, phosphorylation of the Akt targets FOXO1 and PRAS40 was diminished (XREF_SUPPLEMENTARY).	2	11	targets	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Akt	phosphorylation of the Akt	akt	FOXO1	FOXO1	foxo1	5	6	7	8
mTORC2 and the PI3K-Akt and SGK1 pathway negatively regulate FOXO1 activity .	mTORC2 and the PI3K-Akt and SGK1 pathway negatively regulate FOXO1 activity.	3	10	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FOXO1	FOXO1	FOXO1	3	4	9	10
The inhibition of FOXO1 by AKT accelerates the cell cycle by downregulating cyclin dependent kinase inhibitors p27 and p21 .	The inhibition of FOXO1 by AKT accelerates the cell cycle by downregulating cyclin dependent kinase inhibitors p27 and p21.	1	6	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	5	6	3	4
PIP3 , generated by P13-K activates Akt which inactivates AFX and FKHR ; with the consequent decrease in p27 and Kip.1 expression and enhancement of cyclin D1 expression through FRAP and mTOR .	PIP3, generated by P13-K activates Akt which inactivates AFX and FKHR; with the consequent decrease in p27 and Kip.1 expression and enhancement of cyclin D1 expression through FRAP and mTOR.	5	23	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FKHR	FKHR	FKHR	6	7	11	12
Foxo1 nuclear localization and protein stability is attenuated following phosphorylation by the Akt kinase XREF_BIBR , XREF_BIBR .	Foxo1 nuclear localization and protein stability is attenuated following phosphorylation by the Akt kinase XREF_BIBR, XREF_BIBR.	0	14	attenuated	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	12	13	0	1
Considerable data support the idea that Foxo1 drives the liver transcriptional program during fasting and is inhibited by Akt after feeding .	Considerable data support the idea that Foxo1 drives the liver transcriptional program during fasting and is inhibited by Akt after feeding.	6	19	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	18	19	6	7
However , downregulation of Smurf2 in PANC-1 cells removed Akt mediated suppression of Smad3 and FoxO1 , allowing TGF-beta-induced phosphorylation and activation of Smad2/3 , dephosphorylation and activation of FoxO1 , nuclear translocation of both factors , and activation of PUMA mediated apoptosis .	However, downregulation of Smurf2 in PANC-1 cells removed Akt mediated suppression of Smad3 and FoxO1, allowing TGF-beta-induced phosphorylation and activation of Smad2/3, dephosphorylation and activation of FoxO1, nuclear translocation of both factors, and activation of PUMA mediated apoptosis.	9	16	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	9	10	15	16
However , whether Akt dependent inactivation of FoxO1 was responsible for kaempferol effect on PDX-1 expression remains to be determined .	However, whether Akt dependent inactivation of FoxO1 was responsible for kaempferol effect on PDX-1 expression remains to be determined.	3	8	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	3	4	7	8
It is well established that Akt inactivates FoxO1 by phosphorylation to reduce hepatic glucose production .	It is well established that Akt inactivates FoxO1 by phosphorylation to reduce hepatic glucose production.	5	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	5	6	7	8
Furthermore , normalization of the metabolic disturbances in the DLKO liver by additional deletion of Foxo1 argues that the predominant role of Akt is to suppress Foxo1 .	Furthermore, normalization of the metabolic disturbances in the DLKO liver by additional deletion of Foxo1 argues that the predominant role of Akt is to suppress Foxo1.	20	27	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	22	23	26	27
Akt signaling prevents inappropriate activation of FOXO1 and is essential for maintaining homeostasis .	Akt signaling prevents inappropriate activation of FOXO1 and is essential for maintaining homeostasis.	0	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	0	1	6	7
When FOXO1 is inhibited by the PI3K and AKT pathway , effector T cell status is preserved at the expense of memory T cell development .	When FOXO1 is inhibited by the PI3K and AKT pathway, effector T cell status is preserved at the expense of memory T cell development.	1	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	8	9	1	2
Akt also may inhibit forkhead transcription factor FKHR and promote the activation of anti-apoptotic molecules [ XREF_BIBR ] .	Akt also may inhibit forkhead transcription factor FKHR and promote the activation of anti-apoptotic molecules [XREF_BIBR].	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FKHR	FKHR	FKHR	0	1	7	8
Under insulin stimulated conditions , 3-phosphoinositide-dependent kinase-1 phosphorylates and activates Akt , which is thought to suppress hepatic glucose production through two key mechanisms : first , decreased expression of gluconeogenic enzymes by phosphorylation and nuclear exclusion of the fork-head box protein FOXO1 and its pro gluconeogenic targets , and second , activation of glycogen synthase by phosphorylation and inactivation of glycogen synthase kinase-3beta .	Under insulin stimulated conditions, 3-phosphoinositide-dependent kinase-1 phosphorylates and activates Akt, which is thought to suppress hepatic glucose production through two key mechanisms : first, decreased expression of gluconeogenic enzymes by phosphorylation and nuclear exclusion of the fork-head box protein FOXO1 and its pro gluconeogenic targets, and second, activation of glycogen synthase by phosphorylation and inactivation of glycogen synthase kinase-3beta.	10	47	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	10	11	42	43
Akt inactivates Foxo1 as well , preventing it from transcribing pro apoptotic genes .	Akt inactivates Foxo1 as well, preventing it from transcribing pro apoptotic genes.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	0	1	2	3
The transcription factor Foxo1 , which is negatively regulated by AKT , has been implicated in the induction of KLF2 and other migration-regulatory genes XREF_BIBR XREF_BIBR XREF_BIBR .	The transcription factor Foxo1, which is negatively regulated by AKT, has been implicated in the induction of KLF2 and other migration-regulatory genes XREF_BIBR XREF_BIBR XREF_BIBR.	0	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Foxo1	Foxo1	Foxo1	10	11	3	4
Akt phosphorylates and thereby inactivates the transcriptional repressor FoxO1 ; in keeping with the putative FoxO1 binding site in the HuD promoter ( 492 bp from the transcription start site ) , chromatin immunoprecipitation ( ChIP ) analysis in betaTC6 cells revealed an interaction of FoxO1 with the HuD promoter .	Akt phosphorylates and thereby inactivates the transcriptional repressor FoxO1; in keeping with the putative FoxO1 binding site in the HuD promoter (492 bp from the transcription start site), chromatin immunoprecipitation (ChIP) analysis in betaTC6 cells revealed an interaction of FoxO1 with the HuD promoter.	0	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	0	1	8	9
Together our results reveal that Maf1 expression is positively regulated by FoxO1 and negatively regulated through PI3K and AKT inactivation of FoxO1 .	Together our results reveal that Maf1 expression is positively regulated by FoxO1 and negatively regulated through PI3K and AKT inactivation of FoxO1.	16	22	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	18	19	21	22
These results provide evidence that Akt inhibits the transcriptional activity of FKHR by controlling its trafficking into the nucleus and that oncogenic PAX3-FKHR can escape this negative regulation by Akt .	These results provide evidence that Akt inhibits the transcriptional activity of FKHR by controlling its trafficking into the nucleus and that oncogenic PAX3-FKHR can escape this negative regulation by Akt.	5	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FKHR	FKHR	FKHR	5	6	11	12
Moreover , insulin rescued the negative effect of these factors on keratinocyte through migration through Akt , which blocks FOXO1 .	Moreover, insulin rescued the negative effect of these factors on keratinocyte through migration through Akt, which blocks FOXO1.	3	20	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	15	16	19	20
Reduction of Akt phosphorylation caused by a decrease of IGF-1 in the elderly could activate FKHR , thus promoting the transcription of atrogin-1 and MuRF1 ( muscle ring-finger protein 1 ) .	Reduction of Akt phosphorylation caused by a decrease of IGF-1 in the elderly could activate FKHR, thus promoting the transcription of atrogin-1 and MuRF1 (muscle ring-finger protein 1).	2	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	FKHR	FKHR	fkhr	2	3	15	16
Notably , AKT negatively regulates FOXO1 through phosphorylation and prevents FOXO1 nuclear accumulation , thus impairing target gene regulation .	Notably, AKT negatively regulates FOXO1 through phosphorylation and prevents FOXO1 nuclear accumulation, thus impairing target gene regulation.	2	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	2	3	5	6
AKT negatively regulates FOXO1 by direct phosphorylation , resulting in its inactivation and sequestration into the cytoplasm [ XREF_BIBR ] .	AKT negatively regulates FOXO1 by direct phosphorylation, resulting in its inactivation and sequestration into the cytoplasm [XREF_BIBR].	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	0	1	3	4
This suggests that PI3K-AKT signaling is required to prevent FOXO1 from entering the nuclei of gonocytes and activating a cell proliferation program precociously .	This suggests that PI3K-AKT signaling is required to prevent FOXO1 from entering the nuclei of gonocytes and activating a cell proliferation program precociously.	3	10	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO1	FOXO1	FOXO1	3	4	9	10
These results suggest that Akt activation by Tax1 in cells may not be sufficient to inactivate p27 and kip1 and p21 and waf1 functions , and that additional inactivation of p27 and kip1 and p21 and waf1 by genetic and/or epigenetic alterations could be essential for HTLV-1 to transform T-cells .	These results suggest that Akt activation by Tax1 in cells may not be sufficient to inactivate p27 and kip1 and p21 and waf1 functions, and that additional inactivation of p27 and kip1 and p21 and waf1 by genetic and/or epigenetic alterations could be essential for HTLV-1 to transform T-cells.	4	23	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	4	5	16	17
Furthermore , cyclopamine decreased the levels of phosphorylated ( activated ) Akt , which is known to increase p27 degradation via Skp-2-induced ubiquitination .	Furthermore, cyclopamine decreased the levels of phosphorylated (activated) Akt, which is known to increase p27 degradation via Skp-2-induced ubiquitination.	3	19	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	11	12	18	19
Wang et al [ XREF_BIBR ] have reported that over-expression of Akt inhibited p42 MAPK signaling , down-regulated p21 CIP-1 and waf-1 and p27 KIP-1 and blunted differentiation in response to 1,25 ( OH ) 2 D 3 , while knockdown of Akt ( by RNA interference ) gave reverse effects .	Wang et al [XREF_BIBR] have reported that over-expression of Akt inhibited p42 MAPK signaling, down-regulated p21 CIP-1 and waf-1 and p27 KIP-1 and blunted differentiation in response to 1,25 (OH) 2 D 3, while knockdown of Akt (by RNA interference) gave reverse effects.	9	24	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	over-expression of Akt	akt	p27	p27	p27	11	12	23	24
Moreover , combination therapy in vivo may induce additive p27 expression ( XREF_SUPPLEMENTARY ) and thereby cell cycle arrest due to GDC-0980-mediated inhibition of AKT coupled with MLN4924 mediated accumulation of p27 .	Moreover, combination therapy in vivo may induce additive p27 expression (XREF_SUPPLEMENTARY) and thereby cell cycle arrest due to GDC-0980-mediated inhibition of AKT coupled with MLN4924 mediated accumulation of p27.	22	32	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	24	25	31	32
Thus , we show a novel mechanism whereby Akt impairs p27 function that is associated with an aggressive phenotype in human breast cancer .	Thus, we show a novel mechanism whereby Akt impairs p27 function that is associated with an aggressive phenotype in human breast cancer.	8	11	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	8	9	10	11
Cellular proliferation may also be enhanced by activated AKT , which inhibits p27 and GSK-3 ( leading to stabilization of cyclin D1 ) [ XREF_BIBR ] .	Cellular proliferation may also be enhanced by activated AKT, which inhibits p27 and GSK-3 (leading to stabilization of cyclin D1) [XREF_BIBR].	5	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	8	9	12	13
Akt can also down-regulate CDKN1B through FOXO1 41 .	Akt can also down-regulate CDKN1B through FOXO1 41.	0	5	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	CDKN1B	CDKN1B	CDKN1B	0	1	4	5
Akt is known to increase cyclin D1 through inactivation of GSK-3beta and reduce p27 by inhibition of Forkhead family transcription factors and the tumor suppressor tuberin ( TSC2 ) XREF_BIBR .	Akt is known to increase cyclin D1 through inactivation of GSK-3beta and reduce p27 by inhibition of Forkhead family transcription factors and the tumor suppressor tuberin (TSC2) XREF_BIBR.	0	14	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	0	1	13	14
AKT has been shown to downregulate nuclear p27 by at least two mechanisms in human cells .	AKT has been shown to downregulate nuclear p27 by at least two mechanisms in human cells.	0	8	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	0	1	7	8
In addition , AKT negatively regulates p21 and p27 by direct phosphorylation .	In addition, AKT negatively regulates p21 and p27 by direct phosphorylation.	3	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	3	4	8	9
Active AKT inhibits CDKis p21 CIP1 and WAF1 and p27 KIP1 , by phosphorylation at Thr145 and , Thr157 and Thr198 respectively [ XREF_BIBR , XREF_BIBR ] .	Active AKT inhibits CDKis p21 CIP1 and WAF1 and p27 KIP1, by phosphorylation at Thr145 and, Thr157 and Thr198 respectively [XREF_BIBR, XREF_BIBR].	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27 KIP1	p27 KIP1	p27 KIP1	1	2	9	11
IL6 stimulated PI3K and Akt signaling has also been found to phosphorylate and inactivate forkhead transcriptional factor ( FKHR ) resulting in G1/S phase transition , whereas PI3K inhibitors such as LY294002 block this signaling , resulting in up regulation of p27 ( KIP1 ) and G1 growth arrest XREF_BIBR .	IL6 stimulated PI3K and Akt signaling has also been found to phosphorylate and inactivate forkhead transcriptional factor (FKHR) resulting in G1/S phase transition, whereas PI3K inhibitors such as LY294002 block this signaling, resulting in up regulation of p27 (KIP1) and G1 growth arrest XREF_BIBR.	2	49	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	4	5	41	42
Stimulation of TLR5 and overexpression of MyD88 , but not TRIF , TIRAP , or TRAM , result in p27 degradation , which can be suppressed by dominant negative Akt and mutation of the p27 C-terminal Thr ( 187 ) site .	Stimulation of TLR5 and overexpression of MyD88, but not TRIF, TIRAP, or TRAM, result in p27 degradation, which can be suppressed by dominant negative Akt and mutation of the p27 C-terminal Thr (187) site.	19	31	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	29	30	19	20
Lastly , Cyclin E1 is known to be regulated by EGFR signaling [ XREF_BIBR ] , where both AKT and ERK can inhibit p27 kip1 , which is a negative regulator of CDK2 and Cyclin E1 complex [ XREF_BIBR , XREF_BIBR ] .	Lastly, Cyclin E1 is known to be regulated by EGFR signaling [XREF_BIBR], where both AKT and ERK can inhibit p27 kip1, which is a negative regulator of CDK2 and Cyclin E1 complex [XREF_BIBR, XREF_BIBR].	17	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27 kip1	p27 kip1	p27 kip1	18	19	23	25
P-Akt was found to phosphorylate p27 kip1 and promote p27 kip1 degradation in cell culture XREF_BIBR .	P-Akt was found to phosphorylate p27 kip1 and promote p27 kip1 degradation in cell culture XREF_BIBR.	0	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	P-Akt	P-Akt was found to phosphorylate p27 kip1	p-akt	p27 kip1	p27 kip1	p27 kip1	0	1	9	11
In addition , AKT can also promote the degradation of p27 [ XREF_BIBR , XREF_BIBR ] , a cyclin dependent kinase inhibitor that can arrest cells in G1-phase by binding and inhibiting G1-phase cyclin-cdk complexes [ XREF_BIBR ] .	In addition, AKT can also promote the degradation of p27 [XREF_BIBR, XREF_BIBR], a cyclin dependent kinase inhibitor that can arrest cells in G1-phase by binding and inhibiting G1-phase cyclin-cdk complexes [XREF_BIBR].	3	36	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	3	4	10	11
Akt has been reported to suppress p27 ( Kip1 ) promoter activity through Forkhead box O ( FOXO ) in different kinds of cells .	Akt has been reported to suppress p27 (Kip1) promoter activity through Forkhead box O (FOXO) in different kinds of cells.	0	7	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	0	1	6	7
Although both p27 and p21 are inactivated by AKT [ XREF_BIBR ] , p21 was little changed by miR-340 .	Although both p27 and p21 are inactivated by AKT [XREF_BIBR], p21 was little changed by miR-340.	1	10	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	8	9	2	3
Previous studies in human cells , including PCa cells , have shown that AKT enhances p27 degradation through phosphorylation of T157 , which prevents nuclear translocation and thereby enhances degradation in the cytoplasm XREF_BIBR , XREF_BIBR , XREF_BIBR .	Previous studies in human cells, including PCa cells, have shown that AKT enhances p27 degradation through phosphorylation of T157, which prevents nuclear translocation and thereby enhances degradation in the cytoplasm XREF_BIBR, XREF_BIBR, XREF_BIBR.	13	16	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	13	14	15	16
PI3K and AKT and mTORC1 activation are high frequency events in EC , and PI3K and AKT pathway activation is known to both sequester p27 in the cytoplasm and induce degradation .	PI3K and AKT and mTORC1 activation are high frequency events in EC, and PI3K and AKT pathway activation is known to both sequester p27 in the cytoplasm and induce degradation.	14	25	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	16	17	24	25
Activation of the PI3K and AKT pathway by IL6 or OSM in DU145 and PC3 could inhibit the P27 and KIP1 checkpoint and promote cell growth , while LNCaP cells do not exhibit this same behavior and thus respond by growth inhibition and differentiation .	Activation of the PI3K and AKT pathway by IL6 or OSM in DU145 and PC3 could inhibit the P27 and KIP1 checkpoint and promote cell growth, while LNCaP cells do not exhibit this same behavior and thus respond by growth inhibition and differentiation.	3	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	KIP1	KIP1	KIP1	5	6	20	21
Inhibition of PI3K and AKT but not mTOR Signaling Restores Nuclear Localization of p27 .	Inhibition of PI3K and AKT but not mTOR Signaling Restores Nuclear Localization of p27.	0	14	Restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	4	5	13	14
To do this , we exploited the finding that the p27 IRES structure was not inhibited in its activity by heightened AKT activity [ XREF_BIBR ] .	To do this, we exploited the finding that the p27 IRES structure was not inhibited in its activity by heightened AKT activity [XREF_BIBR].	10	22	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	21	22	10	11
Raf : ER activation of AKT promotes degradation of p27 and cell cycle progression in mammary organotypic culture .	Raf : ER activation of AKT promotes degradation of p27 and cell cycle progression in mammary organotypic culture.	3	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	5	6	9	10
AKT promotes cellular proliferation by promoting the cell cycle proteins ( c-Myc and cyclin D1 ) and inactivating the cell cycle inhibitors ( p27 and p21 ) .	AKT promotes cellular proliferation by promoting the cell cycle proteins (c-Myc and cyclin D1) and inactivating the cell cycle inhibitors (p27 and p21).	0	25	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	0	1	23	24
By causing cytoplasmic mislocation of p27 and p21 , the Akt oncogenic kinase functionally inactivates these nuclear tumor suppressor proteins .	By causing cytoplasmic mislocation of p27 and p21, the Akt oncogenic kinase functionally inactivates these nuclear tumor suppressor proteins.	3	15	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	10	11	5	6
XREF_BIBR The beneficial properties of increased cytosolic p27 may depend upon compartmentalization , as Akt inhibits p27 through Akt mediated nuclear exclusion , preventing p27 induced cell cycle inhibition ( XREF_FIG ) .	XREF_BIBR The beneficial properties of increased cytosolic p27 may depend upon compartmentalization, as Akt inhibits p27 through Akt mediated nuclear exclusion, preventing p27 induced cell cycle inhibition (XREF_FIG).	14	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	14	15	16	17
32 Activity of Akt can also inhibit the function of the cell cycle inhibitors p21 and p27 , thus leading to unchecked growth .	32 Activity of Akt can also inhibit the function of the cell cycle inhibitors p21 and p27, thus leading to unchecked growth.	1	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	3	4	16	17
This rapid androgen stimulated p27 degradation was mediated by AKT through the phosphorylation of p27 T157 .	This rapid androgen stimulated p27 degradation was mediated by AKT through the phosphorylation of p27 T157.	4	10	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	9	10	4	5
Comparing these two sets of counterpart lines showed that expression of activated Akt did not prevent p27 kip1 upregulation ( XREF_FIG ) nor did it rescue the shMTH1 associated reduction in proliferation ( XREF_FIG ) .	Comparing these two sets of counterpart lines showed that expression of activated Akt did not prevent p27 kip1 upregulation (XREF_FIG) nor did it rescue the shMTH1 associated reduction in proliferation (XREF_FIG).	9	18	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	expression of activated Akt	akt	p27 kip1	p27 kip1	p27 kip1	12	13	16	18
In cancers where protein kinase B ( PKB )/Akt is constitutively activated by upstream oncogenes , Akt decreases p27 KIP1 by increasing proteolysis and reducing transcription [ XREF_BIBR ] .	In cancers where protein kinase B (PKB)/Akt is constitutively activated by upstream oncogenes, Akt decreases p27 KIP1 by increasing proteolysis and reducing transcription [XREF_BIBR].	16	20	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27 KIP1	p27 KIP1	p27 KIP1	16	17	18	20
It has been suggested that activation of Akt and subsequent deactivation of p27 affects the G1 phase of the cell cycle .	It has been suggested that activation of Akt and subsequent deactivation of p27 affects the G1 phase of the cell cycle.	7	13	deactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	7	8	12	13
The activated AKT can directly or indirectly inhibit p21Cip1 and p27Kip1 , thereby promoting cell cycle progression .	The activated AKT can directly or indirectly inhibit p21Cip1 and p27Kip1, thereby promoting cell cycle progression.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27Kip1	p27Kip1	p27Kip1	2	3	10	11
Expression of dominant negative Akt increased p27 ( kip1 ) protein and resulted in inhibition of CDK2 activity .	Expression of dominant negative Akt increased p27 (kip1) protein and resulted in inhibition of CDK2 activity.	0	8	increased	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Expression of dominant negative Akt	akt	p27	p27	p27	4	5	6	7
Nuclear p27 KIP1 is reduced in human pituitary adenomas , potentially consistent with cytoplasmic sequestration of p27 KIP1 by Akt activity ; however , the lack of correlation between p-Akt ( Ser473 ) and p27 KIP1 expression means conclusions must remain cautious .	Nuclear p27 KIP1 is reduced in human pituitary adenomas, potentially consistent with cytoplasmic sequestration of p27 KIP1 by Akt activity; however, the lack of correlation between p-Akt (Ser473) and p27 KIP1 expression means conclusions must remain cautious.	1	20	reduced	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27 KIP1	p27 KIP1	p27 KIP1	19	20	1	3
p27 ( kip1 ) transcription similarly was decreased by expression of constitutively active Akt kinase in mesangial cells .	p27 (kip1) transcription similarly was decreased by expression of constitutively active Akt kinase in mesangial cells.	0	14	decreased	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	expression of constitutively active Akt	akt	p27	p27	p27	13	14	0	1
AKT directly antagonizes the function of the cell cycle inhibitors p21 WAF1 and p27 Kip1 by phosphorylating a site located near the nuclear localization signal to induce cytoplasmic retention of these cell cycle inhibitors [ XREF_BIBR ] .	AKT directly antagonizes the function of the cell cycle inhibitors p21 WAF1 and p27 Kip1 by phosphorylating a site located near the nuclear localization signal to induce cytoplasmic retention of these cell cycle inhibitors [XREF_BIBR].	0	15	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27 Kip1	p27 Kip1	p27 Kip1	0	1	13	15
Furthermore , ectopic expression of a constitutively active form of AKT blocked the cell cycle arrest and apoptosis triggered by anti-IgM and also abrogated down-regulation of cyclin D2 and up-regulation of p27 ( Kip1 ) expression induced by BCR-engagement .	Furthermore, ectopic expression of a constitutively active form of AKT blocked the cell cycle arrest and apoptosis triggered by anti-IgM and also abrogated down-regulation of cyclin D2 and up-regulation of p27 (Kip1) expression induced by BCR-engagement.	8	32	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	10	11	31	32
These results are consistent with impaired Akt activity since Akt signaling has proliferative effects and negatively regulates p27 KIP1 .	These results are consistent with impaired Akt activity since Akt signaling has proliferative effects and negatively regulates p27 KIP1.	9	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27 KIP1	p27 KIP1	p27 KIP1	9	10	17	19
Constitutively active Akt prevented wild type p27 KIP1 , but not p27 KIP1 -T157A , from causing G1 arrest .	Constitutively active Akt prevented wild type p27 KIP1, but not p27 KIP1 -T157A, from causing G1 arrest.	1	8	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27 KIP1	p27 KIP1	p27 KIP1	2	3	6	8
beta-cyclodextrin cotreatment restored phosphorylation of AKT and STAT3 proteins , suppressed accumulation of IGF1R and HGFR precursors , inhibited upregulation of CDKN1B ( p27 ) protein , reinstated CCND1 ( cyclin D1 ) to control levels , and decreased PARP cleavage ( XREF_FIG ) .	beta-cyclodextrin cotreatment restored phosphorylation of AKT and STAT3 proteins, suppressed accumulation of IGF1R and HGFR precursors, inhibited upregulation of CDKN1B (p27) protein, reinstated CCND1 (cyclin D1) to control levels, and decreased PARP cleavage (XREF_FIG).	0	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	beta-cyclodextrin cotreatment restored phosphorylation of AKT	akt	CDKN1B	CDKN1B	cdkn1b	5	6	21	22
This result indicates p27 reduction in CP treated cells most likely results from AKT mediated p27 degradation .	This result indicates p27 reduction in CP treated cells most likely results from AKT mediated p27 degradation.	11	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	13	14	15	16
AKT also downregulates cyclin dependent kinase inhibitors KIP1 and CIP1 ( p27 and p21 ) , thus promoting cell proliferation [ XREF_BIBR , XREF_BIBR ] .	AKT also downregulates cyclin dependent kinase inhibitors KIP1 and CIP1 (p27 and p21), thus promoting cell proliferation [XREF_BIBR, XREF_BIBR].	0	9	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	KIP1	KIP1	KIP1	0	1	7	8
Pik3cb rescued Yap cKO heart function and our data indicate that this is through both mitogenic and pro survival activities , in keeping with known roles of PI3K-AKT signaling.The cell cycle inhibitor p27 , which is normally down-regulated at the protein level by AKT phosphorylation triggered degradation 20 , was upregulated in Yap cKO .	Pik3cb rescued Yap cKO heart function and our data indicate that this is through both mitogenic and pro survival activities, in keeping with known roles of PI3K-AKT signaling.The cell cycle inhibitor p27, which is normally down-regulated at the protein level by AKT phosphorylation triggered degradation 20, was upregulated in Yap cKO.	30	50	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT phosphorylation	akt	p27	p27	p27	43	44	32	33
Akt has also been shown to reduce p27 protein stability XREF_BIBR , another potential mechanism by which PKCalpha knockdown could lead to p27 accumulation .	Akt has also been shown to reduce p27 protein stability XREF_BIBR, another potential mechanism by which PKCalpha knockdown could lead to p27 accumulation.	0	10	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	0	1	7	8
The results indicated that the knockdown of TUSC3 caused by the overexpression of miR-UL112-3p could enhance the activity of the AKT pathway ( XREF_FIG ) , which resulted in elevated p-GSK3beta , GSK3beta expression and decreased p27 , caspase 9 expression ( XREF_FIG ) .	The results indicated that the knockdown of TUSC3 caused by the overexpression of miR-UL112-3p could enhance the activity of the AKT pathway (XREF_FIG), which resulted in elevated p-GSK3beta, GSK3beta expression and decreased p27, caspase 9 expression (XREF_FIG).	20	42	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	20	21	36	37
This result indicates the reduction in p27 required IGF-1R and most likely resulted from AKT mediated p27 degradation .	This result indicates the reduction in p27 required IGF-1R and most likely resulted from AKT mediated p27 degradation.	12	17	mediated	Positive_early_activation	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	14	15	16	17
In fact , AKT not only indirectly affects cell cycle and apoptosis by mediating FOXO transcription factors , but also directly inhibits p27Kip1 and p21Cip1 to promote cell cycle progression in cell cycle , and suppresses Bad and Caspase-9 to promote cell survival in apoptosis .	In fact, AKT not only indirectly affects cell cycle and apoptosis by mediating FOXO transcription factors, but also directly inhibits p27Kip1 and p21Cip1 to promote cell cycle progression in cell cycle, and suppresses Bad and Caspase-9 to promote cell survival in apoptosis.	3	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27Kip1	p27Kip1	p27Kip1	3	4	22	23
At the level of the cell cycle machinery , RAF and AKT cooperated to induce cyclin D1 and repress p27 ( Kip1 ) expression .	At the level of the cell cycle machinery, RAF and AKT cooperated to induce cyclin D1 and repress p27 (Kip1) expression.	9	21	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	11	12	19	20
These findings establish in vivo that murine p27 is not negatively regulated by AKT and indicate that proliferation in PI3 kinase and AKT pathway driven mouse models is mediated by p27 independent mechanisms that may be distinct from those in human .	These findings establish in vivo that murine p27 is not negatively regulated by AKT and indicate that proliferation in PI3 kinase and AKT pathway driven mouse models is mediated by p27 independent mechanisms that may be distinct from those in human.	6	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	13	14	7	8
The most likely scenario is that IGF-1R inhibition blocks AKT dependent degradation of p27 , and stabilized p27 then mediates cytoprotective arrest or delay in G1-phase .	The most likely scenario is that IGF-1R inhibition blocks AKT dependent degradation of p27, and stabilized p27 then mediates cytoprotective arrest or delay in G1-phase.	9	14	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	9	10	13	14
17 Activation of the PI3K and AKT pathway can downregulate the cyclin dependent kinase ( CDK ) inhibitors p21 and p27 , and stabilize the cell-cycle regulator cyclin D1/2 , consequently leading to increased cell proliferation .	17 Activation of the PI3K and AKT pathway can downregulate the cyclin dependent kinase (CDK) inhibitors p21 and p27, and stabilize the cell-cycle regulator cyclin D1/2, consequently leading to increased cell proliferation.	4	21	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	6	7	20	21
Therefore , we proposed a mechanistic model to illustrate how Twist activates both Akt and ERK pathways through their phosphorylation , further up-regulates phsopho-GSK-3beta and down-regulates p27 , and in turn induces EMT ( XREF_FIG ) .	Therefore, we proposed a mechanistic model to illustrate how Twist activates both Akt and ERK pathways through their phosphorylation, further up-regulates phsopho-GSK-3beta and down-regulates p27, and in turn induces EMT (XREF_FIG).	13	27	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	13	14	26	27
Therefore , to more directly address whether AKT was initially downregulating p27 , and whether a subsequent increase in p27 may be inhibiting progression of PIN lesions , we examined induction of myrAKT and p27 expression at very early times after treatment with doxycycline .	Therefore, to more directly address whether AKT was initially downregulating p27, and whether a subsequent increase in p27 may be inhibiting progression of PIN lesions, we examined induction of myrAKT and p27 expression at very early times after treatment with doxycycline.	7	12	downregulating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	7	8	11	12
Active PTEN results in decreased phosphorylation of Akt and MAPK , the up-regulation of p27 and down-regulation of cyclin D1 protein levels resulting in decreased proliferation and an increase in apoptosis .	Active PTEN results in decreased phosphorylation of Akt and MAPK, the up-regulation of p27 and down-regulation of cyclin D1 protein levels resulting in decreased proliferation and an increase in apoptosis.	1	15	up-regulation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Akt	PTEN results in decreased phosphorylation of Akt	akt	p27	p27	p27	7	8	14	15
Thus , AKT prevents nuclear translocation of cell cycle inhibitors p21 Cip1 and WAF1 and p27 Kip1 , and by phosphorylation and inhibition of the glycogen synthase kinase 3 ( GSK3 ) stabilizes cyclins and increases metabolic activity [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Thus, AKT prevents nuclear translocation of cell cycle inhibitors p21 Cip1 and WAF1 and p27 Kip1, and by phosphorylation and inhibition of the glycogen synthase kinase 3 (GSK3) stabilizes cyclins and increases metabolic activity [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27 Kip1	p27 Kip1	p27 Kip1	2	3	15	17
However , these AKT sites are not conserved in mouse , and it has not been clear whether AKT negatively regulates murine p27 .	However, these AKT sites are not conserved in mouse, and it has not been clear whether AKT negatively regulates murine p27.	18	23	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	18	19	22	23
As noted earlier , activation of PKB alone might not suffice to trigger p27 degradation in some tumors .	As noted earlier, activation of PKB alone might not suffice to trigger p27 degradation in some tumors.	4	14	trigger	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	p27	p27	p27	6	7	13	14
The most likely scenario is that IGF-1R inhibition blocks AKT dependent degradation of p27 , and stabilized p27 then mediates cytoprotective arrest or delay in G1-phase that allows DNA repair and survival ( XREF_FIG ) .	The most likely scenario is that IGF-1R inhibition blocks AKT dependent degradation of p27, and stabilized p27 then mediates cytoprotective arrest or delay in G1-phase that allows DNA repair and survival (XREF_FIG).	9	14	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	9	10	13	14
It has been reported that CTGF stimulates AKT mediated reduction of p27 , which is a key regulator of G 1 / S transition [ XREF_BIBR , XREF_BIBR ] .	It has been reported that CTGF stimulates AKT mediated reduction of p27, which is a key regulator of G 1 / S transition [XREF_BIBR, XREF_BIBR].	6	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	7	8	11	12
The cyclin dependent kinase inhibitors , p27kip1 on T157 and p21Clip and WAF1 on T145 , are phosphorylated by Akt to prevent the localization of p27 and p21 to the nucleus , which attenuates their inhibitory cell-cycle effects .	The cyclin dependent kinase inhibitors, p27kip1 on T157 and p21Clip and WAF1 on T145, are phosphorylated by Akt to prevent the localization of p27 and p21 to the nucleus, which attenuates their inhibitory cell-cycle effects.	1	27	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	cyclin dependent kinase inhibitors, p27kip1 on T157 and p21Clip and WAF1 on T145, are phosphorylated by Akt	akt	p27	p27	p27	19	20	25	26
PI3K-AKT signaling promotes cell cycle progression by inhibiting p27 34 .	PI3K-AKT signaling promotes cell cycle progression by inhibiting p27 34.	0	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	p27	p27	p27	0	1	8	9
Conversely , activation of Akt inhibits p27 and cyclin D1 through phosphorylation and inhibition of the FOXO transcription factors in the extracellular growth factors environment .	Conversely, activation of Akt inhibits p27 and cyclin D1 through phosphorylation and inhibition of the FOXO transcription factors in the extracellular growth factors environment.	2	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	4	5	6	7
Overexpression of CEP55 enhanced the phosphorylation of AKT and inhibited the activity of p21 WAF1 and Cip1 .	Overexpression of CEP55 enhanced the phosphorylation of AKT and inhibited the activity of p21 WAF1 and Cip1.	0	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Overexpression of CEP55 enhanced the phosphorylation of AKT	akt	Cip1	Cip1	cip1	7	8	16	17
Increased Nrf2 stability is dependent on the Akt mediated accumulation of p21 Cip1 and WAF1 and GSK-3 inhibition .	Increased Nrf2 stability is dependent on the Akt mediated accumulation of p21 Cip1 and WAF1 and GSK-3 inhibition.	4	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	WAF1	WAF1	WAF1	7	8	14	15
Further investigations revealed that the overexpression of CEP55 increased the phosphorylation of Akt and inhibited the activity of p21 .	Further investigations revealed that the overexpression of CEP55 increased the phosphorylation of Akt and inhibited the activity of p21.	5	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	overexpression of CEP55 increased the phosphorylation of Akt	akt	p21	p21	p21	12	13	18	19
These data are in accordance with our results such that co-administration of metformin ( 500 and 1000mg/kg , orally ) significantly attenuated mRNA expression of ER- alpha , IGF-1 and IGF-1R as well as the protein expression of pAkt and total Akt induced by testosterone and elevated that of ER-beta and P21 to near control level .	These data are in accordance with our results such that co-administration of metformin (500 and 1000mg/kg, orally) significantly attenuated mRNA expression of ER- alpha, IGF-1 and IGF-1R as well as the protein expression of pAkt and total Akt induced by testosterone and elevated that of ER-beta and P21 to near control level.	12	52	elevated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	metformin (500 and 1000mg/kg, orally) significantly attenuated mRNA expression of ER- alpha, IGF-1 and IGF-1R as well as the protein expression of pAkt and total Akt	akt	P21	P21	p21	41	42	51	52
It was reported that Akt ( an important molecule in mammalian cellular signaling ) also negatively regulates the in vitro lifespan of HUVECs via the p53 and p21 dependent pathway .	It was reported that Akt (an important molecule in mammalian cellular signaling) also negatively regulates the in vitro lifespan of HUVECs via the p53 and p21 dependent pathway.	4	29	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	4	5	27	28
In particular , inhibiting PI3K and AKT appeared to downregulate p21 , but not p27 Kip .	In particular, inhibiting PI3K and AKT appeared to downregulate p21, but not p27 Kip.	4	15	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p21	p21	p21	6	7	10	11
The mechanism investigations showed that overexpression of SZRD1 could downregulate the phosphorylation of ERK1/2 , AKT , STAT3 and downstream signaling molecules , and then arrest the cells in G2 phase by upregulating P21 .	The mechanism investigations showed that overexpression of SZRD1 could downregulate the phosphorylation of ERK1/2, AKT, STAT3 and downstream signaling molecules, and then arrest the cells in G2 phase by upregulating P21.	5	34	arrest	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	overexpression of SZRD1 could downregulate the phosphorylation of ERK1/2, AKT	akt	P21	P21	p21	15	16	33	34
AKT has been shown to inhibit p21 through phosphorylation on two sites and allowing for sustained cellular proliferation .	AKT has been shown to inhibit p21 through phosphorylation on two sites and allowing for sustained cellular proliferation.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p21	p21	p21	0	1	6	7
These results suggest that the cellular responses to AF are determined at least in part by Mdm2 and p21 ( CIP1 and WAF1 ) protein levels , as well as by Akt activity , leading either to cell cycle arrest when Mdm2 and p21 ( CIP1 and WAF1 ) are elevated , or to apoptosis when Mdm2 and p21 ( CIP1 and WAF1 ) are degraded by the proteasome and Akt insufficiently activated to protect against apoptosis .	These results suggest that the cellular responses to AF are determined at least in part by Mdm2 and p21 (CIP1 and WAF1) protein levels, as well as by Akt activity, leading either to cell cycle arrest when Mdm2 and p21 (CIP1 and WAF1) are elevated, or to apoptosis when Mdm2 and p21 (CIP1 and WAF1) are degraded by the proteasome and Akt insufficiently activated to protect against apoptosis.	56	71	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	70	71	58	59
ALO suppressed AKT and ERK phosphorylation , activated caspase 3 and induced activation of the p53 and p21 pathway .	ALO suppressed AKT and ERK phosphorylation, activated caspase 3 and induced activation of the p53 and p21 pathway.	0	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	ALO suppressed AKT and ERK phosphorylation	akt	p21	p21	p21	2	3	17	18
Moreover , AKT activation can inhibit levels of the cell periodic dependence protein kinase inhibitor P21 , thereby promoting the release of PCNA and promoting proliferation and survival of gastric mucosal epithelial cells .	Moreover, AKT activation can inhibit levels of the cell periodic dependence protein kinase inhibitor P21, thereby promoting the release of PCNA and promoting proliferation and survival of gastric mucosal epithelial cells.	2	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	P21	P21	P21	2	3	15	16
For ZD LNCaP cells , Akt hyperphosphorylation was probably mediated through p21 phosphorylation and degradation , thus restricting p21 nuclear entry to induce cell cycle arrest .	For ZD LNCaP cells, Akt hyperphosphorylation was probably mediated through p21 phosphorylation and degradation, thus restricting p21 nuclear entry to induce cell cycle arrest.	5	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt hyperphosphorylation	akt	p21	p21	p21	5	6	18	19
Indeed , upon FGF-BP knockdown we observed Akt suppression and activation of p21 ( see above ) , SAPK and JNK , caspases-3/7 and mediators of apoptosis , the cell death enhancing BH3-only domain proteins Bad and Bax .	Indeed, upon FGF-BP knockdown we observed Akt suppression and activation of p21 (see above), SAPK and JNK, caspases-3/7 and mediators of apoptosis, the cell death enhancing BH3-only domain proteins Bad and Bax.	7	13	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	7	8	12	13
p21 is a cell cycle inhibitory protein and could be inhibited by Akt via phosphorylate at Thr145 [ XREF_BIBR ] .	p21 is a cell cycle inhibitory protein and could be inhibited by Akt via phosphorylate at Thr145 [XREF_BIBR].	0	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	12	13	0	1
Phosphorylation by Akt decreases cell cycle inhibition by p21 Cip1 , suggesting that Akt hyperactivation promotes GMP expansion by inhibiting p21 Cip1 .	Phosphorylation by Akt decreases cell cycle inhibition by p21 Cip1, suggesting that Akt hyperactivation promotes GMP expansion by inhibiting p21 Cip1.	13	22	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21 Cip1	p21 Cip1	p21 Cip1	13	14	20	22
Akt upregulation can also promote cell growth by inactivating the negative cell cycle regulators p21 XREF_BIBR and p27 XREF_BIBR - XREF_BIBR .	Akt upregulation can also promote cell growth by inactivating the negative cell cycle regulators p21 XREF_BIBR and p27 XREF_BIBR - XREF_BIBR.	0	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	0	1	14	15
It also has been reported that AKT blocks the activation of p21 , causing its accumulation in the cytoplasm and consequently promoting cell proliferation XREF_BIBR .	It also has been reported that AKT blocks the activation of p21, causing its accumulation in the cytoplasm and consequently promoting cell proliferation XREF_BIBR.	6	12	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p21	p21	p21	6	7	11	12
The results suggested that Akt inhibition in KYNA treated HT-29 cells might result in previously reported overexpression of p21 Waf1 and Cip1 .	The results suggested that Akt inhibition in KYNA treated HT-29 cells might result in previously reported overexpression of p21 Waf1 and Cip1.	4	22	overexpression	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	Akt	Akt	Akt	Cip1	Cip1	Cip1	4	5	21	22
Thus , GILZ mediated enhancement of AKT activity may contribute to decrease p21 and to promote cell proliferation .	Thus, GILZ mediated enhancement of AKT activity may contribute to decrease p21 and to promote cell proliferation.	6	13	contribute	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p21	p21	p21	6	7	12	13
Akt represses p21 and Bax , promoting cell proliferation and preventing apoptosis [ XREF_BIBR , XREF_BIBR ] .	Akt represses p21 and Bax, promoting cell proliferation and preventing apoptosis [XREF_BIBR, XREF_BIBR].	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	0	1	2	3
In our system , enhanced activity of Akt in senescing hSKPs could reduce accumulation of p53 , p21 , and p16 and mitigate hSKP senescence .	In our system, enhanced activity of Akt in senescing hSKPs could reduce accumulation of p53, p21, and p16 and mitigate hSKP senescence.	5	18	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	7	8	17	18
In the same time we reveal that p21 which is negatively regulated by GILZ , is also reduced by AKT activation .	In the same time we reveal that p21 which is negatively regulated by GILZ, is also reduced by AKT activation.	7	20	reduced	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p21	p21	p21	19	20	7	8
To gain a greater understanding of the relationship between Akt and p21 Cip , we evaluated the mechanisms involved in the modulation of p21 Cip by Akt and the in vivo role of reduced p21 Cip in proliferative responses induced by Akt .	To gain a greater understanding of the relationship between Akt and p21 Cip, we evaluated the mechanisms involved in the modulation of p21 Cip by Akt and the in vivo role of reduced p21 Cip in proliferative responses induced by Akt.	21	35	modulation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	26	27	34	35
Akt upregulation can also promote cell growth by inactivating the negative cell cycle regulators p21 [ XREF_BIBR ] and p27 [ XREF_BIBR - XREF_BIBR ] .	Akt upregulation can also promote cell growth by inactivating the negative cell cycle regulators p21 [XREF_BIBR] and p27 [XREF_BIBR - XREF_BIBR].	0	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	0	1	14	15
Inhibition of PI3K and Akt directly induced premature senescence and increased expression of p21 XREF_BIBR .	Inhibition of PI3K and Akt directly induced premature senescence and increased expression of p21 XREF_BIBR.	0	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	4	5	13	14
The high-glucose-stimulated kinase activity of apoptosis signal regulating kinase 1 ( ASK1 ) , an upstream MAPK kinase kinase for p38 that is negatively regulated by Akt , was inhibited by OGT shRNA .	The high-glucose-stimulated kinase activity of apoptosis signal regulating kinase 1 (ASK1), an upstream MAPK kinase kinase for p38 that is negatively regulated by Akt, was inhibited by OGT shRNA.	3	27	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	26	27	11	12
On the other hand , Src kinase was activated and phosphorylated Cbl , which then recruited the p85 subunit of phosphatidylinositol 3-kinase ( PI-3K ) , resulting in PI-3K activation , and as a consequence increased Akt activation , which inhibited ASK1 activation and down-regulated JNK3 activation .	On the other hand, Src kinase was activated and phosphorylated Cbl, which then recruited the p85 subunit of phosphatidylinositol 3-kinase (PI-3K), resulting in PI-3K activation, and as a consequence increased Akt activation, which inhibited ASK1 activation and down-regulated JNK3 activation.	36	42	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	36	37	41	42
In fact , the absence of eIF-2alpha phosphorylation , IRE-1 phosphorylation and CHOP induction suggest that induction of JNK phosphorylation during DEPTOR silencing is not due to ER stress but mediated by an independent mechanism , possibly secondary to AKT down-regulation as it has been previously reported [ XREF_BIBR ] that AKT negatively regulates the ASK-1 and JNK cascade .	In fact, the absence of eIF-2alpha phosphorylation, IRE-1 phosphorylation and CHOP induction suggest that induction of JNK phosphorylation during DEPTOR silencing is not due to ER stress but mediated by an independent mechanism, possibly secondary to AKT down-regulation as it has been previously reported [XREF_BIBR] that AKT negatively regulates the ASK-1 and JNK cascade.	51	58	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	ASK-1	ASK-1	ASK-1	51	52	55	56
Phosphorylation of ASK1 Ser83 by AKT attenuates ASK1 kinase activity .	Phosphorylation of ASK1 Ser83 by AKT attenuates ASK1 kinase activity.	0	9	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Phosphorylation of ASK1 Ser83 by AKT	akt	ASK1	ASK1	ask1	5	6	7	8
Besides , the activation of Akt that inactivates ASK1 through the phosphorylation in Serine 83 is also redox sensitive [ XREF_BIBR ] .	Besides, the activation of Akt that inactivates ASK1 through the phosphorylation in Serine 83 is also redox sensitive [XREF_BIBR].	3	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	5	6	8	9
It has been shown that Akt suppresses the JNK pathway by phosphorylating and negatively regulating ASK-1 ( apoptosis signal regulating kinase-1 ) , MLK3 ( mixed-lineage protein kinase ) , and MKK4 and SEK1 ( mitogen activated protein and ERK kinase ) .	It has been shown that Akt suppresses the JNK pathway by phosphorylating and negatively regulating ASK-1 (apoptosis signal regulating kinase-1), MLK3 (mixed-lineage protein kinase), and MKK4 and SEK1 (mitogen activated protein and ERK kinase).	5	33	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK-1	ASK-1	ASK-1	5	6	15	16
SIRT1 deacetylates Akt and inhibits ASK1 activation .	SIRT1 deacetylates Akt and inhibits ASK1 activation.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	SIRT1 deacetylates Akt	akt	ASK1	ASK1	ask1	2	3	5	6
However , as AKT is known to negatively regulate ASK1 , clearly additional mechanisms may be operative in active AKT containing cells in which we observed increased SAPK2 and p38 activity following rapamycin exposure .	However, as AKT is known to negatively regulate ASK1, clearly additional mechanisms may be operative in active AKT containing cells in which we observed increased SAPK2 and p38 activity following rapamycin exposure.	3	10	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	ASK1	ASK1	ASK1	3	4	9	10
Indeed , Akt negatively regulates Raf-1 and ASK-1 , both of which are upstream activators of the MAPK signaling cascades .	Indeed, Akt negatively regulates Raf-1 and ASK-1, both of which are upstream activators of the MAPK signaling cascades.	2	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK-1	ASK-1	ASK-1	2	3	7	8
Finally , the inhibition of ASK1 by Akt was responsible for the protection from apoptosis induced by DNA damage , as it prevented c-Jun NH ( 2 )-terminal kinase mediated phosphorylation and activation of p53 .	Finally, the inhibition of ASK1 by Akt was responsible for the protection from apoptosis induced by DNA damage, as it prevented c-Jun NH (2)-terminal kinase mediated phosphorylation and activation of p53.	3	8	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	7	8	5	6
Indeed , Akt has been shown to inhibit Raf-1 and ASK1 , two upstream MAP3Ks critical for LPS signaling .	Indeed, Akt has been shown to inhibit Raf-1 and ASK1, two upstream MAP3Ks critical for LPS signaling.	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	2	3	10	11
It is also well-known that Akt is a negative regulator of ASK1 activity under ischemic conditions and that Akt attenuates ASK1 activity by directly phosphorylating at Ser 83 .	It is also well-known that Akt is a negative regulator of ASK1 activity under ischemic conditions and that Akt attenuates ASK1 activity by directly phosphorylating at Ser 83.	18	21	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	18	19	20	21
NOX4 generated ROS also stimulate phosphorylation of Akt , which in turn inactivates ASK1 by phosphorylating ASK1 on Ser 83 , leading to an antiapoptotic effect [ XREF_BIBR ] .	NOX4 generated ROS also stimulate phosphorylation of Akt, which in turn inactivates ASK1 by phosphorylating ASK1 on Ser 83, leading to an antiapoptotic effect [XREF_BIBR].	2	20	inactivates	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Akt	ROS also stimulate phosphorylation of Akt	akt	ASK1	phosphorylating ASK1 on Ser 83	ask1	7	8	16	17
For example , Akt negatively regulates ASK1 activity by direct phosphorylation of ASK1 on Ser83 , XREF_BIBR , XREF_BIBR ) while calcium/calmodulin dependent protein kinase type II ( CaMKII ) likely activates the ASK1-p38 pathway in response to calcium influx through phosphorylation of an unidentified residue in ASK1 .	For example, Akt negatively regulates ASK1 activity by direct phosphorylation of ASK1 on Ser83, XREF_BIBR, XREF_BIBR) while calcium/calmodulin dependent protein kinase type II (CaMKII) likely activates the ASK1-p38 pathway in response to calcium influx through phosphorylation of an unidentified residue in ASK1.	3	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	3	4	6	7
Furthermore , a marked phosphorylation at Ser 83 of ASK1 ( a specific Akt phosphorylation site ) was present in Resv treated keratinocytes indicating that Akt can inactivate ASK1 via SIRT1 pathway .	Furthermore, a marked phosphorylation at Ser 83 of ASK1 (a specific Akt phosphorylation site) was present in Resv treated keratinocytes indicating that Akt can inactivate ASK1 via SIRT1 pathway.	25	31	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	25	26	28	29
The same authors also show that JNK is regulated by ASK1 which in turn is inhibited by AKT .	The same authors also show that JNK is regulated by ASK1 which in turn is inhibited by AKT.	8	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	ASK1	ASK1	ASK1	17	18	10	11
Previous studies show Akt that can also act as an upstream kinase of ASK1 to phosphorylate and negatively regulate ASK1 at the site of Ser83 .	Previous studies show Akt that can also act as an upstream kinase of ASK1 to phosphorylate and negatively regulate ASK1 at the site of Ser83.	2	20	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	3	4	19	20
Activated Akt inhibits ASK-1 , a proapoptotic member of the MAP kinase kinase family , and protects against stress induced apoptosis in endothelial cells [ XREF_BIBR ] .	Activated Akt inhibits ASK-1, a proapoptotic member of the MAP kinase kinase family, and protects against stress induced apoptosis in endothelial cells [XREF_BIBR].	0	19	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK-1	ASK-1	ASK-1	1	2	3	4
For example , Akt , which is activated by Na 2 S 5 , has been shown to inhibit ASK1 30 and could possibly contribute to the suppression of ASK1 signaling .	For example, Akt, which is activated by Na 2 S 5, has been shown to inhibit ASK1 30 and could possibly contribute to the suppression of ASK1 signaling.	3	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	3	4	19	20
Furthermore , interference with the Akt cascade induced by paclitaxel up-regulated Raf-1 activity , and expression of constitutively active Akt inhibited Raf-1 activity , suggesting that Akt negatively regulates Raf-1 .	Furthermore, interference with the Akt cascade induced by paclitaxel up-regulated Raf-1 activity, and expression of constitutively active Akt inhibited Raf-1 activity, suggesting that Akt negatively regulates Raf-1.	15	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	expression of constitutively active Akt	akt	Raf-1	Raf-1	raf-1	19	20	21	22
AKT has been proposed to inhibit RAF-1 activity by direct phosphorylation at Ser 259 , but this mechanism of negative crosstalk was disputed in subsequent studies .	AKT has been proposed to inhibit RAF-1 activity by direct phosphorylation at Ser 259, but this mechanism of negative crosstalk was disputed in subsequent studies.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	RAF-1	RAF-1	RAF-1	0	1	6	7
Thus , typical for the AKT and RAF crosstalk , initial AKT activity still allows RAF dependent ERK activation , whereas prolonged AKT activity inhibits CRAF by phosphorylation of Ser259 accompanied with reduced ERK activity ( see XREF_FIG ) XREF_BIBR .	Thus, typical for the AKT and RAF crosstalk, initial AKT activity still allows RAF dependent ERK activation, whereas prolonged AKT activity inhibits CRAF by phosphorylation of Ser259 accompanied with reduced ERK activity (see XREF_FIG) XREF_BIBR.	22	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	CRAF	CRAF	CRAF	22	23	25	26
Akt negatively regulates Raf-1 activation ( Ser259 ) , partially explaining the difference between resistant and intermediate cells .	Akt negatively regulates Raf-1 activation (Ser259), partially explaining the difference between resistant and intermediate cells.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Raf-1	Raf-1	Raf-1	0	1	3	4
CNK1 mediates AKT dependent inhibition of CRAF in EGF stimulated cells .	CNK1 mediates AKT dependent inhibition of CRAF in EGF stimulated cells.	2	7	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	CRAF	CRAF	CRAF	2	3	6	7
Thus , at a lower concentration , Akt can inhibit Raf-1 activation through promoting the inhibitory iMST2 and iRaf -1 complex formation and thus , Raf-1 activation was reduced with increasing Akt amount .	Thus, at a lower concentration, Akt can inhibit Raf-1 activation through promoting the inhibitory iMST2 and iRaf -1 complex formation and thus, Raf-1 activation was reduced with increasing Akt amount.	7	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Raf-1	Raf-1	Raf-1	7	8	10	11
Decreased Akt activation and marked downregulation of C-Raf , Mek-1 and 2 , and MAP-kinases were noted with the combination therapy , compared to either agent alone .	Decreased Akt activation and marked downregulation of C-Raf, Mek-1 and 2, and MAP-kinases were noted with the combination therapy, compared to either agent alone.	1	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	C-Raf	C-Raf	C-Raf	1	2	7	8
The RAF-AKT crosstalk describes the interplay between AKT and RAF-1 signalling , whereby a strong PI3K and AKT activation leads to a AKT dependent inhibition of RAF-1 concomitant with abrogation of MAPK p42/44 signalling [ XREF_BIBR ] .	The RAF-AKT crosstalk describes the interplay between AKT and RAF-1 signalling, whereby a strong PI3K and AKT activation leads to a AKT dependent inhibition of RAF-1 concomitant with abrogation of MAPK p42/44 signalling [XREF_BIBR].	22	27	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	RAF-1	RAF-1	RAF-1	22	23	26	27
XREF_BIBR - XREF_BIBR Inhibition of Akt through LY294002 does not activate Raf-1 or inhibit Notch1 ( data not shown ) .	XREF_BIBR - XREF_BIBR Inhibition of Akt through LY294002 does not activate Raf-1 or inhibit Notch1 (data not shown).	3	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Raf-1	Raf-1	Raf-1	5	6	11	12
For example , c-Raf , a component of the Ras-MAPK pathway , is negatively regulated by activated AKT , such that PI3K and AKT inhibitors could inadvertently drive activation of MAPK signaling [ XREF_BIBR , XREF_BIBR ] .	For example, c-Raf, a component of the Ras-MAPK pathway, is negatively regulated by activated AKT, such that PI3K and AKT inhibitors could inadvertently drive activation of MAPK signaling [XREF_BIBR, XREF_BIBR].	3	18	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	c-Raf	c-Raf	c-Raf	17	18	3	4
Confirmatory Western and immunohistochemical analyses indicated activation of the substrate of PI3K , Akt and phosphorylative inactivation of glycogen synthase kinase-3beta and Raf1 .	Confirmatory Western and immunohistochemical analyses indicated activation of the substrate of PI3K, Akt and phosphorylative inactivation of glycogen synthase kinase-3beta and Raf1.	11	23	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Raf1	Raf1	Raf1	13	14	22	23
Our data including effects of the AKT inhibitor MK2206 support the notion that AKT inhibits CRAF by phosphorylation at Ser259 in EGF stimulated cells .	Our data including effects of the AKT inhibitor MK2206 support the notion that AKT inhibits CRAF by phosphorylation at Ser259 in EGF stimulated cells.	13	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	CRAF	CRAF	CRAF	13	14	15	16
ON123300 inhibited U87 glioma cell proliferation with an IC 50 = 3.4 +/- 0.1 muM and reduced phosphorylation of Akt , yet it also unexpectedly induced Erk activation ; both in a dose- and time dependent manner that subsequently was attributed to relieving Akt mediated C-Raf S259 inactivation and activating a p70S6K initiated PI3K negative feedback loop .	ON123300 inhibited U87 glioma cell proliferation with an IC 50 = 3.4 +/- 0.1 muM and reduced phosphorylation of Akt, yet it also unexpectedly induced Erk activation; both in a dose- and time dependent manner that subsequently was attributed to relieving Akt mediated C-Raf S259 inactivation and activating a p70S6K initiated PI3K negative feedback loop.	42	47	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	C-Raf	C-Raf	C-Raf	43	44	45	46
Akt is known to antagonize Raf1 , and such a link has been shown in ECs .	Akt is known to antagonize Raf1, and such a link has been shown in ECs.	0	6	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Raf1	Raf1	Raf1	0	1	5	6
Akt has been reported to inactivate Raf-1 through phosphorylation at Ser 259 .	Akt has been reported to inactivate Raf-1 through phosphorylation at Ser 259.	0	7	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Raf-1	Raf-1	Raf-1	0	1	6	7
Studies have shown also that c-Raf function can be inhibited by Akt dependent phosphorylation on serine 259 , which might lead to inhibition of MEK1/2 , MAPK and ERK , and S6K1 signaling independently of the mTORC1 complex .	Studies have shown also that c-Raf function can be inhibited by Akt dependent phosphorylation on serine 259, which might lead to inhibition of MEK1/2, MAPK and ERK, and S6K1 signaling independently of the mTORC1 complex.	5	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation on serine 259	akt	c-Raf	c-Raf	c-raf	11	12	5	6
Previous studies have shown that AKT can inhibit CRAF activity by phosphorylation at Ser259 XREF_BIBR .	Previous studies have shown that AKT can inhibit CRAF activity by phosphorylation at Ser259 XREF_BIBR.	5	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	CRAF	CRAF	CRAF	5	6	8	9
Akt was first reported to inhibit cRaf activity through direct phosphorylation at S 259 leading to subsequent inhibition of Mek1/2/ERK1/2 pathway in HEK293 cells [ XREF_BIBR ] .	Akt was first reported to inhibit cRaf activity through direct phosphorylation at S 259 leading to subsequent inhibition of Mek1/2/ERK1/2 pathway in HEK293 cells [XREF_BIBR].	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	cRaf	cRaf	cRaf	0	1	6	7
Furthermore , Akt has been reported to inhibit and activate cRaf and Mek pathway , suggesting that their mutual interaction and cooperation may be cell type , stimuli and/or context specific .	Furthermore, Akt has been reported to inhibit and activate cRaf and Mek pathway, suggesting that their mutual interaction and cooperation may be cell type, stimuli and/or context specific.	2	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	cRaf	cRaf	cRaf	2	3	10	11
Metfromin also significantly upregulated the expression of IRbeta ; increased the phosphorylations of IRbeta , IRS2 , and Akt ; increased the activities of PI3K and GS ; and decreased GSK3alpha and GPa activities .	Metfromin also significantly upregulated the expression of IRbeta; increased the phosphorylations of IRbeta, IRS2, and Akt; increased the activities of PI3K and GS; and decreased GSK3alpha and GPa activities.	0	33	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Metfromin also significantly upregulated the expression of IRbeta; increased the phosphorylations of IRbeta, IRS2, and Akt	akt	GSK3alpha	GSK3alpha	gsk3alpha	18	19	30	31
Akt and other kinases phosphorylate and inhibit GSK3alpha and beta , which have been found to regulate the stability of processed , active SREBP isoforms in cell culture models .	Akt and other kinases phosphorylate and inhibit GSK3alpha and beta, which have been found to regulate the stability of processed, active SREBP isoforms in cell culture models.	0	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3alpha	GSK3alpha	GSK3alpha	0	1	7	8
In addition , BAFF promotes the upregulation of the pro survival factor Mcl-1 , which may be due to Akt dependent inactivation of GSK3alpha and beta .	In addition, BAFF promotes the upregulation of the pro survival factor Mcl-1, which may be due to Akt dependent inactivation of GSK3alpha and beta.	19	25	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3alpha	GSK3alpha	GSK3alpha	19	20	23	24
Previous studies have shown that GSK-3alpha and beta activity can be negatively regulated by Akt , a serine/threonine kinase .	Previous studies have shown that GSK-3alpha and beta activity can be negatively regulated by Akt, a serine/threonine kinase.	5	18	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3alpha	GSK-3alpha	GSK-3alpha	14	15	5	6
These results suggest that activated Akt phosphorylates and inactivates GSK3alpha in PC9M2 cells even in the presence of gefitinib .	These results suggest that activated Akt phosphorylates and inactivates GSK3alpha in PC9M2 cells even in the presence of gefitinib.	4	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3alpha	GSK3alpha	GSK3alpha	5	6	9	10
Akt inhibits GSK3alpha and beta by phosphorylation of serine residues in the amino-terminal region ( serine 21 in alpha and serine 9 in beta ) , which are inserted into the kinase domain of GSK3 , hindering the entry of substrates XREF_BIBR .	Akt inhibits GSK3alpha and beta by phosphorylation of serine residues in the amino-terminal region (serine 21 in alpha and serine 9 in beta), which are inserted into the kinase domain of GSK3, hindering the entry of substrates XREF_BIBR.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3alpha	GSK3alpha	GSK3alpha	0	1	2	3
Akt also phosphorylates and inactivates Gsk3alpha in response to insulin XREF_BIBR , and since Gsk3alpha normally inhibits Glycogen Synthase ( GS ) , insulin stimulates GS activity and glycogen synthesis .	Akt also phosphorylates and inactivates Gsk3alpha in response to insulin XREF_BIBR, and since Gsk3alpha normally inhibits Glycogen Synthase (GS), insulin stimulates GS activity and glycogen synthesis.	0	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Gsk3alpha	Gsk3alpha	Gsk3alpha	0	1	5	6
Akt can inhibit both GSK3alpha and beta in response to multiple hormones and growth factors including BDNF , leptin , IGF1 , and insulin itself .	Akt can inhibit both GSK3alpha and beta in response to multiple hormones and growth factors including BDNF, leptin, IGF1, and insulin itself.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3alpha	GSK3alpha	GSK3alpha	0	1	4	5
The above results are consistent with a model in which rhodocytin stimulates GSK3alpha and beta phosphorylation at its negative regulatory site downstream of Akt and ERK , thereby inhibiting GSK3alpha and beta activity .	The above results are consistent with a model in which rhodocytin stimulates GSK3alpha and beta phosphorylation at its negative regulatory site downstream of Akt and ERK, thereby inhibiting GSK3alpha and beta activity.	10	32	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	rhodocytin stimulates GSK3alpha and beta phosphorylation at its negative regulatory site downstream of Akt	akt	GSK3alpha	GSK3alpha	gsk3alpha	23	24	29	30
In separate studies PMECMs were treated with the Akt inhibitor triciribine ( 12.5 uM ) for 1 hour to unmask Akt dependent constitutive suppression of GSK3alpha and beta .	In separate studies PMECMs were treated with the Akt inhibitor triciribine (12.5 uM) for 1 hour to unmask Akt dependent constitutive suppression of GSK3alpha and beta.	20	27	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK3alpha	GSK3alpha	GSK3alpha	20	21	25	26
Akt inhibits nuclear localization of FOXO4 and plays a key role in regulating its activity .	Akt inhibits nuclear localization of FOXO4 and plays a key role in regulating its activity.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO4	FOXO4	FOXO4	0	1	5	6
In addition , BCL6 is upregulated by FoxO4 , which in turn is inactivated by PI3K and AKT signaling .	In addition, BCL6 is upregulated by FoxO4, which in turn is inactivated by PI3K and AKT signaling.	5	18	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO4	FoxO4	FoxO4	17	18	7	8
Activation of SMAD2 , SMAD3 , ERK , p38 and PI3K and Akt signaling occurred during fibrogenesis and BMP-7 significantly attenuated SMAD3 and Akt signaling in vivo .	Activation of SMAD2, SMAD3, ERK, p38 and PI3K and Akt signaling occurred during fibrogenesis and BMP-7 significantly attenuated SMAD3 and Akt signaling in vivo.	12	24	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	SMAD3	SMAD3	SMAD3	12	13	21	22
How PI3K and Akt mediates inhibition of Smad3 remains to be answered .	How PI3K and Akt mediates inhibition of Smad3 remains to be answered.	1	8	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	3	4	7	8
Akt has been shown to inhibit Smad3 mediated growth inhibition and apoptosis by binding to and sequestering Smad3 in the cytosol XREF_BIBR , XREF_BIBR .	Akt has been shown to inhibit Smad3 mediated growth inhibition and apoptosis by binding to and sequestering Smad3 in the cytosol XREF_BIBR, XREF_BIBR.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	0	1	6	7
As Akt can sequester Smad3 away from the TGF-beta type I receptor , thereby preventing its phosphorylation and regulation of transcription , the potentiation of the Akt/mTOR/S6K axis could enable Akt mediated inhibition of Smad3 dependent signals that otherwise repress muscle growth .	As Akt can sequester Smad3 away from the TGF-beta type I receptor, thereby preventing its phosphorylation and regulation of transcription, the potentiation of the Akt/mTOR/S6K axis could enable Akt mediated inhibition of Smad3 dependent signals that otherwise repress muscle growth.	1	5	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	1	2	4	5
160 Akt blocks phospho activation of Smad3 by an Akt kinase dependent mechanism through mTOR and also blocks TGF-beta signals downstream of Smad3 activation , but through a mechanism that does not require the kinase activity of Akt or mTOR .	160 Akt blocks phospho activation of Smad3 by an Akt kinase dependent mechanism through mTOR and also blocks TGF-beta signals downstream of Smad3 activation, but through a mechanism that does not require the kinase activity of Akt or mTOR.	0	17	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	1	2	6	7
Several in vitro studies demonstrated that AKT pathway antagonizes SMAD3 activation where TGF-beta1 enhances ECs survival by increased activation of AKT [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Several in vitro studies demonstrated that AKT pathway antagonizes SMAD3 activation where TGF-beta1 enhances ECs survival by increased activation of AKT [XREF_BIBR, XREF_BIBR - XREF_BIBR].	6	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	SMAD3	SMAD3	SMAD3	6	7	9	10
Phosphorylation of Smad2/3 induces cell cycle arrest in keratinocytes , and Smad3 activity is suppressed by Akt XREF_BIBR .	Phosphorylation of Smad2/3 induces cell cycle arrest in keratinocytes, and Smad3 activity is suppressed by Akt XREF_BIBR.	11	17	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	16	17	11	12
For example , association of Akt with unphosphorylated Smad3 can sequester Smad3 , thus attenuating TGF-beta-induced Smad activation [ XREF_BIBR ] .	For example, association of Akt with unphosphorylated Smad3 can sequester Smad3, thus attenuating TGF-beta-induced Smad activation [XREF_BIBR].	3	12	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	5	6	11	12
It is also noteworthy that Akt mediated Smad3 inhibition by hepcidin was observed in primary hepatocytes ( XREF_SUPPLEMENTARY ) , suggesting the possible contribution of autocrine and anti-fibrotic effect of hepcidin .	It is also noteworthy that Akt mediated Smad3 inhibition by hepcidin was observed in primary hepatocytes (XREF_SUPPLEMENTARY), suggesting the possible contribution of autocrine and anti-fibrotic effect of hepcidin.	5	8	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	5	6	7	8
AKT has been shown to reduce SMAD3 function in Hep3B cells in which TGF-beta induces an apoptotic response XREF_BIBR XREF_BIBR .	AKT has been shown to reduce SMAD3 function in Hep3B cells in which TGF-beta induces an apoptotic response XREF_BIBR XREF_BIBR.	0	7	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	SMAD3	SMAD3	SMAD3	0	1	6	7
This effect is dependent on the downstream PI3K effector Akt , which can sequester Smad3 in the cytoplasm following insulin treatment of epithelial cells .	This effect is dependent on the downstream PI3K effector Akt, which can sequester Smad3 in the cytoplasm following insulin treatment of epithelial cells.	3	15	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	9	10	14	15
[ XREF_BIBR ] SMAD4 activation increases PTEN protein levels , while Akt directly sequesters SMAD3 , down-regulating the TGF-beta pathway .	[XREF_BIBR] SMAD4 activation increases PTEN protein levels, while Akt directly sequesters SMAD3, down-regulating the TGF-beta pathway.	11	15	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	SMAD3	SMAD3	SMAD3	11	12	14	15
Akt can also inhibit the ability of Smad3 to enter into the nucleus and regulate gene expression [ XREF_BIBR ] .	Akt can also inhibit the ability of Smad3 to enter into the nucleus and regulate gene expression [XREF_BIBR].	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	0	1	7	8
Downregulation of SMAD3 by Akt is an EC specific effect .	Downregulation of SMAD3 by Akt is an EC specific effect.	0	5	Downregulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	SMAD3	SMAD3	SMAD3	4	5	2	3
For example , Akt activation can sequester Smad3 through unphosphorylated Smad3 , impacts Smad activation in response to TGF-beta in EMT [ XREF_BIBR ] .	For example, Akt activation can sequester Smad3 through unphosphorylated Smad3, impacts Smad activation in response to TGF-beta in EMT [XREF_BIBR].	3	14	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	3	4	7	8
Several mechanisms have been proposed by which PI3K and Akt restricts Smad3 activity ( XREF_FIG ) .	Several mechanisms have been proposed by which PI3K and Akt restricts Smad3 activity (XREF_FIG).	7	12	restricts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	9	10	11	12
Inhibition of Smad3 by PKB occurs through a kinase-activity-independent mechanism , resulting in a decrease in Smad3 mediated transcription and protection of cells against TGF-beta-induced apoptosis .	Inhibition of Smad3 by PKB occurs through a kinase-activity-independent mechanism, resulting in a decrease in Smad3 mediated transcription and protection of cells against TGF-beta-induced apoptosis.	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PKB	PKB	PKB	Smad3	Smad3	Smad3	4	5	2	3
PI3K and Akt activation has been shown to down-regulate PGC-1alpha through Akt phosphorylation of the forkhead transcription factor , FoxO1 .	PI3K and Akt activation has been shown to down-regulate PGC-1alpha through Akt phosphorylation of the forkhead transcription factor, FoxO1.	0	10	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	9	10
AKT phosphorylates and inhibits PGC-1alpha in response to insulin in liver [ XREF_BIBR ] and activation of AKT causes a reduction in PGC-1alpha levels in heart [ XREF_BIBR ] .	AKT phosphorylates and inhibits PGC-1alpha in response to insulin in liver [XREF_BIBR] and activation of AKT causes a reduction in PGC-1alpha levels in heart [XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	4	5
However , whether the increased Akt activation contributed to the decreased PGC1alpha is uncertain .	However, whether the increased Akt activation contributed to the decreased PGC1alpha is uncertain.	5	12	contributed	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PGC1alpha	PGC1alpha	PGC1alpha	5	6	11	12
In addition , PGC-1alpha activity is inhibited by Akt dependent phosphorylation ( Li etal ., 2007 ) , which might link the observed increase in IIS during aging with attenuated mitochondrial biogenesis .	In addition, PGC-1alpha activity is inhibited by Akt dependent phosphorylation (Li etal., 2007), which might link the observed increase in IIS during aging with attenuated mitochondrial biogenesis.	3	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	PGC-1alpha	PGC-1alpha	pgc-1alpha	8	9	3	4
To further investigate the involvement of Akt and PGC1alpha , cardiomyocytes were transfected with PGC1alpha targeted siRNA to knockdown PGC1alpha or treated with LY294002 to block Akt activation .	To further investigate the involvement of Akt and PGC1alpha, cardiomyocytes were transfected with PGC1alpha targeted siRNA to knockdown PGC1alpha or treated with LY294002 to block Akt activation.	18	27	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Akt	Akt	Akt	PGC1alpha	PGC1alpha	PGC1alpha	26	27	19	20
As many malignant cancer cell lines encompass over-expressed 3-phosphoinositide-dependent kinase 1 or a loss of PTEN function , the anabolism activator , insulin or its mimetics , usually exacerbate AKT mediated PGC-1alpha suppression and reduce mitochondrial metabolism and antioxidant defenses [ XREF_BIBR , XREF_BIBR ] .	As many malignant cancer cell lines encompass over-expressed 3-phosphoinositide-dependent kinase 1 or a loss of PTEN function, the anabolism activator, insulin or its mimetics, usually exacerbate AKT mediated PGC-1alpha suppression and reduce mitochondrial metabolism and antioxidant defenses [XREF_BIBR, XREF_BIBR].	29	34	mediated	Positive_early_activation	Negative_activation	Negative_activation	AKT	AKT	AKT	PGC-1alpha	PGC-1alpha	PGC-1alpha	29	30	31	32
To date it has been known that PGC-1alpha is inactivated by the phosphorylation of Akt and Akt can have a negative impact on the PGC-1alpha expression via inactivation of the FoxOs factors , FoxO1 and FoxO3a which act as transcriptional regulators of PGC-1alpha expression XREF_BIBR , XREF_BIBR .	To date it has been known that PGC-1alpha is inactivated by the phosphorylation of Akt and Akt can have a negative impact on the PGC-1alpha expression via inactivation of the FoxOs factors, FoxO1 and FoxO3a which act as transcriptional regulators of PGC-1alpha expression XREF_BIBR, XREF_BIBR.	7	16	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	phosphorylation of Akt	akt	PGC-1alpha	PGC-1alpha	pgc-1alpha	14	15	7	8
Microarray analysis revealed that this was accompanied in Super-PTEN MEFs by a significant PGC1alpha gene enrichment signature ( XREF_SUPPLEMENTARY ) , in agreement with the fact that Akt is known to suppress PGC1alpha function .	Microarray analysis revealed that this was accompanied in Super-PTEN MEFs by a significant PGC1alpha gene enrichment signature (XREF_SUPPLEMENTARY), in agreement with the fact that Akt is known to suppress PGC1alpha function.	27	33	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PGC1alpha	PGC1alpha	PGC1alpha	27	28	32	33
During the fed state insulin and Akt can suppress PGC-1alpha activity through several mechanisms .	During the fed state insulin and Akt can suppress PGC-1alpha activity through several mechanisms.	4	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PGC-1alpha	PGC-1alpha	PGC-1alpha	6	7	9	10
Class I PI3K ( GDC0941 , BKM120 ) and AKT ( MK2206 ) inhibitors caused partial inhibition of OCR ( XREF_FIG ) and PGC1alpha ( XREF_FIG ) , but less than was observed with mTORC1/2 inhibition .	Class I PI3K (GDC0941, BKM120) and AKT (MK2206) inhibitors caused partial inhibition of OCR (XREF_FIG) and PGC1alpha (XREF_FIG), but less than was observed with mTORC1/2 inhibition.	0	24	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	PGC1alpha	PGC1alpha	PGC1alpha	9	10	23	24
Insulin and Akt can suppress PGC-1alpha activity by several mechanisms .	Insulin and Akt can suppress PGC-1alpha activity by several mechanisms.	0	6	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	5	6
On the other hand , we speculate that AKT mediated PGC-1alpha inhibition and the subsequent inactivation of metabolic gene transcription are more effectively exerted by skin melanoma cells to counteract mTOR inhibited PGC-1alpha degradation upon UA induced IGF-1 receptor signaling ( XREF_FIG ) .	On the other hand, we speculate that AKT mediated PGC-1alpha inhibition and the subsequent inactivation of metabolic gene transcription are more effectively exerted by skin melanoma cells to counteract mTOR inhibited PGC-1alpha degradation upon UA induced IGF-1 receptor signaling (XREF_FIG).	8	11	mediated	Positive_early_activation	Negative_activation	Negative_activation	AKT	AKT	AKT	PGC-1alpha	PGC-1alpha	PGC-1alpha	8	9	10	11
Interestingly , Akt , S6 kinase 1 ( S6K1 ) , and Clk2 , downstream kinases of insulin signaling , suppress PGC-1alpha activity through phosphorylation of the SR domain , where residues are evolutionarily highly conserved .	Interestingly, Akt, S6 kinase 1 (S6K1), and Clk2, downstream kinases of insulin signaling, suppress PGC-1alpha activity through phosphorylation of the SR domain, where residues are evolutionarily highly conserved.	2	22	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	21	22
For example , insulin suppresses the PGC-1alpha-dependent stimulation of fatty acid oxidation , both by reducing hepatocyte cyclic AMP and by promoting the Akt dependent inhibition of PGC-1alpha activity .	For example, insulin suppresses the PGC-1alpha-dependent stimulation of fatty acid oxidation, both by reducing hepatocyte cyclic AMP and by promoting the Akt dependent inhibition of PGC-1alpha activity.	23	28	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	PGC-1alpha	PGC-1alpha	PGC-1alpha	23	24	27	28
Having demonstrated constitutively active Akt inhibition of MST2 but dominant negative Akt activation of MST2 ( XREF_FIG ) , we reasoned Akt regulation of MST2 through a kinase dependent mechanism .	Having demonstrated constitutively active Akt inhibition of MST2 but dominant negative Akt activation of MST2 (XREF_FIG), we reasoned Akt regulation of MST2 through a kinase dependent mechanism.	11	16	activation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	11	12	14	15
The last pattern found for Akt as the controlling protein was M1E1 in which Akt consistently inhibits both ERK and MST2 activation ( XREF_FIG g ) .	The last pattern found for Akt as the controlling protein was M1E1 in which Akt consistently inhibits both ERK and MST2 activation (XREF_FIG g).	14	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	14	15	20	21
Moreover , Ras can activate both the ERK and MST2 pathways , but owing to the Akt mediated MST2 inhibition , Ras inactivates MST2 instead in cells where Akt is strongly activated by Ras [ XREF_BIBR , XREF_BIBR ] .	Moreover, Ras can activate both the ERK and MST2 pathways, but owing to the Akt mediated MST2 inhibition, Ras inactivates MST2 instead in cells where Akt is strongly activated by Ras [XREF_BIBR, XREF_BIBR].	13	19	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	16	17	18	19
The phosphorylation of Thr117 is required for Akt inhibition of MST2 .	The phosphorylation of Thr117 is required for Akt inhibition of MST2.	7	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	7	8	10	11
While Akt always inhibits MST2 activity , its dose specific function towards ERK suggests that Akt has the capacity to independently tune a signalling branch without affecting the other .	While Akt always inhibits MST2 activity, its dose specific function towards ERK suggests that Akt has the capacity to independently tune a signalling branch without affecting the other.	1	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	1	2	4	5
In vitro MST2 kinase activity was also inhibited by ectopic expression of wild-type and constitutively active Akt ( XREF_FIG ) .	In vitro MST2 kinase activity was also inhibited by ectopic expression of wild-type and constitutively active Akt (XREF_FIG).	2	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	expression of wild-type and constitutively active Akt	akt	MST2	MST2	mst2	16	17	2	3
Small molecule inhibitors of PI3K and Akt or depletion of Akt activate MST2 .	Small molecule inhibitors of PI3K and Akt or depletion of Akt activate MST2.	2	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	6	7	12	13
Moreover , Akt inhibits MST2 activation by phosphorylation at T117 and T384 , which leads to inhibition of MST2 cleavage , nuclear translocation , autophosphorylation at T180 and kinase activity XREF_BIBR , XREF_BIBR .	Moreover, Akt inhibits MST2 activation by phosphorylation at T117 and T384, which leads to inhibition of MST2 cleavage, nuclear translocation, autophosphorylation at T180 and kinase activity XREF_BIBR, XREF_BIBR.	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	2	3	4	5
While Akt interacts with MST2 , the regulation of MST2 by Akt depends on its kinase activity since constitutively active Akt inhibits whereas dominant negative Akt induces MST2 activation ( XREF_FIG and XREF_FIG ) .	While Akt interacts with MST2, the regulation of MST2 by Akt depends on its kinase activity since constitutively active Akt inhibits whereas dominant negative Akt induces MST2 activation (XREF_FIG and XREF_FIG).	23	28	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	25	26	27	28
Interestingly , while Akt always decreases MST2 activity , it induces diverse response profiles of ERK activity , provoking a decreasing ERK activity response in some case , and triggering biphasic ERK activity responses in others .	Interestingly, while Akt always decreases MST2 activity, it induces diverse response profiles of ERK activity, provoking a decreasing ERK activity response in some case, and triggering biphasic ERK activity responses in others.	3	7	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	3	4	6	7
Moreover , constitutively active Akt reduced the effect of wild-type MST2 but had no influence on MST2-T117A and MST2-T117D ( XREF_FIG ) .	Moreover, constitutively active Akt reduced the effect of wild-type MST2 but had no influence on MST2-T117A and MST2-T117D (XREF_FIG).	3	12	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	4	5	10	11
Using Ras effector domain mutants , we found that Akt is essential to prevent MST2 activation after mitogenic stimulation .	Using Ras effector domain mutants, we found that Akt is essential to prevent MST2 activation after mitogenic stimulation.	9	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	9	10	14	15
IGF1 and Akt were subsequently reported to also inhibit Mst2 activity , susceptibility to caspase cleavage and apoptotic efficacy , concomitant with phosphorylation of Mst2 [ T117 ] [ XREF_BIBR ] .	IGF1 and Akt were subsequently reported to also inhibit Mst2 activity, susceptibility to caspase cleavage and apoptotic efficacy, concomitant with phosphorylation of Mst2 [T117] [XREF_BIBR].	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Mst2	Mst2	Mst2	2	3	9	10
XREF_BIBR This creates a 2-way positive regulation between Akt and Skp2-SCF , which could potentially generate a threshold gated control for Akt dependent suppression of MST2 pathway .	XREF_BIBR This creates a 2-way positive regulation between Akt and Skp2-SCF, which could potentially generate a threshold gated control for Akt dependent suppression of MST2 pathway.	21	26	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	21	22	25	26
Activation of Akt , with the loss of PTEN , can impair Chk1 through ubiquitination , phosphorylation , and reduction of nuclear localization to mediate genomic instability 43 , but its relationship with the generation of DMs is still unknown .	Activation of Akt, with the loss of PTEN, can impair Chk1 through ubiquitination, phosphorylation, and reduction of nuclear localization to mediate genomic instability 43, but its relationship with the generation of DMs is still unknown.	0	13	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Chk1	Chk1	Chk1	2	3	12	13
Additionally , AKT further inhibits CHK1 function by phosphorylation of Ser280 .	Additionally, AKT further inhibits CHK1 function by phosphorylation of Ser280.	2	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	CHK1	CHK1	CHK1	2	3	5	6
Following previous work demonstrating that p90RSK and AKT kinases inactivate Chk1 , this study showed that in the context of KRAS mutant tumors , wild type H- and N-Ras reinforce Chk1 activation by antagonizing p90RSK and AKT .	Following previous work demonstrating that p90RSK and AKT kinases inactivate Chk1, this study showed that in the context of KRAS mutant tumors, wild type H- and N-Ras reinforce Chk1 activation by antagonizing p90RSK and AKT.	5	11	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Chk1	Chk1	Chk1	7	8	10	11
Inhibition of Akt and PKB restores Chk1 activation and DNA damage processing in late G2 .	Inhibition of Akt and PKB restores Chk1 activation and DNA damage processing in late G2.	0	7	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Chk1	Chk1	Chk1	2	3	6	7
A role of PTEN in promoting DNA repair has also been established because it can coordinate with E2F to upregulate expression of the repair protein Rad51 , as well as block AKT dependent inactivation of the checkpoint protein Chk1 .	A role of PTEN in promoting DNA repair has also been established because it can coordinate with E2F to upregulate expression of the repair protein Rad51, as well as block AKT dependent inactivation of the checkpoint protein Chk1.	31	39	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	Chk1	Chk1	Chk1	31	32	38	39
It was also reported that Akt induced phosphorylation of Chk1 on S280 in non hematopoietic cells , which prevented activation of Chk1 by inducing cytoplasmic translocation and ubiquitination XREF_BIBR , XREF_BIBR , although it has been later reported that Chk1 inhibition by Akt was not mediated by Chk1 phosphorylation on S280 XREF_BIBR , XREF_BIBR .	It was also reported that Akt induced phosphorylation of Chk1 on S280 in non hematopoietic cells, which prevented activation of Chk1 by inducing cytoplasmic translocation and ubiquitination XREF_BIBR, XREF_BIBR, although it has been later reported that Chk1 inhibition by Akt was not mediated by Chk1 phosphorylation on S280 XREF_BIBR, XREF_BIBR.	39	43	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Chk1	Chk1	Chk1	42	43	39	40
PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm , thus impairing the G2/M-checkpoint after irradiation .	PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation.	1	11	sequestered	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	CHK1	CHK1	CHK1	6	7	8	9
In contrast to our data , it has been reported that activation of the PI3K and Akt pathway inhibited Chk1 activation and overrode the G2/M arrest .	In contrast to our data, it has been reported that activation of the PI3K and Akt pathway inhibited Chk1 activation and overrode the G2/M arrest.	14	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Chk1	Chk1	Chk1	16	17	19	20
Our results identify a role for WT-H and N-Ras in facilitating Chk1 activation by suppressing the Erk and p90RSK and PI3K and Akt pathways that inhibit Chk1 via Ser 280 phosphorylation .	Our results identify a role for WT-H and N-Ras in facilitating Chk1 activation by suppressing the Erk and p90RSK and PI3K and Akt pathways that inhibit Chk1 via Ser 280 phosphorylation.	20	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Chk1	Chk1	Chk1	22	23	26	27
Also consistent is the finding that Akt inhibition markedly enhances DNA damage induced Chk1 activation in proliferating cells .	Also consistent is the finding that Akt inhibition markedly enhances DNA damage induced Chk1 activation in proliferating cells.	6	14	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Chk1	Chk1	Chk1	6	7	13	14
Akt was shown to mediate abnormal checkpoint control and aneuploidy in PTEN deficient cells by impairing CHK1 through phosphorylation , ubiquitination , and reduced nuclear localization .	Akt was shown to mediate abnormal checkpoint control and aneuploidy in PTEN deficient cells by impairing CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization.	0	23	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	CHK1	CHK1	CHK1	0	1	16	17
Altogether these results support a model whereby in K-Ras mutant cells , the downregulation WT-H and N-Ras leads to the enhancement of Erk and p90RSK and Akt signaling , which in turn represses Chk1 activation through Chk1 Ser 280 phosphorylation .	Altogether these results support a model whereby in K-Ras mutant cells, the downregulation WT-H and N-Ras leads to the enhancement of Erk and p90RSK and Akt signaling, which in turn represses Chk1 activation through Chk1 Ser 280 phosphorylation.	26	34	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Chk1	Chk1	Chk1	26	27	33	34
Second , IGFBP4 may increase AKT signaling to suppress EZH2 and H3K27me3 activity .	Second, IGFBP4 may increase AKT signaling to suppress EZH2 and H3K27me3 activity.	4	12	signaling	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	5	6	9	10
EZH2 is essential for proliferation and amplified in many primary cancers , and is inhibited by AKT through phosphorylation at Ser 21 .	EZH2 is essential for proliferation and amplified in many primary cancers, and is inhibited by AKT through phosphorylation at Ser 21.	0	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	16	17	0	1
AKT phosphorylation inactivates EZH2 , decreasing levels of H3K27 methylation , a repressive mark that inhibits gene expression , in the developing uterus .	AKT phosphorylation inactivates EZH2, decreasing levels of H3K27 methylation, a repressive mark that inhibits gene expression, in the developing uterus.	0	22	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	EZH2	EZH2	ezh2	0	1	3	4
Indeed , EZH2 is a known target of AKT , and AKT phosphorylation at Ser21 reduces the ability of EZH2 to methylate H3K27 63 .	Indeed, EZH2 is a known target of AKT, and AKT phosphorylation at Ser21 reduces the ability of EZH2 to methylate H3K27 63.	11	20	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation at Ser21	akt	EZH2	EZH2	ezh2	11	12	19	20
Their activities are upregulated by different mechanism such as signaling pathway , post-transcriptional modifications , highly reactive oxygen species , miRNA , and transcriptional factors ; while on the other hand , they are downregulated by Akt signaling pathway which inhibits EZH2 activities and thus reactivate the HIV-1 from latency [ XREF_BIBR , XREF_BIBR ] .	Their activities are upregulated by different mechanism such as signaling pathway, post-transcriptional modifications, highly reactive oxygen species, miRNA, and transcriptional factors; while on the other hand, they are downregulated by Akt signaling pathway which inhibits EZH2 activities and thus reactivate the HIV-1 from latency [XREF_BIBR, XREF_BIBR].	36	42	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	EZH2	EZH2	EZH2	36	37	41	42
Suppression of AKT enhances the activity of the EZH2 histone methyltransferase , a subunit of the epigenetic repressor Polycomb Repressive Complex 2 ( PRC2 ) , while simultaneously stabilizing the protein .	Suppression of AKT enhances the activity of the EZH2 histone methyltransferase, a subunit of the epigenetic repressor Polycomb Repressive Complex 2 (PRC2), while simultaneously stabilizing the protein.	0	10	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	2	3	8	9
It was reported previously that Akt suppresses the activity of the Ezh2 histone methyltransferase by phosphorylation on Serine 21 ( pS21 ) .	It was reported previously that Akt suppresses the activity of the Ezh2 histone methyltransferase by phosphorylation on Serine 21 (pS21).	5	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Ezh2	Ezh2	Ezh2	5	6	11	12
XREF_BIBR , XREF_BIBR Akt dependent phosphorylation does not affect EZH2 binding with other PRC2 components , but does reduce the affinity of EZH2 for histone H3 , leading to H3K27me3 and consequent de-repression of the EZH2 silenced genes .	XREF_BIBR, XREF_BIBR Akt dependent phosphorylation does not affect EZH2 binding with other PRC2 components, but does reduce the affinity of EZH2 for histone H3, leading to H3K27me3 and consequent de-repression of the EZH2 silenced genes.	0	23	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	EZH2	EZH2	EZH2	3	4	22	23
Collectively , our results indicate that PKB activity can influence peripheral deletion under certain conditions ; while it displays no effect on Fas independent deletion mechanisms induced by peptide , PKB can antagonize Fas signaling dependent T cell deletion by SEB in vivo .	Collectively, our results indicate that PKB activity can influence peripheral deletion under certain conditions; while it displays no effect on Fas independent deletion mechanisms induced by peptide, PKB can antagonize Fas signaling dependent T cell deletion by SEB in vivo.	30	34	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	Fas	Fas	Fas	30	31	33	34
The results indicated that overexpression of Akt leads to significantly reduced induction of Fas and cell death in infected cells ( XREF_FIG ) .	The results indicated that overexpression of Akt leads to significantly reduced induction of Fas and cell death in infected cells (XREF_FIG).	4	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	overexpression of Akt	akt	Fas	Fas	fas	6	7	13	14
Inhibition of Akt restored Fas induced liver injury in mice .	Inhibition of Akt restored Fas induced liver injury in mice.	0	5	restored	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Fas	Fas	Fas	2	3	4	5
In our study , the role of Akt in miR150 deficiency mediated resistance to Fas induced hepatocyte apoptosis is supported by the following observations : ( 1 ) the protein levels of Akt1 and Akt2 are higher in miR-150 KO hepatocytes and liver tissues ; ( 2 ) miR-150 directly targets the 3 ' UTR of Akt1 and Akt2 in hepatocytes ; ( 3 ) inhibition of Akt restores Fas induced hepatocyte apoptosis and liver injury in miR-150 KO mice .	In our study, the role of Akt in miR150 deficiency mediated resistance to Fas induced hepatocyte apoptosis is supported by the following observations : (1) the protein levels of Akt1 and Akt2 are higher in miR-150 KO hepatocytes and liver tissues; (2) miR-150 directly targets the 3 ' UTR of Akt1 and Akt2 in hepatocytes; (3) inhibition of Akt restores Fas induced hepatocyte apoptosis and liver injury in miR-150 KO mice.	65	70	restores	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Fas	Fas	Fas	67	68	69	70
Since the PI3K-AKT pathway can antagonize the ability of Fas to initiate apoptosis , we hypothesized that inhibition of PI3K would lead to reacquisition of Fas sensitivity in T-LGL .	Since the PI3K-AKT pathway can antagonize the ability of Fas to initiate apoptosis, we hypothesized that inhibition of PI3K would lead to reacquisition of Fas sensitivity in T-LGL.	2	10	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	Fas	Fas	Fas	2	3	9	10
Collectively , these data indicate that PKB activity is able to inhibit the activation of caspases downstream of Fas .	Collectively, these data indicate that PKB activity is able to inhibit the activation of caspases downstream of Fas.	6	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	Fas	Fas	Fas	6	7	18	19
Active PKB Leads to Reduced Activation of the Fas Apoptotic Pathway .	Active PKB Leads to Reduced Activation of the Fas Apoptotic Pathway.	0	10	Leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	Fas	Fas	Fas	1	2	8	9
PKB mediated regulation of Bcl-X L may also antagonize the apoptotic effects of Fas .	PKB mediated regulation of Bcl-X L may also antagonize the apoptotic effects of Fas.	0	14	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	Fas	Fas	Fas	0	1	13	14
Expectedly , GW4064 induced phosphorylation of Akt , expression of the anti-apoptotic molecules ( Bcl-xL and Bcl-2 ) , and reduced harmful hepatic molecules ( Fas ligand and Fas ) .	Expectedly, GW4064 induced phosphorylation of Akt, expression of the anti-apoptotic molecules (Bcl-xL and Bcl-2), and reduced harmful hepatic molecules (Fas ligand and Fas).	2	29	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	GW4064 induced phosphorylation of Akt	akt	Fas	Fas	fas	6	7	28	29
Blockade of AKT activation enhanced proliferation inhibition and the induction of phosphor-Bcl-2 and Nur77 proteins .	Blockade of AKT activation enhanced proliferation inhibition and the induction of phosphor-Bcl-2 and Nur77 proteins.	2	14	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Nur77	Nur77	Nur77	2	3	13	14
Perhaps surprisingly NUR77 127 which is a potent inducer of HIF1alpha 128 is inactivated by AKT signaling , although this may be cell type dependent .	Perhaps surprisingly NUR77 127 which is a potent inducer of HIF1alpha 128 is inactivated by AKT signaling, although this may be cell type dependent.	2	16	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	NUR77	NUR77	NUR77	15	16	2	3
These studies demonstrate interesting perspectives of Nur77 in which multiple signaling nodes are interconnected through Nur77 , as PI3K-AKT suppresses the pro apoptotic functions of Nur77 and Nur77 itself enhances downstream mTOR signaling to promote tumor progression , possibly in the context of LKB1 or p53 .	These studies demonstrate interesting perspectives of Nur77 in which multiple signaling nodes are interconnected through Nur77, as PI3K-AKT suppresses the pro apoptotic functions of Nur77 and Nur77 itself enhances downstream mTOR signaling to promote tumor progression, possibly in the context of LKB1 or p53.	18	27	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	Nur77	Nur77	Nur77	18	19	25	26
Conversely , PI3K and Akt inhibition does not significantly affect the minocycline effects on LPS induced LOX-1 , Nur77 or LITAF activation , suggesting additional mechanisms involved in the anti-inflammatory effect of minocycline .	Conversely, PI3K and Akt inhibition does not significantly affect the minocycline effects on LPS induced LOX-1, Nur77 or LITAF activation, suggesting additional mechanisms involved in the anti-inflammatory effect of minocycline.	2	21	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Nur77	Nur77	Nur77	4	5	18	19
In addition to inhibiting its DNA binding and transcriptional activity , AKT also prevents Nur77 from inducing apoptosis in T-cell hybridomas [ XREF_BIBR ] .	In addition to inhibiting its DNA binding and transcriptional activity, AKT also prevents Nur77 from inducing apoptosis in T-cell hybridomas [XREF_BIBR].	11	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Nur77	Nur77	Nur77	11	12	14	15
Next , we assessed some key factors mediating insulin signalling and found that protein levels of AKT were decreased in the muscle of female mice lacking Nur77 , whereas no changes were detected for pAKT or PTEN ( XREF_FIG ) .	Next, we assessed some key factors mediating insulin signalling and found that protein levels of AKT were decreased in the muscle of female mice lacking Nur77, whereas no changes were detected for pAKT or PTEN (XREF_FIG).	14	27	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	levels of AKT	akt	Nur77	Nur77	nur77	16	17	26	27
The inhibition of Nur77 by Akt suggests a mechanism that explains how T-cell receptor activation can promote survival in some instances even when Nur77 is induced .	The inhibition of Nur77 by Akt suggests a mechanism that explains how T-cell receptor activation can promote survival in some instances even when Nur77 is induced.	1	6	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Nur77	Nur77	Nur77	5	6	3	4
Thus , Akt negatively regulates Rac1 and POSH function by multiple mechanisms that contribute to its prosurvival effect in the brain .	Thus, Akt negatively regulates Rac1 and POSH function by multiple mechanisms that contribute to its prosurvival effect in the brain.	2	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	2	3	5	6
In some cell types , Rac1 is a downstream target of the PI3K and Akt signaling cascade , such as CEF cells , and inactivation of PI3K or Akt was sufficient to suppress Rac1 activation induced by integrin linked kinase XREF_BIBR .	In some cell types, Rac1 is a downstream target of the PI3K and Akt signaling cascade, such as CEF cells, and inactivation of PI3K or Akt was sufficient to suppress Rac1 activation induced by integrin linked kinase XREF_BIBR.	24	34	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	28	29	33	34
We demonstrated previously that mammalian target of rapamycin , an important effector and regulator of PI3K and AKT , activates phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 ( P-Rex1 ) , a Rac guanine nucleotide exchange factor identified as a target of G betagamma and PI3K , via direct interactions .	We demonstrated previously that mammalian target of rapamycin, an important effector and regulator of PI3K and AKT, activates phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 (P-Rex1), a Rac guanine nucleotide exchange factor identified as a target of G betagamma and PI3K, via direct interactions.	11	26	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	Rac	Rac	Rac	17	18	22	23
In some cell types , such as CEF cells , Rac1 is a downstream target of the PI3K and Akt signaling cascade , and inactivation of PI3K or Akt was sufficient to suppress Rac1 activation induced by integrin linked kinase [ XREF_BIBR ] .	In some cell types, such as CEF cells, Rac1 is a downstream target of the PI3K and Akt signaling cascade, and inactivation of PI3K or Akt was sufficient to suppress Rac1 activation induced by integrin linked kinase [XREF_BIBR].	24	34	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	28	29	33	34
Furthermore , constitutive activation of Akt or PI3-K in the absence of HGF was sufficient to phosphorylate rac1 , inhibit rac1 activation , and suppress rac1 regulated ROS production .	Furthermore, constitutive activation of Akt or PI3-K in the absence of HGF was sufficient to phosphorylate rac1, inhibit rac1 activation, and suppress rac1 regulated ROS production.	3	26	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	rac1	rac1	rac1	5	6	25	26
Upstream of AKT , reducing FAK or Rac1 by siRNA blocked strain stimulated AKT phosphorylation , but inhibiting Src by PP2 or siRNA did not .	Upstream of AKT, reducing FAK or Rac1 by siRNA blocked strain stimulated AKT phosphorylation, but inhibiting Src by PP2 or siRNA did not.	0	8	reducing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Rac1	Rac1	Rac1	2	3	7	8
The metastasis suppressing role of this novel signaling pathway identified for CRMP4 in this study is in agreement with reports implicating that Akt inhibits Rac1 activity by direct phosphorylation of Rac1 [ XREF_BIBR , XREF_BIBR ] .	The metastasis suppressing role of this novel signaling pathway identified for CRMP4 in this study is in agreement with reports implicating that Akt inhibits Rac1 activity by direct phosphorylation of Rac1 [XREF_BIBR, XREF_BIBR].	22	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	22	23	24	25
In addition , Rac1 can also be regulated by phosphorylation by Akt on Ser71 , thereby leading to inhibit the binding of GTP but not Rac1 GTPase activity [ XREF_BIBR ] .	In addition, Rac1 can also be regulated by phosphorylation by Akt on Ser71, thereby leading to inhibit the binding of GTP but not Rac1 GTPase activity [XREF_BIBR].	7	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	11	12	25	26
Furthermore , MKK4 , a central component in the pathway , is antagonized by AKT signaling , which modulates the early degenerative response by limiting activation of downstream JNKs .	Furthermore, MKK4, a central component in the pathway, is antagonized by AKT signaling, which modulates the early degenerative response by limiting activation of downstream JNKs.	2	15	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	MKK4	MKK4	MKK4	14	15	2	3
Akt inhibits the ASK1-SEK1-JNK2 signal transduction pathway by inactivating SEK1 through Ser80 phosphorylation in response to glucose deprivation [ XREF_BIBR ] .	Akt inhibits the ASK1-SEK1-JNK2 signal transduction pathway by inactivating SEK1 through Ser80 phosphorylation in response to glucose deprivation [XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	SEK1	SEK1	SEK1	0	1	9	10
Expression of a constitutively active form of Akt also inhibited both SEK1 and JNK1 activation , but not that of MEKK1 , in transfected 293T cells .	Expression of a constitutively active form of Akt also inhibited both SEK1 and JNK1 activation, but not that of MEKK1, in transfected 293T cells.	5	18	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	SEK1	SEK1	SEK1	7	8	11	12
For example , AKT activation inhibits MAP2K4 .	For example, AKT activation inhibits MAP2K4.	3	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	MAP2K4	MAP2K4	MAP2K4	3	4	6	7
Further , MKK4 , a key component in the Sarm1-MAPK pathway , is antagonized by AKT signaling , which modulates the degenerative response by limiting activation of downstream JNK signaling .	Further, MKK4, a key component in the Sarm1-MAPK pathway, is antagonized by AKT signaling, which modulates the degenerative response by limiting activation of downstream JNK signaling.	2	16	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	MKK4	MKK4	MKK4	15	16	2	3
Interestingly , AKT inhibits MLK3 kinase activity and blocks MLK3 dependent activation of JNK and apoptosis in HEK293 cells [ XREF_BIBR ] .	Interestingly, AKT inhibits MLK3 kinase activity and blocks MLK3 dependent activation of JNK and apoptosis in HEK293 cells [XREF_BIBR].	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	MLK3	MLK3	MLK3	2	3	4	5
The elevated Akt activation can deactivate MLK3 by phosphorylation at the Ser71 residue of Rac1 , a small Rho family of guanidine triphosphatases required for MLK3 autophosphorylation .	The elevated Akt activation can deactivate MLK3 by phosphorylation at the Ser71 residue of Rac1, a small Rho family of guanidine triphosphatases required for MLK3 autophosphorylation.	2	7	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MLK3	MLK3	MLK3	2	3	6	7
The reduction of PKB activity releases PKB induced inhibition of MLK3 and thus further stimulates JNK activity and accelerates the apoptotic effect of GnRH-a .	The reduction of PKB activity releases PKB induced inhibition of MLK3 and thus further stimulates JNK activity and accelerates the apoptotic effect of GnRH-a.	6	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	MLK3	MLK3	MLK3	6	7	10	11
As these different compartments are characterized by having different Rab proteins associated with them , XREF_BIBR , XREF_BIBR , XREF_BIBR it has been difficult to determine which compartment ( s ) and its associated Rab protein ( s ) specifically responds to insulin through inactivation of AS160 by AKT .	As these different compartments are characterized by having different Rab proteins associated with them, XREF_BIBR, XREF_BIBR, XREF_BIBR it has been difficult to determine which compartment (s) and its associated Rab protein (s) specifically responds to insulin through inactivation of AS160 by AKT.	23	49	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	AS160	AS160	AS160	48	49	46	47
Akt then phosphorylates and thereby inactivates the Rab-GAP AS160 ( Akt substrate of 160 kDa , TBC1D4 ) .	Akt then phosphorylates and thereby inactivates the Rab-GAP AS160 (Akt substrate of 160 kDa, TBC1D4).	0	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AS160	AS160	AS160	0	1	8	9
Thus , activated Akt appears to inactivate AS160 , which , in turn , presumably results in the activation of one or more Rabs that are , at least in part , responsible for the recruitment of GLUT4 to the plasma membrane .	Thus, activated Akt appears to inactivate AS160, which, in turn, presumably results in the activation of one or more Rabs that are, at least in part, responsible for the recruitment of GLUT4 to the plasma membrane.	2	15	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AS160	AS160	AS160	3	4	7	8
Moreover , cotransfection of constitutively active Akt significantly inhibited the ability of wild-type PTP1B , but not PTP1B-S50A , to dephosphorylate the insulin receptor .	Moreover, cotransfection of constitutively active Akt significantly inhibited the ability of wild-type PTP1B, but not PTP1B-S50A, to dephosphorylate the insulin receptor.	2	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PTP1B	PTP1B	PTP1B	6	7	13	14
SIRT1 can also enhance post-receptor insulin signalling by increasing serine phosphorylation of Akt and tyrosine phosphorylation of the insulin receptor and IRS-1 , primarily through transcriptional repression of the phosphorylase Ptpn1 ( protein tyrosine phosphatase , non receptor type1 ) .	SIRT1 can also enhance post-receptor insulin signalling by increasing serine phosphorylation of Akt and tyrosine phosphorylation of the insulin receptor and IRS-1, primarily through transcriptional repression of the phosphorylase Ptpn1 (protein tyrosine phosphatase, non receptor type1).	9	34	repression	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Akt	serine phosphorylation of Akt	akt	Ptpn1	Ptpn1	ptpn1	12	13	30	31
MEK and Erk and PI3K and Akt signaling pathways mediate the effect of inhibition of PTP1B on proliferation and migration of RPE cells .	MEK and Erk and PI3K and Akt signaling pathways mediate the effect of inhibition of PTP1B on proliferation and migration of RPE cells.	4	16	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PTP1B	PTP1B	PTP1B	6	7	15	16
The increased Akt activation in PTP1B negative B cells could also contribute to their higher proliferation rate .	The increased Akt activation in PTP1B negative B cells could also contribute to their higher proliferation rate.	2	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	PTP1B	PTP1B	PTP1B	2	3	5	6
In absence of receptor internalization , 65 % inhibition of PTP1B by Akt was required to display a bistable response , whereas , inclusion of receptor internalization demonstrated bistability even at 25 % inhibition of PTP1B .	In absence of receptor internalization, 65% inhibition of PTP1B by Akt was required to display a bistable response, whereas, inclusion of receptor internalization demonstrated bistability even at 25% inhibition of PTP1B.	8	13	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	PTP1B	PTP1B	PTP1B	12	13	10	11
Along with inhibition of phosphorylation of Akt , activation of p70-S6K and phosphorylation of PDCD4 were blocked , whereas PDCD4 level was retained or even upregulated ( XREF_FIG ) , which indicates that the PI3K and Akt pathway mediates the degradation of PDCD4 by pulsatile shear stress .	Along with inhibition of phosphorylation of Akt, activation of p70-S6K and phosphorylation of PDCD4 were blocked, whereas PDCD4 level was retained or even upregulated (XREF_FIG), which indicates that the PI3K and Akt pathway mediates the degradation of PDCD4 by pulsatile shear stress.	34	43	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PDCD4	PDCD4	PDCD4	36	37	42	43
Blockade of AKT activation in ox-LDL-stimulated Pdcd4 -/- macrophages led to significant increase in p-eIF2alpha level and SG formation .	Blockade of AKT activation in ox-LDL-stimulated Pdcd4 -/- macrophages led to significant increase in p-eIF2alpha level and SG formation.	2	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	Pdcd4	Pdcd4	Pdcd4	2	3	6	7
Blockade of AKT signaling in Pdcd4 deficient ADSCs led to a marked decline in cyclinD1 , S-phase entry and cell proliferation , revealing AKT as a target for repressing ADSC self-renewal by Pdcd4 .	Blockade of AKT signaling in Pdcd4 deficient ADSCs led to a marked decline in cyclinD1, S-phase entry and cell proliferation, revealing AKT as a target for repressing ADSC self-renewal by Pdcd4.	2	7	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	Pdcd4	Pdcd4	Pdcd4	2	3	5	6
To further confirm that AKT down-regulates PDCD4 , we determined whether inhibition of AKT increases the expression of PDCD4 .	To further confirm that AKT down-regulates PDCD4, we determined whether inhibition of AKT increases the expression of PDCD4.	2	7	down-regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	PDCD4	PDCD4	PDCD4	4	5	6	7
We found that treatment with MK-2206 , an AKT inhibitor , significantly increased PDCD4 expression in both AKTaro and LTEDaro cells ( XREF_FIG ) , confirming that PDCD4 is down-regulated by AKT .	We found that treatment with MK-2206, an AKT inhibitor, significantly increased PDCD4 expression in both AKTaro and LTEDaro cells (XREF_FIG), confirming that PDCD4 is down-regulated by AKT.	27	32	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	PDCD4	PDCD4	PDCD4	31	32	27	28
AKT inhibits MST1 through phosphorylating it at Thr120 , blocking MST1 mediated phosphorylation and activation of FOXO3a .	AKT inhibits MST1 through phosphorylating it at Thr120, blocking MST1 mediated phosphorylation and activation of FOXO3a.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	MST1	MST1	MST1	0	1	2	3
As explained before , beta-Amyloid seems to activate also the MST-FOXO pathway and it is possible that the loss of AKT direct inhibition of MST1 could explain this observation [ XREF_BIBR ] .	As explained before, beta-Amyloid seems to activate also the MST-FOXO pathway and it is possible that the loss of AKT direct inhibition of MST1 could explain this observation [XREF_BIBR].	20	25	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	MST1	MST1	MST1	20	21	24	25
Under acute stress conditions , AKT promoted cell survival by inhibiting MST1 , but prolonged stress decreased AKT , which allowed pro apoptotic MST1 signaling .	Under acute stress conditions, AKT promoted cell survival by inhibiting MST1, but prolonged stress decreased AKT, which allowed pro apoptotic MST1 signaling.	5	12	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	MST1	MST1	MST1	5	6	11	12
For example , MST1 cleavage by caspases is inhibited by Akt phosphorylation at T387 .	For example, MST1 cleavage by caspases is inhibited by Akt phosphorylation at T387.	3	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	MST1	MST1	mst1	10	11	3	4
Retraction : The RNA Binding Protein KSRP Promotes Decay of beta-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling .	Retraction : The RNA Binding Protein KSRP Promotes Decay of beta-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling.	2	17	Inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	KSRP	KSRP	KSRP	16	17	6	7
Aim of this study was to identify additional KSRP targets whose stability and steady-state levels are enhanced by PI3K-AKT activation .	Aim of this study was to identify additional KSRP targets whose stability and steady-state levels are enhanced by PI3K-AKT activation.	8	19	enhanced	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	KSRP	KSRP	KSRP	18	19	8	9
As a consequence , AKT activation impairs KSRP ability to interact with the exoribonucleolytic complex exosome and , in turn , to promote rapid mRNA decay .	As a consequence, AKT activation impairs KSRP ability to interact with the exoribonucleolytic complex exosome and, in turn, to promote rapid mRNA decay.	4	8	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	KSRP	KSRP	KSRP	4	5	7	8
The RNA Binding Protein KSRP Promotes Decay of beta-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling .	The RNA Binding Protein KSRP Promotes Decay of beta-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling.	0	15	Inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	KSRP	KSRP	KSRP	14	15	4	5
AKT Activation Impairs the Interaction of KSRP with the Exosome .	AKT Activation Impairs the Interaction of KSRP with the Exosome.	0	7	Impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	KSRP	KSRP	KSRP	0	1	6	7
Indeed , Foxa2 is directly inactivated by Akt via phosphorylation of a single site that is conserved in the fly Fkh .	Indeed, Foxa2 is directly inactivated by Akt via phosphorylation of a single site that is conserved in the fly Fkh.	2	9	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxa2	Foxa2	Foxa2	7	8	2	3
Consistent with this finding , a constitutively active Akt consistently phosphorylated N-CoR leading to its misfolding ; while the therapeutic and genetic ablation of Akt largely abrogated the MCDL of N-CoR in AML-M5 cells .	Consistent with this finding, a constitutively active Akt consistently phosphorylated N-CoR leading to its misfolding; while the therapeutic and genetic ablation of Akt largely abrogated the MCDL of N-CoR in AML-M5 cells.	22	31	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	N-CoR	N-CoR	N-CoR	24	25	30	31
Conversely , N-CoR , but not SMRT , can be negatively regulated by Akt in the control of the NF-kappaB transcriptional response [ XREF_BIBR ] .	Conversely, N-CoR, but not SMRT, can be negatively regulated by Akt in the control of the NF-kappaB transcriptional response [XREF_BIBR].	2	16	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	N-CoR	N-CoR	N-CoR	13	14	2	3
In addition , the kinase AKT can simultaneously activate CREB and inactivate NCoR1 , suggesting antagonism between both .	In addition, the kinase AKT can simultaneously activate CREB and inactivate NCoR1, suggesting antagonism between both.	3	13	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	NCoR1	NCoR1	NCoR1	5	6	12	13
Indeed , FOXO6 exhibits major structural differences compared to the other three family members , and , unlike FOXO1 and 3 , activation of the PI3K-AKT pathway by growth factors inhibits FOXO6 transcriptional activity mainly via a mechanism independent of shuttling to the cytosol [ XREF_BIBR , XREF_BIBR ] .	Indeed, FOXO6 exhibits major structural differences compared to the other three family members, and, unlike FOXO1 and 3, activation of the PI3K-AKT pathway by growth factors inhibits FOXO6 transcriptional activity mainly via a mechanism independent of shuttling to the cytosol [XREF_BIBR, XREF_BIBR].	25	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO6	FOXO6	FOXO6	25	26	31	32
Based on our in vivo and in vitro observations , we propose the age related phosphorylation of FoxO6 represses the expression of catalase , and that the transcription factors FoxO6 are suppressed by the activations of Pak1 and Akt when age related oxidative stress is augmented by LPS .	Based on our in vivo and in vitro observations, we propose the age related phosphorylation of FoxO6 represses the expression of catalase, and that the transcription factors FoxO6 are suppressed by the activations of Pak1 and Akt when age related oxidative stress is augmented by LPS.	26	39	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO6	FoxO6	FoxO6	38	39	29	30
In EBV+ B cell lymphomas , the inhibition of SYK also results in the degradation of the caspase 3 inhibitor , XIAP [ XREF_BIBR ] , due to a decrease in the AKT dependent inhibition of HTRA2 , a protease for which XIAP is a known substrate [ XREF_BIBR ] .	In EBV+ B cell lymphomas, the inhibition of SYK also results in the degradation of the caspase 3 inhibitor, XIAP [XREF_BIBR], due to a decrease in the AKT dependent inhibition of HTRA2, a protease for which XIAP is a known substrate [XREF_BIBR].	32	37	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	HTRA2	HTRA2	HTRA2	32	33	36	37
In addition , Akt inhibits the release of HtrA2 and Omi from the mitochondria into the cytoplasm in response to cisplatin treatment .	In addition, Akt inhibits the release of HtrA2 and Omi from the mitochondria into the cytoplasm in response to cisplatin treatment.	3	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Omi	Omi	Omi	3	4	10	11
These results demonstrate that METTL1 is inactivated by PKB and RSK in cells , and the potential implications of this finding are discussed .	These results demonstrate that METTL1 is inactivated by PKB and RSK in cells, and the potential implications of this finding are discussed.	4	10	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	METTL1	METTL1	METTL1	8	9	4	5
AKT suppresses RARalpha transactivation through phosphorylation of Ser96 within the RAR DNA binding domain ; AKT does not alter RAR DNA binding , but most probably results in modification of a region necessary for cofactor binding 52 .	AKT suppresses RARalpha transactivation through phosphorylation of Ser96 within the RAR DNA binding domain; AKT does not alter RAR DNA binding, but most probably results in modification of a region necessary for cofactor binding 52.	0	3	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	RARalpha	RARalpha	RARalpha	0	1	2	3
We observed that RARalpha deletion mediated inhibition of the phosphorylation of PLB was associated with decreased phosphorylation of CaMKIIdelta and Akt , and that activation of CaMKII or Akt abolished the inhibitory effect of RARalpha deletion on PLB phosphorylation at Thr17 .	We observed that RARalpha deletion mediated inhibition of the phosphorylation of PLB was associated with decreased phosphorylation of CaMKIIdelta and Akt, and that activation of CaMKII or Akt abolished the inhibitory effect of RARalpha deletion on PLB phosphorylation at Thr17.	24	35	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	RARalpha	RARalpha	RARalpha	28	29	34	35
The high Akt activity disrupted GAB2 and SHP -2 feedback inhibition of Lyn ; however , the elevated Lyn activity also increased inhibitory signaling via SHP-1 to restrict the Erk1/2 pathway .	The high Akt activity disrupted GAB2 and SHP -2 feedback inhibition of Lyn; however, the elevated Lyn activity also increased inhibitory signaling via SHP-1 to restrict the Erk1/2 pathway.	2	10	disrupted	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GAB2	GAB2	GAB2	2	3	5	6
Because phagocytosis and the PI3K-Akt pathway activation are only partially inhibited Gab2-/- BMM ( XREF_FIG and XREF_FIG ) , other Gab and Dos family members may also function in BMM .	Because phagocytosis and the PI3K-Akt pathway activation are only partially inhibited Gab2-/- BMM (XREF_FIG and XREF_FIG), other Gab and Dos family members may also function in BMM.	4	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	Gab2-/-	Gab2-/-	Gab2-/-	4	5	11	12
AKT , however , can suppress Mad which , in conjunction with the reported suppression of Mad by Hiw , closes the mutual regulation between both pathways .	AKT, however, can suppress Mad which, in conjunction with the reported suppression of Mad by Hiw, closes the mutual regulation between both pathways.	0	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Mad	Mad	Mad	0	1	6	7
Inhibition of Akt phosphorylation by IRAK 1/4 inhibitor and the inability of LY294002 to inhibit IRAK1 - TRAF6 interaction suggested that there was a sequential activation of IRAK followed by PI 3-kinase activation in IL-1beta signaling in human CEC .	Inhibition of Akt phosphorylation by IRAK 1/4 inhibitor and the inability of LY294002 to inhibit IRAK1 - TRAF6 interaction suggested that there was a sequential activation of IRAK followed by PI 3-kinase activation in IL-1beta signaling in human CEC.	2	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation by IRAK	akt	IRAK1	IRAK1	irak1	2	3	15	16
However , opposing the argument are reports from in vitro studies that AKT activation specifically reduces AMPKalpha1 activity by phosphorylating alpha1 at S487 , while having no effect on alpha2 which is a poor ATK substrate [ XREF_BIBR - XREF_BIBR ] .	However, opposing the argument are reports from in vitro studies that AKT activation specifically reduces AMPKalpha1 activity by phosphorylating alpha1 at S487, while having no effect on alpha2 which is a poor ATK substrate [XREF_BIBR - XREF_BIBR].	12	17	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	AMPKalpha1	AMPKalpha1	AMPKalpha1	12	13	16	17
Akt also inhibited the function of transcription factor GATA2 through similar mechanism XREF_BIBR .	Akt also inhibited the function of transcription factor GATA2 through similar mechanism XREF_BIBR.	0	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GATA2	GATA2	GATA2	0	1	8	9
Later , it was shown that PHF20 can transcriptionally activate p53 and be downregulated through phosphorylation by the Akt kinase 17 .	Later, it was shown that PHF20 can transcriptionally activate p53 and be downregulated through phosphorylation by the Akt kinase 17.	6	19	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	PHF20	PHF20	PHF20	18	19	6	7
Our data suggest that the NR3C1 driven proapoptotic response is reduced by an AKT and MEK-ERK-driven antiapoptotic response resulting in steroid resistance .	Our data suggest that the NR3C1 driven proapoptotic response is reduced by an AKT and MEK-ERK-driven antiapoptotic response resulting in steroid resistance.	4	17	reduced	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	NR3C1	NR3C1	NR3C1	13	14	5	6
Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK mediated phosphorylation of TSC2 .	Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK mediated phosphorylation of TSC2.	4	18	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	4	5	16	17
Because the GAP domain of TSC2 is conserved throughout the eukaryotic lineage , the most plausible scenario is that PKB and RSK inhibition of TSC2 is an ancestral function of the PKB-SGK-S6K-RSK ancestral gene ( henceforth we will refer to this ancestor as the ancestral AGC kinase for brevity ) .	Because the GAP domain of TSC2 is conserved throughout the eukaryotic lineage, the most plausible scenario is that PKB and RSK inhibition of TSC2 is an ancestral function of the PKB-SGK-S6K-RSK ancestral gene (henceforth we will refer to this ancestor as the ancestral AGC kinase for brevity).	19	25	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKB	PKB	PKB	TSC2	TSC2	TSC2	19	20	24	25
Moreover , AKT inhibits GAP activity of TSC2 for Rheb GTPase [ XREF_BIBR ] .	Moreover, AKT inhibits GAP activity of TSC2 for Rheb GTPase [XREF_BIBR].	2	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	2	3	7	8
The activation of PI3K-I and Akt pathway inhibits the GTPase activating activity of Tsc2 , leading to the relief of the inhibitory effect of Rheb-GDP on TOR and P70s6K signalling [ XREF_BIBR - XREF_BIBR ] .	The activation of PI3K-I and Akt pathway inhibits the GTPase activating activity of Tsc2, leading to the relief of the inhibitory effect of Rheb-GDP on TOR and P70s6K signalling [XREF_BIBR - XREF_BIBR].	3	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Tsc2	Tsc2	Tsc2	5	6	13	14
We hypothesized that curcumin may alleviate Akt mediated inhibition of TSC2 function , stabilize TSC1/2 interactions , or directly stimulate TSC2 GAP activity .	We hypothesized that curcumin may alleviate Akt mediated inhibition of TSC2 function, stabilize TSC1/2 interactions, or directly stimulate TSC2 GAP activity.	6	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	6	7	10	11
Akt ( also known as PKB ) phosphorylates and inactivates TSC2 in response to growth factors XREF_BIBR , whereas AMPK phosphorylates and activates TSC2 in response to low energy ( high AMP ) XREF_BIBR , XREF_BIBR .	Akt (also known as PKB) phosphorylates and inactivates TSC2 in response to growth factors XREF_BIBR, whereas AMPK phosphorylates and activates TSC2 in response to low energy (high AMP) XREF_BIBR, XREF_BIBR.	0	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	10	11
Akt inhibits the activity of the TSC1 and TSC2 ( proteins harboring mutations in tuberous sclerosis ) complex , a negative regulator of mammalian target of rapamaycin ( mTOR ) , which regulates autophagy [ XREF_BIBR ] .	Akt inhibits the activity of the TSC1 and TSC2 (proteins harboring mutations in tuberous sclerosis) complex, a negative regulator of mammalian target of rapamaycin (mTOR), which regulates autophagy [XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	8	9
Akt activates mTOR by inhibiting tuberous sclerosis complex 2 ( TSC2 ) , which heterodimerizes with TSC1 , thereby inactivating Rheb and mTOR .	Akt activates mTOR by inhibiting tuberous sclerosis complex 2 (TSC2), which heterodimerizes with TSC1, thereby inactivating Rheb and mTOR.	0	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	10	11
Akt is known to directly phosphorylate Ser2448 for activation of mTOR and inhibit tuberous sclerosis complex 2 ( TSC2 ) and AMP Kinase , which otherwise inhibits mTOR activity .	Akt is known to directly phosphorylate Ser2448 for activation of mTOR and inhibit tuberous sclerosis complex 2 (TSC2) and AMP Kinase, which otherwise inhibits mTOR activity.	0	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	18	19
Although the exact mechanism by which Akt inhibits TSC2 and AS160 GAP activities remains unknown , these findings point to a regulatory paradigm in which GAPs integrate signals from Akt to activate small GTPases , which in turn engage with downstream effectors .	Although the exact mechanism by which Akt inhibits TSC2 and AS160 GAP activities remains unknown, these findings point to a regulatory paradigm in which GAPs integrate signals from Akt to activate small GTPases, which in turn engage with downstream effectors.	6	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	6	7	8	9
Activation of the PI3K and AKT signaling cascade inhibits TSC2 [ XREF_BIBR ] , activating the mTORC1 complex and inhibiting formation of a trimeric unc-51-like kinase ( ULK ) complex required for autophagosome formation from the phagophore [ XREF_BIBR ] .	Activation of the PI3K and AKT signaling cascade inhibits TSC2 [XREF_BIBR], activating the mTORC1 complex and inhibiting formation of a trimeric unc-51-like kinase (ULK) complex required for autophagosome formation from the phagophore [XREF_BIBR].	5	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	5	6	9	10
Two mechanisms have linked HPV16 E6 oncoprotein to mTORC1 activation : 1 ) binding to TSC2 and promoting its ubiquitin mediated degradation 39 , 2 ) activation of PDK1 and AKT , which subsequently inhibits TSC1 and TSC2 .	Two mechanisms have linked HPV16 E6 oncoprotein to mTORC1 activation : 1) binding to TSC2 and promoting its ubiquitin mediated degradation 39, 2) activation of PDK1 and AKT, which subsequently inhibits TSC1 and TSC2.	26	38	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	30	31	37	38
Our findings suggest that active Akt may inhibit TSC2 through not only its direct phosphorylation but also attenuation of both AMPK and GSK3 mediated TSC2 phosphorylation under anabolic conditions .	Our findings suggest that active Akt may inhibit TSC2 through not only its direct phosphorylation but also attenuation of both AMPK and GSK3 mediated TSC2 phosphorylation under anabolic conditions.	4	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	5	6	8	9
Because TSC2 suppresses the activity of the Ras related GTPase Rheb , a selective activator of mTORC1 , inhibition of TSC2 by Akt results in activation of mTORC1 .	Because TSC2 suppresses the activity of the Ras related GTPase Rheb, a selective activator of mTORC1, inhibition of TSC2 by Akt results in activation of mTORC1.	18	23	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	22	23	20	21
AKT is an inhibitor of tuberin , and thereby an activator of mTOR , through which it controls the hypoxia inducible factor-1 alfa ( HIF1alpha ) , the major transcriptional factor for VEGF XREF_BIBR .	AKT is an inhibitor of tuberin, and thereby an activator of mTOR, through which it controls the hypoxia inducible factor-1 alfa (HIF1alpha), the major transcriptional factor for VEGF XREF_BIBR.	0	17	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	AKT	AKT	AKT	tuberin	tuberin	tuberin	0	1	5	6
To explore the pathways that mediate the effect of eEF-2 kinase on Akt inhibition induced autophagy , we knocked down TSC2 , a tumor suppressor protein that is negatively regulated by Akt and suppresses mTOR activity .	To explore the pathways that mediate the effect of eEF-2 kinase on Akt inhibition induced autophagy, we knocked down TSC2, a tumor suppressor protein that is negatively regulated by Akt and suppresses mTOR activity.	18	32	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	31	32	20	21
Akt activates mTORC1 through phosphorylation and inhibition of tumor-suppressor protein TSC2 ( tuberin ) thus releasing TSC2 inhibition of Rheb , which subsequently leads to mTORC1 activation [ XREF_BIBR - XREF_BIBR ] .	Akt activates mTORC1 through phosphorylation and inhibition of tumor-suppressor protein TSC2 (tuberin) thus releasing TSC2 inhibition of Rheb, which subsequently leads to mTORC1 activation [XREF_BIBR - XREF_BIBR].	0	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	16	17
Akt is a crucial player in this pathway , thus higher Akt activity inhibits TSC2 and TSC1 GAP activity for Rheb , allowing mTOR to be activated XREF_BIBR .	Akt is a crucial player in this pathway, thus higher Akt activity inhibits TSC2 and TSC1 GAP activity for Rheb, allowing mTOR to be activated XREF_BIBR.	11	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	11	12	14	15
PIP3 activates AKT which inhibits TSC1 and TSC2 ( tuberous sclerosis complex ) , which in turn acts as a negative regulator of mTORC1 .	PIP3 activates AKT which inhibits TSC1 and TSC2 (tuberous sclerosis complex), which in turn acts as a negative regulator of mTORC1.	1	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	2	3	7	8
Akt activation inhibits Tuberose Sclerosis ( TSC ) 1 and TSC2 complex function and leads to enhanced mTOR activity .	Akt activation inhibits Tuberose Sclerosis (TSC) 1 and TSC2 complex function and leads to enhanced mTOR activity.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	10	11
In cancer , there is an increase in the activity of PI3K-AKT axis , and TSC1 and TSC2 is inhibited by AKT , allowing mTORC1 activation and subsequently activation of P70S6K1 and EIF4e .	In cancer, there is an increase in the activity of PI3K-AKT axis, and TSC1 and TSC2 is inhibited by AKT, allowing mTORC1 activation and subsequently activation of P70S6K1 and EIF4e.	15	22	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	21	22	17	18
Inhibition of TSC2 by Akt allows mTORC1 to be activated downstream of mTORC2 .	Inhibition of TSC2 by Akt allows mTORC1 to be activated downstream of mTORC2.	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	4	5	2	3
Mechanistically , REDD1 promotes dephosphorylation of Akt at Thr 308 and represses TSC2 activation through the recruitment of PP2A to the kinase ( XREF_SUPPLEMENTARY ) .	Mechanistically, REDD1 promotes dephosphorylation of Akt at Thr 308 and represses TSC2 activation through the recruitment of PP2A to the kinase (XREF_SUPPLEMENTARY).	2	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	REDD1 promotes dephosphorylation of Akt at Thr 308	akt	TSC2	TSC2	tsc2	6	7	12	13
Further results reveal that influenza A virus H5N1 notably decreases the phosphorylation of the AKT kinase that downregulates the TSC2 .	Further results reveal that influenza A virus H5N1 notably decreases the phosphorylation of the AKT kinase that downregulates the TSC2.	7	20	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	H5N1 notably decreases the phosphorylation of the AKT	akt	TSC2	TSC2	tsc2	14	15	19	20
The TSC2 protein is inactivated by AKT phosphorylation [ Manning etal ., 2002 ] and activated by AMPK phosphorylation [ Inoki etal ., 2006 ] .	The TSC2 protein is inactivated by AKT phosphorylation [Manning etal., 2002] and activated by AMPK phosphorylation [Inoki etal., 2006].	1	8	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	TSC2	TSC2	tsc2	6	7	1	2
Furthermore , AKT phosphorylates and inactivates tumor suppressor TSC2 , a negative regulator of mTOR , to promote glycolysis [ XREF_BIBR ] .	Furthermore, AKT phosphorylates and inactivates tumor suppressor TSC2, a negative regulator of mTOR, to promote glycolysis [XREF_BIBR].	2	17	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	2	3	8	9
In addition to the phosphorylation and direct inhibition on TSC2 , AKT can inhibit TSC2 through inhibition of AMPK XREF_BIBR .	In addition to the phosphorylation and direct inhibition on TSC2, AKT can inhibit TSC2 through inhibition of AMPK XREF_BIBR.	11	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	11	12	14	15
While TSC2 can be inactivated via phosphorylation by Akt , phosphorylation of TSC2 with AMPK enhances its GAP activity , leading to mTOR inhibition [ XREF_BIBR ] .	While TSC2 can be inactivated via phosphorylation by Akt, phosphorylation of TSC2 with AMPK enhances its GAP activity, leading to mTOR inhibition [XREF_BIBR].	1	9	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	8	9	1	2
In addition , AKT directly blocks activation of TSC2 ( an inhibitor of mTOR and inducer of autophagy ) to provide further regulation of the autophagy process .	In addition, AKT directly blocks activation of TSC2 (an inhibitor of mTOR and inducer of autophagy) to provide further regulation of the autophagy process.	3	20	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	3	4	8	9
Thus , inactivation of TSC2 by AKT leads to the accumulation of the GTP bound ( active ) form of Rheb1 , which in turn promotes the phosphorylation and activation of an atypical serine/threonine kinase known as the mammalian target of rapamycin ( mTOR ) .	Thus, inactivation of TSC2 by AKT leads to the accumulation of the GTP bound (active) form of Rheb1, which in turn promotes the phosphorylation and activation of an atypical serine/threonine kinase known as the mammalian target of rapamycin (mTOR).	2	7	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	6	7	4	5
Because TSC2 acts as a GTPase activating protein ( GAP ) specific for Rheb , Akt inhibition of TSC2 promotes Rheb-GTP-dependent mTORC1 activation 11 .	Because TSC2 acts as a GTPase activating protein (GAP) specific for Rheb, Akt inhibition of TSC2 promotes Rheb-GTP-dependent mTORC1 activation 11.	15	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	15	16	18	19
TSC2 is negatively regulated by Akt dependent phosphorylation under anabolic conditions , but is positively regulated by AMPK and GSK3 dependent phosphorylation under catabolic conditions .	TSC2 is negatively regulated by Akt dependent phosphorylation under anabolic conditions, but is positively regulated by AMPK and GSK3 dependent phosphorylation under catabolic conditions.	0	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	TSC2	TSC2	tsc2	5	6	0	1
In MCF-7 cells expressing constitutively active myristoylated AKT ( myr-AKT ) , AKT phosphorylation inactivates TSC2 , with loss of TSC2 from the membrane and peroxisomal fractions and increased TSC2 in the cytosol ( XREF_FIG ) .	In MCF-7 cells expressing constitutively active myristoylated AKT (myr-AKT), AKT phosphorylation inactivates TSC2, with loss of TSC2 from the membrane and peroxisomal fractions and increased TSC2 in the cytosol (XREF_FIG).	12	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	TSC2	TSC2	tsc2	12	13	15	16
For example , AKT inhibits the GTPase activating protein ( GAP ) activity of the tuberous sclerosis complex 1 ( TSC1 ) and TSC2 by phosphorylating TSC2 , leading to the accumulation and activation of mTOR [ XREF_BIBR ] .	For example, AKT inhibits the GTPase activating protein (GAP) activity of the tuberous sclerosis complex 1 (TSC1) and TSC2 by phosphorylating TSC2, leading to the accumulation and activation of mTOR [XREF_BIBR].	3	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	3	4	23	24
It is clear that the activity of mTORC1 is negatively regulated by the tuberous sclerosis 1/2 ( TSC1 and TSC2 ) complex , and TSC2 can be positively regulated by AMPK or negatively regulated by Akt XREF_BIBR XREF_BIBR .	It is clear that the activity of mTORC1 is negatively regulated by the tuberous sclerosis 1/2 (TSC1 and TSC2) complex, and TSC2 can be positively regulated by AMPK or negatively regulated by Akt XREF_BIBR XREF_BIBR.	24	37	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	35	36	24	25
The phosphorylation and the inhibition of TSC2 by AKT is the earliest link between mTORC1 and a pathway dysregulated in cancer [ XREF_BIBR ] .	The phosphorylation and the inhibition of TSC2 by AKT is the earliest link between mTORC1 and a pathway dysregulated in cancer [XREF_BIBR].	4	9	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	8	9	6	7
The hyperphosphorylation of Akt induces a complete inhibition of TSC2 and activation of mTOR through direct phosphorylation .	The hyperphosphorylation of Akt induces a complete inhibition of TSC2 and activation of mTOR through direct phosphorylation.	1	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	hyperphosphorylation of Akt	akt	TSC2	TSC2	tsc2	3	4	9	10
Akt dependent inhibition of TSC2 ( upstream of mTORC1 ) does not require mTORC2 in T cells .	Akt dependent inhibition of TSC2 (upstream of mTORC1) does not require mTORC2 in T cells.	0	5	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	4	5
Akt inhibits TSC2 ( Tuberous Sclerosis 2 or hamartin ) function through direct phosphorylation .	Akt inhibits TSC2 (Tuberous Sclerosis 2 or hamartin) function through direct phosphorylation.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	2	3
In this study , we provide evidence that AKT inhibits the tumor suppressor function of tuberin by altering its subcellular localization .	In this study, we provide evidence that AKT inhibits the tumor suppressor function of tuberin by altering its subcellular localization.	8	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	tuberin	tuberin	tuberin	8	9	15	16
By inhibiting Tsc2 , Akt strongly activates mTORC1 signaling .	By inhibiting Tsc2, Akt strongly activates mTORC1 signaling.	1	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Tsc2	Tsc2	Tsc2	4	5	2	3
The TSC1 ( hamartin ) and TSC2 ( tuberin ) complex is inactivated by Akt dependent phosphorylation .	The TSC1 (hamartin) and TSC2 (tuberin) complex is inactivated by Akt dependent phosphorylation.	6	17	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	TSC2	TSC2	tsc2	14	15	6	7
TSC2 inactivation by AKT reduces Ras homolog enriched in brain ( Rheb ) , a small GTPase that is a member of the Ras ( rat sarcoma ) superfamily .	TSC2 inactivation by AKT reduces Ras homolog enriched in brain (Rheb), a small GTPase that is a member of the Ras (rat sarcoma) superfamily.	0	4	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	3	4	0	1
TSC2 can be activated by AMPK [ XREF_BIBR , XREF_BIBR ] and inhibited by Akt [ XREF_BIBR , XREF_BIBR ] .	TSC2 can be activated by AMPK [XREF_BIBR, XREF_BIBR] and inhibited by Akt [XREF_BIBR, XREF_BIBR].	0	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	14	15	0	1
AKT inhibits the GTPase activating protein ( GAP ) activity of the tuberous sclerosis complex 1 ( TSC1 ) and TSC2 complex by phosphorylating TSC2 tuberin protein , leading to the accumulation and activation of the mTOR complex ( XREF_FIG ) .	AKT inhibits the GTPase activating protein (GAP) activity of the tuberous sclerosis complex 1 (TSC1) and TSC2 complex by phosphorylating TSC2 tuberin protein, leading to the accumulation and activation of the mTOR complex (XREF_FIG).	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	0	1	20	21
Akt dependent inhibition of TSC2 ( upstream of mTORC1 ) does not require mTORC2 .	Akt dependent inhibition of TSC2 (upstream of mTORC1) does not require mTORC2.	0	5	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	4	5
Fully activated AKT inhibits TSC2 by phosphorylation XREF_BIBR , thereby negating its inhibitory effect on mTORC1 .	Fully activated AKT inhibits TSC2 by phosphorylation XREF_BIBR, thereby negating its inhibitory effect on mTORC1.	1	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	2	3	4	5
Downstream from PI 3-K , Akt can block activity of the hamartin ( tuberous sclerosis 1 )/tuberin ( tuberous sclerosis 2 ) ( TSC1 and TSC2 ) complex that inhibits mTORC1 ( Chong et al ., 2012a ; Janku et al ., 2012 ; Maiese , 2013 ; Morgan-Warren et al ., 2013 ) .	Downstream from PI 3-K, Akt can block activity of the hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) (TSC1 and TSC2) complex that inhibits mTORC1 (Chong et al., 2012a; Janku et al., 2012; Maiese, 2013; Morgan-Warren et al., 2013).	5	26	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	5	6	25	26
Protein kinase Akt could inhibit tuberous sclerosis complex 2 ( TSC2 ) by direct phosphorylation , to further up-regulate mTOR XREF_BIBR , which has been considered a key regulator of autophagy XREF_BIBR .	Protein kinase Akt could inhibit tuberous sclerosis complex 2 (TSC2) by direct phosphorylation, to further up-regulate mTOR XREF_BIBR, which has been considered a key regulator of autophagy XREF_BIBR.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	2	3	10	11
PI3K activation can increase protein synthesis through activation of Akt causing the inhibition of TSC2 and consequently the activation of Rheb , which in turn activates mTOR 36 .	PI3K activation can increase protein synthesis through activation of Akt causing the inhibition of TSC2 and consequently the activation of Rheb, which in turn activates mTOR 36.	7	15	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	9	10	14	15
In contrast , growth factor starvation or specific Akt inhibition strongly induces lysosomal localization of TSC2 .	In contrast, growth factor starvation or specific Akt inhibition strongly induces lysosomal localization of TSC2.	8	16	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	8	9	15	16
TSC2 is inactivated by Akt dependent phosphorylation , which destabilizes TSC2 and disrupts its interaction with TSC1 .	TSC2 is inactivated by Akt dependent phosphorylation, which destabilizes TSC2 and disrupts its interaction with TSC1.	0	7	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	TSC2	TSC2	tsc2	4	5	0	1
Here we establish an additional pathway by which Akt inhibits TSC2 and activates mTOR .	Here we establish an additional pathway by which Akt inhibits TSC2 and activates mTOR.	8	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	8	9	10	11
Akt activates mTORC1 by phosphorylating and inhibiting the tumor suppressor gene TSC2 to induce RheB which promotes mTORC1 activity .	Akt activates mTORC1 by phosphorylating and inhibiting the tumor suppressor gene TSC2 to induce RheB which promotes mTORC1 activity.	0	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	11	12
This resembles the scenario in which Akt negatively regulates the GAP activity of TSC2 toward the small GTPase Rheb , although the exact mechanism underlying this intensively investigated process remains unknown .	This resembles the scenario in which Akt negatively regulates the GAP activity of TSC2 toward the small GTPase Rheb, although the exact mechanism underlying this intensively investigated process remains unknown.	6	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	6	7	13	14
Although it is clear that growth factor induced activation of Akt blocks TSC1 and TSC2 inhibition of mTOR signaling [ XREF_BIBR - XREF_BIBR ] , the molecular mechanism by which Akt inhibits the function of TSC1 and TSC2 protein complex as a cell growth suppressor is still undefined .	Although it is clear that growth factor induced activation of Akt blocks TSC1 and TSC2 inhibition of mTOR signaling [XREF_BIBR - XREF_BIBR], the molecular mechanism by which Akt inhibits the function of TSC1 and TSC2 protein complex as a cell growth suppressor is still undefined.	8	15	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	10	11	14	15
Tsc2 activity can be inhibited not only by Akt dependent phosphorylation at Thr1462 and Ser939 , but also by ERK dependent phosphorylation at Ser664 XREF_BIBR , XREF_BIBR .	Tsc2 activity can be inhibited not only by Akt dependent phosphorylation at Thr1462 and Ser939, but also by ERK dependent phosphorylation at Ser664 XREF_BIBR, XREF_BIBR.	0	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation at Thr1462	akt	Tsc2	Tsc2	tsc2	8	9	0	1
With regard to GSK3 , Akt and PKB triggers a network that positively regulates G1/S cell cycle progression through inactivation of GSK3-beta , leading to increased cyclin D1 , and inhibition of the Forkhead family transcription factors and the tumor suppressor tuberin ( TSC2 ) , ultimately resulting in the reduction in p27Kip1 .	With regard to GSK3, Akt and PKB triggers a network that positively regulates G1/S cell cycle progression through inactivation of GSK3-beta, leading to increased cyclin D1, and inhibition of the Forkhead family transcription factors and the tumor suppressor tuberin (TSC2), ultimately resulting in the reduction in p27Kip1.	5	47	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKB	PKB	PKB	tuberin	tuberin	tuberin	7	8	41	42
AKT also inhibits TSC2 mediated degradation of p27 Kip1 , thereby promoting Cdk2 activity and cellular proliferation [ XREF_BIBR ] .	AKT also inhibits TSC2 mediated degradation of p27 Kip1, thereby promoting Cdk2 activity and cellular proliferation [XREF_BIBR].	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	0	1	3	4
TSC2 is negatively regulated by Akt phosphorylation .	TSC2 is negatively regulated by Akt phosphorylation.	0	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	TSC2	TSC2	tsc2	5	6	0	1
Akt inhibits TSC2 , thus , activating TOR .	Akt inhibits TSC2, thus, activating TOR.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	2	3
Akt then inhibits tuberous sclerosis complex 2 ( TSC2 ) , leading to the activation of mTORC1 .	Akt then inhibits tuberous sclerosis complex 2 (TSC2), leading to the activation of mTORC1.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	8	9
Intriguingly , mTor is predicted to be upregulated by Reelin-Dab1 signaling through AKT suppression of TSC2 [ XREF_BIBR , XREF_BIBR ] .	Intriguingly, mTor is predicted to be upregulated by Reelin-Dab1 signaling through AKT suppression of TSC2 [XREF_BIBR, XREF_BIBR].	12	19	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	12	13	15	16
Many studies have shown that the activated Akt kinase not only suppresses the proapoptotic function of Bax XREF_BIBR XREF_BIBR XREF_BIBR but also inhibits the activity of hamartin ( TSC1 ) and tuberin ( TSC2 ) protein complex , which reduces the GTPase activity of Ras homolog enriched in brain ( Rheb ) and leads to activation of mTOR and subsequent inhibition of autophagy XREF_BIBR .	Many studies have shown that the activated Akt kinase not only suppresses the proapoptotic function of Bax XREF_BIBR XREF_BIBR XREF_BIBR but also inhibits the activity of hamartin (TSC1) and tuberin (TSC2) protein complex, which reduces the GTPase activity of Ras homolog enriched in brain (Rheb) and leads to activation of mTOR and subsequent inhibition of autophagy XREF_BIBR.	7	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	tuberin	tuberin	tuberin	7	8	31	32
Akt inhibits TSC2 ( TSC complex subunit 2 ) , a protein associated with hamartin ( TSC1 ) forming a cytosolic complex .	Akt inhibits TSC2 (TSC complex subunit 2), a protein associated with hamartin (TSC1) forming a cytosolic complex.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	2	3
This process critically involves mTOR signaling , activated by PI3K and AKT and MAPK pathways via functional inactivation of TSC2 ( tuberin ) .	This process critically involves mTOR signaling, activated by PI3K and AKT and MAPK pathways via functional inactivation of TSC2 (tuberin).	7	21	inactivation	Negative_activation_syntax_6_noun	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	11	12	19	20
This same pattern was observed for mTOR phosphorylation and for the most pivotal molecules involved in the upstream control of mTOR ( increase of PKB , 14-3-3 , ERK , p38 MAPK , and 4E-BP1 phosphorylation , and reduction of tuberin , sestrin 2 , REDD1 , and phospho AMPK ) .	This same pattern was observed for mTOR phosphorylation and for the most pivotal molecules involved in the upstream control of mTOR (increase of PKB, 14-3-3, ERK, p38 MAPK, and 4E-BP1 phosphorylation, and reduction of tuberin, sestrin 2, REDD1, and phospho AMPK).	20	49	reduction	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PKB	mTOR (increase of PKB, 14-3-3, ERK, p38 MAPK, and 4E-BP1 phosphorylation	pkb	tuberin	tuberin	tuberin	24	25	40	41
Once activated , Akt relieves the inhibition effect of TSC-1 and TSC-2 on the mTORC-1 and -2 complexes , leading to activation of direct downstream S6 and 4EBP-1 , which are intricately involved in cell cycle and mRNA translation XREF_BIBR , XREF_BIBR .	Once activated, Akt relieves the inhibition effect of TSC-1 and TSC-2 on the mTORC-1 and -2 complexes, leading to activation of direct downstream S6 and 4EBP-1, which are intricately involved in cell cycle and mRNA translation XREF_BIBR, XREF_BIBR.	3	12	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC-2	TSC-2	TSC-2	3	4	11	12
AKT activation suppresses TSC1 and TSC2 , which indirectly activates mTOR kinase activity through the GTP binding protein Ras homolog enriched in brain ( Rheb ) .	AKT activation suppresses TSC1 and TSC2, which indirectly activates mTOR kinase activity through the GTP binding protein Ras homolog enriched in brain (Rheb).	0	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	0	1	5	6
Furthermore , TSC2 , a GTPase activating protein for Ras homologue enriched in brain ( Rheb ) , is also inactivated by Akt , which allows Rheb accumulation and thereby activates mTORC1 [ XREF_BIBR , XREF_BIBR ] .	Furthermore, TSC2, a GTPase activating protein for Ras homologue enriched in brain (Rheb), is also inactivated by Akt, which allows Rheb accumulation and thereby activates mTORC1 [XREF_BIBR, XREF_BIBR].	2	30	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	22	23	2	3
Akt also inhibited tuberin mediated degradation of p27 ( KIP1 ) , thereby promoting CDK2 activity and cellular proliferation [ XREF_BIBR ] .	Akt also inhibited tuberin mediated degradation of p27 (KIP1), thereby promoting CDK2 activity and cellular proliferation [XREF_BIBR].	0	4	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	tuberin	tuberin	tuberin	0	1	3	4
AMPK activates TSC2 and Akt inhibits TSC2 both leading to mTOR activation and subsequent increase in protein synthesis and other cellular processes .	AMPK activates TSC2 and Akt inhibits TSC2 both leading to mTOR activation and subsequent increase in protein synthesis and other cellular processes.	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	4	5	6	7
Activated Akt , ERK , and RSK1 kinases phosphorylate and inactivate the tumor suppressor TSC2 , thus relieving its inhibitory role on mTORC1 .	Activated Akt, ERK, and RSK1 kinases phosphorylate and inactivate the tumor suppressor TSC2, thus relieving its inhibitory role on mTORC1.	1	15	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	1	2	14	15
176 Cells expressing constitutively active vGPCR have a high level of activated Akt , inactivated TSC2 ( a tumor suppressor which is inactivated by Akt ) and activated mTOR .	176 Cells expressing constitutively active vGPCR have a high level of activated Akt, inactivated TSC2 (a tumor suppressor which is inactivated by Akt) and activated mTOR.	9	28	inactivated	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Akt	level of activated Akt	akt	TSC2	TSC2	tsc2	12	13	15	16
Because AKT inhibits TSC2 through phosphorylation , it permits mTORC1 activation by Rheb .	Because AKT inhibits TSC2 through phosphorylation, it permits mTORC1 activation by Rheb.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	1	2	3	4
Tsc2 was inactivated by Akt dependent phosphorylation , which destabilizes Tsc2 and disrupts its interaction with Tsc1 [ XREF_BIBR ] .	Tsc2 was inactivated by Akt dependent phosphorylation, which destabilizes Tsc2 and disrupts its interaction with Tsc1 [XREF_BIBR].	0	7	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	Tsc2	Tsc2	tsc2	4	5	0	1
Overexpression of AKT3 increased the protein expression of total AKT , phospho-AKT S473 , phospho-AKT T308 , B-Raf , c-Myc , Skp2 , cyclin E , GSK3beta , phospho-GSK3beta S9 , phospho-mTOR S2448 , and phospho-p70S6K T421 and S424 , but decreased TSC1 ( tuberous sclerosis 1 ) and TSC2 ( tuberous Sclerosis Complex 2 ) proteins in PC-3 PCa cells .	Overexpression of AKT3 increased the protein expression of total AKT, phospho-AKT S473, phospho-AKT T308, B-Raf, c-Myc, Skp2, cyclin E, GSK3beta, phospho-GSK3beta S9, phospho-mTOR S2448, and phospho-p70S6K T421 and S424, but decreased TSC1 (tuberous sclerosis 1) and TSC2 (tuberous Sclerosis Complex 2) proteins in PC-3 PCa cells.	0	53	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Overexpression of AKT3 increased the protein expression of total AKT	akt	TSC2	TSC2	tsc2	9	10	49	50
TSC2 inactivation by Akt and PKB may also inhibit mTOR indirectly through inhibition of the small GTPase , Rheb [ XREF_BIBR ] .	TSC2 inactivation by Akt and PKB may also inhibit mTOR indirectly through inhibition of the small GTPase, Rheb [XREF_BIBR].	0	5	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	3	4	0	1
AKT inhibits the GTPase activating protein ( GAP ) activity of the tuberous sclerosis complex 1 ( TSC1 ) and TSC2 complex by phosphorylating TSC2 tuberin protein , leading to the accumulation and activation of the mTOR complex ( XREF_FIG ) [ XREF_BIBR ] .	AKT inhibits the GTPase activating protein (GAP) activity of the tuberous sclerosis complex 1 (TSC1) and TSC2 complex by phosphorylating TSC2 tuberin protein, leading to the accumulation and activation of the mTOR complex (XREF_FIG) [XREF_BIBR].	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	0	1	20	21
This inactivation of TSC2 by Akt leads to the accumulation of the active Rheb1 , which in turn promotes the activation of mTOR in its complex mTORC1 .	This inactivation of TSC2 by Akt leads to the accumulation of the active Rheb1, which in turn promotes the activation of mTOR in its complex mTORC1.	1	6	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	5	6	3	4
TSC2 is inactivated by Akt dependent phosphorylation , which allows Rheb-GTP to accumulate and bind directly to mTOR within mTORC1 .	TSC2 is inactivated by Akt dependent phosphorylation, which allows Rheb-GTP to accumulate and bind directly to mTOR within mTORC1.	0	7	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt dependent phosphorylation	akt	TSC2	TSC2	tsc2	4	5	0	1
Subsequently , TSC2 can be inhibited by Akt phosphorylation that serves to destabilize TSC2 and disrupt its interaction with TSC1 [ XREF_BIBR , XREF_BIBR ] .	Subsequently, TSC2 can be inhibited by Akt phosphorylation that serves to destabilize TSC2 and disrupt its interaction with TSC1 [XREF_BIBR, XREF_BIBR].	2	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	TSC2	TSC2	tsc2	7	8	2	3
In the canonical pathway , AKT phosphorylates and thereby inhibits TSC2 .	In the canonical pathway, AKT phosphorylates and thereby inhibits TSC2.	5	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	5	6	10	11
We found that the activation of Akt with plasmid myr-Akt repressed p-TSC2 , and the inhibition of Akt with DN-Akt recovered TSC2 activity ( XREF_FIG ) .	We found that the activation of Akt with plasmid myr-Akt repressed p-TSC2, and the inhibition of Akt with DN-Akt recovered TSC2 activity (XREF_FIG).	4	12	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p-TSC2	p-TSC2	p-TSC2	6	7	11	12
Conversely , Akt inhibits TSC2 through phosphorylation , which allows mTORC1 activation .	Conversely, Akt inhibits TSC2 through phosphorylation, which allows mTORC1 activation.	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	2	3	4	5
The authors found that 14-3-3 proteins interact with REDD1 at a motif surrounding S137 of REDD1 and that REDD1 can reverse the AKT mediated inhibition of TSC2 by promoting the movement of 14-3-3 proteins from TSC2 to REDD1 ( XREF_FIG ) .	The authors found that 14-3-3 proteins interact with REDD1 at a motif surrounding S137 of REDD1 and that REDD1 can reverse the AKT mediated inhibition of TSC2 by promoting the movement of 14-3-3 proteins from TSC2 to REDD1 (XREF_FIG).	21	27	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	22	23	26	27
AKT phosphorylation inhibits Tuberous sclerosis protein 2 ( TSC2 ) , a GTPase activating protein ( GAP ) , leading to activation of mTOR1 complex followed by activation of S6K .	AKT phosphorylation inhibits Tuberous sclerosis protein 2 (TSC2), a GTPase activating protein (GAP), leading to activation of mTOR1 complex followed by activation of S6K.	0	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	TSC2	TSC2	tsc2	0	1	8	9
Akt phoshorylates and inhibits TSC1 and TSC2 in order to activate mTORC1 .	Akt phoshorylates and inhibits TSC1 and TSC2 in order to activate mTORC1.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	6	7
AKT inhibits the GTPase activating protein ( GAP ) activity of the tuberous sclerosis complex 1 ( TSC1 ) and TSC2 complex by phosphorylating TSC2 tuberin protein , leading to the accumulation and activation of the mTOR and raptor complex [ XREF_BIBR ] .	AKT inhibits the GTPase activating protein (GAP) activity of the tuberous sclerosis complex 1 (TSC1) and TSC2 complex by phosphorylating TSC2 tuberin protein, leading to the accumulation and activation of the mTOR and raptor complex [XREF_BIBR].	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	0	1	20	21
In turn , Akt inactivates TSC2 , a large protein that is part of the TSC1 and TSC2 complex .	In turn, Akt inactivates TSC2, a large protein that is part of the TSC1 and TSC2 complex.	3	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	3	4	5	6
First , Akt and/or Erk phosphorylate and suppress the tuberous sclerosis complex ( TSC1 and TSC2 ) , relieving its GAP activity toward the Rheb small GTPase that is an essential upstream activator of mTORC1 .	First, Akt and/or Erk phosphorylate and suppress the tuberous sclerosis complex (TSC1 and TSC2), relieving its GAP activity toward the Rheb small GTPase that is an essential upstream activator of mTORC1.	2	16	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	2	3	15	16
During insulin signaling , the PI3K-Akt pathway activates mTOR by phosphorylating and thereby inhibiting TSC2 ; the Akt dependent phosphorylation of PRAS40 may also contribute to mTOR activation .	During insulin signaling, the PI3K-Akt pathway activates mTOR by phosphorylating and thereby inhibiting TSC2; the Akt dependent phosphorylation of PRAS40 may also contribute to mTOR activation.	5	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	TSC2	TSC2	TSC2	5	6	14	15
By contrast , activation of Akt can inhibit the activity of TSC2 , which promotes Rheb accumulation and results in mTOR activation [ XREF_BIBR , XREF_BIBR ] .	By contrast, activation of Akt can inhibit the activity of TSC2, which promotes Rheb accumulation and results in mTOR activation [XREF_BIBR, XREF_BIBR].	3	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	5	6	11	12
Because TSC2 suppresses the activity of the Ras related GTPase Rheb , a selective activator of mTORC1 , inhibition of TSC2 by Akt results in activation of mTORC1 [ XREF_BIBR ] .	Because TSC2 suppresses the activity of the Ras related GTPase Rheb, a selective activator of mTORC1, inhibition of TSC2 by Akt results in activation of mTORC1 [XREF_BIBR].	18	23	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	22	23	20	21
Therefore , it is likely that AKT phosphorylation inhibits tuberin as a result of 14-3-3 binding and cytosolic translocation rather than by impairing its catalytic GAP activity .	Therefore, it is likely that AKT phosphorylation inhibits tuberin as a result of 14-3-3 binding and cytosolic translocation rather than by impairing its catalytic GAP activity.	6	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	tuberin	tuberin	tuberin	6	7	9	10
AKT , which inhibits TSC2 , requires phosphorylation on T308 and S473 for activation , and the PP2A B'alpha holoenzyme has been shown to dephosphorylate AKT on T308 , thereby inactivating it ( XREF_FIG ) .	AKT, which inhibits TSC2, requires phosphorylation on T308 and S473 for activation, and the PP2A B'alpha holoenzyme has been shown to dephosphorylate AKT on T308, thereby inactivating it (XREF_FIG).	0	6	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	0	1	4	5
Akt also inhibits tuberin mediated degradation of p27 ( kip1 ) , thereby promoting CDK2 activity and cellular proliferation .	Akt also inhibits tuberin mediated degradation of p27 (kip1), thereby promoting CDK2 activity and cellular proliferation.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	tuberin	tuberin	tuberin	0	1	3	4
The study found that the protein kinase Akt inactivates TSC-2 ( tuberous sclerosis complex 2 ) , which activates the GTP-ase Rheb .	The study found that the protein kinase Akt inactivates TSC-2 (tuberous sclerosis complex 2), which activates the GTP-ase Rheb.	4	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC-2	TSC-2	TSC-2	7	8	9	10
When upstream signals are activated , TSC1 and TSC2 is inhibited by AKT , allowing mTOR activation .	When upstream signals are activated, TSC1 and TSC2 is inhibited by AKT, allowing mTOR activation.	6	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	12	13	8	9
Akt also phosphorylates and inactivates tumor suppressor TSC2 , a negative regulator of mammalian target of rapamycin ( mTOR ) , to promote glycolysis ( see discussion below ) [ XREF_BIBR ] .	Akt also phosphorylates and inactivates tumor suppressor TSC2, a negative regulator of mammalian target of rapamycin (mTOR), to promote glycolysis (see discussion below) [XREF_BIBR].	0	22	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	7	8
Initiation of the PI3K and Akt signaling pathway inactivates TSC1 and TSC2 and stimulates the small Ras related GTPase Rheb , which in turn directly triggers mTORC1 activity .	Initiation of the PI3K and Akt signaling pathway inactivates TSC1 and TSC2 and stimulates the small Ras related GTPase Rheb, which in turn directly triggers mTORC1 activity.	5	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	5	6	11	12
ERK , Rsk1 , and Akt all directly phosphorylate and inactivate tuberin , thereby leading to mTOR activation .	ERK, Rsk1, and Akt all directly phosphorylate and inactivate tuberin, thereby leading to mTOR activation.	0	12	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	tuberin	tuberin	tuberin	5	6	11	12
HMDB also had an inhibitory effect on the phosphorylation of Akt that negatively regulate TSC2 to release its inhibition on Rheb ( XREF_FIG b ) .	HMDB also had an inhibitory effect on the phosphorylation of Akt that negatively regulate TSC2 to release its inhibition on Rheb (XREF_FIG b).	8	23	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	phosphorylation of Akt	akt	TSC2	TSC2	tsc2	10	11	14	15
These signals activate a family of phosphatidylinositol lipid kinases ( phosphatidylinositol-3 kinases , PI3K ) that in turn activate the serine threonine kinase AKT , which then represses TSC1 and TSC2 .	These signals activate a family of phosphatidylinositol lipid kinases (phosphatidylinositol-3 kinases, PI3K) that in turn activate the serine threonine kinase AKT, which then represses TSC1 and TSC2.	18	31	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	23	24	30	31
In addition , increased plasma levels of ApoC-III ( an inhibitor of LPL ) could also contribute to the decreased catabolism of VLDL in patients with type 2 diabetes , since increased plasma levels of ApoC-III were associated with impaired VLDL clearance in obese insulin resistant men [ XREF_BIBR ] .	In addition, increased plasma levels of ApoC-III (an inhibitor of LPL) could also contribute to the decreased catabolism of VLDL in patients with type 2 diabetes, since increased plasma levels of ApoC-III were associated with impaired VLDL clearance in obese insulin resistant men [XREF_BIBR].	5	13	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ApoC-III	levels of ApoC-III	apoc-iii	LPL	LPL	lpl	7	8	12	13
As noted earlier , APOC3 inhibits LPL activity and thus TG lipolysis .	As noted earlier, APOC3 inhibits LPL activity and thus TG lipolysis.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	LPL	LPL	LPL	4	5	6	7
ApoCIII inhibits lipoprotein lipase activity and interferes with the receptor mediated uptake of TG rich lipoproteins , therefore delaying the clearance of TG rich lipoproteins [ XREF_BIBR , XREF_BIBR ] .	ApoCIII inhibits lipoprotein lipase activity and interferes with the receptor mediated uptake of TG rich lipoproteins, therefore delaying the clearance of TG rich lipoproteins [XREF_BIBR, XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoCIII	ApoCIII	ApoCIII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	2	4
The reason for these differences could not be fully explained by the authors , although the lack of FCR stimulation following fructose was not due to apolipoprotein C-III inhibition of LPL , as this was not significantly affected by fructose feeding .	The reason for these differences could not be fully explained by the authors, although the lack of FCR stimulation following fructose was not due to apolipoprotein C-III inhibition of LPL, as this was not significantly affected by fructose feeding.	26	31	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	apolipoprotein C-III	apolipoprotein C-III	apolipoprotein C-III	LPL	LPL	LPL	26	28	30	31
The amount of apoC-III on the VLDL was very high , judging from the severely elevated triglyceride levels , perhaps in the range in which apoC-III inhibits LpL in vitro , but more than in the previous apoC-III overexpression experiments [ XREF_BIBR , XREF_BIBR ] and in normal or mildly hypertriglyceridemic people [ XREF_BIBR , XREF_BIBR ] .	The amount of apoC-III on the VLDL was very high, judging from the severely elevated triglyceride levels, perhaps in the range in which apoC-III inhibits LpL in vitro, but more than in the previous apoC-III overexpression experiments [XREF_BIBR, XREF_BIBR] and in normal or mildly hypertriglyceridemic people [XREF_BIBR, XREF_BIBR].	25	53	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LpL	LpL	LpL	25	26	27	28
Therefore , we suggest apoC-III as a candidate causative factor for the hypertriglyceridemia observed in FLS mice because an excessive amount of apoC-III attenuates LPL activity in vivo and in vitro .	Therefore, we suggest apoC-III as a candidate causative factor for the hypertriglyceridemia observed in FLS mice because an excessive amount of apoC-III attenuates LPL activity in vivo and in vitro.	20	25	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	amount of apoC-III	apoc-iii	LPL	LPL	lpl	22	23	24	25
Exenatide , a GLP-1R agonist , is thought to potentially promote CM clearance by reducing postprandial levels of apoCIII , which inhibits lipoprotein lipase and hinders hepatic TRL clearance .	Exenatide, a GLP-1R agonist, is thought to potentially promote CM clearance by reducing postprandial levels of apoCIII, which inhibits lipoprotein lipase and hinders hepatic TRL clearance.	0	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoCIII	Exenatide, a GLP-1R agonist, is thought to potentially promote CM clearance by reducing postprandial levels of apoCIII	apociii	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	18	19	22	24
Evidence is now emerging that volanesorsen , a second generation antisense oligonucleotide drug targeting ApoCIII messenger RNA resulting in decreases in TG in patients with familial chylomicronemia syndrome , severe hypertriglyceridemia , and metabolic dyslipidemia with type 2 diabetes giving support to the hypothesis that ApoCIII is a powerful inhibitor of LPL , and when reduced , endogenous clearance of TRLs can result in substantial reductions in TG levels .	Evidence is now emerging that volanesorsen, a second generation antisense oligonucleotide drug targeting ApoCIII messenger RNA resulting in decreases in TG in patients with familial chylomicronemia syndrome, severe hypertriglyceridemia, and metabolic dyslipidemia with type 2 diabetes giving support to the hypothesis that ApoCIII is a powerful inhibitor of LPL, and when reduced, endogenous clearance of TRLs can result in substantial reductions in TG levels.	45	52	is a powerful inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	ApoCIII	ApoCIII	ApoCIII	LPL	LPL	LPL	45	46	51	52
In contrast , apo C-III is an inhibitor of LPL , but also of hepatic lipase .	In contrast, apo C-III is an inhibitor of LPL, but also of hepatic lipase.	3	10	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	apo C-III	apo C-III	apo C-III	LPL	LPL	LPL	3	5	9	10
In circulation , apoCIII , mainly residing on the surface of HDL and TRLs , inhibited LPL activity and disrupted TRLs clearance [ XREF_BIBR ] , thereby leading to hypertriglyceridemia .	In circulation, apoCIII, mainly residing on the surface of HDL and TRLs, inhibited LPL activity and disrupted TRLs clearance [XREF_BIBR], thereby leading to hypertriglyceridemia.	3	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoCIII	apoCIII	apoCIII	LPL	LPL	LPL	3	4	16	17
APOC3 functions to inhibit lipoprotein lipase ( LPL ) , a key regulator of plasma triglyceride and HDL concentrations .	APOC3 functions to inhibit lipoprotein lipase (LPL), a key regulator of plasma triglyceride and HDL concentrations.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	4	6
The mechanisms underlying postprandial hyperlipidaemia also include a modest reduction in LpL and HL activity , increased production and higher plasma levels of apoC-III ( an inhibitor of LpL ) and the defective suppression of hepatic VLDL secretion postprandially [ XREF_BIBR - XREF_BIBR ] .	The mechanisms underlying postprandial hyperlipidaemia also include a modest reduction in LpL and HL activity, increased production and higher plasma levels of apoC-III (an inhibitor of LpL) and the defective suppression of hepatic VLDL secretion postprandially [XREF_BIBR - XREF_BIBR].	21	29	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	apoC-III	levels of apoC-III	apoc-iii	LpL	LpL	lpl	23	24	28	29
Apolipoprotein C-III : Apolipoprotein C-III ( APOC3 ) can inhibit the lipoprotein lipase and reduce the clearance of TG .	Apolipoprotein C-III : Apolipoprotein C-III (APOC3) can inhibit the lipoprotein lipase and reduce the clearance of TG.	3	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Apolipoprotein C-III	Apolipoprotein C-III	Apolipoprotein C-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	5	11	13
The apoC-III knockout mice , whether singly or in combination with apoE knockout , cleared triglyceride from plasma more rapidly than control mice , suggesting that apoC-III inhibits LpL .	The apoC-III knockout mice, whether singly or in combination with apoE knockout, cleared triglyceride from plasma more rapidly than control mice, suggesting that apoC-III inhibits LpL.	26	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LpL	LpL	LpL	26	27	28	29
Inhibition of lipoprotein lipase by APOC3 and subsequent decreased triglyceride clearance may lead to hypertriglyceridemia XREF_BIBR .	Inhibition of lipoprotein lipase by APOC3 and subsequent decreased triglyceride clearance may lead to hypertriglyceridemia XREF_BIBR.	0	10	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	5	6	2	4
APOC3 is one of the protein components of VLDLs and inhibits LPL XREF_BIBR .	APOC3 is one of the protein components of VLDLs and inhibits LPL XREF_BIBR.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	LPL	LPL	LPL	0	1	11	12
The experiment suggests that apoC-III inhibits LpL , in vivo [ XREF_BIBR ] .	The experiment suggests that apoC-III inhibits LpL, in vivo [XREF_BIBR].	4	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LpL	LpL	LpL	4	5	6	7
The apolipoprotein C-III ( apoC-III ) particle , in contrast , inhibits LPL activity , resulting in diminished catabolism of TG containing particles such as VLDL .	The apolipoprotein C-III (apoC-III) particle, in contrast, inhibits LPL activity, resulting in diminished catabolism of TG containing particles such as VLDL.	1	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apolipoprotein C-III	apolipoprotein C-III	apolipoprotein C-III	LPL	LPL	LPL	1	3	12	13
First , apoCIII inhibits the activity of lipoprotein lipase ( LPL ) and disturbs lipids lipolysis [ XREF_BIBR ] .	First, apoCIII inhibits the activity of lipoprotein lipase (LPL) and disturbs lipids lipolysis [XREF_BIBR].	2	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoCIII	apoCIII	apoCIII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	7	9
In particular , PPARalpha activation stimulates the expression of lipoprotein lipase and increases its activity by stimulating apolipoproteins A -- V ( activator of lipoprotein lipase ) and reducing apolipoprotein C-III ( inhibitor of lipoprotein lipase ) .	In particular, PPARalpha activation stimulates the expression of lipoprotein lipase and increases its activity by stimulating apolipoproteins A -- V (activator of lipoprotein lipase) and reducing apolipoprotein C-III (inhibitor of lipoprotein lipase).	29	36	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	apolipoprotein C-III	apolipoprotein C-III	apolipoprotein C-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	29	31	34	36
Apolipoprotein C-III is a potent inhibitor of lipoprotein lipase whereas apolipoprotein C-II is an activator of the same enzyme .	Apolipoprotein C-III is a potent inhibitor of lipoprotein lipase whereas apolipoprotein C-II is an activator of the same enzyme.	0	9	is a potent inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Apolipoprotein C-III	Apolipoprotein C-III	Apolipoprotein C-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	2	7	9
This trend could be mediated by increased apoC-III as higher apoC-III levels in the setting of CKD is likely to impair LPL activity and decrease TG and VLDL metabolism .	This trend could be mediated by increased apoC-III as higher apoC-III levels in the setting of CKD is likely to impair LPL activity and decrease TG and VLDL metabolism.	10	22	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III levels	apoc-iii	LPL	LPL	lpl	10	11	21	22
ApoC-III inhibits lipoprotein lipase ( LPL ) , leading to decreased hydrolysis of TG-laden cholesterol particles and a reciprocal decrease in HDL-C .	ApoC-III inhibits lipoprotein lipase (LPL), leading to decreased hydrolysis of TG-laden cholesterol particles and a reciprocal decrease in HDL-C.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	2	4
APOC3 is an endogenous inhibitor of LPL , the latter of which functions to hydrolyze triglycerides present in circulating lipoproteins , thereby lowering plasma TRL concentration .	APOC3 is an endogenous inhibitor of LPL, the latter of which functions to hydrolyze triglycerides present in circulating lipoproteins, thereby lowering plasma TRL concentration.	0	12	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	LPL	LPL	LPL	0	1	6	7
Several lines of evidence have implicated APOC-II and APOC-III in the regulation of CHYL and VLDL metabolism , as LPL uses APOC-II as a cofactor and is inhibited by APOC-III .	Several lines of evidence have implicated APOC-II and APOC-III in the regulation of CHYL and VLDL metabolism, as LPL uses APOC-II as a cofactor and is inhibited by APOC-III.	19	30	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	APOC-III	APOC-III	APOC-III	LPL	LPL	LPL	29	30	19	20
It has been reported that the N terminus of apoC-III is responsible for inhibiting LPL while its glycan chain is located in the C-terminal domain , and that synthetic apoC-III lacking the carbohydrate moiety can still inhibit LPL .	It has been reported that the N terminus of apoC-III is responsible for inhibiting LPL while its glycan chain is located in the C-terminal domain, and that synthetic apoC-III lacking the carbohydrate moiety can still inhibit LPL.	28	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	29	30	37	38
We present evidence that either apoC-I or apoC-III , when bound to triglyceride rich lipoproteins , prevent binding of LPL to the lipid and water interface .	We present evidence that either apoC-I or apoC-III, when bound to triglyceride rich lipoproteins, prevent binding of LPL to the lipid and water interface.	5	20	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	7	8	19	20
As opposed to APOC2 and APOA5 , APOC1 , APOC3 and APOE inhibit LPL dependent TG clearance [ XREF_BIBR - XREF_BIBR ] .	As opposed to APOC2 and APOA5, APOC1, APOC3 and APOE inhibit LPL dependent TG clearance [XREF_BIBR - XREF_BIBR].	7	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	LPL	LPL	LPL	9	10	13	14
It has been proposed that APOC3 inhibits LPL by displacing the enzyme from the lipid droplets [ XREF_BIBR ] .	It has been proposed that APOC3 inhibits LPL by displacing the enzyme from the lipid droplets [XREF_BIBR].	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	LPL	LPL	LPL	5	6	7	8
ApoCIII inhibits lipoprotein lipase as well as binding of lipoproteins to cell surface heparan sulfate proteoglycans and receptors .	ApoCIII inhibits lipoprotein lipase as well as binding of lipoproteins to cell surface heparan sulfate proteoglycans and receptors.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoCIII	ApoCIII	ApoCIII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	2	4
Apolipoprotein C-III ( APOC3 ) is a VLDL protein and abrogate the hepatic and lipoprotein lipase 39 .	Apolipoprotein C-III (APOC3) is a VLDL protein and abrogate the hepatic and lipoprotein lipase 39.	1	16	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	14	16
ApoC-III suppresses lipoprotein lipase ( LPL ) , and displaces LPL from triglyceride rich lipoproteins .	ApoC-III suppresses lipoprotein lipase (LPL), and displaces LPL from triglyceride rich lipoproteins.	0	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	2	4
ApoC3 inhibits LPL and as a consequence these carriers have decreased triglyceride clearance following an intravenous infusion of lipids and increased postprandial hypertriglyceridemia and postprandial chylomicrons remnants , leading to NAFLD and hepatic insulin resistance .	ApoC3 inhibits LPL and as a consequence these carriers have decreased triglyceride clearance following an intravenous infusion of lipids and increased postprandial hypertriglyceridemia and postprandial chylomicrons remnants, leading to NAFLD and hepatic insulin resistance.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC3	ApoC3	ApoC3	LPL	LPL	LPL	0	1	2	3
These results , they note , may provide an insight into the triglyceride lowering effects of both atorvastatin and fenofibrate , because apoCIII inhibits both lipoprotein lipase activity and removal of remnants via receptor mediated pathways .	These results, they note, may provide an insight into the triglyceride lowering effects of both atorvastatin and fenofibrate, because apoCIII inhibits both lipoprotein lipase activity and removal of remnants via receptor mediated pathways.	22	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoCIII	apoCIII	apoCIII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	22	23	25	27
This is associated with a relative increase in plasma ApoC-III ( a potent inhibitor of lipoprotein lipase ) and relative decline in ApoC-II , which is the activator of lipoprotein lipase [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	This is associated with a relative increase in plasma ApoC-III (a potent inhibitor of lipoprotein lipase) and relative decline in ApoC-II, which is the activator of lipoprotein lipase [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	17	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	9	10	15	17
In conclusion , we show that apoC-I and apoC-III inhibit lipolysis by displacing LPL from lipid emulsion particles .	In conclusion, we show that apoC-I and apoC-III inhibit lipolysis by displacing LPL from lipid emulsion particles.	6	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	8	9	13	14
Lipoprotein lipase ( LPL ) is one of the principal lipases involved ; apoC-III inhibits the activity of LPL , slowing TG catabolism .	Lipoprotein lipase (LPL) is one of the principal lipases involved; apoC-III inhibits the activity of LPL, slowing TG catabolism.	13	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	13	14	18	19
The primary mechanisms of dyslipidemia in CKD are thought to involve impaired TG lipolysis , associated with increased Apolipoprotein C-III ( an inhibitor of lipoprotein lipase ) and reduced insulin sensitivity in the vascular endothelium of skeletal muscle and other major sites of TG ( fatty acid ) energy utilization .	The primary mechanisms of dyslipidemia in CKD are thought to involve impaired TG lipolysis, associated with increased Apolipoprotein C-III (an inhibitor of lipoprotein lipase) and reduced insulin sensitivity in the vascular endothelium of skeletal muscle and other major sites of TG (fatty acid) energy utilization.	18	26	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Apolipoprotein C-III	Apolipoprotein C-III	Apolipoprotein C-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	18	20	24	26
Nowadays , it has become clear that apoCIII inhibition of LPL requires a very high CIII and CII ratio , which is not found in vivo [ XREF_BIBR ] .	Nowadays, it has become clear that apoCIII inhibition of LPL requires a very high CIII and CII ratio, which is not found in vivo [XREF_BIBR].	7	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	apoCIII	apoCIII	apoCIII	LPL	LPL	LPL	7	8	10	11
ApoC-III inhibits the activity of lipoprotein lipase ( LPL ) , the enzyme catalysing the first and rate limiting step of TG rich lipoprotein catabolism XREF_BIBR , and also impairs uptake of TG rich lipoprotein-remnants by the low-density lipoprotein ( LDL )-receptor ( LDL-R ) , increasing remnant residence time in the circulation XREF_BIBR .	ApoC-III inhibits the activity of lipoprotein lipase (LPL), the enzyme catalysing the first and rate limiting step of TG rich lipoprotein catabolism XREF_BIBR, and also impairs uptake of TG rich lipoprotein-remnants by the low-density lipoprotein (LDL)-receptor (LDL-R), increasing remnant residence time in the circulation XREF_BIBR.	0	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	5	7
Secondly , APOC3 inhibits LPL , which is located on the inner side of capillaries and is the main enzyme to hydrolyze TG rich particles [ XREF_BIBR ] .	Secondly, APOC3 inhibits LPL, which is located on the inner side of capillaries and is the main enzyme to hydrolyze TG rich particles [XREF_BIBR].	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	LPL	LPL	LPL	2	3	4	5
Furthermore , the difference in effect of ApoCI and ApoCIII on TG concentrations observed in this study underlines the stronger inhibition of LPL by ApoCIII compared with ApoCI , as shown in experimental studies .	Furthermore, the difference in effect of ApoCI and ApoCIII on TG concentrations observed in this study underlines the stronger inhibition of LPL by ApoCIII compared with ApoCI, as shown in experimental studies.	17	27	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	ApoCIII	ApoCIII	ApoCIII	LPL	LPL	LPL	24	25	22	23
While untreated apoC-III inhibited LPL by 54 % , neuraminidase treated apoC-III inhibited LPL by 26 % ( p < 0.001 ; see XREF_FIG ) .	While untreated apoC-III inhibited LPL by 54%, neuraminidase treated apoC-III inhibited LPL by 26% (p < 0.001; see XREF_FIG).	1	5	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	2	3	4	5
XREF_BIBR , XREF_BIBR While ApoCIII has been shown to inhibit lipoprotein lipase 10 and inhibit the uptake of lipoprotein particles by isolated rat liver , 11 the mechanisms by which ApoCIII levels impact health are not understood .	XREF_BIBR, XREF_BIBR While ApoCIII has been shown to inhibit lipoprotein lipase 10 and inhibit the uptake of lipoprotein particles by isolated rat liver, 11 the mechanisms by which ApoCIII levels impact health are not understood.	4	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoCIII	ApoCIII	ApoCIII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	10	12
Such liver derived LPL regulators include apoC3 and angiopietin like protein 3 ( ANGPTL3 ) , both of which inhibit LPL activity , and apoC2 , which is a potent activator of LPL .	Such liver derived LPL regulators include apoC3 and angiopietin like protein 3 (ANGPTL3), both of which inhibit LPL activity, and apoC2, which is a potent activator of LPL.	5	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC3	apoC3	apoC3	LPL	LPL	LPL	6	7	20	21
ApoC3 is a potent inhibitor of lipoprotein lipase .	ApoC3 is a potent inhibitor of lipoprotein lipase.	0	8	is a potent inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	ApoC3	ApoC3	ApoC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	6	8
APOC-III inhibits very low-density lipoproteins ( VLDL )-triglycerides , hepatic lipase ( HL ) , and lipoprotein lipase ( LPL ) functions ; the major function of LPL is to hydrolyze chylomicrons ( CMs ) .	APOC-III inhibits very low-density lipoproteins (VLDL)-triglycerides, hepatic lipase (HL), and lipoprotein lipase (LPL) functions; the major function of LPL is to hydrolyze chylomicrons (CMs).	0	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC-III	APOC-III	APOC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	16	18
LPL activity is inhibited not only by ApoC-III , but also by soluble secreted proteins including ANGPTL4 .	LPL activity is inhibited not only by ApoC-III, but also by soluble secreted proteins including ANGPTL4.	0	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	LPL	LPL	LPL	7	8	0	1
Apolipoprotein C-III particularly inhibits the actions of lipoprotein lipase and hepatic lipase , which slow TG hydrolysis [ XREF_BIBR ] .	Apolipoprotein C-III particularly inhibits the actions of lipoprotein lipase and hepatic lipase, which slow TG hydrolysis [XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Apolipoprotein C-III	Apolipoprotein C-III	Apolipoprotein C-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	2	7	9
This suggests that it is unlikely that apoC-I and apoC-III inhibit LPL via displacement of apoC-II from the lipoprotein surface .	This suggests that it is unlikely that apoC-I and apoC-III inhibit LPL via displacement of apoC-II from the lipoprotein surface.	7	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	9	10	11	12
In vitro studies have indicated that ApoC3 is a noncompetitive inhibitor of lipoprotein lipase , thereby suggesting an important role in the catabolism of TG rich lipoproteins [ XREF_BIBR ] .	In vitro studies have indicated that ApoC3 is a noncompetitive inhibitor of lipoprotein lipase, thereby suggesting an important role in the catabolism of TG rich lipoproteins [XREF_BIBR].	6	14	is a noncompetitive inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	ApoC3	ApoC3	ApoC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	7	12	14
These two apolipoproteins circulate on chylomicrons and VLDL [ XREF_BIBR , XREF_BIBR ] but have opposite effects : apoC-III inhibits lipoprotein lipase ( LPL ) , promotes VLDL production , and slows hepatic VLDL uptake [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] whereas apoA-V accelerates LPL mediated hydrolysis of TG rich VLDL , blocks VLDL production , and facilitates VLDL clearance [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	These two apolipoproteins circulate on chylomicrons and VLDL [XREF_BIBR, XREF_BIBR] but have opposite effects : apoC-III inhibits lipoprotein lipase (LPL), promotes VLDL production, and slows hepatic VLDL uptake [XREF_BIBR, XREF_BIBR, XREF_BIBR] whereas apoA-V accelerates LPL mediated hydrolysis of TG rich VLDL, blocks VLDL production, and facilitates VLDL clearance [XREF_BIBR, XREF_BIBR, XREF_BIBR].	18	58	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	18	19	20	22
ApoC-III is an inhibitor of lipoprotein lipase and a reduction in apoC-III concentration would be expected to increase the hydrolysis of triglyceride on VLDL enhancing the FCR of VLDL apoB100 .	ApoC-III is an inhibitor of lipoprotein lipase and a reduction in apoC-III concentration would be expected to increase the hydrolysis of triglyceride on VLDL enhancing the FCR of VLDL apoB100.	0	7	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	5	7
ApoC-III may inhibit LpL and also blocks lipoprotein uptake by the liver , and apoE is important for the uptake of triglyceride rich remnants by the liver .	ApoC-III may inhibit LpL and also blocks lipoprotein uptake by the liver, and apoE is important for the uptake of triglyceride rich remnants by the liver.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	LpL	LpL	LpL	0	1	3	4
As discussed above , APOC3 reduces LPL activity .	As discussed above, APOC3 reduces LPL activity.	4	7	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	LPL	LPL	LPL	4	5	6	7
It is noteworthy that apoC-III inhibits lipoprotein lipase and the hepatic uptake of triglyceride rich lipoproteins , which might increase levels of atherogenic triglyceride rich lipoproteins [ XREF_BIBR , XREF_BIBR ] .	It is noteworthy that apoC-III inhibits lipoprotein lipase and the hepatic uptake of triglyceride rich lipoproteins, which might increase levels of atherogenic triglyceride rich lipoproteins [XREF_BIBR, XREF_BIBR].	4	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	6	8
This relative difference between mice expressing WT and A43T APOC3 was abolished when this experiment was repeated in the presence of intravenous Poloxamer P407 ( Pluronic ) , a potent competitive inhibitor of LPL ( XREF_SUPPLEMENTARY ) , suggesting that differences in the ability of A43T and WT apoC-III to inhibit LPL account for their differential effects on postprandial TG clearance .	This relative difference between mice expressing WT and A43T APOC3 was abolished when this experiment was repeated in the presence of intravenous Poloxamer P407 (Pluronic), a potent competitive inhibitor of LPL (XREF_SUPPLEMENTARY), suggesting that differences in the ability of A43T and WT apoC-III to inhibit LPL account for their differential effects on postprandial TG clearance.	43	52	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	48	49	51	52
ApoC-III likely inhibits LPL by competing for lipid binding .	ApoC-III likely inhibits LPL by competing for lipid binding.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	LPL	LPL	LPL	0	1	3	4
these data suggest that the hydrophobic residues F64 and W65 are crucial for the lipid binding properties of apoC-III and that redistribution of the N-terminal helix of apoC-III ( L9T and T20L ) enhances the stability of the lipid bound protein , while LPL inhibition by apoC-III is likely to be due to protein : protein interactions .	these data suggest that the hydrophobic residues F64 and W65 are crucial for the lipid binding properties of apoC-III and that redistribution of the N-terminal helix of apoC-III (L9T and T20L) enhances the stability of the lipid bound protein, while LPL inhibition by apoC-III is likely to be due to protein : protein interactions.	43	47	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	46	47	43	44
Samples used in an LPL inhibitor study were incubated with either PS-80 or PS-20 and 2 muM apoC-III , which has been shown to specifically inhibit LPL activity .	Samples used in an LPL inhibitor study were incubated with either PS-80 or PS-20 and 2 muM apoC-III, which has been shown to specifically inhibit LPL activity.	8	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	17	18	26	27
ApoC3 , which inhibits lipoprotein lipase ( LPL ) , can be seen as regulating access to lipoprotein derived PPARalpha ligands .	ApoC3, which inhibits lipoprotein lipase (LPL), can be seen as regulating access to lipoprotein derived PPARalpha ligands.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC3	ApoC3	ApoC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	4	6
ApoC3 inhibits the lipolytic activity of lipoprotein lipase and is also implicated in the delayed clearance of atherogenic cholesterol rich remnants of the postprandial metabolism of triglyceride rich lipoproteins .	ApoC3 inhibits the lipolytic activity of lipoprotein lipase and is also implicated in the delayed clearance of atherogenic cholesterol rich remnants of the postprandial metabolism of triglyceride rich lipoproteins.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC3	ApoC3	ApoC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	6	8
Although we did not analyze mRNA expressions of LPL or apoA-5 that are related to a PPARalpha stimulation , we confirmed that K-877 significantly downregulates the mRNA expression of apoC-3 that mainly inhibits LPL activity ( XREF_FIG ) .	Although we did not analyze mRNA expressions of LPL or apoA-5 that are related to a PPARalpha stimulation, we confirmed that K-877 significantly downregulates the mRNA expression of apoC-3 that mainly inhibits LPL activity (XREF_FIG).	22	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-3	K-877 significantly downregulates the mRNA expression of apoC-3	apoc-3	LPL	LPL	lpl	29	30	33	34
Defective inhibition of LPL by ApoC-III might raise levels of circulating NEFAs and thus affect insulin sensitivity and beta cell function [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Defective inhibition of LPL by ApoC-III might raise levels of circulating NEFAs and thus affect insulin sensitivity and beta cell function [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	6	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	LPL	LPL	LPL	5	6	3	4
Secondly , apoC-III has been recognised to inhibit LPL mediated lipolysis in vitro ; kinetic studies in human subjects do not however favour this concept [ XREF_BIBR ] .	Secondly, apoC-III has been recognised to inhibit LPL mediated lipolysis in vitro; kinetic studies in human subjects do not however favour this concept [XREF_BIBR].	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	2	3	8	9
This concept is supported by in vitro evidence showing that apoCIII noncompetitively inhibits lipoprotein lipase ( LPL ) , and by the markedly accelerated catabolism of triglyceride rich lipoproteins ( TRL ) in human subjects with a genetic deficiency of apoCIII .	This concept is supported by in vitro evidence showing that apoCIII noncompetitively inhibits lipoprotein lipase (LPL), and by the markedly accelerated catabolism of triglyceride rich lipoproteins (TRL) in human subjects with a genetic deficiency of apoCIII.	10	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoCIII	apoCIII	apoCIII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	10	11	13	15
In vitro experiments have demonstrated that apoC-III inhibits lipoprotein lipase and hepatic lipase and retards clearance of very low-density lipoprotein ( VLDL ) by interfering with binding of apoB100 or apoE to hepatic receptors .	In vitro experiments have demonstrated that apoC-III inhibits lipoprotein lipase and hepatic lipase and retards clearance of very low-density lipoprotein (VLDL) by interfering with binding of apoB100 or apoE to hepatic receptors.	6	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	7	8	10
The high affinity of ApoCIII for the membrane is not surprising given that it has been shown to displace both ApoE [ XREF_BIBR ] and ApoAII [ XREF_BIBR ] from lipoproteins and is proposed to block the lipoprotein lipase activating ApoCII from the lipoprotein surface [ XREF_BIBR , XREF_BIBR ] .	The high affinity of ApoCIII for the membrane is not surprising given that it has been shown to displace both ApoE [XREF_BIBR] and ApoAII [XREF_BIBR] from lipoproteins and is proposed to block the lipoprotein lipase activating ApoCII from the lipoprotein surface [XREF_BIBR, XREF_BIBR].	2	39	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoCIII	ApoCIII	ApoCIII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	37	39
Indeed , our own measurement of in vitro LPL activity inhibition by total plasma ApoC-III ( containing mostly glycosylated isoforms ) and nonglycosylated ApoC-III showed equally potent inhibition of lipolysis of a radiolabeled TG substrate in the presence of recombinant LPL ( XREF_FIG ) .	Indeed, our own measurement of in vitro LPL activity inhibition by total plasma ApoC-III (containing mostly glycosylated isoforms) and nonglycosylated ApoC-III showed equally potent inhibition of lipolysis of a radiolabeled TG substrate in the presence of recombinant LPL (XREF_FIG).	8	15	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	LPL	LPL	LPL	14	15	8	9
21 ApoCIII , an apolipoprotein found on the surface of TG containing lipid particles , inhibits LPL activity .	21 ApoCIII, an apolipoprotein found on the surface of TG containing lipid particles, inhibits LPL activity.	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoCIII	ApoCIII	ApoCIII	LPL	LPL	LPL	1	2	16	17
ApoCII is an endogenous activator , while apoCIII is an endogenous inhibitor of LPL .	ApoCII is an endogenous activator, while apoCIII is an endogenous inhibitor of LPL.	7	14	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	apoCIII	apoCIII	apoCIII	LPL	LPL	LPL	7	8	13	14
APOC3 is and inhibitor of LPL as well as being an inhibitor of hepatic remnant uptake .	APOC3 is and inhibitor of LPL as well as being an inhibitor of hepatic remnant uptake.	0	11	is and inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	LPL	LPL	LPL	0	1	5	6
Apo C-2 is a component of very ( V ) LDL and activates the enzyme lipoprotein lipase ( LPL ) as a cofactor , whereas Apo C-3 inhibits LPL activity [ XREF_BIBR ] .	Apo C-2 is a component of very (V) LDL and activates the enzyme lipoprotein lipase (LPL) as a cofactor, whereas Apo C-3 inhibits LPL activity [XREF_BIBR].	25	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Apo C-3	Apo C-3	Apo C-3	LPL	LPL	LPL	25	27	28	29
The pathogenesis of dyslipidemia is unclear , but an upregulation of circulating levels of apolipoprotein B-100 , apolipoprotein C-III ( an inhibitor of lipoprotein lipase ) , and adipocyte fatty acid binding protein 2 have been reported [ XREF_BIBR , XREF_BIBR ] .	The pathogenesis of dyslipidemia is unclear, but an upregulation of circulating levels of apolipoprotein B-100, apolipoprotein C-III (an inhibitor of lipoprotein lipase), and adipocyte fatty acid binding protein 2 have been reported [XREF_BIBR, XREF_BIBR].	17	25	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	apolipoprotein C-III	apolipoprotein C-III	apolipoprotein C-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	17	19	23	25
Furthermore , apoCIII promotes hypertriglyceridemia by inhibiting both lipoprotein lipase activity and the clearance of TG rich lipoproteins by hepatic receptors .	Furthermore, apoCIII promotes hypertriglyceridemia by inhibiting both lipoprotein lipase activity and the clearance of TG rich lipoproteins by hepatic receptors.	2	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	apoCIII	apoCIII	apoCIII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	8	10
ApoA1 is the main component of high-density lipoprotein ( HDL ) , and apoCIII inhibits lipoprotein lipase activity .	ApoA1 is the main component of high-density lipoprotein (HDL), and apoCIII inhibits lipoprotein lipase activity.	13	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoCIII	apoCIII	apoCIII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	13	14	15	17
14 Apolipoprotein C3 ( ApoC3 ) has been shown to inhibit the lipolytic activity of lipoprotein lipase and can promote delayed clearance of atherogenic lipoproteins .	14 Apolipoprotein C3 (ApoC3) has been shown to inhibit the lipolytic activity of lipoprotein lipase and can promote delayed clearance of atherogenic lipoproteins.	2	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC3	ApoC3	ApoC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	15	17
Apolipoprotein C-III ( APOC3 ) is known to inhibit LPL , although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL independent mechanism .	Apolipoprotein C-III (APOC3) is known to inhibit LPL, although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL independent mechanism.	1	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	LPL	LPL	LPL	3	4	9	10
ApoC-III elevates TG in part by inhibiting LPL .	ApoC-III elevates TG in part by inhibiting LPL.	0	8	elevates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ApoC-III	ApoC-III	ApoC-III	LPL	LPL	LPL	0	1	7	8
Since apoC-III is an inhibitor of LPL , the sole enzyme responsible for plasma triglyceride hydrolysis , we challenged carriers and noncarriers with an oral fat load .	Since apoC-III is an inhibitor of LPL, the sole enzyme responsible for plasma triglyceride hydrolysis, we challenged carriers and noncarriers with an oral fat load.	1	10	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	1	2	6	7
ApoC-III inhibits lipoprotein lipase , thereby delaying the breakdown , metabolism , and hepatic clearance of triglyceride rich lipoprotein particles .	ApoC-III inhibits lipoprotein lipase, thereby delaying the breakdown, metabolism, and hepatic clearance of triglyceride rich lipoprotein particles.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	2	4
Dyslipidemia in CKD is also characterized by elevated levels of apolipoprotein C-III ( apoC-III ) , an exchangeable apolipoprotein on lipoprotein particles that inhibits lipoprotein lipase , thereby reducing clearance of very-low-density-lipoproteins ( VLDL ) and the triglycerides ( TGs ) they carry [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Dyslipidemia in CKD is also characterized by elevated levels of apolipoprotein C-III (apoC-III), an exchangeable apolipoprotein on lipoprotein particles that inhibits lipoprotein lipase, thereby reducing clearance of very-low-density-lipoproteins (VLDL) and the triglycerides (TGs) they carry [XREF_BIBR, XREF_BIBR - XREF_BIBR].	8	26	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	apolipoprotein C-III	levels of apolipoprotein C-III	apolipoprotein c-iii	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	10	12	24	26
APOC3 and ANGTL4 are both inhibitors of lipoprotein lipase ( LPL ) , which is the key enzyme responsible for plasma TG hydrolysis .	APOC3 and ANGTL4 are both inhibitors of lipoprotein lipase (LPL), which is the key enzyme responsible for plasma TG hydrolysis.	0	9	are both inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	7	9
For another member of APOA family , APOC3 inhibits lipoprotein lipase and hepatic lipase ; it is thought to inhibit hepatic uptake of triglyceride rich particles [ XREF_BIBR ] .	For another member of APOA family, APOC3 inhibits lipoprotein lipase and hepatic lipase; it is thought to inhibit hepatic uptake of triglyceride rich particles [XREF_BIBR].	7	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	7	8	9	11
Sitagliptin treatments decreased apoC-III levels and increased LPL activity in the current study ( XREF_TABLE ) .	Sitagliptin treatments decreased apoC-III levels and increased LPL activity in the current study (XREF_TABLE).	0	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	apoC-III	Sitagliptin treatments decreased apoC-III levels	apoc-iii	LPL	LPL	lpl	3	4	7	8
The exact mechanistic reasons remain unclear although it is known that ApoC3 inhibits both lipoprotein lipase ( LPL ) and hepatic lipase mediated lipolysis and that this protein facilitates VLDL 1 assembly and secretion [ XREF_BIBR - XREF_BIBR ] .	The exact mechanistic reasons remain unclear although it is known that ApoC3 inhibits both lipoprotein lipase (LPL) and hepatic lipase mediated lipolysis and that this protein facilitates VLDL 1 assembly and secretion [XREF_BIBR - XREF_BIBR].	11	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC3	ApoC3	ApoC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	11	12	14	16
APOC3 is transported on circulating triglyceride rich lipoproteins and inhibits both lipoprotein lipase and hepatic lipase , thus delaying the catabolism of triglyceride rich particles .	APOC3 is transported on circulating triglyceride rich lipoproteins and inhibits both lipoprotein lipase and hepatic lipase, thus delaying the catabolism of triglyceride rich particles.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOC3	APOC3	APOC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	11	13
All apoC-III proteins inhibited LPL in the presence or absence of apoC-II , with F64A and W65A displaying the most inhibition , suggesting that apoC-III inhibition of LPL is independent of lipid binding and therefore of apoC-II displacement .	All apoC-III proteins inhibited LPL in the presence or absence of apoC-II, with F64A and W65A displaying the most inhibition, suggesting that apoC-III inhibition of LPL is independent of lipid binding and therefore of apoC-II displacement.	24	28	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	24	25	27	28
Lipoprotein lipase activity was also inhibited by the addition of a large excess of lipid-free apolipoprotein C-III to the artificial particles .	Lipoprotein lipase activity was also inhibited by the addition of a large excess of lipid-free apolipoprotein C-III to the artificial particles.	0	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	apolipoprotein C-III	apolipoprotein C-III	apolipoprotein C-III	Lipoprotein lipase	Lipoprotein lipase	Lipoprotein lipase	15	17	0	2
Regarding its atherogenic properties , Apo C-III inhibits lipoprotein lipase activity and interferes with the binding of Apo B- containing lipoproteins to hepatic B/E receptors .	Regarding its atherogenic properties, Apo C-III inhibits lipoprotein lipase activity and interferes with the binding of Apo B- containing lipoproteins to hepatic B/E receptors.	5	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Apo C-III	Apo C-III	Apo C-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	5	7	8	10
In vitro studies have indicated that ApoC-III is a noncompetitive inhibitor of lipoprotein lipase , thereby suggesting an important role in the catabolism of TG rich lipoproteins [ XREF_BIBR ] .	In vitro studies have indicated that ApoC-III is a noncompetitive inhibitor of lipoprotein lipase, thereby suggesting an important role in the catabolism of TG rich lipoproteins [XREF_BIBR].	6	14	is a noncompetitive inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	7	12	14
Since ApoC3 can inhibit LpL activity and limit peripheral fat uptake , ApoC3 transgenic mice have marked hypertriglyceridemia , but normal hepatic lipid content when fed a regular chow fed diet compared to wild-type littermate mice fed the same diet .	Since ApoC3 can inhibit LpL activity and limit peripheral fat uptake, ApoC3 transgenic mice have marked hypertriglyceridemia, but normal hepatic lipid content when fed a regular chow fed diet compared to wild-type littermate mice fed the same diet.	1	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC3	ApoC3	ApoC3	LpL	LpL	LpL	1	2	4	5
ApoC-3 inhibits LPL , playing a critical role in triglyceride hydrolysis and hence in VLDL cholesterol clearance , with elevated apoC-3 common in insulin resistant states such as obesity and hypertriglyceridemia .	ApoC-3 inhibits LPL, playing a critical role in triglyceride hydrolysis and hence in VLDL cholesterol clearance, with elevated apoC-3 common in insulin resistant states such as obesity and hypertriglyceridemia.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC-3	ApoC-3	ApoC-3	LPL	LPL	LPL	0	1	2	3
XREF_BIBR , XREF_BIBR , XREF_BIBR ApoC3 inhibits plasma lipoprotein lipase activity , and is found on TG rich lipoproteins and HDL .	XREF_BIBR, XREF_BIBR, XREF_BIBR ApoC3 inhibits plasma lipoprotein lipase activity, and is found on TG rich lipoproteins and HDL.	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC3	ApoC3	ApoC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	5	6	8	10
ApoC-III inhibits LPL activity and TRL remnant uptake by hepatic lipoprotein receptors .	ApoC-III inhibits LPL activity and TRL remnant uptake by hepatic lipoprotein receptors.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	LPL	LPL	LPL	0	1	2	3
An alternative model could be that MC1R signaling in HR-fish is downregulated by higher concentrations of the inverse antagonist ASIP in the skin , since this gene could be influenced by a higher cortisol level , analogous to how glucocorticoids influence the expression of ASIP in human adipocytes XREF_BIBR .	An alternative model could be that MC1R signaling in HR-fish is downregulated by higher concentrations of the inverse antagonist ASIP in the skin, since this gene could be influenced by a higher cortisol level, analogous to how glucocorticoids influence the expression of ASIP in human adipocytes XREF_BIBR.	6	20	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	19	20	6	7
More recently , alpha-MSH has been shown to inhibit proliferation and adipogenesis in human preadipocytes mediated by MC1R , which is antagonized by agouti and ASIP [ XREF_BIBR ] .	More recently, alpha-MSH has been shown to inhibit proliferation and adipogenesis in human preadipocytes mediated by MC1R, which is antagonized by agouti and ASIP [XREF_BIBR].	15	27	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	25	26	17	18
When overexpressed ectopically , ASIP blocks MC4R and MC1R signaling in the brain and the hair follicle XREF_BIBR , respectively .	When overexpressed ectopically, ASIP blocks MC4R and MC1R signaling in the brain and the hair follicle XREF_BIBR, respectively.	4	9	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	4	5	8	9
In mammals , ASIP inhibits the alpha-MSH and MC1R signaling resulting in the production of phaeomelanin ( yellow pigment ) instead of eumelanin ( brown and black pigment ) .	In mammals, ASIP inhibits the alpha-MSH and MC1R signaling resulting in the production of phaeomelanin (yellow pigment) instead of eumelanin (brown and black pigment).	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	3	4	8	9
In contrast , MC1R activation is inhibited by the binding of the antagonist peptide ASIP ( Agouti Signaling Protein ) , whose action leads to a switch to pheomelanin ( light pigment ) synthesis XREF_BIBR , XREF_BIBR , XREF_BIBR .	In contrast, MC1R activation is inhibited by the binding of the antagonist peptide ASIP (Agouti Signaling Protein), whose action leads to a switch to pheomelanin (light pigment) synthesis XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	14	15	3	4
However , in the pathway of melanogenesis ( XREF_FIG ) , It indicted that ASIP ( ASP ) gene was suppressed MC1R gene .	However, in the pathway of melanogenesis (XREF_FIG), It indicted that ASIP (ASP) gene was suppressed MC1R gene.	14	22	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	14	15	21	22
This suggests that other candidate loci are responsible for the coloration , such as the MC1R antagonist Agouti signaling protein ( ASIP ) .	This suggests that other candidate loci are responsible for the coloration, such as the MC1R antagonist Agouti signaling protein (ASIP).	15	20	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Agouti signaling protein	Agouti signaling protein	Agouti signaling protein	MC1R	MC1R	MC1R	17	20	15	16
Substitution of any of these residues individually or in groups greatly reduces melanocortin receptor affinity and function ; for example , the RFF --> AFF mutation in Asip reduces MC1R affinity by over 760 fold ( K i = 2.6 nM --> K i > 1900nM ) .	Substitution of any of these residues individually or in groups greatly reduces melanocortin receptor affinity and function; for example, the RFF --> AFF mutation in Asip reduces MC1R affinity by over 760 fold (K i = 2.6 nM --> K i> 1900nM).	25	30	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Asip	Asip	Asip	MC1R	MC1R	MC1R	27	28	29	30
It was early shown that ASIP is a potent antagonist of the MC1R explaining its role in melanogenesis .	It was early shown that ASIP is a potent antagonist of the MC1R explaining its role in melanogenesis.	5	13	is a potent antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	5	6	12	13
This gene encodes the agouti signaling protein that antagonizes the Mc1r receptor , leading to a pigment switch from eumelanin to phaeomelanin .	This gene encodes the agouti signaling protein that antagonizes the Mc1r receptor, leading to a pigment switch from eumelanin to phaeomelanin.	4	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	agouti signaling protein	agouti signaling protein	agouti signaling protein	Mc1r	Mc1r	Mc1r	4	7	10	11
Interestingly MC1R variants with reduced affinity for alpha-MSH show a reduced association with , and protection of , PTEN [ XREF_BIBR ] , suggesting that ASIP may inhibit MC1R protection of PTEN and in this manner slow tumor growth .	Interestingly MC1R variants with reduced affinity for alpha-MSH show a reduced association with, and protection of, PTEN [XREF_BIBR], suggesting that ASIP may inhibit MC1R protection of PTEN and in this manner slow tumor growth.	25	29	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	25	26	28	29
As expected , the fixed lung lobes from mice given B16-GFP cells alone were heavily populated by melanotic tumors , whereas pigmentation was inversely proportional to the number of ASIP secreting cells and mice injected with B16-ASIP-mChy cells alone showed little or no eumelanin pigment ( XREF_SUPPLEMENTARY ) , suggesting that inhibition of MC1R by ASIP contributed to the longer survival observed .	As expected, the fixed lung lobes from mice given B16-GFP cells alone were heavily populated by melanotic tumors, whereas pigmentation was inversely proportional to the number of ASIP secreting cells and mice injected with B16-ASIP-mChy cells alone showed little or no eumelanin pigment (XREF_SUPPLEMENTARY), suggesting that inhibition of MC1R by ASIP contributed to the longer survival observed.	51	56	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	55	56	53	54
Then they use nuclear lysates from melanocytes to determine the effects of MC1R antagonists ASIP and HBD3 on the EC 50 s of alpha-MSH and forskolin .	Then they use nuclear lysates from melanocytes to determine the effects of MC1R antagonists ASIP and HBD3 on the EC 50 s of alpha-MSH and forskolin.	12	15	antagonists	Negative_activation_token_1_noun	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	14	15	12	13
These assays enable the authors to carry out detailed evaluations of the activities of MC1R agonists alpha-MSH and adrenocorticotripic hormone ( ACTH ) and MC1R antagonists agouti signaling protein ( ASIP ) and human beta-defensin 3 ( HBD3 ) .	These assays enable the authors to carry out detailed evaluations of the activities of MC1R agonists alpha-MSH and adrenocorticotripic hormone (ACTH) and MC1R antagonists agouti signaling protein (ASIP) and human beta-defensin 3 (HBD3).	2	34	antagonists	Negative_activation_token_1_noun	Negative_activation	Negative_activation	agouti signaling protein	agouti signaling protein	agouti signaling protein	MC1R	MC1R	MC1R	26	29	24	25
ASIP has an epistatic effect with MC1R and can reduce MC1R activity to generate more pheomelanin by preventing cAMP production .	ASIP has an epistatic effect with MC1R and can reduce MC1R activity to generate more pheomelanin by preventing cAMP production.	0	11	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	0	1	10	11
Melanocortins enhance MC1R signaling , ASIP inhibits MC1R signaling directly , and the neutral antagonist betaD3 blunts melanocortin induced signaling by competing with MC1R agonists for MC1R binding .	Melanocortins enhance MC1R signaling, ASIP inhibits MC1R signaling directly, and the neutral antagonist betaD3 blunts melanocortin induced signaling by competing with MC1R agonists for MC1R binding.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	5	6	7	8
A role for MC1R as a growth receptor for melanoma is in agreement with transcriptome analysis of a human melanoma cell line in which MC1R was inhibited by transient transfection of an ASIP cDNA .	A role for MC1R as a growth receptor for melanoma is in agreement with transcriptome analysis of a human melanoma cell line in which MC1R was inhibited by transient transfection of an ASIP cDNA.	24	33	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	32	33	24	25
As ASIP is a well-known antagonist of the receptor molecule MC1R located on the cell surface of melanocytes , it is possible that ASIP becomes secreted by dermal components like fibroblasts to interact with MC1R .	As ASIP is a well-known antagonist of the receptor molecule MC1R located on the cell surface of melanocytes, it is possible that ASIP becomes secreted by dermal components like fibroblasts to interact with MC1R.	1	11	is a well-known antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	1	2	10	11
In 3 species ( 2 lemurs and the howler monkey ) , we report the novel finding that binding and inhibition of MC1R by agouti signaling protein ( ASIP ) can occur when MSH binding has been lost , thus enabling continuing regulation of the melanin type via ASIP expression .	In 3 species (2 lemurs and the howler monkey), we report the novel finding that binding and inhibition of MC1R by agouti signaling protein (ASIP) can occur when MSH binding has been lost, thus enabling continuing regulation of the melanin type via ASIP expression.	18	27	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	agouti signaling protein	agouti signaling protein	agouti signaling protein	MC1R	MC1R	MC1R	24	27	22	23
Gray Lipizzaner horses which are null for the Mc1r antagonist ASIP have a higher incidence of melanoma than horses which carry functional ASIP , indicating that increased Mc1r signaling promotes melanoma in these animals .	Gray Lipizzaner horses which are null for the Mc1r antagonist ASIP have a higher incidence of melanoma than horses which carry functional ASIP, indicating that increased Mc1r signaling promotes melanoma in these animals.	5	11	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	Mc1r	Mc1r	Mc1r	10	11	8	9
In addition , ASIP functions as an inverse agonist to decrease basal MC1R signaling and inhibit eumelanogenesis .	In addition, ASIP functions as an inverse agonist to decrease basal MC1R signaling and inhibit eumelanogenesis.	3	15	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	3	4	12	13
In contrast , MC1R WT -expressing cells pre-treated with the MC1R antagonists ASIP or HBD3 failed to exhibit MSH induced increases in ATR-pS435-XPA association .	In contrast, MC1R WT -expressing cells pre-treated with the MC1R antagonists ASIP or HBD3 failed to exhibit MSH induced increases in ATR-pS435-XPA association.	10	17	antagonists	Negative_activation_token_1_noun	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	12	13	10	11
However , incubation of cells with MC1R antagonists ASIP or human beta-defensin three blocked MSH mediated enhancement of incision ( P < = 0.05 ) .	However, incubation of cells with MC1R antagonists ASIP or human beta-defensin three blocked MSH mediated enhancement of incision (P < = 0.05).	6	9	antagonists	Negative_activation_token_1_noun	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	8	9	6	7
For pigment patterning , antagonism of MC1R by ASIP has received the most attention .	For pigment patterning, antagonism of MC1R by ASIP has received the most attention.	4	9	antagonism	Negative_activation_token_2_noun	Negative_activation	Negative_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	8	9	6	7
In case of low DNA damage , Mdm2 activity is not effectively suppressed by ATM resulting in sustained oscillations of both p53 and Mdm2 .	In case of low DNA damage, Mdm2 activity is not effectively suppressed by ATM resulting in sustained oscillations of both p53 and Mdm2.	7	15	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	14	15	7	8
On the other hand , the mutagenesis study showed that ATM phosphorylation prevents dimerization of the MDM2 RING domain induced by DNA damage , which will significantly diminish MDM2 ' s E3 activity toward p53 .	On the other hand, the mutagenesis study showed that ATM phosphorylation prevents dimerization of the MDM2 RING domain induced by DNA damage, which will significantly diminish MDM2 's E3 activity toward p53.	10	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM phosphorylation	atm	MDM2	MDM2	mdm2	10	11	16	17
ATM and CHK2 cooperate to activate and stabilize the tumor suppressor p53 by directly targeting p53 as well as targeting MDM2 , the ubiquitin ligase that is normally responsible for the rapid turnover of p53 protein .	ATM and CHK2 cooperate to activate and stabilize the tumor suppressor p53 by directly targeting p53 as well as targeting MDM2, the ubiquitin ligase that is normally responsible for the rapid turnover of p53 protein.	0	24	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	0	1	20	21
w xy represents the suppression of Mdm2 by ATM , w yz represents the suppression of p53 by Mdm2 , w zy represents the transcriptional activation of Mdm2 by p53 , w y represents the stability of Mdm2 ( 1-w y represents Mdm2 degradation ) , and w z represents the stability of p53 ( 1-w z represents p53 degradation ) .	w xy represents the suppression of Mdm2 by ATM, w yz represents the suppression of p53 by Mdm2, w zy represents the transcriptional activation of Mdm2 by p53, w y represents the stability of Mdm2 (1-w y represents Mdm2 degradation), and w z represents the stability of p53 (1-w z represents p53 degradation).	2	9	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	8	9	6	7
Eq.2 is composed of the p53 dependent production of Mdm2 ( first term ) , ATM dependent suppression of Mdm2 ( second term ) , and Mdm2 degradation ( third term ) .	Eq.2 is composed of the p53 dependent production of Mdm2 (first term), ATM dependent suppression of Mdm2 (second term), and Mdm2 degradation (third term).	15	20	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	15	16	19	20
ATM also enhances the degradation of Mdm2 .	ATM also enhances the degradation of Mdm2.	0	7	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	0	1	6	7
These phosphorylation events combine with an ATM mediated restriction of MDM2 activity to stabilize p53 .	These phosphorylation events combine with an ATM mediated restriction of MDM2 activity to stabilize p53.	5	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	6	7	10	11
Furthermore , ATM does not cause a general inhibition of MDM2 E3 ligase activity , since p53 mono ubiquitination , MDM2 self ubiquitination and MDMX ubiquitination are not affected .	Furthermore, ATM does not cause a general inhibition of MDM2 E3 ligase activity, since p53 mono ubiquitination, MDM2 self ubiquitination and MDMX ubiquitination are not affected.	2	13	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	2	3	10	11
CDKN2A ( also known as p14 ARF / p19 Arf ) and Ataxia Telangiectasia Mutated ( ATM ) kinase suppress MDM2 in the presence of oncogenic and genotoxic stresses , respectively .	CDKN2A (also known as p14 ARF / p19 Arf) and Ataxia Telangiectasia Mutated (ATM) kinase suppress MDM2 in the presence of oncogenic and genotoxic stresses, respectively.	14	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	16	17	20	21
Combined with previous studies indicating that ATM inhibits MDM2 dimerization and that c-ABL , another downstream target of ATM , can promote MDM2 mediated degradation of MDMX , these results showcase a critical role of ATM phosphorylation in down-regulating MDM2-MDMX heterodimers to allow for p53 activation .	Combined with previous studies indicating that ATM inhibits MDM2 dimerization and that c-ABL, another downstream target of ATM, can promote MDM2 mediated degradation of MDMX, these results showcase a critical role of ATM phosphorylation in down-regulating MDM2-MDMX heterodimers to allow for p53 activation.	16	23	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	18	19	22	23
In case of high DNA damage , ATM level is high and suppresses Mdm2 giving a monotone increase of p53 level .	In case of high DNA damage, ATM level is high and suppresses Mdm2 giving a monotone increase of p53 level.	7	14	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM level	atm	Mdm2	Mdm2	mdm2	7	8	13	14
However , MDM2 is also inhibited by ATM , which in turn is activated by the DNA damage signal , so that p53 is expected to display an oscillatory behavior under DNA damage [ XREF_BIBR ] .	However, MDM2 is also inhibited by ATM, which in turn is activated by the DNA damage signal, so that p53 is expected to display an oscillatory behavior under DNA damage [XREF_BIBR].	2	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	7	8	2	3
Here , we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G , thus downregulating Mdm2 and activating the p53 response .	Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response.	12	24	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	15	16	23	24
In addition , anticancer agents such as Parthenolide accelerate HDM2 autoubiquitination through mechanisms that required ATM and Berberine , which downregulates HDM2 at the posttranslational level through modulation of death domain associated protein ( DAXX ) have recently been shown to induce apoptosis [ XREF_BIBR , XREF_BIBR ] .	In addition, anticancer agents such as Parthenolide accelerate HDM2 autoubiquitination through mechanisms that required ATM and Berberine, which downregulates HDM2 at the posttranslational level through modulation of death domain associated protein (DAXX) have recently been shown to induce apoptosis [XREF_BIBR, XREF_BIBR].	14	25	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	HDM2	HDM2	HDM2	15	16	21	22
P53 is highly inducible by IR through ATM dependent inhibition of the MDM2 E3 ligase .	P53 is highly inducible by IR through ATM dependent inhibition of the MDM2 E3 ligase.	7	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	7	8	12	13
Meanwhile , Mdm2 ( the negative regulator of p53 ) is inactivated by ATM and ATR , and association of p53 with p300 results in increased transcriptional activity of p300 .	Meanwhile, Mdm2 (the negative regulator of p53) is inactivated by ATM and ATR, and association of p53 with p300 results in increased transcriptional activity of p300.	2	15	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	13	14	2	3
Thus , ATM dependent phosphorylation prevents Mdm2 from binding and ubiquitinating p53 , leading to stabilization of p53 and further transactivation of Mdm2 gene .	Thus, ATM dependent phosphorylation prevents Mdm2 from binding and ubiquitinating p53, leading to stabilization of p53 and further transactivation of Mdm2 gene.	2	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM dependent phosphorylation	atm	Mdm2	Mdm2	mdm2	2	3	6	7
To look for other means of Mdm2 deregulation , we examined the effect of ATM kinase on Mdm2 , where ATM kinase mediated phosphorylation of S395 inhibits the Mdm2 mediated degradation of p53 [ XREF_BIBR ] .	To look for other means of Mdm2 deregulation, we examined the effect of ATM kinase on Mdm2, where ATM kinase mediated phosphorylation of S395 inhibits the Mdm2 mediated degradation of p53 [XREF_BIBR].	20	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	20	21	28	29
ATM and ATR also directly inhibit Mdm2 by phosphorylating it on S395 and S407 , respectively [ XREF_BIBR , XREF_BIBR ] .	ATM and ATR also directly inhibit Mdm2 by phosphorylating it on S395 and S407, respectively [XREF_BIBR, XREF_BIBR].	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	0	1	6	7
In addition , the putative tumor suppressor gene , WTX , which is mutated in ~ 30 % of Wilms tumors , was recently shown to induce degradation of CTNNB1 .	In addition, the putative tumor suppressor gene, WTX, which is mutated in ~ 30% of Wilms tumors, was recently shown to induce degradation of CTNNB1.	7	30	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WTX	WTX	WTX	CTNNB1	CTNNB1	CTNNB1	9	10	29	30
In parallel to the reported WTX modulation of beta-catenin degradation in the cytoplasm , these observations suggest an effect of WTX on turnover of nuclear proteins .	In parallel to the reported WTX modulation of beta-catenin degradation in the cytoplasm, these observations suggest an effect of WTX on turnover of nuclear proteins.	5	9	modulation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	WTX	WTX	WTX	beta-catenin	beta-catenin	beta-catenin	5	6	8	9
WTX is also present in the beta-catenin destruction complex and promotes beta-catenin degradation .	WTX is also present in the beta-catenin destruction complex and promotes beta-catenin degradation.	0	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WTX	WTX	WTX	beta-catenin	beta-catenin	beta-catenin	0	1	11	12
WTX directly binds to beta-catenin , Apc , and Axin1/2 and is a component of the beta-catenin destruction complex ; thus , loss-of-function mutations in WTX enhance beta-catenin stability .	WTX directly binds to beta-catenin, Apc, and Axin1/2 and is a component of the beta-catenin destruction complex; thus, loss-of-function mutations in WTX enhance beta-catenin stability.	23	28	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WTX	WTX	WTX	beta-catenin	beta-catenin	beta-catenin	25	26	27	28
Using large-scale interactome mapping a second independent study demonstrated that WTX induces degradation of beta-catenin via the proteasome system , thus identifying this gene as an important modulator of this crucial signaling pathway [ XREF_BIBR ] .	Using large-scale interactome mapping a second independent study demonstrated that WTX induces degradation of beta-catenin via the proteasome system, thus identifying this gene as an important modulator of this crucial signaling pathway [XREF_BIBR].	10	18	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WTX	WTX	WTX	beta-catenin	beta-catenin	beta-catenin	10	11	14	15
Protein interaction studies have suggested that WTX associates with the APC complex and may negatively regulate beta-catenin stability , while recent studies have also suggested a positive effect on WNT signaling through tethering CK1gamma , GSK3beta , Axin and LRP6 .	Protein interaction studies have suggested that WTX associates with the APC complex and may negatively regulate beta-catenin stability, while recent studies have also suggested a positive effect on WNT signaling through tethering CK1gamma, GSK3beta, Axin and LRP6.	6	17	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WTX	WTX	WTX	beta-catenin	beta-catenin	beta-catenin	6	7	16	17
The results showed that ATM triggers MDMX degradation after DNA damage , eliminating its inhibitory effect on p53 .	The results showed that ATM triggers MDMX degradation after DNA damage, eliminating its inhibitory effect on p53.	4	7	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	MDMX	MDMX	MDMX	4	5	6	7
Loss of ATM prevents MDMX degradation and p53 stabilization after DNA damage .	Loss of ATM prevents MDMX degradation and p53 stabilization after DNA damage.	0	5	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	Loss of ATM	atm	MDMX	MDMX	mdmx	2	3	4	5
Furthermore , we found that expression of Amot , but not AmotDeltaN , rescued aPKCzeta-ca cells from stratified growth in 2D cultures , which is consistent with this phenotype being driven by Yap1 activity and Amot sequestering Yap1 from the nucleus ( XREF_FIG ) .	Furthermore, we found that expression of Amot, but not AmotDeltaN, rescued aPKCzeta-ca cells from stratified growth in 2D cultures, which is consistent with this phenotype being driven by Yap1 activity and Amot sequestering Yap1 from the nucleus (XREF_FIG).	30	38	sequestering	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Amot	Amot	Amot	Yap1	Yap1	Yap1	35	36	37	38
Aurora Kinase A Promotes AR Degradation via the E3 Ligase CHIP .	Aurora Kinase A Promotes AR Degradation via the E3 Ligase CHIP.	0	5	Promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Aurora Kinase A	Aurora Kinase A	Aurora Kinase A	AR	AR	AR	0	3	4	5
Included in these studies is the compelling finding that inhibition of beta ARK1 activity or expression significantly enhances cardiac function and potentiates beta AR signaling in failing cardiomyocytes .	Included in these studies is the compelling finding that inhibition of beta ARK1 activity or expression significantly enhances cardiac function and potentiates beta AR signaling in failing cardiomyocytes.	12	24	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ARK1	ARK1	ARK1	AR	AR	AR	12	13	23	24
The same was observed with G1 enriched HEK293T cells transfected with GFP-CtIP and treated with ATM siRNA .	The same was observed with G1 enriched HEK293T cells transfected with GFP-CtIP and treated with ATM siRNA.	9	16	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	ATM	ATM	ATM	GFP-CtIP	GFP-CtIP	GFP-CtIP	15	16	11	12
These findings thus suggested that ATM prevents Ku accumulation on seDSBs by stimulating CtIP activity , likely through direct CtIP phosphorylation .	These findings thus suggested that ATM prevents Ku accumulation on seDSBs by stimulating CtIP activity, likely through direct CtIP phosphorylation.	5	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	CtIP	CtIP	CtIP	5	6	13	14
Therefore , the decreased ATM levels in the presence of HMGA1 overexpression might increase pro survival Akt signaling after treatment of the cancer cells with the antineoplastic drugs .	Therefore, the decreased ATM levels in the presence of HMGA1 overexpression might increase pro survival Akt signaling after treatment of the cancer cells with the antineoplastic drugs.	4	17	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM levels	atm	Akt	Akt	akt	4	5	16	17
In glioma cells , an ATM kinase inhibitor decreased basal levels of Akt phosphorylation and ATM deficient cells were impaired in the activation of Akt in response to ionizing radiation and insulin .	In glioma cells, an ATM kinase inhibitor decreased basal levels of Akt phosphorylation and ATM deficient cells were impaired in the activation of Akt in response to ionizing radiation and insulin.	5	26	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	Akt	Akt	Akt	5	6	24	25
28 Thus , cell death signaling in NBS1- and ATM deficient cells prevented AKT activation and subsequent nuclear cyclin D1 accumulation following long-term FR .	28 Thus, cell death signaling in NBS1- and ATM deficient cells prevented AKT activation and subsequent nuclear cyclin D1 accumulation following long-term FR.	7	14	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	AKT	AKT	AKT	9	10	13	14
We assumed that the inhibition of VRK-1 by LEM-4 in living cells might occur during mitotic exit , since inactivation of the worm temperature sensitive lem-4 mutation specifically during mitosis , but not during interphase , resulted in abnormal NE structure .	We assumed that the inhibition of VRK-1 by LEM-4 in living cells might occur during mitotic exit, since inactivation of the worm temperature sensitive lem-4 mutation specifically during mitosis, but not during interphase, resulted in abnormal NE structure.	4	11	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	LEM-4	LEM-4	LEM-4	VRK-1	VRK-1	VRK-1	8	9	6	7
However , we found that , at least in vitro , LEM-4 can not dephosphorylate BAF , and thus hypothesized that LEM-4 might either inhibit the kinase activity of VRK-1 or activate a so far unidentified phosphatase to dephosphorylate BAF .	However, we found that, at least in vitro, LEM-4 can not dephosphorylate BAF, and thus hypothesized that LEM-4 might either inhibit the kinase activity of VRK-1 or activate a so far unidentified phosphatase to dephosphorylate BAF.	21	31	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LEM-4	LEM-4	LEM-4	VRK-1	VRK-1	VRK-1	21	22	29	30
Inactivation of CDC25C by ATM signaling triggered by DNA damage has been shown to be associated with downregulation of a unique group of highly correlated G 2 checkpoint signature genes and those genes are upregulated in ATM deficient mouse cells .	Inactivation of CDC25C by ATM signaling triggered by DNA damage has been shown to be associated with downregulation of a unique group of highly correlated G 2 checkpoint signature genes and those genes are upregulated in ATM deficient mouse cells.	0	5	Inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	ATM	ATM	ATM	CDC25C	CDC25C	CDC25C	4	5	2	3
The results shown in XREF_FIG reveal that inhibition of ATM by caffeine restored partially the phosphorylated form and protein level of CDC25C .	The results shown in XREF_FIG reveal that inhibition of ATM by caffeine restored partially the phosphorylated form and protein level of CDC25C.	7	22	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	CDC25C	CDC25C	CDC25C	9	10	21	22
Experimental measurements and bioinformatic analyses suggested that the dephosphorylation of Akt after 2h of hypoxic exposure might deactivate RNA binding protein BRF1 , hence resulting in the selective degradation of mRNAs .	Experimental measurements and bioinformatic analyses suggested that the dephosphorylation of Akt after 2h of hypoxic exposure might deactivate RNA binding protein BRF1, hence resulting in the selective degradation of mRNAs.	8	22	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	dephosphorylation of Akt after 2h	akt	BRF1	BRF1	brf1	10	11	21	22
In that study , DeltaNp63 and AKT inhibition were shown to modulate YAP1 .	In that study, DeltaNp63 and AKT inhibition were shown to modulate YAP1.	4	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	YAP1	YAP1	YAP1	6	7	12	13
Furthermore , the aortae of ATM +/- apoE -/- mice exhibited increased JNK1/2 activation but reduced ERK1/2 and Akt1 activation .	Furthermore, the aortae of ATM +/- apoE -/- mice exhibited increased JNK1/2 activation but reduced ERK1/2 and Akt1 activation.	5	19	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	Akt1	Akt1	Akt1	5	6	18	19
In line with this notion , pharmacological inhibition of ATM induced cytoplasmic redistribution of NEMO and PIDD ( which were found constitutively in the nucleus of these cells ) , inhibition of constitutive NF-kappaB activation and cell death .	In line with this notion, pharmacological inhibition of ATM induced cytoplasmic redistribution of NEMO and PIDD (which were found constitutively in the nucleus of these cells), inhibition of constitutive NF-kappaB activation and cell death.	7	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	NEMO	NEMO	NEMO	9	10	14	15
Polyglutamine expanded ataxin-7 suppresses CRX transactivation in transgenic retinas .	Polyglutamine expanded ataxin-7 suppresses CRX transactivation in transgenic retinas.	2	5	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ataxin-7	ataxin-7	ataxin-7	CRX	CRX	CRX	2	3	4	5
Subsequently , the apoptotic cascade is activated , whereas Bcl-2 prevents Bax activity via exerting its pro apoptotic effect [ XREF_BIBR ] .	Subsequently, the apoptotic cascade is activated, whereas Bcl-2 prevents Bax activity via exerting its pro apoptotic effect [XREF_BIBR].	9	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	11	12
The adenovirus Bcl-2 homologue , E1B 19K , inhibits TNF-alpha-mediated apoptosis , interacts with Bax , and blocked the formation of the 500-kDa Bax complex .	The adenovirus Bcl-2 homologue, E1B 19K, inhibits TNF-alpha-mediated apoptosis, interacts with Bax, and blocked the formation of the 500-kDa Bax complex.	2	24	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	23	24
Finally , administration of ABT-737 , a pharmacological inhibitor of Bcl-2 and Bcl-xL , caused Bak and Bax dependent liver injury , but this was clearly ameliorated with a Bid KO background .	Finally, administration of ABT-737, a pharmacological inhibitor of Bcl-2 and Bcl-xL, caused Bak and Bax dependent liver injury, but this was clearly ameliorated with a Bid KO background.	8	20	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	10	11	17	18
Abbott laboratories introduced Bcl-2 and Bcl-X L inhibitor , ABT-737 that competes with BAD for docking to the hydrophobic groove of Bcl-2 and augments Bax and Bak activation .	Abbott laboratories introduced Bcl-2 and Bcl-X L inhibitor, ABT-737 that competes with BAD for docking to the hydrophobic groove of Bcl-2 and augments Bax and Bak activation.	3	27	augments	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	24	25
The results demonstrated that DEX repressed the expression of Bcl-2 and promoted the release of Bax .	The results demonstrated that DEX repressed the expression of Bcl-2 and promoted the release of Bax.	4	16	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	DEX repressed the expression of Bcl-2	bcl-2	Bax	Bax	bax	9	10	15	16
The anti-apoptotic Bcl-2 proteins , such as Bcl-2 and Bcl-XL , can antagonize Bax and Bak to prevent MOMP .	The anti-apoptotic Bcl-2 proteins, such as Bcl-2 and Bcl-XL, can antagonize Bax and Bak to prevent MOMP.	2	15	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	13	14
Thus , Bcl-2 may suppress cell death at least in part by binding to Bax via the BH3 domain and thereby preventing formation of Bax and Bax homodimers .	Thus, Bcl-2 may suppress cell death at least in part by binding to Bax via the BH3 domain and thereby preventing formation of Bax and Bax homodimers.	2	27	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	24	25
BCL-2 BH4 SAHB A Blocks the Conformational Activation of BAX .	BCL-2 BH4 SAHB A Blocks the Conformational Activation of BAX.	0	10	Blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	0	1	9	10
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Bcl-2 and its closest homologues ( Bcl-x L , Bcl-w , Mcl-1 and A1/BFL-1 ) promote MOM integrity , and hence cell survival , by inhibiting activation of very similar but pro apoptotic homologues , Bax and Bak .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Bcl-2 and its closest homologues (Bcl-x L, Bcl-w, Mcl-1 and A1/BFL-1) promote MOM integrity, and hence cell survival, by inhibiting activation of very similar but pro apoptotic homologues, Bax and Bak.	0	44	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	42	43
In addition , increasing expression of atrogin-1 and MAFbx in H9C2 cells after I/R decreases the level of the anti-apoptotic protein Bcl-2 , and increases the pro apoptotic proteins Bax , cleaved caspase-9 , and cleaved caspase-3 .	In addition, increasing expression of atrogin-1 and MAFbx in H9C2 cells after I/R decreases the level of the anti-apoptotic protein Bcl-2, and increases the pro apoptotic proteins Bax, cleaved caspase-9, and cleaved caspase-3.	4	31	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of atrogin-1 and MAFbx in H9C2 cells after I/R decreases the level of the anti-apoptotic protein Bcl-2	bcl-2	Bax	Bax	bax	21	22	29	30
This pocket facilitates protein protein binding between BCL2 and the BH3 domain of pro apoptotic BCL2 family members such as BIM ( Bcl-2-like protein 11 ) , BAX ( BCL2 associated X protein ) and BAK ( BCL2 homologous antagonist killer ) , preventing BAX / BAK activation and consequent apoptosis through mitochondrial outer membrane permeabilization ( MOMP ) [ XREF_BIBR ] .	This pocket facilitates protein protein binding between BCL2 and the BH3 domain of pro apoptotic BCL2 family members such as BIM (Bcl-2-like protein 11), BAX (BCL2 associated X protein) and BAK (BCL2 homologous antagonist killer), preventing BAX / BAK activation and consequent apoptosis through mitochondrial outer membrane permeabilization (MOMP) [XREF_BIBR].	35	50	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	37	38	44	45
XREF_BIBR , who observed that BAX translocates to mitochondria in C. psittaci infected cells and that BAX-inhibitor 1 or Bcl-2 expression perturbs C. psittaci induced caspase independent ' apoptosis ' , here we find that HeLa cells rendered profoundly resistant to apoptosis and/or necroptosis through the selected and iterative deletion of BAK , BAX and RIP1 as well as in the presence of pan-caspase and necroptosis inhibitors still die with the same kinetics as control cells ( XREF_FIG ) .	XREF_BIBR, who observed that BAX translocates to mitochondria in C. psittaci infected cells and that BAX-inhibitor 1 or Bcl-2 expression perturbs C. psittaci induced caspase independent ' apoptosis ', here we find that HeLa cells rendered profoundly resistant to apoptosis and/or necroptosis through the selected and iterative deletion of BAK, BAX and RIP1 as well as in the presence of pan-caspase and necroptosis inhibitors still die with the same kinetics as control cells (XREF_FIG).	19	54	perturbs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	BAX	BAX	bax	19	20	53	54
Indeed , endothelial reticulum containing the whole Bik protein was shown to promote Bax membrane insertion and cytochrome c release , which was inhibited by Bcl-2 .	Indeed, endothelial reticulum containing the whole Bik protein was shown to promote Bax membrane insertion and cytochrome c release, which was inhibited by Bcl-2.	13	26	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	25	26	13	14
In a normal cell , basal levels of pro survival Bcl-2 like proteins prevent Bax and Bak from becoming activated .	In a normal cell, basal levels of pro survival Bcl-2 like proteins prevent Bax and Bak from becoming activated.	6	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	levels of pro survival Bcl-2	bcl-2	Bax	Bax	bax	10	11	14	15
Mcl-1 ( and to a certain extent Bcl-XL ) is the main inhibitor of Bak while Bax is mainly inhibited by Bcl-2 and Bcl-w .	Mcl-1 (and to a certain extent Bcl-XL) is the main inhibitor of Bak while Bax is mainly inhibited by Bcl-2 and Bcl-w.	16	23	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	21	22	16	17
In addition , PFOA administration inhibited activities of superoxide dismutase and catalase , and increased generation of hydrogen peroxide and malondialdehyde , and down-regulated level of Bcl-2 and up-regulated p53 and BAX proteins .	In addition, PFOA administration inhibited activities of superoxide dismutase and catalase, and increased generation of hydrogen peroxide and malondialdehyde, and down-regulated level of Bcl-2 and up-regulated p53 and BAX proteins.	3	32	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	PFOA administration inhibited activities of superoxide dismutase and catalase, and increased generation of hydrogen peroxide and malondialdehyde, and down-regulated level of Bcl-2	bcl-2	BAX	BAX	bax	26	27	31	32
In mouse embryo fibroblasts , Bak is restrained by the pro survival proteins Mcl-1 and Bcl-x L , but not Bcl-2 , 20 whereas Bax is probably inhibited by the pro survival proteins Bcl-2 , Bcl-w , Bcl-x L and Mcl-1 .	In mouse embryo fibroblasts, Bak is restrained by the pro survival proteins Mcl-1 and Bcl-x L, but not Bcl-2, 20 whereas Bax is probably inhibited by the pro survival proteins Bcl-2, Bcl-w, Bcl-x L and Mcl-1.	24	40	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	33	34	24	25
It is known that Bcl-2 inhibits Bax activation , thus we reasoned that overexpressing Bcl-2 would protect 2DG treated lymphomas from death .	It is known that Bcl-2 inhibits Bax activation, thus we reasoned that overexpressing Bcl-2 would protect 2DG treated lymphomas from death.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	6	7
The Co 2+ and Cr 3+ ions inhibited bcl-2 expression but stimulated bax and caspase-3 expression [ XREF_BIBR ] at different periods of incubation with the macrophage .	The Co 2+ and Cr 3+ ions inhibited bcl-2 expression but stimulated bax and caspase-3 expression [XREF_BIBR] at different periods of incubation with the macrophage.	1	17	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	Co 2+ and Cr 3+ ions inhibited bcl-2 expression	bcl-2	bax	bax	bax	8	9	12	13
Furthermore , Bcl-xL and Bcl-2 suppressed Bax toxicity by distinct mechanisms in yeast .	Furthermore, Bcl-xL and Bcl-2 suppressed Bax toxicity by distinct mechanisms in yeast.	2	7	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	6	7
Under normal circumstances , Bcl-2 prevents apoptosis by preventing the activation of Bax or binding the activated Bax ; however , when their competitive balance is disrupted , apoptosis is initiated [ XREF_BIBR ] .	Under normal circumstances, Bcl-2 prevents apoptosis by preventing the activation of Bax or binding the activated Bax; however, when their competitive balance is disrupted, apoptosis is initiated [XREF_BIBR].	4	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	12	13
Bcl-2 and Bcl-xl also inhibit the proapoptotic actions of Bax and Bak , which , upon oligomerization , form large pores .	Bcl-2 and Bcl-xl also inhibit the proapoptotic actions of Bax and Bak, which, upon oligomerization, form large pores.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	9	10
The present study suggested that BB treatment significantly up-regulated the anti-apoptotic Bcl-2 protein expression and markedly decreased the Bax and Bcl -2 ratio , indicating the anti-apoptosis effect might contribute to the protection of BB against DSS induced experimental UC .	The present study suggested that BB treatment significantly up-regulated the anti-apoptotic Bcl-2 protein expression and markedly decreased the Bax and Bcl -2 ratio, indicating the anti-apoptosis effect might contribute to the protection of BB against DSS induced experimental UC.	11	22	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 protein expression	bcl-2	Bax	Bax	bax	11	12	18	19
Increased expression of Bax and reduced levels of Bcl-2 have been reported in skeletal muscles of old experimental animals [ XREF_BIBR - XREF_BIBR ] .	Increased expression of Bax and reduced levels of Bcl-2 have been reported in skeletal muscles of old experimental animals [XREF_BIBR - XREF_BIBR].	3	9	reduced	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Bcl-2	levels of Bcl-2	bcl-2	Bax	Bax	bax	8	9	3	4
Protein families that control apoptosis include the caspases with caspase-3 as the effector enzyme and the Bcl-2 group of proteins , of which Bcl-2 and Bcl-X L suppress cell death and Bax induces it .	Protein families that control apoptosis include the caspases with caspase-3 as the effector enzyme and the Bcl-2 group of proteins, of which Bcl-2 and Bcl-X L suppress cell death and Bax induces it.	23	32	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	23	24	31	32
Moreover , progesterone has been shown to promote BCL2 expression and decrease BAX to BCL2 ratio in bovine luteal cells [ XREF_BIBR ] .	Moreover, progesterone has been shown to promote BCL2 expression and decrease BAX to BCL2 ratio in bovine luteal cells [XREF_BIBR].	2	13	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	progesterone has been shown to promote BCL2 expression	bcl2	BAX	BAX	bax	8	9	12	13
Bcl-2 is associated with the outer mitochondrial membrane of viable cells and prevents Bax from perforating the outer mitochondrial membrane , causing cytochrome c to leak out XREF_BIBR - XREF_BIBR .	Bcl-2 is associated with the outer mitochondrial membrane of viable cells and prevents Bax from perforating the outer mitochondrial membrane, causing cytochrome c to leak out XREF_BIBR - XREF_BIBR.	0	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	13	14
On the one hand , the antiapoptotic protein , Bcl-2 can suppress apoptosis by directly binding the pro apoptotic effector proteins Bax , Bak and Bim via the BH3 binding groove .	On the one hand, the antiapoptotic protein, Bcl-2 can suppress apoptosis by directly binding the pro apoptotic effector proteins Bax, Bak and Bim via the BH3 binding groove.	9	30	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	21	22
By contrast , following hypoxic preconditioning , increased levels of Bcl-2 lowered the Bcl-2 and Bax ratio , inhibiting cell apoptosis .	By contrast, following hypoxic preconditioning, increased levels of Bcl-2 lowered the Bcl-2 and Bax ratio, inhibiting cell apoptosis.	8	16	lowered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	levels of Bcl-2	bcl-2	Bax	Bax	bax	10	11	15	16
EGb761 and alpha-tocopherol treatment reversed the increase in VCMs , decreased Bax expression , increased Bcl-2 expression , and decreased the Bax and Bcl -2 ratio .	EGb761 and alpha-tocopherol treatment reversed the increase in VCMs, decreased Bax expression, increased Bcl-2 expression, and decreased the Bax and Bcl -2 ratio.	0	25	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	EGb761 and alpha-tocopherol treatment reversed the increase in VCMs, decreased Bax expression, increased Bcl-2 expression	bcl-2	Bax	Bax	bax	15	16	21	22
In the most parsimonious case , viral Bcl-2 proteins could simply antagonize the pan-pro-survival antagonist Bim preventing activation of Bax or Bak .	In the most parsimonious case, viral Bcl-2 proteins could simply antagonize the pan-pro-survival antagonist Bim preventing activation of Bax or Bak.	7	21	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	19	20
Angiogenin efficiently up-regulated the p53 target genes Bcl-2 ( anti-apoptotic protein ) , that protects against apoptosis , and down-regulated Bax and p21 ( pro apoptotic proteins ) , while silencing angiogenin reversed this phenomenon .	Angiogenin efficiently up-regulated the p53 target genes Bcl-2 (anti-apoptotic protein), that protects against apoptosis, and down-regulated Bax and p21 (pro apoptotic proteins), while silencing angiogenin reversed this phenomenon.	2	26	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	20	21
Bax and Bak are inhibited by prosurvival Bcl-2 proteins , either via direct interactions or by sequestering ' activator ' BH3-only proteins and thereby preventing their interaction with Bax and Bak .	Bax and Bak are inhibited by prosurvival Bcl-2 proteins, either via direct interactions or by sequestering ' activator ' BH3-only proteins and thereby preventing their interaction with Bax and Bak.	0	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	0	1
Brenner reported that Bax can combine with ANT and form pores in an artificial lipid bilayer in vitro , although the combination of Bcl-2 and ANT can inhibit the formation of Bax channels , thus further inhibiting changes in mitochondrial membrane permeability [ XREF_BIBR ] .	Brenner reported that Bax can combine with ANT and form pores in an artificial lipid bilayer in vitro, although the combination of Bcl-2 and ANT can inhibit the formation of Bax channels, thus further inhibiting changes in mitochondrial membrane permeability [XREF_BIBR].	21	32	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	23	24	31	32
Bcl-2 was down-regulated 30-75 % and the Bax : Bcl-2 ratio elevated in apoptotic PCa cell lines regardless of their androgen dependency or p53 status .	Bcl-2 was down-regulated 30-75% and the Bax : Bcl-2 ratio elevated in apoptotic PCa cell lines regardless of their androgen dependency or p53 status.	0	8	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	7	8
Knockdown of Bim ( but not Puma or Noxa ) by shRNA or ectopic overexpression of Bcl-2 , Bcl-x ( L ) , or Mcl-1 diminished Bax and Bak activation and apoptosis .	Knockdown of Bim (but not Puma or Noxa) by shRNA or ectopic overexpression of Bcl-2, Bcl-x (L), or Mcl-1 diminished Bax and Bak activation and apoptosis.	14	29	diminished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	overexpression of Bcl-2	bcl-2	Bax	Bax	bax	16	17	26	27
Bax , which is inactivated by Bcl-2 , can cause a disruption of the mitochondrial membrane potential , leading to the release of pro apoptotic factors , such as cytochrome c , and the subsequent activation of caspase-9 and caspase-3 .	Bax, which is inactivated by Bcl-2, can cause a disruption of the mitochondrial membrane potential, leading to the release of pro apoptotic factors, such as cytochrome c, and the subsequent activation of caspase-9 and caspase-3.	0	9	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	0	1
In contrast , Bcl-2 can inhibit Bax activation and attenuate apoptosis .	In contrast, Bcl-2 can inhibit Bax activation and attenuate apoptosis.	3	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	6	7
This triangular model further explains that antiapoptotic BCL-2 proteins , of which BCL-x L is the best characterized , protect cells by binding and inhibiting the direct activator BH3-only proteins and the multi-BH proapoptotic proteins BAX and BAK .	This triangular model further explains that antiapoptotic BCL-2 proteins, of which BCL-x L is the best characterized, protect cells by binding and inhibiting the direct activator BH3-only proteins and the multi-BH proapoptotic proteins BAX and BAK.	7	37	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	7	8	35	36
As in mammals , Bcl-2 appears to inactivate Bax by forming mixed dimers : a mutant of Bcl-2 that fails to heterodimerize with Bax does not rescue yeast cell growth .	As in mammals, Bcl-2 appears to inactivate Bax by forming mixed dimers : a mutant of Bcl-2 that fails to heterodimerize with Bax does not rescue yeast cell growth.	4	9	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	8	9
In healthy cells , Bax and Bak activation is strictly suppressed by the pro survival members of the Bcl-2 family : Bcl-2 , Bcl-xL , Mcl-1 , A1 and Bcl-w .	In healthy cells, Bax and Bak activation is strictly suppressed by the pro survival members of the Bcl-2 family : Bcl-2, Bcl-xL, Mcl-1, A1 and Bcl-w.	4	19	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	18	19	4	5
Curcumin inhibited the expressions of Bcl-2 , Bcl-X L , survivin and XIAP , and induced the expressions Bax , Bak , PUMA , Bim , and Noxa and death receptors ( TRAIL-R1 and DR4 and TRAIL-R2 and DR5 ) in both cell lines .	Curcumin inhibited the expressions of Bcl-2, Bcl-X L, survivin and XIAP, and induced the expressions Bax, Bak, PUMA, Bim, and Noxa and death receptors (TRAIL-R1 and DR4 and TRAIL-R2 and DR5) in both cell lines.	0	30	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Curcumin inhibited the expressions of Bcl-2	bcl-2	Bax	Bax	bax	5	6	18	19
Paeoniflorin significantly decreased the expression of the EP2 receptor and Bcl-2 and increased Bax and caspase-3 activation in HepG2 and SMMC-7721 cells on addition of butaprost .	Paeoniflorin significantly decreased the expression of the EP2 receptor and Bcl-2 and increased Bax and caspase-3 activation in HepG2 and SMMC-7721 cells on addition of butaprost.	0	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Paeoniflorin significantly decreased the expression of the EP2 receptor and Bcl-2	bcl-2	Bax	Bax	bax	10	11	13	14
[ XREF_BIBR ] Studies have shown that an increase in Bcl-2 levels limits the effects of Bax and prevents the mitochondrial release of cytochrome c , thereby inhibiting the activation of caspase cascade and apoptosis .	[XREF_BIBR] Studies have shown that an increase in Bcl-2 levels limits the effects of Bax and prevents the mitochondrial release of cytochrome c, thereby inhibiting the activation of caspase cascade and apoptosis.	10	17	limits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 levels	bcl-2	Bax	Bax	bax	10	11	16	17
Western blotting analysis indicated that dioscin suppressed the expression of Bcl-2 , Bcl-w , Bcl-xL , but elevated the expression of Bim and Bax in CL97 and H1975 cells when compared both cells without dioscin treatment .	Western blotting analysis indicated that dioscin suppressed the expression of Bcl-2, Bcl-w, Bcl-xL, but elevated the expression of Bim and Bax in CL97 and H1975 cells when compared both cells without dioscin treatment.	5	28	elevated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	dioscin suppressed the expression of Bcl-2	bcl-2	Bax	Bax	bax	10	11	23	24
As predicted , Bax activation was effectively blocked by Bcl-2 in 2DG treated TCLs ( XREF_FIG ) .	As predicted, Bax activation was effectively blocked by Bcl-2 in 2DG treated TCLs (XREF_FIG).	3	10	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	3	4
Enhancement of Bcl-2 expression by alpha-MSH treatment prevented the Bax and TGF-beta protein increase and induced Bcl-2 protein increase , together with reduction of apoptosis , inflammation , and tubulointerstitial fibrosis XREF_BIBR .	Enhancement of Bcl-2 expression by alpha-MSH treatment prevented the Bax and TGF-beta protein increase and induced Bcl-2 protein increase, together with reduction of apoptosis, inflammation, and tubulointerstitial fibrosis XREF_BIBR.	0	13	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Enhancement of Bcl-2 expression by alpha-MSH	bcl-2	Bax	Bax	bax	2	3	9	10
Bcl-2 can limit the proapoptotic effects of Bax .	Bcl-2 can limit the proapoptotic effects of Bax.	0	8	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	7	8
It is known that Bcl-xL and Mcl-1 , but not Bcl-2 or Bcl-w , can directly sequester Bax and Bak , in particular Bak on the mitochondria [ XREF_BIBR ] .	It is known that Bcl-xL and Mcl-1, but not Bcl-2 or Bcl-w, can directly sequester Bax and Bak, in particular Bak on the mitochondria [XREF_BIBR].	4	19	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	10	11	17	18
In addition , Que significantly alleviated H/R induced the phosphorylation of JNK and p38 , which further increased Bcl-2 expression and inhibited the activation of Bax and caspase-3 directly or indirectly .	In addition, Que significantly alleviated H/R induced the phosphorylation of JNK and p38, which further increased Bcl-2 expression and inhibited the activation of Bax and caspase-3 directly or indirectly.	6	27	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	H/R induced the phosphorylation of JNK and p38, which further increased Bcl-2 expression	bcl-2	Bax	Bax	bax	18	19	25	26
In addition , TMZ augmented Bcl-2 protein expression and diminished Bax protein expression , the Bax and Bcl -2 rate , and cleaved caspase-3 level .	In addition, TMZ augmented Bcl-2 protein expression and diminished Bax protein expression, the Bax and Bcl -2 rate, and cleaved caspase-3 level.	3	13	diminished	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Bcl-2	TMZ augmented Bcl-2 protein expression	bcl-2	Bax	Bax protein expression	bax	5	6	10	11
Increased APE1 and Ref-1 , Bcl-2 , reduced p53 , caspase-3 , Bax , and Cyt-c in the total protein .	Increased APE1/Ref-1, Bcl-2, reduced p53, caspase-3, Bax, and Cyt-c in the total protein.	1	13	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	12	13
In this model , the negation of BCL-2 proteins is sufficient to induce BAX and BAK activation .	In this model, the negation of BCL-2 proteins is sufficient to induce BAX and BAK activation.	7	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	7	8	13	14
There are already two suggested mechanisms for BAX and BAK activation by Bim : 1 ) Bim directly binds to and activation BAX ; and/or 2 ) Bim binds to anti-apoptotic Bcl-2 family proteins such as Bcl-2 so that Bcl-2 can not inhibit BAX anymore , thereby inducing BAX activation XREF_BIBR .	There are already two suggested mechanisms for BAX and BAK activation by Bim : 1) Bim directly binds to and activation BAX; and/or 2) Bim binds to anti-apoptotic Bcl-2 family proteins such as Bcl-2 so that Bcl-2 can not inhibit BAX anymore, thereby inducing BAX activation XREF_BIBR.	39	44	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	39	40	43	44
Bcl-2 inhibited the membrane permeabilizing activity of peptide activated Bax .	Bcl-2 inhibited the membrane permeabilizing activity of peptide activated Bax.	0	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	9	10
Furthermore , administration of L-THP enhanced the expression of Bcl-2 and attenuated the content of Bax , cleaved caspase-3 , and PARP .	Furthermore, administration of L-THP enhanced the expression of Bcl-2 and attenuated the content of Bax, cleaved caspase-3, and PARP.	4	16	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	L-THP enhanced the expression of Bcl-2	bcl-2	Bax	Bax	bax	9	10	15	16
Also , Bcl-2 overexpression abolished JNJ-26481585 and Doxorubicin stimulated activation of Bax and Bak ( XREF_SUPPLEMENTARY ) .	Also, Bcl-2 overexpression abolished JNJ-26481585 and Doxorubicin-stimulated activation of Bax and Bak (XREF_SUPPLEMENTARY).	2	15	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	Bax	Bax	bax	2	3	11	12
Bax , as the key molecule for inducing the mitochondrial apoptosis pathway , can be blocked by Bcl-2 .	Bax, as the key molecule for inducing the mitochondrial apoptosis pathway, can be blocked by Bcl-2.	0	18	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	17	18	0	1
Western blotting analyses suggested that levocarnitine pretreatment increased plasma protein levels of Bcl-2 , reduced Bax , and attenuated cytochrome C leakage from the mitochondria in the cells .	Western blotting analyses suggested that levocarnitine pretreatment increased plasma protein levels of Bcl-2, reduced Bax, and attenuated cytochrome C leakage from the mitochondria in the cells.	5	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	levocarnitine pretreatment increased plasma protein levels of Bcl-2	bcl-2	Bax	Bax	bax	12	13	15	16
Generally , the prosurvival Bcl-2 subfamily members inhibit the activation of Bax and Bak , while the BH3-only subfamily members activate the Bax subfamily members .	Generally, the prosurvival Bcl-2 subfamily members inhibit the activation of Bax and Bak, while the BH3-only subfamily members activate the Bax subfamily members.	4	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	11	12
SS induced Bax promotes apoptosis by competing with Bcl-2 protein , while the presence of Bcl-2 inhibits the activation of Bax following the death signal .	SS induced Bax promotes apoptosis by competing with Bcl-2 protein, while the presence of Bcl-2 inhibits the activation of Bax following the death signal.	13	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	15	16	20	21
One suggestion is that Bcl-2 blocks apoptosis by directly binding to and sequestering Bax XREF_BIBR .	One suggestion is that Bcl-2 blocks apoptosis by directly binding to and sequestering Bax XREF_BIBR.	4	14	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	13	14
In an immunohistochemical review of odontogenic ghost cell carcinoma by Kim , [ XREF_BIBR ] et al ., a relation was observed between the ghost cells and apoptosis using apoptosis related proteins such as Bcl-2 , Bcl-X L which prevent apoptotic cell death and Bax which induces apoptosis .	In an immunohistochemical review of odontogenic ghost cell carcinoma by Kim, [XREF_BIBR] et al., a relation was observed between the ghost cells and apoptosis using apoptosis related proteins such as Bcl-2, Bcl-X L which prevent apoptotic cell death and Bax which induces apoptosis.	31	46	prevent	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	34	35	44	45
Antagonized by the BH3-only protein , Bcl-2 can be inactivated , which in turn can induce the activation of Bax and Bak , thereby interfering with the functions of the mitochondrial outer membrane 8 .	Antagonized by the BH3-only protein, Bcl-2 can be inactivated, which in turn can induce the activation of Bax and Bak, thereby interfering with the functions of the mitochondrial outer membrane 8.	6	21	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	19	20
Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling ( TUNEL ) revealed that myocardial apoptosis was extensively present in SAP rats , and IMD infusion led to increased expression of the prosurvival factor Bcl-2 , but decreased pro apoptotic factors Bax and caspase-3 .	Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) revealed that myocardial apoptosis was extensively present in SAP rats, and IMD infusion led to increased expression of the prosurvival factor Bcl-2, but decreased pro apoptotic factors Bax and caspase-3.	23	42	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	IMD infusion led to increased expression of the prosurvival factor Bcl-2	bcl-2	Bax	Bax	bax	33	34	40	41
Conversely , in this study the BAX and cytochrome c levels remained unaltered in both the control and treated cultures , while BCL-2 expression was up-regulated in the treated cultures , resulting in a reduced BAX and BCL -2 ratio .	Conversely, in this study the BAX and cytochrome c levels remained unaltered in both the control and treated cultures, while BCL-2 expression was up-regulated in the treated cultures, resulting in a reduced BAX and BCL -2 ratio.	22	39	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2 expression	bcl-2	BAX	BAX	bax	22	23	35	36
Antiapoptotic members of Bcl-2 family , including Bcl-2 , Bcl-xL as well as Mcl-1 inhibit apoptosis by sequestering Bax .	Antiapoptotic members of Bcl-2 family, including Bcl-2, Bcl-xL as well as Mcl-1 inhibit apoptosis by sequestering Bax.	3	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	18	19
The apoptotic population in the cells expressing Bax112-192 was not decreased by co-expression of Bcl-2 or Bcl-XL , while Bcl-2 or Bcl-XL suppressed apoptosis in the cells expressing native Bax .	The apoptotic population in the cells expressing Bax112-192 was not decreased by co-expression of Bcl-2 or Bcl-XL, while Bcl-2 or Bcl-XL suppressed apoptosis in the cells expressing native Bax.	19	30	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	19	20	29	30
Compared with the control group , the expression of Bcl-2 and Bax proteins were up-regulated significantly in Epi-CH group ( P < 0.05 and P < 0.01 , respectively ) , resulting in decreased ratio of Bcl-2 and Bax .	Compared with the control group, the expression of Bcl-2 and Bax proteins were up-regulated significantly in Epi-CH group (P < 0.05 and P < 0.01, respectively), resulting in decreased ratio of Bcl-2 and Bax.	7	39	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	9	10	38	39
Overexpression of BCL-2 or simultaneous knockdown of BAX and BAK significantly rescue BI 6727/VCR induced apoptosis , indicating that engagement of the mitochondrial pathway is critical for BI 6727/VCR mediated apoptosis .	Overexpression of BCL-2 or simultaneous knockdown of BAX and BAK significantly rescue BI 6727/VCR induced apoptosis, indicating that engagement of the mitochondrial pathway is critical for BI 6727/VCR mediated apoptosis.	0	9	knockdown	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BCL-2	Overexpression of BCL-2	bcl-2	BAX	BAX	bax	2	3	7	8
They are reversely correlated during PCD process which means that Bcl-2 antagonizes the effect of Bax and vice verse .	They are reversely correlated during PCD process which means that Bcl-2 antagonizes the effect of Bax and vice verse.	10	18	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	10	11	15	16
In addition , l-theanine significantly increased the mRNA and protein expression of Bcl-2 and decreased the expression of Bax , anti- and pro apoptotic molecules , respectively , compared with levels in the ETEC control group .	In addition, l-theanine significantly increased the mRNA and protein expression of Bcl-2 and decreased the expression of Bax, anti- and pro apoptotic molecules, respectively, compared with levels in the ETEC control group.	3	24	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	l-theanine significantly increased the mRNA and protein expression of Bcl-2	bcl-2	Bax	Bax	bax	12	13	18	19
Furthermore , rottlerin reduced the expression of important anti-apoptotic proteins ( e.g ., survivin , XIAP , Bcl-xL and c-FLIP ) and Bcl-2 phosphorylation , and activated the pro apoptotic protein Bax .	Furthermore, rottlerin reduced the expression of important anti-apoptotic proteins (e.g., survivin, XIAP, Bcl-xL and c-FLIP) and Bcl-2 phosphorylation, and activated the pro apoptotic protein Bax.	2	32	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	rottlerin reduced the expression of important anti-apoptotic proteins (e.g., survivin, XIAP, Bcl-xL and c-FLIP) and Bcl-2	bcl-2	Bax	Bax	bax	22	23	31	32
Using both an immunohistochemical and an immunoblot approach , we found that IL-1 increased the expression of Bcl-2 and decreased that of Bax , while having no effect on the expression of Bclx ( L ) , Fas and CD40 .	Using both an immunohistochemical and an immunoblot approach, we found that IL-1 increased the expression of Bcl-2 and decreased that of Bax, while having no effect on the expression of Bclx (L), Fas and CD40.	12	23	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	IL-1 increased the expression of Bcl-2	bcl-2	Bax	Bax	bax	17	18	22	23
The co-treatment of vorinostat and QC reduced the expression of Bcl-2 and Mcl-1 , and increased that of Bax , as compared to the respective levels in the single treatment group .	The co-treatment of vorinostat and QC reduced the expression of Bcl-2 and Mcl-1, and increased that of Bax, as compared to the respective levels in the single treatment group.	3	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	vorinostat and QC reduced the expression of Bcl-2	bcl-2	Bax	Bax	bax	10	11	18	19
Likewise , adenovirus mediated gene delivery of an amino-terminal truncated version of BAX ( DeltaN BAX : corresponding to amino acid 112-192 of full-length BAX ) , that can not be suppressed by the anti-apoptotic BCL-2 family members has been generated .	Likewise, adenovirus mediated gene delivery of an amino-terminal truncated version of BAX (DeltaN BAX : corresponding to amino acid 112-192 of full-length BAX), that can not be suppressed by the anti-apoptotic BCL-2 family members has been generated.	10	40	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	35	36	12	13
Two of the control enzymes are BCL2 , which inhibits apoptosis and BAX , which induces apoptosis and overrides BCL2 inhibition .	Two of the control enzymes are BCL2, which inhibits apoptosis and BAX, which induces apoptosis and overrides BCL2 inhibition.	4	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	6	7	12	13
This increase in the pro survival Bcl-2 proteins may inhibit the activity of either Bak or Bax and stabilize the mitochondrial membrane transition pore ( mPTP ) and reduce cytochrome C release , which is one of the novel findings of the study as this mechanism may partially explain the strong anti-apoptotic effect of lowering GRK2 .	This increase in the pro survival Bcl-2 proteins may inhibit the activity of either Bak or Bax and stabilize the mitochondrial membrane transition pore (mPTP) and reduce cytochrome C release, which is one of the novel findings of the study as this mechanism may partially explain the strong anti-apoptotic effect of lowering GRK2.	6	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	16	17
XREF_BIBR Bcl-2 is one of the key genes known to downregulate Bax and p53 , and therefore has the potency to inhibit this apoptotic pathway .	XREF_BIBR Bcl-2 is one of the key genes known to downregulate Bax and p53, and therefore has the potency to inhibit this apoptotic pathway.	0	17	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	11	12
The decrease of Bcl-2 protein level and binding by nonphosphorylated Bad caused the release of Bax , which was translocated into the mitochondria , where it activated the mitochondrial apoptosis pathway .	The decrease of Bcl-2 protein level and binding by nonphosphorylated Bad caused the release of Bax, which was translocated into the mitochondria, where it activated the mitochondrial apoptosis pathway.	1	19	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	decrease of Bcl-2 protein level and binding by nonphosphorylated Bad	bcl-2	Bax	Bax	bax	3	4	15	16
However , the gamma-herpevirus 68 Bcl-2 homolog M11 does not inhibit Bax and Bak , but instead interferes with autophay via binding to Beclin-1 .	However, the gamma-herpevirus 68 Bcl-2 homolog M11 does not inhibit Bax and Bak, but instead interferes with autophay via binding to Beclin-1.	5	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	11	12
Western blot analysis revealed that Hyp increased the expression of Bcl-2 but decreased that of Bax .	Western blot analysis revealed that Hyp increased the expression of Bcl-2 but decreased that of Bax.	5	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Hyp increased the expression of Bcl-2	bcl-2	Bax	Bax	bax	10	11	15	16
The indirect activation model proposes that anti-apoptotic BCL-2 members negate the activity of BAX or BAK in healthy cells .	The indirect activation model proposes that anti-apoptotic BCL-2 members negate the activity of BAX or BAK in healthy cells.	7	15	negate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	7	8	13	14
Although the anti-apoptotic Bcl-2 , Bcl-x L , Mcl-1 and others may inhibit Bax and Bak mediated mitochondrial permeabilization directly via BH3 domain and hydrophobic groove interactions , there continues to be discussion over the importance of this interaction during actual apoptotic events .	Although the anti-apoptotic Bcl-2, Bcl-x L, Mcl-1 and others may inhibit Bax and Bak mediated mitochondrial permeabilization directly via BH3 domain and hydrophobic groove interactions, there continues to be discussion over the importance of this interaction during actual apoptotic events.	1	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	13	14
In the indirect activation scenario , anti-apoptotic Bcl-2 family proteins antagonise active Bax or Bak proteins .	In the indirect activation scenario, anti-apoptotic Bcl-2 family proteins antagonise active Bax or Bak proteins.	7	15	antagonise	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	12	13
Based on the results of Western blotting ( XREF_FIG A ) and flow cytometry , MA also promoted the expression of Fas and FasL and active form of caspase-8 ; MA inhibited the protein level of Bcl-2 but promoted the Bax , and both proteins led to the release of cytochrome c from mitochondria and activation of caspase-9 and -3 , PARP cleavage , resulting in the apoptotic death which is mediated through the mitochondrial pathway .	Based on the results of Western blotting (XREF_FIG A) and flow cytometry, MA also promoted the expression of Fas and FasL and active form of caspase-8; MA inhibited the protein level of Bcl-2 but promoted the Bax, and both proteins led to the release of cytochrome c from mitochondria and activation of caspase-9 and -3, PARP cleavage, resulting in the apoptotic death which is mediated through the mitochondrial pathway.	30	41	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	MA inhibited the protein level of Bcl-2	bcl-2	Bax	Bax	bax	36	37	40	41
Bcl-2 and p53 inhibited the interaction between full length activated Bax and nucleophosmin .	Bcl-2 and p53 inhibited the interaction between full length activated Bax and nucleophosmin.	0	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	10	11
Bcl-2 regulates the release of cytochrome c by the mitochondrial channel VDAC and inhibits proapoptotic Bax signaling .	Bcl-2 regulates the release of cytochrome c by the mitochondrial channel VDAC and inhibits proapoptotic Bax signaling.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	15	16
It is generally held that through this process , the antiapoptotic proteins Bcl-2 and Bcl-xL prevent Bax and Bak from forming pores in the outer mitochondrial membrane that release factors such as cytochrome c [ XREF_BIBR , XREF_BIBR ] .	It is generally held that through this process, the antiapoptotic proteins Bcl-2 and Bcl-xL prevent Bax and Bak from forming pores in the outer mitochondrial membrane that release factors such as cytochrome c [XREF_BIBR, XREF_BIBR].	9	18	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	12	13	16	17
In addition , melatonin increased Bcl-2 expression and decreased Bax , Caspase-3 , and cleaved Caspase-3 levels in response to MI/R .	In addition, melatonin increased Bcl-2 expression and decreased Bax, Caspase-3, and cleaved Caspase-3 levels in response to MI/R.	3	11	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	melatonin increased Bcl-2 expression	bcl-2	Bax	Bax	bax	5	6	9	10
Bcl 2 binds to and inactivates Bax function , but whether or not Bcl 2 phosphorylation affects its interaction with Bax is still controversial .	Bcl 2 binds to and inactivates Bax function, but whether or not Bcl 2 phosphorylation affects its interaction with Bax is still controversial.	0	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl 2	Bcl 2	Bcl 2	Bax	Bax	Bax	0	2	6	7
BCL-2 may be able to partly restrain Bak at these high , non physiological concentrations , as well as inhibit normal targets Bax and Bad , which also influence platelet life span , XREF_BIBR , XREF_BIBR albeit not to nearly the same extent as loss of Bak .	BCL-2 may be able to partly restrain Bak at these high, non physiological concentrations, as well as inhibit normal targets Bax and Bad, which also influence platelet life span, XREF_BIBR, XREF_BIBR albeit not to nearly the same extent as loss of Bak.	0	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	Bax	Bax	Bax	0	1	22	23
BCL-2 BH4 SAHB C likewise inhibited 6A7 mediated immunoprecipitation of BAX ( XREF_SUPPLEMENTARY ) .	BCL-2 BH4 SAHB C likewise inhibited 6A7 mediated immunoprecipitation of BAX (XREF_SUPPLEMENTARY).	0	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	0	1	10	11
Meanwhile , AQP9 knockdown downregulated bcl-2 expression and induced activation of bax and caspase-3 , suggesting that AQP9 knockdown reduced proliferation and increased apoptosis which contributed to its suppressive effect on tumor growth .	Meanwhile, AQP9 knockdown downregulated bcl-2 expression and induced activation of bax and caspase-3, suggesting that AQP9 knockdown reduced proliferation and increased apoptosis which contributed to its suppressive effect on tumor growth.	2	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	AQP9 knockdown downregulated bcl-2 expression	bcl-2	bax	bax	bax	5	6	11	12
In addition , increased Bcl-2 expression inhibits apoptosis by forming Bcl-2 and Bax dimers [ XREF_BIBR ] .	In addition, increased Bcl-2 expression inhibits apoptosis by forming Bcl-2 and Bax dimers [XREF_BIBR].	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	Bax	Bax	bax	4	5	12	13
Although Bcl-2 was able to inhibit Bax induced photoreceptor cell death , the coexpression of Bcl-2 and Bax in photoreceptors of mice with adRP did not enhance the protective effect against photoreceptor cell death exerted by Bcl-2 alone .	Although Bcl-2 was able to inhibit Bax induced photoreceptor cell death, the coexpression of Bcl-2 and Bax in photoreceptors of mice with adRP did not enhance the protective effect against photoreceptor cell death exerted by Bcl-2 alone.	1	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	6	7
Anti-apoptotic Bcl2 family members usually inhibit the pro apoptotic activity of Bax in healthy cells .	Anti-apoptotic Bcl2 family members usually inhibit the pro apoptotic activity of Bax in healthy cells.	1	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	1	2	11	12
The induction of tumor cell apoptosis is correlated with the increasing expression of Bax and decreasing expression of Bcl-2 and Bcl-xL genes , then facilitated the releasing of cytochrome C and Smac/DIABLO from mitochondria to cytoplasm and increasing the expression of caspase-9 , eventually , resulted in apoptosis .	The induction of tumor cell apoptosis is correlated with the increasing expression of Bax and decreasing expression of Bcl-2 and Bcl-xL genes, then facilitated the releasing of cytochrome C and Smac/DIABLO from mitochondria to cytoplasm and increasing the expression of caspase-9, eventually, resulted in apoptosis.	13	21	decreasing	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	18	19	13	14
Bcl-2 as well as other anti-apoptotic members of the Bcl-2 family , such as Bcl-Xl , can inhibit the multidomain pro apoptotic Bcl-2-family members Bax and Bak that lack the BH4 domain .	Bcl-2 as well as other anti-apoptotic members of the Bcl-2 family, such as Bcl-Xl, can inhibit the multidomain pro apoptotic Bcl-2-family members Bax and Bak that lack the BH4 domain.	0	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	24	25
The BH3-only proteins BAX and BAK are directly sequestered and repressed by the antiapoptotic BCL-2 proteins .	The BH3-only proteins BAX and BAK are directly sequestered and repressed by the antiapoptotic BCL-2 proteins.	0	15	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	14	15	3	4
Hyperoside effectively increased the relative mRNA expression levels of Bcl-2 and decreased those of Bax .	Hyperoside effectively increased the relative mRNA expression levels of Bcl-2 and decreased those of Bax.	0	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Hyperoside effectively increased the relative mRNA expression levels of Bcl-2	bcl-2	Bax	Bax	bax	9	10	14	15
AA post-treatments at 40 and 80 mg per kg BW per day enhanced Bcl-2 expression , and lowered Bax , apoptosis inducing factor and caspase-3 expression in the striatum .	AA post-treatments at 40 and 80 mg per kg BW per day enhanced Bcl-2 expression, and lowered Bax, apoptosis inducing factor and caspase-3 expression in the striatum.	0	20	lowered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	AA post-treatments at 40 and 80 mg per kg BW per day enhanced Bcl-2 expression	bcl-2	Bax	Bax	bax	13	14	18	19
Then we asked whether anti-apoptotic Bcl-2 and Bcl-xL antagonizes the ability of Bax to reduce autophagy .	Then we asked whether anti-apoptotic Bcl-2 and Bcl-xL antagonizes the ability of Bax to reduce autophagy.	4	13	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	12	13
Here we show that Bcl-2 sequesters pro apoptotic Bax into mitochondria in an inactive form after melatonin treatment , thus reducing cell propensity to apoptosis .	Here we show that Bcl-2 sequesters pro apoptotic Bax into mitochondria in an inactive form after melatonin treatment, thus reducing cell propensity to apoptosis.	4	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	8	9
Moreover , the fact that BCL-2 was not co-eluted with the higher ordered BAX and BAK oligomers suggest that BCL-2 is unlikely to inhibit activated BAX and BAK directly ( XREF_SUPPLEMENTARY ) .	Moreover, the fact that BCL-2 was not co-eluted with the higher ordered BAX and BAK oligomers suggest that BCL-2 is unlikely to inhibit activated BAX and BAK directly (XREF_SUPPLEMENTARY).	19	30	inhibit activated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	19	20	25	26
BCL-2 BH4 SAHB A , but not BCL-2 BH4 SAHB A L23A , dose-responsively inhibited 6A7 immunoprecipitation of BAX ( XREF_FIG and XREF_SUPPLEMENTARY ) .	BCL-2 BH4 SAHB A, but not BCL-2 BH4 SAHB A L23A, dose-responsively inhibited 6A7 immunoprecipitation of BAX (XREF_FIG and XREF_SUPPLEMENTARY).	0	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	0	1	18	19
In addition , quercetin pretreatment significantly increased Bcl-2 expression , and reduced Bax , cleaved caspase-3 and p53 expressions .	In addition, quercetin pretreatment significantly increased Bcl-2 expression, and reduced Bax, cleaved caspase-3 and p53 expressions.	3	14	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	quercetin pretreatment significantly increased Bcl-2 expression	bcl-2	Bax	Bax	bax	7	8	12	13
Anti-apoptotic members of the Bcl-2 family ( A1 , Bcl-2 , Bcl-w , Bcl-xL and Mcl-1 ) directly inhibit the pro apoptotic Bcl-2 proteins BAK and BAX .	Anti-apoptotic members of the Bcl-2 family (A1, Bcl-2, Bcl-w, Bcl-xL and Mcl-1) directly inhibit the pro apoptotic Bcl-2 proteins BAK and BAX.	4	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	4	5	26	27
Other researchers support an indirect activation model , in which BH3 proteins neutralize pro life molecules such as Bcl-2 and Bcl-x L , which normally suppress Bax and Bak .	Other researchers support an indirect activation model, in which BH3 proteins neutralize pro life molecules such as Bcl-2 and Bcl-x L, which normally suppress Bax and Bak.	18	28	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	18	19	26	27
The peroxynitrite generator SIN-1 promoted apoptosis in monocytes based on oligonucleosomal DNA fragmentation , caspase-3 and -9 activation , Bcl-2 depletion and accumulation of Bax and p53 proteins .	The peroxynitrite generator SIN-1 promoted apoptosis in monocytes based on oligonucleosomal DNA fragmentation, caspase-3 and -9 activation, Bcl-2 depletion and accumulation of Bax and p53 proteins.	19	27	depletion	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	19	20	24	25
Galangin treatment prior to UVB exposure resulted up-regulation of Bcl-2 proteins whereas down-regulation of Bax proteins .	Galangin treatment prior to UVB exposure resulted up-regulation of Bcl-2 proteins whereas down-regulation of Bax proteins.	9	15	down-regulation	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	14	15
A tumor suppressor protein p53 is activated as a response to cellular lesions such as gamma-ray-induced DNA damage , and activated p53 induces apoptotic factors such as Bax whose function is suppressed by Bcl-2 .	A tumor suppressor protein p53 is activated as a response to cellular lesions such as gamma-ray-induced DNA damage, and activated p53 induces apoptotic factors such as Bax whose function is suppressed by Bcl-2.	24	34	suppressed	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	33	34	27	28
Bax and Bak lethality was suppressed by coexpression of Bcl-2 family members that are anti-apoptotic in vertebrates , namely Bcl-xL , Bcl-2 , Mcl-1 , and A1 .	Bax and Bak lethality was suppressed by coexpression of Bcl-2 family members that are anti-apoptotic in vertebrates, namely Bcl-xL, Bcl-2, Mcl-1, and A1.	0	11	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	coexpression of Bcl-2	bcl-2	Bax	Bax	bax	9	10	0	1
qRT-PCR indicated that the relative mRNA level of Bax increased , while that of Bcl-2 decreased , resulting in a change in the Bax and Bcl -2 ratio , which subsequently activated the mitochondrial pathway ( XREF_FIG ) .	qRT-PCR indicated that the relative mRNA level of Bax increased, while that of Bcl-2 decreased, resulting in a change in the Bax and Bcl -2 ratio, which subsequently activated the mitochondrial pathway (XREF_FIG).	12	27	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	14	15	23	24
A BCL-2 BH4 domain helix , which suppresses BAX activation by engaging a groove formed by alpha1 , alpha1-alpha2 loop , and alpha2 and alpha3 and alpha5 and alpha6 hairpins in the immediate vicinity of the vMIA binding site 7 ( XREF_FIG ) , also competes with BIF-44 for BAX interaction , as assessed by STD NMR ( XREF_SUPPLEMENTARY ) .	A BCL-2 BH4 domain helix, which suppresses BAX activation by engaging a groove formed by alpha1, alpha1-alpha2 loop, and alpha2 and alpha3 and alpha5 and alpha6 hairpins in the immediate vicinity of the vMIA binding site 7 (XREF_FIG), also competes with BIF-44 for BAX interaction, as assessed by STD NMR (XREF_SUPPLEMENTARY).	1	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	1	2	8	9
In platelets , it was long suggested that the Bcl-2 family of pro survival proteins was required to suppress the pro apoptotic signals of BAK and BAX [ XREF_BIBR ] .	In platelets, it was long suggested that the Bcl-2 family of pro survival proteins was required to suppress the pro apoptotic signals of BAK and BAX [XREF_BIBR].	9	28	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	9	10	26	27
Furthermore , anti-apoptotic Bcl-2 proteins such as Bcl-X L and Mcl-1 can abrogate Bax dependent hyperoxic cell death [ XREF_BIBR - XREF_BIBR ] .	Furthermore, anti-apoptotic Bcl-2 proteins such as Bcl-X L and Mcl-1 can abrogate Bax dependent hyperoxic cell death [XREF_BIBR - XREF_BIBR].	3	17	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	13	14
All active plant extracts up-regulated Bax and Smac/DIABLO , down-regulated Bcl-2 ( P < 0.05 ) .	All active plant extracts up-regulated Bax and Smac/DIABLO, down-regulated Bcl-2 (P < 0.05).	4	12	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	10	11	5	6
To test the possibility that GFP-Bax localization to organelles is limited by the endogenous level of either Bcl-2 or Bcl-X L , vectors expressing either Bcl-2 or Bcl-X L were cotransfected with the GFP-Bax vector .	To test the possibility that GFP-Bax localization to organelles is limited by the endogenous level of either Bcl-2 or Bcl-X L, vectors expressing either Bcl-2 or Bcl-X L were cotransfected with the GFP-Bax vector.	5	20	limited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	level of either Bcl-2	bcl-2	GFP-Bax	GFP-Bax	gfp-bax	17	18	5	6
In healthy cells , the BCL-2 sequesters its proapoptotic counterparts , BAX ( BCL-2-associated X protein ) , BAK ( BCL-2 homologous antagonist and killer ) , and BCL-2 homology domain 3 ( BH3 )-only proteins into inactive complexes .	In healthy cells, the BCL-2 sequesters its proapoptotic counterparts, BAX (BCL-2-associated X protein), BAK (BCL-2 homologous antagonist and killer), and BCL-2 homology domain 3 (BH3)-only proteins into inactive complexes.	4	15	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	5	6	11	12
It is firmly established that their BH3 domains can bind to anti-apoptotic Bcl-2 proteins , which prevents their activating Bax and Bak .	It is firmly established that their BH3 domains can bind to anti-apoptotic Bcl-2 proteins, which prevents their activating Bax and Bak.	12	21	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	12	13	19	20
The gammaHV68 v-Bcl-2 shared with host antiapoptotic Bcl-2 family proteins the capacity to block apoptosis in primary lymphocytes induced by antigen receptor signaling , corticosteroids , and gamma irradiation , and to inhibit Bax toxicity in yeast .	The gammaHV68 v-Bcl-2 shared with host antiapoptotic Bcl-2 family proteins the capacity to block apoptosis in primary lymphocytes induced by antigen receptor signaling, corticosteroids, and gamma irradiation, and to inhibit Bax toxicity in yeast.	7	34	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	33	34
Additionally , silibinin and TRAIL significantly decreased the expressions of antiapoptotic Bcl-2 , IAP-1 , and IAP-2 , and induced the apoptotic Bax .	Additionally, silibinin and TRAIL significantly decreased the expressions of antiapoptotic Bcl-2, IAP-1, and IAP-2, and induced the apoptotic Bax.	2	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	silibinin and TRAIL significantly decreased the expressions of antiapoptotic Bcl-2	bcl-2	Bax	Bax	bax	11	12	22	23
Antiapoptotic members of the Bcl-2 family inhibit membrane permeabilization by sequestering or inhibiting Bax and Bak .	Antiapoptotic members of the Bcl-2 family inhibit membrane permeabilization by sequestering or inhibiting Bax and Bak.	4	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	13	14
Thus , increasing concentrations of 17beta-E 2 in the presence of 5 mM glutamate for 18-20 h , increased the levels of Bcl-2 and decreased the Bax protein in a dose dependent manner .	Thus, increasing concentrations of 17beta-E 2 in the presence of 5 mM glutamate for 18-20 h, increased the levels of Bcl-2 and decreased the Bax protein in a dose dependent manner.	5	27	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	17beta-E 2 in the presence of 5 mM glutamate for 18-20 h, increased the levels of Bcl-2	bcl-2	Bax	Bax	bax	22	23	26	27
Presumably , it is at this site that Bcl-2 and Bcl-xL inhibit apoptosis by sequestering Bax , Bak and direct activator sentinels like Bim .	Presumably, it is at this site that Bcl-2 and Bcl-xL inhibit apoptosis by sequestering Bax, Bak and direct activator sentinels like Bim.	8	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	15	16
The results showed that UDCA alleviated renal ER stress evoked cell death , oxidative stress , renal dysfunction , ROS production , upregulated the expression of Bcl-2 and suppressed Bax in vivo and in vitro .	The results showed that UDCA alleviated renal ER stress evoked cell death, oxidative stress, renal dysfunction, ROS production, upregulated the expression of Bcl-2 and suppressed Bax in vivo and in vitro.	19	34	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	ROS production, upregulated the expression of Bcl-2	bcl-2	Bax	Bax	bax	26	27	29	30
PP upregulated Bax and cleaved PARP , inhibited the phosphorylation of NF-kappaB with cytoplasmic accumulation and on other hand downregulated Bcl-2 , survivin , cyclin D1 , caspase-3 , and FOXM1 .	PP upregulated Bax and cleaved PARP, inhibited the phosphorylation of NF-kappaB with cytoplasmic accumulation and on other hand downregulated Bcl-2, survivin, cyclin D1, caspase-3, and FOXM1.	1	30	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	20	21	2	3
Studies that have addressed the manner in which Bcl-2 inactivates Bax suggest that the levels of Bcl-2 and Bax protein present determine the susceptibility or resistance of a cell to undergo apoptosis .	Studies that have addressed the manner in which Bcl-2 inactivates Bax suggest that the levels of Bcl-2 and Bax protein present determine the susceptibility or resistance of a cell to undergo apoptosis.	8	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	10	11
With the increase in heat stress temperature up to 41 centigrade and 43 centigrade , viability of cells showed a lowering trend , with a burst of ROS , and an increase of mRNA and protein of Bax , and the protein of caspase-3 was significantly increased , the mRNA and protein of Bcl-2 were significantly decreased in a temperature dependent manner .	With the increase in heat stress temperature up to 41 centigrade and 43 centigrade, viability of cells showed a lowering trend, with a burst of ROS, and an increase of mRNA and protein of Bax, and the protein of caspase-3 was significantly increased, the mRNA and protein of Bcl-2 were significantly decreased in a temperature dependent manner.	31	57	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	53	54	37	38
Surprisingly , although the TKO cells were resistant to several apoptotic stimuli , robust apoptosis was induced upon the simultaneous inactivation of Bcl-xL and Mcl-1 , two anti-apoptotic Bcl-2 proteins known to suppress Bax and Bak activation and activity .	Surprisingly, although the TKO cells were resistant to several apoptotic stimuli, robust apoptosis was induced upon the simultaneous inactivation of Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins known to suppress Bax and Bak activation and activity.	28	36	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	28	29	33	34
Transient overexpression of bcl-xL or , to a lesser extent , of bcl-2 , significantly decreased apoptotic death and prevented Bax conformational change .	Transient overexpression of bcl-xL or, to a lesser extent, of bcl-2, significantly decreased apoptotic death and prevented Bax conformational change.	1	22	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	overexpression of bcl-xL or, to a lesser extent, of bcl-2	bcl-2	Bax	Bax	bax	12	13	20	21
These SELN also decreased the expression of anti-apoptotic Bcl-2 , meanwhile increasing that of pro apoptotic Bax proteins .	These SELN also decreased the expression of anti-apoptotic Bcl-2, meanwhile increasing that of pro apoptotic Bax proteins.	1	17	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	SELN also decreased the expression of anti-apoptotic Bcl-2	bcl-2	Bax	Bax	bax	8	9	16	17
Prosurvival members of the Bcl-2 family ( Bcl-2 , Bcl-x L , Bcl-w , Mcl-1 , and A1 ) prevent Bax and Bak activation and thereby preclude MOMP and apoptosis .	Prosurvival members of the Bcl-2 family (Bcl-2, Bcl-x L, Bcl-w, Mcl-1, and A1) prevent Bax and Bak activation and thereby preclude MOMP and apoptosis.	4	23	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	20	21
Activated Bax helps second mitochondria derived activator of caspase ( Smac ) and cytochrome-c release that thereby activate caspase-3 into cleaved caspase-3 leading to cell apoptosis , while antiapoptotic protein Bcl-2 prevents Bax activation by binding and sequestering it letting cancer cells escape from apoptosis [ XREF_BIBR , XREF_BIBR ] .	Activated Bax helps second mitochondria derived activator of caspase (Smac) and cytochrome-c release that thereby activate caspase-3 into cleaved caspase-3 leading to cell apoptosis, while antiapoptotic protein Bcl-2 prevents Bax activation by binding and sequestering it letting cancer cells escape from apoptosis [XREF_BIBR, XREF_BIBR].	28	33	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	30	31	32	33
Furthermore , caspase-3 silencing significantly down-regulated mRNA expression of caspase-3 ( P < 0.01 ) and Bax ( P < 0.01 ) , and up-regulated Bcl-2 mRNA expression ( p < 0.01 ) , thereby increasing the ratio of Bcl-2 and Bax ( P < 0.05 ) .	Furthermore, caspase-3 silencing significantly down-regulated mRNA expression of caspase-3 (P < 0.01) and Bax (P < 0.01), and up-regulated Bcl-2 mRNA expression (p < 0.01), thereby increasing the ratio of Bcl-2 and Bax (P < 0.05).	2	42	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	caspase-3 silencing significantly down-regulated mRNA expression of caspase-3 (P < 0.01) and Bax (P < 0.01), and up-regulated Bcl-2 mRNA expression	bcl-2	Bax	Bax	bax	25	26	41	42
Thus , Bcl-2 functions as an inhibitor of mitochondrial permeabilization by changing conformation in the mitochondrial membrane to bind membrane inserted Bax monomers and prevent productive oligomerization of Bax .	Thus, Bcl-2 functions as an inhibitor of mitochondrial permeabilization by changing conformation in the mitochondrial membrane to bind membrane inserted Bax monomers and prevent productive oligomerization of Bax.	2	29	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	28	29
Moreover , overexpression of Bcl-2 disrupts the proapoptotic proteins of Bax and prevents the mitochondrial release of cyt c , thereby inhibiting the activation of caspases and ultimately apoptosis [ XREF_BIBR , XREF_BIBR ] .	Moreover, overexpression of Bcl-2 disrupts the proapoptotic proteins of Bax and prevents the mitochondrial release of cyt c, thereby inhibiting the activation of caspases and ultimately apoptosis [XREF_BIBR, XREF_BIBR].	2	11	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	Bax	Bax	bax	4	5	10	11
Emodin significantly upregulated the expression of Bcl-2 and downregulated the level of Bax protein in a dose dependent manner .	Emodin significantly upregulated the expression of Bcl-2 and downregulated the level of Bax protein in a dose dependent manner.	0	13	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Emodin significantly upregulated the expression of Bcl-2	bcl-2	Bax	Bax	bax	6	7	12	13
ER36009 markedly decreased PPARgamma , 11beta-HSD1 , and Bcl-2 mRNA levels , and increased Bax mRNA in white adipose tissue , while it upregulated UCP1 and UCP3 mRNAs in brown adipose tissue and UCP3 mRNA in gastrocnemial muscle .	ER36009 markedly decreased PPARgamma, 11beta-HSD1, and Bcl-2 mRNA levels, and increased Bax mRNA in white adipose tissue, while it upregulated UCP1 and UCP3 mRNAs in brown adipose tissue and UCP3 mRNA in gastrocnemial muscle.	0	15	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	ER36009 markedly decreased PPARgamma, 11beta-HSD1, and Bcl-2 mRNA levels	bcl-2	Bax	Bax	bax	8	9	14	15
Targeted deletion of Bax , Bak , Bim , Bid , or Bad does not cause compensatory changes in the expression of other BCL-2 family proteins .	Targeted deletion of Bax, Bak, Bim, Bid, or Bad does not cause compensatory changes in the expression of other BCL-2 family proteins.	0	25	Targeted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	expression of other BCL-2	bcl-2	Bax	Bax	bax	23	24	3	4
Simultaneous overexpression of BCL2 reduced the activation of both BAX and BAK ( XREF_FIG ) .	Simultaneous overexpression of BCL2 reduced the activation of both BAX and BAK (XREF_FIG).	1	11	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	overexpression of BCL2	bcl2	BAX	BAX	bax	3	4	9	10
Therefore , over-expression of Bcl-2 can inactivate Bax suppressing apoptosis XREF_BIBR , Qiu et al ..	Therefore, over-expression of Bcl-2 can inactivate Bax suppressing apoptosis XREF_BIBR, Qiu et al..	2	12	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	over-expression of Bcl-2	bcl-2	Bax	Bax	bax	4	5	7	8
We found that 10 micromol/L celecoxib reduced P-glycoprotein , Bcl-x ( L ) , and Bcl-2 expression , and induced translocation of Bax from cytosol to mitochondria and cytochrome c release into cytosol in MDR positive hepatocellular carcinoma cells .	We found that 10 micromol/L celecoxib reduced P-glycoprotein, Bcl-x (L), and Bcl-2 expression, and induced translocation of Bax from cytosol to mitochondria and cytochrome c release into cytosol in MDR positive hepatocellular carcinoma cells.	5	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	celecoxib reduced P-glycoprotein, Bcl-x (L), and Bcl-2 expression	bcl-2	Bax	Bax	bax	15	16	22	23
Changes in the Bcl-2 and Bax ratio have been reported to be caused by downregulation of Bcl-2 and slight downregulation of Bax [ XREF_BIBR ] , downregulation of Bcl-2 and upregulation of Bax [ XREF_BIBR , XREF_BIBR ] , and downregulation of Bcl-2 with no change in the level of Bax [ XREF_BIBR ] .	Changes in the Bcl-2 and Bax ratio have been reported to be caused by downregulation of Bcl-2 and slight downregulation of Bax [XREF_BIBR], downregulation of Bcl-2 and upregulation of Bax [XREF_BIBR, XREF_BIBR], and downregulation of Bcl-2 with no change in the level of Bax [XREF_BIBR].	16	23	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	16	17	21	22
First , in the MCF-7 cells , apoptosis could be blocked by increased expression of antiapoptotic BCL-2 proteins , preventing BAX and BAK activation through sequestering more activators and sensitizers effectively ( XREF_FIG ) .	First, in the MCF-7 cells, apoptosis could be blocked by increased expression of antiapoptotic BCL-2 proteins, preventing BAX and BAK activation through sequestering more activators and sensitizers effectively (XREF_FIG).	16	23	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	16	17	20	21
The apoptotic activity of Florin extracts in bladder cancer cells appears to be mediated by ( 1 ) increase of cyclin B1/Cdc2 kinase activity , ( 2 ) inhibition of tubulin polymerization , ( 3 ) phosphorylation and degradation of Bcl-2 , an antiapoptotic protein , and ( 4 ) increased production of Bax , an apoptotic protein .	The apoptotic activity of Florin extracts in bladder cancer cells appears to be mediated by (1) increase of cyclin B1/Cdc2 kinase activity, (2) inhibition of tubulin polymerization, (3) phosphorylation and degradation of Bcl-2, an antiapoptotic protein, and (4) increased production of Bax, an apoptotic protein.	4	57	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Florin extracts in bladder cancer cells appears to be mediated by (1) increase of cyclin B1/Cdc2 kinase activity, (2) inhibition of tubulin polymerization, (3) phosphorylation and degradation of Bcl-2	bcl-2	Bax	Bax	bax	40	41	53	54
Bcl2 , Bcl-xL and other anti-apoptotic family members act to inhibit Bax and Bak , and a large number of so called BH3-only proteins function to promote apoptosis by either inhibiting Bcl2 and Bcl-xL or by activating Bax and Bak .	Bcl2, Bcl-xL and other anti-apoptotic family members act to inhibit Bax and Bak, and a large number of so called BH3-only proteins function to promote apoptosis by either inhibiting Bcl2 and Bcl-xL or by activating Bax and Bak.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	0	1	11	12
Cap treatment increased Bcl-2 protein expression and decreased calpain-1 , calpain-2 , Bax and total caspase-3 protein expression compared with the DM group .	Cap treatment increased Bcl-2 protein expression and decreased calpain-1, calpain-2, Bax and total caspase-3 protein expression compared with the DM group.	0	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Cap treatment increased Bcl-2 protein expression	bcl-2	Bax	Bax	bax	3	4	12	13
Functional inactivation of both p21 and bax ( by overexpression of Bcl2 ) , but not either alone , allowed some bypass of p53 induced growth arrest , indicating that multiple transcriptional targets of p53 may mediate its antiproliferative action .	Functional inactivation of both p21 and bax (by overexpression of Bcl2), but not either alone, allowed some bypass of p53 induced growth arrest, indicating that multiple transcriptional targets of p53 may mediate its antiproliferative action.	1	12	inactivation	Negative_activation_syntax_1_noun	Negative_activation	Negative_activation	Bcl2	overexpression of Bcl2	bcl2	bax	bax	bax	11	12	6	7
It has previously been reported that Bcl-2 is able to inhibit Bax .	It has previously been reported that Bcl-2 is able to inhibit Bax.	6	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	11	12
As a member of the anti-apoptotic Bcl-2 family , Bcl-2 can prevent mitochondrial permeability transition of tBID and Bax , and is pivotal for the inhibition of apoptosis .	As a member of the anti-apoptotic Bcl-2 family, Bcl-2 can prevent mitochondrial permeability transition of tBID and Bax, and is pivotal for the inhibition of apoptosis.	9	22	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	18	19
In the present study , treatment with TMP is related to an up-regulated level of the anti-apoptotic protein Bcl-2 and a down-regulated pro apoptotic protein Bax , suggesting that TMP exhibit an inhibitory effect on apoptotic cell death due to spinal cord I/R through modulation of Bcl-2 family .	In the present study, treatment with TMP is related to an up-regulated level of the anti-apoptotic protein Bcl-2 and a down-regulated pro apoptotic protein Bax, suggesting that TMP exhibit an inhibitory effect on apoptotic cell death due to spinal cord I/R through modulation of Bcl-2 family.	9	26	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	18	19	25	26
Supporting this , we show that Bcl-2 and Bcl-xL are putative targets of miR-296-5p ; and anti-apoptotic Bcl-2 proteins are known to inhibit mitochondrial outer membrane permeabilization ( MOMP ) by directly binding and activating pro apoptotic BAX and BAK [ XREF_BIBR , XREF_BIBR ] .	Supporting this, we show that Bcl-2 and Bcl-xL are putative targets of miR-296-5p; and anti-apoptotic Bcl-2 proteins are known to inhibit mitochondrial outer membrane permeabilization (MOMP) by directly binding and activating pro apoptotic BAX and BAK [XREF_BIBR, XREF_BIBR].	17	43	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	17	18	37	38
These data suggest that Bcl-2 does not block GraB by directly binding Bax ( or Bak ) , and consequently that ABT-737 does not promote MOMP by displacing Bax or Bak from Bcl-2 .	These data suggest that Bcl-2 does not block GraB by directly binding Bax (or Bak), and consequently that ABT-737 does not promote MOMP by displacing Bax or Bak from Bcl-2.	4	13	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	12	13
Baicalin also promoted the expression of BCL-2 at the mRNA and protein levels but inhibited BAX and caspase-3 ( CASP-3 ) cleavage .	Baicalin also promoted the expression of BCL-2 at the mRNA and protein levels but inhibited BAX and caspase-3 (CASP-3) cleavage.	0	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	Baicalin also promoted the expression of BCL-2	bcl-2	BAX	BAX	bax	6	7	15	16
[ XREF_BIBR XREF_BIBR ] In this study , the Bcl-2 mRNA was down-regulated as well as Bax and Bak1 up-regulated in pancreatic cancer cells by cyclopamine or RNAi for Gli1 .	[XREF_BIBR XREF_BIBR] In this study, the Bcl-2 mRNA was down-regulated as well as Bax and Bak1 up-regulated in pancreatic cancer cells by cyclopamine or RNAi for Gli1.	9	18	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	16	17
In the alternative neutralization model , prosurvival Bcl-2 proteins sequester active Bax and Bak until forced to interact with BH3-only proteins that then can no longer restrain their proapoptotic potential .	In the alternative neutralization model, prosurvival Bcl-2 proteins sequester active Bax and Bak until forced to interact with BH3-only proteins that then can no longer restrain their proapoptotic potential.	7	13	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	11	12
Over-expression of BCL-2 ( but not BCL-X L ) inhibited formation of ER oligomeric BAX and BAK by GA ..	Over-expression of BCL-2 (but not BCL-X L) inhibited formation of ER oligomeric BAX and BAK by GA..	0	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	Over-expression of BCL-2	bcl-2	BAX	BAX	bax	2	3	14	15
Bcl-2 and Bcl-XL antagonize Bax , thus a shift towards their expression restricts programmed cell death .	Bcl-2 and Bcl-XL antagonize Bax, thus a shift towards their expression restricts programmed cell death.	0	5	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	4	5
In addition , BCL-2 , BCL-X L and MCL-1 can sequester partially activated , BH3 exposed , BAX and BAK monomers to prevent the homo-oligomerization of BAX and BAK , serving as a fail-safe mechanism or the second line of defense .	In addition, BCL-2, BCL-X L and MCL-1 can sequester partially activated, BH3 exposed, BAX and BAK monomers to prevent the homo-oligomerization of BAX and BAK, serving as a fail-safe mechanism or the second line of defense.	3	18	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	3	4	17	18
The addition of BCL-2 BH4 SAHB A dose-responsively inhibited BIM SAHB A -triggered BAX activation ( XREF_FIG ) .	The addition of BCL-2 BH4 SAHB A dose-responsively inhibited BIM SAHB A -triggered BAX activation (XREF_FIG).	3	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	3	4	13	14
MeHg could also decrease glutathione level and increase the expressions of caspase-3 , -7 , and -9 , accompanied by Bcl-2 down-regulation and up-regulation of Bax , Bak , and p53 .	MeHg could also decrease glutathione level and increase the expressions of caspase-3, -7, and -9, accompanied by Bcl-2 down-regulation and up-regulation of Bax, Bak, and p53.	20	30	down-regulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	20	21	25	26
Our results showed that SHXT treatment significantly increased Bcl-2 expression and decreased Bax , suggesting that changes in the ratio of proapoptotic and antiapoptotic Bcl-2 family proteins may contribute to the antiapoptotic and cardioprotective effects of SHXT on I/R injury ( XREF_FIG ) .	Our results showed that SHXT treatment significantly increased Bcl-2 expression and decreased Bax, suggesting that changes in the ratio of proapoptotic and antiapoptotic Bcl-2 family proteins may contribute to the antiapoptotic and cardioprotective effects of SHXT on I/R injury (XREF_FIG).	4	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	SHXT treatment significantly increased Bcl-2 expression	bcl-2	Bax	Bax	bax	8	9	12	13
The increased Bax activity was associated with reduced integrin signalling and diminished Bcl-2 levels , which were shown to inhibit Bax .	The increased Bax activity was associated with reduced integrin signalling and diminished Bcl-2 levels, which were shown to inhibit Bax.	2	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bax activity was associated with reduced integrin signalling and diminished Bcl-2 levels	bcl-2	Bax	Bax	bax	12	13	20	21
To determine if BCL-2 BH4 SAHB A suppression of BAX mediated liposomal poration blocks exposure of the 6A7 epitope , we incubated BAX with liposomes , BIM SAHB A , and increasing doses of BCL-2 BH4 SAHB A , and monitored the N-terminal conformational activation of BAX by 6A7 immunoprecipitation .	To determine if BCL-2 BH4 SAHB A suppression of BAX mediated liposomal poration blocks exposure of the 6A7 epitope, we incubated BAX with liposomes, BIM SAHB A, and increasing doses of BCL-2 BH4 SAHB A, and monitored the N-terminal conformational activation of BAX by 6A7 immunoprecipitation.	3	10	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	3	4	9	10
Akt1 transfection increased the levels of intracellular p-Akt , enhanced the expression of the anti-apoptosis protein Bcl-2 , and reduced that of the apoptosis protein Bax ( thereby increasing the Bcl-2 and Bax ratio ) , and caused some increase in hypoxia inducible factor1alpha ( HIF-1alpha ) and vascular endothelial growth factor ( VEGF ) expression after A/R .	Akt1 transfection increased the levels of intracellular p-Akt, enhanced the expression of the anti-apoptosis protein Bcl-2, and reduced that of the apoptosis protein Bax (thereby increasing the Bcl-2 and Bax ratio), and caused some increase in hypoxia inducible factor1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) expression after A/R.	0	28	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Akt1 transfection increased the levels of intracellular p-Akt, enhanced the expression of the anti-apoptosis protein Bcl-2	bcl-2	Bax	Bax	bax	16	17	25	26
Bcl-2 and Mcl-1 are often highly expressed in chemotherapy resistant cancers and prevents apoptosis by inactivating pro apoptotic Bax and Bak [ XREF_BIBR , XREF_BIBR ] .	Bcl-2 and Mcl-1 are often highly expressed in chemotherapy resistant cancers and prevents apoptosis by inactivating pro apoptotic Bax and Bak [XREF_BIBR, XREF_BIBR].	0	20	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 and Mcl-1 are often highly expressed	bcl-2	Bax	Bax	bax	0	1	18	19
Anti-apoptotic Bcl-2 protein was upregulated , thereby inhibiting the pro apoptotic Bax protein in the hippocampus after RF-EMF exposure ( XREF_FIG ) .	Anti-apoptotic Bcl-2 protein was upregulated, thereby inhibiting the pro apoptotic Bax protein in the hippocampus after RF-EMF exposure (XREF_FIG).	1	12	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	11	12
What ' s more , the consistent pattern of BCL-2 pSAHB crosslinking to inactive , monomeric forms of BAX , including the conformationally restricted , alpha9 tethered form , suggests that BH4 mediated BAX inhibition may occur at a mechanistically distinct step from the established mode for BCL-2 inhibition of conformationally activated BAX .	What 's more, the consistent pattern of BCL-2 pSAHB crosslinking to inactive, monomeric forms of BAX, including the conformationally restricted, alpha9 tethered form, suggests that BH4 mediated BAX inhibition may occur at a mechanistically distinct step from the established mode for BCL-2 inhibition of conformationally activated BAX.	47	53	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	47	48	52	53
Overexpression of BCL-2 , BCL-xl , or MCL-1 in WT MEFs effectively blocked BAX- or BAK dependent cell death in response to staurosporine , but did not interfere with MG132 induced cell death in DKO MEFs that stably expressed BOK ( XREF_FIG ) .	Overexpression of BCL-2, BCL-xl, or MCL-1 in WT MEFs effectively blocked BAX- or BAK dependent cell death in response to staurosporine, but did not interfere with MG132 induced cell death in DKO MEFs that stably expressed BOK (XREF_FIG).	0	18	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	Overexpression of BCL-2	bcl-2	BAX-	BAX-	bax-	2	3	13	14
DHM treatment increased the Bcl-2 level and decreased the Bax level and Bax and Bcl -2 ratio of diabetic mice .	DHM treatment increased the Bcl-2 level and decreased the Bax level and Bax and Bcl -2 ratio of diabetic mice.	0	11	decreased	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Bcl-2	DHM treatment increased the Bcl-2 level	bcl-2	Bax	Bax level	bax	4	5	9	10
Bcl-2 inhibits Bax activation , and caspase-3 is the effector molecule that is responsible for DNA fragmentation during the terminal events preceding cell death [ XREF_BIBR , XREF_BIBR ] .	Bcl-2 inhibits Bax activation, and caspase-3 is the effector molecule that is responsible for DNA fragmentation during the terminal events preceding cell death [XREF_BIBR, XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	2	3
The IL-10 gene silencing causes down regulation of both PI3K and AKT and Bcl2 genes expression and also increases the Bbc3 , BAX , caspase3 , and caspase 3 cleavage expression levels .	The IL-10 gene silencing causes down regulation of both PI3K and AKT and Bcl2 genes expression and also increases the Bbc3, BAX, caspase3, and caspase 3 cleavage expression levels.	1	23	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	IL-10 gene silencing causes down regulation of both PI3K and AKT and Bcl2 genes expression	bcl2	BAX	BAX	bax	13	14	22	23
In the present study , we showed that treatment of 20muM of lutein also enhanced Bcl-2 protein expression and abrogated Bax and Bcl -2 ratio after 24 hours of hypoxic injury .	In the present study, we showed that treatment of 20muM of lutein also enhanced Bcl-2 protein expression and abrogated Bax and Bcl -2 ratio after 24 hours of hypoxic injury.	12	24	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	lutein also enhanced Bcl-2 protein expression	bcl-2	Bax	Bax	bax	15	16	20	21
Two anti-apoptotic genes , Mdm2 ( antagonist of p53 ) and Bcl-2 ( inhibitor of Bax ) , were down-regulated , and the activity of capspase-9 and caspase-3 was significantly increased .	Two anti-apoptotic genes, Mdm2 (antagonist of p53) and Bcl-2 (inhibitor of Bax), were down-regulated, and the activity of capspase-9 and caspase-3 was significantly increased.	2	16	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	11	12	15	16
Baicalin has been shown to down-regulate the expression of TLR2 , enhance the expression of Bcl-2 , and inhibit the activities of Bax and caspase-3 in mastitis [ XREF_BIBR ] .	Baicalin has been shown to down-regulate the expression of TLR2, enhance the expression of Bcl-2, and inhibit the activities of Bax and caspase-3 in mastitis [XREF_BIBR].	0	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Baicalin has been shown to down-regulate the expression of TLR2, enhance the expression of Bcl-2	bcl-2	Bax	Bax	bax	15	16	22	23
Additionally , the BH4 domain of Bcl-2 prevented Bax activation by binding to its inactive conformation [ XREF_BIBR ] .	Additionally, the BH4 domain of Bcl-2 prevented Bax activation by binding to its inactive conformation [XREF_BIBR].	4	9	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	8	9
[ XREF_BIBR ] On the contrary , over-expression of Bcl-2 prevents the oligomerization of Bax at the mitochondria , and thereby inhibits death signaling .	[XREF_BIBR] On the contrary, over-expression of Bcl-2 prevents the oligomerization of Bax at the mitochondria, and thereby inhibits death signaling.	7	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	over-expression of Bcl-2	bcl-2	Bax	Bax	bax	9	10	14	15
The antiapoptotic effects of Bcl-2 are linked to Ca 2+ mobilization from the ER to the mitochondrion and blocks homodimerization of pro apoptotic Bax that displaces SERCA from the mitochondrial associated membranes [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The antiapoptotic effects of Bcl-2 are linked to Ca 2+ mobilization from the ER to the mitochondrion and blocks homodimerization of pro apoptotic Bax that displaces SERCA from the mitochondrial associated membranes [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	24	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	23	24
Co-expression with the Bax antagonist Bcl2 was able to greatly reduce the degree of ANT1 induced cell death .	Co-expression with the Bax antagonist Bcl2 was able to greatly reduce the degree of ANT1 induced cell death.	0	6	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	5	6	3	4
This could be explained by the fact that Bcl-2 inhibits Bax action at the mitochondria directly while BI-1 inhibits Bax action indirectly , providing further evidence that BI-1 and Bcl-2 inhibit Bax mediated yeast cell death through different mechanisms .	This could be explained by the fact that Bcl-2 inhibits Bax action at the mitochondria directly while BI-1 inhibits Bax action indirectly, providing further evidence that BI-1 and Bcl-2 inhibit Bax mediated yeast cell death through different mechanisms.	8	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	10	11
In this study , knockdown of GTSE1 downregulated phosphorylation of AKT , BCL-2 , and cyclin B1 but upregulated Bax , which suggested that GTSE1 contributes to high aggressive behavior of HCC through its enhancing effect on AKT survival pathway and apoptosis pathway .	In this study, knockdown of GTSE1 downregulated phosphorylation of AKT, BCL-2, and cyclin B1 but upregulated Bax, which suggested that GTSE1 contributes to high aggressive behavior of HCC through its enhancing effect on AKT survival pathway and apoptosis pathway.	6	22	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	GTSE1 downregulated phosphorylation of AKT, BCL-2	bcl-2	Bax	Bax	bax	12	13	19	20
Overexpression of miR-21 using synthetic miR-21 RNA increased expression of Bcl-2 , an inhibitor of apoptosis , and decreased the Bax : Bcl-2 expression ratio , a cell fate determinant , in SSc fibroblasts .	Overexpression of miR-21 using synthetic miR-21 RNA increased expression of Bcl-2, an inhibitor of apoptosis, and decreased the Bax : Bcl-2 expression ratio, a cell fate determinant, in SSc fibroblasts.	0	24	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of miR-21 using synthetic miR-21 RNA increased expression of Bcl-2	bcl-2	Bax	Bax	bax	10	11	20	21
Also , XREF_FIG shows that similar to Bcl-X L , Bcl-2 alone inhibited the tBid and Bax mediated membrane permeabilization .	Also, XREF_FIG shows that similar to Bcl-X L, Bcl-2 alone inhibited the tBid and Bax mediated membrane permeabilization.	10	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	10	11	16	17
XREF_BIBR , XREF_BIBR However , emerging evidence suggests that the BCL-2 family members that suppress and activate BAX and BAK are cell type- and stimulus specific .	XREF_BIBR, XREF_BIBR However, emerging evidence suggests that the BCL-2 family members that suppress and activate BAX and BAK are cell type- and stimulus specific.	10	19	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	10	11	17	18
Bcl-2 disrupts the proapoptotic proteins of Bax and acts as channel proteins in the mitochondrial membrane to prevent the mitochondrial release of Cytochrome c for induction of caspase cascade and apoptosis XREF_BIBR , XREF_BIBR .	Bcl-2 disrupts the proapoptotic proteins of Bax and acts as channel proteins in the mitochondrial membrane to prevent the mitochondrial release of Cytochrome c for induction of caspase cascade and apoptosis XREF_BIBR, XREF_BIBR.	0	17	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	6	7
The anti-apoptotic Bcl-2 proteins Bcl-2 , Bcl-xL , and myeloid cell leukemia sequence 1 ( Mcl-1 ) prevent cellular apoptosis via their expression and dimerization with the pro apoptotic Bcl-2 proteins Bim and Bax .	The anti-apoptotic Bcl-2 proteins Bcl-2, Bcl-xL, and myeloid cell leukemia sequence 1 (Mcl-1) prevent cellular apoptosis via their expression and dimerization with the pro apoptotic Bcl-2 proteins Bim and Bax.	2	34	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	33	34
Manumycin reduced Bcl-2 expression and induced Bax upregulation in prostate cancer cells .	Manumycin reduced Bcl-2 expression and induced Bax upregulation in prostate cancer cells.	0	7	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Manumycin reduced Bcl-2 expression	bcl-2	Bax	Bax	bax	2	3	6	7
Initiation of apoptosis in LA treated MCF10A cells was detected by mitochondrial localization of the Bax apoptotic protein , which was prevented by overexpression of Bcl-2 .	Initiation of apoptosis in LA treated MCF10A cells was detected by mitochondrial localization of the Bax apoptotic protein, which was prevented by overexpression of Bcl-2.	15	26	prevented	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	Bax	Bax	bax	25	26	15	16
While the pro apoptotic family members BAX and BAK are crucial for the induction of MOMP and the release of the pro apoptotic molecules , the anti-apoptotic family members BCL-2 and BCL-XL inhibit BAX and BAK XREF_BIBR , XREF_BIBR .	While the pro apoptotic family members BAX and BAK are crucial for the induction of MOMP and the release of the pro apoptotic molecules, the anti-apoptotic family members BCL-2 and BCL-XL inhibit BAX and BAK XREF_BIBR, XREF_BIBR.	25	36	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	29	30	33	34
Nevertheless , Bax and Bcl-2 are the major factors that regulate the apoptosis , since Bax can activate or inhibit Bxl and Bad , and also Bcl2 can inhibit Bax .	Nevertheless, Bax and Bcl-2 are the major factors that regulate the apoptosis, since Bax can activate or inhibit Bxl and Bad, and also Bcl2 can inhibit Bax.	26	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	26	27	29	30
The expression of Bcl-2 and heme oxygenase-1 were significantly downregulated , Bax and extracellular dismutase significantly upregulated in Group D. Therefore , chronic hypergravity could have a hormetic effect for allergic asthma and rhinitis via regulation of genes involved in antioxidative and proapoptotic pathways .	The expression of Bcl-2 and heme oxygenase-1 were significantly downregulated, Bax and extracellular dismutase significantly upregulated in Group D. Therefore, chronic hypergravity could have a hormetic effect for allergic asthma and rhinitis via regulation of genes involved in antioxidative and proapoptotic pathways.	1	14	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	3	4	11	12
Downregulation of Bcl-2 and Bcl-xL increases PARP-1 and Bax , thereby decreasing the Bcl-2 and Bax ratio and promoting apoptosis and death .	Downregulation of Bcl-2 and Bcl-xL increases PARP-1 and Bax, thereby decreasing the Bcl-2 and Bax ratio and promoting apoptosis and death.	2	16	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	15	16
Previous evidences have stated that POU4F1 promotes the expression of BCL2 pro survival gene and suppresses BAX activation to protect neurons from programmed cell death XREF_BIBR - XREF_BIBR .	Previous evidences have stated that POU4F1 promotes the expression of BCL2 pro survival gene and suppresses BAX activation to protect neurons from programmed cell death XREF_BIBR - XREF_BIBR.	5	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	POU4F1 promotes the expression of BCL2	bcl2	BAX	BAX	bax	10	11	16	17
Thus Bcl-2 mediated inhibition of Beclin and of Bax allows it to have direct roles in preventing autophagy and apoptosis induction .	Thus Bcl-2 mediated inhibition of Beclin and of Bax allows it to have direct roles in preventing autophagy and apoptosis induction.	1	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	8	9
Obstruction of Cytochrome C release in T. gondii infected cells has been reported to correlate with increase of BCL-2 transcript level inhibition of mitochondrial targeting and activation of BAX , as well as selective degradation of the pro apoptotic proteins BAX , BAD , and BID .	Obstruction of Cytochrome C release in T. gondii infected cells has been reported to correlate with increase of BCL-2 transcript level inhibition of mitochondrial targeting and activation of BAX, as well as selective degradation of the pro apoptotic proteins BAX, BAD, and BID.	18	29	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	18	19	28	29
GSH supplementation significantly increased the expression of BCL2 , but decreased that of BAX .	GSH supplementation significantly increased the expression of BCL2, but decreased that of BAX.	0	14	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	GSH supplementation significantly increased the expression of BCL2	bcl2	BAX	BAX	bax	7	8	13	14
Such Bcl-2 inhibition of Bax activation dynamically generates stochastic variability in apoptosis even when the initial number of molecules present are not small XREF_BIBR , XREF_BIBR .	Such Bcl-2 inhibition of Bax activation dynamically generates stochastic variability in apoptosis even when the initial number of molecules present are not small XREF_BIBR, XREF_BIBR.	1	5	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	4	5
On the other hand , the anti-apoptotic Bcl-2 proteins ( Bcl-2 , Mcl-1 and Bcl-xL ) are located on either cellular membranes or in the cytosol and inhibit the oligomerization of the effector proteins Bax and Bak [ XREF_BIBR ] .	On the other hand, the anti-apoptotic Bcl-2 proteins (Bcl-2, Mcl-1 and Bcl-xL) are located on either cellular membranes or in the cytosol and inhibit the oligomerization of the effector proteins Bax and Bak [XREF_BIBR].	7	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	34	35
BCL-2 may also bind and directly inhibit active conformations of BAX and BAK XREF_BIBR , XREF_BIBR .	BCL-2 may also bind and directly inhibit active conformations of BAX and BAK XREF_BIBR, XREF_BIBR.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	0	1	10	11
In addition , miR-199a-3p inhibited Bcl2 expression , but increased Bax and cleaved caspase-3 expression .	In addition, miR-199a-3p inhibited Bcl2 expression, but increased Bax and cleaved caspase-3 expression.	3	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	miR-199a-3p inhibited Bcl2 expression	bcl2	Bax	Bax	bax	5	6	10	11
Bcl-2 is able to inhibit the formation of Bax containing pores on the mitochondrial outer membrane and reduce the release of calcium and cytochrome C from the mitochondria .	Bcl-2 is able to inhibit the formation of Bax containing pores on the mitochondrial outer membrane and reduce the release of calcium and cytochrome C from the mitochondria.	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	8	9
These results support a model in which Bcl-2 can sequester and inhibit Bax by binding to the BH3-domain of the pro apoptotic protein .	These results support a model in which Bcl-2 can sequester and inhibit Bax by binding to the BH3-domain of the pro apoptotic protein.	7	13	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	12	13
In contrast , BAX is bound to and inhibited by Bcl-2 proteins .	In contrast, BAX is bound to and inhibited by Bcl-2 proteins.	3	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	10	11	3	4
DADS was found to downregulate the expression of insulin like growth factor signaling system , which subsequently leads to inhibition of Akt phosphorylation and the expressions of cyclin D1 , NFkappaB , and antiapoptotic Bcl-2 protein , but increases proapoptotic signaling proteins ( Bad and Bax ) , thereby inhibiting cell cycle progression and survival .	DADS was found to downregulate the expression of insulin like growth factor signaling system, which subsequently leads to inhibition of Akt phosphorylation and the expressions of cyclin D1, NFkappaB, and antiapoptotic Bcl-2 protein, but increases proapoptotic signaling proteins (Bad and Bax), thereby inhibiting cell cycle progression and survival.	0	46	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	DADS was found to downregulate the expression of insulin like growth factor signaling system, which subsequently leads to inhibition of Akt phosphorylation and the expressions of cyclin D1, NFkappaB, and antiapoptotic Bcl-2	bcl-2	Bax	Bax	bax	34	35	45	46
DPF suppressed Bcl-2 levels , enhanced Bax levels and Bax and Bcl -2 ratio , and simultaneously translocated Bax to mitochondria followed by mitochondrial release of cytochrome c into the cytosol and activation of effector caspase-3 .	DPF suppressed Bcl-2 levels, enhanced Bax levels and Bax and Bcl -2 ratio, and simultaneously translocated Bax to mitochondria followed by mitochondrial release of cytochrome c into the cytosol and activation of effector caspase-3.	0	8	enhanced	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Bcl-2	DPF suppressed Bcl-2 levels	bcl-2	Bax	Bax levels	bax	2	3	6	7
While it is clear that Bcl-2 anti-apoptotic protein inhibition of pro apoptotic Bax and Bak is disrupted by BH3-only proteins to elicit mitochondrial cell death , the precise relationships between these different classes of the Bcl-2 family is still under investigation .	While it is clear that Bcl-2 anti-apoptotic protein inhibition of pro apoptotic Bax and Bak is disrupted by BH3-only proteins to elicit mitochondrial cell death, the precise relationships between these different classes of the Bcl-2 family is still under investigation.	5	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	12	13
Jak3 deficient thymocytes express elevated levels of Bax and reduced levels of Bcl-2 relative to those in wild-type littermates .	Jak3 deficient thymocytes express elevated levels of Bax and reduced levels of Bcl-2 relative to those in wild-type littermates.	7	13	reduced	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Bcl-2	levels of Bcl-2	bcl-2	Bax	Bax	bax	12	13	7	8
Up-regulation of mitochondrial Bcl-2 has been shown to prevent Bax activation and , as a result , preserve the integrity of mitochondria and maintain cytochrome c in the organelles [ XREF_BIBR ] .	Up-regulation of mitochondrial Bcl-2 has been shown to prevent Bax activation and, as a result, preserve the integrity of mitochondria and maintain cytochrome c in the organelles [XREF_BIBR].	0	10	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	9	10
Overexpression of Bcl-2 in U937 cells even prevented translocation of proapoptotic Bax but failed to prevent ROS generation XREF_BIBR .	Overexpression of Bcl-2 in U937 cells even prevented translocation of proapoptotic Bax but failed to prevent ROS generation XREF_BIBR.	0	12	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	Bax	Bax	bax	2	3	11	12
Under normal conditions , Bcl-2 and Bcl-X L block the activities of Bax and/or Bak [ XREF_BIBR ] .	Under normal conditions, Bcl-2 and Bcl-X L block the activities of Bax and/or Bak [XREF_BIBR].	4	13	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	12	13
In contrast , the addition of Bcl-2 to Bcl-X L further inhibited the tBid induced Bax activity .	In contrast, the addition of Bcl-2 to Bcl-X L further inhibited the tBid induced Bax activity.	4	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	15	16
Expression of Bax following A/R was also attenuated in cells treated with diterpenes , whereas Bcl-2 and xIAP levels remained unaffected ( XREF_FIG ) .	Expression of Bax following A/R was also attenuated in cells treated with diterpenes, whereas Bcl-2 and xIAP levels remained unaffected (XREF_FIG).	0	18	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	15	16	2	3
The anti-apoptotic protein Bcl-2 is known to prevent Bax redistribution to the mitochondria , caspase activation and apoptosis .	The anti-apoptotic protein Bcl-2 is known to prevent Bax redistribution to the mitochondria, caspase activation and apoptosis.	0	9	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	8	9
Conversely , Bcl-2 and Bcl-xl are pro survival and inhibit the pore forming activities of Bax and Bak .	Conversely, Bcl-2 and Bcl-xl are pro survival and inhibit the pore forming activities of Bax and Bak.	2	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	15	16
The anti-apoptotic protein Bcl-2 impairs the activation of Bax and Bak , thereby maintaining mitochondrial membrane integrity and reducing cytochrome c leakage , which results in a decrease in the probability of apoptosis .	The anti-apoptotic protein Bcl-2 impairs the activation of Bax and Bak, thereby maintaining mitochondrial membrane integrity and reducing cytochrome c leakage, which results in a decrease in the probability of apoptosis.	0	10	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	8	9
By examining the effects of different cytokines individually and together , we demonstrated how subtle differences in the cellular response to these similar cytokines affect T-cell survival by shifting the balance between the different roles of Mcl-1 , specifically its role in antagonizing Bak and its shared role with Bcl-2 antagonizing Bim and Bax .	By examining the effects of different cytokines individually and together, we demonstrated how subtle differences in the cellular response to these similar cytokines affect T-cell survival by shifting the balance between the different roles of Mcl-1, specifically its role in antagonizing Bak and its shared role with Bcl-2 antagonizing Bim and Bax.	47	54	antagonizing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	49	50	53	54
Furthermore , expression of Bcl-2 and DeltaBH3 , Bcl-2 mutant lacking its BH3 domain , inhibited NuBCP-9-induced apoptosis ( XREF_FIG ) and Bax activation ( XREF_FIG ) .	Furthermore, expression of Bcl-2 and DeltaBH3, Bcl-2 mutant lacking its BH3 domain, inhibited NuBCP-9-induced apoptosis (XREF_FIG) and Bax activation (XREF_FIG).	2	23	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	4	5	22	23
In mouse bone marrow extracts , SP prolonged activation of Erk1/2 and enhanced Bcl-2 expression , but attenuated the activation of apoptotic molecules ( e.g ., p38 and cleaved caspase-3 ) and down-regulated Bax .	In mouse bone marrow extracts, SP prolonged activation of Erk1/2 and enhanced Bcl-2 expression, but attenuated the activation of apoptotic molecules (e.g., p38 and cleaved caspase-3) and down-regulated Bax.	6	34	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	SP prolonged activation of Erk1/2 and enhanced Bcl-2 expression	bcl-2	Bax	Bax	bax	13	14	33	34
In cancer cells , resveratrol lowers Bcl-2 expression , activates proapoptotic Bax in a p53 dependent manner , and promotes cytochrome c release from mitochondria XREF_BIBR .	In cancer cells, resveratrol lowers Bcl-2 expression, activates proapoptotic Bax in a p53 dependent manner, and promotes cytochrome c release from mitochondria XREF_BIBR.	4	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	resveratrol lowers Bcl-2 expression	bcl-2	Bax	Bax	bax	6	7	11	12
We found the peroxynitrite generator SIN-1 to promote apoptosis in human and rat HSC , based on oligonucleosomal DNA fragmentation , caspase-3 and -9 activation , Bcl-2 depletion and accumulation of Bax protein .	We found the peroxynitrite generator SIN-1 to promote apoptosis in human and rat HSC, based on oligonucleosomal DNA fragmentation, caspase-3 and -9 activation, Bcl-2 depletion and accumulation of Bax protein.	26	32	depletion	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	26	27	31	32
Although our data does not directly address the role of Bcl-2 , published data places Bim genetically downstream of Bcl-2 , and suggests that the major role of Bcl-2 in thymocytes is to inhibit the activation of Bax and/or Bak by Bim ( Bax activation displayed in XREF_FIG ) .	Although our data does not directly address the role of Bcl-2, published data places Bim genetically downstream of Bcl-2, and suggests that the major role of Bcl-2 in thymocytes is to inhibit the activation of Bax and/or Bak by Bim (Bax activation displayed in XREF_FIG).	26	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	28	29	37	38
BCL2 slows but does not inactivate BAX and BAK induced B cell apoptosis upon withdrawal of survival signals , and consequently BAFFR deficiency , BAFF blockade , or acute loss of the BCR each diminishes the accumulation of mature B cells in Bcl2 transgenic mice .	BCL2 slows but does not inactivate BAX and BAK induced B cell apoptosis upon withdrawal of survival signals, and consequently BAFFR deficiency, BAFF blockade, or acute loss of the BCR each diminishes the accumulation of mature B cells in Bcl2 transgenic mice.	0	7	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	0	1	6	7
In survival conditions , BAX and BAK are sequestered by the anti-apoptotic family members : BCL-2 , BCL-X L , MCL-1 , BCL-W , BCL-B and BCL2A1 .	In survival conditions, BAX and BAK are sequestered by the anti-apoptotic family members : BCL-2, BCL-X L, MCL-1, BCL-W, BCL-B and BCL2A1.	4	16	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	15	16	4	5
Again , following treatment , there was a significant increase in Bax protein , while that of Bcl2 is significantly reduced , resulting in an increase in the Bax : Bcl2 ratio .	Again, following treatment, there was a significant increase in Bax protein, while that of Bcl2 is significantly reduced, resulting in an increase in the Bax : Bcl2 ratio.	15	31	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	17	18	28	29
In addition , overexpression of miR-302b-3p/302c- 3p/302d-3p can reduce the expression of ZEB1 , inhibit the expression of Bcl-2 and promote the expression BAX in EC at the RNA level and the protein level .	In addition, overexpression of miR-302b-3p/302c- 3p/302d-3p can reduce the expression of ZEB1, inhibit the expression of Bcl-2 and promote the expression BAX in EC at the RNA level and the protein level.	3	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	overexpression of miR-302b-3p/302c- 3p/302d-3p can reduce the expression of ZEB1, inhibit the expression of Bcl-2	bcl-2	BAX	BAX	bax	18	19	23	24
Moreover , overexpression of Bcl-2 disrupts the proapoptotic proteins of Bax and prevents the mitochondrial release of cyt c , thereby inhibiting the activation of caspases , and apoptosis [ XREF_BIBR , XREF_BIBR ] .	Moreover, overexpression of Bcl-2 disrupts the proapoptotic proteins of Bax and prevents the mitochondrial release of cyt c, thereby inhibiting the activation of caspases, and apoptosis [XREF_BIBR, XREF_BIBR].	2	11	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	Bax	Bax	bax	4	5	10	11
RA at 8 and 16 microM decreased Bcl-2 expression and at 4 to 16 microM upregulated Bax and cleaved caspase-3 expression .	RA at 8 and 16 microM decreased Bcl-2 expression and at 4 to 16 microM upregulated Bax and cleaved caspase-3 expression.	0	17	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	RA at 8 and 16 microM decreased Bcl-2 expression	bcl-2	Bax	Bax	bax	7	8	16	17
We postulate that miR143 inhibits Bcl-2 expression and activates Bax and caspase-9 and thereby the endogenous mitochondrial pathway , which promotes cell apoptosis .	We postulate that miR143 inhibits Bcl-2 expression and activates Bax and caspase-9 and thereby the endogenous mitochondrial pathway, which promotes cell apoptosis.	3	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	miR143 inhibits Bcl-2 expression	bcl-2	Bax	Bax	bax	5	6	9	10
Both ASA and indomethacin reduced the protein levels of Bcl-2 and Bcl-xl , but upregulated those of Bax and Bcl-xs .	Both ASA and indomethacin reduced the protein levels of Bcl-2 and Bcl-xl, but upregulated those of Bax and Bcl-xs.	1	19	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	ASA and indomethacin reduced the protein levels of Bcl-2	bcl-2	Bax	Bax	bax	9	10	17	18
The Bcl-2 subfamily members inhibit Bax and Bak by either direct binding that results in their sequestration , or by binding to and sequestering specific activators such as the BH3-only effectors .	The Bcl-2 subfamily members inhibit Bax and Bak by either direct binding that results in their sequestration, or by binding to and sequestering specific activators such as the BH3-only effectors.	1	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	5	6
Active Bax and Bak are bound and inhibited by the anti-apoptotic Bcl-2 proteins ( e.g ., Bcl-2 , Bcl-xL , Mcl-1 ) , thereby blocking apoptosis .	Active Bax and Bak are bound and inhibited by the anti-apoptotic Bcl-2 proteins (e.g., Bcl-2, Bcl-xL, Mcl-1), thereby blocking apoptosis.	0	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	11	12	1	2
Overexpression of Bcl-2 antagonized this PI3K and mTOR inhibitor stimulated activation of Bax and permeabilization of mitochondrial outer membrane and profoundly rescued cell death induction following treatment with chemotherapeutics and PI3K and mTOR inhibitors .	Overexpression of Bcl-2 antagonized this PI3K and mTOR inhibitor stimulated activation of Bax and permeabilization of mitochondrial outer membrane and profoundly rescued cell death induction following treatment with chemotherapeutics and PI3K and mTOR inhibitors.	0	14	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	Bax	Bax	bax	2	3	12	13
In the cytosol , Bcl-2 and Bcl-xl protein can sequester Bax protein to inhibit its pro apoptotic function and translocation to the mitochondria XREF_BIBR .	In the cytosol, Bcl-2 and Bcl-xl protein can sequester Bax protein to inhibit its pro apoptotic function and translocation to the mitochondria XREF_BIBR.	4	11	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	10	11
In addition to regulating autophagy through the inhibition of Beclin-1 , Bcl-2 also inhibits the pro apoptotic function of Bax and Bak .	In addition to regulating autophagy through the inhibition of Beclin-1, Bcl-2 also inhibits the pro apoptotic function of Bax and Bak.	11	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	11	12	19	20
In normal neurons , Bax is sequestered by Bcl-2 , so as to prevent the pore formation on mitochondrial membrane and inhibit apoptosis ( Youle & Strasser , 2008 ) .	In normal neurons, Bax is sequestered by Bcl-2, so as to prevent the pore formation on mitochondrial membrane and inhibit apoptosis (Youle & Strasser, 2008).	4	21	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	4	5
In their study , miR-22 overexpression can also increase the expression of the anti-apoptosis gene Bcl-2 and decrease the pro apoptosis gene Bax , which attributed to a reduction in apoptosis .	In their study, miR-22 overexpression can also increase the expression of the anti-apoptosis gene Bcl-2 and decrease the pro apoptosis gene Bax, which attributed to a reduction in apoptosis.	4	25	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	miR-22 overexpression can also increase the expression of the anti-apoptosis gene Bcl-2	bcl-2	Bax	Bax	bax	15	16	22	23
Note that while the level of pro apoptotic protein Bax was not altered , the antiapoptotic Bcl-2 level was reduced , resulting in a higher ratio of Bax over Bcl-2 expression .	Note that while the level of pro apoptotic protein Bax was not altered, the antiapoptotic Bcl-2 level was reduced, resulting in a higher ratio of Bax over Bcl-2 expression.	16	28	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 level	bcl-2	Bax	Bax	bax	16	17	27	28
Similar to cytoplasmic Survivin , Bcl-2 inhibits the proapoptotic functions of Bax and promotes cellular proliferation , which is ultimately reflected in the biological tumor behavior of each type of AM [ XREF_BIBR , XREF_BIBR ] .	Similar to cytoplasmic Survivin, Bcl-2 inhibits the proapoptotic functions of Bax and promotes cellular proliferation, which is ultimately reflected in the biological tumor behavior of each type of AM [XREF_BIBR, XREF_BIBR].	5	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	11	12
The BH3-only proteins trigger apoptosis either by directly activating BAX and BAK or indirectly by binding to the pro survival BCL-2 proteins thereby preventing their restraint of pro apoptotic BAX and BAK .	The BH3-only proteins trigger apoptosis either by directly activating BAX and BAK or indirectly by binding to the pro survival BCL-2 proteins thereby preventing their restraint of pro apoptotic BAX and BAK.	20	31	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	20	21	29	30
Both PD98059 and SP600125 reduced the expression of Cyclin D1 and Bcl-2 but increased the expression of Caspase 3 and Bax ( XREF_FIG ) .	Both PD98059 and SP600125 reduced the expression of Cyclin D1 and Bcl-2 but increased the expression of Caspase 3 and Bax (XREF_FIG).	3	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	SP600125 reduced the expression of Cyclin D1 and Bcl-2	bcl-2	Bax	Bax	bax	11	12	20	21
Bcl-2 is believed to prevent Bax from releasing cytochrome c , thus restricting downstream activation of apoptotic machinery .	Bcl-2 is believed to prevent Bax from releasing cytochrome c, thus restricting downstream activation of apoptotic machinery.	0	6	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	5	6
Consistently , wild-type and mitochondrial Bcl-2 , but not ER-Bcl-2 , blocked Bax activation during ATP depletion , a critical event for mitochondrial outer membrane permeabilization and cytochrome c release .	Consistently, wild-type and mitochondrial Bcl-2, but not ER-Bcl-2, blocked Bax activation during ATP depletion, a critical event for mitochondrial outer membrane permeabilization and cytochrome c release.	2	13	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	12	13
Our data showed that UCP2 enhanced MAPKs activation and reduced Bcl-2 expression , which can reduce Bax stimulated apoptotic events .	Our data showed that UCP2 enhanced MAPKs activation and reduced Bcl-2 expression, which can reduce Bax stimulated apoptotic events.	4	17	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	UCP2 enhanced MAPKs activation and reduced Bcl-2 expression	bcl-2	Bax	Bax	bax	10	11	16	17
In addition , rHV3 treatment significantly increased galactose induced Bcl-2 downregulation , and decreased Bax upregulation .	In addition, rHV3 treatment significantly increased galactose induced Bcl-2 downregulation, and decreased Bax upregulation.	3	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	rHV3 treatment significantly increased galactose induced Bcl-2	bcl-2	Bax	Bax	bax	9	10	14	15
Overexpression of BCL-2 inhibited BAX mediated cytochrome-c release , caspase activation and cell death in nerve growth factor deprived sympathetic neurons .	Overexpression of BCL-2 inhibited BAX mediated cytochrome-c release, caspase activation and cell death in nerve growth factor deprived sympathetic neurons.	0	5	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	Overexpression of BCL-2	bcl-2	BAX	BAX	bax	2	3	4	5
Bax and Bcl-2 are two important mediators of the mitochondrial apoptosis pathway ; Bcl-2 prevents Bax activation and thereby inhibits apoptosis .	Bax and Bcl-2 are two important mediators of the mitochondrial apoptosis pathway; Bcl-2 prevents Bax activation and thereby inhibits apoptosis.	13	19	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	13	14	15	16
ALO also suppressed the expression of anti-apoptotic protein Bcl-2 and upregulated that of pro apoptotic protein Bax in PCa cells .	ALO also suppressed the expression of anti-apoptotic protein Bcl-2 and upregulated that of pro apoptotic protein Bax in PCa cells.	0	19	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	ALO also suppressed the expression of anti-apoptotic protein Bcl-2	bcl-2	Bax	Bax	bax	8	9	16	17
GAS1 suppression promoted multidrug resistance through apoptosis inhibition , partially by up-regulating the Bcl-2 and Bax ratio that was abolished by Bcl-2 inhibition .	GAS1 suppression promoted multidrug resistance through apoptosis inhibition, partially by up-regulating the Bcl-2 and Bax ratio that was abolished by Bcl-2 inhibition.	13	22	abolished	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	21	22	15	16
Bcl-2 antagonizes the effects of BAX ( pro apoptotic gene ) and prevents the release of cytochrome c.	Bcl-2 antagonizes the effects of BAX (pro apoptotic gene) and prevents the release of cytochrome c.	0	12	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	0	1	5	6
We then tested whether the Bcl-2 BH3 peptide could directly inhibit Bcl-X L blocking of tBid induced Bax permeabilization of liposomes encapsulating the large 10-kDa CB-dextrans .	We then tested whether the Bcl-2 BH3 peptide could directly inhibit Bcl-X L blocking of tBid induced Bax permeabilization of liposomes encapsulating the large 10-kDa CB-dextrans.	5	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	17	18
We found that EG treatment of HL-60 cells decreased the expression of Bcl-2 at 75 muM EG , and increased Bax and truncated Bid ( tBid ) expression at 24 h ( XREF_FIG ) .	We found that EG treatment of HL-60 cells decreased the expression of Bcl-2 at 75 muM EG, and increased Bax and truncated Bid (tBid) expression at 24 h (XREF_FIG).	3	21	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	EG treatment of HL-60 cells decreased the expression of Bcl-2	bcl-2	Bax	Bax	bax	12	13	20	21
In healthy cells , antiapoptotic Bcl-2 family proteins , such as Bcl-2 , Bcl-xl , and Mcl-1 , bind and inhibit the multidomain proapoptotic proteins Bax and Bak .	In healthy cells, antiapoptotic Bcl-2 family proteins, such as Bcl-2, Bcl-xl, and Mcl-1, bind and inhibit the multidomain proapoptotic proteins Bax and Bak.	5	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	25	26
Pro survival factors Bcl-2 and Bcl-xl sequester BH3 domain-only molecules ( such as BID ) and prevent Bax- and Bak mediated mitochondrial apoptosis [ XREF_BIBR ] .	Pro survival factors Bcl-2 and Bcl-xl sequester BH3 domain-only molecules (such as BID) and prevent Bax- and Bak mediated mitochondrial apoptosis [XREF_BIBR].	3	19	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax-	Bax-	Bax-	3	4	17	18
Bax activation by wortmannin was prevented by Bcl-2 overexpression ( A-375-Bcl-2 ; XREF_FIG ) , proving Bax suppression by Bcl-2 in wortmannin and TRAIL induced apoptosis .	Bax activation by wortmannin was prevented by Bcl-2 overexpression (A-375-Bcl-2; XREF_FIG), proving Bax suppression by Bcl-2 in wortmannin and TRAIL induced apoptosis.	0	9	prevented	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	Bax	Bax	bax	7	8	0	1
Thus silibinin treatment caused a switch in the Bcl-2 and Bax ratio , which was elevated ( Bcl-2 and Bax > 1 ) in the mucosa of AOM injected rats and was reversed ( Bcl-2 and Bax < 1 ) after silibinin treatment .	Thus silibinin treatment caused a switch in the Bcl-2 and Bax ratio, which was elevated (Bcl-2 and Bax> 1) in the mucosa of AOM injected rats and was reversed (Bcl-2 and Bax < 1) after silibinin treatment.	8	37	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	36	37
Our study revealed that rAGAP upregulated the expression of Bax and caused simultaneous downregulation of Bcl-2 , thereby decreasing the Bcl-2 and Bax ratio .	Our study revealed that rAGAP upregulated the expression of Bax and caused simultaneous downregulation of Bcl-2, thereby decreasing the Bcl-2 and Bax ratio.	13	23	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	15	16	22	23
Meanwhile , apigenin downregulated the expression of Bcl-2 and decreased the ratio of Bcl-2 and Bax ( XREF_FIG ) .	Meanwhile, apigenin downregulated the expression of Bcl-2 and decreased the ratio of Bcl-2 and Bax (XREF_FIG).	2	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	apigenin downregulated the expression of Bcl-2	bcl-2	Bax	Bax	bax	7	8	15	16
In the HNG treated animals , the rise in Bcl-2 levels is also attenuated resulting in a similar Bax and Bcl -2 ratio as controls .	In the HNG treated animals, the rise in Bcl-2 levels is also attenuated resulting in a similar Bax and Bcl -2 ratio as controls.	9	22	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 levels	bcl-2	Bax	Bax	bax	9	10	18	19
This is because less anti-apoptotic BCL-2 proteins will be available to inhibit the subpopulation of partially- or fully activated BAX , and the same for the direct activator .	This is because less anti-apoptotic BCL-2 proteins will be available to inhibit the subpopulation of partially- or fully activated BAX, and the same for the direct activator.	5	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	5	6	19	20
Thus , Bcl-2 is a potent inhibitor of Bax such that the level of functional Bcl-2 serves as a threshold for Bax mediated cell death ( XREF_FIG ) .	Thus, Bcl-2 is a potent inhibitor of Bax such that the level of functional Bcl-2 serves as a threshold for Bax mediated cell death (XREF_FIG).	2	9	is a potent inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	8	9
Minimization of a mitochondrial Bax pool that is susceptible for activation is likely to prevent apoptosis and explains the spatial paradox of Bcl-2 protein inhibition of Bax .	Minimization of a mitochondrial Bax pool that is susceptible for activation is likely to prevent apoptosis and explains the spatial paradox of Bcl-2 protein inhibition of Bax.	22	27	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	22	23	26	27
The results of the current study demonstrate that the endoplasmic reticulum of the pancreatic acinar cell contains significant quantities of Bcl-2 family proteins and that the two small molecule inhibitors of Bcl-2 and Bcl-xl with markedly dissimilar molecular structures cause dissociation of proapoptotic Bax from prosurvival Bcl-2 and Bcl-xl .	The results of the current study demonstrate that the endoplasmic reticulum of the pancreatic acinar cell contains significant quantities of Bcl-2 family proteins and that the two small molecule inhibitors of Bcl-2 and Bcl-xl with markedly dissimilar molecular structures cause dissociation of proapoptotic Bax from prosurvival Bcl-2 and Bcl-xl.	29	44	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	31	32	43	44
The anti-apoptotic protein Bcl-2 can also antagonize Bax by forming heterodimers that prevent the oligomerization of Bax , leading to inhibition of apoptosis [ XREF_BIBR ] .	The anti-apoptotic protein Bcl-2 can also antagonize Bax by forming heterodimers that prevent the oligomerization of Bax, leading to inhibition of apoptosis [XREF_BIBR].	0	8	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	7	8
Compared with Vehicle group , the high dose of DM significantly alleviated neurological deficit , brain water content , infarct volume , increased the Nissl positive cells , upregulated the expression of pJAK2 , pSTAT3 and Bcl-2 and downregulated Bax ( P < 0.05 ) .	Compared with Vehicle group, the high dose of DM significantly alleviated neurological deficit, brain water content, infarct volume, increased the Nissl positive cells, upregulated the expression of pJAK2, pSTAT3 and Bcl-2 and downregulated Bax (P < 0.05).	16	41	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	water content, infarct volume, increased the Nissl positive cells, upregulated the expression of pJAK2, pSTAT3 and Bcl-2	bcl-2	Bax	Bax	bax	36	37	39	40
Our results showed that ovarian injury induced by chemotherapy resulted in increased Bax expression and decreased Bcl-2 expression , which reduced the Bcl-2 and Bax ratio in POI rats .	Our results showed that ovarian injury induced by chemotherapy resulted in increased Bax expression and decreased Bcl-2 expression, which reduced the Bcl-2 and Bax ratio in POI rats.	16	25	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	Bax	Bax	bax	16	17	24	25
Prenatal cocaine exposure decreased levels of Bcl-2 in 21-day and increased Bax in 21- and 30-day rat hearts .	Prenatal cocaine exposure decreased levels of Bcl-2 in 21-day and increased Bax in 21- and 30-day rat hearts.	1	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	cocaine exposure decreased levels of Bcl-2	bcl-2	Bax	Bax	bax	6	7	11	12
This indicates a new mechanism of anti-apoptotic Bcl-2 family member inhibition of Bax activation and apoptosis .	This indicates a new mechanism of anti-apoptotic Bcl-2 family member inhibition of Bax activation and apoptosis.	7	13	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	12	13
The antiapoptotic Bcl-2 family proteins , Bcl-2 or Bcl-xL , prevent the Bax conformational change by heterodimerizing with Bax , whereas various BH3-only proteins induce Bax conformational change in response to apoptotic stimuli [ XREF_BIBR - XREF_BIBR ] .	The antiapoptotic Bcl-2 family proteins, Bcl-2 or Bcl-xL, prevent the Bax conformational change by heterodimerizing with Bax, whereas various BH3-only proteins induce Bax conformational change in response to apoptotic stimuli [XREF_BIBR - XREF_BIBR].	2	14	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	12	13
XREF_BIBR , XREF_BIBR In addition , antiapoptotic Bcl-2 family proteins such as Bcl-2 and Mcl-1 , which suppress Bax and Bak dependent mitochondrial apoptosis , are frequently overexpressed in tumor cells .	XREF_BIBR, XREF_BIBR In addition, antiapoptotic Bcl-2 family proteins such as Bcl-2 and Mcl-1, which suppress Bax and Bak dependent mitochondrial apoptosis, are frequently overexpressed in tumor cells.	7	23	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	18	19
GC Treatment Suppresses Bcl-2 Expression and Enhances Bax and Bcl -2 Ratio in Leukemic Cells .	GC Treatment Suppresses Bcl-2 Expression and Enhances Bax and Bcl -2 Ratio in Leukemic Cells.	0	11	Enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	GC Treatment Suppresses Bcl-2 Expression	bcl-2	Bax	Bax	bax	3	4	7	8
The established mechanism for BCL-2 inhibition of BAX involves capture of the essential BH3 killer domain of BAX in the C-terminal binding groove of BCL-2 .	The established mechanism for BCL-2 inhibition of BAX involves capture of the essential BH3 killer domain of BAX in the C-terminal binding groove of BCL-2.	4	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	4	5	7	8
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR BAX and BAK are inhibited by anti-apoptotic BCL-2 family proteins , which include BCL-2 , BCL-2 regulated gene long isoform ( BCL-xl ) , BCL-2 like protein 2 ( BCL-w ) , A1 and myeloid cell leukemia-1 ( MCL-1 ) .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR BAX and BAK are inhibited by anti-apoptotic BCL-2 family proteins, which include BCL-2, BCL-2 regulated gene long isoform (BCL-xl), BCL-2 like protein 2 (BCL-w), A1 and myeloid cell leukemia-1 (MCL-1).	0	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	16	17	9	10
In the DNR-Cys-CdTe and DNR-GA-Cys-CdTe groups , Bax and caspase-3 were strongly expressed , while the expression of Bcl-2 and P-gp decreased significantly ( P < 0.05 ) , which resulted in an elevated ratio of Bax and Bcl -2 ( P < 0.01 ) compared with those of the other groups .	In the DNR-Cys-CdTe and DNR-GA-Cys-CdTe groups, Bax and caspase-3 were strongly expressed, while the expression of Bcl-2 and P-gp decreased significantly (P < 0.05), which resulted in an elevated ratio of Bax and Bcl -2 (P < 0.01) compared with those of the other groups.	16	38	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	18	19	36	37
Western blot analysis suggested that silence of TLR4 , MyD88 , ERK , JNK , and p38 decreased Bcl-2 expression level and increased Bax and cleaved caspase-3 expression levels , consistent with the FCM analysis results .	Western blot analysis suggested that silence of TLR4, MyD88, ERK, JNK, and p38 decreased Bcl-2 expression level and increased Bax and cleaved caspase-3 expression levels, consistent with the FCM analysis results.	9	24	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	MyD88, ERK, JNK, and p38 decreased Bcl-2 expression level	bcl-2	Bax	Bax	bax	18	19	23	24
Sequence Specific Inhibition of BAX Activation by BCL-2 BH4 SAHBs .	Sequence Specific Inhibition of BAX Activation by BCL-2 BH4 SAHBs.	2	9	Inhibition	Negative_activation_syntax_1_noun	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	7	8	4	5
We conclude that BHRF1 must exert its anti-apoptotic effect at the level of , or prior to , Bax and Bak activation , consistent with a report that BHRF1 prevented Bax and Bak conformational change , oligomerization and activation of the initiator caspase , caspase-9 XREF_BIBR .	We conclude that BHRF1 must exert its anti-apoptotic effect at the level of, or prior to, Bax and Bak activation, consistent with a report that BHRF1 prevented Bax and Bak conformational change, oligomerization and activation of the initiator caspase, caspase-9 XREF_BIBR.	28	34	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BHRF1	BHRF1	BHRF1	Bax	Bax	Bax	28	29	30	31
Bcl-2 and Bcl-xl inhibit Bax ( Bcl-2-associated X protein ) and Bak ( Bcl-2 homologous antagonist and killer ) .	Bcl-2 and Bcl-xl inhibit Bax (Bcl-2-associated X protein) and Bak (Bcl-2 homologous antagonist and killer).	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	4	5
Concomitantly , NGF enhanced expression of anti-apoptotic protein Bcl-2 , but suppressed that of pro apoptotic protein Bax .	Concomitantly, NGF enhanced expression of anti-apoptotic protein Bcl-2, but suppressed that of pro apoptotic protein Bax.	2	18	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	NGF enhanced expression of anti-apoptotic protein Bcl-2	bcl-2	Bax	Bax	bax	8	9	17	18
Bax and Bak can form complexes at the mitochondrial outer membrane to facilitate the release of apoptogenic mediators , whereas Bcl-2 sequesters BH3-only molecules to prevent the activation of Bax and Bak .	Bax and Bak can form complexes at the mitochondrial outer membrane to facilitate the release of apoptogenic mediators, whereas Bcl-2 sequesters BH3-only molecules to prevent the activation of Bax and Bak.	20	31	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	20	21	29	30
Western blot analysis revealed that vaspin upregulates the expression of Bcl-2 and downregulates that of Bax in a dose dependent manner .	Western blot analysis revealed that vaspin upregulates the expression of Bcl-2 and downregulates that of Bax in a dose dependent manner.	5	16	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	vaspin upregulates the expression of Bcl-2	bcl-2	Bax	Bax	bax	10	11	15	16
The Bcl-2 and Bax dimer abrogates the pro apoptotic function of Bax and protects the cells from apoptotic stimuli .	The Bcl-2 and Bax dimer abrogates the pro apoptotic function of Bax and protects the cells from apoptotic stimuli.	1	12	abrogates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	11	12
These data suggest that BCL-2 BH4 engagement blocks and even reverses the N-terminal conformational activation of BAX in the membrane context .	These data suggest that BCL-2 BH4 engagement blocks and even reverses the N-terminal conformational activation of BAX in the membrane context.	4	20	reverses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	4	5	16	17
Anti-apoptotic members of the Bcl-2 family of proteins , like Bcl-2 and Bcl-xL , can inhibit this process by binding and sequestering Puma ( and other BH3-only proteins ) to prevent activation of Bax and Bak .	Anti-apoptotic members of the Bcl-2 family of proteins, like Bcl-2 and Bcl-xL, can inhibit this process by binding and sequestering Puma (and other BH3-only proteins) to prevent activation of Bax and Bak.	4	35	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	33	34
CHOP acts to induce apoptosis by promoting constitutively expressed Bax translocation to the mitochondria through inhibition of anti-apoptotic Bcl-2 transcription , as Bcl-2 functions to inhibit Bax in pro survival conditions .	CHOP acts to induce apoptosis by promoting constitutively expressed Bax translocation to the mitochondria through inhibition of anti-apoptotic Bcl-2 transcription, as Bcl-2 functions to inhibit Bax in pro survival conditions.	22	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	22	23	26	27
20 Thus , Bax is inhibited by Bcl-2 , Bcl-w , Bcl-x L , Mcl-1 , A1 and Bcl-B , whereas Bak is neutralized by Bcl-x L , Mcl-1 and A1 ( XREF_FIG ) .	20 Thus, Bax is inhibited by Bcl-2, Bcl-w, Bcl-x L, Mcl-1, A1 and Bcl-B, whereas Bak is neutralized by Bcl-x L, Mcl-1 and A1 (XREF_FIG).	3	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	3	4
For example , Bax and Bak actions can be inhibited by Bcl-2 , Bc1-xL or other anti-apoptotic members of the Bcl-2 family , and caspases can be inhibited by inhibitor of apoptosis proteins ( IAPs ) .	For example, Bax and Bak actions can be inhibited by Bcl-2, Bc1-xL or other anti-apoptotic members of the Bcl-2 family, and caspases can be inhibited by inhibitor of apoptosis proteins (IAPs).	3	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	11	12	3	4
The Bax protein levels of hyperglycemic rats treated with GFW were unchanged but Bcl-2 protein levels were significantly increased , resulting in a decrease in the Bax and Bcl -2 ratio as compared with hyperglycemic rats .	The Bax protein levels of hyperglycemic rats treated with GFW were unchanged but Bcl-2 protein levels were significantly increased, resulting in a decrease in the Bax and Bcl -2 ratio as compared with hyperglycemic rats.	13	30	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 protein levels	bcl-2	Bax	Bax	bax	13	14	26	27
Conversely , Bcl-2 antagonizes Bax , so the high expression levels of Bcl-2 inhibitor block caspase-3-induced apoptosis .	Conversely, Bcl-2 antagonizes Bax, so the high expression levels of Bcl-2 inhibitor block caspase-3-induced apoptosis.	2	5	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	4	5
Increased expression of Bax and reduced levels of Bcl-2 have been detected in the skeletal muscle of old rodents .	Increased expression of Bax and reduced levels of Bcl-2 have been detected in the skeletal muscle of old rodents.	3	9	reduced	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Bcl-2	levels of Bcl-2	bcl-2	Bax	Bax	bax	8	9	3	4
When corpora lutea of the midluteal phase were incubated with hCG , hCG significantly increased the mRNA and protein levels of Bcl-2 and significantly decreased those of Bax .	When corpora lutea of the midluteal phase were incubated with hCG, hCG significantly increased the mRNA and protein levels of Bcl-2 and significantly decreased those of Bax.	12	28	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	hCG significantly increased the mRNA and protein levels of Bcl-2	bcl-2	Bax	Bax	bax	21	22	27	28
Bcl-2 inhibits relocation of BAX and BAK to the mitochondrial membrane , thus reducing membrane permeability and inhibiting cytochrome c release .	Bcl-2 inhibits relocation of BAX and BAK to the mitochondrial membrane, thus reducing membrane permeability and inhibiting cytochrome c release.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	0	1	4	5
Thus , BAX and BAK1 are dispensable for ABT-737-mediated autophagy , suggesting that BCL2 family members do not activate autophagy by indirectly inhibiting activation of BAX and BAK1 .	Thus, BAX and BAK1 are dispensable for ABT-737-mediated autophagy, suggesting that BCL2 family members do not activate autophagy by indirectly inhibiting activation of BAX and BAK1.	13	27	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	13	14	25	26
Bax directly or indirectly generates cell death signals while Bcl-2 is the dominant inhibitor of Bax .	Bax directly or indirectly generates cell death signals while Bcl-2 is the dominant inhibitor of Bax.	9	16	is the dominant inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	15	16
TM decreased the expression of BCL2 , but increased that of BAX .	TM decreased the expression of BCL2, but increased that of BAX.	0	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	TM decreased the expression of BCL2	bcl2	BAX	BAX	bax	5	6	11	12
Furthermore , rapamycin and curcumin increased caspase 9 , 3 and 7 activity , decreased anti-apoptotic bcl-2 levels , and increased the pro apoptotic protein Bax .	Furthermore, rapamycin and curcumin increased caspase 9, 3 and 7 activity, decreased anti-apoptotic bcl-2 levels, and increased the pro apoptotic protein Bax.	2	26	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	rapamycin and curcumin increased caspase 9, 3 and 7 activity, decreased anti-apoptotic bcl-2 levels	bcl-2	Bax	Bax	bax	16	17	25	26
XREF_BIBR The inhibition of bax , but not bcl-2 , suggests that anti-TNF-alpha antibody blocks the SAH induced apoptosis in the hypothalamus .	XREF_BIBR The inhibition of bax, but not bcl-2, suggests that anti-TNF-alpha antibody blocks the SAH induced apoptosis in the hypothalamus.	0	10	inhibition	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	bax	bax	bax	8	9	4	5
Conversely , prosurvival Bcl-2 proteins dampen apoptotic triggers and enhance chemoresistance by sequestering BH3-only proteins or directly inhibiting Bak and Bax .	Conversely, prosurvival Bcl-2 proteins dampen apoptotic triggers and enhance chemoresistance by sequestering BH3-only proteins or directly inhibiting Bak and Bax.	3	21	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	20	21
We confirmed that glucosamine treatment increased Bcl-2 expression , and decreased Bax , cleaved caspase-9 expressions and cytochrome c release , which were reversed by 10nM of mTOR inhibitor rapamycin pretreatment ( XREF_FIG ) .	We confirmed that glucosamine treatment increased Bcl-2 expression, and decreased Bax, cleaved caspase-9 expressions and cytochrome c release, which were reversed by 10nM of mTOR inhibitor rapamycin pretreatment (XREF_FIG).	3	23	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	glucosamine treatment increased Bcl-2 expression	bcl-2	Bax	Bax	bax	6	7	11	12
At least three EBV encoded proteins ( LMP1 , LMP2A and EBNA2 ) have been shown to induce the upregulation of various anti-apoptotic Bcl-2 family members able to sequester Bax .	At least three EBV encoded proteins (LMP1, LMP2A and EBNA2) have been shown to induce the upregulation of various anti-apoptotic Bcl-2 family members able to sequester Bax.	23	30	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	23	24	29	30
Bak is specifically bound by Bcl-xL and Mcl-1 whereas Bax can be inhibited by Bcl-2 , Bcl-w , Bcl-xL and Mcl-1 .	Bak is specifically bound by Bcl-xL and Mcl-1 whereas Bax can be inhibited by Bcl-2, Bcl-w, Bcl-xL and Mcl-1.	9	20	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	14	15	9	10
Bcl-2 inhibits BAX ( Bcl-2-associated X protein )/BAK ( Bcl-2-antagonist and killer1 ) proteins , which induce the permeabilization of the outer mitochondrial membrane , a crucial step for apoptotic cell death [ XREF_BIBR ] .	Bcl-2 inhibits BAX (Bcl-2-associated X protein)/BAK (Bcl-2-antagonist and killer1) proteins, which induce the permeabilization of the outer mitochondrial membrane, a crucial step for apoptotic cell death [XREF_BIBR].	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	0	1	2	3
Bcl-2 overexpression also blocked the translocation of Bax from the cytosol to the mitochondria only after the induction of ROS .	Bcl-2 overexpression also blocked the translocation of Bax from the cytosol to the mitochondria only after the induction of ROS.	0	8	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	Bax	Bax	bax	0	1	7	8
It is known that adenovirus encodes proteins that can specifically inhibit mitochondrial apoptosis , especially E1B 19K , a Bcl2 homologue that blocks Bax homo and heterodimerisation XREF_BIBR , XREF_BIBR .	It is known that adenovirus encodes proteins that can specifically inhibit mitochondrial apoptosis, especially E1B 19K, a Bcl2 homologue that blocks Bax homo and heterodimerisation XREF_BIBR, XREF_BIBR.	19	24	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	19	20	23	24
Stable RanBPM downregulated cells showed increased protein levels of anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-X L and , following IR treatment , decreased mitochondrial localization of Bax , a pro apoptotic Bcl-2 family member responsible for mitochondrial permeabilization and cytochrome-c release , a central step in the activation of apoptosis through the intrinsic pathway [ XREF_BIBR , XREF_BIBR ] .	Stable RanBPM downregulated cells showed increased protein levels of anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-X L and, following IR treatment, decreased mitochondrial localization of Bax, a pro apoptotic Bcl-2 family member responsible for mitochondrial permeabilization and cytochrome-c release, a central step in the activation of apoptosis through the intrinsic pathway [XREF_BIBR, XREF_BIBR].	1	28	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	RanBPM downregulated cells showed increased protein levels of anti-apoptotic Bcl-2 family members Bcl-2	bcl-2	Bax	Bax	bax	13	14	27	28
For example , Bcl-2 is the main inhibitor of apoptosis and Bax is the main promoter of apoptosis in the Bcl-2 family .	For example, Bcl-2 is the main inhibitor of apoptosis and Bax is the main promoter of apoptosis in the Bcl-2 family.	3	12	is the main inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	11	12
The anti-apoptotic Bcl-2 family member , Bcl-xL , inhibits apoptosis by antagonizing the actions of Bax and Bak , preventing the permeabilization of the mitochondrial outer membrane and activation of caspases [ XREF_BIBR ] .	The anti-apoptotic Bcl-2 family member, Bcl-xL, inhibits apoptosis by antagonizing the actions of Bax and Bak, preventing the permeabilization of the mitochondrial outer membrane and activation of caspases [XREF_BIBR].	2	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	15	16
By contrast , Bcl-2 sequesters Bax to suppress membrane permeabilization .	By contrast, Bcl-2 sequesters Bax to suppress membrane permeabilization.	3	6	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	5	6
In the intrinsic pathway , RACK1 inhibits expression of anti-apoptotic Bcl-2 and Bcl-X ( L ) , induces expression of pro apoptotic Bim , targets Bim and Bax to the mitochondria , induces oligomerization of Bax ( which requires Bim and inhibition of Src ) , depolarizes mitochondria membranes , releases cytochrome c , and activates caspases-9 and -3 and death substrates .	In the intrinsic pathway, RACK1 inhibits expression of anti-apoptotic Bcl-2 and Bcl-X (L), induces expression of pro apoptotic Bim, targets Bim and Bax to the mitochondria, induces oligomerization of Bax (which requires Bim and inhibition of Src), depolarizes mitochondria membranes, releases cytochrome c, and activates caspases-9 and -3 and death substrates.	5	28	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	RACK1 inhibits expression of anti-apoptotic Bcl-2	bcl-2	Bax	Bax	bax	10	11	27	28
Bcl-2 overexpression inhibits Bax activation , mitochondrial perturbations , cleavage of caspases and Bid , and apoptosis , confirming the central role of the mitochondrial pathway for chemosensitization .	Bcl-2 overexpression inhibits Bax activation, mitochondrial perturbations, cleavage of caspases and Bid, and apoptosis, confirming the central role of the mitochondrial pathway for chemosensitization.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	Bax	Bax	bax	0	1	3	4
Bcl-2 , the main anti-apoptotic protein is able to inhibit Bax action , and it has become in an important target for the development of new drugs [ XREF_BIBR , XREF_BIBR ] , so the relationship between both proteins was analyzed .	Bcl-2, the main anti-apoptotic protein is able to inhibit Bax action, and it has become in an important target for the development of new drugs [XREF_BIBR, XREF_BIBR], so the relationship between both proteins was analyzed.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	10	11
IL-10 gene silencing causes down regulation of both PI3K and AKT and Bcl2 gene expression and also increases the Bbc3 , BAX caspase3 , and caspase 3 cleavage expression levels .	IL-10 gene silencing causes down regulation of both PI3K and AKT and Bcl2 gene expression and also increases the Bbc3, BAX caspase3, and caspase 3 cleavage expression levels.	0	22	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	IL-10 gene silencing causes down regulation of both PI3K and AKT and Bcl2 gene expression	bcl2	BAX	BAX	bax	12	13	21	22
Overexpression of Bcl-2 not only suppressed apoptosis but also completely prevented induction of p21 and Bax caused by ceramide in SK-Hep-1 cells .	Overexpression of Bcl-2 not only suppressed apoptosis but also completely prevented induction of p21 and Bax caused by ceramide in SK-Hep-1 cells.	0	16	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	Bax	Bax	bax	2	3	15	16
This compound belongs to a class of BH3 mimetic agents that inhibit the activity of the anti-apoptotic BCL-2 members that antagonize the proapoptotic proteins BAX and BAK [ XREF_BIBR ] .	This compound belongs to a class of BH3 mimetic agents that inhibit the activity of the anti-apoptotic BCL-2 members that antagonize the proapoptotic proteins BAX and BAK [XREF_BIBR].	17	28	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	17	18	24	25
Bcl-2 antagonizes Bax by reducing cytochrome c release .	Bcl-2 antagonizes Bax by reducing cytochrome c release.	0	3	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	2	3
Bcl-2 pro survival proteins negatively regulate pro apoptotic proteins Bax and Bak via interactions between their Bcl-2 homology ( BH ) domains .	Bcl-2 pro survival proteins negatively regulate pro apoptotic proteins Bax and Bak via interactions between their Bcl-2 homology (BH) domains.	0	13	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	9	10
Although both are widely expressed and functionally redundant , genetic and biochemical data suggest that Bak is held in check primarily by Mcl-1 and Bcl-x L , whereas Bax activation is inhibited by all five pro survival Bcl-2 homologues .	Although both are widely expressed and functionally redundant, genetic and biochemical data suggest that Bak is held in check primarily by Mcl-1 and Bcl-x L, whereas Bax activation is inhibited by all five pro survival Bcl-2 homologues.	28	38	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	37	38	28	29
Bcl-2 protein , in contrast , by binding to and inactivating Bax protein , suppresses the apoptotic process .	Bcl-2 protein, in contrast, by binding to and inactivating Bax protein, suppresses the apoptotic process.	0	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	11	12
Anti-apoptotic BCL-2 antagonizes BAX and BAK , preventing MOMP and promoting cell survival -- thus , mutant IDH cells display dependence on BCL-2 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Anti-apoptotic BCL-2 antagonizes BAX and BAK, preventing MOMP and promoting cell survival -- thus, mutant IDH cells display dependence on BCL-2 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	5	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	1	2	3	4
In the present study , we found that Bax and Bcl-2 levels were up- and downregulated , respectively , resulting in an increase in Bax and Bcl -2 ratio in oligoasthenospermia rats .	In the present study, we found that Bax and Bcl-2 levels were up- and downregulated, respectively, resulting in an increase in Bax and Bcl -2 ratio in oligoasthenospermia rats.	8	26	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 levels	bcl-2	Bax	Bax	bax	10	11	24	25
Immunoblot showed that CpG-ODN administration increased Bcl-2 levels by 41 % and attenuated I/R increased levels of Bax and caspase-3 activity in ischemic brain tissues .	Immunoblot showed that CpG-ODN administration increased Bcl-2 levels by 41% and attenuated I/R increased levels of Bax and caspase-3 activity in ischemic brain tissues.	3	20	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	CpG-ODN administration increased Bcl-2 levels	bcl-2	Bax	Bax	bax	6	7	17	18
The results showed that 11.55 nM HHT or 1.12 nM Bortezomib significantly increased cleavage activation of caspase 9 and caspase 3 , inhibited anti-apoptotic protein Bcl-2 expression and upregulated pro apoptotic protein Bax .	The results showed that 11.55 nM HHT or 1.12 nM Bortezomib significantly increased cleavage activation of caspase 9 and caspase 3, inhibited anti-apoptotic protein Bcl-2 expression and upregulated pro apoptotic protein Bax.	6	33	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	HHT or 1.12 nM Bortezomib significantly increased cleavage activation of caspase 9 and caspase 3, inhibited anti-apoptotic protein Bcl-2 expression	bcl-2	Bax	Bax	bax	25	26	32	33
XREF_BIBR Proteins of the Bcl-2 family regulate the mitochondrial pathway of apoptosis , and Bcl-2 can block apoptosis in response to varieties of insults by preventing the activation and homo-oligomerization of both Bax and Bak .	XREF_BIBR Proteins of the Bcl-2 family regulate the mitochondrial pathway of apoptosis, and Bcl-2 can block apoptosis in response to varieties of insults by preventing the activation and homo-oligomerization of both Bax and Bak.	14	34	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	14	15	32	33
Here , the candidate for the rescue factor is BCL2 , which in higher concentrations would outcompete BAX for BH3-domain binding and thus either prevent BAX from activating or , if already activated , from proceeding to MOM permeabilization [ XREF_BIBR ] .	Here, the candidate for the rescue factor is BCL2, which in higher concentrations would outcompete BAX for BH3-domain binding and thus either prevent BAX from activating or, if already activated, from proceeding to MOM permeabilization [XREF_BIBR].	0	35	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	9	10	25	26
While pro survival Bcl-2 proteins bind to and deactivate Bak and Bax XREF_BIBR , other apoptotic Bcl-2 proteins de-repress this inhibition , leaving Bak and Bax free to oligomerize XREF_BIBR .	While pro survival Bcl-2 proteins bind to and deactivate Bak and Bax XREF_BIBR, other apoptotic Bcl-2 proteins de-repress this inhibition, leaving Bak and Bax free to oligomerize XREF_BIBR.	3	12	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	11	12
XREF_BIBR , XREF_BIBR Here , we found that PCAF simultaneously repressed Bcl-2 expression and upregulated BAX in HCC cells , both in vitro and in vivo .	XREF_BIBR, XREF_BIBR Here, we found that PCAF simultaneously repressed Bcl-2 expression and upregulated BAX in HCC cells, both in vitro and in vivo.	8	18	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	PCAF simultaneously repressed Bcl-2 expression	bcl-2	BAX	BAX	bax	11	12	15	16
Yizhi jiannao granule can decrease the neuron apoptosis rate and the Bax level , increase the Bcl-2 level , and modulate the rate of Bcl-2 and Bax in SAMP/8 brain , which is probably part of the mechanisms of inhibiting the apoptosis and improving learning and memory .	Yizhi jiannao granule can decrease the neuron apoptosis rate and the Bax level, increase the Bcl-2 level, and modulate the rate of Bcl-2 and Bax in SAMP/8 brain, which is probably part of the mechanisms of inhibiting the apoptosis and improving learning and memory.	1	27	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	jiannao granule can decrease the neuron apoptosis rate and the Bax level, increase the Bcl-2 level	bcl-2	Bax	Bax	bax	16	17	26	27
Results showed that the expression level of proapoptotic protein Bax in tumor tissue was significantly elevated while expression of antiapoptotic Bcl-2 protein was effectively reduced , resulting in an increased Bax and Bcl -2 ratio .	Results showed that the expression level of proapoptotic protein Bax in tumor tissue was significantly elevated while expression of antiapoptotic Bcl-2 protein was effectively reduced, resulting in an increased Bax and Bcl -2 ratio.	17	34	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of antiapoptotic Bcl-2	bcl-2	Bax	Bax	bax	20	21	30	31
Based on the aforementioned results , the effect of VPA against ER stress induced apoptosis is not only promoting the expression of GRP78 and the anti-apoptotic protein Bcl-2 but also inhibiting the activity of caspase-12 and caspase-3 as well as down-regulating CHOP and the pro apoptotic protein Bax .	Based on the aforementioned results, the effect of VPA against ER stress induced apoptosis is not only promoting the expression of GRP78 and the anti-apoptotic protein Bcl-2 but also inhibiting the activity of caspase-12 and caspase-3 as well as down-regulating CHOP and the pro apoptotic protein Bax.	9	48	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	VPA against ER stress induced apoptosis is not only promoting the expression of GRP78 and the anti-apoptotic protein Bcl-2	bcl-2	Bax	Bax	bax	27	28	47	48
Both STS and Donepezil significantly upregulated the Bcl-2 expression and downregulated the Bax and cleaved Caspase-3 expressions when compared to SCOP group .	Both STS and Donepezil significantly upregulated the Bcl-2 expression and downregulated the Bax and cleaved Caspase-3 expressions when compared to SCOP group.	1	13	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	STS and Donepezil significantly upregulated the Bcl-2 expression	bcl-2	Bax	Bax	bax	7	8	12	13
Here , we suggest that GR mediated inhibition of Bcl-2 and Bcl-xL would relieve repression of Bax activity and thus trigger the apoptotic cascade , thereby slowing tumor growth .	Here, we suggest that GR mediated inhibition of Bcl-2 and Bcl-xL would relieve repression of Bax activity and thus trigger the apoptotic cascade, thereby slowing tumor growth.	7	17	relieve	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	16	17
As a downstream activator of the AKT signaling pathway , BCL2 increases cell survival by inhibiting the proapoptotic protein BAX 39 .	As a downstream activator of the AKT signaling pathway, BCL2 increases cell survival by inhibiting the proapoptotic protein BAX 39.	10	20	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	10	11	19	20
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Ectopic expression of Bcl-2 in EC109 cells , by transfection with a Bcl-2 expression plasmid , inhibited the upregulation of Bax and cleaved PARP expression by metformin ( XREF_FIG ) , indicating that Bcl-2 overexpression can block metformin induced apoptosis .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Ectopic expression of Bcl-2 in EC109 cells, by transfection with a Bcl-2 expression plasmid, inhibited the upregulation of Bax and cleaved PARP expression by metformin (XREF_FIG), indicating that Bcl-2 overexpression can block metformin induced apoptosis.	8	28	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	10	11	27	28
In addition , the anti-apoptotic bcl-2 protein , which sequesters Bax and inhibits the activation of caspase-9 , was reduced by CsA treatment .	In addition, the anti-apoptotic bcl-2 protein, which sequesters Bax and inhibits the activation of caspase-9, was reduced by CsA treatment.	5	11	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	Bax	Bax	Bax	5	6	10	11
XREF_BIBR , XREF_BIBR Anti-apoptotic members of the Bcl-2 family , such as Bcl-2 or Bcl-xL , inhibit Bax or Bak activation , as members of the Bcl-xL protein family contain BH1 and BH2 domains which are required for heterodimerization with Bak and the inhibition of cell apoptosis .	XREF_BIBR, XREF_BIBR Anti-apoptotic members of the Bcl-2 family, such as Bcl-2 or Bcl-xL, inhibit Bax or Bak activation, as members of the Bcl-xL protein family contain BH1 and BH2 domains which are required for heterodimerization with Bak and the inhibition of cell apoptosis.	7	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	17	18
In contrast , the anti-apoptotic Bcl-2 family members block apoptosis by preventing Bax and Bak activation and MOMP [ XREF_BIBR ] .	In contrast, the anti-apoptotic Bcl-2 family members block apoptosis by preventing Bax and Bak activation and MOMP [XREF_BIBR].	5	15	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	12	13
Whether Bim mediates heat shock induced apoptosis through a BAX and BAK dependent pathway that is antagonized by antiapoptotic BCL-2 family members in heat stress induced apoptosis of granulosa cells should be explored in the future .	Whether Bim mediates heat shock induced apoptosis through a BAX and BAK dependent pathway that is antagonized by antiapoptotic BCL-2 family members in heat stress induced apoptosis of granulosa cells should be explored in the future.	5	21	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	19	20	9	10
Sulforaphane also promoted an increase in the expression of the anti-apoptotic protein Bcl-2 ( 60 % ) , decreasing the Bax and Bcl -2 ratio .	Sulforaphane also promoted an increase in the expression of the anti-apoptotic protein Bcl-2 (60%), decreasing the Bax and Bcl -2 ratio.	7	24	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of the anti-apoptotic protein Bcl-2	bcl-2	Bax	Bax	bax	12	13	20	21
In these paradigms of dopaminergic cell death , overexpression of Bcl-2 prevented both STS- and MPP ( + )-induced cell death and its associated cleavage of Bax .	In these paradigms of dopaminergic cell death, overexpression of Bcl-2 prevented both STS- and MPP (+)-induced cell death and its associated cleavage of Bax.	8	27	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	Bax	Bax	bax	10	11	26	27
In contrast , the canonical groove of anti-apoptotic BCL-2 family members , the BCL-2 BH4 motif , and the cytomegalovirus vMIA protein can bind to and inhibit BAX XREF_BIBR - XREF_BIBR .	In contrast, the canonical groove of anti-apoptotic BCL-2 family members, the BCL-2 BH4 motif, and the cytomegalovirus vMIA protein can bind to and inhibit BAX XREF_BIBR - XREF_BIBR.	8	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	8	9	27	28
In accord with evidence of a significant role for Bim and Bax and Bak in BEZ235 and ABT -737 lethality , ectopic expression of Bcl-2 or Bcl-xL , which , like Mcl-1 sequester Bim , and Bax and Bak , significantly protected cells against ABT-737 and BEZ235 or PI-103 lethality ( XREF_SUPPLEMENTARY ) .	In accord with evidence of a significant role for Bim and Bax and Bak in BEZ235 and ABT -737 lethality, ectopic expression of Bcl-2 or Bcl-xL, which, like Mcl-1 sequester Bim, and Bax and Bak, significantly protected cells against ABT-737 and BEZ235 or PI-103 lethality (XREF_SUPPLEMENTARY).	22	38	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	24	25	36	37
VIP increased the levels of the antiapoptotic protein Bcl-2 and decreased those of the proapoptotic protein Bax .	VIP increased the levels of the antiapoptotic protein Bcl-2 and decreased those of the proapoptotic protein Bax.	0	17	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	VIP increased the levels of the antiapoptotic protein Bcl-2	bcl-2	Bax	Bax	bax	8	9	16	17
Very recently , the stapled Bcl-2 BH4 domain helices were revealed to bind directly and inhibit proapoptotic Bax by a noncanonical mechanism [ XREF_BIBR ] .	Very recently, the stapled Bcl-2 BH4 domain helices were revealed to bind directly and inhibit proapoptotic Bax by a noncanonical mechanism [XREF_BIBR].	5	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	17	18
Interestingly , we found that melatonin induces a strong re-localization of Bcl-2 , the main Bax antagonist to mitochondria , suggesting that Bax activation may in fact be antagonized by Bcl-2 at the mitochondrial level .	Interestingly, we found that melatonin induces a strong re-localization of Bcl-2, the main Bax antagonist to mitochondria, suggesting that Bax activation may in fact be antagonized by Bcl-2 at the mitochondrial level.	22	31	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	30	31	22	23
The reduction of Bcl-2 and Mcl-1 frees Bim proteins to activate Bax or Bak and subsequently increases the mitochondria permeability , facilitating Caspase dependent apoptosis .	The reduction of Bcl-2 and Mcl-1 frees Bim proteins to activate Bax or Bak and subsequently increases the mitochondria permeability, facilitating Caspase dependent apoptosis.	1	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	11	12
At the same time , Bcl-2 promotes cell survival by limiting the pro apoptotic effects of Bax and blocking the release of cytochrome C from mitochondria .	At the same time, Bcl-2 promotes cell survival by limiting the pro apoptotic effects of Bax and blocking the release of cytochrome C from mitochondria.	5	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	16	17
Active Bax and caspases kill Saccharomyces cerevisiae , and pro survival Bcl-2 proteins can inhibit Bax induced yeast death .	Active Bax and caspases kill Saccharomyces cerevisiae, and pro survival Bcl-2 proteins can inhibit Bax induced yeast death.	11	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	11	12	15	16
Bax promotes apoptosis by the release of cytochrome c from mitochondria and downstream activation of caspases , while Bcl-2 inhibits cell apoptosis by restraining the pro apoptotic effects of Bax and blocking the release of cytochrome c [ XREF_BIBR , XREF_BIBR ] .	Bax promotes apoptosis by the release of cytochrome c from mitochondria and downstream activation of caspases, while Bcl-2 inhibits cell apoptosis by restraining the pro apoptotic effects of Bax and blocking the release of cytochrome c [XREF_BIBR, XREF_BIBR].	18	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	18	19	29	30
However , the antiapoptotic Bcl-2 family members , such as Bcl-2 , can prevent the oligomerization of Bax and Bak .	However, the antiapoptotic Bcl-2 family members, such as Bcl-2, can prevent the oligomerization of Bax and Bak.	4	19	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	17	18
26 Antiapoptotic Bcl-2 proteins , such as Bcl-X L , were shown to prevent Bax activation and mitochondrial outer membrane permeabilization via several mechanisms , that is , by directly binding to Bax and by sequestering tBid , thereby preventing Bax activation by tBid .	26 Antiapoptotic Bcl-2 proteins, such as Bcl-X L, were shown to prevent Bax activation and mitochondrial outer membrane permeabilization via several mechanisms, that is, by directly binding to Bax and by sequestering tBid, thereby preventing Bax activation by tBid.	2	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	14	15
Furthermore , NPS2390 up-regulated anti-apoptotic protein Bcl-2 expression and down-regulated pro apoptotic protein Bax , and reduced subsequent release of cytochrome c into the cytosol .	Furthermore, NPS2390 up-regulated anti-apoptotic protein Bcl-2 expression and down-regulated pro apoptotic protein Bax, and reduced subsequent release of cytochrome c into the cytosol.	2	14	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	NPS2390 up-regulated anti-apoptotic protein Bcl-2 expression	bcl-2	Bax	Bax	bax	6	7	13	14
Surprisingly , Bcl-2 also blocked Bax membrane insertion .	Surprisingly, Bcl-2 also blocked Bax membrane insertion.	2	7	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	5	6
According to the indirect activation model , BH3-only proteins activate Bax and Bak in an indirect fashion by engaging the multiple anti-apoptotic Bcl-2 proteins that inhibit Bax and Bak , thereby releasing their inhibition on Bax and Bak [ XREF_BIBR , XREF_BIBR ] .	According to the indirect activation model, BH3-only proteins activate Bax and Bak in an indirect fashion by engaging the multiple anti-apoptotic Bcl-2 proteins that inhibit Bax and Bak, thereby releasing their inhibition on Bax and Bak [XREF_BIBR, XREF_BIBR].	22	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	22	23	26	27
Although constitutive Bcl-2 expression prevented Bax activation , it did not alter cyclin D1 induced cell cycle arrest , illustrating the independence of these events .	Although constitutive Bcl-2 expression prevented Bax activation, it did not alter cyclin D1 induced cell cycle arrest, illustrating the independence of these events.	2	6	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	Bax	Bax	bax	2	3	5	6
CM-12 and CM-24 induced the expresssions of Bax , cleaved-caspase 3 and cytochrome c , at the same time reduced Bcl-2 , hence , the Bcl-2 and Bax ratio was significantly decreased .	CM-12 and CM-24 induced the expresssions of Bax, cleaved-caspase 3 and cytochrome c, at the same time reduced Bcl-2, hence, the Bcl-2 and Bax ratio was significantly decreased.	5	32	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	25	26	7	8
In contrast , the proapoptotic protein Bax , is antagonised by the antiapoptotic Bcl-2 protein .	In contrast, the proapoptotic protein Bax, is antagonised by the antiapoptotic Bcl-2 protein.	3	14	antagonised	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	13	14	6	7
Overexpression of anti-apoptotic BCL-2 proteins contributes to tumor development and resistance to therapy by suppressing BAX and its activators .	Overexpression of anti-apoptotic BCL-2 proteins contributes to tumor development and resistance to therapy by suppressing BAX and its activators.	0	18	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	Overexpression of anti-apoptotic BCL-2	bcl-2	BAX	BAX	bax	3	4	15	16
Bcl-2 has been reported to inhibit activation of Bax and Bak to prevent permeabilization of the outer mitochondrial membrane , and it blocks the opening of the mPTP to improve the calcium threshold in heart mitochondria .	Bcl-2 has been reported to inhibit activation of Bax and Bak to prevent permeabilization of the outer mitochondrial membrane, and it blocks the opening of the mPTP to improve the calcium threshold in heart mitochondria.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	8	9
Under normal physiological conditions , bax , a proapoptotic protein , resides in the cytosol and is negatively regulated by the antiapoptotic protein bcl-2 .	Under normal physiological conditions, bax, a proapoptotic protein, resides in the cytosol and is negatively regulated by the antiapoptotic protein bcl-2.	5	24	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	bax	bax	bax	23	24	5	6
PCAF represses Bcl-2 expression and upregulates BAX via negative regulation of GLI1 and consequently induces cell apoptosis .	PCAF represses Bcl-2 expression and upregulates BAX via negative regulation of GLI1 and consequently induces cell apoptosis.	0	9	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	PCAF represses Bcl-2 expression	bcl-2	BAX	BAX	bax	2	3	6	7
Dobutamine decreases Bcl-2 levels , increases mitochondrial Bax contents , reduces mitochondria membrane potential and promotes cytochrome c release in LPS treated adult mouse cardiomyocytes .	Dobutamine decreases Bcl-2 levels, increases mitochondrial Bax contents, reduces mitochondria membrane potential and promotes cytochrome c release in LPS treated adult mouse cardiomyocytes.	0	8	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Dobutamine decreases Bcl-2 levels	bcl-2	Bax	Bax	bax	2	3	7	8
In contrast , Bcl-2 overexpression blocks Bax from the mitochondria , thus inhibiting apoptosis .	In contrast, Bcl-2 overexpression blocks Bax from the mitochondria, thus inhibiting apoptosis.	3	7	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	Bax	Bax	bax	3	4	6	7
Competing models have been presented that describe how Bcl-2 inhibits the cell killing activity of Bax , which is common in treatment resistant tumors where Bcl-2 is overexpressed .	Competing models have been presented that describe how Bcl-2 inhibits the cell killing activity of Bax, which is common in treatment resistant tumors where Bcl-2 is overexpressed.	8	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	15	16
The anti-apoptotic Bcl2 gene is expressed at low levels in interdigital regions but at high levels in digital rays , suggesting that the BCL2 protein might antagonize the activities of BAX and BAK in digits thereby preventing their apoptotic death .	The anti-apoptotic Bcl2 gene is expressed at low levels in interdigital regions but at high levels in digital rays, suggesting that the BCL2 protein might antagonize the activities of BAX and BAK in digits thereby preventing their apoptotic death.	23	32	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	23	24	30	31
Detection of the expression of apoptosis related proteins of Bcl-2 and Bax by immunohistochemistry showed that ChA21 therapy could up-regulate the expression of Bax , and down-regulate the expression of Bcl-2 , thereby reducing the ratio of Bcl-2 and Bax in vitro and in vivo .	Detection of the expression of apoptosis related proteins of Bcl-2 and Bax by immunohistochemistry showed that ChA21 therapy could up-regulate the expression of Bax, and down-regulate the expression of Bcl-2, thereby reducing the ratio of Bcl-2 and Bax in vitro and in vivo.	16	40	reducing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	ChA21 therapy could up-regulate the expression of Bax, and down-regulate the expression of Bcl-2	bcl-2	Bax	Bax	bax	30	31	39	40
NVP-BEZ235 decreased the levels of antiapoptotic proteins Bcl-2 , Mcl-1 and increased proapoptotic proteins Bax , Noxa , which suggested that NVP-BEZ235 could strongly modulate apoptosis in NPC xenografts .	NVP-BEZ235 decreased the levels of antiapoptotic proteins Bcl-2, Mcl-1 and increased proapoptotic proteins Bax, Noxa, which suggested that NVP-BEZ235 could strongly modulate apoptosis in NPC xenografts.	0	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	NVP-BEZ235 decreased the levels of antiapoptotic proteins Bcl-2	bcl-2	Bax	Bax	bax	7	8	14	15
The anti-apoptotic Bcl-2 protein prevents the homo-oligomerization of Bax and Bak , but Bcl-2 is downregulated in AD .	The anti-apoptotic Bcl-2 protein prevents the homo-oligomerization of Bax and Bak, but Bcl-2 is downregulated in AD.	2	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	8	9
PGC-1alpha over-expression enhanced the expression of anti-apoptotic gene Bcl-2 , and inhibited the expression pro apoptotic gene Bax in MSCs .	PGC-1alpha over-expression enhanced the expression of anti-apoptotic gene Bcl-2, and inhibited the expression pro apoptotic gene Bax in MSCs.	0	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	PGC-1alpha over-expression enhanced the expression of anti-apoptotic gene Bcl-2	bcl-2	Bax	Bax	bax	8	9	17	18
BCL-2 and Bcl-xL are anti-apoptotic proteins and prevent the oligomerization of pro apoptotic proteins BAX and BAK , thus blocking the release of cytochrome c from mitochondria [ XREF_BIBR - XREF_BIBR ] .	BCL-2 and Bcl-xL are anti-apoptotic proteins and prevent the oligomerization of pro apoptotic proteins BAX and BAK, thus blocking the release of cytochrome c from mitochondria [XREF_BIBR - XREF_BIBR].	0	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	0	1	14	15
RCE-4 increased the expression of Bax and decreased the expression of Bcl-2 , thus augmenting the Bax and Bcl -2 ratio .	RCE-4 increased the expression of Bax and decreased the expression of Bcl-2, thus augmenting the Bax and Bcl -2 ratio.	0	20	augmenting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	RCE-4 increased the expression of Bax and decreased the expression of Bcl-2	bcl-2	Bax	Bax	bax	11	12	16	17
Conversely , anti-apoptotic Bcl-2 proteins inhibit Bax and Bak by sequestering the BH3-only activators , and possibly also through direct interactions with Bax and Bak .	Conversely, anti-apoptotic Bcl-2 proteins inhibit Bax and Bak by sequestering the BH3-only activators, and possibly also through direct interactions with Bax and Bak.	3	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	6	7
In the displacement model , anti-apoptotic Bcl-2 family proteins bind to and thereby inhibit active forms of Bax and Bak .	In the displacement model, anti-apoptotic Bcl-2 family proteins bind to and thereby inhibit active forms of Bax and Bak.	6	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	17	18
The pro apoptotic multidomain Bcl-2 proteins act to permeabilize the outer mitochondrial membrane , leading to release of cytochrome c , whereas the anti-apoptotic Bcl-2 proteins act to inhibit pro apoptotic Bak and Bax proteins .	The pro apoptotic multidomain Bcl-2 proteins act to permeabilize the outer mitochondrial membrane, leading to release of cytochrome c, whereas the anti-apoptotic Bcl-2 proteins act to inhibit pro apoptotic Bak and Bax proteins.	24	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	24	25	33	34
For the apoptotic markers , astaxanthin promoted the expression of anti-apoptosis protein Bcl-2 but inhibited the pro apoptotic proteins Bax and caspase-9 .	For the apoptotic markers, astaxanthin promoted the expression of anti-apoptosis protein Bcl-2 but inhibited the pro apoptotic proteins Bax and caspase-9.	5	21	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	astaxanthin promoted the expression of anti-apoptosis protein Bcl-2	bcl-2	Bax	Bax	bax	12	13	19	20
XREF_FIG illustrated that SI/R injury induced upregulation of Bax expression and downregulation of Bcl-2 expression , thereby decreasing the Bcl-2 and Bax ratio .	XREF_FIG illustrated that SI/R injury induced upregulation of Bax expression and downregulation of Bcl-2 expression, thereby decreasing the Bcl-2 and Bax ratio.	3	22	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	SI/R injury induced upregulation of Bax expression and downregulation of Bcl-2 expression	bcl-2	Bax	Bax	bax	13	14	21	22
Anti-apoptotic Bcl-2 , a close relative of Bcl-xL [ XREF_BIBR , XREF_BIBR ] , can inhibit pro apoptotic BAX activity by heterodimerizing with BAX [ XREF_BIBR , XREF_BIBR ] or by binding tBID and hence precluding tBID dependent activation of BAX [ XREF_BIBR , XREF_BIBR ] .	Anti-apoptotic Bcl-2, a close relative of Bcl-xL [XREF_BIBR, XREF_BIBR], can inhibit pro apoptotic BAX activity by heterodimerizing with BAX [XREF_BIBR, XREF_BIBR] or by binding tBID and hence precluding tBID dependent activation of BAX [XREF_BIBR, XREF_BIBR].	0	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	1	2	18	19
Diazoxide increased the levels of Bcl2 and inhibited the association of Bax with mitochondria in neurons exposed to an apoptotic insult , suggesting that activation of mitochondrial ATP sensitive potassium channels may stabilize mitochondrial function by differentially modulating proapoptotic and antiapoptotic proteins .	Diazoxide increased the levels of Bcl2 and inhibited the association of Bax with mitochondria in neurons exposed to an apoptotic insult, suggesting that activation of mitochondrial ATP sensitive potassium channels may stabilize mitochondrial function by differentially modulating proapoptotic and antiapoptotic proteins.	0	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Diazoxide increased the levels of Bcl2	bcl2	Bax	Bax	bax	5	6	11	12
We found that the cells transfected with anti-miR-7-1 mimic or exposed to CI increased Bax but decreased Bcl-2 expression at mRNA ( XREF_FIG ) as well as at protein ( XREF_FIG ) level , leading to significant increase in the Bax : Bcl-2 ratio in the cells ( XREF_FIG ) .	We found that the cells transfected with anti-miR-7-1 mimic or exposed to CI increased Bax but decreased Bcl-2 expression at mRNA (XREF_FIG) as well as at protein (XREF_FIG) level, leading to significant increase in the Bax : Bcl-2 ratio in the cells (XREF_FIG).	13	41	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	decreased Bcl-2 expression at mRNA (XREF_FIG) as well as at protein (XREF_FIG) level, leading to significant increase in the Bax	bcl-2	Bax	Bax	bax	17	18	14	15
The activation of Bax in our model is represented by tBid-Bax and Bax2 complexes , which simulate Bax oligomerisation induced directly by BH3-only proteins and by general inhibition of anti-apoptotic Bcl-2 proteins .	The activation of Bax in our model is represented by tBid-Bax and Bax2 complexes, which simulate Bax oligomerisation induced directly by BH3-only proteins and by general inhibition of anti-apoptotic Bcl-2 proteins.	17	31	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	30	31	17	18
EGCG decreased the expression of antiapoptotic protein Bcl-2 but increased proapoptotic protein Bax in these cells .	EGCG decreased the expression of antiapoptotic protein Bcl-2 but increased proapoptotic protein Bax in these cells.	0	13	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	EGCG decreased the expression of antiapoptotic protein Bcl-2	bcl-2	Bax	Bax	bax	7	8	12	13
Calcitriol represses the expression of the anti-apoptotic , pro survival proteins Bcl-2 and Bcl-X L and may induce the expression of pro apoptotic proteins ( Bax , Bak and Bad ) .	Calcitriol represses the expression of the anti-apoptotic, pro survival proteins Bcl-2 and Bcl-X L and may induce the expression of pro apoptotic proteins (Bax, Bak and Bad).	0	29	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Calcitriol represses the expression of the anti-apoptotic, pro survival proteins Bcl-2	bcl-2	Bax	Bax	bax	11	12	25	26
For the former mechanisms , we addressed the rising possibility that Gal-3 is involved in Bcl-2 and Bax heterodimer because anti-apoptotic Bcl-2 normally sequesters pro apoptotic Bax on mitochondria .	For the former mechanisms, we addressed the rising possibility that Gal-3 is involved in Bcl-2 and Bax heterodimer because anti-apoptotic Bcl-2 normally sequesters pro apoptotic Bax on mitochondria.	20	28	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	21	22	26	27
Thus , BIM mediates heat shock induced apoptosis through a BAX and BAK dependent pathway that is antagonized by antiapoptotic BCL-2 family members .	Thus, BIM mediates heat shock induced apoptosis through a BAX and BAK dependent pathway that is antagonized by antiapoptotic BCL-2 family members.	6	22	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	20	21	10	11
These data suggest that Bcl-2 does not function solely to prevent the activation of Bax ( but also must inactivate Bak function ) .	These data suggest that Bcl-2 does not function solely to prevent the activation of Bax (but also must inactivate Bak function).	4	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	14	15
Bcl-2 inhibited Bax auto-activation .	Bcl-2 inhibited Bax auto-activation.	0	3	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	2	3
The conformationally changed Bcl-2 sequesters the integral membrane form of Bax .	The conformationally changed Bcl-2 sequesters the integral membrane form of Bax.	0	11	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	10	11
Antiapoptotic Bcl-2 family proteins suppress pro apoptotic Bax and Bak [ which would otherwise inhibit mitochondrial outer membrane permeabilization ] .	Antiapoptotic Bcl-2 family proteins suppress pro apoptotic Bax and Bak [which would otherwise inhibit mitochondrial outer membrane permeabilization].	1	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	7	8
Mechanism investigation showed that TEO could decrease anti-apoptotic Bcl-2 protein expression , increase proapoptotic Bax and Bid proteins expressions and increase Bax and Bcl -2 ratio .	Mechanism investigation showed that TEO could decrease anti-apoptotic Bcl-2 protein expression, increase proapoptotic Bax and Bid proteins expressions and increase Bax and Bcl -2 ratio.	4	25	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	TEO could decrease anti-apoptotic Bcl-2 protein expression	bcl-2	Bax	Bax	bax	8	9	21	22
By contrast , in MRC-5 and 293T cells , high expression of the UPR feedback protein GADD34 which inhibits proapoptotic UPR signaling , and antiapoptotic Bcl-2 and Bcl-xl which down-regulate Bax and Bak , protect these normal cells from PEG-PE-induced apoptosis .	By contrast, in MRC-5 and 293T cells, high expression of the UPR feedback protein GADD34 which inhibits proapoptotic UPR signaling, and antiapoptotic Bcl-2 and Bcl-xl which down-regulate Bax and Bak, protect these normal cells from PEG-PE-induced apoptosis.	10	32	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of the UPR feedback protein GADD34 which inhibits proapoptotic UPR signaling, and antiapoptotic Bcl-2	bcl-2	Bax	Bax	bax	25	26	30	31
Bax and/or Bak are normally sequestered by pro survival Bcl-2 proteins in viable cells .	Bax and/or Bak are normally sequestered by pro survival Bcl-2 proteins in viable cells.	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	0	1
Bcl-2 , a downstream target for Erk1/2 , is known to inhibit Bax in the intrinsic pro apoptotic pathway .	Bcl-2, a downstream target for Erk1/2, is known to inhibit Bax in the intrinsic pro apoptotic pathway.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	12	13
This pro apoptosis effect was due to Bcl-2 repression and expression of the pro apoptotic proteins caspase 3 and Bax , which demonstrated the chemosensitization of these tumor cells to docetaxel in the presence of ginsenosides R3 .	This pro apoptosis effect was due to Bcl-2 repression and expression of the pro apoptotic proteins caspase 3 and Bax, which demonstrated the chemosensitization of these tumor cells to docetaxel in the presence of ginsenosides R3.	7	22	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	19	20
The distribution of Bcl-2 and Bax in the cytosol of aged rats dramatically decreased the Bcl-2 and Bax ratio , a probable indicator of neuronal vulnerability , which was restored upon treatment with PBN .	The distribution of Bcl-2 and Bax in the cytosol of aged rats dramatically decreased the Bcl-2 and Bax ratio, a probable indicator of neuronal vulnerability, which was restored upon treatment with PBN.	1	18	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	17	18
Bcl2 acts to suppress the actions of Bax .	Bcl2 acts to suppress the actions of Bax.	0	8	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	0	1	7	8
By mimicking BH3-only proteins ( such as NOXA , PUMA , BID , BAD , BIM ) , antiapoptotic BCL2 members can be sequestered , thus , allowing BAK and BAX to activate the intrinsic apoptotic pathway .	By mimicking BH3-only proteins (such as NOXA, PUMA, BID, BAD, BIM), antiapoptotic BCL2 members can be sequestered, thus, allowing BAK and BAX to activate the intrinsic apoptotic pathway.	19	32	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	19	20	30	31
In this model , antiapoptotic Bcl-2 proteins sequester both active Bax and BH3-only activators , and BH3-only sensitizers displace Bax and BH3-only activators from the antiapoptotic proteins .	In this model, antiapoptotic Bcl-2 proteins sequester both active Bax and BH3-only activators, and BH3-only sensitizers displace Bax and BH3-only activators from the antiapoptotic proteins.	5	22	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	19	20
33 On the contrary , overexpression of Bcl-2 prevents the oligimerization of Bax at the mitochondria , and thereby inhibits death signaling .	33 On the contrary, overexpression of Bcl-2 prevents the oligimerization of Bax at the mitochondria, and thereby inhibits death signaling.	5	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	Bax	Bax	bax	7	8	12	13
Anti-apoptotic Bcl-2 family proteins , such as Mcl-1 , Bcl-x L and Bcl-2 , promote cell survival by inhibiting oligomerization of Bak and Bax , while the pro apoptotic BH3-only proteins , including Bim , Bid , PUMA , Noxa and Bad , promote apoptosis by binding to and neutralizing the anti-apoptotic proteins , releasing Bak and Bax inhibition .	Anti-apoptotic Bcl-2 family proteins, such as Mcl-1, Bcl-x L and Bcl-2, promote cell survival by inhibiting oligomerization of Bak and Bax, while the pro apoptotic BH3-only proteins, including Bim, Bid, PUMA, Noxa and Bad, promote apoptosis by binding to and neutralizing the anti-apoptotic proteins, releasing Bak and Bax inhibition.	1	24	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	23	24
KHC-4 suppressed the survival signaling p-PI3K and p-Akt and protein levels of Bcl-2 and Bcl-xL , upregulated Bax , cytochrome c and Caspase 8/9 and induced apoptosis by mitochondrial dependent pathway .	KHC-4 suppressed the survival signaling p-PI3K and p-Akt and protein levels of Bcl-2 and Bcl-xL, upregulated Bax, cytochrome c and Caspase 8/9 and induced apoptosis by mitochondrial dependent pathway.	0	22	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	KHC-4 suppressed the survival signaling p-PI3K and p-Akt and protein levels of Bcl-2	bcl-2	Bax	Bax	bax	12	13	17	18
This led to the proposal of an alternative model where the pro survival Bcl-2 family members inhibit autophagy by restraining their apoptotic interaction partners Bax and Bak , the effectors of intrinsic apoptosis .	This led to the proposal of an alternative model where the pro survival Bcl-2 family members inhibit autophagy by restraining their apoptotic interaction partners Bax and Bak, the effectors of intrinsic apoptosis.	13	29	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	13	14	24	25
They include ( i ) multi-domain proteins , such as Bax or Bak , that are absolutely required for MOMP and subsequent cyto-c release , ( ii ) pro apoptotic BH3-only proteins that are either direct Bax or Bak activators or sensitizer and ( iii ) anti-apoptotic proteins , such as Bcl-2 , Bcl-xL or Mcl-1 , that prevent Bax or Bak activation and MOMP .	They include (i) multi-domain proteins, such as Bax or Bak, that are absolutely required for MOMP and subsequent cyto-c release, (ii) pro apoptotic BH3-only proteins that are either direct Bax or Bak activators or sensitizer and (iii) anti-apoptotic proteins, such as Bcl-2, Bcl-xL or Mcl-1, that prevent Bax or Bak activation and MOMP.	6	62	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	51	52	59	60
It is a well-known fact that the decrease of Bcl-2 enables the oligomerized Bax to re-localize and insert into outer mitochondrial membrane drive apoptosis [ XREF_BIBR ] .	It is a well-known fact that the decrease of Bcl-2 enables the oligomerized Bax to re-localize and insert into outer mitochondrial membrane drive apoptosis [XREF_BIBR].	7	17	enables	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	13	14
Anti-apoptotic Bcl-2 protein is localized on the outer mitochondrial membranes and antagonizes the action of pro apoptotic Bax .	Anti-apoptotic Bcl-2 protein is localized on the outer mitochondrial membranes and antagonizes the action of pro apoptotic Bax.	1	18	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	17	18
Bcl-2 blocks oligomerization of Bak and Bax , thus , preventing loss of MOMP .	Bcl-2 blocks oligomerization of Bak and Bax, thus, preventing loss of MOMP.	0	7	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	6	7
3 Conversely , the ' indirect model ' posits that cell death is initiated when all pro survival BCL-2 proteins sequestering BAX and BAK are neutralised by BH3-only proteins , thereby unleashing the pro apoptotic actions of BAX and BAK .	3 Conversely, the ' indirect model ' posits that cell death is initiated when all pro survival BCL-2 proteins sequestering BAX and BAK are neutralised by BH3-only proteins, thereby unleashing the pro apoptotic actions of BAX and BAK.	15	25	sequestering	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	18	19	21	22
High level overexpression of the anti-apoptotic protein Bcl-2 prevented Bax redistribution to the mitochondria , caspase activation and apoptosis following exposure to staurosporine or etoposide .	High level overexpression of the anti-apoptotic protein Bcl-2 prevented Bax redistribution to the mitochondria, caspase activation and apoptosis following exposure to staurosporine or etoposide.	2	10	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of the anti-apoptotic protein Bcl-2	bcl-2	Bax	Bax	bax	7	8	9	10
Other studies have found that lithium treatment increased the expression of Bcl-2 or heat shock protein and reduced the levels of the pro apoptotic proteins p53 and Bax .	Other studies have found that lithium treatment increased the expression of Bcl-2 or heat shock protein and reduced the levels of the pro apoptotic proteins p53 and Bax.	5	28	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	lithium treatment increased the expression of Bcl-2	bcl-2	Bax	Bax	bax	11	12	27	28
On the other side , the anti-apoptotic Bcl-2 family proteins , such as Bcl-2 and Bcl-XL , inhibit Bax and Bak .	On the other side, the anti-apoptotic Bcl-2 family proteins, such as Bcl-2 and Bcl-XL, inhibit Bax and Bak.	7	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	18	19
Since Bax and Bak are normally sequestered by Bcl-2 and Bcl-xL [ XREF_BIBR ] , our findings suggest that combination of limonoids could directly target mitochondria to induce release of proapoptotic proteins in Bax and Bak independent manner .	Since Bax and Bak are normally sequestered by Bcl-2 and Bcl-xL [XREF_BIBR], our findings suggest that combination of limonoids could directly target mitochondria to induce release of proapoptotic proteins in Bax and Bak independent manner.	1	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	1	2
We show that the gamma-herpesvirus 68 ( gammaHV68 ) Bcl-2 family protein ( gammaHV68 v-Bcl-2 ) , which is known to inhibit apoptosis in cultured cells , inhibits both apoptosis in primary lymphocytes and Bax toxicity in yeast .	We show that the gamma-herpesvirus 68 (gammaHV68) Bcl-2 family protein (gammaHV68 v-Bcl-2), which is known to inhibit apoptosis in cultured cells, inhibits both apoptosis in primary lymphocytes and Bax toxicity in yeast.	9	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	34	35
Bcl-2 antagonizes Bax and Bak to prevent mitochondrial permeabilization and inhibit apoptosis .	Bcl-2 antagonizes Bax and Bak to prevent mitochondrial permeabilization and inhibit apoptosis.	0	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	2	3
These protective proteins either inhibit the activation of caspases or they act as Bcl-2 homologs to prevent Bax and Bak mediated outer mitochondrial membrane permeabilization ( MOMP ) .	These protective proteins either inhibit the activation of caspases or they act as Bcl-2 homologs to prevent Bax and Bak mediated outer mitochondrial membrane permeabilization (MOMP).	13	19	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	13	14	17	18
Antiapoptotic Bcl-2 family proteins perform their pro survival function by binding and sequestering the pro apoptotic effector proteins Bax and Bak and inhibiting membrane pore formation .	Antiapoptotic Bcl-2 family proteins perform their pro survival function by binding and sequestering the pro apoptotic effector proteins Bax and Bak and inhibiting membrane pore formation.	1	20	sequestering	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	18	19
It has been shown that Stat3 leads to the increased transcription of Bcl-2 , which lowers the Bax and Bcl -2 ratio .	It has been shown that Stat3 leads to the increased transcription of Bcl-2, which lowers the Bax and Bcl -2 ratio.	5	21	lowers	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Stat3 leads to the increased transcription of Bcl-2	bcl-2	Bax	Bax	bax	12	13	17	18
Immunohistochemical analysis of the expression of the antiapoptotic protein Bcl-2 and the proapoptotic proteins Bax and caspase-3 showed that MWM and CEE upregulated the expression of Bcl-2 and downregulated that of Bax and caspase-3 in ovarian tissues of perimenopausal rats compared to the levels in untreated controls , with obvious differences observed at 8 weeks ( XREF_FIG ) .	Immunohistochemical analysis of the expression of the antiapoptotic protein Bcl-2 and the proapoptotic proteins Bax and caspase-3 showed that MWM and CEE upregulated the expression of Bcl-2 and downregulated that of Bax and caspase-3 in ovarian tissues of perimenopausal rats compared to the levels in untreated controls, with obvious differences observed at 8 weeks (XREF_FIG).	19	33	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	MWM and CEE upregulated the expression of Bcl-2	bcl-2	Bax	Bax	bax	26	27	31	32
As shown in Figure XREF_FIG , western blots showed that B19 dose-dependently decreased the expression of anti-apoptotic proteins Bcl-2 and increased the expression of pro apoptotic proteins Bax in three gastric cancer cell lines ( SGC-7901 , BGC-823 and KATO III ) .	As shown in Figure XREF_FIG, western blots showed that B19 dose-dependently decreased the expression of anti-apoptotic proteins Bcl-2 and increased the expression of pro apoptotic proteins Bax in three gastric cancer cell lines (SGC-7901, BGC-823 and KATO III).	10	33	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	B19 dose-dependently decreased the expression of anti-apoptotic proteins Bcl-2	bcl-2	Bax	Bax	bax	18	19	27	28
On the other hand , Bcl-2 inhibits Bax , which can help increase mitochondrial membrane potential .	On the other hand, Bcl-2 inhibits Bax, which can help increase mitochondrial membrane potential.	5	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	7	8
In contrast , Bcl-2 ( delta A ) and an NH2-terminal deletion mutant Bcl-2 ( delta 1-82 ) retained Bax binding activity in vitro but failed to suppress Bax mediated cytotoxicity in yeast .	In contrast, Bcl-2 (delta A) and an NH2-terminal deletion mutant Bcl-2 (delta 1-82) retained Bax binding activity in vitro but failed to suppress Bax mediated cytotoxicity in yeast.	3	29	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	28	29
To test whether the upregulation and activation of Bax was necessary for ANT1 induced death , we co-infected cardiomyocytes with the Bax antagonist Bcl2 .	To test whether the upregulation and activation of Bax was necessary for ANT1 induced death, we co-infected cardiomyocytes with the Bax antagonist Bcl2.	17	24	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	23	24	21	22
RT-PCR confirms that Hss significantly inhibits the expression of the Bcl-2 gene and promotes the high expression of the Bax gene .	RT-PCR confirms that Hss significantly inhibits the expression of the Bcl-2 gene and promotes the high expression of the Bax gene.	3	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Hss significantly inhibits the expression of the Bcl-2	bcl-2	Bax	Bax	bax	10	11	19	20
ICA Increased Bcl-2 Expression and Decreased Bax and Cleaved Caspase-3 Expressions in OGD/R Treated PC12 Cells .	ICA Increased Bcl-2 Expression and Decreased Bax and Cleaved Caspase-3 Expressions in OGD/R Treated PC12 Cells.	0	7	Decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	ICA Increased Bcl-2 Expression	bcl-2	Bax	Bax	bax	2	3	6	7
Moreover , both are reduced by transfection with the Bax antagonist Bcl-2 .	Moreover, both are reduced by transfection with the Bax antagonist Bcl-2.	4	12	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	11	12	9	10
Furthermore , AH is found to improve the protein expression of Bcl-2 , phosphorylation of Akt and GSK-3beta , downregulate the protein of Bax .	Furthermore, AH is found to improve the protein expression of Bcl-2, phosphorylation of Akt and GSK-3beta, downregulate the protein of Bax.	9	24	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	11	12	23	24
The antiapoptotic members of the Bcl-2 family such as Bcl-2 and Bcl-XL have been shown to inhibit Bax induced mitochondrial permeabilization .	The antiapoptotic members of the Bcl-2 family such as Bcl-2 and Bcl-XL have been shown to inhibit Bax induced mitochondrial permeabilization.	5	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	17	18
Mdivi-1 Increases Bcl-2 and Decreases Bax , Thereby Increasing the Bcl-2 and Bax Ratio .	Mdivi-1 Increases Bcl-2 and Decreases Bax, Thereby Increasing the Bcl-2 and Bax Ratio.	0	6	Decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	5	6
Judging from our results , we postulate that through co-operation with Diva , Bcl2 is able to sequester Bax as shown by the strong initial binding of Diva to Bax .	Judging from our results, we postulate that through co-operation with Diva, Bcl2 is able to sequester Bax as shown by the strong initial binding of Diva to Bax.	13	19	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	13	14	18	19
Under these conditions , the comparison of co-immunoprecipitated proteins from Ntv-a and PDGF cells treated or not with folate or PDGFri revealed that the Ntv-a and PDGF cells were characterized by the strong inhibition of Bax by Bcl-2 , Bcl-xl , and Bcl-w , a high antagonism of PUMA and Bim by Bcl-2 , Bcl-xl , and Bcl-w , and a low neutralization of Bcl-2 , Bcl-xl , and Bcl-w by Bad .	Under these conditions, the comparison of co-immunoprecipitated proteins from Ntv-a and PDGF cells treated or not with folate or PDGFri revealed that the Ntv-a and PDGF cells were characterized by the strong inhibition of Bax by Bcl-2, Bcl-xl, and Bcl-w, a high antagonism of PUMA and Bim by Bcl-2, Bcl-xl, and Bcl-w, and a low neutralization of Bcl-2, Bcl-xl, and Bcl-w by Bad.	29	46	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	37	38	35	36
Antiapoptotic Bcl-2 family members Bcl-2 and Bcl-xL were downregulated , with proapoptotic member Bax stable or upregulated , resulting in reduced Bcl-2 and Bax and Bcl-xL and Bax ratios .	Antiapoptotic Bcl-2 family members Bcl-2 and Bcl-xL were downregulated, with proapoptotic member Bax stable or upregulated, resulting in reduced Bcl-2 and Bax and Bcl-xL and Bax ratios.	1	24	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	23	24
Antiapoptotic gene Bcl2 is known to inhibit Bax and thus preventing the cell from undergoing apoptosis [ XREF_BIBR ] .	Antiapoptotic gene Bcl2 is known to inhibit Bax and thus preventing the cell from undergoing apoptosis [XREF_BIBR].	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	2	3	7	8
However , this process is tightly controlled antagonistically by anti-apoptotic members of the Bcl-2 protein family , which can inhibit Bax activation through a direct interaction XREF_BIBR .	However, this process is tightly controlled antagonistically by anti-apoptotic members of the Bcl-2 protein family, which can inhibit Bax activation through a direct interaction XREF_BIBR.	13	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	13	14	20	21
Ingestion of DSW600 , DSW1200 , or selenium upregulates Trxnrd1 as well as Bcl-2 expression and downregulates Bax in duodenal cells .	Ingestion of DSW600, DSW1200, or selenium upregulates Trxnrd1 as well as Bcl-2 expression and downregulates Bax in duodenal cells.	2	18	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	DSW600, DSW1200, or selenium upregulates Trxnrd1 as well as Bcl-2 expression	bcl-2	Bax	Bax	bax	13	14	17	18
Interestingly , forced expression of PCAF reduced Bcl-2 expression , upregulated BAX and repressed cell apoptosis .	Interestingly, forced expression of PCAF reduced Bcl-2 expression, upregulated BAX and repressed cell apoptosis.	3	12	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of PCAF reduced Bcl-2 expression	bcl-2	BAX	BAX	bax	7	8	11	12
14 This suggests that anti-apoptotic BCL-2 family proteins preferentially inhibit the activated form of Bax and Bak .	14 This suggests that anti-apoptotic BCL-2 family proteins preferentially inhibit the activated form of Bax and Bak.	5	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	Bax	Bax	Bax	5	6	14	15
Bcl2 like 10 ( Bcl2l10 ) is a anti-apoptotic member of the Bcl2 family [ XREF_BIBR ] acting to suppress cell death by preventing cytochrome c release , casp-3 activation and mitochondrial membrane collapse [ XREF_BIBR ] .	Bcl2 like 10 (Bcl2l10) is a anti-apoptotic member of the Bcl2 family [XREF_BIBR] acting to suppress cell death by preventing cytochrome c release, casp-3 activation and mitochondrial membrane collapse [XREF_BIBR].	12	26	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	12	13	24	26
This receptor activates a transduction cascade of second messengers to stimulate Bcl-2 expression , which inhibits cytochrome c release and blocks the activation of caspases .	This receptor activates a transduction cascade of second messengers to stimulate Bcl-2 expression, which inhibits cytochrome c release and blocks the activation of caspases.	11	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	16	18
Since Bcl-2 can inhibit cytochrome c ( Cyt c ) release and prevent opening of the megachannel by acting on the mitochondria [ XREF_BIBR ] , we speculated that the mitochondrial mediated pathway may be involved in JAK2 and STAT3 signalling induced apoptosis .	Since Bcl-2 can inhibit cytochrome c (Cyt c) release and prevent opening of the megachannel by acting on the mitochondria [XREF_BIBR], we speculated that the mitochondrial mediated pathway may be involved in JAK2 and STAT3 signalling induced apoptosis.	1	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	4	6
The protection of the respiratory activity by Bcl-2 is mainly due to the fact that Bcl-2 blocks the release of the cytochrome c from mitochondria .	The protection of the respiratory activity by Bcl-2 is mainly due to the fact that Bcl-2 blocks the release of the cytochrome c from mitochondria.	15	23	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	21	23
Moreover , MCE treatment significantly augmented the levels of anti-apoptotic Bcl2 and blocks the release of cytochrome c , thereby alleviating the rotenone induced dopaminergic neuronal loss , as evidenced by tyrosine hydroxylase ( TH ) immunostaining in the striatum .	Moreover, MCE treatment significantly augmented the levels of anti-apoptotic Bcl2 and blocks the release of cytochrome c, thereby alleviating the rotenone induced dopaminergic neuronal loss, as evidenced by tyrosine hydroxylase (TH) immunostaining in the striatum.	2	18	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	MCE treatment significantly augmented the levels of anti-apoptotic Bcl2	bcl2	cytochrome c	cytochrome c	cytochrome c	10	11	16	18
Bcl-2 resides in the outer mitochondrial wall and inhibits cytochrome c release .	Bcl-2 resides in the outer mitochondrial wall and inhibits cytochrome c release.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	9	11
XREF_BIBR The anti-apoptotic Bcl-2 and Bcl-xL proteins inhibit cytochrome c release through the mitochondrial pore and also inhibit activation of the cytoplasmic caspase cascade by cytochrome c. XREF_BIBR , XREF_BIBR Previous studies have suggested that activated Akt could phosphorylate Bad , contributing to cell survival , otherwise apoptosis is carried out .	XREF_BIBR The anti-apoptotic Bcl-2 and Bcl-xL proteins inhibit cytochrome c release through the mitochondrial pore and also inhibit activation of the cytoplasmic caspase cascade by cytochrome c. XREF_BIBR, XREF_BIBR Previous studies have suggested that activated Akt could phosphorylate Bad, contributing to cell survival, otherwise apoptosis is carried out.	1	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	8	10
The increase of Bcl-2 expression can prevent the release of cytochrome c and thus caspase activation ( Pinton et al ., 2000 ) .	The increase of Bcl-2 expression can prevent the release of cytochrome c and thus caspase activation (Pinton et al., 2000).	3	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	10	12
Bcl-2 and Bcl-xL inhibit the release of cytochrome c from the mitochondria when they are not bound with Bad .	Bcl-2 and Bcl-xL inhibit the release of cytochrome c from the mitochondria when they are not bound with Bad.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	7	9
The Bcl-2 protein family showed some impact on mitochondrial membrane permeabilization , and Bcl-2 can stabilize mitochondrial membrane permeability and prevent cytochrome c release .	The Bcl-2 protein family showed some impact on mitochondrial membrane permeabilization, and Bcl-2 can stabilize mitochondrial membrane permeability and prevent cytochrome c release.	13	23	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	21	23
Bcl-X L and Bcl-2 not only promote cell survival by binding and inhibiting pro apoptotic Bcl-2 family members XREF_BIBR , XREF_BIBR , but also prevent cytochrome c release by regulating the inner mitochondrial membrane potential .	Bcl-X L and Bcl-2 not only promote cell survival by binding and inhibiting pro apoptotic Bcl-2 family members XREF_BIBR, XREF_BIBR, but also prevent cytochrome c release by regulating the inner mitochondrial membrane potential.	1	27	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	25	27
The underlying mechanism is proposed that blocking of Bcl-2 by VV-miR-34a increases the release of cytochrome c from mitochondria and then synergistically amplifies the antitumor effects of Smac induced cell apoptosis .	The underlying mechanism is proposed that blocking of Bcl-2 by VV-miR-34a increases the release of cytochrome c from mitochondria and then synergistically amplifies the antitumor effects of Smac induced cell apoptosis.	6	17	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	15	17
In contrast , the antiapoptotic proteins Bcl-2 and Bcl-x L , which can form heterodimers with Bax , inhibit cytochrome c release and protect against NGF withdrawal induced death .	In contrast, the antiapoptotic proteins Bcl-2 and Bcl-x L, which can form heterodimers with Bax, inhibit cytochrome c release and protect against NGF withdrawal induced death.	3	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 and Bcl-x L, which can form heterodimers with Bax	bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	19	21
Specifically , Bax is capable of facilitating cytochrome c release , while Bcl-2 is found to impede cytochrome c movement .	Specifically, Bax is capable of facilitating cytochrome c release, while Bcl-2 is found to impede cytochrome c movement.	12	19	impede	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	12	13	17	19
Overexpression of Bcl-2 prevents the release of cytochrome c from the mitochondria , a critical event in the apoptotic pathway .	Overexpression of Bcl-2 prevents the release of cytochrome c from the mitochondria, a critical event in the apoptotic pathway.	0	9	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	7	9
Bcl-2 , an apoptosis inhibitor located on the mitochondrial outer membrane , prevents cytochrome c release , caspase activation , and cell death .	Bcl-2, an apoptosis inhibitor located on the mitochondrial outer membrane, prevents cytochrome c release, caspase activation, and cell death.	0	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
High level of Bcl-2 inhibits apoptosis by preventing cytochrome c release while high level of Bax induces apoptosis by binding to the mitochondrial membrane and increases membrane permeability allowing the release of cytochrome c [ XREF_BIBR ] .	High level of Bcl-2 inhibits apoptosis by preventing cytochrome c release while high level of Bax induces apoptosis by binding to the mitochondrial membrane and increases membrane permeability allowing the release of cytochrome c [XREF_BIBR].	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	level of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	8	10
In contrast , in SKW lymphoblastoid cells , TRAIL induced activation of caspase-8 directly translated into full activation of caspases , cleavage of XIAP , DFF45 or PARP and apoptosis independent of Bcl-2 overexpression , although Bcl-2 similarly inhibited loss of mitochondrial membrane potential and the release of cytochrome c , AIF and Smac from mitochondria in all cell types .	In contrast, in SKW lymphoblastoid cells, TRAIL induced activation of caspase-8 directly translated into full activation of caspases, cleavage of XIAP, DFF45 or PARP and apoptosis independent of Bcl-2 overexpression, although Bcl-2 similarly inhibited loss of mitochondrial membrane potential and the release of cytochrome c, AIF and Smac from mitochondria in all cell types.	36	50	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	36	37	48	50
Transduction of islets with Adv-hHGF-hIL-1Ra greatly enhanced the level of Bcl-2 protein while inhibited Bax protein level , demonstrating the protective effect of hHGF and hIL-1Ra co-expression , since Bcl-2 has been shown to inhibit cytochrome C release and protect against oxidative stress induced apoptosis .	Transduction of islets with Adv-hHGF-hIL-1Ra greatly enhanced the level of Bcl-2 protein while inhibited Bax protein level, demonstrating the protective effect of hHGF and hIL-1Ra co-expression, since Bcl-2 has been shown to inhibit cytochrome C release and protect against oxidative stress induced apoptosis.	29	39	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	29	30	35	37
The anti-apoptotic protein Bcl-2 and the pancaspase inhibitor zVAD-fmk did not prevent cytochrome c release , but completely blocked the reduction in Delta psi ( m ) , DNA fragmentation and apoptosis .	The anti-apoptotic protein Bcl-2 and the pancaspase inhibitor zVAD-fmk did not prevent cytochrome c release, but completely blocked the reduction in Delta psi (m), DNA fragmentation and apoptosis.	0	18	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	12	14
Specific activation of the mitochondrial K-uniporter led to cytochrome c release , which was inhibited by bcl-2 .	Specific activation of the mitochondrial K-uniporter led to cytochrome c release, which was inhibited by bcl-2.	8	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	16	17	8	10
In comparing model simulations with experimental results , we find the best agreement when Bcl-2 blocks the release of cytochrome c by binding to both Bax and truncated Bid instead of Bax , truncated Bid , or Bid alone .	In comparing model simulations with experimental results, we find the best agreement when Bcl-2 blocks the release of cytochrome c by binding to both Bax and truncated Bid instead of Bax, truncated Bid, or Bid alone.	14	21	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	14	15	19	21
BCL2 stabilizes mitochondria and prevents cytochrome c release to activate apoptosis , however BCL2 should not interfere with Caspase 8 cleavage resulting from death receptor activation .	BCL2 stabilizes mitochondria and prevents cytochrome c release to activate apoptosis, however BCL2 should not interfere with Caspase 8 cleavage resulting from death receptor activation.	0	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Pronounced swelling of mitochondria was evident ultrastructurally , and the MPT inhibitor cyclosporin A prevented the release of cytochrome c. Overexpression of Bcl-2 prevented the translocation of Bid , the release of cytochrome c , and cell death .	Pronounced swelling of mitochondria was evident ultrastructurally, and the MPT inhibitor cyclosporin A prevented the release of cytochrome c. Overexpression of Bcl-2 prevented the translocation of Bid, the release of cytochrome c, and cell death.	20	34	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	22	23	32	34
The adenovirus Bcl-2 homologue E1B 19K blocks TNF-alpha-mediated apoptosis by preventing cytochrome c release , caspase-9 activation , and apoptosis of virus infected cells .	The adenovirus Bcl-2 homologue E1B 19K blocks TNF-alpha-mediated apoptosis by preventing cytochrome c release, caspase-9 activation, and apoptosis of virus infected cells.	0	13	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	11	13
Bcl-2 , as antiapoptotic molecule , prevents release of cytochrome C and inactivates caspases ( Chinnaiyan etal .	Bcl-2, as antiapoptotic molecule, prevents release of cytochrome C and inactivates caspases (Chinnaiyan etal.	0	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	9	11
CA also increased the number of sub-G1 hypodiploid cells ; increased mitochondrial dysfunction ( loss of MMP , cytochrome c release , and accompanied by Bcl-2 and Mcl-1 down-regulation and Bax up-regulation ) , and activated the caspase cascades activations , which displayed features of mitochondria dependent apoptosis pathway .	CA also increased the number of sub-G1 hypodiploid cells; increased mitochondrial dysfunction (loss of MMP, cytochrome c release, and accompanied by Bcl-2 and Mcl-1 down-regulation and Bax up-regulation), and activated the caspase cascades activations, which displayed features of mitochondria dependent apoptosis pathway.	14	28	loss	Negative_activation_syntax_1_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	25	26	18	20
Recent findings indicate that Bcl-2 localized specifically on the ER also inhibits cytochrome c release and apoptosis in response to a variety of signals .	Recent findings indicate that Bcl-2 localized specifically on the ER also inhibits cytochrome c release and apoptosis in response to a variety of signals.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	12	14
Bcl-2 , the antiapoptotic protein , inhibits apoptosis by preventing cytochrome c release into the cytoplasm [ XREF_BIBR ] , while Bax , the proapoptotic protein , promotes apoptosis by inducing mitochondrial membrane depolarization .	Bcl-2, the antiapoptotic protein, inhibits apoptosis by preventing cytochrome c release into the cytoplasm [XREF_BIBR], while Bax, the proapoptotic protein, promotes apoptosis by inducing mitochondrial membrane depolarization.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	10	12
XREF_BIBR Bcl-2 translocation to the mitochondrial membrane blocks apoptosis and cytochrome c release .	XREF_BIBR Bcl-2 translocation to the mitochondrial membrane blocks apoptosis and cytochrome c release.	1	12	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 translocation to the mitochondrial membrane	bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	10	12
Bcl-2 stabilizes the mitochondrial membrane potential and prevents the release of mitochondrial cytochrome c , thus blocking activation of the caspase cascade and the onset of cell death XREF_BIBR , XREF_BIBR .	Bcl-2 stabilizes the mitochondrial membrane potential and prevents the release of mitochondrial cytochrome c, thus blocking activation of the caspase cascade and the onset of cell death XREF_BIBR, XREF_BIBR.	0	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	12	14
Overexpression of Bcl-2 and Bcl-X L suppressed caspase activation , mitochondrial cytochrome c release , Deltapsi suppression , and apoptosis and cell death induced by GraB , GraK , or perforin .	Overexpression of Bcl-2 and Bcl-X L suppressed caspase activation, mitochondrial cytochrome c release, Deltapsi suppression, and apoptosis and cell death induced by GraB, GraK, or perforin.	0	13	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	11	13
On the other hand , the overexpression of Bcl-2 has been demonstrated to prevent the efflux of cytochrome c from the mitochondria and subsequent initiation of apoptosis [ XREF_BIBR ] and the increase Bcl-2 expression could be important in the counteract the effect of Bax .	On the other hand, the overexpression of Bcl-2 has been demonstrated to prevent the efflux of cytochrome c from the mitochondria and subsequent initiation of apoptosis [XREF_BIBR] and the increase Bcl-2 expression could be important in the counteract the effect of Bax.	6	19	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	17	19
The best characterized anti-apoptotic proteins , BCL-2 and BCL-xL , appear to directly or indirectly preserve the integrity of the outer mitochondrial membrane , thus preventing cytochrome c release and cell death initiation through the mitochondrial pathways [ XREF_BIBR , XREF_BIBR ] .	The best characterized anti-apoptotic proteins, BCL-2 and BCL-xL, appear to directly or indirectly preserve the integrity of the outer mitochondrial membrane, thus preventing cytochrome c release and cell death initiation through the mitochondrial pathways [XREF_BIBR, XREF_BIBR].	1	28	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	6	7	26	28
Bcl-2 inhibits apoptosis by preventing the release of cytochrome c from mitochondria .	Bcl-2 inhibits apoptosis by preventing the release of cytochrome c from mitochondria.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
Increased BCL-2 protein in tumor cells stabilizes mitochondrial membrane and prevents the release of cytochrome c from mitochondria , consequently interrupting the intrinsic apoptotic signaling cascade .	Increased BCL-2 protein in tumor cells stabilizes mitochondrial membrane and prevents the release of cytochrome c from mitochondria, consequently interrupting the intrinsic apoptotic signaling cascade.	1	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	1	2	14	16
Pro survival proteins , Bcl-2 and Bcl-XL , prevent the release of cytochrome C from the mitochondria .	Pro survival proteins, Bcl-2 and Bcl-XL, prevent the release of cytochrome C from the mitochondria.	2	14	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	4	5	12	14
Not only does IFO decrease the possibility of BCL2 blocking the release of cytochrome c from the mitochondria but IFO can activate BAX and BAK , which are procytochrome c releasers [ XREF_BIBR , XREF_BIBR ] .	Not only does IFO decrease the possibility of BCL2 blocking the release of cytochrome c from the mitochondria but IFO can activate BAX and BAK, which are procytochrome c releasers [XREF_BIBR, XREF_BIBR].	6	15	blocking	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	8	9	13	15
Inhibition of bcl-2 increased release of cytochrome c from ischemia damaged SSM in the absence of calcium as an indicator of MOMP .	Inhibition of bcl-2 increased release of cytochrome c from ischemia damaged SSM in the absence of calcium as an indicator of MOMP.	0	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	6	8
Thus , high levels of Bcl-2 inhibit apoptosis by preventing cytochrome C release while high levels of Bax-alpha induce apoptosis by binding to the mitochondrial membrane and increase the permeability allowing the release of cytochrome C [ XREF_BIBR ] .	Thus, high levels of Bcl-2 inhibit apoptosis by preventing cytochrome C release while high levels of Bax-alpha induce apoptosis by binding to the mitochondrial membrane and increase the permeability allowing the release of cytochrome C [XREF_BIBR].	3	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	levels of Bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome c	5	6	10	12
The other one is that c-Myc regulates apoptosis by repressing the expression of anti-apoptotic proteins , such as Bcl-2 ( B-cell lymphoma 2 ) , which blocks mitochondrial outer membrane permeabilization and inhibits cytochrome c release from mitochondria XREF_BIBR - XREF_BIBR .	The other one is that c-Myc regulates apoptosis by repressing the expression of anti-apoptotic proteins, such as Bcl-2 (B-cell lymphoma 2), which blocks mitochondrial outer membrane permeabilization and inhibits cytochrome c release from mitochondria XREF_BIBR - XREF_BIBR.	11	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	33	35
Because Bcl-2 has been shown to block cytochrome C release potently , we exposed human neuroblastoma cells ( SH-SY5Y ) to TPEN .	Because Bcl-2 has been shown to block cytochrome C release potently, we exposed human neuroblastoma cells (SH-SY5Y) to TPEN.	1	9	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	1	2	7	9
In response to a variety of apoptosis stimuli , over-expression of Bcl-2 or Bax blocks cytochrome c release .	In response to a variety of apoptosis stimuli, over-expression of Bcl-2 or Bax blocks cytochrome c release.	9	17	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	over-expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	15	17
Double immunostaining of cytochrome c and beta-gal demonstrated that Bcl-2 plus hypothermia significantly reduced cytochrome c release .	Double immunostaining of cytochrome c and beta-gal demonstrated that Bcl-2 plus hypothermia significantly reduced cytochrome c release.	9	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	9	10	14	16
Overexpression of Bcl-2 has been found to stabilize the outer mitochondrial membrane and prevent release of cytochrome c and the initiation of apoptosis .	Overexpression of Bcl-2 has been found to stabilize the outer mitochondrial membrane and prevent release of cytochrome c and the initiation of apoptosis.	0	18	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	16	18
These results showed that in cells overexpressing Bcl-2 addition of zVAD-fmk significantly suppressed cytochrome c release and apoptosis .	These results showed that in cells overexpressing Bcl-2 addition of zVAD-fmk significantly suppressed cytochrome c release and apoptosis.	7	15	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	13	15
Bcl-2 can decrease the release of cytochrome C and mitochondrial membrane permeability caused by ischemic episodes 40 .	Bcl-2 can decrease the release of cytochrome C and mitochondrial membrane permeability caused by ischemic episodes 40.	0	8	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	6	8
Bcl-2 blocks the mitochondrial release of cytochrome c and inhibits the activation of caspase-9 by the cytoplasmic scaffolding protein APAF-1 .	Bcl-2 blocks the mitochondrial release of cytochrome c and inhibits the activation of caspase-9 by the cytoplasmic scaffolding protein APAF-1.	0	9	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
Anti-apoptotic Bcl-2 protein has been found to prevent both the loss of the mitochondrial membrane potential and the efflux of cytochrome c release and inhibit apoptosis .	Anti-apoptotic Bcl-2 protein has been found to prevent both the loss of the mitochondrial membrane potential and the efflux of cytochrome c release and inhibit apoptosis.	1	22	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	20	22
This result further demonstrates the protective effect of hHGF and hIL-1Ra co-expression , since Bcl-2 has been shown to inhibit cytochrome C release and protect against oxidative stress induced apoptosis .	This result further demonstrates the protective effect of hHGF and hIL-1Ra co-expression, since Bcl-2 has been shown to inhibit cytochrome C release and protect against oxidative stress induced apoptosis.	14	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	14	15	20	22
Additionally , the expression of the anti-apoptotic factor Bcl-2 was decreased , whereas that of the well-known apoptotic factor Bax was increased , thereby releasing cytochrome c into cytosol in amentoflavone treated cervical cancer cells .	Additionally, the expression of the anti-apoptotic factor Bcl-2 was decreased, whereas that of the well-known apoptotic factor Bax was increased, thereby releasing cytochrome c into cytosol in amentoflavone treated cervical cancer cells.	3	27	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of the anti-apoptotic factor Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	25	27
Bcl-2 , an anti-apoptotic protein , is known to prevent increased mitochondrial permeability , release of cytochrome c and various caspases .	Bcl-2, an anti-apoptotic protein, is known to prevent increased mitochondrial permeability, release of cytochrome c and various caspases.	0	18	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	16	18
The anti-apoptotic protein Bcl-2 is expressed on the outer mitochondrial membrane surface and prevents the release of cytochrome c into the cytosol .	The anti-apoptotic protein Bcl-2 is expressed on the outer mitochondrial membrane surface and prevents the release of cytochrome c into the cytosol.	0	19	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 is expressed	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	17	19
However , STS is a strong apoptosis inducer , and the induction of BCL2 in infected cells may be sufficient to prevent cytochrome c release in the absence of STS .	However, STS is a strong apoptosis inducer, and the induction of BCL2 in infected cells may be sufficient to prevent cytochrome c release in the absence of STS.	11	24	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	13	14	22	24
Moreover , BCL2 directly blocks cytochrome c release and therefore prevents APAF-1 and caspase-9 activation .	Moreover, BCL2 directly blocks cytochrome c release and therefore prevents APAF-1 and caspase-9 activation.	2	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	2	3	5	7
Bcl-2 family proteins can induce or inhibit the release of cytochrome C into the cytosol , which activates caspase-9 and caspase-3 .	Bcl-2 family proteins can induce or inhibit the release of cytochrome C into the cytosol, which activates caspase-9 and caspase-3.	0	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	10	12
In the mitochondrial pathway , antiapoptotic Bcl-2 family proteins prevent mitochondrial membrane permeabilization and thereby inhibit changes in the mitochondrial membrane potential and cytochrome c release [ XREF_BIBR ] .	In the mitochondrial pathway, antiapoptotic Bcl-2 family proteins prevent mitochondrial membrane permeabilization and thereby inhibit changes in the mitochondrial membrane potential and cytochrome c release [XREF_BIBR].	6	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	23	25
Bcl-2 may prevent the accumulation of cytochrome c , subsequently preserving capase-3 in the inactive zymogen state , which leads to the inhibition of the apoptotic cascade .	Bcl-2 may prevent the accumulation of cytochrome c, subsequently preserving capase-3 in the inactive zymogen state, which leads to the inhibition of the apoptotic cascade.	0	8	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
Bcl-2 inhibits the release of cytochrome c from the mitochondria and thereby it may influence apoptosis .	Bcl-2 inhibits the release of cytochrome c from the mitochondria and thereby it may influence apoptosis.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Furthermore , Bcl-2 can inhibit apoptosis by preventing the release of cytochrome c from the mitochondria , and Bax appears as the dominant pro apoptotic protein involved in cytochrome c release .	Furthermore, Bcl-2 can inhibit apoptosis by preventing the release of cytochrome c from the mitochondria, and Bax appears as the dominant pro apoptotic protein involved in cytochrome c release.	2	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	11	13
The anti-apoptotic proteins Bcl-2 and Bcl-XL inhibit cytochrome c ( cyt-c ) release , whereas Bcl-2-associated X protein ( Bax ) , Bcl-2 homologous antagonist and killer ( Bak ) , and BH3 interacting domain death agonist ( Bid ) , all pro apoptotic proteins , promote its release from mitochondria .	The anti-apoptotic proteins Bcl-2 and Bcl-XL inhibit cytochrome c (cyt-c) release, whereas Bcl-2-associated X protein (Bax), Bcl-2 homologous antagonist and killer (Bak), and BH3 interacting domain death agonist (Bid), all pro apoptotic proteins, promote its release from mitochondria.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	7	9
Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis [ XREF_BIBR ] , [ XREF_BIBR ] .	Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis [XREF_BIBR], [XREF_BIBR].	0	9	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	7	9
The anti-apoptotic activity of Bcl-2 protein is attributed to its ability to stabilize the mitochondrial membrane and inhibit the cytoplasmic release of cytochrome c , which prevents the activation of caspases and initiation of cell apoptosis [ XREF_BIBR , XREF_BIBR ] .	The anti-apoptotic activity of Bcl-2 protein is attributed to its ability to stabilize the mitochondrial membrane and inhibit the cytoplasmic release of cytochrome c, which prevents the activation of caspases and initiation of cell apoptosis [XREF_BIBR, XREF_BIBR].	4	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	22	24
Overexpression of Bcl-2 neither altered the normal subcellular localization of BAX nor prevented its redistribution with deprivation but did inhibit the subsequent release of cytochrome c , caspase activation , and cell death .	Overexpression of Bcl-2 neither altered the normal subcellular localization of BAX nor prevented its redistribution with deprivation but did inhibit the subsequent release of cytochrome c, caspase activation, and cell death.	0	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	24	26
Anti-apoptotic Bcl-2 and Bcl-xL proteins of the Bcl-2 family are located at the outer membrane of mitochondria and can inhibit the release of cytochrome-c .	Anti-apoptotic Bcl-2 and Bcl-xL proteins of the Bcl-2 family are located at the outer membrane of mitochondria and can inhibit the release of cytochrome-c.	0	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome-c	cytochrome-c	cytochrome-c	1	2	23	24
The reduction of Bcl-2 and Bax ratio triggered cytochrome c transferring from the mitochondria to the cytoplasm .	The reduction of Bcl-2 and Bax ratio triggered cytochrome c transferring from the mitochondria to the cytoplasm.	3	10	triggered	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	8	10
The direct activator should induce BAK dependent cytochrome c release , which is then inhibited by the added anti-apoptotic BCL-2 protein , and this inhibition is reversed ( referred to as ' de-repressed ' ) by the addition of a de-repressor BH3-only .	The direct activator should induce BAK dependent cytochrome c release, which is then inhibited by the added anti-apoptotic BCL-2 protein, and this inhibition is reversed (referred to as ' de-repressed ') by the addition of a de-repressor BH3-only.	7	20	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	19	20	7	9
Overexpression of Bcl-2 or Bcl-X ( L ) inhibited TG induced loss in mitochondrial membrane potential , release of cytochrome c , and activation of caspase-3 and JNK .	Overexpression of Bcl-2 or Bcl-X (L) inhibited TG induced loss in mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3 and JNK.	0	21	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	19	21
As a result of increased potassium uptake , mitochondria undergo moderate swelling sufficient to release cytochrome c. Overexpression of bcl-2 protein prevented the mitochondrial potassium uptake as well as cytochrome c release in apoptosis .	As a result of increased potassium uptake, mitochondria undergo moderate swelling sufficient to release cytochrome c. Overexpression of bcl-2 protein prevented the mitochondrial potassium uptake as well as cytochrome c release in apoptosis.	17	31	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	Overexpression of bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	19	20	29	31
Bcl-2 can inhibit apoptosis by preventing the release of cytochrome-c from mitochondria .	Bcl-2 can inhibit apoptosis by preventing the release of cytochrome-c from mitochondria.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome-c	cytochrome-c	cytochrome-c	0	1	9	10
Both Bcl-2 and Bcl-xL localize on the outer mitochondrial membrane and are able to stabilize the mitochondrial membrane potential , maintain mitochondrial permeability , and prevent the release of cytochrome c from mitochondrial to cytoplasm upon repressed apoptosis .	Both Bcl-2 and Bcl-xL localize on the outer mitochondrial membrane and are able to stabilize the mitochondrial membrane potential, maintain mitochondrial permeability, and prevent the release of cytochrome c from mitochondrial to cytoplasm upon repressed apoptosis.	0	31	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	29	31
Anti-apoptotic protein Bcl-2 inhibits cytochrome c release in the outer mitochondrial wall .	Anti-apoptotic protein Bcl-2 inhibits cytochrome c release in the outer mitochondrial wall.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	4	6
Presumably the presence of intact Bcl-2 in caspase-3-/- hepatocytes prevents the release of cytochrome c from the mitochondria , a required step for the mitochondrial death pathway .	Presumably the presence of intact Bcl-2 in caspase-3-/- hepatocytes prevents the release of cytochrome c from the mitochondria, a required step for the mitochondrial death pathway.	2	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	13	15
BcL2 proteins control the intrinsic pathway of apoptosis at the mitochondria by preventing the release of the cytochrome c. Therefore , the inhibition of Bcl-2 and Bcl-XL by HDACi treatment promotes the release of cytochrome c followed by caspase-9 and caspase-3 activation leading to apoptosis .	BcL2 proteins control the intrinsic pathway of apoptosis at the mitochondria by preventing the release of the cytochrome c. Therefore, the inhibition of Bcl-2 and Bcl-XL by HDACi treatment promotes the release of cytochrome c followed by caspase-9 and caspase-3 activation leading to apoptosis.	22	36	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	24	25	34	36
HSP70 also increases Bcl-2 expression and inhibits cytochrome C release [ XREF_BIBR ] .	HSP70 also increases Bcl-2 expression and inhibits cytochrome C release [XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	HSP70 also increases Bcl-2 expression	bcl-2	cytochrome C	cytochrome C	cytochrome c	3	4	7	9
BCL2 and Bcl-xL , two members of the BCL2 family , inhibit cell death by preventing the release of cytochrome c from the mitochondria and subsequent caspase activation .	BCL2 and Bcl-xL, two members of the BCL2 family, inhibit cell death by preventing the release of cytochrome c from the mitochondria and subsequent caspase activation.	0	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	0	1	19	21
Among BCL-2 family proteins , prosurvival BCL-2 stabilizes the mitochondrial membrane and prevents the cytochrome C release from the mitochondria and the followed activation of caspases .	Among BCL-2 family proteins, prosurvival BCL-2 stabilizes the mitochondrial membrane and prevents the cytochrome C release from the mitochondria and the followed activation of caspases.	5	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome C	cytochrome C	cytochrome C	6	7	14	16
Bcl-2 inhibits apoptosis by preventing the release of cytochrome c from the mitochondria , and Bax is the dominant proapoptotic protein involved in the release of cytochrome c [ XREF_BIBR ] .	Bcl-2 inhibits apoptosis by preventing the release of cytochrome c from the mitochondria, and Bax is the dominant proapoptotic protein involved in the release of cytochrome c [XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
Bcl-2 , an important member of this family , blocks cytochrome C release by sequestering pro apoptotic BH3-only proteins such as tBid , Bad , Bax , and Bim .	Bcl-2, an important member of this family, blocks cytochrome C release by sequestering pro apoptotic BH3-only proteins such as tBid, Bad, Bax, and Bim.	0	12	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	10	12
The anti-apoptotic protein Bcl-2 blocks caspase-3 activation by preventing cytochrome c release .	The anti-apoptotic protein Bcl-2 blocks caspase-3 activation by preventing cytochrome c release.	0	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	9	11
The apoptosis inhibitors Bcl-2 or Bcl-xL prevent the efflux of cytochrome c from mitochondria .	The apoptosis inhibitors Bcl-2 or Bcl-xL prevent the efflux of cytochrome c from mitochondria.	0	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	10	12
The anti-apoptotic members of the bcl-2 family of proteins inhibit mitochondrial cytochrome c release and caspase activation .	The anti-apoptotic members of the bcl-2 family of proteins inhibit mitochondrial cytochrome c release and caspase activation.	5	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	11	13
Bcl-2 translocation to the mitochondrial membrane blocks apoptosis and cytochrome c release 103 .	Bcl-2 translocation to the mitochondrial membrane blocks apoptosis and cytochrome c release 103.	0	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 translocation to the mitochondrial membrane	bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	9	11
BCL-2 is known to prevent the release of cytochrome c from mitochondria , which activates caspase-9 , followed by caspase-3 cleavage in the intrinsic pathway of apoptotic events .	BCL-2 is known to prevent the release of cytochrome c from mitochondria, which activates caspase-9, followed by caspase-3 cleavage in the intrinsic pathway of apoptotic events.	0	10	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
Basically , the rise in Bcl-2 and drop in Bax would prevent cytochrome c to move outside from the mitochondria , reduce the increased levels of ROS , and thus attenuate programmed cell death in the renal tubule .	Basically, the rise in Bcl-2 and drop in Bax would prevent cytochrome c to move outside from the mitochondria, reduce the increased levels of ROS, and thus attenuate programmed cell death in the renal tubule.	3	14	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	12	14
Members of the Bcl-2 family can inhibit ROS production , membrane potential loss , MPT , cytochrome C release , and caspase activation .	Members of the Bcl-2 family can inhibit ROS production, membrane potential loss, MPT, cytochrome C release, and caspase activation.	3	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	3	4	16	18
Bcl-2 overexpression blocks cytochrome c release and delays caspases activation .	Bcl-2 overexpression blocks cytochrome c release and delays caspases activation.	0	5	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	3	5
In contrast , Bcl-2 blocks cytochrome c efflux by binding to the outer mitochondrial membrane and forming a heterodimer with Bax resulting in neutralization of its proapoptotic effects XREF_BIBR .	In contrast, Bcl-2 blocks cytochrome c efflux by binding to the outer mitochondrial membrane and forming a heterodimer with Bax resulting in neutralization of its proapoptotic effects XREF_BIBR.	3	7	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	5	7
Although the anti-apoptotic protein Bcl-2 inhibits mitochondrial cytochrome c release , Bax protein makes holes in the outer mitochondrial membrane and as a result , disruption of mitochondrial membrane integrity occurs .	Although the anti-apoptotic protein Bcl-2 inhibits mitochondrial cytochrome c release, Bax protein makes holes in the outer mitochondrial membrane and as a result, disruption of mitochondrial membrane integrity occurs.	1	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	7	9
Bcl-2 functions as a stabilizer of the mitochondrial membrane , thereby preventing the loss of mitochondrial membrane potential and the release of cytochrome c and Apaf-1 in response to glucocorticoids .	Bcl-2 functions as a stabilizer of the mitochondrial membrane, thereby preventing the loss of mitochondrial membrane potential and the release of cytochrome c and Apaf-1 in response to glucocorticoids.	0	24	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	22	24
Bcl-2 blocks cytochrome c release and caspase 3 processing in a reconstituted cell free system , thus it has been postulated that cytochrome c release is necessary for downstream caspase activation and apoptosis .	Bcl-2 blocks cytochrome c release and caspase 3 processing in a reconstituted cell free system, thus it has been postulated that cytochrome c release is necessary for downstream caspase activation and apoptosis.	0	4	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	2	4
XREF_BIBR Overexpression of Bcl-2 and Bcl-xl has been found to stabilize the outer mitochondrial membrane and prevent release of cytochrome c following a variety of insults .	XREF_BIBR Overexpression of Bcl-2 and Bcl-xl has been found to stabilize the outer mitochondrial membrane and prevent release of cytochrome c following a variety of insults.	1	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	19	21
The overexpression of Bcl-2 mitochondrial protein inhibits the release of cytochrome c into the cytosol , protecting the cells against early death .	The overexpression of Bcl-2 mitochondrial protein inhibits the release of cytochrome c into the cytosol, protecting the cells against early death.	1	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	10	12
Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis .	Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis.	0	9	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	7	9
Antiapoptotic BCL2 members inhibit intrinsic apoptotic signals by constraining the proapoptotic proteins , BAX and BAK , and , therefore , cytochrome c release .	Antiapoptotic BCL2 members inhibit intrinsic apoptotic signals by constraining the proapoptotic proteins, BAX and BAK, and, therefore, cytochrome c release.	1	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	1	2	21	23
Over-expression of Bcl-2 prevented the efflux of cytochrome C from the mitochondria and the initiation of apoptosis XREF_BIBR , XREF_BIBR .	Over-expression of Bcl-2 prevented the efflux of cytochrome C from the mitochondria and the initiation of apoptosis XREF_BIBR, XREF_BIBR.	0	9	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Over-expression of Bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome c	2	3	7	9
Since GRP78 binds Ca ( 2+ ) and folds damaged protein , bcl-2 stabilizes mitochondrial transmembrane potential and inhibits cytochrome C release , and both GRP78 and bcl-2 have been shown to inhibit oxyradical accumulation , together these findings indicate that valproate may target one or more of these processes in order to produce neuroprotective effects .	Since GRP78 binds Ca (2+) and folds damaged protein, bcl-2 stabilizes mitochondrial transmembrane potential and inhibits cytochrome C release, and both GRP78 and bcl-2 have been shown to inhibit oxyradical accumulation, together these findings indicate that valproate may target one or more of these processes in order to produce neuroprotective effects.	12	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome C	12	13	19	21
Recent studies showed that Bcl-2 targets the voltage dependent anionic channel ( VDAC ) and blocks the release of cytochrome c , thereby blocking apoptosis .	Recent studies showed that Bcl-2 targets the voltage dependent anionic channel (VDAC) and blocks the release of cytochrome c, thereby blocking apoptosis.	4	21	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	19	21
In agreement with previous studies , BCL2 overexpression blocked the release of cytochrome c and effector caspase activation caused by STS ( XREF_FIG ) .	In agreement with previous studies, BCL2 overexpression blocked the release of cytochrome c and effector caspase activation caused by STS (XREF_FIG).	6	14	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2 overexpression	bcl2	cytochrome c	cytochrome c	cytochrome c	6	7	12	14
The apoptotic pathways is initiated by TNF-alpha and facilitated by caspase-3 , whereas Bcl-2 inhibits the release of cytochrome C from the mitochondria to cytosol , which is a pivotal anti-apoptotic signal in the apoptosis cascade .	The apoptotic pathways is initiated by TNF-alpha and facilitated by caspase-3, whereas Bcl-2 inhibits the release of cytochrome C from the mitochondria to cytosol, which is a pivotal anti-apoptotic signal in the apoptosis cascade.	13	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	13	14	18	20
The overexpression of Bcl-2 has been reported to block the mitochondrial release of cytochrome C , and in doing so prevents apoptosis .	The overexpression of Bcl-2 has been reported to block the mitochondrial release of cytochrome C, and in doing so prevents apoptosis.	1	15	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome c	3	4	13	15
The simplest explanation of these results is that Bcl-2 inhibits neither PTP nor PTP dependent release of cytochrome c , however , other possibilities are discussed .	The simplest explanation of these results is that Bcl-2 inhibits neither PTP nor PTP dependent release of cytochrome c, however, other possibilities are discussed.	8	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	17	19
Furthermore , bcl-2 also inhibits the release of cytochrome C to protect cell against apoptosis process , and bcl-2 blocks oxygen-free radicals to cause cell death through antioxidation pathway .	Furthermore, bcl-2 also inhibits the release of cytochrome C to protect cell against apoptosis process, and bcl-2 blocks oxygen-free radicals to cause cell death through antioxidation pathway.	2	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome C	2	3	8	10
The antiapoptotic proteins bcl-2 and bcl-XL inhibit cytochrome C release [ XREF_BIBR ] .	The antiapoptotic proteins bcl-2 and bcl-XL inhibit cytochrome C release [XREF_BIBR].	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome C	3	4	7	9
A decrease in the Bcl-2 and Bax ratio and impairment of mitochondrial electron transport may cause release of cytochrome c involved in the control of cell apoptosis .	A decrease in the Bcl-2 and Bax ratio and impairment of mitochondrial electron transport may cause release of cytochrome c involved in the control of cell apoptosis.	4	20	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	18	20
Furthermore , high concentrations of NO derived from iNOS inhibit the expression of Bcl-2 , activate caspase and subsequently promote the release of cytochrome c , leading to cell death .	Furthermore, high concentrations of NO derived from iNOS inhibit the expression of Bcl-2, activate caspase and subsequently promote the release of cytochrome c, leading to cell death.	5	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	NO derived from iNOS inhibit the expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	23	25
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Multidomain proapoptotic Bax and Bak are essential effectors responsible for the permeabilization of the MOM , whereas anti-apoptotic Bcl-2 , Bcl-xL , and Mcl-1 preserve mitochondrial integrity and prevent cytochrome c efflux triggered by apoptotic stimuli .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Multidomain proapoptotic Bax and Bak are essential effectors responsible for the permeabilization of the MOM, whereas anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 preserve mitochondrial integrity and prevent cytochrome c efflux triggered by apoptotic stimuli.	24	38	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	25	26	36	38
Bcl-2 has been linked to the homeostasis of mitochondrial membranes and has been shown to block the release of cytochrome c and inhibit the activation of caspases .	Bcl-2 has been linked to the homeostasis of mitochondrial membranes and has been shown to block the release of cytochrome c and inhibit the activation of caspases.	0	21	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	19	21
Finally , ectopic Bcl-2 expression marginally attenuated SAHA/FP related apoptosis and cytochrome c release , and failed to restore clonogenicity in cells exposed to these agents .	Finally, ectopic Bcl-2 expression marginally attenuated SAHA/FP related apoptosis and cytochrome c release, and failed to restore clonogenicity in cells exposed to these agents.	3	13	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	11	13
Therefore , as has been previously published for a variety of apoptotic stimuli 405758 , Bcl-2 blocked cytochrome c release in our system .	Therefore, as has been previously published for a variety of apoptotic stimuli 405758, Bcl-2 blocked cytochrome c release in our system.	15	19	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	17	19
Bcl2 and Bcl-XL inhibit apoptosis by preventing the release of cytochrome c from the mitochondria , whereas others like Bax and Bak stimulate the release of cytochrome c from mitochondria .	Bcl2 and Bcl-XL inhibit apoptosis by preventing the release of cytochrome c from the mitochondria, whereas others like Bax and Bak stimulate the release of cytochrome c from mitochondria.	0	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	0	1	10	12
We found that FK228 activated caspase-9 and a subsequent caspase cascade by perturbing the mitochondrial membrane to release cytochrome c , which was almost completely blocked by overexpression of Bcl-2 .	We found that FK228 activated caspase-9 and a subsequent caspase cascade by perturbing the mitochondrial membrane to release cytochrome c, which was almost completely blocked by overexpression of Bcl-2.	18	30	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	29	30	18	20
Furthermore , overexpression of MEG3 could reduce the expression of Bcl-2 and procaspase-9 proteins , enhance the expression of cleaved caspase-9 protein , and promote the release of cytochrome c protein to cytoplasm ( P < 0.05 ) .	Furthermore, overexpression of MEG3 could reduce the expression of Bcl-2 and procaspase-9 proteins, enhance the expression of cleaved caspase-9 protein, and promote the release of cytochrome c protein to cytoplasm (P < 0.05).	2	30	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	overexpression of MEG3 could reduce the expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	28	30
Curcumin also confers radiosensitizing effects in prostate cancer cells by inhibiting TNF mediated NF-kappaB activation resulting in Bcl-2 protein down-regulation and concomitant activation of cytochrome c and caspase-9 and -3 .	Curcumin also confers radiosensitizing effects in prostate cancer cells by inhibiting TNF mediated NF-kappaB activation resulting in Bcl-2 protein down-regulation and concomitant activation of cytochrome c and caspase-9 and -3.	17	26	down-regulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	17	18	24	26
Among these the anti-apoptotic proteins , Bfl-1 and Bcl-2 were upregulated , preventing the release of cytochrome c from the mitochondria and the downstream activation of caspases .	Among these the anti-apoptotic proteins, Bfl-1 and Bcl-2 were upregulated, preventing the release of cytochrome c from the mitochondria and the downstream activation of caspases.	6	18	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	16	18
The anti-apoptotic Bcl-2 family members such as Bcl-2 and Bcl-xl inhibit cytochrome c release by blocking the activation of pro apoptotic proteins .	The anti-apoptotic Bcl-2 family members such as Bcl-2 and Bcl-xl inhibit cytochrome c release by blocking the activation of pro apoptotic proteins.	2	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	11	13
Bcl-2 , an anti-apoptotic protein , prevents mitochondrial permeabilization and block cytochrome c release .	Bcl-2, an anti-apoptotic protein, prevents mitochondrial permeabilization and block cytochrome c release.	0	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	11	13
These events immediately precede release of proapoptotic factors , e.g ., cytochrome c , which in turn is prevented by the antiapoptotic protein Bcl-2 .	These events immediately precede release of proapoptotic factors, e.g., cytochrome c, which in turn is prevented by the antiapoptotic protein Bcl-2.	11	24	prevented	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	23	24	11	13
In mitochondria , Bcl-2 and Bcl-X L act as anti-pore factors and inhibit the release of cytochrome c into the cytosol and apoptosis 52 .	In mitochondria, Bcl-2 and Bcl-X L act as anti-pore factors and inhibit the release of cytochrome c into the cytosol and apoptosis 52.	3	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	16	18
Bcl-xl and Bcl-2 are the anti-apoptotic protein within the Bcl-2 family that inhibits apoptosis by binding proapoptotic proteins and preventing cytochrome c release .	Bcl-xl and Bcl-2 are the anti-apoptotic protein within the Bcl-2 family that inhibits apoptosis by binding proapoptotic proteins and preventing cytochrome c release.	0	22	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	20	22
The anti-apoptotic protein Bcl2 inhibits the cytochrome c release from the mitochondria initiated by Bax [ XREF_BIBR ] .	The anti-apoptotic protein Bcl2 inhibits the cytochrome c release from the mitochondria initiated by Bax [XREF_BIBR].	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	3	4	6	8
Bcl-2 , a potent inhibitor of apoptosis , can prevent disruption of the mitochondria and the subsequent release of cytochrome c , and caspase activation [ XREF_BIBR ] .	Bcl-2, a potent inhibitor of apoptosis, can prevent disruption of the mitochondria and the subsequent release of cytochrome c, and caspase activation [XREF_BIBR].	0	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	19	21
It is generally contended that the anti-apoptotic members of Bcl-2 family work to prevent cytochrome c release by stabilizing the mitochondrial membrane barrier function and the pro apoptotic members tend to induce cytochrome c release by permeabilizing the mitochondrial membrane [ XREF_BIBR ] .	It is generally contended that the anti-apoptotic members of Bcl-2 family work to prevent cytochrome c release by stabilizing the mitochondrial membrane barrier function and the pro apoptotic members tend to induce cytochrome c release by permeabilizing the mitochondrial membrane [XREF_BIBR].	9	34	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	9	10	32	34
It is not fully understood how Bcl-2 regulates this mitochondrial pathway , except that Bcl-2 blocks the permeability of the mitochondrial outer membrane , preventing the release of cytochrome c and other pro apoptotic proteins , which in turn activate proteases and caspases [ XREF_BIBR , XREF_BIBR ] .	It is not fully understood how Bcl-2 regulates this mitochondrial pathway, except that Bcl-2 blocks the permeability of the mitochondrial outer membrane, preventing the release of cytochrome c and other pro apoptotic proteins, which in turn activate proteases and caspases [XREF_BIBR, XREF_BIBR].	6	30	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	28	30
Mechanism study showed that GQ triggered generation of reactive oxygen species ( ROS ) , then activated p38 and JNK signaling pathways , subsequently led to mitochondrial impairment by regulating the expression of Bcl-2 , Bcl-xl and Bax , and finally promoted the release of cytochrome c and the activation of caspases to induce apoptosis .	Mechanism study showed that GQ triggered generation of reactive oxygen species (ROS), then activated p38 and JNK signaling pathways, subsequently led to mitochondrial impairment by regulating the expression of Bcl-2, Bcl-xl and Bax, and finally promoted the release of cytochrome c and the activation of caspases to induce apoptosis.	4	47	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	GQ triggered generation of reactive oxygen species (ROS), then activated p38 and JNK signaling pathways, subsequently led to mitochondrial impairment by regulating the expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	33	34	45	47
It has been well established that the anti-apoptotic protein Bcl-2 can prevent the release of cytochrome c and reduce the activation of caspase-9 and caspase-3 , thus inhibiting caspase-3-dependent apoptosis XREF_BIBR .	It has been well established that the anti-apoptotic protein Bcl-2 can prevent the release of cytochrome c and reduce the activation of caspase-9 and caspase-3, thus inhibiting caspase-3-dependent apoptosis XREF_BIBR.	6	18	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	9	10	15	17
Bcl-2 inhibits apoptosis by preventing the release of cytochrome c whereas , Bax induces apoptosis by dimerizing and inactivating the anti-apoptotic Bcl-2 proteins and enhancing cytochrome c release .	Bcl-2 inhibits apoptosis by preventing the release of cytochrome c whereas, Bax induces apoptosis by dimerizing and inactivating the anti-apoptotic Bcl-2 proteins and enhancing cytochrome c release.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
[ XREF_BIBR ] Several studies have shown that overexpression of Bcl-2 prevents the mitochondrial release of cytochrome c , thereby inhibiting the activation of caspases cascade and apoptosis .	[XREF_BIBR] Several studies have shown that overexpression of Bcl-2 prevents the mitochondrial release of cytochrome c, thereby inhibiting the activation of caspases cascade and apoptosis.	8	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	16	18
Mechanistically , antiapoptotic Bcl-2 proteins block the release of cytochrome c by binding and sequestering activator BH3-only proteins ( aBH3 ) , such as Bid and Bim ( XREF_FIG ) .	Mechanistically, antiapoptotic Bcl-2 proteins block the release of cytochrome c by binding and sequestering activator BH3-only proteins (aBH3), such as Bid and Bim (XREF_FIG).	3	11	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	9	11
Bcl-2 has been reported to block cytochrome c release in response to a variety of apoptotic stimuli 5758 .	Bcl-2 has been reported to block cytochrome c release in response to a variety of apoptotic stimuli 5758.	0	8	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
Up-regulated bcl-2 blocks cytochrome c release and subsequent caspase activation , slowing motor neuron death .	Up-regulated bcl-2 blocks cytochrome c release and subsequent caspase activation, slowing motor neuron death.	0	5	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	3	5
We assessed the protein expression of Bax , a proapoptotic member of the Bcl-2 family that triggers cytochrome c release , and Bcl-2 , an antiapoptotic member of the family that inhibits cytochrome c release .	We assessed the protein expression of Bax, a proapoptotic member of the Bcl-2 family that triggers cytochrome c release, and Bcl-2, an antiapoptotic member of the family that inhibits cytochrome c release.	1	34	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	22	23	32	34
Antiapoptotic Bcl2 family members exist in the outer mitochondrial membrane and prevent cytochrome c release , while proapoptotic members are translocated to the mitochondria to induce apoptosis either by forming pores in mitochondria directly or by antagonizing the antiapoptotic proteins [ XREF_BIBR ] .	Antiapoptotic Bcl2 family members exist in the outer mitochondrial membrane and prevent cytochrome c release, while proapoptotic members are translocated to the mitochondria to induce apoptosis either by forming pores in mitochondria directly or by antagonizing the antiapoptotic proteins [XREF_BIBR].	1	14	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	1	2	12	14
The cytochrome c releasing activity was not blocked by caspase inhibition , but was antagonized by Bcl-2 or Bcl-xL .	The cytochrome c releasing activity was not blocked by caspase inhibition, but was antagonized by Bcl-2 or Bcl-xL.	1	18	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	16	17	1	3
For example , Bcl-2 inhibits the release of cytochrome c by mitochondria , thereby preventing cell death .	For example, Bcl-2 inhibits the release of cytochrome c by mitochondria, thereby preventing cell death.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	8	10
Anti-apoptotic Bcl-2 homologues such as Bcl-2 , Bcl-xL , and A1 inhibit mitochondrial permeability transition pore opening , membrane depolarization , and cytochrome c release whereas members such as Bax , Balk , and Bok promote cell death .	Anti-apoptotic Bcl-2 homologues such as Bcl-2, Bcl-xL, and A1 inhibit mitochondrial permeability transition pore opening, membrane depolarization, and cytochrome c release whereas members such as Bax, Balk, and Bok promote cell death.	1	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	22	24
The BH4 domains of Bcl-2 and Bcl-xl inhibit cytochrome c release and the loss of mitochondrial membrane potential .	The BH4 domains of Bcl-2 and Bcl-xl inhibit cytochrome c release and the loss of mitochondrial membrane potential.	2	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	8	10
Previous reports have demonstrated that Bcl-2 might directly or indirectly prevent the release of cytochrome c from mitochondrial .	Previous reports have demonstrated that Bcl-2 might directly or indirectly prevent the release of cytochrome c from mitochondrial.	5	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	14	16
The inhibition of BCL2 by NR0B2 promotes mitochondrial cytochrome c release and therefore apoptosis .	The inhibition of BCL2 by NR0B2 promotes mitochondrial cytochrome c release and therefore apoptosis.	1	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	3	4	8	10
Bcl-2 can inhibit the generation of free radicals , overload of intracellular calcium , permeability of mitochondrial membranes , release of cytochrome c and activation of caspase-3 .	Bcl-2 can inhibit the generation of free radicals, overload of intracellular calcium, permeability of mitochondrial membranes, release of cytochrome c and activation of caspase-3.	0	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	21	23
Moreover , ISL increased the expression of pro apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2 , and Bcl-xl , thereby increasing cytochromec release .	Moreover, ISL increased the expression of pro apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2, and Bcl-xl, thereby increasing cytochromec release.	2	26	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	ISL increased the expression of pro apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2	bcl-2	cytochromec	cytochromec	cytochromec	18	19	25	26
The Bcl-2 protein is known to inhibit apoptosis by regulating the mitochondrial membrane potential DeltapsiM and cytochrome c release needed for activation of caspase-9 .	The Bcl-2 protein is known to inhibit apoptosis by regulating the mitochondrial membrane potential DeltapsiM and cytochrome c release needed for activation of caspase-9.	1	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	16	18
In a wide range of tumor cells , STAT3 has been shown to induce the expression of Bcl-2 , the prosurvival protein that prevents cytochrome c release and inhibits mitochondria dependent cell death .	In a wide range of tumor cells, STAT3 has been shown to induce the expression of Bcl-2, the prosurvival protein that prevents cytochrome c release and inhibits mitochondria dependent cell death.	8	26	prevents	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Bcl-2	STAT3 has been shown to induce the expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	17	18	24	26
The intrinsic death pathway is initiated by the mitochondrial release of cytochrome c , a process that is inhibited by anti-apoptotic Bcl-2 proteins .	The intrinsic death pathway is initiated by the mitochondrial release of cytochrome c, a process that is inhibited by anti-apoptotic Bcl-2 proteins.	11	22	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	21	22	11	13
Bcl-2 stabilizes mitochondrial membrane and prevents the release of cytochrome c and other pro apoptotic factors , whereas Bax promotes apoptosis .	Bcl-2 stabilizes mitochondrial membrane and prevents the release of cytochrome c and other pro apoptotic factors, whereas Bax promotes apoptosis.	0	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	9	11
Moreover , an increase in Bcl-2 expression prevents cytochrome c release from the mitochondria , thereby inhibiting activation of caspases , such as caspase-9 and caspase-3 , and preventing apoptosis [ XREF_BIBR ] .	Moreover, an increase in Bcl-2 expression prevents cytochrome c release from the mitochondria, thereby inhibiting activation of caspases, such as caspase-9 and caspase-3, and preventing apoptosis [XREF_BIBR].	5	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	8	10
Bcl-2 family pro apoptotic proteins promote cell death by inducing mitochondrial damage , cytochrome c release , and subsequent caspase activation , and the Bcl-2 family of anti-apoptotic proteins inhibit apoptosis by preventing the release of cytochrome c ; however , the mechanism by which parasites utilize this method of apoptotic inhibition has not been elucidated .	Bcl-2 family pro apoptotic proteins promote cell death by inducing mitochondrial damage, cytochrome c release, and subsequent caspase activation, and the Bcl-2 family of anti-apoptotic proteins inhibit apoptosis by preventing the release of cytochrome c; however, the mechanism by which parasites utilize this method of apoptotic inhibition has not been elucidated.	0	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
Cytochrome c release and caspase-9 activation are inhibited by the over-expression of Bcl-2 .	Cytochrome c release and caspase-9 activation are inhibited by the over-expression of Bcl-2.	0	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	over-expression of Bcl-2	bcl-2	Cytochrome c	Cytochrome c	cytochrome c	12	13	0	2
In particular , the anti-apoptotic proteins Bcl-2 and Bcl-xL inhibit cytochrome c release and therefore the activation of the apoptotic pathway .	In particular, the anti-apoptotic proteins Bcl-2 and Bcl-xL inhibit cytochrome c release and therefore the activation of the apoptotic pathway.	3	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	10	12
Similarly , overexpression of Bcl-2 substantially reduced cytochrome c release and DNA fragmentation in islets cultured in medium containing 33.3 mmol/l glucose ( XREF_FIG C and D ) .	Similarly, overexpression of Bcl-2 substantially reduced cytochrome c release and DNA fragmentation in islets cultured in medium containing 33.3 mmol/l glucose (XREF_FIG C and D).	2	9	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	7	9
Bcl-2 , a major antiapoptotic molecule that inhibited mitochondrial cytochrome c release , was decreased significantly after treatment .	Bcl-2, a major antiapoptotic molecule that inhibited mitochondrial cytochrome c release, was decreased significantly after treatment.	0	14	inhibited	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	9	11
Bcl-2 overexpression did not alter overall Bax expression , but inhibited cytosolic accumulation of cytochrome c and caspase-3 activation .	Bcl-2 overexpression did not alter overall Bax expression, but inhibited cytosolic accumulation of cytochrome c and caspase-3 activation.	0	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	14	16
Our results are compatible with either of two scenarios : Bcl-2 may function primarily to inhibit cytochrome c release .	Our results are compatible with either of two scenarios : Bcl-2 may function primarily to inhibit cytochrome c release.	10	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	16	18
Bcl-2 over-expression reduced DENSPM induced release of the pro apoptotic proteins AIF , cytochrome c , and Smac/DIABLO from the mitochondria .	Bcl-2 over-expression reduced DENSPM induced release of the pro apoptotic proteins AIF, cytochrome c, and Smac/DIABLO from the mitochondria.	0	15	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 over-expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
A quantitative titration analysis showed that Bcl-2 in the ER suppresses cytochrome c release as efficiently as that in the mitochondria .	A quantitative titration analysis showed that Bcl-2 in the ER suppresses cytochrome c release as efficiently as that in the mitochondria.	6	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	11	13
This receptor activates a transduction cascade of second messengers to stimulate Bcl-2 expression which inhibits cytochrome c release and blocks in turn caspase activation .	This receptor activates a transduction cascade of second messengers to stimulate Bcl-2 expression which inhibits cytochrome c release and blocks in turn caspase activation.	11	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	15	17
After injection of anti-Fas monoclonal antibody , mitochondrial Bcl-2 was decreased , cytochrome c released , and caspase-3 activated .	After injection of anti-Fas monoclonal antibody, mitochondrial Bcl-2 was decreased, cytochrome c released, and caspase-3 activated.	7	14	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	12	14
Apigenin generates reactive oxygen species , causes loss of mitochondrial Bcl-2 expression , increases mitochondrial permeability , causes cytochrome C release , and induces cleavage of caspase 3 , 7 , 8 , and 9 and the concomitant cleavage of the inhibitor of apoptosis protein , cIAP-2 .	Apigenin generates reactive oxygen species, causes loss of mitochondrial Bcl-2 expression, increases mitochondrial permeability, causes cytochrome C release, and induces cleavage of caspase 3, 7, 8, and 9 and the concomitant cleavage of the inhibitor of apoptosis protein, cIAP-2.	0	20	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Apigenin generates reactive oxygen species, causes loss of mitochondrial Bcl-2 expression	bcl-2	cytochrome C	cytochrome C	cytochrome c	10	11	18	20
In the apoptosis studies , it has been suggested that early in the apoptotic program , the outer mitochondrial membrane becomes impermeable to small molecules such as ATP and creatine phosphate , and that this leads to the eventual loss of outer mitochondrial membrane integrity and cytochrome c release , which can be prevented by anti-apoptotic Bcl-2 family members .	In the apoptosis studies, it has been suggested that early in the apoptotic program, the outer mitochondrial membrane becomes impermeable to small molecules such as ATP and creatine phosphate, and that this leads to the eventual loss of outer mitochondrial membrane integrity and cytochrome c release, which can be prevented by anti-apoptotic Bcl-2 family members.	46	58	prevented	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	56	57	46	48
Increment of Bcl-2 by physical exercise inhibits the release of cytochrome c from the mitochondria to the cytosol , resulting in suppression of neuronal apoptosis .	Increment of Bcl-2 by physical exercise inhibits the release of cytochrome c from the mitochondria to the cytosol, resulting in suppression of neuronal apoptosis.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	10	12
Bcl2 , an anti-apoptotic oncoprotein , has been shown to act on mitochondria and prevent the release of cytochrome c and thus caspases activation , while Bax mediated exactly opposite processes [ XREF_BIBR , XREF_BIBR ] .	Bcl2, an anti-apoptotic oncoprotein, has been shown to act on mitochondria and prevent the release of cytochrome c and thus caspases activation, while Bax mediated exactly opposite processes [XREF_BIBR, XREF_BIBR].	0	20	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	0	1	18	20
The hallmarks of caspase dependent apoptosis as shown by XNT in cancer cells include increased mitochondrial membrane permeability and cytosolic release of cytochrome c , activation of caspase-3 and -9 , reduced Bcl-XL expression , reduced Bcl-2 expression , truncation of Bid and cleavage of DNA repair enzyme poly-( ADP-ribose ) polymerase ( PARP ) .	The hallmarks of caspase dependent apoptosis as shown by XNT in cancer cells include increased mitochondrial membrane permeability and cytosolic release of cytochrome c, activation of caspase-3 and -9, reduced Bcl-XL expression, reduced Bcl-2 expression, truncation of Bid and cleavage of DNA repair enzyme poly-(ADP-ribose) polymerase (PARP).	22	38	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	36	37	22	24
Overexpression of Bcl-2 also may suppress caspase activation downstream of cytochrome c in some circumstances 3334 , consistent with the notion that Bcl-2 can suppress Apaf-1 .	Overexpression of Bcl-2 also may suppress caspase activation downstream of cytochrome c in some circumstances 3334, consistent with the notion that Bcl-2 can suppress Apaf-1.	0	12	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	10	12
While parental RAW 264.7 cells released mitochondrial cytochrome c within 3 h after HNE exposure , expression of Bcl-2 prevented cytochrome c release .	While parental RAW 264.7 cells released mitochondrial cytochrome c within 3 h after HNE exposure, expression of Bcl-2 prevented cytochrome c release.	16	22	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	20	22
The proto-oncogene Bcl-2 is expressed in many cancers and is a major anti-apoptotic protein , inhibiting the release of cytochrome c from the mitochondria .	The proto-oncogene Bcl-2 is expressed in many cancers and is a major anti-apoptotic protein, inhibiting the release of cytochrome c from the mitochondria.	0	21	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 is expressed	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	19	21
Bcl-2 exerts control of mitochondrial permeability and preventing the cytochrome C release while Bax can promote mitochondrial permeability .	Bcl-2 exerts control of mitochondrial permeability and preventing the cytochrome C release while Bax can promote mitochondrial permeability.	0	11	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	9	11
Mcl-1 binds to and inhibits the activation of pro apoptotic Bcl-2 family members , which prevents cytochrome c release and apoptosis [ XREF_BIBR ] .	Mcl-1 binds to and inhibits the activation of pro apoptotic Bcl-2 family members, which prevents cytochrome c release and apoptosis [XREF_BIBR].	10	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	16	18
The best characterized anti-apoptotic proteins , bcl-2 and bcl-x L , L , appear to directly or indirectly preserve the integrity of the outer mitochondrial membrane , thus preventing cytochrome c release and cell death initiation through the cell-intrinsic death pathway .	The best characterized anti-apoptotic proteins, bcl-2 and bcl-x L, L, appear to directly or indirectly preserve the integrity of the outer mitochondrial membrane, thus preventing cytochrome c release and cell death initiation through the cell-intrinsic death pathway.	6	31	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	29	31
On the one hand , Bcl-2 and Bcl-X L have been shown to block release of cytochrome c from mitochondria 202136 , which represents an event upstream of Apaf-1 activation .	On the one hand, Bcl-2 and Bcl-X L have been shown to block release of cytochrome c from mitochondria 202136, which represents an event upstream of Apaf-1 activation.	5	18	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	16	18
Bcl-2 from the mitochondria inhibits the release of cytochrome c , and Bax inactivates the caspase cascade and thus prevents stress induced apoptosis [ XREF_BIBR , XREF_BIBR ] .	Bcl-2 from the mitochondria inhibits the release of cytochrome c, and Bax inactivates the caspase cascade and thus prevents stress induced apoptosis [XREF_BIBR, XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
Bcl-2 is known to stabilize the mitochondrial membrane potential and prevent the release of cytochrome c and APAF-1 into the cytoplasm , thus blocking activation of the caspase cascade and subsequent cell death .	Bcl-2 is known to stabilize the mitochondrial membrane potential and prevent the release of cytochrome c and APAF-1 into the cytoplasm, thus blocking activation of the caspase cascade and subsequent cell death.	0	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	14	16
The overexpression of Bcl-2 inhibited depolarization of mitochondrial membrane , cytochrome c release , and apoptosis .	The overexpression of Bcl-2 inhibited depolarization of mitochondrial membrane, cytochrome c release, and apoptosis.	1	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	10	12
The over expression of Bcl 2 has been reported to block mitochondrial release of cytochrome C , preventing apoptosis [ XREF_BIBR ] .	The over expression of Bcl 2 has been reported to block mitochondrial release of cytochrome C, preventing apoptosis [XREF_BIBR].	2	16	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl 2	expression of Bcl 2	bcl 2	cytochrome C	cytochrome C	cytochrome c	4	6	14	16
Bcl-2 , an anti-apoptotic protein localized to mitochondria , has been shown to inhibit cytochrome c release and protect against oxidative stress induced apoptosis [ XREF_BIBR ] .	Bcl-2, an anti-apoptotic protein localized to mitochondria, has been shown to inhibit cytochrome c release and protect against oxidative stress induced apoptosis [XREF_BIBR].	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	14	16
XREF_BIBR , XREF_BIBR As a major antiapoptosis protein , BCL-2 impedes the mitochondrial release of apoptosis activating factor and cytochrome c initiating the caspase cascade .	XREF_BIBR, XREF_BIBR As a major antiapoptosis protein, BCL-2 impedes the mitochondrial release of apoptosis activating factor and cytochrome c initiating the caspase cascade.	9	21	impedes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	9	10	19	21
Firstly , MCL1 binds to and suppresses the oligomerization of the pro apoptotic BCL-2 proteins , BAK and BAX , thus preventing mitochondrial outer membrane permeabilization , cytochrome c release , and activation of downstream caspases 1 .	Firstly, MCL1 binds to and suppresses the oligomerization of the pro apoptotic BCL-2 proteins, BAK and BAX, thus preventing mitochondrial outer membrane permeabilization, cytochrome c release, and activation of downstream caspases 1.	13	29	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	13	14	27	29
Overexpression of Bcl-2 prevented cytochrome c release and reoxygenation injury without ameliorating ATP depletion or Bax translocation .	Overexpression of Bcl-2 prevented cytochrome c release and reoxygenation injury without ameliorating ATP depletion or Bax translocation.	0	6	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	4	6
Among Bcl-2 family proteins , anti-apoptotic proteins , Bcl-2 and Bcl-xL localize at the mitochondria outer membrane and thereby inhibit cytochrome c release .	Among Bcl-2 family proteins, anti-apoptotic proteins, Bcl-2 and Bcl-xL localize at the mitochondria outer membrane and thereby inhibit cytochrome c release.	6	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	20	22
Bcl2 stabilizes the membrane potential of mitochondria to reduce the release of cytochrome C [ XREF_BIBR ] .	Bcl2 stabilizes the membrane potential of mitochondria to reduce the release of cytochrome C [XREF_BIBR].	0	15	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome C	cytochrome C	cytochrome C	0	1	12	14
Expression of Bcl-2 D/A or Bcl-xL D/A inhibited caspase-9-induced release of Smac and cytochrome c ( XREF_FIG ) , and the activation of endogenous caspase-9 and caspase-3 ( XREF_FIG ) .	Expression of Bcl-2 D/A or Bcl-xL D/A inhibited caspase-9-induced release of Smac and cytochrome c (XREF_FIG), and the activation of endogenous caspase-9 and caspase-3 (XREF_FIG).	0	15	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	13	15
Here we show that stable expression of either constitutively active Akt or Bcl-2 inhibits apoptosis , but only Bcl-2 prevents the release of cytochrome c from mitochondria , suggesting that Akt regulates apoptosis at a postmitochondrial level .	Here we show that stable expression of either constitutively active Akt or Bcl-2 inhibits apoptosis, but only Bcl-2 prevents the release of cytochrome c from mitochondria, suggesting that Akt regulates apoptosis at a postmitochondrial level.	17	25	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	23	25
Previously , it had been demonstrated that high levels of Bcl-2 can prevent the release of cytochrome c and thus caspase activation in response to a number of apoptosis inducing stimuli such as UVB , staurosporine and etoposide [ XREF_BIBR , XREF_BIBR ] .	Previously, it had been demonstrated that high levels of Bcl-2 can prevent the release of cytochrome c and thus caspase activation in response to a number of apoptosis inducing stimuli such as UVB, staurosporine and etoposide [XREF_BIBR, XREF_BIBR].	8	18	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	levels of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	16	18
In contrast , bcl-2 inhibits mitochondrial release of cytochrome C and has anti-apoptotic effects as a result .	In contrast, bcl-2 inhibits mitochondrial release of cytochrome C and has anti-apoptotic effects as a result.	3	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome C	3	4	8	10
Bcl-2 mediates anti-apoptotic effect by suppressing the production of reactive oxygen species by the mitochondrion and reducing the release of cytochrome c XREF_BIBR .	Bcl-2 mediates anti-apoptotic effect by suppressing the production of reactive oxygen species by the mitochondrion and reducing the release of cytochrome c XREF_BIBR.	0	22	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	20	22
This decrease in Bcl-2 expression might rearrange the balance between pro- and anti-apoptotic Bcl-2 family members toward apoptosis , and trigger the release of cytochrome c most probably by activation of Bid and consecutive pore forming ability of Bax to the outer mitochondrial membrane .	This decrease in Bcl-2 expression might rearrange the balance between pro- and anti-apoptotic Bcl-2 family members toward apoptosis, and trigger the release of cytochrome c most probably by activation of Bid and consecutive pore forming ability of Bax to the outer mitochondrial membrane.	3	26	trigger	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	24	26
Our results showed that VPA induced ERK 1/2 phosphorylation in turn causes phosphorylation of the antiapoptotic protein Bcl-2 and inhibits serum starvation induced HUVEC apoptosis and cytochrome c release from the mitochondria .	Our results showed that VPA induced ERK 1/2 phosphorylation in turn causes phosphorylation of the antiapoptotic protein Bcl-2 and inhibits serum starvation induced HUVEC apoptosis and cytochrome c release from the mitochondria.	4	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	VPA induced ERK 1/2 phosphorylation in turn causes phosphorylation of the antiapoptotic protein Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	17	18	26	28
The anti-apoptotic Bcl-2 inhibits mitochondrial cytochrome c release through stabilization of mitochondrial membrane .	The anti-apoptotic Bcl-2 inhibits mitochondrial cytochrome c release through stabilization of mitochondrial membrane.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	5	7
Moreover , Rk3 induced the activation of caspase-8 , -9 , and -3 , promoted changes in mitochondrial membrane potential , decreased the expression of Bcl-2 , increased the expression of Bax , and caused the release of cytochrome c , which indicated that the apoptosis inducing effects of Rk3 were triggered via death receptor mediated mitochondria dependent pathways .	Moreover, Rk3 induced the activation of caspase-8, -9, and -3, promoted changes in mitochondrial membrane potential, decreased the expression of Bcl-2, increased the expression of Bax, and caused the release of cytochrome c, which indicated that the apoptosis inducing effects of Rk3 were triggered via death receptor mediated mitochondria dependent pathways.	2	40	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Rk3 induced the activation of caspase-8, -9, and -3, promoted changes in mitochondrial membrane potential, decreased the expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	25	26	38	40
Bcl-2 and Bcl-x L inhibit cytochrome C release .	Bcl-2 and Bcl-x L inhibit cytochrome C release.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	5	7
Bcl-2 overexpression blocked reoxygenation induced cytochrome c release and activation of caspase -3 and -9 , but caspase inhibition alone did not block cytochrome c release .	Bcl-2 overexpression blocked reoxygenation induced cytochrome c release and activation of caspase -3 and -9, but caspase inhibition alone did not block cytochrome c release.	0	7	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Overexpression of Bcl-2 will prevent the release of cytochrome c , causing HepG2 cells to be resistant to apoptotic induction [ XREF_BIBR ] .	Overexpression of Bcl-2 will prevent the release of cytochrome c, causing HepG2 cells to be resistant to apoptotic induction [XREF_BIBR].	0	10	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	8	10
Overexpression of antiapoptotic molecules Bcl-2 and Bcl-XL blocks cytochrome C release in response to apoptotic stimuli .	Overexpression of antiapoptotic molecules Bcl-2 and Bcl-XL blocks cytochrome C release in response to apoptotic stimuli.	0	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of antiapoptotic molecules Bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome c	4	5	8	10
When used jointly with vitamin C , vitamin E increases the Bcl-2 level in mitochondria and decreases the level of Bcl-2-like protein 4 , suppresses the release of cytochrome C , activates caspase-9 and caspase-3 , and thus , inhibits myocardial cell apoptosis .	When used jointly with vitamin C, vitamin E increases the Bcl-2 level in mitochondria and decreases the level of Bcl-2-like protein 4, suppresses the release of cytochrome C, activates caspase-9 and caspase-3, and thus, inhibits myocardial cell apoptosis.	7	30	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	vitamin E increases the Bcl-2 level	bcl-2	cytochrome C	cytochrome C	cytochrome c	11	12	28	30
Bcl-2 protein is known to inhibit apoptosis by regulating mitochondrial membrane potential and cytochrome c release needed for the activation of caspase-9 XREF_BIBR .	Bcl-2 protein is known to inhibit apoptosis by regulating mitochondrial membrane potential and cytochrome c release needed for the activation of caspase-9 XREF_BIBR.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
An imbalance in the expression of the anti- and pro apoptotic Bcl-2 family of proteins is thought to stabilize the outer mitochondrial membrane , prevent MOMP and the release of cytochrome c , and ultimately , inhibit programmed cell death .	An imbalance in the expression of the anti- and pro apoptotic Bcl-2 family of proteins is thought to stabilize the outer mitochondrial membrane, prevent MOMP and the release of cytochrome c, and ultimately, inhibit programmed cell death.	4	32	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of the anti- and pro apoptotic Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	30	32
Free Bcl-2 prevents release of cytochrome c from mitochondria [ XREF_BIBR ] .	Free Bcl-2 prevents release of cytochrome c from mitochondria [XREF_BIBR].	0	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	5	7
Bcl-2 may prevent the release of cytochrome c from the mitochondria to inhibit apoptosis , and caspase-3 is considered the convergence point of multiple apoptosis activating signals that determines the extent of apoptosis .	Bcl-2 may prevent the release of cytochrome c from the mitochondria to inhibit apoptosis, and caspase-3 is considered the convergence point of multiple apoptosis activating signals that determines the extent of apoptosis.	0	8	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
In contrast , other groups have shown that Bcl-2-transfected 8226 and ARP-1 myeloma cells still remained sensitive to TRAIL ( Gazitt , 1999a ,1999 b ) and that Bcl-2 failed to block cytochrome c release after exposure to TRAIL ( Keogh et al , 2000 ; Walczak et al , 2000 ) .	In contrast, other groups have shown that Bcl-2-transfected 8226 and ARP-1 myeloma cells still remained sensitive to TRAIL (Gazitt, 1999a,1999 b) and that Bcl-2 failed to block cytochrome c release after exposure to TRAIL (Keogh et al, 2000; Walczak et al, 2000).	28	34	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	28	29	32	34
Bcl-2 member inhibits apoptosis by preventing the release of cytochrome c from mitochondria , however , Bcl-2 forms heterodimers with the pro apoptotic member Bax , and they are incapacitated from their protective function .	Bcl-2 member inhibits apoptosis by preventing the release of cytochrome c from mitochondria, however, Bcl-2 forms heterodimers with the pro apoptotic member Bax, and they are incapacitated from their protective function.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	9	11
Thus , it has been proposed that Bcl-2 acts primarily to inhibit the release of cytochrome c from mitochondria and the consequent activation of caspases .	Thus, it has been proposed that Bcl-2 acts primarily to inhibit the release of cytochrome c from mitochondria and the consequent activation of caspases.	7	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	15	17
The virus triggered cytochrome c efflux was suppressed by overexpression of Bcl-2 .	The virus triggered cytochrome c efflux was suppressed by overexpression of Bcl-2.	3	12	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	3	5
In addition , anti-apoptotic members of the bcl family , e.g ., Bcl-2 , MCL-1 and A1 , prevent the mitochondrial cytochrome c release .	In addition, anti-apoptotic members of the bcl family, e.g., Bcl-2, MCL-1 and A1, prevent the mitochondrial cytochrome c release.	8	23	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	12	13	21	23
The decreased expression of Bcl-2 was expected since Bcl-2 prevents induction of apoptosis by blocking the release of cytochrome c from mitochondria [ XREF_BIBR ] .	The decreased expression of Bcl-2 was expected since Bcl-2 prevents induction of apoptosis by blocking the release of cytochrome c from mitochondria [XREF_BIBR].	8	20	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	18	20
Bcl2 prevents the release of cytochrome c from mitochondria , which acts as a cofactor for the activation of caspase-9 , and binds Apaf-1 .	Bcl2 prevents the release of cytochrome c from mitochondria, which acts as a cofactor for the activation of caspase-9, and binds Apaf-1.	0	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Reduction in the Bcl-2 and Bcl-2 associated X protein ( Bax ) ratio leads to release of cytochrome c from mitochondria into the cytoplasm and activates a caspase cascade that culminates in cellular fragmentation 11 .	Reduction in the Bcl-2 and Bcl-2 associated X protein (Bax) ratio leads to release of cytochrome c from mitochondria into the cytoplasm and activates a caspase cascade that culminates in cellular fragmentation 11.	0	19	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	17	19
To determine whether the mitochondrial pathway is important for TAF6delta dependent cell death , we overexpressed the anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-X L to prevent the release of cytochrome c from the mitochondria XREF_BIBR - XREF_BIBR .	To determine whether the mitochondrial pathway is important for TAF6delta dependent cell death, we overexpressed the anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-X L to prevent the release of cytochrome c from the mitochondria XREF_BIBR - XREF_BIBR.	18	32	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	30	32
Bcl-2 and its homologs prevent mitochondrial membrane disruption and the release of cytochrome c and other pro apoptotic factors , while Bax promotes these events .	Bcl-2 and its homologs prevent mitochondrial membrane disruption and the release of cytochrome c and other pro apoptotic factors, while Bax promotes these events.	0	14	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	12	14
The studies show that overexpression of Bcl-2 inhibits the release of cytochrome c from mitochondria and the subsequent apoptotic response is blocked .	The studies show that overexpression of Bcl-2 inhibits the release of cytochrome c from mitochondria and the subsequent apoptotic response is blocked.	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	11	13
Bcl-2 inhibits the release of cytochrome c from the mitochondria and thus prevents the activation of Apaf-1 and subsequently the caspase pathways [ XREF_BIBR ] .	Bcl-2 inhibits the release of cytochrome c from the mitochondria and thus prevents the activation of Apaf-1 and subsequently the caspase pathways [XREF_BIBR].	0	10	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Bcl-2	Bcl-2	bcl-2	cytochrome c	release of cytochrome c from the mitochondria	cytochrome c	0	1	5	7
Bcl-2 , an anti-apoptotic protein localized to mitochondria , has been shown to inhibit cytochrome c release and protect against oxidative stress induced apoptosis .	Bcl-2, an anti-apoptotic protein localized to mitochondria, has been shown to inhibit cytochrome c release and protect against oxidative stress induced apoptosis.	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	14	16
[ XREF_BIBR XREF_BIBR ] Overexpression of Bcl-2 and Bcl-X L prevents the release of cytochrome c from mitochondria ; protecting the cells from apoptosis .	[XREF_BIBR XREF_BIBR] Overexpression of Bcl-2 and Bcl-X L prevents the release of cytochrome c from mitochondria; protecting the cells from apoptosis.	4	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	14	16
Concomitant administration of SP600125 , a selective JNK inhibitor , or aminoguanidine ( AG ) , a selected inducible nitric oxide synthase ( iNOS ) inhibitor , effectively diminished BCL-2 phosphorylation , suppressed cytochrome c release from mitochondria and caspase activation , and significantly prevented ctx induced muscle cell apoptosis .	Concomitant administration of SP600125, a selective JNK inhibitor, or aminoguanidine (AG), a selected inducible nitric oxide synthase (iNOS) inhibitor, effectively diminished BCL-2 phosphorylation, suppressed cytochrome c release from mitochondria and caspase activation, and significantly prevented ctx induced muscle cell apoptosis.	19	35	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	nitric oxide synthase (iNOS) inhibitor, effectively diminished BCL-2 phosphorylation	bcl-2	cytochrome c	cytochrome c	cytochrome c	29	30	33	35
Bcl-2 may play a crucial role in the survival of hematolymphoid cells , where Bcl-2 inhibits apoptosis by preventing cytochrome c release from the mitochondria , thereby blocking caspase activation [ XREF_BIBR ] .	Bcl-2 may play a crucial role in the survival of hematolymphoid cells, where Bcl-2 inhibits apoptosis by preventing cytochrome c release from the mitochondria, thereby blocking caspase activation [XREF_BIBR].	14	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	14	15	19	21
XREF_BIBR , XREF_BIBR BCL2 inhibits mitochondrial release of cytochrome c and subsequently blocks the caspase cascade , thereby inhibiting apoptosis .	XREF_BIBR, XREF_BIBR BCL2 inhibits mitochondrial release of cytochrome c and subsequently blocks the caspase cascade, thereby inhibiting apoptosis.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	3	4	8	10
Bcl-2 also suppresses cytochrome c ( Cyt C ) and caspase by acting on the mitochondrial membrane .	Bcl-2 also suppresses cytochrome c (Cyt C) and caspase by acting on the mitochondrial membrane.	0	5	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	3	5
Previous reports have shown that p53 is up-regulated while BCL2 is down-regulated to induce CYCS release from the mitochondrion , which further activates CASP9 and CASP3 to encourage cell apoptosis .	Previous reports have shown that p53 is up-regulated while BCL2 is down-regulated to induce CYCS release from the mitochondrion, which further activates CASP9 and CASP3 to encourage cell apoptosis.	9	15	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	CYCS	CYCS	CYCS	9	10	14	15
Among the cellular signaling pathways that promote cell survival , antiapoptotic members of Bcl-2 family ( Bcl-2 , Bcl-xL , Mcl-1 ) could inhibit the liberation of cytochrome c from mitochondria [ XREF_BIBR , XREF_BIBR ] .	Among the cellular signaling pathways that promote cell survival, antiapoptotic members of Bcl-2 family (Bcl-2, Bcl-xL, Mcl-1) could inhibit the liberation of cytochrome c from mitochondria [XREF_BIBR, XREF_BIBR].	13	29	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	27	29
Overexpression of Bcl-2 completely inhibits CHENSpm induced cytochrome c release , caspase-3 activation , and poly ( ADP-ribose ) polymerase cleavage .	Overexpression of Bcl-2 completely inhibits CHENSpm induced cytochrome c release, caspase-3 activation, and poly (ADP-ribose) polymerase cleavage.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	7	9
For example , Bcl2 prevents the incidence of apoptosis by preventing the release of cytochrome c from mitochondria [ XREF_BIBR ] .	For example, Bcl2 prevents the incidence of apoptosis by preventing the release of cytochrome c from mitochondria [XREF_BIBR].	3	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	3	4	14	16
The B-cell lymphoma 2 ( Bcl-2 ) family proteins inhibit cytochrome c releasing from the mitochondria .	The B-cell lymphoma 2 (Bcl-2) family proteins inhibit cytochrome c releasing from the mitochondria.	0	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	10	12
Bcl-2 , a protein that protects against apoptosis and blocks cytochrome c release , prevents superoxide production when it is overexpressed .	Bcl-2, a protein that protects against apoptosis and blocks cytochrome c release, prevents superoxide production when it is overexpressed.	0	14	blocks	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	10	12
Overexpression of Bcl-2 and Bcl-xL have recently been reported to inhibit ROS production , cytosolic cytochrome c release , active CPP32 and PARP degradation mediated apoptosis and Beclin-1 and LC3 mediated autophagy [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Overexpression of Bcl-2 and Bcl-xL have recently been reported to inhibit ROS production, cytosolic cytochrome c release, active CPP32 and PARP degradation mediated apoptosis and Beclin-1 and LC3 mediated autophagy [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	15	17
Bcl-2 can prevent the release of cytochrome c , along with dATP and Apaf-1 , and thus protect from apoptosis [ XREF_BIBR ] .	Bcl-2 can prevent the release of cytochrome c, along with dATP and Apaf-1, and thus protect from apoptosis [XREF_BIBR].	0	17	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
Bcl-2 inhibits the release of the cytochrome C from mitochondria and cause inhibition of caspase activation and apoptosis .	Bcl-2 inhibits the release of the cytochrome C from mitochondria and cause inhibition of caspase activation and apoptosis.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	6	8
In addition , naloxone administration dose-dependently increased Bcl-2 levels , decreased Bax levels , stabilized the mitochondrial transmembrane potential , and inhibited cytochrome c release and caspase 3 and caspase 9 activation .	In addition, naloxone administration dose-dependently increased Bcl-2 levels, decreased Bax levels, stabilized the mitochondrial transmembrane potential, and inhibited cytochrome c release and caspase 3 and caspase 9 activation.	3	24	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	naloxone administration dose-dependently increased Bcl-2 levels	bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	22	24
In contrast , the anti-apoptotic protein Bcl-2 stabilizes the mitochondrial membrane potential thereby inhibiting cytochrome c release and inhibiting apoptosis .	In contrast, the anti-apoptotic protein Bcl-2 stabilizes the mitochondrial membrane potential thereby inhibiting cytochrome c release and inhibiting apoptosis.	3	16	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	14	16
Overexpression of Bcl-2 prevented release of both cytochrome c and AIF to the cytosol .	Overexpression of Bcl-2 prevented release of both cytochrome c and AIF to the cytosol.	0	9	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	7	9
Ectopic Bcl-2 attenuated cytochrome c release and apoptosis induction compared with SW480 and neo cells .	Ectopic Bcl-2 attenuated cytochrome c release and apoptosis induction compared with SW480 and neo cells.	0	5	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	3	5
Furthermore , it has been demonstrated that Bcl-2 can prevent the release of cytochrome c from mitochondria in cells triggered to undergo apoptosis .	Furthermore, it has been demonstrated that Bcl-2 can prevent the release of cytochrome c from mitochondria in cells triggered to undergo apoptosis.	7	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	13	15
Surprisingly , Akt did not block cytochrome c release into the cytosol ( XREF_FIG and XREF_FIG ) , whereas Bcl-2 suppressed cytochrome c release ( C and D ) .	Surprisingly, Akt did not block cytochrome c release into the cytosol (XREF_FIG and XREF_FIG), whereas Bcl-2 suppressed cytochrome c release (C and D).	19	23	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	19	20	21	23
Bcl-2 blocks the release of cytochrome C , inhibits caspase-3 activation , and effectively suppresses the occurrence of apoptosis .	Bcl-2 blocks the release of cytochrome C, inhibits caspase-3 activation, and effectively suppresses the occurrence of apoptosis.	0	14	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	5	7
It is well known that BCL-2 prevents activation of caspase cascade , blocks loss of mitochondrial membrane potential , and also inhibits release of cytochrome c from mitochondria [ XREF_BIBR ] .	It is well known that BCL-2 prevents activation of caspase cascade, blocks loss of mitochondrial membrane potential, and also inhibits release of cytochrome c from mitochondria [XREF_BIBR].	5	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	5	6	24	26
In addition , antiapoptotic Bcl-2 blocked mitochondrial cytochrome c release , suppressing TGF-beta1-induced activation of JNK and p38 .	In addition, antiapoptotic Bcl-2 blocked mitochondrial cytochrome c release, suppressing TGF-beta1-induced activation of JNK and p38.	3	9	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	7	9
Of particular note is that Zfra suppresses the expression of Bcl-2 and Bcl-xL , but fails to cause cytochrome c release , which is very unusual and intriguing .	Of particular note is that Zfra suppresses the expression of Bcl-2 and Bcl-xL, but fails to cause cytochrome c release, which is very unusual and intriguing.	5	20	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Zfra suppresses the expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	18	20
The Bcl-2 family proteins , which are located in the outer membrane of mitochondria , can block the release of cytochrome c from mitochondria .	The Bcl-2 family proteins, which are located in the outer membrane of mitochondria, can block the release of cytochrome c from mitochondria.	1	22	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	20	22
The intrinsic death pathway is initiated at the mitochondrion by the release of cytochrome c , a process that can be inhibited by antiapoptotic proteins of the Bcl-2 family .	The intrinsic death pathway is initiated at the mitochondrion by the release of cytochrome c, a process that can be inhibited by antiapoptotic proteins of the Bcl-2 family.	13	28	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	27	28	13	15
Two levels of the pathway at which this might well occur are upon the overexpression of the anti-apoptotic Bcl-2 family proteins , preventing cytochrome c release and caspase activation , or upon XIAP overexpression , blocking the action of caspases .	Two levels of the pathway at which this might well occur are upon the overexpression of the anti-apoptotic Bcl-2 family proteins, preventing cytochrome c release and caspase activation, or upon XIAP overexpression, blocking the action of caspases.	14	25	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of the anti-apoptotic Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	23	25
Bcl-2 blocks the release of cytochrome c , whereas Bax localizes to mitochondria and enhances the release of cytochrome c , promotes nuclear fragmentation and induces cell death .	Bcl-2 blocks the release of cytochrome c, whereas Bax localizes to mitochondria and enhances the release of cytochrome c, promotes nuclear fragmentation and induces cell death.	0	7	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
The Bcl-2 family protein Bcl-x ( L ) suppressed cytochrome c release as well as processing of procaspases-3 , -8 , and -9 in E-73-treated cells .	The Bcl-2 family protein Bcl-x (L) suppressed cytochrome c release as well as processing of procaspases-3, -8, and -9 in E-73-treated cells.	1	11	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	9	11
We show that expression of Bcl-2 in Molt4 cells inhibit depolarization of the mitochondrial membrane potential , the release of cytochrome c and caspase activation consistent with the conclusion that farnesol activates the intrinsic pathway of apoptosis .	We show that expression of Bcl-2 in Molt4 cells inhibit depolarization of the mitochondrial membrane potential, the release of cytochrome c and caspase activation consistent with the conclusion that farnesol activates the intrinsic pathway of apoptosis.	3	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	20	22
Bcl-2 and Bax are the two major factors influencing the regulation of apoptosis ; Bcl-2 prevents the release of cytochrome C from mitochondria , and it also activates caspases to inhibit apoptosis .	Bcl-2 and Bax are the two major factors influencing the regulation of apoptosis; Bcl-2 prevents the release of cytochrome C from mitochondria, and it also activates caspases to inhibit apoptosis.	14	21	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	14	15	19	21
Bcl-2 inhibits the realease of cytochrome c against Bax .	Bcl-2 inhibits the realease of cytochrome c against Bax.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
The anti-apoptotic proteins bcl-2 and bcl-xL block the apoptotic event of mitochondrial cytochrome c release into the cytosol , and have been shown to mainly inhibit these two above mentioned pathways .	The anti-apoptotic proteins bcl-2 and bcl-xL block the apoptotic event of mitochondrial cytochrome c release into the cytosol, and have been shown to mainly inhibit these two above mentioned pathways.	0	25	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	12	14
Sphingosine induced reductions in ADP coupled respiration , membrane potential , mitochondrial cytochrome c content and ATP production , which were partially prevented by cyclosporine A and mitochondrial Bcl-2 overexpression .	Sphingosine induced reductions in ADP coupled respiration, membrane potential, mitochondrial cytochrome c content and ATP production, which were partially prevented by cyclosporine A and mitochondrial Bcl-2 overexpression.	12	30	prevented	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	cytochrome c	cytochrome c	cytochrome c	28	29	12	14
Bcl-2 and BclxL prevent the release of cytochrome c in response to many apoptotic stimuli .	Bcl-2 and BclxL prevent the release of cytochrome c in response to many apoptotic stimuli.	0	9	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	7	9
An antiapoptotic protein , Bcl-2 , inhibits the release of cytochrome c along with the resultant activation of caspase-9 .	An antiapoptotic protein, Bcl-2, inhibits the release of cytochrome c along with the resultant activation of caspase-9.	2	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	10	12
In addition , several reports suggest that bcl-2 , located primarily on the outer membrane of mitochondria , may block apoptosis by preventing the release of cytochrome c from mitochondria .	In addition, several reports suggest that bcl-2, located primarily on the outer membrane of mitochondria, may block apoptosis by preventing the release of cytochrome c from mitochondria.	7	28	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	26	28
Surprisingly , cytochrome c release by BFA is not only blocked by wild-type Bcl-2 but also by a Bcl-2 variant that is exclusively targeted to the ER ( Bcl-2 and cb5 ) .	Surprisingly, cytochrome c release by BFA is not only blocked by wild-type Bcl-2 but also by a Bcl-2 variant that is exclusively targeted to the ER (Bcl-2 and cb5).	2	14	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	2	4
The proteins are located on the outer mitochondrial membrane and the anti-apoptotic members of the Bcl-2 family can also inhibit cytochrome c release .	The proteins are located on the outer mitochondrial membrane and the anti-apoptotic members of the Bcl-2 family can also inhibit cytochrome c release.	15	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	20	22
It has been shown that Parkin is involved in the ubiquitination of Bcl-2 , which prevents cytochrome c release from the mitochondria XREF_BIBR preventing apoptosis .	It has been shown that Parkin is involved in the ubiquitination of Bcl-2, which prevents cytochrome c release from the mitochondria XREF_BIBR preventing apoptosis.	10	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	ubiquitination of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	12	13	16	18
The Bcl-2 protein , an important regulator of programmed cell death , prevents early-stage cell apoptosis by preventing the release of cytochrome c from the mitochondria XREF_BIBR XREF_BIBR XREF_BIBR .	The Bcl-2 protein, an important regulator of programmed cell death, prevents early-stage cell apoptosis by preventing the release of cytochrome c from the mitochondria XREF_BIBR XREF_BIBR XREF_BIBR.	1	23	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	21	23
Anti-apoptotic BCL-2 proteins , including BCL-2 , BCL-XL and MCL-1 , prevent the release of cytochrome c from mitochondria , whereas pro apoptotic BAX and BAK participate in the formation of pores in the mitochondria through which cytochrome c is released .	Anti-apoptotic BCL-2 proteins, including BCL-2, BCL-XL and MCL-1, prevent the release of cytochrome c from mitochondria, whereas pro apoptotic BAX and BAK participate in the formation of pores in the mitochondria through which cytochrome c is released.	1	17	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	1	2	15	17
Western analysis of the tumor lysates indicated that , similar to prostate cancer cells in vitro , treatment with simvastatin significantly impaired phosphorylation of Bad ( p < 0.01 ) , decreased protein levels of Bcl-2 and Bcl-xL ( p < 0.01 and p < 0.001 , respectively ) , increased release of cytochrome C from the mitochondria to cytosol ( p < 0.05 ) as well as increased protein expressions of BimL and BimS , cleaved caspase 9 and cleaved caspase 3 ( p < 0.05 ) , compared to saline treated controls .	Western analysis of the tumor lysates indicated that, similar to prostate cancer cells in vitro, treatment with simvastatin significantly impaired phosphorylation of Bad (p < 0.01), decreased protein levels of Bcl-2 and Bcl-xL (p < 0.01 and p < 0.001, respectively), increased release of cytochrome C from the mitochondria to cytosol (p < 0.05) as well as increased protein expressions of BimL and BimS, cleaved caspase 9 and cleaved caspase 3 (p < 0.05), compared to saline treated controls.	22	55	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	phosphorylation of Bad (p < 0.01), decreased protein levels of Bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome c	35	36	53	55
Bcl-2 over-expression abrogated cytochrome c release and apoptosis , and also blocked caspase-8 activation .	Bcl-2 over-expression abrogated cytochrome c release and apoptosis, and also blocked caspase-8 activation.	0	5	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 over-expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	3	5
Mammalian B-cell lymphoma 2 ( Bcl-2 ) inhibits apoptosis by preventing the release of the Apaf-1 ( apoptotic protease activating factor 1 ) activator cytochrome c from mitochondria .	Mammalian B-cell lymphoma 2 (Bcl-2) inhibits apoptosis by preventing the release of the Apaf-1 (apoptotic protease activating factor 1) activator cytochrome c from mitochondria.	2	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	24	26
In addition , as a chemical compound , rapamycin caused an increase of bcl2 protein level and blocked the release of cytochrome c from mitochondria to cytosal .	In addition, as a chemical compound, rapamycin caused an increase of bcl2 protein level and blocked the release of cytochrome c from mitochondria to cytosal.	8	23	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl2	rapamycin caused an increase of bcl2 protein level	bcl2	cytochrome c	cytochrome c	cytochrome c	13	14	21	23
Bcl-2 overexpression can inhibit the accumulation of cytochrome C in the cytoplasm to inhibit cell apoptosis .	Bcl-2 overexpression can inhibit the accumulation of cytochrome C in the cytoplasm to inhibit cell apoptosis.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	cytochrome C	cytochrome C	cytochrome c	0	1	7	9
Bcl-2 inhibits the release of cytochrome C and ultimately inhibits apoptosis while activation of the Bax protein stimulates the release of cytochrome c from mitochondria and promotes apoptosis [ XREF_BIBR ] .	Bcl-2 inhibits the release of cytochrome C and ultimately inhibits apoptosis while activation of the Bax protein stimulates the release of cytochrome c from mitochondria and promotes apoptosis [XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	5	7
The overexpression of Bcl-2 blocked cytochrome c release in response to a variety of apoptotic stimuli XREF_BIBR .	The overexpression of Bcl-2 blocked cytochrome c release in response to a variety of apoptotic stimuli XREF_BIBR.	1	7	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	5	7
Western blot analysis of oxidative stress pathway related proteins demonstrated that oridonin treatment increased p-JNK , p-p38 and p-p53 , and decreased Bcl-2 protein expression levels , promoted cytochrome c release , decreased mitochondrial membrane potential , and activated caspase-9 and caspase-3 .	Western blot analysis of oxidative stress pathway related proteins demonstrated that oridonin treatment increased p-JNK, p-p38 and p-p53, and decreased Bcl-2 protein expression levels, promoted cytochrome c release, decreased mitochondrial membrane potential, and activated caspase-9 and caspase-3.	11	30	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	oridonin treatment increased p-JNK, p-p38 and p-p53, and decreased Bcl-2 protein expression levels	bcl-2	cytochrome c	cytochrome c	cytochrome c	22	23	28	30
Bcl-2 can prevent the release of cytochrome c ( Cyt-c ) from the mitochondria to the cytoplasm , thus inhibiting apoptosis .	Bcl-2 can prevent the release of cytochrome c (Cyt-c) from the mitochondria to the cytoplasm, thus inhibiting apoptosis.	0	8	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
On the other hand , Bcl-2 blocked the release of mitochondrial cytochrome c in Bid transfected cells , suggesting actions at the mitochondrial level .	On the other hand, Bcl-2 blocked the release of mitochondrial cytochrome c in Bid transfected cells, suggesting actions at the mitochondrial level.	5	13	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	11	13
Bcl-2 resides in the outer mitochondrial wall , maintains membrane integrity and inhibits cytochrome c release .	Bcl-2 resides in the outer mitochondrial wall, maintains membrane integrity and inhibits cytochrome c release.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
Bcl-2 can prevent release of cytochrome c from mitochondria , thus , precluding the apoptotic cascade .	Bcl-2 can prevent release of cytochrome c from mitochondria, thus, precluding the apoptotic cascade.	0	7	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Thus , it inhibits apoptosis pathway differently from bcl-2 , which blocks mitochondrial cytochrome c release into the cytosol , resulting in the inhibition of mitochondrial apoptotic pathway .	Thus, it inhibits apoptosis pathway differently from bcl-2, which blocks mitochondrial cytochrome c release into the cytosol, resulting in the inhibition of mitochondrial apoptotic pathway.	3	15	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	13	15
For example , the Bcl-2 family member BCL2A1 can reduce the release of pro apoptotic cytochrome C from mitochondria and block caspase activation , and is a direct transcriptional target of NF-kappaB in response to inflammatory mediators .	For example, the Bcl-2 family member BCL2A1 can reduce the release of pro apoptotic cytochrome C from mitochondria and block caspase activation, and is a direct transcriptional target of NF-kappaB in response to inflammatory mediators.	4	17	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	4	5	15	17
In our studies , we found the increased expression of Bax ( pro apoptotic ) , decreased expression of Bcl-2 ( anti-apoptotic ) as well as activated mitochondrial dependent pathways via reduced mitochondrial membrane potential , enhanced cytochrome C , increased expression of caspase 9 and caspase 3 in the cytosol and cleavage of PARP in STZ induced diabetic nephropathy .	In our studies, we found the increased expression of Bax (pro apoptotic), decreased expression of Bcl-2 (anti-apoptotic) as well as activated mitochondrial dependent pathways via reduced mitochondrial membrane potential, enhanced cytochrome C, increased expression of caspase 9 and caspase 3 in the cytosol and cleavage of PARP in STZ induced diabetic nephropathy.	8	39	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of Bax (pro apoptotic), decreased expression of Bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome c	19	20	37	39
It has been suggested that bcl-2 prevents the release of cytochrome c , thereby inhibiting the activation of caspases ( Marzo et al , 1998 ) .	It has been suggested that bcl-2 prevents the release of cytochrome c, thereby inhibiting the activation of caspases (Marzo et al, 1998).	5	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	10	12
In an opposite way , Bcl-2 inhibits apoptosis by preventing the release of cytochrome C by stabilizing the membranes ' permeability ; thereby the mitochondrial cellular integrity was maintained [ XREF_BIBR ] .	In an opposite way, Bcl-2 inhibits apoptosis by preventing the release of cytochrome C by stabilizing the membranes ' permeability; thereby the mitochondrial cellular integrity was maintained [XREF_BIBR].	5	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	5	6	13	15
Conversely , both anti-apoptotic proteins , Bcl-2 and Bcl-xl , inhibit the release of cytochrome c from the mitochondria .	Conversely, both anti-apoptotic proteins, Bcl-2 and Bcl-xl, inhibit the release of cytochrome c from the mitochondria.	4	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	14	16
Bcl-2 impedes the release of cytochrome c into the cytosol , and therefore prevents activation of caspase 9 and subsequently caspase 3 .	Bcl-2 impedes the release of cytochrome c into the cytosol, and therefore prevents activation of caspase 9 and subsequently caspase 3.	0	13	impedes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Interestingly , overexpression of Bcl-2 or FADD-DN did not interfere with resveratrol mediated cell cycle arrest or survivin depletion , but blocked release of cytochrome c and Smac from mitochondria into the cytosol , enhanced caspase activation and apoptosis upon combined treatment with resveratrol and TRAIL indicating that overexpression of Bcl-2 or FADD-DN decoupled the effect of resveratrol on the cell cycle and apoptosis .	Interestingly, overexpression of Bcl-2 or FADD-DN did not interfere with resveratrol mediated cell cycle arrest or survivin depletion, but blocked release of cytochrome c and Smac from mitochondria into the cytosol, enhanced caspase activation and apoptosis upon combined treatment with resveratrol and TRAIL indicating that overexpression of Bcl-2 or FADD-DN decoupled the effect of resveratrol on the cell cycle and apoptosis.	2	26	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	24	26
Bcl-2 , an apoptosis inhibitor localized to mitochondrial outer membranes , prevents cytochrome c release , caspase activation and cell death .	Bcl-2, an apoptosis inhibitor localized to mitochondrial outer membranes, prevents cytochrome c release, caspase activation and cell death.	0	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	12	14
In mammals , the Bcl-2 protein prevents the release of cytochrome c from mitochondria , and consequently inhibits the formation of the Apaf-1 apoptosome [ XREF_BIBR ] .	In mammals, the Bcl-2 protein prevents the release of cytochrome c from mitochondria, and consequently inhibits the formation of the Apaf-1 apoptosome [XREF_BIBR].	4	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	10	12
Studies have demonstrated that cytochrome c may participate in the activation of caspase 3 and that Bcl-2 blocks the release of cytochrome c from mitochondria .	Studies have demonstrated that cytochrome c may participate in the activation of caspase 3 and that Bcl-2 blocks the release of cytochrome c from mitochondria.	15	23	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	16	17	21	23
Additionally , subamolide B evoked cell death pathways mediated by FasL and Fas , mitochondria , and endoplasmic reticulum ( ER ) stress , as supported by subamolide B induced FasL upregulation , BCL-2 suppression and cytosolic release of cytochrome c , and UPR activation and CHOP upregulation , respectively .	Additionally, subamolide B evoked cell death pathways mediated by FasL and Fas, mitochondria, and endoplasmic reticulum (ER) stress, as supported by subamolide B induced FasL upregulation, BCL-2 suppression and cytosolic release of cytochrome c, and UPR activation and CHOP upregulation, respectively.	33	41	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	33	34	39	41
Anti-apoptotic Bcl-2 family members , such as Bcl-2 , Bcl-xL , and Mcl-1 sequester pro apoptotic BH3-only proteins , such as Bim , preventing activation of the pro apoptotic proteins Bax and Bak , ultimately preventing mitochondrial outer membrane permeabilization , cytochrome c release , and apoptosis .	Anti-apoptotic Bcl-2 family members, such as Bcl-2, Bcl-xL, and Mcl-1 sequester pro apoptotic BH3-only proteins, such as Bim, preventing activation of the pro apoptotic proteins Bax and Bak, ultimately preventing mitochondrial outer membrane permeabilization, cytochrome c release, and apoptosis.	1	43	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	41	43
Thus to test the hypothesis that Bcl-2 inhibits either the PTP or the PTP dependent release of cytochrome c , the rate and extent of PTP , and PTP dependent release of cytochrome c were compared in liver mitochondria from control and Bcl-2 transgenic mice .	Thus to test the hypothesis that Bcl-2 inhibits either the PTP or the PTP dependent release of cytochrome c, the rate and extent of PTP, and PTP dependent release of cytochrome c were compared in liver mitochondria from control and Bcl-2 transgenic mice.	6	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	17	19
Bcl2 , an anti-apoptotic protein localized to mitochondria , has been shown to inhibit cytochrome c release and protect against oxidative stress induced apoptosis [ XREF_BIBR ] .	Bcl2, an anti-apoptotic protein localized to mitochondria, has been shown to inhibit cytochrome c release and protect against oxidative stress induced apoptosis [XREF_BIBR].	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	0	1	14	16
Bcl-2 is a well studied antiapoptotic protein , and is thought to inhibit apoptosis by stabilizing the outer mitochondrial membrane , preventing release of cytochrome c into the cytosol and thereby blocking caspase activation XREF_BIBR .	Bcl-2 is a well studied antiapoptotic protein, and is thought to inhibit apoptosis by stabilizing the outer mitochondrial membrane, preventing release of cytochrome c into the cytosol and thereby blocking caspase activation XREF_BIBR.	0	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	24	26
The overexpression of anti-apoptotic Bcl-2 family proteins , such as Bcl-2 and Bcl-X L , blocks the release of cytochrome c in response to a variety of apoptotic signals .	The overexpression of anti-apoptotic Bcl-2 family proteins, such as Bcl-2 and Bcl-X L, blocks the release of cytochrome c in response to a variety of apoptotic signals.	1	21	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of anti-apoptotic Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	19	21
XREF_BIBR , XREF_BIBR This fundamental difference between cell types is evidenced by reports demonstrating that overexpression of BCL-2 or BCL-XL , anti-apoptotic BCL-2 family members which inhibit MOMP and cytochrome c release , blocks activation of caspase-8 and caspase-3 as well as FAS mediated apoptosis in type II cells , but not type I cells .	XREF_BIBR, XREF_BIBR This fundamental difference between cell types is evidenced by reports demonstrating that overexpression of BCL-2 or BCL-XL, anti-apoptotic BCL-2 family members which inhibit MOMP and cytochrome c release, blocks activation of caspase-8 and caspase-3 as well as FAS mediated apoptosis in type II cells, but not type I cells.	15	31	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	BCL-2	overexpression of BCL-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	17	18	29	31
Bcl-2 inhibits apoptosis by regulating the release of cytochrome c and other proteins from mitochondria .	Bcl-2 inhibits apoptosis by regulating the release of cytochrome c and other proteins from mitochondria.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
Bcl-2 also suppresses cytochrome c and apoptosis inducing factor release from mitochondria , which prevents the activation of caspases .	Bcl-2 also suppresses cytochrome c and apoptosis inducing factor release from mitochondria, which prevents the activation of caspases.	0	5	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	3	5
Interestingly , caspase activation , DNA fragmentation , and cytochrome c release induced with low alpha-toxin doses were blocked completely by Bcl-2 , whereas cell death induced with high alpha-toxin concentrations proceeded independently of mitochondria mediated caspase activation .	Interestingly, caspase activation, DNA fragmentation, and cytochrome c release induced with low alpha-toxin doses were blocked completely by Bcl-2, whereas cell death induced with high alpha-toxin concentrations proceeded independently of mitochondria mediated caspase activation.	9	22	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	21	22	9	11
Inhibition of anti-apoptotic Bcl-2 family members leads to activation of pro apoptotic proteins Bax and Bak triggering mitochondrial outer membrane permeabilization ( MOMP ) and release of cytochrome C XREF_BIBR , XREF_BIBR , XREF_BIBR .	Inhibition of anti-apoptotic Bcl-2 family members leads to activation of pro apoptotic proteins Bax and Bak triggering mitochondrial outer membrane permeabilization (MOMP) and release of cytochrome C XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	29	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	3	4	27	29
Possible anti-apoptotic mechanisms involve the following steps : improvements in TCA cycle and ATP production , decreased cellular ROS content , enhanced the expression of Bcl-2 , stabilization of MMP , decreased release of mitochondrial cytochrome c , and inhibition of caspase-3 activation .	Possible anti-apoptotic mechanisms involve the following steps : improvements in TCA cycle and ATP production, decreased cellular ROS content, enhanced the expression of Bcl-2, stabilization of MMP, decreased release of mitochondrial cytochrome c, and inhibition of caspase-3 activation.	23	37	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	25	26	35	37
Bcl-2 is an anti-apoptotic member of the Bcl-2 family , by scavenging oxygen-free radicals inside the cells and repressing the release of cytochrome C into the cytoplasm , which play important roles in the regulation of the apoptotic pathway .	Bcl-2 is an anti-apoptotic member of the Bcl-2 family, by scavenging oxygen-free radicals inside the cells and repressing the release of cytochrome C into the cytoplasm, which play important roles in the regulation of the apoptotic pathway.	0	24	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	22	24
In the presence of mutated lkappaB , singular overexpression of only Bcl-2 by adenoviral mediated transduction significantly inhibited cytochrome c release , caspase-3-like activation , and cell death in response to H/R .	In the presence of mutated lkappaB, singular overexpression of only Bcl-2 by adenoviral mediated transduction significantly inhibited cytochrome c release, caspase-3-like activation, and cell death in response to H/R.	8	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of only Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	18	20
For example , BCL2 can inhibit the release of cytochrome c [ XREF_BIBR , XREF_BIBR ] , which prevents triggering of apoptosis and MnSOD averts apoptosis by reducing ROS levels [ XREF_BIBR - XREF_BIBR ] .	For example, BCL2 can inhibit the release of cytochrome c [XREF_BIBR, XREF_BIBR], which prevents triggering of apoptosis and MnSOD averts apoptosis by reducing ROS levels [XREF_BIBR - XREF_BIBR].	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	3	4	9	11
Bcl-2 prevents the disruption of mitochondria , the subsequent release of cytochrome C and activation of the caspase cascade .	Bcl-2 prevents the disruption of mitochondria, the subsequent release of cytochrome C and activation of the caspase cascade.	0	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	11	13
Because miR-34a expression suppressed expression of Bcl-2 and enhanced release of cytochrome c from the mitochondrial endomembrane , miR-34a may significantly amplify the anti-tumor effect of Smac by enhancing Smac induced activation of the Caspase pathway .	Because miR-34a expression suppressed expression of Bcl-2 and enhanced release of cytochrome c from the mitochondrial endomembrane, miR-34a may significantly amplify the anti-tumor effect of Smac by enhancing Smac induced activation of the Caspase pathway.	1	13	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	miR-34a expression suppressed expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	11	13
The anti-apoptotic protein Bcl-2 inhibits cytochrome c release and Caspase 3 activation and thus functions as an antioxidant to prevent apoptosis [ XREF_BIBR ] .	The anti-apoptotic protein Bcl-2 inhibits cytochrome c release and Caspase 3 activation and thus functions as an antioxidant to prevent apoptosis [XREF_BIBR].	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	5	7
Of these proteins , anti-apoptotic Bcl-xL and Bcl-2 reside in the intracellular membranes of mitochondria and prevent cytochrome C release ( XREF_FIG ) , while the remaining pro apoptotic Bcl-2 family members reside in the cytosol as inactive forms and shuttle to the mitochondria following the activation by proteolysis ( i.e ., truncated Bid ) and dephosphorylation ( i.e ., non phosphorylated Bad ) [ XREF_BIBR , XREF_BIBR ] .	Of these proteins, anti-apoptotic Bcl-xL and Bcl-2 reside in the intracellular membranes of mitochondria and prevent cytochrome C release (XREF_FIG), while the remaining pro apoptotic Bcl-2 family members reside in the cytosol as inactive forms and shuttle to the mitochondria following the activation by proteolysis (i.e., truncated Bid) and dephosphorylation (i.e., non phosphorylated Bad) [XREF_BIBR, XREF_BIBR].	5	57	prevent	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Bcl-2	Bcl-2	bcl-2	cytochrome C	cytochrome C release (XREF_FIG), while the remaining pro apoptotic Bcl-2 family members reside in the cytosol as inactive forms and shuttle to the mitochondria following the activation by proteolysis (i.e., truncated Bid) and dephosphorylation	cytochrome c	7	8	17	19
Multidomain proapoptotic BAX and BAK are essential effectors responsible for the permeabilization of the MOM , whereas anti-apoptotic BCL-2 , BCL-X L , and MCL-1 preserve mitochondrial integrity and prevent cytochrome c efflux triggered by apoptotic stimuli .	Multidomain proapoptotic BAX and BAK are essential effectors responsible for the permeabilization of the MOM, whereas anti-apoptotic BCL-2, BCL-X L, and MCL-1 preserve mitochondrial integrity and prevent cytochrome c efflux triggered by apoptotic stimuli.	17	32	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	18	19	30	32
As shown in XREF_FIG , the overexpressing Bcl-2 of cells significantly decreased the heat stress induced apoptosis , the loss of DeltaPsim and cytochrome c release .	As shown in XREF_FIG, the overexpressing Bcl-2 of cells significantly decreased the heat stress induced apoptosis, the loss of DeltaPsim and cytochrome c release.	5	25	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	23	25
Importantly , Bcl-2 and Bcl-x ( L ) inhibited the release of both cytochrome c and Smac from mitochondria .	Importantly, Bcl-2 and Bcl-x (L) inhibited the release of both cytochrome c and Smac from mitochondria.	2	15	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	13	15
For this purpose , Jurkat cells stably expressing the antiapoptotic protein Bcl-2 that is known to prevent mitochondrial cytochrome c release were incubated with increasing concentrations of Wood 46 ( XREF_FIG A ) or RN6390 ( XREF_FIG B ) supernatants .	For this purpose, Jurkat cells stably expressing the antiapoptotic protein Bcl-2 that is known to prevent mitochondrial cytochrome c release were incubated with increasing concentrations of Wood 46 (XREF_FIG A) or RN6390 (XREF_FIG B) supernatants.	7	20	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	18	20
Studies carried out in murine T hybridoma cells suggest that Bcl-2 overexpression also blocks the release of both cytochrome c and AIF in response to GCs [ XREF_BIBR ] .	Studies carried out in murine T hybridoma cells suggest that Bcl-2 overexpression also blocks the release of both cytochrome c and AIF in response to GCs [XREF_BIBR].	10	20	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	18	20
This group also found that overexpressed Bcl-2 or Bcl-xL did not prevent the release of cytochrome c from mitochondria but instead blocked the activation of several caspases [ XREF_BIBR ] .	This group also found that overexpressed Bcl-2 or Bcl-xL did not prevent the release of cytochrome c from mitochondria but instead blocked the activation of several caspases [XREF_BIBR].	5	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	15	17
Conversely , anti-apoptotic members of the Bcl-2 family maintain mitochondrial membrane potential and prevent the release of cytochrome c during apoptotic insults ( Kluck et al ., 1997 ) .	Conversely, anti-apoptotic members of the Bcl-2 family maintain mitochondrial membrane potential and prevent the release of cytochrome c during apoptotic insults (Kluck et al., 1997).	6	19	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	17	19
Bcl-2 family could inhibit the release of cytochrome c which could active Caspae3 [ XREF_BIBR ] .	Bcl-2 family could inhibit the release of cytochrome c which could active Caspae3 [XREF_BIBR].	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	7	9
Importantly , the overexpression of anti-apoptotic Bcl-2 in k562 cells significantly blocked PBTDs induced release of cytochrome c from mitochondria .	Importantly, the overexpression of anti-apoptotic Bcl-2 in k562 cells significantly blocked PBTDs induced release of cytochrome c from mitochondria.	3	18	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of anti-apoptotic Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	16	18
Decreased Bcl-2 and Bax ratios may trigger the release of cytochrome C from the mitochondria and activation of pro caspase 3 .	Decreased Bcl-2 and Bax ratios may trigger the release of cytochrome C from the mitochondria and activation of pro caspase 3.	1	12	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	1	2	10	12
Cytochrome c release , normally preceding STS induced necrosis , was also inhibited by Bcl-2 .	Cytochrome c release, normally preceding STS induced necrosis, was also inhibited by Bcl-2.	0	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Cytochrome c	Cytochrome c	Cytochrome c	14	15	0	2
Bax and Bid proapoptotic proteins enhance the cytochrome C release , whereas the antiapoprotic Bcl-2 inhibits the cytochrome C reflux ; ( 2c ) Ca 2+ release from the endoplasmic reticulum activates cytochrome C release from mitochondria .	Bax and Bid proapoptotic proteins enhance the cytochrome C release, whereas the antiapoprotic Bcl-2 inhibits the cytochrome C reflux; (2c) Ca 2+ release from the endoplasmic reticulum activates cytochrome C release from mitochondria.	12	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	14	15	17	19
Western blot analysis showed that PEITC promoted Bax expression and inhibited Bcl-2 expression associated with the disintegration of the outer mitochondrial membrane causing cytochrome c release , and activation of caspase-9 and -3 cascade leading to apoptosis .	Western blot analysis showed that PEITC promoted Bax expression and inhibited Bcl-2 expression associated with the disintegration of the outer mitochondrial membrane causing cytochrome c release, and activation of caspase-9 and -3 cascade leading to apoptosis.	5	25	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	PEITC promoted Bax expression and inhibited Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	23	25
Moreover , Bcl-2 and its homologs prevent mitochondrial membrane disruption and the release of cytochrome c and other proapoptotic factors .	Moreover, Bcl-2 and its homologs prevent mitochondrial membrane disruption and the release of cytochrome c and other proapoptotic factors.	2	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	14	16
BBR also increased Bcl-2 expression and decreased cytochrome c release .	BBR also increased Bcl-2 expression and decreased cytochrome c release.	0	9	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	BBR also increased Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	7	9
Anti-apoptotic Bcl-2 family proteins ( e.g ., Bcl-2 , Bcl-xL , and Mcl-1 ) antagonize membrane permeabilization and prevent the release of cytochrome c from mitochondria .	Anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-xL, and Mcl-1) antagonize membrane permeabilization and prevent the release of cytochrome c from mitochondria.	1	24	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	22	24
Anti-apoptotic members of the Bcl-2 family such as Bcl-2 and Bcl-X prevent the release of cytochrome C and Smac/DIABLO from mitochondria .	Anti-apoptotic members of the Bcl-2 family such as Bcl-2 and Bcl-X prevent the release of cytochrome C and Smac/DIABLO from mitochondria.	4	17	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	4	5	15	17
It has been suggested that bcl-2 prevents the release of cytochrome c into the cytosol , thereby inhibiting the activation of caspases ( Marzo et al , 1998 ) .	It has been suggested that bcl-2 prevents the release of cytochrome c into the cytosol, thereby inhibiting the activation of caspases (Marzo et al, 1998).	5	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	10	12
Bcl-2 protein prevents the release of cytochrome c from the mitochondria and subsequent activation of caspase cascade .	Bcl-2 protein prevents the release of cytochrome c from the mitochondria and subsequent activation of caspase cascade.	0	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
Bcl-2 protein blocks the release of cytochrome-C , which in turn prevents the propagation of death signals and promotes cell survival .	Bcl-2 protein blocks the release of cytochrome-C, which in turn prevents the propagation of death signals and promotes cell survival.	0	18	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome-C	cytochrome-C	cytochrome-C	0	1	6	7
The multidomain proapoptotic proteins BAX and BAK mediate permeabilization of the MOM , whereas anti-apoptotic BCL-2 , BCL-X L , and MCL-1 proteins prevent cytochrome c efflux triggered by apoptotic stimuli .	The multidomain proapoptotic proteins BAX and BAK mediate permeabilization of the MOM, whereas anti-apoptotic BCL-2, BCL-X L, and MCL-1 proteins prevent cytochrome c efflux triggered by apoptotic stimuli.	14	26	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	15	16	24	26
CypD enhances the limiting effect of Bcl2 on the tBid induced release of cytochrome c from mitochondria , which is not mediated via the MPT .	CypD enhances the limiting effect of Bcl2 on the tBid induced release of cytochrome c from mitochondria, which is not mediated via the MPT.	4	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	6	7	13	15
Aplidine also triggered an early release of cytochrome c from mitochondria , and overexpression of bcl-2 by gene transfer abrogated mitochondrial cytochrome c release and apoptosis .	Aplidine also triggered an early release of cytochrome c from mitochondria, and overexpression of bcl-2 by gene transfer abrogated mitochondrial cytochrome c release and apoptosis.	13	23	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	overexpression of bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	21	23
The over-expression of Bcl2 not only prevents the development of cells apoptosis , but inhibits the release of cytochrome C , nevertheless , Bax may increase the membrane ' s permeability , which leads to the release of cytochrome C from mitochondria , activation of caspase-9 and initiation of the caspase activation pathway for apoptosis [ XREF_BIBR , XREF_BIBR ] .	The over-expression of Bcl2 not only prevents the development of cells apoptosis, but inhibits the release of cytochrome C, nevertheless, Bax may increase the membrane 's permeability, which leads to the release of cytochrome C from mitochondria, activation of caspase-9 and initiation of the caspase activation pathway for apoptosis [XREF_BIBR, XREF_BIBR].	1	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	over-expression of Bcl2	bcl2	cytochrome C	cytochrome C	cytochrome c	3	4	18	20
The increased Bcl-2 and Bax ratio blocks the cytochrome C released from mitochondria , which inhibits the mitochondrial apoptotic pathways .	The increased Bcl-2 and Bax ratio blocks the cytochrome C released from mitochondria, which inhibits the mitochondrial apoptotic pathways.	0	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	2	3	8	10
Curcumin regulates mitochondrial biogenesis [ XREF_BIBR ] , inhibits LPO [ XREF_BIBR ] and ROS synthesis [ XREF_BIBR , XREF_BIBR ] , downregulates Bcl-2 and Bcl-XL expressions [ XREF_BIBR ] , inhibits cytochrome c release [ XREF_BIBR ] , restores MMP [ XREF_BIBR ] , and suppresses caspase-3 activity [ XREF_BIBR ] .	Curcumin regulates mitochondrial biogenesis [XREF_BIBR], inhibits LPO [XREF_BIBR] and ROS synthesis [XREF_BIBR, XREF_BIBR], downregulates Bcl-2 and Bcl-XL expressions [XREF_BIBR], inhibits cytochrome c release [XREF_BIBR], restores MMP [XREF_BIBR], and suppresses caspase-3 activity [XREF_BIBR].	0	34	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Curcumin regulates mitochondrial biogenesis [XREF_BIBR], inhibits LPO [XREF_BIBR] and ROS synthesis [XREF_BIBR, XREF_BIBR], downregulates Bcl-2 and Bcl-XL expressions	bcl-2	cytochrome c	cytochrome c	cytochrome c	23	24	32	34
This shows that Bcl-2 primarily blocks the CAF induced release of cytochrome c , which is the mitochondrial event crucial for execution of apoptosis , while CAF induced MMD remains unaffected .	This shows that Bcl-2 primarily blocks the CAF induced release of cytochrome c, which is the mitochondrial event crucial for execution of apoptosis, while CAF induced MMD remains unaffected.	3	13	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	11	13
Furthermore , the pro apoptotic protein Bax was activated while the anti-apoptotic protein Bcl-2 was inhibited resulting in opening of the mitochondrial permeability transition pores , release of cytochrome c , and activation of caspase-9 and caspase-3 enzymes .	Furthermore, the pro apoptotic protein Bax was activated while the anti-apoptotic protein Bcl-2 was inhibited resulting in opening of the mitochondrial permeability transition pores, release of cytochrome c, and activation of caspase-9 and caspase-3 enzymes.	10	30	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	28	30
Bcl-2 acted in situ on mitochondria to prevent the release of cytochrome c and thus caspase activation .	Bcl-2 acted in situ on mitochondria to prevent the release of cytochrome c and thus caspase activation.	0	13	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	11	13
Other experiments demonstrated that Bcl-2 and Bcl-x L block the release of cytochrome c from mitochondria , preventing cytochrome c mediated caspase activation .	Other experiments demonstrated that Bcl-2 and Bcl-x L block the release of cytochrome c from mitochondria, preventing cytochrome c mediated caspase activation.	4	14	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	12	14
It is generally contended that the anti-apoptotic members of the Bcl-2 family work to prevent cytochrome c release by stabilizing the mitochondrial membrane barrier function and the pro apoptotic members tend to induce cytochrome c release by permeabilizing the mitochondrial membrane [ XREF_BIBR , XREF_BIBR ] .	It is generally contended that the anti-apoptotic members of the Bcl-2 family work to prevent cytochrome c release by stabilizing the mitochondrial membrane barrier function and the pro apoptotic members tend to induce cytochrome c release by permeabilizing the mitochondrial membrane [XREF_BIBR, XREF_BIBR].	10	35	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	33	35
Anti-apoptotic proteins in the Bcl-2 family inhibit the leakage of cytochrome c from mitochondria that initiates the intrinsic apoptotic cascade .	Anti-apoptotic proteins in the Bcl-2 family inhibit the leakage of cytochrome c from mitochondria that initiates the intrinsic apoptotic cascade.	4	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	10	12
To further assess apoptosis at the molecular level , BAX , a key promoter of apoptosis through mitochondrial stress [ XREF_BIBR ] , and pro survival , anti-apoptotic BCL2 , which inhibits mitochondrial cytochrome c release [ XREF_BIBR , XREF_BIBR ] , were also analysed by western blot .	To further assess apoptosis at the molecular level, BAX, a key promoter of apoptosis through mitochondrial stress [XREF_BIBR], and pro survival, anti-apoptotic BCL2, which inhibits mitochondrial cytochrome c release [XREF_BIBR, XREF_BIBR], were also analysed by western blot.	27	44	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	28	29	33	35
HSP70 also increases Bcl-2 expression and inhibits cytochrome C release ; it also binds and sequesters AIF [ XREF_BIBR , XREF_BIBR ] .	HSP70 also increases Bcl-2 expression and inhibits cytochrome C release; it also binds and sequesters AIF [XREF_BIBR, XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	HSP70 also increases Bcl-2 expression	bcl-2	cytochrome C	cytochrome C	cytochrome c	3	4	7	9
Bax proteins induce apoptosis by promoting the release of mitochondrial cytochrome c. Countering the effect of Bax , Bcl-2 inhibits the release of mitochondrial cytochrome c and apoptosis .	Bax proteins induce apoptosis by promoting the release of mitochondrial cytochrome c. Countering the effect of Bax, Bcl-2 inhibits the release of mitochondrial cytochrome c and apoptosis.	18	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	24	26
Moreover , conformationally altered Bax stimulates the release of Smac/DIABLO from mitochondria [ XREF_BIBR ] , and the cytochrome c releasing activity of Bid by cell surface death receptors such as Fas and TNF is antagonized by Bcl-2 [ XREF_BIBR ] .	Moreover, conformationally altered Bax stimulates the release of Smac/DIABLO from mitochondria [XREF_BIBR], and the cytochrome c releasing activity of Bid by cell surface death receptors such as Fas and TNF is antagonized by Bcl-2 [XREF_BIBR].	18	39	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	37	38	18	20
Our results clearly show that beta-elemene induced caspase-3 , -7 and -9 activities , decreased Bcl-2 expression , caused cytochrome c release and increased the levels of cleaved caspase-9 and poly ( ADP-ribose ) polymerase in NSCLC cells .	Our results clearly show that beta-elemene induced caspase-3, -7 and -9 activities, decreased Bcl-2 expression, caused cytochrome c release and increased the levels of cleaved caspase-9 and poly (ADP-ribose) polymerase in NSCLC cells.	5	21	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	beta-elemene induced caspase-3, -7 and -9 activities, decreased Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	19	21
Bcl-2 , Bcl-x L and Mcl-1 inhibit caspase activation and subsequent downstream apoptotic events by preventing the release of cytochrome c from the mitochondrial intermembrane space [ XREF_BIBR - XREF_BIBR ] .	Bcl-2, Bcl-x L and Mcl-1 inhibit caspase activation and subsequent downstream apoptotic events by preventing the release of cytochrome c from the mitochondrial intermembrane space [XREF_BIBR - XREF_BIBR].	0	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	19	21
T cell receptor activates Bcl-2 , which inhibits cytochrome C ( Cyto C ) XREF_BIBR and cell death ( XREF_FIG ) XREF_BIBR .	T cell receptor activates Bcl-2, which inhibits cytochrome C (Cyto C) XREF_BIBR and cell death (XREF_FIG) XREF_BIBR.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	4	5	8	10
Expression of Bcl-2 blocks cytochrome c release and apoptosis but has no effect on Bax translocation , suggesting that Bax translocation acts upstream of Bcl-2 .	Expression of Bcl-2 blocks cytochrome c release and apoptosis but has no effect on Bax translocation, suggesting that Bax translocation acts upstream of Bcl-2.	0	6	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	4	6
Bcl-2 inhibits the release of cytochrome C and inhibits the function of activated caspases while Bax has the opposite effect .	Bcl-2 inhibits the release of cytochrome C and inhibits the function of activated caspases while Bax has the opposite effect.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	5	7
Bcl-2 can suppress the release of cytochrome c from mitochondria and prevent caspase activation .	Bcl-2 can suppress the release of cytochrome c from mitochondria and prevent caspase activation.	0	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	6	8
Bcl-2 has also been shown to interact with VDAC1 through its N- terminal and inhibit cytochrome c release and apoptosis [ XREF_BIBR , XREF_BIBR ] .	Bcl-2 has also been shown to interact with VDAC1 through its N- terminal and inhibit cytochrome c release and apoptosis [XREF_BIBR, XREF_BIBR].	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	15	17
Analysis of the antiapoptotic mechanisms triggered by ACh showed that ACh downregulates expression of FasL induced NF-kappaB RNA expression , upregulates expression of antiapoptotic protein Bcl-2 , downregulates expression of proapoptotic protein Bad , reduces cytochrome c release , and prevents proapoptotic Bid protein cleavage .	Analysis of the antiapoptotic mechanisms triggered by ACh showed that ACh downregulates expression of FasL induced NF-kappaB RNA expression, upregulates expression of antiapoptotic protein Bcl-2, downregulates expression of proapoptotic protein Bad, reduces cytochrome c release, and prevents proapoptotic Bid protein cleavage.	10	37	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	ACh downregulates expression of FasL induced NF-kappaB RNA expression, upregulates expression of antiapoptotic protein Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	25	26	35	37
This explains the observation that ectopic overexpression of Bcl-2 which prevents cytochrome c release can decrease HSV-1-dependent apoptosis [ XREF_BIBR ] .	This explains the observation that ectopic overexpression of Bcl-2 which prevents cytochrome c release can decrease HSV-1-dependent apoptosis [XREF_BIBR].	6	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	11	13
Apoptosis was found to be mediated by the mitochondria through Bax and Bak upregulation , The downregulation of inhibitor of apoptosis such as Bcl-2 , survivin , Bcl-xl and cFLIP downregulation and release of cytochrome c and activation of caspases 9 and 3 to induce apoptosis .	Apoptosis was found to be mediated by the mitochondria through Bax and Bak upregulation, The downregulation of inhibitor of apoptosis such as Bcl-2, survivin, Bcl-xl and cFLIP downregulation and release of cytochrome c and activation of caspases 9 and 3 to induce apoptosis.	23	36	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	23	24	34	36
The pro survival factor Bcl-2 inhibits apoptosis and enhances cell survival by inhibiting the release of cytochrome c during apoptosis .	The pro survival factor Bcl-2 inhibits apoptosis and enhances cell survival by inhibiting the release of cytochrome c during apoptosis.	0	18	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	16	18
The anti-apoptotic Bcl-2 proteins , including Bcl-2 and Bcl-extra large , stimulate cell survival by inhibiting mitochondrial permeability and the release of cytochrome c , therefore , effectively inhibiting apoptosis .	The anti-apoptotic Bcl-2 proteins, including Bcl-2 and Bcl-extra large, stimulate cell survival by inhibiting mitochondrial permeability and the release of cytochrome c, therefore, effectively inhibiting apoptosis.	2	24	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	22	24
We previously showed [ XREF_BIBR ] that Bcl-2 and Bcl-xl inhibitors cause depolarization of pancreatic mitochondria and stimulate cytochrome c release .	We previously showed [XREF_BIBR] that Bcl-2 and Bcl-xl inhibitors cause depolarization of pancreatic mitochondria and stimulate cytochrome c release.	7	20	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	18	20
Indeed , overexpression of Bcl-2 reduced cytochrome c release from the mitochondria and significantly inhibited DNA fragmentation triggered by exposure to 50 mmol/l ribose ( XREF_FIG A and B ) .	Indeed, overexpression of Bcl-2 reduced cytochrome c release from the mitochondria and significantly inhibited DNA fragmentation triggered by exposure to 50 mmol/l ribose (XREF_FIG A and B).	2	8	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	6	8
The expression also induces mitochondrial dysfunction and apoptosis by releasing cytochrome c , which is suppressed by anti-apoptotic proteins Bcl-2 , Bcl-X L , and XIAP .	The expression also induces mitochondrial dysfunction and apoptosis by releasing cytochrome c, which is suppressed by anti-apoptotic proteins Bcl-2, Bcl-X L, and XIAP.	10	25	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	19	20	10	12
Bcl-2 could prevent the release of cytochrome C from the mitochondria to the cytoplasm , and thus inhibit cell apoptosis 24 .	Bcl-2 could prevent the release of cytochrome C from the mitochondria to the cytoplasm, and thus inhibit cell apoptosis 24.	0	17	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	6	8
Subsequently , O-CMC was degraded , C-PC was gradually released , thereby inhibited the expression of Bcl-2 proteins and triggered a lot of cytochrome C released into the cytoplasm , which in turn activated caspase family such as caspase-3 , finally induced the cells apoptosis and the formation of apoptotic bodies .	Subsequently, O-CMC was degraded, C-PC was gradually released, thereby inhibited the expression of Bcl-2 proteins and triggered a lot of cytochrome C released into the cytoplasm, which in turn activated caspase family such as caspase-3, finally induced the cells apoptosis and the formation of apoptotic bodies.	6	25	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	C-PC was gradually released, thereby inhibited the expression of Bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome c	16	17	23	25
It was shown in various models of apoptosis that overexpression of Bcl-2 prevents MMD and cytochrome c release .	It was shown in various models of apoptosis that overexpression of Bcl-2 prevents MMD and cytochrome c release.	9	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	15	17
The decrease of Bcl-2 and Bcl-XL along with this oxidative stress caused release of mitochondrial cytochrome c into the cytosol and subsequent induction of pro-caspase-9 processing .	The decrease of Bcl-2 and Bcl-XL along with this oxidative stress caused release of mitochondrial cytochrome c into the cytosol and subsequent induction of pro-caspase-9 processing.	1	17	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	15	17
Interestingly , Bcl-2 overexpression that blocked cytochrome c release by LMB effectively attenuated the apoptotic response to LMB , suggesting that LMB induced apoptosis is mediated through the mitochondrial pathway .	Interestingly, Bcl-2 overexpression that blocked cytochrome c release by LMB effectively attenuated the apoptotic response to LMB, suggesting that LMB induced apoptosis is mediated through the mitochondrial pathway.	2	8	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	6	8
Data from our cell fractionation study and cell-free assay are consistent with Bcl-2 acting to inhibit apoptosis mainly at the mitochondrial level to suppress cytochrome c release , since Bcl-2 inhibits the release of cytochrome c but fails to inhibit caspase activation induced by added cytochrome c in the cell-free assay .	Data from our cell fractionation study and cell-free assay are consistent with Bcl-2 acting to inhibit apoptosis mainly at the mitochondrial level to suppress cytochrome c release, since Bcl-2 inhibits the release of cytochrome c but fails to inhibit caspase activation induced by added cytochrome c in the cell-free assay.	29	39	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	29	30	34	36
In contrast , paclitaxel induced apoptosis MM depolarization , cytochrome C release and activation of caspase 9 were all blocked by Bcl-2 .	In contrast, paclitaxel induced apoptosis MM depolarization, cytochrome C release and activation of caspase 9 were all blocked by Bcl-2.	9	22	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	21	22	9	11
Here we show that cleavage resistant Bcl-2 or Bcl-xL suppresses the release of Smac and cytochrome c after dimerization of caspase-9 in H9 T cells , leading to inhibition of both endogenous caspase activation and nuclear damage .	Here we show that cleavage resistant Bcl-2 or Bcl-xL suppresses the release of Smac and cytochrome c after dimerization of caspase-9 in H9 T cells, leading to inhibition of both endogenous caspase activation and nuclear damage.	4	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	15	17
In addition , Bcl-2 overexpression inhibited cytochrome c release from mitochondria and subsequent caspase-2 , -3 , and -9 activation .	In addition, Bcl-2 overexpression inhibited cytochrome c release from mitochondria and subsequent caspase-2, -3, and -9 activation.	3	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	6	8
However , anti-apoptotic Bcl-2 proteins , such as Bcl-2 , Bcl-x L , Bcl-w and Mcl-1 , prevent cytochrome c release and subsequent apoptosis .	However, anti-apoptotic Bcl-2 proteins, such as Bcl-2, Bcl-x L, Bcl-w and Mcl-1, prevent cytochrome c release and subsequent apoptosis.	3	20	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	18	20
In addition , consistent with previous findings [ XREF_BIBR ] , we observed that the expression of Bcl-2 D/A or Bcl-xL D/A significantly reduced the translocation of cytochrome c into the cytosol after the activation of caspase-9 by dimerization ( XREF_FIG ) .	In addition, consistent with previous findings [XREF_BIBR], we observed that the expression of Bcl-2 D/A or Bcl-xL D/A significantly reduced the translocation of cytochrome c into the cytosol after the activation of caspase-9 by dimerization (XREF_FIG).	15	29	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	17	18	27	29
Following oxidative stress , DEDC sequentially decreased mitochondrial membrane potential ( DeltaPsim ) , reduced Bcl-2 expression , increased cytochrome c release , and activated caspase-3 , -8 , and -9 .	Following oxidative stress, DEDC sequentially decreased mitochondrial membrane potential (DeltaPsim), reduced Bcl-2 expression, increased cytochrome c release, and activated caspase-3, -8, and -9.	15	21	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	19	21
For example , AKT phosphorylates multiple Bcl-2 family members , including BAD and Bcl-xL [ XREF_BIBR ] , inhibits caspase 3 activation [ XREF_BIBR ] and blocks cytochrome C release from mitochondria [ XREF_BIBR ] .	For example, AKT phosphorylates multiple Bcl-2 family members, including BAD and Bcl-xL [XREF_BIBR], inhibits caspase 3 activation [XREF_BIBR] and blocks cytochrome C release from mitochondria [XREF_BIBR].	6	29	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	6	7	27	29
Antiapoptotic Bcl-2 family members Bcl-2 and Bcl-xL proteins block the release of cytochrome c and suppress the intrinsic pathway .	Antiapoptotic Bcl-2 family members Bcl-2 and Bcl-xL proteins block the release of cytochrome c and suppress the intrinsic pathway.	1	14	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	12	14
Overexpression of Bcl-2 has been shown to prevent the release of cytochrome c in apoptosis , implying that Bcl-2 acts upstream of the release of cytochrome c in apoptosis .	Overexpression of Bcl-2 has been shown to prevent the release of cytochrome c in apoptosis, implying that Bcl-2 acts upstream of the release of cytochrome c in apoptosis.	0	13	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	11	13
The anti-apoptotic protein Bcl-2 located within the outer mitochondrial wall can inhibit cytochrome c release , whereas the pro apoptotic protein Bax promotes the release of cytochrome c. To further elucidate the mechanism of cytochrome c release , we examined the expression of Bcl-2 and Bax in H1299 and A549 cells .	The anti-apoptotic protein Bcl-2 located within the outer mitochondrial wall can inhibit cytochrome c release, whereas the pro apoptotic protein Bax promotes the release of cytochrome c. To further elucidate the mechanism of cytochrome c release, we examined the expression of Bcl-2 and Bax in H1299 and A549 cells.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	12	14
Both Akt and Bcl-2 promote mitochondrial integrity and inhibit cytochrome c release in mammalian cells , but Akt , unlike Bcl-2 , requires the presence of Glc to achieve these effects .	Both Akt and Bcl-2 promote mitochondrial integrity and inhibit cytochrome c release in mammalian cells, but Akt, unlike Bcl-2, requires the presence of Glc to achieve these effects.	1	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	9	11
Activation of GLP-1R markedly reduced the levels of pro apoptotic Bax and cleaved-caspase3 , and increased anti-apoptotic Bcl-2 in IL-1beta-induced chondrocytes , indicating that GLP-1R may be a potential target for the treatment of OA .	Activation of GLP-1R markedly reduced the levels of pro apoptotic Bax and cleaved-caspase3, and increased anti-apoptotic Bcl-2 in IL-1beta-induced chondrocytes, indicating that GLP-1R may be a potential target for the treatment of OA.	2	18	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	GLP-1R markedly reduced the levels of pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	17	18
Compared to levels in 2BG cells , PprI appears to reduce the expression of the pro apoptosis protein Bax and increase the concentration of anti-apoptosis protein Bcl-2 in 2BP cells .	Compared to levels in 2BG cells, PprI appears to reduce the expression of the pro apoptosis protein Bax and increase the concentration of anti-apoptosis protein Bcl-2 in 2BP cells.	7	29	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	PprI appears to reduce the expression of the pro apoptosis protein Bax	bax	Bcl-2	Bcl-2	bcl-2	18	19	26	27
Bcl-2 is anti-apoptotic protein and promotes cell survival , whereas Bax is pro apoptotic protein and antagonizes the effect of Bcl-2 XREF_BIBR .	Bcl-2 is anti-apoptotic protein and promotes cell survival, whereas Bax is pro apoptotic protein and antagonizes the effect of Bcl-2 XREF_BIBR.	10	21	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	10	11	20	21
As shown in XREF_FIG , the pro-caspase-3 and Bcl-2 protein expression levels were downregulated by PDS and Bax was upregulated .	As shown in XREF_FIG, the pro-caspase-3 and Bcl-2 protein expression levels were downregulated by PDS and Bax was upregulated.	6	18	downregulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	17	18	8	9
GLOI depletion upregulated the levels of STAT1 , p53 , and Bax and downregulated c-Myc and Bcl-2 in the CRC cells in vitro .	GLOI depletion upregulated the levels of STAT1, p53, and Bax and downregulated c-Myc and Bcl-2 in the CRC cells in vitro.	0	17	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	GLOI depletion upregulated the levels of STAT1, p53, and Bax	bax	Bcl-2	Bcl-2	bcl-2	11	12	16	17
Results of qRT-PCR analysis revealed that BLM increased mRNA levels of BAX but decreased those of Bcl2 .	Results of qRT-PCR analysis revealed that BLM increased mRNA levels of BAX but decreased those of Bcl2.	6	17	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	BLM increased mRNA levels of BAX	bax	Bcl2	Bcl2	bcl2	11	12	16	17
Thermal trauma in burned animals , compared with the controls , increased the expression of pro apoptotic Bax protein ( 1.37 ( 0.94-1.47 ) ) , decreased anti-apoptotic Bcl-2 protein ( 1.16 ( 1.06-1.23 ) , p < 0.001 ) in epithelial cells , and elevated Bax and Bcl -2 ratios ( p < 0.05 ) .	Thermal trauma in burned animals, compared with the controls, increased the expression of pro apoptotic Bax protein (1.37 (0.94-1.47)), decreased anti-apoptotic Bcl-2 protein (1.16 (1.06-1.23), p < 0.001) in epithelial cells, and elevated Bax and Bcl -2 ratios (p < 0.05).	13	29	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	expression of pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	17	18	28	29
Although Bax overexpression can inhibit Bcl-2 from prolonging cell survival upon growth factor withdrawal , Bax overexpression did not inhibit Bcl-x ( L ) from preventing apoptosis in this cell line .	Although Bax overexpression can inhibit Bcl-2 from prolonging cell survival upon growth factor withdrawal, Bax overexpression did not inhibit Bcl-x (L) from preventing apoptosis in this cell line.	1	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax overexpression	bax	Bcl-2	Bcl-2	bcl-2	1	2	5	6
Neuro2A cells incubated with RAP treated EC-CM , or isoflurane + RAP co-treated EC-CM showed significant upregulation of Bcl-2 , however , Bax protein expression was reduced .	Neuro2A cells incubated with RAP treated EC-CM, or isoflurane + RAP co-treated EC-CM showed significant upregulation of Bcl-2, however, Bax protein expression was reduced.	16	27	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax protein expression	bax	Bcl-2	Bcl-2	bcl-2	22	23	18	19
Further analysis showed that COP increased the miR-122 level and the expression of Bax , cleaved-casp3 and decreased Bcl-2 , Bcl-xL in LPS treated HepG2 cells .	Further analysis showed that COP increased the miR-122 level and the expression of Bax, cleaved-casp3 and decreased Bcl-2, Bcl-xL in LPS treated HepG2 cells.	4	20	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	COP increased the miR-122 level and the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	13	14	18	19
Western blot analysis revealed that TA increased Bax levels and reduced the total levels of Bcl-2 protein in MDA-MB-231 cells .	Western blot analysis revealed that TA increased Bax levels and reduced the total levels of Bcl-2 protein in MDA-MB-231 cells.	5	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	TA increased Bax levels	bax	Bcl-2	Bcl-2	bcl-2	7	8	15	16
Therefore , the overexpression of Bax , caspase-3 and caspase-9 in conjunction with the inhibition of GLI activity might suppress Bcl-2 activation , accelerating apoptosis .	Therefore, the overexpression of Bax, caspase-3 and caspase-9 in conjunction with the inhibition of GLI activity might suppress Bcl-2 activation, accelerating apoptosis.	3	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	overexpression of Bax	bax	Bcl-2	Bcl-2	bcl-2	5	6	20	21
Knockdown of MFN2 decreased the expression of Bax and apoptotic cell death , but increased that of Bcl2 and apoptotic cancer cell death .	Knockdown of MFN2 decreased the expression of Bax and apoptotic cell death, but increased that of Bcl2 and apoptotic cancer cell death.	2	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	MFN2 decreased the expression of Bax	bax	Bcl2	Bcl2	bcl2	7	8	17	18
XREF_FIG b , c , NKP608 obviously promoted the expression of Bax and repressed that of Bcl-2 , which was in line with the fact that NKP608 induced apoptosis in HCT116 cells , in addition , the enzymatic activity of Caspase-3 was found to be evidently increased in NKP608 treated cells .	XREF_FIG b, c, NKP608 obviously promoted the expression of Bax and repressed that of Bcl-2, which was in line with the fact that NKP608 induced apoptosis in HCT116 cells, in addition, the enzymatic activity of Caspase-3 was found to be evidently increased in NKP608 treated cells.	5	21	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	NKP608 obviously promoted the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	11	12	16	17
Ectopic expression of the Bcl-2 antagonist Bax or Bcl-2 shRNA the retards the progression from androgen dependent to androgen independent status of LNCaP cells growing in androgen depleted medium [ XREF_BIBR ] .	Ectopic expression of the Bcl-2 antagonist Bax or Bcl-2 shRNA the retards the progression from androgen dependent to androgen independent status of LNCaP cells growing in androgen depleted medium [XREF_BIBR].	4	9	antagonist	Negative_activation_token_1_noun	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	6	7	4	5
We observed that ApI pretreatment suppressed the expression of protein Bax and increased the protein Bcl-2 in rats .	We observed that ApI pretreatment suppressed the expression of protein Bax and increased the protein Bcl-2 in rats.	3	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	ApI pretreatment suppressed the expression of protein Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	15	16
In addition , quercetin repressed the expression of the pro apoptotic Bax gene and enhanced that of the anti-apoptotic Bcl-2 gene in SH-SY5Y cells .	In addition, quercetin repressed the expression of the pro apoptotic Bax gene and enhanced that of the anti-apoptotic Bcl-2 gene in SH-SY5Y cells.	3	20	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	quercetin repressed the expression of the pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	11	12	19	20
In vitro studies showed that treatment of triple negative breast cancer ( TNBC ) MDA-MB-231 cells with Se-PFPs ( 1 ) inhibited cell growth dose-dependently by arresting cells at G2 phase via inhibiting CDC25C-CyclinB1 and CDC2 pathway ; ( 2 ) caused apoptosis associated with increased p53 , Bax , Puma and Noxa , decreased Bcl2 , increased Bax and Bcl2 ratio and increased activities of caspases 3/9 , suggesting its effect on p53 mediated cytochrome c-caspase pathway .	In vitro studies showed that treatment of triple negative breast cancer (TNBC) MDA-MB-231 cells with Se-PFPs (1) inhibited cell growth dose-dependently by arresting cells at G2 phase via inhibiting CDC25C-CyclinB1 and CDC2 pathway; (2) caused apoptosis associated with increased p53, Bax, Puma and Noxa, decreased Bcl2, increased Bax and Bcl2 ratio and increased activities of caspases 3/9, suggesting its effect on p53 mediated cytochrome c-caspase pathway.	48	63	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl2	Bcl2	Bcl2	48	49	60	61
XREF_BIBR , XREF_BIBR , XREF_BIBR indicated that melatonin suppressed cell propensity to apoptosis through promoting relocalization of the BCL2 to mitochondria and BCL2 sequestering BAX into mitochondria in an inactive form .	XREF_BIBR, XREF_BIBR, XREF_BIBR indicated that melatonin suppressed cell propensity to apoptosis through promoting relocalization of the BCL2 to mitochondria and BCL2 sequestering BAX into mitochondria in an inactive form.	14	25	sequestering	Negative_activation_token_1_noun	Negative_activation	Negative_activation	BAX	BAX	BAX	BCL2	BCL2	BCL2	24	25	22	23
Notably , the chronic administration of testosterone slightly reduced myocardial Akt activation compared to untreated males , but significantly decreased Bax protein levels and elevated the ratio of Bcl-2 and Bax .	Notably, the chronic administration of testosterone slightly reduced myocardial Akt activation compared to untreated males, but significantly decreased Bax protein levels and elevated the ratio of Bcl-2 and Bax.	6	30	elevated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	testosterone slightly reduced myocardial Akt activation compared to untreated males, but significantly decreased Bax protein levels	bax	Bcl-2	Bcl-2	bcl-2	20	21	28	29
TGF-beta1 could upregulate the expressions of Bax and suppress Bcl-2 in mesothelial cells .	TGF-beta1 could upregulate the expressions of Bax and suppress Bcl-2 in mesothelial cells.	0	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	TGF-beta1 could upregulate the expressions of Bax	bax	Bcl-2	Bcl-2	bcl-2	6	7	9	10
Indeed , we found that MPP + caused a significant decrease in the level of Bcl-2 and a significant increase in the level of Bax , thereby decreasing the ratio of Bcl-2 to Bax .	Indeed, we found that MPP + caused a significant decrease in the level of Bcl-2 and a significant increase in the level of Bax, thereby decreasing the ratio of Bcl-2 to Bax.	22	32	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	level of Bax	bax	Bcl-2	Bcl-2	bcl-2	24	25	31	32
Then , further investigation found that overexpression of Hoxa5 elevated the mRNA levels of Bax and Caspase-3 ( P < 0.05 ) , but reduced Bcl-2 ( P < 0.05 ) in Bax interference group .	Then, further investigation found that overexpression of Hoxa5 elevated the mRNA levels of Bax and Caspase-3 (P < 0.05), but reduced Bcl-2 (P < 0.05) in Bax interference group.	6	27	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	overexpression of Hoxa5 elevated the mRNA levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	14	15	25	26
Among these members , Bcl-2 proteins stimulate anti-apoptosis , while Bax protein significantly inhibits the anti-apoptotic actions of Bcl-2 protein [ XREF_BIBR , XREF_BIBR ] .	Among these members, Bcl-2 proteins stimulate anti-apoptosis, while Bax protein significantly inhibits the anti-apoptotic actions of Bcl-2 protein [XREF_BIBR, XREF_BIBR].	10	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	10	11	18	19
Compared with H 2 O 2 alone , Kin decreased the levels of Bax and increased the production of Bcl-2 in RPE cells .	Compared with H 2 O 2 alone, Kin decreased the levels of Bax and increased the production of Bcl-2 in RPE cells.	8	20	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Kin decreased the levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	13	14	19	20
Bcl-2 is an anti-apoptotic protein , whereas Bax is a pro apoptotic protein and antagonizes Bcl-2 effects .	Bcl-2 is an anti-apoptotic protein, whereas Bax is a pro apoptotic protein and antagonizes Bcl-2 effects.	7	16	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	7	8	15	16
DHS treatment drastically increased the BAX expression by 1.1 to 3.1 fold , but reduced that of BCL2 ( 80-90 % ) and BID ( ~ 60 % ) in the WCE , compared to the control during 24-48 h.	DHS treatment drastically increased the BAX expression by 1.1 to 3.1 fold, but reduced that of BCL2 (80-90%) and BID (~ 60%) in the WCE, compared to the control during 24-48 h.	0	27	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	DHS treatment drastically increased the BAX expression	bax	BCL2	BCL2	bcl2	5	6	17	18
because Bax inhibits Bcl-2 death-repressor activity .	because Bax inhibits Bcl-2 death-repressor activity.	1	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	1	2	3	4
Furthermore , IIF upregulated the expression of the pro apoptotic protein Bax and downregulated the anti-apoptotic protein Bcl2 .	Furthermore, IIF upregulated the expression of the pro apoptotic protein Bax and downregulated the anti-apoptotic protein Bcl2.	2	18	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	IIF upregulated the expression of the pro apoptotic protein Bax	bax	Bcl2	Bcl2	bcl2	11	12	17	18
Growing androgen dependent cells under androgen deprivation conditions results in formation of androgen independent colonies ; and the transition from androgen dependent to androgen independent growth is blocked by ectopic expression of the Bcl-2 antagonist Bax or Bcl-2 shRNA .	Growing androgen dependent cells under androgen deprivation conditions results in formation of androgen independent colonies; and the transition from androgen dependent to androgen independent growth is blocked by ectopic expression of the Bcl-2 antagonist Bax or Bcl-2 shRNA.	30	38	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	35	36	33	34
Bax expression stimulates apoptosis , and the Bax gene product attenuates the effect of Bcl-2 protein [ XREF_BIBR , XREF_BIBR ] .	Bax expression stimulates apoptosis, and the Bax gene product attenuates the effect of Bcl-2 protein [XREF_BIBR, XREF_BIBR].	7	15	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	7	8	14	15
Elevated levels of pro apoptotic Bax and/or reduced levels of anti-apoptotic Bcl-2 lead to loss of mitochondrial membrane potential , which is a key process in the initiation of apoptosis .	Elevated levels of pro apoptotic Bax and/or reduced levels of anti-apoptotic Bcl-2 lead to loss of mitochondrial membrane potential, which is a key process in the initiation of apoptosis.	1	12	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	levels of pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	5	6	11	12
Studies on a focal ischemia model have shown that EGb 761 reduces the amount of Bax in cerebral cortex , increasing the amount of Bcl-2 [ XREF_BIBR ] .	Studies on a focal ischemia model have shown that EGb 761 reduces the amount of Bax in cerebral cortex, increasing the amount of Bcl-2 [XREF_BIBR].	9	26	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	EGb 761 reduces the amount of Bax	bax	Bcl-2	Bcl-2	bcl-2	15	16	24	25
Lupeol upregulates the expression of Bak and Bax and downregulates Bcl-2 .	Lupeol upregulates the expression of Bak and Bax and downregulates Bcl-2.	0	11	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Lupeol upregulates the expression of Bak and Bax	bax	Bcl-2	Bcl-2	bcl-2	7	8	10	11
AC decreased Bclxl , Bok and Bax expression , increased Bcl-2 and Bim without affecting p-Bcl-2 and Bad expression .	AC decreased Bclxl, Bok and Bax expression, increased Bcl-2 and Bim without affecting p-Bcl-2 and Bad expression.	6	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax expression	bax	Bcl-2	Bcl-2	bcl-2	6	7	10	11
Curcumin stimulated the expression of pro apoptotic Bax , and inhibited the activation of anti-apoptotic Mcl-1 and Bcl-2 .	Curcumin stimulated the expression of pro apoptotic Bax, and inhibited the activation of anti-apoptotic Mcl-1 and Bcl-2.	0	18	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Curcumin stimulated the expression of pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	7	8	17	18
XREF_FIG d , NAC pre-treatment blocked the expression of p-JNK , Bax , ATF4 , ATF6 , XBP-1 and CHOP , and attenuated the decrease of Bcl-2 in PA treated NCI-H23 and NCI-H460 cells .	XREF_FIG d, NAC pre-treatment blocked the expression of p-JNK, Bax, ATF4, ATF6, XBP-1 and CHOP, and attenuated the decrease of Bcl-2 in PA treated NCI-H23 and NCI-H460 cells.	3	27	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	NAC pre-treatment blocked the expression of p-JNK, Bax	bax	Bcl-2	Bcl-2	bcl-2	11	12	26	27
In addition , PPP-40 could obviously promote the expressions of Bax protein and inhibit the Bcl-2 protein , accordingly improve the expressions of activated Caspase-3 as well , which resulted in the activation of mitochondrial apoptotic pathway of tumor cells in S180 mice eventually .	In addition, PPP-40 could obviously promote the expressions of Bax protein and inhibit the Bcl-2 protein, accordingly improve the expressions of activated Caspase-3 as well, which resulted in the activation of mitochondrial apoptotic pathway of tumor cells in S180 mice eventually.	3	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	PPP-40 could obviously promote the expressions of Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	15	16
We demonstrated that TSS dose-dependently suppresses the expression of pro apoptotic proteins Bax and caspase-3 , and up-regulates anti-apoptotic protein Bcl-2 .	We demonstrated that TSS dose-dependently suppresses the expression of pro apoptotic proteins Bax and caspase-3, and up-regulates anti-apoptotic protein Bcl-2.	3	21	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	TSS dose-dependently suppresses the expression of pro apoptotic proteins Bax	bax	Bcl-2	Bcl-2	bcl-2	12	13	20	21
Flow cytometric assays showed that NMD decreased the level of Bax and Caspase-3 and increased the activity of Bcl-2 in retina .	Flow cytometric assays showed that NMD decreased the level of Bax and Caspase-3 and increased the activity of Bcl-2 in retina.	5	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	NMD decreased the level of Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	18	19
In the case of Bax , this scheme has been well worked out in a rheostat model in which excess pro apoptotic Bax suppresses Bcl-2 and induces apoptosis via cytochrome c [ XREF_BIBR ] .	In the case of Bax, this scheme has been well worked out in a rheostat model in which excess pro apoptotic Bax suppresses Bcl-2 and induces apoptosis via cytochrome c [XREF_BIBR].	19	26	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	22	23	24	25
In response to internal damage to the cells , a Bcl-2 associated protein , Bax , migrates to the mitochondrial membrane and inhibits the action of Bcl-2 , causing damage to the mitochondrial membrane that in turn releases cytochrome-c [ XREF_BIBR - XREF_BIBR ] .	In response to internal damage to the cells, a Bcl-2 associated protein, Bax, migrates to the mitochondrial membrane and inhibits the action of Bcl-2, causing damage to the mitochondrial membrane that in turn releases cytochrome-c [XREF_BIBR - XREF_BIBR].	12	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	14	15	26	27
Administration of EPA and DHA through dietary fish oil supplementation was found to significantly increase expression of Bax , a proapoptotic protein , and reduce anti-apoptotic protein Bcl-2 .	Administration of EPA and DHA through dietary fish oil supplementation was found to significantly increase expression of Bax, a proapoptotic protein, and reduce anti-apoptotic protein Bcl-2.	2	28	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	EPA and DHA through dietary fish oil supplementation was found to significantly increase expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	17	18	27	28
Western blot analysis revealed that beta-elemene up-regulated BAX protein expression and down-regulated that of BCL-2 , BCL-XL , and X linked inhibitor of apoptosis ( XIAP ) in the three brain tumor cell lines .	Western blot analysis revealed that beta-elemene up-regulated BAX protein expression and down-regulated that of BCL-2, BCL-XL, and X linked inhibitor of apoptosis (XIAP) in the three brain tumor cell lines.	5	20	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	beta-elemene up-regulated BAX protein expression	bax	BCL-2	BCL-2	bcl-2	7	8	14	15
Although all three MIF inhibitors inhibit caspase 3 activity , K664-1 and K647-1 suppress pro apoptotic BAX protein expression and up-regulate anti-apoptotic Bcl-2 mRNA .	Although all three MIF inhibitors inhibit caspase 3 activity, K664-1 and K647-1 suppress pro apoptotic BAX protein expression and up-regulate anti-apoptotic Bcl-2 mRNA.	10	23	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	K664-1 and K647-1 suppress pro apoptotic BAX protein expression	bax	Bcl-2	Bcl-2	bcl-2	16	17	22	23
Since Bax promotes apoptosis by inhibiting Bcl-2 , this may imply a molecular mechanism for the resistance of HTLV-I-infected T cell lines to apoptosis inducing stimuli .	Since Bax promotes apoptosis by inhibiting Bcl-2, this may imply a molecular mechanism for the resistance of HTLV-I-infected T cell lines to apoptosis inducing stimuli.	1	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	1	2	6	7
Melatonin further stimulated the expression of the pro apoptotic BAD and BAX genes , and enhanced the inhibition of the anti-apoptotic gene BCL-2 induced by docetaxel .	Melatonin further stimulated the expression of the pro apoptotic BAD and BAX genes, and enhanced the inhibition of the anti-apoptotic gene BCL-2 induced by docetaxel.	0	23	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	Melatonin further stimulated the expression of the pro apoptotic BAD and BAX	bax	BCL-2	BCL-2	bcl-2	11	12	22	23
Luteolin not only significantly increased the viability of macrophages in the presence of Ang II , but also decreased the apoptotic rate , up-regulated Bcl-2 expression , and down-regulated Bax expression , thereby raising the ratio of Bcl-2 to Bax .	Luteolin not only significantly increased the viability of macrophages in the presence of Ang II, but also decreased the apoptotic rate, up-regulated Bcl-2 expression, and down-regulated Bax expression, thereby raising the ratio of Bcl-2 to Bax.	0	38	raising	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Luteolin not only significantly increased the viability of macrophages in the presence of Ang II, but also decreased the apoptotic rate, up-regulated Bcl-2 expression, and down-regulated Bax expression	bax	Bcl-2	Bcl-2	bcl-2	29	30	37	38
Figure XREF_FIG shows that although CDDP was able to tilt the balance between pro apoptotic Bax and anti-apoptotic Bcl-2 in favor of apoptosis , i.e. a decrease in Bcl-2 and Bax ratio , KCZ did not exert its effect through the Bcl-2 and Bax balance since we observed no significant changes in the ratio after co-treating the cells with KCZ compared to CDDP treatment alone .	Figure XREF_FIG shows that although CDDP was able to tilt the balance between pro apoptotic Bax and anti-apoptotic Bcl-2 in favor of apoptosis, i.e. a decrease in Bcl-2 and Bax ratio, KCZ did not exert its effect through the Bcl-2 and Bax balance since we observed no significant changes in the ratio after co-treating the cells with KCZ compared to CDDP treatment alone.	26	31	decrease	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	30	31	28	29
Western blot analysis showed that auristatin-PE up-regulated the expression of wt-p53 , p21WAF1 and Bax , and down-regulated Bcl-2 and cyclin B in HPAC cells , while only up-regulation of p21WAF1 and Bax was observed in PANC-1 cells .	Western blot analysis showed that auristatin-PE up-regulated the expression of wt-p53, p21WAF1 and Bax, and down-regulated Bcl-2 and cyclin B in HPAC cells, while only up-regulation of p21WAF1 and Bax was observed in PANC-1 cells.	5	21	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	auristatin-PE up-regulated the expression of wt-p53, p21WAF1 and Bax	bax	Bcl-2	Bcl-2	bcl-2	14	15	18	19
The protein levels of apoptosis associated proteins also followed a similar pattern , i.e. a decrease in Bcl-2 and an increase in Bad and Bax ( XREF_FIG ) , indicating that the apoptotic response in FaDu cells is associated with the functions of mitochondria .	The protein levels of apoptosis associated proteins also followed a similar pattern, i.e. a decrease in Bcl-2 and an increase in Bad and Bax (XREF_FIG), indicating that the apoptotic response in FaDu cells is associated with the functions of mitochondria.	8	26	decrease	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	24	25	17	18
Our data showed that ING4 gene overexpression significantly increased the mRNA and protein levels of Bax in U-2OS cells , and decreased the Bcl-2 and Bax ratio at the mRNA level ( XREF_FIG ) .	Our data showed that ING4 gene overexpression significantly increased the mRNA and protein levels of Bax in U-2OS cells, and decreased the Bcl-2 and Bax ratio at the mRNA level (XREF_FIG).	4	26	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	ING4 gene overexpression significantly increased the mRNA and protein levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	15	16	23	24
Metformin induced apoptosis by arresting cells in G1 phase and reducing cyclin D level and increasing the expression of p21 and cyclin E. Molecular and cellular studies indicated that metformin significantly elevated p53 and Bax levels and reduced STAT3 and Bcl-2 .	Metformin induced apoptosis by arresting cells in G1 phase and reducing cyclin D level and increasing the expression of p21 and cyclin E. Molecular and cellular studies indicated that metformin significantly elevated p53 and Bax levels and reduced STAT3 and Bcl-2.	29	41	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	metformin significantly elevated p53 and Bax levels	bax	Bcl-2	Bcl-2	bcl-2	34	35	40	41
Our results showed that IL-1beta treatment upregulated the expression of Bax but downregulated that of Bcl-2 ; however , cotreatment with puerarin ( 10 , 25 , and 50muM ) significantly attenuated this effect in a dose dependent manner ( XREF_FIG ) .	Our results showed that IL-1beta treatment upregulated the expression of Bax but downregulated that of Bcl-2; however, cotreatment with puerarin (10, 25, and 50muM) significantly attenuated this effect in a dose dependent manner (XREF_FIG).	4	16	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	IL-1beta treatment upregulated the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	15	16
Res+ PA-L also could raise Bax expressions and reduce Bcl-2 , Bcl-xL expressions compared to the only PA-L treated cells and control cells , the Bax expressions were lower and Bcl-2 , Bcl-xL were higher than PA-H treatment .	Res+ PA-L also could raise Bax expressions and reduce Bcl-2, Bcl-xL expressions compared to the only PA-L treated cells and control cells, the Bax expressions were lower and Bcl-2, Bcl-xL were higher than PA-H treatment.	0	30	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Res+ PA-L also could raise Bax expressions	bax	Bcl-2	Bcl-2	bcl-2	5	6	9	10
The reason might be that the PEDF which successfully expressed in the tumor tissue increased the levels of p53 and BAX and concomitantly inhibited BCL-2 .	The reason might be that the PEDF which successfully expressed in the tumor tissue increased the levels of p53 and BAX and concomitantly inhibited BCL-2.	6	25	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	PEDF which successfully expressed in the tumor tissue increased the levels of p53 and BAX	bax	BCL-2	BCL-2	bcl-2	20	21	24	25
This last effect is triggered via an ARF-Mdm2-p53 tumor suppressor pathway which is regulated by BMI1 , TWIST1 and CUL7 ; the induction of the pro apoptotic BH3-only protein BIM ; and BAX mediated suppression of anti-apoptotic proteins Bcl-2 and BCL-X L , followed by mitochondrial cytochrome c release .	This last effect is triggered via an ARF-Mdm2-p53 tumor suppressor pathway which is regulated by BMI1, TWIST1 and CUL7; the induction of the pro apoptotic BH3-only protein BIM; and BAX mediated suppression of anti-apoptotic proteins Bcl-2 and BCL-X L, followed by mitochondrial cytochrome c release.	32	41	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	BAX	BAX	Bcl-2	Bcl-2	Bcl-2	32	33	38	39
Epoxomicin also increased the expression of Bax and decreased that of Bcl-2 , which may cause mitochondrial dysfunction and release of free radicals .	Epoxomicin also increased the expression of Bax and decreased that of Bcl-2, which may cause mitochondrial dysfunction and release of free radicals.	0	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Epoxomicin also increased the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	6	7	11	12
The same region in BAX was sufficient for binding and blocking the adenovirus BCL-2 homologue E1B 19K 26 .	The same region in BAX was sufficient for binding and blocking the adenovirus BCL-2 homologue E1B 19K 26.	2	16	blocking	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	BAX	BAX	BCL-2	BCL-2	BCL-2	4	5	13	14
Furthermore , Western blot analysis confirmed that BER dose-dependently down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro apoptotic protein Bax , eventually leading the reduction of Bcl-2 and Bax protein ratio in A549 cells .	Furthermore, Western blot analysis confirmed that BER dose-dependently down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro apoptotic protein Bax, eventually leading the reduction of Bcl-2 and Bax protein ratio in A549 cells.	19	35	leading	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	level of pro apoptotic protein Bax	bax	Bcl-2	Bcl-2	bcl-2	24	25	31	32
Another possible reason might be that the Bax could antagonize the antiapoptotic effects of Bcl-2 and Bcl-xl via a binding to one another depending on a BH 3 domain , thereby promoting apoptosis [ XREF_BIBR ] .	Another possible reason might be that the Bax could antagonize the antiapoptotic effects of Bcl-2 and Bcl-xl via a binding to one another depending on a BH 3 domain, thereby promoting apoptosis [XREF_BIBR].	6	16	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	7	8	14	15
The results here demonstrate evidence for approximately 25 % apoptosis after treatment with calcium salicylate , which up-regulatd the expression of p53 , p21 and Bax , and down-regulated Bcl-2 in HT-1080 cells .	The results here demonstrate evidence for approximately 25% apoptosis after treatment with calcium salicylate, which up-regulatd the expression of p53, p21 and Bax, and down-regulated Bcl-2 in HT-1080 cells.	13	30	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	calcium salicylate, which up-regulatd the expression of p53, p21 and Bax	bax	Bcl-2	Bcl-2	bcl-2	25	26	29	30
As shown in XREF_FIG , sevoflurane exposure significantly increased the level of the p-p53 protein ( P = 0.03 ; XREF_FIG ) and Bax ( P = 0.001 ; XREF_FIG ) , and significantly decreased the level of Bcl-2 protein ( P = 0.001 ; XREF_FIG ) in the hippocampus of neonate rat brains when compared with the control rat brains .	As shown in XREF_FIG, sevoflurane exposure significantly increased the level of the p-p53 protein (P = 0.03; XREF_FIG) and Bax (P = 0.001; XREF_FIG), and significantly decreased the level of Bcl-2 protein (P = 0.001; XREF_FIG) in the hippocampus of neonate rat brains when compared with the control rat brains.	5	39	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	sevoflurane exposure significantly increased the level of the p-p53 protein (P = 0.03; XREF_FIG) and Bax	bax	Bcl-2	Bcl-2	bcl-2	23	24	38	39
This increase in TS extracts- and gallic acid induced apoptosis was also associated with a reduction in the levels of Bcl-2 , a potent cell-death inhibitor , and an increase in those of the Bax protein , which heterodimerizes with and thereby inhibits Bcl-2 .	This increase in TS extracts- and gallic acid induced apoptosis was also associated with a reduction in the levels of Bcl-2, a potent cell-death inhibitor, and an increase in those of the Bax protein, which heterodimerizes with and thereby inhibits Bcl-2.	34	44	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	34	35	43	44
Ag NP treatment increased Bax and Bid mRNA levels and downregulated Bcl-2 and Bcl-w mRNAs in a dose dependent manner .	Ag NP treatment increased Bax and Bid mRNA levels and downregulated Bcl-2 and Bcl-w mRNAs in a dose dependent manner.	0	14	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Ag NP treatment increased Bax and Bid mRNA levels	bax	Bcl-2	Bcl-2	bcl-2	4	5	11	12
Our data demonstrated that PA increased the mRNA levels of Bax , Caspase-3 and Caspase-9 , but reduced Bcl-2 ( P < 0.05 or P < 0.01 ) .	Our data demonstrated that PA increased the mRNA levels of Bax, Caspase-3 and Caspase-9, but reduced Bcl-2 (P < 0.05 or P < 0.01).	4	25	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	PA increased the mRNA levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	18	19
Increased levels of pro apoptotic Bax and/or decreased levels of anti-apoptotic Bcl-2 lead to loss of mitochondrial membrane potential , which is a critical process in the initiation of apoptosis .	Increased levels of pro apoptotic Bax and/or decreased levels of anti-apoptotic Bcl-2 lead to loss of mitochondrial membrane potential, which is a critical process in the initiation of apoptosis.	1	12	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	levels of pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	5	6	11	12
As described already , the apoptotic pathway was triggered by decreased PGC-1alpha expression , induced mitochondrial dysfunction , upregulated Cytochrome c , Bax , cleaved Caspase-3 , downregulated Bcl-2 , ultimately leading to apoptosis of H9c2 cells .	As described already, the apoptotic pathway was triggered by decreased PGC-1alpha expression, induced mitochondrial dysfunction, upregulated Cytochrome c, Bax, cleaved Caspase-3, downregulated Bcl-2, ultimately leading to apoptosis of H9c2 cells.	22	29	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	22	23	28	29
Conversely , oleuropein inhibited the expression of proapoptotic protein Bax and induced that of the antiapoptotic protein Bcl- 2 , thereby provided molecular evidence for the protective activity of oleuropein against apoptosis .	Conversely, oleuropein inhibited the expression of proapoptotic protein Bax and induced that of the antiapoptotic protein Bcl- 2, thereby provided molecular evidence for the protective activity of oleuropein against apoptosis.	2	21	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	oleuropein inhibited the expression of proapoptotic protein Bax	bax	Bcl- 2	Bcl- 2	bcl- 2	9	10	17	19
Furthermore , SC decreased UVB induced Bax , cleaved caspase-9 , and cleaved caspase-3 protein levels , but increased that of Bcl-2 , which are well-known key mediators of apoptosis .	Furthermore, SC decreased UVB induced Bax, cleaved caspase-9, and cleaved caspase-3 protein levels, but increased that of Bcl-2, which are well-known key mediators of apoptosis.	2	27	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	SC decreased UVB induced Bax	bax	Bcl-2	Bcl-2	bcl-2	6	7	21	22
Therefore , p53 mediated up-regulation of Bax and concomitant down-regulation of Bcl-2 are important for deciding the cellular fate between apoptosis and cell survival .	Therefore, p53 mediated up-regulation of Bax and concomitant down-regulation of Bcl-2 are important for deciding the cellular fate between apoptosis and cell survival.	6	12	down-regulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	6	7	11	12
The results of the present study showed that JNE2 treatment significantly upregulated the expression of Bax protein and downregulated that of Bcl-2 .	The results of the present study showed that JNE2 treatment significantly upregulated the expression of Bax protein and downregulated that of Bcl-2.	8	22	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	JNE2 treatment significantly upregulated the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	15	16	21	22
Consistent with the possibility that Bcl-2 function in WEHI-231 cells is inhibited by Bax , WEHI-231 cells were found to express a high level of Bax .	Consistent with the possibility that Bcl-2 function in WEHI-231 cells is inhibited by Bax, WEHI-231 cells were found to express a high level of Bax.	5	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	13	14	5	6
In the high-fat diet group , hepatic Bcl-2 expression was detected but the positive cell number remained stable , whereas Bax positive cell number increased steadily with time with progressively increased intensity of Bax protein expression , resulting in gradually decreased Bcl-2 and Bax ratio .	In the high-fat diet group, hepatic Bcl-2 expression was detected but the positive cell number remained stable, whereas Bax positive cell number increased steadily with time with progressively increased intensity of Bax protein expression, resulting in gradually decreased Bcl-2 and Bax ratio.	20	44	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	20	21	41	42
Bax , a homologous gene of the Bcl-2 family , antagonizes the anti-apoptotic effect of the Bcl-2 by forming a heterodimer with Bcl-2 .	Bax, a homologous gene of the Bcl-2 family, antagonizes the anti-apoptotic effect of the Bcl-2 by forming a heterodimer with Bcl-2.	0	17	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	16	17
Furthermore , Bax is an endogenous antagonist of Bcl-2 , as Bax is able to bind to Bcl-2 via an associated protein that is homologous to Bcl-2 , which further inhibits the function of Bcl-2 .	Furthermore, Bax is an endogenous antagonist of Bcl-2, as Bax is able to bind to Bcl-2 via an associated protein that is homologous to Bcl-2, which further inhibits the function of Bcl-2.	2	9	is an endogenous antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	2	3	8	9
In contrast , the pro apoptotic member , BAX , which antagonises BCL-2 , was upregulated .	In contrast, the pro apoptotic member, BAX, which antagonises BCL-2, was upregulated.	6	13	antagonises	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	BAX	BAX	BCL-2	BCL-2	BCL-2	8	9	12	13
Furthermore , lipopolysaccharide treatment upregulated Bax , which heterodimerizes with and thereby inhibits Bcl-2 .	Furthermore, lipopolysaccharide treatment upregulated Bax, which heterodimerizes with and thereby inhibits Bcl-2.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	5	6	13	14
Recently , it has been reported that Bax inactivating Bcl-2 proteins regulates the apoptosis mediated by mitochondria and the ratio of Bax to Bcl-2 proteins increases during apoptosis induction [ XREF_BIBR ] .	Recently, it has been reported that Bax inactivating Bcl-2 proteins regulates the apoptosis mediated by mitochondria and the ratio of Bax to Bcl-2 proteins increases during apoptosis induction [XREF_BIBR].	7	11	inactivating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	7	8	9	10
Lipo-DS and CuGlu , Lipo-DS and DS/CuGlu induced BAX , inhibited Bcl-2 and induced TUNEL staining .	Lipo-DS and CuGlu, Lipo-DS and DS/CuGlu induced BAX, inhibited Bcl-2 and induced TUNEL staining.	6	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	DS/CuGlu induced BAX	bax	Bcl-2	Bcl-2	bcl-2	8	9	11	12
BAX induces programmed cell death by cytokine deprivation and suppresses activity of BCL2 , an apoptotic blocker [ XREF_BIBR , XREF_BIBR ] .	BAX induces programmed cell death by cytokine deprivation and suppresses activity of BCL2, an apoptotic blocker [XREF_BIBR, XREF_BIBR].	0	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	BAX	BAX	BCL2	BCL2	BCL2	0	1	12	13
Apoptosis induced by wild-type p53 but not by serum deprivation was accompanied by G1 cell cycle arrest and increased expression of the Bcl-2 antagonist Bax .	Apoptosis induced by wild-type p53 but not by serum deprivation was accompanied by G1 cell cycle arrest and increased expression of the Bcl-2 antagonist Bax.	19	25	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	24	25	22	23
PRD treatment significantly reduced Bax and caspase-3 protein expression in diabetic rats , and significantly increased Bcl-2 protein expression and Bcl-2 and Bax ratio ( P < 0.01 ; XREF_FIG , XREF_TABLE ) .	PRD treatment significantly reduced Bax and caspase-3 protein expression in diabetic rats, and significantly increased Bcl-2 protein expression and Bcl-2 and Bax ratio (P < 0.01; XREF_FIG, XREF_TABLE).	0	19	increased	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Bax	PRD treatment significantly reduced Bax and caspase-3 protein expression	bax	Bcl-2	Bcl-2 protein expression	bcl-2	4	5	16	17
In the ischemic region , the levels of Bax increase while the levels of Bcl-2 decrease ( Won et al ., 2006 ) , leading to a release of cytochrome c from mitochondria .	In the ischemic region, the levels of Bax increase while the levels of Bcl-2 decrease (Won et al., 2006), leading to a release of cytochrome c from mitochondria.	8	15	increase	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	8	9	14	15
Ado induced cell death was characteristic of apoptosis , and Ado increased the expression of a pro apoptotic product Bax but decreased that of an anti-apoptotic product Bcl-2 .	Ado induced cell death was characteristic of apoptosis, and Ado increased the expression of a pro apoptotic product Bax but decreased that of an anti-apoptotic product Bcl-2.	10	28	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Ado increased the expression of a pro apoptotic product Bax	bax	Bcl-2	Bcl-2	bcl-2	19	20	27	28
Safrole enhanced the levels of the pro apoptotic protein BAX , inhibited those of the anti-apoptotic protein BCL-2 and promoted the levels of apoptosis inducing factor ( AIF ) and endonuclease G ( Endo G ) in HL-60 cells .	Safrole enhanced the levels of the pro apoptotic protein BAX, inhibited those of the anti-apoptotic protein BCL-2 and promoted the levels of apoptosis inducing factor (AIF) and endonuclease G (Endo G) in HL-60 cells.	0	18	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	Safrole enhanced the levels of the pro apoptotic protein BAX	bax	BCL-2	BCL-2	bcl-2	9	10	17	18
By RT-PCR we found that Ptac2S up-regulated p53 and BAX mRNA expression , and decreased Bcl-2 mRNA in a time dependent way ( ANOVA p < 0.01 , XREF_FIG ) .	By RT-PCR we found that Ptac2S up-regulated p53 and BAX mRNA expression, and decreased Bcl-2 mRNA in a time dependent way (ANOVA p < 0.01, XREF_FIG).	5	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	Ptac2S up-regulated p53 and BAX mRNA expression	bax	Bcl-2	Bcl-2	bcl-2	9	10	15	16
K compounds downregulated Bcl-2 , while Bax remained unchanged , reducing the ratio of Bcl-2 to Bax .	K compounds downregulated Bcl-2, while Bax remained unchanged, reducing the ratio of Bcl-2 to Bax.	6	15	reducing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	6	7	14	15
Ang-1 could decrease the expression of Bax , caspase3 and 8 , and increase that of Bcl-2 .	Ang-1 could decrease the expression of Bax, caspase3 and 8, and increase that of Bcl-2.	0	17	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Ang-1 could decrease the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	6	7	16	17
BCL-xL is an anti-apoptotic BCL-2 member that is commercially available , and in a dose dependent manner , inhibits the activity of BAX and BID usually in the range of 5 - 10 fold molar excess of BAX or BID ( XREF_FIG ) .	BCL-xL is an anti-apoptotic BCL-2 member that is commercially available, and in a dose dependent manner, inhibits the activity of BAX and BID usually in the range of 5 - 10 fold molar excess of BAX or BID (XREF_FIG).	4	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	BAX	BAX	BCL-2	BCL-2	BCL-2	22	23	4	5
In this study , we show that in conditions of TFD , tPA reduces the levels of the proapoptotic factors Bad and Bax and increases the antiapoptotic factors Bcl-2 and Bcl- XL .	In this study, we show that in conditions of TFD, tPA reduces the levels of the proapoptotic factors Bad and Bax and increases the antiapoptotic factors Bcl-2 and Bcl- XL.	12	31	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	tPA reduces the levels of the proapoptotic factors Bad and Bax	bax	Bcl-2	Bcl-2	bcl-2	22	23	28	29
This active form of Bax inhibits Bcl-2 , which leads to apoptosis .	This active form of Bax inhibits Bcl-2, which leads to apoptosis.	2	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	4	5	6	7
Curcumin also reduced the expression of pro apoptotic Bax but stimulated anti-apoptotic Bcl-2 to attenuate 5-FU-induced apoptosis of intestinal epithelial cells .	Curcumin also reduced the expression of pro apoptotic Bax but stimulated anti-apoptotic Bcl-2 to attenuate 5-FU-induced apoptosis of intestinal epithelial cells.	0	13	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Curcumin also reduced the expression of pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	8	9	12	13
[ XREF_BIBR ] In addition , when Bax and Bak were present , inhibiting the prosurvival Bcl-2 family members stimulated autophagy .	[XREF_BIBR] In addition, when Bax and Bak were present, inhibiting the prosurvival Bcl-2 family members stimulated autophagy.	7	17	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	7	8	16	17
Bcl-2 overexpression , downregulation of the pro apoptotic Bcl-2 antagonist Bax and a shift in the Bcl-2 and Bax ratio to levels > 1 are correlated with lower apoptotic index in tumors 12 and are associated with chemotherapeutic resistance in SCLC cell lines .	Bcl-2 overexpression, downregulation of the pro apoptotic Bcl-2 antagonist Bax and a shift in the Bcl-2 and Bax ratio to levels> 1 are correlated with lower apoptotic index in tumors 12 and are associated with chemotherapeutic resistance in SCLC cell lines.	3	13	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	10	11	8	9
ZC-B11 Upregulates Bax , Caspase 3 , Cytochrome c , and SMAC , Downregulates Bcl-2 , HSP70 , and XIAP but Did Not Affect Caspase 8 , p53 , and BID .	ZC-B11 Upregulates Bax, Caspase 3, Cytochrome c, and SMAC, Downregulates Bcl-2, HSP70, and XIAP but Did Not Affect Caspase 8, p53, and BID.	2	23	Downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	2	3	14	15
Because Bax was dominant , the increased expression of Bax significantly decreased the ratio of Bcl-2 and Bax .	Because Bax was dominant, the increased expression of Bax significantly decreased the ratio of Bcl-2 and Bax.	7	17	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	9	10	15	16
In this work , we exhibited that baicalein up-regulated the expression level of Bax and down-regulated the level of Bcl-2 mRNA , which increased the permeability of mitochondrial membrane leading to release of cytochrome c and then activating caspase-9 and caspase-3/7 subsequently [ XREF_BIBR ] , shearing substrate PARP , eventually induce cell apoptosis .	In this work, we exhibited that baicalein up-regulated the expression level of Bax and down-regulated the level of Bcl-2 mRNA, which increased the permeability of mitochondrial membrane leading to release of cytochrome c and then activating caspase-9 and caspase-3/7 subsequently [XREF_BIBR], shearing substrate PARP, eventually induce cell apoptosis.	7	20	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	baicalein up-regulated the expression level of Bax	bax	Bcl-2	Bcl-2	bcl-2	13	14	19	20
Carvedilol decreased the protein levels of p53 , Bax and cytochrome c and increased that of Bcl-2 in HL-1 cells expressing E334K MyBPC .	Carvedilol decreased the protein levels of p53, Bax and cytochrome c and increased that of Bcl-2 in HL-1 cells expressing E334K MyBPC.	0	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Carvedilol decreased the protein levels of p53, Bax	bax	Bcl-2	Bcl-2	bcl-2	8	9	16	17
Activation of Bax expression will inhibit that of Bcl-2 [ XREF_BIBR , XREF_BIBR ] .	Activation of Bax expression will inhibit that of Bcl-2 [XREF_BIBR, XREF_BIBR].	2	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax expression	bax	Bcl-2	Bcl-2	bcl-2	2	3	8	9
Overexpression of bcl-2 in multiple tumour cells increases radiation resistance ( Gasparini et al , 1995 ; Weller et al , 1995 ; Mackey et al , 1998 ) , and bax , the other number of the bcl-2 family , antagonises the bcl-2 function by forming a heterodimer .	Overexpression of bcl-2 in multiple tumour cells increases radiation resistance (Gasparini et al, 1995; Weller et al, 1995; Mackey et al, 1998), and bax, the other number of the bcl-2 family, antagonises the bcl-2 function by forming a heterodimer.	31	44	antagonises	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bax	bax	bax	bcl-2	bcl-2	bcl-2	31	32	43	44
Elevation of p53 induces Bax expression , downregulates the anti-apoptotic protein Bcl-2 , and activates the caspase 3/7/9 dependent pathway , which is associated with the inhibition of tumor cell growth 31 .	Elevation of p53 induces Bax expression, downregulates the anti-apoptotic protein Bcl-2, and activates the caspase 3/7/9 dependent pathway, which is associated with the inhibition of tumor cell growth 31.	2	12	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	p53 induces Bax expression	bax	Bcl-2	Bcl-2	bcl-2	4	5	11	12
High levels of Bax or of a smaller Bcl-x variant antagonize the survival function of Bcl-2 .	High levels of Bax or of a smaller Bcl-x variant antagonize the survival function of Bcl-2.	1	16	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	3	4	15	16
Ghrelin also stimulated the mitochondrial pathways of apoptosis and it showed increased Bcl-2 , decreased Bax , prevention cytochrome c release and inhibition of caspase-3 activation in pancreatic beta cell line HIT-T15 .	Ghrelin also stimulated the mitochondrial pathways of apoptosis and it showed increased Bcl-2, decreased Bax, prevention cytochrome c release and inhibition of caspase-3 activation in pancreatic beta cell line HIT-T15.	10	22	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	15	16	12	13
Furthermore , metformin increased the protein expression of Bax after 48 hours of treatment and decreased that of Bcl-2 after 24 , 48 and 72 hours of treatment ( XREF_FIG C-E ) and increased the Bax and Bcl -2 ratio ( XREF_FIG F ) , indicating the involvement of this pathway in cell apoptosis .	Furthermore, metformin increased the protein expression of Bax after 48 hours of treatment and decreased that of Bcl-2 after 24, 48 and 72 hours of treatment (XREF_FIG C-E) and increased the Bax and Bcl -2 ratio (XREF_FIG F), indicating the involvement of this pathway in cell apoptosis.	2	19	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	metformin increased the protein expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	8	9	18	19
Carnosic acid also increased expression of the pro apoptotic protein Bax and decreased the anti-apoptotic Bcl-2 protein leading to the release of cytochrome c from the mitochondria suggestive of a mitochondrial dependent apoptosis .	Carnosic acid also increased expression of the pro apoptotic protein Bax and decreased the anti-apoptotic Bcl-2 protein leading to the release of cytochrome c from the mitochondria suggestive of a mitochondrial dependent apoptosis.	0	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Carnosic acid also increased expression of the pro apoptotic protein Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	15	16
Western blot analysis indicated that LDE markedly down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro apoptotic protein Bax , eventually leading the reduction of Bcl-2 and Bax protein ratios both in the cultured melanoma cells and in the tumors from melanoma bearing mice .	Western blot analysis indicated that LDE markedly down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro apoptotic protein Bax, eventually leading the reduction of Bcl-2 and Bax protein ratios both in the cultured melanoma cells and in the tumors from melanoma bearing mice.	5	33	leading	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	LDE markedly down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro apoptotic protein Bax	bax	Bcl-2	Bcl-2	bcl-2	22	23	29	30
Moreover , the combination of LY294002 and ramentaceone significantly induced the levels of downstream Akt targets , Bax and Bak and downregulated anti-apoptotic Bcl-2 in comparison with single-agent treated cells ( XREF_FIG ) .	Moreover, the combination of LY294002 and ramentaceone significantly induced the levels of downstream Akt targets, Bax and Bak and downregulated anti-apoptotic Bcl-2 in comparison with single-agent treated cells (XREF_FIG).	5	24	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	LY294002 and ramentaceone significantly induced the levels of downstream Akt targets, Bax	bax	Bcl-2	Bcl-2	bcl-2	17	18	23	24
Knockdown of the BH3-only protein Puma and BBC3 , of the Bcl-2 antagonist Bax , or of the pro apoptotic transcription factor ATF3 XREF_BIBR ( XREF_SUPPLEMENTARY ) attenuated the cytotoxic effect of Chk1 inhibition in tetraploid cells , while the depletion of villin 3 ( ezrin ) , spermidine/spermine N1-acetyltransferase ( SSAT ) or of the essential autophagy gene Atg12 had no such effect ( XREF_FIG ) .	Knockdown of the BH3-only protein Puma and BBC3, of the Bcl-2 antagonist Bax, or of the pro apoptotic transcription factor ATF3 XREF_BIBR (XREF_SUPPLEMENTARY) attenuated the cytotoxic effect of Chk1 inhibition in tetraploid cells, while the depletion of villin 3 (ezrin), spermidine/spermine N1-acetyltransferase (SSAT) or of the essential autophagy gene Atg12 had no such effect (XREF_FIG).	5	14	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	13	14	11	12
A large number of studies have shown that EA inhibits expression of the pro apoptotic gene Bax and upregulates the anti-apoptotic gene Bcl-2 to reduce apoptosis in myocardial tissue ( Zhang et al ., 2009 ) .	A large number of studies have shown that EA inhibits expression of the pro apoptotic gene Bax and upregulates the anti-apoptotic gene Bcl-2 to reduce apoptosis in myocardial tissue (Zhang et al., 2009).	8	23	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	EA inhibits expression of the pro apoptotic gene Bax	bax	Bcl-2	Bcl-2	bcl-2	16	17	22	23
Leukaemia cell apoptosis by beta2Mim correlated with an increase in calcium influx , decreased bcl-2 protein and mRNA levels , increase in BAX gene expression and a marked rise in BCL2 and BAX mRNA ratios .	Leukaemia cell apoptosis by beta2Mim correlated with an increase in calcium influx, decreased bcl-2 protein and mRNA levels, increase in BAX gene expression and a marked rise in BCL2 and BAX mRNA ratios.	13	25	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	BAX gene expression	bax	bcl-2	bcl-2	bcl-2	22	23	14	15
Mechanistically , our results also showed that CL-NPs trigger a stronger cleavage of PARP , as well as induction of Bax inhibition of Bcl-2 , compared to free CL and control .	Mechanistically, our results also showed that CL-NPs trigger a stronger cleavage of PARP, as well as induction of Bax inhibition of Bcl-2, compared to free CL and control.	20	24	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	20	21	23	24
Furthermore , pro-caspase-3 and Bcl-2 were observed to be downregulated by PDS and Bax was upregulated in the present study , which was also reported by Park et al .	Furthermore, pro-caspase-3 and Bcl-2 were observed to be downregulated by PDS and Bax was upregulated in the present study, which was also reported by Park et al.	2	15	downregulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	13	14	4	5
OPN stimulated apoptosis in adult rat cardiac myocytes associates with activation of JNKs , increased Bax expression , decreased Bcl 2 / Bax ratio and increased levels of cytosolic cytochrome c.	OPN stimulated apoptosis in adult rat cardiac myocytes associates with activation of JNKs, increased Bax expression, decreased Bcl 2 / Bax ratio and increased levels of cytosolic cytochrome c.	12	21	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	JNKs, increased Bax expression	bax	Bcl 2	Bcl 2	bcl 2	15	16	19	21
CsA induced the expression of p53 ( P < 0.05 ) and Bax ( P < 0.01 ) and decreased that of Bcl-2 ( P < 0.05 ) .	CsA induced the expression of p53 (P < 0.05) and Bax (P < 0.01) and decreased that of Bcl-2 (P < 0.05).	0	24	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	CsA induced the expression of p53 (P < 0.05) and Bax	bax	Bcl-2	Bcl-2	bcl-2	12	13	22	23
This increase in AP extract induced apoptosis was also associated with a reduction in the levels of Bcl-2 , a potent cell-death inhibitor , and an increase in levels of the Bax protein , which heterodimerizes with and thereby inhibits Bcl-2 .	This increase in AP extract induced apoptosis was also associated with a reduction in the levels of Bcl-2, a potent cell-death inhibitor, and an increase in levels of the Bax protein, which heterodimerizes with and thereby inhibits Bcl-2.	31	41	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	31	32	40	41
Baicalein could increase caspase-3 and Bax expression and decrease survivin and Bcl-2 to induce apoptosis .	Baicalein could increase caspase-3 and Bax expression and decrease survivin and Bcl-2 to induce apoptosis.	0	12	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Baicalein could increase caspase-3 and Bax expression	bax	Bcl-2	Bcl-2	bcl-2	5	6	11	12
Compared with I/R , I-MVs decreased the expression of Bax and increased that of Bcl-2 , so the ratio of Bcl-2 and Bax was clearly increased in I-MVs ( 1.18 +/-0.26 vs 0.68 +/-0.10 % , P < 0.001 ) .	Compared with I/R, I-MVs decreased the expression of Bax and increased that of Bcl-2, so the ratio of Bcl-2 and Bax was clearly increased in I-MVs (1.18 +/-0.26 vs 0.68 +/-0.10%, P < 0.001).	4	15	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	I-MVs decreased the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	9	10	14	15
We found that PLM reduced the expression level of Bax , increased the ratio of Bcl-2 and Bax and reduced active caspase 3 .	We found that PLM reduced the expression level of Bax, increased the ratio of Bcl-2 and Bax and reduced active caspase 3.	3	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	PLM reduced the expression level of Bax	bax	Bcl-2	Bcl-2	bcl-2	9	10	15	16
Furthermore , both PF and PN decreased the caspase-3 and Bax expressions but up-regulated Bcl-2 in the left ventricles .	Furthermore, both PF and PN decreased the caspase-3 and Bax expressions but up-regulated Bcl-2 in the left ventricles.	3	15	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	PF and PN decreased the caspase-3 and Bax expressions	bax	Bcl-2	Bcl-2	bcl-2	10	11	14	15
Propofol treatment increased the expression of Bax and decreased that of Bcl-2 .	Propofol treatment increased the expression of Bax and decreased that of Bcl-2.	0	12	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Propofol treatment increased the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	6	7	11	12
TM increases the expression of BAX and decreases that of BCL2 , whereas TUDCA treatment decreases the expression of BAX and upregulates that of BCL2 in bovine embryos [ XREF_BIBR ] .	TM increases the expression of BAX and decreases that of BCL2, whereas TUDCA treatment decreases the expression of BAX and upregulates that of BCL2 in bovine embryos [XREF_BIBR].	0	11	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	TM increases the expression of BAX	bax	BCL2	BCL2	bcl2	5	6	10	11
This increase in A. camphorata induced apoptosis was also associated with a reduction in the levels of Bcl-2 , a potent cell-death inhibitor , and an increase in those of the Bax protein , which heterodimerizes with and thereby inhibits Bcl-2 .	This increase in A. camphorata induced apoptosis was also associated with a reduction in the levels of Bcl-2, a potent cell-death inhibitor, and an increase in those of the Bax protein, which heterodimerizes with and thereby inhibits Bcl-2.	31	41	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	31	32	40	41
Western blot analysis of the expression of proapoptotic or antiapoptotic proteins showed that DOX significantly increased the expression of proapoptotic Bax protein but decreased Bcl-2 protein in NRCs .	Western blot analysis of the expression of proapoptotic or antiapoptotic proteins showed that DOX significantly increased the expression of proapoptotic Bax protein but decreased Bcl-2 protein in NRCs.	13	25	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	DOX significantly increased the expression of proapoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	20	21	24	25
On the other hand , when Bax and Bak were present , inhibiting the prosurvival Bcl-2 family members stimulated autophagy , but this correlated with increased cell death .	On the other hand, when Bax and Bak were present, inhibiting the prosurvival Bcl-2 family members stimulated autophagy, but this correlated with increased cell death.	6	16	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	6	7	15	16
The increase in cellular Bax provides more Bax for translocation to the mitochondria ; and the increase in the Bax and Bcl -2 ratio reduces the anti-apoptotic effect of Bcl-2 .	The increase in cellular Bax provides more Bax for translocation to the mitochondria; and the increase in the Bax and Bcl -2 ratio reduces the anti-apoptotic effect of Bcl-2.	16	30	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	19	20	29	30
Moreover flavocoxid , an inhibitor of COX and 5-lipoxygenase enzymes , reduced prostate weight , increased the expression of Bax and caspase-9 mRNA ( pro apoptotic ) and decreased that of Bcl-2 ( anti-apoptotic ) in mice with induced BPH [ XREF_BIBR ] .	Moreover flavocoxid, an inhibitor of COX and 5-lipoxygenase enzymes, reduced prostate weight, increased the expression of Bax and caspase-9 mRNA (pro apoptotic) and decreased that of Bcl-2 (anti-apoptotic) in mice with induced BPH [XREF_BIBR].	6	33	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	COX and 5-lipoxygenase enzymes, reduced prostate weight, increased the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	19	20	31	32
Moreover , LFM-A13 treatment upregulated the levels of IkappaB , the pro apoptotic proteins Bax , and caspase-3 , and down-regulated p53 and the antiapoptotic protein Bcl-2 in mammary tumors .	Moreover, LFM-A13 treatment upregulated the levels of IkappaB, the pro apoptotic proteins Bax, and caspase-3, and down-regulated p53 and the antiapoptotic protein Bcl-2 in mammary tumors.	2	27	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	LFM-A13 treatment upregulated the levels of IkappaB, the pro apoptotic proteins Bax	bax	Bcl-2	Bcl-2	bcl-2	14	15	26	27
Furthermore , bicuculline could block apoptosis of NSCs by increasing expression of Bcl-2 and decreasing expression of Bax and Caspase-3 .	Furthermore, bicuculline could block apoptosis of NSCs by increasing expression of Bcl-2 and decreasing expression of Bax and Caspase-3.	12	19	decreasing	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Bax	expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	17	18	12	13
Interestingly , LBH589 increased the expression of Bax and PUMA and decreased that of Bcl-2 and Bcl-xL in KK1 cells carrying a non functional p53 mutation .	Interestingly, LBH589 increased the expression of Bax and PUMA and decreased that of Bcl-2 and Bcl-xL in KK1 cells carrying a non functional p53 mutation.	2	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	LBH589 increased the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	7	8	14	15
Bax can accelerate cell death and inhibit the protective function of Bcl-2 ( Cory and Adams , 2002 ; Emdadual , et al ., 2003 ) .	Bax can accelerate cell death and inhibit the protective function of Bcl-2 (Cory and Adams, 2002; Emdadual, et al., 2003).	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	11	12
Supplementation of cisplatin intoxicated mice with AGBE also significantly reduced apoptotic protein levels of Bax , cleaved caspase-3 , cytochrome c and increased anti-apoptotic protein Bcl-2 .	Supplementation of cisplatin intoxicated mice with AGBE also significantly reduced apoptotic protein levels of Bax, cleaved caspase-3, cytochrome c and increased anti-apoptotic protein Bcl-2.	2	26	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	cisplatin intoxicated mice with AGBE also significantly reduced apoptotic protein levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	14	15	25	26
When the cells were infected with Ad-PKG II and treated with 8-pCPT-cGMP before being stimulated with HGF , the HGF induced increase of Bcl-2 was abolished and an increase of Bax expression appeared , causing a decrease of the ratio of Bcl-2 and Bax .	When the cells were infected with Ad-PKG II and treated with 8-pCPT-cGMP before being stimulated with HGF, the HGF induced increase of Bcl-2 was abolished and an increase of Bax expression appeared, causing a decrease of the ratio of Bcl-2 and Bax.	30	43	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax expression	bax	Bcl-2	Bcl-2	bcl-2	30	31	41	42
Indeed , upon FGF-BP reduction a marked activation of members of the bcl-2 family and promoters of apoptosis , Bad and Bax , and to a lesser extent of bcl-2 , was observed in an apoptosis antibody array .	Indeed, upon FGF-BP reduction a marked activation of members of the bcl-2 family and promoters of apoptosis, Bad and Bax, and to a lesser extent of bcl-2, was observed in an apoptosis antibody array.	4	22	activation	Positive_activation_syntax_7_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	bcl-2	bcl-2	bcl-2	21	22	12	13
Cisplatin increased expression of the proapoptotic marker Bax and inhibited the anti-apoptotic protein Bcl-2 , resulting in an overall increase in the Bax and Bcl -2 ratio .	Cisplatin increased expression of the proapoptotic marker Bax and inhibited the anti-apoptotic protein Bcl-2, resulting in an overall increase in the Bax and Bcl -2 ratio.	0	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Cisplatin increased expression of the proapoptotic marker Bax	bax	Bcl-2	Bcl-2	bcl-2	7	8	13	14
Akt blocked the expression of mitochondrial Bcl-2 family protein , Bax and its overexpression inhibited H/R induced loss of Bcl-2 protein on treating with diosgenin [ XREF_FIG ] .	Akt blocked the expression of mitochondrial Bcl-2 family protein, Bax and its overexpression inhibited H/R induced loss of Bcl-2 protein on treating with diosgenin [XREF_FIG].	3	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	expression of mitochondrial Bcl-2 family protein, Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	19	20
Statins also increase the expression of Bax and decrease that of Bcl-2 to induce apoptosis in tumor cells and these effects can be reversed by mevalonate and GGPP but not FPP , suggesting that inhibition of geranylgeranylation mediates statin induced apoptosis .	Statins also increase the expression of Bax and decrease that of Bcl-2 to induce apoptosis in tumor cells and these effects can be reversed by mevalonate and GGPP but not FPP, suggesting that inhibition of geranylgeranylation mediates statin induced apoptosis.	0	12	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Statins also increase the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	6	7	11	12
In addition , the expression of Bcl-2 was upregulated and Bax was downregulated , thereby increasing the Bcl-2 and Bax ratio .	In addition, the expression of Bcl-2 was upregulated and Bax was downregulated, thereby increasing the Bcl-2 and Bax ratio.	10	20	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	10	11	17	18
However , RDPS was demonstrated to significantly decrease the expression levels of caspase-3 and Bax , and increase the expression levels of Bcl-2 and the ratio of Bcl-2 : Bax .	However, RDPS was demonstrated to significantly decrease the expression levels of caspase-3 and Bax, and increase the expression levels of Bcl-2 and the ratio of Bcl-2 : Bax.	2	23	increase	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Bax	RDPS was demonstrated to significantly decrease the expression levels of caspase-3 and Bax	bax	Bcl-2	levels of Bcl-2	bcl-2	14	15	22	23
For example , does Bcl-2 block Bax translocation , activation , or just oligomerization ?	For example, does Bcl-2 block Bax translocation, activation, or just oligomerization?	4	7	block	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	6	7	4	5
Its function is similar to that of Bax , which is to inhibit Bcl-2 activity and promote cell apoptosis [ XREF_BIBR ] .	Its function is similar to that of Bax, which is to inhibit Bcl-2 activity and promote cell apoptosis [XREF_BIBR].	5	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	7	8	13	14
DP regulated the expression of Bcl-2 and Bax , which were mitochondrial pathway proteins , to decrease MMP , and DP promoted the transcription of Bax and inhibited Bcl-2 .	DP regulated the expression of Bcl-2 and Bax, which were mitochondrial pathway proteins, to decrease MMP, and DP promoted the transcription of Bax and inhibited Bcl-2.	20	29	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	DP promoted the transcription of Bax	bax	Bcl-2	Bcl-2	bcl-2	25	26	28	29
Bax has been shown to suppress the antiapoptosis activity of Bcl-2 by forming a heterodimer with Bcl-2 [ XREF_BIBR ] .	Bax has been shown to suppress the antiapoptosis activity of Bcl-2 by forming a heterodimer with Bcl-2 [XREF_BIBR].	0	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	10	11
Furthermore , IG significantly blocked of NF-kappaB signaling by inhibiting IkappaBalpha phosphorylation and degradation and IKKbeta activity , down-regulated the protein and mRNA expressions of Fas and FasL , Bax and caspase-3 , and activated Bcl-2 in intestinal epithelial cells .	Furthermore, IG significantly blocked of NF-kappaB signaling by inhibiting IkappaBalpha phosphorylation and degradation and IKKbeta activity, down-regulated the protein and mRNA expressions of Fas and FasL, Bax and caspase-3, and activated Bcl-2 in intestinal epithelial cells.	2	36	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	IG significantly blocked of NF-kappaB signaling by inhibiting IkappaBalpha phosphorylation and degradation and IKKbeta activity, down-regulated the protein and mRNA expressions of Fas and FasL, Bax	bax	Bcl-2	Bcl-2	bcl-2	29	30	35	36
Bax inhibits Bcl-2 function and allows the cell to enter the death program [ XREF_BIBR ] .	Bax inhibits Bcl-2 function and allows the cell to enter the death program [XREF_BIBR].	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	2	3
The increase in HA induced apoptosis correlated with a reduction in Bcl-2 , a potent cell death inhibitor , and an increase in Bax protein levels , which heterodimerizes with and thereby inhibits Bcl-2 .	The increase in HA induced apoptosis correlated with a reduction in Bcl-2, a potent cell death inhibitor, and an increase in Bax protein levels, which heterodimerizes with and thereby inhibits Bcl-2.	3	34	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	HA induced apoptosis correlated with a reduction in Bcl-2, a potent cell death inhibitor, and an increase in Bax protein levels	bax	Bcl-2	Bcl-2	bcl-2	23	24	33	34
As shown in XREF_FIG , amygdalin increased the expression level of pro apoptotic protein Bax and decreased that of anti-apoptotic Bcl-2 .	As shown in XREF_FIG, amygdalin increased the expression level of pro apoptotic protein Bax and decreased that of anti-apoptotic Bcl-2.	5	21	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	amygdalin increased the expression level of pro apoptotic protein Bax	bax	Bcl-2	Bcl-2	bcl-2	14	15	20	21
In addition , P21 also plays an important role in regulation of apoptosis where overexpression of P21 in human hepatoma cell lines induces the expression of Bax and suppresses the anti-apoptotic effect of Bcl-2 through modulating the ratio of Bcl-2 to Bax XREF_BIBR .	In addition, P21 also plays an important role in regulation of apoptosis where overexpression of P21 in human hepatoma cell lines induces the expression of Bax and suppresses the anti-apoptotic effect of Bcl-2 through modulating the ratio of Bcl-2 to Bax XREF_BIBR.	14	34	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	overexpression of P21 in human hepatoma cell lines induces the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	26	27	33	34
SiDcR3 combined with TRAIL could induce activation of caspases-3 , -8 , and -9 , raise the expression of the apoptotic protein Bax , and reduce the expression of antiapoptotic proteins ( Bcl-2 , Mcl-1 , Bcl-XL , IAP-2 , and survivin ) .	SiDcR3 combined with TRAIL could induce activation of caspases-3, -8, and -9, raise the expression of the apoptotic protein Bax, and reduce the expression of antiapoptotic proteins (Bcl-2, Mcl-1, Bcl-XL, IAP-2, and survivin).	0	41	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	SiDcR3 combined with TRAIL could induce activation of caspases-3, -8, and -9, raise the expression of the apoptotic protein Bax	bax	Bcl-2	Bcl-2	bcl-2	22	23	32	33
In the intrinsic mitochondrial apoptotic signaling , Bcl-2 has been identified as an apoptotic inhibitor and Bax protein inhibits the function of bcl-2 .	In the intrinsic mitochondrial apoptotic signaling, Bcl-2 has been identified as an apoptotic inhibitor and Bax protein inhibits the function of bcl-2.	16	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	bcl-2	bcl-2	bcl-2	16	17	22	23
Morphine dependence decreased the expression of Bax protein and increased Bcl-2 protein expression 24 hr post ischemia ( P < 0.05 vs. IR , XREF_FIG ) .	Morphine dependence decreased the expression of Bax protein and increased Bcl-2 protein expression 24 hr post ischemia (P < 0.05 vs. IR, XREF_FIG).	0	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Morphine dependence decreased the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	6	7	10	11
Silica nanoparticles also activated c-Jun N-terminal kinase ( JNK ) , c-Jun , p53 , caspase-3 and NF-kappaB , increased Bax expression and suppressed Bcl-2 protein .	Silica nanoparticles also activated c-Jun N-terminal kinase (JNK), c-Jun, p53, caspase-3 and NF-kappaB, increased Bax expression and suppressed Bcl-2 protein.	0	25	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Silica nanoparticles also activated c-Jun N-terminal kinase (JNK), c-Jun, p53, caspase-3 and NF-kappaB, increased Bax expression	bax	Bcl-2	Bcl-2	bcl-2	20	21	24	25
TP53 increases the expression of Bax and downregulates Bcl-2 and these could promote cytochrome c release from mitochondria and activate caspase-3 XREF_BIBR , XREF_BIBR , XREF_BIBR .	TP53 increases the expression of Bax and downregulates Bcl-2 and these could promote cytochrome c release from mitochondria and activate caspase-3 XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	9	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	TP53 increases the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	5	6	8	9
MA pretreatments decreased Bax expression , raised the Bcl-2 and Bax ratio , and increased cell viability .	MA pretreatments decreased Bax expression, raised the Bcl-2 and Bax ratio, and increased cell viability.	0	11	raised	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	MA pretreatments decreased Bax expression	bax	Bcl-2	Bcl-2	bcl-2	3	4	8	9
MS-275 increases the expression of apoptotic protein BAX , hence decreasing the BCL2 and BAX ratio , and coordinate with decrease in survival .	MS-275 increases the expression of apoptotic protein BAX, hence decreasing the BCL2 and BAX ratio, and coordinate with decrease in survival.	0	15	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	MS-275 increases the expression of apoptotic protein BAX	bax	BCL2	BCL2	bcl2	7	8	12	13
Similar observations have been made by Park et al ., who reported that snake venom toxin increases the expression of the pro apoptotic protein Bax but downregulated the anti-apoptotic protein Bcl-2 XREF_BIBR .	Similar observations have been made by Park et al., who reported that snake venom toxin increases the expression of the pro apoptotic protein Bax but downregulated the anti-apoptotic protein Bcl-2 XREF_BIBR.	15	31	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	toxin increases the expression of the pro apoptotic protein Bax	bax	Bcl-2	Bcl-2	bcl-2	24	25	30	31
Additionally , it diminished the down-regulation of the anti-apoptotic proteins Mcl-1 ( 6 ) and Bcl-2 ( 7 ) , and decreased the expression level of the pro apoptotic protein Bax ( 8 ) , thus raising the ratio of Bcl-2 and Bax .	Additionally, it diminished the down-regulation of the anti-apoptotic proteins Mcl-1 (6) and Bcl-2 (7), and decreased the expression level of the pro apoptotic protein Bax (8), thus raising the ratio of Bcl-2 and Bax.	24	42	raising	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	level of the pro apoptotic protein Bax	bax	Bcl-2	Bcl-2	bcl-2	30	31	40	41
Additionally , TRX significantly reduced the liver mRNA expressions of Bax ( P < 0.001 ) and increased the Bcl-2 and Bax ratio ( P < 0.001 ) compared with the control group .	Additionally, TRX significantly reduced the liver mRNA expressions of Bax (P < 0.001) and increased the Bcl-2 and Bax ratio (P < 0.001) compared with the control group.	2	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	TRX significantly reduced the liver mRNA expressions of Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	19	20
However , if Bax and Bcl-2 form a heterodimer , Bax will suppress the anti-apoptotic effect of Bcl-2 , and thus , the proportion of the two proteins determines the apoptosis or survival of cells .	However, if Bax and Bcl-2 form a heterodimer, Bax will suppress the anti-apoptotic effect of Bcl-2, and thus, the proportion of the two proteins determines the apoptosis or survival of cells.	10	18	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	10	11	17	18
Compared with expression levels in the control group , Caspase-3 ( P = 0.0031 ) , Caspase-9 ( P = 0.0047 ) and Bax ( P < 0.001 ) were significantly increased , however Bcl-2 ( P < 0.001 ) expression was repressed ( XREF_FIG ) , demonstrating that transfection of PC9-R cells with si-MIR31HG induces cell apoptosis by activating the mitochondrial apoptosis pathway .	Compared with expression levels in the control group, Caspase-3 (P = 0.0031), Caspase-9 (P = 0.0047) and Bax (P < 0.001) were significantly increased, however Bcl-2 (P < 0.001) expression was repressed (XREF_FIG), demonstrating that transfection of PC9-R cells with si-MIR31HG induces cell apoptosis by activating the mitochondrial apoptosis pathway.	9	42	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	23	24	34	35
Administration of CPC significantly inhibited LPS induced caspase-3 and Bax expression but up-regulated Bcl-2 and Bcl-XL proteins , suggesting that reduction of pro apoptotic and anti-apoptotic protein ratio contributes to its anti-apoptotic activity and subsequently maintains the alveolar-capillary barrier intact .	Administration of CPC significantly inhibited LPS induced caspase-3 and Bax expression but up-regulated Bcl-2 and Bcl-XL proteins, suggesting that reduction of pro-apoptotic and anti-apoptotic protein ratio contributes to its anti-apoptotic activity and subsequently maintains the alveolar-capillary barrier intact.	2	16	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	CPC significantly inhibited LPS induced caspase-3 and Bax expression	bax	Bcl-2	Bcl-2	bcl-2	9	10	13	14
BAX can inhibit BCL-2 by forming heterodimer with it , and the ratio relationship of BCL-2 and BAX are the key factors to determinate the inhibition for cell apoptosis .	BAX can inhibit BCL-2 by forming heterodimer with it, and the ratio relationship of BCL-2 and BAX are the key factors to determinate the inhibition for cell apoptosis.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	BAX	BAX	BCL-2	BCL-2	BCL-2	0	1	3	4
IL-11 administration decreased the expression of Bax and increased that of Bcl-2 .	IL-11 administration decreased the expression of Bax and increased that of Bcl-2.	0	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	IL-11 administration decreased the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	6	7	11	12
It is noteworthy that the expression levels of some of these downstream molecules have been reported to be altered in postmortem brains of patients with schizophrenia , for example , increased : Bax , calbindin , and NR2B ; decreased Bcl-2 .	It is noteworthy that the expression levels of some of these downstream molecules have been reported to be altered in postmortem brains of patients with schizophrenia, for example, increased : Bax, calbindin, and NR2B; decreased Bcl-2.	18	41	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	32	33	40	41
Compared with the control group , H/I significantly increased Bax expression and decreased Bcl-2 .	Compared with the control group, H/I significantly increased Bax expression and decreased Bcl-2.	6	14	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	H/I significantly increased Bax expression	bax	Bcl-2	Bcl-2	bcl-2	9	10	13	14
Compared to levels in PBS treated cells , PprI appears to reduce the expression of the pro apoptosis protein Bax and increase the concentration of anti-apoptosis protein Bcl-2 upon cell irradiation ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Compared to levels in PBS treated cells, PprI appears to reduce the expression of the pro apoptosis protein Bax and increase the concentration of anti-apoptosis protein Bcl-2 upon cell irradiation (XREF_FIG and XREF_SUPPLEMENTARY).	8	28	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	PprI appears to reduce the expression of the pro apoptosis protein Bax	bax	Bcl-2	Bcl-2	bcl-2	19	20	27	28
The data showed that SCE increased the amount of proapoptotic Bax and reduced that of antiapoptotic Bcl-2 ( XREF_FIG ) .	The data showed that SCE increased the amount of proapoptotic Bax and reduced that of antiapoptotic Bcl-2 (XREF_FIG).	4	18	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	SCE increased the amount of proapoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	16	17
Neuronal apoptosis induced by Abeta primarily operates through the mitochondrial pathway ( Zheng et al ., 2013 ; Wang et al ., 2014 ) ; thus , a certain concentration of Abeta can increase the expression of pro apoptotic Bax mRNA and decrease the expression of anti-apoptotic Bcl-2 mRNA , consistent with our findings .	Neuronal apoptosis induced by Abeta primarily operates through the mitochondrial pathway (Zheng et al., 2013; Wang et al., 2014); thus, a certain concentration of Abeta can increase the expression of pro apoptotic Bax mRNA and decrease the expression of anti-apoptotic Bcl-2 mRNA, consistent with our findings.	31	48	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Abeta can increase the expression of pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	39	40	47	48
HOG-LDL also increased levels of the pro apoptotic factors caspase-3 and BAX , and decreased anti-apoptotic BCL-2 .	HOG-LDL also increased levels of the pro apoptotic factors caspase-3 and BAX, and decreased anti-apoptotic BCL-2.	0	17	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	HOG-LDL also increased levels of the pro apoptotic factors caspase-3 and BAX	bax	BCL-2	BCL-2	bcl-2	11	12	16	17
Further BAX analysis through gain- or loss-of-function experiments revealed that upregulation of BAX decreased cell proliferation by changing the BAX : BCL-2 ratio .	Further BAX analysis through gain- or loss-of-function experiments revealed that upregulation of BAX decreased cell proliferation by changing the BAX : BCL-2 ratio.	10	22	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	BAX	BAX	BCL-2	BCL-2	BCL-2	12	13	21	22
Also As 2 O 3 plus DTT upregulated Bax and Bak , downregulated Bcl-2 and p53 , caused a loss of mitochondria membrane potential in oral cancer cells .	Also As 2 O 3 plus DTT upregulated Bax and Bak, downregulated Bcl-2 and p53, caused a loss of mitochondria membrane potential in oral cancer cells.	8	17	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	8	9	13	14
Silica nanoparticles ( 50-200 mug/mL ) generated reactive oxygen species , mitochondrial depolarization and apoptosis in human umbilical vein endothelial cells ( HUVECs ) , activated c-Jun N-terminal kinase ( JNK ) , c-Jun , p53 , caspase-3 and NF-kappaB , increased Bax expression and suppressed Bcl-2 protein while the highest concentration significantly increased the necrotic rate , LDH leakage , expression of CD54 and CD62E and release of TF , IL-6 , IL-8 and MCP-1 .	Silica nanoparticles (50-200 mug/mL) generated reactive oxygen species, mitochondrial depolarization and apoptosis in human umbilical vein endothelial cells (HUVECs), activated c-Jun N-terminal kinase (JNK), c-Jun, p53, caspase-3 and NF-kappaB, increased Bax expression and suppressed Bcl-2 protein while the highest concentration significantly increased the necrotic rate, LDH leakage, expression of CD54 and CD62E and release of TF, IL-6, IL-8 and MCP-1.	26	47	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	c-Jun N-terminal kinase (JNK), c-Jun, p53, caspase-3 and NF-kappaB, increased Bax expression	bax	Bcl-2	Bcl-2	bcl-2	42	43	46	47
Results demonstrated that PLM treatment increases protein expression of Bcl-2 , significantly reduces Bax expression and increases ratio of Bcl-2 to Bax in the myocardium after myocardial IR injury when compared with control .	Results demonstrated that PLM treatment increases protein expression of Bcl-2, significantly reduces Bax expression and increases ratio of Bcl-2 to Bax in the myocardium after myocardial IR injury when compared with control.	3	20	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	PLM treatment increases protein expression of Bcl-2, significantly reduces Bax expression	bax	Bcl-2	Bcl-2	bcl-2	13	14	19	20
Furthermore , melatonin reduced the expression of Bax and prevented the loss of Bcl-2 proteins as well as the presence of apoptotic cells caused by DNBS .	Furthermore, melatonin reduced the expression of Bax and prevented the loss of Bcl-2 proteins as well as the presence of apoptotic cells caused by DNBS.	2	14	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	melatonin reduced the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	7	8	13	14
Key elements of the apoptotic pathway include changes in the gene expression of the pro apoptotic protein Bax and the apoptosis suppressing protein Bcl-2 .	Key elements of the apoptotic pathway include changes in the gene expression of the pro apoptotic protein Bax and the apoptosis suppressing protein Bcl-2.	11	24	suppressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	expression of the pro apoptotic protein Bax	bax	Bcl-2	Bcl-2	bcl-2	17	18	23	24
Western blot analysis showed that FUT4 overexpression decreased expression of Bax , Caspase 3 , and PARP proteins , and increased anti-apoptotic Bcl-2 protein in A431 cells .	Western blot analysis showed that FUT4 overexpression decreased expression of Bax, Caspase 3, and PARP proteins, and increased anti-apoptotic Bcl-2 protein in A431 cells.	5	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	FUT4 overexpression decreased expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	22	23
The injection of Trap significantly increased the levels of BAX and decreased the levels of BCL2 protein .	The injection of Trap significantly increased the levels of BAX and decreased the levels of BCL2 protein.	3	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	Trap significantly increased the levels of BAX	bax	BCL2	BCL2	bcl2	9	10	15	16
XREF_BIBR As shown in XREF_FIG E-2H , compared with theCEL and Ctrl groups , hearts treated with siRNA-TR displayed increased Bcl-2 but decreased BAX protein expression and subsequently increased Bcl-2 and BAX ratios .	XREF_BIBR As shown in XREF_FIG E-2H, compared with theCEL and Ctrl groups, hearts treated with siRNA-TR displayed increased Bcl-2 but decreased BAX protein expression and subsequently increased Bcl-2 and BAX ratios.	20	32	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	Bcl-2 but decreased BAX protein expression	bax	Bcl-2	Bcl-2	bcl-2	23	24	29	30
Bad , Bax and Bak inhibit Bcl-2 activity and promote apoptosis [ XREF_BIBR ] .	Bad, Bax and Bak inhibit Bcl-2 activity and promote apoptosis [XREF_BIBR].	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	2	3	6	7
The increased Bax , decreased Bcl-2 , decreased pro caspase 3 , and decreased VEGF protein expressions were shown in brain tissues from MCAO mice .	The increased Bax, decreased Bcl-2, decreased pro caspase 3, and decreased VEGF protein expressions were shown in brain tissues from MCAO mice.	0	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	2	3	5	6
This contrasts dramatically with mammalian models of cellular stress , where Bax increases as much as 12-fold and significantly decreases Bcl-2 : Bax ratios and increases apoptosis .	This contrasts dramatically with mammalian models of cellular stress, where Bax increases as much as 12-fold and significantly decreases Bcl-2 : Bax ratios and increases apoptosis.	11	23	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	11	12	20	21
NGF also reduced the expression of Bax and reversed the reduction of Bcl-2 and the phosphorylated Akt induced by RIR .	NGF also reduced the expression of Bax and reversed the reduction of Bcl-2 and the phosphorylated Akt induced by RIR.	0	13	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	NGF also reduced the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	6	7	12	13
Incubation of MDA-MB-453 cells with AC caused a dramatic reduction in the level of the antiapoptotic protein Bcl-2 and increased the level of the proapoptotic Bax protein , which heterodimerizes with Bcl-2 to inhibit Bcl-2 activity ( XREF_FIG ) .	Incubation of MDA-MB-453 cells with AC caused a dramatic reduction in the level of the antiapoptotic protein Bcl-2 and increased the level of the proapoptotic Bax protein, which heterodimerizes with Bcl-2 to inhibit Bcl-2 activity (XREF_FIG).	25	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	25	26	34	35
In addition , the immunohistochemical detection of Bax and Bcl-2 revealed an extensive expression of Bax ( XREF_FIG ) and decreased Bcl-2 ( XREF_FIG ) in the hepatic tissues of rats treated with cisplatin ; events which were markedly mitigated by administration of tangeretin .	In addition, the immunohistochemical detection of Bax and Bcl-2 revealed an extensive expression of Bax (XREF_FIG) and decreased Bcl-2 (XREF_FIG) in the hepatic tissues of rats treated with cisplatin; events which were markedly mitigated by administration of tangeretin.	5	35	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	7	8	21	22
Moreover , Quantitative PCR showed that morphine significantly increased TLRs and Bax gene expressions and decreased the anti-apoptotic Bcl2 .	Moreover, Quantitative PCR showed that morphine significantly increased TLRs and Bax gene expressions and decreased the anti-apoptotic Bcl2.	6	19	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	morphine significantly increased TLRs and Bax gene expressions	bax	Bcl2	Bcl2	bcl2	11	12	18	19
In contrast , as Bax expression increases , the ratio of Bcl-2 and Bax decreases , resulting in cell death [ XREF_BIBR ] .	In contrast, as Bax expression increases, the ratio of Bcl-2 and Bax decreases, resulting in cell death [XREF_BIBR].	4	14	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax expression	bax	Bcl-2	Bcl-2	bcl-2	4	5	11	12
Metformin increased mRNA levels of Bax and decreased that of Bcl-2 ( data not shown ) .	Metformin increased mRNA levels of Bax and decreased that of Bcl-2 (data not shown).	0	12	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Metformin increased mRNA levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	5	6	10	11
Curcumin inhibited the expression of hippocampal Bax mRNA and increased Bcl-2 mRNA .	Curcumin inhibited the expression of hippocampal Bax mRNA and increased Bcl-2 mRNA.	0	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Curcumin inhibited the expression of hippocampal Bax	bax	Bcl-2	Bcl-2	bcl-2	6	7	10	11
Both hAD-MSC and LIPUS pretreated hAD-MSC transplantation significantly reduced the Bax expression and significantly increased the Bcl-2 expression and the Bcl-2 and Bax ratio in the ovaries of POI rats .	Both hAD-MSC and LIPUS pretreated hAD-MSC transplantation significantly reduced the Bax expression and significantly increased the Bcl-2 expression and the Bcl-2 and Bax ratio in the ovaries of POI rats.	1	18	increased	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Bax	hAD-MSC and LIPUS pretreated hAD-MSC transplantation significantly reduced the Bax expression	bax	Bcl-2	Bcl-2 expression	bcl-2	10	11	16	17
We also found that DGLHD and active ingredients increased the expressions of the anti-apoptotic gene Bcl-2 and the proliferation related gene CyclinD1 , decreased the expression of the pro apoptosis gene Bax , and increased the ratio of Bcl-2 and Bax in NIT-1 cells , a model murine pancreatic beta cell line .	We also found that DGLHD and active ingredients increased the expressions of the anti-apoptotic gene Bcl-2 and the proliferation related gene CyclinD1, decreased the expression of the pro apoptosis gene Bax, and increased the ratio of Bcl-2 and Bax in NIT-1 cells, a model murine pancreatic beta cell line.	4	40	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	DGLHD and active ingredients increased the expressions of the anti-apoptotic gene Bcl-2 and the proliferation related gene CyclinD1, decreased the expression of the pro apoptosis gene Bax	bax	Bcl-2	Bcl-2	bcl-2	31	32	38	39
The induction of Bax and concomitant suppression of Bcl-2 by withaferin-A led to the cleavage of caspase-3 and PARP , and induction of apoptosis in Caski cells [ XREF_BIBR ] .	The induction of Bax and concomitant suppression of Bcl-2 by withaferin-A led to the cleavage of caspase-3 and PARP, and induction of apoptosis in Caski cells [XREF_BIBR].	3	10	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	3	4	8	9
It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2 protein in HK-2 cells , which was reversed by CPU0213 .	It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2 protein in HK-2 cells, which was reversed by CPU0213.	5	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	glucose significantly increased the protein expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	12	13	15	16
Bax , a homologue of Bcl-2 , counters the death repressor activity of Bcl-2 .	Bax, a homologue of Bcl-2, counters the death repressor activity of Bcl-2.	0	14	repressor activity	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	13	14
Conversely , pro apoptotic Bax protein effectively antagonizes Bcl-2 action , thereby promoting apoptosis [ XREF_BIBR ] .	Conversely, pro apoptotic Bax protein effectively antagonizes Bcl-2 action, thereby promoting apoptosis [XREF_BIBR].	4	9	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	4	5	8	9
The increment in cellular Bax provides more Bax for translocation to the mitochondria ; and the enhancement in the Bax and Bcl -2 ratio reduces the anti-apoptotic effect of Bcl-2 .	The increment in cellular Bax provides more Bax for translocation to the mitochondria; and the enhancement in the Bax and Bcl -2 ratio reduces the anti-apoptotic effect of Bcl-2.	16	30	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	19	20	29	30
Bax can not only inhibit the apoptosis inhibition effect of Bcl-2 , but also directly promote the apoptosis of cells [ XREF_BIBR ] .	Bax can not only inhibit the apoptosis inhibition effect of Bcl-2, but also directly promote the apoptosis of cells [XREF_BIBR].	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	10	11
BAX generally promotes apoptosis and antagonizes the effect of BCL2 XREF_BIBR , XREF_BIBR , XREF_BIBR .	BAX generally promotes apoptosis and antagonizes the effect of BCL2 XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	BAX	BAX	BCL2	BCL2	BCL2	0	1	9	10
Western blot analysis of cell lysates revealed that Bcl-2 levels decreased dose-dependently in cells treated with quercetin , but Bax remained unchanged .	Western blot analysis of cell lysates revealed that Bcl-2 levels decreased dose-dependently in cells treated with quercetin, but Bax remained unchanged.	8	20	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	19	20	8	9
Bax , is a dominant inhibitor of Bcl-2 , and induces apoptosis through its overexpression , which damage mitochondria .	Bax, is a dominant inhibitor of Bcl-2, and induces apoptosis through its overexpression, which damage mitochondria.	0	10	is a dominant inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	7	8
Furthermore , at these concentrations , calycosin decreased the percentage of early apoptosis in MCF-7 cells , downregulated mRNA and protein levels of Bax , and upregulated those of Bcl-2 at low concentrations .	Furthermore, at these concentrations, calycosin decreased the percentage of early apoptosis in MCF-7 cells, downregulated mRNA and protein levels of Bax, and upregulated those of Bcl-2 at low concentrations.	6	30	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	calycosin decreased the percentage of early apoptosis in MCF-7 cells, downregulated mRNA and protein levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	23	24	29	30
In mitochondrial dependent pathway , the increased pro apoptotic Bcl-2-related proteins , particularly Bax , which antagonize the anti-apoptotic Bcl-2 , favor cytochrome c release into cytosol through opening of the outer mito-chondrial membrane .	In mitochondrial dependent pathway, the increased pro apoptotic Bcl-2-related proteins, particularly Bax, which antagonize the anti-apoptotic Bcl-2, favor cytochrome c release into cytosol through opening of the outer mito-chondrial membrane.	10	24	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	13	14	19	20
Increased mitochondrial cytochrome c release , increased Bax protein expression , decreased Bcl-2 protein , and reduced Bcl-2 and Bax ratio are found in the studies displayed in Table 3 .	Increased mitochondrial cytochrome c release, increased Bax protein expression, decreased Bcl-2 protein, and reduced Bcl-2 and Bax ratio are found in the studies displayed in Table 3.	2	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	cytochrome c release, increased Bax protein expression	bax	Bcl-2	Bcl-2	bcl-2	7	8	12	13
We also found that MXC increases Bax ( 48 and 96 h ) , increases Bcl2 ( 96 h ) , and decreases Bax and Bcl2 ratios ( 96 h ) at later time points .	We also found that MXC increases Bax (48 and 96 h), increases Bcl2 (96 h), and decreases Bax and Bcl2 ratios (96 h) at later time points.	4	22	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl2	Bcl2	Bcl2	6	7	15	16
TP53 can trigger both intrinsic ( mitochondrial ) and extrinsic ( death receptor induced ) apoptotic pathways : TP53 activates the expression of pro apoptotic proteins Bax , Noxa and PUMA and downregulates anti-apoptotic Bcl-2 .	TP53 can trigger both intrinsic (mitochondrial) and extrinsic (death receptor induced) apoptotic pathways : TP53 activates the expression of pro apoptotic proteins Bax, Noxa and PUMA and downregulates anti-apoptotic Bcl-2.	18	35	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	TP53 activates the expression of pro apoptotic proteins Bax	bax	Bcl-2	Bcl-2	bcl-2	26	27	34	35
Bax is an antagonist of Bcl-2 , and Bcl-2 and Bax ratio determines cell fate .	Bax is an antagonist of Bcl-2, and Bcl-2 and Bax ratio determines cell fate.	0	6	is an antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	5	6
Moreover , MDD patients with a high risk for suicide had increased Bax and FAS mRNA expression and decreased Bcl-2 and Bcl-2 and Bax ratio when compared to patients without risk for suicide ( p < .001 ) .	Moreover, MDD patients with a high risk for suicide had increased Bax and FAS mRNA expression and decreased Bcl-2 and Bcl-2 and Bax ratio when compared to patients without risk for suicide (p <.001).	2	24	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	MDD patients with a high risk for suicide had increased Bax and FAS mRNA expression	bax	Bcl-2	Bcl-2	bcl-2	12	13	19	20
This result implied that alpha-mangostin increased Bax expression in the YD-15 cells and decreased Bcl-2 , ultimately leading to apoptosis .	This result implied that alpha-mangostin increased Bax expression in the YD-15 cells and decreased Bcl-2, ultimately leading to apoptosis.	4	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	alpha-mangostin increased Bax expression	bax	Bcl-2	Bcl-2	bcl-2	6	7	14	15
Quercetin also suppresses the expression of the pro apoptotic Bax gene and enhances the anti-apoptotic Bcl-2 gene in normal cells under oxidative stress XREF_BIBR , XREF_BIBR .	Quercetin also suppresses the expression of the pro apoptotic Bax gene and enhances the anti-apoptotic Bcl-2 gene in normal cells under oxidative stress XREF_BIBR, XREF_BIBR.	0	16	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Quercetin also suppresses the expression of the pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	9	10	15	16
Auranofin also increases levels of pro apoptotic proteins Bax and Bim and reduces anti-apoptotic protein Bcl-2 in ovarian carcinoma cells , and activates caspase-3-mediated apoptosis in a FOXO3 dependent manner [ XREF_BIBR ] .	Auranofin also increases levels of pro apoptotic proteins Bax and Bim and reduces anti-apoptotic protein Bcl-2 in ovarian carcinoma cells, and activates caspase-3-mediated apoptosis in a FOXO3 dependent manner [XREF_BIBR].	0	19	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Auranofin also increases levels of pro apoptotic proteins Bax	bax	Bcl-2	Bcl-2	bcl-2	8	9	15	16
XREF_BIBR Bcl-2 and its relative B-cell lymphoma-extra large ( Bcl-xl ) are negatively regulated by Bax .	XREF_BIBR Bcl-2 and its relative B-cell lymphoma-extra large (Bcl-xl) are negatively regulated by Bax.	0	16	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	15	16	1	2
The present study also demonstrated that PD98059 , a specific ERK inhibitor , promoted HMC apoptosis , inhibited the expression levels of TGF-beta1 , Col-IV , Col-I and Bcl-2 , and upregulated the expression of Bax , therefore , decreasing the Bcl-2 and Bax ratio .	The present study also demonstrated that PD98059, a specific ERK inhibitor, promoted HMC apoptosis, inhibited the expression levels of TGF-beta1, Col-IV, Col-I and Bcl-2, and upregulated the expression of Bax, therefore, decreasing the Bcl-2 and Bax ratio.	10	44	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	ERK inhibitor, promoted HMC apoptosis, inhibited the expression levels of TGF-beta1, Col-IV, Col-I and Bcl-2, and upregulated the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	35	36	41	42
Bax antagonizes the effect of Bcl-2 that results in release of cytochrome c in cytosol .	Bax antagonizes the effect of Bcl-2 that results in release of cytochrome c in cytosol.	0	6	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	5	6
This suggests that Bax antagonized Bcl-2 function , limiting the ability of Bcl-2 to prolong cell survival .	This suggests that Bax antagonized Bcl-2 function, limiting the ability of Bcl-2 to prolong cell survival.	3	6	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	3	4	5	6
However , Bax prevented Bcl-2 from associating with p28 .	However, Bax prevented Bcl-2 from associating with p28.	2	5	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	2	3	4	5
On the contrary , Bax could antagonize the function of Bcl-2 and therefore accelerate cell apoptosis 24 .	On the contrary, Bax could antagonize the function of Bcl-2 and therefore accelerate cell apoptosis 24.	4	13	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	4	5	10	11
In turn , Bcl-xL is able to inhibit Bax by dissociating previously activated Bax oligomers .	In turn, Bcl-xL is able to inhibit Bax by dissociating previously activated Bax oligomers.	3	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	3	4	8	9
OICR766A activated Bax is poorly inhibited by Bcl-XL .	OICR766A activated Bax is poorly inhibited by Bcl-XL.	2	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	7	8	2	3
In one , Bcl-XL binds to an activator , thereby preventing Bax activation .	In one, Bcl-XL binds to an activator, thereby preventing Bax activation.	3	12	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	3	4	11	12
In keeping with this , mitochondrial Bax inhibited by Bcl-XL was membrane inserted .	In keeping with this, mitochondrial Bax inhibited by Bcl-XL was membrane inserted.	5	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	9	10	6	7
If Bcl-XL expression reduced the dissociation of GFP-Bax through an interaction between them , then it might be expected that Bax would similarly stabilize mitochondrial Bcl-XL .	If Bcl-XL expression reduced the dissociation of GFP-Bax through an interaction between them, then it might be expected that Bax would similarly stabilize mitochondrial Bcl-XL.	1	8	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL expression	bcl-xl	GFP-Bax	GFP-Bax	gfp-bax	1	2	7	8
GM-CSF and IL-5 can induce expression of the anti-apoptotic proteins Bcl-xL , cIAP2 and survivin XREF_BIBR , XREF_BIBR , and can prevent the translocation of the pro apoptotic Bax to mitochondria XREF_BIBR .	GM-CSF and IL-5 can induce expression of the anti-apoptotic proteins Bcl-xL, cIAP2 and survivin XREF_BIBR, XREF_BIBR, and can prevent the translocation of the pro apoptotic Bax to mitochondria XREF_BIBR.	0	29	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	GM-CSF and IL-5 can induce expression of the anti-apoptotic proteins Bcl-xL	bcl-xl	Bax	Bax	bax	10	11	28	29
For many of these known and potentially unknown pathways , Bcl-XL may not directly sequester the initial activators of Bax , and hence inhibition of membrane permeabilization may rely on the sequestration of activated Bax to inhibit Bax autoactivation , oligomerization , and membrane permeabilization .	For many of these known and potentially unknown pathways, Bcl-XL may not directly sequester the initial activators of Bax, and hence inhibition of membrane permeabilization may rely on the sequestration of activated Bax to inhibit Bax autoactivation, oligomerization, and membrane permeabilization.	10	20	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	10	11	19	20
Overexpression of Bcl-xL inhibited vinblastine induced Bax activation and Bax dimerization and in parallel inhibited apoptosis .	Overexpression of Bcl-xL inhibited vinblastine induced Bax activation and Bax dimerization and in parallel inhibited apoptosis.	0	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Overexpression of Bcl-xL	bcl-xl	Bax	Bax	bax	2	3	6	7
Whereas Bcl-x L over-expression prevents the localization of Bax DeltaSH to the mitochondria after apoptosis induction , GFP-Bax 1-2/L-6 circumscribes the mitochondria even on Bcl-x L over-expression ( XREF_SUPPLEMENTARY , XREF_SUPPLEMENTARY ) .	Whereas Bcl-x L over-expression prevents the localization of Bax DeltaSH to the mitochondria after apoptosis induction, GFP-Bax 1-2/L-6 circumscribes the mitochondria even on Bcl-x L over-expression (XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY).	1	9	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L over-expression	bcl-x l	Bax	Bax	bax	1	3	8	9
For example , it has been proposed that overexpression of Bcl-XL in cancer may suppress the activity of the proapoptotic molecules Bax and Bak , contributing to cancer progression .	For example, it has been proposed that overexpression of Bcl-XL in cancer may suppress the activity of the proapoptotic molecules Bax and Bak, contributing to cancer progression.	8	23	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	overexpression of Bcl-XL	bcl-xl	Bax	Bax	bax	10	11	21	22
To directly test whether BCLXL selectively blocks membrane insertion of BAX core domain , we assessed the effect of BCLXL on Dox5 mediated quenching of different NBD-BAX variants .	To directly test whether BCLXL selectively blocks membrane insertion of BAX core domain, we assessed the effect of BCLXL on Dox5 mediated quenching of different NBD-BAX variants.	4	12	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCLXL	BCLXL	BCLXL	BAX	BAX	BAX	4	5	10	11
Under oxidative stress , Bcl-X L suppresses Bax activation and cell death [ XREF_BIBR ] .	Under oxidative stress, Bcl-X L suppresses Bax activation and cell death [XREF_BIBR].	4	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	Bax	Bax	Bax	4	6	7	8
As shown above , addition of Bcl-XL prevents tBid induced insertion of Bax into membranes and instead results in Bcl-XL inserting into the membrane ( XREF_FIG and XREF_FIG ) .	As shown above, addition of Bcl-XL prevents tBid induced insertion of Bax into membranes and instead results in Bcl-XL inserting into the membrane (XREF_FIG and XREF_FIG).	4	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	6	7	12	13
It is reported that Bcl-xL inhibits and maintains Bax in the cytosol by constant retro translocation of mitochondrial Bax which undergoes a conformational shift under apoptotic signaling , and inserts into the outer mitochondrial membrane .	It is reported that Bcl-xL inhibits and maintains Bax in the cytosol by constant retro translocation of mitochondrial Bax which undergoes a conformational shift under apoptotic signaling, and inserts into the outer mitochondrial membrane.	4	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	4	5	8	9
For example , Bcl-xL sequesters BH3-only pro apoptotic molecules , Bim , Noxa , and Bad , and prevents the activation of downstream Bax and Bak .	For example, Bcl-xL sequesters BH3-only pro apoptotic molecules, Bim, Noxa, and Bad, and prevents the activation of downstream Bax and Bak.	3	25	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	3	4	23	24
First , they show that Bcl-XL abrogates the transient association of Bax with the liposome surface that is necessary for shifting soluble Bax molecules into a conformation that is susceptible to productive interactions with tBid [ XREF_BIBR ] .	First, they show that Bcl-XL abrogates the transient association of Bax with the liposome surface that is necessary for shifting soluble Bax molecules into a conformation that is susceptible to productive interactions with tBid [XREF_BIBR].	5	12	abrogates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	5	6	11	12
When embedded in the membrane , Bax is proposed to form a positive feed-back loop recruiting Bax , and Bcl-x L inhibits this process by preventing Bax oligomer growth and translocating membrane Bax to the cytosol [ XREF_BIBR ] .	When embedded in the membrane, Bax is proposed to form a positive feed-back loop recruiting Bax, and Bcl-x L inhibits this process by preventing Bax oligomer growth and translocating membrane Bax to the cytosol [XREF_BIBR].	19	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bax	Bax	Bax	19	21	26	27
Our data also support an alternative model where Bcl-xL inhibits Bax by competing with it for binding to organelle membranes .	Our data also support an alternative model where Bcl-xL inhibits Bax by competing with it for binding to organelle membranes.	8	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	8	9	10	11
In our reconstituted systems , antiapoptotic BCLXL inhibited both membrane insertion of BAX core alpha4-alpha5 helices and BAX pore forming activity via canonical BH3-in-groove heterodimeric interactions .	In our reconstituted systems, antiapoptotic BCLXL inhibited both membrane insertion of BAX core alpha4-alpha5 helices and BAX pore forming activity via canonical BH3-in-groove heterodimeric interactions.	5	15	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCLXL	BCLXL	BCLXL	BAX	BAX	BAX	6	7	12	13
To confirm that Bcl-XL inhibited tBid induced binding of Bax to biological membranes , mitochondria purified from mouse liver ( MLM ) of bak -/- mice were assayed .	To confirm that Bcl-XL inhibited tBid induced binding of Bax to biological membranes, mitochondria purified from mouse liver (MLM) of bak -/- mice were assayed.	3	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	3	4	9	10
To try to further discriminate between canonical and non canonical mechanisms of BCLXL mediated BAX inhibition , we used the BCLXLDeltaC R139D and BCLXLDeltaC L17A variants expected to disrupt canonical and non canonical BCLXL : BAX binding interfaces , respectively XREF_BIBR , XREF_BIBR .	To try to further discriminate between canonical and non canonical mechanisms of BCLXL mediated BAX inhibition, we used the BCLXLDeltaC R139D and BCLXLDeltaC L17A variants expected to disrupt canonical and non canonical BCLXL : BAX binding interfaces, respectively XREF_BIBR, XREF_BIBR.	10	15	mediated	Positive_early_activation	Negative_activation	Negative_activation	BCLXL	BCLXL	BCLXL	BAX	BAX	BAX	12	13	14	15
Co-treatment , but not single treatment , with VP16 and TSA induced apoptosis in a caspase dependent manner accompanied by a crucial decrease in Bcl-xL expression allowing Bax activation and subsequent initiation of the apoptosis inducing factor ( AIF )-dependent death pathway .	Co-treatment, but not single treatment, with VP16 and TSA induced apoptosis in a caspase dependent manner accompanied by a crucial decrease in Bcl-xL expression allowing Bax activation and subsequent initiation of the apoptosis inducing factor (AIF)-dependent death pathway.	24	28	allowing	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL expression	bcl-xl	Bax	Bax	bax	24	25	27	28
Interesting observation from both mammalian and yeast cells points to yet another possible mechanism , by which Bcl-XL could antagonize the cell killing activity of Bax .	Interesting observation from both mammalian and yeast cells points to yet another possible mechanism, by which Bcl-XL could antagonize the cell killing activity of Bax.	17	26	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	17	18	25	26
38 Suppression of Bcl-xL and Mcl-1 causes Bax and Bak dependent apoptosis in the TKO cells .	38 Suppression of Bcl-xL and Mcl-1 causes Bax and Bak dependent apoptosis in the TKO cells.	1	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	3	4	7	8
Results with BCL-XL High cells are consistent with a model whereby BCL-XL acts in parallel to BCL-2 to inhibit BAX and BAK and/or sequester BIM and BH3-only proteins , and with a model whereby BCL-XL can also counteract MCL-1 reduction and/or BH3-only protein increases by alvocidib .	Results with BCL-XL High cells are consistent with a model whereby BCL-XL acts in parallel to BCL-2 to inhibit BAX and BAK and/or sequester BIM and BH3-only proteins, and with a model whereby BCL-XL can also counteract MCL-1 reduction and/or BH3-only protein increases by alvocidib.	11	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-XL	BCL-XL	BCL-XL	BAX	BAX	BAX	11	12	19	20
These results further demonstrate that Bcl-XL in the membrane prevents or reverses the conformational change in soluble Bax that occurs upon exposure to a membrane surface .	These results further demonstrate that Bcl-XL in the membrane prevents or reverses the conformational change in soluble Bax that occurs upon exposure to a membrane surface.	5	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	5	6	17	18
The anti-apoptotic protein B-cell lymphoma-extra large ( Bcl-xL ) inhibits Bax mediated MOMP .	The anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL) inhibits Bax mediated MOMP.	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	7	8	10	11
The finding that BCLXL blocks insertion of BAX core alpha4-alpha5 helices into the membrane without significantly affecting membrane insertion of BAX latch alpha6-alpha8 helices further supports that the former process is a more important contributor of BAX pore formation than the latter one .	The finding that BCLXL blocks insertion of BAX core alpha4-alpha5 helices into the membrane without significantly affecting membrane insertion of BAX latch alpha6-alpha8 helices further supports that the former process is a more important contributor of BAX pore formation than the latter one.	3	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCLXL	BCLXL	BCLXL	BAX	BAX	BAX	3	4	7	8
In the event , the real anti-apoptotic signals are conducted by the Bcl-2 family of regulatory proteins including Bcl-xL , Bcl-w and A1 , acting largely by binding to suppress two pro apoptopic proteins ( Bax and Bak ) XREF_BIBR .	In the event, the real anti-apoptotic signals are conducted by the Bcl-2 family of regulatory proteins including Bcl-xL, Bcl-w and A1, acting largely by binding to suppress two pro apoptopic proteins (Bax and Bak) XREF_BIBR.	16	37	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	18	19	35	36
Over expression of anti-apoptotic BCL-2 family proteins ( BCL-X L , BCL-2 , BCL-W , A1 , MCL-1 ) suppresses BAX and BAK and prevents the initiation of the apoptosis , thereby protecting cancer cells from responding to proapoptotic signals .	Over expression of anti-apoptotic BCL-2 family proteins (BCL-X L, BCL-2, BCL-W, A1, MCL-1) suppresses BAX and BAK and prevents the initiation of the apoptosis, thereby protecting cancer cells from responding to proapoptotic signals.	8	22	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-X L	BCL-X L	BCL-X L	BAX	BAX	BAX	8	10	20	21
Antioxidant ( tBHQ ) treatment stabilized Nrf2 up-regulates Bcl-xL expression leading to decrease in Bax and Caspases 3/7 activities .	Antioxidant (tBHQ) treatment stabilized Nrf2 up-regulates Bcl-xL expression leading to decrease in Bax and Caspases 3/7 activities.	6	16	leading	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Nrf2 up-regulates Bcl-xL expression	bcl-xl	Bax	Bax	bax	8	9	14	15
Mcl-1 and Bcl-xL sequester Bak and Bax until their displacement is promoted by the action of activated BH3-only proteins to trigger subsequent mitochondrial cell death [ XREF_BIBR ] .	Mcl-1 and Bcl-xL sequester Bak and Bax until their displacement is promoted by the action of activated BH3-only proteins to trigger subsequent mitochondrial cell death [XREF_BIBR].	0	7	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	2	3	6	7
Furthermore , the anti-apoptotic protein Bcl-xL abolished Bax integration in the presence of Bid BH3 peptide ( XREF_FIG ) .	Furthermore, the anti-apoptotic protein Bcl-xL abolished Bax integration in the presence of Bid BH3 peptide (XREF_FIG).	2	8	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	5	6	7	8
Bcl-xL and Mcl-1 were reported to suppress activation of Bax and Bak , respectively .	Bcl-xL and Mcl-1 were reported to suppress activation of Bax and Bak, respectively.	0	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	0	1	9	10
When the m1Bid BH3 peptide triggered Bcl-XL binding to membranes , the Bcl-XL still inhibited the liposome induced Bax conformational change ( XREF_FIG F , top panel , lanes 2 and 3 ) .	When the m1Bid BH3 peptide triggered Bcl-XL binding to membranes, the Bcl-XL still inhibited the liposome induced Bax conformational change (XREF_FIG F, top panel, lanes 2 and 3).	11	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	12	13	18	19
Thus , our results support a scenario in which Bcl-xL inhibits inserted and oligomerized BAX and emphasize the fact that BAX insertion and oligomerization in the OMM could be dissociated from OMM permeabilization .	Thus, our results support a scenario in which Bcl-xL inhibits inserted and oligomerized BAX and emphasize the fact that BAX insertion and oligomerization in the OMM could be dissociated from OMM permeabilization.	9	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	BAX	BAX	BAX	9	10	14	15
Our findings that the BAD-BAX-caspase-3 cascade is sufficient for LTD induction as demonstrated by infusion of active BAD or caspase-3 into hippocampal neurons and that overexpression of BCL-XL , which antagonizes BAD and BAX , inhibits LTD provide additional support for the importance of mitochondria to synaptic plasticity .	Our findings that the BAD-BAX-caspase-3 cascade is sufficient for LTD induction as demonstrated by infusion of active BAD or caspase-3 into hippocampal neurons and that overexpression of BCL-XL, which antagonizes BAD and BAX, inhibits LTD provide additional support for the importance of mitochondria to synaptic plasticity.	25	34	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-XL	overexpression of BCL-XL	bcl-xl	BAX	BAX	bax	27	28	33	34
To inhibit membrane permeabilization , Bcl-XL might inhibit any or all of the interactions of Bax and its activator with each other or with membranes .	To inhibit membrane permeabilization, Bcl-XL might inhibit any or all of the interactions of Bax and its activator with each other or with membranes.	5	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	5	6	15	16
The presence of Bcl-xL reduces the size of Bax oligomers .	The presence of Bcl-xL reduces the size of Bax oligomers.	1	9	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	3	4	8	9
Recombinant TCTP enhanced Bcl-xL inhibition of both cBid and Bax and cBidmt1 and Bax mediated liposome permeabilization in a dose dependent manner ( XREF_FIG ) .	Recombinant TCTP enhanced Bcl-xL inhibition of both cBid and Bax and cBidmt1 and Bax mediated liposome permeabilization in a dose dependent manner (XREF_FIG).	3	10	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	3	4	9	10
This supports our observation that the upregulation of Bcl-xL seen in MT-4 cells is unable to inhibit PJ-34-induced apoptosis and Bax activation , leading to apoptosis .	This supports our observation that the upregulation of Bcl-xL seen in MT-4 cells is unable to inhibit PJ-34-induced apoptosis and Bax activation, leading to apoptosis.	6	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	8	9	20	21
These results argue that Bcl-XL inhibits membrane permeabilization by preventing the binding of Bax , but not tBid , to membranes .	These results argue that Bcl-XL inhibits membrane permeabilization by preventing the binding of Bax, but not tBid, to membranes.	4	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	4	5	13	14
Over-expression of BCL-xL greatly reduces the availability of direct activator in these cells and also blocks any newly generated molecule of active BAX or BAK , inhibiting the feed-forward activation and considerably slows the rate of effector activation .	Over-expression of BCL-xL greatly reduces the availability of direct activator in these cells and also blocks any newly generated molecule of active BAX or BAK, inhibiting the feed-forward activation and considerably slows the rate of effector activation.	0	24	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-xL	Over-expression of BCL-xL	bcl-xl	BAX	BAX	bax	2	3	22	23
As Bcl-xL was added 1h after Bax activation by cBid , these results suggest a Bax and Bcl-xL interaction post Bax oligomerization and a new mechanism of Bcl-xL inhibition of Bax not reported so far .	As Bcl-xL was added 1h after Bax activation by cBid, these results suggest a Bax and Bcl-xL interaction post Bax oligomerization and a new mechanism of Bcl-xL inhibition of Bax not reported so far.	27	31	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	27	28	30	31
Bcl-xL prevents Bax incorporation .	Bcl-xL prevents Bax incorporation.	0	3	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	0	1	2	3
Next , to determine whether Bax and/or Bak is essential for CB induced glioma cell death , we knocked down Bax and/or Bak with siRNAs and also established T98G and U251 cells stably overexpressing Bcl-2 and B-cell lymphoma-extra large ( Bcl-xl ) , which antagonize Bax and Bak , 12 and examined their effect on CB induced caspase activation and cell death .	Next, to determine whether Bax and/or Bak is essential for CB induced glioma cell death, we knocked down Bax and/or Bak with siRNAs and also established T98G and U251 cells stably overexpressing Bcl-2 and B-cell lymphoma-extra large (Bcl-xl), which antagonize Bax and Bak, 12 and examined their effect on CB induced caspase activation and cell death.	33	49	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xl	Bcl-xl	Bcl-xl	Bax	Bax	Bax	40	41	45	46
Bax activation required the presence of a functional tBid BH3 domain and was prevented by Bcl-x L ( XREF_FIG ) .	Bax activation required the presence of a functional tBid BH3 domain and was prevented by Bcl-x L (XREF_FIG).	0	17	prevented	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bax	Bax	Bax	15	17	0	1
In turn , Bax is regulated primarily by anti-apoptotic Bcl-2 proteins including Bcl-xL , which was recently shown to prevent Bax from accumulating at the mitochondria .	In turn, Bax is regulated primarily by anti-apoptotic Bcl-2 proteins including Bcl-xL, which was recently shown to prevent Bax from accumulating at the mitochondria.	10	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	12	13	20	21
XREF_BIBR , XREF_BIBR , XREF_BIBR In addition , our data support a novel mechanism by which Bcl-xL inhibits the activity of cBid and Bax by restraining their effects on membrane curvature .	XREF_BIBR, XREF_BIBR, XREF_BIBR In addition, our data support a novel mechanism by which Bcl-xL inhibits the activity of cBid and Bax by restraining their effects on membrane curvature.	16	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	16	17	23	24
CCN1 siRNA suppressed c-Myc and Bcl-xL expression and up-regulated the proapoptotic gene Bax but had no effect on Survivin expression .	CCN1 siRNA suppressed c-Myc and Bcl-xL expression and up-regulated the proapoptotic gene Bax but had no effect on Survivin expression.	0	13	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	CCN1 siRNA suppressed c-Myc and Bcl-xL expression	bcl-xl	Bax	Bax	bax	5	6	12	13
Such permeabilization is regulated by anti-apoptotic multi-BH domain proteins such as the Bcl-2 protein itself , Bcl-xl , Bcl-w , Mcl-1 and A1 that prevent Bax and Bak activation by BH3-only pro apoptotic relatives .	Such permeabilization is regulated by anti-apoptotic multi-BH domain proteins such as the Bcl-2 protein itself, Bcl-xl, Bcl-w, Mcl-1 and A1 that prevent Bax and Bak activation by BH3-only pro apoptotic relatives.	14	28	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xl	Bcl-xl	Bcl-xl	Bax	Bax	Bax	16	17	25	26
In our reconstituted systems , antiapoptotic BCLXL formed canonical heterodimeric BH3-in-groove complexes with BAX , and blocked membrane insertion of BAX core alpha4-alpha5 helices , but not BAX latch alpha6-alpha8 helices .	In our reconstituted systems, antiapoptotic BCLXL formed canonical heterodimeric BH3-in-groove complexes with BAX, and blocked membrane insertion of BAX core alpha4-alpha5 helices, but not BAX latch alpha6-alpha8 helices.	5	23	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCLXL	BCLXL	BCLXL	BAX	BAX	BAX	6	7	20	21
Furthermore , when Bcl-XL prevented tBid and Bax mediated membrane permeabilization ( XREF_FIG A ) , Bcl-XL was overwhelmingly membrane bound ( XREF_FIG B ) .	Furthermore, when Bcl-XL prevented tBid and Bax mediated membrane permeabilization (XREF_FIG A), Bcl-XL was overwhelmingly membrane bound (XREF_FIG B).	3	10	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	3	4	7	8
We found that Ki67-ZD55-IL-24 dramatically decreased Bcl-xl and Mcl-1 levels , significantly increased Bax , and induced a much stronger activation of caspase-3 .	We found that Ki67-ZD55-IL-24 dramatically decreased Bcl-xl and Mcl-1 levels, significantly increased Bax, and induced a much stronger activation of caspase-3.	3	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xl	Ki67-ZD55-IL-24 dramatically decreased Bcl-xl and Mcl-1 levels	bcl-xl	Bax	Bax	bax	6	7	13	14
Increased AIM2 expression can inhibit the expression of the anti-apoptotic protein Bcl-xL , increase the expression of the apoptosis proteins Bad and Bax , and activate caspases , resulting in cleavage of the DNA repair protein PARP .	Increased AIM2 expression can inhibit the expression of the anti-apoptotic protein Bcl-xL, increase the expression of the apoptosis proteins Bad and Bax, and activate caspases, resulting in cleavage of the DNA repair protein PARP.	1	23	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	AIM2 expression can inhibit the expression of the anti-apoptotic protein Bcl-xL	bcl-xl	Bax	Bax	bax	11	12	22	23
In this regard , the differential effects exerted by the sequential addition of BCLXL and cBID M97A on BAX membrane topology together with the opposite effects exerted by canonical and non canonical BCLXLDeltaC mutants on BAX membrane activities indicate that BCLXL inhibits BAX proapoptotic action exclusively by sequestering the BAX BH3 domain into its canonical groove .	In this regard, the differential effects exerted by the sequential addition of BCLXL and cBID M97A on BAX membrane topology together with the opposite effects exerted by canonical and non canonical BCLXLDeltaC mutants on BAX membrane activities indicate that BCLXL inhibits BAX proapoptotic action exclusively by sequestering the BAX BH3 domain into its canonical groove.	40	44	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCLXL	BCLXL	BCLXL	BAX	BAX	BAX	40	41	42	43
We demonstrated that probucol treatment significantly increased Bcl-X L expression and decreased Bax along with cleaved caspase-9 expression in lung tissues from hyperoxia exposed mice .	We demonstrated that probucol treatment significantly increased Bcl-X L expression and decreased Bax along with cleaved caspase-9 expression in lung tissues from hyperoxia exposed mice.	3	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-X L	probucol treatment significantly increased Bcl-X L expression	bcl-x l	Bax	Bax	bax	7	9	12	13
XREF_BIBR It is unclear whether Mcl-1 and Bcl-x L also inhibit Bax in DP thymocytes or whether Bax is inactive at this stage .	XREF_BIBR It is unclear whether Mcl-1 and Bcl-x L also inhibit Bax in DP thymocytes or whether Bax is inactive at this stage.	5	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bax	Bax	Bax	7	9	11	12
This may disrupt the interaction of Bcl-xL and Bax , interfering with inhibition of Bax by Bcl-xL and leading cells to be more sensitive to apoptosis .	This may disrupt the interaction of Bcl-xL and Bax, interfering with inhibition of Bax by Bcl-xL and leading cells to be more sensitive to apoptosis.	10	17	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	16	17	14	15
In contrast , when the Bak BH3 peptide was added , membrane bound Bcl-XL did not prevent the liposome induced Bax conformational change ( XREF_FIG F , bottom panel , lanes 2 and 3 ) .	In contrast, when the Bak BH3 peptide was added, membrane bound Bcl-XL did not prevent the liposome induced Bax conformational change (XREF_FIG F, bottom panel, lanes 2 and 3).	13	22	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	13	14	20	21
Bax activation at the mitochondrial membrane requires the generation of ROS and can be prevented by the overexpression of Bcl-XL .	Bax activation at the mitochondrial membrane requires the generation of ROS and can be prevented by the overexpression of Bcl-XL.	0	20	prevented	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-XL	overexpression of Bcl-XL	bcl-xl	Bax	Bax	bax	19	20	0	1
The relative contribution of either potential death suppressing mechanism -- Bcl-xL suppression of Bax and Bak versus modulation of metabolism -- may depend on where Bcl-xL is predominately localized ( OMM versus cristae ) in a given cell type .	The relative contribution of either potential death suppressing mechanism -- Bcl-xL suppression of Bax and Bak versus modulation of metabolism -- may depend on where Bcl-xL is predominately localized (OMM versus cristae) in a given cell type.	10	15	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	10	11	13	14
As a result , not all Bax may be sequestered by Bcl-x L and free Bax appears .	As a result, not all Bax may be sequestered by Bcl-x L and free Bax appears.	5	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bax	Bax	Bax	11	13	6	7
The current view of apoptotic regulation is that Bcl-xL and its relatives bind to and thereby inhibit the pro apoptotic activity of BAX and BAK1 , which are otherwise poised to initiate the apoptotic cell death cascade [ XREF_BIBR , XREF_BIBR ] .	The current view of apoptotic regulation is that Bcl-xL and its relatives bind to and thereby inhibit the pro apoptotic activity of BAX and BAK1, which are otherwise poised to initiate the apoptotic cell death cascade [XREF_BIBR, XREF_BIBR].	8	31	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	BAX	BAX	BAX	8	9	22	23
In Mode 1 , Bcl-xL sequesters activator-type BH3 only proteins like cBid , and thereby prevents Bax activation XREF_BIBR , XREF_BIBR .	In Mode 1, Bcl-xL sequesters activator-type BH3 only proteins like cBid, and thereby prevents Bax activation XREF_BIBR, XREF_BIBR.	4	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	4	5	16	17
Bcl-xL modulates Bax via different mechanisms : ( i ) Bcl-xL inhibits Bax activation by sequestering tBid ; XREF_BIBR , XREF_BIBR ( ii ) Bcl-xL reduces the oligomerization state of Bax within membranes ; 78 and ( iii ) Bcl-xL decreases the membrane bound population of Bax .	Bcl-xL modulates Bax via different mechanisms : (i) Bcl-xL inhibits Bax activation by sequestering tBid; XREF_BIBR, XREF_BIBR (ii) Bcl-xL reduces the oligomerization state of Bax within membranes; 78 and (iii) Bcl-xL decreases the membrane bound population of Bax.	0	5	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	0	1	2	3
Membrane bound Bcl-XL not only prevented the formation of detergent resistant Bax cross-links but also prevented the cross linking of Bax that resulted when Bax contacted the membrane surface ( XREF_FIG D , right panel ) .	Membrane bound Bcl-XL not only prevented the formation of detergent resistant Bax cross-links but also prevented the cross linking of Bax that resulted when Bax contacted the membrane surface (XREF_FIG D, right panel).	2	15	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	2	3	11	12
Of the models , proposed for the inhibition of Bax by Bcl-XL , several others would be consistent with this observation in yeast .	Of the models, proposed for the inhibition of Bax by Bcl-XL, several others would be consistent with this observation in yeast.	4	12	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	11	12	9	10
Overexpressed Bcl-xL and Mcl-1 in cancer cells , localized at the outer membrane of mitochondria , can prevent PUMA or Bim related Bax activation and further prevent Bax related mitochondrial fission and apoptosis .	Overexpressed Bcl-xL and Mcl-1 in cancer cells, localized at the outer membrane of mitochondria, can prevent PUMA or Bim related Bax activation and further prevent Bax related mitochondrial fission and apoptosis.	1	23	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	1	2	22	23
BCLXL blocks membrane insertion of BAX core , not latch domain .	BCLXL blocks membrane insertion of BAX core, not latch domain.	0	6	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCLXL	BCLXL	BCLXL	BAX	BAX	BAX	0	1	5	6
An explanation of this effect could be the fact that BCL-XL attenuates BAX activity , a pro apoptotic protein which is known to induce LMP .	An explanation of this effect could be the fact that BCL-XL attenuates BAX activity, a pro apoptotic protein which is known to induce LMP.	10	13	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-XL	BCL-XL	BCL-XL	BAX	BAX	BAX	10	11	12	13
Taken together , our results indicate that Bcl-XL and Bax compete for binding to tBid and that Bcl-XL prevents membrane permeabilization by forming stable heterodimers with the membrane bound forms of both tBid and Bax .	Taken together, our results indicate that Bcl-XL and Bax compete for binding to tBid and that Bcl-XL prevents membrane permeabilization by forming stable heterodimers with the membrane bound forms of both tBid and Bax.	17	35	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	17	18	34	35
Bcl-xL , a pro survival member of the Bcl-2 family , can not directly inhibit Bax and specifically inhibits certain upstream BH3-only proteins .	Bcl-xL, a pro survival member of the Bcl-2 family, can not directly inhibit Bax and specifically inhibits certain upstream BH3-only proteins.	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	0	1	15	16
It has also been proposed that overexpression of Bcl-XL in prostate cancer may suppress the activity of the proapoptotic molecules Bax and Bak and may contribute to androgen resistance and progression of prostate cancer .	It has also been proposed that overexpression of Bcl-XL in prostate cancer may suppress the activity of the proapoptotic molecules Bax and Bak and may contribute to androgen resistance and progression of prostate cancer.	6	22	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	overexpression of Bcl-XL	bcl-xl	Bax	Bax	bax	8	9	20	21
Bcl-XL can prevent 6A7-epitope exposure of Bax on membranes .	Bcl-XL can prevent 6A7-epitope exposure of Bax on membranes.	0	7	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	0	1	6	7
When tested in the absence of tBid , a stable interaction between Bax and Bcl-XL was not detected ( XREF_FIG A , left panel , lane 3 ) , suggesting that Bcl-XL does not sequester Bax in solution .	When tested in the absence of tBid, a stable interaction between Bax and Bcl-XL was not detected (XREF_FIG A, left panel, lane 3), suggesting that Bcl-XL does not sequester Bax in solution.	31	36	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	31	32	35	36
It is still not established if Bax activity promotes cell death and Bcl-X L inhibits Bax or if Bcl-X L actively promotes cell viability and Bax inhibits Bcl-X L.	It is still not established if Bax activity promotes cell death and Bcl-X L inhibits Bax or if Bcl-X L actively promotes cell viability and Bax inhibits Bcl-X L.	12	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	Bax	Bax	Bax	12	14	15	16
p53 is a direct BAX activator inhibited by BCL-xL , defining a prototype non canonical modulator of BCL-2 proteins mediated MOMP .	p53 is a direct BAX activator inhibited by BCL-xL, defining a prototype non canonical modulator of BCL-2 proteins mediated MOMP.	4	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-xL	BCL-xL	BCL-xL	BAX	BAX	BAX	8	9	4	5
However , based on their inverse localization , Bcl-xL may antagonize Bax in OPCs , at least in part , through indirect mechanisms as reported in other cell types .	However, based on their inverse localization, Bcl-xL may antagonize Bax in OPCs, at least in part, through indirect mechanisms as reported in other cell types.	8	13	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	8	9	11	12
Concomitantly , an increase in Bcl-xL activity inhibited Bax and the proteolytic activity of caspase 3 as well as a decrease in PARP cleavage .	Concomitantly, an increase in Bcl-xL activity inhibited Bax and the proteolytic activity of caspase 3 as well as a decrease in PARP cleavage.	5	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	5	6	8	9
Bcl-xL is known to inhibit the formation of Bax channels in the mitochondrial outer membrane .	Bcl-xL is known to inhibit the formation of Bax channels in the mitochondrial outer membrane.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	0	1	8	9
In contrast , EPO enhanced BAD phosphorylation and Bcl-xL expression but downregulated Bax .	In contrast, EPO enhanced BAD phosphorylation and Bcl-xL expression but downregulated Bax.	3	13	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	EPO enhanced BAD phosphorylation and Bcl-xL	bcl-xl	Bax	Bax	bax	8	9	12	13
Over-expression of BCL-XL inhibits the pro apoptotic molecules BAX and BAK that in turn , inhibit MOMP and the release of pro apoptotic molecules from the mitochondria XREF_BIBR .	Over-expression of BCL-XL inhibits the pro apoptotic molecules BAX and BAK that in turn, inhibit MOMP and the release of pro apoptotic molecules from the mitochondria XREF_BIBR.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-XL	Over-expression of BCL-XL	bcl-xl	BAX	BAX	bax	2	3	8	9
It is not known how membrane bound Bcl-XL prevents a transient change in the conformation of Bax .	It is not known how membrane bound Bcl-XL prevents a transient change in the conformation of Bax.	7	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	7	8	16	17
BCL-XL directly inhibits proapoptotic BAX and BAK .	BCL-XL directly inhibits proapoptotic BAX and BAK.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-XL	BCL-XL	BCL-XL	BAX	BAX	BAX	0	1	4	5
Further , while blocking proteasomal degradation with MG-132 increases Bak levels , suppression of Bcl-2 expression further enhances stability of Bak , suggesting that Bcl-2 may promote Bak degradation by mechanisms that do not involve the proteasome .	Further, while blocking proteasomal degradation with MG-132 increases Bak levels, suppression of Bcl-2 expression further enhances stability of Bak, suggesting that Bcl-2 may promote Bak degradation by mechanisms that do not involve the proteasome.	14	21	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	Bak	Bak	bak	14	15	20	21
The combination of S1 with PD98059 can inhibit Bcl-2 phosphorylation and enhance Bak release from Bcl-2 .	The combination of S1 with PD98059 can inhibit Bcl-2 phosphorylation and enhance Bak release from Bcl-2.	3	13	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	S1 with PD98059 can inhibit Bcl-2 phosphorylation	bcl-2	Bak	Bak	bak	8	9	12	13
Although , the mechanism remains to be confirmed , the authors to proposed that Bcl-2 inhibition allows Bak to interact with CerS5 or 6 resulting in the production of C16 ceramide 67 .	Although, the mechanism remains to be confirmed, the authors to proposed that Bcl-2 inhibition allows Bak to interact with CerS5 or 6 resulting in the production of C16 ceramide 67.	14	19	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	14	15	17	18
XREF_BIBR , XREF_BIBR ABT-737 , a small-molecule inhibitor of BCL-2 , BCL-X L and BCL-W , induces apoptosis in a BAX- and BAK dependent manner .	XREF_BIBR, XREF_BIBR ABT-737, a small-molecule inhibitor of BCL-2, BCL-X L and BCL-W, induces apoptosis in a BAX- and BAK dependent manner.	7	24	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAK	BAK	BAK	9	10	22	23
However , pBcl-2 reduces the S1 cytotoxicity by sequestering Bak and Bim , which are released from Mcl-1 upon S1 exposure .	However, pBcl-2 reduces the S1 cytotoxicity by sequestering Bak and Bim, which are released from Mcl-1 upon S1 exposure.	2	15	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pBcl-2	pBcl-2	pBcl-2	Bak	Bak	Bak	2	3	9	10
Recent results have indicated that Bak is sequestered by Bcl-xL but not by Bcl-2 , and that the Bak BH3 domain is required for this interaction .	Recent results have indicated that Bak is sequestered by Bcl-xL but not by Bcl-2, and that the Bak BH3 domain is required for this interaction.	5	14	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	13	14	5	6
Moreover , knockdown of the endogenous Bax and Bak antagonists Bcl-2 or Bcl-X L sensitized tetraploid cells to Chk1 inhibition ( XREF_FIG ) .	Moreover, knockdown of the endogenous Bax and Bak antagonists Bcl-2 or Bcl-X L sensitized tetraploid cells to Chk1 inhibition (XREF_FIG).	2	11	antagonists	Negative_activation_token_1_noun	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	10	11	8	9
Bcl-xL , not Bcl-2 , is demonstrated to sequester Bak , a pro apoptotic protein [ XREF_BIBR ] .	Bcl-xL, not Bcl-2, is demonstrated to sequester Bak, a pro apoptotic protein [XREF_BIBR].	0	16	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	3	4	9	10
Recent studies identified a small molecule inhibitor of Bcl2 , ABT-737 , which binds with high affinity to Bcl2 and blocks Bcl2 mediated suppression of Bax- Bak dependent apoptosis .	Recent studies identified a small molecule inhibitor of Bcl2, ABT-737, which binds with high affinity to Bcl2 and blocks Bcl2 mediated suppression of Bax- Bak dependent apoptosis.	21	28	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bak	Bak	Bak	21	22	26	27
Before homodimers form , activated Bak can be sequestered by prosurvival Bcl-2 proteins such as Mcl-1 and Bcl-xL , and this sequestration blocks pore formation .	Before homodimers form, activated Bak can be sequestered by prosurvival Bcl-2 proteins such as Mcl-1 and Bcl-xL, and this sequestration blocks pore formation.	4	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	11	12	5	6
Results showed that compared with TAM or CXB alone , TAM-CXB together inhibited the expression of anti-apoptotic Bcl-2 protein and increased the levels of pro apoptotic Bax and Bak proteins .	Results showed that compared with TAM or CXB alone, TAM-CXB together inhibited the expression of anti-apoptotic Bcl-2 protein and increased the levels of pro apoptotic Bax and Bak proteins.	10	29	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	TAM-CXB together inhibited the expression of anti-apoptotic Bcl-2	bcl-2	Bak	Bak	bak	17	18	28	29
DATS treatment decreased Bcl-2 and Bcl-xL protein levels and caused induction of proapoptotic multidomain protein Bak in LNCaP human prostate cancer cell line 55 , which is androgen responsive and expresses wild-type p53 .	DATS treatment decreased Bcl-2 and Bcl-xL protein levels and caused induction of proapoptotic multidomain protein Bak in LNCaP human prostate cancer cell line 55, which is androgen responsive and expresses wild-type p53.	0	22	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	DATS treatment decreased Bcl-2 and Bcl-xL protein levels	bcl-2	Bak	Bak	bak	3	4	15	16
Mcl-1 promotes cell survival through its antagonistic interactions with the pro apoptotic protein Bax , while Bcl-2 and Bcl-xL have been shown to directly antagonize Bak .	Mcl-1 promotes cell survival through its antagonistic interactions with the pro apoptotic protein Bax, while Bcl-2 and Bcl-xL have been shown to directly antagonize Bak.	16	26	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	16	17	25	26
As shown in Figure XREF_FIG , BAK activation was detected in JT/Neo cells but not in JT/BCL -2 cells treated with 0.25 muM cis-3M-RES , indicating that BAK activation , which was blocked by BCL-2 , was involved in cis-3M-RES-induced Deltapsim loss .	As shown in Figure XREF_FIG, BAK activation was detected in JT/Neo cells but not in JT/BCL -2 cells treated with 0.25 muM cis-3M-RES, indicating that BAK activation, which was blocked by BCL-2, was involved in cis-3M-RES-induced Deltapsim loss.	27	35	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAK	BAK	BAK	34	35	27	28
To further assess whether the differential activity of BCL-2 versus BCL-X L in regulating apoptosis is due to the inability of BCL-2 to inhibit BAK , we silenced Bax or Bak in QKO cells overexpressing BCL-2 or BCL-X L.	To further assess whether the differential activity of BCL-2 versus BCL-X L in regulating apoptosis is due to the inability of BCL-2 to inhibit BAK, we silenced Bax or Bak in QKO cells overexpressing BCL-2 or BCL-X L.	6	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAK	BAK	BAK	8	9	24	25
COX-2 is upregulated in MDA-MB-231 and RR10 cells compared with in MDA-MB-231 cells , and silencing of COX-2 expression by shRNA in MDA-MB-231 and RR10 cells decreases the expression of Bcl-2 and Bcl-XL , but increases the proapoptotic protein BAK , leading to the increased apoptosis following treatment with gamma irradiation in comparison with those in control cells .	COX-2 is upregulated in MDA-MB-231 and RR10 cells compared with in MDA-MB-231 cells, and silencing of COX-2 expression by shRNA in MDA-MB-231 and RR10 cells decreases the expression of Bcl-2 and Bcl-XL, but increases the proapoptotic protein BAK, leading to the increased apoptosis following treatment with gamma irradiation in comparison with those in control cells.	17	40	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	COX-2 expression by shRNA in MDA-MB-231 and RR10 cells decreases the expression of Bcl-2	bcl-2	BAK	BAK	bak	30	31	39	40
This interpretation is also consistent with our previous data in which BCL-2 overexpression protected BAX deficient Jurkat T cells from heat shock induced apoptosis XREF_BIBR , even though BCL-2 does not inhibit BAK XREF_BIBR .	This interpretation is also consistent with our previous data in which BCL-2 overexpression protected BAX deficient Jurkat T cells from heat shock induced apoptosis XREF_BIBR, even though BCL-2 does not inhibit BAK XREF_BIBR.	28	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAK	BAK	BAK	28	29	32	33
It has been proposed that BAK is regulated through activation by BH3-only proteins and sequestered by anti-apoptotic BCL-2 family proteins .	It has been proposed that BAK is regulated through activation by BH3-only proteins and sequestered by anti-apoptotic BCL-2 family proteins.	5	19	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAK	BAK	BAK	17	18	5	6
Western blot analysis of Bcl-2 family members in CEC extracts from TRUC samples across the neoplastic continuum and from RAG2 -/- samples revealed increased anti-apoptotic Bcl-2 in dysplastic samples vs non dysplastic samples and decreased pro apoptotic Bak in samples with high grade dysplasia and cancer ( XREF_FIG ) .	Western blot analysis of Bcl-2 family members in CEC extracts from TRUC samples across the neoplastic continuum and from RAG2 -/- samples revealed increased anti-apoptotic Bcl-2 in dysplastic samples vs non dysplastic samples and decreased pro apoptotic Bak in samples with high grade dysplasia and cancer (XREF_FIG).	4	38	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	4	5	37	38
BAK antagonism by two prosurvival BCL-2 family proteins requires a second type of dBH3 to enable activation .	BAK antagonism by two prosurvival BCL-2 family proteins requires a second type of dBH3 to enable activation.	0	7	antagonism	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAK	BAK	BAK	5	6	0	1
Furthermore , we demonstrated that pBcl-2 antagonised S1 by sequestering the Bak and Bim proteins that were released from Mcl-1 , andpBcl-2 and Bak , pBcl-2 and Bax and pBcl-2 and Bim complexes can not be disrupted by S1 .	Furthermore, we demonstrated that pBcl-2 antagonised S1 by sequestering the Bak and Bim proteins that were released from Mcl-1, andpBcl-2 and Bak, pBcl-2 and Bax and pBcl-2 and Bim complexes can not be disrupted by S1.	5	12	antagonised	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pBcl-2	pBcl-2	pBcl-2	Bak	Bak	Bak	5	6	11	12
Bak is mainly inhibited by the antiapoptotic Bcl-2 family members Bcl-x L and Mcl-1 .	Bak is mainly inhibited by the antiapoptotic Bcl-2 family members Bcl-x L and Mcl-1.	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	7	8	0	1
Moreover , apoptosis induced through a cascade starting with Bcl-2 homologous antagonist and killer ( BAK1 ) and ending with Caspase 12 ( CASP12 ) might be inhibited because BCL2 inhibits BAK1 .	Moreover, apoptosis induced through a cascade starting with Bcl-2 homologous antagonist and killer (BAK1) and ending with Caspase 12 (CASP12) might be inhibited because BCL2 inhibits BAK1.	29	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BAK1	BAK1	BAK1	29	30	31	32
These results demonstrate that pBcl-2 was able to sequester the Bak and Bim proteins released from Mcl-1 and that the movement of proapoptotic proteins from Mcl-1 complexes to pBcl-2 complexes is the mechanism underlying the predictive pBcl-2/( Bcl-2+ Mcl-1 ) ratio .	These results demonstrate that pBcl-2 was able to sequester the Bak and Bim proteins released from Mcl-1 and that the movement of proapoptotic proteins from Mcl-1 complexes to pBcl-2 complexes is the mechanism underlying the predictive pBcl-2/(Bcl-2+ Mcl-1) ratio.	4	13	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pBcl-2	pBcl-2	pBcl-2	Bak	Bak	Bak	4	5	10	11
XREF_BIBR A non mitochondrial pool of Bcl-2 and Bcl-X L inhibits the function of Beclin 1 in autophagosome formation .	XREF_BIBR A non mitochondrial pool of Bcl-2 and Bcl-X L inhibits the function of Beclin 1 in autophagosome formation.	6	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	6	7	14	16
Overexpression of Bcl-2 prevent UA induced autophagy , Beclin-1 upregulation , apoptosis and collagen synthesis inhibition in HSFBs .	Overexpression of Bcl-2 prevent UA induced autophagy, Beclin-1 upregulation, apoptosis and collagen synthesis inhibition in HSFBs.	0	9	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	2	3	8	9
For example , Bcl-2 ( an anti-apoptotic oncogene ) was shown to bind to and inhibit Beclin1 , resulting in the prevention of autophagy XREF_BIBR .	For example, Bcl-2 (an anti-apoptotic oncogene) was shown to bind to and inhibit Beclin1, resulting in the prevention of autophagy XREF_BIBR.	3	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	3	4	16	17
XREF_BIBR , XREF_BIBR Further , it has been suggested that binding of various Bcl-2 homologs may prevent higher order oligomerization of Beclin 1 .	XREF_BIBR, XREF_BIBR Further, it has been suggested that binding of various Bcl-2 homologs may prevent higher order oligomerization of Beclin 1.	13	23	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	13	14	21	23
Bcl-2 could inhibit essential autophagic protein Beclin 1 dependent autophagy through the interaction with Beclin 1 [ XREF_BIBR ] .	Bcl-2 could inhibit essential autophagic protein Beclin 1 dependent autophagy through the interaction with Beclin 1 [XREF_BIBR].	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	0	1	6	8
Conversely , Bcl-2 or Bcl-x L reduces the pro autophagy activity of Beclin1 .	Conversely, Bcl-2 or Bcl-x L reduces the pro autophagy activity of Beclin1.	2	13	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	2	3	12	13
Successful inhibition of Beclin 1 by Bcl-2 also requires nutrient deprivation autophagy factor-1 ( NAF-1 ) , a small integral membrane protein in the ER .	Successful inhibition of Beclin 1 by Bcl-2 also requires nutrient deprivation autophagy factor-1 (NAF-1), a small integral membrane protein in the ER.	1	7	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	6	7	3	5
The interaction of Bcl-2 homologs with the BH3 domain can prevent the release of beclin-1 , thereby inhibiting beclin-1-dependent autophagy .	The interaction of Bcl-2 homologs with the BH3 domain can prevent the release of beclin-1, thereby inhibiting beclin-1-dependent autophagy.	3	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	beclin-1	beclin-1	beclin-1	3	4	14	15
Binding of viral Bcl-2 inhibits macroautophagy by interrupting Beclin-1 incorporation in VPS34 complexes , probably via anchoring Beclin-1 at endoplasmic reticulum membranes [ XREF_BIBR ] .	Binding of viral Bcl-2 inhibits macroautophagy by interrupting Beclin-1 incorporation in VPS34 complexes, probably via anchoring Beclin-1 at endoplasmic reticulum membranes [XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	3	4	8	9
A series of investigations have shown that antiapoptotic Bcl-2 proteins inhibit autophagic function of Beclin 1 through binding to its BH3 domain XREF_BIBR , XREF_BIBR , thereby suggesting that Bcl-2 family members also function as inhibitors for autophagic pathways .	A series of investigations have shown that antiapoptotic Bcl-2 proteins inhibit autophagic function of Beclin 1 through binding to its BH3 domain XREF_BIBR, XREF_BIBR, thereby suggesting that Bcl-2 family members also function as inhibitors for autophagic pathways.	8	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	8	9	14	16
For example , the antiapoptotic protein Bcl-2 inhibits autophagy by binding and sequestering Beclin1 away from the class III PI3K complex and eventually suppresses Beclin1 mediated autophagy [ XREF_BIBR ] .	For example, the antiapoptotic protein Bcl-2 inhibits autophagy by binding and sequestering Beclin1 away from the class III PI3K complex and eventually suppresses Beclin1 mediated autophagy [XREF_BIBR].	3	25	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	6	7	24	25
By interacting with Beclin-1 , Bcl-2 blocks the interaction of Beclin-1 with PI3KIII , decreases PI3KIII activity , and down-regulates autophagy .	By interacting with Beclin-1, Bcl-2 blocks the interaction of Beclin-1 with PI3KIII, decreases PI3KIII activity, and down-regulates autophagy.	5	19	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	5	6	10	11
For example , Bcl-2 functions normally as an anti-apoptotic protein , but is anti-autophagic when it is ER located and inhibits the protein Beclin-1 ( Atg6 ) during autophagosome nucleation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	For example, Bcl-2 functions normally as an anti-apoptotic protein, but is anti-autophagic when it is ER located and inhibits the protein Beclin-1 (Atg6) during autophagosome nucleation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	3	4	23	24
Bcl-2 and Bcl-xL suppress autophagy by binding the protein Beclin-1 ( ATG7 ) [ XREF_BIBR ] , an essential component of the mammalian autophagy system , which marks autophagic vesicles for fusion with lysosomes , followed by digestion and recycling of components .	Bcl-2 and Bcl-xL suppress autophagy by binding the protein Beclin-1 (ATG7) [XREF_BIBR], an essential component of the mammalian autophagy system, which marks autophagic vesicles for fusion with lysosomes, followed by digestion and recycling of components.	0	27	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	0	1	9	10
It has been suggested that Bcl-2 could prevent the oligomerization of Beclin 1 and therefore would hamper the assembly of the active VPS34 complex , which results in a block of autophagy [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It has been suggested that Bcl-2 could prevent the oligomerization of Beclin 1 and therefore would hamper the assembly of the active VPS34 complex, which results in a block of autophagy [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	13	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	5	6	11	13
Notably , Beclin-1 may be bound to or inhibited by Bcl-2 protein in order to prevent cell autophagy [ XREF_BIBR , XREF_BIBR ] .	Notably, Beclin-1 may be bound to or inhibited by Bcl-2 protein in order to prevent cell autophagy [XREF_BIBR, XREF_BIBR].	2	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	10	11	2	3
Together , these findings reveal MK2 and MK3 as crucial stress responsive kinases that promote autophagy through Beclin 1 S90 phosphorylation , and identify the blockade of MK2/3 dependent Beclin 1 S90 phosphorylation as a mechanism by which BCL2 inhibits the autophagy function of Beclin 1 .	Together, these findings reveal MK2 and MK3 as crucial stress responsive kinases that promote autophagy through Beclin 1 S90 phosphorylation, and identify the blockade of MK2/3 dependent Beclin 1 S90 phosphorylation as a mechanism by which BCL2 inhibits the autophagy function of Beclin 1.	38	46	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	Beclin 1	Beclin 1	Beclin 1	38	39	44	46
Pik3c3 interacts with ATG14 , PIK3R4 , and Beclin1 to form complex to serve as regulator XREF_BIBR , while Beclin1 is inhibited by Bcl-2 XREF_BIBR , XREF_BIBR .	Pik3c3 interacts with ATG14, PIK3R4, and Beclin1 to form complex to serve as regulator XREF_BIBR, while Beclin1 is inhibited by Bcl-2 XREF_BIBR, XREF_BIBR.	19	24	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	23	24	19	20
They showed that BCL2 can inhibit starvation induced and Beclin 1 dependent autophagy .	They showed that BCL2 can inhibit starvation induced and Beclin 1 dependent autophagy.	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	Beclin 1	Beclin 1	Beclin 1	3	4	9	11
In such a way , more Beclin 1 is sequestered by Bcl-2 and prevented from association with PI3KCIII to initiate autophagy through the PI3K/Akt/mTOR pathway .	In such a way, more Beclin 1 is sequestered by Bcl-2 and prevented from association with PI3KCIII to initiate autophagy through the PI3K/Akt/mTOR pathway.	5	19	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	11	12	6	8
Beclin 1 is negatively regulated by BCL-2 and BCL-X L at ER membranes .	Beclin 1 is negatively regulated by BCL-2 and BCL-X L at ER membranes.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	Beclin 1	Beclin 1	Beclin 1	6	7	0	2
A recent study showed that the upregulation of Bcl-2 could inhibit the dissociation of Beclin1 from Bcl-2 XREF_BIBR .	A recent study showed that the upregulation of Bcl-2 could inhibit the dissociation of Beclin1 from Bcl-2 XREF_BIBR.	6	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	8	9	14	15
Beclin-1 , the essential mediator of autophagy tested in this study , could also be inhibited by antiapoptotic proteins Bcl-2 or Bcl-xl [ XREF_BIBR , XREF_BIBR ] .	Beclin-1, the essential mediator of autophagy tested in this study, could also be inhibited by antiapoptotic proteins Bcl-2 or Bcl-xl [XREF_BIBR, XREF_BIBR].	0	25	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	19	20	0	1
In normal conditions , Beclin 1 is bound to and inhibited by Bcl-2 or the Bcl-2 homolog Bcl-X L.	In normal conditions, Beclin 1 is bound to and inhibited by Bcl-2 or the Bcl-2 homolog Bcl-X L.	4	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	12	13	4	6
Furthermore , Bcl-2 reduces the pro autophagic activity of Beclin-1 .	Furthermore, Bcl-2 reduces the pro autophagic activity of Beclin-1.	2	10	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	2	3	9	10
While Bcl-2 inhibits the autophagic function of Beclin 1 , disruption of the Beclin 1/Bcl -2 complex by mutation of the BH3-only domain within Beclin 1 leads to the stimulation of autophagy [ XREF_BIBR , XREF_BIBR ] .	While Bcl-2 inhibits the autophagic function of Beclin 1, disruption of the Beclin 1/Bcl -2 complex by mutation of the BH3-only domain within Beclin 1 leads to the stimulation of autophagy [XREF_BIBR, XREF_BIBR].	1	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	1	2	7	9
However , BCL2 can sequester BECN1 and GRP78 mediated changes in BCL2 expression could indirectly regulate autophagy .	However, BCL2 can sequester BECN1 and GRP78 mediated changes in BCL2 expression could indirectly regulate autophagy.	2	8	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BECN1	BECN1	BECN1	2	3	5	6
Both galectin-3 and Beclin1 can transport to nuclei XREF_BIBR , XREF_BIBR , reach the Golgi organelle XREF_BIBR and interact with Bcl-2 XREF_BIBR and are inhibited by Bcl-2 XREF_BIBR , XREF_BIBR .	Both galectin-3 and Beclin1 can transport to nuclei XREF_BIBR, XREF_BIBR, reach the Golgi organelle XREF_BIBR and interact with Bcl-2 XREF_BIBR and are inhibited by Bcl-2 XREF_BIBR, XREF_BIBR.	1	27	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	26	27	3	4
Under the condition of nutrient deficiency in the cell , Bcl-2 can inhibit Beclin1 to decrease the level of autophagy , and reduce ischemic cell death and injury of brain tissue caused by hypoxia .	Under the condition of nutrient deficiency in the cell, Bcl-2 can inhibit Beclin1 to decrease the level of autophagy, and reduce ischemic cell death and injury of brain tissue caused by hypoxia.	10	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	10	11	13	14
Interestingly , interaction of Bcl-2 with Beclin-1 through BH-3 domain impedes autophagy inducing activity of Beclin-1 by interfering with the formation of the Beclin-1 and Vps34 complex .	Interestingly, interaction of Bcl-2 with Beclin-1 through BH-3 domain impedes autophagy inducing activity of Beclin-1 by interfering with the formation of the Beclin-1 and Vps34 complex.	2	16	impedes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	4	5	15	16
Accordingly , JNK activation induced phosphorylation of Bcl-2 and prevented the formation of Bcl-2 and Beclin 1 autophagy suppressor complexes .	Accordingly, JNK activation induced phosphorylation of Bcl-2 and prevented the formation of Bcl-2 and Beclin 1 autophagy suppressor complexes.	2	17	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	JNK activation induced phosphorylation of Bcl-2	bcl-2	Beclin 1	Beclin 1	beclin 1	7	8	15	17
Several studies have demonstrated that Bcl-2 , an antiapoptotic protein , inhibits beclin-1 via direct binding .	Several studies have demonstrated that Bcl-2, an antiapoptotic protein, inhibits beclin-1 via direct binding.	5	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	beclin-1	beclin-1	beclin-1	5	6	12	13
Since , Bcl-2 can negatively regulate autophagy by forming complexes with Beclin 1 [ XREF_BIBR , XREF_BIBR ] , the loss of Bcl-2 might help promote autophagy at higher selection doses by promoting Beclin 1 dependent autophagy .	Since, Bcl-2 can negatively regulate autophagy by forming complexes with Beclin 1 [XREF_BIBR, XREF_BIBR], the loss of Bcl-2 might help promote autophagy at higher selection doses by promoting Beclin 1 dependent autophagy.	20	36	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	loss of Bcl-2	bcl-2	Beclin 1	Beclin 1	beclin 1	22	23	33	35
Bcl-2 protein interacts with Beclin 1 protein which is an autophagy factor , and Bcl-2 reduction causes Beclin 1 to release , which triggers autophagy .	Bcl-2 protein interacts with Beclin 1 protein which is an autophagy factor, and Bcl-2 reduction causes Beclin 1 to release, which triggers autophagy.	14	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	14	15	17	19
The phosphorylation of Bcl-2 by the stress activated c-Jun N-terminal protein kinase 1 ( JNK1 ) also relieves Beclin 1 from its functional inhibition .	The phosphorylation of Bcl-2 by the stress activated c-Jun N-terminal protein kinase 1 (JNK1) also relieves Beclin 1 from its functional inhibition.	1	23	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	phosphorylation of Bcl-2	bcl-2	Beclin 1	Beclin 1	beclin 1	3	4	18	20
XREF_BIBR However , BCL2 anti-apoptotic protein inhibits BECN1 dependent autophagy .	XREF_BIBR However, BCL2 anti-apoptotic protein inhibits BECN1 dependent autophagy.	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BECN1	BECN1	BECN1	3	4	7	8
[ XREF_BIBR , XREF_BIBR ] mTOR is known to suppress ULK1 , and BCL-2 is known to suppress Beclin-1 .	[XREF_BIBR, XREF_BIBR] mTOR is known to suppress ULK1, and BCL-2 is known to suppress Beclin-1.	13	19	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	Beclin-1	Beclin-1	Beclin-1	13	14	18	19
Beclin-1 autophagy induction pathway is regarded as deleterious during IR injury , and can not be suppressed by Bcl-2 .	Beclin-1 autophagy induction pathway is regarded as deleterious during IR injury, and can not be suppressed by Bcl-2.	0	19	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	18	19	0	1
Meanwhile , the BH3 domain of Beclin-1 interacts with certain anti-apoptotic B cell lymphoma 2 ( Bcl-2 ) family members , including Bcl-2 or Bcl-xL ; Bcl-2 was shown to inhibit the autophagic function of Beclin-1 .	Meanwhile, the BH3 domain of Beclin-1 interacts with certain anti-apoptotic B cell lymphoma 2 (Bcl-2) family members, including Bcl-2 or Bcl-xL; Bcl-2 was shown to inhibit the autophagic function of Beclin-1.	26	36	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	26	27	35	36
KSHV BCL-2 was shown to block Beclin 1 dependent autophagy in both yeast and mammalian cells [ XREF_BIBR ] .	KSHV BCL-2 was shown to block Beclin 1 dependent autophagy in both yeast and mammalian cells [XREF_BIBR].	0	9	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	Beclin 1	Beclin 1	Beclin 1	1	2	6	8
XREF_BIBR As one of the key regulators of apoptosis and autophagy , Bcl-2 protein possesses four conserved Bcl-2 homology domains ( BH1-4 ) and can inhibit Beclin1 dependent autophagy by binding to Beclin1 under starvation conditions .	XREF_BIBR As one of the key regulators of apoptosis and autophagy, Bcl-2 protein possesses four conserved Bcl-2 homology domains (BH1-4) and can inhibit Beclin1 dependent autophagy by binding to Beclin1 under starvation conditions.	12	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	12	13	26	27
Beclin-1 can be sequestered by the anti-apoptotic Bcl-2 protein , the interaction is also under the control of post-translational modification of both Bcl-2 and Beclin-1 , or their binding to other regulatory proteins XREF_BIBR , XREF_BIBR , XREF_BIBR .	Beclin-1 can be sequestered by the anti-apoptotic Bcl-2 protein, the interaction is also under the control of post-translational modification of both Bcl-2 and Beclin-1, or their binding to other regulatory proteins XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	8	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	7	8	0	1
It has also been proposed that viral Bcl-2 proteins may inhibit Beclin 1 mediated tumor suppression , and so the inhibition of autophagy might promote oncogenic events [ XREF_BIBR ] .	It has also been proposed that viral Bcl-2 proteins may inhibit Beclin 1 mediated tumor suppression, and so the inhibition of autophagy might promote oncogenic events [XREF_BIBR].	7	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	7	8	11	13
Given that ER localized Bcl-2 is the form that inhibits Beclin 1 autophagy function , and the recent finding that preautophagosomal structures originate from the ER membrane , it is possible that Bcl-2 sequesters Beclin 1 in ER membrane subdomains away from preautophagosomal structures in the ER .	Given that ER localized Bcl-2 is the form that inhibits Beclin 1 autophagy function, and the recent finding that preautophagosomal structures originate from the ER membrane, it is possible that Bcl-2 sequesters Beclin 1 in ER membrane subdomains away from preautophagosomal structures in the ER.	32	39	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	32	33	34	36
In addition , Bcl-2 has been shown to inhibit Beclin 1 mediated autophagic death induced by nutrient starvation in cultured cells .	In addition, Bcl-2 has been shown to inhibit Beclin 1 mediated autophagic death induced by nutrient starvation in cultured cells.	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	3	4	9	11
At the high Chal-24 concentrations , the JNK mediated Bcl-2 and Bcl-xL phosphorylation pathway that disrupts the Beclin1 and Bcl -2 and Belin1 and Bcl-xL complexes is required for autophagy , and the ERK- and autophagy mediated degradation of IAPs promotes Ripoptosome formation .	At the high Chal-24 concentrations, the JNK mediated Bcl-2 and Bcl-xL phosphorylation pathway that disrupts the Beclin1 and Bcl -2 and Belin1 and Bcl-xL complexes is required for autophagy, and the ERK- and autophagy mediated degradation of IAPs promotes Ripoptosome formation.	7	19	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	JNK mediated Bcl-2	bcl-2	Beclin1	Beclin1	beclin1	9	10	17	18
Hence free BECLIN 1 , which is preferentially sequestered by BCL2 [ XREF_BIBR ] , was then sufficient to promote autophagy without leading to additional production of BECLIN 1 protein in Afatinib treated NB cells .	Hence free BECLIN 1, which is preferentially sequestered by BCL2 [XREF_BIBR], was then sufficient to promote autophagy without leading to additional production of BECLIN 1 protein in Afatinib treated NB cells.	1	19	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BECLIN 1	BECLIN 1	BECLIN 1	10	11	2	4
Bcl-2 binds directly to a BH3 domain in beclin-1 , inhibiting beclin-1 and consequently autophagy .	Bcl-2 binds directly to a BH3 domain in beclin-1, inhibiting beclin-1 and consequently autophagy.	0	14	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	beclin-1	beclin-1	beclin-1	0	1	11	12
The antiapoptotic protein Bcl2 also prevents autophagy by sequestering Beclin 1 ( see Box 1 ) .	The antiapoptotic protein Bcl2 also prevents autophagy by sequestering Beclin 1 (see Box 1).	0	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Beclin 1	Beclin 1	Beclin 1	3	4	9	11
Recently , Bcl-2 has also been shown to inhibit autophagy by antagonizing the BH3-only protein Beclin1 , an essential inducer of autophagy .	Recently, Bcl-2 has also been shown to inhibit autophagy by antagonizing the BH3-only protein Beclin1, an essential inducer of autophagy.	2	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	2	3	15	16
The autophagy and cell death induced by NRG can be blocked by JNK inhibition , Bcl-2 overexpression , Beclin 1 downregulation and NAC , indicating the requirement of JNK , Beclin 1 and ROS for the process .	The autophagy and cell death induced by NRG can be blocked by JNK inhibition, Bcl-2 overexpression, Beclin 1 downregulation and NAC, indicating the requirement of JNK, Beclin 1 and ROS for the process.	10	32	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	Beclin 1	Beclin 1	beclin 1	15	16	30	32
Interestingly , it has been demonstrated that Bcl-2 and Bcl- XL reduce the pro autophagic activity of Beclin 1 XREF_BIBR ; XREF_BIBR .	Interestingly, it has been demonstrated that Bcl-2 and Bcl- XL reduce the pro autophagic activity of Beclin 1 XREF_BIBR; XREF_BIBR.	7	19	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	7	8	17	19
Binding of these Bcl-2 family proteins to Beclin 1 inhibits autophagy by altering the association of Beclin 1 and Class III phosphatidylinositol 3-kinase ( PI3K ) complexes .	Binding of these Bcl-2 family proteins to Beclin 1 inhibits autophagy by altering the association of Beclin 1 and Class III phosphatidylinositol 3-kinase (PI3K) complexes.	3	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	3	4	16	18
Under normal conditions , Bcl-2 inhibits Beclin 1 , whereas under conditions of stress , Beclin 1 dissociates from Bcl-2 , allowing the activation of Vps34 and the subsequent stimulation of autophagy .	Under normal conditions, Bcl-2 inhibits Beclin 1, whereas under conditions of stress, Beclin 1 dissociates from Bcl-2, allowing the activation of Vps34 and the subsequent stimulation of autophagy.	4	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	4	5	6	8
The anti-apoptotic Bcl-2 homologs , Bcl-2 and Bcl-xL , can downregulate autophagy by interacting with the Beclin 1/class III PI3K complex , and sequestering Beclin 1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The anti-apoptotic Bcl-2 homologs, Bcl-2 and Bcl-xL, can downregulate autophagy by interacting with the Beclin 1/class III PI3K complex, and sequestering Beclin 1 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	31	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	2	3	24	26
The Beclin 1 complex is negatively regulated by the Class I PI3K and Akt pathway , as well by anti-apoptotic Bcl-2 family proteins .	The Beclin 1 complex is negatively regulated by the Class I PI3K and Akt pathway, as well by anti-apoptotic Bcl-2 family proteins.	1	22	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	20	21	1	3
In fact , it is reported in the literature that Beclin-1 is inhibited by Bcl-2 43 and , in turn , Bcl-2 is associated with and inhibited by Bnip3 .	In fact, it is reported in the literature that Beclin-1 is inhibited by Bcl-2 43 and, in turn, Bcl-2 is associated with and inhibited by Bnip3.	10	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	14	15	10	11
Studies have indicated that Bcl-2 as well as viruses can inhibit Beclin1 dependent autophagy in yeast and mammalian cells [ XREF_BIBR ] .	Studies have indicated that Bcl-2 as well as viruses can inhibit Beclin1 dependent autophagy in yeast and mammalian cells [XREF_BIBR].	4	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	4	5	11	12
Bcl2 can block the positive effects of Beclin1 for induction of canonical autophagy , whereas under its overexpression autophagy can be triggered via different non canonical pathways .	Bcl2 can block the positive effects of Beclin1 for induction of canonical autophagy, whereas under its overexpression autophagy can be triggered via different non canonical pathways.	0	8	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Beclin1	Beclin1	Beclin1	0	1	7	8
It was observed on Western blotting that the overexpression of Bcl-2 suppressed the induction of Beclin-1 and LC3 conversion in response to As 4 O 6 , with the suppression of As 4 O 6 -induced caspase-3 activation and PARP cleavages .	It was observed on Western blotting that the overexpression of Bcl-2 suppressed the induction of Beclin-1 and LC3 conversion in response to As 4 O 6, with the suppression of As 4 O 6 -induced caspase-3 activation and PARP cleavages.	8	18	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	10	11	15	16
While Beclin 1 is a key initiator of the functional formation of autophagosomes in mammals and may be induced by IFN-gamma to activate autophagy , the BCL2 antiapoptotic protein inhibits autophagy by binding and sequestering Beclin 1 from the class III PIK3 complex .	While Beclin 1 is a key initiator of the functional formation of autophagosomes in mammals and may be induced by IFN-gamma to activate autophagy, the BCL2 antiapoptotic protein inhibits autophagy by binding and sequestering Beclin 1 from the class III PIK3 complex.	26	37	sequestering	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	Beclin 1	Beclin 1	Beclin 1	26	27	35	37
During nutrient rich conditions , BCL2 directly inhibits autophagy by binding to and preventing BECN1 from associating with the PtdIns3K complex [ XREF_BIBR , XREF_BIBR ] .	During nutrient rich conditions, BCL2 directly inhibits autophagy by binding to and preventing BECN1 from associating with the PtdIns3K complex [XREF_BIBR, XREF_BIBR].	5	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BECN1	BECN1	BECN1	5	6	14	15
Here we will focus on Bcl-2 , an oncogene which negatively regulates Beclin 1 , PI3KIII , and Vps34 complex and autophagy .	Here we will focus on Bcl-2, an oncogene which negatively regulates Beclin 1, PI3KIII, and Vps34 complex and autophagy.	3	21	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	5	6	12	14
First , Bcl-2 can prevent Beclin-1 from binding to PI3KCIII ( class III PI3K ) and then inhibit autophagy initiation through the PI3K/AKT/mTOR pathway XREF_BIBR XREF_BIBR .	First, Bcl-2 can prevent Beclin-1 from binding to PI3KCIII (class III PI3K) and then inhibit autophagy initiation through the PI3K/AKT/mTOR pathway XREF_BIBR XREF_BIBR.	2	17	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	2	3	5	6
These include genes such as ULK2 , which has been shown to be necessary for proper autophagy induction in mammals ; BCL2 , which inhibits Beclin1 dependent autophagy ; and ADNP , which encodes a binding partner of LC3 , a critical component of the autophagosome .	These include genes such as ULK2, which has been shown to be necessary for proper autophagy induction in mammals; BCL2, which inhibits Beclin1 dependent autophagy; and ADNP, which encodes a binding partner of LC3, a critical component of the autophagosome.	1	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	Beclin1	Beclin1	Beclin1	21	22	25	26
In addition , the binding of Bcl-2 antiapoptotic protein to Beclin 1 disrupts the association of Beclin 1 with hVPS34 , leading to the inhibition of autophagy [ XREF_BIBR ] .	In addition, the binding of Bcl-2 antiapoptotic protein to Beclin 1 disrupts the association of Beclin 1 with hVPS34, leading to the inhibition of autophagy [XREF_BIBR].	6	18	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	6	7	16	18
XREF_BIBR Whereas BCL2 inhibits BECLIN 1 when localized to the ER , AMBRA1 binds preferentially and dynamically to the mitochondrial pool of BCL2 .	XREF_BIBR Whereas BCL2 inhibits BECLIN 1 when localized to the ER, AMBRA1 binds preferentially and dynamically to the mitochondrial pool of BCL2.	2	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BECLIN 1	BECLIN 1	BECLIN 1	2	3	4	6
In addition to regulation of mTORC1 , Bnip3 and Bnip3L ( NIX ) have been described to inhibit binding of Bcl-2 to Beclin1 , releasing the Bcl-2 dependent inhibition of Beclin1 , to drive autophagy [ XREF_BIBR ] .	In addition to regulation of mTORC1, Bnip3 and Bnip3L (NIX) have been described to inhibit binding of Bcl-2 to Beclin1, releasing the Bcl-2 dependent inhibition of Beclin1, to drive autophagy [XREF_BIBR].	26	31	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	26	27	30	31
Bcl-2 inhibits Beclin1 dependent autophagy .	Bcl-2 inhibits Beclin1 dependent autophagy.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	0	1	2	3
By interaction with Beclin-1 , Bcl-2 can block Beclin-1 interacting with class III PI-3K and decrease class III PI-3K activity , thereby negatively regulating autophagy [ XREF_BIBR ] .	By interaction with Beclin-1, Bcl-2 can block Beclin-1 interacting with class III PI-3K and decrease class III PI-3K activity, thereby negatively regulating autophagy [XREF_BIBR].	5	15	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	5	6	8	9
In previous study , Bcl2 could inhibit Beclin1 dependent autophagy in human breast carcinoma cells XREF_BIBR .	In previous study, Bcl2 could inhibit Beclin1 dependent autophagy in human breast carcinoma cells XREF_BIBR.	4	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Beclin1	Beclin1	Beclin1	4	5	7	8
Bcl-2 has a controlling function for both apoptosis and autophagy and inhibits Beclin-1 .	Bcl-2 has a controlling function for both apoptosis and autophagy and inhibits Beclin-1.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	0	1	12	13
To date , different models have been brought up to explain the direct BCL2 dependent inhibition of Beclin 1 [ XREF_BIBR ] .	To date, different models have been brought up to explain the direct BCL2 dependent inhibition of Beclin 1 [XREF_BIBR].	13	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	Beclin 1	Beclin 1	Beclin 1	13	14	17	19
The JNK1 signaling pathway is associated with Bcl-2 phosphorylation , which leads to disruption of the Bcl-2 and Beclin1 complex and activation of Bcl-2 inhibition of Beclin1 dependent autophagy .	The JNK1 signaling pathway is associated with Bcl-2 phosphorylation, which leads to disruption of the Bcl-2 and Beclin1 complex and activation of Bcl-2 inhibition of Beclin1 dependent autophagy.	23	28	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	23	24	26	27
Although the significance of viral Bcl-2 inhibition of Beclin 1 function in viral replication and/or pathogenesis is not yet known , two lines of biochemical evidence suggest that viral Bcl-2 family members may have evolved to be more potent inhibitors of autophagy than their cellular counterparts .	Although the significance of viral Bcl-2 inhibition of Beclin 1 function in viral replication and/or pathogenesis is not yet known, two lines of biochemical evidence suggest that viral Bcl-2 family members may have evolved to be more potent inhibitors of autophagy than their cellular counterparts.	5	10	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	5	6	8	10
Our data uncover a previously undescribed mechanism by which BCL2 inhibits the autophagy function of Beclin 1 .	Our data uncover a previously undescribed mechanism by which BCL2 inhibits the autophagy function of Beclin 1.	9	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	Beclin 1	Beclin 1	Beclin 1	9	10	15	17
25 Besides , oncogenic Ras can induce autophagy , which is associated with Beclin-1 and ATG6 , whereas the co-expression of Bcl-2 family members can inhibit Beclin-1 .	25 Besides, oncogenic Ras can induce autophagy, which is associated with Beclin-1 and ATG6, whereas the co-expression of Bcl-2 family members can inhibit Beclin-1.	19	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	co-expression of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	21	22	26	27
Using a more specific autophagy deficient mouse model containing non phosphorylatable mutations in the autophagy inhibitor BCL-2 ( BCL-2 AAA ) , which constitutively inhibits the autophagy protein Becn1 and impairs induction of autophagy by exercise , we demonstrated that exercise mediates metabolic benefits through autophagy stimulation .	Using a more specific autophagy deficient mouse model containing non phosphorylatable mutations in the autophagy inhibitor BCL-2 (BCL-2 AAA), which constitutively inhibits the autophagy protein Becn1 and impairs induction of autophagy by exercise, we demonstrated that exercise mediates metabolic benefits through autophagy stimulation.	8	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	Becn1	Becn1	Becn1	16	17	28	29
Moreover , Bcl-2 and Bcl-xL suppress autophagy by binding to the BH3 domain ( amino acids 114-223 ) of the Beclin-1 protein and sequestering Beclin-1 from hVps34 , which is a significant regulator in the initial steps of autophagy , indicating that Bcl-2 and Bcl-xL play essential roles in the crosstalk between autophagy and apoptosis [ XREF_BIBR ] .	Moreover, Bcl-2 and Bcl-xL suppress autophagy by binding to the BH3 domain (amino acids 114-223) of the Beclin-1 protein and sequestering Beclin-1 from hVps34, which is a significant regulator in the initial steps of autophagy, indicating that Bcl-2 and Bcl-xL play essential roles in the crosstalk between autophagy and apoptosis [XREF_BIBR].	2	25	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	2	3	24	25
BCL2 inhibition of BECN1 is evident in the EnR but not when this interaction occurs at mitochondria .	BCL2 inhibition of BECN1 is evident in the EnR but not when this interaction occurs at mitochondria.	0	4	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BECN1	BECN1	BECN1	0	1	3	4
The apparent ability of BCL2 to sequester AMBRA1 at mitochondria can prevent formation of the beclin-1 complex at the EnR , whereas BCL2 can not bind AMBRA1 when they are localized in the EnR .	The apparent ability of BCL2 to sequester AMBRA1 at mitochondria can prevent formation of the beclin-1 complex at the EnR, whereas BCL2 can not bind AMBRA1 when they are localized in the EnR.	2	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	beclin-1	beclin-1	beclin-1	4	5	15	16
Of note , in the Conserved network , Becn1 localized to the same MCL cluster as Bcl-2 , which is known to inhibit Becn1 depended autophagy [ XREF_BIBR ] .	Of note, in the Conserved network, Becn1 localized to the same MCL cluster as Bcl-2, which is known to inhibit Becn1 depended autophagy [XREF_BIBR].	16	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Becn1	Becn1	Becn1	16	17	23	24
Therefore , we hypothesized that overexpression of Bcl-2 attenuates the formation of the kinase complex Beclin-1 and class III phosphatidylinositol 3-kinase ( PI3KC3 ) which is essential for the formation of autophagosomes [ XREF_BIBR , XREF_BIBR ] .	Therefore, we hypothesized that overexpression of Bcl-2 attenuates the formation of the kinase complex Beclin-1 and class III phosphatidylinositol 3-kinase (PI3KC3) which is essential for the formation of autophagosomes [XREF_BIBR, XREF_BIBR].	5	20	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	7	8	15	16
Using Western blotting , we observed that allicin decreased the level of cytoplasmic p53 , the PI3K and mTOR signaling pathway , and the level of Bcl-2 and increased the expression of AMPK and TSC2 and Beclin-1 signaling pathways in Hep G2 cells .	Using Western blotting, we observed that allicin decreased the level of cytoplasmic p53, the PI3K and mTOR signaling pathway, and the level of Bcl-2 and increased the expression of AMPK and TSC2 and Beclin-1 signaling pathways in Hep G2 cells.	7	38	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	allicin decreased the level of cytoplasmic p53, the PI3K and mTOR signaling pathway, and the level of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	26	27	36	37
On the other hand , Bcl-2 inhibition might then be able to cause Beclin-1 upregulation and cell autophagy [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	On the other hand, Bcl-2 inhibition might then be able to cause Beclin-1 upregulation and cell autophagy [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	14	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	5	6	13	14
Of note , Bcl-2 binds to and inhibits BH3 domain of Beclin-1 that is crucial for autophagic process 22 , 41 .	Of note, Bcl-2 binds to and inhibits BH3 domain of Beclin-1 that is crucial for autophagic process 22, 41.	3	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	3	4	11	12
Beclin-1 is sequestered in the cell by Bcl-2 during non starvation conditions , and can also interact with , and be inhibited by , other anti-apoptotic members of the Bcl-2 family through its BH3 domain .	Beclin-1 is sequestered in the cell by Bcl-2 during non starvation conditions, and can also interact with, and be inhibited by, other anti-apoptotic members of the Bcl-2 family through its BH3 domain.	0	16	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	7	8	0	1
Bcl-2 is reported to decrease the pro autophagic property of Beclin-1 , but Beclin-1 unable to neutralize the apoptotic function of Bcl-2 14 .	Bcl-2 is reported to decrease the pro autophagic property of Beclin-1, but Beclin-1 unable to neutralize the apoptotic function of Bcl-2 14.	0	16	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	0	1	10	11
In addition to regulation of autophagy through the p27 controlled LKB1/AMPK/mTOR pathway , Bcl-2 sequesters Beclin 1 so fewer Beclin 1 molecules bind to Vps34 ( vacuolar protein sorting 34 ) PI3K ( or PI3KCIII in mammalian cells ) to form autophagy inducing complexes [ XREF_BIBR ] .	In addition to regulation of autophagy through the p27 controlled LKB1/AMPK/mTOR pathway, Bcl-2 sequesters Beclin 1 so fewer Beclin 1 molecules bind to Vps34 (vacuolar protein sorting 34) PI3K (or PI3KCIII in mammalian cells) to form autophagy inducing complexes [XREF_BIBR].	13	25	sequesters	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Bcl-2	Bcl-2	bcl-2	Beclin 1	Beclin 1 so fewer Beclin 1 molecules bind to Vps34	beclin 1	13	14	15	17
BCL-2 and BCL2L1 were proved to inhibit autophagy by binding Beclin 1 at the BH3 domain site .	BCL-2 and BCL2L1 were proved to inhibit autophagy by binding Beclin 1 at the BH3 domain site.	0	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	Beclin 1	Beclin 1	Beclin 1	0	1	10	12
Under stress conditions , Beclin 1 , which is normally sequestered by Bcl-2 , is released to induce autophagy .	Under stress conditions, Beclin 1, which is normally sequestered by Bcl-2, is released to induce autophagy.	4	17	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	12	13	4	6
Since the anti-apoptotic protein Bcl-2 inhibits the function of Beclin 1 in the early stages of autophagy [ XREF_BIBR ] , the dissociation of the Beclin-1 and Bcl-2 complex is required for induction of autophagy .	Since the anti-apoptotic protein Bcl-2 inhibits the function of Beclin 1 in the early stages of autophagy [XREF_BIBR], the dissociation of the Beclin-1 and Bcl-2 complex is required for induction of autophagy.	1	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	4	5	9	11
Under nutrient rich conditions , ER associated Bcl-2 and Beclin 1 interact to sequester Beclin 1 from the autophagy complex XREF_BIBR , XREF_BIBR .	Under nutrient rich conditions, ER associated Bcl-2 and Beclin 1 interact to sequester Beclin 1 from the autophagy complex XREF_BIBR, XREF_BIBR.	5	16	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	7	8	14	16
XREF_BIBR As Beclin 1 is a tumor suppressor gene , XREF_BIBR it will be important to determine whether viral Bcl-2 antagonism of Beclin 1 function contributes to the oncogenic potential of the gamma-herpesviruses .	XREF_BIBR As Beclin 1 is a tumor suppressor gene, XREF_BIBR it will be important to determine whether viral Bcl-2 antagonism of Beclin 1 function contributes to the oncogenic potential of the gamma-herpesviruses.	19	24	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	19	20	22	24
Bcl-2 negatively regulates Beclin 1 by sequestering it away from its VPS34 kinase complex partners and thereby preventing autophagy [ XREF_BIBR ] .	Bcl-2 negatively regulates Beclin 1 by sequestering it away from its VPS34 kinase complex partners and thereby preventing autophagy [XREF_BIBR].	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	0	1	3	5
Several anti-apoptotic BCL2 family members inhibit the activity of BECN1 XREF_BIBR , a key regulator of autophagy XREF_BIBR that binds to PIK3C3 to facilitate autophagosome production XREF_BIBR .	Several anti-apoptotic BCL2 family members inhibit the activity of BECN1 XREF_BIBR, a key regulator of autophagy XREF_BIBR that binds to PIK3C3 to facilitate autophagosome production XREF_BIBR.	2	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BECN1	BECN1	BECN1	2	3	9	10
Both BCL-2 and BCL-XL inhibit beclin 1 dependent macroautophagy by sequestering beclin 1 away from the autophagy nucleation complex .	Both BCL-2 and BCL-XL inhibit beclin 1 dependent macroautophagy by sequestering beclin 1 away from the autophagy nucleation complex.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	beclin 1	beclin 1	beclin 1	1	2	11	13
Bcl-2 was suggested to inhibit Beclin1 dependent macroautophagy .	Bcl-2 was suggested to inhibit Beclin1 dependent macroautophagy.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	0	1	5	6
We recently showed that Bcl-2 negatively regulates Beclin 1 dependent autophagy and Beclin 1 dependent autophagic cell death .	We recently showed that Bcl-2 negatively regulates Beclin 1 dependent autophagy and Beclin 1 dependent autophagic cell death.	4	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	4	5	7	9
We thus propose that Bcl-2 antagonizes Beclin1 in an antiapoptosis independent manner .	We thus propose that Bcl-2 antagonizes Beclin1 in an antiapoptosis independent manner.	4	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin1	Beclin1	Beclin1	4	5	6	7
Beclin-1 and Bcl-2 family members represent the best example : Bcl-2 and Bcl-XL inhibit Beclin-1 by binding to it through the Beclin-1 BH3 domain .	Beclin-1 and Bcl-2 family members represent the best example : Bcl-2 and Bcl-XL inhibit Beclin-1 by binding to it through the Beclin-1 BH3 domain.	10	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	10	11	14	15
Bcl-2 and Bcl-X L can inhibit autophagy by sequestering Beclin-1 , whereas BH3-only proteins can induce autophagy by competitively disrupting the interaction between Beclin-1 and Bcl-2 and Bcl-X L.	Bcl-2 and Bcl-X L can inhibit autophagy by sequestering Beclin-1, whereas BH3-only proteins can induce autophagy by competitively disrupting the interaction between Beclin-1 and Bcl-2 and Bcl-X L.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	0	1	9	10
It has been shown that Beclin-1 can not neutralize the Bcl-2 function , but Bcl-2 family proteins suppress the pro autophagic function of Beclin-1 14 .	It has been shown that Beclin-1 can not neutralize the Bcl-2 function, but Bcl-2 family proteins suppress the pro autophagic function of Beclin-1 14.	14	24	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	14	15	23	24
Binding of Bcl-2 family proteins to Beclin 1 inhibits autophagy by preventing the association of Beclin 1 with the class III PI3K complex [ XREF_BIBR - XREF_BIBR ] .	Binding of Bcl-2 family proteins to Beclin 1 inhibits autophagy by preventing the association of Beclin 1 with the class III PI3K complex [XREF_BIBR - XREF_BIBR].	2	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	2	3	15	17
BCL2 inhibits MK2 dependent in vitro phosphorylation of Beclin 1 S90 in a dose dependent manner ; BCL2 binding to Beclin 1 in cultured cells prevents starvation and active MK2 dependent Beclin 1 S90 phosphorylation ; and Bcl2 AAA mice have deficient starvation induced Beclin 1 S90 phosphorylation despite starvation induced activation ( phosphorylation ) of MK2 .	BCL2 inhibits MK2 dependent in vitro phosphorylation of Beclin 1 S90 in a dose dependent manner; BCL2 binding to Beclin 1 in cultured cells prevents starvation and active MK2 dependent Beclin 1 S90 phosphorylation; and Bcl2 AAA mice have deficient starvation induced Beclin 1 S90 phosphorylation despite starvation induced activation (phosphorylation) of MK2.	0	50	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	Beclin 1	Beclin 1	Beclin 1	0	1	44	46
Beclin-1 may bind to and be inhibited by Bcl-2 protein to prevent cell autophagy [ XREF_BIBR , XREF_BIBR ] .	Beclin-1 may bind to and be inhibited by Bcl-2 protein to prevent cell autophagy [XREF_BIBR, XREF_BIBR].	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	8	9	0	1
This study proposed that the oligomerized Beclin 1 , which can be disrupted by vBcl-2 ( M11 ) , provides a platform for the assembly of other Beclin 1 binding partners and the coordination of their functions in autophagy 35 .	This study proposed that the oligomerized Beclin 1, which can be disrupted by vBcl-2 (M11), provides a platform for the assembly of other Beclin 1 binding partners and the coordination of their functions in autophagy 35.	4	19	disrupted	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	vBcl-2	vBcl-2	vBcl-2	Beclin 1	Beclin 1	Beclin 1	14	15	6	8
Binding of Bcl-2 family proteins to Beclin 1 inhibits autophagy by preventing the association of Beclin 1 with the class III PI3K complex .	Binding of Bcl-2 family proteins to Beclin 1 inhibits autophagy by preventing the association of Beclin 1 with the class III PI3K complex.	2	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	2	3	15	17
Modifiers of Beclin-1 activity can alter tumourigenic potential ; positive regulators of Beclin-1 , including UVRAG ( UV radiation associated gene ) and Bif , display tumour suppressor properties [ XREF_BIBR , XREF_BIBR ] , while Beclin-1 function is inhibited by Bcl-2 [ XREF_BIBR ] , a known oncogene .	Modifiers of Beclin-1 activity can alter tumourigenic potential; positive regulators of Beclin-1, including UVRAG (UV radiation associated gene) and Bif, display tumour suppressor properties [XREF_BIBR, XREF_BIBR], while Beclin-1 function is inhibited by Bcl-2 [XREF_BIBR], a known oncogene.	36	43	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	41	42	36	37
Anti-apoptotic Bcl-2 proteins are known to inhibit autophagy by sequestering Beclin 1 thereby inhibiting its pro autophagic actions .	Anti-apoptotic Bcl-2 proteins are known to inhibit autophagy by sequestering Beclin 1 thereby inhibiting its pro autophagic actions.	1	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	1	2	10	12
The protein , which is localized in both ER XREF_BIBR and in mitochondria XREF_BIBR , has been functionally implicated in cell autophagy , possibly as a mediator of Bcl-2 antagonism of Beclin-1 dependent autophagy on the surface of the ER XREF_BIBR .	The protein, which is localized in both ER XREF_BIBR and in mitochondria XREF_BIBR, has been functionally implicated in cell autophagy, possibly as a mediator of Bcl-2 antagonism of Beclin-1 dependent autophagy on the surface of the ER XREF_BIBR.	28	33	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	28	29	31	32
Beclin-1 in human ovarian surface epithelial cells with induced expression of H-Ras , for instance , can be inhibited by Bcl-2 , Bcl-xl , and Mcl-1 .	Beclin-1 in human ovarian surface epithelial cells with induced expression of H-Ras, for instance, can be inhibited by Bcl-2, Bcl-xl, and Mcl-1.	0	25	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	20	21	0	1
Beclin 1 independent mitophagy would no longer be negatively regulated by Bcl2 or rubicon , and thus , is more likely to allow a harmful level of autophagy activation .	Beclin 1 independent mitophagy would no longer be negatively regulated by Bcl2 or rubicon, and thus, is more likely to allow a harmful level of autophagy activation.	0	22	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Beclin 1	Beclin 1	Beclin 1	11	12	0	2
Bcl-2 can inhibit BECN1 activity for autophagy induction .	Bcl-2 can inhibit BECN1 activity for autophagy induction.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	BECN1	BECN1	BECN1	0	1	3	4
Furthermore , both Beclin 1 and Bif-1 can form homo-oligomers , and the binding of Bcl-2 homologs may also prevent higher-order oligomerization of Beclin 1 .	Furthermore, both Beclin 1 and Bif-1 can form homo-oligomers, and the binding of Bcl-2 homologs may also prevent higher-order oligomerization of Beclin 1.	15	25	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	15	16	23	25
Binding of these Bcl-2 family proteins to Beclin 1 inhibits autophagy by preventing the association of Beclin 1 with the class III PI3K complex [ XREF_BIBR , XREF_BIBR ] .	Binding of these Bcl-2 family proteins to Beclin 1 inhibits autophagy by preventing the association of Beclin 1 with the class III PI3K complex [XREF_BIBR, XREF_BIBR].	3	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	3	4	16	18
BCL-2 is reported to reduce the pro autophagocytic actions of beclin-1 , thus a resveratrol induced reduction in BCL-2 would lead to an increase in autophagocytic activity in cells [ XREF_BIBR ] .	BCL-2 is reported to reduce the pro autophagocytic actions of beclin-1, thus a resveratrol induced reduction in BCL-2 would lead to an increase in autophagocytic activity in cells [XREF_BIBR].	0	11	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	beclin-1	beclin-1	beclin-1	0	1	10	11
Unlike Bax , Bak is mainly present at the mitochondria and sequestered by anti-apoptotic Mcl-1 and to a certain extent by Bcl-XL .	Unlike Bax, Bak is mainly present at the mitochondria and sequestered by anti-apoptotic Mcl-1 and to a certain extent by Bcl-XL.	3	22	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bak	Bak	Bak	21	22	3	4
Previous studies showed that Bak protein could be sequestered not only by Bcl-xl but also by Mcl-l ( a member of anti-apoptotic proteins of Bcl-2 family proteins ) XREF_BIBR .	Previous studies showed that Bak protein could be sequestered not only by Bcl-xl but also by Mcl-l (a member of anti-apoptotic proteins of Bcl-2 family proteins) XREF_BIBR.	4	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-xl	Bcl-xl	Bcl-xl	Bak	Bak	Bak	12	13	4	5
Furthermore , pro apoptotic Bak is sequestered by Mcl-1 and Bcl-xL ; therefore , inactivation of these proteins by BH3-only proteins is necessary and sufficient for Bak mediated cell death [ XREF_BIBR ] .	Furthermore, pro apoptotic Bak is sequestered by Mcl-1 and Bcl-xL; therefore, inactivation of these proteins by BH3-only proteins is necessary and sufficient for Bak mediated cell death [XREF_BIBR].	2	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bak	Bak	Bak	10	11	4	5
For example , Bak driven apoptosis can be initiated by loss of the relatively labile Mcl-1 and Bcl-x L following UV , actinomycin D or cycloheximide XREF_BIBR , XREF_BIBR .	For example, Bak driven apoptosis can be initiated by loss of the relatively labile Mcl-1 and Bcl-x L following UV, actinomycin D or cycloheximide XREF_BIBR, XREF_BIBR.	3	19	initiated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-x L	loss of the relatively labile Mcl-1 and Bcl-x L	bcl-x l	Bak	Bak	bak	17	19	3	4
BAK Is Sequestered by BCL-X L and Can Be Released by the BH3 Mimetic ABT-737 .	BAK Is Sequestered by BCL-X L and Can Be Released by the BH3 Mimetic ABT-737.	0	9	Sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-X L	BCL-X L	BCL-X L	BAK	BAK	BAK	4	6	0	1
In DP cells , both Mcl-1 and Bcl-x L can sequester Bak ( XREF_FIG , middle ) , as suggested by biochemical data XREF_BIBR and our previous data in which DP cells were lost when both Mcl-1 and Bcl-x were deleted .	In DP cells, both Mcl-1 and Bcl-x L can sequester Bak (XREF_FIG, middle), as suggested by biochemical data XREF_BIBR and our previous data in which DP cells were lost when both Mcl-1 and Bcl-x were deleted.	5	27	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	7	9	11	12
For example , proapoptotic protein Bak is normally sequestered by Mcl-1 and Bcl-xL .	For example, proapoptotic protein Bak is normally sequestered by Mcl-1 and Bcl-xL.	3	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bak	Bak	Bak	12	13	5	6
Moreover , proapoptotic Bak is sequestered by the antiapoptotic Mcl-1 and Bcl-XL , its displacement by BH3-only proteins being required for cell death .	Moreover, proapoptotic Bak is sequestered by the antiapoptotic Mcl-1 and Bcl-XL, its displacement by BH3-only proteins being required for cell death.	2	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bak	Bak	Bak	11	12	3	4
Over-expression of BCL-xL completely inhibited BAK activation and calpain cleavage induced by low tBID expression ( 50 ng ) .	Over-expression of BCL-xL completely inhibited BAK activation and calpain cleavage induced by low tBID expression (50 ng).	0	6	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-xL	Over-expression of BCL-xL	bcl-xl	BAK	BAK	bak	2	3	5	6
3 In most cells , Bak is normally sequestered by Mcl-1 and Bcl-xL , and only when Bak is freed from both , can it induce apoptosis .	3 In most cells, Bak is normally sequestered by Mcl-1 and Bcl-xL, and only when Bak is freed from both, can it induce apoptosis.	5	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bak	Bak	Bak	12	13	5	6
Supporting evidence for a differential impact of Mcl-1 and Bcl-x L comes from our recent observation that Mcl-1 but not Bcl-x L mediates inhibition of the Bak pathway upon the expression of the BH3-only protein Nbk .	Supporting evidence for a differential impact of Mcl-1 and Bcl-x L comes from our recent observation that Mcl-1 but not Bcl-x L mediates inhibition of the Bak pathway upon the expression of the BH3-only protein Nbk.	17	27	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	20	22	26	27
It has been proposed that BAK is sequestered by MCL-1 and BCL-X L until displaced by BH3-only proteins .	It has been proposed that BAK is sequestered by MCL-1 and BCL-X L until displaced by BH3-only proteins.	5	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-X L	BCL-X L	BCL-X L	BAK	BAK	BAK	11	13	5	6
Bak is generally sequestered by Mcl-1 and Bcl-XL but is released upon DNA damage .	Bak is generally sequestered by Mcl-1 and Bcl-XL but is released upon DNA damage.	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bak	Bak	Bak	7	8	0	1
Overexpression of antiapoptotic BCL-2 family members BCL-X L and MCL-1 restores peroxisome formation in ZP114 cells ( XREF_FIG ) even though the localization of BAK is not altered ( XREF_FIG ) , suggesting that some BCL-X L and MCL-1 may target to peroxisomes to inhibit BAK , at least upon overexpression .	Overexpression of antiapoptotic BCL-2 family members BCL-X L and MCL-1 restores peroxisome formation in ZP114 cells (XREF_FIG) even though the localization of BAK is not altered (XREF_FIG), suggesting that some BCL-X L and MCL-1 may target to peroxisomes to inhibit BAK, at least upon overexpression.	35	48	target	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-X L	BCL-X L	BCL-X L	BAK	BAK	BAK	35	37	45	46
XREF_BIBR Bak can also be directly sequestered by Bcl-X L at the mitochondria .	XREF_BIBR Bak can also be directly sequestered by Bcl-X L at the mitochondria.	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	Bak	Bak	Bak	8	10	1	2
23 XREF_FIG show that Bad phosphorylation decreased its binding with Bcl-xL , and thus pro apoptotic Bak was sequestered by Bcl-xL in untreated LS174T cells .	23 XREF_FIG show that Bad phosphorylation decreased its binding with Bcl-xL, and thus pro apoptotic Bak was sequestered by Bcl-xL in untreated LS174T cells.	14	24	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bak	Bak	Bak	20	21	16	17
The BH3-only proteins therefore play the key role of determining whether Mcl-1 and Bcl-xL are available to sequester Bak .	The BH3-only proteins therefore play the key role of determining whether Mcl-1 and Bcl-xL are available to sequester Bak.	11	19	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bak	Bak	Bak	13	14	18	19
As previously observed for fibroblasts , the cells remained viable because either Mcl-1 or Bcl-x L is sufficient to sequester Bak .	As previously observed for fibroblasts, the cells remained viable because either Mcl-1 or Bcl-x L is sufficient to sequester Bak.	14	21	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	14	16	20	21
Pro apoptotic Bak is sequestered by Mcl-1 and Bcl-x L ; but not Bcl-2 until displaced by Bid , Bad or Bak [ 17 ] .	Pro apoptotic Bak is sequestered by Mcl-1 and Bcl-x L; but not Bcl-2 until displaced by Bid, Bad or Bak [17].	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	8	10	2	3
Thus , BCL-X L does not sequester inactive BAK but a preactivated , BH3-domain-exposed and open-groove conformation .	Thus, BCL-X L does not sequester inactive BAK but a preactivated, BH3-domain-exposed and open-groove conformation.	2	16	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-X L	BCL-X L	BCL-X L	BAK	BAK	BAK	2	4	8	9
Genetic and biochemical studies indicate that Bak activation is prevented primarily by Mcl-1 and Bcl-x L , whereas Bax is held in check by all pro survival Bcl-2 homologues , including Bcl-2 itself .	Genetic and biochemical studies indicate that Bak activation is prevented primarily by Mcl-1 and Bcl-x L, whereas Bax is held in check by all pro survival Bcl-2 homologues, including Bcl-2 itself.	6	16	prevented	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	14	16	6	7
In a Bim and Bak mixture , Bcl-x L and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim .	In a Bim and Bak mixture, Bcl-x L and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim.	7	21	sequestered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	7	9	18	19
The detail mechanism by which BCL-xL replaces MCL-1 and suppresses BAK activation and whether coordinately targeting both MCL-1 and BAK axis and BCL-xL and BAK axis heighten the sensitivity of ESCC cells to cisplatin induced apoptosis need to be further investigated .	The detail mechanism by which BCL-xL replaces MCL-1 and suppresses BAK activation and whether coordinately targeting both MCL-1 and BAK axis and BCL-xL and BAK axis heighten the sensitivity of ESCC cells to cisplatin induced apoptosis need to be further investigated.	5	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-xL	BCL-xL	BCL-xL	BAK	BAK	BAK	5	6	10	11
To analyze the impact of Bcl-x L ( the second major endogenous inhibitor of Bak ) on TRAIL resistance , we down-regulated Bcl-x L by siRNA .	To analyze the impact of Bcl-x L (the second major endogenous inhibitor of Bak) on TRAIL resistance, we down-regulated Bcl-x L by siRNA.	5	15	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	5	7	14	15
Bcl-xL is known to antagonize the effects of pro apoptotic BAK at the level of mitochondria , and the protection by Bcl-xL observed in this study may be attributed to its protective effect against BAK induced permeabilization of mitochondrial membrane .	Bcl-xL is known to antagonize the effects of pro apoptotic BAK at the level of mitochondria, and the protection by Bcl-xL observed in this study may be attributed to its protective effect against BAK induced permeabilization of mitochondrial membrane.	0	11	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	BAK	BAK	BAK	0	1	10	11
The model that Bcl-X L inhibits cluster formation merely by blocking Bax docking to mitochondria can not explain the Bcl-X L inhibition of Bax-S184V and Bak clustering , since they reside in the mitochondrial membrane before apoptosis .	The model that Bcl-X L inhibits cluster formation merely by blocking Bax docking to mitochondria can not explain the Bcl-X L inhibition of Bax-S184V and Bak clustering, since they reside in the mitochondrial membrane before apoptosis.	19	26	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	Bak	Bak	Bak	19	21	25	26
However , recent evidence proposed that Mcl-1 and Bcl-xL cooperatively act to prevent activation of proapoptotic protein Bak .	However, recent evidence proposed that Mcl-1 and Bcl-xL cooperatively act to prevent activation of proapoptotic protein Bak.	6	18	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bak	Bak	Bak	8	9	17	18
BCL-xL efficiently inhibited cytochrome c release and BAK activation at low concentrations of n/c BID ( 1 and 10 nM ) consistent with MODE 1 inhibition ( XREF_FIG , right panel ) .	BCL-xL efficiently inhibited cytochrome c release and BAK activation at low concentrations of n/c BID (1 and 10 nM) consistent with MODE 1 inhibition (XREF_FIG, right panel).	0	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-xL	BCL-xL	BCL-xL	BAK	BAK	BAK	0	1	7	8
Since Bcl-xL also inhibits Bak , an effect not antagonized by Noxa [ XREF_BIBR ] , the lesser sensitivity of U937 cells to DHA and X-11 treatment is probably due to their expression of Bcl-xL .	Since Bcl-xL also inhibits Bak, an effect not antagonized by Noxa [XREF_BIBR], the lesser sensitivity of U937 cells to DHA and X-11 treatment is probably due to their expression of Bcl-xL.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bak	Bak	Bak	1	2	4	5
Notably , Bcl-x L could sequester Bak in response to the BH3 mimetic ABT-737 , despite this molecule targeting Bcl-x L.	Notably, Bcl-x L could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-x L.	2	8	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	2	4	6	7
Supporting the model , Bcl-2 or Bcl-x L have been shown to prevent Bax translocation and activation [ XREF_BIBR - XREF_BIBR ] , and Bcl-x L and Mcl-1 have been shown to sequester Bak in mitochondria [ XREF_BIBR ] .	Supporting the model, Bcl-2 or Bcl-x L have been shown to prevent Bax translocation and activation [XREF_BIBR - XREF_BIBR], and Bcl-x L and Mcl-1 have been shown to sequester Bak in mitochondria [XREF_BIBR].	24	34	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	24	26	33	34
Since Bak is mainly sequestered by Bcl-xL and Mcl-1 whereas Bax could be bound by Bcl-2 , Bcl-w , Bcl-xL and Mcl-1 , it is not surprising that NBK , which specifically binds Bcl-xL and Mcl-1 , is completely dependent on Bak for killing activity in murine iBMK cells .	Since Bak is mainly sequestered by Bcl-xL and Mcl-1 whereas Bax could be bound by Bcl-2, Bcl-w, Bcl-xL and Mcl-1, it is not surprising that NBK, which specifically binds Bcl-xL and Mcl-1, is completely dependent on Bak for killing activity in murine iBMK cells.	1	8	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bak	Bak	Bak	6	7	1	2
It is known that BCL-xL and MCL-1 are the main inhibitors of BAK , that the inhibition by MCL-1 can be relieved by NOXA XREF_BIBR , and that BIM can act as a direct activator of BAK XREF_BIBR .	It is known that BCL-xL and MCL-1 are the main inhibitors of BAK, that the inhibition by MCL-1 can be relieved by NOXA XREF_BIBR, and that BIM can act as a direct activator of BAK XREF_BIBR.	4	13	are the main inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	BCL-xL	BCL-xL	BCL-xL	BAK	BAK	BAK	4	5	12	13
23 Bax likely can be inhibited by all the anti-apoptotic proteins , 24 whereas Bak is inhibited predominantly by Bcl-x L , Mcl-1 and A1 25 ( XREF_FIG ) .	23 Bax likely can be inhibited by all the anti-apoptotic proteins, 24 whereas Bak is inhibited predominantly by Bcl-x L, Mcl-1 and A1 25 (XREF_FIG).	14	21	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	19	21	14	15
Since both Mcl-1 and Bcl-xL can sequester Bak from forming oligomers , loss of Mcl-1-Bak association during 2DG incubation can sensitize cells because ABT can now effectively bind Bcl-xL and free Bak .	Since both Mcl-1 and Bcl-xL can sequester Bak from forming oligomers, loss of Mcl-1-Bak association during 2DG incubation can sensitize cells because ABT can now effectively bind Bcl-xL and free Bak.	2	8	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bak	Bak	Bak	4	5	7	8
Interestingly , Bak is sequestered by the antiapoptotic proteins Bcl-x L and Mcl-1 ( but not by Bcl-2 ) , and activation of Bak requires neutralization of both proteins Bcl-x L and Mcl-1 by BH3-only family members .	Interestingly, Bak is sequestered by the antiapoptotic proteins Bcl-x L and Mcl-1 (but not by Bcl-2), and activation of Bak requires neutralization of both proteins Bcl-x L and Mcl-1 by BH3-only family members.	2	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	9	11	2	3
This possibility is relevant to the suggestion that all the BCL-2 relatives keep BAX in check , whereas only BCL-X L and MCL-1 inhibit BAK according to the so called indirect activation model [ XREF_BIBR ] .	This possibility is relevant to the suggestion that all the BCL-2 relatives keep BAX in check, whereas only BCL-X L and MCL-1 inhibit BAK according to the so called indirect activation model [XREF_BIBR].	19	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-X L	BCL-X L	BCL-X L	BAK	BAK	BAK	19	21	24	25
First , Huang and colleagues showed that Bak is normally sequestered by Mcl-1 and Bcl-xL , and Bak must be released from both before it can form oligomers XREF_BIBR .	First, Huang and colleagues showed that Bak is normally sequestered by Mcl-1 and Bcl-xL, and Bak must be released from both before it can form oligomers XREF_BIBR.	7	15	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bak	Bak	Bak	14	15	7	8
Nevertheless , our functional data delineate that Mcl-1 but not Bcl-x L mediates inhibition of the Bak pathway as an important mechanism of TRAIL resistance in Bax deficient human carcinoma .	Nevertheless, our functional data delineate that Mcl-1 but not Bcl-x L mediates inhibition of the Bak pathway as an important mechanism of TRAIL resistance in Bax deficient human carcinoma.	7	17	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bak	Bak	Bak	10	12	16	17
Similarly , transfused platelets have a half-life of hours to days and undergo apoptosis in a BAK dependent manner that is inhibited by BCL-XL .	Similarly, transfused platelets have a half-life of hours to days and undergo apoptosis in a BAK dependent manner that is inhibited by BCL-XL.	16	24	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-XL	BCL-XL	BCL-XL	BAK	BAK	BAK	23	24	16	17
Interestingly we also observed the translocation of Bim from the cytosol into the mitochondria where Bim is known to bind to and antagonize anti-apoptotic members of the Bcl-2 family .	Interestingly we also observed the translocation of Bim from the cytosol into the mitochondria where Bim is known to bind to and antagonize anti-apoptotic members of the Bcl-2 family.	15	28	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	15	16	27	28
Of all the BH3-only proteins , only Bim and Puma ( along with t-Bid ) can engage with and antagonize every single prosurvival Bcl-2 molecule .	Of all the BH3-only proteins, only Bim and Puma (along with t-Bid) can engage with and antagonize every single prosurvival Bcl-2 molecule.	6	24	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	7	8	23	24
BCL2L11 ( also known as BIM ) could promote the release of apoptogenic proteins and inactivate the anti-apoptosis BCL-2 proteins to trigger apoptosis XREF_BIBR .	BCL2L11 (also known as BIM) could promote the release of apoptogenic proteins and inactivate the anti-apoptosis BCL-2 proteins to trigger apoptosis XREF_BIBR.	0	19	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2L11	BCL2L11	BCL2L11	BCL-2	BCL-2	BCL-2	0	1	18	19
Bid and Bim are sufficient to sequester anti-apoptotic Bcl-2 family members , induce oligomerization of Bak and Bax , permeabilization of liposomes , and release of cytochrome C [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Bid and Bim are sufficient to sequester anti-apoptotic Bcl-2 family members, induce oligomerization of Bak and Bax, permeabilization of liposomes, and release of cytochrome C [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	10	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	2	3	8	9
Although all three Bim isoforms in mouse bind Bcl-2 , Bim S antagonizes Bcl-2 more effectively than Bim L , while Bim EL was the least potent [ XREF_BIBR ] .	Although all three Bim isoforms in mouse bind Bcl-2, Bim S antagonizes Bcl-2 more effectively than Bim L, while Bim EL was the least potent [XREF_BIBR].	10	14	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	10	11	13	14
Bim is thought to inactivate prosurvival Bcl-2 protein members , leading to increased mitochondria permeability .	Bim is thought to inactivate prosurvival Bcl-2 protein members, leading to increased mitochondria permeability.	0	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	6	7
SAH potentiated the expression of Bim , CC-9 , and CC-3 but reduced Bcl-2 , while tozasertib reduced expression of Bim , CC-9 , and CC-3 but enhanced Bcl-2 .	SAH potentiated the expression of Bim, CC-9, and CC-3 but reduced Bcl-2, while tozasertib reduced expression of Bim, CC-9, and CC-3 but enhanced Bcl-2.	0	14	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	SAH potentiated the expression of Bim	bim	Bcl-2	Bcl-2	bcl-2	5	6	13	14
Both Bim and Puma have been shown to sequester Bcl-2 family members equally .	Both Bim and Puma have been shown to sequester Bcl-2 family members equally.	0	11	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	1	2	9	10
Since Bim is an activator and can also inhibit all anti-apoptotic BCL-2 family proteins , loss of its activity may more noticeably affect drug induced death than the other BH3-only proteins .	Since Bim is an activator and can also inhibit all anti-apoptotic BCL-2 family proteins, loss of its activity may more noticeably affect drug induced death than the other BH3-only proteins.	1	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	BCL-2	BCL-2	BCL-2	1	2	11	12
While Bim antagonizes Bcl-2 , Nur77 converts Bcl-2 to a killer form .	While Bim antagonizes Bcl-2, Nur77 converts Bcl-2 to a killer form.	1	4	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	1	2	3	4
However , a previous study demonstrated that the induced Bim is primarily sequestered by Bcl-2 family members Bcl-2 , Bcl-XL and Mcl-1 , 32 which would neutralize its pro apoptotic roles .	However, a previous study demonstrated that the induced Bim is primarily sequestered by Bcl-2 family members Bcl-2, Bcl-XL and Mcl-1, 32 which would neutralize its pro apoptotic roles.	7	23	sequestered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	9	10	17	18
ABBV-075 enhanced the expression of proapoptotic protein BIM and downregulated antiapoptotic proteins BCL2 and BCLxl to a lesser extent .	ABBV-075 enhanced the expression of proapoptotic protein BIM and downregulated antiapoptotic proteins BCL2 and BCLxl to a lesser extent.	0	18	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIM	ABBV-075 enhanced the expression of proapoptotic protein BIM	bim	BCL2	BCL2	bcl2	7	8	12	13
The stress kinase p38 MAPK and CHOP have been known to induce the expression of pro apoptotic gene Bim and down-regulate the anti-apoptotic gene Bcl-2 under ER stress conditions .	The stress kinase p38 MAPK and CHOP have been known to induce the expression of pro apoptotic gene Bim and down-regulate the anti-apoptotic gene Bcl-2 under ER stress conditions.	3	25	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	p38 MAPK and CHOP have been known to induce the expression of pro apoptotic gene Bim	bim	Bcl-2	Bcl-2	bcl-2	18	19	24	25
Bim , as an activator Bcl-2 protein , is capable of direct Bax and Bak activation upon reversible binding and known to potently antagonize all prosurvival Bcl-2 proteins which sequester Bax and Bak under normal circumstances XREF_BIBR , XREF_BIBR .	Bim, as an activator Bcl-2 protein, is capable of direct Bax and Bak activation upon reversible binding and known to potently antagonize all prosurvival Bcl-2 proteins which sequester Bax and Bak under normal circumstances XREF_BIBR, XREF_BIBR.	0	27	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	26	27
CHOP upregulates the transcription of Bim and downregulates the anti-apoptotic protein Bcl-2 which is crucial for the control of ER stress induced apoptosis .	CHOP upregulates the transcription of Bim and downregulates the anti-apoptotic protein Bcl-2 which is crucial for the control of ER stress induced apoptosis.	0	14	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	CHOP upregulates the transcription of Bim	bim	Bcl-2	Bcl-2	bcl-2	5	6	11	12
Upon activation , Bim can antagonize all the prosurvival Bcl-2 proteins , leading to apoptosis .	Upon activation, Bim can antagonize all the prosurvival Bcl-2 proteins, leading to apoptosis.	3	10	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	3	4	9	10
Removal of a single allele of bim is sufficient to prevent the bcl-2 -/- phenotype .	Removal of a single allele of bim is sufficient to prevent the bcl-2 -/- phenotype.	4	14	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bim	bim	bim	bcl-2	bcl-2	bcl-2	6	7	12	13
We have previously reported that apoptosis inducing peptides such as the BH3 domain of the Bcl-2 antagonist Bim and a peptide derived from the Akt-inhibitor CTMP [ CTMP-4 , XREF_BIBR ] can be delivered to cancer cells via the HIV-1-derived transduction domain TAT .	We have previously reported that apoptosis inducing peptides such as the BH3 domain of the Bcl-2 antagonist Bim and a peptide derived from the Akt-inhibitor CTMP [CTMP-4, XREF_BIBR] can be delivered to cancer cells via the HIV-1-derived transduction domain TAT.	12	20	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	17	18	15	16
These results show that the prometaphase arrest dependent phosphorylation of Bcl-2 and Bim , which was mediated by Cdk1 , could reduce the association of Bcl-2 with Bak or Bim to allow Bak activation and mitochondrial apoptotic events in Jurkat T cells exposed to NOC .	These results show that the prometaphase arrest dependent phosphorylation of Bcl-2 and Bim, which was mediated by Cdk1, could reduce the association of Bcl-2 with Bak or Bim to allow Bak activation and mitochondrial apoptotic events in Jurkat T cells exposed to NOC.	8	26	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	phosphorylation of Bcl-2 and Bim	bim	Bcl-2	Bcl-2	bcl-2	12	13	25	26
Bid and PUMA function in facilitating Bax and Bak channel formation , whereas Bad and Bim inhibit prosurvival Bcl-2 and Bcl-xL [ XREF_BIBR ] .	Bid and PUMA function in facilitating Bax and Bak channel formation, whereas Bad and Bim inhibit prosurvival Bcl-2 and Bcl-xL [XREF_BIBR].	13	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	15	16	18	19
The BH3-only proteins Bid and PUMA act to facilitate Bax and Bak channel formation , whereas Bad and Bim inhibit prosurvival Bcl-2 and Bcl-xL .	The BH3-only proteins Bid and PUMA act to facilitate Bax and Bak channel formation, whereas Bad and Bim inhibit prosurvival Bcl-2 and Bcl-xL.	16	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	18	19	21	22
The tumor suppressor bcl2l11 , which encodes B-cell Lymphoma 2 ( BCL2 ) Interacting Mediator of Cell Death ( BIM ) , a proapoptosis factor that blocks BCL2 family members , was found to be amongst the most highly induced LCL genes upon knockout of either IRF4 or BATF .	The tumor suppressor bcl2l11, which encodes B-cell Lymphoma 2 (BCL2) Interacting Mediator of Cell Death (BIM), a proapoptosis factor that blocks BCL2 family members, was found to be amongst the most highly induced LCL genes upon knockout of either IRF4 or BATF.	17	29	blocks	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	BIM	BIM	BIM	BCL2	BCL2	BCL2	19	20	27	28
In addition , tozasertib reduced the levels of Bim , CC-9 and enhanced Bcl-2 .	In addition, tozasertib reduced the levels of Bim, CC-9 and enhanced Bcl-2.	3	14	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	tozasertib reduced the levels of Bim	bim	Bcl-2	Bcl-2	bcl-2	8	9	13	14
Bim can bind to and inhibit most anti-apoptotic Bcl-2 proteins , besides directly activating the pro apoptotic protein Bax XREF_BIBR .	Bim can bind to and inhibit most anti-apoptotic Bcl-2 proteins, besides directly activating the pro apoptotic protein Bax XREF_BIBR.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	8	9
Its occurrence in bim -/- / puma -/- mice indicated that Puma , together with Bim , may antagonize a Bcl-2 prosurvival homologue that is not efficiently blocked by Bim alone and can not be replaced by Bcl-2 overexpression .	Its occurrence in bim -/- / puma -/- mice indicated that Puma, together with Bim, may antagonize a Bcl-2 prosurvival homologue that is not efficiently blocked by Bim alone and can not be replaced by Bcl-2 overexpression.	20	30	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	29	30	20	21
As a BH3-only protein , BCL2L11 ( also called BIM ) can inhibit BCL2 proteins and activate BAX-BAK1 proteins .	As a BH3-only protein, BCL2L11 (also called BIM) can inhibit BCL2 proteins and activate BAX-BAK1 proteins.	5	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2L11	BCL2L11	BCL2L11	BCL2	BCL2	BCL2	5	6	13	14
Bcl2l11 , also known as Bim , antagonizes Bcl-2 and promotes apoptosis .	Bcl2l11, also known as Bim, antagonizes Bcl-2 and promotes apoptosis.	0	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2l11	Bcl2l11	Bcl2l11	Bcl-2	Bcl-2	Bcl-2	0	1	8	9
Bim antagonizes the survival actions of Bcl-2 and Bcl-xL , thereby triggering mitochondrial permeabilization and resultant cell death .	Bim antagonizes the survival actions of Bcl-2 and Bcl-xL, thereby triggering mitochondrial permeabilization and resultant cell death.	0	8	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	6	7
When translocated , Bim is suggested to either interact with and inactivate antiapoptotic bcl-2 proteins or directly interact with and activate the proapoptotic bcl-2 proteins bak and bax ( Marani et al , 2002 ) .	When translocated, Bim is suggested to either interact with and inactivate antiapoptotic bcl-2 proteins or directly interact with and activate the proapoptotic bcl-2 proteins bak and bax (Marani et al, 2002).	3	14	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	bcl-2	bcl-2	bcl-2	3	4	13	14
Bim inhibits the anti-apoptotic function of Bcl-2 ; consequently , inhibition of Bim expression by BART miRNAs should confer enhanced cell survival .	Bim inhibits the anti-apoptotic function of Bcl-2; consequently, inhibition of Bim expression by BART miRNAs should confer enhanced cell survival.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	6	7
Following UVR irradiation , the BH3-only family of proteins , which include BID ( BH3 interacting-domain death agonist ) , BIM , BAD , PUMA ( p53 up regulator of apoptosis ) , and NOXA , bind to and inhibit the anti-apoptotic Bcl-2 proteins [ XREF_BIBR ] .	Following UVR irradiation, the BH3-only family of proteins, which include BID (BH3 interacting-domain death agonist), BIM, BAD, PUMA (p53 up regulator of apoptosis), and NOXA, bind to and inhibit the anti-apoptotic Bcl-2 proteins [XREF_BIBR].	20	43	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIM	BIM	BIM	Bcl-2	Bcl-2	Bcl-2	20	21	42	43
Bim , which inhibits the antiapoptotic Bcl-2 , is down-regulated by miR-17-92 during normal development to promote survival of B-cell progenitors .	Bim, which inhibits the antiapoptotic Bcl-2, is down-regulated by miR-17-92 during normal development to promote survival of B-cell progenitors.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	6	7
Because Bim may be an antagonist of Bcl-2 , we tested whether Bim deficiency affects entry of B cells into the cell cycle .	Because Bim may be an antagonist of Bcl-2, we tested whether Bim deficiency affects entry of B cells into the cell cycle.	1	8	be an antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	1	2	7	8
Moreover , whereas loss of the BH3-only protein Bim rescued mice lacking the prosurvival protein Bcl-2 from fatal polycystic kidney disease and lymphopenia , loss of Bik did not .	Moreover, whereas loss of the BH3-only protein Bim rescued mice lacking the prosurvival protein Bcl-2 from fatal polycystic kidney disease and lymphopenia, loss of Bik did not.	3	16	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	loss of the BH3-only protein Bim	bim	Bcl-2	Bcl-2	bcl-2	8	9	15	16
XREF_BIBR , XREF_BIBR , XREF_BIBR Moreover , it has been shown that loss of Bim can rescue the survival and phenotypic defects of Bcl-2 -/- mice , including thymocyte development .	XREF_BIBR, XREF_BIBR, XREF_BIBR Moreover, it has been shown that loss of Bim can rescue the survival and phenotypic defects of Bcl-2 -/- mice, including thymocyte development.	12	25	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	loss of Bim	bim	Bcl-2	Bcl-2	bcl-2	14	15	23	24
These data also suggest that one of the roles of Bim may be to block the function of Bcl-2 .	These data also suggest that one of the roles of Bim may be to block the function of Bcl-2.	8	19	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	10	11	18	19
Sufficient ionic strength was required for optimal release of Cytochrome C. Bad and Noxa BH3 peptides exhibited their bona fide antagonistic effects against Bcl-2 and Bcl-xL and Mcl-1 proteins , respectively , whereas Bim BH3 peptide antagonized all three anti-apoptotic Bcl-2 members .	Sufficient ionic strength was required for optimal release of Cytochrome C. Bad and Noxa BH3 peptides exhibited their bona fide antagonistic effects against Bcl-2 and Bcl-xL and Mcl-1 proteins, respectively, whereas Bim BH3 peptide antagonized all three anti-apoptotic Bcl-2 members.	33	41	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	33	34	40	41
We have observed that SAH potentiated the levels of Bim and CC-9 and reduced Bcl-2 , and tozasertib reduced Bim and CC-9 but enhanced Bcl-2 and reduced TUNEL positive cells .	We have observed that SAH potentiated the levels of Bim and CC-9 and reduced Bcl-2, and tozasertib reduced Bim and CC-9 but enhanced Bcl-2 and reduced TUNEL positive cells.	4	15	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	SAH potentiated the levels of Bim	bim	Bcl-2	Bcl-2	bcl-2	9	10	14	15
Previous studies have shown that the deletion of HEL specific B cells in HEL-transgenic mice is preceded by down-regulation of surface IgM and is mediated by apoptosis that is inhibited by Bcl2 overexpression and requires the BCL2 antagonist BIM .	Previous studies have shown that the deletion of HEL specific B cells in HEL-transgenic mice is preceded by down-regulation of surface IgM and is mediated by apoptosis that is inhibited by Bcl2 overexpression and requires the BCL2 antagonist BIM.	24	39	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	BIM	BIM	BIM	BCL2	BCL2	BCL2	38	39	36	37
Conceivably , BID , BIM and PUMA can prevent BCL-2 , BCL-X L and MCL-1 from sequestering BAX-BAK whereas NOXA can only inhibit MCL-1 .	Conceivably, BID, BIM and PUMA can prevent BCL-2, BCL-X L and MCL-1 from sequestering BAX-BAK whereas NOXA can only inhibit MCL-1.	2	14	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIM	BIM	BIM	BCL-2	BCL-2	BCL-2	4	5	9	10
Bcl-2-interacting molecule ( Bim ) and Bad , pro apoptotic members of the Bcl-2 family , antagonize the anti-apoptotic activity of Bcl-2 .	Bcl-2-interacting molecule (Bim) and Bad, pro apoptotic members of the Bcl-2 family, antagonize the anti-apoptotic activity of Bcl-2.	1	22	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	3	4	21	22
The Ras/Raf/MEK/ERK pathway can also inhibit apoptosis by phosphorylating and inactivating pro apoptotic Bim and BAD , thus promoting the anti-apoptotic roles of Bcl-2 and Bcl-xL [ XREF_BIBR - XREF_BIBR ] .	The Ras/Raf/MEK/ERK pathway can also inhibit apoptosis by phosphorylating and inactivating pro apoptotic Bim and BAD, thus promoting the anti-apoptotic roles of Bcl-2 and Bcl-xL [XREF_BIBR - XREF_BIBR].	1	27	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Ras/Raf/MEK/ERK pathway can also inhibit apoptosis by phosphorylating and inactivating pro apoptotic Bim	bim	Bcl-2	Bcl-2	bcl-2	13	14	23	24
BIM belongs to the Bcl-2 family , and promotes apoptosis by inhibiting anti-apoptotic Bcl-2 family members 31 .	BIM belongs to the Bcl-2 family, and promotes apoptosis by inhibiting anti-apoptotic Bcl-2 family members 31.	0	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BIM	BIM	BIM	Bcl-2	Bcl-2	Bcl-2	0	1	13	14
Moreover , BIM inhibits other anti-apoptotic Bcl-2 family proteins via its BH3 domain ; accordingly , a splicing variant of BIM lacking the BH3 domain also causes resistance , and this splicing variant is specifically observed in Asians ( 10.9-18.6 % ) .	Moreover, BIM inhibits other anti-apoptotic Bcl-2 family proteins via its BH3 domain; accordingly, a splicing variant of BIM lacking the BH3 domain also causes resistance, and this splicing variant is specifically observed in Asians (10.9-18.6%).	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIM	BIM	BIM	Bcl-2	Bcl-2	Bcl-2	2	3	6	7
Moreover , Bim can bind and antagonizes anti-apoptosis BCL2 proteins , leading to the permeabilization of the outer mitochondrial membrane and activation of the Caspase cascade XREF_BIBR .	Moreover, Bim can bind and antagonizes anti-apoptosis BCL2 proteins, leading to the permeabilization of the outer mitochondrial membrane and activation of the Caspase cascade XREF_BIBR.	2	9	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	BCL2	BCL2	BCL2	2	3	8	9
The BIM splice isoforms regulated by TDP-43 have been functionally characterised ; BIM S antagonizes the pro survival Bcl-2 family members more effectively than BIM L , while BIM EL is the least potent XREF_BIBR .	The BIM splice isoforms regulated by TDP-43 have been functionally characterised; BIM S antagonizes the pro survival Bcl-2 family members more effectively than BIM L, while BIM EL is the least potent XREF_BIBR.	12	20	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIM	BIM	BIM	Bcl-2	Bcl-2	Bcl-2	12	13	18	19
Interestingly , the loss of a single Bim allele in Bcl-2 null mice is sufficient to rescue the cystic phenotype of Bcl-2 null mice , suggesting that gene dosage of Bim is critical during nephrogenesis .	Interestingly, the loss of a single Bim allele in Bcl-2 null mice is sufficient to rescue the cystic phenotype of Bcl-2 null mice, suggesting that gene dosage of Bim is critical during nephrogenesis.	7	23	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	7	8	21	22
BIM has been shown to play a critical role in melanocyte survival , since BIM germline deletion profoundly rescues melanocytic cell death ( coat-color ) in the absence of Bcl-2 .	BIM has been shown to play a critical role in melanocyte survival, since BIM germline deletion profoundly rescues melanocytic cell death (coat-color) in the absence of Bcl-2.	14	30	rescues	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BIM	BIM	BIM	Bcl-2	Bcl-2	Bcl-2	14	15	29	30
The BH3-only proteins BID and PUMA facilitate BAX and BAK channel formation , whereas BAD and BIM acts to inhibit pro survival BCL-2 and BCL-xL .	The BH3-only proteins BID and PUMA facilitate BAX and BAK channel formation, whereas BAD and BIM acts to inhibit pro survival BCL-2 and BCL-xL.	14	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIM	BIM	BIM	BCL-2	BCL-2	BCL-2	16	17	22	23
In addition , both E4 ( 1x10 -7 M ) and E2 ( 1x10 -9 M ) significantly decreased the expression of the pro apoptotic gene BAD and up-regulated the anti-apoptotic gene BCL2 , supporting an impact on apoptosis .	In addition, both E4 (1x10 -7 M) and E2 (1x10 -9 M) significantly decreased the expression of the pro apoptotic gene BAD and up-regulated the anti-apoptotic gene BCL2, supporting an impact on apoptosis.	11	33	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAD	E2 (1x10 -9 M) significantly decreased the expression of the pro apoptotic gene BAD	bad	BCL2	BCL2	bcl2	26	27	32	33
We also showed that MCI-186 pretreatment significantly downregulated artocarpin induced Bad- and Bax and upregulated artocarpin repressed Bcl-2 in U87 cells .	We also showed that MCI-186 pretreatment significantly downregulated artocarpin induced Bad- and Bax and upregulated artocarpin repressed Bcl-2 in U87 cells.	4	18	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad-	MCI-186 pretreatment significantly downregulated artocarpin induced Bad-	bad-	Bcl-2	Bcl-2	bcl-2	10	11	17	18
PAK1 phosphorylates Bad on S111 to prevent Bcl2 binding and induction of apoptosis .	PAK1 phosphorylates Bad on S111 to prevent Bcl2 binding and induction of apoptosis.	0	8	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	PAK1 phosphorylates Bad on S111	bad	Bcl2	Bcl2	bcl2	2	3	7	8
This leads to sequestering of Bcl2 by Bad , which inhibits its downstream anti-apoptotic activity .	This leads to sequestering of Bcl2 by Bad, which inhibits its downstream anti-apoptotic activity.	1	10	sequestering	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl2	Bcl2	Bcl2	7	8	5	6
Certain proapoptotic mediators , such as the transcription factor forkhead ( FOXO ) , the tau kinase GSK-3beta , and the Bcl2 antagonist BAD proteins , are inactivated by Akt [ XREF_BIBR , XREF_BIBR ] .	Certain proapoptotic mediators, such as the transcription factor forkhead (FOXO), the tau kinase GSK-3beta, and the Bcl2 antagonist BAD proteins, are inactivated by Akt [XREF_BIBR, XREF_BIBR].	21	24	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	BAD	BAD	BAD	Bcl2	Bcl2	Bcl2	23	24	21	22
Besides , the western blotting data showed that overexpression of hsa-miR-376c-3p increased the expression of BAD and smad4 and decreased the antiapoptotic gene BCL-2 ( XREF_FIG ) .	Besides, the western blotting data showed that overexpression of hsa-miR-376c-3p increased the expression of BAD and smad4 and decreased the antiapoptotic gene BCL-2 (XREF_FIG).	8	25	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	overexpression of hsa-miR-376c-3p increased the expression of BAD	bad	BCL-2	BCL-2	bcl-2	15	16	23	24
Apparently , Ser128 phosphorylation of BAD inhibits its interaction with 14-3-3 proteins so that the BAD can antagonize the anti-apoptotic Bcl2 proteins to promote apoptosis .	Apparently, Ser128 phosphorylation of BAD inhibits its interaction with 14-3-3 proteins so that the BAD can antagonize the anti-apoptotic Bcl2 proteins to promote apoptosis.	14	21	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	BAD	BAD	Bcl2	Bcl2	Bcl2	15	16	20	21
The anti-apoptosis mechanisms that insulin and IGF -1 inhibit include BAD ( inhibitor of Bcl-2 ) , Forkhead Box O ( FoxO ) , glycogen synthase kinase 3beta ( GSK-3beta ) , and nuclear factor kappa B ( NF-kappaB ) .	The anti-apoptosis mechanisms that insulin and IGF -1 inhibit include BAD (inhibitor of Bcl-2), Forkhead Box O (FoxO), glycogen synthase kinase 3beta (GSK-3beta), and nuclear factor kappa B (NF-kappaB).	9	36	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	BAD	BAD	BAD	Bcl-2	Bcl-2	Bcl-2	10	11	14	15
Along with Bim , Bad has been shown to sequester anti-apoptotic Bcl-2 proteins , and cause cytochrome c release [ XREF_BIBR ] .	Along with Bim, Bad has been shown to sequester anti-apoptotic Bcl-2 proteins, and cause cytochrome c release [XREF_BIBR].	4	15	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	4	5	11	12
BAD promotes cell death by interacting with and inhibiting the pro survival Bcl-2 proteins .	BAD promotes cell death by interacting with and inhibiting the pro survival Bcl-2 proteins.	0	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAD	BAD	BAD	Bcl-2	Bcl-2	Bcl-2	0	1	12	13
PA-MSHA induced BAD and BAX and inhibited BCL-2 , suggesting that PA-MSHA promotes apoptosis in cervical cancer cells by increasing the expression of pro apoptotic genes and reducing the expression of anti-apoptotic genes .	PA-MSHA induced BAD and BAX and inhibited BCL-2, suggesting that PA-MSHA promotes apoptosis in cervical cancer cells by increasing the expression of pro apoptotic genes and reducing the expression of anti-apoptotic genes.	0	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	PA-MSHA induced BAD	bad	BCL-2	BCL-2	bcl-2	2	3	7	8
Moreover , a pharmacological mimic of the BH3-only sensitizer Bad , which inhibits Bcl-XL and Bcl-2 , induces PUMA dependent beta-cell death and potentiates cytokine induced apoptosis .	Moreover, a pharmacological mimic of the BH3-only sensitizer Bad, which inhibits Bcl-XL and Bcl-2, induces PUMA dependent beta-cell death and potentiates cytokine induced apoptosis.	4	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	9	10	15	16
PK11195 induced dephosphorylation of protein kinase B/Akt and Bad and a downregulation of Bcl-2 .	PK11195 induced dephosphorylation of protein kinase B/Akt and Bad and a downregulation of Bcl-2.	0	14	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bad	PK11195 induced dephosphorylation of protein kinase B/Akt and Bad	bad	Bcl-2	Bcl-2	bcl-2	8	9	13	14
Anti-apoptotic mechanisms inhibited by insulin and IGF stimulation include BAD ( inhibitor of Bcl-2 ) , Forkhead Box O ( FoxO ) , glycogen synthase kinase 3beta ( GSK-3beta ) , and nuclear factor kappa B ( NF-kappaB ) .	Anti-apoptotic mechanisms inhibited by insulin and IGF stimulation include BAD (inhibitor of Bcl-2), Forkhead Box O (FoxO), glycogen synthase kinase 3beta (GSK-3beta), and nuclear factor kappa B (NF-kappaB).	8	35	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	BAD	BAD	BAD	Bcl-2	Bcl-2	Bcl-2	9	10	13	14
BAD antagonizes both the cell cycle and antiapoptotic functions of BCL2 and BCL-x ( L ) through BH3 binding .	BAD antagonizes both the cell cycle and antiapoptotic functions of BCL2 and BCL-x (L) through BH3 binding.	0	12	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	BAD	BAD	BCL2	BCL2	BCL2	0	1	10	11
It has been reported that Bad inhibits Bcl2 by directly binding to it and rescues Bax [ XREF_BIBR ] .	It has been reported that Bad inhibits Bcl2 by directly binding to it and rescues Bax [XREF_BIBR].	5	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl2	Bcl2	Bcl2	5	6	7	8
Second , as the BH3-only proteins , NOXA and BAD , selectively antagonize MCL-1 and BCL-2 and BCL-x L / BCL-w , respectively , 40 we expressed NOXA or BAD as mCherry fusion proteins and found that only NOXA sensitized DU145 cells to TRAIL ( XREF_FIG ) .	Second, as the BH3-only proteins, NOXA and BAD, selectively antagonize MCL-1 and BCL-2 and BCL-x L / BCL-w, respectively, 40 we expressed NOXA or BAD as mCherry fusion proteins and found that only NOXA sensitized DU145 cells to TRAIL (XREF_FIG).	5	16	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	BAD	BAD	BCL-2	BCL-2	BCL-2	9	10	15	16
Overall antibodies , which monitor Bcl-2 phosphorylation were elevated whereas antibodies monitoring the Bcl-2 antagonist Bad , were diminished in infected cells ( XREF_SUPPLEMENTARY ) .	Overall antibodies, which monitor Bcl-2 phosphorylation were elevated whereas antibodies monitoring the Bcl-2 antagonist Bad, were diminished in infected cells (XREF_SUPPLEMENTARY).	11	16	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	15	16	13	14
The S118 phosphorylation liberates Bcl-2 and Bcl-Xl sequestered by Bad .	The S118 phosphorylation liberates Bcl-2 and Bcl-Xl sequestered by Bad.	3	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	9	10	4	5
Thus , while activated Bad could sequester Bcl-2 pro survival proteins to prevent them from neutralizing Bak , F1L would ensure the continued inactivation of Bak .	Thus, while activated Bad could sequester Bcl-2 pro survival proteins to prevent them from neutralizing Bak, F1L would ensure the continued inactivation of Bak.	3	10	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	4	5	7	8
Induction of apoptosis was accompanied by upregulation of proapoptotic Bim and a moderate upregulation of Mcl-1 and Bad and a downregulation of Bcl-2 , Bax and Bcl-Xl .	Induction of apoptosis was accompanied by upregulation of proapoptotic Bim and a moderate upregulation of Mcl-1 and Bad and a downregulation of Bcl-2, Bax and Bcl-Xl.	17	26	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	17	18	22	23
Deferasirox treatment decreased the Bax to Bcl-2 ratio by 17 % ( P < 0.05 ) and the amount of Bad , full-length caspase-3 , cleaved caspase-3 ( 19 kDa ) , and cleaved caspase-3 ( 17 kDa ) by 41 , 16 , 22 , and 37 % , respectively ( P < 0.05 ) .	Deferasirox treatment decreased the Bax to Bcl-2 ratio by 17% (P < 0.05) and the amount of Bad, full-length caspase-3, cleaved caspase-3 (19 kDa), and cleaved caspase-3 (17 kDa) by 41, 16, 22, and 37%, respectively (P < 0.05).	2	21	decreased	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Bad	amount of Bad	bad	Bcl-2	Bcl-2	bcl-2	20	21	6	7
For instance , inhibiting the AKT mediated phosphorylation of Bad would limit its sequestration and promote Bcl-2 activation leading to apoptosis .	For instance, inhibiting the AKT mediated phosphorylation of Bad would limit its sequestration and promote Bcl-2 activation leading to apoptosis.	5	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	AKT mediated phosphorylation of Bad	bad	Bcl-2	Bcl-2	bcl-2	9	10	16	17
The apoptotic effects on the 10CA1a cells associated with the combination treatment reflect , in part , decreased Bcl-2 and increased Bad protein levels .	The apoptotic effects on the 10CA1a cells associated with the combination treatment reflect, in part, decreased Bcl-2 and increased Bad protein levels.	17	24	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad protein	Bad protein levels	bad protein	Bcl-2	Bcl-2	bcl-2	21	23	18	19
As shown in XREF_FIG , Dox caused a significant upregulation of Bax and Bad and a downregulation of Bcl-2 and Bcl-xl .	As shown in XREF_FIG, Dox caused a significant upregulation of Bax and Bad and a downregulation of Bcl-2 and Bcl-xl.	13	20	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	13	14	18	19
Additionally , BaD can antagonize anti-apoptotic Bcl-2 proteins , thus promoting apoptosis .	Additionally, BaD can antagonize anti-apoptotic Bcl-2 proteins, thus promoting apoptosis.	2	7	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BaD	BaD	BaD	Bcl-2	Bcl-2	Bcl-2	2	3	6	7
ABT-263 , an oral version of ABT-737 , is a mimetic of BH3-only BAD that inhibits BCL-2 , BCL-XL and BCL-W , but not MCL-1 .	ABT-263, an oral version of ABT-737, is a mimetic of BH3-only BAD that inhibits BCL-2, BCL-XL and BCL-W, but not MCL-1.	0	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	BAD	BAD	BCL-2	BCL-2	BCL-2	13	14	16	17
BAD can inhibit anti-apoptosis Bcl-2 family proteins , resulting in neuronal apoptosis [ XREF_BIBR ] .	BAD can inhibit anti-apoptosis Bcl-2 family proteins, resulting in neuronal apoptosis [XREF_BIBR].	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	BAD	BAD	Bcl-2	Bcl-2	Bcl-2	0	1	4	5
Paclitaxel induces the mitochondrial permeability transition , triggering the release of prodeath molecules ( Bax and Bad , which then inactivate Bcl-2 or Bcl-x L ) and activating caspases , which then induce apoptosis of neoplastic cells .	Paclitaxel induces the mitochondrial permeability transition, triggering the release of prodeath molecules (Bax and Bad, which then inactivate Bcl-2 or Bcl-x L) and activating caspases, which then induce apoptosis of neoplastic cells.	12	22	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	16	17	21	22
The BH3-only protein BAD inhibits antiapoptotic BCL-2 and BCL-xL , and facilitates BAX and BAK activation in response to apoptotic stimuli ( XREF_FIG and XREF_FIG ) .	The BH3-only protein BAD inhibits antiapoptotic BCL-2 and BCL-xL, and facilitates BAX and BAK activation in response to apoptotic stimuli (XREF_FIG and XREF_FIG).	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	BAD	BAD	BCL-2	BCL-2	BCL-2	3	4	6	7
However , a study conducted in newborn piglets exposed to F I O 2 = 1.0 for 1 h showed increased expression of the pro apoptotic proteins Bax and Bad and reduced activation of anti-apoptotic proteins Bcl-2 and Bcl-xl , as mechanisms underlying the loss of anti-apoptotic defense in hyperoxia [ XREF_BIBR ] .	However, a study conducted in newborn piglets exposed to F I O 2 = 1.0 for 1 h showed increased expression of the pro apoptotic proteins Bax and Bad and reduced activation of anti-apoptotic proteins Bcl-2 and Bcl-xl, as mechanisms underlying the loss of anti-apoptotic defense in hyperoxia [XREF_BIBR].	29	38	activation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	29	30	36	37
Subsequently , they showed that the reduction of CDH1 and AXIN2 by miR-544a also activated the wingless ( WNT ) signaling pathway by stabilizing beta-catenin in the nucleus [ XREF_BIBR ] .	Subsequently, they showed that the reduction of CDH1 and AXIN2 by miR-544a also activated the wingless (WNT) signaling pathway by stabilizing beta-catenin in the nucleus [XREF_BIBR].	6	25	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	10	11	24	25
Conversely , Axin2 [ XREF_BIBR ] and Drosophila naked cuticle ( NKD2 ) [ XREF_BIBR ] , which are negative regulators in canonical Wnt signaling , could suppress beta-catenin by inhibiting its transcription while promoting ubiquitination [ XREF_BIBR ] .	Conversely, Axin2 [XREF_BIBR] and Drosophila naked cuticle (NKD2) [XREF_BIBR], which are negative regulators in canonical Wnt signaling, could suppress beta-catenin by inhibiting its transcription while promoting ubiquitination [XREF_BIBR].	2	29	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	2	3	28	29
Based on these results , it was thought that Axin and Axin2 catalyse beta-catenin degradation by binding to the SAMP repeats of APC .	Based on these results, it was thought that Axin and Axin2 catalyse beta-catenin degradation by binding to the SAMP repeats of APC.	9	14	catalyse	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	11	12	13	14
21 A multiprotein complex containing the kinases GSK-3beta and casein kinase-1 ( CK1 ) along with the scaffolding proteins Axis inhibition protein 1 ( Axin1 ) , Axin2 , adenomatous polyposis coli ( APC ) and disheveled mediates the degradation of excess beta-catenin .	21 A multiprotein complex containing the kinases GSK-3beta and casein kinase-1 (CK1) along with the scaffolding proteins Axis inhibition protein 1 (Axin1), Axin2, adenomatous polyposis coli (APC) and disheveled mediates the degradation of excess beta-catenin.	24	43	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	27	28	42	43
Canonical Wnt signalling promotes differentiation , and is controlled at many levels , including via Axin1 and Axin2 mediated beta-catenin degradation .	Canonical Wnt signalling promotes differentiation, and is controlled at many levels, including via Axin1 and Axin2 mediated beta-catenin degradation.	3	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	17	18	19	20
The list of known Wnt targets includes genes that control beta-catenin degradation , such as AXIN1 and AXIN2 .	The list of known Wnt targets includes genes that control beta-catenin degradation, such as AXIN1 and AXIN2.	10	18	degradation	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	17	18	10	11
3.2 Nuclear AXIN2 decreases Wnt and beta-catenin reporter activity .	3.2 Nuclear AXIN2 decreases Wnt and beta-catenin reporter activity.	0	8	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
Mutations in APC , CTNNB1 , AXIN1 or AXIN2 cause impairment in the beta-catenin degradation pathway and result in accumulation of beta-catenin in a wide range of human cancers .	Mutations in APC, CTNNB1, AXIN1 or AXIN2 cause impairment in the beta-catenin degradation pathway and result in accumulation of beta-catenin in a wide range of human cancers.	0	15	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	8	9	13	14
These results indicate that nuclear AXIN2 negatively regulates beta-catenin and TCF dependent transcriptional activity .	These results indicate that nuclear AXIN2 negatively regulates beta-catenin and TCF-dependent transcriptional activity.	4	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	5	6	8	9
Our functional analysis of beta-catenin degradation in cells depleted for AXIN1 or AXIN2 indicates a predominant role of AXIN2 in the TNKSi induced degradation of beta-catenin in SW480 cells .	Our functional analysis of beta-catenin degradation in cells depleted for AXIN1 or AXIN2 indicates a predominant role of AXIN2 in the TNKSi induced degradation of beta-catenin in SW480 cells.	16	26	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	18	19	25	26
For example , the knock-out of the Wnt and beta-catenin antagonist Axin2 leads to enhanced nuclear accumulation of beta-catenin and increased levels of BMP2 , BMP6 and phosphor-Smad , which further promotes osteogenic differentiation of osteoprogenitor cells and enhances bone formation in vitro and in vivo , respectively XREF_BIBR , XREF_BIBR .	For example, the knock-out of the Wnt and beta-catenin antagonist Axin2 leads to enhanced nuclear accumulation of beta-catenin and increased levels of BMP2, BMP6 and phosphor-Smad, which further promotes osteogenic differentiation of osteoprogenitor cells and enhances bone formation in vitro and in vivo, respectively XREF_BIBR, XREF_BIBR.	4	12	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	11	12	9	10
Subsequently , the reduction of CDH1 and AXIN2 by miR-544a induced the nuclear import of beta-catenin , suggesting that miR-544a may activate the WNT signaling pathway through the stabilization of beta-catenin in nucleus .	Subsequently, the reduction of CDH1 and AXIN2 by miR-544a induced the nuclear import of beta-catenin, suggesting that miR-544a may activate the WNT signaling pathway through the stabilization of beta-catenin in nucleus.	3	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	7	8	15	16
AXIN2 serves as a scaffolding component of the multiprotein complex and negatively regulates Wnt and beta-catenin , signaling downstream pathway via degradation of beta-catenin XREF_BIBR .	AXIN2 serves as a scaffolding component of the multiprotein complex and negatively regulates Wnt and beta-catenin, signaling downstream pathway via degradation of beta-catenin XREF_BIBR.	0	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	0	1	15	16
An example of this is the transgenic deletion of Axin2 , a molecule which , as part of a multiprotein complex , represses beta-catenin signaling by targeting catenin for proteosomal degradation ; after 6 months a phenotype resulting from increased osteoblast proliferation and differentiation as well as decreased osteoclast formation ( presumably due to beta-catenin-induced increases in osteoprotegerin ) was found [ XREF_BIBR ] .	An example of this is the transgenic deletion of Axin2, a molecule which, as part of a multiprotein complex, represses beta-catenin signaling by targeting catenin for proteosomal degradation; after 6 months a phenotype resulting from increased osteoblast proliferation and differentiation as well as decreased osteoclast formation (presumably due to beta-catenin-induced increases in osteoprotegerin) was found [XREF_BIBR].	7	24	represses	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	9	10	23	24
Conductin shows reduced binding to Dvl2 compared to axin , and degradation of beta-catenin by conductin is only poorly blocked by Dvl2 .	Conductin shows reduced binding to Dvl2 compared to axin, and degradation of beta-catenin by conductin is only poorly blocked by Dvl2.	11	16	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	conductin	conductin	conductin	beta-catenin	beta-catenin	beta-catenin	15	16	13	14
Furthermore , Axin2 mRNA , a downstream target of Wnt and beta-catenin signaling , is significantly decreased by ~ 70 % in PostnCre ; Ctnnb1 fl/fl animals , compared to Cre negative controls , in isolated AoV leaflets at 3 months of age ( XREF_SUPPLEMENTARY ) .	Furthermore, Axin2 mRNA, a downstream target of Wnt and beta-catenin signaling, is significantly decreased by ~ 70% in PostnCre; Ctnnb1 fl/fl animals, compared to Cre negative controls, in isolated AoV leaflets at 3 months of age (XREF_SUPPLEMENTARY).	2	26	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	Ctnnb1	Ctnnb1	Ctnnb1	2	3	24	25
Axin1 and Axin2 are functionally equivalent and have been shown to inhibit Wnt and beta-catenin signaling and stimulate TGF-beta signaling .	Axin1 and Axin2 are functionally equivalent and have been shown to inhibit Wnt and beta-catenin signaling and stimulate TGF-beta signaling.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	2	3	14	15
TCF4 , APC , axin and axin2 move more slowly than beta-catenin in their respective compartment , and concomitantly decrease beta-catenin mobility .	TCF4, APC, axin and axin2 move more slowly than beta-catenin in their respective compartment, and concomitantly decrease beta-catenin mobility.	0	21	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	axin2	axin2	axin2	beta-catenin	beta-catenin	beta-catenin	6	7	20	21
Furthermore , stabilization of the Axin2 protein using XAV939 promoted beta-catenin degradation and increased the number of PLP+ OLs compared to controls .	Furthermore, stabilization of the Axin2 protein using XAV939 promoted beta-catenin degradation and increased the number of PLP+ OLs compared to controls.	5	11	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
ERK nuclear translocation and anti-apoptosis induced by mechanical stretching or fluid flow is abolished by the Wnt antagonist DKK1 and the stimulator of beta-catenin degradation Axin2 .	ERK nuclear translocation and anti-apoptosis induced by mechanical stretching or fluid flow is abolished by the Wnt antagonist DKK1 and the stimulator of beta-catenin degradation Axin2.	21	26	degradation	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	25	26	23	24
To further address this possibility , we tested the effects of IWR1 , a chemical stabilizer of the AXIN2 protein that degrades beta-catenin to inhibit Wnt signalling 60 , in LRH1 mediated EpiSC reprogramming .	To further address this possibility, we tested the effects of IWR1, a chemical stabilizer of the AXIN2 protein that degrades beta-catenin to inhibit Wnt signalling 60, in LRH1 mediated EpiSC reprogramming.	18	23	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	18	19	22	23
Given its suppressive features as a main component of the beta-catenin destruction complex XREF_BIBR , AXIN2 could also suppress beta-catenin activity downstream of Wnt-receptor binding .	Given its suppressive features as a main component of the beta-catenin destruction complex XREF_BIBR, AXIN2 could also suppress beta-catenin activity downstream of Wnt-receptor binding.	15	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	15	16	19	20
These results suggest that Axin2 overexpression does not lead to beta-catenin degradation , but instead blocks nuclear translocation of beta-catenin induced by CHIR .	These results suggest that Axin2 overexpression does not lead to beta-catenin degradation, but instead blocks nuclear translocation of beta-catenin induced by CHIR.	4	20	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2 overexpression	axin2	beta-catenin	beta-catenin	beta-catenin	4	5	19	20
Axin2 , a known inhibitor of the Wnt signaling pathway , suppresses beta-catenin and bone remodeling .	Axin2, a known inhibitor of the Wnt signaling pathway, suppresses beta-catenin and bone remodeling.	0	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	0	1	12	13
Increased levels of Axin1 and Axin2 stimulate beta-catenin degradation and thereby inhibit beta-catenin-mediated transcription [ XREF_BIBR ] .	Increased levels of Axin1 and Axin2 stimulate beta-catenin degradation and thereby inhibit beta-catenin-mediated transcription [XREF_BIBR].	1	8	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	levels of Axin1 and Axin2	axin2	beta-catenin	beta-catenin	beta-catenin	5	6	7	8
Axin1 and Axin2 are functionally equivalent and are known to inhibit Wnt and CTNNB1 and stimulate TGFbeta signaling .	Axin1 and Axin2 are functionally equivalent and are known to inhibit Wnt and CTNNB1 and stimulate TGFbeta signaling.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	CTNNB1	CTNNB1	CTNNB1	2	3	13	14
Axin2 , similar to Axin1 , inhibits the pathway by promoting beta-catenin turnover .	Axin2, similar to Axin1, inhibits the pathway by promoting beta-catenin turnover.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	0	1	11	12
Axin2 negatively regulates Wnt and beta-catenin signaling and mutations in Axin2 have been described to be oncogenic in colorectal cancer [ XREF_BIBR , XREF_BIBR ] .	Axin2 negatively regulates Wnt and beta-catenin signaling and mutations in Axin2 have been described to be oncogenic in colorectal cancer [XREF_BIBR, XREF_BIBR].	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	0	1	5	6
Notably , target gene Axin2 acts via negative feedback mechanism to inhibit beta-catenin activation .	Notably, target gene Axin2 acts via negative feedback mechanism to inhibit beta-catenin activation.	2	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	4	5	12	13
Since the suppression Axin1 and Axin2 expression by TGF-beta reduces TGF-beta signaling and enhances Wnt and beta-catenin signaling , the overall effect is a shift from TGF-beta toward Wnt and beta-catenin signaling and an acceleration of chondrocyte maturation .	Since the suppression Axin1 and Axin2 expression by TGF-beta reduces TGF-beta signaling and enhances Wnt and beta-catenin signaling, the overall effect is a shift from TGF-beta toward Wnt and beta-catenin signaling and an acceleration of chondrocyte maturation.	5	17	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2 expression	axin2	beta-catenin	beta-catenin	beta-catenin	5	6	16	17
Because Axin2 can inhibit beta-catenin abundance and function , the data implicate AXIN2 in a negative feedback pathway regulating Wnt signaling .	Because Axin2 can inhibit beta-catenin abundance and function, the data implicate AXIN2 in a negative feedback pathway regulating Wnt signaling.	1	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	1	2	4	5
Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor Induced Formation of Degradasomes and beta-Catenin Degradation .	Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor Induced Formation of Degradasomes and beta-Catenin Degradation.	1	15	Induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-Catenin	beta-Catenin	beta-Catenin	5	6	14	15
The transcription of Axin2 is promoted by Tcf and beta-catenin , while the Axin2 protein promotes the degradation of beta-catenin .	The transcription of Axin2 is promoted by Tcf and beta-catenin, while the Axin2 protein promotes the degradation of beta-catenin.	13	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	13	14	19	20
Axin2 is activated by beta-catenin , which in turn is degraded by a complex of GSK3beta and Axin2 .	Axin2 is activated by beta-catenin, which in turn is degraded by a complex of GSK3beta and Axin2.	2	18	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	17	18	4	5
Here we show that while Wnt3a stimulates Axin2 in a negative feedback loop , TGF-beta suppresses the expression of both Axin1 and Axin2 and stimulates beta-catenin signaling .	Here we show that while Wnt3a stimulates Axin2 in a negative feedback loop, TGF-beta suppresses the expression of both Axin1 and Axin2 and stimulates beta-catenin signaling.	14	26	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Axin2	TGF-beta suppresses the expression of both Axin1 and Axin2	axin2	beta-catenin	beta-catenin	beta-catenin	22	23	25	26
Our results indicate that the nuclear pool of AXIN2 negatively regulates Wnt and beta-catenin signaling .	Our results indicate that the nuclear pool of AXIN2 negatively regulates Wnt and beta-catenin signaling.	6	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	8	9	13	14
Our results showed that GEN-27 increased expressions of adenomatous polyposis coli ( APC ) and axis inhibition protein 2 ( AXIN2 ) , and reduced beta-catenin nuclear localization , which resulted from the inhibition of NF-kappaB and p65 nuclear localization and up-regulation of caudal related homeobox transcription factor 2 ( CDX2 ) .	Our results showed that GEN-27 increased expressions of adenomatous polyposis coli (APC) and axis inhibition protein 2 (AXIN2), and reduced beta-catenin nuclear localization, which resulted from the inhibition of NF-kappaB and p65 nuclear localization and up-regulation of caudal related homeobox transcription factor 2 (CDX2).	4	27	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	axis inhibition protein 2	GEN-27 increased expressions of adenomatous polyposis coli (APC) and axis inhibition protein 2	axis inhibition protein 2	beta-catenin	beta-catenin	beta-catenin	15	19	25	26
Conductin induced beta-catenin degradation , whereas mutants of conductin that were deficient in complex formation stabilized beta-catenin .	Conductin induced beta-catenin degradation, whereas mutants of conductin that were deficient in complex formation stabilized beta-catenin.	0	3	induced	Positive_early_activation	Negative_activation	Negative_activation	Conductin	Conductin	Conductin	beta-catenin	beta-catenin	beta-catenin	0	1	2	3
The AXIN homologue conduction , also known as AXIL or AXIN2 , serves as a scaffolding component of the multiprotein complex and negatively regulates the Wnt and beta-catenin pathway [ XREF_BIBR ] .	The AXIN homologue conduction, also known as AXIL or AXIN2, serves as a scaffolding component of the multiprotein complex and negatively regulates the Wnt and beta-catenin pathway [XREF_BIBR].	2	28	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	homologue conduction	homologue conduction	homologue conduction	beta-catenin	beta-catenin	beta-catenin	2	4	27	28
These expression patterns are approximately consistent with those of canonical Wnt target genes such as Axin2 , Sox9 , and Lgr5 , leading to speculation that Msi genes are targets of beta-catenin transactivation , although this has never been formally demonstrated in vivo .	These expression patterns are approximately consistent with those of canonical Wnt target genes such as Axin2, Sox9, and Lgr5, leading to speculation that Msi genes are targets of beta-catenin transactivation, although this has never been formally demonstrated in vivo.	15	32	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	15	16	31	32
We next addressed potential mechanisms that might explain how nuclear AXIN2 was repressing beta-catenin and TCF dependent transcriptional activation .	We next addressed potential mechanisms that might explain how nuclear AXIN2 was repressing beta-catenin and TCF-dependent transcriptional activation.	9	18	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	10	11	13	14
In colon carcinoma cells , forced expression of conductin downregulates beta-catenin , whereas in normal cells mutants of conductin that are deficient in complex formation stabilize beta-catenin .	In colon carcinoma cells, forced expression of conductin downregulates beta-catenin, whereas in normal cells mutants of conductin that are deficient in complex formation stabilize beta-catenin.	6	11	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	conductin	expression of conductin	conductin	beta-catenin	beta-catenin	beta-catenin	8	9	10	11
Genetic knockdown of Axin-2 up-regulates Wnt and beta-catenin signaling by destabilizing the beta-catenin degradation complex in SNpc in parkinsonian rats .	Genetic knockdown of Axin-2 up-regulates Wnt and beta-catenin signaling by destabilizing the beta-catenin degradation complex in SNpc in parkinsonian rats.	1	8	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin-2	Axin-2	Axin-2	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
Because AXIN2 is a negative regulator of WNT signaling and disruption of Axin2 increases beta-catenin signaling , areas strongly expressing Axin2 are likely to have low beta-catenin activity .	Because AXIN2 is a negative regulator of WNT signaling and disruption of Axin2 increases beta-catenin signaling, areas strongly expressing Axin2 are likely to have low beta-catenin activity.	10	15	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	12	13	14	15
The retained beta-catenin in cytoplasm by APC may be down-regulated by Axin 2 , which is induced by beta-catenin and Tcf signaling .	The retained beta-catenin in cytoplasm by APC may be down-regulated by Axin 2, which is induced by beta-catenin and Tcf signaling.	0	16	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Axin 2	Axin 2	Axin 2	beta-catenin	beta-catenin	beta-catenin	11	13	2	3
Axin2 is able to downregulate beta-catenin and acts as a negative regulator of Wnt signaling [ XREF_BIBR ] .	Axin2 is able to downregulate beta-catenin and acts as a negative regulator of Wnt signaling [XREF_BIBR].	0	7	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	0	1	5	6
Bax is counteracted by Bcl-xL that forms heterodimers with dephosphorylation of Bad , which inactivates Bcl-xL , and Bad phosphorylation eliminates this dimerization , which activates Bcl-xL .	Bax is counteracted by Bcl-xL that forms heterodimers with dephosphorylation of Bad, which inactivates Bcl-xL, and Bad phosphorylation eliminates this dimerization, which activates Bcl-xL.	9	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	dephosphorylation of Bad	bad	Bcl-xL	Bcl-xL	bcl-xl	11	12	15	16
Taken together , these data demonstrate that phosphorylation of BAD by IKK at Ser26 prevents BAD from translocating to the mitochondria to bind to and inactivate BCL-X L , thereby inhibiting the pro apoptotic activity of BAD upon TNFalpha stimulation .	Taken together, these data demonstrate that phosphorylation of BAD by IKK at Ser26 prevents BAD from translocating to the mitochondria to bind to and inactivate BCL-X L, thereby inhibiting the pro apoptotic activity of BAD upon TNFalpha stimulation.	7	28	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	phosphorylation of BAD by IKK at Ser26	bad	BCL-X L	BCL-X L	bcl-x l	9	10	26	28
Fenofibrate increased the expression of Bad , but decreased that of Bcl-xL and Survivin , and activated caspase-3 .	Fenofibrate increased the expression of Bad, but decreased that of Bcl-xL and Survivin, and activated caspase-3.	0	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	Fenofibrate increased the expression of Bad	bad	Bcl-xL	Bcl-xL	bcl-xl	5	6	11	12
It has been demonstrated that activated Akt phosphorylates BAD , resulting in its sequestration by cytosolic 14-3-3 proteins [ XREF_BIBR , XREF_BIBR ] Because BAD binds to and inhibits the anti-apoptotic actions of Bcl- XL , the sequestration of BAD in the cytosol by 14-3-3 proteins results in enhanced survival .	It has been demonstrated that activated Akt phosphorylates BAD, resulting in its sequestration by cytosolic 14-3-3 proteins [XREF_BIBR, XREF_BIBR] Because BAD binds to and inhibits the anti-apoptotic actions of Bcl- XL, the sequestration of BAD in the cytosol by 14-3-3 proteins results in enhanced survival.	24	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	BAD	BAD	Bcl- XL	Bcl- XL	Bcl- XL	24	25	33	35
In addition , the activation of AKT blocks apoptosis through the phosphorylation of pro apoptotic protein BAD ( BCL2 antagonist of cell death , Bcl-XL and Bcl-2-association death promoter ) .	In addition, the activation of AKT blocks apoptosis through the phosphorylation of pro apoptotic protein BAD (BCL2 antagonist of cell death, Bcl-XL and Bcl-2-association death promoter).	11	25	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	BAD	phosphorylation of pro apoptotic protein BAD	bad	Bcl-XL	Bcl-XL	bcl-xl	16	17	24	25
Our results indicating that phosphorylation of Bad at Thr201 by Epo activated JNK1 significantly reduced the association of Bad with Bcl-X L in vitro ( XREF_FIG ) , thus inhibiting the pro apoptotic activity of Bad , is consistent with our previous reports .	Our results indicating that phosphorylation of Bad at Thr201 by Epo activated JNK1 significantly reduced the association of Bad with Bcl-X L in vitro (XREF_FIG), thus inhibiting the pro apoptotic activity of Bad, is consistent with our previous reports.	4	22	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	phosphorylation of Bad at Thr201	bad	Bcl-X L	Bcl-X L	bcl-x l	6	7	20	22
Akt also phosphorylates Bad at Ser 136 to block the antagonism between Bad and Bcl-2 or Bad and Bcl-xL and promote cell survival .	Akt also phosphorylates Bad at Ser 136 to block the antagonism between Bad and Bcl-2 or Bad and Bcl-xL and promote cell survival.	0	20	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	Akt also phosphorylates Bad at Ser 136	bad	Bcl-xL	Bcl-xL	bcl-xl	3	4	18	19
Bax is counteracted by Bcl-xL that forms heterodimers with dephosphorylation of Bad , which inactivates Bcl-xL ; and pBad eliminates this dimerization , which activates Bcl-xL [ XREF_BIBR , XREF_BIBR ] .	Bax is counteracted by Bcl-xL that forms heterodimers with dephosphorylation of Bad, which inactivates Bcl-xL; and pBad eliminates this dimerization, which activates Bcl-xL [XREF_BIBR, XREF_BIBR].	9	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	dephosphorylation of Bad	bad	Bcl-xL	Bcl-xL	bcl-xl	11	12	15	16
Apoptosis may also be triggered by inactivation of Bcl-XL by BAD .	Apoptosis may also be triggered by inactivation of Bcl-XL by BAD.	4	11	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	BAD	BAD	BAD	Bcl-XL	Bcl-XL	Bcl-XL	10	11	8	9
That is , jnk mediated cleavage of BID to truncated ( t )-BID results in mitochondrial release of cytochrome C whereas its phosphorylation of BAD at theronine 201 inhibits inactivation of the anti-apoptotic protein , BCL-X l , by BAD .	That is, jnk mediated cleavage of BID to truncated (t)-BID results in mitochondrial release of cytochrome C whereas its phosphorylation of BAD at theronine 201 inhibits inactivation of the anti-apoptotic protein, BCL-X l, by BAD.	22	37	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	phosphorylation of BAD	bad	BCL-X l	BCL-X l	bcl-x l	24	25	35	37
Conversely , loss of even a single Bim allele sufficed to substantially accelerate lymphomagenesis , and only loss of both but not loss of a single allele of Bclx could attenuate this acceleration .	Conversely, loss of even a single Bim allele sufficed to substantially accelerate lymphomagenesis, and only loss of both but not loss of a single allele of Bclx could attenuate this acceleration.	7	29	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bclx	Bclx	Bclx	7	8	28	29
In particular , the increased expression of the pro apoptotic member Bim in T cells after cytokine deprival relieves the inhibitory effect anti-apoptotic Bcl-2 and Bcl-xL exert on Bax and Bak .	In particular, the increased expression of the pro apoptotic member Bim in T cells after cytokine deprival relieves the inhibitory effect anti-apoptotic Bcl-2 and Bcl-xL exert on Bax and Bak.	11	26	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-xL	Bcl-xL	Bcl-xL	11	12	25	26
We also show that BIM BH3 peptide inhibits Bcl-xL dimerization , based on BN-PAGE and NMR studies , possibly to protect Bax oligomerization XREF_BIBR in the membrane by ( a ) engaging the Bcl-xL dimers , thereby preventing Bcl-xL from inhibiting Bax oligomerization or ( b ) a step ahead where they inhibit the Bcl-xL conversion from monomers to dimers .	We also show that BIM BH3 peptide inhibits Bcl-xL dimerization, based on BN-PAGE and NMR studies, possibly to protect Bax oligomerization XREF_BIBR in the membrane by (a) engaging the Bcl-xL dimers, thereby preventing Bcl-xL from inhibiting Bax oligomerization or (b) a step ahead where they inhibit the Bcl-xL conversion from monomers to dimers.	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIM	BIM	BIM	Bcl-xL	Bcl-xL	Bcl-xL	4	5	8	9
Wildtype Bim BH3 peptide ( Bim sequence CEIWIAQELRRIGDEFNAYYAR ) , the natural Bcl-X L ligand , outcompetes the reactive fragments for binding at the BH3 binding site of Bcl-X L and thus suppresses the Bcl-X L -templated assembly of acylsulfonamides SZ7TA2 , SZ9TA1 , and SZ9TA5 .	Wildtype Bim BH3 peptide (Bim sequence CEIWIAQELRRIGDEFNAYYAR), the natural Bcl-X L ligand, outcompetes the reactive fragments for binding at the BH3 binding site of Bcl-X L and thus suppresses the Bcl-X L -templated assembly of acylsulfonamides SZ7TA2, SZ9TA1, and SZ9TA5.	1	37	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-X L	Bcl-X L	Bcl-X L	1	2	34	36
Induction of Bim by FOXO3 is essential for this phenomenon because Bim knockdown or ectopic expression of BCL2L1 ( BclxL ) prevented FOXO3 mediated overproduction of ROS and apoptosis .	Induction of Bim by FOXO3 is essential for this phenomenon because Bim knockdown or ectopic expression of BCL2L1 (BclxL) prevented FOXO3 mediated overproduction of ROS and apoptosis.	11	19	knockdown	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Bim	Bim	Bim	BCL2L1	BCL2L1	BCL2L1	11	12	17	18
Mutation of E18 in Bim to a serine diminishes the binding of Bcl-xL , whereas phosphorylating the resultant serine restores binding , as a result of phopshoryl group interactions with arginine residues [ XREF_BIBR ] .	Mutation of E18 in Bim to a serine diminishes the binding of Bcl-xL, whereas phosphorylating the resultant serine restores binding, as a result of phopshoryl group interactions with arginine residues [XREF_BIBR].	2	13	diminishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-xL	Bcl-xL	Bcl-xL	4	5	12	13
Bim forward , 5 '-GCAGATATGCGCCCAGAGAT-3 ' and reverse , 5 '-AAGCGTTAAACTCGTCTCCGATA-3 ' ; Bcl-xL forward , 5 '-GTGCGTGGAAAGCGTAGACA-3 ' and reverse , 5 '-CAGCCAAGGTGACCCATTAC-3 ' ; beta-actin forward , 5 '-AACAGTCCGCCTAGAAGCAC-3 ' and reverse , 5 '-CGTTGACATCCGTAAAGACC-3 ' .	Bim forward, 5 '-GCAGATATGCGCCCAGAGAT-3 ' and reverse, 5 '-AAGCGTTAAACTCGTCTCCGATA-3 '; Bcl-xL forward, 5 '-GTGCGTGGAAAGCGTAGACA-3 ' and reverse, 5 '-CAGCCAAGGTGACCCATTAC-3 '; beta-actin forward, 5 '-AACAGTCCGCCTAGAAGCAC-3 ' and reverse, 5 '-CGTTGACATCCGTAAAGACC-3 '.	0	33	reverse	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bim	Bim	Bim	Bcl-xL	Bcl-xL	Bcl-xL	0	1	13	14
DEC2 overexpression during cisplatin treatment markedly inhibited expression of the pro apoptotic factor Bim and slightly increased the anti-apoptotic factor Bcl-xL .	DEC2 overexpression during cisplatin treatment markedly inhibited expression of the pro apoptotic factor Bim and slightly increased the anti-apoptotic factor Bcl-xL.	0	21	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	DEC2 overexpression during cisplatin treatment markedly inhibited expression of the pro apoptotic factor Bim	bim	Bcl-xL	Bcl-xL	bcl-xl	13	14	20	21
It has also been proposed that Bcl-X L inhibits Beclin 1 activity by stabilizing Beclin 1 homo-dimerization , which can be disrupted by UVRAG [ XREF_BIBR ] .	It has also been proposed that Bcl-X L inhibits Beclin 1 activity by stabilizing Beclin 1 homo-dimerization, which can be disrupted by UVRAG [XREF_BIBR].	6	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	Beclin 1	Beclin 1	Beclin 1	6	8	9	11
Inhibitors of Bcl-XL and Bcl -2 can induce autophagy by releasing the autophagic protein Beclin 1 from its complexes with these proteins .	Inhibitors of Bcl-XL and Bcl -2 can induce autophagy by releasing the autophagic protein Beclin 1 from its complexes with these proteins.	0	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	Beclin 1	Beclin 1	Beclin 1	2	3	14	16
Bcl-X L can inhibit Beclin-1 activity by stabilizing Beclin-1 homodimerization [ XREF_BIBR ] .	Bcl-X L can inhibit Beclin-1 activity by stabilizing Beclin-1 homodimerization [XREF_BIBR].	0	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	Beclin-1	Beclin-1	Beclin-1	0	2	4	5
In addition , BCL-XL also promotes cell survival by binding to and inhibiting Beclin-1 to inhibit stress induced autophagy .	In addition, BCL-XL also promotes cell survival by binding to and inhibiting Beclin-1 to inhibit stress induced autophagy.	3	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-XL	BCL-XL	BCL-XL	Beclin-1	Beclin-1	Beclin-1	3	4	13	14
Bcl-2 D/A or Bcl-xL D/A inhibits caspase-9-induced release of Smac and cytochrome c. Decreased release of mitochondrial apoptotic effectors involved in caspase mediated cell death in cells expressing Bcl-2 D/A or Bcl-xL D/A could explain the decreased activation of caspases observed in these cells .	Bcl-2 D/A or Bcl-xL D/A inhibits caspase-9-induced release of Smac and cytochrome c. Decreased release of mitochondrial apoptotic effectors involved in caspase mediated cell death in cells expressing Bcl-2 D/A or Bcl-xL D/A could explain the decreased activation of caspases observed in these cells.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Smac	Smac	Smac	0	1	9	10
Mitochondrial Smac release is suppressed by Bcl-2 and Bcl-XL ( Vyas et al , 2004 ) .	Mitochondrial Smac release is suppressed by Bcl-2 and Bcl-XL (Vyas et al, 2004).	1	10	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Smac	Smac	Smac	6	7	1	2
We found that Bcl-2 D/A or Bcl-xL D/A inhibited the release of Smac from the mitochondria after caspase-9 activation ( XREF_FIG ) .	We found that Bcl-2 D/A or Bcl-xL D/A inhibited the release of Smac from the mitochondria after caspase-9 activation (XREF_FIG).	3	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Smac	Smac	Smac	3	4	12	13
Bid knock down and Bcl-2 overexpression delayed Bax-GFP aggregation and completely inhibited Smac and DIABLO-GFP release from mitochondria .	Bid knock down and Bcl-2 overexpression delayed Bax-GFP aggregation and completely inhibited Smac and DIABLO-GFP release from mitochondria.	4	15	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	DIABLO-GFP	DIABLO-GFP	diablo-gfp	4	5	14	15
We find that desflurane preconditioning increased the expression of c-IAP1 and Bcl-2 , inhibited cleavage of caspase-3 and leakage of SMAC in HUVECs submitted to A/R , accompanying attenuation of cell apoptosis .	We find that desflurane preconditioning increased the expression of c-IAP1 and Bcl-2, inhibited cleavage of caspase-3 and leakage of SMAC in HUVECs submitted to A/R, accompanying attenuation of cell apoptosis.	7	21	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	expression of c-IAP1 and Bcl-2	bcl-2	SMAC	SMAC	smac	11	12	20	21
It is reported that Bcl-2 attenuated the release of Smac from the mitochondria .	It is reported that Bcl-2 attenuated the release of Smac from the mitochondria.	4	10	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Smac	Smac	Smac	4	5	9	10
Proapoptotic Bcl-2 family members Bid , Bak , and Bax are essential for the release of cytochrome c and Smac from mitochondria ( Kandasamy et al , 2003 ) , whereas Bcl-2 and Bcl-xL prevent mitochondrial release of Smac ( Sun et al , 2002 ) .	Proapoptotic Bcl-2 family members Bid, Bak, and Bax are essential for the release of cytochrome c and Smac from mitochondria (Kandasamy et al, 2003), whereas Bcl-2 and Bcl-xL prevent mitochondrial release of Smac (Sun et al, 2002).	31	40	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Smac	Smac	Smac	31	32	38	39
Besides inhibiting VDAC1 , Bcl-X L has been reported to enhance VDAC1 activity .	Besides inhibiting VDAC1, Bcl-X L has been reported to enhance VDAC1 activity.	4	12	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-X L	Bcl-X L	Bcl-X L	VDAC1	VDAC1	VDAC1	4	6	11	12
Similarly , both Bcl2 and Bcl-xL prevented apoptosis as induced by various stimuli in cells expressing wild type but not mutated VDAC1 .	Similarly, both Bcl2 and Bcl-xL prevented apoptosis as induced by various stimuli in cells expressing wild type but not mutated VDAC1.	3	22	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	VDAC1	VDAC1	VDAC1	5	6	21	22
Both the antiapoptotic proteins Bcl-2 and Bcl-XL inhibit the MAMs-resident voltage dependent anion channel VDAC1 , by controlling its permeability to Ca 2+ and thereby preventing cyt c release and apoptotic cell death .	Both the antiapoptotic proteins Bcl-2 and Bcl-XL inhibit the MAMs-resident voltage dependent anion channel VDAC1, by controlling its permeability to Ca 2+ and thereby preventing cyt c release and apoptotic cell death.	4	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	VDAC1	VDAC1	VDAC1	6	7	14	15
Using mRNA prepared from 2-month-old VDAC1 +/- and VDAC1 +/+ ( wild-type ) mice , we determined the effects of reduced VDAC1 on 9 genes : Drp1 and Fis1 ( fission ) ; Mfn1 , Mfn2 , and Opa1 ( fusion ) ; VDAC1 ( outermembrane ) ; ANT ( innermembrane ) ; and CypD and BclXL ( matrix genes ) ( XREF_TABLE ) .	Using mRNA prepared from 2-month-old VDAC1 +/- and VDAC1 +/+ (wild-type) mice, we determined the effects of reduced VDAC1 on 9 genes : Drp1 and Fis1 (fission); Mfn1, Mfn2, and Opa1 (fusion); VDAC1 (outermembrane); ANT (innermembrane); and CypD and BclXL (matrix genes) (XREF_TABLE).	18	57	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BclXL	BclXL	BclXL	VDAC1	VDAC1	VDAC1	56	57	21	22
In contrast , anti-apoptotic Bcl-XL prevents VDAC closure , a finding consistent with the interpretation that VDAC opening is anti-apoptotic [ XREF_BIBR ] .	In contrast, anti-apoptotic Bcl-XL prevents VDAC closure, a finding consistent with the interpretation that VDAC opening is anti-apoptotic [XREF_BIBR].	3	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	VDAC	VDAC	VDAC	4	5	6	7
Interestingly , Bcl-2 family members seem to control MPT ; Bcl-2 and Bcl- XL has been shown to inhibit VDAC and ANT activity in liposome experiments [ XREF_BIBR ] , but the relevance of this data is difficult to evaluate in the absence of a clear working model .	Interestingly, Bcl-2 family members seem to control MPT; Bcl-2 and Bcl- XL has been shown to inhibit VDAC and ANT activity in liposome experiments [XREF_BIBR], but the relevance of this data is difficult to evaluate in the absence of a clear working model.	12	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl- XL	Bcl- XL	Bcl- XL	VDAC	VDAC	VDAC	12	14	19	20
There are also reports that Bcl-xl can attenuate VDAC opening which has also been suggested to oppose mPTP [ XREF_BIBR ] .	There are also reports that Bcl-xl can attenuate VDAC opening which has also been suggested to oppose mPTP [XREF_BIBR].	5	9	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xl	Bcl-xl	Bcl-xl	VDAC	VDAC	VDAC	5	6	8	9
This same group reported that the BH4 domain of antiapoptotic Bcl-2 family proteins , Bcl-2 and Bcl-X L , physically interacts with VDAC and inhibits VDAC activity ( VDAC closure ) [ XREF_BIBR ] .	This same group reported that the BH4 domain of antiapoptotic Bcl-2 family proteins, Bcl-2 and Bcl-X L, physically interacts with VDAC and inhibits VDAC activity (VDAC closure) [XREF_BIBR].	14	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	VDAC	VDAC	VDAC	16	18	25	26
In addition , via its BH4 domain , Bcl-XL at MAMs can also target VDAC1 XREF_BIBR , and inhibition of VDAC1 by Bcl-XL prevents mitochondrial Ca 2+ overload and protects against apoptosis XREF_BIBR .	In addition, via its BH4 domain, Bcl-XL at MAMs can also target VDAC1 XREF_BIBR, and inhibition of VDAC1 by Bcl-XL prevents mitochondrial Ca 2+ overload and protects against apoptosis XREF_BIBR.	8	15	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-XL	Bcl-XL	Bcl-XL	VDAC1	VDAC1	VDAC1	8	9	14	15
Hence , Bcl-X L could stimulate basal pro survival and inhibit excessive pro apoptotic VDAC1 mediated mitochondrial Ca 2+ transfer , thereby fine tuning mitochondrial Ca 2+ handling according to cellular needs , with respect to cell fate decisions .	Hence, Bcl-X L could stimulate basal pro survival and inhibit excessive pro apoptotic VDAC1 mediated mitochondrial Ca 2+ transfer, thereby fine tuning mitochondrial Ca 2+ handling according to cellular needs, with respect to cell fate decisions.	2	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	VDAC1	VDAC1	VDAC1	2	4	14	15
Overexpression of Bcl-xL , a protein that inhibits caspase-9 activation , had the same effect on muscle differentiation as knockdown of caspase-9 .	Overexpression of Bcl-xL, a protein that inhibits caspase-9 activation, had the same effect on muscle differentiation as knockdown of caspase-9.	0	9	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Bcl-xL	Overexpression of Bcl-xL	bcl-xl	caspase-9	caspase-9	caspase-9	2	3	8	9
These observations , together with previous results obtained with Bcl-2 , argue that Bcl-xL and Bcl-2 can not block the apoptosome mediated activation of caspase-9 .	These observations, together with previous results obtained with Bcl-2, argue that Bcl-xL and Bcl-2 can not block the apoptosome mediated activation of caspase-9.	13	25	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	caspase-9	caspase-9	caspase-9	13	14	24	25
In addition , MeCP2 shRNA-1 and shRNA-2 also inhibited Bcl-2 and Bcl-xL expressions , and promoted Caspase-9 and Caspase-3 activation in xenograft tumor ( XREF_FIG G ) .	In addition, MeCP2 shRNA-1 and shRNA-2 also inhibited Bcl-2 and Bcl-xL expressions, and promoted Caspase-9 and Caspase-3 activation in xenograft tumor (XREF_FIG G).	3	19	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	MeCP2 shRNA-1 and shRNA-2 also inhibited Bcl-2 and Bcl-xL expressions	bcl-xl	Caspase-9	Caspase-9	caspase-9	11	12	16	17
When grown in coculture with endothelial cells and exposed to LPS in coculture but harvested independently , pericytes showed decreased levels of p11 and p17 and increased levels of Bcl-xL , an antiapoptotic protein that protects the integrity of mitochondria , and prevents cytochrome c release and subsequent caspase-9 activation .	When grown in coculture with endothelial cells and exposed to LPS in coculture but harvested independently, pericytes showed decreased levels of p11 and p17 and increased levels of Bcl-xL, an antiapoptotic protein that protects the integrity of mitochondria, and prevents cytochrome c release and subsequent caspase-9 activation.	27	49	prevents	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Bcl-xL	levels of Bcl-xL	bcl-xl	caspase-9	caspase-9	caspase-9	29	30	48	49
XREF_BIBR Furthermore , M-CSF acts as a survival factor for the OC precursors through Bcl-X ( L )-induced inhibition of caspase-9 activation , which inhibits apoptosis of OC precursors .	XREF_BIBR Furthermore, M-CSF acts as a survival factor for the OC precursors through Bcl-X (L)-induced inhibition of caspase-9 activation, which inhibits apoptosis of OC precursors.	4	24	inhibition	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Bcl-X	Bcl-X	Bcl-X	caspase-9	caspase-9	caspase-9	14	15	20	21
Bcl-xL inhibited processing of caspase-9 , Ac-DEVD-MCA cleavage activity and DNA fragmentation induced by RA/BMP -4 treatment .	Bcl-xL inhibited processing of caspase-9, Ac-DEVD-MCA cleavage activity and DNA fragmentation induced by RA/BMP -4 treatment.	0	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	caspase-9	caspase-9	caspase-9	0	1	4	5
The overexpression of Bcl-xL also prevented the activation of caspase 9 and 3 .	The overexpression of Bcl-xL also prevented the activation of caspase 9 and 3.	1	12	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	overexpression of Bcl-xL	bcl-xl	caspase 9	caspase 9	caspase 9	3	4	9	11
The BH4 domain of Bcl-2 and Bcl-X L can bind to the C-terminal portion of Apaf-1 and consequently inhibits the association of caspase-9 with Apaf-1 [ XREF_BIBR ] .	The BH4 domain of Bcl-2 and Bcl-X L can bind to the C-terminal portion of Apaf-1 and consequently inhibits the association of caspase-9 with Apaf-1 [XREF_BIBR].	4	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	caspase-9	caspase-9	caspase-9	6	8	22	23
VPA treatment at different concentrations for 48 h obviously lowered the protein levels of Bcl-xl , Bcl-2 , and Mcl-1 and induced caspase-9 and caspase-3 activation in SPC-A1 cells .	VPA treatment at different concentrations for 48 h obviously lowered the protein levels of Bcl-xl, Bcl-2, and Mcl-1 and induced caspase-9 and caspase-3 activation in SPC-A1 cells.	0	25	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xl	VPA treatment at different concentrations for 48 h obviously lowered the protein levels of Bcl-xl	bcl-xl	caspase-9	caspase-9	caspase-9	14	15	22	23
We found that overexpression of miR-874-3p decreased Bcl-2 and Bcl-xL expression , but enhanced the activity of caspase-9 and -3 .	We found that overexpression of miR-874-3p decreased Bcl-2 and Bcl-xL expression, but enhanced the activity of caspase-9 and -3.	3	19	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	overexpression of miR-874-3p decreased Bcl-2 and Bcl-xL expression	bcl-xl	caspase-9	caspase-9	caspase-9	9	10	17	18
Furthermore , Bcl-XL failed to inhibit caspase-9 processing mediated by a constitutively active Apaf-1 mutant , suggesting that Bcl-XL regulates caspase-9 through Apaf-1 .	Furthermore, Bcl-XL failed to inhibit caspase-9 processing mediated by a constitutively active Apaf-1 mutant, suggesting that Bcl-XL regulates caspase-9 through Apaf-1.	2	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Bcl-XL	Bcl-XL	caspase-9	caspase-9	caspase-9	2	3	6	7
This pattern of localization is maintained when the proteins are co-expressed in both normal and apoptotic cells , suggesting that Bcl-2 , Bcl-xL or Bax do not significantly sequester cytoplasmic Apaf-1 to intracellular membranes .	This pattern of localization is maintained when the proteins are co-expressed in both normal and apoptotic cells, suggesting that Bcl-2, Bcl-xL or Bax do not significantly sequester cytoplasmic Apaf-1 to intracellular membranes.	20	31	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Apaf-1	Apaf-1	Apaf-1	22	23	30	31
However , neither Bcl-2 nor Bcl-x L could prevent the in vitro activation of Apaf-1 induced by the addition of exogenous cytochrome c. Hence , rather than sequestering Apaf-1 as proposed by the apoptosome model , Bcl-2-like proteins probably regulate Apaf-1 indirectly by controlling upstream events critical for its activation .	However, neither Bcl-2 nor Bcl-x L could prevent the in vitro activation of Apaf-1 induced by the addition of exogenous cytochrome c. Hence, rather than sequestering Apaf-1 as proposed by the apoptosome model, Bcl-2-like proteins probably regulate Apaf-1 indirectly by controlling upstream events critical for its activation.	5	39	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Apaf-1	Apaf-1	Apaf-1	5	7	28	29
Bcl-xL also binds to and suppresses the activity of the caspase activator APAF1 , thereby preventing formation of the apoptosome and thus promoting survival .	Bcl-xL also binds to and suppresses the activity of the caspase activator APAF1, thereby preventing formation of the apoptosome and thus promoting survival.	0	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	APAF1	APAF1	APAF1	0	1	12	13
Furthermore , Bcl-x L is believed to bind to Apaf-1 and may therefore inhibit the association of Apaf-1 with procaspase-9 and thereby prevent caspase-9 activation [ XREF_BIBR ] .	Furthermore, Bcl-x L is believed to bind to Apaf-1 and may therefore inhibit the association of Apaf-1 with procaspase-9 and thereby prevent caspase-9 activation [XREF_BIBR].	2	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Apaf-1	Apaf-1	Apaf-1	2	4	17	18
These results suggest that Bcl-2 and Bcl-x L do not directly prevent Apaf-1 activation , but instead function by controlling events upstream of cytochrome c release .	These results suggest that Bcl-2 and Bcl-x L do not directly prevent Apaf-1 activation, but instead function by controlling events upstream of cytochrome c release.	4	13	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Apaf-1	Apaf-1	Apaf-1	6	8	12	13
Expression of Bcl-XL inhibited the association of Apaf-1 with caspase-9 in mammalian cells .	Expression of Bcl-XL inhibited the association of Apaf-1 with caspase-9 in mammalian cells.	0	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	Expression of Bcl-XL	bcl-xl	Apaf-1	Apaf-1	apaf-1	2	3	7	8
Similarly , AURKB can suppress p53 transcriptional activity through forming complex with novel inhibitor of histone acetyltransferase repressor ( NIR ) and p53 , in which NIR functions as a scaffold protein to mediate AURKB localization to the DNA binding domain ( DBD ) of p53 and then phosphorylates p53 on Ser269 and Thr284 in DBD .	Similarly, AURKB can suppress p53 transcriptional activity through forming complex with novel inhibitor of histone acetyltransferase repressor (NIR) and p53, in which NIR functions as a scaffold protein to mediate AURKB localization to the DNA binding domain (DBD) of p53 and then phosphorylates p53 on Ser269 and Thr284 in DBD.	2	7	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AURKB	AURKB	AURKB	p53	p53	p53	2	3	5	6
However , as Aurkb is degraded at the end of mitosis by APC/C mediated ubiquitination , one has to speculate that the Aurkb present during interphase is adequate to suppress the accumulation of p53 and p21 Cip1 and Waf1 during normal cell cycle .	However, as Aurkb is degraded at the end of mitosis by APC/C mediated ubiquitination, one has to speculate that the Aurkb present during interphase is adequate to suppress the accumulation of p53 and p21 Cip1 and Waf1 during normal cell cycle.	21	36	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Aurkb	Aurkb	Aurkb	p53	p53	p53	22	23	33	34
AURKA could phosphorylate RAS association domain family 1 , isoform A ( RASSF1A ) , a novel tumor suppressor , disrupt RASSF1A mediated microtubules stabilization and M-phase cell cycle arrest , and lead to uncontrolled proliferation in cancers [ XREF_BIBR ] .	AURKA could phosphorylate RAS association domain family 1, isoform A (RASSF1A), a novel tumor suppressor, disrupt RASSF1A mediated microtubules stabilization and M-phase cell cycle arrest, and lead to uncontrolled proliferation in cancers [XREF_BIBR].	0	32	disrupt	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AURKA	AURKA	AURKA	RASSF1A	RASSF1A	RASSF1A	0	1	21	22
However , unlike the Smurf family E3 ligases , regulation of Arkadia function is not well understood , except for a study reporting that Axin1 functions as a scaffold protein to promote Smad7 degradation by Arkadia .	However, unlike the Smurf family E3 ligases, regulation of Arkadia function is not well understood, except for a study reporting that Axin1 functions as a scaffold protein to promote Smad7 degradation by Arkadia.	24	33	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin1	Axin1	Axin1	Smad7	Smad7	Smad7	24	25	32	33
The Silencer Of Death Domain ( SODD ) , a DD containing protein identified by yeast two hybrid assay to interact with TNFR1 , was proposed to prevent constitutive signaling of tumor necrosis factor receptor 1 ( TNFR1 ) in the absence of TNFalpha [ XREF_BIBR ] .	The Silencer Of Death Domain (SODD), a DD containing protein identified by yeast two hybrid assay to interact with TNFR1, was proposed to prevent constitutive signaling of tumor necrosis factor receptor 1 (TNFR1) in the absence of TNFalpha [XREF_BIBR].	4	37	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SODD	SODD	SODD	tumor necrosis factor receptor 1	tumor necrosis factor receptor 1	tumor necrosis factor receptor 1	6	7	31	36
p130Cas inhibits Smad3 activity and alters cytostasis induced by TGF-beta .	p130Cas inhibits Smad3 activity and alters cytostasis induced by TGF-beta.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p130Cas	p130Cas	p130Cas	Smad3	Smad3	Smad3	0	1	2	3
XREF_BIBR In our present study , the downregulation of survivin expression and a significant increase in the expression of active caspase-3 protein were observed at the same time in the K562 cells treated with the copolymer of MNPs-Fe 3 O 4 and ART , suggesting that the potent inhibition of survivin expression could augment the activity of caspase-3 , thus substantially enhancing apoptosis of K562 cells induced by the combination of MNPs-Fe 3 O 4 with ART .	XREF_BIBR In our present study, the downregulation of survivin expression and a significant increase in the expression of active caspase-3 protein were observed at the same time in the K562 cells treated with the copolymer of MNPs-Fe 3 O 4 and ART, suggesting that the potent inhibition of survivin expression could augment the activity of caspase-3, thus substantially enhancing apoptosis of K562 cells induced by the combination of MNPs-Fe 3 O 4 with ART.	50	58	augment	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin expression	survivin	caspase-3	caspase-3	caspase-3	50	51	57	58
Furthermore , survivin is a potent inactivator of caspase-9 and caspase-3 and is regulated via the Akt and mTOR signaling pathway .	Furthermore, survivin is a potent inactivator of caspase-9 and caspase-3 and is regulated via the Akt and mTOR signaling pathway.	2	13	is a potent inactivator	Negative_activation_copula_1	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	2	3	10	11
DHA is an attractive repressor of survivin expression , increases caspase-3 and apoptosis in colorectal cancer cells and may provide a novel approach to the treatment of colorectal cancer at the early stage of tumor initiation .	DHA is an attractive repressor of survivin expression, increases caspase-3 and apoptosis in colorectal cancer cells and may provide a novel approach to the treatment of colorectal cancer at the early stage of tumor initiation.	0	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	DHA is an attractive repressor of survivin expression	survivin	caspase-3	caspase-3	caspase-3	6	7	10	11
Survivin overexpression in cancer cells inhibits activity of caspase-3 and promotes cell survival [ XREF_BIBR ] .	Survivin overexpression in cancer cells inhibits activity of caspase-3 and promotes cell survival [XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin overexpression	survivin	caspase-3	caspase-3	caspase-3	0	1	8	9
Survivin binds to and inhibits caspase-3 activity , thereby inhibiting apoptosis and promoting cell division .	Survivin binds to and inhibits caspase-3 activity, thereby inhibiting apoptosis and promoting cell division.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	5	6
Survivin inhibits active caspase-9 , but not active caspase-3 [ XREF_BIBR ] .	Survivin inhibits active caspase-9, but not active caspase-3 [XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	8	9
Survivin has been demonstrated to inhibit caspase 9 and caspase 3 , resulting in inhibition intrinsic apoptosis pathway [ XREF_BIBR ] .	Survivin has been demonstrated to inhibit caspase 9 and caspase 3, resulting in inhibition intrinsic apoptosis pathway [XREF_BIBR].	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase 3	caspase 3	caspase 3	0	1	9	11
It has been reported that Survivin is a direct inhibitor of Caspase3 .	It has been reported that Survivin is a direct inhibitor of Caspase3.	5	12	is a direct inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	Caspase3	Caspase3	Caspase3	5	6	11	12
The antiapoptotic protein bcl-2 mainly inhibits the mitochondrial pathways , XREF_BIBR , XREF_BIBR while survivin directly blocks the processing and activation of effector caspase-3 and caspase-7 , which commonly acts downstream of both apoptosis signaling pathways , XREF_BIBR which suggests that MNPs-Fe 3 O 4 loaded with GA induced cell apoptosis through various pathways .	The antiapoptotic protein bcl-2 mainly inhibits the mitochondrial pathways, XREF_BIBR, XREF_BIBR while survivin directly blocks the processing and activation of effector caspase-3 and caspase-7, which commonly acts downstream of both apoptosis signaling pathways, XREF_BIBR which suggests that MNPs-Fe 3 O 4 loaded with GA induced cell apoptosis through various pathways.	14	25	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	14	15	23	24
Therefore , we demonstrated that an elevated ZIC1 expression suppressed the expression of survivin through the Akt/mTOR/P70S6K pathway , and then activate caspase-9 and caspase-3 , so as to induce the apoptosis of breast cancer cells .	Therefore, we demonstrated that an elevated ZIC1 expression suppressed the expression of survivin through the Akt/mTOR/P70S6K pathway, and then activate caspase-9 and caspase-3, so as to induce the apoptosis of breast cancer cells.	7	25	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	ZIC1 expression suppressed the expression of survivin	survivin	caspase-3	caspase-3	caspase-3	13	14	24	25
Similarly , silencing of survivin expression in MDA-MB-231 ( p53 mut ) and PC-3 ( p53 null ) cells activates caspase-3 , a hallmark of apoptosis .	Similarly, silencing of survivin expression in MDA-MB-231 (p53 mut) and PC-3 (p53 null) cells activates caspase-3, a hallmark of apoptosis.	4	23	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin expression	survivin	caspase-3	caspase-3	caspase-3	4	5	20	21
Our findings suggest that survivin may inhibit both synthesis and activation of caspase 3 , hence inhibiting cell apoptosis and facilitating eventual development of oral squamous cell carcinoma .	Our findings suggest that survivin may inhibit both synthesis and activation of caspase 3, hence inhibiting cell apoptosis and facilitating eventual development of oral squamous cell carcinoma.	4	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase 3	caspase 3	caspase 3	4	5	12	14
Bcl-xl is anti-apoptotic , and survivin inhibits the release of Cyt c and the level of caspase-3 [ XREF_BIBR ] .	Bcl-xl is anti-apoptotic, and survivin inhibits the release of Cyt c and the level of caspase-3 [XREF_BIBR].	5	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	5	6	16	17
As with other IAP family members , survivin inhibits activation of caspase 3 , 7 and 9 in-vitro .	As with other IAP family members, survivin inhibits activation of caspase 3, 7 and 9 in-vitro.	7	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase 3	caspase 3	caspase 3	7	8	11	13
Some studies have shown that survivin can directly suppress the activities of caspase-3 and caspase-7 , while others have shown survivin to mainly suppress the caspase-9-dependent apoptotic pathway .	Some studies have shown that survivin can directly suppress the activities of caspase-3 and caspase-7, while others have shown survivin to mainly suppress the caspase-9-dependent apoptotic pathway.	5	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	5	6	12	13
It has been reported that Survivin inhibits caspase-3 activation in physiological situations during apoptosis , but this effect is likely not due to the direct inhibition of caspase-3 XREF_BIBR , XREF_BIBR , XREF_BIBR .	It has been reported that Survivin inhibits caspase-3 activation in physiological situations during apoptosis, but this effect is likely not due to the direct inhibition of caspase-3 XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	5	6	7	8
[ XREF_BIBR ] As an inhibitor in IAP family , survivin can directly inhibit caspase-3 and caspase-7 activity to prevent apoptosis [ XREF_BIBR ] .	[XREF_BIBR] As an inhibitor in IAP family, survivin can directly inhibit caspase-3 and caspase-7 activity to prevent apoptosis [XREF_BIBR].	10	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	10	11	14	15
Survivin , a member of the inhibitor of apoptosis protein ( IAP ) family , can directly inhibit caspase-3 and caspase-7 activity and plays an important role in oncogenesis .	Survivin, a member of the inhibitor of apoptosis protein (IAP) family, can directly inhibit caspase-3 and caspase-7 activity and plays an important role in oncogenesis.	0	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	18	19
Survivin is an Inhibitor of Apoptosis Protein ( IAP ) and functions to down-regulate caspase 3 , 7 , and 9 apoptotic activity as well as regulate the cell cycle by interacting with spindle microtubules during mitosis .	Survivin is an Inhibitor of Apoptosis Protein (IAP) and functions to down-regulate caspase 3, 7, and 9 apoptotic activity as well as regulate the cell cycle by interacting with spindle microtubules during mitosis.	0	22	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase 3	caspase 3	caspase 3	0	1	14	16
It has been concluded that survivin can possibly inhibit the synthesis of caspase-3 .	It has been concluded that survivin can possibly inhibit the synthesis of caspase-3.	5	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	5	6	12	13
These results suggest that ERbeta reduces Bcl-2 and survivin expression and increases caspase-8 and caspase-3 activation .	These results suggest that ERbeta reduces Bcl-2 and survivin expression and increases caspase-8 and caspase-3 activation.	4	15	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	ERbeta reduces Bcl-2 and survivin expression	survivin	caspase-3	caspase-3	caspase-3	8	9	14	15
The antiapoptotic protein bcl-2 mainly inhibits the mitochondrial pathways , while survivin directly blocks the processing and activation of effector caspase-3 and caspase-7 , which commonly acts downstream of both apoptosis signaling pathways , which suggests that SPIO loaded with FA induced cell apoptosis through various pathways .	The antiapoptotic protein bcl-2 mainly inhibits the mitochondrial pathways, while survivin directly blocks the processing and activation of effector caspase-3 and caspase-7, which commonly acts downstream of both apoptosis signaling pathways, which suggests that SPIO loaded with FA induced cell apoptosis through various pathways.	11	22	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	11	12	20	21
Survivin , an inhibitor of apoptosis proteins , interacts with partners to inhibit caspase-3 [ XREF_BIBR , XREF_BIBR ] .	Survivin, an inhibitor of apoptosis proteins, interacts with partners to inhibit caspase-3 [XREF_BIBR, XREF_BIBR].	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	13	14
This was due to the proteasomal degradation of X-chromosome-linked inhibitor of apoptosis ( XIAP ) and survivin that inhibits caspase-3 activity .	This was due to the proteasomal degradation of X-chromosome-linked inhibitor of apoptosis (XIAP) and survivin that inhibits caspase-3 activity.	2	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	16	17	19	20
Overexpression of survivin attenuated the L-OHP-induced activation of caspase-3 , but not the accumulation of p53 .	Overexpression of survivin attenuated the L-OHP-induced activation of caspase-3, but not the accumulation of p53.	0	9	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	Overexpression of survivin	survivin	caspase-3	caspase-3	caspase-3	2	3	8	9
The inhibition of survivin expression increased caspase-3 activity in T24 cells , which led to apoptosis .	The inhibition of survivin expression increased caspase-3 activity in T24 cells, which led to apoptosis.	3	7	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin expression	survivin	caspase-3	caspase-3	caspase-3	3	4	6	7
The main function of survivin is to suppress caspase-3 and caspase-7 , which are important apoptosis induction molecules .	The main function of survivin is to suppress caspase-3 and caspase-7, which are important apoptosis induction molecules.	2	17	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	4	5	8	9
Pharmacological or genetic blockade of Survivin expression in mouse and human bone marrow MSC enhances caspase 3 and 7 expression and reduces proliferation resulting in fewer MSC and clonogenic colony forming unit-fibroblasts ( CFU-F ) , whereas ectopic Survivin overexpression in MSC results in their expansion .	Pharmacological or genetic blockade of Survivin expression in mouse and human bone marrow MSC enhances caspase 3 and 7 expression and reduces proliferation resulting in fewer MSC and clonogenic colony forming unit-fibroblasts (CFU-F), whereas ectopic Survivin overexpression in MSC results in their expansion.	5	19	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin expression	survivin	caspase 3	caspase 3	caspase 3	5	6	15	17
FGF-2 reduced apoptosis induced by serum starvation and up-regulated survivin expression in H446 cells in a dose dependent and time dependent manner , and inhibited caspase-3 activity .	FGF-2 reduced apoptosis induced by serum starvation and up-regulated survivin expression in H446 cells in a dose dependent and time dependent manner, and inhibited caspase-3 activity.	0	26	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	FGF-2 reduced apoptosis induced by serum starvation and up-regulated survivin expression	survivin	caspase-3	caspase-3	caspase-3	9	10	25	26
Therefore , survivin overexpression reduced the level of Casp3 activation in CGCs independently of culture conditions .	Therefore, survivin overexpression reduced the level of Casp3 activation in CGCs independently of culture conditions.	2	9	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin overexpression	survivin	Casp3	Casp3	casp3	2	3	8	9
The precise mechanism by which survivin suppresses apoptosis is still in debate , but it is speculated that survivin directly suppresses caspase-3 , a protein which is believed to play a central role in the execution-phase of cell apoptosis 14 .	The precise mechanism by which survivin suppresses apoptosis is still in debate, but it is speculated that survivin directly suppresses caspase-3, a protein which is believed to play a central role in the execution-phase of cell apoptosis 14.	18	24	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	18	19	21	22
Survivin and XIAP directly inhibit the activities of caspase 3 .	Survivin and XIAP directly inhibit the activities of caspase 3.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase 3	caspase 3	caspase 3	0	1	8	10
As shown in XREF_FIG C-3E , downregulation of miR-1266 decreased Bcl-2 , Bcl-xL , Mcl-1 , and Survivin expression but enhanced the activity of caspase-9 and caspase-3 in a dose dependent manner .	As shown in XREF_FIG C-3E, downregulation of miR-1266 decreased Bcl-2, Bcl-xL, Mcl-1, and Survivin expression but enhanced the activity of caspase-9 and caspase-3 in a dose dependent manner.	8	27	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Survivin	miR-1266 decreased Bcl-2, Bcl-xL, Mcl-1, and Survivin expression	survivin	caspase-3	caspase-3	caspase-3	17	18	26	27
Survivin , a member of IAPs ( inhibition of apoptosis proteins ) family , has been revealed by many studies to inhibit the activation of caspase-3 , caspase-7 and caspase-9 , and thus increase the anti-apoptotic effect of cancer cells , which subsequently makes the cells to become resistant to chemotherapy in cancer treatment .	Survivin, a member of IAPs (inhibition of apoptosis proteins) family, has been revealed by many studies to inhibit the activation of caspase-3, caspase-7 and caspase-9, and thus increase the anti-apoptotic effect of cancer cells, which subsequently makes the cells to become resistant to chemotherapy in cancer treatment.	0	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	25	26
XREF_BIBR Controversy in the field arose when a study by Banks et al XREF_BIBR showed that survivin did not inhibit caspase 3 activity , and where recombinant survivin failed to decrease recombinant caspase 3 activity in vitro .	XREF_BIBR Controversy in the field arose when a study by Banks et al XREF_BIBR showed that survivin did not inhibit caspase 3 activity, and where recombinant survivin failed to decrease recombinant caspase 3 activity in vitro.	16	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase 3	caspase 3	caspase 3	16	17	20	22
Functionally , survivin has been demonstrated to inhibit caspase-3 and -7 activity , suggesting a mechanism by which it may suppress apoptosis [ XREF_BIBR ] .	Functionally, survivin has been demonstrated to inhibit caspase-3 and -7 activity, suggesting a mechanism by which it may suppress apoptosis [XREF_BIBR].	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	2	3	8	9
As a member of the inhibitor of apoptosis protein family , survivin has been reported to bind to and inhibit effector caspase-3 and -7 .	As a member of the inhibitor of apoptosis protein family, survivin has been reported to bind to and inhibit effector caspase-3 and -7.	11	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	11	12	21	22
Taken together these results strongly support Survivin mediated caspase-3 inhibition , however they do not prove whether this represents a direct effect on caspase-3 .	Taken together these results strongly support Survivin mediated caspase-3 inhibition, however they do not prove whether this represents a direct effect on caspase-3.	6	9	mediated	Positive_early_activation	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	6	7	8	9
Studies have demonstrated that survivin could directly inhibit the activities of Caspase-3 and 7 , and block the process of apoptosis [ XREF_BIBR ] .	Studies have demonstrated that survivin could directly inhibit the activities of Caspase-3 and 7, and block the process of apoptosis [XREF_BIBR].	4	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	Caspase-3	Caspase-3	Caspase-3	4	5	11	12
Moreover , overexpression of miR-1266 increased Bcl-2 , Bcl-xL , Mcl-1 , and Survivin expression but reduced the activity of caspase-9 or caspase-3 ( XREF_SUPPLEMENTARY E-S3G ) .	Moreover, overexpression of miR-1266 increased Bcl-2, Bcl-xL, Mcl-1, and Survivin expression but reduced the activity of caspase-9 or caspase-3 (XREF_SUPPLEMENTARY E-S3G).	2	23	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	overexpression of miR-1266 increased Bcl-2, Bcl-xL, Mcl-1, and Survivin expression	survivin	caspase-3	caspase-3	caspase-3	13	14	22	23
With regard to AR , after heating sections by autoclaving in Diva Decloaker ( Biocare Medical ) independent of the pH of the AR solution for 5 min ( heating-AR independent of pH , XREF_TABLE ) , there were no cleaved caspase-3 + cells evident ( XREF_FIG c ) whereas lymphoma cells expressed scant expression of Bcl-2 ( XREF_FIG d ) , moderate expression of Flip ( XREF_FIG e ) and strong expression of survivin ( XREF_FIG f ) [ XREF_BIBR ] , suggesting that neoplastic expression of survivin suppresses cleaved caspase-3 .	With regard to AR, after heating sections by autoclaving in Diva Decloaker (Biocare Medical) independent of the pH of the AR solution for 5 min (heating-AR independent of pH, XREF_TABLE), there were no cleaved caspase-3 + cells evident (XREF_FIG c) whereas lymphoma cells expressed scant expression of Bcl-2 (XREF_FIG d), moderate expression of Flip (XREF_FIG e) and strong expression of survivin (XREF_FIG f) [XREF_BIBR], suggesting that neoplastic expression of survivin suppresses cleaved caspase-3.	86	92	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	expression of survivin	survivin	caspase-3	caspase-3	caspase-3	88	89	91	92
Survivin specifically binds to members of the caspase family of proteins and inhibits the activity of caspase-3 to block apoptosis .	Survivin specifically binds to members of the caspase family of proteins and inhibits the activity of caspase-3 to block apoptosis.	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	16	17
Survivin over-expression by transfection of survivin plasmid induced the decrease of activated caspase 3 in podocytes and also in podocyte treated with PAN ( XREF_FIG ) .	Survivin over-expression by transfection of survivin plasmid induced the decrease of activated caspase 3 in podocytes and also in podocyte treated with PAN (XREF_FIG).	0	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin over-expression	survivin	caspase 3	caspase 3	caspase 3	0	1	12	14
Survivin overexpression reduces the basal levels of Casp3 activation in CGCs .	Survivin overexpression reduces the basal levels of Casp3 activation in CGCs.	0	8	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin overexpression	survivin	Casp3	Casp3	casp3	0	1	7	8
The function of IAP family members XIAP and survivin is to inhibit caspase 3 , 7 , 9 activity and caspase dependent cell apoptosis by binding to the active caspases XREF_BIBR .	The function of IAP family members XIAP and survivin is to inhibit caspase 3, 7, 9 activity and caspase dependent cell apoptosis by binding to the active caspases XREF_BIBR.	1	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase 3	caspase 3	caspase 3	8	9	12	14
Although our data indicate a potential link between degradation of survivin and activation of the apoptotic pathway induced by HDAC inhibitors , stable overexpression of survivin does not suppress the activation of caspase-3 or cleavage of p21 ( cip1 and waf1 ) induced by chlamydocin treatment .	Although our data indicate a potential link between degradation of survivin and activation of the apoptotic pathway induced by HDAC inhibitors, stable overexpression of survivin does not suppress the activation of caspase-3 or cleavage of p21 (cip1 and waf1) induced by chlamydocin treatment.	23	34	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	overexpression of survivin	survivin	caspase-3	caspase-3	caspase-3	25	26	32	33
Survivin is a human inhibitor of apoptosis proteins ( IAP ) and inhibits activated caspase-3 and caspase-7 [ XREF_BIBR ] .	Survivin is a human inhibitor of apoptosis proteins (IAP) and inhibits activated caspase-3 and caspase-7 [XREF_BIBR].	0	18	inhibits activated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	14	15
It has been documented that Survivin specifically binds to pro caspase3 and inhibits Caspase3 activation and reduces cell death induced by diverse stimuli .	It has been documented that Survivin specifically binds to pro caspase3 and inhibits Caspase3 activation and reduces cell death induced by diverse stimuli.	5	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	Caspase3	Caspase3	Caspase3	5	6	13	14
CPX markedly decreased Bcl-xL and survivin levels , and increased cleavage of caspase 3 , indicating caspase dependent apoptosis .	CPX markedly decreased Bcl-xL and survivin levels, and increased cleavage of caspase 3, indicating caspase dependent apoptosis.	0	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	CPX markedly decreased Bcl-xL and survivin levels	survivin	caspase 3	caspase 3	caspase 3	5	6	12	14
Recent experiments show that survivin inhibits active caspase-9 but not active caspase-3 and -7 , and that this inhibition requires the IAP family member , X linked IAP ( XIAP ) , and the hepatitis B X interacting protein .	Recent experiments show that survivin inhibits active caspase-9 but not active caspase-3 and -7, and that this inhibition requires the IAP family member, X linked IAP (XIAP), and the hepatitis B X interacting protein.	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	4	5	11	12
In the cells receiving the signal to apoptosis , survivin inhibits caspase 3 , 7 and 9 [ XREF_BIBR ] .	In the cells receiving the signal to apoptosis, survivin inhibits caspase 3, 7 and 9 [XREF_BIBR].	9	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase 3	caspase 3	caspase 3	9	10	11	13
On the other hand , Survivin is the smallest member of the inhibitor of apoptosis ( IAP ) gene family , synergistically inhibits caspase-3 and -9 , suppresses apoptosis , and accelerates tumor progression XREF_BIBR .	On the other hand, Survivin is the smallest member of the inhibitor of apoptosis (IAP) gene family, synergistically inhibits caspase-3 and -9, suppresses apoptosis, and accelerates tumor progression XREF_BIBR.	5	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	5	6	23	24
Moreover , we found that the expression of Survivin ( an inhibitor of caspase-3 ) was down-regulated , indicating that its inhibitory effects on caspase-3 were weakened in the indicated group compared to the DeltaLT ETEC treated group .	Moreover, we found that the expression of Survivin (an inhibitor of caspase-3) was down-regulated, indicating that its inhibitory effects on caspase-3 were weakened in the indicated group compared to the DeltaLT ETEC treated group.	6	14	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Survivin	expression of Survivin	survivin	caspase-3	caspase-3	caspase-3	8	9	13	14
Some investigators have speculated that survivin may inhibit effector caspase-3 directly , even though it lacks a structural motif to bind directly with caspase-3 , as is present in other IAPs .	Some investigators have speculated that survivin may inhibit effector caspase-3 directly, even though it lacks a structural motif to bind directly with caspase-3, as is present in other IAPs.	5	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	5	6	9	10
We then asked whether or not the differences in IF emHcRed1 were indeed correlated to different levels of activation of Casp3 , rather than simply reflecting a better cellular state independent from survivin inhibition of the Casp3 mediated apoptotic drive .	We then asked whether or not the differences in IF emHcRed1 were indeed correlated to different levels of activation of Casp3, rather than simply reflecting a better cellular state independent from survivin inhibition of the Casp3 mediated apoptotic drive.	32	37	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	survivin	survivin	survivin	Casp3	Casp3	Casp3	32	33	36	37
Survivin inhibits cell apoptosis and promotes cell proliferation by directly and indirectly regulating the apoptotic pathway of caspase 3 .	Survivin inhibits cell apoptosis and promotes cell proliferation by directly and indirectly regulating the apoptotic pathway of caspase 3.	0	19	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Survivin	Survivin	Survivin	caspase 3	caspase 3	caspase 3	0	1	17	19
Studies by Tamm et al [ XREF_BIBR ] have shown that survivin inhibits the activities of caspase 3 and 9 whereas studies by Liu et al [ XREF_BIBR ] suggest that the anti-apoptotic function of survivin is related to its ability to inhibit mitochondrial and apoptosis inducing factor dependent pathways .	Studies by Tamm et al [XREF_BIBR] have shown that survivin inhibits the activities of caspase 3 and 9 whereas studies by Liu et al [XREF_BIBR] suggest that the anti-apoptotic function of survivin is related to its ability to inhibit mitochondrial and apoptosis inducing factor dependent pathways.	11	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase 3	caspase 3	caspase 3	11	12	16	18
Survivin was effectively downregulated and cleaved caspase 3 was consumed in the reaction leading to upregulation of cleaved PARP , indicating that inhibition of survivin leads to activation of the apoptotic pathway .	Survivin was effectively downregulated and cleaved caspase 3 was consumed in the reaction leading to upregulation of cleaved PARP, indicating that inhibition of survivin leads to activation of the apoptotic pathway.	0	9	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase 3	caspase 3	caspase 3	0	1	6	8
Because survivin can inhibit caspase-3 , it is possible that the down-regulation of survivin by the two carotenoids could lead to the activation of caspase-3 [ XREF_BIBR ] .	Because survivin can inhibit caspase-3, it is possible that the down-regulation of survivin by the two carotenoids could lead to the activation of caspase-3 [XREF_BIBR].	1	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	1	2	4	5
Increased caspase-3 inhibition by Survivin maintains the stem cell pool and loss of Survivin protein with subsequent increased caspase-3 activity results in loss of HSC function and perhaps increased cell differentiation .	Increased caspase-3 inhibition by Survivin maintains the stem cell pool and loss of Survivin protein with subsequent increased caspase-3 activity results in loss of HSC function and perhaps increased cell differentiation.	1	5	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	4	5	1	2
It has been reported that survivin was able to suppress caspase-3 and -7 even though the in vitro binding experiment failed to show this result .	It has been reported that survivin was able to suppress caspase-3 and -7 even though the in vitro binding experiment failed to show this result.	5	12	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	5	6	10	11
The possible mechanism might be that fucoidan inhibits expression of Bcl-2 , Survivin , ERKs and VEGF and increases activation of Caspase-3 .	The possible mechanism might be that fucoidan inhibits expression of Bcl-2, Survivin, ERKs and VEGF and increases activation of Caspase-3.	6	22	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Survivin	fucoidan inhibits expression of Bcl-2, Survivin	survivin	Caspase-3	Caspase-3	caspase-3	12	13	21	22
Indeed , survivin has been shown to inhibit the executioner caspase-3 [ XREF_BIBR ] .	Indeed, survivin has been shown to inhibit the executioner caspase-3 [XREF_BIBR].	2	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	2	3	10	11
Overexpression of PML could reduce Survivin expression and upregulate caspase3 and cleaved PARP protein expression Our results demonstrated that overexpression of PML could induce bladder cancer cell apoptosis through the caspase dependent pathways .	Overexpression of PML could reduce Survivin expression and upregulate caspase3 and cleaved PARP protein expression Our results demonstrated that overexpression of PML could induce bladder cancer cell apoptosis through the caspase dependent pathways.	0	10	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Survivin	Overexpression of PML could reduce Survivin expression	survivin	caspase3	caspase3	caspase3	5	6	9	10
Survivin directly inhibits caspase-3 and caspase-7 activity , is inversely correlated with apoptosis and is positively correlated with cell proliferation [ XREF_BIBR , XREF_BIBR ] .	Survivin directly inhibits caspase-3 and caspase-7 activity, is inversely correlated with apoptosis and is positively correlated with cell proliferation [XREF_BIBR, XREF_BIBR].	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	3	4
Survivin was downregulated and cleaved caspase-3 was upregulated in XN treated tissues ( XREF_FIG ) .	Survivin was downregulated and cleaved caspase-3 was upregulated in XN treated tissues (XREF_FIG).	0	6	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	5	6
Furthermore , combined knockdown of Livin , XIAP , and Survivin can markedly increase the abundance of active caspase-3 , active caspase-7 , active caspase-9 , and cytosolic Smac .	Furthermore, combined knockdown of Livin, XIAP, and Survivin can markedly increase the abundance of active caspase-3, active caspase-7, active caspase-9, and cytosolic Smac.	3	28	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	10	11	18	19
Because survivin inhibits apoptosis through both direct and indirect inhibitions of caspase-3 , a downstream gene of PUMA , we next investigated whether YM155 and survivin inhibition could upregulate caspase-3 activity .	Because survivin inhibits apoptosis through both direct and indirect inhibitions of caspase-3, a downstream gene of PUMA, we next investigated whether YM155 and survivin inhibition could upregulate caspase-3 activity.	23	30	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	25	26	29	30
Survivin , an apoptosis inhibitor , may prolong cell survival by targeting terminal effector caspase-3 .	Survivin, an apoptosis inhibitor, may prolong cell survival by targeting terminal effector caspase-3.	0	15	prolong	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	14	15
Moreover , cotransfection of Survivin prevented spontaneous processing of caspase 7 and caspase 3 to their active forms 29 .	Moreover, cotransfection of Survivin prevented spontaneous processing of caspase 7 and caspase 3 to their active forms 29.	2	14	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase 3	caspase 3	caspase 3	4	5	12	14
Some published reports suggest that survivin could directly suppress the activity of the effector caspase-3 [ XREF_BIBR ] , whereas others propose that survivin primarily acts at the level of an initiator caspase by binding to caspase-9 and/or neutralizing proapoptotic proteins [ XREF_BIBR ] .	Some published reports suggest that survivin could directly suppress the activity of the effector caspase-3 [XREF_BIBR], whereas others propose that survivin primarily acts at the level of an initiator caspase by binding to caspase-9 and/or neutralizing proapoptotic proteins [XREF_BIBR].	5	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	5	6	14	15
Survivin , a member of inhibitor of apoptosis protein ( IAP ) family , can directly inhibit caspase-3 and caspase-7 activity and plays an important role in oncogenesis .	Survivin, a member of inhibitor of apoptosis protein (IAP) family, can directly inhibit caspase-3 and caspase-7 activity and plays an important role in oncogenesis.	0	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	17	18
In parental ovarian cancer cells , survivin is up-regulated after BPR0L075 treatment ; caspase-3 activation could be suppressed by survivin , which functions a counteraction protein against caspases .	In parental ovarian cancer cells, survivin is up-regulated after BPR0L075 treatment; caspase-3 activation could be suppressed by survivin, which functions a counteraction protein against caspases.	13	22	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	19	20	13	14
These observations are consistent with reports that Brca1 negatively regulates estrogen biosynthesis as well as estrogen receptor signaling .	These observations are consistent with reports that Brca1 negatively regulates estrogen biosynthesis as well as estrogen receptor signaling.	7	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Brca1	Brca1	Brca1	estrogen receptor	estrogen receptor	estrogen receptor	7	8	15	17
It has been shown that BRCA1 also mediates the ligand independent repression of ER-alpha XREF_BIBR .	It has been shown that BRCA1 also mediates the ligand independent repression of ER-alpha XREF_BIBR.	5	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	5	6	13	14
We previously reported that expression of the breast cancer susceptibility gene BRCA1 strongly inhibits the transcriptional activity of the estrogen receptor ( ER-alpha ) in human breast and prostate cancer cell lines but only weakly inhibits ER-alpha activity in cervical cancer cells ( S. Fan et al ., Science ( Wash ..	We previously reported that expression of the breast cancer susceptibility gene BRCA1 strongly inhibits the transcriptional activity of the estrogen receptor (ER-alpha) in human breast and prostate cancer cell lines but only weakly inhibits ER-alpha activity in cervical cancer cells (S. Fan et al., Science (Wash..	4	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	expression of the breast cancer susceptibility gene BRCA1	brca1	estrogen receptor	estrogen receptor	estrogen receptor	11	12	19	21
Previously , we reported that BRCA1 strongly represses the transcriptional activity of estrogen receptor-alpha ( ER-alpha ) in human breast and prostate cancer cells but only weakly inhibits ER-alpha in cervical cancer cells .	Previously, we reported that BRCA1 strongly represses the transcriptional activity of estrogen receptor-alpha (ER-alpha) in human breast and prostate cancer cells but only weakly inhibits ER-alpha in cervical cancer cells.	5	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	5	6	28	29
Here , we found that BRCA1 over-expression not only inhibits ER activity in anti-estrogen-resistant LCC9 cells but also partially restores their sensitivity to Tamoxifen .	Here, we found that BRCA1 over-expression not only inhibits ER activity in anti-estrogen-resistant LCC9 cells but also partially restores their sensitivity to Tamoxifen.	5	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1 over-expression	brca1	ER	ER	er	5	6	10	11
Previously , it is postulated that the transcriptional repression of ERalpha by BRCA1 occurs through estrogen independent interaction between the amino-terminus of BRCA1 and the carboxy-terminal activation domain ( AF-2 ) of ERalpha .	Previously, it is postulated that the transcriptional repression of ERalpha by BRCA1 occurs through estrogen independent interaction between the amino-terminus of BRCA1 and the carboxy-terminal activation domain (AF-2) of ERalpha.	8	13	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	12	13	10	11
Mutation of the ubiquitinization sites abolished BRCA1 mediated inhibition of ER activity XREF_BIBR .	Mutation of the ubiquitinization sites abolished BRCA1 mediated inhibition of ER activity XREF_BIBR.	6	12	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	6	7	10	11
This interpretation is supported by evidence indicating that the BRCA1 protein represses the transcriptional activity of the liganded ER-alpha and estrogen regulated genes [ XREF_BIBR ] .	This interpretation is supported by evidence indicating that the BRCA1 protein represses the transcriptional activity of the liganded ER-alpha and estrogen regulated genes [XREF_BIBR].	9	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	9	10	18	19
BRCA1 has been shown to inhibit ERalpha signaling , which results in negative regulation of expression of downstream genes [ XREF_BIBR ] , as well as regulation of estrogen biosynthesis through transcriptional inhibition of the aromatase encoding genes [ XREF_BIBR ] .	BRCA1 has been shown to inhibit ERalpha signaling, which results in negative regulation of expression of downstream genes [XREF_BIBR], as well as regulation of estrogen biosynthesis through transcriptional inhibition of the aromatase encoding genes [XREF_BIBR].	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	0	1	6	7
Previous studies showed that BRCA1 overexpression inhibited membrane ER and EGFR signaling in breast cancer cells .	Previous studies showed that BRCA1 overexpression inhibited membrane ER and EGFR signaling in breast cancer cells.	4	15	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1 overexpression	brca1	ER	ER	er	4	5	8	9
I3C and breast cancer susceptibility gene 1 ( BRCA1 ) synergistically inhibited transcriptional activity of ER-alpha .	I3C and breast cancer susceptibility gene 1 (BRCA1) synergistically inhibited transcriptional activity of ER-alpha.	0	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	8	9	15	16
Together , these results show that decreased expression of BRCA1 modulates ER mediated transcription and abrogated Tam suppression of endogenous ER target genes .	Together, these results show that decreased expression of BRCA1 modulates ER mediated transcription and abrogated Tam suppression of endogenous ER target genes.	7	22	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	expression of BRCA1	brca1	ER	ER	er	9	10	20	21
It has been reported that ICI182780 inhibited E2 induced BRCA1 mRNA induction in ER positive cells .	It has been reported that ICI182780 inhibited E2 induced BRCA1 mRNA induction in ER positive cells.	5	15	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	BRCA1	ICI182780 inhibited E2 induced BRCA1	brca1	ER	ER	er	9	10	13	14
BRCA1 decreases the transcriptional activity of both PR and ERalpha but the role that ubiquitylation and proteasomal degradation plays remains to be fully determined .	BRCA1 decreases the transcriptional activity of both PR and ERalpha but the role that ubiquitylation and proteasomal degradation plays remains to be fully determined.	0	10	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	0	1	9	10
discovered that BRCA1 Mut tumors fail to express ER due to the loss of BRCA1 mediated transcriptional activation of estrogen receptor 1 ( ESR1 ) .	discovered that BRCA1 Mut tumors fail to express ER due to the loss of BRCA1 mediated transcriptional activation of estrogen receptor 1 (ESR1).	12	21	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	loss of BRCA1	brca1	estrogen receptor	estrogen receptor	estrogen receptor	14	15	19	21
Thus , BRCA1 inhibits ER activity in LCC9 cells and partially restores sensitivity to Tam .	Thus, BRCA1 inhibits ER activity in LCC9 cells and partially restores sensitivity to Tam.	2	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	2	3	4	5
Findings obtained in in vitro assays and animal studies indicate that estrogens might influence the activity of the tumor suppressor gene BRCA1 , and BRCA1 in turn may suppress the activity of the estrogen receptor .	Findings obtained in in vitro assays and animal studies indicate that estrogens might influence the activity of the tumor suppressor gene BRCA1, and BRCA1 in turn may suppress the activity of the estrogen receptor.	24	35	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	24	25	33	35
Decreased BRCA1 expression also results in the ligand independent ER activation , partially through activation of PI3K-AKT signaling XREF_BIBR , suggesting BRCA1 is also a repressor of PI3K-AKT signaling .	Decreased BRCA1 expression also results in the ligand independent ER activation, partially through activation of PI3K-AKT signaling XREF_BIBR, suggesting BRCA1 is also a repressor of PI3K-AKT signaling.	1	11	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	BRCA1	BRCA1 expression	brca1	ER	ER	er	1	2	9	10
While BRCA1 suppresses ERalpha , ERalpha regulation of BRCA1 enhances BRCA1 function .	While BRCA1 suppresses ERalpha, ERalpha regulation of BRCA1 enhances BRCA1 function.	1	4	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	1	2	3	4
On the other hand , ERalpha corepressor BRCA1 not only inhibits ERalpha activity XREF_BIBR but is also responsible for DNA repair XREF_BIBR .	On the other hand, ERalpha corepressor BRCA1 not only inhibits ERalpha activity XREF_BIBR but is also responsible for DNA repair XREF_BIBR.	5	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	7	8	11	12
We showed that BRCA1 knockdown abolished Tam suppression of cell proliferation and ERalpha transcriptional activity .	We showed that BRCA1 knockdown abolished Tam suppression of cell proliferation and ERalpha transcriptional activity.	3	14	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	3	4	12	13
BRCA1 has been reported to interact with the estrogen receptor ( ER ) and inhibit both ligand dependent and -independent ER activation [ XREF_BIBR , XREF_BIBR ] .	BRCA1 has been reported to interact with the estrogen receptor (ER) and inhibit both ligand dependent and -independent ER activation [XREF_BIBR, XREF_BIBR].	0	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	0	1	20	21
Here we show that BRCA1 mediates ligand independent transcriptional repression of the estrogen receptor alpha ( ERalpha ) , a principal determinant of the growth , differentiation , and normal functional status of breasts and ovaries .	Here we show that BRCA1 mediates ligand independent transcriptional repression of the estrogen receptor alpha (ERalpha), a principal determinant of the growth, differentiation, and normal functional status of breasts and ovaries.	4	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	4	5	12	14
For example , both the insulin like growth factor 1 receptor [ XREF_BIBR ] and epidermal growth factor receptor [ XREF_BIBR ] are downstream targets for BRCA1 ; BRCA1 inhibits the transcriptional activity of progesterone receptor ( PR ) in the PR positive breast cancer cell line T47D [ XREF_BIBR ] ; and ER-alpha activity can be suppressed by BRCA1 through regulating the acetylation vs. ubiquitination [ XREF_BIBR ] .	For example, both the insulin like growth factor 1 receptor [XREF_BIBR] and epidermal growth factor receptor [XREF_BIBR] are downstream targets for BRCA1; BRCA1 inhibits the transcriptional activity of progesterone receptor (PR) in the PR positive breast cancer cell line T47D [XREF_BIBR]; and ER-alpha activity can be suppressed by BRCA1 through regulating the acetylation vs. ubiquitination [XREF_BIBR].	53	60	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	59	60	53	54
The same group demonstrated a link between cyclin D1 and another DNA repair protein , BRCA1 , by showing that cyclin D1 antagonizes BRCA1 mediated repression of estrogen receptor alpha transcriptional activity .	The same group demonstrated a link between cyclin D1 and another DNA repair protein, BRCA1, by showing that cyclin D1 antagonizes BRCA1 mediated repression of estrogen receptor alpha transcriptional activity.	23	29	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	23	24	27	29
For instance , BRCA1 is able to repress ER transactivation function by forming complex with ER directly .	For instance, BRCA1 is able to repress ER transactivation function by forming complex with ER directly.	3	10	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	3	4	8	9
The BRCA1 protein directly interacts with ERalpha and inhibits ERalpha transactivation and downstream signaling [ XREF_BIBR ] .	The BRCA1 protein directly interacts with ERalpha and inhibits ERalpha transactivation and downstream signaling [XREF_BIBR].	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	1	2	9	10
Point mutations within the zinc finger domains of E7 and E6 inactivated the binding to the N terminus of BRCA1 and reduced their ability to rescue BRCA1 inhibition of ER-alpha .	Point mutations within the zinc finger domains of E7 and E6 inactivated the binding to the N terminus of BRCA1 and reduced their ability to rescue BRCA1 inhibition of ER-alpha.	26	30	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	26	27	29	30
Thus , BRCA1 was found to inhibit estrogen receptor activity , both in cultured cells and mouse models ; and accumulating evidence suggest that BRCA1 related tumorigene-sis is a hormonally responsive process , both in mice and humans .	Thus, BRCA1 was found to inhibit estrogen receptor activity, both in cultured cells and mouse models; and accumulating evidence suggest that BRCA1 related tumorigene-sis is a hormonally responsive process, both in mice and humans.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	2	3	7	9
BRCA1 is one coregulator of AR , the androgen receptor XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR and inhibits ESR1 ( Estrogen receptor alpha ) activity XREF_BIBR , XREF_BIBR .	BRCA1 is one coregulator of AR, the androgen receptor XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR and inhibits ESR1 (Estrogen receptor alpha) activity XREF_BIBR, XREF_BIBR.	0	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ESR1	ESR1	ESR1	0	1	19	20
Of note is the relative location of these two sites , which form two separate pockets , but because of their physical proximity and the fact that the BRCA1 pocket site is defined in the presence of 4OHTam , the binding of a small molecule at the BRCA1 site and that of 4OHTam are expected to synergistically influence their binding properties and mimic BRCA1 suppression of ER .	Of note is the relative location of these two sites, which form two separate pockets, but because of their physical proximity and the fact that the BRCA1 pocket site is defined in the presence of 4OHTam, the binding of a small molecule at the BRCA1 site and that of 4OHTam are expected to synergistically influence their binding properties and mimic BRCA1 suppression of ER.	63	67	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	63	64	66	67
BRCA1 , which has been implicated in double-strand break repair , represses ERalpha and stimulates AR activity , whilst the modified O 6 -methylgluanine-DNA methyltransferase involved in the reversal of DNA alkylation damage can also repress ERalpha activity and 3-methyladenine DNA glycosylase inhibited transactivation by ERalpha .	BRCA1, which has been implicated in double-strand break repair, represses ERalpha and stimulates AR activity, whilst the modified O 6 -methylgluanine-DNA methyltransferase involved in the reversal of DNA alkylation damage can also repress ERalpha activity and 3-methyladenine DNA glycosylase inhibited transactivation by ERalpha.	0	14	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	0	1	12	13
Somewhat surprisingly , we found that BRCA1 aa 1-100 and BRCA1 aa 101-200 ( but not aa 201-300 ) each inhibited ER-alpha activity , although not as efficiently as full-length BRCA1 .	Somewhat surprisingly, we found that BRCA1 aa 1-100 and BRCA1 aa 101-200 (but not aa 201-300) each inhibited ER-alpha activity, although not as efficiently as full-length BRCA1.	6	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	6	7	21	22
Other studies have proposed wt BRCA1 is essential for differentiation of mammary stem cells to ER+ luminal cells and that loss of wt BRCA1 causes an expansion of ER negative mammary stem cells , offering a mechanism for the common ER-negativity of BRCA1 breast cancers [ XREF_BIBR ] .	Other studies have proposed wt BRCA1 is essential for differentiation of mammary stem cells to ER+ luminal cells and that loss of wt BRCA1 causes an expansion of ER negative mammary stem cells, offering a mechanism for the common ER-negativity of BRCA1 breast cancers [XREF_BIBR].	20	32	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	loss of wt BRCA1	brca1	ER	ER	er	23	24	28	29
As cyclin D1 abundance is regulated by oncogenic and mitogenic signals , the antagonism of the BRCA1 mediated ERalpha repression by cyclin D1 may contribute to the selective induction of BRCA1 regulated target genes .	As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1 mediated ERalpha repression by cyclin D1 may contribute to the selective induction of BRCA1 regulated target genes.	13	19	mediated	Positive_early_activation	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	16	17	18	19
Wild-type BRCA1 was demonstrated to inhibit the ability of ER-alpha to transactivate reporter constructs under the control of estrogen responsive elements .	Wild-type BRCA1 was demonstrated to inhibit the ability of ER-alpha to transactivate reporter constructs under the control of estrogen responsive elements.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	1	2	9	10
In addition , in vitro studies indicate that BRCA1 , in particular , interacts with and represses both nuclear and nongenomic ERalpha signalling pathways ( Fan et al , 1999 ; Fan et al , 2001 ; Razandi et al , 2004 ) .	In addition, in vitro studies indicate that BRCA1, in particular, interacts with and represses both nuclear and nongenomic ERalpha signalling pathways (Fan et al, 1999; Fan et al, 2001; Razandi et al, 2004).	8	23	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	8	9	21	22
The breast cancer and ovarian susceptibility gene 1 ( BRCA1 ) has been shown to inhibit ERalpha signaling by repressing the AF-2 domain of ERalpha , which is linked to the ligand binding domain .	The breast cancer and ovarian susceptibility gene 1 (BRCA1) has been shown to inhibit ERalpha signaling by repressing the AF-2 domain of ERalpha, which is linked to the ligand binding domain.	2	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	9	10	16	17
This interaction differs from the BRCA1 : ER-alpha interaction in several respects : 1 ) ER-alpha contacts the N-terminus of BRCA1 , whereas PR can contact both N- and C-terminal sites on BRCA1 ; 2 ) BRCA1 binds to the AF-2 ( activation function 2 ) domain of ER-alpha but to a different region on PR ; and 3 ) the nuclear receptor coactivator p300 rescues the BRCA1 repression of ER-alpha but not PR [ XREF_BIBR ] .	This interaction differs from the BRCA1 : ER-alpha interaction in several respects : 1) ER-alpha contacts the N-terminus of BRCA1, whereas PR can contact both N- and C-terminal sites on BRCA1; 2) BRCA1 binds to the AF-2 (activation function 2) domain of ER-alpha but to a different region on PR; and 3) the nuclear receptor coactivator p300 rescues the BRCA1 repression of ER-alpha but not PR [XREF_BIBR].	67	71	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	67	68	70	71
XREF_FIG , in the presence of 17beta-estradiol ( E2 ) , BRCA1 decreased the transcriptional activity of ERalpha to an average level of 60 % .	XREF_FIG, in the presence of 17beta-estradiol (E2), BRCA1 decreased the transcriptional activity of ERalpha to an average level of 60%.	11	18	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	11	12	17	18
The ligand dependent repression of ERalpha by BRCA1 is postulated to occur by binding of the N-terminus of BRCA1 ( aa 1-302 ) to the C-terminal activation function ( AF-2 ) domain of ERalpha [ XREF_BIBR , XREF_BIBR ] .	The ligand dependent repression of ERalpha by BRCA1 is postulated to occur by binding of the N-terminus of BRCA1 (aa 1-302) to the C-terminal activation function (AF-2) domain of ERalpha [XREF_BIBR, XREF_BIBR].	3	8	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	7	8	5	6
The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ ER-alpha ] in human breast and prostate cancer cell lines .	The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] in human breast and prostate cancer cell lines.	1	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	1	2	13	15
BRCA1 repression of both ER and CYCLIN D1 mainly relies on protein protein interaction .	BRCA1 repression of both ER and CYCLIN D1 mainly relies on protein protein interaction.	0	7	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	0	1	4	5
This is the first report demonstrating the participation of Ubc9 in BRCA1 E3 ubiquitin ligase mediated degradation of ERalpha .	This is the first report demonstrating the participation of Ubc9 in BRCA1 E3 ubiquitin ligase mediated degradation of ERalpha.	11	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	11	12	18	19
BRCA1 and BRCA1a proteins suppress the growth of human ER-alpha positive , TNBC , and ovarian cancer cells .	BRCA1 and BRCA1a proteins suppress the growth of human ER-alpha positive, TNBC, and ovarian cancer cells.	0	17	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	0	1	9	10
Ectopic expression in Brca1 deficient cells of wild-type BRCA1 , but not clinically validated BRCA1 missense mutants , restored ligand independent repression of ERalpha in a manner dependent upon apparent histone deacetylase activity .	Ectopic expression in Brca1 deficient cells of wild-type BRCA1, but not clinically validated BRCA1 missense mutants, restored ligand independent repression of ERalpha in a manner dependent upon apparent histone deacetylase activity.	1	24	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Brca1	Brca1	Brca1	ERalpha	ERalpha	ERalpha	3	4	23	24
BRCA1 impairs the transcriptional activity of ERalpha , and overexpression of BRCA1 subsequently inhibits the expression of 90 % of estrogen inducible genes [ XREF_BIBR ] .	BRCA1 impairs the transcriptional activity of ERalpha, and overexpression of BRCA1 subsequently inhibits the expression of 90% of estrogen inducible genes [XREF_BIBR].	0	7	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	0	1	6	7
In BRCA1 and ERalpha double knockdown cells , no stimulation was observed with Tam or E2+ Tam , indicating that BRCA1 knockdown induced loss of Tam suppression required ERalpha protein .	In BRCA1 and ERalpha double knockdown cells, no stimulation was observed with Tam or E2+ Tam, indicating that BRCA1 knockdown induced loss of Tam suppression required ERalpha protein.	20	30	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha protein	ERalpha protein	ERalpha protein	20	21	28	30
To simulate the mechanism of BRCA1 inhibition of ER in the setting of Tamoxifen resistance , we created a three-dimensional model of a BRCA1 binding cavity within the ER and Tamoxifen complex ; and we screened a pharmacophore database to identify small molecules that could fit into this cavity .	To simulate the mechanism of BRCA1 inhibition of ER in the setting of Tamoxifen resistance, we created a three-dimensional model of a BRCA1 binding cavity within the ER and Tamoxifen complex; and we screened a pharmacophore database to identify small molecules that could fit into this cavity.	5	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	5	6	8	9
In addition , upregulation of growth factor signaling modulated BRCA1 suppression of ERalpha activity , in part through serine phosphorylation of the ERalpha AF-1 domain .	In addition, upregulation of growth factor signaling modulated BRCA1 suppression of ERalpha activity, in part through serine phosphorylation of the ERalpha AF-1 domain.	9	13	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	9	10	12	13
The relationship has feedback through the regulation of ER itself by cyclin D1 ; for example , cyclin D1 also acts to antagonize BRCA1 repression of ER .	The relationship has feedback through the regulation of ER itself by cyclin D1; for example, cyclin D1 also acts to antagonize BRCA1 repression of ER.	23	27	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	23	24	26	27
We now report that introduction of the human papillomavirus E7 or E6 oncogenes into human papillomavirus negative cells rescues the BRCA1 repression of ER-alpha activity and that the E7 and E6 oncoproteins interact directly with BRCA1 in vitro and associate with BRCA1 in vivo in cultured cells .	We now report that introduction of the human papillomavirus E7 or E6 oncogenes into human papillomavirus negative cells rescues the BRCA1 repression of ER-alpha activity and that the E7 and E6 oncoproteins interact directly with BRCA1 in vitro and associate with BRCA1 in vivo in cultured cells.	20	24	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	20	21	23	24
Therefore , BRCA1 related elevated levels of SIRT1 may resist the adverse effects of ER stress ; ( iii ) Both NAD and SIRT1 play pivotal roles in cell proliferation XREF_BIBR XREF_BIBR , a substantial body of evidence indicates that loss of function of the tumor suppressor gene BRCA1 plays an important role in promoting cancer cell proliferation and survival XREF_BIBR XREF_BIBR .	Therefore, BRCA1 related elevated levels of SIRT1 may resist the adverse effects of ER stress; (iii) Both NAD and SIRT1 play pivotal roles in cell proliferation XREF_BIBR XREF_BIBR, a substantial body of evidence indicates that loss of function of the tumor suppressor gene BRCA1 plays an important role in promoting cancer cell proliferation and survival XREF_BIBR XREF_BIBR.	2	15	resist	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1 related elevated levels	brca1	ER	ER	er	2	3	14	15
Lack of BRCA1 expression was associated with node metastases and decreased estrogen receptor .	Lack of BRCA1 expression was associated with node metastases and decreased estrogen receptor.	2	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1 expression	brca1	estrogen receptor	estrogen receptor	estrogen receptor	2	3	11	13
Exogenous c-Akt conferred estrogen independent ER-alpha activation and rescued the BRCA1 repression of estrogen stimulated ER-alpha activity .	Exogenous c-Akt conferred estrogen independent ER-alpha activation and rescued the BRCA1 repression of estrogen stimulated ER-alpha activity.	10	16	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	10	11	15	16
Studies have shown that wild-type BRCA1 blocks estrogen receptor ( ER ) mediated transcriptional activation , thereby inhibiting estrogenic signalling [ XREF_BIBR ] .	Studies have shown that wild-type BRCA1 blocks estrogen receptor (ER) mediated transcriptional activation, thereby inhibiting estrogenic signalling [XREF_BIBR].	4	9	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	5	6	7	9
Recently , the tumor suppressor BRCA1 has been shown to mediate ligand independent transcriptional repression of ERalpha in a manner dependent on HDAC activity .	Recently, the tumor suppressor BRCA1 has been shown to mediate ligand independent transcriptional repression of ERalpha in a manner dependent on HDAC activity.	2	17	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	5	6	16	17
Cyclin D1 competes with BRCA1 , which represses ER transactivation , for binding to hinge region of ER thereby it display coactivator function .	Cyclin D1 competes with BRCA1, which represses ER transactivation, for binding to hinge region of ER thereby it display coactivator function.	2	9	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	4	5	8	9
We analyzed the effect of tamoxifen , emodin , and plumbagin in BRCA1 blocked ER positive BG-1 ovarian cancer cells .	We analyzed the effect of tamoxifen, emodin, and plumbagin in BRCA1 blocked ER positive BG-1 ovarian cancer cells.	5	16	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	12	13	14	15
Although the BRCA1 and BRCA2 proteins play critical roles in DNA damage repair ( Brodie and Deng , 2001 ; Deng and Brodie , 2001 ; Kerr and Ashworth , 2001 ) , in vitro studies suggest that the BRCA1 gene product can also interact with and suppress the activity of the ERalpha ( Fan et al , 1999 ; Fan et al , 2001 ) .	Although the BRCA1 and BRCA2 proteins play critical roles in DNA damage repair (Brodie and Deng, 2001; Deng and Brodie, 2001; Kerr and Ashworth, 2001), in vitro studies suggest that the BRCA1 gene product can also interact with and suppress the activity of the ERalpha (Fan et al, 1999; Fan et al, 2001).	39	54	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	39	40	52	53
Differential protein associations determine p300 and CBP specificity XREF_BIBR in processes such as in myogenesis XREF_BIBR ; p300 and CBP modulates the BRCA1 inhibition of estrogen receptor XREF_BIBR , and downregulation of p300 and CBP activates a senescence checkpoint in melanocytes XREF_BIBR .	Differential protein associations determine p300 and CBP specificity XREF_BIBR in processes such as in myogenesis XREF_BIBR; p300 and CBP modulates the BRCA1 inhibition of estrogen receptor XREF_BIBR, and downregulation of p300 and CBP activates a senescence checkpoint in melanocytes XREF_BIBR.	22	27	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	22	23	25	27
Overall , BRCA1 negatively regulates the ER activity through P300 with multiple mechanisms involved .	Overall, BRCA1 negatively regulates the ER activity through P300 with multiple mechanisms involved.	2	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	2	3	6	7
BRCA1 inhibition of ER-alpha activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 ( HCC1937 ) .	BRCA1 inhibition of ER-alpha activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 (HCC1937).	0	4	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	0	1	3	4
Similar results were observed for ERalpha-SRC1 interactions in vehicle- and Tam treated cells , indicating that BRCA1 knockdown allows ERalpha to associate with coactivators , such as SRC1 and SRC3 , in the presence of Tam .	Similar results were observed for ERalpha-SRC1 interactions in vehicle- and Tam treated cells, indicating that BRCA1 knockdown allows ERalpha to associate with coactivators, such as SRC1 and SRC3, in the presence of Tam.	16	21	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	16	17	19	20
The finding that BRCA1 is a corepressor of ERalpha provides a potential molecular explanation for the tissue specific nature of BRCA1 associated cancer .	The finding that BRCA1 is a corepressor of ERalpha provides a potential molecular explanation for the tissue specific nature of BRCA1 associated cancer.	3	9	is a corepressor	Negative_activation_copula_1	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	3	4	8	9
They further suggest that the BRCA1 inhibition of ER-alpha activity may be attributable , at least in part , to the down-regulation of p300 .	They further suggest that the BRCA1 inhibition of ER-alpha activity may be attributable, at least in part, to the down-regulation of p300.	5	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	5	6	8	9
In addition to its well established roles in regulation of DNA damage response , the Brca1 protein inhibits ERalpha transcriptional activity through direct action of BRCA1 and ERalpha proteins and down-regulation of p300 , a nuclear receptor co-activator .	In addition to its well established roles in regulation of DNA damage response, the Brca1 protein inhibits ERalpha transcriptional activity through direct action of BRCA1 and ERalpha proteins and down-regulation of p300, a nuclear receptor co-activator.	15	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Brca1	Brca1	Brca1	ERalpha	ERalpha	ERalpha	15	16	18	19
Thus , an emerging model is that BRCA1 mediated monoubiquitylation competes with acetylation to inhibit ERalpha transcriptional activity 69 .	Thus, an emerging model is that BRCA1 mediated monoubiquitylation competes with acetylation to inhibit ERalpha transcriptional activity 69.	7	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	7	8	15	16
Survivin inhibits activation of caspase-9 , which is required for the initiation of the intrinsic mitochondrial pathway of apoptosis [ XREF_BIBR ] .	Survivin inhibits activation of caspase-9, which is required for the initiation of the intrinsic mitochondrial pathway of apoptosis [XREF_BIBR].	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-9	caspase-9	caspase-9	0	1	4	5
Survivin inhibits caspase-9 , blocks apoptosis , and is associated with resistance to chemotherapy and radiation .	Survivin inhibits caspase-9, blocks apoptosis, and is associated with resistance to chemotherapy and radiation.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-9	caspase-9	caspase-9	0	1	2	3
In addition , survivin can inhibit caspase-9 directly and caspase-3 and -7 indirectly by binding to Smac/Diablo XREF_BIBR .	In addition, survivin can inhibit caspase-9 directly and caspase-3 and -7 indirectly by binding to Smac/Diablo XREF_BIBR.	3	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-9	caspase-9	caspase-9	3	4	6	7
Survivin normally inhibits caspase-9 activation within the apoptosome , a key step in the apoptotic cascade .	Survivin normally inhibits caspase-9 activation within the apoptosome, a key step in the apoptotic cascade.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-9	caspase-9	caspase-9	0	1	3	4
Other experiments suggest that survivin inhibits only active caspase 9 by its association with X linked IAP [ XREF_BIBR ] .	Other experiments suggest that survivin inhibits only active caspase 9 by its association with X linked IAP [XREF_BIBR].	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase 9	caspase 9	caspase 9	4	5	8	10
Specifically , XIAP and survivin are potent inhibitors of caspase 9 , while cIAP-2 and XIAP can inhibit caspases 3 and 7 [ XREF_BIBR , XREF_BIBR ] .	Specifically, XIAP and survivin are potent inhibitors of caspase 9, while cIAP-2 and XIAP can inhibit caspases 3 and 7 [XREF_BIBR, XREF_BIBR].	2	11	are potent inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase 9	caspase 9	caspase 9	4	5	9	11
Moreover , PTER-ITC significantly decreased expression of survivin , which blocks caspase-9 and -3 , thereby inhibiting apoptosis .	Moreover, PTER-ITC significantly decreased expression of survivin, which blocks caspase-9 and -3, thereby inhibiting apoptosis.	2	13	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	PTER-ITC significantly decreased expression of survivin	survivin	caspase-9	caspase-9	caspase-9	7	8	11	12
Like other inhibitors of apoptosis ( IAP ) , survivin acts downstream of mitochondria to prevent processing or activation of initiator caspase-9 , leading to inhibition of the activity of the effector caspases .	Like other inhibitors of apoptosis (IAP), survivin acts downstream of mitochondria to prevent processing or activation of initiator caspase-9, leading to inhibition of the activity of the effector caspases.	9	22	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-9	caspase-9	caspase-9	9	10	21	22
Despite a lack of structural motifs that mediate caspase binding , survivin can inhibit active caspase 9 through cooperation with the hepatitis B virus X interacting protein XREF_BIBR .	Despite a lack of structural motifs that mediate caspase binding, survivin can inhibit active caspase 9 through cooperation with the hepatitis B virus X interacting protein XREF_BIBR.	11	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase 9	caspase 9	caspase 9	11	12	15	17
Upon activation of proapoptotic cell signaling , Survivin is released from the mitochondria in the cytosol and inhibits active caspase-9 .	Upon activation of proapoptotic cell signaling, Survivin is released from the mitochondria in the cytosol and inhibits active caspase-9.	7	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-9	caspase-9	caspase-9	7	8	19	20
The balance between Bad and Bax and Bcl-2 regulates mitochondrial membrane integrity and incrementPsim stabilization ; more importantly , c-IAP and survivin are inhibitors of caspase9 and , subsequently , apoptosis XREF_BIBR XREF_BIBR .	The balance between Bad and Bax and Bcl-2 regulates mitochondrial membrane integrity and incrementPsim stabilization; more importantly, c-IAP and survivin are inhibitors of caspase9 and, subsequently, apoptosis XREF_BIBR XREF_BIBR.	19	26	are inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase9	caspase9	caspase9	21	22	25	26
The interaction of survivin with other molecules , such as X linked inhibitor of apoptosis protein , is known to inhibit the catalytic activity of caspase-9 , thereby preventing apoptosis .	The interaction of survivin with other molecules, such as X linked inhibitor of apoptosis protein, is known to inhibit the catalytic activity of caspase-9, thereby preventing apoptosis.	1	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-9	caspase-9	caspase-9	3	4	25	26
Mechanistically , it may not be unexpected that survivin inhibits caspase-9 in concert with XIAP [ XREF_BIBR ] , and antagonizes p53 dependent cell death [ XREF_BIBR ] , two effector pathways of mitotic catastrophe [ XREF_BIBR ] .	Mechanistically, it may not be unexpected that survivin inhibits caspase-9 in concert with XIAP [XREF_BIBR], and antagonizes p53 dependent cell death [XREF_BIBR], two effector pathways of mitotic catastrophe [XREF_BIBR].	8	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-9	caspase-9	caspase-9	8	9	10	11
Studies showed that Survivin , associated with the hepatitis B X interacting protein ( HBXIP ) or X linked IAP ( XIAP ) , inhibited activation of Caspase-9 .	Studies showed that Survivin, associated with the hepatitis B X interacting protein (HBXIP) or X linked IAP (XIAP), inhibited activation of Caspase-9.	3	28	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	Caspase-9	Caspase-9	Caspase-9	3	4	27	28
In order to prevent premature separation of sister chromatids , MAD2L1 and BUB1 , which in turn interact with CDC20 at check point activation , inhibit CDC20 and APC [ XREF_BIBR ] .	In order to prevent premature separation of sister chromatids, MAD2L1 and BUB1, which in turn interact with CDC20 at check point activation, inhibit CDC20 and APC [XREF_BIBR].	10	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BUB1	BUB1, which in turn interact with CDC20	bub1	CDC20	CDC20	cdc20	12	13	26	27
During prophase , while chromosomes start to attach to spindle fibers , Mad1 , 2 , 3 , Bub1 , and Bub3 present at unattached kinetochores prevent activation of Cdc20 and , therefore , degradation of Pds1 and inactivation of mitotic CDKs .	During prophase, while chromosomes start to attach to spindle fibers, Mad1, 2, 3, Bub1, and Bub3 present at unattached kinetochores prevent activation of Cdc20 and, therefore, degradation of Pds1 and inactivation of mitotic CDKs.	16	34	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bub1	Bub1	Bub1	Cdc20	Cdc20	Cdc20	18	19	29	30
A previous study demonstrated that BUB1 inhibited CDC20 in cultured mammalian cells XREF_BIBR .	A previous study demonstrated that BUB1 inhibited CDC20 in cultured mammalian cells XREF_BIBR.	5	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BUB1	BUB1	BUB1	CDC20	CDC20	CDC20	5	6	7	8
Alternatively , because Bub1 can more efficiently phosphorylate Cdc20 that is not bound to BubR1 , Bub1 and BubR1 may inhibit different pools of Cdc20 .	Alternatively, because Bub1 can more efficiently phosphorylate Cdc20 that is not bound to BubR1, Bub1 and BubR1 may inhibit different pools of Cdc20.	16	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bub1	Bub1	Bub1	Cdc20	Cdc20	Cdc20	16	17	24	25
Unattached kinetochores catalyze the formation of the Mitotic Checkpoint Complex ( MCC ) , consisting of proteins encoded by BUB1B , BUB1 , and MAD2L1 , which inhibits the CDC20 subunit of the Anaphase Promoting Complex ( APC ) ; recruitment of the MCC and activation of the SAC are dependent on BUB1 , a mitotic kinase [ XREF_BIBR ] .	Unattached kinetochores catalyze the formation of the Mitotic Checkpoint Complex (MCC), consisting of proteins encoded by BUB1B, BUB1, and MAD2L1, which inhibits the CDC20 subunit of the Anaphase Promoting Complex (APC); recruitment of the MCC and activation of the SAC are dependent on BUB1, a mitotic kinase [XREF_BIBR].	17	37	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BUB1	BUB1	BUB1	CDC20	CDC20	CDC20	21	22	29	30
CDC20 is negatively regulated by BUB1 phosphorylation XREF_BIBR .	CDC20 is negatively regulated by BUB1 phosphorylation XREF_BIBR.	0	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	BUB1	BUB1 phosphorylation	bub1	CDC20	CDC20	cdc20	5	6	0	1
Consistent with the fact that beta-TrCP mediated degradation of beta-catenin occurs mainly in cytoplasm , the isoforms that use exon III are much less able to rescue Wnt8 or beta-catenin-induced embryo axis duplication .	Consistent with the fact that beta-TrCP mediated degradation of beta-catenin occurs mainly in cytoplasm, the isoforms that use exon III are much less able to rescue Wnt8 or beta-catenin-induced embryo axis duplication.	5	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
FWD1 and beta-TrCP induces proteolytic degradation of beta-catenin , thus blocking the Wnt induced beta-catenin-mediated signaling cascade [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	FWD1 and beta-TrCP induces proteolytic degradation of beta-catenin, thus blocking the Wnt induced beta-catenin-mediated signaling cascade [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	8	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
These results are consistent with the well established fact that the degradation of beta-catenin by beta-TrCP depends on beta-catenin phosphorylation at residues T41 , S37 , and S33 by GSK-3beta .	These results are consistent with the well established fact that the degradation of beta-catenin by beta-TrCP depends on beta-catenin phosphorylation at residues T41, S37, and S33 by GSK-3beta.	11	16	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	15	16	13	14
To confirm if beta-TrCP mediates beta-catenin degradation in osteoblasts , we transfected beta-TrCP into 2T3 cells and found that beta-TrCP significantly reduced steady-state protein levels of beta-catenin in 2T3 cells ( XREF_FIG ) .	To confirm if beta-TrCP mediates beta-catenin degradation in osteoblasts, we transfected beta-TrCP into 2T3 cells and found that beta-TrCP significantly reduced steady-state protein levels of beta-catenin in 2T3 cells (XREF_FIG).	3	6	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	3	4	5	6
Since beta-TrCP inhibition would enhance beta-catenin stability and promote tumorigenesis , it was necessary to monitor also beta catening correlation to prostate cancer patients ' outcome .	Since beta-TrCP inhibition would enhance beta-catenin stability and promote tumorigenesis, it was necessary to monitor also beta catening correlation to prostate cancer patients ' outcome.	1	6	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	1	2	5	6
We next investigated whether KCTD1 promotes degradation of beta-catenin by beta-TrCP .	We next investigated whether KCTD1 promotes degradation of beta-catenin by beta-TrCP.	5	11	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	10	11	8	9
It is known that beta-TrCP induces beta-catenin degradation in other cell types [ XREF_BIBR ; XREF_BIBR ] .	It is known that beta-TrCP induces beta-catenin degradation in other cell types [XREF_BIBR; XREF_BIBR].	4	7	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	4	5	6	7
beta-TrCP degrades beta-catenin and thereby maintains low levels of free beta-catenin in the cytoplasm that prevent beta-catenin from entering the nucleus to activate target genes .	beta-TrCP degrades beta-catenin and thereby maintains low levels of free beta-catenin in the cytoplasm that prevent beta-catenin from entering the nucleus to activate target genes.	0	5	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	0	1	2	3
Since Jade-1 is primarily localized in the nucleus [ XREF_BIBR , XREF_BIBR ] , it may mainly regulate the nuclear pool of beta-catenin , whereas beta-TrCP is responsible to degrade cytoplasmic beta-catenin [ XREF_BIBR ] .	Since Jade-1 is primarily localized in the nucleus [XREF_BIBR, XREF_BIBR], it may mainly regulate the nuclear pool of beta-catenin, whereas beta-TrCP is responsible to degrade cytoplasmic beta-catenin [XREF_BIBR].	25	33	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	25	26	31	32
On the other hand , in HCT116 cells , c-Cbl silencing upregulated beta-catenin , while beta-TrCP silencing did not upregulate beta-catenin .	On the other hand, in HCT116 cells, c-Cbl silencing upregulated beta-catenin, while beta-TrCP silencing did not upregulate beta-catenin.	15	21	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	15	16	20	21
In XREF_BIBR , BTRC has been experimentally verified to inhibit the beta-catenin ( CTNNB1 ) pathway that is upregulated after insults such as seizures and promotes adult neurogenesis ( BTRC ---> CTNNB1 ) .	In XREF_BIBR, BTRC has been experimentally verified to inhibit the beta-catenin (CTNNB1) pathway that is upregulated after insults such as seizures and promotes adult neurogenesis (BTRC ---> CTNNB1).	3	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BTRC	BTRC	BTRC	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
BTRC inhibits the beta-catenin ( CTNNB1 ) pathway XREF_BIBR , which in adult animals is upregulated after insults such as seizures XREF_BIBR and promotes adult neurogenesis XREF_BIBR .	BTRC inhibits the beta-catenin (CTNNB1) pathway XREF_BIBR, which in adult animals is upregulated after insults such as seizures XREF_BIBR and promotes adult neurogenesis XREF_BIBR.	0	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BTRC	BTRC	BTRC	beta-catenin	beta-catenin	beta-catenin	0	1	3	4
As shown in XREF_FIG F , the separate transfection of CK1alpha , beta-TrCP , APC , and GSK3beta partially inhibited the miR-135b-induced activation of Wnt and beta-catenin signaling in miR-135b-overexpressing OS cells .	As shown in XREF_FIG F, the separate transfection of CK1alpha, beta-TrCP, APC, and GSK3beta partially inhibited the miR-135b-induced activation of Wnt and beta-catenin signaling in miR-135b-overexpressing OS cells.	8	27	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	12	13	26	27
It was suggested that BNIP3 repressed Rheb activity resulting in reduced mTOR activity and slower cell growth but it is not clear if this is consistent with the interaction of BNIP3 with Rheb taking place exclusively at the OMM .	It was suggested that BNIP3 repressed Rheb activity resulting in reduced mTOR activity and slower cell growth but it is not clear if this is consistent with the interaction of BNIP3 with Rheb taking place exclusively at the OMM.	4	7	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BNIP3	BNIP3	BNIP3	Rheb	Rheb	Rheb	4	5	6	7
In addition , HIF1 induces Bnip3 expression , which in turn inhibits mTORC1 binding Rheb , an mTOR activator .	In addition, HIF1 induces Bnip3 expression, which in turn inhibits mTORC1 binding Rheb, an mTOR activator.	3	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bnip3	HIF1 induces Bnip3 expression	bnip3	Rheb	Rheb	rheb	5	6	14	15
57 BNIP3 can also activate autophagy by inhibiting the RHEB ( Ras homolog enriched in brain ) protein , whose activity is required for mTORC1 activation .	57 BNIP3 can also activate autophagy by inhibiting the RHEB (Ras homolog enriched in brain) protein, whose activity is required for mTORC1 activation.	0	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BNIP3	BNIP3	BNIP3	RHEB	RHEB	RHEB	1	2	9	10
In response to energy stress , FOXO proteins inhibit the mechanistic target of rapamycin complex 1 ( mTORC1 ) signaling through induction of BCL2 and adenovirus E1B 19kDa interacting protein 3 ( BNIP3 ) expression , which in turn negatively regulates the mTORC1 activator RHEB and the BCL2 pro survival family members , resulting in energy stress induced apoptosis [ XREF_BIBR ] .	In response to energy stress, FOXO proteins inhibit the mechanistic target of rapamycin complex 1 (mTORC1) signaling through induction of BCL2 and adenovirus E1B 19kDa interacting protein 3 (BNIP3) expression, which in turn negatively regulates the mTORC1 activator RHEB and the BCL2 pro survival family members, resulting in energy stress induced apoptosis [XREF_BIBR].	32	51	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BNIP3	BNIP3) expression	bnip3	RHEB	RHEB	rheb	32	33	44	45
Oxygen deprivation may activate autophagy by attenuating mitochondrial function or by hypoxia inducible factor 1alpha ( HIF1alpha ) mediated transcription activation of Bcl-2 and adenovirus E1B 19-kDa interacting protein 3 ( BNIP3 ) which inhibits Rheb XREF_BIBR , XREF_BIBR .	Oxygen deprivation may activate autophagy by attenuating mitochondrial function or by hypoxia inducible factor 1alpha (HIF1alpha) mediated transcription activation of Bcl-2 and adenovirus E1B 19-kDa interacting protein 3 (BNIP3) which inhibits Rheb XREF_BIBR, XREF_BIBR.	28	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BNIP3	BNIP3	BNIP3	Rheb	Rheb	Rheb	31	32	35	36
Overexpression of BNIP3 decreased Rheb GTP and GDP ratio by 30 % and resulted in mTORC1 suppression , as measured by a decrease in S6K and 4EBP1 phosphorylation .	Overexpression of BNIP3 decreased Rheb GTP and GDP ratio by 30% and resulted in mTORC1 suppression, as measured by a decrease in S6K and 4EBP1 phosphorylation.	0	5	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BNIP3	Overexpression of BNIP3	bnip3	Rheb	Rheb	rheb	2	3	4	5
This work also reported that BNIP3 repressed Rheb activity resulting in reduced mTOR activity and slower cell growth [ XREF_BIBR ] , consistent with a tumor suppressor function for BNIP3 .	This work also reported that BNIP3 repressed Rheb activity resulting in reduced mTOR activity and slower cell growth [XREF_BIBR], consistent with a tumor suppressor function for BNIP3.	5	8	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BNIP3	BNIP3	BNIP3	Rheb	Rheb	Rheb	5	6	7	8
If indeed survivin inactivates Smac , its overexpression in tumor cells might result in resistance to a broad range of apoptotic stimuli , including chemo- and radiation therapy .	If indeed survivin inactivates Smac, its overexpression in tumor cells might result in resistance to a broad range of apoptotic stimuli, including chemo- and radiation therapy.	1	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	Smac	Smac	Smac	2	3	4	5
Survivin is considered to inhibit Smac by binding to it in the cytosol , XREF_BIBR but the transduction of survivin also suppressed the release of Smac from the mitochondria in our study .	Survivin is considered to inhibit Smac by binding to it in the cytosol, XREF_BIBR but the transduction of survivin also suppressed the release of Smac from the mitochondria in our study.	17	26	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	Smac	Smac	Smac	19	20	25	26
The anti-apoptotic effect of survivin was attributed to a direct interaction with XIAP ( X linked inhibitor of apoptosis ) and to an indirect effect , where survivin antagonizes the anti-XIAP action of Smac .	The anti-apoptotic effect of survivin was attributed to a direct interaction with XIAP (X linked inhibitor of apoptosis) and to an indirect effect, where survivin antagonizes the anti-XIAP action of Smac.	27	34	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	Smac	Smac	Smac	27	28	33	34
Current therapeutic targets within the IAP family include XIAP and Survivin inhibition or delivery of Smac or Omi to enhance chemotherapeutic effects [ XREF_BIBR , XREF_BIBR ] .	Current therapeutic targets within the IAP family include XIAP and Survivin inhibition or delivery of Smac or Omi to enhance chemotherapeutic effects [XREF_BIBR, XREF_BIBR].	8	17	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	Smac	Smac	Smac	10	11	15	16
Survivin expression in melanocytes partially blocked caspase activation and release of mitochondrial release of AIF , cytochrome c , and Smac induced by UVB .	Survivin expression in melanocytes partially blocked caspase activation and release of mitochondrial release of AIF, cytochrome c, and Smac induced by UVB.	0	21	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin expression	survivin	Smac	Smac	smac	0	1	20	21
Bik , Bok , Fas : P21 ( WAF1 ) down-regulation of Bcl-xL ; BCL-2 , clAP , activation of caspases (-3, -7 ,- 8 , -9 ) , loss of mitochondrial potential , and release of cytochrome c. Piceatannol has been shown to suppress the activation of some transcription factors , including NF-kappaB , which plays a central role as a transcriptional regulator in response to cellular stress caused by free radicals , ultraviolet irradiation , cytokines , or microbial antigens .	Bik, Bok, Fas : P21 (WAF1) down-regulation of Bcl-xL; BCL-2, clAP, activation of caspases (-3, -7,- 8, -9), loss of mitochondrial potential, and release of cytochrome c. Piceatannol has been shown to suppress the activation of some transcription factors, including NF-kappaB, which plays a central role as a transcriptional regulator in response to cellular stress caused by free radicals, ultraviolet irradiation, cytokines, or microbial antigens.	0	69	down-regulation	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Bik	Bik	Bik	Bcl-xL	Bcl-xL	Bcl-xL	0	1	12	13
In our system , binding of Nbk inactivates Bcl-x L and releases Bax and Bak ( XREF_FIG ) .	In our system, binding of Nbk inactivates Bcl-x L and releases Bax and Bak (XREF_FIG).	4	10	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Nbk	Nbk	Nbk	Bcl-x L	Bcl-x L	Bcl-x L	6	7	8	10
XREF_BIBR Since centroblastic cells express very little BCL-2 ( XREF_SUPPLEMENTARY and ref 25 ) induction of BIK in this cell type is more likely to antagonise the function of BCL-X L and/or MCL-1 .	XREF_BIBR Since centroblastic cells express very little BCL-2 (XREF_SUPPLEMENTARY and ref 25) induction of BIK in this cell type is more likely to antagonise the function of BCL-X L and/or MCL-1.	14	31	antagonise	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIK	BIK	BIK	BCL-X L	BCL-X L	BCL-X L	16	17	29	31
PUMA , like BIM , interacts with all prosurvival factors while BIK selectively inhibits BCL-X L , BFL-1 , or BCL-w [ XREF_BIBR ] .	PUMA, like BIM, interacts with all prosurvival factors while BIK selectively inhibits BCL-X L, BFL-1, or BCL-w [XREF_BIBR].	11	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIK	BIK	BIK	BCL-X L	BCL-X L	BCL-X L	11	12	14	16
To study if Nbk can inactivate Bcl-x L to release and activate Bak , we performed coimmunoprecipitation experiments using a Bcl-x L -specific antibody ( XREF_FIG ) .	To study if Nbk can inactivate Bcl-x L to release and activate Bak, we performed coimmunoprecipitation experiments using a Bcl-x L -specific antibody (XREF_FIG).	3	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Nbk	Nbk	Nbk	Bcl-x L	Bcl-x L	Bcl-x L	3	4	6	8
BIRC6 is up-regulated in tumours and inhibits active caspase 3 through binding with its BIR domain [ XREF_BIBR ] .	BIRC6 is up-regulated in tumours and inhibits active caspase 3 through binding with its BIR domain [XREF_BIBR].	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIRC6	BIRC6	BIRC6	caspase 3	caspase 3	caspase 3	0	1	8	10
NO blocked caspase 3 activation , PARP degradation , downregulation of the pro apoptotic genes Casp7 , Casp9 , Bax and Bak1 and upregulation of the anti-apoptotic genes Bcl-2 111 , Bcl-2 and Birc6 .	NO blocked caspase 3 activation, PARP degradation, downregulation of the pro apoptotic genes Casp7, Casp9, Bax and Bak1 and upregulation of the anti-apoptotic genes Bcl-2 111, Bcl-2 and Birc6.	1	34	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Birc6	Birc6	Birc6	caspase 3	caspase 3	caspase 3	33	34	2	4
Moreover , simultaneous silencing of Apollon and p53 in these cells induced only a partial rescue of cell viability and a limited decrease in caspase-3 activation ( Ren et al , 2005 ) .	Moreover, simultaneous silencing of Apollon and p53 in these cells induced only a partial rescue of cell viability and a limited decrease in caspase-3 activation (Ren et al, 2005).	3	25	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Apollon	Apollon	Apollon	caspase-3	caspase-3	caspase-3	5	6	24	25
The possibility that Apollon knockdown enhances caspase-3 catalytic activity in a direct way is supported by the observation of Bartke et al ( 2004 ) , who reported that Apollon interacts strongly with caspase-3 and inhibits its activation in a cell-free extract of 293T adenovirus transformed human embryo kidney cells .	The possibility that Apollon knockdown enhances caspase-3 catalytic activity in a direct way is supported by the observation of Bartke et al (2004), who reported that Apollon interacts strongly with caspase-3 and inhibits its activation in a cell-free extract of 293T adenovirus transformed human embryo kidney cells.	3	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Apollon	Apollon	Apollon	caspase-3	caspase-3	caspase-3	3	4	6	7
Apollon silencing promoted mitochondrial depolarization and caspase-2 , caspase-8 , caspase-9 , and caspase-3 activation in response to different antitumor agents and altered the profile of genes modulated by MEK or BRAF V600E -specific inhibitors .	Apollon silencing promoted mitochondrial depolarization and caspase-2, caspase-8, caspase-9, and caspase-3 activation in response to different antitumor agents and altered the profile of genes modulated by MEK or BRAF V600E -specific inhibitors.	0	14	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Apollon	Apollon	Apollon	caspase-3	caspase-3	caspase-3	0	1	13	14
These mutations disrupt the same RING domain that is removed by the t ( 11 ; 18 ) in MALT lymphomas , and the mutated BIRC3 is no longer able to inactivate MAP3K14 via ubiquitination XREF_BIBR , XREF_BIBR .	These mutations disrupt the same RING domain that is removed by the t (11; 18) in MALT lymphomas, and the mutated BIRC3 is no longer able to inactivate MAP3K14 via ubiquitination XREF_BIBR, XREF_BIBR.	23	35	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIRC3	BIRC3	BIRC3	MAP3K14	MAP3K14	MAP3K14	25	26	32	33
XREF_BIBR - XREF_BIBR The Baculoviral IAP repeat containing 3 ( BIRC3 ) gene is one of the components of a protein complex that negatively regulates the MAP3K14 serin-threonine kinase , the downstream activator of non canonical NF-kappaB signaling .	XREF_BIBR - XREF_BIBR The Baculoviral IAP repeat containing 3 (BIRC3) gene is one of the components of a protein complex that negatively regulates the MAP3K14 serin-threonine kinase, the downstream activator of non canonical NF-kappaB signaling.	7	28	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BIRC3	BIRC3	BIRC3	MAP3K14	MAP3K14	MAP3K14	10	11	26	27
XREF_BIBR BIRC3 inactivating mutations and a fraction of BIRC3 deletions cause a truncation of the C-terminal RING domain of the BIRC3 protein , essential for ubiquitination , and the following proteasome degradation , of MAP3K14 , and drives constitutive non canonical NF-kappaB activation ( XREF_FIG ) .	XREF_BIBR BIRC3 inactivating mutations and a fraction of BIRC3 deletions cause a truncation of the C-terminal RING domain of the BIRC3 protein, essential for ubiquitination, and the following proteasome degradation, of MAP3K14, and drives constitutive non canonical NF-kappaB activation (XREF_FIG).	1	35	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BIRC3	BIRC3	BIRC3	MAP3K14	MAP3K14	MAP3K14	1	2	34	35
Proteins c-IAP1 and c-IAP2 directly inhibit the activity of Caspase-3 , Caspase-7 and Caspase-9 , thereby inhibiting cell apoptosis [ XREF_BIBR ] .	Proteins c-IAP1 and c-IAP2 directly inhibit the activity of Caspase-3, Caspase-7 and Caspase-9, thereby inhibiting cell apoptosis [XREF_BIBR].	1	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-IAP2	c-IAP2	c-IAP2	Caspase-9	Caspase-9	Caspase-9	3	4	13	14
Specifically , XIAP , cIAP1 and cIAP2 inhibit caspase 3 , caspase 7 , and caspase 9 .	Specifically, XIAP, cIAP1 and cIAP2 inhibit caspase 3, caspase 7, and caspase 9.	2	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cIAP2	cIAP2	cIAP2	caspase 9	caspase 9	caspase 9	6	7	15	17
The present study has demonstrated another mechanism whereby Bmi1 suppresses necdin by the direct protein protein interaction .	The present study has demonstrated another mechanism whereby Bmi1 suppresses necdin by the direct protein protein interaction.	8	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bmi1	Bmi1	Bmi1	necdin	necdin	necdin	8	9	10	11
Bmi1 overexpression suppresses necdin and induces changes similar to those seen in necdin-null NPCs ( Bmi1 OE ) .	Bmi1 overexpression suppresses necdin and induces changes similar to those seen in necdin-null NPCs (Bmi1 OE).	0	4	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bmi1	Bmi1 overexpression	bmi1	necdin	necdin	necdin	0	1	3	4
Remarkably , Bmi1 almost completely relieved the necdin induced suppression .	Remarkably, Bmi1 almost completely relieved the necdin induced suppression.	2	8	relieved	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bmi1	Bmi1	Bmi1	necdin	necdin	necdin	2	3	7	8
Blocking of NF-kappaB activity reduced IAP-1 expression and prevented IAP-1 RNAi effects .	Blocking of NF-kappaB activity reduced IAP-1 expression and prevented IAP-1 RNAi effects.	2	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	IAP-1	NF-kappaB activity reduced IAP-1 expression	iap-1	IAP-1	IAP-1	iap-1	5	6	9	10
Serum starvation significantly up-regulated the expression of Gli1 , which in turn increased its key target cIAP2 expression and enhanced NF-kappaB and cIAP2 pathway , resulting in promoting cell survival under serum starvation .	Serum starvation significantly up-regulated the expression of Gli1, which in turn increased its key target cIAP2 expression and enhanced NF-kappaB and cIAP2 pathway, resulting in promoting cell survival under serum starvation.	5	23	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cIAP2	expression of Gli1, which in turn increased its key target cIAP2 expression	ciap2	cIAP2	cIAP2	ciap2	16	17	22	23
Simultaneously with caspase-3 activation , there was loss of intact XIAP , cIAP-1 , and cIAP-2 and production of proteolytic products of each IAP protein .	Simultaneously with caspase-3 activation, there was loss of intact XIAP, cIAP-1, and cIAP-2 and production of proteolytic products of each IAP protein.	6	20	was loss	Negative_activation_copula_1	Negative_activation	Negative_activation	cIAP-2	loss of intact XIAP, cIAP-1, and cIAP-2	ciap-2	cIAP-2	cIAP-2	ciap-2	15	16	15	16
Livin can inhibit the pro apoptotic factor SMAC induced activation of the caspasefamily , which causes tumor cells to gain resistance toward apoptosis .	Livin can inhibit the pro apoptotic factor SMAC induced activation of the caspasefamily, which causes tumor cells to gain resistance toward apoptosis.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Livin	Livin	Livin	SMAC	SMAC	SMAC	0	1	7	8
As shown in XREF_FIG , knockdown of beta-TrCP using a siRNA abrogated the mitotic degradation of both Rap1GAP and the known beta-TrCP substrate Wee1 .	As shown in XREF_FIG, knockdown of beta-TrCP using a siRNA abrogated the mitotic degradation of both Rap1GAP and the known beta-TrCP substrate Wee1.	5	23	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	Rap1GAP	Rap1GAP	Rap1GAP	7	8	17	18
CaMKI may inhibit nNOS activity though serine 741 .	CaMKI may inhibit nNOS activity though serine 741.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CaMKI	CaMKI	CaMKI	nNOS	nNOS	nNOS	0	1	3	4
Cabin1 is a repressor of MEF2- ( myocyte enhancer factor 2 ) and calcineurin mediated transcription in the immune system , but its function in the CNS during development is unknown .	Cabin1 is a repressor of MEF2- (myocyte enhancer factor 2) and calcineurin mediated transcription in the immune system, but its function in the CNS during development is unknown.	0	9	is a repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	Cabin1	Cabin1	Cabin1	MEF2-	MEF2-	MEF2-	0	1	5	6
5 In response to death receptor stimulation , caspase-8 is activated through a cleavage step , and subsequently inactivates RIP1 .	5 In response to death receptor stimulation, caspase-8 is activated through a cleavage step, and subsequently inactivates RIP1.	8	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	8	9	19	20
One possibility is that caspase-8 inactivates RIP1 through proteolytic cleavage , 21 and its suppression enhances RIP1 stability , thereby sensitizing cells to RIP1 mediated necrosis .	One possibility is that caspase-8 inactivates RIP1 through proteolytic cleavage, 21 and its suppression enhances RIP1 stability, thereby sensitizing cells to RIP1 mediated necrosis.	4	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	4	5	6	7
Meanwhile , caspase-8 can inhibit necroptosis by cleaving and inactivating RIPK1 and RIPK3 XREF_BIBR , XREF_BIBR , XREF_BIBR .	Meanwhile, caspase-8 can inhibit necroptosis by cleaving and inactivating RIPK1 and RIPK3 XREF_BIBR, XREF_BIBR, XREF_BIBR.	2	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	2	3	10	11
Complexes of caspase-8 with FADD and c-FLIP L also act to inhibit RIPK dependent necrosis .	Complexes of caspase-8 with FADD and c-FLIP L also act to inhibit RIPK dependent necrosis.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK	RIPK	RIPK	2	3	12	13
Caspase-8 inactivates RIP1 and RIP3 by proteolytic cleavage and initiates the pro apoptotic caspase activation cascade [ XREF_BIBR ] .	Caspase-8 inactivates RIP1 and RIP3 by proteolytic cleavage and initiates the pro apoptotic caspase activation cascade [XREF_BIBR].	0	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-8	Caspase-8	Caspase-8	RIP1	RIP1	RIP1	0	1	2	3
Importantly , as previously observed for caspase-3 and PARP , the cleavage of both caspase-8 and caspase-9 was strongly decreased in the absence of Ripk1 , therefore placing Ripk1 upstream of these caspases in the death pathway ( XREF_FIG ) .	Importantly, as previously observed for caspase-3 and PARP, the cleavage of both caspase-8 and caspase-9 was strongly decreased in the absence of Ripk1, therefore placing Ripk1 upstream of these caspases in the death pathway (XREF_FIG).	11	29	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	Ripk1	Ripk1	Ripk1	14	15	28	29
In the TNFR1 pathway , active caspase-8 cleaves and inactivates RIP1 and RIP3 .	In the TNFR1 pathway, active caspase-8 cleaves and inactivates RIP1 and RIP3.	6	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	6	7	10	11
When Caspase-8 is inactivated , RIPK1 associates with RIPK3 , resulting in autophophorylation , transphosphorylation and formation of the necrosome ( XREF_FIG ) XREF_BIBR , XREF_BIBR , XREF_BIBR .	When Caspase-8 is inactivated, RIPK1 associates with RIPK3, resulting in autophophorylation, transphosphorylation and formation of the necrosome (XREF_FIG) XREF_BIBR, XREF_BIBR, XREF_BIBR.	1	6	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-8	Caspase-8	Caspase-8	RIPK1	RIPK1	RIPK1	1	2	5	6
Caspase 8 then cleaves and inactivates RIPK1 , RIPK3 and CYLD and stimulates apoptosis .	Caspase 8 then cleaves and inactivates RIPK1, RIPK3 and CYLD and stimulates apoptosis.	0	10	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase 8	Caspase 8	Caspase 8	RIPK1	RIPK1	RIPK1	0	2	6	7
Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI .	Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI.	4	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	5	6	22	23
This would be particularly important in line of recent observations that caspase-8 signaling suppresses RIP1 and RIP3 dependent necrotic or necroptotic cell death pathways XREF_BIBR and that the suppression of this pathway by the MCMV gene M45 XREF_BIBR , XREF_BIBR plays a crucial role in viral in vivo growth XREF_BIBR .	This would be particularly important in line of recent observations that caspase-8 signaling suppresses RIP1 and RIP3 dependent necrotic or necroptotic cell death pathways XREF_BIBR and that the suppression of this pathway by the MCMV gene M45 XREF_BIBR, XREF_BIBR plays a crucial role in viral in vivo growth XREF_BIBR.	11	23	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	11	12	14	15
However , the mechanism by which caspase-8 , FADD , and FLIP prevent runaway RIPK activation is unknown , and the signals that trigger these events during development and immune cell activation remain at large .	However, the mechanism by which caspase-8, FADD, and FLIP prevent runaway RIPK activation is unknown, and the signals that trigger these events during development and immune cell activation remain at large.	6	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK	RIPK	RIPK	6	7	14	15
Caspase-8 constitutively inactivates RIP1 and RIP3 , thereby allowing apoptosis induction .	Caspase-8 constitutively inactivates RIP1 and RIP3, thereby allowing apoptosis induction.	0	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-8	Caspase-8	Caspase-8	RIP1	RIP1	RIP1	0	1	3	4
When caspase-8 inactivates RIP1 and RIP3 by proteolytic cleavage , a proapoptotic caspase activation instead of a pronecrotic cascade is triggered [ XREF_BIBR - XREF_BIBR ] .	When caspase-8 inactivates RIP1 and RIP3 by proteolytic cleavage, a proapoptotic caspase activation instead of a pronecrotic cascade is triggered [XREF_BIBR - XREF_BIBR].	1	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	1	2	3	4
Moreover , ubiquitination of RIP1 regulates cell death at the pivotal point when the presence of Caspase 8 activity determines apoptosis versus necrosis ; it is not clear how Caspase 8 activity prevents RIP1 and RIP3 from activating necrosis .	Moreover, ubiquitination of RIP1 regulates cell death at the pivotal point when the presence of Caspase 8 activity determines apoptosis versus necrosis; it is not clear how Caspase 8 activity prevents RIP1 and RIP3 from activating necrosis.	29	35	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase 8	Caspase 8	Caspase 8	RIP1	RIP1	RIP1	29	31	33	34
When caspase-8 fails to limit RIPK1 activity , excessive autophagy leading to necrotic death ensues .	When caspase-8 fails to limit RIPK1 activity, excessive autophagy leading to necrotic death ensues.	1	6	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	1	2	5	6
Caspase-8 can inhibit the formation of necrosome by cleaving RIPK1 .	Caspase-8 can inhibit the formation of necrosome by cleaving RIPK1.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-8	Caspase-8	Caspase-8	RIPK1	RIPK1	RIPK1	0	1	9	10
Since RIP1 is inactivated by caspase-8 , prevention of RIP1 cleavage by caspase inhibition is thought to be required for efficient death receptor mediated necrosis induction .	Since RIP1 is inactivated by caspase-8, prevention of RIP1 cleavage by caspase inhibition is thought to be required for efficient death receptor mediated necrosis induction.	1	6	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	5	6	1	2
Towards linking to the caspases involvement into this RIPK dependent cellular necrosis in sepsis , they have noticed that RIPK1- and RIPK3 dependent necroptosis in cells in sepsis could be inhibited by caspase-8 , but not by the executioner caspases , caspase-3 and -7 .	Towards linking to the caspases involvement into this RIPK dependent cellular necrosis in sepsis, they have noticed that RIPK1- and RIPK3 dependent necroptosis in cells in sepsis could be inhibited by caspase-8, but not by the executioner caspases, caspase-3 and -7.	19	33	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1-	RIPK1-	RIPK1-	32	33	19	20
This has been explained by the cleavage of RIPK1 by caspase 8 , which prevents RIPK1 kinase dependent formation of RIPK1-RIPK3 complexes .	This has been explained by the cleavage of RIPK1 by caspase 8, which prevents RIPK1 kinase dependent formation of RIPK1-RIPK3 complexes.	3	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	10	12	15	16
During apoptosis induced by TNF receptor and Fas , activated caspase-8 negatively regulates necrotic signaling by cleaving RIP1 .	During apoptosis induced by TNF receptor and Fas, activated caspase-8 negatively regulates necrotic signaling by cleaving RIP1.	9	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	10	11	17	18
In the third outcome , if caspase-8 heterodimerizes with FLIP , a noncatalytically active homolog of caspase-8 , partial activation of caspase-8 prevents complete cleavage of RIP1 , resulting in cell survival .	In the third outcome, if caspase-8 heterodimerizes with FLIP, a noncatalytically active homolog of caspase-8, partial activation of caspase-8 prevents complete cleavage of RIP1, resulting in cell survival.	19	27	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	21	22	26	27
Active caspase-8 has been reported to inhibit necroptosis by cleaving RIPK1 , RIPK3 , and CYLD XREF_BIBR - XREF_BIBR .	Active caspase-8 has been reported to inhibit necroptosis by cleaving RIPK1, RIPK3, and CYLD XREF_BIBR - XREF_BIBR.	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	1	2	10	11
Caspase inhibition further enhanced the kinetics of RIP1 and RIP3 binding to caspase 8 and programmed necrosis [ XREF_BIBR ] , in part through inhibition of caspase 8 mediated RIP1 cleavage [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Caspase inhibition further enhanced the kinetics of RIP1 and RIP3 binding to caspase 8 and programmed necrosis [XREF_BIBR], in part through inhibition of caspase 8 mediated RIP1 cleavage [XREF_BIBR, XREF_BIBR, XREF_BIBR].	24	30	mediated	Positive_early_activation	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIP1	RIP1	RIP1	26	28	29	30
Active caspase 8 blocks necrosis by proteolytically inactivating RIPK1 and RIPK3 .	Active caspase 8 blocks necrosis by proteolytically inactivating RIPK1 and RIPK3.	0	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	1	3	8	9
When caspase-8 activity is inhibited , preventing cleavage of RIP1 , RIP1 positively activates a necrotic ( necroptosis ) pathway XREF_BIBR .	When caspase-8 activity is inhibited, preventing cleavage of RIP1, RIP1 positively activates a necrotic (necroptosis) pathway XREF_BIBR.	1	10	preventing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	1	2	9	10
Notably , in contrast to the livers of c-Flip F/F ; Alfp-Cre mice , the hepatocytes of c-Flip F/F ; Mx1-Cre mice exhibited strong caspase activation that was induced after injection with poly I : C. Given that strong activation of the caspase dependent pathway might block RIPK1- and RIPK3 dependent necroptosis through caspase-8- dependent degradation of RIPK1 , apoptosis might be preferentially induced in the hepatocytes of c-Flip F/F ; Mx1-Cre mice .	Notably, in contrast to the livers of c-Flip F/F; Alfp-Cre mice, the hepatocytes of c-Flip F/F; Mx1-Cre mice exhibited strong caspase activation that was induced after injection with poly I : C. Given that strong activation of the caspase dependent pathway might block RIPK1- and RIPK3 dependent necroptosis through caspase-8- dependent degradation of RIPK1, apoptosis might be preferentially induced in the hepatocytes of c-Flip F/F; Mx1-Cre mice.	53	58	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	caspase-8-	caspase-8-	caspase-8-	RIPK1	RIPK1	RIPK1	53	54	57	58
After TNF-alpha stimulation , a complex is formed involving RIP1 , RIP3 , Fas associated death domain ( FADD ) , and active caspase-8 , which degrades RIP1 and RIP3 [ XREF_BIBR ] .	After TNF-alpha stimulation, a complex is formed involving RIP1, RIP3, Fas associated death domain (FADD), and active caspase-8, which degrades RIP1 and RIP3 [XREF_BIBR].	8	31	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	23	24	27	28
2 Under apoptotic conditions , active caspase-8 prevents further necroptotic signaling by cleaving and inactivating RIP1 and its kinase partner named receptor interacting protein kinase 3 ( RIP3 ) , ultimately initiating apoptosis .	2 Under apoptotic conditions, active caspase-8 prevents further necroptotic signaling by cleaving and inactivating RIP1 and its kinase partner named receptor interacting protein kinase 3 (RIP3), ultimately initiating apoptosis.	5	19	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	6	7	15	16
However , RIPK inhibition by caspase-8 not only leads to suppression of necroptosis but also potentially death independent , cell specific processes including inflammation .	However, RIPK inhibition by caspase-8 not only leads to suppression of necroptosis but also potentially death independent, cell specific processes including inflammation.	2	6	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK	RIPK	RIPK	5	6	2	3
Caspase-8 can inactivate RIP1 and RIP3 directly by cleaving them .	Caspase-8 can inactivate RIP1 and RIP3 directly by cleaving them.	0	5	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-8	Caspase-8	Caspase-8	RIP1	RIP1	RIP1	0	1	3	4
While fully processed caspase-8 can inhibit all RIPK1 functions , by cleaving it in its KD and ID , the FLIP ( p43 ) : caspase-8 heterodimer only cleaves RIPK1 in the KD domain .	While fully processed caspase-8 can inhibit all RIPK1 functions, by cleaving it in its KD and ID, the FLIP (p43) : caspase-8 heterodimer only cleaves RIPK1 in the KD domain.	2	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	3	4	7	8
In TNFR1-CII , caspase-8 inactivates RIP1 and RIP3 by proteolytic cleavage and initiates the pro apoptotic caspase activation cascade .	In TNFR1-CII, caspase-8 inactivates RIP1 and RIP3 by proteolytic cleavage and initiates the pro apoptotic caspase activation cascade.	3	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	3	4	5	6
Caspase-8 inactivates RIPK1 and RIPK3 by proteolytic cleavage and the proapoptotic caspase activation is initiated .	Caspase-8 inactivates RIPK1 and RIPK3 by proteolytic cleavage and the proapoptotic caspase activation is initiated.	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-8	Caspase-8	Caspase-8	RIPK1	RIPK1	RIPK1	0	1	2	3
In apoptosis sensitive cells , fully activated caspase-8 immediately cleaves RIP1 within the receptor complex , and thus abolishes RIP1 dependent JNK and IKK activation , whereas in cFLIP overexpressing , apoptosis resistant cells , suppression of caspase-8 activity to a moderate level permits as well as limits the formation of the RIP1 , TRAF2 , and cIAP1 complex , resulting in slow and weak activation of the JNK and IKK pathways .	In apoptosis sensitive cells, fully activated caspase-8 immediately cleaves RIP1 within the receptor complex, and thus abolishes RIP1 dependent JNK and IKK activation, whereas in cFLIP overexpressing, apoptosis resistant cells, suppression of caspase-8 activity to a moderate level permits as well as limits the formation of the RIP1, TRAF2, and cIAP1 complex, resulting in slow and weak activation of the JNK and IKK pathways.	6	21	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	7	8	19	20
In addition , RIPK1 can be inhibited by caspase8 and cFLIP mediated cleavage and IKK mediated phosphorylation preventing its incorporation into Complex-II 31 .	In addition, RIPK1 can be inhibited by caspase8 and cFLIP mediated cleavage and IKK mediated phosphorylation preventing its incorporation into Complex-II 31.	3	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase8	caspase8	caspase8	RIPK1	RIPK1	RIPK1	8	9	3	4
Active Caspase-8 cleaves and inactivates RIP1 initiating the extrinsic pathway of apoptosis [ XREF_BIBR , XREF_BIBR ] .	Active Caspase-8 cleaves and inactivates RIP1 initiating the extrinsic pathway of apoptosis [XREF_BIBR, XREF_BIBR].	1	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-8	Caspase-8	Caspase-8	RIP1	RIP1	RIP1	1	2	5	6
Thus , if RIPK1 is not inactivated by caspase-8 cell death can lead to sterile inflammation , similar to the phenotype observed in mice with caspase-8 deficient keratinocytes [ XREF_BIBR ] .	Thus, if RIPK1 is not inactivated by caspase-8 cell death can lead to sterile inflammation, similar to the phenotype observed in mice with caspase-8 deficient keratinocytes [XREF_BIBR].	3	9	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	8	9	3	4
Briefly , caspase-8 inactivates both RIPK1 and RIPK3 by sequestration or proteolytic cleavage XREF_BIBR , XREF_BIBR .	Briefly, caspase-8 inactivates both RIPK1 and RIPK3 by sequestration or proteolytic cleavage XREF_BIBR, XREF_BIBR.	2	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	2	3	5	6
At the same time , caspase 8 ( in multi protein complex IIa ) prevents the activation of RIPK1 blocking the necroptotic pathway .	At the same time, caspase 8 (in multi protein complex IIa) prevents the activation of RIPK1 blocking the necroptotic pathway.	5	19	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	5	7	18	19
Caspase-8 inhibits the initiation of necroptosis by cleaving and inactivating RIP1 , RIP3 [ XREF_BIBR ] and deubiquitinase CYLD , which was shown to be required for necroptosis induction [ XREF_BIBR ] .	Caspase-8 inhibits the initiation of necroptosis by cleaving and inactivating RIP1, RIP3 [XREF_BIBR] and deubiquitinase CYLD, which was shown to be required for necroptosis induction [XREF_BIBR].	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-8	Caspase-8	Caspase-8	RIP1	RIP1	RIP1	0	1	10	11
In addition , active caspase 8 dynamically inhibits necroptosis by cleaving its core regulators , RIPK1 and RIPK3 .	In addition, active caspase 8 dynamically inhibits necroptosis by cleaving its core regulators, RIPK1 and RIPK3.	3	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	4	6	15	16
Intriguingly , although low dose of LPS activated microglia without inducing cell death , blockade of caspase-8 triggered a robust RIP1 dependent necrosis programme .	Intriguingly, although low dose of LPS activated microglia without inducing cell death, blockade of caspase-8 triggered a robust RIP1 dependent necrosis programme.	14	23	triggered	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	16	17	20	21
Necroptosis requires that caspase 8 activity be constrained , but not abolished , since the autocleavage and homodimerization of caspase 8 following TNF ligation inactivates RIPK1 and RIPK3 and induces apoptosis .	Necroptosis requires that caspase 8 activity be constrained, but not abolished, since the autocleavage and homodimerization of caspase 8 following TNF ligation inactivates RIPK1 and RIPK3 and induces apoptosis.	15	27	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	19	21	25	26
Upon TNFalpha receptor stimulation caspase 8 becomes activated causing inhibition of receptor interacting protein kinase 1 ( RIP1 ) [ XREF_BIBR ] .	Upon TNFalpha receptor stimulation caspase 8 becomes activated causing inhibition of receptor interacting protein kinase 1 (RIP1) [XREF_BIBR].	4	20	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIP1	RIP1	RIP1	4	6	17	18
Activation of the necrosome is prevented by caspase 8 , which can inactivate RIPK1 and RIPK3 by cleavage of the two kinases .	Activation of the necrosome is prevented by caspase 8, which can inactivate RIPK1 and RIPK3 by cleavage of the two kinases.	5	15	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	7	9	13	14
In essence , caspase-8 heterodimerized with FLIP L prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis .	In essence, caspase-8 heterodimerized with FLIP L prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis.	3	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	3	4	13	14
Therefore , caspase 8 cleavage will prevent RIPK1 from phosphorylating its downstream substrate RIPK3 ( XREF_FIG ) .	Therefore, caspase 8 cleavage will prevent RIPK1 from phosphorylating its downstream substrate RIPK3 (XREF_FIG).	2	8	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	2	4	7	8
Finally , caspase-8 has been shown to inhibit a type of cell death termed ' programmed necrosis ' or necroptosis by cleaving receptor interacting protein kinase 1 ( RIPK1 ) [ XREF_BIBR - XREF_BIBR ] .	Finally, caspase-8 has been shown to inhibit a type of cell death termed ' programmed necrosis ' or necroptosis by cleaving receptor interacting protein kinase 1 (RIPK1) [XREF_BIBR - XREF_BIBR].	2	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	2	3	28	29
The active caspase-8 in Complex IIa promotes apoptosis and simultaneously negatively regulates necroptosis by cleaving RIPK1 and RIPK3 .	The active caspase-8 in Complex IIa promotes apoptosis and simultaneously negatively regulates necroptosis by cleaving RIPK1 and RIPK3.	0	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	2	3	15	16
Furthermore , active caspase-8 induces apoptosis in response to low-doses radiation and inhibits necrosis by cleaving RIPK1 .	Furthermore, active caspase-8 induces apoptosis in response to low-doses radiation and inhibits necrosis by cleaving RIPK1.	2	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	3	4	16	17
These results suggest that the FADD- and caspase-8- dependent pathways block RIPK1- and RIPK3 dependent necroptosis during normal development .	These results suggest that the FADD- and caspase-8- dependent pathways block RIPK1- and RIPK3 dependent necroptosis during normal development.	7	15	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8-	caspase-8-	caspase-8-	RIPK1-	RIPK1-	RIPK1-	7	8	11	12
Casp8 suppresses RIP3 and RIP1 kinase complex dependent XREF_BIBR - XREF_BIBR necroptosis XREF_BIBR that follows DR activation as well as a RIP3 dependent , RIP1 independent necrotic pathway that has emerged as a host defense mechanism against murine cytomegalovirus ( MCMV ) XREF_BIBR .	Casp8 suppresses RIP3 and RIP1 kinase complex dependent XREF_BIBR - XREF_BIBR necroptosis XREF_BIBR that follows DR activation as well as a RIP3 dependent, RIP1 independent necrotic pathway that has emerged as a host defense mechanism against murine cytomegalovirus (MCMV) XREF_BIBR.	0	6	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Casp8	Casp8	Casp8	RIP1	RIP1	RIP1	0	1	4	5
Importantly , down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-kappaB , which regulates these miRNAs .	Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-kappaB, which regulates these miRNAs.	2	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	receptor interacting protein-1	receptor interacting protein-1	receptor interacting protein-1	4	5	8	11
Presumably , the recruitment of RIPK1 leads to its activation in the complex , whereas the role caspase-8 is to inactivate RIPK1 by cleavage .	Presumably, the recruitment of RIPK1 leads to its activation in the complex, whereas the role caspase-8 is to inactivate RIPK1 by cleavage.	15	22	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	17	18	21	22
Thus , caspase-8 may be required to promote the survival of activated T cells by suppressing RIP1 kinase activity .	Thus, caspase-8 may be required to promote the survival of activated T cells by suppressing RIP1 kinase activity.	2	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	2	3	16	17
It was reported that RIPK1 is negatively regulated by caspase-8 and FADD once incorporated in the ripoptosome complex .	It was reported that RIPK1 is negatively regulated by caspase-8 and FADD once incorporated in the ripoptosome complex.	4	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	9	10	4	5
In a cell undergoing apoptosis , RIP1 and RIP3 are cleaved , and thus inactivated , by caspase 8 .	In a cell undergoing apoptosis, RIP1 and RIP3 are cleaved, and thus inactivated, by caspase 8.	6	19	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIP1	RIP1	RIP1	17	19	6	7
Another group demonstrated that caspase 8 activation is crucial to inhibit the interaction of RIP-1 and -3 which complex formation has been shown to be required for initiation of programmed necrosis [ XREF_BIBR ] .	Another group demonstrated that caspase 8 activation is crucial to inhibit the interaction of RIP-1 and -3 which complex formation has been shown to be required for initiation of programmed necrosis [XREF_BIBR].	4	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIP-1	RIP-1	RIP-1	4	6	14	15
Activation of caspase-8 activity inactivates RIP1 and RIP3 by proteolytic cleavage and triggers caspase dependent apoptosis .	Activation of caspase-8 activity inactivates RIP1 and RIP3 by proteolytic cleavage and triggers caspase dependent apoptosis.	2	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	2	3	5	6
Conversely , treatment with 3-aminobenzadine , a specific PARP-1 inhibitor , was able to completely block PARP-1 activation , but not caspase-3 activation or ethanol induced neurodegeneration in the developing cerebellum .	Conversely, treatment with 3-aminobenzadine, a specific PARP-1 inhibitor, was able to completely block PARP-1 activation, but not caspase-3 activation or ethanol induced neurodegeneration in the developing cerebellum.	15	22	block	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	21	22	16	17
Caspase-3 inactivates PARP impairing its ability to repair damaged DNA , which was in accordance with the increased levels of phospho-PARP ( inactive form ) [ XREF_BIBR ] .	Caspase-3 inactivates PARP impairing its ability to repair damaged DNA, which was in accordance with the increased levels of phospho-PARP (inactive form) [XREF_BIBR].	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	0	1	2	3
PARP , normally involved in DNA repair , is cleaved and subsequently deactivated by the pro-apoptotic-cleaved caspase 3 .	PARP, normally involved in DNA repair, is cleaved and subsequently deactivated by the pro-apoptotic-cleaved caspase 3.	0	18	deactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	16	18	0	1
Cleavage of PARP was observed at 3-4 h following PDT and caspase-3 specific inhibitor DEVD-CHO and broad-spectrum caspases inhibitor z-VAD-fmk blocked caspase-3 activation and PARP cleavage suggesting that caspase-3 plays an important role in HA and HB induced apoptosis .	Cleavage of PARP was observed at 3-4 h following PDT and caspase-3 specific inhibitor DEVD-CHO and broad-spectrum caspases inhibitor z-VAD-fmk blocked caspase-3 activation and PARP cleavage suggesting that caspase-3 plays an important role in HA and HB induced apoptosis.	7	37	blocked	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	11	12	24	25
This activated caspase-3 proteolytically degrades PARP , completing the intrinsic pathway of apoptosis .	This activated caspase-3 proteolytically degrades PARP, completing the intrinsic pathway of apoptosis.	0	6	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	2	3	5	6
These data suggest that picroside II may inhibit caspase-3 expression and reduce PARP degradation after cerebral ischemic injury , which may contribute to the maintenance of NAD + level in penumbra , thereby enabling PARP to utilize residual energy for the reparation of neuronal damage .	These data suggest that picroside II may inhibit caspase-3 expression and reduce PARP degradation after cerebral ischemic injury, which may contribute to the maintenance of NAD + level in penumbra, thereby enabling PARP to utilize residual energy for the reparation of neuronal damage.	4	13	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	picroside II may inhibit caspase-3 expression	caspase-3	PARP	PARP	parp	8	9	12	13
After the increased oxidative stress , PDTC-Cu ( 2+ ) complex differentially activated JNKs , ERK , p38 and caspase 3 , which caused PARP degradation in a time dependent manner .	After the increased oxidative stress, PDTC-Cu (2+) complex differentially activated JNKs, ERK, p38 and caspase 3, which caused PARP degradation in a time dependent manner.	12	25	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	19	21	24	25
PARP can be activated in cells experiencing stress and/or DNA damage , and PARP is inactivated by caspase-3 cleavage during programmed cell death .	PARP can be activated in cells experiencing stress and/or DNA damage, and PARP is inactivated by caspase-3 cleavage during programmed cell death.	13	18	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	17	18	13	14
The proteolytic degradation of PARP-1 by caspase 3 is a hallmark of apoptosis .	The proteolytic degradation of PARP-1 by caspase 3 is a hallmark of apoptosis.	2	8	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	PARP-1	PARP-1	PARP-1	6	8	4	5
Taken together , UVB induced procaspase-3 cleavage into the active caspase-3 form , and caspase-3 induced PARP degradation .	Taken together, UVB induced procaspase-3 cleavage into the active caspase-3 form, and caspase-3 induced PARP degradation.	14	17	induced	Positive_early_activation	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	14	15	16	17
Cleavage of PARP ( or loss of full length PARP ) , caspase 9 and caspase 3 was seen after treatment with GLV-1h68 alone and in combination with EBRT in all cell three lines .	Cleavage of PARP (or loss of full length PARP), caspase 9 and caspase 3 was seen after treatment with GLV-1h68 alone and in combination with EBRT in all cell three lines.	0	17	loss	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	15	17	9	10
Knockdown of caspase-3 also attenuated cisplatin induced cleavage of PARP in A549 cells ( data not shown ) .	Knockdown of caspase-3 also attenuated cisplatin induced cleavage of PARP in A549 cells (data not shown).	0	14	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	2	3	9	10
Meanwhile , PtPT treatment significantly reduced the levels of pro-caspase-3 , and induced PARP cleavage in the primary monocytes ( XREF_FIG ) .	Meanwhile, PtPT treatment significantly reduced the levels of pro-caspase-3, and induced PARP cleavage in the primary monocytes (XREF_FIG).	2	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pro-caspase-3	PtPT treatment significantly reduced the levels of pro-caspase-3	pro-caspase-3	PARP	PARP	parp	9	10	13	14
z-DEVD-fmk , a caspase-3 specific inhibitor , blocked caspase-3 activation and PARP degradation , and significantly attenuated beta-sitosterol-induced apoptosis .	z-DEVD-fmk, a caspase-3 specific inhibitor, blocked caspase-3 activation and PARP degradation, and significantly attenuated beta-sitosterol-induced apoptosis.	3	12	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	3	4	11	12
To investigate if apoptosis upon HEABG treatment was induced via activation of caspase-3 , cells were treated with a caspase-3 inhibitor , z-DEVD-fmk , for 2 h , followed by treatment with HEABG for an additional 24 h. XREF_FIG shows that blockage of caspase-3 activation by z-DEVD-fmk completely abrogated PARP degradation induced by HEABG , and that z-DEVD-fmk attenuated HEABG induced apoptotic features such as chromatin condensation , DNA fragmentation and accumulation of sub-G1 cells in U937 cells ( XREF_FIG ) .	To investigate if apoptosis upon HEABG treatment was induced via activation of caspase-3, cells were treated with a caspase-3 inhibitor, z-DEVD-fmk, for 2 h, followed by treatment with HEABG for an additional 24 h. XREF_FIG shows that blockage of caspase-3 activation by z-DEVD-fmk completely abrogated PARP degradation induced by HEABG, and that z-DEVD-fmk attenuated HEABG induced apoptotic features such as chromatin condensation, DNA fragmentation and accumulation of sub-G1 cells in U937 cells (XREF_FIG).	43	50	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	43	44	49	50
PARP is inactivated by caspase 3 cleavage ( in a specific domain of the enzyme ) during programmed cell death .	PARP is inactivated by caspase 3 cleavage (in a specific domain of the enzyme) during programmed cell death.	0	6	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	4	6	0	1
On the other hand , PARP can be inactivated by caspase-3 cleavage [ XREF_BIBR ] .	On the other hand, PARP can be inactivated by caspase-3 cleavage [XREF_BIBR].	5	13	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	10	11	5	6
During apoptosis , caspase-3 inactivates PARP by cleaving it into 83 and 24kDa fragments and thereby preserves ATP resources of the cell for apoptosis [ XREF_BIBR , XREF_BIBR ] .	During apoptosis, caspase-3 inactivates PARP by cleaving it into 83 and 24kDa fragments and thereby preserves ATP resources of the cell for apoptosis [XREF_BIBR, XREF_BIBR].	3	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	3	4	5	6
Here , melatonin attenuated the expression of survival genes such as Bcl-xL , Mcl-1 , cyclinD1 , and cyclin E , suppressed the phosphorylation of STAT3 , mTOR , and AKT and induced the cleavage of PARP and activated caspase 3 indicating that melatonin can induce apoptosis and inhibit the proliferation via inhibition of anti-apoptotic genes such as BCL-xL , Mcl-1 , cyclin D1 , cyclin E , p-STAT3 , p-mTOR , and p-AKT at high concentration in estrogen negative MDA-MB-231 cells .	Here, melatonin attenuated the expression of survival genes such as Bcl-xL, Mcl-1, cyclinD1, and cyclin E, suppressed the phosphorylation of STAT3, mTOR, and AKT and induced the cleavage of PARP and activated caspase 3 indicating that melatonin can induce apoptosis and inhibit the proliferation via inhibition of anti-apoptotic genes such as BCL-xL, Mcl-1, cyclin D1, cyclin E, p-STAT3, p-mTOR, and p-AKT at high concentration in estrogen negative MDA-MB-231 cells.	34	41	activated	Positive_activation_syntax_3_verb	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	39	41	36	37
Furthermore , inhibition of caspase-3 in the REC-2006 + radiation treated group of the HepG2 cell line also supports the REC-2006 mediated inhibition of ATM and PARP-1 cleavage in the respective treatment group .	Furthermore, inhibition of caspase-3 in the REC-2006 + radiation treated group of the HepG2 cell line also supports the REC-2006 mediated inhibition of ATM and PARP-1 cleavage in the respective treatment group.	2	27	supports	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	4	5	26	27
The results showed that caspase 3 was activated ( cleaved ) and PARP was inactivated by caspase 3 cleavage in a concentration dependent manner .	The results showed that caspase 3 was activated (cleaved) and PARP was inactivated by caspase 3 cleavage in a concentration dependent manner.	12	18	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	16	18	12	13
As a result , alpha-crystallins preserve the integrity of mitochondria , restrict release of cytochrome c , repress activation of caspase-3 and block degradation of PARP .	As a result, alpha-crystallins preserve the integrity of mitochondria, restrict release of cytochrome c, repress activation of caspase-3 and block degradation of PARP.	20	26	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	20	21	25	26
While the caspase-1 inhibitor YVAD was unable to block apoptosis , the caspase-3 specific inhibitor DEVD-cmk , partially inhibited Mn2 +-induced CPP32 activation , PARP cleavage and apoptosis of cells .	While the caspase-1 inhibitor YVAD was unable to block apoptosis, the caspase-3 specific inhibitor DEVD-cmk, partially inhibited Mn2 +-induced CPP32 activation, PARP cleavage and apoptosis of cells.	12	25	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	12	13	24	25
Western blotting analysis of the cleaved Caspase-3 and PARP also indicated that cells treated with 6G increased cleaved Caspase-3 and decreased PARP expression which was partially reversed by NAC pre-treatment and completely reversed by Piffithrin-alpha pre-treatment .	Western blotting analysis of the cleaved Caspase-3 and PARP also indicated that cells treated with 6G increased cleaved Caspase-3 and decreased PARP expression which was partially reversed by NAC pre-treatment and completely reversed by Piffithrin-alpha pre-treatment.	2	19	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	18	19	8	9
Upregulation of caspase-3 expression decreased the PARP-1 at both the mRNA and the protein levels , which contributed to apoptosis .	Upregulation of caspase-3 expression decreased the PARP-1 at both the mRNA and the protein levels, which contributed to apoptosis.	2	17	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3 expression	caspase-3	PARP-1	PARP-1	parp-1	2	3	6	7
PARP-1 is inactivated by cleavage by caspase 3 from a 116 KDa active form into an 89 KDa inactive enzyme .	PARP-1 is inactivated by cleavage by caspase 3 from a 116 KDa active form into an 89 KDa inactive enzyme.	0	8	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	PARP-1	PARP-1	PARP-1	6	8	0	1
Data shown in XREF_FIG and XREF_FIG argue for PARP being highly sensitive to caspase-3 activity because only 25 % of caspase-3 activity ( XREF_FIG , gray bars ) induces practically 60 % degradation of PARP ( XREF_FIG ) .	Data shown in XREF_FIG and XREF_FIG argue for PARP being highly sensitive to caspase-3 activity because only 25% of caspase-3 activity (XREF_FIG, gray bars) induces practically 60% degradation of PARP (XREF_FIG).	20	36	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	20	21	34	35
PARP is activated at an intermediate stage of apoptosis and is inactivated by proteolytic cleavage at a late stage by caspase3 and caspase7 .	PARP is activated at an intermediate stage of apoptosis and is inactivated by proteolytic cleavage at a late stage by caspase3 and caspase7.	0	22	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase3	caspase3	caspase3	PARP	PARP	PARP	20	21	0	1
Significantly increased cleavage of caspase-3 and degradation of PARP by caspase-3 into 85 to 90 kDa fragments were observed after 24 hours of incubation ( XREF_FIG ) .	Significantly increased cleavage of caspase-3 and degradation of PARP by caspase-3 into 85 to 90 kDa fragments were observed after 24 hours of incubation (XREF_FIG).	2	16	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	10	11	8	9
Conversely , in the course of apoptosis , caspase-3 proteolytically inactivates PARP1 , hence avoiding such a rapid drop in intracellular ATP concentrations leading to regulated necrosis .	Conversely, in the course of apoptosis, caspase-3 proteolytically inactivates PARP1, hence avoiding such a rapid drop in intracellular ATP concentrations leading to regulated necrosis.	8	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP1	PARP1	PARP1	8	9	11	12
PARP-1 is inactivated by caspase-3 cleavage into 89- and 24kDa fragments .	PARP-1 is inactivated by caspase-3 cleavage into 89- and 24kDa fragments.	0	5	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	4	5	0	1
However , in the present study , mangiferin increased the expression levels of pro-caspase-3 and decreased the cleavage of caspase-3 and PARP .	However, in the present study, mangiferin increased the expression levels of pro-caspase-3 and decreased the cleavage of caspase-3 and PARP.	7	22	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pro-caspase-3	mangiferin increased the expression levels of pro-caspase-3	pro-caspase-3	PARP	PARP	parp	13	14	21	22
We next analyzed expression of the DNA repair enzyme , PARP-1 , which is proteolytically inactivated by caspase-3 .	We next analyzed expression of the DNA repair enzyme, PARP-1, which is proteolytically inactivated by caspase-3.	8	18	inactivated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	17	18	10	11
This cascade of events allowed us to detect the inactivation of PARP by caspase-3 , leading to PARP proteolysis induced by EspC producing EPEC but not by the espC mutant .	This cascade of events allowed us to detect the inactivation of PARP by caspase-3, leading to PARP proteolysis induced by EspC producing EPEC but not by the espC mutant.	7	14	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	13	14	11	12
PARP is inactivated by activated caspase-3 cleavage , after which , neurons disappear by the process of apoptosis .	PARP is inactivated by activated caspase-3 cleavage, after which, neurons disappear by the process of apoptosis.	0	6	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	5	6	0	1
XREF_BIBR , XREF_BIBR For Rg 3 -induced apoptosis of MDA-MB-231 cells , it is likely that caspase-3 is activated , which results in the degradation of the DNA repair enzyme PARP .	XREF_BIBR, XREF_BIBR For Rg 3 -induced apoptosis of MDA-MB-231 cells, it is likely that caspase-3 is activated, which results in the degradation of the DNA repair enzyme PARP.	16	31	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	16	17	30	31
Western blot showed that Z-DEVD-FMK decreased the expression of CASP3 and upregulated PARP , which is the digestion substrate of caspase-3 .	Western blot showed that Z-DEVD-FMK decreased the expression of CASP3 and upregulated PARP, which is the digestion substrate of caspase-3.	4	18	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CASP3	Z-DEVD-FMK decreased the expression of CASP3	casp3	PARP	PARP	parp	9	10	12	13
Zhang and colleagues demonstrated that oridonin induced cell death in L929 cells was mediated through caspase-3 independent degradation of PARP [ XREF_BIBR ] .	Zhang and colleagues demonstrated that oridonin induced cell death in L929 cells was mediated through caspase-3 independent degradation of PARP [XREF_BIBR].	15	21	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	15	16	19	20
This activated caspase-3 proteolytically degrades the PARP and fails to repair intracellular damaged DNA and thus completes the intrinsic pathway of apoptosis .	This activated caspase-3 proteolytically degrades the PARP and fails to repair intracellular damaged DNA and thus completes the intrinsic pathway of apoptosis.	0	16	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	2	3	6	7
PARP can be inactivated by Caspase-3 cleavage and this will activate programmed cell death .	PARP can be inactivated by Caspase-3 cleavage and this will activate programmed cell death.	0	6	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	5	6	0	1
PARP1 is activated at an intermediate stage of apoptosis and is inactivated by proteolytic cleavage at a late stage by caspase 3 and caspase 7 .	PARP1 is activated at an intermediate stage of apoptosis and is inactivated by proteolytic cleavage at a late stage by caspase 3 and caspase 7.	0	23	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	PARP1	PARP1	PARP1	20	22	0	1
Increased cleavage of caspase-3 and degradation of PARP by caspase-3 into 89 kDa fragments were observed after 48 h of incubation ( XREF_FIG ) .	Increased cleavage of caspase-3 and degradation of PARP by caspase-3 into 89 kDa fragments were observed after 48 h of incubation (XREF_FIG).	1	13	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	9	10	7	8
5 Inactivation of PARP-1 by caspase-3 cleavage is a key event in apoptosis , while overactivation of PARP-1 leads to the depletion of cellular ATP levels and necrosis .	5 Inactivation of PARP-1 by caspase-3 cleavage is a key event in apoptosis, while overactivation of PARP-1 leads to the depletion of cellular ATP levels and necrosis.	1	6	Inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	5	6	3	4
For instance , caspase-3 inactivation of PARP-1 , a hallmark of apoptosis , results from abrogation of the finely balanced interactions of F3 caused by cleavage of the F2-F3 linker .	For instance, caspase-3 inactivation of PARP-1, a hallmark of apoptosis, results from abrogation of the finely balanced interactions of F3 caused by cleavage of the F2-F3 linker.	3	7	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	3	4	6	7
The role of the cleavage and consequent inactivation of PARP-1 by caspase-3 in the activation of DNAS1L3 has now been investigated further both in vitro and in vivo .	The role of the cleavage and consequent inactivation of PARP-1 by caspase-3 in the activation of DNAS1L3 has now been investigated further both in vitro and in vivo.	7	14	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	11	12	9	10
Tunicamycin dose-dependently increased the expression of activated caspase 3 and inactivated PARP in three cell lines ; however , combined treatment obviously enhanced the expression of cleaved caspase 3 and cleaved PARP as compared with the treatment of either drug alone in MCF-7 and HER2 and SKBR3 cells .	Tunicamycin dose-dependently increased the expression of activated caspase 3 and inactivated PARP in three cell lines; however, combined treatment obviously enhanced the expression of cleaved caspase 3 and cleaved PARP as compared with the treatment of either drug alone in MCF-7 and HER2 and SKBR3 cells.	0	12	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 3	Tunicamycin dose-dependently increased the expression of activated caspase 3	caspase 3	PARP	PARP	parp	7	9	11	12
Caspase 3 is responsible for cleavage of nuclear enzyme poly ( ADP-ribose ) polymerase ( PARP ) and inactivates PARP during cell death .	Caspase 3 is responsible for cleavage of nuclear enzyme poly (ADP-ribose) polymerase (PARP) and inactivates PARP during cell death.	0	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase 3	Caspase 3	Caspase 3	PARP	PARP	PARP	0	2	19	20
Upregulation of caspase-3 expression decreased poly ADP-ribose polymerase 1 ( PARP-1 ) at mRNA and protein levels , further promoting apoptosis .	Upregulation of caspase-3 expression decreased poly ADP-ribose polymerase 1 (PARP-1) at mRNA and protein levels, further promoting apoptosis.	2	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3 expression	caspase-3	PARP-1	PARP-1	parp-1	2	3	10	11
During apoptosis , the 116 kDa PARP is degraded by caspase-3 to distinct 89 and 27 kDa fragments ; however , PARP is cleaved by calpain at alternative sites to generate fragments from 70 to 40 kDa in size during necrosis .	During apoptosis, the 116 kDa PARP is degraded by caspase-3 to distinct 89 and 27 kDa fragments; however, PARP is cleaved by calpain at alternative sites to generate fragments from 70 to 40 kDa in size during necrosis.	3	11	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	10	11	6	7
The same work group showed later that Akt is decreased by caspase-3 cleavage in the brains of patients with HD [ XREF_BIBR ] .	The same work group showed later that Akt is decreased by caspase-3 cleavage in the brains of patients with HD [XREF_BIBR].	7	12	decreased	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	Akt	Akt	Akt	11	12	7	8
Treatment of HHT could increase the mRNA expressions of BAX and Bcl2 , caspase-3 , caspase-9 and raptor , and decrease PI3K , AKT and rictor in the HT29 cells .	Treatment of HHT could increase the mRNA expressions of BAX and Bcl2, caspase-3, caspase-9 and raptor, and decrease PI3K, AKT and rictor in the HT29 cells.	2	24	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	HHT could increase the mRNA expressions of BAX and Bcl2, caspase-3	caspase-3	AKT	AKT	akt	13	14	23	24
Caspase-3 activation in apoptosis pathways and glutamate induced reduction of AKT activity in addition to the associated neuronal toxicity are prevented by the lithium treatment [ XREF_BIBR ] .	Caspase-3 activation in apoptosis pathways and glutamate induced reduction of AKT activity in addition to the associated neuronal toxicity are prevented by the lithium treatment [XREF_BIBR].	0	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-3	Caspase-3	Caspase-3	AKT	AKT	AKT	0	1	10	11
Tateishi and colleagues have reported that knockdown of Sca-1 transcripts in CPCs , by inactivating Akt , leads to retarded ex vivo expansion and apoptosis .	Tateishi and colleagues have reported that knockdown of Sca-1 transcripts in CPCs, by inactivating Akt, leads to retarded ex vivo expansion and apoptosis.	8	18	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sca-1	Sca-1	Sca-1	Akt	Akt	Akt	8	9	15	16
Previous reports demonstrated that AKT is an endogenous substrate of caspase 3 and that activated caspase 3 can also reduce AKT activity XREF_BIBR , XREF_BIBR .	Previous reports demonstrated that AKT is an endogenous substrate of caspase 3 and that activated caspase 3 can also reduce AKT activity XREF_BIBR, XREF_BIBR.	14	22	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	AKT	AKT	AKT	15	17	20	21
It was previously demonstrated that AKT is an endogenous substrate of caspase 3 , and activated caspase 3 can also reduce AKT activity XREF_BIBR , XREF_BIBR .	It was previously demonstrated that AKT is an endogenous substrate of caspase 3, and activated caspase 3 can also reduce AKT activity XREF_BIBR, XREF_BIBR.	16	23	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase 3	caspase 3	caspase 3	AKT	AKT	AKT	16	18	21	22
Indeed , in apoptotic neutrophils and granulocyte differentiated HL60 cells , PI3-kinase and AKT were deactivated and followed by GSK-3beta activation , Mcl-1 degradation , MTP loss , and caspase-3 activation .	Indeed, in apoptotic neutrophils and granulocyte differentiated HL60 cells, PI3-kinase and AKT were deactivated and followed by GSK-3beta activation, Mcl-1 degradation, MTP loss, and caspase-3 activation.	11	30	deactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	AKT	AKT	AKT	29	30	13	14
Preconditioning with LY294002 to block Akt caused the protective effects of Ex-4 on H 2 O 2 -treated MSC to disappear , as evidenced by an increase in the number of apoptotic cells and higher caspase3 activity .	Preconditioning with LY294002 to block Akt caused the protective effects of Ex-4 on H 2 O 2 -treated MSC to disappear, as evidenced by an increase in the number of apoptotic cells and higher caspase3 activity.	4	36	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase3	caspase3	caspase3	Akt	Akt	Akt	35	36	5	6
Lumbrokinase could also reduce the protein levels of caspase 8 , caspase 9 , and caspase 3 , and enhance the survival related proteins PI3K and Akt and Bcl2 .	Lumbrokinase could also reduce the protein levels of caspase 8, caspase 9, and caspase 3, and enhance the survival related proteins PI3K and Akt and Bcl2.	0	28	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 3	Lumbrokinase could also reduce the protein levels of caspase 8, caspase 9, and caspase 3	caspase 3	Akt	Akt	akt	15	17	26	27
In contrast to our finding , it has been shown that Sca-1 disruption enhanced Akt activation induced by aortic banding , whereas Sca-1 overexpression inhibited phosphorylation of cardiac Akt , indicating that Sca-1 is a negative regulator of Akt XREF_BIBR .	In contrast to our finding, it has been shown that Sca-1 disruption enhanced Akt activation induced by aortic banding, whereas Sca-1 overexpression inhibited phosphorylation of cardiac Akt, indicating that Sca-1 is a negative regulator of Akt XREF_BIBR.	11	15	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sca-1	Sca-1	Sca-1	Akt	Akt	Akt	11	12	14	15
During the progression of constitutive apoptosis in primary neutrophils and granulocyte differentiated HL60 cells under an in vitro culture system , we previously demonstrated that AKT was deactivated and followed by GSK-3beta activation , Mcl-1 degradation , MTP loss , caspase-3 activation , and cell apoptosis [ XREF_BIBR , XREF_BIBR ] .	During the progression of constitutive apoptosis in primary neutrophils and granulocyte differentiated HL60 cells under an in vitro culture system, we previously demonstrated that AKT was deactivated and followed by GSK-3beta activation, Mcl-1 degradation, MTP loss, caspase-3 activation, and cell apoptosis [XREF_BIBR, XREF_BIBR].	25	41	deactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	AKT	AKT	AKT	40	41	25	26
In C2C12 muscle cells , activated caspase-3 cleaves and activates Rho associated protein kinase 1 ( ROCK1 ) , which enhances the activity of phosphatase and tensin homolog ( PTEN ) and reduces Akt activity .	In C2C12 muscle cells, activated caspase-3 cleaves and activates Rho associated protein kinase 1 (ROCK1), which enhances the activity of phosphatase and tensin homolog (PTEN) and reduces Akt activity.	6	34	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	Akt	Akt	Akt	6	7	33	34
Genetic manipulation of calpastatin to enhance endogenous inhibitory mechanisms enables suppression of both mu- and m-calpain , providing a powerful research tool for understanding the role of pathological calpain proteolysis .	Genetic manipulation of calpastatin to enhance endogenous inhibitory mechanisms enables suppression of both mu- and m-calpain, providing a powerful research tool for understanding the role of pathological calpain proteolysis.	1	16	enables	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	calpastatin	calpastatin	calpastatin	m-calpain	m-calpain	m-calpain	3	4	15	16
However , at pH 5.7 the ability of calpastatin to inhibit m-calpain decreased with increasing ionic strength .	However, at pH 5.7 the ability of calpastatin to inhibit m-calpain decreased with increasing ionic strength.	6	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	calpastatin	calpastatin	calpastatin	m-calpain	m-calpain	m-calpain	8	9	11	12
Treatment with 50 mg/kg of taurine significantly increased the calpastatin protein levels and activities , and markedly reduced the m-calpain and caspase-3 activities in penumbra 24 h after MCAo , however , it had no significant effect on mu-calpain activity .	Treatment with 50 mg/kg of taurine significantly increased the calpastatin protein levels and activities, and markedly reduced the m-calpain and caspase-3 activities in penumbra 24 h after MCAo, however, it had no significant effect on mu-calpain activity.	9	22	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	calpastatin	calpastatin protein levels	calpastatin	m-calpain	m-calpain	m-calpain	9	10	19	20
Calpastatin inhibits the two ubiquitous calpains , mu- and m-calpain , named for their respective micromolar or millimolar Ca 2+ ion concentrations required for in vitro activity .	Calpastatin inhibits the two ubiquitous calpains, mu- and m-calpain, named for their respective micromolar or millimolar Ca 2+ ion concentrations required for in vitro activity.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Calpastatin	Calpastatin	Calpastatin	m-calpain	m-calpain	m-calpain	0	1	9	10
This system consists of mu-calpain and m-calpain activated by Ca 2+ ions and endogenous calpain inhibitor - calpastatin .	This system consists of mu-calpain and m-calpain activated by Ca 2+ ions and endogenous calpain inhibitor - calpastatin.	2	16	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	calpain inhibitor	calpain inhibitor	calpain inhibitor	m-calpain	m-calpain	m-calpain	14	16	6	7
Calpastatin ( CAST ) is a specific inhibitor of the ubiquitous calcium dependent proteases -mu-calpain and m-calpain .	Calpastatin (CAST) is a specific inhibitor of the ubiquitous calcium dependent proteases -mu-calpain and m-calpain.	0	17	is a specific inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Calpastatin	Calpastatin	Calpastatin	m-calpain	m-calpain	m-calpain	0	1	16	17
Calpastatin ( CAST ) is a specific inhibitor of the ubiquitous calcium dependent proteases-mu-calpain and m-calpain , found in mammalian tissues .	Calpastatin (CAST) is a specific inhibitor of the ubiquitous calcium dependent proteases-mu-calpain and m-calpain, found in mammalian tissues.	0	16	is a specific inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Calpastatin	Calpastatin	Calpastatin	m-calpain	m-calpain	m-calpain	0	1	15	16
In mammals , calpastatin directly inhibits CAPN1 and CAPN2 under pathological conditions XREF_BIBR .	In mammals, calpastatin directly inhibits CAPN1 and CAPN2 under pathological conditions XREF_BIBR.	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	calpastatin	calpastatin	calpastatin	CAPN2	CAPN2	CAPN2	3	4	8	9
Calpastatin is the endogenous inhibitor of both mu- and m-calpain , and it is not known to inhibit proteases of any other family .	Calpastatin is the endogenous inhibitor of both mu- and m-calpain, and it is not known to inhibit proteases of any other family.	0	10	is the endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Calpastatin	Calpastatin	Calpastatin	m-calpain	m-calpain	m-calpain	0	1	9	10
Calpastatin ( CAST ) is a protein inhibitor of the ubiquitous calcium dependent proteases-micro-calpain and m-calpain .	Calpastatin (CAST) is a protein inhibitor of the ubiquitous calcium dependent proteases-micro-calpain and m-calpain.	0	16	is a protein inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Calpastatin	Calpastatin	Calpastatin	m-calpain	m-calpain	m-calpain	0	1	15	16
Calpastatin is the endogenous inhibitor of mu-calpain and m-calpain and can reversibly inhibit up to four calpain heterodimers , with inhibitory action requiring calcium induced structural changes to calpain [ XREF_BIBR - XREF_BIBR ] .	Calpastatin is the endogenous inhibitor of mu-calpain and m-calpain and can reversibly inhibit up to four calpain heterodimers, with inhibitory action requiring calcium induced structural changes to calpain [XREF_BIBR - XREF_BIBR].	0	12	is the endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Calpastatin	Calpastatin	Calpastatin	m-calpain	m-calpain	m-calpain	0	1	8	9
Calpastatin is the specific inhibitor of the ubiquitous calcium dependent proteases mu-calpain and m-calpain .	Calpastatin is the specific inhibitor of the ubiquitous calcium dependent proteases mu-calpain and m-calpain.	0	14	is the specific inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Calpastatin	Calpastatin	Calpastatin	m-calpain	m-calpain	m-calpain	0	1	13	14
In gastric cancer cells , Cbl-b could inhibit the survival signal of EGFR pathway to inhibit the proliferation induced by 5-FU treatment [ XREF_BIBR ] .	In gastric cancer cells, Cbl-b could inhibit the survival signal of EGFR pathway to inhibit the proliferation induced by 5-FU treatment [XREF_BIBR].	5	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cbl-b	Cbl-b	Cbl-b	EGFR	EGFR	EGFR	5	6	12	13
Knocking down CBL-B expression phenocopied the effects of miR-30e , whereas ectopic expression of CBL-B suppressed miR-30e-induced EGFR up-regulation and invasion .	Knocking down CBL-B expression phenocopied the effects of miR-30e, whereas ectopic expression of CBL-B suppressed miR-30e-induced EGFR up-regulation and invasion.	12	18	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CBL-B	expression of CBL-B	cbl-b	EGFR	EGFR	egfr	14	15	17	18
Overexpression of Cbl-b reduced total EGFR protein level and inhibited EGFR and downstream ERK and Akt activation in SGC7901 and Adr and MCF-7 and Adr cells ( XREF_FIG A ) .	Overexpression of Cbl-b reduced total EGFR protein level and inhibited EGFR and downstream ERK and Akt activation in SGC7901 and Adr and MCF-7 and Adr cells (XREF_FIG A).	0	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cbl-b	Overexpression of Cbl-b	cbl-b	EGFR	EGFR	egfr	2	3	10	11
These studies have established an important role of Cbl and Cbl-b in ligand induced degradation of EGFR and other RTKs .	These studies have established an important role of Cbl and Cbl-b in ligand induced degradation of EGFR and other RTKs.	6	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cbl-b	Cbl-b	Cbl-b	EGFR	EGFR	EGFR	10	11	16	17
Our analyses show that Cbl-b depletion through knockdown reduced the chemosensitivity of gastric cancer cells and this was associated with increased proliferation and enhanced EGFR survival signaling , thereby leading us to conclude that induction of Cbl-b promotes chemosensitivity in gastric cancer by restricting the activation of EGFR survival signaling .	Our analyses show that Cbl-b depletion through knockdown reduced the chemosensitivity of gastric cancer cells and this was associated with increased proliferation and enhanced EGFR survival signaling, thereby leading us to conclude that induction of Cbl-b promotes chemosensitivity in gastric cancer by restricting the activation of EGFR survival signaling.	34	49	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cbl-b	Cbl-b	Cbl-b	EGFR	EGFR	EGFR	36	37	47	48
These results support the proposal that Cbl-b promotes chemosensitivity of gastric cancer cells by limiting EGFR survival signaling via ERK and Akt .	These results support the proposal that Cbl-b promotes chemosensitivity of gastric cancer cells by limiting EGFR survival signaling via ERK and Akt.	6	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cbl-b	Cbl-b	Cbl-b	EGFR	EGFR	EGFR	6	7	15	16
Cbl-b and Cbl-3 , the other two members of the Cbl family , also accelerate EGFR degradation .	Cbl-b and Cbl-3, the other two members of the Cbl family, also accelerate EGFR degradation.	0	16	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cbl-b	Cbl-b	Cbl-b	EGFR	EGFR	EGFR	0	1	15	16
Calpastatin is also an endogenous inhibitor of Capn1 and Capn2 ; we predicted that reduced calpastatin levels in Rbfox DKO would lead to increased Capn1 and Capn2 activity .	Calpastatin is also an endogenous inhibitor of Capn1 and Capn2; we predicted that reduced calpastatin levels in Rbfox DKO would lead to increased Capn1 and Capn2 activity.	15	27	lead	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	calpastatin	calpastatin levels	calpastatin	Capn1	Capn1	capn1	15	16	24	25
The mentioned pro apoptotic caspase cascade and anti-apoptotic NFkappaB pathway both play negative regulatory roles of one another ; caspase-8 and caspase-3 inhibits RIP and IKKbeta respectively , and the NFkappaB transcribed cellular inhibitor of apoptosis protein 1 and 2 inhibits both caspase-8 as well as caspase-3 .	The mentioned pro apoptotic caspase cascade and anti-apoptotic NFkappaB pathway both play negative regulatory roles of one another; caspase-8 and caspase-3 inhibits RIP and IKKbeta respectively, and the NFkappaB transcribed cellular inhibitor of apoptosis protein 1 and 2 inhibits both caspase-8 as well as caspase-3.	19	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	IKKbeta	IKKbeta	IKKbeta	21	22	25	26
PARP is activated at an intermediate stage of apoptosis and is inactivated by proteolytic cleavage at a late stage by casapase 3 and caspase 7 .	PARP is activated at an intermediate stage of apoptosis and is inactivated by proteolytic cleavage at a late stage by casapase 3 and caspase 7.	0	25	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase 7	caspase 7	caspase 7	PARP	PARP	PARP	23	25	0	1
Expression of exogenous caspase-7 had no impact on Bcl-2 expression , but promoted PARP degradation .	Expression of exogenous caspase-7 had no impact on Bcl-2 expression, but promoted PARP degradation.	0	14	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-7	Expression of exogenous caspase-7	caspase-7	PARP	PARP	parp	3	4	13	14
Among other calpain homologs , CAPN8 and nCL -2 and CAPN9 and nCL-4 , but not CAPN3 and p94 , are inhibited by calpastatin in vitro .	Among other calpain homologs, CAPN8 and nCL -2 and CAPN9/nCL-4, but not CAPN3 and p94, are inhibited by calpastatin in vitro.	5	24	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	calpastatin	calpastatin	calpastatin	CAPN3	CAPN3	CAPN3	23	24	16	17
Expression of active caspase-3 , which degrades alpha-II spectrin , showed significant increase in the frontal cortex after blast exposure at all the time points studied , while cerebellum showed an acute increase which was normalized over time .	Expression of active caspase-3, which degrades alpha-II spectrin, showed significant increase in the frontal cortex after blast exposure at all the time points studied, while cerebellum showed an acute increase which was normalized over time.	0	9	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	Expression of active caspase-3	caspase-3	alpha-II spectrin	alpha-II spectrin	alpha-ii spectrin	3	4	7	9
Caspase-3 mediated alphaII-spectrin degradation yields the formation of 150 kDa SBDP , which is further cleaved into a 120 kDa fragment ( SBDP120 ) and appears to be indicative of apoptotic death .	Caspase-3 mediated alphaII-spectrin degradation yields the formation of 150 kDa SBDP, which is further cleaved into a 120 kDa fragment (SBDP120) and appears to be indicative of apoptotic death.	0	3	mediated	Positive_early_activation	Negative_activation	Negative_activation	Caspase-3	Caspase-3	Caspase-3	alphaII-spectrin	alphaII-spectrin	alphaII-spectrin	0	1	2	3
CARD8 inhibits the activation of caspase-9 .	CARD8 inhibits the activation of caspase-9.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CARD8	CARD8	CARD8	caspase-9	caspase-9	caspase-9	0	1	5	6
CARD8 , a member of the caspase associated recruitment domain ( CARD ) family , inhibits the activation of caspase-9 .	CARD8, a member of the caspase associated recruitment domain (CARD) family, inhibits the activation of caspase-9.	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CARD8	CARD8	CARD8	caspase-9	caspase-9	caspase-9	0	1	19	20
Akt1 degradation is presumably mediated by caspase-3 , breaking the balance between cell survival and apoptosis [ XREF_BIBR ] .	Akt1 degradation is presumably mediated by caspase-3, breaking the balance between cell survival and apoptosis [XREF_BIBR].	0	7	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	Akt1	Akt1	Akt1	6	7	0	1
Thus , proteolysis and inactivation of Akt1 by caspase-3 represents a possible mechanism for caspase-3 involvement in LTD ..	Thus, proteolysis and inactivation of Akt1 by caspase-3 represents a possible mechanism for caspase-3 involvement in LTD..	2	9	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	Akt1	Akt1	Akt1	8	9	6	7
The proto-oncogene c-Cbl negatively regulates Kit and Flt3 by its E3 ligase activity and acts as a scaffold .	The proto-oncogene c-Cbl negatively regulates Kit and Flt3 by its E3 ligase activity and acts as a scaffold.	1	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	proto-oncogene c-Cbl	proto-oncogene c-Cbl	proto-oncogene c-Cbl	Flt3	Flt3	Flt3	1	3	7	8
We therefore assessed if Cbl and Cbl-b proteins negatively regulate c-Kit and FLT3 signaling in HSCs .	We therefore assessed if Cbl and Cbl-b proteins negatively regulate c-Kit and FLT3 signaling in HSCs.	4	13	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cbl	Cbl	Cbl	FLT3	FLT3	FLT3	4	5	12	13
We previously showed that caspase-3 disrupts the NH 2 -terminal PWWP and COOH-terminal domains of LEDGF and p75 , abrogating its ability to protect against stress induced cell death .	We previously showed that caspase-3 disrupts the NH 2 -terminal PWWP and COOH-terminal domains of LEDGF and p75, abrogating its ability to protect against stress induced cell death.	4	17	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	LEDGF	LEDGF	LEDGF	4	5	15	16
This study demonstrated that CaMK IV / Gr mediated phosphorylation of Ser 16 suppresses Op18 activity in intact cells ( Melander Gradin et al ., 1997 ) .	This study demonstrated that CaMK IV / Gr mediated phosphorylation of Ser 16 suppresses Op18 activity in intact cells (Melander Gradin et al., 1997).	4	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CaMK IV	CaMK IV	CaMK IV	Op18	Op18	Op18	4	6	14	15
At the C-terminus of beta-catenin , the Cby binds to the interaction domain of the LEF and TCF transcription complexes and thereby inhibits interaction of beta-catenin with LEF and TCF transcription factors , which results in a suppression of beta-catenin-mediated transcription within the signaling cascade .	At the C-terminus of beta-catenin, the Cby binds to the interaction domain of the LEF and TCF transcription complexes and thereby inhibits interaction of beta-catenin with LEF and TCF transcription factors, which results in a suppression of beta-catenin-mediated transcription within the signaling cascade.	6	34	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	7	8	25	26
Moreover , Cby overexpression caused a molecular weight shift in nuclear beta-catenin and resulted in decreased beta-catenin signaling in AGS cells as measured by the TopFlash assay .	Moreover, Cby overexpression caused a molecular weight shift in nuclear beta-catenin and resulted in decreased beta-catenin signaling in AGS cells as measured by the TopFlash assay.	2	18	signaling	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	Cby	Cby overexpression	cby	beta-catenin	beta-catenin	beta-catenin	2	3	16	17
The decrease of Chibby1 ( CBY1 ) contributes to beta catenin constitutive activation associated with the presence of the BCR-ABL1 fusion gene of chronic myeloid leukemia ( CML ) .	The decrease of Chibby1 (CBY1) contributes to beta catenin constitutive activation associated with the presence of the BCR-ABL1 fusion gene of chronic myeloid leukemia (CML).	1	11	contributes	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	CBY1	CBY1	CBY1	beta catenin	beta catenin	beta catenin	5	6	9	11
CBY1 prevents the transcriptional activity of beta-catenin , which alteration is a key element in radial growth phase of melanoma [ XREF_BIBR ] .	CBY1 prevents the transcriptional activity of beta-catenin, which alteration is a key element in radial growth phase of melanoma [XREF_BIBR].	0	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CBY1	CBY1	CBY1	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
Thus , we speculate that monomeric Cby suppresses beta-catenin signaling by trapping beta-catenin within the cytoplasmic compartment .	Thus, we speculate that monomeric Cby suppresses beta-catenin signaling by trapping beta-catenin within the cytoplasmic compartment.	5	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
On the other hand , cytoplasmic Cby sequesters beta-catenin in the cytoplasmic compartment away from Tcf/Lef transcription factors , eliciting the more potent repressive effect .	On the other hand, cytoplasmic Cby sequesters beta-catenin in the cytoplasmic compartment away from Tcf/Lef transcription factors, eliciting the more potent repressive effect.	5	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
Our review will be focused on the beta-catenin antagonist CBY1 .	Our review will be focused on the beta-catenin antagonist CBY1.	4	10	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	CBY1	CBY1	CBY1	beta-catenin	beta-catenin	beta-catenin	9	10	7	8
Cby antagonizes beta-catenin signaling through two distinct molecular mechanisms .	Cby antagonizes beta-catenin signaling through two distinct molecular mechanisms.	0	3	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	0	1	2	3
Chibby ( Cby ) , a small ( 126 aa ) protein antagonizes Wnt and beta-catenin signaling by forming a ternary complex with protein 14-3-3zeta and beta-catenin [ XREF_BIBR , XREF_BIBR ] .	Chibby (Cby), a small (126 aa) protein antagonizes Wnt and beta-catenin signaling by forming a ternary complex with protein 14-3-3zeta and beta-catenin [XREF_BIBR, XREF_BIBR].	0	16	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	2	3	15	16
Stable expression of Cby inhibits beta-catenin signaling in colon cancer cells .	Stable expression of Cby inhibits beta-catenin signaling in colon cancer cells.	1	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	expression of Cby	cby	beta-catenin	beta-catenin	beta-catenin	3	4	5	6
These data are , therefore , consistent with a model in which Cby cooperates with 14-3-3 to sequester beta-catenin into the cytoplasm , thereby attenuating beta-catenin signaling .	These data are, therefore, consistent with a model in which Cby cooperates with 14-3-3 to sequester beta-catenin into the cytoplasm, thereby attenuating beta-catenin signaling.	12	19	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	12	13	18	19
Ectopic expression of Cby represses endogenous beta-catenin signaling in SW480 colon cancer cells .	Ectopic expression of Cby represses endogenous beta-catenin signaling in SW480 colon cancer cells.	1	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	expression of Cby	cby	beta-catenin	beta-catenin	beta-catenin	3	4	6	7
Our recent study revealed a second mechanism for Cby mediated beta-catenin inhibition in which Cby cooperates with 14-3-3 adaptor proteins to facilitate nuclear export of beta-catenin , following phosphorylation of Cby by Akt kinase .	Our recent study revealed a second mechanism for Cby mediated beta-catenin inhibition in which Cby cooperates with 14-3-3 adaptor proteins to facilitate nuclear export of beta-catenin, following phosphorylation of Cby by Akt kinase.	6	11	mediated	Positive_early_activation	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	8	9	10	11
Taken together , our results suggest that WNT2 opposes activin activity in granulosa cells by up-regulating expression of the activin antagonist Fst in a CTNNB1 and TCF independent manner , and that rat granulosa cells express factors , including Cby1 , that suppress CTNNB1 and TCF dependent signal transduction in the presence of a WNT signal .	Taken together, our results suggest that WNT2 opposes activin activity in granulosa cells by up-regulating expression of the activin antagonist Fst in a CTNNB1 and TCF independent manner, and that rat granulosa cells express factors, including Cby1, that suppress CTNNB1 and TCF dependent signal transduction in the presence of a WNT signal.	36	48	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby1	Cby1	Cby1	CTNNB1	CTNNB1	CTNNB1	39	40	43	44
Mechanistically , Cby promotes adipocyte differentiation , in part by inhibiting beta-catenin , since gain or loss of function of Cby influences beta-catenin signaling in 3T3-L1 cells .	Mechanistically, Cby promotes adipocyte differentiation, in part by inhibiting beta-catenin, since gain or loss of function of Cby influences beta-catenin signaling in 3T3-L1 cells.	2	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
XREF_BIBR Second Mode of beta-Catenin Inhibition by Cby via Cooperation with 14-3-3 .	XREF_BIBR Second Mode of beta-Catenin Inhibition by Cby via Cooperation with 14-3-3.	4	8	Inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-Catenin	beta-Catenin	beta-Catenin	7	8	4	5
Intriguingly , Cby and 14-3-3 form a tripartite complex with beta-catenin and act cooperatively to sequester beta-catenin into the cytoplasmic compartment .	Intriguingly, Cby and 14-3-3 form a tripartite complex with beta-catenin and act cooperatively to sequester beta-catenin into the cytoplasmic compartment.	2	17	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	2	3	16	17
Taken together , our findings suggest that Cby , in cooperation with 14-3-3 proteins , suppresses colon cancer cell growth by modulating subcellular distribution and signaling activity of endogenous beta-catenin .	Taken together, our findings suggest that Cby, in cooperation with 14-3-3 proteins, suppresses colon cancer cell growth by modulating subcellular distribution and signaling activity of endogenous beta-catenin.	7	30	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	7	8	29	30
These data indicate that Cby negatively regulates Wnt and beta-catenin signaling in the lung .	These data indicate that Cby negatively regulates Wnt and beta-catenin signaling in the lung.	4	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	4	5	9	10
When Cnx was co-expressed , it abrogated the Cby mediated repression of beta-catenin activity in a dose dependent manner ( lanes 7 to 10 ) .	When Cnx was co-expressed, it abrogated the Cby mediated repression of beta-catenin activity in a dose dependent manner (lanes 7 to 10).	7	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	8	9	12	13
These data concur with our dual mechanism model in which Cby antagonizes beta-catenin signaling in both the nucleus and cytoplasm , and also imply that cytoplasmic Cby confers a more potent repressive activity than nuclear Cby in regulating beta-catenin signaling .	These data concur with our dual mechanism model in which Cby antagonizes beta-catenin signaling in both the nucleus and cytoplasm, and also imply that cytoplasmic Cby confers a more potent repressive activity than nuclear Cby in regulating beta-catenin signaling.	10	23	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	10	11	12	13
In further support of our model , knockdown of endogenous Cby by shRNA causes nuclear accumulation of beta-catenin ( XREF_FIG ) .	In further support of our model, knockdown of endogenous Cby by shRNA causes nuclear accumulation of beta-catenin (XREF_FIG).	7	19	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	10	11	17	18
These results suggest that Cnx and beta-catenin form mutually exclusive complexes with Cby , thereby allowing Cnx to alleviate Cby mediated repression of beta-catenin signaling activity .	These results suggest that Cnx and beta-catenin form mutually exclusive complexes with Cby, thereby allowing Cnx to alleviate Cby mediated repression of beta-catenin signaling activity.	19	25	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	19	20	23	24
However , this is in agreement with our model in which Cby inhibits beta-catenin signaling through two distinct molecular mechanisms [ XREF_BIBR , XREF_BIBR ] : 1 ) in the nucleus , Cby competes with Tcf/Lef transcription factors for binding to beta-catenin ; 2 ) Cby sequesters beta-catenin in the cytoplasm in collaboration with 14-3-3 proteins .	However, this is in agreement with our model in which Cby inhibits beta-catenin signaling through two distinct molecular mechanisms [XREF_BIBR, XREF_BIBR] : 1) in the nucleus, Cby competes with Tcf/Lef transcription factors for binding to beta-catenin; 2) Cby sequesters beta-catenin in the cytoplasm in collaboration with 14-3-3 proteins.	45	50	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	45	46	47	48
Inhibition of Wnt and beta-catenin signaling by Cby , therefore , involves at least two distinct molecular mechanisms ( XREF_FIG ) , i.e. competing with Tcf/Lef factors for binding to beta-catenin in the nucleus , and facilitating nuclear export of beta-catenin via interaction with 14-3-3 .	Inhibition of Wnt and beta-catenin signaling by Cby, therefore, involves at least two distinct molecular mechanisms (XREF_FIG), i.e. competing with Tcf/Lef factors for binding to beta-catenin in the nucleus, and facilitating nuclear export of beta-catenin via interaction with 14-3-3.	2	8	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	7	8	4	5
In migrating cells , integrin dependent regulation of Cdc42 inhibits GSK-3beta through the activation of the Par6 and PKCzeta complex [ XREF_BIBR , XREF_BIBR ] .	In migrating cells, integrin dependent regulation of Cdc42 inhibits GSK-3beta through the activation of the Par6 and PKCzeta complex [XREF_BIBR, XREF_BIBR].	6	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdc42	Cdc42	Cdc42	GSK-3beta	GSK-3beta	GSK-3beta	8	9	10	11
As Cdc42 dependent signals may suppress GSK3beta , a context specific regulator of apoptosis , we used pharmacological inhibitor studies to explore the role of GSK3beta in apoptosis of PTEN expressing or -deficient colorectal cells .	As Cdc42 dependent signals may suppress GSK3beta, a context specific regulator of apoptosis, we used pharmacological inhibitor studies to explore the role of GSK3beta in apoptosis of PTEN expressing or -deficient colorectal cells.	1	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdc42	Cdc42	Cdc42	GSK3beta	GSK3beta	GSK3beta	1	2	6	7
Atypical PKC is one of the signaling intermediates that phosphorylate this residue ; and , in astrocytes , cell polarity is controlled through Cdc42 mediated GSK-3beta inhibition by a complex consisting of Par6 and atypical PKC .	Atypical PKC is one of the signaling intermediates that phosphorylate this residue; and, in astrocytes, cell polarity is controlled through Cdc42 mediated GSK-3beta inhibition by a complex consisting of Par6 and atypical PKC.	21	26	mediated	Positive_early_activation	Negative_activation	Negative_activation	Cdc42	Cdc42	Cdc42	GSK-3beta	GSK-3beta	GSK-3beta	23	24	25	26
In searching for downstream signaling molecules through which active Cdc42 improves VEGF driven angiogenesis , we found that active Cdc42 strongly inhibited GSK-3beta , a serine threonine kinase that was initially identified as a phosphorylating inactivator of glycogen synthase .	In searching for downstream signaling molecules through which active Cdc42 improves VEGF driven angiogenesis, we found that active Cdc42 strongly inhibited GSK-3beta, a serine threonine kinase that was initially identified as a phosphorylating inactivator of glycogen synthase.	18	27	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdc42	Cdc42	Cdc42	GSK-3beta	GSK-3beta	GSK-3beta	19	20	22	23
Inactivation of eEF2K by cdc2 may serve to keep eEF2 active during mitosis ( where calcium levels rise ) and thereby permit protein synthesis to proceed in mitotic cells .	Inactivation of eEF2K by cdc2 may serve to keep eEF2 active during mitosis (where calcium levels rise) and thereby permit protein synthesis to proceed in mitotic cells.	0	5	Inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	cdc2	cdc2	cdc2	eEF2K	eEF2K	eEF2K	4	5	2	3
eEF2k activity can also be inhibited in an mTOR independent manner through phosphorylation at Ser359 by cyclin dependent kinase 1 ( CDK1 ) or mitogen activated protein kinase 13 ( MAPK13 ) .	eEF2k activity can also be inhibited in an mTOR independent manner through phosphorylation at Ser359 by cyclin dependent kinase 1 (CDK1) or mitogen activated protein kinase 13 (MAPK13).	0	20	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	cyclin dependent kinase 1	cyclin dependent kinase 1	cyclin dependent kinase 1	eEF2k	eEF2k	eEF2k	16	20	0	1
Although Cdk1 phosphorylates and inhibits caspase 9 ( thereby protecting against apoptosis during normal mitosis ) , caspase 9 ultimately becomes dephosphorylated upon prolonged arrest in mitosis [ XREF_BIBR ] .	Although Cdk1 phosphorylates and inhibits caspase 9 (thereby protecting against apoptosis during normal mitosis), caspase 9 ultimately becomes dephosphorylated upon prolonged arrest in mitosis [XREF_BIBR].	1	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	caspase 9	caspase 9	caspase 9	1	2	5	7
Subsequently , it was shown that the inhibitory effect of CP110 over ciliogenesis is mediated by its interaction with CEP290 in discrete protein complexes where CP110 antagonizes the ciliogenic effect of CEP290 [ XREF_BIBR ] .	Subsequently, it was shown that the inhibitory effect of CP110 over ciliogenesis is mediated by its interaction with CEP290 in discrete protein complexes where CP110 antagonizes the ciliogenic effect of CEP290 [XREF_BIBR].	25	33	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CP110	CP110	CP110	CEP290	CEP290	CEP290	25	26	31	32
For example , CP110 binds to and antagonizes the function of Cep290 , a positive regulator of ciliogenesis .	For example, CP110 binds to and antagonizes the function of Cep290, a positive regulator of ciliogenesis.	3	15	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CP110	CP110	CP110	Cep290	Cep290	Cep290	3	4	11	12
By downregulating Cyclin B , Cyclin D1 and Bcl-2 , CDK1 inhibited the progression of non small cell lung cancer .	By downregulating Cyclin B, Cyclin D1 and Bcl-2, CDK1 inhibited the progression of non small cell lung cancer.	1	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	Bcl-2	Bcl-2	Bcl-2	10	11	8	9
For example , CDC14A is able to interact with and inhibit p53 and the Cyclin B and Cdk1 complex ( Paulsen et al , 2006 ) , and PSMD11 has been found to be overexpressed in breast carcinomas ( Deng et al , 2007 ) .	For example, CDC14A is able to interact with and inhibit p53 and the Cyclin B and Cdk1 complex (Paulsen et al, 2006), and PSMD11 has been found to be overexpressed in breast carcinomas (Deng et al, 2007).	3	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDC14A	CDC14A	CDC14A	p53	p53	p53	3	4	11	12
In si-CDK1 and pcDNA3.1/iASPP-co-transfected HCT116 and LoVo cells , the protein levels of p53 pathway related factors : p53 , CDK inhibitor p21 , death receptor Fas and activated Cleaved-caspase 8 showed to be reduced by forced iASPP expression , increased by CDK1 knockdown ; whereas Pro caspase 8 protein was increased by CDK1 knockdown , reduced by forced iASPP expression .	In si-CDK1 and pcDNA3.1/iASPP-co-transfected HCT116 and LoVo cells, the protein levels of p53 pathway related factors : p53, CDK inhibitor p21, death receptor Fas and activated Cleaved-caspase 8 showed to be reduced by forced iASPP expression, increased by CDK1 knockdown; whereas Pro caspase 8 protein was increased by CDK1 knockdown, reduced by forced iASPP expression.	46	54	increased	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	caspase 8	caspase 8	caspase 8	53	54	47	49
Wee1-9ACFP overexpression causes a longer delay than overexpression of Wee1-CFP ( XREF_FIG ) , as expected because mutation of the Cdk1 consensus sites should prevent Cdk1 dependent inactivation of Wee1 .	Wee1-9ACFP overexpression causes a longer delay than overexpression of Wee1-CFP (XREF_FIG), as expected because mutation of the Cdk1 consensus sites should prevent Cdk1 dependent inactivation of Wee1.	25	30	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	25	26	29	30
Both Wee1 and Myt1 are inactivated by Cdk1 , forming a double negative feedback loop XREF_BIBR - XREF_BIBR , which is similar in many respects to a positive feedback loop .	Both Wee1 and Myt1 are inactivated by Cdk1, forming a double negative feedback loop XREF_BIBR - XREF_BIBR, which is similar in many respects to a positive feedback loop.	0	8	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	7	8	1	2
Partially active CDK1 contributes to not only the activation of CDC25 but also the inhibition of Wee1 and Myt1 by direct phosphorylation , thus forming two amplification loops that establish a switch like and retained activation of CDK1 : cyclin B XREF_BIBR , XREF_BIBR .	Partially active CDK1 contributes to not only the activation of CDC25 but also the inhibition of Wee1 and Myt1 by direct phosphorylation, thus forming two amplification loops that establish a switch like and retained activation of CDK1 : cyclin B XREF_BIBR, XREF_BIBR.	1	34	contributes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	Wee1	Wee1	Wee1	2	3	16	17
The opposing activity of PP2A Cdc55 sets a threshold that limits activation of Wee1 by Cdk1 , thereby allowing a low level of Cdk1 activity to escape Wee1 inhibition in early mitosis .	The opposing activity of PP2A Cdc55 sets a threshold that limits activation of Wee1 by Cdk1, thereby allowing a low level of Cdk1 activity to escape Wee1 inhibition in early mitosis.	10	16	activation	Positive_activation_token_2_noun	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	15	16	13	14
As suppression of Cdc2 by either Myt1 or roscovitine had no effect on the rate of apoptotic progression in our extracts , we consider it unlikely that simple suppression of Cdc2 and Cdk2 activities underlies the ability of Wee1 to accelerate apoptosis .	As suppression of Cdc2 by either Myt1 or roscovitine had no effect on the rate of apoptotic progression in our extracts, we consider it unlikely that simple suppression of Cdc2 and Cdk2 activities underlies the ability of Wee1 to accelerate apoptosis.	30	39	underlies	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	30	31	38	39
Removal of these inhibitory modifications is controlled by members of the CDC25 ( cell division cycle 25 ) family of phosphatases and leads to a rapid activation of Cdk1 and cyclin B. Finally , an initial activation of Cdk1 and cyclin B stimulates the activity of Cdc25 and inactivates Wee1 , creating two feedback loops that result in a switch like activation of Cdk1 .	Removal of these inhibitory modifications is controlled by members of the CDC25 (cell division cycle 25) family of phosphatases and leads to a rapid activation of Cdk1 and cyclin B. Finally, an initial activation of Cdk1 and cyclin B stimulates the activity of Cdc25 and inactivates Wee1, creating two feedback loops that result in a switch like activation of Cdk1.	38	50	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	38	39	49	50
Because the mitotic kinases Cdk1 and Polo repress Wee1 kinase XREF_BIBR , it appears that lack of Xpd could cause this phenotype by causing locally elevated mitotic kinase activity that prevents Wee1 from acting on kinesin-5 .	Because the mitotic kinases Cdk1 and Polo repress Wee1 kinase XREF_BIBR, it appears that lack of Xpd could cause this phenotype by causing locally elevated mitotic kinase activity that prevents Wee1 from acting on kinesin-5.	1	10	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	4	5	8	9
The protein kinase Cdk1 in turn is regulated by fast , interlinked positive and double negative feedback loops ( Cdk1 activates its activator Cdc25C and inactivates its inactivator Wee1 ) , which constitutes a bistable switch .	The protein kinase Cdk1 in turn is regulated by fast, interlinked positive and double negative feedback loops (Cdk1 activates its activator Cdc25C and inactivates its inactivator Wee1), which constitutes a bistable switch.	19	29	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	19	20	28	29
Furthermore , CDK1 inactivates Wee1 and , without the antagonistic effect of PP2A-B55 , ensures its activation .	Furthermore, CDK1 inactivates Wee1 and, without the antagonistic effect of PP2A-B55, ensures its activation.	2	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	Wee1	Wee1	Wee1	2	3	4	5
The oscillator circuit possesses a bistable trigger , which is built from interlinked positive ( Cdk1 activates Cdc25 , which activates Cdk1 ) and double negative ( Cdk1 inhibits Wee1 and Myt1 , which inhibit Cdk1 ) feedback loops .	The oscillator circuit possesses a bistable trigger, which is built from interlinked positive (Cdk1 activates Cdc25, which activates Cdk1) and double negative (Cdk1 inhibits Wee1 and Myt1, which inhibit Cdk1) feedback loops.	27	34	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	27	28	29	30
XREF_BIBR developed a numerical model of the embryonic cell-cycle network in which Cdk1 activity is increased by dual positive feedbacks ( active Cdk1 activates its activator Cdc25 and inactivates its inhibitor Wee1 ) , while Cdk1 activity is reduced by a single negative feedback ( active Cdk1 activates APC via Plx1 ) ( XREF_FIG , XREF_SUPPLEMENTARY ) .	XREF_BIBR developed a numerical model of the embryonic cell-cycle network in which Cdk1 activity is increased by dual positive feedbacks (active Cdk1 activates its activator Cdc25 and inactivates its inhibitor Wee1), while Cdk1 activity is reduced by a single negative feedback (active Cdk1 activates APC via Plx1) (XREF_FIG, XREF_SUPPLEMENTARY).	21	32	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	22	23	31	32
In the fission yeast Schizosaccharomyces pombe , mitotic entry is orchestrated by a geometry sensing mechanism that involves the Cdk1 and Cdc2 inhibiting Wee1 kinase .	In the fission yeast Schizosaccharomyces pombe, mitotic entry is orchestrated by a geometry sensing mechanism that involves the Cdk1 and Cdc2 inhibiting Wee1 kinase.	17	24	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	21	22	23	24
The evidence suggested that Wee1 is inactivated by Cdc2 dependent phosphorylation and that Cdc25 is activated by Cdc2 dependent phosphorylation .	The evidence suggested that Wee1 is inactivated by Cdc2 dependent phosphorylation and that Cdc25 is activated by Cdc2 dependent phosphorylation.	4	11	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Cdc2	Cdc2 dependent phosphorylation	cdc2	Wee1	Wee1	wee1	8	9	4	5
This bistability is attributable to the positive feedback loops ( active Cdc2 promotes its activator Cdc25 and suppresses its inhibitor Wee1 ) [ XREF_BIBR , XREF_BIBR ] .	This bistability is attributable to the positive feedback loops (active Cdc2 promotes its activator Cdc25 and suppresses its inhibitor Wee1) [XREF_BIBR, XREF_BIBR].	10	21	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	11	12	20	21
Notable motif-level features of this hybrid model ( XREF_FIG ) include feed-forward regulation ( cyclin A2 promotes chromatin condensation and NEB both directly and through the intermediacy of cyclin B1-Cdk1 ) , interlinked feedback loops , and reciprocal regulation ( Cdk1 activates Cdc25 and inactivates Wee1 ; DNA damage activates Wee1 and inactivates Cdc25 ) .	Notable motif-level features of this hybrid model (XREF_FIG) include feed-forward regulation (cyclin A2 promotes chromatin condensation and NEB both directly and through the intermediacy of cyclin B1-Cdk1), interlinked feedback loops, and reciprocal regulation (Cdk1 activates Cdc25 and inactivates Wee1; DNA damage activates Wee1 and inactivates Cdc25).	40	52	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	40	41	45	46
Because it was shown that at the G2/M transition Wee1 degradation is mediated by Cdk1 primed Plk1 phosphorylation , we then investigated whether the phosphorylation of Ser 139 might be involved in the Wee1-Plk1 interaction .	Because it was shown that at the G2/M transition Wee1 degradation is mediated by Cdk1 primed Plk1 phosphorylation, we then investigated whether the phosphorylation of Ser 139 might be involved in the Wee1-Plk1 interaction.	9	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	14	15	9	10
We developed an antibody recognizing phosphothreonine 239 of Wee1 ( p-T239-Wee1 ) , a crucial phosphorylation for cdk1 dependent inhibition of Wee1 XREF_BIBR XREF_BIBR , whereas p-S83-Myt1 , p-T48-Cdc25C and p-T244-Cdc27 were detected by commercially available antibodies ( XREF_FIG ) .	We developed an antibody recognizing phosphothreonine 239 of Wee1 (p-T239-Wee1), a crucial phosphorylation for cdk1 dependent inhibition of Wee1 XREF_BIBR XREF_BIBR, whereas p-S83-Myt1, p-T48-Cdc25C and p-T244-Cdc27 were detected by commercially available antibodies (XREF_FIG).	17	23	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	cdk1	cdk1	cdk1	Wee1	Wee1	Wee1	17	18	21	22
Cdk1 dependent inhibition of Wee1 and activation of Cdc25 are thought to constitute feedback loops that promote activation of Cdk1 ; however , the mechanisms that trigger the feedback loops are poorly understood .	Cdk1 dependent inhibition of Wee1 and activation of Cdc25 are thought to constitute feedback loops that promote activation of Cdk1; however, the mechanisms that trigger the feedback loops are poorly understood.	0	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	0	1	4	5
Cdc25 activity is stimulated by Cdk1 dependent phosphorylation , whereas Wee1 activity is inhibited by Cdk1 dependent phosphorylation .	Cdc25 activity is stimulated by Cdk1 dependent phosphorylation, whereas Wee1 activity is inhibited by Cdk1 dependent phosphorylation.	10	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Cdk1	Cdk1 dependent phosphorylation	cdk1	Wee1	Wee1	wee1	15	16	10	11
Wee1 and Cdc25 are thought to contribute to the abrupt , switch like activation of Cdk1 via feedback loops in which Cdk1 inhibits Wee1 and activates Cdc25 .	Wee1 and Cdc25 are thought to contribute to the abrupt, switch like activation of Cdk1 via feedback loops in which Cdk1 inhibits Wee1 and activates Cdc25.	21	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	21	22	23	24
An important difference between Xenopus egg Wee1 and Swe1 is that phosphorylation of Cdk1 consensus sites on Wee1 is thought to inactivate Wee1 , although it has not yet been possible to replace endogenous Xenopus egg Wee1 with a phosphorylation site mutant to test this model .	An important difference between Xenopus egg Wee1 and Swe1 is that phosphorylation of Cdk1 consensus sites on Wee1 is thought to inactivate Wee1, although it has not yet been possible to replace endogenous Xenopus egg Wee1 with a phosphorylation site mutant to test this model.	11	23	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	phosphorylation of Cdk1	cdk1	Wee1	Wee1	wee1	13	14	22	23
The duration of the S and G2 phases are controlled by down-regulation of Wee1 by Cdc2 and Cdc13 .	The duration of the S and G2 phases are controlled by down-regulation of Wee1 by Cdc2 and Cdc13.	9	17	down-regulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	15	16	13	14
Previous work identified the cdc2 activating phosphatase cdc25C and the cdc2-inhibitory kinase wee1 as targets of the incomplete replication induced kinase Chk1 .	Previous work identified the cdc2 activating phosphatase cdc25C and the cdc2-inhibitory kinase wee1 as targets of the incomplete replication induced kinase Chk1.	2	13	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cdc2	cdc2	cdc2	wee1	wee1	wee1	4	5	12	13
Cdk1 also inhibits Wee1 , a kinase that itself inhibits Cdk1 activity [ XREF_BIBR , XREF_BIBR ] .	Cdk1 also inhibits Wee1, a kinase that itself inhibits Cdk1 activity [XREF_BIBR, XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	0	1	3	4
Cdc2 inactivates the Wee1 kinases to make a double negative feedback loop , while it activates the Cdc25 phosphatases to complete a positive feedback loop .	Cdc2 inactivates the Wee1 kinases to make a double negative feedback loop, while it activates the Cdc25 phosphatases to complete a positive feedback loop.	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	0	1	3	4
Cdc2 and Cdc13 degrades Wee1 and Mik1 which prevents their system from visiting the two steady states we found without setting any threshold manually .	Cdc2 and Cdc13 degrades Wee1 and Mik1 which prevents their system from visiting the two steady states we found without setting any threshold manually.	0	8	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	0	1	4	5
The model includes a negative feedback loop [ active CDK1 brings about its inactivation through the anaphase promoting complex ( APC ) ] and a pair of positive feedback loops ( active CDK1 activates its activator Cdc25 and inactivates its inhibitor Wee1 ) ( XREF_FIG ) .	The model includes a negative feedback loop [active CDK1 brings about its inactivation through the anaphase promoting complex (APC)] and a pair of positive feedback loops (active CDK1 activates its activator Cdc25 and inactivates its inhibitor Wee1) (XREF_FIG).	31	42	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK1	CDK1	CDK1	Wee1	Wee1	Wee1	32	33	41	42
In summary , active Cdc2 and Cdc13 activates its activator Cdc25 and inactivates its inhibitor Wee1 .	In summary, active Cdc2 and Cdc13 activates its activator Cdc25 and inactivates its inhibitor Wee1.	3	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	4	5	15	16
WEE1 and MYT1 suppression is incomplete , however , and is stimulated by low levels of CDK1 activity , as has been suggested in budding yeast ( Harvey et al ., 2005 ) .	WEE1 and MYT1 suppression is incomplete, however, and is stimulated by low levels of CDK1 activity, as has been suggested in budding yeast (Harvey et al., 2005).	0	17	stimulated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	WEE1	WEE1	WEE1	16	17	0	1
In vertebrates , Separase is inhibited by Cdk1 phosphorylation and binding [ XREF_BIBR , XREF_BIBR ] and this regulation has been shown to act redundantly with Securin inhibition of Separase .	In vertebrates, Separase is inhibited by Cdk1 phosphorylation and binding [XREF_BIBR, XREF_BIBR] and this regulation has been shown to act redundantly with Securin inhibition of Separase.	3	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Cdk1	Cdk1 phosphorylation	cdk1	Separase	Separase	separase	7	8	3	4
In vertebrates Cdk1 dependent inhibition of separase represents a second , securin independent branch of anaphase regulation .	In vertebrates Cdk1 dependent inhibition of separase represents a second, securin independent branch of anaphase regulation.	2	7	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	separase	separase	separase	2	3	6	7
High Cdk1 activity is known to inhibit separase 26 , explaining the close relationship between Cdk1 inactivation , anaphase-onset and spindle migration .	High Cdk1 activity is known to inhibit separase 26, explaining the close relationship between Cdk1 inactivation, anaphase-onset and spindle migration.	1	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	separase	separase	separase	1	2	7	8
These results demonstrate that inhibition of CDK-1 in APC mutant embryos does not result in activation of separase .	These results demonstrate that inhibition of CDK-1 in APC mutant embryos does not result in activation of separase.	4	18	result in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	CDK-1	CDK-1	CDK-1	separase	separase	separase	6	7	17	18
CDK1 can inhibit separase before anaphase .	CDK1 can inhibit separase before anaphase.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	separase	separase	separase	0	1	3	4
For such an effect to be observed , it is necessary to abrogate inhibition of separase by Cdk1 : cyclin B by expressing a version of separase ( S1121A ) refractory to Cdk1 inhibition [ XREF_BIBR ] .	For such an effect to be observed, it is necessary to abrogate inhibition of separase by Cdk1 : cyclin B by expressing a version of separase (S1121A) refractory to Cdk1 inhibition [XREF_BIBR].	12	20	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	separase	separase	separase	17	18	15	16
Unlike in budding yeast where Pds1 ( securin ) is the only known inhibitor of separase , human separase is inhibited by securin binding and Cdk1 phosphorylation .	Unlike in budding yeast where Pds1 (securin) is the only known inhibitor of separase, human separase is inhibited by securin binding and Cdk1 phosphorylation.	17	27	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Cdk1	Cdk1 phosphorylation	cdk1	separase	separase	separase	25	26	18	19
Degradation of cyclin B lowers Cdk1 activity and securin degradation activates separase , which cleaves cohesion holding sister chromatids together [ XREF_BIBR ] .	Degradation of cyclin B lowers Cdk1 activity and securin degradation activates separase, which cleaves cohesion holding sister chromatids together [XREF_BIBR].	5	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	separase	separase	separase	5	6	11	12
Based on our results , we propose that one mechanism by which Myc stimulates origin firing is by lowering the threshold of CDK2 and cyclin E activity required to antagonize the CDK inhibitor p27 .	Based on our results, we propose that one mechanism by which Myc stimulates origin firing is by lowering the threshold of CDK2 and cyclin E activity required to antagonize the CDK inhibitor p27.	22	34	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	p27	p27	p27	22	23	33	34
Treatment of LNCaP cells with KMUP-1 resulted in cell cycle arrest and apoptotic activities , increasing p21 and p27 and decreasing expressions of cyclin D1 , cyclin E , cyclin dependent kinase ( CDK ) 4 , CDK2 and CDK6 .	Treatment of LNCaP cells with KMUP-1 resulted in cell cycle arrest and apoptotic activities, increasing p21 and p27 and decreasing expressions of cyclin D1, cyclin E, cyclin dependent kinase (CDK) 4, CDK2 and CDK6.	18	38	decreasing	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	CDK2	expressions of cyclin D1, cyclin E, cyclin dependent kinase (CDK) 4, CDK2	cdk2	p27	p27	p27	37	38	18	19
MYC induced apoptosis was suppressed in mouse embryonic fibroblasts ( MEF ) knocked out for Cdk2 or normal human fibroblasts ( NHF ) upon expression of the CDK2 inhibitor p27 or treated with RNAi directed at CDK2 .	MYC induced apoptosis was suppressed in mouse embryonic fibroblasts (MEF) knocked out for Cdk2 or normal human fibroblasts (NHF) upon expression of the CDK2 inhibitor p27 or treated with RNAi directed at CDK2.	24	37	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	p27	p27	p27	36	37	29	30
Specifically , activated Cdk2 promotes p27 Kip1 degradation .	Specifically, activated Cdk2 promotes p27 Kip1 degradation.	2	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	p27 Kip1	p27 Kip1	p27 Kip1	3	4	5	7
In those studies , UCN-01-mediated induction of G1 arrest has been attributed to inhibition of CDK2 , which results from CDK2 dephosphorylation at Thr160 and the induction of the CDK2 inhibiting proteins p21 and p27 in various cell lines [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In those studies, UCN-01-mediated induction of G1 arrest has been attributed to inhibition of CDK2, which results from CDK2 dephosphorylation at Thr160 and the induction of the CDK2 inhibiting proteins p21 and p27 in various cell lines [XREF_BIBR, XREF_BIBR, XREF_BIBR].	21	35	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	dephosphorylation at Thr160 and the induction of the CDK2	cdk2	p27	p27	p27	29	30	34	35
The findings here also indicated that aberrant activated LPA and EDG2 signaling contributed to inhibition of p27 Kip1 / CDK2 signaling .	The findings here also indicated that aberrant activated LPA and EDG2 signaling contributed to inhibition of p27 Kip1 / CDK2 signaling.	14	20	inhibition	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	p27 Kip1	p27 Kip1	p27 Kip1	19	20	16	18
Cerivastatin reduced the 3H-thymidine incorporation ( 164 +/- 11 % , p < 0.01 ) , inhibited Cdk2 activation and Rb phosphorylation , but did not prevent p27Kip1 down-regulation , nor p42mapk and p70S6K activation .	Cerivastatin reduced the 3H-thymidine incorporation (164 +/- 11%, p < 0.01), inhibited Cdk2 activation and Rb phosphorylation, but did not prevent p27Kip1 down-regulation, nor p42mapk and p70S6K activation.	0	28	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk2	Cerivastatin reduced the 3H-thymidine incorporation (164 +/- 11%, p < 0.01), inhibited Cdk2 activation and Rb phosphorylation	cdk2	p27Kip1	p27Kip1	p27kip1	17	18	27	28
These results are congruent with our previous observation that Cdk2 deficiency does not prevent p27 deficient mice from developing pituitary tumors 40 .	These results are congruent with our previous observation that Cdk2 deficiency does not prevent p27 deficient mice from developing pituitary tumors 40.	9	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	p27	p27	p27	9	10	14	15
Moreover , the low level of p27 Kip1 after G1/S transition is indeed maintained by high Cdk2 activity promoting p27 Kip1 degradation .	Moreover, the low level of p27 Kip1 after G1/S transition is indeed maintained by high Cdk2 activity promoting p27 Kip1 degradation.	16	21	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	p27 Kip1	p27 Kip1	p27 Kip1	16	17	19	21
As previously shown in several fibroblasts cell lines , expression of dominant negative CDK2 in IIC9 cells blocked serum induced cyclin E/CDK2 activity and p27 ( Kip ) degradation .	As previously shown in several fibroblasts cell lines, expression of dominant negative CDK2 in IIC9 cells blocked serum induced cyclin E/CDK2 activity and p27 (Kip) degradation.	9	28	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	expression of dominant negative CDK2	cdk2	p27	p27	p27	13	14	24	25
Accordingly , expression of dominant negative CDK2 did not impair the down-regulation of p27 ( Kip1 ) induced by MAP kinase activation .	Accordingly, expression of dominant negative CDK2 did not impair the down-regulation of p27 (Kip1) induced by MAP kinase activation.	2	17	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	expression of dominant negative CDK2	cdk2	p27	p27	p27	6	7	13	14
Thus , the activated cyclin E and CDK2 may decrease the CDK inhibitors p21 and p27 to benefit viral replication .	Thus, the activated cyclin E and CDK2 may decrease the CDK inhibitors p21 and p27 to benefit viral replication.	5	17	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	p27	p27	p27	7	8	15	16
Silibinin with 0.5 or 5 microM arsenic induced G1 or G2/M phase arrest , respectively , and decreased the protein levels of CDK2 , -4 , and -6 and cyclin D1 , D3 , and E and increased CDK inhibitors p21 and p27 .	Silibinin with 0.5 or 5 microM arsenic induced G1 or G2/M phase arrest, respectively, and decreased the protein levels of CDK2, -4, and -6 and cyclin D1, D3, and E and increased CDK inhibitors p21 and p27.	0	43	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	Silibinin with 0.5 or 5 microM arsenic induced G1 or G2/M phase arrest, respectively, and decreased the protein levels of CDK2	cdk2	p27	p27	p27	22	23	42	43
These results suggest that CDK1 regulates osteogenesis through suppression of methyltransferase activity of EZH2 and promotes derepression of target genes of EZH2 such as osteogenesis related genes Runx2 and TCF7 .	These results suggest that CDK1 regulates osteogenesis through suppression of methyltransferase activity of EZH2 and promotes derepression of target genes of EZH2 such as osteogenesis related genes Runx2 and TCF7.	4	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK1	CDK1	CDK1	EZH2	EZH2	EZH2	4	5	21	22
Activation of CDK1 by co-transfection of plasmids expressing cyclin B and CDK1 inhibited HMTase activity of wild-type EZH2 ( XREF_FIG ; lane 2 versus 1 ) , but not EZH2 T487A ( XREF_FIG ; lane 4 versus 3 ) .	Activation of CDK1 by co-transfection of plasmids expressing cyclin B and CDK1 inhibited HMTase activity of wild-type EZH2 (XREF_FIG; lane 2 versus 1), but not EZH2 T487A (XREF_FIG; lane 4 versus 3).	0	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	EZH2	EZH2	EZH2	2	3	17	18
EZH2 inactivation by CDK1 leads to the reduction of the H3K27me3 at the RUNX2 promoter , its subsequent activation , and therefore , the triggering of osteogenic differentiation .	EZH2 inactivation by CDK1 leads to the reduction of the H3K27me3 at the RUNX2 promoter, its subsequent activation, and therefore, the triggering of osteogenic differentiation.	0	4	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	EZH2	EZH2	EZH2	3	4	0	1
As inactivation of CDK1 enhances trimethylation of H3K27 , resulting in downregulation of EZH2 targeted gene expression , we next investigated whether CDK1 , a serine/threonine kinase , might inhibit histone methyltransferase ( HMTase ) activity of EZH2 through phosphorylation of EZH2 .	As inactivation of CDK1 enhances trimethylation of H3K27, resulting in downregulation of EZH2 targeted gene expression, we next investigated whether CDK1, a serine/threonine kinase, might inhibit histone methyltransferase (HMTase) activity of EZH2 through phosphorylation of EZH2.	22	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	EZH2	EZH2	EZH2	22	23	37	38
Notably , although CDK1 was previously reported to reduce EZH2 stability ( Wei etal , 2011 ; Wu & Zhang , 2011 ) , GNA002 appears to not be involved in this signaling pathway given that unlike EZH2 , neither CDK1 , Cyclin A nor Cyclin B levels were significantly upregulated by GNA002 treatment ( XREF_SUPPLEMENTARY ) .	Notably, although CDK1 was previously reported to reduce EZH2 stability (Wei etal, 2011; Wu & Zhang, 2011), GNA002 appears to not be involved in this signaling pathway given that unlike EZH2, neither CDK1, Cyclin A nor Cyclin B levels were significantly upregulated by GNA002 treatment (XREF_SUPPLEMENTARY).	3	10	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	EZH2	EZH2	EZH2	3	4	9	10
These results suggest that CDK1 inhibits EZH2 activity and derepresses its target gene expression during cell cycle .	These results suggest that CDK1 inhibits EZH2 activity and derepresses its target gene expression during cell cycle.	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	EZH2	EZH2	EZH2	4	5	6	7
Among the many functions of the widely distributed kinase Cdk1 is the inhibition of the histone 3 methyltransferase Ezh2 by phosphorylation XREF_BIBR , XREF_BIBR .	Among the many functions of the widely distributed kinase Cdk1 is the inhibition of the histone 3 methyltransferase Ezh2 by phosphorylation XREF_BIBR, XREF_BIBR.	9	21	is the inhibition	Negative_activation_copula_1	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Ezh2	Ezh2	Ezh2	9	10	18	19
Specifically , overexpression of CDK1 and CDK2 was found to repress the EZH2 target hoxA9 , an effect that was abrogated when EZH2 levels were reduced .	Specifically, overexpression of CDK1 and CDK2 was found to repress the EZH2 target hoxA9, an effect that was abrogated when EZH2 levels were reduced.	2	14	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	overexpression of CDK1	cdk1	EZH2	EZH2	ezh2	4	5	12	13
Thus , CDK2 silencing dependent activation of FOXO1 represents a new mechanism that links DNA strand breakage to cell death .	Thus, CDK2 silencing dependent activation of FOXO1 represents a new mechanism that links DNA strand breakage to cell death.	2	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	FOXO1	FOXO1	FOXO1	2	3	7	8
However , under DNA damaging conditions , CDK2 activity is inhibited by the FoxO target genes p21 cip1 and p27 kip1 , allowing FoxO1 to activate target gene expression , thereby forming a positive feedback loop .	However, under DNA damaging conditions, CDK2 activity is inhibited by the FoxO target genes p21 cip1 and p27 kip1, allowing FoxO1 to activate target gene expression, thereby forming a positive feedback loop.	7	25	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	FoxO1	FoxO1	FoxO1	7	8	23	24
FoxO1 repressor activity was also inhibited by CDK2 activity , and when CDK2 activity was abolished in response to DNA damage , FoxO1 was activated .	FoxO1 repressor activity was also inhibited by CDK2 activity, and when CDK2 activity was abolished in response to DNA damage, FoxO1 was activated.	0	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	FoxO1	FoxO1	FoxO1	7	8	0	1
CDK2 ( cyclin dependent kinase 2 ) promotes G1/S cell cycle progression by associating with cyclin E and cyclin A. CDK2 can phosphorylate Ser249 and Ser298 of FoxO1 to cause cytoplasmic retention and inhibit FoxO1 activity .	CDK2 (cyclin dependent kinase 2) promotes G1/S cell cycle progression by associating with cyclin E and cyclin A. CDK2 can phosphorylate Ser249 and Ser298 of FoxO1 to cause cytoplasmic retention and inhibit FoxO1 activity.	0	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	FoxO1	FoxO1	FoxO1	0	1	34	35
Another possibility is that Cdk2 inhibition by pan-Cdk inhibitors may activate FOXO1 , which induces Bim transcription 41 .	Another possibility is that Cdk2 inhibition by pan-Cdk inhibitors may activate FOXO1, which induces Bim transcription 41.	4	17	activate	Positive_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Cdk2	Cdk2	cdk2	FOXO1	FOXO1, which induces Bim transcription	foxo1	4	5	11	12
Importantly , activated CDK2 inhibits the pro apoptotic function of FOXO1 .	Importantly, activated CDK2 inhibits the pro apoptotic function of FOXO1.	2	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	FOXO1	FOXO1	FOXO1	3	4	10	11
18 CDK1 and CDK2 are known to inhibit FOXO1 through phosphorylation of FOXO1 at serine residue 249 .	18 CDK1 and CDK2 are known to inhibit FOXO1 through phosphorylation of FOXO1 at serine residue 249.	1	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	FOXO1	FOXO1	FOXO1	3	4	8	9
These results suggest that an increase in the expression of cdk2 and cdc2 in colorectal cancer may have prevented pRB from braking the cell cycle through phosphorylation .	These results suggest that an increase in the expression of cdk2 and cdc2 in colorectal cancer may have prevented pRB from braking the cell cycle through phosphorylation.	8	20	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cdc2	expression of cdk2 and cdc2	cdc2	pRB	pRB	prb	12	13	19	20
While Cdc25A was degraded by 90 min in CDK2 -/- cells , the rate of degradation was decreased ( XREF_FIG ) indicating that Cdk2 contributes to normal Cdc25A protein turnover .	While Cdc25A was degraded by 90 min in CDK2 -/- cells, the rate of degradation was decreased (XREF_FIG) indicating that Cdk2 contributes to normal Cdc25A protein turnover.	1	10	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	Cdc25A	Cdc25A	Cdc25A	8	9	1	2
The G1 arrest and apoptotic effects were associated with an increase in T14 and Y15 phosphorylation of CDK2 and proteasom dependent down-regulation of CDC25A , as well as with up-regulation of p57 , E2F-1 , and p73 .	The G1 arrest and apoptotic effects were associated with an increase in T14 and Y15 phosphorylation of CDK2 and proteasom dependent down-regulation of CDC25A, as well as with up-regulation of p57, E2F-1, and p73.	12	24	down-regulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CDK2	T14 and Y15 phosphorylation of CDK2	cdk2	CDC25A	CDC25A	cdc25a	17	18	23	24
Accordingly , overexpression of CDK1 inhibits the transcriptional activity of FOXO1 in PCa cells through S249 phosphorylation on FOXO1 .	Accordingly, overexpression of CDK1 inhibits the transcriptional activity of FOXO1 in PCa cells through S249 phosphorylation on FOXO1.	2	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	overexpression of CDK1	cdk1	FOXO1	FOXO1	foxo1	4	5	10	11
Consistent with these biochemical data , activity deprivation in neurons increased the nuclear localization of epitope tagged FOXO1 , an event which could be reversed by Cdk1 RNAi .	Consistent with these biochemical data, activity deprivation in neurons increased the nuclear localization of epitope tagged FOXO1, an event which could be reversed by Cdk1 RNAi.	16	27	reversed	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	FOXO1	FOXO1	FOXO1	26	27	17	18
Huang and colleagues reported that Cdk1 activation inhibits the transcriptional and apoptotic activities of the transcription factor FOXO1 , thereby potentiating Ras mediated oncogenesis [ XREF_BIBR ] .	Huang and colleagues reported that Cdk1 activation inhibits the transcriptional and apoptotic activities of the transcription factor FOXO1, thereby potentiating Ras mediated oncogenesis [XREF_BIBR].	5	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	FOXO1	FOXO1	FOXO1	5	6	17	18
Phosphorylation by casein kinase 2 , Cdc2 , and other kinases attenuates the DNA binding affinity of HMGI/Y and the extent of perturbation in DNA structure induced by HMGI/Y binding .	Phosphorylation by casein kinase 2, Cdc2, and other kinases attenuates the DNA binding affinity of HMGI/Y and the extent of perturbation in DNA structure induced by HMGI/Y binding.	0	18	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdc2	Phosphorylation by casein kinase 2, Cdc2	cdc2	HMGI/Y	HMGI/Y	hmgi/y	6	7	17	18
p34cdc2 catalyzes the in vitro phosphorylation of MKK1 on both of these threonine residues and inactivates MKK1 enzymatic activity .	p34cdc2 catalyzes the in vitro phosphorylation of MKK1 on both of these threonine residues and inactivates MKK1 enzymatic activity.	0	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p34cdc2	p34cdc2	p34cdc2	MKK1	MKK1	MKK1	0	1	16	17
The fact that cdc2 kinase inhibits MEK1 activation is based on in vitro analysis .	The fact that cdc2 kinase inhibits MEK1 activation is based on in vitro analysis.	3	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cdc2	cdc2	cdc2	MEK1	MEK1	MEK1	3	4	6	7
To determine whether Cdk1 inhibition could rescue the metaphase localization of NuMA in LGN-knockdown keratinocytes , we treated these cells with purvalanol A or DMSO ( control ) .	To determine whether Cdk1 inhibition could rescue the metaphase localization of NuMA in LGN-knockdown keratinocytes, we treated these cells with purvalanol A or DMSO (control).	3	12	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	NuMA	NuMA	NuMA	3	4	11	12
Cdk1 inhibition was sufficient to restore the metaphase localization of NuMA in LGN depleted cells ( XREF_FIG ) .	Cdk1 inhibition was sufficient to restore the metaphase localization of NuMA in LGN depleted cells (XREF_FIG).	0	11	restore	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	NuMA	NuMA	NuMA	0	1	10	11
If CDK1 phosphorylation prevents membrane association of NuMA , we should expect that inhibition of CDK1 should lead to membrane accumulation of NuMA .	If CDK1 phosphorylation prevents membrane association of NuMA, we should expect that inhibition of CDK1 should lead to membrane accumulation of NuMA.	1	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1 phosphorylation	cdk1	NuMA	NuMA	numa	1	2	7	8
The kinase CDK1 and the phosphatases CDC14A and CDC14B reversibly regulated Sirt2 and therefore control of the cell cycle from G2 to M phase .	The kinase CDK1 and the phosphatases CDC14A and CDC14B reversibly regulated Sirt2 and therefore control of the cell cycle from G2 to M phase.	0	14	reversibly regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	Sirt2	Sirt2	Sirt2	2	3	11	12
Since the levels of PtdIns3P are reduced specifically in mitotic cells , we hypothesize that the mitotic kinase Cdk1 might negatively regulate the activity of the class III PtdIns3 kinase Vps34 complex .	Since the levels of PtdIns3P are reduced specifically in mitotic cells, we hypothesize that the mitotic kinase Cdk1 might negatively regulate the activity of the class III PtdIns3 kinase Vps34 complex.	15	31	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Vps34	Vps34	Vps34	18	19	30	31
Overexpression of Cdk1 phosphorylation site mutant LBR AA further advances ER attachment , indicating that Cdk1 phosphorylation negatively regulates the chromatin binding ability of LBR .	Overexpression of Cdk1 phosphorylation site mutant LBR AA further advances ER attachment, indicating that Cdk1 phosphorylation negatively regulates the chromatin binding ability of LBR.	15	25	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk1	Cdk1 phosphorylation	cdk1	LBR	LBR	lbr	15	16	24	25
Therefore , it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in BRAFV600E CRC cells .	Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in BRAFV600E CRC cells.	6	13	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	MEK	MEK	MEK	6	7	12	13
Prdx1 is inactivated by Cdk1 dependent phosphorylation in early mitosis , thus unshielding mitotic centrosomes from high H 2 O 2 concentrations , and facilitating the inactivation of centrosomal phosphatases .	Prdx1 is inactivated by Cdk1 dependent phosphorylation in early mitosis, thus unshielding mitotic centrosomes from high H 2 O 2 concentrations, and facilitating the inactivation of centrosomal phosphatases.	0	7	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Cdk1	Cdk1 dependent phosphorylation	cdk1	Prdx1	Prdx1	prdx1	4	5	0	1
Cyclin D1 and Cdk4 complex inhibits Rb by partial phosphorylation , decreasing its association with E2F transcription factor and allowing E2F regulated activation of downstream gene transcription [ XREF_BIBR , XREF_BIBR ] .	Cyclin D1 and Cdk4 complex inhibits Rb by partial phosphorylation, decreasing its association with E2F transcription factor and allowing E2F regulated activation of downstream gene transcription [XREF_BIBR, XREF_BIBR].	3	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk4	Cdk4	Cdk4	Rb	Rb	Rb	3	4	6	7
E2F1 transcriptional activity is regulated by glucose and insulin through the CDK4 dependent inactivation of the pRB protein .	E2F1 transcriptional activity is regulated by glucose and insulin through the CDK4 dependent inactivation of the pRB protein.	11	17	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	pRB	pRB	pRB	11	12	16	17
During the G 1 phase , Rb proteins are inactivated by sequential phosphorylation mediated by various Cdks , mainly the D-type cyclin dependent Cdk4 and Cdk6 and the E-type cyclin dependent Cdk2 .	During the G 1 phase, Rb proteins are inactivated by sequential phosphorylation mediated by various Cdks, mainly the D-type cyclin dependent Cdk4 and Cdk6 and the E-type cyclin dependent Cdk2.	6	24	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Cdk4	phosphorylation mediated by various Cdks, mainly the D-type cyclin dependent Cdk4	cdk4	Rb	Rb	rb	23	24	6	7
The pRB cell cycle regulatory cascade is frequently perturbed in neoplasia by overexpression of a component of the pRB phosphorylating cyclin D1 and CDK4 complex or by inactivation of pRB or the CDK4 inhibitors p16 and p15 .	The pRB cell cycle regulatory cascade is frequently perturbed in neoplasia by overexpression of a component of the pRB phosphorylating cyclin D1 and CDK4 complex or by inactivation of pRB or the CDK4 inhibitors p16 and p15.	1	24	perturbed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDK4	pRB phosphorylating cyclin D1 and CDK4	cdk4	pRB	pRB	prb	23	24	1	2
Deletion of p18 ( Ink4c ) ( p18 ) , an inhibitor of CDK4 and CDK6 , functionally inactivates the RB pathway , stimulates mammary luminal stem cell ( LSC ) proliferation , and leads to spontaneous luminal tumor development .	Deletion of p18 (Ink4c) (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development.	11	21	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	RB	RB	RB	13	14	20	21
We confirmed that CDK4 siRNA efficiently abolished p-Rb as well as CDK4 mRNA and protein expression ( XREF_FIG ) .	We confirmed that CDK4 siRNA efficiently abolished p-Rb as well as CDK4 mRNA and protein expression (XREF_FIG).	3	15	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	p-Rb	p-Rb	p-Rb	3	4	7	8
The MDM2 gene product binds and inactivates p53 protein , whereas the CDK4 gene product is a cyclin dependent kinase and possibly inactivates Rb function .	The MDM2 gene product binds and inactivates p53 protein, whereas the CDK4 gene product is a cyclin dependent kinase and possibly inactivates Rb function.	12	24	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	12	13	23	24
In particular a high fraction of tumors exhibit amplification of the p53 negative regulators MDM2 , 4 and WIP1 , as well as CDK4 which negatively regulates Rb .	In particular a high fraction of tumors exhibit amplification of the p53 negative regulators MDM2, 4 and WIP1, as well as CDK4 which negatively regulates Rb.	7	28	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	23	24	27	28
Subsequent studies have demonstrated that overexpression of cyclin D1 or cdk4 , instead of HPV E6/E7 , effectively inhibited Rb activity and might be an alternative method of overcoming premature senescence in primary epithelial cells of other origins .	Subsequent studies have demonstrated that overexpression of cyclin D1 or cdk4, instead of HPV E6/E7, effectively inhibited Rb activity and might be an alternative method of overcoming premature senescence in primary epithelial cells of other origins.	5	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cdk4	overexpression of cyclin D1 or cdk4	cdk4	Rb	Rb	rb	10	11	19	20
Intriguingly , the knockdown of both CDK4 and CDK6 , but not CDK2 , allowed RB to become the most hypophosphorylated form and converted the SN38 sensitive cells to a resistant state .	Intriguingly, the knockdown of both CDK4 and CDK6, but not CDK2, allowed RB to become the most hypophosphorylated form and converted the SN38 sensitive cells to a resistant state.	3	17	allowed	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	RB	RB	RB	6	7	15	16
Nevertheless , in our follow-up experiments , we recapitulated the CDK4-RB interaction as RB ( phosphorylated at Ser 780 and Ser 807 ) was suppressed by PD0332991 and by CDK4 directed siRNA ( XREF_FIG ) .	Nevertheless, in our follow-up experiments, we recapitulated the CDK4-RB interaction as RB (phosphorylated at Ser 780 and Ser 807) was suppressed by PD0332991 and by CDK4 directed siRNA (XREF_FIG).	13	30	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	RB	RB	RB	29	30	13	14
Cyclin D1 and CDK4 phosphorylate and inactivate Rb during the G1/S transition , thereby allowing cell cycle progression to occur [ XREF_BIBR ] .	Cyclin D1 and CDK4 phosphorylate and inactivate Rb during the G1/S transition, thereby allowing cell cycle progression to occur [XREF_BIBR].	1	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	3	4	7	8
Furthermore , the p16 INK4a -driven inhibition of CDK4 and CDK6 promotes changes in cell morphology independent of Rb , suggesting additional kinase targets may contribute to the activity of p16 INK4a .	Furthermore, the p16 INK4a -driven inhibition of CDK4 and CDK6 promotes changes in cell morphology independent of Rb, suggesting additional kinase targets may contribute to the activity of p16 INK4a.	6	19	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	8	9	18	19
p16 is a cyclin dependent kinase inhibitor of CDK4 and CDK6 , which activates the negative cell cycle regulator retinoblastoma protein ( pRB ) .	p16 is a cyclin dependent kinase inhibitor of CDK4 and CDK6, which activates the negative cell cycle regulator retinoblastoma protein (pRB).	6	21	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	8	9	19	21
These four genes are members of the RB signaling pathway involved in G1/S progression ( by Bonferonni corrected hypergeometric test ) : CDKN2A and CDKN2B inhibits CDK4 , which in turn inhibits RB1 .	These four genes are members of the RB signaling pathway involved in G1/S progression (by Bonferonni corrected hypergeometric test) : CDKN2A and CDKN2B inhibits CDK4, which in turn inhibits RB1.	25	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	RB1	RB1	RB1	26	27	32	33
In particular a high fraction of tumors exhibit amplification of the p53 negative regulators MDM2 , 4 and WIP1 , and CDK4 which is also known to negatively regulate Rb .	In particular a high fraction of tumors exhibit amplification of the p53 negative regulators MDM2, 4 and WIP1, and CDK4 which is also known to negatively regulate Rb.	8	30	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	21	22	29	30
Further reinforcing this notion were experiments utilizing supra-physiologic overexpression of D-type cyclins and Cdk4 and Cdk6 that inactivated Rb and drove cells into S phase .	Further reinforcing this notion were experiments utilizing supra-physiologic overexpression of D-type cyclins and Cdk4 and Cdk6 that inactivated Rb and drove cells into S phase.	6	20	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk4	Cdk4	Cdk4	Rb	Rb	Rb	13	14	18	19
Cyclin D1 and cyclin dependent kinase-4 ( CDK4 ) phosphorylate and inhibit RB to induce proliferation .	Cyclin D1 and cyclin dependent kinase-4 (CDK4) phosphorylate and inhibit RB to induce proliferation.	3	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cyclin dependent kinase-4	cyclin dependent kinase-4	cyclin dependent kinase-4	RB	RB	RB	3	6	12	13
Moreover , in this context , E2F1 transcriptional activity is regulated by glucose and insulin through the CDK4 dependent inactivation of the pRB protein .	Moreover, in this context, E2F1 transcriptional activity is regulated by glucose and insulin through the CDK4 dependent inactivation of the pRB protein.	17	23	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	pRB	pRB	pRB	17	18	22	23
Cyclin D1 and Cdk4 complex inhibits Rb by appropriate phosphorylation andreduces its association with E2F transcription factor , leading tothe activation of downstream gene transcription [ XREF_BIBR ] .	Cyclin D1 and Cdk4 complex inhibits Rb by appropriate phosphorylation andreduces its association with E2F transcription factor, leading tothe activation of downstream gene transcription [XREF_BIBR].	3	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk4	Cdk4	Cdk4	Rb	Rb	Rb	3	4	6	7
According to the prevailing model , the major role of CDK4 and CDK6 is to inactivate pRB .	According to the prevailing model, the major role of CDK4 and CDK6 is to inactivate pRB.	8	17	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	pRB	pRB	pRB	10	11	16	17
By contrast , assessment of the CDK4 and cyclin D1 complex and measurement of its kinase activity are entirely congruent with the proliferative response , and suggest that CDK4 compensated for diminished CDK2 activity to inactivate pRb and promote cell cycle progression ( XREF_FIG ) .	By contrast, assessment of the CDK4 and cyclin D1 complex and measurement of its kinase activity are entirely congruent with the proliferative response, and suggest that CDK4 compensated for diminished CDK2 activity to inactivate pRb and promote cell cycle progression (XREF_FIG).	28	37	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	pRb	pRb	pRb	28	29	36	37
Rb itself is inactivated through phosphorylation by the Cyclin D1 and CDK4 complex , liberating E2F to promote cell entry into S phase .	Rb itself is inactivated through phosphorylation by the Cyclin D1 and CDK4 complex, liberating E2F to promote cell entry into S phase.	0	17	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	11	12	0	1
CDK4 inactivates the retinoblastoma protein ( pRb ) by phosphorylation .	CDK4 inactivates the retinoblastoma protein (pRb) by phosphorylation.	0	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	0	1	3	5
CDKN2A inhibits CDK4 and CDK4 inhibits RB1 in the RB signaling pathway .	CDKN2A inhibits CDK4 and CDK4 inhibits RB1 in the RB signaling pathway.	2	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	RB1	RB1	RB1	2	3	6	7
The effects of exogenous human telomerase reverse transcriptase expression , p53 knockdown , disruption of the pRb pathway by over-expression of CDK4 and reduced oxygen concentration on the lifespan of primary HCEC were evaluated .	The effects of exogenous human telomerase reverse transcriptase expression, p53 knockdown, disruption of the pRb pathway by over-expression of CDK4 and reduced oxygen concentration on the lifespan of primary HCEC were evaluated.	13	22	disruption	Negative_activation_syntax_1_noun	Negative_activation	Negative_activation	CDK4	over-expression of CDK4	cdk4	pRb	pRb	prb	21	22	16	17
We used a panel of DLBCL cell lines derived from patients with relapsed and refractory disease ; all lines have decreased or absent p53 activity and CNAs of cell cycle components including CDKN2A , CCND3 , CDK4 , CDK6 , CDK2 and/or copy loss of RB1 ( XREF_SUPPLEMENTARY ) .	We used a panel of DLBCL cell lines derived from patients with relapsed and refractory disease; all lines have decreased or absent p53 activity and CNAs of cell cycle components including CDKN2A, CCND3, CDK4, CDK6, CDK2 and/or copy loss of RB1 (XREF_SUPPLEMENTARY).	32	46	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	RB1	RB1	RB1	36	37	45	46
CDK4 inhibits RB1 , and CDKN2B inhibits CDK4 in the RB signaling pathway .	CDK4 inhibits RB1, and CDKN2B inhibits CDK4 in the RB signaling pathway.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	RB1	RB1	RB1	0	1	2	3
CDK4 inhibition can induce Rb positive cells to exit the cell cycle into a non proliferative state , however , this can take the form of either quiescence , which is readily reversible , or senescence , which is more stable .	CDK4 inhibition can induce Rb positive cells to exit the cell cycle into a non proliferative state, however, this can take the form of either quiescence, which is readily reversible, or senescence, which is more stable.	0	6	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	0	1	4	5
The CKIs , p16 , p15 , p18 and p19 , inhibit the activity of the CDKs CDK4 and CDK6 , thereby preventing phopsphorylation of Rb , and G1 to S phase transition , and a mouse with a Cdk4 point mutation ( Arg24Cys ) that resulted in insensitivity to the CKIs , developed tumours of the pituitary , pancreas and testes .	The CKIs, p16, p15, p18 and p19, inhibit the activity of the CDKs CDK4 and CDK6, thereby preventing phopsphorylation of Rb, and G1 to S phase transition, and a mouse with a Cdk4 point mutation (Arg24Cys) that resulted in insensitivity to the CKIs, developed tumours of the pituitary, pancreas and testes.	13	26	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	17	18	25	26
Cycle inhibitory proteins p15 INK4b and p16 INK4a encoded by this locus are able to induce cell cycle arrest in G1 by inhibiting cyclin dependent kinases CDK4 and CDK6 which normally inactivate two tumour-suppressor pathways , Rb and p53 .	Cycle inhibitory proteins p15 INK4b and p16 INK4a encoded by this locus are able to induce cell cycle arrest in G1 by inhibiting cyclin dependent kinases CDK4 and CDK6 which normally inactivate two tumour-suppressor pathways, Rb and p53.	22	37	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	26	27	36	37
These results are consistent with a model in which the only requirement of cdk4 in MCF-7 cell proliferation is to inactivate pRb family members XREF_BIBR , XREF_BIBR .	These results are consistent with a model in which the only requirement of cdk4 in MCF-7 cell proliferation is to inactivate pRb family members XREF_BIBR, XREF_BIBR.	11	24	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cdk4	cdk4	cdk4	pRb	pRb	pRb	13	14	21	22
CDK2 is an inhibitor of Rb , which acts as an inhibitor of the transcription factor E2F-1 .	CDK2 is an inhibitor of Rb, which acts as an inhibitor of the transcription factor E2F-1.	0	8	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	Rb	Rb	Rb	0	1	5	6
During the G1 phase , the complexes Cyclin D1 : CDK4 and Cyclin E : CDK2 are successively activated leading to the stepwise phosphorylation , and thus , inhibition of the retinoblastoma protein ( Rb ) .	During the G1 phase, the complexes Cyclin D1 : CDK4 and Cyclin E : CDK2 are successively activated leading to the stepwise phosphorylation, and thus, inhibition of the retinoblastoma protein (Rb).	15	33	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	15	16	31	33
At the late G 1 Restriction Point , cyclin E : Cdk2 inactivates Rb by quantum hyper-phosphorylation .	At the late G 1 Restriction Point, cyclin E : Cdk2 inactivates Rb by quantum hyper-phosphorylation.	11	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	Rb	Rb	Rb	11	12	13	14
Cyclin E ( CycE ) mRNA levels were also increased 1.8-fold after I/R ( XREF_FIG ; 1.00 +/-0.05 vs. 1.82 +/-0.22 , P < 0.05 ) suggesting a positive feedback loop may exist where increases in CDK-2 inactivate Rb , further enhancing E2F-1 activity .	Cyclin E (CycE) mRNA levels were also increased 1.8-fold after I/R (XREF_FIG; 1.00 +/-0.05 vs. 1.82 +/-0.22, P < 0.05) suggesting a positive feedback loop may exist where increases in CDK-2 inactivate Rb, further enhancing E2F-1 activity.	34	39	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK-2	CDK-2	CDK-2	Rb	Rb	Rb	36	37	38	39
Cdks involved in cell-cycle regulation include Cdk4 , Cdk6 and Cdk2 that regulate progression through the G 1 phase although additionally , Cdk2 also regulates S phase and Cdk1 that regulates mitosis [ XREF_BIBR ] In early-mid G 1 phase , cyclins-Cdk4/6 and cyclins-Cdk2 complexes phosphorylate and inactivate members of the retinoblastoma family of pocket proteins ( pRb , p107 and p130 ) resulting in de-repression of multiple genes encoding for proteins required for DNA replication [ XREF_BIBR ] .	Cdks involved in cell-cycle regulation include Cdk4, Cdk6 and Cdk2 that regulate progression through the G 1 phase although additionally, Cdk2 also regulates S phase and Cdk1 that regulates mitosis [XREF_BIBR] In early-mid G 1 phase, cyclins-Cdk4/6 and cyclins-Cdk2 complexes phosphorylate and inactivate members of the retinoblastoma family of pocket proteins (pRb, p107 and p130) resulting in de-repression of multiple genes encoding for proteins required for DNA replication [XREF_BIBR].	5	61	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	pRb	pRb	pRb	10	11	57	58
When stimulated by growth factors , activated CDK2 activates the transcription factor E2F by hyperphosphorylation and inactivates pRB , and E2F is a transcription activator for gene expression related to DNA replication ; in another way , CDK2 stimulates the function of histone gene expression related transcription factors , such as SP1 , IRF-2 , CDP-cut and HiNF-D , HiNF-P , and HiNF-M , leading to histone biosynthesis .	When stimulated by growth factors, activated CDK2 activates the transcription factor E2F by hyperphosphorylation and inactivates pRB, and E2F is a transcription activator for gene expression related to DNA replication; in another way, CDK2 stimulates the function of histone gene expression related transcription factors, such as SP1, IRF-2, CDP-cut and HiNF-D, HiNF-P, and HiNF-M, leading to histone biosynthesis.	6	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	pRB	pRB	pRB	7	8	17	18
This leads to high expression levels of Cyclin E/Cyclin A & Cdk2 which in turn further inhibits RB activity .	This leads to high expression levels of Cyclin E/Cyclin A & Cdk2 which in turn further inhibits RB activity.	1	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	RB	RB	RB	11	12	17	18
Overexpression of cdk2 and cdk4 but not a dominant negative cdk2 rescued Rb mediated downregulation of telomerase activity .	Overexpression of cdk2 and cdk4 but not a dominant negative cdk2 rescued Rb mediated downregulation of telomerase activity.	0	14	rescued	Positive_activation_token_1_verb	Negative_activation	Negative_activation	cdk2	cdk2	cdk2	Rb	Rb	Rb	10	11	12	13
This facilitates downstream cyclin E : CDK2 complex activity that , along with cyclin D : CDK4/6 , inactivates Rb and allows activation of E2F transcription factors and progression through the cell cycle .	This facilitates downstream cyclin E : CDK2 complex activity that, along with cyclin D : CDK4/6, inactivates Rb and allows activation of E2F transcription factors and progression through the cell cycle.	6	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	Rb	Rb	Rb	6	7	19	20
The current dogma of G 1 cell-cycle progression relies on growth factor induced increase of cyclin D : Cdk4/6 complex activity to partially inactivate pRb by phosphorylation and to sequester p27 Kip1 -triggering activation of cyclin E : Cdk2 complexes that further inactivate pRb .	The current dogma of G 1 cell-cycle progression relies on growth factor induced increase of cyclin D : Cdk4/6 complex activity to partially inactivate pRb by phosphorylation and to sequester p27 Kip1 -triggering activation of cyclin E : Cdk2 complexes that further inactivate pRb.	38	44	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	pRb	pRb	pRb	38	39	43	44
The protein LIN-35 is orthologous to Rb , CDK-4 and CYD-1 negatively regulates LIN-35 activity [ XREF_BIBR , XREF_BIBR ] , and in mammals , the orthologs of CDK-2 and CYE-1 are needed to fully inhibit the Rb function [ XREF_BIBR , XREF_BIBR ] .	The protein LIN-35 is orthologous to Rb, CDK-4 and CYD-1 negatively regulates LIN-35 activity [XREF_BIBR, XREF_BIBR], and in mammals, the orthologs of CDK-2 and CYE-1 are needed to fully inhibit the Rb function [XREF_BIBR, XREF_BIBR].	26	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK-2	CDK-2	CDK-2	Rb	Rb	Rb	28	29	37	38
SMAD3 activity in cell cycle arrest is blocked by CDK4 and Cyclin D1 in complex [ XREF_BIBR ] .	SMAD3 activity in cell cycle arrest is blocked by CDK4 and Cyclin D1 in complex [XREF_BIBR].	0	12	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	SMAD3	SMAD3	SMAD3	9	10	0	1
A correlation between CDK4 inhibition and restoration of Smad3 function was established .	A correlation between CDK4 inhibition and restoration of Smad3 function was established.	3	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Smad3	Smad3	Smad3	3	4	8	9
This suggests that CDK4 and CDK2 negatively regulate the transcriptional activity and antiproliferative function of Smad3 .	This suggests that CDK4 and CDK2 negatively regulate the transcriptional activity and antiproliferative function of Smad3.	3	16	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Smad3	Smad3	Smad3	3	4	15	16
siRNA knockdown of CDK4 restores Smad3 activity in MCF7 cell lines .	siRNA knockdown of CDK4 restores Smad3 activity in MCF7 cell lines.	1	6	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Smad3	Smad3	Smad3	3	4	5	6
Direct inhibition of CDK4 also restored Smad3 transcriptional activity , and this effect was further augmented by overexpressing Smad3 containing mutated CDK phosphorylation sites .	Direct inhibition of CDK4 also restored Smad3 transcriptional activity, and this effect was further augmented by overexpressing Smad3 containing mutated CDK phosphorylation sites.	1	8	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Smad3	Smad3	Smad3	3	4	6	7
CDK4 inhibition restores Smad3 activity in breast cancer cell lines .	CDK4 inhibition restores Smad3 activity in breast cancer cell lines.	0	4	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	Smad3	Smad3	Smad3	0	1	3	4
One major consequence of PD-1-mediated Cdk2 inhibition and subsequent reprograming of Smad3 transcriptional events is the conversion of naive T cells into induced T regulatory cells .	One major consequence of PD-1-mediated Cdk2 inhibition and subsequent reprograming of Smad3 transcriptional events is the conversion of naive T cells into induced T regulatory cells.	5	13	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	Smad3	Smad3	Smad3	5	6	11	12
Of critical importance is the fact that Cdk2 * Cyclin E inactivates Fzr , suggesting that APC * Fzr oscillations are driven by periodic inhibition of Fzr by Cdk2 * Cyclin E.	Of critical importance is the fact that Cdk2 * Cyclin E inactivates Fzr, suggesting that APC * Fzr oscillations are driven by periodic inhibition of Fzr by Cdk2 * Cyclin E.	21	29	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	Fzr	Fzr	Fzr	28	29	26	27
Not much is known about how this occurs , but inhibition of MEF2C by CDK4 prevents the association of MEF2 with its transcriptional coactivator , glucocorticoid receptor interacting protein 1 ( GRIP1 ) [ XREF_BIBR ] .	Not much is known about how this occurs, but inhibition of MEF2C by CDK4 prevents the association of MEF2 with its transcriptional coactivator, glucocorticoid receptor interacting protein 1 (GRIP1) [XREF_BIBR].	10	15	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	CDK4	CDK4	CDK4	MEF2C	MEF2C	MEF2C	14	15	12	13
Remarkably , live cell imaging showed that depletion of SKP2 , CUL1 , or CDK2 did not rescue the Wee1 inhibition induced karyokinesis and cytokinesis defects .	Remarkably, live cell imaging showed that depletion of SKP2, CUL1, or CDK2 did not rescue the Wee1 inhibition induced karyokinesis and cytokinesis defects.	7	20	rescue	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	Wee1	Wee1	Wee1	14	15	19	20
Previous studies suggested that signaling pathways that induce cyclin D1 , a key regulator of cell cycle progression , also induce increased levels of nuclear Cdk4 , which , in turn , inhibits MyoD and MEF2 function in the dividing cell .	Previous studies suggested that signaling pathways that induce cyclin D1, a key regulator of cell cycle progression, also induce increased levels of nuclear Cdk4, which, in turn, inhibits MyoD and MEF2 function in the dividing cell.	22	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk4	levels of nuclear Cdk4	cdk4	MyoD	MyoD	myod	25	26	33	34
DNMT3L influenced the stability of promyelocytic leukemia zinc finger ( PLZF ) , potentially by downregulating Cdk2 and CDK2 expression , which sequestered CDK2 mediated PLZF degradation .	DNMT3L influenced the stability of promyelocytic leukemia zinc finger (PLZF), potentially by downregulating Cdk2 and CDK2 expression, which sequestered CDK2 mediated PLZF degradation.	22	26	mediated	Positive_early_activation	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	PLZF	PLZF	PLZF	23	24	25	26
At the same time PC1 can lead to Cdk2 inhibition independent of Id2 through the JAK and STAT pathway .	At the same time PC1 can lead to Cdk2 inhibition independent of Id2 through the JAK and STAT pathway.	8	13	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	Id2	Id2	Id2	8	9	12	13
In this context , the increase in p16 produced by the down regulation of Mip130 and LIN -9 blocks inactivation of pocket proteins by CDK4/6 , while a further increase in ARF will activate p53 leading to inhibition of CDK2 by p21 .	In this context, the increase in p16 produced by the down regulation of Mip130 and LIN -9 blocks inactivation of pocket proteins by CDK4/6, while a further increase in ARF will activate p53 leading to inhibition of CDK2 by p21.	33	42	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	41	42	39	40
p21 , which belongs to the Cip and Kip family of cyclin dependent kinase ( CDK ) inhibitors , binds to and inhibits the kinase activity of CDK2 and CDK1 , leading to growth arrest at specific stages of the cell cycle .	p21, which belongs to the Cip and Kip family of cyclin dependent kinase (CDK) inhibitors, binds to and inhibits the kinase activity of CDK2 and CDK1, leading to growth arrest at specific stages of the cell cycle.	0	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	27	28
Studies conducted on epithelial cells have shown that an increase in p15 INK4B leads to the binding of CDK4 and CDK6 , thus displacing the p27 Kip1 and p21 Cip1 kinases that bind to and inhibit CDK2 .	Studies conducted on epithelial cells have shown that an increase in p15 INK4B leads to the binding of CDK4 and CDK6, thus displacing the p27 Kip1 and p21 Cip1 kinases that bind to and inhibit CDK2.	28	37	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 Cip1	p21 Cip1	p21 Cip1	CDK2	CDK2	CDK2	28	30	36	37
Increased levels of p15 , p21 and p27 protein were also accompanied by increased levels of hypo phosphorylated Rb and decreased cdk2 kinase activity .	Increased levels of p15, p21 and p27 protein were also accompanied by increased levels of hypo phosphorylated Rb and decreased cdk2 kinase activity.	1	23	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	levels of p15, p21	p21	cdk2	cdk2	cdk2	5	6	21	22
In addition , it was also well-known that the inhibition of CDK2 by p21 dephosphorylates Rb protein , which causes cell cycle arrest via inhibition of E2F1 dependent gene expression [ XREF_BIBR ] .	In addition, it was also well-known that the inhibition of CDK2 by p21 dephosphorylates Rb protein, which causes cell cycle arrest via inhibition of E2F1 dependent gene expression [XREF_BIBR].	9	14	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	13	14	11	12
113 Degradation of p21 and p27 by SKP2 activates CDK1 and CDK2 and promotes S and G2 cell cycle phase progression , thereby positively regulating the cell cycle 114 ( XREF_FIG ) .	113 Degradation of p21 and p27 by SKP2 activates CDK1 and CDK2 and promotes S and G2 cell cycle phase progression, thereby positively regulating the cell cycle 114 (XREF_FIG).	1	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	3	4	11	12
p21 binds to and inhibits the kinase activity of Cdk2 and Cdk1 , leading to cell cycle arrest .	p21 binds to and inhibits the kinase activity of Cdk2 and Cdk1, leading to cell cycle arrest.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	0	1	9	10
We only observed one p21 depleted cell entering a CDK2 low state ( 1/68 ) , suggesting that the CDK2 low G1pm arrest state is due to p21 dependent inhibition of CDK activity , consistent with previous work XREF_BIBR ( XREF_FIG ) .	We only observed one p21 depleted cell entering a CDK2 low state (1/68), suggesting that the CDK2 low G1pm arrest state is due to p21 dependent inhibition of CDK activity, consistent with previous work XREF_BIBR (XREF_FIG).	2	11	depleted	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	4	5	9	10
Our results showed that p21 WAF1 and CIP1 inhibited [ 3 H ] thymidine incorporation and reduced cdk2 kinase activity in human liver cancer cells but did not affect expression of cdk2 and cdk4 .	Our results showed that p21 WAF1 and CIP1 inhibited [3 H] thymidine incorporation and reduced cdk2 kinase activity in human liver cancer cells but did not affect expression of cdk2 and cdk4.	5	19	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIP1	CIP1	CIP1	cdk2	cdk2	cdk2	7	8	17	18
p21 regulates the progression of cells in the G1 phase of the cell cycle through binding to and inhibiting the activity of CDK2 and CDK4 .	p21 regulates the progression of cells in the G1 phase of the cell cycle through binding to and inhibiting the activity of CDK2 and CDK4.	0	24	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	22	23
p21 also inhibits the function of CDK2 , a cellular kinase activated in early S phase that helps induce the licensing machinery for DNA replication .	p21 also inhibits the function of CDK2, a cellular kinase activated in early S phase that helps induce the licensing machinery for DNA replication.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	6	7
p21 causes cell-cycle arrest by inhibiting the activity of cyclin dependent kinase ( CDK ) complexes that contain the G 1 / S kinases CDK2 , CDK4 and CDK6 .	p21 causes cell-cycle arrest by inhibiting the activity of cyclin dependent kinase (CDK) complexes that contain the G 1 / S kinases CDK2, CDK4 and CDK6.	0	28	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	24	25
In the present study , we show that CDK2 can support HIV-1 reverse transcription through direct phosphorylation of HIV-1 reverse transcriptase ( RT ) at a highly conserved amino acid residue , that this phosphorylation is functionally relevant for maintaining RT activity , stability and viral fitness , and that CDK2 dependent RT phosphorylation can be effectively blocked by p21 .	In the present study, we show that CDK2 can support HIV-1 reverse transcription through direct phosphorylation of HIV-1 reverse transcriptase (RT) at a highly conserved amino acid residue, that this phosphorylation is functionally relevant for maintaining RT activity, stability and viral fitness, and that CDK2 dependent RT phosphorylation can be effectively blocked by p21.	50	60	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	59	60	50	51
5 Transcriptional Activation by P53 Accumulation of P53 in cells induces the P21 mediated inhibition of Cyclin D/cdk4 and cyclinE and cdk2 , resulting in cell cycle arrest in G1 .	5 Transcriptional Activation by P53 Accumulation of P53 in cells induces the P21 mediated inhibition of Cyclin D/cdk4 and cyclinE and cdk2, resulting in cell cycle arrest in G1.	11	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21	P21	cdk2	cdk2	cdk2	12	13	21	22
Consistent with G ( 1 ) arrest in DU145 cells , decursin strongly increased protein levels of Cip1 and p21 but showed a moderate increase in Kip1 and p27 with a decrease in cyclin dependent kinases ( CDK ) ; CDK2 , CDK4 , CDK6 , and cyclin D1 , and inhibited CDK2 , CDK4 , CDK6 , cyclin D1 , and cyclin E kinase activity , and increased binding of CDK inhibitor ( CDKI ) with CDK .	Consistent with G (1) arrest in DU145 cells, decursin strongly increased protein levels of Cip1 and p21 but showed a moderate increase in Kip1 and p27 with a decrease in cyclin dependent kinases (CDK); CDK2, CDK4, CDK6, and cyclin D1, and inhibited CDK2, CDK4, CDK6, cyclin D1, and cyclin E kinase activity, and increased binding of CDK inhibitor (CDKI) with CDK.	11	65	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	decursin strongly increased protein levels of Cip1	cip1	CDK2	CDK2	cdk2	17	18	52	53
BCCIPalpha is a tumor suppressor that binds to p21 ( mda-6 and CIP-1 ) and enhances p21 mediated inhibition of Cdk2 kinase .	BCCIPalpha is a tumor suppressor that binds to p21 (mda-6 and CIP-1) and enhances p21 mediated inhibition of Cdk2 kinase.	16	21	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	16	17	20	21
While we can not eliminate the possibility that CDKN1A up-regulation suppresses CDK2 activity in HPr-1AR , our results demonstrate the importance of cyclin D-CDK4/6 complexes and the G 1 / S-phase transition in AR mediated growth suppression .	While we can not eliminate the possibility that CDKN1A up-regulation suppresses CDK2 activity in HPr-1AR, our results demonstrate the importance of cyclin D-CDK4/6 complexes and the G 1 / S-phase transition in AR mediated growth suppression.	8	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK2	CDK2	CDK2	8	9	11	12
p21 WAF1 and CIP1 is a crucial transcriptional target of p53 and inhibits CDK2 , causing cell cycle arrest at the G1 phase .	p21 WAF1 and CIP1 is a crucial transcriptional target of p53 and inhibits CDK2, causing cell cycle arrest at the G1 phase.	1	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIP1	CIP1	CIP1	CDK2	CDK2	CDK2	3	4	13	14
An earlier study has demonstrated that p21 causes Rb dephosphorylation , which is inactivated in proliferating cells through phosphorylation by CDK2 and CDK4/6 , all of which are suppressed by p21 [ XREF_BIBR ] .	An earlier study has demonstrated that p21 causes Rb dephosphorylation, which is inactivated in proliferating cells through phosphorylation by CDK2 and CDK4/6, all of which are suppressed by p21 [XREF_BIBR].	15	32	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	30	31	20	21
Cell cycle progression through the restriction point is highly dependent on Cdk2 activity which is governed by cyclins E/A for activation and potently suppressed by the CKIs , p21 and p27 .	Cell cycle progression through the restriction point is highly dependent on Cdk2 activity which is governed by cyclins E/A for activation and potently suppressed by the CKIs, p21 and p27.	11	29	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	28	29	11	12
Normal progression through G1 is promoted through activity of the cyclin dependent protein kinases 2 ( CDK2 ) , which is inhibited by p21 .	Normal progression through G1 is promoted through activity of the cyclin dependent protein kinases 2 (CDK2), which is inhibited by p21.	5	24	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	23	24	16	17
In our model , two double negative feedback loops control p21 expression : ( i ) phosphorylation by CDK2 targets p21 for Skp2 dependent degradation XREF_BIBR XREF_BIBR , while high levels of p21 inhibit CDK2 activity XREF_BIBR ; and ( ii ) PCNA in active replication complexes ( aRCs ) recruits CRL4 Cdt2 to degrade p21 , while p21 can bind to PCNA interfering with its function as a processivity factor during DNA replication XREF_BIBR XREF_BIBR .	In our model, two double negative feedback loops control p21 expression : (i) phosphorylation by CDK2 targets p21 for Skp2 dependent degradation XREF_BIBR XREF_BIBR, while high levels of p21 inhibit CDK2 activity XREF_BIBR; and (ii) PCNA in active replication complexes (aRCs) recruits CRL4 Cdt2 to degrade p21, while p21 can bind to PCNA interfering with its function as a processivity factor during DNA replication XREF_BIBR XREF_BIBR.	16	22	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	20	21	18	19
HBx also increases the expression of p21 cip-1/waf1/mda6 and p27 kip-1 in primary mouse hepatocytes , and overexpression of p21 and p27 can inhibit Cdk2 and Cdk4 activity , leading to cell cycle arrest in the G 1 phase , and activates Wnt and beta-catenin signaling in hepatoma cells .	HBx also increases the expression of p21 cip-1/waf1/mda6 and p27 kip-1 in primary mouse hepatocytes, and overexpression of p21 and p27 can inhibit Cdk2 and Cdk4 activity, leading to cell cycle arrest in the G 1 phase, and activates Wnt and beta-catenin signaling in hepatoma cells.	17	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	overexpression of p21	p21	Cdk2	Cdk2	cdk2	19	20	24	25
CDKN1A ( p21 , Cip1 ) can inhibit CDK2 or CDK4 complexes and regulate the cell cycle .	CDKN1A (p21, Cip1) can inhibit CDK2 or CDK4 complexes and regulate the cell cycle.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK2	CDK2	CDK2	0	1	8	9
However , p21 blocked Cdk2 kinase activity induced by both E1A pathways equally .	However, p21 blocked Cdk2 kinase activity induced by both E1A pathways equally.	2	6	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	2	3	4	5
Taken together , these data suggest that DPTH-N10 inhibits HUVEC proliferation by increasing the level of p21 protein , which in turn inhibits CDK2 kinase activity , and finally interrupts the cell cycle .	Taken together, these data suggest that DPTH-N10 inhibits HUVEC proliferation by increasing the level of p21 protein, which in turn inhibits CDK2 kinase activity, and finally interrupts the cell cycle.	16	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	16	17	23	24
p16 is a specific inhibitor of cdk4 , while p21 can inhibit both cdk2 and cdk4 but can also facilitate cdk4-cyclin D complex formation XREF_BIBR , XREF_BIBR .	p16 is a specific inhibitor of cdk4, while p21 can inhibit both cdk2 and cdk4 but can also facilitate cdk4-cyclin D complex formation XREF_BIBR, XREF_BIBR.	9	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	cdk2	cdk2	cdk2	9	10	13	14
Increased expression of p21waf1 and cip1 blocks cdk2 activity in G1 phase , leading to hypophosphorylation of the retinoblastoma protein and inhibition of cell cycle progression into S phase .	Increased expression of p21waf1 and cip1 blocks cdk2 activity in G1 phase, leading to hypophosphorylation of the retinoblastoma protein and inhibition of cell cycle progression into S phase.	1	8	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cip1	expression of p21waf1 and cip1	cip1	cdk2	cdk2	cdk2	5	6	7	8
Mechanistically , SIRT7 reduced p21 expression and increased the levels of Cyclin D1 and cyclin dependent kinase 2 ( CDK2 ) in CCA cells .	Mechanistically, SIRT7 reduced p21 expression and increased the levels of Cyclin D1 and cyclin dependent kinase 2 (CDK2) in CCA cells.	2	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	SIRT7 reduced p21 expression	p21	CDK2	CDK2	cdk2	4	5	19	20
in vitro , C/EBPalpha enhanced p21 inhibition of CDK2 activity .	in vitro, C/EBPalpha enhanced p21 inhibition of CDK2 activity.	5	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	5	6	8	9
p53 triggers cell cycle arrest by upregulating p21 , which inhibits the cell cycle regulator cyclin dependent kinases Cdk4 and Cdk2 [ XREF_BIBR ] .	p53 triggers cell cycle arrest by upregulating p21, which inhibits the cell cycle regulator cyclin dependent kinases Cdk4 and Cdk2 [XREF_BIBR].	1	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	7	8	20	21
Although p27 and p21 are major inhibitors of CDK2 , they also promote G1 progression by facilitating the assembly of cyclin D/CDK4 and cyclin D/CDK6 complexes [ XREF_BIBR , XREF_BIBR ] .	Although p27 and p21 are major inhibitors of CDK2, they also promote G1 progression by facilitating the assembly of cyclin D/CDK4 and cyclin D/CDK6 complexes [XREF_BIBR, XREF_BIBR].	1	9	are major inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	3	4	8	9
p21 binds to and inhibits the activities of CDK2 and CDK4 .	p21 binds to and inhibits the activities of CDK2 and CDK4.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	8	9
XREF_BIBR P21 , a major target of the tumor suppressor p53 , inhibits CDK2 preventing cell cycle progression and promotes cell survival , though the latter is dependent upon Akt inhibition of p21 nuclear translocation .	XREF_BIBR P21, a major target of the tumor suppressor p53, inhibits CDK2 preventing cell cycle progression and promotes cell survival, though the latter is dependent upon Akt inhibition of p21 nuclear translocation.	0	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21	P21	CDK2	CDK2	CDK2	1	2	13	14
Thus , in exponentially growing fibroblasts in tissue culture , p21 is a critical inhibitor of CDK2 .	Thus, in exponentially growing fibroblasts in tissue culture, p21 is a critical inhibitor of CDK2.	10	17	is a critical inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	10	11	16	17
It was assumed that the individual relationships within canonical mechanisms ( for example CDKN1A inhibiting the kinase activity of CDK2 ) can occur in the lung .	It was assumed that the individual relationships within canonical mechanisms (for example CDKN1A inhibiting the kinase activity of CDK2) can occur in the lung.	6	20	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK2	CDK2	CDK2	13	14	19	20
Cyclin E overexpression led to induction of p53 and upregulation of p21 , which partially abrogated cyclin E and Cdk2 kinase activity of the full-length form of cyclin E. Despite having the same levels of protein overexpression as the full-length form , the LMW forms of cyclin E had twofold greater associated kinase activity .	Cyclin E overexpression led to induction of p53 and upregulation of p21, which partially abrogated cyclin E and Cdk2 kinase activity of the full-length form of cyclin E. Despite having the same levels of protein overexpression as the full-length form, the LMW forms of cyclin E had twofold greater associated kinase activity.	5	21	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	11	12	19	20
p21 inhibits the activities of CDK2 in G 1 phase and CDK1 in G 2 / M phase , leading to cell cycle arrest at G 1 and G 2 phase 23 .	p21 inhibits the activities of CDK2 in G 1 phase and CDK1 in G 2 / M phase, leading to cell cycle arrest at G 1 and G 2 phase 23.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	5	6
CDKN1A inhibits the activity of CDK4/6 and CDK2 , the kinases responsible for the phosphorylation of the retinoblastoma ( Rb ) protein .	CDKN1A inhibits the activity of CDK4/6 and CDK2, the kinases responsible for the phosphorylation of the retinoblastoma (Rb) protein.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK2	CDK2	CDK2	0	1	7	8
P21 overexpression inhibits CDK2 activity , thus promoting the entry of cells into the G0/quiescent phase of the cell cycle [ XREF_BIBR ] .	P21 overexpression inhibits CDK2 activity, thus promoting the entry of cells into the G0/quiescent phase of the cell cycle [XREF_BIBR].	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21 overexpression	p21	CDK2	CDK2	cdk2	0	1	3	4
Accumulation of p53 in the cell induces the p21 mediated inhibition of cyclin D/cdk4 and cyclinE and cdk2 , resulting in cell cycle arrest in G1 .	Accumulation of p53 in the cell induces the p21 mediated inhibition of cyclin D/cdk4 and cyclinE and cdk2, resulting in cell cycle arrest in G1.	7	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	cdk2	cdk2	cdk2	8	9	17	18
As a member of the Cip and Kip family of CDK inhibitors , CDKN1A mediates p53 dependent cell-cycle arrest at the G 1 phase by inhibiting the activity of CDK2 and CDK1 ( also known as CDC2 ) .	As a member of the Cip and Kip family of CDK inhibitors, CDKN1A mediates p53 dependent cell-cycle arrest at the G 1 phase by inhibiting the activity of CDK2 and CDK1 (also known as CDC2).	13	31	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDKN1A	CDKN1A	CDKN1A	CDK2	CDK2	CDK2	13	14	29	30
Addition of PD98059 and SB202190 , inhibitors of ERK and p38 , respectively , decreased vanadate induced S phase arrest , reduced p21 levels , restored activation of p-cdk2 , and decreased p53 activity .	Addition of PD98059 and SB202190, inhibitors of ERK and p38, respectively, decreased vanadate induced S phase arrest, reduced p21 levels, restored activation of p-cdk2, and decreased p53 activity.	15	29	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	vanadate induced S phase arrest, reduced p21 levels	p21	p-cdk2	p-cdk2	p-cdk2	22	23	28	29
The expression of both p21 Cip1 and p27 Kip1 in vsmcs inactivates cdk2 and cdk4 [ XREF_BIBR ] .	The expression of both p21 Cip1 and p27 Kip1 in vsmcs inactivates cdk2 and cdk4 [XREF_BIBR].	1	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 Cip1	expression of both p21 Cip1	p21 cip1	cdk2	cdk2	cdk2	4	6	12	13
P21 causes growth arrest , usually in response to injurious stimuli , by inhibiting Cdk2 and halting the cell cycle at G1 .	P21 causes growth arrest, usually in response to injurious stimuli, by inhibiting Cdk2 and halting the cell cycle at G1.	0	15	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	P21	P21	P21	Cdk2	Cdk2	Cdk2	0	1	14	15
p21 can inhibit the kinase activity of Cdk2 , thereby preventing progression into or through the S phase [ XREF_BIBR ] .	p21 can inhibit the kinase activity of Cdk2, thereby preventing progression into or through the S phase [XREF_BIBR].	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	0	1	7	8
Low p27 Kip1 or p21 Waf1 and Cip1 levels also cause a reduction in Cdk2 concentration , inducing cell cycle arrest in G 1 phase and inhibiting EEF1B2 elongation factor , which blocks RNApol II transcription of Newcomb .	Low p27 Kip1 or p21 Waf1 and Cip1 levels also cause a reduction in Cdk2 concentration, inducing cell cycle arrest in G 1 phase and inhibiting EEF1B2 elongation factor, which blocks RNApol II transcription of Newcomb.	7	15	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	Cip1 levels	cip1	Cdk2	Cdk2	cdk2	7	8	14	15
p21 Cip belongs to the Cip and Kip family of inhibitors ( p21 Cip , p27 Kip1 and p57 Kip2 ) and primarily inhibits CDK2 .	p21 Cip belongs to the Cip and Kip family of inhibitors (p21 Cip, p27 Kip1 and p57 Kip2) and primarily inhibits CDK2.	0	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	24	25
Together with our findings demonstrating increased CD45RA : ERK association in myeloma cells , these results raise the possibility that CD45RA localized outside of lipid rafts attenuates K-ras-triggered ERK activation by facilitating CD45RA : galectin-1 : fibronectin interaction and thus induction of P21 , P27 and subsequent inhibition of CdK2 activity and myeloma cells growth inhibition .	Together with our findings demonstrating increased CD45RA : ERK association in myeloma cells, these results raise the possibility that CD45RA localized outside of lipid rafts attenuates K-ras-triggered ERK activation by facilitating CD45RA : galectin-1 : fibronectin interaction and thus induction of P21, P27 and subsequent inhibition of CdK2 activity and myeloma cells growth inhibition.	42	50	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	P21	P21	P21	CdK2	CdK2	CdK2	42	43	49	50
In the non cancer cell line NIH3T3 cells , circ-Foxo3 mainly interacted with p21 and CDK2 , facilitating the inhibition of CDK2 by p21 , and repressing cell cycle progression at the G1 stage .	In the non cancer cell line NIH3T3 cells, circ-Foxo3 mainly interacted with p21 and CDK2, facilitating the inhibition of CDK2 by p21, and repressing cell cycle progression at the G1 stage.	17	24	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	23	24	21	22
Inhibition of CycE and Cdk2 activation by p21 was included as a simple reverse Hill-function .	Inhibition of CycE and Cdk2 activation by p21 was included as a simple reverse Hill-function.	2	8	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	7	8	4	5
The cyclin dependent kinase ( CDK ) inhibitors p27Kip1 and p21Cip1 and Waf1 are members of the CIP and KIP family , which inhibit G1/S transition by binding and blocking activation of the CDK2 and cyclin E and CDK2 and cyclin A complexes .	The cyclin dependent kinase (CDK) inhibitors p27Kip1 and p21Cip1 and Waf1 are members of the CIP and KIP family, which inhibit G1/S transition by binding and blocking activation of the CDK2 and cyclin E and CDK2 and cyclin A complexes.	8	43	blocking	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Waf1	Waf1	waf1	CDK2	CDK2 and cyclin A complexes	cdk2	12	13	38	39
Although p21 and p27 are major inhibitors of Cdk2 , they also promote G1 progression by facilitating the assembly of cyclin D-Cdk4 and cyclin D-Cdk6 complexes [ XREF_BIBR , XREF_BIBR ] .	Although p21 and p27 are major inhibitors of Cdk2, they also promote G1 progression by facilitating the assembly of cyclin D-Cdk4 and cyclin D-Cdk6 complexes [XREF_BIBR, XREF_BIBR].	1	9	are major inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	1	2	8	9
As the name suggests , p21 is induced by p53 and inhibits the complex of cyclin E and CDK2 ( CCNE1 and CDK2 ) .	As the name suggests, p21 is induced by p53 and inhibits the complex of cyclin E and CDK2 (CCNE1 and CDK2).	5	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	5	6	18	19
These possibilities were combined with two different mechanisms for p21 dependent inhibition of Cdk2 activity , via complex formation or activation inhibition .	These possibilities were combined with two different mechanisms for p21 dependent inhibition of Cdk2 activity, via complex formation or activation inhibition.	9	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	9	10	13	14
Both p21 and p27 inhibit the activity of the cyclin D/CDK4 , cyclinE and CDK2 , and of cyclin A/CDK2 complexes , whereby the phosphorylation of pRb is blocked ., In addition , p21 also blocks DNA replication depending on proliferation cell nuclear antigen , resulting in G1 arrest [ XREF_BIBR ] .	Both p21 and p27 inhibit the activity of the cyclin D/CDK4, cyclinE and CDK2, and of cyclin A/CDK2 complexes, whereby the phosphorylation of pRb is blocked., In addition, p21 also blocks DNA replication depending on proliferation cell nuclear antigen, resulting in G1 arrest [XREF_BIBR].	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	1	2	14	15
The stabilization and accumulation of p53 results in increased transcription of targets such as p21 CIP1 and WAF1 that inhibits cyclinE and Cdk2 activity and results in G1 arrest [ XREF_BIBR , XREF_BIBR ] .	The stabilization and accumulation of p53 results in increased transcription of targets such as p21 CIP1 and WAF1 that inhibits cyclinE and Cdk2 activity and results in G1 arrest [XREF_BIBR, XREF_BIBR].	1	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WAF1	WAF1	WAF1	Cdk2	Cdk2	Cdk2	17	18	22	23
The increased p21Waf1 and Cip1 inhibited CDK2 .	The increased p21Waf1 and Cip1 inhibited CDK2.	2	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	Cip1	Cip1	CDK2	CDK2	CDK2	4	5	6	7
To our knowledge , the cyclin dependent kinase ( CDK ) inhibitor p21 ( also known as p21 WAF1 and Cip1 ) promotes cell cycle arrest by inhibiting CDK2 and CDK1 activity in response to many stimuli .	To our knowledge, the cyclin dependent kinase (CDK) inhibitor p21 (also known as p21 WAF1 and Cip1) promotes cell cycle arrest by inhibiting CDK2 and CDK1 activity in response to many stimuli.	4	31	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	12	13	28	29
p21 , in turn , suppresses Cdk2 , blocking NF-YA phosphorylation and releasing NF-YA from the IGF-1 promoter ( XREF_FIG and XREF_FIG ) .	p21, in turn, suppresses Cdk2, blocking NF-YA phosphorylation and releasing NF-YA from the IGF-1 promoter (XREF_FIG and XREF_FIG).	0	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	0	1	6	7
Using live cell imaging , a correlation appeared between the presence of 53BP1 NBs after RS and a p53 mediated increase of p21 , with high p21 levels inducing CDK2 inhibition and G1 arrest , while low p21 levels allow high CDK2 activity and S phase entry [ XREF_BIBR , XREF_BIBR ] .	Using live cell imaging, a correlation appeared between the presence of 53BP1 NBs after RS and a p53 mediated increase of p21, with high p21 levels inducing CDK2 inhibition and G1 arrest, while low p21 levels allow high CDK2 activity and S phase entry [XREF_BIBR, XREF_BIBR].	37	42	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21 levels	p21	CDK2	CDK2	cdk2	37	38	41	42
Fisetin increased WAF1 and p21 levels , suppressed cyclins E and D1 and inhibited the activities of CDK2 and CDK4 .	Fisetin increased WAF1 and p21 levels, suppressed cyclins E and D1 and inhibited the activities of CDK2 and CDK4.	0	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	Fisetin increased WAF1 and p21 levels	p21	CDK2	CDK2	cdk2	4	5	17	18
p21 ( p21 WAF1 and Cip1 ) , a protein transcriptionally regulated by p53 has been reported to inhibit CDK2 activity , leading to G1/S arrest .	p21 (p21 WAF1 and Cip1), a protein transcriptionally regulated by p53 has been reported to inhibit CDK2 activity, leading to G1/S arrest.	0	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	19	20
As p21 induction can also lead to the inhibition of Rb phosphorylation by inhibiting CDK2 and cyclin E activity , 22 we conclude that p21 mediated signaling pathway is involved in the LDM caused senescence .	As p21 induction can also lead to the inhibition of Rb phosphorylation by inhibiting CDK2 and cyclin E activity, 22 we conclude that p21 mediated signaling pathway is involved in the LDM caused senescence.	1	18	lead	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	1	2	14	15
Since p21 is believed to be a mediator of p53 , we speculated that the p21 mediated disruption of the cdk2 containing E2F and p130 complex plays a role in the growth suppression function of p53 .	Since p21 is believed to be a mediator of p53, we speculated that the p21 mediated disruption of the cdk2 containing E2F and p130 complex plays a role in the growth suppression function of p53.	15	21	disruption	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	cdk2	cdk2	cdk2	15	16	20	21
Further , these compounds when treated with A375 cells showed the characteristic features of apoptosis like enhancement in the levels of p53 , p21 and p27 inhibition of cyclin dependent kinase-2 ( CDK2 ) and suppression of NF-kappaB .	Further, these compounds when treated with A375 cells showed the characteristic features of apoptosis like enhancement in the levels of p53, p21 and p27 inhibition of cyclin dependent kinase-2 (CDK2) and suppression of NF-kappaB.	21	31	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	cyclin dependent kinase-2	cyclin dependent kinase-2	cyclin dependent kinase-2	23	24	28	31
While p21 inhibits CDK2 XREF_BIBR , it also plays essential positive roles by stabilizing cyclin D-CDK4 complexes and allowing their nuclear import XREF_BIBR , XREF_BIBR .	While p21 inhibits CDK2 XREF_BIBR, it also plays essential positive roles by stabilizing cyclin D-CDK4 complexes and allowing their nuclear import XREF_BIBR, XREF_BIBR.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	1	2	3	4
Likewise , CDK2 activity in SMIP treated cells was not rescued by knockdown of p27 and p21 ( data not shown ) .	Likewise, CDK2 activity in SMIP treated cells was not rescued by knockdown of p27 and p21 (data not shown).	2	17	rescued	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	16	17	2	3
Here we report for the first time that loss of CDK2 activity , by translational inhibition and through CDK2 inhibition by p21 ( Cip1 and Waf1 ) , may be responsible for endothelial senescence .	Here we report for the first time that loss of CDK2 activity, by translational inhibition and through CDK2 inhibition by p21 (Cip1 and Waf1), may be responsible for endothelial senescence.	18	25	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	21	22	18	19
p21 Is a Physiological Inhibitor of CDK2 .	p21 Is a Physiological Inhibitor of CDK2.	0	7	Is a Physiological Inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	6	7
During the G1/S transition , p53 activates transcription of p21 which , in turn , binds to and inhibits CDK2 , causing cell cycle arrest while the cell attempts to repair the DNA damage .	During the G1/S transition, p53 activates transcription of p21 which, in turn, binds to and inhibits CDK2, causing cell cycle arrest while the cell attempts to repair the DNA damage.	5	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p53 activates transcription of p21	p21	CDK2	CDK2	cdk2	9	10	19	20
We propose that during TNFalpha induced apoptosis , PKCdelta mediated phosphorylation of p21 ( WAF1 and CIP1 ) at ( 146 ) Ser attenuates the Cdk2 binding of p21 ( WAF1 and CIP1 ) and thereby upregulates Cdk2 activity .	We propose that during TNFalpha induced apoptosis, PKCdelta mediated phosphorylation of p21 (WAF1 and CIP1) at (146) Ser attenuates the Cdk2 binding of p21 (WAF1 and CIP1) and thereby upregulates Cdk2 activity.	8	26	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	PKCdelta mediated phosphorylation of p21 (WAF1 and CIP1) at (146) Ser	p21	Cdk2	Cdk2	cdk2	12	13	25	26
Cdkn1a inhibits cyclin dependent kinase 2 activity , contributing to the irreversible withdrawal from the cell cycle and terminal differentiation of myocytes [ XREF_BIBR ] .	Cdkn1a inhibits cyclin dependent kinase 2 activity, contributing to the irreversible withdrawal from the cell cycle and terminal differentiation of myocytes [XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdkn1a	Cdkn1a	Cdkn1a	cyclin dependent kinase 2	cyclin dependent kinase 2	cyclin dependent kinase 2	0	1	2	6
In addition , geraniol induced G1 phase cell cycle arrest in MIA PaCa-2 cells and elevated the expression levels of p21 Cip1 and p27 Kip1 but reduced those of cyclin A , cyclin B1 and CDK2 .	In addition, geraniol induced G1 phase cell cycle arrest in MIA PaCa-2 cells and elevated the expression levels of p21 Cip1 and p27 Kip1 but reduced those of cyclin A, cyclin B1 and CDK2.	3	36	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 Cip1	geraniol induced G1 phase cell cycle arrest in MIA PaCa-2 cells and elevated the expression levels of p21 Cip1	p21 cip1	CDK2	CDK2	cdk2	20	22	35	36
The decrease in Cdk1 activity could not be accounted for by corresponding changes in expression of either Cdk1 protein or cyclins A , B or E , suggesting that either p57 or p21 or both selectively inhibits Cdk1 , but not Cdk2 .	The decrease in Cdk1 activity could not be accounted for by corresponding changes in expression of either Cdk1 protein or cyclins A, B or E, suggesting that either p57 or p21 or both selectively inhibits Cdk1, but not Cdk2.	30	42	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	32	33	41	42
In unperturbed cycling cells , p21 CIP1 and WAF1 accumulates during G1 phase where it may promote cyclin-D/CDK4/6-dependent events and attenuates the activity of cyclin-E and CDK2 and cyclin-A and CDK2 .	In unperturbed cycling cells, p21 CIP1 and WAF1 accumulates during G1 phase where it may promote cyclin-D/CDK4/6-dependent events and attenuates the activity of cyclin-E and CDK2 and cyclin-A and CDK2.	6	27	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WAF1	WAF1	WAF1	CDK2	CDK2	CDK2	8	9	26	27
Although cdk2 kinase activity was higher in PLC/PRF/5 cells than that in HepG2 cells , the p21 WAF1 and CIP1 reduce cdk2 kinase activity by 20 % in both cells ( XREF_FIG ) .	Although cdk2 kinase activity was higher in PLC/PRF/5 cells than that in HepG2 cells, the p21 WAF1 and CIP1 reduce cdk2 kinase activity by 20% in both cells (XREF_FIG).	17	23	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIP1	CIP1	CIP1	cdk2	cdk2	cdk2	19	20	21	22
Furthermore , the main control mechanism of centromere duplication occurs through the CDK2 , where the kinase can be inhibited by p21 , which is a major p53 effector expressed at high levels in Lig4 -/- p53 p/p thymocytes .	Furthermore, the main control mechanism of centromere duplication occurs through the CDK2, where the kinase can be inhibited by p21, which is a major p53 effector expressed at high levels in Lig4 -/- p53 p/p thymocytes.	9	28	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	21	22	12	13
BTZ was previously reported to decrease the levels of CCND1 , CDK4 and CDK2 ( required for G1/S transition ) , while it increases those of p27 and p21 ( inhibitors of CDK2 ) [ XREF_BIBR , XREF_BIBR ] .	BTZ was previously reported to decrease the levels of CCND1, CDK4 and CDK2 (required for G1/S transition), while it increases those of p27 and p21 (inhibitors of CDK2) [XREF_BIBR, XREF_BIBR].	24	33	inhibitors	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	28	29	32	33
In conclusion , RhoA activation decreased p21Waf1 and Cip1 expression and increased basal and serum induced ornithine decarboxylase activity , Cdk2 expression , Cdk2 protein , and Cdk2 activity , leading to the stimulation of IEC proliferation and transformation .	In conclusion, RhoA activation decreased p21Waf1 and Cip1 expression and increased basal and serum induced ornithine decarboxylase activity, Cdk2 expression, Cdk2 protein, and Cdk2 activity, leading to the stimulation of IEC proliferation and transformation.	3	22	increased	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Cip1	RhoA activation decreased p21Waf1 and Cip1 expression	cip1	Cdk2	Cdk2 expression	cdk2	8	9	20	21
Because CDK2 activity is antagonized strongly by the CKIs of the Cip and Kip family , p21 Cip1 and p27 Kip1 , we tested the possibility that the greater CDK2 kinase activity observed in the presence of N1 in WT and p21 -/- cells was due to a lower level of CDK2 inhibition by decreased levels of p27 Kip1 .	Because CDK2 activity is antagonized strongly by the CKIs of the Cip and Kip family, p21 Cip1 and p27 Kip1, we tested the possibility that the greater CDK2 kinase activity observed in the presence of N1 in WT and p21 -/- cells was due to a lower level of CDK2 inhibition by decreased levels of p27 Kip1.	1	18	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21 Cip1	p21 Cip1	p21 Cip1	CDK2	CDK2	CDK2	16	18	1	2
p21 is an inhibitor of cdk2 , which is involved in G1-S transition XREF_BIBR , supporting the idea that modulation of genes that control cell cycle checkpoints might alter the program of differentiated cells and allow increased plasticity .	p21 is an inhibitor of cdk2, which is involved in G1-S transition XREF_BIBR, supporting the idea that modulation of genes that control cell cycle checkpoints might alter the program of differentiated cells and allow increased plasticity.	0	9	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p21	p21	p21	cdk2	cdk2	cdk2	0	1	5	6
At the G1/S transition , the decrease of free p21 levels is initiated via its sequestration by Cdk4-6 and cyclin D complexes priming Cdk2 and cyclin E activation [ XREF_BIBR ] .	At the G1/S transition, the decrease of free p21 levels is initiated via its sequestration by Cdk4-6 and cyclin D complexes priming Cdk2 and cyclin E activation [XREF_BIBR].	9	27	initiated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21 levels	p21	Cdk2	Cdk2	cdk2	9	10	23	24
p21 effectively inhibits Cdk2 , Cdk3 , Cdk4 , and Cdk6 kinases ( Ki 0.5-15 nM ) but is much less effective toward Cdc2 and cyclin B ( Ki approximately 400 nM ) and Cdk5 and p35 ( Ki > 2 microM ) , and does not associate with Cdk7 and cyclin H. Overexpression of P21 arrests cells in G1 .	p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6 kinases (Ki 0.5-15 nM) but is much less effective toward Cdc2 and cyclin B (Ki approximately 400 nM) and Cdk5 and p35 (Ki> 2 microM), and does not associate with Cdk7 and cyclin H. Overexpression of P21 arrests cells in G1.	0	45	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	0	1	3	4
p21 suppresses the kinase activity of CDK2 bonded to cyclin E and cyclin A in G1/S , and of CDK1-2 and cyclin A and CDK1 and cyclin B complexes activities required for G2/mitosis [ XREF_BIBR , XREF_BIBR ] .	p21 suppresses the kinase activity of CDK2 bonded to cyclin E and cyclin A in G1/S, and of CDK1-2 and cyclin A and CDK1 and cyclin B complexes activities required for G2/mitosis [XREF_BIBR, XREF_BIBR].	0	30	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	6	7
One possibility is that this switches off DNA replication in S-phase , while the major mechanism of action of p21 in the G2 arrest might be to inactivate CycB1-Cdk1 rather than Cdk2 .	One possibility is that this switches off DNA replication in S-phase, while the major mechanism of action of p21 in the G2 arrest might be to inactivate CycB1-Cdk1 rather than Cdk2.	17	32	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	19	20	31	32
p21 ( Waf1 and Cip1 ) inhibits CDK4/6 and CDK2 .	p21 (Waf1 and Cip1) inhibits CDK4/6 and CDK2.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	9	10
Taken together , these results suggest that different CDKs are inhibited by different mechanisms following UV induced DNA damage : Cdk2 is inhibited by the elevated level of p21 ; Cdk4 is inhibited by cooperation of p21 with other CDK inhibitors , like p27 , and possibly by phosphorylation ; and Cdc2 is inhibited by Thr 14 and Tyr 15 phosphorylation .	Taken together, these results suggest that different CDKs are inhibited by different mechanisms following UV induced DNA damage : Cdk2 is inhibited by the elevated level of p21; Cdk4 is inhibited by cooperation of p21 with other CDK inhibitors, like p27, and possibly by phosphorylation; and Cdc2 is inhibited by Thr-14 and Tyr-15 phosphorylation.	20	29	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	level of p21	p21	Cdk2	Cdk2	cdk2	28	29	20	21
We report here that exposure of human epithelial cells to ethanol , at concentration ( 100-200 mM ) that do not cause cell death , ( a ) does not affect or only reduces slightly the cellular level of p53 protein , ( b ) upregulates the transcription of the WAF1 and CIP1 gene , ( c ) inhibits the Cdk2 activity , and ( d ) reduces the rate of cellular proliferation by inducing a delay in G1 phase transition .	We report here that exposure of human epithelial cells to ethanol, at concentration (100-200 mM) that do not cause cell death, (a) does not affect or only reduces slightly the cellular level of p53 protein, (b) upregulates the transcription of the WAF1 and CIP1 gene, (c) inhibits the Cdk2 activity, and (d) reduces the rate of cellular proliferation by inducing a delay in G1 phase transition.	52	61	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIP1	CIP1	CIP1	Cdk2	Cdk2	Cdk2	52	53	60	61
Degradation of p21 in early S phase stimulates CDK2 activity , which , in turn , triggers key S phase events , including DNA replication initiation and inhibition of origin licensing [ XREF_BIBR , XREF_BIBR ] .	Degradation of p21 in early S phase stimulates CDK2 activity, which, in turn, triggers key S phase events, including DNA replication initiation and inhibition of origin licensing [XREF_BIBR, XREF_BIBR].	0	9	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	2	3	8	9
The p21 protein binds to and inhibits cdk2 kinase , causing G1 arrest .	The p21 protein binds to and inhibits cdk2 kinase, causing G1 arrest.	1	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	cdk2	cdk2	cdk2	1	2	7	8
According to such a notion , double knockdown of p21 and p27 in cells expressing D2NLS induced activation of CDK2 and CDC2 and BrdU incorporation to levels similar to those in cells expressing D1NLS .	According to such a notion, double knockdown of p21 and p27 in cells expressing D2NLS induced activation of CDK2 and CDC2 and BrdU incorporation to levels similar to those in cells expressing D1NLS.	7	24	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	9	10	19	20
At that point , Cdk2 is inactivated by p21 , but the subsequent phosphorylation of p21 at Y77 ( in human cells ) by different tyrosine kinases induce , similarly to p27 , a reduction of the capability to inhibit Cdk2 [ XREF_BIBR ] .	At that point, Cdk2 is inactivated by p21, but the subsequent phosphorylation of p21 at Y77 (in human cells) by different tyrosine kinases induce, similarly to p27, a reduction of the capability to inhibit Cdk2 [XREF_BIBR].	4	9	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	8	9	4	5
In summary , we have demonstrated that DNA damage by Pt based antitumour agents induces p21 dependent inhibition of G1-phase Cdk4 and cyclin D and Cdk2 and cyclin E activity that is associated with an ~ 150kDa increase in the molecular size of the Cdk complex .	In summary, we have demonstrated that DNA damage by Pt based antitumour agents induces p21 dependent inhibition of G1-phase Cdk4 and cyclin D and Cdk2 and cyclin E activity that is associated with an ~ 150kDa increase in the molecular size of the Cdk complex.	15	29	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	15	16	25	26
The production of CDK2 which is negatively regulated by p21 and p27 was significantly downregulated after PEG10 silencing .	The production of CDK2 which is negatively regulated by p21 and p27 was significantly downregulated after PEG10 silencing.	1	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	9	10	3	4
Treatment with TQ in HCT-116 cells has been found to lead to G1 arrest associated with up-regulation of p21 WAF1 cells which blocks CDK2 activity and possibly CDK4 and CDK6 activities which were suggested the principal transcriptional target of p53 in the context of the G1 checkpoint [ XREF_BIBR ] .	Treatment with TQ in HCT-116 cells has been found to lead to G1 arrest associated with up-regulation of p21 WAF1 cells which blocks CDK2 activity and possibly CDK4 and CDK6 activities which were suggested the principal transcriptional target of p53 in the context of the G1 checkpoint [XREF_BIBR].	16	24	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 WAF1	p21 WAF1	p21 WAF1	CDK2	CDK2	CDK2	18	20	23	24
The three CDK inhibitors ( CKIs ) p21 CIP1 and WAF1 , p27 KIP1 and p57 KIP2 attenuate CDK2 activity .	The three CDK inhibitors (CKIs) p21 CIP1 and WAF1, p27 KIP1 and p57 KIP2 attenuate CDK2 activity.	8	19	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WAF1	WAF1	WAF1	CDK2	CDK2	CDK2	10	11	18	19
The p21 protein binds to and inhibits the activity of CDK1 , CDK2 , and CDK4/6 complexes , and thus functions as a regulator of cell cycle progression at G 1 and S phases [ XREF_BIBR ] .	The p21 protein binds to and inhibits the activity of CDK1, CDK2, and CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at G 1 and S phases [XREF_BIBR].	1	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	1	2	12	13
Alternatively , CDKN1A can inhibit CDK2 , which leads to suppression of E2F dependent transcripts , downregulation of components of the DNA synthesis machinery and reduced firing at origins of replication [ XREF_BIBR ] .	Alternatively, CDKN1A can inhibit CDK2, which leads to suppression of E2F dependent transcripts, downregulation of components of the DNA synthesis machinery and reduced firing at origins of replication [XREF_BIBR].	2	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK2	CDK2	CDK2	2	3	5	6
The Cdk inhibitor p21 and p27 does not inhibit the activity of cyclin D/Cdk4-6 , but inhibits the activity of Cdk1 and Cdk2 .	The Cdk inhibitor p21 and p27 does not inhibit the activity of cyclin D/Cdk4-6, but inhibits the activity of Cdk1 and Cdk2.	0	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	3	4	22	23
However , Cdk2 is inhibited by the CDK inhibitor p21 after occurrence of DNA damage ( Bartek & Lukas , 2001 ) .	However, Cdk2 is inhibited by the CDK inhibitor p21 after occurrence of DNA damage (Bartek & Lukas, 2001).	2	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	9	10	2	3
The protein p53 then initiates the transcription of p21 gene , which inhibits the cyclin dependent kinases Cdk2 and Cdk4 and consequent arrests the cell cycle .	The protein p53 then initiates the transcription of p21 gene, which inhibits the cyclin dependent kinases Cdk2 and Cdk4 and consequent arrests the cell cycle.	2	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p53 then initiates the transcription of p21	p21	Cdk2	Cdk2	cdk2	8	9	17	18
In case of cell cycle regulation , it has been reported that p21 induces G0/G1 arrest by inhibiting CDK2 activity and G2/M arrest by blocking CDK1 activity [ XREF_BIBR ] .	In case of cell cycle regulation, it has been reported that p21 induces G0/G1 arrest by inhibiting CDK2 activity and G2/M arrest by blocking CDK1 activity [XREF_BIBR].	12	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	12	13	18	19
This enhanced the interaction of p21 with CDK2 allowing for a more efficient inhibition of CDK2 by p21 .	This enhanced the interaction of p21 with CDK2 allowing for a more efficient inhibition of CDK2 by p21.	8	18	allowing	Positive_activation_syntax_3_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	17	18	15	16
XREF_BIBR - XREF_BIBR Iron chelators have been shown to induce the expression of p21 , XREF_BIBR , XREF_BIBR which can inhibit CDK2 .	XREF_BIBR - XREF_BIBR Iron chelators have been shown to induce the expression of p21, XREF_BIBR, XREF_BIBR which can inhibit CDK2.	3	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	Iron chelators have been shown to induce the expression of p21	p21	CDK2	CDK2	cdk2	13	14	21	22
In response to DNA damage or metabolic stress , the p53 protein can transcriptionally activate p21 , which in turn inhibits both CDK2 and CDK4 activities , and therefore G1 arrest in mammalian cells 29 .	In response to DNA damage or metabolic stress, the p53 protein can transcriptionally activate p21, which in turn inhibits both CDK2 and CDK4 activities, and therefore G1 arrest in mammalian cells 29.	14	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	15	16	22	23
Expression of p21 , which is located downstream of p53 , was remarkably reduced in the immortalized cells , resulting in increased cdk2 and cdc2 kinase activity .	Expression of p21, which is located downstream of p53, was remarkably reduced in the immortalized cells, resulting in increased cdk2 and cdc2 kinase activity.	0	26	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	Expression of p21	p21	cdk2	cdk2	cdk2	2	3	22	23
In contrast , when P21 inhibits CDK2 and CDK4 , RB becomes dephosphorylated ( producing the active form ) , and the cells are switched to a nonproliferative state .	In contrast, when P21 inhibits CDK2 and CDK4, RB becomes dephosphorylated (producing the active form), and the cells are switched to a nonproliferative state.	4	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21	P21	CDK2	CDK2	CDK2	4	5	6	7
On the other hand , p21 ( also known as p21 WAF1 and Cip1 ) , a key transcriptional target of p53 , causes G1 cell cycle arrest and inhibits the activity of CDK2 and CDK1 .	On the other hand, p21 (also known as p21 WAF1 and Cip1), a key transcriptional target of p53, causes G1 cell cycle arrest and inhibits the activity of CDK2 and CDK1.	5	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	5	6	33	34
The dependence of cisplatin cytotoxicity on cdk2 activity was also demonstrated because 1 ) cisplatin caused a marked increase in cdk2 activity , which was prevented by the p21 expression adenovirus , and 2 ) a cdk2 dominant negative adenovirus also protected cells from cisplatin induced apoptosis .	The dependence of cisplatin cytotoxicity on cdk2 activity was also demonstrated because 1) cisplatin caused a marked increase in cdk2 activity, which was prevented by the p21 expression adenovirus, and 2) a cdk2 dominant negative adenovirus also protected cells from cisplatin induced apoptosis.	20	33	prevented	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	cdk2	cdk2	cdk2	28	29	20	21
RPL31 has been shown to suppress cell growth and cycling via p53 signalling 48 ; induction of p21 by p53 following DNA damage inhibited CDK2 activity 49 .	RPL31 has been shown to suppress cell growth and cycling via p53 signalling 48; induction of p21 by p53 following DNA damage inhibited CDK2 activity 49.	15	25	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	17	18	24	25
In addition , phosphorylation of p21 ( Cip1 ) at Thr 145 decreases the binding of the cyclin dependent kinases Cdk2 and Cdk4 to p21 ( Cip1 ) and attenuates the Cdk2 inhibitory activity of p21 ( Cip1 ) .	In addition, phosphorylation of p21 (Cip1) at Thr 145 decreases the binding of the cyclin dependent kinases Cdk2 and Cdk4 to p21 (Cip1) and attenuates the Cdk2 inhibitory activity of p21 (Cip1).	3	22	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	phosphorylation of p21 (Cip1) at Thr 145	cip1	Cdk2	Cdk2	cdk2	7	8	20	21
XREF_BIBR CDKN1A and p21 CIP1 and CDKN1B and p27 KIP1 block the activity of CDK2 and CDK1 that control the G 1 / S and G 2 / M transitions , respectively .	XREF_BIBR CDKN1A and p21 CIP1 and CDKN1B and p27 KIP1 block the activity of CDK2 and CDK1 that control the G 1 / S and G 2 / M transitions, respectively.	0	16	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK2	CDK2	CDK2	1	2	14	15
Cdkn1a inhibits the kinase activity of cyclin : Cdk2 complexes .	Cdkn1a inhibits the kinase activity of cyclin : Cdk2 complexes.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdkn1a	Cdkn1a	Cdkn1a	Cdk2	Cdk2	Cdk2	0	1	8	9
ATR , ATM , CHEK1 and CHEK2 phosphorylate p53 that mediates the maintenance of G1/S arrest through the activation of cyclin dependent kinase inhibitor 1A ( p21 ) , which in turns inhibits Cdk4/6-Cyclin-D and Cdk2 and Cyclin-E [ XREF_BIBR , XREF_BIBR ] .	ATR, ATM, CHEK1 and CHEK2 phosphorylate p53 that mediates the maintenance of G1/S arrest through the activation of cyclin dependent kinase inhibitor 1A (p21), which in turns inhibits Cdk4/6-Cyclin-D and Cdk2 and Cyclin-E [XREF_BIBR, XREF_BIBR].	24	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	26	27	35	36
After phosphorylation and activation by Chk2 , p53 induces the expression of p21 , a well-known cyclin dependent kinase inhibitors ( CDKI ) that inactivates cyclin dependent kinase 2 ( CDK2 ) to prevent G1/S phase progression .	After phosphorylation and activation by Chk2, p53 induces the expression of p21, a well-known cyclin dependent kinase inhibitors (CDKI) that inactivates cyclin dependent kinase 2 (CDK2) to prevent G1/S phase progression.	7	30	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p53 induces the expression of p21	p21	cyclin dependent kinase 2	cyclin dependent kinase 2	cyclin dependent kinase 2	12	13	25	29
As illustrated in XREF_FIG , through cellular events triggered by genomic stress , stimulated p53 transactivates p21 , which , in turn , inhibits CDK2 and cyclin E and thereby retains Rb ( Retinoblastoma ) in an inactive unphosphorylated state .	As illustrated in XREF_FIG, through cellular events triggered by genomic stress, stimulated p53 transactivates p21, which, in turn, inhibits CDK2 and cyclin E and thereby retains Rb (Retinoblastoma) in an inactive unphosphorylated state.	15	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	16	17	24	25
Shh [ + ] cells sustain CDK2 activity even in the presence of p21 Cip1 , although the undetectable levels of CDK2 kinase activity in controls make conclusions about relative impact of Shh on p21 Cip1 inhibition of CDK2 difficult .	Shh [+] cells sustain CDK2 activity even in the presence of p21 Cip1, although the undetectable levels of CDK2 kinase activity in controls make conclusions about relative impact of Shh on p21 Cip1 inhibition of CDK2 difficult.	34	39	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21 Cip1	p21 Cip1	p21 Cip1	CDK2	CDK2	CDK2	34	36	38	39
BCCIPalpha binds to p21 ( Cip1 / Waf-1 and mda-6 ) and enhances p21 mediated Cdk2 kinase inhibition .	BCCIPalpha binds to p21 (Cip1 / Waf-1 and mda-6) and enhances p21 mediated Cdk2 kinase inhibition.	12	17	mediated	Positive_early_activation	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	13	14	15	16
Interestingly , CDK2 , which is inhibited by p21 and facilitates G1/S phase transition , was upregulated after treatment with quercetin aglycone or PAC DP-9 in both SKOV-3 and OVCAR-8 cells .	Interestingly, CDK2, which is inhibited by p21 and facilitates G1/S phase transition, was upregulated after treatment with quercetin aglycone or PAC DP-9 in both SKOV-3 and OVCAR-8 cells.	2	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	8	9	2	3
We also observed that PDE3A-deficiency , via increased cAMP signaling and PKA induced phosphorylation and activation of CREB , was associated with increased expression of the Cdk inhibitor protein , p21 cip , which is known to inactivate both Cdk2 and Cdk4 , thereby promoting G 0 / G 1 cell cycle arrest .	We also observed that PDE3A-deficiency, via increased cAMP signaling and PKA induced phosphorylation and activation of CREB, was associated with increased expression of the Cdk inhibitor protein, p21 cip, which is known to inactivate both Cdk2 and Cdk4, thereby promoting G 0 / G 1 cell cycle arrest.	30	41	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	30	31	39	40
Concerning inhibitory interactions , our inference predicts a strong inhibition of CDK2 by p21 , with edge weight .	Concerning inhibitory interactions, our inference predicts a strong inhibition of CDK2 by p21, with edge weight.	6	14	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	13	14	11	12
P21 , as a Cdk inhibitor , may also directly inhibit Cdk2 , Cdk3 , Cdk4 , and Cdk6 activity [ XREF_BIBR ] .	P21, as a Cdk inhibitor, may also directly inhibit Cdk2, Cdk3, Cdk4, and Cdk6 activity [XREF_BIBR].	0	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21	P21	Cdk2	Cdk2	Cdk2	0	1	11	12
For example , under some conditions , PC1 interacts with PC2 and JAK2 to positively regulate the JAK-STAT pathway ; this induces p21 , which inhibits Cdk2 , leading to cell cycle arrest [ XREF_BIBR ] .	For example, under some conditions, PC1 interacts with PC2 and JAK2 to positively regulate the JAK-STAT pathway; this induces p21, which inhibits Cdk2, leading to cell cycle arrest [XREF_BIBR].	21	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	22	23	26	27
As a result , the inhibition of CDK2 by p21 and p27 is reduced .	As a result, the inhibition of CDK2 by p21 and p27 is reduced.	5	11	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	9	10	7	8
Essentially , p21 may antagonize CDK2 to block its apoptotic signaling , Interestingly , there is a novel feedback mechanism whereby CDK2 may phosphorylate p21 to block its inhibitory effect on CDKs , Therefore , the fine balance between p21 and CDK2 plays an important role in determining cell death or survival in cisplatin-AKI .	Essentially, p21 may antagonize CDK2 to block its apoptotic signaling, Interestingly, there is a novel feedback mechanism whereby CDK2 may phosphorylate p21 to block its inhibitory effect on CDKs, Therefore, the fine balance between p21 and CDK2 plays an important role in determining cell death or survival in cisplatin-AKI.	2	6	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	2	3	5	6
Using purified , full-length proteins of known concentration ( determined by absorbance ) and cyclin A-Cdk2 of known activity ( calibrated with staurosporine ) , we find that a 1:1 molar ratio of p21 to cyclin A-Cdk2 is able to inhibit Cdk2 activity both in the binary cyclin A and Cdk2 complex and in the presence of proliferating cell nuclear antigen ( PCNA ) .	Using purified, full-length proteins of known concentration (determined by absorbance) and cyclin A-Cdk2 of known activity (calibrated with staurosporine), we find that a 1:1 molar ratio of p21 to cyclin A-Cdk2 is able to inhibit Cdk2 activity both in the binary cyclin A and Cdk2 complex and in the presence of proliferating cell nuclear antigen (PCNA).	31	42	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	33	34	41	42
24 Although p21 and p27 potently inhibit CDK2 , they stabilize cyclin D-CDK4/6 complexes and target them to nuclei , but they can also inhibit CDK4/6 activity .	24 Although p21 and p27 potently inhibit CDK2, they stabilize cyclin D-CDK4/6 complexes and target them to nuclei, but they can also inhibit CDK4/6 activity.	2	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	2	3	7	8
Cdk2 inhibition by p21 is the likely limit for centriole reduplication , because inhibition of Cdk1 activity alone promotes supernumerary centriole assembly during G2 .	Cdk2 inhibition by p21 is the likely limit for centriole reduplication, because inhibition of Cdk1 activity alone promotes supernumerary centriole assembly during G2.	0	4	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	3	4	0	1
Conversely , DNA damage shuts down E2f target gene expression by promoting RB dephosphorylation , mediated in part through induction of p53 dependent expression of p21 , which binds to and represses CDK2 activity XREF_BIBR , and also through the activation of protein phosphatase 2A ( PP2A ) XREF_BIBR , XREF_BIBR .	Conversely, DNA damage shuts down E2f target gene expression by promoting RB dephosphorylation, mediated in part through induction of p53 dependent expression of p21, which binds to and represses CDK2 activity XREF_BIBR, and also through the activation of protein phosphatase 2A (PP2A) XREF_BIBR, XREF_BIBR.	23	34	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	expression of p21	p21	CDK2	CDK2	cdk2	25	26	32	33
In the present study , NCL1 significantly increased p21 WAF1 and p27 KIP protein expression , and decreased CDK2 , CDK4 and cyclin D1 in LNCaP cells in concentrations within their cytotoxic ranges .	In the present study, NCL1 significantly increased p21 WAF1 and p27 KIP protein expression, and decreased CDK2, CDK4 and cyclin D1 in LNCaP cells in concentrations within their cytotoxic ranges.	5	23	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 WAF1	NCL1 significantly increased p21 WAF1 and p27 KIP protein expression	p21 waf1	CDK2	CDK2	cdk2	8	10	18	19
Concomitantly , IR induced the robust expression of p21 and suppressed Cdk2 and cyclin E activity , which might involve in the initiation of G1 checkpoint .	Concomitantly, IR induced the robust expression of p21 and suppressed Cdk2 and cyclin E activity, which might involve in the initiation of G1 checkpoint.	2	15	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	IR induced the robust expression of p21	p21	Cdk2	Cdk2	cdk2	8	9	11	12
Given that p21 is a well-known inhibitor of CDK2 , a kinase required for the transition from G1 to S phase , we next sought to determine whether CDK2 protein levels were down-regulated following the induction of p21 in cells with CUL4B , DDB1 or DCAF11 knock down .	Given that p21 is a well-known inhibitor of CDK2, a kinase required for the transition from G1 to S phase, we next sought to determine whether CDK2 protein levels were down-regulated following the induction of p21 in cells with CUL4B, DDB1 or DCAF11 knock down.	2	9	is a well-known inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	2	3	8	9
HBx can repress the transcription of p21 WAF1 and p16 INK4A , leading to increase the rate and level of activation of the CDK2 and CDK4 .	HBx can repress the transcription of p21 WAF1 and p16 INK4A, leading to increase the rate and level of activation of the CDK2 and CDK4.	0	25	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21 WAF1	HBx can repress the transcription of p21 WAF1	p21 waf1	CDK2	CDK2	cdk2	6	8	23	24
In conclusion , these data suggest that BJ-601 inhibits HDMVECs proliferation by increasing the level of p21 protein , which in turn inhibits CDK2 kinase activity , and finally causes retardation of the cell cycle at the G0/G1 phase .	In conclusion, these data suggest that BJ-601 inhibits HDMVECs proliferation by increasing the level of p21 protein, which in turn inhibits CDK2 kinase activity, and finally causes retardation of the cell cycle at the G0/G1 phase.	16	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	16	17	23	24
CDKN1A represses CDK2 and cyclin activity by simultaneously binding to the ' cyclin groove ' on cyclin and ATP binding pocket on CDK2 [ XREF_BIBR , XREF_BIBR ] , which suggests that CDKN1A has an effect similar to that of an antagonist of CDK2 ' s kinase activity .	CDKN1A represses CDK2 and cyclin activity by simultaneously binding to the ' cyclin groove ' on cyclin and ATP binding pocket on CDK2 [XREF_BIBR, XREF_BIBR], which suggests that CDKN1A has an effect similar to that of an antagonist of CDK2 's kinase activity.	0	5	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK2	CDK2	CDK2	0	1	2	3
In conclusion , these data suggest that progesterone inhibits RASMCs proliferation by increasing the levels of p21 and p27 protein , which in turn inhibit CDK2 kinase activity , and finally interrupt the cell cycle .	In conclusion, these data suggest that progesterone inhibits RASMCs proliferation by increasing the levels of p21 and p27 protein, which in turn inhibit CDK2 kinase activity, and finally interrupt the cell cycle.	16	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	16	17	25	26
p21 directly inhibits CDK2 and plays a pivotal role in p53 induced cell cycle arrest .	p21 directly inhibits CDK2 and plays a pivotal role in p53 induced cell cycle arrest.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	3	4
However , in p53-proficient cells subjected to DNA damage , Cdk2 is inactivated by the CDK inhibitor p21 .	However, in p53-proficient cells subjected to DNA damage, Cdk2 is inactivated by the CDK inhibitor p21.	10	18	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	17	18	10	11
In conjunction with this observation , our results provide evidence for the critical role of p21 mediated Cdk2 inhibition in DNA damage induced cell cycle exit in G2 .	In conjunction with this observation, our results provide evidence for the critical role of p21 mediated Cdk2 inhibition in DNA damage induced cell cycle exit in G2.	13	18	mediated	Positive_early_activation	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	15	16	17	18
This classification may be overly simplistic , as while p21 Cip1 can inhibit CDK2 complexes , p21 Cip1 is conversely important for promoting formation , activation and nuclear enrichment of CDK4/6-cyclin D complexes [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	This classification may be overly simplistic, as while p21 Cip1 can inhibit CDK2 complexes, p21 Cip1 is conversely important for promoting formation, activation and nuclear enrichment of CDK4/6-cyclin D complexes [XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR].	9	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 Cip1	p21 Cip1	p21 Cip1	CDK2	CDK2	CDK2	9	11	13	14
As p21 inhibits CDK2 and regulates proliferation , we examined CDK2 activity in B6/lpr-p 21tg T cells after secondary stimulation ; at 24h post-stimulation , we found reduced CDK2 activity in B6/lpr-p 21tg T cells ( XREF_FIG ) , which could account for their decreased expansion .	As p21 inhibits CDK2 and regulates proliferation, we examined CDK2 activity in B6/lpr-p 21tg T cells after secondary stimulation; at 24h post-stimulation, we found reduced CDK2 activity in B6/lpr-p 21tg T cells (XREF_FIG), which could account for their decreased expansion.	1	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	1	2	3	4
Each of these observations was consistent with the working model that p21 inhibition of Cdk2 activity suppressed G1/S phase transition .	Each of these observations was consistent with the working model that p21 inhibition of Cdk2 activity suppressed G1/S phase transition.	11	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	11	12	14	15
On the other hand , p21 could inhibit the kinase activity of complexes contain CDK2 , CDK4 , and CDK6 , p27 could inhibit the activity of CCNE1-CDK2 and cyclin D-CDK4 , which may explain , in part , why the process of G1 phase to S phase accelerated by degradation of p21 and p27 induced by HBP1 .	On the other hand, p21 could inhibit the kinase activity of complexes contain CDK2, CDK4, and CDK6, p27 could inhibit the activity of CCNE1-CDK2 and cyclin D-CDK4, which may explain, in part, why the process of G1 phase to S phase accelerated by degradation of p21 and p27 induced by HBP1.	5	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	5	6	14	15
Some studies suggest that E7 does not prevent p21 mediated inhibition of cyclins and Cdk2 activity but work down-stream by activating E2F1 .	Some studies suggest that E7 does not prevent p21 mediated inhibition of cyclins and Cdk2 activity but work down-stream by activating E2F1.	8	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	8	9	14	15
Simultaneous induction of p21 Waf1 and Cip1 and p16 Ink4a expression cooperatively blocks the activation of CDK4/6 and CDK2 , the key regulators of G 1 / S and G 2 / M checkpoints .	Simultaneous induction of p21 Waf1 and Cip1 and p16 Ink4a expression cooperatively blocks the activation of CDK4/6 and CDK2, the key regulators of G 1 / S and G 2 / M checkpoints.	6	19	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	Cip1 and p16 Ink4a expression	cip1	CDK2	CDK2	cdk2	6	7	18	19
The sustained activations of B-Raf and p42 ( MAPkinase ) were for more than 5 h. Treatment of PC12 cells with NGF increased p21 ( Cip1 and WAF-1 ) expression , reduced cdk2 activity and inhibited DNA synthesis , the opposite to the effects of NGF treatment of hepatocytes .	The sustained activations of B-Raf and p42 (MAPkinase) were for more than 5 h. Treatment of PC12 cells with NGF increased p21 (Cip1/WAF-1) expression, reduced cdk2 activity and inhibited DNA synthesis, the opposite to the effects of NGF treatment of hepatocytes.	21	35	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	NGF increased p21 (Cip1/WAF-1) expression	p21	cdk2	cdk2	cdk2	23	24	32	33
Expression of p16 ( Ink4a ) , p21 ( Waf1 ) , or p27 ( Kip1 ) in both SiHa and A431 cells strongly inhibited CDK2 activity , indicating functional expression of the CDK inhibitors in both cell lines .	Expression of p16 (Ink4a), p21 (Waf1), or p27 (Kip1) in both SiHa and A431 cells strongly inhibited CDK2 activity, indicating functional expression of the CDK inhibitors in both cell lines.	0	26	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	Expression of p16 (Ink4a), p21	p21	CDK2	CDK2	cdk2	7	8	25	26
Following CLA treatment , p21 associated with and inhibited CDK4 and CDK2 , and this correlated with reduced phosphorylation of retinoblastoma proteins .	Following CLA treatment, p21 associated with and inhibited CDK4 and CDK2, and this correlated with reduced phosphorylation of retinoblastoma proteins.	4	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	4	5	11	12
The expression of p27 ( Kip1 ) and p21 ( Cip1 ) in serum stimulated VSMCs inactivated cdk2 and cdk4 , leading to G ( 1 ) growth arrest .	The expression of p27 (Kip1) and p21 (Cip1) in serum stimulated VSMCs inactivated cdk2 and cdk4, leading to G (1) growth arrest.	1	19	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	expression of p27 (Kip1) and p21	p21	cdk2	cdk2	cdk2	8	9	17	18
In the case of DNA damages , p53 is activated and increases the level of p21 that is directly inhibiting cdk2 .	In the case of DNA damages, p53 is activated and increases the level of p21 that is directly inhibiting cdk2.	7	21	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p53 is activated and increases the level of p21	p21	cdk2	cdk2	cdk2	15	16	20	21
p21 inhibits cdk2 and cell cycle entry or cdk1 and mitosis progression , 28 for instance in response to DNA damage .	p21 inhibits cdk2 and cell cycle entry or cdk1 and mitosis progression, 28 for instance in response to DNA damage.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	cdk2	cdk2	cdk2	0	1	2	3
XREF_FIG B and C , Rb -/-; p21 -/- cells at high densities downregulated CDK2 activity to wild-type levels .	XREF_FIG B and C, Rb -/-; p21 -/- cells at high densities downregulated CDK2 activity to wild-type levels.	1	15	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	7	8	14	15
These results suggested that the increasing P53 upregulated P21 expression and downregulated the interaction of CDK2 and cyclin E and subsequently induced G1 phase arrest in cultured HUVECs from preeclampsia pregnancies .	These results suggested that the increasing P53 upregulated P21 expression and downregulated the interaction of CDK2 and cyclin E and subsequently induced G1 phase arrest in cultured HUVECs from preeclampsia pregnancies.	6	18	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P53 upregulated P21 expression	p21	CDK2	CDK2	cdk2	8	9	15	16
The protein p21 interacts with complexes of CDK2 and cyclin A or cyclin E and thereby inhibits the activity of CDK2 , preventing progression of cell cycle XREF_BIBR .	The protein p21 interacts with complexes of CDK2 and cyclin A or cyclin E and thereby inhibits the activity of CDK2, preventing progression of cell cycle XREF_BIBR.	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	2	3	20	21
Because of this initial interaction , p21 accumulates and , later in G1 , inhibits CDK2 , independent of SCML2 .	Because of this initial interaction, p21 accumulates and, later in G1, inhibits CDK2, independent of SCML2.	6	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	6	7	15	16
It has been hypothesized that the resulting upregulation of p21 WAF1 blocks cdk2 activity and possibly cdk4 and cdk6 activities leading to G1 arrest .	It has been hypothesized that the resulting upregulation of p21 WAF1 blocks cdk2 activity and possibly cdk4 and cdk6 activities leading to G1 arrest.	9	13	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 WAF1	p21 WAF1	p21 WAF1	cdk2	cdk2	cdk2	9	11	12	13
The tumor suppressor protein , p53 , regulates the cell cycle , and its target gene , p21 , directly inhibits cyclin D1 and CDK2 .	The tumor suppressor protein, p53, regulates the cell cycle, and its target gene, p21, directly inhibits cyclin D1 and CDK2.	15	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	17	18	24	25
Because p21 inhibits Cdk2 by physical interaction , we examined whether the OGF induced downregulation of Cdk2 kinase activity was based on p21 and Cdk2 complex formation .	Because p21 inhibits Cdk2 by physical interaction, we examined whether the OGF induced downregulation of Cdk2 kinase activity was based on p21 and Cdk2 complex formation.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	1	2	3	4
Increased p21 will inhibit Cdk2 activity and arrest the cells at G0/G1 phase of the cell cycle .	Increased p21 will inhibit Cdk2 activity and arrest the cells at G0/G1 phase of the cell cycle.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	1	2	4	5
XREF_BIBR In the mouse fibroblast NIH3T3 cell line , circ-Foxo3 interacts with both p21 and CDK2 , facilitating the inhibition of CDK2 by p21 , and repressing cell cycle progression at the G1 stage .	XREF_BIBR In the mouse fibroblast NIH3T3 cell line, circ-Foxo3 interacts with both p21 and CDK2, facilitating the inhibition of CDK2 by p21, and repressing cell cycle progression at the G1 stage.	17	24	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	23	24	21	22
High p21 levels are required to inhibit CDK2 activity .	High p21 levels are required to inhibit CDK2 activity.	1	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21 levels	p21	CDK2	CDK2	cdk2	1	2	7	8
Meanwhile , SMIPs upregulated p21 , inhibited CDK2 activity , induced G1 delay and cell cycle arrest .	Meanwhile, SMIPs upregulated p21, inhibited CDK2 activity, induced G1 delay and cell cycle arrest.	4	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	4	5	7	8
Elevated expression of p21 inhibited Cdk2 activity , preventing cells from entering S phase .	Elevated expression of p21 inhibited Cdk2 activity, preventing cells from entering S phase.	1	6	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	expression of p21	p21	Cdk2	Cdk2	cdk2	3	4	5	6
The cell cycle progression into the S phase requires the enzyme cdk2 , which is inhibited by p21 .	The cell cycle progression into the S phase requires the enzyme cdk2, which is inhibited by p21.	8	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	cdk2	cdk2	cdk2	17	18	11	12
BCCIPalpha binds to p21 and enhances p21 mediated inhibition of Cdk2 kinase .	BCCIPalpha binds to p21 and enhances p21 mediated inhibition of Cdk2 kinase.	6	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	6	7	10	11
By associating with cyclin A-CDK2 complexes , p21 and p27 limited the kinase activity of CDK2 .	By associating with cyclin A-CDK2 complexes, p21 and p27 limited the kinase activity of CDK2.	7	16	limited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	7	8	15	16
P21 generally induces S-phase cell cycle arrest by inhibiting CDK2 activity [ XREF_BIBR - XREF_BIBR ] which , together with cyclin A , is necessary for the progression of cells through the S phase [ XREF_BIBR ] ; inactivation of cyclin A/CDK2 complexes prevents progression beyond the S phase checkpoint .	P21 generally induces S-phase cell cycle arrest by inhibiting CDK2 activity [XREF_BIBR - XREF_BIBR] which, together with cyclin A, is necessary for the progression of cells through the S phase [XREF_BIBR]; inactivation of cyclin A/CDK2 complexes prevents progression beyond the S phase checkpoint.	0	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	P21	P21	P21	CDK2	CDK2	CDK2	0	1	9	10
The oncoprotein cyclin D1 binds to and activates cyclin dependent kinase 4 ( cdk4 ) , whose activity is inhibited by p16INK4 , the product of the putative tumor suppressor gene MTS1 .	The oncoprotein cyclin D1 binds to and activates cyclin dependent kinase 4 (cdk4), whose activity is inhibited by p16INK4, the product of the putative tumor suppressor gene MTS1.	8	24	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	p16INK4	p16INK4	p16INK4	cdk4	cdk4	cdk4	21	22	13	14
On one hand , p15 Ink4b and p16 Ink4a ( called Ink4 hereafter ) inhibit the formation of the cyclin dependent kinases ( CDK4 and CDK6 ) and cyclinD complexes during the G1 phase of the cell cycle .	On one hand, p15 Ink4b and p16 Ink4a (called Ink4 hereafter) inhibit the formation of the cyclin dependent kinases (CDK4 and CDK6) and cyclinD complexes during the G1 phase of the cell cycle.	7	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 Ink4a	p16 Ink4a	p16 Ink4a	CDK4	CDK4	CDK4	7	9	23	24
p16INK4A is induced by oncogenic signals as well by the E2F transcription factor , inhibits cyclin dependent kinase 4 ( CDK4 ) and CDK6 , and thereby suppresses cell proliferation .	p16INK4A is induced by oncogenic signals as well by the E2F transcription factor, inhibits cyclin dependent kinase 4 (CDK4) and CDK6, and thereby suppresses cell proliferation.	0	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16INK4A	p16INK4A	p16INK4A	CDK4	CDK4	CDK4	0	1	20	21
p16 , mainly inhibits CDK4 activity , the loss of p16 expression reduced the response of breast cancer cells to PTX by conferring cancer stem cell properties and the tumorsphere formation was not significantly enhanced [ XREF_BIBR ] , those results indicated that CKIs affect PTX efficacy mainly through the cell cycle regulation .	p16, mainly inhibits CDK4 activity, the loss of p16 expression reduced the response of breast cancer cells to PTX by conferring cancer stem cell properties and the tumorsphere formation was not significantly enhanced [XREF_BIBR], those results indicated that CKIs affect PTX efficacy mainly through the cell cycle regulation.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	0	1	4	5
The p16 is the inhibitor of CDK4 and CDK6 .	The p16 is the inhibitor of CDK4 and CDK6.	0	8	is the inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	1	2	6	7
p16 INK4 inhibits Cdk4 and cyclin D1 activity and promotes RB to block cell cycle progression through the interaction with E2F1 .	p16 INK4 inhibits Cdk4 and cyclin D1 activity and promotes RB to block cell cycle progression through the interaction with E2F1.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4	p16 INK4	p16 INK4	Cdk4	Cdk4	Cdk4	0	2	3	4
The CDKN2A encoded proteins p16-INK4A and p14-ARF are cell cycle inhibitors and tumour suppressors , where p16-INK4A is an inhibitor of CDK4 and CDK6 in the retinoblastoma pathway and p14-ARF through its inhibition of HDM2 , is a regulator of p53 .	The CDKN2A encoded proteins p16-INK4A and p14-ARF are cell cycle inhibitors and tumour suppressors, where p16-INK4A is an inhibitor of CDK4 and CDK6 in the retinoblastoma pathway and p14-ARF through its inhibition of HDM2, is a regulator of p53.	16	23	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p16-INK4A	p16-INK4A	p16-INK4A	CDK4	CDK4	CDK4	16	17	21	22
CDKN2A inhibits CDK4 from participating in cell cycle G1 progression and is associated with growth retardation of MSCs .	CDKN2A inhibits CDK4 from participating in cell cycle G1 progression and is associated with growth retardation of MSCs.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	CDK4	CDK4	CDK4	0	1	2	3
Upon activation by Cyclin D1 , CDK4 acts as a proto-oncogene that promotes the progression from G1 to S phase , allowing cell proliferation , whereas , p16INK4a inhibits CDK4 action , arresting cell division .	Upon activation by Cyclin D1, CDK4 acts as a proto-oncogene that promotes the progression from G1 to S phase, allowing cell proliferation, whereas, p16INK4a inhibits CDK4 action, arresting cell division.	27	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16INK4a	p16INK4a	p16INK4a	CDK4	CDK4	CDK4	27	28	29	30
p16 Ink4a normally functions to sequester Cdk4 , allowing for the degradation of cyclin D1 and release of p27 Kip1 from cyclin D1-Cdk4 complexes .	p16 Ink4a normally functions to sequester Cdk4, allowing for the degradation of cyclin D1 and release of p27 Kip1 from cyclin D1-Cdk4 complexes.	0	7	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 Ink4a	p16 Ink4a	p16 Ink4a	Cdk4	Cdk4	Cdk4	0	2	6	7
Intact p16INK4a inhibits CDK4 activity and loss of p16 , which occurs frequently in melanoma , results in abnormal CDK4 activity .	Intact p16INK4a inhibits CDK4 activity and loss of p16, which occurs frequently in melanoma, results in abnormal CDK4 activity.	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16INK4a	p16INK4a	p16INK4a	CDK4	CDK4	CDK4	1	2	19	20
Additionally , inhibition of CDK4 by p16INK4A over-expression also led to a decrease in TS levels .	Additionally, inhibition of CDK4 by p16INK4A over-expression also led to a decrease in TS levels.	2	8	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p16INK4A	p16INK4A over-expression	p16ink4a	CDK4	CDK4	cdk4	6	7	4	5
Homo sapiens cyclin dependent kinase inhibitor 2A ( CDKN2A ; melanoma , p16 , inhibits CDK4 ) , a major CDK inhibitor , is the product of a tumor-suppressor gene that has been found inactivated in different cancer types .	Homo sapiens cyclin dependent kinase inhibitor 2A (CDKN2A; melanoma, p16, inhibits CDK4), a major CDK inhibitor, is the product of a tumor-suppressor gene that has been found inactivated in different cancer types.	8	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	12	13	15	16
CDKN2B-AS is located next to the CDK inhibitor genes , namely CDKN2A ( cyclin dependent kinase inhibitor 2A ) and CDKN2B , which both inhibit CDK4 and regulate the cell growth .	CDKN2B-AS is located next to the CDK inhibitor genes, namely CDKN2A (cyclin dependent kinase inhibitor 2A) and CDKN2B, which both inhibit CDK4 and regulate the cell growth.	0	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	CDK4	CDK4	CDK4	11	12	25	26
P16 INK4A inhibits CDK4 and CDK6 that are known to phosphorylate pockets proteins .	P16 INK4A inhibits CDK4 and CDK6 that are known to phosphorylate pockets proteins.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P16 INK4A	P16 INK4A	P16 INK4A	CDK4	CDK4	CDK4	0	2	3	4
Relative to control cells , Ras cells express elevated levels of p16 Ink4a ( XREF_FIG ) , which inhibits Cdk4 kinase activity , leading to activation of the retinoblastoma tumour suppressor protein ( Rb ) .	Relative to control cells, Ras cells express elevated levels of p16 Ink4a (XREF_FIG), which inhibits Cdk4 kinase activity, leading to activation of the retinoblastoma tumour suppressor protein (Rb).	9	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 Ink4a	levels of p16 Ink4a	p16 ink4a	Cdk4	Cdk4	cdk4	11	13	19	20
p16 inhibits cyclin dependent kinase 4 and 6 ( CDK4/6 ) .	p16 inhibits cyclin dependent kinase 4 and 6 (CDK4/6).	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	cyclin dependent kinase 4	cyclin dependent kinase 4	cyclin dependent kinase 4	0	1	2	6
These data demonstrate that inhibition of CDK4 activity either by p16 or by treatment with a small molecule inhibitor leads to an accumulation of cells in G 1 and produces a decrease in TS .	These data demonstrate that inhibition of CDK4 activity either by p16 or by treatment with a small molecule inhibitor leads to an accumulation of cells in G 1 and produces a decrease in TS.	4	11	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	10	11	6	7
While p16 INK4a is an inhibitor of the cyclin dependent kinases CDK4 and CDK6 and prevents S-phase entry during cell cycle , p14 ARF acts as a positive regulator of p53 .	While p16 INK4a is an inhibitor of the cyclin dependent kinases CDK4 and CDK6 and prevents S-phase entry during cell cycle, p14 ARF acts as a positive regulator of p53.	1	13	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p16 INK4a	p16 INK4a	p16 INK4a	CDK4	CDK4	CDK4	1	3	11	12
p16INK4a , encoded by the INK4A locus , is a key inhibitor of Cdk4 and a central effector of cellular senescence pathways [ XREF_BIBR ] .	p16INK4a, encoded by the INK4A locus, is a key inhibitor of Cdk4 and a central effector of cellular senescence pathways [XREF_BIBR].	0	14	is a key inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p16INK4a	p16INK4a	p16INK4a	Cdk4	Cdk4	Cdk4	0	1	13	14
In support of this idea , it was shown that preventing p16 mediated Cdk4 inhibition results in beta-cell hyperplasia but does not affect alpha- or delta-cells .	In support of this idea, it was shown that preventing p16 mediated Cdk4 inhibition results in beta-cell hyperplasia but does not affect alpha- or delta-cells.	10	14	mediated	Positive_early_activation	Negative_activation	Negative_activation	p16	p16	p16	Cdk4	Cdk4	Cdk4	11	12	13	14
Homozygous deletion ( log 2 ratio < -1 ) of the region containing the tumor suppressor gene cyclin dependent kinase inhibitor 2A ( melanoma , p16 , inhibits CDK4 ) ( CDKN2A ) was observed in two samples , and heterozygous deletion in one sample [ see Additional file XREF_SUPPLEMENTARY ] .	Homozygous deletion (log 2 ratio < -1) of the region containing the tumor suppressor gene cyclin dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) (CDKN2A) was observed in two samples, and heterozygous deletion in one sample [see Additional file XREF_SUPPLEMENTARY].	23	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	25	26	28	29
p16 ( INK4a ) might not be the inhibitor of CDK4 in GBM-PN cases because seven GBM-PN cases were positive for both CDK4 and p16 ( INK4a ) .	p16 (INK4a) might not be the inhibitor of CDK4 in GBM-PN cases because seven GBM-PN cases were positive for both CDK4 and p16 (INK4a).	0	13	be the inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	0	1	10	11
p16INK4a is a specific inhibitor of the cyclin D dependent kinases CDK4 and CDK6 and antagonizes their ability to phosphorylate the retinoblastoma ( Rb ) family of proteins and so prevent exit from the G1 phase of the cell cycle .	p16INK4a is a specific inhibitor of the cyclin D dependent kinases CDK4 and CDK6 and antagonizes their ability to phosphorylate the retinoblastoma (Rb) family of proteins and so prevent exit from the G1 phase of the cell cycle.	0	15	is a specific inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p16INK4a	p16INK4a	p16INK4a	CDK4	CDK4	CDK4	0	1	11	12
The four members of the INK4 gene family , p16 ( INK4a ) , p15 ( INK4b ) , p18 ( INK4c ) and p19 ( INK4d ) , are known to bind to and inhibit the closely related cyclin dependent kinases CDK4 and CDK6 as part of the regulation of the G1/S transition in the cell division cycle .	The four members of the INK4 gene family, p16 (INK4a), p15 (INK4b), p18 (INK4c) and p19 (INK4d), are known to bind to and inhibit the closely related cyclin dependent kinases CDK4 and CDK6 as part of the regulation of the G1/S transition in the cell division cycle.	2	46	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	9	10	42	43
The p16 family ( p15 , p16 , p18 and p19 ) binds to and inhibits the activities of CDK4 and CDK6 .	The p16 family (p15, p16, p18 and p19) binds to and inhibits the activities of CDK4 and CDK6.	1	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	1	2	19	20
Both proteins affect cell cycle regulation ; p16 inhibits the activity of CDK4 and CDK6 , and thereby influences pRb regulated G1 to S-phase progression .	Both proteins affect cell cycle regulation; p16 inhibits the activity of CDK4 and CDK6, and thereby influences pRb regulated G1 to S-phase progression.	7	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	7	8	12	13
Identified as a molecule that binds to CDK4 , p16 inhibits the catalytic activity of CDK4 and cyclin D enzymes .	Identified as a molecule that binds to CDK4, p16 inhibits the catalytic activity of CDK4 and cyclin D enzymes.	9	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	9	10	15	16
Compared to the GFP control , p16 inhibited the formation of a cyclin D1 and CDK4 complex as expected .	Compared to the GFP control, p16 inhibited the formation of a cyclin D1 and CDK4 complex as expected.	6	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	6	7	15	16
p16 INK4a ( hereafter p16 ) inhibits the cyclin dependent kinases CDK4 and CDK6 , thereby keeping the retinoblastoma protein ( pRB ) in a hypophosphorylated state and arresting cells in the G1 phase of the division cycle XREF_BIBR .	p16 INK4a (hereafter p16) inhibits the cyclin dependent kinases CDK4 and CDK6, thereby keeping the retinoblastoma protein (pRB) in a hypophosphorylated state and arresting cells in the G1 phase of the division cycle XREF_BIBR.	1	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	4	5	11	12
Recurrent focal losses of CDKN2A , encoding p16 INK4A , which inhibits the cyclin dependent kinases CDK4 and CDK6 ( as well as p14 ARF , which also indirectly inhibits CDK4 and CDK6 ) , were observed in 47 % of the tumours 101 -- a substantially higher proportion than reported previously ( 7-15 % ) XREF_BIBR , XREF_BIBR .	Recurrent focal losses of CDKN2A, encoding p16 INK4A, which inhibits the cyclin dependent kinases CDK4 and CDK6 (as well as p14 ARF, which also indirectly inhibits CDK4 and CDK6), were observed in 47% of the tumours 101 -- a substantially higher proportion than reported previously (7-15%) XREF_BIBR, XREF_BIBR.	7	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4A	p16 INK4A	p16 INK4A	CDK4	CDK4	CDK4	7	9	16	17
From a functional point of view , the Arg24Cys mutation , located in the p16CDKN2A binding domain of CDK4 , make the p16 CDKN2A protein unable to inhibit the D1 , cyclin , and CDK4 complex , resulting in a sort of oncogenic activation of CDK4 .	From a functional point of view, the Arg24Cys mutation, located in the p16CDKN2A binding domain of CDK4, make the p16 CDKN2A protein unable to inhibit the D1, cyclin, and CDK4 complex, resulting in a sort of oncogenic activation of CDK4.	23	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	CDK4	CDK4	CDK4	23	24	34	35
In addition , another report showed that p16 phosphorylation at Ser 8 catalyzed by IKKbeta relieved p16 mediated CDK4 inhibition XREF_BIBR .	In addition, another report showed that p16 phosphorylation at Ser 8 catalyzed by IKKbeta relieved p16 mediated CDK4 inhibition XREF_BIBR.	12	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	16	17	18	19
Normally , p16 INK4A inactivates CDK4 and therefore prevents the G1 to S-phase transition .	Normally, p16 INK4A inactivates CDK4 and therefore prevents the G1 to S-phase transition.	2	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4A	p16 INK4A	p16 INK4A	CDK4	CDK4	CDK4	2	4	5	6
Tumour suppressor CDKN2A inhibits the cyclin dependent kinases ( Cdk4 and Cdk6 ) that initiate the phosphorylation of the pRb .	Tumour suppressor CDKN2A inhibits the cyclin dependent kinases (Cdk4 and Cdk6) that initiate the phosphorylation of the pRb.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDKN2A	CDKN2A	CDKN2A	Cdk4	Cdk4	Cdk4	2	3	9	10
These pathways include cyclin dependent kinase inhibitors ( CDKIs ) such as P21 CIP1 ( CDKN1A ) or P16 INK4A ( CDKN2A ) , which respectively inhibited cyclin dependent kinase-2 ( CDK2 ) , CDK4 , and CDK6 .	These pathways include cyclin dependent kinase inhibitors (CDKIs) such as P21 CIP1 (CDKN1A) or P16 INK4A (CDKN2A), which respectively inhibited cyclin dependent kinase-2 (CDK2), CDK4, and CDK6.	18	35	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P16 INK4A	P16 INK4A	P16 INK4A	CDK4	CDK4	CDK4	18	20	34	35
p16 INK4a inhibits CDK4 and CDK6 activity , which regulate the RB-E2F axis and cell cycle progression , while p14 ARF also induces cell cycle arrest through its interaction with MDM2 , resulting in increased p53 levels that trigger cell cycle arrest at both G1 and G2/M phases .	p16 INK4a inhibits CDK4 and CDK6 activity, which regulate the RB-E2F axis and cell cycle progression, while p14 ARF also induces cell cycle arrest through its interaction with MDM2, resulting in increased p53 levels that trigger cell cycle arrest at both G1 and G2/M phases.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4a	p16 INK4a	p16 INK4a	CDK4	CDK4	CDK4	0	2	3	4
High p16 levels likely impair CDK4 activation by diverting CDK4 from cyclin D containing complexes ( Sherr , 1996 ; Asghar etal , 2015 ) in which CDK4 is phosphorylated ( Kato etal , 1994b ) .	High p16 levels likely impair CDK4 activation by diverting CDK4 from cyclin D containing complexes (Sherr, 1996; Asghar etal, 2015) in which CDK4 is phosphorylated (Kato etal, 1994b).	1	6	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16 levels	p16	CDK4	CDK4	cdk4	1	2	5	6
It is worth to mention here that p19ARF sequences are intertwined with p16INK4A ( inhibitor of the CDK4 and CDK6 kinases that plays a role in cell cycle arrest ) .	It is worth to mention here that p19ARF sequences are intertwined with p16INK4A (inhibitor of the CDK4 and CDK6 kinases that plays a role in cell cycle arrest).	10	20	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	p16INK4A	p16INK4A	p16INK4A	CDK4	CDK4	CDK4	12	13	17	18
The p16 ( INK4a ) tumor suppressor inhibits cyclin dependent kinases ( CDK4 and CDK6 ) .	The p16 (INK4a) tumor suppressor inhibits cyclin dependent kinases (CDK4 and CDK6).	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	1	2	12	13
The gene has two alternative first exons , separated by over 10 Kb , that give rise to two structurally and functionally distinct isoforms : p16INK4a ( inhibitor of CDK4 kinase ) and p14ARF ( alternate open reading frame , involved in the stabilization of p53 by sequestering of MDM2 ) .	The gene has two alternative first exons, separated by over 10 Kb, that give rise to two structurally and functionally distinct isoforms : p16INK4a (inhibitor of CDK4 kinase) and p14ARF (alternate open reading frame, involved in the stabilization of p53 by sequestering of MDM2).	6	33	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	p16INK4a	p16INK4a	p16INK4a	CDK4	CDK4	CDK4	25	26	29	30
p16 ( Ink4a ) is known to inhibit the activity of a complex composed by cyclin D , Cdk4 and Cdk6 , leading to inactivation of Rb by phosphorylation , thereby abolishing binding between Rb and E2f , leading to activation of E2f target genes .	p16 (Ink4a) is known to inhibit the activity of a complex composed by cyclin D, Cdk4 and Cdk6, leading to inactivation of Rb by phosphorylation, thereby abolishing binding between Rb and E2f, leading to activation of E2f target genes.	0	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	Cdk4	Cdk4	Cdk4	0	1	18	19
P16 Ink4A belongs to the INK family of CDK inhibitors and suppresses the activity of CDK4 and CDK6 , causing cell cycle arrest .	P16 Ink4A belongs to the INK family of CDK inhibitors and suppresses the activity of CDK4 and CDK6, causing cell cycle arrest.	0	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P16 Ink4A	P16 Ink4A	P16 Ink4A	CDK4	CDK4	CDK4	0	2	15	16
Both p16 INK4A and p15 INK4B have been shown to inhibit the CDK4 and CDK6 retinoblastoma family of tumor suppressor genes to induce G1 cell arrest while p14 ARF has been shown to upregulate TP53 .	Both p16 INK4A and p15 INK4B have been shown to inhibit the CDK4 and CDK6 retinoblastoma family of tumor suppressor genes to induce G1 cell arrest while p14 ARF has been shown to upregulate TP53.	1	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4A	p16 INK4A	p16 INK4A	CDK4	CDK4	CDK4	1	3	12	13
Cdkn2c encodes for p18 INK4c ( p18 ) , one of the four cyclin dependent kinase inhibitors that regulate cell cycle in the G1-to-S phase ; p16 INK4a , p15 INK4b , p18 INK4c , and p19 INKd prevent Cdk4 and Cdk6 from binding to the D cyclins and thereby block cell cycle progression at the restriction point ( R ) .	Cdkn2c encodes for p18 INK4c (p18), one of the four cyclin dependent kinase inhibitors that regulate cell cycle in the G1-to-S phase; p16 INK4a, p15 INK4b, p18 INK4c, and p19 INKd prevent Cdk4 and Cdk6 from binding to the D cyclins and thereby block cell cycle progression at the restriction point (R).	26	41	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4a	p16 INK4a	p16 INK4a	Cdk4	Cdk4	Cdk4	26	28	39	40
The p16 INK4a is a specific inhibitor of CDK4 and potentially blocks G1 cell-cycle progression .	The p16 INK4a is a specific inhibitor of CDK4 and potentially blocks G1 cell-cycle progression.	1	9	is a specific inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p16 INK4a	p16 INK4a	p16 INK4a	CDK4	CDK4	CDK4	1	3	8	9
CDKN2A codes for the p16 INK4a tumor suppressor gene , spliced variants of which inhibit cyclin dependent kinase 4 ( CDK4 ) or p53 degradation , and may play vital roles in cell cycle progression at the G1 stage .	CDKN2A codes for the p16 INK4a tumor suppressor gene, spliced variants of which inhibit cyclin dependent kinase 4 (CDK4) or p53 degradation, and may play vital roles in cell cycle progression at the G1 stage.	0	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	CDK4	CDK4	CDK4	0	1	20	21
Initial studies suggested that p18 INK4c preferentially inhibited cdk6 containing complexes whereas p16 INK4a preferentially inhibited cdk4 containing complexes .	Initial studies suggested that p18 INK4c preferentially inhibited cdk6 containing complexes whereas p16 INK4a preferentially inhibited cdk4 containing complexes.	12	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4a	p16 INK4a	p16 INK4a	cdk4	cdk4	cdk4	12	14	16	17
143 Increased levels of p16 INK4a inhibit CDK4 and CDK6 , leading to stabilization of retinoblastoma associated protein in its phosphorylated form , causing growth arrest .	143 Increased levels of p16 INK4a inhibit CDK4 and CDK6, leading to stabilization of retinoblastoma associated protein in its phosphorylated form, causing growth arrest.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4a	levels of p16 INK4a	p16 ink4a	CDK4	CDK4	cdk4	4	6	7	8
These include ( a ) up-regulation of the RAS/RAF/MEK pathway [ XREF_BIBR , XREF_BIBR ] ; ( b ) down-regulation of the retinoblastoma protein ( RB ) by increased cyclin D1 or CDK4 activity [ XREF_BIBR , XREF_BIBR ] ; and ( c ) inactivation of the CDKN2A p16 suppressor of CDK4 and 6 , in > 50 % of melanoma [ XREF_BIBR , XREF_BIBR ] .	These include (a) up-regulation of the RAS/RAF/MEK pathway [XREF_BIBR, XREF_BIBR]; (b) down-regulation of the retinoblastoma protein (RB) by increased cyclin D1 or CDK4 activity [XREF_BIBR, XREF_BIBR]; and (c) inactivation of the CDKN2A p16 suppressor of CDK4 and 6, in> 50% of melanoma [XREF_BIBR, XREF_BIBR].	47	53	suppressor	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	CDK4	CDK4	CDK4	47	48	51	52
Biochemical studies suggest that p16INK4 mediates its effects by specifically inhibiting the G1 cyclin dependent kinases CDK4 and CDK6 , thereby regulating the progression through G1 into S phase of the cell cycle .	Biochemical studies suggest that p16INK4 mediates its effects by specifically inhibiting the G1 cyclin dependent kinases CDK4 and CDK6, thereby regulating the progression through G1 into S phase of the cell cycle.	4	18	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p16INK4	p16INK4	p16INK4	CDK4	CDK4	CDK4	4	5	16	17
On the other hand , p16 specifically inhibits CDK4 and CDK6 .	On the other hand, p16 specifically inhibits CDK4 and CDK6.	5	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	5	6	8	9
The Ink4 family consists of four members , p15 ink4b , p16 ink4a , p18 ink4c and p19 ink4d , that contain four to five ankyrin repeats and specifically inhibit CDK4 and CDK6 XREF_BIBR - XREF_BIBR .	The Ink4 family consists of four members, p15 ink4b, p16 ink4a, p18 ink4c and p19 ink4d, that contain four to five ankyrin repeats and specifically inhibit CDK4 and CDK6 XREF_BIBR - XREF_BIBR.	11	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 ink4a	p16 ink4a	p16 ink4a	CDK4	CDK4	CDK4	11	13	30	31
Thus , the loss of function of p16 INK4a promotes CDK4 and CDK6 activation , resulting in hyperphosphorylation of pRB , and the activation of the transcription factor E2F1 .	Thus, the loss of function of p16 INK4a promotes CDK4 and CDK6 activation, resulting in hyperphosphorylation of pRB, and the activation of the transcription factor E2F1.	7	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4a	p16 INK4a	p16 INK4a	CDK4	CDK4	CDK4	7	9	10	11
p16 INK4a is a cyclin dependent kinase inhibitor ( CDKI ) encoded by the Cdkn2a locus , which sequesters cdk4 and cdk6 , thus preventing their interaction with the D cyclins .	p16 INK4a is a cyclin dependent kinase inhibitor (CDKI) encoded by the Cdkn2a locus, which sequesters cdk4 and cdk6, thus preventing their interaction with the D cyclins.	14	21	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdkn2a	Cdkn2a	Cdkn2a	cdk4	cdk4	cdk4	14	15	19	20
While p16 INK4a is an inhibitor of the cyclin dependent kinases CDK4 and CDK6 and prevents cell cycle progression , p14 ARF functions as a positive regulator of p53 .	While p16 INK4a is an inhibitor of the cyclin dependent kinases CDK4 and CDK6 and prevents cell cycle progression, p14 ARF functions as a positive regulator of p53.	1	13	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p16 INK4a	p16 INK4a	p16 INK4a	CDK4	CDK4	CDK4	1	3	11	12
CDK4 , CDK6 , and cyclin D is negatively regulated by p16 and p15 .	CDK4, CDK6, and cyclin D is negatively regulated by p16 and p15.	0	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	11	12	0	1
Both p15 INK4b and p16 INK4a are able to induce cell-cycle arrest in G 1 by inhibiting the cyclin dependent kinases CDK4 and CDK6 to inactivate the retinoblastoma ( RB1 ) family of tumor suppressor proteins [ XREF_BIBR , XREF_BIBR ] .	Both p15 INK4b and p16 INK4a are able to induce cell-cycle arrest in G 1 by inhibiting the cyclin dependent kinases CDK4 and CDK6 to inactivate the retinoblastoma (RB1) family of tumor suppressor proteins [XREF_BIBR, XREF_BIBR].	4	25	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p16 INK4a	p16 INK4a	p16 INK4a	CDK4	CDK4	CDK4	4	6	21	22
The tumor suppressor protein p16INK4a ( inhibitor of CDK4 ) is one of the most direct links between cell-cycle control and cancer .	The tumor suppressor protein p16INK4a (inhibitor of CDK4) is one of the most direct links between cell-cycle control and cancer.	0	11	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	p16INK4a	p16INK4a	p16INK4a	CDK4	CDK4	CDK4	4	5	8	9
To obtain further information about the role of factors regulating the G1 cell cycle in the development of endometrial carcinoma , the authors analyzed the expression of cdk4 ( cyclin dependent kinase ) and p16INK4 ( an inhibitor of cdk4 ) .	To obtain further information about the role of factors regulating the G1 cell cycle in the development of endometrial carcinoma, the authors analyzed the expression of cdk4 (cyclin dependent kinase) and p16INK4 (an inhibitor of cdk4).	25	40	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	p16INK4	expression of cdk4 (cyclin dependent kinase) and p16INK4	p16ink4	cdk4	cdk4	cdk4	34	35	39	40
On the other hand , CDKN2A inhibits the CDK4 and cyclin D1 complex and , in this way , the transition G1 --> S. Hypermethylation mediated silencing of RB1 and CDKN2A has been frequently observed in primary glioma tissues [ XREF_BIBR , XREF_BIBR ] .	On the other hand, CDKN2A inhibits the CDK4 and cyclin D1 complex and, in this way, the transition G1 --> S. Hypermethylation mediated silencing of RB1 and CDKN2A has been frequently observed in primary glioma tissues [XREF_BIBR, XREF_BIBR].	5	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	CDK4	CDK4	CDK4	5	6	8	9
p16 negatively regulates the cdk4 , causing cell cycle arrest to promote DNA repair process [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	p16 negatively regulates the cdk4, causing cell cycle arrest to promote DNA repair process [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	cdk4	cdk4	cdk4	0	1	4	5
Because p16 Ink4a induces a G1 cell cycle arrest by inhibiting Cdk4 and allowing the accumulation of hypophosphorylated retinoblastoma protein ( Rb ) , we examined the Rb protein in 10T1/2 cells after ectopic expression of MITF or MITF-DB .	Because p16 Ink4a induces a G1 cell cycle arrest by inhibiting Cdk4 and allowing the accumulation of hypophosphorylated retinoblastoma protein (Rb), we examined the Rb protein in 10T1/2 cells after ectopic expression of MITF or MITF-DB.	1	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p16 Ink4a	p16 Ink4a	p16 Ink4a	Cdk4	Cdk4	Cdk4	1	3	11	12
NE significantly increased p16 expression and decreased CDK4 kinase activity in NHBE cells .	NE significantly increased p16 expression and decreased CDK4 kinase activity in NHBE cells.	0	9	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	NE significantly increased p16 expression	p16	CDK4	CDK4	cdk4	3	4	7	8
CDK4 and CDK6 are inhibited by p16 and p27 .	CDK4 and CDK6 are inhibited by p16 and p27.	0	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	6	7	0	1
p16 Ink4a has been reported to block the CDK4- and CDK6 mediated inactivation of retinoblastoma to prevent cell cycle progression and drive cell entry into senescence .	p16 Ink4a has been reported to block the CDK4- and CDK6 mediated inactivation of retinoblastoma to prevent cell cycle progression and drive cell entry into senescence.	0	9	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 Ink4a	p16 Ink4a	p16 Ink4a	CDK4-	CDK4-	CDK4-	0	2	8	9
The principal function of p16 INK4a is to inhibit cell cycle progression by preventing the cyclin dependent kinases CDK4 and CDK6 from phosphorylating the retinoblastoma protein , pRb .	The principal function of p16 INK4a is to inhibit cell cycle progression by preventing the cyclin dependent kinases CDK4 and CDK6 from phosphorylating the retinoblastoma protein, pRb.	4	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4a	p16 INK4a	p16 INK4a	CDK4	CDK4	CDK4	4	6	18	19
CDKN2A inhibits CDK4 and thereby regulates RB1-E2F1 binding .	CDKN2A inhibits CDK4 and thereby regulates RB1-E2F1 binding.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	CDK4	CDK4	CDK4	0	1	2	3
p16 inhibits CDK4 , keeping RB hypophosphorylated and preventing cell cycle progression .	p16 inhibits CDK4, keeping RB hypophosphorylated and preventing cell cycle progression.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	0	1	2	3
Next , we analyzed the relation between IC 50 for PD and expression of p16 in the MRT cell lines , because not only PD but also p16 is a strong inhibitor of CDK4 .	Next, we analyzed the relation between IC 50 for PD and expression of p16 in the MRT cell lines, because not only PD but also p16 is a strong inhibitor of CDK4.	23	34	is a strong inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	27	28	33	34
XREF_BIBR The normal function of p16 is to suppress cdk4 , an enzyme that controls the G1/S checkpoint by negatively regulating cyclin D1 activity .	XREF_BIBR The normal function of p16 is to suppress cdk4, an enzyme that controls the G1/S checkpoint by negatively regulating cyclin D1 activity.	0	12	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	cdk4	cdk4	cdk4	5	6	9	10
Together with the data derived from Ki67 staining , these results indicate that loss of p16 stimulates CDK4 and/or CDK6 activity toward the Rb protein in MECs , increasing their proliferation and rescuing the proliferative decline observed in Brca1 deficient MECs .	Together with the data derived from Ki67 staining, these results indicate that loss of p16 stimulates CDK4 and/or CDK6 activity toward the Rb protein in MECs, increasing their proliferation and rescuing the proliferative decline observed in Brca1 deficient MECs.	13	18	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p16	loss of p16	p16	CDK4	CDK4	cdk4	15	16	17	18
Loss of p16 INK4A and a related INK family inhibitor , p18 INK4c , synergistically increased beta cell proliferation in a CDK4 dependent manner [ XREF_BIBR ] .	Loss of p16 INK4A and a related INK family inhibitor, p18 INK4c, synergistically increased beta cell proliferation in a CDK4 dependent manner [XREF_BIBR].	0	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p16 INK4A	Loss of p16 INK4A	p16 ink4a	CDK4	CDK4	cdk4	2	4	21	22
p16 was shown to inhibit the kinase activities of the cyclin D dependent kinases CDK4 [ XREF_BIBR ] and CDK6 [ XREF_BIBR ] .	p16 was shown to inhibit the kinase activities of the cyclin D dependent kinases CDK4 [XREF_BIBR] and CDK6 [XREF_BIBR].	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	0	1	14	15
Specifically , p16 inhibits the ability of CDK4 and CDK6 to phosphorylate the retinoblastoma ( Rb ) protein and loss of its normal function might lead to uncontrolled cell growth , escape from senescence and induction of proliferation XREF_BIBR .	Specifically, p16 inhibits the ability of CDK4 and CDK6 to phosphorylate the retinoblastoma (Rb) protein and loss of its normal function might lead to uncontrolled cell growth, escape from senescence and induction of proliferation XREF_BIBR.	2	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	2	3	7	8
p16 suppresses cyclin dependent kinases 4 and 6 ( CDK4 and CDK6 ) and thus activates the retinoblastoma ( Rb ) family members , which inhibit cell cycle from the G1 to the S phase .	p16 suppresses cyclin dependent kinases 4 and 6 (CDK4 and CDK6) and thus activates the retinoblastoma (Rb) family members, which inhibit cell cycle from the G1 to the S phase.	0	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	0	1	9	10
p16 INK4 is a major inhibitor of CDK4 and CDK6 and Cyclin D1 complex , which promotes a signal for cell cycle progression via inhibiting Rb protein and unleashing the transcription factor E2F [ XREF_BIBR ] .	p16 INK4 is a major inhibitor of CDK4 and CDK6 and Cyclin D1 complex, which promotes a signal for cell cycle progression via inhibiting Rb protein and unleashing the transcription factor E2F [XREF_BIBR].	0	9	is a major inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p16 INK4	p16 INK4	p16 INK4	CDK4	CDK4	CDK4	0	2	7	8
The overexpressed p16INK4 failed to suppress CDK4 which indicated possible aberrant changes in this gene .	The overexpressed p16INK4 failed to suppress CDK4 which indicated possible aberrant changes in this gene.	0	8	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16INK4	p16INK4	p16INK4	CDK4	CDK4	CDK4	2	3	6	7
Physiologically CDK4 is itself activated by D cyclines during G1 progression and inhibited by p16 ( INK4a ) .	Physiologically CDK4 is itself activated by D cyclines during G1 progression and inhibited by p16 (INK4a).	1	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	14	15	1	2
Acting as a cyclin dependent kinase inhibitor ( CDKI ) , p16 INK4a binds to and inhibits the activity of CDK4 and CDK6 and arrests the cell cycle in the G1/S phase in a p53 dependent pathway [ XREF_BIBR , XREF_BIBR ] .	Acting as a cyclin dependent kinase inhibitor (CDKI), p16 INK4a binds to and inhibits the activity of CDK4 and CDK6 and arrests the cell cycle in the G1/S phase in a p53 dependent pathway [XREF_BIBR, XREF_BIBR].	11	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4a	p16 INK4a	p16 INK4a	CDK4	CDK4	CDK4	11	13	20	21
Since the discovery of p16 in 1993 , there has been an ongoing , controversial discussion concerning the meaning of increased p16 expression , which acts as a cyclin dependent kinase ( CDK ) inhibitor and specifically blocks CDK4 and CDK6 .	Since the discovery of p16 in 1993, there has been an ongoing, controversial discussion concerning the meaning of increased p16 expression, which acts as a cyclin dependent kinase (CDK) inhibitor and specifically blocks CDK4 and CDK6.	21	40	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16 expression	p16	CDK4	CDK4	cdk4	21	22	38	39
The CDKN2A gene transcription product , p16 INK4A , inhibits CDK4 and CDK6 .	The CDKN2A gene transcription product, p16 INK4A, inhibits CDK4 and CDK6.	6	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4A	p16 INK4A	p16 INK4A	CDK4	CDK4	CDK4	6	8	10	11
CDKN2A and CDKN2B inhibit cyclin dependent kinase 4 ( CDK4 ) and CDK6 and control cellular proliferation by preventing entry into the S phase of the cell cycle .	CDKN2A and CDKN2B inhibit cyclin dependent kinase 4 (CDK4) and CDK6 and control cellular proliferation by preventing entry into the S phase of the cell cycle.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	CDK4	CDK4	CDK4	0	1	9	10
Although p16 may interact with both CDK4 and CDK6 , p16 inhibition of CDK4 may be more important than CDK6 given that some melanoma-prone families have inherited activating mutations in CDK4 , while none with activating CDK6 mutations have been described [ XREF_BIBR ] .	Although p16 may interact with both CDK4 and CDK6, p16 inhibition of CDK4 may be more important than CDK6 given that some melanoma-prone families have inherited activating mutations in CDK4, while none with activating CDK6 mutations have been described [XREF_BIBR].	10	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	10	11	13	14
In the early stages of tumorigenesis , TGF-beta signaling pathway acts as a tumor suppressor preventing progression of cell cycle through G 1 phase by the down regulation of CyclinD1 and Cyclin dependent kinase ( CDK ) proteins and induction of p15 INK4B , p16 INK4A , which inhibit CDK4 and CDK6 ; likewise p21 Cip1 or p27 Kip1 appears to fulfill the function of p15 INK4B in its absence [ XREF_BIBR , XREF_BIBR ] .	In the early stages of tumorigenesis, TGF-beta signaling pathway acts as a tumor suppressor preventing progression of cell cycle through G 1 phase by the down regulation of CyclinD1 and Cyclin dependent kinase (CDK) proteins and induction of p15 INK4B, p16 INK4A, which inhibit CDK4 and CDK6; likewise p21 Cip1 or p27 Kip1 appears to fulfill the function of p15 INK4B in its absence [XREF_BIBR, XREF_BIBR].	44	51	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4A	p16 INK4A	p16 INK4A	CDK4	CDK4	CDK4	44	46	49	50
The tumor suppressor p16 ink4a inhibits the cyclin D dependent kinases CDK4 and CDK6 [ XREF_BIBR ] .	The tumor suppressor p16 ink4a inhibits the cyclin D dependent kinases CDK4 and CDK6 [XREF_BIBR].	3	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p16 ink4a	p16 ink4a	p16 ink4a	CDK4	CDK4	CDK4	3	5	11	12
While Tax competes with CDK4 for p16 binding , thus suppressing p16 inhibition of CDK4 , Tax also binds to cyclin D ( s ) with concomitant increases in both CDK4 activity and the phosphorylation of cyclin D ( s ) .	While Tax competes with CDK4 for p16 binding, thus suppressing p16 inhibition of CDK4, Tax also binds to cyclin D (s) with concomitant increases in both CDK4 activity and the phosphorylation of cyclin D (s).	11	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	11	12	14	15
Activating CDK4 mutations prevent the binding and inhibition of CDK4 by p16INK4a .	Activating CDK4 mutations prevent the binding and inhibition of CDK4 by p16INK4a.	3	12	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p16INK4a	p16INK4a	p16INK4a	CDK4	CDK4	CDK4	11	12	9	10
p16 ( Ink4 ) inhibited cdk4 , but not cdk2 , kinase activity , producing partial inhibition of VSMC growth in vitro .	p16 (Ink4) inhibited cdk4, but not cdk2, kinase activity, producing partial inhibition of VSMC growth in vitro.	0	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	cdk4	cdk4	cdk4	0	1	5	6
The transition from G1 to S phase in the cell cycle is highly regulated by Cdk4 and Cdk6 , which in turn is inhibited by the tumor suppressor p16 ( INK4a ) .	The transition from G1 to S phase in the cell cycle is highly regulated by Cdk4 and Cdk6, which in turn is inhibited by the tumor suppressor p16 (INK4a).	13	30	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	p16	p16	p16	Cdk4	Cdk4	Cdk4	28	29	15	16
The following genes exhibited moderate changes in methylation : O-6-methylguanine-DNA methyltransferase ( MGMT ) ( 20 % , 13/65 ) , mutL homolog 1 , colon cancer , nonpolyposis type 2 ( E. coli ) ( hMLH1 ) ( 18 % , 12/65 ) , cyclin dependent kinase inhibitor 2A ( melanoma , p16 , inhibits CDK4 ) ( p16 ( INK4a ) ) ( 10 % , 10/65 ) , methylated in tumor 1 ( MINT1 ) ( 15 % , 10/65 ) , methylated in tumor 31 ( MINT31 ) ( 11 % , 7/65 ) .	The following genes exhibited moderate changes in methylation : O-6-methylguanine-DNA methyltransferase (MGMT) (20%, 13/65), mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (hMLH1) (18%, 12/65), cyclin dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) (p16 (INK4a)) (10%, 10/65), methylated in tumor 1 (MINT1) (15%, 10/65), methylated in tumor 31 (MINT31) (11%, 7/65).	51	57	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	53	54	56	57
A deletion of p16 INK4A causes altered activity of CDK4 , leading to hyperphosphorylation of Rb and aberrant regulation of the cell cycle XREF_BIBR , XREF_BIBR .	A deletion of p16 INK4A causes altered activity of CDK4, leading to hyperphosphorylation of Rb and aberrant regulation of the cell cycle XREF_BIBR, XREF_BIBR.	3	10	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4A	p16 INK4A	p16 INK4A	CDK4	CDK4	CDK4	3	5	9	10
p16 , also known as p16 INK4a , a member of the INK4 family of CDK inhibitors , inhibits CDK4 and CDK6 , maintaining RB in its hypophosphorylated E2F associated state , and thereby preventing G1-to-S phase progression [ XREF_BIBR , XREF_BIBR ] .	p16, also known as p16 INK4a, a member of the INK4 family of CDK inhibitors, inhibits CDK4 and CDK6, maintaining RB in its hypophosphorylated E2F associated state, and thereby preventing G1-to-S phase progression [XREF_BIBR, XREF_BIBR].	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	0	1	19	20
A different group is comprised of INK4 ( inhibitor of CDK4 ) and Cdkn2a , Cdkn2b , Cdkn2c , and Cdkn2d or p16 , p15 , p18 and p19 , respectively 44 .	A different group is comprised of INK4 (inhibitor of CDK4) and Cdkn2a, Cdkn2b, Cdkn2c, and Cdkn2d or p16, p15, p18 and p19, respectively 44.	6	28	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	22	23	10	11
p16 specifically inhibits cdk4 and is thought to function upstream of Rb , while ARF binds MDM2 which results in p53 stabilization , in addition to having p53 independent functions .	p16 specifically inhibits cdk4 and is thought to function upstream of Rb, while ARF binds MDM2 which results in p53 stabilization, in addition to having p53 independent functions.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	cdk4	cdk4	cdk4	0	1	3	4
Protein p16 suppresses S-phase entry by antagonising the cyclin dependent kinases CDK4 and CDK6 [ XREF_BIBR ] .	Protein p16 suppresses S-phase entry by antagonising the cyclin dependent kinases CDK4 and CDK6 [XREF_BIBR].	0	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	1	2	11	12
p15 and p16 inhibits CDK4 and CDK6 , therefore p15 and p16 act as tumor suppressors and lead to cell cycle arrest in the late G1 phase [ XREF_BIBR ] .	p15 and p16 inhibits CDK4 and CDK6, therefore p15 and p16 act as tumor suppressors and lead to cell cycle arrest in the late G1 phase [XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	2	3	4	5
Both , p16 INK4A and p15 INK4B promote G1 cell cycle arrest by inhibiting the CDK4 and CDK6-retinoblastoma family of tumor suppressors , while p14 ARF upregulates TP53 by inactivating its negative regulator MDM2 .	Both, p16 INK4A and p15 INK4B promote G1 cell cycle arrest by inhibiting the CDK4 and CDK6-retinoblastoma family of tumor suppressors, while p14 ARF upregulates TP53 by inactivating its negative regulator MDM2.	2	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p16 INK4A	p16 INK4A	p16 INK4A	CDK4	CDK4	CDK4	2	4	15	16
P16INK4a is a specific inhibitor of CDK4 and 6 , and thus , inactivation of p16INK4a allows cells to escape cell cycle arrest in G1 .	P16INK4a is a specific inhibitor of CDK4 and 6, and thus, inactivation of p16INK4a allows cells to escape cell cycle arrest in G1.	0	8	is a specific inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	P16INK4a	P16INK4a	P16INK4a	CDK4	CDK4	CDK4	0	1	6	7
Here , AE2 knockdown remarkably decreased Cyclin D1 and CDK4 ( key regulators of G1/S transition ) , but increased p16 ( an inhibitor of CDK4 21 ) , which was consistent with the results of cell cycle distribution analysis .	Here, AE2 knockdown remarkably decreased Cyclin D1 and CDK4 (key regulators of G1/S transition), but increased p16 (an inhibitor of CDK4 21), which was consistent with the results of cell cycle distribution analysis.	19	31	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	20	21	25	26
Since p16 specifically inhibits CDK4 and CDK6 , it is possible that phosphorylation by these kinases plays a role in ELK1 regulation .	Since p16 specifically inhibits CDK4 and CDK6, it is possible that phosphorylation by these kinases plays a role in ELK1 regulation.	1	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	1	2	4	5
p16 and p15 inhibit Cdk4 and Cdk6 , which are critical to relieve the anti-proliferative pressure of Rb ; p19 inhibits Mdm2 , the main ubiquitin ligase targeting p53 for degradation [ XREF_BIBR ] .	p16 and p15 inhibit Cdk4 and Cdk6, which are critical to relieve the anti-proliferative pressure of Rb; p19 inhibits Mdm2, the main ubiquitin ligase targeting p53 for degradation [XREF_BIBR].	0	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	Cdk4	Cdk4	Cdk4	0	1	4	5
Specific degradation of p27 by co-expressing Skp2 or p27 small interfering RNA caused an increase of CDK2 activity and overrode the limited cell cycle .	Specific degradation of p27 by co-expressing Skp2 or p27 small interfering RNA caused an increase of CDK2 activity and overrode the limited cell cycle.	1	17	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27 by co-expressing	p27	CDK2	CDK2	cdk2	3	4	16	17
Interestingly , p27 activates the caspase-9-caspase-3-caspase-7-PARP apoptotic cascade by inhibiting Cdk2 and Cdc2-cyclin A/B1 kinase activities in follicles , thereby inducing follicle atresia in the mouse .	Interestingly, p27 activates the caspase-9-caspase-3-caspase-7-PARP apoptotic cascade by inhibiting Cdk2 and Cdc2-cyclin A/B1 kinase activities in follicles, thereby inducing follicle atresia in the mouse.	2	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	2	3	10	11
p27 inhibits CDK2 , enabling terminally differentiating EBs to exit the cell cycle to form mature RBCs .	p27 inhibits CDK2, enabling terminally differentiating EBs to exit the cell cycle to form mature RBCs.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	0	1	2	3
For instance , both p27 and p57 can inhibit the kinase activity of CDK4/6 and CDK2 whereas p21 acts to control the function of both CDK2 as well as CDK1 [ XREF_BIBR , XREF_BIBR ] .	For instance, both p27 and p57 can inhibit the kinase activity of CDK4/6 and CDK2 whereas p21 acts to control the function of both CDK2 as well as CDK1 [XREF_BIBR, XREF_BIBR].	3	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	4	5	15	16
Induction of p21 ( Waf1 ) or p27 ( Kip1 ) expression inhibited the activities of CDK2 and completely arrested cells at G ( 1 ) phase of the cell cycle by p27 ( Kip1 ) and at G ( 1 ) and G ( 2 ) phases by p21 ( Waf1 ) .	Induction of p21 (Waf1) or p27 (Kip1) expression inhibited the activities of CDK2 and completely arrested cells at G (1) phase of the cell cycle by p27 (Kip1) and at G (1) and G (2) phases by p21 (Waf1).	9	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Kip1	Kip1) expression	kip1	CDK2	CDK2	cdk2	9	10	16	17
The degradation of p27 stimulates the activity of Cdk2 and cyclin E and Cdk2 and cyclin A to promote cell proliferation .	The degradation of p27 stimulates the activity of Cdk2 and cyclin E and Cdk2 and cyclin A to promote cell proliferation.	1	11	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	3	4	8	9
Our data demonstrating that phosphorylation of p27 Kip1 at S140 occurs predominantly in the G0 and G1-phases of the cell cycle ( XREF_FIG ) and that p27 Kip1 is required to reduce CDK2 activity and prevent S-phase entry after DNA damage ( XREF_FIG ) point toward a role for p27 Kip1 in the G1/S DNA damage checkpoint .	Our data demonstrating that phosphorylation of p27 Kip1 at S140 occurs predominantly in the G0 and G1-phases of the cell cycle (XREF_FIG) and that p27 Kip1 is required to reduce CDK2 activity and prevent S-phase entry after DNA damage (XREF_FIG) point toward a role for p27 Kip1 in the G1/S DNA damage checkpoint.	26	33	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	CDK2	CDK2	CDK2	26	28	32	33
p27 negatively regulates protein kinase CDK2 , which is necessary for G1-S progression [ XREF_BIBR ] .	p27 negatively regulates protein kinase CDK2, which is necessary for G1-S progression [XREF_BIBR].	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	0	1	5	6
Both p27 kip1 and roscovitine , cdk2 inhibitors , prevented DNA replication suggesting cdk2 involvement in this process in sea urchin .	Both p27 kip1 and roscovitine, cdk2 inhibitors, prevented DNA replication suggesting cdk2 involvement in this process in sea urchin.	1	14	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 kip1	p27 kip1	p27 kip1	cdk2	cdk2	cdk2	1	3	13	14
p27 mediates Cdk2 inhibition and is also found in cyclin D1-Cdk4 complexes .	p27 mediates Cdk2 inhibition and is also found in cyclin D1-Cdk4 complexes.	0	7	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	0	1	2	3
The cell cycle inhibitor p27 inhibits cyclin-E and cyclin dependent kinase-2 , which prevents the activation of S-phase-specific transcription factors such as elongation factor-2 .	The cell cycle inhibitor p27 inhibits cyclin-E and cyclin-dependent kinase-2, which prevents the activation of S-phase-specific transcription factors such as elongation factor-2.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	cyclin-dependent kinase-2	cyclin-dependent kinase-2	cyclin-dependent kinase-2	4	5	8	11
In contrast , TGF beta 1 upregulated cyclin E associated p27 ( kip1 ) with no effect on the expression of cyclin E. p27 ( kip1 )-immunodepletion upregulated cyclin E dependent kinase activity by more than 10-fold in TGF beta 1 treated cells but not in proliferating cells ; whereas immunodepletion of p27 ( kip1 ) from cdk2-immunoprecipitates markedly downregulated cdk2 kinase activity in the lysates extracted from both proliferating and TGF beta treated cells .	In contrast, TGF beta 1 upregulated cyclin E associated p27 (kip1) with no effect on the expression of cyclin E. p27 (kip1)-immunodepletion upregulated cyclin E dependent kinase activity by more than 10-fold in TGF beta 1 treated cells but not in proliferating cells; whereas immunodepletion of p27 (kip1) from cdk2-immunoprecipitates markedly downregulated cdk2 kinase activity in the lysates extracted from both proliferating and TGF beta treated cells.	50	62	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	cdk2	cdk2	cdk2	52	53	60	61
For this reason , p27 is degraded timely , before the onset of cells into S phase , preventing unwanted Cdk2 inhibition .	For this reason, p27 is degraded timely, before the onset of cells into S phase, preventing unwanted Cdk2 inhibition.	4	21	degraded	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	4	5	20	21
Ubiquitin dependent degradation of p27 kip1 is required to initiate cell cycle progression and entry to S phase by allowing activation of Cdk2 .	Ubiquitin dependent degradation of p27 kip1 is required to initiate cell cycle progression and entry to S phase by allowing activation of Cdk2.	4	23	initiate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 kip1	p27 kip1	p27 kip1	Cdk2	Cdk2	Cdk2	4	6	22	23
Western blot analysis confirmed that key proteins required for transition from G1 to S phase were downregulated Cyclin-E ( 40 % ) and cdk2 ( 80 % ) ] , while p27 which blocks cyclin E and cdk2 function was upregulated ( 50 % ) , in 2B-siRNA transfected cells ( XREF_FIG ) .	Western blot analysis confirmed that key proteins required for transition from G1 to S phase were downregulated Cyclin-E (40%) and cdk2 (80%)], while p27 which blocks cyclin E and cdk2 function was upregulated (50%), in 2B-siRNA transfected cells (XREF_FIG).	31	40	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	cdk2	cdk2	cdk2	31	32	37	38
Initiation of cell cycle progression in T cells requires ubiquitin dependent degradation of p27 kip1 thereby allowing activation of Cdk2 and entry to the S phase of the cell cycle .	Initiation of cell cycle progression in T cells requires ubiquitin dependent degradation of p27 kip1 thereby allowing activation of Cdk2 and entry to the S phase of the cell cycle.	13	21	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 kip1	p27 kip1	p27 kip1	Cdk2	Cdk2	Cdk2	13	15	19	20
These data are consistent with a model whereby Fbxo7 stabilizes p27 levels , which inhibits CDK2 and promotes cell cycle withdrawal .	These data are consistent with a model whereby Fbxo7 stabilizes p27 levels, which inhibits CDK2 and promotes cell cycle withdrawal.	10	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27 levels	p27	CDK2	CDK2	cdk2	10	11	15	16
The cyclin dependent kinase inhibitor p15 ( INK4B ) blocks association of cyclin dependent kinase ( CDK ) 4/cyclin D and p27 ( kip-1 ) blocks activity of CDK2 and cyclin A and CDK2 and cyclin E , complexes that are mandatory for cell-cycle progression .	The cyclin dependent kinase inhibitor p15 (INK4B) blocks association of cyclin dependent kinase (CDK) 4/cyclin D and p27 (kip-1) blocks activity of CDK2 and cyclin A and CDK2 and cyclin E, complexes that are mandatory for cell-cycle progression.	19	31	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	21	22	28	29
CDK2 inhibition by p27 induces hESCs differentiation XREF_BIBR .	CDK2 inhibition by p27 induces hESCs differentiation XREF_BIBR.	0	4	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	3	4	0	1
Previously , we demonstrated that the FA induced inhibition of DNA synthesis in HUVEC is through increasing CDKN1A and CDKN1B expression , which in turn inhibits the CDK2 activity , and finally impairs the transition from the G1 to the S phase XREF_BIBR .	Previously, we demonstrated that the FA induced inhibition of DNA synthesis in HUVEC is through increasing CDKN1A and CDKN1B expression, which in turn inhibits the CDK2 activity, and finally impairs the transition from the G1 to the S phase XREF_BIBR.	6	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1B	FA induced inhibition of DNA synthesis in HUVEC is through increasing CDKN1A and CDKN1B expression	cdkn1b	CDK2	CDK2	cdk2	19	20	27	28
Among the CDKs , only CDK4 levels drop upon RelA induction while up-regulation of p27 may inhibit CDK2 [ XREF_BIBR ] .	Among the CDKs, only CDK4 levels drop upon RelA induction while up-regulation of p27 may inhibit CDK2 [XREF_BIBR].	12	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	14	15	17	18
The current study is concerned with the evaluation of a key cyclin ( cyclin D1 ) which activates cdk4 and p27KIP1 which in turn inhibit cdk2 in the proliferative responses of epidermal growth factor ( EGF ) and platelet derived growth factor ( PDGF ) and their modulation by TGF-beta 1 .	The current study is concerned with the evaluation of a key cyclin (cyclin D1) which activates cdk4 and p27KIP1 which in turn inhibit cdk2 in the proliferative responses of epidermal growth factor (EGF) and platelet derived growth factor (PDGF) and their modulation by TGF-beta 1.	17	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27KIP1	p27KIP1	p27KIP1	cdk2	cdk2	cdk2	20	21	25	26
The importance of Cdk2 activity was demonstrated by p27Kip1 , which attenuated Cdk2 activity and inhibited cell cycle progression in C33A cells .	The importance of Cdk2 activity was demonstrated by p27Kip1, which attenuated Cdk2 activity and inhibited cell cycle progression in C33A cells.	6	15	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27Kip1	p27Kip1	p27Kip1	Cdk2	Cdk2	Cdk2	8	9	12	13
Up-regulation of RASSF10 increased the level of p27 and down-regulated cyclinD1 and CDK2 and CDK4 , which was consistently agreed with the results observed in vitro study ( XREF_FIG ) .	Up-regulation of RASSF10 increased the level of p27 and down-regulated cyclinD1 and CDK2 and CDK4, which was consistently agreed with the results observed in vitro study (XREF_FIG).	2	19	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	RASSF10 increased the level of p27	p27	CDK2	CDK2	cdk2	7	8	12	13
Upon binding to the cyclin E and CDK2 complex , p27 Kip1 inhibits CDK2 activity , thereby inhibiting cell cycle progression and cell proliferation .	Upon binding to the cyclin E and CDK2 complex, p27 Kip1 inhibits CDK2 activity, thereby inhibiting cell cycle progression and cell proliferation.	10	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	CDK2	CDK2	CDK2	10	12	13	14
p27 is an inhibitor of Cdk2 and inhibits origin firing by preventing the loading of some replication proteins , including Cdc45 , in Xenopus extracts .	p27 is an inhibitor of Cdk2 and inhibits origin firing by preventing the loading of some replication proteins, including Cdc45, in Xenopus extracts.	0	7	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	0	1	5	6
As cells enter the S phase , the progressive decrease in p27 level allows phospho-CDK2 and CyclinA ( pCDK2 and CyclinA ) and phospho-CDK2 and Cyclin E ( pCDK2 and Cyclin E ) complexes to regain the activity XREF_BIBR XREF_BIBR .	As cells enter the S phase, the progressive decrease in p27 level allows phospho-CDK2 and CyclinA (pCDK2 and CyclinA) and phospho-CDK2 and Cyclin E (pCDK2 and Cyclin E) complexes to regain the activity XREF_BIBR XREF_BIBR.	11	35	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27 level	p27	phospho-CDK2	phospho-CDK2	phospho-cdk2	11	12	14	15
We show that p27Kip1 , like p21WAF1 , disrupts cyclin and cdk2 containing complexes of E2F-p130 leading to the accumulation of the E2F-p130 complexes , which is found in growth arrested cells .	We show that p27Kip1, like p21WAF1, disrupts cyclin and cdk2 containing complexes of E2F-p130 leading to the accumulation of the E2F-p130 complexes, which is found in growth arrested cells.	3	12	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27Kip1	p27Kip1	p27Kip1	cdk2	cdk2	cdk2	3	4	11	12
Although MEK inhibition does not reduce levels of cyclin E , it is possible that CDK2 activity is modulated by increases in p27 Kip1 .	Although MEK inhibition does not reduce levels of cyclin E, it is possible that CDK2 activity is modulated by increases in p27 Kip1.	15	24	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p27 Kip1	p27 Kip1	p27 Kip1	CDK2	CDK2	CDK2	22	24	15	16
p27 antagonizes the activity of not only Cdc2 , but also Cdk2 and Cdk4 .	p27 antagonizes the activity of not only Cdc2, but also Cdk2 and Cdk4.	0	13	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	0	1	11	12
In response to mitogenic stimuli , the level of p27 protein decreases , allowing CDK2 activation and entry into S phase XREF_BIBR , XREF_BIBR .	In response to mitogenic stimuli, the level of p27 protein decreases, allowing CDK2 activation and entry into S phase XREF_BIBR, XREF_BIBR.	9	15	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	9	10	14	15
Whereas nuclear p27 KIP1 inhibits CDK2 to stop cell cycle progression , excessive cytoplasmic p27 KIP1 appears to have a pro oncogenic effect , promoting cancer invasion and metastasis .	Whereas nuclear p27 KIP1 inhibits CDK2 to stop cell cycle progression, excessive cytoplasmic p27 KIP1 appears to have a pro oncogenic effect, promoting cancer invasion and metastasis.	2	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 KIP1	p27 KIP1	p27 KIP1	CDK2	CDK2	CDK2	2	4	5	6
All the above findings suggested that ATG could increase the levels of p27 ( Kip1 ) protein through inhibition of Akt and improvement of FOXO3a activity , in turn inhibited the CDK2 kinase activity , and eventually caused an overall inhibition of HSCs proliferation .	All the above findings suggested that ATG could increase the levels of p27 (Kip1) protein through inhibition of Akt and improvement of FOXO3a activity, in turn inhibited the CDK2 kinase activity, and eventually caused an overall inhibition of HSCs proliferation.	6	33	inhibited	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	p27	ATG could increase the levels of p27	p27	CDK2	CDK2	cdk2	12	13	31	32
Our results suggest that p27 Kip1 , a CKI known to prevent Cdk2 activity and block G1/S transition , XREF_BIBR is likely involved in the mechanism that prevents tetraploid neurons to undergo successive rounds of endoreplication in the chick retina .	Our results suggest that p27 Kip1, a CKI known to prevent Cdk2 activity and block G1/S transition, XREF_BIBR is likely involved in the mechanism that prevents tetraploid neurons to undergo successive rounds of endoreplication in the chick retina.	4	13	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	Cdk2	Cdk2	Cdk2	4	6	12	13
In summary , these results demonstrate that p27 levels in the CDK2 complex is regulated by DAP induced p21 , and stabilisation of p27 within the complex inhibits CDK2 activity .	In summary, these results demonstrate that p27 levels in the CDK2 complex is regulated by DAP induced p21, and stabilisation of p27 within the complex inhibits CDK2 activity.	21	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	23	24	28	29
There is also evidence that the G 1 phase increase in p27 kip1 protein levels resulting from heparin induced ERK activity decreases is critical for the heparin induced decreases in vascular smooth muscle cell proliferation because the stable accumulated p27 kip1 prevents activation of CDK2 [ XREF_BIBR ] .	There is also evidence that the G 1 phase increase in p27 kip1 protein levels resulting from heparin induced ERK activity decreases is critical for the heparin induced decreases in vascular smooth muscle cell proliferation because the stable accumulated p27 kip1 prevents activation of CDK2 [XREF_BIBR].	39	46	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 kip1	p27 kip1	p27 kip1	CDK2	CDK2	CDK2	39	41	44	45
Geminin blocks loading of the minichromosome maintenance complex onto the DNA , and p27 inhibits the kinase activity of Cdk2 .	Geminin blocks loading of the minichromosome maintenance complex onto the DNA, and p27 inhibits the kinase activity of Cdk2.	13	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	13	14	19	20
The previous results strongly suggested that p27 was inhibiting Cdk2 in CLL cells .	The previous results strongly suggested that p27 was inhibiting Cdk2 in CLL cells.	6	12	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	6	7	9	10
p27 inhibits CDK2 and CDK4 and induces growth arrest .	p27 inhibits CDK2 and CDK4 and induces growth arrest.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	0	1	2	3
As Cdk2 activity is blocked by p27 kip1 overexpression , we propose that mifepristone induced cell cycle arrest in G1 is mediated by p27 kip1 -induced Cdk2 inhibition upstream of PR activation , thus preventing ligand independent PR transcriptional activity required for cell cycle progression .	As Cdk2 activity is blocked by p27 kip1 overexpression, we propose that mifepristone induced cell cycle arrest in G1 is mediated by p27 kip1 -induced Cdk2 inhibition upstream of PR activation, thus preventing ligand independent PR transcriptional activity required for cell cycle progression.	1	9	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p27 kip1	p27 kip1 overexpression	p27 kip1	Cdk2	Cdk2	cdk2	6	8	1	2
In addition , in p27 knockout mice , ablation of CDK2 does not influence either tumor incidence or latency , although p27 impedes cell division by interrupting the interactions of CDK2 with cyclin E and A 59 .	In addition, in p27 knockout mice, ablation of CDK2 does not influence either tumor incidence or latency, although p27 impedes cell division by interrupting the interactions of CDK2 with cyclin E and A 59.	21	31	impedes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	21	22	30	31
p27 injected into cells and added to cell extracts was able to block cdk2 kinase activity and completely abolish DNA replication , most likely by inhibiting prereplication complex formation during the early minutes after fertilization .	p27 injected into cells and added to cell extracts was able to block cdk2 kinase activity and completely abolish DNA replication, most likely by inhibiting prereplication complex formation during the early minutes after fertilization.	0	18	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	cdk2	cdk2	cdk2	0	1	13	14
These results suggest that 4EBP dependent cell cycle arrest involves p27 Kip1 -mediated inhibition of CDK2 kinase activity .	These results suggest that 4EBP dependent cell cycle arrest involves p27 Kip1 -mediated inhibition of CDK2 kinase activity.	10	17	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	CDK2	CDK2	CDK2	10	12	15	16
In a second approach we asked whether the p27 present in the CLL cells was able to inhibit exogenous Cdk2 , using MEC1 extracts as the source of active Cdk2 .	In a second approach we asked whether the p27 present in the CLL cells was able to inhibit exogenous Cdk2, using MEC1 extracts as the source of active Cdk2.	7	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	8	9	19	20
Translation of the intron-1 containing pre-mRNA leads to production of a C-terminal truncated protein isoform p27 * , which is resistant to proteasomal degradation and inhibits CDK2 kinase activity , thereby inhibiting cell growth .	Translation of the intron-1 containing pre-mRNA leads to production of a C-terminal truncated protein isoform p27 *, which is resistant to proteasomal degradation and inhibits CDK2 kinase activity, thereby inhibiting cell growth.	15	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	15	16	26	27
The master regulator of metabolism and autophagy , mTOR , is regulated by cyclin dependent kinase 2 ( Cdk2 ) , which is , in turn , inhibited by p27 ( also known as cyclin dependent kinase inhibitor 1B ) .	The master regulator of metabolism and autophagy, mTOR, is regulated by cyclin dependent kinase 2 (Cdk2), which is, in turn, inhibited by p27 (also known as cyclin dependent kinase inhibitor 1B).	15	32	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	29	30	18	19
When PTHrP production lacking lung adenocarcinoma cells , transfected with with a pciNeo-PTHrP 1-87 expression plasmid , were examined for their growth and intracellular signalization aspects , the reduced mitogenesis observed was found linked to a block in G 1 and , from a molecular point of view , to the decreased expression of cyclin D2 and cyclin A2 , increased expression of p27 , decreased association of cyclin A2 and CDK2 , and increased activation of ERK [ XREF_BIBR ] .	When PTHrP production lacking lung adenocarcinoma cells, transfected with with a pciNeo-PTHrP 1-87 expression plasmid, were examined for their growth and intracellular signalization aspects, the reduced mitogenesis observed was found linked to a block in G 1 and, from a molecular point of view, to the decreased expression of cyclin D2 and cyclin A2, increased expression of p27, decreased association of cyclin A2 and CDK2, and increased activation of ERK [XREF_BIBR].	61	72	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	expression of p27	p27	CDK2	CDK2	cdk2	63	64	71	72
In this context , p27 does not impair Cdk2 and cyclin E activity as it remains in the cytoplasm and is sequestered by Cdk4 and cyclin D1 complexes [ XREF_BIBR ] .	In this context, p27 does not impair Cdk2 and cyclin E activity as it remains in the cytoplasm and is sequestered by Cdk4 and cyclin D1 complexes [XREF_BIBR].	4	12	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	4	5	8	9
Western blotting confirmed that compared with untreated cells , cdk2 , a key protein required for transition from the G1 phase to the S phase , was downregulated by 40 % , whereas p27 , which blocks cdk2 , was upregulated by almost 300 % in PSCs treated with 100 muM Pam ( XREF_FIG ) .	Western blotting confirmed that compared with untreated cells, cdk2, a key protein required for transition from the G1 phase to the S phase, was downregulated by 40%, whereas p27, which blocks cdk2, was upregulated by almost 300% in PSCs treated with 100 muM Pam (XREF_FIG).	33	40	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	cdk2	cdk2	cdk2	33	34	37	38
We further found that indomethacin , celecoxib and dexamethasone increased the mRNA and protein expressions of p27 ( kip1 ) and decreased those of cyclin D2 and p-cdk2 in hOBs .	We further found that indomethacin, celecoxib and dexamethasone increased the mRNA and protein expressions of p27 (kip1) and decreased those of cyclin D2 and p-cdk2 in hOBs.	6	28	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	celecoxib and dexamethasone increased the mRNA and protein expressions of p27	p27	p-cdk2	p-cdk2	p-cdk2	16	17	27	28
ERalpha transcriptional activity is virtually abolished under conditions where CDK2 activity is suppressed by the kinase inhibitor p27 or by a dominant negative CDK2 mutant , regardless the presence or absence of hormones XREF_BIBR .	ERalpha transcriptional activity is virtually abolished under conditions where CDK2 activity is suppressed by the kinase inhibitor p27 or by a dominant negative CDK2 mutant, regardless the presence or absence of hormones XREF_BIBR.	9	18	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	p27	p27	p27	CDK2	CDK2	CDK2	17	18	9	10
Thus , it can be hypothesized that in our experimental models after ribosomal stress , p27 kip1 binds to and inhibits CDK2 activity leading to downregulation of rRNA synthesis .	Thus, it can be hypothesized that in our experimental models after ribosomal stress, p27 kip1 binds to and inhibits CDK2 activity leading to downregulation of rRNA synthesis.	15	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 kip1	p27 kip1	p27 kip1	CDK2	CDK2	CDK2	15	17	21	22
p27 could directly inhibit the activities of CyclinE and Cdk2 which promotes S phase transition , and CyclinD and Cdk4 ,6 which promotes cell cycle progression in early G1 to late G1 [ XREF_BIBR ] .	p27 could directly inhibit the activities of CyclinE and Cdk2 which promotes S phase transition, and CyclinD and Cdk4,6 which promotes cell cycle progression in early G1 to late G1 [XREF_BIBR].	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	0	1	9	10
We previously found that p27 depletion caused increased apoptosis in cells deprived of growth factors and that CDK2 activity was consistently enhanced in these cases , suggesting that the CDK2 inhibition by p27 is instrumental in blocking apoptosis [ XREF_BIBR , XREF_BIBR ] .	We previously found that p27 depletion caused increased apoptosis in cells deprived of growth factors and that CDK2 activity was consistently enhanced in these cases, suggesting that the CDK2 inhibition by p27 is instrumental in blocking apoptosis [XREF_BIBR, XREF_BIBR].	29	33	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	32	33	29	30
Subsequent accumulation of p27 Kip1 protein impairs cyclin dependent kinase 2 ( CDK2 ) , the downstream functions of retinoblastoma ( Rb ) , and the transcription factor mothers against decapentaplegic homolog 3 ( SMAD3 ) .	Subsequent accumulation of p27 Kip1 protein impairs cyclin dependent kinase 2 (CDK2), the downstream functions of retinoblastoma (Rb), and the transcription factor mothers against decapentaplegic homolog 3 (SMAD3).	3	13	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	CDK2	CDK2	CDK2	3	5	12	13
qRT-PCR results showed that siAL359062 increased the mRNA expression level of CDKN1B ( encoding cyclin dependent kinase inhibitor 1B ) and decreased CCND1 ( encoding cyclin D1 ) , CCNE1 ( encoding cyclin E1 ) , CDK2 and 4 ( encoding cyclin dependent kinase 2 and 4 , respectively ) .	qRT-PCR results showed that siAL359062 increased the mRNA expression level of CDKN1B (encoding cyclin dependent kinase inhibitor 1B) and decreased CCND1 (encoding cyclin D1), CCNE1 (encoding cyclin E1), CDK2 and 4 (encoding cyclin dependent kinase 2 and 4, respectively).	4	45	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1B	siAL359062 increased the mRNA expression level of CDKN1B	cdkn1b	cyclin dependent kinase 2	cyclin dependent kinase 2	cyclin dependent kinase 2	11	12	41	45
sst2 antiproliferative effects , characterized by the inhibition of the entry in the S phase and the accumulation of the cells in G1 , due to p27 kip1 overexpression that sequesters cdk2 from cyclin E and induces accumulation of hypophosphorylated retinoblastoma gene product [ XREF_BIBR ] .	sst2 antiproliferative effects, characterized by the inhibition of the entry in the S phase and the accumulation of the cells in G1, due to p27 kip1 overexpression that sequesters cdk2 from cyclin E and induces accumulation of hypophosphorylated retinoblastoma gene product [XREF_BIBR].	26	32	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 kip1	p27 kip1 overexpression	p27 kip1	cdk2	cdk2	cdk2	26	28	31	32
1 In late G 1 , after the cell has committed to the next round of cell division , p27 is eliminated via SCF Skp2 to allow activation of Cdk1 and Cdk2 and , consequently , promote progression through the subsequent phases of the cell cycle .	1 In late G 1, after the cell has committed to the next round of cell division, p27 is eliminated via SCF Skp2 to allow activation of Cdk1 and Cdk2 and, consequently, promote progression through the subsequent phases of the cell cycle.	19	36	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	19	20	31	32
The presence of SCML2B had no effect on the activity of CDK2 and CYCE in the absence of p27 , but resulted in a significant inhibition of p27 containing CDK2 and CYCE complexes ( XREF_SUPPLEMENTARY ) , even considering that p27 alone reduced the activity of CDK2 and CYCE ( XREF_SUPPLEMENTARY , compare bar 1 with 4 ) .	The presence of SCML2B had no effect on the activity of CDK2 and CYCE in the absence of p27, but resulted in a significant inhibition of p27 containing CDK2 and CYCE complexes (XREF_SUPPLEMENTARY), even considering that p27 alone reduced the activity of CDK2 and CYCE (XREF_SUPPLEMENTARY, compare bar 1 with 4).	40	48	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	40	41	46	47
The accumulation of p27 protein in EWS-Fli1-depleted cells inhibited cdk2 kinase activity and was related to the stability of p27 protein , which resulted from a decrease in Skp2 protein .	The accumulation of p27 protein in EWS-Fli1-depleted cells inhibited cdk2 kinase activity and was related to the stability of p27 protein, which resulted from a decrease in Skp2 protein.	3	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	cdk2	cdk2	cdk2	3	4	9	10
Antisense mediated inhibition of p27 ( Kip1 ) expression in 4D5 treated BT474 cells further demonstrated that in the absence of p27 ( Kip1 ) accumulation , p27 ( Kip1 ) redirection onto Cdk2 complexes is sufficient to inactivate Cdk2 and establish the G ( 1 ) block .	Antisense mediated inhibition of p27 (Kip1) expression in 4D5 treated BT474 cells further demonstrated that in the absence of p27 (Kip1) accumulation, p27 (Kip1) redirection onto Cdk2 complexes is sufficient to inactivate Cdk2 and establish the G (1) block.	29	40	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Kip1	Kip1	Kip1	Cdk2	Cdk2	Cdk2	29	30	39	40
The increased p27 protein inhibited cdk2 kinase activity and cell proliferation .	The increased p27 protein inhibited cdk2 kinase activity and cell proliferation.	2	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	cdk2	cdk2	cdk2	2	3	5	6
p27Kip1 inhibited Cdk2 activity , suggesting that Kip CKIs promote G1 arrest in VSMCs by binding cyclin E/Cdk2 .	p27Kip1 inhibited Cdk2 activity, suggesting that Kip CKIs promote G1 arrest in VSMCs by binding cyclin E/Cdk2.	0	3	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27Kip1	p27Kip1	p27Kip1	Cdk2	Cdk2	Cdk2	0	1	2	3
These holoenzymes are inhibited by CDKIs ; specifically , p27kip1 , which is constitutively expressed in resting naive T cells , inhibits the activities of cyclinD2/cdk4/6 and cyclinE and cdk2 .	These holoenzymes are inhibited by CDKIs; specifically, p27kip1, which is constitutively expressed in resting naive T cells, inhibits the activities of cyclinD2/cdk4/6 and cyclinE and cdk2.	9	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27kip1	p27kip1, which is constitutively expressed	p27kip1	cdk2	cdk2	cdk2	9	10	29	30
Indeed , G1 cell cycle arrest due to p27 Kip1 suppression of CDK2 activity is a documented effect of trastuzumab treatment [ XREF_BIBR ] .	Indeed, G1 cell cycle arrest due to p27 Kip1 suppression of CDK2 activity is a documented effect of trastuzumab treatment [XREF_BIBR].	8	13	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	CDK2	CDK2	CDK2	8	10	12	13
We found that p27 ( Kip1 ) overexpression inhibits cdk2 kinase activity , but not cdk6 kinase activity in HeLa cells .	We found that p27 (Kip1) overexpression inhibits cdk2 kinase activity, but not cdk6 kinase activity in HeLa cells.	3	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27 (Kip1) overexpression	p27	cdk2	cdk2	cdk2	3	4	9	10
Nuclear p27 functions to inhibit CDK2 and CDK4 activity resulting in hypophosphorylation of pRB and inhibition of cell cycle progression .	Nuclear p27 functions to inhibit CDK2 and CDK4 activity resulting in hypophosphorylation of pRB and inhibition of cell cycle progression.	1	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	1	2	5	6
As XREF_FIG demonstrated that DAP induced p21 is responsible for the increase in the total level of p27 , it was necessary to examine whether p21 was also required for increasing p27 in the CDK2 complex following DAP treatment , and if this resulted in p27 dependent inhibition of CDK2 kinase activity .	As XREF_FIG demonstrated that DAP induced p21 is responsible for the increase in the total level of p27, it was necessary to examine whether p21 was also required for increasing p27 in the CDK2 complex following DAP treatment, and if this resulted in p27 dependent inhibition of CDK2 kinase activity.	45	51	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	45	46	49	50
Overexpression of p27Kip1 allowed accumulation of the inhibitor in the nucleus but inhibited entry of Cdk2 into the nucleus following serum stimulation .	Overexpression of p27Kip1 allowed accumulation of the inhibitor in the nucleus but inhibited entry of Cdk2 into the nucleus following serum stimulation.	0	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27Kip1	Overexpression of p27Kip1	p27kip1	Cdk2	Cdk2	cdk2	2	3	15	16
Exposure of PDGF , which stimulates cell cycle entry but not progression through G1 , induces the formation of cyclin D1-Cdk4 complexes that bind p27kip1 and titrate the pool of Kip1 available to inhibit Cdk2 .	Exposure of PDGF, which stimulates cell cycle entry but not progression through G1, induces the formation of cyclin D1-Cdk4 complexes that bind p27kip1 and titrate the pool of Kip1 available to inhibit Cdk2.	28	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Kip1	Kip1	Kip1	Cdk2	Cdk2	Cdk2	30	31	34	35
Roscovitine ' s functional effects are not limited to CDK2-inhibition -- for instance , it has been noted elsewhere that ectopic p27 inhibited CDK2 but could not prevent SV40 from inducing quiescent fibroblasts to cycle , whereas roscovitine could prevent cycling XREF_BIBR .	Roscovitine 's functional effects are not limited to CDK2-inhibition -- for instance, it has been noted elsewhere that ectopic p27 inhibited CDK2 but could not prevent SV40 from inducing quiescent fibroblasts to cycle, whereas roscovitine could prevent cycling XREF_BIBR.	20	27	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	21	22	23	24
Interestingly , p27 deficient MEFs downregulate CDK2 kinase activity to wild-type levels ( Koff , A ., personal communication ) and arrest at confluency .	Interestingly, p27 deficient MEFs downregulate CDK2 kinase activity to wild-type levels (Koff, A., personal communication) and arrest at confluency.	2	8	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	2	3	6	7
Thus , while nuclear p27 inhibits CDK2 to restrain cell cycle , excessive cytoplasmic p27 can have a pro oncogenic effect to promote cancer invasion and metastasis .	Thus, while nuclear p27 inhibits CDK2 to restrain cell cycle, excessive cytoplasmic p27 can have a pro oncogenic effect to promote cancer invasion and metastasis.	3	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	4	5	6	7
Preincubation of the anti-p27 Kip1 antibody with a saturating amount of immunogenic peptide completely restored the Cdk2 inhibitory activity , confirming that p27 Kip1 is the major factor responsible for this activity .	Preincubation of the anti-p27 Kip1 antibody with a saturating amount of immunogenic peptide completely restored the Cdk2 inhibitory activity, confirming that p27 Kip1 is the major factor responsible for this activity.	4	18	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Kip1	Kip1	Kip1	Cdk2	Cdk2	Cdk2	4	5	16	17
Mechanistic analysis demonstrated that PTEN induces the expression of p27 Kip1 and reduces the activity of CDK2 to inhibit G1-S transition , leading to suppression of tumor development [ XREF_BIBR ] .	Mechanistic analysis demonstrated that PTEN induces the expression of p27 Kip1 and reduces the activity of CDK2 to inhibit G1-S transition, leading to suppression of tumor development [XREF_BIBR].	4	17	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 Kip1	PTEN induces the expression of p27 Kip1	p27 kip1	CDK2	CDK2	cdk2	9	11	16	17
Alternatively , AKT phosphorylation and downregulation of p21 XREF_BIBR or high level induction of D cyclin translation secondary to TORC1 activation XREF_BIBR may overcome the inhibition of CDK2 by p27 .	Alternatively, AKT phosphorylation and downregulation of p21 XREF_BIBR or high level induction of D cyclin translation secondary to TORC1 activation XREF_BIBR may overcome the inhibition of CDK2 by p27.	23	30	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	29	30	27	28
It is also well established that p27 specifically inhibits the activity of Cdk2 in G1-to-S preventing prmature onset of DNA replication [ XREF_BIBR ] .	It is also well established that p27 specifically inhibits the activity of Cdk2 in G1-to-S preventing prmature onset of DNA replication [XREF_BIBR].	6	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	6	7	12	13
p27 KIP1 inhibits the activity of cyclin-E and CDK2 during G 0 and early G 1 and plays a role in cell cycle exit .	p27 KIP1 inhibits the activity of cyclin-E and CDK2 during G 0 and early G 1 and plays a role in cell cycle exit.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 KIP1	p27 KIP1	p27 KIP1	CDK2	CDK2	CDK2	0	2	8	9
Inactivation of Cdk2 by p27 maintains the interaction between RB and E2F and inhibits cell cycle progression XREF_BIBR .	Inactivation of Cdk2 by p27 maintains the interaction between RB and E2F and inhibits cell cycle progression XREF_BIBR.	0	5	Inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	4	5	2	3
From these results we conclude that androgenic repression of LNCaP 104-R1 and 104-R2 cell proliferation is due to the induction of p27Kip1 , which in turn inhibits Cdk2 , a factor critical for cell cycle progression and proliferation .	From these results we conclude that androgenic repression of LNCaP 104-R1 and 104-R2 cell proliferation is due to the induction of p27Kip1, which in turn inhibits Cdk2, a factor critical for cell cycle progression and proliferation.	19	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27Kip1	p27Kip1	p27Kip1	Cdk2	Cdk2	Cdk2	21	22	27	28
Nonphosphorylated p27 is no longer a target for ubiquitin mediated degradation and this stabilized p27 now also inhibits CDK2 activity .	Nonphosphorylated p27 is no longer a target for ubiquitin mediated degradation and this stabilized p27 now also inhibits CDK2 activity.	14	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK2	CDK2	CDK2	14	15	18	19
Both p27 Kip1 and p57 Kip2 are potent inhibitors of cyclin E dependent kinase Cdk2 , but at high concentrations they also block Cdks4/6 .	Both p27 Kip1 and p57 Kip2 are potent inhibitors of cyclin E dependent kinase Cdk2, but at high concentrations they also block Cdks4/6.	1	15	are potent inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	Cdk2	Cdk2	Cdk2	1	3	14	15
And the Cdk2 and cyclin E , inhibited by p27 [ XREF_BIBR ] , were increased .	And the Cdk2 and cyclin E, inhibited by p27 [XREF_BIBR], were increased.	2	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	9	10	2	3
Two early reports found IR caused p53 and p21 dependent depletion of CDC2 , Cyclin A , and Cyclin B mRNA and protein XREF_BIBR , XREF_BIBR .	Two early reports found IR caused p53 and p21 dependent depletion of CDC2, Cyclin A, and Cyclin B mRNA and protein XREF_BIBR, XREF_BIBR.	6	23	depletion	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	CDC2	CDC2	CDC2	8	9	12	13
Downregulation of cell cycle inhibitor P21 may also inhibit CDK1 , which has a critical role at the G2/M transition XREF_BIBR .	Downregulation of cell cycle inhibitor P21 may also inhibit CDK1, which has a critical role at the G2/M transition XREF_BIBR.	0	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	P21	P21	P21	CDK1	CDK1	CDK1	5	6	9	10
The early induction p21 , which efficiently inhibit CDK1 in response to DNA damage , can cause the arrest of G2 and an increase in efficiency of KSHV reactivation [ XREF_BIBR , XREF_BIBR ] .	The early induction p21, which efficiently inhibit CDK1 in response to DNA damage, can cause the arrest of G2 and an increase in efficiency of KSHV reactivation [XREF_BIBR, XREF_BIBR].	0	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	3	4	8	9
It is thus conceivable that phosphomimetic unstable p21S130D , similar to loss of p21 , resulting in a hyperactive Cdk1 , and non phosphorylatable stable p21 , attenuating the activity of Cdk1 , could disrupt the spatially and timely regulated thresholds of Cdk1 activity and consequently its controlled mitotic events , leading further to segregation failures in anaphase .	It is thus conceivable that phosphomimetic unstable p21S130D, similar to loss of p21, resulting in a hyperactive Cdk1, and non phosphorylatable stable p21, attenuating the activity of Cdk1, could disrupt the spatially and timely regulated thresholds of Cdk1 activity and consequently its controlled mitotic events, leading further to segregation failures in anaphase.	22	34	attenuating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk1	Cdk1	Cdk1	25	26	31	32
p53 can induce p21 up-regulation , which inhibits cdc2 activation , then causes cells to arrest in G 2 / M phase [ XREF_BIBR ] .	p53 can induce p21 up-regulation, which inhibits cdc2 activation, then causes cells to arrest in G 2 / M phase [XREF_BIBR].	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	cdc2	cdc2	cdc2	3	4	8	9
Consequently gnidimacrin inhibited cell growth through G ( 2 )-phase arrest not only by the p21 ( WAF1 and Cip1 )-dependent suppression of cdc2 activity , but also by subsequent transcriptional suppression of cdc2 itself .	Consequently gnidimacrin inhibited cell growth through G (2)-phase arrest not only by the p21 (WAF1 and Cip1)-dependent suppression of cdc2 activity, but also by subsequent transcriptional suppression of cdc2 itself.	12	24	suppression	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	p21	p21	p21	cdc2	cdc2	cdc2	15	16	23	24
Meanwhile , p21 inhibits the activity of cdc2 and mediates assembly and activation of cyclinD-cdk4/6 in the cytoplasm , as well as inhibiting their activity in the nucleus XREF_BIBR .	Meanwhile, p21 inhibits the activity of cdc2 and mediates assembly and activation of cyclinD-cdk4/6 in the cytoplasm, as well as inhibiting their activity in the nucleus XREF_BIBR.	2	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	cdc2	cdc2	cdc2	2	3	7	8
p21 is a potent cyclin dependent kinase inhibitor and inhibits the activity of cyclin-CDK2 or -CDK1 complexes , and thus functions as a regulator of cell cycle progression in G 1 .	p21 is a potent cyclin dependent kinase inhibitor and inhibits the activity of cyclin-CDK2 or -CDK1 complexes, and thus functions as a regulator of cell cycle progression in G 1.	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	-CDK1	-CDK1	-CDK1	0	1	15	16
p21 also inhibits the CDK1 and cyclin B complex and maintains the G2 arrest [ XREF_BIBR - XREF_BIBR ] .	p21 also inhibits the CDK1 and cyclin B complex and maintains the G2 arrest [XREF_BIBR - XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	0	1	4	5
Stabilised and activated p53 can induce cell cycle arrest by enhancing the expression of p21 which itself inhibits Cdk1 ( cyclin dependent kinase 1 ) and other Cdks , decelerating cell cycle progression [ XREF_BIBR ] .	Stabilised and activated p53 can induce cell cycle arrest by enhancing the expression of p21 which itself inhibits Cdk1 (cyclin dependent kinase 1) and other Cdks, decelerating cell cycle progression [XREF_BIBR].	3	27	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	p21	p53 can induce cell cycle arrest by enhancing the expression of p21	p21	Cdk1	Cdk1	cdk1	14	15	18	19
In conclusion , these results demonstrated that HMH upregulates the expression of p21 , activates Myt1 and inhibits cdc2 by phospho-cdc2 ( Y15 ) , and triggers G2 phase arrest in both MGC-803 cells and SMMC-7721 cells .	In conclusion, these results demonstrated that HMH upregulates the expression of p21, activates Myt1 and inhibits cdc2 by phospho-cdc2 (Y15), and triggers G2 phase arrest in both MGC-803 cells and SMMC-7721 cells.	7	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	HMH upregulates the expression of p21	p21	cdc2	cdc2	cdc2	12	13	18	19
As p21 inhibits CDK1 and Cyclin B complexes , these data together with the inhibitory effect of MS-275 on the cell cycle restricting WEE1 and pCDK1 node can explain why such cells traverse from S to G2/M phase .	As p21 inhibits CDK1 and Cyclin B complexes, these data together with the inhibitory effect of MS-275 on the cell cycle restricting WEE1 and pCDK1 node can explain why such cells traverse from S to G2/M phase.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	1	2	3	4
We have recently shown that p21 binds to and inhibits the activity of Cdk1 and cyclin B1 , and is important for a fine tuned mitotic progression .	We have recently shown that p21 binds to and inhibits the activity of Cdk1 and cyclin B1, and is important for a fine tuned mitotic progression.	5	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk1	Cdk1	Cdk1	5	6	13	14
p21 has been shown to efficiently inhibit CDK1 in response to DNA damage , which was sufficient to cause a permanent G2 arrest [ XREF_BIBR ] .	p21 has been shown to efficiently inhibit CDK1 in response to DNA damage, which was sufficient to cause a permanent G2 arrest [XREF_BIBR].	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	0	1	7	8
Previous studies found that IR can cause p53 and p21 dependent downregulation of CDC2 , Cyclin A , and Cyclin B1 , similar to what we observe for Nutlin .	Previous studies found that IR can cause p53 and p21 dependent downregulation of CDC2, Cyclin A, and Cyclin B1, similar to what we observe for Nutlin.	7	20	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	CDC2	CDC2	CDC2	9	10	13	14
One role of p21 during the cell cycle is to inhibit CDK1 , a kinase that associates with cyclin B1 to modulate G2-M phase transition ( XREF_FIG ) .	One role of p21 during the cell cycle is to inhibit CDK1, a kinase that associates with cyclin B1 to modulate G2-M phase transition (XREF_FIG).	1	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	3	4	11	12
Suppression of p53 expression by small interfering RNA in RT4 cells restored Cdc25C expression and down-regulated p21 and WAF1 expression , which allowed Cdc25C and CDK1 activation , which then led to a G ( 2 )-M arrest and an enhanced growth-inhibitory effect by flavokawain A [ XREF_BIBR ] .	Suppression of p53 expression by small interfering RNA in RT4 cells restored Cdc25C expression and down-regulated p21 and WAF1 expression, which allowed Cdc25C and CDK1 activation, which then led to a G (2)-M arrest and an enhanced growth-inhibitory effect by flavokawain A [XREF_BIBR].	2	26	allowed	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p53 expression by small interfering RNA in RT4 cells restored Cdc25C expression and down-regulated p21 and WAF1 expression	p21	CDK1	CDK1	cdk1	16	17	25	26
SAHA increased expression of p21cip1 and waf1 and p27Kip1 , down regulated cyclins A and B , and suppressed CDK1 .	SAHA increased expression of p21cip1 and waf1 and p27Kip1, down regulated cyclins A and B, and suppressed CDK1.	0	20	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	waf1	SAHA increased expression of p21cip1 and waf1	waf1	CDK1	CDK1	cdk1	6	7	19	20
Additionally , by inhibiting CDK2 , p21 inhibits the induction of CDC2 and CCNB1 indirectly , as the expression of these genes at the G1/S transition is mediated by the NF-Y transcription factor following its phosphorylation by CDK2 .	Additionally, by inhibiting CDK2, p21 inhibits the induction of CDC2 and CCNB1 indirectly, as the expression of these genes at the G1/S transition is mediated by the NF-Y transcription factor following its phosphorylation by CDK2.	6	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDC2	CDC2	CDC2	6	7	11	12
R box dependent repression requires p21 and waf1 , and overexpression of p21 and waf1 also represses the cdc2 promoter .	R box dependent repression requires p21 and waf1, and overexpression of p21 and waf1 also represses the cdc2 promoter.	10	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	overexpression of p21	p21	cdc2	cdc2	cdc2	12	13	18	19
Furthermore , p21 directly binds to and inhibits the activity of Cdk1 and cyclin B1 in colorectal cancer cells .	Furthermore, p21 directly binds to and inhibits the activity of Cdk1 and cyclin B1 in colorectal cancer cells.	2	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk1	Cdk1	Cdk1	2	3	11	12
While the present and previous studies demonstrate that in several frequently studied p53-proficient cancer cell lines ( HCT-116 , U2OS , MCF7 ) CycB1-Cdk1 complexes are minor p21 targets XREF_BIBR , XREF_BIBR , XREF_BIBR , we can not exclude that p21 contributes to G2 arrest by inhibiting Cdk1 associated with CycA .	While the present and previous studies demonstrate that in several frequently studied p53-proficient cancer cell lines (HCT-116, U2OS, MCF7) CycB1-Cdk1 complexes are minor p21 targets XREF_BIBR, XREF_BIBR, XREF_BIBR, we can not exclude that p21 contributes to G2 arrest by inhibiting Cdk1 associated with CycA.	40	48	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	Cdk1	Cdk1	Cdk1	40	41	47	48
In particular , paclitaxel treatment of breast cancer cells leads to transcriptional up-regulation of p21 Cip1 , which inhibits Cdc2 ( cell division cycle 2 )/cyclin B kinase activity , thereby delaying entry into mitosis where the microtubule inhibitor paclitaxel is most active [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In particular, paclitaxel treatment of breast cancer cells leads to transcriptional up-regulation of p21 Cip1, which inhibits Cdc2 (cell division cycle 2)/cyclin B kinase activity, thereby delaying entry into mitosis where the microtubule inhibitor paclitaxel is most active [XREF_BIBR, XREF_BIBR, XREF_BIBR].	14	48	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 Cip1	p21 Cip1	p21 Cip1	Cdc2	Cdc2	Cdc2	14	16	19	20
The early induction of p21 described here could therefore inhibit Cdk1 , support the G2 arrest and increase the efficiency of virus reactivation .	The early induction of p21 described here could therefore inhibit Cdk1, support the G2 arrest and increase the efficiency of virus reactivation.	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk1	Cdk1	Cdk1	4	5	10	11
However , p21 and waf1 does not associate with cdk7 and cyclin H and only weakly inhibits cdk1 and cyclin B [ XREF_BIBR ] .	However, p21 and waf1 does not associate with cdk7 and cyclin H and only weakly inhibits cdk1 and cyclin B [XREF_BIBR].	2	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	cdk1	cdk1	cdk1	2	3	17	18
Data obtained with p21 CIP and WAF1 suppression in control cells support the hypothesis that inhibition of CDK1 by p21 CIP and WAF1 is involved in the mitotic exit network ( XREF_FIG ) .	Data obtained with p21 CIP and WAF1 suppression in control cells support the hypothesis that inhibition of CDK1 by p21 CIP and WAF1 is involved in the mitotic exit network (XREF_FIG).	15	22	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	19	20	17	18
When activated , p21 inhibits CDK1 , CKD2 , and CDK4/6 complex , resulting in cell cycle arrest at G1 and S phases .	When activated, p21 inhibits CDK1, CKD2, and CDK4/6 complex, resulting in cell cycle arrest at G1 and S phases.	3	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	3	4	5	6
p21 , a p53 target gene , mediates cell cycle G1 phase arrest through binding and inhibiting the activity of cyclin-CDK2 or CDK1 complexes XREF_BIBR .	p21, a p53 target gene, mediates cell cycle G1 phase arrest through binding and inhibiting the activity of cyclin-CDK2 or CDK1 complexes XREF_BIBR.	0	24	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	0	1	22	23
p21 , as a potent cyclin dependent kinase inhibitor , is a pivotal regulator and can also inhibit the activity of CDK1 and strengthen G 2 / M phase arrest .	p21, as a potent cyclin dependent kinase inhibitor, is a pivotal regulator and can also inhibit the activity of CDK1 and strengthen G 2 / M phase arrest.	0	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	0	1	21	22
However , it was reported that p21 activation inhibits p-CDK1 and results in G2/M arrest , 21 suggesting that p-CDK1 may be regulated by alternative pathway mechanisms and different cancer types may be regulated by different pathways .	However, it was reported that p21 activation inhibits p-CDK1 and results in G2/M arrest, 21 suggesting that p-CDK1 may be regulated by alternative pathway mechanisms and different cancer types may be regulated by different pathways.	6	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	p-CDK1	p-CDK1	p-CDK1	6	7	9	10
CDK1 , at least in some tissues , may be the crucial target of p21 in tumorigenesis XREF_BIBR because p21 effectively inhibits the kinase activity of CDK1 both in unstressed cells and after genotoxic stresses , leading to growth arrest in the G2 phase of the cell cycle XREF_BIBR - XREF_BIBR ( XREF_FIG ) .	CDK1, at least in some tissues, may be the crucial target of p21 in tumorigenesis XREF_BIBR because p21 effectively inhibits the kinase activity of CDK1 both in unstressed cells and after genotoxic stresses, leading to growth arrest in the G2 phase of the cell cycle XREF_BIBR - XREF_BIBR (XREF_FIG).	19	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	19	20	26	27
AGS cells treated with Tan-IIA up-regulated the protein expression of TNFalpha , FAS , p-p38 , p-JNK , p53 , p21 , caspase-3 and caspase-8 but reduced that of p-ERK , CDC2 , cyclin A , and cyclin B1 .	AGS cells treated with Tan-IIA up-regulated the protein expression of TNFalpha, FAS, p-p38, p-JNK, p53, p21, caspase-3 and caspase-8 but reduced that of p-ERK, CDC2, cyclin A, and cyclin B1.	0	32	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	AGS cells treated with Tan-IIA up-regulated the protein expression of TNFalpha, FAS, p-p38, p-JNK, p53, p21	p21	CDC2	CDC2	cdc2	20	21	31	32
p21 can directly inhibit Cdc2 .	p21 can directly inhibit Cdc2.	0	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdc2	Cdc2	Cdc2	0	1	4	5
Previous reports ( Ciardiello et al , 2000 ) have demonstrated that ErbB2 overexpression confers to malignant cells chemoresistance to anticancer drugs , as it activates the cycline dependent kinase inhibitor p21 Cip1 , which in turn inhibits the p34 cdc2 kinase ( Yu et al , 1998 ) .	Previous reports (Ciardiello et al, 2000) have demonstrated that ErbB2 overexpression confers to malignant cells chemoresistance to anticancer drugs, as it activates the cycline dependent kinase inhibitor p21 Cip1, which in turn inhibits the p34 cdc2 kinase (Yu et al, 1998).	31	41	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21 Cip1	p21 Cip1	p21 Cip1	p34 cdc2	p34 cdc2	p34 cdc2	31	33	39	41
They include cyclin A , which activates Cdk1 105 ; the mitotic kinase Nek2 , which is important for centrosome separation 106 ; and the CDK-inhibitor p21 107 .	They include cyclin A, which activates Cdk1 105; the mitotic kinase Nek2, which is important for centrosome separation 106; and the CDK-inhibitor p21 107.	1	27	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	Cdk1	Cdk1	Cdk1	26	27	7	8
The p21 protein binds to and inhibits the activity of cyclin-CDK2 or -CDK1 complexes , and thus functions as a regulator of cell cycle progression in the G1 phase .	The p21 protein binds to and inhibits the activity of cyclin-CDK2 or -CDK1 complexes, and thus functions as a regulator of cell cycle progression in the G1 phase.	1	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	-CDK1	-CDK1	-CDK1	1	2	12	13
XREF_BIBR CDK1 regulates the G2/M phase with specificity , and p21 may cause G2/M phase arrest by inhibiting the functions of CDK1 .	XREF_BIBR CDK1 regulates the G2/M phase with specificity, and p21 may cause G2/M phase arrest by inhibiting the functions of CDK1.	10	22	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK1	CDK1	CDK1	10	11	21	22
Subsequently , P21 binds to and inhibits the activity of cyclin-CDK2 , -CDK1 , and -CDK4/6 complexes , thus functioning as a regulator of cell cycle progression at G1 [ XREF_BIBR , XREF_BIBR ] .	Subsequently, P21 binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, thus functioning as a regulator of cell cycle progression at G1 [XREF_BIBR, XREF_BIBR].	2	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21	P21	-CDK1	-CDK1	-CDK1	2	3	12	13
It is possible that other proteins that affect p34Cdc2 activity , particularly p21 Cip1 and Waf1 that can inhibit p34Cdc2 , and is itself also a caspase-3 target and has an important role in the proliferation of normal HSCs by Survivin , may play a role in the anti-apoptotic Survivin-caspase-3-Wee1-p34Cdc2 axis we have described .	It is possible that other proteins that affect p34Cdc2 activity, particularly p21 Cip1 and Waf1 that can inhibit p34Cdc2, and is itself also a caspase-3 target and has an important role in the proliferation of normal HSCs by Survivin, may play a role in the anti-apoptotic Survivin-caspase-3-Wee1-p34Cdc2 axis we have described.	9	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Waf1	Waf1	Waf1	p34Cdc2	p34Cdc2	p34Cdc2	15	16	19	20
On the other hand , Cdc2 inhibition by p21 requires supraphysiological levels of the inhibitor , which may not be possible in cells following DNA damage [ XREF_BIBR ] .	On the other hand, Cdc2 inhibition by p21 requires supraphysiological levels of the inhibitor, which may not be possible in cells following DNA damage [XREF_BIBR].	5	9	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	p21	p21	p21	Cdc2	Cdc2	Cdc2	8	9	5	6
It could be further speculated that , in the presence of MET inhibitors , nuclear p21 prevents CDK1 from stimulating homologous recombination via the BRCA2 and RAD51 complex ( Esashi etal , 2005 ) .	It could be further speculated that, in the presence of MET inhibitors, nuclear p21 prevents CDK1 from stimulating homologous recombination via the BRCA2 and RAD51 complex (Esashi etal, 2005).	14	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	15	16	17	18
Upregulation of p53 leads to G2/M arrest through the induction of CDK inhibitor p21 , which inhibits cdc2 activity by binding directly to Cdc and Cyclin B1 complexes .	Upregulation of p53 leads to G2/M arrest through the induction of CDK inhibitor p21, which inhibits cdc2 activity by binding directly to Cdc and Cyclin B1 complexes.	9	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	cdc2	cdc2	cdc2	13	14	17	18
In G2 , p21waf1 and cip1 expression blocks cdc2 and cyclin B activity , likely through an indirect mechanism involving inhibition of the cdk2 and cyclin A complex , and prevents progression into M phase .	In G2, p21waf1 and cip1 expression blocks cdc2 and cyclin B activity, likely through an indirect mechanism involving inhibition of the cdk2 and cyclin A complex, and prevents progression into M phase.	3	12	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cip1	cip1 expression	cip1	cdc2	cdc2	cdc2	5	6	8	9
The cell-cycle machinery involves the cyclin dependent kinases ( CDK ) and cyclin complex , and p21 is known to suppress CDK1 activity via a p53 independent pathway .	The cell-cycle machinery involves the cyclin dependent kinases (CDK) and cyclin complex, and p21 is known to suppress CDK1 activity via a p53 independent pathway.	16	22	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	16	17	21	22
Ectopic expression of p27 Kip1 and p21 Waf1 and Cip1 may also inhibit CDK1 , which has a critical role at the G2/M boundary , and has recently been implicated in G1/S control ( Satyanarayana et al , 2008 ) .	Ectopic expression of p27 Kip1 and p21 Waf1 and Cip1 may also inhibit CDK1, which has a critical role at the G2/M boundary, and has recently been implicated in G1/S control (Satyanarayana et al, 2008).	1	29	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	expression of p27 Kip1 and p21 Waf1 and Cip1	cip1	CDK1	CDK1	cdk1	9	10	13	14
To examine how HCV promotes CDK1 activity , we analyzed the expression level of the cytoplasmic p21 protein that directly inhibits CDK1 activity .	To examine how HCV promotes CDK1 activity, we analyzed the expression level of the cytoplasmic p21 protein that directly inhibits CDK1 activity.	16	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	16	17	21	22
Overall , p21 is known to induce cell cycle arrest at G 2 by inhibiting cdc2 [ XREF_BIBR - XREF_BIBR ] .	Overall, p21 is known to induce cell cycle arrest at G 2 by inhibiting cdc2 [XREF_BIBR - XREF_BIBR].	2	17	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	cdc2	cdc2	cdc2	2	3	15	16
Accumulating evidence shows that cdc2 not only promotes G ( 2 )-M transition but is also capable of regulating G ( 1 ) progress and G ( 1 )-S transition via association with multiple interphase cyclins ; cdc2 activity can be inhibited by p21 and p27 , two traditional G ( 1 ) CDK inhibitors .	Accumulating evidence shows that cdc2 not only promotes G (2)-M transition but is also capable of regulating G (1) progress and G (1)-S transition via association with multiple interphase cyclins; cdc2 activity can be inhibited by p21 and p27, two traditional G (1) CDK inhibitors.	37	54	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	cdc2	cdc2	cdc2	43	44	37	38
DH-PMF induced G 2 / M and subG 1 cell cycle arrest , increased the levels of p21 WAF1 and CIP1 and p27 KIP1 , and reduced the expression of cyclin D1 , CDC2 , and c-MYC .	DH-PMF induced G 2 / M and subG 1 cell cycle arrest, increased the levels of p21 WAF1 and CIP1 and p27 KIP1, and reduced the expression of cyclin D1, CDC2, and c-MYC.	0	34	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 WAF1	DH-PMF induced G 2 / M and subG 1 cell cycle arrest, increased the levels of p21 WAF1	p21 waf1	CDC2	CDC2	cdc2	17	19	33	34
Moreover , as a transcription target of p53 , p21 also can effectively inhibit the kinase activity of CDK1 .	Moreover, as a transcription target of p53, p21 also can effectively inhibit the kinase activity of CDK1.	9	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	9	10	18	19
CDK1 is negatively regulated by p21 , a CDK1 inhibitor XREF_BIBR .	CDK1 is negatively regulated by p21, a CDK1 inhibitor XREF_BIBR.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	5	6	0	1
We also observed an increase in Wee1 levels and an accumulation of p21 WAF1 , components of the G2/M checkpoint that inhibits cdc2 .	We also observed an increase in Wee1 levels and an accumulation of p21 WAF1, components of the G2/M checkpoint that inhibits cdc2.	12	23	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	p21 WAF1	p21 WAF1	p21 WAF1	cdc2	cdc2	cdc2	12	14	22	23
p21 suppressed the activity of E2F responsive promoters ( dihydrofolate reductase and cdc2 ) , but E2F-unresponsive promoters ( c-fos and simian virus 40 early ) were unaffected .	p21 suppressed the activity of E2F responsive promoters (dihydrofolate reductase and cdc2), but E2F-unresponsive promoters (c-fos and simian virus 40 early) were unaffected.	0	13	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	cdc2	cdc2	cdc2	0	1	12	13
The upregulation of CDKN1A in combination with decreased cyclin B1 suggested a potential defect in the mitotic machinery of Tet1/2 DKO cells , specifically at the level of CDK1 activity , as CDK1 can be inhibited by CDKN1A activity and rendered inactive in the absence of cyclin B1 .	The upregulation of CDKN1A in combination with decreased cyclin B1 suggested a potential defect in the mitotic machinery of Tet1/2 DKO cells, specifically at the level of CDK1 activity, as CDK1 can be inhibited by CDKN1A activity and rendered inactive in the absence of cyclin B1.	32	40	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK1	CDK1	CDK1	37	38	32	33
G2/M - a later checkpoint , prevents cells from entering into mitosis via inhibition of Cdc2 and cyclin B. Interestingly , three key proteins that regulate this checkpoint are encoded by genes that were highly expressed in the carcinoma tumors : p21 , which inhibits Cdc2 directly , 14-3-3sigma , which anchors Cdc2 in the cytoplasm where it can not induce mitosis , and GAdd45 , which specifically dissociates Cdc2 from cyclin B1 by co-association with Cdc2 [ XREF_BIBR , XREF_BIBR ] .	G2/M - a later checkpoint, prevents cells from entering into mitosis via inhibition of Cdc2 and cyclin B. Interestingly, three key proteins that regulate this checkpoint are encoded by genes that were highly expressed in the carcinoma tumors : p21, which inhibits Cdc2 directly, 14-3-3sigma, which anchors Cdc2 in the cytoplasm where it can not induce mitosis, and GAdd45, which specifically dissociates Cdc2 from cyclin B1 by co-association with Cdc2 [XREF_BIBR, XREF_BIBR].	6	48	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdc2	Cdc2	Cdc2	41	42	45	46
This DNA damage response activates p53 in MCF-7 and Mito R cells , either by the phosphorylated ATR and/or Chk2 leading to the activation of G1/S checkpoint mediated p21 inhibition of cdc2 32 .	This DNA damage response activates p53 in MCF-7 and Mito R cells, either by the phosphorylated ATR and/or Chk2 leading to the activation of G1/S checkpoint mediated p21 inhibition of cdc2 32.	28	32	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	cdc2	cdc2	cdc2	28	29	31	32
P21 , a mitosis regulator , can block the activation of CDK1 though binding to the CDK1 and Cyclin B1 complex and arrest cells at G2/M phase [ XREF_BIBR ] .	P21, a mitosis regulator, can block the activation of CDK1 though binding to the CDK1 and Cyclin B1 complex and arrest cells at G2/M phase [XREF_BIBR].	0	12	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21	P21	CDK1	CDK1	CDK1	0	1	11	12
Elevated p21 expression can inhibit CDK1 activity with a cell cycle block in G2/M phase when cells are most susceptible to DNA damage .	Elevated p21 expression can inhibit CDK1 activity with a cell cycle block in G2/M phase when cells are most susceptible to DNA damage.	1	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21 expression	p21	CDK1	CDK1	cdk1	1	2	5	6
p53 dependent pathways : phosphorylated p53 initiated p21 , which inhibited CDK1 and cyclin B to regulate cell cycle [ XREF_BIBR ] .	p53 dependent pathways : phosphorylated p53 initiated p21, which inhibited CDK1 and cyclin B to regulate cell cycle [XREF_BIBR].	4	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	phosphorylated p53 initiated p21	p21	CDK1	CDK1	cdk1	7	8	11	12
In the nucleus , p21 inhibits CDK1 and 2 and thereby blocks mitosis in response to DNA damage .	In the nucleus, p21 inhibits CDK1 and 2 and thereby blocks mitosis in response to DNA damage.	4	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	4	5	6	7
In this study , CQ showed an inhibitory effect to cdc25C expression and stimulation of p21 that might inactivate cdc2 and cyclin B1 complex .	In this study, CQ showed an inhibitory effect to cdc25C expression and stimulation of p21 that might inactivate cdc2 and cyclin B1 complex.	11	23	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	expression and stimulation of p21	p21	cdc2	cdc2	cdc2	15	16	19	20
With respect to cell-cycle regulation , p21 has been reported to induce G2/M arrest by blocking CDK1 activity .	With respect to cell-cycle regulation, p21 has been reported to induce G2/M arrest by blocking CDK1 activity.	6	17	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK1	CDK1	CDK1	6	7	16	17
P21 Cip1 binds to and inhibits the activity of cyclin-CDK2 , -CDK1 , and -CDK4/6 complexes , promoting cell cycle arrest at the G1 phase .	P21 Cip1 binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, promoting cell cycle arrest at the G1 phase.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21 Cip1	P21 Cip1	P21 Cip1	-CDK1	-CDK1	-CDK1	0	2	11	12
The p21 protein binds to and inhibits the activity of cyclin-CDK2 , -CDK1 , and -CDK4/6 complexes , and thus functions as a regulator of cell cycle progression at the G 1 and S phases .	The p21 protein binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at the G 1 and S phases.	1	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	-CDK1	-CDK1	-CDK1	1	2	12	13
XREF_FIG ( C , D ) showed GLA upregulated the expression level of p21 Waf1 and Cip1 but downregulated Cyclin B1 , CDK1 , and Cdc25C .	XREF_FIG (C, D) showed GLA upregulated the expression level of p21 Waf1 and Cip1 but downregulated Cyclin B1, CDK1, and Cdc25C.	7	23	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	GLA upregulated the expression level of p21 Waf1 and Cip1	cip1	CDK1	CDK1	cdk1	16	17	22	23
The p21 inhibits the CDK1 and cyclin B complex and maintains the G2 arrest .	The p21 inhibits the CDK1 and cyclin B complex and maintains the G2 arrest.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	1	2	4	5
As a tubulin binding agent ( TBA ) , Casticin induces p21 , which in turn inhibits Cdk1 .	As a tubulin binding agent (TBA), Casticin induces p21, which in turn inhibits Cdk1.	10	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk1	Cdk1	Cdk1	11	12	17	18
It is also indicated that VP-16-induced G2/M arrest is caused by p21 , which inactivates cyclin B and Cdc2 complex and eventually prevents mitotic entry .	It is also indicated that VP-16-induced G2/M arrest is caused by p21, which inactivates cyclin B and Cdc2 complex and eventually prevents mitotic entry.	9	22	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdc2	Cdc2	Cdc2	11	12	18	19
P21 could inhibit CDK1 activity through binding to the CDK1 and CyclinB1 complex and inducing G2 phase arrest .	P21 could inhibit CDK1 activity through binding to the CDK1 and CyclinB1 complex and inducing G2 phase arrest.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21	P21	CDK1	CDK1	CDK1	0	1	3	4
CDKN2A is an inhibitor of cyclin dependent kinase 4 ( CDK4 ) and CDK6 , and it functions as a tumor suppressor [ XREF_BIBR ] .	CDKN2A is an inhibitor of cyclin dependent kinase 4 (CDK4) and CDK6, and it functions as a tumor suppressor [XREF_BIBR].	0	14	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	CDK6	CDK6	CDK6	0	1	13	14
Since p15 INK4B and p16 INK4A are inhibitors of CDK6 , a target of miR-449a , this results in an increase in CDK6 expression , dephosphorylation of retinoblastoma protein , and release of E2F1 from inhibition , which induces ANRIL expression .	Since p15 INK4B and p16 INK4A are inhibitors of CDK6, a target of miR-449a, this results in an increase in CDK6 expression, dephosphorylation of retinoblastoma protein, and release of E2F1 from inhibition, which induces ANRIL expression.	4	12	are inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	p16 INK4A	p16 INK4A	p16 INK4A	CDK6	CDK6	CDK6	4	6	9	10
CDKN2A ( the HUGO approved official gene symbol for p16 and ink4a ) is an inhibitor of cyclin dependent kinase 4 ( CDK4 ) and CDK6 , and functions as a tumor suppressor .	CDKN2A (the HUGO approved official gene symbol for p16 and ink4a) is an inhibitor of cyclin dependent kinase 4 (CDK4) and CDK6, and functions as a tumor suppressor.	0	28	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	CDK6	CDK6	CDK6	0	1	25	26
The INK4 family consists of p15 INK4b , p16 INK4a , p18 INK4c and p19 INK4d , which specifically inhibit the activity of G 1 -phase cyclin D-CDK4 and CDK6 .	The INK4 family consists of p15 INK4b, p16 INK4a, p18 INK4c and p19 INK4d, which specifically inhibit the activity of G 1 -phase cyclin D-CDK4 and CDK6.	8	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4a	p16 INK4a	p16 INK4a	CDK6	CDK6	CDK6	8	10	29	30
The CDKs are inhibited by two groups of CDK inhibitors ( CDKIs ) which are also expressed in islets , INK4 proteins ( p16 , p15 , p18 , p19 inhibit CDK 4 and CDK6 ) , and CIP and KIP proteins ( p21 , p27 and p57 ) .	The CDKs are inhibited by two groups of CDK inhibitors (CDKIs) which are also expressed in islets, INK4 proteins (p16, p15, p18, p19 inhibit CDK 4 and CDK6), and CIP and KIP proteins (p21, p27 and p57).	23	35	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK6	CDK6	CDK6	23	24	34	35
p16INK4a , a protein that inhibits cyclin dependent kinase 4 ( Cdk4 ) and Cdk6 , is deficient in many human cancers and in established lines of tumor cells .	p16INK4a, a protein that inhibits cyclin dependent kinase 4 (Cdk4) and Cdk6, is deficient in many human cancers and in established lines of tumor cells.	0	17	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	p16INK4a	p16INK4a	p16INK4a	Cdk6	Cdk6	Cdk6	0	1	14	15
p16 ( INK4a ) , p15 ( INK4b ) , p18 ( INK4c ) , and p19 ( INK4d ) specifically inactivate CDK4 and CDK6 , which prevents their combination with D-type cyclins 20 .	p16 (INK4a), p15 (INK4b), p18 (INK4c), and p19 (INK4d) specifically inactivate CDK4 and CDK6, which prevents their combination with D-type cyclins 20.	0	27	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK6	CDK6	CDK6	0	1	24	25
p16 INK4A ( p16 ) tumour suppressor induces growth arrest by inhibiting function of cyclin dependent kinase ( CDK ) 4 and CDK6 .	p16 INK4A (p16) tumour suppressor induces growth arrest by inhibiting function of cyclin dependent kinase (CDK) 4 and CDK6.	0	23	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p16 INK4A	p16 INK4A	p16 INK4A	CDK6	CDK6	CDK6	0	2	22	23
An NH 2 -terminal domain of p21 Cip1 and WAF1 inhibits cyclin-Cdk kinases and a COOH-terminal domain of p21 Cip1 and WAF1 inhibits proliferating cell nuclear antigen .	An NH 2 -terminal domain of p21 Cip1 and WAF1 inhibits cyclin-Cdk kinases and a COOH-terminal domain of p21 Cip1 and WAF1 inhibits proliferating cell nuclear antigen.	18	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 Cip1	p21 Cip1	p21 Cip1	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	18	20	23	27
p21 can also inhibit proliferating cell nuclear antigen dependent DNA synthesis and E7 can override this inhibition .	p21 can also inhibit proliferating cell nuclear antigen dependent DNA synthesis and E7 can override this inhibition.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	0	1	4	8
This is consistent with the published demonstration that p21 can inhibit PCNA , a protein required for replication beyond the priming step .	This is consistent with the published demonstration that p21 can inhibit PCNA, a protein required for replication beyond the priming step.	8	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	8	9	11	12
Thus , we investigated whether MVM dependent depletion of p21 during infection , mediated by the CRL4 Cdt2 E3 ubiquitin ligase , promoted efficient replication of the MVM genome by abrogating its inhibition of PCNA .	Thus, we investigated whether MVM dependent depletion of p21 during infection, mediated by the CRL4 Cdt2 E3 ubiquitin ligase, promoted efficient replication of the MVM genome by abrogating its inhibition of PCNA.	7	35	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	9	10	34	35
Sequestering of PCNA by p21 is required for p53 dependent G1 arrest in damaged cells XREF_BIBR .	Sequestering of PCNA by p21 is required for p53 dependent G1 arrest in damaged cells XREF_BIBR.	0	5	Sequestering	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	4	5	2	3
Using recombinant proteins in conjunction with immunoprecipitation and immunoblotting , we show that Gadd45 competes with p21 for binding to PCNA and conversely , p21 blocks the ability of Gadd45 to bind PCNA .	Using recombinant proteins in conjunction with immunoprecipitation and immunoblotting, we show that Gadd45 competes with p21 for binding to PCNA and conversely, p21 blocks the ability of Gadd45 to bind PCNA.	24	33	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	24	25	32	33
Cip1 has also been shown to inhibit the DNA polymerase delta auxiliary factor PCNA ( proliferating cell nuclear antigen ) , which is required for replication-fork elongation , and this could be an alternative mechanism by which p53 induced Cip1 blocks cell proliferation .	Cip1 has also been shown to inhibit the DNA polymerase delta auxiliary factor PCNA (proliferating cell nuclear antigen), which is required for replication-fork elongation, and this could be an alternative mechanism by which p53 induced Cip1 blocks cell proliferation.	0	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	Cip1	Cip1	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	0	1	15	19
Sequestering of PCNA by p21waf1 and cip1 is required for p53 dependent G1 arrest in damaged cells .	Sequestering of PCNA by p21waf1 and cip1 is required for p53 dependent G1 arrest in damaged cells.	0	7	Sequestering	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	cip1	cip1	cip1	PCNA	PCNA	PCNA	6	7	2	3
Furthermore , p21 blocks the ability of PCNA to activate DNA polymerase delta , the principal replicative DNA polymerase .	Furthermore, p21 blocks the ability of PCNA to activate DNA polymerase delta, the principal replicative DNA polymerase.	2	8	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	2	3	7	8
Interestingly , it has been reported that upon exposure to UV irradiation , a p21 peptide containing the CDK binding domain is able to promote ubiquitin dependent degradation of PCNA [ XREF_BIBR ] , and conversely , p21 is degraded by DDB1 in a PCNA dependent manner [ XREF_BIBR - XREF_BIBR ] .	Interestingly, it has been reported that upon exposure to UV irradiation, a p21 peptide containing the CDK binding domain is able to promote ubiquitin dependent degradation of PCNA [XREF_BIBR], and conversely, p21 is degraded by DDB1 in a PCNA dependent manner [XREF_BIBR - XREF_BIBR].	14	31	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	14	15	29	30
It has recently been shown that in humans ( h ) , the PCNA function , required for both DNA replication and nucleotide excision repair , can be inactivated by p21 ( CIP1 ) due to a specific interaction between hPCNA and the carboxyl terminus of p21 ( CIP1 ) .	It has recently been shown that in humans (h), the PCNA function, required for both DNA replication and nucleotide excision repair, can be inactivated by p21 (CIP1) due to a specific interaction between hPCNA and the carboxyl terminus of p21 (CIP1).	13	48	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	30	31	13	14
Through the activation of caspases and the induction of apoptosis , p21 causes inhibition of PCNA dependent DNA polymerase activity .	Through the activation of caspases and the induction of apoptosis, p21 causes inhibition of PCNA dependent DNA polymerase activity.	11	19	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	11	12	15	16
This association of p21 and E7 blocks the ability of p21 to inhibit cyclin and CDK activity as well as PCNA dependent DNA synthesis .	This association of p21 and E7 blocks the ability of p21 to inhibit cyclin and CDK activity as well as PCNA dependent DNA synthesis.	1	23	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	3	4	20	21
Overexpression of p21 can block apoptosis induced by the combination chemogene therapy of Ad-E2F-1 and topoisomerase II poisons and does not require its proliferating cell nuclear antigen binding ability .	Overexpression of p21 can block apoptosis induced by the combination chemogene therapy of Ad-E2F-1 and topoisomerase II poisons and does not require its proliferating cell nuclear antigen binding ability.	0	27	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	Overexpression of p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	2	3	23	27
As p21 blocks association of DNA polymerases with PCNA but does not prevent loading of PCNA onto DNA , repair gap filling can occur rapidly as soon as p21 dissociates from PCNA .	As p21 blocks association of DNA polymerases with PCNA but does not prevent loading of PCNA onto DNA, repair gap filling can occur rapidly as soon as p21 dissociates from PCNA.	1	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	1	2	15	16
p21 WAF1 represents one of the best characterized downstream targets of p53 XREF_BIBR , XREF_BIBR , and inhibits various PCNA dependent DNA repair processes by binding to PCNA and interfering with PCNA dependent DNA polymerase activity XREF_BIBR - XREF_BIBR .	p21 WAF1 represents one of the best characterized downstream targets of p53 XREF_BIBR, XREF_BIBR, and inhibits various PCNA dependent DNA repair processes by binding to PCNA and interfering with PCNA dependent DNA polymerase activity XREF_BIBR - XREF_BIBR.	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 WAF1	p21 WAF1	p21 WAF1	PCNA	PCNA	PCNA	0	2	19	20
Ectopic expression of p21 and waf1 in neutrophil differentiated PLB985 cells potentiated apoptosis and reversed the prosurvival effect of PCNA .	Ectopic expression of p21 and waf1 in neutrophil differentiated PLB985 cells potentiated apoptosis and reversed the prosurvival effect of PCNA.	1	20	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	waf1	expression of p21 and waf1	waf1	PCNA	PCNA	pcna	5	6	19	20
We provide evidence that p21 first inhibits the replication factor C catalyzed loading of PCNA onto DNA and second prevents the binding of DNA polymerase delta core to the PCNA clamp assembled on DNA .	We provide evidence that p21 first inhibits the replication factor C catalyzed loading of PCNA onto DNA and second prevents the binding of DNA polymerase delta core to the PCNA clamp assembled on DNA.	4	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	4	5	14	15
It is worth noting that p21 Waf1 and Cip1 can inactivate proliferating cell nuclear antigen ( PCNA ) thereby inhibiting PCNA dependent DNA replication XREF_BIBR .	It is worth noting that p21 Waf1 and Cip1 can inactivate proliferating cell nuclear antigen (PCNA) thereby inhibiting PCNA dependent DNA replication XREF_BIBR.	6	15	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	Cip1	Cip1	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	8	9	11	15
p21 ( Cip1 and Waf1 ) inhibits cell-cycle progression by binding to G1 cyclin and CDK complexes and proliferating cell nuclear antigen ( PCNA ) through its N- and C-terminal domains , respectively .	p21 (Cip1 and Waf1) inhibits cell-cycle progression by binding to G1 cyclin and CDK complexes and proliferating cell nuclear antigen (PCNA) through its N- and C-terminal domains, respectively.	0	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	0	1	18	22
Cip1 also directly inhibits the function of PCNA during DNA synthesis .	Cip1 also directly inhibits the function of PCNA during DNA synthesis.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	Cip1	Cip1	PCNA	PCNA	PCNA	0	1	7	8
p21 also inhibits the activity of PCNA by inhibiting the DNA synthesis directly .	p21 also inhibits the activity of PCNA by inhibiting the DNA synthesis directly.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	0	1	6	7
The findings suggest that the transfected p21 WAF1 and CIP1 likely has no apparent effect on the expression of cdks but may block the ability of PCNA to activate DNA polymerase delta and the cdk kinase activity in human liver cancer cells .	The findings suggest that the transfected p21 WAF1 and CIP1 likely has no apparent effect on the expression of cdks but may block the ability of PCNA to activate DNA polymerase delta and the cdk kinase activity in human liver cancer cells.	6	27	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 WAF1	p21 WAF1	p21 WAF1	PCNA	PCNA	PCNA	6	8	26	27
Induction of the p21 ( WAF1 ) protein ( hereafter called p21 ) following genotoxic stress is known to inhibit proliferating cell nuclear antigen ( PCNA )-dependent DNA repair , downregulate apoptosis , and trigger a sustained growth arrested phenotype called accelerated senescence .	Induction of the p21 (WAF1) protein (hereafter called p21) following genotoxic stress is known to inhibit proliferating cell nuclear antigen (PCNA)-dependent DNA repair, downregulate apoptosis, and trigger a sustained growth arrested phenotype called accelerated senescence.	0	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	3	4	20	24
In this in vitro DNA replication system , p21 WAF1 and CIP1 was able to block PCNA activated DNA polymerase delta activity without the participation of cyclin bound cdks ( Flores-Rozas et al , 1994 ; Waga et al , 1994 ) .	In this in vitro DNA replication system, p21 WAF1 and CIP1 was able to block PCNA activated DNA polymerase delta activity without the participation of cyclin bound cdks (Flores-Rozas et al, 1994; Waga et al, 1994).	8	17	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 WAF1	p21 WAF1	p21 WAF1	PCNA	PCNA	PCNA	8	10	16	17
In addition , p21 appears to disrupt PCNA trimers whereas Gadd45 has a lesser effect .	In addition, p21 appears to disrupt PCNA trimers whereas Gadd45 has a lesser effect.	3	8	disrupt	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	3	4	7	8
In addition , p21 , one of the most potent negative regulators of proliferation , inhibits not only CDKs but also PCNA , through a tight PIP-box mediated association that out-competes DNA polymerases and other interactors .	In addition, p21, one of the most potent negative regulators of proliferation, inhibits not only CDKs but also PCNA, through a tight PIP-box mediated association that out-competes DNA polymerases and other interactors.	3	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	3	4	21	22
Consistent with the notion that p21 inhibits PCNA and CDKs in the nucleus , Western blotting analysis showed that 15-PGDH overexpression caused accumulation of p21 in the nucleus and decrease of p21 in the cytoplasm ( XREF_FIG ) .	Consistent with the notion that p21 inhibits PCNA and CDKs in the nucleus, Western blotting analysis showed that 15-PGDH overexpression caused accumulation of p21 in the nucleus and decrease of p21 in the cytoplasm (XREF_FIG).	5	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	5	6	7	8
However , PCNA dependent synthesis by other DNA pols could be inhibited by endogenous p21 .	However, PCNA dependent synthesis by other DNA pols could be inhibited by endogenous p21.	2	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	14	15	2	3
Furthermore , CDKN1A dependent inhibition of PCNA activity does not appear to be the mechanism for this early G1 arrest .	Furthermore, CDKN1A dependent inhibition of PCNA activity does not appear to be the mechanism for this early G1 arrest.	2	7	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	PCNA	PCNA	PCNA	2	3	6	7
In agreement , p21 degradation after UV irradiation promotes PCNA dependent repair .	In agreement, p21 degradation after UV irradiation promotes PCNA dependent repair.	3	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	3	4	9	10
While p21 inhibits proliferating cell nuclear antigen ( PCNA )-dependent DNA synthesis , it can also directly lower PCNA abundance ; however , it is unclear whether loss of PCNA contributes to growth arrest .	While p21 inhibits proliferating cell nuclear antigen (PCNA)-dependent DNA synthesis, it can also directly lower PCNA abundance; however, it is unclear whether loss of PCNA contributes to growth arrest.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	1	2	3	7
p21 ( p21WAF1 and Cip1 ) , a cyclin dependent kinase inhibitor , induces G1 arrest and can inhibit the activity of the proliferating cell nuclear antigen ( PCNA ) .	p21 (p21WAF1 and Cip1), a cyclin dependent kinase inhibitor, induces G1 arrest and can inhibit the activity of the proliferating cell nuclear antigen (PCNA).	0	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	0	1	23	27
In contrast , p21 stabilization impairs the interaction of PCNA with the specialized polymerase eta ( pol eta ) , thus suggesting that p21 displaces pol eta from PCNA complexes more efficiently than other replication or repair factors .	In contrast, p21 stabilization impairs the interaction of PCNA with the specialized polymerase eta (pol eta), thus suggesting that p21 displaces pol eta from PCNA complexes more efficiently than other replication or repair factors.	3	10	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	3	4	9	10
As nucleotide excision-repair requires PCNA , the physiological relevance of PCNA inhibition by Cip1 is currently unclear .	As nucleotide excision-repair requires PCNA, the physiological relevance of PCNA inhibition by Cip1 is currently unclear.	10	14	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Cip1	Cip1	Cip1	PCNA	PCNA	PCNA	13	14	10	11
The p21 protein blocks the initiation of DNA replication by inhibiting CDK complexes [ XREF_BIBR ] and blocks the action of PCNA .	The p21 protein blocks the initiation of DNA replication by inhibiting CDK complexes [XREF_BIBR] and blocks the action of PCNA.	1	22	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	1	2	21	22
CDKN1A is also able to inhibit PCNA dependent DNA replication directly , by its direct interaction with PCNA and thus prevention of polymerase delta activation by PCNA during the S phase XREF_BIBR .	CDKN1A is also able to inhibit PCNA dependent DNA replication directly, by its direct interaction with PCNA and thus prevention of polymerase delta activation by PCNA during the S phase XREF_BIBR.	0	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	PCNA	PCNA	PCNA	0	1	6	7
The 9-1-1 complex may replace PCNA when active PCNA is depleted by p21 during cell cycle arrest in response to DNA damage .	The 9-1-1 complex may replace PCNA when active PCNA is depleted by p21 during cell cycle arrest in response to DNA damage.	7	13	depleted	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	12	13	8	9
Since p21 and WAF1 inhibits DNA replication by directly binding PCNA , the relative levels of the two proteins can determine cell cycle progression .	Since p21 and WAF1 inhibits DNA replication by directly binding PCNA, the relative levels of the two proteins can determine cell cycle progression.	1	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WAF1	WAF1	WAF1	PCNA	PCNA	PCNA	3	4	10	11
Additionally , p21 can promote the proteasome dependent degradation of the PCNA protein and thus inhibit PCNA dependent DNA replication in adult cardiomyocytes , but p27 could not .	Additionally, p21 can promote the proteasome dependent degradation of the PCNA protein and thus inhibit PCNA dependent DNA replication in adult cardiomyocytes, but p27 could not.	2	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	2	3	11	12
Conversely , forced p21 stabilization prevents the interaction of PCNA with Y polymerases complexes , which leads to persistent defects in S phase progression , accumulation of replication stress markers and genomic instability .	Conversely, forced p21 stabilization prevents the interaction of PCNA with Y polymerases complexes, which leads to persistent defects in S phase progression, accumulation of replication stress markers and genomic instability.	3	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	3	4	9	10
However , p21 does not inhibit the loading of PCNA onto chromatin .	However, p21 does not inhibit the loading of PCNA onto chromatin.	2	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	2	3	9	10
There was reduction in Ki-67 , PCNA , Von Willebrand factor , VEGF , CD31 , VEGFR-2 , ERK1/2 , JNK1/2 , p38 , MMP-2 , MMP-7 , MMP-9 , and MMP-12 and induction of apoptosis , caspase-3 activity , and p21 and WAF1 in tumors of athymic nude mice implanted with human pancreatic cancer AsPC-1 cells suggesting that EGCG inhibited pancreatic cancer growth , invasion , metastasis , and angiogenesis [ XREF_BIBR ] .	There was reduction in Ki-67, PCNA, Von Willebrand factor, VEGF, CD31, VEGFR-2, ERK1/2, JNK1/2, p38, MMP-2, MMP-7, MMP-9, and MMP-12 and induction of apoptosis, caspase-3 activity, and p21 and WAF1 in tumors of athymic nude mice implanted with human pancreatic cancer AsPC-1 cells suggesting that EGCG inhibited pancreatic cancer growth, invasion, metastasis, and angiogenesis [XREF_BIBR].	1	45	was reduction	Negative_activation_copula_1	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	41	42	6	7
p21 may block the ability of PCNA to bind with Gadd45 .	p21 may block the ability of PCNA to bind with Gadd45.	0	7	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	0	1	6	7
p21 inhibits cyclin dependent kinase ( CDK ) activity and proliferating cell nuclear antigen ( PCNA )-dependent DNA replication by binding to CDK and cyclin complexes and to PCNA through distinct domains .	p21 inhibits cyclin dependent kinase (CDK) activity and proliferating cell nuclear antigen (PCNA)-dependent DNA replication by binding to CDK and cyclin complexes and to PCNA through distinct domains.	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	0	1	10	14
p21 disrupts PCNA directed stimulation of flap endonuclease 1 ( FEN1 ) , DNA ligase I , and DNA polymerase delta .	p21 disrupts PCNA directed stimulation of flap endonuclease 1 (FEN1), DNA ligase I, and DNA polymerase delta.	0	4	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	0	1	2	3
It is also possible that these cells could be quiescent ( PCNA negative ) neural stem cells , as it is known that the cell cycle inhibitor p21 promotes degradation of PCNA during an extended G1 phase .	It is also possible that these cells could be quiescent (PCNA negative) neural stem cells, as it is known that the cell cycle inhibitor p21 promotes degradation of PCNA during an extended G1 phase.	23	32	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	27	28	31	32
Human p21 ( also known as WAF1 , CIP1 , or SDI1 ) is a dual inhibitor of cyclin dependent kinases ( CDKs ) and the replication factor PCNA , which plays a role as a downstream mediator of the cell-cycle arrest induced by the tumor suppressor p53 .	Human p21 (also known as WAF1, CIP1, or SDI1) is a dual inhibitor of cyclin dependent kinases (CDKs) and the replication factor PCNA, which plays a role as a downstream mediator of the cell-cycle arrest induced by the tumor suppressor p53.	0	29	is a dual inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	1	2	28	29
p21 ( Cip1 and WAF1 ) inhibits cell-cycle progression by binding to G1 cyclin and CDK complexes and proliferating cell nuclear antigen ( PCNA ) through its N- and C-terminal domains , respectively .	p21 (Cip1 and WAF1) inhibits cell-cycle progression by binding to G1 cyclin and CDK complexes and proliferating cell nuclear antigen (PCNA) through its N- and C-terminal domains, respectively.	0	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	0	1	18	22
Furthermore , numerous studies have determined elevated nuclear p21 binds to and inhibits PCNA activity and subsequently prevents DNA replication and suppresses cell cycle .	Furthermore, numerous studies have determined elevated nuclear p21 binds to and inhibits PCNA activity and subsequently prevents DNA replication and suppresses cell cycle.	6	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	8	9	13	14
Inhibition of the PCNA dependent DNA synthesis by p21 antagonists .	Inhibition of the PCNA dependent DNA synthesis by p21 antagonists.	0	9	Inhibition	Negative_activation_syntax_1_noun	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	8	9	3	4
We show here that p21 also inhibits PCNA stimulation of long patch base excision repair ( BER ) in vitro .	We show here that p21 also inhibits PCNA stimulation of long patch base excision repair (BER) in vitro.	4	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	4	5	7	8
p21 , a specific inhibitor of PCNA dependent DNA replication , inhibits PCNA stimulated synthesis past model abasic template sites .	p21, a specific inhibitor of PCNA dependent DNA replication, inhibits PCNA stimulated synthesis past model abasic template sites.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	0	1	12	13
Addition of p21 did not inhibit RFC dependent PCNA loading ; rather , p21 formed a stable complex with PCNA on the DNA .	Addition of p21 did not inhibit RFC dependent PCNA loading; rather, p21 formed a stable complex with PCNA on the DNA.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	2	3	8	9
The inhibition of CTNNA3 by miR-425 in turn resulted in increased PCNA , decreased p21 Cip1 and Waf1 and Akt activation , as well as the increased MMP-9 .	The inhibition of CTNNA3 by miR-425 in turn resulted in increased PCNA, decreased p21 Cip1 and Waf1 and Akt activation, as well as the increased MMP-9.	8	20	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Waf1	Waf1	Waf1	PCNA	PCNA	PCNA	17	18	11	12
By contrast , Cip1 strongly suppresses the function of PCNA in replicative DNA synthesis under these conditions .	By contrast, Cip1 strongly suppresses the function of PCNA in replicative DNA synthesis under these conditions.	3	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	Cip1	Cip1	PCNA	PCNA	PCNA	3	4	9	10
Similarly , p21 represses MYC dependent transcription and in turn , MYC disrupts the PCNA-p21 interaction , thus alleviating p21 dependent inhibition of PCNA and DNA synthesis 14 .	Similarly, p21 represses MYC dependent transcription and in turn, MYC disrupts the PCNA-p21 interaction, thus alleviating p21 dependent inhibition of PCNA and DNA synthesis 14.	19	26	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	19	20	23	24
Using an in vitro system , we now show that p21 does not block PCNA dependent nucleotide-excision repair , in contrast to its inhibition of simian virus 40 DNA replication .	Using an in vitro system, we now show that p21 does not block PCNA dependent nucleotide-excision repair, in contrast to its inhibition of simian virus 40 DNA replication.	10	15	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	10	11	14	15
These studies revealed that , while very high levels of p21 might impair PCNA driven DNA replication , the much lower p21 levels reached during basal expression are sufficient to selectively block PCNA interaction with TLS polymerases .	These studies revealed that, while very high levels of p21 might impair PCNA driven DNA replication, the much lower p21 levels reached during basal expression are sufficient to selectively block PCNA interaction with TLS polymerases.	8	14	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	levels of p21	p21	PCNA	PCNA	pcna	10	11	13	14
Because there is no direct evidence that REGgamma is involved in the degradation of the PCNA protein , we infer that p21 promoted PCNA protein degradation , which , combined with its inactivation of the PCNA protein , contributes to the arrest of the cell cycle at the G 1 / S phase transition and the inhibition of cell proliferation in SW579 cells .	Because there is no direct evidence that REGgamma is involved in the degradation of the PCNA protein, we infer that p21 promoted PCNA protein degradation, which, combined with its inactivation of the PCNA protein, contributes to the arrest of the cell cycle at the G 1 / S phase transition and the inhibition of cell proliferation in SW579 cells.	21	25	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	21	22	23	24
p21 ( waf1 ) is an inhibitor of cyclin dependent kinases and proliferating cell nuclear antigen and induces cell cycle arrest at G1/S , a requisite early step in cell differentiation .	p21 (waf1) is an inhibitor of cyclin dependent kinases and proliferating cell nuclear antigen and induces cell cycle arrest at G1/S, a requisite early step in cell differentiation.	0	17	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p21	p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	0	1	12	16
In turn , MYC disrupts the PCNA-p21 interaction , thus alleviating p21 dependent inhibition of PCNA and DNA synthesis XREF_BIBR .	In turn, MYC disrupts the PCNA-p21 interaction, thus alleviating p21 dependent inhibition of PCNA and DNA synthesis XREF_BIBR.	11	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	11	12	15	16
p21 is a potent inhibitor of CDKs and PCNA .	p21 is a potent inhibitor of CDKs and PCNA.	0	9	is a potent inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	0	1	8	9
Up-regulation of pRb , p21 , p27 and corresponding inhibition of cyclin D1 and CDK4 were observed .	Up-regulation of pRb, p21, p27 and corresponding inhibition of cyclin D1 and CDK4 were observed.	4	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK4	CDK4	CDK4	4	5	14	15
Consequently , reduced p21 Waf1 and Cip1 levels would be insufficient to inactivate CDK4 and CyclinD1 .	Consequently, reduced p21 Waf1 and Cip1 levels would be insufficient to inactivate CDK4 and CyclinD1.	6	15	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	Cip1 levels	cip1	CDK4	CDK4	cdk4	6	7	13	14
Therefore , an increased p21 expression level , suppressing the CDK4- and CDK6 activation , is considered to be induced by the increase of phosphorylated p53 protein , resulting in a decrease of cell number in the MGFs treated with a lower concentration of H 2 O 2 .	Therefore, an increased p21 expression level, suppressing the CDK4- and CDK6 activation, is considered to be induced by the increase of phosphorylated p53 protein, resulting in a decrease of cell number in the MGFs treated with a lower concentration of H 2 O 2.	4	13	suppressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21 expression level	p21	CDK4-	CDK4-	cdk4-	4	5	10	11
The increased caspase-3 , caspase-7 , p21 immunoreactivity and reduced Cdk4 immunoreactivity in ethanol treated rats confirmed that ethanol increases the apoptosis in testis and a reduced expression in the rats treated with PCA in addition to ethanol indicates a protective role of PCA .	The increased caspase-3, caspase-7, p21 immunoreactivity and reduced Cdk4 immunoreactivity in ethanol treated rats confirmed that ethanol increases the apoptosis in testis and a reduced expression in the rats treated with PCA in addition to ethanol indicates a protective role of PCA.	6	11	reduced	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk4	Cdk4	Cdk4	6	7	10	11
In addition , P21 inhibits CDK4 so that RB remains dephosphorylated to reduce cell cycle activity .	In addition, P21 inhibits CDK4 so that RB remains dephosphorylated to reduce cell cycle activity.	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21	P21	CDK4	CDK4	CDK4	3	4	5	6
CDKN1A ( p21 , Cip1 ) , a protein encoded by the CD-KN1A gene located on chromosome 6 ( 6p21.2 ) [ XREF_BIBR ] , binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes , and thus functions as a regulator of cell cycle progression at the G1 phase [ XREF_BIBR ] .	CDKN1A (p21, Cip1), a protein encoded by the CD-KN1A gene located on chromosome 6 (6p21.2) [XREF_BIBR], binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes, and thus functions as a regulator of cell cycle progression at the G1 phase [XREF_BIBR].	0	39	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	-CDK4	-CDK4	-CDK4	0	1	34	35
Cdkn1a inhibits cyclin-Cdk2 or -Cdk4 complexes , and treatment of slices with Cdk4 inhibitor reduces mGluR dependent LTD in the hippocampal CA1 region .	Cdkn1a inhibits cyclin-Cdk2 or -Cdk4 complexes, and treatment of slices with Cdk4 inhibitor reduces mGluR dependent LTD in the hippocampal CA1 region.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdkn1a	Cdkn1a	Cdkn1a	-Cdk4	-Cdk4	-Cdk4	0	1	4	5
Although the tumor suppressor role of p21 is still controversial , it is clear that p21 inhibits cyclinD1 and CDK4 , which results in retarded cell proliferation in this study .	Although the tumor suppressor role of p21 is still controversial, it is clear that p21 inhibits cyclinD1 and CDK4, which results in retarded cell proliferation in this study.	15	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK4	CDK4	CDK4	15	16	19	20
However , elevated levels of p21 can inhibit the activities of CDK4 and CDK6 by binding with CDK and cyclin complexes and inhibiting CDK activity by disrupting the ATP binding pocket of the CDK subunit thereby causing cell cycle arrest [ XREF_BIBR ] .	However, elevated levels of p21 can inhibit the activities of CDK4 and CDK6 by binding with CDK and cyclin complexes and inhibiting CDK activity by disrupting the ATP binding pocket of the CDK subunit thereby causing cell cycle arrest [XREF_BIBR].	3	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	levels of p21	p21	CDK4	CDK4	cdk4	5	6	11	12
The p21 protein binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes , and disrupts cell cycle progression at G1 phase XREF_BIBR XREF_BIBR .	The p21 protein binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes, and disrupts cell cycle progression at G1 phase XREF_BIBR XREF_BIBR.	1	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	-CDK4	-CDK4	-CDK4	1	2	12	13
A 20 amino-acid peptide based on the carboxy-terminal domain of p21 ( WAF1 ) inhibits Cdk4 activity with a concentration for half-maximal inhibition ( l0.5 ) of 46 nM , and it is only four-fold less active than the full-length protein .	A 20 amino-acid peptide based on the carboxy-terminal domain of p21 (WAF1) inhibits Cdk4 activity with a concentration for half-maximal inhibition (l0.5) of 46 nM, and it is only four-fold less active than the full-length protein.	3	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WAF1	WAF1	WAF1	Cdk4	Cdk4	Cdk4	12	13	15	16
For example , TP53 transcriptionally activates CDKN1A ( p21 ) , which in turn suppresses CDK4 leading to G1 arrest and subsequently cause cell cycle arrest in normal cells , and p.R158L mutation is expected to affect the normal TP53 function .	For example, TP53 transcriptionally activates CDKN1A (p21), which in turn suppresses CDK4 leading to G1 arrest and subsequently cause cell cycle arrest in normal cells, and p.R158L mutation is expected to affect the normal TP53 function.	5	22	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK4	CDK4	CDK4	6	7	15	16
The p21 protein inhibits the activity of cyclin-CDK2 or -CDK4 complexes , and functions as a regulator of cell cycle progression at G1 .	The p21 protein inhibits the activity of cyclin-CDK2 or -CDK4 complexes, and functions as a regulator of cell cycle progression at G1.	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	-CDK4	-CDK4	-CDK4	1	2	9	10
Similar to C4-2B cells , RES enhanced the expression of p53 , which induces the increased expression of p21 WAF1 and CIP1 and p27 KIP1 in combination with DTX ( 22muM +10 nM ) compared to DTX ( 31nM ) and RES ( 35muM ) only , which further inhibit the CDK4 and cyclin D1 complex by down-regulation of the protein expression .	Similar to C4-2B cells, RES enhanced the expression of p53, which induces the increased expression of p21 WAF1 and CIP1 and p27 KIP1 in combination with DTX (22muM +10 nM) compared to DTX (31nM) and RES (35muM) only, which further inhibit the CDK4 and cyclin D1 complex by down-regulation of the protein expression.	8	55	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 WAF1	expression of p53, which induces the increased expression of p21 WAF1	p21 waf1	CDK4	CDK4	cdk4	18	20	51	52
The p21 protein binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes , and disrupts cell cycle progression at G1 phase [ XREF_BIBR , XREF_BIBR ] .	The p21 protein binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes, and disrupts cell cycle progression at G1 phase [XREF_BIBR, XREF_BIBR].	1	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	-CDK4	-CDK4	-CDK4	1	2	12	13
This is consistent with recent reports that Apc initiates tumor formation by up-regulating c-myc expression through altered beta-catenin-Tcf signaling and that c-myc then up-regulates cdk4 , whose activity is inhibited by p21 .	This is consistent with recent reports that Apc initiates tumor formation by up-regulating c-myc expression through altered beta-catenin-Tcf signaling and that c-myc then up-regulates cdk4, whose activity is inhibited by p21.	23	32	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	p21	p21	p21	cdk4	cdk4	cdk4	31	32	24	25
The increased p21 WAF1 expression inhibited cyclin D1 and CDK4 complex activity , which explains cell cycle arrest in the G1 phase , and the cell cycle arrest contributed to the 7E induced inhibition of tumor growth .	The increased p21 WAF1 expression inhibited cyclin D1 and CDK4 complex activity, which explains cell cycle arrest in the G1 phase, and the cell cycle arrest contributed to the 7E induced inhibition of tumor growth.	2	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 WAF1	p21 WAF1 expression	p21 waf1	CDK4	CDK4	cdk4	2	4	9	10
p27 ( Kip1 ) or p21 ( Cip1 ) also increased the abundance of D cyclin-cdk4 complexes and reduced amounts of cdk4 activity when ectopically expressed in p27 and p21 (-/-) MEFs .	p27 (Kip1) or p21 (Cip1) also increased the abundance of D cyclin-cdk4 complexes and reduced amounts of cdk4 activity when ectopically expressed in p27 and p21 (-/-) MEFs.	5	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	Cip1	Cip1	cdk4	cdk4	cdk4	7	8	21	22
p21 acts as a regulator of cell cycle progression at G1 , inhibiting the activity of cyclin-CDK2 or -CDK4 complexes required for G1/S transition XREF_BIBR .	p21 acts as a regulator of cell cycle progression at G1, inhibiting the activity of cyclin-CDK2 or -CDK4 complexes required for G1/S transition XREF_BIBR.	0	19	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	-CDK4	-CDK4	-CDK4	0	1	18	19
Furthermore , we assume that binding of p21 does not impair kinase activity of CDK4 .	Furthermore, we assume that binding of p21 does not impair kinase activity of CDK4.	5	15	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK4	CDK4	CDK4	7	8	14	15
However , fad3b expression inhibited cell proliferation such that cells were arrested in the G0/G1 phase due to p21 induced reduction of Cdk4 .	However, fad3b expression inhibited cell proliferation such that cells were arrested in the G0/G1 phase due to p21 induced reduction of Cdk4.	11	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk4	Cdk4	Cdk4	18	19	22	23
For example , TP53 transcriptionally activate CDKN1A ( p21 ) and p21 suppresses CDK4 that regulate G1 arrest and subsequently cause cell cycle arrest in normal cells .	For example, TP53 transcriptionally activate CDKN1A (p21) and p21 suppresses CDK4 that regulate G1 arrest and subsequently cause cell cycle arrest in normal cells.	6	20	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK4	CDK4	CDK4	6	7	13	14
Recently a study by Liu et al in colon cancer cell lines HT29 and SW480 demonstrated that triptolide induced G1 arrest in these cell lines by increasing levels of p21 which then inhibits CDK-4 and CDK-6 .	Recently a study by Liu et al in colon cancer cell lines HT29 and SW480 demonstrated that triptolide induced G1 arrest in these cell lines by increasing levels of p21 which then inhibits CDK-4 and CDK-6.	27	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	levels of p21	p21	CDK-4	CDK-4	cdk-4	29	30	33	34
On the other hand , p21 dependent inhibition of CDK4 activation might also explain the stronger resistance of pRb-proficient cells to the apoptotic effect of these different treatments , which might be exploited to protect normal cells and hence allow more aggressive treatments of pRb deficient tumors XREF_BIBR , XREF_BIBR .	On the other hand, p21 dependent inhibition of CDK4 activation might also explain the stronger resistance of pRb-proficient cells to the apoptotic effect of these different treatments, which might be exploited to protect normal cells and hence allow more aggressive treatments of pRb deficient tumors XREF_BIBR, XREF_BIBR.	5	10	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK4	CDK4	CDK4	5	6	9	10
The p21WAF-1 and Cip1 inhibits CDK-4 , thus preventing both phosphorylation of RB and the release of transcriptionally active E2F-1 .	The p21WAF-1 and Cip1 inhibits CDK-4, thus preventing both phosphorylation of RB and the release of transcriptionally active E2F-1.	1	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	Cip1	Cip1	CDK-4	CDK-4	CDK-4	3	4	5	6
Indeed , the Cdk and cyclin inhibitor , p21 , was able to restore Cdk4 and cyclin D1 nuclear localization when co-overexpressed with the mutant cyclin D1 noted above .	Indeed, the Cdk and cyclin inhibitor, p21, was able to restore Cdk4 and cyclin D1 nuclear localization when co-overexpressed with the mutant cyclin D1 noted above.	6	19	restore	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk4	Cdk4	Cdk4	8	9	14	15
p21 inhibits CDK4 and Cyclin D , CDK2 and Cyclin B complexes and the proliferating cell nuclear antigen ( PCNA ) which are required for S-phase progression [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	p21 inhibits CDK4 and Cyclin D, CDK2 and Cyclin B complexes and the proliferating cell nuclear antigen (PCNA) which are required for S-phase progression [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK4	CDK4	CDK4	0	1	2	3
Besides , p27 and p21 can inhibit CDK4 and destroy the combination of the complex .	Besides, p27 and p21 can inhibit CDK4 and destroy the combination of the complex.	2	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK4	CDK4	CDK4	4	5	7	8
As a CDKI , p21 inhibits the activity of cyclin-CDK2 or CDK4 complexes , thus regulating cell cycle progression at G1 .	As a CDKI, p21 inhibits the activity of cyclin-CDK2 or CDK4 complexes, thus regulating cell cycle progression at G1.	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK4	CDK4	CDK4	4	5	11	12
The p21 protein inhibits the activity of cyclin-CDK2 or -CDK4 complexes and negatively modulates cell cycle progression at phase G1 XREF_BIBR .	The p21 protein inhibits the activity of cyclin-CDK2 or -CDK4 complexes and negatively modulates cell cycle progression at phase G1 XREF_BIBR.	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	-CDK4	-CDK4	-CDK4	1	2	9	10
p21 binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes , and thus also functions as a regulator of cell cycle progression at G1 .	p21 binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes, and thus also functions as a regulator of cell cycle progression at G1.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	-CDK4	-CDK4	-CDK4	0	1	10	11
Previous studies have shown that enhanced p21 Waf levels induced by an HDAC inhibitor promoted proteasomal degradation of cyclin B1 and resulted in G2/M arrest [ XREF_BIBR ] and that GADD45 promotes G2/M arrest via nuclear export and kinase activity of Cdc2 [ XREF_BIBR ] .	Previous studies have shown that enhanced p21 Waf levels induced by an HDAC inhibitor promoted proteasomal degradation of cyclin B1 and resulted in G2/M arrest [XREF_BIBR] and that GADD45 promotes G2/M arrest via nuclear export and kinase activity of Cdc2 [XREF_BIBR].	6	20	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21 Waf levels	p21	B1	B1	b1	6	7	19	20
The p53 mutant phenotype in Huh7 cells is also related to p21 deficiency , and p21 prevents the activation of the CDK1-Cyclin B1 complex , explaining the lower proportion of G2/M arrest and decreased apoptosis rates in Huh7 cells after the co-treatment .	The p53 mutant phenotype in Huh7 cells is also related to p21 deficiency, and p21 prevents the activation of the CDK1-Cyclin B1 complex, explaining the lower proportion of G2/M arrest and decreased apoptosis rates in Huh7 cells after the co-treatment.	15	33	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	B1	B1	B1	15	16	22	23
The enhanced p21 levels promoted proteasomal degradation of cyclin B1 , the limited supply of which halts the progression of cells into mitosis .	The enhanced p21 levels promoted proteasomal degradation of cyclin B1, the limited supply of which halts the progression of cells into mitosis.	2	10	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21 levels	p21	B1	B1	b1	2	3	9	10
G-1 , on the other hand , not only increased p21 expression and nearly prevented cyclin B1 accumulation at both 24 and 48 hours ( in the presence of 10 % FCS ) , but also inhibited the effects of PDGF-BB on p21 and cyclin B1 in a similar concentration dependent manner ( XREF_FIG ) .	G-1, on the other hand, not only increased p21 expression and nearly prevented cyclin B1 accumulation at both 24 and 48 hours (in the presence of 10% FCS), but also inhibited the effects of PDGF-BB on p21 and cyclin B1 in a similar concentration dependent manner (XREF_FIG).	0	17	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	G-1, on the other hand, not only increased p21 expression	p21	B1	B1	b1	10	11	16	17
In turn , p21 interferes with the activation of CDK1 and thus prevents the activation of the CDK1-Cyclin B1 complex XREF_BIBR .	In turn, p21 interferes with the activation of CDK1 and thus prevents the activation of the CDK1-Cyclin B1 complex XREF_BIBR.	3	20	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	B1	B1	B1	3	4	18	19
A Western blotting analysis showed that PP up-regulated the expressions of p21 , and down-regulated the levels of Cyclin B1 phospho-Cdc25C , Cdc25C , phospho-Cdc2 and Cdc2 .	A Western blotting analysis showed that PP up-regulated the expressions of p21, and down-regulated the levels of Cyclin B1 phospho-Cdc25C, Cdc25C, phospho-Cdc2 and Cdc2.	6	20	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	PP up-regulated the expressions of p21	p21	B1	B1	b1	11	12	19	20
These results indicate that p21 mediated degradation of cyclin B1 in response to DNA damage is necessary for the maintenance of G ( 2 ) cell cycle arrest .	These results indicate that p21 mediated degradation of cyclin B1 in response to DNA damage is necessary for the maintenance of G (2) cell cycle arrest.	4	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	B1	B1	B1	4	5	9	10
Importantly , vFLIP only increased p21 and p27 levels modestly ( 2.2 and 1.5 fold respectively ) and did not significantly down-regulate cyclin B1 in vCyc-G2 cells ( 88 % ) , in dramatic contrast to the HeLa-G control ( 17 % see XREF_FIG lane 3 versus 6 ) .	Importantly, vFLIP only increased p21 and p27 levels modestly (2.2 and 1.5 fold respectively) and did not significantly down-regulate cyclin B1 in vCyc-G2 cells (88%), in dramatic contrast to the HeLa-G control (17% see XREF_FIG lane 3 versus 6).	2	26	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	vFLIP only increased p21 and p27 levels	p21	B1	B1	b1	5	6	23	24
p21 ( waf1 ) induction also inhibited the increased cyclin B1 associated kinase activity induced by paclitaxel .	p21 (waf1) induction also inhibited the increased cyclin B1 associated kinase activity induced by paclitaxel.	0	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	B1	B1	B1	0	1	10	11
Data indicates that the induction of radiation induced division delay appears to be dependent on the p21 inhibition of cyclin B1 and , furthermore , p21 and cyclin B1 expression are highly dependent on cell density .	Data indicates that the induction of radiation induced division delay appears to be dependent on the p21 inhibition of cyclin B1 and, furthermore, p21 and cyclin B1 expression are highly dependent on cell density.	16	21	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	B1	B1	B1	16	17	20	21
In fact , the upregulation of p21 at 3 hours in our model could have stabilized the G2/M checkpoint complex cyclin B1/Cdk1 and prevented the turnover of cyclin B1 .	In fact, the upregulation of p21 at 3 hours in our model could have stabilized the G2/M checkpoint complex cyclin B1/Cdk1 and prevented the turnover of cyclin B1.	4	29	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	B1	B1	B1	6	7	28	29
Also , CQ increased the p21 level but reduced that of cyclin B1 .	Also, CQ increased the p21 level but reduced that of cyclin B1.	2	13	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	CQ increased the p21 level	p21	B1	B1	b1	5	6	12	13
XREF_BIBR Our data resolves this discrepancy as it suggests that a critical role of p21 is to sequester Cyclin B1 in the nucleus , XREF_BIBR which then , in turn , is required for Cyclin B1 degradation .	XREF_BIBR Our data resolves this discrepancy as it suggests that a critical role of p21 is to sequester Cyclin B1 in the nucleus, XREF_BIBR which then, in turn, is required for Cyclin B1 degradation.	12	20	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	B1	B1	B1	14	15	19	20
However , silencing of p53 or p21 prevented Cyclin B1 degradation upon severe replication stress and , in agreement with our previous results , promoted replication recovery after HU removal .	However, silencing of p53 or p21 prevented Cyclin B1 degradation upon severe replication stress and, in agreement with our previous results, promoted replication recovery after HU removal.	2	10	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	B1	B1	B1	6	7	9	10
In addition , upregulated expression of GADD45A , GADD45B , p21 , PIDD and Shisa5 , which contribute to growth arrest and apoptosis induction , and downregulated CCNB1 that promotes cell cycle progression were confirmed by quantitative real-time PCR after KIF4 knockdown .	In addition, upregulated expression of GADD45A, GADD45B, p21, PIDD and Shisa5, which contribute to growth arrest and apoptosis induction, and downregulated CCNB1 that promotes cell cycle progression were confirmed by quantitative real-time PCR after KIF4 knockdown.	4	29	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	expression of GADD45A, GADD45B, p21	p21	CCNB1	CCNB1	ccnb1	10	11	27	28
The over-expression of p21 and down-expression of cyclin B1 caused by MTA inactivated the Cdc2-cyclin B1 complex of G2/M checkpoint and finally caused the G2/M arrest in HeLa cells .	The over-expression of p21 and down-expression of cyclin B1 caused by MTA inactivated the Cdc2-cyclin B1 complex of G2/M checkpoint and finally caused the G2/M arrest in HeLa cells.	1	16	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	over-expression of p21	p21	B1	B1	b1	3	4	15	16
Because p21 and cyclin B1 play positive and negative roles , respectively , in G2/M arrest [ XREF_BIBR , XREF_BIBR ] , we examined the expression of these proteins in CQ treated cancer cells and found that CQ increased the p21 level but decreased that of cyclin B1 ( XREF_FIG ) , compatible with G2/M phase arrest .	Because p21 and cyclin B1 play positive and negative roles, respectively, in G2/M arrest [XREF_BIBR, XREF_BIBR], we examined the expression of these proteins in CQ treated cancer cells and found that CQ increased the p21 level but decreased that of cyclin B1 (XREF_FIG), compatible with G2/M phase arrest.	37	52	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	CQ increased the p21 level	p21	B1	B1	b1	40	41	47	48
Enhanced p21 levels promoted proteasomal degradation of cyclin B1 , causing cells to arrest in stage in G 2 / M and follow an apoptotic cell death .	Enhanced p21 levels promoted proteasomal degradation of cyclin B1, causing cells to arrest in stage in G 2 / M and follow an apoptotic cell death.	1	9	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21 levels	p21	B1	B1	b1	1	2	8	9
To test the functions of Cdk2 more rigorously , we decided to use Skp2 -/- cells with the premise that high levels of p27 in these cells would inhibit Cdk1 activity .	To test the functions of Cdk2 more rigorously, we decided to use Skp2 -/- cells with the premise that high levels of p27 in these cells would inhibit Cdk1 activity.	21	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	levels of p27	p27	Cdk1	Cdk1	cdk1	23	24	29	30
Interestingly , the observed reminiscence of p27 Kip1 in the absence of N-myc was not sufficient to prevent Cdk1 activity in late fiber nuclei .	Interestingly, the observed reminiscence of p27 Kip1 in the absence of N-myc was not sufficient to prevent Cdk1 activity in late fiber nuclei.	6	19	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	Cdk1	Cdk1	Cdk1	6	8	18	19
Our data showed that both p27 and Np27 inhibited CDC2 kinase activity .	Our data showed that both p27 and Np27 inhibited CDC2 kinase activity.	4	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDC2	CDC2	CDC2	5	6	9	10
The effect on mitosis suggests that p27 inhibits mitotic CDK1 in addition to CDK2 ( XREF_FIG ) .	The effect on mitosis suggests that p27 inhibits mitotic CDK1 in addition to CDK2 (XREF_FIG).	6	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK1	CDK1	CDK1	6	7	9	10
However , p27 inhibits cdk1 and proliferation of cdk2-/- mouse embryo fibroblasts , and also stabilizes the cyclin D and cdk4 complex , suggesting that targeting p27 may have global , deleterious effects .	However, p27 inhibits cdk1 and proliferation of cdk2-/- mouse embryo fibroblasts, and also stabilizes the cyclin D and cdk4 complex, suggesting that targeting p27 may have global, deleterious effects.	2	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	cdk1	cdk1	cdk1	2	3	4	5
In addition to promote cell cycle exit , in the lens , p27 Kip1 is important to inhibit Cdk1 activity during fiber cell generation .	In addition to promote cell cycle exit, in the lens, p27 Kip1 is important to inhibit Cdk1 activity during fiber cell generation.	12	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	Cdk1	Cdk1	Cdk1	12	14	18	19
A cyclin dependent kinase ( CDK ) inhibitor , p27 inhibits CDK1 , 2 , 4 , and 6 via interaction with Cyclin and CDK complex XREF_BIBR and inhibits cell cycle progression at the G0-G1 and G1-S transitions XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	A cyclin dependent kinase (CDK) inhibitor, p27 inhibits CDK1, 2, 4, and 6 via interaction with Cyclin and CDK complex XREF_BIBR and inhibits cell cycle progression at the G0-G1 and G1-S transitions XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	9	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27	p27	p27	CDK1	CDK1	CDK1	9	10	11	12
Later , during fiber cell differentiation , p27 Kip1 degradation allows Cdk1 activity in late fiber cells .	Later, during fiber cell differentiation, p27 Kip1 degradation allows Cdk1 activity in late fiber cells.	7	12	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	Cdk1	Cdk1	Cdk1	7	9	11	12
In contrast , p27Kip1 expression also inhibited p34cdc2 but reduced mitotic arrest only slightly , from 87 .	In contrast, p27Kip1 expression also inhibited p34cdc2 but reduced mitotic arrest only slightly, from 87.	3	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27Kip1	p27Kip1 expression	p27kip1	p34cdc2	p34cdc2	p34cdc2	3	4	7	8
AZD5363 inhibited some of these effects ( p27 repression and induction of p21 , cyclin A2 , cyclin D2 , cyclin D3 and CDK1 ) but not others ( induction of cyclin E1 , CDK2 and CDK4 ) .	AZD5363 inhibited some of these effects (p27 repression and induction of p21, cyclin A2, cyclin D2, cyclin D3 and CDK1) but not others (induction of cyclin E1, CDK2 and CDK4).	7	24	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p27	p27	p27	CDK1	CDK1	CDK1	7	8	23	24
In contrast to an earlier report [ XREF_BIBR ] , recent work from several laboratories has revealed that also p27 KIP1 can inhibit CDK1 kinase activity through direct interaction .	In contrast to an earlier report [XREF_BIBR], recent work from several laboratories has revealed that also p27 KIP1 can inhibit CDK1 kinase activity through direct interaction.	19	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 KIP1	p27 KIP1	p27 KIP1	CDK1	CDK1	CDK1	19	21	23	24
p15INK4B is an important inhibitor of CDK4 and CDK6 , which play a critical role in the regulation of G ( 1 )-S-phase transition of the cell cycle .	p15INK4B is an important inhibitor of CDK4 and CDK6, which play a critical role in the regulation of G (1)-S-phase transition of the cell cycle.	0	11	is an important inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	p15INK4B	p15INK4B	p15INK4B	CDK4	CDK4	CDK4	0	1	6	7
CDKN2B is a specific inhibitor of CDK4 and CDK6 , proteins that are important in cell cycle G1 phase progression and G1/S transition .	CDKN2B is a specific inhibitor of CDK4 and CDK6, proteins that are important in cell cycle G1 phase progression and G1/S transition.	0	8	is a specific inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	CDKN2B	CDKN2B	CDKN2B	CDK4	CDK4	CDK4	0	1	6	7
Several cell cycle regulators and key genes of the MAPK pathway , CDKN2B ( cyclin dependent kinase inhibitor 2B , or p15 ) which inhibits CDK4 , and CCNA1 ( Cyclin A1 ) , were found to be expressed at 7-10 fold higher in NAE than in WBFB .	Several cell cycle regulators and key genes of the MAPK pathway, CDKN2B (cyclin dependent kinase inhibitor 2B, or p15) which inhibits CDK4, and CCNA1 (Cyclin A1), were found to be expressed at 7-10 fold higher in NAE than in WBFB.	3	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2B	CDKN2B	CDKN2B	CDK4	CDK4	CDK4	12	13	25	26
XREF_BIBR , XREF_BIBR The CDKN2B gene encodes p15ink4b , which , like p16Ink4a , inhibits the Rb1 regulators CDK4 and CDK6 .	XREF_BIBR, XREF_BIBR The CDKN2B gene encodes p15ink4b, which, like p16Ink4a, inhibits the Rb1 regulators CDK4 and CDK6.	6	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p15ink4b	p15ink4b	p15ink4b	CDK4	CDK4	CDK4	7	8	18	19
CDKN2B prevents activation of CDK4 or CDK6 by forming a complex with them .	CDKN2B prevents activation of CDK4 or CDK6 by forming a complex with them.	0	6	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2B	CDKN2B	CDKN2B	CDK4	CDK4	CDK4	0	1	4	5
As an oncogene , CDK4 is suppressed by CDKN2B in the RB signaling pathway .	As an oncogene, CDK4 is suppressed by CDKN2B in the RB signaling pathway.	4	13	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDKN2B	CDKN2B	CDKN2B	CDK4	CDK4	CDK4	8	9	4	5
CDKN2B negatively regulates CDK4 and CDK6 [ XREF_BIBR ] .	CDKN2B negatively regulates CDK4 and CDK6 [XREF_BIBR].	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2B	CDKN2B	CDKN2B	CDK4	CDK4	CDK4	0	1	3	4
Nonetheless , p16INK4A expression is required for the reduction in cdk4- and cdk6 mediated Rb kinase activity observed in response to DNA damage .	Nonetheless, p16INK4A expression is required for the reduction in cdk4- and cdk6 mediated Rb kinase activity observed in response to DNA damage.	8	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	cdk6	cdk6	cdk6	Rb	Rb	Rb	12	13	14	15
60 CDK6 is normally regulated by p16 and inhibits the activity of RB1 .	60 CDK6 is normally regulated by p16 and inhibits the activity of RB1.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK6	CDK6	CDK6	RB1	RB1	RB1	1	2	12	13
p53 induces growth arrest and cellular senescence via cyclin dependent kinase ( CDK ) 4 and CDK6 , which block the retinoblastoma protein in its active hypophosphorylated state .	p53 induces growth arrest and cellular senescence via cyclin dependent kinase (CDK) 4 and CDK6, which block the retinoblastoma protein in its active hypophosphorylated state.	3	23	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK6	CDK6	CDK6	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	16	17	21	23
CDK6 and CDC25a were downregulated after miR-449a treatment , resulting in the functional accumulation of the pocket proteins Rb and p130 .	CDK6 and CDC25a were downregulated after miR-449a treatment, resulting in the functional accumulation of the pocket proteins Rb and p130.	0	20	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK6	CDK6	CDK6	Rb	Rb	Rb	0	1	18	19
Overexpression of cyclin D1 and D3 frequently associates with MM XREF_BIBR , and mutually exclusive cyclin dependent kinase ( CDK ) 4/cyclin D1 and CDK6 and cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation XREF_BIBR .	Overexpression of cyclin D1 and D3 frequently associates with MM XREF_BIBR, and mutually exclusive cyclin dependent kinase (CDK) 4/cyclin D1 and CDK6 and cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation XREF_BIBR.	24	32	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK6	CDK6	CDK6	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	24	25	30	32
Knockdown of CDK6 should elicit both a decrease of the P-S780 RB1 epitope and an accumulation of cells in G1 phase of the cell cycle .	Knockdown of CDK6 should elicit both a decrease of the P-S780 RB1 epitope and an accumulation of cells in G1 phase of the cell cycle.	0	12	elicit	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	RB1	RB1	RB1	2	3	11	12
p16 INK4a is an inhibitor to the cell cycle activators CDK4 and CDK6 , which inactivate the tumor suppressor protein pRB , and p14 ARF binds and inactivates MDM2 , which is responsible for the degradation of TP53 , thereby leading to the stabilization of TP53 .	p16 INK4a is an inhibitor to the cell cycle activators CDK4 and CDK6, which inactivate the tumor suppressor protein pRB, and p14 ARF binds and inactivates MDM2, which is responsible for the degradation of TP53, thereby leading to the stabilization of TP53.	4	21	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	pRB	pRB	pRB	12	13	20	21
It has also been reported that both p16 and p14 ( ARF ) , which inactivate MDM2 , are on the same chromosome 9p21 [ XREF_BIBR ] .	It has also been reported that both p16 and p14 (ARF), which inactivate MDM2, are on the same chromosome 9p21 [XREF_BIBR].	6	23	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	MDM2	MDM2	MDM2	7	8	16	17
CDKN2A inhibits MDM2 function by directly binding to MDM2 , whereas ATM suppresses MDM2 through post-translational modifications [ XREF_BIBR ] .	CDKN2A inhibits MDM2 function by directly binding to MDM2, whereas ATM suppresses MDM2 through post-translational modifications [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	MDM2	MDM2	MDM2	0	1	2	3
Since MDM2 is negatively regulated by CDKN2A , MDM2 amplification and aberrations in the cyclin pathway will likely lead to suppression of TP53 ( TP53 is negatively regulated by MDM2 ) [ XREF_BIBR ] .	Since MDM2 is negatively regulated by CDKN2A, MDM2 amplification and aberrations in the cyclin pathway will likely lead to suppression of TP53 (TP53 is negatively regulated by MDM2) [XREF_BIBR].	1	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	MDM2	MDM2	MDM2	6	7	1	2
Nucleolar sequestration is a common mechanism in which general protein stability is regulated ; for example , in response to nucleolar stress , MDM2 is sequestered in the nucleolus by CDKN2A ( p14ARF ) , resulting in stabilization of the tumor suppressor p53 .	Nucleolar sequestration is a common mechanism in which general protein stability is regulated; for example, in response to nucleolar stress, MDM2 is sequestered in the nucleolus by CDKN2A (p14ARF), resulting in stabilization of the tumor suppressor p53.	23	32	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	MDM2	MDM2	MDM2	30	31	23	24
p16INK4a is a cyclin dependent kinase ( CDK4/6 ) inhibitor and p14ARF acts in TP53 stabilization , binding and sequestering the MDM2 proto-oncogene .	p16INK4a is a cyclin dependent kinase (CDK4/6) inhibitor and p14ARF acts in TP53 stabilization, binding and sequestering the MDM2 proto-oncogene.	0	22	sequestering	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16INK4a	p16INK4a	p16INK4a	MDM2	MDM2	MDM2	0	1	21	22
In addition , the CDKN2A gene alternative splicing sites that lead to formation of several protein products , such as p14 , may sequester MDM2 , helping stabilize TP53 [ XREF_BIBR ] .	In addition, the CDKN2A gene alternative splicing sites that lead to formation of several protein products, such as p14, may sequester MDM2, helping stabilize TP53 [XREF_BIBR].	4	26	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	MDM2	MDM2	MDM2	4	5	24	25
XREF_FIG shows that CDKN2A ( alias of INK4A ) gene does not inhibit the activity of MDM2 resulting in MDM2 up-regulation .	XREF_FIG shows that CDKN2A (alias of INK4A) gene does not inhibit the activity of MDM2 resulting in MDM2 up-regulation.	3	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	MDM2	MDM2	MDM2	3	4	16	17
The other product of CDKN2A gene , p14 ARF , inhibits the Mdm-2 ( Mouse double minute homolog ) which is a negative regulator of p53 [ XREF_BIBR ] indicating that the CDKN2A controls the cell cycle via two distinct mechanisms .	The other product of CDKN2A gene, p14 ARF, inhibits the Mdm-2 (Mouse double minute homolog) which is a negative regulator of p53 [XREF_BIBR] indicating that the CDKN2A controls the cell cycle via two distinct mechanisms.	4	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	Mdm-2	Mdm-2	Mdm-2	4	5	12	13
CDKN2A , a tumor suppressor protein , has been shown to block MDM2 induced degradation of p53 and enhancing p53 dependent transactivation and apoptosis .	CDKN2A, a tumor suppressor protein, has been shown to block MDM2 induced degradation of p53 and enhancing p53 dependent transactivation and apoptosis.	0	18	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	MDM2	MDM2	MDM2	0	1	12	13
p19ARF , a product of CDKN2A , is known to block MDM2 , resulting in dysregulation of the p53 pathway [ XREF_BIBR ] .	p19ARF, a product of CDKN2A, is known to block MDM2, resulting in dysregulation of the p53 pathway [XREF_BIBR].	3	12	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	MDM2	MDM2	MDM2	5	6	11	12
One such setting is represented by the frequent CDKN2A deletion in human cancer that , through inactivation of p14ARF , activates MDM2 protein , which in turn degrades TP53 tumor suppressor .	One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor.	8	22	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN2A	CDKN2A	CDKN2A	MDM2	MDM2	MDM2	8	9	21	22
Our data suggested that up-regulation of p21 and p27 might inhibit CDK6 activation , leading to the G1 arrest and suppressed growth in GSTP1 overexpressing HCC cells .	Our data suggested that up-regulation of p21 and p27 might inhibit CDK6 activation, leading to the G1 arrest and suppressed growth in GSTP1 overexpressing HCC cells.	4	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK6	CDK6	CDK6	6	7	11	12
Although p21 is known to inhibit CDK6 activity , CDK6 action on p65 dependent promoters does not seem to require kinase activity .	Although p21 is known to inhibit CDK6 activity, CDK6 action on p65 dependent promoters does not seem to require kinase activity.	1	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK6	CDK6	CDK6	1	2	6	7
Western blotting revealed that RKS262 caused cyclin D1 down-regulation and a p21 independent inhibition of CDK-6 .	Western blotting revealed that RKS262 caused cyclin D1 down-regulation and a p21 independent inhibition of CDK-6.	11	16	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p21	p21	p21	CDK-6	CDK-6	CDK-6	11	12	15	16
P21 not only inhibits Cyclin Ds/CDK4 and CDK6 complexes but also inhibits Cyclin Es/CDK2 complexes to arrest cell proliferation .	P21 not only inhibits Cyclin Ds/CDK4 and CDK6 complexes but also inhibits Cyclin Es/CDK2 complexes to arrest cell proliferation.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21	P21	CDK6	CDK6	CDK6	0	1	7	8
Previously , we have reported that CDK8-CycC negatively regulates E2F1 activity in Drosophila [ XREF_BIBR ] .	Previously, we have reported that CDK8-CycC negatively regulates E2F1 activity in Drosophila [XREF_BIBR].	6	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK8-CycC	CDK8-CycC	CDK8-CycC	E2F1	E2F1	E2F1	6	7	9	10
Furthermore , they found CDK8 promotes the phosphorylation of E2F1 and that the ability of CDK8 to repress E2F1 function depends on its kinase activity .	Furthermore, they found CDK8 promotes the phosphorylation of E2F1 and that the ability of CDK8 to repress E2F1 function depends on its kinase activity.	4	10	promotes	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	CDK8	CDK8	cdk8	E2F1	phosphorylation of E2F1	e2f1	4	5	9	10
E2F1 is also downregulated by CDK8 , a colorectal oncogene [ XREF_BIBR ] .	E2F1 is also downregulated by CDK8, a colorectal oncogene [XREF_BIBR].	0	11	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CDK8	CDK8	CDK8	E2F1	E2F1	E2F1	5	6	0	1
Hence , in colorectal cancers , where Wnt and beta-catenin signaling is a driving force , CDK8 represses E2F1 , a negative regulator of beta-catenin .	Hence, in colorectal cancers, where Wnt and beta-catenin signaling is a driving force, CDK8 represses E2F1, a negative regulator of beta-catenin.	16	22	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK8	CDK8	CDK8	E2F1	E2F1	E2F1	16	17	18	19
CDK8 represses E2F1 , a negative regulator of beta-catenin-dependent gene activation .	CDK8 represses E2F1, a negative regulator of beta-catenin-dependent gene activation.	0	6	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK8	CDK8	CDK8	E2F1	E2F1	E2F1	0	1	2	3
CDK8 represses SREBP-1c and E2F1 activity by phosphorylation .	CDK8 represses SREBP-1c and E2F1 activity by phosphorylation.	0	5	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK8	CDK8	CDK8	E2F1	E2F1	E2F1	0	1	4	5
However , induction of p16 ( INK4a ) also causes marked inhibition of CDK2 activity .	However, induction of p16 (INK4a) also causes marked inhibition of CDK2 activity.	2	14	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	CDK2	CDK2	CDK2	4	5	13	14
Alternatively , acting through a pRb independent pathway , expression of p16 INK4a and its disruption of the association of the cyclin D1 and Cdk4 complex have also been shown to directly inhibit Cdk2 activity through a second mechanism .	Alternatively, acting through a pRb independent pathway, expression of p16 INK4a and its disruption of the association of the cyclin D1 and Cdk4 complex have also been shown to directly inhibit Cdk2 activity through a second mechanism.	9	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 INK4a	expression of p16 INK4a	p16 ink4a	Cdk2	Cdk2	cdk2	11	13	33	34
The CDKI Cdkn2c ( p18 Ink4c ) , which inhibits Cdk4 and Cdk6 , was also down-regulated , consistent with G 1 / S phase transition .	The CDKI Cdkn2c (p18 Ink4c), which inhibits Cdk4 and Cdk6, was also down-regulated, consistent with G 1 / S phase transition.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdkn2c	Cdkn2c	Cdkn2c	Cdk4	Cdk4	Cdk4	2	3	10	11
p18Ink4c has been shown to inhibit CDK4 and CDK6 function XREF_BIBR and many types of human cancer have reduced expression of p18Ink4c .	p18Ink4c has been shown to inhibit CDK4 and CDK6 function XREF_BIBR and many types of human cancer have reduced expression of p18Ink4c.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p18Ink4c	p18Ink4c	p18Ink4c	CDK4	CDK4	CDK4	0	1	6	7
No such cooperation is observed between Cdk4 R24C and p18 ( INK4c ) absence , suggesting that the only function of p18INK4c is inhibiting Cdk4 in this model .	No such cooperation is observed between Cdk4 R24C and p18 (INK4c) absence, suggesting that the only function of p18INK4c is inhibiting Cdk4 in this model.	19	27	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p18INK4c	p18INK4c	p18INK4c	Cdk4	Cdk4	Cdk4	21	22	24	25
MS4A3 was present in a complex with cyclin dependent kinase 2 ( CDK2 ) and kinase associated phosphatase ( KAP ) , which inactivates CDK2 by dephosphorylation of Thr160 [ XREF_BIBR ] .	MS4A3 was present in a complex with cyclin dependent kinase 2 (CDK2) and kinase associated phosphatase (KAP), which inactivates CDK2 by dephosphorylation of Thr160 [XREF_BIBR].	17	25	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KAP	KAP	KAP	CDK2	CDK2	CDK2	19	20	24	25
Moreover , the dephosphorylation of Thr160 by KAP prevented Cdk2 kinase activity upon subsequent association with cyclin A.	Moreover, the dephosphorylation of Thr160 by KAP prevented Cdk2 kinase activity upon subsequent association with cyclin A.	3	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KAP	dephosphorylation of Thr160 by KAP	kap	Cdk2	Cdk2	cdk2	7	8	9	10
In leukemia cells , CDK5 was found to phosphorylate and functionally inhibit the proapoptotic protein Noxa XREF_BIBR .	In leukemia cells, CDK5 was found to phosphorylate and functionally inhibit the proapoptotic protein Noxa XREF_BIBR.	4	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK5	CDK5	CDK5	protein Noxa	protein Noxa	protein Noxa	4	5	14	16
We identify Cdk5 as the Noxa kinase and show that Cdk5 knockdown or expression of a Noxa S ( 13 ) to A mutant increases sensitivity to glucose starvation , confirming that the phosphorylation is protective .	We identify Cdk5 as the Noxa kinase and show that Cdk5 knockdown or expression of a Noxa S (13) to A mutant increases sensitivity to glucose starvation, confirming that the phosphorylation is protective.	10	17	knockdown	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Cdk5	Cdk5	Cdk5	Noxa	Noxa	Noxa	10	11	16	17
Instead , CDK5 inhibition increased NOXA mRNA and protein levels by decreasing the expression of miR-23a , whereas overexpressing the CDK5 activator p35 attenuated both of these effects on NOXA and miR-23a expression .	Instead, CDK5 inhibition increased NOXA mRNA and protein levels by decreasing the expression of miR-23a, whereas overexpressing the CDK5 activator p35 attenuated both of these effects on NOXA and miR-23a expression.	2	6	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK5	CDK5	CDK5	NOXA	NOXA	NOXA	2	3	5	6
In the absence of CBX3 , enforced CDK6 levels inhibit cell growth by upregulating inhibitor p21 , but we ca not do it in wild type cells , and promoter activity is suppressed by CBX3 .	In the absence of CBX3, enforced CDK6 levels inhibit cell growth by upregulating inhibitor p21, but we ca n't do it in wild type cells, and promoter activity is suppressed by CBX3.	7	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6 levels	cdk6	p21	p21	p21	7	8	15	16
The G 0 / G 1 arrest was attributed to a decreased expression of cyclinD1 , cyclinE , CDK2 and CDK6 , especially the upregulation of p21 .	The G 0 / G 1 arrest was attributed to a decreased expression of cyclinD1, cyclinE, CDK2 and CDK6, especially the upregulation of p21.	12	27	upregulation	Positive_activation_syntax_7_noun	Negative_activation	Negative_activation	CDK6	expression of cyclinD1, cyclinE, CDK2 and CDK6	cdk6	p21	p21	p21	20	21	26	27
XREF_BIBR The G ( 0 )/G ( 1 ) arrest was attributed to a decreased expression of cyclin D1 , cyclin E , CDK2 , and CDK6 , especially the upregulation of p21 .	XREF_BIBR The G (0)/G (1) arrest was attributed to a decreased expression of cyclin D1, cyclin E, CDK2, and CDK6, especially the upregulation of p21.	15	33	upregulation	Positive_activation_syntax_7_noun	Negative_activation	Negative_activation	CDK6	expression of cyclin D1, cyclin E, CDK2, and CDK6	cdk6	p21	p21	p21	26	27	32	33
Knockdown of Cdk5 Inhibits Cdk5r1 Mediated beta-Cell Proliferation .	Knockdown of Cdk5 Inhibits Cdk5r1 Mediated beta-Cell Proliferation.	0	5	Inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	Cdk5r1	Cdk5r1	Cdk5r1	2	3	4	5
Cdk5 degrades prosurvival transcription factors MEF2A and MEF2D via phosphorylation , promoting neuronal death .	Cdk5 degrades prosurvival transcription factors MEF2A and MEF2D via phosphorylation, promoting neuronal death.	0	11	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk5	Cdk5	Cdk5	MEF2A	MEF2A	MEF2A	0	1	5	6
Phosphorylation of Ser408 by CDK5 , which is induced by neurotoxicity , inhibits MEF2A transcriptional activation , leading to apoptosis of cortical neurons .	Phosphorylation of Ser408 by CDK5, which is induced by neurotoxicity, inhibits MEF2A transcriptional activation, leading to apoptosis of cortical neurons.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK5	Phosphorylation of Ser408 by CDK5	cdk5	MEF2A	MEF2A	mef2a	4	5	13	14
123 Acetylation by p300 HAT stabilizes NICD , whereas phosphorylation by CDK8 induces NICD degradation .	123 Acetylation by p300 HAT stabilizes NICD, whereas phosphorylation by CDK8 induces NICD degradation.	9	14	induces	Positive_activation_token_1_verb	Negative_activation	Negative_activation	CDK8	CDK8	CDK8	NICD	NICD	NICD	11	12	13	14
CDK8 represses NOTCH1 signaling driven transcription by phosphorylating the PEST domain of NOTCH1-ICD , an event required for its ubiquitination by the E3 ligase FBXW7 and subsequent degradation .	CDK8 represses NOTCH1 signaling driven transcription by phosphorylating the PEST domain of NOTCH1-ICD, an event required for its ubiquitination by the E3 ligase FBXW7 and subsequent degradation.	0	13	represses	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	CDK8	CDK8	cdk8	NOTCH1	NOTCH1 signaling driven transcription by phosphorylating the PEST domain of NOTCH1-ICD	notch1	0	1	2	3
Recently , Cdk5 was shown to contribute to the initiation of small-cell lung cancer : overexpression of the NOTCH target ASCL1 induced activation of Cdk5 that phosphorylated and inactivated Rb1 .	Recently, Cdk5 was shown to contribute to the initiation of small-cell lung cancer : overexpression of the NOTCH target ASCL1 induced activation of Cdk5 that phosphorylated and inactivated Rb1.	15	30	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk5	overexpression of the NOTCH target ASCL1 induced activation of Cdk5	cdk5	Rb1	Rb1	rb1	24	25	29	30
While the physiological role of parkin phosphorylation remains unclear , it is conceivable that aberrant CK1 or Cdk5 activity can promote loss of parkin function and play a role in sporadic PD pathogenesis .	While the physiological role of parkin phosphorylation remains unclear, it is conceivable that aberrant CK1 or Cdk5 activity can promote loss of parkin function and play a role in sporadic PD pathogenesis.	17	24	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk5	Cdk5	Cdk5	parkin	parkin	parkin	17	18	23	24
Whereas CFLAR blocks the activation of the initiator caspase-8 , XIAP can block the initiation phase ( by inhibition of caspase-9 ) and the execution phase ( by blocking caspase-3 and caspase-7 ) [ XREF_BIBR ] .	Whereas CFLAR blocks the activation of the initiator caspase-8, XIAP can block the initiation phase (by inhibition of caspase-9) and the execution phase (by blocking caspase-3 and caspase-7) [XREF_BIBR].	1	9	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CFLAR	CFLAR	CFLAR	caspase-8	caspase-8	caspase-8	1	2	8	9
Silencing of c-FLIP has been shown to induce caspase-8 activation in a number of NSCLC cell lines , including H460 [ XREF_BIBR ] .	Silencing of c-FLIP has been shown to induce caspase-8 activation in a number of NSCLC cell lines, including H460 [XREF_BIBR].	0	9	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	8	9
Of the extrinsic pathway only a reduction in c-FLIP ( an inhibitor of caspase-8 ) and elevated cleaved caspase-8 were detected ( XREF_FIG ) .	Of the extrinsic pathway only a reduction in c-FLIP (an inhibitor of caspase-8) and elevated cleaved caspase-8 were detected (XREF_FIG).	6	16	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	8	9	13	14
cFLIP specifically inhibits caspase-8 by interacting with FADD , therefore preventing the activation of procaspase-8 at complex II as well as at the DISC XREF_BIBR .	cFLIP specifically inhibits caspase-8 by interacting with FADD, therefore preventing the activation of procaspase-8 at complex II as well as at the DISC XREF_BIBR.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	0	1	3	4
XREF_BIBR Despite the dual role of c-FLIP L in caspase-8 activation , it should be emphasized that c-FLIP L acts as an antiapoptotic protein to inhibit caspase-8 activation at least in the range of physiological expression level in tumor cells .	XREF_BIBR Despite the dual role of c-FLIP L in caspase-8 activation, it should be emphasized that c-FLIP L acts as an antiapoptotic protein to inhibit caspase-8 activation at least in the range of physiological expression level in tumor cells.	17	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	17	18	26	27
Since the upregulation of cFLIP impairs caspase-8 activation , siRNA mediated silencing of cFLIP could logically be predicted to promote the apoptosis of R27T resistant cells .	Since the upregulation of cFLIP impairs caspase-8 activation, siRNA mediated silencing of cFLIP could logically be predicted to promote the apoptosis of R27T resistant cells.	2	7	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	4	5	6	7
However , since c-FLIP S and v-FLIP variants lack the C-terminal activation domain for caspase-8 that is present in c-FLIP L , c-FLIP S and v-FLIP block further caspase-8 activation XREF_BIBR , XREF_BIBR , which could serve to turn off type I IFN production via the RIG-I helicase pathway .	However, since c-FLIP S and v-FLIP variants lack the C-terminal activation domain for caspase-8 that is present in c-FLIP L, c-FLIP S and v-FLIP block further caspase-8 activation XREF_BIBR, XREF_BIBR, which could serve to turn off type I IFN production via the RIG-I helicase pathway.	22	30	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	22	23	28	29
c-FLIP L may inhibit caspase 8 activity and the de novo synthesis of c-FLIP L may be necessary for maintaining an anti-apoptotic state , leading to speculation that Stx mediated protein synthesis inhibition was required for early caspase 8 activation .	c-FLIP L may inhibit caspase 8 activity and the de novo synthesis of c-FLIP L may be necessary for maintaining an anti-apoptotic state, leading to speculation that Stx mediated protein synthesis inhibition was required for early caspase 8 activation.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	0	1	4	6
cFLIP mediates the initiation of necroptosis by inhibiting caspase-8 , binds to Atg3 and prevents its conjugation to LC3 , and blocks the formation of LC3-II and autophagy XREF_BIBR , XREF_BIBR .	cFLIP mediates the initiation of necroptosis by inhibiting caspase-8, binds to Atg3 and prevents its conjugation to LC3, and blocks the formation of LC3-II and autophagy XREF_BIBR, XREF_BIBR.	0	9	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	0	1	8	9
Thus , c-FLIP S potently blocks procaspase-8 processing , but very high levels of c-FLIP L are required to inhibit caspase-8 ( XREF_FIG ) .	Thus, c-FLIP S potently blocks procaspase-8 processing, but very high levels of c-FLIP L are required to inhibit caspase-8 (XREF_FIG).	14	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	14	15	20	21
Second , it interrupts the transmission of the apoptotic signal from the CD95 DISC by increasing cFLIP expression , which enhances cFLIP mediated inhibition of caspase 8 and prevents not only further activation of the extrinsic apoptotic pathway , but also cleavage of Bid , thereby blocking the initiation of the mitochondrial pathway .	Second, it interrupts the transmission of the apoptotic signal from the CD95 DISC by increasing cFLIP expression, which enhances cFLIP mediated inhibition of caspase 8 and prevents not only further activation of the extrinsic apoptotic pathway, but also cleavage of Bid, thereby blocking the initiation of the mitochondrial pathway.	21	27	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase 8	caspase 8	caspase 8	21	22	25	27
c-FLIP , an enzymatically inactive homologue of caspase-8 , is required in low amounts for processing of caspase-8 in the DISC but can block caspase-8 activation when present in larger amounts XREF_BIBR - XREF_BIBR .	c-FLIP, an enzymatically inactive homologue of caspase-8, is required in low amounts for processing of caspase-8 in the DISC but can block caspase-8 activation when present in larger amounts XREF_BIBR - XREF_BIBR.	0	25	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	24	25
Active caspase 8 generated from an efficient DISC can be inhibited by high levels of c-FLIP , antagonizing caspase 8 activation .	Active caspase 8 generated from an efficient DISC can be inhibited by high levels of c-FLIP, antagonizing caspase 8 activation.	0	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	c-FLIP	levels of c-FLIP	c-flip	caspase 8	caspase 8	caspase 8	15	16	1	3
c-FLIP inhibits caspase-8 activation and cell apoptosis mediated by death receptors .	c-FLIP inhibits caspase-8 activation and cell apoptosis mediated by death receptors.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	2	3
However , under a physiological condition , NF-kappaB activation leads to inducible expression of cFLIP , which in turn competes with caspase-8 for incorporation into the DISC , and consequently limiting caspase-8 activation .	However, under a physiological condition, NF-kappaB activation leads to inducible expression of cFLIP, which in turn competes with caspase-8 for incorporation into the DISC, and consequently limiting caspase-8 activation.	7	32	limiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	NF-kappaB activation leads to inducible expression of cFLIP	cflip	caspase-8	caspase-8	caspase-8	14	15	31	32
Moreover , the suppression of c-FLIP due to inhibition of translation initiation complex by 3-AWA enhanced FAS trafficking , BID and caspase 8 cleavage .	Moreover, the suppression of c-FLIP due to inhibition of translation initiation complex by 3-AWA enhanced FAS trafficking, BID and caspase 8 cleavage.	3	23	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	5	6	21	23
CFLAR ( C-FLIP ) can suppress caspase 8 activation and mediate apoptosis [ XREF_BIBR ] .	CFLAR (C-FLIP) can suppress caspase 8 activation and mediate apoptosis [XREF_BIBR].	0	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CFLAR	CFLAR	CFLAR	caspase 8	caspase 8	caspase 8	0	1	6	8
All of the c-FLIP isoforms , c-FLIP short ( c-FLIP S ) , c-FLIP raji ( c-FLIP R ) and c-FLIP long ( c-FLIP L ) function as anti-apoptotic molecules and inhibit caspase-8 activity XREF_BIBR - XREF_BIBR .	All of the c-FLIP isoforms, c-FLIP short (c-FLIP S), c-FLIP raji (c-FLIP R) and c-FLIP long (c-FLIP L) function as anti-apoptotic molecules and inhibit caspase-8 activity XREF_BIBR - XREF_BIBR.	0	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	32	33
These results clearly show that c-FLIP-specific siRNA triggered apoptosis is primarily due to the silencing of the c-FLIP L gene and not the c-FLIP S gene , and that c-FLIP L expression is required to prevent spontaneous caspase-8 activation from occurring at the DISC .	These results clearly show that c-FLIP-specific siRNA triggered apoptosis is primarily due to the silencing of the c-FLIP L gene and not the c-FLIP S gene, and that c-FLIP L expression is required to prevent spontaneous caspase-8 activation from occurring at the DISC.	29	38	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP L expression	c-flip	caspase-8	caspase-8	caspase-8	29	30	37	38
c-FLIP can inhibit caspase-8 activation via Fas by competing with caspase-8 for recruitment to FADD in the death inducing signal complex [ XREF_BIBR ] .	c-FLIP can inhibit caspase-8 activation via Fas by competing with caspase-8 for recruitment to FADD in the death inducing signal complex [XREF_BIBR].	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	3	4
The downregulation of c-FLIP ( an inhibitor of caspase-8 ) and the upregulation of DR5 participate in the increased sensitization of hepatoma cells to Qu induced apoptosis via TRAIL [ XREF_BIBR ] .	The downregulation of c-FLIP (an inhibitor of caspase-8) and the upregulation of DR5 participate in the increased sensitization of hepatoma cells to Qu induced apoptosis via TRAIL [XREF_BIBR].	1	12	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	8	9
NF-kappaB activation leads to inhibition of caspase-8 by c-FLIP , and thus blocks the execution of apoptosis .	NF-kappaB activation leads to inhibition of caspase-8 by c-FLIP, and thus blocks the execution of apoptosis.	2	9	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	8	9	6	7
Cellular FLICE-inhibitory protein ( c-FLIP ) has a higher affinity for the DISC than caspase-8 and inhibits processing of caspase-8 and induction of apoptosis via the death receptor pathway at high levels of expression .	Cellular FLICE-inhibitory protein (c-FLIP) has a higher affinity for the DISC than caspase-8 and inhibits processing of caspase-8 and induction of apoptosis via the death receptor pathway at high levels of expression.	2	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	4	5	19	20
The finding that the knockdown of RIP , c-FLIP or PED and PEA -15 eliminates the inhibition of caspase-8 cleavage indicates that these adaptors are required for maintaining TRAIL resistance .	The finding that the knockdown of RIP, c-FLIP or PED and PEA -15 eliminates the inhibition of caspase-8 cleavage indicates that these adaptors are required for maintaining TRAIL resistance.	4	19	eliminates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	8	9	18	19
However , in tumor cells , over-expression of cFLIP inhibited the activation of the caspase-8 signal transduction pathway and cell apoptosis [ XREF_BIBR ] .	However, in tumor cells, over-expression of cFLIP inhibited the activation of the caspase-8 signal transduction pathway and cell apoptosis [XREF_BIBR].	6	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	over-expression of cFLIP	cflip	caspase-8	caspase-8	caspase-8	8	9	14	15
Taken together , these reports support our findings that TRAIL mediated upregulation of c-FLIP S blocked the processing of caspase-8 at DISC and promoted survival of NSCLC cells .	Taken together, these reports support our findings that TRAIL mediated upregulation of c-FLIP S blocked the processing of caspase-8 at DISC and promoted survival of NSCLC cells.	13	20	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	13	14	19	20
How do c-FLIP proteins inhibit caspase-8 activation in a DED chain ?	How do c-FLIP proteins inhibit caspase-8 activation in a DED chain?	2	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	5	6
One mechanism is likely through inhibition of caspase-8 by cFLIP , following TLR and NF-kappaB activation XREF_BIBR , XREF_BIBR .	One mechanism is likely through inhibition of caspase-8 by cFLIP, following TLR and NF-kappaB activation XREF_BIBR, XREF_BIBR.	3	10	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	9	10	7	8
Importantly , the silencing of c-FLIP restored SMC sensitivity in previously resistant cancer cells by allowing ligand mediated activation of caspase-8 and caspase-3 to proceed .	Importantly, the silencing of c-FLIP restored SMC sensitivity in previously resistant cancer cells by allowing ligand mediated activation of caspase-8 and caspase-3 to proceed.	3	22	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	5	6	20	21
Furthermore , c-FLIP is an endogenous inhibitor of caspase-8 and has been associated with TRAIL-resistance in cancers .	Furthermore, c-FLIP is an endogenous inhibitor of caspase-8 and has been associated with TRAIL-resistance in cancers.	2	12	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	8	9
c-FLIP induction inhibits caspase-8 , which is not able to truncate Bid , its direct substrate , and thus can not induce cytochrome c release .	c-FLIP induction inhibits caspase-8, which is not able to truncate Bid, its direct substrate, and thus can not induce cytochrome c release.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	3	4
Therefore , although initial procaspase-8 processing upon c-FLIP L overexpression is increased , c-FLIP L would block further caspase-8 activation .	Therefore, although initial procaspase-8 processing upon c-FLIP L overexpression is increased, c-FLIP L would block further caspase-8 activation.	13	19	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	13	14	18	19
By contrast , c-FLIP S decreased caspase-8 activity and IFN-beta secretion during CVB3 infection .	By contrast, c-FLIP S decreased caspase-8 activity and IFN-beta secretion during CVB3 infection.	3	7	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	6	7
In the presence of ongoing NFkappaB activity , cFLIP protein is produced and translocates to complex II to prevent activation of caspase 8 .	In the presence of ongoing NFkappaB activity, cFLIP protein is produced and translocates to complex II to prevent activation of caspase 8.	8	23	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP protein	cFLIP protein	cFLIP protein	caspase 8	caspase 8	caspase 8	8	10	21	23
By contrast , c-FLIP S and v-FLIP reduce caspase-8 activity .	By contrast, c-FLIP S and v-FLIP reduce caspase-8 activity.	3	9	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	8	9
cFLIP inhibits activation of caspase-8 needed for the execution of apoptosis XREF_BIBR , XREF_BIBR .	cFLIP inhibits activation of caspase-8 needed for the execution of apoptosis XREF_BIBR, XREF_BIBR.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	0	1	4	5
The cellular FLICE-inhibitory protein ( c-FLIP ) , which is vastly homologous to caspase 8 but lacks enzymatic activity , can also associate with the DISC , blocking activation of caspase 8 through competition for binding sites .	The cellular FLICE-inhibitory protein (c-FLIP), which is vastly homologous to caspase 8 but lacks enzymatic activity, can also associate with the DISC, blocking activation of caspase 8 through competition for binding sites.	3	32	blocking	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	5	6	30	32
cFLIP can inhibit death receptor signaling and caspase-8 activation , possibly through competition with caspase-8 for the recruitment to FADD .	cFLIP can inhibit death receptor signaling and caspase-8 activation, possibly through competition with caspase-8 for the recruitment to FADD.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	0	1	7	8
High concentrations of c-FLIP L prevent full processing and release of active caspase-8 from the DISC , thus blocking the induction of cell death .	High concentrations of c-FLIP L prevent full processing and release of active caspase-8 from the DISC, thus blocking the induction of cell death.	3	13	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	12	13
Our present findings are in line with these observations and support the notion that association of caspase-8 and c-FLIP L within the same DISC blocks the autoproteolytic cleavage of caspase-8 .	Our present findings are in line with these observations and support the notion that association of caspase-8 and c-FLIP L within the same DISC blocks the autoproteolytic cleavage of caspase-8.	16	30	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	18	19	29	30
Recently , it has also been shown that silencing of cFLIP induced caspase-8 activation via increased co-localisation of DR5 and ceramide , and significantly enhanced TRAIL induced apoptosis [ XREF_BIBR ] .	Recently, it has also been shown that silencing of cFLIP induced caspase-8 activation via increased co-localisation of DR5 and ceramide, and significantly enhanced TRAIL induced apoptosis [XREF_BIBR].	8	13	induced	Positive_early_activation	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	10	11	12	13
Indeed , retroviral expression of c-FLIP L strongly reduced Caspase-8 cleavage ( XREF_FIG ) and considerably protected Ni 2+ -exposed cells from TRAIL mediated apoptosis even at high TRAIL concentrations ( XREF_FIG ) .	Indeed, retroviral expression of c-FLIP L strongly reduced Caspase-8 cleavage (XREF_FIG) and considerably protected Ni 2+ -exposed cells from TRAIL mediated apoptosis even at high TRAIL concentrations (XREF_FIG).	5	10	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	Caspase-8	Caspase-8	Caspase-8	5	6	9	10
The available c-FLIP protein at the DISC now becomes rate limiting and is no longer able to block subsequent release of active caspase-8 .	The available c-FLIP protein at the DISC now becomes rate limiting and is no longer able to block subsequent release of active caspase-8.	2	23	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	22	23
The presence of cFLIP in the complex prevents the autocatalytic activation of caspase-8 , thus sparing the cell from apoptotic death .	The presence of cFLIP in the complex prevents the autocatalytic activation of caspase-8, thus sparing the cell from apoptotic death.	1	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	3	4	12	13
In vitro , knockdown of cFLIP can arrest cell cycle and accelerate cell death by activating caspase-8 , caspase-3 and caspase-9 , and down-regulate proliferating cell nuclear antigen ( PCNA ) .	In vitro, knockdown of cFLIP can arrest cell cycle and accelerate cell death by activating caspase-8, caspase-3 and caspase-9, and down-regulate proliferating cell nuclear antigen (PCNA).	3	20	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	5	6	16	17
The consequence of persistent c-FLIP expression is the suppression of apoptosis , as c-FLIP inhibits caspase-8 to block the progression of cell death .	The consequence of persistent c-FLIP expression is the suppression of apoptosis, as c-FLIP inhibits caspase-8 to block the progression of cell death.	13	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	13	14	15	16
Furthermore , we inspected the mechanism of cordycepin induced apoptosis and discovered that the expression of c-FLIP L was dramatically down-regulated , and the ectopic expression of c-FLIP L decreased the cleavage of caspase-8 , caspase-3 and PARP , protecting H157-FLIP L cells from cordycepin triggered extrinsic apoptosis .	Furthermore, we inspected the mechanism of cordycepin induced apoptosis and discovered that the expression of c-FLIP L was dramatically down-regulated, and the ectopic expression of c-FLIP L decreased the cleavage of caspase-8, caspase-3 and PARP, protecting H157-FLIP L cells from cordycepin triggered extrinsic apoptosis.	27	37	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	27	28	33	34
XREF_BIBR described that c-FLIP makes a heterodimer with caspase-8 and prevents an active homodimer formation of caspase-8 .	XREF_BIBR described that c-FLIP makes a heterodimer with caspase-8 and prevents an active homodimer formation of caspase-8.	3	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	16	17
Several inhibitory proteins , such as c-FLIP , which negatively regulates caspase-8 , and the IAP and Bcl-2 protein families keep the apoptotic program in check [ XREF_BIBR ] .	Several inhibitory proteins, such as c-FLIP, which negatively regulates caspase-8, and the IAP and Bcl-2 protein families keep the apoptotic program in check [XREF_BIBR].	2	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	6	7	11	12
Likewise , inhibition of caspase-8 by Flip also protected against cell death .	Likewise, inhibition of caspase-8 by Flip also protected against cell death.	2	7	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Flip	Flip	Flip	caspase-8	caspase-8	caspase-8	6	7	4	5
vFLIP was originally identified as a viral homologue of cFLIP ( cellular FLICE like inhibitory protein ) , which inhibits Caspase 8 activity induced by death domain containing receptors [ XREF_BIBR ] .	vFLIP was originally identified as a viral homologue of cFLIP (cellular FLICE like inhibitory protein), which inhibits Caspase 8 activity induced by death domain containing receptors [XREF_BIBR].	7	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	Caspase 8	Caspase 8	Caspase 8	9	10	20	22
As shown in XREF_FIG D , expression of c-Flip inhibits caspase-8 activation in detached cells , up to 30 % of the inhibition that is observed when detached cells are treated with the specific caspase-8 inhibitor , z-IETD-fmk .	As shown in XREF_FIG D, expression of c-Flip inhibits caspase-8 activation in detached cells, up to 30% of the inhibition that is observed when detached cells are treated with the specific caspase-8 inhibitor, z-IETD-fmk.	6	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Flip	expression of c-Flip	c-flip	caspase-8	caspase-8	caspase-8	8	9	10	11
c-FLIP L knockdown induced ligand independent apoptosis in a DR5-, FADD- and caspase 8 dependent manner .	c-FLIP L knockdown induced ligand independent apoptosis in a DR5-, FADD- and caspase 8 dependent manner.	0	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	0	1	12	14
These findings were consistent in three independent experiments , and confirmed the requirement of caspase-8 to induce IFN-beta production during CVB3 infection , restoration with non cleavable caspase-8 D387A restored caspase-8 activity , which was augmented by c-FLIP L and reduced by c-FLIP S ( XREF_FIG ) .	These findings were consistent in three independent experiments, and confirmed the requirement of caspase-8 to induce IFN-beta production during CVB3 infection, restoration with non cleavable caspase-8 D387A restored caspase-8 activity, which was augmented by c-FLIP L and reduced by c-FLIP S (XREF_FIG).	30	38	augmented	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	37	38	30	31
In this context , restoration of c-FLIP by NF-kappaB overexpression inhibits the homodimer formation of caspase-8 and normalizes the complex composition so that RIPK3 is not activated .	In this context, restoration of c-FLIP by NF-kappaB overexpression inhibits the homodimer formation of caspase-8 and normalizes the complex composition so that RIPK3 is not activated.	4	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	6	7	15	16
c-FLIP inhibits caspase 8 activation and apoptosis mediated by death receptors such as Fas and DR5 .	c-FLIP inhibits caspase 8 activation and apoptosis mediated by death receptors such as Fas and DR5.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	0	1	2	4
Overexpression of c-FLIP in TECs ( CS3.7-FLIP ) blocked apoptosis and caspase-8 activation with both IFN-gamma and IL-2 .	Overexpression of c-FLIP in TECs (CS3.7-FLIP) blocked apoptosis and caspase-8 activation with both IFN-gamma and IL-2.	0	12	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	Overexpression of c-FLIP	c-flip	caspase-8	caspase-8	caspase-8	2	3	11	12
7 Regardless of the isoform , c-FLIP proteins are co-recruited within the DISC of death domain ( DD )-containing receptors of the TNF superfamily and prevent the release of active caspase-8 to the cytosol , inhibiting apoptosis induced by these death receptors .	7 Regardless of the isoform, c-FLIP proteins are co-recruited within the DISC of death domain (DD)-containing receptors of the TNF superfamily and prevent the release of active caspase-8 to the cytosol, inhibiting apoptosis induced by these death receptors.	6	31	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	6	7	30	31
Western blot showed that the c-FLIP blocked the caspase-8 activation .	Western blot showed that the c-FLIP blocked the caspase-8 activation.	4	9	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	5	6	8	9
FADD recruits procaspase 8 molecules to the DISC following activation of a TNF-receptor through its cognate ligand , while cFLIP antagonizes caspase 8 activation through binding to and blocking FADD or procaspase 8 [ XREF_BIBR ] .	FADD recruits procaspase 8 molecules to the DISC following activation of a TNF-receptor through its cognate ligand, while cFLIP antagonizes caspase 8 activation through binding to and blocking FADD or procaspase 8 [XREF_BIBR].	19	23	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase 8	caspase 8	caspase 8	19	20	21	23
It was shown that c-FLIP L inhibits caspase 8 activation at high expression levels , while it promotes caspase 8 activation at low expression levels .	It was shown that c-FLIP L inhibits caspase 8 activation at high expression levels, while it promotes caspase 8 activation at low expression levels.	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	4	5	7	9
Although cFLIP inhibits apoptotic activation of caspase 8 , caspase 8 and cFLIP heterodimer complexes intriguingly may possess catalytic activity XREF_BIBR .	Although cFLIP inhibits apoptotic activation of caspase 8, caspase 8 and cFLIP heterodimer complexes intriguingly may possess catalytic activity XREF_BIBR.	1	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase 8	caspase 8	caspase 8	1	2	6	8
c-FLIP competes with procaspase 8 for binding to FADD and prevents the autocatlytic activation of caspase 8 ( and 10 ) by the TRADD , RIPK1 , TRAF2 , and FADD complex .	c-FLIP competes with procaspase 8 for binding to FADD and prevents the autocatlytic activation of caspase 8 (and 10) by the TRADD, RIPK1, TRAF2, and FADD complex.	0	19	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	0	1	15	17
c-FLIP has been found to inhibit the activation of caspase-8 .	c-FLIP has been found to inhibit the activation of caspase-8.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	9	10
Cyclosporine was shown to upregulate the expression of TGF-beta in the colonic tissue , enhance the expression of p-Smad2 and cFLIP in epithelial cells , and inhibit caspase-8 activity but not caspase-1 or -9 .	Cyclosporine was shown to upregulate the expression of TGF-beta in the colonic tissue, enhance the expression of p-Smad2 and cFLIP in epithelial cells, and inhibit caspase-8 activity but not caspase-1 or -9.	0	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	Cyclosporine was shown to upregulate the expression of TGF-beta in the colonic tissue, enhance the expression of p-Smad2 and cFLIP	cflip	caspase-8	caspase-8	caspase-8	20	21	27	28
In the present study , we show that MUC16 decreases TRAIL-R2 expression , increases cFLIP expression , blocks recruitment of caspase-8 to the DISC , and consequently attenuates the activation of the TRAIL induced apoptotic pathway .	In the present study, we show that MUC16 decreases TRAIL-R2 expression, increases cFLIP expression, blocks recruitment of caspase-8 to the DISC, and consequently attenuates the activation of the TRAIL induced apoptotic pathway.	8	21	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	MUC16 decreases TRAIL-R2 expression, increases cFLIP expression	cflip	caspase-8	caspase-8	caspase-8	14	15	20	21
These results indicate that c-FLIP inhibits TRAIL independent , DR5- and caspase 8 dependent apoptosis in response to chemotherapy in CRC cells .	These results indicate that c-FLIP inhibits TRAIL independent, DR5- and caspase 8 dependent apoptosis in response to chemotherapy in CRC cells.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	4	5	11	13
Cyclosporin was shown in experimental colitis to upregulate the expression of TGF-beta in the colonic tissue , enhance the expression of p-Smad2 and cFLIP in epithelial cells , and inhibit caspase-8 activity , concurrently protecting from epithelial apoptosis associated with upregulation of TGF-beta-related signaling .	Cyclosporin was shown in experimental colitis to upregulate the expression of TGF-beta in the colonic tissue, enhance the expression of p-Smad2 and cFLIP in epithelial cells, and inhibit caspase-8 activity, concurrently protecting from epithelial apoptosis associated with upregulation of TGF-beta-related signaling.	0	31	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	cFLIP	Cyclosporin was shown in experimental colitis to upregulate the expression of TGF-beta in the colonic tissue, enhance the expression of p-Smad2 and cFLIP	cflip	caspase-8	caspase-8	caspase-8	23	24	30	31
A decrease in endogenous c-FLIP by specific small interfering RNA induces TNF-alpha-mediated apoptotic cell death and caspase-8 activation .	A decrease in endogenous c-FLIP by specific small interfering RNA induces TNF-alpha-mediated apoptotic cell death and caspase-8 activation.	1	17	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	4	5	16	17
In contrast , the shorter form of cFLIP , cFLIP S , can inhibit Casp-8 activation .	In contrast, the shorter form of cFLIP, cFLIP S, can inhibit Casp-8 activation.	5	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	Casp-8	Casp-8	Casp-8	7	8	14	15
c-FLIP is a well described inhibitor of caspase-8 , and we have previously suggested that c-FLIP is involved in regulating MEHP triggered germ cell apoptosis .	c-FLIP is a well described inhibitor of caspase-8, and we have previously suggested that c-FLIP is involved in regulating MEHP triggered germ cell apoptosis.	0	8	described inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	7	8
Intriguingly , c-FLIP L -mediated inhibition of caspase-8 was only observed at high concentrations of c-FLIP L relative to caspase-8 , demonstrating that at physiological concentrations c-FLIP L preferentially activates procaspase-8 ( XREF_FIG ) .	Intriguingly, c-FLIP L -mediated inhibition of caspase-8 was only observed at high concentrations of c-FLIP L relative to caspase-8, demonstrating that at physiological concentrations c-FLIP L preferentially activates procaspase-8 (XREF_FIG).	2	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	7	8
Although it has been shown that both c-FLIP L and c-FLIP S inhibit caspase-8 activation , these two isoforms do have different functions .	Although it has been shown that both c-FLIP L and c-FLIP S inhibit caspase-8 activation, these two isoforms do have different functions.	7	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	7	8	13	14
The human c-FLIP protein , which likewise has an inactive protease domain , down-regulates the activity of caspase-8 for processing of most apoptotic substrates in the heterodimer complex but is able to enhance the processing of non apoptotic substrates , such as HDAC-7 ( histone deacetylase 7 ) , by caspase-8 [ XREF_BIBR ] .	The human c-FLIP protein, which likewise has an inactive protease domain, down-regulates the activity of caspase-8 for processing of most apoptotic substrates in the heterodimer complex but is able to enhance the processing of non apoptotic substrates, such as HDAC-7 (histone deacetylase 7), by caspase-8 [XREF_BIBR].	2	19	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	17	18
Velcade sensitizes cancer cells to apoptosis through several mechanisms , such as the down-regulation of c-FLIP , which inhibits caspase-8 activation at the DISC [ XREF_BIBR ] .	Velcade sensitizes cancer cells to apoptosis through several mechanisms, such as the down-regulation of c-FLIP, which inhibits caspase-8 activation at the DISC [XREF_BIBR].	13	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	15	16	19	20
Through DEDs , c-FLIP L and c-FLIP S interact with FADD and caspase-8 and inhibit caspase-8 activation and TRAIL induced apoptosis .	Through DEDs, c-FLIP L and c-FLIP S interact with FADD and caspase-8 and inhibit caspase-8 activation and TRAIL induced apoptosis.	3	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	15	16
How cFLIP is able to suppress or re-direct the activity of caspase-8 to prevent necroptosis without triggering apoptosis is therefore likely to involve additional factors .	How cFLIP is able to suppress or re-direct the activity of caspase-8 to prevent necroptosis without triggering apoptosis is therefore likely to involve additional factors.	1	12	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	1	2	11	12
Caspase-8 is stimulated in response to external stimuli and is negatively regulated by cFLIP .	Caspase-8 is stimulated in response to external stimuli and is negatively regulated by cFLIP.	0	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	Caspase-8	Caspase-8	Caspase-8	13	14	0	1
As a caspase-8 homolog lacking the catalytic cysteine , cFLIP is recruited to the same complexes , forms heterodimers with caspase-8 , and blocks the formation of the proapoptotic caspase-8 homodimers XREF_BIBR .	As a caspase-8 homolog lacking the catalytic cysteine, cFLIP is recruited to the same complexes, forms heterodimers with caspase-8, and blocks the formation of the proapoptotic caspase-8 homodimers XREF_BIBR.	9	31	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	9	10	29	30
cFLIP inhibits the activation of caspase-8 , the factor that initiates apoptosis .	cFLIP inhibits the activation of caspase-8, the factor that initiates apoptosis.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	0	1	5	6
XREF_BIBR , XREF_BIBR , XREF_BIBR Furthermore , loss of c-FLIP enhances caspase-8 activation of IL-1beta secretion upon treatment with Smac mimetic , FasL or heat killed Candida albicans ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR, XREF_BIBR Furthermore, loss of c-FLIP enhances caspase-8 activation of IL-1beta secretion upon treatment with Smac mimetic, FasL or heat killed Candida albicans (XREF_FIG).	7	12	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	loss of c-FLIP	c-flip	caspase-8	caspase-8	caspase-8	9	10	11	12
For example , it is conceivable to speculate that inhibition of Caspase-8 by c-FLIP unleashes the tumor promoting function of CD95 .	For example, it is conceivable to speculate that inhibition of Caspase-8 by c-FLIP unleashes the tumor promoting function of CD95.	9	14	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	Caspase-8	Caspase-8	Caspase-8	13	14	11	12
In addition , CFLAR and FLIP , which inhibits caspase-8 and suppresses apoptosis , has also been shown to activate ERK and increase NF-kappaB activation in T cells , and to inhibit myeloid cell innate signaling .	In addition, CFLAR and FLIP, which inhibits caspase-8 and suppresses apoptosis, has also been shown to activate ERK and increase NF-kappaB activation in T cells, and to inhibit myeloid cell innate signaling.	3	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CFLAR	CFLAR	CFLAR	caspase-8	caspase-8	caspase-8	3	4	9	10
c-FLIP isoforms are recruited to the TRAIL DISC and inhibit full cleavage and release of active Caspase-8 and Caspase-10 [ XREF_BIBR ] , allowing survival of these cells in the presence of receptor ligation , a finding that has merited great attention since many tumour cells are highly sensitive to TRAIL mediated apoptosis [ XREF_BIBR ] .	c-FLIP isoforms are recruited to the TRAIL DISC and inhibit full cleavage and release of active Caspase-8 and Caspase-10 [XREF_BIBR], allowing survival of these cells in the presence of receptor ligation, a finding that has merited great attention since many tumour cells are highly sensitive to TRAIL mediated apoptosis [XREF_BIBR].	0	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	Caspase-8	Caspase-8	Caspase-8	0	1	16	17
Consistent with previous publications [ XREF_BIBR , XREF_BIBR ] , cFLIP overexpression did not completely inhibit caspase-8 activation and RIP1 processing in response to TRAIL stimulation , indicating that cFLIP allows moderate activation of caspase-8 .	Consistent with previous publications [XREF_BIBR, XREF_BIBR], cFLIP overexpression did not completely inhibit caspase-8 activation and RIP1 processing in response to TRAIL stimulation, indicating that cFLIP allows moderate activation of caspase-8.	29	35	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	29	30	34	35
Thus , c-FLIP L emerges as an activator of caspase-8 during the initiation of cell growth of T cells ( and perhaps other cell types ) , whereas the later upregulation of c-FLIP S , or the presence of v-FLIPs , would be predicted to promote reduced activation of caspase-8 and perhaps serve to terminate T cell growth or function .	Thus, c-FLIP L emerges as an activator of caspase-8 during the initiation of cell growth of T cells (and perhaps other cell types), whereas the later upregulation of c-FLIP S, or the presence of v-FLIPs, would be predicted to promote reduced activation of caspase-8 and perhaps serve to terminate T cell growth or function.	32	50	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	32	33	49	50
As c-FLIP L competes with caspase-8 for binding to complex II and impairs caspase-8 activation , JNK1 mediated c-FLIP L degradation results in full activation of caspase-8 and cell death .	As c-FLIP L competes with caspase-8 for binding to complex II and impairs caspase-8 activation, JNK1 mediated c-FLIP L degradation results in full activation of caspase-8 and cell death.	1	14	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	1	2	13	14
For example at the TRAIL death inducing signaling complex ( DISC ) , variants of a protease deficient caspase homolog called cFLIP ( cellular FLICE-inhibitory protein ) inhibits the activation of caspase-8 and thus the propagation of apoptotic signaling .	For example at the TRAIL death inducing signaling complex (DISC), variants of a protease deficient caspase homolog called cFLIP (cellular FLICE-inhibitory protein) inhibits the activation of caspase-8 and thus the propagation of apoptotic signaling.	18	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase homolog	caspase homolog	caspase homolog	caspase-8	caspase-8	caspase-8	18	20	31	32
In addition , ectopic expression of c-FLIP inhibits the release of active caspase-8 fragments from the DISC , resulting in disruption of the DISC complex .	In addition, ectopic expression of c-FLIP inhibits the release of active caspase-8 fragments from the DISC, resulting in disruption of the DISC complex.	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	expression of c-FLIP	c-flip	caspase-8	caspase-8	caspase-8	6	7	12	13
Previous studies show that NF-kappaB transcriptionally up-regulates the expression of c-FLIP , which inhibits caspase-8 activation and the Bcl-2 family of proteins , including Bcl-2 , Mcl-1 , and Bcl-xL , and counteract the action of pro apoptotic proteins including Bid , Bad , and Bax the action of pro apoptotic proteins including Bid , Bad , and Bax [ XREF_BIBR - XREF_BIBR ] .	Previous studies show that NF-kappaB transcriptionally up-regulates the expression of c-FLIP, which inhibits caspase-8 activation and the Bcl-2 family of proteins, including Bcl-2, Mcl-1, and Bcl-xL, and counteract the action of pro apoptotic proteins including Bid, Bad, and Bax the action of pro apoptotic proteins including Bid, Bad, and Bax [XREF_BIBR - XREF_BIBR].	4	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	NF-kappaB transcriptionally up-regulates the expression of c-FLIP	c-flip	caspase-8	caspase-8	caspase-8	10	11	14	15
c-FLIP and RIP can inhibit Caspase-8 activation and prompting HepG2 and Hep3B resistant to cell apoptosis induced by TRAIL .	c-FLIP and RIP can inhibit Caspase-8 activation and prompting HepG2 and Hep3B resistant to cell apoptosis induced by TRAIL.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	Caspase-8	Caspase-8	Caspase-8	0	1	5	6
In the absence of adequate GC survival signals from cell-cell contact with T cells and follicular dendritic cells , cFLIP is degraded , the initiator pro caspase 8 within the complex is activated , and the cells undergo rapid spontaneous apoptosis [ XREF_BIBR , XREF_BIBR ] .	In the absence of adequate GC survival signals from cell-cell contact with T cells and follicular dendritic cells, cFLIP is degraded, the initiator pro caspase 8 within the complex is activated, and the cells undergo rapid spontaneous apoptosis [XREF_BIBR, XREF_BIBR].	19	32	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase 8	caspase 8	caspase 8	19	20	26	28
c-FLIP L was shown to promote caspase 8 activation at low expression levels and inhibit caspase 8 activation at high expression levels .	c-FLIP L was shown to promote caspase 8 activation at low expression levels and inhibit caspase 8 activation at high expression levels.	0	8	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	0	1	6	8
A decrease in endogenous c-FLIP by specific small interfering RNA induced TNF-alpha-mediated apoptotic cell death and caspase-8 activation .	A decrease in endogenous c-FLIP by specific small interfering RNA induced TNF-alpha-mediated apoptotic cell death and caspase-8 activation.	1	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	4	5	16	17
Thus , Flip inhibits Caspase-8 , preventing the extrinsic form of apoptosis , and also inhibits autophagy .	Thus, Flip inhibits Caspase-8, preventing the extrinsic form of apoptosis, and also inhibits autophagy.	2	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Flip	Flip	Flip	Caspase-8	Caspase-8	Caspase-8	2	3	4	5
For instance , the survival pathway interacts with the apoptotic pathway at different points : cFLIP inhibits CASP8 ; BCL2 blocks mitochondria pore opening through inhibition of BAX ( and BAK , implicitly represented in our model ) ; and XIAP blocks the activity of both CASP9 in the apoptosome and CASP3 .	For instance, the survival pathway interacts with the apoptotic pathway at different points : cFLIP inhibits CASP8; BCL2 blocks mitochondria pore opening through inhibition of BAX (and BAK, implicitly represented in our model); and XIAP blocks the activity of both CASP9 in the apoptosome and CASP3.	15	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	CASP8	CASP8	CASP8	15	16	17	18
Importantly , c-FLIP S inhibits caspase-8 activity within the Ripoptosome and may , therefore , promote necroptosis .	Importantly, c-FLIP S inhibits caspase-8 activity within the Ripoptosome and may, therefore, promote necroptosis.	2	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	5	6
The new observations of cFLIP explain the delayed activation of caspase-8 and the delayed onset of synergy in the execution of apoptosis , because significant concentrations of cFLIP inhibit the activation of caspase-8 .	The new observations of cFLIP explain the delayed activation of caspase-8 and the delayed onset of synergy in the execution of apoptosis, because significant concentrations of cFLIP inhibit the activation of caspase-8.	25	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	27	28	32	33
Thus , the presence of cFLIP in the oligomers likely reduces the activation of caspase-8 , thereby preventing apoptosis [ XREF_BIBR ] .	Thus, the presence of cFLIP in the oligomers likely reduces the activation of caspase-8, thereby preventing apoptosis [XREF_BIBR].	3	15	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	5	6	14	15
While its overexpression has been associated with cancer progression and/or poor prognosis in BL , HCC , and ovarian , endometrial , colon , and prostate cancer [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] , elevated expression of c-FLIP blocks caspase-8 and renders cells resistant to cell receptor mediated apoptosis [ XREF_BIBR ] .	While its overexpression has been associated with cancer progression and/or poor prognosis in BL, HCC, and ovarian, endometrial, colon, and prostate cancer [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR], elevated expression of c-FLIP blocks caspase-8 and renders cells resistant to cell receptor mediated apoptosis [XREF_BIBR].	38	43	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	expression of c-FLIP	c-flip	caspase-8	caspase-8	caspase-8	40	41	42	43
cFLIP is recruited to the Fas Death Inducing Signaling Complex ( DISC ) and inhibits the activation of caspase 8 , thereby preventing Fas mediated AICD .	cFLIP is recruited to the Fas Death Inducing Signaling Complex (DISC) and inhibits the activation of caspase 8, thereby preventing Fas mediated AICD.	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase 8	caspase 8	caspase 8	0	1	18	20
In addition , it has also been shown that the caspase-8 cleavage can be inhibited by c-Flip through DISC formation .	In addition, it has also been shown that the caspase-8 cleavage can be inhibited by c-Flip through DISC formation.	10	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	c-Flip	c-Flip	c-Flip	caspase-8	caspase-8	caspase-8	16	17	10	11
Furthermore , cisplatin downregulated the levels of c-FLIP L ( a competitive inhibitor of caspase-8 at the DISC level ) in osteosarcoma cells , sensitizing them to Fas mediated apoptosis [ XREF_BIBR ] .	Furthermore, cisplatin downregulated the levels of c-FLIP L (a competitive inhibitor of caspase-8 at the DISC level) in osteosarcoma cells, sensitizing them to Fas mediated apoptosis [XREF_BIBR].	7	15	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	7	8	14	15
c-FLIP S completely inhibits caspase-8 processing , whereas c-FLIP L allows partial processing of caspase-8 .	c-FLIP S completely inhibits caspase-8 processing, whereas c-FLIP L allows partial processing of caspase-8.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	4	5
c-FLIP L expression is induced by pro survival NF-kappaB and Akt activation , and when highly expressed , c-FLIP L competes with caspase-8 and prevents the dimeric activation of caspase-8 and apoptosis induction .	c-FLIP L expression is induced by pro survival NF-kappaB and Akt activation, and when highly expressed, c-FLIP L competes with caspase-8 and prevents the dimeric activation of caspase-8 and apoptosis induction.	18	32	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	18	19	29	30
This pro apoptotic pathway is counter balanced by NFkappaB which up-regulates c-FLIP expression and thus inhibits pro caspase 8 activation and apoptosis XREF_BIBR .	This pro apoptotic pathway is counter balanced by NFkappaB which up-regulates c-FLIP expression and thus inhibits pro caspase 8 activation and apoptosis XREF_BIBR.	8	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	NFkappaB which up-regulates c-FLIP expression	c-flip	caspase 8	caspase 8	caspase 8	11	12	17	19
The anti-apoptotic protein c-FLIP contains a death effector domain ( DED ) and suppresses caspase-8 activation , preventing apoptotic processes .	The anti-apoptotic protein c-FLIP contains a death effector domain (DED) and suppresses caspase-8 activation, preventing apoptotic processes.	0	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	14	15
In a reciprocal experiment , we found that enhanced expression of c-Flip in detached cells is sufficient to inhibit caspase-8 activation and anoikis in HUVECs .	In a reciprocal experiment, we found that enhanced expression of c-Flip in detached cells is sufficient to inhibit caspase-8 activation and anoikis in HUVECs.	9	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Flip	expression of c-Flip	c-flip	caspase-8	caspase-8	caspase-8	11	12	19	20
We employed siRNA mediated knockdown of c-FLIP expression to further characterize the role of c-FLIP in the modulation of LeTx induced caspase-8 activation and apoptosis induction .	We employed siRNA mediated knockdown of c-FLIP expression to further characterize the role of c-FLIP in the modulation of LeTx induced caspase-8 activation and apoptosis induction.	6	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP expression	c-flip	caspase-8	caspase-8	caspase-8	6	7	21	22
Upregulation of TNFAIP3 , TNFAIP8 , TNFRSF12A , FAIM3 , and CFLAR are important to inhibit caspase-8 activation , and may be direct targets of Shigella T3SS effector proteins or result from NF-kappaB activation .	Upregulation of TNFAIP3, TNFAIP8, TNFRSF12A, FAIM3, and CFLAR are important to inhibit caspase-8 activation, and may be direct targets of Shigella T3SS effector proteins or result from NF-kappaB activation.	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CFLAR	CFLAR	CFLAR	caspase-8	caspase-8	caspase-8	11	12	16	17
In apoptosis resistant cells , cFLIP restricts caspase-8 activity , resulting in limited RIP1 cleavage and generation of a KD cleaved fragment capable of activating NF-kappaB but not apoptosis .	In apoptosis resistant cells, cFLIP restricts caspase-8 activity, resulting in limited RIP1 cleavage and generation of a KD cleaved fragment capable of activating NF-kappaB but not apoptosis.	5	8	restricts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	5	6	7	8
Upon TNF-alpha binding with TNFR1 , the cellular FLICE like protein ( c-FLIP ) competes with caspase-8 for binding with FADD and inhibits caspase-8 activation .	Upon TNF-alpha binding with TNFR1, the cellular FLICE like protein (c-FLIP) competes with caspase-8 for binding with FADD and inhibits caspase-8 activation.	8	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	12	13	23	24
Apoptosis mediated by both Fas and DR4 and DR5 can also be inhibited by cytoplasmic factors , such as c-FLIP ( FLICE like inhibitory protein ) , which binds to the DISC and inhibits caspase 8 activation .	Apoptosis mediated by both Fas and DR4 and DR5 can also be inhibited by cytoplasmic factors, such as c-FLIP (FLICE like inhibitory protein), which binds to the DISC and inhibits caspase 8 activation.	15	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	19	20	34	36
Caspase 8 activation is likely caused by reduced cFLIP level .	Caspase 8 activation is likely caused by reduced cFLIP level.	0	10	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	cFLIP	cFLIP level	cflip	Caspase 8	Caspase 8	caspase 8	8	9	0	2
Our results indicate that VPA upregulated c-FLIP expression time- and dose-dependently , and inhibited caspase-8 and caspase-3 activation in VSMC .	Our results indicate that VPA upregulated c-FLIP expression time- and dose-dependently, and inhibited caspase-8 and caspase-3 activation in VSMC.	4	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	VPA upregulated c-FLIP expression	c-flip	caspase-8	caspase-8	caspase-8	6	7	14	15
Of note , p-CagA is also capable of forming a complex with and activates Csk , which then inhibits c-Src by phosphorylation at Tyr 529 ; this represents a regulatory mechanism to limit the phosphorylation of CagA .	Of note, p-CagA is also capable of forming a complex with and activates Csk, which then inhibits c-Src by phosphorylation at Tyr 529; this represents a regulatory mechanism to limit the phosphorylation of CagA.	13	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	c-Src	c-Src	c-Src	14	15	19	20
C-terminal Src kinase ( Csk ) has been demonstrated to negatively regulate Src family tyrosine kinases through tyrosine phosphorylation at the C-terminal regulatory site ( Tyr 527 ) .	C-terminal Src kinase (Csk) has been demonstrated to negatively regulate Src family tyrosine kinases through tyrosine phosphorylation at the C-terminal regulatory site (Tyr 527).	2	15	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	4	5	12	13
These results suggest that SHP-2 may function as a positive regulator of Src kinase , which is negatively regulated by CSK .	These results suggest that SHP-2 may function as a positive regulator of Src kinase, which is negatively regulated by CSK.	12	21	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	20	21	12	13
Phosphorylation by Cdc2 partially reactivated Csk inactivated pp60c-src .	Phosphorylation by Cdc2 partially reactivated Csk inactivated pp60c-src.	5	8	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	pp60c-src	pp60c-src	pp60c-src	5	6	7	8
CSK is then recruited and inactivates Src via phosphorylation of its C-terminal tail .	CSK is then recruited and inactivates Src via phosphorylation of its C-terminal tail.	0	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	0	1	6	7
Csk inactivates Src by increasing phosphorylation of Src Y527 , acting as a negative regulator of Src ( XREF_FIG ) [ XREF_BIBR ] .	Csk inactivates Src by increasing phosphorylation of Src Y527, acting as a negative regulator of Src (XREF_FIG) [XREF_BIBR].	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	0	1	2	3
Src itself is tightly regulated by c-Src tyrosine kinase ( CSK ) , which inhibits Src function through phosphorylation of C-terminal tyrosine residues .	Src itself is tightly regulated by c-Src tyrosine kinase (CSK), which inhibits Src function through phosphorylation of C-terminal tyrosine residues.	8	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	10	11	15	16
We find that both the SH2 and SH3 domains are needed for inhibition of Src by Csk .	We find that both the SH2 and SH3 domains are needed for inhibition of Src by Csk.	10	17	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	16	17	14	15
Expression of Csk , which inactivates Src family kinases by phosphorylating the regulatory carboxyl-terminal tyrosine residue , has the same effect .	Expression of Csk, which inactivates Src family kinases by phosphorylating the regulatory carboxyl-terminal tyrosine residue, has the same effect.	0	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Expression of Csk	csk	Src	Src	src	2	3	6	7
JAM-A recruits Csk to the integrin-c and Src complex , where Csk negatively regulates c-Src activation , thereby suppressing the initiation of outside-in signaling .	JAM-A recruits Csk to the integrin-c and Src complex, where Csk negatively regulates c-Src activation, thereby suppressing the initiation of outside-in signaling.	11	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	c-Src	c-Src	c-Src	11	12	14	15
Recruitment to the membrane by scaffolding proteins such as CSK binding protein ( Cbp ) is required for inactivation of Src by CSK and is crucial for preventing tumorigenesis .	Recruitment to the membrane by scaffolding proteins such as CSK binding protein (Cbp) is required for inactivation of Src by CSK and is crucial for preventing tumorigenesis.	16	23	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	22	23	20	21
Choanoflagellates also have Csk ( C-terminal Src kinase ) , the enzyme that regulates Src in metazoans ; however , choanoflagellate Csk kinases fail to repress the cognate Src .	Choanoflagellates also have Csk (C-terminal Src kinase), the enzyme that regulates Src in metazoans; however, choanoflagellate Csk kinases fail to repress the cognate Src.	21	29	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	21	22	28	29
Data in acutely isolated retinas further showed that DA or SKF-38393 increased Csk phosphorylation via activation of D 1 Rs ( XREF_SUPPLEMENTARY ) , confirming that D 1 R activation of Csk inhibits Src in the retina .	Data in acutely isolated retinas further showed that DA or SKF-38393 increased Csk phosphorylation via activation of D 1 Rs (XREF_SUPPLEMENTARY), confirming that D 1 R activation of Csk inhibits Src in the retina.	29	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	31	32	33	34
Cytoplasmic-src tyrosine kinase ( CSK ) down-regulates tyrosine kinase activity of the SRC oncoprotein and might function as an antioncogene ( XREF_FIG ) .	Cytoplasmic-src tyrosine kinase (CSK) down-regulates tyrosine kinase activity of the SRC oncoprotein and might function as an antioncogene (XREF_FIG).	2	13	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	SRC	SRC	SRC	4	5	12	13
Moreover , this ASPP2 mediated inactivation of Src could be abolished by RNA interference with C-terminal Src kinase ( Csk ) , a kinase that can inhibit Src activation .	Moreover, this ASPP2 mediated inactivation of Src could be abolished by RNA interference with C-terminal Src kinase (Csk), a kinase that can inhibit Src activation.	17	28	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	19	20	27	28
Csk associates with the NMDAR signaling complex in the adult brain , inhibiting the Src dependent potentiation of NMDARs in CA1 neurons and attenuating the Src dependent induction of long-term potentiation .	Csk associates with the NMDAR signaling complex in the adult brain, inhibiting the Src dependent potentiation of NMDARs in CA1 neurons and attenuating the Src dependent induction of long-term potentiation.	0	16	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	0	1	14	15
Inhibition of CSK allows relief of the inhibitory effect of pY527 and activation of Src .	Inhibition of CSK allows relief of the inhibitory effect of pY527 and activation of Src.	0	15	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	2	3	14	15
The non receptor tyrosine kinase Src is inactivated by the C-terminal Src kinase Csk .	The non receptor tyrosine kinase Src is inactivated by the C-terminal Src kinase Csk.	0	14	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	13	14	5	6
Characterization of the Src mutants confirmed that inactivation of Src by Csk through tail tyrosine phosphorylation required the Src SH3 domain .	Characterization of the Src mutants confirmed that inactivation of Src by Csk through tail tyrosine phosphorylation required the Src SH3 domain.	7	15	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	11	12	9	10
In contrast , expression of either wild-type CSK or the kinase-dead derivative did not impair the colony forming ability of Kras cells ( XREF_FIG ) , which express oncogenic Kras in the context of wild-type ( non activated ) Src .	In contrast, expression of either wild-type CSK or the kinase-dead derivative did not impair the colony forming ability of Kras cells (XREF_FIG), which express oncogenic Kras in the context of wild-type (non activated) Src.	3	40	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	expression of either wild-type CSK	csk	Src	Src	src	7	8	39	40
Csk binding protein and phosphoprotein associated with glycosphingolipid enriched domains is a transmembrane adaptor protein primarily involved in negative regulation of T-cell activation by recruitment of C-terminal Src kinase ( Csk ) , a protein tyrosine kinase which represses Src kinase activity through C-terminal phosphorylation .	Csk binding protein and phosphoprotein associated with glycosphingolipid enriched domains is a transmembrane adaptor protein primarily involved in negative regulation of T-cell activation by recruitment of C-terminal Src kinase (Csk), a protein tyrosine kinase which represses Src kinase activity through C-terminal phosphorylation.	28	41	represses	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	30	31	39	40
Csk negatively regulates the Src family of cytoplasmic tyrosine kinases .	Csk negatively regulates the Src family of cytoplasmic tyrosine kinases.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	0	1	4	5
Mutation of this residue has previously been shown to abrogate Csk mediated inhibition of Src in a yeast cell based assay 41 .	Mutation of this residue has previously been shown to abrogate Csk mediated inhibition of Src in a yeast cell based assay 41.	10	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	10	11	14	15
Here , we demonstrate that activation of Csk through a prostaglandin E ( 2 )-cAMP-protein kinase A ( PKA ) pathway inhibits Src .	Here, we demonstrate that activation of Csk through a prostaglandin E (2)-cAMP-protein kinase A (PKA) pathway inhibits Src.	7	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	7	8	22	23
On the other hand , the expression of the wild-Type CSK , by infection with the Wt-CSK-Ad-virus , inhibits Src activity .	On the other hand, the expression of the wild-Type CSK, by infection with the Wt-CSK-Ad-virus, inhibits Src activity.	6	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	expression of the wild-Type CSK	csk	Src	Src	src	10	11	19	20
CSK siRNA , which targets c-Src , suppressed MCF7 growth , but not SK-BR-3 growth , on the CBC-1 .	CSK siRNA, which targets c-Src, suppressed MCF7 growth, but not SK-BR-3 growth, on the CBC-1.	0	6	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	c-Src	c-Src	c-Src	0	1	5	6
Src is anchored to specific lipid-raft membrane domains via N-termini , whereas Csk , a cytoplasmic protein , is recruited via adaptor proteins to the membrane and inhibits Src [ XREF_BIBR ] .	Src is anchored to specific lipid-raft membrane domains via N-termini, whereas Csk, a cytoplasmic protein, is recruited via adaptor proteins to the membrane and inhibits Src [XREF_BIBR].	12	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk, a cytoplasmic protein, is recruited via adaptor proteins to the membrane	csk	Src	Src	src	12	13	28	29
Deletion of the SH2 or SH3 domains of Csk abrogates the inhibition of antigen receptor signaling in T cells ; this result is consistent with the ability of similar mutations to suppress Csk induced inactivation of Src in fibroblastoid cells .	Deletion of the SH2 or SH3 domains of Csk abrogates the inhibition of antigen receptor signaling in T cells; this result is consistent with the ability of similar mutations to suppress Csk induced inactivation of Src in fibroblastoid cells.	31	37	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	32	33	36	37
As Csk negatively regulates Src family kinases , this suggested that Src mediates the effect of dCsk on dAbl .	As Csk negatively regulates Src family kinases, this suggested that Src mediates the effect of dCsk on dAbl.	1	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	1	2	4	5
The primary known function of CSK is to phosphorylate c-Src at a specific tyrosine residue in the C-terminal tail and thereby inactivate c-Src .	The primary known function of CSK is to phosphorylate c-Src at a specific tyrosine residue in the C-terminal tail and thereby inactivate c-Src.	3	23	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	c-Src	c-Src	c-Src	5	6	22	23
Isorhamnetin induces CSK expression and inhibits Src activation in vivo .	Isorhamnetin induces CSK expression and inhibits Src activation in vivo.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	Isorhamnetin induces CSK expression	csk	Src	Src	src	2	3	6	7
Alternatively , mRNA and protein levels of c-src kinase ( CSK ) , which inactivates pp60c-src by phosphorylating Y527 , are not altered by the steroid .	Alternatively, mRNA and protein levels of c-src kinase (CSK), which inactivates pp60c-src by phosphorylating Y527, are not altered by the steroid.	5	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-src kinase	levels of c-src kinase	c-src kinase	pp60c-src	pp60c-src	pp60c-src	7	9	15	16
Here , we report that the LspA virulence factors of H.ducreyi inhibit phagocytosis by stimulating the catalytic activity of C-terminal Src kinase ( Csk ) , which itself inhibits Src family protein tyrosine kinases ( SFKs ) that promote phagocytosis .	Here, we report that the LspA virulence factors of H.ducreyi inhibit phagocytosis by stimulating the catalytic activity of C-terminal Src kinase (Csk), which itself inhibits Src family protein tyrosine kinases (SFKs) that promote phagocytosis.	20	29	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	23	24	20	21
Overexpression of Csk that inactivates Src family tyrosine kinases also inhibited ERK activation evoked by GH .	Overexpression of Csk that inactivates Src family tyrosine kinases also inhibited ERK activation evoked by GH.	0	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Overexpression of Csk	csk	Src	Src	src	2	3	5	6
CfrSrc is the only NRTK present in Creolimax ; Csk , which inactivates Src in metazoans , is missing .	CfrSrc is the only NRTK present in Creolimax; Csk, which inactivates Src in metazoans, is missing.	9	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	9	10	13	14
41 Although Csk mediated Src negative regulation is essential in metazoans , studies of ancestral forms of Src have shown that Src can operate without strict control in protists .	41 Although Csk mediated Src negative regulation is essential in metazoans, studies of ancestral forms of Src have shown that Src can operate without strict control in protists.	2	6	mediated	Positive_early_activation	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	2	3	4	5
Co-expression of M. brevicollis Csk did not inhibit M. brevicollis Src tyrosine kinase activity in mammalian cells , or alter the ability of Src to induce gene expression .	Co-expression of M. brevicollis Csk did not inhibit M. brevicollis Src tyrosine kinase activity in mammalian cells, or alter the ability of Src to induce gene expression.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Co-expression of M. brevicollis Csk	csk	Src	Src	src	4	5	10	11
The C-terminal Src kinase ( Csk ) inhibits Src kinase activity .	The C-terminal Src kinase (Csk) inhibits Src kinase activity.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	5	6	8	9
Csk ( like its close relative Chk ) is not regulated by activation loop phosphorylation , and is instead active constitutively , a property that is consistent with the need for Csk to inhibit the Src kinases continually .	Csk (like its close relative Chk) is not regulated by activation loop phosphorylation, and is instead active constitutively, a property that is consistent with the need for Csk to inhibit the Src kinases continually.	0	36	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	0	1	35	36
The overexpression of wild-type Csk caused significant suppression of the c-Src activity during mitosis .	The overexpression of wild-type Csk caused significant suppression of the c-Src activity during mitosis.	1	11	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	overexpression of wild-type Csk	csk	c-Src	c-Src	c-src	4	5	10	11
It is known that Csk , a nonreceptor tyrosine kinase , negatively regulates c-Src activity by phosphorylating Tyr 527 and switching the c-Src from the active open formation to an inactive closed architecture .	It is known that Csk, a nonreceptor tyrosine kinase, negatively regulates c-Src activity by phosphorylating Tyr 527 and switching the c-Src from the active open formation to an inactive closed architecture.	4	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	c-Src	c-Src	c-Src	4	5	13	14
Csk inhibits Src activity by phosphorylating a conserved Tyr residue , and , consistent with this , overexpression of Cav-1 in 293 cells results in Src inhibition [ XREF_BIBR ] .	Csk inhibits Src activity by phosphorylating a conserved Tyr residue, and, consistent with this, overexpression of Cav-1 in 293 cells results in Src inhibition [XREF_BIBR].	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	0	1	2	3
C-terminal Src kinase ( CSK ) , a ubiquitously expressed nonreceptor tyrosine kinase , negatively regulates the Src family kinases by phosphorylation of the Src C-terminal tyrosine .	C-terminal Src kinase (CSK), a ubiquitously expressed nonreceptor tyrosine kinase, negatively regulates the Src family kinases by phosphorylation of the Src C-terminal tyrosine.	2	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	4	5	17	18
Upon complex formation , CagA stimulates Csk , which in turn inactivates the Src family of protein-tyrosine kinases .	Upon complex formation, CagA stimulates Csk, which in turn inactivates the Src family of protein-tyrosine kinases.	5	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	6	7	13	14
These results indicate that isorhamnetin induces expression of CSK and inhibits Src activation in vivo in the colons of AOM and DSS treated mice .	These results indicate that isorhamnetin induces expression of CSK and inhibits Src activation in vivo in the colons of AOM and DSS treated mice.	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	isorhamnetin induces expression of CSK	csk	Src	Src	src	8	9	11	12
Pag1 and Csk , complex in lipid rafts , promotes Src inhibition by phosphorylating the Y 530/535 residue [ XREF_BIBR ] .	Pag1 and Csk, complex in lipid rafts, promotes Src inhibition by phosphorylating the Y 530/535 residue [XREF_BIBR].	0	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	2	3	10	11
In addition , Cox activity was also correlated with c-Src kinase activity , decreasing when Src was down-regulated by the expression of Csk WT or the dominant negative Src KD , and increasing when Src activity was up-regulated by the expression of Csk KD .	In addition, Cox activity was also correlated with c-Src kinase activity, decreasing when Src was down-regulated by the expression of Csk WT or the dominant negative Src KD, and increasing when Src activity was up-regulated by the expression of Csk KD.	34	43	up-regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Csk	expression of Csk	csk	Src	Src	src	42	43	34	35
Although , in this study , we show that Csk is important in targeting Src in NSAID mediated chemoprevention , Csk may also inhibit other members of the Src family of tyrosine kinases .	Although, in this study, we show that Csk is important in targeting Src in NSAID mediated chemoprevention, Csk may also inhibit other members of the Src family of tyrosine kinases.	20	29	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	20	21	28	29
Csk may then directly inactivate the Src kinases by phosphorylation .	Csk may then directly inactivate the Src kinases by phosphorylation.	0	7	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	0	1	6	7
In addition , negative regulators of these pathways , including CSK ( an inhibitor of SRC activity ) and PTP-PEST ( a phosphatase that dephosphorylates p130Cas ) , bind directly to paxillin , thereby bringing them into close proximity with their targets .	In addition, negative regulators of these pathways, including CSK (an inhibitor of SRC activity) and PTP-PEST (a phosphatase that dephosphorylates p130Cas), bind directly to paxillin, thereby bringing them into close proximity with their targets.	4	19	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	CSK	CSK	CSK	SRC	SRC	SRC	10	11	15	16
CSK blocked the RAR-RA-dependent activation of SRC and neurite outgrowth in LA-N-5 cells .	CSK blocked the RAR-RA-dependent activation of SRC and neurite outgrowth in LA-N-5 cells.	0	7	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	SRC	SRC	SRC	0	1	6	7
One of the top ranking screening hits was C-terminal SRC kinase ( CSK , XREF_SUPPLEMENTARY ) , an enzyme that inhibits SRC family kinases ( SFKs ) by phosphorylating a C-terminal tyrosine .	One of the top ranking screening hits was C-terminal SRC kinase (CSK, XREF_SUPPLEMENTARY), an enzyme that inhibits SRC family kinases (SFKs) by phosphorylating a C-terminal tyrosine.	10	23	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	SRC	SRC	SRC	12	13	21	22
Csk negatively regulates Src family kinases ( SFKs ) .	Csk negatively regulates Src family kinases (SFKs).	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	0	1	3	4
37 Interestingly , the kinase CSK , which inactivates Src by phosphorylating Src ( Y527 ) , did not affect LMP1 activation of IRF4 in promoter reporter assays ( data not shown ) , implicating that Src ( Y527 ) phosphorylation status is not involved in Src activation by LMP1 .	37 Interestingly, the kinase CSK, which inactivates Src by phosphorylating Src (Y527), did not affect LMP1 activation of IRF4 in promoter reporter assays (data not shown), implicating that Src (Y527) phosphorylation status is not involved in Src activation by LMP1.	5	19	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	5	6	9	10
CSK negatively regulates Src family kinases , a key class of nonreceptor tyrosine kinases XREF_BIBR .	CSK negatively regulates Src family kinases, a key class of nonreceptor tyrosine kinases XREF_BIBR.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	0	1	3	4
The relative increase in Src kinase activity by Mb ( Yes_1 ) was enhanced in the presence of Csk , as Csk decreases the basal Src activity .	The relative increase in Src kinase activity by Mb (Yes_1) was enhanced in the presence of Csk, as Csk decreases the basal Src activity.	21	26	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	21	22	25	26
However , in comparison with other Csk orthologs , Corallochytrium Csk displays broad substrate specificity and inhibits Src in an activity independent manner .	However, in comparison with other Csk orthologs, Corallochytrium Csk displays broad substrate specificity and inhibits Src in an activity independent manner.	9	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	10	11	17	18
CHK and HYL did not affect the activity of Src , Hck , and Fgr in cultured bone marrow cells , although CSK negatively regulates Src family kinases .	CHK and HYL did not affect the activity of Src, Hck, and Fgr in cultured bone marrow cells, although CSK negatively regulates Src family kinases.	22	27	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	22	23	25	26
The COOH-terminal Src kinase ( Csk ) phosphorylates tyrosine 527 and represses Src activity , and activation requires dephosphorylation of this residue .	The COOH-terminal Src kinase (Csk) phosphorylates tyrosine 527 and represses Src activity, and activation requires dephosphorylation of this residue.	3	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	5	6	12	13
Csk inhibits the Src family kinases ( SFK ) by phosphorylating tyrosine 530 .	Csk inhibits the Src family kinases (SFK) by phosphorylating tyrosine 530.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	0	1	3	4
Specific kinase activity of the proto-oncogene product pp60 ( c-src ) is reported to be elevated in patients with carcinoma of the colon , and a novel cytoplasmic protein-tyrosine kinase , C-terminal Src kinase ( Csk ) , has been found to inactivate the members of the Src family protein-tyrosine kinase .	Specific kinase activity of the proto-oncogene product pp60 (c-src) is reported to be elevated in patients with carcinoma of the colon, and a novel cytoplasmic protein-tyrosine kinase, C-terminal Src kinase (Csk), has been found to inactivate the members of the Src family protein-tyrosine kinase.	33	50	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	35	36	47	48
Csk overexpression in cultured rheumatoid synoviocytes remarkably suppressed Src kinase activity and reduced their proliferation rate and IL-6 production .	Csk overexpression in cultured rheumatoid synoviocytes remarkably suppressed Src kinase activity and reduced their proliferation rate and IL-6 production.	0	10	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk overexpression	csk	Src	Src	src	0	1	8	9
These results demonstrate that Csk phosphorylation inactivates Src and Yes only when they are not previously autophosphorylated and Src autophosphorylation can block the inactivation by Csk phosphorylation .	These results demonstrate that Csk phosphorylation inactivates Src and Yes only when they are not previously autophosphorylated and Src autophosphorylation can block the inactivation by Csk phosphorylation.	4	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk phosphorylation	csk	Src	Src	src	4	5	7	8
Overexpression of Csk decreased Src tyrosine kinase activity in NL-17 cells , the highly metastatic clone of mouse colon adenocarcinoma 26 .	Overexpression of Csk decreased Src tyrosine kinase activity in NL-17 cells, the highly metastatic clone of mouse colon adenocarcinoma 26.	0	7	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Overexpression of Csk	csk	Src	Src	src	2	3	4	5
Src family tyrosine kinases are down-regulated through phosphorylation of a single C-terminal tyrosine by the nonreceptor tyrosine kinase Csk .	Src family tyrosine kinases are down-regulated through phosphorylation of a single C-terminal tyrosine by the nonreceptor tyrosine kinase Csk.	0	19	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	18	19	0	1
CSK , a critical protein that can negatively regulate Src kinase activity , is recruited to lipid rafts by CBP and PAG .	CSK, a critical protein that can negatively regulate Src kinase activity, is recruited to lipid rafts by CBP and PAG.	0	14	negatively regulate	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	0	1	9	10
In T cells , activation through the TCR leads to a rapid PAG dephosphorylation , which results in the release of Csk from the membrane and relief of Csk mediated inhibition of Src kinases .	In T cells, activation through the TCR leads to a rapid PAG dephosphorylation, which results in the release of Csk from the membrane and relief of Csk mediated inhibition of Src kinases.	26	33	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	28	29	32	33
Csk can decrease basal NMDAR activation by binding to GluN1 and GluN2 subunits and inactivating Src directly XREF_BIBR .	Csk can decrease basal NMDAR activation by binding to GluN1 and GluN2 subunits and inactivating Src directly XREF_BIBR.	0	16	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	0	1	15	16
Csk , which negatively regulates Src by phosphorylating Tyr 529 , was also constitutively associated with alphaIIbbeta3 .	Csk, which negatively regulates Src by phosphorylating Tyr 529, was also constitutively associated with alphaIIbbeta3.	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	0	1	5	6
Increased Csk activity would then block Src activity and lead to decreased Ecad endocytosis and increased Ecad .	Increased Csk activity would then block Src activity and lead to decreased Ecad endocytosis and increased Ecad.	1	7	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	1	2	6	7
Phosphorylation of c-Src at Tyr 529 by C-terminal Src kinase ( Csk ) negatively regulates c-Src activity .	Phosphorylation of c-Src at Tyr 529 by C-terminal Src kinase (Csk) negatively regulates c-Src activity.	0	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Phosphorylation of c-Src at Tyr 529 by C-terminal Src kinase (Csk	csk	c-Src	c-Src	c-src	11	12	15	16
Expression of Src and Csk , but not DK-Src and Csk , caused reduction of the specific activities of Src and Fyn in the differentiated P19 cells .	Expression of Src and Csk, but not DK-Src and Csk, caused reduction of the specific activities of Src and Fyn in the differentiated P19 cells.	0	21	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Expression of Src and Csk	csk	Src	Src	src	4	5	19	20
We showed that activation of D 1 Rs , with consequent cAMP accumulation and PKA stimulation , promotes Csk activation , which in turn inhibits Src tyrosine kinase function .	We showed that activation of D 1 Rs, with consequent cAMP accumulation and PKA stimulation, promotes Csk activation, which in turn inhibits Src tyrosine kinase function.	18	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	18	19	25	26
A decreased Csk and c-Src ratio in GEM may cause activation of c-Src because Csk is a negative regulator of c-Src .	A decreased Csk and c-Src ratio in GEM may cause activation of c-Src because Csk is a negative regulator of c-Src.	0	13	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	c-Src	c-Src	c-Src	2	3	12	13
One tyrosine , tyrosine 314 ( Y314 ) in the mouse , interacts with Csk , a protein tyrosine kinase that negatively regulates Src kinases .	One tyrosine, tyrosine 314 (Y314) in the mouse, interacts with Csk, a protein tyrosine kinase that negatively regulates Src kinases.	12	24	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	14	15	23	24
At the same time , Cav1 promotes Csk dependent inactivation of Src and prevents Src and p190RhoGAP inhibition of RhoGTPase signaling , thereby driving cell polarization and motility .	At the same time, Cav1 promotes Csk dependent inactivation of Src and prevents Src and p190RhoGAP inhibition of RhoGTPase signaling, thereby driving cell polarization and motility.	7	12	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	7	8	11	12
From a cellular point of view , our data implicate the Csk mediated Src inhibition in the antiproliferative effects of NSAID through a p21 cip and waf1 -related cell cycle arrest .	From a cellular point of view, our data implicate the Csk mediated Src inhibition in the antiproliferative effects of NSAID through a p21 cip and waf1 -related cell cycle arrest.	10	14	mediated	Positive_early_activation	Negative_activation	Negative_activation	Csk	Csk	Csk	Src	Src	Src	11	12	13	14
PEP was first demonstrated to regulate TCR signaling through association with CSK , a PTK that represses SRC family PTKs .	PEP was first demonstrated to regulate TCR signaling through association with CSK, a PTK that represses SRC family PTKs.	5	19	represses	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	SRC	SRC	SRC	11	12	17	18
Other studies have reported that loss of the Src antagonist Csk in the wing disc can induce activation of JNK and JAK and STAT signaling as well as morphological disorganization .	Other studies have reported that loss of the Src antagonist Csk in the wing disc can induce activation of JNK and JAK and STAT signaling as well as morphological disorganization.	5	14	antagonist	Negative_activation_token_1_noun	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	10	11	8	9
Whereas c-Src activity is basally suppressed by Csk at AJs , this suppression is relieved by Galpha13 interaction with VE-cadherin downstream of oxidative redox signaling 190 .	Whereas c-Src activity is basally suppressed by Csk at AJs, this suppression is relieved by Galpha13 interaction with VE-cadherin downstream of oxidative redox signaling 190.	1	8	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	c-Src	c-Src	c-Src	7	8	1	2
Overexpression of Csk repressed the in vitro kinase activity of Src to as little as 10 % that of control cells and interfered with cell spreading and cell attachment to fibronectin .	Overexpression of Csk repressed the in vitro kinase activity of Src to as little as 10% that of control cells and interfered with cell spreading and cell attachment to fibronectin.	0	11	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Overexpression of Csk	csk	Src	Src	src	2	3	10	11
Chk1 phosphorylation inhibits CDC25C activity and leads to G2/M arrest XREF_BIBR .	Chk1 phosphorylation inhibits CDC25C activity and leads to G2/M arrest XREF_BIBR.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1 phosphorylation	chk1	CDC25C	CDC25C	cdc25c	0	1	3	4
Cell cycle checkpoint kinase 2 ( CHK2 ) is known to inhibit CDC25C phosphatase and stabilize the p53 tumor suppressor protein , leading to cell cycle arrest in G1 XREF_BIBR .	Cell cycle checkpoint kinase 2 (CHK2) is known to inhibit CDC25C phosphatase and stabilize the p53 tumor suppressor protein, leading to cell cycle arrest in G1 XREF_BIBR.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cell cycle checkpoint kinase	Cell cycle checkpoint kinase	Cell cycle checkpoint kinase	CDC25C	CDC25C	CDC25C	0	4	12	13
In addition , Chk1 phosphorylates and , thus , inhibits actions of Cdc25B and Cdc25C phosphatases .	In addition, Chk1 phosphorylates and, thus, inhibits actions of Cdc25B and Cdc25C phosphatases.	3	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	3	4	14	15
CDC25C is regulated by the checkpoint kinase 1 ( CHEK1 ) , which phosphorylates S216 and inactivates CDC25C , and by the Polo like Kinase 1 ( PLK1 ) , which activates CDC25C by phosphorylating S198 and subsequently triggering activation of the CDK1 and Cyclin B1 complex [ XREF_BIBR ] .	CDC25C is regulated by the checkpoint kinase 1 (CHEK1), which phosphorylates S216 and inactivates CDC25C, and by the Polo like Kinase 1 (PLK1), which activates CDC25C by phosphorylating S198 and subsequently triggering activation of the CDK1 and Cyclin B1 complex [XREF_BIBR].	2	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHEK1	CHEK1	CHEK1	CDC25C	CDC25C	CDC25C	9	10	17	18
Immunoblotting analysis demonstrated that UCN-01 alone or in combination with irinotecan affects the ATR mediated phosphorylation of Chk1 and PKC directly blocking the activation of the Chk1 target CDC25C , confirming the contribution of several targets in determining the response of CRC-SCs to UCN-01 .	Immunoblotting analysis demonstrated that UCN-01 alone or in combination with irinotecan affects the ATR mediated phosphorylation of Chk1 and PKC directly blocking the activation of the Chk1 target CDC25C, confirming the contribution of several targets in determining the response of CRC-SCs to UCN-01.	23	29	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	CDC25C	CDC25C	CDC25C	26	27	28	29
Both CHK1 and CHK2 negatively regulate CDC25C via phosphorylation of a serine residue ( ser216 ) ; this event creates a site for the binding to 14-3-3 protein resulting in its cytoplasmic sequestration and G2/M checkpoint activation .	Both CHK1 and CHK2 negatively regulate CDC25C via phosphorylation of a serine residue (ser216); this event creates a site for the binding to 14-3-3 protein resulting in its cytoplasmic sequestration and G2/M checkpoint activation.	0	8	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHK1	CHK1	CHK1	CDC25C	CDC25C	CDC25C	1	2	6	7
Chk1 , involved in cell cycle arrest after activation of ATM and ATR in response to DNA damage , is also down-regulated as well as the protein phosphatases CDC25A ( which is a Chk1 substrate ) and CDC25C , involved respectively in G1/S checkpoint and mitosis entry .	Chk1, involved in cell cycle arrest after activation of ATM and ATR in response to DNA damage, is also down-regulated as well as the protein phosphatases CDC25A (which is a Chk1 substrate) and CDC25C, involved respectively in G1/S checkpoint and mitosis entry.	0	39	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	CDC25C	CDC25C	CDC25C	0	1	37	38
In addition , Cdc25C can be inhibited by Chk1 and Chk2 mediated phosphorylation .	In addition, Cdc25C can be inhibited by Chk1 and Chk2 mediated phosphorylation.	3	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	8	9	3	4
CHEK1 inhibits CDC25C activity upon DNA damage to trigger G2 arrest , and allow cells to repair DNA prior to entering mitosis .	CHEK1 inhibits CDC25C activity upon DNA damage to trigger G2 arrest, and allow cells to repair DNA prior to entering mitosis.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHEK1	CHEK1	CHEK1	CDC25C	CDC25C	CDC25C	0	1	2	3
Chk1 is triggered to inhibit the activation of Cdc25C , consequently resulting in the downregulation of cyclinB1 [ XREF_BIBR ] .	Chk1 is triggered to inhibit the activation of Cdc25C, consequently resulting in the downregulation of cyclinB1 [XREF_BIBR].	0	9	triggered	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	0	1	8	9
DNA damage is associated with many cellular events , including activation of CHK1 , which in turn phosphorylates and inactivates cdc25C , allowing inactivation of the 2-B1 complex and G 2 / M arrest XREF_BIBR .	DNA damage is associated with many cellular events, including activation of CHK1, which in turn phosphorylates and inactivates cdc25C, allowing inactivation of the 2-B1 complex and G 2 / M arrest XREF_BIBR.	10	21	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHK1	CHK1	CHK1	cdc25C	cdc25C	cdc25C	12	13	20	21
Cdc25C itself can be inactivated by the Chk1 kinase , which phosphorylates Ser216 on Cdc25C .	Cdc25C itself can be inactivated by the Chk1 kinase, which phosphorylates Ser216 on Cdc25C.	0	15	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Chk1	Chk1 kinase, which phosphorylates Ser216 on Cdc25C	chk1	Cdc25C	Cdc25C	cdc25c	7	8	0	1
The p38 inhibitor SB203580 or the Chk1 inhibitor UCN-01 or their combination blocked TMZ mediated inactivation of cdc25C and cdc2 , suggesting that p38 and Chk1 pathways work cooperatively and are both necessary to inactivate cdc25C and cdc2 .	The p38 inhibitor SB203580 or the Chk1 inhibitor UCN-01 or their combination blocked TMZ mediated inactivation of cdc25C and cdc2, suggesting that p38 and Chk1 pathways work cooperatively and are both necessary to inactivate cdc25C and cdc2.	23	37	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	cdc25C	cdc25C	cdc25C	25	26	35	36
Chek1 inhibits CDC25C through serine 216 phosphorylation causing a G2/M arrest in response to genotoxic stress [ XREF_BIBR , XREF_BIBR ] .	Chek1 inhibits CDC25C through serine 216 phosphorylation causing a G2/M arrest in response to genotoxic stress [XREF_BIBR, XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chek1	Chek1	Chek1	CDC25C	CDC25C	CDC25C	0	1	2	3
These kinases phosphorylate and activate Chk1 and Chk2 , which in turn phosphorylate and inactivate Cdc25C phosphatase resulting in blocking the activation of Cdk1 and transition into mitosis XREF_BIBR - XREF_BIBR .	These kinases phosphorylate and activate Chk1 and Chk2, which in turn phosphorylate and inactivate Cdc25C phosphatase resulting in blocking the activation of Cdk1 and transition into mitosis XREF_BIBR - XREF_BIBR.	4	16	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	5	6	15	16
Chk1 is activated by phosphorylation on S345 and subsequently inhibits Cdc25C phosphatase by phosphorylating S216 .	Chk1 is activated by phosphorylation on S345 and subsequently inhibits Cdc25C phosphatase by phosphorylating S216.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	0	1	10	11
Active CHK1 inactivates CDC25C by phosphorylation , impairing cell progression to mitosis , since it is responsible to activate CDC2 by removing the inhibitory phosphate groups Thr14 and Tyr15 [ XREF_BIBR ] .	Active CHK1 inactivates CDC25C by phosphorylation, impairing cell progression to mitosis, since it is responsible to activate CDC2 by removing the inhibitory phosphate groups Thr14 and Tyr15 [XREF_BIBR].	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHK1	CHK1	CHK1	CDC25C	CDC25C	CDC25C	1	2	3	4
Cdc25C is inactivated by chk1 , also a client protein , and chk2 [ XREF_BIBR ] .	Cdc25C is inactivated by chk1, also a client protein, and chk2 [XREF_BIBR].	0	14	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	chk1	chk1	chk1	Cdc25C	Cdc25C	Cdc25C	4	5	0	1
CHK1 and CHK2 kinases are activated at G2-phase checkpoint by DNA damage or unreplicated chromosomal DNA , and inactivate Cdc25C through its phosphorylation .	CHK1 and CHK2 kinases are activated at G2-phase checkpoint by DNA damage or unreplicated chromosomal DNA, and inactivate Cdc25C through its phosphorylation.	0	20	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHK1	CHK1	CHK1	Cdc25C	Cdc25C	Cdc25C	0	1	19	20
After activation by ATM and ATR , both Chk1 and Cds1 phosphorylate and inactivate the vertebrate Cdc25 orthologue Cdc25C .	After activation by ATM and ATR, both Chk1 and Cds1 phosphorylate and inactivate the vertebrate Cdc25 orthologue Cdc25C.	7	19	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	8	9	18	19
It is well-known that DNA damage delays G2/M by activating Chk1 , which inhibits Cdc25C by phosphorylation at Ser 216 .	It is well-known that DNA damage delays G2/M by activating Chk1, which inhibits Cdc25C by phosphorylation at Ser 216.	7	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	10	11	14	15
Cdc25C activity can also be inhibited via phosphorylation by checkpoint kinases Chk1 and Chk2 when there is a DNA damage , which will prevent cyclin B/cdk1 activation XREF_BIBR .	Cdc25C activity can also be inhibited via phosphorylation by checkpoint kinases Chk1 and Chk2 when there is a DNA damage, which will prevent cyclin B/cdk1 activation XREF_BIBR.	0	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	11	12	0	1
Since chk1 inhibits cdc25C , it is possible that its decrease following 17-AAG would cause an opposite increase in both cdc25C and cdc2 activity .	Since chk1 inhibits cdc25C, it is possible that its decrease following 17-AAG would cause an opposite increase in both cdc25C and cdc2 activity.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	chk1	chk1	chk1	cdc25C	cdc25C	cdc25C	1	2	3	4
Chk1 and Chk2 in turn phosphorylate and inactivate CDC25C , targeting it for proteasomal degradation .	Chk1 and Chk2 in turn phosphorylate and inactivate CDC25C, targeting it for proteasomal degradation.	0	9	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	CDC25C	CDC25C	CDC25C	0	1	8	9
Chk1 mediates the degradation of Cdc25A and Cdc25C , which results in inhibition of respectively cyclin A-Cdk2 in S phase and Cdk1 at G1/M transition [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Chk1 mediates the degradation of Cdc25A and Cdc25C, which results in inhibition of respectively cyclin A-Cdk2 in S phase and Cdk1 at G1/M transition [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	10	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	0	1	7	8
XREF_BIBR In the p53 independent pathway , CHK1 and CHK2 can inhibit the function of Cdc25C phosphatase through phosphorylation , leading to increase of p-CDK1 , an inactive form of CDK1 .	XREF_BIBR In the p53 independent pathway, CHK1 and CHK2 can inhibit the function of Cdc25C phosphatase through phosphorylation, leading to increase of p-CDK1, an inactive form of CDK1.	7	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHK1	CHK1	CHK1	Cdc25C	Cdc25C	Cdc25C	7	8	15	16
Upon to DDR , Chk1 is activated and inhibits the activation of the downstream target of Cdc25C , resulted in the downregulation of cyclinB1 and Cdc2 kinase XREF_BIBR .	Upon to DDR, Chk1 is activated and inhibits the activation of the downstream target of Cdc25C, resulted in the downregulation of cyclinB1 and Cdc2 kinase XREF_BIBR.	4	17	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	4	5	16	17
The radiation induced G 2 DNA damage checkpoint operates at least in part by maintaining phosphorylation of the checkpoint protein kinase 1 ( Chk1 ) , a modification that prevents the cycle division cycle 25C ( Cdc25C ) phosphatase from activating the cyclin dependent protein kinase 1 ( Cdk1 ; also called Cdc2 ) .	The radiation induced G 2 DNA damage checkpoint operates at least in part by maintaining phosphorylation of the checkpoint protein kinase 1 (Chk1), a modification that prevents the cycle division cycle 25C (Cdc25C) phosphatase from activating the cyclin dependent protein kinase 1 (Cdk1; also called Cdc2).	15	38	prevents	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Chk1	phosphorylation of the checkpoint protein kinase 1 (Chk1	chk1	Cdc25C	Cdc25C	cdc25c	23	24	36	37
Chk1 and 2 then inactivate Cdc25A , Cdc25B , and Cdc25C phosphatases via destruction or relocalization , resulting in elevated inhibitory phosphorylation of Cdk2 on Thr14 and Tyr15 .	Chk1 and 2 then inactivate Cdc25A, Cdc25B, and Cdc25C phosphatases via destruction or relocalization, resulting in elevated inhibitory phosphorylation of Cdk2 on Thr14 and Tyr15.	0	11	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	0	1	10	11
We also showed that Cdc25A activation is blocked by constitutive checkpoint kinase 1 activity under basal conditions in neurons .	We also showed that Cdc25A activation is blocked by constitutive checkpoint kinase 1 activity under basal conditions in neurons.	4	13	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	checkpoint kinase 1	checkpoint kinase 1	checkpoint kinase 1	Cdc25A	Cdc25A	Cdc25A	10	13	4	5
Here , we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase promoting Cdc25A phosphatase , prevented ionizing radiation ( IR )-induced degradation of Cdc25A , and caused radioresistant DNA synthesis ( RDS ) .	Here, we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase promoting Cdc25A phosphatase, prevented ionizing radiation (IR)-induced degradation of Cdc25A, and caused radioresistant DNA synthesis (RDS).	8	21	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	11	12	20	21
5-FU normally confers an S-phase arrest through activation of Chk1 , and Chk1 depletion abrogates this arrest by stabilizing Cdc25A to resume DNA synthesis , resulting in the accumulation of DSBs and apoptosis [ XREF_BIBR ] .	5-FU normally confers an S-phase arrest through activation of Chk1, and Chk1 depletion abrogates this arrest by stabilizing Cdc25A to resume DNA synthesis, resulting in the accumulation of DSBs and apoptosis [XREF_BIBR].	12	20	abrogates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	12	13	19	20
Indeed , CHK1 mediated degradation of CDC25A may also utilize additional degron kinases , such as NEK11 [ XREF_BIBR ] .	Indeed, CHK1 mediated degradation of CDC25A may also utilize additional degron kinases, such as NEK11 [XREF_BIBR].	2	7	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CHK1	CHK1	CHK1	CDC25A	CDC25A	CDC25A	2	3	6	7
The ubiquitin mediated destruction of claspin and WEE1 ( both proteins have conserved beta-TrcP phosphodegrons ) eliminates the essential coactivator of Chk1 and CDK inhibitor respectively allowing reaccumulation of Cdc25A followed by Cdc25B and C , which results in activation of cyclin-Cdk ( cyclinB-Cdk1 ) complex [ XREF_BIBR ] .	The ubiquitin mediated destruction of claspin and WEE1 (both proteins have conserved beta-TrcP phosphodegrons) eliminates the essential coactivator of Chk1 and CDK inhibitor respectively allowing reaccumulation of Cdc25A followed by Cdc25B and C, which results in activation of cyclin-Cdk (cyclinB-Cdk1) complex [XREF_BIBR].	21	37	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	21	22	29	30
CHK1 inhibits CDC25A directly ; thus , DNA damage occurring upon CHK1 inhibition has been suggested to be mediated through deregulation of the CDC25A-Cdk pathway , leading to elevated Cdk activity .	CHK1 inhibits CDC25A directly; thus, DNA damage occurring upon CHK1 inhibition has been suggested to be mediated through deregulation of the CDC25A-Cdk pathway, leading to elevated Cdk activity.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHK1	CHK1	CHK1	CDC25A	CDC25A	CDC25A	0	1	2	3
In previous studies , we showed that overexpression of Chk1 and Chk2 causes premature degradation of Cdc25A and delayed degradation of cyclin E [ XREF_BIBR , XREF_BIBR ] .	In previous studies, we showed that overexpression of Chk1 and Chk2 causes premature degradation of Cdc25A and delayed degradation of cyclin E [XREF_BIBR, XREF_BIBR].	7	17	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	overexpression of Chk1	chk1	Cdc25A	Cdc25A	cdc25a	9	10	16	17
For instance , Worms and colleagues reported that chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding [ XREF_BIBR ] .	For instance, Worms and colleagues reported that chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding [XREF_BIBR].	8	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	chk1	chk1	chk1	Cdc25A	Cdc25A	Cdc25A	8	9	15	16
CHK1 is an Hsp90 client , indeed the 17-AAG Hsp90 inhibitor leads to CHK1 degradation and to the disruption of the CHK1 mediated Cdc25A degradation .	CHK1 is an Hsp90 client, indeed the 17-AAG Hsp90 inhibitor leads to CHK1 degradation and to the disruption of the CHK1 mediated Cdc25A degradation.	18	24	mediated	Positive_early_activation	Negative_activation	Positive_activation	CHK1	CHK1	CHK1	Cdc25A	Cdc25A	Cdc25A	21	22	23	24
Importantly , expression of wild-type Chk1 , but not kinase-dead Chk1 , inhibits the camptothecin induced increase in Cdc25A activity .	Importantly, expression of wild-type Chk1, but not kinase-dead Chk1, inhibits the camptothecin induced increase in Cdc25A activity.	2	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	expression of wild-type Chk1	chk1	Cdc25A	Cdc25A	cdc25a	5	6	18	19
In addition , loss of Chk1 resulted in the accumulation of a hypophosphorylated form of the Cdc25A protein phosphatase , and Chk1 deficient cells failed to degrade Cdc25A after IR .	In addition, loss of Chk1 resulted in the accumulation of a hypophosphorylated form of the Cdc25A protein phosphatase, and Chk1 deficient cells failed to degrade Cdc25A after IR.	21	28	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	21	22	27	28
Depletion of Chk1 from Panc-1 cells prevented the down-regulation of Cdc25A in response to gemcitabine .	Depletion of Chk1 from Panc-1 cells prevented the down-regulation of Cdc25A in response to gemcitabine.	0	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	2	3	10	11
Our model suggested that upon DNA damage , ATM , ATR and CHEK1 were all up-regulated in the absence of p53 , and that CHEK1 inhibits CDC25A .	Our model suggested that upon DNA damage, ATM, ATR and CHEK1 were all up-regulated in the absence of p53, and that CHEK1 inhibits CDC25A.	24	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHEK1	CHEK1	CHEK1	CDC25A	CDC25A	CDC25A	24	25	26	27
Chk1 then inhibits cdc25A phosphatase , resulting in cell cycle arrest in G2 , and activates rad51 and related pathways to accomplish DNA repair [ XREF_BIBR ] .	Chk1 then inhibits cdc25A phosphatase, resulting in cell cycle arrest in G2, and activates rad51 and related pathways to accomplish DNA repair [XREF_BIBR].	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	cdc25A	cdc25A	cdc25A	0	1	3	4
We also investigated the impact of Chk1 inhibition on one of its immediate downstream targets , CDC25A , which is targeted for degradation by Chk1 .	We also investigated the impact of Chk1 inhibition on one of its immediate downstream targets, CDC25A, which is targeted for degradation by Chk1.	14	25	targeted	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	CDC25A	CDC25A	CDC25A	24	25	16	17
Since Vpr had little or no effect on Chk1 mediated Cdc25A protein degradation , we next examined whether Cdc25B/C are the substrates of Chk1 for Vpr to induce G2 arrest .	Since Vpr had little or no effect on Chk1 mediated Cdc25A protein degradation, we next examined whether Cdc25B/C are the substrates of Chk1 for Vpr to induce G2 arrest.	2	12	mediated	Positive_early_activation	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	8	9	10	11
Chk1 and Chk2 trigger the premature degradation of Cdc25A before the MBT whereas Wee1 and Delta34-Xic1 delay the degradation of Cdc25A .	Chk1 and Chk2 trigger the premature degradation of Cdc25A before the MBT whereas Wee1 and Delta34-Xic1 delay the degradation of Cdc25A.	0	9	trigger	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	0	1	8	9
Csk then negatively regulates Src family members Lck and Fyn activity through tyrosine phosphorylation at their C-terminus [ XREF_BIBR ] .	Csk then negatively regulates Src family members Lck and Fyn activity through tyrosine phosphorylation at their C-terminus [XREF_BIBR].	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	0	1	7	8
Phosphorylation of Lck Tyr 505 by Csk inhibits the kinase activity of Lck through an intramolecular interaction between the Lck SH2 domain and pTyr 505 , which induces a closed-clasp conformation .	Phosphorylation of Lck Tyr 505 by Csk inhibits the kinase activity of Lck through an intramolecular interaction between the Lck SH2 domain and pTyr 505, which induces a closed-clasp conformation.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Phosphorylation of Lck Tyr 505 by Csk	csk	Lck	Lck	lck	6	7	12	13
After a few minutes , PAG is rephosphorylated [ XREF_BIBR ] , probably by the Src-kinase Fyn , and subsequently Csk is re-recruited to PAG inhibiting Lck again .	After a few minutes, PAG is rephosphorylated [XREF_BIBR], probably by the Src-kinase Fyn, and subsequently Csk is re-recruited to PAG inhibiting Lck again.	20	27	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	20	21	26	27
Csk recruited to rafts would then be activated and inhibit the kinase activity of Lck to keep resting T cells in a quiescent state .	Csk recruited to rafts would then be activated and inhibit the kinase activity of Lck to keep resting T cells in a quiescent state.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	0	1	14	15
PKA phosphorylation of Csk suppresses T-cell receptor induced activation of the SFK Lck in T cells , and Csk deficient neutrophils exhibit increased adhesion after crosslinking integrin alphaMbeta2 .	PKA phosphorylation of Csk suppresses T-cell receptor induced activation of the SFK Lck in T cells, and Csk deficient neutrophils exhibit increased adhesion after crosslinking integrin alphaMbeta2.	0	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	PKA phosphorylation of Csk	csk	Lck	Lck	lck	3	4	12	13
Csk is anchored by Cbp and PAG to lipid rafts and constitutively inhibits Lck and Fyn .	Csk is anchored by Cbp and PAG to lipid rafts and constitutively inhibits Lck and Fyn.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	0	1	13	14
An important role of Csk is to inhibit LcK activity by phosphorylation of aa 508 of the Lck molecule .	An important role of Csk is to inhibit LcK activity by phosphorylation of aa 508 of the Lck molecule.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	LcK	LcK	LcK	4	5	8	9
Therefore , it appears that FAK regulates Csk recruitment to or retention at the TCR , where Csk could inhibit the pool of active Lck that is found at the stimulated receptor .	Therefore, it appears that FAK regulates Csk recruitment to or retention at the TCR, where Csk could inhibit the pool of active Lck that is found at the stimulated receptor.	17	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	17	18	24	25
The most TCR proximal target for type I PKA is C-terminal Src kinase ( Csk ) , which upon activation by raft recruitment and phosphorylation inhibits the Src family tyrosine kinases Lck and Fyn and thus functions to maintain T cell homeostasis .	The most TCR proximal target for type I PKA is C-terminal Src kinase (Csk), which upon activation by raft recruitment and phosphorylation inhibits the Src family tyrosine kinases Lck and Fyn and thus functions to maintain T cell homeostasis.	12	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	14	15	31	32
Thus , endogenous Csk can not effectively inhibit or regulate Lck function , explaining the overshoot seen with 3-IB-PP1 inhibition of Csk AS function .	Thus, endogenous Csk can not effectively inhibit or regulate Lck function, explaining the overshoot seen with 3-IB-PP1 inhibition of Csk AS function.	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	3	4	10	11
Lck activity is negatively regulated by both Csk and PTPN22 , with Csk being the most widely recognized Lck inhibitor 5 .	Lck activity is negatively regulated by both Csk and PTPN22, with Csk being the most widely recognized Lck inhibitor 5.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	7	8	0	1
Lck is negatively regulated by the balanced actions of the kinase Csk , and the phosphatases CD45 and PEP .	Lck is negatively regulated by the balanced actions of the kinase Csk, and the phosphatases CD45 and PEP.	0	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	11	12	0	1
In physiological conditions cAMP production by a TCR coupled adenylate cyclase is part of a negative feed-back loop which ensures extinction of TCR signaling through PKA dependent activation of Csk , a kinase that inhibits Lck by phosphorylating its C-terminal tyrosine residue XREF_BIBR .	In physiological conditions cAMP production by a TCR coupled adenylate cyclase is part of a negative feed-back loop which ensures extinction of TCR signaling through PKA dependent activation of Csk, a kinase that inhibits Lck by phosphorylating its C-terminal tyrosine residue XREF_BIBR.	27	36	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	29	30	35	36
We conclude that Csk inhibits the catalytic activity of Lck mainly through increasing Y505 phosphorylation .	We conclude that Csk inhibits the catalytic activity of Lck mainly through increasing Y505 phosphorylation.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	3	4	9	10
The latter is phosphorylated by CSK , which inhibits LCK because the protein folds up and binds its own SH2 domain .	The latter is phosphorylated by CSK, which inhibits LCK because the protein folds up and binds its own SH2 domain.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	LCK	LCK	LCK	5	6	9	10
Indeed , Csk negatively regulates Lck by phosphorylation of a C-terminal inhibitory tyrosine residue , Y505 that contributes to stabilize Lck in an inactive conformation .	Indeed, Csk negatively regulates Lck by phosphorylation of a C-terminal inhibitory tyrosine residue, Y505 that contributes to stabilize Lck in an inactive conformation.	2	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	2	3	5	6
PKA has the ability to negatively regulate TCR signaling by enhancing the activity of the kinase Csk , which inhibits the initiating kinase Lck .	PKA has the ability to negatively regulate TCR signaling by enhancing the activity of the kinase Csk, which inhibits the initiating kinase Lck.	12	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	16	17	23	24
As previously shown , inhibition of Csk AS alone induced strong activation of Lck , as well as Fyn , which was indicated by the hyperphosphorylation of their activation loop tyrosines and the reduced phosphorylation of their inhibitory tyrosines .	As previously shown, inhibition of Csk AS alone induced strong activation of Lck, as well as Fyn, which was indicated by the hyperphosphorylation of their activation loop tyrosines and the reduced phosphorylation of their inhibitory tyrosines.	6	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	6	7	13	14
The Csk tyrosine kinase negatively regulates the Src family kinases Lck and Fyn in T cells .	The Csk tyrosine kinase negatively regulates the Src family kinases Lck and Fyn in T cells.	1	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	1	2	10	11
An important role of Csk is to inhibit Lck activity by phosphorylation of amino acid 505 of the Lck molecule .	An important role of Csk is to inhibit Lck activity by phosphorylation of amino acid 505 of the Lck molecule.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	4	5	8	9
As PKA activates Csk and Csk inhibits Lck , this pathway in response to cAMP shuts down proximal T cell activation .	As PKA activates Csk and Csk inhibits Lck, this pathway in response to cAMP shuts down proximal T cell activation.	3	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	3	4	7	8
In opposition to CD45 , Csk negatively regulates Lck and Fyn , as shown by their 2-5-fold increased basal catalytic activities in Csk-conditional deficient thymocytes XREF_BIBR .	In opposition to CD45, Csk negatively regulates Lck and Fyn, as shown by their 2-5-fold increased basal catalytic activities in Csk-conditional deficient thymocytes XREF_BIBR.	5	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	5	6	8	9
In addition , Fyn can phosphorylate PAG ( phosphoprotein associated with glycolipid enriched membranes ) also called Cbp ( Csk binding protein ) , which acts to downregulate TCR signaling through its recruitment to the membrane of Csk , a kinase that inhibits both Fyn and Lck through phosphorylation of negative regulatory tyrosines near their C-termini .	In addition, Fyn can phosphorylate PAG (phosphoprotein associated with glycolipid enriched membranes) also called Cbp (Csk binding protein), which acts to downregulate TCR signaling through its recruitment to the membrane of Csk, a kinase that inhibits both Fyn and Lck through phosphorylation of negative regulatory tyrosines near their C-termini.	35	47	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lck	Lck	Lck	37	38	46	47
TLK1 is rapidly , but transiently , suppressed by Chk1 immediately after DNA damage .	TLK1 is rapidly, but transiently, suppressed by Chk1 immediately after DNA damage.	0	10	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	TLK1	TLK1	TLK1	9	10	0	1
Previous studies have shown that Chk1 dependent inhibition of TLK1 following irradiation is transient and gradually returns to a baseline level of activity [ XREF_BIBR ] .	Previous studies have shown that Chk1 dependent inhibition of TLK1 following irradiation is transient and gradually returns to a baseline level of activity [XREF_BIBR].	5	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	TLK1	TLK1	TLK1	5	6	9	10
Since , Chk1 activation prevents TLK1 kinase activity after DNA damage [ XREF_BIBR ] , and Chk1 activation is required for Rad9A stabilization ( Figs XREF_FIG and XREF_FIG ) , a possible explanation for Rad9A stabilization could be TLK1 inactivation by Chk1 .	Since, Chk1 activation prevents TLK1 kinase activity after DNA damage [XREF_BIBR], and Chk1 activation is required for Rad9A stabilization (Figs XREF_FIG and XREF_FIG), a possible explanation for Rad9A stabilization could be TLK1 inactivation by Chk1.	2	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	TLK1	TLK1	TLK1	2	3	5	6
TLK1 plays a role in chromatin remodeling and S-phase progression [ XREF_BIBR , XREF_BIBR ] , and is inhibited by Chk1 dependent phosphorylation at S695 in response to DNA damage [ XREF_BIBR - XREF_BIBR ] .	TLK1 plays a role in chromatin remodeling and S-phase progression [XREF_BIBR, XREF_BIBR], and is inhibited by Chk1 dependent phosphorylation at S695 in response to DNA damage [XREF_BIBR - XREF_BIBR].	0	25	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Chk1	Chk1 dependent phosphorylation at S695	chk1	TLK1	TLK1	tlk1	20	21	0	1
The protein kinase Chk1 is phosphorylated in response to DNA damage in an ATM- and ATR dependent manner , and activated Chk1 down-regulates TLK1 transiently through phosphorylation at S695 8 .	The protein kinase Chk1 is phosphorylated in response to DNA damage in an ATM- and ATR dependent manner, and activated Chk1 down-regulates TLK1 transiently through phosphorylation at S695 8.	21	24	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	TLK1	TLK1	TLK1	21	22	23	24
Therefore , it was anticipated that treatment with GA post-radiation would not affect Chk1 mediated transient suppression of TLK1 activity , but rather hasten its recovery .	Therefore, it was anticipated that treatment with GA post-radiation would not affect Chk1 mediated transient suppression of TLK1 activity, but rather hasten its recovery.	12	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	TLK1	TLK1	TLK1	13	14	18	19
Tlk1 activity normally peaks in S phase , but is strongly inhibited by DNA damage in a Chk1 dependent manner , and Tlk1 can be phosphorylated by Chk1 in vitro .	Tlk1 activity normally peaks in S phase, but is strongly inhibited by DNA damage in a Chk1 dependent manner, and Tlk1 can be phosphorylated by Chk1 in vitro.	0	19	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Tlk1	Tlk1	Tlk1	17	18	0	1
It may be that Tlk1 inhibition by Chk1 slows replication fork progression by blocking chromatin assembly at replication forks .	It may be that Tlk1 inhibition by Chk1 slows replication fork progression by blocking chromatin assembly at replication forks.	4	8	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Tlk1	Tlk1	Tlk1	7	8	4	5
We identified several differentially expressed genes involved in nuclear transport and regulation of beta-catenin , such as increased CHD8 , a nuclear protein that inhibits beta-catenin signaling 65 , and decreased MAP3K7 .	We identified several differentially expressed genes involved in nuclear transport and regulation of beta-catenin, such as increased CHD8, a nuclear protein that inhibits beta-catenin signaling 65, and decreased MAP3K7.	9	26	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	18	19	25	26
In Xenopus laevis embryos , the CHD8 homologue Duplin negatively regulates WNT and beta-catenin signalling , especially in the context of head and brain development XREF_BIBR , XREF_BIBR .	In Xenopus laevis embryos, the CHD8 homologue Duplin negatively regulates WNT and beta-catenin signalling, especially in the context of head and brain development XREF_BIBR, XREF_BIBR.	6	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	6	7	13	14
In the in vivo setting , CHD8 was first examined in the context of beta-catenin signaling due to its nuclear localization and ability to repress beta-catenin dependent transcription .	In the in vivo setting, CHD8 was first examined in the context of beta-catenin signaling due to its nuclear localization and ability to repress beta-catenin dependent transcription.	6	27	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	6	7	25	26
There is mounting evidence from work in both fly and humans that CHD8 negatively regulates beta-catenin ( CTNNB1 ) function , either through direct binding to beta-catenin , or by recruitment to promoter regions of beta-catenin-responsive genes .	There is mounting evidence from work in both fly and humans that CHD8 negatively regulates beta-catenin (CTNNB1) function, either through direct binding to beta-catenin, or by recruitment to promoter regions of beta-catenin-responsive genes.	12	30	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	12	13	15	16
CHD8 inhibits beta-catenin signaling by recruiting histone H1 to promoters of WNT target genes .	CHD8 inhibits beta-catenin signaling by recruiting histone H1 to promoters of WNT target genes.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	0	1	2	3
CHD8 negatively regulates beta-catenin via direct binding and , furthermore , downregulates beta-catenin-responsive genes by recruitment to their promoter regions [ XREF_BIBR ] .	CHD8 negatively regulates beta-catenin via direct binding and, furthermore, downregulates beta-catenin-responsive genes by recruitment to their promoter regions [XREF_BIBR].	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	0	1	3	4
Mammalian CHD8 is thought to repress beta-catenin and p53 target genes by recruiting linker histone H1 .	Mammalian CHD8 is thought to repress beta-catenin and p53 target genes by recruiting linker histone H1.	0	10	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
More recently , the chromo-helicase domain protein 8 ( CHD8 ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , which inhibits beta-catenin through direct binding [ XREF_BIBR ] , and DYRK1A that modulates Wnt signaling through interaction with the p120 catenin [ XREF_BIBR ] have been found to be associated with ASDs .	More recently, the chromo-helicase domain protein 8 (CHD8) [XREF_BIBR, XREF_BIBR, XREF_BIBR], which inhibits beta-catenin through direct binding [XREF_BIBR], and DYRK1A that modulates Wnt signaling through interaction with the p120 catenin [XREF_BIBR] have been found to be associated with ASDs.	3	49	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	9	10	21	22
The presence of CHD8 negatively regulates beta-catenin signaling , suppresses p53-dependence XREF_BIBR , XREF_BIBR , and negatively regulates HOXA2 gene expression XREF_BIBR .	The presence of CHD8 negatively regulates beta-catenin signaling, suppresses p53-dependence XREF_BIBR, XREF_BIBR, and negatively regulates HOXA2 gene expression XREF_BIBR.	1	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	3	4	6	7
Other studies suggest CHD8 may repress Wnt and beta-catenin target genes and p53 dependent apoptosis XREF_BIBR XREF_BIBR .	Other studies suggest CHD8 may repress Wnt and beta-catenin target genes and p53 dependent apoptosis XREF_BIBR XREF_BIBR.	3	10	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
Interestingly , when IKKalpha was co-expressed in the transfection experiments , only FOXA2 ( HNF3beta )-upregulated NUMB mRNA level was reduced , indicating that FOXA2 activated NUMB transcription can be inhibited by IKKalpha ( XREF_FIG ) .	Interestingly, when IKKalpha was co-expressed in the transfection experiments, only FOXA2 (HNF3beta)-upregulated NUMB mRNA level was reduced, indicating that FOXA2 activated NUMB transcription can be inhibited by IKKalpha (XREF_FIG).	11	34	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	FOXA2	FOXA2	FOXA2	32	33	12	13
To determine how IKKalpha inhibits FOXA2 activity , we first tested whether IKKalpha interacts with FOXA2 .	To determine how IKKalpha inhibits FOXA2 activity, we first tested whether IKKalpha interacts with FOXA2.	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	FOXA2	FOXA2	FOXA2	3	4	5	6
We identified forkhead box protein A2 ( FOXA2 ) as the transcription factor for NUMB gene transcription and demonstrated that IKKalpha reduces the transcriptional activity of FOXA2 via binding to and phosphorylating it at Ser107 and Ser111 [ XREF_BIBR ] .	We identified forkhead box protein A2 (FOXA2) as the transcription factor for NUMB gene transcription and demonstrated that IKKalpha reduces the transcriptional activity of FOXA2 via binding to and phosphorylating it at Ser107 and Ser111 [XREF_BIBR].	20	31	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	FOXA2	FOXA2	FOXA2	20	21	26	27
WT IKKalpha , but not KD IKKalpha , abrogated WT FOXA2 mediated growth suppression , presumably as a result of phosphorylation of WT FOXA2 by IKKalpha , and thus FOXA2 lost its ability to inhibit cell growth ( XREF_SUPPLEMENTARY ) .	WT IKKalpha, but not KD IKKalpha, abrogated WT FOXA2 mediated growth suppression, presumably as a result of phosphorylation of WT FOXA2 by IKKalpha, and thus FOXA2 lost its ability to inhibit cell growth (XREF_SUPPLEMENTARY).	0	11	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	FOXA2	FOXA2	FOXA2	1	2	10	11
To test whether IKKalpha inhibits FOXA2 activity through the identified IKKalpha phosphorylation sites ( S107/111 ) , we generated two double mutants , FOXA2-SSAA and FOXA2-SSEE , which mimic the nonphosphorylated and phosphorylated state of FOXA2 , respectively , by IKKalpha .	To test whether IKKalpha inhibits FOXA2 activity through the identified IKKalpha phosphorylation sites (S107/111), we generated two double mutants, FOXA2-SSAA and FOXA2-SSEE, which mimic the nonphosphorylated and phosphorylated state of FOXA2, respectively, by IKKalpha.	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	FOXA2	FOXA2	FOXA2	3	4	5	6
Such an association is absent in unstimulated B cells in which Lyn activity is apparently suppressed by Csk .	Such an association is absent in unstimulated B cells in which Lyn activity is apparently suppressed by Csk.	11	18	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Csk	Csk	Csk	Lyn	Lyn	Lyn	17	18	11	12
With this assay method , we demonstrated that CSK inactivated p56lyn with a significantly higher efficiency than pp60c-src .	With this assay method, we demonstrated that CSK inactivated p56lyn with a significantly higher efficiency than pp60c-src.	8	11	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	p56lyn	p56lyn	p56lyn	8	9	10	11
Dephosphorylation of the activating tyrosine or phosphorylation of the inhibitory tyrosine by Csk ( c-Src kinase ) decreases the kinase activity of Lyn and other SFKs .	Dephosphorylation of the activating tyrosine or phosphorylation of the inhibitory tyrosine by Csk (c-Src kinase) decreases the kinase activity of Lyn and other SFKs.	6	25	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Csk	phosphorylation of the inhibitory tyrosine by Csk	csk	Lyn	Lyn	lyn	12	13	22	23
Thus , the higher efficiency of inactivation of p56lyn by CSK is a result of the ability of p56lyn to serve as a better substrate of CSK .	Thus, the higher efficiency of inactivation of p56lyn by CSK is a result of the ability of p56lyn to serve as a better substrate of CSK.	6	11	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	CSK	CSK	CSK	p56lyn	p56lyn	p56lyn	10	11	8	9
The mechanism for this effect is unknown , but it does not appear to be mediated through loss of Cbp phosphorylation and , thus , the loss of Csk mediated control of Lyn activity , since Cbp phosphorylation was enhanced .	The mechanism for this effect is unknown, but it does not appear to be mediated through loss of Cbp phosphorylation and, thus, the loss of Csk mediated control of Lyn activity, since Cbp phosphorylation was enhanced.	26	33	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	loss of Csk	csk	Lyn	Lyn	lyn	28	29	32	33
In our murine model , heterozygous and homozygous knockout of Csnk1a1 induced strong nuclear accumulation of beta-catenin ( XREF_FIG ) .	In our murine model, heterozygous and homozygous knockout of Csnk1a1 induced strong nuclear accumulation of beta-catenin (XREF_FIG).	8	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Csnk1a1	Csnk1a1	Csnk1a1	beta-catenin	beta-catenin	beta-catenin	10	11	16	17
More precisely , Csnk1a1 suppression increases beta catenin and p53 activity .	More precisely, Csnk1a1 suppression increases beta catenin and p53 activity.	3	8	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Csnk1a1	Csnk1a1	Csnk1a1	beta catenin	beta catenin	beta catenin	3	4	6	8
Instead , this response occurred through reduced abundance of Csnk1a1 ( CK1alpha ) , a kinase that inhibits beta-catenin .	Instead, this response occurred through reduced abundance of Csnk1a1 (CK1alpha), a kinase that inhibits beta-catenin.	7	19	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Csnk1a1	Csnk1a1	Csnk1a1	beta-catenin	beta-catenin	beta-catenin	9	10	18	19
XREF_BIBR - XREF_BIBR In a hematopoietic specific conditional knockout mouse model , homozygous inactivation of Csnk1a1 induces apoptosis via p53 activation , while heterozygous loss of Csnk1a1 causes beta-catenin accumulation and stem cell expansion 15 .	XREF_BIBR - XREF_BIBR In a hematopoietic specific conditional knockout mouse model, homozygous inactivation of Csnk1a1 induces apoptosis via p53 activation, while heterozygous loss of Csnk1a1 causes beta-catenin accumulation and stem cell expansion 15.	24	29	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csnk1a1	loss of Csnk1a1	csnk1a1	beta-catenin	beta-catenin	beta-catenin	26	27	28	29
Jab1 induced Smad4 degradation results in reduced TGF-beta and BMP mediated gene transcription [ XREF_BIBR ] .	Jab1 induced Smad4 degradation results in reduced TGF-beta and BMP mediated gene transcription [XREF_BIBR].	0	3	induced	Positive_early_activation	Negative_activation	Negative_activation	Jab1	Jab1	Jab1	Smad4	Smad4	Smad4	0	1	2	3
Jab1 can cause degradation of Smad4 via TGF-beta signal pathway , consequently contributing to the proliferation of PC cells .	Jab1 can cause degradation of Smad4 via TGF-beta signal pathway, consequently contributing to the proliferation of PC cells.	0	9	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Jab1	Jab1	Jab1	Smad4	Smad4	Smad4	0	1	5	6
Examination of the effects of JAB1 induced Smad4 degradation indicates that Jab1 inhibited TGF-beta-induced gene transcription .	Examination of the effects of JAB1 induced Smad4 degradation indicates that Jab1 inhibited TGF-beta-induced gene transcription.	3	8	induced	Positive_early_activation	Negative_activation	Negative_activation	JAB1	JAB1	JAB1	Smad4	Smad4	Smad4	5	6	7	8
Jab1 and CSN5 induced Smad4 degradation results in reduced TGF-beta-mediated gene transcription , whereas its degradation of Smad7 leads to enhanced TGF-beta signaling effects [ XREF_BIBR , XREF_BIBR ] .	Jab1 and CSN5 induced Smad4 degradation results in reduced TGF-beta-mediated gene transcription, whereas its degradation of Smad7 leads to enhanced TGF-beta signaling effects [XREF_BIBR, XREF_BIBR].	0	5	induced	Positive_early_activation	Negative_activation	Negative_activation	CSN5	CSN5	CSN5	Smad4	Smad4	Smad4	2	3	4	5
Phosphorylation of these residues by ATM and CHK2 triggers MDMX degradation .	Phosphorylation of these residues by ATM and CHK2 triggers MDMX degradation.	3	10	triggers	Positive_activation_token_1_verb	Negative_activation	Negative_activation	CHK2	CHK2	CHK2	MDMX	MDMX	MDMX	7	8	9	10
The MDMX degradation is MDM2 dependent , but is not associated with increased phosphorylation of MDMX-Serine367 , so is distinct from the ATM and Chk2 stimulated MDMX degradation .	The MDMX degradation is MDM2 dependent, but is not associated with increased phosphorylation of MDMX-Serine367, so is distinct from the ATM and Chk2 stimulated MDMX degradation.	24	27	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk2	Chk2	Chk2	MDMX	MDMX	MDMX	24	25	26	27
XREF_BIBR CFH prevents the assembly of the C3/C5-convertase of the alternative pathway by multiple mechanisms due to its affinity for C3b .	XREF_BIBR CFH prevents the assembly of the C3/C5-convertase of the alternative pathway by multiple mechanisms due to its affinity for C3b.	0	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CFH	CFH	CFH	C3/C5-convertase	C3/C5-convertase	C3/C5-convertase	1	2	7	8
It also provides an explanation for how CFH blocks the interaction of CFB and promotes decay acceleration activity ( DAA ) and cofactor activity .	It also provides an explanation for how CFH blocks the interaction of CFB and promotes decay acceleration activity (DAA) and cofactor activity.	7	14	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CFH	CFH	CFH	CFB	CFB	CFB	7	8	12	13
To this end , CRP has been demonstrated to inhibit GTP cyclohydrolase 1 through the p38 kinase pathway [ XREF_BIBR ] ; this enzyme is the first step in the de novo synthesis of tetrahydrobiopterin , an important cofactor for eNOS .	To this end, CRP has been demonstrated to inhibit GTP cyclohydrolase 1 through the p38 kinase pathway [XREF_BIBR]; this enzyme is the first step in the de novo synthesis of tetrahydrobiopterin, an important cofactor for eNOS.	4	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CRP	CRP	CRP	GTP cyclohydrolase 1	GTP cyclohydrolase 1	GTP cyclohydrolase 1	4	5	10	13
Here , we sought to gain insight into how CIITA inhibits the activity of myogenin .	Here, we sought to gain insight into how CIITA inhibits the activity of myogenin.	9	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIITA	CIITA	CIITA	myogenin	myogenin	myogenin	9	10	14	15
In men , the HF F & V diet increased endothelium dependent microvascular reactivity ( P = 0.017 ) with +2 portions/d ( at 6 wk ) and reduced C-reactive protein ( P = 0.001 ) , E-selectin ( P = 0.0005 ) , and vascular cell adhesion molecule ( P = 0.0468 ) with +4 portions/d ( at 12 wk ) .	In men, the HF F&V diet increased endothelium dependent microvascular reactivity (P = 0.017) with +2 portions/d (at 6 wk) and reduced C-reactive protein (P = 0.001), E-selectin (P = 0.0005), and vascular cell adhesion molecule (P = 0.0468) with +4 portions/d (at 12 wk).	4	31	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HF	HF	HF	C-reactive protein	C-reactive protein	C-reactive protein	4	5	29	31
Inactivation of CKIdelta by shRNA treatment also partially blocked DNA damage induced destruction of Mdm2 ( XREF_SUPPLEMENTARY ) .	Inactivation of CKIdelta by shRNA treatment also partially blocked DNA damage induced destruction of Mdm2 (XREF_SUPPLEMENTARY).	0	16	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CKIdelta	CKIdelta	CKIdelta	Mdm2	Mdm2	Mdm2	2	3	14	15
As CKIgamma2 inhibits Smad3 activity in a kinase dependent manner , we examined whether Smad3 is a direct substrate of CKIgamma2 .	As CKIgamma2 inhibits Smad3 activity in a kinase dependent manner, we examined whether Smad3 is a direct substrate of CKIgamma2.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CKIgamma2	CKIgamma2	CKIgamma2	Smad3	Smad3	Smad3	1	2	3	4
This latter result suggests that CKIgamma2 downregulates P-Smad3 by promoting its degradation , a notion consistent with the gradual loss of Smad3 protein after prolonged TGF-beta stimulation as seen in XREF_FIG .	This latter result suggests that CKIgamma2 downregulates P-Smad3 by promoting its degradation, a notion consistent with the gradual loss of Smad3 protein after prolonged TGF-beta stimulation as seen in XREF_FIG.	5	8	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CKIgamma2	CKIgamma2	CKIgamma2	P-Smad3	P-Smad3	P-Smad3	5	6	7	8
CKIgamma2 promotes proteasomal degradation of activated Smad3 .	CKIgamma2 promotes proteasomal degradation of activated Smad3.	0	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CKIgamma2	CKIgamma2	CKIgamma2	Smad3	Smad3	Smad3	0	1	6	7
Overexpression of CKIgamma2 ( WT ) , but not CKIgamma2 ( KD ) , considerably attenuated the induction of those genes and also downregulated Smad3 in the presence of TGF-beta ( XREF_FIG ) .	Overexpression of CKIgamma2 (WT), but not CKIgamma2 (KD), considerably attenuated the induction of those genes and also downregulated Smad3 in the presence of TGF-beta (XREF_FIG).	0	25	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CKIgamma2	Overexpression of CKIgamma2 (WT), but not CKIgamma2	ckigamma2	Smad3	Smad3	smad3	9	10	24	25
All together , these data demonstrate that CKIgamma2 accelerates the proteasomal degradation of activated Smad3 , thereby shortening its signaling duration and inhibiting TGF-beta activity .	All together, these data demonstrate that CKIgamma2 accelerates the proteasomal degradation of activated Smad3, thereby shortening its signaling duration and inhibiting TGF-beta activity.	7	15	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CKIgamma2	CKIgamma2	CKIgamma2	Smad3	Smad3	Smad3	7	8	14	15
These results further demonstrate that CKIgamma2 negatively regulates TGF-beta and Smad3 activity in a kinase dependent manner .	These results further demonstrate that CKIgamma2 negatively regulates TGF-beta and Smad3 activity in a kinase dependent manner.	5	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CKIgamma2	CKIgamma2	CKIgamma2	Smad3	Smad3	Smad3	5	6	10	11
CKIgamma2 inhibits Smad3 transcriptional activity .	CKIgamma2 inhibits Smad3 transcriptional activity.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CKIgamma2	CKIgamma2	CKIgamma2	Smad3	Smad3	Smad3	0	1	2	3
CERT is subjected to regulation within a serine repeat ( SR ) domain where phosphorylation by Protein Kinase D and hyperphosphorylation by Casein Kinase Igamma2 ( CKIgamma2 ) inactivates CERT while dephosphorylation by Protein Phosphatase 2Cepsilon activates CERT XREF_BIBR , XREF_BIBR , XREF_BIBR .	CERT is subjected to regulation within a serine repeat (SR) domain where phosphorylation by Protein Kinase D and hyperphosphorylation by Casein Kinase Igamma2 (CKIgamma2) inactivates CERT while dephosphorylation by Protein Phosphatase 2Cepsilon activates CERT XREF_BIBR, XREF_BIBR, XREF_BIBR.	14	30	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CKIgamma2	phosphorylation by Protein Kinase D and hyperphosphorylation by Casein Kinase Igamma2 (CKIgamma2	ckigamma2	CERT	CERT	cert	26	27	29	30
Altogether , ICAT contributed to EMT by inhibiting the adherence of beta-catenin with E-cadherin , whereas miR-424-5p reversed this EMT process by directly targeting ICAT .	Altogether, ICAT contributed to EMT by inhibiting the adherence of beta-catenin with E-cadherin, whereas miR-424-5p reversed this EMT process by directly targeting ICAT.	2	12	contributed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
In these studies , Col2a1- inhibitor of beta-catenin and T-cell factor ( ICAT )-transgenic mice inhibited beta-catenin signaling in chondrocytes and significantly increased cleaved PARP , caspase-3 and TUNEL positive cells ( XREF_FIG ) expression .	In these studies, Col2a1- inhibitor of beta-catenin and T-cell factor (ICAT)-transgenic mice inhibited beta-catenin signaling in chondrocytes and significantly increased cleaved PARP, caspase-3 and TUNEL positive cells (XREF_FIG) expression.	12	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	12	13	16	17
As such , ICAT disrupts the ability of beta-catenin and TCF/LEF to form a complex , blocking the transcription of downstream target genes .	As such, ICAT disrupts the ability of beta-catenin and TCF/LEF to form a complex, blocking the transcription of downstream target genes.	3	10	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
Overexpression of ICAT specifically inhibits beta-catenin signaling without disturbing cell adhesion .	Overexpression of ICAT specifically inhibits beta-catenin signaling without disturbing cell adhesion.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	Overexpression of ICAT	icat	beta-catenin	beta-catenin	beta-catenin	2	3	5	6
XREF_BIBR - XREF_BIBR Mutations in APC , beta-catenin , Axin1 , or ICAT ( inhibitor of beta-catenin and Tcf interacting protein ) result in the deregulated accumulation of beta-catenin and the constitutive activation of Wnt signaling , XREF_BIBR - XREF_BIBR a major cause of cancer , including colorectal cancer .	XREF_BIBR - XREF_BIBR Mutations in APC, beta-catenin, Axin1, or ICAT (inhibitor of beta-catenin and Tcf interacting protein) result in the deregulated accumulation of beta-catenin and the constitutive activation of Wnt signaling, XREF_BIBR - XREF_BIBR a major cause of cancer, including colorectal cancer.	3	22	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	12	13	16	17
Because ICAT inhibition of beta-catenin signaling is leaky and starts at a later stage than Wnt3a , which is detected as early as E6.5 , the tail deformity described in this study is milder than that of Wnt3a mutation mice .	Because ICAT inhibition of beta-catenin signaling is leaky and starts at a later stage than Wnt3a, which is detected as early as E6.5, the tail deformity described in this study is milder than that of Wnt3a mutation mice.	1	5	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	1	2	4	5
Nuclear Chibby Homolog 1 and Inhibitor of beta-catenin and Tcf ( ICAT ) inhibit the interaction of beta-catenin with Tcf/Lef , repressing beta-catenin-Tcf / Lef mediated transactivation .	Nuclear Chibby Homolog 1 and Inhibitor of beta-catenin and Tcf (ICAT) inhibit the interaction of beta-catenin with Tcf/Lef, repressing beta-catenin-Tcf / Lef mediated transactivation.	2	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	11	12	17	18
miR-215 directly regulates Catenin-beta Interacting Protein ( CTNNBIP1 ) , which suppresses Wnt and beta-catenin signaling that leads to activation of alpha-SMA and fibronectin expression in TGF-beta1 treated mouse mesangial cells ( MMCs ) [ XREF_BIBR ] .	miR-215 directly regulates Catenin-beta Interacting Protein (CTNNBIP1), which suppresses Wnt and beta-catenin signaling that leads to activation of alpha-SMA and fibronectin expression in TGF-beta1 treated mouse mesangial cells (MMCs) [XREF_BIBR].	5	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTNNBIP1	CTNNBIP1	CTNNBIP1	beta-catenin	beta-catenin	beta-catenin	7	8	14	15
ICAT ( beta-catenin-interacting protein 1 ) , an inhibitor of beta-catenin and TCF , can inhibit the canonical Wnt and beta-catenin signaling pathway by binding to beta-catenin [ XREF_BIBR ] .	ICAT (beta-catenin-interacting protein 1), an inhibitor of beta-catenin and TCF, can inhibit the canonical Wnt and beta-catenin signaling pathway by binding to beta-catenin [XREF_BIBR].	0	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	0	1	20	21
, which ICAT ( inhibitor of beta-catenin and Tcf4 ) uses to inhibit the interaction between beta-catenin and Tcf4 .	, which ICAT (inhibitor of beta-catenin and Tcf4) uses to inhibit the interaction between beta-catenin and Tcf4.	2	10	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
ICAT , niclosamide , or XAV939 inhibit WNT and beta-catenin pathway activation and exert anti-proliferative effects in primary cultures of human leiomyoma cells .	ICAT, niclosamide, or XAV939 inhibit WNT and beta-catenin pathway activation and exert anti-proliferative effects in primary cultures of human leiomyoma cells.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	0	1	9	10
Here we provide evidence that beta-catenin interacting protein 1 ( CTNNBIP1 ) , also known as ICAT ( inhibitor of beta-catenin and TCF4 ) , functions as a crucial node to mediate the cross talk between E2F1 and beta-catenin signaling .	Here we provide evidence that beta-catenin interacting protein 1 (CTNNBIP1), also known as ICAT (inhibitor of beta-catenin and TCF4), functions as a crucial node to mediate the cross talk between E2F1 and beta-catenin signaling.	14	22	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	16	17	20	21
Meanwhile , dowmregulation of negative regulation of ICAT could promote glioma tumorigenesis by activating the Wnt and beta-catenin signaling pathway [ XREF_BIBR ] .	Meanwhile, dowmregulation of negative regulation of ICAT could promote glioma tumorigenesis by activating the Wnt and beta-catenin signaling pathway [XREF_BIBR].	5	19	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	7	8	17	18
Moreover , ICAT ( inhibitor of beta-catenin and TCF ) decreased while TCF7L2 and beta-catenin enhanced 0.44 kb SM22alpha promoter induction by Wnt3a + TGFbeta 1 .	Moreover, ICAT (inhibitor of beta-catenin and TCF) decreased while TCF7L2 and beta-catenin enhanced 0.44 kb SM22alpha promoter induction by Wnt3a + TGFbeta 1.	2	10	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
We show that ICAT is a direct transcriptional target of E2F1 , and that activation of ICAT by E2F1 is required for E2F1 to inhibit beta-catenin activity .	We show that ICAT is a direct transcriptional target of E2F1, and that activation of ICAT by E2F1 is required for E2F1 to inhibit beta-catenin activity.	14	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	16	17	25	26
Mechanistic studies revealed that CTNNBIP1 suppresses Wnt and beta-catenin signaling and that miR-215 promotes beta-catenin activation and upregulates alpha-SMA and fibronectin expression in TGF-beta1-treated MMCs by targeting CTNNBIP1 .	Mechanistic studies revealed that CTNNBIP1 suppresses Wnt and beta-catenin signaling and that miR-215 promotes beta-catenin activation and upregulates alpha-SMA and fibronectin expression in TGF-beta1-treated MMCs by targeting CTNNBIP1.	4	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTNNBIP1	CTNNBIP1	CTNNBIP1	beta-catenin	beta-catenin	beta-catenin	4	5	8	9
Using yeast two-hybrid screening , we identified ICAT ( inhibitor of beta-catenin and Tcf4 ) as a novel Ptf1a interactor .	Using yeast two-hybrid screening, we identified ICAT (inhibitor of beta-catenin and Tcf4) as a novel Ptf1a interactor.	6	13	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	7	8	11	12
The expression of ICAT may disrupt the interaction of beta catenin with other proteins besides TCF / LEF family members , such as p300 .	The expression of ICAT may disrupt the interaction of beta catenin with other proteins besides TCF / LEF family members, such as p300.	1	11	disrupt	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	expression of ICAT	icat	beta catenin	beta catenin	beta catenin	3	4	9	11
ICAT ( Inhibitor of beta-CAtenin and TCF ) is a small acidic protein that negatively regulates beta-catenin co-transcriptional activity by competing with TCF/LEF factors in their binding to beta-catenin superhelical core .	ICAT (Inhibitor of beta-CAtenin and TCF) is a small acidic protein that negatively regulates beta-catenin co-transcriptional activity by competing with TCF/LEF factors in their binding to beta-catenin superhelical core.	0	12	Inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-CAtenin	beta-CAtenin	beta-CAtenin	0	1	4	5
Furthermore , ICAT ( inhibitor of beta-catenin and TCF4 ) and Chibby are identified as nuclear proteins that repress Wnt signaling by competing with TCF for binding to beta-catenin .	Furthermore, ICAT (inhibitor of beta-catenin and TCF4) and Chibby are identified as nuclear proteins that repress Wnt signaling by competing with TCF for binding to beta-catenin.	2	13	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
Structure based mutational analysis of ICAT residues mediating negative regulation of beta-catenin co-transcriptional activity .	Structure based mutational analysis of ICAT residues mediating negative regulation of beta-catenin co-transcriptional activity.	5	13	mediating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	5	6	11	12
Experiments in which ICAT expression was utilized to block interaction of beta-catenin with TCF1 showed that beta-catenin-TCF1 pathway was important for T cell development .	Experiments in which ICAT expression was utilized to block interaction of beta-catenin with TCF1 showed that beta-catenin-TCF1 pathway was important for T cell development.	3	12	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	ICAT expression	icat	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
To determine whether beta-catenin and TCF signaling regulates VSMC proliferation via modulation of the beta-catenin and TCF responsive cell cycle genes , cyclin D1 and p21 , we inhibited beta-catenin and TCF signaling by adenoviral mediated over-expression of N-Cadherin , ICAT ( an endogenous inhibitor of beta-catenin and TCF signaling ) , or a dominant negative ( dn ) mutant of TCF-4 .	To determine whether beta-catenin and TCF signaling regulates VSMC proliferation via modulation of the beta-catenin and TCF responsive cell cycle genes, cyclin D1 and p21, we inhibited beta-catenin and TCF signaling by adenoviral mediated over-expression of N-Cadherin, ICAT (an endogenous inhibitor of beta-catenin and TCF signaling), or a dominant negative (dn) mutant of TCF-4.	38	49	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	40	41	46	47
In addition , in accordance with two other WNT and beta-catenin pathway inhibitors , niclosamide and XAV939 , ICAT inhibited WNT and beta-catenin pathway activation and exerted antitumor effects in primary cultures of human leiomyoma cells .	In addition, in accordance with two other WNT and beta-catenin pathway inhibitors, niclosamide and XAV939, ICAT inhibited WNT and beta-catenin pathway activation and exerted antitumor effects in primary cultures of human leiomyoma cells.	18	26	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	18	19	22	23
The binding site of one group of ligands was mapped to the interaction region of the translational Wnt inhibitor ICAT ( inhibitor of beta-catenin and Tcf ) , which is a prime target site on beta-catenin for therapeutic intervention , and to which no ligands could be developed before .	The binding site of one group of ligands was mapped to the interaction region of the translational Wnt inhibitor ICAT (inhibitor of beta-catenin and Tcf), which is a prime target site on beta-catenin for therapeutic intervention, and to which no ligands could be developed before.	13	33	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	19	20	23	24
Previous studies have indicated that CTNNBIP1 antagonizes Wnt and beta-catenin signaling and its downstream genes by repressing constitutively activated beta-catenin activity XREF_BIBR .	Previous studies have indicated that CTNNBIP1 antagonizes Wnt and beta-catenin signaling and its downstream genes by repressing constitutively activated beta-catenin activity XREF_BIBR.	5	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTNNBIP1	CTNNBIP1	CTNNBIP1	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
These results are consistent with our observations in vitro and suggest that miR-215 directly targets endogenous CTNNBIP1 , which inhibits Wnt and beta-catenin signaling and its downstream genes alpha-SMA and fibronectin in db/db mice in vivo .	These results are consistent with our observations in vitro and suggest that miR-215 directly targets endogenous CTNNBIP1, which inhibits Wnt and beta-catenin signaling and its downstream genes alpha-SMA and fibronectin in db/db mice in vivo.	14	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTNNBIP1	CTNNBIP1	CTNNBIP1	beta-catenin	beta-catenin	beta-catenin	16	17	22	23
ICAT can inhibit the Wnt and beta-catenin signaling pathway by binding to beta-catenin and competing with its ability to bind the transcription factor TCF [ XREF_BIBR , XREF_BIBR ] .	ICAT can inhibit the Wnt and beta-catenin signaling pathway by binding to beta-catenin and competing with its ability to bind the transcription factor TCF [XREF_BIBR, XREF_BIBR].	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
We found that Icat inhibits proliferation of colorectal tumor cells mutated in APC or beta-catenin and hepatocellular carcinoma cells mutated in AXIN : By contrast , Icat did not inhibit growth of either normal or tumor cells containing the wild-type APC , beta-catenin , and Axin genes .	We found that Icat inhibits proliferation of colorectal tumor cells mutated in APC or beta-catenin and hepatocellular carcinoma cells mutated in AXIN : By contrast, Icat did not inhibit growth of either normal or tumor cells containing the wild-type APC, beta-catenin, and Axin genes.	26	43	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Icat	Icat	Icat	beta-catenin	beta-catenin	beta-catenin	26	27	42	43
For example , mechanically activated beta-catenin downregulates PPARgamma activity XREF_BIBR , and beta-catenin is activated by mechanical stimuli XREF_BIBR .	For example, mechanically activated beta-catenin downregulates PPARgamma activity XREF_BIBR, and beta-catenin is activated by mechanical stimuli XREF_BIBR.	4	9	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	5	6	7	8
As beta-Catenin mediates repression of PPARG , this could explain the observed increase in PPARG expression in DEPP-knockdown cells , which in turn increases ROS resistance and further shuts down FOXO3 transcriptional activity .	As beta-Catenin mediates repression of PPARG, this could explain the observed increase in PPARG expression in DEPP-knockdown cells, which in turn increases ROS resistance and further shuts down FOXO3 transcriptional activity.	1	6	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-Catenin	beta-Catenin	beta-Catenin	PPARG	PPARG	PPARG	1	2	5	6
Additional negative regulators of adipocyte differentiation of BMSC include molecules in Wnt signaling pathway that consists of several ligands , receptors , co-receptors and transcriptional mediators , e.g ., beta-catenin , which blocks PPARgamma and its downstream regulated genes .	Additional negative regulators of adipocyte differentiation of BMSC include molecules in Wnt signaling pathway that consists of several ligands, receptors, co-receptors and transcriptional mediators, e.g., beta-catenin, which blocks PPARgamma and its downstream regulated genes.	25	38	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	29	30	33	34
In addition , beta-catenin interacts with and inhibits the activity of PPARgamma , the master regulator of adipogenesis [ XREF_BIBR ] .	In addition, beta-catenin interacts with and inhibits the activity of PPARgamma, the master regulator of adipogenesis [XREF_BIBR].	3	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	3	4	11	12
As a negative regulator of adipocyte differentiation , beta-catenin can directly suppress the activity of PPAR-gamma by means of the functional interaction between the TCF/LEF binding domain of beta-catenin and the catenin binding domain of PPAR-gamma XREF_BIBR , XREF_BIBR .	As a negative regulator of adipocyte differentiation, beta-catenin can directly suppress the activity of PPAR-gamma by means of the functional interaction between the TCF/LEF binding domain of beta-catenin and the catenin binding domain of PPAR-gamma XREF_BIBR, XREF_BIBR.	8	16	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPAR-gamma	PPAR-gamma	PPAR-gamma	8	9	15	16
We observed the same effect with regard to adipogenesis when cells were incubated with LiCl , which increased GSK-3beta phosphorylation and nuclear beta-catenin content and reduced nuclear content of PPAR-gamma , a fundamental regulator of adipogenesis .	We observed the same effect with regard to adipogenesis when cells were incubated with LiCl, which increased GSK-3beta phosphorylation and nuclear beta-catenin content and reduced nuclear content of PPAR-gamma, a fundamental regulator of adipogenesis.	14	33	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	LiCl, which increased GSK-3beta phosphorylation and nuclear beta-catenin	beta-catenin	PPAR-gamma	PPAR-gamma	ppar-gamma	22	23	29	30
The signalling pathways of PI3K and AKT pathway , beta-catenin , and Shh ( one of three types of protein hedgehog which regulate cell fate decision ) can mediate leptin induced inhibition of PPARgamma in HSCs 15 , 22 whereas NADPH oxidase pathway appears to play the key role in activating many signalling pathways 24 , 25 and can be induced by leptin in HSCs 26 , thus the researches were focused on these signalling pathways .	The signalling pathways of PI3K and AKT pathway, beta-catenin, and Shh (one of three types of protein hedgehog which regulate cell fate decision) can mediate leptin induced inhibition of PPARgamma in HSCs 15, 22 whereas NADPH oxidase pathway appears to play the key role in activating many signalling pathways 24, 25 and can be induced by leptin in HSCs 26, thus the researches were focused on these signalling pathways.	2	34	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	9	10	33	34
Of specific interest here was that LiCl , a Wnt and beta-catenin signaling specific activator , attenuated the FTO induced upregulation of PPARgamma and downregulation of beta-catenin .	Of specific interest here was that LiCl, a Wnt and beta-catenin signaling specific activator, attenuated the FTO induced upregulation of PPARgamma and downregulation of beta-catenin.	9	24	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	11	12	22	23
The non canonical Wnt and beta-catenin pathway , which has been associated with osteogenic differentiation , has been shown to inhibit PPARgamma transactivation by H3K9 methylation of its target genes .	The non canonical Wnt and beta-catenin pathway, which has been associated with osteogenic differentiation, has been shown to inhibit PPARgamma transactivation by H3K9 methylation of its target genes.	5	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	5	6	21	22
It has been shown that under mechanical stress beta-catenin suppresses adipocyte differentiation and PPARgamma activity through a mechanism which involves inactivation of GSK3beta , comprising of mTORC2 mediated phosphorylation of Akt protein and resulting in increased beta-catenin stability XREF_BIBR , XREF_BIBR .	It has been shown that under mechanical stress beta-catenin suppresses adipocyte differentiation and PPARgamma activity through a mechanism which involves inactivation of GSK3beta, comprising of mTORC2 mediated phosphorylation of Akt protein and resulting in increased beta-catenin stability XREF_BIBR, XREF_BIBR.	8	14	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	8	9	13	14
Constitutive activation of the Wnt and beta-catenin pathway in preadipocytes inhibits differentiation by preventing the induction of C/EBPalpha and PPARgamma [ XREF_BIBR , XREF_BIBR ] .	Constitutive activation of the Wnt and beta-catenin pathway in preadipocytes inhibits differentiation by preventing the induction of C/EBPalpha and PPARgamma [XREF_BIBR, XREF_BIBR].	4	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	6	7	19	20
Activation of Wnt and beta-catenin signaling enhances myogenesis but inhibits adipogenic transcription factors C/EBPalpha and PPARgamma and maintains pre-adipocytes in an undifferentiated state [ XREF_BIBR ] .	Activation of Wnt and beta-catenin signaling enhances myogenesis but inhibits adipogenic transcription factors C/EBPalpha and PPARgamma and maintains pre-adipocytes in an undifferentiated state [XREF_BIBR].	2	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	4	5	15	16
Stabilization of beta-catenin suppressed PPARgamma mediated adipogenic effects , but PPARgamma dependent suppression of Wnt10b was maintained and resulted in an anti-osteogenic phenotype .	Stabilization of beta-catenin suppressed PPARgamma mediated adipogenic effects, but PPARgamma dependent suppression of Wnt10b was maintained and resulted in an anti-osteogenic phenotype.	0	7	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	2	3	4	5
Here , we demonstrate that transient activation of Wnt and beta-catenin signaling rapidly suppresses C/EBPalpha and PPARgamma , followed by activation of osteoblastogenic transcription factors .	Here, we demonstrate that transient activation of Wnt and beta-catenin signaling rapidly suppresses C/EBPalpha and PPARgamma, followed by activation of osteoblastogenic transcription factors.	8	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	10	11	16	17
A balance of transcriptional activity determines the fate of MSCs , with PPARgamma promoting adipogenesis and negatively regulating Runx2 , and Runx2 promoting osteogenesis following Wnt and beta-catenin suppression of PPARgamma .	A balance of transcriptional activity determines the fate of MSCs, with PPARgamma promoting adipogenesis and negatively regulating Runx2, and Runx2 promoting osteogenesis following Wnt and beta-catenin suppression of PPARgamma.	25	31	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	27	28	30	31
In preadipocytes , constitutive activation of Wnt and beta-catenin signaling leads to maintenance of the undifferentiated state and prevents induction of C/EBPalpha and PPARgamma .	In preadipocytes, constitutive activation of Wnt and beta-catenin signaling leads to maintenance of the undifferentiated state and prevents induction of C/EBPalpha and PPARgamma.	6	24	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	8	9	23	24
Wnt and beta-catenin signaling suppresses C/EBPalpha and PPARgamma , which shifts mesenchymal cell fate toward osteoblastogenesis at the expense of adipogenesis [ XREF_BIBR , XREF_BIBR ] .	Wnt and beta-catenin signaling suppresses C/EBPalpha and PPARgamma, which shifts mesenchymal cell fate toward osteoblastogenesis at the expense of adipogenesis [XREF_BIBR, XREF_BIBR].	0	10	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	2	3	7	8
In particular it may act via stabilization and enhancement of PPAR-gamma activity , as seen in various experimental models [ XREF_BIBR - XREF_BIBR ] where the beta-catenin pathway has been shown to inhibit PPAR-gamma signaling .	In particular it may act via stabilization and enhancement of PPAR-gamma activity, as seen in various experimental models [XREF_BIBR - XREF_BIBR] where the beta-catenin pathway has been shown to inhibit PPAR-gamma signaling.	26	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPAR-gamma	PPAR-gamma	PPAR-gamma	26	27	33	34
Western blotting results showed that Am-CHS increased the expression of beta-catenin , a negative regulator in adipogenesis , and decreased that of SREBP-1c , PPARgamma and C/EBPalpha , the positive regulators of adipogenesis in the adipose tissue compared to the HFSD fed group .	Western blotting results showed that Am-CHS increased the expression of beta-catenin, a negative regulator in adipogenesis, and decreased that of SREBP-1c, PPARgamma and C/EBPalpha, the positive regulators of adipogenesis in the adipose tissue compared to the HFSD fed group.	5	25	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	Am-CHS increased the expression of beta-catenin	beta-catenin	PPARgamma	PPARgamma	ppargamma	10	11	24	25
The beta-catenin can also decrease the activity of PPAR-gamma and C/EBP-alpha by increasing CCND1 transcription XREF_BIBR , XREF_BIBR , XREF_BIBR .	The beta-catenin can also decrease the activity of PPAR-gamma and C/EBP-alpha by increasing CCND1 transcription XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	10	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPAR-gamma	PPAR-gamma	PPAR-gamma	1	2	8	9
Constitutive activation of Wnt and beta-catenin signalling in preadipocytes , inhibits differentiation , by preventing the induction of C/EBPalpha and PPARgamma .	Constitutive activation of Wnt and beta-catenin signalling in preadipocytes, inhibits differentiation, by preventing the induction of C/EBPalpha and PPARgamma.	3	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	5	6	20	21
To determine whether PPARgamma agonist induced repression of beta-catenin signaling correlated with the capacity to activate PPARgamma dependent transcription , we compared the effects of troglitazone , rosiglitazone , GW1929 and Fmoc-Leu on PPARgamma activation using a peroxisome proliferator response element ( PPRE )-driven promoter reporter , ( AOX ) 3 -TK-Luc .	To determine whether PPARgamma agonist induced repression of beta-catenin signaling correlated with the capacity to activate PPARgamma dependent transcription, we compared the effects of troglitazone, rosiglitazone, GW1929 and Fmoc-Leu on PPARgamma activation using a peroxisome proliferator response element (PPRE)-driven promoter reporter, (AOX) 3 -TK-Luc.	8	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	8	9	16	17
Moreover , we discovered a novel strategy of unlocking such mitotic block by p120 siRNA knockdown , which selectively activates p120 and Kaiso and RhoA-ROCK , but does not affect Wnt and beta-catenin signaling .	Moreover, we discovered a novel strategy of unlocking such mitotic block by p120 siRNA knockdown, which selectively activates p120 and Kaiso and RhoA-ROCK, but does not affect Wnt and beta-catenin signaling.	13	23	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	13	14	22	23
The study found that p120ctn suppresses Kaiso dependent transcription activity in human vascular ECs , providing the first evidence of a transcriptional role of p120ctn in endothelium .	The study found that p120ctn suppresses Kaiso dependent transcription activity in human vascular ECs, providing the first evidence of a transcriptional role of p120ctn in endothelium.	4	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p120ctn	p120ctn	p120ctn	Kaiso	Kaiso	Kaiso	4	5	6	7
Previous studies have reported that nuclear p120 can interact and functionally antagonize the activity of the transcriptional repressor Kaiso .	Previous studies have reported that nuclear p120 can interact and functionally antagonize the activity of the transcriptional repressor Kaiso.	5	19	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	6	7	18	19
Recent evidence has suggested that p120ctn , by binding to Kaiso , acts to relieve Kaiso mediated transcriptional repression of certain genes XREF_BIBR , and in particular , our previous study has shown that restitution of p120ctn isoform 3A induced redistribution of Kaiso from the nucleus to cytoplasm of lung cancer cells XREF_BIBR .	Recent evidence has suggested that p120ctn, by binding to Kaiso, acts to relieve Kaiso mediated transcriptional repression of certain genes XREF_BIBR, and in particular, our previous study has shown that restitution of p120ctn isoform 3A induced redistribution of Kaiso from the nucleus to cytoplasm of lung cancer cells XREF_BIBR.	5	16	relieve	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p120ctn	p120ctn	p120ctn	Kaiso	Kaiso	Kaiso	5	6	15	16
Indeed , basal Kaiso reporter activity in PMC-1 cells was significantly reduced compared to mILC cell lines , suggesting that p120 antagonizes Kaiso mediated transcriptional repression ( XREF_FIG ) .	Indeed, basal Kaiso reporter activity in PMC-1 cells was significantly reduced compared to mILC cell lines, suggesting that p120 antagonizes Kaiso mediated transcriptional repression (XREF_FIG).	20	23	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	20	21	22	23
Although it is still largely unknown how p120 transverses the nuclear pore and what factors mediate this transport , our observations support previous data showing that p120 relieves Kaiso mediated transcriptional repression .	Although it is still largely unknown how p120 transverses the nuclear pore and what factors mediate this transport, our observations support previous data showing that p120 relieves Kaiso mediated transcriptional repression.	26	29	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	26	27	28	29
Because Kaiso transcript was also lowered by p120 siRNA ( XREF_FIG ) , we would like to rule out whether the use of Kaiso siRNA , which decreased Kaiso transcript and protein , but to a less extent ( XREF_SUPPLEMENTARY A , B ) , could have indirectly contributed the aforementioned effect by p120 siRNA .	Because Kaiso transcript was also lowered by p120 siRNA (XREF_FIG), we would like to rule out whether the use of Kaiso siRNA, which decreased Kaiso transcript and protein, but to a less extent (XREF_SUPPLEMENTARY A, B), could have indirectly contributed the aforementioned effect by p120 siRNA.	1	8	lowered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	7	8	1	2
Kaiso inhibits beta-catenin and TCF activation of target genes , and CTNND1 inhibits Kaiso activity .	Kaiso inhibits beta-catenin and TCF activation of target genes, and CTNND1 inhibits Kaiso activity.	11	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTNND1	CTNND1	CTNND1	Kaiso	Kaiso	Kaiso	11	12	13	14
In the current study , the loss of p120ctn activated Kaiso , NFkappaB and AP-1 activities , clearly indicating that regulation of transcriptional events was not limited to Kaiso .	In the current study, the loss of p120ctn activated Kaiso, NFkappaB and AP-1 activities, clearly indicating that regulation of transcriptional events was not limited to Kaiso.	6	18	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p120ctn	loss of p120ctn	p120ctn	Kaiso	Kaiso	kaiso	8	9	10	11
The finding that p120 siRNA knockdown activates p120 and Kaiso signaling was supported by a dramatic shift of its cytolocalization from the junction and membrane to the nucleus , where it was correlated with the release of nuclear Kaiso ( XREF_FIG ) .	The finding that p120 siRNA knockdown activates p120 and Kaiso signaling was supported by a dramatic shift of its cytolocalization from the junction and membrane to the nucleus, where it was correlated with the release of nuclear Kaiso (XREF_FIG).	3	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	3	4	9	10
Analogous to beta-catenin relief of TCF repressive activity , we show that p120-catenin relieves Kaiso mediated repression of Siamois .	Analogous to beta-catenin relief of TCF repressive activity, we show that p120-catenin relieves Kaiso mediated repression of Siamois.	12	15	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p120-catenin	p120-catenin	p120-catenin	Kaiso	Kaiso	Kaiso	12	13	14	15
Besides that , cytoplasmic p120-catenin sequesters the nuclear transcriptional modulator Kaiso , which thus exhibits a cytoplasmic mislocalization , once E-cadherin is lost XREF_BIBR .	Besides that, cytoplasmic p120-catenin sequesters the nuclear transcriptional modulator Kaiso, which thus exhibits a cytoplasmic mislocalization, once E-cadherin is lost XREF_BIBR.	3	14	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p120-catenin	p120-catenin	p120-catenin	Kaiso	Kaiso	Kaiso	4	5	10	11
Kaiso dependent transcriptional repression is inhibited by nuclear p120 in mILC .	Kaiso dependent transcriptional repression is inhibited by nuclear p120 in mILC.	0	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	8	9	0	1
alphaE-catenin negatively regulates Yap1 nuclear localization .	alphaE-catenin negatively regulates Yap1 nuclear localization.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	alphaE-catenin	alphaE-catenin	alphaE-catenin	Yap1	Yap1	Yap1	0	1	3	4
To analyze whether alphaE-catenin inhibits Yap1 transcriptional activity , we performed Yap1 transcription coactivation assays with the TEAD family of transcription factors .	To analyze whether alphaE-catenin inhibits Yap1 transcriptional activity, we performed Yap1 transcription coactivation assays with the TEAD family of transcription factors.	3	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	alphaE-catenin	alphaE-catenin	alphaE-catenin	Yap1	Yap1	Yap1	3	4	5	6
In gain-of-function experiments in HEK293 cells , overexpression of alphaE-catenin significantly decreased Yap1 mediated transcriptional activity in a dose dependent manner ( XREF_FIG ) .	In gain-of-function experiments in HEK293 cells, overexpression of alphaE-catenin significantly decreased Yap1 mediated transcriptional activity in a dose dependent manner (XREF_FIG).	7	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	alphaE-catenin	overexpression of alphaE-catenin	alphae-catenin	Yap1	Yap1	yap1	9	10	12	13
We reasoned that if alphaE-catenin inhibits nuclear localization of Yap1 , human keratoacanthoma tumors with low abundance of alphaE-catenin should show increased nuclear Yap1 .	We reasoned that if alphaE-catenin inhibits nuclear localization of Yap1, human keratoacanthoma tumors with low abundance of alphaE-catenin should show increased nuclear Yap1.	4	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	alphaE-catenin	alphaE-catenin	alphaE-catenin	Yap1	Yap1	Yap1	4	5	9	10
Accommodating the conflicting requirements that XIAP be sufficiently abundant to fully block C3 * in the pre-MOMP interval and that XIAP be efficiently sequestered by cytosolic Smac following MOMP involved careful adjustment of species concentrations and reaction rates , a fragility that implies the existence of additional as-yet unknown regulatory processes [ XREF_BIBR ] .	Accommodating the conflicting requirements that XIAP be sufficiently abundant to fully block C3 * in the pre-MOMP interval and that XIAP be efficiently sequestered by cytosolic Smac following MOMP involved careful adjustment of species concentrations and reaction rates, a fragility that implies the existence of additional as-yet unknown regulatory processes [XREF_BIBR].	20	31	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	26	27	20	21
It was also shown that mitochondrial release of Smac , upon threshold Bax activation , can inhibit XIAP and thus modulates the type 1/type 2 choice in apoptosis activation [ XREF_BIBR ] .	It was also shown that mitochondrial release of Smac, upon threshold Bax activation, can inhibit XIAP and thus modulates the type 1/type 2 choice in apoptosis activation [XREF_BIBR].	6	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	8	9	17	18
Smac release disrupts the interaction of XIAP with caspase 9 and caspase 3 XREF_BIBR , leading to activation of these caspases and subsequent apoptosis .	Smac release disrupts the interaction of XIAP with caspase 9 and caspase 3 XREF_BIBR, leading to activation of these caspases and subsequent apoptosis.	0	7	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	0	1	6	7
We selected a monovalent SMAC mimetic GDC-0152 described to antagonize cIAP1 , cIAP2 , XIAP and , above all , ML-IAP .	We selected a monovalent SMAC mimetic GDC-0152 described to antagonize cIAP1, cIAP2, XIAP and, above all, ML-IAP.	4	20	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	4	5	14	15
Caspase independent mitochondrial SMAC release in response to cytostatic agents diminishes the anti-apoptotic potential of XIAP .	Caspase independent mitochondrial SMAC release in response to cytostatic agents diminishes the anti-apoptotic potential of XIAP.	3	16	diminishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	3	4	15	16
But if SMAC is not able to down-regulates XIAP , there will be less apoptosis and so more chances of cancer [ XREF_BIBR ] .	But if SMAC is not able to down-regulates XIAP, there will be less apoptosis and so more chances of cancer [XREF_BIBR].	2	9	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	2	3	8	9
The release of Smac has been modeled to inhibit anti-apoptotic XIAP proteins .	The release of Smac has been modeled to inhibit anti-apoptotic XIAP proteins.	1	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	3	4	10	11
Birinapant , a novel SMAC mimetic , sensitized multiple HNSCC lines to cell death by agonists TNFalpha or TRAIL , and inhibited cIAP1 > XIAP > IAP2 .	Birinapant, a novel SMAC mimetic, sensitized multiple HNSCC lines to cell death by agonists TNFalpha or TRAIL, and inhibited cIAP1> XIAP> IAP2.	0	26	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	4	5	24	25
Depletion of SRSF2 also resulted in decreased expression of proapoptotic Smac3 ( a splice variant of DIABLO that inhibits XIAP ( X linked inhibitor of apoptosis ) [ XREF_BIBR ] ) , Surv-2B , MCL-1S , and BimS .	Depletion of SRSF2 also resulted in decreased expression of proapoptotic Smac3 (a splice variant of DIABLO that inhibits XIAP (X linked inhibitor of apoptosis) [XREF_BIBR]), Surv-2B, MCL-1S, and BimS.	14	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DIABLO	DIABLO	DIABLO	XIAP	XIAP	XIAP	16	17	19	20
SMAC binds to and inhibits the anti-apoptotic protein XIAP XREF_BIBR , XREF_BIBR , while CytoC activates Caspase 9 to induce the execution of downstream apoptotic events .	SMAC binds to and inhibits the anti-apoptotic protein XIAP XREF_BIBR, XREF_BIBR, while CytoC activates Caspase 9 to induce the execution of downstream apoptotic events.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	0	1	8	9
Smac mediated inhibition of XIAP , a protein that negatively regulates active caspase-3/7 , and apoptosome mediated cleavage of pro-caspase-3/7 generates a burst of active effector caspase able to cleave essential cellular substrates and cause cell death .	Smac mediated inhibition of XIAP, a protein that negatively regulates active caspase-3/7, and apoptosome mediated cleavage of pro-caspase-3/7 generates a burst of active effector caspase able to cleave essential cellular substrates and cause cell death.	0	7	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	0	1	4	5
Smac mimetic Inhibitors of XIAP , c-IAP-1 , and c-IAP-2 can induce significant cell death in some cancer cell lines .	Smac mimetic Inhibitors of XIAP, c-IAP-1, and c-IAP-2 can induce significant cell death in some cancer cell lines.	0	9	Inhibitors	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	0	1	4	5
Since Smac triggers the proteasomal degradation of XIAP , MAP activation resulted in XIAP stabilization .	Since Smac triggers the proteasomal degradation of XIAP, MAP activation resulted in XIAP stabilization.	1	8	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	1	2	7	8
Cytosolic Smac promotes degradation of cIAP1 and XIAP , further enhancing ripoptosome formation and activation in an amplification loop .	Cytosolic Smac promotes degradation of cIAP1 and XIAP, further enhancing ripoptosome formation and activation in an amplification loop.	0	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	1	2	7	8
These data provide strong evidence that Smac mimetics induce apoptosis in tumor cells by concurrently targeting cIAP-1/2 and XIAP , suggesting that XIAP and cIAP-1/2 are important cellular targets for Smac mimetics .	These data provide strong evidence that Smac mimetics induce apoptosis in tumor cells by concurrently targeting cIAP-1/2 and XIAP, suggesting that XIAP and cIAP-1/2 are important cellular targets for Smac mimetics.	6	19	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	6	7	18	19
The XIAP BIR3 protein effectively inhibits the activity of caspase-3/-7, and these Smac mimetics dose-dependently antagonize XIAP and restore caspase activity ( XREF_FIG and XREF_SUPPLEMENTARY ) .	The XIAP BIR3 protein effectively inhibits the activity of caspase-3/-7, and these Smac mimetics dose-dependently antagonize XIAP and restore caspase activity (XREF_FIG and XREF_SUPPLEMENTARY).	12	17	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	12	13	16	17
Since Smac mimetics such as BV6 antagonize XIAP in addition to cIAP1 and cIAP2 proteins , the Smac mimetic induced release of XIAP mediated inhibition of caspase-9 , -7 and -3 results in enforced caspase activation .	Since Smac mimetics such as BV6 antagonize XIAP in addition to cIAP1 and cIAP2 proteins, the Smac mimetic induced release of XIAP mediated inhibition of caspase-9, -7 and -3 results in enforced caspase activation.	16	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	17	18	22	23
Because Smac binds with XIAP leading to the induction of apoptotic cell death [ XREF_BIBR ] , various Smac mimetics have been developed to inhibit prosurvival function of XIAP , which could have significance in cancer therapy [ XREF_BIBR - XREF_BIBR ] .	Because Smac binds with XIAP leading to the induction of apoptotic cell death [XREF_BIBR], various Smac mimetics have been developed to inhibit prosurvival function of XIAP, which could have significance in cancer therapy [XREF_BIBR - XREF_BIBR].	18	32	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	18	19	28	29
As Smac ( second mitochondria derived activator of caspase ) is an endogenous antagonist of XIAP , PPI between XIAP and Smac can be used to design a platform to search for small-molecule Smac mimics .	As Smac (second mitochondria derived activator of caspase) is an endogenous antagonist of XIAP, PPI between XIAP and Smac can be used to design a platform to search for small-molecule Smac mimics.	1	16	is an endogenous antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	1	2	15	16
If retained inside mitochondria , Smac would not impair cytosolic XIAP function .	If retained inside mitochondria, Smac would not impair cytosolic XIAP function.	5	11	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	5	6	10	11
The bivalent Smac mimetic BV6 that antagonizes XIAP , cIAP1 and cIAP2 6 was kindly provided by Genentech Inc. ( South San Francisco , CA , USA ) and Enbrel by Pfizer ( Berlin , Germany ) .	The bivalent Smac mimetic BV6 that antagonizes XIAP, cIAP1 and cIAP2 6 was kindly provided by Genentech Inc. (South San Francisco, CA, USA) and Enbrel by Pfizer (Berlin, Germany).	2	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	2	3	7	8
In summary , using a rational design approach we have systematically optimized small molecule monovalent Smac mimetics that inhibit XIAP by binding preferentially to the BIR2 domain .	In summary, using a rational design approach we have systematically optimized small molecule monovalent Smac mimetics that inhibit XIAP by binding preferentially to the BIR2 domain.	15	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	15	16	19	20
Smac promotes caspase activation by binding the inhibitors of apoptosis proteins ( IAP ) , particularly XIAP and eliminating their inhibitory activity .	Smac promotes caspase activation by binding the inhibitors of apoptosis proteins (IAP), particularly XIAP and eliminating their inhibitory activity.	0	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	0	1	16	17
In cancer cells where XIAP is over expressed Smac levels may be insufficient to block XIAP activity , and this disturbed XIAP and Smac balance may contribute to apoptotic resistance .	In cancer cells where XIAP is over expressed Smac levels may be insufficient to block XIAP activity, and this disturbed XIAP and Smac balance may contribute to apoptotic resistance.	8	16	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac levels	smac	XIAP	XIAP	xiap	8	9	15	16
However , the inhibition of the apoptosome associated CS-9 by XIAP can be reverted by Smac protein , which sequesters XIAP and relieves CS-9 to activate PC-3 to CS-3 .	However, the inhibition of the apoptosome associated CS-9 by XIAP can be reverted by Smac protein, which sequesters XIAP and relieves CS-9 to activate PC-3 to CS-3.	15	21	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	15	16	20	21
The SMAC mimetic RMT5265.2 HCL induces apoptosis in EBV AND HTLV-I associated lymphoma cells by inhibiting XIAP and promoting the mitochondrial release of cytochrome C and Smac .	The SMAC mimetic RMT5265.2 HCL induces apoptosis in EBV AND HTLV-I associated lymphoma cells by inhibiting XIAP and promoting the mitochondrial release of cytochrome C and Smac.	1	17	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	1	2	16	17
Although the exact mechanism by which Smac inhibits XIAP is being elucidated , multiple lines of evidence from structural studies indicate that Smac in dimeric conformation , utilizes its tetrapeptide region harboring alanine , valine , proline and isoleucine ( AVPI ) to interact with BIR2 or BIR3 domains of XIAP .	Although the exact mechanism by which Smac inhibits XIAP is being elucidated, multiple lines of evidence from structural studies indicate that Smac in dimeric conformation, utilizes its tetrapeptide region harboring alanine, valine, proline and isoleucine (AVPI) to interact with BIR2 or BIR3 domains of XIAP.	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	6	7	8	9
Sensitivity analyses predicted a critical role for caspase-3-dependent feedback signalling and the X-linked-inhibitor-of-apoptosis-protein ( XIAP ) , but a less prominent role for the XIAP antagonist Smac .	Sensitivity analyses predicted a critical role for caspase-3-dependent feedback signalling and the X-linked-inhibitor-of-apoptosis-protein (XIAP), but a less prominent role for the XIAP antagonist Smac.	21	27	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	26	27	24	25
145 One proposed mechanism of enhanced XIAP activity involves co-expression of survivin , another IAP family member , which can bind to SMAC to block SMAC mediated inhibition of XIAP .	145 One proposed mechanism of enhanced XIAP activity involves co-expression of survivin, another IAP family member, which can bind to SMAC to block SMAC mediated inhibition of XIAP.	25	30	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	25	26	29	30
The crystal structure of the XIAP BIR3 domain in complex with the SMAC AVPI peptide has been determined and is being used to design SMAC mimetics that potently inhibit XIAP , cIAP1 , cIAP2 and ML-IAP [ XREF_BIBR , XREF_BIBR ] .	The crystal structure of the XIAP BIR3 domain in complex with the SMAC AVPI peptide has been determined and is being used to design SMAC mimetics that potently inhibit XIAP, cIAP1, cIAP2 and ML-IAP [XREF_BIBR, XREF_BIBR].	24	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	24	25	29	30
Monovalent Smac mimetics based on the AVPI tetrapeptide have previously been shown to inhibit the interaction of XIAP with caspase-9 by binding to the XIAP BIR3 domain .	Monovalent Smac mimetics based on the AVPI tetrapeptide have previously been shown to inhibit the interaction of XIAP with caspase-9 by binding to the XIAP BIR3 domain.	1	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	1	2	17	18
The fully human agonist monoclonal TRAIL-R2 antibody Drozitumab 19 and the bivalent Smac mimetic BV6 that potently antagonizes XIAP , cIAP1 and cIAP2 9 were kind gifts from Genentech ( South San Francisco , CA , USA ) .	The fully human agonist monoclonal TRAIL-R2 antibody Drozitumab 19 and the bivalent Smac mimetic BV6 that potently antagonizes XIAP, cIAP1 and cIAP2 9 were kind gifts from Genentech (South San Francisco, CA, USA).	12	22	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	12	13	18	19
Upon activation of the mitochondria through Bax and Bak , SMAC , released into the cytosol , inhibits XIAP and prevents degradation of caspase-3 subunits resulting in strong caspase-3 activation ( XREF_FIG ) .	Upon activation of the mitochondria through Bax and Bak, SMAC, released into the cytosol, inhibits XIAP and prevents degradation of caspase-3 subunits resulting in strong caspase-3 activation (XREF_FIG).	10	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	10	11	18	19
Recently , XIAP associated factor 1 ( XAF1 ) and two mitochondrial proteins , Smac / DIABLO and HtrA2 , have been identified to negatively regulate the caspase inhibiting activity of XIAP .	Recently, XIAP associated factor 1 (XAF1) and two mitochondrial proteins, Smac / DIABLO and HtrA2, have been identified to negatively regulate the caspase inhibiting activity of XIAP.	4	32	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	14	15	31	32
We show that the RIPK2 binding site in XIAP overlaps with the BIR2 IBM binding pocket and find that a bivalent Smac mimetic compound ( SMC ) potently antagonises XIAP function downstream of NOD2 to limit signalling .	We show that the RIPK2 binding site in XIAP overlaps with the BIR2 IBM binding pocket and find that a bivalent Smac mimetic compound (SMC) potently antagonises XIAP function downstream of NOD2 to limit signalling.	21	30	antagonises	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	21	22	29	30
Smac mimetic compounds antagonize XIAP function to inhibit NOD1/2 dependent immune signaling .	Smac mimetic compounds antagonize XIAP function to inhibit NOD1/2 dependent immune signaling.	0	5	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	0	1	4	5
Mitochondrial Smac release inhibited XIAP and assisted type 1 activation to proceed .	Mitochondrial Smac release inhibited XIAP and assisted type 1 activation to proceed.	1	5	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	1	2	4	5
If , indeed , the mitochondrial release of SMAC was responsible for the neutralisation of XIAP , then downregulation of SMAC should restore the caspase-inhibitory function of XIAP and increase resistance towards cytostatic agents .	If, indeed, the mitochondrial release of SMAC was responsible for the neutralisation of XIAP, then downregulation of SMAC should restore the caspase-inhibitory function of XIAP and increase resistance towards cytostatic agents.	18	30	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	20	21	27	28
These studies demonstrated that SMAC inhibits XIAP through interaction of a four-amino-acid peptide motif ( AVPI ) on SMAC with the BIR3 domain of XIAP .	These studies demonstrated that SMAC inhibits XIAP through interaction of a four-amino-acid peptide motif (AVPI) on SMAC with the BIR3 domain of XIAP.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	4	5	6	7
SMAC and Omi and HtrA2 then antagonize the inflammatory action of XIAP .	SMAC and Omi and HtrA2 then antagonize the inflammatory action of XIAP.	0	12	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	0	1	11	12
In type II HCT116 cells , by contrast , the key role of MOMP in extrinsic apoptosis is to cause Smac dependent inhibition of XIAP .	In type II HCT116 cells, by contrast, the key role of MOMP in extrinsic apoptosis is to cause Smac dependent inhibition of XIAP.	20	25	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	20	21	24	25
Moreover , the authors used the bivalent SMAC mimetic BV6 described to antagonize cIAP1 , cIAP2 and XIAP .	Moreover, the authors used the bivalent SMAC mimetic BV6 described to antagonize cIAP1, cIAP2 and XIAP.	7	18	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	7	8	17	18
On the other hand , Smac blocks XIAP by concurrently binding to its BIR2 and BIR3 domains as a homodimer , thus removing the ability of XIAP to inhibit caspases .	On the other hand, Smac blocks XIAP by concurrently binding to its BIR2 and BIR3 domains as a homodimer, thus removing the ability of XIAP to inhibit caspases.	5	8	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	5	6	7	8
However , Smac mimetic BV6 , which antagonizes XIAP , cIAP1 , and cIAP2 , together with the demethylating agent 5-azacytidine or 5-aza-2 '-deoxycytidine can induce cell death more efficiently in otherwise resistant AML cells .	However, Smac mimetic BV6, which antagonizes XIAP, cIAP1, and cIAP2, together with the demethylating agent 5-azacytidine or 5-aza-2 '-deoxycytidine can induce cell death more efficiently in otherwise resistant AML cells.	2	13	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	2	3	8	9
XREF_BIBR - XREF_BIBR Smac mimetics can induce rapid degradation of cIAP1 and cIAP2 in cells and antagonize the functions of XIAP in functional assays .	XREF_BIBR - XREF_BIBR Smac mimetics can induce rapid degradation of cIAP1 and cIAP2 in cells and antagonize the functions of XIAP in functional assays.	3	21	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	3	4	20	21
XREF_BIBR , XREF_BIBR SMAC released from mitochondria during apoptosis inactivates XIAP , an inhibitor of caspases-3 , -7 and -9 , further activating these caspases .	XREF_BIBR, XREF_BIBR SMAC released from mitochondria during apoptosis inactivates XIAP, an inhibitor of caspases-3, -7 and -9, further activating these caspases.	0	22	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	3	4	10	11
However , some SMAC mimetics additionally block XIAP activation of the NOD signally pathway , suggesting some potential immunocompetence in treating cancer patients with SMAC mimetics .	However, some SMAC mimetics additionally block XIAP activation of the NOD signally pathway, suggesting some potential immunocompetence in treating cancer patients with SMAC mimetics.	3	8	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	3	4	7	8
In the cytoplasm , Smac relieves the XIAP associated inhibition of the caspases by binding XIAP ' s BIR domains and by promoting their auto-ubiquitination and rapid degradation [ XREF_BIBR , XREF_BIBR ] .	In the cytoplasm, Smac relieves the XIAP associated inhibition of the caspases by binding XIAP 's BIR domains and by promoting their auto-ubiquitination and rapid degradation [XREF_BIBR, XREF_BIBR].	4	8	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	4	5	7	8
XREF_BIBR - XREF_BIBR Smac , the second mitochondria derived activator of caspases , is an endogenous antagonist of cIAP1/2 and XIAP .	XREF_BIBR - XREF_BIBR Smac, the second mitochondria derived activator of caspases, is an endogenous antagonist of cIAP1/2 and XIAP.	2	21	is an endogenous antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	3	4	20	21
Furthermore , the Smac mimetics in combination with TRAIL induced the degradation of cIAP1 and XIAP and thus induced apoptosis in vitro and in vivo .	Furthermore, the Smac mimetics in combination with TRAIL induced the degradation of cIAP1 and XIAP and thus induced apoptosis in vitro and in vivo.	3	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	3	4	15	16
Combined treatment with imatinib ( IM ) and YM155 had significant agonistic antiproliferative effects in imatinib resistant GIST48 ( p = 0,006 , compared to single YM and IM ) , imatinib resistant GIST430-654 ( p < 0,001 , compared to single YM ) and imatinib sensitive GIST430 ( p = 0,01 compared to single IM , Figure XREF_FIG ) , whereas only minor increase of apoptosis , as measured by PARP cleavage , was observed SMAC mimetics downregulate XIAP and induce apoptosis .	Combined treatment with imatinib (IM) and YM155 had significant agonistic antiproliferative effects in imatinib resistant GIST48 (p = 0,006, compared to single YM and IM), imatinib resistant GIST430-654 (p < 0,001, compared to single YM) and imatinib sensitive GIST430 (p = 0,01 compared to single IM, Figure XREF_FIG), whereas only minor increase of apoptosis, as measured by PARP cleavage, was observed SMAC mimetics downregulate XIAP and induce apoptosis.	76	80	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	76	77	79	80
One suggested mechanism has proposed that Survivin can bind to Smac , thereby neutralizing the inhibition of XIAP by Smac .	One suggested mechanism has proposed that Survivin can bind to Smac, thereby neutralizing the inhibition of XIAP by Smac.	13	20	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	19	20	17	18
We did not observe any significant change in the expression of Smac by PEITC treatment indicating Smac independent suppression of XIAP in our model .	We did not observe any significant change in the expression of Smac by PEITC treatment indicating Smac independent suppression of XIAP in our model.	16	23	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	16	17	20	21
Because DIABLO inhibits XIAP only when it is released from mitochondria to enter the cytosol , we fractionated iPSC-CMs to obtain both mitochondrial and mitochondria-free cytosolic fractions , followed by western blotting to detect DIABLO in each fraction ( XREF_FIG C , right panel ) .	Because DIABLO inhibits XIAP only when it is released from mitochondria to enter the cytosol, we fractionated iPSC-CMs to obtain both mitochondrial and mitochondria-free cytosolic fractions, followed by western blotting to detect DIABLO in each fraction (XREF_FIG C, right panel).	1	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DIABLO	DIABLO	DIABLO	XIAP	XIAP	XIAP	1	2	3	4
Conversely , Smac , when released from the mitochondria , inhibits XIAP and thus the positive sign of sensitivity with respect to the mitochondrial store of Smac , Smac m , agrees with its pro apoptotic nature .	Conversely, Smac, when released from the mitochondria, inhibits XIAP and thus the positive sign of sensitivity with respect to the mitochondrial store of Smac, Smac m, agrees with its pro apoptotic nature.	2	31	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	2	3	11	12
When XIAP was highly expressed ( ~ 90 nM ) , type 1 activation was observed to proceed only after XIAP was inhibited by mitochondrial Smac release ( XREF_FIG f ) [ XREF_BIBR ] .	When XIAP was highly expressed (~ 90 nM), type 1 activation was observed to proceed only after XIAP was inhibited by mitochondrial Smac release (XREF_FIG f) [XREF_BIBR].	20	26	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	25	26	20	21
Rather , knockdown of the XIAP antagonist Smac resulted in enhanced caspase-3 degradation after stimulation of cells with TRAIL .	Rather, knockdown of the XIAP antagonist Smac resulted in enhanced caspase-3 degradation after stimulation of cells with TRAIL.	2	8	antagonist	Negative_activation_token_1_noun	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	7	8	5	6
Smac and inhibitors of apoptosis ( IAPs ) such as X linked IAP ( XIAP ) establish an additional layer of regulation in the intrinsic pathway : XIAP inhibits the catalytic activities of Casp9 and Casp3 through reversible binding , and cytosolic Smac relieves this inhibition by sequestering XIAP away from caspases [ XREF_BIBR ] .	Smac and inhibitors of apoptosis (IAPs) such as X linked IAP (XIAP) establish an additional layer of regulation in the intrinsic pathway : XIAP inhibits the catalytic activities of Casp9 and Casp3 through reversible binding, and cytosolic Smac relieves this inhibition by sequestering XIAP away from caspases [XREF_BIBR].	41	49	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	42	43	48	49
Birinapant is a SMAC mimetic that demonstrated activity in FADD and IAP amplified tumor models in combination with death factors TNF and TRAIL , and radiation.52 Seven patients with HNSCC out of a cohort of 50 patients were treated with the bivalent SMAC mimetic with dose range of 0.18 to 63 mg/m3 in a 3 +3 dose escalation design once weekly , defining a phase II dose.53 Debio 1143 is SMAC mimetic that antagonizes IAP activity ( XIAP , cIAP-1 , 2 , and ML-IAP ) and promotes apoptosis .	Birinapant is a SMAC mimetic that demonstrated activity in FADD and IAP amplified tumor models in combination with death factors TNF and TRAIL, and radiation.52 Seven patients with HNSCC out of a cohort of 50 patients were treated with the bivalent SMAC mimetic with dose range of 0.18 to 63 mg/m3 in a 3 +3 dose escalation design once weekly, defining a phase II dose.53 Debio 1143 is SMAC mimetic that antagonizes IAP activity (XIAP, cIAP-1, 2, and ML-IAP) and promotes apoptosis.	70	84	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	70	71	77	78
Caspases-9 , -3 and -7 can be inhibited by XIAP , which itself is inhibited by Smac .	Caspases-9, -3 and -7 can be inhibited by XIAP, which itself is inhibited by Smac.	7	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	16	17	9	10
To determine if endogenous Smac is able to inhibit XIAP and permit apoptosis in cardiomyocytes , isolated neonatal rat cardiomyocytes were transfected with the tBid-GFP plasmid and GFP or GFP alone .	To determine if endogenous Smac is able to inhibit XIAP and permit apoptosis in cardiomyocytes, isolated neonatal rat cardiomyocytes were transfected with the tBid-GFP plasmid and GFP or GFP alone.	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	4	5	9	10
SMAC/DIABLO ( SMAC ) is released during MOMP to the cytosol , where it is able to inactivate the caspase inhibitor XIAP XREF_BIBR .	SMAC/DIABLO (SMAC) is released during MOMP to the cytosol, where it is able to inactivate the caspase inhibitor XIAP XREF_BIBR.	0	22	inactivate	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	SMAC/DIABLO	SMAC/DIABLO (SMAC) is released during MOMP to the cytosol	smac/diablo	XIAP	XIAP	xiap	0	1	21	22
Our recent study further shows that Smac mimetics induce apoptosis in tumor cells by targeting not only cIAP-1/2 but also XIAP .	Our recent study further shows that Smac mimetics induce apoptosis in tumor cells by targeting not only cIAP-1/2 but also XIAP.	6	21	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	6	7	20	21
In turn , XIAP is blocked by DIABLO , thus facilitating apoptosis progression .	In turn, XIAP is blocked by DIABLO, thus facilitating apoptosis progression.	3	8	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	DIABLO	DIABLO	DIABLO	XIAP	XIAP	XIAP	7	8	3	4
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR It has been proposed that Smac protein binds to XIAP BIR2 via its AVPI motif , preventing the binding of XIAP to caspase-3/-7.	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR It has been proposed that Smac protein binds to XIAP BIR2 via its AVPI motif, preventing the binding of XIAP to caspase-3/-7.	12	28	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	12	13	27	28
Although most of the research efforts have been focused on the design of small molecule inhibitors targeting either the BIR2 or BIR3 domain in XIAP , one study has shown that a bivalent , small molecule Smac mimetic antagonizes XIAP with a potency equal or greater than that of the Smac protein in a cell-free functional assay .	Although most of the research efforts have been focused on the design of small molecule inhibitors targeting either the BIR2 or BIR3 domain in XIAP, one study has shown that a bivalent, small molecule Smac mimetic antagonizes XIAP with a potency equal or greater than that of the Smac protein in a cell-free functional assay.	31	42	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	36	37	39	40
However , these authors also show that low concentrations of TNF can also induce neutrophil cell death when cIAPs alone , or both cIAPs and XIAP , are blocked by Smac mimetics 31 .	However, these authors also show that low concentrations of TNF can also induce neutrophil cell death when cIAPs alone, or both cIAPs and XIAP, are blocked by Smac mimetics 31.	18	31	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	30	31	25	26
We also realised that SMAC down-regulates XIAP and XIAP down-regulates Casp3 , a pro apoptotic protein .	We also realised that SMAC down-regulates XIAP and XIAP down-regulates Casp3, a pro apoptotic protein.	4	8	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	4	5	6	7
Smac promotes apoptosis by repressing the anticaspase activity of XIAP , thereby inducing the enzymatic activity of mature caspase-3 .	Smac promotes apoptosis by repressing the anticaspase activity of XIAP, thereby inducing the enzymatic activity of mature caspase-3.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	0	1	9	10
During apoptosis , XIAP is antagonized by SMAC , which is released from the mitochondria upon caspase mediated activation of BID .	During apoptosis, XIAP is antagonized by SMAC, which is released from the mitochondria upon caspase mediated activation of BID.	3	11	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	7	8	3	4
Molecular analysis further revealed that DEPTOR inhibited the activation of AKT and mTOR pathway , indicating DEPTOR might control the progression of ESCC by downregulating this signaling pathway .	Molecular analysis further revealed that DEPTOR inhibited the activation of AKT and mTOR pathway, indicating DEPTOR might control the progression of ESCC by downregulating this signaling pathway.	5	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	5	6	12	13
Cardiac specific reduction of DEPTOR expression in p38gamma and delta -/- mice was confirmed by western blot and was sufficient to restore mTOR activation ( XREF_FIG ) .	Cardiac specific reduction of DEPTOR expression in p38gamma and delta -/- mice was confirmed by western blot and was sufficient to restore mTOR activation (XREF_FIG).	4	23	restore	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR expression	deptor	mTOR	mTOR	mtor	4	5	22	23
And in KYSE-510 cells , knockout of DEPTOR expression significantly enhanced the activation of AKT and mTOR pathway .	And in KYSE-510 cells, knockout of DEPTOR expression significantly enhanced the activation of AKT and mTOR pathway.	7	17	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR expression	deptor	mTOR	mTOR	mtor	7	8	16	17
mTORC1 is a multi-subunit protein kinase complex that , in addition to the core kinase mTOR , includes the large adaptor subunit RAPTOR ( KOG1 in yeast ) , which is thought to mediate substrate binding and subcellular localization of the complex ; two components , PRAS40 and DEPTOR , that inhibit intrinsic mTOR kinase activity , and G protein beta subunit like mLST8 , whose function remains obscure .	mTORC1 is a multi-subunit protein kinase complex that, in addition to the core kinase mTOR, includes the large adaptor subunit RAPTOR (KOG1 in yeast), which is thought to mediate substrate binding and subcellular localization of the complex; two components, PRAS40 and DEPTOR, that inhibit intrinsic mTOR kinase activity, and G protein beta subunit like mLST8, whose function remains obscure.	44	55	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	48	49	53	54
Activating mTOR signaling by DEPTOR silencing successfully attenuated leucine deprivation induced IGFBP-1 secretion ( +400 % ) ( XREF_FIG ) but was unable to prevent leucine deprivation induced phosphorylation ( Ser101 , +2000 % , Ser119 , +1000 % and Ser169 , +2300 % ) of IGFBP-1 at all three phosphosites ( XREF_FIG ) .	Activating mTOR signaling by DEPTOR silencing successfully attenuated leucine deprivation induced IGFBP-1 secretion (+400%) (XREF_FIG) but was unable to prevent leucine deprivation induced phosphorylation (Ser101, +2000%, Ser119, +1000% and Ser169, +2300%) of IGFBP-1 at all three phosphosites (XREF_FIG).	1	5	signaling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	4	5	1	2
Consistently , cardiac specific overexpression of DEPTOR in WT mice resulted in reduced mTOR activation and lower heart mass , correlating with the presence of cardiomyocytes of below-normal size , determined from cell cross-sectional area on histological sections ( XREF_FIG ) .	Consistently, cardiac specific overexpression of DEPTOR in WT mice resulted in reduced mTOR activation and lower heart mass, correlating with the presence of cardiomyocytes of below-normal size, determined from cell cross-sectional area on histological sections (XREF_FIG).	4	15	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	DEPTOR	overexpression of DEPTOR	deptor	mTOR	mTOR	mtor	6	7	13	14
DEPTOR , also known as DEPDC6 , directly suppresses mTOR by interacting with the FAT domain of mTOR via a PDZ ( postsynaptic density 95 , discs large , zonula occludens-1 ) domain located at its C-terminus .	DEPTOR, also known as DEPDC6, directly suppresses mTOR by interacting with the FAT domain of mTOR via a PDZ (postsynaptic density 95, discs large, zonula occludens-1) domain located at its C-terminus.	0	10	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	0	1	9	10
Thus , we demontrated that DEPTOR negatively regulated the activation of AKT and mTOR pathway which may be responsible for its tumor suppressive function .	Thus, we demontrated that DEPTOR negatively regulated the activation of AKT and mTOR pathway which may be responsible for its tumor suppressive function.	5	14	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	5	6	13	14
Accompanying DEPTOR accumulation , mTOR activity , as reflected by S6K1 phosphorylation , was reduced ( XREF_FIG ) , consistent with the previous observation that DEPTOR is an inhibitor of mTOR .	Accompanying DEPTOR accumulation, mTOR activity, as reflected by S6K1 phosphorylation, was reduced (XREF_FIG), consistent with the previous observation that DEPTOR is an inhibitor of mTOR.	25	31	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	25	26	30	31
DEPTOR overexpression promotes the progression of OS by inhibiting mTOR and activating the PI3K and Akt pathway .	DEPTOR overexpression promotes the progression of OS by inhibiting mTOR and activating the PI3K and Akt pathway.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DEPTOR	DEPTOR overexpression	deptor	mTOR	mTOR	mtor	0	1	9	10
We have recently shown that TGFbeta induced inhibition of deptor increases the mTOR activity .	We have recently shown that TGFbeta induced inhibition of deptor increases the mTOR activity.	7	13	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	deptor	deptor	deptor	mTOR	mTOR	mTOR	9	10	12	13
Furthermore , we found that DEPTOR knockdown notably activated mTOR and inhibited the PI3K and Akt pathway .	Furthermore, we found that DEPTOR knockdown notably activated mTOR and inhibited the PI3K and Akt pathway.	5	10	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	5	6	9	10
As DEPTOR is an endogenous inhibitor of mTOR , its abundance modulates activity of mTORC1/2 , and it is found to be overexpressed in some cancer types .	As DEPTOR is an endogenous inhibitor of mTOR, its abundance modulates activity of mTORC1/2, and it is found to be overexpressed in some cancer types.	1	8	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	1	2	7	8
Using quantitative RT-PCR we demonstrate for first time that there is a significant downregulation of mTOR , DEPTOR , and Raptor in preterm labouring myometria when compared to non pregnant tissues taken from the same area ( lower segment ) .	Using quantitative RT-PCR we demonstrate for first time that there is a significant downregulation of mTOR, DEPTOR, and Raptor in preterm labouring myometria when compared to non pregnant tissues taken from the same area (lower segment).	10	18	is a significant downregulation	Negative_activation_copula_1	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	17	18	15	16
DEPTOR accumulation inhibits mTOR pathway and consequently growth .	DEPTOR accumulation inhibits mTOR pathway and consequently growth.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	0	1	3	4
Interestingly , Deptor induces the autophagy process by suppressing mTOR kinase activity , a well-known negative regulator of autophagy [ XREF_BIBR , XREF_BIBR ] .	Interestingly, Deptor induces the autophagy process by suppressing mTOR kinase activity, a well-known negative regulator of autophagy [XREF_BIBR, XREF_BIBR].	2	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	2	3	9	10
While this gradual degradation of DEPTOR may underlie prolonged or basal mTOR activation , it can not explain how acute stimulation of mTOR triggers maximal signaling activity long before DEPTOR protein levels are affected .	While this gradual degradation of DEPTOR may underlie prolonged or basal mTOR activation, it can not explain how acute stimulation of mTOR triggers maximal signaling activity long before DEPTOR protein levels are affected.	3	12	underlie	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	5	6	11	12
DEPTOR appears to play a key role in mTOR signaling and directly inhibits mTOR activity by binding to the FAT domain .	DEPTOR appears to play a key role in mTOR signaling and directly inhibits mTOR activity by binding to the FAT domain.	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	0	1	13	14
Raptor positively regulates mTOR activity and is thought to function as a scaffold that recruits mTORC1 substrates , whereas PRAS40 , Deptor and FKBP38 negatively regulate mTOR activity .	Raptor positively regulates mTOR activity and is thought to function as a scaffold that recruits mTORC1 substrates, whereas PRAS40, Deptor and FKBP38 negatively regulate mTOR activity.	19	27	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	21	22	26	27
DEPTOR suppresses the activation of AKT and mTOR pathway in ESCC cells .	DEPTOR suppresses the activation of AKT and mTOR pathway in ESCC cells.	0	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	0	1	7	8
XREF_BIBR , XREF_BIBR Inhibition of the UPS blocks DEPTOR turnover and the resultant DEPTOR accumulation inhibits mTOR , activating autophagy .	XREF_BIBR, XREF_BIBR Inhibition of the UPS blocks DEPTOR turnover and the resultant DEPTOR accumulation inhibits mTOR, activating autophagy.	13	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	13	14	16	17
Inhibition of neddylation regulates dendritic cell functions via Deptor accumulation driven mTOR inactivation .	Inhibition of neddylation regulates dendritic cell functions via Deptor accumulation driven mTOR inactivation.	8	12	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	8	9	11	12
DEPTOR suppresses mTOR activity to induce autophagy .	DEPTOR suppresses mTOR activity to induce autophagy.	0	3	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	0	1	2	3
DEPTOR is an endogenous inhibitor of mTOR .	DEPTOR is an endogenous inhibitor of mTOR.	0	7	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	0	1	6	7
In addition , DEPTOR knockdown notably activates mTOR and inhibits the PI3K and Akt pathway in OS cells .	In addition, DEPTOR knockdown notably activates mTOR and inhibits the PI3K and Akt pathway in OS cells.	3	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	3	4	7	8
Although DEPTOR has been shown to inhibit mTOR activity and may act as a tumor suppressor in some cell culture settings [ XREF_BIBR , XREF_BIBR ] , it has not been previously tested whether and how DEPTOR plays a role in pancreatic cancer .	Although DEPTOR has been shown to inhibit mTOR activity and may act as a tumor suppressor in some cell culture settings [XREF_BIBR, XREF_BIBR], it has not been previously tested whether and how DEPTOR plays a role in pancreatic cancer.	1	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	1	2	7	8
DEPTOR is a natural inhibitor of mTOR via directly binding to both mTORC1 and mTORC2 ( XREF_FIG ) .	DEPTOR is a natural inhibitor of mTOR via directly binding to both mTORC1 and mTORC2 (XREF_FIG).	0	15	is a natural inhibitor	Negative_regulation_copula_1	Negative_activation	Negative_regulation	DEPTOR	DEPTOR	deptor	mTOR	mTOR via directly binding to both mTORC1 and mTORC2	mtor	0	1	6	7
Gene expression analysis performed with RT2 profiler array for mTOR regulatory pathway indicated an increase in genes that encode for AMPK subunits as well as its targets such as Deptor and Tsc1 , which are known to directly inhibit mTOR function .	Gene expression analysis performed with RT2 profiler array for mTOR regulatory pathway indicated an increase in genes that encode for AMPK subunits as well as its targets such as Deptor and Tsc1, which are known to directly inhibit mTOR function.	26	40	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	29	30	39	40
The overlap between differentially expressed mTOR signaling related genes in 3 different SOX2 overexpressing CSC like cell lines revealed a notable downregulation of 3 genes , PRKAA1 ( which codes for the catalytic alpha 1 subunit of AMPK ) , DDIT4 and REDD1 ( a stress response gene that operates as a negative regulator of mTOR ) , and DEPTOR ( a naturally occurring endogenous inhibitor of mTOR activity ) .	The overlap between differentially expressed mTOR signaling related genes in 3 different SOX2 overexpressing CSC like cell lines revealed a notable downregulation of 3 genes, PRKAA1 (which codes for the catalytic alpha 1 subunit of AMPK), DDIT4 and REDD1 (a stress response gene that operates as a negative regulator of mTOR), and DEPTOR (a naturally occurring endogenous inhibitor of mTOR activity).	18	68	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	59	60	67	68
This demonstrated that mTOR signaling activation by DEPTOR silencing attenuated the inhibition of System A activity in response to infected conditioned medium by approximately 30 % ( P = 0.004 ) .	This demonstrated that mTOR signaling activation by DEPTOR silencing attenuated the inhibition of System A activity in response to infected conditioned medium by approximately 30% (P = 0.004).	3	8	signaling activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	7	8	3	4
Finally , our results show that pharmacologic inhibition of CK1 increases DEPTOR levels and inhibits mTOR signaling , suggesting that CK1 inhibition may be a viable therapeutic option for the treatment of cancers characterized by low DEPTOR levels and activation of mTOR .	Finally, our results show that pharmacologic inhibition of CK1 increases DEPTOR levels and inhibits mTOR signaling, suggesting that CK1 inhibition may be a viable therapeutic option for the treatment of cancers characterized by low DEPTOR levels and activation of mTOR.	9	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	DEPTOR	CK1 increases DEPTOR levels	deptor	mTOR	mTOR	mtor	11	12	15	16
This suggests contrasting roles of DEPTOR induced mTOR complexes inhibition in regulating oscillatory dynamics , which could be explained as follows .	This suggests contrasting roles of DEPTOR induced mTOR complexes inhibition in regulating oscillatory dynamics, which could be explained as follows.	3	9	induced	Positive_early_activation	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	5	6	7	8
Deptor is an inhibitor of mTOR , which directly binds to mTOR and negatively regulates the functions of both mTORC1 and mTORC2 [ XREF_BIBR ] .	Deptor is an inhibitor of mTOR, which directly binds to mTOR and negatively regulates the functions of both mTORC1 and mTORC2 [XREF_BIBR].	0	14	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	0	1	5	6
The suppressive effect of Sag deletion is most likely attributable to inactivation of PI3K/AKT/mTOR pathway via accumulation of PHLPP1 , a Ser/Thr protein phosphate , that directly dephosphorylates pAkt , and of Deptor , that directly inhibits the mTOR activity .	The suppressive effect of Sag deletion is most likely attributable to inactivation of PI3K/AKT/mTOR pathway via accumulation of PHLPP1, a Ser/Thr protein phosphate, that directly dephosphorylates pAkt, and of Deptor, that directly inhibits the mTOR activity.	14	39	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	32	33	38	39
These results suggest that p38gamma and p38delta modulate heart growth in vivo by controlling DEPTOR degradation and in consequence mTOR activity .	These results suggest that p38gamma and p38delta modulate heart growth in vivo by controlling DEPTOR degradation and in consequence mTOR activity.	7	20	modulate	Positive_activation_syntax_3_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	14	15	19	20
Consequently , activation of mTORC1 and 2 leads to Deptor inhibition , leading to further mTOR activity and in contrast , high levels of Deptor inhibit mTOR activity .	Consequently, activation of mTORC1 and 2 leads to Deptor inhibition, leading to further mTOR activity and in contrast, high levels of Deptor inhibit mTOR activity.	22	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Deptor	levels of Deptor	deptor	mTOR	mTOR	mtor	24	25	26	27
This could also be obtained by negatively targeting mTOR , which is antagonistic to Smg1 ( possibly also by enhancing Deptor activity , which negatively regulates mTOR signaling ) .	This could also be obtained by negatively targeting mTOR, which is antagonistic to Smg1 (possibly also by enhancing Deptor activity, which negatively regulates mTOR signaling).	20	27	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	20	21	26	27
We propose that DEPTOR is an endogenous inhibitor of mTOR whose deregulated overexpression promotes cell survival in a subset of Multiple Myelomas .	We propose that DEPTOR is an endogenous inhibitor of mTOR whose deregulated overexpression promotes cell survival in a subset of Multiple Myelomas.	3	10	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	3	4	9	10
Upon growth factor stimulation , DEPTOR is rapidly degraded by the ubiquitin-proteasome pathway to ensure a proper activation of mTOR for cell proliferation and survival .	Upon growth factor stimulation, DEPTOR is rapidly degraded by the ubiquitin-proteasome pathway to ensure a proper activation of mTOR for cell proliferation and survival.	5	20	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	5	6	19	20
DEPTOR , a DEP domain containing mTOR interacting protein , is an endogenous inhibitor of mTOR .	DEPTOR, a DEP domain containing mTOR interacting protein, is an endogenous inhibitor of mTOR.	0	16	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	0	1	15	16
It is unknown how DEPTOR suppresses mTOR .	It is unknown how DEPTOR suppresses mTOR.	4	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	4	5	6	7
DEPTOR levels increase in response to serum deprivation , resulting in mTOR inhibition , whereas serum stimulation leads to phosphorylation dependent degradation of DEPTOR and enhanced mTOR activity XREF_BIBR XREF_BIBR .	DEPTOR levels increase in response to serum deprivation, resulting in mTOR inhibition, whereas serum stimulation leads to phosphorylation dependent degradation of DEPTOR and enhanced mTOR activity XREF_BIBR XREF_BIBR.	0	12	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR levels	deptor	mTOR	mTOR	mtor	0	1	11	12
Thus , because of the inhibitory feedback signal from mTORC1 to the PI3K pathway , partial mTOR inhibition caused by either DEPTOR overexpression or chemical inhibitors leads to an asymmetrical state of mTOR signaling characterized by an inhibition of mTORC1 but an activation of mTORC2 dependent outputs .	Thus, because of the inhibitory feedback signal from mTORC1 to the PI3K pathway, partial mTOR inhibition caused by either DEPTOR overexpression or chemical inhibitors leads to an asymmetrical state of mTOR signaling characterized by an inhibition of mTORC1 but an activation of mTORC2 dependent outputs.	16	23	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR overexpression	deptor	mTOR	mTOR	mtor	21	22	16	17
Feed-forward mechanisms involve Deptor , PRAS40 and ULK1/2 , which are each inhibited by mTORC1 mediated phosphorylation and , in turn , inhibit mTOR activity .	Feed-forward mechanisms involve Deptor, PRAS40 and ULK1/2, which are each inhibited by mTORC1 mediated phosphorylation and, in turn, inhibit mTOR activity.	2	24	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	3	4	23	24
As far as the role of DEPTOR in ESCC progression , we found that ectopic expression of DEPTOR inhibited the activation of AKT and mTOR pathway , and suppressed proliferation , migration , and invasion as well as in vivo tumor growth of ESCC cells with relatively low DEPTOR expression .	As far as the role of DEPTOR in ESCC progression, we found that ectopic expression of DEPTOR inhibited the activation of AKT and mTOR pathway, and suppressed proliferation, migration, and invasion as well as in vivo tumor growth of ESCC cells with relatively low DEPTOR expression.	15	25	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	expression of DEPTOR	deptor	mTOR	mTOR	mtor	17	18	24	25
It is conceivable that resistance to rapamycin is attributable to DEPTOR mediated mTOR inhibition , since cancer cells with higher mTOR activity are in general more sensitive to the drug .	It is conceivable that resistance to rapamycin is attributable to DEPTOR mediated mTOR inhibition, since cancer cells with higher mTOR activity are in general more sensitive to the drug.	8	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	10	11	12	13
As an mTOR interacting protein , DEPTOR endogenously inhibits the activity of mTOR .	As an mTOR interacting protein, DEPTOR endogenously inhibits the activity of mTOR.	6	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	6	7	12	13
Among these components , Raptor and Deptor positively and negatively regulate mTOR activation , respectively XREF_BIBR , XREF_BIBR .	Among these components, Raptor and Deptor positively and negatively regulate mTOR activation, respectively XREF_BIBR, XREF_BIBR.	4	12	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	6	7	11	12
As deptor is an inhibitor of mTOR , we examined activation of mTORC1 employing phosphorylation of S6 kinase ( Thr 389 ) and 4EBP-1 ( Thr 37/46 ) as indicators .	As deptor is an inhibitor of mTOR, we examined activation of mTORC1 employing phosphorylation of S6 kinase (Thr 389) and 4EBP-1 (Thr 37/46) as indicators.	1	7	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	deptor	deptor	deptor	mTOR	mTOR	mTOR	1	2	6	7
As a tumor suppressor , DEPTOR generally blocks mTOR activity and inhibits protein synthesis and cell proliferation .	As a tumor suppressor, DEPTOR generally blocks mTOR activity and inhibits protein synthesis and cell proliferation.	5	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	5	6	8	9
Previous studies have reported that Deptor induces autophagy by suppressing mTOR activity in response to stress [ XREF_BIBR , XREF_BIBR ] and , in the absence of Deptor , a decrease of the autophagy pathway occurs , leading to a greater MM cell death rate [ XREF_BIBR ] .	Previous studies have reported that Deptor induces autophagy by suppressing mTOR activity in response to stress [XREF_BIBR, XREF_BIBR] and, in the absence of Deptor, a decrease of the autophagy pathway occurs, leading to a greater MM cell death rate [XREF_BIBR].	5	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	5	6	10	11
Dkk1 has an oscillatory behavior during the segmentation process in mouse embryos XREF_BIBR and lowered expression of Dkk1 results in smaller and more irregular vertebrae in mice XREF_BIBR , XREF_BIBR ; similar to the phenotype produced by overexpression of Wnt3a .	Dkk1 has an oscillatory behavior during the segmentation process in mouse embryos XREF_BIBR and lowered expression of Dkk1 results in smaller and more irregular vertebrae in mice XREF_BIBR, XREF_BIBR; similar to the phenotype produced by overexpression of Wnt3a.	0	40	lowered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	0	1	39	40
Importantly , because P3 mutations primarily affected Wnt3a , but not Wnt1 signaling through LRP6 , we investigated whether Dkk1 inhibits Wnt3a and Wnt1 signaling through LRP6 via a common or different mechanism ( s ) .	Importantly, because P3 mutations primarily affected Wnt3a, but not Wnt1 signaling through LRP6, we investigated whether Dkk1 inhibits Wnt3a and Wnt1 signaling through LRP6 via a common or different mechanism (s).	19	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	19	20	21	22
mAb135 enhanced Wnt dependent TCF reporter activation and antagonized DKK1 dependent inhibition of Wnt3A signaling , suggesting a role in modulation of LRP6 function .	mAb135 enhanced Wnt dependent TCF reporter activation and antagonized DKK1 dependent inhibition of Wnt3A signaling, suggesting a role in modulation of LRP6 function.	9	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3A	Wnt3A	Wnt3A	9	10	13	14
Interestingly , SFRP3 and DKK1 co-treatment did not fully suppress the effects of Wnt3a on gene repression , although it did block beta-catenin protein stabilization .	Interestingly, SFRP3 and DKK1 co-treatment did not fully suppress the effects of Wnt3a on gene repression, although it did block beta-catenin protein stabilization.	2	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	4	5	13	14
The presence of DKK1 and knockdown of Dishevelled proteins block formation of the 2 MDa Dvl3 based complexes and also block Wnt3a stimulation of the canonical pathway .	The presence of DKK1 and knockdown of Dishevelled proteins block formation of the 2 MDa Dvl3 based complexes and also block Wnt3a stimulation of the canonical pathway.	1	22	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	3	4	21	22
Noggin and Dkk-1 suppressed the synergistic effect of BMP-4 and Wnt3a , but Smad7 did not .	Noggin and Dkk-1 suppressed the synergistic effect of BMP-4 and Wnt3a, but Smad7 did not.	0	11	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk-1	Dkk-1	Dkk-1	Wnt3a	Wnt3a	Wnt3a	2	3	10	11
Dkk1 and -2 partially restored the Wnt3a dependent reduction of RANKL in cells treated with 1,25 ( OH ) 2 D 3 , pointing to another molecular mechanism by which canonical Wnt inhibitors may promote osteoclastogenesis in situ .	Dkk1 and -2 partially restored the Wnt3a dependent reduction of RANKL in cells treated with 1,25 (OH) 2 D 3, pointing to another molecular mechanism by which canonical Wnt inhibitors may promote osteoclastogenesis in situ.	0	8	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	0	1	6	7
DKK1 does not suppress Wnt3A induced accumulation of beta-catenin when clathrin mediated endocytosis is disrupted using MDC or in clathrin knockdown cells , suggesting that DKK1 dependent internalization of LRP6 through clathrin is required for its inhibitory effects on beta-catenin signalling .	DKK1 does not suppress Wnt3A induced accumulation of beta-catenin when clathrin mediated endocytosis is disrupted using MDC or in clathrin knockdown cells, suggesting that DKK1 dependent internalization of LRP6 through clathrin is required for its inhibitory effects on beta-catenin signalling.	0	5	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3A	Wnt3A	Wnt3A	0	1	4	5
Early Wnt-3A signaling as measured by beta-catenin accumulation was not affected by the BMP antagonists but was blocked by Dkk-1 .	Early Wnt-3A signaling as measured by beta-catenin accumulation was not affected by the BMP antagonists but was blocked by Dkk-1.	1	20	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Dkk-1	Dkk-1	Dkk-1	Wnt-3A	Wnt-3A	Wnt-3A	19	20	1	2
To demonstrate that WNT3A mediated induction of an osteoblastic phenotype is effectively inhibited by DKK-1 , C2C12 cells were treated with increasing concentrations of DKK-1 in the presence of WNT3A .	To demonstrate that WNT3A mediated induction of an osteoblastic phenotype is effectively inhibited by DKK-1, C2C12 cells were treated with increasing concentrations of DKK-1 in the presence of WNT3A.	3	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	DKK-1	DKK-1	DKK-1	WNT3A	WNT3A	WNT3A	14	15	3	4
Addition of Dkk1 or -2 did not alter the levels of p53 in Wnt3a stimulated cells ( compare lanes 7 and 11 with lane 3 ) , but slightly attenuated the Wnt3a dependent restoration of p53 under conditions of ongoing BMP2 signaling ( compare lanes 8 and 12 with lane 4 ) .	Addition of Dkk1 or -2 did not alter the levels of p53 in Wnt3a stimulated cells (compare lanes 7 and 11 with lane 3), but slightly attenuated the Wnt3a dependent restoration of p53 under conditions of ongoing BMP2 signaling (compare lanes 8 and 12 with lane 4).	0	33	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	2	3	31	32
In contrast to Dkk3 and -4 ( results not shown ) , Dkk1 and -2 inhibited the Wnt3a dependent induction of OCN mRNA , with Dkk2 being once again more potent in C2C12 than C3H10T1/2 cells .	In contrast to Dkk3 and -4 (results not shown), Dkk1 and -2 inhibited the Wnt3a dependent induction of OCN mRNA, with Dkk2 being once again more potent in C2C12 than C3H10T1/2 cells.	12	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	12	13	17	18
As shown in Figure XREF_FIG , Dkk1 inhibited Wnt3a induced signaling to an equivalent extent in the Dkk3 and vector stable cell lines .	As shown in Figure XREF_FIG, Dkk1 inhibited Wnt3a induced signaling to an equivalent extent in the Dkk3 and vector stable cell lines.	6	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	6	7	8	9
We co-treated SFZ cultures with Wnt3a and Dkk-1 or IWR-1 both of which inhibited Wnt 3a stimulated beta-catenin signaling pathway ( XREF_FIG ) , and found that Dkk-1 and IWR-1 suppressed Wnt3a action on maintenance of Prg4 expression ( XREF_FIG ) .	We co-treated SFZ cultures with Wnt3a and Dkk-1 or IWR-1 both of which inhibited Wnt 3a stimulated beta-catenin signaling pathway (XREF_FIG), and found that Dkk-1 and IWR-1 suppressed Wnt3a action on maintenance of Prg4 expression (XREF_FIG).	27	32	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk-1	Dkk-1	Dkk-1	Wnt3a	Wnt3a	Wnt3a	27	28	31	32
This may be due to differential WNT inhibition since dkk1 , unlike frzb , inhibits Wnt3a signalling .	This may be due to differential WNT inhibition since dkk1, unlike frzb, inhibits Wnt3a signalling.	9	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	dkk1	dkk1	dkk1	Wnt3a	Wnt3a	Wnt3a	9	10	15	16
We found that Dkk1 and -2 restored the Wnt3a dependent reduction of alkaline phosphatase ( ALP ) , Osterix and p53 , indicating that mitigated Wnt and beta-catenin signaling promotes certain aspects of early osteoblastogenesis through the BMP-p53-Osterix-ALP axis .	We found that Dkk1 and -2 restored the Wnt3a dependent reduction of alkaline phosphatase (ALP), Osterix and p53, indicating that mitigated Wnt and beta-catenin signaling promotes certain aspects of early osteoblastogenesis through the BMP-p53-Osterix-ALP axis.	3	10	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	3	4	8	9
DKK1 , an inhibitor of Wnt signaling blocked the action of Wnt3a on pGSK-3beta and beta-catenin but had a lesser effect on 14-3-3sigma transfected CCE cells ( XREF_FIG ) .	DKK1, an inhibitor of Wnt signaling blocked the action of Wnt3a on pGSK-3beta and beta-catenin but had a lesser effect on 14-3-3sigma transfected CCE cells (XREF_FIG).	0	17	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	0	1	11	12
Dynamic expression of Dkk1 in ventral limb bud , anterior and posterior mesenchyme , and the AER antagonizes Wnt3a and Wnt7a signals that maintain FGF8 and Shh expression 17 .	Dynamic expression of Dkk1 in ventral limb bud, anterior and posterior mesenchyme, and the AER antagonizes Wnt3a and Wnt7a signals that maintain FGF8 and Shh expression 17.	1	21	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	expression of Dkk1	dkk1	Wnt3a	Wnt3a	wnt3a	3	4	18	19
Presence of the Wnt signaling antagonist Dkk1 decreased the Wnt3a response ( XREF_FIG ) .	Presence of the Wnt signaling antagonist Dkk1 decreased the Wnt3a response (XREF_FIG).	0	10	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	6	7	9	10
Although DKK1 attenuated the effect of Wnt3a on the BMP and Smad reporter , it did not block BMP2 induced activation of the reporter .	Although DKK1 attenuated the effect of Wnt3a on the BMP and Smad reporter, it did not block BMP2 induced activation of the reporter.	1	7	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	1	2	6	7
Moreover , DKK1 , a LRP5/6 antagonist , blocked Wnt3a mediated prostasphere expansion ( XREF_SUPPLEMENTARY ) .	Moreover, DKK1, a LRP5/6 antagonist, blocked Wnt3a mediated prostasphere expansion (XREF_SUPPLEMENTARY).	2	10	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	2	3	9	10
While Dickkopf1 blocked Rspo2 and Wnt3a dependent down-regulation , a number of down-regulated genes were not affected by beta-catenin knockdown , suggesting that in these instances down-regulation was mediated by a beta-catenin-independent mechanism .	While Dickkopf1 blocked Rspo2 and Wnt3a dependent down-regulation, a number of down-regulated genes were not affected by beta-catenin knockdown, suggesting that in these instances down-regulation was mediated by a beta-catenin-independent mechanism.	1	7	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dickkopf1	Dickkopf1	Dickkopf1	Wnt3a	Wnt3a	Wnt3a	1	2	5	6
Notably , Wnt3a dependent protection was reversed by the Wnt signaling inhibitor Dkk1 .	Notably, Wnt3a dependent protection was reversed by the Wnt signaling inhibitor Dkk1.	2	13	reversed	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	12	13	2	3
The naturally occurring Wnt antagonist DKK1 ( 30 nM ) failed to inhibit Wnt3a induced exosome release from microglia .	The naturally occurring Wnt antagonist DKK1 (30 nM) failed to inhibit Wnt3a induced exosome release from microglia.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	5	6	13	14
Similarly , DKK1 inhibited WNT3a but not FGF2 mediated activation of Topflash ( XREF_FIG ) .	Similarly, DKK1 inhibited WNT3a but not FGF2 mediated activation of Topflash (XREF_FIG).	2	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	WNT3a	WNT3a	WNT3a	2	3	4	5
Dkk-1 , when combined with the Wnt proteins , abrogated the effects of Wnt3a but not Wnt5a .	Dkk-1, when combined with the Wnt proteins, abrogated the effects of Wnt3a but not Wnt5a.	0	14	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk-1	Dkk-1	Dkk-1	Wnt3a	Wnt3a	Wnt3a	0	1	13	14
As a control , DKK1 did successfully block Wnt3a induced increase in alkaline phosphatase staining in murine calvarial osteoblasts ( XREF_FIG B ) .	As a control, DKK1 did successfully block Wnt3a induced increase in alkaline phosphatase staining in murine calvarial osteoblasts (XREF_FIG B).	4	10	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	4	5	8	9
Noggin ( 1 mug/ml ) partially blocked Wnt3a mediated osteoblast activity ; whereas , DKK-1 ( 1 mug/ml ) completely blocked Wnt3a mediated osteoblast activity ; and both together did not show further inhibition ( XREF_FIG ) .	Noggin (1 mug/ml) partially blocked Wnt3a mediated osteoblast activity; whereas, DKK-1 (1 mug/ml) completely blocked Wnt3a mediated osteoblast activity; and both together did not show further inhibition (XREF_FIG).	14	22	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK-1	DKK-1	DKK-1	Wnt3a	Wnt3a	Wnt3a	14	15	21	22
Interestingly , Dkk1 also inhibited the down-regulation of Wnt3a and Rspo2 target genes , but only a subset of these decreases in expression was disrupted by knockdown of beta-catenin .	Interestingly, Dkk1 also inhibited the down-regulation of Wnt3a and Rspo2 target genes, but only a subset of these decreases in expression was disrupted by knockdown of beta-catenin.	2	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	2	3	8	9
However , the observation that DKK-1 completely blocked Wnt3a induced osteoblast differentiation indicates that Noggin-repressible BMP induced activity is dependent on Wnt3a .	However, the observation that DKK-1 completely blocked Wnt3a induced osteoblast differentiation indicates that Noggin-repressible BMP induced activity is dependent on Wnt3a.	5	9	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK-1	DKK-1	DKK-1	Wnt3a	Wnt3a	Wnt3a	5	6	8	9
Intriguingly , we found that although Dkk1 inhibited Wnt1 and Wnt3a with different efficacy , an identical set of LRP6 mutations were identified that reduced Dkk1 inhibition of both Wnt1 and Wnt3a , in particular Y706A , E708A and W767A ( XREF_FIG ) .	Intriguingly, we found that although Dkk1 inhibited Wnt1 and Wnt3a with different efficacy, an identical set of LRP6 mutations were identified that reduced Dkk1 inhibition of both Wnt1 and Wnt3a, in particular Y706A, E708A and W767A (XREF_FIG).	25	32	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	25	26	31	32
In addition to its direct inhibitory effect of Dkk-1 on osteoblasts , Dkk-1 disrupts the Wnt3a regulated osteoprotegerin and receptor activator of NF-kappaB ligand ( RANKL ) expression in osteoblasts and thus it indirectly enhances osteoclast function in MM .	In addition to its direct inhibitory effect of Dkk-1 on osteoblasts, Dkk-1 disrupts the Wnt3a regulated osteoprotegerin and receptor activator of NF-kappaB ligand (RANKL) expression in osteoblasts and thus it indirectly enhances osteoclast function in MM.	12	16	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk-1	Dkk-1	Dkk-1	Wnt3a	Wnt3a	Wnt3a	12	13	15	16
Our finding that Dkk1 and -2 abolished the Wnt3a dependent down regulation of ALP message and protein in otherwise untreated or BMP2 stimulated C2C12 and C3H10T1/2 cells indicated that Wnt3a inhibits certain aspects of osteoprogenitor differentiation in vitro .	Our finding that Dkk1 and -2 abolished the Wnt3a dependent down regulation of ALP message and protein in otherwise untreated or BMP2 stimulated C2C12 and C3H10T1/2 cells indicated that Wnt3a inhibits certain aspects of osteoprogenitor differentiation in vitro.	3	9	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	3	4	8	9
Analogous to YW211.31 antibody , one of these antibodies inhibits exogenous DKK1 antagonism of Wnt3a signaling , and also blocks DKK1 binding to LRP6 in vitro XREF_BIBR .	Analogous to YW211.31 antibody, one of these antibodies inhibits exogenous DKK1 antagonism of Wnt3a signaling, and also blocks DKK1 binding to LRP6 in vitro XREF_BIBR.	11	15	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	11	12	14	15
However , unlike noggin which substantially attenuated both BMP2 induced and Wnt-3a-induced ALP activity , DKK1 only attenuated Wnt3a induced increase in ALP activity ( XREF_FIG ) .	However, unlike noggin which substantially attenuated both BMP2 induced and Wnt-3a-induced ALP activity, DKK1 only attenuated Wnt3a induced increase in ALP activity (XREF_FIG).	15	20	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	15	16	18	19
Addition of Dkk-1 was able to significantly reduce the Wnt3a stimulated increase in AXIN2 transcript expression , confirming the specificity of Wnt activation .	Addition of Dkk-1 was able to significantly reduce the Wnt3a stimulated increase in AXIN2 transcript expression, confirming the specificity of Wnt activation.	0	10	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk-1	Dkk-1	Dkk-1	Wnt3a	Wnt3a	Wnt3a	2	3	9	10
DKK1 , similarly to Dab2 , inhibits Wnt3A dependent stabilization of beta-catenin .	DKK1, similarly to Dab2, inhibits Wnt3A dependent stabilization of beta-catenin.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3A	Wnt3A	Wnt3A	0	1	7	8
DKK1 blocks Wnt3a stimulated trophoblast migration and invasion through matrigel and also reduces basal migration , invasion , and proliferation of cytotrophoblasts [ XREF_BIBR ] .	DKK1 blocks Wnt3a stimulated trophoblast migration and invasion through matrigel and also reduces basal migration, invasion, and proliferation of cytotrophoblasts [XREF_BIBR].	0	12	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	0	1	2	3
The E663A mutation appeared to show enhanced Dkk1 inhibition of Wnt3a but not Wnt1 through LRP6 ( XREF_FIG ) .	The E663A mutation appeared to show enhanced Dkk1 inhibition of Wnt3a but not Wnt1 through LRP6 (XREF_FIG).	7	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	7	8	10	11
The physiological significance of this interaction is yet unclear , as mutagenesis of residues in this second interface did not alter the Dkk1 mediated inhibition of Wnt3a activity in a Wnt reporter assay XREF_BIBR .	The physiological significance of this interaction is yet unclear, as mutagenesis of residues in this second interface did not alter the Dkk1 mediated inhibition of Wnt3a activity in a Wnt reporter assay XREF_BIBR.	21	27	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	22	23	26	27
On the contrary , an introduced expression of Wnt and beta-catenin pathway inhibitor DKK1 could significantly reversed the effect of Wnt3a .	On the contrary, an introduced expression of Wnt and beta-catenin pathway inhibitor DKK1 could significantly reversed the effect of Wnt3a.	6	21	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	expression of Wnt and beta-catenin pathway inhibitor DKK1	dkk1	Wnt3a	Wnt3a	wnt3a	13	14	20	21
DKK1 virtually abrogated the ability of WNT3A to activate TOP-Flash , as expected , but only partially blocked the effect of SOX11 ( XREF_FIG ) .	DKK1 virtually abrogated the ability of WNT3A to activate TOP-Flash, as expected, but only partially blocked the effect of SOX11 (XREF_FIG).	0	17	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	WNT3A	WNT3A	WNT3A	0	1	6	7
As Smac mimetics trigger the degradation of cIAP1 and cIAP2 associated with the TNF receptor signaling complex , receptor stimulation promotes activation of caspase-8 through the RIP1/FADD/caspase -8 complex in a manner dependent on RIP1 kinase activity .	As Smac mimetics trigger the degradation of cIAP1 and cIAP2 associated with the TNF receptor signaling complex, receptor stimulation promotes activation of caspase-8 through the RIP1/FADD/caspase -8 complex in a manner dependent on RIP1 kinase activity.	1	10	trigger	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	1	2	7	8
In contrast , Smac or a synthetic IAP antagonist triggers the selective degradation of c-IAP1 , but not TRAF2 , through the RING domain of c-IAP1 .	In contrast, Smac or a synthetic IAP antagonist triggers the selective degradation of c-IAP1, but not TRAF2, through the RING domain of c-IAP1.	3	15	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	c-IAP1	c-IAP1	c-IAP1	3	4	14	15
Recent studies showed that Smac mimetics induce cIAP-1 degradation in cells , which is crucial for apoptosis induction by Smac mimetics .	Recent studies showed that Smac mimetics induce cIAP-1 degradation in cells, which is crucial for apoptosis induction by Smac mimetics.	4	8	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP-1	cIAP-1	cIAP-1	4	5	7	8
The SMAC mimetic in turn enhances the cytotoxicity of the compound by negating the activity of two anti-apoptotic proteins , cIAP-1 and cIAP-2 , thus establishing an intracellular environment that is conducive for NF-kB activation .	The SMAC mimetic in turn enhances the cytotoxicity of the compound by negating the activity of two anti-apoptotic proteins, cIAP-1 and cIAP-2, thus establishing an intracellular environment that is conducive for NF-kB activation.	0	21	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	cIAP-1	cIAP-1	cIAP-1	1	2	20	21
These findings suggest that the mechanism by which Smac regulates c-IAP1 expression is distinct from the mechanism by which c-IAP1 and TRAF2 are targeted following CD30 activation , since only c-IAP1 protein levels are altered in the presence of Smac , and an intact RING is necessary for Smac mediated c-IAP1 degradation .	These findings suggest that the mechanism by which Smac regulates c-IAP1 expression is distinct from the mechanism by which c-IAP1 and TRAF2 are targeted following CD30 activation, since only c-IAP1 protein levels are altered in the presence of Smac, and an intact RING is necessary for Smac mediated c-IAP1 degradation.	46	51	mediated	Positive_early_activation	Negative_activation	Negative_activation	Smac	Smac	Smac	c-IAP1	c-IAP1	c-IAP1	48	49	50	51
Several recent studies have demonstrated shown that Smac mimetics induce rapid cIAP-1 degradation in cells .	Several recent studies have demonstrated shown that Smac mimetics induce rapid cIAP-1 degradation in cells.	7	12	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP-1	cIAP-1	cIAP-1	7	8	11	12
37 Degradation of cIAP1 by Smac mimetics takes place in cell lines both responsive and resistant to Smac mimetics , indicating that the degradation of cIAP1 is necessary but not sufficient for apoptosis induction .	37 Degradation of cIAP1 by Smac mimetics takes place in cell lines both responsive and resistant to Smac mimetics, indicating that the degradation of cIAP1 is necessary but not sufficient for apoptosis induction.	1	6	Degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	5	6	3	4
A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation induced cell death in vitro and to enhance radiation mediated suppression of STS xenografts in vivo .	A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation induced cell death in vitro and to enhance radiation mediated suppression of STS xenografts in vivo.	4	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	4	5	8	9
Likewise , SMAC mimetic mediated depletion of cIAP1 or cIAP2 decreased ubiquitinated BCL10 in BCR dependent ABC DLBCL lines but not in GCB DLBCL lines ( XREF_FIG ) .	Likewise, SMAC mimetic mediated depletion of cIAP1 or cIAP2 decreased ubiquitinated BCL10 in BCR dependent ABC DLBCL lines but not in GCB DLBCL lines (XREF_FIG).	2	9	depletion	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	cIAP1	cIAP1	cIAP1	2	3	7	8
Work from a number of laboratories has shown that Smac mimetics rapidly induce auto-ubiquitylation and proteasomal degradation of cIAP1 and cIAP2 resulting in the activation of non canonical NF-kappaB signaling and subsequent increased TNFalpha production and autocrine stimulation of TNFR1 [ XREF_BIBR - XREF_BIBR ] .	Work from a number of laboratories has shown that Smac mimetics rapidly induce auto-ubiquitylation and proteasomal degradation of cIAP1 and cIAP2 resulting in the activation of non canonical NF-kappaB signaling and subsequent increased TNFalpha production and autocrine stimulation of TNFR1 [XREF_BIBR - XREF_BIBR].	9	20	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	9	10	18	19
XREF_BIBR , XREF_BIBR Smac antagonizes cIAP-1 and cIAP-2 by binding to the BIR3 domain of these two proteins and inducing their rapid degradation .	XREF_BIBR, XREF_BIBR Smac antagonizes cIAP-1 and cIAP-2 by binding to the BIR3 domain of these two proteins and inducing their rapid degradation.	2	7	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP-1	cIAP-1	cIAP-1	3	4	5	6
Inhibition of cIAP1 by SMAC mimetics leads to the accumulation of NIK , phosphorylation of IKKalpha , and the subsequent processing of p100 to p52 .	Inhibition of cIAP1 by SMAC mimetics leads to the accumulation of NIK, phosphorylation of IKKalpha, and the subsequent processing of p100 to p52.	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	cIAP1	cIAP1	cIAP1	4	5	2	3
Several recent studies have demonstrated that Smac mimetics induce rapid degradation of cIAP1 and that such degradation is a key early event in apoptosis induction by Smac mimetics as single agents in cancer cells .	Several recent studies have demonstrated that Smac mimetics induce rapid degradation of cIAP1 and that such degradation is a key early event in apoptosis induction by Smac mimetics as single agents in cancer cells.	6	13	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	6	7	12	13
Smac prevented cIAP1 from inhibiting procaspase-3 activation and reversed the inhibition by prior addition of cIAP1 .	Smac prevented cIAP1 from inhibiting procaspase-3 activation and reversed the inhibition by prior addition of cIAP1.	0	8	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	0	1	2	3
Molecular determinants of Smac mimetic induced degradation of cIAP1 and cIAP2 .	Molecular determinants of Smac mimetic induced degradation of cIAP1 and cIAP2.	1	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	3	4	8	9
Several groups have recently reported that SMAC mimetic compounds induced a rapid degradation of cIAP-1 .	Several groups have recently reported that SMAC mimetic compounds induced a rapid degradation of cIAP-1.	6	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	cIAP-1	cIAP-1	cIAP-1	6	7	14	15
XREF_BIBR On one hand , Smac antagonizes cIAP-1 and cIAP-2 by direct binding , followed by induction of their rapid degradation .	XREF_BIBR On one hand, Smac antagonizes cIAP-1 and cIAP-2 by direct binding, followed by induction of their rapid degradation.	5	9	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP-1	cIAP-1	cIAP-1	5	6	7	8
To investigate the ability of proteasome inhibitors to antagonize SMAC mimetic induced degradation of cIAP1 and cIAP2 XREF_BIBR , XREF_BIBR , we first tested the effect of Cf on TNFR1 complex I dependent signaling in HT-29 cells .	To investigate the ability of proteasome inhibitors to antagonize SMAC mimetic induced degradation of cIAP1 and cIAP2 XREF_BIBR, XREF_BIBR, we first tested the effect of Cf on TNFR1 complex I dependent signaling in HT-29 cells.	9	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	cIAP1	cIAP1	cIAP1	9	10	14	15
Furthermore , we used a novel Smac mimetic that promotes degradation of cIAP1 and cIAP2 , and found that unlike the basal regulatory mechanism , active endogenous NIK turnover does not require the cIAPs .	Furthermore, we used a novel Smac mimetic that promotes degradation of cIAP1 and cIAP2, and found that unlike the basal regulatory mechanism, active endogenous NIK turnover does not require the cIAPs.	4	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	6	7	12	13
Smac was previously reported to mediate degradation of cIAP-1 , which culminates in NF-kappaB-mediated TNFalpha production .	Smac was previously reported to mediate degradation of cIAP-1, which culminates in NF-kappaB-mediated TNFalpha production.	0	11	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP-1	cIAP-1	cIAP-1	0	1	8	9
Our previous studies demonstrated that the Smac mimetic compound 3 ( SMC3 ) specifically suppresses c-IAP1 and induces TNF-alpha autocrine to kill cancer cells .	Our previous studies demonstrated that the Smac mimetic compound 3 (SMC3) specifically suppresses c-IAP1 and induces TNF-alpha autocrine to kill cancer cells.	6	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	c-IAP1	c-IAP1	c-IAP1	6	7	15	16
SMAC mimetic compounds cause cIAP-1 and cIAP-2 degradation , resulting in production of TNF-alpha via activation of NF-kappaB , generating a TNF-alpha autocrine loop which results in enhanced TNF-alpha and TNF-R 1 mediated apoptosis [ XREF_BIBR , XREF_BIBR ] .	SMAC mimetic compounds cause cIAP-1 and cIAP-2 degradation, resulting in production of TNF-alpha via activation of NF-kappaB, generating a TNF-alpha autocrine loop which results in enhanced TNF-alpha and TNF-R 1 mediated apoptosis [XREF_BIBR, XREF_BIBR].	0	7	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	cIAP-1	cIAP-1	cIAP-1	0	1	4	5
The Smac mimetic induced loss of cIAP1 and cIAP2 , two critical regulators of tumor necrosis factor ( TNF ) receptor superfamily and nuclear factor-kappaB ( NF-kappaB ) signaling , sensitizes cancer cells to TNFalpha- or TNF related apoptosis inducing TNF ligand ( i.e ., TRAIL )-mediated death .	The Smac mimetic induced loss of cIAP1 and cIAP2, two critical regulators of tumor necrosis factor (TNF) receptor superfamily and nuclear factor-kappaB (NF-kappaB) signaling, sensitizes cancer cells to TNFalpha- or TNF related apoptosis inducing TNF ligand (i.e., TRAIL)-mediated death.	1	8	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	1	2	6	7
3 To our knowledge , our work provides the first evidence that loss of endogenous SMAC is sufficient to promote NF-kappaB activation and tumorigenesis selectively via cIAP2 , consistent with sensitization to SMAC mimetics upon cIAP2 , but not cIAP1 , knockdown in lung cancer cells .	3 To our knowledge, our work provides the first evidence that loss of endogenous SMAC is sufficient to promote NF-kappaB activation and tumorigenesis selectively via cIAP2, consistent with sensitization to SMAC mimetics upon cIAP2, but not cIAP1, knockdown in lung cancer cells.	12	41	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	loss of endogenous SMAC	smac	cIAP1	cIAP1	ciap1	15	16	39	40
Several reports have shown that Smac mimetics induce rapid cIAP-1 degradation in cancer cells and that cIAP-1 is a direct and critical cellular target for Smac mimetics .	Several reports have shown that Smac mimetics induce rapid cIAP-1 degradation in cancer cells and that cIAP-1 is a direct and critical cellular target for Smac mimetics.	5	10	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	cIAP-1	cIAP-1	cIAP-1	5	6	9	10
It was recently shown that Smac mimetic mediated depletion of c-IAP1 , which is also a repressor of non canonical NF-kappaB signalling , could activate transcriptional activity and reverse HIV-1 latency .	It was recently shown that Smac mimetic mediated depletion of c-IAP1, which is also a repressor of non canonical NF-kappaB signalling, could activate transcriptional activity and reverse HIV-1 latency.	5	11	depletion	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Smac	Smac	Smac	c-IAP1	c-IAP1	c-IAP1	5	6	10	11
Dickkopf1 ( Dkk1 ) is a secreted antagonist of the Wnt and beta-catenin signaling pathway that acts by direct binding to and inhibiting the Wnt co-receptor LRP6 .	Dickkopf1 (Dkk1) is a secreted antagonist of the Wnt and beta-catenin signaling pathway that acts by direct binding to and inhibiting the Wnt co-receptor LRP6.	0	27	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	2	3	26	27
To test this possibility , C4-2B cells were transfected with a luciferase reporter vector driven by the BMP-4 promoter ( pGL3-BMP4 ) , the BMP-6 promoter ( pGL3-BMP6 ) or empty control vector ( pGL3-basic ) and treated with Wnt 3a or Wnt 5a in the absence or presence of two different inhibitors of canonical Wnt signaling : ( 1 ) DKK-1 ( 1ug/ml ) , which inhibits the Wnt receptor LRP-6 and ( 2 ) sFRP-1 ( 5ug/ml ) , that sequesters Wnts from the membrane bound Frizzled ( FZD ) which trimerizes with LRP-6 and Wnt .	To test this possibility, C4-2B cells were transfected with a luciferase reporter vector driven by the BMP-4 promoter (pGL3-BMP4), the BMP-6 promoter (pGL3-BMP6) or empty control vector (pGL3-basic) and treated with Wnt 3a or Wnt 5a in the absence or presence of two different inhibitors of canonical Wnt signaling : (1) DKK-1 (1ug/ml), which inhibits the Wnt receptor LRP-6 and (2) sFRP-1 (5ug/ml), that sequesters Wnts from the membrane bound Frizzled (FZD) which trimerizes with LRP-6 and Wnt.	37	76	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK-1	DKK-1	DKK-1	LRP-6	LRP-6	LRP-6	61	62	71	72
Two different models have been proposed to account for the mechanism by which DKK1 antagonizes LRP6 function .	Two different models have been proposed to account for the mechanism by which DKK1 antagonizes LRP6 function.	13	16	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	13	14	15	16
Similar to the results above , co-transfection of Dkk1 alone stabilized LRP6 ( XREF_FIG ) , but decreased Wnt and LRP6 signaling ( XREF_FIG ) .	Similar to the results above, co-transfection of Dkk1 alone stabilized LRP6 (XREF_FIG), but decreased Wnt and LRP6 signaling (XREF_FIG).	6	21	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	8	9	20	21
LRP6 receptor complex in PC12 cells and that this activity can be antagonized by Dickkopf-1 and Dickkopf-3 .	LRP6 receptor complex in PC12 cells and that this activity can be antagonized by Dickkopf-1 and Dickkopf-3.	0	16	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Dickkopf-1	Dickkopf-1	Dickkopf-1	LRP6	LRP6	LRP6	14	15	0	1
DKK1 impedes the signaling pathway by isolating the LRP6 co-receptor XREF_BIBR .	DKK1 impedes the signaling pathway by isolating the LRP6 co-receptor XREF_BIBR.	0	10	impedes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	0	1	8	9
The expression and requirement of Dkk1 , which binds to and inhibits the Wnt coreceptor LRP6 , is shared among frogs , zebrafish , and mice , supporting the notion that the main role of the head organizer is to antagonize Wnt signaling , which instructs posterior patterning .	The expression and requirement of Dkk1, which binds to and inhibits the Wnt coreceptor LRP6, is shared among frogs, zebrafish, and mice, supporting the notion that the main role of the head organizer is to antagonize Wnt signaling, which instructs posterior patterning.	1	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	expression and requirement of Dkk1	dkk1	LRP6	LRP6	lrp6	5	6	15	16
We conclude that DKK1 inhibition of LRP6 is independent of LRP6 internalization and degradation .	We conclude that DKK1 inhibition of LRP6 is independent of LRP6 internalization and degradation.	3	7	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	3	4	6	7
Dkk1 can also block the Wnt and beta-catenin pathway by inducing Lrp6 endocytosis in the presence of Kremen proteins XREF_BIBR .	Dkk1 can also block the Wnt and beta-catenin pathway by inducing Lrp6 endocytosis in the presence of Kremen proteins XREF_BIBR.	0	12	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Lrp6	Lrp6	Lrp6	0	1	11	12
Dkk-1 inhibits the Wnt pathway by sequestering the Wnt co-receptor , LRP6 and preventing the Wnt induced coalescence of Frz and LRP6 at the membrane .	Dkk-1 inhibits the Wnt pathway by sequestering the Wnt co-receptor, LRP6 and preventing the Wnt induced coalescence of Frz and LRP6 at the membrane.	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk-1	Dkk-1	Dkk-1	LRP6	LRP6	LRP6	0	1	21	22
Semi-quantitative-RT-PCR analysis revealed that DKK1 was highly expressed in spleen and lymph node at two developmental stages , while in skeletal muscle , further real-time PCR quantified that DKK1 was down-regulated in Large White pigs compared to Tongcheng pigs , accompanied by the down-regulation of CTTNB1 and TCF4 , the up-regulation of LRP6 , suggesting that the phenotypic difference between lean and obese pigs might be correlated with the activity of Wnt and beta-cantenin signalling pathway .	Semi-quantitative-RT-PCR analysis revealed that DKK1 was highly expressed in spleen and lymph node at two developmental stages, while in skeletal muscle, further real-time PCR quantified that DKK1 was down-regulated in Large White pigs compared to Tongcheng pigs, accompanied by the down-regulation of CTTNB1 and TCF4, the up-regulation of LRP6, suggesting that the phenotypic difference between lean and obese pigs might be correlated with the activity of Wnt and beta-cantenin signalling pathway.	28	53	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	28	29	52	53
Here , evidence is presented that Wnt3a dependent phosphorylation of LRP6 occurs in the lipid raft and that Dkk1 inhibits the formation of a complex between LRP6 and casein kinase 1gamma ( CK1gamma ) by removing LRP6 from the lipid raft .	Here, evidence is presented that Wnt3a dependent phosphorylation of LRP6 occurs in the lipid raft and that Dkk1 inhibits the formation of a complex between LRP6 and casein kinase 1gamma (CK1gamma) by removing LRP6 from the lipid raft.	18	37	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	18	19	36	37
As shown in XREF_FIG B , DKK1 inhibited the TOPflash luciferase activity stimulated by co-expression of GRK5 or GRK6 with LRP6 , as well as the activity of LRP6 alone ( XREF_FIG B ) .	As shown in XREF_FIG B, DKK1 inhibited the TOPflash luciferase activity stimulated by co-expression of GRK5 or GRK6 with LRP6, as well as the activity of LRP6 alone (XREF_FIG B).	6	32	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	6	7	28	29
Furthermore , treatment of prostate cancer cells with Wnt3A CM or purified recombinant Wnt3A protein significantly enhanced cell growth and migration [ XREF_BIBR , XREF_BIBR ] , while treatment of prostate cancer cells with the LRP6 antagonist Dkk1 and Nilcosmaide significantly inhibited cell growth and migration [ XREF_BIBR , XREF_BIBR ] .	Furthermore, treatment of prostate cancer cells with Wnt3A CM or purified recombinant Wnt3A protein significantly enhanced cell growth and migration [XREF_BIBR, XREF_BIBR], while treatment of prostate cancer cells with the LRP6 antagonist Dkk1 and Nilcosmaide significantly inhibited cell growth and migration [XREF_BIBR, XREF_BIBR].	32	39	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	37	38	35	36
Dkk-1 is a potent regulator of the Wnt signalling pathway and inhibits the Frizzled co-receptor LRP6 [ XREF_BIBR ] .	Dkk-1 is a potent regulator of the Wnt signalling pathway and inhibits the Frizzled co-receptor LRP6 [XREF_BIBR].	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk-1	Dkk-1	Dkk-1	LRP6	LRP6	LRP6	0	1	15	16
Dkk1 inhibits the Wnt signaling pathway by binding to ( and presumably inactivating ) Lrp5 and Lrp6 XREF_BIBR .	Dkk1 inhibits the Wnt signaling pathway by binding to (and presumably inactivating) Lrp5 and Lrp6 XREF_BIBR.	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	Lrp6	Lrp6	Lrp6	0	1	16	17
XREF_BIBR that clathrin mediated down-regulation of LRP6 by Dkk1 depends on the presence of Kremen .	XREF_BIBR that clathrin mediated down-regulation of LRP6 by Dkk1 depends on the presence of Kremen.	3	9	down-regulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	8	9	6	7
On the other hand LRP6 blockade by Dickkopf 1 treatment abrogated the WNT and beta-catenin pathway without affecting WNT/ERK1/2 signaling .	On the other hand LRP6 blockade by Dickkopf 1 treatment abrogated the WNT and beta-catenin pathway without affecting WNT/ERK1/2 signaling.	4	9	blockade	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Dickkopf 1	Dickkopf 1	Dickkopf 1	LRP6	LRP6	LRP6	7	9	4	5
These results suggest that down-regulation of LRP6 by Dkk1 requires the internalization of Kremen1 and the LV sorting signal .	These results suggest that down-regulation of LRP6 by Dkk1 requires the internalization of Kremen1 and the LV sorting signal.	4	9	down-regulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	8	9	6	7
Exhaustive studies by Semenov et al demonstrated that DKK1 inhibition of LRP6 is independent of LRP6 internalization and degradation 19 .	Exhaustive studies by Semenov et al demonstrated that DKK1 inhibition of LRP6 is independent of LRP6 internalization and degradation 19.	8	12	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	8	9	11	12
Treatment of prostate cancer cells with Wnt3A CM or purified recombinant Wnt3A protein significantly enhanced cell growth and migration XREF_BIBR , XREF_BIBR , while treatment of prostate cancer cells with the LRP6 antagonist Dkk1 significantly inhibited cell growth and migration XREF_BIBR .	Treatment of prostate cancer cells with Wnt3A CM or purified recombinant Wnt3A protein significantly enhanced cell growth and migration XREF_BIBR, XREF_BIBR, while treatment of prostate cancer cells with the LRP6 antagonist Dkk1 significantly inhibited cell growth and migration XREF_BIBR.	28	34	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	33	34	31	32
DKK1 is known to inhibit both Wnt and LRP5 and Wnt and LRP6 responses XREF_BIBR , XREF_BIBR , XREF_BIBR .	DKK1 is known to inhibit both Wnt and LRP5 and Wnt and LRP6 responses XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	0	1	12	13
LRP6 is inhibited by the proteins Kremen and DKK1 , which combine to induce endocytosis of LRP6 , reducing its cell surface levels .	LRP6 is inhibited by the proteins Kremen and DKK1, which combine to induce endocytosis of LRP6, reducing its cell surface levels.	2	17	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	8	9	16	17
Conversely , the secreted Dickkopt1 ( Dkk1 ) protein inhibits canonical signaling by extracting LRP6 away from the lipid raft domains ( more detailed discussion below ) ( XREF_FIG ) .	Conversely, the secreted Dickkopt1 (Dkk1) protein inhibits canonical signaling by extracting LRP6 away from the lipid raft domains (more detailed discussion below) (XREF_FIG).	6	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	6	7	14	15
In addition , Dkk1 has also been shown to antagonize LRP6 function via LRP6 degradation with or without clathrindependent internalization , thereby suppressing the beta-catenin pathway .	In addition, Dkk1 has also been shown to antagonize LRP6 function via LRP6 degradation with or without clathrindependent internalization, thereby suppressing the beta-catenin pathway.	3	11	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	3	4	10	11
Once cleaved , iCAD no longer inhibits caspase activated DNAse permitting DNA degradation XREF_BIBR .	Once cleaved, iCAD no longer inhibits caspase activated DNAse permitting DNA degradation XREF_BIBR.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	iCAD	iCAD	iCAD	caspase activated DNAse	caspase activated DNAse	caspase activated DNAse	3	4	7	10
DFF45 ( also called ICAD ' Inhibition of CAD ' ) is an inhibitor of DFF40 , that also functions as a chaperone for native DFF40 ( Gu et al , 1999 ; Sakahira et al , 2000 ) .	DFF45 (also called ICAD ' Inhibition of CAD ') is an inhibitor of DFF40, that also functions as a chaperone for native DFF40 (Gu et al, 1999; Sakahira et al, 2000).	0	19	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	DFF45	DFF45	DFF45	DFF40	DFF40	DFF40	0	1	15	16
DFF40 interacts and is specifically inhibited by DFF45 and ICAD .	DFF40 interacts and is specifically inhibited by DFF45 and ICAD.	0	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	DFF45	DFF45	DFF45	DFF40	DFF40	DFF40	7	8	0	1
Ensuing studies show that ICAD and DFF45 sequesters the nonfunctional CAD and DFF40 monomer and is also able to disassemble the functional CAD and DFF40 dimer .	Ensuing studies show that ICAD and DFF45 sequesters the nonfunctional CAD and DFF40 monomer and is also able to disassemble the functional CAD and DFF40 dimer.	4	13	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DFF45	DFF45	DFF45	DFF40	DFF40	DFF40	6	7	12	13
In non apoptotic cells , DFF40 is inhibited by DFF45 , which also has a chaperone role allowing for appropriate folding of DFF40 into an active nuclease [ XREF_BIBR ] .	In non apoptotic cells, DFF40 is inhibited by DFF45, which also has a chaperone role allowing for appropriate folding of DFF40 into an active nuclease [XREF_BIBR].	5	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	DFF45	DFF45	DFF45	DFF40	DFF40	DFF40	9	10	5	6
DFF-45 is the inhibitor of DFF-40 ( also known as CAD ) , which is responsible for double stranded DNA cleavage in apoptosis .	DFF-45 is the inhibitor of DFF-40 (also known as CAD), which is responsible for double stranded DNA cleavage in apoptosis.	0	6	is the inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	DFF-45	DFF-45	DFF-45	DFF-40	DFF-40	DFF-40	0	1	5	6
The functional loss of DFF-45 allows DFF-40 to dimerize into the catalytic form , inducing DNA fragmentation [ XREF_BIBR ] .	The functional loss of DFF-45 allows DFF-40 to dimerize into the catalytic form, inducing DNA fragmentation [XREF_BIBR].	2	8	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DFF-45	loss of DFF-45	dff-45	DFF-40	DFF-40	dff-40	4	5	6	7
These results establish that DFF35 and ICAD ( S ) is the endogenous inhibitor of DFF40 and CAD and caspase dependent apoptotic DNA fragmentation in neurons .	These results establish that DFF35 and ICAD (S) is the endogenous inhibitor of DFF40 and CAD and caspase dependent apoptotic DNA fragmentation in neurons.	4	17	is the endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	ICAD	ICAD	ICAD	DFF40	DFF40	DFF40	6	7	15	16
XREF_BIBR DFF45 deficiency was also reported as a cause of abnormal cell apoptosis ; this seems counterintuitive , as DFF45 is an inhibitor of DFF40 and , thus , the lack of an inhibitor should result in increased activity of DNAse .	XREF_BIBR DFF45 deficiency was also reported as a cause of abnormal cell apoptosis; this seems counterintuitive, as DFF45 is an inhibitor of DFF40 and, thus, the lack of an inhibitor should result in increased activity of DNAse.	19	25	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	DFF45	DFF45	DFF45	DFF40	DFF40	DFF40	19	20	24	25
CYLD negatively regulates BCL3 , preventing nuclear entry where it forms a dimer with p50 and p52 , resulting in transcription of genes involved in proliferation including cyclin D1 .	CYLD negatively regulates BCL3, preventing nuclear entry where it forms a dimer with p50 and p52, resulting in transcription of genes involved in proliferation including cyclin D1.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	BCL3	BCL3	BCL3	0	1	3	4
CYLD inhibits Bcl3 by antagonizing the K63 linked polyubiquitination of Bcl3 thus preventing its nuclear translocation .	CYLD inhibits Bcl3 by antagonizing the K63 linked polyubiquitination of Bcl3 thus preventing its nuclear translocation.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	Bcl3	Bcl3	Bcl3	0	1	2	3
CYLD also inactivates BCL-3 by deubiquitination [ XREF_BIBR ] .	CYLD also inactivates BCL-3 by deubiquitination [XREF_BIBR].	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	BCL-3	BCL-3	BCL-3	0	1	3	4
Interestingly , the ubiquitin ligase CYLD , which negatively regulates bcl3 nuclear localization , was increased 2.7-fold in the RNA-Seq analysis ( XREF_SUPPLEMENTARY ) .	Interestingly, the ubiquitin ligase CYLD, which negatively regulates bcl3 nuclear localization, was increased 2.7-fold in the RNA-Seq analysis (XREF_SUPPLEMENTARY).	2	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	bcl3	bcl3	bcl3	5	6	10	11
Here , decreasing CYLD levels activated BCL3 accumulation followed by its import into the nucleus , probably mediated by an interaction between the polyubiquitin chains of BCL-3 and importins .	Here, decreasing CYLD levels activated BCL3 accumulation followed by its import into the nucleus, probably mediated by an interaction between the polyubiquitin chains of BCL-3 and importins.	3	7	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD levels	cyld	BCL3	BCL3	bcl3	3	4	6	7
Furthermore , siRNA against Snail1 , which up-regulated CYLD expression ( XREF_FIG ) , reduced nuclear BCL-3 levels , confirming that reexpression of CYLD blocks nuclear translocation of BCL-3 in melanoma ( XREF_FIG ) .	Furthermore, siRNA against Snail1, which up-regulated CYLD expression (XREF_FIG), reduced nuclear BCL-3 levels, confirming that reexpression of CYLD blocks nuclear translocation of BCL-3 in melanoma (XREF_FIG).	21	30	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	reexpression of CYLD	cyld	BCL-3	BCL-3	bcl-3	23	24	28	29
CYLD prevents nuclear accumulation of BCL-3 and hence reduces Cyclin D1 expression and proliferation of keratinocytes .	CYLD prevents nuclear accumulation of BCL-3 and hence reduces Cyclin D1 expression and proliferation of keratinocytes.	0	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	BCL-3	BCL-3	BCL-3	0	1	5	6
CYLD , but not C/S-CYLD , abrogated BCL-3 binding of IL-10 promoter , confirming the important role of CYLD in the regulation of BCL-3 .	CYLD, but not C/S-CYLD, abrogated BCL-3 binding of IL-10 promoter, confirming the important role of CYLD in the regulation of BCL-3.	0	8	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	BCL-3	BCL-3	BCL-3	0	1	7	8
It was observed in malignant melanoma that loss of CYLD also induces nuclear accumulation of BCL-3 and NF-kappaB activation , with the consequence of induced N-cadherin ( migration ) and cyclin D1 ( proliferation ) activity .	It was observed in malignant melanoma that loss of CYLD also induces nuclear accumulation of BCL-3 and NF-kappaB activation, with the consequence of induced N-cadherin (migration) and cyclin D1 (proliferation) activity.	7	18	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CYLD	loss of CYLD	cyld	BCL-3	BCL-3	bcl-3	9	10	15	16
Further , the de-ubiquitinase CYLD has been shown to inactivate TRAF6 downstream of RANK in osteoclasts , as evidenced by removal of polyubiquitin chains , and the physiologic relevance of this mechanism is supported by the phenotype of CYLD deficient osteoclasts , which exhibit hyper-responsiveness to RANK .	Further, the de-ubiquitinase CYLD has been shown to inactivate TRAF6 downstream of RANK in osteoclasts, as evidenced by removal of polyubiquitin chains, and the physiologic relevance of this mechanism is supported by the phenotype of CYLD deficient osteoclasts, which exhibit hyper-responsiveness to RANK.	2	13	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	TRAF6	TRAF6	TRAF6	4	5	10	11
The ubiquitin editing enzyme CYLD inhibits TRAF6 and -7 and TLR2 [ XREF_BIBR ] .	The ubiquitin editing enzyme CYLD inhibits TRAF6 and -7 and TLR2 [XREF_BIBR].	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	TRAF6	TRAF6	TRAF6	4	5	6	7
As we described here for YOD1 , CYLD is acting on TRAF6 and p62 complexes , but - in contrast to YOD1 - CYLD is not preventing the formation of TRAF6 and p62 aggregates , but is recruited to TRAF6 by p62 .	As we described here for YOD1, CYLD is acting on TRAF6 and p62 complexes, but - in contrast to YOD1 - CYLD is not preventing the formation of TRAF6 and p62 aggregates, but is recruited to TRAF6 by p62.	23	37	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	TRAF6	TRAF6	TRAF6	23	24	30	31
Moreover , DAB2IP could suppress AKT and facilitate ASK1 activation under TNF-alpha treatment [ XREF_BIBR ] .	Moreover, DAB2IP could suppress AKT and facilitate ASK1 activation under TNF-alpha treatment [XREF_BIBR].	2	7	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	AKT	AKT	AKT	2	3	5	6
Since DAB2IP can deactivate Akt through suppressing PI3K pathway [ XREF_BIBR ] and activating Akt is known to prevent Skp2 degradation [ XREF_BIBR ] , DAB2IP is able to modulate Skp2 protein degradation through Akt pathway .	Since DAB2IP can deactivate Akt through suppressing PI3K pathway [XREF_BIBR] and activating Akt is known to prevent Skp2 degradation [XREF_BIBR], DAB2IP is able to modulate Skp2 protein degradation through Akt pathway.	1	5	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	Akt	Akt	Akt	1	2	4	5
Gain of function study showed that DAB2IP can suppress the PI3K-Akt pathway and enhance ASK1 activation leading to cell apoptosis , whereas loss of DAB2IP expression resulted in PI3K-Akt activation and ASK1-JNK inactivation leading to accelerated PCa growth in vivo .	Gain of function study showed that DAB2IP can suppress the PI3K-Akt pathway and enhance ASK1 activation leading to cell apoptosis, whereas loss of DAB2IP expression resulted in PI3K-Akt activation and ASK1-JNK inactivation leading to accelerated PCa growth in vivo.	6	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	PI3K-Akt	PI3K-Akt	PI3K-Akt	6	7	10	11
XREF_BIBR In the present study , we showed that knockdown of DAB2IP could activate the ERK or Akt pathways in vitro .	XREF_BIBR In the present study, we showed that knockdown of DAB2IP could activate the ERK or Akt pathways in vitro.	9	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	Akt	Akt	Akt	11	12	17	18
The phosphorylated GSK-3beta and total GSK-3 are detected by western blot , while PERK are inhibited by the transfection of P58IPK plasmid and AMPK are inhibited by the inhibitor Compound C. Finally , the interaction between PERK and GSK-3 are identified by co- immunoprecipitation and direct immuno-fluorescence .	The phosphorylated GSK-3beta and total GSK-3 are detected by western blot, while PERK are inhibited by the transfection of P58IPK plasmid and AMPK are inhibited by the inhibitor Compound C. Finally, the interaction between PERK and GSK-3 are identified by co- immunoprecipitation and direct immuno-fluorescence.	13	21	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	P58IPK	P58IPK	P58IPK	PERK	PERK	PERK	20	21	13	14
A second possibility is that PERK is actively repressed in photoreceptors such as by inhibition of its cytosolic kinase by binding of p58IPK or Nck proteins [ XREF_BIBR , XREF_BIBR ] .	A second possibility is that PERK is actively repressed in photoreceptors such as by inhibition of its cytosolic kinase by binding of p58IPK or Nck proteins [XREF_BIBR, XREF_BIBR].	5	25	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p58IPK	p58IPK	p58IPK	PERK	PERK	PERK	22	23	5	6
They found that the cytosolic isoform of GRP78 with a molecular weight of about 62 kDa was expressed in several cell types as a result of alternative splicing and involved in PERK activation by antagonizing the PERK inhibitor P58IPK , a DnaJ family protein that could inhibit the PERK kinase activity .	They found that the cytosolic isoform of GRP78 with a molecular weight of about 62 kDa was expressed in several cell types as a result of alternative splicing and involved in PERK activation by antagonizing the PERK inhibitor P58IPK, a DnaJ family protein that could inhibit the PERK kinase activity.	34	50	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	P58IPK	P58IPK	P58IPK	PERK	PERK	PERK	38	39	48	49
PERK is activated by decreasing levels of free BiP in the ER , and is inhibited by DNAJC3 which acts to turn off this portion of the ER stress response .	PERK is activated by decreasing levels of free BiP in the ER, and is inhibited by DNAJC3 which acts to turn off this portion of the ER stress response.	0	21	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	DNAJC3	DNAJC3	DNAJC3	PERK	PERK	PERK	17	18	0	1
Our result suggests that the induction of P58IPK by oxidized LDL inhibits the induction of PERK .	Our result suggests that the induction of P58IPK by oxidized LDL inhibits the induction of PERK.	5	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P58IPK	P58IPK	P58IPK	PERK	PERK	PERK	7	8	15	16
P58IPK and K3L repress PKR activation and activity .	P58IPK and K3L repress PKR activation and activity.	0	5	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P58IPK	P58IPK	P58IPK	PKR	PKR	PKR	0	1	4	5
These data , taken together , suggest that P58IPK and K3L may mediate PKR inhibition by distinct mechanisms .	These data, taken together, suggest that P58IPK and K3L may mediate PKR inhibition by distinct mechanisms.	8	14	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	P58IPK	P58IPK	P58IPK	PKR	PKR	PKR	8	9	13	14
DNAJC3 reportedly blocks PKR dimerization XREF_BIBR .	DNAJC3 reportedly blocks PKR dimerization XREF_BIBR.	0	5	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DNAJC3	DNAJC3	DNAJC3	PKR	PKR	PKR	0	1	3	4
In contrast , a nonfunctional form of P58IPK lacking a TPR motif did not inhibit kinase activity or perturb PKR dimers .	In contrast, a nonfunctional form of P58IPK lacking a TPR motif did not inhibit kinase activity or perturb PKR dimers.	5	20	perturb	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P58IPK	P58IPK	P58IPK	PKR	PKR	PKR	7	8	19	20
We demonstrated , utilizing both the yeast and lambda systems , that P58IPK , a member of the tetratricopeptide repeat protein family , can block kinase activity by preventing PKR dimerization .	We demonstrated, utilizing both the yeast and lambda systems, that P58IPK, a member of the tetratricopeptide repeat protein family, can block kinase activity by preventing PKR dimerization.	12	30	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P58IPK	P58IPK	P58IPK	PKR	PKR	PKR	12	13	29	30
The results of western blot analysis indicated that chrysotoxene ( 5 , 10 or 20 microg/ml ) significantly ( P < 0.05 ) promoted the release of second mitochondria derived activator of caspase ( Smac ) and Cytochrome c from the mitochondria to the cytoplasm , downregulated Survivin and B cell lymphoma-2 ( Bcl-2 ) proteins levels , and upregulated Bcl-2-associated X factor ( Bax ) , apoptotic protease activating factor-1 ( Apaf-1 ) , cleaved ( c )-caspase-9 and c-caspase-3 protein levels in HepG2 cells , compared with the control group .	The results of western blot analysis indicated that chrysotoxene (5, 10 or 20 microg/ml) significantly (P < 0.05) promoted the release of second mitochondria derived activator of caspase (Smac) and Cytochrome c from the mitochondria to the cytoplasm, downregulated Survivin and B cell lymphoma-2 (Bcl-2) proteins levels, and upregulated Bcl-2-associated X factor (Bax), apoptotic protease activating factor-1 (Apaf-1), cleaved (c)-caspase-9 and c-caspase-3 protein levels in HepG2 cells, compared with the control group.	32	51	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	Survivin	Survivin	Survivin	34	35	47	48
Some studies reported that IAP proteins , such as XIAP , c-IAP1 , c-IAP2 and Apollon , degraded Smac through the ubiquitin pathway , while others reported that Smac promoted the degradation of survivin , cIAP1 , cIAP2 , but not XIAP and livin .	Some studies reported that IAP proteins, such as XIAP, c-IAP1, c-IAP2 and Apollon, degraded Smac through the ubiquitin pathway, while others reported that Smac promoted the degradation of survivin, cIAP1, cIAP2, but not XIAP and livin.	28	34	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	survivin	survivin	survivin	28	29	33	34
The increased cytosolic levels of Smac could potentially inhibit survivin , one of the IAPs , to promote the activation of caspases and thereby induce cell death .	The increased cytosolic levels of Smac could potentially inhibit survivin, one of the IAPs, to promote the activation of caspases and thereby induce cell death.	3	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	levels of Smac	smac	survivin	survivin	survivin	5	6	9	10
For example , the transmembrane protein DLK1 has been shown to negatively regulate NOTCH1 [ XREF_BIBR ] , which is overexpressed in prostate cancer and is associated with human prostate cancer cell invasion [ XREF_BIBR ] ; this suggests that DLK1 downregulation may promote cell invasion via increased NOTCH1 expression .	For example, the transmembrane protein DLK1 has been shown to negatively regulate NOTCH1 [XREF_BIBR], which is overexpressed in prostate cancer and is associated with human prostate cancer cell invasion [XREF_BIBR]; this suggests that DLK1 downregulation may promote cell invasion via increased NOTCH1 expression.	3	26	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DLK1	DLK1	DLK1	NOTCH1	NOTCH1	NOTCH1	6	7	13	14
DLK1 is thought to act as a ligand for Notch-1 XREF_BIBR and has been shown to antagonize Notch-1 activity XREF_BIBR - XREF_BIBR .	DLK1 is thought to act as a ligand for Notch-1 XREF_BIBR and has been shown to antagonize Notch-1 activity XREF_BIBR - XREF_BIBR.	0	19	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DLK1	DLK1	DLK1	Notch-1	Notch-1	Notch-1	0	1	17	18
These anomalies are due to increased expression of the Notch1 antagonist Dlk1 and suppression of Notch signaling .	These anomalies are due to increased expression of the Notch1 antagonist Dlk1 and suppression of Notch signaling.	6	12	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Dlk1	Dlk1	Dlk1	Notch1	Notch1	Notch1	11	12	9	10
M063R shows sequence similarity with its C-terminal half a with a glutamate rich domain of the cellular death-domain associated protein , Daxx , leading to the hypothesis that M063R can inhibit Fas associated cell death through interfering with the function of Daxx [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] However , this model remains unproven and it is still not completely understood under which circumstances Daxx functions as either a pro apoptotic or an anti-apoptotic protein [ XREF_BIBR , XREF_BIBR ] .	M063R shows sequence similarity with its C-terminal half a with a glutamate rich domain of the cellular death-domain associated protein, Daxx, leading to the hypothesis that M063R can inhibit Fas associated cell death through interfering with the function of Daxx [XREF_BIBR, XREF_BIBR, XREF_BIBR] However, this model remains unproven and it is still not completely understood under which circumstances Daxx functions as either a pro apoptotic or an anti-apoptotic protein [XREF_BIBR, XREF_BIBR].	19	32	leading	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Daxx	Daxx	Daxx	Fas	Fas	Fas	21	22	31	32
XREF_BIBR , XREF_BIBR , XREF_BIBR Our data clearly show that DAB2IP could inhibit STAT3 activity through dephosphorylation of its two residues , tyrosine 705 and serine 727 , both of which are critical for STAT3 dimerization and transactivation , XREF_BIBR , XREF_BIBR and then selectively control the expression of these target genes ( i.e ., survivin and Bcl-2 ) in vitro and in vivo .	XREF_BIBR, XREF_BIBR, XREF_BIBR Our data clearly show that DAB2IP could inhibit STAT3 activity through dephosphorylation of its two residues, tyrosine 705 and serine 727, both of which are critical for STAT3 dimerization and transactivation, XREF_BIBR, XREF_BIBR and then selectively control the expression of these target genes (i.e., survivin and Bcl-2) in vitro and in vivo.	10	45	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	STAT3	STAT3	STAT3	10	11	13	14
There are many other mechanisms such as promoter hypermethylation , autophosphorylation of calmodulin-domain , protein degradation or inhibitory phosphorylations of the DAPK molecule itself that might inactivate DAPK .	There are many other mechanisms such as promoter hypermethylation, autophosphorylation of calmodulin-domain, protein degradation or inhibitory phosphorylations of the DAPK molecule itself that might inactivate DAPK.	18	28	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	DAPK	phosphorylations of the DAPK	dapk	DAPK	DAPK	dapk	21	22	27	28
The KLHL20-Cul3-ROC1 E3 ligase complex promotes DAPK polyubiquitination , thereby inducing the proteasomal degradation of DAPK .	The KLHL20-Cul3-ROC1 E3 ligase complex promotes DAPK polyubiquitination, thereby inducing the proteasomal degradation of DAPK.	2	16	inducing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DAPK	E3 ligase complex promotes DAPK polyubiquitination	dapk	DAPK	DAPK	dapk	6	7	15	16
TSC2 and a splice variant of DAPK mediate the lysosomal degradation of DAPK1 .	TSC2 and a splice variant of DAPK mediate the lysosomal degradation of DAPK1.	4	13	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DAPK	DAPK	DAPK	DAPK1	DAPK1	DAPK1	6	7	12	13
These results suggest that Dab2 sequesters LRP6 towards clathrin , away from its interaction with caveolin , and that its inhibitory effect does not require LRP6 endocytosis .	These results suggest that Dab2 sequesters LRP6 towards clathrin, away from its interaction with caveolin, and that its inhibitory effect does not require LRP6 endocytosis.	4	8	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dab2	Dab2	Dab2	LRP6	LRP6	LRP6	4	5	6	7
Deletion analyses of the Lef-1 protein demonstrate that the beta-catenin binding region is not required for its interaction with Dlx2 or synergistic activation of the Msx2 promoter .	Deletion analyses of the Lef-1 protein demonstrate that the beta-catenin binding region is not required for its interaction with Dlx2 or synergistic activation of the Msx2 promoter.	19	26	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Dlx2	Dlx2	Dlx2	Msx2	Msx2	Msx2	19	20	25	26
Interestingly , Msx2 repression of the synergistic activation by Dlx2 and the shorter Lef-1 isoform ( Lef-1 DeltaN113 ) was increased compared to Lef-1 FL ( XREF_FIG ) .	Interestingly, Msx2 repression of the synergistic activation by Dlx2 and the shorter Lef-1 isoform (Lef-1 DeltaN113) was increased compared to Lef-1 FL (XREF_FIG).	2	14	repression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Dlx2	Dlx2	Dlx2	Msx2	Msx2	Msx2	9	10	2	3
We also found that DTX4 expression alone did not cause TBK1 degradation , but coexpression of DTX4 and NLRP4 resulted in more TBK1 degradation than did expression of NLRP4 alone ( XREF_FIG ) .	We also found that DTX4 expression alone did not cause TBK1 degradation, but coexpression of DTX4 and NLRP4 resulted in more TBK1 degradation than did expression of NLRP4 alone (XREF_FIG).	4	11	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DTX4	DTX4 expression	dtx4	TBK1	TBK1	tbk1	4	5	10	11
6 Furthermore , knockdown of DTX4 using shRNA prevented the inhibition and degradation of TBK1 by NLRP4 .	6 Furthermore, knockdown of DTX4 using shRNA prevented the inhibition and degradation of TBK1 by NLRP4.	3	15	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DTX4	DTX4	DTX4	TBK1	TBK1	TBK1	5	6	14	15
As a consequence the DAB2IP could block the genomic and non genomic pathway of AR activation .	As a consequence the DAB2IP could block the genomic and non genomic pathway of AR activation.	3	15	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	AR	AR	AR	4	5	14	15
Recent studies have demonstrated that the loss of DAB2IP in castration resistant prostate cancer can enhance androgen receptor signaling .	Recent studies have demonstrated that the loss of DAB2IP in castration resistant prostate cancer can enhance androgen receptor signaling.	6	18	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DAB2IP	loss of DAB2IP	dab2ip	androgen receptor	androgen receptor	androgen receptor	8	9	16	18
Dact2 has also been shown to attenuate TGF-beta and Nodal signaling by facilitating lysosomal degradation of type I receptors ALK4 and ALK5 during mesoderm induction .	Dact2 has also been shown to attenuate TGF-beta and Nodal signaling by facilitating lysosomal degradation of type I receptors ALK4 and ALK5 during mesoderm induction.	0	24	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dact2	Dact2	Dact2	ALK5	ALK5	ALK5	0	1	21	22
Interestingly , we found that double PHD fingers protein DPF2 and BAF45d suppressed PGC-1alpha-dependent transactivation of ERRalpha by recognizing acetylated histone H3 and associating with HDAC1 .	Interestingly, we found that double PHD fingers protein DPF2 and BAF45d suppressed PGC-1alpha-dependent transactivation of ERRalpha by recognizing acetylated histone H3 and associating with HDAC1.	9	17	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAF45d	BAF45d	BAF45d	ERRalpha	ERRalpha	ERRalpha	11	12	16	17
Msx2 mRNA abundance was reduced by 60 % in the anterior half , and by 50 % in the posterior half of Dlx5 ; Dlx6 DKO HLs from the same embryo , as compared to WT .	Msx2 mRNA abundance was reduced by 60% in the anterior half, and by 50% in the posterior half of Dlx5; Dlx6 DKO HLs from the same embryo, as compared to WT.	0	23	reduced	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Dlx5	Dlx5	Dlx5	Msx2	Msx2	Msx2	22	23	0	1
Cftr deficiency results in accelerated Dpr1 induced lysosomal degradation of Dvl2 .	Cftr deficiency results in accelerated Dpr1 induced lysosomal degradation of Dvl2.	2	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Dpr1	Dpr1	Dpr1	Dvl2	Dvl2	Dvl2	5	6	10	11
Specifically , DAB2IP inhibits the RAS pathway by directly binding to and inactivating H-Ras and R-Ras through its Ras GTPase activity [ XREF_BIBR ] , regulates the ASK1 pathway by blocking interaction of ASK1 with its inhibitor 14-3-3 [ XREF_BIBR ] , and binds to and inactivates the Akt kinase [ XREF_BIBR ] .	Specifically, DAB2IP inhibits the RAS pathway by directly binding to and inactivating H-Ras and R-Ras through its Ras GTPase activity [XREF_BIBR], regulates the ASK1 pathway by blocking interaction of ASK1 with its inhibitor 14-3-3 [XREF_BIBR], and binds to and inactivates the Akt kinase [XREF_BIBR].	2	46	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	H-Ras	H-Ras	H-Ras	2	3	13	14
Loss of NF1 , RASAL2 , and DAB2IP led to H- and K-Ras activation followed by ERK and AKT activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Loss of NF1, RASAL2, and DAB2IP led to H- and K-Ras activation followed by ERK and AKT activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	13	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	DAB2IP	Loss of NF1, RASAL2, and DAB2IP	dab2ip	K-Ras	K-Ras	k-ras	7	8	12	13
Overexpression of DUSP6 in NSCLC may inactivate ERK2 and further act as a natural terminator of AKT and MAPK signal transduction .	Overexpression of DUSP6 in NSCLC may inactivate ERK2 and further act as a natural terminator of AKT and MAPK signal transduction.	0	10	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP6	Overexpression of DUSP6	dusp6	ERK2	ERK2	erk2	2	3	7	8
For example , after transfection into mammalian cells , DUSP6 completely inactivates ERK1 and ERK2 , even at low concentrations , but not JNK or p38 kinases [ XREF_BIBR , XREF_BIBR ] ; similarly , DUSP9 also displays some specificity towards ERK [ XREF_BIBR ] .	For example, after transfection into mammalian cells, DUSP6 completely inactivates ERK1 and ERK2, even at low concentrations, but not JNK or p38 kinases [XREF_BIBR, XREF_BIBR]; similarly, DUSP9 also displays some specificity towards ERK [XREF_BIBR].	9	15	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP6	DUSP6	DUSP6	ERK2	ERK2	ERK2	9	10	14	15
Moreover , the coexpression of MKP3 and rVH6 , an ERK2 specific phosphatase , suppressed the anchorage independent activation of ERK2 induced by vinexin beta .	Moreover, the coexpression of MKP3 and rVH6, an ERK2 specific phosphatase, suppressed the anchorage independent activation of ERK2 induced by vinexin beta.	3	21	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MKP3	coexpression of MKP3	mkp3	ERK2	ERK2	erk2	5	6	20	21
DUSP6 is an upstream inhibitor of ERK2 , which is an important signaling protein in the AKT signaling pathway .	DUSP6 is an upstream inhibitor of ERK2, which is an important signaling protein in the AKT signaling pathway.	0	13	is an upstream inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	DUSP6	DUSP6	DUSP6	ERK2	ERK2	ERK2	0	1	6	7
This evidence suggests that constitutive activation of MAPK1 synergistically induced by frequent mutation of KRAS2 and the loss of function of DUSP6 plays key roles in pancreatic carcinogenesis and progression .	This evidence suggests that constitutive activation of MAPK1 synergistically induced by frequent mutation of KRAS2 and the loss of function of DUSP6 plays key roles in pancreatic carcinogenesis and progression.	5	22	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	DUSP6	DUSP6	DUSP6	MAPK1	MAPK1	MAPK1	21	22	7	8
ERK2 plays a critical role in regulation of the activity of the dual specificity phosphatase MKP3 ( DUSP6 ) , which inactivates ERK2 by dephosphorylation .	ERK2 plays a critical role in regulation of the activity of the dual specificity phosphatase MKP3 (DUSP6), which inactivates ERK2 by dephosphorylation.	15	23	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP6	DUSP6	DUSP6	ERK2	ERK2	ERK2	17	18	22	23
DUSP6 is known to bind to and inactivate ERK1 and ERK2 [ XREF_BIBR ] , and previous studies have suggested a genetic association between DUSP6 and both schizophrenia and BP [ XREF_BIBR , XREF_BIBR ] .	DUSP6 is known to bind to and inactivate ERK1 and ERK2 [XREF_BIBR], and previous studies have suggested a genetic association between DUSP6 and both schizophrenia and BP [XREF_BIBR, XREF_BIBR].	0	11	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP6	DUSP6	DUSP6	ERK2	ERK2	ERK2	0	1	10	11
In addition to mutational activation of the ERK cascade , increased ERK activation can result from silencing of the DUSP6 phosphatase that normally serves to inactivate ERK-2 [ XREF_BIBR ] .	In addition to mutational activation of the ERK cascade, increased ERK activation can result from silencing of the DUSP6 phosphatase that normally serves to inactivate ERK-2 [XREF_BIBR].	19	28	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP6	DUSP6	DUSP6	ERK-2	ERK-2	ERK-2	19	20	26	27
It is noteworthy that the activity of MKP3 and DUSP6 has been shown to be regulated by cell adhesion and suppresses the anchorage independent activation of Erk2 induced by vinexin beta , a focal adhesion scaffold protein XREF_BIBR , making this phosphatase a likely Bit1 target .	It is noteworthy that the activity of MKP3 and DUSP6 has been shown to be regulated by cell adhesion and suppresses the anchorage independent activation of Erk2 induced by vinexin beta, a focal adhesion scaffold protein XREF_BIBR, making this phosphatase a likely Bit1 target.	5	27	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP6	DUSP6	DUSP6	Erk2	Erk2	Erk2	9	10	26	27
Local inhibition of GSK-3beta by DVL-1 may result in local changes in the phosphorylation of GSK-3beta targets that regulate MT dynamics .	Local inhibition of GSK-3beta by DVL-1 may result in local changes in the phosphorylation of GSK-3beta targets that regulate MT dynamics.	1	6	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	DVL-1	DVL-1	DVL-1	GSK-3beta	GSK-3beta	GSK-3beta	5	6	3	4
Dishevelled 1 ( DVL1 ) is thought to act as a positive regulator of the wnt signalling pathway , and inhibits GSK3beta activity preventing beta-catenin degradation and thus allowing wnt target gene expression .	Dishevelled 1 (DVL1) is thought to act as a positive regulator of the wnt signalling pathway, and inhibits GSK3beta activity preventing beta-catenin degradation and thus allowing wnt target gene expression.	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dishevelled 1	Dishevelled 1	Dishevelled 1	GSK3beta	GSK3beta	GSK3beta	0	2	21	22
Thus , inhibition of GSK-3beta by DVL-1 may change the ability of MAPs to stabilize MTs .	Thus, inhibition of GSK-3beta by DVL-1 may change the ability of MAPs to stabilize MTs.	2	7	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	DVL-1	DVL-1	DVL-1	GSK-3beta	GSK-3beta	GSK-3beta	6	7	4	5
During developmental and homoeostatic events , the Wnt signalling mechanism can be regulated by Dishevelled ( Dvl1 ) which inhibits GSK3beta activity and reduces the degree of beta-catenin degradation .	During developmental and homoeostatic events, the Wnt signalling mechanism can be regulated by Dishevelled (Dvl1) which inhibits GSK3beta activity and reduces the degree of beta-catenin degradation.	12	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dvl1	Dvl1	Dvl1	GSK3beta	GSK3beta	GSK3beta	16	17	20	21
Recently , the CL100 phosphatase has been shown to inactivate p42mapk in vitro by dephosphorylating Thr 183 and Tyr 185 at similar rates .	Recently, the CL100 phosphatase has been shown to inactivate p42mapk in vitro by dephosphorylating Thr 183 and Tyr 185 at similar rates.	3	11	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CL100	CL100	CL100	p42mapk	p42mapk	p42mapk	3	4	10	11
In T cell acute lymphoblastic leukaemia ( T-ALL ) , ERK1 , ERK2 and p38 are inactivated by the ERK and p38 phosphatase MKP1 ( also known as DUSP1 ) 48 .	In T cell acute lymphoblastic leukaemia (T-ALL), ERK1, ERK2 and p38 are inactivated by the ERK and p38 phosphatase MKP1 (also known as DUSP1) 48.	10	24	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MKP1	MKP1	MKP1	ERK2	ERK2	ERK2	23	24	12	13
Overexpression of DUSP1 , -2 , or -4 prevented ERK2 activation , but only DUSP2 and -4 caused ERK2-GFP nuclear accumulation or could be immunoprecipitated with ERK2 .	Overexpression of DUSP1, -2, or -4 prevented ERK2 activation, but only DUSP2 and -4 caused ERK2-GFP nuclear accumulation or could be immunoprecipitated with ERK2.	0	10	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP1	Overexpression of DUSP1	dusp1	ERK2	ERK2	erk2	2	3	9	10
Conditional expression of MKP-1 inhibited PMA induced ERK2 , SAPK , and p38 MAPK activity .	Conditional expression of MKP-1 inhibited PMA induced ERK2, SAPK, and p38 MAPK activity.	1	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MKP-1	expression of MKP-1	mkp-1	ERK2	ERK2	erk2	3	4	7	8
We previously found that Dyrk1A suppresses tau E10 inclusion by inhibiting ASF induced promotion of tau E10 inclusion .	We previously found that Dyrk1A suppresses tau E10 inclusion by inhibiting ASF induced promotion of tau E10 inclusion.	4	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dyrk1A	Dyrk1A	Dyrk1A	tau	tau	tau	4	5	6	7
DYRK1A induced tau phosphorylation inhibits tau activity to stimulate microtubule assembly and promotes its self-assembly into filaments [ XREF_BIBR ] .	DYRK1A induced tau phosphorylation inhibits tau activity to stimulate microtubule assembly and promotes its self-assembly into filaments [XREF_BIBR].	0	4	induced	Positive_early_regulation	Negative_activation	Positive_regulation	DYRK1A	DYRK1A	dyrk1a	tau	tau phosphorylation	tau	0	1	2	3
In neuronal N2a cells , we found that over-expression of Dyrk1A suppressed tau E10 inclusion , whereas inhibition of Dyrk1A led to increased E10 inclusion .	In neuronal N2a cells, we found that over-expression of Dyrk1A suppressed tau E10 inclusion, whereas inhibition of Dyrk1A led to increased E10 inclusion.	8	14	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dyrk1A	over-expression of Dyrk1A	dyrk1a	tau	tau	tau	10	11	12	13
DYRK1A induced tau phosphorylation inhibits tau activity to stimulate microtubule assembly and promotes its self-assembly into filaments .	DYRK1A induced tau phosphorylation inhibits tau activity to stimulate microtubule assembly and promotes its self-assembly into filaments.	0	4	induced	Positive_early_regulation	Negative_activation	Positive_regulation	DYRK1A	DYRK1A	dyrk1a	tau	tau phosphorylation	tau	0	1	2	3
In the neuronal cells , Dyrk1A suppressed tau E10 inclusion .	In the neuronal cells, Dyrk1A suppressed tau E10 inclusion.	5	9	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dyrk1A	Dyrk1A	Dyrk1A	tau	tau	tau	5	6	7	8
Both in vitro and in vivo , wild type MKP-2 effectively inactivated ERK2 whereas MKP-2 mutants incapable of binding to ERK and p38 did not .	Both in vitro and in vivo, wild type MKP-2 effectively inactivated ERK2 whereas MKP-2 mutants incapable of binding to ERK and p38 did not.	7	13	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MKP-2	MKP-2	MKP-2	ERK2	ERK2	ERK2	9	10	12	13
Dusp26 ( dual specificity phosphatase 26 ) is a negative regulator of p53 , and miR-200-mediated reduction of DUSP26 induces p53 activation and apoptosis .	Dusp26 (dual specificity phosphatase 26) is a negative regulator of p53, and miR-200-mediated reduction of DUSP26 induces p53 activation and apoptosis.	16	21	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP26	DUSP26	DUSP26	p53	p53	p53	18	19	20	21
Dual specificity protein phosphatase 26 ( DUSP26 ) is overexpressed in high-risk neuroblastoma ( NB ) and contributes to chemoresistance by inhibiting p53 function .	Dual specificity protein phosphatase 26 (DUSP26) is overexpressed in high-risk neuroblastoma (NB) and contributes to chemoresistance by inhibiting p53 function.	0	23	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dual specificity protein phosphatase 26	Dual specificity protein phosphatase 26 (DUSP26) is overexpressed	dual specificity protein phosphatase 26	p53	p53	p53	0	5	22	23
The MAP kinase phosphatase 1 ( MKP-1 ) , a dual serine threonine phosphatase , inactivates the MAP kinases ERK and JNK and SAPK which are involved in neuronal survival and neuronal cell death following injury and degenerative stimuli .	The MAP kinase phosphatase 1 (MKP-1), a dual serine threonine phosphatase, inactivates the MAP kinases ERK and JNK and SAPK which are involved in neuronal survival and neuronal cell death following injury and degenerative stimuli.	1	26	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAP kinase phosphatase 1	MAP kinase phosphatase 1	MAP kinase phosphatase 1	SAPK	SAPK	SAPK	1	5	23	24
Thus , both ERK activation and MKP-1 , which down-regulates SAPK and JNK , are required for S1P mediated inhibition of apoptosis .	Thus, both ERK activation and MKP-1, which down-regulates SAPK and JNK, are required for S1P mediated inhibition of apoptosis.	4	15	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MKP-1	MKP-1	MKP-1	SAPK	SAPK	SAPK	6	7	10	11
MKP-1 antagonizes SAPK and JNK activation in response to diverse environmental stresses .	MKP-1 antagonizes SAPK and JNK activation in response to diverse environmental stresses.	0	5	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MKP-1	MKP-1	MKP-1	SAPK	SAPK	SAPK	0	1	2	3
MKP-1 antagonizes SAPK activity and its enhanced expression and activity under hypoxia had been regarded as one possible explanation for the rapid decline of JNK and SAPK activity after 4 hours [ XREF_BIBR ] .	MKP-1 antagonizes SAPK activity and its enhanced expression and activity under hypoxia had been regarded as one possible explanation for the rapid decline of JNK and SAPK activity after 4 hours [XREF_BIBR].	0	3	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MKP-1	MKP-1	MKP-1	SAPK	SAPK	SAPK	0	1	2	3
The MKP-1 mutant did not affect ERK activity , indicating that MKP-1 preferentially down-regulates SAPK and JNK in C3H10T 1/2 cells .	The MKP-1 mutant did not affect ERK activity, indicating that MKP-1 preferentially down-regulates SAPK and JNK in C3H10T 1/2 cells.	11	20	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MKP-1	MKP-1	MKP-1	SAPK	SAPK	SAPK	11	12	14	15
To establish whether Dvl2 inhibition of RBPJkappa was independent of NICD , we used a VP16-RBPJkappa molecule that carries a point mutation ( K275M ) to abolish the RBPJkappa and NICD interaction .	To establish whether Dvl2 inhibition of RBPJkappa was independent of NICD, we used a VP16-RBPJkappa molecule that carries a point mutation (K275M) to abolish the RBPJkappa and NICD interaction.	3	7	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Dvl2	Dvl2	Dvl2	RBPJkappa	RBPJkappa	RBPJkappa	3	4	6	7
Consequently , we examined whether Dvl2 could inhibit RBPJkappa .	Consequently, we examined whether Dvl2 could inhibit RBPJkappa.	5	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dvl2	Dvl2	Dvl2	RBPJkappa	RBPJkappa	RBPJkappa	5	6	8	9
Although MKP-3 blocks ERK1 activation by oncogenic p21 ( ras ) , but ERK1 activated by p21 ( ras ) ( G12V ) is insensitive to the M3/6 dual phosphatase [ XREF_BIBR ] .	Although MKP-3 blocks ERK1 activation by oncogenic p21 (ras), but ERK1 activated by p21 (ras) (G12V) is insensitive to the M3/6 dual phosphatase [XREF_BIBR].	1	4	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MKP-3	MKP-3	MKP-3	ERK1	ERK1	ERK1	1	2	3	4
However , such a model in C. elegans substantially differs from the model suggested by previous work in mammalian cells [ XREF_BIBR ] , which implies that DYRK1A is an inhibitor of FOXO1 .	However, such a model in C. elegans substantially differs from the model suggested by previous work in mammalian cells [XREF_BIBR], which implies that DYRK1A is an inhibitor of FOXO1.	27	33	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	DYRK1A	DYRK1A	DYRK1A	FOXO1	FOXO1	FOXO1	27	28	32	33
The knockdown of endogenous Dyrk1A by siRNA mediates cellular localization of FoxO1 in immortalized cells .	The knockdown of endogenous Dyrk1A by siRNA mediates cellular localization of FoxO1 in immortalized cells.	1	12	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Dyrk1A	Dyrk1A	Dyrk1A	FoxO1	FoxO1	FoxO1	4	5	11	12
Our results indicate DUSP4 down-regulates ERK1/2 , JNK1 , and p38 signaling in both MDA-MB-231 and SUM 159 cells .	Our results indicate DUSP4 down-regulates ERK1/2, JNK1, and p38 signaling in both MDA-MB-231 and SUM 159 cells.	3	8	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP4	DUSP4	DUSP4	JNK1	JNK1	JNK1	3	4	7	8
DUSP2 and -4 inactivate and anchor ERK2 , whereas DUSP1 dephosphorylates ERK in the nucleus but allows its traffic back to the cytoplasm .	DUSP2 and -4 inactivate and anchor ERK2, whereas DUSP1 dephosphorylates ERK in the nucleus but allows its traffic back to the cytoplasm.	0	7	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP2	DUSP2	DUSP2	ERK2	ERK2	ERK2	0	1	6	7
The apoptotic effect was due to complete dephosphorylation of 4E-BP1 , which subsequently inactivated eIF4E [ XREF_BIBR ; XREF_BIBR ] .	The apoptotic effect was due to complete dephosphorylation of 4E-BP1, which subsequently inactivated eIF4E [XREF_BIBR; XREF_BIBR].	7	15	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	dephosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	9	10	14	15
Unphosphorylated 4EBP1 binds to and inhibits eIF4E , which is a DEAD-box helicase necessary for unwinding secondary structures at the 5 ' ends of transcripts , and that serves as a critical factor in recruiting 40S ribosomal subunits to mRNAs for cap dependent translation initiation ( thought to be the rate limiting step in protein synthesis ) ; this inhibition is relieved by mTORC1 mediated phosphorylation of 4EBP1 [ XREF_BIBR ] .	Unphosphorylated 4EBP1 binds to and inhibits eIF4E, which is a DEAD-box helicase necessary for unwinding secondary structures at the 5 ' ends of transcripts, and that serves as a critical factor in recruiting 40S ribosomal subunits to mRNAs for cap dependent translation initiation (thought to be the rate limiting step in protein synthesis); this inhibition is relieved by mTORC1 mediated phosphorylation of 4EBP1 [XREF_BIBR].	0	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	Unphosphorylated 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	1	2	6	7
In the presence of an IRES , eIF4G is capable of initiating translation in the absence of a functional 5 ' cap binding complex , as is the case when eIF4E is sequestered by eIF4E Binding Protein 1 ( 4EBP1 ) .	In the presence of an IRES, eIF4G is capable of initiating translation in the absence of a functional 5 ' cap binding complex, as is the case when eIF4E is sequestered by eIF4E Binding Protein 1 (4EBP1).	30	38	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	eIF4E Binding Protein 1	eIF4E Binding Protein 1	eIF4E Binding Protein 1	eIF4E	eIF4E	eIF4E	34	38	30	31
FRAP1 exerts its effect by phosphorylating EIF4EBP1 ( 4E-BP1 ) which binds to and inactivates EIF4E , thus inhibiting 5 '-cap-dependent mRNA translation .	FRAP1 exerts its effect by phosphorylating EIF4EBP1 (4E-BP1) which binds to and inactivates EIF4E, thus inhibiting 5 '-cap-dependent mRNA translation.	0	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	EIF4EBP1	FRAP1 exerts its effect by phosphorylating EIF4EBP1	eif4ebp1	EIF4E	EIF4E	eif4e	6	7	15	16
The ability of eIF4E to stimulate the initiation of translation is dependent on mTORC1 activity as the loss of inhibitory EIF4EBP1 phosphorylation sequesters eIF4E from the eIF4F complex 71 .	The ability of eIF4E to stimulate the initiation of translation is dependent on mTORC1 activity as the loss of inhibitory EIF4EBP1 phosphorylation sequesters eIF4E from the eIF4F complex 71.	20	24	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	EIF4EBP1	EIF4EBP1 phosphorylation	eif4ebp1	eIF4E	eIF4E	eif4e	20	21	23	24
Cells expressing the 4E-BP1 5A mutant that suppresses eIF4E dependent translation became more responsive to JAK2 inhibition .	Cells expressing the 4E-BP1 5A mutant that suppresses eIF4E dependent translation became more responsive to JAK2 inhibition.	3	10	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	3	4	8	9
Because 4EBP-1 sequesters eIF4E from cap dependent translation initiation and 4EBP-1 phosphorylation releases eIF4E , the down regulation of 4EBP-1 after TCR engagement might provide an additional mechanism to promote protein translation during T cell activation .	Because 4EBP-1 sequesters eIF4E from cap dependent translation initiation and 4EBP-1 phosphorylation releases eIF4E, the down regulation of 4EBP-1 after TCR engagement might provide an additional mechanism to promote protein translation during T cell activation.	1	4	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP-1	4EBP-1	4EBP-1	eIF4E	eIF4E	eIF4E	1	2	3	4
On the contrary , in the established model , these signaling pathways would retain 4E-BP1 associated with eIF4E , thus inhibiting eIF4E .	On the contrary, in the established model, these signaling pathways would retain 4E-BP1 associated with eIF4E, thus inhibiting eIF4E.	13	22	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	14	15	21	22
4E-BP1 hypo phosphorylation increases its binding to eIF4E and prevents the formation of eIF4F complex [ XREF_BIBR ] .	4E-BP1 hypo phosphorylation increases its binding to eIF4E and prevents the formation of eIF4F complex [XREF_BIBR].	0	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1 hypo phosphorylation	4e-bp1	eIF4F	eIF4F	eif4f	0	1	13	14
4E-BP1 is an mTORC1 substrate that negatively regulates translation by binding and blocking the function of eIF4E , an initiation factor that binds to the 5 ' mRNA cap structure to promote mRNA translation .	4E-BP1 is an mTORC1 substrate that negatively regulates translation by binding and blocking the function of eIF4E, an initiation factor that binds to the 5 ' mRNA cap structure to promote mRNA translation.	0	29	blocking	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	4E-BP1	4E-BP1	4e-bp1	eIF4E	eIF4E, an initiation factor that binds to the 5 ' mRNA cap	eif4e	0	1	16	17
Phlorizin treatment of diabetic mice also reduced the amount of 4E-BP1 in eIF4E immunoprecipitates ( XREF_FIG ) and concomitantly elevated the interaction of eIF4E with eIF4G ( XREF_FIG ) .	Phlorizin treatment of diabetic mice also reduced the amount of 4E-BP1 in eIF4E immunoprecipitates (XREF_FIG) and concomitantly elevated the interaction of eIF4E with eIF4G (XREF_FIG).	0	24	elevated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Phlorizin treatment of diabetic mice also reduced the amount of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	10	11	23	24
As such , high 4EBP1 abundance directly inhibited the activity of eIF4E by skewing the amount of eIF4G bound to eIF4E thereby lowering the amount of protein synthesis and conferring resistance to PI3K-AKT-mTOR pathway inhibitors .	As such, high 4EBP1 abundance directly inhibited the activity of eIF4E by skewing the amount of eIF4G bound to eIF4E thereby lowering the amount of protein synthesis and conferring resistance to PI3K-AKT-mTOR pathway inhibitors.	4	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	4	5	11	12
S6K1 plays a critical role in promoting translation of mRNA and is activated by mTORC1 , whereas 4E-BP1 is an inhibitor of eIF-4E , a cap binding protein , and its phosphorylation by mTOR leads to its inactivation .	S6K1 plays a critical role in promoting translation of mRNA and is activated by mTORC1, whereas 4E-BP1 is an inhibitor of eIF-4E, a cap binding protein, and its phosphorylation by mTOR leads to its inactivation.	17	27	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF-4E	eIF-4E	eIF-4E	17	18	22	23
Constitutively active 4E-BP1 A37 and A46 inhibits activation of the eIF4F complex in mesothelioma .	Constitutively active 4E-BP1 A37 and A46 inhibits activation of the eIF4F complex in mesothelioma.	2	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4F	eIF4F	eIF4F	2	3	10	11
As a consequence , both the increased total expression of 4E-BP1 and the decreased phosphorylation of 4E-BP1 at Thr 37/46 will promote binding of eIF4E resulting in inhibition of cap dependent translation initiation in the IUGR placenta .	As a consequence, both the increased total expression of 4E-BP1 and the decreased phosphorylation of 4E-BP1 at Thr 37/46 will promote binding of eIF4E resulting in inhibition of cap dependent translation initiation in the IUGR placenta.	8	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	expression of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	10	11	24	25
While it is not clear how eIF4E contributes to the suppression of Rb phosphorylation , it was reported that a constitutively active 4EBP-1 , which suppresses eIF4E , caused a cell cycle arrest in MCF7 cells that correlated with decreased cyclin E-CDK2 activity and increased association of CDK2 with p27 Kip1 [ XREF_BIBR ] .	While it is not clear how eIF4E contributes to the suppression of Rb phosphorylation, it was reported that a constitutively active 4EBP-1, which suppresses eIF4E, caused a cell cycle arrest in MCF7 cells that correlated with decreased cyclin E-CDK2 activity and increased association of CDK2 with p27 Kip1 [XREF_BIBR].	19	44	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP-1	4EBP-1	4EBP-1	eIF4E	eIF4E	eIF4E	22	23	26	27
Although mice with increased amounts of eIF4E available for translation initiation due to lack of the eIF4E antagonists 4E-BP1 and 4E-BP2 are hypersensitive to oncogenic stimuli , they do not develop spontaneous tumors .	Although mice with increased amounts of eIF4E available for translation initiation due to lack of the eIF4E antagonists 4E-BP1 and 4E-BP2 are hypersensitive to oncogenic stimuli, they do not develop spontaneous tumors.	13	20	antagonists	Negative_activation_token_1_noun	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	18	19	16	17
4E-BP1 represses the activity of eIF4E , and phosphorylation of 4E-BP1 by mTORC1 releases its suppression of eIF4E and promotes protein translation .	4E-BP1 represses the activity of eIF4E, and phosphorylation of 4E-BP1 by mTORC1 releases its suppression of eIF4E and promotes protein translation.	0	6	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	0	1	5	6
Having established that JNK inhibition decreased 4E-BP1 phosphorylation and thereby repressed formation of the eIF4F complex , we sought to determine the mechanism involved .	Having established that JNK inhibition decreased 4E-BP1 phosphorylation and thereby repressed formation of the eIF4F complex, we sought to determine the mechanism involved.	3	15	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	JNK inhibition decreased 4E-BP1 phosphorylation	4e-bp1	eIF4F	eIF4F	eif4f	6	7	14	15
A coimmunoprecipitation assay of eIF4G and eIF4E and a pull-down assay using m 7 GTP-Sepharose were performed to evaluate whether 4E-BP1 and 4EGi-1 effectively inhibit eIF4E from forming an initiation complex for eIF4E dependent translation in our system .	A coimmunoprecipitation assay of eIF4G and eIF4E and a pull-down assay using m 7 GTP-Sepharose were performed to evaluate whether 4E-BP1 and 4EGi-1 effectively inhibit eIF4E from forming an initiation complex for eIF4E dependent translation in our system.	20	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	20	21	25	26
PHAS-I binds to and inhibits the function of eIF-4e , which normally recognizes the 7-methylguanine cap on mRNA to initiate translation .	PHAS-I binds to and inhibits the function of eIF-4e, which normally recognizes the 7-methylguanine cap on mRNA to initiate translation.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHAS-I	PHAS-I	PHAS-I	eIF-4e	eIF-4e	eIF-4e	0	1	8	9
In these conditions however eIF4E phosphorylation appeared not affected probably because in the presence of FCS , 4E-BP1 and 4E-BP2 are hyperphosphorylated and are therefore not expected to sequester eIF4E .	In these conditions however eIF4E phosphorylation appeared not affected probably because in the presence of FCS, 4E-BP1 and 4E-BP2 are hyperphosphorylated and are therefore not expected to sequester eIF4E.	17	30	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1 and 4E-BP2 are hyperphosphorylated	4e-bp1	eIF4E	eIF4E	eif4e	17	18	29	30
eIF4E :4 E-BP1 binding efficiency is negatively regulated by 4E-BP1 phosphorylation XREF_BIBR , XREF_BIBR .	eIF4E :4 E-BP1 binding efficiency is negatively regulated by 4E-BP1 phosphorylation XREF_BIBR, XREF_BIBR.	0	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	9	10	0	1
However , combined inhibition of both pathways effectively inhibits 4E-BP1 phosphorylation , which in turn activates 4E-BP1 binding to the eIF4E mRNA cap complex and thus represses eIF4E initiated cap dependent translation , with an associated synergistic induction of apoptosis and suppression of tumor growth [ XREF_BIBR ] .	However, combined inhibition of both pathways effectively inhibits 4E-BP1 phosphorylation, which in turn activates 4E-BP1 binding to the eIF4E mRNA cap complex and thus represses eIF4E initiated cap dependent translation, with an associated synergistic induction of apoptosis and suppression of tumor growth [XREF_BIBR].	9	28	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	9	10	27	28
Although 4EBP1 levels limit the availability of eIF4E to bind and form the protein translational complex eIF4F , rapalog mediated eIF4E phosphorylation is independent of 4EBP1 XREF_BIBR .	Although 4EBP1 levels limit the availability of eIF4E to bind and form the protein translational complex eIF4F, rapalog mediated eIF4E phosphorylation is independent of 4EBP1 XREF_BIBR.	1	8	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	4EBP1 levels	4ebp1	eIF4E	eIF4E	eif4e	1	2	7	8
In its hypophosphorylated state , 4E-BP1 binds to and inhibits the activity of eIF4E , and 4E-BP1 phosphorylation induces the release of 4E-BP1 from eIF4E , which leads to subsequent mRNA translation [ XREF_BIBR ] .	In its hypophosphorylated state, 4E-BP1 binds to and inhibits the activity of eIF4E, and 4E-BP1 phosphorylation induces the release of 4E-BP1 from eIF4E, which leads to subsequent mRNA translation [XREF_BIBR].	5	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	5	6	13	14
eIF4E function is negatively regulated by 4EBP1 , and we further substantiated the above finding by silencing 4EBP1 in HRas V12 -transformed human astrocytes and U251 using siRNA ( XREF_FIG ) , then assessing the ability of 4EBP1 to alter the effects of rapamycin on growth in soft agar .	eIF4E function is negatively regulated by 4EBP1, and we further substantiated the above finding by silencing 4EBP1 in HRas V12 -transformed human astrocytes and U251 using siRNA (XREF_FIG), then assessing the ability of 4EBP1 to alter the effects of rapamycin on growth in soft agar.	0	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	6	7	0	1
4E-BP1 negatively regulates the eIF4F complex , which drives mRNA translation initiation [ XREF_BIBR ] .	4E-BP1 negatively regulates the eIF4F complex, which drives mRNA translation initiation [XREF_BIBR].	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4F	eIF4F	eIF4F	0	1	4	5
4E-BP1 represses eIF4E , a rate limiting protein of cap dependent translation .	4E-BP1 represses eIF4E, a rate limiting protein of cap dependent translation.	0	5	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	0	1	2	3
The key best studied targets of mTORC1 kinase activity are the kinase S6K1 and the translational inhibitor 4EBP1 , which blocks eIF4E .	The key best studied targets of mTORC1 kinase activity are the kinase S6K1 and the translational inhibitor 4EBP1, which blocks eIF4E.	12	22	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	17	18	21	22
These results indicated that eIF4E was transiently sequestered by 4E-BP1 through the process of myoblast differentiation .	These results indicated that eIF4E was transiently sequestered by 4E-BP1 through the process of myoblast differentiation.	4	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	9	10	4	5
Perhaps the increased RNA : DNA in muscles of Mstn (-/-) mice is a compensatory mechanism for the repression of eIF4E by 4E-BP1 , which may compromise translation of mRNA .	Perhaps the increased RNA : DNA in muscles of Mstn (-/-) mice is a compensatory mechanism for the repression of eIF4E by 4E-BP1, which may compromise translation of mRNA.	15	26	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	22	23	20	21
Interestingly , tumors derived from both cell types displayed similar patterns and extent of tumor hypoxia , but our data suggest that decreased 4E-BP1 expression , and commensurate increases in eIF4E activity , provide a proliferative and survival benefit to Rh30 cells under these conditions .	Interestingly, tumors derived from both cell types displayed similar patterns and extent of tumor hypoxia, but our data suggest that decreased 4E-BP1 expression, and commensurate increases in eIF4E activity, provide a proliferative and survival benefit to Rh30 cells under these conditions.	23	31	increases	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	4E-BP1	4E-BP1 expression	4e-bp1	eIF4E	eIF4E	eif4e	23	24	30	31
Consistent with these observations , rapamycin completely blocked leucine induced phosphorylation of mTOR ( XREF_FIG ) , S6K1 , and 4EBP1 , as well as the leucine induced formation of an active eIF4E .	Consistent with these observations, rapamycin completely blocked leucine induced phosphorylation of mTOR (XREF_FIG), S6K1, and 4EBP1, as well as the leucine induced formation of an active eIF4E.	8	33	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	leucine induced phosphorylation of mTOR (XREF_FIG), S6K1, and 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	20	21	32	33
Phosphorylation of S6K1 mediates translation initiation and polypeptide elongation , while 4EBP1 is a repressor of eukaryotic initiation factor 4E ( eIF4E ) .	Phosphorylation of S6K1 mediates translation initiation and polypeptide elongation, while 4EBP1 is a repressor of eukaryotic initiation factor 4E (eIF4E).	11	20	is a repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eukaryotic initiation factor 4E	eukaryotic initiation factor 4E	eukaryotic initiation factor 4E	11	12	16	20
On the other hand , hypo phosphorylation of 4EBP1 is thought to inhibit binding eIF4E to eIF4G , blocking pre and initiation complex formation and inhibiting protein synthesis .	On the other hand, hypo phosphorylation of 4EBP1 is thought to inhibit binding eIF4E to eIF4G, blocking pre and initiation complex formation and inhibiting protein synthesis.	6	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	phosphorylation of 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	8	9	14	15
More specifically , 4E-BP1 is a suppressor of the translation initiation factor eIF-4E , which itself recognizes the cap structure present at the 5 ' end of all nuclear transcribed eukaryotic mRNAs .	More specifically, 4E-BP1 is a suppressor of the translation initiation factor eIF-4E, which itself recognizes the cap structure present at the 5 ' end of all nuclear transcribed eukaryotic mRNAs.	3	16	is a suppressor	Negative_activation_copula_1	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF-4E	eIF-4E	eIF-4E	3	4	12	13
Reduction of eIF4E by overexpression of 4E-BP1 resulted in suppression of cap dependent protein expression of basic fibroblast growth factor ( bFGF or FGF-2 ) and vascular endothelial growth factor ( VEGF ) .	Reduction of eIF4E by overexpression of 4E-BP1 resulted in suppression of cap dependent protein expression of basic fibroblast growth factor (bFGF or FGF-2) and vascular endothelial growth factor (VEGF).	0	7	Reduction	Negative_activation_token_2_noun	Negative_activation	Negative_activation	4E-BP1	overexpression of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	6	7	2	3
Another important downstream target of mTOR is 4EBP1 that sequesters the initiation factor eIF4E to control the initiation of cap dependent translation .	Another important downstream target of mTOR is 4EBP1 that sequesters the initiation factor eIF4E to control the initiation of cap dependent translation.	3	15	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	7	8	13	14
The hypophosphorylated forms of 4E-BP1 indeed sequester eIF4E and thus block translation initiation and consequent protein synthesis .	The hypophosphorylated forms of 4E-BP1 indeed sequester eIF4E and thus block translation initiation and consequent protein synthesis.	2	8	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	4	5	7	8
Its other substrate , 4E-BP1 , inhibits mRNA translation initiation by preventing formation of the eIF4F complex which facilitates recruitment of the small ( 40S ) ribosomal subunit to the 5 ' end of mRNA [ XREF_BIBR ] .	Its other substrate, 4E-BP1, inhibits mRNA translation initiation by preventing formation of the eIF4F complex which facilitates recruitment of the small (40S) ribosomal subunit to the 5 ' end of mRNA [XREF_BIBR].	2	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4F	eIF4F	eIF4F	4	5	15	16
Formation of eIF4F is blocked by the translational repressor 4E-BP1 ( eIF4E binding protein 1 ) , which inhibits eIF4E from complexing with eIF4A and 4G .	Formation of eIF4F is blocked by the translational repressor 4E-BP1 (eIF4E binding protein 1), which inhibits eIF4E from complexing with eIF4A and 4G.	4	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	9	10	19	20
We found that activation of 4E-BP1 by IL24 dependent de-phosphorylation inhibits eIF4F complex assembly , whereas IL-24-mediated phosphorylation of eIF2alpha inhibits Ternary complex .	We found that activation of 4E-BP1 by IL24 dependent de-phosphorylation inhibits eIF4F complex assembly, whereas IL-24-mediated phosphorylation of eIF2alpha inhibits Ternary complex.	3	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4F	eIF4F	eIF4F	5	6	11	12
4E-BP1 prevents formation of active eIF4F complex by sequestering mRNA cap binding protein eIF4E and rendering it inactive .	4E-BP1 prevents formation of active eIF4F complex by sequestering mRNA cap binding protein eIF4E and rendering it inactive.	0	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	mRNA cap binding protein	mRNA cap binding protein	mRNA cap binding protein	0	1	9	13
Taken together , our data and these previous reports could suggest that Thr46 phosphorylation is sufficient to block the initial binding between eIF4E and 4E-BP1 as observed by far western analyses , but that hyperphosphorylation of 4E-BP1 , including at Ser65 , is required to disrupt existing 4E-BP1 : eIF4E complexes .	Taken together, our data and these previous reports could suggest that Thr46 phosphorylation is sufficient to block the initial binding between eIF4E and 4E-BP1 as observed by far western analyses, but that hyperphosphorylation of 4E-BP1, including at Ser65, is required to disrupt existing 4E-BP1 : eIF4E complexes.	34	50	disrupt	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	hyperphosphorylation of 4E-BP1, including at Ser65	4e-bp1	eIF4E	eIF4E	eif4e	36	37	49	50
HER3 has a highly structured 5 ' UTR with a free energy of -61.8 kkal and mol ( XREF_FIG , shown in comparison to actin with a free energy of -14.1 kkal and mol ) rendering it more dependent on eIF4E , which is negatively regulated by 4EBP1 ( XREF_FIG ) .	HER3 has a highly structured 5 ' UTR with a free energy of -61.8 kkal and mol (XREF_FIG, shown in comparison to actin with a free energy of -14.1 kkal and mol) rendering it more dependent on eIF4E, which is negatively regulated by 4EBP1 (XREF_FIG).	35	49	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	47	48	40	41
Ectopic expression of Sesn2 inhibits phosphorylation of 4EBP1 and stimulates its binding to the translation initiation factor eIF-4E , thereby inhibiting the initiation of mRNA translation .	Ectopic expression of Sesn2 inhibits phosphorylation of 4EBP1 and stimulates its binding to the translation initiation factor eIF-4E, thereby inhibiting the initiation of mRNA translation.	1	18	stimulates	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	4EBP1	expression of Sesn2 inhibits phosphorylation of 4EBP1	4ebp1	eIF-4E	eIF-4E	eif-4e	7	8	17	18
In the hypophosphorylated state , 4E-BP1 binds to and inhibits the activity of eIF4E .	In the hypophosphorylated state, 4E-BP1 binds to and inhibits the activity of eIF4E.	5	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	5	6	13	14
PHAS-I in its unphosphorylated state sequesters eIF4E , a mRNA cap binding protein in the eIF4G elongation complex .	PHAS-I in its unphosphorylated state sequesters eIF4E, a mRNA cap binding protein in the eIF4G elongation complex.	0	12	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHAS-I	PHAS-I	PHAS-I	eIF4E	eIF4E	eIF4E	0	1	6	7
Inhibiting the mTOR mediated phosphorylation of 4E-BP1 severely limits eIF4E availability and thus eIF4F complex formation , essentially mimicking the knockdown of eIF4E .	Inhibiting the mTOR mediated phosphorylation of 4E-BP1 severely limits eIF4E availability and thus eIF4F complex formation, essentially mimicking the knockdown of eIF4E.	2	23	limits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	mTOR mediated phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	6	7	22	23
The hypophosphorylated active form of 4E-BP1 , sequesters eIF4E and prevents it from binding to eIF4G , thus blocking the formation of the cap dependent translation complex ( eIF4F ) .	The hypophosphorylated active form of 4E-BP1, sequesters eIF4E and prevents it from binding to eIF4G, thus blocking the formation of the cap dependent translation complex (eIF4F).	1	9	sequesters	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	4E-BP1	hypophosphorylated active form of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	5	6	8	9
In response to selenite treatment , 4EBP1 disrupts the assembly of translationally-competent eIF4F complexes , resulting in the assembly of SGs .	In response to selenite treatment, 4EBP1 disrupts the assembly of translationally-competent eIF4F complexes, resulting in the assembly of SGs.	6	13	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4F	eIF4F	eIF4F	6	7	12	13
4EBP1 negatively regulates eIF4E , a key rate limiting initiation factor for cap dependent translation .	4EBP1 negatively regulates eIF4E, a key rate limiting initiation factor for cap dependent translation.	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	0	1	3	4
The mTOR mediated phosphorylation of 4E-BP1 diminishes the stability of the 4E , BP1 , and eIF4E complex and facilitates the eIF4E action , enhancing translation of several mRNAs , such as cyclin D1 , c-myc , hypoxia inducible factor 1alpha ( HIF1alpha ) , ornithine decarboxylase , VEGF , fibroblast growth factor , and ribosomal proteins ( XREF_FIG ) .	The mTOR mediated phosphorylation of 4E-BP1 diminishes the stability of the 4E, BP1, and eIF4E complex and facilitates the eIF4E action, enhancing translation of several mRNAs, such as cyclin D1, c-myc, hypoxia inducible factor 1alpha (HIF1alpha), ornithine decarboxylase, VEGF, fibroblast growth factor, and ribosomal proteins (XREF_FIG).	1	17	diminishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	mTOR mediated phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	5	6	16	17
Unphosphorylated 4EBP1 binds to and sequesters eIF4E away from the cap binding complex , resulting in a block of cap dependent mRNA translation ( Thoreen , 2017 ) .	Unphosphorylated 4EBP1 binds to and sequesters eIF4E away from the cap binding complex, resulting in a block of cap dependent mRNA translation (Thoreen, 2017).	0	7	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	Unphosphorylated 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	1	2	6	7
The decreases in both 4EBP1 and 4EBP2 in the pAKT overexpressing HCC samples examined upregulate eIF4E to facilitate SKP2 translation and finally increase its protein level .	The decreases in both 4EBP1 and 4EBP2 in the pAKT overexpressing HCC samples examined upregulate eIF4E to facilitate SKP2 translation and finally increase its protein level.	1	16	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	4	5	15	16
In addition , the inhibition of eIF4E by 4E-BP1 impairs translation directed by HAV IRES XREF_BIBR , but surprisingly , these authors reported that HAV IRES can be translated in presence of the carboxy fragment of eIF4G in RRL depleted of this factor .	In addition, the inhibition of eIF4E by 4E-BP1 impairs translation directed by HAV IRES XREF_BIBR, but surprisingly, these authors reported that HAV IRES can be translated in presence of the carboxy fragment of eIF4G in RRL depleted of this factor.	4	9	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	8	9	6	7
4EBP1 , when dephosphorylated interacts strongly with eIF4E to impede its function but is unable to sequester eIF4E when hyperphosphorylated in cancer XREF_BIBR .	4EBP1, when dephosphorylated interacts strongly with eIF4E to impede its function but is unable to sequester eIF4E when hyperphosphorylated in cancer XREF_BIBR.	0	18	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	4EBP1, when dephosphorylated interacts strongly with eIF4E	4ebp1	eIF4E	eIF4E	eif4e	0	1	17	18
Phosphorylation of 4EBP1 by mTORC1 releases this inhibition of eIF4E .	Phosphorylation of 4EBP1 by mTORC1 releases this inhibition of eIF4E.	0	10	inhibition	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	4EBP1	Phosphorylation of 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	2	3	9	10
The 4EBP1 protein prevents the assembly of eIF4F by competing with eIF4G to bind to eIF4E .	The 4EBP1 protein prevents the assembly of eIF4F by competing with eIF4G to bind to eIF4E.	1	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1 protein	4EBP1 protein	4EBP1 protein	eIF4F	eIF4F	eIF4F	1	3	7	8
While we did not observe a difference in MYC protein levels , baseline phospho-4EBP1 levels were reduced in 8988T KRAS deficient cells , permitting enhanced 4EBP1 sequestration of EIF4E to restrain cap dependent translation .	While we did not observe a difference in MYC protein levels, baseline phospho-4EBP1 levels were reduced in 8988T KRAS deficient cells, permitting enhanced 4EBP1 sequestration of EIF4E to restrain cap dependent translation.	13	29	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phospho-4EBP1	phospho-4EBP1 levels	phospho-4ebp1	EIF4E	EIF4E	eif4e	13	14	28	29
eIF4E inactivation is mediated by inhibition of 4E-BP1 phosphorylation , which results in a shift of equilibrium from eIF4E and eIF4G complexes to eIF4E/4E-BP 1 complexes .	eIF4E inactivation is mediated by inhibition of 4E-BP1 phosphorylation, which results in a shift of equilibrium from eIF4E and eIF4G complexes to eIF4E/4E-BP 1 complexes.	0	9	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	7	8	0	1
According to the closed-loop model of translational initiation , we have analyzed components of the 5 -mRNA cap binding complex eIF4F ( eIF4E , eIF4G , eIF4A ) , the eIF4E repressor 4E-BP1 , and 3 -mRNA poly-( A ) tail associated proteins ( PABP1 and 3 , PAIP1 and 2 , CPEB1 , Maskin ) during in vitro maturation of bovine oocytes and early embryonic development up to the 16-cell stage .	According to the closed-loop model of translational initiation, we have analyzed components of the 5 -mRNA cap binding complex eIF4F (eIF4E, eIF4G, eIF4A), the eIF4E repressor 4E-BP1, and 3 -mRNA poly-(A) tail associated proteins (PABP1 and 3, PAIP1 and 2, CPEB1, Maskin) during in vitro maturation of bovine oocytes and early embryonic development up to the 16-cell stage.	11	33	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	32	33	30	31
In its hypophosphorylated state , 4E-BP1 sequesters eukaryotic initiation factor 4E and thereby prevents cap dependent mRNA translation XREF_BIBR .	In its hypophosphorylated state, 4E-BP1 sequesters eukaryotic initiation factor 4E and thereby prevents cap dependent mRNA translation XREF_BIBR.	5	13	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eukaryotic initiation factor 4E	eukaryotic initiation factor 4E	eukaryotic initiation factor 4E	5	6	7	11
Next , we sought to determine whether eIF4E , whose activity is inhibited by 4EBP1 , is oncogenic in the mouse liver .	Next, we sought to determine whether eIF4E, whose activity is inhibited by 4EBP1, is oncogenic in the mouse liver.	7	17	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	14	15	7	8
The authors did show however , that the 4E-BP1 memetic 4EGI-1 did inhibit translation of the eIF4E sensitive oncogenes including c-myc and cyclin D1 and induced cell death of AML cells in culture .	The authors did show however, that the 4E-BP1 memetic 4EGI-1 did inhibit translation of the eIF4E sensitive oncogenes including c-myc and cyclin D1 and induced cell death of AML cells in culture.	8	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	8	9	16	17
4E-BP1 inhibits the 5 ' mRNA cap recognition of eIF4F complex repressing translation .	4E-BP1 inhibits the 5 ' mRNA cap recognition of eIF4F complex repressing translation.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4F	eIF4F	eIF4F	0	1	9	10
A major regulator of this pathway is the eukaryotic translation initiation factor 4E binding protein 1 ( 4E-BP1 ) , which sequesters eIF4F to prevent eIF4F complex formation [ XREF_BIBR ] .	A major regulator of this pathway is the eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which sequesters eIF4F to prevent eIF4F complex formation [XREF_BIBR].	2	23	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4F	eIF4F	eIF4F	17	18	22	23
Results from pull-down assay using 7-methyl-GTP Sepharose 4B beads indicated that PEITC treatment reduced cap bound eIF4E , confirming that increased 4E-BP1 expression and inhibition of 4E-BP1 phosphorylation indeed reduced the availability of eIF4E for translation initiation .	Results from pull-down assay using 7-methyl-GTP Sepharose 4B beads indicated that PEITC treatment reduced cap bound eIF4E, confirming that increased 4E-BP1 expression and inhibition of 4E-BP1 phosphorylation indeed reduced the availability of eIF4E for translation initiation.	26	34	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	26	27	33	34
The eIF4E pathway is a target for cancer therapy with drugs that either inhibit eIF4E activity indirectly ( mTOR inhibitors that reduce 4E-BP1 phosphorylation thereby inhibiting eIF4E ( Smolewski , 2006 ) ) , or directly ( by binding to/reducing expression of eIF4E ( Graff et al , 2008 ) ) .	The eIF4E pathway is a target for cancer therapy with drugs that either inhibit eIF4E activity indirectly (mTOR inhibitors that reduce 4E-BP1 phosphorylation thereby inhibiting eIF4E (Smolewski, 2006)), or directly (by binding to/reducing expression of eIF4E (Graff et al, 2008)).	18	28	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	mTOR inhibitors that reduce 4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	22	23	26	27
Direct genetic targeting of the eIF4F in ERBB2 amplified EAC cells with a constitutively active form of the eIF4F repressor 4E-BP1 decreased colony formation and proliferation and triggered apoptosis .	Direct genetic targeting of the eIF4F in ERBB2 amplified EAC cells with a constitutively active form of the eIF4F repressor 4E-BP1 decreased colony formation and proliferation and triggered apoptosis.	15	21	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4F	eIF4F	eIF4F	20	21	18	19
mTOR1 is active in the presence of normal amounts of amino acids and phosphorylates 4EBP1 , the binding protein which inhibits eIF-4E , a key factor in the translation of mRNA .	mTOR1 is active in the presence of normal amounts of amino acids and phosphorylates 4EBP1, the binding protein which inhibits eIF-4E, a key factor in the translation of mRNA.	0	25	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	4EBP1	mTOR1 is active in the presence of normal amounts of amino acids and phosphorylates 4EBP1	4ebp1	eIF-4E	eIF-4E	eif-4e	14	15	21	22
Taken together , these observations are consistent with two interpretations , which are not mutually exclusive : 1 ) the kinetics of inhibition of eIF4E by 4E-BP1 in vivo , is delayed , indicating that eIF4E actively engaged in eIF4F , recycles to the mRNA , rather than binding to free 4E-BPs .	Taken together, these observations are consistent with two interpretations, which are not mutually exclusive : 1) the kinetics of inhibition of eIF4E by 4E-BP1 in vivo, is delayed, indicating that eIF4E actively engaged in eIF4F, recycles to the mRNA, rather than binding to free 4E-BPs.	22	28	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	26	27	24	25
Under basal conditions , eIF4E activity is negatively regulated by the eIF4E binding protein 1 ( 4EBP1 ) .	Under basal conditions, eIF4E activity is negatively regulated by the eIF4E binding protein 1 (4EBP1).	4	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	eIF4E binding protein 1	eIF4E binding protein 1	eIF4E binding protein 1	eIF4E	eIF4E	eIF4E	11	15	4	5
4EBP1 represses translation at the initiation step by preventing assembly of the eIF4F complex .	4EBP1 represses translation at the initiation step by preventing assembly of the eIF4F complex.	0	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4F	eIF4F	eIF4F	0	1	12	13
IL24 mediated activation of 4E-BP1 appears to inhibit eIF4F complex assembly .	IL24 mediated activation of 4E-BP1 appears to inhibit eIF4F complex assembly.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	IL24 mediated activation of 4E-BP1	4e-bp1	eIF4F	eIF4F	eif4f	4	5	8	9
S6K1 , a member of the AGC kinase family , is involved in cell growth , insulin resistance and regulation of protein translation through the ribosomal S6 protein XREF_BIBR , while 4EBP1 impairs eIF4E function and plays a role in the repression of translation initiation XREF_BIBR .	S6K1, a member of the AGC kinase family, is involved in cell growth, insulin resistance and regulation of protein translation through the ribosomal S6 protein XREF_BIBR, while 4EBP1 impairs eIF4E function and plays a role in the repression of translation initiation XREF_BIBR.	31	36	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	31	32	33	34
p70S6K positively regulates 40S ribosomal protein S6 ( RPS6 ) , leading to increased expression of SREBP1 and consequent de novo lipogenesis in cells , whereas 4EBP1 negatively regulates eIF4E , the rate limiting enzyme for cap dependent translation [ XREF_BIBR ] .	p70S6K positively regulates 40S ribosomal protein S6 (RPS6), leading to increased expression of SREBP1 and consequent de novo lipogenesis in cells, whereas 4EBP1 negatively regulates eIF4E, the rate limiting enzyme for cap dependent translation [XREF_BIBR].	26	32	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	26	27	29	30
In murine xenograft models of breast [ XREF_BIBR ] and lung cancer [ XREF_BIBR ] eIF4E inhibition by ectopic overexpression of an activated 4EBP1 led to abrogated tumorigenicity .	In murine xenograft models of breast [XREF_BIBR] and lung cancer [XREF_BIBR] eIF4E inhibition by ectopic overexpression of an activated 4EBP1 led to abrogated tumorigenicity.	15	24	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	4EBP1	overexpression of an activated 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	23	24	15	16
The apoptotic effect of rapamycin was due to complete suppression of eIF4E by 4E-BP1 , since apoptosis could be achieved by knockdown of eIF4E .	The apoptotic effect of rapamycin was due to complete suppression of eIF4E by 4E-BP1, since apoptosis could be achieved by knockdown of eIF4E.	8	14	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	13	14	11	12
This is based in part on the existence of intricate feedback loops involved in ERK signaling that can inhibit RAF and MEK .	This is based in part on the existence of intricate feedback loops involved in ERK signaling that can inhibit RAF and MEK.	14	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	14	15	21	22
One possibility is that the late increase in p-p38 MAPK ( XREF_FIG ) produces a feed-forward late inhibition of MEK1/2 .	One possibility is that the late increase in p-p38 MAPK (XREF_FIG) produces a feed-forward late inhibition of MEK1/2.	6	20	produces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	MEK1/2	MEK1/2	MEK1/2	9	10	19	20
One plausible explanation is that cells permanently stimulated by autoactive KRAS or MEK1 were desensitized via multiple mechanisms including the previously reported ERK mediated feedback inhibition of MEK and possible increased basal levels of MAPK phosphatases , a phenomenon previously observed in rodent fibroblasts .	One plausible explanation is that cells permanently stimulated by autoactive KRAS or MEK1 were desensitized via multiple mechanisms including the previously reported ERK mediated feedback inhibition of MEK and possible increased basal levels of MAPK phosphatases, a phenomenon previously observed in rodent fibroblasts.	17	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	22	23	27	28
XREF_FIG d , inhibition of the early JNK activity by the JNK1/2/3 inhibitor SP600125 ( left panel ) or the early and late ERK1/2 activity using UO126 ( an inhibitor of the upstream MEK1/2 ; both panels ) resulted in significant abrogation of c-Fos expression , whereas inhibition of p38K by SB203580 had no effect on c-Fos expression .	XREF_FIG d, inhibition of the early JNK activity by the JNK1/2/3 inhibitor SP600125 (left panel) or the early and late ERK1/2 activity using UO126 (an inhibitor of the upstream MEK1/2; both panels) resulted in significant abrogation of c-Fos expression, whereas inhibition of p38K by SB203580 had no effect on c-Fos expression.	23	36	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MEK1/2	MEK1/2	MEK1/2	23	24	33	34
Under fluid shear stress conditions , the expression of most SMAD2/3 target genes is partially repressed by MAPK and ERK possibly via TGF-beta and ALK5 mediated activation of MEK1/2 or via activation of this pathway by other yet unidentified autocrine ( growth ) factors .	Under fluid shear stress conditions, the expression of most SMAD2/3 target genes is partially repressed by MAPK and ERK possibly via TGF-beta and ALK5-mediated activation of MEK1/2 or via activation of this pathway by other yet unidentified autocrine (growth) factors.	15	29	activation	Positive_activation_syntax_6_noun	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	MEK1/2	MEK1/2	MEK1/2	17	18	28	29
ERK -| Raf Feedback Causes MEK Knockdown and Inhibitor Discrepancies in Cells .	ERK -| Raf Feedback Causes MEK Knockdown and Inhibitor Discrepancies in Cells.	0	6	Causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	0	1	5	6
We next investigated whether the reduced inflammatory nociception was associated with reduced ERK activation in the DN MEK mice .	We next investigated whether the reduced inflammatory nociception was associated with reduced ERK activation in the DN MEK mice.	12	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	12	13	17	18
This unique binding to u-MEK could explain why JTP-74057 effectively inhibits ERK phosphorylation and prolongs the unphosphorylation state of MEK .	This unique binding to u-MEK could explain why JTP-74057 effectively inhibits ERK phosphorylation and prolongs the unphosphorylation state of MEK.	8	20	prolongs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	JTP-74057 effectively inhibits ERK phosphorylation	erk	MEK	MEK	mek	11	12	19	20
To investigate this function of PEA-15 , we examined its effect on the progressive decline of phospho-ERK1/2 following block of MEK activity .	To investigate this function of PEA-15, we examined its effect on the progressive decline of phospho-ERK1/2 following block of MEK activity.	16	21	block	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	phospho-ERK1/2	phospho-ERK1/2	phospho-ERK1/2	MEK	MEK	MEK	16	17	20	21
The effectiveness of each individual inhibitor was confirmed by monitoring the reduced phosphorylation of ERK 1/2 ( a direct target of MEK-1/2 ) , c-Jun ( a direct target of JNK ) , and HSP27 ( a downstream target of the p38 pathway ) ( XREF_FIG ) .	The effectiveness of each individual inhibitor was confirmed by monitoring the reduced phosphorylation of ERK 1/2 (a direct target of MEK-1/2), c-Jun (a direct target of JNK), and HSP27 (a downstream target of the p38 pathway) (XREF_FIG).	12	34	target	Positive_activation_syntax_7_noun	Negative_activation	Negative_activation	ERK 1/2	phosphorylation of ERK 1/2	erk 1/2	MEK-1/2	MEK-1/2	mek-1/2	14	16	21	22
EGFR signaling involves crosstalk and feedback loops both internally ( e.g ., active ERK attenuates upstream RAF or MEK signaling via negative feedback ) XREF_BIBR and with other signaling pathways ( e.g ., WNT and TGF-beta pathways ) XREF_BIBR , XREF_BIBR .	EGFR signaling involves crosstalk and feedback loops both internally (e.g., active ERK attenuates upstream RAF or MEK signaling via negative feedback) XREF_BIBR and with other signaling pathways (e.g., WNT and TGF-beta pathways) XREF_BIBR, XREF_BIBR.	12	19	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	13	14	18	19
Although ~ 25 % of ERK phosphatases are assumed to be serine/threonine phosphatases and thus are able to dephosphorylate MEKp and MEKpp , it should be noted , however , that only a fraction of the ERK phosphatases can deactivate the activated MEK kinase XREF_BIBR .	Although ~ 25% of ERK phosphatases are assumed to be serine/threonine phosphatases and thus are able to dephosphorylate MEKp and MEKpp, it should be noted, however, that only a fraction of the ERK phosphatases can deactivate the activated MEK kinase XREF_BIBR.	36	44	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	36	37	42	43
Initially , ERK inhibition results in upregulation of RAF and MEK activities by dephosphorylating inhibitory phosphorylation sites on these proteins .	Initially, ERK inhibition results in upregulation of RAF and MEK activities by dephosphorylating inhibitory phosphorylation sites on these proteins.	2	11	results in upregulation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	2	3	10	11
These reports support our current findings that demonstrate the importance of the post-fertilization ERK1 peak for cdk2 activation and cyclinE and cdk2 pronuclei translocation , and are consistent with our earlier reports that show that ERK activation is essential for S-phase onset Inhibiting MEK activity abolished both the post-fertilization and the NEB peak in ERK activity ; it prevented not only sperm decondensation but also GFP-cyclinE and GFP-cdk2 accumulation in both pronuclei .	These reports support our current findings that demonstrate the importance of the post-fertilization ERK1 peak for cdk2 activation and cyclinE and cdk2 pronuclei translocation, and are consistent with our earlier reports that show that ERK activation is essential for S-phase onset Inhibiting MEK activity abolished both the post-fertilization and the NEB peak in ERK activity; it prevented not only sperm decondensation but also GFP-cyclinE and GFP-cdk2 accumulation in both pronuclei.	35	44	Inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	35	36	43	44
Inhibition of the ERK activator MEK , as well as of p38 , significantly reduced caspase activation and necrosis , whereas c-Jun N-terminal kinase ( JNK ) inhibition diminished only caspase activity .	Inhibition of the ERK activator MEK, as well as of p38, significantly reduced caspase activation and necrosis, whereas c-Jun N-terminal kinase (JNK) inhibition diminished only caspase activity.	0	6	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	3	4	5	6
Biomarker analysis of tumors following MAPK pathway inhibition of MEK by binimetinib demonstrated that , the tumor genetic landscape was concordant with what was reported in the TCGA melanoma database .	Biomarker analysis of tumors following MAPK pathway inhibition of MEK by binimetinib demonstrated that, the tumor genetic landscape was concordant with what was reported in the TCGA melanoma database.	5	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	5	6	9	10
Thus , we contemplated three possible scenarios ( XREF_FIG ) : 1 ) both MEK substrates , ERK and HSF1 , compete for MEK interaction ; 2 ) ERK , like MEK , binds HSF1 and thereby competes for HSF1 interaction ; and 3 ) ERK inhibits MEK kinase activity towards HSF1 .	Thus, we contemplated three possible scenarios (XREF_FIG) : 1) both MEK substrates, ERK and HSF1, compete for MEK interaction; 2) ERK, like MEK, binds HSF1 and thereby competes for HSF1 interaction; and 3) ERK inhibits MEK kinase activity towards HSF1.	45	49	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	45	46	47	48
XREF_BIBR has found that low concentration of ERK alone can not reverse BRAF-inhibitor and MEK-inhibitor double resistance ( DDR , double-drugs-resistance ) unless co-targeting BRAF and MEK .	XREF_BIBR has found that low concentration of ERK alone can not reverse BRAF-inhibitor and MEK-inhibitor double resistance (DDR, double-drugs-resistance) unless co-targeting BRAF and MEK.	5	27	reverse	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	7	8	26	27
Although it remains unclear how MEK and ERK signaling represses differentiation , MEK and ERK signaling plays an essential role in the maintenance of undifferentiated spermatogonial stem cells .	Although it remains unclear how MEK and ERK signaling represses differentiation, MEK and ERK signaling plays an essential role in the maintenance of undifferentiated spermatogonial stem cells.	5	15	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	7	8	12	13
ERK1/2 in both cells were inactivated after Oligonol treatment in a time dependent manner , and also inactivated upstream MEK1/2 .	ERK1/2 in both cells were inactivated after Oligonol treatment in a time dependent manner, and also inactivated upstream MEK1/2.	0	20	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MEK1/2	MEK1/2	MEK1/2	0	1	19	20
CI-1040 ( PD184352 ) is highly selective inhibitor of the MAPK signalling cascade specifically targeting the inhibition of MEK ( Delaney et al , 2002 ) .	CI-1040 (PD184352) is highly selective inhibitor of the MAPK signalling cascade specifically targeting the inhibition of MEK (Delaney et al, 2002).	10	20	targeting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	10	11	18	19
By contrast , treatment with 10 muM U0126 completely abrogated EGF induced ERK1/2 phosphorylation in pancreatic cancer CAPAN-1 cells ( XREF_SUPPLEMENTARY , lower panel ) , and has also been reported to prevent MEK1/2 signaling to ERK1/2 in a variety of other EGF responsive epithelial cells [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	By contrast, treatment with 10 muM U0126 completely abrogated EGF induced ERK1/2 phosphorylation in pancreatic cancer CAPAN-1 cells (XREF_SUPPLEMENTARY, lower panel), and has also been reported to prevent MEK1/2 signaling to ERK1/2 in a variety of other EGF responsive epithelial cells [XREF_BIBR, XREF_BIBR - XREF_BIBR].	10	34	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	EGF induced ERK1/2 phosphorylation	erk1/2	MEK1/2	MEK1/2	mek1/2	12	13	33	34
Molecular evidence from patient tumor biopsies revealed enhanced activation of NF-kappaB and MAPK pathway elements downstream of EGFR , potentially due to antagonism of radiation induced EGFR degradation following proteasome inhibition .	Molecular evidence from patient tumor biopsies revealed enhanced activation of NF-kappaB and MAPK pathway elements downstream of EGFR, potentially due to antagonism of radiation induced EGFR degradation following proteasome inhibition.	10	27	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	12	13	26	27
Regarding E2 effects , we found that ( i ) E2 rapidly induced IGF-1-R and EGF-R phosphorylation and MAPK activation ; ( ii ) blockade or knockdown of either IGF-1-R or EGF-R abrogated E2-inducd MAPK phosphorylation ; ( iii ) knockdown or blockade of either IGF-1-R or EGF-R counteracted the stimulation of cell growth and protection against cell death induced by E2 .	Regarding E2 effects, we found that (i) E2 rapidly induced IGF-1-R and EGF-R phosphorylation and MAPK activation; (ii) blockade or knockdown of either IGF-1-R or EGF-R abrogated E2-inducd MAPK phosphorylation; (iii) knockdown or blockade of either IGF-1-R or EGF-R counteracted the stimulation of cell growth and protection against cell death induced by E2.	34	48	knockdown	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	MAPK	MAPK phosphorylation	mapk	EGF-R	EGF-R	egf-r	34	35	47	48
Our results indicate that clathrin plays a critical regulator in the ERK mediated negative feedback regulation of HER2 and EGFR activity and Akt activity .	Our results indicate that clathrin plays a critical regulator in the ERK mediated negative feedback regulation of HER2 and EGFR activity and Akt activity.	8	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	11	12	19	20
Inhibition of the MAPK pathway can promote EGFR activation and resultant signaling via the PI3K pathway by releasing EGFR from ERK dependent negative feedback [ 3 ] , [ 4 ] , [ 5 ] , [ 6 ] , and/or inducing EGFR-ligand expression [ 7 ] .	Inhibition of the MAPK pathway can promote EGFR activation and resultant signaling via the PI3K pathway by releasing EGFR from ERK dependent negative feedback [3], [4], [5], [6], and/or inducing EGFR-ligand expression [7].	3	8	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	3	4	7	8
On the other hand , ERK phosphorylation enhanced by BRAF V600E and BRAF L525R was not affected by cetuximab , suggesting that cells with BRAF V600E or BRAF L525R mutants were resistant to cetuximab induced inhibition of EGFR .	On the other hand, ERK phosphorylation enhanced by BRAF V600E and BRAF L525R was not affected by cetuximab, suggesting that cells with BRAF V600E or BRAF L525R mutants were resistant to cetuximab induced inhibition of EGFR.	5	38	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK phosphorylation	erk	EGFR	EGFR	egfr	5	6	37	38
An interesting aspect of this ERK-EGFR feedback is that it connects ERK signaling with AKT activity in an EGFR dependent manner , as ERK inhibits the EGF receptor that also stimulates AKT signaling .	An interesting aspect of this ERK-EGFR feedback is that it connects ERK signaling with AKT activity in an EGFR dependent manner, as ERK inhibits the EGF receptor that also stimulates AKT signaling.	23	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	EGF receptor	EGF receptor	EGF receptor	23	24	26	28
As in XREF_FIG , silencing TACE or p38alpha MAPK expression decreased the basal EGFR activation , resulting in decreased Erk MAPK activation ( XREF_FIG , middle panel ) , a downstream effect of EGFR signaling that regulates proliferation ( Pages et al ., 1993 ) .	As in XREF_FIG, silencing TACE or p38alpha MAPK expression decreased the basal EGFR activation, resulting in decreased Erk MAPK activation (XREF_FIG, middle panel), a downstream effect of EGFR signaling that regulates proliferation (Pages et al., 1993).	8	14	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK expression	mapk	EGFR	EGFR	egfr	8	9	13	14
In accord with these findings in GEMMs , clinical trials of inhibitors targeting the epidermal growth factor receptor ( EGFR ) , the RAF-mitogen-activated protein kinase ( MAPK ) pathway , phosphoinositide 3-kinase , or the Hedgehog pathway have been largely unsuccessful .	In accord with these findings in GEMMs, clinical trials of inhibitors targeting the epidermal growth factor receptor (EGFR), the RAF-mitogen-activated protein kinase (MAPK) pathway, phosphoinositide 3-kinase, or the Hedgehog pathway have been largely unsuccessful.	12	29	targeting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	27	28	14	18
AKT inhibition did not influence the cooperation on proliferation or invasion after HGF+ EGF treatment , while ERK1/2 inhibition abolished MET and EGFR cooperation on proliferation .	AKT inhibition did not influence the cooperation on proliferation or invasion after HGF+EGF treatment, while ERK1/2 inhibition abolished MET and EGFR cooperation on proliferation.	17	23	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	17	18	22	23
Reduced AKT activity enhances ERK and RSK activation in an EGFR dependent manner .	Reduced AKT activity enhances ERK and RSK activation in an EGFR dependent manner.	4	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	4	5	10	11
CQ did not enhance erlotinib induced inhibition of EGFR , AKT and ERK phosphorylation , suggesting that the cytotoxicity sensitization effect is not due to further inhibition of the EGFR pathway .	CQ did not enhance erlotinib induced inhibition of EGFR, AKT and ERK phosphorylation, suggesting that the cytotoxicity sensitization effect is not due to further inhibition of the EGFR pathway.	5	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK phosphorylation	erk	EGFR	EGFR	egfr	12	13	8	9
In addition , AG1478 prevented ERK1/2 phosphorylation and decrease in megalin protein levels , further implicating EGFR transactivation by the AT 1 R as a major player .	In addition, AG1478 prevented ERK1/2 phosphorylation and decrease in megalin protein levels, further implicating EGFR transactivation by the AT 1 R as a major player.	3	17	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	AG1478 prevented ERK1/2 phosphorylation	erk1/2	EGFR	EGFR	egfr	5	6	16	17
Pretreatment with internalization inhibitor dansylcadaverine ( DC ) also enhanced U0126 induced EGFR and HER2 and Akt activations , implying that inhibition of ERK prolongs the duration of EGFR and HER2 signaling by retaining these receptors on the cell surface membrane .	Pretreatment with internalization inhibitor dansylcadaverine (DC) also enhanced U0126 induced EGFR and HER2 and Akt activations, implying that inhibition of ERK prolongs the duration of EGFR and HER2 signaling by retaining these receptors on the cell surface membrane.	21	31	prolongs	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	23	24	28	29
These data imply that the adaptive reactivation of MAPK pathway may limit initial EGFR TKI response , reminiscent of recent findings using irreversible EGFR inhibitor WZ4002 XREF_BIBR .	These data imply that the adaptive reactivation of MAPK pathway may limit initial EGFR TKI response, reminiscent of recent findings using irreversible EGFR inhibitor WZ4002 XREF_BIBR.	8	15	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	8	9	13	14
However , we found that gefitinib treatment of these cells did not result in dephosphorylation of ERK1/2 ( XREF_FIG A ) or substantial apoptosis ( XREF_FIG B ) , presumably due to the presence of the additional ( T790M ) mutation , known to reduce the kinase activity of EGFR , rendering it effectively wild type [ XREF_BIBR ] .	However, we found that gefitinib treatment of these cells did not result in dephosphorylation of ERK1/2 (XREF_FIG A) or substantial apoptosis (XREF_FIG B), presumably due to the presence of the additional (T790M) mutation, known to reduce the kinase activity of EGFR, rendering it effectively wild type [XREF_BIBR].	5	50	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	gefitinib treatment of these cells did not result in dephosphorylation of ERK1/2	erk1/2	EGFR	EGFR	egfr	16	17	49	50
The PGE 2 -induced elevation in ERK1/2 activation was significantly inhibited by co-treatment of FPS cells with FP receptor antagonist ( AL8810 ) , EP2 receptor antagonist ( AH6809 ) , EP4 receptor antagonist ( ONOAE2227 ) and PLC inhibitor ( U73122 ) and abolished by treatment of cells with the PKA ( 4C3MQ ) , EGFR kinase ( AG1478 ) and ERK1/2 kinase ( PD98059 ) inhibitors , but not the PKC inhibitor ( GF109203x ; XREF_FIG B , P < 0.05 ) .	The PGE 2 -induced elevation in ERK1/2 activation was significantly inhibited by co-treatment of FPS cells with FP receptor antagonist (AL8810), EP2 receptor antagonist (AH6809), EP4 receptor antagonist (ONOAE2227) and PLC inhibitor (U73122) and abolished by treatment of cells with the PKA (4C3MQ), EGFR kinase (AG1478) and ERK1/2 kinase (PD98059) inhibitors, but not the PKC inhibitor (GF109203x; XREF_FIG B, P < 0.05).	6	57	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	6	7	56	57
MAPK pathway inhibition promotes EGFR activation by releasing EGFR from extracellular signal regulated kinases ( ERK )-dependent negative feedback [ 3 ] , [ 4 ] , [ 5 ] , [ 6 ] and/or inducing EGFR-ligand expression [ 7 ] .	MAPK pathway inhibition promotes EGFR activation by releasing EGFR from extracellular signal regulated kinases (ERK)-dependent negative feedback [3], [4], [5], [6] and/or inducing EGFR-ligand expression [7].	0	5	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	0	1	4	5
ERK activation induces several negative feedback regulators of EGFR signaling including SPRY2 , SPRED , and others [ XREF_BIBR ] .	ERK activation induces several negative feedback regulators of EGFR signaling including SPRY2, SPRED, and others [XREF_BIBR].	0	9	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	0	1	8	9
The inhibition of ERK1/2 activation in vitro and in vivo by compounds targeting the EGF receptor points to the interest of ERK1/2 as potential surrogate markers of EGF-receptor signaling in clinical therapeutic studies .	The inhibition of ERK1/2 activation in vitro and in vivo by compounds targeting the EGF receptor points to the interest of ERK1/2 as potential surrogate markers of EGF-receptor signaling in clinical therapeutic studies.	3	16	targeting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	EGF receptor	EGF receptor	EGF receptor	3	4	14	16
The interruption of the ERK signaling pathway by EGCG reduces the trans-activation activity of Egr-1 and the promoter activity of EGFR gene in HSC .	The interruption of the ERK signaling pathway by EGCG reduces the trans-activation activity of Egr-1 and the promoter activity of EGFR gene in HSC.	4	21	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	4	5	20	21
These results suggest that the involvement of other members of HER kinase family in the ERK dependent feedback downregulation of EGFR and Akt signaling may be context specific ( Hendriks etal ., 2003 ) .	These results suggest that the involvement of other members of HER kinase family in the ERK dependent feedback downregulation of EGFR and Akt signaling may be context specific (Hendriks etal., 2003).	15	23	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	15	16	20	21
A similar observation has also been reported in previous studies showing that the inhibited ERK activity promotes the EGFR activation and augments EGFR driven motility of prostate cancer cells [ XREF_BIBR ] .	A similar observation has also been reported in previous studies showing that the inhibited ERK activity promotes the EGFR activation and augments EGFR driven motility of prostate cancer cells [XREF_BIBR].	14	23	augments	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	14	15	22	23
EEF2 is essential for translation elongation , and Thr56 is phosphorylated by eEF2 kinase ( eEF2K ) , the only known kinase for eEF2 , to block eEF2 activity .	EEF2 is essential for translation elongation, and Thr56 is phosphorylated by eEF2 kinase (eEF2K), the only known kinase for eEF2, to block eEF2 activity.	13	28	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	15	16	27	28
Thus activated eEF2K inhibits eEF2 function via phosphorylation XREF_BIBR .	Thus activated eEF2K inhibits eEF2 function via phosphorylation XREF_BIBR.	1	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	2	3	4	5
eEF2K phosphorylates and inhibits eukaryotic elongation factor 2 , to slow down the elongation stage of protein synthesis providing protection against nutrient starvation and proteotoxicity [ XREF_BIBR , XREF_BIBR ] .	eEF2K phosphorylates and inhibits eukaryotic elongation factor 2, to slow down the elongation stage of protein synthesis providing protection against nutrient starvation and proteotoxicity [XREF_BIBR, XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	elongation factor 2	elongation factor 2	elongation factor 2	0	1	5	8
To prove that inhibition of eEF2K by S6K is required to allow increased eEF2 activity following Apc loss , we intercrossed VillinCRE ER Apc fl/fl to Eef2k -/- mice and treated these with rapamycin .	To prove that inhibition of eEF2K by S6K is required to allow increased eEF2 activity following Apc loss, we intercrossed VillinCRE ER Apc fl/fl to Eef2k -/- mice and treated these with rapamycin.	3	14	allow	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	5	6	13	14
XREF_BIBR eEF2K downregulates eEF2 to inhibit protein synthesis when conservation of resources is necessary .	XREF_BIBR eEF2K downregulates eEF2 to inhibit protein synthesis when conservation of resources is necessary.	0	4	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	1	2	3	4
Classically , eEF2K phosphorylates and inactivates eEF2 leading to an arrest in mRNA translation [ XREF_BIBR - XREF_BIBR ] .	Classically, eEF2K phosphorylates and inactivates eEF2 leading to an arrest in mRNA translation [XREF_BIBR - XREF_BIBR].	2	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	2	3	6	7
During DNA replication in the S-phase , eEF2K slowly dephosphorylates to fully inhibit eEF2 at the start of the G2 and M phase , where proofreading and mitosis take place .	During DNA replication in the S-phase, eEF2K slowly dephosphorylates to fully inhibit eEF2 at the start of the G2 and M phase, where proofreading and mitosis take place.	7	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	7	8	13	14
S6K1 phosphorylates and inactivates eEF2K , which negatively regulates eukaryotic elongation factor 2 ( eEF2 ) and thus regulates the elongation step of translation [ XREF_BIBR ] .	S6K1 phosphorylates and inactivates eEF2K, which negatively regulates eukaryotic elongation factor 2 (eEF2) and thus regulates the elongation step of translation [XREF_BIBR].	0	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	S6K1 phosphorylates and inactivates eEF2K	eef2k	elongation factor 2	elongation factor 2	elongation factor 2	4	5	10	13
Once activated , p70S6K phosphorylates eukaryotic elongation factor 2 kinase ( eEF2K ) to relieve elongation factor 2 ( eEF2 ) from inhibition by eEF2K in addition to promoting autophagy XREF_BIBR .	Once activated, p70S6K phosphorylates eukaryotic elongation factor 2 kinase (eEF2K) to relieve elongation factor 2 (eEF2) from inhibition by eEF2K in addition to promoting autophagy XREF_BIBR.	3	18	relieve	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eukaryotic elongation factor 2 kinase	p70S6K phosphorylates eukaryotic elongation factor 2 kinase	eukaryotic elongation factor 2 kinase	elongation factor 2	elongation factor 2	elongation factor 2	5	10	15	18
XREF_BIBR Knockdown of EEF2K can activate EEF2 by reduction of EEF2 phosphorylation at Thr56 resulting in promotion of protein synthesis .	XREF_BIBR Knockdown of EEF2K can activate EEF2 by reduction of EEF2 phosphorylation at Thr56 resulting in promotion of protein synthesis.	1	7	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	EEF2K	EEF2K	EEF2K	EEF2	EEF2	EEF2	3	4	6	7
Because mTOR mediated inhibition of eEF2K induces dephophorylation and activation of eEF2 , the reduced phosphorylation of mTOR in IRS1KO beta-cells might also contribute to the phosphorylation of eEF2 in this study .	Because mTOR mediated inhibition of eEF2K induces dephophorylation and activation of eEF2, the reduced phosphorylation of mTOR in IRS1KO beta-cells might also contribute to the phosphorylation of eEF2 in this study.	3	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	5	6	11	12
Moreover , p70 S6K phosphorylates eukaryotic elongation factor 2 kinase ( eEF2K ) and thus relieving elongation factor 2 ( eEF2 ) from the negative regulation of eEF2K as well as inhibiting and inducing autophagy .	Moreover, p70 S6K phosphorylates eukaryotic elongation factor 2 kinase (eEF2K) and thus relieving elongation factor 2 (eEF2) from the negative regulation of eEF2K as well as inhibiting and inducing autophagy.	2	19	relieving	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eukaryotic elongation factor 2 kinase	p70 S6K phosphorylates eukaryotic elongation factor 2 kinase	eukaryotic elongation factor 2 kinase	elongation factor 2	elongation factor 2	elongation factor 2	5	10	16	19
eEF2K catalyzes the phosphorylation of eEF2 and subsequently inactivates eEF2 by impairing its ability to bind to the ribosome , thereby negatively modulates protein synthesis .	eEF2K catalyzes the phosphorylation of eEF2 and subsequently inactivates eEF2 by impairing its ability to bind to the ribosome, thereby negatively modulates protein synthesis.	0	10	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	0	1	9	10
Upon activation , eEF2K phosphorylates and thereby inhibits eEF2 , resulting in a dramatic reduction of mRNA translation .	Upon activation, eEF2K phosphorylates and thereby inhibits eEF2, resulting in a dramatic reduction of mRNA translation.	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	3	4	8	9
Acteoside decreased tyrosinase activity and melanin biosynthesis in B16F10 cells by activating ERK signalling , which down-regulated MITF , tyrosinase and TRP 1 production .	Acteoside decreased tyrosinase activity and melanin biosynthesis in B16F10 cells by activating ERK signalling, which down-regulated MITF, tyrosinase and TRP 1 production.	12	23	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	12	13	17	18
This suggests that MITF is degraded by the ubiquitin pathway after S73 phosphorylation by ERK .	This suggests that MITF is degraded by the ubiquitin pathway after S73 phosphorylation by ERK.	3	15	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	14	15	3	4
Taken together , G-Rg3 inhibits melanogenesis by activating the ERK pathway mediated suppression of MITF and downstream signaling molecules such as tyrosinase and TRP1 .	Taken together, G-Rg3 inhibits melanogenesis by activating the ERK pathway mediated suppression of MITF and downstream signaling molecules such as tyrosinase and TRP1.	9	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	9	10	14	15
However , the melanogenesis inhibitors , MDQ ( XREF_FIG d ) [ XREF_BIBR ] and baicalein ( XREF_FIG h ) [ XREF_BIBR ] , were found not to activate Akt , although they inhibited melanogenesis through MITF degradation mediated by ERK activation .	However, the melanogenesis inhibitors, MDQ (XREF_FIG d) [XREF_BIBR] and baicalein (XREF_FIG h) [XREF_BIBR], were found not to activate Akt, although they inhibited melanogenesis through MITF degradation mediated by ERK activation.	36	41	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	40	41	36	37
The ERK phosphorylation was rapidly decreased to the alpha-MSH-treated state within 3 h and induced the degradation of MITF and TYR .	The ERK phosphorylation was rapidly decreased to the alpha-MSH-treated state within 3 h and induced the degradation of MITF and TYR.	1	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK phosphorylation	erk	MITF	MITF	mitf	1	2	18	19
Thus , although strong constitutive activation of the MAPK pathway clearly promotes MITF degradation , the situation appears to be more complex .	Thus, although strong constitutive activation of the MAPK pathway clearly promotes MITF degradation, the situation appears to be more complex.	8	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	8	9	12	13
Lyoniresinol decreased tyrosinase activity and melanin biosynthesis in B16F10 cells by activating ERK signaling , which downregulated MITF , tyrosinase , but not TRP 1 and TRP 2 protein expression .	Lyoniresinol decreased tyrosinase activity and melanin biosynthesis in B16F10 cells by activating ERK signaling, which downregulated MITF, tyrosinase, but not TRP 1 and TRP 2 protein expression.	12	29	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	12	13	17	18
Previous studies have also shown that tyrosinase , TRP1 , and TRP2 are regulated by MITF , which is downregulated by both ERK and AKT activation XREF_BIBR .	Previous studies have also shown that tyrosinase, TRP1, and TRP2 are regulated by MITF, which is downregulated by both ERK and AKT activation XREF_BIBR.	13	26	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	22	23	15	16
The activation of ERK signal pathway induced the degradation of MITF XREF_BIBR .	The activation of ERK signal pathway induced the degradation of MITF XREF_BIBR.	3	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	3	4	10	11
Flow cytometry analysis of Lyoniresinol treated cells showed that the latter activates extracellular receptor kinase ( ERK ) phosphorylation , which causes MITF protein degradation and suppression of tyrosinase activity .	Flow cytometry analysis of Lyoniresinol treated cells showed that the latter activates extracellular receptor kinase (ERK) phosphorylation, which causes MITF protein degradation and suppression of tyrosinase activity.	16	24	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK) phosphorylation	erk	MITF	MITF	mitf	16	17	22	23
These data suggest that inhibition of the ERK1/2 pathway in melanoma cells relieves suppression of MITF and PGC1alpha , which in turn , controls expression of oxidative phosphorylation genes .	These data suggest that inhibition of the ERK1/2 pathway in melanoma cells relieves suppression of MITF and PGC1alpha, which in turn, controls expression of oxidative phosphorylation genes.	7	23	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MITF	MITF	MITF	7	8	15	16
In turn , MITF is inhibited by the ERK pathway and hence activated by vemurafenib [ XREF_BIBR , XREF_BIBR ] .	In turn, MITF is inhibited by the ERK pathway and hence activated by vemurafenib [XREF_BIBR, XREF_BIBR].	3	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	8	9	3	4
Previous studies reported that the activation of Erk1/2 or Akt induces degradation of MITF , which decreases the level of tyrosinase expression .	Previous studies reported that the activation of Erk1/2 or Akt induces degradation of MITF, which decreases the level of tyrosinase expression.	5	22	induces	Positive_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Erk1/2	Erk1/2	erk1/2	MITF	MITF, which decreases the level of tyrosinase expression	mitf	7	8	13	14
Hesperidin , A Popular Antioxidant Inhibits Melanogenesis via Erk1/2 Mediated MITF Degradation .	Hesperidin, A Popular Antioxidant Inhibits Melanogenesis via Erk1/2 Mediated MITF Degradation.	8	11	Mediated	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Erk1/2	Erk1/2	Erk1/2	MITF	MITF	MITF	8	9	10	11
Taken together , these results demonstrate that phytol stimulates ROS production and modulates ERK mediated proteasomal degradation of MITF in B16F10 murine melanoma cells .	Taken together, these results demonstrate that phytol stimulates ROS production and modulates ERK mediated proteasomal degradation of MITF in B16F10 murine melanoma cells.	13	19	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	13	14	18	19
ERK and RSK initiate the degradation of MITF , resulting in the attenuation of melanogenesis [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	ERK and RSK initiate the degradation of MITF, resulting in the attenuation of melanogenesis [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	8	initiate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	0	1	7	8
As already described , 4-n-butylresorcinol is a strong tyrosinase inhibitor , whereas a signal regulator such as terrain affects pigmentation through ERK induced MITF degradation .	As already described, 4-n-butylresorcinol is a strong tyrosinase inhibitor, whereas a signal regulator such as terrain affects pigmentation through ERK induced MITF degradation.	19	24	induced	Positive_early_activation	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	21	22	23	24
These findings are concordant with previous observations that the activation of the ERK signaling pathway induces MITF degradation , resulting in reduced melanogenesis XREF_BIBR , XREF_BIBR , XREF_BIBR .	These findings are concordant with previous observations that the activation of the ERK signaling pathway induces MITF degradation, resulting in reduced melanogenesis XREF_BIBR, XREF_BIBR, XREF_BIBR.	12	17	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	12	13	16	17
Taken together , hesperidin , a popular antioxidant , stimulated Erk1/2 phosphorylation which subsequently degraded MITF which resulted in suppression of melanogenic enzymes and melanin synthesis .	Taken together, hesperidin, a popular antioxidant, stimulated Erk1/2 phosphorylation which subsequently degraded MITF which resulted in suppression of melanogenic enzymes and melanin synthesis.	3	17	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Erk1/2	hesperidin, a popular antioxidant, stimulated Erk1/2 phosphorylation	erk1/2	MITF	MITF	mitf	10	11	15	16
Taken together , these results suggested that hUCB-MSC-CM regulates melanogenesis through the proteasomal degradation of MITF by ERK activation .	Taken together, these results suggested that hUCB-MSC-CM regulates melanogenesis through the proteasomal degradation of MITF by ERK activation.	13	18	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	MITF	MITF	MITF	17	18	15	16
The ability of Lunasin to suppress ERK1/2 expression is particularly intriguing given reports that activation of ERK1/2 can upregulate ubiquitin dependent degradation of MITF [ XREF_BIBR ] .	The ability of Lunasin to suppress ERK1/2 expression is particularly intriguing given reports that activation of ERK1/2 can upregulate ubiquitin dependent degradation of MITF [XREF_BIBR].	14	25	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MITF	MITF	MITF	16	17	23	24
Cpc exerted dual antimelanogenic mechanisms by upregulation of MAPK and ERK dependent degradation of MITF and downregulation of p38 MAPK regulated CREB activation to modulate melanin formation .	Cpc exerted dual antimelanogenic mechanisms by upregulation of MAPK and ERK dependent degradation of MITF and downregulation of p38 MAPK regulated CREB activation to modulate melanin formation.	8	16	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	8	9	14	15
Thus , these results suggest that hesperidin inhibited melanogenesis through the acceleration of Erk1/2 mediated MITF proteasomal degradation .	Thus, these results suggest that hesperidin inhibited melanogenesis through the acceleration of Erk1/2 mediated MITF proteasomal degradation.	11	17	mediated	Positive_early_activation	Negative_activation	Negative_activation	Erk1/2	Erk1/2	Erk1/2	MITF	MITF	MITF	13	14	15	16
For example , a genetic variant in the gene encoding ectonucleotide pyrophosphatase phosphodiesterase 1 ( ENPP1 ) , which inhibits IR signaling , is an independent risk factor for CAD with particular potency in obese subjects with type 2 diabetes .	For example, a genetic variant in the gene encoding ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), which inhibits IR signaling, is an independent risk factor for CAD with particular potency in obese subjects with type 2 diabetes.	9	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ENPP1	ENPP1	ENPP1	IR	IR	IR	15	16	20	21
Overexpression of PC-1 in MCF-7 cells inhibited tyrosine kinase activity of the IR , but not of the IGF-I receptor .	Overexpression of PC-1 in MCF-7 cells inhibited tyrosine kinase activity of the IR, but not of the IGF-I receptor.	0	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	Overexpression of PC-1	pc-1	IR	IR	ir	2	3	12	13
The human plasma-cell membrane differentiation antigen-1 ( PC-1 ) has been shown to inhibit insulin receptor tyrosine kinase activity .	The human plasma-cell membrane differentiation antigen-1 (PC-1) has been shown to inhibit insulin receptor tyrosine kinase activity.	1	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	PC-1	PC-1	insulin receptor	insulin receptor	insulin receptor	7	8	14	16
Plasma cell differentiation antigen ( PC-1 ) glycoprotein inhibits insulin receptor signaling and is associated with insulin resistance .	Plasma cell differentiation antigen (PC-1) glycoprotein inhibits insulin receptor signaling and is associated with insulin resistance.	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	PC-1	PC-1	insulin receptor	insulin receptor	insulin receptor	5	6	9	11
The ectoenzyme nucleotide pyrophosphate phosphodiesterase ( ENPP1 ) inhibits insulin receptor signaling .	The ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) inhibits insulin receptor signaling.	4	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ENPP1	ENPP1	ENPP1	insulin receptor	insulin receptor	insulin receptor	6	7	9	11
Increased levels of ENPP1 expression inhibit tyrosine kinase activity of the insulin receptor in several cell types , leading to insulin resistance .	Increased levels of ENPP1 expression inhibit tyrosine kinase activity of the insulin receptor in several cell types, leading to insulin resistance.	3	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ENPP1	ENPP1 expression	enpp1	insulin receptor	insulin receptor	insulin receptor	3	4	11	13
Thus , it can be concluded that ENPP1 inhibits IR by blocking the conformational change of IR upon insulin binding .	Thus, it can be concluded that ENPP1 inhibits IR by blocking the conformational change of IR upon insulin binding.	7	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ENPP1	ENPP1	ENPP1	IR	IR	IR	7	8	9	10
In conclusion our data indicate that the overexpression of ENPP1 ( an inhibitor of insulin receptor signaling ) as well as the down-regulation of insulin receptor itself , blunt GLP-1 action on beta cell insulin secretion , proliferation and survival , thus providing evidence that integral insulin receptor function is a prerequisite for such GLP-1 positive effects to be fully expressed .	In conclusion our data indicate that the overexpression of ENPP1 (an inhibitor of insulin receptor signaling) as well as the down-regulation of insulin receptor itself, blunt GLP-1 action on beta cell insulin secretion, proliferation and survival, thus providing evidence that integral insulin receptor function is a prerequisite for such GLP-1 positive effects to be fully expressed.	7	16	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ENPP1	overexpression of ENPP1	enpp1	insulin receptor	insulin receptor	insulin receptor	9	10	14	16
Prior studies in both fibroblasts from insulin- resistant non-insulin-dependent diabetes mellitus patients and transfected cells indicate that overexpression of membrane glycoprotein PC-1 reduces IR tyrosine kinase activity .	Prior studies in both fibroblasts from insulin- resistant non-insulin-dependent diabetes mellitus patients and transfected cells indicate that overexpression of membrane glycoprotein PC-1 reduces IR tyrosine kinase activity.	17	26	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	overexpression of membrane glycoprotein PC-1	pc-1	IR	IR	ir	21	22	23	24
The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 ( ENPP1 ) inhibits insulin receptor signalling and has recently emerged as a key player in the development of insulin resistance .	The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin receptor signalling and has recently emerged as a key player in the development of insulin resistance.	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ENPP1	ENPP1	ENPP1	insulin receptor	insulin receptor	insulin receptor	8	9	11	13
Transfection and expression of PC-1 in cultured cells demonstrate that overexpression of PC-1 produces impairments in insulin receptor tyrosine kinase activity , and the subsequent cellular responses to insulin .	Transfection and expression of PC-1 in cultured cells demonstrate that overexpression of PC-1 produces impairments in insulin receptor tyrosine kinase activity, and the subsequent cellular responses to insulin.	10	20	produces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	overexpression of PC-1	pc-1	insulin receptor	insulin receptor	insulin receptor	12	13	16	18
These studies suggest , therefore , that , in addition to blocking insulin receptor tyrosine kinase activation , PC-1 can also block insulin receptor signaling at a post-receptor site .	These studies suggest, therefore, that, in addition to blocking insulin receptor tyrosine kinase activation, PC-1 can also block insulin receptor signaling at a post-receptor site.	18	24	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	PC-1	PC-1	insulin receptor	insulin receptor	insulin receptor	18	19	22	24
PC-1 inhibits the insulin receptor by blocking the connecting domain in the receptor ' s alpha-subunit , which transmits insulin induced conformational change .	PC-1 inhibits the insulin receptor by blocking the connecting domain in the receptor 's alpha-subunit, which transmits insulin induced conformational change.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	PC-1	PC-1	insulin receptor	insulin receptor	insulin receptor	0	1	3	5
The function of the gene can be directly related to obesity : ENPP1 inhibits insulin receptor activity [ XREF_BIBR ] , and up- or downregulation of ENPP1 expression in liver is associated with decreased or enhanced insulin sensitivity , respectively , in rodents [ XREF_BIBR , XREF_BIBR ] .	The function of the gene can be directly related to obesity : ENPP1 inhibits insulin receptor activity [XREF_BIBR], and up- or downregulation of ENPP1 expression in liver is associated with decreased or enhanced insulin sensitivity, respectively, in rodents [XREF_BIBR, XREF_BIBR].	12	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ENPP1	ENPP1	ENPP1	insulin receptor	insulin receptor	insulin receptor	12	13	14	16
Membrane glycoprotein ENNP1 ( also known as PC-1 ) inhibits insulin receptor signalling and , when overexpressed , causes insulin resistance .	Membrane glycoprotein ENNP1 (also known as PC-1) inhibits insulin receptor signalling and, when overexpressed, causes insulin resistance.	0	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ENNP1	ENNP1	ENNP1	insulin receptor	insulin receptor	insulin receptor	2	3	10	12
Ectonucleotide pyrophosphatase phosphodiesterase 1 ( ENPP1 ) inhibits insulin-receptor ( IR ) signaling and , when over-expressed , induces insulin resistance in vitro and in vivo .	Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin-receptor (IR) signaling and, when over-expressed, induces insulin resistance in vitro and in vivo.	2	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ENPP1	ENPP1	ENPP1	IR	IR	IR	5	6	10	11
However , the mechanisms whereby PC-1 inhibits insulin receptor signaling remain to be determined .	However, the mechanisms whereby PC-1 inhibits insulin receptor signaling remain to be determined.	5	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	PC-1	PC-1	insulin receptor	insulin receptor	insulin receptor	5	6	7	9
These studies indicate , therefore , that PC-1 may inhibit the IR by interacting directly with a specific region in the IR alpha-subunit .	These studies indicate, therefore, that PC-1 may inhibit the IR by interacting directly with a specific region in the IR alpha-subunit.	7	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	PC-1	PC-1	IR	IR	IR	7	8	11	12
Transfection of PC-1 into cultured cells has confirmed that overexpression of PC-1 can produce impairments in insulin receptor tyrosine kinase activity and the subsequent cellular responses to insulin .	Transfection of PC-1 into cultured cells has confirmed that overexpression of PC-1 can produce impairments in insulin receptor tyrosine kinase activity and the subsequent cellular responses to insulin.	9	20	produce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	overexpression of PC-1	pc-1	insulin receptor	insulin receptor	insulin receptor	11	12	16	18
Although previous studies in 3T3-L1 have failed to detect effects of ENPP1 over-expression on cellular insulin sensitivity XREF_BIBR , our results show that ENPP1 over-expression can impair insulin receptor activation in 3T3-L1 cells ( XREF_FIG ) .	Although previous studies in 3T3-L1 have failed to detect effects of ENPP1 over-expression on cellular insulin sensitivity XREF_BIBR, our results show that ENPP1 over-expression can impair insulin receptor activation in 3T3-L1 cells (XREF_FIG).	23	29	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ENPP1	ENPP1 over-expression	enpp1	insulin receptor	insulin receptor	insulin receptor	23	24	27	29
PC-1 overexpression inhibits IR tyrosine kinase and possibly other downstream signaling events .	PC-1 overexpression inhibits IR tyrosine kinase and possibly other downstream signaling events.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	PC-1 overexpression	pc-1	IR	IR	ir	0	1	3	4
Plasma-cell membrane differentiation antigene-1 ( PC-1 ) inhibits insulin receptor signalling when overexpressed and thus causes insulin resistance .	Plasma-cell membrane differentiation antigene-1 (PC-1) inhibits insulin receptor signalling when overexpressed and thus causes insulin resistance.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	PC-1	PC-1	insulin receptor	insulin receptor	insulin receptor	5	6	8	10
Overexpression of plasma cell membrane glycoprotein-1 ( PC-1 ) inhibits insulin receptor tyrosine kinase activity and thus favours insulin resistance and atherosclerotic vascular disease .	Overexpression of plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor tyrosine kinase activity and thus favours insulin resistance and atherosclerotic vascular disease.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PC-1	PC-1	PC-1	insulin receptor	insulin receptor	insulin receptor	7	8	10	12
The discovery of BRAF mutations and MAPK pathway dependence of human cancers led to the therapeutic strategy targeting BRAF and MAPK pathway .	The discovery of BRAF mutations and MAPK pathway dependence of human cancers led to the therapeutic strategy targeting BRAF and MAPK pathway.	6	21	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	6	7	18	19
Phosphoproteomic analysis revealed loss of ERK mediated feedback regulation of both BRAF and MEK1 ( XREF_FIG ) .	Phosphoproteomic analysis revealed loss of ERK mediated feedback regulation of both BRAF and MEK1 (XREF_FIG).	3	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	loss of ERK	erk	BRAF	BRAF	braf	5	6	11	12
Phosphorylation of ERK1/2 , downstream molecules of MEK , was effectively inhibited with selumetinib in melanoma , colorectal cancer , pancreatic cancer , non-small-cell lung cancer , and hepatocellular cancer cell lines harboring BRAF , NRAS , or KRAS mutations .	Phosphorylation of ERK1/2, downstream molecules of MEK, was effectively inhibited with selumetinib in melanoma, colorectal cancer, pancreatic cancer, non-small-cell lung cancer, and hepatocellular cancer cell lines harboring BRAF, NRAS, or KRAS mutations.	0	39	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	Phosphorylation of ERK1/2	erk1/2	BRAF	BRAF	braf	2	3	33	34
MEK inhibitors can potentiate the MAPK inhibition in BRAF mutant cells , while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild type cells that lead to side effects when using BRAF inhibitors alone .	MEK inhibitors can potentiate the MAPK inhibition in BRAF mutant cells, while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild type cells that lead to side effects when using BRAF inhibitors alone.	18	24	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	18	19	21	22
XREF_BIBR However , MAPK pathway dysregulation at points both upstream and downstream of BRAF likely play a critical role in acquired resistance .	XREF_BIBR However, MAPK pathway dysregulation at points both upstream and downstream of BRAF likely play a critical role in acquired resistance.	3	15	dysregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	3	4	13	14
A better understanding of how melanoma derived immunologically active molecules change in response to MAPK inhibition of BRAF mutated ( BRAF ) and BRAF wild type ( BRAF ) melanomas could help identify promising treatment combinations of small molecule inhibitors and immunotherapy .	A better understanding of how melanoma derived immunologically active molecules change in response to MAPK inhibition of BRAF mutated (BRAF) and BRAF wild type (BRAF) melanomas could help identify promising treatment combinations of small molecule inhibitors and immunotherapy.	14	18	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	14	15	17	18
RAF inhibitors suppress monomeric BRAF V600E , but they have been shown to induce RAF priming ( CRAF S338 phosphorylation ) and BRAF and CRAF dimerization and activation of downstream ERK signaling in BRAF WT -expressing cells .	RAF inhibitors suppress monomeric BRAF V600E, but they have been shown to induce RAF priming (CRAF S338 phosphorylation) and BRAF and CRAF dimerization and activation of downstream ERK signaling in BRAF WT -expressing cells.	30	36	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	30	31	33	34
MAPK inhibition may exert significant effects on immune cells as well , particularly for BRAF inhibitors ( e.g ., vemurafenib , FDA approved for melanoma ) that paradoxically activate MAPK signaling in BRAF wild-type cells .	MAPK inhibition may exert significant effects on immune cells as well, particularly for BRAF inhibitors (e.g., vemurafenib, FDA approved for melanoma) that paradoxically activate MAPK signaling in BRAF wild-type cells.	29	34	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	29	30	32	33
How can ERK activity be suppressed in MDCK cells expressing the active Ras or BRaf ?	How can ERK activity be suppressed in MDCK cells expressing the active Ras or BRaf?	2	15	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	BRaf	BRaf	BRaf	2	3	14	15
LKB1 and RAS/RAF/MEK ( MAPK ) signalling pathways are linked through RHEB , which when active , activates mTOR and inhibits wild-type BRAF , but not the mutated form ( Im et al , 2002 ; Garami et al , 2003 ; Karbowniczek et al , 2004 ) .	LKB1 and RAS/RAF/MEK (MAPK) signalling pathways are linked through RHEB, which when active, activates mTOR and inhibits wild-type BRAF, but not the mutated form (Im et al, 2002; Garami et al, 2003; Karbowniczek et al, 2004).	0	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	4	5	22	23
These mutants are capable of signaling as monomers or RAS dependent dimers ; the feedback inhibition of RAS by ERK causes BRAF V600 mutants to exist as drug sensitive monomers in these tumors .	These mutants are capable of signaling as monomers or RAS dependent dimers; the feedback inhibition of RAS by ERK causes BRAF V600 mutants to exist as drug sensitive monomers in these tumors.	17	23	causes	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	19	20	21	22
Furthermore suppression of MAPK feedback at mitosis enhanced B-Raf activity , whereas constitutive activation of MAPK at mitosis strongly suppressed B-Raf activity .	Furthermore suppression of MAPK feedback at mitosis enhanced B-Raf activity, whereas constitutive activation of MAPK at mitosis strongly suppressed B-Raf activity.	13	21	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	B-Raf	B-Raf	B-Raf	15	16	20	21
Previous reports have shown that ERK feedback inhibition targeted both CRAF and Raf -1 and BRAF XREF_BIBR - XREF_BIBR .	Previous reports have shown that ERK feedback inhibition targeted both CRAF and Raf -1 and BRAF XREF_BIBR - XREF_BIBR.	5	16	targeted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	5	6	15	16
In NRAS-mutant melanoma , extracellular signal regulated kinase ( ERK )-mediated feedback inactivates BRAF , RAF isoform switching occurs , and mutant NRAS mediates downstream signaling through CRAF .	In NRAS-mutant melanoma, extracellular signal regulated kinase (ERK)-mediated feedback inactivates BRAF, RAF isoform switching occurs, and mutant NRAS mediates downstream signaling through CRAF.	7	14	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	9	10	13	14
Here , we hypothesized that ROS generated in response to TPA inhibit Erk1/2 directed phosphatase activity , which leads to an increase phosphorylation of Erk1/2 to signal p21 WAF1 and Cip1 -mediated growth arrest in ML-1 cells .	Here, we hypothesized that ROS generated in response to TPA inhibit Erk1/2 directed phosphatase activity, which leads to an increase phosphorylation of Erk1/2 to signal p21 WAF1 and Cip1 -mediated growth arrest in ML-1 cells.	5	33	signal	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk1/2	ROS generated in response to TPA inhibit Erk1/2 directed phosphatase activity, which leads to an increase phosphorylation of Erk1/2	erk1/2	Cip1	Cip1	cip1	24	25	30	31
As p21 can be induced by MEK and ERK pathway inhibition in RMS cells 6 and we have previously shown that TBX2 regulates p21 and p14 54 , this suggests that targeting TBX2 might block downstream targets of both the PI3K/AKT/mTOR pathway and the RAS/RAF/MEK/ERK pathway .	As p21 can be induced by MEK and ERK pathway inhibition in RMS cells 6 and we have previously shown that TBX2 regulates p21 and p14 54, this suggests that targeting TBX2 might block downstream targets of both the PI3K/AKT/mTOR pathway and the RAS/RAF/MEK/ERK pathway.	1	10	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	p21	p21	p21	8	9	1	2
106 Once activated , ERK/p38/JNK MAPK can upregulate CDK6 ( a member of cyclin dependent kinases ) , CCND1 and CCNE1 ( members of cyclins ) , and downregulate p16 , p21 and p27 ( members of CDKIs ) , thus inducing the G1/S and G 2 / M transitions and cell proliferation .	106 Once activated, ERK/p38/JNK MAPK can upregulate CDK6 (a member of cyclin dependent kinases), CCND1 and CCNE1 (members of cyclins), and downregulate p16, p21 and p27 (members of CDKIs), thus inducing the G1/S and G 2 / M transitions and cell proliferation.	4	32	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	p21	p21	p21	5	6	31	32
TEM8 knock-down attenuated ERK1/2 phosphorylation , down-regulated cyclinD1 expression and upregulated p21 and p27 in osteosarcoma .	TEM8 knock-down attenuated ERK1/2 phosphorylation, down-regulated cyclinD1 expression and upregulated p21 and p27 in osteosarcoma.	0	13	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	TEM8 knock-down attenuated ERK1/2 phosphorylation	erk1/2	p21	p21	p21	3	4	11	12
Eight hours after MAPK activation , loss of C/EBPbeta or Ets2 function significantly reduced MAPK stimulated transcription from the p21 promoter and abolished increased p21 protein expression .	Eight hours after MAPK activation, loss of C/EBPbeta or Ets2 function significantly reduced MAPK stimulated transcription from the p21 promoter and abolished increased p21 protein expression.	8	25	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	C/EBPbeta or Ets2 function significantly reduced MAPK stimulated transcription	mapk	p21	p21	p21	14	15	24	25
These results suggest that while DNA synthesis in Panc-1 cells is enhanced by ERK and strongly suppressed by p38 , in AsPC-1 cells , p38 exerts a pro mitogenic effect through MEK and ERK dependent downregulation of p21 .	These results suggest that while DNA synthesis in Panc-1 cells is enhanced by ERK and strongly suppressed by p38, in AsPC-1 cells, p38 exerts a pro mitogenic effect through MEK and ERK dependent downregulation of p21.	31	38	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	p21	p21	p21	33	34	37	38
BMP induced growth suppression is mediated in part by p21 ( WAF1 ) , not by transcriptional upregulation but by improved p21 protein stability , which is inhibited by RAS and ERK .	BMP induced growth suppression is mediated in part by p21 (WAF1), not by transcriptional upregulation but by improved p21 protein stability, which is inhibited by RAS and ERK.	21	32	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	p21	p21	p21	31	32	21	22
Constitutively active components in the MAPK pathway activate p21 expression , and inhibitors or dominant negative constructs for the MAPK pathway significantly decrease p21 induction by TGF-beta .	Constitutively active components in the MAPK pathway activate p21 expression, and inhibitors or dominant negative constructs for the MAPK pathway significantly decrease p21 induction by TGF-beta.	5	24	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	p21	p21	p21	5	6	23	24
Activation of the Ras and MAPK pathway enhances the mitogenic action of TGF-beta by suppressing its growth-inhibitory function and inhibition of p15 INK4B or p21 WAF1 [ XREF_BIBR ] .	Activation of the Ras and MAPK pathway enhances the mitogenic action of TGF-beta by suppressing its growth-inhibitory function and inhibition of p15 INK4B or p21 WAF1 [XREF_BIBR].	3	27	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21 WAF1	p21 WAF1	p21 WAF1	5	6	24	26
Pharmacological inactivation of the PI-3 ' K/AKT and MAPK completely prevented HRG induced accumulation of p21WAF1 and CIP1 .	Pharmacological inactivation of the PI-3 ' K/AKT and MAPK completely prevented HRG induced accumulation of p21WAF1 and CIP1.	1	18	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	CIP1	CIP1	CIP1	8	9	17	18
The combination of specific inhibitors of ERK1/2 , JNK or PI3K and Akt pathway and metformin further promoted cell apoptosis and the up-regulation of p21 , Bax , Bad , cleaved caspase-3 and -9 as well as the down-regulation of Bcl-2 mediated by metformin alone , but inhibition of p38 pathway exhibited the opposite results .	The combination of specific inhibitors of ERK1/2, JNK or PI3K and Akt pathway and metformin further promoted cell apoptosis and the up-regulation of p21, Bax, Bad, cleaved caspase-3 and -9 as well as the down-regulation of Bcl-2 mediated by metformin alone, but inhibition of p38 pathway exhibited the opposite results.	4	30	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	p21	p21	p21	6	7	24	25
By contrast , overexpression of ClC-3 potentiated cell proliferation induced by IGF-1 , raised the percentage of S phase cells , enhanced phosphorylation of ERK1/2 , downregulated p27 and p21 and upregulated cyclin E and cyclin D1 .	By contrast, overexpression of ClC-3 potentiated cell proliferation induced by IGF-1, raised the percentage of S phase cells, enhanced phosphorylation of ERK1/2, downregulated p27 and p21 and upregulated cyclin E and cyclin D1.	3	30	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	overexpression of ClC-3 potentiated cell proliferation induced by IGF-1, raised the percentage of S phase cells, enhanced phosphorylation of ERK1/2	erk1/2	p21	p21	p21	24	25	29	30
We next utilized PKR knockdown by siRNA to further document the down-regulation of P-eIF2alpha through inhibiting PKR phosphorylation .	We next utilized PKR knockdown by siRNA to further document the down-regulation of P-eIF2alpha through inhibiting PKR phosphorylation.	3	14	knockdown	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKR	PKR	PKR	P-eIF2alpha	P-eIF2alpha	P-eIF2alpha	3	4	13	14
Taken together , our data suggest that PC1 inhibits PKR phosphorylation through which it down-regulates the eIF2alpha activity .	Taken together, our data suggest that PC1 inhibits PKR phosphorylation through which it down-regulates the eIF2alpha activity.	7	17	down-regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PKR	PC1 inhibits PKR phosphorylation	pkr	eIF2alpha	eIF2alpha	eif2alpha	9	10	16	17
Although earlier studies suggested that PKR could suppress HCV replication , subsequent studies indicate that PKR has no effect on HCV and that the inactivation of eIF2alpha by PKR is actually beneficial to HCV , as it suppresses the expression of IFNs and interferon stimulated genes ( ISGs ) .	Although earlier studies suggested that PKR could suppress HCV replication, subsequent studies indicate that PKR has no effect on HCV and that the inactivation of eIF2alpha by PKR is actually beneficial to HCV, as it suppresses the expression of IFNs and interferon stimulated genes (ISGs).	24	29	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	28	29	26	27
6 Therefore , we next performed Annexin V ( AV )/propidium iodide ( PI ) staining of cells treated as above to determine whether silencing of PKR and consequent inactivation of eIF2alpha abrogated Smad7 antisense driven cell death .	6 Therefore, we next performed Annexin V (AV)/propidium iodide (PI) staining of cells treated as above to determine whether silencing of PKR and consequent inactivation of eIF2alpha abrogated Smad7 antisense driven cell death.	26	32	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	26	27	31	32
Our findings suggest that HCV may appropriate Stau1 to its advantage to prevent PKR mediated inhibition of eIF2alpha , which is required for the synthesis of HCV proteins for translocation of viral RNA genome to the polysomes for efficient translation and replication .	Our findings suggest that HCV may appropriate Stau1 to its advantage to prevent PKR mediated inhibition of eIF2alpha, which is required for the synthesis of HCV proteins for translocation of viral RNA genome to the polysomes for efficient translation and replication.	13	21	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	13	14	17	18
A PKR dependent reduction of eIF2alpha activity is associated with a predominant expression of the larger C/EBPbeta isoforms under certain conditions , whereas an increased eIF2alpha activity favours the formation of LIP [ XREF_BIBR ] .	A PKR dependent reduction of eIF2alpha activity is associated with a predominant expression of the larger C/EBPbeta isoforms under certain conditions, whereas an increased eIF2alpha activity favours the formation of LIP [XREF_BIBR].	1	6	reduction	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	1	2	5	6
Overactivation of PKR also inactivates its substrate eIF2alpha , inhibiting the translation of specific mRNAs , such as the DNA repair factor MRG15 .	Overactivation of PKR also inactivates its substrate eIF2alpha, inhibiting the translation of specific mRNAs, such as the DNA repair factor MRG15.	0	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	2	3	7	8
The late HSV-1 protein Us11 directly binds PKR or PACT , an activator of PKR , thus antagonizing the PKR and eIF2alpha pathway .	The late HSV-1 protein Us11 directly binds PKR or PACT, an activator of PKR, thus antagonizing the PKR and eIF2alpha pathway.	7	22	antagonizing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	7	8	21	22
Consistent with this hypothesis , poxviruses encode a PKR pseudosubstrate that structurally mimics eIF2alpha and competitively inhibits eIF2alpha docking by binding to the alphaG helix .	Consistent with this hypothesis, poxviruses encode a PKR pseudosubstrate that structurally mimics eIF2alpha and competitively inhibits eIF2alpha docking by binding to the alphaG helix.	8	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	8	9	17	18
A conserved upstream open reading frame ( uORF ) located between this non canonical translation initiation site and that corresponding to the 42-kd isoform , but with a different reading frame , is thought to control the ratio of p42 vs. p30 translation , dependent upon mTOR activation of eIF-4E and PKR inhibition of eIF-2alpha , with increased initiation from the uORF due to reduced PKR or increased mTOR activity leading to increased p30 translation [ XREF_BIBR , XREF_BIBR ] .	A conserved upstream open reading frame (uORF) located between this non canonical translation initiation site and that corresponding to the 42-kd isoform, but with a different reading frame, is thought to control the ratio of p42 vs. p30 translation, dependent upon mTOR activation of eIF-4E and PKR inhibition of eIF-2alpha, with increased initiation from the uORF due to reduced PKR or increased mTOR activity leading to increased p30 translation [XREF_BIBR, XREF_BIBR].	49	55	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF-2alpha	eIF-2alpha	eIF-2alpha	51	52	54	55
HCV protein synthesis requires the activity of eIF2alpha , which is strongly inhibited by PKR .	HCV protein synthesis requires the activity of eIF2alpha, which is strongly inhibited by PKR.	5	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	14	15	7	8
Under conditions of protein overloading , PERK attenuates protein translation by dimerising and activating eIF2alpha , the central regulator of protein synthesis .	Under conditions of protein overloading, PERK attenuates protein translation by dimerising and activating eIF2alpha, the central regulator of protein synthesis.	6	18	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	6	7	14	15
Upon detection of unfolded proteins and ER stress , PERK phosporylates and inactivates the translation initiation factor eIF2a to shut down protein synthesis .	Upon detection of unfolded proteins and ER stress, PERK phosporylates and inactivates the translation initiation factor eIF2a to shut down protein synthesis.	9	18	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PERK	PERK	PERK	eIF2a	eIF2a	eIF2a	9	10	17	18
GSK2606414 , a PERK inhibitor , and PERK specific siRNA prevent eIF2alpha down-regulation and restore cell survival .	GSK2606414, a PERK inhibitor, and PERK specific siRNA prevent eIF2alpha down-regulation and restore cell survival.	7	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	7	8	11	12
Here , we explore the converse experiment : Perk haploinsufficiency reduces P-eIF2alpha in S63del nerves as expected , but surprisingly , ameliorates , rather than worsens S63del neuropathy .	Here, we explore the converse experiment : Perk haploinsufficiency reduces P-eIF2alpha in S63del nerves as expected, but surprisingly, ameliorates, rather than worsens S63del neuropathy.	8	12	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Perk	Perk	Perk	P-eIF2alpha	P-eIF2alpha	P-eIF2alpha	8	9	11	12
When overexpressing 4R tau in neurons , PERK activator treatment still increased pNRF2 , but not pEIF2A ( Fig XREF_FIG F and G ) , while PERK inhibitor treatment decreased pEIF2A but not pNRF2 .	When overexpressing 4R tau in neurons, PERK activator treatment still increased pNRF2, but not pEIF2A (Fig XREF_FIG F and G), while PERK inhibitor treatment decreased pEIF2A but not pNRF2.	7	33	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PERK	PERK	PERK	pEIF2A	pEIF2A	pEIF2A	7	8	30	31
Although PERK activation causes global inhibition of protein translation by blocking eIF-2alpha activity , it paradoxically enhances translation of the transcription factor ATF4 .	Although PERK activation causes global inhibition of protein translation by blocking eIF-2alpha activity, it paradoxically enhances translation of the transcription factor ATF4.	1	12	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF-2alpha	eIF-2alpha	eIF-2alpha	1	2	11	12
ER stress is known to result in the oligomerization and autophosphorylation of PERK , which then phosphorylates and thus inactivates eIF2alpha , although other kinases can also influence eIF2alpha activity XREF_BIBR .	ER stress is known to result in the oligomerization and autophosphorylation of PERK, which then phosphorylates and thus inactivates eIF2alpha, although other kinases can also influence eIF2alpha activity XREF_BIBR.	8	21	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	12	13	20	21
When this is insufficient to reestablish homeostasis , the cells die , a process that is exacerbated when eIF2alpha can not be inhibited by PERK .	When this is insufficient to reestablish homeostasis, the cells die, a process that is exacerbated when eIF2alpha can not be inhibited by PERK.	18	25	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	24	25	18	19
ER stress may activate autophagy through the ability of IRE1 to associate with TRAF2 and activate JNK or through PERK mediated inhibition of eIF2alpha .	ER stress may activate autophagy through the ability of IRE1 to associate with TRAF2 and activate JNK or through PERK mediated inhibition of eIF2alpha.	3	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	19	20	23	24
Deletion of ERp29 selectively impairs the activation of ATF6 and CHOP , but has no effect on other UPR branches , such as the PERK downstream activating transcription factor 4 ( ATF4 ) and eukaryotic initiation factor 2 alpha ( eIF2alpha ) , and the X-box binding protein 1 ( XBP1 ) pathways .	Deletion of ERp29 selectively impairs the activation of ATF6 and CHOP, but has no effect on other UPR branches, such as the PERK downstream activating transcription factor 4 (ATF4) and eukaryotic initiation factor 2 alpha (eIF2alpha), and the X-box binding protein 1 (XBP1) pathways.	15	41	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	24	25	40	41
Furthermore , some cancer cell lines display decreased PERK mediated eIF2alpha signaling , suggesting that PERK activation and CHOP expression may attenuate malignant transformation and progression under certain conditions or in a cell type dependent manner XREF_BIBR , XREF_BIBR .	Furthermore, some cancer cell lines display decreased PERK mediated eIF2alpha signaling, suggesting that PERK activation and CHOP expression may attenuate malignant transformation and progression under certain conditions or in a cell type dependent manner XREF_BIBR, XREF_BIBR.	6	11	mediated	Positive_early_activation	Negative_activation	Negative_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	8	9	10	11
7 The PERK and EIF2alpha pathway is a component of the UPR signaling pathway : when no ER stress is present , PERK is combined with GRP78 and Bip in an inactive state ; under ER stress conditions , PERK separates from its molecular chaperone GRP78 and Bip and becomes activated , and phosphorylates and inactivates EIF2alpha leading to termination of the majority of cellular protein synthesis , which in turn regulates the cell cycle .	7 The PERK and EIF2alpha pathway is a component of the UPR signaling pathway : when no ER stress is present, PERK is combined with GRP78 and Bip in an inactive state; under ER stress conditions, PERK separates from its molecular chaperone GRP78 and Bip and becomes activated, and phosphorylates and inactivates EIF2alpha leading to termination of the majority of cellular protein synthesis, which in turn regulates the cell cycle.	39	62	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PERK	PERK	PERK	EIF2alpha	EIF2alpha	EIF2alpha	39	40	56	57
Concurrently , ATF6 , PERK and IRE1alpha , upon dissociated from GRP78 , initiate following three UPR signaling cascades : ( 1 ) ATF6 is transferred to Golgi apparatus where it is cleaved by site-1 protease ( S1P ) and site-2 protease ( S2P ) and then translocates to the nucleus as activated transcription factor ( aka ATF6N ) [ XREF_BIBR ] ; ( 2 ) PERK reduces translational initiation and decreases global protein synthesis by inactivating eIF2alpha via increasing its phosphorylation levels .	Concurrently, ATF6, PERK and IRE1alpha, upon dissociated from GRP78, initiate following three UPR signaling cascades : (1) ATF6 is transferred to Golgi apparatus where it is cleaved by site-1 protease (S1P) and site-2 protease (S2P) and then translocates to the nucleus as activated transcription factor (aka ATF6N) [XREF_BIBR]; (2) PERK reduces translational initiation and decreases global protein synthesis by inactivating eIF2alpha via increasing its phosphorylation levels.	66	79	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	66	67	77	78
Phosphorylation of Ser112 by ERK1/2 inactivates Bad and protects the tumor cell from apoptosis .	Phosphorylation of Ser112 by ERK1/2 inactivates Bad and protects the tumor cell from apoptosis.	0	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	Phosphorylation of Ser112 by ERK1/2	erk1/2	Bad	Bad	bad	4	5	6	7
In addition , kinases downstream of ERK ( e.g ., RSK , S6K ) directly phosphorylate and inactivate the pro apoptotic BCL-2 family member BAD , as well as caspase-9 and APAF-1 [ XREF_BIBR - XREF_BIBR ] .	In addition, kinases downstream of ERK (e.g., RSK, S6K) directly phosphorylate and inactivate the pro apoptotic BCL-2 family member BAD, as well as caspase-9 and APAF-1 [XREF_BIBR - XREF_BIBR].	3	35	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	BAD	BAD	BAD	6	7	24	25
Phosphorylation of Bad protein at Serine 75 and Serine 99 by ERK signaling may decrease Bad expression by its degradation by ubiquitin proteasomes XREF_BIBR - XREF_BIBR .	Phosphorylation of Bad protein at Serine 75 and Serine 99 by ERK signaling may decrease Bad expression by its degradation by ubiquitin proteasomes XREF_BIBR - XREF_BIBR.	0	16	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	Phosphorylation of Bad protein at Serine 75 and Serine 99 by ERK	erk	Bad	Bad	bad	11	12	15	16
This endogenous process involves MEK and ERK mediated inhibition of the pro apoptotic molecule Bad and caspase 3 .	This endogenous process involves MEK and ERK mediated inhibition of the pro apoptotic molecule Bad and caspase 3.	4	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	Bad	Bad	Bad	6	7	14	15
In the FOXO3 = OFF , MAPK = 1 case the apoptosis propensity is decreased because MAPK = 1 inhibits BAD .	In the FOXO3 = OFF, MAPK = 1 case the apoptosis propensity is decreased because MAPK = 1 inhibits BAD.	16	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	BAD	BAD	BAD	16	17	20	21
Both ERK , through the activity of its downstream effector p90RSK , and p70S6 kinase can phosphorylate and thereby deactivate the pro apoptotic protein BAD [ XREF_BIBR , XREF_BIBR ] .	Both ERK, through the activity of its downstream effector p90RSK, and p70S6 kinase can phosphorylate and thereby deactivate the pro apoptotic protein BAD [XREF_BIBR, XREF_BIBR].	0	26	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	BAD	BAD	BAD	1	2	24	25
Rescue was based on the fact that RAS effector pathways and the JAK2-PIM1 and ERK pathway can each redundantly phosphorylate and inactivate BAD , the pro apoptotic protein whose activation status determines survival in these cells .	Rescue was based on the fact that RAS effector pathways and the JAK2-PIM1 and ERK pathway can each redundantly phosphorylate and inactivate BAD, the pro apoptotic protein whose activation status determines survival in these cells.	12	27	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	BAD	BAD	BAD	14	15	22	23
All these results suggest that the ERK and PI-3K-Akt signaling cascades converge at BAD to suppress the apoptotic effect of BAD .	All these results suggest that the ERK and PI-3K-Akt signaling cascades converge at BAD to suppress the apoptotic effect of BAD.	5	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	BAD	BAD	BAD	6	7	20	21
For instance , the ERK signaling pathway can inhibit the pro apoptotic protein BAD in addition to inducing the expression of pro survival genes 30 .	For instance, the ERK signaling pathway can inhibit the pro apoptotic protein BAD in addition to inducing the expression of pro survival genes 30.	4	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	BAD	BAD	BAD	4	5	13	14
The precise mechanism of zen de-repression by the terminal system has been unclear , but it is likely to depend on MAPK dependent downregulation of Cic .	The precise mechanism of zen de-repression by the terminal system has been unclear, but it is likely to depend on MAPK dependent downregulation of Cic.	21	26	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	Cic	Cic	Cic	21	22	25	26
Together with another anteriorly localized MAPK substrate , Hunchback ( Hb ) , Bcd antagonizes MAPK dependent downregulation of Cic .	Together with another anteriorly localized MAPK substrate, Hunchback (Hb), Bcd antagonizes MAPK dependent downregulation of Cic.	15	20	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	Cic	Cic	Cic	15	16	19	20
RNA sequencing analysis revealed a differential transcriptome profile and activated MAPK signalling pathway in cadmium treated hPSC-CMs , and suppression of P38 MAPK but not ERK MAPK or JNK MAPK rescued CIC phenotype .	RNA sequencing analysis revealed a differential transcriptome profile and activated MAPK signalling pathway in cadmium treated hPSC-CMs, and suppression of P38 MAPK but not ERK MAPK or JNK MAPK rescued CIC phenotype.	25	32	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK MAPK	ERK MAPK	ERK MAPK	CIC	CIC	CIC	25	27	31	32
Briefly , we propose that MAPK dependent downregulation of Cic is responsible for zen de-repression at the poles .	Briefly, we propose that MAPK dependent downregulation of Cic is responsible for zen de-repression at the poles.	5	10	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	Cic	Cic	Cic	5	6	9	10
Moreover , ERK inhibition with trametinib augmented CIC and decreased ETV4 , MMP24 , and invasion in Kras mutant A549 cells , without impacting growth ( XREF_SUPPLEMENTARY ) .	Moreover, ERK inhibition with trametinib augmented CIC and decreased ETV4, MMP24, and invasion in Kras mutant A549 cells, without impacting growth (XREF_SUPPLEMENTARY).	2	8	augmented	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	CIC	CIC	CIC	2	3	7	8
Thus , transcriptionally inert Bcd can inhibit MAPK dependent downregulation of Cic and this effect propagates to the Dl dependent gene expression .	Thus, transcriptionally inert Bcd can inhibit MAPK dependent downregulation of Cic and this effect propagates to the Dl dependent gene expression.	7	12	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	Cic	Cic	Cic	7	8	11	12
Additionally , ERK signaling inhibition with rociletinib increased CIC and reduced ETV4 promoter activity , leading to decreased ETV4 and MMP24 expression in H1975 cells ( XREF_FIG ) .	Additionally, ERK signaling inhibition with rociletinib increased CIC and reduced ETV4 promoter activity, leading to decreased ETV4 and MMP24 expression in H1975 cells (XREF_FIG).	2	9	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	CIC	CIC	CIC	2	3	8	9
Altered MAPK signaling through the ERK pathway also suppresses endogenous CIC in lung cancer .	Altered MAPK signaling through the ERK pathway also suppresses endogenous CIC in lung cancer.	1	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	CIC	CIC	CIC	1	2	10	11
One of the ERK the substrates in this system is a transcriptional repressor Capicua ( Cic ) , which is excluded from nuclei and degraded in the cytoplasm in response to phosphorylation by ERK ( XREF_FIG ) .	One of the ERK the substrates in this system is a transcriptional repressor Capicua (Cic), which is excluded from nuclei and degraded in the cytoplasm in response to phosphorylation by ERK (XREF_FIG).	13	35	degraded	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	Cic	Cic	Cic	33	34	15	16
Or results suggest instead that transcriptional activation of pnt and Ets21c via MAPK dependent loss of Cic mediated repression is the predominant mode of downstream regulation by MAPK in midgut ISCs .	Or results suggest instead that transcriptional activation of pnt and Ets21c via MAPK dependent loss of Cic mediated repression is the predominant mode of downstream regulation by MAPK in midgut ISCs.	12	17	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	Cic	Cic	Cic	12	13	16	17
We propose a model in which oncogenic MAPK signaling in RAS- or BRAF-mutant cells constitutively inactivates CIC .	We propose a model in which oncogenic MAPK signaling in RAS- or BRAF-mutant cells constitutively inactivates CIC.	7	17	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	CIC	CIC	CIC	7	8	16	17
To explore this possibility , we examined the distribution of Cic , which is downregulated at the poles as a result of its direct phosphorylation by MAPK ( XREF_FIG ) .	To explore this possibility, we examined the distribution of Cic, which is downregulated at the poles as a result of its direct phosphorylation by MAPK (XREF_FIG).	8	28	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	Cic	Cic	Cic	26	27	10	11
In a process essential for the development of the terminal structures , Cic is degraded at the poles in direct response to its phosphorylation by MAPK .	In a process essential for the development of the terminal structures, Cic is degraded at the poles in direct response to its phosphorylation by MAPK.	12	26	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	Cic	Cic	Cic	25	26	12	13
Specifically , at least two ERK substrates , the transcription factors Bicoid and Hunchback , are localized to the anterior pole where they act as competitive inhibitors of ERK dependent downregulation of Cic .	Specifically, at least two ERK substrates, the transcription factors Bicoid and Hunchback, are localized to the anterior pole where they act as competitive inhibitors of ERK dependent downregulation of Cic.	28	33	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	Cic	Cic	Cic	28	29	32	33
The activity of the core Raf1-MEK1/2-ERK1/2 cascade is auto-regulated by ERK1/2 inactivation of MEK1 or by ERK1/2 upregulation of ERK1/2 specific phosphatases , for example , MKP2 and 3 ( MAPK dual-specificity phosphatases ) [ XREF_BIBR , XREF_BIBR ] .	The activity of the core Raf1-MEK1/2-ERK1/2 cascade is auto-regulated by ERK1/2 inactivation of MEK1 or by ERK1/2 upregulation of ERK1/2 specific phosphatases, for example, MKP2 and 3 (MAPK dual-specificity phosphatases) [XREF_BIBR, XREF_BIBR].	10	14	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MEK1	MEK1	MEK1	10	11	13	14
Like ERK1 and ERK2 , ERK5 is expressed in neurons , and ERK5 stimulation by epidermal growth factor is blocked by the MAP kinase and ERK kinase 1 ( MEK1 ) inhibitors PD98059 and U0126 .	Like ERK1 and ERK2, ERK5 is expressed in neurons, and ERK5 stimulation by epidermal growth factor is blocked by the MAP kinase and ERK kinase 1 (MEK1) inhibitors PD98059 and U0126.	19	34	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK1	MEK1	MEK1	25	26	29	30
Mutations of two ERK1/2 target sequences within FOXM1c completely abolish the MEK1 enhancing effect , suggesting a direct link between Raf/MEK/MAPK signaling and FOXM1 function .	Mutations of two ERK1/2 target sequences within FOXM1c completely abolish the MEK1 enhancing effect, suggesting a direct link between Raf/MEK/MAPK signaling and FOXM1 function.	3	12	abolish	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MEK1	MEK1	MEK1	3	4	11	12
Finally , we tested whether ERK disrupts MEK1 and TRIB1 -3 complexes with equal efficiency .	Finally, we tested whether ERK disrupts MEK1 and TRIB1 -3 complexes with equal efficiency.	5	11	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK1	MEK1	MEK1	5	6	7	8
Two scaffold proteins are known to facilitate ERK activation in mammalian cells : the kinase suppressor of Ras 1 ( KSR1 ) and MEK1 partner ( MP1 ) .	Two scaffold proteins are known to facilitate ERK activation in mammalian cells : the kinase suppressor of Ras 1 (KSR1) and MEK1 partner (MP1).	7	24	suppressor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK1	MEK1	MEK1	7	8	23	24
We suggest histone acetyltransferases and histones as targets for EID1 action and propose that SHP inhibition of transcription involves EID1 antagonism of CBP and p300 dependent coactivator functions .	We suggest histone acetyltransferases and histones as targets for EID1 action and propose that SHP inhibition of transcription involves EID1 antagonism of CBP and p300 dependent coactivator functions.	19	27	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	EID1	EID1	EID1	p300	p300	p300	19	20	24	25
Histone acetyltransferases and histones might act as targets for EID1 action and SHP inhibition of transcription might involve EID1 antagonism of CBP and p300 dependent coactivator functions .	Histone acetyltransferases and histones might act as targets for EID1 action and SHP inhibition of transcription might involve EID1 antagonism of CBP and p300 dependent coactivator functions.	18	26	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	EID1	EID1	EID1	p300	p300	p300	18	19	23	24
Overexpression of EID1 in human brain could negatively regulate CBP and p300 activity and lead to the impairment of neuronal function .	Overexpression of EID1 in human brain could negatively regulate CBP and p300 activity and lead to the impairment of neuronal function.	0	12	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	EID1	Overexpression of EID1	eid1	p300	p300	p300	2	3	11	12
It is suggested that the mechanism of these transcriptional inhibitions involves EID1 antagonism of the p300 and CBP ( CREB binding protein )-dependent co-activator functions .	It is suggested that the mechanism of these transcriptional inhibitions involves EID1 antagonism of the p300 and CBP (CREB binding protein)-dependent co-activator functions.	11	16	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	EID1	EID1	EID1	p300	p300	p300	11	12	15	16
In order to elucidate if EID3 could inhibit CBP dependent transcriptional activity similar to the EID1 inhibition of p300 , HuH7 cells were co-transfected with a plasmid containing the GAL4 DNA binding domain fused to the C-terminus of CBP ( amino acids 1678-2441 ) , a reporter plasmid containing GAL4 DNA binding sites , and a plasmid expressing wild-type EID1 or EID3 .	In order to elucidate if EID3 could inhibit CBP dependent transcriptional activity similar to the EID1 inhibition of p300, HuH7 cells were co-transfected with a plasmid containing the GAL4 DNA binding domain fused to the C-terminus of CBP (amino acids 1678-2441), a reporter plasmid containing GAL4 DNA binding sites, and a plasmid expressing wild-type EID1 or EID3.	15	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	EID1	EID1	EID1	p300	p300	p300	15	16	18	19
Eid-1 mediates degradation of the p300 histone acetylase , a co-activator of MyoD transcription .	Eid-1 mediates degradation of the p300 histone acetylase, a co-activator of MyoD transcription.	0	7	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Eid-1	Eid-1	Eid-1	p300	p300	p300	0	1	5	6
Similarly , EID-1 can inhibit p300 and CBP acetylase activity that is necessary for MyoD to activate transcription .	Similarly, EID-1 can inhibit p300 and CBP acetylase activity that is necessary for MyoD to activate transcription.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	EID-1	EID-1	EID-1	p300	p300	p300	2	3	5	6
However , depletion of epsin or eps15 using RNA interference only modestly inhibits EGFR internalization .	However, depletion of epsin or eps15 using RNA interference only modestly inhibits EGFR internalization.	2	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	eps15	eps15	eps15	EGFR	EGFR	EGFR	6	7	13	14
Indeed , EGFR levels increased in cells lacking both SPOPL and EPS15 , demonstrating that EPS15 is necessary to promote EGFR degradation in the absence of SPOPL ( XREF_FIG ) .	Indeed, EGFR levels increased in cells lacking both SPOPL and EPS15, demonstrating that EPS15 is necessary to promote EGFR degradation in the absence of SPOPL (XREF_FIG).	15	21	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	EPS15	EPS15	EPS15	EGFR	EGFR	EGFR	15	16	20	21
Finally , we investigated why loss of SPOPL mediated ubiquitination of EPS15 increased EGFR degradation in lysosomes .	Finally, we investigated why loss of SPOPL mediated ubiquitination of EPS15 increased EGFR degradation in lysosomes.	5	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	EPS15	loss of SPOPL mediated ubiquitination of EPS15	eps15	EGFR	EGFR	egfr	11	12	13	14
Ubiquitination of Eps15 is believed to negatively regulate the internalization of activated EGF receptor by binding to and inactivating the UIMs in an intramolecular interaction .	Ubiquitination of Eps15 is believed to negatively regulate the internalization of activated EGF receptor by binding to and inactivating the UIMs in an intramolecular interaction.	0	14	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Eps15	Ubiquitination of Eps15	eps15	EGF receptor	EGF receptor	egf receptor	2	3	12	14
Similarly , depletion of Eps15b but not Eps15 delays degradation and promotes recycling of EGFR .	Similarly, depletion of Eps15b but not Eps15 delays degradation and promotes recycling of EGFR.	7	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Eps15	Eps15	Eps15	EGFR	EGFR	EGFR	7	8	14	15
Overexpression of EPS15-GFP only decreased the EGFR levels in the absence of SPOPL ( XREF_FIG ) , implying that EPS15 accumulation alone may not be sufficient to promote EGFR degradation .	Overexpression of EPS15-GFP only decreased the EGFR levels in the absence of SPOPL (XREF_FIG), implying that EPS15 accumulation alone may not be sufficient to promote EGFR degradation.	19	29	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	EPS15	EPS15	EPS15	EGFR	EGFR	EGFR	19	20	28	29
An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor .	An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor.	3	17	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Eps15	Eps15	Eps15	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	5	6	13	17
These results suggest that repression of ERK mediated negative feedback loops following BRAF inhibitor treatment primes total MET and GAB1 for HGF rescue , activating downstream signaling pathways and promoting tumor growth ( XREF_SUPPLEMENTARY ) .	These results suggest that repression of ERK mediated negative feedback loops following BRAF inhibitor treatment primes total MET and GAB1 for HGF rescue, activating downstream signaling pathways and promoting tumor growth (XREF_SUPPLEMENTARY).	4	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	GAB1	GAB1	GAB1	6	7	19	20
[ XREF_BIBR XREF_BIBR XREF_BIBR ] In general , ERKs activation suppresses the cleavage of caspase 8 and inhibits chemotherapeutic agent induced apoptosis in tumor cells .	[XREF_BIBR XREF_BIBR XREF_BIBR] In general, ERKs activation suppresses the cleavage of caspase 8 and inhibits chemotherapeutic agent induced apoptosis in tumor cells.	8	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERKs	ERKs	ERKs	caspase 8	caspase 8	caspase 8	8	9	14	16
Taken together , activation of caspase-8 contributes to and results in confluent cell death , whereas elevated p-Erk activity serves to prevent confluent cell death by regulating activation of caspase-8 .	Taken together, activation of caspase-8 contributes to and results in confluent cell death, whereas elevated p-Erk activity serves to prevent confluent cell death by regulating activation of caspase-8.	17	30	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p-Erk	p-Erk	p-Erk	caspase-8	caspase-8	caspase-8	17	18	29	30
It was also known that the p42 and p44 MAPK is inhibiting the activation of caspase-8 [ XREF_BIBR ] .	It was also known that the p42 and p44 MAPK is inhibiting the activation of caspase-8 [XREF_BIBR].	5	17	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	caspase-8	caspase-8	caspase-8	9	10	15	16
In the FasL mediated apoptosis process , ERK activity inhibits the caspase-8 cleavage .	In the FasL mediated apoptosis process, ERK activity inhibits the caspase-8 cleavage.	7	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	caspase-8	caspase-8	caspase-8	7	8	11	12
In addition , MGRX mediated inhibition of [ Formula : see text ] 1 integrin attenuates ERK phosphorylation ( p-ERK ) , which up-regulates caspase-8 and Bax .	In addition, MGRX mediated inhibition of [Formula : see text] 1 integrin attenuates ERK phosphorylation (p-ERK), which up-regulates caspase-8 and Bax.	14	26	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	integrin attenuates ERK phosphorylation	erk	caspase-8	caspase-8	caspase-8	16	17	24	25
Nevertheless , despite the sufficient role of the Raf/MEK/ERK pathway , ERK1/2 depletion or U0126 treatment could not block c.s.FBS-induced AR downregulation in NE1.3 and NE1.8 cells ( data not shown ) , indicating that the pathway activation is not necessary for the AR downregulation observed during LNCaP differentiation under a long term androgen withdrawal condition .	Nevertheless, despite the sufficient role of the Raf/MEK/ERK pathway, ERK1/2 depletion or U0126 treatment could not block c.s.FBS-induced AR downregulation in NE1.3 and NE1.8 cells (data not shown), indicating that the pathway activation is not necessary for the AR downregulation observed during LNCaP differentiation under a long term androgen withdrawal condition.	11	21	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	AR	AR	AR	11	12	20	21
The pattern of retention or loss of association with AR ( A/B ) due to the various deletions and mutations in ELK1 mirrored the pattern for activation by ERK with one exception , i.e. a deletion within the transactivation domain of ELK1 , which disrupted activation by ERK but did not affect association with AR ( A/B ) .	The pattern of retention or loss of association with AR (A/B) due to the various deletions and mutations in ELK1 mirrored the pattern for activation by ERK with one exception, i.e. a deletion within the transactivation domain of ELK1, which disrupted activation by ERK but did not affect association with AR (A/B).	44	56	disrupted	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	AR	AR	AR	47	48	54	55
We also examined the effects of these GPRC6A ligands on ERK activation in androgen receptor positive 22Rv1 and androgen receptor negative PC-3 cells ( XREF_FIG ) .	We also examined the effects of these GPRC6A ligands on ERK activation in androgen receptor positive 22Rv1 and androgen receptor negative PC-3 cells (XREF_FIG).	10	22	activation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	androgen receptor	androgen receptor	androgen receptor	10	11	18	20
Furthermore , we found that MNB and DYRK1A suppressed NOTCH signaling , counteracted the pro proliferative action of the NOTCH intracellular domain ( NICD ) , stimulated Delta1 expression and was required for the neuronal differentiation induced by the decrease in NOTCH signaling .	Furthermore, we found that MNB and DYRK1A suppressed NOTCH signaling, counteracted the pro proliferative action of the NOTCH intracellular domain (NICD), stimulated Delta1 expression and was required for the neuronal differentiation induced by the decrease in NOTCH signaling.	5	10	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DYRK1A	DYRK1A	DYRK1A	NOTCH	NOTCH	NOTCH	7	8	9	10
For example , NOTCH function is inhibited by DYRK1A phosphorylation , as previously mentioned .	For example, NOTCH function is inhibited by DYRK1A phosphorylation, as previously mentioned.	3	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	DYRK1A	DYRK1A phosphorylation	dyrk1a	NOTCH	NOTCH	notch	8	9	3	4
Furthermore , Dyrk1A suppresses Notch signaling and reduces its capacity to sustain transcription in neural cells , counteracting its antidifferentiative actions .	Furthermore, Dyrk1A suppresses Notch signaling and reduces its capacity to sustain transcription in neural cells, counteracting its antidifferentiative actions.	2	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dyrk1A	Dyrk1A	Dyrk1A	Notch	Notch	Notch	2	3	4	5
DYRK1A attenuates Notch signalling in neural cells both in culture and in vivo , constituting a novel mechanism capable of modulating different developmental processes that can also contribute to the alterations observed during brain development in animal models of Down syndrome .	DYRK1A attenuates Notch signalling in neural cells both in culture and in vivo, constituting a novel mechanism capable of modulating different developmental processes that can also contribute to the alterations observed during brain development in animal models of Down syndrome.	0	3	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DYRK1A	DYRK1A	DYRK1A	Notch	Notch	Notch	0	1	2	3
In addition , phosphorylation of eEF2K Ser366 , catalyzed by p90RSK downstream of Ras-Erk to inhibit eEF2K , was retained in transformed cells under ND ( XREF_FIG ) .	In addition, phosphorylation of eEF2K Ser366, catalyzed by p90RSK downstream of Ras-Erk to inhibit eEF2K, was retained in transformed cells under ND (XREF_FIG).	3	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	phosphorylation of eEF2K Ser366	eef2k	eEF2K	eEF2K	eef2k	5	6	16	17
XREF_BIBR Leptin induced ROS production in mouse hepatocytes is inhibited by nicotinamide adenine dinucleotide phosphate ( NADPH ) oxidase , MAP kinase and ERK kinase 1 ( MEK1 ) , and Janus kinase 2 ( JAK2 ) inhibitors , suggesting the possible involvement of these pathways in leptin induced ROS production .	XREF_BIBR Leptin induced ROS production in mouse hepatocytes is inhibited by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, MAP kinase and ERK kinase 1 (MEK1), and Janus kinase 2 (JAK2) inhibitors, suggesting the possible involvement of these pathways in leptin induced ROS production.	9	34	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	Janus kinase 2	Janus kinase 2	Janus kinase 2	23	24	31	34
XREF_BIBR In fact , Dyrk1A overexpression decreases the interaction of Spry2 and growth factor receptor bound protein 2 ( Grb2 ) , an adaptor between RTK and the ERK pathway .	XREF_BIBR In fact, Dyrk1A overexpression decreases the interaction of Spry2 and growth factor receptor bound protein 2 (Grb2), an adaptor between RTK and the ERK pathway.	4	14	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Dyrk1A	Dyrk1A overexpression	dyrk1a	Spry2	Spry2	spry2	4	5	10	11
Such a mechanism has been shown for Necdin , which sequesters EID-1 , an E1A like protein that inhibits MyoD by suppressing the acetyltransferase activity of its transcriptional co-activator p300 [ XREF_BIBR ] .	Such a mechanism has been shown for Necdin, which sequesters EID-1, an E1A like protein that inhibits MyoD by suppressing the acetyltransferase activity of its transcriptional co-activator p300 [XREF_BIBR].	10	20	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	EID-1	EID-1	EID-1	MyoD	MyoD	MyoD	11	12	19	20
FLG was downregulated by STAT3 ( signal transducer and activator of transcription 3 ) and ERK phosphorylation , as well XREF_BIBR .	FLG was downregulated by STAT3 (signal transducer and activator of transcription 3) and ERK phosphorylation, as well XREF_BIBR.	0	17	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK	ERK phosphorylation	erk	FLG	FLG	flg	15	16	0	1
The DYRK1A gene can suppress Notch1 induced transactivation , in a kinase dependent manner , without affecting protein stability XREF_BIBR .	The DYRK1A gene can suppress Notch1 induced transactivation, in a kinase dependent manner, without affecting protein stability XREF_BIBR.	1	6	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DYRK1A	DYRK1A	DYRK1A	Notch1	Notch1	Notch1	1	2	5	6
ERRFI1 loss of function causes hyperactivation of EGFR and persistent mitogen activated protein kinase ( MAPK ) signaling , with tumors in mice responsive to gefitinib and it has been shown to accelerate initiation and progression of EGFR mutated lung adenocarcinoma in mice .	ERRFI1 loss of function causes hyperactivation of EGFR and persistent mitogen activated protein kinase (MAPK) signaling, with tumors in mice responsive to gefitinib and it has been shown to accelerate initiation and progression of EGFR mutated lung adenocarcinoma in mice.	0	10	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERRFI1	ERRFI1	ERRFI1	EGFR	EGFR	EGFR	0	1	7	8
In vitro , a high concentration corticosterone ( 1250nM ) upregulated Mig-6 expression , inhibit EGFR and c-Jun N-terminal kinase ( JNK ) signaling pathway and terminal differentiation genes expression in chondrocytes and reduced cell apoptosis , and these above alterations could be partly reversed step-by-step after Mig-6 and EGFR knockdown .	In vitro, a high concentration corticosterone (1250nM) upregulated Mig-6 expression, inhibit EGFR and c-Jun N-terminal kinase (JNK) signaling pathway and terminal differentiation genes expression in chondrocytes and reduced cell apoptosis, and these above alterations could be partly reversed step-by-step after Mig-6 and EGFR knockdown.	6	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig-6	corticosterone (1250nM) upregulated Mig-6 expression	mig-6	EGFR	EGFR	egfr	11	12	15	16
Hence , we tested whether MIG-6 could mediate additional feedback inhibition of the EGFR in cells expressing BRAF V600E .	Hence, we tested whether MIG-6 could mediate additional feedback inhibition of the EGFR in cells expressing BRAF V600E.	5	14	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG-6	MIG-6	MIG-6	EGFR	EGFR	EGFR	5	6	13	14
As Tyr394 is located within segment 2 of Mig6 , it is conceivable that Mig6 phosphorylation could modulate its inhibition of EGFR , which is the subject of this study .	As Tyr394 is located within segment 2 of Mig6, it is conceivable that Mig6 phosphorylation could modulate its inhibition of EGFR, which is the subject of this study.	14	26	modulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6 phosphorylation	mig6	EGFR	EGFR	egfr	14	15	21	22
This is mediated in part through the negative regulation of AKT signaling by direct ERRFI1 dependent inhibition of EGFR .	This is mediated in part through the negative regulation of AKT signaling by direct ERRFI1 dependent inhibition of EGFR.	14	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ERRFI1	ERRFI1	ERRFI1	EGFR	EGFR	EGFR	14	15	18	19
As beta cell fate dictates progression to diabetes , it is essential to determine whether stress inducible MIG6 promotes beta cell dysfunction and destruction by attenuating EGFR signalling .	As beta cell fate dictates progression to diabetes, it is essential to determine whether stress inducible MIG6 promotes beta cell dysfunction and destruction by attenuating EGFR signalling.	15	27	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	17	18	26	27
These results might be explained by the recent data which showed that Mig6 inhibits EGFR via a two tiered mechanism which involves receptor degradation and trafficking in addition to kinase suppression XREF_BIBR , XREF_BIBR .	These results might be explained by the recent data which showed that Mig6 inhibits EGFR via a two tiered mechanism which involves receptor degradation and trafficking in addition to kinase suppression XREF_BIBR, XREF_BIBR.	12	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	12	13	14	15
On the contrary , Mig6 lacking the short EGFR interaction motif homologous to Ack1 , the AH1 domain , failed to bind to and inhibit EGFR ( XREF_FIG D ) .	On the contrary, Mig6 lacking the short EGFR interaction motif homologous to Ack1, the AH1 domain, failed to bind to and inhibit EGFR (XREF_FIG D).	4	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	4	5	25	26
The tumor-suppressor protein Mig-6 has been found to directly target and inhibit the human ErbB receptor tyrosine kinases ErbB1 and ErbB2 .	The tumor-suppressor protein Mig-6 has been found to directly target and inhibit the human ErbB receptor tyrosine kinases ErbB1 and ErbB2.	0	20	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mig-6	Mig-6	Mig-6	ErbB1	ErbB1	ErbB1	3	4	18	19
Therefore , loss of Mig6 enhances EGFR mediated signaling and promotes EGFR dependent carcinogenesis .	Therefore, loss of Mig6 enhances EGFR mediated signaling and promotes EGFR dependent carcinogenesis.	2	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mig6	loss of Mig6	mig6	EGFR	EGFR	egfr	4	5	11	12
Here , we show that deletion of the mouse gene encoding Mig6 ( designated Errfi1 , which stands for ERBB receptor feedback inhibitor 1 ) causes hyperactivation of endogenous epidermal growth factor receptor ( EGFR ) and sustained signaling through the mitogen activated protein kinase ( MAPK ) pathway , resulting in overproliferation and impaired differentiation of epidermal keratinocytes .	Here, we show that deletion of the mouse gene encoding Mig6 (designated Errfi1, which stands for ERBB receptor feedback inhibitor 1) causes hyperactivation of endogenous epidermal growth factor receptor (EGFR) and sustained signaling through the mitogen activated protein kinase (MAPK) pathway, resulting in overproliferation and impaired differentiation of epidermal keratinocytes.	5	33	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	11	12	29	33
Mig6 was proposed to inhibit EGFR signaling by direct binding to EGFR and ErbB2 -- by suppressing the EGFR kinase activity -- and by a receptor distal mechanism .	Mig6 was proposed to inhibit EGFR signaling by direct binding to EGFR and ErbB2 -- by suppressing the EGFR kinase activity -- and by a receptor distal mechanism.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	0	1	5	6
Mig-6 is a feedback inhibitor of EGFR and its down-stream pathway ; it has been shown to play a role in gefitinib sensitivity .	Mig-6 is a feedback inhibitor of EGFR and its down-stream pathway; it has been shown to play a role in gefitinib sensitivity.	0	10	is a feedback inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Mig-6	Mig-6	Mig-6	EGFR	EGFR	EGFR	0	1	6	7
The analysis of a cohort of primary PTC patient samples suggests that MIG-6 feedback inhibition of the EGFR is clinically relevant and may determine the prognosis of BRAF mutated PTC patients .	The analysis of a cohort of primary PTC patient samples suggests that MIG-6 feedback inhibition of the EGFR is clinically relevant and may determine the prognosis of BRAF mutated PTC patients.	12	18	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MIG-6	MIG-6	MIG-6	EGFR	EGFR	EGFR	12	13	17	18
This is consistent with a switch like mechanism , whereby Mig6 either interacts with and attenuates EGFR activity or , upon inactivation and absence of EGFR , activates c-Abl .	This is consistent with a switch like mechanism, whereby Mig6 either interacts with and attenuates EGFR activity or, upon inactivation and absence of EGFR, activates c-Abl.	10	17	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	10	11	16	17
Structural studies indicate that MIG6 ( segment 1 ) is able to inhibit EGFR kinase activity in the presence of the asymmetric dimer .	Structural studies indicate that MIG6 (segment 1) is able to inhibit EGFR kinase activity in the presence of the asymmetric dimer.	4	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	4	5	13	14
MIG6 and RALT ( mitogen inducible gene and receptor associated late transducer ) inhibits EGFR [ XREF_BIBR - XREF_BIBR ] by associating with the receptor through a carboxy-terminal ERB binding region ( EBR ) .	MIG6 and RALT (mitogen inducible gene and receptor associated late transducer) inhibits EGFR [XREF_BIBR - XREF_BIBR] by associating with the receptor through a carboxy-terminal ERB binding region (EBR).	0	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	0	1	14	15
We also speculate that MIG6 inhibits heterodimers of mutant and WT EGFR and promotes their degradation in the early stages of doxycycline induction of mutant EGFRs in these models , thus explaining the dramatic tumor suppressive role .	We also speculate that MIG6 inhibits heterodimers of mutant and WT EGFR and promotes their degradation in the early stages of doxycycline induction of mutant EGFRs in these models, thus explaining the dramatic tumor suppressive role.	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	4	5	11	12
MIG6 blocks EGFR activation by inhibiting catalytic domain dimerization and the 25-amino acid peptide used in the SNAP-tag fusions binds to the dimerization interface without occupying the active site of this kinase .	MIG6 blocks EGFR activation by inhibiting catalytic domain dimerization and the 25-amino acid peptide used in the SNAP-tag fusions binds to the dimerization interface without occupying the active site of this kinase.	0	3	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	0	1	2	3
MIG6 is known to inhibit EGFR kinase activity and promote the degradation of WT EGFR , so it is considered a suppressor of tumors with active WT EGFR signaling .	MIG6 is known to inhibit EGFR kinase activity and promote the degradation of WT EGFR, so it is considered a suppressor of tumors with active WT EGFR signaling.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	0	1	5	6
Based on the evidence that ERRFI1 mainly inhibits EGFR in EGFR-high cells ( Figs XREF_FIG C and XREF_FIG A ) , but activates AKT directly in EGFR-low cells ( Figs XREF_FIG C and XREF_FIG B ) , we hypothesize that EGFR inhibitor and AKT inhibitor will have differential sensitization effects depending on the EGFR level .	Based on the evidence that ERRFI1 mainly inhibits EGFR in EGFR-high cells (Figs XREF_FIG C and XREF_FIG A), but activates AKT directly in EGFR-low cells (Figs XREF_FIG C and XREF_FIG B), we hypothesize that EGFR inhibitor and AKT inhibitor will have differential sensitization effects depending on the EGFR level.	5	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERRFI1	ERRFI1	ERRFI1	EGFR	EGFR	EGFR	5	6	8	9
In agreement with this inhibitory function towards the EGFR , MIG-6 has been shown to block the activation of EGFR induced signaling modules , such as the RAS-ERK and PI3K and AKT pathways [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In agreement with this inhibitory function towards the EGFR, MIG-6 has been shown to block the activation of EGFR induced signaling modules, such as the RAS-ERK and PI3K and AKT pathways [XREF_BIBR, XREF_BIBR, XREF_BIBR].	10	22	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG-6	MIG-6	MIG-6	EGFR	EGFR	EGFR	10	11	19	20
The only difference between the EGFR-WT model and the L858R model A is in the negative EGFR regulation produced by Mig6 , therefore , which can be experimentally verified by overexpressing Mig6 .	The only difference between the EGFR-WT model and the L858R model A is in the negative EGFR regulation produced by Mig6, therefore, which can be experimentally verified by overexpressing Mig6.	16	21	produced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	20	21	16	17
Because Mig6 inhibits EGFR on a strict per-molecule basis , reduced ERRFI1 gene dosage and consequent lower levels of Mig6 expression could be expected to confer a growth advantage in the context of an EGFR driven tumor , particularly in the face of high levels of EGFR expression resulting from increased EGFR copy number .	Because Mig6 inhibits EGFR on a strict per-molecule basis, reduced ERRFI1 gene dosage and consequent lower levels of Mig6 expression could be expected to confer a growth advantage in the context of an EGFR driven tumor, particularly in the face of high levels of EGFR expression resulting from increased EGFR copy number.	1	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	1	2	3	4
In addition , the CTD deletion mutants may have altered EGFR substrate specificity and receptor degradation or no longer bind regulatory proteins including Mig6 which has been found to negatively regulate EGFR kinase activity by blocking the activating dimer interface .	In addition, the CTD deletion mutants may have altered EGFR substrate specificity and receptor degradation or no longer bind regulatory proteins including Mig6 which has been found to negatively regulate EGFR kinase activity by blocking the activating dimer interface.	21	33	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	23	24	31	32
Deletion of ERRFI1 has been reported to activate EGFR and sustain MAPK signaling , resulting in tumor phenotypes in numerous tissues in ERRFI1 knockout mice [ XREF_BIBR - XREF_BIBR ] .	Deletion of ERRFI1 has been reported to activate EGFR and sustain MAPK signaling, resulting in tumor phenotypes in numerous tissues in ERRFI1 knockout mice [XREF_BIBR - XREF_BIBR].	0	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERRFI1	ERRFI1	ERRFI1	EGFR	EGFR	EGFR	2	3	8	9
Tissue specific knockout of Mig6 increases EGFR signaling and the proliferation of epithelial cells in mouse lungs , suggesting that Mig6 is essential for lung homeostasis .	Tissue specific knockout of Mig6 increases EGFR signaling and the proliferation of epithelial cells in mouse lungs, suggesting that Mig6 is essential for lung homeostasis.	4	7	increases	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	4	5	6	7
As MIG6 regulates the activity of EGFR signal pathway negatively , high level of MIG6 can increase the EGFR TKI resistance of cancer cells , and limit the therapeutic action of EGFR TKI , such as gefitinib or erlotinib .	As MIG6 regulates the activity of EGFR signal pathway negatively, high level of MIG6 can increase the EGFR TKI resistance of cancer cells, and limit the therapeutic action of EGFR TKI, such as gefitinib or erlotinib.	12	32	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	level of MIG6	mig6	EGFR	EGFR	egfr	14	15	31	32
24 Our data also show that , in murine thyroid , Mig-6 blocks EGFR activation and attenuates ERK , a subunit of the MAPK signaling pathway .	24 Our data also show that, in murine thyroid, Mig-6 blocks EGFR activation and attenuates ERK, a subunit of the MAPK signaling pathway.	11	16	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig-6	Mig-6	Mig-6	EGFR	EGFR	EGFR	11	12	13	14
In this study , we determined plasma levels of MIG-6 , which suppresses the EGFR RTK pathway in autistic children , and compared MIG-6 levels with the EGFR ligand , epidermal growth factor ( EGF ) , and the cMET ligand , hepatocyte growth factor ( HGF ) .	In this study, we determined plasma levels of MIG-6, which suppresses the EGFR RTK pathway in autistic children, and compared MIG-6 levels with the EGFR ligand, epidermal growth factor (EGF), and the cMET ligand, hepatocyte growth factor (HGF).	7	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG-6	levels of MIG-6	mig-6	EGFR	EGFR	egfr	9	10	14	15
Consistent with the structure , kinetic studies confirm that Mig6 inhibits EGFR in a peptide substrate competitive manner with a Ki = 15.85 nM ( XREF_SUPPLEMENTARY ) .	Consistent with the structure, kinetic studies confirm that Mig6 inhibits EGFR in a peptide substrate competitive manner with a Ki = 15.85 nM (XREF_SUPPLEMENTARY).	9	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	9	10	11	12
Therefore the M-110 induced up regulation of MIG6 is expected to inhibit EGFR activation in PC3 and DU-145 cells .	Therefore the M-110 induced up regulation of MIG6 is expected to inhibit EGFR activation in PC3 and DU-145 cells.	5	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	7	8	12	13
This may reflect differences in the basal levels of EGFR receptor mediated endocytosis in these distinct cell types or may suggest that Mig-6 attenuates EGFR signaling instead of affecting EGFR degradation in the thyroid .	This may reflect differences in the basal levels of EGFR receptor mediated endocytosis in these distinct cell types or may suggest that Mig-6 attenuates EGFR signaling instead of affecting EGFR degradation in the thyroid.	22	25	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig-6	Mig-6	Mig-6	EGFR	EGFR	EGFR	22	23	24	25
Mig-6 inhibits EGFR catalytic activity by interfering with its dimerization .	Mig-6 inhibits EGFR catalytic activity by interfering with its dimerization.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig-6	Mig-6	Mig-6	EGFR	EGFR	EGFR	0	1	2	3
Stable expression of miR-200 in mesenchymal UMUC3 cells increased E-cadherin levels , decreased expression of ZEB-1 , ZEB-2 , ERRFI-1 , and cell migration , and increased sensitivity to EGFR blocking agents .	Stable expression of miR-200 in mesenchymal UMUC3 cells increased E-cadherin levels, decreased expression of ZEB-1, ZEB-2, ERRFI-1, and cell migration, and increased sensitivity to EGFR blocking agents.	1	30	increased	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	ERRFI-1	expression of miR-200 in mesenchymal UMUC3 cells increased E-cadherin levels, decreased expression of ZEB-1, ZEB-2, ERRFI-1	errfi-1	EGFR	EGFR	egfr	19	20	29	30
Importantly , exogenous MIG-6 expression was not affected by MEK inhibition and still functioned to inhibit the EGFR ( XREF_FIG ) .	Importantly, exogenous MIG-6 expression was not affected by MEK inhibition and still functioned to inhibit the EGFR (XREF_FIG).	3	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG-6	MIG-6 expression	mig-6	EGFR	EGFR	egfr	3	4	17	18
MIG6 inhibits ERBB kinase activities by direct binding of its EBR region to ERBB catalytic domain .	MIG6 inhibits ERBB kinase activities by direct binding of its EBR region to ERBB catalytic domain.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	ERBB	ERBB	ERBB	0	1	2	3
The cytosolic protein Mig6 ( the product of mitogen inducible gene 6 , now formally designated ERRFI1 ) is a feedback inhibitor of the epidermal growth factor receptor ( EGFR ) and other ErbB family members XREF_BIBR - XREF_BIBR .	The cytosolic protein Mig6 (the product of mitogen inducible gene 6, now formally designated ERRFI1) is a feedback inhibitor of the epidermal growth factor receptor (EGFR) and other ErbB family members XREF_BIBR - XREF_BIBR.	0	28	is a feedback inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	3	4	24	28
Gain and loss of function analyses in a wide range of cultured cells show that MIG6 inhibits downstream ERBB signaling , including activation of ERK and AKT , as well as biological responses regulated by ERBB receptors , such as cell proliferation and migration [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Gain and loss of function analyses in a wide range of cultured cells show that MIG6 inhibits downstream ERBB signaling, including activation of ERK and AKT, as well as biological responses regulated by ERBB receptors, such as cell proliferation and migration [XREF_BIBR, XREF_BIBR - XREF_BIBR].	15	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	ERBB	ERBB	ERBB	15	16	18	19
This group also showed that the stable expression of miR-200 in mesenchymal UMUC3 cells increased E-cadherin levels ; decreased protein expression of ZEB1 , ZEB2 , and ERRFI-1 ; decreased cell migration ; and increased sensitivity to EGFR blocking agents .	This group also showed that the stable expression of miR-200 in mesenchymal UMUC3 cells increased E-cadherin levels; decreased protein expression of ZEB1, ZEB2, and ERRFI-1; decreased cell migration; and increased sensitivity to EGFR blocking agents.	7	38	increased	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	ERRFI-1	expression of miR-200 in mesenchymal UMUC3 cells increased E-cadherin levels; decreased protein expression of ZEB1, ZEB2, and ERRFI-1	errfi-1	EGFR	EGFR	egfr	27	28	37	38
The cytoplasmic protein Mig6 ( Mitogen induced gene 6 ) interacts with and inhibits the kinase domains of EGFR and ErbB2 XREF_BIBR - XREF_BIBR .	The cytoplasmic protein Mig6 (Mitogen induced gene 6) interacts with and inhibits the kinase domains of EGFR and ErbB2 XREF_BIBR - XREF_BIBR.	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	3	4	18	19
Next , we examined whether a reduction in MIG6 would increase EGFR signalling and promote beta cell survival .	Next, we examined whether a reduction in MIG6 would increase EGFR signalling and promote beta cell survival.	6	12	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	8	9	11	12
In a recent study , overexpression of ERRFI1 was shown to decrease proliferation in glioblastoma cells , binding EGFR with STX8 , and driving internalized EGFR to late endosomes for degradation , whereas knockdown of ERRFI1 expression resulted in increased tumor invasion [ XREF_BIBR ] .	In a recent study, overexpression of ERRFI1 was shown to decrease proliferation in glioblastoma cells, binding EGFR with STX8, and driving internalized EGFR to late endosomes for degradation, whereas knockdown of ERRFI1 expression resulted in increased tumor invasion [XREF_BIBR].	5	26	driving	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERRFI1	overexpression of ERRFI1	errfi1	EGFR	EGFR	egfr	7	8	25	26
ERRFI1 ( the product of mitogen inducible gene 6 , also known as MIG6 ) is known to inhibit EGFR activation as well as downstream signaling by docking onto EGFR kinase domain via its ERBB binding region 23 .	ERRFI1 (the product of mitogen inducible gene 6, also known as MIG6) is known to inhibit EGFR activation as well as downstream signaling by docking onto EGFR kinase domain via its ERBB binding region 23.	0	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERRFI1	ERRFI1	ERRFI1	EGFR	EGFR	EGFR	0	1	19	20
There is currently much interest in the antidiabetogenic effects of EGFR signalling [ XREF_BIBR ] , and we are specifically interested in MIG6 inhibition of stress inducible EGFR feedback .	There is currently much interest in the antidiabetogenic effects of EGFR signalling [XREF_BIBR], and we are specifically interested in MIG6 inhibition of stress inducible EGFR feedback.	22	28	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	22	23	27	28
We show that the Mig6 mediated reduction of EGFR occurs concomitantly with a TGFbeta induced EMT associated kinase switch of tumor cells to an AKT activated state , thereby leading to an EGFR independent phenotype that is refractory to EGFR TKI .	We show that the Mig6 mediated reduction of EGFR occurs concomitantly with a TGFbeta induced EMT associated kinase switch of tumor cells to an AKT activated state, thereby leading to an EGFR independent phenotype that is refractory to EGFR TKI.	4	9	reduction	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	4	5	8	9
MIG6 inhibits EGFR kinase activity and promotes WT EGFR trafficking to the degradation pathway .	MIG6 inhibits EGFR kinase activity and promotes WT EGFR trafficking to the degradation pathway.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	0	1	2	3
ERRFI1 is an endogenous inhibitor of EGFR , ERRB2 , ERRB3 and ERRB4 through direct interaction with the kinase domains of these proteins XREF_BIBR , XREF_BIBR and endocytosis and lysosomal degradation of ERBB receptors XREF_BIBR .	ERRFI1 is an endogenous inhibitor of EGFR, ERRB2, ERRB3 and ERRB4 through direct interaction with the kinase domains of these proteins XREF_BIBR, XREF_BIBR and endocytosis and lysosomal degradation of ERBB receptors XREF_BIBR.	0	12	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	ERRFI1	ERRFI1	ERRFI1	EGFR	EGFR	EGFR	0	1	6	7
This sophisticated mechanism is consistent with a switch like mechanism , whereby MIG6 interacts with and attenuates EGFR activity , while in the absence of ERBB stimulation , it activates ABL pro apoptotic function .	This sophisticated mechanism is consistent with a switch like mechanism, whereby MIG6 interacts with and attenuates EGFR activity, while in the absence of ERBB stimulation, it activates ABL pro apoptotic function.	12	18	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	12	13	17	18
The derepression of MIG6 by TGFbeta allows the EGF receptor to signal through the downstream Akt kinase in a constitutive manner , thus partially explaining how cells that undergo EMT develop resistance to EGF receptor inhibitors , such as erlotinib .	The derepression of MIG6 by TGFbeta allows the EGF receptor to signal through the downstream Akt kinase in a constitutive manner, thus partially explaining how cells that undergo EMT develop resistance to EGF receptor inhibitors, such as erlotinib.	1	10	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MIG6	MIG6	MIG6	EGF receptor	EGF receptor	EGF receptor	3	4	8	10
We further found that Mig6 inhibition of EGFR is modulated by Src via phosphorylation of Mig6 on Y395 .	We further found that Mig6 inhibition of EGFR is modulated by Src via phosphorylation of Mig6 on Y395.	4	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	4	5	7	8
To see how Mig6 inhibits EGFR , we determined three crystal structures of Mig6 fragments bound to EGFR , representing distinct steps in the course of Mig6 inhibition ( XREF_TABLE and XREF_FIG ) .	To see how Mig6 inhibits EGFR, we determined three crystal structures of Mig6 fragments bound to EGFR, representing distinct steps in the course of Mig6 inhibition (XREF_TABLE and XREF_FIG).	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	3	4	5	6
Several studies have reported that Mig6 inhibits EGFR by blocking its kinase activity , as well as by promoting its degradation .	Several studies have reported that Mig6 inhibits EGFR by blocking its kinase activity, as well as by promoting its degradation.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	5	6	7	8
We suggest that PIM1 could affect STAT3 activation in RWPE-1 cells through modulation of EGFR activity mediated by inhibition of MIG6 expression .	We suggest that PIM1 could affect STAT3 activation in RWPE-1 cells through modulation of EGFR activity mediated by inhibition of MIG6 expression.	14	22	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	MIG6	MIG6 expression	mig6	EGFR	EGFR	egfr	20	21	14	15
Mig-6 is reportedly induced by the RAS-MEK-MAPK and ERK pathway , and prevents EGFR activation through binding to the C-lobe in the kinase domain of EGFR.31 , 32 In the NSCLC cells with the sensitive EGFR mutation , the overexpression of Mig-6 enhanced the inhibitory effect of gefitinib.33 In PC-9 cells harboring the sensitive mutated EGFR , the expression of Mig-6 was significantly induced by treatment with the ATM inhibitor in combination with gefitinib , as compared to that with gefitinib alone ( Figs XREF_FIG d , S2c ) .	Mig-6 is reportedly induced by the RAS-MEK-MAPK and ERK pathway, and prevents EGFR activation through binding to the C-lobe in the kinase domain of EGFR.31, 32 In the NSCLC cells with the sensitive EGFR mutation, the overexpression of Mig-6 enhanced the inhibitory effect of gefitinib.33 In PC-9 cells harboring the sensitive mutated EGFR, the expression of Mig-6 was significantly induced by treatment with the ATM inhibitor in combination with gefitinib, as compared to that with gefitinib alone (Figs XREF_FIG d, S2c).	0	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig-6	Mig-6	Mig-6	EGFR	EGFR	EGFR	0	1	13	14
Deletion of the mouse gene encoding MIG6 causes hyperactivation of endogenous EGFR and sustained signaling through the MAPK pathway [ XREF_BIBR ] .	Deletion of the mouse gene encoding MIG6 causes hyperactivation of endogenous EGFR and sustained signaling through the MAPK pathway [XREF_BIBR].	0	14	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	6	7	11	12
Based in part on a crystal structure of Mig6 segment 1 in complex with EGFR , Mig6 was proposed to inhibit EGFR in an allosteric manner by blocking formation of the activating receptor dimer 8 .	Based in part on a crystal structure of Mig6 segment 1 in complex with EGFR, Mig6 was proposed to inhibit EGFR in an allosteric manner by blocking formation of the activating receptor dimer 8.	16	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	16	17	21	22
Biochemical experiments confirmed this binding mode , showing that MIG6 segment 1 only inhibits kinase activity of EGFR in the context of asymmetric dimer , but not the basal activity of the monomeric kinase in solution .	Biochemical experiments confirmed this binding mode, showing that MIG6 segment 1 only inhibits kinase activity of EGFR in the context of asymmetric dimer, but not the basal activity of the monomeric kinase in solution.	9	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	9	10	17	18
Mig6 inhibits EGFR mediated signals in mouse skin 8 , and deletion of the Mig6 gene leads to hyper-activation of EGFR XREF_BIBR , XREF_BIBR .	Mig6 inhibits EGFR mediated signals in mouse skin 8, and deletion of the Mig6 gene leads to hyper-activation of EGFR XREF_BIBR, XREF_BIBR.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	0	1	2	3
MIG-6 is a feedback inhibitor of EGFR .	MIG-6 is a feedback inhibitor of EGFR.	0	7	is a feedback inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	MIG-6	MIG-6	MIG-6	EGFR	EGFR	EGFR	0	1	6	7
The MIG6 binding site on EGFR overlaps with the allosteric activator interface on the C-lobe of EGFR , and MIG6 was shown to block formation of the asymmetric EGFR kinase dimer .	The MIG6 binding site on EGFR overlaps with the allosteric activator interface on the C-lobe of EGFR, and MIG6 was shown to block formation of the asymmetric EGFR kinase dimer.	19	30	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	19	20	28	29
These data indicate that upregulation of PI3K-AKT-mTOR by alternative growth factor receptors promotes Mig6 mediated inhibition of EGFR activity , enabling EGFR independent growth of tumor cells and rendering them insensitive to EGFR targeted TKIs .	These data indicate that upregulation of PI3K-AKT-mTOR by alternative growth factor receptors promotes Mig6 mediated inhibition of EGFR activity, enabling EGFR independent growth of tumor cells and rendering them insensitive to EGFR targeted TKIs.	13	18	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	13	14	17	18
Priming may serve to accelerate the time course and/or efficiency of Mig6 inhibition of EGFR when Src is also active .	Priming may serve to accelerate the time course and/or efficiency of Mig6 inhibition of EGFR when Src is also active.	11	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	11	12	14	15
Furthermore , a recent study has demonstrated that Prx1-Cre-driven deletion of Mig6 causes increased SOX9 and EGFR activation in cartilage as well as increased cell proliferation in the knee joint , similar to what we found in the present studies .	Furthermore, a recent study has demonstrated that Prx1-Cre-driven deletion of Mig6 causes increased SOX9 and EGFR activation in cartilage as well as increased cell proliferation in the knee joint, similar to what we found in the present studies.	9	17	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	11	12	16	17
The footprint of MIG6 segment 1 on the EGFR kinase domain overlaps largely with the C-lobe face of the asymmetric activating dimer interface , suggesting that binding of MIG6 segment 1 can inhibit EGFR by preventing the formation of the asymmetric dimer .	The footprint of MIG6 segment 1 on the EGFR kinase domain overlaps largely with the C-lobe face of the asymmetric activating dimer interface, suggesting that binding of MIG6 segment 1 can inhibit EGFR by preventing the formation of the asymmetric dimer.	28	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	28	29	33	34
Additionally , because ERK signalling has been implicated in beta cell integrity and function , and MIG6 suppressed EGFR signalling ( including ERK phosphorylation ) , we investigated whether MIG6 suppresses the downstream effectors of ERK .	Additionally, because ERK signalling has been implicated in beta cell integrity and function, and MIG6 suppressed EGFR signalling (including ERK phosphorylation), we investigated whether MIG6 suppresses the downstream effectors of ERK.	16	19	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	16	17	18	19
Mig6 is a direct inhibitor of EGFR itself [ XREF_BIBR , XREF_BIBR ] , while DUSPs are specialized phosphatases that can dephosphorylate and thereby inactivate MAPKs on both threonine and tyrosine phosphorylation sites [ XREF_BIBR ] .	Mig6 is a direct inhibitor of EGFR itself [XREF_BIBR, XREF_BIBR], while DUSPs are specialized phosphatases that can dephosphorylate and thereby inactivate MAPKs on both threonine and tyrosine phosphorylation sites [XREF_BIBR].	0	7	is a direct inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	0	1	6	7
In this case , MIG-6 transfection and U0126 would synergistically act to inhibit the EGFR .	In this case, MIG-6 transfection and U0126 would synergistically act to inhibit the EGFR.	4	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG-6	MIG-6	MIG-6	EGFR	EGFR	EGFR	4	5	14	15
On the other hand , the increased EGFR activation and TNF-alpha or il-1beta production in LPS treatment could be inhibited by Mig6 overexpression .	On the other hand, the increased EGFR activation and TNF-alpha or il-1beta production in LPS treatment could be inhibited by Mig6 overexpression.	7	23	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Mig6	Mig6 overexpression	mig6	EGFR	EGFR	egfr	21	22	7	8
There is collaborative inactivation of the translational repressor 4E-BP1 by both AKT and ERK signalling [ XREF_BIBR ] , ERK directly inactivates TSC2 by phosphorylation [ XREF_BIBR ] .	There is collaborative inactivation of the translational repressor 4E-BP1 by both AKT and ERK signalling [XREF_BIBR], ERK directly inactivates TSC2 by phosphorylation [XREF_BIBR].	19	23	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	19	20	22	23
Also , it is described that MAPK inhibit the tuberous sclerosis complex ( TSC1 and TSC2 ) , which in turn inhibits mTOR activation [ XREF_BIBR ] .	Also, it is described that MAPK inhibit the tuberous sclerosis complex (TSC1 and TSC2), which in turn inhibits mTOR activation [XREF_BIBR].	6	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	TSC2	TSC2	TSC2	6	7	15	16
Both ERK1/2 and p90RSK phosphorylate and inactivate TSC2 , functioning as a molecular switch that regulates mTOR ' s activity [ XREF_BIBR - XREF_BIBR ] .	Both ERK1/2 and p90RSK phosphorylate and inactivate TSC2, functioning as a molecular switch that regulates mTOR 's activity [XREF_BIBR - XREF_BIBR].	0	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	TSC2	TSC2	TSC2	1	2	7	8
In addition , we show that inhibition of ERK1/2 rescues GSK3beta activity and restores protein synthesis in Tsc2 -/- MEFs to normal levels .	In addition, we show that inhibition of ERK1/2 rescues GSK3beta activity and restores protein synthesis in Tsc2 -/- MEFs to normal levels.	6	19	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	Tsc2	Tsc2	Tsc2	8	9	17	18
With respect to ERK ' s involvement in the control of translation and its interaction with mTOR , ERK can also inhibit tuberin ( TSC2 ) , and therefore influence mTOR activity .	With respect to ERK 's involvement in the control of translation and its interaction with mTOR, ERK can also inhibit tuberin (TSC2), and therefore influence mTOR activity.	18	29	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	tuberin	tuberin	tuberin	18	19	22	23
Where enhanced cytotoxicity was observed this could be due to increased inhibition of mTORC1 as combined inhibition of both pathways relieves the AKT- and ERK mediated inhibition of TSC2 .	Where enhanced cytotoxicity was observed this could be due to increased inhibition of mTORC1 as combined inhibition of both pathways relieves the AKT- and ERK mediated inhibition of TSC2.	22	29	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	24	25	28	29
Members of the MAPK pathway have been shown to activate Akt as well : ERK and RSK inhibit TSC2 , which can result in mTOR activation despite effective PI3K inhibition , as reviewed [ XREF_BIBR ] .	Members of the MAPK pathway have been shown to activate Akt as well : ERK and RSK inhibit TSC2, which can result in mTOR activation despite effective PI3K inhibition, as reviewed [XREF_BIBR].	14	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	14	15	18	19
This result demonstrates that the miR-634-induced up-regulation of mTOR activity is at least partially dependent on the phosphorylation and degradation of TSC2 by ERK1/2 .	This result demonstrates that the miR-634-induced up-regulation of mTOR activity is at least partially dependent on the phosphorylation and degradation of TSC2 by ERK1/2.	14	24	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	TSC2	TSC2	TSC2	23	24	21	22
We have previously demonstrated that ERK1/2 inactivates TSC2 through a direct phosphorylation event , which leads to TSC2 dissociation from TSC1 and impairment of TSC2 inhibition of mTOR signalling .	We have previously demonstrated that ERK1/2 inactivates TSC2 through a direct phosphorylation event, which leads to TSC2 dissociation from TSC1 and impairment of TSC2 inhibition of mTOR signalling.	5	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	TSC2	TSC2	TSC2	5	6	7	8
These tumors also exhibited decreased levels of the mTOR regulatory protein , tuberin ( TSC2 gene product ) , which is inhibited by ERK phosphorylation .	These tumors also exhibited decreased levels of the mTOR regulatory protein, tuberin (TSC2 gene product), which is inhibited by ERK phosphorylation.	10	25	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	ERK	ERK phosphorylation	erk	tuberin	tuberin	tuberin	23	24	12	13
XREF_BIBR found that EPHA receptor activation by EPHRIN-A ligands in neurons inhibited ERK1/2 kinase activity , decreasing the ERK1/2 mediated inhibition of TSC2 and thus inactivating the mTOR pathway by enhancing TSC2 activity .	XREF_BIBR found that EPHA receptor activation by EPHRIN-A ligands in neurons inhibited ERK1/2 kinase activity, decreasing the ERK1/2 mediated inhibition of TSC2 and thus inactivating the mTOR pathway by enhancing TSC2 activity.	17	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	TSC2	TSC2	TSC2	18	19	22	23
ERK can inhibit TSC2 as well [ XREF_BIBR , XREF_BIBR ] .	ERK can inhibit TSC2 as well [XREF_BIBR, XREF_BIBR].	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	0	1	3	4
This lack of evidence has led some investigators to postulate that hamartin or tuberin may be inactivated through post-translational modifications such as phosphorylation by ERK [ XREF_BIBR ] .	This lack of evidence has led some investigators to postulate that hamartin or tuberin may be inactivated through post-translational modifications such as phosphorylation by ERK [XREF_BIBR].	11	26	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	tuberin	tuberin	tuberin	24	25	13	14
For example , ERK and RSK inhibit TSC2 , resulting in mTOR activation and downstream PI3K pathway activation that is independent of PI3K and Akt .	For example, ERK and RSK inhibit TSC2, resulting in mTOR activation and downstream PI3K pathway activation that is independent of PI3K and Akt.	3	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	3	4	7	8
Because ERK ( extracellular signal regulated kinase ) can phosphorylate and negatively regulate the GAP activity of TSC2 and activate mTORC1 XREF_BIBR , we examined whether activation of ERK downstream of LPS is responsible for mTORC1-S6K activation .	Because ERK (extracellular signal regulated kinase) can phosphorylate and negatively regulate the GAP activity of TSC2 and activate mTORC1 XREF_BIBR, we examined whether activation of ERK downstream of LPS is responsible for mTORC1-S6K activation.	1	19	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	1	2	17	18
XREF_BIBR Enhancement by estrogens of the survival and growth of intravenously injected Tsc2 -/- cells in mice XREF_BIBR was blocked by the MAPK and ERK kinase ( MEK ) inhibitor CI-1040 .	XREF_BIBR Enhancement by estrogens of the survival and growth of intravenously injected Tsc2 -/- cells in mice XREF_BIBR was blocked by the MAPK and ERK kinase (MEK) inhibitor CI-1040.	11	25	blocked	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	Tsc2	Tsc2	Tsc2	22	23	12	13
Inhibition of TSC2 by Erk also promoted tumorigenesis in vitro and in vivo .	Inhibition of TSC2 by Erk also promoted tumorigenesis in vitro and in vivo.	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Erk	Erk	Erk	TSC2	TSC2	TSC2	4	5	2	3
In non T cell lines , ERK1/2 phosphorylate and inactivate TSC2 , a negative regulator of mTOR complex 1 activation , to promote signaling via mTOR complex 1 .	In non T cell lines, ERK1/2 phosphorylate and inactivate TSC2, a negative regulator of mTOR complex 1 activation, to promote signaling via mTOR complex 1.	6	14	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	TSC2	TSC2	TSC2	6	7	10	11
Inhibition of ERK restores both GSK3beta activity and levels of protein synthesis in Tsc2 -/- cells , thus identifying ERK as a candidate therapeutic target for the treatment of tuberous sclerosis .	Inhibition of ERK restores both GSK3beta activity and levels of protein synthesis in Tsc2 -/- cells, thus identifying ERK as a candidate therapeutic target for the treatment of tuberous sclerosis.	0	14	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	Tsc2	Tsc2	Tsc2	2	3	13	14
Growth factor induced PI3K and Akt- and Ras and Erk mediated TSC2 inhibition is well defined .	Growth factor induced PI3K and Akt- and Ras and Erk mediated TSC2 inhibition is well defined.	3	12	mediated	Positive_early_activation	Negative_activation	Negative_activation	Erk	Erk	Erk	TSC2	TSC2	TSC2	9	10	11	12
Downstream of RAS , in the mitogen activated protein kinase ( MAPK ) pathway , ERK has been shown to negatively regulate TSC2 [ XREF_BIBR ] .	Downstream of RAS, in the mitogen activated protein kinase (MAPK) pathway, ERK has been shown to negatively regulate TSC2 [XREF_BIBR].	15	24	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	15	16	22	23
XREF_BIBR - XREF_BIBR Ras and MAPK signaling can also inhibit TSC2 leading to mTOR activation .	XREF_BIBR - XREF_BIBR Ras and MAPK signaling can also inhibit TSC2 leading to mTOR activation.	5	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	TSC2	TSC2	TSC2	5	6	10	11
By contrast to these reports , however , it has also been shown that ERK can inhibit TSC2 and promotes tumourigenesis in vitro and in vivo .	By contrast to these reports, however, it has also been shown that ERK can inhibit TSC2 and promotes tumourigenesis in vitro and in vivo.	14	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	14	15	17	18
As both the PI3K and MAPK pathways inhibit TSC2 , which is directly upstream of mTORC1 , the increased synergy exhibited by PI3K and MEK inhibition may be due to increased inhibition of mTORC1 .	As both the PI3K and MAPK pathways inhibit TSC2, which is directly upstream of mTORC1, the increased synergy exhibited by PI3K and MEK inhibition may be due to increased inhibition of mTORC1.	5	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	TSC2	TSC2	TSC2	5	6	8	9
However , phosphorylation of TSC2 by Akt , extracellular signal regulated kinases ( ERK ) , RSK1 , AMPK , or glycogen synthase kinase -3 beta ( GSK-3beta ) may be more important to block TSC1 and TSC2 activity .	However, phosphorylation of TSC2 by Akt, extracellular signal regulated kinases (ERK), RSK1, AMPK, or glycogen synthase kinase -3 beta (GSK-3beta) may be more important to block TSC1 and TSC2 activity.	2	38	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	phosphorylation of TSC2 by Akt, extracellular signal regulated kinases (ERK	erk	TSC2	TSC2	tsc2	13	14	37	38
These results show that Emi1 can inhibit APC and Cdh1 activation at the end of mitosis and suggest that Emi1 protein degradation is insufficient to completely inhibit Emi1 activity in the presence of continued Emi1 synthesis .	These results show that Emi1 can inhibit APC and Cdh1 activation at the end of mitosis and suggest that Emi1 protein degradation is insufficient to completely inhibit Emi1 activity in the presence of continued Emi1 synthesis.	4	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Emi1	Emi1	Emi1	Cdh1	Cdh1	Cdh1	4	5	9	10
In late G1 , when Cdh1 is inactivated by phosphorylation and its inhibitor Emi1 , Skp2 becomes stable and can degrade p21 , p27 and Cdh1 leading to S phase entry and cell cycle progression .	In late G1, when Cdh1 is inactivated by phosphorylation and its inhibitor Emi1, Skp2 becomes stable and can degrade p21, p27 and Cdh1 leading to S phase entry and cell cycle progression.	5	14	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Emi1	phosphorylation and its inhibitor Emi1	emi1	Cdh1	Cdh1	cdh1	13	14	5	6
Because Cdh1 restrains cell proliferation and is inhibited by Emi1 , it has been proposed that Cdh1 functions as a tumour suppressor ( XREF_FIG ) .	Because Cdh1 restrains cell proliferation and is inhibited by Emi1, it has been proposed that Cdh1 functions as a tumour suppressor (XREF_FIG).	1	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Emi1	Emi1	Emi1	Cdh1	Cdh1	Cdh1	9	10	1	2
Strikingly , translational repression of Emi1 in mitosis allowed a substantially higher degree of APC and Cdh1 activation at comparable Emi1 expression levels ( XREF_FIG and XREF_FIG ) .	Strikingly, translational repression of Emi1 in mitosis allowed a substantially higher degree of APC and Cdh1 activation at comparable Emi1 expression levels (XREF_FIG and XREF_FIG).	3	17	allowed	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Emi1	Emi1	Emi1	Cdh1	Cdh1	Cdh1	5	6	16	17
In addition to inhibitory phosphorylation by Cdks , Cdh1 is also inhibited by Emi1 , which acts as a pseudosubstrate that inactivates APC and C-Cdh 1 at G2 and the G1/S transition [ XREF_BIBR - XREF_BIBR ] .	In addition to inhibitory phosphorylation by Cdks, Cdh1 is also inhibited by Emi1, which acts as a pseudosubstrate that inactivates APC and C-Cdh 1 at G2 and the G1/S transition [XREF_BIBR - XREF_BIBR].	8	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Emi1	Emi1	Emi1	Cdh1	Cdh1	Cdh1	13	14	8	9
In G2 phase , Emi1 inhibits APC and Cdh1 , and this inhibition is required to allow accumulation of cyclins in G2 and for mitotic entry .	In G2 phase, Emi1 inhibits APC and Cdh1, and this inhibition is required to allow accumulation of cyclins in G2 and for mitotic entry.	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Emi1	Emi1	Emi1	Cdh1	Cdh1	Cdh1	4	5	8	9
To date , whereas the F-box protein , Emi-1 , has been shown to repress APC and Cdh1 activity , it does so not by affecting Cdh1 stability but rather by blocking the ability of Cdh1 to degrade its physiological substrates .	To date, whereas the F-box protein, Emi-1, has been shown to repress APC and Cdh1 activity, it does so not by affecting Cdh1 stability but rather by blocking the ability of Cdh1 to degrade its physiological substrates.	6	18	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Emi-1	Emi-1	Emi-1	Cdh1	Cdh1	Cdh1	8	9	17	18
Growth effects mediated by RelA deletion paralleled a downregulation of growth-inhibitory Cdh1 ( officially known as FZR1 ) and upregulation of the endogenous Cdh1 suppressor EMI1 ( officially known as FBXO5 ) .	Growth effects mediated by RelA deletion paralleled a downregulation of growth-inhibitory Cdh1 (officially known as FZR1) and upregulation of the endogenous Cdh1 suppressor EMI1 (officially known as FBXO5).	19	26	suppressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	EMI1	EMI1	EMI1	Cdh1	Cdh1	Cdh1	25	26	23	24
Emi1 is required to antagonize Cdh1 .	Emi1 is required to antagonize Cdh1.	0	6	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Emi1	Emi1	Emi1	Cdh1	Cdh1	Cdh1	0	1	5	6
We found that FBXO11 downregulates the oncoprotein Cdt2 to restrain CRL4 Cdt2 activity on its substrates p21 and Set8 .	We found that FBXO11 downregulates the oncoprotein Cdt2 to restrain CRL4 Cdt2 activity on its substrates p21 and Set8.	3	9	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	3	4	7	8
We thus investigated whether the migration of A549 cells , in standard wound healing assays , is dependent on FBXO11 mediated decrease of Cdt2 and consequent increase of Set8 .	We thus investigated whether the migration of A549 cells, in standard wound healing assays, is dependent on FBXO11 mediated decrease of Cdt2 and consequent increase of Set8.	19	24	decrease	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	19	20	23	24
These results indicate that FBXO11 degrades Cdt2 to induce Set8 at 12-20 hr post TGF-beta treatment , and the induction of Set8 during this critical period decreases both P-Smad2 and N-cadherin at 24-48 hr .	These results indicate that FBXO11 degrades Cdt2 to induce Set8 at 12-20 hr post TGF-beta treatment, and the induction of Set8 during this critical period decreases both P-Smad2 and N-cadherin at 24-48 hr.	4	7	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	4	5	6	7
Our results also demonstrate a critical role for the FBXO11 mediated degradation of Cdt2 in cellular migration through the stabilization of catalytically active Set8 because overexpression of Set8 rescued the migration deficits produced by constitutively stable Cdt2 .	Our results also demonstrate a critical role for the FBXO11 mediated degradation of Cdt2 in cellular migration through the stabilization of catalytically active Set8 because overexpression of Set8 rescued the migration deficits produced by constitutively stable Cdt2.	6	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	9	10	13	14
FBXO11 degrades Cdt2 to upregulate Set8 and to limit the phospho-Smad2 in response to TGF-beta .	FBXO11 degrades Cdt2 to upregulate Set8 and to limit the phospho-Smad2 in response to TGF-beta.	0	3	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	0	1	2	3
The conserved D457 of Cdt2 is also important for the degradation of Cdt2 by FBXO11 in vivo , in that the level of Cdt2 D457A was not increased when FBXO11 was knocked down ( XREF_FIG , lanes 8-10 ) .	The conserved D457 of Cdt2 is also important for the degradation of Cdt2 by FBXO11 in vivo, in that the level of Cdt2 D457A was not increased when FBXO11 was knocked down (XREF_FIG, lanes 8-10).	7	27	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	14	15	12	13
Thus , FBXO11 mediated degradation of Cdt2 is critical for providing sufficient levels of catalytically active Set8 to promote cellular migration .	Thus, FBXO11 mediated degradation of Cdt2 is critical for providing sufficient levels of catalytically active Set8 to promote cellular migration.	2	8	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	2	3	6	7
In summary , our findings indicate that the FBXO11 and DRE-1-dependent degradation of CDT2 and CDT -2 is part of a highly conserved cellular program that controls the timing of cell cycle exit and differentiation .	In summary, our findings indicate that the FBXO11 and DRE-1-dependent degradation of CDT2 and CDT -2 is part of a highly conserved cellular program that controls the timing of cell cycle exit and differentiation.	8	15	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	CDT2	CDT2	CDT2	8	9	13	14
Thus , we hypothesized that the degradation of Cdt2 by FBXO11 is important for the normal response of a cell to TGF-beta .	Thus, we hypothesized that the degradation of Cdt2 by FBXO11 is important for the normal response of a cell to TGF-beta.	6	11	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	10	11	8	9
Here , we show that the CRL1 ( FBXO11 ) also promotes the degradation of Cdt2 during an unperturbed cell cycle to promote efficient progression through S and G 2/M phases of the cell cycle .	Here, we show that the CRL1 (FBXO11) also promotes the degradation of Cdt2 during an unperturbed cell cycle to promote efficient progression through S and G 2/M phases of the cell cycle.	6	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	8	9	15	16
In this study , we show that FBXO11 is essential to degrade the Cdt2 that is initially induced when TGF-beta is added , and thus stabilizes CRL4 Cdt2 substrates p21 and Set8 during a critical window of 12-20 hr after TGF beta addition .	In this study, we show that FBXO11 is essential to degrade the Cdt2 that is initially induced when TGF-beta is added, and thus stabilizes CRL4 Cdt2 substrates p21 and Set8 during a critical window of 12-20 hr after TGF beta addition.	7	17	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	7	8	13	14
Taken together , these results indicate that FBXO11 dependent degradation of CDT2 plays a role in controlling the timing of cell cycle exit .	Taken together, these results indicate that FBXO11 dependent degradation of CDT2 plays a role in controlling the timing of cell cycle exit.	7	12	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	CDT2	CDT2	CDT2	7	8	11	12
FBXO11 degrades Cdt2 to stabilize the CRL4 Cdt2 substrates p21 and Set8 .	FBXO11 degrades Cdt2 to stabilize the CRL4 Cdt2 substrates p21 and Set8.	0	3	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	0	1	2	3
However , FBXO11 mediated Cdt2 degradation was shown to stabilize p21 , leading in increased p21 level .	However, FBXO11 mediated Cdt2 degradation was shown to stabilize p21, leading in increased p21 level.	2	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	2	3	4	5
To test whether FBXO11 mediated degradation of Cdt2 alone was sufficient for the induction of Set8 seen at 12-20 hr after TGF-beta , we repeated the TGF-beta treatment in control A549 ( pMSCV ) or in cells expressing wt-Cdt2 or FBXO11 resistant mutants of Cdt2 ( XREF_FIG ) .	To test whether FBXO11 mediated degradation of Cdt2 alone was sufficient for the induction of Set8 seen at 12-20 hr after TGF-beta, we repeated the TGF-beta treatment in control A549 (pMSCV) or in cells expressing wt-Cdt2 or FBXO11 resistant mutants of Cdt2 (XREF_FIG).	3	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	3	4	7	8
During atrophy , Atrogin-1 and MuRF-1 are the crucial muscle specific ubiquitin ligases that direct the polyubiquitination of proteins to target them for proteolysis by the 26S proteasome [ XREF_BIBR ] , shifting gene expression towards a less myogenic phenotype ( Atrogin-1 , which degrades MyoD ) or mediating sarcomeric breakdown ( MuRF-1 , which degrades myosins ) [ XREF_BIBR ] , which has vital significance in the research of mechanism of muscular atrophy of cancer cachexia .	During atrophy, Atrogin-1 and MuRF-1 are the crucial muscle specific ubiquitin ligases that direct the polyubiquitination of proteins to target them for proteolysis by the 26S proteasome [XREF_BIBR], shifting gene expression towards a less myogenic phenotype (Atrogin-1, which degrades MyoD) or mediating sarcomeric breakdown (MuRF-1, which degrades myosins) [XREF_BIBR], which has vital significance in the research of mechanism of muscular atrophy of cancer cachexia.	41	46	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Atrogin-1	Atrogin-1	Atrogin-1	MyoD	MyoD	MyoD	41	42	45	46
Altogether these results show that activation of MAFbx expression suppresses MyoD in C2C12 myotubes .	Altogether these results show that activation of MAFbx expression suppresses MyoD in C2C12 myotubes.	7	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAFbx	MAFbx expression	mafbx	MyoD	MyoD	myod	7	8	10	11
Atrogin-1 is known to promote the degradation of MyoD and elF3f [ XREF_BIBR ] : MyoD is an important transcription factor of muscle and elF3f is one of the enhancer proteins of protein synthesis [ XREF_BIBR , XREF_BIBR ] .	Atrogin-1 is known to promote the degradation of MyoD and elF3f [XREF_BIBR] : MyoD is an important transcription factor of muscle and elF3f is one of the enhancer proteins of protein synthesis [XREF_BIBR, XREF_BIBR].	0	12	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Atrogin-1	Atrogin-1	Atrogin-1	MyoD	MyoD	MyoD	0	1	8	9
Atrogin-1 promotes degradation of MyoD , a key muscle transcription factor , and of eIF3f , an important activator of protein synthesis ( XREF_FIG ) .	Atrogin-1 promotes degradation of MyoD, a key muscle transcription factor, and of eIF3f, an important activator of protein synthesis (XREF_FIG).	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Atrogin-1	Atrogin-1	Atrogin-1	MyoD	MyoD	MyoD	0	1	4	5
However , atrogin-1 degrades MyoD , which in turn positively regulates miR-206 ; however , the existence of a miR-206/MyoD/atrogin -1 regulatory loop has not been investigated .	However, atrogin-1 degrades MyoD, which in turn positively regulates miR-206; however, the existence of a miR-206/MyoD/atrogin -1 regulatory loop has not been investigated.	2	10	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	atrogin-1	atrogin-1	atrogin-1	MyoD	MyoD	MyoD	2	3	4	5
Inhibition of Atrogin-1 and MAFbx Mediated MyoD Proteolysis Prevents Skeletal Muscle Atrophy In Vivo .	Inhibition of Atrogin-1 and MAFbx Mediated MyoD Proteolysis Prevents Skeletal Muscle Atrophy In Vivo.	0	7	Mediated	Positive_early_activation	Negative_activation	Negative_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	4	5	6	7
Atrogin-1 promotes degradation of MyoD , a key muscle transcription factor , and of eIF3-f , an important activator of protein synthesis .	Atrogin-1 promotes degradation of MyoD, a key muscle transcription factor, and of eIF3-f, an important activator of protein synthesis.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Atrogin-1	Atrogin-1	Atrogin-1	MyoD	MyoD	MyoD	0	1	4	5
During atrophy , MuRF-1 and atrogin-1 are the crucial muscle specific ubiquitin ligases that direct the polyubiquitination of proteins to target them for proteolysis by the 26S proteasome , mediating sarcomeric breakdown ( MuRF-1 , which degrades myosins ) [ XREF_BIBR ] or shifting gene expression towards a less myogenic phenotype ( atrogin-1 , which degrades MyoD ) [ XREF_BIBR ] .	During atrophy, MuRF-1 and atrogin-1 are the crucial muscle specific ubiquitin ligases that direct the polyubiquitination of proteins to target them for proteolysis by the 26S proteasome, mediating sarcomeric breakdown (MuRF-1, which degrades myosins) [XREF_BIBR] or shifting gene expression towards a less myogenic phenotype (atrogin-1, which degrades MyoD) [XREF_BIBR].	50	57	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	atrogin-1	atrogin-1	atrogin-1	MyoD	MyoD	MyoD	52	53	56	57
Atrogin-1 induces degradation of MyoD and eukaryotic translation initiation factor 3 subunit F ( eIF3f ) , which are important for activation of myogenic transcription factors and activation of protein synthesis , respectively .	Atrogin-1 induces degradation of MyoD and eukaryotic translation initiation factor 3 subunit F (eIF3f), which are important for activation of myogenic transcription factors and activation of protein synthesis, respectively.	0	5	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Atrogin-1	Atrogin-1	Atrogin-1	MyoD	MyoD	MyoD	0	1	4	5
MAFbx promotes the degradation of MyoD 51 , a muscle transcription factor involved in the expression of muscle specific genes , and eIF3-f ( eukaryotic initiation factor-3f ) , an activator of translation initiation 52 , whereas MURF1 catalyses the ubiquitination and degradation of myofibrillar proteins , including troponin 53 and myosin heavy chains 54 , myosin light chains 55 and actin 56 .	MAFbx promotes the degradation of MyoD 51, a muscle transcription factor involved in the expression of muscle specific genes, and eIF3-f (eukaryotic initiation factor-3f), an activator of translation initiation 52, whereas MURF1 catalyses the ubiquitination and degradation of myofibrillar proteins, including troponin 53 and myosin heavy chains 54, myosin light chains 55 and actin 56.	0	61	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	0	1	5	6
Clearly there is a connection between satellite cell activation and proliferation through HGF , a rise in myostatin , MAFbx and subsequent suppression of MyoD and myogenin .	Clearly there is a connection between satellite cell activation and proliferation through HGF, a rise in myostatin, MAFbx and subsequent suppression of MyoD and myogenin.	17	26	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	19	20	24	25
In addition , expression of a protein Fbxo32 , which degrades MyoD and eIF3-f in skeletal muscle , was also increased in muscle of CTG550 mice .	In addition, expression of a protein Fbxo32, which degrades MyoD and eIF3-f in skeletal muscle, was also increased in muscle of CTG550 mice.	3	16	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Fbxo32	expression of a protein Fbxo32	fbxo32	MyoD	MyoD	myod	7	8	11	12
Recently , we have shown that overexpression of MAFbx in proliferating myoblasts antagonizes differentiation by inducing MyoD degradation XREF_BIBR .	Recently, we have shown that overexpression of MAFbx in proliferating myoblasts antagonizes differentiation by inducing MyoD degradation XREF_BIBR.	6	18	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAFbx	overexpression of MAFbx	mafbx	MyoD	MyoD	myod	8	9	16	17
Reconstitution of FBXO11 in DLBCL cell lines induces BCL6 degradation and cell death .	Reconstitution of FBXO11 in DLBCL cell lines induces BCL6 degradation and cell death.	0	9	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	2	3	8	9
FBXO11 loss or mutation may contribute to DLBCL pathogenesis by allowing the accumulation of BCL6 , an oncoprotein that has a critical role in lymphomagenesis .	FBXO11 loss or mutation may contribute to DLBCL pathogenesis by allowing the accumulation of BCL6, an oncoprotein that has a critical role in lymphomagenesis.	0	17	contribute	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	0	1	14	15
By loss of function and gain of function studies , we show that FBXO11 acts as a tumor suppressor , promotes apoptosis and mediates the degradation of the oncogenic protein BCL6 .	By loss of function and gain of function studies, we show that FBXO11 acts as a tumor suppressor, promotes apoptosis and mediates the degradation of the oncogenic protein BCL6.	13	31	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	13	14	30	31
Restoration of FBXO11 expression in FBXO11 deficient cells promoted BCL6 degradation and suppressed proliferation and tumorigenesis in a xenograft mouse animal model of DLBCL [ XREF_BIBR ] .	Restoration of FBXO11 expression in FBXO11 deficient cells promoted BCL6 degradation and suppressed proliferation and tumorigenesis in a xenograft mouse animal model of DLBCL [XREF_BIBR].	2	10	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11 expression	fbxo11	BCL6	BCL6	bcl6	2	3	9	10
Fbxo11 promotes apoptosis and the degradation of the oncogenic protein Bcl6 , and silencing Fbxo11 in miR-21 knockout cancer cells restores their high tumorigenicity .	Fbxo11 promotes apoptosis and the degradation of the oncogenic protein Bcl6, and silencing Fbxo11 in miR-21 knockout cancer cells restores their high tumorigenicity.	0	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Fbxo11	Fbxo11	Fbxo11	Bcl6	Bcl6	Bcl6	0	1	10	11
First , we observed that treatment of cells with UO126 did not stabilize BCL6 ( compare the 4-h time point with cycloheximide in the presence or absence of UO126 in XREF_FIG ) , further supporting the conclusion that the FBXO11 mediated degradation of BCL6 is ERK independent .	First, we observed that treatment of cells with UO126 did not stabilize BCL6 (compare the 4-h time point with cycloheximide in the presence or absence of UO126 in XREF_FIG), further supporting the conclusion that the FBXO11 mediated degradation of BCL6 is ERK independent.	38	45	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	39	40	43	44
Recently , FBXO11 was shown to mediate degradation of the oncoprotein BCL6 ( B cell lymphoma 6 ) , suggesting that FBXO11 is a tumour suppressor 13 .	Recently, FBXO11 was shown to mediate degradation of the oncoprotein BCL6 (B cell lymphoma 6), suggesting that FBXO11 is a tumour suppressor 13.	2	15	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	2	3	11	12
Loss of Fbxo11 promotes BCL6 stability .	Loss of Fbxo11 promotes BCL6 stability.	0	5	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Fbxo11	Loss of Fbxo11	fbxo11	BCL6	BCL6	bcl6	2	3	4	5
Reconstitution of FBXO11 enhanced BCL6 degradation , leading to inhibition of cell proliferation and induction of cell death .	Reconstitution of FBXO11 enhanced BCL6 degradation, leading to inhibition of cell proliferation and induction of cell death.	0	5	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	2	3	4	5
Notably , FBXO11 silencing induced BCL6 stabilization in the absence of ligand mediated receptor activation ( XREF_FIG and XREF_SUPPLEMENTARY ) , which has been reported to accelerate BCL6 degradation by stimulating its ERK dependent phosphorylation 7 .	Notably, FBXO11 silencing induced BCL6 stabilization in the absence of ligand mediated receptor activation (XREF_FIG and XREF_SUPPLEMENTARY), which has been reported to accelerate BCL6 degradation by stimulating its ERK dependent phosphorylation 7.	2	6	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	2	3	5	6
FBXO11 promotes apoptosis by mediating the degradation of oncogenic BCL6 .	FBXO11 promotes apoptosis by mediating the degradation of oncogenic BCL6.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	0	1	9	10
Another tumor suppressive F-box protein FBXO11 was found to target BCL-6 ( B cell lymphoma 6 ) for degradation , which is crucial in the pathogenesis of diffused large B cell lymphoma ( DLBCL ) , the most common adult lymphoma [ XREF_BIBR ] .	Another tumor suppressive F-box protein FBXO11 was found to target BCL-6 (B cell lymphoma 6) for degradation, which is crucial in the pathogenesis of diffused large B cell lymphoma (DLBCL), the most common adult lymphoma [XREF_BIBR].	0	18	target	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL-6	BCL-6	BCL-6	5	6	10	11
Together , these results indicate that the FBXO11 dependent degradation of BCL6 is ERK independent .	Together, these results indicate that the FBXO11 dependent degradation of BCL6 is ERK independent.	7	12	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	7	8	11	12
While Snail factors were hereby identified as physiological substrates of FBXO11 , FBXO11 was shown to promote the degradation of BCL6 and BLIMP1 , both of which are zinc finger transcription factors critical for B cell development , and CDT2 , a cell cycle regulator [ XREF_BIBR - XREF_BIBR ] .	While Snail factors were hereby identified as physiological substrates of FBXO11, FBXO11 was shown to promote the degradation of BCL6 and BLIMP1, both of which are zinc finger transcription factors critical for B cell development, and CDT2, a cell cycle regulator [XREF_BIBR - XREF_BIBR].	12	48	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	12	13	20	21
MiR-621 enhances chemosensitivity of breast cancer cells through its suppression of Fbxo11 mediated p53 inhibition .	MiR-621 enhances chemosensitivity of breast cancer cells through its suppression of Fbxo11 mediated p53 inhibition.	9	14	mediated	Positive_early_activation	Negative_activation	Positive_activation	Fbxo11	Fbxo11	Fbxo11	p53	p53	p53	11	12	13	14
Consistent with a previous report , our data support that FBXO11 could suppress p53 transactivity and reduce breast cancer apoptosis upon chemotherapy ( XREF_FIG ) .	Consistent with a previous report, our data support that FBXO11 could suppress p53 transactivity and reduce breast cancer apoptosis upon chemotherapy (XREF_FIG).	10	16	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	10	11	13	14
Besides , FBXO11 may also antagonize p53 by indirectly destabilizing p53 protein via Set8-depedent Numb acetylation , thereby promoting breast cancer progression .	Besides, FBXO11 may also antagonize p53 by indirectly destabilizing p53 protein via Set8-depedent Numb acetylation, thereby promoting breast cancer progression.	2	7	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	2	3	6	7
To investigate further the relationship between FBXO11 and p53 in the developing mouse , we wished to assess whether FBXO11 might inhibit the activity of p53 in the developing lung .	To investigate further the relationship between FBXO11 and p53 in the developing mouse, we wished to assess whether FBXO11 might inhibit the activity of p53 in the developing lung.	19	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	19	20	25	26
Interestingly , ectopic expression of FBXO11 also attenuated miR-621-depedent increase of p53 transactivation , suggesting a critical role of FBXO11 repression in enhancing p53 activity by miR-621 ( XREF_FIG ) .	Interestingly, ectopic expression of FBXO11 also attenuated miR-621-depedent increase of p53 transactivation, suggesting a critical role of FBXO11 repression in enhancing p53 activity by miR-621 (XREF_FIG).	3	12	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	expression of FBXO11	fbxo11	p53	p53	p53	5	6	11	12
Accordingly , miR-621-dependent FBXO11 suppression enhanced p53 activity and increased apoptosis in breast cancer cells exposed to chemotherapeutics .	Accordingly, miR-621-dependent FBXO11 suppression enhanced p53 activity and increased apoptosis in breast cancer cells exposed to chemotherapeutics.	3	7	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	3	4	6	7
Our results indicated that the miR-621-mediated suppression of FBXO11 could enhance the p53 transcriptional pathway , thereby promoting breast cancer cell apoptosis , especially in those harboring functional p53 , in response to PTX and CBP treatment ( XREF_FIG , XREF_FIG and XREF_FIG ) .	Our results indicated that the miR-621-mediated suppression of FBXO11 could enhance the p53 transcriptional pathway, thereby promoting breast cancer cell apoptosis, especially in those harboring functional p53, in response to PTX and CBP treatment (XREF_FIG, XREF_FIG and XREF_FIG).	6	38	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	8	9	12	13
It was reported that FBXO11 could inhibit p53 transactivity by promoting p53 neddylation [ XREF_BIBR ] .	It was reported that FBXO11 could inhibit p53 transactivity by promoting p53 neddylation [XREF_BIBR].	4	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	4	5	7	8
MEK1/2 is involved in a Sos1 negative feedback loop whereby cyclic activity of all the proteins in the loop is induced by ERK1/2 and/or p90RSK inhibiting Sos1 activity while also being activated downstream of Sos1 via a Ras-Raf-MEK cascade of activation .	MEK1/2 is involved in a Sos1 negative feedback loop whereby cyclic activity of all the proteins in the loop is induced by ERK1/2 and/or p90RSK inhibiting Sos1 activity while also being activated downstream of Sos1 via a Ras-Raf-MEK cascade of activation.	20	27	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	Sos1	Sos1	Sos1	22	23	26	27
Interruption of Ror2 and ERK1/2 significantly inhibited the activation of LKB1 which has been identified as a key molecule in inducing complete polarity in intestinal epithelial cells .	Interruption of Ror2 and ERK1/2 significantly inhibited the activation of LKB1 which has been identified as a key molecule in inducing complete polarity in intestinal epithelial cells.	0	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	LKB1	LKB1	LKB1	4	5	10	11
XREF_BIBR - XREF_BIBR Activation of mammalian target of rapamycin ( mTOR ) signaling downstream of PKA through ERK mediated phosphorylation of tuberin XREF_BIBR , XREF_BIBR has been linked to transcriptional activation of aerobic glycolysis , increased levels of ATP , and together with ERK dependent inhibition of liver kinase B1 , inhibition of AMP kinase , which may further enhance mTOR signaling .	XREF_BIBR - XREF_BIBR Activation of mammalian target of rapamycin (mTOR) signaling downstream of PKA through ERK mediated phosphorylation of tuberin XREF_BIBR, XREF_BIBR has been linked to transcriptional activation of aerobic glycolysis, increased levels of ATP, and together with ERK dependent inhibition of liver kinase B1, inhibition of AMP kinase, which may further enhance mTOR signaling.	43	50	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	liver kinase B1	liver kinase B1	liver kinase B1	43	44	47	50
Conversely , a subset of oncogenic mutants of K-Ras , the main upstream regulator of ERK , blocks 2-DG -- induced LKB1 and AMPK signaling .	Conversely, a subset of oncogenic mutants of K-Ras, the main upstream regulator of ERK, blocks 2-DG -- induced LKB1 and AMPK signaling.	13	24	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	LKB1	LKB1	LKB1	15	16	21	22
In addition , at least in certain cell types , the ERK-substrate 90 kD ribosomal protein S6 kinase ( RSK ) can inhibit death associated protein kinase ( DAPK ) , a potential positive regulator of Beclin-1 dependent autophagy [ XREF_BIBR , XREF_BIBR ] , and both ERK and RSK can inhibit the Ser and Thr kinase LKB1 [ XREF_BIBR ] and thus interfere with activation of the pro autophagic kinase AMPK ( see below ) [ XREF_BIBR ] .	In addition, at least in certain cell types, the ERK-substrate 90 kD ribosomal protein S6 kinase (RSK) can inhibit death associated protein kinase (DAPK), a potential positive regulator of Beclin-1 dependent autophagy [XREF_BIBR, XREF_BIBR], and both ERK and RSK can inhibit the Ser and Thr-kinase LKB1 [XREF_BIBR] and thus interfere with activation of the pro autophagic kinase AMPK (see below) [XREF_BIBR].	46	58	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	LKB1	LKB1	LKB1	47	48	57	58
The LKB1 and AMPK pathway is negatively activated by ERK in AML cells , and ERK is activated in the 50 % of AML cases with mutations in intracellular signal transduction pathways .	The LKB1 and AMPK pathway is negatively activated by ERK in AML cells, and ERK is activated in the 50% of AML cases with mutations in intracellular signal transduction pathways.	1	12	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	LKB1	LKB1	LKB1	9	10	1	2
Although no changes were observed in extracellular signal regulated kinases 1 and 2 or c-Jun N-terminal kinase expression at either the phospho or total levels , the phosphorylation of p38 and MAPK at T180 and Y182 were significantly diminished ( 0.52-fold , P < 0.01 ) in the LKB1 expressing MDA-MB-231 cells .	Although no changes were observed in extracellular signal regulated kinases 1 and 2 or c-Jun N-terminal kinase expression at either the phospho or total levels, the phosphorylation of p38 and MAPK at T180 and Y182 were significantly diminished (0.52-fold, P < 0.01) in the LKB1 expressing MDA-MB-231 cells.	27	49	diminished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	phosphorylation of p38 and MAPK at T180	mapk	LKB1	LKB1	lkb1	31	32	48	49
Prostaglandins were postulated as an essential signaling molecule in FcgammaRIIb mediated inhibition of TLR4 in mouse macrophages XREF_BIBR .	Prostaglandins were postulated as an essential signaling molecule in FcgammaRIIb mediated inhibition of TLR4 in mouse macrophages XREF_BIBR.	7	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FcgammaRIIb	FcgammaRIIb	FcgammaRIIb	TLR4	TLR4	TLR4	9	10	13	14
The IC mediated inhibition of LPS induced TNFalpha production was abrogated in the presence of Wortmannin or LY294002 , confirming the role of the PI3K pathway in FcgammaRIIb mediated TLR4 signaling inhibition in gmMphi ( XREF_FIG and data not shown ) .	The IC mediated inhibition of LPS induced TNFalpha production was abrogated in the presence of Wortmannin or LY294002, confirming the role of the PI3K pathway in FcgammaRIIb mediated TLR4 signaling inhibition in gmMphi (XREF_FIG and data not shown).	25	31	mediated	Positive_early_activation	Negative_activation	Negative_activation	FcgammaRIIb	FcgammaRIIb	FcgammaRIIb	TLR4	TLR4	TLR4	27	28	29	30
FcgammaRIIb inhibits TLR4 mediated DC maturation , reduces secretion of pro inflammatory cytokines , which in turn inhibits T cell proliferation , and primes T cells to produce anti- inflammatory Th2 cytokines [ XREF_BIBR ] .	FcgammaRIIb inhibits TLR4 mediated DC maturation, reduces secretion of pro inflammatory cytokines, which in turn inhibits T cell proliferation, and primes T cells to produce anti- inflammatory Th2 cytokines [XREF_BIBR].	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FcgammaRIIb	FcgammaRIIb	FcgammaRIIb	TLR4	TLR4	TLR4	0	1	2	3
It seems unlikely that fibulin-5 facilitates deposition of individual tropoelastin monomers onto microfibrils , since oxidation by LOX precedes elastin deposition on microfibrils , whereas we have shown that fibrillin-1 inhibits the ternary complexes of fibulin-4 , LOX , and tropoelastin that may facilitate cross linking .	It seems unlikely that fibulin-5 facilitates deposition of individual tropoelastin monomers onto microfibrils, since oxidation by LOX precedes elastin deposition on microfibrils, whereas we have shown that fibrillin-1 inhibits the ternary complexes of fibulin-4, LOX, and tropoelastin that may facilitate cross linking.	29	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	fibrillin-1	fibrillin-1	fibrillin-1	fibulin-4	fibulin-4	fibulin-4	29	30	35	36
Pin1 also promotes breast CSC self-renewal and metastasis by inhibiting FBXW7 mediated degradation of NOTCH1 and NOTCH4 32 .	Pin1 also promotes breast CSC self-renewal and metastasis by inhibiting FBXW7 mediated degradation of NOTCH1 and NOTCH4 32.	9	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXW7	FBXW7	FBXW7	NOTCH4	NOTCH4	NOTCH4	10	11	16	17
N4 degradation was investigated by , who showed that Notch4 is targeted by ubiquitin ligase SEL-10 ; ubiquitylation and/or SEL-10 binding of C-terminal constructs distal to the ankryn repeats of Notch4 targeted the protein for proteasome mediated destruction .	N4 degradation was investigated by, who showed that Notch4 is targeted by ubiquitin ligase SEL-10; ubiquitylation and/or SEL-10 binding of C-terminal constructs distal to the ankryn repeats of Notch4 targeted the protein for proteasome mediated destruction.	9	24	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SEL-10	SEL-10	SEL-10	Notch4	Notch4	Notch4	15	16	9	10
Mechanistically , phosphorylation of CCDC6 at Thr434 by ATM during DNA damage response prevents FBXW6-CCDC6 interaction and FBXW7 mediated CCDC6 degradation .	Mechanistically, phosphorylation of CCDC6 at Thr434 by ATM during DNA damage response prevents FBXW6-CCDC6 interaction and FBXW7 mediated CCDC6 degradation.	15	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	FBXW7	FBXW7	FBXW7	CCDC6	CCDC6	CCDC6	17	18	19	20
The inhibition of myostatin by follistatin attenuated the DEX induced proteolysis by initiating the ubiquitin-proteasome system .	The inhibition of myostatin by follistatin attenuated the DEX induced proteolysis by initiating the ubiquitin-proteasome system.	1	6	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	5	6	3	4
Myostatin inhibition by follistatin ( FS ) offers a new approach for muscle mass enhancement .	Myostatin inhibition by follistatin (FS) offers a new approach for muscle mass enhancement.	0	4	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	Myostatin	Myostatin	Myostatin	3	4	0	1
In mice in which myostatin signaling was blocked by Fst transgene expression , the massive initial muscle hypertrophy was clearly outweighed by the subsequent detrimental effects leading to accelerated muscle degeneration .	In mice in which myostatin signaling was blocked by Fst transgene expression, the massive initial muscle hypertrophy was clearly outweighed by the subsequent detrimental effects leading to accelerated muscle degeneration.	4	12	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Fst	Fst transgene expression	fst	myostatin	myostatin	myostatin	9	10	4	5
The therapeutic potential of HDAC inhibitors for muscular dystrophy has been previously confirmed , with their therapeutic effect partly relying on a myostatin antagonist follistatin XREF_BIBR .	The therapeutic potential of HDAC inhibitors for muscular dystrophy has been previously confirmed, with their therapeutic effect partly relying on a myostatin antagonist follistatin XREF_BIBR.	22	25	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	24	25	22	23
Follistatin treatment inhibited the DEX induced increase in myostatin ( P < 0.05 ) and the activation of phosphor-FoxO1/3a ( Thr 24/32 ) ( P < 0.05 ) and MuRF1 ( P < 0.05 ) .	Follistatin treatment inhibited the DEX induced increase in myostatin (P < 0.05) and the activation of phosphor-FoxO1/3a (Thr 24/32) (P < 0.05) and MuRF1 (P < 0.05).	0	29	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	8	9
Finally , by establishing that follistatin can inhibit myostatin with an adeno associated virus , our studies provide the basis for tests of other integrating viruses , such as lentivirus , which transduce muscle and stem cells effectively and may be less affected by rounds of muscle degeneration and regeneration .	Finally, by establishing that follistatin can inhibit myostatin with an adeno associated virus, our studies provide the basis for tests of other integrating viruses, such as lentivirus, which transduce muscle and stem cells effectively and may be less affected by rounds of muscle degeneration and regeneration.	5	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	5	6	8	9
It has been shown that FST antagonizes MSTN by a direct protein interaction , preventing MSTN from executing its inhibitory effect on muscle development .	It has been shown that FST antagonizes MSTN by a direct protein interaction, preventing MSTN from executing its inhibitory effect on muscle development.	5	8	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FST	FST	FST	MSTN	MSTN	MSTN	5	6	7	8
Follistatin is a powerful inhibitor of myostatin plus having the advantage of controlling muscle mass through pathways independent of the myostatin signaling cascade [ XREF_BIBR ] .	Follistatin is a powerful inhibitor of myostatin plus having the advantage of controlling muscle mass through pathways independent of the myostatin signaling cascade [XREF_BIBR].	0	8	is a powerful inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	6	7
On the other hand , the expression of follistatin , which antagonizes myostatin and promotes myocyte fusion XREF_BIBR , XREF_BIBR , is not restricted to muscle .	On the other hand, the expression of follistatin, which antagonizes myostatin and promotes myocyte fusion XREF_BIBR, XREF_BIBR, is not restricted to muscle.	6	13	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	expression of follistatin	follistatin	myostatin	myostatin	myostatin	8	9	12	13
Finally , follistatin expression encoded by adeno associated virus chronically inhibited myostatin and produced sustained increases in muscle mass , myofiber number , and fiber diameter , but these increases did not affect survival .	Finally, follistatin expression encoded by adeno associated virus chronically inhibited myostatin and produced sustained increases in muscle mass, myofiber number, and fiber diameter, but these increases did not affect survival.	2	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin expression	follistatin	myostatin	myostatin	myostatin	2	3	11	12
Delivery of follistatin ( FST ) represents a promising strategy for both muscular dystrophies and diabetes , as FST is a robust antagonist of myostatin and activin , which are critical regulators of skeletal muscle and adipose tissues .	Delivery of follistatin (FST) represents a promising strategy for both muscular dystrophies and diabetes, as FST is a robust antagonist of myostatin and activin, which are critical regulators of skeletal muscle and adipose tissues.	18	31	is a robust antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	FST	FST	FST	myostatin	myostatin	myostatin	18	19	24	25
Indeed , follistatin mRNA expression was strongly upregulated in skeletal muscle from Mstn -/- mice as well as following siRNA mediated Mstn knockdown .	Indeed, follistatin mRNA expression was strongly upregulated in skeletal muscle from Mstn -/- mice as well as following siRNA mediated Mstn knockdown.	2	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin mRNA expression	follistatin	Mstn	Mstn	mstn	2	3	21	22
Follistatin also antagonizes myostatin , a negative regulator of muscle growth and also a member of the TGF-beta superfamily XREF_BIBR , XREF_BIBR .	Follistatin also antagonizes myostatin, a negative regulator of muscle growth and also a member of the TGF-beta superfamily XREF_BIBR, XREF_BIBR.	0	21	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	3	4
Follistatin , a physiological inhibitor of myostatin , was used to reduce the effect of myostatin by binding to myostatin and acting as an effective myostatin inhibitor [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Follistatin, a physiological inhibitor of myostatin, was used to reduce the effect of myostatin by binding to myostatin and acting as an effective myostatin inhibitor [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	16	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	15	16
Follistatin is a member of the TGF-beta super family and inhibits the action of myostatin to regulate skeletal muscle growth .	Follistatin is a member of the TGF-beta super family and inhibits the action of myostatin to regulate skeletal muscle growth.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	14	15
Here , we show that myostatin inhibition by follistatin transgene expression in Dysf -/- mice results in early improvement in histopathology but ultimately exacerbates muscle degeneration ; this effect was not observed in dystrophin deficient ( mdx ) mice , suggesting that accelerated degeneration induced by follistatin transgene expression is specific to mice lacking dysferlin .	Here, we show that myostatin inhibition by follistatin transgene expression in Dysf -/- mice results in early improvement in histopathology but ultimately exacerbates muscle degeneration; this effect was not observed in dystrophin deficient (mdx) mice, suggesting that accelerated degeneration induced by follistatin transgene expression is specific to mice lacking dysferlin.	5	11	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	follistatin	follistatin transgene expression	follistatin	myostatin	myostatin	myostatin	8	9	5	6
Considering our current results , myostatin antagonists such as follistatin may have the potential to benefit muscle protein turnover ; however , the influence of such agents on clinical outcomes have not yet been fully examined , and additional investigations will be required.22 , 29 , 30 Several limitations need to be acknowledged in our current analysis .	Considering our current results, myostatin antagonists such as follistatin may have the potential to benefit muscle protein turnover; however, the influence of such agents on clinical outcomes have not yet been fully examined, and additional investigations will be required.22, 29, 30 Several limitations need to be acknowledged in our current analysis.	5	10	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	9	10	5	6
Mstn inhibition by FS represents a potential therapeutic approach of muscle atrophy .	Mstn inhibition by FS represents a potential therapeutic approach of muscle atrophy.	0	4	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	FS	FS	FS	Mstn	Mstn	Mstn	3	4	0	1
In addition , the myostatin antagonist follistatin is decreased with loading XREF_BIBR - XREF_BIBR , providing additional support for the hypothesis presented here that myostatin signaling plays an important role in regulating cell proliferation and extracellular matrix synthesis in tendons and ligaments .	In addition, the myostatin antagonist follistatin is decreased with loading XREF_BIBR - XREF_BIBR, providing additional support for the hypothesis presented here that myostatin signaling plays an important role in regulating cell proliferation and extracellular matrix synthesis in tendons and ligaments.	3	8	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	6	7	4	5
Several studies have indicated that MSTN gene KO can alter various MSTN signaling pathway related factors , including myogenic regulatory factors ( MRFs ) ( MYOD , MYOG , and MYF5 ) , downstream signaling mediators ( SMAD2 and SMAD3 ) , the cell cycle regulator p21 , the MSTN receptor ACVR2B and the MSTN antagonist follistatin ( FST ) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Several studies have indicated that MSTN gene KO can alter various MSTN signaling pathway related factors, including myogenic regulatory factors (MRFs) (MYOD, MYOG, and MYF5), downstream signaling mediators (SMAD2 and SMAD3), the cell cycle regulator p21, the MSTN receptor ACVR2B and the MSTN antagonist follistatin (FST) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	15	63	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	MSTN	MSTN	MSTN	56	57	54	55
Intramuscular follistatin gene transfer ( follistatin is a naturally occurring antagonist of myostatin ) is also being tested in an open-trial enrolling nine IBM patients [ XREF_BIBR ] .	Intramuscular follistatin gene transfer (follistatin is a naturally occurring antagonist of myostatin) is also being tested in an open-trial enrolling nine IBM patients [XREF_BIBR].	1	13	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	1	2	12	13
Follistatin , in contrast , is a direct antagonist of the myostatin receptor , responsible for Increasing muscle mass , preventing muscle atrophy in response to disuse , and increases proliferation and differentiation of myogenic progenitors .	Follistatin, in contrast, is a direct antagonist of the myostatin receptor, responsible for Increasing muscle mass, preventing muscle atrophy in response to disuse, and increases proliferation and differentiation of myogenic progenitors.	0	12	is a direct antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	11	12
To explore the effect of myostatin on protein metabolism , follistatin was used to inhibit myostatin in C2C12 cells .	To explore the effect of myostatin on protein metabolism, follistatin was used to inhibit myostatin in C2C12 cells.	10	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	10	11	15	16
Follistatin treatment inhibited the DEX induced increase of myostatin ( P < 0.05 , XREF_FIG ) .	Follistatin treatment inhibited the DEX induced increase of myostatin (P < 0.05, XREF_FIG).	0	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	8	9
Both follistatin and GASPs inhibit the activities of GDF11 and myostatin ; accordingly , follistatin ( Fst )-heterozygous 47 and Gasp1-null or Gasp2-null 48 mice have smaller muscles and increased GDF11 and myostatin bioactivity .	Both follistatin and GASPs inhibit the activities of GDF11 and myostatin; accordingly, follistatin (Fst)-heterozygous 47 and Gasp1-null or Gasp2-null 48 mice have smaller muscles and increased GDF11 and myostatin bioactivity.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	1	2	10	11
Follistatin is a powerful inhibitor of myostatin plus having the advantage of controlling muscle mass through pathways independent of the myostatin signaling cascade [ 65 ] .	Follistatin is a powerful inhibitor of myostatin plus having the advantage of controlling muscle mass through pathways independent of the myostatin signaling cascade [65].	0	8	is a powerful inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	6	7
Follistatin is an antagonist of myostatin ( GDF-8 ) in addition to inhibiting Act A.	Follistatin is an antagonist of myostatin (GDF-8) in addition to inhibiting Act A.	0	14	is an antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	5	6
Moreover , fiber hypertrophy was also observed in all muscles , demonstrating that myostatin inhibition by follistatin is a good method to improve myoblast transplantation and muscle function .	Moreover, fiber hypertrophy was also observed in all muscles, demonstrating that myostatin inhibition by follistatin is a good method to improve myoblast transplantation and muscle function.	13	17	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	16	17	13	14
Both GDF11 and myostatin stimulate the TGF-beta signalling pathway through activin receptors type 2A ( ACVR2A ) and 2B ( ACVR2B ) , and are antagonized by the activin binding protein follistatin .	Both GDF11 and myostatin stimulate the TGF-beta signalling pathway through activin receptors type 2A (ACVR2A) and 2B (ACVR2B), and are antagonized by the activin binding protein follistatin.	1	32	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	31	32	3	4
Follistatin is a natural inhibitor of myostatin .	Follistatin is a natural inhibitor of myostatin.	0	7	is a natural inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	6	7
In accordance with this , modifiers of myostatin , such as follistatin ( Fst ) , which inhibits myostatin , are currently under review as therapeutics [ XREF_BIBR , XREF_BIBR ] .	In accordance with this, modifiers of myostatin, such as follistatin (Fst), which inhibits myostatin, are currently under review as therapeutics [XREF_BIBR, XREF_BIBR].	5	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	11	12	18	19
Some scholars have shown that FST could promote skeletal muscle hypertrophy in mice by activating IGF-1R ( type 1 insulin like growth factor receptor )/Akt ( protein kinase B ) signalling and inhibiting MSTN ( myostatin ) signalling [ XREF_BIBR , XREF_BIBR ] .	Some scholars have shown that FST could promote skeletal muscle hypertrophy in mice by activating IGF-1R (type 1 insulin like growth factor receptor)/Akt (protein kinase B) signalling and inhibiting MSTN (myostatin) signalling [XREF_BIBR, XREF_BIBR].	5	37	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FST	FST	FST	MSTN	MSTN	MSTN	5	6	33	34
Myostatin inhibition by follistatin in combination with myoblast transplantation is thus a promising novel therapeutic approach for the treatment of muscle wasting in diseases such as Duchenne muscular dystrophy .	Myostatin inhibition by follistatin in combination with myoblast transplantation is thus a promising novel therapeutic approach for the treatment of muscle wasting in diseases such as Duchenne muscular dystrophy.	0	5	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	Myostatin	Myostatin	Myostatin	3	4	0	1
The lack of consistency demonstrated that the FST protein , as a binding protein for MSTN , may prevent MSTN from binding to receptors on the myoblast cells and thus block the MSTN signal [ XREF_BIBR ] .	The lack of consistency demonstrated that the FST protein, as a binding protein for MSTN, may prevent MSTN from binding to receptors on the myoblast cells and thus block the MSTN signal [XREF_BIBR].	7	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FST	FST	FST	MSTN	MSTN	MSTN	7	8	19	20
Interestingly , ectopic GDF11 can induce expression of FS 122 , which as discussed above inhibits both GDF11 and MSTN signaling .	Interestingly, ectopic GDF11 can induce expression of FS 122, which as discussed above inhibits both GDF11 and MSTN signaling.	3	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FS	GDF11 can induce expression of FS	fs	MSTN	MSTN	mstn	8	9	19	20
Follistatin is an inhibitor of myostatin and works through activation of the IGF1 receptor .	Follistatin is an inhibitor of myostatin and works through activation of the IGF1 receptor.	0	7	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	5	6
Treatment of the diabetic mice with the myostatin antagonist follistatin , or with the Alk5 inhibitor of TGF-beta receptor 1 ( which did not diminish the blood glucose levels ) rescued muscle regenerative responses and attenuated the myostatin and TGFbeta receptor and pSmad3 signaling .	Treatment of the diabetic mice with the myostatin antagonist follistatin, or with the Alk5 inhibitor of TGF-beta receptor 1 (which did not diminish the blood glucose levels) rescued muscle regenerative responses and attenuated the myostatin and TGFbeta receptor and pSmad3 signaling.	4	10	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	9	10	7	8
Follistatin can antagonize the function of myostatin as a competitive binding protein and promote muscle growth in vivo .	Follistatin can antagonize the function of myostatin as a competitive binding protein and promote muscle growth in vivo.	0	13	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	6	7
XREF_BIBR Therefore , one may postulate that a reduced expression of FNDC5 leads to a reduced expression of follistatin ( inhibitor of myostatin ) , which eventually caused a reduction in muscle mass -- a phenomenon often observed in heart failure .	XREF_BIBR Therefore, one may postulate that a reduced expression of FNDC5 leads to a reduced expression of follistatin (inhibitor of myostatin), which eventually caused a reduction in muscle mass -- a phenomenon often observed in heart failure.	9	27	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	follistatin	expression of FNDC5 leads to a reduced expression of follistatin	follistatin	myostatin	myostatin	myostatin	18	19	22	23
XREF_BIBR Follistatin is a potent antagonist of myostatin that takes advantage of its ability to hinder access to signaling receptors on skeletal muscle .	XREF_BIBR Follistatin is a potent antagonist of myostatin that takes advantage of its ability to hinder access to signaling receptors on skeletal muscle.	0	8	is a potent antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	1	2	7	8
The exogenous genes most likely to be utilized for gene doping include erythropoietin ( EPO ) , growth hormone ( GH ) , vascular endothelial growth factor ( VEGF-A and VEGF-D ) , insulin like growth factor 1 ( IGF-1 ) and myostatin antagonists such as follistatin ( FST ) .	The exogenous genes most likely to be utilized for gene doping include erythropoietin (EPO), growth hormone (GH), vascular endothelial growth factor (VEGF-A and VEGF-D), insulin like growth factor 1 (IGF-1) and myostatin antagonists such as follistatin (FST).	42	47	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	46	47	42	43
ELISA assays showed significant increases in skeletal muscle IGF-1 , leptin , and the myostatin antagonist follistatin with tryptophan supplementation .	ELISA assays showed significant increases in skeletal muscle IGF-1, leptin, and the myostatin antagonist follistatin with tryptophan supplementation.	2	17	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	16	17	14	15
Because GDF-11 and BMP-11 is highly related to MSTN ( the two are greater than 90 % identical at the amino acid level in the C-terminal domain ) [ XREF_BIBR , XREF_BIBR ] , these findings raised the possibility that follistatin might also be capable of binding and inhibiting MSTN .	Because GDF-11 and BMP-11 is highly related to MSTN (the two are greater than 90% identical at the amino acid level in the C-terminal domain) [XREF_BIBR, XREF_BIBR], these findings raised the possibility that follistatin might also be capable of binding and inhibiting MSTN.	40	50	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	MSTN	MSTN	MSTN	40	41	49	50
To this end , we focused on blocking myostatin , a member of the transforming growth factor-beta superfamily and a negative regulator of muscle regeneration , with the myostatin antagonist follistatin .	To this end, we focused on blocking myostatin, a member of the transforming growth factor-beta superfamily and a negative regulator of muscle regeneration, with the myostatin antagonist follistatin.	5	31	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	30	31	28	29
Therefore , the regulators that potentially display a myostatin like activity presumably activate this pathway , whereas myostatin antagonists , such as follistatin , can antagonize it .	Therefore, the regulators that potentially display a myostatin like activity presumably activate this pathway, whereas myostatin antagonists, such as follistatin, can antagonize it.	17	23	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	22	23	17	18
We next tested whether Follistatin suppresses Myostatin activity during muscle development .	We next tested whether Follistatin suppresses Myostatin activity during muscle development.	4	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	Myostatin	Myostatin	Myostatin	4	5	6	7
These findings suggest that follistatin not only blocks myostatin but also allows other activators to function in muscle development , emphasizing that follistatin could be a very potent molecule in combating muscle loss during dystrophies and muscle ageing , disuse , or denervation .	These findings suggest that follistatin not only blocks myostatin but also allows other activators to function in muscle development, emphasizing that follistatin could be a very potent molecule in combating muscle loss during dystrophies and muscle ageing, disuse, or denervation.	4	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	4	5	8	9
FST inhibits MSTN in two ways .	FST inhibits MSTN in two ways.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FST	FST	FST	MSTN	MSTN	MSTN	0	1	2	3
Therefore , the ratio of myostatin to follistatin is higher than in the UT group not just in the SC group ( over 2-fold ) but also in the SC+ M ol and Mol groups , indicating in the latter treatments some residual bioavailable myostatin not blocked by follistatin .	Therefore, the ratio of myostatin to follistatin is higher than in the UT group not just in the SC group (over 2-fold) but also in the SC+M ol and Mol groups, indicating in the latter treatments some residual bioavailable myostatin not blocked by follistatin.	36	49	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	48	49	44	45
In addition , exogenous LAP , follistatin , or FLGR could be used to sequester MSTN and enhance muscling , as demonstrated in mouse models .	In addition, exogenous LAP, follistatin, or FLGR could be used to sequester MSTN and enhance muscling, as demonstrated in mouse models.	4	16	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	MSTN	MSTN	MSTN	6	7	15	16
Finally , recent data suggest that leptin may also stimulate follistatin production in a circadian manner , and follistatin is a potent antagonist of myostatin .	Finally, recent data suggest that leptin may also stimulate follistatin production in a circadian manner, and follistatin is a potent antagonist of myostatin.	18	25	is a potent antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	18	19	24	25
The knockdown of MSTN expression was accompanied with concomitant downregulation of myogenic regulatory factor MYOD ( 77 % , p = 0.001 ) , MYOG ( 94 % , p = 0.000 ) , and MYF5 ( 36 % , p = 0.000 ) , cell cycle regulator p21 ( 62 % , p = 0.000 ) , MSTN receptor ACVR2B ( 23 % , p = 0.061 ) , MSTN antagonist follistatin ( 81 % , p = 0.000 ) , and downstream signaling mediators SMAD2 ( 20 % , p = 0.060 ) and SMAD3 ( 49 % , p = 0.006 ) .	The knockdown of MSTN expression was accompanied with concomitant downregulation of myogenic regulatory factor MYOD (77%, p = 0.001), MYOG (94%, p = 0.000), and MYF5 (36%, p = 0.000), cell cycle regulator p21 (62%, p = 0.000), MSTN receptor ACVR2B (23%, p = 0.061), MSTN antagonist follistatin (81%, p = 0.000), and downstream signaling mediators SMAD2 (20%, p = 0.060) and SMAD3 (49%, p = 0.006).	70	103	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	MSTN	MSTN	MSTN	72	73	70	71
Although the use of the deacetylase inhibitors to increase the levels of follistatin ( an antagonist of myostatin ) has not lead to any positive results in the treatment of cachexia in experimental animals [ XREF_BIBR , XREF_BIBR ] , the use of the activin receptor extracellular domain/Fc fusion protein ( ACVR2B-Fc ) has been shown to be effective in the treatment of muscle wasting in tumor bearing animals [ XREF_BIBR ] .	Although the use of the deacetylase inhibitors to increase the levels of follistatin (an antagonist of myostatin) has not lead to any positive results in the treatment of cachexia in experimental animals [XREF_BIBR, XREF_BIBR], the use of the activin receptor extracellular domain/Fc fusion protein (ACVR2B-Fc) has been shown to be effective in the treatment of muscle wasting in tumor bearing animals [XREF_BIBR].	10	18	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	follistatin	levels of follistatin	follistatin	myostatin	myostatin	myostatin	12	13	17	18
FST antagonizes myostatin activity by binding to it and also by interfering with the binding of myostatin to its receptor XREF_BIBR XREF_BIBR XREF_BIBR , but in vivo studies indicate that myostatin may not be the only regulator of muscle mass and may not be the only target of FST XREF_BIBR .	FST antagonizes myostatin activity by binding to it and also by interfering with the binding of myostatin to its receptor XREF_BIBR XREF_BIBR XREF_BIBR, but in vivo studies indicate that myostatin may not be the only regulator of muscle mass and may not be the only target of FST XREF_BIBR.	0	28	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FST	FST	FST	myostatin	myostatin	myostatin	0	1	2	3
Therefore , although Fst has been shown to antagonize activin and myostatin during myogenesis , the role of Fstl1 in this process remains unknown .	Therefore, although Fst has been shown to antagonize activin and myostatin during myogenesis, the role of Fstl1 in this process remains unknown.	3	12	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Fst	Fst	Fst	myostatin	myostatin	myostatin	3	4	11	12
We previously showed that follistatin can also block myostatin activity in vivo ; specifically , we showed that follistatin can ameliorate the cachexia induced by high level expression of myostatin in nude mice XREF_BIBR and that transgenic mice expressing follistatin in muscle have dramatic increases in muscle mass XREF_BIBR .	We previously showed that follistatin can also block myostatin activity in vivo; specifically, we showed that follistatin can ameliorate the cachexia induced by high level expression of myostatin in nude mice XREF_BIBR and that transgenic mice expressing follistatin in muscle have dramatic increases in muscle mass XREF_BIBR.	4	9	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	4	5	8	9
Myostatin can be inactivated by binding to proteins including follistatin , follistatin related gene ( FLRG ) and GASP-1 .	Myostatin can be inactivated by binding to proteins including follistatin, follistatin related gene (FLRG) and GASP-1.	0	13	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	Myostatin	Myostatin	Myostatin	11	12	0	1
Fst was originally thought to promote muscle fiber hypertrophy by preventing the repressive effects of myostatin on myogenic precursor differentiation and growth of developing muscle fibers , which have been demonstrated in many species , including humans .	Fst was originally thought to promote muscle fiber hypertrophy by preventing the repressive effects of myostatin on myogenic precursor differentiation and growth of developing muscle fibers, which have been demonstrated in many species, including humans.	0	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Fst	Fst	Fst	myostatin	myostatin	myostatin	0	1	15	16
Although the inhibition of myostatin by follistatin has been reported previously [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] , this is the first study to demonstrate the causal role of myostatin in the reduced skeletal muscle mass in PSS that commonly accompanies cirrhosis .	Although the inhibition of myostatin by follistatin has been reported previously [XREF_BIBR, XREF_BIBR - XREF_BIBR], this is the first study to demonstrate the causal role of myostatin in the reduced skeletal muscle mass in PSS that commonly accompanies cirrhosis.	2	7	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	6	7	4	5
Myostatin was most significantly inhibited by Follistatin ( 23 fold decrease ) and Myostatin neutralizing antibody ( 244 fold decrease ) administration .	Myostatin was most significantly inhibited by Follistatin (23 fold decrease) and Myostatin neutralizing antibody (244 fold decrease) administration.	0	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	Myostatin	Myostatin	Myostatin	6	7	0	1
Follistatin is known to functionally block myostatin ( MSTN ) , a potent inhibitor of muscle development .	Follistatin is known to functionally block myostatin (MSTN), a potent inhibitor of muscle development.	0	13	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	6	7
In this BMD proof-of-principle clinical trial , a potent myostatin antagonist , follistatin ( FS ) , was used to inhibit the myostatin pathway .	In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway.	10	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	12	13	22	23
The ability of several myostatin antagonists , such as follistatin , follistatin related gene , soluble activin receptor IIB and suramin to block MSTN signaling transduction has been tested [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The ability of several myostatin antagonists, such as follistatin, follistatin related gene, soluble activin receptor IIB and suramin to block MSTN signaling transduction has been tested [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	20	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	9	10	4	5
Follistatin also directly antagonize myostatin during myogenesis [ XREF_BIBR ] .	Follistatin also directly antagonize myostatin during myogenesis [XREF_BIBR].	0	8	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	4	5
These results indicate that myostatin blockade by FS I-I has a therapeutic potential for muscular dystrophy .	These results indicate that myostatin blockade by FS I-I has a therapeutic potential for muscular dystrophy.	4	8	blockade	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	FS	FS	FS	myostatin	myostatin	myostatin	7	8	4	5
To determine whether FST , which inhibits MSTN activity in vitro and in vivo , is involved in the mechanism by which 1,25-D 3 promotes muscle growth , we investigated FST expression in primary cultures of skeletal muscle derived satellite cells , with and without 1,25-D 3 incubation .	To determine whether FST, which inhibits MSTN activity in vitro and in vivo, is involved in the mechanism by which 1,25-D 3 promotes muscle growth, we investigated FST expression in primary cultures of skeletal muscle derived satellite cells, with and without 1,25-D 3 incubation.	3	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FST	FST	FST	MSTN	MSTN	MSTN	3	4	7	8
Because follistatin acts as an antagonist to myostatin and inhibits myostatin from binding to the ACTIIB receptor site , this may be affecting myostatin ' s role as a negative regulator of muscle mass .	Because follistatin acts as an antagonist to myostatin and inhibits myostatin from binding to the ACTIIB receptor site, this may be affecting myostatin 's role as a negative regulator of muscle mass.	1	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	1	2	10	11
In this sense , follistatin prevents myostatin from connecting to its receptor by connecting to the point of activin type IIb receptor .	In this sense, follistatin prevents myostatin from connecting to its receptor by connecting to the point of activin type IIb receptor.	4	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	4	5	6	7
Another interesting muscle target is the myostatin-follistatin pathway , in which myostatin acts as a negative regulator of muscle growth and is itself inhibited by follistatin .	Another interesting muscle target is the myostatin-follistatin pathway, in which myostatin acts as a negative regulator of muscle growth and is itself inhibited by follistatin.	11	26	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	25	26	11	12
An alternative means of inhibiting myostatin effects is to increase follistatin , which inhibits myostatin activity by attaching to it and interfering with receptor binding [ XREF_BIBR ] .	An alternative means of inhibiting myostatin effects is to increase follistatin, which inhibits myostatin activity by attaching to it and interfering with receptor binding [XREF_BIBR].	9	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	10	11	14	15
Having these aspects in mind we conclude that the beneficial effects of strength training observed for MQ and functional parameters in our study might be due to blocking of activin A and myostatin by enhanced levels of follistatin rather than by lower circulating levels of activin A and myostatin .	Having these aspects in mind we conclude that the beneficial effects of strength training observed for MQ and functional parameters in our study might be due to blocking of activin A and myostatin by enhanced levels of follistatin rather than by lower circulating levels of activin A and myostatin.	27	38	blocking	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	follistatin	levels of follistatin	follistatin	myostatin	myostatin	myostatin	37	38	32	33
In contrast , Fst ( +/-) heterozygotes have normal body weight but reduced muscle mass reflecting increased myostatin and activin bioactivity .	In contrast, Fst (+/-) heterozygotes have normal body weight but reduced muscle mass reflecting increased myostatin and activin bioactivity.	3	20	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Fst	Fst	Fst	myostatin	myostatin	myostatin	3	4	17	18
by combining follistatin -- an inhibitor of myostatin -- to increase muscle mass and strength , and muDys .	by combining follistatin -- an inhibitor of myostatin -- to increase muscle mass and strength, and muDys.	1	8	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	2	3	7	8
Fst is an inhibitor of myostatin ( Mstn ) , a negative regulator of muscle mass .	Fst is an inhibitor of myostatin (Mstn), a negative regulator of muscle mass.	0	12	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Fst	Fst	Fst	myostatin	myostatin	myostatin	0	1	5	6
Follistatin antagonizes both myostatin and activin A activity , and mice overexpressing follistatin in skeletal muscle show a more dramatic phenotype than mice lacking myostatin alone .	Follistatin antagonizes both myostatin and activin A activity, and mice overexpressing follistatin in skeletal muscle show a more dramatic phenotype than mice lacking myostatin alone.	0	7	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	3	4
Follistatin , another member of the TGF-beta superfamily , prevents myostatin from binding to its receptor , thereby neutralizing it [ XREF_BIBR ] .	Follistatin, another member of the TGF-beta superfamily, prevents myostatin from binding to its receptor, thereby neutralizing it [XREF_BIBR].	0	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	10	11
Follistatin is a small , conserved protein that is secreted locally and binds to and inhibits myostatin , a transforming growth factor beta ( TGF-beta ) family member that is expressed almost exclusively in developing and mature muscle and acts to shut down muscle growth .	Follistatin is a small, conserved protein that is secreted locally and binds to and inhibits myostatin, a transforming growth factor beta (TGF-beta) family member that is expressed almost exclusively in developing and mature muscle and acts to shut down muscle growth.	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	16	17
Inhibition of Myostatin by Follistatin enhances osteogenic differentiation and calcification in vitro .	Inhibition of Myostatin by Follistatin enhances osteogenic differentiation and calcification in vitro.	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	Myostatin	Myostatin	Myostatin	4	5	2	3
For example , targeted deletion of the myostatin gene ( GDF-8 ; a negative regulator of skeletal muscle growth ) or muscle specific overexpression of follistatin ( an inhibitor of myostatin ) -- produce a dramatic increase in skeletal muscle mass .	For example, targeted deletion of the myostatin gene (GDF-8; a negative regulator of skeletal muscle growth) or muscle specific overexpression of follistatin (an inhibitor of myostatin) -- produce a dramatic increase in skeletal muscle mass.	23	31	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	follistatin	overexpression of follistatin	follistatin	myostatin	myostatin	myostatin	25	26	30	31
Myostatin function can be blocked by the action of Follistatin , which can be induced in muscle cells by treatment with HDAC inhibitors .	Myostatin function can be blocked by the action of Follistatin, which can be induced in muscle cells by treatment with HDAC inhibitors.	0	10	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	Myostatin	Myostatin	Myostatin	9	10	0	1
Our data indicate that myostatin inhibition by this follistatin derived peptide has therapeutic potential for muscular dystrophy .	Our data indicate that myostatin inhibition by this follistatin derived peptide has therapeutic potential for muscular dystrophy.	4	9	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	8	9	4	5
Follistatin antagonizes myostatin and activin A and as such it is regarded as a positive regulator of muscle mass .	Follistatin antagonizes myostatin and activin A and as such it is regarded as a positive regulator of muscle mass.	0	5	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	2	3
In a phase I trial , AAV mediated regional expression of the myostatin antagonist follistatin improved walking distance in 5 out of 6 BMD patients 169 .	In a phase I trial, AAV mediated regional expression of the myostatin antagonist follistatin improved walking distance in 5 out of 6 BMD patients 169.	9	15	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	14	15	12	13
MiR-1 increases follistatin expression by suppressing histone deacetylase 4 ( HDAC4 , an inhibitor of follistatin expression ) and thereby inactivates circulating myostatin , XREF_BIBR miR-499 binds to the myostatin 3 '-untranslated region XREF_BIBR and both are predicted to target the activin IIB receptor .	MiR-1 increases follistatin expression by suppressing histone deacetylase 4 (HDAC4, an inhibitor of follistatin expression) and thereby inactivates circulating myostatin, XREF_BIBR miR-499 binds to the myostatin 3 '-untranslated region XREF_BIBR and both are predicted to target the activin IIB receptor.	0	23	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	MiR-1 increases follistatin expression	follistatin	myostatin	myostatin	myostatin	2	3	22	23
Activin A was shown to be involved in positively regulating bone formation , however we were able to show that osteogenic differentiation and SMAD 2/3 decrease were mediated primarily through inhibition of Myostatin by Follistatin .	Activin A was shown to be involved in positively regulating bone formation, however we were able to show that osteogenic differentiation and SMAD 2/3 decrease were mediated primarily through inhibition of Myostatin by Follistatin.	27	35	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	Myostatin	Myostatin	Myostatin	34	35	32	33
HDAC4 inhibits serum response factor , an important regulator of MHC1 expression , and the expression of follistatin , XREF_BIBR which may activate the myostatin pathway .	HDAC4 inhibits serum response factor, an important regulator of MHC1 expression, and the expression of follistatin, XREF_BIBR which may activate the myostatin pathway.	0	25	activate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	follistatin	HDAC4 inhibits serum response factor, an important regulator of MHC1 expression, and the expression of follistatin	follistatin	myostatin	myostatin	myostatin	17	18	24	25
Follistatin has been also found to block the activity of myostatin , a negative regulator of skeletal muscle mass , thus leading to muscle hypertrophy .	Follistatin has been also found to block the activity of myostatin, a negative regulator of skeletal muscle mass, thus leading to muscle hypertrophy.	0	14	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	10	11
In supernatant from untreated HuSKMCs , SMAD2/3 activity mainly represents TGF-beta isoforms , as indicated by the marked reduction of SMAD2/3 CAGA-luc activity ( by about 74 % ) after the soluble TGF-betaRIIb/Fc chimera was added to the supernatant , and the lack of further reduction after addition of either a neutralizing Activin A antibody or follistatin ( a natural blocker of myostatin ; data not shown ) , GDF-11 , and activins .	In supernatant from untreated HuSKMCs, SMAD2/3 activity mainly represents TGF-beta isoforms, as indicated by the marked reduction of SMAD2/3 CAGA-luc activity (by about 74%) after the soluble TGF-betaRIIb/Fc chimera was added to the supernatant, and the lack of further reduction after addition of either a neutralizing Activin A antibody or follistatin (a natural blocker of myostatin; data not shown), GDF-11, and activins.	48	64	blocker	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	56	57	62	63
Other types of molecules , such as Follistatin ( an inhibitor of GDF11 and ActivinbetaB ) , and bone morphogenetic proteins ( BMPs ) , may also regulate the lineage [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Other types of molecules, such as Follistatin (an inhibitor of GDF11 and ActivinbetaB), and bone morphogenetic proteins (BMPs), may also regulate the lineage [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	18	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	GDF11	GDF11	GDF11	7	8	12	13
Follistatin antagonizes GDF11 , and follistatin mutants show a shortened period of ath5 expression and RGC production in the retina .	Follistatin antagonizes GDF11, and follistatin mutants show a shortened period of ath5 expression and RGC production in the retina.	0	3	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	GDF11	GDF11	GDF11	0	1	2	3
GDF 11 as agonist at the Activin receptor 2 was inhibited by Follistatin .	GDF 11 as agonist at the Activin receptor 2 was inhibited by Follistatin.	0	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	GDF 11	GDF 11	GDF 11	12	13	0	2
GDF11 is antagonized by follistatin ( FST ) , which is also produced locally .	GDF11 is antagonized by follistatin (FST), which is also produced locally.	0	12	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	GDF11	GDF11	GDF11	4	5	0	1
The inhibitory function of GDF11 in skeletal muscle development was also demonstrated by GDF11 antagonists such as follistatin and GASP-2 .	The inhibitory function of GDF11 in skeletal muscle development was also demonstrated by GDF11 antagonists such as follistatin and GASP-2.	13	19	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	GDF11	GDF11	GDF11	17	18	13	14
Gdf11 , expressed primarily in olfactory progenitor cells , inhibits basal cell proliferation while follistatin , expressed primarily in cells of the underlying lamina propria , stimulates proliferation by inhibiting Gdf11 .	Gdf11, expressed primarily in olfactory progenitor cells, inhibits basal cell proliferation while follistatin, expressed primarily in cells of the underlying lamina propria, stimulates proliferation by inhibiting Gdf11.	14	31	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	follistatin	follistatin, expressed	follistatin	Gdf11	Gdf11	gdf11	14	15	30	31
Though Follistatin is not very selective and putatively inhibits GDF11 and Activin A , it is one of best available most cost-effective inhibitors of Myostatin XREF_BIBR - XREF_BIBR .	Though Follistatin is not very selective and putatively inhibits GDF11 and Activin A, it is one of best available most cost-effective inhibitors of Myostatin XREF_BIBR - XREF_BIBR.	1	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Follistatin	Follistatin	Follistatin	GDF11	GDF11	GDF11	1	2	9	10
Interestingly , the activin antagonist , follistatin , but not noggin , an antagonist of BMPs 2 and 4 , inhibited BMP-11 activity on animal caps .	Interestingly, the activin antagonist, follistatin, but not noggin, an antagonist of BMPs 2 and 4, inhibited BMP-11 activity on animal caps.	4	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	BMP-11	BMP-11	BMP-11	6	7	21	22
FKBP38 is an endogenous inhibitor of mTOR and reduces the activity of mTOR through association with mTORC1 .	FKBP38 is an endogenous inhibitor of mTOR and reduces the activity of mTOR through association with mTORC1.	0	8	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	FKBP38	FKBP38	FKBP38	mTOR	mTOR	mTOR	0	1	6	7
Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR , whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability .	Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability.	4	16	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	FKBP38	FKBP38	FKBP38	mTOR	mTOR	mTOR	4	5	10	11
In the current model of the Rheb-FKBP38-mTOR relationship , FKBP38 is an endogenous inhibitor of mTOR .	In the current model of the Rheb-FKBP38-mTOR relationship, FKBP38 is an endogenous inhibitor of mTOR.	9	16	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	FKBP38	FKBP38	FKBP38	mTOR	mTOR	mTOR	9	10	15	16
Thus , FKBP38 gene silencing activates mTOR signaling in goat cells .	Thus, FKBP38 gene silencing activates mTOR signaling in goat cells.	2	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FKBP38	FKBP38	FKBP38	mTOR	mTOR	mTOR	2	3	6	7
Moreover , the FK506 Binding Protein 5 ( FKBP5 ) by changing the conformation of the receptor complex can reduce the sensitivity of NR3C1 to corticosterone and the efficiency of the negative feedback on the HPA axis .	Moreover, the FK506 Binding Protein 5 (FKBP5) by changing the conformation of the receptor complex can reduce the sensitivity of NR3C1 to corticosterone and the efficiency of the negative feedback on the HPA axis.	3	24	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FK506 Binding Protein 5	FK506 Binding Protein 5	FK506 Binding Protein 5	NR3C1	NR3C1	NR3C1	3	7	23	24
Moreover , a comprehensive series of experiments in rodents , led by Binder and colleagues among others , detailed a mechanism by which FKBP5 acts to reduce the sensitivity of the glucocorticoid receptor to cortisol .	Moreover, a comprehensive series of experiments in rodents, led by Binder and colleagues among others, detailed a mechanism by which FKBP5 acts to reduce the sensitivity of the glucocorticoid receptor to cortisol.	23	33	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	23	24	31	33
A potential mechanism explaining this link has been demonstrated through reduced glucocorticoid receptor sensitivity modulated by a polymorphic expression of the FKBP5 gene XREF_BIBR .	A potential mechanism explaining this link has been demonstrated through reduced glucocorticoid receptor sensitivity modulated by a polymorphic expression of the FKBP5 gene XREF_BIBR.	11	23	modulated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	21	22	11	13
On the other hand , FKBP5 can decrease the affinity of the glucocorticoid receptor ( GR ) to corticosteroids by a complex interaction with the mature GR , thus resulting in impaired GR signaling XREF_BIBR XREF_BIBR .	On the other hand, FKBP5 can decrease the affinity of the glucocorticoid receptor (GR) to corticosteroids by a complex interaction with the mature GR, thus resulting in impaired GR signaling XREF_BIBR XREF_BIBR.	5	14	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	5	6	12	14
High levels of FKBP5 in the brain can suppress glucocorticoid receptor mediated enhancement of synaptic plasticity , and this action has been shown to have detrimental effects on dendritic architecture .	High levels of FKBP5 in the brain can suppress glucocorticoid receptor mediated enhancement of synaptic plasticity, and this action has been shown to have detrimental effects on dendritic architecture.	1	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FKBP5	levels of FKBP5	fkbp5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	3	4	9	11
Increased FKBP5 expression reduces glucocorticoid receptor sensitivity , resulting in decreased negative feedback inhibition of the HPA axis and elevated glucocorticoid levels .	Increased FKBP5 expression reduces glucocorticoid receptor sensitivity, resulting in decreased negative feedback inhibition of the HPA axis and elevated glucocorticoid levels.	1	6	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FKBP5	FKBP5 expression	fkbp5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	1	2	4	6
FKBP5 modulates glucocorticoid activity by decreasing glucocorticoid receptor affinity for glucocorticoids .	FKBP5 modulates glucocorticoid activity by decreasing glucocorticoid receptor affinity for glucocorticoids.	0	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	0	1	6	8
In vitro studies showed that overexpression of human FKBP5 reduced cortisol binding affinity and nuclear translocation of the glucocorticoid receptor , and thus influenced the transcriptional activity of the genes regulated by the steroid hormone signaling pathway .	In vitro studies showed that overexpression of human FKBP5 reduced cortisol binding affinity and nuclear translocation of the glucocorticoid receptor, and thus influenced the transcriptional activity of the genes regulated by the steroid hormone signaling pathway.	5	20	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FKBP5	overexpression of human FKBP5	fkbp5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	8	9	18	20
However , FSTL3 and GASP2 more potently inhibited the actions of GDF8 relative to GDF11 .	However, FSTL3 and GASP2 more potently inhibited the actions of GDF8 relative to GDF11.	2	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FSTL3	FSTL3	FSTL3	GDF8	GDF8	GDF8	2	3	11	12
FLRG is an inhibitor of myostatin , yet its effects on aging has received considerably less attention .	FLRG is an inhibitor of myostatin, yet its effects on aging has received considerably less attention.	0	6	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	FLRG	FLRG	FLRG	myostatin	myostatin	myostatin	0	1	5	6
Functional studies show that FLRG inhibits myostatin activity in a reporter gene assay .	Functional studies show that FLRG inhibits myostatin activity in a reporter gene assay.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FLRG	FLRG	FLRG	myostatin	myostatin	myostatin	4	5	6	7
To determine whether FLRG can also inhibit myostatin activity in vivo , I generated a construct in which the FLRG coding sequence was placed downstream of a myosin light chain promoter and enhancer .	To determine whether FLRG can also inhibit myostatin activity in vivo, I generated a construct in which the FLRG coding sequence was placed downstream of a myosin light chain promoter and enhancer.	3	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FLRG	FLRG	FLRG	myostatin	myostatin	myostatin	3	4	7	8
FHIT expression has been reported to suppress proliferation and promote apoptosis by blocking the PI3K-Akt pathway .	FHIT expression has been reported to suppress proliferation and promote apoptosis by blocking the PI3K-Akt pathway.	0	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FHIT	FHIT expression	fhit	PI3K-Akt	PI3K-Akt	pi3k-akt	0	1	14	15
Loss of FHIT , leads to increase AKT activity both in vitro and in vivo .	Loss of FHIT, leads to increase AKT activity both in vitro and in vivo.	0	8	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FHIT	Loss of FHIT	fhit	AKT	AKT	akt	2	3	7	8
FHIT has been shown to modulate the Akt-survivin pathway by inhibiting the activity of Akt , a key effector in the phosphatidylinositol 3-OH kinase ( PI3K ) pathway .	FHIT has been shown to modulate the Akt-survivin pathway by inhibiting the activity of Akt, a key effector in the phosphatidylinositol 3-OH kinase (PI3K) pathway.	0	18	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FHIT	FHIT	FHIT	Akt	Akt	Akt	0	1	14	15
Fhit also inhibits the activity of Akt , a key effector in the phosphatidylinositol 3-OH kinase ( PI3K ) pathway [ XREF_BIBR ] , and serves as a physiological target of the Src tyrosine kinase [ XREF_BIBR ] .	Fhit also inhibits the activity of Akt, a key effector in the phosphatidylinositol 3-OH kinase (PI3K) pathway [XREF_BIBR], and serves as a physiological target of the Src tyrosine kinase [XREF_BIBR].	0	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Fhit	Fhit	Fhit	Akt	Akt	Akt	0	1	6	7
In fact , FKBP 12 has been shown to inhibit TGF-beta type I receptor signaling [ XREF_BIBR ] .	In fact, FKBP 12 has been shown to inhibit TGF-beta type I receptor signaling [XREF_BIBR].	3	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FKBP 12	FKBP 12	FKBP 12	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	3	5	10	14
In contrast , the immunophilin FKBP12 , which physically binds to the GS domain of TbetaRI , does not interrupt receptor complex formation , but blocks TbetaRI activation by TbetaRII [ XREF_BIBR - XREF_BIBR ] .	In contrast, the immunophilin FKBP12, which physically binds to the GS domain of TbetaRI, does not interrupt receptor complex formation, but blocks TbetaRI activation by TbetaRII [XREF_BIBR - XREF_BIBR].	4	27	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	immunophilin FKBP12	immunophilin FKBP12	immunophilin FKBP12	TbetaRI	TbetaRI	TbetaRI	4	6	26	27
Inhba codes for the inhibin subunit b , a component of activin A which is directly inhibited by follistatin and is also involved with fibrosis .	Inhba codes for the inhibin subunit b, a component of activin A which is directly inhibited by follistatin and is also involved with fibrosis.	0	19	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	Inhba	Inhba	Inhba	18	19	0	1
The EDF activity of the mesoderm inducing HPLC-fractions is inhibited by follistatin , an EDF binding protein .	The EDF activity of the mesoderm inducing HPLC-fractions is inhibited by follistatin, an EDF binding protein.	1	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	EDF	EDF	EDF	11	12	1	2
Both INHBA and INHBB are inhibited by follistatin ( FST ) [ XREF_BIBR ] , which is also expressed at elevated levels in late-passage cells .	Both INHBA and INHBB are inhibited by follistatin (FST) [XREF_BIBR], which is also expressed at elevated levels in late-passage cells.	0	19	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	follistatin	follistatin (FST) [XREF_BIBR], which is also expressed	follistatin	INHBA	INHBA	inhba	7	8	1	2
In addition , some factors are expressed and function in just one of the lineages , specifically Klf1 ( formerly Eklf ) , an essential driver of erythropoiesis , and Fli-1 , which promotes megakaryopoiesis and antagonizes Klf1 .	In addition, some factors are expressed and function in just one of the lineages, specifically Klf1 (formerly Eklf), an essential driver of erythropoiesis, and Fli-1, which promotes megakaryopoiesis and antagonizes Klf1.	11	38	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Fli-1	Fli-1	Fli-1	Klf1	Klf1	Klf1	30	31	37	38
Finally , Fli-1 antagonizes Klf1 activity through protein protein interaction , indicating Fli-1-Klf1 cross-antagonism as a potential mechanism for Mk-E-lineage separation .	Finally, Fli-1 antagonizes Klf1 activity through protein protein interaction, indicating Fli-1-Klf1 cross-antagonism as a potential mechanism for Mk-E-lineage separation.	2	5	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Fli-1	Fli-1	Fli-1	Klf1	Klf1	Klf1	2	3	4	5
FoxO1 depletion attenuated the HDAC9 induced promoter activity of both PGC-1alpha and G6Pase , further suggesting the participation of HDAC9-FoxO1 signalling in the regulation of gluconeogenic transcription factors and gluconeogenic enzymes .	FoxO1 depletion attenuated the HDAC9 induced promoter activity of both PGC-1alpha and G6Pase, further suggesting the participation of HDAC9-FoxO1 signalling in the regulation of gluconeogenic transcription factors and gluconeogenic enzymes.	0	12	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	FoxO1	FoxO1	FoxO1	PGC-1alpha	PGC-1alpha	PGC-1alpha	0	1	10	11
As PGC-1alpha is repressed by FOXO1 [ XREF_BIBR ] , it is likely that insulin dependent biogenesis of mitochondria might occur through NRF-1-mediated transcription of mtTfa as its downstream target [ XREF_BIBR - XREF_BIBR ] .	As PGC-1alpha is repressed by FOXO1 [XREF_BIBR], it is likely that insulin dependent biogenesis of mitochondria might occur through NRF-1-mediated transcription of mtTfa as its downstream target [XREF_BIBR - XREF_BIBR].	1	7	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	FOXO1	FOXO1	FOXO1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	1	2
hypothesized that FOXO inhibits PGC-1alpha function by binding PGC-1alpha .	hypothesized that FOXO inhibits PGC-1alpha function by binding PGC-1alpha.	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FOXO	FOXO	FOXO	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	4	5
This might be supported by previous studies in which FHIT represses transcriptional activity of beta-catenin that is essential for physiological growth of skeletal muscle .	This might be supported by previous studies in which FHIT represses transcriptional activity of beta-catenin that is essential for physiological growth of skeletal muscle.	9	15	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FHIT	FHIT	FHIT	beta-catenin	beta-catenin	beta-catenin	9	10	14	15
A recent study indicates that the FHIT protein , a known tumor suppressor , which like HINT1 is a member of the HIT family of proteins , also inhibits beta-catenin activity but does so by binding directly to the C-terminus of beta-catenin rather than to pontin or reptin XREF_BIBR .	A recent study indicates that the FHIT protein, a known tumor suppressor, which like HINT1 is a member of the HIT family of proteins, also inhibits beta-catenin activity but does so by binding directly to the C-terminus of beta-catenin rather than to pontin or reptin XREF_BIBR.	6	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FHIT	FHIT	FHIT	beta-catenin	beta-catenin	beta-catenin	6	7	29	30
[ XREF_BIBR ] Some studies strongly suggest that the interaction of FHIT with MDM2 blocks the interaction of MDM2 with p53 , thus enhancing the stability of p53 .	[XREF_BIBR] Some studies strongly suggest that the interaction of FHIT with MDM2 blocks the interaction of MDM2 with p53, thus enhancing the stability of p53.	9	19	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FHIT	FHIT	FHIT	MDM2	MDM2	MDM2	11	12	18	19
The inhibitory activity of sFRP3 appears to be specific , since sFRP3 blocks WNT-1 and WNT-8 signaling in both X laevis embryos and a mammalian cell line , but not Wnt-3A or -5 A signaling .	The inhibitory activity of sFRP3 appears to be specific, since sFRP3 blocks WNT-1 and WNT-8 signaling in both X laevis embryos and a mammalian cell line, but not Wnt-3A or -5 A signaling.	11	16	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	sFRP3	sFRP3	sFRP3	WNT-1	WNT-1	WNT-1	11	12	13	14
Fiz1 suppressed NRL- but not CRX mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells .	Fiz1 suppressed NRL- but not CRX mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells.	0	7	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Fiz1	Fiz1	Fiz1	CRX	CRX	CRX	0	1	5	6
Our results suggest a pathway in which CAL can arrest plasma membrane trafficking of DeltaF508 CFTR in the ER through binding .	Our results suggest a pathway in which CAL can arrest plasma membrane trafficking of DeltaF508 CFTR in the ER through binding.	7	18	arrest	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	7	8	15	16
Interestingly , GOPC promotes the lysosomal targeting of CFTR and Muc3 but promotes cell surface targeting of receptors such as Frizzled .	Interestingly, GOPC promotes the lysosomal targeting of CFTR and Muc3 but promotes cell surface targeting of receptors such as Frizzled.	2	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GOPC	GOPC	GOPC	CFTR	CFTR	CFTR	2	3	8	9
Several lines of evidence presented here support the contention that MARCH2 plays a role in the CAL complex mediated degradation of CFTR : ( 1 ) MARCH2 co-localized with and interacts with the CAL complex .	Several lines of evidence presented here support the contention that MARCH2 plays a role in the CAL complex mediated degradation of CFTR : (1) MARCH2 co-localized with and interacts with the CAL complex.	16	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	16	17	21	22
Cotransfection of CAL with CFTR reduced CFTR currents and surface expression of CFTR .	Cotransfection of CAL with CFTR reduced CFTR currents and surface expression of CFTR.	0	13	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	2	3	12	13
PIST has been described to induce targeting of the CFTR from the TGN to lysosomes , thereby reducing cellular CFTR levels XREF_BIBR , XREF_BIBR , XREF_BIBR .	PIST has been described to induce targeting of the CFTR from the TGN to lysosomes, thereby reducing cellular CFTR levels XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	10	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIST	PIST	PIST	CFTR	CFTR	CFTR	0	1	9	10
Finally , we tested whether MARCH2 is required for CAL mediated degradation of CFTR .	Finally, we tested whether MARCH2 is required for CAL mediated degradation of CFTR.	9	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	9	10	13	14
Overexpression of CAL reduces CFTR chloride currents in mammalian cells and decreases expression , rate of insertion and half-life of CFTR in the plasma membrane .	Overexpression of CAL reduces CFTR chloride currents in mammalian cells and decreases expression, rate of insertion and half-life of CFTR in the plasma membrane.	0	6	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	Overexpression of CAL	cal	CFTR	CFTR	cftr	2	3	4	5
However , if a corrector combination increases the cell surface stability of DeltaF508 CFTR by reducing its binding affinity to CAL , it is possible that the effects of stabilizing peptides that competitively inhibit CAL mediated degradation of DeltaF508 CFTR , such as kCAL1 , may be reduced as well .	However, if a corrector combination increases the cell surface stability of DeltaF508 CFTR by reducing its binding affinity to CAL, it is possible that the effects of stabilizing peptides that competitively inhibit CAL mediated degradation of DeltaF508 CFTR, such as kCAL1, may be reduced as well.	33	43	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	34	35	39	40
The cystic fibrosis transmembrane conductance regulator ( CFTR )-interacting protein , CFTR associated ligand ( CAL ) down-regulates total and cell surface CFTR by targeting CFTR for degradation in the lysosome .	The cystic fibrosis transmembrane conductance regulator (CFTR)-interacting protein, CFTR associated ligand (CAL) down-regulates total and cell surface CFTR by targeting CFTR for degradation in the lysosome.	13	23	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	15	16	22	23
To test the hypothesis that inhibition of the binding site could also reverse CAL mediated suppression of CFTR , a three-dimensional homology model of the CAL.CFTR complex was constructed and used to generate a CAL mutant whose binding pocket is correctly folded but has lost its ability to bind CFTR .	To test the hypothesis that inhibition of the binding site could also reverse CAL mediated suppression of CFTR, a three-dimensional homology model of the CAL.CFTR complex was constructed and used to generate a CAL mutant whose binding pocket is correctly folded but has lost its ability to bind CFTR.	13	18	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	13	14	17	18
Our data confirm that CAL knockdown in DeltaF508-CFBE cells increases the immature B band and mature C band of DeltaF508 CFTR to statistically significant levels ( XREF_FIG ) .	Our data confirm that CAL knockdown in DeltaF508-CFBE cells increases the immature B band and mature C band of DeltaF508 CFTR to statistically significant levels (XREF_FIG).	4	21	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	4	5	20	21
How the binding to Golgi localized CAL complexes promotes the lysosomal targeting of CFTR is , however , still unknown .	How the binding to Golgi localized CAL complexes promotes the lysosomal targeting of CFTR is, however, still unknown.	6	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	6	7	13	14
CAL also mediates degradation of wild-type CFTR , targeting it to lysosomes following endocytosis .	CAL also mediates degradation of wild-type CFTR, targeting it to lysosomes following endocytosis.	0	7	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	0	1	6	7
We showed previously that CAL reduces the half-life of CFTR at the cell surface .	We showed previously that CAL reduces the half-life of CFTR at the cell surface.	4	10	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	4	5	9	10
These data indicate the association of ubiquitin E3 ligases MARCH2 with the CAL complex and suggest a possible role of MARCH2 in the CAL mediated lysosomal degradation of CFTR .	These data indicate the association of ubiquitin E3 ligases MARCH2 with the CAL complex and suggest a possible role of MARCH2 in the CAL mediated lysosomal degradation of CFTR.	20	29	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	23	24	28	29
Taken together , these data suggest that the recruitment of the E3 ubiquitin ligase MARCH2 to the CAL complex and subsequent ubiquitination of CFTR are responsible for the CAL mediated lysosomal degradation of mature CFTR .	Taken together, these data suggest that the recruitment of the E3 ubiquitin ligase MARCH2 to the CAL complex and subsequent ubiquitination of CFTR are responsible for the CAL mediated lysosomal degradation of mature CFTR.	27	35	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	28	29	34	35
Since CAL mediates post-endocytic degradation of CFTR , the low underlying affinity of the interaction may be essential for CFTR to avoid a potentially fatal interaction through many rounds of endocytic recycling .	Since CAL mediates post-endocytic degradation of CFTR, the low underlying affinity of the interaction may be essential for CFTR to avoid a potentially fatal interaction through many rounds of endocytic recycling.	1	7	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	1	2	6	7
Importantly , bafilomycin A1 reverses CAL mediated CFTR degradation .	Importantly, bafilomycin A1 reverses CAL mediated CFTR degradation.	4	8	mediated	Positive_early_activation	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	5	6	7	8
Importantly , TC10Q75L reverses CAL mediated CFTR degradation , suggesting that TC10Q75L inhibits CAL mediated degradation of CFTR .	Importantly, TC10Q75L reverses CAL mediated CFTR degradation, suggesting that TC10Q75L inhibits CAL mediated degradation of CFTR.	3	7	mediated	Positive_early_activation	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	4	5	6	7
We have shown that a structurally conservative mutation of the CAL binding pocket abrogates CAL mediated degradation of CFTR .	We have shown that a structurally conservative mutation of the CAL binding pocket abrogates CAL mediated degradation of CFTR.	13	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	14	15	18	19
Previously , we have shown that bafilomycin A1 inhibits CAL mediated lysosomal degradation of CFTR [ XREF_BIBR , XREF_BIBR ] .	Previously, we have shown that bafilomycin A1 inhibits CAL mediated lysosomal degradation of CFTR [XREF_BIBR, XREF_BIBR].	8	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	9	10	14	15
CAL was also reported to regulate the expression of mature CFTR , because co-expression of CAL with CFTR in COS-7 cells causes a dose dependent reduction in mature CFTR .	CAL was also reported to regulate the expression of mature CFTR, because co-expression of CAL with CFTR in COS-7 cells causes a dose dependent reduction in mature CFTR.	13	29	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	co-expression of CAL	cal	CFTR	CFTR	cftr	15	16	28	29
A previous study reported that CAL knockdown enhanced DeltaF508 CFTR maturation and chloride currents .	A previous study reported that CAL knockdown enhanced DeltaF508 CFTR maturation and chloride currents.	5	10	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	5	6	9	10
Co-expression of CAL enhances the degradation of CFTR .	Co-expression of CAL enhances the degradation of CFTR.	0	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	Co-expression of CAL	cal	CFTR	CFTR	cftr	2	3	7	8
Additionally , we have also shown that the mature cell surface DeltaF508 CFTR produced by CAL inhibition is functional .	Additionally, we have also shown that the mature cell surface DeltaF508 CFTR produced by CAL inhibition is functional.	7	18	produced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	15	16	12	13
Previously , silencing of CAL and STX6 in a CF bronchial epithelial cell line ( CFBE-CFTR ) was shown to increase the abundance of CFTR protein [ XREF_BIBR - XREF_BIBR ] .	Previously, silencing of CAL and STX6 in a CF bronchial epithelial cell line (CFBE-CFTR) was shown to increase the abundance of CFTR protein [XREF_BIBR - XREF_BIBR].	2	25	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	4	5	24	25
Syntaxin 6 and CAL Mediate the Degradation of the Cystic Fibrosis Transmembrane Conductance Regulator .	Syntaxin 6 and CAL Mediate the Degradation of the Cystic Fibrosis Transmembrane Conductance Regulator.	0	14	Mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	Cystic Fibrosis Transmembrane Conductance Regulator	Cystic Fibrosis Transmembrane Conductance Regulator	Cystic Fibrosis Transmembrane Conductance Regulator	3	4	9	14
Our lab has previously shown that CAL associates with the Golgi apparatus and reduces cell surface WT CFTR through promotion of lysosomal degradation [ XREF_BIBR , XREF_BIBR ] .	Our lab has previously shown that CAL associates with the Golgi apparatus and reduces cell surface WT CFTR through promotion of lysosomal degradation [XREF_BIBR, XREF_BIBR].	6	18	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	6	7	17	18
In order to elucidate the mechanism by which CAL knockdown causes the production of mature cell surface DeltaF508 CFTR , we selected a set of chaperone proteins for assessment that are known to interact with both WT CFTR and DeltaF508 CFTR .	In order to elucidate the mechanism by which CAL knockdown causes the production of mature cell surface DeltaF508 CFTR, we selected a set of chaperone proteins for assessment that are known to interact with both WT CFTR and DeltaF508 CFTR.	8	19	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	8	9	18	19
RNA silencing of CAL or STX6 increases the production of mature CFTR , whereas overexpression of CAL or STX6 reduces CFTR abundance [ XREF_BIBR - XREF_BIBR ] .	RNA silencing of CAL or STX6 increases the production of mature CFTR, whereas overexpression of CAL or STX6 reduces CFTR abundance [XREF_BIBR - XREF_BIBR].	1	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	3	4	11	12
GOPC , a coiled-coil motif and PDZ containing protein , negatively regulates CFTR , mutations in which result in cystic fibrosis [ XREF_BIBR ] .	GOPC, a coiled-coil motif and PDZ containing protein, negatively regulates CFTR, mutations in which result in cystic fibrosis [XREF_BIBR].	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GOPC	GOPC	GOPC	CFTR	CFTR	CFTR	0	1	12	13
Because overexpression of myc-CAL alone is already known to reduce the steady-state levels of CFTR protein , we next examined whether the overexpression of STX6 by itself is capable of reducing the amount of CFTR protein .	Because overexpression of myc-CAL alone is already known to reduce the steady-state levels of CFTR protein, we next examined whether the overexpression of STX6 by itself is capable of reducing the amount of CFTR protein.	1	15	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myc-CAL	overexpression of myc-CAL	myc-cal	CFTR	CFTR	cftr	3	4	14	15
Through its association with Cdc2 , GADD45 disrupts the interactions of Cdc2 with cyclin B1 and , thus , may induce G 2 / M arrest [ XREF_BIBR ] .	Through its association with Cdc2, GADD45 disrupts the interactions of Cdc2 with cyclin B1 and, thus, may induce G 2 / M arrest [XREF_BIBR].	6	20	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GADD45	GADD45	GADD45	Cdc2	Cdc2	Cdc2	6	7	11	12
Therefore , GADD45 inhibition of Cdc2 kinase activity through alteration of cyclin B1 subcellular localization may be an essential step in the GADD45 induced cell cycle G2-M arrest and growth suppression .	Therefore, GADD45 inhibition of Cdc2 kinase activity through alteration of cyclin B1 subcellular localization may be an essential step in the GADD45 induced cell cycle G2-M arrest and growth suppression.	2	7	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GADD45	GADD45	GADD45	Cdc2	Cdc2	Cdc2	2	3	5	6
By inverting the two annotated negated expressions , we get the positive expression : Gadd45 expression suppresses Cdc2 and Cyclin B1 activity and thus the MIM fact can be inferred from these negated expressions .	By inverting the two annotated negated expressions, we get the positive expression : Gadd45 expression suppresses Cdc2 and Cyclin B1 activity and thus the MIM fact can be inferred from these negated expressions.	14	21	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Gadd45	Gadd45 expression	gadd45	Cdc2	Cdc2	cdc2	14	15	17	18
The Cdc2 binding domain of Gadd45 is also required for Gadd45 inhibition of Cdc2 kinase activity .	The Cdc2 binding domain of Gadd45 is also required for Gadd45 inhibition of Cdc2 kinase activity.	10	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Gadd45	Gadd45	Gadd45	Cdc2	Cdc2	Cdc2	10	11	13	14
Recent findings indicate that Gadd45 interacts with Cdc2 protein and inhibits Cdc2 kinase activity .	Recent findings indicate that Gadd45 interacts with Cdc2 protein and inhibits Cdc2 kinase activity.	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Gadd45	Gadd45	Gadd45	Cdc2	Cdc2	Cdc2	4	5	11	12
GADD45A and BTG2 are two major inhibitors of CDK1 , which have been implicated in breast tumor formation .	GADD45A and BTG2 are two major inhibitors of CDK1, which have been implicated in breast tumor formation.	0	13	are two major inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	GADD45A	GADD45A	GADD45A	CDK1	CDK1	CDK1	0	1	8	9
GADD45 proteins have been shown to interact with and inhibit the kinase activity of CDK1 [ XREF_BIBR , XREF_BIBR ] .	GADD45 proteins have been shown to interact with and inhibit the kinase activity of CDK1 [XREF_BIBR, XREF_BIBR].	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GADD45	GADD45	GADD45	CDK1	CDK1	CDK1	0	1	14	15
A previous report described GADD45A inhibited Cdc2 kinase and induced G2/M arrest 29 .	A previous report described GADD45A inhibited Cdc2 kinase and induced G2/M arrest 29.	4	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GADD45A	GADD45A	GADD45A	Cdc2	Cdc2	Cdc2	4	5	6	7
In addition , GADD45 inhibition of Cdc2 kinase activity was compared with Myd118 and CR6 , two other members of the GADD45 family .	In addition, GADD45 inhibition of Cdc2 kinase activity was compared with Myd118 and CR6, two other members of the GADD45 family.	3	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GADD45	GADD45	GADD45	Cdc2	Cdc2	Cdc2	3	4	6	7
7 The 14-3-3 protein binds to and inhibits the phosphatase activity of Cdc25 , whereas GADD45 attenuates the activity of mitotic cdc2 ( cdk1 ) kinase by sequestering its cyclin partner , cyclin B. 8 Activity of cdk1 is also regulated by two checkpoint kinases Chek1 and Wee1 .	7 The 14-3-3 protein binds to and inhibits the phosphatase activity of Cdc25, whereas GADD45 attenuates the activity of mitotic cdc2 (cdk1) kinase by sequestering its cyclin partner, cyclin B. 8 Activity of cdk1 is also regulated by two checkpoint kinases Chek1 and Wee1.	15	22	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GADD45	GADD45	GADD45	cdc2	cdc2	cdc2	15	16	21	22
Evidence has emerged that GADD45 , a cell cycle regulated nuclear protein , disrupts the interactions of Cdc2 with cyclin B1 and that GADD45 may thus induce G2/M arrest .	Evidence has emerged that GADD45, a cell cycle regulated nuclear protein, disrupts the interactions of Cdc2 with cyclin B1 and that GADD45 may thus induce G2/M arrest.	4	18	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GADD45	GADD45	GADD45	Cdc2	Cdc2	Cdc2	4	5	17	18
While inhibitory phosphorylation of Cdc2 and suppression of cyclin B1 levels are known to be involved in G2 delays after genotoxic stress , Gadd45 has now been found to directly inhibit the activity of Cdc2 and Cyclin B1 complex , while it had no appreciable effect on Cdk2 / Cyclin E activity even at very high levels of Gadd45 .	While inhibitory phosphorylation of Cdc2 and suppression of cyclin B1 levels are known to be involved in G2 delays after genotoxic stress, Gadd45 has now been found to directly inhibit the activity of Cdc2 and Cyclin B1 complex, while it had no appreciable effect on Cdk2 / Cyclin E activity even at very high levels of Gadd45.	23	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Gadd45	Gadd45	Gadd45	Cdc2	Cdc2	Cdc2	23	24	34	35
CDK1 is inhibited by the tumor suppressor proteins , GADD45A and BTG2 .	CDK1 is inhibited by the tumor suppressor proteins, GADD45A and BTG2.	0	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GADD45A	GADD45A	GADD45A	CDK1	CDK1	CDK1	9	10	0	1
FPR1 activates MAPK p38 which prevents GRK2 inactivation of FPR1 while FPR2 activates Erk which activates GRK2 and promotes FPR1 internalization .	FPR1 activates MAPK p38 which prevents GRK2 inactivation of FPR1 while FPR2 activates Erk which activates GRK2 and promotes FPR1 internalization.	6	10	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GRK2	GRK2	GRK2	FPR1	FPR1	FPR1	6	7	9	10
This p38 mediated phosphorylation prevented GRK2 binding to the same receptor , thus inhibiting GRK2 mediated FPR1 desensitization .	This p38 mediated phosphorylation prevented GRK2 binding to the same receptor, thus inhibiting GRK2 mediated FPR1 desensitization.	13	17	mediated	Positive_early_activation	Negative_activation	Negative_activation	GRK2	GRK2	GRK2	FPR1	FPR1	FPR1	14	15	16	17
GFRP inhibits GCH1 by a direct binding mechanism that requires BH4 at the interface between the two proteins .	GFRP inhibits GCH1 by a direct binding mechanism that requires BH4 at the interface between the two proteins.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GFRP	GFRP	GFRP	GCH1	GCH1	GCH1	0	1	2	3
In vitro , GFRP inhibits GTPCH-1 activity in the presence of BH 4 by forming a complex with GTPCH-1 .	In vitro, GFRP inhibits GTPCH-1 activity in the presence of BH 4 by forming a complex with GTPCH-1.	1	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GFRP	GFRP	GFRP	GTPCH-1	GTPCH-1	GTPCH-1	3	4	5	6
Crystal structures of the GTPCH-1 and GFRP complex have shown that BH 4 is bound at the interface of these two proteins , and enzymatic studies have shown that BH 4 promotes inhibition of GTPCH-1 by GFRP in a negative feedback fashion XREF_BIBR .	Crystal structures of the GTPCH-1 and GFRP complex have shown that BH 4 is bound at the interface of these two proteins, and enzymatic studies have shown that BH 4 promotes inhibition of GTPCH-1 by GFRP in a negative feedback fashion XREF_BIBR.	31	42	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	GFRP	GFRP	GFRP	GTPCH-1	GTPCH-1	GTPCH-1	36	37	34	35
Agents that disrupt the binding of GTPCH-1 and GFRP might therefore have therapeutic potential because they would reduce GFRP inhibition of GTPCH-1 and enhance intracellular BH 4 production .	Agents that disrupt the binding of GTPCH-1 and GFRP might therefore have therapeutic potential because they would reduce GFRP inhibition of GTPCH-1 and enhance intracellular BH 4 production.	18	22	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GFRP	GFRP	GFRP	GTPCH-1	GTPCH-1	GTPCH-1	18	19	21	22
4 We have recently demonstrated that endogenous GFRP inhibits GTPCH-1 activity , thereby limiting BH 4 levels and NO production in human endothelial cells .	4 We have recently demonstrated that endogenous GFRP inhibits GTPCH-1 activity, thereby limiting BH 4 levels and NO production in human endothelial cells.	6	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GFRP	GFRP	GFRP	GTPCH-1	GTPCH-1	GTPCH-1	7	8	9	10
While GFRP is generally considered to inhibit GTPCH-1 in the presence of BH 4 XREF_BIBR , the ubiquitously present amino acid phenylalanine reverses the inhibition of GTPCH-1 without causing the dissociation of GFRP in vitro .	While GFRP is generally considered to inhibit GTPCH-1 in the presence of BH 4 XREF_BIBR, the ubiquitously present amino acid phenylalanine reverses the inhibition of GTPCH-1 without causing the dissociation of GFRP in vitro.	1	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GFRP	GFRP	GFRP	GTPCH-1	GTPCH-1	GTPCH-1	1	2	7	8
Since Grb10 has been demonstrated to negatively regulate IGF-1 and IGF-1R signaling , [ XREF_BIBR ] we then determined whether catalpol mediated down-regulation of Grb10 expression was coupled to up-regulation of IGF-1 and IGF-1R signaling in diabetic kidneys .	Since Grb10 has been demonstrated to negatively regulate IGF-1 and IGF-1R signaling, [XREF_BIBR] we then determined whether catalpol mediated down-regulation of Grb10 expression was coupled to up-regulation of IGF-1 and IGF-1R signaling in diabetic kidneys.	1	11	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Grb10	Grb10	Grb10	IGF-1R	IGF-1R	IGF-1R	1	2	10	11
Furthermore , simultaneous loss of Nedd4 and Grb10 restores cell surface IGF-1R , indicating that Nedd4 acts to oppose the function of the negative regulator Grb10 .	Furthermore, simultaneous loss of Nedd4 and Grb10 restores cell surface IGF-1R, indicating that Nedd4 acts to oppose the function of the negative regulator Grb10.	3	12	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Grb10	loss of Nedd4 and Grb10	grb10	IGF-1R	IGF-1R	igf-1r	7	8	11	12
[ XREF_BIBR ] It has been shown that Grb10 inhibits IGF-1 and IGF-1R signaling via blocking the access of phosphatase to the activated IGF-I receptor .	[XREF_BIBR] It has been shown that Grb10 inhibits IGF-1 and IGF-1R signaling via blocking the access of phosphatase to the activated IGF-I receptor.	8	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Grb10	Grb10	Grb10	IGF-1R	IGF-1R	IGF-1R	8	9	12	13
Previous studies have also shown that Grb10 is an inhibitor of both IGF-1R and IR signaling .	Previous studies have also shown that Grb10 is an inhibitor of both IGF-1R and IR signaling.	6	15	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Grb10	Grb10	Grb10	IGF-1R	IGF-1R	IGF-1R	6	7	12	13
Moreover , introduction of CD26 into Cos-1 cells was accompanied by the up-regulation of cell growth , while inclusion of recombinant GPC3 in the media reduced the growth of CD26 transfected Cos-1 cells , drastically .	Moreover, introduction of CD26 into Cos-1 cells was accompanied by the up-regulation of cell growth, while inclusion of recombinant GPC3 in the media reduced the growth of CD26 transfected Cos-1 cells, drastically.	18	30	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GPC3	GPC3	GPC3	CD26	CD26	CD26	21	22	29	30
Glypican-3 , one of the six mammalian glypicans ( heparin sulphate proteoglycans attached to the plasma membrane via a glycosyl phosphatidyl-inositol linkage ) , has been shown to inhibit DPP-4 activity in hepatocarcinoma cells and hematopoietic stem and progenitor cells [ XREF_BIBR - XREF_BIBR ] .	Glypican-3, one of the six mammalian glypicans (heparin sulphate proteoglycans attached to the plasma membrane via a glycosyl phosphatidyl-inositol linkage), has been shown to inhibit DPP-4 activity in hepatocarcinoma cells and hematopoietic stem and progenitor cells [XREF_BIBR - XREF_BIBR].	0	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Glypican-3	Glypican-3	Glypican-3	DPP-4	DPP-4	DPP-4	0	1	29	30
Since Grb10 has been shown to inhibit IR signaling in adipocytes via binding and inhibition of the catalytic domains of IR , we postulated that Grb10 might mediate a similar inhibitory action on the c-kit receptor in HSCs , since c-kit activation induces Akt and mTORC1 signaling in HSCs .	Since Grb10 has been shown to inhibit IR signaling in adipocytes via binding and inhibition of the catalytic domains of IR, we postulated that Grb10 might mediate a similar inhibitory action on the c-kit receptor in HSCs, since c-kit activation induces Akt and mTORC1 signaling in HSCs.	1	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Grb10	Grb10	Grb10	IR	IR	IR	1	2	7	8
In addition to inhibiting insulin receptor and IGF1R kinase activity by directly binding to the receptors , GRB10 can also negatively regulate insulin and IGF1 signaling by mediating insulin receptor and IGF1R degradation through ubiquitination .	In addition to inhibiting insulin receptor and IGF1R kinase activity by directly binding to the receptors, GRB10 can also negatively regulate insulin and IGF1 signaling by mediating insulin receptor and IGF1R degradation through ubiquitination.	17	30	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GRB10	GRB10	GRB10	insulin receptor	insulin receptor	insulin receptor	17	18	28	30
Conversely , GATA3 inhibits TBET and IFN-.	Conversely, GATA3 inhibits TBET and IFN-.	2	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GATA3	GATA3	GATA3	TBET	TBET	TBET	2	3	4	5
Interestingly , Gata3 deletion during Th2 cell differentiation results in an IL-12 and STAT4 and IFNgamma and T-bet independent IFNgamma production , which is mediated by Runx3 and Eomesodermin ( Eomes ) pathway XREF_BIBR , XREF_BIBR - XREF_BIBR , XREF_BIBR .	Interestingly, Gata3 deletion during Th2 cell differentiation results in an IL-12 and STAT4 and IFNgamma and T-bet independent IFNgamma production, which is mediated by Runx3 and Eomesodermin (Eomes) pathway XREF_BIBR, XREF_BIBR - XREF_BIBR, XREF_BIBR.	2	21	production	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	Gata3	Gata3	Gata3	T-bet	T-bet	T-bet	2	3	17	18
Fyn phosphorylation negatively regulates ITCH function .	Fyn phosphorylation negatively regulates ITCH function.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Fyn	Fyn phosphorylation	fyn	ITCH	ITCH	itch	0	1	4	5
Recently , Fyn , a Src family kinase was shown to negatively regulate Itch by tyrosine phosphorylation , impairing its ubiquitinating activity [ XREF_BIBR ] .	Recently, Fyn, a Src family kinase was shown to negatively regulate Itch by tyrosine phosphorylation, impairing its ubiquitinating activity [XREF_BIBR].	2	14	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Fyn	Fyn	Fyn	Itch	Itch	Itch	2	3	13	14
GATA-2 and GATA-3 are also found to inhibit the transcriptional activities of C/EBPalpha and C/EBPbeta through physical interactions , thus offering an additional mechanism by which GATA-2/3 inhibit adipogenesis and PPARgamma expression [ XREF_BIBR ] .	GATA-2 and GATA-3 are also found to inhibit the transcriptional activities of C/EBPalpha and C/EBPbeta through physical interactions, thus offering an additional mechanism by which GATA-2/3 inhibit adipogenesis and PPARgamma expression [XREF_BIBR].	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GATA-3	GATA-3	GATA-3	C/EBPalpha	C/EBPalpha	C/EBPalpha	2	3	12	13
For example , it is not clear whether GATA-3 can prevent C/EBPalpha from downregulating Notch and E protein expression [ XREF_BIBR ] , which would independently be required for full T-cell development .	For example, it is not clear whether GATA-3 can prevent C/EBPalpha from downregulating Notch and E protein expression [XREF_BIBR], which would independently be required for full T-cell development.	8	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GATA-3	GATA-3	GATA-3	C/EBPalpha	C/EBPalpha	C/EBPalpha	8	9	11	12
Previous studies have revealed that Gata2 represses the transcriptional activity of Spi1 through the inhibition of the interaction between Spi1 and its cofactor , c-Jun .	Previous studies have revealed that Gata2 represses the transcriptional activity of Spi1 through the inhibition of the interaction between Spi1 and its cofactor, c-Jun.	5	12	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Gata2	Gata2	Gata2	Spi1	Spi1	Spi1	5	6	11	12
Here we report that the Src family kinases ( SFKs ) Fyn and Yes act downstream of PrP-1 to prevent the endocytosis and degradation of E-cadherin and beta-catenin adhesion complexes in vivo .	Here we report that the Src family kinases (SFKs) Fyn and Yes act downstream of PrP-1 to prevent the endocytosis and degradation of E-cadherin and beta-catenin adhesion complexes in vivo.	4	29	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Fyn	Fyn	Fyn	beta-catenin	beta-catenin	beta-catenin	11	12	27	28
Luciferase ( Luc ) assays using artificial reporters showed that GFI1 repressed ETS1 mediated transcriptional activation and ETS1 repressed GFI1 mediated transcriptional activation , in a dose dependent manner .	Luciferase (Luc) assays using artificial reporters showed that GFI1 repressed ETS1 mediated transcriptional activation and ETS1 repressed GFI1 mediated transcriptional activation, in a dose dependent manner.	10	13	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GFI1	GFI1	GFI1	ETS1	ETS1	ETS1	10	11	12	13
140 Interestingly , although GSK-3beta negatively regulates beta-catenin , treatment with an inhibitor of GSK-3beta ( SB216763 ) in combination with imatinib was found to decrease CML stem cells in vitro ( as assessed by leukemic LTCIC ) , but this might be mediated by effects on other substrates such as p27 .	140 Interestingly, although GSK-3beta negatively regulates beta-catenin, treatment with an inhibitor of GSK-3beta (SB216763) in combination with imatinib was found to decrease CML stem cells in vitro (as assessed by leukemic LTCIC), but this might be mediated by effects on other substrates such as p27.	4	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	7	8
Importantly , inhibition of GSK-3beta , a key component of the beta-catenin degradation complex determining the fate of beta-catenin , in CF mice and Caco-2 cells rescued beta-catenin activity and suppressed the CFTR dysfuction induced NF-kappaB/COX-2/PGE 2 activity , suggesting that beta-catenin may serve as an inhibitor of the NF-kappaB-mediated inflammatory response .	Importantly, inhibition of GSK-3beta, a key component of the beta-catenin degradation complex determining the fate of beta-catenin, in CF mice and Caco-2 cells rescued beta-catenin activity and suppressed the CFTR dysfuction induced NF-kappaB/COX-2/PGE 2 activity, suggesting that beta-catenin may serve as an inhibitor of the NF-kappaB-mediated inflammatory response.	2	28	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	27	28
To further confirm that the Wnt and beta-catenin pathway may be associated with the role of LGR5 in cancer stemness , CHIR-99021 ( CT99021 ) , an inhibitor of GSK-3beta that suppresses beta-catenin degradation , was used to activate the Wnt and beta-catenin pathway in LGR5-knockdown SiHa and HeLa cells .	To further confirm that the Wnt and beta-catenin pathway may be associated with the role of LGR5 in cancer stemness, CHIR-99021 (CT99021), an inhibitor of GSK-3beta that suppresses beta-catenin degradation, was used to activate the Wnt and beta-catenin pathway in LGR5-knockdown SiHa and HeLa cells.	27	43	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	29	30	42	43
In contrast , Wnt signalling is absent in the future lens , partially because of the expression of Wnt antagonists XREF_BIBR XREF_BIBR , and active GSK3beta may mediate the degradation of both beta-catenin and Smad3 .	In contrast, Wnt signalling is absent in the future lens, partially because of the expression of Wnt antagonists XREF_BIBR XREF_BIBR, and active GSK3beta may mediate the degradation of both beta-catenin and Smad3.	24	34	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	25	26	32	33
In embryos treated with the phosphatidylinositol 3-kinase inhibitor , angiogenesis was severely inhibited , along with reduced Wnt , phosphorylated AKT and phosphorylated Gsk3b , suggesting that the remaining Gsk3b in somites could still degrade beta-catenin , resulting in decreased vascular endothelial growth factor Aa ( VegfAa ) expression .	In embryos treated with the phosphatidylinositol 3-kinase inhibitor, angiogenesis was severely inhibited, along with reduced Wnt, phosphorylated AKT and phosphorylated Gsk3b, suggesting that the remaining Gsk3b in somites could still degrade beta-catenin, resulting in decreased vascular endothelial growth factor Aa (VegfAa) expression.	27	46	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3b	Gsk3b	Gsk3b	beta-catenin	beta-catenin	beta-catenin	29	30	35	36
During Wnt activation , GSK3beta activity is inhibited , allowing beta-catenin to escape degradation and to accumulate in both cytoplasmic and nuclear compartments .	During Wnt activation, GSK3beta activity is inhibited, allowing beta-catenin to escape degradation and to accumulate in both cytoplasmic and nuclear compartments.	4	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	4	5	10	11
GSK3beta inhibition attenuates activation of the pro inflammatory transcription factor NFkappaB , and activates the immuno-modulatory transcription factor beta-catenin .	GSK3beta inhibition attenuates activation of the pro inflammatory transcription factor NFkappaB, and activates the immuno-modulatory transcription factor beta-catenin.	0	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	0	1	18	19
Since pAKT is known to phosphorylate , and thereby inhibit , GSK-3beta , and since inhibition of GSK-3beta enhances nuclear localization of beta-catenin , we sought to determine if this signal transduction pathway was suppressed in TIEG1 KO calvarial osteoblasts relative to WT controls .	Since pAKT is known to phosphorylate, and thereby inhibit, GSK-3beta, and since inhibition of GSK-3beta enhances nuclear localization of beta-catenin, we sought to determine if this signal transduction pathway was suppressed in TIEG1 KO calvarial osteoblasts relative to WT controls.	15	23	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	17	18	22	23
CHIR99021 activated Wnt signaling pathway and then initiated the differentiation of hESCs by inhibiting the GSK3beta mediated degradation of beta-catenin ; meanwhile , RA upregulated c-Kit .	CHIR99021 activated Wnt signaling pathway and then initiated the differentiation of hESCs by inhibiting the GSK3beta mediated degradation of beta-catenin; meanwhile, RA upregulated c-Kit.	13	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	15	16	19	20
P130 is a transcription factor associated with GSK3beta which sequesters beta-catenin in an inactive form as a P130 , GSK3beta , beta , and catenin complex in the cell nucleus [ XREF_BIBR ] .	P130 is a transcription factor associated with GSK3beta which sequesters beta-catenin in an inactive form as a P130, GSK3beta, beta, and catenin complex in the cell nucleus [XREF_BIBR].	5	14	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	10	11
30 However , suppression of GSK-3beta through activation of the Wnt signaling pathway allows beta-catenin to translocate to the nucleus where it binds and inhibits the transcriptional repressors TCF/LEF , resulting in transcription of genes associated with cell proliferation , such as c-myc and cyclin D1 .	30 However, suppression of GSK-3beta through activation of the Wnt signaling pathway allows beta-catenin to translocate to the nucleus where it binds and inhibits the transcriptional repressors TCF/LEF, resulting in transcription of genes associated with cell proliferation, such as c-myc and cyclin D1.	3	16	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	14	15
miR-26a-mediated reduction of GSK-3beta resulted in activation of beta-catenin and induction of several downstream genes including c-Myc , cyclinD1 , and peroxisome proliferator activated receptor delta .	miR-26a-mediated reduction of GSK-3beta resulted in activation of beta-catenin and induction of several downstream genes including c-Myc, cyclinD1, and peroxisome proliferator activated receptor delta.	1	10	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
This mechanism is distinct from GSK3beta mediated beta-catenin degradation and is conserved in humans .	This mechanism is distinct from GSK3beta mediated beta-catenin degradation and is conserved in humans.	3	8	mediated	Positive_early_activation	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	5	6	7	8
IGFBP6 knockdown increased GSK3beta phosphorylation and cyclin D1 expression and induced beta-catenin accumulation .	IGFBP6 knockdown increased GSK3beta phosphorylation and cyclin D1 expression and induced beta-catenin accumulation.	0	12	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	IGFBP6 knockdown increased GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
Interestingly , non canonical signaling has been shown to exert an antagonistic effect on canonical signaling , with Wnt5a promoting GSK3beta independent degradation of beta-catenin [ XREF_BIBR ] and competing with Wnt3a for binding to the receptor complex [ XREF_BIBR ] .	Interestingly, non canonical signaling has been shown to exert an antagonistic effect on canonical signaling, with Wnt5a promoting GSK3beta independent degradation of beta-catenin [XREF_BIBR] and competing with Wnt3a for binding to the receptor complex [XREF_BIBR].	20	26	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	20	21	24	25
This protein is an inhibitor of GSK-3beta , thus preventing the degradation of beta-catenin .	This protein is an inhibitor of GSK-3beta, thus preventing the degradation of beta-catenin.	4	14	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	13	14
XREF_BIBR GSK3beta increases the degradation of beta-catenin through the ubiquitin-proteasome pathway via phosphorylation of three specific amino acids , ie , Ser33 , Ser3 , and Thr41 .	XREF_BIBR GSK3beta increases the degradation of beta-catenin through the ubiquitin-proteasome pathway via phosphorylation of three specific amino acids, ie, Ser33, Ser3, and Thr41.	0	7	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
These results suggest that canonical Wnt and beta-catenin signaling , activated by inhibition of GSK3beta , may positively regulate the OPC state and functions to block the transition to oligodendrocytes 27 .	These results suggest that canonical Wnt and beta-catenin signaling, activated by inhibition of GSK3beta, may positively regulate the OPC state and functions to block the transition to oligodendrocytes 27.	7	15	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	14	15	7	8
Our data show that NDRG2 introduction into SW620 cells induces a decrease in GSK-3beta phosphorylation , which increases its kinase activity ( XREF_FIG ) and subsequently induces beta-catenin downregulation ( XREF_FIG and XREF_FIG ) .	Our data show that NDRG2 introduction into SW620 cells induces a decrease in GSK-3beta phosphorylation, which increases its kinase activity (XREF_FIG) and subsequently induces beta-catenin downregulation (XREF_FIG and XREF_FIG).	4	28	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	NDRG2 introduction into SW620 cells induces a decrease in GSK-3beta phosphorylation	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	13	14	27	28
On the other hand , treatment with LiCl , a potent inhibitor of GSK3beta dependent degradation of beta-catenin resulted in a substantial and comparable induction of the transcriptional response in all cases .	On the other hand, treatment with LiCl, a potent inhibitor of GSK3beta dependent degradation of beta-catenin resulted in a substantial and comparable induction of the transcriptional response in all cases.	13	18	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	13	14	17	18
The suppressive activity of RBBP7 may be mediated by up-regulation of GSK-3beta , which attenuates beta-catenin and TCF signaling [ XREF_BIBR ] .	The suppressive activity of RBBP7 may be mediated by up-regulation of GSK-3beta, which attenuates beta-catenin and TCF signaling [XREF_BIBR].	9	18	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	11	12	15	16
We also demonstrated that scratching caused the inhibitory phosphorylation of GSK3beta probably through the PKC signaling pathway , and resulted in beta-catenin accumulation which was abolished by the GSK3beta over-expression or GF109203X , a PKC inhibitor .	We also demonstrated that scratching caused the inhibitory phosphorylation of GSK3beta probably through the PKC signaling pathway, and resulted in beta-catenin accumulation which was abolished by the GSK3beta over-expression or GF109203X, a PKC inhibitor.	21	30	abolished	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta over-expression	gsk3beta	beta-catenin	beta-catenin	beta-catenin	28	29	21	22
Several groups have shown that suppressing GSK-3beta , the protein that targets beta-catenin for proteosomal degradation , also mitigates AKI .	Several groups have shown that suppressing GSK-3beta, the protein that targets beta-catenin for proteosomal degradation, also mitigates AKI.	5	18	targets	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	12	13
In a mouse model of mammary tumorigenesis , inhibition of GSK3beta by overexpression of kinase-inactive GSK3beta in mouse mammary glands promotes mammary tumorigenesis ; this is accompanied by the over-expression of beta-catenin and cyclin D1 [ XREF_BIBR ] , supporting that GSK3beta inhibition causes dysregulation of the Wnt and beta-catenin pathway which results in tumor promotion .	In a mouse model of mammary tumorigenesis, inhibition of GSK3beta by overexpression of kinase-inactive GSK3beta in mouse mammary glands promotes mammary tumorigenesis; this is accompanied by the over-expression of beta-catenin and cyclin D1 [XREF_BIBR], supporting that GSK3beta inhibition causes dysregulation of the Wnt and beta-catenin pathway which results in tumor promotion.	41	50	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	41	42	49	50
When the Wnt pathway is activated , cytoplasmic beta-catenin is no longer degraded by GSK3beta , and large amount of beta-catenin translocates to the nucleus , where it interacts with lymphoid enhancer and T-cell transcription factors ( TCF/LEF ) and cAMP response element binding protein binding protein ( CBP ) , thereby regulating the transcription of genes such as E-cadherin , MMP or VEGF XREF_BIBR XREF_BIBR XREF_BIBR .	When the Wnt pathway is activated, cytoplasmic beta-catenin is no longer degraded by GSK3beta, and large amount of beta-catenin translocates to the nucleus, where it interacts with lymphoid enhancer and T-cell transcription factors (TCF/LEF) and cAMP response element binding protein binding protein (CBP), thereby regulating the transcription of genes such as E-cadherin, MMP or VEGF XREF_BIBR XREF_BIBR XREF_BIBR.	7	15	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	14	15	8	9
Under normal circumstances , beta-catenin forms a complex with cadherins in the cell membrane , while free beta-catenin is rapidly degraded via phosphorylation by the complex of GSK-3beta , axin and adenomatous polyposis coli in the cytoplasm .	Under normal circumstances, beta-catenin forms a complex with cadherins in the cell membrane, while free beta-catenin is rapidly degraded via phosphorylation by the complex of GSK-3beta, axin and adenomatous polyposis coli in the cytoplasm.	16	28	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	27	28	17	18
The active GSK-3beta promotes proteasome dependent degradation of beta-catenin [ XREF_BIBR - XREF_BIBR ] , which downregulates the canonical Wnt and beta-catenin pathway [ XREF_BIBR ] .	The active GSK-3beta promotes proteasome dependent degradation of beta-catenin [XREF_BIBR - XREF_BIBR], which downregulates the canonical Wnt and beta-catenin pathway [XREF_BIBR].	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
Because Sef inhibits activation of Akt , and because Akt inhibits GSK3beta , which phosphorylated and inactivates beta-catenin [ XREF_BIBR ] , it is possible that reduced levels of Sef in aggressive breast tumors may result in increased Akt activation leading to decreased GSK3beta activity with subsequent increases in active and nuclear beta-catenin .	Because Sef inhibits activation of Akt, and because Akt inhibits GSK3beta, which phosphorylated and inactivates beta-catenin [XREF_BIBR], it is possible that reduced levels of Sef in aggressive breast tumors may result in increased Akt activation leading to decreased GSK3beta activity with subsequent increases in active and nuclear beta-catenin.	9	19	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	Akt inhibits GSK3beta, which phosphorylated	gsk3beta	beta-catenin	beta-catenin	beta-catenin	11	12	17	18
This includes activation of ERK and MAPK , PI3K , and CREB , upregulation of Bcl-2 , BDNF and seladin-1 as well as inhibition of GSK-3beta and dickkopf-1 ( an antagonist of the Wnt and beta-catenin signaling pathway ) , attenuation of NADPH oxidase activity and reduction of superoxide production [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	This includes activation of ERK and MAPK, PI3K, and CREB, upregulation of Bcl-2, BDNF and seladin-1 as well as inhibition of GSK-3beta and dickkopf-1 (an antagonist of the Wnt and beta-catenin signaling pathway), attenuation of NADPH oxidase activity and reduction of superoxide production [XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR].	23	69	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	25	26	35	36
Akt was also shown to phosphorylateand inactivate GSK-3beta at Ser 9 , thereby preventing GSK-3beta mediated beta-catenin degradation .	Akt was also shown to phosphorylateand inactivate GSK-3beta at Ser 9, thereby preventing GSK-3beta mediated beta-catenin degradation.	14	17	mediated	Positive_early_activation	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	14	15	16	17
Finally , we demonstrated that GSK3beta over-expression promoted the degradation of beta-catenin and abolished beta-catenin and TCF transcriptional activity that was induced by CSE in alveolar epithelial cells .	Finally, we demonstrated that GSK3beta over-expression promoted the degradation of beta-catenin and abolished beta-catenin and TCF transcriptional activity that was induced by CSE in alveolar epithelial cells.	5	18	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta over-expression	gsk3beta	beta-catenin	beta-catenin	beta-catenin	5	6	14	15
GSK-3beta also functions as a tumor suppressor , because GSK3beta can suppress the Wnt and beta-catenin pathway by phosphorylating beta-catenin [ XREF_BIBR ] .	GSK-3beta also functions as a tumor suppressor, because GSK3beta can suppress the Wnt and beta-catenin pathway by phosphorylating beta-catenin [XREF_BIBR].	9	21	suppress	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	GSK3beta	GSK3beta	gsk3beta	beta-catenin	phosphorylating beta-catenin	beta-catenin	9	10	19	20
Therefore , the re-expression of GSK-3beta in malignant cells could block Wnt and beta-catenin signaling pathway and regain epithelial junction proteins , in turn preventing cell disassociation .	Therefore, the re-expression of GSK-3beta in malignant cells could block Wnt and beta-catenin signaling pathway and regain epithelial junction proteins, in turn preventing cell disassociation.	3	15	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	re-expression of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	13	14
BIO , CHIR99021 , LY2090314 and TWS119 are GSK3beta or GSK3 inhibitors that can activate the WNT and beta-catenin signaling cascade ( XREF_TABLE ) .	BIO, CHIR99021, LY2090314 and TWS119 are GSK3beta or GSK3 inhibitors that can activate the WNT and beta-catenin signaling cascade (XREF_TABLE).	8	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	8	9	18	19
Lithium inhibition of GSK3beta increases WNT and beta-catenin , known to be associated with cancer XREF_BIBR , XREF_BIBR , XREF_BIBR .	Lithium inhibition of GSK3beta increases WNT and beta-catenin, known to be associated with cancer XREF_BIBR, XREF_BIBR, XREF_BIBR.	1	8	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
CK1alpha and GSK-3beta mediate the degradation of beta-catenin molecules by phosphorylating specific amino N terminal residues ( Ser45 by CK1alpha , and Thr41 , Ser 37 , and Ser33 by GSK-3beta in this sequential order ) , thereby marking the protein and rendering it as recognizable by beta-transducin repeat containing protein ( beta-TrCP ) , a component of the E3 ubiquitin ligase , leading to its degradation by the 26S proteasome complex .	CK1alpha and GSK-3beta mediate the degradation of beta-catenin molecules by phosphorylating specific amino N terminal residues (Ser45 by CK1alpha, and Thr41, Ser 37, and Ser33 by GSK-3beta in this sequential order), thereby marking the protein and rendering it as recognizable by beta-transducin repeat containing protein (beta-TrCP), a component of the E3 ubiquitin ligase, leading to its degradation by the 26S proteasome complex.	0	8	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
In cultured ventral telencephalic slices , where Wnt and beta-catenin signalling was activated by inhibition of Gsk3beta activity , Lef1 expression increased with an increased inhibition of this activity .	In cultured ventral telencephalic slices, where Wnt and beta-catenin signalling was activated by inhibition of Gsk3beta activity, Lef1 expression increased with an increased inhibition of this activity.	7	17	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	16	17	9	10
Fibulin-5 impedes Wnt and beta-catenin signaling by inhibiting extracellular signal regulated kinase ( ERK ) to activate glycogen synthase kinase-3 beta ( GSK3beta ) , which downregulates beta-catenin and prevents its nuclear accumulation , leading to suppression of MMP-7 and c-Myc expression .	Fibulin-5 impedes Wnt and beta-catenin signaling by inhibiting extracellular signal regulated kinase (ERK) to activate glycogen synthase kinase-3 beta (GSK3beta), which downregulates beta-catenin and prevents its nuclear accumulation, leading to suppression of MMP-7 and c-Myc expression.	20	28	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	22	23	27	28
We also examined possible point mutations in the phosphorylation sites of beta-catenin and found in one HCC sample mutation of Thr 41 ( XREF_FIG ) , which would prevent phosphorylation at the site and inactivation of beta-catenin by GSK3beta XREF_BIBR .	We also examined possible point mutations in the phosphorylation sites of beta-catenin and found in one HCC sample mutation of Thr 41 (XREF_FIG), which would prevent phosphorylation at the site and inactivation of beta-catenin by GSK3beta XREF_BIBR.	28	39	prevent	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	38	39	36	37
Both GSK-3beta and Nur77 mediate beta-catenin degradation , suggesting a role of NDRG1 in beta-catenin regulation .	Both GSK-3beta and Nur77 mediate beta-catenin degradation, suggesting a role of NDRG1 in beta-catenin regulation.	0	6	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	1	2	5	6
LiCl is widely used to repress the activity of GSK3beta , which phosphorylates and subsequently degrades cytoplasmic beta-catenin leading to activation of beta-catenin signaling .	LiCl is widely used to repress the activity of GSK3beta, which phosphorylates and subsequently degrades cytoplasmic beta-catenin leading to activation of beta-catenin signaling.	7	18	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	9	10	17	18
Active GSK3beta stimulates beta-catenin protein degradation .	Active GSK3beta stimulates beta-catenin protein degradation.	0	5	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	1	2	3	4
Wnt signaling can lead to EMT through inhibition of glycogen synthase kinase-3beta ( GSK-3beta ) mediated degradation of beta-catenin which then translocates into the nucleus to activate transcription factors involved inducing EMT associated genes .	Wnt signaling can lead to EMT through inhibition of glycogen synthase kinase-3beta (GSK-3beta) mediated degradation of beta-catenin which then translocates into the nucleus to activate transcription factors involved inducing EMT associated genes.	11	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	13	14	18	19
However , in the presence of Wnt ligand , GSK3beta is inhibited resulting in accumulation of cytoplasmic beta-catenin .	However, in the presence of Wnt ligand, GSK3beta is inhibited resulting in accumulation of cytoplasmic beta-catenin.	9	18	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	9	10	17	18
On the other hand , GSK3beta inhibition enhances beta-catenin signaling by preventing its degradation , which in turn can activate a transcriptional program for the regeneration of the damaged intestinal epithelium XREF_BIBR , XREF_BIBR .	On the other hand, GSK3beta inhibition enhances beta-catenin signaling by preventing its degradation, which in turn can activate a transcriptional program for the regeneration of the damaged intestinal epithelium XREF_BIBR, XREF_BIBR.	5	9	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	5	6	8	9
Upon binding of Wnt to the seven-transmembrane domain spanning frizzled ( Fzd ) receptor and the co-receptor lipoprotein receptor related 5/6 ( Lrp5/6 ) proteins , GSK3beta is inactivated , thereby preventing the breakdown of beta-catenin .	Upon binding of Wnt to the seven-transmembrane domain spanning frizzled (Fzd) receptor and the co-receptor lipoprotein receptor related 5/6 (Lrp5/6) proteins, GSK3beta is inactivated, thereby preventing the breakdown of beta-catenin.	26	36	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	26	27	35	36
As active GSK3beta promotes beta-catenin degradation , a reduction of GSK-3beta activity would increase cytosolic levels of beta-catenin and allow for its translocation from the cytoplasm to the nucleus XREF_BIBR , XREF_BIBR .	As active GSK3beta promotes beta-catenin degradation, a reduction of GSK-3beta activity would increase cytosolic levels of beta-catenin and allow for its translocation from the cytoplasm to the nucleus XREF_BIBR, XREF_BIBR.	1	5	promotes	Positive_activation_token_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
However , in the active state , GSK-3beta is inactivated ( by phosphorylation ) which permits beta-catenin to go into the cell nucleus which will interact with transcription factors and regulate gene expressions .	However, in the active state, GSK-3beta is inactivated (by phosphorylation) which permits beta-catenin to go into the cell nucleus which will interact with transcription factors and regulate gene expressions.	7	17	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	16	17
Inactive GSK3beta can not mediate the proteolytic degradation of beta-catenin and the resultant activation of beta-catenin-dependent genes such as cyclinD , matrix metalloproteinases , and various basement-repair proteins can mediate the cellular hyperplasia and migration aspects of EMT [ XREF_BIBR ] .	Inactive GSK3beta can not mediate the proteolytic degradation of beta-catenin and the resultant activation of beta-catenin-dependent genes such as cyclinD, matrix metalloproteinases, and various basement-repair proteins can mediate the cellular hyperplasia and migration aspects of EMT [XREF_BIBR].	0	10	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	1	2	9	10
So that RES was found to disrupt beta , catenin , and TCF complex , while did not affect the GSK-3 beta inactivation and nuclear localization of beta-catenin .	So that RES was found to disrupt beta, catenin, and TCF complex, while did not affect the GSK-3 beta inactivation and nuclear localization of beta-catenin.	20	28	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK-3 beta	GSK-3 beta	GSK-3 beta	beta-catenin	beta-catenin	beta-catenin	20	22	27	28
GSK-3beta negatively regulates beta-catenin by sequestration and promotion of its proteosome degradation .	GSK-3beta negatively regulates beta-catenin by sequestration and promotion of its proteosome degradation.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	3	4
Enlarged otic vesicles are also observed in zebrafish embryos treated during somitogenesis with a chemical activator of Wnt signaling , BIO , which inhibits glycogen synthase kinase 3beta ( GSK3beta )-mediated degradation of beta-catenin [ XREF_BIBR ] .	Enlarged otic vesicles are also observed in zebrafish embryos treated during somitogenesis with a chemical activator of Wnt signaling, BIO, which inhibits glycogen synthase kinase 3beta (GSK3beta)-mediated degradation of beta-catenin [XREF_BIBR].	29	35	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	29	30	33	34
beta-catenin is degraded by GSK3beta , an enzyme inactivated via phosphorylation of its serine 9 residue by upstream kinase Akt .	beta-catenin is degraded by GSK3beta, an enzyme inactivated via phosphorylation of its serine 9 residue by upstream kinase Akt.	0	5	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	4	5	0	1
These studies with 6-BIO indicate that GSK-3beta inhibition induces beta-catenin stabilization and the consequent activation of the canonical Wnt and beta-catenin signaling , which in turn protects neurons from the apoptotic effects of Abeta oligomers .	These studies with 6-BIO indicate that GSK-3beta inhibition induces beta-catenin stabilization and the consequent activation of the canonical Wnt and beta-catenin signaling, which in turn protects neurons from the apoptotic effects of Abeta oligomers.	6	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	9	10
Inhibitors of GSK3beta reduce the catalytic activity of GSK3beta , which allows beta-catenin to escape degradation .	Inhibitors of GSK3beta reduce the catalytic activity of GSK3beta, which allows beta-catenin to escape degradation.	6	14	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	8	9	12	13
Similarly , inhibition of GSK3beta has been shown to promote apoptosis in neuroblastoma by promoting G2/M cell cycle arrest , accumulation of beta-catenin and subsequent inhibition of NFkappaB activity .	Similarly, inhibition of GSK3beta has been shown to promote apoptosis in neuroblastoma by promoting G2/M cell cycle arrest, accumulation of beta-catenin and subsequent inhibition of NFkappaB activity.	2	23	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	4	5	22	23
A multi protein complex that includes adenomatous polyposis coli ( APC ) and glycogen synthase kinase-3 beta ( GSK3 beta ) promotes the degradation of beta-catenin thus controls the levels of free beta-catenin in cells .	A multi protein complex that includes adenomatous polyposis coli (APC) and glycogen synthase kinase-3 beta (GSK3 beta) promotes the degradation of beta-catenin thus controls the levels of free beta-catenin in cells.	13	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta	beta-catenin	beta-catenin	beta-catenin	13	17	25	26
In normal PGC development , Wnt and beta-catenin signaling is suppressed by the GSK3beta mediated active degradation of beta-catenin and the low expression of canonical Wnt molecules .	In normal PGC development, Wnt and beta-catenin signaling is suppressed by the GSK3beta mediated active degradation of beta-catenin and the low expression of canonical Wnt molecules.	10	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	13	14	18	19
miR-26a-mediated reduction of GSK-3beta results in activation of beta-catenin and induction of several downstream genes including c-Myc , cyclinD1 , and peroxisome proliferator activated receptor delta .	miR-26a-mediated reduction of GSK-3beta results in activation of beta-catenin and induction of several downstream genes including c-Myc, cyclinD1, and peroxisome proliferator activated receptor delta.	1	10	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
However , the two key kinases in Wnt signaling , GSK-3beta and CK1alpha , negatively regulate the Wnt and beta-catenin signaling pathway , and therefore can not serve as therapeutic targets for anti-tumor treatment .	However, the two key kinases in Wnt signaling, GSK-3beta and CK1alpha, negatively regulate the Wnt and beta-catenin signaling pathway, and therefore can not serve as therapeutic targets for anti-tumor treatment.	5	21	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	10	11	19	20
Furthermore , lithium chloride ( LiCl ) , an established inhibitor of GSK-3beta , was administrated to activate Wnt and beta-catenin 31 .	Furthermore, lithium chloride (LiCl), an established inhibitor of GSK-3beta, was administrated to activate Wnt and beta-catenin 31.	10	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	12	13	20	21
Thus , inhibition of Gsk3beta prevents the degradation of beta-catenin , permitting the activated Wnt and beta-catenin signaling pathway .	Thus, inhibition of Gsk3beta prevents the degradation of beta-catenin, permitting the activated Wnt and beta-catenin signaling pathway.	2	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	4	5	9	10
The Wnt signaling dependent phosphorylation of GSK-3beta inhibits its kinase activity , thereby preventing degradation of beta-catenin by GSK-3beta .	The Wnt signaling dependent phosphorylation of GSK-3beta inhibits its kinase activity, thereby preventing degradation of beta-catenin by GSK-3beta.	13	19	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	18	19	16	17
GSK-3beta phosphorylation by Akt on Ser9 inhibits its activity and prevents beta-catenin from degradation [ XREF_BIBR , XREF_BIBR ] .	GSK-3beta phosphorylation by Akt on Ser9 inhibits its activity and prevents beta-catenin from degradation [XREF_BIBR, XREF_BIBR].	0	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta phosphorylation by Akt on Ser9	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	11	12
Functional cell based experiments demonstrated direct interaction between miRNA-26a and GSK-3beta ; in addition , miRNA-26a-mediated reduction of GSK-3beta resulted in activation of beta-Catenin and expression of cancer driving genes such as cell cycle promoters .	Functional cell based experiments demonstrated direct interaction between miRNA-26a and GSK-3beta; in addition, miRNA-26a-mediated reduction of GSK-3beta resulted in activation of beta-Catenin and expression of cancer driving genes such as cell cycle promoters.	16	29	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-Catenin	beta-Catenin	beta-Catenin	18	19	23	24
Gsk3beta inhibition by mechanical strain stimulated Nfatc1 as well as beta-catenin signaling to induce osteogenesis and inhibit adipo-genesis of multipotent mesenchymal cells .	Gsk3beta inhibition by mechanical strain stimulated Nfatc1 as well as beta-catenin signaling to induce osteogenesis and inhibit adipo-genesis of multipotent mesenchymal cells.	0	11	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	0	1	10	11
Pharmacologic inhibition of GSK3beta using ( 2 ' Z ,3 ' E )-6-Bromoindirubin-3 '-oxime ( BIO ) also recapitulates the RBM3 induced beta-catenin activity .	Pharmacologic inhibition of GSK3beta using (2 ' Z,3 ' E)-6-Bromoindirubin-3 '-oxime (BIO) also recapitulates the RBM3 induced beta-catenin activity.	1	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	22	23
By contrast , a doubling of the GSK3beta concentration only decreases the half-life of beta-catenin by 10 % .	By contrast, a doubling of the GSK3beta concentration only decreases the half-life of beta-catenin by 10%.	7	15	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	14	15
The process of generation of HPV-16-associated cervical tumorigenesis is synergized with GSK3beta inactivation and overactivation of Wnt and beta-catenin pathway .	The process of generation of HPV-16-associated cervical tumorigenesis is synergized with GSK3beta inactivation and overactivation of Wnt and beta-catenin pathway.	11	19	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	11	12	18	19
To clarify the mechanism causing the down-regulation of beta-catenin , we further evaluated the expression of GSK3beta ( glycogen synthase kinase 3beta ) , which is known to negatively regulate the classic Wnt and beta-catenin signaling pathway by phosphorylating beta-catenin , which leads to its degradation XREF_BIBR .	To clarify the mechanism causing the down-regulation of beta-catenin, we further evaluated the expression of GSK3beta (glycogen synthase kinase 3beta), which is known to negatively regulate the classic Wnt and beta-catenin signaling pathway by phosphorylating beta-catenin, which leads to its degradation XREF_BIBR.	14	36	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	expression of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	16	17	34	35
Gsk3beta specific inhibitor ( SB216763 ) was used to activate Wnt and beta-catenin signaling .	Gsk3beta specific inhibitor (SB216763) was used to activate Wnt and beta-catenin signaling.	0	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	0	1	12	13
Inhibitory phosphorylation of GSK3beta by AKT results in the activation of beta-catenin .	Inhibitory phosphorylation of GSK3beta by AKT results in the activation of beta-catenin.	1	12	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
By promoting degradation of beta-catenin , GSK-3beta effectively prevents intranuclear accumulation of beta-catenin and subsequent gene transcription XREF_BIBR .	By promoting degradation of beta-catenin, GSK-3beta effectively prevents intranuclear accumulation of beta-catenin and subsequent gene transcription XREF_BIBR.	2	9	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	4	5
Moreover , active GSK3beta increased the degradation of beta-catenin and down-regulated the activity of the Wnt and beta-catenin signaling pathway and the expression of related molecules , such as beta-catenin , c-myc and cyclin D1 .	Moreover, active GSK3beta increased the degradation of beta-catenin and down-regulated the activity of the Wnt and beta-catenin signaling pathway and the expression of related molecules, such as beta-catenin, c-myc and cyclin D1.	2	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
In contrast , BIO mediated inhibition of GSK3beta stimulated beta-catenin but did not significantly alter AMPK activation .	In contrast, BIO mediated inhibition of GSK3beta stimulated beta-catenin but did not significantly alter AMPK activation.	5	10	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
Levels of beta-catenin are decreased in the brains of people with schizophrenia , presumably due to aberrant regulation of beta-catenin degradation mediated by activated GSK-3beta .	Levels of beta-catenin are decreased in the brains of people with schizophrenia, presumably due to aberrant regulation of beta-catenin degradation mediated by activated GSK-3beta.	19	25	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	24	25	19	20
In consistency , our study demonstrated that knockout of GSK3beta barely activate beta-catenin in podocytes .	In consistency, our study demonstrated that knockout of GSK3beta barely activate beta-catenin in podocytes.	7	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	9	10	12	13
The present study suggests a novel function of the canonical Wnt signaling in human colon cancer cells , regulating cell proliferation and differentiation by GSK3beta mediated , reciprocal degradation of beta-catenin or Hath1 , respectively , which further emphasizes the importance of aberrant Wnt signaling in colonocyte transformation .	The present study suggests a novel function of the canonical Wnt signaling in human colon cancer cells, regulating cell proliferation and differentiation by GSK3beta mediated, reciprocal degradation of beta-catenin or Hath1, respectively, which further emphasizes the importance of aberrant Wnt signaling in colonocyte transformation.	18	38	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	24	25	30	31
On the other hand , inhibition of GSK-3beta in cultured adult human Sertoli cells by its inhibitors ( SB216763 and lithium chloride ) activates Wnt and beta-catenin signaling , induces an increase in c-Myc expression and cell proliferation .	On the other hand, inhibition of GSK-3beta in cultured adult human Sertoli cells by its inhibitors (SB216763 and lithium chloride) activates Wnt and beta-catenin signaling, induces an increase in c-Myc expression and cell proliferation.	5	27	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	26	27
GSK-3beta has been shown to promote degradation of beta-Catenin through N-terminal phosphorylation on serine 33 , serine 37 and threonine 41 leading to beta-Catenin ubiquitination , and subsequent targeting to the proteosome where it is degraded [ XREF_BIBR ] .	GSK-3beta has been shown to promote degradation of beta-Catenin through N-terminal phosphorylation on serine 33, serine 37 and threonine 41 leading to beta-Catenin ubiquitination, and subsequent targeting to the proteosome where it is degraded [XREF_BIBR].	0	9	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-Catenin	beta-Catenin	beta-Catenin	0	1	8	9
The membrane association of Axin and GSK3beta disrupts the beta-catenin destruction complex , resulting in accumulation of beta-catenin in the nucleus , where it triggers target gene activation by displacing transcriptional repressors from DNA bound lymphoid enhancer factor ( LEF )/T-cell factor ( TCF ) .	The membrane association of Axin and GSK3beta disrupts the beta-catenin destruction complex, resulting in accumulation of beta-catenin in the nucleus, where it triggers target gene activation by displacing transcriptional repressors from DNA bound lymphoid enhancer factor (LEF)/T-cell factor (TCF).	2	11	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	6	7	9	10
GSK3A or GSK3B knockout also led to increased beta-catenin in the presence of AC220 , suggesting activation of Wnt signaling in the knockouts in the presence of AC220 ( XREF_FIG ) .	GSK3A or GSK3B knockout also led to increased beta-catenin in the presence of AC220, suggesting activation of Wnt signaling in the knockouts in the presence of AC220 (XREF_FIG).	0	11	led	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	GSK3B	GSK3B	GSK3B	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
In the absence of Wnt signaling , beta-catenin is constantly degraded in cytoplasm due to phosphorylation by GSK3beta .	In the absence of Wnt signaling, beta-catenin is constantly degraded in cytoplasm due to phosphorylation by GSK3beta.	7	18	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	17	18	7	8
These findings were also supported by the previous study that inhibitions of GSK-3beta activate beta-catenin and attenuate the regulation of the mutant FLT3 receptor on the beta-catenin activity in leukemogenesis [ XREF_BIBR ] .	These findings were also supported by the previous study that inhibitions of GSK-3beta activate beta-catenin and attenuate the regulation of the mutant FLT3 receptor on the beta-catenin activity in leukemogenesis [XREF_BIBR].	10	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	12	13	14	15
In the absence of Wnt ligand , the inhibitory complex that is composed of axin , adenomatous polyposis coli ( APC ) and glycogen synthase kinase-3beta ( GSK3beta ) induces the degradation of beta-catenin and maintains low steady-state levels of free beta-catenin either in the cytosol or the nucleus .	In the absence of Wnt ligand, the inhibitory complex that is composed of axin, adenomatous polyposis coli (APC) and glycogen synthase kinase-3beta (GSK3beta) induces the degradation of beta-catenin and maintains low steady-state levels of free beta-catenin either in the cytosol or the nucleus.	25	34	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	27	28	33	34
HMS inhibition of GSK3beta causes preservation and activation of beta-catenin .	HMS inhibition of GSK3beta causes preservation and activation of beta-catenin.	1	10	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	9	10
Upon binding of Wnt to the seven-transmembrane domain spanning frizzled ( Fzd ) receptor and the co-receptor lipoprotein receptor related 5/6 ( Lrp5/6 ) proteins GSK3beta is inactivated , thereby preventing the breakdown of beta-catenin .	Upon binding of Wnt to the seven-transmembrane domain spanning frizzled (Fzd) receptor and the co-receptor lipoprotein receptor related 5/6 (Lrp5/6) proteins GSK3beta is inactivated, thereby preventing the breakdown of beta-catenin.	25	35	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	25	26	34	35
Treatment with MCP30 increased the expression of phospho-beta-catenin protein , presumably resulting from increased GSK-3beta activity , which promoted beta-catenin degradation leading to decreased nuclear accumulation of beta-catenin in these cell lines .	Treatment with MCP30 increased the expression of phospho-beta-catenin protein, presumably resulting from increased GSK-3beta activity, which promoted beta-catenin degradation leading to decreased nuclear accumulation of beta-catenin in these cell lines.	14	20	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	14	15	19	20
The GSK-3beta independent degradation of beta-catenin is a novel finding in HCT-8 cells and indicates that the MSeA effect involves other signaling pathways than Wnt and beta-catenin , which will be investigated in future studies .	The GSK-3beta independent degradation of beta-catenin is a novel finding in HCT-8 cells and indicates that the MSeA effect involves other signaling pathways than Wnt and beta-catenin, which will be investigated in future studies.	1	6	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	1	2	5	6
Thus , the reduced expression of GSK-3beta can cause the increase of beta-catenin activity .	Thus, the reduced expression of GSK-3beta can cause the increase of beta-catenin activity.	4	13	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	expression of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	12	13
Furthermore , we discovered that DAX1 transcriptionally repressed the expression of GSK3beta , thus allowing beta-catenin to escape degradation , which consequently elevated the levels of downstream oncogenic genes .	Furthermore, we discovered that DAX1 transcriptionally repressed the expression of GSK3beta, thus allowing beta-catenin to escape degradation, which consequently elevated the levels of downstream oncogenic genes.	5	17	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	DAX1 transcriptionally repressed the expression of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	11	12	15	16
It was revealed that the inhibition of GSK-3beta activates Wnt and beta-catenin signaling via dephosphorylation , and that GSK-3beta acts as an inhibitor in the Wnt signaling pathway .	It was revealed that the inhibition of GSK-3beta activates Wnt and beta-catenin signaling via dephosphorylation, and that GSK-3beta acts as an inhibitor in the Wnt signaling pathway.	5	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	11	12
When Wnt signals are absent , the cytoplasm beta-catenin is degraded by APC , GSK3beta , and Axin complex , while Wnt ligands bind to Frizzled receptor , cytoplasm beta-catenin is accumulated and translocates to the nucleus where beta-catenin promotes the transcription of myc gene [ XREF_BIBR ] .	When Wnt signals are absent, the cytoplasm beta-catenin is degraded by APC, GSK3beta, and Axin complex, while Wnt ligands bind to Frizzled receptor, cytoplasm beta-catenin is accumulated and translocates to the nucleus where beta-catenin promotes the transcription of myc gene [XREF_BIBR].	6	18	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	14	15	8	9
GSK-3beta suppresses the proliferation of hepatic oval cells by modulating the Wnt and beta-catenin signaling pathway .	GSK-3beta suppresses the proliferation of hepatic oval cells by modulating the Wnt and beta-catenin signaling pathway.	0	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	13	14
beta-catenin activation by GSK-3beta inhibition leads to cyclin D gene transcription dependent on the action of beta-catenin and TCF4 transcription complex .	beta-catenin activation by GSK-3beta inhibition leads to cyclin D gene transcription dependent on the action of beta-catenin and TCF4 transcription complex.	0	4	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	0	1
Using LiCl as a well-known chemical activator of the Wnt pathway , XREF_BIBR , XREF_BIBR which negatively regulates GSK3beta inhibition of beta-catenin , 37 it was possible to rescue the adverse phenotype in nipblb-MO-injected embryos at all levels : anatomical cephalic structures appeared morphologically normal , the programmed cell death levels were restored to physiological levels seen in controls , and Ccnd1 protein levels were increased .	Using LiCl as a well-known chemical activator of the Wnt pathway, XREF_BIBR, XREF_BIBR which negatively regulates GSK3beta inhibition of beta-catenin, 37 it was possible to rescue the adverse phenotype in nipblb-MO-injected embryos at all levels : anatomical cephalic structures appeared morphologically normal, the programmed cell death levels were restored to physiological levels seen in controls, and Ccnd1 protein levels were increased.	18	23	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	18	19	21	22
GSK-3beta inhibition induced neuroprotection also involves beta-catenin , which is regulated by E2 through the ERalpha/PI3K/AKT/GSK3beta signaling pathway .	GSK-3beta inhibition induced neuroprotection also involves beta-catenin, which is regulated by E2 through the ERalpha/PI3K/AKT/GSK3beta signaling pathway.	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
Glycogen Synthase Kinase-3beta ( GSK-3beta ) negatively regulates Wnt and beta-catenin signaling pathway through degrading beta-catenin protein .	Glycogen Synthase Kinase-3beta (GSK-3beta) negatively regulates Wnt and beta-catenin signaling pathway through degrading beta-catenin protein.	2	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	10	11
The phospho-GSK-3beta directly degraded beta-catenin , leading to loss of function in the Wnt and beta-catenin signaling .	The phospho-GSK-3beta directly degraded beta-catenin, leading to loss of function in the Wnt and beta-catenin signaling.	0	5	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phospho-GSK-3beta	phospho-GSK-3beta	phospho-GSK-3beta	beta-catenin	beta-catenin	beta-catenin	1	2	4	5
Previous studies have shown that the inhibition of GSK-3beta promoted the accumulation of beta-catenin in the nucleus XREF_BIBR and at the plasma membrane XREF_BIBR , XREF_BIBR , which our data confirmed .	Previous studies have shown that the inhibition of GSK-3beta promoted the accumulation of beta-catenin in the nucleus XREF_BIBR and at the plasma membrane XREF_BIBR, XREF_BIBR, which our data confirmed.	6	14	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	8	9	13	14
To determine the mechanisms involved , TLR4 activation phosphorylated the upstream inhibitory kinase GSK3beta , causing beta-catenin degradation .	To determine the mechanisms involved, TLR4 activation phosphorylated the upstream inhibitory kinase GSK3beta, causing beta-catenin degradation.	6	17	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	TLR4 activation phosphorylated the upstream inhibitory kinase GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	13	14	16	17
As shown in XREF_FIG , inhibition of GSK-3beta by LiCl prevented DHA induced reduction of beta-catenin protein and TCF/LEF reporter activity .	As shown in XREF_FIG, inhibition of GSK-3beta by LiCl prevented DHA induced reduction of beta-catenin protein and TCF/LEF reporter activity.	5	16	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	15	16
In other words , an increase in Nkx2.5 by apicidin results in GSK3beta mediated beta-catenin degradation .	In other words, an increase in Nkx2.5 by apicidin results in GSK3beta mediated beta-catenin degradation.	10	15	mediated	Positive_early_activation	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	12	13	14	15
Conversely , pharmacologic inhibition of GSK3beta ( using 1-azakenpaullone ) increased supporting cell proliferation in a beta-catenin dependent manner , indicating that the effects are mediated by canonical Wnt signaling .	Conversely, pharmacologic inhibition of GSK3beta (using 1-azakenpaullone) increased supporting cell proliferation in a beta-catenin dependent manner, indicating that the effects are mediated by canonical Wnt signaling.	3	18	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	5	6	16	17
Another consideration is that chronic inhibition of GSK-3beta could increase several transcription factors and beta-catenin , which could contribute to the development of cancer .	Another consideration is that chronic inhibition of GSK-3beta could increase several transcription factors and beta-catenin, which could contribute to the development of cancer.	5	18	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	14	15
Stimulation of primary OSE cells in vitro with LiCl or Wnt3a led to GSK-3beta inhibition and stabilization of beta-catenin but failed to induce beta-catenin and Tcf mediated lacZ expression .	Stimulation of primary OSE cells in vitro with LiCl or Wnt3a led to GSK-3beta inhibition and stabilization of beta-catenin but failed to induce beta-catenin and Tcf-mediated lacZ expression.	13	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	13	14	18	19
Inhibition of Gsk3b using lithium chloride in Runx2 overexpressing osteoporotic female mice rescued the Wnt and beta-catenin signaling invivo and completely restored trabecular bone volume by increasing bone formation and decreasing bone resorption .	Inhibition of Gsk3b using lithium chloride in Runx2 overexpressing osteoporotic female mice rescued the Wnt and beta-catenin signaling invivo and completely restored trabecular bone volume by increasing bone formation and decreasing bone resorption.	0	18	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3b	Gsk3b	Gsk3b	beta-catenin	beta-catenin	beta-catenin	2	3	16	17
Thus , adenomatous polyposis coli ( APC ) , AXIN and glycogen synthase kinase-3 ( GSK-3beta ) form the beta-catenin destruction complex and mediate degradation of beta-catenin in the proteasome [ XREF_BIBR ] .	Thus, adenomatous polyposis coli (APC), AXIN and glycogen synthase kinase-3 (GSK-3beta) form the beta-catenin destruction complex and mediate degradation of beta-catenin in the proteasome [XREF_BIBR].	13	27	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	15	16	26	27
Reduction of GCKR expression inhibits Wnt3a induced phosphorylation of GSK3beta at serine 9 and decreases the accumulation of cytosolic beta-catenin .	Reduction of GCKR expression inhibits Wnt3a induced phosphorylation of GSK3beta at serine 9 and decreases the accumulation of cytosolic beta-catenin.	5	20	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	Wnt3a induced phosphorylation of GSK3beta at serine 9	gsk3beta	beta-catenin	beta-catenin	beta-catenin	9	10	19	20
Mutant HOS which lacks the F-box blocked TNF alpha induced degradation of IkappaB as well as GSK3beta mediated degradation of beta-catenin .	Mutant HOS which lacks the F-box blocked TNF alpha induced degradation of IkappaB as well as GSK3beta mediated degradation of beta-catenin.	9	21	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	16	17	20	21
These results indicate that PDH induction and PKM2 repression by NEFH are mediated through Gsk3beta mediated degradation of beta-catenin .	These results indicate that PDH induction and PKM2 repression by NEFH are mediated through Gsk3beta mediated degradation of beta-catenin.	12	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	14	15	18	19
GSK-3beta degrades beta-catenin and negatively regulates Wnt and beta-catenin pathway .	GSK-3beta degrades beta-catenin and negatively regulates Wnt and beta-catenin pathway.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	8	9
Following Wnt ligand binding , the beta-catenin degradation complex , comprising AXIN , APC , and GSK3beta , translocates to the plasma membrane where its activity is inhibited by several mechanisms : the stability of components of the complex is diminished and GSK3beta kinase activity is reduced resulting in relative stabilization of beta-catenin .	Following Wnt ligand binding, the beta-catenin degradation complex, comprising AXIN, APC, and GSK3beta, translocates to the plasma membrane where its activity is inhibited by several mechanisms : the stability of components of the complex is diminished and GSK3beta kinase activity is reduced resulting in relative stabilization of beta-catenin.	42	53	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	42	43	52	53
GSK-3beta is an important inhibitor of MYC and beta-catenin as well as of cyclin D1 when cells are not ready for entry into S phase .	GSK-3beta is an important inhibitor of MYC and beta-catenin as well as of cyclin D1 when cells are not ready for entry into S phase.	0	9	is an important inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	8	9
Downregulation of phosphorylated Akt and GSK-3beta by deguelin promoted proteosomal degradation of beta-catenin that resulted in decreased nuclear accumulation and inhibited transactivation of beta-catenin-responsive genes .	Downregulation of phosphorylated Akt and GSK-3beta by deguelin promoted proteosomal degradation of beta-catenin that resulted in decreased nuclear accumulation and inhibited transactivation of beta-catenin-responsive genes.	0	13	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	Downregulation of phosphorylated Akt and GSK-3beta by deguelin	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	12	13
Treatment with wortmannin , a PI3K inhibitor , inhibited the Ex-4-induced increases of pPI3K and p-AKT , increased the level of p-GSK3beta , and abrogated the cytoplasmic and nuclear accumulation of beta-catenin ( XREF_FIG F and 5H-5L ) .	Treatment with wortmannin, a PI3K inhibitor, inhibited the Ex-4-induced increases of pPI3K and p-AKT, increased the level of p-GSK3beta, and abrogated the cytoplasmic and nuclear accumulation of beta-catenin (XREF_FIG F and 5H-5L).	5	36	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p-GSK3beta	PI3K inhibitor, inhibited the Ex-4-induced increases of pPI3K and p-AKT, increased the level of p-GSK3beta	p-gsk3beta	beta-catenin	beta-catenin	beta-catenin	21	22	31	32
Activation of GSK3beta induces ubiquitin dependent degradation of beta-catenin , which acts as an important regulator of cell motility , invasion , and adhesion [ XREF_BIBR ] .	Activation of GSK3beta induces ubiquitin dependent degradation of beta-catenin, which acts as an important regulator of cell motility, invasion, and adhesion [XREF_BIBR].	0	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
Furthermore , salusin-beta substantially decreased the expression of p-GSK-3beta and GSK-3beta , but stimulated the beta-catenin expression and downstream genes of wnt and beta-catenin including cyclinD1 and C-myc .	Furthermore, salusin-beta substantially decreased the expression of p-GSK-3beta and GSK-3beta, but stimulated the beta-catenin expression and downstream genes of wnt and beta-catenin including cyclinD1 and C-myc.	2	17	stimulated	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	p-GSK-3beta	salusin-beta substantially decreased the expression of p-GSK-3beta	p-gsk-3beta	beta-catenin	beta-catenin expression	beta-catenin	8	9	15	16
Thus BAD inactivates AKT , which may activate GSK-3beta ( XREF_FIG ) causing reduction of beta-catenin ( XREF_FIG ) .	Thus BAD inactivates AKT, which may activate GSK-3beta (XREF_FIG) causing reduction of beta-catenin (XREF_FIG).	7	17	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	8	9	15	16
As GSK3beta promotes the degradation of beta-catenin , its inactivation results in the upregulation of WNT-beta-catenin signalling ( XREF_FIG ) .	As GSK3beta promotes the degradation of beta-catenin, its inactivation results in the upregulation of WNT-beta-catenin signalling (XREF_FIG).	1	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
WNT induced inhibition of GSK3-beta causes beta-catenin stabilization which results in its increased level in the uncomplexed soluble form .	WNT induced inhibition of GSK3-beta causes beta-catenin stabilization which results in its increased level in the uncomplexed soluble form.	2	7	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3-beta	GSK3-beta	GSK3-beta	beta-catenin	beta-catenin	beta-catenin	4	5	6	7
These findings would suggest that GSK-3beta inhibition in naive CD8 + T cells preferentially enhances beta-catenin signaling over its effect on mTORC1 .	These findings would suggest that GSK-3beta inhibition in naive CD8 + T cells preferentially enhances beta-catenin signaling over its effect on mTORC1.	5	16	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	15	16
It is known that C2 domain in DAB2IP can recruit PP2A to activate GSK3beta that is able to inhibit beta-catenin and Wnt signaling .	It is known that C2 domain in DAB2IP can recruit PP2A to activate GSK3beta that is able to inhibit beta-catenin and Wnt signaling.	12	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	13	14	19	20
In order to maintain IEC homeostasis , intracellular Wingless-Int ( Wnt ) signaling cascades act to regulate glycogen synthase kinase 3beta ( GSK3beta )-dependent proteosomal degradation of beta-catenin XREF_BIBR - XREF_BIBR .	In order to maintain IEC homeostasis, intracellular Wingless-Int (Wnt) signaling cascades act to regulate glycogen synthase kinase 3beta (GSK3beta)-dependent proteosomal degradation of beta-catenin XREF_BIBR - XREF_BIBR.	22	28	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	22	23	27	28
These data indicate that GSK-3beta inhibition by TWS119 might activate the Wnt and beta-catenin signaling pathway , which is associated with increased ZO-1 expression and attenuated BBB disruption .	These data indicate that GSK-3beta inhibition by TWS119 might activate the Wnt and beta-catenin signaling pathway, which is associated with increased ZO-1 expression and attenuated BBB disruption.	4	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	13	14
We propose a model in which inhibition of GSK3beta activity upon Wnt signaling leads to the dephosphorylation of GSK3beta sites in Axin , resulting in the release of beta-catenin from the phosphorylation complex .	We propose a model in which inhibition of GSK3beta activity upon Wnt signaling leads to the dephosphorylation of GSK3beta sites in Axin, resulting in the release of beta-catenin from the phosphorylation complex.	8	29	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	8	9	28	29
These results showed that NDRG2 diminishes the phosphorylation of GSK-3beta , which enhances its kinase activity , and subsequently down-regulates beta-catenin in SW620 cells .	These results showed that NDRG2 diminishes the phosphorylation of GSK-3beta, which enhances its kinase activity, and subsequently down-regulates beta-catenin in SW620 cells.	4	21	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	NDRG2 diminishes the phosphorylation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	9	10	20	21
When Wnt is present , GSK3beta phosphorylation is inhibited , allowing beta-catenin to escape ubiquination , and enter the nucleus where it can bind to T-cell factor and lymphoid-enhancer factor ( Tcf/Lef ) transcription factor proteins thereby activating transcription of downstream effectors [ XREF_BIBR ] .	When Wnt is present, GSK3beta phosphorylation is inhibited, allowing beta-catenin to escape ubiquination, and enter the nucleus where it can bind to T-cell factor and lymphoid-enhancer factor (Tcf/Lef) transcription factor proteins thereby activating transcription of downstream effectors [XREF_BIBR].	5	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	5	6	11	12
GSK3beta is an active form and can degrade beta-catenin .	GSK3beta is an active form and can degrade beta-catenin.	0	9	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	0	1	8	9
When activated , GSK3beta promotes proteosomal degradation of the transcriptional co-activator beta-catenin .	When activated, GSK3beta promotes proteosomal degradation of the transcriptional co-activator beta-catenin.	3	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
A decrease in GSK-3beta activity increases the stability of beta-catenin and enhances its biological function .	A decrease in GSK-3beta activity increases the stability of beta-catenin and enhances its biological function.	3	10	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	9	10
Once inhibited GSK3beta can no longer target beta-catenin for degradation and thus the stabilised beta-catenin protein can translocate to the nucleus where it co-operates with a host of other factors to transactivate gene expression .	Once inhibited GSK3beta can no longer target beta-catenin for degradation and thus the stabilised beta-catenin protein can translocate to the nucleus where it co-operates with a host of other factors to transactivate gene expression.	1	8	target	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
LiCl and SB415286 are specific inhibitors of GSK3beta , which can inhibit Wnt and beta-catenin signaling .	LiCl and SB415286 are specific inhibitors of GSK3beta, which can inhibit Wnt and beta-catenin signaling.	5	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	14	15
Thus , the relationship between GSK-3beta inhibition and stability of beta-catenin also warrants further investigation in the context of VEGF and pathological neovascularization .	Thus, the relationship between GSK-3beta inhibition and stability of beta-catenin also warrants further investigation in the context of VEGF and pathological neovascularization.	5	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
As for GSK-3beta , a crucial part of the degradation complex formed by beta-catenin and Axin-APC-GSK-3beta in cytoplasm , and the inhibition of the activity of GSK-3beta can promote the accumulation of beta-catenin in cells .	As for GSK-3beta, a crucial part of the degradation complex formed by beta-catenin and Axin-APC-GSK-3beta in cytoplasm, and the inhibition of the activity of GSK-3beta can promote the accumulation of beta-catenin in cells.	24	33	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	26	27	32	33
Degradation of beta-catenin by GSK-3beta is not a general mechanism but it is cell type dependent .	Degradation of beta-catenin by GSK-3beta is not a general mechanism but it is cell type dependent.	0	5	Degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	2	3
Thus , these findings suggest that DACH1 could suppress the hepatocellular carcinoma growth through inhibition on Wnt signaling , which might be mediated by phosphorylation of GSK3beta to suppress the activation of beta-catenin .	Thus, these findings suggest that DACH1 could suppress the hepatocellular carcinoma growth through inhibition on Wnt signaling, which might be mediated by phosphorylation of GSK3beta to suppress the activation of beta-catenin.	22	33	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	26	27	32	33
These results suggest that an increase of Wnt3a or an inhibition of GSK3beta specifically induce accumulation of beta-catenin protein in the preosteoclast cell line and in primary osteoclast cells from bone marrow of patients with MM .	These results suggest that an increase of Wnt3a or an inhibition of GSK3beta specifically induce accumulation of beta-catenin protein in the preosteoclast cell line and in primary osteoclast cells from bone marrow of patients with MM.	10	18	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	12	13	17	18
This result suggests that TRAIL may directly block the beta-catenin signaling by activating GSK3beta mediated beta-catenin degradation .	This result suggests that TRAIL may directly block the beta-catenin signaling by activating GSK3beta mediated beta-catenin degradation.	13	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	13	14	15	16
GSK3- beta is then free to inhibit beta-catenin .	GSK3- beta is then free to inhibit beta-catenin.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3- beta	GSK3- beta	GSK3- beta	beta-catenin	beta-catenin	beta-catenin	0	2	7	8
The phosphorylation of GSK-3beta inhibits beta-catenin for proteolysis , which leads to active beta-catenin nuclear translocation and transcriptional regulation of genes involved in osteoblastic proliferation and differentiation such as Runx2 XREF_BIBR .	The phosphorylation of GSK-3beta inhibits beta-catenin for proteolysis, which leads to active beta-catenin nuclear translocation and transcriptional regulation of genes involved in osteoblastic proliferation and differentiation such as Runx2 XREF_BIBR.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	5	6
For example , expressions of beta-catenin proteins decreased in the brains of schizophrenia patients , presumably due to aberrant regulation of beta-catenin degradation mediated by activated GSK-3beta [ XREF_BIBR , XREF_BIBR ] .	For example, expressions of beta-catenin proteins decreased in the brains of schizophrenia patients, presumably due to aberrant regulation of beta-catenin degradation mediated by activated GSK-3beta [XREF_BIBR, XREF_BIBR].	21	28	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	26	27	21	22
Thus , GSK3beta suppresses beta-catenin activation through proteosome targeting while inhibition of GSK3beta allows accumulation of beta-catenin followed by nuclear translocation and beta-catenin-dependent gene transcription .	Thus, GSK3beta suppresses beta-catenin activation through proteosome targeting while inhibition of GSK3beta allows accumulation of beta-catenin followed by nuclear translocation and beta-catenin-dependent gene transcription.	2	5	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
HFD induces GSK-3beta inhibition , which reduces beta-catenin degradation .	HFD induces GSK-3beta inhibition, which reduces beta-catenin degradation.	2	8	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
These results suggest that galectin-3 mediates Wnt signaling , at least in part , by regulating GSK-3beta phosphorylation and activity via the PI3K and AKT pathway , and thus the degradation of beta-catenin in colon cancer cells .	These results suggest that galectin-3 mediates Wnt signaling, at least in part, by regulating GSK-3beta phosphorylation and activity via the PI3K and AKT pathway, and thus the degradation of beta-catenin in colon cancer cells.	4	33	degradation	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	GSK-3beta	galectin-3 mediates Wnt signaling, at least in part, by regulating GSK-3beta phosphorylation	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	16	17	32	33
ILK phosphorylation of GSK3-beta also inhibits Beta-catenin and Lymphoid enhancer factor/T cell factor proteins ( LEF and TCF ) interaction , which in turn regulates the function of Myc , cadherins and cAMP-response-element-binding protein ( CREB ) .	ILK phosphorylation of GSK3-beta also inhibits Beta-catenin and Lymphoid enhancer factor/T cell factor proteins (LEF and TCF) interaction, which in turn regulates the function of Myc, cadherins and cAMP-response-element-binding protein (CREB).	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3-beta	ILK phosphorylation of GSK3-beta	gsk3-beta	Beta-catenin	Beta-catenin	beta-catenin	3	4	6	7
Our results suggest that PCDH20 induces Erks and Akt mediated activation of GSK-3beta , which in turn inhibits Wnt and beta-catenin signalling and leads to inhibition of HCC growth and migration .	Our results suggest that PCDH20 induces Erks and Akt mediated activation of GSK-3beta, which in turn inhibits Wnt and beta-catenin signalling and leads to inhibition of HCC growth and migration.	4	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	PCDH20 induces Erks and Akt mediated activation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	12	13	20	21
In the absence of Wnt signaling , the complex is assembled and GSK-3beta phosphorylates and consequently degrades cytoplasm beta-catenin [ XREF_BIBR , XREF_BIBR ] .	In the absence of Wnt signaling, the complex is assembled and GSK-3beta phosphorylates and consequently degrades cytoplasm beta-catenin [XREF_BIBR, XREF_BIBR].	12	20	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	12	13	18	19
These results demonstrate that mechanical inhibition of GSK3beta induces activation of both beta-catenin and NFATc1 signaling , limiting adipogenesis via the former and promoting osteoblastic differentiation via NFATc1 and COX2 .	These results demonstrate that mechanical inhibition of GSK3beta induces activation of both beta-catenin and NFATc1 signaling, limiting adipogenesis via the former and promoting osteoblastic differentiation via NFATc1 and COX2.	5	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	12	13
As an example of the latter , GSK3beta inhibits the accumulation of beta-catenin through phosphorylation leading to ubiquitination , 134 while DISC1 has been proven to stabilize beta-catenin through an inhibitory effect on GSK3beta .	As an example of the latter, GSK3beta inhibits the accumulation of beta-catenin through phosphorylation leading to ubiquitination, 134 while DISC1 has been proven to stabilize beta-catenin through an inhibitory effect on GSK3beta.	7	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	12	13
Prolonged Inhibition of GSK3beta in Snake Dental Organ Cultures Activates Wnt and beta-catenin Signalling , Increasing the Number of Tooth Germs and Altering the Morphology of the Dental Lamina .	Prolonged Inhibition of GSK3beta in Snake Dental Organ Cultures Activates Wnt and beta-catenin Signalling, Increasing the Number of Tooth Germs and Altering the Morphology of the Dental Lamina.	1	13	Activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	12	13
Previous studies have shown that inhibition of glycogen synthase kinase 3 ( GSK3beta ) signaling induces beta-catenin transcriptional activity resulting in cell cycle progression [ XREF_BIBR ] .	Previous studies have shown that inhibition of glycogen synthase kinase 3 (GSK3beta) signaling induces beta-catenin transcriptional activity resulting in cell cycle progression [XREF_BIBR].	5	18	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	12	13	16	17
A strong decrease of a ratio GSK3beta-Ser9 and total GSK3beta was observed in osteoblasts upon exposure to the sera of all obese subjects , demonstrating that the canonical beta-catenin pathway is inactivated by the presence of nonphosphorylated ( then active ) GSK3beta , and normal regulation within cells disrupted by obese subjects sera .	A strong decrease of a ratio GSK3beta-Ser9 and total GSK3beta was observed in osteoblasts upon exposure to the sera of all obese subjects, demonstrating that the canonical beta-catenin pathway is inactivated by the presence of nonphosphorylated (then active) GSK3beta, and normal regulation within cells disrupted by obese subjects sera.	28	42	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	41	42	28	29
Here we show that GSK-3beta inhibition activates beta-catenin in cord blood CD34 ( + ) cells and upregulates beta-catenin transcriptional targets c-myc and HoxB4 , both known to regulate HSC self-renewal .	Here we show that GSK-3beta inhibition activates beta-catenin in cord blood CD34 (+) cells and upregulates beta-catenin transcriptional targets c-myc and HoxB4, both known to regulate HSC self-renewal.	4	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	7	8
XREF_BIBR Moreover , GSK3-beta inhibition also enhances the stability and transcriptional function of beta-catenin , an activity upregulated in migrating and invasive tumoral cells ( XREF_FIG ) .	XREF_BIBR Moreover, GSK3-beta inhibition also enhances the stability and transcriptional function of beta-catenin, an activity upregulated in migrating and invasive tumoral cells (XREF_FIG).	3	16	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3-beta	GSK3-beta	GSK3-beta	beta-catenin	beta-catenin	beta-catenin	3	4	13	14
On the other hand , GSK-3beta is responsible for the degradation of beta-catenin and negatively regulates beta-catenin expression XREF_BIBR .	On the other hand, GSK-3beta is responsible for the degradation of beta-catenin and negatively regulates beta-catenin expression XREF_BIBR.	5	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	16	17
Silymarin induces GSK3beta dependent proteasomal degradation of beta-catenin and Axin dependent downregulation of TCF4 .	Silymarin induces GSK3beta dependent proteasomal degradation of beta-catenin and Axin dependent downregulation of TCF4.	2	11	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
Given that GSK-3beta mediates beta-catenin degradation via phosphorylation of its serine ( Ser33/37/45 ) and threonine ( Thr41 ) residues , we examined the expression of total beta-catenin and activated beta-catenin ( ABC ) in hBMSCs with miR-346 overexpression .	Given that GSK-3beta mediates beta-catenin degradation via phosphorylation of its serine (Ser33/37/45) and threonine (Thr41) residues, we examined the expression of total beta-catenin and activated beta-catenin (ABC) in hBMSCs with miR-346 overexpression.	2	5	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
Suppression of UBE2T also inhibits gastric tumor invasion and metastasis via the WNT signal pathway by inhibiting WNT5A and WNT7B , which in turn promotes GSK3B expression , activates beta-Catenin , and inhibits the key oncogene c-Myc .	Suppression of UBE2T also inhibits gastric tumor invasion and metastasis via the WNT signal pathway by inhibiting WNT5A and WNT7B, which in turn promotes GSK3B expression, activates beta-Catenin, and inhibits the key oncogene c-Myc.	17	30	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3B	WNT5A and WNT7B, which in turn promotes GSK3B expression	gsk3b	beta-Catenin	beta-Catenin	beta-catenin	25	26	29	30
Higher expression of GSK-3B is thought to cause proteosomal degradation of beta-catenin via the formation of a cytoplasmic multiprotein complex XREF_BIBR , XREF_BIBR .	Higher expression of GSK-3B is thought to cause proteosomal degradation of beta-catenin via the formation of a cytoplasmic multiprotein complex XREF_BIBR, XREF_BIBR.	1	14	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3B	expression of GSK-3B	gsk-3b	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
The second effect was that prolonged incubation with VacA resulted in inactivation of Akt and activation of GSK3beta , which then down-regulated beta-catenin activity .	The second effect was that prolonged incubation with VacA resulted in inactivation of Akt and activation of GSK3beta, which then down-regulated beta-catenin activity.	11	23	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	17	18	22	23
Wnt inhibits GSK-3beta , which inhibits beta-catenin .	Wnt inhibits GSK-3beta, which inhibits beta-catenin.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
We conclude that PS1 negatively regulates the stability and transcriptional activity of beta-catenin at different levels in the Wnt pathway , that the effect on transcriptional activity appears to be independent of the GSK-3beta mediated degradation of beta-catenin , and that mutations in PS1 differentially affect the stability and transcriptional activity of beta-catenin .	We conclude that PS1 negatively regulates the stability and transcriptional activity of beta-catenin at different levels in the Wnt pathway, that the effect on transcriptional activity appears to be independent of the GSK-3beta mediated degradation of beta-catenin, and that mutations in PS1 differentially affect the stability and transcriptional activity of beta-catenin.	30	38	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	33	34	37	38
GSK-inhibitor ( CHIR99021 ) , a glycogen synthase kinase 3beta ( GSK3beta ) inhibitor , has been shown to promote the proliferation of crypts cells and can synergisze with Wnt3A to activate the beta-catenin signaling pathway , which plays a role in downstream hISCs differentiation [ XREF_BIBR ] .	GSK-inhibitor (CHIR99021), a glycogen synthase kinase 3beta (GSK3beta) inhibitor, has been shown to promote the proliferation of crypts cells and can synergisze with Wnt3A to activate the beta-catenin signaling pathway, which plays a role in downstream hISCs differentiation [XREF_BIBR].	11	35	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	11	12	33	34
Likewise , GSK3beta negatively regulates the stability of beta-catenin .	Likewise, GSK3beta negatively regulates the stability of beta-catenin.	2	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
As expected , the inhibition of GSK-3beta up-regulated the active form of beta-catenin , resulting in SREBP-1c down-regulation .	As expected, the inhibition of GSK-3beta up-regulated the active form of beta-catenin, resulting in SREBP-1c down-regulation.	4	13	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	12	13
The results of the present study suggest that nuclear FRAT1 activates the Wnt and beta-catenin signaling pathway and confers an increase in prostate cancer cell growth , potentially by preventing nuclear GSK3beta mediated inhibition of beta-catenin and TCF activity .	The results of the present study suggest that nuclear FRAT1 activates the Wnt and beta-catenin signaling pathway and confers an increase in prostate cancer cell growth, potentially by preventing nuclear GSK3beta mediated inhibition of beta-catenin and TCF activity.	30	38	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	31	32	35	36
Wnt and beta-catenin signaling activation by inhibiting GSK3beta maintains the ability of hDPCs to induce hair growth , and beta-catenin activity in the DP regulates morphogenesis and regeneration of hair [ XREF_BIBR , XREF_BIBR ] .	Wnt and beta-catenin signaling activation by inhibiting GSK3beta maintains the ability of hDPCs to induce hair growth, and beta-catenin activity in the DP regulates morphogenesis and regeneration of hair [XREF_BIBR, XREF_BIBR].	0	8	signaling activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	2	3
Although TFAM cKO keratinocytes show defective induction of beta-catenin-dependent transcription downstream of Wnt stimulation , both sets of keratinocytes could induce gene expression upon treatment with lithium chloride ( LiCl ) , which activates beta-catenin-dependent transcription by inhibiting glycogen synthase kinase 3beta ( GSK-3beta )-mediated degradation of beta-catenin ( XREF_FIG ) .	Although TFAM cKO keratinocytes show defective induction of beta-catenin-dependent transcription downstream of Wnt stimulation, both sets of keratinocytes could induce gene expression upon treatment with lithium chloride (LiCl), which activates beta-catenin-dependent transcription by inhibiting glycogen synthase kinase 3beta (GSK-3beta)-mediated degradation of beta-catenin (XREF_FIG).	43	49	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	43	44	47	48
beta-Catenin can be degraded by GSK3beta dependent and GSK3beta independent proteasomal pathways .	beta-Catenin can be degraded by GSK3beta dependent and GSK3beta independent proteasomal pathways.	0	8	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-Catenin	beta-Catenin	beta-Catenin	5	6	0	1
Axin , GSK-3beta and APC cause a robust suppression in the activity of Wnt and beta-catenin signaling by forming a destruction complex and inducing beta-catenin degradation [ XREF_BIBR ] .	Axin, GSK-3beta and APC cause a robust suppression in the activity of Wnt and beta-catenin signaling by forming a destruction complex and inducing beta-catenin degradation [XREF_BIBR].	0	25	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	24	25
These results suggest that Gsk3beta dependent degradation of beta-catenin contributes at least part to the tumor suppressive role of NEFH .	These results suggest that Gsk3beta dependent degradation of beta-catenin contributes at least part to the tumor suppressive role of NEFH.	4	9	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	4	5	8	9
When the Wnt signal is activated , the activity of GSK3beta is inhibited , resulting in the accumulation of beta-catenin .	When the Wnt signal is activated, the activity of GSK3beta is inhibited, resulting in the accumulation of beta-catenin.	8	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	10	11	19	20
Inhibition of GSK3beta allows beta-catenin to translocate to the nucleus , form complexes with T-cell factor and lymphoid enhancer factor and thereby activates target gene expression XREF_BIBR .	Inhibition of GSK3beta allows beta-catenin to translocate to the nucleus, form complexes with T-cell factor and lymphoid enhancer factor and thereby activates target gene expression XREF_BIBR.	0	6	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
The accumulation of beta-catenin in cytoplasm will not occur without Wnt signaling since the GSK3beta complex degrades beta-catenin by targeting it for ubiquitination .	The accumulation of beta-catenin in cytoplasm will not occur without Wnt signaling since the GSK3beta complex degrades beta-catenin by targeting it for ubiquitination.	14	18	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	14	15	17	18
In cultured bovine luteal cells , LH stimulation of cAMP and PKA results in phosphorylation and inhibition of GSK3beta allowing stabilization of beta-catenin .	In cultured bovine luteal cells, LH stimulation of cAMP and PKA results in phosphorylation and inhibition of GSK3beta allowing stabilization of beta-catenin.	14	23	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	phosphorylation and inhibition of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	18	19	22	23
Activation of canonical Wnt signaling with 5 mM LiCl , which inhibits GSK3beta mediated degradation of beta-catenin , elevated beta-catenin transcriptional activity in both ASD and control NPCs .	Activation of canonical Wnt signaling with 5 mM LiCl, which inhibits GSK3beta mediated degradation of beta-catenin, elevated beta-catenin transcriptional activity in both ASD and control NPCs.	11	21	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	12	13	16	17
Inhibition of GSK-3beta by DVL increases beta-catenin stability and TCF transcriptional activation .	Inhibition of GSK-3beta by DVL increases beta-catenin stability and TCF transcriptional activation.	0	7	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
GSK-3beta also negatively regulates transcription factors involved in muscle specific gene expression , including nuclear factors of activated T cells ( NFAT ) , GATA4 , and beta-catenin [ XREF_BIBR - XREF_BIBR ] suggesting a critical role in ASM growth .	GSK-3beta also negatively regulates transcription factors involved in muscle specific gene expression, including nuclear factors of activated T cells (NFAT), GATA4, and beta-catenin [XREF_BIBR - XREF_BIBR] suggesting a critical role in ASM growth.	0	31	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	27	28
Moreover , GSK3beta inhibition enables beta-catenin to act as a transcription factor .	Moreover, GSK3beta inhibition enables beta-catenin to act as a transcription factor.	2	6	enables	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	5	6
In mouse embryonic fibroblasts , on the other hand , loss of Gsk3beta function itself enhances Wnt and beta-catenin signaling activity ( Kapoor et al ., 2008 ) .	In mouse embryonic fibroblasts, on the other hand, loss of Gsk3beta function itself enhances Wnt and beta-catenin signaling activity (Kapoor et al., 2008).	12	20	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	12	13	18	19
We previously found that Wnt simulation induces monoubiquitination of GSK3beta by beta-TrCP , which is required for Wnt induced inhibition of beta-catenin recruitment of beta-TrCP and subsequent stabilization of beta-catenin .	We previously found that Wnt simulation induces monoubiquitination of GSK3beta by beta-TrCP, which is required for Wnt induced inhibition of beta-catenin recruitment of beta-TrCP and subsequent stabilization of beta-catenin.	7	30	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	monoubiquitination of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	9	10	29	30
The inhibition of GSK-3beta activity prevented degradation of beta-catenin .	The inhibition of GSK-3beta activity prevented degradation of beta-catenin.	3	9	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
AZD7969 is a potent inhibitor of glycogen synthase kinase 3 ( GSK3beta ) , which is a multifunctional serine/threonine kinase that negatively regulates the Wnt and beta-catenin signaling pathway .	AZD7969 is a potent inhibitor of glycogen synthase kinase 3 (GSK3beta), which is a multifunctional serine/threonine kinase that negatively regulates the Wnt and beta-catenin signaling pathway.	4	28	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	11	12	26	27
Conversely , when the Wnt canonical pathway is turned off , increased levels of GSK-3beta promote beta-catenin degradation .	Conversely, when the Wnt canonical pathway is turned off, increased levels of GSK-3beta promote beta-catenin degradation.	12	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	levels of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	14	15	16	17
Inhibition of GSK-3beta via p38MAPK stimulates accumulation of beta-catenin .	Inhibition of GSK-3beta via p38MAPK stimulates accumulation of beta-catenin.	0	9	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
Akt is known to phosphorylate and inhibit GSK-3beta , which could allow beta-catenin to translocate to the nuclei .	Akt is known to phosphorylate and inhibit GSK-3beta, which could allow beta-catenin to translocate to the nuclei.	0	14	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	Akt is known to phosphorylate and inhibit GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	12	13
In the absence of Wnt signaling the activation of a complex of proteins including Axins , GSK3beta and APC induces proteasomal degradation of beta-catenin XREF_BIBR .	In the absence of Wnt signaling the activation of a complex of proteins including Axins, GSK3beta and APC induces proteasomal degradation of beta-catenin XREF_BIBR.	16	24	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	16	17	23	24
To do this , we used Chir99021 , a potent and specific GSK3beta inhibitor involved in the beta-catenin destruction complex , such that inhibition of GSK3beta with Chir99021 allows beta-catenin stabilization downstream of ligand and receptors .	To do this, we used Chir99021, a potent and specific GSK3beta inhibitor involved in the beta-catenin destruction complex, such that inhibition of GSK3beta with Chir99021 allows beta-catenin stabilization downstream of ligand and receptors.	23	30	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	25	26	29	30
Furthermore , inhibition of GSK-3beta by SGK-1 up-regulates oncogenic beta-catenin XREF_BIBR , XREF_BIBR .	Furthermore, inhibition of GSK-3beta by SGK-1 up-regulates oncogenic beta-catenin XREF_BIBR, XREF_BIBR.	2	10	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	9	10
Thus , beta-catenin signaling increases neurogenesis in the subgranular zone ; and inhibition of GSK-3beta increases beta-catenin signaling [ XREF_BIBR , XREF_BIBR ] .	Thus, beta-catenin signaling increases neurogenesis in the subgranular zone; and inhibition of GSK-3beta increases beta-catenin signaling [XREF_BIBR, XREF_BIBR].	12	17	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	14	15	16	17
Next , we tested the effect of GSK-3beta repression on EDD induced beta-catenin activity using the luciferase pTOPFLASH and pFOPFLASH assay ( XREF_FIG ) .	Next, we tested the effect of GSK-3beta repression on EDD induced beta-catenin activity using the luciferase pTOPFLASH and pFOPFLASH assay (XREF_FIG).	7	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	12	13
LANA binding of GSK3beta leads to nuclear sequestration and inactivation of the kinase , removing its negative regulation of beta-catenin and promoting cell proliferation .	LANA binding of GSK3beta leads to nuclear sequestration and inactivation of the kinase, removing its negative regulation of beta-catenin and promoting cell proliferation.	1	20	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	19	20
Following phosphorylation on Ser9 , GSK3beta is degraded by the proteasome pathway , thus releasing beta-catenin .	Following phosphorylation on Ser9, GSK3beta is degraded by the proteasome pathway, thus releasing beta-catenin.	5	16	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	5	6	15	16
Indeed , increased levels of GSK3beta , which promotes beta-catenin degradation , has been found in AD brains and correlates with neurodegeneration and deficiency in spatial learning [ XREF_BIBR - XREF_BIBR ] .	Indeed, increased levels of GSK3beta, which promotes beta-catenin degradation, has been found in AD brains and correlates with neurodegeneration and deficiency in spatial learning [XREF_BIBR - XREF_BIBR].	3	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	levels of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
To verify the role of GSK3beta in PPARgamma2 mediated degradation of beta-catenin and suppression of adipogenesis , U-33 and gamma2 cells were treated with a GSK3beta specific reversible competitive ATP inhibitor 6-6-bromoindirubin-3 '-oxime ( BIO ) .	To verify the role of GSK3beta in PPARgamma2 mediated degradation of beta-catenin and suppression of adipogenesis, U-33 and gamma2 cells were treated with a GSK3beta specific reversible competitive ATP inhibitor 6-6-bromoindirubin-3 '-oxime (BIO).	9	34	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	25	26	11	12
Ectopic expression of a dominant negative form of GSK-3beta in FLT3-ITD-expressing cells activated beta-catenin and blocked the downregulation of the TCF and beta-catenin transcriptional activity induced by inhibition of FLT3 kinase .	Ectopic expression of a dominant negative form of GSK-3beta in FLT3-ITD-expressing cells activated beta-catenin and blocked the downregulation of the TCF and beta-catenin transcriptional activity induced by inhibition of FLT3 kinase.	6	24	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	8	9	22	23
GSK3beta promotes the ubiquitin-proteasome degradation of beta-catenin by phosphorylating three specific amino acids , Ser33/Ser37/Thr41 , on beta-catenin .	GSK3beta promotes the ubiquitin-proteasome degradation of beta-catenin by phosphorylating three specific amino acids, Ser33/Ser37/Thr41, on beta-catenin.	0	18	promotes	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	GSK3beta	GSK3beta	gsk3beta	beta-catenin	phosphorylating three specific amino acids, Ser33/Ser37/Thr41, on beta-catenin	beta-catenin	0	1	17	18
In summary , our results revealed that FIBP may promote CRC cell proliferation and stemness via inhibition of the GSK3beta mediated beta-catenin and cyclin D1 pathway and methylation of stemness genes .	In summary, our results revealed that FIBP may promote CRC cell proliferation and stemness via inhibition of the GSK3beta mediated beta-catenin and cyclin D1 pathway and methylation of stemness genes.	16	25	mediated	Positive_early_activation	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	19	20	21	22
Lithium chloride inhibition of GSK-3beta increased nuclear beta-catenin content and normalized nuclear PPAR-gamma in Ob-MSCs .	Lithium chloride inhibition of GSK-3beta increased nuclear beta-catenin content and normalized nuclear PPAR-gamma in Ob-MSCs.	2	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	7	8
Pharmacological inhibition of GSK-3beta , independently of HGF treatment , strongly increased both beta-catenin activity and cell survival , suggesting that beta-catenin alone has a pronounced anti-apoptotic effect .	Pharmacological inhibition of GSK-3beta, independently of HGF treatment, strongly increased both beta-catenin activity and cell survival, suggesting that beta-catenin alone has a pronounced anti-apoptotic effect.	1	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	13	14
GSK-3beta regulates the breakdown of beta-catenin ; consequently , GSK-3beta inhibition increases the availability of beta-catenin .	GSK-3beta regulates the breakdown of beta-catenin; consequently, GSK-3beta inhibition increases the availability of beta-catenin.	9	16	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	9	10	15	16
In contrast , in the presence of Dkk1 , binding of Wnts to Fz/LRP6 is blocked , resulting in enhanced Gsk3beta mediated beta-catenin degradation by the proteasome pathway ( XREF_SUPPLEMENTARY ) [ XREF_BIBR , XREF_BIBR ] .	In contrast, in the presence of Dkk1, binding of Wnts to Fz/LRP6 is blocked, resulting in enhanced Gsk3beta mediated beta-catenin degradation by the proteasome pathway (XREF_SUPPLEMENTARY) [XREF_BIBR, XREF_BIBR].	17	23	mediated	Positive_early_activation	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	20	21	22	23
XREF_BIBR In contrast , when Wnt conjugates with its receptor , GSK3beta activity decreases , enabling beta-catenin accumulation and its nuclear localization , resulting in increased beta-catenin-orchestrated transcriptional activity and gene expression .	XREF_BIBR In contrast, when Wnt conjugates with its receptor, GSK3beta activity decreases, enabling beta-catenin accumulation and its nuclear localization, resulting in increased beta-catenin-orchestrated transcriptional activity and gene expression.	11	17	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	11	12	16	17
The effects of APC mutation or endogenous GSK3beta preventing activation of WNT and beta-catenin signaling result in unable to differentiate normally in either embryoid body ( EB ) or teratoma differentiation assays 179 .	The effects of APC mutation or endogenous GSK3beta preventing activation of WNT and beta-catenin signaling result in unable to differentiate normally in either embryoid body (EB) or teratoma differentiation assays 179.	1	14	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	13	14
beta-Catenin stability was not visibly enhanced by GSK-3beta inhibition in Huh7.5 M cells since its levels remained unaltered .	beta-Catenin stability was not visibly enhanced by GSK-3beta inhibition in Huh7.5 M cells since its levels remained unaltered.	0	8	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-Catenin	beta-Catenin	beta-Catenin	7	8	0	1
These findings can be explained either by the very low expression of proteins involved in beta-catenin degradation such as GSK-3beta and axin-1 ( target of XAV939 , IWR1-endo , IWP2 compounds ) observed in MCL-ICs or by a contribution of redundant and additional pathways to beta-catenin activation , such as autocrine fibroblast growth factor receptor signaling [ XREF_BIBR , XREF_BIBR ] .	These findings can be explained either by the very low expression of proteins involved in beta-catenin degradation such as GSK-3beta and axin-1 (target of XAV939, IWR1-endo, IWP2 compounds) observed in MCL-ICs or by a contribution of redundant and additional pathways to beta-catenin activation, such as autocrine fibroblast growth factor receptor signaling [XREF_BIBR, XREF_BIBR].	15	55	degradation	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	19	20	15	16
The inhibition of GSK3beta kinase activates beta-catenin , which stimulates endoderm induction via the degradation of Tcf7l1 and forkhead box A2 ( FoxA2 ) expression [ XREF_BIBR ] .	The inhibition of GSK3beta kinase activates beta-catenin, which stimulates endoderm induction via the degradation of Tcf7l1 and forkhead box A2 (FoxA2) expression [XREF_BIBR].	3	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	6	7
GSK3beta gene silencing increases expression and membrane localization of beta-catenin .	GSK3beta gene silencing increases expression and membrane localization of beta-catenin.	0	10	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	0	1	9	10
The results infer that the multimeric protein complex of beta-catenin could be increased by CGA upregulated genes GSK-3beta and APC , which could inhibit the free beta-catenin into the nucleus to connect with TCF .	The results infer that the multimeric protein complex of beta-catenin could be increased by CGA upregulated genes GSK-3beta and APC, which could inhibit the free beta-catenin into the nucleus to connect with TCF.	15	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	17	18	26	27
This is consistent with previous reports showing that : i ) GSK3beta activity is required to enable PPARgamma dependent beta-catenin degradation during pre-adipocyte differentiation [ XREF_BIBR ] ; ii ) inhibition of GSK3beta activity , restricted to the early step of differentiation , is sufficient to impair adipogenic differentiation of human adipose derived stem cells [ XREF_BIBR ] .	This is consistent with previous reports showing that : i) GSK3beta activity is required to enable PPARgamma dependent beta-catenin degradation during pre-adipocyte differentiation [XREF_BIBR]; ii) inhibition of GSK3beta activity, restricted to the early step of differentiation, is sufficient to impair adipogenic differentiation of human adipose derived stem cells [XREF_BIBR].	11	20	enable	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	11	12	19	20
An Ub like modifier , FAT10 , non covalently binds beta-catenin and prevent GSK3beta induced beta-catenin degradation .	An Ub like modifier, FAT10, non covalently binds beta-catenin and prevent GSK3beta induced beta-catenin degradation.	13	16	induced	Positive_early_activation	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	13	14	15	16
Canonical Wnt signaling was repressed following miR-148a expression , as indicated by the marked reduction of Wnt1 protein ( XREF_FIG , Day 0 ) , increased phosphorylation of GSK-3beta ( p-GSK-3beta ) ( XREF_FIG , Day 10 ) , and reduced nuclear beta-catenin ( XREF_FIG , Day 10 ) .	Canonical Wnt signaling was repressed following miR-148a expression, as indicated by the marked reduction of Wnt1 protein (XREF_FIG, Day 0), increased phosphorylation of GSK-3beta (p-GSK-3beta) (XREF_FIG, Day 10), and reduced nuclear beta-catenin (XREF_FIG, Day 10).	1	44	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p-GSK-3beta	Wnt signaling was repressed following miR-148a expression, as indicated by the marked reduction of Wnt1 protein (XREF_FIG, Day 0), increased phosphorylation of GSK-3beta (p-GSK-3beta	p-gsk-3beta	beta-catenin	beta-catenin	beta-catenin	30	31	42	43
In the Wnt and beta-catenin pathway GSK3beta mediates beta-catenin degradation .	In the Wnt and beta-catenin pathway GSK3beta mediates beta-catenin degradation.	6	9	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
In PI3K/Akt/GSK-3beta/beta-catenin signaling pathway , GSK-3beta plays an important role in beta-catenin phosphorylation and degradation and thus prevents beta-catenin from translocating into the nucleus , in which it forms a complex with TCF transcription factor family members to enhance beta-catenin-responsive c-Myc , Cyclin D1 and MMP-7 gene expression .	In PI3K/Akt/GSK-3beta/beta-catenin signaling pathway, GSK-3beta plays an important role in beta-catenin phosphorylation and degradation and thus prevents beta-catenin from translocating into the nucleus, in which it forms a complex with TCF transcription factor family members to enhance beta-catenin-responsive c-Myc, Cyclin D1 and MMP-7 gene expression.	5	19	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	18	19
The inhibition of GSK-3beta blocks this digestion and increases the accumulation of intracellular beta-catenin [ XREF_BIBR ] .	The inhibition of GSK-3beta blocks this digestion and increases the accumulation of intracellular beta-catenin [XREF_BIBR].	1	15	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	13	14
Since Gsk3beta sequesters beta-catenin for degradation in the cytoplasm , thereby suggesting suppression of canonical Wnt signaling in neonatal CPCs and the promotion of canonical Wnt signaling in adult CPCs , we measured non canonical Wnt ligand expression and that of genes in the Wnt/Ca 2+ pathway .	Since Gsk3beta sequesters beta-catenin for degradation in the cytoplasm, thereby suggesting suppression of canonical Wnt signaling in neonatal CPCs and the promotion of canonical Wnt signaling in adult CPCs, we measured non canonical Wnt ligand expression and that of genes in the Wnt/Ca 2+ pathway.	1	4	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	1	2	3	4
Conditional loss of BMPR1a in telogen follicles also results in the precocious entry of follicles into anagen and the stabilization of beta-catenin , and , at least in part , this appears to be caused by the activation of PI3 kinase signaling , which , in turn , phosphorylates and inactivates GSK3beta , the kinase that otherwise targets beta-catenin for phosphorylation and ubiquitin mediated degradation .	Conditional loss of BMPR1a in telogen follicles also results in the precocious entry of follicles into anagen and the stabilization of beta-catenin, and, at least in part, this appears to be caused by the activation of PI3 kinase signaling, which, in turn, phosphorylates and inactivates GSK3beta, the kinase that otherwise targets beta-catenin for phosphorylation and ubiquitin mediated degradation.	39	62	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	GSK3beta	PI3 kinase signaling, which, in turn, phosphorylates and inactivates GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	51	52	58	59
Our results suggest that inhibition of GSK3beta activity in mESCs enhances both the beta-catenin and E-cadherin-mediated adhesion and the Tcf and beta-catenin-dependent transcription , but does not activate transcription in most of the examined genes involved in EMT and cell cycle progression .	Our results suggest that inhibition of GSK3beta activity in mESCs enhances both the beta-catenin and E-cadherin-mediated adhesion and the Tcf and beta-catenin-dependent transcription, but does not activate transcription in most of the examined genes involved in EMT and cell cycle progression.	6	22	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	6	7	13	14
Taken together , our results demonstrated a molecular mechanism by which glucose deprivation could induce the GSK3beta independent degradation of beta-catenin protein , leading to autophagy .	Taken together, our results demonstrated a molecular mechanism by which glucose deprivation could induce the GSK3beta independent degradation of beta-catenin protein, leading to autophagy.	16	21	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	16	17	20	21
DIF-1 activated glycogen synthase kinase-3beta ( GSK-3beta ) and inhibition of GSK-3beta attenuated the DIF-1-induced beta-catenin degradation , indicating the involvement of GSK-3beta in this effect .	DIF-1 activated glycogen synthase kinase-3beta (GSK-3beta) and inhibition of GSK-3beta attenuated the DIF-1-induced beta-catenin degradation, indicating the involvement of GSK-3beta in this effect.	4	16	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	15	16
In this study , knocking down TACC3 increased p-GSK3beta levels , which then suppressed beta-catenin activation , leading to reduced c-Myc and cyclin D1 levels .	In this study, knocking down TACC3 increased p-GSK3beta levels, which then suppressed beta-catenin activation, leading to reduced c-Myc and cyclin D1 levels.	6	15	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p-GSK3beta	TACC3 increased p-GSK3beta levels	p-gsk3beta	beta-catenin	beta-catenin	beta-catenin	8	9	14	15
These results suggest that BPA induced cytotoxicity is at least partly relieved by beta-catenin transcriptional activation modulated by GSK3beta inhibition .	These results suggest that BPA induced cytotoxicity is at least partly relieved by beta-catenin transcriptional activation modulated by GSK3beta inhibition.	13	19	modulated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	18	19	13	14
Therefore , the decreased expression level or activity of GSK3beta will inhibit the degradation of beta-catenin , which results in accumulating of beta-catenin in the cytoplasm and then enter the nucleus to activate the target genes expression XREF_BIBR - XREF_BIBR .	Therefore, the decreased expression level or activity of GSK3beta will inhibit the degradation of beta-catenin, which results in accumulating of beta-catenin in the cytoplasm and then enter the nucleus to activate the target genes expression XREF_BIBR - XREF_BIBR.	5	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	level or activity of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	9	10	15	16
In the present study , we found GSK-3beta activation mediated beta-catenin degradation and monolayer hyperpermeability in IAV infected HUVECs , and we propose a mechanism for the disruption of the adherens junctional complexes of vascular endothelial cells after severe IAV infection .	In the present study, we found GSK-3beta activation mediated beta-catenin degradation and monolayer hyperpermeability in IAV infected HUVECs, and we propose a mechanism for the disruption of the adherens junctional complexes of vascular endothelial cells after severe IAV infection.	7	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	10	11
GSK-3beta activation reduces the stability of beta-catenin and leads to its degradation through ubiquitination , whereas GSK-3beta inhibition stabilizes beta-catenin and increases its nuclear translocation to regulate gene expression , synaptic plasticity , and neurogenesis , which in turn exerts antidepressant effects .	GSK-3beta activation reduces the stability of beta-catenin and leads to its degradation through ubiquitination, whereas GSK-3beta inhibition stabilizes beta-catenin and increases its nuclear translocation to regulate gene expression, synaptic plasticity, and neurogenesis, which in turn exerts antidepressant effects.	0	7	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
Indeed , based on the observations that down-regulation of alpha6A levels results in a reduction of the relative amounts of both active ( evaluated as the non GSK3beta phosphorylated form ) and nuclear beta-catenin , whereas the pharmacological inhibition of GSK3beta restored the activity of the Wnt and beta-catenin pathway as evaluated by TOPflash assays and the modulation of specific target genes including LGR5 and CCD2 , we suggest that alpha6A interferes with the activity of GSK3beta .	Indeed, based on the observations that down-regulation of alpha6A levels results in a reduction of the relative amounts of both active (evaluated as the non GSK3beta phosphorylated form) and nuclear beta-catenin, whereas the pharmacological inhibition of GSK3beta restored the activity of the Wnt and beta-catenin pathway as evaluated by TOPflash assays and the modulation of specific target genes including LGR5 and CCD2, we suggest that alpha6A interferes with the activity of GSK3beta.	38	49	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	40	41	48	49
The expression of both Dkk1 and Gsk3beta , which decrease Wnt and beta-catenin activity , was reduced in cells exposed to high phosphate .	The expression of both Dkk1 and Gsk3beta, which decrease Wnt and beta-catenin activity, was reduced in cells exposed to high phosphate.	1	13	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	expression of both Dkk1 and Gsk3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	6	7	12	13
Inhibition of GSK3beta rescues Wnt and beta-catenin pathway .	Inhibition of GSK3beta rescues Wnt and beta-catenin pathway.	0	7	rescues	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
This suggests that inhibition of GSK3beta activity with LiCl prevents proteolytic degradation of beta-catenin and that GSK3beta is implicated in beta-catenin degradation after Rosi treatment .	This suggests that inhibition of GSK3beta activity with LiCl prevents proteolytic degradation of beta-catenin and that GSK3beta is implicated in beta-catenin degradation after Rosi treatment.	5	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	5	6	13	14
As expected , LiCl , a selective inhibitor of GSK-3beta , activated Wnt and beta-catenin signaling as indicated by the translocation of beta-catenin into the nucleus ( XREF_SUPPLEMENTARY ) and reduced BzATP mediated cell death ( XREF_FIG ) .	As expected, LiCl, a selective inhibitor of GSK-3beta, activated Wnt and beta-catenin signaling as indicated by the translocation of beta-catenin into the nucleus (XREF_SUPPLEMENTARY) and reduced BzATP mediated cell death (XREF_FIG).	7	15	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	9	10	14	15
Recently , DISC1 was shown to regulate the proliferative ability of progenitors in the SGZ by negatively regulating GSK3beta mediated inhibition of beta-catenin .	Recently, DISC1 was shown to regulate the proliferative ability of progenitors in the SGZ by negatively regulating GSK3beta mediated inhibition of beta-catenin.	18	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	18	19	22	23
Cell cycle and proliferation are regulated by beta-catenin , and beta-catenin activity is negatively regulated by GSK3beta .	Cell cycle and proliferation are regulated by beta-catenin, and beta-catenin activity is negatively regulated by GSK3beta.	10	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	16	17	10	11
In our cultures , application of LiCl , an inhibitor of GSK3beta , produced a strong increase in the intensity of ' active ' beta-catenin in both the nucleus and soma , verifying the effectiveness of the antibody ( Additional file XREF_SUPPLEMENTARY ) .	In our cultures, application of LiCl, an inhibitor of GSK3beta, produced a strong increase in the intensity of ' active ' beta-catenin in both the nucleus and soma, verifying the effectiveness of the antibody (Additional file XREF_SUPPLEMENTARY).	9	30	produced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	11	12	24	25
Moreover , WNT-5A attenuates beta-catenin signaling activated by pharmacological inhibition of GSK-3beta , indicating that the ligand additionally activates an intracellular signaling cascade that negatively influences beta-catenin signaling .	Moreover, WNT-5A attenuates beta-catenin signaling activated by pharmacological inhibition of GSK-3beta, indicating that the ligand additionally activates an intracellular signaling cascade that negatively influences beta-catenin signaling.	4	12	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	11	12	4	5
Degradation of beta-catenin was inhibited by pretreatment of a proteasomal inhibitor , MG132 or lactacystin ( XREF_FIG ) , but inhibition of GSK3beta had almost no effect on TNF induced beta-catenin degradation .	Degradation of beta-catenin was inhibited by pretreatment of a proteasomal inhibitor, MG132 or lactacystin (XREF_FIG), but inhibition of GSK3beta had almost no effect on TNF induced beta-catenin degradation.	20	31	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	22	23	30	31
Inhibition of GSK3beta activates Wnt and beta-catenin signalling in cultured cerebellar slices .	Inhibition of GSK3beta activates Wnt and beta-catenin signalling in cultured cerebellar slices.	0	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	6	7
In addition , a mutation in GSK3beta has been shown to inhibit its ability to phosphorylate substrates , thereby allowing beta-catenin to accumulate in the cells [ XREF_BIBR ] .	In addition, a mutation in GSK3beta has been shown to inhibit its ability to phosphorylate substrates, thereby allowing beta-catenin to accumulate in the cells [XREF_BIBR].	4	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	6	7	20	21
The promoting effect of alpha6A on the expression of the active and nuclear form of beta-catenin and the fact that inhibition of GSK3beta could rescue the activity of the Wnt and beta-catenin pathway suggest that alpha6A could interfere with a signalling event upstream to GSK3beta .	The promoting effect of alpha6A on the expression of the active and nuclear form of beta-catenin and the fact that inhibition of GSK3beta could rescue the activity of the Wnt and beta-catenin pathway suggest that alpha6A could interfere with a signalling event upstream to GSK3beta.	20	32	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	22	23	31	32
On one hand , GSK3beta can inhibit beta-catenin and subsequent tumor progression , and its downstream targets ( c-myc , cyclin D1 , PPARdelta ) are also reported to be involved in this process XREF_BIBR - XREF_BIBR .	On one hand, GSK3beta can inhibit beta-catenin and subsequent tumor progression, and its downstream targets (c-myc, cyclin D1, PPARdelta) are also reported to be involved in this process XREF_BIBR - XREF_BIBR.	4	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	4	5	7	8
Based on previous research , beta-catenin is inhibited by phosphorylation of GSK-3beta .	Based on previous research, beta-catenin is inhibited by phosphorylation of GSK-3beta.	5	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	11	12	5	6
After GSK3beta inhibition , which activates beta-catenin , stimulation of monocytes or PBMCs with various TLR agonists induced IL-10 production while suppressing the release of proinflammatory cytokines [ XREF_BIBR ] .	After GSK3beta inhibition, which activates beta-catenin, stimulation of monocytes or PBMCs with various TLR agonists induced IL-10 production while suppressing the release of proinflammatory cytokines [XREF_BIBR].	1	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
Phosphorylation of beta-catenin by GSK3beta is required for proteasomal destruction of beta-catenin and inhibition of GSK3beta activates beta-catenin .	Phosphorylation of beta-catenin by GSK3beta is required for proteasomal destruction of beta-catenin and inhibition of GSK3beta activates beta-catenin.	13	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	15	16	17	18
Consequently , PPARgamma PTEN mediated antagonism of AKT may reduce the inhibition of GSK3beta enhancing proteasomal degradation of beta-catenin , in agreement with other reports that have implicated PTEN as a negative regulator of beta-catenin by way of AKT and GSK3beta [ XREF_BIBR ] .	Consequently, PPARgamma PTEN mediated antagonism of AKT may reduce the inhibition of GSK3beta enhancing proteasomal degradation of beta-catenin, in agreement with other reports that have implicated PTEN as a negative regulator of beta-catenin by way of AKT and GSK3beta [XREF_BIBR].	11	19	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	13	14	18	19
The loss of APC and GSK3-beta did not lead to augmentation of the Wnt target protein cyclin D1 or the Wnt oncoprotein beta-catenin .	The loss of APC and GSK3-beta did not lead to augmentation of the Wnt target protein cyclin D1 or the Wnt oncoprotein beta-catenin.	1	23	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	GSK3-beta	loss of APC and GSK3-beta	gsk3-beta	beta-catenin	beta-catenin	beta-catenin	5	6	22	23
Inhibition of GSK3beta kinase by activated Akt prevents beta-catenin degradation that may be especially important for activating beta-catenin-dependent genes such as cyclin D , laminin , fibronectin , and metalloproteinases needed for epithelial cell proliferation , migration , and restoring adhesion of repaired cells to the basement membrane .	Inhibition of GSK3beta kinase by activated Akt prevents beta-catenin degradation that may be especially important for activating beta-catenin-dependent genes such as cyclin D, laminin, fibronectin, and metalloproteinases needed for epithelial cell proliferation, migration, and restoring adhesion of repaired cells to the basement membrane.	2	9	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
Upon pathological stress , Wnt3a binds to its receptor , frizzled1 ( FZD1 ) , a seven-transmembrane receptor abundantly expressed in the heart tissue , increased the phosphorylation of GSK-3beta and consequently blocked the beta-catenin degradation [ XREF_BIBR ] .	Upon pathological stress, Wnt3a binds to its receptor, frizzled1 (FZD1), a seven-transmembrane receptor abundantly expressed in the heart tissue, increased the phosphorylation of GSK-3beta and consequently blocked the beta-catenin degradation [XREF_BIBR].	10	35	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	frizzled1 (FZD1), a seven-transmembrane receptor abundantly expressed in the heart tissue, increased the phosphorylation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	29	30	34	35
Increases in GSK-3beta activity during aging inactivate beta-catenin through phosphorylation .	Increases in GSK-3beta activity during aging inactivate beta-catenin through phosphorylation.	2	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
Cordycepin reduced beta-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3beta , indicating that cordycepin suppressed beta-catenin stability is mediated by the activation of GSK-3beta .	Cordycepin reduced beta-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3beta, indicating that cordycepin suppressed beta-catenin stability is mediated by the activation of GSK-3beta.	2	15	restored	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	14	15	2	3
As a negative regulator of the Wnt signaling pathway , GSK3beta promotes the degradation of beta-catenin and inhibits the activity of the canonical Wnt signaling pathway XREF_BIBR .	As a negative regulator of the Wnt signaling pathway, GSK3beta promotes the degradation of beta-catenin and inhibits the activity of the canonical Wnt signaling pathway XREF_BIBR.	10	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	10	11	15	16
Small molecule glycogen synthase kinase 3 beta ( GSK-3beta ) inhibitors have been investigated to activate the Wnt and beta-catenin pathway and tested preclinically , such as 603281-31-8 ( Eli Lilly ) , which increased bone formation markers in ovariectomized rats , 21 and AZD2858 ( AstraZeneca ) , which enhanced osteoblastic activity and fracture healing in rats .	Small molecule glycogen synthase kinase 3 beta (GSK-3beta) inhibitors have been investigated to activate the Wnt and beta-catenin pathway and tested preclinically, such as 603281-31-8 (Eli Lilly), which increased bone formation markers in ovariectomized rats, 21 and AZD2858 (AstraZeneca), which enhanced osteoblastic activity and fracture healing in rats.	8	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	8	9	19	20
Specifically , Wnt5a was reported to promote GSK3beta independent degradation of beta-catenin in the regulation of limb development .	Specifically, Wnt5a was reported to promote GSK3beta independent degradation of beta-catenin in the regulation of limb development.	7	12	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	11	12
It is well known that GSK3beta negatively regulates the classical Wnt signaling pathway by phosphorylation of beta-catenin , and activation of GSK3beta induces ubiquitin dependent degradation of beta-catenin [ XREF_BIBR ] .	It is well known that GSK3beta negatively regulates the classical Wnt signaling pathway by phosphorylation of beta-catenin, and activation of GSK3beta induces ubiquitin dependent degradation of beta-catenin [XREF_BIBR].	19	29	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	21	22	27	28
Inhibition of GSK-3beta can upregulate HIF-1alphaexpression and increase beta-catenin activity [ XREF_BIBR ] .	Inhibition of GSK-3beta can upregulate HIF-1alphaexpression and increase beta-catenin activity [XREF_BIBR].	0	9	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
GSK-3beta activity promotes phophorylation of beta-catenin and protein degradation .	GSK-3beta activity promotes phophorylation of beta-catenin and protein degradation.	0	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	5	6
First , we analyzed whether proliferation could be rescued by inhibition of GSK3beta , thereby activating beta-catenin .	First, we analyzed whether proliferation could be rescued by inhibition of GSK3beta, thereby activating beta-catenin.	10	17	activating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	12	13	16	17
As Glycogen synthase kinase-3beta ( GSK-3beta ) prevents beta-catenin from translocating into the nucleus , we tested the sub-cellular distribution of beta-catenin .	As Glycogen synthase kinase-3beta (GSK-3beta) prevents beta-catenin from translocating into the nucleus, we tested the sub-cellular distribution of beta-catenin.	3	9	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	8	9
GSK-3beta plays an important role in beta-catenin phosphorylation and degradation and thus prevents beta-catenin from translocating into the nucleus , in which it forms a complex with the TCF transcription factor family members to enhance beta-catenin-responsive gene expression , such as E-cadherin .	GSK-3beta plays an important role in beta-catenin phosphorylation and degradation and thus prevents beta-catenin from translocating into the nucleus, in which it forms a complex with the TCF transcription factor family members to enhance beta-catenin-responsive gene expression, such as E-cadherin.	0	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	13	14
Deletion of APC or GSK3beta in the murine intestine activates the WNT and beta-catenin pathway , resulting in rapid development of adenomas and early lethality [ XREF_BIBR ] .	Deletion of APC or GSK3beta in the murine intestine activates the WNT and beta-catenin pathway, resulting in rapid development of adenomas and early lethality [XREF_BIBR].	0	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	4	5	13	14
Consistent with these findings , we found that GSK3beta inhibition induced accumulation of beta-catenin in the hippocampus .	Consistent with these findings, we found that GSK3beta inhibition induced accumulation of beta-catenin in the hippocampus.	8	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	8	9	13	14
Wnt-3a or pharmacological inhibition of GSK-3beta induce beta-catenin stabilization and beta-catenin-dependent transcriptional activity in differentiating myoblasts .	Wnt-3a or pharmacological inhibition of GSK-3beta induce beta-catenin stabilization and beta-catenin-dependent transcriptional activity in differentiating myoblasts.	3	8	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	7	8
This implies that GSK3beta independent or suppressed regulation might play a prominent role in EGF induced beta-catenin transactivation .	This implies that GSK3beta independent or suppressed regulation might play a prominent role in EGF induced beta-catenin transactivation.	3	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	16	17
PKA phosphorylates GSK3beta at the amino acid Ser 9 , which inhibits its kinase activity and then inactivates the beta-catenin destruction complex .	PKA phosphorylates GSK3beta at the amino acid Ser 9, which inhibits its kinase activity and then inactivates the beta-catenin destruction complex.	0	21	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	PKA phosphorylates GSK3beta at the amino acid Ser 9	gsk3beta	beta-catenin	beta-catenin	beta-catenin	2	3	19	20
For example , if actbeta-cat ( a stabilized form of beta-catenin that can not be negatively regulated by GSK-3beta ) is overexpressed in whole embryos , they become vegetalized , produce high amounts of endomesoderm at the expense of ectoderm [ XREF_BIBR ] , and are radialized ( body axis formation is disrupted and serotonergic neurons are lost , likely due to loss of the ANE ) [ XREF_BIBR , XREF_BIBR ] .	For example, if actbeta-cat (a stabilized form of beta-catenin that can not be negatively regulated by GSK-3beta) is overexpressed in whole embryos, they become vegetalized, produce high amounts of endomesoderm at the expense of ectoderm [XREF_BIBR], and are radialized (body axis formation is disrupted and serotonergic neurons are lost, likely due to loss of the ANE) [XREF_BIBR, XREF_BIBR].	8	19	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	18	19	10	11
Additionally , it has been suggested that activation of GSK3beta may inhibit the proliferative effects of Wnt and beta-catenin in PCa .	Additionally, it has been suggested that activation of GSK3beta may inhibit the proliferative effects of Wnt and beta-catenin in PCa.	7	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	9	10	18	19
GSK3beta is a repressor of beta-catenin and Snail able of inhibiting E-cadherin expression and subsequently promotes EMT and tumor progression .	GSK3beta is a repressor of beta-catenin and Snail able of inhibiting E-cadherin expression and subsequently promotes EMT and tumor progression.	0	15	is a repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	0	1	5	6
GSK3beta has been shown to suppress c-MYC , beta-catenin , and other proteins important for lung tumorigenesis , thus its inhibition by PI3K signaling in KPiP cells may contribute to their enhanced proliferative capacity .	GSK3beta has been shown to suppress c-MYC, beta-catenin, and other proteins important for lung tumorigenesis, thus its inhibition by PI3K signaling in KPiP cells may contribute to their enhanced proliferative capacity.	0	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	0	1	8	9
In the absence of Wnt signalling , beta-Catenin is degraded by the GSK3-beta , Axin and APC destruction complex .	In the absence of Wnt signalling, beta-Catenin is degraded by the GSK3-beta, Axin and APC destruction complex.	7	18	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3-beta	GSK3-beta	GSK3-beta	beta-Catenin	beta-Catenin	beta-Catenin	12	13	7	8
Since GSK3beta could catalyze the phosphorylation of serine or threonine residues on CTNNB1 substrates , the upregulation of GSK3beta may promote the degradation of CTNNB1 in the cytoplasm and inhibit the Wnt pathway , which , together with the increase in CTNNB1 expression on the membrane , could strengthen the E , cadherin , and CTNNB1 complex , making it difficult for the GC cells to move .	Since GSK3beta could catalyze the phosphorylation of serine or threonine residues on CTNNB1 substrates, the upregulation of GSK3beta may promote the degradation of CTNNB1 in the cytoplasm and inhibit the Wnt pathway, which, together with the increase in CTNNB1 expression on the membrane, could strengthen the E, cadherin, and CTNNB1 complex, making it difficult for the GC cells to move.	16	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	CTNNB1	CTNNB1	CTNNB1	18	19	24	25
Since beta-catenin can induce the expression of genes for myocardial hypertrophy , the increased degradation of beta-catenin by GSK-3beta reduces the expression of these hypertrophy inducing genes , such as yes associated protein ( YAP ) [ XREF_BIBR , XREF_BIBR ] .	Since beta-catenin can induce the expression of genes for myocardial hypertrophy, the increased degradation of beta-catenin by GSK-3beta reduces the expression of these hypertrophy inducing genes, such as yes associated protein (YAP) [XREF_BIBR, XREF_BIBR].	14	19	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	18	19	16	17
Thus , inhibition of GSK-3beta should induce the accumulation of beta-catenin .	Thus, inhibition of GSK-3beta should induce the accumulation of beta-catenin.	2	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	10	11
Activation of GSK3beta leads to increased phosphorylation and accelerated degradation of beta-catenin which results in suppression of canonical Wnt signals .	Activation of GSK3beta leads to increased phosphorylation and accelerated degradation of beta-catenin which results in suppression of canonical Wnt signals.	0	12	accelerated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
However , GBP-1 appears to represses beta- catenin through a different mechanism , as GSK3-beta and proteasomal inhibition was unable to rescue the loss of beta-catenin and TCF activity ( XREF_FIG and XREF_SUPPLEMENTARY ) .	However, GBP-1 appears to represses beta- catenin through a different mechanism, as GSK3-beta and proteasomal inhibition was unable to rescue the loss of beta-catenin and TCF activity (XREF_FIG and XREF_SUPPLEMENTARY).	14	28	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3-beta	GSK3-beta	GSK3-beta	beta-catenin	beta-catenin	beta-catenin	14	15	25	26
For example , GSK-3beta activity indirectly induces proteasome degradation of beta-catenin , leading to reduced beta-cell replication [ XREF_BIBR ] , so its inhibition may have stimulating effects on beta-cell mass .	For example, GSK-3beta activity indirectly induces proteasome degradation of beta-catenin, leading to reduced beta-cell replication [XREF_BIBR], so its inhibition may have stimulating effects on beta-cell mass.	3	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	10	11
When Wnt signaling is active , GSK-3beta is inhibited , allowing beta-catenin to accumulate in the nucleus where it binds to TCF-LEF transcription factors and activates Wnt-target genes .	When Wnt signaling is active, GSK-3beta is inhibited, allowing beta-catenin to accumulate in the nucleus where it binds to TCF-LEF transcription factors and activates Wnt-target genes.	6	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	11	12
We focused on Tat because : 1 ) Tat enhances activity of GSK3beta which would likely disrupt beta-catenin signaling , 2 ) Tat is secreted and is internalized by non infected cells , and 3 ) Tat has a well established role in promoting HIV neuropathogenesis by enhancing oxidative stress in target cells and inducing gliosis in astrocytes , contributing to neurodegeneration .	We focused on Tat because : 1) Tat enhances activity of GSK3beta which would likely disrupt beta-catenin signaling, 2) Tat is secreted and is internalized by non infected cells, and 3) Tat has a well established role in promoting HIV neuropathogenesis by enhancing oxidative stress in target cells and inducing gliosis in astrocytes, contributing to neurodegeneration.	10	18	disrupt	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	12	13	17	18
As shown in XREF_FIG , Ser 9 phosphorylation of GSK3beta was significantly decreased in the shNRP-2 cells , indicating that in these cells there were increased levels of active GSK3beta protein , which promotes beta-catenin degradation .	As shown in XREF_FIG, Ser 9 phosphorylation of GSK3beta was significantly decreased in the shNRP-2 cells, indicating that in these cells there were increased levels of active GSK3beta protein, which promotes beta-catenin degradation.	29	35	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	29	30	34	35
Cadherin bound beta-catenin is stable and involved in the maintenance of cell-cell adhesion , whereas cytoplasmic free beta-catenin is degraded in the proteasome through priming phosphorylation at S45 by CK1 , following phosphorylation at S33 , S37 and T41 by GSK3beta , and subsequent poly-ubiquitylation at K19 by E3 ubiquitin ligase .	Cadherin bound beta-catenin is stable and involved in the maintenance of cell-cell adhesion, whereas cytoplasmic free beta-catenin is degraded in the proteasome through priming phosphorylation at S45 by CK1, following phosphorylation at S33, S37 and T41 by GSK3beta, and subsequent poly-ubiquitylation at K19 by E3 ubiquitin ligase.	15	41	degraded	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	40	41	17	18
As previous studies show that GSK3beta can destabilize beta-catenin [ XREF_BIBR ] , we speculate that GSK3beta may negatively regulate Akt or beta-catenin , leading to a lowered STAT5 and dysregulated cytokine patterns .	As previous studies show that GSK3beta can destabilize beta-catenin [XREF_BIBR], we speculate that GSK3beta may negatively regulate Akt or beta-catenin, leading to a lowered STAT5 and dysregulated cytokine patterns.	16	23	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	16	17	22	23
As GSK3beta was shown to inhibit the degradation process of beta-catenin , we found corresponding results that phosphorylated GSK3beta leads to an increase of cellular beta-catenin in CIP treated DPCs ( XREF_FIG ) .	As GSK3beta was shown to inhibit the degradation process of beta-catenin, we found corresponding results that phosphorylated GSK3beta leads to an increase of cellular beta-catenin in CIP treated DPCs (XREF_FIG).	1	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	1	2	10	11
Glycogen synthase kinase-3beta ( GSK3beta ) , serine/threonine protein kinase , has been reported to repress the Wnt and beta-catenin pathway and regulate the balance between cellular proliferation and apoptosis .	Glycogen synthase kinase-3beta (GSK3beta), serine/threonine protein kinase, has been reported to repress the Wnt and beta-catenin pathway and regulate the balance between cellular proliferation and apoptosis.	2	20	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	4	5	19	20
Gsk3beta phosphorylates and promotes degradation of beta-catenin and thus downregulates canonical Wnt signaling .	Gsk3beta phosphorylates and promotes degradation of beta-catenin and thus downregulates canonical Wnt signaling.	0	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
GSK-3beta protein inhibits Wnt and beta-catenin pathway in two ways : one is by anchoring beta-catenin to E-cadherin on the cell membrane ; the other is by phosphorylating beta-catenin , targeting it for ubiquitination and proteasomal degradation XREF_BIBR , consequently , gene transcription can not be initiated XREF_BIBR , XREF_BIBR .	GSK-3beta protein inhibits Wnt and beta-catenin pathway in two ways : one is by anchoring beta-catenin to E-cadherin on the cell membrane; the other is by phosphorylating beta-catenin, targeting it for ubiquitination and proteasomal degradation XREF_BIBR, consequently, gene transcription can not be initiated XREF_BIBR, XREF_BIBR.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta protein	GSK-3beta protein	GSK-3beta protein	beta-catenin	beta-catenin	beta-catenin	0	2	5	6
Pharmacologic inhibition of GSK-3beta using lithium chloride is known to increase beta-catenin nuclear localization and enhance Wnt signaling in vitro and in vivo .	Pharmacologic inhibition of GSK-3beta using lithium chloride is known to increase beta-catenin nuclear localization and enhance Wnt signaling in vitro and in vivo.	1	13	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
Inhibition of GSK3beta with SB216763 blocks intracellular beta-catenin degradation and stimulates canonical signaling , independent of Wnt signals .	Inhibition of GSK3beta with SB216763 blocks intracellular beta-catenin degradation and stimulates canonical signaling, independent of Wnt signals.	0	8	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
The simplest explanation would be that there is a cooperative effect between h-Prune and the other drugs used here , for the inhibition of beta-catenin degradation by Gsk-3beta .	The simplest explanation would be that there is a cooperative effect between h-Prune and the other drugs used here, for the inhibition of beta-catenin degradation by Gsk-3beta.	24	28	degradation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Gsk-3beta	Gsk-3beta	Gsk-3beta	beta-catenin	beta-catenin	beta-catenin	27	28	24	25
30 beta-catenin is also negatively regulated by GSK3beta .	30 beta-catenin is also negatively regulated by GSK3beta.	0	8	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	1	2
In summary , pharmacological inhibition of GSK3beta with lithium significantly increased pGSK3beta ser9 and decreased pbeta-catenin ser33/37/thr41 , thereby suggesting GSK3beta inhibition and reduced beta-catenin degradation .	In summary, pharmacological inhibition of GSK3beta with lithium significantly increased pGSK3beta ser9 and decreased pbeta-catenin ser33/37/thr41, thereby suggesting GSK3beta inhibition and reduced beta-catenin degradation.	4	25	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	6	7	24	25
This active pool of Gsk3beta could antagonize the differentiating beta-catenin stimulus in hESCs [ XREF_BIBR ] .	This active pool of Gsk3beta could antagonize the differentiating beta-catenin stimulus in hESCs [XREF_BIBR].	2	10	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	4	5	9	10
XREF_BIBR , XREF_BIBR Interestingly , previous studies demonstrated that GSK3beta inhibits the Wnt and beta-catenin signaling pathway and that miR-135a may activate the Wnt and beta-catenin signaling pathway by inhibiting GSK3beta .	XREF_BIBR, XREF_BIBR Interestingly, previous studies demonstrated that GSK3beta inhibits the Wnt and beta-catenin signaling pathway and that miR-135a may activate the Wnt and beta-catenin signaling pathway by inhibiting GSK3beta.	9	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	9	10	14	15
Wnt signaling is mediated by blocking the activity of glycogen synthase kinase 3beta ( GSK3beta ) , which promotes beta-catenin degradation .	Wnt signaling is mediated by blocking the activity of glycogen synthase kinase 3beta (GSK3beta), which promotes beta-catenin degradation.	12	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	14	15	19	20
Thereby , Gsk3beta is inactivated , causing a stabilization of beta-catenin .	Thereby, Gsk3beta is inactivated, causing a stabilization of beta-catenin.	2	11	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	2	3	10	11
EZH2 mediated repression of GSK-3beta and TP53 promotes Wnt and beta-catenin signaling dependent cell expansion in cervical carcinoma .	EZH2 mediated repression of GSK-3beta and TP53 promotes Wnt and beta-catenin signaling dependent cell expansion in cervical carcinoma.	2	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	10	11
Further , degradation of beta-catenin by GSK-3beta is not a general mechanism but is cell type dependent .	Further, degradation of beta-catenin by GSK-3beta is not a general mechanism but is cell type dependent.	2	7	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	4	5
Moreover , upregulation of GSK3beta induced the degradation of beta-catenin , which resulted in apoptosis of neurons .	Moreover, upregulation of GSK3beta induced the degradation of beta-catenin, which resulted in apoptosis of neurons.	2	12	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	4	5	9	10
An inhibitor of GSK-3beta , LiCl can increase the nuclear accumulation of beta-catenin through suppressing degradation of beta-catenin in cytoplasm .	An inhibitor of GSK-3beta, LiCl can increase the nuclear accumulation of beta-catenin through suppressing degradation of beta-catenin in cytoplasm.	1	13	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	12	13
Although GSK-3beta inhibits the Wnt and beta-catenin pathway by beta-catenin degradation and by down-regulation of Wnt target genes , GSK-3beta also has the capacity to positively regulate NF-kappaB by targeting IkappaB , which inhibits NF-kappaB , leading to proteasomal degradation [ XREF_BIBR ] .	Although GSK-3beta inhibits the Wnt and beta-catenin pathway by beta-catenin degradation and by down-regulation of Wnt target genes, GSK-3beta also has the capacity to positively regulate NF-kappaB by targeting IkappaB, which inhibits NF-kappaB, leading to proteasomal degradation [XREF_BIBR].	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
On the other hand , active Notch signaling can enhance GSK3beta mediated beta-catenin degradation .	On the other hand, active Notch signaling can enhance GSK3beta mediated beta-catenin degradation.	9	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	10	11	12	13
beta-catenin is phosphorylated by GSK3beta and undergoes proteasomal degradation , while phosphorylation of GSK3beta inactivates and allows nuclear translocation of beta-catenin .	beta-catenin is phosphorylated by GSK3beta and undergoes proteasomal degradation, while phosphorylation of GSK3beta inactivates and allows nuclear translocation of beta-catenin.	11	21	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	13	14	20	21
The active form of GSK3beta directly interacts with the N-terminus of MAML1 to inhibit MAML1 transcriptional activity XREF_BIBR .	The active form of GSK3beta directly interacts with the N-terminus of MAML1 to inhibit MAML1 transcriptional activity XREF_BIBR.	2	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	4	5	14	15
MAML1 interacted equally well with both the active and inactive states of GSK3beta in a cellular assay , but GSK3beta must be active to decrease MAML1 transcriptional activity .	MAML1 interacted equally well with both the active and inactive states of GSK3beta in a cellular assay, but GSK3beta must be active to decrease MAML1 transcriptional activity.	19	27	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	19	20	25	26
In this report , we show that active GSK3beta directly interacts with the MAML1 N-terminus and decreases MAML1 transcriptional activity , suggesting that GSK3beta might target a coactivator in its regulation of gene expression .	In this report, we show that active GSK3beta directly interacts with the MAML1 N-terminus and decreases MAML1 transcriptional activity, suggesting that GSK3beta might target a coactivator in its regulation of gene expression.	7	19	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	8	9	17	18
GSK3beta was demonstrated to phosphorylate and negatively regulate Notch2 195 and the Notch co-activator MAML1 .	GSK3beta was demonstrated to phosphorylate and negatively regulate Notch2 195 and the Notch co-activator MAML1.	0	15	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	0	1	14	15
We found that GSK3beta inhibits MAML1 transcriptional activity by directly targeting the N-terminal domain of MAML1 .	We found that GSK3beta inhibits MAML1 transcriptional activity by directly targeting the N-terminal domain of MAML1.	3	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	3	4	5	6
In this study we showed that GSK3beta directly interacts with and decreases the activity of MAML1 , which is a coactivator of Notch , p53 and beta-catenin ,.	In this study we showed that GSK3beta directly interacts with and decreases the activity of MAML1, which is a coactivator of Notch, p53 and beta-catenin,.	6	20	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	6	7	15	16
As shown in XREF_FIG F , GSK3beta decreased the transcriptional activity of both MAML1 1-1016 and 1-300 ~ 4-fold .	As shown in XREF_FIG F, GSK3beta decreased the transcriptional activity of both MAML1 1-1016 and 1-300 ~ 4-fold.	6	17	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	6	7	13	14
We also found that GSK3beta interacts strongly with MAML1 regardless of its activity status , but that GSK3beta must be active to inhibit MAML1 activity .	We also found that GSK3beta interacts strongly with MAML1 regardless of its activity status, but that GSK3beta must be active to inhibit MAML1 activity.	17	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	17	18	23	24
To investigate if GSK3beta inhibits the activity of the MAML1 N-terminus in cellular assays , we cotransfected cells with a GAL4 reporter gene , GAL4-MAML1 1-1016 or 1-300 , and HA-GSK3beta .	To investigate if GSK3beta inhibits the activity of the MAML1 N-terminus in cellular assays, we cotransfected cells with a GAL4 reporter gene, GAL4-MAML1 1-1016 or 1-300, and HA-GSK3beta.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	3	4	9	10
Thus , we conclude that in our cell culture assay , GSK3beta inhibits Notch1 ICD activity to the same extent in both the presence and absence of overexpressed MAML1 .	Thus, we conclude that in our cell culture assay, GSK3beta inhibits Notch1 ICD activity to the same extent in both the presence and absence of overexpressed MAML1.	11	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	11	12	28	29
GSK3beta decreases MAML1 transcriptional activity .	GSK3beta decreases MAML1 transcriptional activity.	0	4	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	0	1	2	3
MICAL-1 binds CRMP-2 , and other CRMP family members [ XREF_BIBR ] , and is required for the oxidation dependent phosphorylation and inactivation of CRMP-2 by GSK-3beta ( glycogen synthase kinase-3beta ) leading to microtubule disassembly [ XREF_BIBR ] .	MICAL-1 binds CRMP-2, and other CRMP family members [XREF_BIBR], and is required for the oxidation dependent phosphorylation and inactivation of CRMP-2 by GSK-3beta (glycogen synthase kinase-3beta) leading to microtubule disassembly [XREF_BIBR].	1	32	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	CRMP-2	CRMP-2	CRMP-2	26	27	24	25
Phosphorylation of T514 by GSK-3beta , or of T555 by Rho Kinase , disrupts the interaction of CRMP2 with tubulin heterodimers preventing increases in axon length and branching [ XREF_BIBR ] .	Phosphorylation of T514 by GSK-3beta, or of T555 by Rho Kinase, disrupts the interaction of CRMP2 with tubulin heterodimers preventing increases in axon length and branching [XREF_BIBR].	0	18	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	Phosphorylation of T514 by GSK-3beta, or of T555	gsk-3beta	CRMP2	CRMP2	crmp2	4	5	17	18
Wnt may also promote optic nerve regeneration by blocking GSK-3beta inactivation of CRMP2 , which promotes axonal regrowth in the presence of inhibitory molecules ( Leibinger et al ., 2017 ) .	Wnt may also promote optic nerve regeneration by blocking GSK-3beta inactivation of CRMP2, which promotes axonal regrowth in the presence of inhibitory molecules (Leibinger et al., 2017).	9	15	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	CRMP2	CRMP2	CRMP2	9	10	12	13
In this work we demonstrate that CRMP-2 is critically involved in primary cilium formation and that GSK-3beta modulates primary cilium targeting of CRMP-2 : specific inhibition of GSK-3beta results in a reduction of the level of phosphorylated pCRMP-2 at the basal body and an enhanced localization of CRMP-2 at the primary cilium .	In this work we demonstrate that CRMP-2 is critically involved in primary cilium formation and that GSK-3beta modulates primary cilium targeting of CRMP-2 : specific inhibition of GSK-3beta results in a reduction of the level of phosphorylated pCRMP-2 at the basal body and an enhanced localization of CRMP-2 at the primary cilium.	16	23	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	CRMP-2	CRMP-2	CRMP-2	16	17	22	23
When applying lovastatin , the pGSK-3beta was decreased but the total GSK-3beta was not change , indicating that lovastatin mostly reduced pGSK-3beta and decreased pGSK-3beta and GSK-3beta ratio , further to inactivate CRMP-2 and to inhibit MFS .	When applying lovastatin, the pGSK-3beta was decreased but the total GSK-3beta was not change, indicating that lovastatin mostly reduced pGSK-3beta and decreased pGSK-3beta and GSK-3beta ratio, further to inactivate CRMP-2 and to inhibit MFS.	4	33	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pGSK-3beta	pGSK-3beta	pGSK-3beta	CRMP-2	CRMP-2	CRMP-2	5	6	32	33
Moreover it seems likely that in absence of the priming phosphorylation of HSF1 by ERK1/2 , the secondary effect of the activated Gsk3beta failed to inhibit HSF1 activity .	Moreover it seems likely that in absence of the priming phosphorylation of HSF1 by ERK1/2, the secondary effect of the activated Gsk3beta failed to inhibit HSF1 activity.	18	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	HSF1	HSF1	HSF1	22	23	26	27
Phosphorylation of GSK-3beta blocks the GSK-3 inactivation of HSF-1 and thereby increases activity of HSF-1 .	Phosphorylation of GSK-3beta blocks the GSK-3 inactivation of HSF-1 and thereby increases activity of HSF-1.	0	9	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	Phosphorylation of GSK-3beta	gsk-3beta	HSF-1	HSF-1	hsf-1	2	3	8	9
Although the molecular mechanism of HSF-1 ' s transcriptional regulation is not well elucidated , some evidence indicates that the activation of glycogen synthase kinase-3beta ( GSK-3beta ) signaling attenuates HSF-1 activity [ XREF_BIBR - XREF_BIBR ] .	Although the molecular mechanism of HSF-1 's transcriptional regulation is not well elucidated, some evidence indicates that the activation of glycogen synthase kinase-3beta (GSK-3beta) signaling attenuates HSF-1 activity [XREF_BIBR - XREF_BIBR].	26	31	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	HSF-1	HSF-1	HSF-1	26	27	30	31
This regulation might rely on the fact that the activation of AKT inhibited GSK-3beta [ XREF_BIBR ] , and the inhibition of GSK-3beta could activate HSF1 .	This regulation might rely on the fact that the activation of AKT inhibited GSK-3beta [XREF_BIBR], and the inhibition of GSK-3beta could activate HSF1.	20	26	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	HSF1	HSF1	HSF1	22	23	25	26
HSF1 transcriptional activity is negatively regulated by GSK3beta XREF_BIBR , which suggests that RPN2 knockdown may promote GSK3beta induced downregulation of HSP70 ( XREF_SUPPLEMENTARY ) .	HSF1 transcriptional activity is negatively regulated by GSK3beta XREF_BIBR, which suggests that RPN2 knockdown may promote GSK3beta induced downregulation of HSP70 (XREF_SUPPLEMENTARY).	0	8	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	HSF1	HSF1	HSF1	7	8	0	1
Indeed , GSK-3beta inhibition activates NFAT , TCF/Lef -1 , and Hsf1 .	Indeed, GSK-3beta inhibition activates NFAT, TCF/Lef -1, and Hsf1.	2	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Hsf1	Hsf1	Hsf1	2	3	11	12
GSK3beta also suppresses the activities of the HSF-1 and CREB transcriptional factors , which promote cell survival .	GSK3beta also suppresses the activities of the HSF-1 and CREB transcriptional factors, which promote cell survival.	0	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	HSF-1	HSF-1	HSF-1	0	1	7	8
Inhibition of GSK3beta results in activation of GYS and thereby glycogen synthesis [ XREF_BIBR ] .	Inhibition of GSK3beta results in activation of GYS and thereby glycogen synthesis [XREF_BIBR].	0	8	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	GYS	GYS	GYS	2	3	7	8
Since GSK3beta promotes the degradation of gephyrin and reduces GABA A R clustering XREF_BIBR , XREF_BIBR , the activation of GSK3beta by PRR7 overexpression is likely responsible for the GABA synapse loss .	Since GSK3beta promotes the degradation of gephyrin and reduces GABA A R clustering XREF_BIBR, XREF_BIBR, the activation of GSK3beta by PRR7 overexpression is likely responsible for the GABA synapse loss.	1	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	gephyrin	gephyrin	gephyrin	1	2	6	7
BDNF signaling through phosphatidylinositol 3-kinase ( PI3K )-Akt also activates mTOR and represses GSK3beta , which was previously shown to reduce gephyrin clustering .	BDNF signaling through phosphatidylinositol 3-kinase (PI3K)-Akt also activates mTOR and represses GSK3beta, which was previously shown to reduce gephyrin clustering.	12	22	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	gephyrin	gephyrin	gephyrin	13	14	21	22
Pharmacological blockade of the GSK3beta pathway or expression of the S270A gephyrin mutant is sufficient to increase gephyrin cluster size .	Pharmacological blockade of the GSK3beta pathway or expression of the S270A gephyrin mutant is sufficient to increase gephyrin cluster size.	4	19	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	gephyrin	gephyrin	gephyrin	4	5	17	18
The pharmacological inhibition of GSK-3beta similarly induced greater post-synaptic clustering of gephyrin .	The pharmacological inhibition of GSK-3beta similarly induced greater post-synaptic clustering of gephyrin.	2	12	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	gephyrin	gephyrin	gephyrin	4	5	11	12
GSK3beta in turn promotes postsynaptic GABA A R clustering and mIPSCs by reducing calpain-1-mediated cleavage of gephyrin ( XREF_FIG , XREF_FIG ) .	GSK3beta in turn promotes postsynaptic GABA A R clustering and mIPSCs by reducing calpain-1-mediated cleavage of gephyrin (XREF_FIG, XREF_FIG).	0	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	gephyrin	gephyrin	gephyrin	0	1	16	17
Inhibition of GSK3beta Activity Enhances BMAL1 Stability .	Inhibition of GSK3beta Activity Enhances BMAL1 Stability.	2	6	Enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	BMAL1	BMAL1	BMAL1	2	3	5	6
Moreover , CLOCK and BMAL1 activation via the Nlgn1 gene fragment was repressed by GSK3beta .	Moreover, CLOCK and BMAL1 activation via the Nlgn1 gene fragment was repressed by GSK3beta.	2	15	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	BMAL1	BMAL1	BMAL1	14	15	4	5
Similarly , expression of dominant negative GSK3beta can rescue the decreased CREBH cleavage activity in the Bmal1 knockdown hepatocytes under the circadian clock ( XREF_FIG ) , thus confirming that BMAL1 controls circadian regulated CREBH cleavage and activation through AKT and GSK3beta signaling in hepatocytes .	Similarly, expression of dominant negative GSK3beta can rescue the decreased CREBH cleavage activity in the Bmal1 knockdown hepatocytes under the circadian clock (XREF_FIG), thus confirming that BMAL1 controls circadian regulated CREBH cleavage and activation through AKT and GSK3beta signaling in hepatocytes.	2	18	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	expression of dominant negative GSK3beta	gsk3beta	Bmal1	Bmal1	bmal1	6	7	16	17
These findings suggest that GSK3beta and Fbw7 mediated degradation of c-Jun may not be necessary for c-Jun turnover in MEFs .	These findings suggest that GSK3beta and Fbw7 mediated degradation of c-Jun may not be necessary for c-Jun turnover in MEFs.	4	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	c-Jun	c-Jun	c-Jun	4	5	10	11
In particular , degradation of p53 by GRK-5 prevented apoptosis in osteosarcoma cells .	In particular, degradation of p53 by GRK-5 prevented apoptosis in osteosarcoma cells.	3	8	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	GRK-5	GRK-5	GRK-5	p53	p53	p53	7	8	5	6
GRK5 mediated p53 degradation directly affects apoptosis , as knockdown of GRK5 in the osteosarcoma cell line , U2OS , increases apoptosis by 40 % following cisplatin treatment .	GRK5 mediated p53 degradation directly affects apoptosis, as knockdown of GRK5 in the osteosarcoma cell line, U2OS, increases apoptosis by 40% following cisplatin treatment.	0	3	mediated	Positive_early_activation	Negative_activation	Negative_activation	GRK5	GRK5	GRK5	p53	p53	p53	0	1	2	3
GRK5 knockout mice display tissue-wide upregulation of p53 implying that GRK5 negatively regulates p53 in vivo .	GRK5 knockout mice display tissue-wide upregulation of p53 implying that GRK5 negatively regulates p53 in vivo.	10	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GRK5	GRK5	GRK5	p53	p53	p53	10	11	13	14
However , unlike TRAF4 , Axin , and GADD45 , GSK3beta inhibits MEKK4 activity and prevents its activation of JNK and p38 .	However, unlike TRAF4, Axin, and GADD45, GSK3beta inhibits MEKK4 activity and prevents its activation of JNK and p38.	10	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MEKK4	MEKK4	MEKK4	10	11	12	13
GSK3beta inhibits the activation of p38 and JNK by binding the MAP3K MEKK4 .	GSK3beta inhibits the activation of p38 and JNK by binding the MAP3K MEKK4.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MEKK4	MEKK4	MEKK4	0	1	12	13
Although GSK3a is generally thought to be a target of AKT , in the IL-1-stimulated Th17 cells , GSK3a negatively regulates AKT activation .	Although GSK3a is generally thought to be a target of AKT, in the IL-1-stimulated Th17 cells, GSK3a negatively regulates AKT activation.	18	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3a	GSK3a	GSK3a	AKT	AKT	AKT	18	19	21	22
Additionally , GSK3alpha can also inhibit the activity of Akt via phosphorylation on a recently discovered regulatory site at threonine312-Akt .	Additionally, GSK3alpha can also inhibit the activity of Akt via phosphorylation on a recently discovered regulatory site at threonine312-Akt.	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3alpha	GSK3alpha	GSK3alpha	Akt	Akt	Akt	2	3	9	10
GSK3beta dependent NO production activates LPS induced glycolysis and HDAC4 degradation .	GSK3beta dependent NO production activates LPS induced glycolysis and HDAC4 degradation.	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	HDAC4	HDAC4	HDAC4	0	1	9	10
In addition , it was recently reported that Notch1 ICD can be negatively regulated by the GSK3alpha isoform .	In addition, it was recently reported that Notch1 ICD can be negatively regulated by the GSK3alpha isoform.	8	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3alpha	GSK3alpha	GSK3alpha	Notch1	Notch1	Notch1	16	17	8	9
However , GRK6 , but not GRK2 , was able to inhibit MC1R agonist independent constitutive signaling .	However, GRK6, but not GRK2, was able to inhibit MC1R agonist independent constitutive signaling.	2	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GRK6	GRK6	GRK6	MC1R	MC1R	MC1R	2	3	12	13
The titration of HDAC4 proposed in this model may disrupt the repressive HDAC4 , Smad3 , and Runx2 complex , resulting in the improper activation of Runx2 ( XREF_FIG ) .	The titration of HDAC4 proposed in this model may disrupt the repressive HDAC4, Smad3, and Runx2 complex, resulting in the improper activation of Runx2 (XREF_FIG).	1	18	disrupt	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	3	4	17	18
A previous study reported that HDAC4 inhibits Runx2 from binding to its target gene , such as osteocalcin .	A previous study reported that HDAC4 inhibits Runx2 from binding to its target gene, such as osteocalcin.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	5	6	7	8
Hdac4 expression overlaps with that of Trps1 in proliferating and prehypertrophic chondrocytes , interacts , and represses Runx2 similar to Trps1 and , therefore , seemed to be a good candidate for such an interaction .	Hdac4 expression overlaps with that of Trps1 in proliferating and prehypertrophic chondrocytes, interacts, and represses Runx2 similar to Trps1 and, therefore, seemed to be a good candidate for such an interaction.	0	18	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hdac4	Hdac4 expression	hdac4	Runx2	Runx2	runx2	0	1	17	18
Co-transfection of HDAC4 cDNA significantly inhibited the increase of Runx2 promoted by miR-365 ( XREF_FIG ) .	Co-transfection of HDAC4 cDNA significantly inhibited the increase of Runx2 promoted by miR-365 (XREF_FIG).	2	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	2	3	9	10
Real-time PCR demonstrated that HDAC4 inhibited Runx2 mRNA in a dose dependent manner .	Real-time PCR demonstrated that HDAC4 inhibited Runx2 mRNA in a dose dependent manner.	4	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	4	5	6	7
Moreover , SHP competed with HDAC4 for an influence over Runx2 transactivity ( see XREF_FIG ) , and inhibition of endogenous HDAC4 increased Runx2 transactivity ( see XREF_FIG ) , demonstrating that HDAC4 is a substantial corepressor of Runx2 .	Moreover, SHP competed with HDAC4 for an influence over Runx2 transactivity (see XREF_FIG), and inhibition of endogenous HDAC4 increased Runx2 transactivity (see XREF_FIG), demonstrating that HDAC4 is a substantial corepressor of Runx2.	18	24	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	21	22	23	24
We observed that cultured Schwann cells abundantly express Runx2 mRNA , which is blocked by expression of HDAC4 3SA Flag ( 40 +/- 12 % ; XREF_FIG ) .	We observed that cultured Schwann cells abundantly express Runx2 mRNA, which is blocked by expression of HDAC4 3SA Flag (40 +/- 12%; XREF_FIG).	8	19	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HDAC4	expression of HDAC4	hdac4	Runx2	Runx2	runx2	17	18	8	9
As mentioned , HDAC4 is ubiquitously expressed , however , its initial biological function was described in chondrocytes : direct inhibition of RUNX2 by HDAC4 led to chondrocyte hypertrophy .	As mentioned, HDAC4 is ubiquitously expressed, however, its initial biological function was described in chondrocytes : direct inhibition of RUNX2 by HDAC4 led to chondrocyte hypertrophy.	20	25	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	RUNX2	RUNX2	RUNX2	24	25	22	23
Subsequent studies have shown that Runx2 binds and is functionally inhibited by HDAC3 , HDAC4 , HDAC5 , and HDAC7 [ XREF_BIBR - XREF_BIBR ] .	Subsequent studies have shown that Runx2 binds and is functionally inhibited by HDAC3, HDAC4, HDAC5, and HDAC7 [XREF_BIBR - XREF_BIBR].	5	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	14	15	5	6
Lastly , HDAC4 does not inhibit Runx2 functions in osteoblasts in vivo because catecholamines disrupt the physical interaction between HDAC4 and Runx2 .	Lastly, HDAC4 does not inhibit Runx2 functions in osteoblasts in vivo because catecholamines disrupt the physical interaction between HDAC4 and Runx2.	2	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	2	3	6	7
Thus HDAC4 repression of RUNX2 and MEF2C is critical for normal bone development .	Thus HDAC4 repression of RUNX2 and MEF2C is critical for normal bone development.	1	6	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	RUNX2	RUNX2	RUNX2	1	2	4	5
Runx2 or MMP-13 promoter activity was repressed in a dose dependent manner by HDAC4 .	Runx2 or MMP-13 promoter activity was repressed in a dose dependent manner by HDAC4.	0	14	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	13	14	0	1
Besides , a study revealed that HDAC4 inhibited Runx2 promoter activity in a dosage dependent manner .	Besides, a study revealed that HDAC4 inhibited Runx2 promoter activity in a dosage dependent manner.	6	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	6	7	8	9
Further , Runx2 itself is directly suppressed by HDAC4 , and absence of HDAC4 results in transcriptional activation and increased ossification [ XREF_BIBR ] .	Further, Runx2 itself is directly suppressed by HDAC4, and absence of HDAC4 results in transcriptional activation and increased ossification [XREF_BIBR].	2	9	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	8	9	2	3
In OA , the levels of HDAC4 are decreased , relieving its inhibition of Runx2 .	In OA, the levels of HDAC4 are decreased, relieving its inhibition of Runx2.	4	15	relieving	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	levels of HDAC4	hdac4	Runx2	Runx2	runx2	6	7	14	15
HDAC4 also inhibited Runx2 promoter activity and MMP13 promotor activity in a dose dependent manner .	HDAC4 also inhibited Runx2 promoter activity and MMP13 promotor activity in a dose dependent manner.	0	5	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	0	1	3	4
In addition , HDAC4 was shown to inhibit the differentiation of hypertrophic chondrocytes by negatively regulating Runx2 activity .	In addition, HDAC4 was shown to inhibit the differentiation of hypertrophic chondrocytes by negatively regulating Runx2 activity.	3	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	3	4	16	17
Our recent studies [ XREF_BIBR , XREF_BIBR ] showed that HDAC4 inhibited Runx2 promoter activities in a dose dependent manner .	Our recent studies [XREF_BIBR, XREF_BIBR] showed that HDAC4 inhibited Runx2 promoter activities in a dose dependent manner.	10	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	10	11	12	13
This suggests that HDAC4 normally inhibits Runx2 function in prehypertrophic or proliferating chondrocytes .	This suggests that HDAC4 normally inhibits Runx2 function in prehypertrophic or proliferating chondrocytes.	3	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	3	4	6	7
HDAC4 has been shown to interact with and inhibit the activity of RUNX2 [ XREF_BIBR ] .	HDAC4 has been shown to interact with and inhibit the activity of RUNX2 [XREF_BIBR].	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	RUNX2	RUNX2	RUNX2	0	1	12	13
Thus , we put forward the hypothesis that decreased HDAC4 may be associated with human OA cartilage degeneration by releasing HDAC4 inhibition of Runx2 and resulting in increased type X collagen , Ihh , and MMP-13 .	Thus, we put forward the hypothesis that decreased HDAC4 may be associated with human OA cartilage degeneration by releasing HDAC4 inhibition of Runx2 and resulting in increased type X collagen, Ihh, and MMP-13.	20	24	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	20	21	23	24
In contrast , inhibition of HDAC4 by TSA increased Runx2 and MMP-13 promoter activities .	In contrast, inhibition of HDAC4 by TSA increased Runx2 and MMP-13 promoter activities.	3	13	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	5	6	9	10
Our recent studies [ XREF_BIBR , XREF_BIBR ] demonstrated that HDAC4 inhibited Runx2 and MMP-13 promoter activities in a dose dependent manner .	Our recent studies [XREF_BIBR, XREF_BIBR] demonstrated that HDAC4 inhibited Runx2 and MMP-13 promoter activities in a dose dependent manner.	10	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	10	11	12	13
Interaction of Hdac4 with the DNA binding domain of Runx2 may prevent Runx2 from associating with promoter elements of target genes .	Interaction of Hdac4 with the DNA binding domain of Runx2 may prevent Runx2 from associating with promoter elements of target genes.	0	13	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hdac4	Hdac4	Hdac4	Runx2	Runx2	Runx2	2	3	12	13
HDAC4 and HDAC5 also negatively regulated Runx2 activity by deacetylating lysines in the Runx2 protein , leading to ubiquitin mediated proteolysis [ XREF_BIBR ] .	HDAC4 and HDAC5 also negatively regulated Runx2 activity by deacetylating lysines in the Runx2 protein, leading to ubiquitin mediated proteolysis [XREF_BIBR].	0	19	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	0	1	6	7
We show here that , in vivo , HDAC4 does not inhibit Runx2 functions in osteoblasts but instead integrates PTH and sympathetic signaling .	We show here that, in vivo, HDAC4 does not inhibit Runx2 functions in osteoblasts but instead integrates PTH and sympathetic signaling.	8	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	8	9	12	13
HDAC4 inhibits Runx2 promoter activity in a dosage dependent manner .	HDAC4 inhibits Runx2 promoter activity in a dosage dependent manner.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	0	1	2	3
Since HDAC4 inhibits RUNX2 , the overall effect is that miR-140 activates RUNX2 .	Since HDAC4 inhibits RUNX2, the overall effect is that miR-140 activates RUNX2.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	RUNX2	RUNX2	RUNX2	1	2	3	4
Because HDAC4 inhibits Runx2 functions in chondrocytes , we expected that it would do the same in osteoblasts and that Hdac4 osb -/- mice would display a high bone mass because of an increase in bone formation parameters .	Because HDAC4 inhibits Runx2 functions in chondrocytes, we expected that it would do the same in osteoblasts and that Hdac4 osb -/- mice would display a high bone mass because of an increase in bone formation parameters.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	1	2	3	4
This p38-caspase3-HDAC4-Runx2 signaling cascade releases HDAC4 inhibition of Runx2 , which results in the hypertrophic state of chondrocytes and bone formation .	This p38-caspase3-HDAC4-Runx2 signaling cascade releases HDAC4 inhibition of Runx2, which results in the hypertrophic state of chondrocytes and bone formation.	5	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	5	6	8	9
In addition to the experimental evidence supporting the HDAC4 and Runx2 interaction provided in this manuscript and by XREF_BIBR , we also showed HDAC4 inhibits Runx2 promoter in a dose dependent manner .	In addition to the experimental evidence supporting the HDAC4 and Runx2 interaction provided in this manuscript and by XREF_BIBR, we also showed HDAC4 inhibits Runx2 promoter in a dose dependent manner.	23	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	23	24	25	26
HDAC4 also inhibits RUNX2 by binding to its promoter and inhibiting transcription .	HDAC4 also inhibits RUNX2 by binding to its promoter and inhibiting transcription.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	RUNX2	RUNX2	RUNX2	0	1	3	4
HDAC4 appears to interact with and inhibit the activity of runt related transcription factor 2 ( Runx2 ) .	HDAC4 appears to interact with and inhibit the activity of runt related transcription factor 2 (Runx2).	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	0	1	16	17
We hypothesize that decreased HDAC4 in OA cartilage will release the HDAC4 inhibition of Runx2 , thus resulting in the increase of Runx2 activity .	We hypothesize that decreased HDAC4 in OA cartilage will release the HDAC4 inhibition of Runx2, thus resulting in the increase of Runx2 activity.	11	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	11	12	14	15
Hdac4 and Hdac5 , in conjunction with TGF-beta , repress Runx2 transcriptional activity .	Hdac4 and Hdac5, in conjunction with TGF-beta, repress Runx2 transcriptional activity.	0	12	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hdac4	Hdac4	Hdac4	Runx2	Runx2	Runx2	0	1	10	11
HDAC4 was also shown to inhibit RUNX2 and MMP13 promoter activity [ XREF_BIBR ] .	HDAC4 was also shown to inhibit RUNX2 and MMP13 promoter activity [XREF_BIBR].	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	RUNX2	RUNX2	RUNX2	0	1	6	7
Moreover , we also demonstrated that HDAC4 inhibited Runx2 and MMP-13 promoter activities in a dose dependent manner .	Moreover, we also demonstrated that HDAC4 inhibited Runx2 and MMP-13 promoter activities in a dose dependent manner.	6	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	6	7	8	9
The signaling kinase GSK-3beta has been shown to control Snail activity by impairing its function , and inhibitory phosphorylation of GSK-3beta promotes Snail transcriptional activity [ XREF_BIBR ] .	The signaling kinase GSK-3beta has been shown to control Snail activity by impairing its function, and inhibitory phosphorylation of GSK-3beta promotes Snail transcriptional activity [XREF_BIBR].	18	24	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta	gsk-3beta	Snail	Snail	snail	20	21	22	23
Wnt signaling also inhibits GSK3beta mediated degradation of the mesenchymal transcription factors , Snail and Slug [ XREF_BIBR , XREF_BIBR ] .	Wnt signaling also inhibits GSK3beta mediated degradation of the mesenchymal transcription factors, Snail and Slug [XREF_BIBR, XREF_BIBR].	4	14	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Snail	Snail	Snail	4	5	13	14
These GSK-3beta activities limit the ability of Snail to function as an E-cadherin transcriptional repressor .	These GSK-3beta activities limit the ability of Snail to function as an E-cadherin transcriptional repressor.	1	8	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	1	2	7	8
For example , as GSK3beta inhibition upregulates Snail , a transcriptional repressor of E-cadherin , ILK activation leads to the transition of cancer cells from an epithelial to mesenchymal phenotype XREF_BIBR .	For example, as GSK3beta inhibition upregulates Snail, a transcriptional repressor of E-cadherin, ILK activation leads to the transition of cancer cells from an epithelial to mesenchymal phenotype XREF_BIBR.	4	11	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Snail	Snail	Snail	4	5	7	8
In contrast , CRHR2 + cells had higher levels of critical EMT-suppressor genes including CDH1 ( E-cadherin ) and GSK3beta ( inhibitor of Snail and b-catenin ) ( XREF_FIG B , lower panel ) .	In contrast, CRHR2 + cells had higher levels of critical EMT-suppressor genes including CDH1 (E-cadherin) and GSK3beta (inhibitor of Snail and b-catenin) (XREF_FIG B, lower panel).	12	29	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Snail	Snail	Snail	19	20	23	24
The enhancement of GSK-3beta activity by NDRG2 overexpression causes the proteasomal degradation of Snail followed by the transcriptional de-repression of E-cadherin .	The enhancement of GSK-3beta activity by NDRG2 overexpression causes the proteasomal degradation of Snail followed by the transcriptional de-repression of E-cadherin.	3	14	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	3	4	13	14
Conversely , inhibition of GSK-3beta function results in upregulation of Snail by an NF-kappaB-dependent pathway , loss of E-cadherin expression , and EMT .	Conversely, inhibition of GSK-3beta function results in upregulation of Snail by an NF-kappaB-dependent pathway, loss of E-cadherin expression, and EMT.	4	11	results in upregulation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	4	5	10	11
Although Slug and Snail are members of Snail family transcription factor and share similarly degradation pathway via GSK-3beta XREF_BIBR , XREF_BIBR , cypripedin suppressing Akt and GSK-3beta could not mediate Snail reduction .	Although Slug and Snail are members of Snail family transcription factor and share similarly degradation pathway via GSK-3beta XREF_BIBR, XREF_BIBR, cypripedin suppressing Akt and GSK-3beta could not mediate Snail reduction.	20	31	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	26	27	30	31
In addition , related evidence has shown that the enhancement of GSK-3beta activity by NDRG2 overexpression causes proteasomal degradation of the Snail transcription factor and subsequent transcriptional regulation of EMT related genes , 44 which is consistent with this study .	In addition, related evidence has shown that the enhancement of GSK-3beta activity by NDRG2 overexpression causes proteasomal degradation of the Snail transcription factor and subsequent transcriptional regulation of EMT related genes, 44 which is consistent with this study.	11	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	11	12	21	22
The suppression of GSK-3beta through phosphorylation of Ser 9 promotes Snail to be much more stable and reside exclusively in the nucleus to induce EMT .	The suppression of GSK-3beta through phosphorylation of Ser 9 promotes Snail to be much more stable and reside exclusively in the nucleus to induce EMT.	1	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	3	4	10	11
RPN2 stabilized mtp53 by inactivation of glycogen synthase kinase-3beta ( GSK3beta ) which suppresses Snail , a master regulator of epithelial to mesenchymal transition .	RPN2 stabilized mtp53 by inactivation of glycogen synthase kinase-3beta (GSK3beta) which suppresses Snail, a master regulator of epithelial to mesenchymal transition.	8	18	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Snail	Snail	Snail	10	11	14	15
Since treatment with 4D5 and IFN-gamma activated GSK3-beta and active GSK3-beta promotes Snail degradation , expression of a version of Snail with the GSK3-beta phosphorylation sites mutated to alanines should prevent this degradation .	Since treatment with 4D5 and IFN-gamma activated GSK3-beta and active GSK3-beta promotes Snail degradation, expression of a version of Snail with the GSK3-beta phosphorylation sites mutated to alanines should prevent this degradation.	7	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3-beta	GSK3-beta	GSK3-beta	Snail	Snail	Snail	7	8	12	13
Active Wnt signaling can prevent GSK-3beta induced degradation of Snail , and thereby promote EMT [ XREF_BIBR ] .	Active Wnt signaling can prevent GSK-3beta induced degradation of Snail, and thereby promote EMT [XREF_BIBR].	4	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	5	6	9	10
Since GSK3beta negatively regulates Snail , inactivated GSK3beta results in Snail activation which would then down regulate E-cadherin resulting in EMT .	Since GSK3beta negatively regulates Snail, inactivated GSK3beta results in Snail activation which would then down regulate E-cadherin resulting in EMT.	1	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Snail	Snail	Snail	1	2	4	5
The mechanism of GSK3beta inhibition of Snail and Slug was phosphorylation which makes Snail and Slug transferred from nucleus to cytoplasm and thereby was degraded by ubiquitinated [ XREF_BIBR ] .	The mechanism of GSK3beta inhibition of Snail and Slug was phosphorylation which makes Snail and Slug transferred from nucleus to cytoplasm and thereby was degraded by ubiquitinated [XREF_BIBR].	3	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Snail	Snail	Snail	3	4	6	7
As GSK-3beta deactivates Snail by phosphorylation [ XREF_BIBR ] we tested transfected cells for activated GSK-3alpha and beta by FACS analysis ( XREF_FIG D ) and showed a significant reduction in activated GSK-3alpha and beta present in ZIP6 transfected cells compared with controls .	As GSK-3beta deactivates Snail by phosphorylation [XREF_BIBR] we tested transfected cells for activated GSK-3alpha and beta by FACS analysis (XREF_FIG D) and showed a significant reduction in activated GSK-3alpha and beta present in ZIP6 transfected cells compared with controls.	1	4	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	1	2	3	4
We postulated that inhibitory phosphorylation of GSK-3beta at Ser9 by Akt might cause the increase in Snail , Zeb2 , and Twist mRNA .	We postulated that inhibitory phosphorylation of GSK-3beta at Ser9 by Akt might cause the increase in Snail, Zeb2, and Twist mRNA.	4	18	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta at Ser9	gsk-3beta	Snail	Snail	snail	6	7	16	17
These data suggest that inhibition of GSK-3beta allows Snail to induce EndMT .	These data suggest that inhibition of GSK-3beta allows Snail to induce EndMT.	4	10	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	6	7	8	9
The enhancement of glycogen synthase kinase 3beta ( GSK-3beta ) activity by NDRG2 overexpression caused proteasomal degradation of Snail transcription factor followed by transcriptional de-repression of E-cadherin .	The enhancement of glycogen synthase kinase 3beta (GSK-3beta) activity by NDRG2 overexpression caused proteasomal degradation of Snail transcription factor followed by transcriptional de-repression of E-cadherin.	8	20	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	8	9	18	19
When the nuclear transcription factor Snail is degraded by activated GSK3-beta , the expression of E-cadherin will increase .	When the nuclear transcription factor Snail is degraded by activated GSK3-beta, the expression of E-cadherin will increase.	1	11	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3-beta	GSK3-beta	GSK3-beta	Snail	Snail	Snail	10	11	5	6
Our data show that inhibition of GSK-3beta by TGF-beta2-induced PI3K signaling or by direct inhibition with LiCl allows Snail to function to induce EndMT .	Our data show that inhibition of GSK-3beta by TGF-beta2-induced PI3K signaling or by direct inhibition with LiCl allows Snail to function to induce EndMT.	4	20	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	6	7	18	19
Future studies will have to determine whether EGFR dependent GSK-3beta inactivation and subsequent degradation of Snail are involved in CSE mediated disruption of epithelial junctions .	Future studies will have to determine whether EGFR dependent GSK-3beta inactivation and subsequent degradation of Snail are involved in CSE mediated disruption of epithelial junctions.	9	16	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	9	10	15	16
glycogen synthase kinase-3 beta ( GSK-3beta ) is a target of Akt and inactivates the transcriptional repressor Snail , a potent inducer of EMT .	glycogen synthase kinase-3 beta (GSK-3beta) is a target of Akt and inactivates the transcriptional repressor Snail, a potent inducer of EMT.	0	21	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta	Snail	Snail	Snail	0	4	17	18
Therefore , inhibitory phosphorylation of GSK-3beta by kinases such as AKT , a downstream signaling molecule from PI3K [ XREF_BIBR ] , is sufficient to prevent GSK-3beta-dependent inhibition of Snail .	Therefore, inhibitory phosphorylation of GSK-3beta by kinases such as AKT, a downstream signaling molecule from PI3K [XREF_BIBR], is sufficient to prevent GSK-3beta-dependent inhibition of Snail.	3	30	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta	gsk-3beta	Snail	Snail	snail	5	6	29	30
These data indicate that the increase in the Snail protein level in TD cells is due to Snail protein stabilization mediated by increased Akt activity and subsequent inhibition of GSK3beta activity .	These data indicate that the increase in the Snail protein level in TD cells is due to Snail protein stabilization mediated by increased Akt activity and subsequent inhibition of GSK3beta activity.	17	30	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Snail	Snail	Snail	29	30	17	18
Given that active GSK3beta promoted the degradation of Slug and Snail , XREF_BIBR , XREF_BIBR this study suggests that PI3K/Akt/GSK3beta axis might also be involved in Pellino-1-mediated stabilization of Slug and Snail protein .	Given that active GSK3beta promoted the degradation of Slug and Snail, XREF_BIBR, XREF_BIBR this study suggests that PI3K/Akt/GSK3beta axis might also be involved in Pellino-1-mediated stabilization of Slug and Snail protein.	2	11	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Snail	Snail	Snail	3	4	10	11
GSK-3beta ( glycogen synthase kinase 3beta ) deactivates Snail by phosphorylation , promoting nuclear export and priming it for ubiquitination by beta-TrCP ( beta transducing repeat containing protein ; also known as BTRC ] and subsequent degradation [ XREF_BIBR ] .	GSK-3beta (glycogen synthase kinase 3beta) deactivates Snail by phosphorylation, promoting nuclear export and priming it for ubiquitination by beta-TrCP (beta transducing repeat containing protein; also known as BTRC] and subsequent degradation [XREF_BIBR].	0	9	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	0	1	8	9
We also demonstrate that GSK-3beta ( shaggy ) is a common suppressor of tau , Abeta42 and TDP-43 toxicity , and that GSK-3beta activity is strongly upregulated due to mutant TDP-43 expression .	We also demonstrate that GSK-3beta (shaggy) is a common suppressor of tau, Abeta42 and TDP-43 toxicity, and that GSK-3beta activity is strongly upregulated due to mutant TDP-43 expression.	4	18	is a common suppressor	Negative_activation_copula_1	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	tau	tau	tau	4	5	13	14
Silencing GSK3beta blocked the Mcl-1 reduction in ATO treated NB4 cells ( XREF_FIG ) .	Silencing GSK3beta blocked the Mcl-1 reduction in ATO treated NB4 cells (XREF_FIG).	0	5	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Mcl-1	Mcl-1	Mcl-1	1	2	4	5
As GSK-3beta is known to degrade Mcl-1 , we cotransfected GSK-3beta with either WT Pin1 or R68 ,69 A Pin 1 in 293T cells and showed that only the WT Pin1 counteracted GSK-3beta-mediated Mcl-1 degradation to further support the notion that Pin1 stabilizes Mcl-1 ( XREF_FIG ) .	As GSK-3beta is known to degrade Mcl-1, we cotransfected GSK-3beta with either WT Pin1 or R68,69 A Pin 1 in 293T cells and showed that only the WT Pin1 counteracted GSK-3beta-mediated Mcl-1 degradation to further support the notion that Pin1 stabilizes Mcl-1 (XREF_FIG).	1	7	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	1	2	6	7
Consistent with inhibition of GSKbeta by Akt and GSK3beta dependent degradation of the prosurvival factor MCL1 , bPTEN and SHIP -/- B cells expressed elevated amounts of MCL1 compared with WT , bPTEN -/-, or bSHIP -/- B cells at all time points examined ( XREF_FIG ) .	Consistent with inhibition of GSKbeta by Akt and GSK3beta dependent degradation of the prosurvival factor MCL1, bPTEN and SHIP -/- B cells expressed elevated amounts of MCL1 compared with WT, bPTEN -/-, or bSHIP -/- B cells at all time points examined (XREF_FIG).	8	19	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MCL1	MCL1	MCL1	8	9	15	16
Our results also showed that knock-down of GSK-3beta decreases ZA induced Mcl-1 downregulation , mitochondrial damage , and apoptosis .	Our results also showed that knock-down of GSK-3beta decreases ZA induced Mcl-1 downregulation, mitochondrial damage, and apoptosis.	5	12	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	7	8	11	12
Propofol activated GSK-3beta and inhibiting GSK-3beta prevented Mcl-1 destabilization , MTP loss , and lysosomal and mitochondrial apoptosis .	Propofol activated GSK-3beta and inhibiting GSK-3beta prevented Mcl-1 destabilization, MTP loss, and lysosomal and mitochondrial apoptosis.	2	8	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	5	6	7	8
GSK3beta increases Mcl-1 degradation while deubiquitinase USP9X stabilizes Mcl-1 .	GSK3beta increases Mcl-1 degradation while deubiquitinase USP9X stabilizes Mcl-1.	0	3	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Mcl-1	Mcl-1	Mcl-1	0	1	2	3
GSK3beta also promotes the degradation of Mcl-1 through phosphorylation on Ser 159 ( mouse Ser 140 ) XREF_BIBR .	GSK3beta also promotes the degradation of Mcl-1 through phosphorylation on Ser 159 (mouse Ser 140) XREF_BIBR.	0	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Mcl-1	Mcl-1	Mcl-1	0	1	6	7
Mcl-1 is targeted for proteasomal degradation following phosphorylation by GSK3beta .	Mcl-1 is targeted for proteasomal degradation following phosphorylation by GSK3beta.	0	10	targeted	Positive_activation_syntax_4_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Mcl-1	Mcl-1	Mcl-1	9	10	0	1
Additionally , increased glucose uptake and metabolism has been reported to protect cells by blocking GSK-3beta mediated degradation of Mcl-1 , a member of the anti-apoptotic Bcl2 family [ XREF_BIBR ] .	Additionally, increased glucose uptake and metabolism has been reported to protect cells by blocking GSK-3beta mediated degradation of Mcl-1, a member of the anti-apoptotic Bcl2 family [XREF_BIBR].	15	22	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	15	16	19	20
For example , activation of GSK3beta upon inhibition of PI3K/Akt/mTOR signaling favors downregulation of Mcl-1 proteins , since GSK3beta promotes the proteasomal degradation of Mcl-1 by phosphorylation of its serine residue at position 159 .	For example, activation of GSK3beta upon inhibition of PI3K/Akt/mTOR signaling favors downregulation of Mcl-1 proteins, since GSK3beta promotes the proteasomal degradation of Mcl-1 by phosphorylation of its serine residue at position 159.	18	25	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Mcl-1	Mcl-1	Mcl-1	18	19	24	25
The silencing of GSK-3beta reduced Mcl-1 degradation caused by APAP treatment .	The silencing of GSK-3beta reduced Mcl-1 degradation caused by APAP treatment.	1	6	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	3	4	5	6
Taken together , our data indicate that amsacrine abolishes ERK- and Pin1 mediated stabilization of MCL1 and promotes GSK3beta mediated degradation of MCL1 , leading to activate mitochondria mediated apoptosis pathway in U937 cells .	Taken together, our data indicate that amsacrine abolishes ERK- and Pin1 mediated stabilization of MCL1 and promotes GSK3beta mediated degradation of MCL1, leading to activate mitochondria mediated apoptosis pathway in U937 cells.	17	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MCL1	MCL1	MCL1	18	19	22	23
84 GSK3beta promotes the degradation of Mcl1 , a member of BCL-2 family that sequesters Beclin 1 from the class III PI3K complex .	84 GSK3beta promotes the degradation of Mcl1, a member of BCL-2 family that sequesters Beclin 1 from the class III PI3K complex.	0	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Mcl1	Mcl1	Mcl1	1	2	6	7
Furthermore , we found that activation of GSK-3beta could down-regulate Mcl-1 and was required for proteasome mediated Mcl-1 degradation .	Furthermore, we found that activation of GSK-3beta could down-regulate Mcl-1 and was required for proteasome mediated Mcl-1 degradation.	5	11	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	7	8	10	11
Protein analysis showed that knock-down of GSK-3beta reversed ZA induced Mcl-1 downregulation ( XREF_FIG ) and caused a decrease in ZA induced caspase-3 activation ( XREF_FIG ) .	Protein analysis showed that knock-down of GSK-3beta reversed ZA induced Mcl-1 downregulation (XREF_FIG) and caused a decrease in ZA induced caspase-3 activation (XREF_FIG).	4	11	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	6	7	10	11
Pharmacologic inhibition of GSK-3beta prevents the disappearance of Noxa induced by sorafenib and enhances the down-modulation of Mcl-1 .	Pharmacologic inhibition of GSK-3beta prevents the disappearance of Noxa induced by sorafenib and enhances the down-modulation of Mcl-1.	1	18	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	3	4	17	18
It has been shown that the N-terminal domain of HDAC4 is necessary and sufficient to bind and repress Mef2 dependent transcriptional activity , whereas the nuclear exportation signal of HDAC4 is located in the C-terminal end of the protein .	It has been shown that the N-terminal domain of HDAC4 is necessary and sufficient to bind and repress Mef2 dependent transcriptional activity, whereas the nuclear exportation signal of HDAC4 is located in the C-terminal end of the protein.	7	19	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Mef2	Mef2	Mef2	9	10	18	19
HDAC4 inhibits the activity of MEF-2 and SRF , both of which are important regulators of MHCI expression , providing a mechanism by which the reduction in miR-1 may contribute to reduced MHCI and fibre shift .	HDAC4 inhibits the activity of MEF-2 and SRF, both of which are important regulators of MHCI expression, providing a mechanism by which the reduction in miR-1 may contribute to reduced MHCI and fibre shift.	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	MEF-2	MEF-2	MEF-2	0	1	5	6
miR-1 targets the histone deacetylase 4 ( HDAC4 ) mRNA , a transcriptional repressor of Mef2 dependent activation of muscle specific gene expression , suggesting that translational repression of HDAC4 by miR-1 enhances gene activation of Mef2 dependent promoters .	miR-1 targets the histone deacetylase 4 (HDAC4) mRNA, a transcriptional repressor of Mef2 dependent activation of muscle specific gene expression, suggesting that translational repression of HDAC4 by miR-1 enhances gene activation of Mef2 dependent promoters.	27	38	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Mef2	Mef2	Mef2	29	30	36	37
HDAC4 is a repressor of the pro differentiation transcription factor MEF-2 and is capable of inhibiting myoblast differentiation .	HDAC4 is a repressor of the pro differentiation transcription factor MEF-2 and is capable of inhibiting myoblast differentiation.	0	13	is a repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	MEF-2	MEF-2	MEF-2	0	1	10	11
Recent studies suggested that HDAC4 suppresses Mef2 in a histone deacetylation activity independent manner .	Recent studies suggested that HDAC4 suppresses Mef2 in a histone deacetylation activity independent manner.	4	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Mef2	Mef2	Mef2	4	5	6	7
Moreover , the high expression of the hdac4 mRNA in the fast- and slow-twitch muscles of younger pacus inhibited the regulation of Mef2 dependent genes , contributing to the maintenance of myoblasts in a proliferative state in these animals .	Moreover, the high expression of the hdac4 mRNA in the fast- and slow-twitch muscles of younger pacus inhibited the regulation of Mef2 dependent genes, contributing to the maintenance of myoblasts in a proliferative state in these animals.	7	24	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	hdac4	hdac4	hdac4	Mef2	Mef2	Mef2	7	8	22	23
The lower levels of the hdac4 mRNA in the fast- and slow-twitch muscles of adult pacus , most likely due to silencing by the increased expression of miR-1 , promoted Mef2 action and therefore muscle differentiation .	The lower levels of the hdac4 mRNA in the fast- and slow-twitch muscles of adult pacus, most likely due to silencing by the increased expression of miR-1, promoted Mef2 action and therefore muscle differentiation.	5	31	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	hdac4	hdac4	hdac4	Mef2	Mef2	Mef2	5	6	30	31
This mechanism occurs after CaMKIIdelta selectively phosphorylates HDAC4 , which becomes exported outside the nucleus with other class II HDACs and can no longer repress Mef2 [ XREF_BIBR , XREF_BIBR ] .	This mechanism occurs after CaMKIIdelta selectively phosphorylates HDAC4, which becomes exported outside the nucleus with other class II HDACs and can no longer repress Mef2 [XREF_BIBR, XREF_BIBR].	6	29	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	phosphorylates HDAC4	hdac4	Mef2	Mef2	mef2	7	8	25	26
Specifically , miR1 promotes myogenesis by inhibiting the expression of Hdac4 , which can block Mef2 [ XREF_BIBR ] .	Specifically, miR1 promotes myogenesis by inhibiting the expression of Hdac4, which can block Mef2 [XREF_BIBR].	2	17	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hdac4	miR1 promotes myogenesis by inhibiting the expression of Hdac4	hdac4	Mef2	Mef2	mef2	10	11	15	16
We also found that once it has moved to the nucleus , HDAC4 directly suppresses MEF2- and CREB dependent transcriptional activities .	We also found that once it has moved to the nucleus, HDAC4 directly suppresses MEF2- and CREB dependent transcriptional activities.	12	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	MEF2-	MEF2-	MEF2-	12	13	15	16
miR-1 promotes skeletal muscle differentiation by targeting the histone deacetylase 4 ( HDAC4 ) , that in turn represses Mef2C , an essential muscle transcription factor .	miR-1 promotes skeletal muscle differentiation by targeting the histone deacetylase 4 (HDAC4), that in turn represses Mef2C, an essential muscle transcription factor.	8	25	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	histone deacetylase 4	histone deacetylase 4	histone deacetylase 4	Mef2C	Mef2C	Mef2C	8	11	19	20
Thus , this forms a positive feedforward loop in which MEF2c induces miR-1 expression , causing inhibition of the MEF2c repressor HDAC4 , leading to enhancement of MEF2 activity [ XREF_BIBR ] .	Thus, this forms a positive feedforward loop in which MEF2c induces miR-1 expression, causing inhibition of the MEF2c repressor HDAC4, leading to enhancement of MEF2 activity [XREF_BIBR].	16	22	repressor	Negative_activation_token_1_noun	Negative_activation	Positive_activation	HDAC4	HDAC4	HDAC4	MEF2c	MEF2c	MEF2c	21	22	19	20
Furthermore , PC4 localizes in the nucleus of differentiating myoblasts , associates with MEF2C , and is able to counteract the HDAC4 mediated inhibition of MEF2C .	Furthermore, PC4 localizes in the nucleus of differentiating myoblasts, associates with MEF2C, and is able to counteract the HDAC4 mediated inhibition of MEF2C.	20	26	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	MEF2C	MEF2C	MEF2C	21	22	25	26
36 Hdac4 also inhibits Mef2C transcriptional activity to control chondrocyte hypertrophy .	36 Hdac4 also inhibits Mef2C transcriptional activity to control chondrocyte hypertrophy.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hdac4	Hdac4	Hdac4	Mef2C	Mef2C	Mef2C	1	2	4	5
miR-1/206 inhibits the expression of histone deacetylase 4 ( HDAC4 ) , which suppresses the MEF2c transcriptional activity to induce muscle gene expression .	miR-1/206 inhibits the expression of histone deacetylase 4 (HDAC4), which suppresses the MEF2c transcriptional activity to induce muscle gene expression.	6	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	MEF2c	MEF2c	MEF2c	9	10	15	16
It has also been shown that miR-1 targets Hdac4 39 , a histone deacetylase which represses Mef2C , an essential myogenic transcription factor .	It has also been shown that miR-1 targets Hdac4 39, a histone deacetylase which represses Mef2C, an essential myogenic transcription factor.	4	22	represses	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Hdac4	Hdac4	Hdac4	Mef2C	Mef2C	Mef2C	8	9	16	17
These findings are consistent with our observation that Sik3 deletion or pterosin B administration protected cartilage from osteoarthritic change through activation of Hdac4 , which prevented Mef2c from activating the hypertrophy programme in articular chondrocytes .	These findings are consistent with our observation that Sik3 deletion or pterosin B administration protected cartilage from osteoarthritic change through activation of Hdac4, which prevented Mef2c from activating the hypertrophy programme in articular chondrocytes.	20	27	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hdac4	Hdac4	Hdac4	Mef2c	Mef2c	Mef2c	22	23	26	27
Mef2C is negatively regulated by the histone deacetylase HDAC4 .	Mef2C is negatively regulated by the histone deacetylase HDAC4.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Mef2C	Mef2C	Mef2C	8	9	0	1
HDAC4 inhibits osteoclast differentiation by preventing MEF2c to transactivate Rankl .	HDAC4 inhibits osteoclast differentiation by preventing MEF2c to transactivate Rankl.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	MEF2c	MEF2c	MEF2c	0	1	6	7
Intriguingly , although HDAC4 is located primarily in the cytoplasm , coexpression of SMRTe dramatically translocates HDAC4 from the cytoplasm into the nucleus , where HDAC4 prevents MEF2C from activating muscle differentiation .	Intriguingly, although HDAC4 is located primarily in the cytoplasm, coexpression of SMRTe dramatically translocates HDAC4 from the cytoplasm into the nucleus, where HDAC4 prevents MEF2C from activating muscle differentiation.	25	28	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	MEF2C	MEF2C	MEF2C	25	26	27	28
Myocardin induced ANF transcription and increase in total protein amount were enhanced by GSK3beta blockade ( 10 mmol/L LiCl ) , indicating that GSK3beta inhibits myocardin .	Myocardin induced ANF transcription and increase in total protein amount were enhanced by GSK3beta blockade (10 mmol/L LiCl), indicating that GSK3beta inhibits myocardin.	23	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	myocardin	myocardin	myocardin	23	24	25	26
Because HDAC5 , which is not part of the NuRD complex , also antagonizes Runx2 , we next tested the function of Zfp521 in rat osteosarcoma cell line ( ROS ) cells that stably express a dominant negative form of HDAC5 .	Because HDAC5, which is not part of the NuRD complex, also antagonizes Runx2, we next tested the function of Zfp521 in rat osteosarcoma cell line (ROS) cells that stably express a dominant negative form of HDAC5.	1	15	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC5	HDAC5	HDAC5	Runx2	Runx2	Runx2	1	2	14	15
LiCl , an inhibitor of GSK3beta , abolished inhibitory effect of PTEN on cyclin D2 expression , and TCF members could directly bind to the promoter of cyclin D2 and regulate its transcription in a CREB dependent manner .	LiCl, an inhibitor of GSK3beta, abolished inhibitory effect of PTEN on cyclin D2 expression, and TCF members could directly bind to the promoter of cyclin D2 and regulate its transcription in a CREB dependent manner.	3	12	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	PTEN	PTEN	PTEN	5	6	11	12
In our study , baicalein administration significantly enhanced phosphorylation of Akt and GSK-3beta and supressed PTEN , the negative regulator of the pathway [ XREF_BIBR ] .	In our study, baicalein administration significantly enhanced phosphorylation of Akt and GSK-3beta and supressed PTEN, the negative regulator of the pathway [XREF_BIBR].	4	19	supressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	baicalein administration significantly enhanced phosphorylation of Akt and GSK-3beta	gsk-3beta	PTEN	PTEN	pten	12	13	15	16
Western blotting found that PTEN was down-regulated by Hes1 when Notch1 was activated , which consequently promoted Akt and GSK-3beta phosphorylation .	Western blotting found that PTEN was down-regulated by Hes1 when Notch1 was activated, which consequently promoted Akt and GSK-3beta phosphorylation.	4	21	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	Hes1 when Notch1 was activated, which consequently promoted Akt and GSK-3beta phosphorylation	gsk-3beta	PTEN	PTEN	pten	19	20	4	5
EGCG significantly promoted the phosphorylation of Akt and GSK-3beta and down-regulated PTEN , thus activating PI3 and Akt signalling .	EGCG significantly promoted the phosphorylation of Akt and GSK-3beta and down-regulated PTEN, thus activating PI3 and Akt signalling.	0	12	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	EGCG significantly promoted the phosphorylation of Akt and GSK-3beta	gsk-3beta	PTEN	PTEN	pten	8	9	11	12
HDAC9 is a direct transcriptional target of MEF2 and acts to inhibit the transcriptional activity of MEF2C XREF_BIBR , consistent with the striking downregulation of this gene in MEF2D rearranged ALL ( XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY ) .	HDAC9 is a direct transcriptional target of MEF2 and acts to inhibit the transcriptional activity of MEF2C XREF_BIBR, consistent with the striking downregulation of this gene in MEF2D rearranged ALL (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC9	HDAC9	HDAC9	MEF2C	MEF2C	MEF2C	0	1	16	17
In contrast , deregulated MEF2D activity , with activation of HDAC9 and resulting inhibition of MEF2C were characteristic of this form of leukaemia .	In contrast, deregulated MEF2D activity, with activation of HDAC9 and resulting inhibition of MEF2C were characteristic of this form of leukaemia.	10	16	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	HDAC9	HDAC9	HDAC9	MEF2C	MEF2C	MEF2C	10	11	15	16
These levels are high in proliferating myoblasts , and HDAC5 represses MEF2C activity before being exported to the cytosol upon differentiation XREF_BIBR .	These levels are high in proliferating myoblasts, and HDAC5 represses MEF2C activity before being exported to the cytosol upon differentiation XREF_BIBR.	9	12	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC5	HDAC5	HDAC5	MEF2C	MEF2C	MEF2C	9	10	11	12
HDAC9 and HDAC5 ( two class II HDACs ) act as negative regulators of cardiac hypertrophy , repressing the activity of MEF2c , a transcription factor that regulates the expression of pro hypertrophic genes [ XREF_BIBR , XREF_BIBR ] .	HDAC9 and HDAC5 (two class II HDACs) act as negative regulators of cardiac hypertrophy, repressing the activity of MEF2c, a transcription factor that regulates the expression of pro hypertrophic genes [XREF_BIBR, XREF_BIBR].	0	22	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC5	HDAC5	HDAC5	MEF2c	MEF2c	MEF2c	2	3	21	22
This confirms our model that HDAC5 knockdown causes a MEF2C gain of function phenotype which drives high sclerostin production .	This confirms our model that HDAC5 knockdown causes a MEF2C gain of function phenotype which drives high sclerostin production.	5	10	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC5	HDAC5	HDAC5	MEF2C	MEF2C	MEF2C	5	6	9	10
Indeed , the extent of MEF2C repression by HDAC5 depends on the amount of HDAC5 present in the nucleus XREF_BIBR XREF_BIBR XREF_BIBR .	Indeed, the extent of MEF2C repression by HDAC5 depends on the amount of HDAC5 present in the nucleus XREF_BIBR XREF_BIBR XREF_BIBR.	5	9	repression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	HDAC5	HDAC5	HDAC5	MEF2C	MEF2C	MEF2C	8	9	5	6
HDAC1 sumoylation attenuates MyoD induced transcriptional activity of MCK and myogenin promoter .	HDAC1 sumoylation attenuates MyoD induced transcriptional activity of MCK and myogenin promoter.	0	4	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC1	HDAC1 sumoylation	hdac1	MyoD	MyoD	myod	0	1	3	4
Indeed , since HDAC1 was reported to inhibit MyoD induced activation of the myogenic program , XREF_BIBR , XREF_BIBR many reports have elucidated that HDAC is required for repression of MyoD .	Indeed, since HDAC1 was reported to inhibit MyoD induced activation of the myogenic program, XREF_BIBR, XREF_BIBR many reports have elucidated that HDAC is required for repression of MyoD.	3	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC1	HDAC1	HDAC1	MyoD	MyoD	MyoD	3	4	8	9
HDAC1 is able to inhibit MyoD in cycling cells and upon induction of differentiation pRB titrates HDAC1 away from MyoD allowing it to activate transcription .	HDAC1 is able to inhibit MyoD in cycling cells and upon induction of differentiation pRB titrates HDAC1 away from MyoD allowing it to activate transcription.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC1	HDAC1	HDAC1	MyoD	MyoD	MyoD	0	1	5	6
These results suggest that inv ( 16 ) + AML stem and prognitors are selectively dependent on HDAC8 activity for survival , and that inhibiting HDAC8 activates p53 thereby sensitizing for apoptosis .	These results suggest that inv (16) + AML stem and prognitors are selectively dependent on HDAC8 activity for survival, and that inhibiting HDAC8 activates p53 thereby sensitizing for apoptosis.	24	29	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC8	HDAC8	HDAC8	p53	p53	p53	25	26	27	28
Inhibiting HDAC8 substantially enhances p53 activation and diminishes AML cell survival under oncogenic or genotoxic stress , supporting HDAC8 as a promising therapeutic target .	Inhibiting HDAC8 substantially enhances p53 activation and diminishes AML cell survival under oncogenic or genotoxic stress, supporting HDAC8 as a promising therapeutic target.	0	7	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC8	HDAC8	HDAC8	p53	p53	p53	1	2	4	5
To determine whether HDAC8 is responsible for HDAC inhibitors to suppress wild-type p53 transcription , HDAC8 was knocked down in HCT116 cells .	To determine whether HDAC8 is responsible for HDAC inhibitors to suppress wild-type p53 transcription, HDAC8 was knocked down in HCT116 cells.	3	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC8	HDAC8	HDAC8	p53	p53	p53	3	4	12	13
Considering another Nfat family member , Nfatc2 , in vitro cell studies demonstrated that Notch1 , Hey1 and Hey2 inhibit Nfatc2 transactivation by suppressing Gsk3beta , which activates Nfatc2 by phosphorylation , in ST-2 stromal cells as well as in primary osteoblast cells from Notch GOF mice [ XREF_BIBR ] .	Considering another Nfat family member, Nfatc2, in vitro cell studies demonstrated that Notch1, Hey1 and Hey2 inhibit Nfatc2 transactivation by suppressing Gsk3beta, which activates Nfatc2 by phosphorylation, in ST-2 stromal cells as well as in primary osteoblast cells from Notch GOF mice [XREF_BIBR].	19	29	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Gsk3beta	Gsk3beta	Gsk3beta	Nfatc2	Nfatc2	Nfatc2	24	25	28	29
The loss of Hdac5 or Hdac9 triggers Mef2 to activate its target gene ERalpha In the presence of estrogen ( E2 ) , ERalpha then activates Vegf-a expression .	The loss of Hdac5 or Hdac9 triggers Mef2 to activate its target gene ERalpha In the presence of estrogen (E2), ERalpha then activates Vegf-a expression.	1	8	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Hdac5	loss of Hdac5	hdac5	Mef2	Mef2	mef2	3	4	7	8
Both Fbw7 and GSK3beta-CA reduced Nrf1 in HEK293 cells ( XREF_FIG ) .	Both Fbw7 and GSK3beta-CA reduced Nrf1 in HEK293 cells (XREF_FIG).	1	6	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta-CA	GSK3beta-CA	GSK3beta-CA	Nrf1	Nrf1	Nrf1	3	4	5	6
Particularly , XIAP binds to caspase-3 , caspase-7 , and caspase-9 , a process that may be regulated by Smac/Diablo ( a mitochondrial protein and negative regulator of XIAP ) and HtrA2 and Omi ( an inhibitor of XIAP ) [ XREF_BIBR ] .	Particularly, XIAP binds to caspase-3, caspase-7, and caspase-9, a process that may be regulated by Smac/Diablo (a mitochondrial protein and negative regulator of XIAP) and HtrA2 and Omi (an inhibitor of XIAP) [XREF_BIBR].	17	39	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	31	32	38	39
In turn , XIAP is inhibited by the mitochondrial proapoptotic protein Smac/DIABLO and HtrA2 and OMI , when they are released into the cytosol [ XREF_BIBR ] .	In turn, XIAP is inhibited by the mitochondrial proapoptotic protein Smac/DIABLO and HtrA2 and OMI, when they are released into the cytosol [XREF_BIBR].	3	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	13	14	3	4
During the mitochondrial apoptotic process , the inhibitory function of XIAP , a ubiquitous member of IAP family , can be antagonized by Smac/Diablo and Omi and HtrA2 which are also released from mitochondria along with cytochrome c. BAG2 exhibits pro apoptotic properties and is demonstrated to be up-regulated in proteasome inhibitor induced apoptosis in thyroid carcinoma cell [ XREF_BIBR ] .	During the mitochondrial apoptotic process, the inhibitory function of XIAP, a ubiquitous member of IAP family, can be antagonized by Smac/Diablo and Omi and HtrA2 which are also released from mitochondria along with cytochrome c. BAG2 exhibits pro apoptotic properties and is demonstrated to be up-regulated in proteasome inhibitor induced apoptosis in thyroid carcinoma cell [XREF_BIBR].	10	26	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Omi	Omi	Omi	XIAP	XIAP	XIAP	25	26	10	11
HtrA2 degrades XIAP to relieve the inhibition on Caspases .	HtrA2 degrades XIAP to relieve the inhibition on Caspases.	0	3	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	0	1	2	3
XIAP is inhibited by HtrA2 ( High temperature requirement protein A2 ) , a mitochondrial serine protease released during mitochondrial injury .	XIAP is inhibited by HtrA2 (High temperature requirement protein A2), a mitochondrial serine protease released during mitochondrial injury.	0	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	4	5	0	1
Recent findings demonstrate that HtrA2 and Omi inactivates XIAP by both direct binding to XIAP through its reaper motif and by serine protease degradation .	Recent findings demonstrate that HtrA2 and Omi inactivates XIAP by both direct binding to XIAP through its reaper motif and by serine protease degradation.	4	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Omi	Omi	Omi	XIAP	XIAP	XIAP	6	7	8	9
Omi and HtrA2 inactivates XIAP irreversibly and facilitates caspase activity in the cytoplasm XREF_BIBR .	Omi and HtrA2 inactivates XIAP irreversibly and facilitates caspase activity in the cytoplasm XREF_BIBR.	0	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	2	3	4	5
Following its release , cytosolic HtrA2 triggers degradation of the anti-apoptotic protein XIAP , caspase activation and eventually apoptosis .	Following its release, cytosolic HtrA2 triggers degradation of the anti-apoptotic protein XIAP, caspase activation and eventually apoptosis.	4	18	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	5	6	12	13
For example , it is known that XIAP antagonists , such as Smac/DIABLO and Omi and Htra2 , share the IBM ( IAP Binding Motif ) ; and it is also known that peptides corresponding to the N-terminal of Smac/DIABLO sensitize lung cancer to cisplatin and taxol .	For example, it is known that XIAP antagonists, such as Smac/DIABLO and Omi and Htra2, share the IBM (IAP Binding Motif); and it is also known that peptides corresponding to the N-terminal of Smac/DIABLO sensitize lung cancer to cisplatin and taxol.	7	17	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	Htra2	Htra2	Htra2	XIAP	XIAP	XIAP	16	17	7	8
XIAP and related IAPs ( cIAP1/2 ) are negatively regulated by SMAC/DIABLO XREF_BIBR , XREF_BIBR and OMI and HTRA2 proteins that are released from the mitochondria during apoptosis XREF_BIBR , XREF_BIBR .	XIAP and related IAPs (cIAP1/2) are negatively regulated by SMAC/DIABLO XREF_BIBR, XREF_BIBR and OMI and HTRA2 proteins that are released from the mitochondria during apoptosis XREF_BIBR, XREF_BIBR.	0	19	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HTRA2	HTRA2	HTRA2	XIAP	XIAP	XIAP	18	19	0	1
Conversely , the serine protease activity of Omi and HtrA2 can also inactivate cIAPs and XIAP by proteolytic cleavage .	Conversely, the serine protease activity of Omi and HtrA2 can also inactivate cIAPs and XIAP by proteolytic cleavage.	5	16	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	9	10	15	16
HtrA2 , a serine protease , diminishes XIAP through catalytic cleavage [ XREF_BIBR ] .	HtrA2, a serine protease, diminishes XIAP through catalytic cleavage [XREF_BIBR].	0	8	diminishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	0	1	7	8
Recently , XIAP associated factor 1 ( XAF1 ) and two mitochondrial proteins , Smac/DIABLO and HtrA2 , have been identified to negatively regulate the caspase inhibiting activity of XIAP .	Recently, XIAP associated factor 1 (XAF1) and two mitochondrial proteins, Smac/DIABLO and HtrA2, have been identified to negatively regulate the caspase inhibiting activity of XIAP.	12	30	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	16	17	29	30
Released mitochondrial proteins include Smac/DIABLO and HTRA2 and Omi , which inhibit the cytosolic E3 ubiquitin ligase XIAP and other inhibitors of apoptosis proteins .	Released mitochondrial proteins include Smac/DIABLO and HTRA2 and Omi, which inhibit the cytosolic E3 ubiquitin ligase XIAP and other inhibitors of apoptosis proteins.	0	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Omi	Omi	Omi	XIAP	XIAP	XIAP	8	9	17	18
Thus , Syk drives EBV+ B cell lymphoma survival through PI3K and Akt activation , which prevents the HtrA2 dependent loss of XIAP .	Thus, Syk drives EBV+ B cell lymphoma survival through PI3K and Akt activation, which prevents the HtrA2 dependent loss of XIAP.	18	23	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	18	19	22	23
When XIAP was inhibited by HtrA2 ( serine protease ) , it would induce apoptotic cell death [ XREF_BIBR ] .	When XIAP was inhibited by HtrA2 (serine protease), it would induce apoptotic cell death [XREF_BIBR].	1	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	5	6	1	2
XREF_BIBR In the present study , we showed that the increase in cytosolic HtrA2 and Omi after H 2 O 2 treatment correlates with a significant decrease in XIAP levels , presumably by HtrA2 and Omi mediated XIAP inhibition and degradation .	XREF_BIBR In the present study, we showed that the increase in cytosolic HtrA2 and Omi after H 2 O 2 treatment correlates with a significant decrease in XIAP levels, presumably by HtrA2 and Omi mediated XIAP inhibition and degradation.	22	38	mediated	Positive_early_activation	Negative_activation	Negative_activation	Omi	Omi	Omi	XIAP	XIAP	XIAP	35	36	37	38
XIAP is negatively regulated by the mitochondrial serine protease , HtrA2 and Omi .	XIAP is negatively regulated by the mitochondrial serine protease, HtrA2 and Omi.	0	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Omi	Omi	Omi	XIAP	XIAP	XIAP	12	13	0	1
XIAP is inhibited by both Smac/DIABLO and Omi and HtrA2 .	XIAP is inhibited by both Smac/DIABLO and Omi and HtrA2.	0	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	9	10	0	1
HSP27 is known to prevent proteolytic processing of caspase-3 through association with its prodomain [ XREF_BIBR , XREF_BIBR ] .	HSP27 is known to prevent proteolytic processing of caspase-3 through association with its prodomain [XREF_BIBR, XREF_BIBR].	0	9	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HSP27	HSP27	HSP27	caspase-3	caspase-3	caspase-3	0	1	8	9
Furthermore , HSP27 could increase the ratio of Bcl-2 and Bax and inhibit caspase-3 activity .	Furthermore, HSP27 could increase the ratio of Bcl-2 and Bax and inhibit caspase-3 activity.	2	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HSP27	HSP27	HSP27	caspase-3	caspase-3	caspase-3	2	3	13	14
Studies showed that HSP27 can lessen the induction of proinflammatory messenger , reduce neutrophil infiltration , decrease apoptosis ( caspase 3 fragmentation and DNA laddering ) , and reduce disruption of filamentous actin .	Studies showed that HSP27 can lessen the induction of proinflammatory messenger, reduce neutrophil infiltration, decrease apoptosis (caspase 3 fragmentation and DNA laddering), and reduce disruption of filamentous actin.	3	28	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HSP27	HSP27	HSP27	caspase 3	caspase 3	caspase 3	3	4	19	21
Both Hsp27 WT and Hsp27 C137A reduced the caspase-3 activity to a similar extent ( XREF_FIG ) .	Both Hsp27 WT and Hsp27 C137A reduced the caspase-3 activity to a similar extent (XREF_FIG).	1	9	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	caspase-3	caspase-3	caspase-3	1	2	8	9
In addition , inhibition of HSP27 increased caspase 3 , caspase 7 and PARP cleavage .	In addition, inhibition of HSP27 increased caspase 3, caspase 7 and PARP cleavage.	3	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HSP27	HSP27	HSP27	caspase 3	caspase 3	caspase 3	5	6	7	9
siRNA transfection and 215muM RA treatment suppressed Hsp27 expression level by 90.5 % and increased caspase-3 activity by 58 % .	siRNA transfection and 215muM RA treatment suppressed Hsp27 expression level by 90.5% and increased caspase-3 activity by 58%.	4	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Hsp27	RA treatment suppressed Hsp27 expression level	hsp27	caspase-3	caspase-3	caspase-3	7	8	15	16
Moreover , knockdown of the protein level of Hsp27 using small interfering RNA in Rac1N17 cells significantly increased the paclitaxel elicited caspase-3 activation and apoptosis .	Moreover, knockdown of the protein level of Hsp27 using small interfering RNA in Rac1N17 cells significantly increased the paclitaxel elicited caspase-3 activation and apoptosis.	6	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	level of Hsp27	hsp27	caspase-3	caspase-3	caspase-3	8	9	21	22
Hsp27 inhibits the activation of caspase-3 , induced after cytochrome-c release from mitochondria and after the activation of death receptors such as Fas [ XREF_BIBR , XREF_BIBR ] .	Hsp27 inhibits the activation of caspase-3, induced after cytochrome-c release from mitochondria and after the activation of death receptors such as Fas [XREF_BIBR, XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	caspase-3	caspase-3	caspase-3	0	1	5	6
These results are similar to the parent protein molecules from which they are derived , as Hsp27 has been shown to inhibit cytochrome c release and activation of caspase-3 [ XREF_BIBR , XREF_BIBR ] .	These results are similar to the parent protein molecules from which they are derived, as Hsp27 has been shown to inhibit cytochrome c release and activation of caspase-3 [XREF_BIBR, XREF_BIBR].	16	32	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	caspase-3	caspase-3	caspase-3	16	17	28	29
Consistent with the in vivo data , AAV mediated Hsp27 overexpression in neurons attenuated caspase-3 and caspase-9 activation and cytochrome c release following OGD ( XREF_FIG ) .	Consistent with the in vivo data, AAV mediated Hsp27 overexpression in neurons attenuated caspase-3 and caspase-9 activation and cytochrome c release following OGD (XREF_FIG).	9	17	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27 overexpression	hsp27	caspase-3	caspase-3	caspase-3	9	10	14	15
XREF_BIBR HSP27 is constitutively activated in CD133 + CRC stem cells , and HSP27 activation is required in CD133 + cells to prevent caspase-3 and caspase-9 cleavages in the apoptosis cascade .	XREF_BIBR HSP27 is constitutively activated in CD133 + CRC stem cells, and HSP27 activation is required in CD133 + cells to prevent caspase-3 and caspase-9 cleavages in the apoptosis cascade.	13	26	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HSP27	HSP27	HSP27	caspase-3	caspase-3	caspase-3	13	14	23	24
In addition , HSP27 acts both upstream and downstream of cytochrome c release in a stimulus dependent manner [ XREF_BIBR ] and inhibits caspase-3 activity through interaction with its inactive form , procaspase-3 [ XREF_BIBR ] .	In addition, HSP27 acts both upstream and downstream of cytochrome c release in a stimulus dependent manner [XREF_BIBR] and inhibits caspase-3 activity through interaction with its inactive form, procaspase-3 [XREF_BIBR].	3	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HSP27	HSP27	HSP27	caspase-3	caspase-3	caspase-3	3	4	23	24
XREF_BIBR - XREF_BIBR In addition , Hsp27 can inhibit caspase 3 activity via direct interaction with the pro caspase 3 molecule .	XREF_BIBR - XREF_BIBR In addition, Hsp27 can inhibit caspase 3 activity via direct interaction with the pro caspase 3 molecule.	6	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	caspase 3	caspase 3	caspase 3	6	7	9	11
MK2 inactivation or inhibition of MK2 or Hsp27 expression increases caspase-3 and PARP cleavage and DNA breaks and therefore cell death .	MK2 inactivation or inhibition of MK2 or Hsp27 expression increases caspase-3 and PARP cleavage and DNA breaks and therefore cell death.	0	12	increases	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Hsp27	MK2 inactivation or inhibition of MK2 or Hsp27 expression	hsp27	caspase-3	caspase-3	caspase-3	7	8	10	11
In human monocytes undergoing spontaneous apoptosis , HSP27 has been shown to associate to and block active caspase-3 [ XREF_BIBR ] .	In human monocytes undergoing spontaneous apoptosis, HSP27 has been shown to associate to and block active caspase-3 [XREF_BIBR].	7	19	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HSP27	HSP27	HSP27	caspase-3	caspase-3	caspase-3	7	8	17	18
Hsp27 interacts with and inhibits caspase-3 activation , an effect related to the ability of Hsp27 to stabilize actin microfilaments .	Hsp27 interacts with and inhibits caspase-3 activation, an effect related to the ability of Hsp27 to stabilize actin microfilaments.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	caspase-3	caspase-3	caspase-3	0	1	5	6
Furthermore , HSP27 can inhibit caspase-3 activity by interacting with the pro-caspase-3 molecule [ XREF_BIBR , XREF_BIBR ] .	Furthermore, HSP27 can inhibit caspase-3 activity by interacting with the pro-caspase-3 molecule [XREF_BIBR, XREF_BIBR].	2	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HSP27	HSP27	HSP27	caspase-3	caspase-3	caspase-3	2	3	5	6
Elevated expression of Hsp27 decreased caspase-3 activity in colorectal cancer cells .	Elevated expression of Hsp27 decreased caspase-3 activity in colorectal cancer cells.	1	6	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	expression of Hsp27	hsp27	caspase-3	caspase-3	caspase-3	3	4	5	6
The majority of studies have focused on the effects of Hsp27 on downstream death-execution pathways ; Hsp27 may directly inactivate caspase-3 and caspase-9 , or indirectly suppress caspase activation via inhibition of apoptosome formation .	The majority of studies have focused on the effects of Hsp27 on downstream death-execution pathways; Hsp27 may directly inactivate caspase-3 and caspase-9, or indirectly suppress caspase activation via inhibition of apoptosome formation.	16	26	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	caspase-3	caspase-3	caspase-3	16	17	20	21
Hhip inhibits Shh signaling by sequestering the Shh ligand , which in turn decreases repression of Fgf10 at the expanding tip .	Hhip inhibits Shh signaling by sequestering the Shh ligand, which in turn decreases repression of Fgf10 at the expanding tip.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	0	1	2	3
The expansion of Pax7 included expression in cells that did not express Hhip , indicating that Hhip inhibited the Shh response in neighbouring cells .	The expansion of Pax7 included expression in cells that did not express Hhip, indicating that Hhip inhibited the Shh response in neighbouring cells.	16	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	16	17	19	20
In particular our finding that Hhip can inhibit the Shh response in cells that are located between the Shh source and the sites of Hhip synthesis strongly indicates that Hhip is able to act at a distance .	In particular our finding that Hhip can inhibit the Shh response in cells that are located between the Shh source and the sites of Hhip synthesis strongly indicates that Hhip is able to act at a distance.	5	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	5	6	9	10
While our data are consistent with those previously reported in placing Hhip inhibition of Shh activity upstream of Smo activation XREF_BIBR , XREF_BIBR , our study does not address whether Hhip inhibits Shh activity via Smo .	While our data are consistent with those previously reported in placing Hhip inhibition of Shh activity upstream of Smo activation XREF_BIBR, XREF_BIBR, our study does not address whether Hhip inhibits Shh activity via Smo.	11	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	11	12	14	15
In models where Shh is blocked by HHIP over-expression , no villi form and the epithelium remains pseudostratified and poorly differentiated with unfettered proliferation [ XREF_BIBR ] .	In models where Shh is blocked by HHIP over-expression, no villi form and the epithelium remains pseudostratified and poorly differentiated with unfettered proliferation [XREF_BIBR].	3	9	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	HHIP	HHIP over-expression	hhip	Shh	Shh	shh	7	8	3	4
Our data show a sharp decrease in Hhip when co-expressed with SmoM2 , yet , in vivo when Hhip and SmoM2 are co-expressed there remains a robust Hhip cell non autonomous inhibition of Shh activity .	Our data show a sharp decrease in Hhip when co-expressed with SmoM2, yet, in vivo when Hhip and SmoM2 are co-expressed there remains a robust Hhip cell non autonomous inhibition of Shh activity.	27	34	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	27	28	33	34
Consistent with earlier findings , we find that Hhip inhibits the Shh response in neighboring cells .	Consistent with earlier findings, we find that Hhip inhibits the Shh response in neighboring cells.	8	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	8	9	11	12
First , although there is a drastic decrease in Hhip expression , the remaining Hhip may be enough to inhibit Shh activity .	First, although there is a drastic decrease in Hhip expression, the remaining Hhip may be enough to inhibit Shh activity.	12	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	14	15	20	21
This demonstrates that Hhip non cell autonomously inhibited the Shh response in nearby cells .	This demonstrates that Hhip non cell autonomously inhibited the Shh response in nearby cells.	3	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	3	4	9	10
Moreover , HhipDeltaAR and HhipDeltaEGF inhibited the Shh response similar to wild type Hhip ( XREF_FIG ) , indicating that these domains are dispensable for Hhip inhibition of Shh .	Moreover, HhipDeltaAR and HhipDeltaEGF inhibited the Shh response similar to wild type Hhip (XREF_FIG), indicating that these domains are dispensable for Hhip inhibition of Shh.	25	29	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	25	26	28	29
HHIP inhibits Shh signaling by sequestering Hh ligands which then can not activate the pathway , and its epigenetically mediated downregulation was observed in gastrointestinal , hepatocellular , and pancreatic tumors [ XREF_BIBR - XREF_BIBR ] .	HHIP inhibits Shh signaling by sequestering Hh ligands which then can not activate the pathway, and its epigenetically mediated downregulation was observed in gastrointestinal, hepatocellular, and pancreatic tumors [XREF_BIBR - XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HHIP	HHIP	HHIP	Shh	Shh	Shh	0	1	2	3
However , rather than just acting to cell autonomously sequester Shh to lower the amount of Shh available to neighboring cells , we find that Hhip is also released from the sites of synthesis to inhibit the Shh response at a distance .	However, rather than just acting to cell autonomously sequester Shh to lower the amount of Shh available to neighboring cells, we find that Hhip is also released from the sites of synthesis to inhibit the Shh response at a distance.	25	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	25	26	37	38
Hhip sequesters Shh , leading to a non cell autonomous inhibition of the pathway .	Hhip sequesters Shh, leading to a non cell autonomous inhibition of the pathway.	0	3	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	0	1	2	3
OSM downregulated myocyte enhancer binding factor 2A ( MEF2A ) , upregulated the expression of Id1 and Id2 , and inhibited the transcriptional activity of MyoD and MEF2 .	OSM downregulated myocyte enhancer binding factor 2A (MEF2A), upregulated the expression of Id1 and Id2, and inhibited the transcriptional activity of MyoD and MEF2.	0	27	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id1	OSM downregulated myocyte enhancer binding factor 2A (MEF2A), upregulated the expression of Id1	id1	MyoD	MyoD	myod	15	16	25	26
While Id is thought to inhibit MyoD by binding and sequestering potential dimerization partners , MITF-2B appears to inhibit MyoD activity by forming an inactive heterodimer with MyoD .	While Id is thought to inhibit MyoD by binding and sequestering potential dimerization partners, MITF-2B appears to inhibit MyoD activity by forming an inactive heterodimer with MyoD.	1	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id	Id	Id	MyoD	MyoD	MyoD	1	2	6	7
Interestingly , Id expression , as well as the other network components , is also modulated by BMP that inhibits MyoD and consequent muscle differentiation from the lateral somite [ XREF_BIBR ] while promoting endothelial development [ XREF_BIBR ] .	Interestingly, Id expression, as well as the other network components, is also modulated by BMP that inhibits MyoD and consequent muscle differentiation from the lateral somite [XREF_BIBR] while promoting endothelial development [XREF_BIBR].	2	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id	Id expression, as well as the other network components, is also modulated by BMP	id	MyoD	MyoD	myod	2	3	20	21
Finally , to compare the activities of Id2 , Id3 , and Id4 , we use animal cap explants and in vivo overexpression to show that Id proteins can differentially inhibit the activities of neurogenin and neuroD , both neurogenic bHLH molecules and MyoD , a myogenic bHLH protein .	Finally, to compare the activities of Id2, Id3, and Id4, we use animal cap explants and in vivo overexpression to show that Id proteins can differentially inhibit the activities of neurogenin and neuroD, both neurogenic bHLH molecules and MyoD, a myogenic bHLH protein.	26	48	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id	Id	Id	MyoD	MyoD	MyoD	26	27	43	44
Prior studies suggested that the expression of Id proteins in myoblasts competed with MyoD for E protein dimerization and limited the formation of MyoD : E protein heterodimers .	Prior studies suggested that the expression of Id proteins in myoblasts competed with MyoD for E protein dimerization and limited the formation of MyoD : E protein heterodimers.	5	24	limited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id	expression of Id	id	MyoD	MyoD	myod	7	8	23	24
MyoD activity was also inhibited by Id , a HLH protein , and this inhibition was reversed by the addition of excess E12 or MITF-2A .	MyoD activity was also inhibited by Id, a HLH protein, and this inhibition was reversed by the addition of excess E12 or MITF-2A.	0	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Id	Id	Id	MyoD	MyoD	MyoD	6	7	0	1
Transcriptional activation by MyoD can also be negatively controlled by protein protein interactions , which includes I-mf that prevents nuclear localization of MyoD , Id proteins that sequester functional E-box proteins as well as MyoD , and Twist that inhibits transactivation of MyoD .	Transcriptional activation by MyoD can also be negatively controlled by protein protein interactions, which includes I-mf that prevents nuclear localization of MyoD, Id proteins that sequester functional E-box proteins as well as MyoD, and Twist that inhibits transactivation of MyoD.	24	35	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id	Id	Id	MyoD	MyoD	MyoD	24	25	34	35
In undifferentiated myoblasts , abundant Id proteins prevent the formation of E2A and MyoD heterodimers that can bind DNA [ XREF_BIBR ] .	In undifferentiated myoblasts, abundant Id proteins prevent the formation of E2A and MyoD heterodimers that can bind DNA [XREF_BIBR].	5	14	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id	Id	Id	MyoD	MyoD	MyoD	5	6	13	14
Evidence is available showing that Id1 forms heterodimers with E12 and E47 and prevents MyoD from forming complexes with E12 and E47 in myoblasts [ XREF_BIBR , XREF_BIBR ] .	Evidence is available showing that Id1 forms heterodimers with E12 and E47 and prevents MyoD from forming complexes with E12 and E47 in myoblasts [XREF_BIBR, XREF_BIBR].	5	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id1	Id1	Id1	MyoD	MyoD	MyoD	5	6	14	15
The overexpression of Id , a dominant negative repressor of MyoD , prevents maternal MyoD from binding to its consensus sequences ; nevertheless , muscle genes are activated in somatic nuclei to the same extent as without Id .	The overexpression of Id, a dominant negative repressor of MyoD, prevents maternal MyoD from binding to its consensus sequences; nevertheless, muscle genes are activated in somatic nuclei to the same extent as without Id.	1	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id	overexpression of Id	id	MyoD	MyoD	myod	3	4	14	15
It has been shown that Id inhibits MyoD activity either by forming transcriptionally inactive complexes of MyoD-Id or by forming heterodimers with E-proteins and effectively blocking the formation of active MyoD/E protein complexes [ XREF_BIBR ] .	It has been shown that Id inhibits MyoD activity either by forming transcriptionally inactive complexes of MyoD-Id or by forming heterodimers with E-proteins and effectively blocking the formation of active MyoD/E protein complexes [XREF_BIBR].	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id	Id	Id	MyoD	MyoD	MyoD	5	6	7	8
Conversely , boosting PGC-1alpha expression by either ectopic expression or exposure to BRAF V600E inhibitor vemurafenib suppresses metastasis , which involves direct regulation of ID2 and consequent inhibition of TCF4 mediated gene transcription ( XREF_FIG ) [ XREF_BIBR ] .	Conversely, boosting PGC-1alpha expression by either ectopic expression or exposure to BRAF V600E inhibitor vemurafenib suppresses metastasis, which involves direct regulation of ID2 and consequent inhibition of TCF4 mediated gene transcription (XREF_FIG) [XREF_BIBR].	24	30	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	ID2	ID2	ID2	TCF4	TCF4	TCF4	24	25	29	30
For example , high expression of the cDC marker Id2 inhibits the pDC gene Tcf4 and vice versa , resulting in cDC or pDC development , respectively .	For example, high expression of the cDC marker Id2 inhibits the pDC gene Tcf4 and vice versa, resulting in cDC or pDC development, respectively.	4	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id2	expression of the cDC marker Id2	id2	Tcf4	Tcf4	tcf4	9	10	14	15
The present study suggests that FIH1 is required to repress Notch activity and maintain proliferative potential , while miR-184 , by repressing FIH1 , induces the Notch pathway and commitment to differentiation .	The present study suggests that FIH1 is required to repress Notch activity and maintain proliferative potential, while miR-184, by repressing FIH1, induces the Notch pathway and commitment to differentiation.	5	13	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FIH1	FIH1	FIH1	Notch	Notch	Notch	5	6	10	11
FIH-1 not only negatively regulates Notch ICD , but also influences the intracellular localization of FIH-1 by recruiting FIH-1 into the nucleus [ XREF_BIBR ] .	FIH-1 not only negatively regulates Notch ICD, but also influences the intracellular localization of FIH-1 by recruiting FIH-1 into the nucleus [XREF_BIBR].	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FIH-1	FIH-1	FIH-1	Notch	Notch	Notch	0	1	5	6
FIH-1 negatively regulates Notch activity and accelerates myogenic differentiation .	FIH-1 negatively regulates Notch activity and accelerates myogenic differentiation.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FIH-1	FIH-1	FIH-1	Notch	Notch	Notch	0	1	3	4
Loss of FIH-1 in vivo increased Notch activity in the limbal epithelium , resulting in a more differentiated phenotype .	Loss of FIH-1 in vivo increased Notch activity in the limbal epithelium, resulting in a more differentiated phenotype.	0	7	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FIH-1	Loss of FIH-1	fih-1	Notch	Notch	notch	2	3	6	7
In vitro data suggest that FIH1 negatively regulates Notch signaling , but the biological significance of the FIH1 mediated modifications is not fully understood , and mice targeted for FIH1 do not display an overt Notch gain-of-function phenotype 1.2 Notch ligands .	In vitro data suggest that FIH1 negatively regulates Notch signaling, but the biological significance of the FIH1 mediated modifications is not fully understood, and mice targeted for FIH1 do not display an overt Notch gain-of-function phenotype 1.2 Notch ligands.	5	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FIH1	FIH1	FIH1	Notch	Notch	Notch	5	6	8	9
For instance , it has been shown that Hsp27 is overexpressed in myeloma and inhibits the release of Smac , an activator of caspases from the mitochondria , thereby confering dexamethasone resistance [ XREF_BIBR ] .	For instance, it has been shown that Hsp27 is overexpressed in myeloma and inhibits the release of Smac, an activator of caspases from the mitochondria, thereby confering dexamethasone resistance [XREF_BIBR].	8	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27 is overexpressed	hsp27	Smac	Smac	smac	8	9	18	19
HSP27 of the inducible small HSP family has been shown to inhibit the mitochondrial release of SMAC ( second mitochondrial derived activator of caspase ) , the master regulator of apoptosis , to confer resistance of multiple myeloma cells to dexamethasone [ XREF_BIBR ] .	HSP27 of the inducible small HSP family has been shown to inhibit the mitochondrial release of SMAC (second mitochondrial derived activator of caspase), the master regulator of apoptosis, to confer resistance of multiple myeloma cells to dexamethasone [XREF_BIBR].	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HSP27	HSP27	HSP27	SMAC	SMAC	SMAC	0	1	16	17
Hsp27 can also inactivate Bax and block the release of Smac and cytochrome C.	Hsp27 can also inactivate Bax and block the release of Smac and cytochrome C.	0	13	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	Smac	Smac	Smac	0	1	10	11
It has been found that Hsp27 can block the tBID entering the mitochondria and reduce SMAC and Cytochrome C releasing from mitochondria so as to block the apoptotic process XREF_BIBR .	It has been found that Hsp27 can block the tBID entering the mitochondria and reduce SMAC and Cytochrome C releasing from mitochondria so as to block the apoptotic process XREF_BIBR.	5	18	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	SMAC	SMAC	SMAC	5	6	15	16
These data demonstrate that Hsp27 inhibits the release of Smac , and thereby confers Dex resistance in MM cells .	These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	Smac	Smac	Smac	4	5	9	10
Hsp27 attenuates mitochondrial release of cytochrome c and Smac following cerebral ischemia .	Hsp27 attenuates mitochondrial release of cytochrome c and Smac following cerebral ischemia.	0	9	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	Smac	Smac	Smac	0	1	8	9
Alternatively , pRb inhibition of Id2 has been suggested to potentiate MyoD activity .	Alternatively, pRb inhibition of Id2 has been suggested to potentiate MyoD activity.	3	12	potentiate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Id2	Id2	Id2	MyoD	MyoD	MyoD	5	6	11	12
Id4 is able to inhibit the activity all these bHLH molecules , Id2 inhibits MyoD and neuroD , while Id3 blocks only neuroD activity in our assays .	Id4 is able to inhibit the activity all these bHLH molecules, Id2 inhibits MyoD and neuroD, while Id3 blocks only neuroD activity in our assays.	12	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id2	Id2	Id2	MyoD	MyoD	MyoD	12	13	14	15
Furthermore , it has been observed , that Id2 reduces the myogenic markers MyoD and myogenin in myoblasts , however , ENH1 overexpression restores myogenic differentiation by binding Id2 [ XREF_BIBR ] .	Furthermore, it has been observed, that Id2 reduces the myogenic markers MyoD and myogenin in myoblasts, however, ENH1 overexpression restores myogenic differentiation by binding Id2 [XREF_BIBR].	8	17	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id2	Id2	Id2	MyoD	MyoD	MyoD	8	9	13	14
Id3 can interact with a wide range of bHLH factors and blocks transcriptional activity of E12 , E47 , and HEB .	Id3 can interact with a wide range of bHLH factors and blocks transcriptional activity of E12, E47, and HEB.	0	21	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id3	Id3	Id3	HEB	HEB	HEB	0	1	20	21
We provide evidence that inhibition of HEB by Id3 leads to repression of the gammadeltaT17 cell network , linking it to gammadelta TCR mediated repression of the gammadeltaT17 cell fate .	We provide evidence that inhibition of HEB by Id3 leads to repression of the gammadeltaT17 cell network, linking it to gammadelta TCR mediated repression of the gammadeltaT17 cell fate.	4	9	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Id3	Id3	Id3	HEB	HEB	HEB	8	9	6	7
HEB is required in immature CD24 + CD73 - gammadelta T cells for the expression of Sox4 , Sox13 , and Rorc , and these genes are repressed by acute expression of the HEB antagonist Id3 .	HEB is required in immature CD24 + CD73 - gammadelta T cells for the expression of Sox4, Sox13, and Rorc, and these genes are repressed by acute expression of the HEB antagonist Id3.	30	36	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Id3	Id3	Id3	HEB	HEB	HEB	35	36	33	34
Gurzov et al XREF_BIBR showed that Hrk inhibited Bcl-xL which was an antiapoptotic protein and therefore , blocked apoptosis .	Gurzov et al XREF_BIBR showed that Hrk inhibited Bcl-xL which was an antiapoptotic protein and therefore, blocked apoptosis.	6	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hrk	Hrk	Hrk	Bcl-xL	Bcl-xL	Bcl-xL	6	7	8	9
The antiapoptotic Bcl-XL protein is localized mainly at the mitochondria of the beta-cells and antagonizes PUMA action , but Bcl-XL is inactivated by the BH3-only sensitizer DP5 and Hrk in cytokine exposed beta-cells .	The antiapoptotic Bcl-XL protein is localized mainly at the mitochondria of the beta-cells and antagonizes PUMA action, but Bcl-XL is inactivated by the BH3-only sensitizer DP5 and Hrk in cytokine exposed beta-cells.	19	29	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Hrk	Hrk	Hrk	Bcl-XL	Bcl-XL	Bcl-XL	28	29	19	20
Previous reports showed that HIPK2 can signal cell death via p53 , and independently of p53 by activating the c-Jun NH2-terminal kinase ( JNK ) pathway or mediating CtBP degradation .	Previous reports showed that HIPK2 can signal cell death via p53, and independently of p53 by activating the c-Jun NH2-terminal kinase (JNK) pathway or mediating CtBP degradation.	4	29	signal	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HIPK2	HIPK2	HIPK2	CtBP	CtBP	CtBP	4	5	28	29
Furthermore , tumor suppressors such as HIPK2 , Ink4a and Arf , and APC target CtBP for down-regulation to induce apoptosis .	Furthermore, tumor suppressors such as HIPK2, Ink4a and Arf, and APC target CtBP for down-regulation to induce apoptosis.	3	19	suppressors	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	HIPK2	HIPK2	HIPK2	CtBP	CtBP	CtBP	6	7	15	16
In addition , HIPK2 has also been shown to interact with and promote the degradation of CtBP in response to ultraviolet induced DNA damage , and can induce p53 independent apoptosis .	In addition, HIPK2 has also been shown to interact with and promote the degradation of CtBP in response to ultraviolet induced DNA damage, and can induce p53 independent apoptosis.	3	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HIPK2	HIPK2	HIPK2	CtBP	CtBP	CtBP	3	4	16	17
Indeed , we found downregulation of Notch1 , Jag1 , and Notch downstream target genes Hey1 , Hey2 , and Hey1L in RGS6 -/- / CaMKII VV embryos and yolk sacs , favoring the arterial specification defects we observed .	Indeed, we found downregulation of Notch1, Jag1, and Notch downstream target genes Hey1, Hey2, and Hey1L in RGS6 -/- / CaMKII VV embryos and yolk sacs, favoring the arterial specification defects we observed.	4	26	downregulation	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Hey2	Hey2	Hey2	Notch1	Notch1	Notch1	17	18	6	7
Moreover , liver regeneration is compromised in absence of Nrf2 as a result of blunted Notch 1 signaling caused by reduced expression of Notch1 , p21 , Hes1 , Homocysteine responsive endoplasmic reticulum-resident 1 ( Herp1 ) and NOTCH regulated ankyrin repeat protein ( Nrarp ) XREF_BIBR .	Moreover, liver regeneration is compromised in absence of Nrf2 as a result of blunted Notch 1 signaling caused by reduced expression of Notch1, p21, Hes1, Homocysteine responsive endoplasmic reticulum-resident 1 (Herp1) and NOTCH regulated ankyrin repeat protein (Nrarp) XREF_BIBR.	15	36	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Herp1	expression of Notch1, p21, Hes1, Homocysteine responsive endoplasmic reticulum-resident 1 (Herp1	herp1	Notch 1	Notch 1	notch 1	35	36	15	17
Similarly , there were significant reductions in Notch 1 , Dll4 , and Hrt-2 mRNA expression in aneurysmal tissue compared with nonaneurysmal tissue , with no significant change in Hrt-1 mRNA expression ( XREF_FIG ) .	Similarly, there were significant reductions in Notch 1, Dll4, and Hrt-2 mRNA expression in aneurysmal tissue compared with nonaneurysmal tissue, with no significant change in Hrt-1 mRNA expression (XREF_FIG).	3	16	were significant reductions	Negative_activation_copula_1	Negative_activation	Negative_activation	Hrt-2	Hrt-2 mRNA expression	hrt-2	Notch 1	Notch 1	notch 1	13	14	7	9
Independently , HtrA2 and Omi degrades IAPs , the caspase-8 inhibitor Pea-15 and the anti-apoptotic protein HAX-1 through its serine protease activity , further promoting apoptosis [ XREF_BIBR ] .	Independently, HtrA2 and Omi degrades IAPs, the caspase-8 inhibitor Pea-15 and the anti-apoptotic protein HAX-1 through its serine protease activity, further promoting apoptosis [XREF_BIBR].	2	12	degrades	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Omi	Omi	Omi	Pea-15	Pea-15	Pea-15	4	5	11	12
The mitochondrial protein Htra2 and OMI promotes apoptosis by targeting PEA-15 to proteasome .	The mitochondrial protein Htra2 and OMI promotes apoptosis by targeting PEA-15 to proteasome.	0	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Htra2	Htra2	Htra2	PEA-15	PEA-15	PEA-15	3	4	10	11
Antiapoptotic proteins block apoptotic program by inhibiting the proapoptotic proteins such as Bax ; 15 ( 5 ) HRK gene encodes for the proapoptotic protein HRK ( harakiri ) , which belongs to the BH3-only protein family and selectively antagonizes the antiapoptotic proteins Bcl-2 and Bcl-xl ; 16 ( 6 ) bax gene encodes for the p21 bcl associated X protein or Baxalpha .	Antiapoptotic proteins block apoptotic program by inhibiting the proapoptotic proteins such as Bax; 15 (5) HRK gene encodes for the proapoptotic protein HRK (harakiri), which belongs to the BH3-only protein family and selectively antagonizes the antiapoptotic proteins Bcl-2 and Bcl-xl; 16 (6) bax gene encodes for the p21 bcl associated X protein or Baxalpha.	20	45	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HRK	HRK	HRK	Bcl-2	Bcl-2	Bcl-2	25	26	43	44
Interestingly , HRK , a BH3-only Bcl-2 family member , that can antagonize antiapoptotic proteins Bcl-2 and Bcl-xL , 25 was the top induced gene .	Interestingly, HRK, a BH3-only Bcl-2 family member, that can antagonize antiapoptotic proteins Bcl-2 and Bcl-xL, 25 was the top induced gene.	2	22	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HRK	HRK	HRK	Bcl-2	Bcl-2	Bcl-2	2	3	15	16
XREF_BIBR , XREF_BIBR During this response , regulation of NOTCH signalling occurs when FIH-1 ( factor inhibiting HIF-1 ) negatively regulates NICD by hydroxylating the Asn 1,945 and Asn 2,012 residues that are associated with Notch mediated transcriptional activation , resulting in severe impairment of NICD function .	XREF_BIBR, XREF_BIBR During this response, regulation of NOTCH signalling occurs when FIH-1 (factor inhibiting HIF-1) negatively regulates NICD by hydroxylating the Asn 1,945 and Asn 2,012 residues that are associated with Notch mediated transcriptional activation, resulting in severe impairment of NICD function.	13	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FIH-1	FIH-1	FIH-1	NICD	NICD	NICD	13	14	21	22
However , Hes1 promotes rapid tumorigenesis in a well studied model of T-ALL in which expression of Id1 inhibits the function of E2A and HEB transcription factors XREF_BIBR , whose deficiency leads to T cell lymphoma XREF_BIBR .	However, Hes1 promotes rapid tumorigenesis in a well studied model of T-ALL in which expression of Id1 inhibits the function of E2A and HEB transcription factors XREF_BIBR, whose deficiency leads to T cell lymphoma XREF_BIBR.	15	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id1	expression of Id1	id1	HEB	HEB	heb	17	18	24	25
Consistently , T cell specific overexpression of Id1 in transgenic mice diminishes the function of both E2A and HEB proteins and results in a severe developmental arrest at the earliest progenitor stages that is also accompanied by massive apoptosis [ XREF_BIBR - XREF_BIBR ] .	Consistently, T cell specific overexpression of Id1 in transgenic mice diminishes the function of both E2A and HEB proteins and results in a severe developmental arrest at the earliest progenitor stages that is also accompanied by massive apoptosis [XREF_BIBR - XREF_BIBR].	5	19	diminishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id1	overexpression of Id1	id1	HEB	HEB	heb	7	8	18	19
HIPK2 depletion by RNA interference suppressed the antiapoptotic effect of HMGA1 , which indicates that HIPK2 is the target required for HMGA1 to repress the apoptotic activity of p53 .	HIPK2 depletion by RNA interference suppressed the antiapoptotic effect of HMGA1, which indicates that HIPK2 is the target required for HMGA1 to repress the apoptotic activity of p53.	0	13	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	HIPK2	HIPK2	HIPK2	HMGA1	HMGA1	HMGA1	0	1	10	11
Since ID2 suppresses the activity of TCF3 [ XREF_BIBR ] , we analyzed BIM expression in transduced JURKAT cells .	Since ID2 suppresses the activity of TCF3 [XREF_BIBR], we analyzed BIM expression in transduced JURKAT cells.	1	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ID2	ID2	ID2	TCF3	TCF3	TCF3	1	2	6	7
Since endogenous TCF3 proteins are bona fide inactivated by ID2 and MSC in cHL , we overexpressed E47 , a TCF3 transcription variant , in KM-H2 and SUP-HD1 cell lines using doxycycline ( DOX )-inducible vector pRTS containing GFP as a fluorescent marker .	Since endogenous TCF3 proteins are bona fide inactivated by ID2 and MSC in cHL, we overexpressed E47, a TCF3 transcription variant, in KM-H2 and SUP-HD1 cell lines using doxycycline (DOX)-inducible vector pRTS containing GFP as a fluorescent marker.	2	11	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ID2	ID2	ID2	TCF3	TCF3	TCF3	9	10	2	3
In contrast , HHIP expression in the stromal cell population was dramatically higher than in PB , BM or CB CD34 + cells ( XREF_FIG ) , suggesting that HHIP expressed by stromal cells inhibited Ihh signaling in hematopoietic cells when the two cell types were present in the BM microenvironment .	In contrast, HHIP expression in the stromal cell population was dramatically higher than in PB, BM or CB CD34 + cells (XREF_FIG), suggesting that HHIP expressed by stromal cells inhibited Ihh signaling in hematopoietic cells when the two cell types were present in the BM microenvironment.	29	36	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HHIP	HHIP expressed	hhip	Ihh	Ihh	ihh	29	30	35	36
Insulin also inhibits gluconeogenic gene expression by excluding FOXO1 from the nucleus and reducing PGC-1alpha ' s impact on gluconeogenic genes .	Insulin also inhibits gluconeogenic gene expression by excluding FOXO1 from the nucleus and reducing PGC-1alpha 's impact on gluconeogenic genes.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	8	9
Impaired insulin mediated activation of Foxo1 , as reported in response to defective pulsatile insulin delivery here , would be predicted to lead to impaired expression of Gck and favor gluconeogenesis over glycolysis with inappropriately increased hepatic glucose release and hyperglycemia .	Impaired insulin mediated activation of Foxo1, as reported in response to defective pulsatile insulin delivery here, would be predicted to lead to impaired expression of Gck and favor gluconeogenesis over glycolysis with inappropriately increased hepatic glucose release and hyperglycemia.	1	6	mediated	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	1	2	5	6
Insulin Inhibits Transcriptional Activity of FOXO1 in C2C12 myotubes .	Insulin Inhibits Transcriptional Activity of FOXO1 in C2C12 myotubes.	0	8	Inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	5	6
Addition of IGF-1 ( 13nM ) or insulin ( 35uM ) at 30 min causes a rapid decrease in nuclear content of Foxo1-GFP , as shown by presence of dark nuclei at 60 and 90 min for IGF1 or insulin ( XREF_FIG ) .	Addition of IGF-1 (13nM) or insulin (35uM) at 30 min causes a rapid decrease in nuclear content of Foxo1-GFP, as shown by presence of dark nuclei at 60 and 90 min for IGF1 or insulin (XREF_FIG).	0	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1-GFP	Foxo1-GFP	Foxo1-GFP	7	8	22	23
Insulin inhibits FOXO1 activity leading to the repression of these genes .	Insulin inhibits FOXO1 activity leading to the repression of these genes.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	2	3
In physiological conditions , insulin suppresses FoxO1 activity through Akt phosphorylation signaling , while high glucose elevates FoxO1 O-GlcNAc modification , and subsequent FoxO1 activation .	In physiological conditions, insulin suppresses FoxO1 activity through Akt phosphorylation signaling, while high glucose elevates FoxO1 O-GlcNAc modification, and subsequent FoxO1 activation.	4	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	4	5	6	7
XREF_BIBR , XREF_BIBR Our results in SZ95 sebocytes showed that IGF-1 and insulin reduce nuclear FoxO1 and FoxO transcriptional activity via PI3K and Akt pathway activation .	XREF_BIBR, XREF_BIBR Our results in SZ95 sebocytes showed that IGF-1 and insulin reduce nuclear FoxO1 and FoxO transcriptional activity via PI3K and Akt pathway activation.	10	25	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	12	13	15	16
We conclude that insulin can inhibit Foxo1 stimulated transcription even when nuclear export of Foxo1 is prevented , indicating that insulin inhibition can occur by direct mechanisms that do not depend on altering the subcellular distribution of the transcription factor .	We conclude that insulin can inhibit Foxo1 stimulated transcription even when nuclear export of Foxo1 is prevented, indicating that insulin inhibition can occur by direct mechanisms that do not depend on altering the subcellular distribution of the transcription factor.	3	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	3	4	6	7
On the other hand , insulin signaling inactivates FOXO1 .	On the other hand, insulin signaling inactivates FOXO1.	5	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	5	6	8	9
IGF1 and insulin prevented Foxo1 from inhibiting Runx2 activity by promoting Foxo1 phosphorylation and nuclear exclusion .	IGF1 and insulin prevented Foxo1 from inhibiting Runx2 activity by promoting Foxo1 phosphorylation and nuclear exclusion.	0	5	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	2	3	4	5
Insulin mediated FoxO1 suppression is critical for steroidogenic genes expression .	Insulin mediated FoxO1 suppression is critical for steroidogenic genes expression.	0	3	mediated	Positive_early_activation	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FoxO1	FoxO1	FoxO1	0	1	2	3
As insulin acts to reduce nuclear FoxO1 activity following activation of Akt , these results support that in insulin-resistance states , the increased production of VLDL apoB containing lipoproteins is related to unrestrained FoxO1 dependent MTP transcription .	As insulin acts to reduce nuclear FoxO1 activity following activation of Akt, these results support that in insulin-resistance states, the increased production of VLDL apoB containing lipoproteins is related to unrestrained FoxO1 dependent MTP transcription.	1	7	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	1	2	6	7
In contrast to its importance in regulating the transcriptional activity of Foxo1 in the absence of insulin , acetylation plays only a minor role compared with phosphorylation in insulin inhibition of Foxo1 transcriptional activity .	In contrast to its importance in regulating the transcriptional activity of Foxo1 in the absence of insulin, acetylation plays only a minor role compared with phosphorylation in insulin inhibition of Foxo1 transcriptional activity.	28	33	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	28	29	31	32
IGF1 or insulin abolish the Foxo1 occupancy of these promoters .	IGF1 or insulin abolish the Foxo1 occupancy of these promoters.	0	6	abolish	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	2	3	5	6
By contrast , insulin treatment of Lepr EGFPDeltaIrs2 mice did not reduce the percentage of ARC LepR-b neurons containing nuclear FoxO1 .	By contrast, insulin treatment of Lepr EGFPDeltaIrs2 mice did not reduce the percentage of ARC LepR-b neurons containing nuclear FoxO1.	3	21	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	3	4	20	21
Insulin inhibits FOXO1 mediated transcriptional activation through the PI 3-kinase dependent activation of PKB , which leads to the phosphorylation and nuclear exclusion of this factor [ XREF_BIBR ] .	Insulin inhibits FOXO1 mediated transcriptional activation through the PI 3-kinase dependent activation of PKB, which leads to the phosphorylation and nuclear exclusion of this factor [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	2	3
Insulin inhibits FOXO1 activity .	Insulin inhibits FOXO1 activity.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	2	3
Since insulin signaling reduces FOXO1 activity via Akt and promotes insulin responsiveness , it has been suggested that inhibition of PERK might improve insulin signaling in the liver .	Since insulin signaling reduces FOXO1 activity via Akt and promotes insulin responsiveness, it has been suggested that inhibition of PERK might improve insulin signaling in the liver.	1	5	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	1	2	4	5
Insulin reduced FOXO1 activity almost two-fold ( XREF_FIG , p < 0.05 ) .	Insulin reduced FOXO1 activity almost two-fold (XREF_FIG, p < 0.05).	0	3	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	2	3
Previous reports concerned with the mode of suppression of FoxO1 by insulin have focused on insulin activity in exporting nuclear FoxO1 by its phosphorylation by activated Akt .	Previous reports concerned with the mode of suppression of FoxO1 by insulin have focused on insulin activity in exporting nuclear FoxO1 by its phosphorylation by activated Akt.	2	12	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	11	12	9	10
Insulin inhibits the action of FOXO1 by binding insulin growth factor ( IGF ) -1 and FOXO1 receptor , which subsequently activates certain intracellular kinases involved in the PI3K and Akt pathway .	Insulin inhibits the action of FOXO1 by binding insulin growth factor (IGF) -1 and FOXO1 receptor, which subsequently activates certain intracellular kinases involved in the PI3K and Akt pathway.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	5	6
FOXO1 protein is decreased by insulin activated CRY1 .	FOXO1 protein is decreased by insulin activated CRY1.	0	6	decreased	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	5	6	0	1
For experiments , insulin was excluded from the culture media to prevent inactivation of FOXO1 .	For experiments, insulin was excluded from the culture media to prevent inactivation of FOXO1.	3	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	3	4	14	15
Whereas insulin resistance fails to inhibit FoxO1 driven gluconeogenesis it promotes lipogenesis ( dyslipidemia ) .	Whereas insulin resistance fails to inhibit FoxO1 driven gluconeogenesis it promotes lipogenesis (dyslipidemia).	1	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	1	2	6	7
Hepatic IR selectively removes the blockade of FoxO1 by insulin what increases gluconeogenesis and increases activation of SREBP-1c .	Hepatic IR selectively removes the blockade of FoxO1 by insulin what increases gluconeogenesis and increases activation of SREBP-1c.	3	12	blockade	Negative_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	9	10	7	8
Accordingly , dose response curves for insulin mediated suppression of the FoxO1 induced gluconeogenic genes and for de novo glucose production were right shifted , and insulin stimulated glucose oxidation and glycogen synthesis were impaired .	Accordingly, dose response curves for insulin mediated suppression of the FoxO1 induced gluconeogenic genes and for de novo glucose production were right shifted, and insulin stimulated glucose oxidation and glycogen synthesis were impaired.	4	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	6	7	11	12
First , we show that the insulin dependent inhibition of Foxo1 and activation of mTorc1 by Akt is both necessary and sufficient for the induction of lipogenesis and the lipogenic gene program .	First, we show that the insulin dependent inhibition of Foxo1 and activation of mTorc1 by Akt is both necessary and sufficient for the induction of lipogenesis and the lipogenic gene program.	6	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	6	7	10	11
Because insulin essentially inhibits FoxO1 transcriptional activity through nuclear exclusion , insulin increases glucose utilization and lipid synthesis as well as decreases glucose production ( XREF_FIG ) .	Because insulin essentially inhibits FoxO1 transcriptional activity through nuclear exclusion, insulin increases glucose utilization and lipid synthesis as well as decreases glucose production (XREF_FIG).	1	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	1	2	4	5
In parallel , mRNAs of established FoxO target genes were analyzed : like CP mRNA , selenoprotein P and glucose 6-phosphatase mRNAs were upregulated by FoxO1 , which was prevented by insulin .	In parallel, mRNAs of established FoxO target genes were analyzed : like CP mRNA, selenoprotein P and glucose 6-phosphatase mRNAs were upregulated by FoxO1, which was prevented by insulin.	23	32	prevented	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	31	32	25	26
Under physiological conditions , FoxO1 activity is inhibited by insulin .	Under physiological conditions, FoxO1 activity is inhibited by insulin.	4	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	9	10	4	5
We combined experimental data with mathematical modelling to show that the impaired insulin signalling in FOXO1 inhibited cells to a large extent can be explained by reduced mTORC1 activity - a mechanism that defines much of the diabetic state in human adipocytes .	We combined experimental data with mathematical modelling to show that the impaired insulin signalling in FOXO1 inhibited cells to a large extent can be explained by reduced mTORC1 activity - a mechanism that defines much of the diabetic state in human adipocytes.	12	16	signalling	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	12	13	15	16
Mammalian FoxO1 , 3 and 4 are negatively regulated by insulin and growth factors via the serine/threonine kinase Akt XREF_BIBR .	Mammalian FoxO1, 3 and 4 are negatively regulated by insulin and growth factors via the serine/threonine kinase Akt XREF_BIBR.	0	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	10	11	1	2
Insulin treatment was shown to decrease endogenous FKHR proteins in HepG2 cells , which was inhibited by proteasome inhibitors [ XREF_BIBR ] .	Insulin treatment was shown to decrease endogenous FKHR proteins in HepG2 cells, which was inhibited by proteasome inhibitors [XREF_BIBR].	0	8	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FKHR	FKHR	FKHR	0	1	7	8
Although it has been widely accepted that the cellular signaling of insulin represses Foxo1 function through Akt dependent phosphorylation , the molecular mechanism behind the modulation of Foxo1 function by nutrient responses , including feeding or fasting , remains unknown in vivo .	Although it has been widely accepted that the cellular signaling of insulin represses Foxo1 function through Akt dependent phosphorylation, the molecular mechanism behind the modulation of Foxo1 function by nutrient responses, including feeding or fasting, remains unknown in vivo.	9	14	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	11	12	13	14
72 Insulin negatively regulates FOXO1 activity via phosphorylation , 73 whereas Sirt2 plays a role in inhibiting adipocyte differentiation by deacetylating and activating FOXO1 .	72 Insulin negatively regulates FOXO1 activity via phosphorylation, 73 whereas Sirt2 plays a role in inhibiting adipocyte differentiation by deacetylating and activating FOXO1.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	1	2	4	5
Also , insulin induces FOXO1 protein degradation in HepG2 cells [ XREF_BIBR ] , and this degradation requires FOXO1 phosphorylation mediated by the PI3K and Akt pathway .	Also, insulin induces FOXO1 protein degradation in HepG2 cells [XREF_BIBR], and this degradation requires FOXO1 phosphorylation mediated by the PI3K and Akt pathway.	2	6	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	2	3	4	5
Impaired insulin signaling may contribute to increased FoxO1 nuclear retention .	Impaired insulin signaling may contribute to increased FoxO1 nuclear retention.	1	9	contribute	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	1	2	7	8
Whereas the mechanism ( s ) by which PDE3B mediates insulin action on POMC gene expression was not addressed in this study , insulin is known to increase POMC transcription by repressing FOXO1 , which reduces POMC promoter activity [ XREF_BIBR ] .	Whereas the mechanism (s) by which PDE3B mediates insulin action on POMC gene expression was not addressed in this study, insulin is known to increase POMC transcription by repressing FOXO1, which reduces POMC promoter activity [XREF_BIBR].	23	35	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	23	24	32	33
Therefore , we postulated that the upregulation of SF-1 and its steroidogenic target genes by insulin might be as a result of phosphorylation and inactivation of FoxO1 by insulin .	Therefore, we postulated that the upregulation of SF-1 and its steroidogenic target genes by insulin might be as a result of phosphorylation and inactivation of FoxO1 by insulin.	20	29	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	28	29	26	27
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Nuclear FoxO1 levels are negatively regulated by insulin and IGF-1 .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Nuclear FoxO1 levels are negatively regulated by insulin and IGF-1.	0	16	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	14	15	8	9
Furthermore , endogenous FOXO1 can be pulled down efficiently by anti-MED23 antibody in AML12 hepatocytes cultured under fasting condition , while insulin addition eliminated the precipitated FOXO1 signal ( XREF_FIG ) .	Furthermore, endogenous FOXO1 can be pulled down efficiently by anti-MED23 antibody in AML12 hepatocytes cultured under fasting condition, while insulin addition eliminated the precipitated FOXO1 signal (XREF_FIG).	21	27	eliminated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	21	22	26	27
This study suggests that insulin dysregulates FOXO1 induced genes upon decidualization , although morphological transformation is not inhibited .	This study suggests that insulin dysregulates FOXO1 induced genes upon decidualization, although morphological transformation is not inhibited.	4	8	dysregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	4	5	6	7
In the Cry1 depletion condition , insulin fails to reduce the nuclear FOXO1 abundance and suppress gluconeogenic gene expression .	In the Cry1 depletion condition, insulin fails to reduce the nuclear FOXO1 abundance and suppress gluconeogenic gene expression.	6	15	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	6	7	12	13
Insulin suppresses FoxO1 activity through activation of the PI3K and AKT signaling pathway .	Insulin suppresses FoxO1 activity through activation of the PI3K and AKT signaling pathway.	0	3	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FoxO1	FoxO1	FoxO1	0	1	2	3
Insulin and other growth factors repress FoxO1 activity through activation of the phosphoinositide 3-kinase-Akt/SGK signaling pathway causing FoxO1 phosphorylation , for instance , on Ser319 .	Insulin and other growth factors repress FoxO1 activity through activation of the phosphoinositide 3-kinase-Akt/SGK signaling pathway causing FoxO1 phosphorylation, for instance, on Ser319.	0	7	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FoxO1	FoxO1	FoxO1	0	1	6	7
Since cross talk between the GnRH and growth factor signaling pathways might blunt insulin or IGF1 inhibition of FOXO1 , we also investigated the effects of GnRH treatment on insulin or IGF1 activation of PI3K/AKT/FOXO1 signaling .	Since cross talk between the GnRH and growth factor signaling pathways might blunt insulin or IGF1 inhibition of FOXO1, we also investigated the effects of GnRH treatment on insulin or IGF1 activation of PI3K/AKT/FOXO1 signaling.	13	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	13	14	18	19
Consistent with impaired insulin stimulated Akt activation , FoxO1 inactivation and gluconeogenic gene expression , it was found that insulin-suppression of gluconeogenesis ( from 2 mM pyruvate ) was similarly impaired in hepatocytes treated with palmitate ( XREF_FIG ) .	Consistent with impaired insulin stimulated Akt activation, FoxO1 inactivation and gluconeogenic gene expression, it was found that insulin-suppression of gluconeogenesis (from 2 mM pyruvate) was similarly impaired in hepatocytes treated with palmitate (XREF_FIG).	0	9	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	3	4	8	9
3.1 IGF-1 , Insulin and EGCG cause a decrease in Foxo1 nuclear content .	3.1 IGF-1, Insulin and EGCG cause a decrease in Foxo1 nuclear content.	1	12	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	Foxo1	Foxo1	Foxo1	3	4	10	11
Insulin is known to inhibit FOXO1 so the elevation seen may be due to reduced efficacy of insulin .	Insulin is known to inhibit FOXO1 so the elevation seen may be due to reduced efficacy of insulin.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	5	6
This raises an interesting question as to why insulin promotes FoxO1 , but not FoxO6 , translocation from the nucleus to the cytoplasm , an compartmental effect that is sufficient , but not necessary , for insulin inhibition of FoxO1 activity .	This raises an interesting question as to why insulin promotes FoxO1, but not FoxO6, translocation from the nucleus to the cytoplasm, an compartmental effect that is sufficient, but not necessary, for insulin inhibition of FoxO1 activity.	36	40	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	36	37	39	40
In the fed state hepatic and pancreatic FoxO1 is inhibited by insulin .	In the fed state hepatic and pancreatic FoxO1 is inhibited by insulin.	4	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	11	12	7	8
By contrast to LY294002 ( 20 muM ) , the reversal of insulin mediated repression of FOXO1 activity was markedly delayed after administration of MAPK MEK inhibitor PD98059 ( 50 muM ( XREF_FIG , p > 0.05 compared to control ) .	By contrast to LY294002 (20 muM), the reversal of insulin mediated repression of FOXO1 activity was markedly delayed after administration of MAPK MEK inhibitor PD98059 (50 muM (XREF_FIG, p> 0.05 compared to control).	10	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	12	13	16	17
In addition , insulin signaling targets osteoblasts and inactivates FoxO1 in a PI3K and AKT dependent manner XREF_BIBR , XREF_BIBR .	In addition, insulin signaling targets osteoblasts and inactivates FoxO1 in a PI3K and AKT dependent manner XREF_BIBR, XREF_BIBR.	3	10	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	3	4	9	10
43 Mammalian FoxO1 , 3 and 4 activity is inhibited by growth factors and the insulin signaling pathways and stimulated by nutrient depletion and a plethora of ROS induced post-translational modifications .	43 Mammalian FoxO1, 3 and 4 activity is inhibited by growth factors and the insulin signaling pathways and stimulated by nutrient depletion and a plethora of ROS induced post-translational modifications.	0	19	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	15	16	2	3
Insulin 100 nM was able to reverse FOXO1 nuclear accumulation induced by apigenin 1-50 microM nearly completely , when applied 30 ' following apigenin treatment ( XREF_FIG ) .	Insulin 100 nM was able to reverse FOXO1 nuclear accumulation induced by apigenin 1-50 microM nearly completely, when applied 30 ' following apigenin treatment (XREF_FIG).	0	9	reverse	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	7	8
Because FoxO1 is inactive in the cytoplasm , insulin and IGF -1 pathway essentially inhibits FoxO1 transcriptional activity XREF_BIBR , XREF_BIBR , XREF_BIBR .	Because FoxO1 is inactive in the cytoplasm, insulin and IGF -1 pathway essentially inhibits FoxO1 transcriptional activity XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	16	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	8	9	15	16
Forkhead box protein O1 ( FoxO1 ) is one of several signaling molecules downstream of insulin ; FoxO1 drives gluconeogenesis and is suppressed by insulin .	Forkhead box protein O1 (FoxO1) is one of several signaling molecules downstream of insulin; FoxO1 drives gluconeogenesis and is suppressed by insulin.	0	25	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	Forkhead box protein O1	Forkhead box protein O1	Forkhead box protein O1	24	25	0	4
Finally , inactivation of FoxO1 by insulin treatment confirmed that FoxO1 induced by oxidative stress played a pivotal role in up-regulating the expression of downstream apoptosis related genes in MGCs .	Finally, inactivation of FoxO1 by insulin treatment confirmed that FoxO1 induced by oxidative stress played a pivotal role in up-regulating the expression of downstream apoptosis related genes in MGCs.	2	7	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	6	7	4	5
Concomitant use of insulin and PD98059 initially inhibited FOXO1 activity , but this effect had vanished after 60 minutes of treatment ( XREF_FIG , p > 0.05 ) .	Concomitant use of insulin and PD98059 initially inhibited FOXO1 activity, but this effect had vanished after 60 minutes of treatment (XREF_FIG, p> 0.05).	1	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	3	4	8	9
In these cells , insulin signaling repressed the FOXO1 activation and accompanied upregulation of p21 cip1 expression , resulting in increased proliferation .	In these cells, insulin signaling repressed the FOXO1 activation and accompanied upregulation of p21 cip1 expression, resulting in increased proliferation.	4	9	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	4	5	8	9
Since the expression of ectopic FoxO1 was driven by a constitutively active promoter ( retroviral LTR promoter ) , it suggests that insulin reduces the stability of FoxO1 protein .	Since the expression of ectopic FoxO1 was driven by a constitutively active promoter (retroviral LTR promoter), it suggests that insulin reduces the stability of FoxO1 protein.	22	28	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	22	23	27	28
FOXO1 is active during fasting and is inhibited by insulin after feeding , which drives the nuclear exclusion of FOXO1 via Akt dependent phosphorylation XREF_BIBR , XREF_BIBR .	FOXO1 is active during fasting and is inhibited by insulin after feeding, which drives the nuclear exclusion of FOXO1 via Akt dependent phosphorylation XREF_BIBR, XREF_BIBR.	0	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	9	10	0	1
Therefore , a physiological dose of insulin inhibits FoxO1 activity through activation of the PI3K and Akt signalling pathway , as illustrated in Fig .	Therefore, a physiological dose of insulin inhibits FoxO1 activity through activation of the PI3K and Akt signalling pathway, as illustrated in Fig.	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	6	7	8	9
We show that insulin treatment decreases endogenous FKHR proteins in HepG2 cells , which is inhibited by proteasome inhibitors .	We show that insulin treatment decreases endogenous FKHR proteins in HepG2 cells, which is inhibited by proteasome inhibitors.	3	8	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FKHR	FKHR	FKHR	3	4	7	8
Thus , a reduction in insulin signaling leads to reduced Akt and increased FOXO1 activation to promote hyperglycemia .	Thus, a reduction in insulin signaling leads to reduced Akt and increased FOXO1 activation to promote hyperglycemia.	5	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	5	6	13	14
Since insulin-action on Akt , and in turn inactivation of FoxO1 , was impaired in hepatocytes treated with palmitate , insulin ' s ability to suppress transcription of G6pc and Pepck mRNA was investigated .	Since insulin-action on Akt, and in turn inactivation of FoxO1, was impaired in hepatocytes treated with palmitate, insulin 's ability to suppress transcription of G6pc and Pepck mRNA was investigated.	8	22	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	20	21	10	11
XREF_BIBR Transient rises of insulin and IGF-1 occurring during the normal course of puberty inhibit FoxO1 regulation and allow the activated androgen receptor to trigger a chain of metabolic events , which lead to an excess production of keratinocytes and sebum .	XREF_BIBR Transient rises of insulin and IGF-1 occurring during the normal course of puberty inhibit FoxO1 regulation and allow the activated androgen receptor to trigger a chain of metabolic events, which lead to an excess production of keratinocytes and sebum.	2	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	4	5	15	16
Reduced insulin action increases FoxO1 activity and induces microsomal triglyceride transfer protein favoring VLDL assembly and induces apoCIII reducing peripheral triglyceride catabolism .	Reduced insulin action increases FoxO1 activity and induces microsomal triglyceride transfer protein favoring VLDL assembly and induces apoCIII reducing peripheral triglyceride catabolism.	1	5	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	1	2	4	5
Glucagon enhances CREB activity in a fasting state , and insulin suppresses transcriptional activities of CREB and FoxO1 by activating phosphoinositide 3-kinase ( PI3-K ) after eating .	Glucagon enhances CREB activity in a fasting state, and insulin suppresses transcriptional activities of CREB and FoxO1 by activating phosphoinositide 3-kinase (PI3-K) after eating.	10	18	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	10	11	17	18
In addition , insulin signaling via Akt-PI3K also promotes proteasome dependent degradation of FoxO1 XREF_BIBR XREF_BIBR .	In addition, insulin signaling via Akt-PI3K also promotes proteasome dependent degradation of FoxO1 XREF_BIBR XREF_BIBR.	3	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	3	4	13	14
Interestingly , insulin also decreased the total FoxO1 protein content ( XREF_FIG ) , which is likely due to protein degradation XREF_BIBR XREF_BIBR .	Interestingly, insulin also decreased the total FoxO1 protein content (XREF_FIG), which is likely due to protein degradation XREF_BIBR XREF_BIBR.	2	9	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	2	3	7	8
Taken together , these data highly suggests that FoxO1 negatively regulates the expression of SF-1 and steroidogenic genes and that suppression of FoxO1 by insulin treatment might stimulate steroidogenesis , at least in part , through activation of SF-1 .	Taken together, these data highly suggests that FoxO1 negatively regulates the expression of SF-1 and steroidogenic genes and that suppression of FoxO1 by insulin treatment might stimulate steroidogenesis, at least in part, through activation of SF-1.	20	25	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	24	25	22	23
As previous work had indicated that PP2A inhibition could rescue hepatic Akt activity in insulin resistant states [ XREF_BIBR ] we hypothesized that PP2A inhibition in the liver would lead to increased insulin stimulated inhibition of FoxO1 , thus potentially having therapeutic applications in T2D .	As previous work had indicated that PP2A inhibition could rescue hepatic Akt activity in insulin resistant states [XREF_BIBR] we hypothesized that PP2A inhibition in the liver would lead to increased insulin stimulated inhibition of FoxO1, thus potentially having therapeutic applications in T2D.	29	37	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	32	33	36	37
In diabetes , the impaired insulin response led to dysfunctional Foxo1 , which drives bile salt synthesis towards 12alpha hydroxylated bile salts , leading to an abnormally hydrophilic bile salt pool affecting cholesterol and triglyceride metabolism .	In diabetes, the impaired insulin response led to dysfunctional Foxo1, which drives bile salt synthesis towards 12alpha hydroxylated bile salts, leading to an abnormally hydrophilic bile salt pool affecting cholesterol and triglyceride metabolism.	5	13	led	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	5	6	10	11
The most parsimonious conclusion that can be drawn from this compendium of experiments is that insulin can inactivate hepatocyte FOXO1 to acutely repress G6pc expression , without secondary input from other hormones or extra-hepatic tissues .	The most parsimonious conclusion that can be drawn from this compendium of experiments is that insulin can inactivate hepatocyte FOXO1 to acutely repress G6pc expression, without secondary input from other hormones or extra-hepatic tissues.	15	22	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	15	16	19	20
Interestingly , in a feedback mechanism of regulation , insulin signaling suppresses FoxO1 activity in osteoblasts , stimulating the activity of osteocalcin [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Interestingly, in a feedback mechanism of regulation, insulin signaling suppresses FoxO1 activity in osteoblasts, stimulating the activity of osteocalcin [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	9	10	12	13
In liver , insulin , through activation of IR and AKT , suppress hepatic glyconeogenesis by negatively regulating Foxo1 , PCG-1a , and CRTC2 .	In liver, insulin, through activation of IR and AKT, suppress hepatic glyconeogenesis by negatively regulating Foxo1, PCG-1a, and CRTC2.	3	23	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	3	4	18	19
Elevated insulin levels inactivate Foxo1 via PI3K-Akt signaling , furthermore Foxo1 was able to control the upstream signaling elements to govern insulin sensitivity and glucose metabolism .	Elevated insulin levels inactivate Foxo1 via PI3K-Akt signaling, furthermore Foxo1 was able to control the upstream signaling elements to govern insulin sensitivity and glucose metabolism.	1	7	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin levels	insulin	Foxo1	Foxo1	foxo1	1	2	4	5
Blockade of PI3-K-mediated insulin signaling instantly restored FOXO1 transcriptional activity to control level ( XREF_FIG , p > 0.05 ) .	Blockade of PI3-K-mediated insulin signaling instantly restored FOXO1 transcriptional activity to control level (XREF_FIG, p> 0.05).	3	9	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	3	4	7	8
Interestingly , insulin inactivates FOXO1 via Akt leading to its nuclear export and degradation .	Interestingly, insulin inactivates FOXO1 via Akt leading to its nuclear export and degradation.	2	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	2	3	4	5
FOXO1 is particularly important in inhibition of hepatic gluconeogenesis by insulin ; insulin inhibits FOXO1 activity through the PI3K and AKT signaling pathway .	FOXO1 is particularly important in inhibition of hepatic gluconeogenesis by insulin; insulin inhibits FOXO1 activity through the PI3K and AKT signaling pathway.	12	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	12	13	14	15
Insulin signalling inactivates FOXO1 , which is mediated by insulin receptor substrates-1 and -2 through AKT .	Insulin signalling inactivates FOXO1, which is mediated by insulin receptor substrates-1 and -2 through AKT.	0	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	3	4
It is established that under insulin resistance , insulin fails to block FOXO1 that can induce gluconeogenesis via PEPCK and G6P , but an outstanding question remaining to be addressed is how insulin resistance promotes dyslipidemia in the liver .	It is established that under insulin resistance, insulin fails to block FOXO1 that can induce gluconeogenesis via PEPCK and G6P, but an outstanding question remaining to be addressed is how insulin resistance promotes dyslipidemia in the liver.	8	15	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	8	9	12	13
Very limited data is available on transcriptional down-regulation of FOXO1 by insulin , however it was previously demonstrated that both transcriptional and post-translational regulation share the PI3K pathway [ XREF_BIBR , XREF_BIBR ] .	Very limited data is available on transcriptional down-regulation of FOXO1 by insulin, however it was previously demonstrated that both transcriptional and post-translational regulation share the PI3K pathway [XREF_BIBR, XREF_BIBR].	4	12	down-regulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	11	12	9	10
Physiologically , insulin inhibits adipose tissue FOXO1 that in turn represses its downstream target PPARgamma , a transcriptional inducer of the adiponectin gene .	Physiologically, insulin inhibits adipose tissue FOXO1 that in turn represses its downstream target PPARgamma, a transcriptional inducer of the adiponectin gene.	2	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	2	3	6	7
When FOXO1 is inhibited by insulin signaling , expression of IL-1beta is reduced .	When FOXO1 is inhibited by insulin signaling, expression of IL-1beta is reduced.	1	6	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	5	6	1	2
The transcription factor FOXO1 has a central role in the regulation of glucose levels by insulin : reduced insulin signaling causes FOXO1 activation , which increases hepatic glucose production by activating transcription of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNAs .	The transcription factor FOXO1 has a central role in the regulation of glucose levels by insulin : reduced insulin signaling causes FOXO1 activation, which increases hepatic glucose production by activating transcription of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNAs.	18	35	causes	Positive_regulation_syntax_1_verb	Negative_activation	Negative_regulation	insulin	insulin	insulin	FOXO1	FOXO1 activation, which increases hepatic glucose production by activating transcription of phosphoenolpyruvate carboxykinase	foxo1	18	19	21	22
Insulin can inhibit the transcriptional activity of forkhead box protein O1 , which regulates the transcription of PEPCK .	Insulin can inhibit the transcriptional activity of forkhead box protein O1, which regulates the transcription of PEPCK.	0	16	inhibit	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Insulin	Insulin	insulin	forkhead box protein O1	forkhead box protein O1, which regulates the transcription	forkhead box protein o1	0	1	7	11
Insulin dramatically reduced the FoxO1 nuclear level and the stability of FoxO1 protein [ XREF_BIBR , XREF_BIBR ] , suggesting that insulin triggered FoxO1 nuclear exclusion and protein degradation to reverse inhibited myogenesis by FoxO1 .	Insulin dramatically reduced the FoxO1 nuclear level and the stability of FoxO1 protein [XREF_BIBR, XREF_BIBR], suggesting that insulin triggered FoxO1 nuclear exclusion and protein degradation to reverse inhibited myogenesis by FoxO1.	21	25	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	21	22	23	24
These data fully indicated that FoxO1 transcriptional activity is suppressed by insulin and IGF signaling .	These data fully indicated that FoxO1 transcriptional activity is suppressed by insulin and IGF signaling.	5	14	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	11	12	5	6
Although it is not clear whether the inhibition of FOXO1 by insulin or LiCl directly leads to the increase of COX-1 and COX IV proteins the fusion indices and myosin sarcomere expression levels were markedly elevated every time insulin or LiCl or both were administered ( XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY Figs ) .	Although it is not clear whether the inhibition of FOXO1 by insulin or LiCl directly leads to the increase of COX-1 and COX IV proteins the fusion indices and myosin sarcomere expression levels were markedly elevated every time insulin or LiCl or both were administered (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY Figs).	7	13	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	11	12	9	10
Mammalian FoxO1 , 3 , and 4 are negatively regulated by insulin and growth factors via the serine/threonine kinase Akt [ XREF_BIBR ] .	Mammalian FoxO1, 3, and 4 are negatively regulated by insulin and growth factors via the serine/threonine kinase Akt [XREF_BIBR].	0	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	11	12	1	2
Insulin caused a significant dose dependent inhibition of the verified FOXO1 target genes .	Insulin caused a significant dose dependent inhibition of the verified FOXO1 target genes.	0	12	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	10	11
The decrease in insulin and Igf signaling induces Foxo1 and Gsk-3beta function .	The decrease in insulin and Igf signaling induces Foxo1 and Gsk-3beta function.	3	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	3	4	8	9
As shown in XREF_FIG , expression of G6pc and Pck1 was suppressed by insulin to the same extent in the TLKO livers as in the control livers , indicating that insulin was able to suppress the transcription of these two genes independent of Akt and Foxo1 in liver .	As shown in XREF_FIG, expression of G6pc and Pck1 was suppressed by insulin to the same extent in the TLKO livers as in the control livers, indicating that insulin was able to suppress the transcription of these two genes independent of Akt and Foxo1 in liver.	30	46	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	30	31	45	46
Finally , COP1 , an insulin regulated ubiquitin ligase that is involved in mammalian cell survival , growth and metabolism , degrades FoxO1 resulting in a reduction of FoxO1-target genes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase , both of which play an important role in gluconeogenesis [ XREF_BIBR ] ( see XREF_FIG ) .	Finally, COP1, an insulin regulated ubiquitin ligase that is involved in mammalian cell survival, growth and metabolism, degrades FoxO1 resulting in a reduction of FoxO1-target genes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, both of which play an important role in gluconeogenesis [XREF_BIBR] (see XREF_FIG).	2	23	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	5	6	22	23
Since FOXO1 is inhibited by insulin , a reduction in insulin signaling will tend to enhance FOXO1 activation and to promote inflammation .	Since FOXO1 is inhibited by insulin, a reduction in insulin signaling will tend to enhance FOXO1 activation and to promote inflammation.	1	6	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	5	6	1	2
Furthermore , PI3Ks mediated the insulin induced changes of lipid metabolism by targeting FOXO1 and inhibition FOXO1 with AS not only reduced lipogenesis but also lipolysis and lipid transport in hepatocytes from yellow catfish .	Furthermore, PI3Ks mediated the insulin induced changes of lipid metabolism by targeting FOXO1 and inhibition FOXO1 with AS not only reduced lipogenesis but also lipolysis and lipid transport in hepatocytes from yellow catfish.	4	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	5	6	16	17
The increased hepatic insulin resistance was counterbalanced by PI3K-AKT-independent GSK3 inhibition and AR mediated inhibition of FOXO1 , reducing hepatic PEPCK level and hepatic gluconeogenesis .	The increased hepatic insulin resistance was counterbalanced by PI3K-AKT-independent GSK3 inhibition and AR mediated inhibition of FOXO1, reducing hepatic PEPCK level and hepatic gluconeogenesis.	3	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	3	4	16	17
Thus , in hepatocytes as in other cell lines , all three FKHR PKB sites participate in insulin mediated inhibition of FKHR action and in insulin mediated accumulation of FKHR in cytoplasm .	Thus, in hepatocytes as in other cell lines, all three FKHR PKB sites participate in insulin mediated inhibition of FKHR action and in insulin mediated accumulation of FKHR in cytoplasm.	15	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FKHR	FKHR	FKHR	17	18	21	22
These findings suggest that FOXO1 can protect against excessive hepatic lipid production during hyperglycemia and may indicate that insulin treatment , which inhibits FOXO1 , may indirectly worsen lipid abnormalities in diabetics [ XREF_BIBR ] .	These findings suggest that FOXO1 can protect against excessive hepatic lipid production during hyperglycemia and may indicate that insulin treatment, which inhibits FOXO1, may indirectly worsen lipid abnormalities in diabetics [XREF_BIBR].	18	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	18	19	23	24
In this study , we observed that HCV infection of human hepatocytes impaired insulin induced FoxO1 translocation from the nucleus to the cytoplasm and significantly reduced accumulation of FoxA2 in the nucleus .	In this study, we observed that HCV infection of human hepatocytes impaired insulin induced FoxO1 translocation from the nucleus to the cytoplasm and significantly reduced accumulation of FoxA2 in the nucleus.	11	16	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	13	14	15	16
In contrast , insulin signaling in osteoblasts increases osteocalcin secretion and promotes glucose homeostasis , at least in part , by attenuating FoxO activity and preventing the inhibitory actions of FoxO1 on Runx2 and osteocalcin expression [ XREF_BIBR , XREF_BIBR ] .	In contrast, insulin signaling in osteoblasts increases osteocalcin secretion and promotes glucose homeostasis, at least in part, by attenuating FoxO activity and preventing the inhibitory actions of FoxO1 on Runx2 and osteocalcin expression [XREF_BIBR, XREF_BIBR].	3	31	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	3	4	30	31
All three effectors , namely , Malphaalpha , metformin , and insulin , suppressed the nuclear and cytosolic ratio of FoxO1 ( XREF_FIG ) , implying its nuclear exclusion .	All three effectors, namely, Malphaalpha, metformin, and insulin, suppressed the nuclear and cytosolic ratio of FoxO1 (XREF_FIG), implying its nuclear exclusion.	0	22	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	11	12	20	21
Insulin inhibits FOXO1 induced target genes in decidualizing human endometrial stromal cells .	Insulin inhibits FOXO1 induced target genes in decidualizing human endometrial stromal cells.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	2	3
Insulin suppresses activity of osteoblastic FoxO1 thus promoting beneficial effects of osteoblasts on glucose metabolism .	Insulin suppresses activity of osteoblastic FoxO1 thus promoting beneficial effects of osteoblasts on glucose metabolism.	0	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FoxO1	FoxO1	FoxO1	0	1	5	6
Unexpectedly , we found that SRA overexpression increased FoxO1 nuclear retention by 60 % in the absence of insulin , but insulin eliminated this effect and decreased nuclear FoxO1 to low levels .	Unexpectedly, we found that SRA overexpression increased FoxO1 nuclear retention by 60% in the absence of insulin, but insulin eliminated this effect and decreased nuclear FoxO1 to low levels.	21	29	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	21	22	28	29
The phosphorylation of insulin and IGF-I receptor , Akt , glycogen synthase kinase-3beta , and FoxO1 was decreased in Uchl3 (-/-) MEFs treated with insulin .	The phosphorylation of insulin and IGF-I receptor, Akt, glycogen synthase kinase-3beta, and FoxO1 was decreased in Uchl3 (-/-) MEFs treated with insulin.	1	25	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	24	25	15	16
Thus postprandial inactivation of Foxo1 by insulin is essential for the usual systemic effect of growth hormone and hormonal Igf1 upon body growth ( XREF_FIG ) .	Thus postprandial inactivation of Foxo1 by insulin is essential for the usual systemic effect of growth hormone and hormonal Igf1 upon body growth (XREF_FIG).	2	7	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	6	7	4	5
Insulin inhibits the ability of FOXO1 to express genes encoding gluconeogenic enzymes .	Insulin inhibits the ability of FOXO1 to express genes encoding gluconeogenic enzymes.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO1	FOXO1	FOXO1	0	1	5	6
In hepatocytes , however , the middle PKB site ( PKB2 ) of FKHR was required for insulin to phosphorylate FKHR and was the only PKB site that participated in insulin inhibition of FKHR action , indicating that insulin utilizes a unique pathway to regulate FKHR action in hepatocytes .	In hepatocytes, however, the middle PKB site (PKB2) of FKHR was required for insulin to phosphorylate FKHR and was the only PKB site that participated in insulin inhibition of FKHR action, indicating that insulin utilizes a unique pathway to regulate FKHR action in hepatocytes.	30	34	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FKHR	FKHR	FKHR	30	31	33	34
It follows that in insulin resistant states , loss of insulin inhibition of FoxO1 activity consequently results in unrestrained IL-1beta expression in activated macrophages ( XREF_FIG ) .	It follows that in insulin resistant states, loss of insulin inhibition of FoxO1 activity consequently results in unrestrained IL-1beta expression in activated macrophages (XREF_FIG).	10	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	10	11	13	14
However , if insulin dependent inhibition of Foxo1 serves primarily a permissive function , then deletion of Foxo1 alone or deletion of both Akt and Foxo1 would restore normal postprandial regulation .	However, if insulin dependent inhibition of Foxo1 serves primarily a permissive function, then deletion of Foxo1 alone or deletion of both Akt and Foxo1 would restore normal postprandial regulation.	3	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	3	4	7	8
A forkhead transcription factor O1 ( FOXO1 ) plays a critical role in metabolism , and insulin inactivates FOXO1 through Akt dependent phosphorylation and nuclear exclusion .	A forkhead transcription factor O1 (FOXO1) plays a critical role in metabolism, and insulin inactivates FOXO1 through Akt dependent phosphorylation and nuclear exclusion.	16	19	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	16	17	18	19
FoxO1 drives gluconeogenic gene expression and is inhibited by insulin XREF_BIBR XREF_BIBR .	FoxO1 drives gluconeogenic gene expression and is inhibited by insulin XREF_BIBR XREF_BIBR.	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	9	10	0	1
Inhibition of insulin induced FOXO1 ( regulator of gluconeogenic genes ) degradation persisted even after 48h of palmitate removal from the culture media .	Inhibition of insulin induced FOXO1 (regulator of gluconeogenic genes) degradation persisted even after 48h of palmitate removal from the culture media.	0	12	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	2	3	4	5
Oxidative stress and inflammation through activtion of IKK-beta could determine insulin resistance impairing IRS-1 ability to activate the metabolic branch of insulin signalling .	Oxidative stress and inflammation through activtion of IKK-beta could determine insulin resistance impairing IRS-1 ability to activate the metabolic branch of insulin signalling.	10	14	impairing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	10	11	13	14
Insulin stimulated IRS-1 association with SHP2 was reduced to 79 +/- 5 % ( P < 0.05 ) in liver of the fructose fed rats .	Insulin stimulated IRS-1 association with SHP2 was reduced to 79 +/- 5% (P < 0.05) in liver of the fructose fed rats.	0	3	stimulated	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	2	3
In summary , our results indicate that the insulin stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser ( 312 ) phosphorylation of IRS-1 .	In summary, our results indicate that the insulin stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser (312) phosphorylation of IRS-1.	7	21	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	12	13
Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers .	Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers.	1	9	resistance	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	7	8
H 2 O 2 stimulation increased serine307 phosphorylation and decreased tyrosine phosphorylation of IRS-1 in mouse skeletal muscle cells treated with insulin , similar to the pattern seen in aged mice .	H 2 O 2 stimulation increased serine307 phosphorylation and decreased tyrosine phosphorylation of IRS-1 in mouse skeletal muscle cells treated with insulin, similar to the pattern seen in aged mice.	11	23	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	21	22	13	14
In HepG2 cells , pre-treatment with PANDER ranging from 4 pM to 4 nM for 8h resulted in a maximal inhibition of insulin stimulated activation of insulin receptor and insulin receptor substrate 1 by 52 % and 63 % , respectively .	In HepG2 cells, pre-treatment with PANDER ranging from 4 pM to 4 nM for 8h resulted in a maximal inhibition of insulin stimulated activation of insulin receptor and insulin receptor substrate 1 by 52% and 63%, respectively.	20	33	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	22	23	29	33
LY294002 completely blocked insulin induced degradation of IRS1 ( XREF_FIG , panel 3 , lane g versus lanes e and a ) , suggesting that PI3K mediates the insulin induced degradation of IRS1 .	LY294002 completely blocked insulin induced degradation of IRS1 (XREF_FIG, panel 3, lane g versus lanes e and a), suggesting that PI3K mediates the insulin induced degradation of IRS1.	2	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	3	4	7	8
Second , knockout cells lacking one of the key effectors of this cascade , the phosphoinositide dependent kinase-1 , were found to be deficient in the insulin stimulated degradation of IRS-1 .	Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide dependent kinase-1, were found to be deficient in the insulin stimulated degradation of IRS-1.	23	31	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	26	27	30	31
Overexpression of beta-arrestin-1 attenuated insulin induced IRS-1 degradation , leading to enhanced insulin signaling downstream of IRS-1 .	Overexpression of beta-arrestin-1 attenuated insulin induced IRS-1 degradation, leading to enhanced insulin signaling downstream of IRS-1.	4	7	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	6	7
Inflammatory mediators enhanced by high dietary salt include the tumor necrosis factor-alpha ( TNF-alpha ) or JNK might possibly interfere with normal insulin signaling via a number of mechanisms including : i ) disruption of insulin induced insulin receptor substrate-1 ( IRS-1 ) and phosphoinositide-3 kinase ( PI3K ) phosphorylation and cellular distribution , ii ) reduction in glucose transporter ( GLUT4 ) expression levels , or iii ) reduction in GLUT4 translocation to the plasma membrane [ XREF_BIBR - XREF_BIBR ] .	Inflammatory mediators enhanced by high dietary salt include the tumor necrosis factor-alpha (TNF-alpha) or JNK might possibly interfere with normal insulin signaling via a number of mechanisms including : i) disruption of insulin induced insulin receptor substrate-1 (IRS-1) and phosphoinositide-3 kinase (PI3K) phosphorylation and cellular distribution, ii) reduction in glucose transporter (GLUT4) expression levels, or iii) reduction in GLUT4 translocation to the plasma membrane [XREF_BIBR - XREF_BIBR].	33	40	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	35	36	37	40
Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signaling pathways and cellular glucose uptake , as well as a reduced capacity of these cells to execute insulin induced degradation of IRS-1 .	Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signaling pathways and cellular glucose uptake, as well as a reduced capacity of these cells to execute insulin induced degradation of IRS-1.	32	38	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	33	34	37	38
Approximately 50 % of IRbeta and 65 % of IRS-1 expression levels were suppressed when adipocytes were simultaneously treated with both 1 nM insulin and 100 nM ET-1 for 3 h.	Approximately 50% of IRbeta and 65% of IRS-1 expression levels were suppressed when adipocytes were simultaneously treated with both 1 nM insulin and 100 nM ET-1 for 3 h.	9	27	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	23	24	9	10
To test if CRL7 participates in insulin mediated IRS1 degradation , CUL7 siRNA and control transfected C2C12 myotubes were treated with the ribosomal inhibitor emetine and chased with insulin for 4 , 8 and 16 hrs .	To test if CRL7 participates in insulin mediated IRS1 degradation, CUL7 siRNA and control transfected C2C12 myotubes were treated with the ribosomal inhibitor emetine and chased with insulin for 4, 8 and 16 hrs.	4	9	mediated	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	6	7	8	9
Surprisingly , at 37 degrees C , insulin action on 3T3-L1 adipocytes progressively decreased the amount of IRS-1 protein associated with the low density microsome fraction and increased that in the cytosol .	Surprisingly, at 37 degrees C, insulin action on 3T3-L1 adipocytes progressively decreased the amount of IRS-1 protein associated with the low density microsome fraction and increased that in the cytosol.	7	18	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	17	18
Moreover , insulin induced IRS-1 degradation was enhanced by expression of p110CAAX ( 61 +/-16% vs. 13 +/-15% at 20 min , and 80 +/-8% vs. 41 +/-12% at 60 min , after insulin stimulation with or without p110CAAX expression , respectively ) .	Moreover, insulin induced IRS-1 degradation was enhanced by expression of p110CAAX (61 +/-16% vs. 13 +/-15% at 20 min, and 80 +/-8% vs. 41 +/-12% at 60 min, after insulin stimulation with or without p110CAAX expression, respectively).	2	5	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	2	3	4	5
Despite reduced insulin stimulated IRS1 activation , insulin stimulated Akt ( S473 ) and Akt ( T308 ) phosphorylation was not impaired in alphaHZ-HFD , but was impaired in WT-HFD versus CON mice ( XREF_FIG ) .	Despite reduced insulin stimulated IRS1 activation, insulin stimulated Akt (S473) and Akt (T308) phosphorylation was not impaired in alphaHZ-HFD, but was impaired in WT-HFD versus CON mice (XREF_FIG).	0	8	stimulated	Positive_activation_token_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	2	3	4	5
The above results suggested that p38 activation was required for chronic insulin induced IRS1 and IRS2 degradation and insulin resistance .	The above results suggested that p38 activation was required for chronic insulin induced IRS1 and IRS2 degradation and insulin resistance.	10	16	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	11	12	13	14
In this study , we show that insulin , IGF-1 , or osmotic stress promoted ubiquitin and proteasome mediated degradation of IRS-2 in 3T3-L1 cells , Fao hepatoma , cells and mouse embryo fibroblasts ; however , insulin and IGF -1 did not promote degradation of IRS-1 in 3T3-L1 preadipocytes or mouse embryo fibroblasts .	In this study, we show that insulin, IGF-1, or osmotic stress promoted ubiquitin and proteasome mediated degradation of IRS-2 in 3T3-L1 cells, Fao hepatoma, cells and mouse embryo fibroblasts; however, insulin and IGF -1 did not promote degradation of IRS-1 in 3T3-L1 preadipocytes or mouse embryo fibroblasts.	37	47	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	37	38	46	47
HG and insulin induce degradation of IRS1 through distinct signaling pathways .	HG and insulin induce degradation of IRS1 through distinct signaling pathways.	0	7	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	2	3	6	7
Our results demonstrate that resistin is able to induce a selective vascular insulin resistance impairing endothelial IRS-1 signaling pathway that leads to eNOS activation and vasodilation .	Our results demonstrate that resistin is able to induce a selective vascular insulin resistance impairing endothelial IRS-1 signaling pathway that leads to eNOS activation and vasodilation.	12	18	impairing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	12	13	16	17
Chronic insulin stimulation degrades IRS1 and IRS2 protein and causes insulin resistance in vitro .	Chronic insulin stimulation degrades IRS1 and IRS2 protein and causes insulin resistance in vitro.	1	7	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	1	2	4	5
Ang II inhibition of insulin stimulated IRS-1 tyrosyl phophorylation and Akt activation were reversed by PD98059 but not by SP600125 .	Ang II inhibition of insulin stimulated IRS-1 tyrosyl phophorylation and Akt activation were reversed by PD98059 but not by SP600125.	2	8	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	6	7
In type 2 diabetes patients , it has been shown that insulin induced IRS-1 tyrosine phosphorylation , PI3K and Akt activities are decreased in skeletal muscles .	In type 2 diabetes patients, it has been shown that insulin induced IRS-1 tyrosine phosphorylation, PI3K and Akt activities are decreased in skeletal muscles.	11	20	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	11	12	13	14
Insulin induced degradation of insulin receptor substrate 1 ( IRS1 ) represents a key negative feedback loop that restricts insulin signaling .	Insulin induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling.	0	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	0	1	4	8
For example , insulin induced IRS-1 degradation requires the PI3 kinase pathway .	For example, insulin induced IRS-1 degradation requires the PI3 kinase pathway.	3	6	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	3	4	5	6
Notably , we observed in these studies an insulin dependent loss of IRS-1 from the HSP fraction that was presumably due to the redistribution of this protein to the cytosol ( Figs .	Notably, we observed in these studies an insulin dependent loss of IRS-1 from the HSP fraction that was presumably due to the redistribution of this protein to the cytosol (Figs.	8	16	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	12	13
Moreover , knockdown of endogenous R-Ras levels in MCF-7 cells inhibits IRS-1 degradation induced by estrogen signaling blockade but not by long-term insulin treatment .	Moreover, knockdown of endogenous R-Ras levels in MCF-7 cells inhibits IRS-1 degradation induced by estrogen signaling blockade but not by long-term insulin treatment.	11	23	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	22	23	11	12
In summary , the in vitro experiments in MEFs and C2C12 cells provide evidence that loss of CUL7 leads to increased activation of insulin signalling pathways and cellular glucose uptake , as well as diminished capacity of these cells to execute insulin induced degradation of IRS1 .	In summary, the in vitro experiments in MEFs and C2C12 cells provide evidence that loss of CUL7 leads to increased activation of insulin signalling pathways and cellular glucose uptake, as well as diminished capacity of these cells to execute insulin induced degradation of IRS1.	23	46	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	23	24	45	46
In contrast to the insulin induced degradation of IRS1 , HG induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity .	In contrast to the insulin induced degradation of IRS1, HG induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity.	1	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	4	5	8	9
We further determined whether the 26S proteasome activated ubiquitination pathway mediates p38- or chronic insulin induced IRS1 or IRS2 degradation .	We further determined whether the 26S proteasome activated ubiquitination pathway mediates p38- or chronic insulin induced IRS1 or IRS2 degradation.	11	19	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	14	15	16	17
There is a possibility for the effect of insulin on HG induced degradation of IRS1 being minimized by the insulin induced degradation of IRS1 during overnight exposure of CHO/IR cells to high-dose insulin ( 10 nM ) .	There is a possibility for the effect of insulin on HG induced degradation of IRS1 being minimized by the insulin induced degradation of IRS1 during overnight exposure of CHO/IR cells to high-dose insulin (10 nM).	16	24	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	19	20	23	24
Depletion of CUL7 impairs insulin induced IRS1 degradation in C2C12 myotubes .	Depletion of CUL7 impairs insulin induced IRS1 degradation in C2C12 myotubes.	3	7	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	4	5	6	7
IRS-1 phosphorylation showed no significant change in muscle , but insulin stimulated IRS-1 associated PI 3-kinase was decreased by 41 % .	IRS-1 phosphorylation showed no significant change in muscle, but insulin stimulated IRS-1 associated PI 3-kinase was decreased by 41%.	10	17	stimulated	Positive_activation_token_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	10	11	12	13
Five-nanomolar insulin in normal glucose induced degradation of IRS1 at a slow rate .	Five-nanomolar insulin in normal glucose induced degradation of IRS1 at a slow rate.	0	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	1	2	8	9
We report that chronic insulin treatment induces the degradation of IRS-1 , but not IRS-2 , protein in cultured cells .	We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells.	4	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	10	11
Most important , an IRS-1 mutant in which Ser ( 312 ) was changed to alanine was found to be resistant to insulin stimulated IRS-1 degradation .	Most important, an IRS-1 mutant in which Ser (312) was changed to alanine was found to be resistant to insulin stimulated IRS-1 degradation.	20	25	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	22	23	24	25
Impaired insulin induced IRS-1 serine 632/635 phosphorylation also accompanies decreased PI3K and ROCK activation in skeletal muscle of obese , insulin resistant or diabetic mice and rats ( unpublished data ) , suggesting that impaired IRS-1 serine 632/635 phosphorylation may be an important mechanism contributing to the pathogenesis of insulin resistance in obesity .	Impaired insulin induced IRS-1 serine 632/635 phosphorylation also accompanies decreased PI3K and ROCK activation in skeletal muscle of obese, insulin resistant or diabetic mice and rats (unpublished data), suggesting that impaired IRS-1 serine 632/635 phosphorylation may be an important mechanism contributing to the pathogenesis of insulin resistance in obesity.	0	4	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	3	4
Here , we show that insulin stimulated degradation of IRS-1 requires the presence of a highly conserved Ser/Thr rich domain that we named domain involved in degradation of IRS-1 ( DIDI ) .	Here, we show that insulin stimulated degradation of IRS-1 requires the presence of a highly conserved Ser/Thr rich domain that we named domain involved in degradation of IRS-1 (DIDI).	5	10	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	5	6	9	10
When 3T3-L1 adipocytes were treated directly with MG , the impaired insulin signaling was also observed , indicated by decreased insulin induced insulin-receptor substrate-1 ( IRS-1 ) tyrosine phosphorylation and the decreased kinase activity of phosphatidylinositol ( PI ) 3-kinase ( PI3K ) .	When 3T3-L1 adipocytes were treated directly with MG, the impaired insulin signaling was also observed, indicated by decreased insulin induced insulin-receptor substrate-1 (IRS-1) tyrosine phosphorylation and the decreased kinase activity of phosphatidylinositol (PI) 3-kinase (PI3K).	17	24	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	insulin-receptor substrate-1	insulin-receptor substrate-1	insulin-receptor substrate-1	20	21	22	24
Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signalling pathways and cellular glucose uptake , as well as a reduced capacity of these cells to execute insulin induced degradation of insulin receptor substrate 1 ( IRS1 ) .	Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signalling pathways and cellular glucose uptake, as well as a reduced capacity of these cells to execute insulin induced degradation of insulin receptor substrate 1 (IRS1).	32	41	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	33	34	37	41
Conversely , overexpression of this enzyme potentiated insulin stimulated IRS-1 degradation .	Conversely, overexpression of this enzyme potentiated insulin stimulated IRS-1 degradation.	6	10	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	9	10
By contrast , IRS-1 activation of Akt and ERK1/2 was not inhibited by chronic insulin and IGF -1 stimulation in IRS-2-deficient mouse embryo fibroblasts .	By contrast, IRS-1 activation of Akt and ERK1/2 was not inhibited by chronic insulin and IGF -1 stimulation in IRS-2-deficient mouse embryo fibroblasts.	3	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	14	15	3	4
This was likely due to enhanced insulin induced IRS1 degradation after CD36 knockdown .	This was likely due to enhanced insulin induced IRS1 degradation after CD36 knockdown.	3	9	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	6	7	8	9
As shown in XREF_FIG and XREF_SUPPLEMENTARY , insulin elicited IRS-1 , Akt and ERK1/2 activation was dramatically decreased by MG53 overexpression .	As shown in XREF_FIG and XREF_SUPPLEMENTARY, insulin elicited IRS-1, Akt and ERK1/2 activation was dramatically decreased by MG53 overexpression.	7	14	elicited	Positive_activation_token_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	9	10
Prior treatment with proteasome inhibitors can block the insulin induced degradation of IRS1 , but not its intracellular transit or the desensitisation of downstream signalling and glucose uptake [ XREF_BIBR ] .	Prior treatment with proteasome inhibitors can block the insulin induced degradation of IRS1, but not its intracellular transit or the desensitisation of downstream signalling and glucose uptake [XREF_BIBR].	6	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	8	9	12	13
In summary , we have found the following : ( i ) beta-arrestin-1 can alter insulin signaling by inhibiting insulin induced proteasomal degradation of IRS-1 ; ( ii ) beta-arrestin-1 decreases the rate of ubiquitination of IRS-1 by competitively binding to endogenous Mdm2 , an E3 ligase that can ubiquitinate IRS-1 ; ( iii ) dephosphorylation of S412 on beta-arrestin and the amino terminus of beta-arrestin-1 are required for this effect of beta-arrestin on IRS-1 degradation ; and ( iv ) inhibition of beta-arrestin-1 leads to enhanced IRS-1 degradation and accentuated cellular insulin resistance .	In summary, we have found the following : (i) beta-arrestin-1 can alter insulin signaling by inhibiting insulin induced proteasomal degradation of IRS-1; (ii) beta-arrestin-1 decreases the rate of ubiquitination of IRS-1 by competitively binding to endogenous Mdm2, an E3 ligase that can ubiquitinate IRS-1; (iii) dephosphorylation of S412 on beta-arrestin and the amino terminus of beta-arrestin-1 are required for this effect of beta-arrestin on IRS-1 degradation; and (iv) inhibition of beta-arrestin-1 leads to enhanced IRS-1 degradation and accentuated cellular insulin resistance.	19	25	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	19	20	24	25
C6 ceramide exposure significantly increased the mean levels of insulin , insulin receptor , IGF-1 receptor , and IRS-4 , and decreased the mean levels of IGF-2 receptor and IRS-1 mRNA as demonstrated by qRT-PCR analysis and one-way ANOVA tests ( XREF_FIG ) .	C6 ceramide exposure significantly increased the mean levels of insulin, insulin receptor, IGF-1 receptor, and IRS-4, and decreased the mean levels of IGF-2 receptor and IRS-1 mRNA as demonstrated by qRT-PCR analysis and one-way ANOVA tests (XREF_FIG).	0	30	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	C6 ceramide exposure significantly increased the mean levels of insulin	insulin	IRS-1	IRS-1	irs-1	9	10	29	30
This was associated with reduced insulin stimulated IRS-1 and p85 associated PI 3-kinase activities in the LDM ( 84 and 96 % inhibition , respectively ) .	This was associated with reduced insulin stimulated IRS-1 and p85 associated PI 3-kinase activities in the LDM (84 and 96% inhibition, respectively).	2	10	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	5	6	7	8
When C9 cells were exposed to 100 nM insulin or 100 nM Ang II , and IRS-1 protein integrity was evaluated with an anti-IRS-1 antibody , insulin treatment reduced IRS-1 protein by about 44 % as detected by Western blot analysis .	When C9 cells were exposed to 100 nM insulin or 100 nM Ang II, and IRS-1 protein integrity was evaluated with an anti-IRS-1 antibody, insulin treatment reduced IRS-1 protein by about 44% as detected by Western blot analysis.	26	30	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	26	27	29	30
PDK1 , mTOR , and MAPK inhibitors did not block insulin induced reduction of IRS-1 , suggesting that the PI3K serine kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation .	PDK1, mTOR, and MAPK inhibitors did not block insulin induced reduction of IRS-1, suggesting that the PI3K serine kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation.	10	15	reduction	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	10	11	14	15
Whereas insulin induced degradation of IRS-1 was increased in cells treated with beta-arrestin1 siRNA , stimulation of IR promotes the formation of a complex between IRS-1 and Mdm2 , an E3 ubiquitin ligase enzyme , and this complex could be inhibited by beta-arrestin1 , resulting in a decreased ubiquitin content of IRS-1 .	Whereas insulin induced degradation of IRS-1 was increased in cells treated with beta-arrestin1 siRNA, stimulation of IR promotes the formation of a complex between IRS-1 and Mdm2, an E3 ubiquitin ligase enzyme, and this complex could be inhibited by beta-arrestin1, resulting in a decreased ubiquitin content of IRS-1.	1	7	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	5	6
Since insulin induced degradation of IRS1 is a GSK3beta independent process ( LiCl can not block insulin induced IRS1 degradation , data not shown ) , long-term insulin exposure - even at lower concentrations that initially counter HG ' s effects on GSK3beta - would eventually trigger insulin induced proteasome degradation ( XREF_FIG , XREF_FIG - and 12-h versus 24-h insulin co-treatment with HG ) .	Since insulin induced degradation of IRS1 is a GSK3beta independent process (LiCl can not block insulin induced IRS1 degradation, data not shown), long-term insulin exposure - even at lower concentrations that initially counter HG 's effects on GSK3beta - would eventually trigger insulin induced proteasome degradation (XREF_FIG, XREF_FIG - and 12-h versus 24-h insulin co-treatment with HG).	15	19	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	16	17	18	19
PI 3-kinase inhibitors or rapamycin , but not the MEK inhibitor , blocked both the insulin induced electrophoretic mobility shift and degradation of IRS-1 .	PI 3-kinase inhibitors or rapamycin, but not the MEK inhibitor, blocked both the insulin induced electrophoretic mobility shift and degradation of IRS-1.	14	24	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	15	16	23	24
Furthermore , in the mouse myoblast C2C12 cell line differentiated to myotubes , Esr1 knockdown ( KD ) [ using lentiviral mediated Esr1 targeted short hairpin RNA ( shRNA ) ] ( XREF_FIG ) impaired insulin signal transduction , as evidenced by the observations that insulin stimulated insulin receptor substrate 1 ( IRS-1 ) tyrosine phosphorylation and IRS-1-p85 association were markedly reduced compared to control scramble shRNA ( Scr ) ( XREF_FIG ) , thus recapitulating insulin resistance similar to that observed in MERKO mice .	Furthermore, in the mouse myoblast C2C12 cell line differentiated to myotubes, Esr1 knockdown (KD) [using lentiviral mediated Esr1 targeted short hairpin RNA (shRNA)] (XREF_FIG) impaired insulin signal transduction, as evidenced by the observations that insulin stimulated insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and IRS-1-p85 association were markedly reduced compared to control scramble shRNA (Scr) (XREF_FIG), thus recapitulating insulin resistance similar to that observed in MERKO mice.	45	52	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	45	46	47	51
Functionally , PDGF mediated IRS-1 and IRS-2 dysregulation resulted in the attenuation of insulin induced IRS-1 and IRS-2-associated PI 3-kinase activity .	Functionally, PDGF mediated IRS-1 and IRS-2 dysregulation resulted in the attenuation of insulin induced IRS-1 and IRS-2-associated PI 3-kinase activity.	11	20	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	13	14	15	16
The insulin induced degradation of IRS-1 can be prevented by pretreatment with lactacystin , a specific inhibitor for proteasome degradation .	The insulin induced degradation of IRS-1 can be prevented by pretreatment with lactacystin, a specific inhibitor for proteasome degradation.	0	8	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	5	6
Yet , lactacystin and MG132 , two unrelated proteasome inhibitors , prevented IRS1 degradation induced by prolonged insulin but not by oxidative stress .	Yet, lactacystin and MG132, two unrelated proteasome inhibitors, prevented IRS1 degradation induced by prolonged insulin but not by oxidative stress.	12	18	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	17	18	12	13
An impaired IRS-1 activation by insulin in macrovascular endothelial cells because of a point mutation is associated with endothelial dysfunction .	An impaired IRS-1 activation by insulin in macrovascular endothelial cells because of a point mutation is associated with endothelial dysfunction.	2	14	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	5	6	2	3
Third , chronic insulin exposure promotes IRS1 and IRS2 degradation , resulting in myocardial insulin resistance , in which p38 activation is necessary and sufficient for the effect of chronic insulin action .	Third, chronic insulin exposure promotes IRS1 and IRS2 degradation, resulting in myocardial insulin resistance, in which p38 activation is necessary and sufficient for the effect of chronic insulin action.	3	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	3	4	6	7
The dynamic changes in HG induced degradation of IRS1 by insulin were consistent with changes in GSK3beta activity ( XREF_FIG , panel 2 ) , further supporting the involvement of GSK3beta in HG induced degradation of IRS1 .	The dynamic changes in HG induced degradation of IRS1 by insulin were consistent with changes in GSK3beta activity (XREF_FIG, panel 2), further supporting the involvement of GSK3beta in HG induced degradation of IRS1.	6	11	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	10	11	8	9
To determine whether the observed improvements in insulin resistance and phosphorylation status of IRS-1 and AKT are directly linked to TNF blockade or are secondary to reduction in disease activity and inflammation , we studied seven patients with RA , who received abatacept ( CTLA4.Ig ) due to high disease activity .	To determine whether the observed improvements in insulin resistance and phosphorylation status of IRS-1 and AKT are directly linked to TNF blockade or are secondary to reduction in disease activity and inflammation, we studied seven patients with RA, who received abatacept (CTLA4.Ig) due to high disease activity.	7	15	resistance	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	13	14
Several studies have showed that FFAs decrease NOS activity and reduce NO production in endothelial cells by impairing PLC medicated Ca 2+ signaling or inhibiting insulin induced insulin receptor substrate 1 ( IRS-1 ) and Akt pathway [ XREF_BIBR , XREF_BIBR ] .	Several studies have showed that FFAs decrease NOS activity and reduce NO production in endothelial cells by impairing PLC medicated Ca 2+ signaling or inhibiting insulin induced insulin receptor substrate 1 (IRS-1) and Akt pathway [XREF_BIBR, XREF_BIBR].	19	32	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	25	26	27	31
As expected , IR was required for insulin induced degradation under normal glucose conditions , which was evidenced by the observation that insulin induced IRS1 degradation only in CHO/IR cells , but not in CHO cells ( XREF_FIG , panels 1 and 3 , lane e versus lane a ) .	As expected, IR was required for insulin induced degradation under normal glucose conditions, which was evidenced by the observation that insulin induced IRS1 degradation only in CHO/IR cells, but not in CHO cells (XREF_FIG, panels 1 and 3, lane e versus lane a).	22	25	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	22	23	24	25
The mechanisms leading to this down-regulation in oxidized cells are complicated , involving increased serine/threonine phosphorylation of insulin receptor substrate-1 ( IRS1 ) , impaired insulin stimulated redistribution of IRS1 and phosphatidylinositol-kinase between cytosol and low-density microsomal fraction , followed by a reduced protein kinase-B phosphorylation and GLUT4 translocation to the plasma membrane .	The mechanisms leading to this down-regulation in oxidized cells are complicated, involving increased serine/threonine phosphorylation of insulin receptor substrate-1 (IRS1), impaired insulin stimulated redistribution of IRS1 and phosphatidylinositol-kinase between cytosol and low-density microsomal fraction, followed by a reduced protein kinase-B phosphorylation and GLUT4 translocation to the plasma membrane.	24	31	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	25	26	29	30
Reduction of insulin stimulated association of IRS-1 with p85-type PI 3-kinase by TGFbeta may be one potential mechanism through which TGFbeta blocks 3T3-L1 adipose cell differentiation .	Reduction of insulin stimulated association of IRS-1 with p85-type PI 3-kinase by TGFbeta may be one potential mechanism through which TGFbeta blocks 3T3-L1 adipose cell differentiation.	0	7	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	2	3	6	7
In vitro , 4-HHE impaired insulin stimulated glucose uptake and signalling ( protein kinase B/Akt and IRS1 ) in L6 muscle cells .	In vitro, 4-HHE impaired insulin stimulated glucose uptake and signalling (protein kinase B/Akt and IRS1) in L6 muscle cells.	1	17	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	5	6	16	17
In addition , it has been suggested that insulin induced IRS-1 degradation is mediated by a rapamycin sensitive pathway [ XREF_BIBR ] .	In addition, it has been suggested that insulin induced IRS-1 degradation is mediated by a rapamycin sensitive pathway [XREF_BIBR].	8	11	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	10	11
However , we again observed an insulin dependent loss of IRS-1 from the HSP which was presumably due to the re-distribution of this protein to the cytosol .	However, we again observed an insulin dependent loss of IRS-1 from the HSP which was presumably due to the re-distribution of this protein to the cytosol.	6	11	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	6	7	10	11
Impairment of insulin mediated p-IRS-1 and p-Akt in liver lysates was evident at 8 weeks of high-fat feeding ( XREF_FIG ) after the onset of reduction of liver NO content and activation of Kupffer cells .	Impairment of insulin mediated p-IRS-1 and p-Akt in liver lysates was evident at 8 weeks of high-fat feeding (XREF_FIG) after the onset of reduction of liver NO content and activation of Kupffer cells.	0	6	mediated	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	p-IRS-1	p-IRS-1	p-IRS-1	2	3	4	5
Agpat2 -/- mice developed a severe whole body insulin resistance and reduced expression of IR , IRS-1 and IRS-2 might be responsible for hepatic insulin resistance in the Agpat2 -/- mice ; a finding that is consistent with previous observations , The observed islet hypertrophy is likely a compensatory phenomenon in response to severe insulin resistance .	Agpat2 -/- mice developed a severe whole body insulin resistance and reduced expression of IR, IRS-1 and IRS-2 might be responsible for hepatic insulin resistance in the Agpat2 -/- mice; a finding that is consistent with previous observations, The observed islet hypertrophy is likely a compensatory phenomenon in response to severe insulin resistance.	8	17	resistance	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	16	17
Quantified results summarizing three sets of repeated blot data further confirmed inhibition of insulin induced IRS-1 , ERK1/2 and AKT activations with 1alpha ( OH ) ase silence in L02 hepatocytes .	Quantified results summarizing three sets of repeated blot data further confirmed inhibition of insulin induced IRS-1, ERK1/2 and AKT activations with 1alpha (OH) ase silence in L02 hepatocytes.	11	20	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	13	14	15	16
Insulin resistance causes the impairment of IRS1 and GLUT4 , which lead to obstacle of glucose utilization [ XREF_BIBR ] .	Insulin resistance causes the impairment of IRS1 and GLUT4, which lead to obstacle of glucose utilization [XREF_BIBR].	0	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	IRS1	IRS1	IRS1	0	1	6	7
Neither high glucose plus insulin nor GlcN plus insulin prevented acute insulin stimulation ( approximately 20-fold ) of insulin receptor substrate 1 associated phosphatidylinositol ( PI ) -3 kinase .	Neither high glucose plus insulin nor GlcN plus insulin prevented acute insulin stimulation (approximately 20-fold) of insulin receptor substrate 1 associated phosphatidylinositol (PI) -3 kinase.	6	22	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	8	9	18	22
Furthermore , STAMP2 prevented HBx induced degradation of IRS1 protein , which mediates hepatic insulin signaling , as well as restored insulin mediated inhibition of gluconeogenic enzyme expression , which are gluconeogenic genes .	Furthermore, STAMP2 prevented HBx induced degradation of IRS1 protein, which mediates hepatic insulin signaling, as well as restored insulin mediated inhibition of gluconeogenic enzyme expression, which are gluconeogenic genes.	3	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	21	22	8	9
A total of 100 nM of insulin allowed degradation of IRS-1 after 6 h of incubation .	A total of 100 nM of insulin allowed degradation of IRS-1 after 6 h of incubation.	4	11	allowed	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	6	7	10	11
However , some investigators reported that feeding rats a high-fat diet results in decreased activation of IRS-1 , PI 3-kinase and PKB ( Akt ) by insulin in muscles within 4 wk [ XREF_BIBR - XREF_BIBR ] , which could account for the development of insulin resistance .	However, some investigators reported that feeding rats a high-fat diet results in decreased activation of IRS-1, PI 3-kinase and PKB (Akt) by insulin in muscles within 4 wk [XREF_BIBR - XREF_BIBR], which could account for the development of insulin resistance.	14	27	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	26	27	16	17
Whereas insulin decreased coprecipitation of IRS-1 with PKCalpha , it increased coprecipitation of IRS-1 with PKCdelta .	Whereas insulin decreased coprecipitation of IRS-1 with PKCalpha, it increased coprecipitation of IRS-1 with PKCdelta.	1	6	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	5	6
This involves increased JNK ( c-Jun N-terminal kinase ) 1-mediated-serine/threonine phosphorylation of IRS1 , increased proteasomal degradation of IRS1 , impaired insulin stimulated redistribution of IRS1 and PI3K ( phosphoinositide 3-kinase ) activity causing reduced Akt and PKB ( protein kinase B ) phosphorylation .	This involves increased JNK (c-Jun N-terminal kinase) 1-mediated-serine/threonine phosphorylation of IRS1, increased proteasomal degradation of IRS1, impaired insulin stimulated redistribution of IRS1 and PI3K (phosphoinositide 3-kinase) activity causing reduced Akt and PKB (protein kinase B) phosphorylation.	1	27	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	21	22	25	26
To determine the contribution of co-stimulatory signals to the regulation of apoptosis by IL-4 , we first analyzed whether tumor necrosis factor ( TNF )-alpha , which has been shown to inhibit the activation of IRS-1 by insulin , could modify IL-4 signaling and protection from apoptosis .	To determine the contribution of co-stimulatory signals to the regulation of apoptosis by IL-4, we first analyzed whether tumor necrosis factor (TNF)-alpha, which has been shown to inhibit the activation of IRS-1 by insulin, could modify IL-4 signaling and protection from apoptosis.	31	38	activation	Positive_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	37	38	35	36
PA attenuated insulin mediated insulin receptor substrate-1 ( IRS-1 ) tyrosine phosphorylation , leading to decreased glucose uptake , and phosphorylation of eNOS , leading to a reduction in the production of NO .	PA attenuated insulin mediated insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, leading to decreased glucose uptake, and phosphorylation of eNOS, leading to a reduction in the production of NO.	1	20	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	2	3	4	7
As expected , the levels of IRS1 tyrosine phosphorylation were reduced in the HBx expressing cells treated with insulin , as compared to the control vector transfected cells ( XREF_FIG ) .	As expected, the levels of IRS1 tyrosine phosphorylation were reduced in the HBx expressing cells treated with insulin, as compared to the control vector transfected cells (XREF_FIG).	6	19	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	18	19	6	7
In summary , ( i ) PI3K mediates insulin induced reduction of IRS-1 by phosphorylating it while a PI3K and mTOR pathway controls insulin induced reduction of IRS-2 , ( ii ) in L6 cells , IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK , ( iii ) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes .	In summary, (i) PI3K mediates insulin induced reduction of IRS-1 by phosphorylating it while a PI3K and mTOR pathway controls insulin induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK, (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes.	8	13	reduction	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	12	13
Overexpression of wild-type ( WT ) beta-arrestin-1 attenuated insulin induced degradation of IRS-1 , leading to increased insulin signaling downstream of IRS-1 .	Overexpression of wild-type (WT) beta-arrestin-1 attenuated insulin induced degradation of IRS-1, leading to increased insulin signaling downstream of IRS-1.	7	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	12	13
These findings suggest that an impaired insulin signalling may upregulate insulin receptor substrate-1 and that this , in turn , leads to increased IGF-1 signalling , a phenomenon that is possibly associated with increased cell growth in diabetes .	These findings suggest that an impaired insulin signalling may upregulate insulin receptor substrate-1 and that this, in turn, leads to increased IGF-1 signalling, a phenomenon that is possibly associated with increased cell growth in diabetes.	6	13	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	6	7	10	13
Moreover , dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown and inhibition accelerated insulin induced IRS1 degradation , likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7 .	Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown and inhibition accelerated insulin induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7.	20	23	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	20	21	22	23
These results indicate that insulin stimulates PI 3-kinase-mediated degradation of IRS-1 via both mTOR dependent and -independent pathways .	These results indicate that insulin stimulates PI 3-kinase-mediated degradation of IRS-1 via both mTOR dependent and -independent pathways.	4	17	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	10	11
Insulin also decreased IRS-1 protein by approximately 60 % within 9 h but did so without altering IRS-1 mRNA levels or chloramphenicol acetyl transferase activity .	Insulin also decreased IRS-1 protein by approximately 60% within 9 h but did so without altering IRS-1 mRNA levels or chloramphenicol acetyl transferase activity.	0	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	3	4
Insulin also reduced the IRS-1 ( s ) level similar to that of SXF exposure ( P < 0.05 ) .	Insulin also reduced the IRS-1 (s) level similar to that of SXF exposure (P < 0.05).	0	9	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	4	5
In cultured cell such as 3T3-L1 or 3T3-F442A adipocytes , IRS-1 was negatively regulated both by insulin and dexamethasone by different mechanisms .	In cultured cell such as 3T3-L1 or 3T3-F442A adipocytes, IRS-1 was negatively regulated both by insulin and dexamethasone by different mechanisms.	10	18	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	16	17	10	11
At the same time , the HS induced glucose intolerance , impaired postprandial glycemic control , and decrease in muscle and liver insulin induced activation of insulin receptor substrate 1 and Akt were prevented by increasing the level of dietary cysteine , a major original finding .	At the same time, the HS induced glucose intolerance, impaired postprandial glycemic control, and decrease in muscle and liver insulin induced activation of insulin receptor substrate 1 and Akt were prevented by increasing the level of dietary cysteine, a major original finding.	17	30	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	22	23	26	30
Thus , HG and insulin induce degradation of IRS1 via distinct pathways .	Thus, HG and insulin induce degradation of IRS1 via distinct pathways.	2	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	4	5	8	9
High insulin concentrations ( 100 nM ) markedly suppressed IRS1 protein in both TH mice and B6 controls ( XREF_SUPPLEMENTARY ) .	High insulin concentrations (100 nM) markedly suppressed IRS1 protein in both TH mice and B6 controls (XREF_SUPPLEMENTARY).	0	10	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	1	2	9	10
However , leptin + insulin decreased IRS-1 pY by 57 % ( P < 0.01 vs. insulin ) .	However, leptin + insulin decreased IRS-1 pY by 57% (P < 0.01 vs. insulin).	2	7	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	6	7
In addition , chronic insulin exposure induced degradation of IRS1 and IRS2 proteins while increasing p38 phosphorylation , thereby revealing a molecular mechanism for the development of insulin resistance .	In addition, chronic insulin exposure induced degradation of IRS1 and IRS2 proteins while increasing p38 phosphorylation, thereby revealing a molecular mechanism for the development of insulin resistance.	4	12	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	4	5	9	10
When endogenous beta-arrestin-1 was knocked down by transfection of beta-arrestin-1 small interfering RNA , insulin induced IRS-1 degradation was enhanced .	When endogenous beta-arrestin-1 was knocked down by transfection of beta-arrestin-1 small interfering RNA, insulin induced IRS-1 degradation was enhanced.	14	17	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	14	15	16	17
In Gab1 knockout liver , insulin stimulated IRS1 phospho-S612 ( hS616 ) is clearly decreased [ XREF_BIBR ] .	In Gab1 knockout liver, insulin stimulated IRS1 phospho-S612 (hS616) is clearly decreased [XREF_BIBR].	5	8	stimulated	Positive_activation_token_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	5	6	7	8
In the present study we have examined the potential role of different signaling cascades in the insulin induced degradation of IRS-1 .	In the present study we have examined the potential role of different signaling cascades in the insulin induced degradation of IRS-1.	6	21	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	16	17	20	21
Using neonatal rat ventricular cardiomyocytes , we further found that chronic insulin exposure reduced IRS1 and IRS2 proteins and prevented insulin action through activation of p38 , revealing a fundamental mechanism of cardiac dysfunction during insulin resistance and type 2 diabetes .	Using neonatal rat ventricular cardiomyocytes, we further found that chronic insulin exposure reduced IRS1 and IRS2 proteins and prevented insulin action through activation of p38, revealing a fundamental mechanism of cardiac dysfunction during insulin resistance and type 2 diabetes.	11	17	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	11	12	14	15
Previous studies have demonstrated a negative feedback loop in which long-term IGF and insulin stimulation induces the degradation of IRS-1 in a PI3K and mTOR complex 1 ( mTORC1 )-sensitive and proteasome dependent fashion .	Previous studies have demonstrated a negative feedback loop in which long-term IGF and insulin stimulation induces the degradation of IRS-1 in a PI3K and mTOR complex 1 (mTORC1)-sensitive and proteasome dependent fashion.	13	20	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	13	14	19	20
Lactacystin , a specific proteasome inhibitor , inhibited insulin induced degradation of IRS-1 without any effect on its electrophoretic mobility .	Lactacystin, a specific proteasome inhibitor, inhibited insulin induced degradation of IRS-1 without any effect on its electrophoretic mobility.	7	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	12	13
Among these kinase inhibitors , the p38 inhibitor SB completely prevented chronic insulin induced IRS1 and IRS2 degradation and rescued Akt --> Foxo1 phosphorylation ( XREF_FIG ) , suggesting that p38 activation is necessary for chronic insulin induced IRS1 and IRS2 degradation and insulin resistance .	Among these kinase inhibitors, the p38 inhibitor SB completely prevented chronic insulin induced IRS1 and IRS2 degradation and rescued Akt --> Foxo1 phosphorylation (XREF_FIG), suggesting that p38 activation is necessary for chronic insulin induced IRS1 and IRS2 degradation and insulin resistance.	35	41	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	36	37	38	39
MEF studies show that Hsf-1 , JNK , and Akt are activated , and their activation is directly correlated with glucose uptake in response to insulin ; FOXO is inactivated by insulin , and its activity is inversely correlated with insulin dependent glucose uptake .	MEF studies show that Hsf-1, JNK, and Akt are activated, and their activation is directly correlated with glucose uptake in response to insulin; FOXO is inactivated by insulin, and its activity is inversely correlated with insulin dependent glucose uptake.	27	32	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	31	32	27	28
However , the mechanisms by which inhibition of insulin and IGF -1 signaling and germline loss activate DAF-16 and FOXO are distinct .	However, the mechanisms by which inhibition of insulin and IGF -1 signaling and germline loss activate DAF-16 and FOXO are distinct.	8	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	8	9	19	20
24 h luteolin 30 microM resulted in a 1.6-fold FOXO import which increased to 1.9- and 2-fold in the presence of NAC 5 mM and 25 mM respectively , the latter not being reduced by insulin ( XREF_FIG ) .	24 h luteolin 30 microM resulted in a 1.6-fold FOXO import which increased to 1.9- and 2-fold in the presence of NAC 5 mM and 25 mM respectively, the latter not being reduced by insulin (XREF_FIG).	9	36	reduced	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	35	36	9	10
By contrast , insulin stimulation of Irs1 (-/-) MEFs caused FoxO degradation , not only because Irs2 expression increased but also because Irs2 efficiently activated p110alpha --> Akt cascade .	By contrast, insulin stimulation of Irs1 (-/-) MEFs caused FoxO degradation, not only because Irs2 expression increased but also because Irs2 efficiently activated p110alpha --> Akt cascade.	3	11	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	3	4	10	11
Insulin resistance before and after the discovery of FOXO .	Insulin resistance before and after the discovery of FOXO.	0	9	resistance	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO	FOXO	FOXO	0	1	8	9
FOXO proteins are negatively regulated by the insulin signaling pathway , because Akt mediated phosphorylation of FOXO molecules prevents them from being translocated to the nucleus .	FOXO proteins are negatively regulated by the insulin signaling pathway, because Akt mediated phosphorylation of FOXO molecules prevents them from being translocated to the nucleus.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	7	8	0	1
Further , we show that the effects of JH on growth rate are dependent on the forkhead box O transcription factor ( FOXO ) , which is negatively regulated by the insulin signaling pathway .	Further, we show that the effects of JH on growth rate are dependent on the forkhead box O transcription factor (FOXO), which is negatively regulated by the insulin signaling pathway.	20	33	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	31	32	22	23
Insulin and growth factors also block FoxO action by promoting proteasome mediated FoxO degradation and , consequently , decreasing FoxO protein levels [ XREF_BIBR ] .	Insulin and growth factors also block FoxO action by promoting proteasome mediated FoxO degradation and, consequently, decreasing FoxO protein levels [XREF_BIBR].	0	22	block	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Insulin	Insulin	insulin	FoxO	proteasome mediated FoxO degradation and, consequently, decreasing FoxO protein levels	foxo	0	1	19	20
Insulin and IGF -1 signaling inhibits both DAF-16 ( homolog of FOXO ) and SKN-1 ( homolog of NRF2 ) .	Insulin and IGF -1 signaling inhibits both DAF-16 (homolog of FOXO) and SKN-1 (homolog of NRF2).	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO	FOXO	FOXO	0	1	11	12
These predictions are based on numerous studies , showing that FoxO is negatively regulated by insulin signaling ( see above ) .	These predictions are based on numerous studies, showing that FoxO is negatively regulated by insulin signaling (see above).	10	16	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	15	16	10	11
Insulin and growth factor signaling negatively regulate FOXO transcriptional activity through AKT and SGK1 dependent phosphorylation , leading to FOXO exclusion from the nucleus and inhibition of its transcriptional activity .	Insulin and growth factor signaling negatively regulate FOXO transcriptional activity through AKT and SGK1 dependent phosphorylation, leading to FOXO exclusion from the nucleus and inhibition of its transcriptional activity.	0	9	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO	FOXO	FOXO	0	1	7	8
Since FOXO can be inactivated by insulin and growth factors , scientists have explored the relationship among these three essential signaling cascades .	Since FOXO can be inactivated by insulin and growth factors, scientists have explored the relationship among these three essential signaling cascades.	1	9	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	6	7	1	2
This extended survival was reminiscent of that seen in daf-2 insulin signaling deficient mutants and was ultimately dependent on daf-16 , which encodes a FOXO transcription factor whose activity is inhibited by insulin signaling .	This extended survival was reminiscent of that seen in daf-2 insulin signaling deficient mutants and was ultimately dependent on daf-16, which encodes a FOXO transcription factor whose activity is inhibited by insulin signaling.	24	33	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	32	33	24	25
However , upon feeding , insulin inhibits FOXO .	However, upon feeding, insulin inhibits FOXO.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	5	6	7	8
Insulin signaling via AKT reduces activity of FOXO transcription factors .	Insulin signaling via AKT reduces activity of FOXO transcription factors.	0	9	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO	FOXO	FOXO	0	1	7	8
Insulin and IGF -1 signaling inhibits the transcriptional activity of DAF-16 and FOXO .	Insulin and IGF -1 signaling inhibits the transcriptional activity of DAF-16 and FOXO.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO	FOXO	FOXO	0	1	12	13
FOXO is normally activated by suppression of insulin signaling ; thus FOXO may be involved in increasing transcript levels of genes involved in fatty acid synthesis , as observed in newly emerged diapausing females .	FOXO is normally activated by suppression of insulin signaling; thus FOXO may be involved in increasing transcript levels of genes involved in fatty acid synthesis, as observed in newly emerged diapausing females.	0	8	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	7	8	0	1
This speculation has got strong support from previous findings that ( 1 ) insulin signaling can inhibit the FoxO mediated target gene transactivation even their NES signal was destroyed XREF_BIBR , and ( 2 ) the phosphrylation of FoxOs is increased during terminal differentiation and most of them are still in the nucleus of mononucleated myoblasts XREF_BIBR , XREF_BIBR .	This speculation has got strong support from previous findings that (1) insulin signaling can inhibit the FoxO mediated target gene transactivation even their NES signal was destroyed XREF_BIBR, and (2) the phosphrylation of FoxOs is increased during terminal differentiation and most of them are still in the nucleus of mononucleated myoblasts XREF_BIBR, XREF_BIBR.	13	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	13	14	18	19
Thus , when nutrients become abundant , the cells are hypersensitized to the concomitant increase in insulin levels , which inhibit FOXO and promote cell growth and proliferation .	Thus, when nutrients become abundant, the cells are hypersensitized to the concomitant increase in insulin levels, which inhibit FOXO and promote cell growth and proliferation.	16	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin levels	insulin	FOXO	FOXO	foxo	16	17	21	22
JNK induces the release of FoxOs from 14-3-3 , thereby overriding FoxO inhibition caused by insulin and growth factors .	JNK induces the release of FoxOs from 14-3-3, thereby overriding FoxO inhibition caused by insulin and growth factors.	11	18	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	15	16	11	12
Reduction in insulin signaling activates DAF-16 and FOXO , which represses the transcription of germline and intestinal genes required to deliver PUFAs to oocytes in lipoprotein complexes .	Reduction in insulin signaling activates DAF-16 and FOXO, which represses the transcription of germline and intestinal genes required to deliver PUFAs to oocytes in lipoprotein complexes.	2	13	activates	Positive_regulation_syntax_1_verb	Negative_activation	Negative_regulation	insulin	insulin	insulin	DAF-16	DAF-16 and FOXO, which represses the transcription	daf-16	2	3	5	6
Studies in mammalian cells have also shown that insulin negatively regulates FOXO ( Forkhead box , subclass O ) transcription factors , which in turn arrest the cell cycle and , in some types of cell , induce cell death .	Studies in mammalian cells have also shown that insulin negatively regulates FOXO (Forkhead box, subclass O) transcription factors, which in turn arrest the cell cycle and, in some types of cell, induce cell death.	8	25	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	8	9	11	12
An important implication of these findings is that insulin inhibition of FoxO transcriptional activity and FoxO nucleocytoplasmic trafficking are two separate events .	An important implication of these findings is that insulin inhibition of FoxO transcriptional activity and FoxO nucleocytoplasmic trafficking are two separate events.	8	13	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	8	9	11	12
However , addition of 3 % fNJ + insulin significantly lowered total FoxO proteins compared with all the other groups , but phosphorylated FoxO remained unchanged compared with the other groups except the control group ( XREF_FIG ) .	However, addition of 3% fNJ + insulin significantly lowered total FoxO proteins compared with all the other groups, but phosphorylated FoxO remained unchanged compared with the other groups except the control group (XREF_FIG).	2	13	lowered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	8	9	12	13
FOXO transcription factors ( FOXOs ) are evolutionarily conserved regulators of longevity and are inhibited by the insulin and insulin like growth factor ( IGF ) signaling pathway ( Kenyon , 2010 ) .	FOXO transcription factors (FOXOs) are evolutionarily conserved regulators of longevity and are inhibited by the insulin and insulin like growth factor (IGF) signaling pathway (Kenyon, 2010).	0	27	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	17	18	0	1
Inhibition of the insulin and insulin like growth factor 1 signaling ( IIS ) pathway in strains carrying mutations in the DAF-2 receptor ( or the downstream PI ( 3 ) kinase AGE-1 ) activates the DAF-16 and FOXO transcription factor and leads to a dramatic lifespan extension .	Inhibition of the insulin and insulin like growth factor 1 signaling (IIS) pathway in strains carrying mutations in the DAF-2 receptor (or the downstream PI (3) kinase AGE-1) activates the DAF-16 and FOXO transcription factor and leads to a dramatic lifespan extension.	0	40	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	3	4	38	39
DAF-2 insulin and IGF -1 receptor activity negatively regulates daf-16 FOXO ; in addition , the longevity and dauer phenotypes of daf-2 mutants require daf-16 FOXO activity .	DAF-2 insulin and IGF -1 receptor activity negatively regulates daf-16 FOXO; in addition, the longevity and dauer phenotypes of daf-2 mutants require daf-16 FOXO activity.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	1	2	10	11
cAMP promotes FoxO nuclear retention and dephosphorylation , whereas insulin at low concentrations promptly inactivates FoxO by driving its nuclear exclusion via Akt dependent phosphorylation .	cAMP promotes FoxO nuclear retention and dephosphorylation, whereas insulin at low concentrations promptly inactivates FoxO by driving its nuclear exclusion via Akt dependent phosphorylation.	9	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	9	10	15	16
Ten years ago , it was appreciated that CREB and FOXO transcription factors are critical mediators of the promoters of the core gluconeogenic enzymes Pepck and G6pc , with CREB mediating positive effects from glucagon and FOXO being suppressed by insulin dependent signaling .	Ten years ago, it was appreciated that CREB and FOXO transcription factors are critical mediators of the promoters of the core gluconeogenic enzymes Pepck and G6pc, with CREB mediating positive effects from glucagon and FOXO being suppressed by insulin dependent signaling.	30	42	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	40	41	36	37
Translocation of DAF-16 and FOXO to the nucleus implies that the transcription factor DAF-16 and FOXO was activated under purple wheat treatment by inhibition of the insulin and IGF-1-like signaling pathway which includes the insulin receptor DAF-2 .	Translocation of DAF-16 and FOXO to the nucleus implies that the transcription factor DAF-16 and FOXO was activated under purple wheat treatment by inhibition of the insulin and IGF-1-like signaling pathway which includes the insulin receptor DAF-2.	13	32	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	26	27	15	16
The insulin and IGF -1 receptor , through activating a cascade of conserved kinases , inhibits the forkhead transcription factor FoxO .	The insulin and IGF -1 receptor, through activating a cascade of conserved kinases, inhibits the forkhead transcription factor FoxO.	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	1	2	20	21
In both systems , the lifespan phenotype was dependent on insulin and IGF1 signaling ( hereafter IIS ) mediated inhibition of the daf-16 and FOXO transcription factor [ XREF_BIBR ] which is involved in diverse processes such as stress response , immunity and metabolism .	In both systems, the lifespan phenotype was dependent on insulin and IGF1 signaling (hereafter IIS) mediated inhibition of the daf-16 and FOXO transcription factor [XREF_BIBR] which is involved in diverse processes such as stress response, immunity and metabolism.	10	26	inhibition	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	10	11	24	25
Under conditions of reduced insulin signaling FoxO should enter the nucleus and up-regulate luciferase activity .	Under conditions of reduced insulin signaling FoxO should enter the nucleus and up-regulate luciferase activity.	1	12	signaling	Positive_activation_token_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	4	5	6	7
In C. elegans , Drosophila and mouse , reduction of Insulin and IGF -1 signaling ultimately activates DAF-16 and FOXO function and extends lifespan .	In C. elegans, Drosophila and mouse, reduction of Insulin and IGF -1 signaling ultimately activates DAF-16 and FOXO function and extends lifespan.	10	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO	FOXO	FOXO	10	11	19	20
The apl-1 ( yn5 ) phenotypes require activity of the DAF-16 and FOXO transcription factor , which is negatively regulated by the insulin pathway .	The apl-1 (yn5) phenotypes require activity of the DAF-16 and FOXO transcription factor, which is negatively regulated by the insulin pathway.	12	23	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	22	23	12	13
One way to overcome the secretory block in ire-1 mutants is by activating the FOXO transcription factor DAF-16 , which is inhibited by the insulin and IGF -1 signaling ( IIS ) pathway [ XREF_BIBR ] .	One way to overcome the secretory block in ire-1 mutants is by activating the FOXO transcription factor DAF-16, which is inhibited by the insulin and IGF -1 signaling (IIS) pathway [XREF_BIBR].	14	28	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	24	25	14	15
Insulin and insulin like growth factor-1 ( IGF-1 ) can suppress FoxO protein activity through activation of Akt XREF_BIBR , XREF_BIBR .	Insulin and insulin like growth factor-1 (IGF-1) can suppress FoxO protein activity through activation of Akt XREF_BIBR, XREF_BIBR.	0	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FoxO	FoxO	FoxO	0	1	11	12
Briefly , the insulin signaling pathway is not activated in diapausing adult females , thus lifting suppression of FOXO .	Briefly, the insulin signaling pathway is not activated in diapausing adult females, thus lifting suppression of FOXO.	3	19	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	3	4	18	19
It follows that insulin inhibition of FoxO transcriptional activity can ensue without necessarily altering FoxO subcellular redistribution , but this mechanism depends on insulin stimulated FoxO phosphorylation .	It follows that insulin inhibition of FoxO transcriptional activity can ensue without necessarily altering FoxO subcellular redistribution, but this mechanism depends on insulin stimulated FoxO phosphorylation.	3	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	3	4	6	7
This result provides evidence that insulin and IGF -1 signaling , which acts through the PI3K/Akt/SGK pathway , reduces Hydra FoxO activity .	This result provides evidence that insulin and IGF -1 signaling, which acts through the PI3K/Akt/SGK pathway, reduces Hydra FoxO activity.	5	21	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	5	6	20	21
In normal cells , antagonistic mechanisms regulate FOXOs activity , depending on the context : ( 1 ) insulin and growth factors signaling through the PI3K and Akt pathway inhibits FOXO transcriptional activity by phosphorylation and subsequent cytoplasmic retention of FOXOs through increased binding to their 14-3-3 regulator XREF_BIBR ; ( 2 ) JNK mediated nuclear translocation of FOXO in response to an intense oxidative burst augments its transcriptional activity and tumor suppressor function XREF_BIBR .	In normal cells, antagonistic mechanisms regulate FOXOs activity, depending on the context : (1) insulin and growth factors signaling through the PI3K and Akt pathway inhibits FOXO transcriptional activity by phosphorylation and subsequent cytoplasmic retention of FOXOs through increased binding to their 14-3-3 regulator XREF_BIBR; (2) JNK mediated nuclear translocation of FOXO in response to an intense oxidative burst augments its transcriptional activity and tumor suppressor function XREF_BIBR.	18	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	18	19	30	31
DAF-16 and FOXO proteins are inactivated by the insulin and IGF -1 signaling ( IIS ) through PI3K and the AGC kinases Akt and SGK , which promote its cytosolic localization .	DAF-16 and FOXO proteins are inactivated by the insulin and IGF -1 signaling (IIS) through PI3K and the AGC kinases Akt and SGK, which promote its cytosolic localization.	0	12	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	8	9	2	3
Our data consolidate the idea that 14-3-3 , which is present in both nucleus and cytoplasm , participates in post-translational modification of FoxO activity , consistent with the idea that insulin inhibition of FoxO transcriptional activity and FoxO nucleocytoplasmic trafficking are two distinct events .	Our data consolidate the idea that 14-3-3, which is present in both nucleus and cytoplasm, participates in post-translational modification of FoxO activity, consistent with the idea that insulin inhibition of FoxO transcriptional activity and FoxO nucleocytoplasmic trafficking are two distinct events.	30	35	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	30	31	33	34
Insulin negatively regulates FOXO via phosphorylation by Akt in both flies and rodents .	Insulin negatively regulates FOXO via phosphorylation by Akt in both flies and rodents.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO	FOXO	FOXO	0	1	3	4
DAF-16 and FOXO is also stimulated independently by decreased insulin and IGF receptor ( IR ) signaling , since the longevity of daf-2/IR and germlineless glp-1 mutants is additive .	DAF-16 and FOXO is also stimulated independently by decreased insulin and IGF receptor (IR) signaling, since the longevity of daf-2/IR and germlineless glp-1 mutants is additive.	0	12	stimulated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	9	10	2	3
Since FOXO activity is repressed by insulin signaling , pudgy expression should also be repressed by insulin .	Since FOXO activity is repressed by insulin signaling, pudgy expression should also be repressed by insulin.	1	7	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	6	7	1	2
Insulin suppresses the function of FoxO proteins , including effects on ATGL dependent lipolysis and FAO , which serves to increases glycolysis and lipogenesis , and decreases gluconeogenesis .	Insulin suppresses the function of FoxO proteins, including effects on ATGL dependent lipolysis and FAO, which serves to increases glycolysis and lipogenesis, and decreases gluconeogenesis.	0	6	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FoxO	FoxO	FoxO	0	1	5	6
Furthermore , Upd2 and AKH appear to not impact secondary phenotypes associated with Foxo attenuation in muscle , such as hyperactivity and elevated insulin signaling activity ( XREF_SUPPLEMENTARY ) , indicating a relatively direct Foxo/Upd2/AKH inter-tissue communication axis between muscle and the fat body and intestine .	Furthermore, Upd2 and AKH appear to not impact secondary phenotypes associated with Foxo attenuation in muscle, such as hyperactivity and elevated insulin signaling activity (XREF_SUPPLEMENTARY), indicating a relatively direct Foxo/Upd2/AKH inter-tissue communication axis between muscle and the fat body and intestine.	13	25	attenuation	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	insulin	insulin	insulin	Foxo	Foxo	Foxo	23	24	13	14
The insulin and IGF -1 signaling pathway ultimately represses the activity of the FOXO family transcription factor DAF-16 .	The insulin and IGF -1 signaling pathway ultimately represses the activity of the FOXO family transcription factor DAF-16.	0	17	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	1	2	13	14
Another major regulatory pathway involves insulin signaling , which negatively regulates the FOXO transcription factor DAF-16 .	Another major regulatory pathway involves insulin signaling, which negatively regulates the FOXO transcription factor DAF-16.	5	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	5	6	12	13
In both C. elegans and Drosophila , FOXO transcription factors are inhibited predominantly by the activation of insulin ( Ins ) or insulin like growth factor receptors ( Ins and IGF1R ) .	In both C. elegans and Drosophila, FOXO transcription factors are inhibited predominantly by the activation of insulin (Ins) or insulin like growth factor receptors (Ins and IGF1R).	7	19	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	17	18	7	8
FOXO , which is one of the most important transcription factors in improving functional longevity during fasting , is negatively regulated by insulin [ XREF_BIBR ] .	FOXO, which is one of the most important transcription factors in improving functional longevity during fasting, is negatively regulated by insulin [XREF_BIBR].	0	24	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	22	23	0	1
Taken together , this study helps to support the hypothesis from in vitro results that in vivo high glycemic load diet which increases IGF-1 and insulin may contribute to induce activation of the PI3K pathway , reduction of FoxO transcriptional activity , and increase of proliferation in human primary T cells .	Taken together, this study helps to support the hypothesis from in vitro results that in vivo high glycemic load diet which increases IGF-1 and insulin may contribute to induce activation of the PI3K pathway, reduction of FoxO transcriptional activity, and increase of proliferation in human primary T cells.	23	40	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	25	26	38	39
In C. elegans , the sole insulin and IGF -1 receptor , DAF-2 , negatively regulates the FOXO transcription factor , DAF-16 .	In C. elegans, the sole insulin and IGF -1 receptor, DAF-2, negatively regulates the FOXO transcription factor, DAF-16.	4	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	6	7	17	18
There is , therefore , an emerging consensus that loss of insulin signaling and , more specifically , insulin stimulated Akt and FoxO signaling , accelerates atherosclerosis .	There is, therefore, an emerging consensus that loss of insulin signaling and, more specifically, insulin stimulated Akt and FoxO signaling, accelerates atherosclerosis.	9	23	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	loss of insulin signaling and, more specifically, insulin	insulin	FoxO	FoxO	foxo	18	19	22	23
Insulin inhibits transcription factor Forkhead box O ( FoxO ) activity , and the steroid hormone 20-hydroxyecdysone ( 20E ) activates FoxO ; however , the mechanism is unclear .	Insulin inhibits transcription factor Forkhead box O (FoxO) activity, and the steroid hormone 20-hydroxyecdysone (20E) activates FoxO; however, the mechanism is unclear.	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FoxO	FoxO	FoxO	0	1	21	22
Together these results suggest that insulin inhibition of FoxO activity and FoxO nucleocytoplasmic trafficking are two distinct events .	Together these results suggest that insulin inhibition of FoxO activity and FoxO nucleocytoplasmic trafficking are two distinct events.	5	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	5	6	8	9
FoxO activity is inhibited by growth factors and the insulin signaling pathways and stimulated by nutrient depletion and a plethora of reactive oxygen species ( ROS )-induced post-translational modifications .	FoxO activity is inhibited by growth factors and the insulin signaling pathways and stimulated by nutrient depletion and a plethora of reactive oxygen species (ROS)-induced post-translational modifications.	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	9	10	0	1
IGF-1 and insulin reduce FoxO transcriptional activity in human primary T cells .	IGF-1 and insulin reduce FoxO transcriptional activity in human primary T cells.	0	6	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	2	3	4	5
FoxO factors are inhibited by the insulin and insulin like growth factor-1 ( IGF ) signaling pathway [ XREF_BIBR - XREF_BIBR ] and have emerged as regulators of adult NSCs both in vitro and in vivo [ XREF_BIBR , XREF_BIBR ] .	FoxO factors are inhibited by the insulin and insulin like growth factor-1 (IGF) signaling pathway [XREF_BIBR - XREF_BIBR] and have emerged as regulators of adult NSCs both in vitro and in vivo [XREF_BIBR, XREF_BIBR].	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	6	7	0	1
In wild-type worms , the insulin and IGF -1 receptor DAF-2 activates a series of conserved kinases that ultimately phosphorylate and inactivate DAF-16 and FOXO XREF_BIBR - XREF_BIBR .	In wild-type worms, the insulin and IGF -1 receptor DAF-2 activates a series of conserved kinases that ultimately phosphorylate and inactivate DAF-16 and FOXO XREF_BIBR - XREF_BIBR.	4	27	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	5	6	24	25
DAF-16 and FOXO proteins are inactivated by the insulin and IGF -1 signaling ( IIS ) through PI3K and the AGC kinases Akt and SGK which promote its cytosolic localization XREF_BIBR - XREF_BIBR .	DAF-16 and FOXO proteins are inactivated by the insulin and IGF -1 signaling (IIS) through PI3K and the AGC kinases Akt and SGK which promote its cytosolic localization XREF_BIBR - XREF_BIBR.	0	12	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	8	9	2	3
In Drosophila , SIK3 activity can be activated by insulin , which antagonizes FOXO activated gene expression XREF_BIBR .	In Drosophila, SIK3 activity can be activated by insulin, which antagonizes FOXO activated gene expression XREF_BIBR.	7	14	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	9	10	13	14
FOXO activity is suppressed by insulin signalling in the short term , but this suppression is lost in the longer term - especially under stressful conditions , and involves a feed back loop that upregulates components of the Akt insulin signalling pathway [ XREF_BIBR ] .	FOXO activity is suppressed by insulin signalling in the short term, but this suppression is lost in the longer term - especially under stressful conditions, and involves a feed back loop that upregulates components of the Akt insulin signalling pathway [XREF_BIBR].	0	6	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	5	6	0	1
Also , a lf mutation in daf-16 , which encodes a FOXO transcription factor that is negatively regulated by the insulin pathway , did not enhance the let-60 ( gf ) Muv phenotype ( XREF_TABLE , row 13 ) .	Also, a lf mutation in daf-16, which encodes a FOXO transcription factor that is negatively regulated by the insulin pathway, did not enhance the let-60 (gf) Muv phenotype (XREF_TABLE, row 13).	11	21	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	20	21	11	12
In Drosophila , glucose activates insulin signaling , which acts through PI3K and Akt pathway to activate TOR and repress FOXO [ XREF_BIBR ] .	In Drosophila, glucose activates insulin signaling, which acts through PI3K and Akt pathway to activate TOR and repress FOXO [XREF_BIBR].	5	22	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	5	6	20	21
The insulin signalling pathway negatively regulates the FOXO factor [ XREF_BIBR ] .	The insulin signalling pathway negatively regulates the FOXO factor [XREF_BIBR].	1	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	1	2	7	8
JNK Silencing Modulates the Activity of the Downstream Substrates of Insulin Signaling GSK3beta and FoxO in Cytokine treated Cells .	JNK Silencing Modulates the Activity of the Downstream Substrates of Insulin Signaling GSK3beta and FoxO in Cytokine treated Cells.	8	14	Signaling	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	GSK3beta	GSK3beta	GSK3beta	10	11	12	13
Likewise , as early as 15 min and at 60 min following the combination of trauma and hemorrhage following hemorrhage , there was a complete loss in insulin induced P-GSK-3beta ( XREF_FIG ) .	Likewise, as early as 15 min and at 60 min following the combination of trauma and hemorrhage following hemorrhage, there was a complete loss in insulin induced P-GSK-3beta (XREF_FIG).	25	31	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	P-GSK-3beta	P-GSK-3beta	P-GSK-3beta	27	28	29	30
First , activated UPR sensors , particularly IRE1 and PERK , can either inhibit Akt or suppress insulin induced inhibition of GSK3beta , leading to increased GSK3beta activity [ XREF_BIBR , XREF_BIBR ] .	First, activated UPR sensors, particularly IRE1 and PERK, can either inhibit Akt or suppress insulin induced inhibition of GSK3beta, leading to increased GSK3beta activity [XREF_BIBR, XREF_BIBR].	16	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	17	18	21	22
HFD causes insulin resistance in cortical and limbic structures , including decreased insulin stimulation of Akt , S6K , GSK3beta , and mTORC1 signaling , while AMP activated protein kinase ( AMPK ) stimulation is increased 104 .	HFD causes insulin resistance in cortical and limbic structures, including decreased insulin stimulation of Akt, S6K, GSK3beta, and mTORC1 signaling, while AMP activated protein kinase (AMPK) stimulation is increased 104.	12	23	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	12	13	19	20
When mTORC2 was blocked , mechanical GSK3beta inactivation was prevented , whereas insulin inhibition of GSK3beta was still measured in the absence of Ser 473 phosphorylation , presumably through phosphorylation of Akt at Thr 308 .	When mTORC2 was blocked, mechanical GSK3beta inactivation was prevented, whereas insulin inhibition of GSK3beta was still measured in the absence of Ser 473 phosphorylation, presumably through phosphorylation of Akt at Thr 308.	12	16	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	12	13	15	16
In the absence of a diminution in LRP1 ( only a trend seen here ) which in turn serves as the clearance pathway preventing accumulation of amyloid beta peptide , we can surmise that in our present study amyloid-beta42 accumulates not due solely to a defect in the clearance but rather secondary to enhanced production perhaps reliant on reduced insulin signaling related activation of GSK-3beta .	In the absence of a diminution in LRP1 (only a trend seen here) which in turn serves as the clearance pathway preventing accumulation of amyloid beta peptide, we can surmise that in our present study amyloid-beta42 accumulates not due solely to a defect in the clearance but rather secondary to enhanced production perhaps reliant on reduced insulin signaling related activation of GSK-3beta.	59	65	activation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	59	60	64	65
Indeed , insulin mediated GSK3beta inhibition is involved .	Indeed, insulin mediated GSK3beta inhibition is involved.	2	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	2	3	4	5
In PCOS adipocytes , GSK3beta tyrosine phosphorylation is increased and insulin stimulated serine phosphorylation is decreased , which could result in an overactive GSK3beta that is less able to be suppressed by insulin , possibly explaining impaired insulin stimulated glycogen synthesis .	In PCOS adipocytes, GSK3beta tyrosine phosphorylation is increased and insulin stimulated serine phosphorylation is decreased, which could result in an overactive GSK3beta that is less able to be suppressed by insulin, possibly explaining impaired insulin stimulated glycogen synthesis.	19	33	suppressed	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	32	33	23	24
As impaired IRS/PI3K/Akt insulin signaling and overactivation of GSK3beta are involved in type 2 diabetes induced cognitive deficits , we investigated whether TAC altered the IRS/PI3K/Akt/GSK3beta signaling pathway in the brain of type 2 diabetic rats .	As impaired IRS/PI3K/Akt insulin signaling and overactivation of GSK3beta are involved in type 2 diabetes induced cognitive deficits, we investigated whether TAC altered the IRS/PI3K/Akt/GSK3beta signaling pathway in the brain of type 2 diabetic rats.	3	9	signaling	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	3	4	8	9
In CHO/IR cells , although 10 nM insulin induced the inhibition of GSK3beta ( increased phosphorylation ; XREF_FIG , panel 4 , lanes e-f ) , it induced the degradation of IRS1 under both normal and HG conditions ( XREF_FIG , panel 3 , lanes e-f ) , suggesting a mechanism independent of GSK3beta activity .	In CHO/IR cells, although 10 nM insulin induced the inhibition of GSK3beta (increased phosphorylation; XREF_FIG, panel 4, lanes e-f), it induced the degradation of IRS1 under both normal and HG conditions (XREF_FIG, panel 3, lanes e-f), suggesting a mechanism independent of GSK3beta activity.	5	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	7	8	12	13
Most studies indicate that the mechanisms promoting Wnt- versus insulin induced GSK-3beta inhibition are distinct , and this may be one way that cells avoid a potentially harmful activation of Wnt signaling by insulin and vice versa .	Most studies indicate that the mechanisms promoting Wnt- versus insulin induced GSK-3beta inhibition are distinct, and this may be one way that cells avoid a potentially harmful activation of Wnt signaling by insulin and vice versa.	7	12	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	9	10	11	12
Hence , both fulvestrant and insulin could potentially block GSK-3beta activity in MCF-7 cells and thereby reduce proteosome dependent degradation of proteins .	Hence, both fulvestrant and insulin could potentially block GSK-3beta activity in MCF-7 cells and thereby reduce proteosome dependent degradation of proteins.	3	10	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	5	6	9	10
Since both Wnt and insulin signals inhibit GSK 3beta and thus facilitate the accumulation of beta-Catenin in the cytoplasm XREF_BIBR , the synergism between insulin and LiCl treatments implies that other additional mechanisms must also be employed by them to promote and rescue FoxO1 blocked myogeneis .	Since both Wnt and insulin signals inhibit GSK 3beta and thus facilitate the accumulation of beta-Catenin in the cytoplasm XREF_BIBR, the synergism between insulin and LiCl treatments implies that other additional mechanisms must also be employed by them to promote and rescue FoxO1 blocked myogeneis.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK 3beta	GSK 3beta	GSK 3beta	4	5	7	9
We found that insulin signaling inactivates GSK3beta to control Myc protein stability , and a similar biochemical regulation is also shared by activation of the TOR pathways .	We found that insulin signaling inactivates GSK3beta to control Myc protein stability, and a similar biochemical regulation is also shared by activation of the TOR pathways.	3	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	3	4	6	7
The blockade of hypothalamic insulin signaling partially blunted GK induction ( resulting in only 8- and 2.5-fold increases in GK mRNA and protein expression ; XREF_FIG ) and completely prevented the suppression of GSK3beta mRNA and protein levels caused by eightfold insulin ( XREF_FIG ) .	The blockade of hypothalamic insulin signaling partially blunted GK induction (resulting in only 8- and 2.5-fold increases in GK mRNA and protein expression; XREF_FIG) and completely prevented the suppression of GSK3beta mRNA and protein levels caused by eightfold insulin (XREF_FIG).	4	34	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	4	5	33	34
Inhaled aerosolized insulin , known to inhibit GSK3beta , has been proposed as a treatment for sepsis induced ARDS [ XREF_BIBR ] .	Inhaled aerosolized insulin, known to inhibit GSK3beta, has been proposed as a treatment for sepsis induced ARDS [XREF_BIBR].	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	2	3	7	8
These observations indicate that PI3K dependent inactivation of GSK3beta by insulin leads to upregulation of ET-1 gene expression and Vezf1 may be a target for ET-1 regulation by insulin .	These observations indicate that PI3K dependent inactivation of GSK3beta by insulin leads to upregulation of ET-1 gene expression and Vezf1 may be a target for ET-1 regulation by insulin.	6	11	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	10	11	8	9
pAkt S473 can promote insulin mediated inhibition of GSK3beta .	pAkt S473 can promote insulin mediated inhibition of GSK3beta.	3	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	4	5	8	9
Because insulin is reported to negatively regulate GSK-3beta activity , we propose that STZ induced lack of insulin contributes to the resulting overexpression and activation of GSK-3beta in the early stages of experimental diabetes .	Because insulin is reported to negatively regulate GSK-3beta activity, we propose that STZ induced lack of insulin contributes to the resulting overexpression and activation of GSK-3beta in the early stages of experimental diabetes.	1	8	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	1	2	7	8
The fact that HG and insulin imposed opposite effects on GSK3beta activity ( HG activates GSK3beta while insulin inhibits GSK3beta ; XREF_FIG , panels 2 and 4 ) prompted us to examine whether insulin signaling had any effect on HG induced degradation of IRS1 .	The fact that HG and insulin imposed opposite effects on GSK3beta activity (HG activates GSK3beta while insulin inhibits GSK3beta; XREF_FIG, panels 2 and 4) prompted us to examine whether insulin signaling had any effect on HG induced degradation of IRS1.	17	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	17	18	19	20
Taken together , it may be concluded that the insulin treatment does not inhibit GSK3beta activity so much as those had been thought .	Taken together, it may be concluded that the insulin treatment does not inhibit GSK3beta activity so much as those had been thought.	9	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	9	10	14	15
GSK-3beta ( XREF_FIG , XREF_FIG , XREF_FIG ) activity is downregulated by either insulin or insulin growth factor 1 ( IGF-1 ) because it is downstream event of the insulin signaling pathway .	GSK-3beta (XREF_FIG, XREF_FIG, XREF_FIG) activity is downregulated by either insulin or insulin growth factor 1 (IGF-1) because it is downstream event of the insulin signaling pathway.	0	20	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	13	14	0	1
Both insulin and IGF and Wnt signalling negatively regulate the activity of GSK3beta [ 39 ] , expression of which was significantly up-regulated in cases with a high neuronal DDR .	Both insulin and IGF and Wnt signalling negatively regulate the activity of GSK3beta [39], expression of which was significantly up-regulated in cases with a high neuronal DDR.	0	13	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	1	2	12	13
Given that insulin inactivates GSK3beta by a PI3K and Akt dependent pathway , we used chick atrial myocytes to determine the effect of inhibition of GSK3beta on insulin regulation of SREBP-1 levels and GIRK4 expression .	Given that insulin inactivates GSK3beta by a PI3K and Akt dependent pathway, we used chick atrial myocytes to determine the effect of inhibition of GSK3beta on insulin regulation of SREBP-1 levels and GIRK4 expression.	2	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	2	3	4	5
Insulin and TDZD-8 ( 4-benzyl-2-methyl-1 ,2,4-thiadiazolidine-3 ,5-dione ) are inhibitors of GSK-3beta that have been shown to possess organ-protective effects in inflammatory mediated organ injury models .	Insulin and TDZD-8 (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione) are inhibitors of GSK-3beta that have been shown to possess organ-protective effects in inflammatory mediated organ injury models.	0	12	are inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	GSK-3beta	GSK-3beta	GSK-3beta	0	1	11	12
Insulin also acts via stimulation of Akt and PKB to inactivate GSK-3beta via Ser9 phosphorylation , resulting in a long lasting depression of AMPAR mediated synaptic transmission , which in turn occludes low frequency induced LTD [ XREF_BIBR ] .	Insulin also acts via stimulation of Akt and PKB to inactivate GSK-3beta via Ser9 phosphorylation, resulting in a long lasting depression of AMPAR mediated synaptic transmission, which in turn occludes low frequency induced LTD [XREF_BIBR].	0	14	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	GSK-3beta	GSK-3beta	GSK-3beta	0	1	11	12
Insulin signaling can inactivate GSK-3beta through the PI3K and Akt pathway ; hence , the low-insulin levels associated with diabetes can result in a reduction in the level of GSK-3beta phosphorylation and enhanced GSK-3beta activation .	Insulin signaling can inactivate GSK-3beta through the PI3K and Akt pathway; hence, the low-insulin levels associated with diabetes can result in a reduction in the level of GSK-3beta phosphorylation and enhanced GSK-3beta activation.	0	5	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	GSK-3beta	GSK-3beta	GSK-3beta	0	1	4	5
Silencing of IKKbeta had no effect on basal or insulin stimulated GSK3beta Ser 9 and prevented the TNF-alpha-induced increase in GSK3beta phosphorylation .	Silencing of IKKbeta had no effect on basal or insulin stimulated GSK3beta Ser 9 and prevented the TNF-alpha-induced increase in GSK3beta phosphorylation.	9	15	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	9	10	11	12
Moreover , we previously showed that insulin prevented neuronal IR/IGF-1R inactivation upon oxidative stress and , by inhibiting GSK-3beta ( via PI-3K and Akt activation ) , insulin stimulated the synthesis of proteins involved in neuronal antioxidant defence , glucose metabolism , and antiapoptotic mechanisms [ XREF_BIBR ] .	Moreover, we previously showed that insulin prevented neuronal IR/IGF-1R inactivation upon oxidative stress and, by inhibiting GSK-3beta (via PI-3K and Akt activation), insulin stimulated the synthesis of proteins involved in neuronal antioxidant defence, glucose metabolism, and antiapoptotic mechanisms [XREF_BIBR].	17	29	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	27	28	18	19
Glycogen synthase is activated when insulin signaling turns on and inhibits GSK3beta .	Glycogen synthase is activated when insulin signaling turns on and inhibits GSK3beta.	5	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	5	6	11	12
In addition , insulin deactivates GSK-3beta through PI3K-Akt signaling pathway , resulting in cyclin D1 nuclear accumulation ; therefore , insulin utilizes cyclin D1-CDK4 machinery to regulate glucose homeostasis independent of their function in cell cycle regulation .	In addition, insulin deactivates GSK-3beta through PI3K-Akt signaling pathway, resulting in cyclin D1 nuclear accumulation; therefore, insulin utilizes cyclin D1-CDK4 machinery to regulate glucose homeostasis independent of their function in cell cycle regulation.	3	6	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	3	4	5	6
Further , GSK-3beta , a prime enzyme responsible for pathological phosphorylation of tau can be inactivated by insulin [ XREF_BIBR ] .	Further, GSK-3beta, a prime enzyme responsible for pathological phosphorylation of tau can be inactivated by insulin [XREF_BIBR].	2	19	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	17	18	2	3
GSK-3beta is a downstream negative regulator of the insulin response and is inhibited by insulin signaling [ XREF_BIBR , XREF_BIBR ] .	GSK-3beta is a downstream negative regulator of the insulin response and is inhibited by insulin signaling [XREF_BIBR, XREF_BIBR].	0	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	14	15	0	1
On the other hand , the activation of the insulin pathway also inhibits GSK3beta activity and thereby increases Myc stability ( see below ) .	On the other hand, the activation of the insulin pathway also inhibits GSK3beta activity and thereby increases Myc stability (see below).	9	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	9	10	13	14
Of relevance to diabetes , GSK3beta is inhibited by insulin signaling through the PI3 kinase pathway [ XREF_BIBR ] .	Of relevance to diabetes, GSK3beta is inhibited by insulin signaling through the PI3 kinase pathway [XREF_BIBR].	5	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	9	10	5	6
Both fasting and fed insulin levels were significantly reduced in mice lacking one allele of Gsk-3beta , thus indicating that genetic deficiency of Gsk-3beta activity improves insulin sensitivity .	Both fasting and fed insulin levels were significantly reduced in mice lacking one allele of Gsk-3beta, thus indicating that genetic deficiency of Gsk-3beta activity improves insulin sensitivity.	4	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin levels	insulin	Gsk-3beta	Gsk-3beta	gsk-3beta	4	5	15	16
Because the amount of phospho-Tyr216 can serve well as a substitute for the kinase activity , we used it to evaluate the insulin dependent inhibition of GSK3beta in several cell lines .	Because the amount of phospho-Tyr216 can serve well as a substitute for the kinase activity, we used it to evaluate the insulin dependent inhibition of GSK3beta in several cell lines.	22	27	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	22	23	26	27
Given that insulin and IGF1 can inhibit GSK3B activity through PI3K and Akt pathway [ XREF_BIBR , XREF_BIBR ] , we hypothesized that insulin and IGF1 might enhance IL-17-induced expression of inflammatory chemokines and cytokines through a GSK3B dependent mechanism , which can be inhibited by melatonin .	Given that insulin and IGF1 can inhibit GSK3B activity through PI3K and Akt pathway [XREF_BIBR, XREF_BIBR], we hypothesized that insulin and IGF1 might enhance IL-17-induced expression of inflammatory chemokines and cytokines through a GSK3B dependent mechanism, which can be inhibited by melatonin.	2	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3B	GSK3B	GSK3B	2	3	7	8
The insulin treatment decreased the GSK3beta kinase activity by 27 % , which was fairly consistent with the phospho-Tyr216 levels detected by the Phos-tag technique .	The insulin treatment decreased the GSK3beta kinase activity by 27%, which was fairly consistent with the phospho-Tyr216 levels detected by the Phos-tag technique.	1	7	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	1	2	5	6
Therefore , insulin does not completely block GSK-3beta activity , as LiCl can further increase protein expression of Mfn-2 and COX IV ( XREF_FIG ) .	Therefore, insulin does not completely block GSK-3beta activity, as LiCl can further increase protein expression of Mfn-2 and COX IV (XREF_FIG).	2	8	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	2	3	7	8
XREF_BIBR Since GSK3beta can be suppressed by insulin and some other activators of the PI3K signaling pathway , this intriguing finding suggests that GSK3beta phosphorylation on PTEN is likely to be involved in the negative feedback loop of the PI3K signaling pathway .	XREF_BIBR Since GSK3beta can be suppressed by insulin and some other activators of the PI3K signaling pathway, this intriguing finding suggests that GSK3beta phosphorylation on PTEN is likely to be involved in the negative feedback loop of the PI3K signaling pathway.	2	11	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	7	8	2	3
Glucose starvation conferred about a fourfold enhancement of insulin stimulated Akt-Thr308 and a twofold enhancement of GSK3beta at both insulin concentrations .	Glucose starvation conferred about a fourfold enhancement of insulin stimulated Akt-Thr308 and a twofold enhancement of GSK3beta at both insulin concentrations.	6	17	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	8	9	16	17
Our dynein centrosome accumulation data suggest a model in which insulin signaling inactivates GSK-3beta at or near the plasma membrane , creating an environment that favors dynein dephosphorylation .	Our dynein centrosome accumulation data suggest a model in which insulin signaling inactivates GSK-3beta at or near the plasma membrane, creating an environment that favors dynein dephosphorylation.	10	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	10	11	13	14
GSK3B is negatively regulated by insulin and its inhibition is associated to increased insulin sensitivity .	GSK3B is negatively regulated by insulin and its inhibition is associated to increased insulin sensitivity.	0	6	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	GSK3B	GSK3B	GSK3B	5	6	0	1
p-IkappaBalpha , the downstream target of canonical IKK activation , was more strongly inhibited by IKKbeta specific or combinatory knockdowns in the cytoplasmic or nuclear fraction .	p-IkappaBalpha, the downstream target of canonical IKK activation, was more strongly inhibited by IKKbeta specific or combinatory knockdowns in the cytoplasmic or nuclear fraction.	0	19	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	p-IkappaBalpha	p-IkappaBalpha	p-IkappaBalpha	15	16	0	1
BAFF-R can induce canonical NF-kappaB activation through IKKbeta dependent degradation of IkappaBalpha .	BAFF-R can induce canonical NF-kappaB activation through IKKbeta dependent degradation of IkappaBalpha.	7	12	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	7	8	11	12
The activation and nuclear translocation of NF-kappaB requires phosphorylation , ubiquitination and proteolytic degradation of IkappaBalpha by IKKbeta .	The activation and nuclear translocation of NF-kappaB requires phosphorylation, ubiquitination and proteolytic degradation of IkappaBalpha by IKKbeta.	7	18	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	17	18	15	16
IkappaB kinase beta ( IKKbeta ) initiates the degradation of IkappaB-alpha , and thus liberates NFkappaB resulting in a higher gene transcription of , for example , iNOS 97 [ XREF_FIG ] .	IkappaB kinase beta (IKKbeta) initiates the degradation of IkappaB-alpha, and thus liberates NFkappaB resulting in a higher gene transcription of, for example, iNOS 97 [XREF_FIG].	2	11	initiates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	4	5	10	11
Induction of NF-kappaB via the alternate pathway is accompanied by IkappaB kinase beta ( IKKbeta ) phosphorylation , IkappaBalpha phosphorylation , and IkappaBalpha degradation , and inhibition of IKKbeta blocked IkappaBalpha degradation .	Induction of NF-kappaB via the alternate pathway is accompanied by IkappaB kinase beta (IKKbeta) phosphorylation, IkappaBalpha phosphorylation, and IkappaBalpha degradation, and inhibition of IKKbeta blocked IkappaBalpha degradation.	26	31	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	28	29	30	31
Upon stimulation of cell surface or intracellular receptors , or DNA damage , IkappaB-alpha is degraded by UPS after phosphorylation by IKKbeta ( IkappaB kinase beta ) , associated with the kinase IKKalpha , and the regulatory protein IKKgamma ( also named NEMO for NF-kappaB essential modulator ) in the IKK complex .	Upon stimulation of cell surface or intracellular receptors, or DNA damage, IkappaB-alpha is degraded by UPS after phosphorylation by IKKbeta (IkappaB kinase beta), associated with the kinase IKKalpha, and the regulatory protein IKKgamma (also named NEMO for NF-kappaB essential modulator) in the IKK complex.	13	38	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	21	22	13	14
We showed that pharmacological inhibition of IKKbeta activity using IMD-0354 during unloading blocked IkappaBalpha degradation .	We showed that pharmacological inhibition of IKKbeta activity using IMD-0354 during unloading blocked IkappaBalpha degradation.	6	14	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	6	7	13	14
Canonical NF-kappaB signaling is regarded to be strictly dependent on IKKbeta mediated degradation of IkappaBalpha XREF_BIBR .	Canonical NF-kappaB signaling is regarded to be strictly dependent on IKKbeta mediated degradation of IkappaBalpha XREF_BIBR.	8	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	10	11	14	15
It has been shown that IKKbeta and IKK2 mediated degradation of IkappaBalpha and NF-kappaB activation is induced by a number of pro inflammatory stimuli including CS , lipopolysaccharide ( LPS ) , tumor necrosis factor ( TNF )-alpha and interleukin ( IL )-1beta [ XREF_BIBR - XREF_BIBR ] .	It has been shown that IKKbeta and IKK2 mediated degradation of IkappaBalpha and NF-kappaB activation is induced by a number of pro inflammatory stimuli including CS, lipopolysaccharide (LPS), tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta [XREF_BIBR - XREF_BIBR].	5	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKK2	IKK2	IKK2	IkappaBalpha	IkappaBalpha	IkappaBalpha	7	8	11	12
Without PP2Ac deactivation , however , almost total dephosphorylation of IKKbeta would occur , preventing relevant IkappaBalpha degradation .	Without PP2Ac deactivation, however, almost total dephosphorylation of IKKbeta would occur, preventing relevant IkappaBalpha degradation.	8	17	preventing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	dephosphorylation of IKKbeta	ikkbeta	IkappaBalpha	IkappaBalpha	ikappabalpha	10	11	16	17
However , CA treatment significantly decreased the phosphorylation levels of IKKbeta and IkappaB-alpha , and blocked the IkappaB-alpha degradation .	However, CA treatment significantly decreased the phosphorylation levels of IKKbeta and IkappaB-alpha, and blocked the IkappaB-alpha degradation.	2	18	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	CA treatment significantly decreased the phosphorylation levels of IKKbeta	ikkbeta	IkappaB-alpha	IkappaB-alpha	ikappab-alpha	10	11	17	18
More recently , it was shown that the same developmental signals can also activate the canonical RelA : p50 NF-kappaB complexes not through IKKbeta dependent degradation of IkappaBalpha , but rather via the degradation of a fourth IkappaB activity , termed IkappaBdelta ( XREF_FIG ) .	More recently, it was shown that the same developmental signals can also activate the canonical RelA : p50 NF-kappaB complexes not through IKKbeta dependent degradation of IkappaBalpha, but rather via the degradation of a fourth IkappaB activity, termed IkappaBdelta (XREF_FIG).	23	28	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	23	24	27	28
In contrast , over-expression of dominant negative IKK2 and pre-treatment of cells with MG132 proteasome inhibitor totally blocked IkappaBalpha removal .	In contrast, over-expression of dominant negative IKK2 and pre-treatment of cells with MG132 proteasome inhibitor totally blocked IkappaBalpha removal.	3	19	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKK2	over-expression of dominant negative IKK2	ikk2	IkappaBalpha	IkappaBalpha	ikappabalpha	7	8	18	19
We next examined whether knockdown of BiP affects IKKbeta mediated degradation of IkappaBalpha .	We next examined whether knockdown of BiP affects IKKbeta mediated degradation of IkappaBalpha.	7	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	8	9	12	13
IkappaBalpha is rapidly degraded upon phosphorylation by IKKbeta , thus it is an inverse indicator of IKKbeta activity .	IkappaBalpha is rapidly degraded upon phosphorylation by IKKbeta, thus it is an inverse indicator of IKKbeta activity.	0	8	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	7	8	0	1
Although the IkappaB-alpha gene is a well-known target of p50 and p65 , the IkappaB-alpha protein is normally degraded upon activation of the classical pathway following phosphorylation by IKK-beta , leading to an autofeedback loop ( Karin and Ben-Neriah , 2000 ) .	Although the IkappaB-alpha gene is a well-known target of p50 and p65, the IkappaB-alpha protein is normally degraded upon activation of the classical pathway following phosphorylation by IKK-beta, leading to an autofeedback loop (Karin and Ben-Neriah, 2000).	14	29	degraded	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	IKK-beta	IKK-beta	IKK-beta	IkappaB-alpha protein	IkappaB-alpha protein	IkappaB-alpha protein	28	29	14	16
IKKbeta phosphorylation induces complete IkappaBalpha degradation , followed by its resynthesis yielding an overshoot after about 90 min .	IKKbeta phosphorylation induces complete IkappaBalpha degradation, followed by its resynthesis yielding an overshoot after about 90 min.	0	5	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta phosphorylation	ikkbeta	IkappaBalpha	IkappaBalpha	ikappabalpha	0	1	4	5
In these cells , IkappaBalphaAA was resistant to Adriamycin induced degradation , further confirmed that Adriamycin induced NF-kappaB activation is via by IKKbeta mediated IkappaBalpha degradation ( XREF_SUPPLEMENTARY ) .	In these cells, IkappaBalphaAA was resistant to Adriamycin induced degradation, further confirmed that Adriamycin induced NF-kappaB activation is via by IKKbeta mediated IkappaBalpha degradation (XREF_SUPPLEMENTARY).	16	25	mediated	Positive_early_activation	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	22	23	24	25
We show here that IL-3 induces a SFK- and Ca 2+ -dependent activation of the inhibitor of kappaB kinases 2 ( IKK2 ) which results in mast cell proliferation and survival but does not induce IkappaBalpha degradation and NFkappaB activation .	We show here that IL-3 induces a SFK- and Ca 2+ -dependent activation of the inhibitor of kappaB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IkappaBalpha degradation and NFkappaB activation.	7	36	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKK2	IKK2	IKK2	IkappaBalpha	IkappaBalpha	IkappaBalpha	21	22	35	36
IKKB activation causes the degradation of IkBa protein , and , hence , a decrease in IkBa protein content is often used as a marker of IKKB activation .	IKKB activation causes the degradation of IkBa protein, and, hence, a decrease in IkBa protein content is often used as a marker of IKKB activation.	0	7	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKB	IKKB	IKKB	IkBa	IkBa	IkBa	0	1	6	7
Then , auto-activated TAK1 phosphorylates and activates IKKbeta , facilitating IKKbeta mediated IkappaBalpha degradation and downstream NF-kappaB activation XREF_BIBR , XREF_BIBR .	Then, auto-activated TAK1 phosphorylates and activates IKKbeta, facilitating IKKbeta mediated IkappaBalpha degradation and downstream NF-kappaB activation XREF_BIBR, XREF_BIBR.	10	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	10	11	12	13
Concordantly , miR-500 overexpression led to elevated phosphorylation of IKKbeta and reduced IkappaBalpha , which was abrogated by the antagomiR-500 .	Concordantly, miR-500 overexpression led to elevated phosphorylation of IKKbeta and reduced IkappaBalpha, which was abrogated by the antagomiR-500.	2	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	miR-500 overexpression led to elevated phosphorylation of IKKbeta	ikkbeta	IkappaBalpha	IkappaBalpha	ikappabalpha	9	10	12	13
IKKbeta mediated IkappaBalpha degradation is regarded as the central step in canonical NF-kappaB activation in T cells XREF_BIBR .	IKKbeta mediated IkappaBalpha degradation is regarded as the central step in canonical NF-kappaB activation in T cells XREF_BIBR.	0	3	mediated	Positive_early_activation	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	0	1	2	3
In our further study , we showed that HBV Pol suppressed the phosphorylation of IKKalpha and IKKbeta , blocked IkappaBalpha degradation and inhibited NF-kappaB activation via interaction with Hsp90beta .	In our further study, we showed that HBV Pol suppressed the phosphorylation of IKKalpha and IKKbeta, blocked IkappaBalpha degradation and inhibited NF-kappaB activation via interaction with Hsp90beta.	9	20	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	Pol suppressed the phosphorylation of IKKalpha and IKKbeta	ikkbeta	IkappaBalpha	IkappaBalpha	ikappabalpha	16	17	19	20
This is consistent with the experimental observation that co-expression of B14 and IKKbeta inhibits the IKKbeta trans autoactivation induced by overexpression ( XREF_FIG A ) .	This is consistent with the experimental observation that co-expression of B14 and IKKbeta inhibits the IKKbeta trans autoactivation induced by overexpression (XREF_FIG A).	8	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	co-expression of B14 and IKKbeta	ikkbeta	IKKbeta	IKKbeta	ikkbeta	12	13	15	16
In HeLa cells , PPM1B was shown to dephosphorylate serine 177 and 181 in P-IKKbeta , thereby reducing the activity of IKKbeta .	In HeLa cells, PPM1B was shown to dephosphorylate serine 177 and 181 in P-IKKbeta, thereby reducing the activity of IKKbeta.	8	22	reducing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P-IKKbeta	dephosphorylate serine 177 and 181 in P-IKKbeta	p-ikkbeta	IKKbeta	IKKbeta	ikkbeta	14	15	21	22
Ratio of the wound closure at 24hours demonstrated that although the loss of either IKKalpha or IKKbeta impaired wound healing , loss of IKKbeta had a more pronounced effect .	Ratio of the wound closure at 24hours demonstrated that although the loss of either IKKalpha or IKKbeta impaired wound healing, loss of IKKbeta had a more pronounced effect.	11	24	loss	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	IKKbeta	loss of IKKbeta	ikkbeta	IKKbeta	IKKbeta	ikkbeta	23	24	16	17
For example , dephosphorylation of IKKbeta by protein phosphatase 1 , 2A or 2Cbeta decreases IKKbeta activity .	For example, dephosphorylation of IKKbeta by protein phosphatase 1, 2A or 2Cbeta decreases IKKbeta activity.	3	16	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	dephosphorylation of IKKbeta by protein phosphatase 1, 2A	ikkbeta	IKKbeta	IKKbeta	ikkbeta	5	6	15	16
Expression of IKBKE induced more significant degradation of FOXO3a than FOXO3a-S644A ( XREF_FIG ) .	Expression of IKBKE induced more significant degradation of FOXO3a than FOXO3a-S644A (XREF_FIG).	0	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKBKE	Expression of IKBKE	ikbke	FOXO3a	FOXO3a	foxo3a	2	3	8	9
Moreover , IKBKE induced FOXO3a degradation was largely abrogated by treatment with proteasome inhibitor MG132 ( XREF_FIG ) .	Moreover, IKBKE induced FOXO3a degradation was largely abrogated by treatment with proteasome inhibitor MG132 (XREF_FIG).	2	5	induced	Positive_early_activation	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	2	3	4	5
Together , these findings suggest that IKBKE inhibition of FOXO3a activity is independent of Akt .	Together, these findings suggest that IKBKE inhibition of FOXO3a activity is independent of Akt.	6	10	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	6	7	9	10
In the present study , we show that IKBKE inhibits FOXO3a and FOXO3a-A3 , an Akt-nonphosphorylatable form , function by direct phosphorylation of FOXO3a .	In the present study, we show that IKBKE inhibits FOXO3a and FOXO3a-A3, an Akt-nonphosphorylatable form, function by direct phosphorylation of FOXO3a.	8	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	8	9	10	11
As a result , IKBKE induces FOXO3a degradation and nuclear cytoplasmic translocation leading to abrogation of FOXO3a cellular function .	As a result, IKBKE induces FOXO3a degradation and nuclear cytoplasmic translocation leading to abrogation of FOXO3a cellular function.	4	7	induces	Positive_activation_token_1_verb	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	4	5	6	7
Based on these results , we conclude that IKBKE induces FOXO3a protein degradation primarily via phosphorylation of Ser644 .	Based on these results, we conclude that IKBKE induces FOXO3a protein degradation primarily via phosphorylation of Ser644.	8	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	8	9	10	11
To further examine the effect of IKBKE on FOXO3a expression , we transfected H1299 cells with IKBKE and found that ectopic expression of IKBKE reduced FOXO3a protein but not mRNA level in a dose dependent manner ( XREF_FIG ) .	To further examine the effect of IKBKE on FOXO3a expression, we transfected H1299 cells with IKBKE and found that ectopic expression of IKBKE reduced FOXO3a protein but not mRNA level in a dose dependent manner (XREF_FIG).	21	26	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKBKE	expression of IKBKE	ikbke	FOXO3a	FOXO3a	foxo3a	23	24	25	26
These findings suggest that IKBKE represses FOXO3a primarily through direct phosphorylation of Ser644 and that phosphorylation of FOXO3a by IKBKE-Akt axis has a less important role .	These findings suggest that IKBKE represses FOXO3a primarily through direct phosphorylation of Ser644 and that phosphorylation of FOXO3a by IKBKE-Akt axis has a less important role.	4	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	4	5	6	7
As a result , FOXO3a cellular function was inhibited by IKBKE .	As a result, FOXO3a cellular function was inhibited by IKBKE.	4	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	10	11	4	5
These data indicate that IKBKE inhibits FOXO3a largely through phosphorylation of Ser644 and , to a much less extent , through IKBKE activated Akt phosphorylation of Ser32 , Ser253 and Ser315 ( XREF_FIG ) .	These data indicate that IKBKE inhibits FOXO3a largely through phosphorylation of Ser644 and, to a much less extent, through IKBKE activated Akt phosphorylation of Ser32, Ser253 and Ser315 (XREF_FIG).	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	4	5	6	7
IKBKE inhibits cellular function of FOXO3a and FOXO3a-A3 but , to a much less extent , of FOXO3a-S644A .	IKBKE inhibits cellular function of FOXO3a and FOXO3a-A3 but, to a much less extent, of FOXO3a-S644A.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	0	1	5	6
Research revealed that IKBKE can inhibit the function of cell growth inhibitor FOXO3a in NSCLC and breast cancer cells through SerS644 phosphorylation .	Research revealed that IKBKE can inhibit the function of cell growth inhibitor FOXO3a in NSCLC and breast cancer cells through SerS644 phosphorylation.	3	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	3	4	12	13
Since IKBKE directly phosphorylates FOXO3a-S644 leading to FOXO3a nuclear cytoplasmic translocation and protein degradation , IKBKE could suppress FOXO3a cellular function via a Ser644 phosphorylation dependent manner .	Since IKBKE directly phosphorylates FOXO3a-S644 leading to FOXO3a nuclear cytoplasmic translocation and protein degradation, IKBKE could suppress FOXO3a cellular function via a Ser644 phosphorylation dependent manner.	15	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	15	16	18	19
Based on our findings , we propose a model IKBKE dependent repression of FOXO3a that promotes cell survival , growth and tumorigenesis .	Based on our findings, we propose a model IKBKE dependent repression of FOXO3a that promotes cell survival, growth and tumorigenesis.	9	14	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	9	10	13	14
IRAKM prevents the dissociation of IRAK1 and IRAK4 from MyD88 .	IRAKM prevents the dissociation of IRAK1 and IRAK4 from MyD88.	0	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAKM	IRAKM	IRAKM	IRAK4	IRAK4	IRAK4	0	1	7	8
IRAK-M prevents IRAK and IRAK-4 dissociation from MyD88 and TRAF6 complex formation XREF_BIBR ; Triad3A interacts with TIR domains of TLRs , TRIF , TIRAP and RIP1 XREF_BIBR ; and SARM blocks gene induction downstream of TRIF XREF_BIBR .	IRAK-M prevents IRAK and IRAK-4 dissociation from MyD88 and TRAF6 complex formation XREF_BIBR; Triad3A interacts with TIR domains of TLRs, TRIF, TIRAP and RIP1 XREF_BIBR; and SARM blocks gene induction downstream of TRIF XREF_BIBR.	0	5	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK-M	IRAK-M	IRAK-M	IRAK-4	IRAK-4	IRAK-4	0	1	4	5
It is noticed that several negative regulators such as SOC1 ( inhibitor of TIRAP ( MAL ) and p56 ) , IRAK3 ( inhibitor of IRAK1 and IRAK4 ) and A20 ( inhibitor of TRAF6 ) are significantly expressed at this stage , reflecting the inhibitory effect of anti-inflammation .	It is noticed that several negative regulators such as SOC1 (inhibitor of TIRAP (MAL) and p56), IRAK3 (inhibitor of IRAK1 and IRAK4) and A20 (inhibitor of TRAF6) are significantly expressed at this stage, reflecting the inhibitory effect of anti-inflammation.	6	28	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	IRAK3	IRAK3	IRAK3	IRAK4	IRAK4	IRAK4	21	22	27	28
IRAK-M inhibits the release of IRAK1 and IRAK4 from MyD88 .	IRAK-M inhibits the release of IRAK1 and IRAK4 from MyD88.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK-M	IRAK-M	IRAK-M	IRAK4	IRAK4	IRAK4	0	1	7	8
Among these inhibitors , A20 suppresses TLR signaling by triggering TRAF-6 degradation [ XREF_BIBR ] , while IRAK-M inhibits the dissociation of IRAK-1 and IRAK-4 from the TLR/IRAK-1/IRAK-4 signaling complex [ XREF_BIBR ] .	Among these inhibitors, A20 suppresses TLR signaling by triggering TRAF-6 degradation [XREF_BIBR], while IRAK-M inhibits the dissociation of IRAK-1 and IRAK-4 from the TLR/IRAK-1/IRAK-4 signaling complex [XREF_BIBR].	17	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK-M	IRAK-M	IRAK-M	IRAK-4	IRAK-4	IRAK-4	17	18	24	25
IRAK-M mediates LPS tolerance by inhibiting the association of IRAK-1 and IRAK-4 with TRAF6 .	IRAK-M mediates LPS tolerance by inhibiting the association of IRAK-1 and IRAK-4 with TRAF6.	0	12	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IRAK-M	IRAK-M	IRAK-M	IRAK-4	IRAK-4	IRAK-4	0	1	11	12
IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes .	IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes.	0	7	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK-M	IRAK-M	IRAK-M	IRAK-4	IRAK-4	IRAK-4	0	1	6	7
IRAK-M negatively regulates TLR signaling by preventing the dissociation of IRAK1 and IRAK4 from MyD88 and the formation of IRAK1-TRAF6 complexes , as revealed by co-transfection experiments into heterologous cells followed by co-immunoprecipitation [ XREF_BIBR ] .	IRAK-M negatively regulates TLR signaling by preventing the dissociation of IRAK1 and IRAK4 from MyD88 and the formation of IRAK1-TRAF6 complexes, as revealed by co-transfection experiments into heterologous cells followed by co-immunoprecipitation [XREF_BIBR].	0	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK-M	IRAK-M	IRAK-M	IRAK4	IRAK4	IRAK4	0	1	12	13
It has been suggested that IRAK-M may prevent dissociation of IRAK-1 and IRAK-4 from their complex with the adaptor protein MyD88 , thus preventing formation of IRAK-1 and TNF receptor associated factor 6 ( TRAF6 ) complexes and inhibiting downstream NF-kappaB and activator protein ( AP ) -1 signaling [ XREF_BIBR ] .	It has been suggested that IRAK-M may prevent dissociation of IRAK-1 and IRAK-4 from their complex with the adaptor protein MyD88, thus preventing formation of IRAK-1 and TNF receptor associated factor 6 (TRAF6) complexes and inhibiting downstream NF-kappaB and activator protein (AP) -1 signaling [XREF_BIBR].	5	13	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK-M	IRAK-M	IRAK-M	IRAK-4	IRAK-4	IRAK-4	5	6	12	13
In contrast , IRAK-M , which lacks the kinase activity , has been shown to prevent dissociation of IRAK1 and IRAK4 from receptor complex , thereby negatively regulating the TLR signaling [ XREF_BIBR , XREF_BIBR ] .	In contrast, IRAK-M, which lacks the kinase activity, has been shown to prevent dissociation of IRAK1 and IRAK4 from receptor complex, thereby negatively regulating the TLR signaling [XREF_BIBR, XREF_BIBR].	3	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK-M	IRAK-M	IRAK-M	IRAK4	IRAK4	IRAK4	3	4	20	21
IRAK-M inhibits MyD88 dependent TLR signaling by preventing dissociation of IRAK1 and IRAK4 from MyD88 and formation of the IRAK1 and TRAF6 complex XREF_BIBR .	IRAK-M inhibits MyD88 dependent TLR signaling by preventing dissociation of IRAK1 and IRAK4 from MyD88 and formation of the IRAK1 and TRAF6 complex XREF_BIBR.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK-M	IRAK-M	IRAK-M	IRAK4	IRAK4	IRAK4	0	1	12	13
IRAK3 negatively regulates signaling by preventing dissociation of IRAK1 and IRAK4 from MyD88 and formation of IRAK - TNF receptor associated factor-6 ( TRAF6 ) complexes .	IRAK3 negatively regulates signaling by preventing dissociation of IRAK1 and IRAK4 from MyD88 and formation of IRAK - TNF receptor associated factor-6 (TRAF6) complexes.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK3	IRAK3	IRAK3	IRAK4	IRAK4	IRAK4	0	1	10	11
IRAK-M disrupts the interactions of IRAK-1 and IRAK-4 from the TLR signaling domain , resulting in inhibition of the signal-transduction pathways .	IRAK-M disrupts the interactions of IRAK-1 and IRAK-4 from the TLR signaling domain, resulting in inhibition of the signal-transduction pathways.	0	8	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK-M	IRAK-M	IRAK-M	IRAK-4	IRAK-4	IRAK-4	0	1	7	8
In contrast to IRAK1 and IRAK4 that are positive regulators of TLR7/9 signaling pathway , IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling by preventing the dissociation of IRAK1 and IRAK4 from MyD88 and the formation of IRAK1-TRAF6 complexes .	In contrast to IRAK1 and IRAK4 that are positive regulators of TLR7/9 signaling pathway, IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling by preventing the dissociation of IRAK1 and IRAK4 from MyD88 and the formation of IRAK1-TRAF6 complexes.	15	34	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRAK-M	IRAK-M	IRAK-M	IRAK4	IRAK4	IRAK4	15	16	33	34
At this moment , it is still not clear which E3 ligase is responsible for IKKbeta mediated degradation of FOXO3a .	At this moment, it is still not clear which E3 ligase is responsible for IKKbeta mediated degradation of FOXO3a.	13	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	FOXO3a	FOXO3a	FOXO3a	15	16	19	20
To confirm if over-expression of IKKbeta induces FOXO3 protein degradation , we showed that co-transfection of FOXO3 with IKKbeta into 293T cells resulted in reduction of the protein level of FOXO3 and this reducing effect could be overridden by treating cells with various proteasome inhibitors ( XREF_SUPPLEMENTARY ) , suggesting that IKKbeta mediates proteasomal degradation of FOXO3 protein .	To confirm if over-expression of IKKbeta induces FOXO3 protein degradation, we showed that co-transfection of FOXO3 with IKKbeta into 293T cells resulted in reduction of the protein level of FOXO3 and this reducing effect could be overridden by treating cells with various proteasome inhibitors (XREF_SUPPLEMENTARY), suggesting that IKKbeta mediates proteasomal degradation of FOXO3 protein.	3	9	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	over-expression of IKKbeta	ikkbeta	FOXO3	FOXO3	foxo3	5	6	7	8
At this moment , it is still not yet clear which E3 ligase responds to IKKbeta mediated degradation of FOXO3a .	At this moment, it is still not yet clear which E3 ligase responds to IKKbeta mediated degradation of FOXO3a.	13	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	FOXO3a	FOXO3a	FOXO3a	15	16	19	20
It was suggested that FOXO3 could antagonize NF-kappaB activity , while IKK-beta was demonstrated to inactivate FOXO3 , suggesting a cross-talk between the two pathways .	It was suggested that FOXO3 could antagonize NF-kappaB activity, while IKK-beta was demonstrated to inactivate FOXO3, suggesting a cross-talk between the two pathways.	11	17	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKK-beta	IKK-beta	IKK-beta	FOXO3	FOXO3	FOXO3	11	12	16	17
On the other hand , IKK-beta ( IkappaB kinase ) appears to inhibit FOXO3 action after cisplatin treatment and promotes chemoresistance in MDA-MB-231 cells .	On the other hand, IKK-beta (IkappaB kinase) appears to inhibit FOXO3 action after cisplatin treatment and promotes chemoresistance in MDA-MB-231 cells.	5	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKK-beta	IKK-beta	IKK-beta	FOXO3	FOXO3	FOXO3	5	6	13	14
IKKbeta triggers the degradation of FOXO3a and TSC1 , thereby exerting anti-apoptosis effects [ XREF_BIBR ] and promoting angiogenesis [ XREF_BIBR ] .	IKKbeta triggers the degradation of FOXO3a and TSC1, thereby exerting anti-apoptosis effects [XREF_BIBR] and promoting angiogenesis [XREF_BIBR].	0	7	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	FOXO3a	FOXO3a	FOXO3a	0	1	5	6
In addition , we showed that the IKKbeta inhibitor significantly repressed IKKbeta activity in phosphorylation of its cellular substrate IkappaB and overrode the IKKbeta mediated FOXO3 degradation in the treated cells ( XREF_SUPPLEMENTARY -C ) .	In addition, we showed that the IKKbeta inhibitor significantly repressed IKKbeta activity in phosphorylation of its cellular substrate IkappaB and overrode the IKKbeta mediated FOXO3 degradation in the treated cells (XREF_SUPPLEMENTARY -C).	21	26	mediated	Positive_early_activation	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	FOXO3	FOXO3	FOXO3	23	24	25	26
Therefore , inhibition of IKKbeta can increase Foxo3a anti-tumor function .	Therefore, inhibition of IKKbeta can increase Foxo3a anti-tumor function.	2	9	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	Foxo3a	Foxo3a	Foxo3a	4	5	7	8
Our previous study shows that IKK-beta activation phosphorylates the serine 644 residue in the FOXO3 protein and subsequently triggers faster protein degradation of FOXO3 via the proteasome mediated ubiquitination ( Ub ) mechanism , which results in the stimulation of human breast cancer cell proliferation in vitro and the development of breast tumor in vivo .	Our previous study shows that IKK-beta activation phosphorylates the serine 644 residue in the FOXO3 protein and subsequently triggers faster protein degradation of FOXO3 via the proteasome mediated ubiquitination (Ub) mechanism, which results in the stimulation of human breast cancer cell proliferation in vitro and the development of breast tumor in vivo.	5	26	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IKK-beta	IKK-beta	IKK-beta	FOXO3	FOXO3	FOXO3	5	6	23	24
IKKbeta activity in v-Abl transformed cells inactivates FoxO3a .	IKKbeta activity in v-Abl transformed cells inactivates FoxO3a.	0	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	FoxO3a	FoxO3a	FoxO3a	0	1	7	8
These observations indicated that up-regulation of mTOR and S6K1 activity via suppression of TSC1 by IKKbeta may contribute to diet- and obesity induced insulin resistance .	These observations indicated that up-regulation of mTOR and S6K1 activity via suppression of TSC1 by IKKbeta may contribute to diet- and obesity induced insulin resistance.	11	16	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	TSC1	TSC1	TSC1	15	16	13	14
TSC1 is also negatively regulated by IKK-beta , which physically interacts with and phophorylates TSC1 at its Ser487 and Ser511 residues in response to inflammatory pathway activation [ XREF_BIBR ] .	TSC1 is also negatively regulated by IKK-beta, which physically interacts with and phophorylates TSC1 at its Ser487 and Ser511 residues in response to inflammatory pathway activation [XREF_BIBR].	0	20	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	IKK-beta	IKK-beta, which physically interacts with and phophorylates TSC1 at its Ser487 and Ser511	ikk-beta	TSC1	TSC1	tsc1	6	7	0	1
Since IKKbeta can suppress TSC1 leading to mTORC1 activation XREF_BIBR , and LPS can activate IKKbeta directly XREF_BIBR , we asked whether LPS activates mTORC1 via IKKbeta .	Since IKKbeta can suppress TSC1 leading to mTORC1 activation XREF_BIBR, and LPS can activate IKKbeta directly XREF_BIBR, we asked whether LPS activates mTORC1 via IKKbeta.	1	5	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	TSC1	TSC1	TSC1	1	2	4	5
IKKbeta suppression of TSC1 function links the mTOR pathway with insulin resistance .	IKKbeta suppression of TSC1 function links the mTOR pathway with insulin resistance.	0	4	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	TSC1	TSC1	TSC1	0	1	3	4
IKKbeta , the crucial kinase of proinflammatory NFkappaB activation , inhibits TSC1 and thereby activates mTORC1 XREF_BIBR , XREF_BIBR .	IKKbeta, the crucial kinase of proinflammatory NFkappaB activation, inhibits TSC1 and thereby activates mTORC1 XREF_BIBR, XREF_BIBR.	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	TSC1	TSC1	TSC1	0	1	11	12
TNFalpha activated IKKbeta suppressed TSC1 and triggered the mTOR pathway [ XREF_BIBR , XREF_BIBR ] .	TNFalpha activated IKKbeta suppressed TSC1 and triggered the mTOR pathway [XREF_BIBR, XREF_BIBR].	2	6	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	TSC1	TSC1	TSC1	2	3	4	5
IKKbeta can phosphorylate and inactivate the tuberous sclerosis 1 ( TSC1 ) tumor suppressor complex [ XREF_BIBR ] that represses the serine/threonine kinase , the mTOR , leading to mTOR activation [ XREF_BIBR ] .	IKKbeta can phosphorylate and inactivate the tuberous sclerosis 1 (TSC1) tumor suppressor complex [XREF_BIBR] that represses the serine/threonine kinase, the mTOR, leading to mTOR activation [XREF_BIBR].	0	14	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	TSC1	TSC1	TSC1	0	1	10	11
Given that a major reported function of SHIP2 is to dampen PI3K and AKT signaling , and that aberrant PI3K and AKT signaling results in lymphatic dysfunction in both mouse XREF_BIBR - XREF_BIBR and humans XREF_BIBR , XREF_BIBR , we examined the effect of SHIP2 knockdown upon HGF- and VEGFC induced AKT activation in LEC .	Given that a major reported function of SHIP2 is to dampen PI3K and AKT signaling, and that aberrant PI3K and AKT signaling results in lymphatic dysfunction in both mouse XREF_BIBR - XREF_BIBR and humans XREF_BIBR, XREF_BIBR, we examined the effect of SHIP2 knockdown upon HGF- and VEGFC induced AKT activation in LEC.	44	52	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHIP2	SHIP2	SHIP2	AKT	AKT	AKT	44	45	51	52
Although loss of Ship2 is not sufficient to activate Akt , the absence of Ship2 allows for greater activity upon Akt stimulation XREF_BIBR , XREF_BIBR .	Although loss of Ship2 is not sufficient to activate Akt, the absence of Ship2 allows for greater activity upon Akt stimulation XREF_BIBR, XREF_BIBR.	1	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ship2	loss of Ship2	ship2	Akt	Akt	akt	3	4	9	10
Both SHIP1 and SHIP2 can negatively regulate the activity of Akt .	Both SHIP1 and SHIP2 can negatively regulate the activity of Akt.	1	11	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHIP2	SHIP2	SHIP2	Akt	Akt	Akt	3	4	10	11
Although SHIP2 expression resulted in suppression of interleukin-6-mediated mitogen activated protein kinase activation , expression of SHIP and SHIP2 in a PTEN-null myeloma line did not suppress Akt activity .	Although SHIP2 expression resulted in suppression of interleukin-6-mediated mitogen activated protein kinase activation, expression of SHIP and SHIP2 in a PTEN-null myeloma line did not suppress Akt activity.	14	28	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHIP2	expression of SHIP and SHIP2	ship2	Akt	Akt	akt	18	19	27	28
However , Ship2 knock down did not prevent ephrin-A1-dependent Akt inactivation ( XREF_FIG ) , suggesting that regulation of Ship2 activity by EphA2 is not critical for Akt inhibition .	However, Ship2 knock down did not prevent ephrin-A1-dependent Akt inactivation (XREF_FIG), suggesting that regulation of Ship2 activity by EphA2 is not critical for Akt inhibition.	2	10	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ship2	Ship2	Ship2	Akt	Akt	Akt	2	3	9	10
SHIP2 negatively regulates the PI3K and AKT pathway by hydrolysing phosphatidylinositol ( 3,4,5 )-trisphosphate ( PI ( 3,4,5 ) P 3 ) to phosphatidylinositol ( 3,4 )-bisphosphate ( PI ( 3,4 ) P 2 ) 12 , and overexpression of SHIP2 induces podocyte apoptosis 11 .	SHIP2 negatively regulates the PI3K and AKT pathway by hydrolysing phosphatidylinositol (3,4,5)-trisphosphate (PI (3,4,5) P 3) to phosphatidylinositol (3,4)-bisphosphate (PI (3,4) P 2) 12, and overexpression of SHIP2 induces podocyte apoptosis 11.	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHIP2	SHIP2	SHIP2	AKT	AKT	AKT	0	1	6	7
Moreover , overexpression of SHIP2 inactivated Akt , and upregulated p21 , p27 , and the pro apoptotic protein Bim .	Moreover, overexpression of SHIP2 inactivated Akt, and upregulated p21, p27, and the pro apoptotic protein Bim.	2	7	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHIP2	overexpression of SHIP2	ship2	Akt	Akt	akt	4	5	6	7
Reduction of SHIP-2 levels using antisense oligonucleotides increased PKB activity .	Reduction of SHIP-2 levels using antisense oligonucleotides increased PKB activity.	2	9	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHIP-2	SHIP-2 levels	ship-2	PKB	PKB	pkb	2	3	8	9
Why loss of SHIP2 would lead to increased AKT activation but increased apoptosis of LEC is unclear but may be explained by still greater increases in pro apoptotic ERK activation ( see Discussion ) .	Why loss of SHIP2 would lead to increased AKT activation but increased apoptosis of LEC is unclear but may be explained by still greater increases in pro apoptotic ERK activation (see Discussion).	1	9	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	SHIP2	loss of SHIP2	ship2	AKT	AKT	akt	3	4	8	9
We noted that Frk , Inpp4b , Inppl1 and Phlda3 all negatively regulate the PI3K and Akt pathway XREF_BIBR - XREF_BIBR .	We noted that Frk, Inpp4b, Inppl1 and Phlda3 all negatively regulate the PI3K and Akt pathway XREF_BIBR - XREF_BIBR.	3	18	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Inppl1	Inppl1	Inppl1	Akt	Akt	Akt	7	8	16	17
Also , in glioblastoma cells , overexpression of SHIP2 inhibits Akt activation and leads to cell cycle arrest [ XREF_BIBR ] .	Also, in glioblastoma cells, overexpression of SHIP2 inhibits Akt activation and leads to cell cycle arrest [XREF_BIBR].	6	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHIP2	overexpression of SHIP2	ship2	Akt	Akt	akt	8	9	10	11
In hepatocytes , overexpression of a dominant negative , inactive form of SHIP2 enhances AKT activation and reduces ROS generation and apoptosis induced by palmitate 13 .	In hepatocytes, overexpression of a dominant negative, inactive form of SHIP2 enhances AKT activation and reduces ROS generation and apoptosis induced by palmitate 13.	10	15	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHIP2	SHIP2	SHIP2	AKT	AKT	AKT	12	13	14	15
Our previous data revealed that overexpression of SHIP2 in podocytes reduces AKT activation and enhances apoptosis 11 , suggesting that increased expression of SHIP2 could contribute to increased apoptosis in CD2AP-/- podocytes .	Our previous data revealed that overexpression of SHIP2 in podocytes reduces AKT activation and enhances apoptosis 11, suggesting that increased expression of SHIP2 could contribute to increased apoptosis in CD2AP-/- podocytes.	5	12	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHIP2	overexpression of SHIP2	ship2	AKT	AKT	akt	7	8	11	12
In a recent study , we showed that IKK2 ( IKKbeta ) inhibits IRS-1 function through activation of S6K , which directly phosphorylates IRS-1 at multiple sites such as S312/307 and S270/265 in cells treated with TNF-alpha [ XREF_BIBR , XREF_BIBR ] .	In a recent study, we showed that IKK2 (IKKbeta) inhibits IRS-1 function through activation of S6K, which directly phosphorylates IRS-1 at multiple sites such as S312/307 and S270/265 in cells treated with TNF-alpha [XREF_BIBR, XREF_BIBR].	8	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKK2	IKK2	IKK2	IRS-1	IRS-1	IRS-1	8	9	13	14
IKKbeta may also inhibit insulin signalling intermediates downstream of IRS-1 at the level of PI3K ( phosphoinositide 3-kinase ) and Akt [ XREF_BIBR ] .	IKKbeta may also inhibit insulin signalling intermediates downstream of IRS-1 at the level of PI3K (phosphoinositide 3-kinase) and Akt [XREF_BIBR].	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IRS-1	IRS-1	IRS-1	0	1	9	10
The effectors of IR in HF diet induced inflammation are suggested to involve hyperactivation of stress sensitive Ser/Thr kinases , such as JNK and IKKbeta , which in turn inhibits insulin receptor and IRS1 axis .	The effectors of IR in HF diet induced inflammation are suggested to involve hyperactivation of stress sensitive Ser/Thr kinases, such as JNK and IKKbeta, which in turn inhibits insulin receptor and IRS1 axis.	13	34	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IRS1	IRS1	IRS1	24	25	33	34
MEK and ERK pathway mediates insulin promoted degradation of MKP-3 protein in liver cells .	MEK and ERK pathway mediates insulin promoted degradation of MKP-3 protein in liver cells.	4	10	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	MKP-3	MKP-3	MKP-3	5	6	9	10
Then , three classical insulin stimulated pathways , MEK and ERK , PI3K and Akt and mTOR/S6 were examined individually for their potential involvement in insulin promoted MKP-3 degradation by either constitutive activation of the pathways or blockade of the pathways .	Then, three classical insulin stimulated pathways, MEK and ERK, PI3K and Akt and mTOR/S6 were examined individually for their potential involvement in insulin promoted MKP-3 degradation by either constitutive activation of the pathways or blockade of the pathways.	2	28	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	MKP-3	MKP-3	MKP-3	4	5	27	28
We previously reported that injection of insulin into lean male C57BL/6 mice markedly reduces expression level of MKP-3 protein in the liver .	We previously reported that injection of insulin into lean male C57BL/6 mice markedly reduces expression level of MKP-3 protein in the liver.	4	18	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	MKP-3	MKP-3	MKP-3	6	7	17	18
In conclusion , insulin likely promotes MKP-3 protein degradation through activation of MEK and ERK pathway in liver cells and MKP-3 protein level affects the capability of Fao cells to output glucose .	In conclusion, insulin likely promotes MKP-3 protein degradation through activation of MEK and ERK pathway in liver cells and MKP-3 protein level affects the capability of Fao cells to output glucose.	3	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	MKP-3	MKP-3	MKP-3	3	4	6	7
As shown in XREF_FIG , the wild type MKP-3 protein was significantly reduced by insulin treatment compared to vehicle control but MKP-3 S159AS197A protein level remained unchanged in response to insulin treatment .	As shown in XREF_FIG, the wild type MKP-3 protein was significantly reduced by insulin treatment compared to vehicle control but MKP-3 S159AS197A protein level remained unchanged in response to insulin treatment.	8	15	reduced	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	MKP-3	MKP-3	MKP-3	14	15	8	9
Consistent with this result , application of MEK inhibitor U0126 not only prevented insulin induced MKP-3 protein degradation but also markedly slowed down MKP-3 protein degradation in general compared to DMSO treated samples ( XREF_FIG , XREF_SUPPLEMENTARY ) , indicating that blockage of the ERK pathway also prevents MKP-3 protein degradation induced by factors other than insulin .	Consistent with this result, application of MEK inhibitor U0126 not only prevented insulin induced MKP-3 protein degradation but also markedly slowed down MKP-3 protein degradation in general compared to DMSO treated samples (XREF_FIG, XREF_SUPPLEMENTARY), indicating that blockage of the ERK pathway also prevents MKP-3 protein degradation induced by factors other than insulin.	13	17	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	MKP-3	MKP-3	MKP-3	13	14	15	16
To determine whether serine residues 159 and 197 are the target sites for insulin induced degradation of MKP-3 protein , adenoviruses expressing MKP-3 or MKP-3 S159AS197A were used to transduce Fao cells followed by treatment of insulin in the presence of 10 M cycloheximide .	To determine whether serine residues 159 and 197 are the target sites for insulin induced degradation of MKP-3 protein, adenoviruses expressing MKP-3 or MKP-3 S159AS197A were used to transduce Fao cells followed by treatment of insulin in the presence of 10 M cycloheximide.	11	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	MKP-3	MKP-3	MKP-3	13	14	17	18
We further confirmed that the MEK and ERK pathway is responsible for insulin promoted MKP-3 protein degradation by demonstrating that the MKP-3 mutant deficient in serine residues 159 and 197 , two sites for ERK dependent phosphorylation , is resistant to protein degradation induced by insulin or constitutive activation of the ERK pathway .	We further confirmed that the MEK and ERK pathway is responsible for insulin promoted MKP-3 protein degradation by demonstrating that the MKP-3 mutant deficient in serine residues 159 and 197, two sites for ERK dependent phosphorylation, is resistant to protein degradation induced by insulin or constitutive activation of the ERK pathway.	12	16	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	MKP-3	MKP-3	MKP-3	12	13	14	15
Application of mTOR inhibitor rapamycin , which effectively blocked S6 phosphorylation , did not prevent insulin induced MKP-3 protein degradation ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Application of mTOR inhibitor rapamycin, which effectively blocked S6 phosphorylation, did not prevent insulin induced MKP-3 protein degradation (XREF_FIG, XREF_SUPPLEMENTARY).	14	19	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	MKP-3	MKP-3	MKP-3	15	16	17	18
Conversely , knockdown of Numb or Itch in Sufu deficient lung cells led to increased Gli1 protein levels ( XREF_SUPPLEMENTARY ) by eliminating Numb and Itch mediated Gli1 degradation .	Conversely, knockdown of Numb or Itch in Sufu deficient lung cells led to increased Gli1 protein levels (XREF_SUPPLEMENTARY) by eliminating Numb and Itch mediated Gli1 degradation.	23	28	mediated	Positive_early_activation	Negative_activation	Negative_activation	Itch	Itch	Itch	Gli1	Gli1	Gli1	25	26	27	28
In this study , we showed that Sufu counters the effects of Numb and Itch mediated Gli1 protein degradation .	In this study, we showed that Sufu counters the effects of Numb and Itch mediated Gli1 protein degradation.	14	18	mediated	Positive_early_activation	Negative_activation	Negative_activation	Itch	Itch	Itch	Gli1	Gli1	Gli1	14	15	16	17
These results confirmed that ITCH down-regulated Gli1 in PANC-1 cells .	These results confirmed that ITCH down-regulated Gli1 in PANC-1 cells.	4	7	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ITCH	ITCH	ITCH	Gli1	Gli1	Gli1	4	5	6	7
Here , we characterize the regulation of an ubiquitin mediated mechanism of Gli1 degradation , promoted by the coordinated action of the E3 ligase Itch and the adaptor protein Numb .	Here, we characterize the regulation of an ubiquitin mediated mechanism of Gli1 degradation, promoted by the coordinated action of the E3 ligase Itch and the adaptor protein Numb.	12	25	promoted	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Itch	Itch	Itch	Gli1	Gli1	Gli1	24	25	12	13
It is interesting to note that rather than inhibiting ubiquitination , Numb can enhance the degradation of Gli1 by Itch - again pointing to a rather specific effect of Numb on the stability of p53 .	It is interesting to note that rather than inhibiting ubiquitination, Numb can enhance the degradation of Gli1 by Itch - again pointing to a rather specific effect of Numb on the stability of p53.	13	20	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Itch	Itch	Itch	Gli1	Gli1	Gli1	19	20	17	18
Our studies illustrate a novel mechanism by which lithium suppresses Hh signaling via simultaneously promoting ITCH dependent Gli1 ubiquitination and degradation and SUFU mediated Gli1 inhibition .	Our studies illustrate a novel mechanism by which lithium suppresses Hh signaling via simultaneously promoting ITCH dependent Gli1 ubiquitination and degradation and SUFU mediated Gli1 inhibition.	14	25	mediated	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	ITCH	ITCH	ITCH	Gli1	Gli1	Gli1	15	16	24	25
ITCH also induces Numb mediated suppression of Hedgehog signaling via ubiquitylation and degradation of transcription factor Gli1 .	ITCH also induces Numb mediated suppression of Hedgehog signaling via ubiquitylation and degradation of transcription factor Gli1.	0	17	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ITCH	ITCH	ITCH	Gli1	Gli1	Gli1	0	1	16	17
Otherwise , Numb and Itch would induce Gli1 protein degradation .	Otherwise, Numb and Itch would induce Gli1 protein degradation.	2	9	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Itch	Itch	Itch	Gli1	Gli1	Gli1	4	5	7	8
IRF5 enhances the IFN-gamma/JAK/STAT1-dependent production of the M1 cytokine IL-12 [ XREF_BIBR ] , whereas IRF4 suppresses the effect of IRF5 [ XREF_BIBR ] .	IRF5 enhances the IFN-gamma/JAK/STAT1-dependent production of the M1 cytokine IL-12 [XREF_BIBR], whereas IRF4 suppresses the effect of IRF5 [XREF_BIBR].	15	22	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRF4	IRF4	IRF4	IRF5	IRF5	IRF5	15	16	20	21
In addition , IRF-4 negatively regulates IRF-5 promoter reporter activities and binds to IRF-5 promoters in vivo and in vitro .	In addition, IRF-4 negatively regulates IRF-5 promoter reporter activities and binds to IRF-5 promoters in vivo and in vitro.	3	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRF-4	IRF-4	IRF-4	IRF-5	IRF-5	IRF-5	3	4	6	7
Another member of the IRF family , IRF4 , known to inhibit IRF5 activation by competing for interaction with the adaptor Myd88 , is reported to control the expression of prototypical mouse M2 macrophage markers [ XREF_BIBR ] .	Another member of the IRF family, IRF4, known to inhibit IRF5 activation by competing for interaction with the adaptor Myd88, is reported to control the expression of prototypical mouse M2 macrophage markers [XREF_BIBR].	5	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRF4	IRF4	IRF4	IRF5	IRF5	IRF5	7	8	12	13
84 In addition , as with its role in antiviral responses , 220 IRF4 may negatively regulate TLR7 activation of IRF5 in EBV latency ( XREF_FIG ) .	84 In addition, as with its role in antiviral responses, 220 IRF4 may negatively regulate TLR7 activation of IRF5 in EBV latency (XREF_FIG).	12	21	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRF4	IRF4	IRF4	IRF5	IRF5	IRF5	13	14	20	21
IRF-4 negatively regulates IRF-5 activation , and IRF-4 was also present in type III latently infected cells .	IRF-4 negatively regulates IRF-5 activation, and IRF-4 was also present in type III latently infected cells.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRF-4	IRF-4	IRF-4	IRF-5	IRF-5	IRF-5	0	1	3	4
The upregulation of ID3 decreases TCF3 activity , by forming heterodimers .	The upregulation of ID3 decreases TCF3 activity, by forming heterodimers.	1	6	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ID3	ID3	ID3	TCF3	TCF3	TCF3	3	4	5	6
Additionally , although the mutation frequency is lower than that of ID3 , recurrent activating mutations in TCF3 , which is negatively regulated by ID3 , were also identified in BL ( 18.3 % ) .	Additionally, although the mutation frequency is lower than that of ID3, recurrent activating mutations in TCF3, which is negatively regulated by ID3, were also identified in BL (18.3%).	15	25	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ID3	ID3	ID3	TCF3	TCF3	TCF3	24	25	17	18
ID3 inhibits the transcriptional activity of TCF3 .	ID3 inhibits the transcriptional activity of TCF3.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ID3	ID3	ID3	TCF3	TCF3	TCF3	0	1	6	7
XREF_BIBR - XREF_BIBR One such ID3 inhibited protein is Transcription Factor 3 ( TCF3 ) , which is consecutively expressed at high levels during B-cell development .	XREF_BIBR - XREF_BIBR One such ID3 inhibited protein is Transcription Factor 3 (TCF3), which is consecutively expressed at high levels during B-cell development.	3	20	inhibited	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	ID3	ID3	id3	Transcription Factor 3	Transcription Factor 3 (TCF3), which is consecutively expressed	transcription factor 3	5	6	9	12
Northern blot analysis showed that PatA had no effect on the levels of the iNOS mRNA , but it prevented the IFNgamma and TNFalpha induced loss of the Myogenin and MyoD messages ( XREF_SUPPLEMENTARY ) .	Northern blot analysis showed that PatA had no effect on the levels of the iNOS mRNA, but it prevented the IFNgamma and TNFalpha induced loss of the Myogenin and MyoD messages (XREF_SUPPLEMENTARY).	20	31	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IFNgamma	IFNgamma	IFNgamma	MyoD	MyoD	MyoD	21	22	30	31
MyoD mRNA was also down-regulated by TNF and IFN-gamma expression in mouse muscle in vivo .	MyoD mRNA was also down-regulated by TNF and IFN-gamma expression in mouse muscle in vivo.	0	10	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	IFN-gamma	IFN-gamma expression	ifn-gamma	MyoD	MyoD	myod	8	9	0	1
MyoD impaired activity in dystrophin deficient muscle can be caused by activation of NFkB and IFNG pathways that result in MyoD destabilization XREF_BIBR .	MyoD impaired activity in dystrophin deficient muscle can be caused by activation of NFkB and IFNG pathways that result in MyoD destabilization XREF_BIBR.	0	16	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	IFNG	IFNG	IFNG	MyoD	MyoD	MyoD	15	16	0	1
In mice , genetically deleting Itch , a HECT E3 ubiquitin ligase which negatively regulates NOTCH1 , produces a progressive autoimmune phenotype that is exacerbated when Itch -/- mice are crossed with mice carrying an activated Notch1 transgene .	In mice, genetically deleting Itch, a HECT E3 ubiquitin ligase which negatively regulates NOTCH1, produces a progressive autoimmune phenotype that is exacerbated when Itch -/- mice are crossed with mice carrying an activated Notch1 transgene.	5	17	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Itch	Itch	Itch	NOTCH1	NOTCH1	NOTCH1	5	6	15	16
Suppressor of deltex and Itch and SCF Fbxw7 directly target NICD , whereas LNX degrades Numb , an antagonist of NICD .	Suppressor of deltex and Itch and SCF Fbxw7 directly target NICD, whereas LNX degrades Numb, an antagonist of NICD.	0	14	target	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Itch	Itch	Itch	NICD	NICD	NICD	4	5	10	11
Prior to the description of Itch as an E3 ligase for JunB , Itch was shown biochemically to degrade Notch .	Prior to the description of Itch as an E3 ligase for JunB, Itch was shown biochemically to degrade Notch.	13	20	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Itch	Itch	Itch	Notch	Notch	Notch	13	14	19	20
The Notch receptor can be degraded through the lysosomes by the ubiquitin ligase Itch and AIP4 [ XREF_BIBR ] or another ubiquitin ligase , Nedd4 [ XREF_BIBR ] , which act together with Numb [ XREF_BIBR ] and Itch and AIP4 to stimulate endocytosis and lysosomal degradation of the Notch receptor [ XREF_BIBR ] .	The Notch receptor can be degraded through the lysosomes by the ubiquitin ligase Itch and AIP4 [XREF_BIBR] or another ubiquitin ligase, Nedd4 [XREF_BIBR], which act together with Numb [XREF_BIBR] and Itch and AIP4 to stimulate endocytosis and lysosomal degradation of the Notch receptor [XREF_BIBR].	1	26	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Itch	Itch	Itch	Notch	Notch	Notch	13	14	1	2
For example , a complex of Numb and Itch E3 ubiquitin ligase mediates lysosomal degradation of Notch ICD in the cytoplasm .	For example, a complex of Numb and Itch E3 ubiquitin ligase mediates lysosomal degradation of Notch ICD in the cytoplasm.	8	17	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Itch	Itch	Itch	Notch	Notch	Notch	8	9	16	17
IL-1 beta also depressed adipoconversion , inhibited markedly LPL activity , and partially reduced GPDH activity .	IL-1 beta also depressed adipoconversion, inhibited markedly LPL activity, and partially reduced GPDH activity.	0	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IL-1 beta	IL-1 beta	IL-1 beta	LPL	LPL	LPL	0	2	8	9
Interestingly , separate studies demonstrate not only that IL-1beta signaling directly decreases the activity of the LPL enzyme [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] but that repeated exposure to the protein also reduces insulin sensitivity [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Interestingly, separate studies demonstrate not only that IL-1beta signaling directly decreases the activity of the LPL enzyme [XREF_BIBR, XREF_BIBR, XREF_BIBR] but that repeated exposure to the protein also reduces insulin sensitivity [XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	17	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	LPL	LPL	LPL	8	9	16	17
These data suggest that in aged skin , IL-1beta signalling is diminished due to altered expression of IL1B and decoy receptor gene IL1R2 .	These data suggest that in aged skin, IL-1beta signalling is diminished due to altered expression of IL1B and decoy receptor gene IL1R2.	8	23	diminished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL1R2	IL1R2	IL1R2	8	9	22	23
They expressed PTCH1 , which is negatively regulated by IHH , a hypertrophic marker .	They expressed PTCH1, which is negatively regulated by IHH, a hypertrophic marker.	1	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	IHH	IHH	IHH	PTCH1	PTCH1	PTCH1	9	10	2	3
Overexpression Keap1 protein inhibited the Nrf2 protein via ER associated degradation , resulting in the inhibition of Nrf2 and Keap1 dependent antioxidant systems in the sodium selenite treated HLECs .	Overexpression Keap1 protein inhibited the Nrf2 protein via ER associated degradation, resulting in the inhibition of Nrf2 and Keap1 dependent antioxidant systems in the sodium selenite treated HLECs.	1	6	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	1	2	5	6
Oxidative stress abrogates the Keap1 mediated degradation of Nrf2 which in turn accumulates in the nucleus where it heterodimerizes with a small musculoaponeurotic fibrosarcoma ( Maf ) protein on antioxidant response elements ( AREs ) to stimulate the expression of a wide arrays of phase II and antioxidant enzymes including NAD ( P ) H quinone oxidoreductase 1 ( Nqo1 ) , heme oxygenase 1 ( Hmox1 ) , glutamane-cysteine ligase ( GCL ) and glutathione S transferases ( GSTs ) XREF_BIBR .	Oxidative stress abrogates the Keap1 mediated degradation of Nrf2 which in turn accumulates in the nucleus where it heterodimerizes with a small musculoaponeurotic fibrosarcoma (Maf) protein on antioxidant response elements (AREs) to stimulate the expression of a wide arrays of phase II and antioxidant enzymes including NAD (P) H quinone oxidoreductase 1 (Nqo1), heme oxygenase 1 (Hmox1), glutamane-cysteine ligase (GCL) and glutathione S transferases (GSTs) XREF_BIBR.	2	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	8	9
Nrf2 is sequestered in the cytoplasm by Keap1 under unstimulated conditions but translocates into the nucleus and transactivates the antioxidant responsive element ( ARE ) upon exposure to oxidative insults .	Nrf2 is sequestered in the cytoplasm by Keap1 under unstimulated conditions but translocates into the nucleus and transactivates the antioxidant responsive element (ARE) upon exposure to oxidative insults.	0	17	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	0	1
Keap1 , an adaptor protein for a Cullin 3 ( Cul3 )-based ubiquitin E3 ligase , sequesters Nrf2 in the cytosol and ensures its degradation by the proteasome .	Keap1, an adaptor protein for a Cullin 3 (Cul3)-based ubiquitin E3 ligase, sequesters Nrf2 in the cytosol and ensures its degradation by the proteasome.	0	22	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	17	18
Nrf2 is repressed by the cysteine rich Keap1 protein , which targets Nrf2 for ubiquitination and subsequent degradation by a Cul3 mediated ubiquitination complex .	Nrf2 is repressed by the cysteine rich Keap1 protein, which targets Nrf2 for ubiquitination and subsequent degradation by a Cul3 mediated ubiquitination complex.	7	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
Evidence is presented that CETP affected Nrf2 mediated induction of ARE driven transcription by inhibiting Kelch like ECH associated protein 1 ( Keap1 ) , a ubiquitin ligase substrate adaptor that negatively regulates Nrf2 .	Evidence is presented that CETP affected Nrf2 mediated induction of ARE driven transcription by inhibiting Kelch like ECH associated protein 1 (Keap1), a ubiquitin ligase substrate adaptor that negatively regulates Nrf2.	19	34	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	33	34
Mutation of either Cys273 or Cys288 residues of KEAP1 could not repress NRF2 activity and , therefore , NRF2 accumulated within the cell , indicating these residues are required for KEAP1 dependent ubiquitylation of NRF2 .	Mutation of either Cys273 or Cys288 residues of KEAP1 could not repress NRF2 activity and, therefore, NRF2 accumulated within the cell, indicating these residues are required for KEAP1 dependent ubiquitylation of NRF2.	0	13	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	8	9	12	13
Mutation of either the ETGE or the DLG motif largely abolishes Keap1 mediated Nrf2 degradation [ XREF_BIBR - XREF_BIBR ] .	Mutation of either the ETGE or the DLG motif largely abolishes Keap1 mediated Nrf2 degradation [XREF_BIBR - XREF_BIBR].	10	14	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	13	14
Under normal conditions , KEAP1 represses NRF2 activity by degrading the NRF2 protein .	Under normal conditions, KEAP1 represses NRF2 activity by degrading the NRF2 protein.	4	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	4	5	6	7
Further , the activity of NRF2 is influenced via the action of miR-200a which targets Keap1 , that represses NRF2 , and via miR-34a that targets sirtuin1 ( Sirt1 ) , deacetylates NRF2 and promotes its nuclear export .	Further, the activity of NRF2 is influenced via the action of miR-200a which targets Keap1, that represses NRF2, and via miR-34a that targets sirtuin1 (Sirt1), deacetylates NRF2 and promotes its nuclear export.	14	20	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	15	16	19	20
Keap1 prevents Nrf2 activation by sequestering Nrf2 in the cytoplasm .	Keap1 prevents Nrf2 activation by sequestering Nrf2 in the cytoplasm.	0	3	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
In cancer tissues and cells , loss of Keap1 , an Nrf2 negatively regulator , leads to nuclear localization and constitutive activation of Nrf2 [ XREF_BIBR - XREF_BIBR ] .	In cancer tissues and cells, loss of Keap1, an Nrf2 negatively regulator, leads to nuclear localization and constitutive activation of Nrf2 [XREF_BIBR - XREF_BIBR].	6	25	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Keap1	loss of Keap1	keap1	Nrf2	Nrf2	nrf2	8	9	23	24
Under basal conditions , Keap1 , functioning as a substrate adaptor for a Cul3 based E3 ubiquitin ligase , constantly targets Nrf2 for ubiquitin dependent degradation to maintain low levels of Nrf2 .	Under basal conditions, Keap1, functioning as a substrate adaptor for a Cul3 based E3 ubiquitin ligase, constantly targets Nrf2 for ubiquitin dependent degradation to maintain low levels of Nrf2.	4	25	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	21	22
Under the physiology condition , Nrf2 is sequestered in the cytoplasm by the repressor protein Keap1 .	Under the physiology condition, Nrf2 is sequestered in the cytoplasm by the repressor protein Keap1.	5	16	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	5	6
Under basal conditions , Keap1 acts to negatively regulate Nrf2 , sequestering it through interaction via the Kelch domain and leading to its ubiquitination ( and subsequent proteasomal degradation ) as a consequence of its resulting proximity to Cul3 and Rbx1 .	Under basal conditions, Keap1 acts to negatively regulate Nrf2, sequestering it through interaction via the Kelch domain and leading to its ubiquitination (and subsequent proteasomal degradation) as a consequence of its resulting proximity to Cul3 and Rbx1.	4	10	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	9	10
Residues C273 and C288 at the intervening region ( IVR ) domain of Keap1 are necessary for Keap1 to repress Nrf2 , indicating a critical role of the IVR domain in the functional interaction of Keap1 with Nrf2 .	Residues C273 and C288 at the intervening region (IVR) domain of Keap1 are necessary for Keap1 to repress Nrf2, indicating a critical role of the IVR domain in the functional interaction of Keap1 with Nrf2.	1	21	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	20	21
It has been shown that SESN2 interacts with the Nrf2 suppressor Keap1 , the autophagy substrate p62 , and the ubiquitin ligase Rbx1 .	It has been shown that SESN2 interacts with the Nrf2 suppressor Keap1, the autophagy substrate p62, and the ubiquitin ligase Rbx1.	6	22	suppressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	9	10
Nrf2 Could Be Partially Inhibited by Keap1 DeltaC .	Nrf2 Could Be Partially Inhibited by Keap1 DeltaC.	0	7	Inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	0	1
Under normal homeostatic redox conditions , Nrf2 is sequestered by Keap1 ( Kelch like ECH associated protein 1 ) in the cytoplasm where it negatively regulates Nrf2 through ubiquitin mediated proteasomal degradation XREF_BIBR .	Under normal homeostatic redox conditions, Nrf2 is sequestered by Keap1 (Kelch like ECH associated protein 1) in the cytoplasm where it negatively regulates Nrf2 through ubiquitin mediated proteasomal degradation XREF_BIBR.	6	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	6	7
Under the basal resting condition , Nrf2 is sequestered in the cytoplasm by Keap1 , which functions as a negative modulator of Nrf2 by promoting ubiquitination and proteasomal degradation of Nrf2 .	Under the basal resting condition, Nrf2 is sequestered in the cytoplasm by Keap1, which functions as a negative modulator of Nrf2 by promoting ubiquitination and proteasomal degradation of Nrf2.	6	16	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	6	7
Somatic mutations in Nrf2 or Keap1 can abolish Keap1 dependent degradation of Nrf2 , resulting in its accumulation and translocation to the nucleus to upregulate antioxidant response genes XREF_BIBR .	Somatic mutations in Nrf2 or Keap1 can abolish Keap1 dependent degradation of Nrf2, resulting in its accumulation and translocation to the nucleus to upregulate antioxidant response genes XREF_BIBR.	8	13	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	12	13
KEAP1 senses cellular ROS and directly inhibits NRF2 in the cytoplasm XREF_BIBR .	KEAP1 senses cellular ROS and directly inhibits NRF2 in the cytoplasm XREF_BIBR.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	7	8
Gastric administration of lansoprazole ( 10-100 mg/kg ) to male Wistar rats produced a dose dependent increase in hepatic mRNA levels of nuclear factor , erythroid derived 2 , -like 2 ( Nrf2 ) , a redox sensitive transcription factor , at 3 h and Nrf2 immunoreactivity ( IR ) in whole hepatic lysates at 6 h. Conversely , the levels of Kelch like ECH associated protein ( Keap1 ) , which sequesters Nrf2 in the cytoplasm under un stimulated conditions , were unchanged .	Gastric administration of lansoprazole (10-100 mg/kg) to male Wistar rats produced a dose dependent increase in hepatic mRNA levels of nuclear factor, erythroid derived 2, -like 2 (Nrf2), a redox sensitive transcription factor, at 3 h and Nrf2 immunoreactivity (IR) in whole hepatic lysates at 6 h. Conversely, the levels of Kelch like ECH associated protein (Keap1), which sequesters Nrf2 in the cytoplasm under un stimulated conditions, were unchanged.	66	74	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	68	69	73	74
Nrf2 , once stabilized , is no longer repressed by Keap1 and becomes free to heterodimerize with members of the Maf family of transcription factors .	Nrf2, once stabilized, is no longer repressed by Keap1 and becomes free to heterodimerize with members of the Maf family of transcription factors.	0	12	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	0	1
Specifically , Keap1 sequesters the bZIP protein of Nrf2 in the cytoplasm , leading to low expression of ARE driven genes .	Specifically, Keap1 sequesters the bZIP protein of Nrf2 in the cytoplasm, leading to low expression of ARE driven genes.	2	11	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	8	9
In defending the body from oxidative , inflammatory , or toxic stress , Keap1 negatively regulates Nrf2 by enhancing the rate of Nrf2 proteasomal degradation and alters its subcellular distribution .	In defending the body from oxidative, inflammatory, or toxic stress, Keap1 negatively regulates Nrf2 by enhancing the rate of Nrf2 proteasomal degradation and alters its subcellular distribution.	13	26	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	16	17
Sensitive to S glutathionylation in vitro , C23 can also form a disulfide bond with C38 under in vitro conditions of oxidative stress , suggesting C23-C38 disulfide bond formation might reduce Keap1 repression of Nrf2 .	Sensitive to S glutathionylation in vitro, C23 can also form a disulfide bond with C38 under in vitro conditions of oxidative stress, suggesting C23-C38 disulfide bond formation might reduce Keap1 repression of Nrf2.	31	35	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	31	32	34	35
It has been shown that Nrf2 is repressed by Keap1 in the cytosol and degraded by the 26S proteasome in nonstressed cells .	It has been shown that Nrf2 is repressed by Keap1 in the cytosol and degraded by the 26S proteasome in nonstressed cells.	5	14	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	5	6
Sustained NRF2 activity levels likely lead to NRF2 dependent production of KEAP1 , which in turn leads to suppressed NRF2 mediated gene expression through a negative feedback mechanism .	Sustained NRF2 activity levels likely lead to NRF2 dependent production of KEAP1, which in turn leads to suppressed NRF2 mediated gene expression through a negative feedback mechanism.	9	20	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	11	12	19	20
Under unstimulated conditions , Nrf2 is sequestered in the cytosol by Keap1 and is targeted for ubiquitin dependent proteosomal degradation [ XREF_BIBR - XREF_BIBR ] .	Under unstimulated conditions, Nrf2 is sequestered in the cytosol by Keap1 and is targeted for ubiquitin dependent proteosomal degradation [XREF_BIBR - XREF_BIBR].	4	14	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
Under basal conditions , NRF2 dependent transcription is repressed by KEAP1 .	Under basal conditions, NRF2 dependent transcription is repressed by KEAP1.	4	11	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	10	11	4	5
The Neh6 domain mediates the Keap1 independent degradation of Nrf2 through recruitment by the DSGIS and DSAPGS motifs of the dimeric beta-transducin repeat containing protein ( beta-TrCP ) [ XREF_BIBR ] .	The Neh6 domain mediates the Keap1 independent degradation of Nrf2 through recruitment by the DSGIS and DSAPGS motifs of the dimeric beta-transducin repeat containing protein (beta-TrCP) [XREF_BIBR].	5	10	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	9	10
Transcription factor Nrf2 ( nuclear factor E2 related factor 2 ) is a master regulator of cellular defense system against oxidative and electrophilic stresses and is negatively regulated by an adaptor protein Keap1 ( Kelch like ECH associated protein 1 ) .	Transcription factor Nrf2 (nuclear factor E2 related factor 2) is a master regulator of cellular defense system against oxidative and electrophilic stresses and is negatively regulated by an adaptor protein Keap1 (Kelch like ECH associated protein 1).	0	34	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	32	33	2	3
Co-transfection of wt Keap1 and Nrf2 was observed to significantly decrease the level of Nrf2 protein as expected ( XREF_FIG ) .	Co-transfection of wt Keap1 and Nrf2 was observed to significantly decrease the level of Nrf2 protein as expected (XREF_FIG).	0	15	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	14	15
It is well established that Nrf2 activity is controlled , in part , by the cytosolic protein Keap1 , but the nature of this pathway and the mechanisms by which Keap1 acts to repress Nrf2 activity remain to be fully characterized and are the topics of discussion in this minireview .	It is well established that Nrf2 activity is controlled, in part, by the cytosolic protein Keap1, but the nature of this pathway and the mechanisms by which Keap1 acts to repress Nrf2 activity remain to be fully characterized and are the topics of discussion in this minireview.	30	35	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	30	31	34	35
Studies on tissue specific Keap1 null mutation have demonstrated the important roles of Keap1 mediated Nrf2 degradation .	Studies on tissue specific Keap1 null mutation have demonstrated the important roles of Keap1 mediated Nrf2 degradation.	11	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	15	16
Upon exposure to oxidative stress , xenobiotics , or electrophilic metabolites of phase I enzymes , repression of Nrf2 by Keap1 ubiquitination is disrupted and newly produced Nrf2 enters the nucleus [ XREF_BIBR ] .	Upon exposure to oxidative stress, xenobiotics, or electrophilic metabolites of phase I enzymes, repression of Nrf2 by Keap1 ubiquitination is disrupted and newly produced Nrf2 enters the nucleus [XREF_BIBR].	16	22	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1 ubiquitination	keap1	Nrf2	Nrf2	nrf2	20	21	18	19
Upon cellular exposure , as an E3 ubiquitin ligase component , Keap1 is inhibited , which provokes Nrf2 stabilization .	Upon cellular exposure, as an E3 ubiquitin ligase component, Keap1 is inhibited, which provokes Nrf2 stabilization.	11	18	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	17	18
We believe that this Keap1 inhibition may be due to the reactive nature of EGCG , which may directly interact with the cysteinyl residues present in Keap1 , thereby stimulating Nrf2 dissociation ( XREF_FIG ) .	We believe that this Keap1 inhibition may be due to the reactive nature of EGCG, which may directly interact with the cysteinyl residues present in Keap1, thereby stimulating Nrf2 dissociation (XREF_FIG).	4	31	stimulating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	30	31
The N-terminal domain of Nrf2 is bound to the cytoskeletal associated protein , Keap1 , that negatively regulates Nrf2 by both repressing Nrf2 transcriptional activity [ XREF_BIBR ] and enhancing its rate of proteasomal degradation [ XREF_BIBR , XREF_BIBR ] in the cytoplasm .	The N-terminal domain of Nrf2 is bound to the cytoskeletal associated protein, Keap1, that negatively regulates Nrf2 by both repressing Nrf2 transcriptional activity [XREF_BIBR] and enhancing its rate of proteasomal degradation [XREF_BIBR, XREF_BIBR] in the cytoplasm.	11	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	18	19
In this study , ABC treatment decreased the expression of Keap-1 in the cytosol and induced the translocation of Nrf2 to the nucleus .	In this study, ABC treatment decreased the expression of Keap-1 in the cytosol and induced the translocation of Nrf2 to the nucleus.	4	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap-1	ABC treatment decreased the expression of Keap-1	keap-1	Nrf2	Nrf2	nrf2	10	11	19	20
When wild-type or C151S mutant Keap1 was overexpressed with Nrf2 , no GFP expression was observed , indicating that Keap1 suppressed GFP inducing activity of Nrf2 ( XREF_FIG ) .	When wild-type or C151S mutant Keap1 was overexpressed with Nrf2, no GFP expression was observed, indicating that Keap1 suppressed GFP inducing activity of Nrf2 (XREF_FIG).	19	27	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	19	20	25	26
VPA induced ER stress and unfolded protein response ( UPR ) by activation the ER stress sensor proteins and transcription factor 6 in HLECs , resulting in DNA demethylation of the Keap1 promoter ( Palsamy etal ., 2014c ) , which suppresses the Nrf2 dependent antioxidant system and results in cataract formation .	VPA induced ER stress and unfolded protein response (UPR) by activation the ER stress sensor proteins and transcription factor 6 in HLECs, resulting in DNA demethylation of the Keap1 promoter (Palsamy etal., 2014c), which suppresses the Nrf2 dependent antioxidant system and results in cataract formation.	28	46	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	demethylation of the Keap1	keap1	Nrf2	Nrf2	nrf2	31	32	43	44
NRF2 controls cellular adaptation to oxidative stress by inducing antioxidant and detoxification genes , whereas KEAP1 sequesters NRF2 in cytoplasm and promotes the degradation of NRF2 .	NRF2 controls cellular adaptation to oxidative stress by inducing antioxidant and detoxification genes, whereas KEAP1 sequesters NRF2 in cytoplasm and promotes the degradation of NRF2.	15	21	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	15	16	17	18
The Nrf2 signaling pathway is negatively controlled by Keap1 , and Nrf2 is sequestered in the cytoplasm under non stimulated conditions by Keap1 .	The Nrf2 signaling pathway is negatively controlled by Keap1, and Nrf2 is sequestered in the cytoplasm under non stimulated conditions by Keap1.	11	23	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	11	12
While the UPS downregulates Nrf2 activity by Keap1 mediated degradation of Nrf2 , the ALP seems to increase Nrf2 activity via autophagic clearance of Keap1 .	While the UPS downregulates Nrf2 activity by Keap1 mediated degradation of Nrf2, the ALP seems to increase Nrf2 activity via autophagic clearance of Keap1.	3	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	11	12
Autophagy previously was shown to degrade p62 , a protein that sequesters KEAP1 , and KEAP1 in turn sequesters Nrf2 , a master regulator of the antioxidant response .	Autophagy previously was shown to degrade p62, a protein that sequesters KEAP1, and KEAP1 in turn sequesters Nrf2, a master regulator of the antioxidant response.	15	23	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	15	16	19	20
Decreased Keap1 activity in these cancer cells induced greater nuclear accumulation of Nrf2 and constitutive over expression of ARE containing genes including MRP , NQO1 and GCL .	Decreased Keap1 activity in these cancer cells induced greater nuclear accumulation of Nrf2 and constitutive over expression of ARE containing genes including MRP, NQO1 and GCL.	1	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	1	2	12	13
FA promoted Keap1 expression in the cytoplasm , where Keap1 could degrade and release Nrf2 ( p < 0.05 ) .	FA promoted Keap1 expression in the cytoplasm, where Keap1 could degrade and release Nrf2 (p < 0.05).	0	16	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	FA promoted Keap1 expression	keap1	Nrf2	Nrf2	nrf2	2	3	14	15
Evidence supporting this notion in lung cancer has emerged whereby down-regulation of KEAP1 by DNA CpG methylation has been shown to occur in both NSCLC cell lines and tumour tissues [ XREF_BIBR ] , and an additional study in NSCLC cell lines showed that loss of KEAP1 function activated NRF2 and provided cellular growth advantages [ XREF_BIBR ] .	Evidence supporting this notion in lung cancer has emerged whereby down-regulation of KEAP1 by DNA CpG methylation has been shown to occur in both NSCLC cell lines and tumour tissues [XREF_BIBR], and an additional study in NSCLC cell lines showed that loss of KEAP1 function activated NRF2 and provided cellular growth advantages [XREF_BIBR].	46	50	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	46	47	49	50
In agreement with previous studies showing that KEAP1 negatively regulates NFE2L2 , the NFE2L2 target genes GSTA4 and GCLC were up-regulated in the thyroid tissues of the patient .	In agreement with previous studies showing that KEAP1 negatively regulates NFE2L2, the NFE2L2 target genes GSTA4 and GCLC were up-regulated in the thyroid tissues of the patient.	7	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NFE2L2	NFE2L2	NFE2L2	7	8	10	11
Nrf2 is sequestered by keap-1 , but such sequestration can be abrogated by electrophiles leading to release of Nrf2 as an active transcriptional factor to enhance the expression of antioxidant molecules .	Nrf2 is sequestered by keap-1, but such sequestration can be abrogated by electrophiles leading to release of Nrf2 as an active transcriptional factor to enhance the expression of antioxidant molecules.	0	5	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	keap-1	keap-1	keap-1	Nrf2	Nrf2	Nrf2	4	5	0	1
Cancer Cell Growth Is Differentially Affected by Constitutive Activation of NRF2 by KEAP1 Deletion and Pharmacological Activation of NRF2 by the Synthetic Triterpenoid , RTA 405 .	Cancer Cell Growth Is Differentially Affected by Constitutive Activation of NRF2 by KEAP1 Deletion and Pharmacological Activation of NRF2 by the Synthetic Triterpenoid, RTA 405.	8	13	Activation	Positive_activation_token_2_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	12	13	10	11
Keap1 inhibition causes sustained Nrf2 activation , which leads to the constitutive expression of phase II detoxifying enzymes and antioxidative stress enzymes .	Keap1 inhibition causes sustained Nrf2 activation, which leads to the constitutive expression of phase II detoxifying enzymes and antioxidative stress enzymes.	0	5	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	4	5
As a proof , Nrf2 constitutive activation by Keap1 silencing is able to rescue ROS levels , Nqo1 down-regulation , and in vivo survival caused by Brca1 deficiency ( XREF_FIG ) .	As a proof, Nrf2 constitutive activation by Keap1 silencing is able to rescue ROS levels, Nqo1 down-regulation, and in vivo survival caused by Brca1 deficiency (XREF_FIG).	4	9	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
The transcription factor NF-E2-related factor 2 ( Nrf2 ) regulates the expression of a battery of antioxidative enzymes and Nrf2 signaling can be activated by small-molecule drugs that disrupt Keap1 mediated repression of Nrf2 signaling .	The transcription factor NF-E2-related factor 2 (Nrf2) regulates the expression of a battery of antioxidative enzymes and Nrf2 signaling can be activated by small-molecule drugs that disrupt Keap1 mediated repression of Nrf2 signaling.	29	34	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	29	30	33	34
Keap1 is a repressor of Nrf2 , a transcription factor responsible for activation of genes that code for defensive proteins .	Keap1 is a repressor of Nrf2, a transcription factor responsible for activation of genes that code for defensive proteins.	0	9	is a repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	5	6
On the other hand , NLRP3 inflammasome activation induces a rapid and partly caspase-1- and Keap1 independent degradation of Nrf2 .	On the other hand, NLRP3 inflammasome activation induces a rapid and partly caspase-1- and Keap1 independent degradation of Nrf2.	15	20	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	19	20
Overexpression of Keap1 in human colon Caco-2 carcinoma cells repressed Nrf2 and its target genes , resulting in cellular remodeling .	Overexpression of Keap1 in human colon Caco-2 carcinoma cells repressed Nrf2 and its target genes, resulting in cellular remodeling.	0	14	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Overexpression of Keap1	keap1	Nrf2	Nrf2	nrf2	2	3	10	11
Protein levels of NRF2 and KEAP1 , which promotes NRF2 degradation via the CAND1/cullin3/RBX1 pathway , were unaffected by progerin in HGPS fibroblasts or upon induction of GFP-progerin in WT cells ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Protein levels of NRF2 and KEAP1, which promotes NRF2 degradation via the CAND1/cullin3/RBX1 pathway, were unaffected by progerin in HGPS fibroblasts or upon induction of GFP-progerin in WT cells (XREF_FIG, XREF_SUPPLEMENTARY).	1	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	levels of NRF2 and KEAP1	keap1	NRF2	NRF2	nrf2	5	6	9	10
Under normal physiological conditions , the inhibitor of Nrf2 , Keap1 ( Kelch ECH Associating Protein 1 ) mediates ubiquitin-26S proteasomal degradation of Nrf2 .	Under normal physiological conditions, the inhibitor of Nrf2, Keap1 (Kelch ECH Associating Protein 1) mediates ubiquitin-26S proteasomal degradation of Nrf2.	10	24	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	23	24
Nrf2 is normally sequestered in the cytoplasm by Keap1 which contains several reactive cysteine residues serving as sensors of the intracellular redox state .	Nrf2 is normally sequestered in the cytoplasm by Keap1 which contains several reactive cysteine residues serving as sensors of the intracellular redox state.	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
The putative molecular sensor for inducers is Keap1 , a sulfhydryl rich protein that sequesters the transcription factor Nrf2 in the cytoplasm .	The putative molecular sensor for inducers is Keap1, a sulfhydryl rich protein that sequesters the transcription factor Nrf2 in the cytoplasm.	3	21	sequesters	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	18	19
Normally , Nrf2 is sequestered in the cytosol by Keap1 , and released by ROS signaling .	Normally, Nrf2 is sequestered in the cytosol by Keap1, and released by ROS signaling.	2	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	2	3
Nrf2 is negatively regulated by KEAP1 protein .	Nrf2 is negatively regulated by KEAP1 protein.	0	6	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	5	6	0	1
On the other hand , the expression of Keap1 protein in lens epithelial cells of cataract patients is abnormally increased , decreasing the Nrf2 content by the negative regulatory mechanism .	On the other hand, the expression of Keap1 protein in lens epithelial cells of cataract patients is abnormally increased, decreasing the Nrf2 content by the negative regulatory mechanism.	6	24	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	expression of Keap1	keap1	Nrf2	Nrf2	nrf2	8	9	23	24
Detailed analysis of the regulatory mechanism governing Nrf2 activity led to the identification of Keap1 , which represses Nrf2 activity by directly binding to the N-terminal Neh2 domain .	Detailed analysis of the regulatory mechanism governing Nrf2 activity led to the identification of Keap1, which represses Nrf2 activity by directly binding to the N-terminal Neh2 domain.	12	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	18	19
Under homeostatic redox conditions , Nrf2 is bound to and sequestered by Keap1 , and increases in intracellular oxidation leads to activation and degradation of Keap1 .	Under homeostatic redox conditions, Nrf2 is bound to and sequestered by Keap1, and increases in intracellular oxidation leads to activation and degradation of Keap1.	5	15	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	5	6
The transgenic expression of mutant Keap1 ( C273A ) and/or Keap1 ( C288A ) protein in Keap1 null mice failed to reverse constitutive Nrf2 activation , indicating that cysteine residues at positions 273 and 288 are essential for Keap1 to repress Nrf2 activity in vivo .	The transgenic expression of mutant Keap1 (C273A) and/or Keap1 (C288A) protein in Keap1 null mice failed to reverse constitutive Nrf2 activation, indicating that cysteine residues at positions 273 and 288 are essential for Keap1 to repress Nrf2 activity in vivo.	16	24	reverse	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	23	24
( DJ-1 is a protein that stabilizes NRF2 by impairing KEAP1 dependent proteasomal degradation of NRF2 ) .	(DJ-1 is a protein that stabilizes NRF2 by impairing KEAP1 dependent proteasomal degradation of NRF2).	10	16	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	10	11	15	16
Thus in the absence of stress , Keap1 constitutively suppresses Nrf2 signaling by both degrading Nrf2 and preventing Nrf2 translocation to the nucleus , which results in a low baseline expression of antioxidant genes .	Thus in the absence of stress, Keap1 constitutively suppresses Nrf2 signaling by both degrading Nrf2 and preventing Nrf2 translocation to the nucleus, which results in a low baseline expression of antioxidant genes.	7	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	10	11
The cytoplasmic protein Keap1 interacts with and represses Nrf2 function .	The cytoplasmic protein Keap1 interacts with and represses Nrf2 function.	0	9	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	8	9
Particularly , inhibition of Nrf2 by Keap1 was blunted by Keap1 DeltaC , leading to a rise in reporter gene activity ( XREF_FIG F ) .	Particularly, inhibition of Nrf2 by Keap1 was blunted by Keap1 DeltaC, leading to a rise in reporter gene activity (XREF_FIG F).	2	7	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	4	5
It has been speculated that cells may have a normal ( but at that time unidentified ) ability to limit NRF2 protein levels under conditions where KEAP1 can not drive NRF2 degradation , i.e. under conditions of oxidative stress and especially under chronic oxidative stress where the uncontrolled accumulation of NRF2 protein and the resulting uncontrolled NRF2 driven transcription could be harmful or lethal .	It has been speculated that cells may have a normal (but at that time unidentified) ability to limit NRF2 protein levels under conditions where KEAP1 can not drive NRF2 degradation, i.e. under conditions of oxidative stress and especially under chronic oxidative stress where the uncontrolled accumulation of NRF2 protein and the resulting uncontrolled NRF2 driven transcription could be harmful or lethal.	26	31	drive	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	26	27	30	31
Under basal conditions , Nrf2 is sequestered in the cytoplasm by Keap1 , a multidomain , cysteinerich protein that is bound to the actin cytoskeleton .	Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1, a multidomain, cysteinerich protein that is bound to the actin cytoskeleton.	4	17	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
As expected , overexpression of Keap1 effectively prevented translocation of Nrf2 to the nucleus ( XREF_FIG ) .	As expected, overexpression of Keap1 effectively prevented translocation of Nrf2 to the nucleus (XREF_FIG).	3	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	overexpression of Keap1	keap1	Nrf2	Nrf2	nrf2	5	6	10	11
Results showed that enhancement of Keap1 expression by 5-Aza-dC significantly reduced Nrf2 and its target antioxidant enzyme levels , and that in turn suppressed cell proliferation and colony formation of the transformed cells .	Results showed that enhancement of Keap1 expression by 5-Aza-dC significantly reduced Nrf2 and its target antioxidant enzyme levels, and that in turn suppressed cell proliferation and colony formation of the transformed cells.	5	14	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1 expression	keap1	Nrf2	Nrf2	nrf2	5	6	11	12
Our data indicate that NRF2 activity is primarily affected through increased ROS production in this context and can be reversed by KEAP1 overexpression , which inhibits metabolic reprogramming and results in drastically reduced iPSC colony formation .	Our data indicate that NRF2 activity is primarily affected through increased ROS production in this context and can be reversed by KEAP1 overexpression, which inhibits metabolic reprogramming and results in drastically reduced iPSC colony formation.	4	23	reversed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1 overexpression	keap1	NRF2	NRF2	nrf2	21	22	4	5
Western blotting confirmed upregulation , phosphorylation , and nuclear translocation of Nrf2 protein followed by Keap1 decrease and upregulation of Nrf2 target genes ( AKR1B10 , FTL , GGTLA4 , HMOX1 , and MT1 ) and glutathione synthesis genes ( GCLC and GCLM ) .	Western blotting confirmed upregulation, phosphorylation, and nuclear translocation of Nrf2 protein followed by Keap1 decrease and upregulation of Nrf2 target genes (AKR1B10, FTL, GGTLA4, HMOX1, and MT1) and glutathione synthesis genes (GCLC and GCLM).	15	22	decrease	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	20	21
Under basal conditions , Nrf2 is sequestered by Keap1 in the cytosol .	Under basal conditions, Nrf2 is sequestered by Keap1 in the cytosol.	4	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
Keap-1 inhibits Nrf-2 action by binding and retention of the transcription factor in the cytoplasm [ XREF_BIBR ] .	Keap-1 inhibits Nrf-2 action by binding and retention of the transcription factor in the cytoplasm [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap-1	Keap-1	Keap-1	Nrf-2	Nrf-2	Nrf-2	0	1	2	3
The RTCA experiments clearly revealed a Nrf2 driven decrease of proliferation in response to TNF-alpha in HSE cells stably transduced with shRNA directed against Keap1 ( the inhibitor of Nrf2 ) .	The RTCA experiments clearly revealed a Nrf2 driven decrease of proliferation in response to TNF-alpha in HSE cells stably transduced with shRNA directed against Keap1 (the inhibitor of Nrf2).	22	30	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	24	25	29	30
In the resting condition , KEAP1 represses Nrf2 activity by directly binding to Nrf2 N-terminal Neh2 domain , leading to Nrf2 cytosol sequestration and proteasomal degradation XREF_BIBR .	In the resting condition, KEAP1 represses Nrf2 activity by directly binding to Nrf2 N-terminal Neh2 domain, leading to Nrf2 cytosol sequestration and proteasomal degradation XREF_BIBR.	5	8	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	5	6	7	8
However , Nrf2 activity is inhibited by Keap1 , and deletion of this second protein gene in mice caused death of these animals within the first 3weeks after birth due to hyperkeratosis in the esophagus and stomach , resulting in nutrient obstruction and stomach ulceration .	However, Nrf2 activity is inhibited by Keap1, and deletion of this second protein gene in mice caused death of these animals within the first 3weeks after birth due to hyperkeratosis in the esophagus and stomach, resulting in nutrient obstruction and stomach ulceration.	2	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	2	3
In resting cells , Kelch like-ECH-associated protein 1 ( Keap1 ) sequesters Nrf2 in the cytoplasm as an inactive complex 41 .	In resting cells, Kelch like-ECH-associated protein 1 (Keap1) sequesters Nrf2 in the cytoplasm as an inactive complex 41.	6	13	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	12	13
These results reveal that Nrf2 is degraded through both Keap1 dependent and Keap1 independent proteasomal pathways , but both CPDT and SF only block Keap1 mediated Nrf2 degradation .	These results reveal that Nrf2 is degraded through both Keap1 dependent and Keap1 independent proteasomal pathways, but both CPDT and SF only block Keap1 mediated Nrf2 degradation.	23	27	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	24	25	26	27
While siRNA knockdown of Nrf2 markedly decreased steady-state levels of Nrf2 protein , siRNA knockdown of Keap1 increased steady-state levels of Nrf2 protein as lack of Keap1 mediated degradation results in accumulation of Nrf2 .	While siRNA knockdown of Nrf2 markedly decreased steady-state levels of Nrf2 protein, siRNA knockdown of Keap1 increased steady-state levels of Nrf2 protein as lack of Keap1 mediated degradation results in accumulation of Nrf2.	14	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	21	22
Keap1 represses the Nrf2 activation , which is a master regulator of antioxidant genes , hence making it a potential drug target towards treatment of oxidative stress related disorders , including neurodegenerative disorders .	Keap1 represses the Nrf2 activation, which is a master regulator of antioxidant genes, hence making it a potential drug target towards treatment of oxidative stress related disorders, including neurodegenerative disorders.	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
As a CUL3-RBX1-dependent E3 ubiquitin ligase , Keap1 degrades Nrf2 by directly interacting with it and conjugating ubiquitin onto the N-terminal Neh2 domain of Nrf2 [ XREF_BIBR ] .	As a CUL3-RBX1-dependent E3 ubiquitin ligase, Keap1 degrades Nrf2 by directly interacting with it and conjugating ubiquitin onto the N-terminal Neh2 domain of Nrf2 [XREF_BIBR].	7	10	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	9	10
For example , Cys151 is critical for inhibition of KEAP1 dependent degradation of NRF2 by certain chemical inducers while Cys273 and Cys288 are required for NRF2 degradation via ubiquitination [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	For example, Cys151 is critical for inhibition of KEAP1 dependent degradation of NRF2 by certain chemical inducers while Cys273 and Cys288 are required for NRF2 degradation via ubiquitination [XREF_BIBR, XREF_BIBR - XREF_BIBR].	9	17	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	9	10	13	14
Keap1 is an inhibitor of the transcription factor Nrf2 and located in the cytoplasm , binding with Nrf2 to prevent its translocation to the nucleus Keap1 and Nrf2 dissociation , which results in Nrf2 nuclear translocation and increases the expression of target antioxidant enzymes such as SOD , further playing the role of antioxidation .	Keap1 is an inhibitor of the transcription factor Nrf2 and located in the cytoplasm, binding with Nrf2 to prevent its translocation to the nucleus Keap1 and Nrf2 dissociation, which results in Nrf2 nuclear translocation and increases the expression of target antioxidant enzymes such as SOD, further playing the role of antioxidation.	0	48	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	8	9
Under normal physiological conditions , most Nrf2 are sequestered in the cytoplasm through interactions with its inhibitor , Keap1 , which also directs Nrf2 toward ubiquitination and subsequent proteosomal degradation .	Under normal physiological conditions, most Nrf2 are sequestered in the cytoplasm through interactions with its inhibitor, Keap1, which also directs Nrf2 toward ubiquitination and subsequent proteosomal degradation.	16	24	directs	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	18	19	23	24
Under normal conditions , Nrf2 is sequestered in the cytoplasm by Keap1 , which facilitates its degradation via the ubiquitin-proteasome pathway .	Under normal conditions, Nrf2 is sequestered in the cytoplasm by Keap1, which facilitates its degradation via the ubiquitin-proteasome pathway.	4	14	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
This change in cellular metabolism requires loss of Nrf2 repression by Keap1 as well as costimulation via the PI3K-Akt pathway .	This change in cellular metabolism requires loss of Nrf2 repression by Keap1 as well as costimulation via the PI3K-Akt pathway.	8	12	repression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	8	9
Biochemical studies indicated that modification of Cys151 of Keap1 by AI-1 disrupted the ability of Keap1 to serve as an adaptor for Cul3-Keap1 ubiquitin ligase complex , thereby causing stabilization and transcriptional activation of Nrf2 .	Biochemical studies indicated that modification of Cys151 of Keap1 by AI-1 disrupted the ability of Keap1 to serve as an adaptor for Cul3-Keap1 ubiquitin ligase complex, thereby causing stabilization and transcriptional activation of Nrf2.	6	35	disrupted	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	34	35
In this study , hypoxia suppressed Nrf2 protein , and its hypoxic suppression was not recovered with knockdown of the Nrf2 repressor Keap1 .	In this study, hypoxia suppressed Nrf2 protein, and its hypoxic suppression was not recovered with knockdown of the Nrf2 repressor Keap1.	17	23	repressor	Negative_activation_token_1_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	20	21
Critically , inhibition of NRF2 by KEAP1 overexpression compromises metabolic reprogramming and results in reduced efficiency of iPSC colony formation .	Critically, inhibition of NRF2 by KEAP1 overexpression compromises metabolic reprogramming and results in reduced efficiency of iPSC colony formation.	2	8	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	6	7	4	5
Conversely , ubiquitylation of K7 by tripartite motif family 21 ( TRIM21 ) in the PB1 domain of p62 prevents its oligomerization and interaction with KEAP1 , keeping the KEAP1 dependent degradation of NRF2 intact [ XREF_BIBR ] .	Conversely, ubiquitylation of K7 by tripartite motif family 21 (TRIM21) in the PB1 domain of p62 prevents its oligomerization and interaction with KEAP1, keeping the KEAP1 dependent degradation of NRF2 intact [XREF_BIBR].	29	36	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	29	30	33	34
15 In addition , Keap1 may also promote degradation of Nrf2 in the nucleus via the proteasome .	15 In addition, Keap1 may also promote degradation of Nrf2 in the nucleus via the proteasome.	4	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	10	11
When cells are in a non stressed basal state , NRF2 is sequestered in the cytoplasm by KEAP1 through binding between NRF2 and KEAP1 .	When cells are in a non stressed basal state, NRF2 is sequestered in the cytoplasm by KEAP1 through binding between NRF2 and KEAP1.	10	18	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	17	18	10	11
At baseline , the Nrf2 pathway is negatively regulated by Keap1 , a cytoplasmic regulatory protein that targets Nrf2 for proteasomal degradation through interaction with the Cullin-E3 ubiquitin ligase [ XREF_BIBR , XREF_BIBR ] .	At baseline, the Nrf2 pathway is negatively regulated by Keap1, a cytoplasmic regulatory protein that targets Nrf2 for proteasomal degradation through interaction with the Cullin-E3 ubiquitin ligase [XREF_BIBR, XREF_BIBR].	8	21	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	18	19
Since p21 competitively bind to the DLG and ETCG motifs in Nrf2 , the same motifs bound by KEAP1 , Nrf2- KEAP1 interaction is reduced , so as KEAP1 mediated Nrf2 degradation , in other words , Nrf2 level and Nrf2 and EpRE signaling is increased [ XREF_BIBR ] .	Since p21 competitively bind to the DLG and ETCG motifs in Nrf2, the same motifs bound by KEAP1, Nrf2- KEAP1 interaction is reduced, so as KEAP1 mediated Nrf2 degradation, in other words, Nrf2 level and Nrf2 and EpRE signaling is increased [XREF_BIBR].	28	31	mediated	Positive_early_activation	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	28	29	30	31
Nrf2 activity is regulated by Keap1 , which under normal conditions degrades Nrf2 .	Nrf2 activity is regulated by Keap1, which under normal conditions degrades Nrf2.	3	13	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	12	13
Similarly , overexpression of Keap1 reversed the effect of Nrf2 on protein levels of TYR and TRP 1 ( XREF_FIG ) .	Similarly, overexpression of Keap1 reversed the effect of Nrf2 on protein levels of TYR and TRP 1 (XREF_FIG).	2	10	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	overexpression of Keap1	keap1	Nrf2	Nrf2	nrf2	4	5	9	10
Under basal conditions , Keap1 sequesters Nrf2 in the cytoplasm by binding to its Neh2 domain .	Under basal conditions, Keap1 sequesters Nrf2 in the cytoplasm by binding to its Neh2 domain.	4	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
The ARE driven gene transcription is regulated partially by nuclear factor Nrf2 , which under normal conditions is sequestered in the cytoplasm by Keap1 ) .	The ARE driven gene transcription is regulated partially by nuclear factor Nrf2, which under normal conditions is sequestered in the cytoplasm by Keap1).	6	24	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	23	24	11	12
Keap1 has been shown to translocate into the nucleus and downregulate Nrf2 expression XREF_BIBR , XREF_BIBR .	Keap1 has been shown to translocate into the nucleus and downregulate Nrf2 expression XREF_BIBR, XREF_BIBR.	0	13	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	11	12
Keap1 suppresses the activity of Nrf2 both passively by sequestering it in the cytoplasm , as well as actively by targeting it for polyubiquitination by a Cullin3 based E3 ligase complex and thus facilitating its proteasomal degradation ( XREF_FIG ) .	Keap1 suppresses the activity of Nrf2 both passively by sequestering it in the cytoplasm, as well as actively by targeting it for polyubiquitination by a Cullin3 based E3 ligase complex and thus facilitating its proteasomal degradation (XREF_FIG).	0	6	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	5	6
The purpose of this study was to determine how Keap1 knockdown ( Keap1-KD ) , which is known to increase Nrf2 activity , affects the CR response , such as weight loss , hepatic lipid decrease , and induction of fatty acid oxidation gene expression .	The purpose of this study was to determine how Keap1 knockdown (Keap1-KD), which is known to increase Nrf2 activity, affects the CR response, such as weight loss, hepatic lipid decrease, and induction of fatty acid oxidation gene expression.	9	21	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	20	21
These opposing expression changes suggest that Nrf2 is activated by Keap1 suppression after ICH .	These opposing expression changes suggest that Nrf2 is activated by Keap1 suppression after ICH.	6	11	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	6	7
Oxidative stress promotes HO-1 up-regulation through a double mechanism : ( i ) by inducing conformational modification of Bach1 structure , which leads to its translocation from the nucleus to the cytoplasm where Bach1 is ubiquitinated and degraded thereby , releasing transcriptional repression ; and ( ii ) by promoting the ubiquitination and consequent degradation of Keap1 , which under normal conditions sequesters Nrf-2 into the cytoplasm , avoiding its transcriptional activity ( XREF_FIG ) .	Oxidative stress promotes HO-1 up-regulation through a double mechanism : (i) by inducing conformational modification of Bach1 structure, which leads to its translocation from the nucleus to the cytoplasm where Bach1 is ubiquitinated and degraded thereby, releasing transcriptional repression; and (ii) by promoting the ubiquitination and consequent degradation of Keap1, which under normal conditions sequesters Nrf-2 into the cytoplasm, avoiding its transcriptional activity (XREF_FIG).	54	64	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf-2	Nrf-2	Nrf-2	56	57	63	64
To examine in which cells Keap1 deletion activates Nrf2 , we carried out immunostaining for NQO1 , which is a prototypical Nrf2 target gene XREF_BIBR .	To examine in which cells Keap1 deletion activates Nrf2, we carried out immunostaining for NQO1, which is a prototypical Nrf2 target gene XREF_BIBR.	5	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	8	9
The keap1 protein is normally bound to the Nrf2 transcription factor , thereby promoting Nrf2 protein degradation .	The keap1 protein is normally bound to the Nrf2 transcription factor, thereby promoting Nrf2 protein degradation.	1	16	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	keap1	keap1	keap1	Nrf2	Nrf2	Nrf2	1	2	14	15
Impairment of KEAP1 function by succination diminishes NRF2 proteosomal degradation and thereby increases NRF2 stability and activity .	Impairment of KEAP1 function by succination diminishes NRF2 proteosomal degradation and thereby increases NRF2 stability and activity.	2	9	diminishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	2	3	7	8
In the 12h PUN treatment group , the Keap1 level significantly increased , while the Nrf2 level notably decreased , suggesting that the inhibitory effect of PUN ( 100muM ) on the Keap1-Nrf2 ubiquitination sustained no longer than 12h , as Keap1 rapidly accumulated and degraded Nrf2 protein , keeping Nrf2 at a low concentration .	In the 12h PUN treatment group, the Keap1 level significantly increased, while the Nrf2 level notably decreased, suggesting that the inhibitory effect of PUN (100muM) on the Keap1-Nrf2 ubiquitination sustained no longer than 12h, as Keap1 rapidly accumulated and degraded Nrf2 protein, keeping Nrf2 at a low concentration.	41	47	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	41	42	46	47
HBx associates with the UBA and PB1 domains of the adaptor protein p62 and augments the interaction between p62 and the Nrf2 repressor Keap1 to form HBx , p62 , and Keap1 complex in the cytoplasm .	HBx associates with the UBA and PB1 domains of the adaptor protein p62 and augments the interaction between p62 and the Nrf2 repressor Keap1 to form HBx, p62, and Keap1 complex in the cytoplasm.	16	24	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	23	24	21	22
Transcription factor Nrf2 , which is sequestered in the cytoplasm by Keap1 ( Kelch like ECH associated protein-1 ) under unstimulated conditions , regulates the induction of phase 2 enzymes .	Transcription factor Nrf2, which is sequestered in the cytoplasm by Keap1 (Kelch like ECH associated protein-1) under unstimulated conditions, regulates the induction of phase 2 enzymes.	0	23	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	2	3
Altogether , the gene expression data showed that the chronic administration of either siKeap1-1 * or siKeap1-2 * suppressed hepatic Keap1 expression and stimulated Nrf2 signaling in liver , but had no effect on genes encoding proteins that are involved in the metabolism of either fatty acids or carbohydrates .	Altogether, the gene expression data showed that the chronic administration of either siKeap1-1 * or siKeap1-2 * suppressed hepatic Keap1 expression and stimulated Nrf2 signaling in liver, but had no effect on genes encoding proteins that are involved in the metabolism of either fatty acids or carbohydrates.	13	25	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	siKeap1-1 * or siKeap1-2 * suppressed hepatic Keap1 expression	keap1	Nrf2	Nrf2	nrf2	20	21	24	25
SF reacts with cysteine residues of the Nrf2 repressor Keap1 , resulting in nuclear translocation of Nrf2 and binding of the transcription factor to DNA [ XREF_BIBR ] .	SF reacts with cysteine residues of the Nrf2 repressor Keap1, resulting in nuclear translocation of Nrf2 and binding of the transcription factor to DNA [XREF_BIBR].	4	10	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	7	8
Depending on the binding affinity between Nrf2 and Keap1 and their respective intracellular concentrations , the Keap1 mediated Nrf2 degradation may operate close to saturation , making the degradation essentially a near zero-order process .	Depending on the binding affinity between Nrf2 and Keap1 and their respective intracellular concentrations, the Keap1 mediated Nrf2 degradation may operate close to saturation, making the degradation essentially a near zero-order process.	15	19	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	18	19
We find that Keap1 sequesters Nrf2 in the cytoplasm , not by docking it to the actin cytoskeleton but instead through an active Crm1 and exportin dependent nuclear export mechanism .	We find that Keap1 sequesters Nrf2 in the cytoplasm, not by docking it to the actin cytoskeleton but instead through an active Crm1 and exportin dependent nuclear export mechanism.	3	8	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	5	6
In addition , XREF_FIG western analysis of K562 KEAP1 silencing revealed an increase in NQO1 protein from two different KEAP1 silenced clone cells lines indicating that NRF2 downstream gene targets were induced in KEAP1 silenced cells allowing us to examine NRF2 mediated regulation of hematopoietic gene targets in erythroid cells .	In addition, XREF_FIG western analysis of K562 KEAP1 silencing revealed an increase in NQO1 protein from two different KEAP1 silenced clone cells lines indicating that NRF2 downstream gene targets were induced in KEAP1 silenced cells allowing us to examine NRF2 mediated regulation of hematopoietic gene targets in erythroid cells.	31	42	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	33	34	40	41
Under basal conditions , Nrf2 is sequestered in the cytoplasm by Keap1 .	Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1.	4	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
Under normal conditions , Keap1 sequesters Nrf2 in the cytoplasm and promotes its rapid degradation via ubiquitination [ XREF_BIBR ] .	Under normal conditions, Keap1 sequesters Nrf2 in the cytoplasm and promotes its rapid degradation via ubiquitination [XREF_BIBR].	4	11	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
In agreement , pharmacological ( by SFN ) or genetic ( by Keap1 knockdown ) upregulation of Nrf2 in human nontumorigenic breast epithelial MCF10A cells causes increases in the PPP enzymes [ XREF_BIBR ] .	In agreement, pharmacological (by SFN) or genetic (by Keap1 knockdown) upregulation of Nrf2 in human nontumorigenic breast epithelial MCF10A cells causes increases in the PPP enzymes [XREF_BIBR].	12	21	upregulation	Positive_activation_syntax_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	17	18
In summary , our results show that the chronic suppression of Keap1 expression in liver stimulates Nrf2 target genes involved in antioxidative stress response and xenobiotic metabolism , but has no significant effect on hepatic lipid and glucose metabolism in mice fed a WD .	In summary, our results show that the chronic suppression of Keap1 expression in liver stimulates Nrf2 target genes involved in antioxidative stress response and xenobiotic metabolism, but has no significant effect on hepatic lipid and glucose metabolism in mice fed a WD.	11	18	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1 expression	keap1	Nrf2	Nrf2	nrf2	11	12	16	17
[ XREF_BIBR ] This response , a major defense mechanism against carcinogens , aging , and neurodegeneration , is regulated by Nrf2 transcription factor , which is sequestered in the cytoplasm by Keap1 .	[XREF_BIBR] This response, a major defense mechanism against carcinogens, aging, and neurodegeneration, is regulated by Nrf2 transcription factor, which is sequestered in the cytoplasm by Keap1.	21	33	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	32	33	21	22
The cyclic sequential attachment and regeneration model of Keap1 mediated degradation of Nrf2 .	The cyclic sequential attachment and regeneration model of Keap1 mediated degradation of Nrf2.	3	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	12	13
Under physiological conditions , Nrf2 is sequestered in the cytoplasm by the repressor protein Keap1 , but in response to oxidant stimuli Nrf2 is activated and translocated into the nucleus where mediate the transcription of antioxidant and cytoprotective genes by binding to the antioxidant response element ( ARE ) within DNA [ XREF_BIBR ] .	Under physiological conditions, Nrf2 is sequestered in the cytoplasm by the repressor protein Keap1, but in response to oxidant stimuli Nrf2 is activated and translocated into the nucleus where mediate the transcription of antioxidant and cytoprotective genes by binding to the antioxidant response element (ARE) within DNA [XREF_BIBR].	4	15	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	4	5
When the body is not under oxidative stress , Keap1 inhibits the activity of Nrf2 and accelerates the degradation of Nrf2 .	When the body is not under oxidative stress, Keap1 inhibits the activity of Nrf2 and accelerates the degradation of Nrf2.	9	21	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	20	21
In PC3 cells , attenuation of Keap1 expression by RNAi approach resulted in upregulation of Nrf2 target genes and enhanced resistance to paclitaxel induced cell death ( XREF_SUPPLEMENTARY ) .	In PC3 cells, attenuation of Keap1 expression by RNAi approach resulted in upregulation of Nrf2 target genes and enhanced resistance to paclitaxel induced cell death (XREF_SUPPLEMENTARY).	6	17	resulted in upregulation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	Keap1	Keap1 expression	keap1	Nrf2	Nrf2	nrf2	6	7	15	16
KEAP1 is a repressor of the transcription factor Nrf2 , which in turn induces the expression of cytoprotective and antioxidant enzymes , including some of the enzymes of the GSH metabolism like gamma-GCS and GSH S-transferase [ XREF_BIBR ] .	KEAP1 is a repressor of the transcription factor Nrf2, which in turn induces the expression of cytoprotective and antioxidant enzymes, including some of the enzymes of the GSH metabolism like gamma-GCS and GSH S-transferase [XREF_BIBR].	0	13	is a repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	0	1	8	9
In vertebrates , the basic leucine zipper class transcription factor Nrf2 regulates the expression of antioxidant genes , and is negatively regulated by Keap1 ( kelch like ECH associated protein 1 ) .	In vertebrates, the basic leucine zipper class transcription factor Nrf2 regulates the expression of antioxidant genes, and is negatively regulated by Keap1 (kelch like ECH associated protein 1).	3	25	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	23	24	10	11
However , in the case of KEAP1 mediated Nrf2 repression , high levels of intracellular ROS facilitated an ablation of the quiescent state in intestinal stem cells and age related degeneration in the intestinal epithelium [ XREF_BIBR ] .	However, in the case of KEAP1 mediated Nrf2 repression, high levels of intracellular ROS facilitated an ablation of the quiescent state in intestinal stem cells and age related degeneration in the intestinal epithelium [XREF_BIBR].	4	9	mediated	Positive_early_activation	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	6	7	8	9
They presumed that the demethylation of the CpG islands in the Keap1 promoter might activate the expression of Keap1 protein , which then decreased Nrf2 activity by increasing Nrf2 degradation .	They presumed that the demethylation of the CpG islands in the Keap1 promoter might activate the expression of Keap1 protein, which then decreased Nrf2 activity by increasing Nrf2 degradation.	16	25	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	expression of Keap1	keap1	Nrf2	Nrf2	nrf2	18	19	24	25
Under normal or unstressed conditions , Keap1 suppresses Nrf2 in the cytoplasm .	Under normal or unstressed conditions, Keap1 suppresses Nrf2 in the cytoplasm.	6	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	8	9
Notably , a number of small molecules have been found to disrupt the Keap1 mediated degradation of Nrf2 and cause Nrf2 accumulation , and some of these molecules are approved or being developed for Nrf2 inducing therapy .	Notably, a number of small molecules have been found to disrupt the Keap1 mediated degradation of Nrf2 and cause Nrf2 accumulation, and some of these molecules are approved or being developed for Nrf2 inducing therapy.	11	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	17	18
Oxidants , xenobiotics and electrophiles hamper the Keap1 mediated proteasomal degradation of Nrf2 , which results in increased nuclear accumulation and transcriptional induction of target genes .	Oxidants, xenobiotics and electrophiles hamper the Keap1 mediated proteasomal degradation of Nrf2, which results in increased nuclear accumulation and transcriptional induction of target genes.	6	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
Keap1 is an OS sensor and negatively regulates Nrf2 .	Keap1 is an OS sensor and negatively regulates Nrf2.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	8	9
Therefore , we stably transduced HSE cells with the pLKO.1 vector containing a shRNA targeting Keap1 ( the inhibitor of Nrf2 ) to achieve an increased Nrf2 expression and activation , and performed a real-time analysis of cell proliferation .	Therefore, we stably transduced HSE cells with the pLKO.1 vector containing a shRNA targeting Keap1 (the inhibitor of Nrf2) to achieve an increased Nrf2 expression and activation, and performed a real-time analysis of cell proliferation.	14	21	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	20	21
Keap1 represses Nrf2 activity by binding to its Neh2 domain and consequently promoting contact between Nrf2 and the Cul3 and Rbx1 ubiquitin ligase complex , leading to ubiquitination and degradation of Nrf2 by proteasomes [ XREF_BIBR ] .	Keap1 represses Nrf2 activity by binding to its Neh2 domain and consequently promoting contact between Nrf2 and the Cul3 and Rbx1 ubiquitin ligase complex, leading to ubiquitination and degradation of Nrf2 by proteasomes [XREF_BIBR].	0	3	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
INrf2 ( Inhibitor of Nrf2 ) or KEAP1 ( Kelch like ECH associated protein1 ) , protein retains Nrf2 in the cytoplasm ( XREF_FIG ) .	INrf2 (Inhibitor of Nrf2) or KEAP1 (Kelch like ECH associated protein1), protein retains Nrf2 in the cytoplasm (XREF_FIG).	0	17	Inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	7	8	4	5
Dh404 Inhibits Keap1 Mediated Nrf2 Degradation by Interfering with the Ability of Keap1-Cul3-Rbx1 E3 Ligase Complex to Target Nrf2 for Ubiquitination .	Dh404 Inhibits Keap1 Mediated Nrf2 Degradation by Interfering with the Ability of Keap1-Cul3-Rbx1 E3 Ligase Complex to Target Nrf2 for Ubiquitination.	1	5	Mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	4	5
Pretreatment with various HDACi increases the expression of NRF2 and the associated antioxidant responsive genes in an in vitro model of stroke by repressing the NRF2 suppressor Keap1 [ XREF_BIBR ] .	Pretreatment with various HDACi increases the expression of NRF2 and the associated antioxidant responsive genes in an in vitro model of stroke by repressing the NRF2 suppressor Keap1 [XREF_BIBR].	23	29	suppressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	27	28	25	26
KEAP1 constitutively suppresses NRF2 activity in the absence of stress ; however , oxidants , xenobiotics , and electrophiles hamper the KEAP1 mediated proteasomal degradation of NRF2 , which results in increased nuclear accumulation and , in turn , the transcriptional induction of target genes that ensure cell survival .	KEAP1 constitutively suppresses NRF2 activity in the absence of stress; however, oxidants, xenobiotics, and electrophiles hamper the KEAP1 mediated proteasomal degradation of NRF2, which results in increased nuclear accumulation and, in turn, the transcriptional induction of target genes that ensure cell survival.	20	29	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	21	22	26	27
Under physiological conditions , Nrf2 is sequestered in the cytosol by Keap1 and is targeted for proteasomal degradation XREF_BIBR , XREF_BIBR .	Under physiological conditions, Nrf2 is sequestered in the cytosol by Keap1 and is targeted for proteasomal degradation XREF_BIBR, XREF_BIBR.	4	14	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
These mutations block proper NRF2-KEAP1 binding and inhibit KEAP1 mediated degradation of NRF2 .	These mutations block proper NRF2-KEAP1 binding and inhibit KEAP1 mediated degradation of NRF2.	7	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	8	9	12	13
Under basal conditions , Nrf2 protein is rapidly degraded with a t 1/2 of < 20 min ; Nrf2 degradation is also mediated by Keap1 via specific ubiquitin-26S proteasomal pathway .	Under basal conditions, Nrf2 protein is rapidly degraded with a t 1/2 of < 20 min; Nrf2 degradation is also mediated by Keap1 via specific ubiquitin-26S proteasomal pathway.	18	29	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	24	25	18	19
Nrf2 resides predominantly in the cytoplasm where it interacts with actin associated cytosolic protein , INrf2 ( inhibitor of Nrf2 ) or Keap1 ( Kelch like ECH associated protein 1 ) .	Nrf2 resides predominantly in the cytoplasm where it interacts with actin associated cytosolic protein, INrf2 (inhibitor of Nrf2) or Keap1 (Kelch like ECH associated protein 1).	11	20	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	15	16	19	20
Under normal conditions , Nrf2 is repressed by Keap1 ( Kelch like erythroid cell derived protein with CNC homology [ ECH ]-associated protein 1 ) , which is an adaptor protein for the degradation of Nrf2 [ XREF_BIBR ] .	Under normal conditions, Nrf2 is repressed by Keap1 (Kelch like erythroid cell derived protein with CNC homology [ECH]-associated protein 1), which is an adaptor protein for the degradation of Nrf2 [XREF_BIBR].	4	30	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
Inducers block the cycle of Keap1 mediated degradation of Nrf2 by chemically modifying specific cysteine residues within Keap1 XREF_BIBR , XREF_BIBR or by directly disrupting the Keap1 : Nrf2 binding interface XREF_BIBR , XREF_BIBR .	Inducers block the cycle of Keap1 mediated degradation of Nrf2 by chemically modifying specific cysteine residues within Keap1 XREF_BIBR, XREF_BIBR or by directly disrupting the Keap1 : Nrf2 binding interface XREF_BIBR, XREF_BIBR.	3	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	9	10
The actual mechanism by which rapamycin increases Nrf2 levels is not completely elucidated ; however , this seems to occur at the level of protein stabilization rather than increasing Nrf2 gene expression because rapamycin did not increase Nrf2 mRNA levels , but decreased Keap1 , a protein that triggers Nrf2 degradation ( Kobayashi etal ., 2004 ) .	The actual mechanism by which rapamycin increases Nrf2 levels is not completely elucidated; however, this seems to occur at the level of protein stabilization rather than increasing Nrf2 gene expression because rapamycin did not increase Nrf2 mRNA levels, but decreased Keap1, a protein that triggers Nrf2 degradation (Kobayashi etal., 2004).	42	50	triggers	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	43	44	49	50
Autophagic degradation of Keap1 allows Nrf2 to translocate to the nucleus and bind the antioxidant responsive elements ( ARE ) in the promoter region of antioxidant genes .	Autophagic degradation of Keap1 allows Nrf2 to translocate to the nucleus and bind the antioxidant responsive elements (ARE) in the promoter region of antioxidant genes.	1	7	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	5	6
Furthermore , we found that Keap1shRNA could efficiently suppress Keap1 expression and enhance Nrf2 expression , which suggest that Keap1 negatively regulates Nrf2 .	Furthermore, we found that Keap1shRNA could efficiently suppress Keap1 expression and enhance Nrf2 expression, which suggest that Keap1 negatively regulates Nrf2.	19	23	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	19	20	22	23
The working model of indirect electrophilic inducer ( SFN ) and direct , non electrophilic inducer ( PMI ) strategies to inhibit the Keap1 mediated degradation of Nrf2 is reported in Fig .	The working model of indirect electrophilic inducer (SFN) and direct, non electrophilic inducer (PMI) strategies to inhibit the Keap1 mediated degradation of Nrf2 is reported in Fig.	21	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	23	24	27	28
Nrf2 signaling is repressed by Keap1 at basal condition and induced by oxidative stress .	Nrf2 signaling is repressed by Keap1 at basal condition and induced by oxidative stress.	0	6	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	0	1
Keap1 knockdown activates Nrf2 in astrocytes .	Keap1 knockdown activates Nrf2 in astrocytes.	0	5	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
In this report , we demonstrate that Keap1 does not passively sequester Nrf2 in the cytoplasm but actively targets Nrf2 for ubiquitination and degradation by the proteosome under basal culture conditions .	In this report, we demonstrate that Keap1 does not passively sequester Nrf2 in the cytoplasm but actively targets Nrf2 for ubiquitination and degradation by the proteosome under basal culture conditions.	7	13	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
Nrf2 is normally sequestered in the cytosol by Keap1 ( Kelch like ECH associating protein 1 ) , which results in its ubiquination and degradation by the 26S proteasome [ XREF_BIBR ] .	Nrf2 is normally sequestered in the cytosol by Keap1 (Kelch like ECH associating protein 1), which results in its ubiquination and degradation by the 26S proteasome [XREF_BIBR].	0	19	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
Keap1 functions as a sensor of oxidative stress , such that the inhibition of Keap1 dependent degradation of Nrf2 activates a genetic program that protects cells from reactive chemicals and maintains cellular redox homeostasis .	Keap1 functions as a sensor of oxidative stress, such that the inhibition of Keap1 dependent degradation of Nrf2 activates a genetic program that protects cells from reactive chemicals and maintains cellular redox homeostasis.	14	19	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	18	19
Consistent with the direct inhibition of NRF2 by KEAP1 , mutations striking both KEAP1 and NRF2 within the same tumor are typically not observed .	Consistent with the direct inhibition of NRF2 by KEAP1, mutations striking both KEAP1 and NRF2 within the same tumor are typically not observed.	4	10	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	8	9	6	7
It has been proposed that ITCs interact with Keap1 , the protein that , under normal conditions , sequesters Nrf2 in the cytosol and targets it for degradation .	It has been proposed that ITCs interact with Keap1, the protein that, under normal conditions, sequesters Nrf2 in the cytosol and targets it for degradation.	6	20	sequesters	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	19	20
The mechanism for this effect has been proposed to involve thiol dependent modulation of Keap1 , leading to loss of its ability to negatively regulate Nrf2 .	The mechanism for this effect has been proposed to involve thiol dependent modulation of Keap1, leading to loss of its ability to negatively regulate Nrf2.	12	26	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	25	26
Keap1 is related to the actin cytoskeleton and functions to prevents Nrf2 entry into the nucleus .	Keap1 is related to the actin cytoskeleton and functions to prevents Nrf2 entry into the nucleus.	0	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	11	12
In unstressed cells , Nrf2 is sequestered in the cytoplasm by Keap1 promoting its rapid proteasomal degradation .	In unstressed cells, Nrf2 is sequestered in the cytoplasm by Keap1 promoting its rapid proteasomal degradation.	4	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
On the other hand , non disassociated Nrf2 arrested by Keap1 was detected under reducing conditions ( top row , XREF_FIG B ) .	On the other hand, non disassociated Nrf2 arrested by Keap1 was detected under reducing conditions (top row, XREF_FIG B).	6	11	arrested	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	7	8
Nrf2 is negatively regulated by Keap1 thereby providing inducible antioxidant defense .	Nrf2 is negatively regulated by Keap1 thereby providing inducible antioxidant defense.	0	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	0	1
However , in the presence of electrophiles or oxidative stress , these molecules can bind KEAP1 cysteine residues resulting in an allosteric conformational change that diminishes KEAP1 dependent degradation of NRF2 [ XREF_BIBR ] .	However, in the presence of electrophiles or oxidative stress, these molecules can bind KEAP1 cysteine residues resulting in an allosteric conformational change that diminishes KEAP1 dependent degradation of NRF2 [XREF_BIBR].	26	32	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	26	27	30	31
Under physiological conditions , Nrf2 is sequestered in the cytoplasm by Keap1 , which facilitates its ubiquitination and proteasomic degradation .	Under physiological conditions, Nrf2 is sequestered in the cytoplasm by Keap1, which facilitates its ubiquitination and proteasomic degradation.	4	14	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
KEAP1 inhibits nuclear factor erythroid 2 related factor 2 ( NRF2 )-induced cytoprotection , and is considered to be a candidate tumour suppressor .	KEAP1 inhibits nuclear factor erythroid 2 related factor 2 (NRF2)-induced cytoprotection, and is considered to be a candidate tumour suppressor.	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	10	11
Under homeostatic conditions , Nrf2 is sequestered by Keap1 protein in the cytoplasm .	Under homeostatic conditions, Nrf2 is sequestered by Keap1 protein in the cytoplasm.	4	9	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
Under conditions of low oxidative stress , Nrf2 is kept transcriptionally inactive by Kelch like ECH associated protein 1 ( Keap1 ) , which sequesters Nrf2 in the cytoplasmic compartment .	Under conditions of low oxidative stress, Nrf2 is kept transcriptionally inactive by Kelch like ECH associated protein 1 (Keap1), which sequesters Nrf2 in the cytoplasmic compartment.	17	29	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	25	26
In response to activators , Nrf2 is transiently induced , and functional Keap1 will reduce Nrf2 to basal levels once redox balance is restored .	In response to activators, Nrf2 is transiently induced, and functional Keap1 will reduce Nrf2 to basal levels once redox balance is restored.	11	16	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	15	16
As a result , in lysates derived from Imp-11-depleted cells , more KEAP1 is available to limit Nrf2 coprecipitation by an ARE probe ( XREF_FIG ) .	As a result, in lysates derived from Imp-11-depleted cells, more KEAP1 is available to limit Nrf2 coprecipitation by an ARE probe (XREF_FIG).	11	18	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	12	13	17	18
Keap1 negatively regulates Nrf2 function by controlling its subcellular location .	Keap1 negatively regulates Nrf2 function by controlling its subcellular location.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
After its intake , Keap-1 expression was downregulated , promoting the translocation of Nrf2 to the nucleus and the expression of its driven target genes , NQO-1 and glutathione S-transferase P1 ( GST-P1 ) .	After its intake, Keap-1 expression was downregulated, promoting the translocation of Nrf2 to the nucleus and the expression of its driven target genes, NQO-1 and glutathione S-transferase P1 (GST-P1).	4	14	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap-1	Keap-1 expression	keap-1	Nrf2	Nrf2	nrf2	4	5	13	14
Previous studies described that under normal conditions , Keap1 sequestered Nrf2 in the cytoplasm and that translocation of Nrf2 into the nucleus is essential for the transactivation of various targeted genes [ XREF_BIBR , XREF_BIBR ] .	Previous studies described that under normal conditions, Keap1 sequestered Nrf2 in the cytoplasm and that translocation of Nrf2 into the nucleus is essential for the transactivation of various targeted genes [XREF_BIBR, XREF_BIBR].	8	11	sequestered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	10	11
The loss of KEAP1 heterozygosity and KEAP1 promoter hypermethylation likely activate Nrf2 by decreasing Keap1 protein abundance .	The loss of KEAP1 heterozygosity and KEAP1 promoter hypermethylation likely activate Nrf2 by decreasing Keap1 protein abundance.	6	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1 promoter hypermethylation	keap1	Nrf2	Nrf2	nrf2	6	7	11	12
Keap1 , a protein that is considered one of the key oxidant sensors within the cell , represses Nrf2 transcriptional activity .	Keap1, a protein that is considered one of the key oxidant sensors within the cell, represses Nrf2 transcriptional activity.	0	20	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	18	19
These results confirm that KEAP1 silencing can effectively activate NRF2 signaling in colon cancer cell lines .	These results confirm that KEAP1 silencing can effectively activate NRF2 signaling in colon cancer cell lines.	4	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	4	5	9	10
Exposure to oxidative and electrophilic stresses , such as reactive oxygen species ( ROS ) or chemotherapeutic agents , impairs Keap1 mediated proteasomal degradation of Nrf2 , causing Nrf2 activation and translocation to the nucleus XREF_BIBR .	Exposure to oxidative and electrophilic stresses, such as reactive oxygen species (ROS) or chemotherapeutic agents, impairs Keap1 mediated proteasomal degradation of Nrf2, causing Nrf2 activation and translocation to the nucleus XREF_BIBR.	20	26	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	25	26
Moreover , Niture and Jaiswal found that tBHQ antagonized Bcl-2 , INrf2 ( inhibitor of Nrf2 ) interaction , led to the release and stabilization of Bcl-2 , increased Bcl-2 , Bax heterodimers , and reduced the apoptosis of mouse Hepa-1 cells .	Moreover, Niture and Jaiswal found that tBHQ antagonized Bcl-2, INrf2 (inhibitor of Nrf2) interaction, led to the release and stabilization of Bcl-2, increased Bcl-2, Bax heterodimers, and reduced the apoptosis of mouse Hepa-1 cells.	9	17	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	11	12	15	16
Interestingly , 24 h after treatment , the nuclear translocation of Nrf2 was correlated to a significant ( p < 0.05 ) decrease of the expression of Keap-1 ( an inhibitor of Nrf2 activation ) into the cytosol in limonoids co-treated cells .	Interestingly, 24 h after treatment, the nuclear translocation of Nrf2 was correlated to a significant (p < 0.05) decrease of the expression of Keap-1 (an inhibitor of Nrf2 activation) into the cytosol in limonoids co-treated cells.	25	33	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	Keap-1	expression of Keap-1	keap-1	Nrf2	Nrf2	nrf2	27	28	32	33
Nrf2 activity is downregulated by nuclear import of Keap1 where it binds Nrf2 and exports it back to the cytoplasm .	Nrf2 activity is downregulated by nuclear import of Keap1 where it binds Nrf2 and exports it back to the cytoplasm.	0	9	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
Keap1 knockdown induced the Nrf2 target gene heme oxygenase-1 ( HO1 , a positive control for Nrf2 activation ) to a similar extent as SFN treatment , whereas HDAC3 knockdown had no effect on HO1 .	Keap1 knockdown induced the Nrf2 target gene heme oxygenase-1 (HO1, a positive control for Nrf2 activation) to a similar extent as SFN treatment, whereas HDAC3 knockdown had no effect on HO1.	0	8	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	4	5
There is strong evidence that structurally diverse compounds produced from within the cell as well as from exogenous sources ( including a number of plant polyphenols ) can perturb Keap1 mediated repression of Nrf2 , leading to increased levels of Nrf2 and subsequent transcriptional activation of Nrf2 dependent genes [ XREF_BIBR ] .	There is strong evidence that structurally diverse compounds produced from within the cell as well as from exogenous sources (including a number of plant polyphenols) can perturb Keap1 mediated repression of Nrf2, leading to increased levels of Nrf2 and subsequent transcriptional activation of Nrf2 dependent genes [XREF_BIBR].	29	34	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	29	30	33	34
Under physiological conditions , Keap1 promoted cytosolic Nrf2 degradation via the Cul3 dependent ubiquitin proteasome pathway .	Under physiological conditions, Keap1 promoted cytosolic Nrf2 degradation via the Cul3 dependent ubiquitin proteasome pathway.	4	8	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	7	8
Under normal conditions , Nrf2 is sequestered in the cytoplasm by Keap1 .	Under normal conditions, Nrf2 is sequestered in the cytoplasm by Keap1.	4	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
Under normal conditions , Nrf2 is degraded by Keap1 , an E3 ligase .	Under normal conditions, Nrf2 is degraded by Keap1, an E3 ligase.	4	12	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
Such Keap1 DeltaC retains no or less ability to inhibit Nrf2 , so that it functions as a dominant negative competitor of Keap1 against its inhibition of Nrf2 due to its antagonist effect on Keap1 mediated turnover of Nrf2 protein .	Such Keap1 DeltaC retains no or less ability to inhibit Nrf2, so that it functions as a dominant negative competitor of Keap1 against its inhibition of Nrf2 due to its antagonist effect on Keap1 mediated turnover of Nrf2 protein.	20	39	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	38	39
XREF_BIBR - XREF_BIBR Because Nrf2 activity is normally restricted by Keap1 , which sequesters Nrf2 in the cytoplasm and directs it to the proteasomal degradation pathway , XREF_BIBR , XREF_BIBR it is expected that downregulation of the Keap1 protein using an RNAi approach will result in liberation and translocation of Nrf2 and subsequent expression of antioxidant genes , thereby providing cytoprotection to brain cells .	XREF_BIBR - XREF_BIBR Because Nrf2 activity is normally restricted by Keap1, which sequesters Nrf2 in the cytoplasm and directs it to the proteasomal degradation pathway, XREF_BIBR, XREF_BIBR it is expected that downregulation of the Keap1 protein using an RNAi approach will result in liberation and translocation of Nrf2 and subsequent expression of antioxidant genes, thereby providing cytoprotection to brain cells.	4	19	restricted	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	4	5
Genes with an ARE-promoter are activated by the transcription factor Nrf2 , which is sequestered by Keap1 in unstressed cells [ XREF_BIBR , XREF_BIBR ] .	Genes with an ARE-promoter are activated by the transcription factor Nrf2, which is sequestered by Keap1 in unstressed cells [XREF_BIBR, XREF_BIBR].	5	17	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	10	11
37 Nrf2 is inhibited by modifications of cysteine residues of Keap1 that apparently alter the interaction of Keap1 with Nrf2 and lead to its relocation to the cytoplasm where it is subsequently degraded by the ubiquitin proteasome .	37 Nrf2 is inhibited by modifications of cysteine residues of Keap1 that apparently alter the interaction of Keap1 with Nrf2 and lead to its relocation to the cytoplasm where it is subsequently degraded by the ubiquitin proteasome.	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	1	2
Induction of Nqo1 transcripts by WA was compared in wild-type MEF , Nrf2 disrupted MEF , Keap1 disrupted MEF and Keap1 & Nrf2 double disrupted MEF .	Induction of Nqo1 transcripts by WA was compared in wild-type MEF, Nrf2 disrupted MEF, Keap1 disrupted MEF and Keap1 & Nrf2 double disrupted MEF.	16	24	disrupted	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	22	23
Conversely , deletion of the KEAP1 gene significantly activated NRF2 .	Conversely, deletion of the KEAP1 gene significantly activated NRF2.	5	10	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	5	6	9	10
H 2 S also S-sulfhydrates the C226 and C613 residues in Kelch like ECH associated protein-1 ( Keap1 ) , which is a redox sensitive ubiquitin ligase substrate adaptor that represses Nrf2 .	H 2 S also S-sulfhydrates the C226 and C613 residues in Kelch like ECH associated protein-1 (Keap1), which is a redox sensitive ubiquitin ligase substrate adaptor that represses Nrf2.	15	32	represses	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	31	32
Under quiescent conditions , Nrf2 is typically sequestered by Keap1 , an inhibitory partner of Nrf2 , in the cytoplasm , where it is degraded .	Under quiescent conditions, Nrf2 is typically sequestered by Keap1, an inhibitory partner of Nrf2, in the cytoplasm, where it is degraded.	4	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	4	5
Nrf2 was abundantly transcribed in HSCs , but its activity was maintained at low levels due to the Keap1 mediated degradation of Nrf2 protein .	Nrf2 was abundantly transcribed in HSCs, but its activity was maintained at low levels due to the Keap1 mediated degradation of Nrf2 protein.	11	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	18	19	22	23
Under basal conditions , Nrf2 is sequestered by Keap1 in the cytosol , and maintained in a low constitutive level through constant ubiquitination and degradation by the 26S proteasome .	Under basal conditions, Nrf2 is sequestered by Keap1 in the cytosol, and maintained in a low constitutive level through constant ubiquitination and degradation by the 26S proteasome.	4	14	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
Functional and transcript analyses revealed R34 mutation prevents KEAP1 mediated NRF2 degradation , stabilizes the protein , and leads to NRF2 activation .	Functional and transcript analyses revealed R34 mutation prevents KEAP1 mediated NRF2 degradation, stabilizes the protein, and leads to NRF2 activation.	7	11	mediated	Positive_early_activation	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	8	9	10	11
In RAW 264.7 macrophages , treatment of 30 nM of TSA for 16 h decreased the protein levels of Keap1 , allowing NRF2 to translocate to the nucleus , and NRF2 binding to the promoter of heme oxygenase 1 was also increased [ XREF_BIBR ] .	In RAW 264.7 macrophages, treatment of 30 nM of TSA for 16 h decreased the protein levels of Keap1, allowing NRF2 to translocate to the nucleus, and NRF2 binding to the promoter of heme oxygenase 1 was also increased [XREF_BIBR].	10	24	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	TSA for 16 h decreased the protein levels of Keap1	keap1	NRF2	NRF2	nrf2	19	20	22	23
Under normal physiological conditions , Nrf2 is sequestered in the cytoplasm by its inhibitor Keap-1 and constantly targeted for proteasomal degradation .	Under normal physiological conditions, Nrf2 is sequestered in the cytoplasm by its inhibitor Keap-1 and constantly targeted for proteasomal degradation.	5	17	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap-1	Keap-1	Keap-1	Nrf2	Nrf2	Nrf2	14	15	5	6
To investigate whether inhibition of Nrf2 by Keap1 is interfered by distinct expression of Keap1 DeltaC in four different cell lines , thus we examined basal protein levels of Keap1 and Nrf2 , along with its downstream target genes HO-1 , GCLM and NQO1 .	To investigate whether inhibition of Nrf2 by Keap1 is interfered by distinct expression of Keap1 DeltaC in four different cell lines, thus we examined basal protein levels of Keap1 and Nrf2, along with its downstream target genes HO-1, GCLM and NQO1.	3	8	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	5	6
The decreased Keap1 transcription and thereby reduced expression , leads to elevated Nrf2 synthesis and activity .	The decreased Keap1 transcription and thereby reduced expression, leads to elevated Nrf2 synthesis and activity.	0	13	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1 transcription	keap1	Nrf2	Nrf2	nrf2	2	3	12	13
Under unstressed conditions , Keap1 represses Nrf2 transactivation activity .	Under unstressed conditions, Keap1 represses Nrf2 transactivation activity.	4	8	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
Under normal conditions , Nrf2 is sequestered in the cytosol by Keap1 , the cytosolic repressor of Nrf2 .	Under normal conditions, Nrf2 is sequestered in the cytosol by Keap1, the cytosolic repressor of Nrf2.	4	15	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
Repression of Nrf2 by Keap1 .	Repression of Nrf2 by Keap1.	0	5	Repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	2	3
The last function involves NRF2 activation , which can be mediated through SIRT1 expression or by decreasing KEAP1 levels , as we describe here .	The last function involves NRF2 activation, which can be mediated through SIRT1 expression or by decreasing KEAP1 levels, as we describe here.	4	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1 levels	keap1	NRF2	NRF2	nrf2	17	18	4	5
Mutations in KEAP1 , NFE2L2 ( Nrf2 ) , CUL3 or RBX1 are the most common mechanisms that impair KEAP1 mediated degradation of NFE2L2 and thereby activate the transcriptional effects of NFE2L2 .	Mutations in KEAP1, NFE2L2 (Nrf2), CUL3 or RBX1 are the most common mechanisms that impair KEAP1 mediated degradation of NFE2L2 and thereby activate the transcriptional effects of NFE2L2.	18	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NFE2L2	NFE2L2	NFE2L2	19	20	23	24
Detailed analysis of the regulatory mechanisms of Nrf2 activity has ultimately led us to the identification of a new protein , which we have named Keap1 , that suppresses Nrf2 activity by specific binding to its evolutionarily conserved N-terminal Neh2 regulatory domain .	Detailed analysis of the regulatory mechanisms of Nrf2 activity has ultimately led us to the identification of a new protein, which we have named Keap1, that suppresses Nrf2 activity by specific binding to its evolutionarily conserved N-terminal Neh2 regulatory domain.	24	30	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	25	26	29	30
Under oxidative stress KEAP1 is inactivated , thus allowing nuclear accumulation and activation of Nrf2 .	Under oxidative stress KEAP1 is inactivated, thus allowing nuclear accumulation and activation of Nrf2.	3	15	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	3	4	14	15
In an equilibrium with Keap1 mediated Nrf2 degradation , this low activity of constitutive translation of Nrf2 is likely sufficient for cells to keep surveillance of the slight redox fluctuation and maintain basal antioxidant activity .	In an equilibrium with Keap1 mediated Nrf2 degradation, this low activity of constitutive translation of Nrf2 is likely sufficient for cells to keep surveillance of the slight redox fluctuation and maintain basal antioxidant activity.	2	7	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
Under normal conditions , NRF2 is sequestered by KEAP1 ubiquitination and degradation .	Under normal conditions, NRF2 is sequestered by KEAP1 ubiquitination and degradation.	4	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1 ubiquitination	keap1	NRF2	NRF2	nrf2	8	9	4	5
Nrf2 is negatively regulated by specific suppressor protein Keap1 , which is also a receptor of electrophiles and adapter for Cul3 ubiquitin ligase .	Nrf2 is negatively regulated by specific suppressor protein Keap1, which is also a receptor of electrophiles and adapter for Cul3 ubiquitin ligase.	0	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
Functional KEAP1 represses NRF2 activity by recruiting the NRF2 protein to the actin cytoskeleton [ XREF_BIBR ] .	Functional KEAP1 represses NRF2 activity by recruiting the NRF2 protein to the actin cytoskeleton [XREF_BIBR].	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	1	2	3	4
We then showed that electrophilic agents antagonize Keap1 inhibition of Nrf2 activity in vivo , allowing Nrf2 to traverse from the cytoplasm to the nucleus and potentiate the ARE response .	We then showed that electrophilic agents antagonize Keap1 inhibition of Nrf2 activity in vivo, allowing Nrf2 to traverse from the cytoplasm to the nucleus and potentiate the ARE response.	7	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	10	11
Whereas , cells with stable KEAP1 knockdown , which causes a modest NRF2 activation , demonstrated substantially increased levels of AKR1A1 , 1B1 , 1B10 , 1C1 , 1C2 , and 1C3 .	Whereas, cells with stable KEAP1 knockdown, which causes a modest NRF2 activation, demonstrated substantially increased levels of AKR1A1, 1B1, 1B10, 1C1, 1C2, and 1C3.	5	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	5	6	12	13
Keap1 has been known to sequester Nrf2 in the cytoplasm and also leads to the proteasomal degradation of Nrf2 .	Keap1 has been known to sequester Nrf2 in the cytoplasm and also leads to the proteasomal degradation of Nrf2.	0	12	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	6	7
In response to numerous types of stress , most notably oxidative stress , KEAP1 , a cysteine rich protein , acts as a redox sensor , and oxidative modification of critical cysteines , particularly C151 , of KEAP1 dissociates Nrf2-KEAP1 from CUL3 thereby preventing Nrf2 degradation XREF_BIBR , XREF_BIBR , XREF_BIBR .	In response to numerous types of stress, most notably oxidative stress, KEAP1, a cysteine rich protein, acts as a redox sensor, and oxidative modification of critical cysteines, particularly C151, of KEAP1 dissociates Nrf2-KEAP1 from CUL3 thereby preventing Nrf2 degradation XREF_BIBR, XREF_BIBR, XREF_BIBR.	31	46	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	37	38	44	45
MGO activates Keap1 overexpression by loss of Keap1 promoter DNA methylation , thereby suppressing the Nrf2 and its downstream target genes .	MGO activates Keap1 overexpression by loss of Keap1 promoter DNA methylation, thereby suppressing the Nrf2 and its downstream target genes.	0	20	suppressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	MGO activates Keap1 overexpression	keap1	Nrf2	Nrf2	nrf2	2	3	15	16
Contrary to this , hepatocyte specific deletion of Keap1 activates Nrf2 and confers resistance against APAP toxicity [ XREF_BIBR ] .	Contrary to this, hepatocyte specific deletion of Keap1 activates Nrf2 and confers resistance against APAP toxicity [XREF_BIBR].	6	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	10	11
In response to RA treatment , overexpression of Nrf2 resulted in further up-regulation of NF-M , whereas knockdown of Nrf2 by Keap1 overexpression suppressed upregualtion of NF-M by RA ( XREF_FIG , compare lanes 4 and 6 with lane 2 ) .	In response to RA treatment, overexpression of Nrf2 resulted in further up-regulation of NF-M, whereas knockdown of Nrf2 by Keap1 overexpression suppressed upregualtion of NF-M by RA (XREF_FIG, compare lanes 4 and 6 with lane 2).	17	23	knockdown	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1 overexpression	keap1	Nrf2	Nrf2	nrf2	21	22	19	20
Following oxidative damage , Keap1 is inhibited allowing NRF2 to rapidly accumulate and initiate transcription .	Following oxidative damage, Keap1 is inhibited allowing NRF2 to rapidly accumulate and initiate transcription.	4	13	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	4	5	8	9
Keap1 knockdown also was used to induce Nrf2 ; following siRNA mediated silencing of NMRAL2P , a significant reduction was observed in the inducibility of both NMRAL2P ( XREF_FIG ) and NQO1 ( XREF_FIG ) .	Keap1 knockdown also was used to induce Nrf2; following siRNA mediated silencing of NMRAL2P, a significant reduction was observed in the inducibility of both NMRAL2P (XREF_FIG) and NQO1 (XREF_FIG).	0	8	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	7	8
As expected , none of the inhibitors was able to restore the level of Nrf2 in ENC1 overexpressed cells ( XREF_FIG , compare lane 4-8 with lane 3 ) , indicating that the recovery of endogenous Nrf2 following proteasomal inhibition is solely due to blockage of the Keap1 mediated Nrf2 degradation ( XREF_FIG , compare lanes 4-6 with lane 3 ) .	As expected, none of the inhibitors was able to restore the level of Nrf2 in ENC1 overexpressed cells (XREF_FIG, compare lane 4-8 with lane 3), indicating that the recovery of endogenous Nrf2 following proteasomal inhibition is solely due to blockage of the Keap1 mediated Nrf2 degradation (XREF_FIG, compare lanes 4-6 with lane 3).	44	50	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	47	48	49	50
The Keap1-Nrf2 system mitigates OS : Nrf2 activates cellular reactions against OS whereas Keap1 negatively regulates Nrf2 .	The Keap1-Nrf2 system mitigates OS : Nrf2 activates cellular reactions against OS whereas Keap1 negatively regulates Nrf2.	13	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	16	17
As a stress response , cysteine residues in Keap1 disrupted , causing Nrf2 to be released and translocate into the nucleus to bind to ARE .	As a stress response, cysteine residues in Keap1 disrupted, causing Nrf2 to be released and translocate into the nucleus to bind to ARE.	6	13	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	12	13
Since the degradation of Keap1 is dependent on the activity of p62 and SQSTM1 21 , it is plausible that Keap1 , a cytosolic inhibitor of Nrf2 , would accumulate in p62 and SQSTM1 knockout mice , thus blocking the activation of Nrf2 .	Since the degradation of Keap1 is dependent on the activity of p62 and SQSTM1 21, it is plausible that Keap1, a cytosolic inhibitor of Nrf2, would accumulate in p62 and SQSTM1 knockout mice, thus blocking the activation of Nrf2.	23	43	blocking	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cytosolic inhibitor of Nrf2	cytosolic inhibitor of Nrf2	cytosolic inhibitor of Nrf2	Nrf2	Nrf2	Nrf2	23	27	42	43
Nrf2 is inhibited in the cytoplasm by the anchor protein Kelch like ECH associated protein-1 ( Keap1 ) , a cytosolic protein that inhibits Nrf2 signalling by promoting Nrf2 degradation through proteasomal pathway [ XREF_BIBR ] .	Nrf2 is inhibited in the cytoplasm by the anchor protein Kelch like ECH associated protein-1 (Keap1), a cytosolic protein that inhibits Nrf2 signalling by promoting Nrf2 degradation through proteasomal pathway [XREF_BIBR].	14	25	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	24	25
Keap1 negatively regulates Nrf2 activity by targeting it for proteasomal degradation .	Keap1 negatively regulates Nrf2 activity by targeting it for proteasomal degradation.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
Keap1 can suppress the Nrf2 function by binding to the N-terminal Neh2 domain of Nrf2 and retains Nrf2 in the cytoplasma [ XREF_BIBR , XREF_BIBR ] .	Keap1 can suppress the Nrf2 function by binding to the N-terminal Neh2 domain of Nrf2 and retains Nrf2 in the cytoplasma [XREF_BIBR, XREF_BIBR].	0	16	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	4	5
KEAP1 negatively regulates Nrf2 activity by targeting it for proteasomal degradation [ XREF_BIBR - XREF_BIBR ] .	KEAP1 negatively regulates Nrf2 activity by targeting it for proteasomal degradation [XREF_BIBR - XREF_BIBR].	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	0	1	3	4
Under basal conditions , Nrf2 dependent transcription is suppressed by Keap1 , a negative regulator of Nrf2 , which facilitates the degradation of Nrf2 through ubiquitin mediated proteasomal degradation .	Under basal conditions, Nrf2 dependent transcription is suppressed by Keap1, a negative regulator of Nrf2, which facilitates the degradation of Nrf2 through ubiquitin mediated proteasomal degradation.	4	11	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	4	5
Additionally , microRNA mediated silence of Keap1 also activated Nrf2 signaling in RPEs and RGCs , therefore offering protection against UVR induced oxidative stress [ XREF_BIBR ] .	Additionally, microRNA mediated silence of Keap1 also activated Nrf2 signaling in RPEs and RGCs, therefore offering protection against UVR induced oxidative stress [XREF_BIBR].	4	10	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	9	10
The antagonistic relationship of Nrf2 and the NLRP3 inflammasome is also reflected by the fast and Keap1 independent degradation of Nrf2 upon NLRP3 inflammasome activation ( XREF_FIG ) [ XREF_BIBR ] .	The antagonistic relationship of Nrf2 and the NLRP3 inflammasome is also reflected by the fast and Keap1 independent degradation of Nrf2 upon NLRP3 inflammasome activation (XREF_FIG) [XREF_BIBR].	16	21	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	20	21
Keap1 and Nrf2 complex prevents oxidative injury in IR stressed OLTs through Keap1 signaling , which negatively regulates Nrf2 pathway .	Keap1 and Nrf2 complex prevents oxidative injury in IR stressed OLTs through Keap1 signaling, which negatively regulates Nrf2 pathway.	12	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	18	19
In the inactive state , KEAP-1 sequesters Nrf-2 in the cytoplasm , facilitating the E3 ubiquitin ligase cullin-3 mediated Nrf-2 proteolysis .	In the inactive state, KEAP-1 sequesters Nrf-2 in the cytoplasm, facilitating the E3 ubiquitin ligase cullin-3 mediated Nrf-2 proteolysis.	5	10	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP-1	KEAP-1	KEAP-1	Nrf-2	Nrf-2	Nrf-2	5	6	7	8
The activation of Nrf2 either by overexpression or by Keap1 knockdown repressed LC3B-I and II and also decreased autophagosome number .	The activation of Nrf2 either by overexpression or by Keap1 knockdown repressed LC3B-I and II and also decreased autophagosome number.	1	10	activation	Positive_activation_syntax_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	3	4
While Nrf2 target genes were upregulated by Keap1 loss , NFkB target genes were not differentially enriched in either of K/P-LSCC or P-LSCC cells ( XREF_FIG ) .	While Nrf2 target genes were upregulated by Keap1 loss, NFkB target genes were not differentially enriched in either of K/P-LSCC or P-LSCC cells (XREF_FIG).	1	8	upregulated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	1	2
Thus , Keap 1 inhibition of Nrf2 is present in unstressed cells and is released by oxidative stress , allowing Nrf2 to translocate into the nucleus and transcribe Prdx6 .	Thus, Keap 1 inhibition of Nrf2 is present in unstressed cells and is released by oxidative stress, allowing Nrf2 to translocate into the nucleus and transcribe Prdx6.	2	7	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap 1	Keap 1	Keap 1	Nrf2	Nrf2	Nrf2	2	4	6	7
4-HNE can react with cysteine sites in the KEAP1 protein and that may disrupt the KEAP1 dependent degradation of NRF2 [ XREF_BIBR ] .	4-HNE can react with cysteine sites in the KEAP1 protein and that may disrupt the KEAP1 dependent degradation of NRF2 [XREF_BIBR].	15	21	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	15	16	19	20
KEAP1 is the suppressor of NRF2 .	KEAP1 is the suppressor of NRF2.	0	6	is the suppressor	Negative_activation_copula_1	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	5	6
In spite of its importance in organismal and cellular protection , Nrf2 is repressed under normal conditions by Keap1 , a Cullin3 dependent ubiquitin ligase adaptor protein that sequesters Nrf2 in the cytoplasm and targets it for ubiquitination and proteasomal degradation XREF_BIBR , XREF_BIBR .	In spite of its importance in organismal and cellular protection, Nrf2 is repressed under normal conditions by Keap1, a Cullin3 dependent ubiquitin ligase adaptor protein that sequesters Nrf2 in the cytoplasm and targets it for ubiquitination and proteasomal degradation XREF_BIBR, XREF_BIBR.	13	30	sequesters	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	18	19	29	30
Keap1 suppresses Nrf2 activity by specifically binding to its evolutionarily conserved N-terminal Neh2 regulatory domain .	Keap1 suppresses Nrf2 activity by specifically binding to its evolutionarily conserved N-terminal Neh2 regulatory domain.	0	3	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
These observations suggest that treatment with these inhibitors partially activates NRF2 , and that loss of KEAP1 leads to further NRF2 activation , which decreases drug sensitivity .	These observations suggest that treatment with these inhibitors partially activates NRF2, and that loss of KEAP1 leads to further NRF2 activation, which decreases drug sensitivity.	14	21	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	loss of KEAP1	keap1	NRF2	NRF2	nrf2	16	17	20	21
Keap1 tightly represses Nrf2 activity in normal conditions , and Nrf2 activity is induced by loss of Keap1 .	Keap1 tightly represses Nrf2 activity in normal conditions, and Nrf2 activity is induced by loss of Keap1.	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
It is primarily regulated by its inhibitory protein -Kelch like ECH associated protein 1 ( Keap1 ) , which sequesters Nrf2 in the cytoplasm and facilitates its proteasomal degradation , maintaining a low level of Nrf2 in cytoplasm .	It is primarily regulated by its inhibitory protein -Kelch like ECH associated protein 1 (Keap1), which sequesters Nrf2 in the cytoplasm and facilitates its proteasomal degradation, maintaining a low level of Nrf2 in cytoplasm.	12	21	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	20	21
Nuclear factor erythroid 2 related factor 2 ( NRF2 ) activates expression of cytoprotective proteins such as GCLC and enhances cancer cell survival , whereas KEAP1 inhibits NRF2 by mediating NRF2 degradation .	Nuclear factor erythroid 2 related factor 2 (NRF2) activates expression of cytoprotective proteins such as GCLC and enhances cancer cell survival, whereas KEAP1 inhibits NRF2 by mediating NRF2 degradation.	25	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	25	26	30	31
In fact , Keap1 sequesters Nrf2 in the cytoplasm , thereby promoting its ubiquitination and degradation by 26 S proteasome complex .	In fact, Keap1 sequesters Nrf2 in the cytoplasm, thereby promoting its ubiquitination and degradation by 26 S proteasome complex.	3	6	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	5	6
However , we are planning to conduct experiments using tagged Nrf2 and Keap1 in cell culture that MGO mediated overexpression of Keap1 prevents Nrf2 from translocating to the nucleus in near future .	However, we are planning to conduct experiments using tagged Nrf2 and Keap1 in cell culture that MGO mediated overexpression of Keap1 prevents Nrf2 from translocating to the nucleus in near future.	17	24	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	MGO mediated overexpression of Keap1	keap1	Nrf2	Nrf2	nrf2	21	22	23	24
NRF2 is sequestered by the inhibitor Keap1 and is transcriptionally inactive until Keap1 is dissociated by ROS .	NRF2 is sequestered by the inhibitor Keap1 and is transcriptionally inactive until Keap1 is dissociated by ROS.	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	6	7	0	1
Nrf2 protein is maintained at low levels by its inhibitor , kelch like ECH associated protein 1 ( Keap1 ) , which sequesters Nrf2 in the cytosol and facilitates its degradation via the proteasome [ XREF_BIBR ] .	Nrf2 protein is maintained at low levels by its inhibitor, kelch like ECH associated protein 1 (Keap1), which sequesters Nrf2 in the cytosol and facilitates its degradation via the proteasome [XREF_BIBR].	9	24	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	kelch like ECH associated protein 1	kelch like ECH associated protein 1	kelch like ECH associated protein 1	Nrf2	Nrf2	Nrf2	11	17	23	24
The activity of Nrf2 is controlled by the cysteine rich cytosolic INrf2 ( Inhibitor of Nrf2 ) , also known as Keap1 ( Kelch like ECH associated protein1 ) .	The activity of Nrf2 is controlled by the cysteine rich cytosolic INrf2 (Inhibitor of Nrf2), also known as Keap1 (Kelch like ECH associated protein1).	5	19	Inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	11	12	15	16
Under basal conditions , Keap1 negatively regulates Nrf2 through direct association .	Under basal conditions, Keap1 negatively regulates Nrf2 through direct association.	4	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	7	8
Keap1 limits the activity of NRF2 by sequestering it in the cytoplasm and promoting its proteasomal degradation .	Keap1 limits the activity of NRF2 by sequestering it in the cytoplasm and promoting its proteasomal degradation.	0	6	limits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	0	1	5	6
Through the analysis of NEKO mice , we identified a novel phenotype in which Nrf2 hyperactivation mediated by the loss of Keap1 in the developing kidney causes NDI and hydronephrosis .	Through the analysis of NEKO mice, we identified a novel phenotype in which Nrf2 hyperactivation mediated by the loss of Keap1 in the developing kidney causes NDI and hydronephrosis.	14	22	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	loss of Keap1	keap1	Nrf2	Nrf2	nrf2	21	22	14	15
Through binding to the Neh2 domain of NRF2 , KEAP1 mediates ubiquitinylation and subsequent proteasomal degradation of NRF2 .	Through binding to the Neh2 domain of NRF2, KEAP1 mediates ubiquitinylation and subsequent proteasomal degradation of NRF2.	9	18	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	9	10	17	18
For example , NRF2 , a critical nuclear transcription factor regulating oxidative stress , is degraded by KEAP1 and cullin -3 ubiquitin ligase [ XREF_BIBR , XREF_BIBR ] .	For example, NRF2, a critical nuclear transcription factor regulating oxidative stress, is degraded by KEAP1 and cullin -3 ubiquitin ligase [XREF_BIBR, XREF_BIBR].	3	22	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	17	18	3	4
Butein modulation of Keap1 and Nrf2 as well as HO-1 upregulation was reversed by pretreatment with p38 MAPK inhibitor SB203580 , indicating the involvement of p38 MAPK in butein activation of Nrf2 in adipocytes .	Butein modulation of Keap1 and Nrf2 as well as HO-1 upregulation was reversed by pretreatment with p38 MAPK inhibitor SB203580, indicating the involvement of p38 MAPK in butein activation of Nrf2 in adipocytes.	1	33	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	31	32
28 A key regulator of this oxidative stress response is the transcription factor NRF2 , which in unstressed cells is sequestered in the cytoplasm by the adaptor protein KEAP1 .	28 A key regulator of this oxidative stress response is the transcription factor NRF2, which in unstressed cells is sequestered in the cytoplasm by the adaptor protein KEAP1.	0	29	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	28	29	13	14
Functional disorder of Keap1 inhibits Nrf2 degradation XREF_BIBR .	Functional disorder of Keap1 inhibits Nrf2 degradation XREF_BIBR.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	5	6
Thus , podocyte injury can not effectively activate Nrf2 , but Nrf2 activation by Keap1 knockdown attenuates glomerulosclerosis .	Thus, podocyte injury can not effectively activate Nrf2, but Nrf2 activation by Keap1 knockdown attenuates glomerulosclerosis.	11	15	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	11	12
Keap1 enhances Nrf2 degradation by acting as an adaptor protein for the Nrf2 and Cullin3-Rbx1 E3 ubiquitin ligase complex .	Keap1 enhances Nrf2 degradation by acting as an adaptor protein for the Nrf2 and Cullin3-Rbx1 E3 ubiquitin ligase complex.	0	3	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
However , upon exposure to ROS , Keap1 undergoes a conformational change when its multiple cysteine residues interact with ROS , which releases Nrf2 , and inhibits Keap1 mediated proteasomal degradation of Nrf2 .	However, upon exposure to ROS, Keap1 undergoes a conformational change when its multiple cysteine residues interact with ROS, which releases Nrf2, and inhibits Keap1 mediated proteasomal degradation of Nrf2.	27	33	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	27	28	32	33
Nrf2 is normally sequestered and inhibited at the cytoplasm by Keap1 .	Nrf2 is normally sequestered and inhibited at the cytoplasm by Keap1.	0	11	sequestered	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	0	1
In conclusion , Keap1 and Nrf2 complex ameliorated hepatic IRI in OLTs through Keap1 negatively regulating Nrf2 activity ( XREF_SUPPLEMENTARY ) .	In conclusion, Keap1 and Nrf2 complex ameliorated hepatic IRI in OLTs through Keap1 negatively regulating Nrf2 activity (XREF_SUPPLEMENTARY).	7	17	negatively regulating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	16	17
The Nrf2 transcription factor , which plays important roles in oxidative and xenobiotic stress , is negatively regulated by the cytoplasmic repressor Keap1 .	The Nrf2 transcription factor, which plays important roles in oxidative and xenobiotic stress, is negatively regulated by the cytoplasmic repressor Keap1.	1	23	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	1	2
Nrf2 is normally inactivated by Keap1 in cytoplasm .	Nrf2 is normally inactivated by Keap1 in cytoplasm.	0	7	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	0	1
BHA and TBHQ activate Nrf2 , a transcription factor that is negatively regulated by Keap1 and plays a role in the initial response to chemicals causing oxidative or electrophilic stress , although , the exact mechanism of Nrf2 activation remains unclear .	BHA and TBHQ activate Nrf2, a transcription factor that is negatively regulated by Keap1 and plays a role in the initial response to chemicals causing oxidative or electrophilic stress, although, the exact mechanism of Nrf2 activation remains unclear.	4	25	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	4	5
The independent mechanisms of CncC inhibition by Keap1 and Fs ( 1 ) h are consistent with the synergistic effect of combined JQ1 and oltipraz treatment on Nrf2 target gene expression .	The independent mechanisms of CncC inhibition by Keap1 and Fs (1) h are consistent with the synergistic effect of combined JQ1 and oltipraz treatment on Nrf2 target gene expression.	4	9	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	CncC	CncC	CncC	7	8	4	5
In experimental mice , mutation of the gene encoding NRF2 or overexpression of NRF2 by KEAP1 knockout enhances cancer cell proliferation .	In experimental mice, mutation of the gene encoding NRF2 or overexpression of NRF2 by KEAP1 knockout enhances cancer cell proliferation.	9	16	overexpression	Positive_activation_token_2_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	15	16	13	14
Keap1 , a cytoplasmic protein , sequesters Nrf2 in the cytoplasm under normal conditions .	Keap1, a cytoplasmic protein, sequesters Nrf2 in the cytoplasm under normal conditions.	0	10	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	7	8
The induction of UGT1A1 proceeded following the overexpression of Nrf2 and was blocked following overexpression of Keap1 , demonstrating that Keap1 suppresses Nrf2 activation of the UGT1A1 gene .	The induction of UGT1A1 proceeded following the overexpression of Nrf2 and was blocked following overexpression of Keap1, demonstrating that Keap1 suppresses Nrf2 activation of the UGT1A1 gene.	20	23	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	22	23
Keap1 represses Nrf2 transcription functions and targets Nrf2 for ubiquitin dependent degradation , under unstressed conditions , by associating with the Neh2 domain of Nrf2 .	Keap1 represses Nrf2 transcription functions and targets Nrf2 for ubiquitin dependent degradation, under unstressed conditions, by associating with the Neh2 domain of Nrf2.	0	9	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	7	8
In non stressed cells , Nrf2 is localized primarily in the cytoplasm due to its binding to kelch like ECH associating protein 1 ( Keap1 ) , which negatively regulates Nrf2 function by initiating its proteasomal degradation .	In non stressed cells, Nrf2 is localized primarily in the cytoplasm due to its binding to kelch like ECH associating protein 1 (Keap1), which negatively regulates Nrf2 function by initiating its proteasomal degradation.	21	31	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	24	25	30	31
We were able to validate the regulatory role of Nrf2 on TMEM173 mRNA levels by multiple qPCR experiments in A549 and also in human keratinocyte HaCat cells , which were instead silenced for the Nrf2 repressor Keap1 .	We were able to validate the regulatory role of Nrf2 on TMEM173 mRNA levels by multiple qPCR experiments in A549 and also in human keratinocyte HaCat cells, which were instead silenced for the Nrf2 repressor Keap1.	31	37	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	36	37	34	35
NRF2 is negatively regulated by the redox sensitive ubiquitin ligase KEAP1 in the cytosol .	NRF2 is negatively regulated by the redox sensitive ubiquitin ligase KEAP1 in the cytosol.	0	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	10	11	0	1
As a result , NRF2 is constantly translated by the cell ; however , under stress-free conditions , when NRF2 activation is not needed , its negative regulator KEAP1 constantly targets NRF2 for degradation [ XREF_BIBR , XREF_BIBR ] .	As a result, NRF2 is constantly translated by the cell; however, under stress-free conditions, when NRF2 activation is not needed, its negative regulator KEAP1 constantly targets NRF2 for degradation [XREF_BIBR, XREF_BIBR].	25	37	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	28	29	31	32
KEAP1 inhibits NRF2 both by sequestering it in the cytoplasm and targeting it for polyubiquitination and proteasomal degradation [ XREF_BIBR ] .	KEAP1 inhibits NRF2 both by sequestering it in the cytoplasm and targeting it for polyubiquitination and proteasomal degradation [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	2	3
According to Zhang and colleagues , the Nrf2 signaling pathway is mainly regulated by the inhibition of Nrf2 protein degradation , which is mediated by Keap1 dependent ubiquitin conjugation XREF_BIBR .	According to Zhang and colleagues, the Nrf2 signaling pathway is mainly regulated by the inhibition of Nrf2 protein degradation, which is mediated by Keap1 dependent ubiquitin conjugation XREF_BIBR.	17	29	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	25	26	17	18
Nrf2 is sequestered by Keap1 ; upon entering the nucleus , Nrf2 forms heterodimer with Maf .	Nrf2 is sequestered by Keap1; upon entering the nucleus, Nrf2 forms heterodimer with Maf.	0	5	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	0	1
Nrf2 resides in the cytoplasm and is constitutively degraded by Keap1 .	Nrf2 resides in the cytoplasm and is constitutively degraded by Keap1.	0	11	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	0	1
Nrf2 could be activated either by degradation of Keap1 via autophagy , or by association of phosphorylated p62 with Keap1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Nrf2 could be activated either by degradation of Keap1 via autophagy, or by association of phosphorylated p62 with Keap1 [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
A recent publication demonstrates that NO regulates the nuclear localization of the transcription factor Nrf2 by S nitrosylation of Keap1 , which normally functions to sequester Nrf2 in the cytoplasm [ XREF_BIBR ] .	A recent publication demonstrates that NO regulates the nuclear localization of the transcription factor Nrf2 by S nitrosylation of Keap1, which normally functions to sequester Nrf2 in the cytoplasm [XREF_BIBR].	17	27	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	19	20	26	27
In Drosophila ISCs , Nrf2 is constitutively active and reduces ROS levels , and repression of Nrf2 by Keap1 is required for ISC proliferation .	In Drosophila ISCs, Nrf2 is constitutively active and reduces ROS levels, and repression of Nrf2 by Keap1 is required for ISC proliferation.	14	19	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	18	19	16	17
Our results demonstrated that transfection of wild-type KEAP1 potently attenuated NRF2 signaling and sensitized A549 and H460 cells to platinum based treatment .	Our results demonstrated that transfection of wild-type KEAP1 potently attenuated NRF2 signaling and sensitized A549 and H460 cells to platinum based treatment.	4	11	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	7	8	10	11
Transcription of many detoxifying enzymes is regulated through the antioxidant response element ( ARE ) and its transcription factor Nrf2 , which is repressed under basal conditions by Keap1 .	Transcription of many detoxifying enzymes is regulated through the antioxidant response element (ARE) and its transcription factor Nrf2, which is repressed under basal conditions by Keap1.	6	29	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	28	29	19	20
In addition , Keap1 negatively regulates Nrf2 through inhibiting the Nrf2 activation .	In addition, Keap1 negatively regulates Nrf2 through inhibiting the Nrf2 activation.	3	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	6	7
INrf2 functions as an adapter for Cul3 and Rbx1 mediated degradation of Nrf2 .	INrf2 functions as an adapter for Cul3 and Rbx1 mediated degradation of Nrf2.	0	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	0	1	12	13
Nrf2 is a major transcriptional activator of cytoprotective genes against oxidative and electrophilic stress , and Keap1 negatively regulates Nrf2 .	Nrf2 is a major transcriptional activator of cytoprotective genes against oxidative and electrophilic stress, and Keap1 negatively regulates Nrf2.	16	20	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	19	20
Finally , although Keap1 and Cul3 E3 ligase was reported to promote NRF2 degradation , we found that Keap1 silencing had no effect on Nrf2 levels in either of the paired keratinocytes ( XREF_FIG ) .	Finally, although Keap1 and Cul3 E3 ligase was reported to promote NRF2 degradation, we found that Keap1 silencing had no effect on Nrf2 levels in either of the paired keratinocytes (XREF_FIG).	3	13	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	3	4	12	13
In the absence of ongoing KEAP1 directed degradation of NRF2 , the half-life of newly synthesized protein is prolonged permitting rapid nuclear translocation and accumulation with subsequent antioxidant gene induction .	In the absence of ongoing KEAP1 directed degradation of NRF2, the half-life of newly synthesized protein is prolonged permitting rapid nuclear translocation and accumulation with subsequent antioxidant gene induction.	2	10	directed	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	5	6	9	10
Under unstressed conditions , Keap1 sequesters Nrf2 in the cytoplasm ( XREF_FIG ) , targeting it for proteasomal degradation .	Under unstressed conditions, Keap1 sequesters Nrf2 in the cytoplasm (XREF_FIG), targeting it for proteasomal degradation.	4	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
The transcription factor Nrf2 , which enhances cytoprotective gene expression following pathological insults , is sequestered by KEAP1 in cytoplasm , where it is subsequently degraded by proteosomes .	The transcription factor Nrf2, which enhances cytoprotective gene expression following pathological insults, is sequestered by KEAP1 in cytoplasm, where it is subsequently degraded by proteosomes.	0	18	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	17	18	3	4
It is likely that the C151 residue present in these mutant proteins could be modified by sulforaphane , leading to a loss of Keap1 repression of Nrf2 .	It is likely that the C151 residue present in these mutant proteins could be modified by sulforaphane, leading to a loss of Keap1 repression of Nrf2.	23	27	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	23	24	26	27
Hepatocytic disruption of Keap1 activates the Nrf2 pathway and results in increased resistance to oxidative challenges XREF_BIBR .	Hepatocytic disruption of Keap1 activates the Nrf2 pathway and results in increased resistance to oxidative challenges XREF_BIBR.	1	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	6	7
Nrf2 is sequestered in the cytosol by Keap1 ( Kelch ECH associating protein ) , an actin bound protein [ XREF_BIBR , XREF_BIBR ] .	Nrf2 is sequestered in the cytosol by Keap1 (Kelch ECH associating protein), an actin bound protein [XREF_BIBR, XREF_BIBR].	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	0	1
Nrf2 belongs to the basic leucine zipper ( bZIP ) transcription factors and is repressed by Keap1 ( Kelch like erythroid cell derived protein with CNC homology ( ECH )-associated protein 1 , also known as INrf2 , inhibitor of Nrf2 ) and the Cul3 and Rbx1 E3 ubiquitin ligase complex under physiologic conditions XREF_BIBR .	Nrf2 belongs to the basic leucine zipper (bZIP) transcription factors and is repressed by Keap1 (Kelch like erythroid cell derived protein with CNC homology (ECH)-associated protein 1, also known as INrf2, inhibitor of Nrf2) and the Cul3 and Rbx1 E3 ubiquitin ligase complex under physiologic conditions XREF_BIBR.	0	50	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	0	1
INrf2 functions as an adapter for Cul3 and Rbx1 mediated degradation of Nrf2 [ XREF_BIBR - XREF_BIBR ] .	INrf2 functions as an adapter for Cul3 and Rbx1 mediated degradation of Nrf2 [XREF_BIBR - XREF_BIBR].	0	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	0	1	12	13
Our data indicate that the HBx-p62-Keap1 complexes immobilize Keap1 in the aggregates thereby prevent Nrf2 from the inhibition by Keap1 , leading to the activation of Nrf2 .	Our data indicate that the HBx-p62-Keap1 complexes immobilize Keap1 in the aggregates thereby prevent Nrf2 from the inhibition by Keap1, leading to the activation of Nrf2.	8	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	14	15
Under basal conditions , Nrf2 is sequestered in the cytoplasm by the cytosolic regulatory protein Keap1 .	Under basal conditions, Nrf2 is sequestered in the cytoplasm by the cytosolic regulatory protein Keap1.	4	16	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	4	5
Nrf2 activity is repressed by Keap 1 ( Kelch like ECH associated protein ) .	Nrf2 activity is repressed by Keap 1 (Kelch like ECH associated protein).	0	8	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap 1	Keap 1	Keap 1	Nrf2	Nrf2	Nrf2	5	7	0	1
Nrf2 activity is usually suppressed by a cytoplasmic repressor , Keap1 , so disruption of the keap1 gene causes constitutive activation of Nrf2 .	Nrf2 activity is usually suppressed by a cytoplasmic repressor, Keap1, so disruption of the keap1 gene causes constitutive activation of Nrf2.	16	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	keap1	keap1	keap1	Nrf2	Nrf2	Nrf2	16	17	22	23
When transfected into MCF-7 cells , we found that Vps34 docks directly onto Keap1 to release Nrf2 from the complex sequestered by Keap1 , an adaptor of the Cul3-ubiquitin E3 ligase complex that degrades Nrf2 .	When transfected into MCF-7 cells, we found that Vps34 docks directly onto Keap1 to release Nrf2 from the complex sequestered by Keap1, an adaptor of the Cul3-ubiquitin E3 ligase complex that degrades Nrf2.	20	35	degrades	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	34	35
Regarding the molecular mechanism underlying Nrf2 activation , Keap1 has been reported to modulate the ubiquitin mediated proteosomal degradation of Nrf2 by binding Nrf2 in cytoplasm [ XREF_BIBR ] .	Regarding the molecular mechanism underlying Nrf2 activation, Keap1 has been reported to modulate the ubiquitin mediated proteosomal degradation of Nrf2 by binding Nrf2 in cytoplasm [XREF_BIBR].	8	21	modulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	20	21
XREF_BIBR A later similar study in 65 Japanese patients with lung cancer also verified that loss of Keap1 function ( due to mutations or low-level expression ) increased nuclear accumulation and induced constitutive activation of Nrf2 , leading to the expression of its target genes , and thus resulted in growth advantages and cisplatin resistance of lung cancer cells .	XREF_BIBR A later similar study in 65 Japanese patients with lung cancer also verified that loss of Keap1 function (due to mutations or low-level expression) increased nuclear accumulation and induced constitutive activation of Nrf2, leading to the expression of its target genes, and thus resulted in growth advantages and cisplatin resistance of lung cancer cells.	17	36	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	35	36
Under normal conditions , Nrf2 is targeted by Keap1 , which promotes Nrf2 proteasomal degradation via interactions with an ubiquitin ligase [ XREF_BIBR ] .	Under normal conditions, Nrf2 is targeted by Keap1, which promotes Nrf2 proteasomal degradation via interactions with an ubiquitin ligase [XREF_BIBR].	6	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	12	13
In physiological conditions , Keap1 constitutively suppresses Nrf2 activity ; however , electrophilic compounds hamper the Keap1 mediated proteasomal degradation of Nrf2 , leading to the transcriptional induction of target genes that ensure cell survival XREF_BIBR .	In physiological conditions, Keap1 constitutively suppresses Nrf2 activity; however, electrophilic compounds hamper the Keap1 mediated proteasomal degradation of Nrf2, leading to the transcriptional induction of target genes that ensure cell survival XREF_BIBR.	4	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	7	8
Under resting condition , Nrf2 is sequestered in the cytosol by Keap1 , and chamomile treatment to RAW 264.7 macrophages resulted in significant increase of Nrf2 and Keap1 in the cytosol .	Under resting condition, Nrf2 is sequestered in the cytosol by Keap1, and chamomile treatment to RAW 264.7 macrophages resulted in significant increase of Nrf2 and Keap1 in the cytosol.	4	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
Keap1 inhibits Nrf2 signaling by promoting Nrf2 degradation through the proteasomal pathway [ XREF_BIBR ] .	Keap1 inhibits Nrf2 signaling by promoting Nrf2 degradation through the proteasomal pathway [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
To more strongly down-regulate Nrf2 activity , we used a lentiviral vector expressing Nrf2 repressor KEAP1 ( Kelch Like ECH Associated Protein 1 ) , alongside GFP ( XREF_SUPPLEMENTARY ) .	To more strongly down-regulate Nrf2 activity, we used a lentiviral vector expressing Nrf2 repressor KEAP1 (Kelch Like ECH Associated Protein 1), alongside GFP (XREF_SUPPLEMENTARY).	12	28	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	15	16	13	14
Theoretically , while Keap1 represses Nfe2l2 protein at posttranslational level , and Bach1 simply competes for the ARE with Nfe2l2 , neither of them affects the Nfe2l2 mRNA levels .	Theoretically, while Keap1 represses Nfe2l2 protein at posttranslational level, and Bach1 simply competes for the ARE with Nfe2l2, neither of them affects the Nfe2l2 mRNA levels.	3	6	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nfe2l2	Nfe2l2	Nfe2l2	3	4	5	6
Under unstressed conditions , Nrf2 is negatively regulated by Keap1 via proteasomal degradation to remain at low cellular concentrations .	Under unstressed conditions, Nrf2 is negatively regulated by Keap1 via proteasomal degradation to remain at low cellular concentrations.	4	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	4	5
Keap1 is an inhibitor of Nrf2 , which binds Nrf2 to prevent its nuclear translocation [ XREF_BIBR ] , and Keap1 dissociation from Nrf2 and Keap1 enhances Nrf2 nuclear translocation [ XREF_BIBR ] .	Keap1 is an inhibitor of Nrf2, which binds Nrf2 to prevent its nuclear translocation [XREF_BIBR], and Keap1 dissociation from Nrf2 and Keap1 enhances Nrf2 nuclear translocation [XREF_BIBR].	0	8	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	5	6
Under normal conditions , NRF2 is actively sequestered by KEAP1 and targeted for proteolytic degradation [ XREF_BIBR ] ; however , under conditions of oxidative or chemical stress , NRF2 dissociates from KEAP1 and migrates to the nucleus to initiate a stress related response .	Under normal conditions, NRF2 is actively sequestered by KEAP1 and targeted for proteolytic degradation [XREF_BIBR]; however, under conditions of oxidative or chemical stress, NRF2 dissociates from KEAP1 and migrates to the nucleus to initiate a stress related response.	4	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	9	10	4	5
Under basal conditions , KEAP1 sequesters NRF2 within a complex with Cullin 3 ( CUL3 ) , which is an ubiquitin ligase E3 that targets NRF2 for proteosomal degradation .	Under basal conditions, KEAP1 sequesters NRF2 within a complex with Cullin 3 (CUL3), which is an ubiquitin ligase E3 that targets NRF2 for proteosomal degradation.	4	7	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	4	5	6	7
In contrast , knockdown of KEAP1 augmented the protein accumulation of NRF2 under basal and iAs 3+ -exposed conditions ( XREF_FIG ) .	In contrast, knockdown of KEAP1 augmented the protein accumulation of NRF2 under basal and iAs 3+ -exposed conditions (XREF_FIG).	3	12	augmented	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	5	6	11	12
Under basal conditions , Nrf2 is sequestered in the cytoplasm by Keap1 and , therefore , is not involved in the induction of phase II enzymes .	Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1 and, therefore, is not involved in the induction of phase II enzymes.	4	18	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
In contrast , knockdown of Keap1 by RNAi reversed loss of p62 increased degradation of NRF2 in ferroptosis ( XREF_FIG ) .	In contrast, knockdown of Keap1 by RNAi reversed loss of p62 increased degradation of NRF2 in ferroptosis (XREF_FIG).	3	16	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	5	6	15	16
Silencing Keap1 induced higher basal levels of Nrf2 regulated genes such as HMOX1 , NQO1 , and P62 than from NTP siRNA ( Supplemental XREF_SUPPLEMENTARY ) .	Silencing Keap1 induced higher basal levels of Nrf2 regulated genes such as HMOX1, NQO1, and P62 than from NTP siRNA (Supplemental XREF_SUPPLEMENTARY).	0	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	1	2	7	8
However , under oxidative stress , Keap 1 repression of Nrf2 is inhibited , Nrf2 protein is then translocated into the nucleus and activates its target genes [ XREF_BIBR ] .	However, under oxidative stress, Keap 1 repression of Nrf2 is inhibited, Nrf2 protein is then translocated into the nucleus and activates its target genes [XREF_BIBR].	6	11	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap 1	Keap 1	Keap 1	Nrf2	Nrf2	Nrf2	6	8	10	11
In mammals , Keap1 represses basal Nrf2 activity through a direct interaction that promotes ubiquitylation and degradation , and there is strong support for a model in which small molecules directly react with Keap1 releasing Nrf2 from repression [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In mammals, Keap1 represses basal Nrf2 activity through a direct interaction that promotes ubiquitylation and degradation, and there is strong support for a model in which small molecules directly react with Keap1 releasing Nrf2 from repression [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	6	7
In the absence of ROS binding of Keap1 promotes proteasomal degradation of Nrf2 .	In the absence of ROS binding of Keap1 promotes proteasomal degradation of Nrf2.	5	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
Under unstressed conditions , Nrf2 is mainly sequestered in the cytoplasm by a cytoskeleton anchoring protein Keap1 ( Kelch like ECH associated protein 1 ) .	Under unstressed conditions, Nrf2 is mainly sequestered in the cytoplasm by a cytoskeleton anchoring protein Keap1 (Kelch like ECH associated protein 1).	4	18	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	4	5
When compared with non COPD lungs , the COPD patient lungs showed ( 1 ) marked decline in NRF2 dependent antioxidants and glutathione levels , ( 2 ) increased oxidative stress markers , ( 3 ) significant decrease in NRF2 protein with no change in NRF2 mRNA levels , and ( 4 ) similar KEAP1 but significantly decreased DJ-1 levels ( a protein that stabilizes NRF2 protein by impairing KEAP1 dependent proteasomal degradation of NRF2 ) .	When compared with non COPD lungs, the COPD patient lungs showed (1) marked decline in NRF2 dependent antioxidants and glutathione levels, (2) increased oxidative stress markers, (3) significant decrease in NRF2 protein with no change in NRF2 mRNA levels, and (4) similar KEAP1 but significantly decreased DJ-1 levels (a protein that stabilizes NRF2 protein by impairing KEAP1 dependent proteasomal degradation of NRF2).	69	75	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	69	70	74	75
The NRF2 transcription factor regulates antioxidant defenses and is sequestered in the cytoplasm by KEAP1 , but oxidation of cysteines in KEAP1 leads to the release of NRF2 and the induction of antioxidant and cytoprotective enzymes which enhances chemoresistance of cancer cells [ XREF_BIBR ] .	The NRF2 transcription factor regulates antioxidant defenses and is sequestered in the cytoplasm by KEAP1, but oxidation of cysteines in KEAP1 leads to the release of NRF2 and the induction of antioxidant and cytoprotective enzymes which enhances chemoresistance of cancer cells [XREF_BIBR].	1	15	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	14	15	1	2
We find that reducing the dosage of keap1 ( the cytosolic inhibitor of the Nrf2 transcription factor ) gene almost completely suppresses the dominant CLN3 eye phenotype .	We find that reducing the dosage of keap1 (the cytosolic inhibitor of the Nrf2 transcription factor) gene almost completely suppresses the dominant CLN3 eye phenotype.	5	16	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	keap1	keap1	keap1	Nrf2	Nrf2	Nrf2	7	8	14	15
KEAP1 not only blocks nuclear localization of NRF2 , but also targets it for degradation by the E3/Cul3 mediated ubiquitin-proteasome pathway , hence the relatively short half-life of NRF2 [ XREF_BIBR , XREF_BIBR ] .	KEAP1 not only blocks nuclear localization of NRF2, but also targets it for degradation by the E3/Cul3 mediated ubiquitin-proteasome pathway, hence the relatively short half-life of NRF2 [XREF_BIBR, XREF_BIBR].	0	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	7	8
Keap1 negatively regulates intracellular Nrf2 protein abundance and represses the activation of Nrf2 signal [ XREF_BIBR ] .	Keap1 negatively regulates intracellular Nrf2 protein abundance and represses the activation of Nrf2 signal [XREF_BIBR].	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	4	5
In normal conditions , NRF2 is not active ; it resides in the cytoplasm bound to KEAP1 ( kelch like ECH association protein 1 ) , a ubiquitin E3 ligase complex , which mediates NRF2 degradation by the proteasome .	In normal conditions, NRF2 is not active; it resides in the cytoplasm bound to KEAP1 (kelch like ECH association protein 1), a ubiquitin E3 ligase complex, which mediates NRF2 degradation by the proteasome.	14	35	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	16	17	34	35
These data suggest that Keap1 negatively regulates Nrf2 by both enhancing its rate of proteasomal degradation and altering its subcellular distribution .	These data suggest that Keap1 negatively regulates Nrf2 by both enhancing its rate of proteasomal degradation and altering its subcellular distribution.	4	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	7	8
There is evidence in the literature that GSK-3 can promote the KEAP1 independent degradation of Nrf2 [ XREF_BIBR ] .	There is evidence in the literature that GSK-3 can promote the KEAP1 independent degradation of Nrf2 [XREF_BIBR].	11	17	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	11	12	15	16
We therefore performed siRNA mediated KEAP1 knockdown ( XREF_SUPPLEMENTARY ) , which increased NRF2 activity and promoted a significant increase in HMOX1 ( p < 0.05 ) and NQO1 ( p < 0.01 ) expression ( XREF_SUPPLEMENTARY ) .	We therefore performed siRNA mediated KEAP1 knockdown (XREF_SUPPLEMENTARY), which increased NRF2 activity and promoted a significant increase in HMOX1 (p < 0.05) and NQO1 (p < 0.01) expression (XREF_SUPPLEMENTARY).	5	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	5	6	13	14
Under basal conditions , Nrf2 is sequestered in the cytoplasm by the cytoskeletal anchoring protein Keap1 , and is targeted for ubiquitin mediated proteasome degradation .	Under basal conditions, Nrf2 is sequestered in the cytoplasm by the cytoskeletal anchoring protein Keap1, and is targeted for ubiquitin mediated proteasome degradation.	4	19	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	4	5
We suggest that Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination by the CUL3-ROC1 ligase and subsequent degradation by the proteasome .	We suggest that Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination by the CUL3-ROC1 ligase and subsequent degradation by the proteasome.	3	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	6	7
The protein expression level of Keap1 is increased 1.8 fold and that of Nrf2 is decreased 0.4 fold in HLECs treated with MGO ( XREF_FIG ) .	The protein expression level of Keap1 is increased 1.8 fold and that of Nrf2 is decreased 0.4 fold in HLECs treated with MGO (XREF_FIG).	3	15	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	level of Keap1	keap1	Nrf2	Nrf2	nrf2	5	6	13	14
The nuclear protein level of Keap1 is reduced , resulting in nuclear Nrf2 stabilization and its transcriptional activity increases in cancer cells , which contributes to tumor cell resistance to chemotherapy [ XREF_BIBR ] .	The nuclear protein level of Keap1 is reduced, resulting in nuclear Nrf2 stabilization and its transcriptional activity increases in cancer cells, which contributes to tumor cell resistance to chemotherapy [XREF_BIBR].	3	13	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	level of Keap1	keap1	Nrf2	Nrf2	nrf2	5	6	12	13
Under basal conditions , NRF2 is sequestered by a KEAP1 homodimer , an E3-ligase that presents NRF2 to the CULLIN3 and RBX1 protein complex , resulting in ubiquitination and proteasomal degradation .	Under basal conditions, NRF2 is sequestered by a KEAP1 homodimer, an E3-ligase that presents NRF2 to the CULLIN3 and RBX1 protein complex, resulting in ubiquitination and proteasomal degradation.	4	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	9	10	4	5
Our preliminary results indicate that keap1 ( an inhibitor of Nrf2 ) signal ( canonical mechanism ) is important in the activation of inducible Nrf2 by luteolin in normal cells while the p62 pathway ( noncanonical mechanism ) activated by autophagy deficiency of Cr ( VI )-transformed cells is important for the inactivation of constitutive Nr2 by the same natural compound in these transformed cells .	Our preliminary results indicate that keap1 (an inhibitor of Nrf2) signal (canonical mechanism) is important in the activation of inducible Nrf2 by luteolin in normal cells while the p62 pathway (noncanonical mechanism) activated by autophagy deficiency of Cr (VI)-transformed cells is important for the inactivation of constitutive Nr2 by the same natural compound in these transformed cells.	5	18	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	keap1	keap1	keap1	Nrf2	Nrf2	Nrf2	5	6	10	11
Reaction of Cys151 with EPs is thus critical for inhibition of NRF2 degradation mediated by KEAP1 dependent degradation of NRF2 XREF_BIBR - XREF_BIBR .	Reaction of Cys151 with EPs is thus critical for inhibition of NRF2 degradation mediated by KEAP1 dependent degradation of NRF2 XREF_BIBR - XREF_BIBR.	11	17	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	15	16	11	12
Under normal conditions , the antioxidant transcription factor Nrf2 is sequestered in the cytoplasm by Keap-1 .	Under normal conditions, the antioxidant transcription factor Nrf2 is sequestered in the cytoplasm by Keap-1.	4	16	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap-1	Keap-1	Keap-1	Nrf2	Nrf2	Nrf2	15	16	8	9
Under normal conditions , Nrf2 is sequestered by Keap1 , a substrate adaptor , which helps Cullin 3 ubiquitinate Nrf2 in the cytoplasm , and ARE activation signals ( i.e ., protein kinase pathway and redox-active components ) disrupt the Nrf2 and Keap1 complex , leading to phosphorylation and nuclear translocation of Nrf2 .	Under normal conditions, Nrf2 is sequestered by Keap1, a substrate adaptor, which helps Cullin 3 ubiquitinate Nrf2 in the cytoplasm, and ARE activation signals (i.e., protein kinase pathway and redox-active components) disrupt the Nrf2 and Keap1 complex, leading to phosphorylation and nuclear translocation of Nrf2.	4	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
We also tested whether ectopic expression of WT Keap1 cDNA reconstituted the keap1 activity and inhibited Nrf2 activity .	We also tested whether ectopic expression of WT Keap1 cDNA reconstituted the keap1 activity and inhibited Nrf2 activity.	8	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	16	17
We have identified a third cysteine residue in Keap1 , C151 , that is uniquely required for inhibition of Keap1 dependent degradation of Nrf2 by sulforaphane and oxidative stress .	We have identified a third cysteine residue in Keap1, C151, that is uniquely required for inhibition of Keap1 dependent degradation of Nrf2 by sulforaphane and oxidative stress.	19	24	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	19	20	23	24
Disruption of Keap1 in male Drosophila melanogaster increases Nrf2 activity and longevity [ XREF_BIBR ] .	Disruption of Keap1 in male Drosophila melanogaster increases Nrf2 activity and longevity [XREF_BIBR].	0	9	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	8	9
Under basal conditions , Nrf2 is sequestered in the cytoplasm by Keap1 ( Kelch like ECH associating protein 1 ) , which facilatites its polyubiquitylation and proteasome mediated degradation .	Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1 (Kelch like ECH associating protein 1), which facilatites its polyubiquitylation and proteasome mediated degradation.	4	22	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
NFE2L2 mutations are mostly missense and occur within the first 100 amino acids ( D29 * , R34 * , E79 and G81 * ) that contains the Neh2 domain which includes the two degrons that are specifically bound by KEAP1 and thus likely impede KEAP1 mediated NRF2 degradation .	NFE2L2 mutations are mostly missense and occur within the first 100 amino acids (D29 *, R34 *, E79 and G81 *) that contains the Neh2 domain which includes the two degrons that are specifically bound by KEAP1 and thus likely impede KEAP1 mediated NRF2 degradation.	45	48	mediated	Positive_early_activation	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	45	46	47	48
Collectively , these results demonstrate that Keap1 mediated degradation of Nrf2 in cells is partially inhibited by Keap1 DeltaC ( XREF_FIG H ) .	Collectively, these results demonstrate that Keap1 mediated degradation of Nrf2 in cells is partially inhibited by Keap1 DeltaC (XREF_FIG H).	6	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	10	11
Besides the above proteins , Nrf2 and Keap1 association can be directly regulated by phosphorylation of several serine/threonine residues in Nrf2 by p38 mitogen activated protein kinase , which then promotes its association with Keap1 increasing Nrf2 degradation .	Besides the above proteins, Nrf2 and Keap1 association can be directly regulated by phosphorylation of several serine/threonine residues in Nrf2 by p38 mitogen activated protein kinase, which then promotes its association with Keap1 increasing Nrf2 degradation.	30	37	increasing	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	34	35	36	37
Many studies have shown that cancers can harbor somatic mutations in NRF2 , KEAP1 , or CUL3 that disrupt the KEAP1 mediated negative regulation of NRF2 , resulting in a constitutive high level of NRF2 , which correlates with chemoresistance in cancer cells .	Many studies have shown that cancers can harbor somatic mutations in NRF2, KEAP1, or CUL3 that disrupt the KEAP1 mediated negative regulation of NRF2, resulting in a constitutive high level of NRF2, which correlates with chemoresistance in cancer cells.	7	26	disrupt	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	13	14	25	26
47 The level of intracellular ROS is monitored by the transcription factor Nuclear factor erythroid 2 related factor 2 ( NRF2 ) , which is negatively regulated by KEAP1 .	47 The level of intracellular ROS is monitored by the transcription factor Nuclear factor erythroid 2 related factor 2 (NRF2), which is negatively regulated by KEAP1.	17	29	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	28	29	20	21
Notably , Keap1 knockdown induced Nrf2 stabilization and accumulation .	Notably, Keap1 knockdown induced Nrf2 stabilization and accumulation.	2	6	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	5	6
Nrf2 is negatively regulated by Keap1 , a substrate adaptor protein for the Cullin3 ( Cul3 )-containing E3 and ligase complex , which targets Nrf2 for ubiquitination and degradation by the ubiquitin proteasome system ( UPS ) .	Nrf2 is negatively regulated by Keap1, a substrate adaptor protein for the Cullin3 (Cul3)-containing E3 and ligase complex, which targets Nrf2 for ubiquitination and degradation by the ubiquitin proteasome system (UPS).	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	0	1
Keap1 is an inhibitor of Nrf2 , which is a transcriptional activator of ARE .	Keap1 is an inhibitor of Nrf2, which is a transcriptional activator of ARE.	0	11	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	5	6
Keap1 binds to the Neh2 domain of Nrf2 through its Kelch repeat to inhibit Nrf2 in the cytoplasm .	Keap1 binds to the Neh2 domain of Nrf2 through its Kelch repeat to inhibit Nrf2 in the cytoplasm.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	14	15
Nrf2 , which is negatively regulated by Keap1 , is critical in the regulation of antioxidant genes in response to the oxidative stress .	Nrf2, which is negatively regulated by Keap1, is critical in the regulation of antioxidant genes in response to the oxidative stress.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	0	1
KEAP 1 promotes the degradation of Nrf2 via ubiquitination and rapid proteasomal degradation .	KEAP 1 promotes the degradation of Nrf2 via ubiquitination and rapid proteasomal degradation.	0	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP 1	KEAP 1	KEAP 1	Nrf2	Nrf2	Nrf2	0	2	6	7
Keap1 serves to negatively regulate Nrf2 , for example , Keap1-knockdown mice are less vulnerable to oxidative liver injuries during obstructive cholestasis mediated by enhanced expression of Nrf2 .	Keap1 serves to negatively regulate Nrf2, for example, Keap1-knockdown mice are less vulnerable to oxidative liver injuries during obstructive cholestasis mediated by enhanced expression of Nrf2.	0	6	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	5	6
Nrf2 is sequestered in the cytoplasm by Keap1 under normal conditions , which results in its proteosomal degradation .	Nrf2 is sequestered in the cytoplasm by Keap1 under normal conditions, which results in its proteosomal degradation.	0	8	sequestered	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	0	1
It is well recognized that chemicals causing oxidative stress or electrophiles activate a transcription factor Nrf2 that is negatively regulated by Keap1 , leading to up-regulation of downstream proteins responsible for detoxification of electrophiles in cells .	It is well recognized that chemicals causing oxidative stress or electrophiles activate a transcription factor Nrf2 that is negatively regulated by Keap1, leading to up-regulation of downstream proteins responsible for detoxification of electrophiles in cells.	11	22	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	21	22	15	16
In this report , we have characterized the importance of substrate adaptor recycling for regulation of Keap1 mediated repression of Nrf2 .	In this report, we have characterized the importance of substrate adaptor recycling for regulation of Keap1 mediated repression of Nrf2.	14	21	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	20	21
Blocking Keap1 is necessary to activate Nrf2 XREF_BIBR .	Blocking Keap1 is necessary to activate Nrf2 XREF_BIBR.	0	7	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	1	2	6	7
INrf2 ( Inhibitor of Nrf2 ) or KEAP1 ( Kelch like ECH associated protein1 ) , a homodimeric protein , retains Nrf2 in the cytoplasm [ XREF_BIBR - XREF_BIBR ] .	INrf2 (Inhibitor of Nrf2) or KEAP1 (Kelch like ECH associated protein1), a homodimeric protein, retains Nrf2 in the cytoplasm [XREF_BIBR - XREF_BIBR].	0	20	Inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	7	8	4	5
In the canonical pathway , Nrf2 is negatively regulated by Keap1 , an adaptor for the cullin-3-type ubiquitin ligase , which targets Nrf2 for its ubiquitination and proteasome mediated degradation .	In the canonical pathway, Nrf2 is negatively regulated by Keap1, an adaptor for the cullin-3-type ubiquitin ligase, which targets Nrf2 for its ubiquitination and proteasome mediated degradation.	5	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	5	6
Because we did not find any interaction between caveolin-1 and Keap1 before or after oxidative stress in fibroblasts ( Supplemental Figure S2B ) , we propose a novel model in which the sequestration of Nrf2 in caveolar membranes contributes to the inhibition of Nrf2 dependent signaling under resting conditions independently of Keap1 mediated degradation of Nrf2 in the cytoplasm .	Because we did not find any interaction between caveolin-1 and Keap1 before or after oxidative stress in fibroblasts (Supplemental Figure S2B), we propose a novel model in which the sequestration of Nrf2 in caveolar membranes contributes to the inhibition of Nrf2 dependent signaling under resting conditions independently of Keap1 mediated degradation of Nrf2 in the cytoplasm.	48	56	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	51	52	55	56
Specifically , in human HaCaT keratinocytes , MCF10A mammary cells , IMR-32 neuroblastoma cells , and U937 lymphoma cells , treatment with SFN or tBHQ , or knockdown of the Nrf2 repressor Keap1 , has been reported to result in substantial induction of AKR1B10 , AKR1C1 , AKR1C2 , and AKR1C3 , which is as least as great as that observed for NQO1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Specifically, in human HaCaT keratinocytes, MCF10A mammary cells, IMR-32 neuroblastoma cells, and U937 lymphoma cells, treatment with SFN or tBHQ, or knockdown of the Nrf2 repressor Keap1, has been reported to result in substantial induction of AKR1B10, AKR1C1, AKR1C2, and AKR1C3, which is as least as great as that observed for NQO1 [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	27	33	repressor	Negative_activation_token_1_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	32	33	30	31
Under normal conditions , Nrf2 is sequestered in cytoplasm by Keap 1 and is subject to ubiquitination and proteasomal degradation .	Under normal conditions, Nrf2 is sequestered in cytoplasm by Keap 1 and is subject to ubiquitination and proteasomal degradation.	4	14	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap 1	Keap 1	Keap 1	Nrf2	Nrf2	Nrf2	10	12	4	5
XREF_BIBR Under resting conditions , KEAP1 sequesters NFE2L2 and targets it for proteosomal degradation .	XREF_BIBR Under resting conditions, KEAP1 sequesters NFE2L2 and targets it for proteosomal degradation.	5	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NFE2L2	NFE2L2	NFE2L2	5	6	7	8
TauCl binds directly to Kelch like ECH association protein 1 ( Keap1 ) , which appears to retard the Keap1 driven degradation of Nrf2 .	TauCl binds directly to Kelch like ECH association protein 1 (Keap1), which appears to retard the Keap1 driven degradation of Nrf2.	17	24	driven	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	19	20	23	24
The protective effect of Nrf2 induction caused by the loss of Keap1 was reduced when p65 was depleted , implying a role for p65 as a modulator of Nrf2 dependent cell protection .	The protective effect of Nrf2 induction caused by the loss of Keap1 was reduced when p65 was depleted, implying a role for p65 as a modulator of Nrf2 dependent cell protection.	4	12	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	loss of Keap1	keap1	Nrf2	Nrf2	nrf2	11	12	4	5
XREF_BIBR Thus , Nrf2 is sequestered in the cytoplasm by Keap1 and maintained at a low level ( XREF_FIG ) .	XREF_BIBR Thus, Nrf2 is sequestered in the cytoplasm by Keap1 and maintained at a low level (XREF_FIG).	3	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	3	4
As discussed earlier , Keap1 normally sequesters Nrf2 in the cytosol , which blocks the transcription of antioxidant genes .	As discussed earlier, Keap1 normally sequesters Nrf2 in the cytosol, which blocks the transcription of antioxidant genes.	4	8	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	7	8
Nrf2 suppression by Keap1 directed ubiquitylation or expression of independent shRNA and siRNA sequences enhanced cellular ROS , Smad dependent tumor cell motility , and growth in soft agar .	Nrf2 suppression by Keap1 directed ubiquitylation or expression of independent shRNA and siRNA sequences enhanced cellular ROS, Smad dependent tumor cell motility, and growth in soft agar.	0	4	suppression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	0	1
p62 competes with Nrf2 to bind to Kelch like ECH associated protein 1 ( KEAP1 ) XREF_BIBR , XREF_BIBR , preventing KEAP1 mediated degradation of Nrf2 .	p62 competes with Nrf2 to bind to Kelch like ECH associated protein 1 (KEAP1) XREF_BIBR, XREF_BIBR, preventing KEAP1 mediated degradation of Nrf2.	20	26	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	21	22	25	26
Because Nrf2 is constantly degraded by the proteasomal activity of Keap1 , the inhibition of Keap1 can activate the Nrf2-ARE pathway upon oxidative and electrophilic stresses XREF_BIBR .	Because Nrf2 is constantly degraded by the proteasomal activity of Keap1, the inhibition of Keap1 can activate the Nrf2-ARE pathway upon oxidative and electrophilic stresses XREF_BIBR.	1	11	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	1	2
In the presence of ROS , the cytosolic Nrf2 repressor Keap1 undergoes structural alterations that cause dissociation from the Nrf2 and Keap1 complex .	In the presence of ROS, the cytosolic Nrf2 repressor Keap1 undergoes structural alterations that cause dissociation from the Nrf2 and Keap1 complex.	6	11	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	8	9
Normally , Keap1 sequesters Nrf2 in the cytoplasm and bridges it to a ubiquitin ligase , cullin 3 ( Cul3 ) , to facilitate proteasomal Nrf2 degradation .	Normally, Keap1 sequesters Nrf2 in the cytoplasm and bridges it to a ubiquitin ligase, cullin 3 (Cul3), to facilitate proteasomal Nrf2 degradation.	2	5	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	4	5
According to their studies , ozone therpy could reacts with polyunsaturated fatty acid to generate H 2 O 2 and alkenals including 4-hydroxynonenal , which in turn alters the cysteine residues of Keap1 to inhibit ubiquitin conjugation to Nrf2 by the Keap1 complex and stimulate the release and nuclear translocation of Nrf2 .	According to their studies, ozone therpy could reacts with polyunsaturated fatty acid to generate H 2 O 2 and alkenals including 4-hydroxynonenal, which in turn alters the cysteine residues of Keap1 to inhibit ubiquitin conjugation to Nrf2 by the Keap1 complex and stimulate the release and nuclear translocation of Nrf2.	34	42	inhibit	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	41	42	38	39
Keap1 constitutively suppresses Nrf2 activity in the absence of stress .	Keap1 constitutively suppresses Nrf2 activity in the absence of stress.	0	4	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
Overexpression Keap1 protein suppresses the Nrf2 protein through ERAD leading to suppression of Nrf2 and Keap1 dependent antioxidant protection in the HLECs treated with sodium selenite .	Overexpression Keap1 protein suppresses the Nrf2 protein through ERAD leading to suppression of Nrf2 and Keap1 dependent antioxidant protection in the HLECs treated with sodium selenite.	1	6	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	1	2	5	6
In other words , activation of Nrf2 enhances the expression of Rbx1 , Cul3 , and Keap1 complex , which acts to sequester Nrf2 and mediate its rapid degradation .	In other words, activation of Nrf2 enhances the expression of Rbx1, Cul3, and Keap1 complex, which acts to sequester Nrf2 and mediate its rapid degradation.	6	24	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Nrf2 enhances the expression of Rbx1, Cul3, and Keap1	keap1	Nrf2	Nrf2	nrf2	16	17	23	24
In response to gut damage Nrf2 is inhibited by Keap1 , leading to increased ROS levels in ISCs .	In response to gut damage Nrf2 is inhibited by Keap1, leading to increased ROS levels in ISCs.	4	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	5	6
This is evident from the fact that the molecular targets of the synthetic oleanane triterpenoids include IKK and also pathways involving STAT , IL-6 , TGF-beta , and KEAP1 ( the inhibitor of the transcription factor Nrf2 ) .	This is evident from the fact that the molecular targets of the synthetic oleanane triterpenoids include IKK and also pathways involving STAT, IL-6, TGF-beta, and KEAP1 (the inhibitor of the transcription factor Nrf2).	20	37	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	28	29	36	37
In addition , Keap1 , as an oxidative stress sensor , mediates degradation of Nrf2 , and the association between the aberrant Keap1 expression and the poor prognosis has been largely investigated in various malignant tumors , especially companied with dysregulation Nrf2 expression 9 , 10 .	In addition, Keap1, as an oxidative stress sensor, mediates degradation of Nrf2, and the association between the aberrant Keap1 expression and the poor prognosis has been largely investigated in various malignant tumors, especially companied with dysregulation Nrf2 expression 9, 10.	3	15	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	14	15
Keap1 inhibits the transcriptional activation activity of Nrf2 in unstressed cells by facilitating its degradation .	Keap1 inhibits the transcriptional activation activity of Nrf2 in unstressed cells by facilitating its degradation.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	7	8
Modification of cysteine residues on Keap1 by electrophiles , particularly Cys 151 in the BTB ( Broad complex Tramtrack , and Bric-brac ) domain and Cys 273 and Cys 288 in the central intervening region ( IVR ) domain , suppress Keap1 mediated degradation of Nrf2 XREF_BIBR .	Modification of cysteine residues on Keap1 by electrophiles, particularly Cys 151 in the BTB (Broad complex Tramtrack, and Bric-brac) domain and Cys 273 and Cys 288 in the central intervening region (IVR) domain, suppress Keap1 mediated degradation of Nrf2 XREF_BIBR.	40	46	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	41	42	45	46
Under basal conditions , Nrf2 binds to its negative regulator , Keap1 , an adaptor for the ubiquitin ligase Cul3 , which targets Nrf2 to ubiquitination and proteasomal degradation .	Under basal conditions, Nrf2 binds to its negative regulator, Keap1, an adaptor for the ubiquitin ligase Cul3, which targets Nrf2 to ubiquitination and proteasomal degradation.	9	24	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	23	24
Under normal conditions , Nrf2 is targeted by Keap1 , which promotes Nrf2 proteasomal degradation via interactions with ubiquitin ligase .	Under normal conditions, Nrf2 is targeted by Keap1, which promotes Nrf2 proteasomal degradation via interactions with ubiquitin ligase.	4	11	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
Keap1 ( Kelch like ECH associated protein 1 ) is an adaptor protein for cullin3 based ubiquitin E3 ligase and negatively regulates Nrf2 .	Keap1 (Kelch like ECH associated protein 1) is an adaptor protein for cullin3 based ubiquitin E3 ligase and negatively regulates Nrf2.	0	23	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	22	23
The study shows an important role of Cys273 and Cys288 in the suppression of Nrf2 by Keap1 and a critical function of Cys151 in arsenic responsiveness .	The study shows an important role of Cys273 and Cys288 in the suppression of Nrf2 by Keap1 and a critical function of Cys151 in arsenic responsiveness.	12	20	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	14	15
The Neh6 domain represents a second negative regulatory domain which mediates Keap1 independent degradation of Nrf2 .	The Neh6 domain represents a second negative regulatory domain which mediates Keap1 independent degradation of Nrf2.	11	16	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	15	16
In this way , Keap1 and Cul3 act in concert to mediate the degradation of Nrf2 in the cytoplasm when homeostatic levels of ROS are present .	In this way, Keap1 and Cul3 act in concert to mediate the degradation of Nrf2 in the cytoplasm when homeostatic levels of ROS are present.	4	16	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	15	16
Lack of p62 blocked CCCP induced Keap1 degradation and inhibited Nrf2 activation , and thereby increased the accumulation of ROS .	Lack of p62 blocked CCCP induced Keap1 degradation and inhibited Nrf2 activation, and thereby increased the accumulation of ROS.	2	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	p62 blocked CCCP induced Keap1	keap1	Nrf2	Nrf2	nrf2	6	7	10	11
To explore whether the enhanced induction of HMOX1 by BRD4 knockdown after stimulation was due to an increase in NRF2 caused by a decreased KEAP1 protein level ( as already seen after BRD4 knockdown ) , we treated HEK293T cells ( +/-BRD4 knockdown ) with 20muM CoPP and analyzed the endogenous NRF2 protein level at different time points .	To explore whether the enhanced induction of HMOX1 by BRD4 knockdown after stimulation was due to an increase in NRF2 caused by a decreased KEAP1 protein level (as already seen after BRD4 knockdown), we treated HEK293T cells (+/-BRD4 knockdown) with 20muM CoPP and analyzed the endogenous NRF2 protein level at different time points.	17	27	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1 protein level	keap1	NRF2	NRF2	nrf2	24	25	19	20
Consistently , the oxidation of EPA and DHA also leads to the production of oxylipins that react with thiols in the Keap1 protein that normally inhibits the SKN-1 ortholog Nrf2 by retaining the protein in the cytoplasm ( Gao etal ., 2007 ) .	Consistently, the oxidation of EPA and DHA also leads to the production of oxylipins that react with thiols in the Keap1 protein that normally inhibits the SKN-1 ortholog Nrf2 by retaining the protein in the cytoplasm (Gao etal., 2007).	21	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	21	22	29	30
Keap1 protein ( a cytoplasmic repressor of NRF2 ) levels were not changed in response to shikonin treatment .	Keap1 protein (a cytoplasmic repressor of NRF2) levels were not changed in response to shikonin treatment.	0	8	repressor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	0	1	7	8
We now show that Sesn1 and Sesn2 interact with the Nrf2 suppressor Keap1 , the autophagy substrate p62 , and the ubiquitin ligase Rbx1 and that the antioxidant function of Sesns is mediated through activation of Nrf2 in a manner reliant on p62 dependent autophagic degradation of Keap1 .	We now show that Sesn1 and Sesn2 interact with the Nrf2 suppressor Keap1, the autophagy substrate p62, and the ubiquitin ligase Rbx1 and that the antioxidant function of Sesns is mediated through activation of Nrf2 in a manner reliant on p62 dependent autophagic degradation of Keap1.	7	23	suppressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	10	11
Nrf2 is negatively regulated by the cysteine rich protein Keap1 .	Nrf2 is negatively regulated by the cysteine rich protein Keap1.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	0	1
Keap1 not only sequesters Nrf2 in cytoplasm but also plays a role in its subsequent ubiquitination and proteasomal degradation [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Keap1 not only sequesters Nrf2 in cytoplasm but also plays a role in its subsequent ubiquitination and proteasomal degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	4	5
This indicates that Nrf2 is activated by CPDT , as it is well known that Nrf2 when repressed by Keap1 in the cytoplasm is targeted for degradation , but free Nrf2 is more stable and translocates to the nucleus .	This indicates that Nrf2 is activated by CPDT, as it is well known that Nrf2 when repressed by Keap1 in the cytoplasm is targeted for degradation, but free Nrf2 is more stable and translocates to the nucleus.	15	24	repressed	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	19	20	15	16
Upon exposure to ROS and electrophiles , Keap1 is inactivated , resulting in stabilization and nuclear localization of Nrf2 .	Upon exposure to ROS and electrophiles, Keap1 is inactivated, resulting in stabilization and nuclear localization of Nrf2.	7	19	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	18	19
These changes result in the prevention of Keap1 dependent inhibition of Nrf2 [ XREF_BIBR ] .	These changes result in the prevention of Keap1 dependent inhibition of Nrf2 [XREF_BIBR].	7	13	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	11	12
Thus , formation of a type 2 disulfide involving Cys23 could indeed alter Keap1 repression of Nrf2 .	Thus, formation of a type 2 disulfide involving Cys23 could indeed alter Keap1 repression of Nrf2.	13	17	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	16	17
Reportedly , evidence suggests that fumarates can activate the Nrf2 pathway by direct modification or succination of cysteine residues in Keap1 , which sequesters and degrades Nrf2 in the cytosol , leading to constitutive degradation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Reportedly, evidence suggests that fumarates can activate the Nrf2 pathway by direct modification or succination of cysteine residues in Keap1, which sequesters and degrades Nrf2 in the cytosol, leading to constitutive degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	7	31	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	26	27
Keap1 functions as a substrate adaptor protein for Cul3 dependent ubiquitin ligase complex and directs degradation of Nrf2 by facilitating ubiquitination and proteasomal degradation .	Keap1 functions as a substrate adaptor protein for Cul3 dependent ubiquitin ligase complex and directs degradation of Nrf2 by facilitating ubiquitination and proteasomal degradation.	0	19	directs	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	17	18
Keap1 is the major repressor of Nrf2 and facilitates the degradation of Nrf2 through the ubiquitin-proteasome pathway in cytosol .	Keap1 is the major repressor of Nrf2 and facilitates the degradation of Nrf2 through the ubiquitin-proteasome pathway in cytosol.	0	8	is the major repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	6	7
Consistent with this observation , Nrf2 activation by Keap1 knockdown results in a reduction in the metastasis of 3LL cells ; this observation was reproducible in a second cell line , melanoma derived B16-F10 .	Consistent with this observation, Nrf2 activation by Keap1 knockdown results in a reduction in the metastasis of 3LL cells; this observation was reproducible in a second cell line, melanoma derived B16-F10.	5	10	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	5	6
Nrf2 is normally sequestered in the cytoplasm by Keap1 ( XREF_FIG ) ; however , conditions such as oxidative stress or hypoxia can result in the activation of Nrf2 and its translocation to the nucleus and consequential altered gene expression [ XREF_BIBR ] .	Nrf2 is normally sequestered in the cytoplasm by Keap1 (XREF_FIG); however, conditions such as oxidative stress or hypoxia can result in the activation of Nrf2 and its translocation to the nucleus and consequential altered gene expression [XREF_BIBR].	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
Like in the previously mentioned studies involving Keap1 and diabetic complications , activation of Keap1 by SetD7 restricts Nrf2 activity .	Like in the previously mentioned studies involving Keap1 and diabetic complications, activation of Keap1 by SetD7 restricts Nrf2 activity.	12	19	restricts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	18	19
Oxidized omega 3 reacts directly with Keap1 , a negative regulator of Nrf2 , initiating Keap1 dissociation with Cullin3 and thereby inducing Nrf2 dependent target antioxidant genes such as heme oxygenase-1 .	Oxidized omega 3 reacts directly with Keap1, a negative regulator of Nrf2, initiating Keap1 dissociation with Cullin3 and thereby inducing Nrf2 dependent target antioxidant genes such as heme oxygenase-1.	6	24	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	22	23
Nrf2 is normally sequestered in the cytoplasm by the cysteine rich Keap1 protein , a substrate adaptor protein for a Cul3 dependent ubiquitin ligase complex that targets Nrf2 for proteasome mediated degradation .	Nrf2 is normally sequestered in the cytoplasm by the cysteine rich Keap1 protein, a substrate adaptor protein for a Cul3 dependent ubiquitin ligase complex that targets Nrf2 for proteasome mediated degradation.	11	29	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	27	28
They showed that remnant kidney tissue Nrf2 activity ( nuclear translocation ) was reduced , whereas the Nrf2 repressor Keap1 was upregulated [ XREF_BIBR ] .	They showed that remnant kidney tissue Nrf2 activity (nuclear translocation) was reduced, whereas the Nrf2 repressor Keap1 was upregulated [XREF_BIBR].	16	21	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	19	20	17	18
Nrf2 resides in the cytoplasm and is sequestered by Keap1 for targeted degradation by Cullin 3-base E3 ubiquitin ligase .	Nrf2 resides in the cytoplasm and is sequestered by Keap1 for targeted degradation by Cullin 3-base E3 ubiquitin ligase.	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	0	1
At the present time , little is known about Keap1 independent proteasomal degradation of Nrf2 .	At the present time, little is known about Keap1 independent proteasomal degradation of Nrf2.	9	15	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	14	15
KEAP-1 ( Kelch like ECH associated protein 1 ) represses the function of Nrf-2 and contributes to a regulatory balance over hundreds of genes that control oxidation / antioxidation and detoxification within cells .	KEAP-1 (Kelch like ECH associated protein 1) represses the function of Nrf-2 and contributes to a regulatory balance over hundreds of genes that control oxidation / antioxidation and detoxification within cells.	0	15	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP-1	KEAP-1	KEAP-1	Nrf-2	Nrf-2	Nrf-2	0	1	13	14
NRF2 is negatively regulated by the cytoplasmic redox-sensor protein Keap1 via its Neh2 ( Nrf2 and ECH homology 2 ) domain XREF_BIBR .	NRF2 is negatively regulated by the cytoplasmic redox-sensor protein Keap1 via its Neh2 (Nrf2 and ECH homology 2) domain XREF_BIBR.	0	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	9	10	0	1
Detailed analysis of differential Nrf2 activity displayed in transfected cell lines ultimately led to the identification of a new protein , which we named Keap1 , that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal regulatory domain .	Detailed analysis of differential Nrf2 activity displayed in transfected cell lines ultimately led to the identification of a new protein, which we named Keap1, that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal regulatory domain.	23	30	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	24	25	28	29
It is increased in response to various stimuli and interacts with Keap1 , and causes Keap1 accumulation and subsequent autophagic degradation , resulting in the inhibition of the binding of Keap1 and Nrf2 , and inhibition of Keap1 mediated Nrf2 degradation [ XREF_BIBR ] .	It is increased in response to various stimuli and interacts with Keap1, and causes Keap1 accumulation and subsequent autophagic degradation, resulting in the inhibition of the binding of Keap1 and Nrf2, and inhibition of Keap1 mediated Nrf2 degradation [XREF_BIBR].	35	40	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	37	38	39	40
It is known that Keap1 tethers Nrf2 in the cytoplasm and represses the transactivation activity of Nrf2 [ XREF_BIBR ] .	It is known that Keap1 tethers Nrf2 in the cytoplasm and represses the transactivation activity of Nrf2 [XREF_BIBR].	4	18	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	16	17
Despite this , there is evidence that Cys273 and Cys288 are critical in Keap1 repression of Nrf2 .	Despite this, there is evidence that Cys273 and Cys288 are critical in Keap1 repression of Nrf2.	13	17	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	16	17
Exposure of cells to ROS , toxins , or electrophilic radicals leads to post-translational modification and inactivation of Keap1 which ultimately leads to attenuation of Keap1 mediated degradation of Nrf2 .	Exposure of cells to ROS, toxins, or electrophilic radicals leads to post-translational modification and inactivation of Keap1 which ultimately leads to attenuation of Keap1 mediated degradation of Nrf2.	23	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	25	26	29	30
By directly interacting with Keap1 , p62 blots Keap1 mediated Nrf2 degradation [ XREF_BIBR ] .	By directly interacting with Keap1, p62 blots Keap1 mediated Nrf2 degradation [XREF_BIBR].	6	11	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	10	11
XREF_BIBR , XREF_BIBR , XREF_BIBR Binding of a regulatory protein , Keap1 , sequesters Nrf2 in the cytoplasm , targeting Nrf2 for polyubiquitinylation and proteasomal degration and , thus , silencing the Nrf2 gene program .	XREF_BIBR, XREF_BIBR, XREF_BIBR Binding of a regulatory protein, Keap1, sequesters Nrf2 in the cytoplasm, targeting Nrf2 for polyubiquitinylation and proteasomal degration and, thus, silencing the Nrf2 gene program.	0	15	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	14	15
At the same time , the Nrf2 signaling pathway was activated and oxidative stress disrupted the critical cysteine residues in Keap1 , enabling Nrf2 to translocate into the nucleus from the cytoplasm .	At the same time, the Nrf2 signaling pathway was activated and oxidative stress disrupted the critical cysteine residues in Keap1, enabling Nrf2 to translocate into the nucleus from the cytoplasm.	14	24	enabling	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	23	24
Dh404 activated Nrf2 transcriptional activity in the cells transfected with Nrf2 and Keap1 but not with Nrf2 and C151S Keap1 mutant , suggesting that dh404 specifically interacts with the Cys 151 residue in Keap1 leading to disruption of the Keap1 dependent suppression of Nrf2 .	Dh404 activated Nrf2 transcriptional activity in the cells transfected with Nrf2 and Keap1 but not with Nrf2 and C151S Keap1 mutant, suggesting that dh404 specifically interacts with the Cys 151 residue in Keap1 leading to disruption of the Keap1 dependent suppression of Nrf2.	39	44	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	39	40	43	44
Under normal cellular conditions , Nrf2 is sequestered in the cytoplasm by the repressor protein Keap1 .	Under normal cellular conditions, Nrf2 is sequestered in the cytoplasm by the repressor protein Keap1.	5	16	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	5	6
Thus , Keap1 is the main repressor of Nrf2 , having three functional domains , namely , the broad complex , Tramtrack , and Bric-a-Brac ( BTB ) domain , the intervening region ( IVR ) domain , and the double glycine repeat ( DGR )/Kelch domain [ XREF_BIBR ] ( XREF_FIG ) .	Thus, Keap1 is the main repressor of Nrf2, having three functional domains, namely, the broad complex, Tramtrack, and Bric-a-Brac (BTB) domain, the intervening region (IVR) domain, and the double glycine repeat (DGR)/Kelch domain [XREF_BIBR] (XREF_FIG).	2	9	is the main repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	8	9
Oxidative and electrophilic stresses such as reactive oxygen species ( ROS ) impair Keap1 mediated proteasomal degradation of Nrf2 , causing Nrf2 activation and its subsequent nuclear translocation [ XREF_BIBR , XREF_BIBR ] .	Oxidative and electrophilic stresses such as reactive oxygen species (ROS) impair Keap1 mediated proteasomal degradation of Nrf2, causing Nrf2 activation and its subsequent nuclear translocation [XREF_BIBR, XREF_BIBR].	13	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	18	19
In flies and mammals , NRF-2 and CncC is negatively inhibited through cytosolic sequestration and proteasomal degradation by the canonical Keap1 .	In flies and mammals, NRF-2 and CncC is negatively inhibited through cytosolic sequestration and proteasomal degradation by the canonical Keap1.	5	21	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF-2	NRF-2	NRF-2	20	21	5	6
Under basal conditions , Nrf2 resides mainly in the cytoplasm bound to its cysteine rich , Kelch domain containing partner Keap1 , which is itself anchored to the actin cytoskeleton and represses Nrf2 activity .	Under basal conditions, Nrf2 resides mainly in the cytoplasm bound to its cysteine rich, Kelch domain containing partner Keap1, which is itself anchored to the actin cytoskeleton and represses Nrf2 activity.	18	33	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	32	33
Under unstimulated conditions , Nrf2 is sequestered in the cytoplasm by the anchor protein Keap1 , and maintained at a stable level by the ubiquitin-proteasome-dependent degradation system [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Under unstimulated conditions, Nrf2 is sequestered in the cytoplasm by the anchor protein Keap1, and maintained at a stable level by the ubiquitin-proteasome-dependent degradation system [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	17	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	4	5
The binding between p62 and Keap1 makes Keap1 unavailable to inhibit Nrf2 , leading to Nrf2 constitutive activation .	The binding between p62 and Keap1 makes Keap1 unavailable to inhibit Nrf2, leading to Nrf2 constitutive activation.	7	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	11	12
Thus , Keap1 negatively regulates Nrf2 both by enhancing its rate of proteasomal degradation and by altering its subcellular distribution .	Thus, Keap1 negatively regulates Nrf2 both by enhancing its rate of proteasomal degradation and by altering its subcellular distribution.	2	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	5	6
We found a general consensus in the literature that the presence of oxidizing agents as well as the inhibition of the NRF2 repressor Keap1 maintain NRF2 expression at basal levels .	We found a general consensus in the literature that the presence of oxidizing agents as well as the inhibition of the NRF2 repressor Keap1 maintain NRF2 expression at basal levels.	18	24	repressor	Negative_activation_token_1_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	23	24	21	22
Under unstressed conditions , Nrf2 is repressed in the cytoplasm by the binding of the Keap1 .	Under unstressed conditions, Nrf2 is repressed in the cytoplasm by the binding of the Keap1.	4	16	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	4	5
Keap1 represses Nrf2 activity in the cytoplasm by its sequestering , ubiquitination and proteosomal degradation .	Keap1 represses Nrf2 activity in the cytoplasm by its sequestering, ubiquitination and proteosomal degradation.	0	3	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
However , overexpression of constitutive active NRF2 in liver or NRF2 activation by liver specific Keap1 deletion does not induce HCC without further support [ XREF_BIBR , XREF_BIBR ] .	However, overexpression of constitutive active NRF2 in liver or NRF2 activation by liver specific Keap1 deletion does not induce HCC without further support [XREF_BIBR, XREF_BIBR].	8	16	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	15	16	10	11
When cells are exposed to stresses , KEAP1 stops promoting NRF2 degradation , and NRF2 rapidly accumulates and activates the transcription of target genes .	When cells are exposed to stresses, KEAP1 stops promoting NRF2 degradation, and NRF2 rapidly accumulates and activates the transcription of target genes.	7	11	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	7	8	10	11
The results suggested that the decreased expression of KEAP1 might result in activation of NFE2L2 target genes , at least in the thyroid of the patients .	The results suggested that the decreased expression of KEAP1 might result in activation of NFE2L2 target genes, at least in the thyroid of the patients.	6	16	result in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	KEAP1	expression of KEAP1	keap1	NFE2L2	NFE2L2	nfe2l2	8	9	14	15
Keap1 silence , mutation or in activation shall cause Nrf2 stabilization and accumulation , which then activates Nrf2 cascade [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Keap1 silence, mutation or in activation shall cause Nrf2 stabilization and accumulation, which then activates Nrf2 cascade [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	10	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	9	10
Nrf2 , which is negatively regulated by Keap1 , mediates the cell ' s response to stress by controlling the expression of several hundred genes , including proteasome expression .	Nrf2, which is negatively regulated by Keap1, mediates the cell 's response to stress by controlling the expression of several hundred genes, including proteasome expression.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	0	1
Here we report that the deubiquitinating enzyme , USP15 , specifically deubiquitinates Keap1 , which suppresses the Nrf2 pathway .	Here we report that the deubiquitinating enzyme, USP15, specifically deubiquitinates Keap1, which suppresses the Nrf2 pathway.	8	18	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	USP15, specifically deubiquitinates Keap1	keap1	Nrf2	Nrf2	nrf2	12	13	17	18
XREF_BIBR Nrf2 resides predominantly in the cytoplasm where it interacts with actin associated cytosolic protein , INrf2 ( inhibitor of Nrf2 ) or Keap1 ( Kelch like ECH associated protein .	XREF_BIBR Nrf2 resides predominantly in the cytoplasm where it interacts with actin associated cytosolic protein, INrf2 (inhibitor of Nrf2) or Keap1 (Kelch like ECH associated protein.	2	21	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	16	17	20	21
Nrf2 is normally sequestered in the cytoplasm by a composite of Keap1 and actin , where it is degraded by Cullin 3 via ubiquitination .	Nrf2 is normally sequestered in the cytoplasm by a composite of Keap1 and actin, where it is degraded by Cullin 3 via ubiquitination.	0	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	0	1
Kelch like-ECH-associated protein 1 ( Keap1 ) can sequester Nrf2 in the cytosol and help in maintaining redox balance [ XREF_BIBR ] .	Kelch like-ECH-associated protein 1 (Keap1) can sequester Nrf2 in the cytosol and help in maintaining redox balance [XREF_BIBR].	2	10	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	9	10
Normally , Nrf2 is sequestered in cytosol by its inhibitor Keap-1 ( Kelch like ECH associated protein 1 ) ; when MM arises , the ROS levels increase and one or multiple cysteines bind to Keap-1 , which undergoes a conformational change releasing Nrf2 .	Normally, Nrf2 is sequestered in cytosol by its inhibitor Keap-1 (Kelch like ECH associated protein 1); when MM arises, the ROS levels increase and one or multiple cysteines bind to Keap-1, which undergoes a conformational change releasing Nrf2.	2	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap-1	Keap-1	Keap-1	Nrf2	Nrf2	Nrf2	10	11	2	3
Without such stresses , Nrf2 is normally repressed by the oxidative stress sensor Keap1 XREF_BIBR , which binds and degrades Nrf2 through the ubiquitin-proteasome system .	Without such stresses, Nrf2 is normally repressed by the oxidative stress sensor Keap1 XREF_BIBR, which binds and degrades Nrf2 through the ubiquitin-proteasome system.	4	21	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1 XREF_BIBR, which binds and degrades Nrf2	keap1	Nrf2	Nrf2	nrf2	13	14	4	5
Knockdown of the Nrf2 repressor Keap1 ( siKP ) was used as a positive control for Nrf2 activation .	Knockdown of the Nrf2 repressor Keap1 (siKP) was used as a positive control for Nrf2 activation.	0	6	repressor	Negative_activation_token_1_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	3	4
Oxidative stress abrogates the Keap1 mediated degradation of Nrf2 , which in turn accumulates in the nucleus where it heterodimerizes with a small musculoaponeurotic fibrosarcoma ( Maf ) protein on antioxidant response elements ( AREs ) to stimulate the expression of phase II and antioxidant enzymes .	Oxidative stress abrogates the Keap1 mediated degradation of Nrf2, which in turn accumulates in the nucleus where it heterodimerizes with a small musculoaponeurotic fibrosarcoma (Maf) protein on antioxidant response elements (AREs) to stimulate the expression of phase II and antioxidant enzymes.	2	37	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	8	9
Damage induced intestines with Nrf2 loss triggered by Keap1 overexpression exhibit increased ISC proliferative activity .	Damage induced intestines with Nrf2 loss triggered by Keap1 overexpression exhibit increased ISC proliferative activity.	4	10	triggered	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1 overexpression	keap1	Nrf2	Nrf2	nrf2	8	9	4	5
Nrf2 is sequestered by Keap1 in the cytosol and constitutively targeted for poly-ubiquitination under a basal condition .	Nrf2 is sequestered by Keap1 in the cytosol and constitutively targeted for poly-ubiquitination under a basal condition.	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	0	1
INrf2 tethering of the transcription factor Nrf2 in the cytosol prevents Nrf2 activation of antioxidant response element ( ARE ) mediated gene expression .	INrf2 tethering of the transcription factor Nrf2 in the cytosol prevents Nrf2 activation of antioxidant response element (ARE) mediated gene expression.	0	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	0	1	11	12
Although NRF2 activity is cytoprotective XREF_BIBR , XREF_BIBR , XREF_BIBR , limitation of its activity by KEAP1 is crucial : mutations that impair KEAP1 mediated degradation of NRF2 are associated with tumorigenesis XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Although NRF2 activity is cytoprotective XREF_BIBR, XREF_BIBR, XREF_BIBR, limitation of its activity by KEAP1 is crucial : mutations that impair KEAP1 mediated degradation of NRF2 are associated with tumorigenesis XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	22	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	23	24	27	28
Upon exposure to ROS , Keap1 undergoes a conformational change when its multiple cysteine residues interact with ROS , which releases Nrf2 , and inhibits Keap1 mediated proteasomal degradation of Nrf2 .	Upon exposure to ROS, Keap1 undergoes a conformational change when its multiple cysteine residues interact with ROS, which releases Nrf2, and inhibits Keap1 mediated proteasomal degradation of Nrf2.	25	31	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	25	26	30	31
At basal levels , INrf2 functions as a substrate adaptor to sequester Nrf2 into the Cul3-Rbx1 E3 ligase complex for ubiquitylation and proteasomal degradation .	At basal levels, INrf2 functions as a substrate adaptor to sequester Nrf2 into the Cul3-Rbx1 E3 ligase complex for ubiquitylation and proteasomal degradation.	4	13	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	4	5	12	13
It is known that Keap1 is another inhibitor of Nrf2 , and our previous data has indicated that hyperoside induces Keap1 inhibition probably by facilitating Keap1 protein degradation [ XREF_BIBR ] .	It is known that Keap1 is another inhibitor of Nrf2, and our previous data has indicated that hyperoside induces Keap1 inhibition probably by facilitating Keap1 protein degradation [XREF_BIBR].	4	10	is another inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	9	10
Implications of the cyclical nature of the Keap1 mediated degradation of Nrf2 .	Implications of the cyclical nature of the Keap1 mediated degradation of Nrf2.	4	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	11	12
In contrast , overactivation of Nrf2 induced by Keap1 deletion resulted in a strong decrease of 4-HNE-positive cells at levels even lower than the control group ( c-met fx/fx ) ( XREF_FIG ) .	In contrast, overactivation of Nrf2 induced by Keap1 deletion resulted in a strong decrease of 4-HNE-positive cells at levels even lower than the control group (c-met fx/fx) (XREF_FIG).	3	9	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	5	6
Cys 273 and Cys 288 are essential for Keap1 dependent ubiquitination of Nrf2 and Keap1 mediated repression of Nrf2 activity XREF_BIBR , XREF_BIBR .	Cys 273 and Cys 288 are essential for Keap1 dependent ubiquitination of Nrf2 and Keap1 mediated repression of Nrf2 activity XREF_BIBR, XREF_BIBR.	8	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1 dependent ubiquitination of Nrf2	keap1	Nrf2	Nrf2	nrf2	8	9	18	19
For instance , the prototype of BTB-kelch protein Keap1 ( designated as KLHL19 ) mediates the ubiquitin dependent degradation of Nrf2 , a master regulator of anti-oxidant responses [ XREF_BIBR , XREF_BIBR ] .	For instance, the prototype of BTB-kelch protein Keap1 (designated as KLHL19) mediates the ubiquitin dependent degradation of Nrf2, a master regulator of anti-oxidant responses [XREF_BIBR, XREF_BIBR].	4	21	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	20	21
Keap1 negatively regulates Nrf2 activity through interactions with Roc1 and Cul3 which recruit E2 ubiquitin ligase , driving the proteasomal degradation of Nrf2 [ XREF_BIBR ] .	Keap1 negatively regulates Nrf2 activity through interactions with Roc1 and Cul3 which recruit E2 ubiquitin ligase, driving the proteasomal degradation of Nrf2 [XREF_BIBR].	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
Keap1 , a key regulator of Nrf2 , sequesters Nrf2 in the cytoplasm , preventing entry into the nucleus .	Keap1, a key regulator of Nrf2, sequesters Nrf2 in the cytoplasm, preventing entry into the nucleus.	0	12	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	9	10
Previous studies in normal somatic cells and cancer cells indicated that the inhibition of either Keap1 or Cul3 increases the nuclear accumulation of Nrf2 , leading to the activation of Nrf2 dependent antioxidative gene expression [ XREF_BIBR , XREF_BIBR ] .	Previous studies in normal somatic cells and cancer cells indicated that the inhibition of either Keap1 or Cul3 increases the nuclear accumulation of Nrf2, leading to the activation of Nrf2 dependent antioxidative gene expression [XREF_BIBR, XREF_BIBR].	12	24	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	23	24
The INrf2 ( Keap1 ) , Cul3 , and Rbx1 complex constantly degrades Nrf2 under normal conditions .	The INrf2 (Keap1), Cul3, and Rbx1 complex constantly degrades Nrf2 under normal conditions.	0	14	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	1	2	13	14
However , its induction of HO-1 appears to be primarily mediated by releasing Keap1 inhibition of Nrf2 nuclear import , likely by direct interaction with Keap1 cysteine residues [ XREF_BIBR ] .	However, its induction of HO-1 appears to be primarily mediated by releasing Keap1 inhibition of Nrf2 nuclear import, likely by direct interaction with Keap1 cysteine residues [XREF_BIBR].	13	18	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	16	17
This is the first time that the endogenous repressor Keap1 has been targeted to increase Nrf2 signaling in fibroblasts and proposes a new therapeutic strategy in combating ROS mishandling within diabetic wounds .	This is the first time that the endogenous repressor Keap1 has been targeted to increase Nrf2 signaling in fibroblasts and proposes a new therapeutic strategy in combating ROS mishandling within diabetic wounds.	6	20	targeted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	15	16
The combined decrease in both nuclear and cytoplasmic Nrf2 in the macrophages of emphysema patients suggests a global reduction in the abundance of Nrf2 rather than a defect in nuclear localization , which is consistent with the increased Keap1 that would reduce Nrf2 protein abundance by promoting proteasomal degradation .	The combined decrease in both nuclear and cytoplasmic Nrf2 in the macrophages of emphysema patients suggests a global reduction in the abundance of Nrf2 rather than a defect in nuclear localization, which is consistent with the increased Keap1 that would reduce Nrf2 protein abundance by promoting proteasomal degradation.	34	44	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	38	39	42	43
In the modulation of Nrf2 pathway , Keap1 can inactivate the function of Nrf2 by sequestering it in the cytoplasm and preventing it from entering the nucleus .	In the modulation of Nrf2 pathway, Keap1 can inactivate the function of Nrf2 by sequestering it in the cytoplasm and preventing it from entering the nucleus.	7	14	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	13	14
Under basal conditions NRF2 is kept transcriptionally inactive through binding to its inhibitor , KEAP1 , which targets NRF2 for proteasomal degradation .	Under basal conditions NRF2 is kept transcriptionally inactive through binding to its inhibitor, KEAP1, which targets NRF2 for proteasomal degradation.	12	21	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	14	15	18	19
Nrf2 is normally sequestered in the cytoplasm by its inhibitor Keap1 .	Nrf2 is normally sequestered in the cytoplasm by its inhibitor Keap1.	0	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	0	1
HNE is a potent inducer of Nrf2 either by covalently binding to cysteine sites in Keap1 protein and thus disrupting Keap1 dependent degradation of Nrf2 , or by activating Nrf2 through activation of upstream kinases such as PKC , ERK and PI3K XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	HNE is a potent inducer of Nrf2 either by covalently binding to cysteine sites in Keap1 protein and thus disrupting Keap1 dependent degradation of Nrf2, or by activating Nrf2 through activation of upstream kinases such as PKC, ERK and PI3K XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	20	25	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	24	25
As KEAP1 is the repressor of NFE2L2 , the expression of NFE2L2 target genes was analyzed in KEAP1 depleted MDMs and showed at least partial activation of NFE2L2 with induction of NQO1 and SLC7A11 .	As KEAP1 is the repressor of NFE2L2, the expression of NFE2L2 target genes was analyzed in KEAP1 depleted MDMs and showed at least partial activation of NFE2L2 with induction of NQO1 and SLC7A11.	1	7	is the repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NFE2L2	NFE2L2	NFE2L2	1	2	6	7
Keap1 sequesters NRF2 in the cytoplasm and acts as an adaptor enhancing the interaction of the Cullin 3 based E3-ubiquitin ligase complex 2 .	Keap1 sequesters NRF2 in the cytoplasm and acts as an adaptor enhancing the interaction of the Cullin 3 based E3-ubiquitin ligase complex 2.	0	7	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	0	1	2	3
The complex p62 , Keap1 , and LC3II promotes Keap1 degradation , which further activates Nrf2 in a positive feedback loop .	The complex p62, Keap1, and LC3II promotes Keap1 degradation, which further activates Nrf2 in a positive feedback loop.	9	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	15	16
Under basal conditions , Nrf2 is sequestered in the cytoplasm by Keap1 ( Kelch like ECH associated protein 1 , its repressor protein ) .	Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1 (Kelch like ECH associated protein 1, its repressor protein).	4	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
NRF2 is repressed by the inhibitor Keap1 .	NRF2 is repressed by the inhibitor Keap1.	0	7	repressed	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	6	7	0	1
Under homeostatic conditions , HSF1 is bound and silenced by its natural repressor HSP90 chaperone , and NRF2 is similarly repressed by KEAP1 ( Kelch like ECH associated protein1 ) .	Under homeostatic conditions, HSF1 is bound and silenced by its natural repressor HSP90 chaperone, and NRF2 is similarly repressed by KEAP1 (Kelch like ECH associated protein1).	17	24	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	22	23	17	18
These cysteines are considered to be potential sensors , as mutation of these cysteines to serine renders Keap1 unable to repress Nrf2 [ XREF_BIBR , XREF_BIBR ] .	These cysteines are considered to be potential sensors, as mutation of these cysteines to serine renders Keap1 unable to repress Nrf2 [XREF_BIBR, XREF_BIBR].	17	25	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	21	22
Absence of either Cys273 or Cys288 was found to be sufficient to disrupt Keap1 repression of Nrf2 .	Absence of either Cys273 or Cys288 was found to be sufficient to disrupt Keap1 repression of Nrf2.	13	17	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	16	17
We demonstrate that lack of Keap1 decreases autophagy as well as increases Nrf2 transcriptional activity and antioxidant gene expression .	We demonstrate that lack of Keap1 decreases autophagy as well as increases Nrf2 transcriptional activity and antioxidant gene expression.	3	14	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	12	13
To test this , we transfected cells with the promoter or enhancer constructs and treated the cells with selected phytoestrogens ; we found that these compounds differentially relieved Nrf2 repression by Keap1 , restoring luciferase expression to levels similar to those with Nrf2 alone ( XREF_FIG B-D ) .	To test this, we transfected cells with the promoter or enhancer constructs and treated the cells with selected phytoestrogens; we found that these compounds differentially relieved Nrf2 repression by Keap1, restoring luciferase expression to levels similar to those with Nrf2 alone (XREF_FIG B-D).	28	32	repression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	31	32	28	29
Under resting conditions , Nrf-2 is sequestered in cytoplasm by Keap1 , an adaptor for Cul3 based E3 ubiquitin ligase that promotes constitutive proteasome mediated degradation of Nrf-2 XREF_BIBR .	Under resting conditions, Nrf-2 is sequestered in cytoplasm by Keap1, an adaptor for Cul3 based E3 ubiquitin ligase that promotes constitutive proteasome mediated degradation of Nrf-2 XREF_BIBR.	4	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf-2	Nrf-2	Nrf-2	10	11	4	5
When cells are in normal conditions without exposure to stress , Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2 , while Nrf2 is stabilized when Keap1 is inactivated upon oxidative stress .	When cells are in normal conditions without exposure to stress, Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2, while Nrf2 is stabilized when Keap1 is inactivated upon oxidative stress.	11	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	25	26
But in many cancer cells , loss of Keap1 function activates Nrf2 and promotes cancer growth [ XREF_BIBR ] .	But in many cancer cells, loss of Keap1 function activates Nrf2 and promotes cancer growth [XREF_BIBR].	8	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	11	12
One mechanism by which XH might induce QR could be through interaction with Keap1 , which sequesters Nrf2 in the cytoplasm , so that it can not activate the ARE .	One mechanism by which XH might induce QR could be through interaction with Keap1, which sequesters Nrf2 in the cytoplasm, so that it can not activate the ARE.	11	20	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	17	18
In contrast , both Keap1 overexpression and Nrf2 RNAi decreased nuclear Nrf2 .	In contrast, both Keap1 overexpression and Nrf2 RNAi decreased nuclear Nrf2.	4	12	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1 overexpression	keap1	Nrf2	Nrf2	nrf2	4	5	11	12
Taken together , these results demonstrate that Nrf2 activation by renal Keap1 deletion during development , but not during adulthood , leads to a reduction in the level of the AQP2 protein in the kidney , thereby leading to NDI .	Taken together, these results demonstrate that Nrf2 activation by renal Keap1 deletion during development, but not during adulthood, leads to a reduction in the level of the AQP2 protein in the kidney, thereby leading to NDI.	7	12	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	7	8
Nrf2 is sequestered in the cytoplasm by Keap1 and subjected to constant degradation .	Nrf2 is sequestered in the cytoplasm by Keap1 and subjected to constant degradation.	0	9	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	0	1
In response to oxidative stress , the inhibitor Keap1 can not degrade NRF2 , and newly synthesized NRF2 accumulates , translocates to the nucleus and drives the transcription of ARE containing genes [ XREF_BIBR ] .	In response to oxidative stress, the inhibitor Keap1 can not degrade NRF2, and newly synthesized NRF2 accumulates, translocates to the nucleus and drives the transcription of ARE containing genes [XREF_BIBR].	6	13	degrade	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	8	9	12	13
Nrf2 resides predominantly in the cytoplasm where it interacts with actin associated cytosolic protein , Keap1 ( Kelch like ECH associated protein 1 , also known as Nrf2 inhibitor , INrf2 ) , which inhibits the Nrf2 activity .	Nrf2 resides predominantly in the cytoplasm where it interacts with actin associated cytosolic protein, Keap1 (Kelch like ECH associated protein 1, also known as Nrf2 inhibitor, INrf2), which inhibits the Nrf2 activity.	13	37	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	36	37
Similarly , NRF2 is sequestered in the cytoplasm and targeted for degradation by KEAP1 , a zinc metalloprotein XREF_BIBR , XREF_BIBR , in which cobalt has been shown to substitute for zinc XREF_BIBR .	Similarly, NRF2 is sequestered in the cytoplasm and targeted for degradation by KEAP1, a zinc metalloprotein XREF_BIBR, XREF_BIBR, in which cobalt has been shown to substitute for zinc XREF_BIBR.	2	27	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	13	14	2	3
KEAP1 serves as an adaptor to CUL3 to initiate degradation of NRF2 [ XREF_BIBR ] .	KEAP1 serves as an adaptor to CUL3 to initiate degradation of NRF2 [XREF_BIBR].	0	13	initiate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	11	12
INrf2 functions as an adapter for Cul3 and Rbx1 E3 ubiquitin ligase mediated degradation of Nrf2 .	INrf2 functions as an adapter for Cul3 and Rbx1 E3 ubiquitin ligase mediated degradation of Nrf2.	0	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	0	1	15	16
Under resting conditions , Nrf2 is sequestered in the cytoplasm by Keap1 , an adaptor for a Cul3 based E3 ligase that promotes constitutive proteasome mediated Nrf2 degradation .	Under resting conditions, Nrf2 is sequestered in the cytoplasm by Keap1, an adaptor for a Cul3 based E3 ligase that promotes constitutive proteasome mediated Nrf2 degradation.	4	14	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
In addition to Cys273 and Cys288 , Cys 151 was reported to be required for inhibition of KEAP1 dependent degradation of NRF2 by SFN and t-butylhydroxy toluene ( tBHQ ) .	In addition to Cys273 and Cys288, Cys 151 was reported to be required for inhibition of KEAP1 dependent degradation of NRF2 by SFN and t-butylhydroxy toluene (tBHQ).	17	22	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	17	18	21	22
In basal conditions , Nrf2 activity is limited by its cognate inhibitor Keap1 , which serves as an adaptor protein for a Cul3 based ubiquitin ligase , thereby targeting Nrf2 for proteolysis ( XREF_FIG ) .	In basal conditions, Nrf2 activity is limited by its cognate inhibitor Keap1, which serves as an adaptor protein for a Cul3 based ubiquitin ligase, thereby targeting Nrf2 for proteolysis (XREF_FIG).	4	15	limited	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	4	5
Substitution of C273 or C288 with either serine or alanine leads to a complete loss of repressor activity , and KEAP1 is unable to repress NRF2 even under basal conditions [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Substitution of C273 or C288 with either serine or alanine leads to a complete loss of repressor activity, and KEAP1 is unable to repress NRF2 even under basal conditions [XREF_BIBR, XREF_BIBR, XREF_BIBR].	20	26	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	20	21	25	26
This suggests that increased Keap1 can decrease Nrf2 .	This suggests that increased Keap1 can decrease Nrf2.	3	8	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	7	8
Previous reports suggest that the lack of autophagy causes the accumulation of P62 , which leads to persistent activation of Nrf2 via Keap1 ( the cellular inhibitor of Nrf2 ) sequestration XREF_BIBR , XREF_BIBR .	Previous reports suggest that the lack of autophagy causes the accumulation of P62, which leads to persistent activation of Nrf2 via Keap1 (the cellular inhibitor of Nrf2) sequestration XREF_BIBR, XREF_BIBR.	20	31	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	28	29
Upon normal conditions , NRF2 is sequestered by KEAP1 and inactivated by proteasomal degradation .	Upon normal conditions, NRF2 is sequestered by KEAP1 and inactivated by proteasomal degradation.	4	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	8	9	4	5
Nrf2 plays a crucial role in cellular defense and is sequestered by Keap1 in the cytoplasm , which in turn undergoes proteasomal degradation under certain stress conditions , releasing Nrf2 .	Nrf2 plays a crucial role in cellular defense and is sequestered by Keap1 in the cytoplasm, which in turn undergoes proteasomal degradation under certain stress conditions, releasing Nrf2.	0	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	0	1
Under normal ( unstressed ) conditions , Keap1 activates and rapidly degrades Nrf2 through the proteasome pathway .	Under normal (unstressed) conditions, Keap1 activates and rapidly degrades Nrf2 through the proteasome pathway.	7	13	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
Under physiological conditions , cytosolic Nrf2 protein is maintained at very low levels by its selective negative regulator , Kelch like ECH associated protein 1 ( KEAP1 ) , a cytoplasmic protein which sequesters Nrf2 in the cytoplasm and directs it to CUL3 E3 ligase for ubiquitylation and subsequent degradation by the proteasome XREF_BIBR XREF_BIBR .	Under physiological conditions, cytosolic Nrf2 protein is maintained at very low levels by its selective negative regulator, Kelch like ECH associated protein 1 (KEAP1), a cytoplasmic protein which sequesters Nrf2 in the cytoplasm and directs it to CUL3 E3 ligase for ubiquitylation and subsequent degradation by the proteasome XREF_BIBR XREF_BIBR.	19	35	sequesters	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	26	27	34	35
In unstressed cells , NRF2 is degraded following ubiquitination by the E3 ligase KEAP1 .	In unstressed cells, NRF2 is degraded following ubiquitination by the E3 ligase KEAP1.	4	14	degraded	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	13	14	4	5
Most of the cytoprotective antioxidant genes like SOD , GPX , etc. are under the control of the master regulator , transcription factor Nrf2 , which is negatively regulated by Keap1 .	Most of the cytoprotective antioxidant genes like SOD, GPX, etc. are under the control of the master regulator, transcription factor Nrf2, which is negatively regulated by Keap1.	19	31	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	30	31	23	24
Keap1 knockout activates Nrf2 whereas double knockout of both Keap1 and Nrf2 completely rescues the phenotype of Keap1 knockout [ XREF_BIBR ] .	Keap1 knockout activates Nrf2 whereas double knockout of both Keap1 and Nrf2 completely rescues the phenotype of Keap1 knockout [XREF_BIBR].	0	4	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
The use of small molecule activators of Nrf2 , which act by antagonizing Keap1 mediated Nrf2 degradation , represents a promising form of antioxidant therapy .	The use of small molecule activators of Nrf2, which act by antagonizing Keap1 mediated Nrf2 degradation, represents a promising form of antioxidant therapy.	13	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	15	16
Degradation of Keap1 allows Nrf2 to be translocated to the nucleus to upregulate antioxidant gene expression ( Ichimura etal .	Degradation of Keap1 allows Nrf2 to be translocated to the nucleus to upregulate antioxidant gene expression (Ichimura etal.	0	7	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	4	5
However , redox modification of KEAP1 impedes presentation of NRF2 to the UPS represented by CULLIN3 and RBX1 .	However, redox modification of KEAP1 impedes presentation of NRF2 to the UPS represented by CULLIN3 and RBX1.	3	10	impedes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	5	6	9	10
Nrf2 is sequestered in cytoplasm by its repressor Keap1 , released and translocated into nucleus under oxidative stress .	Nrf2 is sequestered in cytoplasm by its repressor Keap1, released and translocated into nucleus under oxidative stress.	0	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
In human diabetic cataractous lenses , CpG demethylation in the Keap1 promoter increased levels of Keap1 protein which increases Nrf2 degradation .	In human diabetic cataractous lenses, CpG demethylation in the Keap1 promoter increased levels of Keap1 protein which increases Nrf2 degradation.	7	20	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	demethylation in the Keap1 promoter increased levels of Keap1	keap1	Nrf2	Nrf2	nrf2	15	16	19	20
Nrf2 is a key transcription factor regulating the expression of a wide array of phase II and antioxidant enzymes ; under normal conditions Nrf2 is inhibited in the cytoplasm by Keap1 12 .	Nrf2 is a key transcription factor regulating the expression of a wide array of phase II and antioxidant enzymes; under normal conditions Nrf2 is inhibited in the cytoplasm by Keap1 12.	23	31	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	30	31	23	24
Loss of Keap1 in murine embryonic fibroblasts ( MEFs ) results in constitutive Nrf2 activation and increased MEF survival [ XREF_BIBR , XREF_BIBR ] .	Loss of Keap1 in murine embryonic fibroblasts (MEFs) results in constitutive Nrf2 activation and increased MEF survival [XREF_BIBR, XREF_BIBR].	0	15	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Keap1	Loss of Keap1	keap1	Nrf2	Nrf2	nrf2	2	3	13	14
Keap1 represses the ability of Nrf2 to induce endogenous antioxidants by binding very tightly to Nrf2 and anchoring it in the cytoplasm .	Keap1 represses the ability of Nrf2 to induce endogenous antioxidants by binding very tightly to Nrf2 and anchoring it in the cytoplasm.	0	6	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	5	6
Furthermore , we found evidence indicating that Keap1 may repress Nrf2 activity by transiently shuttling into the nucleus to promote its ubiquitylation .	Furthermore, we found evidence indicating that Keap1 may repress Nrf2 activity by transiently shuttling into the nucleus to promote its ubiquitylation.	7	11	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	10	11
NRF2 is sequestered by KEAP1 in the cytosol and constitutively targeted for polyubiquitination under normal conditions .	NRF2 is sequestered by KEAP1 in the cytosol and constitutively targeted for polyubiquitination under normal conditions.	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	4	5	0	1
Nrf2 is normally sequestered in the cytoplasm by Keap-1 .	Nrf2 is normally sequestered in the cytoplasm by Keap-1.	0	9	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap-1	Keap-1	Keap-1	Nrf2	Nrf2	Nrf2	8	9	0	1
Under basal conditions , Keap1 acts as an adaptor between Nrf2 and the ubiquitination ligase Cullin-3 ( Cul3 ) and promotes the proteasomal degradation of Nrf2 .	Under basal conditions, Keap1 acts as an adaptor between Nrf2 and the ubiquitination ligase Cullin-3 (Cul3) and promotes the proteasomal degradation of Nrf2.	4	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	25	26
Under normal conditions , Nrf2 is targeted by Keap1 , which promotes Nrf2 proteasomal degradation via interactions with an ubiquitin ligase .	Under normal conditions, Nrf2 is targeted by Keap1, which promotes Nrf2 proteasomal degradation via interactions with an ubiquitin ligase.	6	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	12	13
DJ-1 stabilizes the Nrf2 protein by impairing Keap1 dependent proteasomal degradation of Nrf2 [ XREF_BIBR ] .	DJ-1 stabilizes the Nrf2 protein by impairing Keap1 dependent proteasomal degradation of Nrf2 [XREF_BIBR].	7	14	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
Recent data shows that accumulating p62 and SQSTM1 in autophagy deficient cells , directly binds to Keap1 , thereby disrupting Keap1 mediated degradation of Nrf2 and promoting the aberrant upregulation of Nrf2 and it downstream transcriptional targets .	Recent data shows that accumulating p62 and SQSTM1 in autophagy deficient cells, directly binds to Keap1, thereby disrupting Keap1 mediated degradation of Nrf2 and promoting the aberrant upregulation of Nrf2 and it downstream transcriptional targets.	19	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	24	25
Keap1 , a culin 3 based E3 ligase that targets Nrf2 for degradation , sequesters Nrf2 in cytoplasm .	Keap1, a culin 3 based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm.	0	17	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	15	16
Under normal physiology , Nrf2 is sequestered by Keap1 ; however under oxidative stress , Keap1 undergoes S nitrosylation of its cysteine residues and releases Nrf2 leading to nuclear translocation and anti-oxidant gene induction [ XREF_BIBR , XREF_BIBR ] .	Under normal physiology, Nrf2 is sequestered by Keap1; however under oxidative stress, Keap1 undergoes S nitrosylation of its cysteine residues and releases Nrf2 leading to nuclear translocation and anti-oxidant gene induction [XREF_BIBR, XREF_BIBR].	4	9	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
These show that KEAP1 knockdown in HK2 effectively elevates NRF2 activity .	These show that KEAP1 knockdown in HK2 effectively elevates NRF2 activity.	3	10	elevates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	3	4	9	10
Under homeostatic conditions , cytosolic Nrf2 is sequestered by the protein Keap1 and ubiquinated for degradation .	Under homeostatic conditions, cytosolic Nrf2 is sequestered by the protein Keap1 and ubiquinated for degradation.	4	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	5	6
Under basal conditions , Nrf2 is rapidly degraded through ubiquitination by the cytosolic Keap1 , Cul3 , and Rbx1 complex .	Under basal conditions, Nrf2 is rapidly degraded through ubiquitination by the cytosolic Keap1, Cul3, and Rbx1 complex.	4	15	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	4	5
These results thus demonstrate that DLG motif plays essential roles in the Keap1 mediated proteasomal degradation of Nrf2 in the cytoplasm .	These results thus demonstrate that DLG motif plays essential roles in the Keap1 mediated proteasomal degradation of Nrf2 in the cytoplasm.	9	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	17	18
Second , epigenetic silencing of the KEAP1 gene has also been found to cause KEAP1 downregulation and NRF2 upregulation .	Second, epigenetic silencing of the KEAP1 gene has also been found to cause KEAP1 downregulation and NRF2 upregulation.	6	18	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	6	7	17	18
Briefly , KEAP-1 sequesters nrf-2 in the cytoplasm 193 .	Briefly, KEAP-1 sequesters nrf-2 in the cytoplasm 193.	2	7	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP-1	KEAP-1	KEAP-1	nrf-2	nrf-2	nrf-2	2	3	4	5
Keap1 is thought to deplete Nrf2 from the cytoplasm , however the F-box protein beta-TrCP , a component of the Skp1-Cullin1-beta-TrCP E3 ligase complex , controls nuclear Nrf2 levels [ XREF_BIBR , XREF_BIBR ] .	Keap1 is thought to deplete Nrf2 from the cytoplasm, however the F-box protein beta-TrCP, a component of the Skp1-Cullin1-beta-TrCP E3 ligase complex, controls nuclear Nrf2 levels [XREF_BIBR, XREF_BIBR].	0	6	deplete	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	5	6
KEAP1 was found to promote NRF2 degradation by targeting it for ubiquitination through the cullin 3 ligase complex [ XREF_BIBR , XREF_BIBR ] , thus preventing NRF2 activity under normal cellular conditions [ XREF_BIBR ] .	KEAP1 was found to promote NRF2 degradation by targeting it for ubiquitination through the cullin 3 ligase complex [XREF_BIBR, XREF_BIBR], thus preventing NRF2 activity under normal cellular conditions [XREF_BIBR].	0	6	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	5	6
Under basal conditions , Nrf2 is anchored in the cytoplasm and inhibited by Keap1 and maintained at a low expression level .	Under basal conditions, Nrf2 is anchored in the cytoplasm and inhibited by Keap1 and maintained at a low expression level.	4	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	4	5
Strikingly , although KEAP1 mediated degradation of NRF2 typically maintains NRF2 at undetectable levels , both unstressed melanocyte lines expressed NRF2 ( XREF_FIG ) .	Strikingly, although KEAP1 mediated degradation of NRF2 typically maintains NRF2 at undetectable levels, both unstressed melanocyte lines expressed NRF2 (XREF_FIG).	3	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	3	4	7	8
Under normal physiological conditions , Nrf2 is bound to and negatively regulated by Keap1 .	Under normal physiological conditions, Nrf2 is bound to and negatively regulated by Keap1.	5	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	5	6
Reduced nuclear KEAP1 would increase the residency time of Nrf2 on certain AREs .	Reduced nuclear KEAP1 would increase the residency time of Nrf2 on certain AREs.	0	10	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	2	3	9	10
As Nrf2 activity is negatively regulated by Keap1 , we next determined whether overexpression of Keap1 inhibited the effect of Nrf2 on melanogenesis .	As Nrf2 activity is negatively regulated by Keap1, we next determined whether overexpression of Keap1 inhibited the effect of Nrf2 on melanogenesis.	1	8	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	1	2
NRF2 is normally repressed by KEAP1 , but oxidative stress ( as well as NRF2 phosphorylation by protein kinases such as AKT ) causes dissociation of the NRF2 and KEAP1 complex , culminating in nuclear translocation of NRF2 and transcriptional activation of antioxidant enzymes .	NRF2 is normally repressed by KEAP1, but oxidative stress (as well as NRF2 phosphorylation by protein kinases such as AKT) causes dissociation of the NRF2 and KEAP1 complex, culminating in nuclear translocation of NRF2 and transcriptional activation of antioxidant enzymes.	0	6	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	5	6	0	1
Under basal conditions , Nrf2 is negatively regulated through ubiquitination by Keap1 .	Under basal conditions, Nrf2 is negatively regulated through ubiquitination by Keap1.	4	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
On the other hand , nuclear EGFR directly interacts with and phosphorylates nuclear Keap1 , a protein that suppresses Nrf2 .	On the other hand, nuclear EGFR directly interacts with and phosphorylates nuclear Keap1, a protein that suppresses Nrf2.	6	20	suppresses	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Keap1	EGFR directly interacts with and phosphorylates nuclear Keap1	keap1	Nrf2	Nrf2	nrf2	13	14	19	20
Under conditions where oxidative stress is low , kelch like ECH associated protein-1 ( Keap1 ) sequesters Nrf2 in the cytosol and acts as an adaptor for Cul3 based E3 ligase to regulate proteasomal degradation of Nrf2 .	Under conditions where oxidative stress is low, kelch like ECH associated protein-1 (Keap1) sequesters Nrf2 in the cytosol and acts as an adaptor for Cul3 based E3 ligase to regulate proteasomal degradation of Nrf2.	12	18	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	17	18
Under basal conditions , Nrf2 is sequestered in the cytoplasm by Keap1 and rapidly degraded in an ubiquitin-proteasome-dependent manner , whereas under conditions of oxidative stress , Nrf2 escapes Keap1 mediated repression and translocates into nucleus to activate the expression of antioxidant and phase II drug metabolizing enzymes through ARE .	Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1 and rapidly degraded in an ubiquitin-proteasome-dependent manner, whereas under conditions of oxidative stress, Nrf2 escapes Keap1 mediated repression and translocates into nucleus to activate the expression of antioxidant and phase II drug metabolizing enzymes through ARE.	4	14	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
Elegant biochemical and molecular studies have yielded detailed mechanistic insights into how Nrf2 is inhibited by the ubiquitin ligase component Keap1 and how electrophilic compounds that bind specific Cys residues in Keap1 activate Nrf2 by relieving it from degradation [ XREF_BIBR , XREF_BIBR ] .	Elegant biochemical and molecular studies have yielded detailed mechanistic insights into how Nrf2 is inhibited by the ubiquitin ligase component Keap1 and how electrophilic compounds that bind specific Cys residues in Keap1 activate Nrf2 by relieving it from degradation [XREF_BIBR, XREF_BIBR].	26	34	activate	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	31	32	33	34
Finally , we uncovered the underlying mechanism that DADS promoted the endogenous interaction between p21 and Nrf2 , which was critical for impairing the Keap1 mediated degradation of Nrf2 .	Finally, we uncovered the underlying mechanism that DADS promoted the endogenous interaction between p21 and Nrf2, which was critical for impairing the Keap1 mediated degradation of Nrf2.	22	29	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	24	25	28	29
Conversely , NRF2 activation by KEAP1 knockdown significantly reduced both TBH and H 2 O 2 induction of ROS .	Conversely, NRF2 activation by KEAP1 knockdown significantly reduced both TBH and H 2 O 2 induction of ROS.	2	6	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	5	6	2	3
Nrf2 is negatively regulated by Kelch-likeECH-associated protein 1 ( Keap1 ) [ XREF_BIBR ] .	Nrf2 is negatively regulated by Kelch-likeECH-associated protein 1 (Keap1) [XREF_BIBR].	0	8	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Kelch-likeECH-associated protein 1	Kelch-likeECH-associated protein 1	Kelch-likeECH-associated protein 1	Nrf2	Nrf2	Nrf2	5	8	0	1
It has also been postulated that combined inhibition of both GSK-3 and Keap1 may activate Nrf2 , and confer protection , at lower doses than either intervention alone , hence limiting their detrimental effects [ XREF_BIBR ] .	It has also been postulated that combined inhibition of both GSK-3 and Keap1 may activate Nrf2, and confer protection, at lower doses than either intervention alone, hence limiting their detrimental effects [XREF_BIBR].	7	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	15	16
Molecular targets of SO include KEAP1 ( the inhibitor of the transcription factor Nrf2 ) , PPARgamma , IkappaB kinase , TGF-beta signaling and STAT signaling XREF_BIBR .	Molecular targets of SO include KEAP1 (the inhibitor of the transcription factor Nrf2), PPARgamma, IkappaB kinase, TGF-beta signaling and STAT signaling XREF_BIBR.	4	26	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	5	6	13	14
Keap1 serves as an adaptor between the Cullin3 ( Cul3 )-based E3-ligase ubiquitination complex and Nrf2 , and thus directs proteasomal degradation of Nrf2 .	Keap1 serves as an adaptor between the Cullin3 (Cul3)-based E3-ligase ubiquitination complex and Nrf2, and thus directs proteasomal degradation of Nrf2.	0	24	directs	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	23	24
Oxidative stress can lead to modification of Keap1 cysteine residues , detaching Nrf2 from Keap1 , which prevents Nrf2 from proteosomal degradation and leads Nrf2 to translocate into the nucleus .	Oxidative stress can lead to modification of Keap1 cysteine residues, detaching Nrf2 from Keap1, which prevents Nrf2 from proteosomal degradation and leads Nrf2 to translocate into the nucleus.	11	25	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	24	25
Our previous study [ XREF_BIBR ] indicated that knockdown of Keap1 in 3T3-L1 cells results in activation of Nrf2 and an enhanced DMIRI induced adipogenesis .	Our previous study [XREF_BIBR] indicated that knockdown of Keap1 in 3T3-L1 cells results in activation of Nrf2 and an enhanced DMIRI induced adipogenesis.	8	19	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	18	19
However , when oxidants or electrophiles are present , KEAP1 is inactivated , causing Nrf2 to accumulate and activate expression of its targets .	However, when oxidants or electrophiles are present, KEAP1 is inactivated, causing Nrf2 to accumulate and activate expression of its targets.	9	15	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	9	10	14	15
Even under oxidative stress conditions , where Nrf2 is liberated from Keap1 repression , Nrf2 is still subjected to proteasome degradation , indicating the existence of Keap1 independent degradation of Nrf2 .	Even under oxidative stress conditions, where Nrf2 is liberated from Keap1 repression, Nrf2 is still subjected to proteasome degradation, indicating the existence of Keap1 independent degradation of Nrf2.	26	31	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	26	27	30	31
Both loss- and gain-of-function analyses demonstrated that Nrf2 is the primary regulator of a subset of cytoprotective enzyme genes , while Keap1 suppresses Nrf2 activity in zebrafish .	Both loss- and gain-of-function analyses demonstrated that Nrf2 is the primary regulator of a subset of cytoprotective enzyme genes, while Keap1 suppresses Nrf2 activity in zebrafish.	21	24	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	21	22	23	24
Under normal conditions , Keap1 promotes eventual degradation of Nrf2 .	Under normal conditions, Keap1 promotes eventual degradation of Nrf2.	4	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	9	10
XREF_BIBR , XREF_BIBR Keap1 constitutively targets Nrf2 for ubiquitin dependent proteasomal degradation under basal ( reducing ) conditions of cell growth .	XREF_BIBR, XREF_BIBR Keap1 constitutively targets Nrf2 for ubiquitin dependent proteasomal degradation under basal (reducing) conditions of cell growth.	0	11	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	6	7
We further show that while the inhibitory effects of CPDT and SF on Nrf2 ubiquitination depend entirely on Keap1 , Nrf2 is also degraded by a Keap1 independent mechanism .	We further show that while the inhibitory effects of CPDT and SF on Nrf2 ubiquitination depend entirely on Keap1, Nrf2 is also degraded by a Keap1 independent mechanism.	20	28	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	26	27	20	21
Despite severe oxidative stress and inflammation , remnant kidney tissue Nrf2 activity ( nuclear translocation ) was mildly reduced at 6 wk and markedly reduced at 12 wk , whereas the Nrf2 repressor Keap1 was upregulated and the products of Nrf2 target genes [ catalase , superoxide dismutase , glutathione peroxidase , heme oxygenase-1 , NAD ( P ) H quinone oxidoreductase , and glutamate cysteine ligase ] were reduced or unchanged at 6 wk and significantly diminished at 12 wk .	Despite severe oxidative stress and inflammation, remnant kidney tissue Nrf2 activity (nuclear translocation) was mildly reduced at 6 wk and markedly reduced at 12 wk, whereas the Nrf2 repressor Keap1 was upregulated and the products of Nrf2 target genes [catalase, superoxide dismutase, glutathione peroxidase, heme oxygenase-1, NAD (P) H quinone oxidoreductase, and glutamate cysteine ligase] were reduced or unchanged at 6 wk and significantly diminished at 12 wk.	30	35	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	33	34	31	32
Under normal conditions , Nrf2 is repressed by Keap1 ( Kelch like erythroid cell derived protein with CNC homology [ ECH ]-associated protein 1 ) , which is an adaptor protein for the degradation of Nrf2 25,26 .	Under normal conditions, Nrf2 is repressed by Keap1 (Kelch like erythroid cell derived protein with CNC homology [ECH]-associated protein 1), which is an adaptor protein for the degradation of Nrf2 25,26.	4	30	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
Simultaneous deletion of the PTEN and KEAP1 genes activated NRF2 much more strongly than the KEAP1 single deletion .	Simultaneous deletion of the PTEN and KEAP1 genes activated NRF2 much more strongly than the KEAP1 single deletion.	4	10	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	6	7	9	10
Also , constitutive Nrf2 activation and ROS suppression by Keap1 deletion promoted tumor aggressiveness , metastasis , and resistance to oxidative stress and radiotherapy ( RT ) .	Also, constitutive Nrf2 activation and ROS suppression by Keap1 deletion promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT).	3	10	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	3	4
Since KEAP1 is an inhibitor of NRF2 mediated gene expression , we monitored the expression of NRF2 and its downstream target genes in lung cancer samples .	Since KEAP1 is an inhibitor of NRF2 mediated gene expression, we monitored the expression of NRF2 and its downstream target genes in lung cancer samples.	1	7	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	1	2	6	7
Nrf2 is a key regulator of many detoxifying enzyme genes , and cytoplasmic protein Keap1 represses the Nrf2 activity under quiescent conditions .	Nrf2 is a key regulator of many detoxifying enzyme genes, and cytoplasmic protein Keap1 represses the Nrf2 activity under quiescent conditions.	12	18	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	17	18
Next , we studied the mRNA expression profiles of Nrf2-target genes such as , Gclc , Gclm , Nqo1 , TrxR1 and Srxn1 in HLECs treated with sodium selenite for 24 h , because the Nrf2 protein is suppressed by higher levels of Keap1 protein leading to suppress the availability of Nrf2 for these transcription of Nrf2-target genes [ XREF_BIBR - XREF_BIBR ] .	Next, we studied the mRNA expression profiles of Nrf2-target genes such as, Gclc, Gclm, Nqo1, TrxR1 and Srxn1 in HLECs treated with sodium selenite for 24 h, because the Nrf2 protein is suppressed by higher levels of Keap1 protein leading to suppress the availability of Nrf2 for these transcription of Nrf2-target genes [XREF_BIBR - XREF_BIBR].	35	44	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	43	44	35	36
Overall , these results suggest that increased p62 levels sequester KEAP1 into autophagic vacuoles and probably these results in KEAP1 autophagic degradation allowing NRF2 activation ( XREF_FIG ) .	Overall, these results suggest that increased p62 levels sequester KEAP1 into autophagic vacuoles and probably these results in KEAP1 autophagic degradation allowing NRF2 activation (XREF_FIG).	19	24	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	19	20	23	24
In the revised model , ROS are detoxified by glutathione peroxidase and further act as an oxidant and inhibitor of KEAP1 , which degrades NRF2 .	In the revised model, ROS are detoxified by glutathione peroxidase and further act as an oxidant and inhibitor of KEAP1, which degrades NRF2.	18	25	degrades	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	20	21	24	25
Generally , in the absence of oxidative stress , Nrf2 is sequestered in the cytosol by the Keap1 homodimer , which acts as a substrate adaptor for the ubiquitination of Nrf2 in a cullin-3 ( Cul3 )-dependent manner .	Generally, in the absence of oxidative stress, Nrf2 is sequestered in the cytosol by the Keap1 homodimer, which acts as a substrate adaptor for the ubiquitination of Nrf2 in a cullin-3 (Cul3)-dependent manner.	9	18	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	9	10
Inducers of phase 2 genes modify specific cysteine residues of Keap1 resulting in conformational changes that render Keap1 unable to repress Nrf2 .	Inducers of phase 2 genes modify specific cysteine residues of Keap1 resulting in conformational changes that render Keap1 unable to repress Nrf2.	17	22	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	21	22
This is achieved through constant Keap1 mediated degradation of Nrf2 by the ubiquitin mediated proteasomal degradation system [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	This is achieved through constant Keap1 mediated degradation of Nrf2 by the ubiquitin mediated proteasomal degradation system [XREF_BIBR, XREF_BIBR - XREF_BIBR].	2	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	9	10
The cytoplasmic protein Keap1 suppresses Nrf2 transcriptional activity under basal conditions through direct binding to Nrf2 and promoting proteasomal degradation [ XREF_BIBR - XREF_BIBR ] .	The cytoplasmic protein Keap1 suppresses Nrf2 transcriptional activity under basal conditions through direct binding to Nrf2 and promoting proteasomal degradation [XREF_BIBR - XREF_BIBR].	0	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	5	6
Results of this study indicated that hydrogen peroxide treatment promoted KEAP1 level and suppressed NRF2 .	Results of this study indicated that hydrogen peroxide treatment promoted KEAP1 level and suppressed NRF2.	6	15	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	hydrogen peroxide treatment promoted KEAP1 level	keap1	NRF2	NRF2	nrf2	10	11	14	15
Under conditions when oxidative and electrophilic stress is low , Keap1 sequesters Nrf2 in the cytosol , by acting as an adaptor for Cullin ( Cul ) 3 based E3 ligase , to target Nrf2 for proteasomal degradation [ XREF_BIBR ] .	Under conditions when oxidative and electrophilic stress is low, Keap1 sequesters Nrf2 in the cytosol, by acting as an adaptor for Cullin (Cul) 3 based E3 ligase, to target Nrf2 for proteasomal degradation [XREF_BIBR].	10	15	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	12	13
Nrf2 is inhibited in the cytoplasm by the anchor protein Kelch like ECH associated protein-1 ( Keap1 ) , a cytosolic protein that inhibits Nrf2 signaling by promoting proteasomal degradation of Nrf2 .	Nrf2 is inhibited in the cytoplasm by the anchor protein Kelch like ECH associated protein-1 (Keap1), a cytosolic protein that inhibits Nrf2 signaling by promoting proteasomal degradation of Nrf2.	14	25	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	24	25
These results indicate that Keap1 is an upstream repressor of Nfe2l2 , and Nfe2l2-Keap1 homeostasis is essential for cellular defense against oxidative stress .	These results indicate that Keap1 is an upstream repressor of Nfe2l2, and Nfe2l2-Keap1 homeostasis is essential for cellular defense against oxidative stress.	4	11	is an upstream repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nfe2l2	Nfe2l2	Nfe2l2	4	5	10	11
In the absence of acute stress , Keap1 constitutively suppresses Nrf2 signaling by both degrading Nrf2 through the ubiquitin-proteasomal degradation , which results in a baseline , low antioxidant gene expression [ XREF_BIBR ] .	In the absence of acute stress, Keap1 constitutively suppresses Nrf2 signaling by both degrading Nrf2 through the ubiquitin-proteasomal degradation, which results in a baseline, low antioxidant gene expression [XREF_BIBR].	7	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	10	11
Oxidative stresses or electrophilic xenobiotics abolish the inhibition of Nrf2 by Keap1 .	Oxidative stresses or electrophilic xenobiotics abolish the inhibition of Nrf2 by Keap1.	5	12	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	9	10
Under normal physiological conditions , transcription factor Nrf2 is sequestered in the cytosol by Keap1 , which recruits ubiquitin ligase E3 that ubiquitinates Nrf2 and directs it to the proteasome degradation pathway .	Under normal physiological conditions, transcription factor Nrf2 is sequestered in the cytosol by Keap1, which recruits ubiquitin ligase E3 that ubiquitinates Nrf2 and directs it to the proteasome degradation pathway.	5	17	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	7	8
Moreover , knockdown of Keap1 by shRNA reversed loss of p62 increased degradation of NRF2 following erastin treatment ( XREF_FIG ) .	Moreover, knockdown of Keap1 by shRNA reversed loss of p62 increased degradation of NRF2 following erastin treatment (XREF_FIG).	2	17	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	4	5	14	15
It was shown that similarly to the mechanism observed in mammals , inhibition of Nrf2 by Keap1 is dependent on the interaction between Neh2 and Kelch domains as the specific mutation of the ETGE motif in Neh2 domain in zebrafish Nrf2 led to its escape from Keap1 mediated sequestration and nuclear localization [ XREF_BIBR , XREF_BIBR ] .	It was shown that similarly to the mechanism observed in mammals, inhibition of Nrf2 by Keap1 is dependent on the interaction between Neh2 and Kelch domains as the specific mutation of the ETGE motif in Neh2 domain in zebrafish Nrf2 led to its escape from Keap1 mediated sequestration and nuclear localization [XREF_BIBR, XREF_BIBR].	8	17	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	14	15
Thus , Keap1 mediated Nrf2 activation is no longer limited to the sensing of exogenous electrophiles and oxidants , but can be regulated by p53 activation , autophagy defects , and changes in tricarboxylic acid ( TCA ) cycle enzyme activity .	Thus, Keap1 mediated Nrf2 activation is no longer limited to the sensing of exogenous electrophiles and oxidants, but can be regulated by p53 activation, autophagy defects, and changes in tricarboxylic acid (TCA) cycle enzyme activity.	2	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	4	5
Keap1 knockdown in mice , which induces Nrf2 activation , also blunted ethanol mediated increase in serum triglycerides and hepatic free fatty acids [ XREF_BIBR ] .	Keap1 knockdown in mice, which induces Nrf2 activation, also blunted ethanol mediated increase in serum triglycerides and hepatic free fatty acids [XREF_BIBR].	0	8	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	7	8
Keap1 ( Kelch like ECH associated protein-1 ) is a cytoplasmic inhibitor of Nrf2 and an adaptor for the Cullin 3 ubiquitin ligase .	Keap1 (Kelch like ECH associated protein-1) is a cytoplasmic inhibitor of Nrf2 and an adaptor for the Cullin 3 ubiquitin ligase.	0	14	is a cytoplasmic inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	13	14
First , we determined whether Keap1 could prevent the activation of Nrf2 in NHMCs .	First, we determined whether Keap1 could prevent the activation of Nrf2 in NHMCs.	5	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	11	12
In related experiments , dose dependent overexpression of INrf2 ( inhibitor of Nrf2 or Keap1 ) in Hepa-1 cells by transient transfection or Flag-tagged-INrf2 overexpression in Hek-293 cells by tetracycline treatment led to degradation of Nrf2 and subsequent decrease in the expression of Bcl-xL and stabilization of Bax protein ( XREF_FIG ) .	In related experiments, dose dependent overexpression of INrf2 (inhibitor of Nrf2 or Keap1) in Hepa-1 cells by transient transfection or Flag-tagged-INrf2 overexpression in Hek-293 cells by tetracycline treatment led to degradation of Nrf2 and subsequent decrease in the expression of Bcl-xL and stabilization of Bax protein (XREF_FIG).	6	18	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	INrf2	overexpression of INrf2	inrf2	Nrf2	Nrf2	nrf2	8	9	12	13
In the quiescent state , Nrf2 is held inactive in the cytoplasm by strong binding of its repressor regulator , Keap1 which inactivates Nrf2 through sustained ubiquitination and subsequent proteasomal degradation XREF_BIBR , XREF_BIBR , XREF_BIBR .	In the quiescent state, Nrf2 is held inactive in the cytoplasm by strong binding of its repressor regulator, Keap1 which inactivates Nrf2 through sustained ubiquitination and subsequent proteasomal degradation XREF_BIBR, XREF_BIBR, XREF_BIBR.	18	24	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	23	24
Suppression of Nrf2 by Keap1 directed ubiquitylation or by Nrf2 shRNA and siRNA enhanced cell migration and plasticity in A549 cells .	Suppression of Nrf2 by Keap1 directed ubiquitylation or by Nrf2 shRNA and siRNA enhanced cell migration and plasticity in A549 cells.	0	5	Suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	2	3
Thus , liver specific disruption of Keap1 and Pten augments Nrf2 activity through inactivation of Keap1 dependent and -independent degradation of Nrf2 and establishes the Nrf2 dependent molecular network promoting the hepatomegaly and cholangiocyte expansion .	Thus, liver specific disruption of Keap1 and Pten augments Nrf2 activity through inactivation of Keap1 dependent and -independent degradation of Nrf2 and establishes the Nrf2 dependent molecular network promoting the hepatomegaly and cholangiocyte expansion.	4	11	augments	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	10	11
NFE2L2 encodes the transcription factor NRF2 whose function is negatively regulated by KEAP1 .	NFE2L2 encodes the transcription factor NRF2 whose function is negatively regulated by KEAP1.	1	13	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	12	13	5	6
Upon stress stimulation , the nuclear protein prothymosin alpha binds the Kelch-repeat domain and liberates Nrf2 , thus activating its target genes ; ( 3 ) Nrf2 protein stabilization : under normal homeostatic conditions , Nrf2 is continuously degraded by the 26S proteasome in a Keap1 dependent fashion .	Upon stress stimulation, the nuclear protein prothymosin alpha binds the Kelch-repeat domain and liberates Nrf2, thus activating its target genes; (3) Nrf2 protein stabilization : under normal homeostatic conditions, Nrf2 is continuously degraded by the 26S proteasome in a Keap1 dependent fashion.	35	47	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	45	46	35	36
Under basal conditions , Keap1 represses Nrf2 by targeting the transcription factor for ubiquitination and degradation by the proteasome .	Under basal conditions, Keap1 represses Nrf2 by targeting the transcription factor for ubiquitination and degradation by the proteasome.	4	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
The transcription factor Nrf2 is sequestered in the cytosol by Keap1 , a redox sensitive protein , which releases Nrf2 upon modification of regulatory cysteines in Keap1 .	The transcription factor Nrf2 is sequestered in the cytosol by Keap1, a redox sensitive protein, which releases Nrf2 upon modification of regulatory cysteines in Keap1.	0	18	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	3	4
Nrf2 is negatively regulated by the cytoplasmic redox-sensor protein Keap1 via its Neh2 ( Nrf2 and ECH homology 2 ) domain [ XREF_BIBR ] .	Nrf2 is negatively regulated by the cytoplasmic redox-sensor protein Keap1 via its Neh2 (Nrf2 and ECH homology 2) domain [XREF_BIBR].	0	20	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	0	1
In such circumstances , Keap1 repression of Nrf2 is restored by Nrf2 mediated induction of Keap1 [ XREF_BIBR ] .	In such circumstances, Keap1 repression of Nrf2 is restored by Nrf2 mediated induction of Keap1 [XREF_BIBR].	4	8	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	7	8
Further experiments are required to determine whether CRL Keap1 and SCF beta-TrCP repress Nrf2 in different organs , cell types , or subcellular compartments , and whether either principally controls the magnitude or the duration of Nrf2 activation .	Further experiments are required to determine whether CRL Keap1 and SCF beta-TrCP repress Nrf2 in different organs, cell types, or subcellular compartments, and whether either principally controls the magnitude or the duration of Nrf2 activation.	7	14	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	13	14
Nrf2 in the cytoplasm is sequestered by the protein Keap1 which facilitates its ubiquitination and proteosomal degradation .	Nrf2 in the cytoplasm is sequestered by the protein Keap1 which facilitates its ubiquitination and proteosomal degradation.	0	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	0	1
This alteration appears to be enforced by an extended hydrogen bonding network between residues on the glutathione moiety attached to Cys434 and amino acid side chains that have been shown to be essential for repression of Nrf2 by Keap1 .	This alteration appears to be enforced by an extended hydrogen bonding network between residues on the glutathione moiety attached to Cys434 and amino acid side chains that have been shown to be essential for repression of Nrf2 by Keap1.	32	39	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	38	39	36	37
Missence mutations in KEAP1 suppress the DC domain of KEAP1 to bind Nrf2 , and as a result , Nrf2 is constitutively stabilized under these conditions leading to cancer .	Missence mutations in KEAP1 suppress the DC domain of KEAP1 to bind Nrf2, and as a result, Nrf2 is constitutively stabilized under these conditions leading to cancer.	1	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	3	4	12	13
Similarly , the Nrf2 transcription factor is degraded by the E3 ligase Keap1 until oxidative stress disables Keap1 , allowing Nrf2 levels to rise and regulate redox responsive stress genes .	Similarly, the Nrf2 transcription factor is degraded by the E3 ligase Keap1 until oxidative stress disables Keap1, allowing Nrf2 levels to rise and regulate redox responsive stress genes.	3	13	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	3	4
Since the cloning of Keap1 , great progress has been made in understanding the mechanism of Keap1 mediated negative regulation of Nrf2 .	Since the cloning of Keap1, great progress has been made in understanding the mechanism of Keap1 mediated negative regulation of Nrf2.	14	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	21	22
Under unstimulated conditions , Nrf2 is constantly degraded by Keap1 in the cytoplasm , which keeps the level of Nrf2 low in the cytoplasm [ XREF_BIBR ] .	Under unstimulated conditions, Nrf2 is constantly degraded by Keap1 in the cytoplasm, which keeps the level of Nrf2 low in the cytoplasm [XREF_BIBR].	4	10	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	4	5
A single cysteine to serine mutation was also made in C273 or C288 , which rendered Keap1 unable to repress Nrf2 , even though the Keap1-C273S or Keap1 C288S mutants were highly expressed and were capable of binding Nrf2 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	A single cysteine to serine mutation was also made in C273 or C288, which rendered Keap1 unable to repress Nrf2, even though the Keap1-C273S or Keap1 C288S mutants were highly expressed and were capable of binding Nrf2 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	16	21	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	20	21
As a oxidative stress sensor , Keap1 functions as both an adaptor for Cul3.Rbx1 E3 ligase complex mediated degradation of the transcription factor Nrf2 , and a master regulator of cytoprotective gene expression .	As a oxidative stress sensor, Keap1 functions as both an adaptor for Cul3.Rbx1 E3 ligase complex mediated degradation of the transcription factor Nrf2, and a master regulator of cytoprotective gene expression.	6	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	23	24
NRF2 , which is negatively regulated by KEAP1 ( kelch like ECH associated protein 1 ) , controls the expression of a series of proteins involved in different steps of ROS detoxification -- such as NADPH generation .	NRF2, which is negatively regulated by KEAP1 (kelch like ECH associated protein 1), controls the expression of a series of proteins involved in different steps of ROS detoxification -- such as NADPH generation.	0	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	7	8	0	1
As previously mentioned , Nrf2 is mainly located and repressed in the cytoplasm by Keap1 in its inactive state , so it was decided to present the immunolocalization data also as Nrf2 and Keap1 signal ratios .	As previously mentioned, Nrf2 is mainly located and repressed in the cytoplasm by Keap1 in its inactive state, so it was decided to present the immunolocalization data also as Nrf2 and Keap1 signal ratios.	4	18	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	4	5
INrf2 ( inhibitor of Nrf2 ) or Keap1 retains Nrf2 in the cytoplasm , once upon exposure of cells to oxidative stress or electrophilic compounds , Nrf2 is free from Keap1 and translocates into the nucleus where it up-regulates the expression of numerous cytoprotective phase II detoxifying enzymes and antioxidant genes XREF_BIBR .	INrf2 (inhibitor of Nrf2) or Keap1 retains Nrf2 in the cytoplasm, once upon exposure of cells to oxidative stress or electrophilic compounds, Nrf2 is free from Keap1 and translocates into the nucleus where it up-regulates the expression of numerous cytoprotective phase II detoxifying enzymes and antioxidant genes XREF_BIBR.	0	8	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	4	5
Subsequent gene expression analysis showed the functional activation of nuclear factor ( erythroid derived 2 )-like 2 ( NFE2L2 ) , which is negatively regulated by KEAP1 , in the thyroid tissue of the patient .	Subsequent gene expression analysis showed the functional activation of nuclear factor (erythroid derived 2)-like 2 (NFE2L2), which is negatively regulated by KEAP1, in the thyroid tissue of the patient.	16	27	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NFE2L2	NFE2L2	NFE2L2	26	27	18	19
Interestingly , targeting KEAP1 by siRNA or the small-molecule activator sulforaphane restored induction of NRF2 dependent antioxidants in DJ-1-disrupted cells in response to cigarette smoke .	Interestingly, targeting KEAP1 by siRNA or the small-molecule activator sulforaphane restored induction of NRF2 dependent antioxidants in DJ-1-disrupted cells in response to cigarette smoke.	2	16	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	3	4	14	15
We assessed reactive oxygen species ( ROS ) production and antioxidant gene expression following alterations in the Nrf2 suppressor Keap1 and the subsequent changes in Nrf2 signaling .	We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor Keap1 and the subsequent changes in Nrf2 signaling.	14	20	suppressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	19	20	17	18
Activation of Nrf2 by SFN was previously shown to be independent of ROS , because SFN directly binds to cysteine residues within the Nrf2 repressor Keap1 invitro , XREF_BIBR , XREF_BIBR with C151 serving as the main sensor cysteine .	Activation of Nrf2 by SFN was previously shown to be independent of ROS, because SFN directly binds to cysteine residues within the Nrf2 repressor Keap1 invitro, XREF_BIBR, XREF_BIBR with C151 serving as the main sensor cysteine.	23	26	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	25	26	23	24
The rate of Nrf2 degradation , measured under conditions where the majority of Nrf2 was not tethered , exhibited a T ( 1/2 ) of approximately 3 h. Over-expression of human INrf2 , KIAA0132 , blocked Nrf2 conjugation to the ubiquitin polymer and blocked Nrf2 degradation .	The rate of Nrf2 degradation, measured under conditions where the majority of Nrf2 was not tethered, exhibited a T (1/2) of approximately 3 h. Over-expression of human INrf2, KIAA0132, blocked Nrf2 conjugation to the ubiquitin polymer and blocked Nrf2 degradation.	28	37	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	INrf2	Over-expression of human INrf2	inrf2	Nrf2	Nrf2	nrf2	31	32	36	37
These results are all consistent with the known action of L-SUL in inhibiting KEAP1 mediated proteosomal degradation of NRF2 XREF_BIBR , and thus these changes in metabolic function are likely due to decreased proteosomal degradation of NRF2 .	These results are all consistent with the known action of L-SUL in inhibiting KEAP1 mediated proteosomal degradation of NRF2 XREF_BIBR, and thus these changes in metabolic function are likely due to decreased proteosomal degradation of NRF2.	13	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	13	14	18	19
In normal physiological conditions , KEAP1 sequesters Nrf2 in the cytoplasm where it is targeted for ubiquitin mediated degradation .	In normal physiological conditions, KEAP1 sequesters Nrf2 in the cytoplasm where it is targeted for ubiquitin mediated degradation.	5	8	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	5	6	7	8
The KEAP1 and NRF2 mutations associated with human cancers impair the Keap1 mediated repression of Nrf2 .	The KEAP1 and NRF2 mutations associated with human cancers impair the Keap1 mediated repression of Nrf2.	10	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	15	16
In the absence of electrophilic or oxidative stressors , Nrf2 is negatively regulated by Keap1 ( Kelch like ECH associated protein 1 ) , a 69 kDa sensor protein that contains 27 cysteine residues [ XREF_BIBR ] .	In the absence of electrophilic or oxidative stressors, Nrf2 is negatively regulated by Keap1 (Kelch like ECH associated protein 1), a 69 kDa sensor protein that contains 27 cysteine residues [XREF_BIBR].	9	28	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	9	10
Dh404 Activates Nrf2 by Disrupting Keap1 Dependent Suppression of Nrf2 .	Dh404 Activates Nrf2 by Disrupting Keap1 Dependent Suppression of Nrf2.	5	10	Suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	9	10
Due to the presence of six KELCH regions in the binding domain of NRF2 , a loss of NRF2 inhibition by KEAP1 should also occur as a result of mutations in the KELCH binding region of the KEAP1 protein itself .	Due to the presence of six KELCH regions in the binding domain of NRF2, a loss of NRF2 inhibition by KEAP1 should also occur as a result of mutations in the KELCH binding region of the KEAP1 protein itself.	18	22	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	21	22	18	19
KEAP1 has been shown to shuttle between the cytoplasm and nucleus , and is able to repress NRF2 in the nucleus XREF_BIBR .	KEAP1 has been shown to shuttle between the cytoplasm and nucleus, and is able to repress NRF2 in the nucleus XREF_BIBR.	0	18	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	17	18
Under physiological conditions , Nrf2 resides in the cytoplasm bound to its inhibitor , Keap 1 , which targets Nrf2 toward proteosomal degradation .	Under physiological conditions, Nrf2 resides in the cytoplasm bound to its inhibitor, Keap 1, which targets Nrf2 toward proteosomal degradation.	12	22	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap 1	Keap 1	Keap 1	Nrf2	Nrf2	Nrf2	14	16	19	20
Nrf2 signaling was activated by the suppression of Keap1 as described previously [ XREF_BIBR ] .	Nrf2 signaling was activated by the suppression of Keap1 as described previously [XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
The results of a study concerning the graded expression of the Keap1 gene in mice demonstrated that a 50 % reduction of Keap1 activity does not induce Nrf2 accumulation , whereas a 75 % reduction is enough to elicit this effect .	The results of a study concerning the graded expression of the Keap1 gene in mice demonstrated that a 50% reduction of Keap1 activity does not induce Nrf2 accumulation, whereas a 75% reduction is enough to elicit this effect.	22	28	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	27	28
We demonstrated that : i ) MitoQ induces autophagy independent of Beclin-1 and dependent on Atg7 ; ii ) deletion of Atg7 increases ROS levels in response to MitoQ treatment ; iii ) Atg7 is required for Keap1 degradation ; and iv ) knockdown of Keap1 increases Nrf2 transcriptional activity , upregulates antioxidant genes expression , and decreases autophagy .	We demonstrated that : i) MitoQ induces autophagy independent of Beclin-1 and dependent on Atg7; ii) deletion of Atg7 increases ROS levels in response to MitoQ treatment; iii) Atg7 is required for Keap1 degradation; and iv) knockdown of Keap1 increases Nrf2 transcriptional activity, upregulates antioxidant genes expression, and decreases autophagy.	43	49	increases	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	45	46	47	48
Keap1 negatively regulates Nrf2 but not Nrf1 .	Keap1 negatively regulates Nrf2 but not Nrf1.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
Under normal physiologic conditions , the inhibitor of Nrf2 , Keap1 , mediates the ubiquitin-26S proteasome mediated turnover of Nrf2 .	Under normal physiologic conditions, the inhibitor of Nrf2, Keap1, mediates the ubiquitin-26S proteasome mediated turnover of Nrf2.	8	20	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	19	20
In unstressed cells , Keap1 sequesters Nrf2 in the cytoplasm by binding to the N-terminal Neh2 domain and facilitating the degradation of Nrf2 via the ubiquitin dependent proteosomal degradation pathway [ XREF_BIBR ] .	In unstressed cells, Keap1 sequesters Nrf2 in the cytoplasm by binding to the N-terminal Neh2 domain and facilitating the degradation of Nrf2 via the ubiquitin dependent proteosomal degradation pathway [XREF_BIBR].	4	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
Under basal conditions , Nrf2 is sequestered in the cytoplasm by Keap1 , but induction of oxidative stress is able to dissociate Nrf2 from Keap1 , leading to its translocation to the nucleus and subsequent increase on antioxidant genes expression XREF_BIBR .	Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1, but induction of oxidative stress is able to dissociate Nrf2 from Keap1, leading to its translocation to the nucleus and subsequent increase on antioxidant genes expression XREF_BIBR.	4	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
Loss of Keap1 or PGAM5 activates Nrf2 dependent genes .	Loss of Keap1 or PGAM5 activates Nrf2 dependent genes.	0	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Loss of Keap1	keap1	Nrf2	Nrf2	nrf2	2	3	6	7
tBHQ treatment did not affect the Nrf2 repressor Keap1 ( tBHQ , F 1,20 = 1.75 , P = 0.20 ; Gene , F 1,20 = 3.79 , P = 0.07 ; tBHQ x Gene , F 1,20 = 0.76 , P = 0.39 ) .	tBHQ treatment did not affect the Nrf2 repressor Keap1 (tBHQ, F 1,20 = 1.75, P = 0.20; Gene, F 1,20 = 3.79, P = 0.07; tBHQ x Gene, F 1,20 = 0.76, P = 0.39).	4	10	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	6	7
There is other evidence , discussed later , that implicates some of the CLR cysteines , as well as others outside the CLR , as important residues in the maintenance of Keap1 repression of Nrf2 .	There is other evidence, discussed later, that implicates some of the CLR cysteines, as well as others outside the CLR, as important residues in the maintenance of Keap1 repression of Nrf2.	31	35	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	31	32	34	35
Under basal conditions , Nrf2 is sequestered by Keap1 in the cytoplasm XREF_BIBR , and is constitutively targeted for ubiquitination by the Cul3 dependent E3 ubiquitin ligase complex , which results in its subsequent proteasomal degradation XREF_BIBR .	Under basal conditions, Nrf2 is sequestered by Keap1 in the cytoplasm XREF_BIBR, and is constitutively targeted for ubiquitination by the Cul3 dependent E3 ubiquitin ligase complex, which results in its subsequent proteasomal degradation XREF_BIBR.	4	17	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
It is constitutively expressed , and under basal conditions the majority of the population is bound to the inhibitor KEAP1 , which sequesters Nrf2 within the cytoplasm and promotes its constant degradation by the ubiquitin protease system ( UPS ) via the E3 ligase Cul-3 XREF_BIBR .	It is constitutively expressed, and under basal conditions the majority of the population is bound to the inhibitor KEAP1, which sequesters Nrf2 within the cytoplasm and promotes its constant degradation by the ubiquitin protease system (UPS) via the E3 ligase Cul-3 XREF_BIBR.	15	28	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	19	20	23	24
But in response to oxidative stress , KEAP1 dependent down-regulation of NRF2 function is diminished , thereby promoting the anti-oxidant response .	But in response to oxidative stress, KEAP1 dependent down-regulation of NRF2 function is diminished, thereby promoting the anti-oxidant response.	7	12	down-regulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	7	8	11	12
However , under conditions of redox imbalance , oxidative modification of Keap1 inhibits the Nrf2 degradation process , leading to Nrf2 accumulation in the nucleus , and the induction of ARE containing genes XREF_BIBR , XREF_BIBR , XREF_BIBR .	However, under conditions of redox imbalance, oxidative modification of Keap1 inhibits the Nrf2 degradation process, leading to Nrf2 accumulation in the nucleus, and the induction of ARE containing genes XREF_BIBR, XREF_BIBR, XREF_BIBR.	9	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	14	15
KEAP1 represses NRF2 activity under quiescent conditions , whereas NRF2 is liberated from KEAP1 mediated repression on exposure to stresses .	KEAP1 represses NRF2 activity under quiescent conditions, whereas NRF2 is liberated from KEAP1 mediated repression on exposure to stresses.	0	14	represses	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	2	3
It was observed that while the Keap1 inhibiting Nrf2 activator tBHQ induced ARE containing genes GSTP1 and NQO1 in astrocytes , cerebellar granule neurons failed to respond .	It was observed that while the Keap1 inhibiting Nrf2 activator tBHQ induced ARE containing genes GSTP1 and NQO1 in astrocytes, cerebellar granule neurons failed to respond.	5	13	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	8	9
In all three cell lines tested , which vary in KEAP1 genotype , we observed a consistent pattern of KEAP1 mediated NRF2 suppression ( XREF_FIG ) .	In all three cell lines tested, which vary in KEAP1 genotype, we observed a consistent pattern of KEAP1 mediated NRF2 suppression (XREF_FIG).	17	22	mediated	Positive_early_activation	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	19	20	21	22
The use of ectopically expressed Keap1 or of Keap1 carrying mutations in some of the identified inducer modified cysteine residues revealed that substitution of C273 or C288 with either serine or alanine ( i.e ., C237A/S and C288A/S ) rendered Keap1 unable to repress Nrf2 activity under homeostatic conditions in cells XREF_BIBR , XREF_BIBR , XREF_BIBR .	The use of ectopically expressed Keap1 or of Keap1 carrying mutations in some of the identified inducer modified cysteine residues revealed that substitution of C273 or C288 with either serine or alanine (i.e., C237A/S and C288A/S) rendered Keap1 unable to repress Nrf2 activity under homeostatic conditions in cells XREF_BIBR, XREF_BIBR, XREF_BIBR.	40	45	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	40	41	44	45
It is believed that under basal conditions , the transcription factor Nrf2 is sequestered by Keap1 in the cytoplasm .	It is believed that under basal conditions, the transcription factor Nrf2 is sequestered by Keap1 in the cytoplasm.	8	18	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	11	12
Moreover , constitutive activation of Nrf2 induced by Keap1 gene knockdown promoted high fat diet ( HFD )-induced fatty liver and glucose intolerance in Leptin-null ( Lepob/ob ) mice XREF_BIBR .	Moreover, constitutive activation of Nrf2 induced by Keap1 gene knockdown promoted high fat diet (HFD)-induced fatty liver and glucose intolerance in Leptin-null (Lepob/ob) mice XREF_BIBR.	3	10	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	5	6
XREF_BIBR Cancer cells acquire a growth advantage by eliminating Keap1 mediated negative control of Nrf2 , which leads to activation of the Nrf2 dependent defense response .	XREF_BIBR Cancer cells acquire a growth advantage by eliminating Keap1 mediated negative control of Nrf2, which leads to activation of the Nrf2 dependent defense response.	9	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	14	15
While Keap1 constitutively suppresses Nrf2 activity under unstressed conditions , oxidants or electrophiles provoke the repression of Keap1 activity , inducing the Nrf2 activation .	While Keap1 constitutively suppresses Nrf2 activity under unstressed conditions, oxidants or electrophiles provoke the repression of Keap1 activity, inducing the Nrf2 activation.	1	5	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	1	2	4	5
S guanylation of Keap1 at Cys434 by 8-nitro-cGMP abrogates the Keap1 mediated inhibition of Nrf2 [ XREF_BIBR ] .	S guanylation of Keap1 at Cys434 by 8-nitro-cGMP abrogates the Keap1 mediated inhibition of Nrf2 [XREF_BIBR].	9	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	14	15
Relative to Wt-Scr , Rxra expression is reduced in Nrf2-Kd ( green ) and increased in Keap1-Kd ( Keap1 knockdown produces constitutive activation of Nrf2 ) .	Relative to Wt-Scr, Rxra expression is reduced in Nrf2-Kd (green) and increased in Keap1-Kd (Keap1 knockdown produces constitutive activation of Nrf2).	18	25	produces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	18	19	24	25
Keap1 either sequesters Nrf2 in the cytoplasm or facilitates Nrf2 ubiquitination and degradation .	Keap1 either sequesters Nrf2 in the cytoplasm or facilitates Nrf2 ubiquitination and degradation.	0	8	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
KEAP1 recruits most nascently synthesized Nrf2 for ubiquitylation and subsequent degradation by the proteasome and additionally represses Nrf2 transcriptional activity by removing it from target gene promoters and returning the transcription factor to the cytoplasm for degradation .	KEAP1 recruits most nascently synthesized Nrf2 for ubiquitylation and subsequent degradation by the proteasome and additionally represses Nrf2 transcriptional activity by removing it from target gene promoters and returning the transcription factor to the cytoplasm for degradation.	0	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	0	1	17	18
Thus , the overexpression of NTRK2 in altered samples clearly suggests that NTRK2 inhibits the expression of KEAP1 , initiates the hyperactivation of genes downstream of NRF2 , and is involved in HNSCC tumorigenesis .	Thus, the overexpression of NTRK2 in altered samples clearly suggests that NTRK2 inhibits the expression of KEAP1, initiates the hyperactivation of genes downstream of NRF2, and is involved in HNSCC tumorigenesis.	12	27	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	NTRK2 inhibits the expression of KEAP1	keap1	NRF2	NRF2	nrf2	17	18	26	27
INrf2 constitutively suppresses Nrf2 by functioning as an adapter protein for the Cul3 and Rbx1 mediated ubiquitination and degradation of Nrf2 .	INrf2 constitutively suppresses Nrf2 by functioning as an adapter protein for the Cul3 and Rbx1 mediated ubiquitination and degradation of Nrf2.	0	4	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	0	1	3	4
Subsequently , ARE driven luciferase reporter assays of HepG2 ( XREF_FIG C ) and MHCC97H ( XREF_FIG D ) cell lines demonstrated that Nrf2 mediated transactivation activity was significantly suppressed by Keap1 , but was only marginally diminished by Keap1 DeltaC .	Subsequently, ARE driven luciferase reporter assays of HepG2 (XREF_FIG C) and MHCC97H (XREF_FIG D) cell lines demonstrated that Nrf2 mediated transactivation activity was significantly suppressed by Keap1, but was only marginally diminished by Keap1 DeltaC.	23	32	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	31	32	23	24
During non stressed conditions , NFE2L2 is sequestered in the cytoplasm by the repressor protein KEAP1 ( kelch like ECH [ erythroid cell derived protein with CNC homology ]-associated protein 1 ) and targeted for proteasomal degradation 10 , 11 .	During non stressed conditions, NFE2L2 is sequestered in the cytoplasm by the repressor protein KEAP1 (kelch like ECH [erythroid cell derived protein with CNC homology]-associated protein 1) and targeted for proteasomal degradation 10, 11.	5	33	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NFE2L2	NFE2L2	NFE2L2	15	16	5	6
Under unstressed conditions , Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2 , but Nrf2 is stabilized when Keap1 is inactivated under oxidative and electrophilic stress conditions .	Under unstressed conditions, Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2, but Nrf2 is stabilized when Keap1 is inactivated under oxidative and electrophilic stress conditions.	4	19	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	18	19
Loss of KEAP1 leads to further activation of NRF2 , which decreases drug sensitivity in part by increasing glutathione and decreasing ROS .	Loss of KEAP1 leads to further activation of NRF2, which decreases drug sensitivity in part by increasing glutathione and decreasing ROS.	0	11	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	Loss of KEAP1	keap1	NRF2	NRF2	nrf2	2	3	8	9
Under resting conditions , Keap1 sequesters the transcription factor Nrf2 in the cytoplasm , where it is ubiquitinated and degraded via the proteasomal pathway .	Under resting conditions, Keap1 sequesters the transcription factor Nrf2 in the cytoplasm, where it is ubiquitinated and degraded via the proteasomal pathway.	4	12	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	9	10
Nrf2 is normally sequestered in the cytoplasm by Keap1 , which must be dissociated in order for Nrf2 to translocate into the nucleus and promote gene transcription .	Nrf2 is normally sequestered in the cytoplasm by Keap1, which must be dissociated in order for Nrf2 to translocate into the nucleus and promote gene transcription.	0	24	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
In solid tumors , the KEAP1 and NRF2 system is constitutively activated by the loss of KEAP1 or gain of NFE2L2 functions that leads to its nuclear accumulation and enhances the transcription of many cytoprotective genes .	In solid tumors, the KEAP1 and NRF2 system is constitutively activated by the loss of KEAP1 or gain of NFE2L2 functions that leads to its nuclear accumulation and enhances the transcription of many cytoprotective genes.	5	21	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	loss of KEAP1	keap1	NRF2	NRF2	nrf2	16	17	7	8
Stable knockdown of Nrf2 by Keap1 overexpression significantly sensitized both SPEC-2 cells and xenografts to chemotherapeutic drugs , suggesting that combined therapy with an Nrf2 inhibitor may represent a new avenue in cancer treatment .	Stable knockdown of Nrf2 by Keap1 overexpression significantly sensitized both SPEC-2 cells and xenografts to chemotherapeutic drugs, suggesting that combined therapy with an Nrf2 inhibitor may represent a new avenue in cancer treatment.	1	7	knockdown	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1 overexpression	keap1	Nrf2	Nrf2	nrf2	5	6	3	4
It needs to be considered , however , that mice lacking the Nrf2 antagonist Keap1 show hyperkeratosis in the skin and that Nrf2 activating mutations have been identified in cutaneous squamous cell carcinomas .	It needs to be considered, however, that mice lacking the Nrf2 antagonist Keap1 show hyperkeratosis in the skin and that Nrf2 activating mutations have been identified in cutaneous squamous cell carcinomas.	10	15	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	12	13
Under normal conditions , Nrf2 is sequestered by cytosolic Keap1 , which serves as an adaptor to link Nrf2 to the ubiquitin ligase Cul3 and Rbx1 complex that ubiquitinates and degrades Nrf2 .	Under normal conditions, Nrf2 is sequestered by cytosolic Keap1, which serves as an adaptor to link Nrf2 to the ubiquitin ligase Cul3 and Rbx1 complex that ubiquitinates and degrades Nrf2.	4	12	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	4	5
Thus , Nrf2 molecules may not only be sequestered by Keap1 but also subjected to constant degradation .	Thus, Nrf2 molecules may not only be sequestered by Keap1 but also subjected to constant degradation.	2	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	2	3
KEAP1 is a known inhibitor of the transcription factor NRF2 that promotes the expression GCLC and other key enzymes in the glutathione synthesis pathway [ XREF_BIBR - XREF_BIBR ] .	KEAP1 is a known inhibitor of the transcription factor NRF2 that promotes the expression GCLC and other key enzymes in the glutathione synthesis pathway [XREF_BIBR - XREF_BIBR].	0	10	is a known inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	9	10
A recent study using Nrf2 mutant lacking the Keap1 interacting motif reported its ability to accumulate rapidly in the presence of MG132 , suggesting Keap1 independent proteasome mediated degradation of Nrf2 .	A recent study using Nrf2 mutant lacking the Keap1 interacting motif reported its ability to accumulate rapidly in the presence of MG132, suggesting Keap1 independent proteasome mediated degradation of Nrf2.	24	31	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	24	25	30	31
Somatic Mutations Reduce KEAP1 Mediated Repression of NRF2 .	Somatic Mutations Reduce KEAP1 Mediated Repression of NRF2.	2	8	Mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	3	4	7	8
Recently , evidences showed a high incidence occurrence of loss of Keap1 function in cancer , Keap1 mutations affected the repressive activity of Keap1 against Nrf2 , the loss of Keap1 function enhanced the nuclear accumulation of Nrf2 and elevated the expression of antioxidative and antixenobiotic stress enzymes and drug efflux pumps XREF_BIBR .	Recently, evidences showed a high incidence occurrence of loss of Keap1 function in cancer, Keap1 mutations affected the repressive activity of Keap1 against Nrf2, the loss of Keap1 function enhanced the nuclear accumulation of Nrf2 and elevated the expression of antioxidative and antixenobiotic stress enzymes and drug efflux pumps XREF_BIBR.	30	38	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	30	31	37	38
In lung cancer , ATF4 is commonly activated by NRF2 due to mutations in the NRF2 suppressor KEAP1 .	In lung cancer, ATF4 is commonly activated by NRF2 due to mutations in the NRF2 suppressor KEAP1.	12	18	suppressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	17	18	15	16
Under basal conditions , NRF2 is sequestered by cytoplasmic KEAP1 and targeted to proteasomal degradation .	Under basal conditions, NRF2 is sequestered by cytoplasmic KEAP1 and targeted to proteasomal degradation.	4	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	9	10	4	5
The transcription factor Nrf2 binds to small Maf proteins at the antioxidant response element ( ARE ) in the promoter regions of target genes , and Kelch like ECH associated protein 1 ( Keap1 ) , a cytoplasmic anchor of Nrf2 , promotes Nrf2 degradation by the ubiquitin proteasome pathway .	The transcription factor Nrf2 binds to small Maf proteins at the antioxidant response element (ARE) in the promoter regions of target genes, and Kelch like ECH associated protein 1 (Keap1), a cytoplasmic anchor of Nrf2, promotes Nrf2 degradation by the ubiquitin proteasome pathway.	30	44	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	33	34	43	44
In mice , however , loss of keap1 causes Nrf2 dependent hyperplasia of the esophagus and occlusion of its lumen , which leads to early postnatal lethality from the inability to feed .	In mice, however, loss of keap1 causes Nrf2 dependent hyperplasia of the esophagus and occlusion of its lumen, which leads to early postnatal lethality from the inability to feed.	5	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	keap1	loss of keap1	keap1	Nrf2	Nrf2	nrf2	7	8	9	10
NRF2 is negatively regulated by KEAP1 , which directly interacts with NRF2 to facilitate CUL3 based E3 ubiquitin ligase complex mediated ubiquitination and subsequent proteasome mediated degradation .	NRF2 is negatively regulated by KEAP1, which directly interacts with NRF2 to facilitate CUL3 based E3 ubiquitin ligase complex mediated ubiquitination and subsequent proteasome mediated degradation.	0	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	KEAP1	KEAP1, which directly interacts with NRF2	keap1	NRF2	NRF2	nrf2	5	6	0	1
Keap1 regulates these activities in conditions of oxidative stress and inhibits NRF2 activity through ubiquitin dependent degradation [ XREF_BIBR ] .	Keap1 regulates these activities in conditions of oxidative stress and inhibits NRF2 activity through ubiquitin dependent degradation [XREF_BIBR].	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	0	1	11	12
33 Thus , SF reacts with cysteine residues of the Nrf2 repressor Keap1 , which results in nuclear translocation of Nrf2 and binding of the transcription factor to DNA .	33 Thus, SF reacts with cysteine residues of the Nrf2 repressor Keap1, which results in nuclear translocation of Nrf2 and binding of the transcription factor to DNA.	7	15	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	10	11
Keap1 ( Kelch like ECH associated protein 1 ) is an adaptor protein for Cullin3 based ubiquitin E3 ligase and negatively regulates Nrf2 .	Keap1 (Kelch like ECH associated protein 1) is an adaptor protein for Cullin3 based ubiquitin E3 ligase and negatively regulates Nrf2.	0	23	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	22	23
Our findings thus suggest that while NRF-2 activation either by loss of Keap1 or inhibition of GSK-3 is beneficial for longevity and stress resistance , at low levels of activation , stronger induction is detrimental for lifespan .	Our findings thus suggest that while NRF-2 activation either by loss of Keap1 or inhibition of GSK-3 is beneficial for longevity and stress resistance, at low levels of activation, stronger induction is detrimental for lifespan.	6	14	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Keap1	loss of Keap1	keap1	NRF-2	NRF-2	nrf-2	12	13	6	7
Conversely , upon removal of Keap1 , which normally sequesters Nrf2 and CncC in the cytosol , males and females showed a slight increase in lifespan , matching earlier findings [ XREF_BIBR ] .	Conversely, upon removal of Keap1, which normally sequesters Nrf2 and CncC in the cytosol, males and females showed a slight increase in lifespan, matching earlier findings [XREF_BIBR].	3	15	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	10	11
Keap1 is a cytoplasmic repressor of the transcription factor Nrf2 , and its degradation induces Nrf2 activation , leading to upregulation of antioxidant phase II genes .	Keap1 is a cytoplasmic repressor of the transcription factor Nrf2, and its degradation induces Nrf2 activation, leading to upregulation of antioxidant phase II genes.	0	10	is a cytoplasmic repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	9	10
NRF2 is regulated by KEAP1 , which sequesters NRF2 to the cytoplasm , facilitating its degradation .	NRF2 is regulated by KEAP1, which sequesters NRF2 to the cytoplasm, facilitating its degradation.	2	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	4	5	8	9
We found that hepatocyte disruption of Keap1 activated Nrf2 , which then increased induction of Trx1 , a key redox regulation component , whereas Nrf2 HKO abolished Trx1 expression .	We found that hepatocyte disruption of Keap1 activated Nrf2, which then increased induction of Trx1, a key redox regulation component, whereas Nrf2 HKO abolished Trx1 expression.	4	12	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	8	9
Under basal conditions , Nrf2 - a member of the Cap-N-Collar family of transcription factors - is sequestered in the cytoplasm by Keap1 resulting in enhanced proteasomal degradation of Nrf2 .	Under basal conditions, Nrf2 - a member of the Cap-N-Collar family of transcription factors - is sequestered in the cytoplasm by Keap1 resulting in enhanced proteasomal degradation of Nrf2.	4	23	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	4	5
Transcription factor Nrf2 ( encoded by Nfe2l2 ) regulates a battery of detoxifying and antioxidant genes , and Keap1 represses Nrf2 function .	Transcription factor Nrf2 (encoded by Nfe2l2) regulates a battery of detoxifying and antioxidant genes, and Keap1 represses Nrf2 function.	18	21	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	18	19	20	21
Under unstimulated conditions , Nrf2 , which is sequestered by Keap1 in the cytoplasm , is rapidly degraded by the proteasome pathway .	Under unstimulated conditions, Nrf2, which is sequestered by Keap1 in the cytoplasm, is rapidly degraded by the proteasome pathway.	4	17	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	4	5
149 When stimulated by agents that can modify thiol groups , Keap1 no longer represses Nrf2 activity , and Nrf2 translocates to the nucleus .	149 When stimulated by agents that can modify thiol groups, Keap1 no longer represses Nrf2 activity, and Nrf2 translocates to the nucleus.	11	16	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	15	16
Under resting conditions , Nrf2 is sequestered in the cytosol by the binding of Keap1 .	Under resting conditions, Nrf2 is sequestered in the cytosol by the binding of Keap1.	4	15	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	4	5
Lrig1 is known to negatively regulate EGFR signalling , thereby maintaining epidermal stem cells in a quiescent , nondividing state XREF_BIBR .	Lrig1 is known to negatively regulate EGFR signalling, thereby maintaining epidermal stem cells in a quiescent, nondividing state XREF_BIBR.	0	7	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Lrig1	Lrig1	Lrig1	EGFR	EGFR	EGFR	0	1	6	7
EGFR was negatively regulated by LRIG1 on bladder cancer cells .	EGFR was negatively regulated by LRIG1 on bladder cancer cells.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	5	6	0	1
XREF_BIBR , XREF_BIBR Specifically , loss of LRIG1 resulted in upregulation of EGFR , HER2 and HER3 , and , depending on the model , either increased crypt size 74 or led to duodenal adenomas .	XREF_BIBR, XREF_BIBR Specifically, loss of LRIG1 resulted in upregulation of EGFR, HER2 and HER3, and, depending on the model, either increased crypt size 74 or led to duodenal adenomas.	5	16	upregulation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	LRIG1	loss of LRIG1	lrig1	EGFR	EGFR	egfr	7	8	12	13
Indeed , overexpression of LRIG1 in U87MG-EGFRvIII and U251 glioblastoma cells and H4 glioma cells inhibited EGFR signaling and decreased cell proliferation and invasion .	Indeed, overexpression of LRIG1 in U87MG-EGFRvIII and U251 glioblastoma cells and H4 glioma cells inhibited EGFR signaling and decreased cell proliferation and invasion.	2	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	overexpression of LRIG1	lrig1	EGFR	EGFR	egfr	4	5	16	17
Human epidermal stem cells express high levels of beta1 integrins , delta like 1 ( DLL1 ) and the EGFR antagonist LRIG1 .	Human epidermal stem cells express high levels of beta1 integrins, delta like 1 (DLL1) and the EGFR antagonist LRIG1.	11	22	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	21	22	19	20
Molecular studies have shown that LRIG1 inhibits tyrosine kinase receptors of the EGFR family , MET , and RET .	Molecular studies have shown that LRIG1 inhibits tyrosine kinase receptors of the EGFR family, MET, and RET.	5	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	5	6	12	13
XREF_BIBR , XREF_BIBR , XREF_BIBR In addition , LRIG1 can negatively regulate c-Met receptor signaling , XREF_BIBR LRIG1 deletion induces upregulation of EGFR , ErbB2 and ErbB3 , downregulation of LRIG1 can promote the proliferation of squamous cell carcinoma , breast cancer cells and so on .	XREF_BIBR, XREF_BIBR, XREF_BIBR In addition, LRIG1 can negatively regulate c-Met receptor signaling, XREF_BIBR LRIG1 deletion induces upregulation of EGFR, ErbB2 and ErbB3, downregulation of LRIG1 can promote the proliferation of squamous cell carcinoma, breast cancer cells and so on.	8	26	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	8	9	22	23
We demonstrate that LRIG1 forms a ternary complex between LRIG1 , E-cadherin , and EGFR , which upon cell-cell contact negatively regulates EGFR signalling .	We demonstrate that LRIG1 forms a ternary complex between LRIG1, E-cadherin, and EGFR, which upon cell-cell contact negatively regulates EGFR signalling.	9	23	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	9	10	22	23
At the IDH-only associated locus 3p14.1 , LRIG1 is highly expressed in the brain and negatively regulates the epidermal growth factor receptor ( EGFR ) signalling pathway [ XREF_BIBR ] .	At the IDH-only associated locus 3p14.1, LRIG1 is highly expressed in the brain and negatively regulates the epidermal growth factor receptor (EGFR) signalling pathway [XREF_BIBR].	7	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1 is highly expressed	lrig1	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	7	8	18	22
Based on these data , LRIG1 overexpression inhibits the phosphorylation of MET but not that of EGFR in TB107 DoxLRIG1 cells .	Based on these data, LRIG1 overexpression inhibits the phosphorylation of MET but not that of EGFR in TB107 DoxLRIG1 cells.	5	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1 overexpression	lrig1	EGFR	EGFR	egfr	5	6	16	17
The ectodomain of LRIG1 alone inhibits EGFR signaling , but does so in a ubiquitin independent fashion , showing that EGFR inhibition by LRIGs is not exclusively through ubiquitination XREF_BIBR .	The ectodomain of LRIG1 alone inhibits EGFR signaling, but does so in a ubiquitin independent fashion, showing that EGFR inhibition by LRIGs is not exclusively through ubiquitination XREF_BIBR.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	3	4	6	7
Loss of Lrig1 in mice leads to heightened Egfr signalling in keratinocytes , and multiple groups have reported that LRIG1 regulates ERBB receptor degradation .	Loss of Lrig1 in mice leads to heightened Egfr signalling in keratinocytes, and multiple groups have reported that LRIG1 regulates ERBB receptor degradation.	0	9	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Lrig1	Loss of Lrig1	lrig1	Egfr	Egfr	egfr	2	3	8	9
Based on these results , we concluded that the upregulation of LRIG1 expression inhibited the EGFR signaling pathway , activated the mitochondrial pathway of apoptosis and eventually increased the sensitivity of bladder cancer cells to CDDP .	Based on these results, we concluded that the upregulation of LRIG1 expression inhibited the EGFR signaling pathway, activated the mitochondrial pathway of apoptosis and eventually increased the sensitivity of bladder cancer cells to CDDP.	11	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1 expression	lrig1	EGFR	EGFR	egfr	11	12	15	16
Published studies indicate that LRIG1 triggers EGFR degradation and that mutated EGFR induces beta-catenin activity .	Published studies indicate that LRIG1 triggers EGFR degradation and that mutated EGFR induces beta-catenin activity.	4	7	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	4	5	6	7
This is because LRIG1 with the intracellular domain , including c-Cbl E3 ubiquitin ligase binding domain deleted , still attenuates EGFR activity without physical down-regulation of the protein and without competing for EGF binding XREF_BIBR .	This is because LRIG1 with the intracellular domain, including c-Cbl E3 ubiquitin ligase binding domain deleted, still attenuates EGFR activity without physical down-regulation of the protein and without competing for EGF binding XREF_BIBR.	3	21	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	3	4	20	21
Molecular studies have shown that LRIG1 negatively regulates wild-type tyrosine kinase receptors of the epidermal growth factor receptor ( EGFR ) family , hepatocyte growth factor receptor ( MET ) , RET , platelet derived growth factor receptor alpha ( PDGFRA ) , and neurotrophic tyrosine kinase receptor type 2 ( NTRK2 , also known as TRKB ) .	Molecular studies have shown that LRIG1 negatively regulates wild-type tyrosine kinase receptors of the epidermal growth factor receptor (EGFR) family, hepatocyte growth factor receptor (MET), RET, platelet derived growth factor receptor alpha (PDGFRA), and neurotrophic tyrosine kinase receptor type 2 (NTRK2, also known as TRKB).	5	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	5	6	14	18
Previous data suggest that LRIG1 blocks EGFR activation through two possible mechanisms .	Previous data suggest that LRIG1 blocks EGFR activation through two possible mechanisms.	4	7	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	4	5	6	7
XREF_BIBR - XREF_BIBR Therefore , LRIG1 negatively regulates EGFR and high expression of LRIG1 correlates with increased sensitivity to platinum based and other cytostatic drugs in bladder cancer and esophageal carcinoma .	XREF_BIBR - XREF_BIBR Therefore, LRIG1 negatively regulates EGFR and high expression of LRIG1 correlates with increased sensitivity to platinum based and other cytostatic drugs in bladder cancer and esophageal carcinoma.	5	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	5	6	8	9
Two markers of SG stem cells have been described : the EGFR antagonist Lrig1 and the transcriptional co-repressor Blimp1 .	Two markers of SG stem cells have been described : the EGFR antagonist Lrig1 and the transcriptional co-repressor Blimp1.	1	18	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Lrig1	Lrig1	Lrig1	EGFR	EGFR	EGFR	13	14	11	12
In two independent studies , LRIG1 co-immunoprecipitated with and downregulated all four members of the ERBB receptor family by heterologous expression ; in the specific case of EGFR , LRIG1 can reduce receptor levels by promoting receptor ubiquitylation and lysosomal degradation , independent of EGFR ligands ( see XREF_FIG ) .	In two independent studies, LRIG1 co-immunoprecipitated with and downregulated all four members of the ERBB receptor family by heterologous expression; in the specific case of EGFR, LRIG1 can reduce receptor levels by promoting receptor ubiquitylation and lysosomal degradation, independent of EGFR ligands (see XREF_FIG).	5	17	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	ERBB	ERBB	ERBB	5	6	15	16
LRIG1 , whose extracellular region was organized with leucine rich repeats ( LRRs ) and immunoglobulin like domains homologous to mammalian decorin and the Drosophila Kekkon-1 gene , antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases and acts within a framework of a negative feedback loop [ XREF_BIBR ] .	LRIG1, whose extracellular region was organized with leucine rich repeats (LRRs) and immunoglobulin like domains homologous to mammalian decorin and the Drosophila Kekkon-1 gene, antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases and acts within a framework of a negative feedback loop [XREF_BIBR].	0	41	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	32	36
LRIG1 interacts with the ErbB receptor tyrosine kinase to negatively regulate EGFR signalling XREF_BIBR .	LRIG1 interacts with the ErbB receptor tyrosine kinase to negatively regulate EGFR signalling XREF_BIBR.	0	13	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	0	1	11	12
Interestingly , LRIG1 has been shown to inhibit mammalian EGFR activation by a different mechanism ( see XREF_TABLE ) .	Interestingly, LRIG1 has been shown to inhibit mammalian EGFR activation by a different mechanism (see XREF_TABLE).	2	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	2	3	9	10
However , LRIG1 has also been reported to decrease EGFR protein and transcript levels when ectopically expressed in neuroglioma cells .	However, LRIG1 has also been reported to decrease EGFR protein and transcript levels when ectopically expressed in neuroglioma cells.	2	10	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	2	3	9	10
It has been demonstrated recently that a recombinant soluble ectodomain of LRIG1 antagonizes epidermal growth factor receptor signaling XREF_BIBR , although the physiological shedding of LRIG protein ectodomains has not previously been described .	It has been demonstrated recently that a recombinant soluble ectodomain of LRIG1 antagonizes epidermal growth factor receptor signaling XREF_BIBR, although the physiological shedding of LRIG protein ectodomains has not previously been described.	9	18	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	11	12	13	17
LRIG1 negatively regulates various oncogenic receptor tyrosine kinases ( RTKs ) , 2 including the epidermal growth factor receptor ( EGFR ) family members EGFR , ERBB2 ( also called HER2 ) , ERBB3 , and ERBB4 ; hepatocyte growth factor receptor ( MET ) ; rearranged during transfection ( RET ) ; platelet derived growth factor receptor alpha ( PDGFRA ) ; and neurotrophic receptor tyrosine kinase 2 ( NTRK2 , also called TrkB ) .	LRIG1 negatively regulates various oncogenic receptor tyrosine kinases (RTKs), 2 including the epidermal growth factor receptor (EGFR) family members EGFR, ERBB2 (also called HER2), ERBB3, and ERBB4; hepatocyte growth factor receptor (MET); rearranged during transfection (RET); platelet derived growth factor receptor alpha (PDGFRA); and neurotrophic receptor tyrosine kinase 2 (NTRK2, also called TrkB).	0	36	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	0	1	24	25
LRIG1 has also been reported to negatively regulate RET 18 and EGFR .	LRIG1 has also been reported to negatively regulate RET 18 and EGFR.	0	12	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	0	1	11	12
This in turn has led to the identification of a number of markers that enrich for highly clonogenic cells , the putative stem cells , including high expression of beta1 integrins and the EGF receptor antagonist Lrig1 .	This in turn has led to the identification of a number of markers that enrich for highly clonogenic cells, the putative stem cells, including high expression of beta1 integrins and the EGF receptor antagonist Lrig1.	27	37	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Lrig1	Lrig1	Lrig1	EGF receptor	EGF receptor	EGF receptor	36	37	33	35
A recently discovered transmembrane glycoprotein , LRIG1 , antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases and acts as a negative feedback loop of EGFR and proposed tumor suppressors .	A recently discovered transmembrane glycoprotein, LRIG1, antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases and acts as a negative feedback loop of EGFR and proposed tumor suppressors.	4	19	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	6	7	12	16
LRIG1 is highly expressed in the brain and negatively regulates the EGFR signaling pathway .	LRIG1 is highly expressed in the brain and negatively regulates the EGFR signaling pathway.	0	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1 is highly expressed	lrig1	EGFR	EGFR	egfr	0	1	11	12
The recombinant leucine rich repeat ( LRR ) domain of Lrig1 has previously been shown to attenuate EGFR signaling by acting as a competitive inhibitor for EGF binding .	The recombinant leucine rich repeat (LRR) domain of Lrig1 has previously been shown to attenuate EGFR signaling by acting as a competitive inhibitor for EGF binding.	8	18	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Lrig1	Lrig1	Lrig1	EGFR	EGFR	EGFR	10	11	17	18
These results contradict those of several previous studies reporting that LRIG1 negatively regulates EGFR XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR .	These results contradict those of several previous studies reporting that LRIG1 negatively regulates EGFR XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR.	10	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	10	11	13	14
Markers that enrich for cells with high colony forming ability include beta1 integrin extracellular matrix ( ECM ) receptors , the Notch ligand delta like 1 ( DLL1 ) , the transmembrane proteoglycan MCSP ( NG2 , CSPG4 ) and LRIG1 , a transmembrane protein that negatively regulates the EGF receptor ( EGFR ) .	Markers that enrich for cells with high colony forming ability include beta1 integrin extracellular matrix (ECM) receptors, the Notch ligand delta like 1 (DLL1), the transmembrane proteoglycan MCSP (NG2, CSPG4) and LRIG1, a transmembrane protein that negatively regulates the EGF receptor (EGFR).	18	51	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGF receptor	EGF receptor	EGF receptor	40	41	49	51
Although the precise mechanism of LRIG1 downregulation in cancer cells remains unclear , the findings of a recent study demonstrated that LRIG1 forms a ternary complex between LRIG1 , E-cadherin , and EGFR , which upon cell-to-cell contact negatively regulates EGFR signaling XREF_BIBR .	Although the precise mechanism of LRIG1 downregulation in cancer cells remains unclear, the findings of a recent study demonstrated that LRIG1 forms a ternary complex between LRIG1, E-cadherin, and EGFR, which upon cell-to-cell contact negatively regulates EGFR signaling XREF_BIBR.	27	42	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	27	28	40	41
EGFR degradation by LRIG1 appears to be dependent on the E3 ligase , Cbl , as recruitment of Cbl to either EGFR or LRIG1 is sufficient to induce EGFR ubiquitylation and degradation .	EGFR degradation by LRIG1 appears to be dependent on the E3 ligase, Cbl, as recruitment of Cbl to either EGFR or LRIG1 is sufficient to induce EGFR ubiquitylation and degradation.	0	4	degradation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	3	4	0	1
LRIG1 , a LIG family member akin to LINGO-1 , down-regulates EGFR by promoting lysosomal degradation of EGFR .	LRIG1, a LIG family member akin to LINGO-1, down-regulates EGFR by promoting lysosomal degradation of EGFR.	0	12	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	0	1	11	12
LRIG1 repression induced marked activation of epidermal growth factor receptor ( EGFR ) , protein kinase B ( Akt ) and c-Myc signaling molecules .	LRIG1 repression induced marked activation of epidermal growth factor receptor (EGFR), protein kinase B (Akt) and c-Myc signaling molecules.	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	6	10
In early Xenopus embryos , high level of nuclear JNK negatively regulates the canonical Wnt and beta-catenin signaling pathway by expelling beta-catenin from the nucleus [ XREF_BIBR ] .	In early Xenopus embryos, high level of nuclear JNK negatively regulates the canonical Wnt and beta-catenin signaling pathway by expelling beta-catenin from the nucleus [XREF_BIBR].	6	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK	level of nuclear JNK	jnk	beta-catenin	beta-catenin	beta-catenin	9	10	16	17
Taken together , these results suggest that JNK antagonizes the canonical Wnt pathway by regulating the nucleocytoplasmic transport of beta-catenin rather than its cytoplasmic stability .	Taken together, these results suggest that JNK antagonizes the canonical Wnt pathway by regulating the nucleocytoplasmic transport of beta-catenin rather than its cytoplasmic stability.	7	20	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	7	8	19	20
As to the effect of JNK2 on beta-catenin downstream targets , our most recent in vitro study demonstrated that selenium stimulated phosphorylation of JNK1/2 dramatically inhibited beta-catenin and its downstream targets , such as c-myc , cyclin D1 and CDK4 , in human colon cancer cells ( Fang and Yang , et al , submitted ) , supporting the notion of activated JNK1 and JNK2 in the suppression of beta-catenin signaling .	As to the effect of JNK2 on beta-catenin downstream targets, our most recent in vitro study demonstrated that selenium stimulated phosphorylation of JNK1/2 dramatically inhibited beta-catenin and its downstream targets, such as c-myc, cyclin D1 and CDK4, in human colon cancer cells (Fang and Yang, et al, submitted), supporting the notion of activated JNK1 and JNK2 in the suppression of beta-catenin signaling.	19	34	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK1/2	selenium stimulated phosphorylation of JNK1/2	jnk1/2	beta-catenin	beta-catenin	beta-catenin	23	24	26	27
JNK also prevents nuclear beta-catenin accumulation and regulates axis formation in Xenopus embryos .	JNK also prevents nuclear beta-catenin accumulation and regulates axis formation in Xenopus embryos.	0	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	0	1	4	5
A recent study has shown that c-Jun NH2-terminal kinases ( JNKs ) 2 interacts with and inhibits beta-catenin signaling in vitro .	A recent study has shown that c-Jun NH2-terminal kinases (JNKs) 2 interacts with and inhibits beta-catenin signaling in vitro.	8	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNKs	JNKs	JNKs	beta-catenin	beta-catenin	beta-catenin	10	11	17	18
Moreover , JNK suppressed beta-catenin and its target gene Survivin , and enhanced the effects of Imatinib Mesylate .	Moreover, JNK suppressed beta-catenin and its target gene Survivin, and enhanced the effects of Imatinib Mesylate.	2	12	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
In general , JNK interacts with and suppresses beta-catenin signaling in vitro and in vivo , and GSK3beta , a beta-catenin-phosphorylating kinase , plays a key role in this signaling .	In general, JNK interacts with and suppresses beta-catenin signaling in vitro and in vivo, and GSK3beta, a beta-catenin-phosphorylating kinase, plays a key role in this signaling.	3	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
JNK activation by anisomycin however had no effect on beta-catenin stability ( XREF_FIG ) , indicating that JNK activation alone was not sufficient to induce beta-catenin degradation .	JNK activation by anisomycin however had no effect on beta-catenin stability (XREF_FIG), indicating that JNK activation alone was not sufficient to induce beta-catenin degradation.	17	26	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	17	18	25	26
JNK1/2 inhibit the Wnt and beta-catenin pathway , suggesting that JNK1/2 may contribute to the altered Wnt signaling in diabetic embryopathy .	JNK1/2 inhibit the Wnt and beta-catenin pathway, suggesting that JNK1/2 may contribute to the altered Wnt signaling in diabetic embryopathy.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK1/2	JNK1/2	JNK1/2	beta-catenin	beta-catenin	beta-catenin	0	1	5	6
Inhibition of TG2 induced beta-catenin signaling by the small molecule inhibitor FJ9 , which disrupts Dishevelled dependent nuclear translocation of beta-catenin without affecting the non canonical JNK mediated beta-catenin pathway [ XREF_BIBR ] further supports that TG2 acts in a manner similar to that of canonical ligands .	Inhibition of TG2 induced beta-catenin signaling by the small molecule inhibitor FJ9, which disrupts Dishevelled dependent nuclear translocation of beta-catenin without affecting the non canonical JNK mediated beta-catenin pathway [XREF_BIBR] further supports that TG2 acts in a manner similar to that of canonical ligands.	22	29	mediated	Positive_early_activation	Negative_activation	Positive_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	26	27	28	29
Compared with the effects of Wnt5a knockdown cells , Wnt5a overexpressing cells triggered the phosphorylation of c-Jun N-terminal kinase ( JNK ) and beta-catenin , which leads to beta-catenin degradation and inactivates the canonical Wnt and beta-catenin pathway .	Compared with the effects of Wnt5a knockdown cells, Wnt5a overexpressing cells triggered the phosphorylation of c-Jun N-terminal kinase (JNK) and beta-catenin, which leads to beta-catenin degradation and inactivates the canonical Wnt and beta-catenin pathway.	9	37	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Jun N-terminal kinase	Wnt5a overexpressing cells triggered the phosphorylation of c-Jun N-terminal kinase	c-jun n-terminal kinase	beta-catenin	beta-catenin	beta-catenin	16	19	36	37
JNK mediated beta-catenin signaling inhibition increases the protein level of proapoptotic Bax by regulating the JNK and beta-catenin pathway , which is negatively correlated with the effect of antiapoptotic Bcl-2 ( XREF_FIG ) .	JNK mediated beta-catenin signaling inhibition increases the protein level of proapoptotic Bax by regulating the JNK and beta-catenin pathway, which is negatively correlated with the effect of antiapoptotic Bcl-2 (XREF_FIG).	0	4	mediated	Positive_early_activation	Negative_activation	Negative_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	0	1	2	3
Reduction of PTP1B in wild-type immortalized hepatocytes decreased APAP induced JNK phosphorylation and levels of the active caspase-3 fragment , and also maintained IGFIR tyrosine phosphorylation , IRS1 and IRS2 expression , Akt phosphorylation and abolished downregulation of BclxL upon APAP treatment ( XREF_FIG ) .	Reduction of PTP1B in wild-type immortalized hepatocytes decreased APAP induced JNK phosphorylation and levels of the active caspase-3 fragment, and also maintained IGFIR tyrosine phosphorylation, IRS1 and IRS2 expression, Akt phosphorylation and abolished downregulation of BclxL upon APAP treatment (XREF_FIG).	2	39	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	PTP1B in wild-type immortalized hepatocytes decreased APAP induced JNK phosphorylation	jnk	BclxL	BclxL	bclxl	10	11	38	39
In parallel to these studies , among isothiocyanates , exposure of BITC and AITC against a panel of human cancer cell lines ( human prostate , colon and leukaemia cancer cells ) resulted in activation of JNK and / or suppression of the anti-apoptotic proteins Bcl-2 and Bcl-XL directing apoptotic pathways ( Patten and DeLong , 1999 ; Xiao et al ., 2003 ) .	In parallel to these studies, among isothiocyanates, exposure of BITC and AITC against a panel of human cancer cell lines (human prostate, colon and leukaemia cancer cells) resulted in activation of JNK and / or suppression of the anti-apoptotic proteins Bcl-2 and Bcl-XL directing apoptotic pathways (Patten and DeLong, 1999; Xiao et al., 2003).	34	58	suppression	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	JNK	JNK	JNK	Bcl-XL	Bcl-XL	Bcl-XL	36	37	47	48
In parallel , Sustained IRE1 activity , due to ER stressor , leads to activation of c-Jun NH2-terminal kinase ( JNK ) which activates pro apoptotic member of the BCL-2 family Bim and inhibit anti-apoptotic Bcl-2 , Bcl-XL , and Mcl-1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In parallel, Sustained IRE1 activity, due to ER stressor, leads to activation of c-Jun NH2-terminal kinase (JNK) which activates pro apoptotic member of the BCL-2 family Bim and inhibit anti-apoptotic Bcl-2, Bcl-XL, and Mcl-1 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	16	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Jun NH2-terminal kinase	c-Jun NH2-terminal kinase	c-Jun NH2-terminal kinase	Bcl-XL	Bcl-XL	Bcl-XL	16	19	37	38
These activities reflect an essential role for Tyr 14 phosphorylation because wtCAV1 expression , but not a phosphorylation deficient mutant ( Y14F ) , inactivates BCL2 and BCLxL through activation of c-Jun N-terminal kinase ( JNK ) .	These activities reflect an essential role for Tyr 14 phosphorylation because wtCAV1 expression, but not a phosphorylation deficient mutant (Y14F), inactivates BCL2 and BCLxL through activation of c-Jun N-terminal kinase (JNK).	24	34	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	BCLxL	BCLxL	BCLxL	31	34	27	28
Mitochondrial JNK inactivated Bcl-2 and Bcl-xL through phosphorylation , thereby promoting apoptosis .	Mitochondrial JNK inactivated Bcl-2 and Bcl-xL through phosphorylation, thereby promoting apoptosis.	0	6	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK	JNK	JNK	Bcl-xL	Bcl-xL	Bcl-xL	1	2	5	6
XREF_BIBR - XREF_BIBR In addition , JNK also phosphorylates and thus inactivates the anti-apoptotic Bcl-xL and Bcl-2 .	XREF_BIBR - XREF_BIBR In addition, JNK also phosphorylates and thus inactivates the anti-apoptotic Bcl-xL and Bcl-2.	6	16	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK	JNK	JNK	Bcl-xL	Bcl-xL	Bcl-xL	6	7	14	15
In the mitochondria , activated JNK translocates to the mitochondria and antagonizes the anti-apoptotic function of Bcl-2 and Bcl-xL .	In the mitochondria, activated JNK translocates to the mitochondria and antagonizes the anti-apoptotic function of Bcl-2 and Bcl-xL.	4	19	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK	JNK translocates to the mitochondria	jnk	Bcl-xL	Bcl-xL	bcl-xl	5	6	18	19
Curcumin significantly activates the JNK and p38 MAPK , but not the ERK , signaling pathways via phosphorylation , thus down-regulating anti-apoptotic proteins Bcl-2 , Bcl-XL , Mcl-1 , and survivin in human HCT-116 colon cancer cells during apoptosis process .	Curcumin significantly activates the JNK and p38 MAPK, but not the ERK, signaling pathways via phosphorylation, thus down-regulating anti-apoptotic proteins Bcl-2, Bcl-XL, Mcl-1, and survivin in human HCT-116 colon cancer cells during apoptosis process.	4	26	down-regulating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK	JNK	JNK	Bcl-XL	Bcl-XL	Bcl-XL	4	5	25	26
NF-kappaB and Klf4 Cooperatively Repressed Transcriptional Activity of the Myocardin Gene in Response to IL-1beta Treatment and Vascular Injury .	NF-kappaB and Klf4 Cooperatively Repressed Transcriptional Activity of the Myocardin Gene in Response to IL-1beta Treatment and Vascular Injury.	0	10	Repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Klf4	Klf4	Klf4	Myocardin	Myocardin	Myocardin	2	3	9	10
KLF4 is a repressor of SRF and MYOCD 40 , and itself is repressed by the miR-143/145/SRF/MYOCD axis in a complicated feedback loop 35 .	KLF4 is a repressor of SRF and MYOCD 40, and itself is repressed by the miR-143/145/SRF/MYOCD axis in a complicated feedback loop 35.	0	8	is a repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	KLF4	KLF4	KLF4	MYOCD	MYOCD	MYOCD	0	1	7	8
It has also been shown that klf4 down-regulates Myocd and MRTF-A , two of the critical signaling molecules involved in promoting the contractile phenotype via miR-143 and miR-145 activation [ XREF_BIBR , XREF_BIBR ] .	It has also been shown that klf4 down-regulates Myocd and MRTF-A, two of the critical signaling molecules involved in promoting the contractile phenotype via miR-143 and miR-145 activation [XREF_BIBR, XREF_BIBR].	6	12	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	klf4	klf4	klf4	Myocd	Myocd	Myocd	6	7	8	9
Moreover , although overexpression of Klf4 decreased the transcriptional activity of the myocardin promoter , mutation of the consensus Klf4 binding site at -29/-23 bp blunted the Klf4 effect ( XREF_FIG D ) .	Moreover, although overexpression of Klf4 decreased the transcriptional activity of the myocardin promoter, mutation of the consensus Klf4 binding site at -29/-23 bp blunted the Klf4 effect (XREF_FIG D).	3	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Klf4	overexpression of Klf4	klf4	myocardin	myocardin	myocardin	5	6	12	13
Interestingly , KLF4 inhibits myocardin by binding to the promoter in cooperation with NF-kappaB 86 .	Interestingly, KLF4 inhibits myocardin by binding to the promoter in cooperation with NF-kappaB 86.	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KLF4	KLF4	KLF4	myocardin	myocardin	myocardin	2	3	4	5
XREF_BIBR , XREF_BIBR , XREF_BIBR Following vascular injury myocardin is inhibited by KLF4 and SMC induced inflammatory mediators .	XREF_BIBR, XREF_BIBR, XREF_BIBR Following vascular injury myocardin is inhibited by KLF4 and SMC induced inflammatory mediators.	0	14	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	KLF4	KLF4	KLF4	myocardin	myocardin	myocardin	12	13	8	9
Klf4 significantly decreased Myocd mRNA , while Klf4 silencing abolished PDGF-BB-mediated repression of PrmM directed gene expression in SMC .	Klf4 significantly decreased Myocd mRNA, while Klf4 silencing abolished PDGF-BB-mediated repression of PrmM directed gene expression in SMC.	0	4	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Klf4	Klf4	Klf4	Myocd	Myocd	Myocd	0	1	3	4
Through downregulation of Kruppel like factor 4 ( Klf4 ) , myocardin , Elk-1 and numerous other targets , miR-143/145 can direct the reprogramming of fibroblasts into SMCs during development .	Through downregulation of Kruppel like factor 4 (Klf4), myocardin, Elk-1 and numerous other targets, miR-143/145 can direct the reprogramming of fibroblasts into SMCs during development.	1	21	downregulation	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	Klf4	Klf4	Klf4	myocardin	myocardin	myocardin	8	9	11	12
We have also reported previously that inactivation of CFL-1 by overexpression of LIMK , which phosphorylates CFL-1 , or knockdown of slingshot , which dephosphorylates CFL-1 , interferes with protein secretion .	We have also reported previously that inactivation of CFL-1 by overexpression of LIMK, which phosphorylates CFL-1, or knockdown of slingshot, which dephosphorylates CFL-1, interferes with protein secretion.	6	19	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	LIMK	overexpression of LIMK	limk	CFL-1	CFL-1	cfl-1	12	13	8	9
Targeted mutations at this interface disrupt cofilin-1 phosphorylation by LIMK1 in vitro and in mammalian cells , and block functional inactivation of cofilin-1 by LIMK1 in yeast .	Targeted mutations at this interface disrupt cofilin-1 phosphorylation by LIMK1 in vitro and in mammalian cells, and block functional inactivation of cofilin-1 by LIMK1 in yeast.	18	26	inactivation	Negative_activation_token_2_noun	Negative_activation	Positive_activation	LIMK1	LIMK1	LIMK1	cofilin-1	cofilin-1	cofilin-1	24	25	22	23
Phosphorylation of CFL-1 at Serine 3 ( Ser3 ) by LIM kinase ( LIMK ) inactivates CFL-1 , whereas dephosphorylation reactivates it .	Phosphorylation of CFL-1 at Serine 3 (Ser3) by LIM kinase (LIMK) inactivates CFL-1, whereas dephosphorylation reactivates it.	0	17	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LIMK	Phosphorylation of CFL-1 at Serine 3 (Ser3) by LIM kinase (LIMK	limk	CFL-1	CFL-1	cfl-1	13	14	16	17
In addition , expression of either constitutively active or inactive and dominant negative mutants of CFL1or CFL1 kinase LIMK1 induced loss of receptor function suggesting a critical role of the LIMK1 mediated CFL1 pathway in receptor dependent transcription .	In addition, expression of either constitutively active or inactive and dominant negative mutants of CFL1or CFL1 kinase LIMK1 induced loss of receptor function suggesting a critical role of the LIMK1 mediated CFL1 pathway in receptor dependent transcription.	27	33	mediated	Positive_early_activation	Negative_activation	Negative_activation	LIMK1	LIMK1	LIMK1	CFL1	CFL1	CFL1	30	31	32	33
CFL , a downstream target of the PAK1 cascade , stimulates actin severance and depolymerization to increase actin turnover and is inactivated by LIMK phosphorylation at Ser3 , potentially stabilizing cell-cell contacts .	CFL, a downstream target of the PAK1 cascade, stimulates actin severance and depolymerization to increase actin turnover and is inactivated by LIMK phosphorylation at Ser3, potentially stabilizing cell-cell contacts.	0	27	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	LIMK	LIMK phosphorylation at Ser3	limk	CFL	CFL	cfl	23	24	0	1
To determine whether the down-regulation of LIMK1 by DADS caused the decreased activity of cofilin1 in MGC803 cells , which resulted in the inhibition of cell migration and invasion , we used microRNAs to interfere with LIMK1 protein expression .	To determine whether the down-regulation of LIMK1 by DADS caused the decreased activity of cofilin1 in MGC803 cells, which resulted in the inhibition of cell migration and invasion, we used microRNAs to interfere with LIMK1 protein expression.	4	15	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	LIMK1	LIMK1	LIMK1	cofilin1	cofilin1	cofilin1	6	7	14	15
In addition , YAP1 is negatively regulated by large tumor suppressor kinases ( LATS1 and LATS2 ) , which are commonly deleted in mesothelioma ; in contrast , forced expression of LATS2 inactivates YAP1 and causes a reduction in cell growth [ XREF_BIBR ] .	In addition, YAP1 is negatively regulated by large tumor suppressor kinases (LATS1 and LATS2), which are commonly deleted in mesothelioma; in contrast, forced expression of LATS2 inactivates YAP1 and causes a reduction in cell growth [XREF_BIBR].	29	34	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LATS2	expression of LATS2	lats2	YAP1	YAP1	yap1	31	32	33	34
Hippo kinases Mst1 and Lats2 can inhibit Pax3-Taz and Yap65 synergistic activation .	Hippo kinases Mst1 and Lats2 can inhibit Pax3-Taz and Yap65 synergistic activation.	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Lats2	Lats2	Lats2	Yap65	Yap65	Yap65	4	5	9	10
To explore the functional significance concerning the inhibition of Kif2b by GSK3beta mediated phosphorylation of SKAP , we examined the metaphase chromosome alignment in HeLa cells expressing GFP-SKAP and its phosphorylation mutants .	To explore the functional significance concerning the inhibition of Kif2b by GSK3beta mediated phosphorylation of SKAP, we examined the metaphase chromosome alignment in HeLa cells expressing GFP-SKAP and its phosphorylation mutants.	7	16	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SKAP	GSK3beta mediated phosphorylation of SKAP	skap	Kif2b	Kif2b	kif2b	15	16	9	10
To address how GSK3beta mediated phosphorylation of SKAP acts to inhibit the MT depolymerase of Kif2b , we sought to test whether the phosphorylation could affect the interaction between SKAP and Kif2b .	To address how GSK3beta mediated phosphorylation of SKAP acts to inhibit the MT depolymerase of Kif2b, we sought to test whether the phosphorylation could affect the interaction between SKAP and Kif2b.	3	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKAP	GSK3beta mediated phosphorylation of SKAP	skap	Kif2b	Kif2b	kif2b	7	8	15	16
The inhibitory effect on Kif2b caused by GSK3beta mediated phosphorylation of SKAP is necessary to maintain proper spindle dynamics and to ensure faithful chromosome segregation .	The inhibitory effect on Kif2b caused by GSK3beta mediated phosphorylation of SKAP is necessary to maintain proper spindle dynamics and to ensure faithful chromosome segregation.	2	12	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	SKAP	GSK3beta mediated phosphorylation of SKAP	skap	Kif2b	Kif2b	kif2b	11	12	4	5
Phosphorylation of SKAP by GSK3beta inhibits Kif2b depolymerase activity .	Phosphorylation of SKAP by GSK3beta inhibits Kif2b depolymerase activity.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKAP	Phosphorylation of SKAP	skap	Kif2b	Kif2b	kif2b	2	3	6	7
SKAP inhibits the MT depolymerase activity of Kif2b .	SKAP inhibits the MT depolymerase activity of Kif2b.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKAP	SKAP	SKAP	Kif2b	Kif2b	Kif2b	0	1	7	8
Taken together , we concluded GSK3beta mediated phosphorylation of SKAP inhibits the MT depolymerase activity of Kif2b , which governs the spindle stability during metaphase .	Taken together, we concluded GSK3beta mediated phosphorylation of SKAP inhibits the MT depolymerase activity of Kif2b, which governs the spindle stability during metaphase.	5	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKAP	GSK3beta mediated phosphorylation of SKAP	skap	Kif2b	Kif2b	kif2b	9	10	16	17
The results were further confirmed by our in vitro MT reconstitution assays , since the presence of SKAP significantly inhibited the MT depolymerization activity of Kif2b ( XREF_FIG and XREF_SUPPLEMENTARY ) .	The results were further confirmed by our in vitro MT reconstitution assays, since the presence of SKAP significantly inhibited the MT depolymerization activity of Kif2b (XREF_FIG and XREF_SUPPLEMENTARY).	15	29	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKAP	SKAP	SKAP	Kif2b	Kif2b	Kif2b	17	18	25	26
Given that LRIG1 negatively regulates the ERBB2 receptor and the proliferation of ERBB2 positive breast cancer cells , it will be interesting to investigate whether LRIG1 also has prognostic value in ERBB2 positive breast cancer .	Given that LRIG1 negatively regulates the ERBB2 receptor and the proliferation of ERBB2 positive breast cancer cells, it will be interesting to investigate whether LRIG1 also has prognostic value in ERBB2 positive breast cancer.	2	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	ERBB2	ERBB2	ERBB2	2	3	6	7
Jazf1 inhibits the abilities of TR4 as transcription regulator , thereby suppressing gluconeogenesis [ XREF_BIBR ] .	Jazf1 inhibits the abilities of TR4 as transcription regulator, thereby suppressing gluconeogenesis [XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Jazf1	Jazf1	Jazf1	TR4	TR4	TR4	0	1	5	6
Previously , Jazf1 was shown to inhibit nuclear receptor TR4 by means of ligand binding in hepatocytes [ XREF_BIBR ] .	Previously, Jazf1 was shown to inhibit nuclear receptor TR4 by means of ligand binding in hepatocytes [XREF_BIBR].	2	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Jazf1	Jazf1	Jazf1	TR4	TR4	TR4	2	3	9	10
JAZF1 is a transcriptional repressor of NR2C2 , which results in low IGF1 serum concentrations , perinatal and early postnatal hypoglycemia and growth retardation when knocked out in mice .	JAZF1 is a transcriptional repressor of NR2C2, which results in low IGF1 serum concentrations, perinatal and early postnatal hypoglycemia and growth retardation when knocked out in mice.	0	9	is a transcriptional repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	JAZF1	JAZF1	JAZF1	NR2C2	NR2C2	NR2C2	0	1	6	7
Previously , Jazf1 was mainly researched in the context of diabetes , because Jazf1 is a novel repressor of TR4 , a kind of nuclear receptor that regulates gluconeogenesis [ XREF_BIBR , XREF_BIBR ] .	Previously, Jazf1 was mainly researched in the context of diabetes, because Jazf1 is a novel repressor of TR4, a kind of nuclear receptor that regulates gluconeogenesis [XREF_BIBR, XREF_BIBR].	13	25	is a novel repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	Jazf1	Jazf1	Jazf1	TR4	TR4	TR4	13	14	19	20
JAZF1 protein interacts with NR2C2 ( nuclear receptor subfamily 2 , group C , member 2 ) protein and represses NR2C2 mediated transactivation .	JAZF1 protein interacts with NR2C2 (nuclear receptor subfamily 2, group C, member 2) protein and represses NR2C2 mediated transactivation.	0	22	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JAZF1	JAZF1	JAZF1	NR2C2	NR2C2	NR2C2	0	1	20	21
Jazf1 inhibits testicular nuclear receptor 4 ( TR4 ) activation through protein protein interaction , which results in weight loss and alleviates diabetes .	Jazf1 inhibits testicular nuclear receptor 4 (TR4) activation through protein protein interaction, which results in weight loss and alleviates diabetes.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Jazf1	Jazf1	Jazf1	TR4	TR4	TR4	0	1	7	8
In our present study , we provide evidence that UV irradiation induced Tip60 proteins reduced Notch1 activity to a marked degree .	In our present study, we provide evidence that UV irradiation induced Tip60 proteins reduced Notch1 activity to a marked degree.	12	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tip60	Tip60	Tip60	Notch1	Notch1	Notch1	12	13	15	16
Collectively , our data suggest that Tip60 is an inhibitor of the Notch1 signaling pathway and that Tip60 dependent acetylation of Notch1-IC may be relevant to the mechanism by which Tip60 suppresses Notch1 signaling .	Collectively, our data suggest that Tip60 is an inhibitor of the Notch1 signaling pathway and that Tip60 dependent acetylation of Notch1-IC may be relevant to the mechanism by which Tip60 suppresses Notch1 signaling.	30	33	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tip60	Tip60	Tip60	Notch1	Notch1	Notch1	30	31	32	33
Accumulated UV irradiation induced Tip60 suppresses Notch1 transcriptional activity via the dissociation of the Notch1-IC and CSL complex .	Accumulated UV irradiation induced Tip60 suppresses Notch1 transcriptional activity via the dissociation of the Notch1-IC and CSL complex.	4	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tip60	Tip60	Tip60	Notch1	Notch1	Notch1	4	5	6	7
Using a cell co-culture assay , we find that mammalian Lunatic fringe ( Lfng ) inhibits Jagged1 mediated signalling and potentiates Delta1 mediated signalling through Notch1 .	Using a cell co-culture assay, we find that mammalian Lunatic fringe (Lfng) inhibits Jagged1 mediated signalling and potentiates Delta1 mediated signalling through Notch1.	11	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Lfng	Lfng	Lfng	Jagged1	Jagged1	Jagged1	13	14	16	17
Lfng does not prevent binding of soluble Jagged1 or Delta1 to Notch1 expressing cells .	Lfng does not prevent binding of soluble Jagged1 or Delta1 to Notch1 expressing cells.	0	9	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Lfng	Lfng	Lfng	Jagged1	Jagged1	Jagged1	0	1	7	8
Notch pathway activation is further supported by an 8.2-fold downregulation of lunatic fringe ( Lfng ) , which has been previously shown to suppress Jagged-1 and Notch-1 signaling [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	Notch pathway activation is further supported by an 8.2-fold downregulation of lunatic fringe (Lfng), which has been previously shown to suppress Jagged-1 and Notch-1 signaling [XREF_BIBR; XREF_BIBR; XREF_BIBR].	12	31	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Lfng	Lfng	Lfng	Jagged-1	Jagged-1	Jagged-1	14	15	24	25
These data suggest that ERalpha dependent expression of LRIG1 dampens ErbB3 signaling in luminal breast cancer cells , and by blocking ERalpha activity with fulvestrant , LRIG1 is decreased thus permitting ErbB3 accumulation , enhanced ErbB3 signaling to cell survival pathways , and blunting therapeutic response to fulvestrant .	These data suggest that ERalpha dependent expression of LRIG1 dampens ErbB3 signaling in luminal breast cancer cells, and by blocking ERalpha activity with fulvestrant, LRIG1 is decreased thus permitting ErbB3 accumulation, enhanced ErbB3 signaling to cell survival pathways, and blunting therapeutic response to fulvestrant.	26	32	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	ErbB3	ErbB3	ErbB3	26	27	31	32
Furthermore , oncogenic YAP1 activation occurs as a consequence of a loss in NF2 dependent inactivation of LATS1 ( a key inhibitor of YAP1 ) , and decreased LATS1 activity has also been associated with glioma progression .	Furthermore, oncogenic YAP1 activation occurs as a consequence of a loss in NF2 dependent inactivation of LATS1 (a key inhibitor of YAP1), and decreased LATS1 activity has also been associated with glioma progression.	15	24	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	LATS1	LATS1	LATS1	YAP1	YAP1	YAP1	17	18	23	24
Nuclear localization and transcriptional activity of YAP1 were up-regulated by hypoxia via down-regulation of LATS1 , a kinase that inactivates YAP1 .	Nuclear localization and transcriptional activity of YAP1 were up-regulated by hypoxia via down-regulation of LATS1, a kinase that inactivates YAP1.	12	21	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	LATS1	LATS1	LATS1	YAP1	YAP1	YAP1	14	15	20	21
In the myeloproliferative neoplasm , oncogenic JAK2 phosphorylates and inhibits PRMT5 , preventing histone methylation .	In the myeloproliferative neoplasm, oncogenic JAK2 phosphorylates and inhibits PRMT5, preventing histone methylation.	5	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JAK2	JAK2	JAK2	PRMT5	PRMT5	PRMT5	6	7	10	11
Inhibition of PRMT5 by JAK2 phosphorylation .	Inhibition of PRMT5 by JAK2 phosphorylation.	0	6	Inhibition	Negative_activation_syntax_1_noun	Negative_activation	Negative_activation	JAK2	JAK2 phosphorylation	jak2	PRMT5	PRMT5	prmt5	4	5	2	3
Taken together , these results suggest Itch targets the negative regulator Smad7 to positively regulate TGF-beta signaling .	Taken together, these results suggest Itch targets the negative regulator Smad7 to positively regulate TGF-beta signaling.	6	12	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Itch	Itch	Itch	Smad7	Smad7	Smad7	6	7	11	12
In conclusion , ASPP2 suppresses invasion , peritoneal dissemination and TGF-beta1-induced EMT by inhibiting Smad7 degradation mediated by ITCH .	In conclusion, ASPP2 suppresses invasion, peritoneal dissemination and TGF-beta1-induced EMT by inhibiting Smad7 degradation mediated by ITCH.	14	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	ITCH	ITCH	ITCH	Smad7	Smad7	Smad7	18	19	14	15
Next , to address the physiological role of the Itch mediated inhibition of Smad7 in TGF-beta signaling , we examined the effect of Itch depletion on TGF-beta-induced EMT related gene expression .	Next, to address the physiological role of the Itch mediated inhibition of Smad7 in TGF-beta signaling, we examined the effect of Itch depletion on TGF-beta-induced EMT related gene expression.	6	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Itch	Itch	Itch	Smad7	Smad7	Smad7	9	10	13	14
Jun dimerization protein 2 ( JDP2 ) is a repressor of transcription factor AP-1 .	Jun dimerization protein 2 (JDP2) is a repressor of transcription factor AP-1.	0	14	is a repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	Jun dimerization protein 2	Jun dimerization protein 2	Jun dimerization protein 2	transcription factor AP-1	transcription factor AP-1	transcription factor AP-1	0	4	11	14
Thus , c-Jun inhibition by JDP2 during pregnancy is effective only from day 10-12 and therefore may bypass the critical timing resulting in the adverse effect of inhibition of fetal liver development .	Thus, c-Jun inhibition by JDP2 during pregnancy is effective only from day 10-12 and therefore may bypass the critical timing resulting in the adverse effect of inhibition of fetal liver development.	2	7	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	JDP2	JDP2	JDP2	c-Jun	c-Jun	c-Jun	5	6	2	3
Pyrvinium pamoate , an antiparasitic drug , has been shown to inhibit LRP6 mediated axin degradation and the potency of beta-catenin stabilization .	Pyrvinium pamoate, an antiparasitic drug, has been shown to inhibit LRP6 mediated axin degradation and the potency of beta-catenin stabilization.	11	15	mediated	Positive_early_activation	Negative_activation	Negative_activation	LRP6	LRP6	LRP6	axin	axin	axin	12	13	14	15
It would thus be interesting to see if similar JAK2 mediated EZH2 degradation exists in NKTCL or that EZH2 switch to non canonical function can be mediated by JAK1/2 as well .	It would thus be interesting to see if similar JAK2 mediated EZH2 degradation exists in NKTCL or that EZH2 switch to non canonical function can be mediated by JAK1/2 as well.	8	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	JAK2	JAK2	JAK2	EZH2	EZH2	EZH2	9	10	11	12
If a JAK2 mediated EZH2 degradation exists , an increase in the levels of EZH2 , cyclin D1 and the H3K27me3 mark that EZH2 catalyses would be expected upon JAK2 inhibition by ruxolitinib .	If a JAK2 mediated EZH2 degradation exists, an increase in the levels of EZH2, cyclin D1 and the H3K27me3 mark that EZH2 catalyses would be expected upon JAK2 inhibition by ruxolitinib.	1	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	JAK2	JAK2	JAK2	EZH2	EZH2	EZH2	2	3	4	5
It is also plausible that the previously reported repression of Fli1 by KLF1 , was in fact modulated by KLF3 .	It is also plausible that the previously reported repression of Fli1 by KLF1, was in fact modulated by KLF3.	8	13	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	KLF1	KLF1	KLF1	Fli1	Fli1	Fli1	12	13	10	11
The erythrocyte specific transcription factor EKLF is upregulated and represses the activity of Fli-1 , its counter-antagonist in the megakaryocyte lineage .	The erythrocyte specific transcription factor EKLF is upregulated and represses the activity of Fli-1, its counter-antagonist in the megakaryocyte lineage.	0	16	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	EKLF	EKLF	EKLF	Fli-1	Fli-1	Fli-1	5	6	13	14
First of all , Jmj interacts with two important cardiac transcription factors , Nkx2.5 and GATA4 , and inhibits the activation of Nkx2.5 and GATA4 target promoters .	First of all, Jmj interacts with two important cardiac transcription factors, Nkx2.5 and GATA4, and inhibits the activation of Nkx2.5 and GATA4 target promoters.	2	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Jmj	Jmj	Jmj	Nkx2.5	Nkx2.5	Nkx2.5	4	5	22	23
JMJ represses the Nkx2.5- or GATA4 dependent activation of the reporter genes containing the ANF promoter-enhancer or containing the Nkx2.5 or GATA4 binding consensus sequence .	JMJ represses the Nkx2.5- or GATA4 dependent activation of the reporter genes containing the ANF promoter-enhancer or containing the Nkx2.5 or GATA4 binding consensus sequence.	0	11	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JMJ	JMJ	JMJ	Nkx2.5-	Nkx2.5-	Nkx2.5-	0	1	3	4
miR-145 targets KLF4 and KLF5 , which repress SRF activity , as well as Slit-Robo GTPase activating proteins , which modulate cell migration by inactivating the small GTPase Cdc42 and inhibiting actin polymerization 115 .	miR-145 targets KLF4 and KLF5, which repress SRF activity, as well as Slit-Robo GTPase activating proteins, which modulate cell migration by inactivating the small GTPase Cdc42 and inhibiting actin polymerization 115.	0	9	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KLF4	KLF4	KLF4	SRF	SRF	SRF	2	3	8	9
Kremen2 induces LRP6 down-regulation and Wnt and LRP6 signaling inhibition .	Kremen2 induces LRP6 down-regulation and Wnt and LRP6 signaling inhibition.	0	3	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Kremen2	Kremen2	Kremen2	LRP6	LRP6	LRP6	0	1	2	3
We speculate that reduced JDP2 allows ATF2 to form other hetero- or homodimers that are subsequently activated via JNK and p38 kinases as has been previously shown [ XREF_BIBR - XREF_BIBR ] , resulting in the increased phosphorylation of ATF2 as we observe .	We speculate that reduced JDP2 allows ATF2 to form other hetero- or homodimers that are subsequently activated via JNK and p38 kinases as has been previously shown [XREF_BIBR - XREF_BIBR], resulting in the increased phosphorylation of ATF2 as we observe.	3	8	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	JDP2	JDP2	JDP2	ATF2	ATF2	ATF2	4	5	6	7
The TIP60 protein interacts with SC35 ( XREF_SUPPLEMENTARY ) and , upon genotoxic stress , ceases to inhibit SC35 , which causes to G 2 / M arrest .	The TIP60 protein interacts with SC35 (XREF_SUPPLEMENTARY) and, upon genotoxic stress, ceases to inhibit SC35, which causes to G 2 / M arrest.	1	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIP60	TIP60	TIP60	SC35	SC35	SC35	1	2	18	19
Moreover , LRIG3 has been shown to act in an opposite manner to LRIG1 and LRIG1 , in turn , has been shown to attenuate LRIG3 activity by its proteolytic degradation .	Moreover, LRIG3 has been shown to act in an opposite manner to LRIG1 and LRIG1, in turn, has been shown to attenuate LRIG3 activity by its proteolytic degradation.	15	26	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	LRIG3	LRIG3	LRIG3	15	16	25	26
Nuclear Mek1 Sequesters Ppargamma And Restricts Its Genomic Functions .	Nuclear Mek1 Sequesters Ppargamma And Restricts Its Genomic Functions.	0	5	Sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mek1	Mek1	Mek1	Ppargamma	Ppargamma	Ppargamma	1	2	3	4
Thus our results suggested that MEK1 , through the ERK1/2 activation , inhibited PPAR-gamma by Serine 112 phosphorylation and that inactivation of PPAR-gamma may activate autophagy that might be involved in GR turnover .	Thus our results suggested that MEK1, through the ERK1/2 activation, inhibited PPAR-gamma by Serine 112 phosphorylation and that inactivation of PPAR-gamma may activate autophagy that might be involved in GR turnover.	5	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MEK1	MEK1	MEK1	PPAR-gamma	PPAR-gamma	PPAR-gamma	5	6	13	14
This modification disrupts the export and leads to the nuclear segregation of MEK1 , which consequently sequesters PPARgamma , the master regulator of adipogenesis , away from its target genes .	This modification disrupts the export and leads to the nuclear segregation of MEK1, which consequently sequesters PPARgamma, the master regulator of adipogenesis, away from its target genes.	10	29	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MEK1	MEK1	MEK1	PPARgamma	PPARgamma	PPARgamma	12	13	17	18
Nuclear MEK1 Sequesters PPARgamma and Bisects MEK1 and ERK Signaling : A Non Canonical Pathway of Retinoic Acid Inhibition of Adipocyte Differentiation .	Nuclear MEK1 Sequesters PPARgamma and Bisects MEK1 and ERK Signaling : A Non Canonical Pathway of Retinoic Acid Inhibition of Adipocyte Differentiation.	0	5	Sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MEK1	MEK1	MEK1	PPARgamma	PPARgamma	PPARgamma	1	2	3	4
The anisomycin induced phosphorylation of Ser359 was unaffected by SB 203580 , U0126 or rapamycin , and was prevented by overexpression of a catalytically inactive SAPK4 and p38delta mutant , suggesting that SAPK4 and p38delta may mediate the inhibition of eEF2K by this stress .	The anisomycin induced phosphorylation of Ser359 was unaffected by SB 203580, U0126 or rapamycin, and was prevented by overexpression of a catalytically inactive SAPK4 and p38delta mutant, suggesting that SAPK4 and p38delta may mediate the inhibition of eEF2K by this stress.	32	41	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SAPK4	SAPK4	SAPK4	eEF2K	eEF2K	eEF2K	32	33	40	41
Maf has been shown to interact with Myb and repress Myb transactivation of certain targets in both myeloid and T lineages .	Maf has been shown to interact with Myb and repress Myb transactivation of certain targets in both myeloid and T lineages.	0	11	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Maf	Maf	Maf	Myb	Myb	Myb	0	1	10	11
Collectively , these data demonstrate that MAF silencing in HPCs is able to reverse at least in part the effects of MYB silencing on erythroid versus megakaryocyte lineage choice .	Collectively, these data demonstrate that MAF silencing in HPCs is able to reverse at least in part the effects of MYB silencing on erythroid versus megakaryocyte lineage choice.	6	22	reverse	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAF	MAF	MAF	MYB	MYB	MYB	6	7	21	22
In mammals , the ERK pathway is associated with the regulation of apoptosis 57 , and ERK2 inhibits caspase-9 by direct phosphorylation at Thr125 XREF_BIBR , XREF_BIBR .	In mammals, the ERK pathway is associated with the regulation of apoptosis 57, and ERK2 inhibits caspase-9 by direct phosphorylation at Thr125 XREF_BIBR, XREF_BIBR.	16	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK2	ERK2	ERK2	caspase-9	caspase-9	caspase-9	16	17	18	19
A potential target of MAPK1 ,3 is caspase 9 whose activation in vitro is inhibited through direct phosphorylation at Thr 125 by MAPK1 [ XREF_BIBR ] .	A potential target of MAPK1,3 is caspase 9 whose activation in vitro is inhibited through direct phosphorylation at Thr 125 by MAPK1 [XREF_BIBR].	2	24	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	MAPK1	MAPK1	MAPK1	caspase 9	caspase 9	caspase 9	22	23	7	9
Since U0126 and PD98059 also inhibit MEK5 and ERK5 , a pathway involved in Raf-1 signaling [ XREF_BIBR ] , we used PD184161 a specific MEK1 ,2 inhibitor [ XREF_BIBR ] at low concentrations [ XREF_BIBR ] to show that the MEK and MAPK1 ,3 pathway mediates caspase 9 inhibition .	Since U0126 and PD98059 also inhibit MEK5 and ERK5, a pathway involved in Raf-1 signaling [XREF_BIBR], we used PD184161 a specific MEK1,2 inhibitor [XREF_BIBR] at low concentrations [XREF_BIBR] to show that the MEK and MAPK1,3 pathway mediates caspase 9 inhibition.	43	49	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK1	MAPK1	MAPK1	caspase 9	caspase 9	caspase 9	43	44	47	49
Here , we show that sustained stimulation of the Raf-1 and MAPK1 ,3 pathway prevents caspase-9 activation induced by serum depletion in CCL39 and DeltaRaf-1 : ER fibroblasts .	Here, we show that sustained stimulation of the Raf-1 and MAPK1,3 pathway prevents caspase-9 activation induced by serum depletion in CCL39/DeltaRaf-1: ER fibroblasts.	11	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK1	MAPK1	MAPK1	caspase-9	caspase-9	caspase-9	11	12	15	16
In this study , we further investigated the mechanism by which MAPK1 ,3 activation blocks serum deprivation induced caspase 9 cleavage .	In this study, we further investigated the mechanism by which MAPK1,3 activation blocks serum deprivation induced caspase 9 cleavage.	11	20	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK1	MAPK1	MAPK1	caspase 9	caspase 9	caspase 9	11	12	18	20
Caspase 9 Activation Is Inhibited by the MEK and MAPK1 ,3 Pathway .	Caspase 9 Activation Is Inhibited by the MEK and MAPK1,3 Pathway.	0	11	Inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MAPK1	MAPK1	MAPK1	Caspase 9	Caspase 9	Caspase 9	9	10	0	2
Activated MEK phosphorylates its known targets , ERK1 and ERK2 , leading to dimerisation , nuclear translocation , and induction of target genes .	Activated MEK phosphorylates its known targets, ERK1 and ERK2, leading to dimerisation, nuclear translocation, and induction of target genes.	0	10	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK2	ERK2	ERK2	MEK	MEK	MEK	9	10	1	2
Thus , candidate ERK2 GOF mutants should rescue the proliferative effects of RAF or MEK inhibition , whereas mutants with wild-type or LOF activity should not .	Thus, candidate ERK2 GOF mutants should rescue the proliferative effects of RAF or MEK inhibition, whereas mutants with wild-type or LOF activity should not.	3	15	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK2	ERK2	ERK2	MEK	MEK	MEK	3	4	14	15
In contrast , ERK2 FRS mutants behaved equivalently to kinase impaired ERK2 ( ERK2 K54R ) , were unable to signal to DUSP6 , FOS and FRA1 ( XREF_FIG , XREF_SUPPLEMENTARY ) and could not rescue the anti-proliferative effects of MEK inhibition ( XREF_FIG ) .	In contrast, ERK2 FRS mutants behaved equivalently to kinase impaired ERK2 (ERK2 K54R), were unable to signal to DUSP6, FOS and FRA1 (XREF_FIG, XREF_SUPPLEMENTARY) and could not rescue the anti-proliferative effects of MEK inhibition (XREF_FIG).	3	41	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK2	ERK2	ERK2	MEK	MEK	MEK	3	4	40	41
Double mutation of these sites abolished ERK2 mediated p21 ( Cip1 ) translocation and degradation , thereby impairing ERK2 dependent cell cycle progression at the G ( 1 )/S transition .	Double mutation of these sites abolished ERK2 mediated p21 (Cip1) translocation and degradation, thereby impairing ERK2 dependent cell cycle progression at the G (1)/S transition.	5	14	mediated	Positive_early_activation	Negative_activation	Negative_activation	ERK2	ERK2	ERK2	p21	p21	p21	6	7	8	9
We demonstrated the involvement of an autocrine loop involving endogenous FGF1 in the mechanisms that govern FGF2 induced resistance to apoptosis by showing : ( 1 ) higher levels of apoptosis in cells treated with antisense FGF1 oligonucleotide or after neutralization of excreted FGF1 ; ( 2 ) the long-term activation of FGFR1 and of ERK2 , ( 3 ) the inhibition of FGFR1 and ERK2 activation and an increase in apoptosis if excreted FGF1 was neutralized .	We demonstrated the involvement of an autocrine loop involving endogenous FGF1 in the mechanisms that govern FGF2 induced resistance to apoptosis by showing : (1) higher levels of apoptosis in cells treated with antisense FGF1 oligonucleotide or after neutralization of excreted FGF1; (2) the long-term activation of FGFR1 and of ERK2, (3) the inhibition of FGFR1 and ERK2 activation and an increase in apoptosis if excreted FGF1 was neutralized.	50	69	inhibition	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ERK2	ERK2	ERK2	FGFR1	FGFR1	FGFR1	55	56	63	64
Knockdown of ERK1 or ERK2 consistently attenuated B-Raf V600E -induced MEK1 upregulation in IMR90E1A cells , whereas knockdown of ERK2 , but not ERK1 , was sufficient to suppress B-Raf V600E -induced MEK2 downregulation in IMR90E1A ( XREF_FIG ) .	Knockdown of ERK1 or ERK2 consistently attenuated B-Raf V600E -induced MEK1 upregulation in IMR90E1A cells, whereas knockdown of ERK2, but not ERK1, was sufficient to suppress B-Raf V600E -induced MEK2 downregulation in IMR90E1A (XREF_FIG).	0	11	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK2	ERK2	ERK2	MEK1	MEK1	MEK1	4	5	10	11
These results indicate that TC45 can inhibit the Delta EGFR mediated activation of ERK2 and suppress the tumorigenicity of Delta EGFR expressing glioblastoma cells in vivo .	These results indicate that TC45 can inhibit the Delta EGFR mediated activation of ERK2 and suppress the tumorigenicity of Delta EGFR expressing glioblastoma cells in vivo.	4	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK2	TC45 can inhibit the Delta EGFR mediated activation of ERK2	erk2	EGFR	EGFR	egfr	13	14	20	21
MiR-195 ( upregulated in older age ) and miR-24 ( downregulated in older age ) both regulate MAPK14 , which negatively regulates EGFR .	MiR-195 (upregulated in older age) and miR-24 (downregulated in older age) both regulate MAPK14, which negatively regulates EGFR.	16	23	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK14	MAPK14	MAPK14	EGFR	EGFR	EGFR	17	18	22	23
For example , mammalian Raf-1 ( a MAPKKK ) can be negatively regulated by the feedback phosphorylation of ERK2 ( a MAPK ) both in vitro and in vivo .	For example, mammalian Raf-1 (a MAPKKK) can be negatively regulated by the feedback phosphorylation of ERK2 (a MAPK) both in vitro and in vivo.	3	23	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK2	phosphorylation of ERK2	erk2	Raf-1	Raf-1	raf-1	18	19	4	5
FSK treatment of osteoblasts , which raised intracellular cAMP levels and inhibited DNA synthesis , blocked PKC stimulated tyrosine phosphorylation of p44mapk ( ERK1 ) and p42mapk ( ERK2 ) as well as inhibited PKC stimulated MAPK and Raf-1 activities .	FSK treatment of osteoblasts, which raised intracellular cAMP levels and inhibited DNA synthesis, blocked PKC stimulated tyrosine phosphorylation of p44mapk (ERK1) and p42mapk (ERK2) as well as inhibited PKC stimulated MAPK and Raf-1 activities.	16	39	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK2	PKC stimulated tyrosine phosphorylation of p44mapk (ERK1) and p42mapk (ERK2	erk2	Raf-1	Raf-1	raf-1	28	29	38	39
In addition to Akt , other kinases are capable of phosphorylating TSC2 and regulating its function in mTORC1 signaling , and these include : Erk2 and RSK , which inhibit the TSC2 activity , while AMPK and GSK3beta activate it XREF_BIBR , XREF_BIBR .	In addition to Akt, other kinases are capable of phosphorylating TSC2 and regulating its function in mTORC1 signaling, and these include : Erk2 and RSK, which inhibit the TSC2 activity, while AMPK and GSK3beta activate it XREF_BIBR, XREF_BIBR.	22	32	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Erk2	Erk2	Erk2	TSC2	TSC2	TSC2	24	25	31	32
Whereas ERK1 depletion promoted MEK-HSF1 interactions ( XREF_FIG ) , ERK1 overexpression mitigated these interactions and suppressed HSF1 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Whereas ERK1 depletion promoted MEK-HSF1 interactions (XREF_FIG), ERK1 overexpression mitigated these interactions and suppressed HSF1 (XREF_FIG and XREF_SUPPLEMENTARY).	10	21	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1	ERK1 overexpression	erk1	HSF1	HSF1	hsf1	10	11	17	18
Furthermore , SHP2 ( tyrosine phosphatase ) and JNK1 ( serine/threonine kinase ) can inhibit the IRS1 transcription pathway .	Furthermore, SHP2 (tyrosine phosphatase) and JNK1 (serine/threonine kinase) can inhibit the IRS1 transcription pathway.	2	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK1	JNK1	JNK1	IRS1	IRS1	IRS1	8	9	16	17
The kinases IKK ( IkB kinase ) and JNK-1 ( c-Jun N-terminal kinase 1 ) negatively regulate IRS-1 and IRS-2 by serine phosphorylation , inducing degradation of IRS proteins and inhibition of insulin receptor signaling .	The kinases IKK (IkB kinase) and JNK-1 (c-Jun N-terminal kinase 1) negatively regulate IRS-1 and IRS-2 by serine phosphorylation, inducing degradation of IRS proteins and inhibition of insulin receptor signaling.	2	19	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK-1	JNK-1	JNK-1	IRS-1	IRS-1	IRS-1	8	9	17	18
Furthermore , activated BMK1 notably inhibited PML dependent activation of p21 .	Furthermore, activated BMK1 notably inhibited PML dependent activation of p21.	2	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BMK1	BMK1	BMK1	PML	PML	PML	3	4	6	7
BMK1 Suppress PML Function through Phosphorylation .	BMK1 Suppress PML Function through Phosphorylation.	0	3	Suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BMK1	BMK1	BMK1	PML	PML	PML	0	1	2	3
Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation .	Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation.	4	9	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BMK1	BMK1	BMK1	PML	PML	PML	4	5	8	9
Pertinently currently there are emerging several potentially druggable targets such as CK2 , BMK1 , KLHL20 , and E6AP that has been demonstrated to negatively regulate PML stability in various pre-clinical cancer models .	Pertinently currently there are emerging several potentially druggable targets such as CK2, BMK1, KLHL20, and E6AP that has been demonstrated to negatively regulate PML stability in various pre-clinical cancer models.	8	27	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BMK1	BMK1	BMK1	PML	PML	PML	13	14	26	27
In previous studies , BMK1 and MEK5 has been found to induce AP-1-mediated transcription , and BMK1 can suppress the functions of promyelocytic leukemia protein , which is associated with the transcription factors through phosphorylation .	In previous studies, BMK1 and MEK5 has been found to induce AP-1-mediated transcription, and BMK1 can suppress the functions of promyelocytic leukemia protein, which is associated with the transcription factors through phosphorylation.	16	25	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BMK1	BMK1	BMK1	promyelocytic leukemia protein	promyelocytic leukemia protein	promyelocytic leukemia protein	16	17	22	25
These results indicate that BMK1 suppresses PML function through phosphorylation of S403 and T409 of PML ( XREF_FIG ) .	These results indicate that BMK1 suppresses PML function through phosphorylation of S403 and T409 of PML (XREF_FIG).	4	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BMK1	BMK1	BMK1	PML	PML	PML	4	5	6	7
Recently , BMK1 was shown to inhibit the tumor suppressor activity of PML by blocking PML ' s capacity in upregulating the expression of p21 , which is critically involved in the G1/S transition of a cell cycle .	Recently, BMK1 was shown to inhibit the tumor suppressor activity of PML by blocking PML 's capacity in upregulating the expression of p21, which is critically involved in the G1/S transition of a cell cycle.	2	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BMK1	BMK1	BMK1	PML	PML	PML	2	3	12	13
BMK1 mediated PML modification reduces the capacity of PML to upregulate p21 expression , and in the consequent proliferation inhibition of tumor cells .	BMK1 mediated PML modification reduces the capacity of PML to upregulate p21 expression, and in the consequent proliferation inhibition of tumor cells.	0	3	mediated	Positive_early_activation	Negative_activation	Negative_activation	BMK1	BMK1	BMK1	PML	PML	PML	0	1	2	3
Blocking MAPK8 with the inhibitor SP600125 effectively reduced degradation of BCL2L1 and expression of the autophagy suppressing BCL2L1-BECN1complex .	Blocking MAPK8 with the inhibitor SP600125 effectively reduced degradation of BCL2L1 and expression of the autophagy suppressing BCL2L1-BECN1complex.	0	12	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK8	MAPK8	MAPK8	BCL2L1	BCL2L1	BCL2L1	1	2	10	11
In addition , sustained activation of the JNK1 pathway by cisplatin similarly triggered CtBP degradation .	In addition, sustained activation of the JNK1 pathway by cisplatin similarly triggered CtBP degradation.	7	14	triggered	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	JNK1	JNK1	JNK1	CtBP	CtBP	CtBP	7	8	13	14
Here , we show that JIP1 suppresses Notch1 activity .	Here, we show that JIP1 suppresses Notch1 activity.	5	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JIP1	JIP1	JIP1	Notch1	Notch1	Notch1	5	6	7	8
Additionally , PI103 decreases expression of Mcl-1 , XIAP , and cFLIP , thereby promoting Bax and Bak activation , mitochondrial perturbations , and caspase dependent apoptosis .	Additionally, PI103 decreases expression of Mcl-1, XIAP, and cFLIP, thereby promoting Bax and Bak activation, mitochondrial perturbations, and caspase dependent apoptosis.	2	18	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	PI103 decreases expression of Mcl-1	mcl-1	Bak	Bak	bak	6	7	17	18
MCL-1 negatively regulates pro apoptotic factors ( Bak and Bax ) ( Chen et al , 2007 ) and accelerates leukaemogenesis ( Beverly and Varmus , 2009 ) .	MCL-1 negatively regulates pro apoptotic factors (Bak and Bax) (Chen et al, 2007) and accelerates leukaemogenesis (Beverly and Varmus, 2009).	0	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	Bak	Bak	Bak	0	1	7	8
Thus , although TRAIL receptor stimulation led to near-complete cleavage of BID , the intracellular concentration of tBID was apparently insufficient to fully antagonize MCL-1 and alleviate the inhibition of BAK by MCL-1 ; or alternatively , MCL-1 sequestered all of the available tBID and prevented its activation of BAK .	Thus, although TRAIL receptor stimulation led to near-complete cleavage of BID, the intracellular concentration of tBID was apparently insufficient to fully antagonize MCL-1 and alleviate the inhibition of BAK by MCL-1; or alternatively, MCL-1 sequestered all of the available tBID and prevented its activation of BAK.	26	33	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAK	BAK	BAK	32	33	30	31
Mcl-1 has been shown to preferentially inhibit Bak versus Bax activation , and this finding along with the release of Bak from Mcl-1 may be important contributors to the ability of sorafenib to enhance TRAIL mediated apoptosis .	Mcl-1 has been shown to preferentially inhibit Bak versus Bax activation, and this finding along with the release of Bak from Mcl-1 may be important contributors to the ability of sorafenib to enhance TRAIL mediated apoptosis.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	0	1	7	8
The immunoprecipitation results of XREF_FIG indicated that Mcl-1 sequesters the activator Bim as well as the effector Bak .	The immunoprecipitation results of XREF_FIG indicated that Mcl-1 sequesters the activator Bim as well as the effector Bak.	7	18	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	7	8	17	18
Mcl-1 has been shown to inhibit apoptosis , in part , by binding and sequestering the proapoptotic multi-domain Bcl-2 protein Bak , an association which is antagonized by BH3-only proteins .	Mcl-1 has been shown to inhibit apoptosis, in part, by binding and sequestering the proapoptotic multi-domain Bcl-2 protein Bak, an association which is antagonized by BH3-only proteins.	0	23	sequestering	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	0	1	20	21
Mcl-1 selectively inhibits Bax and Bak signaling , preventing cross-talk between the death receptor pathway and the intrinsic apoptotic pathway [ XREF_BIBR ] .	Mcl-1 selectively inhibits Bax and Bak signaling, preventing cross-talk between the death receptor pathway and the intrinsic apoptotic pathway [XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	0	1	5	6
In addition , the expression of Mcl-1 inhibited Bak activation and apoptosis during infection with a recombinant vaccinia virus devoid of F1L , highlighting the similar functions of F1L and Mcl-1 in regulating Bak and inhibiting apoptosis .	In addition, the expression of Mcl-1 inhibited Bak activation and apoptosis during infection with a recombinant vaccinia virus devoid of F1L, highlighting the similar functions of F1L and Mcl-1 in regulating Bak and inhibiting apoptosis.	4	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	expression of Mcl-1	mcl-1	Bak	Bak	bak	6	7	8	9
Like Bcl-2 and Bcl- XL , loss of antiapoptotic Mcl-1 promotes the oligomerisation of Bax and Bak and thus death during prolonged mitotic arrest .	Like Bcl-2 and Bcl- XL, loss of antiapoptotic Mcl-1 promotes the oligomerisation of Bax and Bak and thus death during prolonged mitotic arrest.	6	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	loss of antiapoptotic Mcl-1	mcl-1	Bak	Bak	bak	9	10	16	17
In contrast to VVDeltaF1L , the presence of Mcl-1 in VVDeltaF1L-FLAG-Mcl-1 was sufficient to prevent Bak activation during infection and in response to STS treatment ( XREF_FIG d ) .	In contrast to VVDeltaF1L, the presence of Mcl-1 in VVDeltaF1L-FLAG-Mcl-1 was sufficient to prevent Bak activation during infection and in response to STS treatment (XREF_FIG d).	6	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	8	9	15	16
58 This differential requirement has been attributed to the selective suppression of Bak by Mcl-1 .	58 This differential requirement has been attributed to the selective suppression of Bak by Mcl-1.	6	15	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	14	15	12	13
Although Bak deficiency did not rescue under these conditions , Mcl-1 could still inhibit Bak ( indicated by the dotted line in XREF_SUPPLEMENTARY ) .	Although Bak deficiency did not rescue under these conditions, Mcl-1 could still inhibit Bak (indicated by the dotted line in XREF_SUPPLEMENTARY).	10	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	10	11	14	15
According to a recent paper , Bak is not only sequestered by Mcl-1 but also by Bcl-x L.	According to a recent paper, Bak is not only sequestered by Mcl-1 but also by Bcl-x L.	6	13	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	12	13	6	7
Mcl-1 , a key anti-apoptotic member of the Bcl-2 family , inhibits cell death by suppressing the release of cytochrome c from mitochondria via binding and sequestering the pro apoptotic protein Bak on the outer mitochondrial membrane XREF_BIBR .	Mcl-1, a key anti-apoptotic member of the Bcl-2 family, inhibits cell death by suppressing the release of cytochrome c from mitochondria via binding and sequestering the pro apoptotic protein Bak on the outer mitochondrial membrane XREF_BIBR.	0	37	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	0	1	31	32
While activation of Bax is controlled by Bcl-2 , Mcl-1 , and Bcl-xL , Mcl-1 also cooperates with Bcl-xL to sequester Bak and prevent its activation .	While activation of Bax is controlled by Bcl-2, Mcl-1, and Bcl-xL, Mcl-1 also cooperates with Bcl-xL to sequester Bak and prevent its activation.	14	23	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	14	15	21	22
Remarkably , we found that TRAIL activates a TGF-beta-activated kinase 1 ( TAK1 ) --> MKK3 and MKK6 --> p38 pathway that transcriptionally upregulates the expression of MCL-1 and suppresses BAK activation , MOMP , and cell death , despite caspase-8 activation and robust BID cleavage .	Remarkably, we found that TRAIL activates a TGF-beta-activated kinase 1 (TAK1) --> MKK3 and MKK6 --> p38 pathway that transcriptionally upregulates the expression of MCL-1 and suppresses BAK activation, MOMP, and cell death, despite caspase-8 activation and robust BID cleavage.	5	31	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	TRAIL activates a TGF-beta-activated kinase 1 (TAK1) --> MKK3 and MKK6 --> p38 pathway that transcriptionally upregulates the expression of MCL-1	mcl-1	BAK	BAK	bak	27	28	30	31
Pro apoptotic Bak is sequestered by Mcl-1 [ 17 ] therefore upregulation of Mcl-1 expression would result in a coordinate decrease in available Bak leading to further downregulation of apoptosis .	Pro apoptotic Bak is sequestered by Mcl-1 [17] therefore upregulation of Mcl-1 expression would result in a coordinate decrease in available Bak leading to further downregulation of apoptosis.	0	8	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	6	7	2	3
In DN cells , Mcl-1 sequesters Bak , and loss of Mcl-1 leads to Bak activation ( XREF_FIG , left ) .	In DN cells, Mcl-1 sequesters Bak, and loss of Mcl-1 leads to Bak activation (XREF_FIG, left).	4	7	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	4	5	6	7
Mcl-1 is known to prevent the activation of the pro apoptotic proteins , Bax and BAK .	Mcl-1 is known to prevent the activation of the pro apoptotic proteins, Bax and BAK.	0	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	BAK	BAK	BAK	0	1	15	16
Therefore , a much larger pool of Mcl-1 is available to sequester Bak from initiating apoptosis .	Therefore, a much larger pool of Mcl-1 is available to sequester Bak from initiating apoptosis.	5	13	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	7	8	12	13
MCL1 is a pro survival member of the BCL2 family and prevents activation of pro apoptotic BCL2-homology ( BH ) 3-only proteins and the effector BAK1 [ XREF_BIBR ] .	MCL1 is a pro survival member of the BCL2 family and prevents activation of pro apoptotic BCL2-homology (BH) 3-only proteins and the effector BAK1 [XREF_BIBR].	0	27	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL1	MCL1	MCL1	BAK1	BAK1	BAK1	0	1	25	26
In addition , although RV treatment induced a significant degradation of Mcl-1 , knockdown of Mcl-1 by shRNA only modestly increased RV induced Bak activation .	In addition, although RV treatment induced a significant degradation of Mcl-1, knockdown of Mcl-1 by shRNA only modestly increased RV induced Bak activation.	13	24	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	15	16	23	24
According to the unified model that is being widely accepted [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , Mcl-1 blocks MOMP by inactivating the pro apoptotic proteins Bak and Bax .	According to the unified model that is being widely accepted [XREF_BIBR, XREF_BIBR, XREF_BIBR], Mcl-1 blocks MOMP by inactivating the pro apoptotic proteins Bak and Bax.	18	29	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	18	19	27	28
The induction of Mcl-1 , likely the consequence of a combination of viral RNA replication , protein synthesis and cellular signal cascades triggered by all these events , would then attenuate Bak activation and subsequent apoptosis .	The induction of Mcl-1, likely the consequence of a combination of viral RNA replication, protein synthesis and cellular signal cascades triggered by all these events, would then attenuate Bak activation and subsequent apoptosis.	1	32	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	3	4	31	32
It is possible that , during the regulation of the PI induced apoptosis , the elevated Mcl-1 protein level blocks pro apoptotic Bak protein [ XREF_BIBR ] , whereas the active Akt phosphorylate and sequester pro apoptotic Bad protein from interacting with Bcl-X L [ XREF_BIBR ] .	It is possible that, during the regulation of the PI induced apoptosis, the elevated Mcl-1 protein level blocks pro apoptotic Bak protein [XREF_BIBR], whereas the active Akt phosphorylate and sequester pro apoptotic Bad protein from interacting with Bcl-X L [XREF_BIBR].	16	23	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1 protein	Mcl-1 protein level	mcl-1 protein	Bak	Bak	bak	16	18	22	23
Notably the level of Mcl-1 , a Bcl-2 family member that antagonizes pro apoptotic Bax and Bak , is a determinant of cell survival in response to multiple apoptotic stimuli .	Notably the level of Mcl-1, a Bcl-2 family member that antagonizes pro apoptotic Bax and Bak, is a determinant of cell survival in response to multiple apoptotic stimuli.	2	17	antagonizes	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Mcl-1	level of Mcl-1	mcl-1	Bak	Bak	bak	4	5	16	17
By this mechanism , Nbk enforces inhibition of Bak by Mcl-1 .	By this mechanism, Nbk enforces inhibition of Bak by Mcl-1.	5	11	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	10	11	8	9
Importantly , besides Bax also Bak needs to be activated to trigger mitochondrial cell death [ XREF_BIBR ] and Mcl-1 has been described to antagonize Bak at the mitochondrial membrane [ XREF_BIBR ] .	Importantly, besides Bax also Bak needs to be activated to trigger mitochondrial cell death [XREF_BIBR] and Mcl-1 has been described to antagonize Bak at the mitochondrial membrane [XREF_BIBR].	19	26	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	19	20	25	26
Thus , proteasome dependent MCL-1 degradation during mitotic arrest leads to loss of sequestration of BAK permitting BAK activation and apoptosis .	Thus, proteasome dependent MCL-1 degradation during mitotic arrest leads to loss of sequestration of BAK permitting BAK activation and apoptosis.	4	18	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAK	BAK	BAK	4	5	17	18
Interestingly , in response to MazF induction , NBK and BIK activated BAK by displacing it from anti-apoptotic proteins MCL-1 and BCL-X ( L ) that sequester BAK .	Interestingly, in response to MazF induction, NBK and BIK activated BAK by displacing it from anti-apoptotic proteins MCL-1 and BCL-X (L) that sequester BAK.	11	28	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAK	BAK	BAK	19	20	27	28
Additionally , Mcl-1 expression prevented Bak activation and apoptosis during infection with a proapoptotic vaccinia virus devoid of F1L .	Additionally, Mcl-1 expression prevented Bak activation and apoptosis during infection with a proapoptotic vaccinia virus devoid of F1L.	2	6	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1 expression	mcl-1	Bak	Bak	bak	2	3	5	6
It has been shown that Mcl-1 promotes CLL cell survival by inhibiting the intrinsic Bak and Bax mediated apoptotic pathway .	It has been shown that Mcl-1 promotes CLL cell survival by inhibiting the intrinsic Bak and Bax mediated apoptotic pathway.	5	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	5	6	14	15
These observations are consistent with our idea that MCL-1 degradation during mitotic arrest leads to loss of sequestration of BAK permitting BAK activation and apoptosis .	These observations are consistent with our idea that MCL-1 degradation during mitotic arrest leads to loss of sequestration of BAK permitting BAK activation and apoptosis.	8	22	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAK	BAK	BAK	8	9	21	22
Because Mcl-1 blocks the progression of apoptosis by binding and sequestering the pro apoptotic protein Bak , we examined the association between Bak and Mcl-1 .	Because Mcl-1 blocks the progression of apoptosis by binding and sequestering the pro apoptotic protein Bak, we examined the association between Bak and Mcl-1.	1	16	sequestering	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	1	2	15	16
Mcl-1 can inhibit apoptosis by sequestering pro apoptotic BH3-only proteins including Bim and Noxa , as well as the multidomain Bak protein that regulates the permeability of the outer mitochondrial membrane .	Mcl-1 can inhibit apoptosis by sequestering pro apoptotic BH3-only proteins including Bim and Noxa, as well as the multidomain Bak protein that regulates the permeability of the outer mitochondrial membrane.	0	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	0	1	20	21
Inhibition of Bak by Mcl-1 , which in turn can not be inactivated by Nbk , is therefore responsible for the failure of Nbk to induce Bak activation .	Inhibition of Bak by Mcl-1, which in turn can not be inactivated by Nbk, is therefore responsible for the failure of Nbk to induce Bak activation.	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	4	5	2	3
Mcl-1 , an anti-apoptotic member of the Bcl-2 family , sequesters Bak on the outer mitochondrial membrane , thereby preventing Bak oligomerization .	Mcl-1, an anti-apoptotic member of the Bcl-2 family, sequesters Bak on the outer mitochondrial membrane, thereby preventing Bak oligomerization.	0	12	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	0	1	11	12
Moreover , the inhibition of anti-apoptotic BCL-2 proteins with ABT-263 , a BH3-only protein mimetic , led to BAK dependent activation of ceramide synthase that was inhibited by MCL-1 .	Moreover, the inhibition of anti-apoptotic BCL-2 proteins with ABT-263, a BH3-only protein mimetic, led to BAK dependent activation of ceramide synthase that was inhibited by MCL-1.	18	29	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAK	BAK	BAK	28	29	18	19
By sequestering the pro apoptotic proteins Bax and Bak , Mcl-1 inhibits permeabilization of the mitochondrial membrane , preventing cyctochrome C release , Caspase-9 activation , and ultimately apoptosis .	By sequestering the pro apoptotic proteins Bax and Bak, Mcl-1 inhibits permeabilization of the mitochondrial membrane, preventing cyctochrome C release, Caspase-9 activation, and ultimately apoptosis.	1	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	10	11	8	9
Mcl-1 is thought to inhibit apoptosis by sequestering the proapoptotic BH3-only proteins ( i.e. Bim ) and/or binding the proapoptotic , multidomain Bak [ XREF_BIBR ] .	Mcl-1 is thought to inhibit apoptosis by sequestering the proapoptotic BH3-only proteins (i.e. Bim) and/or binding the proapoptotic, multidomain Bak [XREF_BIBR].	0	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	0	1	22	23
Furthermore , we show that Mcl-1 sequesters the BH3-only protein Noxa and Bim and the apoptotic effector Bak .	Furthermore, we show that Mcl-1 sequesters the BH3-only protein Noxa and Bim and the apoptotic effector Bak.	5	18	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	5	6	17	18
Obatoclax disrupted Mcl-1 inhibition of Bak in cell free systems and induced activation of Bax in isolated mitochondria .	Obatoclax disrupted Mcl-1 inhibition of Bak in cell free systems and induced activation of Bax in isolated mitochondria.	2	6	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	2	3	5	6
Noxa is known to bind to the anti-apoptotic protein Mcl-1 thus promoting its degradation and release of activated Bak to trigger mitochondrial apoptosis [ XREF_BIBR ] .	Noxa is known to bind to the anti-apoptotic protein Mcl-1 thus promoting its degradation and release of activated Bak to trigger mitochondrial apoptosis [XREF_BIBR].	4	19	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	9	10	18	19
Mcl-1 sequesters the pro apoptotic multi-domain effector protein Bak 4 .	Mcl-1 sequesters the pro apoptotic multi-domain effector protein Bak 4.	0	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	0	1	8	9
XREF_BIBR Together , these results are supportive of a model in which Mcl-1 directly sequesters Bak in thymocytes .	XREF_BIBR Together, these results are supportive of a model in which Mcl-1 directly sequesters Bak in thymocytes.	12	17	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	12	13	15	16
When over-expressed , supra-physiological levels of Mcl-1 repressed Bak , while supra-physiological levels of Bcl-X L repressed both Bak and Bax .	When over-expressed, supra-physiological levels of Mcl-1 repressed Bak, while supra-physiological levels of Bcl-X L repressed both Bak and Bax.	4	9	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	levels of Mcl-1	mcl-1	Bak	Bak	bak	6	7	8	9
Perhaps more consistent with the latter interpretation , knockdown of MCL-1 by RNAi failed to induce spontaneous BAK activation , whereas treatment of MCL-1-deficient cells with TRAIL alone ( which triggered BID cleavage ) induced significant BAK activation , similar to that observed in TRAIL and SB203580 treated vector control cells ( compare XREF_FIG with b ) .	Perhaps more consistent with the latter interpretation, knockdown of MCL-1 by RNAi failed to induce spontaneous BAK activation, whereas treatment of MCL-1-deficient cells with TRAIL alone (which triggered BID cleavage) induced significant BAK activation, similar to that observed in TRAIL and SB203580 treated vector control cells (compare XREF_FIG with b).	8	18	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAK	BAK	BAK	10	11	17	18
Mcl-1 sequesters Bak to inhibit cytochrome c release and favor cell survival .	Mcl-1 sequesters Bak to inhibit cytochrome c release and favor cell survival.	0	3	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	0	1	2	3
Ectopic Mcl-1 expression attenuates Bak activation and apoptosis by ABT-737+ roscovitine , whereas cells overexpressing Bcl-2 or Bcl-xL remain fully sensitive .	Ectopic Mcl-1 expression attenuates Bak activation and apoptosis by ABT-737+ roscovitine, whereas cells overexpressing Bcl-2 or Bcl-xL remain fully sensitive.	1	5	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1 expression	mcl-1	Bak	Bak	bak	1	2	4	5
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Inhibition of Bak by Mcl-1 is critical in thymocytes : Bak deficiency , but not Bax deficiency or Bcl-2 overexpression , rescued the phenotype of Mcl-1-deficient thymocytes .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Inhibition of Bak by Mcl-1 is critical in thymocytes : Bak deficiency, but not Bax deficiency or Bcl-2 overexpression, rescued the phenotype of Mcl-1-deficient thymocytes.	9	14	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	13	14	11	12
Since Noxa was not transcriptionally upregulated , and was found to be associated with Mcl-1 constitutively , it is reasonable to suggest that Noxa functions as a constitutive inhibitor for Mcl-1 , which is known to sequester both tBid and Bak , two mediators of TRAIL induced apoptosis XREF_BIBR , XREF_BIBR .	Since Noxa was not transcriptionally upregulated, and was found to be associated with Mcl-1 constitutively, it is reasonable to suggest that Noxa functions as a constitutive inhibitor for Mcl-1, which is known to sequester both tBid and Bak, two mediators of TRAIL induced apoptosis XREF_BIBR, XREF_BIBR.	28	41	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	30	31	40	41
These results confirm the hypothesis that loss of Mcl-1 leads to the activation of Bak , which in turn initiates apoptosis .	These results confirm the hypothesis that loss of Mcl-1 leads to the activation of Bak, which in turn initiates apoptosis.	6	19	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Mcl-1	loss of Mcl-1	mcl-1	Bak	Bak	bak	8	9	14	15
Inhibition of Bak by Mcl-1 might be enforced by this stabilization of Mcl-1 .	Inhibition of Bak by Mcl-1 might be enforced by this stabilization of Mcl-1.	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	4	5	2	3
MCL-1 belongs to the BCL-2 family and prevents oligomerization of BAK or BAX and subsequent cytochrome C release and apoptosis .	MCL-1 belongs to the BCL-2 family and prevents oligomerization of BAK or BAX and subsequent cytochrome C release and apoptosis.	0	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAK	BAK	BAK	0	1	10	11
Loss of Mcl-1 leads to activation of Bak .	Loss of Mcl-1 leads to activation of Bak.	0	8	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Mcl-1	Loss of Mcl-1	mcl-1	Bak	Bak	bak	2	3	7	8
As hypothesized , loss of Mcl-1 led to the activation of Bak , while total levels of Bak remained unchanged , and active Bak was not detectable in cells transfected with control siRNA ( XREF_FIG ) .	As hypothesized, loss of Mcl-1 led to the activation of Bak, while total levels of Bak remained unchanged, and active Bak was not detectable in cells transfected with control siRNA (XREF_FIG).	3	12	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Mcl-1	loss of Mcl-1	mcl-1	Bak	Bak	bak	5	6	11	12
This suggests that the dominant role of Mcl-1 in thymocytes is to antagonize Bak .	This suggests that the dominant role of Mcl-1 in thymocytes is to antagonize Bak.	5	14	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	7	8	13	14
Besides our finding showing a direct role of K63 linked ubiquitination in inhibiting the binding between p53 and BAK , mitochondrial BAK is also suppressed by MCL-1 .	Besides our finding showing a direct role of K63 linked ubiquitination in inhibiting the binding between p53 and BAK, mitochondrial BAK is also suppressed by MCL-1.	20	27	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAK	BAK	BAK	26	27	21	22
The fact that Noxa sensitizes Bax -/- cells to ABT-737 suggests that Bak is inhibited by Mcl-1 in the absence of Bax .	The fact that Noxa sensitizes Bax -/- cells to ABT-737 suggests that Bak is inhibited by Mcl-1 in the absence of Bax.	12	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	16	17	12	13
Thus phosphorylation dependent Mcl-1 degradation during mitotic arrest leads to loss of sequestration of Bak permitting Bak activation and apoptosis .	Thus phosphorylation dependent Mcl-1 degradation during mitotic arrest leads to loss of sequestration of Bak permitting Bak activation and apoptosis.	3	17	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	3	4	16	17
By sequestering the proapoptotic multidomain proteins BAX and BAK , MCL-1 inhibits permeabilization of the mitochondrial membrane and ultimately preventing apoptosis .	By sequestering the proapoptotic multidomain proteins BAX and BAK, MCL-1 inhibits permeabilization of the mitochondrial membrane and ultimately preventing apoptosis.	1	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAK	BAK	BAK	10	11	8	9
A decrease in Mcl-1 level can lead to their release and thus activating Bak resulting in increased cell death .	A decrease in Mcl-1 level can lead to their release and thus activating Bak resulting in increased cell death.	3	14	activating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1 level	mcl-1	Bak	Bak	bak	3	4	13	14
XREF_BIBR , XREF_BIBR , XREF_BIBR In untreated HeLa cells , one of the functions of the major survival protein Mcl-1 is to sequester Bak , and during mitotic arrest , the phosphorylation and degradation of Mcl-1 release bound Bak .	XREF_BIBR, XREF_BIBR, XREF_BIBR In untreated HeLa cells, one of the functions of the major survival protein Mcl-1 is to sequester Bak, and during mitotic arrest, the phosphorylation and degradation of Mcl-1 release bound Bak.	13	24	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	19	20	23	24
In contrast , over-expression of Mcl-1 partially reduced Bax conformational change after exposure to quercetin ( XREF_FIG ) .	In contrast, over-expression of Mcl-1 partially reduced Bax conformational change after exposure to quercetin (XREF_FIG).	3	10	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	over-expression of Mcl-1	mcl-1	Bax	Bax	bax	5	6	8	9
Conversely , blockade of IL-6 induces upregulation of the proapoptotic BH3-only protein , Bim , concomitant with Mcl-1 downregulation and activation of Bax , thereby inducing MM cell apoptosis [ XREF_BIBR ] .	Conversely, blockade of IL-6 induces upregulation of the proapoptotic BH3-only protein, Bim, concomitant with Mcl-1 downregulation and activation of Bax, thereby inducing MM cell apoptosis [XREF_BIBR].	17	23	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	17	18	22	23
Conversely , blockade of IL-6 induces upregulation of the pro apoptotic BH3-only protein Bim concomitant with Mcl-1 downregulation and activation of Bax , thereby inducing MM cell apoptosis .	Conversely, blockade of IL-6 induces upregulation of the pro apoptotic BH3-only protein Bim concomitant with Mcl-1 downregulation and activation of Bax, thereby inducing MM cell apoptosis.	16	22	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	16	17	21	22
In addition , Mcl-1 sequesters Bax in the cytosol of healthy cells , and as such upregulation of MCL1 contributes to the ability of growth factors such as G-CSF and GM-CSF to extend PMN lifespan [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, Mcl-1 sequesters Bax in the cytosol of healthy cells, and as such upregulation of MCL1 contributes to the ability of growth factors such as G-CSF and GM-CSF to extend PMN lifespan [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	6	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	3	4	5	6
In combination with NVP-BEZ235 and CDDP , there was dramatic synergy in shrinking tumor volumes and inducing apoptosis through increasing Noxa , Bax and decreasing Mcl-1 , Bcl-2 .	In combination with NVP-BEZ235 and CDDP, there was dramatic synergy in shrinking tumor volumes and inducing apoptosis through increasing Noxa, Bax and decreasing Mcl-1, Bcl-2.	20	27	decreasing	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	25	26	22	23
Scutellarin Treatment Upregulated the Expression of Mcl1 , and Suppressed Bax and Caspase-3 p17 .	Scutellarin Treatment Upregulated the Expression of Mcl1, and Suppressed Bax and Caspase-3 p17.	0	13	Suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl1	Scutellarin Treatment Upregulated the Expression of Mcl1	mcl1	Bax	Bax	bax	6	7	10	11
As Mcl-1 can antagonize Bax activation , Mcl-1 overexpression contributes to the resistance to ABT-737 [ XREF_BIBR ] .	As Mcl-1 can antagonize Bax activation, Mcl-1 overexpression contributes to the resistance to ABT-737 [XREF_BIBR].	1	5	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	1	2	4	5
One possible explanation for the inhibition of Bax by Mcl-1 is that Bax is sequestered in a Bax and Mcl -1 complex .	One possible explanation for the inhibition of Bax by Mcl-1 is that Bax is sequestered in a Bax and Mcl -1 complex.	5	10	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	9	10	7	8
Taken together , it may be concluded that Mcl-1 inhibits Bax activation without a direction interaction between these two proteins .	Taken together, it may be concluded that Mcl-1 inhibits Bax activation without a direction interaction between these two proteins.	8	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	8	9	10	11
A cytosolic localization of Mcl-1 , for example , might be required to sequester cytosolic Bax or similar proteins , while a nuclear localization has been proposed to be required for interactions with CDK-1 and PCNA , suggesting a role for Mcl-1 in cell cycle regulation or DNA repair XREF_BIBR , XREF_BIBR .	A cytosolic localization of Mcl-1, for example, might be required to sequester cytosolic Bax or similar proteins, while a nuclear localization has been proposed to be required for interactions with CDK-1 and PCNA, suggesting a role for Mcl-1 in cell cycle regulation or DNA repair XREF_BIBR, XREF_BIBR.	2	18	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	4	5	15	16
ERK also phosphorylates Mcl-1 and Bim which allows Bcl-2 , Bcl-xL and Mcl-1 to bind Bax and prevent Bax activation and the formation of Bax : Bax homodimers .	ERK also phosphorylates Mcl-1 and Bim which allows Bcl-2, Bcl-xL and Mcl-1 to bind Bax and prevent Bax activation and the formation of Bax : Bax homodimers.	0	19	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	ERK also phosphorylates Mcl-1	mcl-1	Bax	Bax	bax	3	4	18	19
Mcl-1 has previously been shown to inhibit Bax activation when over-expressed at high levels .	Mcl-1 has previously been shown to inhibit Bax activation when over-expressed at high levels.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	0	1	7	8
Mcl-1 significantly reduced induction of cell death and loss of mitochondrial membrane potential induced by its interaction partner Bak , and attenuated the function of Bax and Bok .	Mcl-1 significantly reduced induction of cell death and loss of mitochondrial membrane potential induced by its interaction partner Bak, and attenuated the function of Bax and Bok.	0	27	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	0	1	25	26
In HeLa cells , Mcl-1 was demonstrated to inhibit Bax downstream to its mitochondrial translocation .	In HeLa cells, Mcl-1 was demonstrated to inhibit Bax downstream to its mitochondrial translocation.	4	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	4	5	9	10
We hypothesize that MCL-1 functions as a sink in reserve that sequesters free BIM and prevents subsequent BAX activation .	We hypothesize that MCL-1 functions as a sink in reserve that sequesters free BIM and prevents subsequent BAX activation.	3	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAX	BAX	BAX	3	4	17	18
Diminishing Mcl-1 levels release Bax from the heterocomplex Bax : Mcl-1 , and allow Bax to translocate to the mitochondria where it can exercise its pro apoptotic function [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Diminishing Mcl-1 levels release Bax from the heterocomplex Bax : Mcl-1, and allow Bax to translocate to the mitochondria where it can exercise its pro apoptotic function [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	16	allow	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1 levels	mcl-1	Bax	Bax	bax	1	2	14	15
The inhibition of Bax by Mcl-1 in the absence of direct interactions between the two proteins could occur through several possible mechanisms .	The inhibition of Bax by Mcl-1 in the absence of direct interactions between the two proteins could occur through several possible mechanisms.	1	8	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	5	6	3	4
Under physiological conditions , Bax is controlled by a set of anti-apoptotic genes that includes Mcl-1 , an anti-apoptotic member of the Bcl-2 family that binds to and sequesters Bax .	Under physiological conditions, Bax is controlled by a set of anti-apoptotic genes that includes Mcl-1, an anti-apoptotic member of the Bcl-2 family that binds to and sequesters Bax.	14	30	sequesters	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	15	16	29	30
When compared with the heat stressed Ad-empty group , PAR1 overexpression significantly decreased the heat stress induced high protein expression levels of Mcl-1 and significantly increased those of Bax at 6 h ( XREF_FIG ) .	When compared with the heat stressed Ad-empty group, PAR1 overexpression significantly decreased the heat stress induced high protein expression levels of Mcl-1 and significantly increased those of Bax at 6 h (XREF_FIG).	9	29	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	PAR1 overexpression significantly decreased the heat stress induced high protein expression levels of Mcl-1	mcl-1	Bax	Bax	bax	22	23	28	29
Mcl-1 in turn inhibits Bax mediated intrinsic apoptotic pathway and hence allows Tregs to proliferate in another way .	Mcl-1 in turn inhibits Bax mediated intrinsic apoptotic pathway and hence allows Tregs to proliferate in another way.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	0	1	4	5
Suppression of Bcl-xL/Bcl-2/Bcl-w and Mcl-1 activates Bax in the absence of Bid , Bim , Puma , and Bak .	Suppression of Bcl-xL/Bcl-2/Bcl-w and Mcl-1 activates Bax in the absence of Bid, Bim, Puma, and Bak.	0	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	4	5	6	7
In this scenario , although M11 can not neutralize BAD and BIK , MCL-1 , having very low affinity for BAD and BIK [ XREF_BIBR ] , and other prosurvival protein molecules saved by M11 can inhibit BAX when M11 is expressed in the infected cell .	In this scenario, although M11 can not neutralize BAD and BIK, MCL-1, having very low affinity for BAD and BIK [XREF_BIBR], and other prosurvival protein molecules saved by M11 can inhibit BAX when M11 is expressed in the infected cell.	13	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAX	BAX	BAX	13	14	37	38
Mcl-1 prevented formation of Bax oligomers at mitochondria , required for pore formation , but this inhibition required no direct interaction [ XREF_BIBR ] .	Mcl-1 prevented formation of Bax oligomers at mitochondria, required for pore formation, but this inhibition required no direct interaction [XREF_BIBR].	0	5	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	0	1	4	5
MGCD0103 decreased the expression of Mcl-1 and induced translocation of Bax to the mitochondria , mitochondrial depolarization , and release of cytochrome c in the cytosol .	MGCD0103 decreased the expression of Mcl-1 and induced translocation of Bax to the mitochondria, mitochondrial depolarization, and release of cytochrome c in the cytosol.	0	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	MGCD0103 decreased the expression of Mcl-1	mcl-1	Bax	Bax	bax	5	6	10	11
Over-expression of Mcl-1 reversed the activation of Bax and attenuated clitocine induced apoptosis , suggesting that clitocine induced apoptosis was at least partially by inducing Mcl-1 degradation to release Bax and Bak .	Over-expression of Mcl-1 reversed the activation of Bax and attenuated clitocine induced apoptosis, suggesting that clitocine induced apoptosis was at least partially by inducing Mcl-1 degradation to release Bax and Bak.	0	8	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Over-expression of Mcl-1	mcl-1	Bax	Bax	bax	2	3	7	8
Generally , Mcl-1 inhibits the activation of Bid and Bax [ XREF_BIBR - XREF_BIBR ] , which are both triggers of LMP [ XREF_BIBR - XREF_BIBR ] , as well as MTP reduction [ XREF_BIBR ] .	Generally, Mcl-1 inhibits the activation of Bid and Bax [XREF_BIBR - XREF_BIBR], which are both triggers of LMP [XREF_BIBR - XREF_BIBR], as well as MTP reduction [XREF_BIBR].	2	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	2	3	9	10
The consequence of the up-regulation of Mcl-1 is seen at the mitochondrial level , as Mcl-1 is an inhibitor of Bax , a pro apoptotic Bcl-2 family member that mediates the loss of mitochondrial membrane integrity .	The consequence of the up-regulation of Mcl-1 is seen at the mitochondrial level, as Mcl-1 is an inhibitor of Bax, a pro apoptotic Bcl-2 family member that mediates the loss of mitochondrial membrane integrity.	15	27	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	15	16	20	21
These results indicated that the loss of Mcl-1 itself can modulate the subcellular distribution of Bax .	These results indicated that the loss of Mcl-1 itself can modulate the subcellular distribution of Bax.	5	16	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	loss of Mcl-1	mcl-1	Bax	Bax	bax	7	8	15	16
As Mcl-1 can antagonize Bax activation XREF_BIBR , it is likely that the ability of obatoclax to bind Mcl-1 also contributes to Bax activation in these cells .	As Mcl-1 can antagonize Bax activation XREF_BIBR, it is likely that the ability of obatoclax to bind Mcl-1 also contributes to Bax activation in these cells.	1	6	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	1	2	4	5
Rather , MDM2 blocks p73 transcriptional activities interfering with its modification by the acetyl-transferase p300 and CBP [ XREF_BIBR , XREF_BIBR ] .	Rather, MDM2 blocks p73 transcriptional activities interfering with its modification by the acetyl-transferase p300 and CBP [XREF_BIBR, XREF_BIBR].	2	6	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	2	3	4	5
Taken together , our data support a model by which Mdm2 inhibition of p53 and p73 cooperate in lymphomagenesis via inhibition of apoptosis .	Taken together, our data support a model by which Mdm2 inhibition of p53 and p73 cooperate in lymphomagenesis via inhibition of apoptosis.	10	16	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p73	p73	p73	10	11	15	16
As expected , p19 ras blocked MDM2 mediated transcriptional repression of p73 and led to the activation of p73 .	As expected, p19 ras blocked MDM2 mediated transcriptional repression of p73 and led to the activation of p73.	5	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	6	7	11	12
Moreover , our findings reveal that the E3 ligase activity of MDM2 is required to repress p73 dependent apoptosis and cell cycle arrest but not p73 dependent transcriptional activity .	Moreover, our findings reveal that the E3 ligase activity of MDM2 is required to repress p73 dependent apoptosis and cell cycle arrest but not p73 dependent transcriptional activity.	9	18	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	11	12	16	17
In this study , we elucidated the molecular mechanism by which MDM2 inhibits p73 function .	In this study, we elucidated the molecular mechanism by which MDM2 inhibits p73 function.	11	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	11	12	13	14
As expected siRNA silencing of MDM2 resulted in upregulation of p73 ( XREF_FIG ) .	As expected siRNA silencing of MDM2 resulted in upregulation of p73 (XREF_FIG).	3	12	resulted in upregulation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	5	6	10	11
In addition to p53 , previous studies indicate that Mdm2 also suppresses two other p53 family members , p63 and p73 [ XREF_BIBR - XREF_BIBR ] .	In addition to p53, previous studies indicate that Mdm2 also suppresses two other p53 family members, p63 and p73 [XREF_BIBR - XREF_BIBR].	9	22	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p73	p73	p73	9	10	20	21
These results suggest that Mdm2 attenuates TAp73 transactivation function , at least in part , by promoting NEDD8 dependent TAp73 cytoplasmic localization and provide the first evidence of a covalent post-translational modification exclusively targeting the TA isoforms of p73 .	These results suggest that Mdm2 attenuates TAp73 transactivation function, at least in part, by promoting NEDD8 dependent TAp73 cytoplasmic localization and provide the first evidence of a covalent post-translational modification exclusively targeting the TA isoforms of p73.	4	8	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	TAp73	TAp73	TAp73	4	5	6	7
In this study , we elucidated the mechanism by which MDM2 negatively regulates p73 function .	In this study, we elucidated the mechanism by which MDM2 negatively regulates p73 function.	10	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	10	11	13	14
MDM2 represses p53 and p73 activity by binding to their N-termini , obstructing the transactivation domain and hence the ability of p53 and p73 to transactivate downstream target genes .	MDM2 represses p53 and p73 activity by binding to their N-termini, obstructing the transactivation domain and hence the ability of p53 and p73 to transactivate downstream target genes.	0	5	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	4	5
However , Mdm2 does not initiate the proteasomal degradation of p63 or p73 .	However, Mdm2 does not initiate the proteasomal degradation of p63 or p73.	2	13	initiate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p73	p73	p73	2	3	12	13
This suggests that Itch is essential for Mdm2 mediated p73 degradation in Mdm2-null MEFs .	This suggests that Itch is essential for Mdm2 mediated p73 degradation in Mdm2-null MEFs.	5	10	mediated	Positive_early_activation	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p73	p73	p73	7	8	9	10
Next , we examined whether overexpression of MDM2 inhibits p73 dependent apoptosis .	Next, we examined whether overexpression of MDM2 inhibits p73 dependent apoptosis.	5	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	overexpression of MDM2	mdm2	p73	p73	p73	7	8	9	10
Loss of Mdm2 increased p73 protein ( XREF_FIG ) .	Loss of Mdm2 increased p73 protein (XREF_FIG).	0	5	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mdm2	Loss of Mdm2	mdm2	p73	p73	p73	2	3	4	5
That is partially explained why MDM2 repressed p73 dependent apoptosis in some cell types , which we do not see significant p73 degradation .	That is partially explained why MDM2 repressed p73 dependent apoptosis in some cell types, which we do not see significant p73 degradation.	5	9	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	5	6	7	8
We observed that p73 induced G1 arrest was partially prevented by overexpression of MDM2 ; however , MDM2DeltaRING was unable to prevent p73 induced G1 arrest , suggesting that the E3 ligase activity of MDM2 is required to inhibit p73 dependent cell cycle arrest .	We observed that p73 induced G1 arrest was partially prevented by overexpression of MDM2; however, MDM2DeltaRING was unable to prevent p73 induced G1 arrest, suggesting that the E3 ligase activity of MDM2 is required to inhibit p73 dependent cell cycle arrest.	32	43	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	34	35	39	40
Instead , MDM2 over-expression inhibits p73 transcriptional activity and enhances its stability .	Instead, MDM2 over-expression inhibits p73 transcriptional activity and enhances its stability.	2	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2 over-expression	mdm2	p73	p73	p73	2	3	5	6
To investigate whether Itch is required for the Mdm2 mediated degradation of p73 in vivo , Mdm2-null MEFs were transfected with Itch-siRNA or control siRNA .	To investigate whether Itch is required for the Mdm2 mediated degradation of p73 in vivo, Mdm2-null MEFs were transfected with Itch-siRNA or control siRNA.	5	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p73	p73	p73	8	9	12	13
It ' s known that p73 can transactivate MDM2 in its up-regulation though there is no indication of it down-regulating MDM2 directly being cited and though MDM2 is known to be a negative regulator of p53 [ XREF_BIBR - XREF_BIBR ] promoting its degradation though MDM2 does not degrade p73 [ XREF_BIBR - XREF_BIBR ] .	It 's known that p73 can transactivate MDM2 in its up-regulation though there is no indication of it down-regulating MDM2 directly being cited and though MDM2 is known to be a negative regulator of p53 [XREF_BIBR - XREF_BIBR] promoting its degradation though MDM2 does not degrade p73 [XREF_BIBR - XREF_BIBR].	45	51	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	45	46	49	50
The resistant cells also overexpressed MDM2 , which could inactivate p53 or p73 , leading to the defence of apoptosis induced by arsenic trioxide .	The resistant cells also overexpressed MDM2, which could inactivate p53 or p73, leading to the defence of apoptosis induced by arsenic trioxide.	4	13	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	5	6	12	13
Notably , overexpression of Mdm2 promotes p73 degradation in Mdm2-null MEFs .	Notably, overexpression of Mdm2 promotes p73 degradation in Mdm2-null MEFs.	2	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	overexpression of Mdm2	mdm2	p73	p73	p73	4	5	6	7
However , in contrast to p53 , mdm2 does not induce the degradation of p73 .	However, in contrast to p53, mdm2 does not induce the degradation of p73.	7	15	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mdm2	mdm2	mdm2	p73	p73	p73	7	8	14	15
HDM2 has been shown to attenuate P73 protein function by suppressing P73 transcriptional activity .	HDM2 has been shown to attenuate P73 protein function by suppressing P73 transcriptional activity.	0	8	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDM2	HDM2	HDM2	P73	P73	P73	0	1	6	7
MDM2 was recently reported to promote p73 degradation through interaction with ITCH in HeLa cells [ XREF_BIBR ] .	MDM2 was recently reported to promote p73 degradation through interaction with ITCH in HeLa cells [XREF_BIBR].	0	7	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	6	7
MDM2 is unable to promote p73 degradation in most tested cell lines .	MDM2 is unable to promote p73 degradation in most tested cell lines.	0	6	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	5	6
The transient overexpression of Mdm2 decreased the levels of endogenous p73 protein , suggesting that the p73 proteins are target of Mdm2 .	The transient overexpression of Mdm2 decreased the levels of endogenous p73 protein, suggesting that the p73 proteins are target of Mdm2.	2	11	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	overexpression of Mdm2	mdm2	p73	p73	p73	4	5	10	11
These conflict observations suggest that MDM2 mediated degradation of p73 is not as robust as that for p53 [ XREF_BIBR ] .	These conflict observations suggest that MDM2 mediated degradation of p73 is not as robust as that for p53 [XREF_BIBR].	5	10	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	5	6	9	10
56 As TAp73 transcriptional activity is abrogated by overexpressed MDM2 and MDMX proteins , which directly bind to and inhibit transactivation domain of TAp73 , 52 we investigated whether WA treatment could ablate the interaction between TAp73 and MDM2 .	56 As TAp73 transcriptional activity is abrogated by overexpressed MDM2 and MDMX proteins, which directly bind to and inhibit transactivation domain of TAp73, 52 we investigated whether WA treatment could ablate the interaction between TAp73 and MDM2.	2	19	abrogated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MDM2	MDM2 and MDMX proteins, which directly bind	mdm2	TAp73	TAp73	tap73	9	10	2	3
We demonstrate that Itch is essential for overexpression of Mdm2 mediated p73 degradation in Mdm2-null MEFs .	We demonstrate that Itch is essential for overexpression of Mdm2 mediated p73 degradation in Mdm2-null MEFs.	7	12	mediated	Positive_early_activation	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p73	p73	p73	9	10	11	12
It is worth to mention the role of MDM2 in the mutp53 , p63 , and p73 interplay : a recent work shows that MDM2 , a negative regulator of wt-p53 , competes with p63 for binding to mutp53R175H and in this way p63 activity is restored ; but , on the other hand , MDM2 forms a trimeric complex with p73 and mutp53R273H strongly inhibiting p73 function .	It is worth to mention the role of MDM2 in the mutp53, p63, and p73 interplay : a recent work shows that MDM2, a negative regulator of wt-p53, competes with p63 for binding to mutp53R175H and in this way p63 activity is restored; but, on the other hand, MDM2 forms a trimeric complex with p73 and mutp53R273H strongly inhibiting p73 function.	55	67	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	55	56	66	67
MDM2 did not promote the degradation of p73 but instead disrupted the interaction of p73 , but not of p53 , with p300 and CBP by competing with p73 for binding to the p300 and CBP N terminus .	MDM2 did not promote the degradation of p73 but instead disrupted the interaction of p73, but not of p53, with p300 and CBP by competing with p73 for binding to the p300 and CBP N terminus.	0	15	disrupted	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	14	15
MDM2 is transcriptionally activated by p73 and represses the functions of p73 , including p73 dependent transactivation and growth suppression .	MDM2 is transcriptionally activated by p73 and represses the functions of p73, including p73 dependent transactivation and growth suppression.	0	12	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	11	12
However , the molecular mechanism by which MDM2 represses p73 function is not clear .	However, the molecular mechanism by which MDM2 represses p73 function is not clear.	7	10	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	7	8	9	10
Thus , Mdm2 seems to effectively attenuate the activity of the Egr1-p73-p53 network during LTP , which might be explained by the capability of Mdm2 to suppress the transcriptional function of both p53 and p73 [ XREF_BIBR ] .	Thus, Mdm2 seems to effectively attenuate the activity of the Egr1-p73-p53 network during LTP, which might be explained by the capability of Mdm2 to suppress the transcriptional function of both p53 and p73 [XREF_BIBR].	22	36	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p73	p73	p73	24	25	34	35
To further determine whether endogenous MDM2 is required to inhibit p73 dependent apoptosis , H1299 cells were exposed to either control-siRNA or MDM2-siRNA .	To further determine whether endogenous MDM2 is required to inhibit p73 dependent apoptosis, H1299 cells were exposed to either control-siRNA or MDM2-siRNA.	4	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	5	6	10	11
Overexpression of Mdm2 promotes p73 degradation in Mdm2-null MEFs .	Overexpression of Mdm2 promotes p73 degradation in Mdm2-null MEFs.	0	5	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Overexpression of Mdm2	mdm2	p73	p73	p73	2	3	4	5
MDM2 also binds to and inhibits the transcriptional activity of p53 family member p63 and p73 .	MDM2 also binds to and inhibits the transcriptional activity of p53 family member p63 and p73.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	15	16
This is the first report in which p73 ubiquitination mediated by MDM2 has been linked to MDM2 repression of p73 dependent apoptosis and cell cycle arrest but not for p73 dependent transcriptional activity .	This is the first report in which p73 ubiquitination mediated by MDM2 has been linked to MDM2 repression of p73 dependent apoptosis and cell cycle arrest but not for p73 dependent transcriptional activity.	16	21	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	16	17	19	20
HDM2 binds to and inhibits the transcriptional activity of both p53 and p73 ; however , it only promotes ubiquitination and degradation of p53 , and instead results in increased steady state levels of p73 XREF_BIBR .	HDM2 binds to and inhibits the transcriptional activity of both p53 and p73; however, it only promotes ubiquitination and degradation of p53, and instead results in increased steady state levels of p73 XREF_BIBR.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDM2	HDM2	HDM2	p73	p73	p73	0	1	12	13
However , our findings reveal that overexpression of Mdm2 promotes p73 degradation in Mdm2-null MEFs , and is dependent on Itch .	However, our findings reveal that overexpression of Mdm2 promotes p73 degradation in Mdm2-null MEFs, and is dependent on Itch.	6	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	overexpression of Mdm2	mdm2	p73	p73	p73	8	9	10	11
This is consistent with the observation that p73 transcriptional activity is inhibited by MDM2 overexpression .	This is consistent with the observation that p73 transcriptional activity is inhibited by MDM2 overexpression.	7	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MDM2	MDM2 overexpression	mdm2	p73	p73	p73	13	14	7	8
MDM2 is a suppressor of both p53 and p73 ; however , while the interaction between p53 and MDM2 results in degradation of p53 , MDM2 associates with , but does not degrade , p73 XREF_BIBR - XREF_BIBR .	MDM2 is a suppressor of both p53 and p73; however, while the interaction between p53 and MDM2 results in degradation of p53, MDM2 associates with, but does not degrade, p73 XREF_BIBR - XREF_BIBR.	0	9	is a suppressor	Negative_activation_copula_1	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	8	9
Surprisingly , we observe that overexpression of Mdm2 promotes p73 degradation mainly through Itch in Mdm2-null MEFs .	Surprisingly, we observe that overexpression of Mdm2 promotes p73 degradation mainly through Itch in Mdm2-null MEFs.	5	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	overexpression of Mdm2	mdm2	p73	p73	p73	7	8	9	10
We showed that MDM2 relieves the inhibition of p63 activity by mutant p53 , but can enhance the inhibition of p73 by mutant p53 .	We showed that MDM2 relieves the inhibition of p63 activity by mutant p53, but can enhance the inhibition of p73 by mutant p53.	3	21	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	3	4	20	21
In addition to p53 , p73 has been shown to activate puma expression [ XREF_BIBR ] , therefore it is possible that ERalpha and Mdm2 inhibit p73 transactivation .	In addition to p53, p73 has been shown to activate puma expression [XREF_BIBR], therefore it is possible that ERalpha and Mdm2 inhibit p73 transactivation.	22	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p73	p73	p73	24	25	26	27
MDM2 represses the transcriptional activity of p73 and thus attenuates its activity .	MDM2 represses the transcriptional activity of p73 and thus attenuates its activity.	0	9	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	6	7
As mentioned in The Activation and Suppression functional categories section , MDM2 suppresses the p73 activity .	As mentioned in The Activation and Suppression functional categories section, MDM2 suppresses the p73 activity.	11	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	11	12	14	15
Interestingly MDM2 siRNA knockdown also resulted in p73 upregulation which confirms that MDM2 blocks p73 function which can be re-activated by inhibitors such as MI-319 .	Interestingly MDM2 siRNA knockdown also resulted in p73 upregulation which confirms that MDM2 blocks p73 function which can be re-activated by inhibitors such as MI-319.	1	9	upregulation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	1	2	7	8
Notably , the MDM2DeltaRING mutant significantly repressed p73 dependent transactivation , suggesting that MDM2 impairs the transactivation function of p73 without targeting it for degradation and indicating that the RING domain of MDM2 is not necessary for MDM2 inhibition of p73 transcriptional activity .	Notably, the MDM2DeltaRING mutant significantly repressed p73 dependent transactivation, suggesting that MDM2 impairs the transactivation function of p73 without targeting it for degradation and indicating that the RING domain of MDM2 is not necessary for MDM2 inhibition of p73 transcriptional activity.	13	20	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	13	14	19	20
In contrast to p53 , however , p73 degradation is not mediated by MDM2 , although p73 binds to MDM2 and blocks its transcription promoting activity .	In contrast to p53, however, p73 degradation is not mediated by MDM2, although p73 binds to MDM2 and blocks its transcription promoting activity.	7	14	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	13	14	7	8
Given that Mdm2 can inhibit p73 transcriptional activity and that both overexpression of Mdm2 and loss of TAp73 have been implicated in genomic instability and tumor development , we first examined whether these two alterations may have an additive effect on genomic instability by examining metaphase spreads in Mdm2 Tg ; p73 +/- and Mdm2 Tg ; p73-/- mouse embryonic fibroblasts ( MEFs ) .	Given that Mdm2 can inhibit p73 transcriptional activity and that both overexpression of Mdm2 and loss of TAp73 have been implicated in genomic instability and tumor development, we first examined whether these two alterations may have an additive effect on genomic instability by examining metaphase spreads in Mdm2 Tg; p73 +/- and Mdm2 Tg; p73-/- mouse embryonic fibroblasts (MEFs).	2	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p73	p73	p73	2	3	5	6
MDM2 did not promote p73 degradation in most tested cell lines .	MDM2 did not promote p73 degradation in most tested cell lines.	0	5	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	4	5
This may explain why MDM2 is unable to degrade p73 proteins in certain cell types .	This may explain why MDM2 is unable to degrade p73 proteins in certain cell types.	4	10	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	4	5	9	10
MDM2 which targets p53 for ubiquitin and proteasome dependent degradation , bound to NH 2 -terminal transactivation domain of p73 but did not promote its degradation even though MDM2 inhibited p73 mediated transcriptional as well as proapoptotic activity [ XREF_BIBR - XREF_BIBR ] .	MDM2 which targets p53 for ubiquitin and proteasome dependent degradation, bound to NH 2 -terminal transactivation domain of p73 but did not promote its degradation even though MDM2 inhibited p73 mediated transcriptional as well as proapoptotic activity [XREF_BIBR - XREF_BIBR].	28	31	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	28	29	30	31
However , MDM2 is unable to promote p73 degradation in most tested cell lines .	However, MDM2 is unable to promote p73 degradation in most tested cell lines.	2	8	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	2	3	7	8
Enhancers of p73 transcription are p300 , E2F-1 , CREB binding protein ( CBP ) , YAP , and MM1 ( my modulator 1 ) , while MDM2 and c-myc inhibit p73 transcriptional activity .	Enhancers of p73 transcription are p300, E2F-1, CREB binding protein (CBP), YAP, and MM1 (my modulator 1), while MDM2 and c-myc inhibit p73 transcriptional activity.	27	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	27	28	31	32
An important consideration is why MDM2 is unable to promote p73 degradation in HEK293 cells .	An important consideration is why MDM2 is unable to promote p73 degradation in HEK293 cells.	5	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	5	6	10	11
To determine whether MDM2 can inhibit p73 induced G1 arrest , human bladder carcinoma EJ cells , which lack functional p53 [ XREF_BIBR , XREF_BIBR ] , were transfected with a plasmid expressing p73alpha alone , with MDM2 , or with MDM2DeltaRING .	To determine whether MDM2 can inhibit p73 induced G1 arrest, human bladder carcinoma EJ cells, which lack functional p53 [XREF_BIBR, XREF_BIBR], were transfected with a plasmid expressing p73alpha alone, with MDM2, or with MDM2DeltaRING.	3	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	3	4	6	7
MDM2 represses p73 apoptosis and cell cycle arrest but not p73 dependent transcriptional activity via E3 ligase activity in tested cells .	MDM2 represses p73 apoptosis and cell cycle arrest but not p73 dependent transcriptional activity via E3 ligase activity in tested cells.	0	3	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	2	3
As MDM2 does not degrade TAp73 , thus in this setup the inhibition of reporter is related to the direct binding of MDM2 to TAp73 .	As MDM2 does not degrade TAp73, thus in this setup the inhibition of reporter is related to the direct binding of MDM2 to TAp73.	1	6	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	TAp73	TAp73	TAp73	1	2	5	6
Moreover , we observe that the E3 ligase activity of MDM2 is required for MDM2 to suppress p73 dependent apoptosis and cell cycle arrest .	Moreover, we observe that the E3 ligase activity of MDM2 is required for MDM2 to suppress p73 dependent apoptosis and cell cycle arrest.	8	19	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	10	11	17	18
MDM2 in turn mediates ubiquitin dependent degradation of MDMX , leading to destruction of its complex with p53 and activation of apoptosis .	MDM2 in turn mediates ubiquitin dependent degradation of MDMX, leading to destruction of its complex with p53 and activation of apoptosis.	0	9	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	0	1	8	9
Taken together , these results suggest that MLN4924 activates ATM , which then results in Mdm2 mediated degradation of MdmX through the ring domain of MdmX .	Taken together, these results suggest that MLN4924 activates ATM, which then results in Mdm2 mediated degradation of MdmX through the ring domain of MdmX.	13	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	MdmX	MdmX	MdmX	15	16	19	20
We next investigated whether S341 , S367 , and S402 phosphorylations affect binding to Mdm2 , as Mdmx degradation upon DNA damage is mediated by Mdm2 .	We next investigated whether S341, S367, and S402 phosphorylations affect binding to Mdm2, as Mdmx degradation upon DNA damage is mediated by Mdm2.	17	26	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Mdmx	Mdmx	Mdmx	25	26	17	18
These results suggest that overexpression of Otub1 alleviates MDM2 mediated MDMX degradation .	These results suggest that overexpression of Otub1 alleviates MDM2 mediated MDMX degradation.	7	11	mediated	Positive_early_activation	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	8	9	10	11
Although the RING domain of Mdmx does not contain intrinsic ubiquitin ligase activity for either p53 or itself , this domain is crucial for Mdmx degradation induced by Mdm2 .	Although the RING domain of Mdmx does not contain intrinsic ubiquitin ligase activity for either p53 or itself, this domain is crucial for Mdmx degradation induced by Mdm2.	24	29	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Mdmx	Mdmx	Mdmx	28	29	24	25
After stress , MDM2 degrades itself and MDMX , leading to the accumulation and activation of p53 .	After stress, MDM2 degrades itself and MDMX, leading to the accumulation and activation of p53.	3	8	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	3	4	7	8
As activated p53 transactivates MDM2 , the increasingly abundant MDM2 degrades MDMX more efficiently , enabling full p53 activation : the transcriptional stress response is at its peak .	As activated p53 transactivates MDM2, the increasingly abundant MDM2 degrades MDMX more efficiently, enabling full p53 activation : the transcriptional stress response is at its peak.	6	12	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	9	10	11	12
ARF also promotes MDM2 mediated degradation of MDMX .	ARF also promotes MDM2 mediated degradation of MDMX.	2	8	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	3	4	7	8
Germline inactivation of Rps27l triggers ribosomal stress to stabilize Mdm2 , which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase towards p53 , leading to p53 dependent apoptotic depletion of hematopoietic stem cells and postnatal death , which is rescued by Trp53 deletion .	Germline inactivation of Rps27l triggers ribosomal stress to stabilize Mdm2, which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase towards p53, leading to p53 dependent apoptotic depletion of hematopoietic stem cells and postnatal death, which is rescued by Trp53 deletion.	9	22	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Mdm4	Mdm4	Mdm4	9	10	13	14
The high level of MDM2 causes degradation of MDM4 leading to a further stabilization of p53 .	The high level of MDM2 causes degradation of MDM4 leading to a further stabilization of p53.	2	9	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	level of MDM2	mdm2	MDM4	MDM4	mdm4	4	5	8	9
To further support these data , MDM2 antagonized MDM4 mediated stimulation of p53Ser46 P and reduction of cell viability in Mdm4 -/- p53 -/- MEFs , whereas it was ineffective towards MDM4C437G , a mutant MDM4 unable to bind MDM2 ( XREF_FIG ) .	To further support these data, MDM2 antagonized MDM4 mediated stimulation of p53Ser46 P and reduction of cell viability in Mdm4 -/- p53 -/- MEFs, whereas it was ineffective towards MDM4C437G, a mutant MDM4 unable to bind MDM2 (XREF_FIG).	6	10	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	6	7	8	9
Other studies have shown that ATM activation after DNA damage results in ATM mediated phosphorylation of Mdm2 , which blocks nuclear export of p53 [ XREF_BIBR ] and MdmX , which results in rapid destabilization of MdmX .	Other studies have shown that ATM activation after DNA damage results in ATM mediated phosphorylation of Mdm2, which blocks nuclear export of p53 [XREF_BIBR] and MdmX, which results in rapid destabilization of MdmX.	12	31	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	ATM mediated phosphorylation of Mdm2	mdm2	MdmX	MdmX	mdmx	16	17	28	29
In addition , the different ratio of MDM4 and MDM2 levels may further contribute to impair MDM4 activities .	In addition, the different ratio of MDM4 and MDM2 levels may further contribute to impair MDM4 activities.	7	17	contribute	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2 levels	mdm2	MDM4	MDM4	mdm4	9	10	16	17
The mechanism for this is thought to be MDM2 mediated proteasomal degradation of MDM4 [ XREF_BIBR , XREF_BIBR ] .	The mechanism for this is thought to be MDM2 mediated proteasomal degradation of MDM4 [XREF_BIBR, XREF_BIBR].	1	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	8	9	13	14
Interestingly , in response to DNA damage , MDM2 promotes MDMX degradation .	Interestingly, in response to DNA damage, MDM2 promotes MDMX degradation.	8	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	8	9	10	11
These results clearly demonstrated that in the absence of Rps27l , Mdm2 actually has a higher binding affinity towards Mdm4 , which might facilitate Mdm2 mediated Mdm4 degradation , leading to a decreased level of Mdm4 , compromised Mdm2-Mdm4 ligase activity towards p53 , and consequent p53 accumulation .	These results clearly demonstrated that in the absence of Rps27l, Mdm2 actually has a higher binding affinity towards Mdm4, which might facilitate Mdm2 mediated Mdm4 degradation, leading to a decreased level of Mdm4, compromised Mdm2-Mdm4 ligase activity towards p53, and consequent p53 accumulation.	23	47	mediated	Positive_early_activation	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Mdm4	Mdm4	Mdm4	24	25	26	27
Following DNA damage by ionizing radiation , MDMX is rapidly degraded by MDM2 , allowing a buildup and activation of p53 .	Following DNA damage by ionizing radiation, MDMX is rapidly degraded by MDM2, allowing a buildup and activation of p53.	7	13	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	12	13	7	8
Mdmx degradation is primarily mediated by Mdm2 dependent ubiquitination .	Mdmx degradation is primarily mediated by Mdm2 dependent ubiquitination.	0	9	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Mdm2	Mdm2 dependent ubiquitination	mdm2	Mdmx	Mdmx	mdmx	6	7	0	1
The complex interplay is further demonstrated by the observation that MDM2 induced in a p53 dependent manner by DNA damaging agents then promotes MDM4 degradation as part of the facile cytotoxic response .	The complex interplay is further demonstrated by the observation that MDM2 induced in a p53 dependent manner by DNA damaging agents then promotes MDM4 degradation as part of the facile cytotoxic response.	10	24	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	10	11	23	24
89 In another study analyzing RPS27l knockout mouse cells , the induction of ribosomal stress by the absence of RPS27l resulted in MDM2 mediated MDMX degradation , which reduced MDM2-MDMX heterooligomer formation and stabilized p53 .	89 In another study analyzing RPS27l knockout mouse cells, the induction of ribosomal stress by the absence of RPS27l resulted in MDM2 mediated MDMX degradation, which reduced MDM2-MDMX heterooligomer formation and stabilized p53.	20	25	mediated	Positive_early_activation	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	22	23	24	25
The p14 defective state increased MDM2 levels and subsequently decreased a role of MDM4 in the p53 degradation since MDM2 by itself forms a homodimeric structure and the homodimer has a lower activity for p53 ubiquitination [ XREF_BIBR ] .	The p14 defective state increased MDM2 levels and subsequently decreased a role of MDM4 in the p53 degradation since MDM2 by itself forms a homodimeric structure and the homodimer has a lower activity for p53 ubiquitination [XREF_BIBR].	1	17	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	p14 defective state increased MDM2 levels	mdm2	MDM4	MDM4	mdm4	5	6	13	14
The emerging view is that damage induced phosphorylation of the Mdmx C terminus , and a p53 dependent increase in Mdm2 levels triggers Mdmx degradation .	The emerging view is that damage induced phosphorylation of the Mdmx C terminus, and a p53 dependent increase in Mdm2 levels triggers Mdmx degradation.	16	24	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	p53 dependent increase in Mdm2 levels	mdm2	Mdmx	Mdmx	mdmx	20	21	23	24
A putative involvement of S7 in MDM2 mediated degradation of MDMX was not investigated .	A putative involvement of S7 in MDM2 mediated degradation of MDMX was not investigated.	4	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	6	7	10	11
Although it is well know that degradation of p53 by Mdm2 is prevented after DNA damage through post-translational modification of both proteins , it has also been shown that MdmX degradation by Mdm2 is induced following DNA damage .	Although it is well know that degradation of p53 by Mdm2 is prevented after DNA damage through post-translational modification of both proteins, it has also been shown that MdmX degradation by Mdm2 is induced following DNA damage.	29	33	degradation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	MdmX	MdmX	MdmX	32	33	29	30
These data suggest that basal levels of Mdm2 expressed from the P1-promoter are sufficient to degrade Mdm4 .	These data suggest that basal levels of Mdm2 expressed from the P1-promoter are sufficient to degrade Mdm4.	5	17	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	levels of Mdm2	mdm2	Mdm4	Mdm4	mdm4	7	8	16	17
There are no detectable levels of MDM2 in retinoblastoma cells but it is possible that low levels of MDM2 are present and inhibition of both MDM2 and MDMX is important for the cytotoxic effect in retinoblastoma .	There are no detectable levels of MDM2 in retinoblastoma cells but it is possible that low levels of MDM2 are present and inhibition of both MDM2 and MDMX is important for the cytotoxic effect in retinoblastoma.	16	28	are present and inhibition	Negative_activation_copula_1	Negative_activation	Negative_activation	MDM2	levels of MDM2	mdm2	MDMX	MDMX	mdmx	18	19	27	28
These data provide evidence that Src phosphorylation of Mdm2 prevents Mdm2 mediated destabilization of MdmX .	These data provide evidence that Src phosphorylation of Mdm2 prevents Mdm2 mediated destabilization of MdmX.	5	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Src phosphorylation of Mdm2	mdm2	MdmX	MdmX	mdmx	8	9	14	15
Mdm2 has been shown to degrade MdmX upon DNA damage , suggesting that cleaved Mdm2 p60 could enhance MdmX levels and counter p53 activity .	Mdm2 has been shown to degrade MdmX upon DNA damage, suggesting that cleaved Mdm2 p60 could enhance MdmX levels and counter p53 activity.	0	7	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	MdmX	MdmX	MdmX	0	1	6	7
We also demonstrate that DNA damage induced MDMX reduction is mediated by MDM2 , which targets MDMX for proteasomal degradation by a distinct mechanism that permits preferential MDMX degradation and therefore ensures optimal p53 activation .	We also demonstrate that DNA damage induced MDMX reduction is mediated by MDM2, which targets MDMX for proteasomal degradation by a distinct mechanism that permits preferential MDMX degradation and therefore ensures optimal p53 activation.	7	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	12	13	7	8
It is possible that excess MDM2 in normal cells allows MDMX degradation , whereas excess MDMX in tumor cells saturates the capacity of MDM2 .	It is possible that excess MDM2 in normal cells allows MDMX degradation, whereas excess MDMX in tumor cells saturates the capacity of MDM2.	4	11	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	5	6	10	11
26 In addition , 5S RNA binds and stabilizes the MDMX protein , and the binding between the 5S RNA and MDMX is disrupted , and MDMX is quickly degraded by MDM2 , in response to ribosomal stress .	26 In addition, 5S RNA binds and stabilizes the MDMX protein, and the binding between the 5S RNA and MDMX is disrupted, and MDMX is quickly degraded by MDM2, in response to ribosomal stress.	26	32	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	31	32	26	27
This apparent inverse relationship between MDM2 and MDM4 may be due to MDM2 dependent proteosomal degradation of MDM4 , as has been proposed .	This apparent inverse relationship between MDM2 and MDM4 may be due to MDM2 dependent proteosomal degradation of MDM4, as has been proposed.	12	18	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	12	13	17	18
Our previous study revealed that under physiological Trp53 +/+ background , Rps27l inactivation triggers ribosomal stress to stabilize Mdm2 , which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase towards p53 , leading to p53 accumulation and activation 19 .	Our previous study revealed that under physiological Trp53 +/+ background, Rps27l inactivation triggers ribosomal stress to stabilize Mdm2, which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase towards p53, leading to p53 accumulation and activation 19.	18	31	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Mdm4	Mdm4	Mdm4	18	19	22	23
This is consistent with the severity of p53 dependent effects on normal tissues in mouse knockout models in which loss of MDM2 is more deleterious than loss of MDMX and targeting MDMX and MDM2 simultaneously has the greatest impact [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	This is consistent with the severity of p53 dependent effects on normal tissues in mouse knockout models in which loss of MDM2 is more deleterious than loss of MDMX and targeting MDMX and MDM2 simultaneously has the greatest impact [XREF_BIBR, XREF_BIBR - XREF_BIBR].	19	33	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	loss of MDM2	mdm2	MDMX	MDMX	mdmx	21	22	31	32
MDM4 is negatively regulated by MDM2 via MDM2 mediated degradation .	MDM4 is negatively regulated by MDM2 via MDM2 mediated degradation.	0	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	5	6	0	1
As shown in Figures XREF_FIG , MDM2 knockdown induced mild MDM4 accumulation in NUGC-3 and DLD-1 cells , but not KATOIII cells .	As shown in Figures XREF_FIG, MDM2 knockdown induced mild MDM4 accumulation in NUGC-3 and DLD-1 cells, but not KATOIII cells.	6	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	6	7	10	11
These sequential changes supported the notion that Rps27l depletion somehow stabilizes Mdm2 , which promotes Mdm4 degradation , as also shown previously , leading to a suboptimal Mdm2 and Mdm4 complex with reduced ligase activity toward p53 , and eventually p53 accumulation .	These sequential changes supported the notion that Rps27l depletion somehow stabilizes Mdm2, which promotes Mdm4 degradation, as also shown previously, leading to a suboptimal Mdm2 and Mdm4 complex with reduced ligase activity toward p53, and eventually p53 accumulation.	10	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Mdm4	Mdm4	Mdm4	11	12	15	16
To confirm the role of Mdm2 in 5S rRNA mediated effect on Mdmx in vivo , we examined whether inactivation of Mdm2 could rescue Mdmx degradation induced by 5S rRNA knockdown .	To confirm the role of Mdm2 in 5S rRNA mediated effect on Mdmx in vivo, we examined whether inactivation of Mdm2 could rescue Mdmx degradation induced by 5S rRNA knockdown.	19	25	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Mdmx	Mdmx	Mdmx	21	22	24	25
These results indicate that increase of MDM2 is not sufficient to eliminate MDMX in tumor cells .	These results indicate that increase of MDM2 is not sufficient to eliminate MDMX in tumor cells.	4	13	eliminate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	6	7	12	13
If degradation of p53 is dependent on an optimal ratio of MDM4 to MDM2 , then reduction of either MDM2 or MDM4 in A2780 , 2780CP/Cl -16 and 2780CP/Cl -24 cells will substantially increase or decrease the MDM4 : MDM2 ratio , respectively , and should stabilize p53 .	If degradation of p53 is dependent on an optimal ratio of MDM4 to MDM2, then reduction of either MDM2 or MDM4 in A2780, 2780CP/Cl -16 and 2780CP/Cl -24 cells will substantially increase or decrease the MDM4 : MDM2 ratio, respectively, and should stabilize p53.	16	40	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	19	20	37	38
Ectopic expression of wild-type USP2a but not a catalytic mutant prevents Mdm2 mediated degradation of MdmX .	Ectopic expression of wild-type USP2a but not a catalytic mutant prevents Mdm2 mediated degradation of MdmX.	10	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	MdmX	MdmX	MdmX	11	12	15	16
However , as suggested [ XREF_BIBR ] , p53 induced up-regulation of MDM2 might promote MDM4 degradation in some cell lines , which , in turn , would activate apoptosis cascade .	However, as suggested [XREF_BIBR], p53 induced up-regulation of MDM2 might promote MDM4 degradation in some cell lines, which, in turn, would activate apoptosis cascade.	10	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	12	13	15	16
We propose that Mdmx phosphorylation at S367 plays an important role in p53 activation after DNA damage by triggering Mdm2 dependent degradation of Mdmx .	We propose that Mdmx phosphorylation at S367 plays an important role in p53 activation after DNA damage by triggering Mdm2 dependent degradation of Mdmx.	19	24	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Mdmx	Mdmx	Mdmx	19	20	23	24
MdmX is stable in unstressed cells , but upon DNA-damage , MdmX is rapidly degraded by Mdm2 E3 ligase activity .	MdmX is stable in unstressed cells, but upon DNA-damage, MdmX is rapidly degraded by Mdm2 E3 ligase activity.	0	19	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	MdmX	MdmX	MdmX	16	17	0	1
Wild-type ( wt ) p53 activation in response to stresses not only results from its release from the MDM2 but is compounded by MDM2 mediated degradation of MDM4 .	Wild-type (wt) p53 activation in response to stresses not only results from its release from the MDM2 but is compounded by MDM2 mediated degradation of MDM4.	21	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	23	24	27	28
Furthermore , the presence of p76 ( MDM2 ) decreases the association of MDM4 with p53 and p90 ( MDM2 ) , and antagonizes p53 degradation by the heterodimer MDM4 and p90 ( MDM2 ) .	Furthermore, the presence of p76 (MDM2) decreases the association of MDM4 with p53 and p90 (MDM2), and antagonizes p53 degradation by the heterodimer MDM4 and p90 (MDM2).	5	14	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	7	8	13	14
Interestingly , overexpression of an MDM2 transgene ( Mdm2 Tg/+ ) can rescue MDMX deletion , hinting that MDM2 is perhaps capable of restraining undue p53 activity in vivo but its efficiency is compromised by MDMX loss .	Interestingly, overexpression of an MDM2 transgene (Mdm2 Tg/+) can rescue MDMX deletion, hinting that MDM2 is perhaps capable of restraining undue p53 activity in vivo but its efficiency is compromised by MDMX loss.	2	14	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	overexpression of an MDM2	mdm2	MDMX	MDMX	mdmx	5	6	13	14
Thus , the mechanism by which Mdmx is degraded by Mdm2 needs further elucidation .	Thus, the mechanism by which Mdmx is degraded by Mdm2 needs further elucidation.	6	11	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Mdmx	Mdmx	Mdmx	10	11	6	7
Moreover , although MDM2 can promote MDMX degradation , induction of MDM2 expression by XI-006 ( XREF_FIG ) was rather a consequence than a cause of MDMX inhibition because the MDMX inhibitor retained its ability to decrease MDMX expression levels in cells where MDM2 or p53 expression was knocked down by shRNA ( XREF_SUPPLEMENTARY ) .	Moreover, although MDM2 can promote MDMX degradation, induction of MDM2 expression by XI-006 (XREF_FIG) was rather a consequence than a cause of MDMX inhibition because the MDMX inhibitor retained its ability to decrease MDMX expression levels in cells where MDM2 or p53 expression was knocked down by shRNA (XREF_SUPPLEMENTARY).	3	7	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	3	4	6	7
Our prediction that Nutlin does not interfere with the MDM2/MDM4 interaction is supported by data showing that MDM2 and MDM4 co-immunoprecipitate following Nutlin treatment , which is consistent with Nutlin stimulated , MDM2-dependant degradation of MDM4 [ XREF_BIBR , XREF_BIBR ] .	Our prediction that Nutlin does not interfere with the MDM2/MDM4 interaction is supported by data showing that MDM2 and MDM4 co-immunoprecipitate following Nutlin treatment, which is consistent with Nutlin stimulated, MDM2-dependant degradation of MDM4 [XREF_BIBR, XREF_BIBR].	17	39	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	17	18	35	36
As activated p53 transactivates MDM2 , the increasingly abundant MDM2 degrades MDMX more efficiently , enabling full p53 activation ; the transcriptional stress response is at ., its peak .	As activated p53 transactivates MDM2, the increasingly abundant MDM2 degrades MDMX more efficiently, enabling full p53 activation; the transcriptional stress response is at., its peak.	6	12	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	9	10	11	12
Some of them play a significant role in p53 regulation ; for example , the feedback loops involving p53 , MDM2 and MDM4 ( Mdm4 p53 binding protein homolog ( mouse ) ) , which include five interactions : p53 activates MDM2 ; MDM2 inhibits p53 ; MDM2 inhibits MDM4 ; MDM4 activates MDM2 and MDM4 inhibits MDM2 XREF_BIBR .	Some of them play a significant role in p53 regulation; for example, the feedback loops involving p53, MDM2 and MDM4 (Mdm4 p53 binding protein homolog (mouse)), which include five interactions : p53 activates MDM2; MDM2 inhibits p53; MDM2 inhibits MDM4; MDM4 activates MDM2 and MDM4 inhibits MDM2 XREF_BIBR.	47	50	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	47	48	49	50
Our recent in vivo study showed that Rps27l disruption triggers ribosomal stress to stabilize Mdm2 , which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase activity towards p53 , leading to p53 dependent apoptotic depletion of hematopoietic stem cells and postnatal death , which can be rescued by heterozygous deletion of Trp53 19 .	Our recent in vivo study showed that Rps27l disruption triggers ribosomal stress to stabilize Mdm2, which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase activity towards p53, leading to p53 dependent apoptotic depletion of hematopoietic stem cells and postnatal death, which can be rescued by heterozygous deletion of Trp53 19.	14	28	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Mdm4	Mdm4	Mdm4	14	15	18	19
As shown in XREF_FIG , knockdown of MDM2 moderately increased MDM4 in control drug-naive cells .	As shown in XREF_FIG, knockdown of MDM2 moderately increased MDM4 in control drug-naive cells.	5	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	7	8	10	11
In summary , the predictions from our high-throughput sequencing data analysis , indicating that MK2 dependent inactivation of TTP is required for signal transduction , were validated .	In summary, the predictions from our high-throughput sequencing data analysis, indicating that MK2 dependent inactivation of TTP is required for signal transduction, were validated.	14	19	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	14	15	18	19
Following TLR mediated signal transduction , MK2 down-regulates TTP affinity to AREs of TNF-alpha mRNA via directly phosphorylating Ser52 and Ser178 of TTP [ XREF_BIBR ] , which facilitates HuR binding to AREs of TNF-alpha mRNA to promote TNF-alpha transcription [ XREF_BIBR ] ( XREF_FIG ) .	Following TLR mediated signal transduction, MK2 down-regulates TTP affinity to AREs of TNF-alpha mRNA via directly phosphorylating Ser52 and Ser178 of TTP [XREF_BIBR], which facilitates HuR binding to AREs of TNF-alpha mRNA to promote TNF-alpha transcription [XREF_BIBR] (XREF_FIG).	6	9	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	6	7	8	9
In this study , we applied an inhibitor to MAPKAP2 ( MK2 ) that suppresses TTP function .	In this study, we applied an inhibitor to MAPKAP2 (MK2) that suppresses TTP function.	9	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	11	12	15	16
Others have shown that TTP degradation is mediated by phosphorylation of MAPKAPK2 by p38 [ XREF_BIBR ] .	Others have shown that TTP degradation is mediated by phosphorylation of MAPKAPK2 by p38 [XREF_BIBR].	4	12	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	MAPKAPK2	phosphorylation of MAPKAPK2	mapkapk2	TTP	TTP	ttp	11	12	4	5
A previous study reported that activation of p38 and MK2 pathway can abolish TTP mediated repression of IL-6 3 '-UTR reporter activity .	A previous study reported that activation of p38 and MK2 pathway can abolish TTP mediated repression of IL-6 3 '-UTR reporter activity.	7	14	abolish	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	9	10	13	14
Phosphorylation of TTP by MK2 has been reported in vitro and in vivo ; data suggest that MK2 activation inactivates the function of TTP as a destabilizing protein .	Phosphorylation of TTP by MK2 has been reported in vitro and in vivo; data suggest that MK2 activation inactivates the function of TTP as a destabilizing protein.	17	24	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	17	18	23	24
MK2 inhibits the TTP function in AMD by phosphorylating two specific serine residues , which serve as docking sites for multifunctional adaptor 14-3-3 proteins .	MK2 inhibits the TTP function in AMD by phosphorylating two specific serine residues, which serve as docking sites for multifunctional adaptor 14-3-3 proteins.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	0	1	3	4
MK2 , the downstream target of p38 MAPK , inactivates TTP by phosphorylation XREF_BIBR , XREF_BIBR .	MK2, the downstream target of p38 MAPK, inactivates TTP by phosphorylation XREF_BIBR, XREF_BIBR.	0	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	0	1	10	11
Activation of the MK2 and p-MK 2 pathway has been reported to abolish TTP mediated suppression of IL-6 3 '-UTR reporter activity .	Activation of the MK2 and p-MK 2 pathway has been reported to abolish TTP mediated suppression of IL-6 3 '-UTR reporter activity.	0	14	abolish	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	3	4	13	14
It is intriguing to speculate that an increased activity of MK2 combined with elevated protein expression of 14-3-3tau inhibits the destabilising effect of TTP on TNF-alpha mRNA thereby promoting TNF-alpha protein expression , but further studies are needed to clarify this .	It is intriguing to speculate that an increased activity of MK2 combined with elevated protein expression of 14-3-3tau inhibits the destabilising effect of TTP on TNF-alpha mRNA thereby promoting TNF-alpha protein expression, but further studies are needed to clarify this.	8	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	10	11	23	24
However , the ability of TTP to bind to TNFalpha mRNA can be suppressed by the p38 and MK2 pathway , which phosphorylates and transiently inactivates TTP and causes it to translocate to the cytoplasm , allowing TNFalpha to be expressed XREF_BIBR , XREF_BIBR .	However, the ability of TTP to bind to TNFalpha mRNA can be suppressed by the p38 and MK2 pathway, which phosphorylates and transiently inactivates TTP and causes it to translocate to the cytoplasm, allowing TNFalpha to be expressed XREF_BIBR, XREF_BIBR.	16	27	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	18	19	26	27
MK-2 , in turn , inactivates transacting RNA binding protein tristetraprolin ( TTP ) by phosphorylation at serine 52 and 178 .	MK-2, in turn, inactivates transacting RNA binding protein tristetraprolin (TTP) by phosphorylation at serine 52 and 178.	0	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK-2	MK-2	MK-2	tristetraprolin	tristetraprolin	tristetraprolin	0	1	10	11
The close similarity of the transcriptomes of TTP deficient and TTP expressing macrophages upon short LPS stimulation suggested an effective inactivation of TTP by MK2 , whereas retained RNA binding capacity of TTP-AA to 3 ' UTRs caused profound changes in the transcriptome and translatome , altered NF-kappaB-activation and induced cell death .	The close similarity of the transcriptomes of TTP deficient and TTP expressing macrophages upon short LPS stimulation suggested an effective inactivation of TTP by MK2, whereas retained RNA binding capacity of TTP-AA to 3 ' UTRs caused profound changes in the transcriptome and translatome, altered NF-kappaB-activation and induced cell death.	17	25	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	MK2	MK2	MK2	TTP	TTP	TTP	24	25	22	23
The knockdown of MR-1 inhibited proliferation and induced blast cell differentiation forward MK lineage through activation of the MEK and ERK signaling pathway induced by the upregulation of MEK phosphorylation .	The knockdown of MR-1 inhibited proliferation and induced blast cell differentiation forward MK lineage through activation of the MEK and ERK signaling pathway induced by the upregulation of MEK phosphorylation.	4	30	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	MEK	MEK phosphorylation	mek	MEK	MEK	mek	28	29	18	19
They showed that the phosphorylation of MEK1/2 was also inhibited but not that of Raf , an upstream kinase of MEK1/2 , suggesting that the effect was at the level of MEK1/2 .	They showed that the phosphorylation of MEK1/2 was also inhibited but not that of Raf, an upstream kinase of MEK1/2, suggesting that the effect was at the level of MEK1/2.	4	21	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MEK1/2	phosphorylation of MEK1/2	mek1/2	MEK1/2	MEK1/2	mek1/2	6	7	20	21
Note that LPS induced MEK and ERK activation was completely blocked the two traditional MEK and ERK inhibitors ( Data not shown ) .	Note that LPS induced MEK and ERK activation was completely blocked the two traditional MEK and ERK inhibitors (Data not shown).	2	19	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MEK	LPS induced MEK	mek	MEK	MEK	mek	4	5	14	15
This result is in agreement with a previous study that demonstrated that MDM2 protein levels increased in Ras G12V -overexpressing NIH3T3 cells and induced CBP and p300 degradation .	This result is in agreement with a previous study that demonstrated that MDM2 protein levels increased in Ras G12V -overexpressing NIH3T3 cells and induced CBP and p300 degradation.	12	27	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2 protein levels	mdm2	p300	p300	p300	12	13	26	27
Conversely , Mdm2 can inhibit both p300 and CBP and PCAF mediated acetylation of p53 by suppressing the acetyltransferase activity and by recruiting the histone deacetylase HDAC1 to p53 .	Conversely, Mdm2 can inhibit both p300 and CBP and PCAF mediated acetylation of p53 by suppressing the acetyltransferase activity and by recruiting the histone deacetylase HDAC1 to p53.	2	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p300	p300	p300	2	3	6	7
Finally , we demonstrate that the Ras-PI3K-AKT pathway specifically targets H3K56ac via the MDM2 dependent degradation of CBP and p300 .	Finally, we demonstrate that the Ras-PI3K-AKT pathway specifically targets H3K56ac via the MDM2 dependent degradation of CBP and p300.	13	20	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p300	p300	p300	13	14	19	20
To confirm that the up-regulation of MDM2 caused the observed degradation of p300 and CBP , we next knocked down MDM2 expression in H-Ras G12V and Y40C -expressing cells using MDM2 siRNA .	To confirm that the up-regulation of MDM2 caused the observed degradation of p300 and CBP, we next knocked down MDM2 expression in H-Ras G12V and Y40C -expressing cells using MDM2 siRNA.	4	14	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p300	p300	p300	6	7	12	13
Results : Ras-PI3K regulates H3K56 acetylation ( H3K56ac ) via the MDM2 dependent degradation of CBP and p300 .	Results : Ras-PI3K regulates H3K56 acetylation (H3K56ac) via the MDM2 dependent degradation of CBP and p300.	11	18	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p300	p300	p300	11	12	17	18
As a negative regulator of gene expression , Mdm2 was also described to activate histone deacetylase 1 ( HDAC1 ) and inhibit p300 and CBP and other effectors of transcriptional activation .	As a negative regulator of gene expression, Mdm2 was also described to activate histone deacetylase 1 (HDAC1) and inhibit p300 and CBP and other effectors of transcriptional activation.	8	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p300	p300	p300	8	9	22	23
Our results suggest that MDM2 is involved in the down-regulation of CBP and p300 and H3K56ac given that the depletion of MDM2 , under the condition of Ras activation , rescued both the degradation of both CBP and p300 and the reduction in H3K56ac ( XREF_FIG ) .	Our results suggest that MDM2 is involved in the down-regulation of CBP and p300 and H3K56ac given that the depletion of MDM2, under the condition of Ras activation, rescued both the degradation of both CBP and p300 and the reduction in H3K56ac (XREF_FIG).	19	39	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	p300	p300	p300	21	22	38	39
Furthermore , we provide evidence that Mdm2 ( murine double minute 2 ) , in the presence of active H-Ras or N-Ras , induces CBP and p300 degradation in NIH 3T3 cells .	Furthermore, we provide evidence that Mdm2 (murine double minute 2), in the presence of active H-Ras or N-Ras, induces CBP and p300 degradation in NIH 3T3 cells.	6	27	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p300	p300	p300	6	7	26	27
We recently reported that MDM2 , a negative feedback regulator of the tumor suppressor p53 , inhibits p300 and CREB binding protein associated factor ( PCAF )-mediated p53 acetylation .	We recently reported that MDM2, a negative feedback regulator of the tumor suppressor p53, inhibits p300 and CREB binding protein associated factor (PCAF)-mediated p53 acetylation.	4	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p300	p300	p300	4	5	17	18
Unlike in unstressed cells , in which Mdm2 prevents p300 from associating with p53 , both CBP and p300 transcriptional coactivators and Strap , a partner protein of p300 , associate with p53 in response to DNA damage , increasing its level and half-life through a mechanism that involves p53 acetylation .	Unlike in unstressed cells, in which Mdm2 prevents p300 from associating with p53, both CBP and p300 transcriptional coactivators and Strap, a partner protein of p300, associate with p53 in response to DNA damage, increasing its level and half-life through a mechanism that involves p53 acetylation.	7	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	p300	p300	p300	7	8	9	10
Thus , inhibition of MK2 activity was expected to reactivate the Hsp27 capping activity on actin , resulting in reduced actin polymerization .	Thus, inhibition of MK2 activity was expected to reactivate the Hsp27 capping activity on actin, resulting in reduced actin polymerization.	4	12	reactivate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	Hsp27	Hsp27	Hsp27	4	5	11	12
MK2 inhibits BRF1 function via phosphorylation of Ser54 , Ser92 and Ser203 of BRF1 [ XREF_BIBR ] .	MK2 inhibits BRF1 function via phosphorylation of Ser54, Ser92 and Ser203 of BRF1 [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	BRF1	BRF1	BRF1	0	1	2	3
Coexpression of an active form of MK2 inhibits ARE mRNA decay activity of BRF1 .	Coexpression of an active form of MK2 inhibits ARE mRNA decay activity of BRF1.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MK2	MK2	MK2	BRF1	BRF1	BRF1	6	7	13	14
In vascular smooth muscle cells ( VSMCs ) , NFATc3 was activated upon application of high intravascular pressure to intact arteries [ XREF_BIBR ] , which was due to influx of extracellular Ca 2+ and also negatively regulated by the intracellular kinase JNK2 .	In vascular smooth muscle cells (VSMCs), NFATc3 was activated upon application of high intravascular pressure to intact arteries [XREF_BIBR], which was due to influx of extracellular Ca 2+ and also negatively regulated by the intracellular kinase JNK2.	9	43	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	JNK2	JNK2	JNK2	NFATc3	NFATc3	NFATc3	42	43	9	10
Ubiquitin ligase MDM2 , which mediates constitutive degradation of p53 , also induces degradation of Numb , an endocytic mediator that inhibits Notch signaling .	Ubiquitin ligase MDM2, which mediates constitutive degradation of p53, also induces degradation of Numb, an endocytic mediator that inhibits Notch signaling.	0	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	Numb	Numb	Numb	2	3	15	16
Notably , binding of Mdm2 does not impair the ability of Numb to interact with and inhibit Notch activity .	Notably, binding of Mdm2 does not impair the ability of Numb to interact with and inhibit Notch activity.	2	12	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	Mdm2	Mdm2	Numb	Numb	Numb	4	5	11	12
Various kinases , including PAKs , Aurora A , Cdk1 and PAR1b ( also known as MARK2 ) can inactivate GEF-H1 by phosphorylating inhibitory sites , whereas extracellular signal regulated kinase 1 and 2 ( ERK1/2 , also known as MAPK3 and MAPK1 , respectively ) phosphorylates GEF-H1 at the activating site Thr678 .	Various kinases, including PAKs, Aurora A, Cdk1 and PAR1b (also known as MARK2) can inactivate GEF-H1 by phosphorylating inhibitory sites, whereas extracellular signal regulated kinase 1 and 2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) phosphorylates GEF-H1 at the activating site Thr678.	9	21	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAR1b	PAR1b	PAR1b	GEF-H1	GEF-H1	GEF-H1	11	12	20	21
Menin represses p65 mediated transcriptional activation on NF-kappaB sites in a dose dependent and specific manner .	Menin represses p65 mediated transcriptional activation on NF-kappaB sites in a dose dependent and specific manner.	0	3	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Menin	Menin	Menin	p65	p65	p65	0	1	2	3
Previous studies in human cells revealed that RNAi mediated depletion of MCM10 in HeLa cells disrupts the localisation of RECQ4 to chromatin [ XREF_BIBR ] .	Previous studies in human cells revealed that RNAi mediated depletion of MCM10 in HeLa cells disrupts the localisation of RECQ4 to chromatin [XREF_BIBR].	9	20	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MCM10	MCM10	MCM10	RECQ4	RECQ4	RECQ4	11	12	19	20
It has been proposed that in resting platelets CD36 anchored Lyn is negatively regulated by Csk homologous kinase ( CHK ) XREF_BIBR .	It has been proposed that in resting platelets CD36 anchored Lyn is negatively regulated by Csk homologous kinase (CHK) XREF_BIBR.	10	18	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Csk homologous kinase	Csk homologous kinase	Csk homologous kinase	Lyn	Lyn	Lyn	15	18	10	11
To this end , autophagy genes that are upregulated include members of the Unc-51-like kinase 1 ( ULK1 ) complex that are negatively regulated by mTOR , and which initiate autophagy and genes that are important for the formation and elongation of the isolation membrane , both early events in the autophagy pathway .	To this end, autophagy genes that are upregulated include members of the Unc-51-like kinase 1 (ULK1) complex that are negatively regulated by mTOR, and which initiate autophagy and genes that are important for the formation and elongation of the isolation membrane, both early events in the autophagy pathway.	13	26	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Unc-51-like kinase 1	Unc-51-like kinase 1	Unc-51-like kinase 1	25	26	13	16
Interestingly , overexpression of Htt significantly relieved this mTOR mediated repression of basal ULK1 kinase activity ( XREF_FIG ) , suggesting that Htt antagonizes the negative regulation of mTOR on ULK1 and promotes activation of selective autophagy even in the presence of active mTOR ( rich media ) by directly competing away ULK1 from the mTORC1 and ULK1 complex .	Interestingly, overexpression of Htt significantly relieved this mTOR mediated repression of basal ULK1 kinase activity (XREF_FIG), suggesting that Htt antagonizes the negative regulation of mTOR on ULK1 and promotes activation of selective autophagy even in the presence of active mTOR (rich media) by directly competing away ULK1 from the mTORC1 and ULK1 complex.	7	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	8	9	13	14
By hyper-phosphorylating Atg13 , mTOR is able to prevent the complexing of Atg13 and Atg1 , which is a critical step in the formation of the Atg1k complex XREF_BIBR .	By hyper-phosphorylating Atg13, mTOR is able to prevent the complexing of Atg13 and Atg1, which is a critical step in the formation of the Atg1k complex XREF_BIBR.	4	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Atg1	Atg1	Atg1	4	5	14	15
This led to the finding that mTOR prevents the induction of autophagy by phosphorylating and thereby inactivating the ULK1 complex .	This led to the finding that mTOR prevents the induction of autophagy by phosphorylating and thereby inactivating the ULK1 complex.	6	19	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	6	7	18	19
Firstly we looked at ULK1 , the autophagy initiating kinase that can be directly inhibited by mTOR phosphorylation .	Firstly we looked at ULK1, the autophagy initiating kinase that can be directly inhibited by mTOR phosphorylation.	2	18	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	mTOR	mTOR phosphorylation	mtor	ULK1	ULK1	ulk1	16	17	4	5
ULK1 is regulated in part by mTOR and AMPK , which inhibit and activate ULK1 , respectively [ XREF_BIBR ] .	ULK1 is regulated in part by mTOR and AMPK, which inhibit and activate ULK1, respectively [XREF_BIBR].	2	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	6	7	14	15
mTOR activation blocks ATG1 kinase activity resulting in inhibition of autophagy XREF_BIBR .	mTOR activation blocks ATG1 kinase activity resulting in inhibition of autophagy XREF_BIBR.	0	5	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ATG1	ATG1	ATG1	0	1	3	4
Given that mTOR inhibition induces ULK1 activation ( XREF_FIG and XREF_SUPPLEMENTARY ) and ULK1 siRNA or 6965 suppresses autophagy induced by mTOR inhibitors ( XREF_FIG ) , we examined whether 6965 would reduce cell survival in the face of mTOR inhibition .	Given that mTOR inhibition induces ULK1 activation (XREF_FIG and XREF_SUPPLEMENTARY) and ULK1 siRNA or 6965 suppresses autophagy induced by mTOR inhibitors (XREF_FIG), we examined whether 6965 would reduce cell survival in the face of mTOR inhibition.	2	6	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	2	3	5	6
Inhibition of mTOR is considered to promote autophagy by regulating Atg1 in yeast and Atg1 complex , ULK ( UNC-51-like kinase ) , in mammals .	Inhibition of mTOR is considered to promote autophagy by regulating Atg1 in yeast and Atg1 complex, ULK (UNC-51-like kinase), in mammals.	0	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Atg1	Atg1	Atg1	2	3	10	11
The mTOR complex suppresses autophagy via phosphorylation and inactivation of ULK1 , an initiator of autophagosome formation .	The mTOR complex suppresses autophagy via phosphorylation and inactivation of ULK1, an initiator of autophagosome formation.	1	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	1	2	10	11
The mTOR and Raptor pathway is thought to suppress ULK1 and ULK2 and their regulatory subunits , while AMPK phosphorylates ULK1 , leading to autophagy mediated cancer cell death .	The mTOR and Raptor pathway is thought to suppress ULK1 and ULK2 and their regulatory subunits, while AMPK phosphorylates ULK1, leading to autophagy mediated cancer cell death.	1	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	1	2	9	10
Suppression of mTOR activates association of Atg13 and Atg1 which is important for autophagy [ XREF_BIBR , XREF_BIBR ] .	Suppression of mTOR activates association of Atg13 and Atg1 which is important for autophagy [XREF_BIBR, XREF_BIBR].	0	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Atg1	Atg1	Atg1	2	3	8	9
For instance , mTOR is reported to negatively regulate the ULK1 complex .	For instance, mTOR is reported to negatively regulate the ULK1 complex.	3	11	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	3	4	10	11
Rapamycin acts to remove the mTOR mediated inhibition of the Ulk1 complex thereby resulting in an increase in autophagy .	Rapamycin acts to remove the mTOR mediated inhibition of the Ulk1 complex thereby resulting in an increase in autophagy.	4	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Ulk1	Ulk1	Ulk1	5	6	10	11
The newly synthesized ULK1 is inhibited by mTOR phosphorylation , contributing to autophagy inhibition after prolonged starvation ( XREF_FIG ) .	The newly synthesized ULK1 is inhibited by mTOR phosphorylation, contributing to autophagy inhibition after prolonged starvation (XREF_FIG).	0	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR phosphorylation	mtor	ULK1	ULK1	ulk1	7	8	3	4
Knockdown of mTOR , but not Raptor or Rictor , reduced p-ULK1 at Ser ( 757 ) and enhanced chemotherapy induced autophagy that resulted in a similar cytoprotective effect as shown for AZD8055 .	Knockdown of mTOR, but not Raptor or Rictor, reduced p-ULK1 at Ser (757) and enhanced chemotherapy induced autophagy that resulted in a similar cytoprotective effect as shown for AZD8055.	0	12	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p-ULK1	p-ULK1	p-ULK1	2	3	11	12
Mechanistically , the high glucose induced inhibition of autophagy was mediated at least partly by increased mTOR signaling that likely inactivated ULK1 through phosphorylation at serine 467 .	Mechanistically, the high glucose induced inhibition of autophagy was mediated at least partly by increased mTOR signaling that likely inactivated ULK1 through phosphorylation at serine 467.	16	22	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	16	17	21	22
ULK1 is suppressed by mTOR , but unlike DAP1 , signals the activation of autophagy as part of a larger complex [ XREF_BIBR , XREF_BIBR ] .	ULK1 is suppressed by mTOR, but unlike DAP1, signals the activation of autophagy as part of a larger complex [XREF_BIBR, XREF_BIBR].	0	5	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	4	5	0	1
AMPK suppresses mTOR activity , and mTOR inhibits ULK1 .	AMPK suppresses mTOR activity, and mTOR inhibits ULK1.	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	6	7	8	9
ULK1 can activate autophagy and rapamycin sensitive mTOR has been reported to inhibit ULK1 via phosphorylation of the Ser757 residue XREF_BIBR .	ULK1 can activate autophagy and rapamycin sensitive mTOR has been reported to inhibit ULK1 via phosphorylation of the Ser757 residue XREF_BIBR.	6	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	7	8	13	14
XREF_BIBR The formation of the autophagosome begins with the mammalian target of rapamycin ( mTOR ) which modulates the initiator protein Ulk1 .	XREF_BIBR The formation of the autophagosome begins with the mammalian target of rapamycin (mTOR) which modulates the initiator protein Ulk1.	9	22	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Ulk1	Ulk1	Ulk1	9	13	21	22
Under feeding conditions , increased mTOR activity blocks ULK1 activation through Ser757 phosphorylation , leading to ULK1 and AMPK complex dissociation and inhibition of autophagy [ XREF_BIBR ] .	Under feeding conditions, increased mTOR activity blocks ULK1 activation through Ser757 phosphorylation, leading to ULK1 and AMPK complex dissociation and inhibition of autophagy [XREF_BIBR].	5	9	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	5	6	8	9
XREF_BIBR , XREF_BIBR Under nutrient rich conditions , mTOR complex 1 suppresses the ULK1 complex .	XREF_BIBR, XREF_BIBR Under nutrient rich conditions, mTOR complex 1 suppresses the ULK1 complex.	8	14	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	8	9	13	14
We show that an acute ethanol dose is capable of inhibiting mTOR , which in turn elicits ULK1 activation through its phosphorylation .	We show that an acute ethanol dose is capable of inhibiting mTOR, which in turn elicits ULK1 activation through its phosphorylation.	8	18	elicits	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	11	12	17	18
The complexity of the regulation of autophagy by MTOR is illustrated by the fact that MTOR not only inhibits ULK1 but that , conversely , ULK1 also inhibits MTOR by phosphorylation .	The complexity of the regulation of autophagy by MTOR is illustrated by the fact that MTOR not only inhibits ULK1 but that, conversely, ULK1 also inhibits MTOR by phosphorylation.	15	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MTOR	MTOR	MTOR	ULK1	ULK1	ULK1	15	16	19	20
In fact , MTOR not only inhibits ULK1 during early stages of autophagy but also reduces late stages of autophagy through the inhibition of lysosomal function .	In fact, MTOR not only inhibits ULK1 during early stages of autophagy but also reduces late stages of autophagy through the inhibition of lysosomal function.	3	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MTOR	MTOR	MTOR	ULK1	ULK1	ULK1	3	4	7	8
Recent studies have found that mTOR inhibits autophagy by producing ULK1 , a member of the autophagy initiation associated complex ULK1 , ATG13 , and FIP200 , resulting in loss of its kinase activity by phosphorylating Ser757 , and participating in a variety of pathological and physiological processes XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Recent studies have found that mTOR inhibits autophagy by producing ULK1, a member of the autophagy initiation associated complex ULK1, ATG13, and FIP200, resulting in loss of its kinase activity by phosphorylating Ser757, and participating in a variety of pathological and physiological processes XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	5	6	10	11
XREF_BIBR One protein is the serine threonine kinase , autophagy related 1 ( Atg1 ) , which is required for preautophagosomal structure formation , and is negatively regulated by mTOR .	XREF_BIBR One protein is the serine threonine kinase, autophagy related 1 (Atg1), which is required for preautophagosomal structure formation, and is negatively regulated by mTOR.	9	30	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Atg1	Atg1	Atg1	29	30	13	14
AMP activated protein kinase ( AMPK ) and mammalian target of rapamycin ( mTOR ) have been suggested to regulate ULK1 activity , with activation of ULK1 by AMPK through phosphorylation of ULK Ser317 and ULK Ser555 and inhibition of ULK1 by mTOR through phosphorylation of ULK Ser757 ( Egan etal .	AMP activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) have been suggested to regulate ULK1 activity, with activation of ULK1 by AMPK through phosphorylation of ULK Ser317 and ULK Ser555 and inhibition of ULK1 by mTOR through phosphorylation of ULK Ser757 (Egan etal.	19	43	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	42	43	40	41
However , in a state of nutrition deprivation , mTOR activity is suppressed , which leads to the activation of UNC-51-like kinase 1 ( ULK1 ) , an initiating step of the autophagic process .	However, in a state of nutrition deprivation, mTOR activity is suppressed, which leads to the activation of UNC-51-like kinase 1 (ULK1), an initiating step of the autophagic process.	9	29	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	9	10	24	25
XREF_BIBR Autophagy is initiated by stress signals from the mammalian target of rapamycin complex 1 ( mTORC1 ) , which activates the kinase ULK1 ( ATG1 ) , and which then forms a complex with ATG13 and ATG17 .	XREF_BIBR Autophagy is initiated by stress signals from the mammalian target of rapamycin complex 1 (mTORC1), which activates the kinase ULK1 (ATG1), and which then forms a complex with ATG13 and ATG17.	9	25	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	ULK1	ULK1	ULK1	9	13	23	24
Under nutrient rich conditions , active mTOR phosphorylates and inactivates the Atg1 complex , and when nutrients are scarce , mTOR dependent inactivation of Atg1 is released .	Under nutrient rich conditions, active mTOR phosphorylates and inactivates the Atg1 complex, and when nutrients are scarce, mTOR dependent inactivation of Atg1 is released.	20	25	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Atg1	Atg1	Atg1	20	21	24	25
All these results together indicate that OLE activates AMPK , which can allow the formation of ULK1 quaternary complex directly or indirectly by the inhibition of mTOR that inhibits ULK1 ( XREF_FIG ) .	All these results together indicate that OLE activates AMPK, which can allow the formation of ULK1 quaternary complex directly or indirectly by the inhibition of mTOR that inhibits ULK1 (XREF_FIG).	24	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	26	27	29	30
Mechanistically , the estradiol-ERalpha signaling activated mTOR , which phosphorylated and inhibited ULK1 , thereby suppressing autophagy and adipogenesis .	Mechanistically, the estradiol-ERalpha signaling activated mTOR, which phosphorylated and inhibited ULK1, thereby suppressing autophagy and adipogenesis.	3	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	estradiol-ERalpha signaling activated mTOR, which phosphorylated	mtor	ULK1	ULK1	ulk1	6	7	12	13
Briefly , AMPK activation or mTOR inhibition result in ULK1 activation .	Briefly, AMPK activation or mTOR inhibition result in ULK1 activation.	5	11	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	5	6	9	10
GRP78 also affects autophagy through its regulation of AMPK mediated mTOR inhibition of the ULK1 complex , a key component in the onset of autophagy [ XREF_BIBR ] .	GRP78 also affects autophagy through its regulation of AMPK mediated mTOR inhibition of the ULK1 complex, a key component in the onset of autophagy [XREF_BIBR].	8	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	AMPK mediated mTOR	mtor	ULK1	ULK1	ulk1	10	11	14	15
As mTOR inhibition results in ULK1 and autophagy activation , this might give an advantage to cancer cells in order to survive drug treatment .	As mTOR inhibition results in ULK1 and autophagy activation, this might give an advantage to cancer cells in order to survive drug treatment.	1	9	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	1	2	5	6
Recent studies revealed that activated AMPK was involved in processes that synergize to activate autophagy , by directly activating UNC-51-like autophagy activating kinase 1 ( ULK1 ) , a key initiator of the autophagic processes , and indirectly impairing mammalian target of rapamycin ( mTOR )-dependent inhibition of ULK1 [ XREF_BIBR - XREF_BIBR ] .	Recent studies revealed that activated AMPK was involved in processes that synergize to activate autophagy, by directly activating UNC-51-like autophagy activating kinase 1 (ULK1), a key initiator of the autophagic processes, and indirectly impairing mammalian target of rapamycin (mTOR)-dependent inhibition of ULK1 [XREF_BIBR - XREF_BIBR].	44	52	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	44	45	48	49
XREF_BIBR , XREF_BIBR , XREF_BIBR It is plausible that mTOR blocks the activation of exogenously expressed ULK1 .	XREF_BIBR, XREF_BIBR, XREF_BIBR It is plausible that mTOR blocks the activation of exogenously expressed ULK1.	9	17	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	9	10	16	17
The mTORC1 inhibitor rapamycin can effectively induce autophagy by eliminating mTOR mediated inhibition of the ULK1 autophagy initiation complex .	The mTORC1 inhibitor rapamycin can effectively induce autophagy by eliminating mTOR mediated inhibition of the ULK1 autophagy initiation complex.	10	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	10	11	15	16
Autophagy inducing stimuli release mTOR repression of ULK1 , allowing it to activate the Beclin-1 complex [ XREF_BIBR ] .	Autophagy inducing stimuli release mTOR repression of ULK1, allowing it to activate the Beclin-1 complex [XREF_BIBR].	4	8	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	4	5	7	8
As AMPK suppresses mTOR activity and mTOR inhibits ULK1 , AMPK controls ULK1 via a two pronged mechanism , ensuring activation only under the appropriate cellular conditions ( XREF_FIG , XREF_SUPPLEMENTARY ) .	As AMPK suppresses mTOR activity and mTOR inhibits ULK1, AMPK controls ULK1 via a two pronged mechanism, ensuring activation only under the appropriate cellular conditions (XREF_FIG, XREF_SUPPLEMENTARY).	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	3	4	8	9
In contrast , glucose deprivation , which activated AMPK , induced Beclin1 S93 phosphorylation , while amino acid deprivation , which inactivated mTOR and abrogated mTOR mediated inhibition of ULK1 , resulted in moderate increase in Beclin1 S15 phosphorylation .	In contrast, glucose deprivation, which activated AMPK, induced Beclin1 S93 phosphorylation, while amino acid deprivation, which inactivated mTOR and abrogated mTOR mediated inhibition of ULK1, resulted in moderate increase in Beclin1 S15 phosphorylation.	25	30	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	25	26	29	30
ULK1 associates with GABARAP , ATG13 , and mTOR and is inhibited by mTOR .	ULK1 associates with GABARAP, ATG13, and mTOR and is inhibited by mTOR.	0	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	13	14	0	1
Macroautophagy initiation is controlled by ULK1 ( Unc-51-like kinase 1 ) , mTOR negatively regulates ULK1 by phosphorylation .	Macroautophagy initiation is controlled by ULK1 (Unc-51-like kinase 1), mTOR negatively regulates ULK1 by phosphorylation.	12	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	12	13	15	16
Even under nutrient-sufficient conditions , increased mTOR activity inhibits ULK1 activation by ULK1 phosphorylation on Ser757 , thereby abrogating the interaction between ULK1 and AMPK [ XREF_BIBR ] .	Even under nutrient-sufficient conditions, increased mTOR activity inhibits ULK1 activation by ULK1 phosphorylation on Ser757, thereby abrogating the interaction between ULK1 and AMPK [XREF_BIBR].	6	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	6	7	9	10
We , too , observed mTOR dependent inhibition of ULK1 in GAA-KO muscle following TSC knockdown , but in the setting of Pompe disease , this suppression of autophagy turned out to be beneficial as shown by the removal of the autophagic buildup .	We, too, observed mTOR dependent inhibition of ULK1 in GAA-KO muscle following TSC knockdown, but in the setting of Pompe disease, this suppression of autophagy turned out to be beneficial as shown by the removal of the autophagic buildup.	5	20	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	5	6	9	10
One of the functions of MTOR is to inhibit ULK1 , a regulatory protein in the autophagy pathway .	One of the functions of MTOR is to inhibit ULK1, a regulatory protein in the autophagy pathway.	3	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MTOR	MTOR	MTOR	ULK1	ULK1	ULK1	5	6	9	10
The mTOR complex inhibits the activity of Atg1 and Atg13 protein kinase complex under normal conditions ; thus , acting as a negative regulator of autophagy .	The mTOR complex inhibits the activity of Atg1 and Atg13 protein kinase complex under normal conditions; thus, acting as a negative regulator of autophagy.	1	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Atg1	Atg1	Atg1	1	2	7	8
Therefore , p38 MAPK and mTOR share the inhibitory site S757 to inhibit ULK1 .	Therefore, p38 MAPK and mTOR share the inhibitory site S757 to inhibit ULK1.	3	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	5	6	13	14
mTOR may then inhibit ULK1 activity and block autophagy progression in the absence of new stimuli .	mTOR may then inhibit ULK1 activity and block autophagy progression in the absence of new stimuli.	0	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	0	1	4	5
Consistently , overexpression of Htt significantly blocked mTOR mediated repression of ULK1 .	Consistently, overexpression of Htt significantly blocked mTOR mediated repression of ULK1.	7	12	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	7	8	11	12
In one important pathway , the mTOR complex negatively regulates Atg1 in nutrient rich conditions XREF_BIBR .	In one important pathway, the mTOR complex negatively regulates Atg1 in nutrient rich conditions XREF_BIBR.	6	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Atg1	Atg1	Atg1	6	7	10	11
Studies in S. cerevisiae , D. melanogaster , and mammalian cells have demonstrated that mTOR acutely inhibits Atg1 and ULK1 function through phosphorylation of Atg1 and ULK1 and/or some of its associated regulatory subunits Beyond this inhibitory event , ULK1 also receives positive inputs from the cellular energy sensor AMP activated protein kinase ( AMPK ) , which is activated in response to cellular stresses that lower intracellular ATP levels , such as is caused by glucose or oxygen deprivation as well as mitochondrial insults .	Studies in S. cerevisiae, D. melanogaster, and mammalian cells have demonstrated that mTOR acutely inhibits Atg1 and ULK1 function through phosphorylation of Atg1 and ULK1 and/or some of its associated regulatory subunits Beyond this inhibitory event, ULK1 also receives positive inputs from the cellular energy sensor AMP activated protein kinase (AMPK), which is activated in response to cellular stresses that lower intracellular ATP levels, such as is caused by glucose or oxygen deprivation as well as mitochondrial insults.	14	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Atg1	Atg1	Atg1	14	15	17	18
As we have previously mentioned , mTOR inhibits Atg1 and ULK1 function via phosphorylation of Atg1 and ULK1 .	As we have previously mentioned, mTOR inhibits Atg1 and ULK1 function via phosphorylation of Atg1 and ULK1.	6	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	6	7	10	11
This process is negatively regulated by mTOR kinase , which , when activated , blocks the ULK1 complex .	This process is negatively regulated by mTOR kinase, which, when activated, blocks the ULK1 complex.	6	17	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	6	7	16	17
In addition , m-TOR was significantly downregulated by miR-363-3p overexpression , while 4E-BP1 , which known to be negatively regulated by m-TOR , had the opposite pattern of regulation by miR-363-3p .	In addition, m-TOR was significantly downregulated by miR-363-3p overexpression, while 4E-BP1, which known to be negatively regulated by m-TOR, had the opposite pattern of regulation by miR-363-3p.	12	23	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	m-TOR	m-TOR	m-TOR	4E-BP1	4E-BP1	4E-BP1	21	22	12	13
In total , these data indicate that Snail promotes recruitment of capping mRNAs to eIF4F for their active translation in polysomes , and that mTOR regulated cap dependent translation rate is altered by Snail mediated repression of 4E-BP1 .	In total, these data indicate that Snail promotes recruitment of capping mRNAs to eIF4F for their active translation in polysomes, and that mTOR regulated cap dependent translation rate is altered by Snail mediated repression of 4E-BP1.	24	38	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	24	25	37	38
mTOR phosphorylates and inactivate the translation inhibitor 4E-BP1 , inducing its dissociation from the translation initiation factor eIF4E , which can bind the cap structure at the 5 ' termini of mRNAs , thereby allowing cap dependent translation ( in fact , dephosphorylated 4E-BP1 binds and inhibits eIF4E ) of proteins involved in cell proliferation and survival [ XREF_BIBR ] .	mTOR phosphorylates and inactivate the translation inhibitor 4E-BP1, inducing its dissociation from the translation initiation factor eIF4E, which can bind the cap structure at the 5 ' termini of mRNAs, thereby allowing cap dependent translation (in fact, dephosphorylated 4E-BP1 binds and inhibits eIF4E) of proteins involved in cell proliferation and survival [XREF_BIBR].	0	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	0	1	7	8
Additional phosphorylation of 4E-BPs on Thr 37 or Thr 46 by mammalian target of rapamycin [ mTOR , also known as FKBP-12-rapamycin-associated protein ( FRAP ) ] , S6 kinase p70 ( S6K ) , MAPKs , or PKC causes release of 4E-BP1 from eIF4E , leading to the subsequent assembly of the translation initiation complex [ XREF_BIBR - XREF_BIBR ] .	Additional phosphorylation of 4E-BPs on Thr 37 or Thr 46 by mammalian target of rapamycin [mTOR, also known as FKBP-12-rapamycin-associated protein (FRAP)], S6 kinase p70 (S6K), MAPKs, or PKC causes release of 4E-BP1 from eIF4E, leading to the subsequent assembly of the translation initiation complex [XREF_BIBR - XREF_BIBR].	1	43	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mammalian target of rapamycin	phosphorylation of 4E-BPs on Thr 37 or Thr 46 by mammalian target of rapamycin [mTOR, also known as FKBP-12-rapamycin-associated protein (FRAP)], S6 kinase p70	mammalian target of rapamycin	4E-BP1	4E-BP1	4e-bp1	11	15	42	43
We observed that angiogenic stimulation of BM endothelial cells activates mTOR and engages its downstream pathways 4E-BP1 and S6K1 , which are inhibited by the mTOR specific blockers rapamycin and CCI-779 .	We observed that angiogenic stimulation of BM endothelial cells activates mTOR and engages its downstream pathways 4E-BP1 and S6K1, which are inhibited by the mTOR specific blockers rapamycin and CCI-779.	9	28	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	25	26	16	17
Thus , induction of apoptosis by paclitaxel and inhibition of mTOR by rapamycin both simultaneously decrease the availability of 4E-BP-1 , and this may be a plausible explanation for the potentiation of apoptosis by mTOR inhibition in the setting of cytotoxic injury .	Thus, induction of apoptosis by paclitaxel and inhibition of mTOR by rapamycin both simultaneously decrease the availability of 4E-BP-1, and this may be a plausible explanation for the potentiation of apoptosis by mTOR inhibition in the setting of cytotoxic injury.	4	20	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4E-BP-1	4E-BP-1	4E-BP-1	10	11	19	20
PI3P recruits proteins containing FYVE or PX to enhance phosphorylation and activation of mTOR , which finally inhibits 4EBP-1 and activates S6K1 [ XREF_BIBR ] .	PI3P recruits proteins containing FYVE or PX to enhance phosphorylation and activation of mTOR, which finally inhibits 4EBP-1 and activates S6K1 [XREF_BIBR].	9	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	phosphorylation and activation of mTOR	mtor	4EBP-1	4EBP-1	4ebp-1	13	14	18	19
mTOR suppression consequently inhibited the activation of mTOR downstream targets p70S6K and 4E-BP-1 .	mTOR suppression consequently inhibited the activation of mTOR downstream targets p70S6K and 4E-BP-1.	0	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP-1	4E-BP-1	4E-BP-1	0	1	12	13
Assessment of downstream signalling indicated that mTOR kinase inhibitors blocked the phosphorylation of the mTORC1 targets S6 and 4EBP1 ( XREF_FIG ) .	Assessment of downstream signalling indicated that mTOR kinase inhibitors blocked the phosphorylation of the mTORC1 targets S6 and 4EBP1 (XREF_FIG).	6	19	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	6	7	18	19
This partial dissociation of mTOR and Raptor is enough to prevent S6K , but not 4E-BP1 , phosphorylation ( XREF_FIG ) .	This partial dissociation of mTOR and Raptor is enough to prevent S6K, but not 4E-BP1, phosphorylation (XREF_FIG).	2	17	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	4	5	15	16
Here , we show that VV activated host PI3K to stimulate downstream mammalian target of rapamycin ( mTOR ) , a kinase that inactivates the translational repressor 4E-BP1 .	Here, we show that VV activated host PI3K to stimulate downstream mammalian target of rapamycin (mTOR), a kinase that inactivates the translational repressor 4E-BP1.	15	28	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	17	18	27	28
However , knockdown of raptor , rictor , or mTOR by siRNA did not cause apoptosis or loss of p4EBP1 ( XREF_SUPPLEMENTARY ) , supporting mTOR independent 4E-BP1 phosphorylation in CRC cells .	However, knockdown of raptor, rictor, or mTOR by siRNA did not cause apoptosis or loss of p4EBP1 (XREF_SUPPLEMENTARY), supporting mTOR independent 4E-BP1 phosphorylation in CRC cells.	2	21	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	p4EBP1	p4EBP1	p4EBP1	9	10	19	20
With mTOR inhibition and down-regulation of p70S6K and 4E-BP1 , our data further depicted an essential role of RBM20 expression through activation of downstream effectors of mTOR signalling in the regulation of titin splicing ( depicted in XREF_FIG ) .	With mTOR inhibition and down-regulation of p70S6K and 4E-BP1, our data further depicted an essential role of RBM20 expression through activation of downstream effectors of mTOR signalling in the regulation of titin splicing (depicted in XREF_FIG).	1	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	1	2	8	9
Thus , AKT signaling activates elF4E through inhibition of 4E-BP1 by mTOR , which promotes the cap dependent translation of many target mRNAs essential for proliferation , including cyclin D1 and c-Myc [ XREF_BIBR , XREF_BIBR ] .	Thus, AKT signaling activates elF4E through inhibition of 4E-BP1 by mTOR, which promotes the cap dependent translation of many target mRNAs essential for proliferation, including cyclin D1 and c-Myc [XREF_BIBR, XREF_BIBR].	4	14	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	11	12	9	10
In contrast , in AMPK KO MEFs , silymarin treatment no longer inhibited mTOR phosphorylation or increased the mobility of 4EBP1 , although higher doses of silymarin still partly inhibited S6K phosphorylation ( XREF_FIG ) .	In contrast, in AMPK KO MEFs, silymarin treatment no longer inhibited mTOR phosphorylation or increased the mobility of 4EBP1, although higher doses of silymarin still partly inhibited S6K phosphorylation (XREF_FIG).	8	21	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	silymarin treatment no longer inhibited mTOR phosphorylation	mtor	4EBP1	4EBP1	4ebp1	13	14	20	21
After its phosphorylation by mTOR , 4E-BP1 is inactivated , leading to its dissociation from eIF4E .	After its phosphorylation by mTOR, 4E-BP1 is inactivated, leading to its dissociation from eIF4E.	2	9	inactivated	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	4	5	6	7
When cells are exposed to external stimuli , 4EBP1 is inactivated by activated mTOR which causes dissociation from eIF-4E .	When cells are exposed to external stimuli, 4EBP1 is inactivated by activated mTOR which causes dissociation from eIF-4E.	8	15	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	13	14	8	9
The blockade of mTOR signaling with Torin1 , but not rapamycin , disrupts the assembly of the eIF4F complex and increases the association of the translational repressor 4EBP1 to the 7-methylguanosine cap binding complex .	The blockade of mTOR signaling with Torin1, but not rapamycin, disrupts the assembly of the eIF4F complex and increases the association of the translational repressor 4EBP1 to the 7-methylguanosine cap binding complex.	3	28	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	3	4	27	28
With regards to cell cycle progression , inhibition of 4E-BP1 by mTOR is required for promoting expression of Cyclin D3 [ XREF_BIBR ] .	With regards to cell cycle progression, inhibition of 4E-BP1 by mTOR is required for promoting expression of Cyclin D3 [XREF_BIBR].	7	12	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	11	12	9	10
Rapamycin , an inhibitor of mammalian target of rapamycin ( mTOR ) , suppressed leucine induced activation of p70 S6 kinase and 4E-BP1 and negated the stimulatory effect of leucine on HGF production .	Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), suppressed leucine induced activation of p70 S6 kinase and 4E-BP1 and negated the stimulatory effect of leucine on HGF production.	5	23	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	4E-BP1	4E-BP1	4E-BP1	5	9	22	23
Phosphorylation of mTOR leads to more phosphorylation and inactivation of the repressor of mRNA translation 4E-BP1 ( eukaryotic initiation factor 4E binding protein ) .	Phosphorylation of mTOR leads to more phosphorylation and inactivation of the repressor of mRNA translation 4E-BP1 (eukaryotic initiation factor 4E binding protein).	0	19	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	Phosphorylation of mTOR	mtor	4E-BP1	4E-BP1	4e-bp1	2	3	15	16
PHAS-I is inhibited by mTOR , while S6K is activated .	PHAS-I is inhibited by mTOR, while S6K is activated.	0	5	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	PHAS-I	PHAS-I	PHAS-I	4	5	0	1
mTOR , when coupled with other proteins , inhibits 4EBP1 , which is a translation repressor .	mTOR, when coupled with other proteins, inhibits 4EBP1, which is a translation repressor.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	0	1	9	10
MG-2477 treatment also induced a sharp decrease in the phosphorylation of the mTOR targets p70 ribosomal protein S6 kinase and 4E-BP1 , revealing a potent inhibitory effect of MG-2477 treatment on Akt and mTOR signaling .	MG-2477 treatment also induced a sharp decrease in the phosphorylation of the mTOR targets p70 ribosomal protein S6 kinase and 4E-BP1, revealing a potent inhibitory effect of MG-2477 treatment on Akt and mTOR signaling.	9	22	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	phosphorylation of the mTOR	mtor	4E-BP1	4E-BP1	4e-bp1	12	13	20	21
In the present study , we found that mTOR signaling promotes Vip mRNA translation by repressing 4E-BP1 .	In the present study, we found that mTOR signaling promotes Vip mRNA translation by repressing 4E-BP1.	8	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	8	9	16	17
Chronic alcohol intake significantly dampened whole body glucose tolerance , enhanced expression of caspase-3 and mTOR , reduced p70s6k and 4E-BP1 with little effect on Akt signaling in alcohol consuming mice .	Chronic alcohol intake significantly dampened whole body glucose tolerance, enhanced expression of caspase-3 and mTOR, reduced p70s6k and 4E-BP1 with little effect on Akt signaling in alcohol consuming mice.	11	21	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	expression of caspase-3 and mTOR	mtor	4E-BP1	4E-BP1	4e-bp1	15	16	20	21
mTOR , a central regulator of cell metabolism , growth , proliferation and survival XREF_BIBR , deactivates 4E-BP1 XREF_BIBR .	mTOR, a central regulator of cell metabolism, growth, proliferation and survival XREF_BIBR, deactivates 4E-BP1 XREF_BIBR.	0	18	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	0	1	17	18
Then phosphorylated mTOR ( p-mTOR ) will activate P70S6K and inhibit 4EBP1 , regulating ribosome biogenesis and protein synthesis [ XREF_BIBR ] .	Then phosphorylated mTOR (p-mTOR) will activate P70S6K and inhibit 4EBP1, regulating ribosome biogenesis and protein synthesis [XREF_BIBR].	1	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	2	3	11	12
Others have attributed the effect of ADI-PEG20 treatment to downregulation of the mTOR pathway and induction of the unfolded protein response 26 , a possibility corroborated by the reduced phosphorylation of the mTOR targets 4E-BP1 and S6 after 72h of arginine deiminase treatment .	Others have attributed the effect of ADI-PEG20 treatment to downregulation of the mTOR pathway and induction of the unfolded protein response 26, a possibility corroborated by the reduced phosphorylation of the mTOR targets 4E-BP1 and S6 after 72h of arginine deiminase treatment.	29	36	targets	Positive_activation_token_1_verb	Negative_activation	Negative_activation	mTOR	phosphorylation of the mTOR	mtor	4E-BP1	4E-BP1	4e-bp1	32	33	34	35
Mammalian target of rapamycin ( mTOR ) , an important downstream target of PI3K and Akt , positively regulates the serine/threonine kinase p70 S6 kinase ( p70S6K ) and eukaryotic translation initiation factor 4E binding protein 1 ( 4E-BP1 ) , which constitutes a main pathway for cell proliferation , survival , differentiation and angiogenesis XREF_BIBR , XREF_BIBR .	Mammalian target of rapamycin (mTOR), an important downstream target of PI3K and Akt, positively regulates the serine/threonine kinase p70 S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which constitutes a main pathway for cell proliferation, survival, differentiation and angiogenesis XREF_BIBR, XREF_BIBR.	0	42	positively regulates	Positive_activation_syntax_1b_verb	Negative_activation	Positive_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	4E-BP1	4E-BP1	4E-BP1	0	4	38	39
In addition , it has been suggested that up-regulation of myostatin expression was caused by inflammatory diseases such as sepsis and deactivated Akt signaling pathway XREF_BIBR .	In addition, it has been suggested that up-regulation of myostatin expression was caused by inflammatory diseases such as sepsis and deactivated Akt signaling pathway XREF_BIBR.	10	25	deactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin expression	myostatin	Akt	Akt	akt	10	11	22	23
Myostatin suppresses Akt signaling and acts via forkhead box protein O1 transcription factors to promote protein breakdown through activation of the ubiquitin-proteasome system ( XREF_FIG ) .	Myostatin suppresses Akt signaling and acts via forkhead box protein O1 transcription factors to promote protein breakdown through activation of the ubiquitin-proteasome system (XREF_FIG).	0	14	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	2	3
For instance we have previously demonstrated that myostatin can inhibit Akt , a critical mediator of insulin mediated glucose uptake .	For instance we have previously demonstrated that myostatin can inhibit Akt, a critical mediator of insulin mediated glucose uptake.	7	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	7	8	10	11
In vivo , Myostatin suppresses heart and skeletal muscle growth by negatively regulating Akt and mTOR related signals [ XREF_BIBR , XREF_BIBR ] .	In vivo, Myostatin suppresses heart and skeletal muscle growth by negatively regulating Akt and mTOR related signals [XREF_BIBR, XREF_BIBR].	1	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	3	4	13	14
Myostatin increases the activity of the ubiquitin-proteasome system and negatively regulates the activity of the Akt pathway , thereby inducing muscle atrophy [ XREF_BIBR ] .	Myostatin increases the activity of the ubiquitin-proteasome system and negatively regulates the activity of the Akt pathway, thereby inducing muscle atrophy [XREF_BIBR].	0	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	15	16
Myostatin and activin suppress Akt activity , leading to disinhibition of FoxO3 and subsequent upregulation of MuRF-1 , Atrogin-1 ( or MAFbx ) and autophagy genes to induce muscle protein degradation .	Myostatin and activin suppress Akt activity, leading to disinhibition of FoxO3 and subsequent upregulation of MuRF-1, Atrogin-1 (or MAFbx) and autophagy genes to induce muscle protein degradation.	0	5	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	4	5
We found that myostatin inhibition resulted in increased activation of Akt and NFAT3 , while myostatin overexpression caused decreased activation of Akt and NFAT3 .	We found that myostatin inhibition resulted in increased activation of Akt and NFAT3, while myostatin overexpression caused decreased activation of Akt and NFAT3.	3	12	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	3	4	10	11
Furthermore , to cause muscle hypertrophy , AKT kinase may be inhibited by myostatin through partially suppressing protein synthesis .	Furthermore, to cause muscle hypertrophy, AKT kinase may be inhibited by myostatin through partially suppressing protein synthesis.	7	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	AKT	AKT	AKT	13	14	7	8
Here , we provide further insights into the mechanisms by which myostatin regulates skeletal muscle mass by showing that myostatin negatively regulates Akt and mTOR signaling pathway .	Here, we provide further insights into the mechanisms by which myostatin regulates skeletal muscle mass by showing that myostatin negatively regulates Akt and mTOR signaling pathway.	19	26	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	19	20	22	23
It is likely that under conditions of muscle wasting , myostatin can reverse the Akt and mTOR pathway , which is normally responsible for protein synthesis , to inhibit protein synthesis via FoxO , GSK-3beta , or other unknown patterns , leading to the loss of muscle mass [ XREF_BIBR ] .	It is likely that under conditions of muscle wasting, myostatin can reverse the Akt and mTOR pathway, which is normally responsible for protein synthesis, to inhibit protein synthesis via FoxO, GSK-3beta, or other unknown patterns, leading to the loss of muscle mass [XREF_BIBR].	10	17	reverse	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	10	11	14	15
In addition , our data support the hypothesis that myostatin negatively regulates cardiac growth by modulating signaling through the cardiac growth pathways Akt and NFAT .	In addition, our data support the hypothesis that myostatin negatively regulates cardiac growth by modulating signaling through the cardiac growth pathways Akt and NFAT.	9	24	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	9	10	22	23
Amirouche et al ( 2009 ) found that myostatin overexpression suppressed muscle protein synthesis by downregulating Akt and mTOR pathway [ XREF_BIBR ] .	Amirouche et al (2009) found that myostatin overexpression suppressed muscle protein synthesis by downregulating Akt and mTOR pathway [XREF_BIBR].	8	21	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin overexpression	myostatin	Akt	Akt	akt	8	9	16	17
The overexpression of myostatin decreases Akt and mTORC1 components , such as p70S6K1 , S6 , and 4EBP1 .	The overexpression of myostatin decreases Akt and mTORC1 components, such as p70S6K1, S6, and 4EBP1.	1	8	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	overexpression of myostatin	myostatin	Akt	Akt	akt	3	4	5	6
XREF_BIBR Moreover , myostatin signaling can inhibit the PI3K-Akt axis and reduce p70 s6k activation .	XREF_BIBR Moreover, myostatin signaling can inhibit the PI3K-Akt axis and reduce p70 s6k activation.	3	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	PI3K-Akt	PI3K-Akt	PI3K-Akt	3	4	8	9
Myostatin treatment blocks Akt , which reduces MPS via mTORC1 complex assembly and increases MPB by activating the FOXO transcription factors [ XREF_BIBR ] as well as other transcriptional regulators such as SMAD family members [ XREF_BIBR ] .	Myostatin treatment blocks Akt, which reduces MPS via mTORC1 complex assembly and increases MPB by activating the FOXO transcription factors [XREF_BIBR] as well as other transcriptional regulators such as SMAD family members [XREF_BIBR].	0	13	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	3	4
Myostatin inhibits the Akt and mTOR pathway , activates Fox-O , and decreases satellite cells number and regeneration [ XREF_BIBR , XREF_BIBR ] .	Myostatin inhibits the Akt and mTOR pathway, activates Fox-O, and decreases satellite cells number and regeneration [XREF_BIBR, XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	3	4
In skeletal muscle , myostatin negatively regulates Akt signaling .	In skeletal muscle, myostatin negatively regulates Akt signaling.	4	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	4	5	7	8
In culture experiments , overexpression of myostatin decreases the phosphorylation state of Akt and the dephosphorylates of its downstream target FoxO3a , and silencing myostatin increases the phosphorylation state of Akt and phosphorylates of its downstream target FoxO3a in C2C12 myotubes despite the presence of TNF-alpha .	In culture experiments, overexpression of myostatin decreases the phosphorylation state of Akt and the dephosphorylates of its downstream target FoxO3a, and silencing myostatin increases the phosphorylation state of Akt and phosphorylates of its downstream target FoxO3a in C2C12 myotubes despite the presence of TNF-alpha.	4	15	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	overexpression of myostatin	myostatin	Akt	Akt	akt	6	7	12	13
Stimulation of myostatin and activin signaling in skeletal muscles activates Smad2/3 signaling and inhibits Akt signaling , which increases catabolism of musole proteins .	Stimulation of myostatin and activin signaling in skeletal muscles activates Smad2/3 signaling and inhibits Akt signaling, which increases catabolism of musole proteins.	2	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	2	3	14	15
In a feedback loop , MSTN inhibits IGF-1-dependent prohypertrophic serine/threonine kinase AKT [ XREF_BIBR ] , and inhibition of p38 by MSTN has also been described [ XREF_BIBR ] .	In a feedback loop, MSTN inhibits IGF-1-dependent prohypertrophic serine/threonine kinase AKT [XREF_BIBR], and inhibition of p38 by MSTN has also been described [XREF_BIBR].	5	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MSTN	MSTN	MSTN	AKT	AKT	AKT	5	6	11	12
Myostatin ( MSTN ) mRNA levels as well as downstream SMAD signaling are also down-regulated in humans following one or multiple resistance exercise bouts , and these events likely result in enhanced mTORC1 activity given that MSTN signaling abrogates Akt activation .	Myostatin (MSTN) mRNA levels as well as downstream SMAD signaling are also down-regulated in humans following one or multiple resistance exercise bouts, and these events likely result in enhanced mTORC1 activity given that MSTN signaling abrogates Akt activation.	36	40	abrogates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MSTN	MSTN	MSTN	Akt	Akt	Akt	36	37	39	40
For example , myostatin has been shown to inhibit activation of Akt in phenylephrine treated cardiomyocytes XREF_BIBR and reduce the basal level of phosphorylated Akt in C2C12 myotubes XREF_BIBR .	For example, myostatin has been shown to inhibit activation of Akt in phenylephrine treated cardiomyocytes XREF_BIBR and reduce the basal level of phosphorylated Akt in C2C12 myotubes XREF_BIBR.	3	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	3	4	11	12
Myostatin can reduce protein synthesis by suppressing Akt or increase degradation by elevating FoxO transcription , whilst also impairing satellite cell formation .	Myostatin can reduce protein synthesis by suppressing Akt or increase degradation by elevating FoxO transcription, whilst also impairing satellite cell formation.	0	10	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	7	8
Myostatin also reduces the level of Akt activation in C2C12 undifferentiated myoblasts engineered to overexpress Akt XREF_BIBR .	Myostatin also reduces the level of Akt activation in C2C12 undifferentiated myoblasts engineered to overexpress Akt XREF_BIBR.	0	7	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	6	7
Myostatin negatively regulates the activity of the Akt pathway , which promotes protein synthesis , and increases the activity of the ubiquitin-proteasome system to induce atrophy .	Myostatin negatively regulates the activity of the Akt pathway, which promotes protein synthesis, and increases the activity of the ubiquitin-proteasome system to induce atrophy.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	7	8
Myostatin also acts to block muscle size and the AKT pathway .	Myostatin also acts to block muscle size and the AKT pathway.	0	10	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	AKT	AKT	AKT	0	1	9	10
Since phospho-S6 protein levels remained unchanged after training , the higher myostatin levels after PT were unlikely to inhibit Akt and mTOR signalling but rather seem to have increased the rate of protein degradation which is reflected by higher MuRF-1 mRNA levels .	Since phospho-S6 protein levels remained unchanged after training, the higher myostatin levels after PT were unlikely to inhibit Akt and mTOR signalling but rather seem to have increased the rate of protein degradation which is reflected by higher MuRF-1 mRNA levels.	11	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin levels	myostatin	Akt	Akt	akt	11	12	19	20
Recently , Amirouche and workers have shown that MSTN negatively regulates Akt and mTOR signalling pathway [ XREF_BIBR ] .	Recently, Amirouche and workers have shown that MSTN negatively regulates Akt and mTOR signalling pathway [XREF_BIBR].	8	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MSTN	MSTN	MSTN	Akt	Akt	Akt	8	9	11	12
Myostatin negatively regulates Akt by dephosphorylation of serine 473 which induces Foxo transcription factors and activates the expression of components of the ubiquitin-proteasome pathway such as MAFbx , to degrade muscle protein .	Myostatin negatively regulates Akt by dephosphorylation of serine 473 which induces Foxo transcription factors and activates the expression of components of the ubiquitin-proteasome pathway such as MAFbx, to degrade muscle protein.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	3	4
Current mTOR inhibition causes the upregulation of the Ras and Raf pathway and inhibition of the negative feedback loop of IRS1 while inhibition of IGF signaling has been shown to inhibit growth and induce death of cancer cells with upregulated PI3K .	Current mTOR inhibition causes the upregulation of the Ras and Raf pathway and inhibition of the negative feedback loop of IRS1 while inhibition of IGF signaling has been shown to inhibit growth and induce death of cancer cells with upregulated PI3K.	1	21	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS1	IRS1	IRS1	1	2	20	21
Although activation of mTOR is necessary and sufficient to induce IRS-1 degradation , our data suggest that the phosphorylation of mTOR did not differ between the two groups .	Although activation of mTOR is necessary and sufficient to induce IRS-1 degradation, our data suggest that the phosphorylation of mTOR did not differ between the two groups.	1	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	3	4	10	11
mTOR dependent degradation of IRS-1 is required for the initiation of IGF-IR internalization .	mTOR dependent degradation of IRS-1 is required for the initiation of IGF-IR internalization.	0	5	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	0	1	4	5
Calorie restriction and/or GH resistance decreases mTOR signaling and phosphoSer inhibition of IRS-1 in skeletal muscle .	Calorie restriction and/or GH resistance decreases mTOR signaling and phosphoSer inhibition of IRS-1 in skeletal muscle.	6	15	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	6	7	12	13
A negative feedback loop has been described , whereby mTOR and S6K1 activation attenuates PI3K signaling by suppressing insulin receptor substrate-1 ( IRS1 ) function , a mediator of insulin receptor- dependent activation of PI3K .	A negative feedback loop has been described, whereby mTOR and S6K1 activation attenuates PI3K signaling by suppressing insulin receptor substrate-1 (IRS1) function, a mediator of insulin receptor- dependent activation of PI3K.	9	21	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	9	10	18	21
In these cells , Shh upregulates IRS-1 by interfering with mTOR mediated IRS-1 degradation , and by enhancing IRS-1 translation .	In these cells, Shh upregulates IRS-1 by interfering with mTOR mediated IRS-1 degradation, and by enhancing IRS-1 translation.	10	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	10	11	12	13
In early studies mTOR inhibition led to p70 ribosomal protein S6 kinase ( S6K ) suppression , IRS1 upregulation , and PI3K-AKT activation 181 .	In early studies mTOR inhibition led to p70 ribosomal protein S6 kinase (S6K) suppression, IRS1 upregulation, and PI3K-AKT activation 181.	3	18	led	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS1	IRS1	IRS1	3	4	17	18
Therefore , mTOR inhibition will induce IRS-1 activation releasing the inhibition mediated by S6K1 and provoking the activation of AKT via an insulin growth factor receptor 1 ( IGF-1R ) dependent signaling process .	Therefore, mTOR inhibition will induce IRS-1 activation releasing the inhibition mediated by S6K1 and provoking the activation of AKT via an insulin growth factor receptor 1 (IGF-1R) dependent signaling process.	2	7	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	2	3	6	7
Inhibition of mTOR has been shown to inhibit proteasomal degradation of IRS-1 enhancing signaling through the PI-3 kinase and Akt pathway .	Inhibition of mTOR has been shown to inhibit proteasomal degradation of IRS-1 enhancing signaling through the PI-3 kinase and Akt pathway.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	2	3	11	12
UA agonizes signaling of insulin and IGF -1 receptor and elicits AMPK mediated p53 activation , which is abolished by mTOR mediated IRS-1 degradation downstream of IGF-1 receptor signaling [ XREF_BIBR ] .	UA agonizes signaling of insulin and IGF -1 receptor and elicits AMPK mediated p53 activation, which is abolished by mTOR mediated IRS-1 degradation downstream of IGF-1 receptor signaling [XREF_BIBR].	18	23	mediated	Positive_early_activation	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	20	21	22	23
Rapamycin has been reported to have alternate effects on Akt phosphorylation ; prolonged rapamycin exposure has been shown to inhibit assembly of mTORC2 , thereby inhibiting Akt , and mTOR inhibition has also been described to induce insulin receptor substrate-1 ( IRS-1 ) , leading to Akt activation .	Rapamycin has been reported to have alternate effects on Akt phosphorylation; prolonged rapamycin exposure has been shown to inhibit assembly of mTORC2, thereby inhibiting Akt, and mTOR inhibition has also been described to induce insulin receptor substrate-1 (IRS-1), leading to Akt activation.	29	40	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	29	30	37	40
This restoration of IRS-1 mRNA abundance by sustained rapamycin treatment is reversed by actinomycin D ( XREF_FIG ) , indicating that mTOR and S6K1 signaling likely reduces IRS-1 mRNA abundance primarily at the level of gene transcription .	This restoration of IRS-1 mRNA abundance by sustained rapamycin treatment is reversed by actinomycin D (XREF_FIG), indicating that mTOR and S6K1 signaling likely reduces IRS-1 mRNA abundance primarily at the level of gene transcription.	21	29	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	21	22	27	28
Mechanistically , PI3K and mTOR inhibition increased IRS1 dependent activation of JAK2 and STAT5 and secretion of IL-8 in several cell lines and primary breast tumors .	Mechanistically, PI3K and mTOR inhibition increased IRS1 dependent activation of JAK2 and STAT5 and secretion of IL-8 in several cell lines and primary breast tumors.	2	9	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS1	IRS1	IRS1	4	5	7	8
Thus , the CUL7 E3 appears to be responsible for mediating mTOR dependent degradation of IRS-1 , thereby functioning as a critical component of the mTOR and IRS -1 negative feedback loop , which fine-tunes the PI3K activity in accordance with the magnitude and duration of mTOR and S6K activities .	Thus, the CUL7 E3 appears to be responsible for mediating mTOR dependent degradation of IRS-1, thereby functioning as a critical component of the mTOR and IRS -1 negative feedback loop, which fine-tunes the PI3K activity in accordance with the magnitude and duration of mTOR and S6K activities.	11	16	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	11	12	15	16
This suggests that inhibiting mTOR can promote IRS1 stabilization in CGNPs .	This suggests that inhibiting mTOR can promote IRS1 stabilization in CGNPs.	3	8	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS1	IRS1	IRS1	4	5	7	8
Interestingly , inhibition of mTOR partially prevented the decrease in IRS1 protein ( decrease to 74 % compared to control ) .	Interestingly, inhibition of mTOR partially prevented the decrease in IRS1 protein (decrease to 74% compared to control).	2	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS1	IRS1	IRS1	4	5	10	11
For example , mTOR and its downstream S6K can inhibit the upstream insulin signaling molecule IRS-1 to regulate glucose uptake and protein synthesis [ XREF_BIBR , XREF_BIBR ] .	For example, mTOR and its downstream S6K can inhibit the upstream insulin signaling molecule IRS-1 to regulate glucose uptake and protein synthesis [XREF_BIBR, XREF_BIBR].	3	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	3	4	15	16
On the other hand , chronic beta-cell hyperfunction , a consequence of excessive leucine exposure , results in accelerated beta-cell apoptosis and eventual secretory deficiency through a negative feedback loop involving the mTOR dependent inhibition of IRS-1 [ XREF_BIBR ] .	On the other hand, chronic beta-cell hyperfunction, a consequence of excessive leucine exposure, results in accelerated beta-cell apoptosis and eventual secretory deficiency through a negative feedback loop involving the mTOR dependent inhibition of IRS-1 [XREF_BIBR].	32	38	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	32	33	36	37
mTOR can function in a negative feedback loop and produce glucose intolerance by inhibiting the insulin receptor substrate 1 ( IRS-1 ) .	mTOR can function in a negative feedback loop and produce glucose intolerance by inhibiting the insulin receptor substrate 1 (IRS-1).	0	19	produce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	0	1	15	19
XREF_BIBR - XREF_BIBR Recent data suggest that the inhibition of mTOR relieves negative feedback regulation of IRS-1 , resulting in increased IRS-1 expression and activation of AKT .	XREF_BIBR - XREF_BIBR Recent data suggest that the inhibition of mTOR relieves negative feedback regulation of IRS-1, resulting in increased IRS-1 expression and activation of AKT.	8	17	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	10	11	16	17
The transcription factor EB ( TFEB ) , a master regulator of lysosomal and autophagy genes , which is negatively regulated by mTOR , is substantially up-regulated in C9orf72 loss-of-function animal and cellular models .	The transcription factor EB (TFEB), a master regulator of lysosomal and autophagy genes, which is negatively regulated by mTOR, is substantially up-regulated in C9orf72 loss-of-function animal and cellular models.	1	23	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	transcription factor EB	transcription factor EB	transcription factor EB	22	23	1	4
Importantly , mTOR inhibition activated TFEB for a limited duration of 1.5 hours , and thereafter the cell population was progressively re-inactivated , with distinct kinetics for Torin1 and nutrient deprivation treatments .	Importantly, mTOR inhibition activated TFEB for a limited duration of 1.5 hours, and thereafter the cell population was progressively re-inactivated, with distinct kinetics for Torin1 and nutrient deprivation treatments.	2	6	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	2	3	5	6
Concomitantly , mTOR also inhibits the Transcription Factor EB ( TFEB ) , a master regulator of lysosome biogenesis .	Concomitantly, mTOR also inhibits the Transcription Factor EB (TFEB), a master regulator of lysosome biogenesis.	2	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Transcription Factor EB	Transcription Factor EB	Transcription Factor EB	2	3	6	9
While we show that mTOR activation maximally inhibits TFEB , mTOR inhibition only fractionally activated TFEB .	While we show that mTOR activation maximally inhibits TFEB, mTOR inhibition only fractionally activated TFEB.	10	16	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	10	11	15	16
Several lines of evidence indicate that mTOR inhibits TFEB activity .	Several lines of evidence indicate that mTOR inhibits TFEB activity.	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	6	7	8	9
This is consistent with an earlier report showing that mTOR colocalizes with TFEB and that inhibition of mTOR activates TFEB , which in turns facilitates lysosomal biogenesis [ XREF_BIBR ] .	This is consistent with an earlier report showing that mTOR colocalizes with TFEB and that inhibition of mTOR activates TFEB, which in turns facilitates lysosomal biogenesis [XREF_BIBR].	15	24	activates	Positive_activation_token_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	17	18	19	20
Conversely , pharmacological inhibition of mTOR resulting from PEX5 depletion during nutrient starvation activates TFEB by promoting nuclear localization of the protein .	Conversely, pharmacological inhibition of mTOR resulting from PEX5 depletion during nutrient starvation activates TFEB by promoting nuclear localization of the protein.	3	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	5	6	14	15
Inhibition of mTOR also triggered nuclear localization of TFEB , a transcription factor that regulates lysosome biogenesis and function , but the rescue phenotype did not require the presence of TFEB .	Inhibition of mTOR also triggered nuclear localization of TFEB, a transcription factor that regulates lysosome biogenesis and function, but the rescue phenotype did not require the presence of TFEB.	0	12	triggered	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	2	3	8	9
Lysosomal biogenesis can be activated by the transcription factor EB ( TFEB ) , which is negatively regulated by mTOR ( Pena-Llopis et al ., 2011 ) .	Lysosomal biogenesis can be activated by the transcription factor EB (TFEB), which is negatively regulated by mTOR (Pena-Llopis et al., 2011).	4	21	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	19	20	11	12
Previous studies show that mTOR inhibition is sufficient to induce nuclear shuttling of TFEB without inhibition of phosphatase activity XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , whereas our results demonstrate that PP2A modulates the FGF21-TFEB signaling axis during fasting .	Previous studies show that mTOR inhibition is sufficient to induce nuclear shuttling of TFEB without inhibition of phosphatase activity XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, whereas our results demonstrate that PP2A modulates the FGF21-TFEB signaling axis during fasting.	4	14	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	4	5	13	14
Pharmacological suppression of mTOR can activate TFEB through driving its dephosphorylation at serine residues and thereby facilitating its nuclear translocation ; after translocation into the nucleus , TFEB can regulate lysosomal biogenesis and autophagosome formation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Pharmacological suppression of mTOR can activate TFEB through driving its dephosphorylation at serine residues and thereby facilitating its nuclear translocation; after translocation into the nucleus, TFEB can regulate lysosomal biogenesis and autophagosome formation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	7	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	3	4	6	7
Although TFEB is negatively regulated by mTOR [ XREF_BIBR ] , we detected concurrent mTOR and TFEB activation in SBMA glycolytic , but not oxidative muscles , providing evidence that in disease conditions the two signaling pathways can be simultaneously activated .	Although TFEB is negatively regulated by mTOR [XREF_BIBR], we detected concurrent mTOR and TFEB activation in SBMA glycolytic, but not oxidative muscles, providing evidence that in disease conditions the two signaling pathways can be simultaneously activated.	1	8	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	6	7	1	2
XREF_BIBR TFEB is phosphorylated by MTOR and is also associated with the lysosomal surface in well fed cells , and it gets released from there when MTOR is inactivated and released , enabling TFEB to translocate to the nucleus and induce the expression of its target genes .	XREF_BIBR TFEB is phosphorylated by MTOR and is also associated with the lysosomal surface in well fed cells, and it gets released from there when MTOR is inactivated and released, enabling TFEB to translocate to the nucleus and induce the expression of its target genes.	26	34	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MTOR	MTOR	MTOR	TFEB	TFEB	TFEB	26	27	33	34
TFEB activity is inhibited by mTOR phosphorylation , which signals its cytoplasmic retention .	TFEB activity is inhibited by mTOR phosphorylation, which signals its cytoplasmic retention.	0	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR phosphorylation	mtor	TFEB	TFEB	tfeb	5	6	0	1
This could be mediated through enhanced activity of the master regulator of lysosomal biosynthesis , the transcription factor EB , which is negatively regulated by mTOR ( XREF_FIG ) .	This could be mediated through enhanced activity of the master regulator of lysosomal biosynthesis, the transcription factor EB, which is negatively regulated by mTOR (XREF_FIG).	16	27	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	transcription factor EB	transcription factor EB	transcription factor EB	25	26	16	19
The observation that rapamycin treatment can rescue qNSC activation in aged animals supports this possibility , as mTOR is known to inhibit TFEB .	The observation that rapamycin treatment can rescue qNSC activation in aged animals supports this possibility, as mTOR is known to inhibit TFEB.	17	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	17	18	22	23
Previous studies indicate that mTOR signalling inhibits lysosomal biogenesis and autophagy by negatively regulating the transcription factor TFEB 21 .	Previous studies indicate that mTOR signalling inhibits lysosomal biogenesis and autophagy by negatively regulating the transcription factor TFEB 21.	4	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	4	5	17	18
TFEB function is negatively regulated by mTOR and ERK .	TFEB function is negatively regulated by mTOR and ERK.	0	8	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	6	7	0	1
mTOR inhibition rapidly activates TFEB in a fraction of cells , for a limited duration , with distinct TFEB subpopulation re-inactivation dynamics in response to Torin1 vs. nutrient deprivation .	mTOR inhibition rapidly activates TFEB in a fraction of cells, for a limited duration, with distinct TFEB subpopulation re-inactivation dynamics in response to Torin1 vs. nutrient deprivation.	0	5	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	0	1	4	5
It has been shown that mTOR significantly inhibits the p73 factor and the transcription factor EB ( TFEB ) that can induce autophagy through the upregulation of autophagic proteins such as Atg7 42 .	It has been shown that mTOR significantly inhibits the p73 factor and the transcription factor EB (TFEB) that can induce autophagy through the upregulation of autophagic proteins such as Atg7 42.	5	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	transcription factor EB	transcription factor EB	transcription factor EB	5	6	13	16
mTOR inhibits TFEB by phosphorylation , thereby coupling autophagy induction and lysosomal activity [ XREF_BIBR ] .	mTOR inhibits TFEB by phosphorylation, thereby coupling autophagy induction and lysosomal activity [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	0	1	2	3
TFEB nuclear localization is normally inhibited by mTOR when growth and nutritional signals are adequate .	TFEB nuclear localization is normally inhibited by mTOR when growth and nutritional signals are adequate.	0	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	7	8	0	1
In addition to this direct metabolic regulation , mTOR inhibition also relieves its inhibition of TFEB which , in turn , stimulates lysosomal biogenesis to help with the increased delivery of material to lysosomes caused by increased autophagy .	In addition to this direct metabolic regulation, mTOR inhibition also relieves its inhibition of TFEB which, in turn, stimulates lysosomal biogenesis to help with the increased delivery of material to lysosomes caused by increased autophagy.	8	16	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	8	9	15	16
Further , mTOR phosphorylates and cytoplasmically sequesters the transcription factor EB ( TFEB ) , a master regulator of autophagic and lysosomal genes , thereby inhibiting autophagy at the level of gene expression .	Further, mTOR phosphorylates and cytoplasmically sequesters the transcription factor EB (TFEB), a master regulator of autophagic and lysosomal genes, thereby inhibiting autophagy at the level of gene expression.	2	11	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	transcription factor EB	transcription factor EB	transcription factor EB	2	3	8	11
We then turned our attention to the three apoAI methionine residues , which were previously implicated by Heinecke and colleagues in the MPO induced loss of apoAI function XREF_BIBR .	We then turned our attention to the three apoAI methionine residues, which were previously implicated by Heinecke and colleagues in the MPO induced loss of apoAI function XREF_BIBR.	19	28	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	apoAI	apoAI	apoAI	22	23	26	27
Therefore , we hypothesized that MPO mediated ApoA-I oxidation would impair its promotion of reverse cholesterol transport ( RCT ) in vivo and the beneficial effects on atherosclerotic plaques .	Therefore, we hypothesized that MPO mediated ApoA-I oxidation would impair its promotion of reverse cholesterol transport (RCT) in vivo and the beneficial effects on atherosclerotic plaques.	5	8	mediated	Positive_early_activation	Negative_activation	Negative_activation	MPO	MPO	MPO	ApoA-I	ApoA-I	ApoA-I	5	6	7	8
Because MPO is secreted into the pericellular environment and because the membrane associated NADPH oxidase of macrophages is an important source of H 2 O 2 ( which the enzyme needs for its oxidative reactions ) , we determined whether MPO dependent oxidation prevented apoA-I from promoting cholesterol efflux from cells .	Because MPO is secreted into the pericellular environment and because the membrane associated NADPH oxidase of macrophages is an important source of H 2 O 2 (which the enzyme needs for its oxidative reactions), we determined whether MPO dependent oxidation prevented apoA-I from promoting cholesterol efflux from cells.	40	45	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	40	41	44	45
MPO was shown to reduce the RCT function of apoA-I [ XREF_BIBR - XREF_BIBR ] , and apoA-I chlorination by MPO impaired ABCA1 dependent cholesterol transport [ XREF_BIBR ] .	MPO was shown to reduce the RCT function of apoA-I [XREF_BIBR - XREF_BIBR], and apoA-I chlorination by MPO impaired ABCA1 dependent cholesterol transport [XREF_BIBR].	0	11	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	0	1	9	10
Given that MPO can act on apoA-I and impairs apoA-I and HDL function , it is intriguing to speculate that MPO mediated modifications may trigger HDL trafficking to the autophagosome and autophagy , resulting in clearance of these functionally impaired HDL particles and making way for intact HDL to reduce inflammation .	Given that MPO can act on apoA-I and impairs apoA-I and HDL function, it is intriguing to speculate that MPO mediated modifications may trigger HDL trafficking to the autophagosome and autophagy, resulting in clearance of these functionally impaired HDL particles and making way for intact HDL to reduce inflammation.	2	12	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	2	3	9	10
MPO oxidation also reduces the ability of apoA-I to exchange between lipid associated and lipid-free states , a property of apoA-I that is critical for ABCA1 mediated cholesterol efflux XREF_BIBR .	MPO oxidation also reduces the ability of apoA-I to exchange between lipid associated and lipid-free states, a property of apoA-I that is critical for ABCA1 mediated cholesterol efflux XREF_BIBR.	0	8	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	0	1	7	8
The present studies thus suggest that apoAI tryptophan residues are responsible for MPO dependent oxidative loss of apoAI function in vivo .	The present studies thus suggest that apoAI tryptophan residues are responsible for MPO dependent oxidative loss of apoAI function in vivo.	12	18	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	MPO	MPO	MPO	apoAI	apoAI	apoAI	12	13	17	18
HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation , whereupon PON1 binding partially inhibits MPO activity , and MPO promotes site specific oxidative modification and impairment of PON1 and APOA1 function .	HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site specific oxidative modification and impairment of PON1 and APOA1 function.	24	36	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	APOA1	APOA1	APOA1	24	25	35	36
MPO impairs the ability of apoA-I to promote cholesterol transport by ABCA1 .	MPO impairs the ability of apoA-I to promote cholesterol transport by ABCA1.	0	6	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	0	1	5	6
Our previous work showed that tryptophan oxidation in apoAI was responsible for the myeloperoxidase mediated loss of apoAI function and impairment of cholesterol efflux capacity 11 .	Our previous work showed that tryptophan oxidation in apoAI was responsible for the myeloperoxidase mediated loss of apoAI function and impairment of cholesterol efflux capacity 11.	13	18	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	myeloperoxidase	myeloperoxidase	myeloperoxidase	apoAI	apoAI	apoAI	13	14	17	18
Lysine modification by MPO is an attractive candidate to be responsible for MPO induced loss of apoAI function as we previously demonstrated that apoAI lysine residues can undergo modification by MPO XREF_BIBR , and that extensive chemical modification of apoAI lysine residues that alter its positive charge led to loss of apoAI cholesterol acceptor activity XREF_BIBR .	Lysine modification by MPO is an attractive candidate to be responsible for MPO induced loss of apoAI function as we previously demonstrated that apoAI lysine residues can undergo modification by MPO XREF_BIBR, and that extensive chemical modification of apoAI lysine residues that alter its positive charge led to loss of apoAI cholesterol acceptor activity XREF_BIBR.	12	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	apoAI	apoAI	apoAI	12	13	16	17
HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation , with PON1 binding partially inhibiting MPO activity , and MPO promoting site specific oxidative modification and impairment of PON1 and ApoA-I function [ XREF_BIBR ] .	HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, with PON1 binding partially inhibiting MPO activity, and MPO promoting site specific oxidative modification and impairment of PON1 and ApoA-I function [XREF_BIBR].	24	38	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	ApoA-I	ApoA-I	ApoA-I	24	25	35	36
MPO is known to inhibit cholesterol efflux from lipid-laden macrophages by oxidizing apoA-I in HDL XREF_BIBR .	MPO is known to inhibit cholesterol efflux from lipid-laden macrophages by oxidizing apoA-I in HDL XREF_BIBR.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	0	1	12	13
Here , we describe how MPO dependent chlorination impairs the ability of apolipoprotein A-I ( apoA-I ) , HDL ' s major protein , to transport cholesterol by the ATP binding cassette transporter A1 ( ABCA1 ) pathway .	Here, we describe how MPO dependent chlorination impairs the ability of apolipoprotein A-I (apoA-I), HDL 's major protein, to transport cholesterol by the ATP binding cassette transporter A1 (ABCA1) pathway.	5	14	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MPO	MPO	MPO	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	5	6	12	14
Since Msi1 activates the Notch pathway by directly targeting Numb , our findings suggest a common endpoint between the Msi1 and ErbB2 pathways that merits further examination in a larger subset of patients .	Since Msi1 activates the Notch pathway by directly targeting Numb, our findings suggest a common endpoint between the Msi1 and ErbB2 pathways that merits further examination in a larger subset of patients.	1	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Msi1	Msi1	Msi1	Numb	Numb	Numb	1	2	9	10
However , Numb translation is repressed by MSI1 , which further activates Notch signaling [ XREF_BIBR ] .	However, Numb translation is repressed by MSI1, which further activates Notch signaling [XREF_BIBR].	2	11	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MSI1	MSI1	MSI1	Numb	Numb	Numb	7	8	2	3
Musashi1 may promote maintenance of neural progenitor cells by blocking translation of Numb , a repressor of Notch signaling .	Musashi1 may promote maintenance of neural progenitor cells by blocking translation of Numb, a repressor of Notch signaling.	0	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Musashi1	Musashi1	Musashi1	Numb	Numb	Numb	0	1	12	13
Several observations suggest that MSI1 upregulates Notch and Wnt signaling by repressing the translation of Numb and APC ( adenomatous polyposis coli ) , which act as negative regulators of Notch and Wnt signaling , respectively .	Several observations suggest that MSI1 upregulates Notch and Wnt signaling by repressing the translation of Numb and APC (adenomatous polyposis coli), which act as negative regulators of Notch and Wnt signaling, respectively.	4	16	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MSI1	MSI1	MSI1	Numb	Numb	Numb	4	5	15	16
Thus , in the cytoplasm during mitosis , Msi1 is available to repress translation of Numb and thereby inhibit stable cadherin localization .	Thus, in the cytoplasm during mitosis, Msi1 is available to repress translation of Numb and thereby inhibit stable cadherin localization.	8	18	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msi1	Msi1	Msi1	Numb	Numb	Numb	8	9	15	16
Msi1 blocks translation of Numb , a negative regulator of Notch 4 , as well as Ttk69 , a transcriptional repressor downstream of Notch 5 , and each gene is inherited asymmetrically and separately by the daughter cells .	Msi1 blocks translation of Numb, a negative regulator of Notch 4, as well as Ttk69, a transcriptional repressor downstream of Notch 5, and each gene is inherited asymmetrically and separately by the daughter cells.	0	5	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msi1	Msi1	Msi1	Numb	Numb	Numb	0	1	4	5
Our working model in XREF_FIG shows that in cells with MSI1 overexpression , MSI1 blocks the translation of NUMB and APC mRNA , which leads to the up-regulation of both Notch and Wnt signaling pathways .	Our working model in XREF_FIG shows that in cells with MSI1 overexpression, MSI1 blocks the translation of NUMB and APC mRNA, which leads to the up-regulation of both Notch and Wnt signaling pathways.	13	19	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MSI1	MSI1	MSI1	NUMB	NUMB	NUMB	13	14	18	19
Msi1 dependent suppression of Numb translation has been reported to contribute to the self-renewal of neural stem cells XREF_BIBR .	Msi1 dependent suppression of Numb translation has been reported to contribute to the self-renewal of neural stem cells XREF_BIBR.	0	5	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Msi1	Msi1	Msi1	Numb	Numb	Numb	0	1	4	5
Although the roles of Musashi proteins are far from clear , Msi1 has been shown to block the translation of Numb by binding to the 3 ' UTR of Numb mRNA XREF_BIBR .	Although the roles of Musashi proteins are far from clear, Msi1 has been shown to block the translation of Numb by binding to the 3 ' UTR of Numb mRNA XREF_BIBR.	11	31	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msi1	Msi1	Msi1	Numb	Numb	Numb	11	12	20	21
Numb , a negative regulator of Notch signalling , has been reported to be a target of vertebrate Msi2 in hematopoietic cells XREF_BIBR and Msi1 can repress Numb in NIH3T3 cells XREF_BIBR .	Numb, a negative regulator of Notch signalling, has been reported to be a target of vertebrate Msi2 in hematopoietic cells XREF_BIBR and Msi1 can repress Numb in NIH3T3 cells XREF_BIBR.	22	31	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msi1	Msi1	Msi1	Numb	Numb	Numb	24	25	27	28
Maf1 is a transcriptional inhibitor of tRNA genes and mTOR prevents Maf1 activation through phosphorylation [ XREF_BIBR - XREF_BIBR ] .	Maf1 is a transcriptional inhibitor of tRNA genes and mTOR prevents Maf1 activation through phosphorylation [XREF_BIBR - XREF_BIBR].	4	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	Maf1	Maf1	Maf1	9	10	11	12
For example , the transcription factor Myc , which is over-expressed and amplified in many tumors , promotes tRNA transcription by directly binding to tRNA genes , 38 whereas the mTOR signaling complex inactivates the Pol III transcriptional repressor Maf1 .	For example, the transcription factor Myc, which is over-expressed and amplified in many tumors, promotes tRNA transcription by directly binding to tRNA genes, 38 whereas the mTOR signaling complex inactivates the Pol III transcriptional repressor Maf1.	30	40	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	Maf1	Maf1	Maf1	30	31	39	40
Msx2 represses the Dlx2 promoter in CHO cells and coexpression of both PITX2 and Msx2 resulted in transcriptional antagonism of the Dlx2 promoter .	Msx2 represses the Dlx2 promoter in CHO cells and coexpression of both PITX2 and Msx2 resulted in transcriptional antagonism of the Dlx2 promoter.	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msx2	Msx2	Msx2	Dlx2	Dlx2	Dlx2	0	1	3	4
Msx2 repression of Dlx2 activation is dose specific and both bind a common DNA binding element .	Msx2 repression of Dlx2 activation is dose specific and both bind a common DNA binding element.	0	4	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Msx2	Msx2	Msx2	Dlx2	Dlx2	Dlx2	0	1	3	4
These results may indicate the presence of other factors binding to upstream Msx2 promoter sequences that attenuate Dlx2 activation .	These results may indicate the presence of other factors binding to upstream Msx2 promoter sequences that attenuate Dlx2 activation.	12	18	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msx2	Msx2	Msx2	Dlx2	Dlx2	Dlx2	12	13	17	18
Furthermore , Msx2 can auto-regulate its promoter and Msx2 can attenuate Dlx2 activation .	Furthermore, Msx2 can auto-regulate its promoter and Msx2 can attenuate Dlx2 activation.	6	12	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msx2	Msx2	Msx2	Dlx2	Dlx2	Dlx2	8	9	11	12
Together these data demonstrate that Msx2 can negatively auto-regulate its promoter and repress Dlx2 activation through direct binding to a common site or a physical interaction between the two proteins .	Together these data demonstrate that Msx2 can negatively auto-regulate its promoter and repress Dlx2 activation through direct binding to a common site or a physical interaction between the two proteins.	5	14	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msx2	Msx2	Msx2	Dlx2	Dlx2	Dlx2	5	6	13	14
Thus , Dlx2 and Lef-1 interact to synergistically activate Msx2 ; Msx2 can attenuate Dlx2 activation or directly repress Msx2 promoter activity .	Thus, Dlx2 and Lef-1 interact to synergistically activate Msx2; Msx2 can attenuate Dlx2 activation or directly repress Msx2 promoter activity.	11	18	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msx2	Msx2	Msx2	Dlx2	Dlx2	Dlx2	11	12	14	15
Msx2 repression of Dlx2 activation is dose responsive and independent of Lef-1 .	Msx2 repression of Dlx2 activation is dose responsive and independent of Lef-1.	0	4	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Msx2	Msx2	Msx2	Dlx2	Dlx2	Dlx2	0	1	3	4
Msx2 can auto-regulate its promoter and repress Dlx2 activation .	Msx2 can auto-regulate its promoter and repress Dlx2 activation.	0	8	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msx2	Msx2	Msx2	Dlx2	Dlx2	Dlx2	0	1	7	8
Classic nutrient stress induces autophagy through the inhibition of the mammalian target of rapamycin , which indirectly results in dephos phorylation of Atg13 [ XREF_BIBR ] , allowing Atg13 to interact with the serine/threonine kinase , Atg1 ( UNC-51-like kinases 1 and 2 in mammals ) to initiate autophagy in concert with other proteins [ XREF_BIBR , XREF_BIBR ] .	Classic nutrient stress induces autophagy through the inhibition of the mammalian target of rapamycin, which indirectly results in dephos phorylation of Atg13 [XREF_BIBR], allowing Atg13 to interact with the serine/threonine kinase, Atg1 (UNC-51-like kinases 1 and 2 in mammals) to initiate autophagy in concert with other proteins [XREF_BIBR, XREF_BIBR].	10	30	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Atg13	Atg13	Atg13	10	14	28	29
Inhibition of mTOR activates Atg13 kinase activity , leading to phosphorylation of ULK1/2 and FIP200 , which in turn induces autophagy .	Inhibition of mTOR activates Atg13 kinase activity, leading to phosphorylation of ULK1/2 and FIP200, which in turn induces autophagy.	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Atg13	Atg13	Atg13	2	3	4	5
Akt directly phosphorylates and activates mTOR , as well as inhibits the mTOR inhibitor proteins PRAS40 and tuberin .	Akt directly phosphorylates and activates mTOR, as well as inhibits the mTOR inhibitor proteins PRAS40 and tuberin.	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	Akt directly phosphorylates and activates mTOR	mtor	PRAS40	PRAS40	pras40	5	6	15	16
In the presence of nutrients and growth factors such as insulin , IGF-1 , PDGF and EGF , Akt is activated and , in turn , phosphorylates and activates mTOR or inhibits PRAS40 , an endogenous mTORC1 inhibitor XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR .	In the presence of nutrients and growth factors such as insulin, IGF-1, PDGF and EGF, Akt is activated and, in turn, phosphorylates and activates mTOR or inhibits PRAS40, an endogenous mTORC1 inhibitor XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR.	18	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	Akt is activated and, in turn, phosphorylates and activates mTOR	mtor	PRAS40	PRAS40	pras40	29	30	32	33
This finding agrees with previous research which demonstrated that feedback regulation of the MTOR signaling pathways ultimately represses DEPDC6 expression XREF_BIBR , XREF_BIBR , XREF_BIBR .	This finding agrees with previous research which demonstrated that feedback regulation of the MTOR signaling pathways ultimately represses DEPDC6 expression XREF_BIBR, XREF_BIBR, XREF_BIBR.	13	20	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MTOR	MTOR	MTOR	DEPDC6	DEPDC6	DEPDC6	13	14	18	19
We also measured the activity of the mTOR pathway in cells with RNAi mediated DEPTOR silencing .	We also measured the activity of the mTOR pathway in cells with RNAi mediated DEPTOR silencing.	7	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	DEPTOR	DEPTOR	DEPTOR	7	8	14	15
Deptor , an mTOR inhibitor , is also negatively regulated by mTOR .	Deptor, an mTOR inhibitor, is also negatively regulated by mTOR.	0	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Deptor	Deptor	Deptor	11	12	0	1
Additionally , active mTOR was reported to promote the degradation of DEPTOR XREF_BIBR .	Additionally, active mTOR was reported to promote the degradation of DEPTOR XREF_BIBR.	2	12	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	DEPTOR	DEPTOR	DEPTOR	3	4	11	12
DEPTOR is degraded by the 26S proteasome in response to phosphorylation by mTOR leading to SCF ( TrCP )-mediated degradation .	DEPTOR is degraded by the 26S proteasome in response to phosphorylation by mTOR leading to SCF (TrCP)-mediated degradation.	0	13	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	DEPTOR	DEPTOR	DEPTOR	12	13	0	1
Our data for hMC4R constitutive activity contrast with previous studies showing that MRAP2 mouse and zebrafish homologues decrease MC4R constitutive activity [ XREF_BIBR , XREF_BIBR ] .	Our data for hMC4R constitutive activity contrast with previous studies showing that MRAP2 mouse and zebrafish homologues decrease MC4R constitutive activity [XREF_BIBR, XREF_BIBR].	12	20	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MRAP2	MRAP2	MRAP2	MC4R	MC4R	MC4R	12	13	18	19
MRAP2 can also reduce the responsiveness of MC1R , MC3R , MC4R and MC5R to alpha-MSH .	MRAP2 can also reduce the responsiveness of MC1R, MC3R, MC4R and MC5R to alpha-MSH.	0	12	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MRAP2	MRAP2	MRAP2	MC4R	MC4R	MC4R	0	1	11	12
Both MRAP and MRAP2 decreased the abundance of MC4R at the cell surface ( XREF_FIG ) , as previously reported .	Both MRAP and MRAP2 decreased the abundance of MC4R at the cell surface (XREF_FIG), as previously reported.	1	9	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MRAP2	MRAP2	MRAP2	MC4R	MC4R	MC4R	3	4	8	9
Paradoxically , we also showed that MIB1 overexpression activates Wnt signaling yet degrades RYK .	Paradoxically, we also showed that MIB1 overexpression activates Wnt signaling yet degrades RYK.	6	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MIB1	MIB1 overexpression	mib1	RYK	RYK	ryk	6	7	13	14
Our biochemical data suggest that MIB1 promotes RYK degradation by the lysosome .	Our biochemical data suggest that MIB1 promotes RYK degradation by the lysosome.	5	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MIB1	MIB1	MIB1	RYK	RYK	RYK	5	6	7	8
Collectively these results show that MIB1 overexpression is sufficient to promote the degradation of RYK by the proteasome and the lysosome .	Collectively these results show that MIB1 overexpression is sufficient to promote the degradation of RYK by the proteasome and the lysosome.	5	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MIB1	MIB1 overexpression	mib1	RYK	RYK	ryk	5	6	14	15
By contrast , overexpression of wild-type MTMR3 does not upregulate autophagy 31 , although our data indicate that even overexpression of the wild-type MTMR3 also inhibits mTOR activity .	By contrast, overexpression of wild-type MTMR3 does not upregulate autophagy 31, although our data indicate that even overexpression of the wild-type MTMR3 also inhibits mTOR activity.	19	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MTMR3	overexpression of the wild-type MTMR3	mtmr3	mTOR	mTOR	mtor	23	24	26	27
Moreover , the cellular location of Msx1 protein is modulated by Msx1-as and Msx1-as can abolish the inhibition of Dlx5 by Msx1 .	Moreover, the cellular location of Msx1 protein is modulated by Msx1-as and Msx1-as can abolish the inhibition of Dlx5 by Msx1.	15	22	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Msx1	Msx1	Msx1	Dlx5	Dlx5	Dlx5	21	22	19	20
Based on the function of Mest during adipocytogenesis , we hypothesize that in developing mdDA neurons Mest has a similar function and loss of Mest may lead to an increase of LRP6 on the cell-membrane , eventually resulting in cell loss in the SNc .	Based on the function of Mest during adipocytogenesis, we hypothesize that in developing mdDA neurons Mest has a similar function and loss of Mest may lead to an increase of LRP6 on the cell-membrane, eventually resulting in cell loss in the SNc.	22	32	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Mest	loss of Mest	mest	LRP6	LRP6	lrp6	24	25	31	32
If Mest has a similar function in mdDA neurons , loss of Mest would result in an increase of mature LRP6 , thus favoring canonical over non canonical WNT signaling .	If Mest has a similar function in mdDA neurons, loss of Mest would result in an increase of mature LRP6, thus favoring canonical over non canonical WNT signaling.	10	21	increase	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Mest	loss of Mest	mest	LRP6	LRP6	lrp6	12	13	20	21
In the case of MC5R , MRAP appeared to disrupt MC5R dimerization .	In the case of MC5R, MRAP appeared to disrupt MC5R dimerization.	6	11	disrupt	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MRAP	MRAP	MRAP	MC5R	MC5R	MC5R	6	7	10	11
Significantly , nonphosphorylated HGF receptor prevents FAP68 from stimulating p70S6K .	Significantly, nonphosphorylated HGF receptor prevents FAP68 from stimulating p70S6K.	2	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HGF receptor	nonphosphorylated HGF receptor	hgf receptor	FAP68	FAP68	fap68	3	5	6	7
Another study , which systematically examined the effects of tumor suppressor genes on telomere maintenance , suggested that loss of menin function might stimulate telomerase ( hTERT ) expression [ XREF_BIBR ] and that menin might be involved in tumorigenesis through this mechanism .	Another study, which systematically examined the effects of tumor suppressor genes on telomere maintenance, suggested that loss of menin function might stimulate telomerase (hTERT) expression [XREF_BIBR] and that menin might be involved in tumorigenesis through this mechanism.	20	30	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	menin	menin	menin	telomerase	telomerase	telomerase	20	21	24	25
Furthermore , Msx2 has been suggested to inhibit Dlx5 regulation of BMP-2-mediated osteogenesis and inhibit osteoblast differentiation [ XREF_BIBR , XREF_BIBR ] .	Furthermore, Msx2 has been suggested to inhibit Dlx5 regulation of BMP-2-mediated osteogenesis and inhibit osteoblast differentiation [XREF_BIBR, XREF_BIBR].	2	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Msx2	Msx2	Msx2	Dlx5	Dlx5	Dlx5	2	3	8	9
Remarkably , the transcriptional regulatory network of the SMAD2 promoter is dramatically altered in human aneurysmal VSMCs in vitro and in situ with a switch from Myc dependent repression of SMAD2 in normal vessel to a p53 dependent activation of SMAD2 in aneurysms .	Remarkably, the transcriptional regulatory network of the SMAD2 promoter is dramatically altered in human aneurysmal VSMCs in vitro and in situ with a switch from Myc dependent repression of SMAD2 in normal vessel to a p53 dependent activation of SMAD2 in aneurysms.	26	33	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Myc	Myc	Myc	SMAD2	SMAD2	SMAD2	26	27	30	31
For example , we show here that BMP and Wnt signaling are up-regulated by Shh blockade , and it has been shown that , during avian somite patterning , the BMP inhibitor noggin acts downstream of both Shh and Wnt signaling to inhibit BMP4 activity XREF_BIBR .	For example, we show here that BMP and Wnt signaling are up-regulated by Shh blockade, and it has been shown that, during avian somite patterning, the BMP inhibitor noggin acts downstream of both Shh and Wnt signaling to inhibit BMP4 activity XREF_BIBR.	29	45	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	32	33	43	44
Addition of the BMP4 antagonist noggin during Stage 1 led to significantly reduced levels of expression of SOX17 , FOXA2 , Brachyury , and PDX1 at the end of stage 2 , suggesting that the observed differentiation requires BMP4 signaling ( XREF_SUPPLEMENTARY ) .	Addition of the BMP4 antagonist noggin during Stage 1 led to significantly reduced levels of expression of SOX17, FOXA2, Brachyury, and PDX1 at the end of stage 2, suggesting that the observed differentiation requires BMP4 signaling (XREF_SUPPLEMENTARY).	0	7	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	5	6	3	4
To further confirm the requirement of BMP4 in PGC specification , the BMP4 antagonist noggin was introduced to these samples .	To further confirm the requirement of BMP4 in PGC specification, the BMP4 antagonist noggin was introduced to these samples.	11	16	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	14	15	12	13
For instance , Noggin and Gremlin could greatly inhibit BMP2 , BMP4 and BMP5 signals .	For instance, Noggin and Gremlin could greatly inhibit BMP2, BMP4 and BMP5 signals.	3	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	3	4	11	12
In addition , MSCs derived from children after finishing therapy show increased Noggin expression that could be antagonizing BMP4 effects and promoting disease relapse .	In addition, MSCs derived from children after finishing therapy show increased Noggin expression that could be antagonizing BMP4 effects and promoting disease relapse.	12	19	antagonizing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin expression	noggin	BMP4	BMP4	bmp4	12	13	18	19
It has been demonstrated that Noggin antagonizes bone morphogenetic protein-4 ( BMP4 ) to create a niche for subventricular zone neurogenesis .	It has been demonstrated that Noggin antagonizes bone morphogenetic protein-4 (BMP4) to create a niche for subventricular zone neurogenesis.	5	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	bone morphogenetic protein-4	bone morphogenetic protein-4	bone morphogenetic protein-4	5	6	7	10
Systemic delivery of NOG Delta B2 adenovirus resulted in systemic levels of noggin that persisted for more than two weeks in a mouse model and were sufficient to block BMP4 induced heterotopic ossification .	Systemic delivery of NOG Delta B2 adenovirus resulted in systemic levels of noggin that persisted for more than two weeks in a mouse model and were sufficient to block BMP4 induced heterotopic ossification.	10	30	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	levels of noggin	noggin	BMP4	BMP4	bmp4	12	13	29	30
When BMP4 signaling is inhibited in the mouse intestine by transgenic overexpression of Noggin , villus morphogenesis is suppressed in the small intestine , and crypts become highly proliferative .	When BMP4 signaling is inhibited in the mouse intestine by transgenic overexpression of Noggin, villus morphogenesis is suppressed in the small intestine, and crypts become highly proliferative.	1	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Noggin	overexpression of Noggin	noggin	BMP4	BMP4	bmp4	13	14	1	2
Experimental use of the Bmp4 antagonist noggin , in chick , has indirectly demonstrated that Bmp4 plays a crucial role in sensory and non sensory vestibular development , as all three semicircular ducts and their cristae are absent in the severe phenotypes [ XREF_BIBR , XREF_BIBR ] .	Experimental use of the Bmp4 antagonist noggin, in chick, has indirectly demonstrated that Bmp4 plays a crucial role in sensory and non sensory vestibular development, as all three semicircular ducts and their cristae are absent in the severe phenotypes [XREF_BIBR, XREF_BIBR].	1	7	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	Bmp4	Bmp4	Bmp4	6	7	4	5
Although Noggin inhibits BMP2 and BMP7 as well as BMP4 , BMP2 and BMP7 mRNAs were not detected in the GPCs or surrounding cells at E2.0 ( XREF_SUPPLEMENTARY ) .	Although Noggin inhibits BMP2 and BMP7 as well as BMP4, BMP2 and BMP7 mRNAs were not detected in the GPCs or surrounding cells at E2.0 (XREF_SUPPLEMENTARY).	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	1	2	9	10
Finally , when we co-treated wildtype ureters with the HH signaling activator puromorphamine and the BMP4 antagonist NOGGIN for 6 days , inner mesenchymal and epithelial cells were hypoplastic and did not differentiate .	Finally, when we co-treated wildtype ureters with the HH signaling activator puromorphamine and the BMP4 antagonist NOGGIN for 6 days, inner mesenchymal and epithelial cells were hypoplastic and did not differentiate.	4	18	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	NOGGIN	NOGGIN	NOGGIN	BMP4	BMP4	BMP4	17	18	15	16
Noggin did not alter metanephric development in vitro , but did block the effect of BMP4 .	Noggin did not alter metanephric development in vitro, but did block the effect of BMP4.	0	16	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	0	1	15	16
In addition , noggin reduced BMP4 upregulation in high-glucose-treated endothelial cells and in C57BL/6 mouse aortae and in aortae from db/db mice .	In addition, noggin reduced BMP4 upregulation in high-glucose-treated endothelial cells and in C57BL/6 mouse aortae and in aortae from db/db mice.	3	6	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	3	4	5	6
In rabbit ESC in the absence of serum and feeder cells , long-term self-renewal is maintained by a mixture of TGFbeta ligands ( activin A , Nodal , or TGFbeta1 ) with FGF2 and the BMP4 antagonist Noggin .	In rabbit ESC in the absence of serum and feeder cells, long-term self-renewal is maintained by a mixture of TGFbeta ligands (activin A, Nodal, or TGFbeta1) with FGF2 and the BMP4 antagonist Noggin.	15	38	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	37	38	35	36
Coapplication of the BMP-4 antagonist noggin counteracted the effect of exogenous BMP-4 , but noggin alone had no effect on neuralization in either the absence or presence of retinoids .	Coapplication of the BMP-4 antagonist noggin counteracted the effect of exogenous BMP-4, but noggin alone had no effect on neuralization in either the absence or presence of retinoids.	0	6	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-4	BMP-4	BMP-4	5	6	3	4
By contrast , increased CGRP like immunoreactivity was detected in epidermal keratinocytes of transgenic mice with keratin-14 promoter driven overexpression of Noggin , which blocks BMP4 signaling XREF_BIBR .	By contrast, increased CGRP like immunoreactivity was detected in epidermal keratinocytes of transgenic mice with keratin-14 promoter driven overexpression of Noggin, which blocks BMP4 signaling XREF_BIBR.	16	27	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	keratin-14 promoter driven overexpression of Noggin	noggin	BMP4	BMP4	bmp4	21	22	25	26
Exogenous Bmp4 ( 10 ng/ml ) in primary smooth muscle cell culture repressed smooth muscle differentiation and repression was partially rescued by the Bmp4 antagonist Noggin ( R & D Systems ) ( 300 ng/ml ) .	Exogenous Bmp4 (10 ng/ml) in primary smooth muscle cell culture repressed smooth muscle differentiation and repression was partially rescued by the Bmp4 antagonist Noggin (R&D Systems) (300 ng/ml).	20	34	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	Bmp4	Bmp4	Bmp4	25	26	23	24
These results demonstrated that inhibition of BMP-4 by noggin leads to reduced cardiogenin enhanced CDE of MSCs in vitro .	These results demonstrated that inhibition of BMP-4 by noggin leads to reduced cardiogenin enhanced CDE of MSCs in vitro.	4	9	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-4	BMP-4	BMP-4	8	9	6	7
The findings of the present in vitro studies are likely of great in vivo relevance , as transgenic mice in which BMP-4 action is antagonized by overexpression of its physiologic inhibitor noggin in hair follicles have a markedly darker coat color [ XREF_BIBR ] .	The findings of the present in vitro studies are likely of great in vivo relevance, as transgenic mice in which BMP-4 action is antagonized by overexpression of its physiologic inhibitor noggin in hair follicles have a markedly darker coat color [XREF_BIBR].	21	32	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	noggin	overexpression of its physiologic inhibitor noggin	noggin	BMP-4	BMP-4	bmp-4	31	32	21	22
Moreover , as mentioned above , RANKL stimulates BMP4 production by VSMCs , providing an autocrine stimulus for osteochondrogenic transdifferentiation -- if not held in check by BMP4 antagonists such as noggin XREF_BIBR or MGP XREF_BIBR .	Moreover, as mentioned above, RANKL stimulates BMP4 production by VSMCs, providing an autocrine stimulus for osteochondrogenic transdifferentiation -- if not held in check by BMP4 antagonists such as noggin XREF_BIBR or MGP XREF_BIBR.	27	32	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	31	32	27	28
NOGGIN locally inhibits BMP4 and reduces its effective concentration .	NOGGIN locally inhibits BMP4 and reduces its effective concentration.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NOGGIN	NOGGIN	NOGGIN	BMP4	BMP4	BMP4	0	1	3	4
Noggin ( an inhibitor of BMP4 ) and SB431542 ( an inhibitor of Lefty/Activin/TGFbeta pathways ) were used for this purpose , in addition to Dorsomorphin ( a chemical BMP inhibitor ) which acts as a partial substitute for Noggin .	Noggin (an inhibitor of BMP4) and SB431542 (an inhibitor of Lefty/Activin/TGFbeta pathways) were used for this purpose, in addition to Dorsomorphin (a chemical BMP inhibitor) which acts as a partial substitute for Noggin.	0	17	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	0	1	5	6
We propose that the BMP4 antagonist Noggin plays an important role in promoting medial somite patterning in vivo .	We propose that the BMP4 antagonist Noggin plays an important role in promoting medial somite patterning in vivo.	3	7	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	6	7	4	5
During development , the ectoderm generates keratinocytes through BMP4 signaling which is blocked by the release of noggin from the notochord to induce the formation of neurons [ XREF_BIBR ] .	During development, the ectoderm generates keratinocytes through BMP4 signaling which is blocked by the release of noggin from the notochord to induce the formation of neurons [XREF_BIBR].	8	18	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	17	18	8	9
For instance BMP-4 , the ventral signal that is inhibited by Noggin and other BMP inhibitors , did show lower expression in the Dor samples , but the difference was not declared significant by our statistical test .	For instance BMP-4, the ventral signal that is inhibited by Noggin and other BMP inhibitors, did show lower expression in the Dor samples, but the difference was not declared significant by our statistical test.	2	18	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-4	BMP-4	BMP-4	11	12	2	3
Noggin antagonizes both BMP2 and BMP4 , which are potent ligands of BMPR1A .	Noggin antagonizes both BMP2 and BMP4, which are potent ligands of BMPR1A.	0	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	0	1	5	6
Noggin reversed the antiproliferative and proapoptotic effects of BMP4 .	Noggin reversed the antiproliferative and proapoptotic effects of BMP4.	0	9	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	0	1	8	9
Expression of Gremlin mRNA was twofold higher in MP cells compared with SP cells ( XREF_FIG ) , whereas other known BMP4 antagonists such as Chordin , Noggin , and Follistatin were not up-regulated in MP compared with SP cells at the mRNA level ( not depicted ) .	Expression of Gremlin mRNA was twofold higher in MP cells compared with SP cells (XREF_FIG), whereas other known BMP4 antagonists such as Chordin, Noggin, and Follistatin were not up-regulated in MP compared with SP cells at the mRNA level (not depicted).	21	28	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	27	28	21	22
Coexpression of ashwin with the bone morphogenetic protein-4 antagonist noggin has a synergistic effect on neural specific gene expression in isolated animal cap ectoderm .	Coexpression of ashwin with the bone morphogenetic protein-4 antagonist noggin has a synergistic effect on neural specific gene expression in isolated animal cap ectoderm.	2	10	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	bone morphogenetic protein-4	bone morphogenetic protein-4	bone morphogenetic protein-4	9	10	5	8
Interestingly , the BMP4 antagonist Noggin was unaffected in our study at all-time points , suggesting a Noggin independent modulation of BMP4 .	Interestingly, the BMP4 antagonist Noggin was unaffected in our study at all-time points, suggesting a Noggin independent modulation of BMP4.	2	15	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	5	6	3	4
BMP4 antagonist Noggin abolished the effect of BMP4.50 Stretching healthy human VICs in tubular molds of collagen gel for 3weeks at 15 % resulted in a modest increase of BMP2 and BMP4 mRNA and BMP2 protein.68 Microarray studies of human sclerotic , stenotic , and control aortic valves showed an increased expression of BMP4 in both diseased groups .	BMP4 antagonist Noggin abolished the effect of BMP4.50 Stretching healthy human VICs in tubular molds of collagen gel for 3weeks at 15% resulted in a modest increase of BMP2 and BMP4 mRNA and BMP2 protein.68 Microarray studies of human sclerotic, stenotic, and control aortic valves showed an increased expression of BMP4 in both diseased groups.	0	3	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	2	3	0	1
Moreover , pretreatment of cultured spermatogonia with the BMP4 antagonist Noggin could inhibit RA induced expression of these two marker genes .	Moreover, pretreatment of cultured spermatogonia with the BMP4 antagonist Noggin could inhibit RA induced expression of these two marker genes.	4	11	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	10	11	8	9
As the antagonist of BMP4 , Noggin almost completely blocked all these BMP4 responses .	As the antagonist of BMP4, Noggin almost completely blocked all these BMP4 responses.	6	13	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	6	7	12	13
At the time of the replacement of the columnar cells with a squamous epithelium , a BMP antagonist , noggin , is expressed in the epithelium and inhibits the BMP4 signal from the mesenchymal cells and thereby induces a squamous cell fate [ XREF_BIBR ] .	At the time of the replacement of the columnar cells with a squamous epithelium, a BMP antagonist, noggin, is expressed in the epithelium and inhibits the BMP4 signal from the mesenchymal cells and thereby induces a squamous cell fate [XREF_BIBR].	17	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	19	20	29	30
This implies a stronger inhibition of BMP4 by NOGGIN at the center of the micropattern ( XREF_FIG ) .	This implies a stronger inhibition of BMP4 by NOGGIN at the center of the micropattern (XREF_FIG).	1	11	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	NOGGIN	NOGGIN	NOGGIN	BMP4	BMP4	BMP4	8	9	6	7
Ex vivo treatment with the BMP4 antagonist noggin significantly improved endothelium dependent relaxations and inhibited accumulation of ROS in saphenous veins from patients with diabetes .	Ex vivo treatment with the BMP4 antagonist noggin significantly improved endothelium dependent relaxations and inhibited accumulation of ROS in saphenous veins from patients with diabetes.	2	8	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	7	8	5	6
Subsequent differentiation of pancreatic cells in vitro requires treatment with TGF-beta and BMP4 antagonists such as SU5402 and Noggin , which suppress hepatic differentiation [ XREF_BIBR ] .	Subsequent differentiation of pancreatic cells in vitro requires treatment with TGF-beta and BMP4 antagonists such as SU5402 and Noggin, which suppress hepatic differentiation [XREF_BIBR].	10	21	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	18	19	12	13
Specifically , we used the BMP4 antagonist noggin ( NOG ) , which has been previously used to generate anterior foregut ( AFG ) and PFG [ XREF_BIBR ] [ XREF_BIBR ] , the TGF-beta family member Activin A [ XREF_BIBR ] , and the WNT and beta catenin inhibitor IWR-1 [ XREF_BIBR ] [ XREF_BIBR ] .	Specifically, we used the BMP4 antagonist noggin (NOG), which has been previously used to generate anterior foregut (AFG) and PFG [XREF_BIBR] [XREF_BIBR], the TGF-beta family member Activin A [XREF_BIBR], and the WNT and beta catenin inhibitor IWR-1 [XREF_BIBR] [XREF_BIBR].	3	55	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	7	8	5	6
BMP4 signaling is inhibited by the antagonistic factor Noggin , which interferes with its binding to the BMP receptor ( BMPR ) .	BMP4 signaling is inhibited by the antagonistic factor Noggin, which interferes with its binding to the BMP receptor (BMPR).	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	8	9	0	1
XREF_BIBR , XREF_BIBR Third , it also might be due to a possible inhibitory mechanism by BMP-4 antagonists such as gremlin , matrix Gla protein , follistatin , and noggin .	XREF_BIBR, XREF_BIBR Third, it also might be due to a possible inhibitory mechanism by BMP-4 antagonists such as gremlin, matrix Gla protein, follistatin, and noggin.	16	30	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-4	BMP-4	BMP-4	29	30	16	17
We show that BMP4 antagonist Noggin attenuates VIC activation and biomineralization .	We show that BMP4 antagonist Noggin attenuates VIC activation and biomineralization.	3	6	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	5	6	3	4
Noggin and chordin commonly antagonize the activities of BMP2 and BMP4 ( secreted factors belonging to the TGFbeta family ) , which instruct the ectoderm to differentiate into epidermis [ XREF_BIBR ] .	Noggin and chordin commonly antagonize the activities of BMP2 and BMP4 (secreted factors belonging to the TGFbeta family), which instruct the ectoderm to differentiate into epidermis [XREF_BIBR].	0	11	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	0	1	10	11
Noggin is expressed in the pituitary organizer and inhibits BMP4 activity .	Noggin is expressed in the pituitary organizer and inhibits BMP4 activity.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin is expressed	noggin	BMP4	BMP4	bmp4	0	1	9	10
For example , BMP4 has been identified as an inhibitor of oligodendrocyte maturation and overexpression of the BMP4 antagonist noggin was shown to protect the white matter from hypoxia-ischemia-induced neonatal brain injury in mice ( Dizon , Maa , & Kessler , 2011 ; See et al ., 2004 ) .	For example, BMP4 has been identified as an inhibitor of oligodendrocyte maturation and overexpression of the BMP4 antagonist noggin was shown to protect the white matter from hypoxia-ischemia-induced neonatal brain injury in mice (Dizon, Maa, & Kessler, 2011; See et al., 2004).	12	20	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	19	20	17	18
Addition of Noggin decreased the BMP4 induced expression of trophoblast transcription factors as well as Cdh3 in the differentiated cells .	Addition of Noggin decreased the BMP4 induced expression of trophoblast transcription factors as well as Cdh3 in the differentiated cells.	0	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	2	3	5	6
Active pSMAD1 levels can be modeled by a Hill equation with mild cooperativity : pSMAD1 = B f 1.4 / ( B f 1.4 + K 1.4 ) in which BMP4 is sequestered by NOGGIN limiting its availability to the free BMP4 pool B f.	Active pSMAD1 levels can be modeled by a Hill equation with mild cooperativity : pSMAD1 = B f 1.4 / (B f 1.4 + K 1.4) in which BMP4 is sequestered by NOGGIN limiting its availability to the free BMP4 pool B f.	30	35	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	NOGGIN	NOGGIN	NOGGIN	BMP4	BMP4	BMP4	34	35	30	31
The addition of low dose noggin ( 5 ng/mL ) , a BMP4 signaling antagonist 31 , with CHIR in the first step of differentiation suppressed BMP4 to an optimal level to yield cells that expressed T and TBX6 but not FOXF1 on day 4 ( XREF_SUPPLEMENTARY ) .	The addition of low dose noggin (5 ng/mL), a BMP4 signaling antagonist 31, with CHIR in the first step of differentiation suppressed BMP4 to an optimal level to yield cells that expressed T and TBX6 but not FOXF1 on day 4 (XREF_SUPPLEMENTARY).	1	27	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	5	6	26	27
Remarkably , in our studies , only Gremlin is differentially expressed between SP and MP cells , whereas other BMP4 antagonists , such as Chordin , Noggin , and Follistatin , are not up-regulated in MP cells .	Remarkably, in our studies, only Gremlin is differentially expressed between SP and MP cells, whereas other BMP4 antagonists, such as Chordin, Noggin, and Follistatin, are not up-regulated in MP cells.	19	27	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	26	27	19	20
Infusion of BMP4 antagonist noggin into db/db mice ( 15 mug/kg/day , 4 weeks ) abolished eNOS uncoupling activity while restoring tetrahydrobiopterin ( H ( 4 ) B ) bioavailability .	Infusion of BMP4 antagonist noggin into db/db mice (15 mug/kg/day, 4 weeks) abolished eNOS uncoupling activity while restoring tetrahydrobiopterin (H (4) B) bioavailability.	0	7	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	4	5	2	3
The BMP4 antagonist Noggin is a direct target gene for BMP signaling .	The BMP4 antagonist Noggin is a direct target gene for BMP signaling.	0	8	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	3	4	1	2
For instance , Noggin inhibits BMP2 and BMP4 but can not block BMP6 and BMP9 activity [ XREF_BIBR ] .	For instance, Noggin inhibits BMP2 and BMP4 but can not block BMP6 and BMP9 activity [XREF_BIBR].	3	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	3	4	7	8
BMP4 inhibits the latter process and the BMP4 inhibitor , Noggin , blocks the inhibitory effect of BMP4 .	BMP4 inhibits the latter process and the BMP4 inhibitor, Noggin, blocks the inhibitory effect of BMP4.	8	18	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	10	11	17	18
Similar to the effects on the inner ear seen after exposure of otocysts to the BMP4 antagonist noggin , semicircular canals were truncated or eliminated based upon the site of pellet implantation .	Similar to the effects on the inner ear seen after exposure of otocysts to the BMP4 antagonist noggin, semicircular canals were truncated or eliminated based upon the site of pellet implantation.	8	18	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	17	18	15	16
However , the activity of BMP-4 can be attenuated by adding high concentrations of noggin , which sequesters BMP-4 , as several groups have demonstrated .	However, the activity of BMP-4 can be attenuated by adding high concentrations of noggin, which sequesters BMP-4, as several groups have demonstrated.	12	19	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-4	BMP-4	BMP-4	14	15	18	19
In order to confirm that the increased survival of SGNs was due to the effects of BMP4 , we treated cells with the BMP4 antagonist Noggin and found that the total numbers of SGNs were significantly decreased compared to the controls .	In order to confirm that the increased survival of SGNs was due to the effects of BMP4, we treated cells with the BMP4 antagonist Noggin and found that the total numbers of SGNs were significantly decreased compared to the controls.	19	26	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	25	26	23	24
In contrast , BMP4 antagonist noggin and BMP4 knockdown reduced the division of Sertoli cells .	In contrast, BMP4 antagonist noggin and BMP4 knockdown reduced the division of Sertoli cells.	3	9	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	5	6	3	4
The observed down-regulation of BMP2 in rat liver following partial hepatectomy suggests that such down-regulation may be necessary for hepatocyte proliferation.121 Mice driven to maintain BMP4 expression in the liver , display inhibited hepatocyte proliferation and restoration of liver mass after hepatectomy , suggesting that reduced BMP4 is necessary for normal regeneration.120 Consistent with this finding , the BMP receptors also follow an inverse pattern of up-regulation compared with TGF-beta activation and are mostly up-regulated in the anti-proliferative and termination phase.116 Hepatocyte specific deletion of the BMP receptor Activin receptor like kinase 3 enhances regeneration.120 The BMP4 antagonist Noggin has also been reported to enhance regeneration .	The observed down-regulation of BMP2 in rat liver following partial hepatectomy suggests that such down-regulation may be necessary for hepatocyte proliferation.121 Mice driven to maintain BMP4 expression in the liver, display inhibited hepatocyte proliferation and restoration of liver mass after hepatectomy, suggesting that reduced BMP4 is necessary for normal regeneration.120 Consistent with this finding, the BMP receptors also follow an inverse pattern of up-regulation compared with TGF-beta activation and are mostly up-regulated in the anti-proliferative and termination phase.116 Hepatocyte specific deletion of the BMP receptor Activin receptor like kinase 3 enhances regeneration.120 The BMP4 antagonist Noggin has also been reported to enhance regeneration.	96	105	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	98	99	96	97
Noggin was able to block the effects of BMP-4 in vitro but was unable to block the effects of BMP-7 .	Noggin was able to block the effects of BMP-4 in vitro but was unable to block the effects of BMP-7.	0	15	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-4	BMP-4	BMP-4	0	1	8	9
The project we offered in a multi-team BME senior undergraduate design class was based on the general observation that morphogenetic growth factors , including the bone morphogenetic protein 4 antagonist noggin , XREF_BIBR - XREF_BIBR the cytokine macrophage migration inhibitory protein ( MIF ) , XREF_BIBR , XREF_BIBR - XREF_BIBR and retinoic acid , have profound effects at the cellular level during neural axis formation and neural and sensory cell development .	The project we offered in a multi-team BME senior undergraduate design class was based on the general observation that morphogenetic growth factors, including the bone morphogenetic protein 4 antagonist noggin, XREF_BIBR - XREF_BIBR the cytokine macrophage migration inhibitory protein (MIF), XREF_BIBR, XREF_BIBR - XREF_BIBR and retinoic acid, have profound effects at the cellular level during neural axis formation and neural and sensory cell development.	25	31	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	bone morphogenetic protein 4	bone morphogenetic protein 4	bone morphogenetic protein 4	30	31	25	29
Endogenous Noggin , which is secreted by the intermediate mesoderm at E2 , then by the proximal somatopleure at E4 , could be sufficient to suppress BMP4 signaling in the proximal somatopleural mesoderm and then in part of the distal somatopleure , thus in turn allowing the formation of the dense dermis of the future pterylae .	Endogenous Noggin, which is secreted by the intermediate mesoderm at E2, then by the proximal somatopleure at E4, could be sufficient to suppress BMP4 signaling in the proximal somatopleural mesoderm and then in part of the distal somatopleure, thus in turn allowing the formation of the dense dermis of the future pterylae.	0	27	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	1	2	26	27
During these processes , NOGGIN inhibition of BMP2 and BMP4 regulates activities of chondrocytes , osteoblasts , and osteoclasts 15 ; 16 .	During these processes, NOGGIN inhibition of BMP2 and BMP4 regulates activities of chondrocytes, osteoblasts, and osteoclasts 15; 16.	4	10	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	NOGGIN	NOGGIN	NOGGIN	BMP4	BMP4	BMP4	4	5	9	10
Consistent with these findings , the BMP4 antagonist Noggin enhances regeneration .	Consistent with these findings, the BMP4 antagonist Noggin enhances regeneration.	3	9	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	8	9	6	7
This effect was even more pronounced when cells were treated with Noggin , which inhibits both BMP2 and BMP4 ( XREF_FIG ) .	This effect was even more pronounced when cells were treated with Noggin, which inhibits both BMP2 and BMP4 (XREF_FIG).	9	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	11	12	18	19
Noggin appeared to reduce BMP4 mRNA in hESC cultured in conditioned medium as compared to unconditioned medium .	Noggin appeared to reduce BMP4 mRNA in hESC cultured in conditioned medium as compared to unconditioned medium.	0	5	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	0	1	4	5
To test the requirement of BMP4 downstream of HH signaling and FOXF1 , we treated wildtype and Axin2creERT2/+ ; Hprt Foxf1/y ureter explants with 10 mug/ml NOGGIN , which sequesters BMP4 from its receptor [ XREF_BIBR ] or with a combination of NOGGIN and the SMO inhibitor cyclopamine .	To test the requirement of BMP4 downstream of HH signaling and FOXF1, we treated wildtype and Axin2creERT2/+; Hprt Foxf1/y ureter explants with 10 mug/ml NOGGIN, which sequesters BMP4 from its receptor [XREF_BIBR] or with a combination of NOGGIN and the SMO inhibitor cyclopamine.	22	31	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NOGGIN	NOGGIN	NOGGIN	BMP4	BMP4	BMP4	26	27	30	31
Reaction-diffusion , instead , is created by BMP4 mediated induction of inhibitors such as Noggin ( Etoc et al ., unpublished ) that progressively reduce the effective BMP4 concentration sensed by the cells ( XREF_FIG ) .	Reaction-diffusion, instead, is created by BMP4 mediated induction of inhibitors such as Noggin (Etoc et al., unpublished) that progressively reduce the effective BMP4 concentration sensed by the cells (XREF_FIG).	11	28	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	14	15	27	28
Consistently , we found that the application of BMP4 recombinant protein promoted HepG2 cells growth while Noggin could effectively inhibit that ( Additional file 1 : Figure S3a-c ) , indicating the pro growth effect of BMP4 in HCC .	Consistently, we found that the application of BMP4 recombinant protein promoted HepG2 cells growth while Noggin could effectively inhibit that (Additional file 1 : Figure S3a-c), indicating the pro growth effect of BMP4 in HCC.	16	37	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	16	17	36	37
Our results show that up-regulation of BMP4 leads to an increase of the number of blood vessels , whereas inhibition of BMP4 by noggin results in a reduction of blood vessels .	Our results show that up-regulation of BMP4 leads to an increase of the number of blood vessels, whereas inhibition of BMP4 by noggin results in a reduction of blood vessels.	19	24	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	23	24	21	22
Combination of 3-MA and BMP4 blocked the autophagic flux induced by BMP4 , representing a similar effect of BMP4 antagonist Noggin .	Combination of 3-MA and BMP4 blocked the autophagic flux induced by BMP4, representing a similar effect of BMP4 antagonist Noggin.	16	21	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	20	21	18	19
To rule out the possibility that Notum is required for the BMP antagonists to function properly , we showed that Chordin or Noggin inhibited BMP4 induction of the ventral Vent2 regardless of Notum depletion ( XREF_SUPPLEMENTARY ) .	To rule out the possibility that Notum is required for the BMP antagonists to function properly, we showed that Chordin or Noggin inhibited BMP4 induction of the ventral Vent2 regardless of Notum depletion (XREF_SUPPLEMENTARY).	20	25	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	22	23	24	25
Inhibition of BMP4 by Noggin notably decreased the ratio of astrocytes to neuron numbers XREF_BIBR .	Inhibition of BMP4 by Noggin notably decreased the ratio of astrocytes to neuron numbers XREF_BIBR.	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	4	5	2	3
In addition , others have shown that Noggin expression is suppressed by FGF2 and syndromic FGFR2 signaling , as well as demonstrating that Noggin is an antagonist of BMP4 .	In addition, others have shown that Noggin expression is suppressed by FGF2 and syndromic FGFR2 signaling, as well as demonstrating that Noggin is an antagonist of BMP4.	23	29	is an antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	23	24	28	29
As expected , the presence of Noggin markedly reduced the effect of BMP4 ( XREF_FIG ) .	As expected, the presence of Noggin markedly reduced the effect of BMP4 (XREF_FIG).	4	14	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	6	7	12	13
This approach combines Noggin ( an inhibitor of BMP4 ) and SB431542 ( an inhibitor of Lefty/Activin/TGFbeta pathways ) to achieve robust neural differentiation .	This approach combines Noggin (an inhibitor of BMP4) and SB431542 (an inhibitor of Lefty/Activin/TGFbeta pathways) to achieve robust neural differentiation.	2	20	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	3	4	8	9
The specificity of the BMP-4-mediated effects was further supported by knock-down experiments of the BMP-4 antagonist noggin ( small interfering RNA [ siRNA ] ) .	The specificity of the BMP-4-mediated effects was further supported by knock-down experiments of the BMP-4 antagonist noggin (small interfering RNA [siRNA]).	11	17	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-4	BMP-4	BMP-4	16	17	14	15
Conversely , treatment with the TGFbeta signaling cascade inhibitor latency associated peptide ( LAP ) [ XREF_BIBR ] significantly diminished the size and number of these areas at day 9 , while alternative inhibition with the BMP4 antagonist NOG [ XREF_BIBR ] abrogated the development of contractile foci .	Conversely, treatment with the TGFbeta signaling cascade inhibitor latency associated peptide (LAP) [XREF_BIBR] significantly diminished the size and number of these areas at day 9, while alternative inhibition with the BMP4 antagonist NOG [XREF_BIBR] abrogated the development of contractile foci.	33	40	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	NOG	NOG	NOG	BMP4	BMP4	BMP4	38	39	36	37
Noggin , a BMP antagonist , is secreted by cells surrounding the BMP4 producing mesenchyme and presumably reduces the effect of BMP4 on migratory ENCDCs .	Noggin, a BMP antagonist, is secreted by cells surrounding the BMP4 producing mesenchyme and presumably reduces the effect of BMP4 on migratory ENCDCs.	0	24	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	0	1	21	22
Antagonism of BMP4 by Noggin could enhance remyelination and ablate the proastrogenesis effect of BMP4 , suggesting that BMPs may act in a phase specific fashion [ XREF_BIBR ] .	Antagonism of BMP4 by Noggin could enhance remyelination and ablate the proastrogenesis effect of BMP4, suggesting that BMPs may act in a phase specific fashion [XREF_BIBR].	0	5	Antagonism	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	4	5	2	3
Transcriptional activity was increased in a BMP4 dose dependent manner in transfected mESCs , whereas Noggin ( 300ng/ml ) decreased BMP4 induced transcriptional activity .	Transcriptional activity was increased in a BMP4 dose dependent manner in transfected mESCs, whereas Noggin (300ng/ml) decreased BMP4 induced transcriptional activity.	15	21	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	15	16	20	21
BMP4 upregulated PDGF-AA in human and mouse endothelial cells , which was abolished by BMP4 antagonist noggin or knockdown of SMAD1/5 or SMAD4 .	BMP4 upregulated PDGF-AA in human and mouse endothelial cells, which was abolished by BMP4 antagonist noggin or knockdown of SMAD1/5 or SMAD4.	12	18	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	16	17	14	15
Conversely , inhibition of BMP-4 by Noggin notably decreased the ratio of astrocyte to neuron numbers .	Conversely, inhibition of BMP-4 by Noggin notably decreased the ratio of astrocyte to neuron numbers.	2	7	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-4	BMP-4	BMP-4	6	7	4	5
The student team ' s scientific objectives were therefore ( 1 ) to design a microfluidic bioreactor that would provide continuous external focal application of MIF , retinoic acid , BMPs , and BMP antagonists , including the BMP4 antagonist noggin ( singly and in combination ) , to selected circumscribed external areas of the developing zebrafish embryo for periods from 3 to 24 h in the device itself , ( 2 ) to document the exposed regions by BDC marking of either the anterior or posterior dorsal neural axis and to follow the marked cells ( either by the marker dye or rough positional identification through photomicrography ) and the embryo itself through development on a daily basis for at least a week after removal of the embryo from the device , and ( 3 ) to observe the results of circumscribed exposure compared to immersion of the fish in the same growth factors on embryonic development in general and nervous system development in particular .	The student team 's scientific objectives were therefore (1) to design a microfluidic bioreactor that would provide continuous external focal application of MIF, retinoic acid, BMPs, and BMP antagonists, including the BMP4 antagonist noggin (singly and in combination), to selected circumscribed external areas of the developing zebrafish embryo for periods from 3 to 24 h in the device itself, (2) to document the exposed regions by BDC marking of either the anterior or posterior dorsal neural axis and to follow the marked cells (either by the marker dye or rough positional identification through photomicrography) and the embryo itself through development on a daily basis for at least a week after removal of the embryo from the device, and (3) to observe the results of circumscribed exposure compared to immersion of the fish in the same growth factors on embryonic development in general and nervous system development in particular.	38	165	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	40	41	38	39
Bone morphogenic protein ( BMP ) 4 signaling increases the numbers of GFAP positive astrocytes from NSCs [ XREF_BIBR ] , whereas intraventricular infusion of the BMP4 antagonist Noggin during demyelination significantly enhances the density of mature OLs and remyelinated axons [ XREF_BIBR ] .	Bone morphogenic protein (BMP) 4 signaling increases the numbers of GFAP positive astrocytes from NSCs [XREF_BIBR], whereas intraventricular infusion of the BMP4 antagonist Noggin during demyelination significantly enhances the density of mature OLs and remyelinated axons [XREF_BIBR].	23	30	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	28	29	26	27
We also believe that BMP2 can indirectly induce NT2/D1 cells into mesodermal derivatives like cardiac muscle , because : 1 ) observations from amphibians , chicks and more recently from mice , have proposed that the factors produced by embryonic endoderm are good candidates to be cardiogenic inducers [ XREF_BIBR ] ; 2 ) BMPs , as BMP2 , have a role in visceral endoderm differentiation in the mouse [ XREF_BIBR ] and in the human ESCs system [ XREF_BIBR ] ; 3 ) the mouse P19CL6noggin EC cell line that overexpresses the BMP2 antagonist noggin and has lost it potential to differentiate into cardiomyocytes , can regain that property when in the presence of excess BMP2 protein [ XREF_BIBR ] ; 4 ) recently , it has been shown that the mouse visceral endoderm like cell line END2 , derived from P19 EC , when cocultured with the parental cells [ XREF_BIBR ] or mouse ESCs [ XREF_BIBR ] induces spontaneous aggregation and differentiation into cardiac muscle , in the absence of BMP2 .	We also believe that BMP2 can indirectly induce NT2/D1 cells into mesodermal derivatives like cardiac muscle, because : 1) observations from amphibians, chicks and more recently from mice, have proposed that the factors produced by embryonic endoderm are good candidates to be cardiogenic inducers [XREF_BIBR]; 2) BMPs, as BMP2, have a role in visceral endoderm differentiation in the mouse [XREF_BIBR] and in the human ESCs system [XREF_BIBR]; 3) the mouse P19CL6noggin EC cell line that overexpresses the BMP2 antagonist noggin and has lost it potential to differentiate into cardiomyocytes, can regain that property when in the presence of excess BMP2 protein [XREF_BIBR]; 4) recently, it has been shown that the mouse visceral endoderm like cell line END2, derived from P19 EC, when cocultured with the parental cells [XREF_BIBR] or mouse ESCs [XREF_BIBR] induces spontaneous aggregation and differentiation into cardiac muscle, in the absence of BMP2.	93	173	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP2	BMP2	BMP2	95	96	93	94
Inhibition of BMP2 signaling by Noggin weakens the effect of FGF2 on induction of later-stage osteoblastic differentiation of cranial suture cells .	Inhibition of BMP2 signaling by Noggin weakens the effect of FGF2 on induction of later-stage osteoblastic differentiation of cranial suture cells.	2	6	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	5	6	2	3
BMP-2 levels are increased in the serum of uremic patients ; incubation of bovine VSMCs with noggin ( an inhibitor of BMP-2 ) decreased uremic serum induced Runx2 and Cbfa1 expression .	BMP-2 levels are increased in the serum of uremic patients; incubation of bovine VSMCs with noggin (an inhibitor of BMP-2) decreased uremic serum induced Runx2 and Cbfa1 expression.	14	22	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	16	17	21	22
Noggin is a known antagonist of BMP-2 , and we demonstrated that increased osteogenic differentiation can occur by placing cells directly on a scaffold that releases both noggin shRNA and BMP-2 .	Noggin is a known antagonist of BMP-2, and we demonstrated that increased osteogenic differentiation can occur by placing cells directly on a scaffold that releases both noggin shRNA and BMP-2.	0	7	is a known antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	0	1	6	7
We hypothesized that the engineered BMP2 variant L51P stimulates osteoinduction by antagonizing Noggin mediated inhibition of BMP2 .	We hypothesized that the engineered BMP2 variant L51P stimulates osteoinduction by antagonizing Noggin mediated inhibition of BMP2.	12	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	12	13	16	17
These results show that high glucose levels can evoke the calcification of HASMCs by inducing osteoblastic trans-differentiation and intracellular calcium deposition via the BMP-2 and Cbfalpha-1 pathway , which can be partially blocked by Noggin protein .	These results show that high glucose levels can evoke the calcification of HASMCs by inducing osteoblastic trans-differentiation and intracellular calcium deposition via the BMP-2 and Cbfalpha-1 pathway, which can be partially blocked by Noggin protein.	23	35	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	34	35	23	24
These affinity isolated HS species enhanced BMP-2-induced osteogenesis overall by improving BMP-2 interaction with its receptor , thereby prolonging downstream signalling and , coincidentally , by also decoying the BMP-2 antagonist noggin .	These affinity isolated HS species enhanced BMP-2-induced osteogenesis overall by improving BMP-2 interaction with its receptor, thereby prolonging downstream signalling and, coincidentally, by also decoying the BMP-2 antagonist noggin.	27	32	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	31	32	29	30
It has been previously reported that exogenous noggin inhibits BMP-2- and BMP-4-induced invasion and migration of PC-3 cells , in vitro , and that noggin over-expression in the same cells limits their expansion and osteolytic activity , in vivo XREF_BIBR .	It has been previously reported that exogenous noggin inhibits BMP-2- and BMP-4-induced invasion and migration of PC-3 cells, in vitro, and that noggin over-expression in the same cells limits their expansion and osteolytic activity, in vivo XREF_BIBR.	6	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2-	BMP-2-	BMP-2-	7	8	9	10
Chordin and Noggin have the highest affinity for BMP4 , but also antagonize BMP2 , and to a lesser extent , BMP7 .	Chordin and Noggin have the highest affinity for BMP4, but also antagonize BMP2, and to a lesser extent, BMP7.	0	21	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	2	3	13	14
In contrast , BMP2 and BMP7 homodimers were largely inhibited by Noggin .	In contrast, BMP2 and BMP7 homodimers were largely inhibited by Noggin.	3	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	11	12	3	4
Addition of purified BMP-2 protein did not increase the up-regulation of ALP activity and osteocalcin by osthole , whereas the BMP-2 antagonist noggin blocked both osthole and BMP-2-mediated ALP activity enhancement , indicating that BMP-2 production is required in osthole mediated osteoblast maturation .	Addition of purified BMP-2 protein did not increase the up-regulation of ALP activity and osteocalcin by osthole, whereas the BMP-2 antagonist noggin blocked both osthole and BMP-2-mediated ALP activity enhancement, indicating that BMP-2 production is required in osthole mediated osteoblast maturation.	19	23	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	22	23	20	21
Noggin can antagonize not only the BMP-2 but other members in BMP family ( BMP-4 , BMP-7 , BMP-13 ) .	Noggin can antagonize not only the BMP-2 but other members in BMP family (BMP-4, BMP-7, BMP-13).	0	9	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	0	1	6	7
BMP antagonist , noggin inhibited BMP2 osteogenesis , however SMAD phosphorylation by BMP9 was not inhibited by exogenous noggin ( Bergeron et al ., 2009 ; Nakamura , Shinohara , Momozaki , Yoshimoto , & Noguchi , 2013 ; Wang et al ., 2013 ) .	BMP antagonist, noggin inhibited BMP2 osteogenesis, however SMAD phosphorylation by BMP9 was not inhibited by exogenous noggin (Bergeron et al., 2009; Nakamura, Shinohara, Momozaki, Yoshimoto, & Noguchi, 2013; Wang et al., 2013).	1	6	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP2	BMP2	BMP2	3	4	5	6
BMP-2 Signaling and Repair of a Critical Sized Calvarial Defect Is Enhanced by Noggin Suppression .	BMP-2 Signaling and Repair of a Critical Sized Calvarial Defect Is Enhanced by Noggin Suppression.	0	14	Enhanced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	13	14	0	1
The regenerative potential of bone at a site of injury is often diminished by locally expressed inhibitory molecules such as the BMP-2 antagonist noggin .	The regenerative potential of bone at a site of injury is often diminished by locally expressed inhibitory molecules such as the BMP-2 antagonist noggin.	17	24	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	23	24	21	22
The expression of BMP-2 , BMP-4 and noggin ( the inducible antagonist of BMP-2 ) are known to affect proliferation and cell survival as a result of FGF9 activation in human tissue .	The expression of BMP-2, BMP-4 and noggin (the inducible antagonist of BMP-2) are known to affect proliferation and cell survival as a result of FGF9 activation in human tissue.	1	14	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	noggin	expression of BMP-2, BMP-4 and noggin	noggin	BMP-2	BMP-2	bmp-2	7	8	13	14
We further demonstrated that the expression of p-Smad1/5 , ALP , OCN , COL1 and Runx2 by Rg1 was reduced in the presence of the BMP-2 antagonist noggin and siBMP-2 , indicating that the stimulatory effect of Rg1 on osteogenic differentiation was likely mediated by increased expression of BMP-2 .	We further demonstrated that the expression of p-Smad1/5, ALP, OCN, COL1 and Runx2 by Rg1 was reduced in the presence of the BMP-2 antagonist noggin and siBMP-2, indicating that the stimulatory effect of Rg1 on osteogenic differentiation was likely mediated by increased expression of BMP-2.	22	29	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	27	28	25	26
Furthermore , endogenous BMP-2 antagonists , such as noggin , chordin , and matrix gamma-carboxyglutamic acid protein , were all downregulated in the dedifferentiated VSMCs .	Furthermore, endogenous BMP-2 antagonists, such as noggin, chordin, and matrix gamma-carboxyglutamic acid protein, were all downregulated in the dedifferentiated VSMCs.	3	16	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	8	9	3	4
The results showed that rbSWH can increase mRNA levels of BMP-2 and Runx2 using real-time reverse transcription-quantitative polymerase chain reaction , whereas the BMP-2 antagonist Noggin attenuated the increase of ALP activity induced by rbSWH , indicating that BMP-2 expression was required for the action of rbSWH in osteoblastic .	The results showed that rbSWH can increase mRNA levels of BMP-2 and Runx2 using real-time reverse transcription-quantitative polymerase chain reaction, whereas the BMP-2 antagonist Noggin attenuated the increase of ALP activity induced by rbSWH, indicating that BMP-2 expression was required for the action of rbSWH in osteoblastic.	22	26	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	25	26	23	24
These BMP-2-mediated stimulatory effects were reversed by recombinant human Noggin , a glycoprotein that blocks BMP-2 action .	These BMP-2-mediated stimulatory effects were reversed by recombinant human Noggin, a glycoprotein that blocks BMP-2 action.	5	16	blocks	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	9	10	15	16
BMP2 is also inhibited by NOG , which indicates that this amino acid change seems to have an effect on the receptor specificity only , but otherwise it is well tolerated by the BMP antagonist NOG .	BMP2 is also inhibited by NOG, which indicates that this amino acid change seems to have an effect on the receptor specificity only, but otherwise it is well tolerated by the BMP antagonist NOG.	0	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	NOG	NOG	NOG	BMP2	BMP2	BMP2	5	6	0	1
Other studies as well have shown that a variety of endogenous BMP2 antagonists , such as noggin , chordin , and matrix gamma-carboxyglutamic acid protein regulate the BMP2 expression [ XREF_BIBR ] in smooth muscle cells .	Other studies as well have shown that a variety of endogenous BMP2 antagonists, such as noggin, chordin, and matrix gamma-carboxyglutamic acid protein regulate the BMP2 expression [XREF_BIBR] in smooth muscle cells.	11	24	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP2	BMP2	BMP2	16	17	11	12
Noggin reversed the effects of BMP-2 on gene expression and on mineralization .	Noggin reversed the effects of BMP-2 on gene expression and on mineralization.	0	6	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	0	1	5	6
L51P stimulated OB differentiation by blocking Noggin mediated inhibition of BMP2 .	L51P stimulated OB differentiation by blocking Noggin mediated inhibition of BMP2.	6	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	6	7	10	11
Imperatorin and bergapten increased mRNA levels of BMP-2 using quantitative RT-PCR , whereas the BMP-2 antagonist noggin attenuated the increase of ALP activity induced by imperatorin and bergapten , indicating that BMP-2 expression is required for the action of imperatorin and bergapten in osteoblastic maturation .	Imperatorin and bergapten increased mRNA levels of BMP-2 using quantitative RT-PCR, whereas the BMP-2 antagonist noggin attenuated the increase of ALP activity induced by imperatorin and bergapten, indicating that BMP-2 expression is required for the action of imperatorin and bergapten in osteoblastic maturation.	13	17	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	16	17	14	15
It was found that BMP-2 markedly increased the luciferase reporter activity by about 5 folds and again , Noggin specifically blocked the BMP-2 activity .	It was found that BMP-2 markedly increased the luciferase reporter activity by about 5 folds and again, Noggin specifically blocked the BMP-2 activity.	18	23	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	18	19	22	23
Analysis of WISP-1 protein structure by our laboratory and others has indicated a region in the CT domain with high homology to the BMP-2 antagonist noggin and another cysteine rich region homologous to chordin in the VWF like domain .	Analysis of WISP-1 protein structure by our laboratory and others has indicated a region in the CT domain with high homology to the BMP-2 antagonist noggin and another cysteine rich region homologous to chordin in the VWF like domain.	11	26	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	25	26	23	24
Noggin addition to the medium inhibited the potential of BMP-2 to stimulate HA deposition ( XREF_FIG ) .	Noggin addition to the medium inhibited the potential of BMP-2 to stimulate HA deposition (XREF_FIG).	0	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	0	1	9	10
Noggin Suppression Enhances BMP-2 Signaling .	Noggin Suppression Enhances BMP-2 Signaling.	0	4	Enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	0	1	3	4
Although GlaMGP binds and inactivates bone morphogenic protein ( BMP )-2, a proposed mediator of vascular calcification through up-regulation of the osteogenic transcription factor runx2 , neither warfarin , BMP-2 , nor the BMP-2 antagonist noggin altered runx2 mRNA content in aortas , and noggin did not prevent warfarin induced calcification .	Although GlaMGP binds and inactivates bone morphogenic protein (BMP)-2, a proposed mediator of vascular calcification through up-regulation of the osteogenic transcription factor runx2, neither warfarin, BMP-2, nor the BMP-2 antagonist noggin altered runx2 mRNA content in aortas, and noggin did not prevent warfarin induced calcification.	31	47	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	35	36	33	34
Noggin inhibited cellular migration and invasion of BMP-2- and -7-stimulated LAPC-4 cells .	Noggin inhibited cellular migration and invasion of BMP-2- and -7-stimulated LAPC-4 cells.	0	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2-	BMP-2-	BMP-2-	0	1	7	8
Although noggin mRNA was induced by BMP-2 within 1 h regardless of the presence of heparin , noggin failed to inhibit BMP-2 activity in the presence of heparin .	Although noggin mRNA was induced by BMP-2 within 1 h regardless of the presence of heparin, noggin failed to inhibit BMP-2 activity in the presence of heparin.	17	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	17	18	21	22
We determine the structure of AB204 to 2.3 A that reveals a distinct BMP2 like fold in which the Activin A sequence segments confer insensitivity to the BMP2 antagonist Noggin and an affinity for the Activin and BMP type II receptor ActRII that is 100-fold greater than that of BMP2 .	We determine the structure of AB204 to 2.3 A that reveals a distinct BMP2 like fold in which the Activin A sequence segments confer insensitivity to the BMP2 antagonist Noggin and an affinity for the Activin and BMP type II receptor ActRII that is 100-fold greater than that of BMP2.	23	32	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	29	30	27	28
Addition of purified BMP-2 protein did not increase the upregulation of alkaline phosphatase activity and osteocalcin secretion by piceatannol , whereas the BMP-2 antagonist noggin blocked piceatannol and BMP-2-mediated alkaline phosphatase activity , and osteocalcin secretion enhancement , indicating that BMP-2 production is required in piceatannol mediated osteoblast maturation and differentiation .	Addition of purified BMP-2 protein did not increase the upregulation of alkaline phosphatase activity and osteocalcin secretion by piceatannol, whereas the BMP-2 antagonist noggin blocked piceatannol and BMP-2-mediated alkaline phosphatase activity, and osteocalcin secretion enhancement, indicating that BMP-2 production is required in piceatannol mediated osteoblast maturation and differentiation.	21	25	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	24	25	22	23
The BMP-2 antagonist noggin abrogated BMP-2-induced angiogenic response , and knocking down BMP-2 decreased blood vessel formation in the Matrigel assays XREF_BIBR .	The BMP-2 antagonist noggin abrogated BMP-2-induced angiogenic response, and knocking down BMP-2 decreased blood vessel formation in the Matrigel assays XREF_BIBR.	0	4	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	3	4	1	2
While Noggin potently inhibited the ability of BMP-2 to mediate differentiation , it had no significant effect on BMP-9 .	While Noggin potently inhibited the ability of BMP-2 to mediate differentiation, it had no significant effect on BMP-9.	1	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	1	2	7	8
Bone morphogenetic protein 2 ( BMP2 ) , BMP receptor-IA ( BMPR-IA ) , and the BMP2 antagonist Noggin are important proteins involved in regulating the hair follicle ( HF ) cycle in skin .	Bone morphogenetic protein 2 (BMP2), BMP receptor-IA (BMPR-IA), and the BMP2 antagonist Noggin are important proteins involved in regulating the hair follicle (HF) cycle in skin.	16	19	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	18	19	16	17
Noggin , which is known to block Bmp2 , -4 and -7 activity , showed similar expression pattern in both groups over time .	Noggin, which is known to block Bmp2, -4 and -7 activity, showed similar expression pattern in both groups over time.	0	14	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	Bmp2	Bmp2	Bmp2	0	1	7	8
In this case , we investigated the ability to knock down the BMP-2 antagonist noggin through the use of siRNA .	In this case, we investigated the ability to knock down the BMP-2 antagonist noggin through the use of siRNA.	9	15	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	14	15	12	13
Furthermore , BMP-2 significantly increased microvessel formation in Matrigel plug assay , and BMP-2 antagonist noggin prevented BMP-2-induced in vivo angiogenesis .	Furthermore, BMP-2 significantly increased microvessel formation in Matrigel plug assay, and BMP-2 antagonist noggin prevented BMP-2-induced in vivo angiogenesis.	13	16	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	15	16	13	14
Treatment of RAW264.7 cells with RANKL increased BMP-2 expression , Smad1/5/8 phosphorylation and Id1 expression , which triggered osteoclast differentiation , whereas co-treatment with WSS25 or the endogenous BMP-2 antagonist noggin suppressed the BMP-2/Smad/Id1 signaling pathway .	Treatment of RAW264.7 cells with RANKL increased BMP-2 expression, Smad1/5/8 phosphorylation and Id1 expression, which triggered osteoclast differentiation, whereas co-treatment with WSS25 or the endogenous BMP-2 antagonist noggin suppressed the BMP-2/Smad/Id1 signaling pathway.	22	31	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	30	31	28	29
The BMP-2 antagonist Noggin and GR antagonist RU486 were added to cultures 1h before dexamethasone and Rg1 treatments .	The BMP-2 antagonist Noggin and GR antagonist RU486 were added to cultures 1h before dexamethasone and Rg1 treatments.	0	12	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	3	4	1	2
Consequently , in cells that were co-stimulated with recombinant TGF-beta1 and BMP-2 , we showed a significant stimulatory and dose dependent effect of TGF-beta1 on BMP-2-induced osteoblast differentiation due to prolonged BMP signaling and reduced expression of the BMP-2 antagonist noggin .	Consequently, in cells that were co-stimulated with recombinant TGF-beta1 and BMP-2, we showed a significant stimulatory and dose dependent effect of TGF-beta1 on BMP-2-induced osteoblast differentiation due to prolonged BMP signaling and reduced expression of the BMP-2 antagonist noggin.	35	41	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	40	41	38	39
Interestingly , noggin treatment also reduced BMP2 promoter activity induced by forced expression of beta-catenin and TCF4 ( XREF_FIG ) .	Interestingly, noggin treatment also reduced BMP2 promoter activity induced by forced expression of beta-catenin and TCF4 (XREF_FIG).	2	8	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP2	BMP2	BMP2	2	3	6	7
The BMP-2 antagonist noggin abrogated BMP-2-induced angiogenic response .	The BMP-2 antagonist noggin abrogated BMP-2-induced angiogenic response.	0	4	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	3	4	1	2
Previous studies indicated that the inhibition of BMP2 by Noggin prevented from osteogenic differentiation through blockage of Smad signalling .	Previous studies indicated that the inhibition of BMP2 by Noggin prevented from osteogenic differentiation through blockage of Smad signalling.	5	10	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	9	10	7	8
Mechanistically , HS5 sustains BMP-2 activity in a similar fashion to heparin by ( i ) prolonging its half-life , ( ii ) decreasing interactions with the BMP-2 antagonist noggin , and ( iii ) decreasing BMP-2 localization on cell surface HSPG .	Mechanistically, HS5 sustains BMP-2 activity in a similar fashion to heparin by (i) prolonging its half-life, (ii) decreasing interactions with the BMP-2 antagonist noggin, and (iii) decreasing BMP-2 localization on cell surface HSPG.	24	30	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	29	30	27	28
Of these , noggin , a secreted polypeptide present in several mammalian tissues , has been shown to bind to and inhibit the actions of BMP-2 , BMP-4 , and , to a lesser degree , BMP-7 .	Of these, noggin, a secreted polypeptide present in several mammalian tissues, has been shown to bind to and inhibit the actions of BMP-2, BMP-4, and, to a lesser degree, BMP-7.	3	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	3	4	25	26
While noggin and follistatin inhibited the effects of recombinant BMP-2 and BMP-6 , respectively , they had only minimal effects on the spontaneous maturation of chondrocytes in culture , suggesting that more than one subgroup of BMPs regulates chondrocyte maturation .	While noggin and follistatin inhibited the effects of recombinant BMP-2 and BMP-6, respectively, they had only minimal effects on the spontaneous maturation of chondrocytes in culture, suggesting that more than one subgroup of BMPs regulates chondrocyte maturation.	1	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	1	2	9	10
In contrast , noggin preferentially antagonizes BMP-2 , -4 , and -7 .	In contrast, noggin preferentially antagonizes BMP-2, -4, and -7.	3	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	3	4	6	7
Bone morphogenetic proteins ( BMPs ) are known to promote periodontal tissue regeneration , while noggin inhibits the biological activities of BMP-2 , -4 , and -7 .	Bone morphogenetic proteins (BMPs) are known to promote periodontal tissue regeneration, while noggin inhibits the biological activities of BMP-2, -4, and -7.	15	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	15	16	21	22
Cultured rat BMSCs were exposed to different concentrations of Sr , noggin ( an inhibitor of BMP-2 ) or Smad1 siRNA .	Cultured rat BMSCs were exposed to different concentrations of Sr, noggin (an inhibitor of BMP-2) or Smad1 siRNA.	9	20	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	11	12	16	17
Enhanced Osteogenesis of Adipose Derived Stem Cells with Noggin Suppression and Delivery of BMP-2 .	Enhanced Osteogenesis of Adipose Derived Stem Cells with Noggin Suppression and Delivery of BMP-2.	8	14	Suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP-2	BMP-2	BMP-2	8	9	13	14
Finally , to determine whether inhibition of BMP2 action is involved in modulating BMP2 action , cells were treated with exogenous Noggin in addition to blocking the effects of BMP inhibitors using specific antibodies .	Finally, to determine whether inhibition of BMP2 action is involved in modulating BMP2 action, cells were treated with exogenous Noggin in addition to blocking the effects of BMP inhibitors using specific antibodies.	7	22	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	21	22	7	8
BMP-2 protein induced medulloblastoma cell apoptosis , whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis .	BMP-2 protein induced medulloblastoma cell apoptosis, whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis.	8	12	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	11	12	9	10
Moreover , BMP2 treatment promoted osteosarcoma cell migration and invasion whereas the BMP antagonist Noggin abrogated the stimulatory effects of BMP2 .	Moreover, BMP2 treatment promoted osteosarcoma cell migration and invasion whereas the BMP antagonist Noggin abrogated the stimulatory effects of BMP2.	11	21	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	14	15	20	21
A hallmark of NFkappaB signaling is negative feedback control mediated by IkappaBalpha that ensures post-induction repression of RelA : p50 activity following transient exposure to inflammatory cytokines .	A hallmark of NFkappaB signaling is negative feedback control mediated by IkappaBalpha that ensures post-induction repression of RelA : p50 activity following transient exposure to inflammatory cytokines.	9	20	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	11	12	19	20
In the classical NF-kappaB pathway , the IkappaB kinase complex directly phosphorylates IkappaBalpha , which sequesters the NF and kappaB heterodimer p65 ( also known as RelA ) and p50 in the cytosol , leading to the ubiquitination and proteasomal degradation of IkappaBalpha [ XREF_BIBR , XREF_BIBR ] .	In the classical NF-kappaB pathway, the IkappaB kinase complex directly phosphorylates IkappaBalpha, which sequesters the NF and kappaB heterodimer p65 (also known as RelA) and p50 in the cytosol, leading to the ubiquitination and proteasomal degradation of IkappaBalpha [XREF_BIBR, XREF_BIBR].	7	32	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaB kinase complex directly phosphorylates IkappaBalpha	ikappabalpha	p50	p50	p50	12	13	29	30
IkappaB-alpha is subsequently ubiquitinated and then degraded , allowing the NF-kappaB p50 and p65 subunits to translocate to the nucleus [ XREF_BIBR ] .	IkappaB-alpha is subsequently ubiquitinated and then degraded, allowing the NF-kappaB p50 and p65 subunits to translocate to the nucleus [XREF_BIBR].	0	12	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha is subsequently ubiquitinated	ikappab-alpha	NF-kappaB p50	NF-kappaB p50	nf-kappab p50	0	1	10	12
IKBalpha inhibits NFkB activation by cytoplasmic sequestration , while a decrease in IKBalpha releases NFkB from the cytoplasm to enter the nucleus in an active state .	IKBalpha inhibits NFkB activation by cytoplasmic sequestration, while a decrease in IKBalpha releases NFkB from the cytoplasm to enter the nucleus in an active state.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKBalpha	IKBalpha	IKBalpha	NFkB	NFkB	NFkB	0	1	2	3
A heterozygous gain-of-function mutation in NFKBIA was shown to impair NFkB activation and associate with X linked anhidrotic ectodermal dysplasia , T-cell immunodeficiency and polyclonal lymphocytosis .	A heterozygous gain-of-function mutation in NFKBIA was shown to impair NFkB activation and associate with X linked anhidrotic ectodermal dysplasia, T-cell immunodeficiency and polyclonal lymphocytosis.	3	11	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NFKBIA	NFKBIA	NFKBIA	NFkB	NFkB	NFkB	5	6	10	11
Degradation of the IkappaB-gamma component of p105 and partial reduction IkappaB-alpha selectively activate p50 and p50 dimers .	Degradation of the IkappaB-gamma component of p105 and partial reduction IkappaB-alpha selectively activate p50 and p50 dimers.	4	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	p50	p50	p50	10	11	13	14
Here , we show for the first time that activation of TNF-R1 in pinealocytes reduces the expression of NFKBIA , allowing the migration of NFKB to the nuclei , as observed in immune-competent cells and neurons .	Here, we show for the first time that activation of TNF-R1 in pinealocytes reduces the expression of NFKBIA, allowing the migration of NFKB to the nuclei, as observed in immune-competent cells and neurons.	11	25	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NFKBIA	TNF-R1 in pinealocytes reduces the expression of NFKBIA	nfkbia	NFKB	NFKB	nfkb	18	19	24	25
NFKB DNA binding activity and NFKBIA ( IkappaB-alpha ; inhibitor of NFKB ) protein degradation were analyzed by ELISA and Western blotting , respectively .	NFKB DNA binding activity and NFKBIA (IkappaB-alpha; inhibitor of NFKB) protein degradation were analyzed by ELISA and Western blotting, respectively.	5	12	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	NFKB	NFKB	NFKB	7	8	11	12
However , depletion of p100 , owing to non canonical mutations , altered the cellular homeostasis with RelB : p50 being sequestered by IkappaBalpha and consequently , induced upon TNF stimulation as an early NFkappaB activity ( XREF_FIG , XREF_FIG , XREF_FIG ) .	However, depletion of p100, owing to non canonical mutations, altered the cellular homeostasis with RelB : p50 being sequestered by IkappaBalpha and consequently, induced upon TNF stimulation as an early NFkappaB activity (XREF_FIG, XREF_FIG, XREF_FIG).	15	27	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	23	24	19	20
The increased level of IkappaBalpha degradation and translocation of p65 and p50 as a result of TPA stimulation were significantly suppressed by treatment with BVT948 ( XREF_FIG B ) .	The increased level of IkappaBalpha degradation and translocation of p65 and p50 as a result of TPA stimulation were significantly suppressed by treatment with BVT948 (XREF_FIG B).	4	12	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	4	5	11	12
Specifically , NFkB induced IkBa ( nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor , alpha ) will supress NFkB activity in a self-regulatory cycle .	Specifically, NFkB induced IkBa (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) will supress NFkB activity in a self-regulatory cycle.	2	23	supress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkBa	NFkB induced IkBa	ikba	NFkB	NFkB	nfkb	4	5	22	23
Here we show that the bacterially expressed and purified carboxy-terminal region ( CTR ) of p105 abolishes the binding of p50 homodimers to a kappa B motif but minimally affects the binding of p65 homodimers and NF-kappa B. By contrast , MAD-3 inhibits the binding of p65 and NF-kappa B but not p50 .	Here we show that the bacterially expressed and purified carboxy-terminal region (CTR) of p105 abolishes the binding of p50 homodimers to a kappa B motif but minimally affects the binding of p65 homodimers and NF-kappa B. By contrast, MAD-3 inhibits the binding of p65 and NF-kappa B but not p50.	41	53	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAD-3	MAD-3	MAD-3	p50	p50	p50	41	42	52	53
77 Loss-of-function mutations of the NFkB inhibitor NFKBIA will enhance NFkB activity .	77 Loss-of-function mutations of the NFkB inhibitor NFKBIA will enhance NFkB activity.	2	11	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NFKBIA	NFKBIA	NFKBIA	NFkB	NFkB	NFkB	7	8	10	11
The IkBalpha protein inhibits NFkB proteins by keeping them in an inactive state .	The IkBalpha protein inhibits NFkB proteins by keeping them in an inactive state.	1	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkBalpha protein	IkBalpha protein	IkBalpha protein	NFkB	NFkB	NFkB	1	3	4	5
In non stimulated cells , p50 and p65 NF-kappaB is sequestered in the cytoplasm by the inhibitor protein IkappaBalpha and upon stimulation , it undergoes phosphorylation and degradation in the proteasome , leading to the release of the p50 and p65 heterodimer , nuclear translocation , and DNA binding , leading to gene transcription XREF_BIBR XREF_BIBR .	In non stimulated cells, p50 and p65 NF-kappaB is sequestered in the cytoplasm by the inhibitor protein IkappaBalpha and upon stimulation, it undergoes phosphorylation and degradation in the proteasome, leading to the release of the p50 and p65 heterodimer, nuclear translocation, and DNA binding, leading to gene transcription XREF_BIBR XREF_BIBR.	5	19	sequestered	Negative_activation_syntax_4_verb	Negative_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	18	19	5	6
This mutant form of IkBalpha can not be phosphorylated and hence inhibits translocation of NFkB into the nucleus .	This mutant form of IkBalpha can not be phosphorylated and hence inhibits translocation of NFkB into the nucleus.	2	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkBalpha	IkBalpha can not be phosphorylated	ikbalpha	NFkB	NFkB	nfkb	4	5	14	15
In these cells nuclear export was necessary to prevent the cell growth factor Nfkb inactivation by Ikba accumulation in the nucleus [ XREF_BIBR ] .	In these cells nuclear export was necessary to prevent the cell growth factor Nfkb inactivation by Ikba accumulation in the nucleus [XREF_BIBR].	13	17	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Ikba	Ikba	Ikba	Nfkb	Nfkb	Nfkb	16	17	13	14
Bortezomib is a proteasome inhibitor , which blocks degradation of phosphorylated IkBalpha , subsequently inhibiting NFkB activity .	Bortezomib is a proteasome inhibitor, which blocks degradation of phosphorylated IkBalpha, subsequently inhibiting NFkB activity.	10	16	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkBalpha	phosphorylated IkBalpha	ikbalpha	NFkB	NFkB	nfkb	11	12	15	16
IkBalpha inhibits the transcription factor activity of NFkB by binding to it and sequestering it in the cytoplasm .	IkBalpha inhibits the transcription factor activity of NFkB by binding to it and sequestering it in the cytoplasm.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkBalpha	IkBalpha	IkBalpha	NFkB	NFkB	NFkB	0	1	7	8
Since NFKBIA suppresses NFKB function , inhibition of NFKBIA by overexpression of the lncRNA might further enhance cell proliferation .	Since NFKBIA suppresses NFKB function, inhibition of NFKBIA by overexpression of the lncRNA might further enhance cell proliferation.	1	4	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NFKBIA	NFKBIA	NFKBIA	NFKB	NFKB	NFKB	1	2	3	4
IkappaBalpha sequesters p65 : p50 in the cytoplasm and is a confirmed target of miR-30e * [ XREF_BIBR ] .	IkappaBalpha sequesters p65 : p50 in the cytoplasm and is a confirmed target of miR-30e * [XREF_BIBR].	0	7	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	0	1	4	5
3.1.4 IkappaBalpha SR prevents p65 , but not p50 , binding to IL-1beta responsive gene promoters .	3.1.4 IkappaBalpha SR prevents p65, but not p50, binding to IL-1beta responsive gene promoters.	0	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	1	2	8	9
Furthermore , salusin-beta in the PVN accelerated the nuclear translocation of the p65 subunit of nuclear factor kappa B ( NF-KB ) and the degradation of IKB-alpha ( an endogenous inhibitor of NF-KB ) .	Furthermore, salusin-beta in the PVN accelerated the nuclear translocation of the p65 subunit of nuclear factor kappa B (NF-KB) and the degradation of IKB-alpha (an endogenous inhibitor of NF-KB).	24	33	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	IKB-alpha	IKB-alpha	IKB-alpha	NF-KB	NF-KB	NF-KB	26	27	32	33
In order to gain further insight into the mechanism , AGE-BSA induced IkappaBalpha degradation and nuclear translocation of NF-kappaB p65 , p50 and Rel B have been studies in this report ( XREF_FIG and XREF_FIG ) .	In order to gain further insight into the mechanism, AGE-BSA induced IkappaBalpha degradation and nuclear translocation of NF-kappaB p65, p50 and Rel B have been studies in this report (XREF_FIG and XREF_FIG).	12	22	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	12	13	21	22
After addition of doxycycline ( dox ) , expression of IkBalpha-DN in the lungs of these transgenic mice has been shown to block NFkB activation 18 .	After addition of doxycycline (dox), expression of IkBalpha-DN in the lungs of these transgenic mice has been shown to block NFkB activation 18.	8	24	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkBalpha-DN	expression of IkBalpha-DN	ikbalpha-dn	NFkB	NFkB	nfkb	10	11	23	24
It is expected that some compounds are able to inhibit this degradation , and the phosphorylated form of IkBa can accumulate to inactivate NFkB .	It is expected that some compounds are able to inhibit this degradation, and the phosphorylated form of IkBa can accumulate to inactivate NFkB.	16	24	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkBa	IkBa	IkBa	NFkB	NFkB	NFkB	18	19	23	24
The NF and kappaB dimer p50 and p65 is normally sequestered in the cytosol by IkappaBalpha .	The NF and kappaB dimer p50 and p65 is normally sequestered in the cytosol by IkappaBalpha.	1	16	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	15	16	5	6
Activation of the canonical NF-kappaB pathway occurs when the IKKbeta ( IkappaB kinase beta ) kinase phosphorylates IkappaBalpha causing its degradation and release of the p50 and p65 ( RelA ) heterodimer allowing for translocation to the nucleus where it regulates gene expression .	Activation of the canonical NF-kappaB pathway occurs when the IKKbeta (IkappaB kinase beta) kinase phosphorylates IkappaBalpha causing its degradation and release of the p50 and p65 (RelA) heterodimer allowing for translocation to the nucleus where it regulates gene expression.	9	31	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	IKKbeta (IkappaB kinase beta) kinase phosphorylates IkappaBalpha	ikappabalpha	p50	p50	p50	17	18	25	26
The p-IkappaBalpha is then degraded by the proteasome , releasing the p50 and p65 NF-kappaB dimers and activating NF-kappaB signaling .	The p-IkappaBalpha is then degraded by the proteasome, releasing the p50 and p65 NF-kappaB dimers and activating NF-kappaB signaling.	0	15	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p-IkappaBalpha	p-IkappaBalpha	p-IkappaBalpha	p50	p50	p50	1	2	11	12
Given that IkappaBalpha proteins inhibit the transcriptional activity of p50 : p65 NFkappaB dimers , we sought to investigate if the anti-proliferative role of NFKBIA , indicated by the GSEA , was associated with changes in the expression pattern of NFkappaB target genes .	Given that IkappaBalpha proteins inhibit the transcriptional activity of p50 : p65 NFkappaB dimers, we sought to investigate if the anti-proliferative role of NFKBIA, indicated by the GSEA, was associated with changes in the expression pattern of NFkappaB target genes.	2	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	2	3	9	10
The compound also decreased tumor necrosis factor-alpha , interleukin ( IL )-1beta , and IL-12 production ; inhibited the phosphorylation and degradation of IkappaB-alpha ; and blocked the nuclear translocation of p50 and p65 in mouse BV2 microglia induced by LPS .	The compound also decreased tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-12 production; inhibited the phosphorylation and degradation of IkappaB-alpha; and blocked the nuclear translocation of p50 and p65 in mouse BV2 microglia induced by LPS.	8	33	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaB-alpha	interleukin (IL)-1beta, and IL-12 production; inhibited the phosphorylation and degradation of IkappaB-alpha	ikappab-alpha	p50	p50	p50	23	24	31	32
Pre-incubating the cells with 10 muM of the proteasome inhibitor MG-132 for 4 hr completely blocked IkappaBalpha degradation and nuclear translocation of p50 and p65 ( XREF_FIG ) .	Pre-incubating the cells with 10 muM of the proteasome inhibitor MG-132 for 4 hr completely blocked IkappaBalpha degradation and nuclear translocation of p50 and p65 (XREF_FIG).	16	26	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	16	17	22	23
Activation of the NF-kappaB1 pathway is initiated by signal dependent phosphorylation , ubiquitination , and subsequent degradation of IkappaBalpha , which allows cytoplasmic NF-kappaB1 ( p50 )-RelA complexes to stably translocate to the nucleus and activate gene transcription .	Activation of the NF-kappaB1 pathway is initiated by signal dependent phosphorylation, ubiquitination, and subsequent degradation of IkappaBalpha, which allows cytoplasmic NF-kappaB1 (p50)-RelA complexes to stably translocate to the nucleus and activate gene transcription.	10	35	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaBalpha	phosphorylation, ubiquitination, and subsequent degradation of IkappaBalpha	ikappabalpha	NF-kappaB1	NF-kappaB1	nf-kappab1	18	19	23	24
Under basal conditions , IkappaBalpha sequesters the NF-kappaB transcription factor heterodimer ( p50 and p65 ) in the cytoplasm .	Under basal conditions, IkappaBalpha sequesters the NF-kappaB transcription factor heterodimer (p50 and p65) in the cytoplasm.	4	14	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	4	5	12	13
NFKBIA is an inhibitor of NFKB , which has been associated with resistance to chemotherapeutics such as doxorubicin [ XREF_BIBR ] .	NFKBIA is an inhibitor of NFKB, which has been associated with resistance to chemotherapeutics such as doxorubicin [XREF_BIBR].	0	10	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	NFKBIA	NFKBIA	NFKBIA	NFKB	NFKB	NFKB	0	1	5	6
Following phosphorylation , IkappaBalpha becomes ubiquitinated by an E3 ligase complex consisting of beta transducing repeat containing protein ( beta-TrCP ) and is subsequently degraded by the proteasome , thus releasing p65 and p50 into the nucleus and allowing transcription to occur .	Following phosphorylation, IkappaBalpha becomes ubiquitinated by an E3 ligase complex consisting of beta transducing repeat containing protein (beta-TrCP) and is subsequently degraded by the proteasome, thus releasing p65 and p50 into the nucleus and allowing transcription to occur.	3	34	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	3	4	33	34
XREF_BIBR Overexpression of the IkappaBalpha superrepressor with an adenoviral vector markedly inhibited translocation of p50 and p65 into the nucleus in PASMCs from IPAH patients ( with the -254 G allele ) and significantly inhibited TNF-alpha-mediated upregulation of TRPC6 ( XREF_FIG ) .	XREF_BIBR Overexpression of the IkappaBalpha superrepressor with an adenoviral vector markedly inhibited translocation of p50 and p65 into the nucleus in PASMCs from IPAH patients (with the -254 G allele) and significantly inhibited TNF-alpha-mediated upregulation of TRPC6 (XREF_FIG).	1	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	Overexpression of the IkappaBalpha	ikappabalpha	p50	p50	p50	4	5	14	15
Myeloproliferative neoplasms ( MPN ) or myeloproliferation can be induced by deletion of IkBa ( an inhibitor of NFkB ) 176 , Mindbomb-1 ( a notch ligand regulator ) or retinoic acid receptor-gamma in the bone marrow microenvironment XREF_BIBR , XREF_BIBR .	Myeloproliferative neoplasms (MPN) or myeloproliferation can be induced by deletion of IkBa (an inhibitor of NFkB) 176, Mindbomb-1 (a notch ligand regulator) or retinoic acid receptor-gamma in the bone marrow microenvironment XREF_BIBR, XREF_BIBR.	11	19	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	IkBa	IkBa	IkBa	NFkB	NFkB	NFkB	13	14	18	19
In resting cells , cytoplasmic IkappaBalpha sequesters the canonical NFkappaB subunits p65 and p50 , preventing their nuclear translocation .	In resting cells, cytoplasmic IkappaBalpha sequesters the canonical NFkappaB subunits p65 and p50, preventing their nuclear translocation.	4	14	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	5	6	13	14
In contrast to IkappaBalpha , which sequesters p50 in the cytoplasm , BCL-3 is localized in the nucleus and alters the subnuclear localization of p50 .	In contrast to IkappaBalpha, which sequesters p50 in the cytoplasm, BCL-3 is localized in the nucleus and alters the subnuclear localization of p50.	1	10	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	3	4	7	8
Upon stimulation by cytokines or UV radiation , IkappaBalpha is phosphorylated , ubiquitinated , and degraded , releasing NF-kappaB p50 and p65 to translocate to the nucleus and transactivate target genes .	Upon stimulation by cytokines or UV radiation, IkappaBalpha is phosphorylated, ubiquitinated, and degraded, releasing NF-kappaB p50 and p65 to translocate to the nucleus and transactivate target genes.	8	20	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	IkappaBalpha is phosphorylated	ikappabalpha	NF-kappaB p50	NF-kappaB p50	nf-kappab p50	8	9	18	20
The inactivated NFKBIA sequesters NFKB1 in the cytosol [ XREF_BIBR ] .	The inactivated NFKBIA sequesters NFKB1 in the cytosol [XREF_BIBR].	0	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NFKBIA	NFKBIA	NFKBIA	NFKB1	NFKB1	NFKB1	2	3	4	5
In contrast , the expression of Bcl2 , XIAP and IkappaBalpha mRNA stimulated by cisplatin or mitomycin C treatment were unaffected by depletion of either p65 , p50 or BRCA1 ( XREF_FIG ) , indicating that activation by these damagers in our system is independent of p65 and p50 the most abundant NF and kappaB complex .	In contrast, the expression of Bcl2, XIAP and IkappaBalpha mRNA stimulated by cisplatin or mitomycin C treatment were unaffected by depletion of either p65, p50 or BRCA1 (XREF_FIG), indicating that activation by these damagers in our system is independent of p65 and p50 the most abundant NF and kappaB complex.	4	28	were unaffected by depletion	Negative_activation_copula_1	Negative_activation	Negative_activation	IkappaBalpha	expression of Bcl2, XIAP and IkappaBalpha	ikappabalpha	p50	p50	p50	10	11	27	28
Neurofibromin , the tumor suppressor encoded by the neurofibromatosis type 1 ( NF1 ) gene , potentially suppresses the activation of H-Ras , N-Ras and K-Ras .	Neurofibromin, the tumor suppressor encoded by the neurofibromatosis type 1 (NF1) gene, potentially suppresses the activation of H-Ras, N-Ras and K-Ras.	0	25	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Neurofibromin	Neurofibromin	Neurofibromin	H-Ras	H-Ras	H-Ras	0	1	21	22
The other MAPkinase activating genetic alteration include NF1 loss of function , MAP2K1 , C-RAF , K- or H-RAS , and alternate -non V600 mutations in the BRAF gene .	The other MAPkinase activating genetic alteration include NF1 loss of function, MAP2K1, C-RAF, K- or H-RAS, and alternate -non V600 mutations in the BRAF gene.	7	19	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	NF1	NF1	NF1	H-RAS	H-RAS	H-RAS	7	8	18	19
In NF1 , a mutation disrupts neurofibromin , a GTPase that negatively regulates p21Ras , resulting in an enhancement of Ras activity and upregulation of PI3K [ XREF_BIBR , XREF_BIBR ] .	In NF1, a mutation disrupts neurofibromin, a GTPase that negatively regulates p21Ras, resulting in an enhancement of Ras activity and upregulation of PI3K [XREF_BIBR, XREF_BIBR].	5	14	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	neurofibromin	neurofibromin	neurofibromin	p21Ras	p21Ras	p21Ras	6	7	13	14
The NF1 gene encodes neurofibromin 1 , which inhibits the GTPase HRAS and thus disrupts the RAS signaling pathway [ XREF_BIBR ] .	The NF1 gene encodes neurofibromin 1, which inhibits the GTPase HRAS and thus disrupts the RAS signaling pathway [XREF_BIBR].	3	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	neurofibromin	neurofibromin	neurofibromin	GTPase HRAS	GTPase HRAS	GTPase HRAS	4	5	10	12
NF1 is caused by mutations in the gene encoding neurofibromin , which inhibits p21Ras function .	NF1 is caused by mutations in the gene encoding neurofibromin, which inhibits p21Ras function.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	neurofibromin	neurofibromin	neurofibromin	p21Ras	p21Ras	p21Ras	9	10	13	14
A switch from the type 1 neurofibromin that can efficiently downregulate p21-ras to the type 2 isoform with reduced activity may facilitate a p21-ras signaling pathway associated with Schwann cell differentiation .	A switch from the type 1 neurofibromin that can efficiently downregulate p21-ras to the type 2 isoform with reduced activity may facilitate a p21-ras signaling pathway associated with Schwann cell differentiation.	1	12	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	neurofibromin	neurofibromin	neurofibromin	p21-ras	p21-ras	p21-ras	6	7	11	12
This particular GAP related domain of the NF1 gene ( NF1-GRD ) stimulates ras GTPase and inactivates ras protein p21ras .	This particular GAP related domain of the NF1 gene (NF1-GRD) stimulates ras GTPase and inactivates ras protein p21ras.	7	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NF1	NF1	NF1	p21ras	p21ras	p21ras	7	8	19	20
Our previous studies have shown that heterozygous loss of Nf1 ( Nf1 +/-) in MSPCs led to increased proliferation , hyper activation of p21-Ras and impaired MSPC differentiation into osteoblasts [ XREF_BIBR ] .	Our previous studies have shown that heterozygous loss of Nf1 (Nf1 +/-) in MSPCs led to increased proliferation, hyper activation of p21-Ras and impaired MSPC differentiation into osteoblasts [XREF_BIBR].	7	27	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Nf1	loss of Nf1	nf1	p21-Ras	p21-Ras	p21-ras	9	10	23	24
Cx32 protein was increased in optic-nerve lysates after Nf1 loss or hyperactivation of HRas ( XREF_FIG ) .	Cx32 protein was increased in optic-nerve lysates after Nf1 loss or hyperactivation of HRas (XREF_FIG).	8	15	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Nf1	Nf1	Nf1	HRas	HRas	HRas	8	9	13	14
3.3 SMRT repression of AR is dependent on the AR/corepressor ratio .	3.3 SMRT repression of AR is dependent on the AR/corepressor ratio.	1	5	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SMRT	SMRT	SMRT	AR	AR	AR	1	2	4	5
Both NCOR1 and NCOR2 are recruited to PSA promoter in an AR dependent manner and can inhibit both agonist and partial antagonist dependent AR activity .	Both NCOR1 and NCOR2 are recruited to PSA promoter in an AR dependent manner and can inhibit both agonist and partial antagonist dependent AR activity.	1	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NCOR2	NCOR2	NCOR2	AR	AR	AR	3	4	23	24
The degree to which SMRT was able to repress AR increased from 17 % to 56 % as the AR polyglutamine repeat length was increased from 9 to 42 residues , but critically this effect could be abolished by increasing the SMRT : AR molar ratio .	The degree to which SMRT was able to repress AR increased from 17% to 56% as the AR polyglutamine repeat length was increased from 9 to 42 residues, but critically this effect could be abolished by increasing the SMRT : AR molar ratio.	4	10	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMRT	SMRT	SMRT	AR	AR	AR	4	5	9	10
In this study , we have shown that SMRT is able to reduce agonist activated AR responses on multiple responsive sites .	In this study, we have shown that SMRT is able to reduce agonist activated AR responses on multiple responsive sites.	8	16	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMRT	SMRT	SMRT	AR	AR	AR	8	9	15	16
In particular , Dicer mediated maturation of microRNAs ( miRNAs ) suppresses the expression level of AR co-repressors , NCoR and SMRT , leading to enhance AR transcriptional activity .	In particular, Dicer mediated maturation of microRNAs (miRNAs) suppresses the expression level of AR co-repressors, NCoR and SMRT, leading to enhance AR transcriptional activity.	17	27	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMRT	SMRT	SMRT	AR	AR	AR	21	22	26	27
3.1 SMRT repression of agonist activated AR .	3.1 SMRT repression of agonist activated AR.	1	7	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SMRT	SMRT	SMRT	AR	AR	AR	1	2	6	7
Although evidence supports that AR transcriptional activity is repressed by nuclear receptor corepressor 1 ( NCOR1 ) , NCOR2 , and PLZF and ZBTB16 [ XREF_BIBR - XREF_BIBR ] , genomic alterations in AR , FOXA1 , and these corepressors were reported in a large CRPC cohort [ XREF_BIBR ] .	Although evidence supports that AR transcriptional activity is repressed by nuclear receptor corepressor 1 (NCOR1), NCOR2, and PLZF and ZBTB16 [XREF_BIBR - XREF_BIBR], genomic alterations in AR, FOXA1, and these corepressors were reported in a large CRPC cohort [XREF_BIBR].	4	19	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	NCOR2	NCOR2	NCOR2	AR	AR	AR	18	19	4	5
NCOR2 is a repressor of AR , and an additional target of miR-125b that was confirmed by luciferase binding assay .	NCOR2 is a repressor of AR, and an additional target of miR-125b that was confirmed by luciferase binding assay.	0	6	is a repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	NCOR2	NCOR2	NCOR2	AR	AR	AR	0	1	5	6
Using specific small interference RNAs to knock down SMRT and/or N-CoR in LNCaP cells , we found that SMRT and N-CoR not only mediate antagonist dependent inhibition of AR activation but also have a widespread role in suppressing agonist dependent activation of several AR target genes we have tested , including PSA ( prostate specific antigen ) , TSC22 ( TSC22 domain family member 1 ) , NKX3-1 ( NK3 transcription factor locus 1 ) , and B2M ( beta-2-microglobulin ) .	Using specific small interference RNAs to knock down SMRT and/or N-CoR in LNCaP cells, we found that SMRT and N-CoR not only mediate antagonist dependent inhibition of AR activation but also have a widespread role in suppressing agonist dependent activation of several AR target genes we have tested, including PSA (prostate specific antigen), TSC22 (TSC22 domain family member 1), NKX3-1 (NK3 transcription factor locus 1), and B2M (beta-2-microglobulin).	18	32	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SMRT	SMRT	SMRT	AR	AR	AR	18	19	28	29
IKK mediated p105 degradation results in activation of the Cot and Tpl2 kinase , resulting in activation of extracellular signal regulated kinase ( ERK ) .	IKK mediated p105 degradation results in activation of the Cot and Tpl2 kinase, resulting in activation of extracellular signal regulated kinase (ERK).	0	12	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	p105	IKK mediated p105	p105	Cot	Cot	cot	2	3	9	10
TPL2 forms a stable complex with p105 , in which p105 both stabilizes TPL2 and prevents the access of TPL2 to its substrate protein MEK1/2 .	TPL2 forms a stable complex with p105, in which p105 both stabilizes TPL2 and prevents the access of TPL2 to its substrate protein MEK1/2.	10	20	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p105	p105	p105	TPL2	TPL2	TPL2	10	11	19	20
Interestingly , p105 does not inhibit the catalytic activity of TPL2 , so it is possible that other targets of this molecule are being phosphorylated , but being in complex with p105 somehow prevents phosphorylation of MEK .	Interestingly, p105 does not inhibit the catalytic activity of TPL2, so it is possible that other targets of this molecule are being phosphorylated, but being in complex with p105 somehow prevents phosphorylation of MEK.	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p105	p105	p105	TPL2	TPL2	TPL2	2	3	10	11
Future studies will determine whether direct interaction of GRK2 with p105 might block IKKbeta phosphorylation of p105 thus preventing p105 degradation and TPL2 release .	Future studies will determine whether direct interaction of GRK2 with p105 might block IKKbeta phosphorylation of p105 thus preventing p105 degradation and TPL2 release.	8	23	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p105	GRK2 with p105 might block IKKbeta phosphorylation of p105	p105	TPL2	TPL2	tpl2	16	17	22	23
LPS activation of ERK requires TPL-2 release from associated NF-kappaB1 p105 , which blocks TPL-2 access to its substrate , the ERK kinase MEK .	LPS activation of ERK requires TPL-2 release from associated NF-kappaB1 p105, which blocks TPL-2 access to its substrate, the ERK kinase MEK.	4	15	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p105	p105	p105	TPL-2	TPL-2	TPL-2	10	11	14	15
The death domain ( DD ) of p105 directly interacts with the kinase domain ( KD ) of TPL2 , thereby inhibiting the access of TPL2 by its substrate , MEK1 .	The death domain (DD) of p105 directly interacts with the kinase domain (KD) of TPL2, thereby inhibiting the access of TPL2 by its substrate, MEK1.	2	26	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p105	p105	p105	TPL2	TPL2	TPL2	7	8	25	26
Binding of p105 prevents TPL-2 from phosphorylating its downstream targets , MEK-1/2 , and is also required to maintain TPL-2 protein stability .	Binding of p105 prevents TPL-2 from phosphorylating its downstream targets, MEK-1/2, and is also required to maintain TPL-2 protein stability.	0	5	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p105	p105	p105	TPL-2	TPL-2	TPL-2	2	3	4	5
Also , we included in our study another variant form of GDF5 that was designed by Biopharm to be insensitive to the GDF5 antagonist noggin .	Also, we included in our study another variant form of GDF5 that was designed by Biopharm to be insensitive to the GDF5 antagonist noggin.	19	25	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	GDF5	GDF5	GDF5	24	25	22	23
On the one hand insensitivity to the main GDF5 antagonist NOGGIN ( NOG ) leads to a GDF5 gain of function and subsequent SYNS2 phenotype .	On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype.	4	14	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	NOGGIN	NOGGIN	NOGGIN	GDF5	GDF5	GDF5	10	11	8	9
A relationship between Ror2 and BMP signaling was reproduced in a second study where mutations were detected in the gene encoding the GDF5 antagonist NOGGIN , in patients with BDB without Ror2 mutations [ XREF_BIBR ] .	A relationship between Ror2 and BMP signaling was reproduced in a second study where mutations were detected in the gene encoding the GDF5 antagonist NOGGIN, in patients with BDB without Ror2 mutations [XREF_BIBR].	20	27	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	NOGGIN	NOGGIN	NOGGIN	GDF5	GDF5	GDF5	24	25	22	23
In addition , we used a second variant form of GDF5 , also designed by Biopharm that is insensitive to the GDF5 antagonist noggin ( variant B ) .	In addition, we used a second variant form of GDF5, also designed by Biopharm that is insensitive to the GDF5 antagonist noggin (variant B).	18	26	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	GDF5	GDF5	GDF5	23	24	21	22
We also studied variants of GDF5 , one that has a higher affinity for the receptor BMPR-IA and one that is insensitive to the GDF5 antagonist noggin .	We also studied variants of GDF5, one that has a higher affinity for the receptor BMPR-IA and one that is insensitive to the GDF5 antagonist noggin.	21	27	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	GDF5	GDF5	GDF5	26	27	24	25
We next tested whether knockdown of Necdin induces recovery of transcriptional activity of E2F1 reduced by CB1R activation .	We next tested whether knockdown of Necdin induces recovery of transcriptional activity of E2F1 reduced by CB1R activation.	4	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Necdin	Necdin	Necdin	E2F1	E2F1	E2F1	6	7	13	14
Previous studies have shown that necdin binds to the transactivation domain of E2F1 at the carboxyl terminus to repress E2F1 transactivation .	Previous studies have shown that necdin binds to the transactivation domain of E2F1 at the carboxyl terminus to repress E2F1 transactivation.	5	20	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	necdin	necdin	necdin	E2F1	E2F1	E2F1	5	6	19	20
In HEK293A cells transfected with luciferase reporter constructs , necdin relieves Bmi1 dependent repression of p16 promoter activity , whereas Bmi1 counteracts necdin mediated repression of E2F1 dependent Cdk1 promoter activity .	In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1 dependent repression of p16 promoter activity, whereas Bmi1 counteracts necdin mediated repression of E2F1 dependent Cdk1 promoter activity.	22	30	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	necdin	necdin	necdin	E2F1	E2F1	E2F1	22	23	26	27
Ndn binds to the transactivational domain of E2f1 and E2f4 , and represses E2f1 induced transactivation .	Ndn binds to the transactivational domain of E2f1 and E2f4, and represses E2f1 induced transactivation.	0	15	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ndn	Ndn	Ndn	E2f1	E2f1	E2f1	0	1	13	14
Necdin is located in the nucleus and is proposed as a transcription factor to repress E2F1 .	Necdin is located in the nucleus and is proposed as a transcription factor to repress E2F1.	0	16	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Necdin	Necdin	Necdin	E2F1	E2F1	E2F1	0	1	15	16
The enhanced adiposity in the mice is due in part to greater caloric intake , however , there was also enhanced adipogenesis , likely due to the absence of SMRT repression of PPARgamma .	The enhanced adiposity in the mice is due in part to greater caloric intake, however, there was also enhanced adipogenesis, likely due to the absence of SMRT repression of PPARgamma.	29	33	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SMRT	SMRT	SMRT	PPARgamma	PPARgamma	PPARgamma	29	30	32	33
Recent evidence , however , suggests that NCoR and SMRT repress PPARgamma mediated transcriptional activity on specific promoters in the adipocyte .	Recent evidence, however, suggests that NCoR and SMRT repress PPARgamma mediated transcriptional activity on specific promoters in the adipocyte.	7	12	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMRT	SMRT	SMRT	PPARgamma	PPARgamma	PPARgamma	9	10	11	12
Recently , we have shown that NCoR and SMRT down-regulate PPARgamma mediated transcriptional activity in 3T3-L1 cells , a fibroblast cell line that retains the ability to differentiate into adipocytes in the appropriate hormone milieu [ XREF_BIBR ] .	Recently, we have shown that NCoR and SMRT down-regulate PPARgamma mediated transcriptional activity in 3T3-L1 cells, a fibroblast cell line that retains the ability to differentiate into adipocytes in the appropriate hormone milieu [XREF_BIBR].	6	11	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMRT	SMRT	SMRT	PPARgamma	PPARgamma	PPARgamma	8	9	10	11
Given that N-CoR and SMRT are co-repressors of PPARgamma , we performed DNA-pull down assay to determine their association with the miR-122 DR1 and DR2 motifs .	Given that N-CoR and SMRT are co-repressors of PPARgamma, we performed DNA-pull down assay to determine their association with the miR-122 DR1 and DR2 motifs.	2	9	are co-repressors	Negative_activation_copula_1	Negative_activation	Negative_activation	SMRT	SMRT	SMRT	PPARgamma	PPARgamma	PPARgamma	4	5	8	9
C14orf166 interacts with ninein to block the phosphorylation of ninein catalyzed by GSK-3beta [ XREF_BIBR ] , suggesting C14orf166 may inhibit ninein , and activate JAK2 to promote breast cancer progression , but this speculation remain to be confirmation .	C14orf166 interacts with ninein to block the phosphorylation of ninein catalyzed by GSK-3beta [XREF_BIBR], suggesting C14orf166 may inhibit ninein, and activate JAK2 to promote breast cancer progression, but this speculation remain to be confirmation.	0	26	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ninein	C14orf166 interacts with ninein to block the phosphorylation of ninein	ninein	JAK2	JAK2	jak2	9	10	25	26
We showed that JAK2 directly phosphorylates the N terminus of ninein while the C terminus of ninein inhibits JAK2 kinase activity in vitro .	We showed that JAK2 directly phosphorylates the N terminus of ninein while the C terminus of ninein inhibits JAK2 kinase activity in vitro.	14	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ninein	ninein	ninein	JAK2	JAK2	JAK2	16	17	18	19
NEK11 mediated phosphorylation of CDC25A required the priming phosphorylation of Ser76 by CHK1 , and CHK1 dependent phosphorylation of NEK11 activated CDC25A degradation .	NEK11 mediated phosphorylation of CDC25A required the priming phosphorylation of Ser76 by CHK1, and CHK1 dependent phosphorylation of NEK11 activated CDC25A degradation.	0	5	mediated	Positive_early_regulation	Negative_activation	Positive_regulation	NEK11	NEK11	nek11	CDC25A	phosphorylation of CDC25A	cdc25a	0	1	4	5
NEK11 controls degradation of CDC25A by directly phosphorylating CDC25A on residues whose phosphorylation is required for beta-TrCP mediated CDC25A polyubiquitylation and degradation .	NEK11 controls degradation of CDC25A by directly phosphorylating CDC25A on residues whose phosphorylation is required for beta-TrCP mediated CDC25A polyubiquitylation and degradation.	0	7	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	NEK11	NEK11	NEK11	CDC25A	CDC25A	CDC25A	0	1	4	5
Moreover , Nek11 was identified in a screen for genes required for G2/M arrest in U2OS cells exposed to IR , with Nek11 promoting Cdc25A degradation downstream of Chk1 [ XREF_BIBR ] .	Moreover, Nek11 was identified in a screen for genes required for G2/M arrest in U2OS cells exposed to IR, with Nek11 promoting Cdc25A degradation downstream of Chk1 [XREF_BIBR].	10	25	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Nek11	Nek11	Nek11	Cdc25A	Cdc25A	Cdc25A	22	23	24	25
Cell based transcription assays show that PPARgamma coactivator 1alpha ( PGC-1alpha ) and cAMP response element binding protein binding protein ( CBP ) enhance the basal and ligand stimulated receptor activity acting as coactivators of PPARgamma , whereas the receptor interacting protein 140 ( RIP140 ) and the nuclear corepressor 1 ( N-CoR1 ) repress the transcriptional activity of PPARgamma .	Cell based transcription assays show that PPARgamma coactivator 1alpha (PGC-1alpha) and cAMP response element binding protein binding protein (CBP) enhance the basal and ligand stimulated receptor activity acting as coactivators of PPARgamma, whereas the receptor interacting protein 140 (RIP140) and the nuclear corepressor 1 (N-CoR1) repress the transcriptional activity of PPARgamma.	44	60	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	N-CoR1	N-CoR1	N-CoR1	PPARgamma	PPARgamma	PPARgamma	52	53	59	60
In this study , we show that exogenous expression of NCoR or SMRT suppresses all 8-bromo-cAMP-mediated potentiation of PR transcriptional activity .	In this study, we show that exogenous expression of NCoR or SMRT suppresses all 8-bromo-cAMP-mediated potentiation of PR transcriptional activity.	8	20	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMRT	expression of NCoR or SMRT	smrt	PR	PR	pr	12	13	18	19
SMRT represses PR in the presence of either progestins or progesterone receptor antagonist RU486 [ XREF_BIBR , XREF_BIBR ] .	SMRT represses PR in the presence of either progestins or progesterone receptor antagonist RU486 [XREF_BIBR, XREF_BIBR].	0	5	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMRT	SMRT	SMRT	PR	PR	PR	0	1	2	3
nNOS causes nitric oxide production , S nitrosylation and subsequent inhibition of HDAC2 that directly controls expression of miR-133 and miR-1 and miR-29 .	nNOS causes nitric oxide production, S nitrosylation and subsequent inhibition of HDAC2 that directly controls expression of miR-133 and miR-1 and miR-29.	0	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	nNOS	nNOS	nNOS	HDAC2	HDAC2	HDAC2	0	1	12	13
Western blotting experiments showed that the full length NAIP and its BIR3 domain inhibited the cleavage of procaspase-3 by apoptosome activated caspase-9 .	Western blotting experiments showed that the full length NAIP and its BIR3 domain inhibited the cleavage of procaspase-3 by apoptosome activated caspase-9.	5	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NAIP	NAIP	NAIP	caspase-9	caspase-9	caspase-9	8	9	21	22
We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity .	We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity.	12	18	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	nucleolin	nucleolin	nucleolin	Myb	Myb	Myb	14	15	16	17
However , Nck knockdown or inhibition of Abl did not affect their phosphorylation levels compared to control cells ( XREF_FIG ) .	However, Nck knockdown or inhibition of Abl did not affect their phosphorylation levels compared to control cells (XREF_FIG).	2	8	knockdown	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Nck	Nck	Nck	Abl	Abl	Abl	2	3	7	8
The prostate specific homeobox protein , NKX3.1 , was found to negatively regulate VEGF-C synthesis by binding to a specific promoter site on the VEGF-C gene , recruiting histone deacetylase 1 and thereby inhibiting its transcription [ XREF_BIBR ] .	The prostate specific homeobox protein, NKX3.1, was found to negatively regulate VEGF-C synthesis by binding to a specific promoter site on the VEGF-C gene, recruiting histone deacetylase 1 and thereby inhibiting its transcription [XREF_BIBR].	4	31	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NKX3.1	NKX3.1	NKX3.1	histone deacetylase 1	histone deacetylase 1	histone deacetylase 1	6	7	28	31
NKX3-1 negatively regulates the PI3K-AKT pathway to suppress tumor growth , and heterozygous deletions of NKX3-1 and PTEN cause prostate adenocarcinomas in mice .	NKX3-1 negatively regulates the PI3K-AKT pathway to suppress tumor growth, and heterozygous deletions of NKX3-1 and PTEN cause prostate adenocarcinomas in mice.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NKX3-1	NKX3-1	NKX3-1	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	4	5
Notch antagonist Numb and Brat function cooperatively to promote the INP fate XREF_BIBR .	Notch antagonist Numb and Brat function cooperatively to promote the INP fate XREF_BIBR.	0	8	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	2	3	0	1
Here , we investigate how Numb or Numbl -- inhibitors of Notch signalling -- modulate EMT , a process that can contribute to both metastasis and drug resistance .	Here, we investigate how Numb or Numbl -- inhibitors of Notch signalling -- modulate EMT, a process that can contribute to both metastasis and drug resistance.	5	14	inhibitors	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	11	12
Increased level of NUMB and APC protein will block Notch and Wnt signaling , respectively .	Increased level of NUMB and APC protein will block Notch and Wnt signaling, respectively.	1	12	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	level of NUMB	numb	Notch	Notch	notch	3	4	9	10
This observation is consistent with reports that Numb promotes NICD degradation downstream of Notch cleavage [ XREF_BIBR ] .	This observation is consistent with reports that Numb promotes NICD degradation downstream of Notch cleavage [XREF_BIBR].	7	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	7	8	13	14
We found that sustained or late Numb overexpression does not promote hair cell differentiation , and Numb does not prevent the reception of Notch signaling .	We found that sustained or late Numb overexpression does not promote hair cell differentiation, and Numb does not prevent the reception of Notch signaling.	16	24	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	16	17	23	24
Second , decreased expression of NUMB can result in increased Notch signaling .	Second, decreased expression of NUMB can result in increased Notch signaling.	3	12	signaling	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	NUMB	expression of NUMB	numb	Notch	Notch	notch	5	6	10	11
Since Numb can antagonize Notch signaling in several systems XREF_BIBR , XREF_BIBR , XREF_BIBR , we tested whether Numb and Notch had a reciprocal relationship in CML .	Since Numb can antagonize Notch signaling in several systems XREF_BIBR, XREF_BIBR, XREF_BIBR, we tested whether Numb and Notch had a reciprocal relationship in CML.	1	5	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	1	2	4	5
Hence , they investigated whether Numb , which inhibits Notch signaling by facilitating proteasome mediated degradation of the Notch receptor , might induce ADCs to differentiate into hepatocytes .	Hence, they investigated whether Numb, which inhibits Notch signaling by facilitating proteasome mediated degradation of the Notch receptor, might induce ADCs to differentiate into hepatocytes.	5	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	9	10
Since Numb will block Notch signaling from specifying a sib fate , the daughter cells of those GMCs in which the distribution of Numb is non asymmetric will inherit Numb and are expected to adopt an RP2 fate in neur mutants .	Since Numb will block Notch signaling from specifying a sib fate, the daughter cells of those GMCs in which the distribution of Numb is non asymmetric will inherit Numb and are expected to adopt an RP2 fate in neur mutants.	1	5	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	1	2	4	5
Numb is an antagonist of the transcription factor Notch and both proteins regulate the pro proliferative Ras signaling cascade .	Numb is an antagonist of the transcription factor Notch and both proteins regulate the pro proliferative Ras signaling cascade.	0	9	is an antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	8	9
In SOP cells , Numb , a known endocytic regulator , is asymmetrically localized during progenitor mitosis and acts to block Notch pathway activation cell-autonomously in the pIIb daughter cell that inherits it .	In SOP cells, Numb, a known endocytic regulator, is asymmetrically localized during progenitor mitosis and acts to block Notch pathway activation cell-autonomously in the pIIb daughter cell that inherits it.	4	23	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	21	22
Furthermore , the mechanism for initiating myogenic differentiation in undifferentiated precursors implicates the Notch antagonist Numb , which is asymmetrically distributed into dividing cells .	Furthermore, the mechanism for initiating myogenic differentiation in undifferentiated precursors implicates the Notch antagonist Numb, which is asymmetrically distributed into dividing cells.	11	20	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	15	16	13	14
In this regard , Notch 3 and Notch ligands Jagged 1 and 2 were downregulated in Terc-/- tumors and the Notch antagonist Numb was upregulated .	In this regard, Notch 3 and Notch ligands Jagged 1 and 2 were downregulated in Terc-/- tumors and the Notch antagonist Numb was upregulated.	19	24	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	22	23	20	21
GFRA1 has been shown to increase NUMB expression which in turn degrades NOTCH ; the net result of decreased GFRA1 expression is increased NOTCH .	GFRA1 has been shown to increase NUMB expression which in turn degrades NOTCH; the net result of decreased GFRA1 expression is increased NOTCH.	6	13	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	6	7	12	13
Numb is an antagonist of Notch , a receptor involved in cell fate determination and in differentiation and survival .	Numb is an antagonist of Notch, a receptor involved in cell fate determination and in differentiation and survival.	0	8	is an antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	5	6
NUMB inhibits Notch signaling by binding to its intracellular domain , directing it into degradation pathways , and it has been implicated in the regulation of some aspects of neuronal differentiation .	NUMB inhibits Notch signaling by binding to its intracellular domain, directing it into degradation pathways, and it has been implicated in the regulation of some aspects of neuronal differentiation.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	0	1	2	3
Thus , Numb functions in endosomes to prevent AP-1-mediated recycling of Notch and Sanpodo to the pIIb cell surface , in line with previous studies implicating Numb in the regulation of endosomal traffic in mammals and C. elegans .	Thus, Numb functions in endosomes to prevent AP-1-mediated recycling of Notch and Sanpodo to the pIIb cell surface, in line with previous studies implicating Numb in the regulation of endosomal traffic in mammals and C. elegans.	2	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	2	3	11	12
NUMB negatively regulates notch signaling and plays a role in retinal neurogenesis , influencing the proliferation and differentiation of retinal progenitors and maturation of postmitotic neurons XREF_BIBR .	NUMB negatively regulates notch signaling and plays a role in retinal neurogenesis, influencing the proliferation and differentiation of retinal progenitors and maturation of postmitotic neurons XREF_BIBR.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	notch	notch	notch	0	1	3	4
Our findings support the model that the formation of a Numb , Sanpodo , and Notch complex results in Numb mediated Notch cleavage inhibition , perhaps through posttranslational modification and degradation or endocytosis of the Notch receptor .	Our findings support the model that the formation of a Numb, Sanpodo, and Notch complex results in Numb mediated Notch cleavage inhibition, perhaps through posttranslational modification and degradation or endocytosis of the Notch receptor.	19	23	mediated	Positive_early_activation	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	19	20	21	22
NUMB inhibits Notch signaling in progenitor cells to induce differentiation , while JAG1 activates Notch signaling in stem cells to maintain self-renewal potential .	NUMB inhibits Notch signaling in progenitor cells to induce differentiation, while JAG1 activates Notch signaling in stem cells to maintain self-renewal potential.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	0	1	2	3
However , the mechanisms by which Numb influences tumorigenicity and cancer remain to be determined and the exact mechanism by which Numb antagonizes Notch are still elusive .	However, the mechanisms by which Numb influences tumorigenicity and cancer remain to be determined and the exact mechanism by which Numb antagonizes Notch are still elusive.	21	24	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	21	22	23	24
Numb negatively regulated Notch signaling pathway in EMT of DN , implying that they had great potentials to serve as therapeutic targets or diagnostic biomarkers for DN .	Numb negatively regulated Notch signaling pathway in EMT of DN, implying that they had great potentials to serve as therapeutic targets or diagnostic biomarkers for DN.	0	5	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	3	4
Glycogen showed particularly strong associations with the JAK-STAT activated transcription factor chinmo 34 , the EGFR responsive transcription factor seven up ( svp ) , as well as the morphogen nuf ; numb ( an antagonist of Notch signaling ) and CG5867 , which contains a protein domain for juvenile hormone binding .	Glycogen showed particularly strong associations with the JAK-STAT activated transcription factor chinmo 34, the EGFR responsive transcription factor seven up (svp), as well as the morphogen nuf; numb (an antagonist of Notch signaling) and CG5867, which contains a protein domain for juvenile hormone binding.	30	38	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	numb	numb	numb	Notch	Notch	Notch	32	33	37	38
Fly and mouse studies have shown that Numb suppresses Notch signaling in the developing nervous system , raising the possibility that Numb might restrict the GMC potential by antagonizing Notch signaling .	Fly and mouse studies have shown that Numb suppresses Notch signaling in the developing nervous system, raising the possibility that Numb might restrict the GMC potential by antagonizing Notch signaling.	21	30	restrict	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	21	22	29	30
In Drosophila , Numb function is to suppress Notch signaling during neurogenesis .	In Drosophila, Numb function is to suppress Notch signaling during neurogenesis.	3	9	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	3	4	8	9
In presence of DETA-NO or HIF-In , expression of Dll1 and of Notch was delayed ; the Notch antagonist Numb was upregulated at early times , and myoblast specific Myf5 expression was not evident after 24h ( XREF_FIG ) .	In presence of DETA-NO or HIF-In, expression of Dll1 and of Notch was delayed; the Notch antagonist Numb was upregulated at early times, and myoblast specific Myf5 expression was not evident after 24h (XREF_FIG).	16	21	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	19	20	17	18
One of the canonical functions of Numb is to inhibit Notch signaling by recruiting ubiquitin ligases to degrade cell surface associated and intracellular Notch proteins .	One of the canonical functions of Numb is to inhibit Notch signaling by recruiting ubiquitin ligases to degrade cell surface associated and intracellular Notch proteins.	4	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	10	11
The Notch pathway is negatively regulated by NUMB , which interacts with the NICD in such a way to interfere with its nuclear translocation and to allow for the ubiquitination of the NICD prior to its proteasomal degradation [ XREF_BIBR - XREF_BIBR ] .	The Notch pathway is negatively regulated by NUMB, which interacts with the NICD in such a way to interfere with its nuclear translocation and to allow for the ubiquitination of the NICD prior to its proteasomal degradation [XREF_BIBR - XREF_BIBR].	1	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	NUMB	NUMB, which interacts with the NICD	numb	Notch	Notch	notch	7	8	1	2
However , recent evidence suggests that although forced expression of Numb in myogenic progenitors does not abrogate canonical Notch signaling , it can stimulate the self-renewal of myogenic progenitors [ XREF_BIBR ] .	However, recent evidence suggests that although forced expression of Numb in myogenic progenitors does not abrogate canonical Notch signaling, it can stimulate the self-renewal of myogenic progenitors [XREF_BIBR].	8	19	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	expression of Numb	numb	Notch	Notch	notch	10	11	18	19
Numb may inhibit canonical Notch activity by direct interaction or as a mediator recruiting other factors to prevent the nuclear translocation of Notch protein [ XREF_BIBR , XREF_BIBR ] .	Numb may inhibit canonical Notch activity by direct interaction or as a mediator recruiting other factors to prevent the nuclear translocation of Notch protein [XREF_BIBR, XREF_BIBR].	0	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	4	5
The daughter cell that received Numb and NEUR follows the neural specialization to form neuron and thecogen , as Numb blocks the transmission of Notch signal into this cell , while NEUR enhances the signal transduction into the other cell free of the proteins in question .	The daughter cell that received Numb and NEUR follows the neural specialization to form neuron and thecogen, as Numb blocks the transmission of Notch signal into this cell, while NEUR enhances the signal transduction into the other cell free of the proteins in question.	19	25	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	19	20	24	25
Combining this previous lineage information with our Ilp7 analysis indicates that the MP2 precursor division in A6-A9 generates an Ilp7 + neuron ( dMP2 ) , in which Numb suppresses Notch signalling , and an Ilp7 - Numb - sibling neuron ( vMP2 ) with active Notch signalling .	Combining this previous lineage information with our Ilp7 analysis indicates that the MP2 precursor division in A6-A9 generates an Ilp7 + neuron (dMP2), in which Numb suppresses Notch signalling, and an Ilp7 - Numb - sibling neuron (vMP2) with active Notch signalling.	28	31	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	28	29	30	31
Numb overexpression does not strongly inhibit Notch activity in the ear .	Numb overexpression does not strongly inhibit Notch activity in the ear.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	6	7
This leads to decreased Numb expression , which then initiates downstream Notch signaling and facilitates cell proliferation and tumorigenesis [ XREF_BIBR ] .	This leads to decreased Numb expression, which then initiates downstream Notch signaling and facilitates cell proliferation and tumorigenesis [XREF_BIBR].	4	12	initiates	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	11	12
Thus , it is unclear whether Numb suppresses glioblastoma growth by antagonizing Notch signaling , whether it establishes the differentiation hierarchy of GSCs as it does for normal neural stem and progenitor cells , or whether it plays no role in glioblastoma .	Thus, it is unclear whether Numb suppresses glioblastoma growth by antagonizing Notch signaling, whether it establishes the differentiation hierarchy of GSCs as it does for normal neural stem and progenitor cells, or whether it plays no role in glioblastoma.	6	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	12	13
Notch signaling is negatively regulated by Numb , an intrinsic factor that regulates cellular competence .	Notch signaling is negatively regulated by Numb, an intrinsic factor that regulates cellular competence.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	0	1
We further show that Eya1 protein regulates cell polarity , spindle orientation and the localization of Numb , which inhibits Notch signaling .	We further show that Eya1 protein regulates cell polarity, spindle orientation and the localization of Numb, which inhibits Notch signaling.	14	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	16	17	20	21
Other studies suggest that notch signaling is inhibited by the cell fate determinant Numb .	Other studies suggest that notch signaling is inhibited by the cell fate determinant Numb.	4	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	notch	notch	notch	13	14	4	5
Numb antagonizes Notch signaling through multiple mechanisms .	Numb antagonizes Notch signaling through multiple mechanisms.	0	3	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	2	3
When Numb was overexpressed to inhibit Notch signaling in T cells , T cell maturation and development also remained intact XREF_BIBR .	When Numb was overexpressed to inhibit Notch signaling in T cells, T cell maturation and development also remained intact XREF_BIBR.	1	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb was overexpressed	numb	Notch	Notch	notch	1	2	6	7
One example for such an interaction is the inhibition of Notch by Numb in the ' Notch signaling pathway ' .	One example for such an interaction is the inhibition of Notch by Numb in the ' Notch signaling pathway '.	8	14	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	12	13	10	11
In the mammary epithelium , the Notch antagonist Numb is expressed throughout the luminal layer and in rare basal cells .	In the mammary epithelium, the Notch antagonist Numb is expressed throughout the luminal layer and in rare basal cells.	5	11	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb is expressed	numb	Notch	Notch	notch	8	9	6	7
Thus during mouse cortical neurogenesis , as in Drosophila neurogenesis , asymmetric segregation of Numb could inhibit Notch activity in one daughter to induce neuronal differentiation .	Thus during mouse cortical neurogenesis, as in Drosophila neurogenesis, asymmetric segregation of Numb could inhibit Notch activity in one daughter to induce neuronal differentiation.	12	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	14	15	17	18
Furthermore , low levels of the Notch antagonist Numb was found to correlate with both high Notch signaling and sensitivity to a gamma-secretase inhibitor ( Pece et al , 2004 ) .	Furthermore, low levels of the Notch antagonist Numb was found to correlate with both high Notch signaling and sensitivity to a gamma-secretase inhibitor (Pece et al, 2004).	3	9	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	8	9	6	7
Studies have reported that Numb completely prevents EMT by antagonizing Notch signaling [ XREF_BIBR , XREF_BIBR ] .	Studies have reported that Numb completely prevents EMT by antagonizing Notch signaling [XREF_BIBR, XREF_BIBR].	4	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	10	11
Pon mutants that are not capable of forming phase transition with Numb lose its ability to direct Numb basal localization , have impaired Notch inhibition by Numb , and result in tumor like over-proliferation of Drosophila NBs .	Pon mutants that are not capable of forming phase transition with Numb lose its ability to direct Numb basal localization, have impaired Notch inhibition by Numb, and result in tumor like over-proliferation of Drosophila NBs.	22	27	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	26	27	23	24
Brat and the Notch antagonist Numb , function cooperatively to ensure that immature INPs undergo maturation and commit to the INP fate [ XREF_BIBR ] .	Brat and the Notch antagonist Numb, function cooperatively to ensure that immature INPs undergo maturation and commit to the INP fate [XREF_BIBR].	0	6	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	3	4
Numb mutants defective for binding to Itch , Eps15 or adaptin , fail to promote Notch 1 degradation , suggesting Numb suppresses Notch activity by regulating post-endocytic sorting pathways that lead to the degradation of Notch .	Numb mutants defective for binding to Itch, Eps15 or adaptin, fail to promote Notch 1 degradation, suggesting Numb suppresses Notch activity by regulating post-endocytic sorting pathways that lead to the degradation of Notch.	20	23	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	20	21	22	23
A non localized Numb in GMC-1 , due to its segregation into both daughter cells , instead of one cell as in wild type , blocks Notch signaling from specifying a sib fate .	A non localized Numb in GMC-1, due to its segregation into both daughter cells, instead of one cell as in wild type, blocks Notch signaling from specifying a sib fate.	0	27	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	3	4	26	27
The presence of Numb inhibits Notch and Sanpodo signaling and causes this daughter cell to take the muscle founder cell fate ( DA1 ) .	The presence of Numb inhibits Notch and Sanpodo signaling and causes this daughter cell to take the muscle founder cell fate (DA1).	1	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	3	4	5	6
Pon is required for the asymmetric segregation of Numb into the GMC daughter , where Numb inhibits Notch activity by regulating its degradation to drive GMC daughter toward differentiation process XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Pon is required for the asymmetric segregation of Numb into the GMC daughter, where Numb inhibits Notch activity by regulating its degradation to drive GMC daughter toward differentiation process XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	15	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	15	16	17	18
The notch ligand gene Jag1 is known as an evolutionarily conserved target of the canonical Wnt signaling pathway and is a key molecule for induction of self-renewal and maintenance of homeostasis of stem and progenitor cells XREF_BIBR , while Numb and Numbl induce differentiation by inhibiting notch signaling in progenitor cells XREF_BIBR .	The notch ligand gene Jag1 is known as an evolutionarily conserved target of the canonical Wnt signaling pathway and is a key molecule for induction of self-renewal and maintenance of homeostasis of stem and progenitor cells XREF_BIBR, while Numb and Numbl induce differentiation by inhibiting notch signaling in progenitor cells XREF_BIBR.	39	47	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	notch	notch	notch	39	40	46	47
Notch activity can be inhibited by Numb , an intracellular protein , and differential Numb expression can produce disparate levels of Notch signaling [ XREF_BIBR ] .	Notch activity can be inhibited by Numb, an intracellular protein, and differential Numb expression can produce disparate levels of Notch signaling [XREF_BIBR].	0	10	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	0	1
For instance , asymmetric segregation of Numb , which down-regulates Notch signaling through polarized receptor mediated endocytosis , in the progeny of sensory organ precursors ( SOPs ) makes the Numb positive cell Notch sending .	For instance, asymmetric segregation of Numb, which down-regulates Notch signaling through polarized receptor mediated endocytosis, in the progeny of sensory organ precursors (SOPs) makes the Numb positive cell Notch sending.	4	11	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	10	11
In breast cancers , loss of NUMB expression causes increased activity of the receptor NOTCH .	In breast cancers, loss of NUMB expression causes increased activity of the receptor NOTCH.	6	15	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB expression	numb	NOTCH	NOTCH	notch	6	7	14	15
In the developing Drosophila nervous system , a key determinant of daughter cell fates is the endocytic adaptor protein Numb , which is asymmetrically inherited and antagonizes Notch signaling .	In the developing Drosophila nervous system, a key determinant of daughter cell fates is the endocytic adaptor protein Numb, which is asymmetrically inherited and antagonizes Notch signaling.	3	28	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	19	20	27	28
Attenuation of Notch signaling by Numb overexpression leads to the commitment of progenitor cells to the myoblast cell fate with increased expression of Myf5 and desmin [ XREF_BIBR ] .	Attenuation of Notch signaling by Numb overexpression leads to the commitment of progenitor cells to the myoblast cell fate with increased expression of Myf5 and desmin [XREF_BIBR].	2	6	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	2	3
While Numb antagonizes Notch signaling XREF_BIBR in one daughter cell XREF_BIBR , Spdo promotes Notch signaling in the other sibling XREF_BIBR , XREF_BIBR resulting in differential activation of Notch signaling which ultimately generates two distinctly specified binary cell fates .	While Numb antagonizes Notch signaling XREF_BIBR in one daughter cell XREF_BIBR, Spdo promotes Notch signaling in the other sibling XREF_BIBR, XREF_BIBR resulting in differential activation of Notch signaling which ultimately generates two distinctly specified binary cell fates.	1	5	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	1	2	3	4
Numb represses Notch [ XREF_BIBR ] and Hedgehog [ XREF_BIBR ] .	Numb represses Notch [XREF_BIBR] and Hedgehog [XREF_BIBR].	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	2	3
By contrast , the other daughter cell asymmetrically acquired Numb , which inhibited Notch signaling , leading to a different fate choice .	By contrast, the other daughter cell asymmetrically acquired Numb, which inhibited Notch signaling, leading to a different fate choice.	8	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	9	10	13	14
Numb interacts with a cytoplasmic domain of the plasma membrane receptor Notch and inhibits Notch signaling , suggesting one mechanism whereby Numb regulates cell differentiation .	Numb interacts with a cytoplasmic domain of the plasma membrane receptor Notch and inhibits Notch signaling, suggesting one mechanism whereby Numb regulates cell differentiation.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	14	15
In this model , it was noted that the Notch antagonist Numb is asymmetrically distributed in cells dividing lateral to the BM .	In this model, it was noted that the Notch antagonist Numb is asymmetrically distributed in cells dividing lateral to the BM.	8	14	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	11	12	9	10
In parallel , Numb likely promotes targeting of Sanpodo from the plasma membrane to endosomes , perhaps as consequence of Numb mediated Notch inhibition .	In parallel, Numb likely promotes targeting of Sanpodo from the plasma membrane to endosomes, perhaps as consequence of Numb mediated Notch inhibition.	18	23	mediated	Positive_early_activation	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	20	21	22	23
87 A study reported asymmetric segregation of Numb , which inhibits Notch signaling in murine HSCs , suggesting that Numb polarity is important for HSC self-renewal .	87 A study reported asymmetric segregation of Numb, which inhibits Notch signaling in murine HSCs, suggesting that Numb polarity is important for HSC self-renewal.	5	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	7	8	11	12
This loss of function prevents NUMB mediated NOTCH inhibition and could explain the increase in oncogenic expression of NOTCH in the prostate .	This loss of function prevents NUMB mediated NOTCH inhibition and could explain the increase in oncogenic expression of NOTCH in the prostate.	4	8	mediated	Positive_early_activation	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	5	6	7	8
In esophageal squamous cell carcinoma and breast cancer , Numb overexpression suppresses tumor cell growth and epithelial-mesenchymal transition ( EMT ) by antagonizing Notch signaling , and loss of Numb expression is associated with poor prognosis [ XREF_BIBR , XREF_BIBR ] .	In esophageal squamous cell carcinoma and breast cancer, Numb overexpression suppresses tumor cell growth and epithelial-mesenchymal transition (EMT) by antagonizing Notch signaling, and loss of Numb expression is associated with poor prognosis [XREF_BIBR, XREF_BIBR].	9	24	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	9	10	23	24
For instance , how does Numb act at the molecular level to inhibit the recycling of Notch and Spdo and promote their late endosomal sorting ?	For instance, how does Numb act at the molecular level to inhibit the recycling of Notch and Spdo and promote their late endosomal sorting?	5	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	16	17
In addition , both Numb and Numbl can inhibit the Notch pathway .	In addition, both Numb and Numbl can inhibit the Notch pathway.	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	10	11
Based on these data , we propose that the suppression of NUMB mediated activation of Notch signaling contributes to the EMT program in TNBC cells .	Based on these data, we propose that the suppression of NUMB mediated activation of Notch signaling contributes to the EMT program in TNBC cells.	9	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	11	12	15	16
LNX has been reported to target the cell fate determinant and Notch antagonist Numb for proteasome dependent degradation , thereby causing an increase in transactivational activity of Notch .	LNX has been reported to target the cell fate determinant and Notch antagonist Numb for proteasome dependent degradation, thereby causing an increase in transactivational activity of Notch.	5	14	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	13	14	11	12
This result indicates that the ACBD3 binding region is dispensable for Numb mediated suppression of Notch signaling in sensory organ precursor cells in the peripheral nervous system .	This result indicates that the ACBD3 binding region is dispensable for Numb mediated suppression of Notch signaling in sensory organ precursor cells in the peripheral nervous system.	11	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	11	12	15	16
Therefore , these results reveal a novel role of Galphas in control of neural progenitor asymmetric cell division via suppressing Numb mediated Notch signaling inhibition .	Therefore, these results reveal a novel role of Galphas in control of neural progenitor asymmetric cell division via suppressing Numb mediated Notch signaling inhibition.	20	24	mediated	Positive_early_activation	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	20	21	22	23
During asymmetric division , Numb localizes to one side of the dividing cell and causes degradation of membrane bound Notch receptors and NICD .	During asymmetric division, Numb localizes to one side of the dividing cell and causes degradation of membrane bound Notch receptors and NICD.	4	20	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	19	20
NUMB , a direct transcriptional target of the WNT signaling pathway , could ubiquitously degrade NOTCH intracellular domain and negatively regulate NOTCH signaling pathway .	NUMB, a direct transcriptional target of the WNT signaling pathway, could ubiquitously degrade NOTCH intracellular domain and negatively regulate NOTCH signaling pathway.	0	20	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	0	1	15	16
Unexpectedly , neither ectopic expression of Numb nor depletion of miR-146a repressed Notch signalling , indicating that Numb operates in this CRCSC context predominantly by targeting beta-catenin ( XREF_FIG ) .	Unexpectedly, neither ectopic expression of Numb nor depletion of miR-146a repressed Notch signalling, indicating that Numb operates in this CRCSC context predominantly by targeting beta-catenin (XREF_FIG).	4	13	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	expression of Numb	numb	Notch	Notch	notch	6	7	12	13
The UPS regulates Notch signaling by its interaction with and regulation of the Notch antagonist Numb .	The UPS regulates Notch signaling by its interaction with and regulation of the Notch antagonist Numb.	10	16	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	15	16	13	14
Msi proteins were originally identified as regulators of cell cycle progression and differentiation by their translational repression of cyclin dependent kinase inhibitor p21 WAF1 and Notch antagonist Numb .	Msi proteins were originally identified as regulators of cell cycle progression and differentiation by their translational repression of cyclin dependent kinase inhibitor p21 WAF1 and Notch antagonist Numb.	4	28	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	27	28	25	26
Electroporation of a Numb construct was used to inhibit endogenous Notch signaling in the lateral DM .	Electroporation of a Numb construct was used to inhibit endogenous Notch signaling in the lateral DM.	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	3	4	10	11
Future studies will certainly shed new light on how Numb inhibits Notch at the molecular level .	Future studies will certainly shed new light on how Numb inhibits Notch at the molecular level.	9	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	9	10	11	12
This transformation depends on the presence of Notch , indicating that Numb antagonizes Notch .	This transformation depends on the presence of Notch, indicating that Numb antagonizes Notch.	11	14	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	11	12	13	14
In addition , miR-146a , which targets the Notch antagonist Numb , is elevated in muscle from ethanol treated fish .	In addition, miR-146a, which targets the Notch antagonist Numb, is elevated in muscle from ethanol treated fish.	6	11	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	10	11	8	9
Specifically , the Notch antagonist Numb is upregulated , whereas the Notch target genes Hes1 and Hey1 are downregulated drastically .	Specifically, the Notch antagonist Numb is upregulated, whereas the Notch target genes Hes1 and Hey1 are downregulated drastically.	2	7	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	3	4
Other studies indicate that elevated NOTCH1 and JAG1 in patients with BC is correlated with poor overall survival [ XREF_BIBR ] , and that the loss of NUMB expression increases Notch activity and thus increases proliferation of tumor cells [ XREF_BIBR ] .	Other studies indicate that elevated NOTCH1 and JAG1 in patients with BC is correlated with poor overall survival [XREF_BIBR], and that the loss of NUMB expression increases Notch activity and thus increases proliferation of tumor cells [XREF_BIBR].	27	31	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB expression	numb	Notch	Notch	notch	27	28	30	31
Meanwhile , we found that Notch signaling is highly activated in TNBC cells with mutant p53 , and overexpression of NUMB suppressed the Notch activation as well as EMT in TNBC cells .	Meanwhile, we found that Notch signaling is highly activated in TNBC cells with mutant p53, and overexpression of NUMB suppressed the Notch activation as well as EMT in TNBC cells.	18	24	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	overexpression of NUMB	numb	Notch	Notch	notch	20	21	23	24
In the absence of both notch and numb , however , the two daughter cells adopt the RP2 fate indicating that Numb is necessary to specify an RP2 fate only when there is an intact N signaling ; Numb , thus , blocks Notch signaling from specifying a sib fate to a cell .	In the absence of both notch and numb, however, the two daughter cells adopt the RP2 fate indicating that Numb is necessary to specify an RP2 fate only when there is an intact N signaling; Numb, thus, blocks Notch signaling from specifying a sib fate to a cell.	38	44	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	38	39	43	44
In Wnt7a treated NCSC-cells , Numb depletion increased the expression of Notch target genes HES1 , HEY1 , and WNT5A , suggesting that NUMB is mediating the inhibition of Notch signaling in NCSC like cells ( XREF_FIG ) .	In Wnt7a treated NCSC-cells, Numb depletion increased the expression of Notch target genes HES1, HEY1, and WNT5A, suggesting that NUMB is mediating the inhibition of Notch signaling in NCSC like cells (XREF_FIG).	23	30	mediating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	23	24	29	30
Additionally , Notch activity is inhibited by Numb through an endocytotic mechanism .	Additionally, Notch activity is inhibited by Numb through an endocytotic mechanism.	2	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	7	8	2	3
A well-known mechanism for enabling asymmetric division is the cell fate determinant Numb , which , like miR-34a , also suppresses Notch signaling .	A well-known mechanism for enabling asymmetric division is the cell fate determinant Numb, which, like miR-34a, also suppresses Notch signaling.	2	22	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	12	13	21	22
We found that Numb interfered with the ability of Notch to cause nuclear translocation of Su ( H ) ; both the C-terminal half of the phosphotyrosine binding domain and the C terminus of Numb are required to inhibit Notch .	We found that Numb interfered with the ability of Notch to cause nuclear translocation of Su (H); both the C-terminal half of the phosphotyrosine binding domain and the C terminus of Numb are required to inhibit Notch.	32	40	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	34	35	39	40
XREF_BIBR In summary , a current model proposes that Numb inhibits the recycling of Notch in pIIb , hence creating an asymmetry of Notch at the surface of the anterior ( low Notch ) and posterior ( high Notch ) daughter cells , leading to the binary pIIa and pIIb fate choice ( XREF_FIG ) .	XREF_BIBR In summary, a current model proposes that Numb inhibits the recycling of Notch in pIIb, hence creating an asymmetry of Notch at the surface of the anterior (low Notch) and posterior (high Notch) daughter cells, leading to the binary pIIa and pIIb fate choice (XREF_FIG).	9	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	9	10	14	15
Since Numb will block Notch signaling from specifying a sib fate , the daughter cells of those GMCs in which the distribution of Numb is non asymmetric will inherit Numb and are expected to adopt an RP2 fate .	Since Numb will block Notch signaling from specifying a sib fate, the daughter cells of those GMCs in which the distribution of Numb is non asymmetric will inherit Numb and are expected to adopt an RP2 fate.	1	5	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	1	2	4	5
We further determined that these Wnt agonists suppress Notch signaling by inducing a Notch antagonist Numb .	We further determined that these Wnt agonists suppress Notch signaling by inducing a Notch antagonist Numb.	11	16	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	15	16	13	14
Additionally , Notch is known to maintain neural stem cell character and prevent neuronal differentiation and is also inhibited by Numb through ubiquitin dependent processing of Notch1 [ XREF_BIBR ] .	Additionally, Notch is known to maintain neural stem cell character and prevent neuronal differentiation and is also inhibited by Numb through ubiquitin dependent processing of Notch1 [XREF_BIBR].	2	21	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	20	21	2	3
Our experiments demonstrate however , that Numb-dependant depletion of Sanpodo from the plasma membrane in pIIb cells is unlikely to be the primary mechanism by which Numb inhibits Notch following asymmetric cell division .	Our experiments demonstrate however, that Numb-dependant depletion of Sanpodo from the plasma membrane in pIIb cells is unlikely to be the primary mechanism by which Numb inhibits Notch following asymmetric cell division.	26	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	26	27	28	29
Following NICD internalization , NUMB could inhibit NOTCH signal transduction by preventing NICD from initiating gene transcription .	Following NICD internalization, NUMB could inhibit NOTCH signal transduction by preventing NICD from initiating gene transcription.	4	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	4	5	7	8
Since the over-expression of Neur was done just prior to the division of GMC-1 , it seems more likely that Numb localization is not disrupted but gain of function for Neur overcomes the Numb mediated blocking of Notch signaling and induce a sib phenotype to daughters of a GMC-1 .	Since the over-expression of Neur was done just prior to the division of GMC-1, it seems more likely that Numb localization is not disrupted but gain of function for Neur overcomes the Numb mediated blocking of Notch signaling and induce a sib phenotype to daughters of a GMC-1.	32	40	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	33	34	37	38
NUMB inhibits the Notch pathway through its interaction with ITCH and NICD ( Notch IntraCellular Domain ) , labeling NICD for ubiquitination and degradation [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	NUMB inhibits the Notch pathway through its interaction with ITCH and NICD (Notch IntraCellular Domain), labeling NICD for ubiquitination and degradation [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	0	1	3	4
In that study , transient expression of Numb or dnMAML1 was also used , with similar effects , to downregulate Notch activity .	In that study, transient expression of Numb or dnMAML1 was also used, with similar effects, to downregulate Notch activity.	5	21	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	expression of Numb	numb	Notch	Notch	notch	7	8	20	21
Numb protein was known to bind Notch-1 protein and inhibit the activation of the Notch signaling pathway .	Numb protein was known to bind Notch-1 protein and inhibit the activation of the Notch signaling pathway.	0	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb protein	Numb protein	Numb protein	Notch	Notch	Notch	0	2	14	15
In mammals , MSI1 activates Notch signaling through the translational repression of Numb which inhibits intracellular Notch signaling [ XREF_BIBR ] .	In mammals, MSI1 activates Notch signaling through the translational repression of Numb which inhibits intracellular Notch signaling [XREF_BIBR].	10	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	12	13	16	17
XREF_BIBR , XREF_BIBR Furthermore , previous studies demonstrated that inhibition of NUMB resulted in activation of NOTCH signaling pathway .	XREF_BIBR, XREF_BIBR Furthermore, previous studies demonstrated that inhibition of NUMB resulted in activation of NOTCH signaling pathway.	9	18	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	11	12	16	17
Conversely , Notch pathway overactivation promotes neuroepithelial cell expansion while suppressing medulla neuroblast formation and neurogenesis ; numb loss of function mimics Notch overactivation , suggesting that Numb may inhibit Notch signaling activity in the optic lobe neuroepithelial cells .	Conversely, Notch pathway overactivation promotes neuroepithelial cell expansion while suppressing medulla neuroblast formation and neurogenesis; numb loss of function mimics Notch overactivation, suggesting that Numb may inhibit Notch signaling activity in the optic lobe neuroepithelial cells.	27	32	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	27	28	30	31
For example , asymmetric segregation of Numb into the pIIb cell acts to inhibit Notch membrane localization in pIIb cells and promote pIIb cell fate .	For example, asymmetric segregation of Numb into the pIIb cell acts to inhibit Notch membrane localization in pIIb cells and promote pIIb cell fate.	4	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	14	15
Mechanistic studies show that Numb inactivates Notch via endocytosis and proteasomal degradation that directly reduce Notch protein levels at the cell surface .	Mechanistic studies show that Numb inactivates Notch via endocytosis and proteasomal degradation that directly reduce Notch protein levels at the cell surface.	4	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	6	7
To investigate the role of Notch signaling in preterm labor , Notch receptors ( Notch1-4 ) , its ligand Delta like protein-1 , transcriptional repressor hairy and enhancer of split-1 , and Notch deregulator Numb were assessed .	To investigate the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligand Delta like protein-1, transcriptional repressor hairy and enhancer of split-1, and Notch deregulator Numb were assessed.	32	36	deregulator	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	34	35	32	33
Second , Numb inhibits the Notch pathway , a crucial regulator of stem cell behavior [ XREF_BIBR ] .	Second, Numb inhibits the Notch pathway, a crucial regulator of stem cell behavior [XREF_BIBR].	2	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	2	3	5	6
In fact , in Drosophila , NUMB antagonizes NOTCH signaling by influencing the recycling of NOTCH complexes via AP-1 and AP-2 .	In fact, in Drosophila, NUMB antagonizes NOTCH signaling by influencing the recycling of NOTCH complexes via AP-1 and AP-2.	6	9	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	6	7	8	9
In the absence of both Notch and Numb , however , the two daughter cells adopt the RP2 fate indicating that Numb is necessary to specify an RP2 fate only when there is an intact N signaling ; Numb , thus , blocks Notch signaling from specifying a sib fate to a cell .	In the absence of both Notch and Numb, however, the two daughter cells adopt the RP2 fate indicating that Numb is necessary to specify an RP2 fate only when there is an intact N signaling; Numb, thus, blocks Notch signaling from specifying a sib fate to a cell.	38	44	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	38	39	43	44
In this cell , Numb inhibits the Notch signaling pathway , whereas the TF Pros represses cell-cycle genes and activates neuronal differentiation genes .	In this cell, Numb inhibits the Notch signaling pathway, whereas the TF Pros represses cell-cycle genes and activates neuronal differentiation genes.	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	7	8
Numb interacts with endocytic proteins such as alpha-adaptin and EPS15 , and a recent live-cell imaging study supports the notion that Numb suppresses Notch receptor accumulation at the membrane interface between pIIb and pIIa cells through endocytosis , thereby inhibiting Notch activation in the pIIb cell .	Numb interacts with endocytic proteins such as alpha-adaptin and EPS15, and a recent live-cell imaging study supports the notion that Numb suppresses Notch receptor accumulation at the membrane interface between pIIb and pIIa cells through endocytosis, thereby inhibiting Notch activation in the pIIb cell.	21	25	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	21	22	23	24
Two new studies show that Numb antagonizes Notch signaling by also regulating recycling of Sanpodo-Notch complexes via AP-1 .	Two new studies show that Numb antagonizes Notch signaling by also regulating recycling of Sanpodo-Notch complexes via AP-1.	5	8	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	7	8
Loss of endocytic mediator Numb has been suggested to cause increased Notch activity in a fraction of breast cancers .	Loss of endocytic mediator Numb has been suggested to cause increased Notch activity in a fraction of breast cancers.	0	12	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Loss of endocytic mediator Numb	numb	Notch	Notch	notch	4	5	11	12
Overexpression of Numb during wing development , which is sensitive to Notch dosage , revealed that Numb is also able to inhibit the Notch receptor in vivo .	Overexpression of Numb during wing development, which is sensitive to Notch dosage, revealed that Numb is also able to inhibit the Notch receptor in vivo.	16	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	16	17	23	24
In parallel , Wnt3a , secreted by macrophages in reaction to phagocytosis of apoptotic hepatocytes , suppresses a default Notch signaling in HPCs through an induction of Notch antagonist NUMB , a direct target of the canonical-Wnt signaling , leading HPCs to attain the hepatocyte lineage .	In parallel, Wnt3a, secreted by macrophages in reaction to phagocytosis of apoptotic hepatocytes, suppresses a default Notch signaling in HPCs through an induction of Notch antagonist NUMB, a direct target of the canonical-Wnt signaling, leading HPCs to attain the hepatocyte lineage.	27	39	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	29	30	27	28
NUMB and NUMBL , however , directly antagonize Notch signalling through endocytic control 49 , preventing surface localization and , presumably , activation of Notch .	NUMB and NUMBL, however, directly antagonize Notch signalling through endocytic control 49, preventing surface localization and, presumably, activation of Notch.	0	25	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	0	1	24	25
Conversely , the protein Numb is thought to antagonize Notch signaling byincreasing Notch degradation through polyubiquitination .	Conversely, the protein Numb is thought to antagonize Notch signaling byincreasing Notch degradation through polyubiquitination.	2	13	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	12	13
Numb is a well-known inhibitor of Notch , and Notch activation has been found to specify mammary luminal fate .	Numb is a well-known inhibitor of Notch, and Notch activation has been found to specify mammary luminal fate.	0	7	is a well-known inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	6	7
60 NUMB also suppresses the NOTCH signaling pathway through proteolytic degradation of the NOTCH intracellular domain .	60 NUMB also suppresses the NOTCH signaling pathway through proteolytic degradation of the NOTCH intracellular domain.	0	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	1	2	5	6
NUMB inhibits NOTCH signaling via direct interaction with NOTCH receptors , preventing their nuclear translocation .	NUMB inhibits NOTCH signaling via direct interaction with NOTCH receptors, preventing their nuclear translocation.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	0	1	2	3
MiR-146a is upregulated in BE and has been shown to target the Notch antagonist NUMB , raising the possibility that miR-146a is involved in re-establishing Notch signaling upon dysplastic progression of BE [ XREF_BIBR , XREF_BIBR ] .	MiR-146a is upregulated in BE and has been shown to target the Notch antagonist NUMB, raising the possibility that miR-146a is involved in re-establishing Notch signaling upon dysplastic progression of BE [XREF_BIBR, XREF_BIBR].	10	15	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	14	15	12	13
Numb is an endocytic accessory protein that regulates clathrin mediated endocytosis of its cargo proteins and the absence of Numb and Numbl reduces Notch endocytosis producing higher levels of Notch and Notch signaling .	Numb is an endocytic accessory protein that regulates clathrin mediated endocytosis of its cargo proteins and the absence of Numb and Numbl reduces Notch endocytosis producing higher levels of Notch and Notch signaling.	17	24	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	19	20	23	24
Thus , both its daughters inherit Numb , which prevents Notch from specifying a sib identity .	Thus, both its daughters inherit Numb, which prevents Notch from specifying a sib identity.	5	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	10	11
The ubiquitin ligase LNX can ubiquitinate Numb , preventing internal sequestration of Notch , resulting in enhanced downstream Notch signaling XREF_BIBR .	The ubiquitin ligase LNX can ubiquitinate Numb, preventing internal sequestration of Notch, resulting in enhanced downstream Notch signaling XREF_BIBR.	5	14	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	ubiquitinate Numb	numb	Notch	Notch	notch	6	7	12	13
Numb inhibits Notch whereas Neur positively regulates the signaling activity of the Notch ligand Delta .	Numb inhibits Notch whereas Neur positively regulates the signaling activity of the Notch ligand Delta.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	2	3
Surprisingly , they found that Numb did not significantly repress Notch activity in the inner ear .	Surprisingly, they found that Numb did not significantly repress Notch activity in the inner ear.	5	11	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	10	11
Finally , the cell-fate determinant Numb , which is localized by partner of numb ( PON ) , inhibits Notch signaling after the first division by polarizing the distribution of alpha-adaptin , resulting in enhanced endocytosis of Notch at one pole [ XREF_BIBR - XREF_BIBR ] .	Finally, the cell-fate determinant Numb, which is localized by partner of numb (PON), inhibits Notch signaling after the first division by polarizing the distribution of alpha-adaptin, resulting in enhanced endocytosis of Notch at one pole [XREF_BIBR - XREF_BIBR].	2	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	19	20
These finding suggests that L ( 2 ) gl and Numb may function together to suppress the pool of recycled Notch receptors at the pIIa and pIIb cell interface and that L ( 2 ) gl may regulate the apical-basal polarity of the recycled pool receptors .	These finding suggests that L (2) gl and Numb may function together to suppress the pool of recycled Notch receptors at the pIIa and pIIb cell interface and that L (2) gl may regulate the apical-basal polarity of the recycled pool receptors.	4	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	10	11	20	21
Therefore , both Numb and Numbl and Fringe tend to antagonize Notch Jagged signalling predominantly ( electronic supplementary material , figures S22 and S23 ) .	Therefore, both Numb and Numbl and Fringe tend to antagonize Notch Jagged signalling predominantly (electronic supplementary material, figures S22 and S23).	2	13	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	3	4	11	12
Recent evidence in flies and Caenorhabditis elegans points to a model in which Numb inhibits Notch receptor recycling , thereby decreasing Notch plasma membrane levels , whereas in mammalian cells , evidence points to Numb promoting Notch targeting to late endosome compartments through the ubiquitin ligase Itch .	Recent evidence in flies and Caenorhabditis elegans points to a model in which Numb inhibits Notch receptor recycling, thereby decreasing Notch plasma membrane levels, whereas in mammalian cells, evidence points to Numb promoting Notch targeting to late endosome compartments through the ubiquitin ligase Itch.	13	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	13	14	15	16
This activation of miR-146 promotes symmetric division of TICs by targeting and inhibiting NUMB , a protein that negatively regulates Notch ( see Glossary , Box2 ) and the stability of beta-catenin .	This activation of miR-146 promotes symmetric division of TICs by targeting and inhibiting NUMB, a protein that negatively regulates Notch (see Glossary, Box2) and the stability of beta-catenin.	10	29	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	13	14	20	21
Notch pathway inhibition by NUMB has been observed in flies and mammals .	Notch pathway inhibition by NUMB has been observed in flies and mammals.	0	5	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	4	5	0	1
These results support the notion that Numb promotes GMC daughter differentiation by inhibiting the Notch function .	These results support the notion that Numb promotes GMC daughter differentiation by inhibiting the Notch function.	6	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	14	15
These results suggest that in the inner ear at least , Numb does not significantly repress Notch activity and that its asymmetric distribution in dividing precursor cells does not govern the choice between hair cell and supporting cell fates .	These results suggest that in the inner ear at least, Numb does not significantly repress Notch activity and that its asymmetric distribution in dividing precursor cells does not govern the choice between hair cell and supporting cell fates.	11	17	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	11	12	16	17
Second , molecules , such as the numb protein , that antagonize Notch signaling activity may be targeted in disc progenitor cells .	Second, molecules, such as the numb protein, that antagonize Notch signaling activity may be targeted in disc progenitor cells.	7	14	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	numb protein	numb protein	numb protein	Notch	Notch	Notch	7	9	12	13
Although the precise mechanism of NOTCH inhibition by NUMB is not yet known , the complexity of the isoforms and functions of NUMB enable it to encompass a variety of functions within different signalling pathways .	Although the precise mechanism of NOTCH inhibition by NUMB is not yet known, the complexity of the isoforms and functions of NUMB enable it to encompass a variety of functions within different signalling pathways.	5	9	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	8	9	5	6
Our results provide the first evidence that Numb , an important cell fate determinant , modulates intestinal epithelial cells towards the goblet cell phenotype by inhibiting the Notch signaling pathway .	Our results provide the first evidence that Numb, an important cell fate determinant, modulates intestinal epithelial cells towards the goblet cell phenotype by inhibiting the Notch signaling pathway.	7	29	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	7	8	27	28
Moreover , up-regulation of Numb negatively regulated the Notch pathway , resulting in inhibition of the biliary differentiation of hESC with FZHY treatment .	Moreover, up-regulation of Numb negatively regulated the Notch pathway, resulting in inhibition of the biliary differentiation of hESC with FZHY treatment.	2	9	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	8	9
Apparently , loss of function of NUMB in TNBC activates the Notch pathway , which further maintains the mesenchymal phenotype of TNBC .	Apparently, loss of function of NUMB in TNBC activates the Notch pathway, which further maintains the mesenchymal phenotype of TNBC.	4	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	6	7	11	12
Whereas in small cell lung cancer , Notch may act as a tumor suppressive pathway , gain-of-function mutations and a chromosomal translocation leading to constitutive activation of Notch1 were identified in human T-cell acute lymphoblastic leukemia , gene amplification of Notch3 was detected in ovarian cancer , and relatively low levels of the Notch antagonist Numb were noted in breast tumors .	Whereas in small cell lung cancer, Notch may act as a tumor suppressive pathway, gain-of-function mutations and a chromosomal translocation leading to constitutive activation of Notch1 were identified in human T-cell acute lymphoblastic leukemia, gene amplification of Notch3 was detected in ovarian cancer, and relatively low levels of the Notch antagonist Numb were noted in breast tumors.	50	56	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	55	56	53	54
How does Numb antagonize Notch signaling in type II neuroblasts ?	How does Numb antagonize Notch signaling in type II neuroblasts?	2	5	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	2	3	4	5
These findings have led to the suggestion that Numb may antagonize Notch signaling by inhibiting Sanpodo membrane localization , but the role of Sanpodo membrane trafficking in Notch signaling regulation is currently unclear .	These findings have led to the suggestion that Numb may antagonize Notch signaling by inhibiting Sanpodo membrane localization, but the role of Sanpodo membrane trafficking in Notch signaling regulation is currently unclear.	8	12	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	8	9	11	12
Similar to ACDs that produce two surviving cells , Notch promotes the fate of one daughter cell , in this case the apoptotic cell , and Numb antagonizes Notch in the surviving cell .	Similar to ACDs that produce two surviving cells, Notch promotes the fate of one daughter cell, in this case the apoptotic cell, and Numb antagonizes Notch in the surviving cell.	26	32	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	26	27	28	29
Attenuation of Notch signaling by increasing expression of inhibitor Numb leads to the commitment of satellite cells to the myoblasts fate XREF_BIBR , XREF_BIBR .	Attenuation of Notch signaling by increasing expression of inhibitor Numb leads to the commitment of satellite cells to the myoblasts fate XREF_BIBR, XREF_BIBR.	2	10	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Numb	expression of inhibitor Numb	numb	Notch	Notch	notch	9	10	2	3
In lung adenocarcinoma , Numb impairs tumor growth and inhibits the Notch pathway and epithelial-mesenchymal transition , whereas in lung squamous cell carcinoma it may promote proliferation .	In lung adenocarcinoma, Numb impairs tumor growth and inhibits the Notch pathway and epithelial-mesenchymal transition, whereas in lung squamous cell carcinoma it may promote proliferation.	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	11	12
Numb and Numbl directly block Notch to prevent signaling .	Numb and Numbl directly block Notch to prevent signaling.	0	6	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	5	6
However , the absence of Numb in pIIa cells prevents sequestration of Notch in late endosomes , resulting instead in Rab11 dependent basolateral membrane Notch recycling and activation of Notch signaling .	However, the absence of Numb in pIIa cells prevents sequestration of Notch in late endosomes, resulting instead in Rab11 dependent basolateral membrane Notch recycling and activation of Notch signaling.	3	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	12	13
Furthermore , we observed that Numb looses its characteristic membrane localization in fibrotic kidneys and therefore is likely unable to inhibit Notch resulting in tubular cell death .	Furthermore, we observed that Numb looses its characteristic membrane localization in fibrotic kidneys and therefore is likely unable to inhibit Notch resulting in tubular cell death.	5	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	21	22
Numb mediated Notch inhibition is disrupted in approximately 50 % of breast carcinomas , due to degradation of Numb [ XREF_BIBR ] .	Numb mediated Notch inhibition is disrupted in approximately 50% of breast carcinomas, due to degradation of Numb [XREF_BIBR].	0	3	mediated	Positive_early_activation	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	2	3
Inhibition of Notch signaling by Numb is critical for many cell fate decisions .	Inhibition of Notch signaling by Numb is critical for many cell fate decisions.	2	6	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	2	3
Although overexpression experiments suggested that Numb might also antagonize some Notch activity in vertebrates , the developmental processes in which Numb is involved remained elusive .	Although overexpression experiments suggested that Numb might also antagonize some Notch activity in vertebrates, the developmental processes in which Numb is involved remained elusive.	5	11	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	10	11
NUMB negatively regulates the epithelial-mesenchymal transition of triple negative breast cancer by antagonizing Notch signaling .	NUMB negatively regulates the epithelial-mesenchymal transition of triple negative breast cancer by antagonizing Notch signaling.	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	0	1	13	14
This regulation is crucial to the expression of NUMB , which suppresses the NOTCH signaling pathway .	This regulation is crucial to the expression of NUMB, which suppresses the NOTCH signaling pathway.	6	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	expression of NUMB	numb	NOTCH	NOTCH	notch	8	9	13	14
Whereas the mechanisms underlying unequal inheritance of Numb are understood , how Numb antagonizes Notch has remained unsolved .	Whereas the mechanisms underlying unequal inheritance of Numb are understood, how Numb antagonizes Notch has remained unsolved.	12	15	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	12	13	14	15
In other cases of NOTCH mediated asymmetric cell fate determination , NUMB , an inhibitor of NOTCH , localizes to one side of the dividing cell and causes degradation of membrane bound NOTCH receptors and NICD , which creates differential NOTCH signaling levels in daughter cells .	In other cases of NOTCH mediated asymmetric cell fate determination, NUMB, an inhibitor of NOTCH, localizes to one side of the dividing cell and causes degradation of membrane bound NOTCH receptors and NICD, which creates differential NOTCH signaling levels in daughter cells.	11	33	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	11	12	32	33
These data , consistent with our functional studies , imply that , in the absence of the queen , Numb may degrade the Notch receptor , relieving the direct repressive effect of Notch cell signalling in the germarium , allowing activation of the ovary and thus worker reproduction ( XREF_FIG ) .	These data, consistent with our functional studies, imply that, in the absence of the queen, Numb may degrade the Notch receptor, relieving the direct repressive effect of Notch cell signalling in the germarium, allowing activation of the ovary and thus worker reproduction (XREF_FIG).	19	24	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	19	20	23	24
Our findings reveal that Numb is responsible for regulating Notch accumulation in Rab7 positive late endosomes and that Numb restricts a population of recycled Notch receptors in SOP daughter cells .	Our findings reveal that Numb is responsible for regulating Notch accumulation in Rab7 positive late endosomes and that Numb restricts a population of recycled Notch receptors in SOP daughter cells.	18	25	restricts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	18	19	24	25
Recent work now demonstrates in vivo that Numb inactivates Notch by promoting its endocytosis .	Recent work now demonstrates in vivo that Numb inactivates Notch by promoting its endocytosis.	7	10	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	7	8	9	10
In contrast to lateral inhibition , this function requires the asymmetric inheritance of the Notch antagonist Numb by one of the two sibling neurons in a terminal cell division .	In contrast to lateral inhibition, this function requires the asymmetric inheritance of the Notch antagonist Numb by one of the two sibling neurons in a terminal cell division.	11	17	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	16	17	14	15
In addition to Dll1 and Dll4 , several other Notch signaling pathway components were identified as ATOH1 associated genes , such as CBF1 , Suppressor of hairless , Lag-1 ( CSL ) transcriptional co-activator Maml3 and Crebbp , CSL transcriptional co-repressor Hdac1 , Ncor2 , Ctbp1 and Ctbp2 , Notch ligand Jag1 , Notch receptor Notch1 , and Notch antagonist Numb .	In addition to Dll1 and Dll4, several other Notch signaling pathway components were identified as ATOH1 associated genes, such as CBF1, Suppressor of hairless, Lag-1 (CSL) transcriptional co-activator Maml3 and Crebbp, CSL transcriptional co-repressor Hdac1, Ncor2, Ctbp1 and Ctbp2, Notch ligand Jag1, Notch receptor Notch1, and Notch antagonist Numb.	14	61	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	60	61	58	59
Wnt3a promotes expression of Numb in liver progenitor cells which inhibits Notch and promotes differentiation into hepatocytes instead of biliary cells [ XREF_BIBR ] .	Wnt3a promotes expression of Numb in liver progenitor cells which inhibits Notch and promotes differentiation into hepatocytes instead of biliary cells [XREF_BIBR].	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Wnt3a promotes expression of Numb	numb	Notch	Notch	notch	4	5	11	12
Second , Notch signalling is restricted by the asymmetric segregation of Numb , as the tip mother cell divides , so that achaete expression is maintained only in the tip cell .	Second, Notch signalling is restricted by the asymmetric segregation of Numb, as the tip mother cell divides, so that achaete expression is maintained only in the tip cell.	2	12	restricted	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	11	12	2	3
It is thought that NUMB negatively regulates NOTCH , potentially through a direct protein protein interaction that requires the phosphotyrosine binding ( PTB ) domain of NUMB and either the RAM23 region or the very C-terminal end of NOTCH .	It is thought that NUMB negatively regulates NOTCH, potentially through a direct protein protein interaction that requires the phosphotyrosine binding (PTB) domain of NUMB and either the RAM23 region or the very C-terminal end of NOTCH.	4	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	4	5	7	8
Accordingly , the Notch antagonist Numb was shown to be asymmetrically located in the committed Myog positive daughter cell .	Accordingly, the Notch antagonist Numb was shown to be asymmetrically located in the committed Myog positive daughter cell.	2	11	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	3	4
This transfer was blocked in the absence of Numb , suggesting that Numb inhibits Notch signaling in pIIb cells by sorting Sanpodo ( and , presumably , Notch ) to late endosomes and lysosomes for degradation .	This transfer was blocked in the absence of Numb, suggesting that Numb inhibits Notch signaling in pIIb cells by sorting Sanpodo (and, presumably, Notch) to late endosomes and lysosomes for degradation.	12	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	12	13	14	15
NUMB INHIBITS THE RECYCLING OF NOTCH IN pIIb .	NUMB INHIBITS THE RECYCLING OF NOTCH IN pIIb.	0	6	INHIBITS	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	0	1	5	6
NUMB can inhibit NOTCH signalling by binding directly to the NICD domain , preventing access of NICD to the nucleus .	NUMB can inhibit NOTCH signalling by binding directly to the NICD domain, preventing access of NICD to the nucleus.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	0	1	3	4
XREF_BIBR - XREF_BIBR NUMB is also able to directly inhibit NOTCH by recruiting Itch for polyubiquitination and degradation of Notch proteins .	XREF_BIBR - XREF_BIBR NUMB is also able to directly inhibit NOTCH by recruiting Itch for polyubiquitination and degradation of Notch proteins.	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	NOTCH	NOTCH	3	4	10	11
In this daughter cell , Numb might inhibit Notch activation by linking Notch to transport vesicles that target it for accelerated degradation [ XREF_BIBR ] and/or by sequestering and inactivating the positive Notch effector Sanpodo within endocytic vesicles [ XREF_BIBR - XREF_BIBR ] .	In this daughter cell, Numb might inhibit Notch activation by linking Notch to transport vesicles that target it for accelerated degradation [XREF_BIBR] and/or by sequestering and inactivating the positive Notch effector Sanpodo within endocytic vesicles [XREF_BIBR - XREF_BIBR].	5	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	8	9
In this cell , Numb represses Notch signaling by promoting endocytosis of the Notch receptor ; Pros activates or inhibits transcription of cell cycle related regulators and self-renewal and differentiation related genes ; Brat is involved in translational regulation and cell growth inhibition .	In this cell, Numb represses Notch signaling by promoting endocytosis of the Notch receptor; Pros activates or inhibits transcription of cell cycle related regulators and self-renewal and differentiation-related genes; Brat is involved in translational regulation and cell growth inhibition.	4	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	6	7
The PTB domain is critical for Numb mediated Notch degradation [ XREF_BIBR ] .	The PTB domain is critical for Numb mediated Notch degradation [XREF_BIBR].	6	9	mediated	Positive_early_activation	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	8	9
XREF_BIBR - XREF_BIBR Although the precise mechanisms for Notch transmembrane receptor inhibition by NUMB remain unknown , several models have been proposed ( XREF_FIG ) .	XREF_BIBR - XREF_BIBR Although the precise mechanisms for Notch transmembrane receptor inhibition by NUMB remain unknown, several models have been proposed (XREF_FIG).	8	14	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	13	14	8	9
Recent live imaging studies , using a GFP tagged Notch , have shown that Numb blocks the accumulation of Notch along the membrane interface between pIIa and pIIb cells at cytokinesis [ XREF_BIBR ] .	Recent live imaging studies, using a GFP tagged Notch, have shown that Numb blocks the accumulation of Notch along the membrane interface between pIIa and pIIb cells at cytokinesis [XREF_BIBR].	14	23	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	14	15	19	20
These include Suppressor of deltex and Itch and Sel-10 , which both regulate Notch , Neuralized , which regulates the Notch ligand Delta , and LNX , which regulates the Notch antagonist Numb .	These include Suppressor of deltex and Itch and Sel-10, which both regulate Notch, Neuralized, which regulates the Notch ligand Delta, and LNX, which regulates the Notch antagonist Numb.	28	33	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	32	33	30	31
Notch inhibition by DAPT , ectopic miR-34a , or Numb expression also increased apoptotic cells shed into the lumen , a process reminiscent of the shedding of terminally differentiated cells in vivo ( XREF_SUPPLEMENTARY ) .	Notch inhibition by DAPT, ectopic miR-34a, or Numb expression also increased apoptotic cells shed into the lumen, a process reminiscent of the shedding of terminally differentiated cells in vivo (XREF_SUPPLEMENTARY).	0	10	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	9	10	0	1
Numb inhibits Notch signaling in this daughter cell , resulting in a different cell fate from the Notch induced fate in the other-Numb-negative-daughter cell .	Numb inhibits Notch signaling in this daughter cell, resulting in a different cell fate from the Notch induced fate in the other-Numb-negative-daughter cell.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	2	3
Several factors that control asymmetric cell division of satellite cells have been described : the Notch antagonist Numb is located in committed myogenic progenitors during cell division [ XREF_BIBR ] ; unequally distributed polarity proteins PAR3 and aPKC asymmetrically activate the p38 MAPK pathway to promote the transcription of a myogenic regulatory factor MyoD , which promotes cells to undergo myogenic differentiation [ XREF_BIBR , XREF_BIBR ] .	Several factors that control asymmetric cell division of satellite cells have been described : the Notch antagonist Numb is located in committed myogenic progenitors during cell division [XREF_BIBR]; unequally distributed polarity proteins PAR3 and aPKC asymmetrically activate the p38 MAPK pathway to promote the transcription of a myogenic regulatory factor MyoD, which promotes cells to undergo myogenic differentiation [XREF_BIBR, XREF_BIBR].	15	19	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	17	18	15	16
Together with our finding that Numb antagonizes Notch signaling in late-stage RPCs , and that blocking Notch signaling in late RPCs almost completely abolishes the generation of terminal asymmetric divisions , these results suggest a model in which asymmetric inheritance of Numb in sister cells of terminal divisions might create unequal Notch activity , which in turn drives the production of terminal asymmetric divisions .	Together with our finding that Numb antagonizes Notch signaling in late-stage RPCs, and that blocking Notch signaling in late RPCs almost completely abolishes the generation of terminal asymmetric divisions, these results suggest a model in which asymmetric inheritance of Numb in sister cells of terminal divisions might create unequal Notch activity, which in turn drives the production of terminal asymmetric divisions.	5	8	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	7	8
As one mechanism , Numb inhibits Notch signaling by trafficking membrane bound Notch into the lysosome for degradation 33 .	As one mechanism, Numb inhibits Notch signaling by trafficking membrane bound Notch into the lysosome for degradation 33.	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	12	13
The biochemical mechanisms through which Numb antagonizes Notch are not yet clear ; however , one leading hypothesis is that direct binding of Numb to Notch prevents nuclear translocation and hence transcriptional activity of the ICD .	The biochemical mechanisms through which Numb antagonizes Notch are not yet clear; however, one leading hypothesis is that direct binding of Numb to Notch prevents nuclear translocation and hence transcriptional activity of the ICD.	5	8	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	7	8
Such transient inclusion of E3 in Numb ( PTB L ) causes Notch inhibition and thereby initiates neuronal differentiation .	Such transient inclusion of E3 in Numb (PTB L) causes Notch inhibition and thereby initiates neuronal differentiation.	4	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	12	13
During neurogenesis , Notch signaling promotes proliferative signaling , and Numb mediated Notch inhibition promotes neural differentiation .	During neurogenesis, Notch signaling promotes proliferative signaling, and Numb mediated Notch inhibition promotes neural differentiation.	10	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	10	11	12	13
XREF_BIBR , XREF_BIBR , XREF_BIBR Recent studies confirmed that the NOTCH signaling pathway is suppressed by overexpressed NUMB , suggesting that the latter acts as a tumor suppressor .	XREF_BIBR, XREF_BIBR, XREF_BIBR Recent studies confirmed that the NOTCH signaling pathway is suppressed by overexpressed NUMB, suggesting that the latter acts as a tumor suppressor.	10	18	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	17	18	10	11
This transition is correlated with a 20- to 30-fold increase in the relative ratio of expression of Notch and Numb ( a putative inhibitor of Notch signaling ) .	This transition is correlated with a 20- to 30-fold increase in the relative ratio of expression of Notch and Numb (a putative inhibitor of Notch signaling).	15	26	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Numb	expression of Notch and Numb	numb	Notch	Notch	notch	19	20	25	26
Unlike Numb , which attenuates Notch signaling by interacting with NICD and regulating the endocytosis and ubiquitination of Notch , Stra13 represses Notch signaling in the nucleus by reducing its interaction with CBF-1 .	Unlike Numb, which attenuates Notch signaling by interacting with NICD and regulating the endocytosis and ubiquitination of Notch, Stra13 represses Notch signaling in the nucleus by reducing its interaction with CBF-1.	0	21	attenuates	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Numb	Numb	numb	Notch	ubiquitination of Notch	notch	1	2	18	19
Our results indicate that when Numb inhibits Notch signaling , cells undergo neuronal differentiation , whereas cells that maintain Notch signaling initiate apoptosis .	Our results indicate that when Numb inhibits Notch signaling, cells undergo neuronal differentiation, whereas cells that maintain Notch signaling initiate apoptosis.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	7	8
Numb suppresses Notch signaling by physical interaction with the intracellular domain of Notch 1 .	Numb suppresses Notch signaling by physical interaction with the intracellular domain of Notch 1.	0	3	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	2	3
Using an integrated computational-experimental approach , we examine the role of Numb -- an inhibitor of Notch intercellular signalling -- in mediating EMT and clusters formation .	Using an integrated computational-experimental approach, we examine the role of Numb -- an inhibitor of Notch intercellular signalling -- in mediating EMT and clusters formation.	9	18	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	11	12	16	17
In this model Numb negatively regulates Notch , Akt1 and Itch , and each pathway further affects defined downstream signaling .	In this model Numb negatively regulates Notch, Akt1 and Itch, and each pathway further affects defined downstream signaling.	3	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	3	4	6	7
Considering that the segregating determinants , Numb , Prox1 and Trim directly or indirectly inhibits Notch , we opted to validate Notch1 as a direct target of miR-200b-3p .	Considering that the segregating determinants, Numb, Prox1 and Trim directly or indirectly inhibits Notch, we opted to validate Notch1 as a direct target of miR-200b-3p.	6	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	6	7	15	16
Overexpression of the Notch intra cellular domain , circumventing Notch repression by Numb , gives rise to two ' sib ' cells .	Overexpression of the Notch intra cellular domain, circumventing Notch repression by Numb, gives rise to two ' sib ' cells.	9	13	repression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	12	13	9	10
The set of basaly segregating fate determinants includes the Notch repressor Numb , the NHL-domain protein Brain tumor ( Brat ) , and the homeodomein transcription factor Prospero ( Pros ) XREF_BIBR - XREF_BIBR .	The set of basaly segregating fate determinants includes the Notch repressor Numb, the NHL-domain protein Brain tumor (Brat), and the homeodomein transcription factor Prospero (Pros) XREF_BIBR - XREF_BIBR.	7	33	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	11	12	9	10
As Numb inhibits Notch signaling in the cytoplasm , the translocation of Numb from the membrane or cytoplasm into the nucleus may activate Notch signaling .	As Numb inhibits Notch signaling in the cytoplasm, the translocation of Numb from the membrane or cytoplasm into the nucleus may activate Notch signaling.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	1	2	3	4
XREF_BIBR Importantly , Numb localizes asymmetrically in dividing SOPs : it localizes at the basal-anterior cortex of SOPs and is specifically inherited by the pIIb cell ( XREF_FIG ( c )-( c '' '' ) ) , XREF_BIBR indicating that Numb acts in pIIb to inhibit Notch .	XREF_BIBR Importantly, Numb localizes asymmetrically in dividing SOPs : it localizes at the basal-anterior cortex of SOPs and is specifically inherited by the pIIb cell (XREF_FIG (c)-(c '' '')), XREF_BIBR indicating that Numb acts in pIIb to inhibit Notch.	40	47	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	40	41	46	47
Numb gain or loss of function results in two IIb cell or IIa cells , respectively , and it was discovered that Numb promotes IIb cell fate by inhibiting Notch signaling .	Numb gain or loss of function results in two IIb cell or IIa cells, respectively, and it was discovered that Numb promotes IIb cell fate by inhibiting Notch signaling.	22	30	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	22	23	29	30
Our results differ from those obtained by Conboy and Rando , where down-regulation of Notch signaling in differentiating myoblast by retrovirally delivered Notch antagonist Numb did not have an effect on the level of Pax7 .	Our results differ from those obtained by Conboy and Rando, where down-regulation of Notch signaling in differentiating myoblast by retrovirally delivered Notch antagonist Numb did not have an effect on the level of Pax7.	22	27	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	24	25	22	23
The farsenoid X receptor ( FXR ) was also shown to induce SHP transcription , which then inactivates LRH-1 to repress the expression of CYP7A1 , the rate limiting enzyme in the bile acid biosynthesis pathway ; thus , resulting in the coordinated regulation of hepatic cholesterol metabolism [ XREF_BIBR XREF_BIBR ] .	The farsenoid X receptor (FXR) was also shown to induce SHP transcription, which then inactivates LRH-1 to repress the expression of CYP7A1, the rate limiting enzyme in the bile acid biosynthesis pathway; thus, resulting in the coordinated regulation of hepatic cholesterol metabolism [XREF_BIBR XREF_BIBR].	5	19	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	FXR) was also shown to induce SHP transcription	shp	LRH-1	LRH-1	lrh-1	12	13	18	19
However , the dominant negative SIRT1 mutant SIRT1H363Y showed no observable effect of LRH1 transactivity , thereby suggesting that SIRT1 deacetylase activity is needed for the repression of LRH1 by SHP .	However, the dominant negative SIRT1 mutant SIRT1H363Y showed no observable effect of LRH1 transactivity, thereby suggesting that SIRT1 deacetylase activity is needed for the repression of LRH1 by SHP.	23	31	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH1	LRH1	LRH1	30	31	28	29
Then SHP inhibits the transactivation ability of LRH-1 which enhances the expression of both cytochromeP450 7a1 ( Cyp7a1 ) and SHP .	Then SHP inhibits the transactivation ability of LRH-1 which enhances the expression of both cytochromeP450 7a1 (Cyp7a1) and SHP.	1	21	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	SHP	SHP	shp	LRH-1	LRH-1 which enhances the expression of both cytochromeP450 7a1 (Cyp7a1) and SHP	lrh-1	1	2	7	8
In the liver , bile acids activate FXR , which induces the expression of SHP to inhibit the activity of LRH-1 and HNF4alpha , which are the positive regulators of Cyp7a1 [ XREF_BIBR , XREF_BIBR ] .	In the liver, bile acids activate FXR, which induces the expression of SHP to inhibit the activity of LRH-1 and HNF4alpha, which are the positive regulators of Cyp7a1 [XREF_BIBR, XREF_BIBR].	7	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	FXR, which induces the expression of SHP	shp	LRH-1	LRH-1	lrh-1	14	15	20	21
As SHP levels were enhanced simultaneously and SHP is a classic FXR downstream gene , which suggests that FXR has been activated simultaneously [ XREF_BIBR ] , whereas the LRH-1 was not inhibited by the overexpressed SHP .	As SHP levels were enhanced simultaneously and SHP is a classic FXR downstream gene, which suggests that FXR has been activated simultaneously [XREF_BIBR], whereas the LRH-1 was not inhibited by the overexpressed SHP.	28	37	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	36	37	29	30
Hepatic Fxr ( encoded by Nr1h4 ) represses Cyp7a1 and Cyp8b1 by inducing the nuclear co-repressor Shp ( encoded by Nr0b2 ) , which inhibits transcription factor Lrh-1 ( encoded by Nr5a2 ) .	Hepatic Fxr (encoded by Nr1h4) represses Cyp7a1 and Cyp8b1 by inducing the nuclear co-repressor Shp (encoded by Nr0b2), which inhibits transcription factor Lrh-1 (encoded by Nr5a2).	12	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Shp	Shp	Shp	Lrh-1	Lrh-1	Lrh-1	16	17	27	28
Consistent with these reports , our earlier observations ( XREF_FIG A and C , left ) suggest that SIRT1 is involved , at least in part , in the SHP mediated repression of LRH1 transcriptional activity .	Consistent with these reports, our earlier observations (XREF_FIG A and C, left) suggest that SIRT1 is involved, at least in part, in the SHP mediated repression of LRH1 transcriptional activity.	28	35	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH1	LRH1	LRH1	29	30	33	34
It was demonstrated that an increase in SHP subsequently attenuates the transcriptional activity of LRH-1 , leading to the repression of LRH-1 targets , including the rate limiting enzyme of the bile acid biosynthesis pathway , cholesterol 7alpha-hydroxylase ( CYP7A1 ) [ XREF_BIBR , XREF_BIBR ] , and the enzyme catalyzing the production of cholic acid , cholesterol 12alpha-hydroxylase ( CYP8B1 ) [ XREF_BIBR , XREF_BIBR ] .	It was demonstrated that an increase in SHP subsequently attenuates the transcriptional activity of LRH-1, leading to the repression of LRH-1 targets, including the rate limiting enzyme of the bile acid biosynthesis pathway, cholesterol 7alpha-hydroxylase (CYP7A1) [XREF_BIBR, XREF_BIBR], and the enzyme catalyzing the production of cholic acid, cholesterol 12alpha-hydroxylase (CYP8B1) [XREF_BIBR, XREF_BIBR].	5	15	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	7	8	14	15
It has been shown , using chenodeoxycholic acid as FXR activator , that activated FXR induces small heterodimer partner ( SHP ) gene expression , decreases scavenger receptor class B , type I ( SR-B1 ) gene expression , and inhibits LXR and liver receptor homolog-1 ( LRH-1 ) activation .	It has been shown, using chenodeoxycholic acid as FXR activator, that activated FXR induces small heterodimer partner (SHP) gene expression, decreases scavenger receptor class B, type I (SR-B1) gene expression, and inhibits LXR and liver receptor homolog-1 (LRH-1) activation.	14	46	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	small heterodimer partner	FXR induces small heterodimer partner (SHP) gene expression	small heterodimer partner	liver receptor homolog-1	liver receptor homolog-1	liver receptor homolog-1	16	19	43	46
Small heterodimer partner , a repressor of LRH-1 , abolishes the potentiation effect of LRH-1 but not its basal transactivation of the CETP promoter .	Small heterodimer partner, a repressor of LRH-1, abolishes the potentiation effect of LRH-1 but not its basal transactivation of the CETP promoter.	0	15	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Small heterodimer partner	Small heterodimer partner	Small heterodimer partner	LRH-1	LRH-1	LRH-1	0	3	14	15
In hepatic pathway , FXR induces SHP which inhibits LRH1 and HNF4alpha [ XREF_BIBR ] .	In hepatic pathway, FXR induces SHP which inhibits LRH1 and HNF4alpha [XREF_BIBR].	5	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH1	LRH1	LRH1	6	7	9	10
On the other hand , small heterodimeric partner ( SHP ) represses HNF-4alpha , LRH-1 and HNF-1alpha activities by interacting with these factors [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	On the other hand, small heterodimeric partner (SHP) represses HNF-4alpha, LRH-1 and HNF-1alpha activities by interacting with these factors [XREF_BIBR, XREF_BIBR, XREF_BIBR].	7	17	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	9	10	14	15
In the liver , BAs activate FXR , which induce the expression of small heterodimer partner ( SHP ) that represses liver receptor homolog-1 ( LRH-1 ) , leading to decreased transcription of Cyp7a1 [ XREF_BIBR ] .	In the liver, BAs activate FXR, which induce the expression of small heterodimer partner (SHP) that represses liver receptor homolog-1 (LRH-1), leading to decreased transcription of Cyp7a1 [XREF_BIBR].	4	24	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	small heterodimer partner	BAs activate FXR, which induce the expression of small heterodimer partner	small heterodimer partner	liver receptor homolog-1	liver receptor homolog-1	liver receptor homolog-1	13	16	21	24
Interestingly , SHP did not affect the CLOCK-BMAL1-mediated promoter activity , but strongly repressed the synergistic activation of CLOCK-BMAL1 and LRH-1 .	Interestingly, SHP did not affect the CLOCK-BMAL1-mediated promoter activity, but strongly repressed the synergistic activation of CLOCK-BMAL1 and LRH-1.	2	21	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	2	3	20	21
Based on the findings described above , the TO901317 downregulating apoM expression in hepatic cells may be due to the activation of the FXR and SHP pathway that inhibits LRH-1 .	Based on the findings described above, the TO901317 downregulating apoM expression in hepatic cells may be due to the activation of the FXR and SHP pathway that inhibits LRH-1.	23	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	25	26	29	30
In summary cell line- and species specific negative feedback regulation of ASBT by bile acids is mediated by farnesoid X receptor via small heterodimer partner dependent repression of LRH-1 activation of the ASBT promoter .	In summary cell line- and species specific negative feedback regulation of ASBT by bile acids is mediated by farnesoid X receptor via small heterodimer partner dependent repression of LRH-1 activation of the ASBT promoter.	22	29	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	small heterodimer partner	small heterodimer partner	small heterodimer partner	LRH-1	LRH-1	LRH-1	22	25	28	29
In the liver , SHP antagonizes the effects of liver receptor homologue 1 ( LRH-1 ) and hepatocyte nuclear factor 4 alpha ( HNF4alpha ) that positively regulate the expression of Cyp7a1 and Cyp8b1 , the rate limiting enzymes in the synthesis of CDCA and CA ( XREF_FIG ) .	In the liver, SHP antagonizes the effects of liver receptor homologue 1 (LRH-1) and hepatocyte nuclear factor 4 alpha (HNF4alpha) that positively regulate the expression of Cyp7a1 and Cyp8b1, the rate limiting enzymes in the synthesis of CDCA and CA (XREF_FIG).	4	19	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	4	5	14	15
Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation .	Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	2	3	9	10
In the case of CYP7A1 and CYP8B1 , SHP inhibits the transcription factors LRH-1 and alpha-fetoprotein transcription factor ( FTF ) .	In the case of CYP7A1 and CYP8B1, SHP inhibits the transcription factors LRH-1 and alpha-fetoprotein transcription factor (FTF).	8	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	8	9	13	14
Taken together , these results indicate that SHP recruits SIRT1 and utilizes SIRT1 deacetylase activity to inhibit LRH1 mediated transcriptional activation .	Taken together, these results indicate that SHP recruits SIRT1 and utilizes SIRT1 deacetylase activity to inhibit LRH1 mediated transcriptional activation.	7	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH1	LRH1	LRH1	7	8	17	18
SHP can dimerize with and inactivate both LRH1 and LXRa , resulting in a decrease in Cyp7a1 expression .	SHP can dimerize with and inactivate both LRH1 and LXRa, resulting in a decrease in Cyp7a1 expression.	0	9	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH1	LRH1	LRH1	0	1	7	8
Consistent with these earlier studies , FLAG-HA-tagged SHP co-immunoprecipitated FLAG tagged HNF4alpha and LRH-1 ( XREF_FIG B ) , and SHP overexpression repressed HNF4alpha and LRH-1 transcriptional activity on the SHP and Cyp7a1 promoters in luciferase reporter assays ( XREF_FIG , C and D ) .	Consistent with these earlier studies, FLAG-HA-tagged SHP co-immunoprecipitated FLAG tagged HNF4alpha and LRH-1 (XREF_FIG B), and SHP overexpression repressed HNF4alpha and LRH-1 transcriptional activity on the SHP and Cyp7a1 promoters in luciferase reporter assays (XREF_FIG, C and D).	20	27	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP overexpression	shp	LRH-1	LRH-1	lrh-1	20	21	25	26
Taken together , these results suggest that SHP and SIRT1 works co-operatively to inhibit LRH1 mediated target gene induction , though , under basal conditions the role of various other transcription factors which are reported to be common target of both SHP and SIRT1 , like HNF4alpha , can not be ruled out completely .	Taken together, these results suggest that SHP and SIRT1 works co-operatively to inhibit LRH1 mediated target gene induction, though, under basal conditions the role of various other transcription factors which are reported to be common target of both SHP and SIRT1, like HNF4alpha, can not be ruled out completely.	7	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH1	LRH1	LRH1	7	8	14	15
As a negative regulator of nuclear receptors , SHP inhibits activation of HNF4alpha and LRH-1 in hepatocytes .	As a negative regulator of nuclear receptors, SHP inhibits activation of HNF4alpha and LRH-1 in hepatocytes.	8	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	8	9	14	15
SHP recruits SIRT1 and utilizes SIRT1 deacetylase activity to inhibit LRH1 mediated gene transcription .	SHP recruits SIRT1 and utilizes SIRT1 deacetylase activity to inhibit LRH1 mediated gene transcription.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH1	LRH1	LRH1	0	1	10	11
Elevated SHP protein then inactivated LRH-1 by forming a heterodimeric complex leading to promoter specific repression of SHP , thereby establishing an elaborate autoregulatory negative feedback loop for SHP and a cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism [ XREF_BIBR , XREF_BIBR ] .	Elevated SHP protein then inactivated LRH-1 by forming a heterodimeric complex leading to promoter specific repression of SHP, thereby establishing an elaborate autoregulatory negative feedback loop for SHP and a cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism [XREF_BIBR, XREF_BIBR].	1	6	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	1	2	5	6
BAs also feedback-regulate BA biosynthesis , where activated FXR induces SHP gene expression , and SHP in turn inhibits LRH-1 and/or HNF4alpha activities on the BA response elements ( BAREs ) of CYP7A1 promoter .	BAs also feedback-regulate BA biosynthesis, where activated FXR induces SHP gene expression, and SHP in turn inhibits LRH-1 and/or HNF4alpha activities on the BA response elements (BAREs) of CYP7A1 promoter.	15	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	15	16	19	20
SHP inhibits the function of LRH-1 , the master transcription factor required for expression of Cyp7a1 , and JNK activates SHP function via phosphorylation [ XREF_BIBR , XREF_BIBR ] .	SHP inhibits the function of LRH-1, the master transcription factor required for expression of Cyp7a1, and JNK activates SHP function via phosphorylation [XREF_BIBR, XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	0	1	5	6
In vivo , loss of Lrh1 leads to induced adipogenesis , while loss of Shp causes uncontrolled activation of Lrh1 and reduced adipogenesis .	In vivo, loss of Lrh1 leads to induced adipogenesis, while loss of Shp causes uncontrolled activation of Lrh1 and reduced adipogenesis.	12	20	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shp	loss of Shp	shp	Lrh1	Lrh1	lrh1	14	15	19	20
We also demonstrate that LRH-1 stimulation of the FAS LXR response is blocked by the addition of small heterodimer partner ( SHP ) and that FAS mRNA is overexpressed in SHP knock-out animals , providing evidence that FAS is an in vivo target of SHP repression .	We also demonstrate that LRH-1 stimulation of the FAS LXR response is blocked by the addition of small heterodimer partner (SHP) and that FAS mRNA is overexpressed in SHP knock-out animals, providing evidence that FAS is an in vivo target of SHP repression.	4	20	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	small heterodimer partner	small heterodimer partner	small heterodimer partner	LRH-1	LRH-1	LRH-1	17	20	4	5
SHP inhibits transactivation of liver receptor homolog-1 ( LRH-1 , NR5A2 ) through which to repress the expression of cytochrome p450 ( Cyp ) cholesterol 7alpha-hydroxylase 1 ( Cyp7a1 ) .	SHP inhibits transactivation of liver receptor homolog-1 (LRH-1, NR5A2) through which to repress the expression of cytochrome p450 (Cyp) cholesterol 7alpha-hydroxylase 1 (Cyp7a1).	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	liver receptor homolog-1	liver receptor homolog-1	liver receptor homolog-1	0	1	4	7
It was reported that Otub1 , a deubiquitinase , also negatively regulates the DDR in a catalytically independent manner by regulating the activity of UBC13 , an E2 ubiquitin conjugating enzyme for RNF8 .	It was reported that Otub1, a deubiquitinase, also negatively regulates the DDR in a catalytically independent manner by regulating the activity of UBC13, an E2 ubiquitin conjugating enzyme for RNF8.	4	28	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Otub1	Otub1	Otub1	UBC13	UBC13	UBC13	4	5	24	25
OTUB1 inhibits the RNF168 E2 enzyme UBE2N ( and probably also other E2s ) independently of its de-ubiquitylating activity [ XREF_BIBR , XREF_BIBR ] .	OTUB1 inhibits the RNF168 E2 enzyme UBE2N (and probably also other E2s) independently of its de-ubiquitylating activity [XREF_BIBR, XREF_BIBR].	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	OTUB1	OTUB1	OTUB1	UBE2N	UBE2N	UBE2N	0	1	6	7
OTUB1 strongly suppresses UBC13 dependent Lys-63-linked tri-Ub production , whereas it allows di-Ub production in vitro .	OTUB1 strongly suppresses UBC13 dependent Lys-63-linked tri-Ub production, whereas it allows di-Ub production in vitro.	0	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	OTUB1	OTUB1	OTUB1	UBC13	UBC13	UBC13	0	1	3	4
Intriguingly , OTUB1 inhibits UBC13 and UBE2D/2E family E2 conjugating enzymes in a DUB activity independent manner [ XREF_BIBR ] .	Intriguingly, OTUB1 inhibits UBC13 and UBE2D/2E family E2 conjugating enzymes in a DUB activity independent manner [XREF_BIBR].	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	OTUB1	OTUB1	OTUB1	UBC13	UBC13	UBC13	2	3	4	5
Although human ovarian tumor domain containing ubiquitin aldehyde binding protein 1 ( OTUB1 ) was previously identified as a K48 linkage specific deubiquitinating enzyme that positively regulates p53 stability 22 , OTUB1 strongly suppresses E2-ubiquitin-conjugating enzyme UBC13 dependent K63 linked ubiquitination XREF_BIBR , XREF_BIBR .	Although human ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) was previously identified as a K48 linkage specific deubiquitinating enzyme that positively regulates p53 stability 22, OTUB1 strongly suppresses E2-ubiquitin-conjugating enzyme UBC13 dependent K63 linked ubiquitination XREF_BIBR, XREF_BIBR.	31	38	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	OTUB1	OTUB1	OTUB1	UBC13	UBC13	UBC13	31	32	36	37
Intriguingly , the functional active site of OTUB1 is not required to inhibit Ubc13 .	Intriguingly, the functional active site of OTUB1 is not required to inhibit Ubc13.	5	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	OTUB1	OTUB1	OTUB1	Ubc13	Ubc13	Ubc13	7	8	13	14
Here we describe structural and biochemical studies elucidating how OTUB1 inhibits UBC13 and other E2 enzymes .	Here we describe structural and biochemical studies elucidating how OTUB1 inhibits UBC13 and other E2 enzymes.	9	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	OTUB1	OTUB1	OTUB1	UBC13	UBC13	UBC13	9	10	11	12
Our rationale was to test whether OTUB1 can inhibit yeast Ubc13 .	Our rationale was to test whether OTUB1 can inhibit yeast Ubc13.	6	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	OTUB1	OTUB1	OTUB1	Ubc13	Ubc13	Ubc13	6	7	10	11
Surprisingly , UBC13 , which is inhibited by OTUB1 , did not stimulate OTUB1 as strongly as the other activating E2s .	Surprisingly, UBC13, which is inhibited by OTUB1, did not stimulate OTUB1 as strongly as the other activating E2s.	2	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	OTUB1	OTUB1	OTUB1	UBC13	UBC13	UBC13	8	9	2	3
Comparisons of AR structures bound to coactivator peptides and the SHP peptide revealed structural similarity of their binding sites , suggesting that transcriptional AR activity may be inhibited by SHP by competing with AR coactivators .	Comparisons of AR structures bound to coactivator peptides and the SHP peptide revealed structural similarity of their binding sites, suggesting that transcriptional AR activity may be inhibited by SHP by competing with AR coactivators.	23	30	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	AR	AR	AR	29	30	23	24
Conversely , FHL2 and TIF2 counteracted SHP mediated inhibition of AR .	Conversely, FHL2 and TIF2 counteracted SHP mediated inhibition of AR.	6	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	AR	AR	AR	6	7	10	11
Moreover , enforced expression of Shp or inhibition of miR-141 function by anti-miR-141 attenuated AR regulated transcriptional activity in AR responsive LNCaP cells .	Moreover, enforced expression of Shp or inhibition of miR-141 function by anti-miR-141 attenuated AR regulated transcriptional activity in AR responsive LNCaP cells.	3	15	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Shp	expression of Shp	shp	AR	AR	ar	5	6	14	15
Finally , we showed that TSA reversed SHP induced repression of AR , further emphasizing the relevance of the interaction between SHP and HDACs .	Finally, we showed that TSA reversed SHP induced repression of AR, further emphasizing the relevance of the interaction between SHP and HDACs.	7	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	AR	AR	AR	7	8	11	12
The orphan receptor small heterodimer partner ( Shp ) is a co-repressor to androgen receptor ( AR ) and represses AR regulated transcriptional activity .	The orphan receptor small heterodimer partner (Shp) is a co-repressor to androgen receptor (AR) and represses AR regulated transcriptional activity.	3	21	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	small heterodimer partner	small heterodimer partner	small heterodimer partner	AR	AR	AR	3	6	20	21
The short heterodimer partner ( SHP ) represses the actions of AR and ER .	The short heterodimer partner (SHP) represses the actions of AR and ER.	3	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	AR	AR	AR	5	6	11	12
The orphan receptor , small heterodimer partner ( Shp ) , is a corepressor of AR and represses AR regulated transcriptional activity .	The orphan receptor, small heterodimer partner (Shp), is a corepressor of AR and represses AR regulated transcriptional activity.	4	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	small heterodimer partner	small heterodimer partner	small heterodimer partner	AR	AR	AR	4	7	18	19
We further characterized the SHP mechanism of action by showing that SHP reversed AR coactivator mediated activation .	We further characterized the SHP mechanism of action by showing that SHP reversed AR coactivator mediated activation.	11	16	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	AR	AR	AR	11	12	13	14
In addition to PAK1 , AKT phosphorylates merlin at Thr230 and Ser315 , which promotes merlin degradation by proteasome [ XREF_BIBR ] .	In addition to PAK1, AKT phosphorylates merlin at Thr230 and Ser315, which promotes merlin degradation by proteasome [XREF_BIBR].	0	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK1	PAK1, AKT phosphorylates merlin at Thr230	pak1	merlin	merlin	merlin	3	4	15	16
The underlying mechanism of inactivation of NF2 in the liver is intriguing because agrin activates an integrin-FAK-ILK signaling axis to stimulate p21 Activated kinase ( PAK1 ) that subsequently inactivates Merlin [ XREF_BIBR ] .	The underlying mechanism of inactivation of NF2 in the liver is intriguing because agrin activates an integrin-FAK-ILK signaling axis to stimulate p21 Activated kinase (PAK1) that subsequently inactivates Merlin [XREF_BIBR].	23	32	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK1	PAK1	PAK1	Merlin	Merlin	Merlin	25	26	30	31
XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR Conversely , merlin inhibits PAK1 , and the PAK1 specific inhibitors could reduce the growth of NF2 deficient mesothelioma cells .	XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR Conversely, merlin inhibits PAK1, and the PAK1 specific inhibitors could reduce the growth of NF2 deficient mesothelioma cells.	14	26	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK1	PAK1	PAK1	NF2	NF2	NF2	15	16	23	24
Furthermore , interrogation of signaling partners in the NF2 cascade revealed high levels of PAK1 , an upstream oncogene that inactivates NF2 in cancer cells through phosphorylation [ XREF_BIBR ] .	Furthermore, interrogation of signaling partners in the NF2 cascade revealed high levels of PAK1, an upstream oncogene that inactivates NF2 in cancer cells through phosphorylation [XREF_BIBR].	12	24	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PAK1	levels of PAK1	pak1	NF2	NF2	nf2	14	15	21	22
Pak1 , a downstream target of Rac1 , has been demonstrated to inhibit MLCK and relax permeabilized intestinal smooth muscle .	Pak1, a downstream target of Rac1, has been demonstrated to inhibit MLCK and relax permeabilized intestinal smooth muscle.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pak1	Pak1	Pak1	MLCK	MLCK	MLCK	0	1	13	14
PAK1 directly inhibits MLCK by phosphorylation [ XREF_BIBR ] , indicating that Cdc42 and Rac1 dampen the amoeboid mode of invasion .	PAK1 directly inhibits MLCK by phosphorylation [XREF_BIBR], indicating that Cdc42 and Rac1 dampen the amoeboid mode of invasion.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK1	PAK1	PAK1	MLCK	MLCK	MLCK	0	1	3	4
In contrast , the dominant negative PAK1 shows no effect either on the invasion or on MLC phosphorylation or phospho-MLC recruitment to the actin focal points , suggesting that activated PAK1 inactivates MLCK .	In contrast, the dominant negative PAK1 shows no effect either on the invasion or on MLC phosphorylation or phospho-MLC recruitment to the actin focal points, suggesting that activated PAK1 inactivates MLCK.	29	33	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK1	PAK1	PAK1	MLCK	MLCK	MLCK	30	31	32	33
In addition , Numb inhibits Sonic Hedgehog and Gli1 signaling activation which is required for fibroblast and macrophage activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, Numb inhibits Sonic Hedgehog and Gli1 signaling activation which is required for fibroblast and macrophage activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Gli1	Gli1	Gli1	3	4	8	9
While inhibitory complex comprising of GSK-3beta is inactivated , GLI1 repressor NUMB is degraded .	While inhibitory complex comprising of GSK-3beta is inactivated, GLI1 repressor NUMB is degraded.	9	13	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	GLI1	GLI1	GLI1	11	12	9	10
Recently , it has been demonstrated that GLI signaling is suppressed by Numb , an evolutionarily conserved developmental protein that has critical roles in cell differentiation .	Recently, it has been demonstrated that GLI signaling is suppressed by Numb, an evolutionarily conserved developmental protein that has critical roles in cell differentiation.	7	25	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	GLI	GLI	GLI	12	13	7	8
This is achieved by antagonizing Numb through Sufu ; otherwise , Numb would induce Gli1 degradation ( XREF_SUPPLEMENTARY ) .	This is achieved by antagonizing Numb through Sufu; otherwise, Numb would induce Gli1 degradation (XREF_SUPPLEMENTARY).	11	15	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Gli1	Gli1	Gli1	11	12	14	15
Rifampicin activated PXR is negatively regulated by the small heterodimer partner ( SHP ) , which can be induced by farnesoid X receptor ( FXR ) ligands XREF_BIBR .	Rifampicin activated PXR is negatively regulated by the small heterodimer partner (SHP), which can be induced by farnesoid X receptor (FXR) ligands XREF_BIBR.	2	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	small heterodimer partner	small heterodimer partner	small heterodimer partner	PXR	PXR	PXR	8	11	2	3
SHP suppresses the transcriptional activity of PXR both in vitro and in vivo [ XREF_BIBR - XREF_BIBR ] .	SHP suppresses the transcriptional activity of PXR both in vitro and in vivo [XREF_BIBR - XREF_BIBR].	0	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	PXR	PXR	PXR	0	1	6	7
It was shown that SHP inhibits PXR mediated transactivation of the CYP3A4 gene by interfering with PXR binding to promoter response elements .	It was shown that SHP inhibits PXR mediated transactivation of the CYP3A4 gene by interfering with PXR binding to promoter response elements.	4	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	PXR	PXR	PXR	4	5	6	7
In cell based transient transfection reporter assays , the overexpression of SHP produced a dose dependent inhibition of both mouse Pxr and human PXR transcriptional activities .	In cell based transient transfection reporter assays, the overexpression of SHP produced a dose dependent inhibition of both mouse Pxr and human PXR transcriptional activities.	9	25	produced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	overexpression of SHP	shp	PXR	Pxr	pxr	11	12	20	21
SHP was shown to prevent the PXR and RXR heterodimer from binding to DNA in a pull-down assay , while over-expression of SHP inhibited transactivation of PXR by rifampicin XREF_BIBR .	SHP was shown to prevent the PXR and RXR heterodimer from binding to DNA in a pull-down assay, while over-expression of SHP inhibited transactivation of PXR by rifampicin XREF_BIBR.	0	10	prevent	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	SHP	SHP	shp	PXR	PXR and RXR heterodimer	pxr	0	1	6	7
Although SHP suppresses PXR , the effect of SHP up-regulation by metformin on PXR transcriptional regulation of its target genes has not been analyzed .	Although SHP suppresses PXR, the effect of SHP up-regulation by metformin on PXR transcriptional regulation of its target genes has not been analyzed.	1	4	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	PXR	PXR	PXR	1	2	3	4
Depletion of NUAK1 using two independent siRNAs also reduced phospho-MYPT1 S445 , confirming the specificity of the inhibitor effect ( XREF_FIG ) .	Depletion of NUAK1 using two independent siRNAs also reduced phospho-MYPT1 S445, confirming the specificity of the inhibitor effect (XREF_FIG).	0	10	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	NUAK1	NUAK1	NUAK1	phospho-MYPT1	phospho-MYPT1	phospho-MYPT1	2	3	9	10
Finally , previous work has suggested that NUAK1 phosphorylates and inhibits PP1beta MYPT1 ( where PP1 is protein phosphatase 1 ) and that a major role for the PP1beta MYPT1 complex is to inhibit PLK1 by dephosphorylating its T-loop ( Thr 210 ) .	Finally, previous work has suggested that NUAK1 phosphorylates and inhibits PP1beta MYPT1 (where PP1 is protein phosphatase 1) and that a major role for the PP1beta MYPT1 complex is to inhibit PLK1 by dephosphorylating its T-loop (Thr 210).	7	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUAK1	NUAK1	NUAK1	MYPT1	MYPT1	MYPT1	7	8	12	13
Lastly , consistent with NUAK1 inhibiting PP1beta MYPT1 and PP1beta MYPT1 acting on PLK1 , we demonstrate that cell detachment that promotes phosphorylation and inhibition of PP1beta MYPT1 by NUAK1 markedly enhances the T-loop phosphorylation of PLK1 .	Lastly, consistent with NUAK1 inhibiting PP1beta MYPT1 and PP1beta MYPT1 acting on PLK1, we demonstrate that cell detachment that promotes phosphorylation and inhibition of PP1beta MYPT1 by NUAK1 markedly enhances the T-loop phosphorylation of PLK1.	2	11	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUAK1	NUAK1	NUAK1	MYPT1	MYPT1	MYPT1	4	5	7	8
Activation of p90rsk has been reported to inhibit GSK3beta and to feedback inhibition of the Ras-ERK pathway though phosphorylation of the Ras GTP and GDP-exchange factor , Son of sevenless ( SOS ) [ XREF_BIBR ] .	Activation of p90rsk has been reported to inhibit GSK3beta and to feedback inhibition of the Ras-ERK pathway though phosphorylation of the Ras GTP and GDP-exchange factor, Son of sevenless (SOS) [XREF_BIBR].	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p90rsk	p90rsk	p90rsk	GSK3beta	GSK3beta	GSK3beta	2	3	8	9
Since the ribosomal S6 kinase ( p90RSK ) is a well-known target of ERK XREF_BIBR , XREF_BIBR and activated p90RSK can inactivate GSK-3beta by phosphorylation at Ser9 , we then analyzed the effect of TDZD-8 treatment on the phosphorylation status of these enzymes .	Since the ribosomal S6 kinase (p90RSK) is a well-known target of ERK XREF_BIBR, XREF_BIBR and activated p90RSK can inactivate GSK-3beta by phosphorylation at Ser9, we then analyzed the effect of TDZD-8 treatment on the phosphorylation status of these enzymes.	16	23	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p90RSK	p90RSK	p90RSK	GSK-3beta	GSK-3beta	GSK-3beta	19	20	22	23
Both Erk1/2 and p90RSK can inhibit GSK3beta at this site via dephosphorylation .	Both Erk1/2 and p90RSK can inhibit GSK3beta at this site via dephosphorylation.	1	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p90RSK	p90RSK	p90RSK	GSK3beta	GSK3beta	GSK3beta	3	4	6	7
Second , NUMB was stimulated as an adaptive response to HDM2 overexpression to balance the effects of HDM2 , which is p53 can be inhibited by HDM2 and NUMB can protect p53 from the inhibition of HDM2 XREF_BIBR , XREF_BIBR .	Second, NUMB was stimulated as an adaptive response to HDM2 overexpression to balance the effects of HDM2, which is p53 can be inhibited by HDM2 and NUMB can protect p53 from the inhibition of HDM2 XREF_BIBR, XREF_BIBR.	2	21	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NUMB	NUMB	NUMB	HDM2	HDM2	HDM2	2	3	17	18
In our previous study , SMILE regulates the inhibition of ER by SHP in a cell-type specific manner .	In our previous study, SMILE regulates the inhibition of ER by SHP in a cell-type specific manner.	6	17	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SHP	SHP	SHP	ER	ER	ER	12	13	10	11
Rac1 and Pak1 signaling appears to negatively regulate Op18 and stathmin [ XREF_BIBR , XREF_BIBR ] .	Rac1 and Pak1 signaling appears to negatively regulate Op18 and stathmin [XREF_BIBR, XREF_BIBR].	0	11	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pak1	Pak1	Pak1	stathmin	stathmin	stathmin	2	3	10	11
Recently , overexpression of Xenopus Pak5 was shown to enhance microtubule stabilization , and it was shown that mammalian Pak1 may inhibit a microtubule destabilizing protein , Op18 and Stathmin .	Recently, overexpression of Xenopus Pak5 was shown to enhance microtubule stabilization, and it was shown that mammalian Pak1 may inhibit a microtubule destabilizing protein, Op18 and Stathmin.	18	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pak1	Pak1	Pak1	Op18	Op18	Op18	19	20	27	28
Here we showed that hyperglycemic conditions or PAK1 loss is sufficient to trigger the up-regulation of Bad protein in islet beta-cells , while up-regulation of Bad protein level induced by glucotoxic stress was further exacerbated in PAK1 +/- mouse islets .	Here we showed that hyperglycemic conditions or PAK1 loss is sufficient to trigger the up-regulation of Bad protein in islet beta-cells, while up-regulation of Bad protein level induced by glucotoxic stress was further exacerbated in PAK1 +/- mouse islets.	7	18	trigger	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK1	PAK1	PAK1	Bad protein	Bad protein	Bad protein	7	8	16	18
We found that suppression of both Pak1 and CtBP and BARS activity by siRNA or expression of a DN form of Pak1 reduced virus entry and infection .	We found that suppression of both Pak1 and CtBP and BARS activity by siRNA or expression of a DN form of Pak1 reduced virus entry and infection.	3	22	suppression	Negative_activation_syntax_1_noun	Negative_activation	Positive_activation	Pak1	Pak1	Pak1	CtBP	CtBP	CtBP	21	22	8	9
Constitutive over-expression of COUP-TF II cDNA in mouse C2C12 myogenic cells suppressed the levels of myoD mRNA and blocked the induction of myogenin mRNA , whereas constitutive expression of anti-sense COUP-TF II cDNA significantly increased the steady state levels of myoD mRNA and hyper-induced myogenin mRNA .	Constitutive over-expression of COUP-TF II cDNA in mouse C2C12 myogenic cells suppressed the levels of myoD mRNA and blocked the induction of myogenin mRNA, whereas constitutive expression of anti-sense COUP-TF II cDNA significantly increased the steady state levels of myoD mRNA and hyper-induced myogenin mRNA.	30	41	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	COUP-TF II	COUP-TF II	COUP-TF II	myoD	myoD	myoD	30	32	40	41
When over-expressed in myoblasts , COUP-TFII blocks the induction of myoD and myogenin , two genes involved in the differentiation process of these cells [ XREF_BIBR , XREF_BIBR ] .	When over-expressed in myoblasts, COUP-TFII blocks the induction of myoD and myogenin, two genes involved in the differentiation process of these cells [XREF_BIBR, XREF_BIBR].	5	12	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	COUP-TFII	COUP-TFII	COUP-TFII	myoD	myoD	myoD	5	6	10	11
Cellular mechanisms that may modulate the reduced leukocyte deformability include ANP signaling via GC-A receptors on leukocytes that activate Rac GTPase and its effector PAK1 , which in turn downregulates GEF-H1 activation via phosphorylation at Ser 855 .	Cellular mechanisms that may modulate the reduced leukocyte deformability include ANP signaling via GC-A receptors on leukocytes that activate Rac GTPase and its effector PAK1, which in turn downregulates GEF-H1 activation via phosphorylation at Ser 855.	18	31	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK1	PAK1	PAK1	GEF-H1	GEF-H1	GEF-H1	24	25	30	31
ANP signaling through Rac GTPase and its effector PAK1 , which down-regulates GEF-H1 activation via phosphorylation at Ser 855 .	ANP signaling through Rac GTPase and its effector PAK1, which down-regulates GEF-H1 activation via phosphorylation at Ser 855.	1	13	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK1	PAK1	PAK1	GEF-H1	GEF-H1	GEF-H1	8	9	12	13
In our hands , PHLPP1 silencing in a series of PTEN positive cells of different origins had no effect on Akt phosphorylation , suggesting that PHLPP loss can not efficiently activate Akt in the presence of PTEN .	In our hands, PHLPP1 silencing in a series of PTEN positive cells of different origins had no effect on Akt phosphorylation, suggesting that PHLPP loss can not efficiently activate Akt in the presence of PTEN.	25	32	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	25	26	31	32
While it is commonly downregulated , overexpression of PHLPP1 reduces Akt activation and inhibits melanoma cell proliferation in vitro , and retards melanoma growth in a xenograft model .	While it is commonly downregulated, overexpression of PHLPP1 reduces Akt activation and inhibits melanoma cell proliferation in vitro, and retards melanoma growth in a xenograft model.	6	11	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	overexpression of PHLPP1	phlpp1	Akt	Akt	akt	8	9	10	11
The overexpression of PHLPP1 in cells impairs AKT and PKB and GSK3 activity , resulting in a decrease of the glycogen synthesis and glucose transport .	The overexpression of PHLPP1 in cells impairs AKT and PKB and GSK3 activity, resulting in a decrease of the glycogen synthesis and glucose transport.	1	12	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	overexpression of PHLPP1	phlpp1	AKT	AKT	akt	3	4	7	8
Conditional deletion of Ar in the epithelium promotes the proliferation of Pten-null cancer cells , at least in part , by down-regulating androgen responsive gene Fkbp5 and preventing PHLPP mediated AKT inhibition .	Conditional deletion of Ar in the epithelium promotes the proliferation of Pten-null cancer cells, at least in part, by down-regulating androgen responsive gene Fkbp5 and preventing PHLPP mediated AKT inhibition.	28	31	mediated	Positive_early_activation	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	AKT	AKT	AKT	28	29	30	31
In contrast , knockdown of PHLPP1 increases Akt activation , enhances melanoma cell and melanocyte proliferation , and results in anchorage independent growth of melanocytes .	In contrast, knockdown of PHLPP1 increases Akt activation, enhances melanoma cell and melanocyte proliferation, and results in anchorage independent growth of melanocytes.	3	8	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	5	6	7	8
Phlpp1 blocks Akt activation at the epithelial plasma membrane .	Phlpp1 blocks Akt activation at the epithelial plasma membrane.	0	3	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Phlpp1	Phlpp1	Phlpp1	Akt	Akt	Akt	0	1	2	3
The work presented here is the first to show in a neuronal system , that inhibition of PHLPP1alpha increases AKT activity while inhibition of PHLPP1beta and SCOP promotes AKT and PKCalpha activity .	The work presented here is the first to show in a neuronal system, that inhibition of PHLPP1alpha increases AKT activity while inhibition of PHLPP1beta and SCOP promotes AKT and PKCalpha activity.	22	31	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SCOP	SCOP	SCOP	AKT	AKT	AKT	26	27	28	29
Also , a pH domain leucine rich repeat protein phosphatase ( PHLPP ) has also been shown to specifically dephosphorylate Ser 473 and inactivate Akt .	Also, a pH domain leucine rich repeat protein phosphatase (PHLPP) has also been shown to specifically dephosphorylate Ser 473 and inactivate Akt.	5	25	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	11	12	24	25
PHLPP negatively regulates PI3K and Akt and RAF/RAS/' signaling activation , which is crucial in development , growth , and proliferation of lung cancer .	PHLPP negatively regulates PI3K and Akt and RAF/RAS/' signaling activation, which is crucial in development, growth, and proliferation of lung cancer.	0	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	0	1	5	6
PHLPP negatively regulates PI3K and Akt and the RAF/RAS/ERK signaling pathways .	PHLPP negatively regulates PI3K and Akt and the RAF/RAS/ERK signaling pathways.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	0	1	5	6
Calpain-1 down-regulation results in increased cerebellar PHLPP1 levels , which inhibit Akt and cause cerebellar granule cell death during a critical period of postnatal cerebellar development , and reduced granule cell density in adult KO mice .	Calpain-1 down-regulation results in increased cerebellar PHLPP1 levels, which inhibit Akt and cause cerebellar granule cell death during a critical period of postnatal cerebellar development, and reduced granule cell density in adult KO mice.	6	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1 levels	phlpp1	Akt	Akt	akt	6	7	11	12
In contrast , the phosphatases in the PH domain and leucine rich repeat protein phosphatases ( PHLPP ) family have been shown to directly dephosphorylate and therefore inactivate distinct Akt isoforms .	In contrast, the phosphatases in the PH domain and leucine rich repeat protein phosphatases (PHLPP) family have been shown to directly dephosphorylate and therefore inactivate distinct Akt isoforms.	4	30	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	16	17	29	30
Previous studies have established that PHLPP1 and PHLPP2 inhibit AKT signaling differently by interacting with distinct AKT isoforms .	Previous studies have established that PHLPP1 and PHLPP2 inhibit AKT signaling differently by interacting with distinct AKT isoforms.	5	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	AKT	AKT	AKT	5	6	9	10
Selective PHLPP1 inhibition ( such as by shRNA KD ) activates AKT survival signaling in neurons and astrocytes .	Selective PHLPP1 inhibition (such as by shRNA KD) activates AKT survival signaling in neurons and astrocytes.	1	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	AKT	AKT	AKT	1	2	11	12
Notably , PHLPP1 silencing following PTEN silencing significantly and massively activated Akt by phosphorylation on both Ser473 and Thr308 .	Notably, PHLPP1 silencing following PTEN silencing significantly and massively activated Akt by phosphorylation on both Ser473 and Thr308.	2	12	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	2	3	11	12
Indeed , PHLPP mediated Akt inhibition required FKBP5 activity , and PHLPP knock-out caused mouse prostate neoplasia .	Indeed, PHLPP mediated Akt inhibition required FKBP5 activity, and PHLPP knock-out caused mouse prostate neoplasia.	2	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	2	3	4	5
We obtained evidence that this PHLPP1 mediated Akt inhibition underlies the in vitro and/or in vivo efficacy of 3 in suppressing the proliferation of PTEN negative LNCaP and PC-3 prostate cancer cells .	We obtained evidence that this PHLPP1 mediated Akt inhibition underlies the in vitro and/or in vivo efficacy of 3 in suppressing the proliferation of PTEN negative LNCaP and PC-3 prostate cancer cells.	4	9	mediated	Positive_early_activation	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	5	6	7	8
PHLPP1 3 is known to negatively regulate Akt by direct dephosphorylation and play an important role in cell survival , proliferation , migration , and cell death .	PHLPP1 3 is known to negatively regulate Akt by direct dephosphorylation and play an important role in cell survival, proliferation, migration, and cell death.	0	12	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	0	1	7	8
Mechanistic study demonstrated PHLPP has the ability to dephosphorylate S473 and inactivate Akt [ XREF_BIBR ] ( XREF_FIG ) .	Mechanistic study demonstrated PHLPP has the ability to dephosphorylate S473 and inactivate Akt [XREF_BIBR] (XREF_FIG).	3	14	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	3	4	12	13
Two isoforms , PHLPP1 and PHLPP2 , directly dephosphorylate Ser473 and therefore inactivate Akt .	Two isoforms, PHLPP1 and PHLPP2, directly dephosphorylate Ser473 and therefore inactivate Akt.	1	14	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	3	4	13	14
Here , we show that USP46 and PHLPP function together to suppress Akt signaling in a mutually dependent manner .	Here, we show that USP46 and PHLPP function together to suppress Akt signaling in a mutually dependent manner.	5	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	7	8	12	13
Also , PHLPP1 levels are markedly reduced in several cancer cell lines that have elevated Akt phosphorylation , and the reintroduction of PHLPP1 reduces cell growth by inactivating the Akt pathway .	Also, PHLPP1 levels are markedly reduced in several cancer cell lines that have elevated Akt phosphorylation, and the reintroduction of PHLPP1 reduces cell growth by inactivating the Akt pathway.	20	30	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	22	23	29	30
Mechanistic Validation of the Mode of Action of 20 and 22 in Facilitating PHLPP1 Targeted Akt Inhibition .	Mechanistic Validation of the Mode of Action of 20 and 22 in Facilitating PHLPP1 Targeted Akt Inhibition.	12	16	Targeted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	13	14	15	16
Calpain-1-mediated degradation of PHLPP1 activates Akt and promotes neuronal survival , and we postulated that calpain-1 mediated regulation of PHLPP1 and Akt could be involved in NMDAR dependent CGC survival during postnatal development .	Calpain-1-mediated degradation of PHLPP1 activates Akt and promotes neuronal survival, and we postulated that calpain-1 mediated regulation of PHLPP1 and Akt could be involved in NMDAR dependent CGC survival during postnatal development.	1	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	3	4	5	6
Thus , we conclude that Phlpp1 acts at the prostate epithelial membrane to antagonize Ser 473 -activation of Akt and that its loss , especially after Pten deregulation , can direct pAkt signaling to the plasma membrane .	Thus, we conclude that Phlpp1 acts at the prostate epithelial membrane to antagonize Ser 473 -activation of Akt and that its loss, especially after Pten deregulation, can direct pAkt signaling to the plasma membrane.	5	19	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Phlpp1	Phlpp1	Phlpp1	Akt	Akt	Akt	5	6	18	19
PHLPP has been identified to negatively regulate PI3K and Akt and RAF/RAS/ERK signaling activation [ XREF_BIBR , XREF_BIBR ] .	PHLPP has been identified to negatively regulate PI3K and Akt and RAF/RAS/ERK signaling activation [XREF_BIBR, XREF_BIBR].	0	15	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	0	1	9	10
USP46 enhances PHLPP mediated negative regulation of Akt in cells .	USP46 enhances PHLPP mediated negative regulation of Akt in cells.	1	8	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	2	3	7	8
Studies using non neuronal culture models indicate PHLPP1 inhibits the kinases AKT and PKCalpha .	Studies using non neuronal culture models indicate PHLPP1 inhibits the kinases AKT and PKCalpha.	7	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	AKT	AKT	AKT	7	8	11	12
To investigate whether the sulfonamide derivatives retained the ability of 3 to facilitate PHLPP1 mediated Akt inhibition , we examined the effects of these sulfonamides vis-a-vis 3 on Akt signaling in LNCaP and PC-3 cells .	To investigate whether the sulfonamide derivatives retained the ability of 3 to facilitate PHLPP1 mediated Akt inhibition, we examined the effects of these sulfonamides vis-a-vis 3 on Akt signaling in LNCaP and PC-3 cells.	12	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	13	14	15	16
Importantly , the amplitude of AKT inactivation by PHLPP phosphatases largely depends on the isoform type .	Importantly, the amplitude of AKT inactivation by PHLPP phosphatases largely depends on the isoform type.	5	9	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	AKT	AKT	AKT	8	9	5	6
Since PHLPP protein inhibits Akt activity , differences in protein levels are more relevant for our studies than mRNA levels , and we have focused less on PHLPP as a likely myelin brake candidate .	Since PHLPP protein inhibits Akt activity, differences in protein levels are more relevant for our studies than mRNA levels, and we have focused less on PHLPP as a likely myelin brake candidate.	1	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	1	2	4	5
However , it has not been directly shown PHLPP1 can inhibit AKT and PKCalpha in neurons .	However, it has not been directly shown PHLPP1 can inhibit AKT and PKCalpha in neurons.	8	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	AKT	AKT	AKT	8	9	11	12
In some cells , including those of a breast cancer lineage , AKT activation is inhibited by over-expression of PHLPP proteins .	In some cells, including those of a breast cancer lineage, AKT activation is inhibited by over-expression of PHLPP proteins.	12	20	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PHLPP	over-expression of PHLPP	phlpp	AKT	AKT	akt	19	20	12	13
Intriguingly , pAKT473 levels appear to track the expression of PHLPP1beta and SCOP ( XREF_FIG ) , suggesting that PHLPP1beta and SCOP may not antagonize AKT activity .	Intriguingly, pAKT473 levels appear to track the expression of PHLPP1beta and SCOP (XREF_FIG), suggesting that PHLPP1beta and SCOP may not antagonize AKT activity.	19	26	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SCOP	SCOP	SCOP	AKT	AKT	AKT	21	22	25	26
Remarkably , infarct size was smaller ( by 45 % ) , evidence that potentiation of Akt activation by PHLPP-1 deletion protects the heart against I/R injury ( XREF_FIG ) .	Remarkably, infarct size was smaller (by 45%), evidence that potentiation of Akt activation by PHLPP-1 deletion protects the heart against I/R injury (XREF_FIG).	16	20	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	PHLPP-1	PHLPP-1	PHLPP-1	Akt	Akt	Akt	19	20	16	17
A decrease in membrane localized PHLPP1 , by calpain mediated cleavage , would allow increased AKT activity .	A decrease in membrane localized PHLPP1, by calpain mediated cleavage, would allow increased AKT activity.	1	16	allow	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	AKT	AKT	AKT	5	6	15	16
While accumulatoin of p21 and p27 induces cellular senesense , accumulation of PHLPP1 would inactivate AKT and mTORC , leading to autophagy .	While accumulatoin of p21 and p27 induces cellular senesense, accumulation of PHLPP1 would inactivate AKT and mTORC, leading to autophagy.	10	19	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	AKT	AKT	AKT	12	13	15	16
PHLPP overexpression inactivated Akt , whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells .	PHLPP overexpression inactivated Akt, whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells.	6	12	increased	Positive_regulation_syntax_1_verb	Negative_activation	Negative_regulation	PHLPP	PHLPP	phlpp	Akt	phosphorylation of Akt	akt	6	7	11	12
As this PHLPP1 targeted Akt inhibition appears to take place at the membrane cytoplasmic interface , we postulate that this new class of inhibitors requires unique physicochemical properties that allow their membrane association .	As this PHLPP1 targeted Akt inhibition appears to take place at the membrane cytoplasmic interface, we postulate that this new class of inhibitors requires unique physicochemical properties that allow their membrane association.	1	8	targeted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	2	3	4	5
Accordingly , PHLPP expression decreases Akt activity in vitro and the phosphorylation of numerous Akt substrates in cells , while depletion of either or both PHLPP isozymes results in increased Akt substrate phosphorylation [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Accordingly, PHLPP expression decreases Akt activity in vitro and the phosphorylation of numerous Akt substrates in cells, while depletion of either or both PHLPP isozymes results in increased Akt substrate phosphorylation [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	2	6	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP expression	phlpp	Akt	Akt	akt	2	3	5	6
PHLPP-1 Negatively Regulates Akt Activity and Survival in the Heart .	PHLPP-1 Negatively Regulates Akt Activity and Survival in the Heart.	0	4	Negatively Regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP-1	PHLPP-1	PHLPP-1	Akt	Akt	Akt	0	1	3	4
In non immune cells , expression of PHLPP blocks Akt activation , triggers apoptosis , suppresses tumor growth , and controls circadian rhythms .	In non immune cells, expression of PHLPP blocks Akt activation, triggers apoptosis, suppresses tumor growth, and controls circadian rhythms.	5	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	expression of PHLPP	phlpp	Akt	Akt	akt	7	8	9	10
However , from a chemopreventive perspective , the high concentrations required for alpha- and gamma-tocopherol to induce PHLPP1 mediated Akt inhibition ( greater than 150 muM ) might not be attainable in humans through vitamin E supplementation .	However, from a chemopreventive perspective, the high concentrations required for alpha- and gamma-tocopherol to induce PHLPP1 mediated Akt inhibition (greater than 150 muM) might not be attainable in humans through vitamin E supplementation.	16	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	17	18	19	20
PHLPP1 inhibits AKT signaling in hippocampal neurons .	PHLPP1 inhibits AKT signaling in hippocampal neurons.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	AKT	AKT	AKT	0	1	2	3
PHLPP can inhibit the activity of AKT signaling pathway [ XREF_BIBR ] .	PHLPP can inhibit the activity of AKT signaling pathway [XREF_BIBR].	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	AKT	AKT	AKT	0	1	6	7
On the other hand , the phosphatase PHLPP ( PH domain leucine rich repeat protein phosphatase ) was shown to specifically dephosphorylate the hydrophobic motif of Akt ( Ser473 in Akt1 ) and inhibit Akt activity .	On the other hand, the phosphatase PHLPP (PH domain leucine rich repeat protein phosphatase) was shown to specifically dephosphorylate the hydrophobic motif of Akt (Ser473 in Akt1) and inhibit Akt activity.	5	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP (PH domain leucine rich repeat protein phosphatase) was shown to specifically dephosphorylate the hydrophobic motif of Akt (Ser473	phlpp	Akt	Akt	akt	7	8	34	35
PHLPP negatively regulates the activity of Akt and MEK and ERK in pancreatic cells .	PHLPP negatively regulates the activity of Akt and MEK and ERK in pancreatic cells.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	0	1	6	7
It has been shown recently that PHLPP negatively regulates mitochondrial Akt activity in cardiac cell survival .	It has been shown recently that PHLPP negatively regulates mitochondrial Akt activity in cardiac cell survival.	6	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	6	7	10	11
Nonspecific PHLPP inhibition ( by NSC117079 and NSC45586 ) only activates AKT in neurons .	Nonspecific PHLPP inhibition (by NSC117079 and NSC45586) only activates AKT in neurons.	1	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	AKT	AKT	AKT	1	2	11	12
Thus , deletion of PHLPP1 can enhance Akt activation in neurons and astrocytes , and can significantly increase cell survival and diminish infarct size after MCAO .	Thus, deletion of PHLPP1 can enhance Akt activation in neurons and astrocytes, and can significantly increase cell survival and diminish infarct size after MCAO.	2	8	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	4	5	7	8
The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP dependent attenuation of Akt signaling in colon cancer .	The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP dependent attenuation of Akt signaling in colon cancer.	11	16	attenuation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	11	12	15	16
XREF_BIBR Conversely heterologous expression of PHLPP in cancer cells can prevent Akt activation and promote apoptotic death .	XREF_BIBR Conversely heterologous expression of PHLPP in cancer cells can prevent Akt activation and promote apoptotic death.	3	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	expression of PHLPP	phlpp	Akt	Akt	akt	5	6	11	12
PH domain Leucine rich repeat protein phosphatase ( PHLPP ) directly dephosphorylates and inactivates Akt and protein kinase C , poising it as a prime target for pharmacological intervention of two major survival pathways .	PH domain Leucine rich repeat protein phosphatase (PHLPP) directly dephosphorylates and inactivates Akt and protein kinase C, poising it as a prime target for pharmacological intervention of two major survival pathways.	2	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	8	9	14	15
PHLPP1 suppresses Akt and ERK pathways under basal conditions ; following synaptic NMDAR activation , calpain cleaves PHLPP1alpha and beta , thus releasing the inhibition of these two major pro survival signaling cascades in neurons .	PHLPP1 suppresses Akt and ERK pathways under basal conditions; following synaptic NMDAR activation, calpain cleaves PHLPP1alpha and beta, thus releasing the inhibition of these two major pro survival signaling cascades in neurons.	0	5	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	0	1	2	3
PHLPP1 and PHLPP2 selectively inactivate the 2 Akt isoforms ; PHLPP1 dephosphorylates Akt2 , whereas PHLPP2 dephosphorylates Akt1 .	PHLPP1 and PHLPP2 selectively inactivate the 2 Akt isoforms; PHLPP1 dephosphorylates Akt2, whereas PHLPP2 dephosphorylates Akt1.	0	8	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	0	1	7	8
It also resulted in the degradation of two splice variants of PH domain and Leucine rich repeat Protein Phosphatase 1 ( PHLPP1 ) , PHLPP1alpha and PHLPP1beta , which inhibit the Akt and ERK1/2 pathways .	It also resulted in the degradation of two splice variants of PH domain and Leucine rich repeat Protein Phosphatase 1 (PHLPP1), PHLPP1alpha and PHLPP1beta, which inhibit the Akt and ERK1/2 pathways.	2	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	21	22	31	32
XREF_BIBR , who demonstrated that AR inhibition , either by castration or AR loss , released PHLPP mediated suppression of Akt activity and induced Akt dependent but AR independent PCa cell proliferation .	XREF_BIBR, who demonstrated that AR inhibition, either by castration or AR loss, released PHLPP mediated suppression of Akt activity and induced Akt dependent but AR independent PCa cell proliferation.	15	21	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	16	17	20	21
AKT activation is suppressed by the phosphatase PHLPP ( PH domain leucine rich repeat protein phosphatase ) , which dephosphorylates S473 [ XREF_BIBR , XREF_BIBR ] , and T308 by PP2A [ XREF_BIBR ] .	AKT activation is suppressed by the phosphatase PHLPP (PH domain leucine rich repeat protein phosphatase), which dephosphorylates S473 [XREF_BIBR, XREF_BIBR], and T308 by PP2A [XREF_BIBR].	0	20	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PHLPP	PHLPP (PH domain leucine rich repeat protein phosphatase), which dephosphorylates	phlpp	AKT	AKT	akt	7	8	0	1
PHLPP , a known tumor suppressor , can negatively regulate Akt and its downstream kinases , thereby antagonizing the PI3K and Akt signaling pathway and inhibit tumor growth .	PHLPP, a known tumor suppressor, can negatively regulate Akt and its downstream kinases, thereby antagonizing the PI3K and Akt signaling pathway and inhibit tumor growth.	0	25	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	0	1	10	11
If Akt were not released fast enough from an SRPK containing complex , a recruited PHLPP would rapidly inactivate Akt within the complex .	If Akt were not released fast enough from an SRPK containing complex, a recruited PHLPP would rapidly inactivate Akt within the complex.	13	20	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	15	16	19	20
In line with this possibility , miR-190 directly inhibits the PH domain leucine rich repeat protein phosphatase ( PHLPP ) , a tumor suppressor protein that inactivates the kinase AKT through Ser437 dephosphorylation [ XREF_BIBR - XREF_BIBR ] .	In line with this possibility, miR-190 directly inhibits the PH domain leucine rich repeat protein phosphatase (PHLPP), a tumor suppressor protein that inactivates the kinase AKT through Ser437 dephosphorylation [XREF_BIBR - XREF_BIBR].	16	30	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	AKT	AKT	AKT	18	19	29	30
PH domain leucine rich repeat protein phosphatase ( PHLPP ) has been shown to attenuate AKT signaling through the regulation of distinct AKT isoforms [ XREF_BIBR ] .	PH domain leucine rich repeat protein phosphatase (PHLPP) has been shown to attenuate AKT signaling through the regulation of distinct AKT isoforms [XREF_BIBR].	2	16	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	AKT	AKT	AKT	8	9	15	16
XREF_BIBR , XREF_BIBR The protein phosphatases PP2A ( protein phosphatase 2A ) and PHLPP ( PH domain and leucine rich repeat protein phosphatase ) inhibit Akt activity via dephosphorylation of the activating sites .	XREF_BIBR, XREF_BIBR The protein phosphatases PP2A (protein phosphatase 2A) and PHLPP (PH domain and leucine rich repeat protein phosphatase) inhibit Akt activity via dephosphorylation of the activating sites.	0	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	13	14	25	26
It was recently demonstrated that loss of AR expression , in the absence of PTEN , can lead to downregulation of Fkbp5 and PHLPP mediated Akt inhibition resulting in increased cellular proliferation [ XREF_BIBR , XREF_BIBR ] .	It was recently demonstrated that loss of AR expression, in the absence of PTEN, can lead to downregulation of Fkbp5 and PHLPP mediated Akt inhibition resulting in increased cellular proliferation [XREF_BIBR, XREF_BIBR].	19	26	mediated	Positive_early_activation	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	23	24	25	26
Thus , a two pronged facilitation of GPCR signaling can occur : PKC activity removes tonic inhibition of Raf-1 by RKIP and , simultaneously , GRK2 mediated phosphorylation and internalization of the GPCR is prevented .	Thus, a two pronged facilitation of GPCR signaling can occur : PKC activity removes tonic inhibition of Raf-1 by RKIP and, simultaneously, GRK2 mediated phosphorylation and internalization of the GPCR is prevented.	14	21	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	20	21	18	19
3.4 Raf-1 signaling is inhibited by RKIP in B-Raf-compromised cells .	3.4 Raf-1 signaling is inhibited by RKIP in B-Raf-compromised cells.	1	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	6	7	1	2
An alternative model is that B-Raf , by binding to RKIP , limits the ability of RKIP to interact with or inhibit Raf-1 ; thus , when B-Raf is not expressed , the higher concentration of unbound RKIP would more effectively suppress Raf-1 activation .	An alternative model is that B-Raf, by binding to RKIP, limits the ability of RKIP to interact with or inhibit Raf-1; thus, when B-Raf is not expressed, the higher concentration of unbound RKIP would more effectively suppress Raf-1 activation.	34	43	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	37	38	42	43
If RKIP functions to suppress Raf-1 activation in cells , then loss of RKIP might enable Raf-1 and ERK activation in MEFs with compromised B-Raf expression .	If RKIP functions to suppress Raf-1 activation in cells, then loss of RKIP might enable Raf-1 and ERK activation in MEFs with compromised B-Raf expression.	1	6	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	1	2	5	6
In mammalian cells , RKIP inhibits Raf-1 signaling to Erk , suppressing Raf-1-induced transformation [ XREF_BIBR ] .	In mammalian cells, RKIP inhibits Raf-1 signaling to Erk, suppressing Raf-1-induced transformation [XREF_BIBR].	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	4	5	6	7
In this scenario , RKIP might inhibit both pro tumorigenic RAF-1 and MDA-9 , thereby significantly augmenting the tumor suppressor properties of RKIP .	In this scenario, RKIP might inhibit both pro tumorigenic RAF-1 and MDA-9, thereby significantly augmenting the tumor suppressor properties of RKIP.	4	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	RAF-1	RAF-1	RAF-1	4	5	10	11
Early on , PEBP-1 was shown to bind to and inhibit the function of Raf-1 , leading to the term RKIP .	Early on, PEBP-1 was shown to bind to and inhibit the function of Raf-1, leading to the term RKIP.	3	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PEBP-1	PEBP-1	PEBP-1	Raf-1	Raf-1	Raf-1	3	4	14	15
In metazoans , RKIP is a specific inhibitor of Raf-1 in the classical Raf/MEK/ERK , also called the MAPK pathway .	In metazoans, RKIP is a specific inhibitor of Raf-1 in the classical Raf/MEK/ERK, also called the MAPK pathway.	3	13	is a specific inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	3	4	9	10
RKIP inhibits the activation of Raf-1 by binding to it , disrupting the interaction between Raf-1 and MEK , thus playing a part in regulating the activity of the ERK pathway .	RKIP inhibits the activation of Raf-1 by binding to it, disrupting the interaction between Raf-1 and MEK, thus playing a part in regulating the activity of the ERK pathway.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	0	1	5	6
13 However , RKIP depletion in cells revealed that RKIP blocks Raf-1 activation under physiological conditions .	13 However, RKIP depletion in cells revealed that RKIP blocks Raf-1 activation under physiological conditions.	9	12	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	9	10	11	12
Overexpression of RKIP was shown to inhibit Raf-1 kinase activity and ERK activation , and RKIP depletion caused up-regulation of ERK activity in several cell types including human 293-T cells [ XREF_BIBR , XREF_BIBR ] .	Overexpression of RKIP was shown to inhibit Raf-1 kinase activity and ERK activation, and RKIP depletion caused up-regulation of ERK activity in several cell types including human 293-T cells [XREF_BIBR, XREF_BIBR].	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	Overexpression of RKIP	rkip	Raf-1	Raf-1	raf-1	2	3	7	8
Here we show that the pocket integrates two regulatory signals , phosphorylation and ligand binding , to control RKIP inhibition of Raf-1 .	Here we show that the pocket integrates two regulatory signals, phosphorylation and ligand binding, to control RKIP inhibition of Raf-1.	18	22	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	18	19	21	22
RKIP inhibits Raf-1 but not B-Raf activation , and B-Raf is a more potent activator of ERK than Raf-1 [ XREF_BIBR ] .	RKIP inhibits Raf-1 but not B-Raf activation, and B-Raf is a more potent activator of ERK than Raf-1 [XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	0	1	2	3
This may be attributed to RKIP ' s inhibitory effect on Raf-1 ; RKIP also decreases Raf-1 function by preventing its kinase activity .	This may be attributed to RKIP 's inhibitory effect on Raf-1; RKIP also decreases Raf-1 function by preventing its kinase activity.	13	17	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	13	14	16	17
RKIP inhibits Raf-1 subsequent to Raf-1 membrane translocation but prior to phosphorylation of downstream targets such as MEK and ERK .	RKIP inhibits Raf-1 subsequent to Raf-1 membrane translocation but prior to phosphorylation of downstream targets such as MEK and ERK.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	0	1	2	3
RKIP has been shown to inhibit Raf-1 signalling ( Yeung etal .	RKIP has been shown to inhibit Raf-1 signalling (Yeung etal.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	0	1	6	7
Accordingly , we had expected that relatively lower levels of pRKIP might correlate with a residual higher RKIP levels that would inhibit the Raf-1 and NF-kB pathways and presumably result in a better prognosis .	Accordingly, we had expected that relatively lower levels of pRKIP might correlate with a residual higher RKIP levels that would inhibit the Raf-1 and NF-kB pathways and presumably result in a better prognosis.	17	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	RKIP levels	rkip	Raf-1	Raf-1	raf-1	17	18	23	24
In many cell types , overexpression of RKIP inhibits Raf-1 activation and subsequent ERK activation , whereas knockdown of RKIP potentiates ERK activation [ XREF_BIBR , XREF_BIBR ] .	In many cell types, overexpression of RKIP inhibits Raf-1 activation and subsequent ERK activation, whereas knockdown of RKIP potentiates ERK activation [XREF_BIBR, XREF_BIBR].	5	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RKIP	overexpression of RKIP	rkip	Raf-1	Raf-1	raf-1	7	8	9	10
Thus , Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1 , -2 , and -3 via phosphorylation on Ser 473 , resulting in the proliferation of CML cells .	Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser 473, resulting in the proliferation of CML cells.	2	25	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP1	Bcr-Abl represses the expression of PHLPP1	phlpp1	Akt1	Akt1	akt1	7	8	13	14
We found that PHLPP1 siRNA knockdown specifically increased pAkt2 but not pAkt1 , whereas PHLPP2 knockdown increased pAkt1 but not pAkt2 ( XREF_FIG ) .	We found that PHLPP1 siRNA knockdown specifically increased pAkt2 but not pAkt1, whereas PHLPP2 knockdown increased pAkt1 but not pAkt2 (XREF_FIG).	3	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	pAkt1	pAkt1	pAkt1	3	4	11	12
We further showed that miR-331-3p-mediated inhibition of PHLPP resulted in stimulation of protein kinase B ( AKT ) and subsequent epithelial mesenchymal transition ( EMT ) .	We further showed that miR-331-3p-mediated inhibition of PHLPP resulted in stimulation of protein kinase B (AKT) and subsequent epithelial mesenchymal transition (EMT).	5	15	resulted in stimulation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	protein kinase B	protein kinase B	protein kinase B	7	8	12	15
Release of the inhibitory effect of mTORC2 and Akt1 and subsequent activation of CMA is attained through the association with the lysosomal membrane of the phosphatase PHLPP1 that inactivates Akt1 by dephosphorylation .	Release of the inhibitory effect of mTORC2 and Akt1 and subsequent activation of CMA is attained through the association with the lysosomal membrane of the phosphatase PHLPP1 that inactivates Akt1 by dephosphorylation.	22	30	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt1	Akt1	Akt1	26	27	29	30
PAK2 also impairs the ability of merlin to bind to two interacting proteins , CD44 and HRS , both critical for merlin growth suppression .	PAK2 also impairs the ability of merlin to bind to two interacting proteins, CD44 and HRS, both critical for merlin growth suppression.	0	7	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK2	PAK2	PAK2	merlin	merlin	merlin	0	1	6	7
In COS-1 fibroblasts , PAK1 stimulates mitogenic MAP kinase signaling XREF_BIBR and in human fibroblasts , PAK2 inhibits the tumor suppressor NF2 by phosphorylation , resulting in an increase in proliferation XREF_BIBR .	In COS-1 fibroblasts, PAK1 stimulates mitogenic MAP kinase signaling XREF_BIBR and in human fibroblasts, PAK2 inhibits the tumor suppressor NF2 by phosphorylation, resulting in an increase in proliferation XREF_BIBR.	16	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PAK2	PAK2	PAK2	NF2	NF2	NF2	16	17	21	22
Lastly , we show that PAK2 phosphorylation impairs the ability of merlin to bind to two interacting proteins , CD44 and hepatocyte growth factor regulated tyrosine kinase substrate ( HRS ) , both critical for merlin growth suppression .	Lastly, we show that PAK2 phosphorylation impairs the ability of merlin to bind to two interacting proteins, CD44 and hepatocyte growth factor regulated tyrosine kinase substrate (HRS), both critical for merlin growth suppression.	5	12	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK2	PAK2 phosphorylation	pak2	merlin	merlin	merlin	5	6	11	12
While mesenchymal TGF-beta signaling induces PAK2 mediated inhibition of Merlin function in the absence of Erbin , Erbin and Merlin complexes bind and inactivate GTPase bound PAK2 in epithelia .	While mesenchymal TGF-beta signaling induces PAK2 mediated inhibition of Merlin function in the absence of Erbin, Erbin and Merlin complexes bind and inactivate GTPase bound PAK2 in epithelia.	5	10	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PAK2	PAK2	PAK2	Merlin	Merlin	Merlin	5	6	9	10
Our results show that PAK2 inhibits caspase-7 by two divergent mechanisms prior to and following caspase activation : initial phosphorylation allosterically slows activation by upstream initiator caspases by impeding cleavage at the intersubunit linker and a second phosphorylation site directly blocks substrate binding .	Our results show that PAK2 inhibits caspase-7 by two divergent mechanisms prior to and following caspase activation : initial phosphorylation allosterically slows activation by upstream initiator caspases by impeding cleavage at the intersubunit linker and a second phosphorylation site directly blocks substrate binding.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK2	PAK2	PAK2	caspase-7	caspase-7	caspase-7	4	5	6	7
Accordingly , higher levels of FKBP51 , as is observed under HFD conditions , favors PHLPP1 mediated inactivation of AKT2 , activation of AS160 , and ultimately lower glucose uptake .	Accordingly, higher levels of FKBP51, as is observed under HFD conditions, favors PHLPP1 mediated inactivation of AKT2, activation of AS160, and ultimately lower glucose uptake.	15	20	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	AKT2	AKT2	AKT2	15	16	19	20
PHLPP1 dephosphorylates and thereby inactivates Akt2 , whereby PHLPP2 targets Akt1 for dephosphorylation [ XREF_BIBR ] .	PHLPP1 dephosphorylates and thereby inactivates Akt2, whereby PHLPP2 targets Akt1 for dephosphorylation [XREF_BIBR].	0	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP1	PHLPP1	PHLPP1	Akt2	Akt2	Akt2	0	1	5	6
Expression of PEA-15 reduced membrane associated ERK2 compared with PEA-15 ( L123R ) or an empty vector ( XREF_FIG A ) .	Expression of PEA-15 reduced membrane associated ERK2 compared with PEA-15 (L123R) or an empty vector (XREF_FIG A).	0	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PEA-15	Expression of PEA-15	pea-15	ERK2	ERK2	erk2	2	3	6	7
Thus , PEA-15 sequesters ERK2 in the cytosol , limiting its association with the cell membrane ( XREF_FIG C ) .	Thus, PEA-15 sequesters ERK2 in the cytosol, limiting its association with the cell membrane (XREF_FIG C).	2	7	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PEA-15	PEA-15	PEA-15	ERK2	ERK2	ERK2	2	3	4	5
Previous reports have suggested that PEA-15 is not an inhibitor of ERK2 ; however , it is shown here to potently inhibit the ability of ERK2 to phosphorylate two transcription factors , Elk-1 and Ets-1 , which contain docking sites for the DRS of ERK2 .	Previous reports have suggested that PEA-15 is not an inhibitor of ERK2; however, it is shown here to potently inhibit the ability of ERK2 to phosphorylate two transcription factors, Elk-1 and Ets-1, which contain docking sites for the DRS of ERK2.	5	12	is not an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PEA-15	PEA-15	PEA-15	ERK2	ERK2	ERK2	5	6	11	12
These results suggest that PEA-15 sequesters ERK2 in the cytoplasm at least in part by interfering with its ability to interact with nucleoporins , presenting a potential paradigm for regulation of ERK2 localization .	These results suggest that PEA-15 sequesters ERK2 in the cytoplasm at least in part by interfering with its ability to interact with nucleoporins, presenting a potential paradigm for regulation of ERK2 localization.	4	13	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PEA-15	PEA-15	PEA-15	ERK2	ERK2	ERK2	4	5	6	7
In addition , par-4 augmented WT1 mediated repression , possibly by contributing an additional repression domain .	In addition, par-4 augmented WT1 mediated repression, possibly by contributing an additional repression domain.	3	7	augmented	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	par-4	par-4	par-4	WT1	WT1	WT1	3	4	5	6
Par-4 is known to down-regulate transcription by enhancing the repression activity of the tumor suppressor protein Wilms ' Tumor 1 ( WT1 ) .	Par-4 is known to down-regulate transcription by enhancing the repression activity of the tumor suppressor protein Wilms ' Tumor 1 (WT1).	0	22	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Par-4	Par-4	Par-4	WT1	WT1	WT1	0	1	21	22
PAK7 prevents apoptosis induced by camptothecin and C2-ceramide by phosphorylating BAD at Ser 112 in a protein kinase A independent manner and prevents the localization of BAD to mitochondria .	PAK7 prevents apoptosis induced by camptothecin and C2-ceramide by phosphorylating BAD at Ser 112 in a protein kinase A independent manner and prevents the localization of BAD to mitochondria.	0	27	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK7	PAK7	PAK7	BAD	BAD	BAD	0	1	26	27
PAK7 inhibits the mitochondrial localization of Bcl-2-associated death promoter ( BAD ) by inhibiting phosphorylation of BAD on Ser 112 in a protein independent manner and thus inhibits the apoptotic cascade XREF_BIBR .	PAK7 inhibits the mitochondrial localization of Bcl-2-associated death promoter (BAD) by inhibiting phosphorylation of BAD on Ser 112 in a protein independent manner and thus inhibits the apoptotic cascade XREF_BIBR.	0	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PAK7	PAK7	PAK7	BAD	BAD	BAD	0	1	10	11
Interestingly , here we also found that down-regulation of PHB2 in RD cells enhanced the binding of MyoD to the promoter of rDNA , suggesting that PHB2 not only represses the transcriptional activity of MyoD but also alleviates the repressive effect of MyoD on rRNA transcription .	Interestingly, here we also found that down-regulation of PHB2 in RD cells enhanced the binding of MyoD to the promoter of rDNA, suggesting that PHB2 not only represses the transcriptional activity of MyoD but also alleviates the repressive effect of MyoD on rRNA transcription.	26	37	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHB2	PHB2	PHB2	MyoD	MyoD	MyoD	26	27	34	35
In C2C12 myoblasts , the PHB2 repressed the transcriptional activation of the transcription factors MEF2 and MyoD , a process mediated by recruitment of the repressor HDAC1 .	In C2C12 myoblasts, the PHB2 repressed the transcriptional activation of the transcription factors MEF2 and MyoD, a process mediated by recruitment of the repressor HDAC1.	4	17	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHB2	PHB2	PHB2	MyoD	MyoD	MyoD	5	6	16	17
Thus , the presence of either Pdx1 or Sox9 is sufficient to repress the intestinal marker Cdx2 in the pancreatic domain , whereas loss of both Pdx1 and Sox9 results in ectopic Cdx2 expression .	Thus, the presence of either Pdx1 or Sox9 is sufficient to repress the intestinal marker Cdx2 in the pancreatic domain, whereas loss of both Pdx1 and Sox9 results in ectopic Cdx2 expression.	3	17	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pdx1	Pdx1	Pdx1	Cdx2	Cdx2	Cdx2	6	7	16	17
An obvious defeat was also observed in LPC mediated degradation of IkappaBalpha under the treatment of LXR agonist .	An obvious defeat was also observed in LPC mediated degradation of IkappaBalpha under the treatment of LXR agonist.	5	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	LPC	LPC	LPC	IkappaBalpha	IkappaBalpha	IkappaBalpha	7	8	11	12
In addition , Pdx1 inhibited Pax-6 mediated activation through G3 , to which Pdx1 was unable to bind .	In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind.	3	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pdx1	Pdx1	Pdx1	Pax-6	Pax-6	Pax-6	3	4	5	6
A novel mechanism is revealed showing that nuclear-Smad6 acts as a novel PIAS3 interacting protein and antagonizes PIAS3 mediated STAT3 transcriptional activity inhibition by accelerating PIAS3 ubiquitination and degradation .	A novel mechanism is revealed showing that nuclear-Smad6 acts as a novel PIAS3 interacting protein and antagonizes PIAS3 mediated STAT3 transcriptional activity inhibition by accelerating PIAS3 ubiquitination and degradation.	16	22	mediated	Positive_early_activation	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	17	18	19	20
Through the combination of these bioinformatics prediction methods and a literature review , we found that PIAS3 ( a specific inhibitor of activated STAT3 ) and p27 ( a negative cell-cycle regulator ) are likely targets of miR-199a-5p .	Through the combination of these bioinformatics prediction methods and a literature review, we found that PIAS3 (a specific inhibitor of activated STAT3) and p27 (a negative cell-cycle regulator) are likely targets of miR-199a-5p.	16	35	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	16	17	23	24
Conversely , PIAS3 over-expression inhibited STAT-3 transcriptional activity , expression of STAT-3 regulated genes , and cell proliferation .	Conversely, PIAS3 over-expression inhibited STAT-3 transcriptional activity, expression of STAT-3 regulated genes, and cell proliferation.	2	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3 over-expression	pias3	STAT-3	STAT-3	stat-3	2	3	5	6
The results indicate that PIAS3 is a specific inhibitor of Stat3 .	The results indicate that PIAS3 is a specific inhibitor of Stat3.	4	11	is a specific inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	Stat3	Stat3	Stat3	4	5	10	11
Indeed , E2/ER complexes induce the expression of PIAS3 ( protein inhibitor of activated STAT3 ) , one inhibitor of activated STAT3 ( signal transducer and activator of transcription 3 ) at the transcriptional level [ XREF_BIBR ] .	Indeed, E2/ER complexes induce the expression of PIAS3 (protein inhibitor of activated STAT3), one inhibitor of activated STAT3 (signal transducer and activator of transcription 3) at the transcriptional level [XREF_BIBR].	2	15	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	E2/ER complexes induce the expression of PIAS3	pias3	STAT3	STAT3	stat3	8	9	14	15
However , because p53 is also known to inhibit STAT3 activity 13 , it was of interest to determine its role in PIAS3 induced STAT3 inhibition .	However, because p53 is also known to inhibit STAT3 activity 13, it was of interest to determine its role in PIAS3 induced STAT3 inhibition.	18	25	induced	Positive_early_activation	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	22	23	24	25
PIAS3 mediated inhibition of ROS generation may be caused by PIAS3 mediated inhibition of JAK and STAT3 signalling .	PIAS3 mediated inhibition of ROS generation may be caused by PIAS3 mediated inhibition of JAK and STAT3 signalling.	0	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	16	17
In cancer cells , however , the expression of PIAS3 is posttranscriptionally suppressed , possibly enhancing the oncogenic effects of activated STAT3 .	In cancer cells, however, the expression of PIAS3 is posttranscriptionally suppressed, possibly enhancing the oncogenic effects of activated STAT3.	7	22	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	expression of PIAS3	pias3	STAT3	STAT3	stat3	9	10	21	22
Together , these results indicate that AR not only releases the PIAS3 inhibition of the Stat3 but also promotes ERK activation in G-CSF signaling ( XREF_FIG ) .	Together, these results indicate that AR not only releases the PIAS3 inhibition of the Stat3 but also promotes ERK activation in G-CSF signaling (XREF_FIG).	11	16	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	Stat3	Stat3	Stat3	11	12	15	16
These results suggest that attenuation of PIAS3 causes aberrant activation of STAT3 in endometriosis , leading to inflammatory changes that may impair fertility or cause pain .	These results suggest that attenuation of PIAS3 causes aberrant activation of STAT3 in endometriosis, leading to inflammatory changes that may impair fertility or cause pain.	4	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	6	7	11	12
Mouse PIAS3 ( protein inhibitor of activated STAT3 ) is a specific inhibitor of STAT3 that downregulates its signaling pathway .	Mouse PIAS3 (protein inhibitor of activated STAT3) is a specific inhibitor of STAT3 that downregulates its signaling pathway.	0	15	is a specific inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	1	2	14	15
PIAS3 ( a repressor of STAT3 activity ) is a verified target of miR-18a .	PIAS3 (a repressor of STAT3 activity) is a verified target of miR-18a.	0	11	repressor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	5	6
Indeed , both SOCS3 and PIAS-3 are induced by Stat3 activation and act as negative feedback regulators to suppress Stat3 function .	Indeed, both SOCS3 and PIAS-3 are induced by Stat3 activation and act as negative feedback regulators to suppress Stat3 function.	3	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS-3	PIAS-3	PIAS-3	Stat3	Stat3	Stat3	5	6	19	20
Together , these data suggest that in an EGF driven model , PIAS3 can inhibit STAT3 transcriptional activity irrespective of p53 status .	Together, these data suggest that in an EGF driven model, PIAS3 can inhibit STAT3 transcriptional activity irrespective of p53 status.	12	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	12	13	15	16
It has also been reported that the overexpression of PIAS-3 inhibits STAT3 transcriptional activity and consistently decreased proliferation of NSCLC cell lines [ XREF_BIBR ] .	It has also been reported that the overexpression of PIAS-3 inhibits STAT3 transcriptional activity and consistently decreased proliferation of NSCLC cell lines [XREF_BIBR].	7	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS-3	overexpression of PIAS-3	pias-3	STAT3	STAT3	stat3	9	10	11	12
Based on these findings we hypothesized that miR-18a inhibitor can reduce the level of STAT3 by increasing the level of PIAS3 ( an inhibitor of STAT3 ) which ultimately will help to overcome sorafenib resistance .	Based on these findings we hypothesized that miR-18a inhibitor can reduce the level of STAT3 by increasing the level of PIAS3 (an inhibitor of STAT3) which ultimately will help to overcome sorafenib resistance.	7	26	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	miR-18a inhibitor can reduce the level of STAT3 by increasing the level of PIAS3	pias3	STAT3	STAT3	stat3	20	21	25	26
Based on this , we hypothesized that the intermediary PIAS3 is suppressed by TRIM8 to upregulate STAT3 .	Based on this, we hypothesized that the intermediary PIAS3 is suppressed by TRIM8 to upregulate STAT3.	7	17	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	9	10	16	17
Taken together , our findings suggest that nuclear-Smad6 enhances malignant properties of human GBM cells through blocking PIAS3 inhibition of STAT3 activity .	Taken together, our findings suggest that nuclear-Smad6 enhances malignant properties of human GBM cells through blocking PIAS3 inhibition of STAT3 activity.	17	21	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	17	18	20	21
PIAS3 inhibits STAT3 signaling by interacting with the DNA binding domain of STAT3 and preventing its transcriptional activator function [ XREF_BIBR ] .	PIAS3 inhibits STAT3 signaling by interacting with the DNA binding domain of STAT3 and preventing its transcriptional activator function [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	2	3
We have also identified a lack of PIAS3 protein expression in the majority of human squamous cell carcinomas of the lung 8 and demonstrated that PIAS3 negatively regulates STAT3 transcriptional activity and cell growth in a concentration dependent manner .	We have also identified a lack of PIAS3 protein expression in the majority of human squamous cell carcinomas of the lung 8 and demonstrated that PIAS3 negatively regulates STAT3 transcriptional activity and cell growth in a concentration dependent manner.	25	29	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	25	26	28	29
Reciprocally , HMGI-C expression also coordinately enhances PIAS3 mediated repression of STAT3 dependent transactivation .	Reciprocally, HMGI-C expression also coordinately enhances PIAS3 mediated repression of STAT3 dependent transactivation.	7	13	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	7	8	11	12
Both PIAS3 and the multifunctional protein Hrs selectively inhibit STAT3 , and thus possibly inhibit the action of ciliary derived neurotrophic factor , a factor that has been shown to inhibit rod differentiation in rodents .	Both PIAS3 and the multifunctional protein Hrs selectively inhibit STAT3, and thus possibly inhibit the action of ciliary derived neurotrophic factor, a factor that has been shown to inhibit rod differentiation in rodents.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	1	2	9	10
A reporter assay further showed that suppression of constitutively active Stat3 ( CA-Stat3 ) transactivation by PIAS3 was relieved by AR in a dose dependent manner ( XREF_FIG ) .	A reporter assay further showed that suppression of constitutively active Stat3 (CA-Stat3) transactivation by PIAS3 was relieved by AR in a dose dependent manner (XREF_FIG).	6	17	suppression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	Stat3	Stat3	Stat3	16	17	10	11
The loss of Bcl-xL expression likely results from PIAS3 inhibition of STAT3 activity , as Bcl-xL is an established transcriptional target of STAT3 .	The loss of Bcl-xL expression likely results from PIAS3 inhibition of STAT3 activity, as Bcl-xL is an established transcriptional target of STAT3.	8	12	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	8	9	11	12
It has been proposed that nuclear translocation of PKM2 happens after sumoylation by the SUMO-E3 ligase protein PIAS3 ( inhibitor of activated STAT3 ) [ XREF_BIBR ] .	It has been proposed that nuclear translocation of PKM2 happens after sumoylation by the SUMO-E3 ligase protein PIAS3 (inhibitor of activated STAT3) [XREF_BIBR].	9	25	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	17	18	22	23
PIAS3 , a protein inhibitor of STAT3 , inhibits STAT3 activation and significantly ameliorates the histopathology and clinical severities of aGHVD involving liver , lung , intestine , and skin comparing with control group .	PIAS3, a protein inhibitor of STAT3, inhibits STAT3 activation and significantly ameliorates the histopathology and clinical severities of aGHVD involving liver, lung, intestine, and skin comparing with control group.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	9	10
PIAS3 inhibits STAT3 signaling by interrupting the interaction of p-STAT3 with its target genes [ XREF_BIBR ] ; SHP2 is a non receptor type protein tyrosine phosphatases and its phosphorylated form ( p-SHP2 ) interferes STAT-3 activation by dephosphorylating the active STAT-3 complexes in the cytoplasm and in nucleus [ XREF_BIBR ] .	PIAS3 inhibits STAT3 signaling by interrupting the interaction of p-STAT3 with its target genes [XREF_BIBR]; SHP2 is a non receptor type protein tyrosine phosphatases and its phosphorylated form (p-SHP2) interferes STAT-3 activation by dephosphorylating the active STAT-3 complexes in the cytoplasm and in nucleus [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	2	3
We have shown that PIAS3 , an endogenous inhibitor of STAT3 , can be modulated to decrease STAT3 transcriptional activity and decrease growth of lung cancer cells .	We have shown that PIAS3, an endogenous inhibitor of STAT3, can be modulated to decrease STAT3 transcriptional activity and decrease growth of lung cancer cells.	4	21	modulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	4	5	17	18
As a specific protein inhibitor of activated STAT3 , PIAS3 can interfere with the phosphorylation of STAT3 and inhibit STAT3 mediated gene activation , thereby influencing cell proliferation by regulating proliferation associated genes , such as PCNA and KI67 XREF_BIBR XREF_BIBR .	As a specific protein inhibitor of activated STAT3, PIAS3 can interfere with the phosphorylation of STAT3 and inhibit STAT3 mediated gene activation, thereby influencing cell proliferation by regulating proliferation associated genes, such as PCNA and KI67 XREF_BIBR XREF_BIBR.	9	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	9	10	19	20
Because early studies have demonstrated that PIAS3 could inhibit Stat3 signaling via blocking Stat3 DNA binding , we sought to explore if AR interacts with PIAS3 and affects its inhibition on Stat3 activity .	Because early studies have demonstrated that PIAS3 could inhibit Stat3 signaling via blocking Stat3 DNA binding, we sought to explore if AR interacts with PIAS3 and affects its inhibition on Stat3 activity.	6	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	Stat3	Stat3	Stat3	6	7	9	10
Subsequent yeast two-hybrid screening identified PIAS3 ( protein inhibitor of activated STAT3 ) as an ATF1 binding protein .	Subsequent yeast two-hybrid screening identified PIAS3 (protein inhibitor of activated STAT3) as an ATF1 binding protein.	4	17	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	5	6	11	12
In vitro experiments revealed that PIAS3 significantly inhibited the activation of NF-kappaB and STAT3 and demonstrated that activated NF-kappaB and STAT3 transcriptionally regulated miR-18a level , and up-regulation of miR-18a expression led to defective PIAS3 expression .	In vitro experiments revealed that PIAS3 significantly inhibited the activation of NF-kappaB and STAT3 and demonstrated that activated NF-kappaB and STAT3 transcriptionally regulated miR-18a level, and up-regulation of miR-18a expression led to defective PIAS3 expression.	5	15	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	5	6	13	14
We further demonstrated that miR-199a-5p could directly bind to the 3 ' UTRs of the mRNA of both PIAS3 and p27 and mediate a decrease in the protein levels of PIAS3 and p27 , thereby stimulating STAT3 activation and cell cycle progression in OS cells .	We further demonstrated that miR-199a-5p could directly bind to the 3 ' UTRs of the mRNA of both PIAS3 and p27 and mediate a decrease in the protein levels of PIAS3 and p27, thereby stimulating STAT3 activation and cell cycle progression in OS cells.	4	37	stimulating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS3	miR-199a-5p could directly bind to the 3 ' UTRs of the mRNA of both PIAS3 and p27 and mediate a decrease in the protein levels of PIAS3	pias3	STAT3	STAT3	stat3	30	31	36	37
SHP2 , SOCS3 and PIAS3 Expression Patterns in Medulloblastomas : Relevance to STAT3 Activation and Resveratrol Suppressed STAT3 Signaling .	SHP2, SOCS3 and PIAS3 Expression Patterns in Medulloblastomas : Relevance to STAT3 Activation and Resveratrol Suppressed STAT3 Signaling.	0	18	Suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	4	5	17	18
Other fine mapped IPA networked genes include ZFHX3 ( also known as ATBF1 ) , which encodes a large enhancer binding transcription factor that is known to be polymorphic XREF_BIBR and interacts with a number of proteins , including PIAS3 ( protein inhibitor of activated STAT , NP_006090 ) that inhibits STAT3 ( signal transducer and activator of transcription-3 , NP_644805 ) XREF_BIBR .	Other fine mapped IPA networked genes include ZFHX3 (also known as ATBF1), which encodes a large enhancer binding transcription factor that is known to be polymorphic XREF_BIBR and interacts with a number of proteins, including PIAS3 (protein inhibitor of activated STAT, NP_006090) that inhibits STAT3 (signal transducer and activator of transcription-3, NP_644805) XREF_BIBR.	2	62	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	39	40	51	52
PIAS3 is an endogenous inhibitor of STAT3 through prohibiting its DNA binding , and the loss of PIAS3 in cancers contributes to enhanced STAT3 activity and subsequent tumor growth , as well as impacts patient survival , identifying PIAS3 a promising therapeutic target XREF_BIBR , XREF_BIBR - XREF_BIBR .	PIAS3 is an endogenous inhibitor of STAT3 through prohibiting its DNA binding, and the loss of PIAS3 in cancers contributes to enhanced STAT3 activity and subsequent tumor growth, as well as impacts patient survival, identifying PIAS3 a promising therapeutic target XREF_BIBR, XREF_BIBR - XREF_BIBR.	0	7	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	6	7
PIAS1 and PIAS3 repress transcriptional activity of STAT1 and STAT3 , respectively [ XREF_BIBR , XREF_BIBR ] , whereas PIASx and PIASy repress the transcriptional activity of STAT1 and STAT4 [ XREF_BIBR , XREF_BIBR ] .	PIAS1 and PIAS3 repress transcriptional activity of STAT1 and STAT3, respectively [XREF_BIBR, XREF_BIBR], whereas PIASx and PIASy repress the transcriptional activity of STAT1 and STAT4 [XREF_BIBR, XREF_BIBR].	0	10	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	2	3	9	10
By directly interacting with phosphorylated STAT3 , PIAS3 can block the downstream transcriptional activity of STAT3 , which is hyper-activated in various cancers .	By directly interacting with phosphorylated STAT3, PIAS3 can block the downstream transcriptional activity of STAT3, which is hyper-activated in various cancers.	7	19	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	7	8	15	16
The overexpression of PIAS-3 can inhibit STAT-3 transcriptional activity and induces apoptosis in vitro [ XREF_BIBR ] .	The overexpression of PIAS-3 can inhibit STAT-3 transcriptional activity and induces apoptosis in vitro [XREF_BIBR].	1	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS-3	overexpression of PIAS-3	pias-3	STAT-3	STAT-3	stat-3	3	4	6	7
Furthermore , PIAS3 inhibition of STAT3 activity was also p53 independent .	Furthermore, PIAS3 inhibition of STAT3 activity was also p53 independent.	2	6	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	2	3	5	6
XREF_BIBR Another miRNA , miR-301a , was also shown to participate in EAE pathology by silencing PIAS3 , a protein that inhibits STAT3 by sumoylating the transactivation domain .	XREF_BIBR Another miRNA, miR-301a, was also shown to participate in EAE pathology by silencing PIAS3, a protein that inhibits STAT3 by sumoylating the transactivation domain.	10	23	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	16	17	22	23
Thus , in the present study , miR-18a worked within a positive feedback loop whereby a reduction in PIAS3 expression increased STAT3 and NF-kappaB activity .	Thus, in the present study, miR-18a worked within a positive feedback loop whereby a reduction in PIAS3 expression increased STAT3 and NF-kappaB activity.	18	24	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3 expression	pias3	STAT3	STAT3	stat3	18	19	21	22
In the absence of ER ( e.g ., MDA-MB-231 and SKBR3 cells ) , PIAS3 may inhibit STAT3 signaling directly or indirectly .	In the absence of ER (e.g., MDA-MB-231 and SKBR3 cells), PIAS3 may inhibit STAT3 signaling directly or indirectly.	14	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	14	15	17	18
Additionally , the STAT3 activities in aGVHD target organs were suppressed by PIAS3 overexpression .	Additionally, the STAT3 activities in aGVHD target organs were suppressed by PIAS3 overexpression.	3	14	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PIAS3	PIAS3 overexpression	pias3	STAT3	STAT3	stat3	12	13	3	4
On the other hand , this modification promotes the binding of PIAS3 ( protein inhibitor of activated STAT3 ) that involves the N-terminal fragment of PIAS3 and the leucine zipper of MITF [ XREF_BIBR , XREF_BIBR ] .	On the other hand, this modification promotes the binding of PIAS3 (protein inhibitor of activated STAT3) that involves the N-terminal fragment of PIAS3 and the leucine zipper of MITF [XREF_BIBR, XREF_BIBR].	9	20	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	11	12	17	18
The SUMO E3 protein PIAS3 ( protein inhibitor of activated STAT3 ) is up-regulated in a number of different cancer types [ XREF_BIBR ] , and elevated levels of the SUMO E1 enzyme are associated with lower survival rates in patients with hepatocellular carcinoma [ XREF_BIBR ] .	The SUMO E3 protein PIAS3 (protein inhibitor of activated STAT3) is up-regulated in a number of different cancer types [XREF_BIBR], and elevated levels of the SUMO E1 enzyme are associated with lower survival rates in patients with hepatocellular carcinoma [XREF_BIBR].	0	13	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	4	5	10	11
XREF_BIBR In addition , activated Stat3 is also inhibited by PIAS3 ( protein inhibitor of activated Stat3 ) .	XREF_BIBR In addition, activated Stat3 is also inhibited by PIAS3 (protein inhibitor of activated Stat3).	8	17	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	Stat3	Stat3	Stat3	10	11	16	17
Over-expression of PIAS3 , using a PIAS3 expression construct , decreases STAT3 transcriptional activity .	Over-expression of PIAS3, using a PIAS3 expression construct, decreases STAT3 transcriptional activity.	0	13	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	Over-expression of PIAS3	pias3	STAT3	STAT3	stat3	2	3	11	12
Thus , by promoting STAT3 activation , repression of PIAS3 expression in tumor cells can indirectly contribute to NK cell dysfunction by altering the cytokine profile of the cancer .	Thus, by promoting STAT3 activation, repression of PIAS3 expression in tumor cells can indirectly contribute to NK cell dysfunction by altering the cytokine profile of the cancer.	4	17	contribute	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3 expression	pias3	STAT3	STAT3	stat3	9	10	4	5
Moreover , the knockdown of PIAS-3 using siRNA suppressed the induction of PIAS-3 and reversed the inhibition of STAT3 activation , and resulted in increased cell viability and decreased apoptotic effect .	Moreover, the knockdown of PIAS-3 using siRNA suppressed the induction of PIAS-3 and reversed the inhibition of STAT3 activation, and resulted in increased cell viability and decreased apoptotic effect.	3	19	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS-3	PIAS-3	PIAS-3	STAT3	STAT3	STAT3	5	6	18	19
Taken together , the above data indicate that the presence of p53 has little effect on the degree of PIAS3 inhibition of STAT3 luciferase activity .	Taken together, the above data indicate that the presence of p53 has little effect on the degree of PIAS3 inhibition of STAT3 luciferase activity.	19	24	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	19	20	22	23
Thus , these observations suggest that the MH2 domain of Smad6 is essential for Smad6 induced PIAS3 degradation and promotion of STAT3 activity .	Thus, these observations suggest that the MH2 domain of Smad6 is essential for Smad6 induced PIAS3 degradation and promotion of STAT3 activity.	14	22	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIAS3	Smad6 induced PIAS3	pias3	STAT3	STAT3	stat3	16	17	21	22
9 Taken together , these studies show that PIAS3 can inhibit the function of constitutively active STAT3 present in lung cancer .	9 Taken together, these studies show that PIAS3 can inhibit the function of constitutively active STAT3 present in lung cancer.	8	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	8	9	16	17
We further examined CCL2 upstream genes STAT3 6 and protein inhibitor of activated STAT3 ( PIAS3 ) , 16 as previous studies found that androgen/AR signaling could induce the PIAS3 expression that suppressed the STAT3 activation .	We further examined CCL2 upstream genes STAT3 6 and protein inhibitor of activated STAT3 (PIAS3), 16 as previous studies found that androgen/AR signaling could induce the PIAS3 expression that suppressed the STAT3 activation.	24	35	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	androgen/AR signaling could induce the PIAS3 expression	pias3	STAT3	STAT3	stat3	29	30	34	35
We found that PIAS3 inhibited wild type STAT3 transcriptional activity but failed to inhibit mutant STAT3 ( XREF_FIG ) .	We found that PIAS3 inhibited wild type STAT3 transcriptional activity but failed to inhibit mutant STAT3 (XREF_FIG).	3	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	3	4	7	8
Although STAT3 is not modified with SUMO , PIAS3 inhibited the STAT3 activity in a manner partially depending on its SUMO E3 ligase activity .	Although STAT3 is not modified with SUMO, PIAS3 inhibited the STAT3 activity in a manner partially depending on its SUMO E3 ligase activity.	8	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	8	9	11	12
Taken together , these results suggest that overexpression of PIAS3 by lycopene contributes to suppression of tumor growth by inhibiting the function of constitutively active STAT3 in ovarian cancer cells .	Taken together, these results suggest that overexpression of PIAS3 by lycopene contributes to suppression of tumor growth by inhibiting the function of constitutively active STAT3 in ovarian cancer cells.	7	29	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS3	overexpression of PIAS3	pias3	STAT3	STAT3	stat3	9	10	25	26
PIAS1 and PIAS3 can inhibit the activity of STAT1 and STAT3 , respectively .	PIAS1 and PIAS3 can inhibit the activity of STAT1 and STAT3, respectively.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	2	3	10	11
Additionally , PIAS3 overexpression led to a significant decrease in IL-6-stimulated STAT3 activity , and inhibition of PIAS3 increased STAT3 activity , which indicated an interaction between PIAS3 and STAT3 in vitro .	Additionally, PIAS3 overexpression led to a significant decrease in IL-6-stimulated STAT3 activity, and inhibition of PIAS3 increased STAT3 activity, which indicated an interaction between PIAS3 and STAT3 in vitro.	15	20	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	17	18	19	20
PIAS3 blocked the binding of STAT3 on SLUG promoter .	PIAS3 blocked the binding of STAT3 on SLUG promoter.	0	6	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	5	6
Of the three STAT3 negative regulators , PIAS3 correlated most negatively with STAT3 nuclear translocation and may inhibit STAT3 signaling in both histological CC subtypes .	Of the three STAT3 negative regulators, PIAS3 correlated most negatively with STAT3 nuclear translocation and may inhibit STAT3 signaling in both histological CC subtypes.	7	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	7	8	18	19
Others have shown that PIAS3 directly inhibits the transactivation of STAT3 [ XREF_BIBR ] .	Others have shown that PIAS3 directly inhibits the transactivation of STAT3 [XREF_BIBR].	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	4	5	10	11
PIAS3 ( protein inhibitor of activated STAT3 ) , was originally identified as a specific inhibitor of the STAT3 signaling pathway XREF_BIBR .	PIAS3 (protein inhibitor of activated STAT3), was originally identified as a specific inhibitor of the STAT3 signaling pathway XREF_BIBR.	0	11	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	6	7
PIAS3 can bind to the activated form of the latent STAT3 transcription factor and is able to down-regulate the activity of STAT3 as a transcriptional transactivator .	PIAS3 can bind to the activated form of the latent STAT3 transcription factor and is able to down-regulate the activity of STAT3 as a transcriptional transactivator.	0	22	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	21	22
STAT3 mediated signaling pathways can be inhibited by PIAS3 ( protein inhibitor of activated STAT3 ) , which was recently found to regulate protein stability and function by its SUMO ( small-ubiquitin like modifiers ) ligase activity in promoting sumoylation of important nuclear proteins .	STAT3 mediated signaling pathways can be inhibited by PIAS3 (protein inhibitor of activated STAT3), which was recently found to regulate protein stability and function by its SUMO (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins.	6	22	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	8	9	14	15
Furthermore our data indicate that STAT3 transcriptional activity can be further decreased by increasing PIAS3 expression .	Furthermore our data indicate that STAT3 transcriptional activity can be further decreased by increasing PIAS3 expression.	5	16	decreased	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PIAS3	PIAS3 expression	pias3	STAT3	STAT3	stat3	14	15	5	6
The loss of PIAS3 protein , either by rapid degradation or another mechanism , may allow activated STAT-3 to sustain transcription of genes which control proliferation and the cell cycle .	The loss of PIAS3 protein, either by rapid degradation or another mechanism, may allow activated STAT-3 to sustain transcription of genes which control proliferation and the cell cycle.	3	19	allow activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT-3	STAT-3	STAT-3	3	4	17	18
PIAS3 is the endogenous inhibitor of STAT3 , which has been implicated in the pathogenesis of many cancers .	PIAS3 is the endogenous inhibitor of STAT3, which has been implicated in the pathogenesis of many cancers.	0	11	is the endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	6	7
Additionally , PIAS3 over-expression in COS-7 cells suppressed gene induction by v-src activated STAT-3 .	Additionally, PIAS3 over-expression in COS-7 cells suppressed gene induction by v-src activated STAT-3.	2	14	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3 over-expression	pias3	STAT-3	STAT-3	stat-3	2	3	13	14
These considerations led us to evaluate whether lower expression of RANKL in BMSCs stably expressing miR-21 inhibitors could be ascribed to PIAS3 dependent inhibition of STAT3 signaling .	These considerations led us to evaluate whether lower expression of RANKL in BMSCs stably expressing miR-21 inhibitors could be ascribed to PIAS3 dependent inhibition of STAT3 signaling.	21	26	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	21	22	25	26
PIAS3 was found to suppress NF-kappaB and STAT3 activation in mouse myeloblast cells and human MCF-7 cells XREF_BIBR , XREF_BIBR .	PIAS3 was found to suppress NF-kappaB and STAT3 activation in mouse myeloblast cells and human MCF-7 cells XREF_BIBR, XREF_BIBR.	0	8	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	7	8
We found that ectopic PIAS3 overexpression increased the activation of STAT3 in ER positive MCF7 cells and decreased the activation of STAT3 in MDA-MB-231 cells ( Additional file 2 : Figure S2A ) .	We found that ectopic PIAS3 overexpression increased the activation of STAT3 in ER positive MCF7 cells and decreased the activation of STAT3 in MDA-MB-231 cells (Additional file 2 : Figure S2A).	4	22	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3 overexpression	pias3	STAT3	STAT3	stat3	4	5	21	22
Thus we proposed that miR-18a inhibitor can reduce the level of STAT3 by increasing the level of PIAS3 ( an inhibitor of STAT3 ) which ultimately will help to overcome sorafenib resistance .	Thus we proposed that miR-18a inhibitor can reduce the level of STAT3 by increasing the level of PIAS3 (an inhibitor of STAT3) which ultimately will help to overcome sorafenib resistance.	4	23	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	miR-18a inhibitor can reduce the level of STAT3 by increasing the level of PIAS3	pias3	STAT3	STAT3	stat3	17	18	22	23
We thus hypothesized that : 1 ) PIAS3 is expressed in NSCLC ; 2 ) PIAS3 will interact with STAT3 upon ligand induced STAT3 activation ; 3 ) over-expression of PIAS3 will inhibit STAT3 transcriptional activity and NSCLC tumor growth ; 4 ) EGFR blockade in conjunction with PIAS3 over-expression will augment the growth inhibitory effects of EGFR inhibitors .	We thus hypothesized that : 1) PIAS3 is expressed in NSCLC; 2) PIAS3 will interact with STAT3 upon ligand induced STAT3 activation; 3) over-expression of PIAS3 will inhibit STAT3 transcriptional activity and NSCLC tumor growth; 4) EGFR blockade in conjunction with PIAS3 over-expression will augment the growth inhibitory effects of EGFR inhibitors.	28	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	over-expression of PIAS3	pias3	STAT3	STAT3	stat3	30	31	33	34
As indicated by early studies , androgen/AR signaling could induce the expression of protein inhibitor of activated STAT3 ( PIAS3 ) , which could suppress the STAT3 activation in prostate cancer .	As indicated by early studies, androgen/AR signaling could induce the expression of protein inhibitor of activated STAT3 (PIAS3), which could suppress the STAT3 activation in prostate cancer.	17	27	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	19	20	26	27
Transducible peptide of PIAS3 efficiently inhibits STAT3 signaling and subsequently GBM cell migration , proliferation , and survival XREF_BIBR , XREF_BIBR .	Transducible peptide of PIAS3 efficiently inhibits STAT3 signaling and subsequently GBM cell migration, proliferation, and survival XREF_BIBR, XREF_BIBR.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	3	4	6	7
Accordingly , silencing of PIAS3 restored pSTAT3 in anti-miR-21 transduced-HS-5 cells .	Accordingly, silencing of PIAS3 restored pSTAT3 in anti-miR-21 transduced-HS-5 cells.	2	7	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	pSTAT3	pSTAT3	pSTAT3	4	5	6	7
Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3 mediated STAT3 inhibition .	Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3 mediated STAT3 inhibition.	7	10	mediated	Positive_early_activation	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	7	8	9	10
Although PIAS3 ( protein inhibitor of activated STAT3 ) , an E3-SUMO ligase implicated in photoreceptor differentiation , can be immunoprecipitated with NRL , there appears to be redundancy in E3 ligases , and PIAS3 does not seem to be essential for NRL sumoylation .	Although PIAS3 (protein inhibitor of activated STAT3), an E3-SUMO ligase implicated in photoreceptor differentiation, can be immunoprecipitated with NRL, there appears to be redundancy in E3 ligases, and PIAS3 does not seem to be essential for NRL sumoylation.	1	20	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	1	2	7	8
miR-301 targets PIAS3 , an E3 SUMO ligase that inhibits STAT3 transcription factor , critical for IL-6 and IL-23-induced Th17 development .	miR-301 targets PIAS3, an E3 SUMO ligase that inhibits STAT3 transcription factor, critical for IL-6 and IL-23-induced Th17 development.	0	12	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	2	3	10	11
These results indicated that over-expression of PIAS3 can reduce STAT-3 transcriptional activity and inhibit the expression of the STAT-3 target gene , SOCS-3 .	These results indicated that over-expression of PIAS3 can reduce STAT-3 transcriptional activity and inhibit the expression of the STAT-3 target gene, SOCS-3.	4	11	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	over-expression of PIAS3	pias3	STAT-3	STAT-3	stat-3	6	7	9	10
On this evidence , we speculated that antagonizing miR-21 in our experimental system may result in a reduced STAT3 signaling mediated by PIAS3 upregulation .	On this evidence, we speculated that antagonizing miR-21 in our experimental system may result in a reduced STAT3 signaling mediated by PIAS3 upregulation.	18	23	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	22	23	18	19
The founding member , PIAS1 , inhibits STAT1 activation to block the expression of some , but not all IFN responsive genes XREF_BIBR .	The founding member, PIAS1, inhibits STAT1 activation to block the expression of some, but not all IFN responsive genes XREF_BIBR.	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	4	5	7	8
Despite the conservation of the DDR pathway in higher eukaryotes , important DSB repair associated proteins such as BARD1 ( BRCA1 associated RING domain 1 ) and PIAS1 ( protein inhibitor of activated STAT1 ) emerged only before the split of plants .	Despite the conservation of the DDR pathway in higher eukaryotes, important DSB repair associated proteins such as BARD1 (BRCA1 associated RING domain 1) and PIAS1 (protein inhibitor of activated STAT1) emerged only before the split of plants.	13	35	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	27	28	33	34
PIAS1 has also been shown to bind directly to STAT1 and repress STAT1 transcriptional activity .	PIAS1 has also been shown to bind directly to STAT1 and repress STAT1 transcriptional activity.	0	14	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	0	1	12	13
On the other hand , because PIAS1 inhibits STAT1 activity , the present results are congruent with the reports showing that STAT1 regulates cell death [ XREF_BIBR , XREF_BIBR ] and STAT1 mediates the neurotoxicity of amyloid-beta [ XREF_BIBR ] , although the apoptotic role of STAT1 may depend on the cell type and the specific STAT1 dimers formed [ XREF_BIBR , XREF_BIBR ] .	On the other hand, because PIAS1 inhibits STAT1 activity, the present results are congruent with the reports showing that STAT1 regulates cell death [XREF_BIBR, XREF_BIBR] and STAT1 mediates the neurotoxicity of amyloid-beta [XREF_BIBR], although the apoptotic role of STAT1 may depend on the cell type and the specific STAT1 dimers formed [XREF_BIBR, XREF_BIBR].	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	6	7	8	9
In this issue , Shuai and colleagues identify the SUMO E3 ligase PIAS1 ( protein inhibitor of activated STAT1 ) as a key regulator of DNA methylation of HSC required for their maintenance and lineage commitment ( Liu et al , 2014 ) .	In this issue, Shuai and colleagues identify the SUMO E3 ligase PIAS1 (protein inhibitor of activated STAT1) as a key regulator of DNA methylation of HSC required for their maintenance and lineage commitment (Liu et al, 2014).	7	23	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	12	13	18	19
Because PIAS1 inhibits STAT1 activity , these results imply that STAT1 may negatively regulate learning and memory function .	Because PIAS1 inhibits STAT1 activity, these results imply that STAT1 may negatively regulate learning and memory function.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	1	2	3	4
Alternatively , IFN-gamma-induced STAT1 signaling may be negatively regulated by PIAS1 and STAT3 , as observed in IL-15-induced DCs .	Alternatively, IFN-gamma-induced STAT1 signaling may be negatively regulated by PIAS1 and STAT3, as observed in IL-15-induced DCs.	3	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	10	11	3	4
For example , both PIAS1 and PIAS4 inhibit STAT1 and PLAG1 XREF_BIBR , XREF_BIBR , XREF_BIBR ; both PIAS1 and PIAS2 regulate SMAD4 , p53 , p73 , JUN , MDM2 , AR and C/EBPepsilon 1 ; and PIAS2 , PIAS3 and PIAS4 suppress C/EBPdelta 14 .	For example, both PIAS1 and PIAS4 inhibit STAT1 and PLAG1 XREF_BIBR, XREF_BIBR, XREF_BIBR; both PIAS1 and PIAS2 regulate SMAD4, p53, p73, JUN, MDM2, AR and C/EBPepsilon 1; and PIAS2, PIAS3 and PIAS4 suppress C/EBPdelta 14.	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	4	5	8	9
Due to the overlap in CMC and other clinical features between patients with APECED and STAT1 GOF mutations , and because AIRE interacts functionally with a protein inhibitor of activated STAT1 ( PIAS1 ) , which inhibits STAT1 activation , we aimed to study STAT1 protein level and phosphorylation upon IFN-gamma stimulation in patients with AIRE mutations and determine whether human AIRE deficiency phenocopies the cell-intrinsic enhanced STAT1 levels seen in patients with STAT1 GOF mutations .	Due to the overlap in CMC and other clinical features between patients with APECED and STAT1 GOF mutations, and because AIRE interacts functionally with a protein inhibitor of activated STAT1 (PIAS1), which inhibits STAT1 activation, we aimed to study STAT1 protein level and phosphorylation upon IFN-gamma stimulation in patients with AIRE mutations and determine whether human AIRE deficiency phenocopies the cell-intrinsic enhanced STAT1 levels seen in patients with STAT1 GOF mutations.	30	38	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	32	33	37	38
PRMT1 catalyzes methylation of STAT1 XREF_BIBR as well as of PIAS1 ( protein inhibitor of activated STAT1 ) XREF_BIBR .	PRMT1 catalyzes methylation of STAT1 XREF_BIBR as well as of PIAS1 (protein inhibitor of activated STAT1) XREF_BIBR.	0	17	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PRMT1 catalyzes methylation of STAT1 XREF_BIBR as well as of PIAS1	pias1	STAT1	STAT1	stat1	10	11	16	17
PIAS1 ( protein inhibitor of activated STAT1 ) is another gene whose protein product is directly involved in regulation of transcriptional activity of Smad2 function .	PIAS1 (protein inhibitor of activated STAT1) is another gene whose protein product is directly involved in regulation of transcriptional activity of Smad2 function.	0	10	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	0	1	6	7
These findings suggest that PIAS1 could augment anti-inflammatory activity by inhibiting STAT1 , thus attenuating the severity of SAP associated with ALI .	These findings suggest that PIAS1 could augment anti-inflammatory activity by inhibiting STAT1, thus attenuating the severity of SAP associated with ALI.	4	12	augment	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	4	5	11	12
Our data thus suggest that human colon carcinoma cells silence IFN-gamma-activated IRF8 expression through MBD1 dependent and PIAS1 mediated inhibition of pSTAT1 function at the methylated IRF8 promoter .	Our data thus suggest that human colon carcinoma cells silence IFN-gamma-activated IRF8 expression through MBD1 dependent and PIAS1 mediated inhibition of pSTAT1 function at the methylated IRF8 promoter.	17	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	pSTAT1	pSTAT1	pSTAT1	17	18	21	22
In response to inflammatory stimuli , PIAS1 is rapidly phosphorylated at Ser 90 , which is required for PIAS1 mediated inhibition of STAT1 or NF-kappaB .	In response to inflammatory stimuli, PIAS1 is rapidly phosphorylated at Ser 90, which is required for PIAS1 mediated inhibition of STAT1 or NF-kappaB.	18	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	18	19	22	23
Because PIAS1 is a potent inhibitor of pSTAT1 , contact between PIAS1 and pSTAT1 would effectively inhibit pSTAT1 function even though pSTAT1 is associated with the GAS element in the methylated IRF8 promoter .	Because PIAS1 is a potent inhibitor of pSTAT1, contact between PIAS1 and pSTAT1 would effectively inhibit pSTAT1 function even though pSTAT1 is associated with the GAS element in the methylated IRF8 promoter.	1	8	is a potent inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	pSTAT1	pSTAT1	pSTAT1	1	2	7	8
PIAS1 ( protein inhibitor of activated STAT1 ( signal transducer and activator of transcription-1 ) ) is known to be an important cell cycle regulator and PIAS1 mediated SUMOylation is essential for DNA repair .	PIAS1 (protein inhibitor of activated STAT1 (signal transducer and activator of transcription-1)) is known to be an important cell cycle regulator and PIAS1 mediated SUMOylation is essential for DNA repair.	0	23	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	0	1	6	7
Recent studies indicate that proinflammatory stimuli , such as tumor necrosis factor alpha and lipopolysaccharide , can activate PIAS1 [ protein inhibitor of activated STAT1 ( signal transducer and activator of transcription 1 ) ] SUMO E3 ligase through a SUMO dependent , inhibitor of kappaB kinase alpha ( IKKalpha )-mediated phosphorylation event .	Recent studies indicate that proinflammatory stimuli, such as tumor necrosis factor alpha and lipopolysaccharide, can activate PIAS1 [protein inhibitor of activated STAT1 (signal transducer and activator of transcription 1)] SUMO E3 ligase through a SUMO dependent, inhibitor of kappaB kinase alpha (IKKalpha)-mediated phosphorylation event.	18	37	inhibitor	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	18	19	24	25
We report here that PIAS1 ( protein inhibitor of activated STAT1 ) is an important negative regulator of NF-kappaB .	We report here that PIAS1 (protein inhibitor of activated STAT1) is an important negative regulator of NF-kappaB.	4	16	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	4	5	10	11
Tissue arrays of liver biopsies were used to study the expression of STAT1 , STAT2 , STAT5 and PIAS1 ( protein inhibitor of activated STAT1 ) .	Tissue arrays of liver biopsies were used to study the expression of STAT1, STAT2, STAT5 and PIAS1 (protein inhibitor of activated STAT1).	10	25	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	expression of STAT1, STAT2, STAT5 and PIAS1	pias1	STAT1	STAT1	stat1	18	19	24	25
We have identified PIAS1 ( protein inhibitor of activated STAT-1 ) , -3 , -xalpha , and -xbeta as SOX9 associated polypeptides using the Gal4 based yeast two-hybrid system and a cDNA library derived from a chondrocytic cell line .	We have identified PIAS1 (protein inhibitor of activated STAT-1), -3, -xalpha, and -xbeta as SOX9 associated polypeptides using the Gal4 based yeast two-hybrid system and a cDNA library derived from a chondrocytic cell line.	2	17	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT-1	STAT-1	STAT-1	3	4	9	10
These reactions are performed mainly by SUMO E3 , PIAS1 ( protein inhibitor of activated STAT1 ) and PIAS4 ( protein inhibitor of activated STAT4 ) proteins .	These reactions are performed mainly by SUMO E3, PIAS1 (protein inhibitor of activated STAT1) and PIAS4 (protein inhibitor of activated STAT4) proteins.	3	26	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	9	10	15	16
In addition , six other SNPs , residing in five different genes CCNG1 ( Cyclin G1 ) , PIAS1 ( Protein inhibitor of activated Stat1 ) , PPP2R2B ( PP2A , regulatory subunit B , beta isoform ) , PRKAG2 ( AMP activated protein kinase gamma2 subunit ) and YWHAQ ( 14-3-3epsilon ) , whose products have been shown to regulate TP53 through protein protein interactions and post-translational modifications , were indicated for genotype-drug response association .	In addition, six other SNPs, residing in five different genes CCNG1 (Cyclin G1), PIAS1 (Protein inhibitor of activated Stat1), PPP2R2B (PP2A, regulatory subunit B, beta isoform), PRKAG2 (AMP activated protein kinase gamma2 subunit) and YWHAQ (14-3-3epsilon), whose products have been shown to regulate TP53 through protein protein interactions and post-translational modifications, were indicated for genotype-drug response association.	11	25	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	Stat1	Stat1	Stat1	18	19	24	25
It has also been reported that PIAS1 negatively regulates NF-kappaB and STAT1 transcriptional activation by directly interacting with NF-kappaB p65 and STAT1 , respectively 4 .	It has also been reported that PIAS1 negatively regulates NF-kappaB and STAT1 transcriptional activation by directly interacting with NF-kappaB p65 and STAT1, respectively 4.	6	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	6	7	11	12
Based on our data we hypothesize that elevated PIAS1 expression in docetaxel resistant cells impairs transcriptional activity of STAT1 via inhibition of its DNA binding ability .	Based on our data we hypothesize that elevated PIAS1 expression in docetaxel resistant cells impairs transcriptional activity of STAT1 via inhibition of its DNA binding ability.	8	20	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1 expression	pias1	STAT1	STAT1	stat1	8	9	18	19
These genes are also regulated by the STAT1 inhibitor PIAS1 ( protein inhibitor of activated STAT1 ) .	These genes are also regulated by the STAT1 inhibitor PIAS1 (protein inhibitor of activated STAT1).	4	16	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	9	10	15	16
Finally , we identified PIAS1 ( protein inhibitor of activated STAT1 ) , as an interactive partner to CP2 proteins and a potent co-activator for CP2c and CP2b mediated alpha-globin expression in erythroid cells .	Finally, we identified PIAS1 (protein inhibitor of activated STAT1), as an interactive partner to CP2 proteins and a potent co-activator for CP2c and CP2b mediated alpha-globin expression in erythroid cells.	3	11	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	4	5	10	11
PIAS1 ( protein inhibitor of activated STAT1 ) and other SUMO ligase family members were shown to directly bind and SUMOylate SOX9 in vitro .	PIAS1 (protein inhibitor of activated STAT1) and other SUMO ligase family members were shown to directly bind and SUMOylate SOX9 in vitro.	0	20	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	0	1	6	7
Further , in a recent study , Liu and co-workers demonstrated that PIAS1 ( protein inhibitor of activated STAT1 ) , which is an E3 ligase , limits inflammatory responses through selective inhibition of NF-kappaB and STAT1 binding to relevant gene promoters [ XREF_BIBR ] .	Further, in a recent study, Liu and co-workers demonstrated that PIAS1 (protein inhibitor of activated STAT1), which is an E3 ligase, limits inflammatory responses through selective inhibition of NF-kappaB and STAT1 binding to relevant gene promoters [XREF_BIBR].	10	25	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	12	13	18	19
PIAS1 inactivates STAT1 by promoting SUMOylation Type III IFN signaling .	PIAS1 inactivates STAT1 by promoting SUMOylation Type III IFN signaling.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	0	1	2	3
Furthermore , PIM1 represses the pro apoptotic molecule BAD through its phosphorylation at Ser112 gatekeeper site .	Furthermore, PIM1 represses the pro apoptotic molecule BAD through its phosphorylation at Ser112 gatekeeper site.	2	9	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIM1	PIM1	PIM1	BAD	BAD	BAD	2	3	8	9
These results indicate that hypoxia increases Pim-1 which phosphorylates and inactivates Bad to inhibit apoptosis .	These results indicate that hypoxia increases Pim-1 which phosphorylates and inactivates Bad to inhibit apoptosis.	5	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pim-1	Pim-1	Pim-1	Bad	Bad	Bad	6	7	11	12
We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment , but rather inactivated the pro apoptotic protein BAD , thereby permitting survival signaling through BCL-XL .	We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro apoptotic protein BAD, thereby permitting survival signaling through BCL-XL.	4	26	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIM1	PIM1	PIM1	BAD	BAD	BAD	6	7	25	26
Co-expression of Pim-1 , 2 or 3 resulted in phosphorylation of GST-Bad and reduced the interaction of GST-Bad with Bcl-X L.	Co-expression of Pim-1, 2 or 3 resulted in phosphorylation of GST-Bad and reduced the interaction of GST-Bad with Bcl-X L.	0	18	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pim-1	Co-expression of Pim-1	pim-1	GST-Bad	GST-Bad	gst-bad	2	3	17	18
Pim1 inactivation of BAD may depend on Tyr113 , which could be required for example for optimal binding of phosphorylated BAD to 14-3-3 proteins .	Pim1 inactivation of BAD may depend on Tyr113, which could be required for example for optimal binding of phosphorylated BAD to 14-3-3 proteins.	0	4	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Pim1	Pim1	Pim1	BAD	BAD	BAD	0	1	3	4
In a lymphoma cell line , it is demonstrated that 60 % reduction in expression of PHLPPL increases Akt-Ser473 several fold XREF_BIBR .	In a lymphoma cell line, it is demonstrated that 60% reduction in expression of PHLPPL increases Akt-Ser473 several fold XREF_BIBR.	14	21	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPPL	expression of PHLPPL	phlppl	Akt-Ser473	Akt-Ser473	akt-ser473	16	17	18	19
Collectively ( see XREF_SUPPLEMENTARY ) these data are consistent with a model where Pten and Trp53 deficient prostate metastasis progresses through an Akt independent pathway , which requires the activation of Myc by Il6 , and Phlpp2 mediated suppression of Akt to drive proliferation and castration-resistance .	Collectively (see XREF_SUPPLEMENTARY) these data are consistent with a model where Pten and Trp53 deficient prostate metastasis progresses through an Akt independent pathway, which requires the activation of Myc by Il6, and Phlpp2 mediated suppression of Akt to drive proliferation and castration-resistance.	36	41	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Phlpp2	Phlpp2	Phlpp2	Akt	Akt	Akt	36	37	40	41
Here we describe a second family member , PHLPP2 , which also inactivates Akt , inhibits cell-cycle progression , and promotes apoptosis .	Here we describe a second family member, PHLPP2, which also inactivates Akt, inhibits cell-cycle progression, and promotes apoptosis.	6	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP2	PHLPP2	PHLPP2	Akt	Akt	Akt	8	9	13	14
One critical distinction between Phlpp1 and Phlpp2 is their differential response to PI 3-Kinase pathway activation in genetically controlled experiments : while Phlpp1 levels remain constant , Phlpp2 is surging to antagonize Akt .	One critical distinction between Phlpp1 and Phlpp2 is their differential response to PI 3-Kinase pathway activation in genetically controlled experiments : while Phlpp1 levels remain constant, Phlpp2 is surging to antagonize Akt.	27	33	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Phlpp2	Phlpp2	Phlpp2	Akt	Akt	Akt	27	28	32	33
PHLPP2 , as one member of PHLPP , attenuate the amplitude of Akt signaling by dephosphorylate and inactivate Akt1 and Akt3 [ XREF_BIBR ] .	PHLPP2, as one member of PHLPP, attenuate the amplitude of Akt signaling by dephosphorylate and inactivate Akt1 and Akt3 [XREF_BIBR].	0	17	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP2	PHLPP2	PHLPP2	Akt	Akt	Akt	0	1	12	13
Conversely , a modest free Raptor induced increase in PHLPP2 levels can reduce Akt regulated DNL via increased Insig2a expression , but remarkably , does not impair glucose homoeostasis .	Conversely, a modest free Raptor induced increase in PHLPP2 levels can reduce Akt regulated DNL via increased Insig2a expression, but remarkably, does not impair glucose homoeostasis.	9	14	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP2	PHLPP2 levels	phlpp2	Akt	Akt	akt	9	10	13	14
The phosphatase Phlpp2 inactivates the PI3K downstream effector Akt , and is a miR-17 ~ 92 target in human mantle cell lymphoma cell lines 33 .	The phosphatase Phlpp2 inactivates the PI3K downstream effector Akt, and is a miR-17 ~ 92 target in human mantle cell lymphoma cell lines 33.	0	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Phlpp2	Phlpp2	Phlpp2	Akt	Akt	Akt	2	3	8	9
The Wee1B and Myt1 kinase inhibits Cdc2 by phosphorylation of Thr14 and Tyr15 on Cdc2 and arrests oocytes at prophase I XREF_BIBR , XREF_BIBR .	The Wee1B and Myt1 kinase inhibits Cdc2 by phosphorylation of Thr14 and Tyr15 on Cdc2 and arrests oocytes at prophase I XREF_BIBR, XREF_BIBR.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myt1 kinase	Myt1 kinase	Myt1 kinase	Cdc2	Cdc2	Cdc2	3	5	6	7
Bora is degraded by proteasomes in a Plk1 dependent manner .	Bora is degraded by proteasomes in a Plk1 dependent manner.	0	9	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Bora	Bora	Bora	7	8	0	1
Plk1- and beta-TrCP-dependent degradation of Bora controls mitotic progression .	Plk1- and beta-TrCP-dependent degradation of Bora controls mitotic progression.	0	6	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Plk1-	Plk1-	Plk1-	Bora	Bora	Bora	0	1	5	6
Subsequently , Plk1 triggers the degradation of both Bora XREF_BIBR , XREF_BIBR and Aurora A XREF_BIBR .	Subsequently, Plk1 triggers the degradation of both Bora XREF_BIBR, XREF_BIBR and Aurora A XREF_BIBR.	2	11	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Bora	Bora	Bora	2	3	8	9
This process requires PLK1 mediated degradation of BORA during early mitosis [ XREF_BIBR , XREF_BIBR ] .	This process requires PLK1 mediated degradation of BORA during early mitosis [XREF_BIBR, XREF_BIBR].	2	8	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	BORA	BORA	BORA	3	4	7	8
To further determine whether Ser83 of ASK1 contributes to PIM1 inhibition of ASK1 , ASK1 ( WT or S83A ) with either empty vector or WT PIM1 were co-transfected into cells and cell viability was determined ( XREF_FIG ) .	To further determine whether Ser83 of ASK1 contributes to PIM1 inhibition of ASK1, ASK1 (WT or S83A) with either empty vector or WT PIM1 were co-transfected into cells and cell viability was determined (XREF_FIG).	9	13	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIM1	PIM1	PIM1	ASK1	ASK1	ASK1	9	10	12	13
We found that PIM1 did not inhibit deltaN-ASK1-dependent JNK and p38 and caspase-3 activation , suggesting that PIM1 inhibits ASK1 dependent apoptosis only through Ser83 phosphorylation of WT ASK1 .	We found that PIM1 did not inhibit deltaN-ASK1-dependent JNK and p38 and caspase-3 activation, suggesting that PIM1 inhibits ASK1 dependent apoptosis only through Ser83 phosphorylation of WT ASK1.	17	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIM1	PIM1	PIM1	ASK1	ASK1	ASK1	17	18	19	20
It is possible that PIM1 inhibits the endogenous ASK1 activity and thus leads to this result .	It is possible that PIM1 inhibits the endogenous ASK1 activity and thus leads to this result.	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIM1	PIM1	PIM1	ASK1	ASK1	ASK1	4	5	8	9
The kinase activity of S83A ASK1 was not affected by WT PIM1 , whereas WT ASK1 kinase activity was greatly inhibited by WT PIM1 .	The kinase activity of S83A ASK1 was not affected by WT PIM1, whereas WT ASK1 kinase activity was greatly inhibited by WT PIM1.	15	24	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PIM1	PIM1	PIM1	ASK1	ASK1	ASK1	23	24	15	16
To further determine whether Ser83 is required in a PIM1 dependent inhibition of ASK1 activity , we co-transfected HA-ASK1 ( WT , S83A or KM ( kinase mutant ASK1 ) ) with or without WT PIM1 and then pulled down the HA tagged ASK1 to perform an in vitro kinase assay using MBP as the substrate for ASK1 ( XREF_FIG ) .	To further determine whether Ser83 is required in a PIM1 dependent inhibition of ASK1 activity, we co-transfected HA-ASK1 (WT, S83A or KM (kinase mutant ASK1)) with or without WT PIM1 and then pulled down the HA tagged ASK1 to perform an in vitro kinase assay using MBP as the substrate for ASK1 (XREF_FIG).	9	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PIM1	PIM1	PIM1	ASK1	ASK1	ASK1	9	10	13	14
These results demonstrate that PIM1 decreases ASK1 kinase activity through phosphorylation of ASK1 Ser83 .	These results demonstrate that PIM1 decreases ASK1 kinase activity through phosphorylation of ASK1 Ser83.	4	8	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIM1	PIM1	PIM1	ASK1	ASK1	ASK1	4	5	6	7
To further confirm that PIM1 negatively regulates ASK1 through phosphorylation of Ser83 , we co-transfected deltaN-ASK1 ( an N terminal deleted ASK1 which is constitutively active ) with or without PIM1 ( XREF_FIG ) .	To further confirm that PIM1 negatively regulates ASK1 through phosphorylation of Ser83, we co-transfected deltaN-ASK1 (an N terminal deleted ASK1 which is constitutively active) with or without PIM1 (XREF_FIG).	4	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIM1	PIM1	PIM1	ASK1	ASK1	ASK1	4	5	7	8
Plk1 overexpression can trigger Evi5 and Emi1 degradation and activate the APC/C [ XREF_BIBR , XREF_BIBR ] .	Plk1 overexpression can trigger Evi5 and Emi1 degradation and activate the APC/C [XREF_BIBR, XREF_BIBR].	0	7	trigger	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1 overexpression	plk1	Emi1	Emi1	emi1	0	1	6	7
However , FBXO5 was negatively regulated by PLK1 , which was associated with important clinicopathological characteristics , and FBXO5 siRNA promoted bladder cancer cell proliferation , invasion and migration .	However, FBXO5 was negatively regulated by PLK1, which was associated with important clinicopathological characteristics, and FBXO5 siRNA promoted bladder cancer cell proliferation, invasion and migration.	2	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	FBXO5	FBXO5	FBXO5	7	8	2	3
Emi1 is degraded at prophase by a Plk1 dependent pathway .	Emi1 is degraded at prophase by a Plk1 dependent pathway.	0	9	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Emi1	Emi1	Emi1	7	8	0	1
The proposed mechanism is that the loss of PLK1 activity allows Emi1 accumulation , APC inactivation , and geminin accumulation , which lead to chromatin disruption and subsequent DNA damage [ XREF_BIBR ] .	The proposed mechanism is that the loss of PLK1 activity allows Emi1 accumulation, APC inactivation, and geminin accumulation, which lead to chromatin disruption and subsequent DNA damage [XREF_BIBR].	8	19	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	Emi1	Emi1	Emi1	8	9	11	12
To corroborate this notion , we tested whether Plk1 dependent degradation of Emi1 is indeed needed for the unique DNA-damage response we find in antephase cells .	To corroborate this notion, we tested whether Plk1 dependent degradation of Emi1 is indeed needed for the unique DNA-damage response we find in antephase cells.	8	13	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Emi1	Emi1	Emi1	8	9	12	13
Data also suggests that Pim-3 inhibits apoptosis by phosphorylating and inactivating the pro apoptotic BH3-only protein Bad to promote pancreatic and colorectal tumorigenesis [ XREF_BIBR , XREF_BIBR ] .	Data also suggests that Pim-3 inhibits apoptosis by phosphorylating and inactivating the pro apoptotic BH3-only protein Bad to promote pancreatic and colorectal tumorigenesis [XREF_BIBR, XREF_BIBR].	4	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pim-3	Pim-3	Pim-3	Bad	Bad	Bad	4	5	16	17
Thus , we provide the first evidence that Pim-3 can inactivate Bad and maintain the expression of Bcl-X ( L ) and thus prevent apoptosis of human pancreatic cancer cells .	Thus, we provide the first evidence that Pim-3 can inactivate Bad and maintain the expression of Bcl-X (L) and thus prevent apoptosis of human pancreatic cancer cells.	8	13	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pim-3	Pim-3	Pim-3	Bad	Bad	Bad	8	9	11	12
Depletion of Plk1 by RNA interference suppresses BRCA2 modification .	Depletion of Plk1 by RNA interference suppresses BRCA2 modification.	0	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	BRCA2	BRCA2	BRCA2	2	3	7	8
In the case of BRCA2 , PLK1 dependent phosphorylation at S 193 , 205 , 206 and T 203 , 207 causes dissociation from the histone acetyltransferase protein p300 and CBP associated factor ( P/CAF ) , and CDK dependent S 3291 phosphorylation at the onset of mitosis inhibits BRCA2 mediated stabilization of RAD51 nucleofilaments that are normally generated at sites of recombination .	In the case of BRCA2, PLK1 dependent phosphorylation at S 193, 205, 206 and T 203, 207 causes dissociation from the histone acetyltransferase protein p300 and CBP associated factor (P/CAF), and CDK dependent S 3291 phosphorylation at the onset of mitosis inhibits BRCA2 mediated stabilization of RAD51 nucleofilaments that are normally generated at sites of recombination.	6	51	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1 dependent phosphorylation	plk1	BRCA2	BRCA2	brca2	6	7	49	50
Taken together , these results suggest that Aurora-A modulates CHK1 activity through PLK1 triggered Claspin degradation .	Taken together, these results suggest that Aurora-A modulates CHK1 activity through PLK1 triggered Claspin degradation.	10	15	triggered	Positive_activation_token_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	Claspin	Claspin	Claspin	12	13	14	15
In addition , these results suggest that the APC/C Cdh1 -mediated degradation of Plk1 promotes Claspin stabilization and the consequent activation of Chk1 .	In addition, these results suggest that the APC/C Cdh1 -mediated degradation of Plk1 promotes Claspin stabilization and the consequent activation of Chk1.	11	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Claspin	Claspin	Claspin	13	14	15	16
Since Plk1 promotes Claspin degradation , the stabilization of Plk1 , which occurred in cells where Cdh1 expression was silenced , may explain why Claspin levels decrease under these conditions .	Since Plk1 promotes Claspin degradation, the stabilization of Plk1, which occurred in cells where Cdh1 expression was silenced, may explain why Claspin levels decrease under these conditions.	1	4	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Claspin	Claspin	Claspin	1	2	3	4
Another possibility is that adenovirus mediated disruption of PP2A phosphatase activity by the viral E4orf4 protein [ XREF_BIBR , XREF_BIBR ] could stabilize pPlk1 thereby inducing Claspin degradation , as PP2A was shown to de-phosphorylate Plk1 in response to DNA damage [ XREF_BIBR ] .	Another possibility is that adenovirus mediated disruption of PP2A phosphatase activity by the viral E4orf4 protein [XREF_BIBR, XREF_BIBR] could stabilize pPlk1 thereby inducing Claspin degradation, as PP2A was shown to de-phosphorylate Plk1 in response to DNA damage [XREF_BIBR].	22	27	inducing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pPlk1	pPlk1	pPlk1	Claspin	Claspin	Claspin	23	24	26	27
Since Plk1 initiates the SCF betaTrcp -dependent degradation of Claspin following recovery from DNA damage stresses , these data argue for a role of Cdh1 in limiting Plk1 levels to preserve Claspin stability and Chk1 activation in response to DNA damage in G2 .	Since Plk1 initiates the SCF betaTrcp -dependent degradation of Claspin following recovery from DNA damage stresses, these data argue for a role of Cdh1 in limiting Plk1 levels to preserve Claspin stability and Chk1 activation in response to DNA damage in G2.	1	11	initiates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Claspin	Claspin	Claspin	1	2	9	10
These findings suggest that Plk1 may negatively regulate the stability of PinX1 by mitotic phosphorylation .	These findings suggest that Plk1 may negatively regulate the stability of PinX1 by mitotic phosphorylation.	4	12	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	PinX1	PinX1	PinX1	4	5	11	12
PIASy is an inhibitor of STAT1 , and it has the shortest and least conserved C-terminal region .	PIASy is an inhibitor of STAT1, and it has the shortest and least conserved C-terminal region.	0	6	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PIASy	PIASy	PIASy	STAT1	STAT1	STAT1	0	1	5	6
Protein inhibitor of activated STAT Y ( PIASy ) is the shortest member of the PIAS family and has been reported to modulate the transcriptional activities of STAT1 , lymphoid enhancer factor 1 ( LEF-1 ) , and the androgen receptor .	Protein inhibitor of activated STAT Y (PIASy) is the shortest member of the PIAS family and has been reported to modulate the transcriptional activities of STAT1, lymphoid enhancer factor 1 (LEF-1), and the androgen receptor.	5	40	modulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIASy	PIASy	PIASy	STAT1	STAT1	STAT1	7	8	27	28
On the other hand , PIASx and PIASy repress the transcriptional activity of STAT1 and STAT4 by recruiting co-repressor molecules such as histone deacetylases [ XREF_BIBR ] .	On the other hand, PIASx and PIASy repress the transcriptional activity of STAT1 and STAT4 by recruiting co-repressor molecules such as histone deacetylases [XREF_BIBR].	5	15	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIASy	PIASy	PIASy	STAT1	STAT1	STAT1	7	8	13	14
For instance , PIM2 phosphorylates and inhibits the pro apoptotic protein Bcl-2-associated death promoter ( BAD ) and also targets the eukaryotic translation initiation factor 4B ( eIF4B ) [ XREF_BIBR ] .	For instance, PIM2 phosphorylates and inhibits the pro apoptotic protein Bcl-2-associated death promoter (BAD) and also targets the eukaryotic translation initiation factor 4B (eIF4B) [XREF_BIBR].	3	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIM2	PIM2	PIM2	BAD	BAD	BAD	3	4	15	16
We found that PIM1 knockdown upregulated CDKN1B and p27 , suggesting a mechanism by which PIM1 promotes cell cycle progression in TNBC .	We found that PIM1 knockdown upregulated CDKN1B and p27, suggesting a mechanism by which PIM1 promotes cell cycle progression in TNBC.	3	8	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIM1	PIM1	PIM1	CDKN1B	CDKN1B	CDKN1B	3	4	6	7
The lower level of PIM1 induces an increase in the cell cycle inhibitor p27 ( Kip1 ) and blocks cell proliferation even in the absence of p53 .	The lower level of PIM1 induces an increase in the cell cycle inhibitor p27 (Kip1) and blocks cell proliferation even in the absence of p53.	2	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIM1	level of PIM1	pim1	p27	p27	p27	4	5	13	14
Consistent with this notion , depletion of Plk1 prolongs PBIP1 localization to the centromeres ( Y. H. Kang and K. S. Lee , unpublished ) , suggesting that Plk1 negatively regulates PBIP1 localization to the centromeres .	Consistent with this notion, depletion of Plk1 prolongs PBIP1 localization to the centromeres (Y. H. Kang and K. S. Lee, unpublished), suggesting that Plk1 negatively regulates PBIP1 localization to the centromeres.	28	32	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	PBIP1	PBIP1	PBIP1	28	29	31	32
In early mitosis , PLK1 induces PBIP1 degradation ; however , PLK1 is retained at the kinetochores even after degradation of PBIP1 .	In early mitosis, PLK1 induces PBIP1 degradation; however, PLK1 is retained at the kinetochores even after degradation of PBIP1.	4	7	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	PBIP1	PBIP1	PBIP1	4	5	6	7
Ironically , Plk1 also induces PBIP1 degradation in a S77-p-T78 motif dependent manner [ XREF_BIBR ] , suggesting that both S77 and T78 residues that are central for PBD binding are also required for proper PBIP1 degradation .	Ironically, Plk1 also induces PBIP1 degradation in a S77-p-T78 motif dependent manner [XREF_BIBR], suggesting that both S77 and T78 residues that are central for PBD binding are also required for proper PBIP1 degradation.	2	6	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	PBIP1	PBIP1	PBIP1	2	3	5	6
Moreover , we found that other Smads including Smad3 also associated with PIASy through its MH2 domain , and PIASy suppressed TGF-beta-mediated activation of Smad3 .	Moreover, we found that other Smads including Smad3 also associated with PIASy through its MH2 domain, and PIASy suppressed TGF-beta-mediated activation of Smad3.	19	25	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIASy	PIASy	PIASy	Smad3	Smad3	Smad3	19	20	24	25
In addition , WIP1 inactivates p53 in several ways .	In addition, WIP1 inactivates p53 in several ways.	3	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	3	4	5	6
PPM1D could inhibit p53 signaling , and is putatively oncogenic [ XREF_BIBR ] .	PPM1D could inhibit p53 signaling, and is putatively oncogenic [XREF_BIBR].	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	0	1	3	4
PPM1D overexpression inhibits p53 functions and reduces selection for p53 mutations during cancer progression .	PPM1D overexpression inhibits p53 functions and reduces selection for p53 mutations during cancer progression.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D overexpression	ppm1d	p53	p53	p53	0	1	3	4
Thus , alerted levels of MDM2 , MDM4 , or WIP1 , which are often mutually exclusive with p53 mutations , could attenuate p53 function in tumor suppression .	Thus, alerted levels of MDM2, MDM4, or WIP1, which are often mutually exclusive with p53 mutations, could attenuate p53 function in tumor suppression.	3	24	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	levels of MDM2, MDM4, or WIP1	wip1	p53	p53	p53	10	11	23	24
Since BRCA1-IRIS upregulates Wip1 , the authors conclude that the mechanism by which BRCA1-IRIS inhibits UV radiation induced apoptosis is through Wip1 inhibition of the p38 MAPK and p53 pathway .	Since BRCA1-IRIS upregulates Wip1, the authors conclude that the mechanism by which BRCA1-IRIS inhibits UV radiation induced apoptosis is through Wip1 inhibition of the p38 MAPK and p53 pathway.	21	29	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	21	22	28	29
WIP1 directly inhibits p53 through its dephosphorylation and subsequent degradation .	WIP1 directly inhibits p53 through its dephosphorylation and subsequent degradation.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	0	1	3	4
The discovery that PPM1D attenuates p53 activation and our own observations that Akt may stabilize PPM1D and enhance its content reveals a new mechanism by which Akt can regulate p53 , besides the well established Akt-MDM2 axis .	The discovery that PPM1D attenuates p53 activation and our own observations that Akt may stabilize PPM1D and enhance its content reveals a new mechanism by which Akt can regulate p53, besides the well established Akt-MDM2 axis.	3	6	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	3	4	5	6
Furthermore , the miR-29 family directly suppresses cell division cycle 42 ( CDC42 ) and PPM1D phosphatase , both of which negatively regulate p53 [ XREF_BIBR , XREF_BIBR ] .	Furthermore, the miR-29 family directly suppresses cell division cycle 42 (CDC42) and PPM1D phosphatase, both of which negatively regulate p53 [XREF_BIBR, XREF_BIBR].	15	27	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	15	16	23	24
Overexpression of PPM1D contributes to the development of human cancers by suppressing p53 activation XREF_BIBR .	Overexpression of PPM1D contributes to the development of human cancers by suppressing p53 activation XREF_BIBR.	0	14	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPM1D	Overexpression of PPM1D	ppm1d	p53	p53	p53	2	3	12	13
This demonstrates that lower basal Wip1 levels increase the responsiveness of the p53 system .	This demonstrates that lower basal Wip1 levels increase the responsiveness of the p53 system.	5	13	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1 levels	wip1	p53	p53	p53	5	6	12	13
In our study [ XREF_BIBR ] , we tested whether the simultaneous inhibition of both p53-antagonists , Mdm2 and Wip1 , might induce p53 more potently than single inhibitors .	In our study [XREF_BIBR], we tested whether the simultaneous inhibition of both p53-antagonists, Mdm2 and Wip1, might induce p53 more potently than single inhibitors.	15	24	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	19	20	23	24
Wip1 may act to suppress DNA damage signaling kinases Ataxia telangiectasia mutated ( ATM ) and Tumor suppressor protein TP53 ( p53 ) in human tumor cells XREF_BIBR .	Wip1 may act to suppress DNA damage signaling kinases Ataxia telangiectasia mutated (ATM) and Tumor suppressor protein TP53 (p53) in human tumor cells XREF_BIBR.	0	27	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	TP53	TP53	TP53	0	1	19	20
Wip1 inhibition of p53 is dependent on MdmX and Mdm2 .	Wip1 inhibition of p53 is dependent on MdmX and Mdm2.	0	4	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	0	1	3	4
PPM1D knockdown also increased the level of p53 protein and decreased CDC25C ( XREF_FIG ) .	PPM1D knockdown also increased the level of p53 protein and decreased CDC25C (XREF_FIG).	0	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	0	1	7	8
Inhibition of WIP1 potentiates activation of p53 pathway .	Inhibition of WIP1 potentiates activation of p53 pathway.	0	7	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	2	3	6	7
Here we show that disruption of the gene Ppm1d encoding Wip1 phosphatase activated the p53 and p16 ( also called Ink4a )-p19 ( also called ARF ) pathways through p38 MAPK signaling and suppressed in vitro transformation of mouse embryo fibroblasts ( MEFs ) by oncogenes .	Here we show that disruption of the gene Ppm1d encoding Wip1 phosphatase activated the p53 and p16 (also called Ink4a)-p19 (also called ARF) pathways through p38 MAPK signaling and suppressed in vitro transformation of mouse embryo fibroblasts (MEFs) by oncogenes.	8	27	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ppm1d	Ppm1d	Ppm1d	p53	p53	p53	8	9	14	15
U-2 OS cells exhibit increased expression of the p53 antagonist PPM1D , but shRNA mediated knockdown of this protein only slightly increases the activation of p53 .	U-2 OS cells exhibit increased expression of the p53 antagonist PPM1D, but shRNA mediated knockdown of this protein only slightly increases the activation of p53.	5	11	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	10	11	8	9
Although the mechanism is unknown , it would be interesting to test whether Wip1 inhibits p53 dependent apoptosis in mammary tumor stem cells , as is the case in intestinal stem cells .	Although the mechanism is unknown, it would be interesting to test whether Wip1 inhibits p53 dependent apoptosis in mammary tumor stem cells, as is the case in intestinal stem cells.	13	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	13	14	15	16
Wip1 may inhibit p53 signaling by multiple mechanisms , but our data suggests that its largest effects are due to dephosphorylation of Mdm2 .	Wip1 may inhibit p53 signaling by multiple mechanisms, but our data suggests that its largest effects are due to dephosphorylation of Mdm2.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	0	1	3	4
Investigators have previously shown that WIP1 inactivates p53 32 and that p53 and GLI1 function in a negative feedback loop .	Investigators have previously shown that WIP1 inactivates p53 32 and that p53 and GLI1 function in a negative feedback loop.	5	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	5	6	7	8
p53 is negatively regulated by Wip1 , a stress response phosphatase that presents an attractive target in the treatment of many tumors .	p53 is negatively regulated by Wip1, a stress response phosphatase that presents an attractive target in the treatment of many tumors.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	5	6	0	1
Conversely , Wip1 negatively regulates p53 by inactivating upstream kinases , including Ataxia telangiectasia mutated ( ATM ) and MAPK p38 , by reducing DNA-damage signaling through dephosphorylation of gammaH2AX , and by stabilizing MDM2 , the major negative regulator of p53 stability .	Conversely, Wip1 negatively regulates p53 by inactivating upstream kinases, including Ataxia telangiectasia mutated (ATM) and MAPK p38, by reducing DNA-damage signaling through dephosphorylation of gammaH2AX, and by stabilizing MDM2, the major negative regulator of p53 stability.	2	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	2	3	5	6
Currently , our confocal imaging results suggest a colocalization between Tax , Wip1 , and p53 within the nucleus , but we still lack sufficient data to decipher mechanistically how Tax and Wip1 cooperate to inactivate p53 .	Currently, our confocal imaging results suggest a colocalization between Tax, Wip1, and p53 within the nucleus, but we still lack sufficient data to decipher mechanistically how Tax and Wip1 cooperate to inactivate p53.	30	37	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	32	33	36	37
Wip1 overexpression suppressed p53 activity in the stressed cells even in the absence of MdmX , but the reduction of p53 activity in the p53-/-MdmX-/- cells was relatively modest ( 33 % ) in contrast with a more profound reduction ( 61 % ) observed in the p53-/- cells ( XREF_FIG ) .	Wip1 overexpression suppressed p53 activity in the stressed cells even in the absence of MdmX, but the reduction of p53 activity in the p53-/-MdmX-/- cells was relatively modest (33%) in contrast with a more profound reduction (61%) observed in the p53-/- cells (XREF_FIG).	0	4	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1 overexpression	wip1	p53	p53	p53	0	1	3	4
WIP1 activation in p53 negative tumors .	WIP1 activation in p53 negative tumors.	0	5	activation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	0	1	3	4
The finding that Wip1 enhances the negative effects of MDMX on p53 signaling indicates that Wip1 and MDMX cooperate to reduce p53 activity and stability .	The finding that Wip1 enhances the negative effects of MDMX on p53 signaling indicates that Wip1 and MDMX cooperate to reduce p53 activity and stability.	15	22	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	15	16	21	22
Here , we found that PPM1D inhibits p53 mRNA translation through dephosphorylation of RBM38 at serine 195 .	Here, we found that PPM1D inhibits p53 mRNA translation through dephosphorylation of RBM38 at serine 195.	5	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	5	6	7	8
XREF_BIBR , XREF_BIBR WIP1 , on chromosome 17q22-q23 , inhibits p53 activity and functions as an oncogene when expressed at high levels along with oncogenes , including Myc .	XREF_BIBR, XREF_BIBR WIP1, on chromosome 17q22-q23, inhibits p53 activity and functions as an oncogene when expressed at high levels along with oncogenes, including Myc.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	3	4	10	11
The two major mechanisms in which this occurs , apart from the selection for p53 mutations , are i ) deletion of chromosome 17p on which the p53 gene resides , often in a process that leads to the occurrence of isochromosome 17 in human medulloblastomas ( De Smaele etal ., 2004 ) , and ii ) frequent overexpression of the phosphatase Wip1 that efficiently dephosphorylates and hence deactivates wild-type p53 ( Castellino etal ., 2008 ) .	The two major mechanisms in which this occurs, apart from the selection for p53 mutations, are i) deletion of chromosome 17p on which the p53 gene resides, often in a process that leads to the occurrence of isochromosome 17 in human medulloblastomas (De Smaele etal., 2004), and ii) frequent overexpression of the phosphatase Wip1 that efficiently dephosphorylates and hence deactivates wild-type p53 (Castellino etal., 2008).	58	74	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	overexpression of the phosphatase Wip1	wip1	p53	p53	p53	62	63	70	71
The results showed that Wip1 negatively regulates p53 specifically in the DNA damage response ( XREF_FIG ) .	The results showed that Wip1 negatively regulates p53 specifically in the DNA damage response (XREF_FIG).	4	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	4	5	7	8
Ppm1d could inhibit p53 signaling , and is putatively oncogenic XREF_BIBR , XREF_BIBR .	Ppm1d could inhibit p53 signaling, and is putatively oncogenic XREF_BIBR, XREF_BIBR.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ppm1d	Ppm1d	Ppm1d	p53	p53	p53	0	1	3	4
Because PPM1D is transcriptionally activated by p53 in response to DNA damage , PPM1D may serve as a critical component of a p53 negative feedback regulatory loop since it now appears that PPM1D can inhibit p53 activity by at least four different molecular mechanisms .	Because PPM1D is transcriptionally activated by p53 in response to DNA damage, PPM1D may serve as a critical component of a p53 negative feedback regulatory loop since it now appears that PPM1D can inhibit p53 activity by at least four different molecular mechanisms.	32	36	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	32	33	35	36
Furthermore , we showed that PPM1D modulates p53 mRNA translation and p53 dependent growth suppression through dephosphorylation of RBM38 .	Furthermore, we showed that PPM1D modulates p53 mRNA translation and p53 dependent growth suppression through dephosphorylation of RBM38.	5	9	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	5	6	7	8
WIP1 can inhibit p53 activity , especially in response to DNA damage , which forms another negative feedback loop to regulate p53 function .	WIP1 can inhibit p53 activity, especially in response to DNA damage, which forms another negative feedback loop to regulate p53 function.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	0	1	3	4
Since p53 enhances NER [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] and WIP1 negatively regulates p53 ( as part of a negative feedback regulatory loop ) [ XREF_BIBR , XREF_BIBR ] , it might be that the increased NER activity in Wip1 -/- MEFs and the decreased NER activity in WIP1 overexpressed U2-OS cells was simply due to increased and decreased p53 activity , respectively , and not due to the direct effects of WIP1 on NER functions .	Since p53 enhances NER [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR] and WIP1 negatively regulates p53 (as part of a negative feedback regulatory loop) [XREF_BIBR, XREF_BIBR], it might be that the increased NER activity in Wip1 -/- MEFs and the decreased NER activity in WIP1 overexpressed U2-OS cells was simply due to increased and decreased p53 activity, respectively, and not due to the direct effects of WIP1 on NER functions.	14	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	14	15	17	18
Once expressed , Wip1 negatively regulates p53 either by dephosphorylation and subsequent inactivation or by destabilization of the p53 protein through Mdm2 .	Once expressed, Wip1 negatively regulates p53 either by dephosphorylation and subsequent inactivation or by destabilization of the p53 protein through Mdm2.	3	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	3	4	6	7
PPM1D may inhibit p53 activity through inactivating dephosphorylation of the p38 MAP kinase .	PPM1D may inhibit p53 activity through inactivating dephosphorylation of the p38 MAP kinase.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	0	1	3	4
These data suggest that Wip1 functionally inactivates p53 and regulates the p38MAPK-p53-Wip1 signal transduction pathway .	These data suggest that Wip1 functionally inactivates p53 and regulates the p38MAPK-p53-Wip1 signal transduction pathway.	4	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	4	5	7	8
Wip1 over-expression inhibits p53 function and reduces selection for TP53 mutations during cancer progression .	Wip1 over-expression inhibits p53 function and reduces selection for TP53 mutations during cancer progression.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1 over-expression	wip1	p53	p53	p53	0	1	3	4
Importantly , WIP1 suppresses p53 by multiple mechanisms , including dephosphorylation of p53 kinases ( ATM , CHK1 , CHK2 ) , p53 itself ( at serine 15 ) , and MDM2 , which facilitates MDM2 mediated degradation of p53 .	Importantly, WIP1 suppresses p53 by multiple mechanisms, including dephosphorylation of p53 kinases (ATM, CHK1, CHK2), p53 itself (at serine 15), and MDM2, which facilitates MDM2 mediated degradation of p53.	2	5	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	2	3	4	5
Our results suggested that Wip1 suppression of p53 signaling by augmenting the stability of MdmX may be an important component of its oncogenicity .	Our results suggested that Wip1 suppression of p53 signaling by augmenting the stability of MdmX may be an important component of its oncogenicity.	4	8	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	4	5	7	8
The Wip1 activation in p53 negative cells was a first example of such kind of strategy .	The Wip1 activation in p53 negative cells was a first example of such kind of strategy.	1	6	activation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	1	2	4	5
Wip1 ( wild-type p53 induced phosphatase 1 ) belongs to PP2C family and is encoded by PPM1D gene , which inhibits p53 functions and activity in cancer cells .	Wip1 (wild-type p53 induced phosphatase 1) belongs to PP2C family and is encoded by PPM1D gene, which inhibits p53 functions and activity in cancer cells.	16	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	16	17	21	22
Our study showed that Wip1 can suppress p53 gene and p-p53 protein .	Our study showed that Wip1 can suppress p53 gene and p-p53 protein.	4	8	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	4	5	7	8
Notably , the Wip1 -/- MEFs showed statistically significant higher levels of pG13-Luc expression ( p = 0.0076 ; t-test ) and higher levels of p21 mRNA ( p = 0.0425 ; t-test ) than the Wip1 +/+ MEFs , suggesting that cell endogenous Wip1 does physiologically reduce p53 function in primary cells .	Notably, the Wip1 -/- MEFs showed statistically significant higher levels of pG13-Luc expression (p = 0.0076; t-test) and higher levels of p21 mRNA (p = 0.0425; t-test) than the Wip1 +/+ MEFs, suggesting that cell endogenous Wip1 does physiologically reduce p53 function in primary cells.	42	49	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	44	45	48	49
XREF_BIBR , XREF_BIBR Wip1 mediates negative feedback of p38 MAPK and p53 signaling by dephosphorylating p-p53 ( S15 ) in response to ultraviolet radiation .	XREF_BIBR, XREF_BIBR Wip1 mediates negative feedback of p38 MAPK and p53 signaling by dephosphorylating p-p53 (S15) in response to ultraviolet radiation.	0	12	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	3	4	11	12
PPM1D contributes to the development of human cancers by suppressing p53 activation and thus has been an attractive therapeutic target in tumors that overexpress PPM1D and those with wild-type functional p53 activity [ XREF_BIBR ] .	PPM1D contributes to the development of human cancers by suppressing p53 activation and thus has been an attractive therapeutic target in tumors that overexpress PPM1D and those with wild-type functional p53 activity [XREF_BIBR].	0	11	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	0	1	10	11
We have previously found that p53 activated gene PPM1D , whose product Wip1 inhibits p53 signaling , 32 is repressed upon RITA .	We have previously found that p53 activated gene PPM1D, whose product Wip1 inhibits p53 signaling, 32 is repressed upon RITA.	6	15	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	8	9	14	15
Correspondingly , the p53 target gene products p21 and Mdm2 were somewhat increased by Wip1 inhibition in U2OS cells but not in MCF-7 cells .	Correspondingly, the p53 target gene products p21 and Mdm2 were somewhat increased by Wip1 inhibition in U2OS cells but not in MCF-7 cells.	3	15	increased	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	14	15	3	4
Since Wip1 overexpression in both p53 null ( SKOV3 ) and wild type ( OVCA433 ) cell lines suppressed the cellul motility in our results , we presume that Wip1 may also inhibit ovarian cancer metastasis in a p53 independent manner .	Since Wip1 overexpression in both p53 null (SKOV3) and wild type (OVCA433) cell lines suppressed the cellul motility in our results, we presume that Wip1 may also inhibit ovarian cancer metastasis in a p53 independent manner.	29	40	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	29	30	38	39
XREF_BIBR , XREF_BIBR As a result , WIP1 abrogates cell cycle checkpoints and suppresses p53 activities .	XREF_BIBR, XREF_BIBR As a result, WIP1 abrogates cell cycle checkpoints and suppresses p53 activities.	7	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	7	8	14	15
Gain-of-function mutations of PPM1D and Wip1 impair the p53 dependent G1 checkpoint .	Gain-of-function mutations of PPM1D and Wip1 impair the p53 dependent G1 checkpoint.	1	11	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	5	6	8	9
Wip1 may inhibit the TP53 and p14 ( ARF ) pathway .	Wip1 may inhibit the TP53 and p14 (ARF) pathway.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	TP53	TP53	TP53	0	1	4	5
These results imply that , in addition to PPM1D amplification , up-regulation of Wip1 expression is important in breast cancer and suggest that Wip1 inhibition of p53 may be an important mechanism by which Wip1 promotes breast tumorigenesis .	These results imply that, in addition to PPM1D amplification, up-regulation of Wip1 expression is important in breast cancer and suggest that Wip1 inhibition of p53 may be an important mechanism by which Wip1 promotes breast tumorigenesis.	23	27	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	23	24	26	27
In addition , p38 mitogen activated protein kinase ( MAPK ) was considered as a downstream target of Wip1 , which regulated the cell cycle by inhibiting cyclin D1 under stress and directly suppressed p53 activities through Ser33 and Ser46 dephosphorylation by controlling cellular apoptosis .	In addition, p38 mitogen activated protein kinase (MAPK) was considered as a downstream target of Wip1, which regulated the cell cycle by inhibiting cyclin D1 under stress and directly suppressed p53 activities through Ser33 and Ser46 dephosphorylation by controlling cellular apoptosis.	16	35	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	18	19	34	35
These data suggest that Wip1 down-regulates p53 activation in the thymus and is required for normal alphabeta T cell development .	These data suggest that Wip1 down-regulates p53 activation in the thymus and is required for normal alphabeta T cell development.	4	13	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	4	5	6	7
For example , we recently demonstrated that one mechanism by which p21 exerts its inhibitory effects on p53 and apoptosis is through regulating WIP1 , an oncogenic phosphatase that inactivates p53 and its upstream kinases [ XREF_BIBR ] .	For example, we recently demonstrated that one mechanism by which p21 exerts its inhibitory effects on p53 and apoptosis is through regulating WIP1, an oncogenic phosphatase that inactivates p53 and its upstream kinases [XREF_BIBR].	22	34	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	23	24	30	31
XREF_BIBR , XREF_BIBR These findings strongly suggest that aberrant activation of MDM2 , MDM4 , or WIP1 can attenuate p53 function , which in turn serves as an important mechanism of tumorigenesis .	XREF_BIBR, XREF_BIBR These findings strongly suggest that aberrant activation of MDM2, MDM4, or WIP1 can attenuate p53 function, which in turn serves as an important mechanism of tumorigenesis.	9	20	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	16	17	19	20
In breast carcinomas with amplified and overexpressed WIP1 , the TP53 locus is rarely mutated , suggesting that WIP1 amplification inhibits p53 activity and reduces selection for p53 mutations during tumor progression [ XREF_BIBR ] .	In breast carcinomas with amplified and overexpressed WIP1, the TP53 locus is rarely mutated, suggesting that WIP1 amplification inhibits p53 activity and reduces selection for p53 mutations during tumor progression [XREF_BIBR].	18	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	18	19	21	22
When overexpressed , WIP1 impairs p53 function and contributes to tumorigenesis , usually in combination with other oncogenes .	When overexpressed, WIP1 impairs p53 function and contributes to tumorigenesis, usually in combination with other oncogenes.	3	8	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	3	4	5	6
Here we show that the simultaneous inhibition of an additional p53-antagonist , Wip1 and PPM1D , further enhances the activity of p53 .	Here we show that the simultaneous inhibition of an additional p53-antagonist, Wip1 and PPM1D, further enhances the activity of p53.	6	22	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	14	15	21	22
Although the oncogenic phosphatase protein phosphatase magnesium dependent 1 ( PPM1D ) can deactivate both p53 and Chk1 through site specific dephosphorylation , whether PPM1D has a role in CDDP resistance is unknown .	Although the oncogenic phosphatase protein phosphatase magnesium dependent 1 (PPM1D) can deactivate both p53 and Chk1 through site specific dephosphorylation, whether PPM1D has a role in CDDP resistance is unknown.	6	17	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	10	11	15	16
A plausible mechanistic scenario could be that Wip1 acts to inhibit p53 activity , thereby contributing to tumorigenesis .	A plausible mechanistic scenario could be that Wip1 acts to inhibit p53 activity, thereby contributing to tumorigenesis.	7	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	7	8	11	12
In addition , Wip1 dependent inactivation of p53 is thought to play a major role in control of checkpoint recovery .	In addition, Wip1 dependent inactivation of p53 is thought to play a major role in control of checkpoint recovery.	3	8	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	3	4	7	8
Additionally , Wip1 inhibits p53 through MdmX and enhances the interaction of MdmX with ubiquitin specific peptidase 7 ( USP7 ) , which deubiquitinates and stabilizes MdmX .	Additionally, Wip1 inhibits p53 through MdmX and enhances the interaction of MdmX with ubiquitin specific peptidase 7 (USP7), which deubiquitinates and stabilizes MdmX.	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	2	3	4	5
PPM1D is overexpressed in chemoresistant OVCA cells and inhibits the action of p53 and Chk1 [ XREF_BIBR , XREF_BIBR ] , leading to the inhibition of Chk1-Cdc25c pathway and promotion of mitosis and cell cycle progression .	PPM1D is overexpressed in chemoresistant OVCA cells and inhibits the action of p53 and Chk1 [XREF_BIBR, XREF_BIBR], leading to the inhibition of Chk1-Cdc25c pathway and promotion of mitosis and cell cycle progression.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D is overexpressed	ppm1d	p53	p53	p53	0	1	12	13
When overexpressed , WIP1 impairs p53 function and contributes to tumorigenesis , usually in combination with activation of other oncogenes .	When overexpressed, WIP1 impairs p53 function and contributes to tumorigenesis, usually in combination with activation of other oncogenes.	3	8	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	3	4	5	6
Previous work demonstrated that loss of Ppm1d leads to functional activation of the p19 ARF and p53 pathways and increased senescence .	Previous work demonstrated that loss of Ppm1d leads to functional activation of the p19 ARF and p53 pathways and increased senescence.	4	17	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Ppm1d	loss of Ppm1d	ppm1d	p53	p53	p53	6	7	16	17
The above results show that both Wip1 and Tax inactivate p53 function .	The above results show that both Wip1 and Tax inactivate p53 function.	5	11	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	6	7	10	11
PPM1D phosphatase , a target of p53 and RBM38 RNA binding protein , inhibits p53 mRNA translation via dephosphorylation of RBM38 .	PPM1D phosphatase, a target of p53 and RBM38 RNA binding protein, inhibits p53 mRNA translation via dephosphorylation of RBM38.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	0	1	14	15
Additionally , like HCT116 wild type cells , Wip1 depleted HCT116 p53 -/- cells were able to recover from G2 arrest , indicating that activated p53 in Wip1 depleted cells caused the failure to recover from G2 arrest .	Additionally, like HCT116 wild type cells, Wip1 depleted HCT116 p53 -/- cells were able to recover from G2 arrest, indicating that activated p53 in Wip1 depleted cells caused the failure to recover from G2 arrest.	8	15	depleted	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	8	9	11	12
Therefore , Wip1 inhibition of p53 appears to be a major mechanism by which Wip1 inhibits apoptosis .	Therefore, Wip1 inhibition of p53 appears to be a major mechanism by which Wip1 inhibits apoptosis.	2	6	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	2	3	5	6
These ' immediate early ' decreasing proteins include protein phosphatase 1D ( PPM1D ) , which has been shown to inactivate the checkpoint proteins p53 and Chk1 and the sprouty homologue 4 ( SPRY4 ) , which suppresses insulin receptor- and epidermal growth factor dependent ERK and MAPK signalling .	These ' immediate early ' decreasing proteins include protein phosphatase 1D (PPM1D), which has been shown to inactivate the checkpoint proteins p53 and Chk1 and the sprouty homologue 4 (SPRY4), which suppresses insulin receptor- and epidermal growth factor dependent ERK and MAPK signalling.	10	33	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	12	13	24	25
Thus our results extend the current knowledge about the role of Wip1 in cancer progression and therapy , and strongly argue for further examination into the therapeutic potential of Wip1 targeting in p53 negative tumors .	Thus our results extend the current knowledge about the role of Wip1 in cancer progression and therapy, and strongly argue for further examination into the therapeutic potential of Wip1 targeting in p53 negative tumors.	29	34	targeting	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	29	30	32	33
Wip1 , on chromosome 17q22-q23 , functions as an oncogene and inhibits p53 activity when overexpressed in proliferation of certain self- renewing cell types , including carcinogens , with advancing age [ XREF_BIBR ] .	Wip1, on chromosome 17q22-q23, functions as an oncogene and inhibits p53 activity when overexpressed in proliferation of certain self- renewing cell types, including carcinogens, with advancing age [XREF_BIBR].	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	0	1	12	13
These results strongly suggest that the increased levels of MDM2 , MDM4 , or WIP1 could significantly attenuate p53 function in tumor suppression and play an important role in the pathogenesis of neuroendocrine tumors .	These results strongly suggest that the increased levels of MDM2, MDM4, or WIP1 could significantly attenuate p53 function in tumor suppression and play an important role in the pathogenesis of neuroendocrine tumors.	7	19	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	levels of MDM2, MDM4, or WIP1	wip1	p53	p53	p53	14	15	18	19
Along this line , almost all Wip1 overexpressing breast tumors were found to have a structurally intact p53 gene , confirming that Wip1 could functionally inactivate p53 .	Along this line, almost all Wip1 overexpressing breast tumors were found to have a structurally intact p53 gene, confirming that Wip1 could functionally inactivate p53.	22	27	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	22	23	26	27
This was in agreement with synergistic amplification in HK-2 cells of Cis-P toxicity after WIP1 inhibition downstream of p53 gene .	This was in agreement with synergistic amplification in HK-2 cells of Cis-P toxicity after WIP1 inhibition downstream of p53 gene.	14	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	14	15	18	19
Since p53 is a central regulator of apoptosis , Wip1 inhibition of p53 by direct dephosphorylation and through the inactivation of upstream proteins promotes cell survival by suppressing apoptosis ( XREF_FIG ) .	Since p53 is a central regulator of apoptosis, Wip1 inhibition of p53 by direct dephosphorylation and through the inactivation of upstream proteins promotes cell survival by suppressing apoptosis (XREF_FIG).	9	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	9	10	12	13
Interestingly , inhibition of Wip1 also activated the p53 pathway during LR .	Interestingly, inhibition of Wip1 also activated the p53 pathway during LR.	2	9	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	4	5	8	9
Regulation of ATM and p53 dependent suppression of myc induced lymphomas by Wip1 phosphatase .	Regulation of ATM and p53 dependent suppression of myc induced lymphomas by Wip1 phosphatase.	4	13	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	12	13	4	5
WIP1 overexpression appears to antagonize p53 activation , and provides medulloblastoma cells the ability to resist arrest and apoptosis due to genotoxic stress .	WIP1 overexpression appears to antagonize p53 activation, and provides medulloblastoma cells the ability to resist arrest and apoptosis due to genotoxic stress.	0	6	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1 overexpression	wip1	p53	p53	p53	0	1	5	6
Thus , this scenario results in inactivation of p53 by Plk1 .	Thus, this scenario results in inactivation of p53 by Plk1.	4	11	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	10	11	8	9
Additionally , a recent study has shown that Plk1 in vivo phosphorylation of Ser718 on Topors , an ubiquitin and SUMO E3 ligase , inhibits Topors mediated sumylation of p53 and enhances p53 degradation through ubiquitination .	Additionally, a recent study has shown that Plk1 in vivo phosphorylation of Ser718 on Topors, an ubiquitin and SUMO E3 ligase, inhibits Topors mediated sumylation of p53 and enhances p53 degradation through ubiquitination.	8	33	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	8	9	32	33
As expected , re-introduction of Plk1 partially restored cell cycle arrest and cell growth of G9a-knockout HC116 p53 +/+ cells .	As expected, re-introduction of Plk1 partially restored cell cycle arrest and cell growth of G9a-knockout HC116 p53 +/+ cells.	3	19	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	p53	p53	p53	5	6	17	18
PLK1 antagonizes p53 during DNA damage response , and alteration of mRNA and protein expression related to DNA damaging , replication and repairing was detected in PLK1 silenced tumor cells , including the DNA dependent protein kinase ( DNAPK ) and topoisomerase II alpha ( TOPO2A ) [ XREF_BIBR ] .	PLK1 antagonizes p53 during DNA damage response, and alteration of mRNA and protein expression related to DNA damaging, replication and repairing was detected in PLK1 silenced tumor cells, including the DNA dependent protein kinase (DNAPK) and topoisomerase II alpha (TOPO2A) [XREF_BIBR].	0	3	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	p53	p53	p53	0	1	2	3
PLK1 also inhibits proapoptotic function of p53 via its phosphorylation XREF_BIBR .	PLK1 also inhibits proapoptotic function of p53 via its phosphorylation XREF_BIBR.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	p53	p53	p53	0	1	6	7
These data are consistent with the idea that deregulation of PLK1 during tumourigenesis may help suppress p53 function .	These data are consistent with the idea that deregulation of PLK1 during tumourigenesis may help suppress p53 function.	8	17	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	p53	p53	p53	10	11	16	17
Plk-1 knockdown and inhibition led to induction of apoptosis , which was caspase-3/8-dependent and p53 independent , and involved BID and Bcl-2 proteins .	Plk-1 knockdown and inhibition led to induction of apoptosis, which was caspase-3/8-dependent and p53 independent, and involved BID and Bcl-2 proteins.	0	18	led	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	Plk-1	Plk-1	Plk-1	p53	p53	p53	0	1	14	15
In addition , Plk1 inhibition elevated the level of the tumor suppressor p53 in both subcutaneous and visceral ASCs , in line with the notion that Plk1 negatively regulates the stability of p53 by downstream targets like GTSE1 or Topors [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, Plk1 inhibition elevated the level of the tumor suppressor p53 in both subcutaneous and visceral ASCs, in line with the notion that Plk1 negatively regulates the stability of p53 by downstream targets like GTSE1 or Topors [XREF_BIBR, XREF_BIBR, XREF_BIBR].	26	33	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	26	27	32	33
In NF-YA knocked-down tsp53-H1299 cells , PLK1 silencing abrogated the suppressive effect of NF-YA depletion on p53 transcriptional activity ( XREF_FIG ) , suggesting that the increased PLK1 expression resulting from NF-YA silencing may underlie the inhibition of p53 activity .	In NF-YA knocked-down tsp53-H1299 cells, PLK1 silencing abrogated the suppressive effect of NF-YA depletion on p53 transcriptional activity (XREF_FIG), suggesting that the increased PLK1 expression resulting from NF-YA silencing may underlie the inhibition of p53 activity.	27	39	underlie	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1 expression	plk1	p53	p53	p53	27	28	38	39
Evidence suggests that PLK1 inhibits the transactivation and pro apoptotic functions of p53 by physical interaction and phosphorylation [ XREF_BIBR ] .	Evidence suggests that PLK1 inhibits the transactivation and pro apoptotic functions of p53 by physical interaction and phosphorylation [XREF_BIBR].	3	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	p53	p53	p53	3	4	12	13
Plk1 inhibits the function of p53 , directly and indirectly .	Plk1 inhibits the function of p53, directly and indirectly.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	0	1	5	6
We show that Wip1 function is required throughout the arrest , and that Wip1 acts by antagonizing p53 dependent repression of crucial mitotic inducers , such as Cyclin B and Plk1 .	We show that Wip1 function is required throughout the arrest, and that Wip1 acts by antagonizing p53 dependent repression of crucial mitotic inducers, such as Cyclin B and Plk1.	17	31	repression	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	30	31	17	18
Over-expression of Plk1 rescue UV induced mitotic arrest cells by inhibiting p53 activation .	Over-expression of Plk1 rescue UV induced mitotic arrest cells by inhibiting p53 activation.	0	12	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Over-expression of Plk1	plk1	p53	p53	p53	2	3	11	12
Plk1 has been shown to negatively regulate p53 through transcription and protein destabilization .	Plk1 has been shown to negatively regulate p53 through transcription and protein destabilization.	0	8	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	0	1	7	8
Evidence suggests that PLK1 can inhibit the transactivation and proapoptotic functions of p53 by physical interaction and phosphorylation .	Evidence suggests that PLK1 can inhibit the transactivation and proapoptotic functions of p53 by physical interaction and phosphorylation.	3	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	p53	p53	p53	3	4	12	13
PLK1 plays a crucial role at checkpoint controls during G2/M transition of the mitotic cell cycle and inhibits p53 function directly by phosphorylation .	PLK1 plays a crucial role at checkpoint controls during G2/M transition of the mitotic cell cycle and inhibits p53 function directly by phosphorylation.	0	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	p53	p53	p53	0	1	18	19
Overexpression of Plk1 can inhibit the activity of p53 through phosphorylation p53 , which cause the apoptosis process failure , then cancerous cells survival which bring out the occurrence of cancer eventually XREF_BIBR , XREF_BIBR .	Overexpression of Plk1 can inhibit the activity of p53 through phosphorylation p53, which cause the apoptosis process failure, then cancerous cells survival which bring out the occurrence of cancer eventually XREF_BIBR, XREF_BIBR.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Overexpression of Plk1	plk1	p53	p53	p53	2	3	8	9
Inhibition of PP2A was associated with prevention of G1/S phase arrest by p53 and mitotic arrest mediated by Plk-1 .	Inhibition of PP2A was associated with prevention of G1/S phase arrest by p53 and mitotic arrest mediated by Plk-1.	12	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Plk-1	Plk-1	Plk-1	p53	p53	p53	18	19	12	13
However , there are still arguments in relation between cytotoxic effect by Plk1 depletion and role of p53 , and a number of studies have reported that inhibition of Plk1 induces similar cytotoxicity and sensitivity regardless of any type of cell or status of p53 .	However, there are still arguments in relation between cytotoxic effect by Plk1 depletion and role of p53, and a number of studies have reported that inhibition of Plk1 induces similar cytotoxicity and sensitivity regardless of any type of cell or status of p53.	12	18	depletion	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	12	13	17	18
Since PLK1 has been shown to induce p53 degradation through phosphorylation of Topors , Aurora-A-PLK1 functional interaction , therefore , could interfere with p53 function on the centrosome at G2/M phase .	Since PLK1 has been shown to induce p53 degradation through phosphorylation of Topors, Aurora-A-PLK1 functional interaction, therefore, could interfere with p53 function on the centrosome at G2/M phase.	1	8	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	p53	p53	p53	1	2	7	8
Mounting evidence suggests that Plk1 negatively regulates p53 through direct and indirect mechanisms .	Mounting evidence suggests that Plk1 negatively regulates p53 through direct and indirect mechanisms.	4	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	4	5	7	8
Meanwhile , Plk1 also negatively regulates p53 , thereby inhibiting its pro apoptotic function XREF_BIBR .	Meanwhile, Plk1 also negatively regulates p53, thereby inhibiting its pro apoptotic function XREF_BIBR.	2	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	2	3	6	7
Inhibition of PLK-1 restores functioning of wild type p53 .	Inhibition of PLK-1 restores functioning of wild type p53.	0	9	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK-1	PLK-1	PLK-1	p53	p53	p53	2	3	8	9
These data support the idea that PLK1 inhibition activates p53 through the DNA damage pathways .	These data support the idea that PLK1 inhibition activates p53 through the DNA damage pathways.	6	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	p53	p53	p53	6	7	9	10
In tumor cells with wild type p53 or wild type but inactive p53 , such as HeLa cells , Plk1 inhibition induces mitotic cellular stress and activates p53 leading further to a strong induction of apoptosis [ XREF_BIBR ] .	In tumor cells with wild type p53 or wild type but inactive p53, such as HeLa cells, Plk1 inhibition induces mitotic cellular stress and activates p53 leading further to a strong induction of apoptosis [XREF_BIBR].	19	28	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	19	20	27	28
p53 inactivation by Plk1 is further underscored by other studies [ XREF_BIBR - XREF_BIBR ] .	p53 inactivation by Plk1 is further underscored by other studies [XREF_BIBR - XREF_BIBR].	0	4	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	3	4	0	1
Plk1 was also shown to be required for the viability of cells harboring activated Ras XREF_BIBR or inactivated p53 , particularly in the presence of genotoxic damage XREF_BIBR .	Plk1 was also shown to be required for the viability of cells harboring activated Ras XREF_BIBR or inactivated p53, particularly in the presence of genotoxic damage XREF_BIBR.	0	19	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	0	1	18	19
PLK1 negatively regulates the activity and stability of p53 through phosphorylation .	PLK1 negatively regulates the activity and stability of p53 through phosphorylation.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	p53	p53	p53	0	1	8	9
A possible explanation could be that the p53 deficient cells are not able to repair their DNA damage induced by the Plk1 inhibition at the G1/S checkpoint because of their loss of intact p53 function , so they are forced to begin mitosis with unrepaired DNA damage , resulting in an elevated number of cells in S and in G2/M phase .	A possible explanation could be that the p53 deficient cells are not able to repair their DNA damage induced by the Plk1 inhibition at the G1/S checkpoint because of their loss of intact p53 function, so they are forced to begin mitosis with unrepaired DNA damage, resulting in an elevated number of cells in S and in G2/M phase.	6	22	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	21	22	7	8
Of significance , we showed that Plk1 mediated phosphorylation of Numb leads to its enhanced proteasomal degradation and impaired Numb and p53 pathway , thus providing another mechanism how Plk1 antagonizes p53 during DNA damage response .	Of significance, we showed that Plk1 mediated phosphorylation of Numb leads to its enhanced proteasomal degradation and impaired Numb and p53 pathway, thus providing another mechanism how Plk1 antagonizes p53 during DNA damage response.	29	32	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	29	30	31	32
We previously found that Plk1 inhibited the p53 and p73 activity through its direct phosphorylation .	We previously found that Plk1 inhibited the p53 and p73 activity through its direct phosphorylation.	4	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	4	5	7	8
For example , it has been shown that Plk1 inhibits p53 transcriptional activity and pro apoptotic function through direct binding to a sequence specific DNA binding domain of p53 .	For example, it has been shown that Plk1 inhibits p53 transcriptional activity and pro apoptotic function through direct binding to a sequence specific DNA binding domain of p53.	8	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	8	9	10	11
It has been reported that PLK1 inhibits p53 transcriptional activity via direct binding ; thus , inhibition of PLK1 by NF-YA should relieve its suppression on the p53 activity .	It has been reported that PLK1 inhibits p53 transcriptional activity via direct binding; thus, inhibition of PLK1 by NF-YA should relieve its suppression on the p53 activity.	5	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	p53	p53	p53	5	6	7	8
Thus , these data strongly suggest that Plk1 inhibits its rival p53 through either directly physical binding to block its function or indirectly inactivating p53 by promoting its turnover , as illustrated in Fig .	Thus, these data strongly suggest that Plk1 inhibits its rival p53 through either directly physical binding to block its function or indirectly inactivating p53 by promoting its turnover, as illustrated in Fig.	7	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	7	8	11	12
Although the molecular basis for these observations is unknown , Plk1 can inhibit p53 39 and leads to the stabilization of Myc proteins 40 , suggesting possible mechanisms for proliferative functions .	Although the molecular basis for these observations is unknown, Plk1 can inhibit p53 39 and leads to the stabilization of Myc proteins 40, suggesting possible mechanisms for proliferative functions.	10	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	10	11	13	14
In addition , Plk1 inhibited the pro apoptotic function of p53 in H1299 cells .	In addition, Plk1 inhibited the pro apoptotic function of p53 in H1299 cells.	3	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	3	4	10	11
Restored inhibition of SERCA2 by PLB would cause a gradual rise in cytoplasmic Ca 2+ consistent with a gradual increase in calcineurin activity during the second half of the night .	Restored inhibition of SERCA2 by PLB would cause a gradual rise in cytoplasmic Ca 2+ consistent with a gradual increase in calcineurin activity during the second half of the night.	0	6	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PLB	PLB	PLB	SERCA2	SERCA2	SERCA2	5	6	3	4
The PLN monomer is able to inhibit SERCA2 function , while the PLN pentamer acts as an inactive reservoir that is unable to interact with SERCA2A [ XREF_BIBR ] .	The PLN monomer is able to inhibit SERCA2 function, while the PLN pentamer acts as an inactive reservoir that is unable to interact with SERCA2A [XREF_BIBR].	1	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLN	PLN	PLN	SERCA2	SERCA2	SERCA2	1	2	7	8
PLN encoded phospholamban ( PLN ) negatively-regulates the Ca 2+ uptake action of SERCA2 .	PLN encoded phospholamban (PLN) negatively-regulates the Ca 2+ uptake action of SERCA2.	2	14	negatively-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLN	PLN	PLN	SERCA2	SERCA2	SERCA2	4	5	13	14
PLM is an inhibitor of NKA activity that functions in a manner analogous to PLN inhibition of SERCA2 , such that it can generally inhibit NKA activity 32 .	PLM is an inhibitor of NKA activity that functions in a manner analogous to PLN inhibition of SERCA2, such that it can generally inhibit NKA activity 32.	14	18	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PLN	PLN	PLN	SERCA2	SERCA2	SERCA2	14	15	17	18
PLB inhibits SERCA2 activity ; however , beta-adrenergic stimulation enhances PKA phosphorylation of PLB , which promotes its oligomerization and the derepression of SERCA2 activity .	PLB inhibits SERCA2 activity; however, beta-adrenergic stimulation enhances PKA phosphorylation of PLB, which promotes its oligomerization and the derepression of SERCA2 activity.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLB	PLB	PLB	SERCA2	SERCA2	SERCA2	0	1	2	3
SR calcium uptake is mediated by a Ca 2+ -ATPase ( SERCA2 ) , whose activity is reversibly regulated by phospholamban ( PLN ) .	SR calcium uptake is mediated by a Ca 2+ -ATPase (SERCA2), whose activity is reversibly regulated by phospholamban (PLN).	9	23	reversibly regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	PLN	PLN	PLN	SERCA2	SERCA2	SERCA2	22	23	11	12
Cytosolic Ca 2+ is sequestered into the sarcoplasmic lumen by the SERCA2 , whose activity is reversibly regulated by PLN [ XREF_BIBR ] .	Cytosolic Ca 2+ is sequestered into the sarcoplasmic lumen by the SERCA2, whose activity is reversibly regulated by PLN [XREF_BIBR].	4	21	reversibly regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	PLN	PLN	PLN	SERCA2	SERCA2	SERCA2	19	20	11	12
Phosphorylation of both the protein kinase A ( PKA ) site Ser 16 and the CaMKII site Thr 17 relieves the PLB inhibition of SERCA2 and thus increases its capacity to remove cytosolic Ca 2+ .	Phosphorylation of both the protein kinase A (PKA) site Ser 16 and the CaMKII site Thr 17 relieves the PLB inhibition of SERCA2 and thus increases its capacity to remove cytosolic Ca 2+.	21	25	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PLB	PLB	PLB	SERCA2	SERCA2	SERCA2	21	22	24	25
Phospholamban ( PLN ) inhibits the activity of SERCA2 in a phosphorylation dependent manner .	Phospholamban (PLN) inhibits the activity of SERCA2 in a phosphorylation dependent manner.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLN	PLN	PLN	SERCA2	SERCA2	SERCA2	2	3	8	9
Two mutations ( R9C and R14del ) result in enhanced inhibition of SERCA2 by PLN , partly due to decreased PKA mediated phosphorylation XREF_BIBR , XREF_BIBR .	Two mutations (R9C and R14del) result in enhanced inhibition of SERCA2 by PLN, partly due to decreased PKA mediated phosphorylation XREF_BIBR, XREF_BIBR.	10	15	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PLN	PLN	PLN	SERCA2	SERCA2	SERCA2	14	15	12	13
Phospholamban ( PLB ) inhibits SERCA2 activity and is therefore a potential target to improve the cardiac performance in heart failure .	Phospholamban (PLB) inhibits SERCA2 activity and is therefore a potential target to improve the cardiac performance in heart failure.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLB	PLB	PLB	SERCA2	SERCA2	SERCA2	2	3	5	6
Given that PLB inhibits the action of the SR calcium-regulatory pump [ XREF_BIBR ] , or SERCA2 , our data indicate that intracellular calcium reuptake is superior in the ASrAOGEN strain ( XREF_FIG ) .	Given that PLB inhibits the action of the SR calcium-regulatory pump [XREF_BIBR], or SERCA2, our data indicate that intracellular calcium reuptake is superior in the ASrAOGEN strain (XREF_FIG).	2	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLB	PLB	PLB	SERCA2	SERCA2	SERCA2	2	3	16	17
55 This finding may be explained by de-phosphorylation of SERCA inhibitor phospholamban ( PLB ) , which would block SERCA2 action through physical interaction with this transporter .	55 This finding may be explained by de-phosphorylation of SERCA inhibitor phospholamban (PLB), which would block SERCA2 action through physical interaction with this transporter.	7	20	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLB	de-phosphorylation of SERCA inhibitor phospholamban (PLB	plb	SERCA2	SERCA2	serca2	13	14	19	20
On the other hand , CaMKII is well known to phosphorylate phospholamban ( PLB ) , the small SR transmembrane protein that binds to and inhibits SERCA2 in cardiac myocytes .	On the other hand, CaMKII is well known to phosphorylate phospholamban (PLB), the small SR transmembrane protein that binds to and inhibits SERCA2 in cardiac myocytes.	5	27	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PLB	CaMKII is well known to phosphorylate phospholamban (PLB	plb	SERCA2	SERCA2	serca2	13	14	26	27
On the other hand , SR calcium uptake is mediated by a calcium ATPase Serca2 , whose activity is reversibly regulated by PLN XREF_BIBR .	On the other hand, SR calcium uptake is mediated by a calcium ATPase Serca2, whose activity is reversibly regulated by PLN XREF_BIBR.	9	23	reversibly regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	PLN	PLN	PLN	Serca2	Serca2	Serca2	22	23	14	15
In resting conditions SERCA2 is inhibited by unphopshorylated PLN .	In resting conditions SERCA2 is inhibited by unphopshorylated PLN.	3	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PLN	PLN	PLN	SERCA2	SERCA2	SERCA2	8	9	3	4
After sevoflurane inhalation , the protein expression of SERCA2 was reduced , whereas that of PLB increased , resulting in a decreased SERCA2 and PLB in all rats treated with sevoflurane ( all P < 0.05 ) .	After sevoflurane inhalation, the protein expression of SERCA2 was reduced, whereas that of PLB increased, resulting in a decreased SERCA2 and PLB in all rats treated with sevoflurane (all P < 0.05).	13	27	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PLB	PLB	PLB	SERCA2	SERCA2	SERCA2	15	16	22	23
Our results showed that sevoflurane increased PLB expression , decreased SERCA2 expression , and decreased the SERCA2 and PLB ratio similarly in PAH group and NS group .	Our results showed that sevoflurane increased PLB expression, decreased SERCA2 expression, and decreased the SERCA2 and PLB ratio similarly in PAH group and NS group.	4	12	decreased	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	PLB	sevoflurane increased PLB expression	plb	SERCA2	SERCA2 expression	serca2	6	7	10	11
Wip1 suppresses ATM activity through dephosphorylation of ATM , resulting in restoration of ATM to its dephosphorylated state after completion of DNA repair .	Wip1 suppresses ATM activity through dephosphorylation of ATM, resulting in restoration of ATM to its dephosphorylated state after completion of DNA repair.	0	3	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	0	1	2	3
On the other hand , overexpression of Wip1 , as occurs in certain types of cancers , may accelerate tumorigenesis by inhibiting ATM .	On the other hand, overexpression of Wip1, as occurs in certain types of cancers, may accelerate tumorigenesis by inhibiting ATM.	5	23	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	overexpression of Wip1	wip1	ATM	ATM	atm	7	8	22	23
Absence of Wip1 reduces chromosomal instability in Atm null splenocytes .	Absence of Wip1 reduces chromosomal instability in Atm null splenocytes.	0	9	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	Atm	Atm	Atm	2	3	7	8
Recent evidence suggested that Wip1 is a critical inhibitor in the ATM and ATR -p53 DNA damage signaling pathway .	Recent evidence suggested that Wip1 is a critical inhibitor in the ATM and ATR -p53 DNA damage signaling pathway.	4	12	is a critical inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	4	5	11	12
We present evidence that the suppression of p53 , p38 MAP kinase , and ATM and ATR signaling pathways by Wip1 are important components of its oncogenicity when it is amplified and overexpressed in human cancers .	We present evidence that the suppression of p53, p38 MAP kinase, and ATM and ATR signaling pathways by Wip1 are important components of its oncogenicity when it is amplified and overexpressed in human cancers.	5	21	suppression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	20	21	14	15
As shown in Figure XREF_FIG , inhibition of Wip1 increased ATM activation in a time dependent manner , which was consistent with a previous study [ XREF_BIBR ] .	As shown in Figure XREF_FIG, inhibition of Wip1 increased ATM activation in a time dependent manner, which was consistent with a previous study [XREF_BIBR].	6	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	8	9	10	11
Wip1 knockout activates ATM in macrophages and initiates autophagy , which in turn increases cholesterol efflux and prevents formation of macrophage foam cells .	Wip1 knockout activates ATM in macrophages and initiates autophagy, which in turn increases cholesterol efflux and prevents formation of macrophage foam cells.	0	5	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	0	1	3	4
Thus , Wip1 inactivates ATM signaling to p53 and promotes cell survival when myc expression levels are high .	Thus, Wip1 inactivates ATM signaling to p53 and promotes cell survival when myc expression levels are high.	2	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	2	3	4	5
The same initial amounts and forward rate constants were used as in the previous model , except in this case an initial condition of one active ATM molecule was used , and the inactivation of ATM by Wip1 was given a forward rate of 10 -5 molec -1 s -1 .	The same initial amounts and forward rate constants were used as in the previous model, except in this case an initial condition of one active ATM molecule was used, and the inactivation of ATM by Wip1 was given a forward rate of 10 -5 molec -1 s -1.	33	38	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	37	38	35	36
These include the definition of ELKS K63 ubiquitination mechanisms , NEMO SUMO protease ( s ) , and phosphatases for NEMO and other components , such as WIP1 that negatively regulates ATM and NF-kappaB .	These include the definition of ELKS K63 ubiquitination mechanisms, NEMO SUMO protease (s), and phosphatases for NEMO and other components, such as WIP1 that negatively regulates ATM and NF-kappaB.	18	33	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	ATM	ATM	ATM	27	28	31	32
Overexpression of Wip1 resulted in a significantly impaired induction of gamma-H2AX after IR and UV and decreased gamma-H2AX foci staining in an ATM independent manner [ XREF_BIBR , XREF_BIBR ] .	Overexpression of Wip1 resulted in a significantly impaired induction of gamma-H2AX after IR and UV and decreased gamma-H2AX foci staining in an ATM independent manner [XREF_BIBR, XREF_BIBR].	0	28	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Overexpression of Wip1	wip1	ATM	ATM	atm	2	3	22	23
In turn , overexpression of Wip1 was sufficient to reduce activation of the ATM dependent signaling cascade after DNA damage .	In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM dependent signaling cascade after DNA damage.	3	16	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	overexpression of Wip1	wip1	ATM	ATM	atm	5	6	13	14
Thus , the absence of Wip1 significantly decreases the genomic instability of Atm null cells .	Thus, the absence of Wip1 significantly decreases the genomic instability of Atm null cells.	3	14	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	Atm	Atm	Atm	5	6	12	13
Importantly , Wip1 knockdown enhanced ATM dependent signaling pathway and rendered cells more sensitive to cisplatin treatment .	Importantly, Wip1 knockdown enhanced ATM dependent signaling pathway and rendered cells more sensitive to cisplatin treatment.	2	8	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	2	3	5	6
However , squalene increased Wip1 expression in cells and suppressed ATM activation in gammaIR treated cells .	However, squalene increased Wip1 expression in cells and suppressed ATM activation in gammaIR treated cells.	2	11	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	squalene increased Wip1 expression	wip1	ATM	ATM	atm	4	5	10	11
Wip1 phosphatase inactivates ATM kinase leading to reduced phosphorylation of p53 , whereas MDM2 interacts directly with p53 as described above .	Wip1 phosphatase inactivates ATM kinase leading to reduced phosphorylation of p53, whereas MDM2 interacts directly with p53 as described above.	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	0	1	3	4
ATM was found to be directly dephosphorylated by PPM1D at Ser 1981 , which significantly downregulated ATM activity .	ATM was found to be directly dephosphorylated by PPM1D at Ser 1981, which significantly downregulated ATM activity.	6	17	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	dephosphorylated by PPM1D at Ser 1981	ppm1d	ATM	ATM	atm	8	9	16	17
The exact mechanism through which PPARgamma represses STAT3 has not been fully elucidated .	The exact mechanism through which PPARgamma represses STAT3 has not been fully elucidated.	5	8	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	5	6	7	8
XREF_BIBR - XREF_BIBR Here , we found that PPAR-gamma inhibited STAT3 activation by directly binding to STAT3 in cerulein stimulated cells .	XREF_BIBR - XREF_BIBR Here, we found that PPAR-gamma inhibited STAT3 activation by directly binding to STAT3 in cerulein stimulated cells.	8	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	STAT3	STAT3	STAT3	8	9	10	11
PPAR-gamma inactivates STAT3 by directly interacting with STAT3 in cerulein stimulated pancreatic acinar cells [ XREF_BIBR ] .	PPAR-gamma inactivates STAT3 by directly interacting with STAT3 in cerulein stimulated pancreatic acinar cells [XREF_BIBR].	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	STAT3	STAT3	STAT3	0	1	2	3
Because PPARgamma activation is insufficient to drive the Stat3 inhibitory effects of 15d-PGJ 2 in oral SCC cells ( Nikitakis et al , 2002 ) , we tested the possibility that specific downmodulation of JAK and Stat3 activation following treatment with 15d-PGJ 2 requires the reactive electrophilic alpha , beta unsaturated carbonyl group within the cyclopentenone ring .	Because PPARgamma activation is insufficient to drive the Stat3 inhibitory effects of 15d-PGJ 2 in oral SCC cells (Nikitakis et al, 2002), we tested the possibility that specific downmodulation of JAK and Stat3 activation following treatment with 15d-PGJ 2 requires the reactive electrophilic alpha,beta-unsaturated carbonyl group within the cyclopentenone ring.	1	10	drive	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	Stat3	Stat3	Stat3	1	2	8	9
These results show that PPAR-gamma inactivates STAT3 by directly interacting with STAT3 in cerulein stimulated pancreatic acinar cells .	These results show that PPAR-gamma inactivates STAT3 by directly interacting with STAT3 in cerulein stimulated pancreatic acinar cells.	4	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	STAT3	STAT3	STAT3	4	5	6	7
Conversally , PPARgamma inhibits STAT3 XREF_BIBR which , when overexpressed , induces Wnt5a and causes a psoriasis like phenotype in vivo XREF_BIBR .	Conversally, PPARgamma inhibits STAT3 XREF_BIBR which, when overexpressed, induces Wnt5a and causes a psoriasis like phenotype in vivo XREF_BIBR.	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	2	3	4	5
While not effecting STAT3 levels or phosphorylation of STAT3 in response to IL-6 treatment , PPARgamma disrupted STAT3 transcriptional activity by interfering with its DNA binding capacity , in keeping with previous observations .	While not effecting STAT3 levels or phosphorylation of STAT3 in response to IL-6 treatment, PPARgamma disrupted STAT3 transcriptional activity by interfering with its DNA binding capacity, in keeping with previous observations.	15	19	disrupted	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	15	16	17	18
The exact mechanism through which PPAR-gamma represses STAT3 is not yet fully elucidated .	The exact mechanism through which PPAR-gamma represses STAT3 is not yet fully elucidated.	5	8	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	STAT3	STAT3	STAT3	5	6	7	8
Interestingly , although inactivation of STAT3 by PPARgamma agonists is in a PPARgamma dependent manner , the molecular mechanism by which two structurally distinct PPARgamma agonists suppress IL-6-activated STAT3 shows the divergent interactions between PPARgamma and STAT3 including direct or SMRT mediated association .	Interestingly, although inactivation of STAT3 by PPARgamma agonists is in a PPARgamma dependent manner, the molecular mechanism by which two structurally distinct PPARgamma agonists suppress IL-6-activated STAT3 shows the divergent interactions between PPARgamma and STAT3 including direct or SMRT mediated association.	3	8	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	7	8	5	6
An alternative mechanism for PPARgamma mediated STAT3 repression has also been suggested , in which PPARgamma agonist treatment of multiple myeloma cells induces the corepressor protein SMRT to dissociate from PPARgamma ; SMRT could then complex with and inhibit the transcriptional activities of STAT3 .	An alternative mechanism for PPARgamma mediated STAT3 repression has also been suggested, in which PPARgamma agonist treatment of multiple myeloma cells induces the corepressor protein SMRT to dissociate from PPARgamma; SMRT could then complex with and inhibit the transcriptional activities of STAT3.	2	7	mediated	Positive_early_activation	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	4	5	6	7
The corepressor SMRT has also to be demonstrated to mediate PPARgamma downregulation of STAT3 in multiple myeloma cells .	The corepressor SMRT has also to be demonstrated to mediate PPARgamma downregulation of STAT3 in multiple myeloma cells.	10	14	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	10	11	13	14
It remains a matter of further study whether PPAR-gamma ligands inhibit STAT3 by promoting its dissociation from Hsp90 .	It remains a matter of further study whether PPAR-gamma ligands inhibit STAT3 by promoting its dissociation from Hsp90.	8	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	STAT3	STAT3	STAT3	8	9	11	12
Moreover , the enhancement of this interaction by 15-d-PGJ2 , but not troglitazone , suggests that these two classes of PPAR-gamma ligands inactivate STAT3 through different mechanisms .	Moreover, the enhancement of this interaction by 15-d-PGJ2, but not troglitazone, suggests that these two classes of PPAR-gamma ligands inactivate STAT3 through different mechanisms.	20	24	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	STAT3	STAT3	STAT3	20	21	23	24
Elevated levels of PPARgamma blocked IL-6-induced STAT3 activation and downstream IL-21 production that subsequently stimulates the production of IL-17 .	Elevated levels of PPARgamma blocked IL-6-induced STAT3 activation and downstream IL-21 production that subsequently stimulates the production of IL-17.	1	7	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPARgamma	levels of PPARgamma	ppargamma	STAT3	STAT3	stat3	3	4	6	7
In that PPARgamma agonists inhibit the IL-6-regulated Stat3 signaling cascade , a role for PPARgamma agonists in regulating expression of miRNAs critical to the pathogenesis of hematological malignancies may be an important avenue of future scientific investigations .	In that PPARgamma agonists inhibit the IL-6-regulated Stat3 signaling cascade, a role for PPARgamma agonists in regulating expression of miRNAs critical to the pathogenesis of hematological malignancies may be an important avenue of future scientific investigations.	0	32	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	Stat3	Stat3	Stat3	2	3	7	8
Negative modulation of STAT3 by peroxisome proliferator activated receptor gamma ( PPARgamma ) and ER was shown in MM via a direct mechanism or by recruitment of the coregulators NCOR2 or PIAS [ XREF_BIBR ] .	Negative modulation of STAT3 by peroxisome proliferator activated receptor gamma (PPARgamma) and ER was shown in MM via a direct mechanism or by recruitment of the coregulators NCOR2 or PIAS [XREF_BIBR].	1	10	modulation	Positive_activation_token_2_noun	Negative_activation	Negative_activation	peroxisome proliferator activated receptor gamma	peroxisome proliferator activated receptor gamma	peroxisome proliferator activated receptor gamma	STAT3	STAT3	STAT3	5	10	3	4
For example , PGC-1alpha overexpression in adult rodents suppressed FoxO3a activity , promoted muscle mass maintenance [ XREF_BIBR ] , and similarly prevented starvation associated protein degradation and atrophy in myotubes [ XREF_BIBR ] .	For example, PGC-1alpha overexpression in adult rodents suppressed FoxO3a activity, promoted muscle mass maintenance [XREF_BIBR], and similarly prevented starvation associated protein degradation and atrophy in myotubes [XREF_BIBR].	3	10	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha overexpression	pgc-1alpha	FoxO3a	FoxO3a	foxo3a	3	4	9	10
Third , PGC-1alpha overexpression has been documented to block FoxO3 mediated transcriptional activity [ XREF_BIBR ] , and since FoxO3 drives the expression of multiple mitophagy factors such as Mul1 and Bnip3 [ XREF_BIBR , XREF_BIBR ] , repression of FoxO3activity may be sufficient to protect mitochondria from elimination .	Third, PGC-1alpha overexpression has been documented to block FoxO3 mediated transcriptional activity [XREF_BIBR], and since FoxO3 drives the expression of multiple mitophagy factors such as Mul1 and Bnip3 [XREF_BIBR, XREF_BIBR], repression of FoxO3activity may be sufficient to protect mitochondria from elimination.	2	10	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha overexpression	pgc-1alpha	FoxO3	FoxO3	foxo3	2	3	9	10
2007 ) , whereas peroxisome-proliferator-activated receptor-gamma coactivator-1 alpha ( PGC1alpha ) inhibits FoxO3 function ( Sandri etal .	2007), whereas peroxisome-proliferator-activated receptor-gamma coactivator-1 alpha (PGC1alpha) inhibits FoxO3 function (Sandri etal.	7	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC1alpha	PGC1alpha	PGC1alpha	FoxO3	FoxO3	FoxO3	9	10	12	13
PGC-1alpha may then activate mitochondrial biogenesis , mitochondrial antioxidants and inhibit FoxO3a activity .	PGC-1alpha may then activate mitochondrial biogenesis, mitochondrial antioxidants and inhibit FoxO3a activity.	0	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3a	FoxO3a	FoxO3a	0	1	11	12
Importantly , the role of PGC-1alpha inhibition of FoxO3a to increase muscle resistance to catabolic wasting does not compromise the capacity of PGC-1alpha to reduce oxidative stress in cardiac muscle XREF_BIBR .	Importantly, the role of PGC-1alpha inhibition of FoxO3a to increase muscle resistance to catabolic wasting does not compromise the capacity of PGC-1alpha to reduce oxidative stress in cardiac muscle XREF_BIBR.	5	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3a	FoxO3a	FoxO3a	5	6	8	9
2007 ) and PGC1alpha inhibits FoxO3 function ( Sandri etal .	2007) and PGC1alpha inhibits FoxO3 function (Sandri etal.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC1alpha	PGC1alpha	PGC1alpha	FoxO3	FoxO3	FoxO3	3	4	5	6
It is involved in the disease the activation of proteolysis due to AKT and FoxO3a dephosphorylation , whereas PGC-1alpha is able to inhibit the transcriptional activity of FoxO3a , suppressing atrogenes expression and protein degradation .	It is involved in the disease the activation of proteolysis due to AKT and FoxO3a dephosphorylation, whereas PGC-1alpha is able to inhibit the transcriptional activity of FoxO3a, suppressing atrogenes expression and protein degradation.	18	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3a	FoxO3a	FoxO3a	18	19	27	28
PGC1alpha , the transcription of atrophy specific genes , inhibits the activity of the transcription factor FOXO3 , with protects skeletal muscle from atrophy XREF_BIBR .	PGC1alpha, the transcription of atrophy specific genes, inhibits the activity of the transcription factor FOXO3, with protects skeletal muscle from atrophy XREF_BIBR.	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC1alpha	PGC1alpha	PGC1alpha	FOXO3	FOXO3	FOXO3	0	1	16	17
In addition , PGC-1alpha inhibits FoxO3 activity on transcription of atrophy specific genes and thereby decreases muscle atrophy [ XREF_BIBR ] .	In addition, PGC-1alpha inhibits FoxO3 activity on transcription of atrophy specific genes and thereby decreases muscle atrophy [XREF_BIBR].	3	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3	FoxO3	FoxO3	3	4	5	6
In addition , PGC-1alpha can suppress FoxO3 activity and expression of FoxO target genes [ XREF_BIBR ] .	In addition, PGC-1alpha can suppress FoxO3 activity and expression of FoxO target genes [XREF_BIBR].	3	7	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3	FoxO3	FoxO3	3	4	6	7
PGC-1alpha impeded the activity of FoxO3 , a transcription factor involved in regulating the expression of these genes .	PGC-1alpha impeded the activity of FoxO3, a transcription factor involved in regulating the expression of these genes.	0	9	impeded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3	FoxO3	FoxO3	0	1	5	6
Sandri et al [ XREF_BIBR ] reported that overexpression of PGC-1alpha attenuated FoxO3a activity , thereby providing a protective effect against atrophy .	Sandri et al [XREF_BIBR] reported that overexpression of PGC-1alpha attenuated FoxO3a activity, thereby providing a protective effect against atrophy.	8	13	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	overexpression of PGC-1alpha	pgc-1alpha	FoxO3a	FoxO3a	foxo3a	10	11	12	13
Furthermore , PGC-1alpha overexpression suppressed FoxO1 and FoxO3 activation along with a decreased LC3II and LC3I ratio .	Furthermore, PGC-1alpha overexpression suppressed FoxO1 and FoxO3 activation along with a decreased LC3II and LC3I ratio.	2	8	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha overexpression	pgc-1alpha	FoxO3	FoxO3	foxo3	2	3	7	8
Transfection of PGC-1alpha into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter .	Transfection of PGC-1alpha into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter.	0	11	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3	FoxO3	FoxO3	2	3	10	11
Furthermore , this study demonstrated that elevated PGC1-alpha content prevented transcriptional activity of FoxO3a .	Furthermore, this study demonstrated that elevated PGC1-alpha content prevented transcriptional activity of FoxO3a.	7	14	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC1-alpha	PGC1-alpha	PGC1-alpha	FoxO3a	FoxO3a	FoxO3a	7	8	13	14
The presence of excess PGC-1alpha reduces the FoxO3 occupancy on the Atrogin-1 promoter [ XREF_BIBR ] , suggesting that PGC-1alpha is not acting as a direct inhibitor of transcription .	The presence of excess PGC-1alpha reduces the FoxO3 occupancy on the Atrogin-1 promoter [XREF_BIBR], suggesting that PGC-1alpha is not acting as a direct inhibitor of transcription.	1	8	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3	FoxO3	FoxO3	4	5	7	8
Reciprocally , Plk1 reduces the stability of the endogenous p73 and depletion of Plk1 stabilizes p73 .	Reciprocally, Plk1 reduces the stability of the endogenous p73 and depletion of Plk1 stabilizes p73.	2	16	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p73	p73	p73	2	3	15	16
Plk1 inhibits p73 and p63 in cancer cells lacking functional p53 .	Plk1 inhibits p73 and p63 in cancer cells lacking functional p53.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p73	p73	p73	0	1	2	3
Collectively , these findings indicate that Plk1 inhibits p73 by blocking its function and increasing its degradation in cancer cells lacking functional p53 .	Collectively, these findings indicate that Plk1 inhibits p73 by blocking its function and increasing its degradation in cancer cells lacking functional p53.	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p73	p73	p73	6	7	8	9
Luciferase reporter assay and reverse transcription-PCR analysis revealed that Plk1 is able to block the p73 mediated transcriptional activation .	Luciferase reporter assay and reverse transcription-PCR analysis revealed that Plk1 is able to block the p73 mediated transcriptional activation.	9	16	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p73	p73	p73	9	10	15	16
In addition , we have demonstrated that p73 is strongly inhibited by Plk1 through physical interaction and phosphorylation at Thr 27 [ XREF_BIBR ] .	In addition, we have demonstrated that p73 is strongly inhibited by Plk1 through physical interaction and phosphorylation at Thr 27 [XREF_BIBR].	7	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p73	p73	p73	12	13	7	8
Recently , we have found for the first time that Plk1 attenuates transcriptional as well as proapoptotic function of p73 [ XREF_BIBR ] .	Recently, we have found for the first time that Plk1 attenuates transcriptional as well as proapoptotic function of p73 [XREF_BIBR].	10	21	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p73	p73	p73	10	11	19	20
Plk1 also leads to a further increase in Cdk1 activity by additionally inhibiting Myt1 and inducing the degradation of Wee1 by phosphorylation .	Plk1 also leads to a further increase in Cdk1 activity by additionally inhibiting Myt1 and inducing the degradation of Wee1 by phosphorylation.	0	20	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Wee1	Wee1	Wee1	0	1	19	20
Although the Plk1 homolog in budding yeast , Cdc5 , had been shown to interact with and negatively regulate yeast Wee1 , this was the first example of negative regulation of Wee1 by Plk1 in higher eukaryotes [ XREF_BIBR ] .	Although the Plk1 homolog in budding yeast, Cdc5, had been shown to interact with and negatively regulate yeast Wee1, this was the first example of negative regulation of Wee1 by Plk1 in higher eukaryotes [XREF_BIBR].	2	21	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Wee1	Wee1	Wee1	2	3	20	21
Furthermore , Plk1 triggers betaTrCP dependent ubiquitinylation and degradation of the Cdk1 inhibiting kinase Wee1 .	Furthermore, Plk1 triggers betaTrCP dependent ubiquitinylation and degradation of the Cdk1 inhibiting kinase Wee1.	2	15	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	Wee1	Wee1	Wee1	2	3	14	15
However , once released from a double-thymidine block into nocodazole containing medium , PLK1 T210D/+ cells degraded Wee1 and dephosphorylated Cdk1 on schedule ( XREF_FIG ) and accumulated in mitosis with the same kinetics as their isogenic wildtype counterparts ( XREF_FIG ) .	However, once released from a double-thymidine block into nocodazole containing medium, PLK1 T210D/+ cells degraded Wee1 and dephosphorylated Cdk1 on schedule (XREF_FIG) and accumulated in mitosis with the same kinetics as their isogenic wildtype counterparts (XREF_FIG).	13	18	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	Wee1	Wee1	Wee1	13	14	17	18
Progression through the cell cycle requires PLK1 mediated degradation of WEE1 , which increases CDK1 activity and promotes M-phase [ XREF_BIBR ] .	Progression through the cell cycle requires PLK1 mediated degradation of WEE1, which increases CDK1 activity and promotes M-phase [XREF_BIBR].	6	17	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	WEE1	WEE1	WEE1	6	7	10	11
Moreover , by promoting Wee1 stabilization , the degradation of Plk1 also induces a direct inhibition of Cdk1 .	Moreover, by promoting Wee1 stabilization, the degradation of Plk1 also induces a direct inhibition of Cdk1.	4	13	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Wee1	Wee1	Wee1	10	11	4	5
Conversely , knockdown of Plk-1 expression diminishes cyclin B-Cdc2 activity and leads to G2/M arrest by increasing the activity of the Wee1 and Myt1 kinases and inhibiting the activity of the Cdc25 phosphatases .	Conversely, knockdown of Plk-1 expression diminishes cyclin B-Cdc2 activity and leads to G2/M arrest by increasing the activity of the Wee1 and Myt1 kinases and inhibiting the activity of the Cdc25 phosphatases.	4	24	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk-1	Plk-1 expression	plk-1	Wee1	Wee1	wee1	4	5	21	22
It also participates in the activation of M-phase promoting factor , CDK1-cyclin B , both by phosphorylating and activating the phosphatase CDC25B and by facilitating PLK1 mediated Wee1 inhibition .	It also participates in the activation of M-phase promoting factor, CDK1-cyclin B, both by phosphorylating and activating the phosphatase CDC25B and by facilitating PLK1 mediated Wee1 inhibition.	25	28	mediated	Positive_early_activation	Negative_activation	Negative_activation	PLK1	PLK1	PLK1	Wee1	Wee1	Wee1	25	26	27	28
Moreover , in the presence of CDDP , Ssd decreases PPM1D level , activates Chk1 and increases phospho-Cdc25c content , resulting in G2/M arrest and apoptosis .	Moreover, in the presence of CDDP, Ssd decreases PPM1D level, activates Chk1 and increases phospho-Cdc25c content, resulting in G2/M arrest and apoptosis.	8	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPM1D	Ssd decreases PPM1D level	ppm1d	Chk1	Chk1	chk1	10	11	14	15
Accordingly , Wip1 overexpression was identified to suppress checkpoint kinase 1 ( CHK1 ) activity , whereas downregulation of Wip1 elevated CHK1 to activate the G 2 / M checkpoint following DNA damage .	Accordingly, Wip1 overexpression was identified to suppress checkpoint kinase 1 (CHK1) activity, whereas downregulation of Wip1 elevated CHK1 to activate the G 2 / M checkpoint following DNA damage.	2	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1 overexpression	wip1	CHK1	CHK1	chk1	2	3	12	13
In our proposed hypothetical model , in chemoresistant cells which often exhibit high incidence of p53 mutation and increased PPM1D stability , which inhibits Chk1 activity , CDDP fails to induce G1/S arrest and Opa1 processing .	In our proposed hypothetical model, in chemoresistant cells which often exhibit high incidence of p53 mutation and increased PPM1D stability, which inhibits Chk1 activity, CDDP fails to induce G1/S arrest and Opa1 processing.	19	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1D	PPM1D	PPM1D	Chk1	Chk1	Chk1	19	20	24	25
reported that overexpression of PGC-1alpha attenuates FOXO activity ; this effect decreased the expression of atrogenes and protected muscles from denervation or starvation induced atrophy .	reported that overexpression of PGC-1alpha attenuates FOXO activity; this effect decreased the expression of atrogenes and protected muscles from denervation or starvation induced atrophy.	2	7	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	overexpression of PGC-1alpha	pgc-1alpha	FOXO	FOXO	foxo	4	5	6	7
These pathways are known to be inhibited in slow-twitch fibers due to the high expression of peroxisome proliferator activated receptor-g coactivator-1 ( PGC1alpha ) , which inactivates FoxO , protecting slow-twitch fibers from atrophy [ XREF_BIBR ] .	These pathways are known to be inhibited in slow-twitch fibers due to the high expression of peroxisome proliferator activated receptor-g coactivator-1 (PGC1alpha), which inactivates FoxO, protecting slow-twitch fibers from atrophy [XREF_BIBR].	20	28	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC1alpha	PGC1alpha	PGC1alpha	FoxO	FoxO	FoxO	22	23	27	28
Conversely , PGC1-alpha protein is recognized to prevent muscle atrophy by masking the effect of FOXO protein on Atrogin-1 [ XREF_BIBR ] .	Conversely, PGC1-alpha protein is recognized to prevent muscle atrophy by masking the effect of FOXO protein on Atrogin-1 [XREF_BIBR].	2	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC1-alpha protein	PGC1-alpha protein	PGC1-alpha protein	FOXO	FOXO	FOXO	2	4	15	16
Thus , the high levels of PGC-1alpha in dark and exercising muscles can explain their resistance to atrophy , and the rapid fall in PGC-1alpha during atrophy should enhance the FoxO dependent loss of muscle mass .	Thus, the high levels of PGC-1alpha in dark and exercising muscles can explain their resistance to atrophy, and the rapid fall in PGC-1alpha during atrophy should enhance the FoxO dependent loss of muscle mass.	22	32	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO	FoxO	FoxO	24	25	30	31
This is important because increased PGC-1alpha expression is known to suppress FoxO activity resulting in reduced expression of FoxO target genes .	This is important because increased PGC-1alpha expression is known to suppress FoxO activity resulting in reduced expression of FoxO target genes.	5	12	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha expression	pgc-1alpha	FoxO	FoxO	foxo	5	6	11	12
also showed reasonable data to suggest that PGC-1alpha inhibits FOXO function .	also showed reasonable data to suggest that PGC-1alpha inhibits FOXO function.	7	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FOXO	FOXO	FOXO	7	8	9	10
The apparent role of PGC1alpha at high expression levels that inhibits FoxO and induces skeletal muscle atrophy in contrast to activation of FoxO that also induces skeletal muscle wasting , underscores an important but poorly understood paradox in that genetic manipulations that result in either enhanced macroautophagy or inhibition of macroautophagy both result in similar skeletal muscle atrophy and wasting phenotypes .	The apparent role of PGC1alpha at high expression levels that inhibits FoxO and induces skeletal muscle atrophy in contrast to activation of FoxO that also induces skeletal muscle wasting, underscores an important but poorly understood paradox in that genetic manipulations that result in either enhanced macroautophagy or inhibition of macroautophagy both result in similar skeletal muscle atrophy and wasting phenotypes.	2	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC1alpha	PGC1alpha	PGC1alpha	FoxO	FoxO	FoxO	4	5	11	12
Following disuse and upon restoration of activity , the increased PGC-1alpha levels and IGF-1 and PI3K-Akt signaling inactivate FoxO leading to decreased expression of atrogenes .	Following disuse and upon restoration of activity, the increased PGC-1alpha levels and IGF-1 and PI3K-Akt signaling inactivate FoxO leading to decreased expression of atrogenes.	10	19	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha levels	pgc-1alpha	FoxO	FoxO	foxo	10	11	18	19
As Ppm1b inhibits IKKbeta in HeLa but not in L929 and HT-29 cells , and Rip3 is expressed in L929 and HT-29 but not in HeLa ( XREF_FIG ) , one would ask whether the presence of Rip3 makes Ppm1b unable to target IKKbeta .	As Ppm1b inhibits IKKbeta in HeLa but not in L929 and HT-29 cells, and Rip3 is expressed in L929 and HT-29 but not in HeLa (XREF_FIG), one would ask whether the presence of Rip3 makes Ppm1b unable to target IKKbeta.	39	44	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ppm1b	Ppm1b	Ppm1b	IKKbeta	IKKbeta	IKKbeta	39	40	43	44
Moreover , PPM1B overexpression can block the activation of the IKKbeta and NF-kappaB pathway induced by TNF-alpha treatment .	Moreover, PPM1B overexpression can block the activation of the IKKbeta and NF-kappaB pathway induced by TNF-alpha treatment.	2	13	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1B	PPM1B overexpression	ppm1b	IKKbeta	IKKbeta	ikkbeta	2	3	10	11
Although several studies have shown that Mg 2+ / Mn 2+ -dependent protein phosphatase 1B ( PPM1B ) inactivated IKKbeta , few studies have investigated the role of PPM1B in denervated skeletal muscle .	Although several studies have shown that Mg 2+ / Mn 2+ -dependent protein phosphatase 1B (PPM1B) inactivated IKKbeta, few studies have investigated the role of PPM1B in denervated skeletal muscle.	6	20	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1B	PPM1B	PPM1B	IKKbeta	IKKbeta	IKKbeta	16	17	19	20
Overexpression of PPM1A inhibits CDK9 but not CDK8 activation of reporter plasmid .	Overexpression of PPM1A inhibits CDK9 but not CDK8 activation of reporter plasmid.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1A	Overexpression of PPM1A	ppm1a	CDK9	CDK9	cdk9	2	3	4	5
Using an artificial CDK tethering system , we further found that PPM1A inhibits CDK9 , but not CDK8 mediated activation of the HIV-1 LTR .	Using an artificial CDK tethering system, we further found that PPM1A inhibits CDK9, but not CDK8 mediated activation of the HIV-1 LTR.	11	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1A	PPM1A	PPM1A	CDK9	CDK9	CDK9	11	12	13	14
These data suggest that PPM1A negatively regulates CDK9 but not CDK8 in vivo .	These data suggest that PPM1A negatively regulates CDK9 but not CDK8 in vivo.	4	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1A	PPM1A	PPM1A	CDK9	CDK9	CDK9	4	5	7	8
Furthermore , utilizing an artificial CDK tethering system [ XREF_BIBR , XREF_BIBR ] , we show that suppression of HIV-1 transcription is due to selective inhibition of CDK9 by PPM1A , as the CDK8 kinase , part of the mediator complex involved in transcriptional initiation [ XREF_BIBR ] , was not inhibited by PPM1A in this system .	Furthermore, utilizing an artificial CDK tethering system [XREF_BIBR, XREF_BIBR], we show that suppression of HIV-1 transcription is due to selective inhibition of CDK9 by PPM1A, as the CDK8 kinase, part of the mediator complex involved in transcriptional initiation [XREF_BIBR], was not inhibited by PPM1A in this system.	22	30	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PPM1A	PPM1A	PPM1A	CDK9	CDK9	CDK9	29	30	27	28
PPM1A also inhibited CDK9 mediated but not CDK8 mediated activation of the HIV LTR in an artificial CDK tethering system .	PPM1A also inhibited CDK9 mediated but not CDK8 mediated activation of the HIV LTR in an artificial CDK tethering system.	0	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1A	PPM1A	PPM1A	CDK9	CDK9	CDK9	0	1	3	4
CAPS , PP1A and PP2A inactivate PKCalpha [ XREF_BIBR ] , and AKT ( or protein kinase B [ PFB ] ) [ XREF_BIBR ] .	CAPS, PP1A and PP2A inactivate PKCalpha [XREF_BIBR], and AKT (or protein kinase B [PFB]) [XREF_BIBR].	0	23	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PP1A	PP1A	PP1A	AKT	AKT	AKT	2	3	12	13
Studies on COS-7 cell cultures have shown that protein phosphatase 2Cdelta ( PP2Cdelta ) decreases the activity of RSK2 following EGF stimulation .	Studies on COS-7 cell cultures have shown that protein phosphatase 2Cdelta (PP2Cdelta) decreases the activity of RSK2 following EGF stimulation.	10	21	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PP2Cdelta	PP2Cdelta	PP2Cdelta	RSK2	RSK2	RSK2	12	13	18	19
Similarly , two phosphatases , POPX1 and POPX2 dephosphorylate and inactivate PAK1 .	Similarly, two phosphatases, POPX1 and POPX2 dephosphorylate and inactivate PAK1.	3	12	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	POPX2	POPX2	POPX2	PAK1	PAK1	PAK1	7	8	11	12
All of these results lead to the conclusion that PPM1A inhibits the TGF-beta-induced the activity of Smad2 , Smad3 and transcriotional responses , whereas depletion of PPM1A enhances the activation of TGF-beta and Smads signaling in BCa cells .	All of these results lead to the conclusion that PPM1A inhibits the TGF-beta-induced the activity of Smad2, Smad3 and transcriotional responses, whereas depletion of PPM1A enhances the activation of TGF-beta and Smads signaling in BCa cells.	9	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPM1A	PPM1A	PPM1A	Smad3	Smad3	Smad3	9	10	18	19
Moreover , phosphate tensin homolog on chromosome 10 depletion in human kidney-2 cells resulted in loss of expression and decreased nuclear levels of PPM1A , which enhanced SMAD3 mediated fibrotic gene induction and growth arrest that were reversed by ectopic PPM1A expression .	Moreover, phosphate tensin homolog on chromosome 10 depletion in human kidney-2 cells resulted in loss of expression and decreased nuclear levels of PPM1A, which enhanced SMAD3 mediated fibrotic gene induction and growth arrest that were reversed by ectopic PPM1A expression.	27	42	reversed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PPM1A	PPM1A expression	ppm1a	SMAD3	SMAD3	smad3	40	41	27	28
PPARgamma agonists downregulate the PI3K and Akt signaling pathway by stimulating PTEN activity in fibrotic process .	PPARgamma agonists downregulate the PI3K and Akt signaling pathway by stimulating PTEN activity in fibrotic process.	0	12	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	0	1	11	12
Activation of the PPARgamma pathway by PPARgamma agonists represses TGF-beta1 mRNA expression via dephosphorylation of zinc finger transcription factor-9 ( Zf9 ) , which has been shown to be caused by p70 ribosomal S6 kinase-1 ( p70S6K ) inhibition due to PPARgamma induced PTEN induction .	Activation of the PPARgamma pathway by PPARgamma agonists represses TGF-beta1 mRNA expression via dephosphorylation of zinc finger transcription factor-9 (Zf9), which has been shown to be caused by p70 ribosomal S6 kinase-1 (p70S6K) inhibition due to PPARgamma induced PTEN induction.	39	44	induced	Positive_early_activation	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	41	42	43	44
Activation of CEBPA expression by CEBPB during adipogenesis requires a PPARG -associated repression of HDAC1 at the CEBPA gene promoter , though they mutually promote the expression of each other thereafter [ XREF_BIBR ] .	Activation of CEBPA expression by CEBPB during adipogenesis requires a PPARG -associated repression of HDAC1 at the CEBPA gene promoter, though they mutually promote the expression of each other thereafter [XREF_BIBR].	10	15	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PPARG	PPARG	PPARG	HDAC1	HDAC1	HDAC1	10	11	14	15
In addition , the finding that simultaneous mutations in the prolyl and Plk3 targeting phosphorylation sites ( P402A , P564A , S576A , and S657A ) further increased the levels of HIF-1alpha strongly suggested that Plk3 decreases HIF-1alpha stability in a PHD independent way .	In addition, the finding that simultaneous mutations in the prolyl and Plk3 targeting phosphorylation sites (P402A, P564A, S576A, and S657A) further increased the levels of HIF-1alpha strongly suggested that Plk3 decreases HIF-1alpha stability in a PHD independent way.	35	38	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk3	Plk3	Plk3	HIF-1alpha	HIF-1alpha	HIF-1alpha	35	36	37	38
Our recent studies indicate that PP2Cepsilon , a member of the PP2C family , associates with and inactivates ASK1 by dephosphorylating T845 .	Our recent studies indicate that PP2Cepsilon, a member of the PP2C family, associates with and inactivates ASK1 by dephosphorylating T845.	5	19	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PP2Cepsilon	PP2Cepsilon	PP2Cepsilon	ASK1	ASK1	ASK1	5	6	18	19
It also appears to be distinct from the recently described Plk2 mediated degradation of Fbw7 , which requires phosphorylation of a residue in the common region to trigger degradation XREF_BIBR .	It also appears to be distinct from the recently described Plk2 mediated degradation of Fbw7, which requires phosphorylation of a residue in the common region to trigger degradation XREF_BIBR.	5	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk2	Plk2	Plk2	Fbw7	Fbw7	Fbw7	10	11	14	15
In the absence of PML , PP2a can not inhibit Akt , with a consequent increase in IP3R phosphorylation , limited Ca 2+ release , and protection from apoptosis [ XREF_BIBR ] ( see also below , PP2a section ) .	In the absence of PML, PP2a can not inhibit Akt, with a consequent increase in IP3R phosphorylation, limited Ca 2+ release, and protection from apoptosis [XREF_BIBR] (see also below, PP2a section).	6	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PP2a	PP2a	PP2a	Akt	Akt	Akt	6	7	10	11
In contrast , Ppp2ca overexpression in WT keratinocytes suppressed IKKbeta and p65 activation .	In contrast, Ppp2ca overexpression in WT keratinocytes suppressed IKKbeta and p65 activation.	3	12	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ppp2ca	Ppp2ca overexpression	ppp2ca	p65	p65	p65	3	4	11	12
Ppp2ca knockdown restored the impaired TNF-alpha-induced p65 activation in AQP3 knockdown cells ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Ppp2ca knockdown restored the impaired TNF-alpha-induced p65 activation in AQP3 knockdown cells (XREF_FIG, XREF_SUPPLEMENTARY).	0	7	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ppp2ca	Ppp2ca	Ppp2ca	p65	p65	p65	0	1	6	7
Ppp2ca knockdown in AQP3 -/- keratinocytes rescued the reduced IKKbeta and p65 activation , while Ppp2ca knockdown in WT cells abrogated the effect of catalase on TNF-alpha-induced NF-kappaB activation .	Ppp2ca knockdown in AQP3 -/- keratinocytes rescued the reduced IKKbeta and p65 activation, while Ppp2ca knockdown in WT cells abrogated the effect of catalase on TNF-alpha-induced NF-kappaB activation.	0	12	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ppp2ca	Ppp2ca	Ppp2ca	p65	p65	p65	0	1	11	12
3.10 Selective PRCP deletion in AgRP neurons increases alpha-MSH immunoreactivity in the paraventricular nucleus of the hypothalamus .	3.10 Selective PRCP deletion in AgRP neurons increases alpha-MSH immunoreactivity in the paraventricular nucleus of the hypothalamus.	2	9	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	2	3	8	9
Once released from the Hcrt and/or MCH terminals in the PVN , PRCP will degrade alpha -MSH 1-13 extracellularly ( XREF_FIG ) thus increasing the antagonist effect of AgRP , while in the DMH , PRCP will degrade alpha-MSH intracellularly thus shortening the effect of alpha -MSH on MC4R and enhancing the overall orexigenic tone of the melanocortin system ( XREF_FIG ) .	Once released from the Hcrt and/or MCH terminals in the PVN, PRCP will degrade alpha -MSH 1-13 extracellularly (XREF_FIG) thus increasing the antagonist effect of AgRP, while in the DMH, PRCP will degrade alpha-MSH intracellularly thus shortening the effect of alpha -MSH on MC4R and enhancing the overall orexigenic tone of the melanocortin system (XREF_FIG).	35	39	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	35	36	38	39
Recently Wallingford and colleagues have identified an enzyme , prolylcarboxypeptidase ( PRCP ) , that inactivates alpha-MSH by removing the C-terminal valine residue .	Recently Wallingford and colleagues have identified an enzyme, prolylcarboxypeptidase (PRCP), that inactivates alpha-MSH by removing the C-terminal valine residue.	9	17	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	11	12	16	17
So , PRCP may be poised in the synaptic space to degrade alpha-MSH 1-13 thereby reducing its action and promoting satiety .	So, PRCP may be poised in the synaptic space to degrade alpha-MSH 1-13 thereby reducing its action and promoting satiety.	2	19	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	2	3	12	13
This suggests that PRCP is an endogenous inactivator of alpha-MSH and an appetite stimulant .	This suggests that PRCP is an endogenous inactivator of alpha-MSH and an appetite stimulant.	3	13	is an endogenous inactivator	Positive_activation_copula_1	Negative_activation	Positive_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	3	4	9	10
The serine protease prolylcarboxypeptidase ( PRCP ) inactivates alpha-MSH by catalyzing cleavage at the carboxyl terminal Pro Val bond , producing inactive alpha-MSH 1-12 .	The serine protease prolylcarboxypeptidase (PRCP) inactivates alpha-MSH by catalyzing cleavage at the carboxyl terminal Pro Val bond, producing inactive alpha-MSH 1-12.	3	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	5	6	8	9
The molecular mechanisms underlying the suppression of food intake in PRCP deficient mice or by the inhibitor of PRCP clearly provide physiological evidence that PRCP is an inactivator of alpha-MSH .	The molecular mechanisms underlying the suppression of food intake in PRCP deficient mice or by the inhibitor of PRCP clearly provide physiological evidence that PRCP is an inactivator of alpha-MSH.	24	30	is an inactivator	Positive_activation_copula_1	Negative_activation	Positive_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	24	25	29	30
Taken together , these results demonstrate that B55alpha ( PPP2R2A ) induced by Pitx2 inhibited the Akt pathway , which may be responsible for suppressing PDAC cell invasion .	Taken together, these results demonstrate that B55alpha (PPP2R2A) induced by Pitx2 inhibited the Akt pathway, which may be responsible for suppressing PDAC cell invasion.	7	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPP2R2A	PPP2R2A	PPP2R2A	Akt	Akt	Akt	9	10	16	17
And Pitx2 protein promotes PPP2R2A expression which may inhibit Akt pathway .	And Pitx2 protein promotes PPP2R2A expression which may inhibit Akt pathway.	1	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPP2R2A	Pitx2 protein promotes PPP2R2A expression	ppp2r2a	Akt	Akt	akt	4	5	9	10
To determine whether PPP2R2A expression inhibited Akt in PDAC , lentivirus mediated PPP2R2A-overexpression vector or the control was stably transduced into Panc-1 and Miacapa-2 cells .	To determine whether PPP2R2A expression inhibited Akt in PDAC, lentivirus mediated PPP2R2A-overexpression vector or the control was stably transduced into Panc-1 and Miacapa-2 cells.	3	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPP2R2A	PPP2R2A expression	ppp2r2a	Akt	Akt	akt	3	4	6	7
However , PPP2R2C has been shown to negatively regulate the activity of the SRC oncogene in osteosarcoma cells .	However, PPP2R2C has been shown to negatively regulate the activity of the SRC oncogene in osteosarcoma cells.	2	14	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPP2R2C	PPP2R2C	PPP2R2C	SRC	SRC	SRC	2	3	13	14
Previous experimentation in non epithelial cancer models indicate that PPP2R2C may negatively regulate the activity of the v-src sarcoma viral oncogene homolog SRC .	Previous experimentation in non epithelial cancer models indicate that PPP2R2C may negatively regulate the activity of the v-src sarcoma viral oncogene homolog SRC.	9	23	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPP2R2C	PPP2R2C	PPP2R2C	SRC	SRC	SRC	9	10	22	23
Loss of PPP2R2B results in aberrant activation of PDK1 , a master kinase often linked to AKT activation .	Loss of PPP2R2B results in aberrant activation of PDK1, a master kinase often linked to AKT activation.	0	12	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PPP2R2B	Loss of PPP2R2B	ppp2r2b	PDK1	PDK1	pdk1	2	3	8	9
XREF_FIG also shows the shortest path between D-glucose and Ppp2r5b , which directly inhibits AKT via dephosphorylation .	XREF_FIG also shows the shortest path between D-glucose and Ppp2r5b, which directly inhibits AKT via dephosphorylation.	5	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ppp2r5b	Ppp2r5b	Ppp2r5b	AKT	AKT	AKT	9	10	14	15
Very recently it has been reported that in primary mouse adipocytes , PKA associates with and phosphorylates AMPKalpha1 at Ser173 to restrict Thr172 phosphorylation and thus activation of AMPKalpha1 by LKB1 kinase in response to lipolytic signals 63 .	Very recently it has been reported that in primary mouse adipocytes, PKA associates with and phosphorylates AMPKalpha1 at Ser173 to restrict Thr172 phosphorylation and thus activation of AMPKalpha1 by LKB1 kinase in response to lipolytic signals 63.	16	29	activation	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	AMPKalpha1	phosphorylates AMPKalpha1 at Ser173 to restrict Thr172	ampkalpha1	AMPKalpha1	AMPKalpha1	ampkalpha1	17	18	28	29
However , AMPKalpha1 deletion significantly induced ( P < 0.001 ) the iNOS level ( XREF_FIG ) and gene expression ( XREF_FIG ) in unstimulated Abcd1-KO mixed glial cells .	However, AMPKalpha1 deletion significantly induced (P < 0.001) the iNOS level (XREF_FIG) and gene expression (XREF_FIG) in unstimulated Abcd1-KO mixed glial cells.	2	25	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AMPKalpha1	AMPKalpha1	AMPKalpha1	iNOS	iNOS	iNOS	2	3	12	13
Inhibition of PKC-beta with 100 nM ruboxistaurin prevented eNOS suppression in high-glucose media .	Inhibition of PKC-beta with 100 nM ruboxistaurin prevented eNOS suppression in high-glucose media.	0	9	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKC-beta	PKC-beta	PKC-beta	eNOS	eNOS	eNOS	2	3	8	9
This upregulation of PKCb II actually inhibits Akt and downregulates eNOS .	This upregulation of PKCb II actually inhibits Akt and downregulates eNOS.	1	11	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKCb	PKCb	PKCb	eNOS	eNOS	eNOS	3	4	10	11
Hyperglycemia increases DAG activates PKC-beta and -delta , which can decrease eNOS , increase ET-1 , and effect blood flow .	Hyperglycemia increases DAG activates PKC-beta and -delta, which can decrease eNOS, increase ET-1, and effect blood flow.	3	19	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKC-beta	PKC-beta	PKC-beta	eNOS	eNOS	eNOS	4	5	11	12
Collectively , our findings support the concept that PKCbeta activity impedes regulation of eNOS activation in diabetes .	Collectively, our findings support the concept that PKCbeta activity impedes regulation of eNOS activation in diabetes.	8	14	impedes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKCbeta	PKCbeta	PKCbeta	eNOS	eNOS	eNOS	8	9	13	14
Thus , activation of PKCbeta in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF , inhibits Akt dependent eNOS regulation by insulin , and causes endothelial dysfunction in obesity associated insulin resistance .	Thus, activation of PKCbeta in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF, inhibits Akt dependent eNOS regulation by insulin, and causes endothelial dysfunction in obesity associated insulin resistance.	2	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKCbeta	PKCbeta	PKCbeta	eNOS	eNOS	eNOS	4	5	22	23
Thus , we speculate that even without overexpression of PKCbeta , the activation of endogenous PKCbeta will also inhibit insulin activation of phospho-Akt and eNOS and the loss of inhibition of VCAM-1 .	Thus, we speculate that even without overexpression of PKCbeta, the activation of endogenous PKCbeta will also inhibit insulin activation of phospho-Akt and eNOS and the loss of inhibition of VCAM-1.	12	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKCbeta	PKCbeta	PKCbeta	eNOS	eNOS	eNOS	15	16	24	25
24 Ruboxistaurin ( RBX ) , a PKCb II inhibitor , is undergoing clinical trials evaluating its ability to normalize eNOS function that has been decreased by glucose induced PKCb II activation .	24 Ruboxistaurin (RBX), a PKCb II inhibitor, is undergoing clinical trials evaluating its ability to normalize eNOS function that has been decreased by glucose induced PKCb II activation.	20	30	decreased	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PKCb	glucose induced PKCb	pkcb	eNOS	eNOS	enos	29	30	20	21
Ruboxistaurin , a specific inhibitor of PKC-beta , however , can increase active Akt , eNOS , and GSK3 in diabetic and obese rats to almost normal levels after insulin , suggesting that PKC-beta may be responsible for the abnormal molecular signaling in insulin resistance .	Ruboxistaurin, a specific inhibitor of PKC-beta, however, can increase active Akt, eNOS, and GSK3 in diabetic and obese rats to almost normal levels after insulin, suggesting that PKC-beta may be responsible for the abnormal molecular signaling in insulin resistance.	4	16	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PKC-beta	PKC-beta	PKC-beta	eNOS	eNOS	eNOS	6	7	15	16
The reduced PKCbeta expression impairs eNOS activation , which can be reversed by a PKCbeta specific synthetic inhibitor , LY379196 [ XREF_BIBR ] .	The reduced PKCbeta expression impairs eNOS activation, which can be reversed by a PKCbeta specific synthetic inhibitor, LY379196 [XREF_BIBR].	5	15	reversed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PKCbeta	PKCbeta	PKCbeta	eNOS	eNOS	eNOS	14	15	5	6
The data indicate that TNF induces endothelial activation that is modulated by a PKCalpha dependent inhibition of GSK3beta .	The data indicate that TNF induces endothelial activation that is modulated by a PKCalpha dependent inhibition of GSK3beta.	13	18	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKCalpha	PKCalpha	PKCalpha	GSK3beta	GSK3beta	GSK3beta	13	14	17	18
Taken together , these results suggest that neuronal differentiation is dependent on calcineurin mediated activation of nNOS ; this induces PKCalpha dependent inactivation of GSK3beta , which leads to inhibition of the proliferation of hippocampal NPCs .	Taken together, these results suggest that neuronal differentiation is dependent on calcineurin mediated activation of nNOS; this induces PKCalpha dependent inactivation of GSK3beta, which leads to inhibition of the proliferation of hippocampal NPCs.	20	27	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PKCalpha	PKCalpha	PKCalpha	GSK3beta	GSK3beta	GSK3beta	20	21	24	25
However , the expression of DN-PKC-alpha prevented the translocation of MARCKs from membrane to cytosol in WT P. aeruginosa infected cells suggesting that activation of PKC is necessary for this translocation .	However, the expression of DN-PKC-alpha prevented the translocation of MARCKs from membrane to cytosol in WT P. aeruginosa infected cells suggesting that activation of PKC is necessary for this translocation.	3	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DN-PKC-alpha	expression of DN-PKC-alpha	dn-pkc-alpha	MARCKs	MARCKs	marcks	5	6	10	11
In B cells , a signaling link between PKCbeta and BTK has been described ; PKCbeta can downregulate BTK function through the direct phosphorylation of BTK at Ser 180 , inhibiting its membrane translocation and subsequent activation .	In B cells, a signaling link between PKCbeta and BTK has been described; PKCbeta can downregulate BTK function through the direct phosphorylation of BTK at Ser 180, inhibiting its membrane translocation and subsequent activation.	15	19	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKCbeta	PKCbeta	PKCbeta	BTK	BTK	BTK	15	16	18	19
In B cells , Btk membrane localization is negatively regulated by PKCbeta , which is itself activated by PLCgamma-2-mediated increases in DAG and Ca 2+ .	In B cells, Btk membrane localization is negatively regulated by PKCbeta, which is itself activated by PLCgamma-2-mediated increases in DAG and Ca 2+.	4	16	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PKCbeta	PKCbeta	PKCbeta	Btk	Btk	Btk	11	12	4	5
Moreover , caspase-3 activates PKCdelta and activated PKCdelta further activates caspase-3 XREF_BIBR , and proteolytically activated PKCdelta down-regulates hnRNP K protein in a proteasome dependent manner XREF_BIBR .	Moreover, caspase-3 activates PKCdelta and activated PKCdelta further activates caspase-3 XREF_BIBR, and proteolytically activated PKCdelta down-regulates hnRNP K protein in a proteasome dependent manner XREF_BIBR.	15	20	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKCdelta	PKCdelta	PKCdelta	hnRNP K	hnRNP K	hnRNP K	16	17	18	20
Overexpression of PKCgamma enhanced green fluorescent protein ( EGFP ) increased the interaction of PKCgamma-EGFP with Cav-1 and Cx43 and decreased gap junction Cx43 plaques without exogenous growth factors .	Overexpression of PKCgamma enhanced green fluorescent protein (EGFP) increased the interaction of PKCgamma-EGFP with Cav-1 and Cx43 and decreased gap junction Cx43 plaques without exogenous growth factors.	0	24	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PKCgamma	Overexpression of PKCgamma	pkcgamma	Cx43	Cx43	cx43	2	3	23	24
On inhibition of CaM , PKCdelta promotes the formation of enlarged early endosomes and blocks EGFR recycling and degradation .	On inhibition of CaM, PKCdelta promotes the formation of enlarged early endosomes and blocks EGFR recycling and degradation.	5	16	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKCdelta	PKCdelta	PKCdelta	EGFR	EGFR	EGFR	5	6	15	16
Treatment of T-ALL with the glucocorticoid dexamethasone often leads to acquired drug resistance in patients , which can be partly attributed to PTEN loss and activation of the Akt pathway .	Treatment of T-ALL with the glucocorticoid dexamethasone often leads to acquired drug resistance in patients, which can be partly attributed to PTEN loss and activation of the Akt pathway.	22	29	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	22	23	28	29
Previous reports showed that PTEN was a direct target of miR-19a and loss of PTEN could activate PI3K and Akt pathway which can elevate MDR-1 XREF_BIBR , MRP1 XREF_BIBR and BCRP XREF_BIBR .	Previous reports showed that PTEN was a direct target of miR-19a and loss of PTEN could activate PI3K and Akt pathway which can elevate MDR-1 XREF_BIBR, MRP1 XREF_BIBR and BCRP XREF_BIBR.	12	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	14	15	19	20
Reduced PTEN leads to accumulation of phosphatidylinositol-3 ,4,5-trisphosphate and then activates the Akt signaling pathway.6 Collectively , our results indicated that the oncogenic property of GATAD1 in HCC is , at least in part , dependent on the transcriptional induction of PRL3 , which reduces the Akt negative regulator PTEN by dephosphorylation of PTEN at the tyrosine site and consequently activates the Akt signaling pathway .	Reduced PTEN leads to accumulation of phosphatidylinositol-3,4,5-trisphosphate and then activates the Akt signaling pathway.6 Collectively, our results indicated that the oncogenic property of GATAD1 in HCC is, at least in part, dependent on the transcriptional induction of PRL3, which reduces the Akt negative regulator PTEN by dephosphorylation of PTEN at the tyrosine site and consequently activates the Akt signaling pathway.	0	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	12	13
In addition , up-regulation of Ataxin-3 inhibited the expression of PTEN and activated the AKT and mTOR pathway .	In addition, up-regulation of Ataxin-3 inhibited the expression of PTEN and activated the AKT and mTOR pathway.	5	17	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Ataxin-3 inhibited the expression of PTEN	pten	AKT	AKT	akt	10	11	14	15
As a serine threonine phosphatase , PTEN inhibits the activation of PI3K and suppresses the PI3K-Akt pathway signal transmission mediated by CK2 .	As a serine threonine phosphatase, PTEN inhibits the activation of PI3K and suppresses the PI3K-Akt pathway signal transmission mediated by CK2.	6	18	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	6	7	15	16
It has been well established that PTEN negatively regulates Akt activation in various types of cells including immune cells .	It has been well established that PTEN negatively regulates Akt activation in various types of cells including immune cells.	6	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	9	10
Interestingly , PTEN and E2F3 were downregulated after transfection with the miR-26a mimetic ; PTEN is one of the most commonly mutated tumor suppressors in cancer and has been shown to negatively regulate the AKT and PKB signaling pathway , favoring tumor development and progression .	Interestingly, PTEN and E2F3 were downregulated after transfection with the miR-26a mimetic; PTEN is one of the most commonly mutated tumor suppressors in cancer and has been shown to negatively regulate the AKT and PKB signaling pathway, favoring tumor development and progression.	14	38	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	34	35
TKI TKI inhibits the activation of PI3K , and PTEN inhibits the activation of AKT .	TKI TKI inhibits the activation of PI3K, and PTEN inhibits the activation of AKT.	9	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	14	15
Conversely , PTEN suppresses the activation of the PI3K and Akt pathway and loss of PTEN activity results in increased Akt activity and resistance to trastuzumab .	Conversely, PTEN suppresses the activation of the PI3K and Akt pathway and loss of PTEN activity results in increased Akt activity and resistance to trastuzumab.	2	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	10	11
Restoration of PTEN expression suppressed IGF-I-induced Akt activity , suggesting that loss of PTEN is responsible for uncontrolled Akt activity in MM lines [ XREF_BIBR ] .	Restoration of PTEN expression suppressed IGF-I-induced Akt activity, suggesting that loss of PTEN is responsible for uncontrolled Akt activity in MM lines [XREF_BIBR].	2	7	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	2	3	6	7
It has been widely known that PTEN negatively regulated the activity of PI3K and Akt pathway .	It has been widely known that PTEN negatively regulated the activity of PI3K and Akt pathway.	6	15	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	14	15
The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers , particularly in more advanced cancers , suggesting that the AKT and protein kinase B ( PKB ) kinase , which is negatively regulated by PTEN , may be involved in human prostate cancer progression .	The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT and protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer progression.	21	38	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	37	38	22	23
In summary , we demonstrated that PTEN loss or activation of AKT promotes IAS and this process is mediated by hyperactivation of RUNX2 and its downstream OCN-GPRC6A-CREB signaling cascade and increased expression of steroid biosynthesis enzyme genes CYP11A1 and CYP17A1 .	In summary, we demonstrated that PTEN loss or activation of AKT promotes IAS and this process is mediated by hyperactivation of RUNX2 and its downstream OCN-GPRC6A-CREB signaling cascade and increased expression of steroid biosynthesis enzyme genes CYP11A1 and CYP17A1.	6	12	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	11	12
XREF_BIBR - XREF_BIBR MiR-21 was shown to regulate the function of several tumor suppressor genes , including PTEN , a phosphatase and tensin homolog gene that negatively regulates the PIK3 and Akt survival pathway .	XREF_BIBR - XREF_BIBR MiR-21 was shown to regulate the function of several tumor suppressor genes, including PTEN, a phosphatase and tensin homolog gene that negatively regulates the PIK3 and Akt survival pathway.	17	33	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	20	24	31	32
PTEN status is inversely correlated with activation of the oncogenic PI3K and protein kinase B ( AKT ) pathway in diffuse large B-cell lymphoma cell lines and patient samples , whereas overexpression of PTEN induced cytotoxicity in PTEN deficient cell lines by inhibiting PI3K and AKT signaling [ XREF_BIBR ] .	PTEN status is inversely correlated with activation of the oncogenic PI3K and protein kinase B (AKT) pathway in diffuse large B-cell lymphoma cell lines and patient samples, whereas overexpression of PTEN induced cytotoxicity in PTEN deficient cell lines by inhibiting PI3K and AKT signaling [XREF_BIBR].	31	48	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	overexpression of PTEN	pten	AKT	AKT	akt	33	34	45	46
Similar effects were observed in NPC and exacerbated with PTEN ( negative modulator of the PI3K and Akt pathway ) deficiency , background associated with autism like behavior , schizophrenia , and epilepsy .	Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K and Akt pathway) deficiency, background associated with autism like behavior, schizophrenia, and epilepsy.	7	18	modulator	Positive_activation_syntax_7_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	17	18
The loss of the tumour suppressor gene PTEN on chromosome 10 , which normally represses Akt activation , is also typically observed .	The loss of the tumour suppressor gene PTEN on chromosome 10, which normally represses Akt activation, is also typically observed.	1	16	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	loss of the tumour suppressor gene PTEN	pten	Akt	Akt	akt	7	8	15	16
As AKT is commonly activated by PTEN loss , we evaluated the role of Pten in responsiveness to 1,25 ( OH ) 2 D 3 using shRNA knockdown and by in vitro knockout of Pten .	As AKT is commonly activated by PTEN loss, we evaluated the role of Pten in responsiveness to 1,25 (OH) 2 D 3 using shRNA knockdown and by in vitro knockout of Pten.	1	7	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	1	2
It has been well documented that PTEN functions upstream of Akt , and negatively regulates Akt activity XREF_BIBR , XREF_BIBR .	It has been well documented that PTEN functions upstream of Akt, and negatively regulates Akt activity XREF_BIBR, XREF_BIBR.	6	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	15	16
The ectopic expression of the protein-phosphatase proficient PTEN is sufficient to limit the activation of AKT in OVCAR-3 cells .	The ectopic expression of the protein-phosphatase proficient PTEN is sufficient to limit the activation of AKT in OVCAR-3 cells.	2	16	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of the protein-phosphatase proficient PTEN	pten	AKT	AKT	akt	7	8	15	16
Since PIP 3 is required for the activation of 3-phosphoinositide-dependent protein kinase-1 ( PDK1 ) , and this kinase in turn phosphorylates and activates Akt , PTEN essentially suppresses Akt activity .	Since PIP 3 is required for the activation of 3-phosphoinositide-dependent protein kinase-1 (PDK1), and this kinase in turn phosphorylates and activates Akt, PTEN essentially suppresses Akt activity.	26	30	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	26	27	29	30
Reduced levels of PTEN enhance PI3K-AKT signaling which is an essential mediator of TGF-beta1-induced type II endometrial cancer cell migration .	Reduced levels of PTEN enhance PI3K-AKT signaling which is an essential mediator of TGF-beta1-induced type II endometrial cancer cell migration.	1	6	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	levels of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	3	4	5	6
Since the loss of PTEN results in activation of Akt , that in turn up-regulates mTOR activity , cancer cells deficient in PTEN are thought to be major targets of mTOR inhibitors .	Since the loss of PTEN results in activation of Akt, that in turn up-regulates mTOR activity, cancer cells deficient in PTEN are thought to be major targets of mTOR inhibitors.	2	14	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	4	5	9	10
This implication is supported by the observation that ectopic expression of dN-Hes1 slightly increased Pten expression and reduced AKT activity in PB-NICD luminal sphere cells ( XREF_FIG ) .	This implication is supported by the observation that ectopic expression of dN-Hes1 slightly increased Pten expression and reduced AKT activity in PB-NICD luminal sphere cells (XREF_FIG).	9	19	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	expression of dN-Hes1 slightly increased Pten expression	pten	AKT	AKT	akt	14	15	18	19
Since PTEN loss activates AKT , AKT inhibitors could also be tested for their efficacy in inhibiting HCC development in this model .	Since PTEN loss activates AKT, AKT inhibitors could also be tested for their efficacy in inhibiting HCC development in this model.	1	5	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	4	5
Loss of PTEN and coordinate activation of Akt is correlated with increased proliferative index of primary human medulloblastoma tumors [ XREF_BIBR , XREF_BIBR ] .	Loss of PTEN and coordinate activation of Akt is correlated with increased proliferative index of primary human medulloblastoma tumors [XREF_BIBR, XREF_BIBR].	2	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	7	8
Among various mechanisms mutation and deletion or malfunctioning of the tumor suppressor protein PTEN activates Akt by constitutively increasing the levels of PI 3 kinase product PIP 3 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Among various mechanisms mutation and deletion or malfunctioning of the tumor suppressor protein PTEN activates Akt by constitutively increasing the levels of PI 3 kinase product PIP 3 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	16	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	15	16
We investigated Akt activity to determine the mechanisms of the Pten loss induced spiral ganglion neuronal phenotype , as it is well known that PTEN loss promotes Akt signaling pathway activity .	We investigated Akt activity to determine the mechanisms of the Pten loss induced spiral ganglion neuronal phenotype, as it is well known that PTEN loss promotes Akt signaling pathway activity.	24	30	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	24	25	27	28
Further investigation revealed that loss of PTEN activated Akt and HDM2 and promoted degradation of p53 , which attributes to resistance of CCRCC cell apoptosis induced by etoposide .	Further investigation revealed that loss of PTEN activated Akt and HDM2 and promoted degradation of p53, which attributes to resistance of CCRCC cell apoptosis induced by etoposide.	4	10	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	6	7	8	9
By converting PIP3 into phosphatidylinositol 4,5-bisphosphate ( PIP2 ) , PTEN negatively regulates PI3K-AKT signaling and subsequent downstream pathways : ( i ) apoptosis ; ( ii ) protein synthesis ; ( iii ) metabolism ; ( iv ) cell cycle ; ( v ) proliferation ; ( vi ) invasion ; ( vii ) metastasis ; ( viii ) angiogenesis , and overall survival .	By converting PIP3 into phosphatidylinositol 4,5-bisphosphate (PIP2), PTEN negatively regulates PI3K-AKT signaling and subsequent downstream pathways : (i) apoptosis; (ii) protein synthesis; (iii) metabolism; (iv) cell cycle; (v) proliferation; (vi) invasion; (vii) metastasis; (viii) angiogenesis, and overall survival.	10	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	10	11	13	14
PTEN antagonizes the effects of the PI3K and AKT pathway on TORC1 and thus , positively regulates autophagy .	PTEN antagonizes the effects of the PI3K and AKT pathway on TORC1 and thus, positively regulates autophagy.	0	16	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
Pten negatively regulates the Akt activity by converting PIP3 to phosphatidylinositol 4,5-bisphosphate ( PIP2 ) , thus functioning as the suppressor of the PI3K and Akt pathway [ XREF_BIBR ] .	Pten negatively regulates the Akt activity by converting PIP3 to phosphatidylinositol 4,5-bisphosphate (PIP2), thus functioning as the suppressor of the PI3K and Akt pathway [XREF_BIBR].	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	0	1	4	5
Decrease in PTEN expression , thus , causes an aberrant activation of Akt and resistance of the tumor cells to chemotherapy , such as cisplatin treatment [ XREF_BIBR ] .	Decrease in PTEN expression, thus, causes an aberrant activation of Akt and resistance of the tumor cells to chemotherapy, such as cisplatin treatment [XREF_BIBR].	2	14	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	2	3	12	13
PTEN negatively regulates Akt activation through its ability to dephosphorylate the 3-position phosphate from phosphatidylinositol ( 3,4,5 ) trisphosphate ( PIP 3 ) to produce phosphatidylinositol ( 4,5 ) bisphosphate ( PIP 2 ) .	PTEN negatively regulates Akt activation through its ability to dephosphorylate the 3-position phosphate from phosphatidylinositol (3,4,5) trisphosphate (PIP 3) to produce phosphatidylinositol (4,5) bisphosphate (PIP 2).	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
Mechanistically , the testis of PRL1 +/- / PRL2 -/- mice has the highest level of PTEN , leading to attenuated Akt activation and increased germ cell apoptosis .	Mechanistically, the testis of PRL1 +/- / PRL2 -/- mice has the highest level of PTEN, leading to attenuated Akt activation and increased germ cell apoptosis.	14	22	leading	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	level of PTEN	pten	Akt	Akt	akt	16	17	21	22
Moreover , co-transfection of miR-32-5p mimics with PTEN expressing vector rescued the PTEN expression and inhibited the activation of the PI3K and Akt pathway caused by the miR-32-5p mimics , but co-transfection of miR-32-5p inhibitor and siPTEN reverses the effects caused by the inhibitor .	Moreover, co-transfection of miR-32-5p mimics with PTEN expressing vector rescued the PTEN expression and inhibited the activation of the PI3K and Akt pathway caused by the miR-32-5p mimics, but co-transfection of miR-32-5p inhibitor and siPTEN reverses the effects caused by the inhibitor.	4	23	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	miR-32-5p mimics with PTEN expressing vector rescued the PTEN expression	pten	Akt	Akt	akt	12	13	22	23
Deletion of PTEN results in activation of Akt , TSC and mTOR and S6K signaling activation that results in feedback inhibition of IRS and Akt signaling [ XREF_BIBR - XREF_BIBR ] .	Deletion of PTEN results in activation of Akt, TSC and mTOR and S6K signaling activation that results in feedback inhibition of IRS and Akt signaling [XREF_BIBR - XREF_BIBR].	0	11	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	7	8
Our microarray data demonstrate that AKT alteration is caused by inhibition of PTEN in Plac1 overexpressing cells .	Our microarray data demonstrate that AKT alteration is caused by inhibition of PTEN in Plac1 overexpressing cells.	5	13	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	12	13	5	6
Taken together , miR-21 inhibited PTEN expression , which in turn decreased AKT and ERK activation for inhibiting HIF-1alpha and VEGF expression , thus inducing tumor angiogenesis .	Taken together, miR-21 inhibited PTEN expression, which in turn decreased AKT and ERK activation for inhibiting HIF-1alpha and VEGF expression, thus inducing tumor angiogenesis.	3	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	miR-21 inhibited PTEN expression	pten	AKT	AKT	akt	5	6	12	13
Treatment of pten dko embryos with the PI3K inhibitor LY294002 reduced the pAKT and AKT ratio by about one-half and partially rescued the defect in vasculogenesis .	Treatment of pten dko embryos with the PI3K inhibitor LY294002 reduced the pAKT and AKT ratio by about one-half and partially rescued the defect in vasculogenesis.	2	15	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pten	pten	pten	AKT	AKT	AKT	2	3	14	15
PTEN inhibits AKT activation and works as a tumour suppressor ( Testa and Bellacosa , 2001 ) .	PTEN inhibits AKT activation and works as a tumour suppressor (Testa and Bellacosa, 2001).	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	2	3
In that context , GCC signaling increases PTEN expression inhibiting AKT activity ( unpublished data ) .	In that context, GCC signaling increases PTEN expression inhibiting AKT activity (unpublished data).	7	11	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	7	8	10	11
PTEN can negatively regulate the PI3K and Akt signal pathway mediating cell survival by promoting reproduction of cells and inhibiting apoptosis .	PTEN can negatively regulate the PI3K and Akt signal pathway mediating cell survival by promoting reproduction of cells and inhibiting apoptosis.	0	9	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	7	8
These studies confirm that HER2 overexpressing cells induce the PI3K pathway in addition to PI3K independent pathways and that PTEN loss cooperates with HER2 to maximally activate AKT .	These studies confirm that HER2 overexpressing cells induce the PI3K pathway in addition to PI3K independent pathways and that PTEN loss cooperates with HER2 to maximally activate AKT.	19	28	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	19	20	27	28
22 PTEN inhibits PI3K and AKT signaling .	22 PTEN inhibits PI3K and AKT signaling.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	5	6
Because NHERF1 associates with PTEN , these results suggested that PTEN is fully active at the PM to suppress Akt only in LN229 cells that express membrane NHERF1 .	Because NHERF1 associates with PTEN, these results suggested that PTEN is fully active at the PM to suppress Akt only in LN229 cells that express membrane NHERF1.	10	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	19	20
Additional studies have demonstrated that loss of PTEN in melanoma promotes activation of the PI3K-AKT pathway , tumor invasiveness , and resistance to cell killing by BRAF and MEK inhibitors .	Additional studies have demonstrated that loss of PTEN in melanoma promotes activation of the PI3K-AKT pathway, tumor invasiveness, and resistance to cell killing by BRAF and MEK inhibitors.	5	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	7	8	14	15
AKT activity is antagonized by the gene product PTEN ( phosphatase and tensin homolog deleted on chromosome 10 ) through the degradation of PIP2 and PIP3 .	AKT activity is antagonized by the gene product PTEN (phosphatase and tensin homolog deleted on chromosome 10) through the degradation of PIP2 and PIP3.	0	13	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	0	1
PTEN is a negative modulator of the Akt signaling pathway , and inhibition of PTEN by a small-molecule inhibitor could significantly activate Akt .	PTEN is a negative modulator of the Akt signaling pathway, and inhibition of PTEN by a small-molecule inhibitor could significantly activate Akt.	12	23	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	22	23
PTEN and LKB1 loss synergistically enhances the activation of AKT and mTOR pathway , promotes the proliferation of pNET cell lines and confers the attenuated sensitivity of pNET cells to mTOR inhibitors .	PTEN and LKB1 loss synergistically enhances the activation of AKT and mTOR pathway, promotes the proliferation of pNET cell lines and confers the attenuated sensitivity of pNET cells to mTOR inhibitors.	0	12	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	9	10
We have shown that Pten deletion in hepatocytes leads to AKT dependent , increased , de novo lipogenesis through the induction of fatty acid synthase ( FASn ) .13 , 26 , 27 The inhibition of AMPK phosphorylation observed here appears to be necessary to allow lipogenesis to occur in the Pten-null hepatocytes because induction of AMPK phosphorylation with either AICAR or the introduction of constitutively active AMPK reduced the levels of FASn .	We have shown that Pten deletion in hepatocytes leads to AKT dependent, increased, de novo lipogenesis through the induction of fatty acid synthase (FASn).13, 26, 27 The inhibition of AMPK phosphorylation observed here appears to be necessary to allow lipogenesis to occur in the Pten-null hepatocytes because induction of AMPK phosphorylation with either AICAR or the introduction of constitutively active AMPK reduced the levels of FASn.	4	13	leads	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	4	5	10	11
Thus , PTEN blocks the activation of downstream AKT .	Thus, PTEN blocks the activation of downstream AKT.	2	9	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	8	9
Another example is PTEN , a protein tyrosine phosphatase that negatively regulates the AKT and PKB signaling pathway .	Another example is PTEN, a protein tyrosine phosphatase that negatively regulates the AKT and PKB signaling pathway.	1	17	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	3	4	15	16
Mutations which lead to constitutive activation of EGFR , or the loss of NF1 or PTEN , allow stabilization of Akt , which activates cyclin D1 through NFkappa B and disinhibits cyclin E through phosphorylation of p27kip .	Mutations which lead to constitutive activation of EGFR, or the loss of NF1 or PTEN, allow stabilization of Akt, which activates cyclin D1 through NFkappa B and disinhibits cyclin E through phosphorylation of p27kip.	11	23	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of NF1 or PTEN	pten	Akt	Akt	akt	15	16	20	21
Subsequent activation of PTEN by MEK1 then inhibits Akt in concert with the negative feedback provided by indirect Akt inhibition of mTORC2 .	Subsequent activation of PTEN by MEK1 then inhibits Akt in concert with the negative feedback provided by indirect Akt inhibition of mTORC2.	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	8	9
In cancer , activation of oncogenic kinases , loss of the tumor suppressor PTEN , or activating mutations in PI3K can all activate the PI3K and Akt pathway to promote glucose metabolism [ XREF_BIBR - XREF_BIBR ] .	In cancer, activation of oncogenic kinases, loss of the tumor suppressor PTEN, or activating mutations in PI3K can all activate the PI3K and Akt pathway to promote glucose metabolism [XREF_BIBR - XREF_BIBR].	8	27	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of the tumor suppressor PTEN	pten	Akt	Akt	akt	13	14	26	27
For instance , it has been observed that the ectopic overexpression of wild-type PTEN in the human U373 glioblastoma derived cell line lacking functional PTEN reduced IGF-1- and hypoxia induced Akt activation and consequently the HIF-1alpha stabilization and expression of its target gene products , including glycolytic enzymes , PGK-1 and PFK , COX-1 and VEGF [ XREF_BIBR ] .	For instance, it has been observed that the ectopic overexpression of wild-type PTEN in the human U373 glioblastoma derived cell line lacking functional PTEN reduced IGF-1- and hypoxia induced Akt activation and consequently the HIF-1alpha stabilization and expression of its target gene products, including glycolytic enzymes, PGK-1 and PFK, COX-1 and VEGF [XREF_BIBR].	10	31	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	overexpression of wild-type PTEN	pten	Akt	Akt	akt	13	14	30	31
P53 has also been reported to promote PTEN expression , thus blocking AKT activation downstream of PI3K .	P53 has also been reported to promote PTEN expression, thus blocking AKT activation downstream of PI3K.	0	13	blocking	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	P53 has also been reported to promote PTEN expression	pten	AKT	AKT	akt	7	8	12	13
PTEN antagonizes PI3K by cleaving its major product , lipid PtdIns ( 3,4,5 ) P 3 , and thus preventing activation of downstream Akt signaling cascade .	PTEN antagonizes PI3K by cleaving its major product, lipid PtdIns (3,4,5) P 3, and thus preventing activation of downstream Akt signaling cascade.	0	25	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	23	24
PPARbeta and delta was shown to indirectly inhibit the expression of PTEN in keratinocytes , thereby activating the Pi3K and Akt pathway , which enabled keratinocyte survival [ XREF_BIBR ] .	PPARbeta and delta was shown to indirectly inhibit the expression of PTEN in keratinocytes, thereby activating the Pi3K and Akt pathway, which enabled keratinocyte survival [XREF_BIBR].	0	21	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PPARbeta and delta was shown to indirectly inhibit the expression of PTEN	pten	Akt	Akt	akt	11	12	20	21
Since Akt is negatively regulated by Pten , whether the aberrant accumulation of PIP 3 and subsequent heightened activation of Akt in Cbl-b -/- T cells results from reduced Pten activity remains to be further elucidated .	Since Akt is negatively regulated by Pten, whether the aberrant accumulation of PIP 3 and subsequent heightened activation of Akt in Cbl-b -/- T cells results from reduced Pten activity remains to be further elucidated.	1	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	6	7	1	2
It may represent an alternative pathway to activate FGF signaling in those PCas without PTEN loss and/or AKT activation , although at least in some contexts ( such as 22RV1 cells ) , it can be induced by decreased PTEN activity .	It may represent an alternative pathway to activate FGF signaling in those PCas without PTEN loss and/or AKT activation, although at least in some contexts (such as 22RV1 cells), it can be induced by decreased PTEN activity.	17	40	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	39	40	17	18
In concordance with our prior findings , PTEN knockdown activated AKT signaling and resulted in increased SKP-2 and decreased p27 levels ( XREF_FIG , compare lanes 1 and 2 ) .	In concordance with our prior findings, PTEN knockdown activated AKT signaling and resulted in increased SKP-2 and decreased p27 levels (XREF_FIG, compare lanes 1 and 2).	7	11	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	10	11
PTEN negatively regulates the activity of PI3K and AKT signaling through converting phosphatidylinositol 3,4,5-triphosphate ( PIP3 ) into phosphatidylinositol 4,5-bisphosphate ( PIP2 ) .	PTEN negatively regulates the activity of PI3K and AKT signaling through converting phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2).	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
Within this pathway , the PTEN gene ( phosphatase and tensin homologue on human chromosome 10 ) encodes the Pten protein and negatively regulates activation of Akt .	Within this pathway, the PTEN gene (phosphatase and tensin homologue on human chromosome 10) encodes the Pten protein and negatively regulates activation of Akt.	5	27	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	26	27
It is thus likely that PTEN loss activates a pathway independent of Akt signaling that leads to the activation of Smads , thus overriding the suppression of Smads by Akt and mTOR .	It is thus likely that PTEN loss activates a pathway independent of Akt signaling that leads to the activation of Smads, thus overriding the suppression of Smads by Akt and mTOR.	5	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	12	13
In contrast , PTEN initiates apoptotic pathways , in part , by inhibiting AKT activation .	In contrast, PTEN initiates apoptotic pathways, in part, by inhibiting AKT activation.	3	14	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	13	14
PTEN inhibits PI3K-Akt and protects p53 by attenuating the mouse double minute 2 homolog ( Mdm2 ) translocation into the nucleus ( XREF_FIG ) [ XREF_BIBR ] .	PTEN inhibits PI3K-Akt and protects p53 by attenuating the mouse double minute 2 homolog (Mdm2) translocation into the nucleus (XREF_FIG) [XREF_BIBR].	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	2	3
We found that Pten loss in the pancreas causes the elevation of AKT signaling in the liver .	We found that Pten loss in the pancreas causes the elevation of AKT signaling in the liver.	3	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	3	4	12	13
PTEN loss of function promotes AKT activation , which in turn can lead to dysregulation of the pro apoptotic Bcl-2 like proteins .	PTEN loss of function promotes AKT activation, which in turn can lead to dysregulation of the pro apoptotic Bcl-2 like proteins.	0	6	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
The increase in ROS might have activated PTEN , which in turn diminished AKT activation .	The increase in ROS might have activated PTEN, which in turn diminished AKT activation.	6	14	diminished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	13	14
found that deletion of PTEN gene by CRISPR and Cas9 mediated genome editing increases AKT activity in human neural progenitors , promotes cell cycle re-entry , and transiently delays neuronal differentiation , resulting in a pronounced expansion of the radial glia and intermediate progenitor cells .	found that deletion of PTEN gene by CRISPR and Cas9 mediated genome editing increases AKT activity in human neural progenitors, promotes cell cycle re-entry, and transiently delays neuronal differentiation, resulting in a pronounced expansion of the radial glia and intermediate progenitor cells.	4	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	14	15
Functional loss of PTEN leads to aberrant activation of the oncogenic PI3K and Akt pathway and is instrumental in promoting cancer development , progression and metastasis [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Functional loss of PTEN leads to aberrant activation of the oncogenic PI3K and Akt pathway and is instrumental in promoting cancer development, progression and metastasis [XREF_BIBR, XREF_BIBR - XREF_BIBR].	1	14	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	3	4	13	14
The EP1 mediated regulation of phospho-AKT levels was associated with activation of the phosphatase PTEN that via its depletion of PIP3 could inactivate AKT .	The EP1 mediated regulation of phospho-AKT levels was associated with activation of the phosphatase PTEN that via its depletion of PIP3 could inactivate AKT.	10	24	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	23	24
PTEN , a potent tumor suppressor , antagonizes PI3-K-Akt and PKB function through PIP 3 dephosphorylation .	PTEN, a potent tumor suppressor, antagonizes PI3-K-Akt and PKB function through PIP 3 dephosphorylation.	0	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	0	1	10	11
XREF_BIBR XREF_BIBR - XREF_BIBR The tumour suppressor PTEN is crucial for multiple cellular processes including cell proliferation , apoptosis and cell migration , XREF_BIBR , XREF_BIBR and negatively regulates AKT signalling .	XREF_BIBR XREF_BIBR - XREF_BIBR The tumour suppressor PTEN is crucial for multiple cellular processes including cell proliferation, apoptosis and cell migration, XREF_BIBR, XREF_BIBR and negatively regulates AKT signalling.	4	30	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	29	30
Akt is itself inhibited by the activity of PTEN ( phosphatase and tensin homolog deleted on chromosome 10 ) .	Akt is itself inhibited by the activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10).	0	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	0	1
The hypoacetylated TRB3 and PTEN can inhibit the Akt activity in a rat model of prenatal alcohol exposure , which suggests that HDACI treatment could inhibit the activity of TRB3 and PTEN , which in turn would enhance the Akt signaling .	The hypoacetylated TRB3 and PTEN can inhibit the Akt activity in a rat model of prenatal alcohol exposure, which suggests that HDACI treatment could inhibit the activity of TRB3 and PTEN, which in turn would enhance the Akt signaling.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	8	9
17 Constitutive Akt signaling may be initiated by post-EGFR alterations including PIK3CA activating mutations , or disrupted negative regulation by phosphatase and tensin homolog ( PTEN ) through mutation or epigenetic silencing .	17 Constitutive Akt signaling may be initiated by post-EGFR alterations including PIK3CA activating mutations, or disrupted negative regulation by phosphatase and tensin homolog (PTEN) through mutation or epigenetic silencing.	2	24	disrupted	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	20	24	2	3
Thus , loss of PTEN leads to constitutive activation of the PI3K and AKT pathway and could induce RAS and MAPK signaling downstream .	Thus, loss of PTEN leads to constitutive activation of the PI3K and AKT pathway and could induce RAS and MAPK signaling downstream.	2	14	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	4	5	13	14
PTEN up regulation , caused by non genomic mechanisms , such as post transcriptional regulation by non coding RNA , antagonizes the PI3K-AKT pathway [ XREF_BIBR ] .	PTEN up regulation, caused by non genomic mechanisms, such as post transcriptional regulation by non coding RNA, antagonizes the PI3K-AKT pathway [XREF_BIBR].	0	23	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	22	23
45 PTEN , a phosphatase and tensin homologue deleted on chromosome 10 , negatively regulates the PI3K and Akt pathway .	45 PTEN, a phosphatase and tensin homologue deleted on chromosome 10, negatively regulates the PI3K and Akt pathway.	0	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	18	19
40 The transcription factor SOX4 binds to the promoter region of multiple components of the AKT signaling pathways and facilitates their transcription , 27 whereas TXNIP has been shown to play a role in activating PTEN 26 - an important antagonist of AKT activation - which can directly interfere with MDM2 .	40 The transcription factor SOX4 binds to the promoter region of multiple components of the AKT signaling pathways and facilitates their transcription, 27 whereas TXNIP has been shown to play a role in activating PTEN 26 - an important antagonist of AKT activation - which can directly interfere with MDM2.	34	48	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	35	36	42	43
In the progression of BC , reduction of PTEN could activate the AKT and PKB signaling pathway , thereby increasing cancer cell growth and survival .	In the progression of BC, reduction of PTEN could activate the AKT and PKB signaling pathway, thereby increasing cancer cell growth and survival.	6	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	8	9	14	15
As PTEN negatively regulates the AKT pathway by antagonizing PI3K activity by dephosphorylating PIP 3 28 , we evaluated the phosphorylation of Akt ( p-AKT ) in APE1-kd cells .	As PTEN negatively regulates the AKT pathway by antagonizing PI3K activity by dephosphorylating PIP 3 28, we evaluated the phosphorylation of Akt (p-AKT) in APE1-kd cells.	1	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	5	6
AKT activation is down-regulated by PTEN .	AKT activation is down-regulated by PTEN.	0	6	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	0	1
Previous studies have shown that PTEN can specifically inhibit the activation of phosphatidylinositol-3-kinase-dependent protein kinase B ( PKB or Akt ) , and PI3K catalyzes the phosphorylation of phosphoinositide on cell membranes to produce PIP2 and PIP3 , the latter of which further activates the downstream Akt .	Previous studies have shown that PTEN can specifically inhibit the activation of phosphatidylinositol-3-kinase-dependent protein kinase B (PKB or Akt), and PI3K catalyzes the phosphorylation of phosphoinositide on cell membranes to produce PIP2 and PIP3, the latter of which further activates the downstream Akt.	5	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	5	6	17	18
Moreover , PTEN , which negatively regulates AKT , was more than twofold up-regulated at the mRNA level in the resistant cells .	Moreover, PTEN, which negatively regulates AKT, was more than twofold up-regulated at the mRNA level in the resistant cells.	2	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	7	8
In contrast , the phosphatase and tensin homolog deleted from chromosome 10 ( PTEN ) , which specifically dephosphorylates PI-3 ,4-P 2 and PI-3 ,4,5-P 3 at the D3 position can block PI 3-K signaling and inhibit Akt activation .	In contrast, the phosphatase and tensin homolog deleted from chromosome 10 (PTEN), which specifically dephosphorylates PI-3,4-P 2 and PI-3,4,5-P 3 at the D3 position can block PI 3-K signaling and inhibit Akt activation.	4	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	4	8	37	38
Thus PTEN inhibits Akt activation by inhibiting Akt phosphorylation [ XREF_BIBR ] .	Thus PTEN inhibits Akt activation by inhibiting Akt phosphorylation [XREF_BIBR].	1	9	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	PTEN	PTEN	pten	Akt	Akt phosphorylation	akt	1	2	7	8
Normally , PI3K and AKT signaling is negatively regulated by phosphatase and tensin homolog ( PTEN ) and protein phosphatase 2A ( PP2A ) .	Normally, PI3K and AKT signaling is negatively regulated by phosphatase and tensin homolog (PTEN) and protein phosphatase 2A (PP2A).	2	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	10	14	4	5
While inhibition of PTEN significantly increased the expression of p-AKT and p-GSK3beta in PA treated cells , PA-MSHA inhibited the activation of the AKT pathway induced by PTEN siRNA .	While inhibition of PTEN significantly increased the expression of p-AKT and p-GSK3beta in PA treated cells, PA-MSHA inhibited the activation of the AKT pathway induced by PTEN siRNA.	23	28	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	27	28	23	24
PTEN negatively regulates Akt activation through its ability to dephosphorylate the 3-position phosphate from PtdIns ( 3,4,5 ) P 3 to produce PtdIns ( 4,5 ) P 2 .	PTEN negatively regulates Akt activation through its ability to dephosphorylate the 3-position phosphate from PtdIns (3,4,5) P 3 to produce PtdIns (4,5) P 2.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
While PTEN properly antagonized PI3K and Akt signaling in our experiments , no effect on HIF-2alpha protein levels was observed , suggesting that HIF-2alpha expression is not regulated by PI3K and Akt in VHL-/- RCC cells .	While PTEN properly antagonized PI3K and Akt signaling in our experiments, no effect on HIF-2alpha protein levels was observed, suggesting that HIF-2alpha expression is not regulated by PI3K and Akt in VHL-/- RCC cells.	1	7	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	6	7
Furthermore , western blotting showed suppression of PTEN in JARID2-knockdown cells rescued AKT activities of HCC cells , whereas up-regulation of PTEN abolished the AKT activities induced by JARID2 ectopic expression .	Furthermore, western blotting showed suppression of PTEN in JARID2-knockdown cells rescued AKT activities of HCC cells, whereas up-regulation of PTEN abolished the AKT activities induced by JARID2 ectopic expression.	19	25	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	21	22	24	25
Among these initial triggering events , epithelial Pten , a multiple phosphatase that negatively regulates the PI3K and Akt pathway and is crucial for lung development , is essential for the prevention of alveolar flooding and lung fibrosis through the regulation of AEC barrier integrity after injury .	Among these initial triggering events, epithelial Pten, a multiple phosphatase that negatively regulates the PI3K and Akt pathway and is crucial for lung development, is essential for the prevention of alveolar flooding and lung fibrosis through the regulation of AEC barrier integrity after injury.	6	28	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	7	8	18	19
PTEN can be used to suppress tumors and inhibit the activation of PI3K and AKT signaling pathway [ XREF_BIBR ] .	PTEN can be used to suppress tumors and inhibit the activation of PI3K and AKT signaling pathway [XREF_BIBR].	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	14	15
In addition , the 3-phosphatase PTEN downregulates PI ( 3,4,5 ) P 3 ( XREF_FIG , step 2 ) and thereby negatively regulates Akt signaling in the control of myelination [ XREF_BIBR , XREF_BIBR ] .	In addition, the 3-phosphatase PTEN downregulates PI (3,4,5) P 3 (XREF_FIG, step 2) and thereby negatively regulates Akt signaling in the control of myelination [XREF_BIBR, XREF_BIBR].	3	24	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	23	24
Therefore , we believe that PTEN inhibition in these acute conditions mediates subsequent activation of PI3K and Akt signaling , which is known to be key to the endogenous protective effect , similar to the neuronal adaptive response .	Therefore, we believe that PTEN inhibition in these acute conditions mediates subsequent activation of PI3K and Akt signaling, which is known to be key to the endogenous protective effect, similar to the neuronal adaptive response.	5	18	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	17	18
The phosphatase and tensin homolog ( PTEN ) is a tumor suppressor that negatively regulates the PI-3K and Akt pathway by dephosphorylation of the lipid second message , phosphatidylinositol-3 ,4,5-trisphosphate , a product of phosphatidylinositol 3-kinase ( PI-3K ) , by which PTEN inhibits Akt activation 23 .	The phosphatase and tensin homolog (PTEN) is a tumor suppressor that negatively regulates the PI-3K and Akt pathway by dephosphorylation of the lipid second message, phosphatidylinositol-3,4,5-trisphosphate, a product of phosphatidylinositol 3-kinase (PI-3K), by which PTEN inhibits Akt activation 23.	42	45	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	42	43	44	45
We found that all were downregulated in mice brains treated with hUCBSC ( XREF_FIG ) , showing that PTEN upregulation is inhibiting the PI3K and Akt pathway , thereby regulating the growth of tumor cells .	We found that all were downregulated in mice brains treated with hUCBSC (XREF_FIG), showing that PTEN upregulation is inhibiting the PI3K and Akt pathway, thereby regulating the growth of tumor cells.	18	26	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	25	26
The tumor suppressor gene PTEN negatively regulates the PI3K and Akt signaling pathway .	The tumor suppressor gene PTEN negatively regulates the PI3K and Akt signaling pathway.	0	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	10	11
Loss of PTEN may result in AKT activation .	Loss of PTEN may result in AKT activation.	0	8	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	6	7
PTEN loss triggered activation of the PI3K and AKT pathway and escaped of BRAF V600E -mediated senescence .	PTEN loss triggered activation of the PI3K and AKT pathway and escaped of BRAF V600E -mediated senescence.	0	9	triggered	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
PTEN negatively regulates the AKT pathway and is essential to homeostatis .	PTEN negatively regulates the AKT pathway and is essential to homeostatis.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	4	5
The tumor suppressor phosphatase and tensin homolog ( PTEN ) antagonizes this PI3K and Akt pathway .	The tumor suppressor phosphatase and tensin homolog (PTEN) antagonizes this PI3K and Akt pathway.	3	15	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	14	15
PTEN antagonizes AKT activation by depleting phosphatidylinositol-3 ,4,5-trisphosphate [ XREF_BIBR ] .	PTEN antagonizes AKT activation by depleting phosphatidylinositol-3,4,5-trisphosphate [XREF_BIBR].	0	3	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	2	3
In accordance with the aforementioned findings , our present data suggested that PEE treatment increased profilin 1 expression to up-regulate PTEN gene expression , which might in turn inhibited Akt and mTORC1 signaling pathway to prevent UBUC cell proliferation and migration .	In accordance with the aforementioned findings, our present data suggested that PEE treatment increased profilin 1 expression to up-regulate PTEN gene expression, which might in turn inhibited Akt and mTORC1 signaling pathway to prevent UBUC cell proliferation and migration.	20	33	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN gene expression	pten	Akt	Akt	akt	20	21	29	30
Restoration of PTEN expression impedes Akt activation and increases apoptosis [ XREF_BIBR ] .	Restoration of PTEN expression impedes Akt activation and increases apoptosis [XREF_BIBR].	2	6	impedes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	2	3	5	6
PTEN can block FAK , PI3K , and Akt signaling .	PTEN can block FAK, PI3K, and Akt signaling.	0	9	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	8	9
PTEN is an important down-regulator of Akt and mTOR , a pathway that is involved in MTC tumorigenesis .	PTEN is an important down-regulator of Akt and mTOR, a pathway that is involved in MTC tumorigenesis.	0	8	is an important down-regulator	Negative_activation_copula_1	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	6	7
Experiments in both human melanocytes and murine models demonstrated that concurrent loss of PTEN , which activates the PI3K-AKT pathway , complements BRAF mutations to produce invasive and metastatic melanomas .	Experiments in both human melanocytes and murine models demonstrated that concurrent loss of PTEN, which activates the PI3K-AKT pathway, complements BRAF mutations to produce invasive and metastatic melanomas.	11	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	13	14	18	19
PTEN , through its lipid phosphatase activity , antagonizes PI3-K and Akt signaling .	PTEN, through its lipid phosphatase activity, antagonizes PI3-K and Akt signaling.	0	12	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	11	12
Increasing PTEN could inhibit AKT activation , and thus suppress HepG2 cell proliferation and inhibit apoptosis [ XREF_BIBR ] .	Increasing PTEN could inhibit AKT activation, and thus suppress HepG2 cell proliferation and inhibit apoptosis [XREF_BIBR].	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	4	5
The main function of PTEN is to negatively regulate the PI3K-Akt pathway .	The main function of PTEN is to negatively regulate the PI3K-Akt pathway.	2	11	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	4	5	10	11
Western blot analysis revealed that Ang II infusion markedly decreased PTEN levels but increased AKT activation in the WT retina , and this effect was reversed in LMP10 KO mice ( XREF_FIG E and F ) , suggesting that LMP10 promotes PTEN degradation , leading to activation of AKT-IKKalpha and beta signaling .	Western blot analysis revealed that Ang II infusion markedly decreased PTEN levels but increased AKT activation in the WT retina, and this effect was reversed in LMP10 KO mice (XREF_FIG E and F), suggesting that LMP10 promotes PTEN degradation, leading to activation of AKT-IKKalpha and beta signaling.	5	15	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Ang II infusion markedly decreased PTEN levels	pten	AKT	AKT	akt	10	11	14	15
By preventing the accumulation of PIP 3 within the cell , PTEN limits the activation of Akt and PKB and therefore blunts the survival and proliferative signal delivered by PI3K .	By preventing the accumulation of PIP 3 within the cell, PTEN limits the activation of Akt and PKB and therefore blunts the survival and proliferative signal delivered by PI3K.	11	21	limits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	11	12	18	19
The study of Wei also found that PTEN negatively regulated Akt and lowered Akt phosphorylation level [ XREF_BIBR ] .	The study of Wei also found that PTEN negatively regulated Akt and lowered Akt phosphorylation level [XREF_BIBR].	7	16	lowered	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	PTEN	PTEN	pten	Akt	Akt phosphorylation level	akt	7	8	13	14
Concomitant with SchuS4 mediated suppression of Akt phosphorylation was an increase in the levels of the Akt antagonist PTEN .	Concomitant with SchuS4 mediated suppression of Akt phosphorylation was an increase in the levels of the Akt antagonist PTEN.	13	19	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	16	17
Of interest here is that the PI3K and Akt signalling pathway is negatively regulated by PTEN and we have reported that PTEN is downregulated by HSPB1 ( HSP27 ) , both proteins have been implicated in HER2 positive tumours [ XREF_BIBR ] .	Of interest here is that the PI3K and Akt signalling pathway is negatively regulated by PTEN and we have reported that PTEN is downregulated by HSPB1 (HSP27), both proteins have been implicated in HER2 positive tumours [XREF_BIBR].	8	16	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	15	16	8	9
Upregulation of PTEN inhibited the activity of the Akt pathway and regulated downstream genes involved in the cell cycle .	Upregulation of PTEN inhibited the activity of the Akt pathway and regulated downstream genes involved in the cell cycle.	0	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	8	9
PTEN negatively regulates Akt and PKB signaling by antagonizing activated phosphatidylinositol ( 3,4,5 ) trisphosphate ( PIP 3 ) , which is a canonical pathway employed by growth factors to regulate neuronal survival .	PTEN negatively regulates Akt and PKB signaling by antagonizing activated phosphatidylinositol (3,4,5) trisphosphate (PIP 3), which is a canonical pathway employed by growth factors to regulate neuronal survival.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	0	1	5	6
Conversely , increased PRL2 expression in GC-1 cells reduces PTEN level and promotes Akt activation .	Conversely, increased PRL2 expression in GC-1 cells reduces PTEN level and promotes Akt activation.	3	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PRL2 expression in GC-1 cells reduces PTEN level	pten	Akt	Akt	akt	9	10	13	14
PTEN , which suppresses PI3K and AKT signaling , is often mutated in melanomas [ XREF_BIBR , XREF_BIBR ] .	PTEN, which suppresses PI3K and AKT signaling, is often mutated in melanomas [XREF_BIBR, XREF_BIBR].	0	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
Furthermore , the P13K and AKT signaling pathway and hTERT , which were activated by the miR-21 mimic , were inhibited by PTEN overexpression .	Furthermore, the P13K and AKT signaling pathway and hTERT, which were activated by the miR-21 mimic, were inhibited by PTEN overexpression.	5	24	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN overexpression	pten	AKT	AKT	akt	22	23	5	6
It is well known that the tumor suppressor PTEN negatively regulates the PI3K and AKT signaling pathway , so we also examined PTEN expression .	It is well known that the tumor suppressor PTEN negatively regulates the PI3K and AKT signaling pathway, so we also examined PTEN expression.	5	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	14	15
The tumor suppressor phosphatase and tensin homolog ( PTEN ) , whose expression is also induced by TP53 [ XREF_BIBR ] , can also suppress mTORC1 by inhibiting PI3K and AKT signaling [ XREF_BIBR ] , a well established signaling pathway that stimulates mTORC1 .	The tumor suppressor phosphatase and tensin homolog (PTEN), whose expression is also induced by TP53 [XREF_BIBR], can also suppress mTORC1 by inhibiting PI3K and AKT signaling [XREF_BIBR], a well established signaling pathway that stimulates mTORC1.	0	31	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	3	7	30	31
Ablation of Pten ( an inhibitor of Akt signaling ) in the murine hematopoietic system results in the rapid onset of myeloid and/or lymphoid neoplasia .	Ablation of Pten (an inhibitor of Akt signaling) in the murine hematopoietic system results in the rapid onset of myeloid and/or lymphoid neoplasia.	0	14	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	2	3	7	8
In addition , upregulation of PTEN inhibited the activity of Akt and activated the FoxO transcription factor .	In addition, upregulation of PTEN inhibited the activity of Akt and activated the FoxO transcription factor.	3	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	10	11
19 Akt activation in tumors may be caused by loss of tumor suppressor phosphatase and tensin homolog deleted on chromosome ten ( PTEN ) function , amplification or mutation of PI3K or growth factor receptors .	19 Akt activation in tumors may be caused by loss of tumor suppressor phosphatase and tensin homolog deleted on chromosome ten (PTEN) function, amplification or mutation of PI3K or growth factor receptors.	1	17	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	loss of tumor suppressor phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	13	17	1	2
Conversely , PTEN ( phosphatase and tensin homolog deleted on chromosome 10 ) inhibits Akt , allowing PTEN to promote apoptosis and regulate cellular processes such as cell cycling and translation .	Conversely, PTEN (phosphatase and tensin homolog deleted on chromosome 10) inhibits Akt, allowing PTEN to promote apoptosis and regulate cellular processes such as cell cycling and translation.	2	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	14	15
With respect to the anti-fibrotic effects of PGE2 , accumulating evidence has suggested that treatment with PGE2 inhibits TGF-beta1-induced activation and fibroblast proliferation , thereby reducing the production of alpha-SMA and collagens by elevating intracellular cAMP levels ; there is also evidence that treatment with PGE2 induces apoptosis in myofibroblasts by increasing the activity of the PTEN protein , which blocks the PI3K and Akt signalling pathway XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	With respect to the anti-fibrotic effects of PGE2, accumulating evidence has suggested that treatment with PGE2 inhibits TGF-beta1-induced activation and fibroblast proliferation, thereby reducing the production of alpha-SMA and collagens by elevating intracellular cAMP levels; there is also evidence that treatment with PGE2 induces apoptosis in myofibroblasts by increasing the activity of the PTEN protein, which blocks the PI3K and Akt signalling pathway XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	56	72	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	56	57	64	65
PI3K phosphorylates phosphatidylinositol-4 ,5-bisphosphate ( PIP2 ) to phosphatidylinositol-3 ,4,5-triphosphate ( PIP3 ) which phosphorylates and activates AKT , whereas PTEN deposphorylates PIP3 to PIP2 by its lipid phosphatase activity and inhibits PI3K and AKT activation .	PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3) which phosphorylates and activates AKT, whereas PTEN deposphorylates PIP3 to PIP2 by its lipid phosphatase activity and inhibits PI3K and AKT activation.	20	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	20	21	34	35
Another interesting protein recognized by HspB1 is the tumor suppressor PTEN that , by acting as a protein tyrosine phosphatase and a phosphatidylinositol phosphate ( PIP ) phosphatase , can negatively regulate the survival PI3K and Akt signaling pathway .	Another interesting protein recognized by HspB1 is the tumor suppressor PTEN that, by acting as a protein tyrosine phosphatase and a phosphatidylinositol phosphate (PIP) phosphatase, can negatively regulate the survival PI3K and Akt signaling pathway.	2	38	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	36	37
The major function of PTEN is to negatively regulate the PI3K and Akt cell survival pathway .	The major function of PTEN is to negatively regulate the PI3K and Akt cell survival pathway.	2	15	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	12	13
PTEN expression was not detected in 3/4 cell lines tested , suggesting the loss of PTEN mediated Akt activation .	PTEN expression was not detected in 3/4 cell lines tested, suggesting the loss of PTEN mediated Akt activation.	13	18	mediated	Positive_early_activation	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	15	16	17	18
Loss of phosphatase and tensin homolog ( PTEN ) protein expression may lead to constitutive activation of AKT resulting in cell survival and proliferation .	Loss of phosphatase and tensin homolog (PTEN) protein expression may lead to constitutive activation of AKT resulting in cell survival and proliferation.	0	18	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	Loss of phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	akt	2	6	17	18
Thus , by preventing AKT activation PTEN inhibits cell proliferation and growth [ XREF_BIBR ] .	Thus, by preventing AKT activation PTEN inhibits cell proliferation and growth [XREF_BIBR].	3	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	4	5
We concluded that pharmacologic PTEN inhibition enhances Akt activation , improving metabolic , cardiovascular , and neurologic recovery with increased survival after SCA .	We concluded that pharmacologic PTEN inhibition enhances Akt activation, improving metabolic, cardiovascular, and neurologic recovery with increased survival after SCA.	4	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	7	8
Pei and coworkers demonstrated that Notch1 inhibition increased Pten expression and decreased Akt activity in a reperfused myocardium [ XREF_BIBR ] .	Pei and coworkers demonstrated that Notch1 inhibition increased Pten expression and decreased Akt activity in a reperfused myocardium [XREF_BIBR].	5	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Notch1 inhibition increased Pten expression	pten	Akt	Akt	akt	8	9	12	13
Akt activity in cancers can either be deregulated by constitutive activation or by mutation of PTEN and MMAC1 , a phosphatase that directly counteracts Akt through the dephosphorylation of PI-3-, 4-, and 5-P 3 ( Stambolic et al , 1998 ) .	Akt activity in cancers can either be deregulated by constitutive activation or by mutation of PTEN and MMAC1, a phosphatase that directly counteracts Akt through the dephosphorylation of PI-3-, 4-, and 5-P 3 (Stambolic et al, 1998).	0	18	deregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MMAC1	MMAC1	MMAC1	Akt	Akt	Akt	17	18	0	1
Because the lipid phosphatase , phosphatase and tensin homolog ( PTEN ) inhibits Akt , we generated a mouse with conditional knock-out of PTEN in dopamine neurons , leading to constitutive expression of Akt in these neurons .	Because the lipid phosphatase, phosphatase and tensin homolog (PTEN) inhibits Akt, we generated a mouse with conditional knock-out of PTEN in dopamine neurons, leading to constitutive expression of Akt in these neurons.	3	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	5	9	13	14
In PTEN disrupted cells , PDK1 , AKT , and PKCzeta exhibited elevated basal activities , which prevented EGF induced further activation of these molecules .	In PTEN disrupted cells, PDK1, AKT, and PKCzeta exhibited elevated basal activities, which prevented EGF induced further activation of these molecules.	0	11	disrupted	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	7	8
Importantly , PTEN antagonizes PI3K function and negatively regulates Akt activities by stripping a phosphate off PIP3 thereby returning it to its original PI ( 4,5 ) P2 form .	Importantly, PTEN antagonizes PI3K function and negatively regulates Akt activities by stripping a phosphate off PIP3 thereby returning it to its original PI (4,5) P2 form.	2	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	9	10
MicroRNA-21-mediated suppression of PTEN mRNA thus promotes PI3K and AKT signaling , which downregulates nuclear FoxO1 .	MicroRNA-21-mediated suppression of PTEN mRNA thus promotes PI3K and AKT signaling, which downregulates nuclear FoxO1.	3	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	9	10
Moreover , PTEN is a suppressor of the PI3K and Akt pathway and therefore , the enhanced expression of PTEN induced by GA would have definitely blocked the PI3K and Akt signaling pathway .	Moreover, PTEN is a suppressor of the PI3K and Akt pathway and therefore, the enhanced expression of PTEN induced by GA would have definitely blocked the PI3K and Akt signaling pathway.	17	32	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	19	20	30	31
In our experiments , we assessed the PI3-kinase pathway not only because active PTEN prevents the PI3-kinase-mediated AKT signaling , but also because PI3-kinase is able to block PTEN activity XREF_BIBR , XREF_BIBR .	In our experiments, we assessed the PI3-kinase pathway not only because active PTEN prevents the PI3-kinase-mediated AKT signaling, but also because PI3-kinase is able to block PTEN activity XREF_BIBR, XREF_BIBR.	12	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	13	14	17	18
The loss of PTEN results in activation of Akt which subsequently upregulates mTOR activity .	The loss of PTEN results in activation of Akt which subsequently upregulates mTOR activity.	1	9	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	3	4	8	9
On the other hand , cytoplasmic PTEN inhibits Akt , serving a pro apoptotic function .	On the other hand, cytoplasmic PTEN inhibits Akt, serving a pro apoptotic function.	5	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	8	9
The nuclear PTEN inhibits the PI3K and AKT signaling axis , blocks cyclin D1 and induces cell cycle arrest .	The nuclear PTEN inhibits the PI3K and AKT signaling axis, blocks cyclin D1 and induces cell cycle arrest.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	7	8
Furthermore , Dlgh1 silencing abrogated Treg function , impaired NFATc1 activation , reduced phosphatase and tensin homolog levels , and increased Akt activation .	Furthermore, Dlgh1 silencing abrogated Treg function, impaired NFATc1 activation, reduced phosphatase and tensin homolog levels, and increased Akt activation.	2	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	Dlgh1 silencing abrogated Treg function, impaired NFATc1 activation, reduced phosphatase and tensin homolog levels	phosphatase and tensin homolog	Akt	Akt	akt	13	17	21	22
Interestingly , it has been shown recently that loss of Pten induces ER UDPase ectonucleoside triphosphate diphosphohydrolase 5 ( ENTPD5 ) , and activation of the AKT and mTOR pathway leads to induction of pyruvate kinase isoenzyme type M2 ( PKM2 ) , which contribute to aerobic glycolysis , also known as the Warburg effect , and tumor growth in a xenograft model of prostate cancer .	Interestingly, it has been shown recently that loss of Pten induces ER UDPase ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), and activation of the AKT and mTOR pathway leads to induction of pyruvate kinase isoenzyme type M2 (PKM2), which contribute to aerobic glycolysis, also known as the Warburg effect, and tumor growth in a xenograft model of prostate cancer.	8	29	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	loss of Pten	pten	AKT	AKT	akt	10	11	26	27
Resistance to glucocorticoid therapy can also be conferred via the genetic loss of PTEN ( phosphatase and tensin homology ) , which leads to AKT ( protein kinase B )-mediated hyperphosphorylation of GR to block its nuclear entry [ XREF_BIBR ] .	Resistance to glucocorticoid therapy can also be conferred via the genetic loss of PTEN (phosphatase and tensin homology), which leads to AKT (protein kinase B)-mediated hyperphosphorylation of GR to block its nuclear entry [XREF_BIBR].	11	28	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	13	14	24	25
We next examined whether changing miR-21 by exogenous transfection could lead to the change of PTEN protein expression and the activation of Akt , which is negatively regulated by PTEN [ XREF_BIBR ] .	We next examined whether changing miR-21 by exogenous transfection could lead to the change of PTEN protein expression and the activation of Akt, which is negatively regulated by PTEN [XREF_BIBR].	20	31	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	29	30	22	23
Although it is known that PTEN ( phosphatase and tensin homologue deleted on chromosome 10 ) negatively regulates PI3K and Akt pathway , we could not detect any change in PTEN expression in the ischaemic hindlimb in donepezil treated mice ( results not shown ) .	Although it is known that PTEN (phosphatase and tensin homologue deleted on chromosome 10) negatively regulates PI3K and Akt pathway, we could not detect any change in PTEN expression in the ischaemic hindlimb in donepezil treated mice (results not shown).	5	21	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	20	21
PTEN negatively regulates the AKT signaling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate ( PIP 3 ) , a second messenger generated by PI3K that promotes the recruitment of 3-phosphoinositide-dependent protein kinase 1 ( PDK1 ) to the TCR signaling complex .	PTEN negatively regulates the AKT signaling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP 3), a second messenger generated by PI3K that promotes the recruitment of 3-phosphoinositide-dependent protein kinase 1 (PDK1) to the TCR signaling complex.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	4	5
PTEN inactivation and constitutive activation of AKT are well defined genetic alterations in the initiation and progression of tumours ( Vivanco and Sawyers , 2002 ) .	PTEN inactivation and constitutive activation of AKT are well defined genetic alterations in the initiation and progression of tumours (Vivanco and Sawyers, 2002).	0	7	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
The results are consistent with a model in which Tat competes with PTEN for p53 binding , causing p53 destabilization and a consequent reduction in PTEN mRNA and protein levels , relieving the PTEN inhibition of Akt activation .	The results are consistent with a model in which Tat competes with PTEN for p53 binding, causing p53 destabilization and a consequent reduction in PTEN mRNA and protein levels, relieving the PTEN inhibition of Akt activation.	33	37	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	33	34	36	37
The PI3K and AKT pathway is negatively regulated by PTEN ( phosphatase and tensin homologue ) , a lipid phosphatase that removes the 3-phosphate from PI ( 3,4 ) P2 and PI ( 3,4,5 ) P3 , thus inactivating the signaling cascade [ XREF_BIBR ] .	The PI3K and AKT pathway is negatively regulated by PTEN (phosphatase and tensin homologue), a lipid phosphatase that removes the 3-phosphate from PI (3,4) P2 and PI (3,4,5) P3, thus inactivating the signaling cascade [XREF_BIBR].	1	19	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	3	4
Studies in PTEN +/- and PTEN -/- MEFs , which used PTEN knockdown as a means to increase Akt activity , demonstrated that knockdown of ectonucleoside triphosphate diphosphohydrolase 5 ( ENTPD5 ) , which hydrolyzes UDP in the ER to promote protein N glycosylation and refolding , increased CHOP and GRP78 expression while at the same time reducing protein glycosylation XREF_BIBR , XREF_BIBR .	Studies in PTEN +/- and PTEN -/- MEFs, which used PTEN knockdown as a means to increase Akt activity, demonstrated that knockdown of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), which hydrolyzes UDP in the ER to promote protein N glycosylation and refolding, increased CHOP and GRP78 expression while at the same time reducing protein glycosylation XREF_BIBR, XREF_BIBR.	10	19	knockdown	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	18	19
Akt activation is negatively regulated by PTEN ( phosphatase and tensin homolog ) [ XREF_BIBR ] in a redox dependent oxidation of the cysteine residues of PTEN [ XREF_BIBR ] .	Akt activation is negatively regulated by PTEN (phosphatase and tensin homolog) [XREF_BIBR] in a redox dependent oxidation of the cysteine residues of PTEN [XREF_BIBR].	0	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	0	1
Our results showed that the knockdown of HES1 increased PTEN expression and decreased p-AKT protein levels and AKT activity , and overexpression of HES1 decreased PTEN expression and increased the p-AKT protein levels and AKT activity .	Our results showed that the knockdown of HES1 increased PTEN expression and decreased p-AKT protein levels and AKT activity, and overexpression of HES1 decreased PTEN expression and increased the p-AKT protein levels and AKT activity.	21	35	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	overexpression of HES1 decreased PTEN expression	pten	AKT	AKT	akt	25	26	34	35
In addition , because of the feedback of S6 kinase to insulin receptor substrate 1 , Akt is activated by Pten deletion but inhibited in Tsc mutants .	In addition, because of the feedback of S6 kinase to insulin receptor substrate 1, Akt is activated by Pten deletion but inhibited in Tsc mutants.	16	23	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	20	21	16	17
PTEN negatively regulates the PI3K and Akt pathway , while it was reported that PTEN played a critical role in the functional coupling between JNK and Akt pathways .	PTEN negatively regulates the PI3K and Akt pathway, while it was reported that PTEN played a critical role in the functional coupling between JNK and Akt pathways.	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	6	7
Moreover , PTEN normally suppresses the PI3K-AKT pathway and thus inhibits cell survival and growth 144 .	Moreover, PTEN normally suppresses the PI3K-AKT pathway and thus inhibits cell survival and growth 144.	2	10	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	2	3	6	7
XREF_BIBR , XREF_BIBR In contrast , S1PR2 is thought to primarily couple to G 12/13 to mediate Rac and Rho dependent inhibition of cell migration , and through Rho mediated PTEN ( phosphatase and tensin homolog ) activation , antagonize Akt activation .	XREF_BIBR, XREF_BIBR In contrast, S1PR2 is thought to primarily couple to G 12/13 to mediate Rac and Rho dependent inhibition of cell migration, and through Rho mediated PTEN (phosphatase and tensin homolog) activation, antagonize Akt activation.	28	41	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Rho mediated PTEN	pten	Akt	Akt	akt	30	31	40	41
There is also evidence showing that tumors with PI3K and AKT pathway activation including PTEN loss or PIK3CA mutation or both are less sensitive to trastuzumab treatment [ XREF_BIBR ] .	There is also evidence showing that tumors with PI3K and AKT pathway activation including PTEN loss or PIK3CA mutation or both are less sensitive to trastuzumab treatment [XREF_BIBR].	8	15	activation	Positive_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	10	11
The tumor suppressor gene MMAC and PTEN located on chromosome10q23.3 has dual phosphatase activity in the phosphoinositide-3-kinase signaling pathway and inhibits Akt activation , a serine threonine kinase , which is involved in proliferative and antiapoptotic pathways .	The tumor suppressor gene MMAC and PTEN located on chromosome10q23.3 has dual phosphatase activity in the phosphoinositide-3-kinase signaling pathway and inhibits Akt activation, a serine threonine kinase, which is involved in proliferative and antiapoptotic pathways.	4	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	21	22
PTEN negatively regulates the activity of PI3K and Akt signaling through converting phosphatidylinositol 3,4,5-triphosphate ( PIP3 ) into phosphatidylinositol 4,5-bisphosphate ( PIP2 ) .	PTEN negatively regulates the activity of PI3K and Akt signaling through converting phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2).	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	8	9
25 Tumor suppressor PTEN negatively regulates the activity of Akt by converting PIP3 back to PIP2 .	25 Tumor suppressor PTEN negatively regulates the activity of Akt by converting PIP3 back to PIP2.	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	9	10
Additional proteins involved in negative regulation of apoptosis , such as STAT3 that mediates cellular responses to growth factors and interleukins , and the tumor suppressor phosphatase PTEN that antagonizes the PI3K-AKT and PKB signaling pathway and cell survival , had roles in both positive and negative regulation of proliferation .	Additional proteins involved in negative regulation of apoptosis, such as STAT3 that mediates cellular responses to growth factors and interleukins, and the tumor suppressor phosphatase PTEN that antagonizes the PI3K-AKT and PKB signaling pathway and cell survival, had roles in both positive and negative regulation of proliferation.	1	35	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	27	28	33	34
There is also the possibility that knockout of Pten activates AKT independent of the adherens junctions , but the in vitro data supports our hypothesis that adherens junction formation is important for PI3K signaling and its effects on osteogenesis .	There is also the possibility that knockout of Pten activates AKT independent of the adherens junctions, but the in vitro data supports our hypothesis that adherens junction formation is important for PI3K signaling and its effects on osteogenesis.	6	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	8	9	10	11
In BT474 cells , however , it is not the loss of PTEN that supports AKT activity in the absence of upstream kinase activity , rather it is the constitutively active mutation in PINK ( PTEN induced putative kinase ) 3CA [ XREF_BIBR ] .	In BT474 cells, however, it is not the loss of PTEN that supports AKT activity in the absence of upstream kinase activity, rather it is the constitutively active mutation in PINK (PTEN induced putative kinase) 3CA [XREF_BIBR].	10	16	supports	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	12	13	15	16
PTEN negatively regulates PI3K and Akt pathway by dephosphorylating phosphatidylinositol-3 ,4,5-triphosphate [ XREF_BIBR ] .	PTEN negatively regulates PI3K and Akt pathway by dephosphorylating phosphatidylinositol-3,4,5-triphosphate [XREF_BIBR].	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
PTEN is the direct inhibitor of AKT because it converts AKT activating PIP 3 into PIP 2 , which does not activate AKT .	PTEN is the direct inhibitor of AKT because it converts AKT activating PIP 3 into PIP 2, which does not activate AKT.	0	7	is the direct inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
XREF_BIBR , XREF_BIBR As illustrated in XREF_FIG , ectopic expression of wild-type p100 in NFkappaB2-/- cells restored PTEN expression and attenuated aberrant Akt activation , whereas p100DeltaC did not had any observed effects on either PTEN protein expression or Akt activation .	XREF_BIBR, XREF_BIBR As illustrated in XREF_FIG, ectopic expression of wild-type p100 in NFkappaB2-/- cells restored PTEN expression and attenuated aberrant Akt activation, whereas p100DeltaC did not had any observed effects on either PTEN protein expression or Akt activation.	9	23	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of wild-type p100 in NFkappaB2-/- cells restored PTEN expression	pten	Akt	Akt	akt	17	18	22	23
The tumor suppressor gene PTEN ( phosphatase and tensin homologue deleted on chromosome 10 ) antagonizes the pro survival signaling of Akt and promotes cell death .	The tumor suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) antagonizes the pro survival signaling of Akt and promotes cell death.	0	23	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	21	22
To our knowledge , no study has addressed the effect of PTEN antagonism of PI3K and Akt signaling on stabilized HIF-2alpha protein resulting from VHL inactivation in RCC cells .	To our knowledge, no study has addressed the effect of PTEN antagonism of PI3K and Akt signaling on stabilized HIF-2alpha protein resulting from VHL inactivation in RCC cells.	11	17	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	16	17
PTEN phosphorylation levels were also determined , since disruption of PTEN promotes unrestrained Akt activation XREF_BIBR .	PTEN phosphorylation levels were also determined, since disruption of PTEN promotes unrestrained Akt activation XREF_BIBR.	8	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	13	14
We also showed that in breast cancer but not thyroid cancer cells , PTEN suppresses nuclear P-AKT mainly through decreasing P-AKT nuclear translocation by reducing the PIP3 and P-AKT reservoir in the cytoplasm .	We also showed that in breast cancer but not thyroid cancer cells, PTEN suppresses nuclear P-AKT mainly through decreasing P-AKT nuclear translocation by reducing the PIP3 and P-AKT reservoir in the cytoplasm.	13	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	P-AKT	P-AKT	P-AKT	13	14	16	17
It is well known that PTEN deletion causes upregulation of PI3K-AKT pathway which plays a significant role in proliferation and progression of cancer and since mTOR is a downstream signal for the PI3K-AKT pathway , blocking this mTOR signal may cause decrease in tumor proliferation .	It is well known that PTEN deletion causes upregulation of PI3K-AKT pathway which plays a significant role in proliferation and progression of cancer and since mTOR is a downstream signal for the PI3K-AKT pathway, blocking this mTOR signal may cause decrease in tumor proliferation.	5	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	5	6	10	11
In addition , the PTEN gene can inhibit mTOR activity by negatively regulating the PI3K and Akt signaling pathway , therefore inhibiting cancer cell proliferation , promoting apoptosis and reversing multidrug resistance .	In addition, the PTEN gene can inhibit mTOR activity by negatively regulating the PI3K and Akt signaling pathway, therefore inhibiting cancer cell proliferation, promoting apoptosis and reversing multidrug resistance.	4	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	16	17
This syndrome is caused by inactivating mutations in PTEN , a dual-specificity phosphatase which negatively regulates the PI3 Kinase and AKT pathway .	This syndrome is caused by inactivating mutations in PTEN, a dual-specificity phosphatase which negatively regulates the PI3 Kinase and AKT pathway.	5	21	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	20	21
PTEN can be considered as a tumour suppressor , preventing Akt activation through the dephosphorylation of a PI3K lipid signalling product .	PTEN can be considered as a tumour suppressor, preventing Akt activation through the dephosphorylation of a PI3K lipid signalling product.	0	11	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	10	11
However , DU145 spheres display low levels of AKT activation while PTEN knockdown marginally increased AKT activation and did not affect sphere maintenance , suggesting that PTEN function may not be critical for PCSC self-renewal in vitro [ XREF_BIBR ] .	However, DU145 spheres display low levels of AKT activation while PTEN knockdown marginally increased AKT activation and did not affect sphere maintenance, suggesting that PTEN function may not be critical for PCSC self-renewal in vitro [XREF_BIBR].	11	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	11	12	15	16
In addition to their involvement in inflammation related processes , both miRNA-132 and miRNA-212 protect neurons against H 2 O 2 -mediated cell death , and their loss causes neuronal apoptosis via elevated levels of the cell death associated proteins PTEN , FOXO3 and P300 that antagonize Akt pro survival signaling .	In addition to their involvement in inflammation related processes, both miRNA-132 and miRNA-212 protect neurons against H 2 O 2 -mediated cell death, and their loss causes neuronal apoptosis via elevated levels of the cell death associated proteins PTEN, FOXO3 and P300 that antagonize Akt pro survival signaling.	38	50	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	40	41	47	48
In xenografts models of PTEN positive and PTEN-knock-in endometrial cancer , JQ1 significantly upregulated the expression of PTEN , blocked the PI3K and AKT signaling pathway and suppressed tumor growth .	In xenografts models of PTEN positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K and AKT signaling pathway and suppressed tumor growth.	11	25	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	JQ1 significantly upregulated the expression of PTEN	pten	AKT	AKT	akt	17	18	23	24
100 P-Rex2a can directly bind and inhibit the lipid phosphatase activity of the PTEN tumor suppressor , thereby causing activation of PI3K and Akt and subsequent stimulation of pro growth and survival pathways .	100 P-Rex2a can directly bind and inhibit the lipid phosphatase activity of the PTEN tumor suppressor, thereby causing activation of PI3K and Akt and subsequent stimulation of pro growth and survival pathways.	13	24	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	23	24
PTEN is known to inhibit the PI3K and AKT signaling axis , and beta-catenin is known to mediate the effect of AKT signaling on stem cells [ XREF_BIBR ] .	PTEN is known to inhibit the PI3K and AKT signaling axis, and beta-catenin is known to mediate the effect of AKT signaling on stem cells [XREF_BIBR].	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
The PI3K and Akt pathway is negatively regulated by phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) , which is a phosphatase that dephosphorylate PIP 3 to PIP 2 thus deactivating PIP 3 -dependent pathways .	The PI3K and Akt pathway is negatively regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which is a phosphatase that dephosphorylate PIP 3 to PIP 2 thus deactivating PIP 3 -dependent pathways.	1	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	9	13	3	4
For example , p53 activates transcription of PTEN , a phosphoinositide phosphatase that normally inhibits AKT signaling .	For example, p53 activates transcription of PTEN, a phosphoinositide phosphatase that normally inhibits AKT signaling.	3	16	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	p53 activates transcription of PTEN	pten	AKT	AKT	akt	7	8	15	16
Through its phosphatase activity , PTEN antagonizes PiK3 activity and inhibits the Pi3K and Akt pathway involved in the regulation of apoptosis , cell proliferation and growth , and metabolism [ XREF_BIBR , XREF_BIBR ] .	Through its phosphatase activity, PTEN antagonizes PiK3 activity and inhibits the Pi3K and Akt pathway involved in the regulation of apoptosis, cell proliferation and growth, and metabolism [XREF_BIBR, XREF_BIBR].	5	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	14	15
In primary and immortalized mouse fibroblast cell lines , both p110alpha and p110beta controlled steady-state PtdIns ( 3,4,5 ) P 3 levels and Akt signalling induced by heterozygous PTEN loss .	In primary and immortalized mouse fibroblast cell lines, both p110alpha and p110beta controlled steady-state PtdIns (3,4,5) P 3 levels and Akt signalling induced by heterozygous PTEN loss.	23	29	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	28	29	23	24
However , PTEN ( a suppressor gene ) encoding a lipid phosphatase could negatively regulate PI3K and Akt signal pathway by inhibiting the activity of mTOR [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	However, PTEN (a suppressor gene) encoding a lipid phosphatase could negatively regulate PI3K and Akt signal pathway by inhibiting the activity of mTOR [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	19	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	17	18
PTEN negatively regulates the PI3K and Akt pathway but is frequently lost or mutated in GBM .	PTEN negatively regulates the PI3K and Akt pathway but is frequently lost or mutated in GBM.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	6	7
Papilloma cells overexpress the EGFR and have constitutively active extracellular signal regulated kinase ( ERK ) and enhanced phosphatidylinositol 3-kinase ( PI3K ) activity , but overexpression of the lipid phosphatase PTEN ( Phosphatase and Tensin Homolog ) reduces activation of Akt by PI3K .	Papilloma cells overexpress the EGFR and have constitutively active extracellular signal regulated kinase (ERK) and enhanced phosphatidylinositol 3-kinase (PI3K) activity, but overexpression of the lipid phosphatase PTEN (Phosphatase and Tensin Homolog) reduces activation of Akt by PI3K.	26	42	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	overexpression of the lipid phosphatase PTEN	pten	Akt	Akt	akt	31	32	41	42
There is intriguing data that PTEN loss and constitutive activation of the PI3K-AKT pathway may play a role in resistance patterns seen with BRAF and MEK inhibitors .	There is intriguing data that PTEN loss and constitutive activation of the PI3K-AKT pathway may play a role in resistance patterns seen with BRAF and MEK inhibitors.	5	13	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	5	6	12	13
The tumour suppressor PTEN , that rivals p53 in being the most frequently mutated gene in human cancer XREF_BIBR , promotes autophagy in HT-29 colon cancer cells by blocking the Akt survival pathway .	The tumour suppressor PTEN, that rivals p53 in being the most frequently mutated gene in human cancer XREF_BIBR, promotes autophagy in HT-29 colon cancer cells by blocking the Akt survival pathway.	0	32	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	30	31
PTEN inhibits the activation of Akt , a serine threonine kinase involved in proliferative metabolic and antiapoptotic pathways , and has tumor suppressive properties .	PTEN inhibits the activation of Akt, a serine threonine kinase involved in proliferative metabolic and antiapoptotic pathways, and has tumor suppressive properties.	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
These data indicate an important role of HDAC3 in PTEN loss mediated AKT activation .	These data indicate an important role of HDAC3 in PTEN loss mediated AKT activation.	9	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	12	13
Moreover , our results implicate PTEN in the Spry1 induced inhibition of AKT where increased amount and activity of PTEN accompanied attenuation of AKT phosphorylation .	Moreover, our results implicate PTEN in the Spry1 induced inhibition of AKT where increased amount and activity of PTEN accompanied attenuation of AKT phosphorylation.	5	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	12	13
To explore the molecular mechanism ( s ) underlying the activation of AKT signaling in ST1-N6 cells , we first investigated the expression levels of PTEN in ST1-N6 and TL-Om1-N8 cells , as PTEN is known to negatively regulate AKT activation in many types of cells , including ATL cells .	To explore the molecular mechanism (s) underlying the activation of AKT signaling in ST1-N6 cells, we first investigated the expression levels of PTEN in ST1-N6 and TL-Om1-N8 cells, as PTEN is known to negatively regulate AKT activation in many types of cells, including ATL cells.	33	40	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	33	34	39	40
In HCT116 cells , PTEN inhibits Akt signaling and proliferation .	In HCT116 cells, PTEN inhibits Akt signaling and proliferation.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	6	7
The decreased PTEN levels may lead to AKT activation ( XREF_FIG and XREF_FIG ) .	The decreased PTEN levels may lead to AKT activation (XREF_FIG and XREF_FIG).	2	8	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN levels	pten	AKT	AKT	akt	2	3	7	8
PTEN antagonizes PI3K function , and the loss of PTEN activates the Akt and mTOR pathway .	PTEN antagonizes PI3K function, and the loss of PTEN activates the Akt and mTOR pathway.	7	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	9	10	12	13
Since PTEN is a negative regulator of Akt and its activity can be modulated by acetylation , we investigated if SIRT1 deacetylated PTEN to downregulate Akt to trigger apoptosis in anti-oxidant-free culture conditions .	Since PTEN is a negative regulator of Akt and its activity can be modulated by acetylation, we investigated if SIRT1 deacetylated PTEN to downregulate Akt to trigger apoptosis in anti-oxidant-free culture conditions.	20	26	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	SIRT1 deacetylated PTEN	pten	Akt	Akt	akt	22	23	25	26
These results suggested that PTEN knockdown activated the Akt and HDM2 signaling pathway and blocked p53 dependent cell apoptosis ( XREF_FIG ) .	These results suggested that PTEN knockdown activated the Akt and HDM2 signaling pathway and blocked p53 dependent cell apoptosis (XREF_FIG).	4	12	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	8	9
By antagonizing PI3K-PKB and Akt , PTEN represses cell proliferation through induction of apoptosis and/or cell cycle arrest [ XREF_BIBR , XREF_BIBR ] .	By antagonizing PI3K-PKB and Akt, PTEN represses cell proliferation through induction of apoptosis and/or cell cycle arrest [XREF_BIBR, XREF_BIBR].	1	8	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	4	5
The decrease in PTEN protein , which dephosphorylates PIP3 , was responsible for maintaining high levels of PIP3 in replicative aged HDFs and consequently mediated the activation of the PI3K and Akt pathway .	The decrease in PTEN protein, which dephosphorylates PIP3, was responsible for maintaining high levels of PIP3 in replicative aged HDFs and consequently mediated the activation of the PI3K and Akt pathway.	3	32	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	31	32
In this way , PTEN inhibits PIP3 dependent downstream signaling events like membrane recruitment and activation of AKT to prevent cell growth and proliferation .	In this way, PTEN inhibits PIP3 dependent downstream signaling events like membrane recruitment and activation of AKT to prevent cell growth and proliferation.	4	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	17	18
PPAR gamma agonists also stimulate phosphatase and tensin homolog ( PTEN ) expression , which decreases both TGF-beta1 and PI3K and Akt pathways .	PPAR gamma agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-beta1 and PI3K and Akt pathways.	0	22	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	PPAR gamma agonists also stimulate phosphatase and tensin homolog (PTEN) expression	phosphatase and tensin homolog	Akt	Akt	akt	5	9	21	22
One study on GB cells reiterates the importance of PTEN mutation in PI3K and Akt pathway activation ; loss of PTEN triggers the accumulation of PIP3 and Akt activation , which in turn inhibits mTOR pathway .	One study on GB cells reiterates the importance of PTEN mutation in PI3K and Akt pathway activation; loss of PTEN triggers the accumulation of PIP3 and Akt activation, which in turn inhibits mTOR pathway.	18	28	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	20	21	27	28
205 The tumor suppressor gene PTEN encodes a lipid phosphatase that negatively regulates the PI3K and AKT pathway , and loss of PTEN leads to constitutive PI3K-AKT signaling .	205 The tumor suppressor gene PTEN encodes a lipid phosphatase that negatively regulates the PI3K and AKT pathway, and loss of PTEN leads to constitutive PI3K-AKT signaling.	20	27	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	22	23	26	27
Up-regulation of PTEN expression in BGC-823 cells by PEAK8-PTEN transient transfection obviously decreased the basal and anticancer drugs induced Akt activities , then sensitized BGC-823 cells to etoposide and doxorubicin .	Up-regulation of PTEN expression in BGC-823 cells by PEAK8-PTEN transient transfection obviously decreased the basal and anticancer drugs induced Akt activities, then sensitized BGC-823 cells to etoposide and doxorubicin.	2	20	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	2	3	19	20
Furthermore , the tumor suppressor PTEN negatively regulates the PI3K and AKT pathway through its lipid phosphatase activity , which is recognized as one of the most frequently deleted and/or mutated genes in human cancer .	Furthermore, the tumor suppressor PTEN negatively regulates the PI3K and AKT pathway through its lipid phosphatase activity, which is recognized as one of the most frequently deleted and/or mutated genes in human cancer.	2	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	11	12
Loss of PTEN results in constitutive activation of Akt and alteration of downstream factors in Akt signaling in multiple preclinical models ( XREF_FIG ) .	Loss of PTEN results in constitutive activation of Akt and alteration of downstream factors in Akt signaling in multiple preclinical models (XREF_FIG).	0	13	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	8	9
Other possibilities ( see XREF_FIG ) include ( a ) inhibition of pro apoptotic MAPKs such as ASK1 and JNK via S nitrosation of cysteine residues ; ( b ) S-nitrosation-inhibition of caspases ; ( c ) S nitrosation of Bcl-2 , which inhibits its proteosomal degradation ; and ( d ) S-nitrosation-inhibition of PTEN , the phosphoinositide phosphatase that negatively regulates Akt .	Other possibilities (see XREF_FIG) include (a) inhibition of pro apoptotic MAPKs such as ASK1 and JNK via S nitrosation of cysteine residues; (b) S-nitrosation-inhibition of caspases; (c) S nitrosation of Bcl-2, which inhibits its proteosomal degradation; and (d) S-nitrosation-inhibition of PTEN, the phosphoinositide phosphatase that negatively regulates Akt.	52	63	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	54	55	62	63
However , PTEN loss in hepatocytes results in increased activation of Akt leading to the development of hepatic steatosis , which has been proposed to underlie HCC development in this model .	However, PTEN loss in hepatocytes results in increased activation of Akt leading to the development of hepatic steatosis, which has been proposed to underlie HCC development in this model.	2	12	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	11	12
Consistent with this result , knocking out PTEN , which negatively regulates AKT , leads to a similar phenotype [ XREF_BIBR ] .	Consistent with this result, knocking out PTEN, which negatively regulates AKT, leads to a similar phenotype [XREF_BIBR].	5	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	12	13
Inhibition of PTEN expression by miR-21 leads to a constitutive activation of AKT that desensitizes the cells to further insulin action ( Vinciguerra etal .	Inhibition of PTEN expression by miR-21 leads to a constitutive activation of AKT that desensitizes the cells to further insulin action (Vinciguerra etal.	0	13	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Inhibition of PTEN expression by miR-21	pten	AKT	AKT	akt	2	3	12	13
Protein kinase B ( more commonly referred as Akt ) is a serine/threonine kinase , which plays a role in BCa growth by promoting cell survival and inhibiting cell death XREF_BIBR , XREF_BIBR and is being considered as a potential target for BCa therapy XREF_BIBR , XREF_BIBR , whereas PTEN , a well recognized tumor suppressor gene , negatively regulates Akt and has been shown to inhibit BCa growth XREF_BIBR , XREF_BIBR .	Protein kinase B (more commonly referred as Akt) is a serine/threonine kinase, which plays a role in BCa growth by promoting cell survival and inhibiting cell death XREF_BIBR, XREF_BIBR and is being considered as a potential target for BCa therapy XREF_BIBR, XREF_BIBR, whereas PTEN, a well recognized tumor suppressor gene, negatively regulates Akt and has been shown to inhibit BCa growth XREF_BIBR, XREF_BIBR.	49	66	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	49	50	60	61
Also , the PTEN ( phosphatase and tensin homologue ) , a dual specificity PIP3 phosphatase that antagonizes AKT signaling , is capable of blocking MDM2 nuclear translocations , thus preventing the negative effects of growth factors on p53 activity .	Also, the PTEN (phosphatase and tensin homologue), a dual specificity PIP3 phosphatase that antagonizes AKT signaling, is capable of blocking MDM2 nuclear translocations, thus preventing the negative effects of growth factors on p53 activity.	2	22	antagonizes	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	18	19
Whereas , PTEN ( phosphatase and tensin homolog deleted on chromosome 10 ) , which negatively regulates PI3-K and Akt pathway , plays a central role in cell migration , survival and apoptosis For example , PTEN deletion has been reported to prevent ischemic brain injury , and enhances regenerative ability of adult corticospinal neurons .	Whereas, PTEN (phosphatase and tensin homolog deleted on chromosome 10), which negatively regulates PI3-K and Akt pathway, plays a central role in cell migration, survival and apoptosis For example, PTEN deletion has been reported to prevent ischemic brain injury, and enhances regenerative ability of adult corticospinal neurons.	2	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	19	20
Thus PTEN negatively regulates the Akt signaling pathway and inhibits cellular growth , and PTEN is now recognized as a potential therapeutic target in tissues that regenerate poorly , such as those of the CNS .	Thus PTEN negatively regulates the Akt signaling pathway and inhibits cellular growth, and PTEN is now recognized as a potential therapeutic target in tissues that regenerate poorly, such as those of the CNS.	1	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	5	6
On the other hand , since PTEN can directly inhibit the PI3K and Akt signaling pathway , there might exsit a complex balance between the neutralizing vs. reinforcing effects of upstream gene regulation , which would require further studies to draw a complete picture about the regulatory network .	On the other hand, since PTEN can directly inhibit the PI3K and Akt signaling pathway, there might exsit a complex balance between the neutralizing vs. reinforcing effects of upstream gene regulation, which would require further studies to draw a complete picture about the regulatory network.	6	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	13	14
Thus , in ethanol rats , HDACs may cause insulin resistance of skeletal muscle both through a decrease of glut4 expression and through PTEN mediated Akt inhibition .	Thus, in ethanol rats, HDACs may cause insulin resistance of skeletal muscle both through a decrease of glut4 expression and through PTEN mediated Akt inhibition.	8	26	mediated	Positive_early_activation	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	23	24	25	26
The decreased expression of PTEN may result in the activation of the AKT and ERK pathways , leading to the proliferation and migration of HCC cells .	The decreased expression of PTEN may result in the activation of the AKT and ERK pathways, leading to the proliferation and migration of HCC cells.	2	15	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	AKT	AKT	akt	4	5	12	13
Phosphatase and tensin homolog ( PTEN ) negatively regulates the PI3K and Akt pathway and is mutated or deficient in a spectrum of sporadic cancers and hereditary cancer syndromes characterized by hyperproliferation and resistance to apoptosis [ XREF_BIBR ] .	Phosphatase and tensin homolog (PTEN) negatively regulates the PI3K and Akt pathway and is mutated or deficient in a spectrum of sporadic cancers and hereditary cancer syndromes characterized by hyperproliferation and resistance to apoptosis [XREF_BIBR].	3	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	12	13
In contrast , aberrant oncogenic PI3K activation as well as a decrease in the expression of the tumor suppressor PTEN induces AKT activation accompanied by GSK-3beta inactivation and SHP2 activation .	In contrast, aberrant oncogenic PI3K activation as well as a decrease in the expression of the tumor suppressor PTEN induces AKT activation accompanied by GSK-3beta inactivation and SHP2 activation.	14	22	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of the tumor suppressor PTEN	pten	AKT	AKT	akt	19	20	21	22
Decreased Akt activity leads to reduction of MZ B cells , while increased Akt activity caused by PTEN deficiency results in an increase of MZ B cells [ XREF_BIBR , XREF_BIBR ] .	Decreased Akt activity leads to reduction of MZ B cells, while increased Akt activity caused by PTEN deficiency results in an increase of MZ B cells [XREF_BIBR, XREF_BIBR].	13	18	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	17	18	13	14
Additionally , the loss of phosphatase and tensin homolog ( PTEN ) activates the phosphatidylinositide 3-kinase/Akt ( PI3K and Akt ) and mammalian target of rapamycin ( mTOR ) pathways , which leads to upregulation of PD-L1 on glioma and breast cancer cells [ XREF_BIBR , XREF_BIBR ] .	Additionally, the loss of phosphatase and tensin homolog (PTEN) activates the phosphatidylinositide 3-kinase/Akt (PI3K and Akt) and mammalian target of rapamycin (mTOR) pathways, which leads to upregulation of PD-L1 on glioma and breast cancer cells [XREF_BIBR, XREF_BIBR].	3	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	loss of phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	5	9	19	20
The serine threonine kinase Akt has been shown to mediate IPC , and Akt activation is negatively regulated by the phosphatase PTEN , but whether PTEN activity is modulated by IPC has not been investigated .	The serine threonine kinase Akt has been shown to mediate IPC, and Akt activation is negatively regulated by the phosphatase PTEN, but whether PTEN activity is modulated by IPC has not been investigated.	13	22	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	21	22	13	14
Loss of PTEN results in activation of downstream effector Akt 58 .	Loss of PTEN results in activation of downstream effector Akt 58.	0	10	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	9	10
As a negative regulator of the PI3K pathway , loss of PTEN function through mutational inactivation or downregulation of expression results in activation of PI3K-AKT signaling and prevents trastuzumab mediated growth arrest in HER2 amplified breast cancer cells .	As a negative regulator of the PI3K pathway, loss of PTEN function through mutational inactivation or downregulation of expression results in activation of PI3K-AKT signaling and prevents trastuzumab mediated growth arrest in HER2 amplified breast cancer cells.	11	25	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	11	12	24	25
PTEN deletions activate the PI3K and Akt pathway , possibly involved in the pathogenesis of medulloblastomas .	PTEN deletions activate the PI3K and Akt pathway, possibly involved in the pathogenesis of medulloblastomas.	0	7	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	6	7
PTEN has been shown to be a natural inhibitor for PI3K at the 3-phosphate site and negatively regulates the AKT signaling pathway .	PTEN has been shown to be a natural inhibitor for PI3K at the 3-phosphate site and negatively regulates the AKT signaling pathway.	0	21	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	19	20
Also , PTEN can inhibit the activation of Akt .	Also, PTEN can inhibit the activation of Akt.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	8	9
PI3K-Akt signaling is antagonized by PTEN , and loss of PTEN enhances mTOR activation .	PI3K-Akt signaling is antagonized by PTEN, and loss of PTEN enhances mTOR activation.	0	6	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	5	6	0	1
Recent work suggests that cytosolic PTEN needs to be recruited to the plasma membrane , where it is activated and is then in the right location to inhibit PI3K-Akt .	Recent work suggests that cytosolic PTEN needs to be recruited to the plasma membrane, where it is activated and is then in the right location to inhibit PI3K-Akt.	4	29	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	5	6	28	29
PTEN activity then further suppressed Akt , permitting full restoration of PTEN expression .	PTEN activity then further suppressed Akt, permitting full restoration of PTEN expression.	0	6	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
Loss of PTEN and constitutive activation of AKT in T-ALL induce increased glucose metabolism and bypass the requirement of NOTCH1 signaling to sustain cell growth .	Loss of PTEN and constitutive activation of AKT in T-ALL induce increased glucose metabolism and bypass the requirement of NOTCH1 signaling to sustain cell growth.	2	9	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	7	8
PTEN acts as a tumor suppressor gene , and loss of PTEN can cause activation of the Akt signaling pathway leading to increased cell proliferation and inhibition of apoptosis [ XREF_BIBR ] .	PTEN acts as a tumor suppressor gene, and loss of PTEN can cause activation of the Akt signaling pathway leading to increased cell proliferation and inhibition of apoptosis [XREF_BIBR].	9	19	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	11	12	17	18
AR and JAK and STAT activity drives proliferation while loss of PTEN enhances AKT mediated cancer cell survival and proliferation .	AR and JAK and STAT activity drives proliferation while loss of PTEN enhances AKT mediated cancer cell survival and proliferation.	9	14	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	11	12	13	14
Some also show loss of PTEN , which leads to the activation of downstream Akt anti-apoptotic effectors such as Bcl-xl , Bcl-2 ( B-cell lymphoma 2 ) , and NF-kappaB , and other Akt effectors such as mTOR and p70 S6K .	Some also show loss of PTEN, which leads to the activation of downstream Akt anti-apoptotic effectors such as Bcl-xl, Bcl-2 (B-cell lymphoma 2), and NF-kappaB, and other Akt effectors such as mTOR and p70 S6K.	3	34	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	5	6	33	34
The exogenous expression of PTEN inhibits the PI3K and Akt signal and promotes the anti-proliferative effects of Res in HCT116 cells , while knockdown of PTEN increases PI3K and Akt signal but reduces the anti-proliferative function of Res .	The exogenous expression of PTEN inhibits the PI3K and Akt signal and promotes the anti-proliferative effects of Res in HCT116 cells, while knockdown of PTEN increases PI3K and Akt signal but reduces the anti-proliferative function of Res.	2	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	4	5	9	10
Akt is negatively regulated by the phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) , a tumor suppressor gene that dephosphorylates PIP3 .	Akt is negatively regulated by the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor gene that dephosphorylates PIP3.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	6	10	0	1
Either loss of PTEN alone ( KPTEN alveolar cells ) or high expression levels of ENTPD5 and IGF1R ( Kp53 and wild-type bronchiolar tumors ) are not sufficient to drive high Akt activation .	Either loss of PTEN alone (KPTEN alveolar cells) or high expression levels of ENTPD5 and IGF1R (Kp53 and wild-type bronchiolar tumors) are not sufficient to drive high Akt activation.	1	32	drive	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	3	4	31	32
As an important tumor suppressor , the pro apoptotic function of PTEN has been linked to its capacity antagonizing the PI3K and Akt signaling pathway .	As an important tumor suppressor, the pro apoptotic function of PTEN has been linked to its capacity antagonizing the PI3K and Akt signaling pathway.	9	24	antagonizing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	22	23
Remarkably , simultaneous knockdown of PTEN and NHERF1 , or of PTEN and PHLPP1 that is recruited by NHERF1 at the plasma membrane , significantly activates Akt and increases cell tumorigenicity .	Remarkably, simultaneous knockdown of PTEN and NHERF1, or of PTEN and PHLPP1 that is recruited by NHERF1 at the plasma membrane, significantly activates Akt and increases cell tumorigenicity.	3	27	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	26	27
This unexpected observation suggests that the effects of PTEN on AKT phosphorylation are context dependent with PTEN limiting AKT activation under glucose replete conditions , but increasing AKT activation by an unknown mechanism under glucose deprived conditions .	This unexpected observation suggests that the effects of PTEN on AKT phosphorylation are context dependent with PTEN limiting AKT activation under glucose replete conditions, but increasing AKT activation by an unknown mechanism under glucose deprived conditions.	14	19	limiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	16	17	18	19
Under normal conditions , Akt activation is inhibited by PTEN , a phosphatase that converts PIP3 to PIP2 [ XREF_BIBR ] .	Under normal conditions, Akt activation is inhibited by PTEN, a phosphatase that converts PIP3 to PIP2 [XREF_BIBR].	4	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	4	5
The fact that Jurkat T cells , which are deficient in the PIP3 phosphatase PTEN that inactivates AKT , express high levels of beta-catenin compared to primary T cells is entirely consistent with this finding [ 5 , and data not shown ] .	The fact that Jurkat T cells, which are deficient in the PIP3 phosphatase PTEN that inactivates AKT, express high levels of beta-catenin compared to primary T cells is entirely consistent with this finding [5, and data not shown].	9	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	17	18
This is perhaps mediated by increased expression of PTEN and PKCdelta asboth PTEN and PKCdelta can inhibit Akt .	This is perhaps mediated by increased expression of PTEN and PKCdelta asboth PTEN and PKCdelta can inhibit Akt.	12	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	12	13	17	18
PTEN negatively regulates activity of the PI3K and AKT pathway , which is a dual-specificity phosphatase acting as both protein phosphatase and lipid phosphatase that suppresses PI3K activity through converting PIP3 to PIP2 [ XREF_BIBR ] .	PTEN negatively regulates activity of the PI3K and AKT pathway, which is a dual-specificity phosphatase acting as both protein phosphatase and lipid phosphatase that suppresses PI3K activity through converting PIP3 to PIP2 [XREF_BIBR].	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
Transient overexpression of PTEN in SMCs of SV and IMA inhibited AKT and PKB activity and upstream of AKT and PKB , caused a reduction of IGF-1 receptors .	Transient overexpression of PTEN in SMCs of SV and IMA inhibited AKT and PKB activity and upstream of AKT and PKB, caused a reduction of IGF-1 receptors.	1	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	overexpression of PTEN	pten	PKB	PKB	pkb	3	4	13	14
Phosphatase and tensin homolog ( PTEN ) negatively regulates Akt signaling by antagonizing the action of phosphatidylinositol 3-kinase ( PI3K ) [ XREF_BIBR ] .	Phosphatase and tensin homolog (PTEN) negatively regulates Akt signaling by antagonizing the action of phosphatidylinositol 3-kinase (PI3K) [XREF_BIBR].	3	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	9	10
Loss of Pten results in activation of the Akt and PKB signaling pathway .	Loss of Pten results in activation of the Akt and PKB signaling pathway.	0	12	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Pten	Loss of Pten	pten	Akt	Akt	akt	2	3	8	9
For example , PTEN , which negatively regulates the PI3K-AKT survival pathway , was upregulated after DOX treatment .	For example, PTEN, which negatively regulates the PI3K-AKT survival pathway, was upregulated after DOX treatment.	3	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	9	10
Transfection of PTEN into the PC3 cells decreased the activation of Akt and the downstream mTOR regulated 70-kDa S6 ( p70 ( s6k ) ) kinase and reversed the resistance to doxorubicin in these cells , indicating that changes in PTEN status and Akt activation modulate the cellular response to doxorubicin .	Transfection of PTEN into the PC3 cells decreased the activation of Akt and the downstream mTOR regulated 70-kDa S6 (p70 (s6k)) kinase and reversed the resistance to doxorubicin in these cells, indicating that changes in PTEN status and Akt activation modulate the cellular response to doxorubicin.	0	12	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	11	12
Taken together , our data suggest that DZNep treatment of human CCSCs causes an increase in expression of PTEN , which may in turn repress the pro survival signaling pathway PI3K and Akt , thereby leading to apoptosis ( summarized in XREF_FIG ) .	Taken together, our data suggest that DZNep treatment of human CCSCs causes an increase in expression of PTEN, which may in turn repress the pro survival signaling pathway PI3K and Akt, thereby leading to apoptosis (summarized in XREF_FIG).	16	33	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	18	19	32	33
PTEN can inhibit Akt and mTOR signaling [ XREF_BIBR ] .	PTEN can inhibit Akt and mTOR signaling [XREF_BIBR].	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
PTEN loss can be activated AKT , thus promoting the progression of tumor .	PTEN loss can be activated AKT, thus promoting the progression of tumor.	0	6	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
Since the AKT pathway has been shown to be activated by Toxoplasma infection [ XREF_BIBR ] , an interesting possibility is that miR-17-92 mediated decrease in levels of PTEN during Toxoplasma infection in brain cells could be activating AKT pathways which may result in the development of brain cancer .	Since the AKT pathway has been shown to be activated by Toxoplasma infection [XREF_BIBR], an interesting possibility is that miR-17-92 mediated decrease in levels of PTEN during Toxoplasma infection in brain cells could be activating AKT pathways which may result in the development of brain cancer.	26	39	activating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	levels of PTEN	pten	AKT	AKT	akt	28	29	38	39
Over-expressed PTEN and PTPRJ potentially blocked B-As cell Ras and Akt signaling ; however , it appeared not to be sufficient enough to halt malignant transformation of As exposed BEAS-2B cells .	Over-expressed PTEN and PTPRJ potentially blocked B-As cell Ras and Akt signaling; however, it appeared not to be sufficient enough to halt malignant transformation of As exposed BEAS-2B cells.	0	11	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	10	11
PTEN antagonizes PI3K function , and the loss of PTEN increases PI3K-AKT signaling [ XREF_BIBR ] .	PTEN antagonizes PI3K function, and the loss of PTEN increases PI3K-AKT signaling [XREF_BIBR].	7	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	9	10	11	12
Interestingly , RNAi mediated knockdown of EZH2 restored PTEN expression and down-regulated the AKT and mTOR activities in Evi1 transduced BM cells , suggesting that Evi1 functions as a platform to recruit PcG proteins to the PTEN locus .	Interestingly, RNAi mediated knockdown of EZH2 restored PTEN expression and down-regulated the AKT and mTOR activities in Evi1 transduced BM cells, suggesting that Evi1 functions as a platform to recruit PcG proteins to the PTEN locus.	6	16	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	EZH2 restored PTEN expression	pten	AKT	AKT	akt	8	9	13	14
These results revealed that HES1 suppressed PTEN expression and promoted activation of the AKT signalling pathway in breast cancer .	These results revealed that HES1 suppressed PTEN expression and promoted activation of the AKT signalling pathway in breast cancer.	4	15	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	HES1 suppressed PTEN expression	pten	AKT	AKT	akt	6	7	13	14
Using this model , we have shown that PTEN expression loss in MECs results in constitutive AKT activation and induces multiple phenotypic alterations characteristic of breast tumor cells , including growth factor independent proliferation and protection from anoikis .	Using this model, we have shown that PTEN expression loss in MECs results in constitutive AKT activation and induces multiple phenotypic alterations characteristic of breast tumor cells, including growth factor independent proliferation and protection from anoikis.	8	18	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	16	17
In addition , studies show that mTOR inhibition decreases PTEN transcription and subsequently activates AKT .	In addition, studies show that mTOR inhibition decreases PTEN transcription and subsequently activates AKT.	6	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	mTOR inhibition decreases PTEN transcription	pten	AKT	AKT	akt	9	10	14	15
PTEN inhibits Akt signaling pathway and regulates glucose metabolism [ XREF_BIBR ] .	PTEN inhibits Akt signaling pathway and regulates glucose metabolism [XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	2	3
Loss of PTEN ( phosphatase and tensin homologue deleted on chromosome 10 ) , which counters the activity of PI3K , leads to constitutive activation of Akt .	Loss of PTEN (phosphatase and tensin homologue deleted on chromosome 10), which counters the activity of PI3K, leads to constitutive activation of Akt.	0	27	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	26	27
Patients with TNBC tumors that lose PTEN expression have poorer survival , as PTEN negatively regulates the PI3K-AKT signaling pathway .	Patients with TNBC tumors that lose PTEN expression have poorer survival, as PTEN negatively regulates the PI3K-AKT signaling pathway.	13	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	13	14	17	18
MAPK-ERK is also activated by mutations in the BRAF gene , while PI3K-AKT is activated by loss of the tumor suppressor gene PTEN .	MAPK-ERK is also activated by mutations in the BRAF gene, while PI3K-AKT is activated by loss of the tumor suppressor gene PTEN.	12	23	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of the tumor suppressor gene PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	22	23	12	13
We also found that treatment of HeLa cells with PTEN siRNA significantly increased the expression of p-AKT and p-GSK3beta , but further treatment with PA-MSHA suppressed the activation of the AKT pathway induced by PTEN siRNA .	We also found that treatment of HeLa cells with PTEN siRNA significantly increased the expression of p-AKT and p-GSK3beta, but further treatment with PA-MSHA suppressed the activation of the AKT pathway induced by PTEN siRNA.	30	35	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	34	35	30	31
Furthermore , PTEN may enhance the enzymatic activity of glutathione peroxidase , superoxide dismutase and catalase by suppressing the PI3K and AKT signaling pathway in lung cancer cells .	Furthermore, PTEN may enhance the enzymatic activity of glutathione peroxidase, superoxide dismutase and catalase by suppressing the PI3K and AKT signaling pathway in lung cancer cells.	2	23	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	21	22
Whereas PTEN deletion increased basal Akt activation , PDK1 knockdown did not .	Whereas PTEN deletion increased basal Akt activation, PDK1 knockdown did not.	1	6	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	5	6
27 These findings suggested that downregulation of TET1 reduces the expression of PTEN , which subsequently activate AKT and MTOR pathway in COX-2-driven HCC .	27 These findings suggested that downregulation of TET1 reduces the expression of PTEN, which subsequently activate AKT and MTOR pathway in COX-2-driven HCC.	7	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	TET1 reduces the expression of PTEN	pten	AKT	AKT	akt	12	13	17	18
Phosphoinositide dependent kinase-1 ( PDK-1 ) , an upstream regulator of Akt and PKB , demonstrated increased phosphorylation of an activating residue , Ser241 ( XREF_FIG ) , while the polyphosphoinositide phosphatase PTEN , which prevents Akt and PKB activation , was downregulated to some extent ( XREF_FIG ) .	Phosphoinositide dependent kinase-1 (PDK-1), an upstream regulator of Akt and PKB, demonstrated increased phosphorylation of an activating residue, Ser241 (XREF_FIG), while the polyphosphoinositide phosphatase PTEN, which prevents Akt and PKB activation, was downregulated to some extent (XREF_FIG).	29	42	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	32	33	38	39
The N-terminal phosphatase domain of PTEN antagonizes the PI3K and AKT pathway , but its C-terminal function is less defined .	The N-terminal phosphatase domain of PTEN antagonizes the PI3K and AKT pathway, but its C-terminal function is less defined.	3	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	10	11
XREF_BIBR In addition , the tumor suppressor gene PTEN can inhibit Akt activation via a reduction in levels of P13K in the cell membrane .	XREF_BIBR In addition, the tumor suppressor gene PTEN can inhibit Akt activation via a reduction in levels of P13K in the cell membrane.	4	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	11	12
The PI3K and AKT pathway is negatively regulated by the lipid phosphatase , phosphatase and tensin homolog ( PTEN ) [ XREF_BIBR ] , which has been identified as a tumor suppressor [ XREF_BIBR ] .	The PI3K and AKT pathway is negatively regulated by the lipid phosphatase, phosphatase and tensin homolog (PTEN) [XREF_BIBR], which has been identified as a tumor suppressor [XREF_BIBR].	1	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	13	17	3	4
Knockdown of PTEN in cells containing wild-type PTEN enhanced nuclear P-AKT , whereas expression of wild-type PTEN , but not phosphatase dead mutants ( C124S or G129E ) , markedly reduced nuclear P-AKT in PTEN null cells .	Knockdown of PTEN in cells containing wild-type PTEN enhanced nuclear P-AKT, whereas expression of wild-type PTEN, but not phosphatase dead mutants (C124S or G129E), markedly reduced nuclear P-AKT in PTEN null cells.	0	11	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	P-AKT	P-AKT	P-AKT	2	3	10	11
By exhibiting dual-specificity protein- and lipid-phosphatase activity , phosphatase and tensin homolog ( PTEN ) directly antagonizes the PI3K and Akt signaling by dephosphorylation of phosphatidylinositol-3 ,4,5-trisphosphate , the lipid product of PI3K .	By exhibiting dual-specificity protein- and lipid-phosphatase activity, phosphatase and tensin homolog (PTEN) directly antagonizes the PI3K and Akt signaling by dephosphorylation of phosphatidylinositol-3,4,5-trisphosphate, the lipid product of PI3K.	11	21	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	20	21
One well-known target gene of miR-25 , phosphatase and tensin homologue ( PTEN ) , represses tumorigenicity by downregulating the highly oncogenic PI3K and Akt signaling pathway XREF_BIBR .	One well-known target gene of miR-25, phosphatase and tensin homologue (PTEN), represses tumorigenicity by downregulating the highly oncogenic PI3K and Akt signaling pathway XREF_BIBR.	10	27	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	12	13	24	25
In this scenario , in white adipocytes lacking Ecscr , elevated PTEN activity reduces AKT activation , thereby impairing basal and insulin dependent suppression of lipolysis .	In this scenario, in white adipocytes lacking Ecscr, elevated PTEN activity reduces AKT activation, thereby impairing basal and insulin dependent suppression of lipolysis.	11	15	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	11	12	14	15
PTEN negatively regulates the PI3K-AKT signaling pathway via its principal catalytic function to dephosphorylate phosphatidylinositol3 ,4,5 trisphosphate ( PIP3 ) , a messenger that contributes to partial AKT activation XREF_BIBR XREF_BIBR .	PTEN negatively regulates the PI3K-AKT signaling pathway via its principal catalytic function to dephosphorylate phosphatidylinositol3,4,5 trisphosphate (PIP3), a messenger that contributes to partial AKT activation XREF_BIBR XREF_BIBR.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	4	5
Pten deletion restores AKT and ERK1/2 activation in Fgfr2 deficient lenses .	Pten deletion restores AKT and ERK1/2 activation in Fgfr2 deficient lenses.	0	6	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	0	1	3	4
This is of particular interest as Akt is negatively regulated by PTEN , suggesting that the loss of PTEN in prostate cancer could possibly inactivate DAB2IP through Akt activation , thereby perhaps leading to greater prevalence of prostate cancer metastasis Recent results have shown that DAB2IP can suppress the Akt pathway through direct interaction .	This is of particular interest as Akt is negatively regulated by PTEN, suggesting that the loss of PTEN in prostate cancer could possibly inactivate DAB2IP through Akt activation, thereby perhaps leading to greater prevalence of prostate cancer metastasis Recent results have shown that DAB2IP can suppress the Akt pathway through direct interaction.	6	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	6	7
Here , reduction in PTEN increases the levels of upstream activator of AKT ( PIP 3 ) and compensates for the reduction in AKT by increased de-phosphorylation .	Here, reduction in PTEN increases the levels of upstream activator of AKT (PIP 3) and compensates for the reduction in AKT by increased de-phosphorylation.	2	14	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	12	13
Furthermore , we also show that homozygous Grp78 deletion in the endometrial epithelial cells not only prevents EAC development , it also interrupts and attenuates AKT activation mediated by PTEN loss .	Furthermore, we also show that homozygous Grp78 deletion in the endometrial epithelial cells not only prevents EAC development, it also interrupts and attenuates AKT activation mediated by PTEN loss.	25	30	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	29	30	25	26
P-PI3K and p-Akt activate PI3K and Akt signaling pathway , while PTEN can inhibit PI3K and Akt signaling pathway [ XREF_BIBR ] .	P-PI3K and p-Akt activate PI3K and Akt signaling pathway, while PTEN can inhibit PI3K and Akt signaling pathway [XREF_BIBR].	11	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	16	17
The tumor suppressor phosphatase , PTEN , downregulates the PI3K and Akt signaling pathway by dephosphorylation of PIP3 back to PIP2 XREF_BIBR .	The tumor suppressor phosphatase, PTEN, downregulates the PI3K and Akt signaling pathway by dephosphorylation of PIP3 back to PIP2 XREF_BIBR.	3	13	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	11	12
The loss of functional PTEN leads to increased activity of AKT and mammalian target of rapamycin ( mTOR ) kinase pathways , which promotes both cell survival and proliferation through the phosphorylation as well as inactivation of multiple downstream mediators 27 , 28 .	The loss of functional PTEN leads to increased activity of AKT and mammalian target of rapamycin (mTOR) kinase pathways, which promotes both cell survival and proliferation through the phosphorylation as well as inactivation of multiple downstream mediators 27, 28.	1	11	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of functional PTEN	pten	AKT	AKT	akt	4	5	10	11
Unlike classical OIS , such as that induced by Ha-rasV12 , Mos and CDK6 , senescence induced by PTEN loss or activated AKT is not accompanied by DNA damage responses [ XREF_BIBR , XREF_BIBR ] .	Unlike classical OIS, such as that induced by Ha-rasV12, Mos and CDK6, senescence induced by PTEN loss or activated AKT is not accompanied by DNA damage responses [XREF_BIBR, XREF_BIBR].	15	25	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	18	19	22	23
The presence of wild-type PTEN allele ( s ) may compromise the efficacy of rapamycin , as recent studies show that mTOR inhibition decreases PTEN transcription and thus increases AKT activation [ XREF_BIBR ; XREF_BIBR ] .	The presence of wild-type PTEN allele (s) may compromise the efficacy of rapamycin, as recent studies show that mTOR inhibition decreases PTEN transcription and thus increases AKT activation [XREF_BIBR; XREF_BIBR].	21	30	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	mTOR inhibition decreases PTEN transcription	pten	AKT	AKT	akt	24	25	29	30
The loss of PTEN results in the activation of PI3K and Akt and ERK pathways , leading to a reduction in cellular apoptosis and an increase in mitogen signaling [ XREF_BIBR , XREF_BIBR ] .	The loss of PTEN results in the activation of PI3K and Akt and ERK pathways, leading to a reduction in cellular apoptosis and an increase in mitogen signaling [XREF_BIBR, XREF_BIBR].	1	12	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	3	4	11	12
Loss of PTEN causes increased and constitutive activation of the PI3K-AKT pathway .	Loss of PTEN causes increased and constitutive activation of the PI3K-AKT pathway.	0	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	2	3	10	11
A primary function of the lipid phosphatase activity of PTEN is downregulating the PI3K-Akt signaling pathway 6 .	A primary function of the lipid phosphatase activity of PTEN is downregulating the PI3K-Akt signaling pathway 6.	7	15	downregulating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	9	10	13	14
Both in the brain and in cultured cells , DJ-1 deficiency is associated with accumulation of the phosphatase PTEN that antagonizes the kinase AKT .	Both in the brain and in cultured cells, DJ-1 deficiency is associated with accumulation of the phosphatase PTEN that antagonizes the kinase AKT.	14	24	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	18	19	23	24
Previous studies have shown that PTEN phosphatase negatively regulates PI3K and Akt signaling , XREF_BIBR , XREF_BIBR but is frequently inactivated by a gene deletion or mutation , and also degraded in the proteosomes of many types of cancer cells .	Previous studies have shown that PTEN phosphatase negatively regulates PI3K and Akt signaling, XREF_BIBR, XREF_BIBR but is frequently inactivated by a gene deletion or mutation, and also degraded in the proteosomes of many types of cancer cells.	5	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	11	12
In this model , ligand activated PR-B by inducing PTEN expression inhibits the AKT pathway which in turn lets UVRAG to be expressed thus allowing autophagosome formation .	In this model, ligand activated PR-B by inducing PTEN expression inhibits the AKT pathway which in turn lets UVRAG to be expressed thus allowing autophagosome formation.	9	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	9	10	13	14
PTEN loss contributes to activate the PI3K and AKT signaling pathway and consequent tumor genesis .	PTEN loss contributes to activate the PI3K and AKT signaling pathway and consequent tumor genesis.	0	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
PTEN , a known tumour suppressor , inhibits the PI3K pathway and prevents Akt activation 36 .	PTEN, a known tumour suppressor, inhibits the PI3K pathway and prevents Akt activation 36.	0	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	13	14
Loss of PTEN leads to increased PDK1 and AKT due to PIP3 accumulation resulting in activation of mTORC1 and its downstream effectors [ XREF_BIBR ] .	Loss of PTEN leads to increased PDK1 and AKT due to PIP3 accumulation resulting in activation of mTORC1 and its downstream effectors [XREF_BIBR].	0	9	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	8	9
Thus , PTEN negatively regulates the Akt pathway , while loss of PTEN results in overactive Akt , which induces proliferation and promotes survival by inhibiting apoptosis [ XREF_BIBR , XREF_BIBR ] .	Thus, PTEN negatively regulates the Akt pathway, while loss of PTEN results in overactive Akt, which induces proliferation and promotes survival by inhibiting apoptosis [XREF_BIBR, XREF_BIBR].	2	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	6	7
Two protein phosphatases , PTEN and SHIP ( SH2 containing inositol phosphatase ) , negatively regulate Akt activation by blocking Akt translocation to the plasma membrane ( XREF_FIG ) .	Two protein phosphatases, PTEN and SHIP (SH2 containing inositol phosphatase), negatively regulate Akt activation by blocking Akt translocation to the plasma membrane (XREF_FIG).	2	17	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	16	17
The PI3K and AKT pathway is the major effector of insulin action , and PTEN antagonizes AKT , thus negatively regulating insulin signaling ( Schultze etal .	The PI3K and AKT pathway is the major effector of insulin action, and PTEN antagonizes AKT, thus negatively regulating insulin signaling (Schultze etal.	14	17	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	16	17
The IIS pathway has an internal negative regulator : the phosphatase DAF-18 ( a PTEN orthologue ) , which acts in opposition to AGE-1 , mediates PtdIns ( 3,4,5 ) P 3 dissociation and reduces AKT activation XREF_BIBR .	The IIS pathway has an internal negative regulator : the phosphatase DAF-18 (a PTEN orthologue), which acts in opposition to AGE-1, mediates PtdIns (3,4,5) P 3 dissociation and reduces AKT activation XREF_BIBR.	14	37	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	35	36
Transactivation of PTEN negatively regulates AKT activity together with AKT dependent activation of mTORC1 [ XREF_BIBR ] .	Transactivation of PTEN negatively regulates AKT activity together with AKT dependent activation of mTORC1 [XREF_BIBR].	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	5	6
PTEN , a tumor suppressor gene , negatively regulates PI3K and Akt driven cell growth and survival .	PTEN, a tumor suppressor gene, negatively regulates PI3K and Akt driven cell growth and survival.	0	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	11	12
In addition , several studies have also shown that cardiac HIF-1alpha expression can increase sublethal ROS production , resulting in oxidation and inactivation of the protein and lipid phosphatase and tensin homolog ( PTEN ) , which negatively regulates the PI3K and Akt survival pathway .	In addition, several studies have also shown that cardiac HIF-1alpha expression can increase sublethal ROS production, resulting in oxidation and inactivation of the protein and lipid phosphatase and tensin homolog (PTEN), which negatively regulates the PI3K and Akt survival pathway.	20	44	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	28	32	42	43
PTEN antagonizes the PI3K and AKT survival pathway by its phospholipid 3-phosphatase activity , which , in turn , regulates proliferation , migration , and apoptosis .	PTEN antagonizes the PI3K and AKT survival pathway by its phospholipid 3-phosphatase activity, which, in turn, regulates proliferation, migration, and apoptosis.	0	7	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
The tumor suppressor PTEN , which antagonizes the PI3K and Akt pathway , has increasingly been recognized to play a key role in neural functions and its level found reduced in AD brains .	The tumor suppressor PTEN, which antagonizes the PI3K and Akt pathway, has increasingly been recognized to play a key role in neural functions and its level found reduced in AD brains.	0	18	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	10	11
Importantly , ceramide induced translocation of PTEN to the cell membrane inhibits the PI3K-Akt pathway , resulting in increased BAD mobilization to the mitochondria and subsequent release of additional pro apoptotic mediators [ XREF_BIBR , XREF_BIBR ] .	Importantly, ceramide induced translocation of PTEN to the cell membrane inhibits the PI3K-Akt pathway, resulting in increased BAD mobilization to the mitochondria and subsequent release of additional pro apoptotic mediators [XREF_BIBR, XREF_BIBR].	2	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	ceramide induced translocation of PTEN to the cell membrane	pten	PI3K-Akt	PI3K-Akt	pi3k-akt	6	7	13	14
As a lipid phosphatase , PTEN directly antagonizes the PI3K and AKT pathway which regulates growth , proliferation , survival , apoptosis and cell migration as well as the development and maintenance of the nervous system XREF_BIBR , XREF_BIBR .	As a lipid phosphatase, PTEN directly antagonizes the PI3K and AKT pathway which regulates growth, proliferation, survival, apoptosis and cell migration as well as the development and maintenance of the nervous system XREF_BIBR, XREF_BIBR.	5	12	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	11	12
Overexpression of PTEN reinforced the anti-proliferative effect of EVO in the 143Bcells , while knockdown of PTEN upregulated PI3K and Akt signaling transduction and reversed the inhibitory effect of EVO on 143B cell proliferation .	Overexpression of PTEN reinforced the anti-proliferative effect of EVO in the 143Bcells, while knockdown of PTEN upregulated PI3K and Akt signaling transduction and reversed the inhibitory effect of EVO on 143B cell proliferation.	14	22	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	20	21
Loss of PTEN leads to constitutive activation of AKT , which leads to up-regulation of mTOR .	Loss of PTEN leads to constitutive activation of AKT, which leads to up-regulation of mTOR.	0	9	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	8	9
Loss of PTEN can lead to activation of Akt pathway , suppression of apoptosis , and increased cell survival [ XREF_BIBR ] .	Loss of PTEN can lead to activation of Akt pathway, suppression of apoptosis, and increased cell survival [XREF_BIBR].	0	9	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	8	9
Moreover , the level of Akt phosphorylation increased with Pten depletion , consistent with activation of Akt by loss of Pten ( XREF_FIG ) .	Moreover, the level of Akt phosphorylation increased with Pten depletion, consistent with activation of Akt by loss of Pten (XREF_FIG).	14	22	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Pten	loss of Pten	pten	Akt	Akt	akt	20	21	16	17
As an important tumor suppressor gene , PTEN can negatively regulate the PI3K-AKT signal pathway to inhibit tumor occurrence and progression .	As an important tumor suppressor gene, PTEN can negatively regulate the PI3K-AKT signal pathway to inhibit tumor occurrence and progression.	7	14	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	7	8	12	13
To assess how well endogenous PTEN suppresses Akt , we also depleted PTEN in the same cells ( XREF_FIG ) .	To assess how well endogenous PTEN suppresses Akt, we also depleted PTEN in the same cells (XREF_FIG).	4	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	7	8
The tumor suppressor protein phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) that dephosphorylates the 3 position of phosphoinositides and thereby inactivates Akt is also deregulated in breast carcinoma .	The tumor suppressor protein phosphatase and tensin homolog deleted on chromosome 10 (PTEN) that dephosphorylates the 3 position of phosphoinositides and thereby inactivates Akt is also deregulated in breast carcinoma.	10	26	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	25	26
Moreover , our study showed that rAGAP significantly increased expression of PTEN , and decreased expression of PI3K and phosphorylation activation of Akt .	Moreover, our study showed that rAGAP significantly increased expression of PTEN, and decreased expression of PI3K and phosphorylation activation of Akt.	6	23	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	rAGAP significantly increased expression of PTEN, and decreased expression of PI3K	pten	Akt	Akt	akt	11	12	22	23
Deletion of Pten results in activation of the PI3K and Akt pathway and may promote genomic instability .	Deletion of Pten results in activation of the PI3K and Akt pathway and may promote genomic instability.	0	11	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	2	3	10	11
XREF_BIBR PTEN inhibits Akt and mTOR and MAPK signaling , leading to cell death and growth regulation .	XREF_BIBR PTEN inhibits Akt and mTOR and MAPK signaling, leading to cell death and growth regulation.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	3	4
Here , we show that EpCAM overexpression inhibits PTEN expression and activates AKT and mTOR signalling in NPC cells .	Here, we show that EpCAM overexpression inhibits PTEN expression and activates AKT and mTOR signalling in NPC cells.	5	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	EpCAM overexpression inhibits PTEN expression	pten	AKT	AKT	akt	8	9	12	13
It is reported that PTEN gene inhibits Akt activation ( phosphorylation ) XREF_BIBR - XREF_BIBR , which plays a central role in an outermost complex network of cell growth modulation that affects protein biosynthesis , cell cycle arrest and apoptosis XREF_BIBR , XREF_BIBR .	It is reported that PTEN gene inhibits Akt activation (phosphorylation) XREF_BIBR - XREF_BIBR, which plays a central role in an outermost complex network of cell growth modulation that affects protein biosynthesis, cell cycle arrest and apoptosis XREF_BIBR, XREF_BIBR.	4	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	7	8
PTEN prevents the activation of AKT via the de-phosphorilation of phosphatidylinositol -trisphosphate ( PIP3 ) to phosphatidylinositol 4,5-bisphosphate ( PIP2 ) .	PTEN prevents the activation of AKT via the de-phosphorilation of phosphatidylinositol -trisphosphate (PIP3) to phosphatidylinositol 4,5-bisphosphate (PIP2).	0	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
PTEN is a negative regulator of PI3K ; therefore , loss of PTEN enables continued Akt activation .	PTEN is a negative regulator of PI3K; therefore, loss of PTEN enables continued Akt activation.	10	16	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	12	13	15	16
Our findings imply that loss of PTEN in a tumor model with low growth factor receptors does not necessarily result in Akt activation .	Our findings imply that loss of PTEN in a tumor model with low growth factor receptors does not necessarily result in Akt activation.	4	23	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	6	7	21	22
As expected , PTEN overexpression inhibited AKT activation and it increased PLZF expression accordingly ( XREF_FIG ) .	As expected, PTEN overexpression inhibited AKT activation and it increased PLZF expression accordingly (XREF_FIG).	3	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN overexpression	pten	AKT	AKT	akt	3	4	6	7
The authors found no phosphatidyl inositol 3-kinase catalytic subunit ( PIK3CA ) mutations in the primary specimens or cell lines , suggesting that loss of PTEN activates the PI3K and AKT pathway in MCL .	The authors found no phosphatidyl inositol 3-kinase catalytic subunit (PIK3CA) mutations in the primary specimens or cell lines, suggesting that loss of PTEN activates the PI3K and AKT pathway in MCL.	23	31	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	25	26	30	31
Our data suggest that UA inhibits miR-21 expression and increases PTEN expression , which in turn inhibits Akt and mTOR and restores normal levels of autophagy .	Our data suggest that UA inhibits miR-21 expression and increases PTEN expression, which in turn inhibits Akt and mTOR and restores normal levels of autophagy.	4	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	UA inhibits miR-21 expression and increases PTEN expression	pten	Akt	Akt	akt	10	11	17	18
PTEN inhibition activates PI3K and AKT signalling and ER stress both in vitro and in vivo and results in pulmonary fibrosis .	PTEN inhibition activates PI3K and AKT signalling and ER stress both in vitro and in vivo and results in pulmonary fibrosis.	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
Loss of PTEN leads to Akt activation in cancer cells .	Loss of PTEN leads to Akt activation in cancer cells.	0	6	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	5	6
Reduced PTEN levels leads to hyperactive Akt through PDK1 ( 3-phosphoinositide-dependent kinase 1 )-mediated phosphorylation .	Reduced PTEN levels leads to hyperactive Akt through PDK1 (3-phosphoinositide-dependent kinase 1)-mediated phosphorylation.	1	7	leads	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	PTEN	PTEN levels	pten	Akt	Akt	akt	1	2	6	7
However , PTEN can inhibit Akt and mTOR signaling [ XREF_BIBR ] .	However, PTEN can inhibit Akt and mTOR signaling [XREF_BIBR].	2	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	5	6
By converting PIP3 into PIP2 , PTEN negatively regulates PI3K and AKT signaling and subsequent downstream pathways .	By converting PIP3 into PIP2, PTEN negatively regulates PI3K and AKT signaling and subsequent downstream pathways.	6	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	11	12
Conversely , the lipid phosphatase PTEN attenuates Akt activation by dephosphorylating the 3 ' position of phosphatidyl-inositols [ XREF_BIBR ] .	Conversely, the lipid phosphatase PTEN attenuates Akt activation by dephosphorylating the 3 ' position of phosphatidyl-inositols [XREF_BIBR].	2	8	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	7	8
Finally , because reduced PTEN activates the PI3 and AKT mediated pathway of cell growth and survival , we demonstrate that PTEN deficiency is associated with activated AKT in skin resident but not circulating SS cells , suggesting that the cutaneous milieu may strongly contribute to the SS cell growth .	Finally, because reduced PTEN activates the PI3 and AKT mediated pathway of cell growth and survival, we demonstrate that PTEN deficiency is associated with activated AKT in skin resident but not circulating SS cells, suggesting that the cutaneous milieu may strongly contribute to the SS cell growth.	3	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	9	10
In contrast to control fibroblasts where high PTEN activity inhibits PI3K-Akt , we have discovered that in IPF fibroblasts , beta1 integrin interaction with polymerized collagen generates an aberrant matrix recognition signal characterized by activated Akt-S6K1 activity because of inappropriately low PTEN activity .	In contrast to control fibroblasts where high PTEN activity inhibits PI3K-Akt, we have discovered that in IPF fibroblasts, beta1 integrin interaction with polymerized collagen generates an aberrant matrix recognition signal characterized by activated Akt-S6K1 activity because of inappropriately low PTEN activity.	7	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	7	8	10	11
The PTEN protein antagonizes PI3K function and negatively regulates Akt and mTOR activity [ XREF_BIBR * * ] .	The PTEN protein antagonizes PI3K function and negatively regulates Akt and mTOR activity [XREF_BIBR **].	1	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	9	10
Clones that acquired loss of Pten had increased PI3K and Akt signaling and may , therefore , have had a selective advantage over tumors that retained wild-type Pten within the same animal .	Clones that acquired loss of Pten had increased PI3K and Akt signaling and may, therefore, have had a selective advantage over tumors that retained wild-type Pten within the same animal.	3	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	loss of Pten	pten	Akt	Akt	akt	5	6	10	11
Overall , PTEN loss and activation of PI3K and AKT signal lead to the improved ability to handle metabolic stress in mice .	Overall, PTEN loss and activation of PI3K and AKT signal lead to the improved ability to handle metabolic stress in mice.	2	11	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	9	10
Suppression of PTEN by miR-21 is shown to induce phosphatidylinositide 3-kinases ( PI3K ) and Akt activity , and subsequently induces metalloproteinase-2 ( MMP-2 ) expression [ XREF_BIBR ] .	Suppression of PTEN by miR-21 is shown to induce phosphatidylinositide 3-kinases (PI3K) and Akt activity, and subsequently induces metalloproteinase-2 (MMP-2) expression [XREF_BIBR].	0	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	15	16
It has been reported that the PTEN and AKT signaling is a pivotal signaling pathway involved in EMT ; PTEN accumulation in tumor cells might negatively regulate Akt by decreasing Akt phosphorylation level , thus contributes to E-cadherin expression increase and suppression of the EMT [ XREF_BIBR , XREF_BIBR ] .	It has been reported that the PTEN and AKT signaling is a pivotal signaling pathway involved in EMT; PTEN accumulation in tumor cells might negatively regulate Akt by decreasing Akt phosphorylation level, thus contributes to E-cadherin expression increase and suppression of the EMT [XREF_BIBR, XREF_BIBR].	19	28	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	19	20	27	28
The PI3K and Akt signaling pathway is negatively regulated by PTEN .	The PI3K and Akt signaling pathway is negatively regulated by PTEN.	3	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	3	4
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR It is well established that PTEN negatively regulates PI3K and Akt signaling pathway and neurite outgrowth by reducing PIP3 level .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR It is well established that PTEN negatively regulates PI3K and Akt signaling pathway and neurite outgrowth by reducing PIP3 level.	12	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	12	13	17	18
Loss of PTEN expression induced activation of the PI3K and AKT pathway , resulting in increased phosphorylation of AKT in both cell lines .	Loss of PTEN expression induced activation of the PI3K and AKT pathway, resulting in increased phosphorylation of AKT in both cell lines.	2	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	2	3	10	11
43 Yet the AKT expression levels of the UACC-3199 and UACC-3171 tumor xenografts were not statistically different from each other , suggesting that the increased expression of PTEN in the UACC-3199 xenograft did not negatively regulate AKT in this tumor model , and therefore did not reduce cell proliferation .	43 Yet the AKT expression levels of the UACC-3199 and UACC-3171 tumor xenografts were not statistically different from each other, suggesting that the increased expression of PTEN in the UACC-3199 xenograft did not negatively regulate AKT in this tumor model, and therefore did not reduce cell proliferation.	25	40	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	AKT	AKT	akt	27	28	36	37
For example , PI3K phosphorylates PIP2 to active PIP3 , whereas the tumor suppressor phosphatase and tensin homolog ( PTEN ) converts PIP3 to inactive PIP2 and thereby impairs AKT activation [ XREF_BIBR ] .	For example, PI3K phosphorylates PIP2 to active PIP3, whereas the tumor suppressor phosphatase and tensin homolog (PTEN) converts PIP3 to inactive PIP2 and thereby impairs AKT activation [XREF_BIBR].	14	30	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	19	20	29	30
It is well established that loss of PTEN results in activated PI3K-AKT signaling .	It is well established that loss of PTEN results in activated PI3K-AKT signaling.	5	13	signaling	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	7	8	11	12
PTEN inhibits PI3K and Akt signaling after its activation by receptor tyrosine kinases ( RTKs ) and other receptors .	PTEN inhibits PI3K and Akt signaling after its activation by receptor tyrosine kinases (RTKs) and other receptors.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	4	5
Overexpression of constitutively active Akt or hyperactivation of the PI3K-Akt pathway by deletion of PTEN in OLs caused hypermyelination , while deleting TSC1 was detrimental to OL myelination .	Overexpression of constitutively active Akt or hyperactivation of the PI3K-Akt pathway by deletion of PTEN in OLs caused hypermyelination, while deleting TSC1 was detrimental to OL myelination.	0	16	Overexpression	Positive_activation_syntax_1_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	4	5
PTEN reconstitution suppressed AKT activation in SPARC expressing and control cells but suppressed the SHC-RAF-ERK signaling pathway only in SPARC expressing cells .	PTEN reconstitution suppressed AKT activation in SPARC expressing and control cells but suppressed the SHC-RAF-ERK signaling pathway only in SPARC expressing cells.	0	4	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	3	4
PTEN encodes a protein phosphatase , which can remove a phosphate from phosphoinositides at the plasma membrane XREF_BIBR and negatively regulates the PI3K and Akt pathway XREF_BIBR XREF_BIBR .	PTEN encodes a protein phosphatase, which can remove a phosphate from phosphoinositides at the plasma membrane XREF_BIBR and negatively regulates the PI3K and Akt pathway XREF_BIBR XREF_BIBR.	0	27	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	24	25
Suppression of PTEN , such as that which occurs in PH , will constitutively activate the Akt and PKB pathway [ XREF_BIBR ] .	Suppression of PTEN, such as that which occurs in PH, will constitutively activate the Akt and PKB pathway [XREF_BIBR].	0	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	2	3	18	19
The PTEN loss of function , which may result , in particular , from the reviewed genomic abnormality , has been shown to cause an upregulation of the AKT and mTOR pathway , primarily via activation of the kinase AKT1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The PTEN loss of function, which may result, in particular, from the reviewed genomic abnormality, has been shown to cause an upregulation of the AKT and mTOR pathway, primarily via activation of the kinase AKT1 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	31	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	28	29
Expression of PTEN , a phosphatase that opposes PI3 kinase action and inhibits Akt activation , was similar in diabetic patients and non diabetic controls ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Expression of PTEN, a phosphatase that opposes PI3 kinase action and inhibits Akt activation, was similar in diabetic patients and non diabetic controls (XREF_FIG, XREF_SUPPLEMENTARY).	0	14	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	Expression of PTEN	pten	Akt	Akt	akt	2	3	13	14
In this context , it should be mentioned that PD1.6 cells do not express PTEN , a phosphatase that inhibits the PI3K-Akt signaling pathway ( unpublished data ) .	In this context, it should be mentioned that PD1.6 cells do not express PTEN, a phosphatase that inhibits the PI3K-Akt signaling pathway (unpublished data).	13	23	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	14	15	21	22
XREF_BIBR , XREF_BIBR , XREF_BIBR For instance , GRP78 deficiency in the mouse prostate epithelium potently suppresses prostate tumorigenesis and AKT activation mediated by the loss of PTEN .	XREF_BIBR, XREF_BIBR, XREF_BIBR For instance, GRP78 deficiency in the mouse prostate epithelium potently suppresses prostate tumorigenesis and AKT activation mediated by the loss of PTEN.	20	28	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	27	28	20	21
PTEN , a tumor suppressor gene which antagonizes the PI3K and Akt pathway , is mutated in many human cancers , including HCC , and is essential for maintaining homeostasis and preventing oncogenesis in the liver .	PTEN, a tumor suppressor gene which antagonizes the PI3K and Akt pathway, is mutated in many human cancers, including HCC, and is essential for maintaining homeostasis and preventing oncogenesis in the liver.	0	26	antagonizes	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	11	12
XREF_BIBR Decreased PTEN expression levels up-regulate AKT activity .	XREF_BIBR Decreased PTEN expression levels up-regulate AKT activity.	2	7	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression levels	pten	AKT	AKT	akt	2	3	6	7
Consistently , Pten overexpression in RAW osteoclast derived cells reduces the anti-apoptotic function of Akt .	Consistently, Pten overexpression in RAW osteoclast derived cells reduces the anti-apoptotic function of Akt.	2	15	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten overexpression	pten	Akt	Akt	akt	2	3	14	15
Most importantly , they found no evidence that these mutations in PIK3CA resulted in activation of Akt pathway as compared with the wild-type PIK3CA , but there was a strong correlation between PTEN inactivating mutation and activation of Akt signaling XREF_BIBR .	Most importantly, they found no evidence that these mutations in PIK3CA resulted in activation of Akt pathway as compared with the wild-type PIK3CA, but there was a strong correlation between PTEN inactivating mutation and activation of Akt signaling XREF_BIBR.	30	40	inactivating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	32	33	38	39
Stahl et al 17 reported that the loss or haploinsufficiency of the phosphatase and tensin homolog ( PTEN ) gene caused the deregulation of AKT in 43 % to 60 % of melanomas .	Stahl et al 17 reported that the loss or haploinsufficiency of the phosphatase and tensin homolog (PTEN) gene caused the deregulation of AKT in 43% to 60% of melanomas.	7	25	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	loss or haploinsufficiency of the phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	akt	12	16	24	25
The PI3K and Akt signaling pathway is negatively regulated by PTEN , which inhibits cell growth , proliferation , cell survival , protein synthesis , and transcription .	The PI3K and Akt signaling pathway is negatively regulated by PTEN, which inhibits cell growth, proliferation, cell survival, protein synthesis, and transcription.	3	27	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN, which inhibits cell growth, proliferation, cell survival, protein synthesis, and transcription	pten	Akt	Akt	akt	10	11	3	4
Mechanistically , Pten acts as a negative regulator of this pathway and inhibits Akt activation by dephosphorylating PIP3 ( phosphatidylinositol 3,4,5 trisphosphate ) .	Mechanistically, Pten acts as a negative regulator of this pathway and inhibits Akt activation by dephosphorylating PIP3 (phosphatidylinositol 3,4,5 trisphosphate).	2	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	2	3	13	14
Since PPAR has been shown to positively regulate PTEN gene expression , inhibition of PPAR would be predicted to suppress PTEN expression thereby increasing PI3k-Akt signaling .	Since PPAR has been shown to positively regulate PTEN gene expression, inhibition of PPAR would be predicted to suppress PTEN expression thereby increasing PI3k-Akt signaling.	20	25	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	PI3k-Akt	PI3k-Akt	pi3k-akt	20	21	24	25
PTEN phosphatase is a novel tumor suppressor and negatively regulates the PI3K and Akt signaling network [ XREF_BIBR ] .	PTEN phosphatase is a novel tumor suppressor and negatively regulates the PI3K and Akt signaling network [XREF_BIBR].	0	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	13	14
Thus , Akt is progressively activated by a reduction in the Pten dose , which in turn results in its recruitment to the plasma membrane .	Thus, Akt is progressively activated by a reduction in the Pten dose, which in turn results in its recruitment to the plasma membrane.	2	12	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	11	12	2	3
The tumor suppressor PTEN restrains cell migration and invasion by a mechanism that is independent of inhibition of the PI3K pathway and decreased activation of the kinase AKT .	The tumor suppressor PTEN restrains cell migration and invasion by a mechanism that is independent of inhibition of the PI3K pathway and decreased activation of the kinase AKT.	0	28	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	27	28
Since PTEN inhibits Akt activation , we next evaluated the role of Akt on serotonin secretion from BON cells .	Since PTEN inhibits Akt activation, we next evaluated the role of Akt on serotonin secretion from BON cells.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	3	4
PI3K and AKT signaling is negatively regulated by the tumor suppressor PTEN , a lipid phosphatase that opposes the activity of PI3K by dephosphorylating PIP 3 .	PI3K and AKT signaling is negatively regulated by the tumor suppressor PTEN, a lipid phosphatase that opposes the activity of PI3K by dephosphorylating PIP 3.	0	25	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN, a lipid phosphatase that opposes the activity of PI3K by dephosphorylating PIP	pten	AKT	AKT	akt	11	12	2	3
Furthermore , we show that increased PTEN levels augment apoptosis of SMC by inhibiting the activation of Akt , thereby interfering with its downstream anti-apoptotic effects .	Furthermore, we show that increased PTEN levels augment apoptosis of SMC by inhibiting the activation of Akt, thereby interfering with its downstream anti-apoptotic effects.	6	18	augment	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN levels	pten	Akt	Akt	akt	6	7	17	18
34 As a lipid phosphatase , PTEN has been proved to suppress the activity of Akt kinase and even further restrain tumor progression .	34 As a lipid phosphatase, PTEN has been proved to suppress the activity of Akt kinase and even further restrain tumor progression.	6	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	15	16
In conclusion , this study demonstrates that PTEN overexpression inhibits the proliferation and migration of human ASMCs by down-regulating the activity of the Akt and FAK signaling pathways .	In conclusion, this study demonstrates that PTEN overexpression inhibits the proliferation and migration of human ASMCs by down-regulating the activity of the Akt and FAK signaling pathways.	7	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN overexpression	pten	Akt	Akt	akt	7	8	23	24
Akt is also negatively regulated by the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) .	Akt is also negatively regulated by the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN).	0	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	9	13	0	1
PTEN negatively regulates the AKT activity at a point upstream of AKT , and the loss of PTEN function leads to the constitutive activation of the PI3K-AKT pathway XREF_BIBR .	PTEN negatively regulates the AKT activity at a point upstream of AKT, and the loss of PTEN function leads to the constitutive activation of the PI3K-AKT pathway XREF_BIBR.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	4	5
Loss of Pten leads to activation of the PI3-Kinase and AKT pathway , which is believed to be the pathway responsible for the majority of phenotypes associated with loss of Pten in human tumors 34 .	Loss of Pten leads to activation of the PI3-Kinase and AKT pathway, which is believed to be the pathway responsible for the majority of phenotypes associated with loss of Pten in human tumors 34.	0	11	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Pten	Loss of Pten	pten	AKT	AKT	akt	2	3	10	11
Along with the remarkable remodeling of the tumor microenvironment , loss of Pten in stromal fibroblasts resulted in activation of the Ras , JNK and Akt pathways .	Along with the remarkable remodeling of the tumor microenvironment, loss of Pten in stromal fibroblasts resulted in activation of the Ras, JNK and Akt pathways.	10	26	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Pten	loss of Pten	pten	Akt	Akt	akt	12	13	25	26
These data indicate that HDAC3 plays a pivotal role in PTEN loss induced AKT activation and prostate tumorigenesis and progression .	These data indicate that HDAC3 plays a pivotal role in PTEN loss induced AKT activation and prostate tumorigenesis and progression.	10	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	13	14
PTEN negatively regulates Akt activation , which negatively regulates collagen induced platelet activation , 37 by converting phosphatidylinositol 3,4,5-trisphosphate ( PIP 3 ) to phosphatidylinositol 4,5-bisphosphate ( PIP 2 ) .	PTEN negatively regulates Akt activation, which negatively regulates collagen induced platelet activation, 37 by converting phosphatidylinositol 3,4,5-trisphosphate (PIP 3) to phosphatidylinositol 4,5-bisphosphate (PIP 2).	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
It was previously reported that BMP negatively regulates intestinal homeostasis by blocking the nuclear accumulation of beta-catenin via PTEN dependent suppression of Akt activity in BrdU retaining +4 quiescent stem cells XREF_BIBR .	It was previously reported that BMP negatively regulates intestinal homeostasis by blocking the nuclear accumulation of beta-catenin via PTEN dependent suppression of Akt activity in BrdU retaining +4 quiescent stem cells XREF_BIBR.	18	23	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	22	23
It has been shown that overexpression of wild-type PTEN decreases Akt activity , whereas dominant negative PTEN increases Akt activity in neurons .	It has been shown that overexpression of wild-type PTEN decreases Akt activity, whereas dominant negative PTEN increases Akt activity in neurons.	14	19	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	18	19
PTEN functions as a tumor suppressor gene , specifically by negatively regulating the Akt and PKB signaling pathway .	PTEN functions as a tumor suppressor gene, specifically by negatively regulating the Akt and PKB signaling pathway.	0	17	negatively regulating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	13	14
Previous studies from our group and others suggested that the loss of PTEN or reduced expression of PTEN leads to prolonged activation of the PI3K and Akt pathway , resulting in carcinogenesis [ XREF_BIBR , XREF_BIBR ] as well as treatment resistance [ XREF_BIBR ] .	Previous studies from our group and others suggested that the loss of PTEN or reduced expression of PTEN leads to prolonged activation of the PI3K and Akt pathway, resulting in carcinogenesis [XREF_BIBR, XREF_BIBR] as well as treatment resistance [XREF_BIBR].	10	27	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	12	13	26	27
XREF_BIBR PTEN , a dual-specificity phosphatase and tumor suppressor gene , inhibits Akt and mTOR and MAPK signaling , leading to cell death .	XREF_BIBR PTEN, a dual-specificity phosphatase and tumor suppressor gene, inhibits Akt and mTOR and MAPK signaling, leading to cell death.	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	12	13
Pten haplodeletion causes an increase in Akt and MAPkinase ( MsAPK ) activation in prostate tissue , as assessed by Western analysis of total lysates with alpha-phospho-Akt and alpha-phospho42/44 antibodies ( alpha-pAkt and alpha-p42/44 , respectively ) ( XREF_FIG A ) .	Pten haplodeletion causes an increase in Akt and MAPkinase (MsAPK) activation in prostate tissue, as assessed by Western analysis of total lysates with alpha-phospho-Akt and alpha-phospho42/44 antibodies (alpha-pAkt and alpha-p42/44, respectively) (XREF_FIG A).	0	8	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	0	1	6	7
These data corroborate our observation that siRNA against Pten , which inhibits Akt activity ( XREF_FIG ) also enhances reprogramming ( XREF_FIG ) , consistent with two recent reports XREF_BIBR , XREF_BIBR .	These data corroborate our observation that siRNA against Pten, which inhibits Akt activity (XREF_FIG) also enhances reprogramming (XREF_FIG), consistent with two recent reports XREF_BIBR, XREF_BIBR.	6	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	8	9	12	13
Overexpression of miR-21 in cancer likely results in PTEN inhibition and activation of the PI3K and AKT pathway and DNA repair , resulting in tumor cell survival .	Overexpression of miR-21 in cancer likely results in PTEN inhibition and activation of the PI3K and AKT pathway and DNA repair, resulting in tumor cell survival.	8	17	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	16	17
PTEN negatively regulates the PI3K and Akt signaling , which takes place in the lipid raft regions , by converting PIP 3 ( phosphatidylinostol ( 3,4,5 )-triphosphate ) to PIP 2 ( phosphatidylinositol ( 4,5 )-biphosphate ) .	PTEN negatively regulates the PI3K and Akt signaling, which takes place in the lipid raft regions, by converting PIP 3 (phosphatidylinostol (3,4,5)-triphosphate) to PIP 2 (phosphatidylinositol (4,5)-biphosphate).	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	6	7
It has been shown that PTEN inhibits the activity of AKT and PKB , a key effector of the phosphatidylinositol 3-kinase ( PI3K ) signaling pathway , and functions as a tumor suppressor [ XREF_BIBR ] .	It has been shown that PTEN inhibits the activity of AKT and PKB, a key effector of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, and functions as a tumor suppressor [XREF_BIBR].	5	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	10	11
Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT , which leads to up-regulation of mTOR .	Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT, which leads to up-regulation of mTOR.	0	13	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	12	13
The induction of PTEN prevents activation of Akt by BDNF and leads to cell death .	The induction of PTEN prevents activation of Akt by BDNF and leads to cell death.	1	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	7	8
PTEN protein levels are decreased in conjunction with preconditioning concomitant with increased AKT activation , supporting reciprocity in the PTEN antagonism of AKT activity .	PTEN protein levels are decreased in conjunction with preconditioning concomitant with increased AKT activation, supporting reciprocity in the PTEN antagonism of AKT activity.	19	23	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	19	20	22	23
Our mouse model of HNSCC allows for conditional deletion of two important tumor suppressors in the oral epithelium : Transforming Growth Factor-beta Receptor 1 ( TGFbetaRI ) , an inhibitor of epithelial proliferation , and phosphatase and tensin homolog ( PTEN ) , an enzyme that negatively regulates PI3K and Akt signaling to prevent uncontrolled cell growth .	Our mouse model of HNSCC allows for conditional deletion of two important tumor suppressors in the oral epithelium : Transforming Growth Factor-beta Receptor 1 (TGFbetaRI), an inhibitor of epithelial proliferation, and phosphatase and tensin homolog (PTEN), an enzyme that negatively regulates PI3K and Akt signaling to prevent uncontrolled cell growth.	35	51	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	35	39	50	51
PTEN functions as a tumor suppressor and the loss of functional PTEN results in AKT activation , suppression of apoptosis , and promotion of tumorigenesis [ XREF_BIBR ] .	PTEN functions as a tumor suppressor and the loss of functional PTEN results in AKT activation, suppression of apoptosis, and promotion of tumorigenesis [XREF_BIBR].	8	16	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	loss of functional PTEN	pten	AKT	AKT	akt	11	12	14	15
Restoring PTEN function in these cells blocks Akt activity and restores nuclear localization of FOXO and , therefore , its ability to activate downstream factors .	Restoring PTEN function in these cells blocks Akt activity and restores nuclear localization of FOXO and, therefore, its ability to activate downstream factors.	1	8	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	7	8
PTEN is a suppressor of PI3K and Akt .	PTEN is a suppressor of PI3K and Akt.	0	8	is a suppressor	Negative_activation_copula_1	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	7	8
Expression of total PTEN , as well as phosphorylated PTEN , an antagonist of PI3K function and negatively regulates Akt activities , was not different between HER2 overexpressing and low expressing cell lines ( XREF_FIG ) , indicating that PTEN is not involved in the constitutive activation of PI3K and Akt pathway in HER2 overexpressing cells .	Expression of total PTEN, as well as phosphorylated PTEN, an antagonist of PI3K function and negatively regulates Akt activities, was not different between HER2 overexpressing and low expressing cell lines (XREF_FIG), indicating that PTEN is not involved in the constitutive activation of PI3K and Akt pathway in HER2 overexpressing cells.	0	20	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Expression of total PTEN	pten	Akt	Akt	akt	3	4	19	20
The loss of PTEN , therefore , results in the activation of AKT , which subsequently upregulates mTOR activity .	The loss of PTEN, therefore, results in the activation of AKT, which subsequently upregulates mTOR activity.	1	13	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	3	4	12	13
By Western blot analysis we also found that the Akt and PKB signaling , which is negatively regulated by PTEN , was upregulated in the HCCs in comparison to its expression in the surrounding liver tissue .	By Western blot analysis we also found that the Akt and PKB signaling, which is negatively regulated by PTEN, was upregulated in the HCCs in comparison to its expression in the surrounding liver tissue.	9	20	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	19	20	9	10
PTEN lipid phosphatase degrades PIP3 and negatively regulates Akt , whereas this is activated by EGFR through PI3 .	PTEN lipid phosphatase degrades PIP3 and negatively regulates Akt, whereas this is activated by EGFR through PI3.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	8	9
PTEN inhibits AKT activity in preventing cancer growth both in in vitro and an animal model .	PTEN inhibits AKT activity in preventing cancer growth both in in vitro and an animal model.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	2	3
PTEN , acting as a tumor inhibitor , negatively regulates the PI3K and Akt signaling cascade by converting PIP-3 back to PIP-2 [ XREF_BIBR , XREF_BIBR ] .	PTEN, acting as a tumor inhibitor, negatively regulates the PI3K and Akt signaling cascade by converting PIP-3 back to PIP-2 [XREF_BIBR, XREF_BIBR].	0	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	13	14
Dysregulated PI3K signaling pathway is a frequent event in MM , including ( 1 ) increased insulin like growth factor 1 ( IGF-1 ) and interleukin-6 , both of which promote MM cell proliferation and survival [ XREF_BIBR , XREF_BIBR ] ; ( 2 ) silenced phosphatase and tensin homolog ( PTEN ) that antagonizes the PI3K and AKT signaling [ XREF_BIBR ] ; ( 3 ) overactivated PI3K and AKT [ XREF_BIBR ] .	Dysregulated PI3K signaling pathway is a frequent event in MM, including (1) increased insulin like growth factor 1 (IGF-1) and interleukin-6, both of which promote MM cell proliferation and survival [XREF_BIBR, XREF_BIBR]; (2) silenced phosphatase and tensin homolog (PTEN) that antagonizes the PI3K and AKT signaling [XREF_BIBR]; (3) overactivated PI3K and AKT [XREF_BIBR].	49	59	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	51	52	58	59
Therefore , the regulation of IGF-BP3 and PTEN by p53 negatively regulates IGF-1 and AKT signaling , which further leads to the negative regulation of mTORC1 activity through the direct phosphorylation of TSC2 by AKT .	Therefore, the regulation of IGF-BP3 and PTEN by p53 negatively regulates IGF-1 and AKT signaling, which further leads to the negative regulation of mTORC1 activity through the direct phosphorylation of TSC2 by AKT.	3	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	14	15
Specifically , in DIO models , an increase in Akt activity by phosphatase and tensin homolog ( PTEN ) inhibition restores skeletal muscle regeneration .	Specifically, in DIO models, an increase in Akt activity by phosphatase and tensin homolog (PTEN) inhibition restores skeletal muscle regeneration.	7	16	increase	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	12	16	9	10
Our results also prove that , through autocrine uPA induced TGF-beta activation , PAI-1-deficient fibroblasts undergo a hyperproliferative response mediated by persistent activation of the cell proliferation and survival AKT pathway , which is caused by miR-21-mediated PTEN inhibition .	Our results also prove that, through autocrine uPA induced TGF-beta activation, PAI-1-deficient fibroblasts undergo a hyperproliferative response mediated by persistent activation of the cell proliferation and survival AKT pathway, which is caused by miR-21-mediated PTEN inhibition.	29	38	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	37	38	29	30
Activation of downstream signaling includes PI3K and AKT signaling activation , usually caused by loss of PTEN [ XREF_BIBR ] , and MAPK signaling activation , usually caused by ERK2 activation [ XREF_BIBR ] , EML4 ALK mutation [ XREF_BIBR ] , BRAF mutation [ XREF_BIBR ] or KRAS mutation [ XREF_BIBR ] .	Activation of downstream signaling includes PI3K and AKT signaling activation, usually caused by loss of PTEN [XREF_BIBR], and MAPK signaling activation, usually caused by ERK2 activation [XREF_BIBR], EML4 ALK mutation [XREF_BIBR], BRAF mutation [XREF_BIBR] or KRAS mutation [XREF_BIBR].	5	18	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	16	17	7	8
By eliminating its negative regulation function , loss of PTEN will lead to activation of the PI3K and Akt pathway and activation of the anti-apoptotic signaling as mentioned above [ XREF_BIBR - XREF_BIBR ] .	By eliminating its negative regulation function, loss of PTEN will lead to activation of the PI3K and Akt pathway and activation of the anti-apoptotic signaling as mentioned above [XREF_BIBR - XREF_BIBR].	7	19	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	9	10	18	19
Since PTEN inhibits the action of Akt , the down-regulation of ERK ultimately leads to the up-regulation of Akt ( XREF_FIG ) .	Since PTEN inhibits the action of Akt, the down-regulation of ERK ultimately leads to the up-regulation of Akt (XREF_FIG).	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	6	7
Accordingly , we conclude the PTEN deletion in VSMC constitutively activates AKT and promotes upregulation of Runx2 and osteogenic differentiation of VSMC .	Accordingly, we conclude the PTEN deletion in VSMC constitutively activates AKT and promotes upregulation of Runx2 and osteogenic differentiation of VSMC.	5	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	11	12
PTEN negatively regulates the PI3K and AKT pathway by inhibiting the PIP3 dependent activation of AKT [ XREF_BIBR ] .	PTEN negatively regulates the PI3K and AKT pathway by inhibiting the PIP3 dependent activation of AKT [XREF_BIBR].	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
Western blotting showed that transfection with pBabe-puro-PTEN resulted in the up-regulation of PTEN protein expression and the down-regulation of P-AKT protein expression in NCI-N87 and NCI-N87/TR cells compared with transfection of the blank vector implying that PTEN gene transfection might inhibit activation of the downstream PI3K-AKT signaling pathway ( both P = 0.000 ) ( XREF_FIG ) .	Western blotting showed that transfection with pBabe-puro-PTEN resulted in the up-regulation of PTEN protein expression and the down-regulation of P-AKT protein expression in NCI-N87 and NCI-N87/TR cells compared with transfection of the blank vector implying that PTEN gene transfection might inhibit activation of the downstream PI3K-AKT signaling pathway (both P = 0.000) (XREF_FIG).	36	47	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	36	37	45	46
PTEN function loss causes the activation of the PI3K and AKT pathway , resulting in the phosphorylation of the Akt molecule .	PTEN function loss causes the activation of the PI3K and AKT pathway, resulting in the phosphorylation of the Akt molecule.	0	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	10	11
Overexpression of miR-486-3p reduces PTEN and Foxo1a protein expression and enhances PI3K and AKT signaling , eventually leading to muscle hypertrophy .	Overexpression of miR-486-3p reduces PTEN and Foxo1a protein expression and enhances PI3K and AKT signaling, eventually leading to muscle hypertrophy.	0	14	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Overexpression of miR-486-3p reduces PTEN and Foxo1a protein expression	pten	AKT	AKT	akt	4	5	13	14
Overall , these results show that Pten loss and consequent constitutive activation of the PI3K-AKT pathway can confer resistance to anti-NOTCH1 GSI therapy in vivo .	Overall, these results show that Pten loss and consequent constitutive activation of the PI3K-AKT pathway can confer resistance to anti-NOTCH1 GSI therapy in vivo.	6	15	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Pten	Pten	Pten	PI3K-AKT	PI3K-AKT	PI3K-AKT	6	7	14	15
Loss of PTEN enhances PI3K and AKT signaling XREF_BIBR to increase cell proliferation , KLF5 has been linked to Ras and MAPK proliferation signaling XREF_BIBR , XREF_BIBR , and loss of KLF5 downregulates the p15 cell cycle inhibitor in the context of transforming growth factor-beta ( TGF-beta ) XREF_BIBR , XREF_BIBR .	Loss of PTEN enhances PI3K and AKT signaling XREF_BIBR to increase cell proliferation, KLF5 has been linked to Ras and MAPK proliferation signaling XREF_BIBR, XREF_BIBR, and loss of KLF5 downregulates the p15 cell cycle inhibitor in the context of transforming growth factor-beta (TGF-beta) XREF_BIBR, XREF_BIBR.	0	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	6	7
A proposed mechanism is that ligand activation of PgR induces PTEN expression and thereby inhibits the PI3K and AKT pathway [ XREF_BIBR ] .	A proposed mechanism is that ligand activation of PgR induces PTEN expression and thereby inhibits the PI3K and AKT pathway [XREF_BIBR].	8	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PgR induces PTEN expression	pten	AKT	AKT	akt	10	11	18	19
PTEN can suppress PI3K and AKT activity , and regulate cell proliferation , apoptosis , and drug resistance .	PTEN can suppress PI3K and AKT activity, and regulate cell proliferation, apoptosis, and drug resistance.	0	9	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
PTEN attenuates PIP 3 / Akt signaling in the cochlea of the aging CBA/J mouse .	PTEN attenuates PIP 3 / Akt signaling in the cochlea of the aging CBA/J mouse.	0	6	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
Loss of PTEN increases activation of AKT , which in turn increases proliferation and protein synthesis , and decreases apoptosis .	Loss of PTEN increases activation of AKT, which in turn increases proliferation and protein synthesis, and decreases apoptosis.	0	18	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	6	7
PTEN , a tumor suppressor phosphatase and tensin homolog , may antagonize PI3K and Akt signaling .	PTEN, a tumor suppressor phosphatase and tensin homolog, may antagonize PI3K and Akt signaling.	0	15	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	5	9	14	15
In addition , C1 domain containing phosphatase and tensin homolog ( C1-TEN ) , a focal adhesion molecule with phosphatase properties and highly similar to PTEN , has been described to interact directly with AXL and negatively regulate the downstream activation of AKT .	In addition, C1 domain containing phosphatase and tensin homolog (C1-TEN), a focal adhesion molecule with phosphatase properties and highly similar to PTEN, has been described to interact directly with AXL and negatively regulate the downstream activation of AKT.	5	43	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	6	10	42	43
The loss of PTEN leads to activation of Akt , also known as Protein kinase B ( PKB ) , a regulator of endothelial cell apoptosis and angiogenesis [ XREF_BIBR ] .	The loss of PTEN leads to activation of Akt, also known as Protein kinase B (PKB), a regulator of endothelial cell apoptosis and angiogenesis [XREF_BIBR].	1	9	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	3	4	8	9
Thus , loss of PTEN , as demonstrated by genetic inactivation in human cancer or mouse knockout ( KO ) models , causes constitutive activation of Akt in cells , resulting in dysregulated cell proliferation , growth , and survival , which are hallmarks of tumorigenesis .	Thus, loss of PTEN, as demonstrated by genetic inactivation in human cancer or mouse knockout (KO) models, causes constitutive activation of Akt in cells, resulting in dysregulated cell proliferation, growth, and survival, which are hallmarks of tumorigenesis.	2	28	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	4	5	26	27
PTEN inhibits the PI3K and Akt branch of the IIS pathway .	PTEN inhibits the PI3K and Akt branch of the IIS pathway.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
Through its lipid phosphatase activity , PTEN antagonizes PI3K signaling , and , thus , the major effect of PTEN loss is constitutive activation of the PI3K-Akt pathway .	Through its lipid phosphatase activity, PTEN antagonizes PI3K signaling, and, thus, the major effect of PTEN loss is constitutive activation of the PI3K-Akt pathway.	6	27	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	6	7	26	27
Two recent studies examined the lens specific deletion of PTEN , the lipid phosphatase that negatively regulates AKT activity and antagonizes PI3K signaling by dephosphorylation of PIP 3 .	Two recent studies examined the lens specific deletion of PTEN, the lipid phosphatase that negatively regulates AKT activity and antagonizes PI3K signaling by dephosphorylation of PIP 3.	7	18	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	17	18
We therefore hypothesized that miR-494 might inhibit the expression of PTEN , which activates the PI3K and AKT pathway and reduces the H/R induced hepatic apoptosis .	We therefore hypothesized that miR-494 might inhibit the expression of PTEN, which activates the PI3K and AKT pathway and reduces the H/R induced hepatic apoptosis.	4	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	miR-494 might inhibit the expression of PTEN	pten	AKT	AKT	akt	10	11	17	18
Phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) negatively regulates PI3K and Akt signaling pathway , which is critical for IR development and progression of cirrhosis to hepatocellular carcinoma ( HCC ) .	Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates PI3K and Akt signaling pathway, which is critical for IR development and progression of cirrhosis to hepatocellular carcinoma (HCC).	0	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Akt	Akt	Akt	0	4	15	16
Rosiglitazone increased the expression of phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) and inhibited the PI3K and Akt pathway .	Rosiglitazone increased the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and inhibited the PI3K and Akt pathway.	0	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	Rosiglitazone increased the expression of phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	5	9	21	22
Akt is activated by growth factors via a phosphorylation dependent pathway involving the kinases phosphoinositide 3 ( PI3 ) kinase and phosphoinositide dependent protein kinase-1 ( PDK1 ) and is negatively regulated by phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) .	Akt is activated by growth factors via a phosphorylation dependent pathway involving the kinases phosphoinositide 3 (PI3) kinase and phosphoinositide dependent protein kinase-1 (PDK1) and is negatively regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN).	0	37	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	33	37	0	1
PTEN negatively regulates the PI3K and AKT pathway , so Tay and colleagues examined if ceRNA modulation affected the phosphorylation of AKT .	PTEN negatively regulates the PI3K and AKT pathway, so Tay and colleagues examined if ceRNA modulation affected the phosphorylation of AKT.	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
Wu et al reported that malignant esophageal cells exhibited excessive Akt expression , which was implicated in uncontrollable cancer cell proliferation , and that PTEN repressed the Akt activity .	Wu et al reported that malignant esophageal cells exhibited excessive Akt expression, which was implicated in uncontrollable cancer cell proliferation, and that PTEN repressed the Akt activity.	24	28	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	24	25	27	28
PTEN negatively regulates the PI3Ks and hence the AKT signaling [ XREF_BIBR ] .	PTEN negatively regulates the PI3Ks and hence the AKT signaling [XREF_BIBR].	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
Overexpression of miR-486 reduces the protein level of PTEN and Foxo1a and enhances PI3K and AKT signaling , eventually leading to muscle hypertrophy [ XREF_BIBR ] .	Overexpression of miR-486 reduces the protein level of PTEN and Foxo1a and enhances PI3K and AKT signaling, eventually leading to muscle hypertrophy [XREF_BIBR].	0	16	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Overexpression of miR-486 reduces the protein level of PTEN	pten	AKT	AKT	akt	8	9	15	16
PIK3R1 has also been shown to have a positive regulatory effect on tumor suppressor PTEN , which negatively regulates the PI3K and AKT pathway XREF_BIBR .	PIK3R1 has also been shown to have a positive regulatory effect on tumor suppressor PTEN, which negatively regulates the PI3K and AKT pathway XREF_BIBR.	10	24	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	22	23
Loss of PTEN results in constitutive activation of Akt and subsequently leads to promotion of cellular proliferation and resistance to apoptosis .	Loss of PTEN results in constitutive activation of Akt and subsequently leads to promotion of cellular proliferation and resistance to apoptosis.	0	9	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	8	9
Although little is known regarding PTEN function in BCC , loss of PTEN function in BCC would upregulate the PI3K and AKT pathway to stimulate even low-level ligand dependent or ligand independent Shh signaling caused by mutations in Hedgehog pathway components .	Although little is known regarding PTEN function in BCC, loss of PTEN function in BCC would upregulate the PI3K and AKT pathway to stimulate even low-level ligand dependent or ligand independent Shh signaling caused by mutations in Hedgehog pathway components.	12	22	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	12	13	21	22
The AKT activation induced by SC51089 was associated with phosphorylation of PTEN , the phosphatase that negatively regulates AKT .	The AKT activation induced by SC51089 was associated with phosphorylation of PTEN, the phosphatase that negatively regulates AKT.	9	19	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	phosphorylation of PTEN	pten	AKT	AKT	akt	11	12	18	19
Loss of PTEN expression usually results in activation of AKT and mTOR pathway due to its antagonizing function to the PI3K/AKT/mTOR pathway , and activation of PI3K/AKT/mTOR pathway has been reported in human SGTs [ XREF_BIBR ] .	Loss of PTEN expression usually results in activation of AKT and mTOR pathway due to its antagonizing function to the PI3K/AKT/mTOR pathway, and activation of PI3K/AKT/mTOR pathway has been reported in human SGTs [XREF_BIBR].	2	12	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	2	3	9	10
Although our data is preliminary , we propose that phosphorylation of PTEN at Ser380 leads to stabilization of PTEN , increased PIP2 , and decreased Akt activation which is observed in the UPCI-SCC90 cells ; whereas , the reverse is seen in the UMSCC47 cells .	Although our data is preliminary, we propose that phosphorylation of PTEN at Ser380 leads to stabilization of PTEN, increased PIP2, and decreased Akt activation which is observed in the UPCI-SCC90 cells; whereas, the reverse is seen in the UMSCC47 cells.	9	26	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	phosphorylation of PTEN at Ser380	pten	Akt	Akt	akt	11	12	25	26
Since Akt is negatively regulated by the tumor suppressor PTEN , we examined the TRAIL sensitivity in PTEN knockdown mouse prostate epithelial cells and found that PTEN -/- cells are more resistant than PTEN +/+ cells while the sensitivity of PTEN +/- cells fell in between .	Since Akt is negatively regulated by the tumor suppressor PTEN, we examined the TRAIL sensitivity in PTEN knockdown mouse prostate epithelial cells and found that PTEN -/- cells are more resistant than PTEN +/+ cells while the sensitivity of PTEN +/- cells fell in between.	1	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	1	2
The alpha , beta-enone , Delta12-PGJ 2 , interferes with PTEN suppression of Akt kinase .	The alpha, beta-enone, Delta12-PGJ 2, interferes with PTEN suppression of Akt kinase.	10	14	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	13	14
In addition , atorvastatin treatment prevented the increase in the phosphorylation of Akt and GSK-3beta caused by cardiac hypertrophy , and this effect correlated with an increase in protein levels of phosphatase and tensin homolog on chromosome 10 ( PTEN ) , which negatively regulates the phosphoinositide-3 kinase and Akt pathway .	In addition, atorvastatin treatment prevented the increase in the phosphorylation of Akt and GSK-3beta caused by cardiac hypertrophy, and this effect correlated with an increase in protein levels of phosphatase and tensin homolog on chromosome 10 (PTEN), which negatively regulates the phosphoinositide-3 kinase and Akt pathway.	36	50	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	39	40	49	50
PTEN negatively regulates the PI3K and AKT pathways through its lipid phosphatase activity .	PTEN negatively regulates the PI3K and AKT pathways through its lipid phosphatase activity.	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
On the other hand , PTEN induces cell death and inhibits the PI3K and Akt signalling that reduces inflammation and promotes cell proliferation and survival .	On the other hand, PTEN induces cell death and inhibits the PI3K and Akt signalling that reduces inflammation and promotes cell proliferation and survival.	5	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	14	15
Expression of cloned PTEN isoform generated a protein with a size about 15 kDa bigger than PTEN and suppressed PI3K-Akt signaling pathway in cells .	Expression of cloned PTEN isoform generated a protein with a size about 15 kDa bigger than PTEN and suppressed PI3K-Akt signaling pathway in cells.	0	21	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Expression of cloned PTEN	pten	PI3K-Akt	PI3K-Akt	pi3k-akt	3	4	19	20
These findings indicate that miR-21 suppresses PTEN that decreases AKT activity , resulting in the up-regulation of miR-21 .	These findings indicate that miR-21 suppresses PTEN that decreases AKT activity, resulting in the up-regulation of miR-21.	5	10	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	9	10
There is an accumulating evidence to indicate that genetic loss of PTEN in cell lines and animal will lead to activation of Akt and mTOR XREF_BIBR , XREF_BIBR .	There is an accumulating evidence to indicate that genetic loss of PTEN in cell lines and animal will lead to activation of Akt and mTOR XREF_BIBR, XREF_BIBR.	9	25	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	11	12	22	23
Restoration of PTEN expression suppressed IGF-I-induced Akt activity , suggesting that loss of PTEN is responsible for uncontrolled Akt activity in these 2 lines .	Restoration of PTEN expression suppressed IGF-I-induced Akt activity, suggesting that loss of PTEN is responsible for uncontrolled Akt activity in these 2 lines.	2	7	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	2	3	6	7
Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers , but targeting AKT has been difficult due to the mechanism based toxicities of inhibitors that target the inactive conformation of AKT .	Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism based toxicities of inhibitors that target the inactive conformation of AKT.	2	6	signaling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	2	3
Furthermore , PTEN inhibition activates Akt , which consequently activates Ikk , leading to degradation of IkappaB and nuclear translocation of the transcription factor NF-kappaB .	Furthermore, PTEN inhibition activates Akt, which consequently activates Ikk, leading to degradation of IkappaB and nuclear translocation of the transcription factor NF-kappaB.	2	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	5	6
Modulation of PTEN expression and activity may be of particular clinical relevance in MM , since PTEN mutations are rare events in this disease and PTEN downregulates AKT and ERK activity , thereby decreasing MM cell proliferation , survival , and drug resistance .	Modulation of PTEN expression and activity may be of particular clinical relevance in MM, since PTEN mutations are rare events in this disease and PTEN downregulates AKT and ERK activity, thereby decreasing MM cell proliferation, survival, and drug resistance.	25	30	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	25	26	27	28
PTEN is an endogenous inhibitor of Akt , and its phosphorylation results in its deactivation .	PTEN is an endogenous inhibitor of Akt, and its phosphorylation results in its deactivation.	0	7	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	6	7
Loss of PTEN function causes hyperactivation of the PI3K and AKT pathway , altering cell growth , apoptosis , invasion and metastasis [ XREF_BIBR ] .	Loss of PTEN function causes hyperactivation of the PI3K and AKT pathway, altering cell growth, apoptosis, invasion and metastasis [XREF_BIBR].	2	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	10	11
They show that loss of Nox1 results in increased PTEN activity that in turn inhibits Akt signaling pathway , as well as Wnt and beta-catenin and Notch1 signaling .	They show that loss of Nox1 results in increased PTEN activity that in turn inhibits Akt signaling pathway, as well as Wnt and beta-catenin and Notch1 signaling.	9	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	15	16
PTEN also antagonises phosphatidylinositol 3 kinase ( PI3K ) function and negatively regulates Akt activity .	PTEN also antagonises phosphatidylinositol 3 kinase (PI3K) function and negatively regulates Akt activity.	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	13	14
Conversely , mice were more sensitive to Legionella infection when mTOR activation was augmented by maintaining Akt activation , which was achieved by treating mice with bisperoxo ( 1,10-phenanthroline ) oxovanadate [ bpV ( phen ) ] to interfere with the phosphatase PTEN that negatively regulates Akt ( XREF_FIG ) .	Conversely, mice were more sensitive to Legionella infection when mTOR activation was augmented by maintaining Akt activation, which was achieved by treating mice with bisperoxo (1,10-phenanthroline) oxovanadate [bpV (phen)] to interfere with the phosphatase PTEN that negatively regulates Akt (XREF_FIG).	38	48	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	42	43	46	47
The current study indicates that TSC2 is a key target for Akt activation of IKK and NF-kappaB in PTEN deficient prostate cancer in which PTEN loss causes constitutive activation of Akt and is insensitive to the feedback regulation by mTORC1 ( XREF_FIG ) .	The current study indicates that TSC2 is a key target for Akt activation of IKK and NF-kappaB in PTEN deficient prostate cancer in which PTEN loss causes constitutive activation of Akt and is insensitive to the feedback regulation by mTORC1 (XREF_FIG).	24	31	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	24	25	30	31
Earlier reports showed that androgen dependent LNCaP cells are TRAIL resistant due to increased AKT activity caused by PTEN deletion ; therefore inhibition of AKT signaling by either wortmannin or LY294002 greatly sensitizes LNCaP cells to TRAIL [ XREF_BIBR , XREF_BIBR ] .	Earlier reports showed that androgen dependent LNCaP cells are TRAIL resistant due to increased AKT activity caused by PTEN deletion; therefore inhibition of AKT signaling by either wortmannin or LY294002 greatly sensitizes LNCaP cells to TRAIL [XREF_BIBR, XREF_BIBR].	14	19	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	18	19	14	15
A similar period lengthening was observed when myr-Akt was driven by one copy of Pdf-Gal4 in flies that have reduced expression of PTEN , a phosphatase that negatively regulates AKT activation .	A similar period lengthening was observed when myr-Akt was driven by one copy of Pdf-Gal4 in flies that have reduced expression of PTEN, a phosphatase that negatively regulates AKT activation.	20	30	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	AKT	AKT	akt	22	23	29	30
Reduced PTEN levels result in an activation and phosphorylation of AKT and a downstream inactivation of Foxo3a by nuclear exclusion , thus promoting fibroblast survival .	Reduced PTEN levels result in an activation and phosphorylation of AKT and a downstream inactivation of Foxo3a by nuclear exclusion, thus promoting fibroblast survival.	1	11	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN levels	pten	AKT	AKT	akt	1	2	10	11
Immunohistochemical ( IHC ) analysis of fibroblasts within the fibroblastic foci of IPF patient specimens also revealed that PTEN , caveolin-1 ( cav-1 ) and forkhead box O3a ( FoxO3a ) expression are all suppressed , while AKT activity is upregulated , further supporting the importance of the PTEN-PI3K and AKT axis in the pathogenesis of pulmonary fibrosis [ XREF_BIBR , XREF_BIBR ] .	Immunohistochemical (IHC) analysis of fibroblasts within the fibroblastic foci of IPF patient specimens also revealed that PTEN, caveolin-1 (cav-1) and forkhead box O3a (FoxO3a) expression are all suppressed, while AKT activity is upregulated, further supporting the importance of the PTEN-PI3K and AKT axis in the pathogenesis of pulmonary fibrosis [XREF_BIBR, XREF_BIBR].	18	51	supporting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	18	19	50	51
PTEN negatively regulates the activity of PI3K and AKT signaling through converting PIP3 to PIP2 .	PTEN negatively regulates the activity of PI3K and AKT signaling through converting PIP3 to PIP2.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
Canonically , PTEN inhibits the action of AKT , which in turn inhibits GSK3beta [ XREF_BIBR ] .	Canonically, PTEN inhibits the action of AKT, which in turn inhibits GSK3beta [XREF_BIBR].	2	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	7	8
These findings indicate that reduced PTEN protein abundance in the thyroids of TRbeta PV/PV Pten +/- mice resulted in a further activation of AKT .	These findings indicate that reduced PTEN protein abundance in the thyroids of TRbeta PV/PV Pten +/- mice resulted in a further activation of AKT.	5	24	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	23	24
Accordingly , selective down-regulation of MTA1 in breast cancer cells increases PTEN expression and inhibits stimulation of the PI3K and AKT signaling .	Accordingly, selective down-regulation of MTA1 in breast cancer cells increases PTEN expression and inhibits stimulation of the PI3K and AKT signaling.	5	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	MTA1 in breast cancer cells increases PTEN expression	pten	AKT	AKT	akt	11	12	20	21
Most widely reported as a tumor suppressor , PTEN may negatively regulate the PI3K and Akt pathway in cancer cells , which suggests that activated PTEN might decrease the expression of the PI3K and Akt pathway and promote apoptosis of cancer cells [ XREF_BIBR ] .	Most widely reported as a tumor suppressor, PTEN may negatively regulate the PI3K and Akt pathway in cancer cells, which suggests that activated PTEN might decrease the expression of the PI3K and Akt pathway and promote apoptosis of cancer cells [XREF_BIBR].	24	37	decrease	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	PTEN	PTEN	pten	Akt	expression of the PI3K and Akt	akt	25	26	34	35
12 Similarly , loss of the phosphatase and tensin homolog in macrophages increases PI3K and Akt signaling and induces high levels of M2 macrophage markers .	12 Similarly, loss of the phosphatase and tensin homolog in macrophages increases PI3K and Akt signaling and induces high levels of M2 macrophage markers.	3	16	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	loss of the phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	6	10	15	16
PTEN , both a protein and lipid phosphatase XREF_BIBR , negatively regulates PI3K-Akt pathway through dephosphorylation of phosphatidylinositol ( 4,5 )-phosphate ( PIP2 ) and phosphatidylinositol ( 3,4,5 )-phosphate ( PIP3 ) at the D-3 position and prevents Akt activation XREF_BIBR .	PTEN, both a protein and lipid phosphatase XREF_BIBR, negatively regulates PI3K-Akt pathway through dephosphorylation of phosphatidylinositol (4,5)-phosphate (PIP2) and phosphatidylinositol (3,4,5)-phosphate (PIP3) at the D-3 position and prevents Akt activation XREF_BIBR.	0	40	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	38	39
Overexpression of miR-486 reduces PTEN levels and activates PI3K and AKT signalling , which eventually leads to cardiac hypertrophy .	Overexpression of miR-486 reduces PTEN levels and activates PI3K and AKT signalling, which eventually leads to cardiac hypertrophy.	0	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Overexpression of miR-486 reduces PTEN levels	pten	AKT	AKT	akt	4	5	10	11
In PTEN-/- cells treated with mTORC1 inhibitors , the combination of elevated RTK activity and PTEN loss leads to unfettered PI3K activity , culminating in marked downstream AKT activation .	In PTEN-/- cells treated with mTORC1 inhibitors, the combination of elevated RTK activity and PTEN loss leads to unfettered PI3K activity, culminating in marked downstream AKT activation.	15	28	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	15	16	27	28
The PI3K and Akt pathway is negatively regulated by the lipid phosphatase PTEN , which dephosphorylates PIP3 [ XREF_BIBR ] .	The PI3K and Akt pathway is negatively regulated by the lipid phosphatase PTEN, which dephosphorylates PIP3 [XREF_BIBR].	1	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN, which dephosphorylates PIP3	pten	Akt	Akt	akt	12	13	3	4
PTEN negatively regulates PI3K and AKT signaling and is often inactivated by mutations ( including deletions ) in a variety of cancer types [ XREF_BIBR ] .	PTEN negatively regulates PI3K and AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types [XREF_BIBR].	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
AKT activation is antagonised by the expression of the lipid phosphatase PTEN .	AKT activation is antagonised by the expression of the lipid phosphatase PTEN.	0	12	antagonised	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	expression of the lipid phosphatase PTEN	pten	AKT	AKT	akt	11	12	0	1
The direct effect of BMP on ISCs is mediated by PTEN inhibition of AKT , which , in turn , inhibits activation of beta-catenin .	The direct effect of BMP on ISCs is mediated by PTEN inhibition of AKT, which, in turn, inhibits activation of beta-catenin.	10	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	13	14
PTEN loss upregulated PI3K and AKT and enhanced IGF-IR and IRS -1 and HER3 signaling , implicating PTEN in the modulation of RTK signaling upstream of PI3K .	PTEN loss upregulated PI3K and AKT and enhanced IGF-IR and IRS -1 and HER3 signaling, implicating PTEN in the modulation of RTK signaling upstream of PI3K.	0	6	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
By dephosphorylating PIP ( 3 ) , PTEN normally acts to inhibit the PI3-Kinase and AKT pathway .	By dephosphorylating PIP (3), PTEN normally acts to inhibit the PI3-Kinase and AKT pathway.	7	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	15	16
Furthermore , phosphatase and tensin homolog ( PTEN ) can inhibit the activity of the PI3K and AKT pathway , and PTEN gene loss has been reported in 15 % of breast cancer patients [ XREF_BIBR ] .	Furthermore, phosphatase and tensin homolog (PTEN) can inhibit the activity of the PI3K and AKT pathway, and PTEN gene loss has been reported in 15% of breast cancer patients [XREF_BIBR].	2	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	2	6	17	18
We demonstrate that miR-26a targets PTEN to increase Akt signal transduction , which activates mTOR necessary for mesangial cell hypertrophy and matrix protein expression .	We demonstrate that miR-26a targets PTEN to increase Akt signal transduction, which activates mTOR necessary for mesangial cell hypertrophy and matrix protein expression.	4	10	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	8	9
Enhanced activity of PI3K or decreased activity of PTEN activates AKT .	Enhanced activity of PI3K or decreased activity of PTEN activates AKT.	6	11	activates	Positive_activation_token_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	10	11
To examine whether the mechanism of PTEN induction of HIF-2alpha activity and the MT1-MMP promoter was mediated by the ability of this tumor suppressor to antagonize PI3K and Akt signaling , we first treated the 786-0 cells with inhibitors of PI3K , Akt , or mTOR , and measured both HIF-2alpha and YY1 protein expression .	To examine whether the mechanism of PTEN induction of HIF-2alpha activity and the MT1-MMP promoter was mediated by the ability of this tumor suppressor to antagonize PI3K and Akt signaling, we first treated the 786-0 cells with inhibitors of PI3K, Akt, or mTOR, and measured both HIF-2alpha and YY1 protein expression.	6	29	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	28	29
PTEN normally inhibits the PI3K-Akt pathway , which is an upstream activator of mTORC1 ( XREF_FIG ) .	PTEN normally inhibits the PI3K-Akt pathway, which is an upstream activator of mTORC1 (XREF_FIG).	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	4	5
The results are further supported by evidence that the PI3K inhibitor wortmannin increases cardiac contractility , and that Akt downstream of PIP3 is activated by PTEN inhibition in the myocardium .	The results are further supported by evidence that the PI3K inhibitor wortmannin increases cardiac contractility, and that Akt downstream of PIP3 is activated by PTEN inhibition in the myocardium.	18	26	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	25	26	18	19
Mutational analysis of PTEN and pharmacological inhibition of Akt revealed that modulation of Akt phosphorylation is unnecessary for cell size checkpoint control .	Mutational analysis of PTEN and pharmacological inhibition of Akt revealed that modulation of Akt phosphorylation is unnecessary for cell size checkpoint control.	3	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	8	9
PTEN negatively regulates the PI3K and AKT signaling pathway .	PTEN negatively regulates the PI3K and AKT signaling pathway.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
Reexpression of PTEN induced cytotoxicity in PTEN deficient GCB DLBCL cell line models by inhibiting PI3K and AKT signaling , indicating an addiction to this pathway in this subset of GCB DLBCLs .	Reexpression of PTEN induced cytotoxicity in PTEN deficient GCB DLBCL cell line models by inhibiting PI3K and AKT signaling, indicating an addiction to this pathway in this subset of GCB DLBCLs.	0	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Reexpression of PTEN	pten	AKT	AKT	akt	2	3	17	18
F4 Positive feedback p53 KILLER --> PTEN -| Akt --> Mdm2 -| p53 KILLER : p53 KILLER activates transcription of PTEN which ( indirectly ) deactivates Akt ; Akt phosphorylates Mdm2 allowing for its import to the nucleus where Mdm2 ubiquitinates p53 inducing its rapid degradation .	F4 Positive feedback p53 KILLER --> PTEN -| Akt --> Mdm2 -| p53 KILLER : p53 KILLER activates transcription of PTEN which (indirectly) deactivates Akt; Akt phosphorylates Mdm2 allowing for its import to the nucleus where Mdm2 ubiquitinates p53 inducing its rapid degradation.	15	27	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	p53 KILLER activates transcription of PTEN	pten	Akt	Akt	akt	20	21	26	27
Furthermore , PTEN could inhibit the AKT signaling pathway to attenuate the proliferation and migration of human PASMCs and pulmonary arterial remodeling XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Furthermore, PTEN could inhibit the AKT signaling pathway to attenuate the proliferation and migration of human PASMCs and pulmonary arterial remodeling XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	2	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	6	7
As expected , overexpression of PTEN in the MDA-MB-231 BR cells reduced AKT pathway activation , which was due to reduced Akt1 activity .	As expected, overexpression of PTEN in the MDA-MB-231 BR cells reduced AKT pathway activation, which was due to reduced Akt1 activity.	3	14	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	overexpression of PTEN	pten	AKT	AKT	akt	5	6	12	13
Deletion of PTEN or enforced genetic activation of AKT stimulated HSC proliferation and depletion , and led to the development of acute leukemia .	Deletion of PTEN or enforced genetic activation of AKT stimulated HSC proliferation and depletion, and led to the development of acute leukemia.	2	9	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	8	9
PTEN negatively regulates the PI3K and Akt signaling pathway , which is involved in the regulation of cell survival [ XREF_BIBR ] .	PTEN negatively regulates the PI3K and Akt signaling pathway, which is involved in the regulation of cell survival [XREF_BIBR].	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	6	7
Our analysis showed that in a tumor model where PI3K and AKT signaling is upregulated by Pten loss , Akt2 deletion still does not induce any cell death .	Our analysis showed that in a tumor model where PI3K and AKT signaling is upregulated by Pten loss, Akt2 deletion still does not induce any cell death.	9	17	upregulated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	16	17	11	12
The tumor suppressor PTEN , a lipid phosphatase that antagonizes the PI3K-AKT pathway , is frequently lost in human cancer [ XREF_BIBR ] .	The tumor suppressor PTEN, a lipid phosphatase that antagonizes the PI3K-AKT pathway, is frequently lost in human cancer [XREF_BIBR].	0	16	antagonizes	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	11	12
In addition , the combination of miR-370 and PTEN inactivated AKT , MDM2 and mTOR while stimulated caspase-3 , p53 and GSK3beta expression , promoting apoptosis and suppressing proliferation of gastric cancer cells .	In addition, the combination of miR-370 and PTEN inactivated AKT, MDM2 and mTOR while stimulated caspase-3, p53 and GSK3beta expression, promoting apoptosis and suppressing proliferation of gastric cancer cells.	4	14	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	10	11
Pten , a phosphatase that directly inactivates Akt , was identified as a likely candidate .	Pten, a phosphatase that directly inactivates Akt, was identified as a likely candidate.	0	10	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	0	1	7	8
Here , we show that loss of Pten in the mouse endometrium activates Akt and results in increased phosphorylation of estrogen receptor alpha ( ERalpha ) on Ser ( 167 ) .	Here, we show that loss of Pten in the mouse endometrium activates Akt and results in increased phosphorylation of estrogen receptor alpha (ERalpha) on Ser (167).	5	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	loss of Pten	pten	Akt	Akt	akt	7	8	13	14
Our studies indicated that upregulation of PTEN by hUCBSC in glioma cells and in the nude mice tumors downregulated Akt and PI3K signaling pathway molecules .	Our studies indicated that upregulation of PTEN by hUCBSC in glioma cells and in the nude mice tumors downregulated Akt and PI3K signaling pathway molecules.	4	24	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	19	20
It has been reported that PTEN mediates negative regulation of the PI3K and AKT pathway XREF_BIBR , XREF_BIBR , with some studies showing that PTEN loss enhances PI3K and AKT activation XREF_BIBR .	It has been reported that PTEN mediates negative regulation of the PI3K and AKT pathway XREF_BIBR, XREF_BIBR, with some studies showing that PTEN loss enhances PI3K and AKT activation XREF_BIBR.	24	31	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	24	25	29	30
We present evidence that miR-26a suppresses the expression of the tumor suppressor protein PTEN to increase the Akt signal transduction .	We present evidence that miR-26a suppresses the expression of the tumor suppressor protein PTEN to increase the Akt signal transduction.	4	19	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	miR-26a suppresses the expression of the tumor suppressor protein PTEN	pten	Akt	Akt	akt	13	14	17	18
Akt mediated inactivation of FOXO proteins is negatively regulated by the lipid phosphatase and tensin homolog ( PTEN ) which is involved in the degradation of PIP3 , thus inhibiting Akt activation by the PI3K pathway 72 .	Akt mediated inactivation of FOXO proteins is negatively regulated by the lipid phosphatase and tensin homolog (PTEN) which is involved in the degradation of PIP3, thus inhibiting Akt activation by the PI3K pathway 72.	8	31	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	12	16	30	31
GCB DLBCLs are additionally frequently characterized by addiction to the PI3K and AKT pathway that is caused by either loss of the tumor suppressor PTEN or by BCR signaling [ XREF_BIBR , XREF_BIBR ] .	GCB DLBCLs are additionally frequently characterized by addiction to the PI3K and AKT pathway that is caused by either loss of the tumor suppressor PTEN or by BCR signaling [XREF_BIBR, XREF_BIBR].	10	25	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of the tumor suppressor PTEN	pten	AKT	AKT	akt	24	25	12	13
The PTEN phosphatase , which inhibits the pro growth PI3K and Akt pathway , is lost in the majority of TNBC tumours , particularly African-American and Hispanic patients XREF_BIBR .	The PTEN phosphatase, which inhibits the pro growth PI3K and Akt pathway, is lost in the majority of TNBC tumours, particularly African-American and Hispanic patients XREF_BIBR.	1	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	11	12
In the present study , we showed that overexpression of PTEN attenuated TGF-beta1-induced activation of AKT and cell migration in type II endometrial cancer cells .	In the present study, we showed that overexpression of PTEN attenuated TGF-beta1-induced activation of AKT and cell migration in type II endometrial cancer cells.	8	18	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	overexpression of PTEN	pten	AKT	AKT	akt	10	11	15	16
Therefore , it is not difficult to understand that JARID2 mediated suppression of PTEN can activate downstream AKT signaling , and enhance cancer cell invasion ability by inducing EMT in HCC cells .	Therefore, it is not difficult to understand that JARID2 mediated suppression of PTEN can activate downstream AKT signaling, and enhance cancer cell invasion ability by inducing EMT in HCC cells.	11	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	13	14	17	18
PTEN counters the effects of PI3K and inhibits AKT .	PTEN counters the effects of PI3K and inhibits AKT.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
Loss of PTEN through genetic alterations can lead to activation of the AKT pathway ; however , activation without PTEN mutations is likely to occur in the majority of cancers , suggesting that different mechanisms such as PIK3CA mutations involve activation of AKT XREF_BIBR .	Loss of PTEN through genetic alterations can lead to activation of the AKT pathway; however, activation without PTEN mutations is likely to occur in the majority of cancers, suggesting that different mechanisms such as PIK3CA mutations involve activation of AKT XREF_BIBR.	0	13	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	12	13
The diminished AKT activity may be mediated by PTEN .	The diminished AKT activity may be mediated by PTEN.	2	9	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	2	3
PTEN converts phosphatidylinositol-3 ,4,5-trisphosphate ( PIP3 ) to phosphatidylinositol-4 ,5-bisphosphate ( PIP2 ) at the cellular membrane and thereby negatively regulates oncogenic PI3K-AKT signalling XREF_BIBR .	PTEN converts phosphatidylinositol-3,4,5-trisphosphate (PIP3) to phosphatidylinositol-4,5-bisphosphate (PIP2) at the cellular membrane and thereby negatively regulates oncogenic PI3K-AKT signalling XREF_BIBR.	0	24	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	22	23
The gene that normally antagonises Akt , PTEN , is mutated ( loss of function mutation ) in a large number of cancers .	The gene that normally antagonises Akt, PTEN, is mutated (loss of function mutation) in a large number of cancers.	1	8	antagonises	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	5	6
Moreover , PTEN re-expression in these PTEN deficient cells prevented Akt activation and restored the sensitivity to rapamycin .	Moreover, PTEN re-expression in these PTEN deficient cells prevented Akt activation and restored the sensitivity to rapamycin.	2	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN re-expression	pten	Akt	Akt	akt	2	3	10	11
PTEN prevents tumor genesis by antagonizing the PI3 kinase and Akt pathway through D3 site phosphatase activity toward PI ( 3,4 ) P 2 and PI ( 3,4,5 ) P 3 .	PTEN prevents tumor genesis by antagonizing the PI3 kinase and Akt pathway through D3 site phosphatase activity toward PI (3,4) P 2 and PI (3,4,5) P 3.	0	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	10	11
PTEN loss leads to resistance to drug action ( resistance to HER2 inhibition ) and causes robust activation of the AKT output signal .	PTEN loss leads to resistance to drug action (resistance to HER2 inhibition) and causes robust activation of the AKT output signal.	0	22	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	20	21
PTEN suppresses AKT by catalyzing the conversion of phosphatidylinositol ( 3 , 4 , 5 )-trisphosphate ( PIP 3 ) into phosphatidylinositol ( 4 , 5 )-bisphosphate ( PIP 2 ) .	PTEN suppresses AKT by catalyzing the conversion of phosphatidylinositol (3, 4, 5)-trisphosphate (PIP 3) into phosphatidylinositol (4, 5)-bisphosphate (PIP 2).	0	3	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	2	3
The deletion of Pten increased the activation of both AKT and ERK above the level of the wild type lens in the presence or absence of FGFR2 .	The deletion of Pten increased the activation of both AKT and ERK above the level of the wild type lens in the presence or absence of FGFR2.	1	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	3	4	9	10
PTEN negatively regulates the PI3K-AKT signaling pathway through its lipid phosphatase activity , and acts as a tumor suppressor gene .	PTEN negatively regulates the PI3K-AKT signaling pathway through its lipid phosphatase activity, and acts as a tumor suppressor gene.	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	4	5
PTEN inhibits activation of Akt by converting PIP 3 into PIP 2 , and reduction of the level of PTEN causes the activation of Akt in pulmonary fibrosis .	PTEN inhibits activation of Akt by converting PIP 3 into PIP 2, and reduction of the level of PTEN causes the activation of Akt in pulmonary fibrosis.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	4	5
Our data strongly demonstrated that FMG up-regulated p-PTEN expression and markedly suppressed PI3K and AKT signaling pathway in lung cancer cells .	Our data strongly demonstrated that FMG up-regulated p-PTEN expression and markedly suppressed PI3K and AKT signaling pathway in lung cancer cells.	5	16	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p-PTEN	FMG up-regulated p-PTEN expression	p-pten	AKT	AKT	akt	7	8	14	15
We demonstrated that PTEN expression is upregulated in WT mice after MI , suggesting that increased PTEN activity may inhibit the activation of the PI3K and Akt signaling pathway in the infarcted heart .	We demonstrated that PTEN expression is upregulated in WT mice after MI, suggesting that increased PTEN activity may inhibit the activation of the PI3K and Akt signaling pathway in the infarcted heart.	16	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	26	27
To investigate whether PTEN antagonism of Akt activation had any effect on HIF-2alpha target gene expression , we measured MT1-MMP expression , a HIF-2alpha target gene we characterized as playing an important role in RCC tumor cell invasion .	To investigate whether PTEN antagonism of Akt activation had any effect on HIF-2alpha target gene expression, we measured MT1-MMP expression, a HIF-2alpha target gene we characterized as playing an important role in RCC tumor cell invasion.	3	7	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	6	7
PTEN acts as a phosphatase to deactivate phosphatidylinositol ( 3,4,5 )-trisphosphate ( PIP3 ) and inhibit the activation of the PI3K and AKT prosurvival pathway [ XREF_BIBR ] .	PTEN acts as a phosphatase to deactivate phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and inhibit the activation of the PI3K and AKT prosurvival pathway [XREF_BIBR].	0	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	22	23
To further identify the specific role of ERK2 in this regulation , we found that only dominant negative mutant of ERK2 ( DN-ERK2 ) , but not DN-ERK1 , increased PTEN protein expression and inactivated c-Jun and Akt ( XREF_FIG ) .	To further identify the specific role of ERK2 in this regulation, we found that only dominant negative mutant of ERK2 (DN-ERK2), but not DN-ERK1, increased PTEN protein expression and inactivated c-Jun and Akt (XREF_FIG).	22	38	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	DN-ERK2), but not DN-ERK1, increased PTEN protein expression	pten	Akt	Akt	akt	30	31	37	38
This was confirmed by knockdown of PTEN in ACHN cells , as decreased expression of PTEN in ACHN cells markedly reversed the etoposide mediated inhibition of Akt and HDM2 and led to downregulation of p53 .	This was confirmed by knockdown of PTEN in ACHN cells, as decreased expression of PTEN in ACHN cells markedly reversed the etoposide mediated inhibition of Akt and HDM2 and led to downregulation of p53.	13	28	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	15	16	26	27
Several alternative pathways known to increase beta-catenin expression are activated in breast cancer , including the NF-kappaB pathway in ER negative , HER2 positive tumors XREF_BIBR ; Pin1 upregulation in breast cancer patient sp.ecimens is proportional to increasing tumor grade and associated with increased beta-catenin expression XREF_BIBR , XREF_BIBR ; while loss of PTEN activates Akt and beta-catenin resulting in increased proliferation in breast cells .	Several alternative pathways known to increase beta-catenin expression are activated in breast cancer, including the NF-kappaB pathway in ER negative, HER2 positive tumors XREF_BIBR; Pin1 upregulation in breast cancer patient sp.ecimens is proportional to increasing tumor grade and associated with increased beta-catenin expression XREF_BIBR, XREF_BIBR; while loss of PTEN activates Akt and beta-catenin resulting in increased proliferation in breast cells.	51	58	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	53	54	55	56
Therefore , the loss of PTEN activity allows PI3K and AKT constitutive activation .	Therefore, the loss of PTEN activity allows PI3K and AKT constitutive activation.	5	12	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	10	11
We show here that the resistance of MDA-468 cells to ZD1839 is attributable to EGFR independent constitutive Akt activation caused by loss of PTEN function in these cells .	We show here that the resistance of MDA-468 cells to ZD1839 is attributable to EGFR independent constitutive Akt activation caused by loss of PTEN function in these cells.	17	24	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	23	24	17	18
PTEN negatively regulates Akt activity by de-phosphorylating phosphatidylinositol ( 3,4,5 )-trisphosphate ( PIP3 ) which Akt requires for membrane localization .	PTEN negatively regulates Akt activity by de-phosphorylating phosphatidylinositol (3,4,5)-trisphosphate (PIP3) which Akt requires for membrane localization.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
PTEN loss induced maximal activation of PI3K and AKT in T47D cells ( XREF_FIG ) .	PTEN loss induced maximal activation of PI3K and AKT in T47D cells (XREF_FIG).	0	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
Among many functions , PTEN negatively regulates the cytoplasmic phosphatidylinositol-3-kinase and AKT anti-apoptotic pathway ; and nuclear PTEN affects the cell cycle by also negatively regulating the MAPK pathway via cyclin D. Decreased PTEN expression is correlated with prostate cancer progression .	Among many functions, PTEN negatively regulates the cytoplasmic phosphatidylinositol-3-kinase and AKT anti-apoptotic pathway; and nuclear PTEN affects the cell cycle by also negatively regulating the MAPK pathway via cyclin D. Decreased PTEN expression is correlated with prostate cancer progression.	4	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	11	12
However , loss of PTEN activates AKT , which in turn results in nuclear exclusion of FOXO1 and abolishes FOXO1 mediated inhibition of AR , thereby driving castration resistant progression of PCa .	However, loss of PTEN activates AKT, which in turn results in nuclear exclusion of FOXO1 and abolishes FOXO1 mediated inhibition of AR, thereby driving castration resistant progression of PCa.	2	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	4	5	6	7
In xenografts , miR-494-mediated pten inhibition activated the PI3K and Akt oncogenic pathway favoring the accumulation of tumor expanded myeloid derived suppressor cells in tumor microenvironment and facilitating metastatic tumor spreading 20 .	In xenografts, miR-494-mediated pten inhibition activated the PI3K and Akt oncogenic pathway favoring the accumulation of tumor expanded myeloid derived suppressor cells in tumor microenvironment and facilitating metastatic tumor spreading 20.	4	12	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pten	pten	pten	Akt	Akt	Akt	4	5	10	11
PIP 3 binds PDK-1 , allowing PDK-1 to activate Akt ; thus , PTEN prevents Akt activation through the depletion of available PIP 3 .	PIP 3 binds PDK-1, allowing PDK-1 to activate Akt; thus, PTEN prevents Akt activation through the depletion of available PIP 3.	13	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	15	16
PTEN loss or activation of the PI3K and AKT pathway leads to enhanced cell proliferation , survival and migration as well as castration resistant growth .	PTEN loss or activation of the PI3K and AKT pathway leads to enhanced cell proliferation, survival and migration as well as castration resistant growth.	0	9	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
PTEN can negatively regulate PI3K and AKT signaling pathway , a factor also demonstrated by the obtained data : When PTEN was decreased by Cr ( VI ) , the mRNA level of AKT1 was elevated at low concentrations of Cr ( VI ) ; but when the cells were exposed to higher concentrations , both mRNA levels of PTEN and AKT1 were downregulated , probably as a consequence of the sub-cytotoxic effect exerted by this compound .	PTEN can negatively regulate PI3K and AKT signaling pathway, a factor also demonstrated by the obtained data : When PTEN was decreased by Cr (VI), the mRNA level of AKT1 was elevated at low concentrations of Cr (VI); but when the cells were exposed to higher concentrations, both mRNA levels of PTEN and AKT1 were downregulated, probably as a consequence of the sub-cytotoxic effect exerted by this compound.	0	8	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
Loss of PTEN activity attributed to homozygous deletions of the PTEN gene correlate with elevated levels of Akt activity , and reconstitution of PTEN restores normal Akt regulation .	Loss of PTEN activity attributed to homozygous deletions of the PTEN gene correlate with elevated levels of Akt activity, and reconstitution of PTEN restores normal Akt regulation.	21	27	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	23	24	26	27
Elevated expression of PTEN may inhibit the activity of PI3K-AKT pathway and induce these cells to apoptosis .	Elevated expression of PTEN may inhibit the activity of PI3K-AKT pathway and induce these cells to apoptosis.	1	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	3	4	9	10
In the nucleus , PTEN can mediate cell cycle arrest and growth inhibition via downregulation of MAPK and cyclin D1 , while in the cytoplasm , PTEN can downregulate AKT activity and upregulate p27 resulting in caspase mediated apoptosis [ XREF_BIBR ] .	In the nucleus, PTEN can mediate cell cycle arrest and growth inhibition via downregulation of MAPK and cyclin D1, while in the cytoplasm, PTEN can downregulate AKT activity and upregulate p27 resulting in caspase mediated apoptosis [XREF_BIBR].	26	32	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	26	27	29	30
The cell killing activity disappeared when the cellular Akt activity was lowered by ectopic PTEN expression .	The cell killing activity disappeared when the cellular Akt activity was lowered by ectopic PTEN expression.	8	16	lowered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	14	15	8	9
However , there is a concern that in Treg , which overexpress PD-1 in the TME , PDL-1 signaling up-regulates PTEN expression , blocks the Akt and mTOR pathway and activates STAT5 and STAT3 signaling , leading to expansion of Treg and promoting their suppressive functions .	However, there is a concern that in Treg, which overexpress PD-1 in the TME, PDL-1 signaling up-regulates PTEN expression, blocks the Akt and mTOR pathway and activates STAT5 and STAT3 signaling, leading to expansion of Treg and promoting their suppressive functions.	17	28	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PDL-1 signaling up-regulates PTEN expression	pten	Akt	Akt	akt	20	21	25	26
PTEN Negatively Regulates Akt Signaling in the Developing Retina .	PTEN Negatively Regulates Akt Signaling in the Developing Retina.	0	4	Negatively Regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
PTEN inhibits its downstream signal cascade by self dephosphorylation , and this dephosphorylation can be inhibited by a baculovirus phosphatase ( BVP ) , which induces the phosphorylation of PTEN and activates the Akt pathway XREF_BIBR .	PTEN inhibits its downstream signal cascade by self dephosphorylation, and this dephosphorylation can be inhibited by a baculovirus phosphatase (BVP), which induces the phosphorylation of PTEN and activates the Akt pathway XREF_BIBR.	19	35	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	phosphatase (BVP), which induces the phosphorylation of PTEN	pten	Akt	Akt	akt	29	30	33	34
We know from a previous study that PTEN can negatively regulate AKT activation through PI3K signal pathway because of it ' s lipid phosphatase activity .	We know from a previous study that PTEN can negatively regulate AKT activation through PI3K signal pathway because of it 's lipid phosphatase activity.	7	12	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	11	12
PTEN , a negative regulator of AKT , inhibits the PI3K and AKT pathway and promotes apoptosis .	PTEN, a negative regulator of AKT, inhibits the PI3K and AKT pathway and promotes apoptosis.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	12	13
TSC2 and PTEN are two key inhibitors of the Akt and mammalian target of rapamycin ( mTOR ) pathway and the specific inhibition of mTOR with rapamycin or RAD001 inhibited cell proliferation of PET cell lines .	TSC2 and PTEN are two key inhibitors of the Akt and mammalian target of rapamycin (mTOR) pathway and the specific inhibition of mTOR with rapamycin or RAD001 inhibited cell proliferation of PET cell lines.	0	10	are two key inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	9	10
For example , as PTEN negatively regulates the PI3K and AKT pathway , it is easy to speculate that PTEN inactivation leads to EGFR inhibitor resistance [ XREF_BIBR ] .	For example, as PTEN negatively regulates the PI3K and AKT pathway, it is easy to speculate that PTEN inactivation leads to EGFR inhibitor resistance [XREF_BIBR].	4	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	10	11
As PTEN is a lipid phosphatase that antagonizes PI3K activity , and thus inhibits PI3K-AKT signaling , loss of PTEN results in activation of the PI3K-AKT pathway in several tumor types , including melanoma .	As PTEN is a lipid phosphatase that antagonizes PI3K activity, and thus inhibits PI3K-AKT signaling, loss of PTEN results in activation of the PI3K-AKT pathway in several tumor types, including melanoma.	17	26	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	19	20	25	26
Therefore PTEN suppression should cause Akt activation .	Therefore PTEN suppression should cause Akt activation.	1	6	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	5	6
The phosphatase and tensin homolog deleted from chromosome 10 ( PTEN ) , which specifically dephosphorylates PI-3 , 4-P 2 and PI-3 , 4 , 5-P 3 at the D3 position can block PI 3-K signaling and subsequent Akt activation ( XREF_TABLE ) .	The phosphatase and tensin homolog deleted from chromosome 10 (PTEN), which specifically dephosphorylates PI-3, 4-P 2 and PI-3, 4, 5-P 3 at the D3 position can block PI 3-K signaling and subsequent Akt activation (XREF_TABLE).	1	39	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	1	5	38	39
Reconstitution of PTEN inhibited Akt by > 80 % and inhibited cell growth by ~ 70-75 % in both cell lines in vitro .	Reconstitution of PTEN inhibited Akt by> 80% and inhibited cell growth by ~ 70-75% in both cell lines in vitro.	0	5	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	4	5
28 Similarly , PTEN deletion , which increases PI3K and AKT signaling , promotes axonal regeneration upon optic nerve injury .	28 Similarly, PTEN deletion, which increases PI3K and AKT signaling, promotes axonal regeneration upon optic nerve injury.	3	11	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	10	11
XREF_BIBR reported that ErbB2 activates NF-kappaB via PI3K-Akt , which can be inhibited by PTEN and is mediated by calpain rather than IkappaB complex .	XREF_BIBR reported that ErbB2 activates NF-kappaB via PI3K-Akt, which can be inhibited by PTEN and is mediated by calpain rather than IkappaB complex.	5	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	14	15	7	8
One of the functions of PTEN is to inhibit the PI3K and AKT pathway .	One of the functions of PTEN is to inhibit the PI3K and AKT pathway.	3	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	12	13
PTEN inhibits the PI3K and AKT pathway by dephosphorylating PIP3 and increasing PIP2 , resulting in a reduction of membrane recruitment of AKTs .	PTEN inhibits the PI3K and AKT pathway by dephosphorylating PIP3 and increasing PIP2, resulting in a reduction of membrane recruitment of AKTs.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
Loss of Pten resulted in activation of the AKT ( protein kinase B ) pathway components from P28 onward , which in turn gradually suppressed RAF1 proto-oncogene serine/threonine kinase ( RAF1 )/ERK signaling through the interaction between AKT and RAF1 .	Loss of Pten resulted in activation of the AKT (protein kinase B) pathway components from P28 onward, which in turn gradually suppressed RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK signaling through the interaction between AKT and RAF1.	0	9	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Pten	Loss of Pten	pten	AKT	AKT	akt	2	3	8	9
It is well known that the tumor suppressor PTEN negatively regulates the PI3K and Akt pathway [ XREF_BIBR - XREF_BIBR ] .	It is well known that the tumor suppressor PTEN negatively regulates the PI3K and Akt pathway [XREF_BIBR - XREF_BIBR].	5	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	14	15
This line was stably transfected with a wild-type PTEN construct which markedly downregulated AKT activity .	This line was stably transfected with a wild-type PTEN construct which markedly downregulated AKT activity.	8	14	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	13	14
Conditional Deletion of the Pten Gene in Mouse Prostatic Cells Activates the AKT Signaling Pathway and Induces Prostatic Cell Proliferation .	Conditional Deletion of the Pten Gene in Mouse Prostatic Cells Activates the AKT Signaling Pathway and Induces Prostatic Cell Proliferation.	4	14	Activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	4	5	12	13
In the cytoplasm , PTEN antagonizes the phosphatidylinositol 3-kinase ( PI3K and AKT ) signaling pathway .	In the cytoplasm, PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K and AKT) signaling pathway.	4	13	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	12	13
However , further in-depth evaluations revealed that PTEN negatively regulated the mTORC2 and Akt signaling only in adult , but not neonatal hematopoietic stem cells XREF_BIBR .	However, further in-depth evaluations revealed that PTEN negatively regulated the mTORC2 and Akt signaling only in adult, but not neonatal hematopoietic stem cells XREF_BIBR.	7	14	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	13	14
PTEN inhibits the PI3K and AKT pathway leading to decreased activation of the mTOR signaling pathway ( XREF_FIG ) and increased autophagy [ XREF_BIBR ] .	PTEN inhibits the PI3K and AKT pathway leading to decreased activation of the mTOR signaling pathway (XREF_FIG) and increased autophagy [XREF_BIBR].	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
By contrast , PIASx-alpha opposes PI3K and AKT signaling by directly SUMOylating the tumor suppressor PTEN , which inhibits PI3K and AKT signaling through its phosphatase activity .	By contrast, PIASx-alpha opposes PI3K and AKT signaling by directly SUMOylating the tumor suppressor PTEN, which inhibits PI3K and AKT signaling through its phosphatase activity.	3	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PIASx-alpha opposes PI3K and AKT signaling by directly SUMOylating the tumor suppressor PTEN	pten	AKT	AKT	akt	15	16	21	22
Recent studies have also demonstrated that activation of PI3K and Akt signaling by 4-HNE in hepatocytes occurs via modification and inhibition of PTEN , a regulatory protein that suppresses Akt activity .	Recent studies have also demonstrated that activation of PI3K and Akt signaling by 4-HNE in hepatocytes occurs via modification and inhibition of PTEN, a regulatory protein that suppresses Akt activity.	18	30	suppresses	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	22	23	29	30
Since PTEN negatively regulates AKT activity , our data suggests a synergistic mechanism involving miR200c in creating the metastatic state [ XREF_BIBR ] .	Since PTEN negatively regulates AKT activity, our data suggests a synergistic mechanism involving miR200c in creating the metastatic state [XREF_BIBR].	1	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	4	5
Taken together , the results suggest that an increase in miR-21 in colonospheres that leads to reduction in PTEN activates Akt signaling pathway , which may play a role in regulating the tumorigenic properties of colonospheres that are enriched in CSCs and CSLCs .	Taken together, the results suggest that an increase in miR-21 in colonospheres that leads to reduction in PTEN activates Akt signaling pathway, which may play a role in regulating the tumorigenic properties of colonospheres that are enriched in CSCs and CSLCs.	16	22	activates	Positive_activation_token_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	20	21
Silencing of PTEN and PP2A will activate the PI3K and AKT pathway and promote metastasis .	Silencing of PTEN and PP2A will activate the PI3K and AKT pathway and promote metastasis.	0	11	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	10	11
miR-214 activates the Akt pathway by targeting PTEN , which normally negatively regulates Akt .	miR-214 activates the Akt pathway by targeting PTEN, which normally negatively regulates Akt.	6	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	13	14
ERbeta is linked to PTEN , the PTEN gene negatively regulates the PI3K and AKT pathway , and the PI3K and AKT pathway inhibition may lead to autophagy .	ERbeta is linked to PTEN, the PTEN gene negatively regulates the PI3K and AKT pathway, and the PI3K and AKT pathway inhibition may lead to autophagy.	7	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	14	15
These results strongly suggest that MC1R preferentially interacts with , and protects the non phosphorylated , active form of PTEN from destruction to suppress AKT activation .	These results strongly suggest that MC1R preferentially interacts with, and protects the non phosphorylated, active form of PTEN from destruction to suppress AKT activation.	14	25	suppress	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	phosphorylated, active form of PTEN	pten	AKT	AKT	akt	19	20	24	25
It suggested that miR-221/222 could serve as potential therapeutic targets for radioresistance of glioblastoma cells since miR-221/222 played a crucial role in radio induced DNA damage repair and silencing of miR-221/222 could significantly increase radiosensitivity of glioblastoma cells by PTEN independent inhibition of Akt .	It suggested that miR-221/222 could serve as potential therapeutic targets for radioresistance of glioblastoma cells since miR-221/222 played a crucial role in radio induced DNA damage repair and silencing of miR-221/222 could significantly increase radiosensitivity of glioblastoma cells by PTEN independent inhibition of Akt.	39	44	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	39	40	43	44
Western blot reveals PTEN suppressing both PI3K and AKT and MAPK and ERK pathways ( XREF_FIG , right ) .	Western blot reveals PTEN suppressing both PI3K and AKT and MAPK and ERK pathways (XREF_FIG, right).	3	9	suppressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	8	9
The transient expansion but later depletion of HSC in Itpkb -/- mice is reminiscent of the phenotypes resulting from PTEN inactivation or expression of dominant-active Akt .	The transient expansion but later depletion of HSC in Itpkb -/- mice is reminiscent of the phenotypes resulting from PTEN inactivation or expression of dominant-active Akt.	19	26	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	19	20	25	26
The PI3K-Akt pathway , which is negatively regulated by the PTEN protein , activates antiapoptotic and survival signals ( XREF_FIG , top panel ) .	The PI3K-Akt pathway, which is negatively regulated by the PTEN protein, activates antiapoptotic and survival signals (XREF_FIG, top panel).	1	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	10	11	1	2
Considering that the enzyme phosphatase and tension homologue ( PTEN ) , whose expression is increased by TNF-alpha , reduces Akt signaling and , consequently , nitric oxide ( NO ) production , we hypothesized that PTEN contributes to TNF-alpha-mediated vascular resistance to insulin induced by HFD .	Considering that the enzyme phosphatase and tension homologue (PTEN), whose expression is increased by TNF-alpha, reduces Akt signaling and, consequently, nitric oxide (NO) production, we hypothesized that PTEN contributes to TNF-alpha-mediated vascular resistance to insulin induced by HFD.	4	21	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	20	21
Whereas PTEN and Delta85 both inhibited activation of AKT and protein kinase B , only Deltap85 inhibited c-Jun NH2-terminal kinase ( JNK ) activity .	Whereas PTEN and Delta85 both inhibited activation of AKT and protein kinase B, only Deltap85 inhibited c-Jun NH2-terminal kinase (JNK) activity.	1	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	8	9
To determine whether PTEN activity changes in accordance with imatinib mediated inhibition of Akt , we examined PTEN expression and phosphorylation after 1 uM imatinib treatment for 1 h. Imatinib treatment resulted in increased PTEN expression and phosphorylation , but only in PDGF stimulated Daoy cells ( XREF_FIG ) .	To determine whether PTEN activity changes in accordance with imatinib mediated inhibition of Akt, we examined PTEN expression and phosphorylation after 1 uM imatinib treatment for 1 h. Imatinib treatment resulted in increased PTEN expression and phosphorylation, but only in PDGF stimulated Daoy cells (XREF_FIG).	3	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	13	14
Many reports showed activating PTEN is able to downregulate the PI3K and Akt pathway , which led to antitumor potential in cancer treatment [ XREF_BIBR - XREF_BIBR ] .	Many reports showed activating PTEN is able to downregulate the PI3K and Akt pathway, which led to antitumor potential in cancer treatment [XREF_BIBR - XREF_BIBR].	4	13	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	12	13
Although the lipid phosphatase PTEN suppresses Akt activity the control of PTEN activity is poorly studied in T cells .	Although the lipid phosphatase PTEN suppresses Akt activity the control of PTEN activity is poorly studied in T cells.	1	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	6	7
Deletion of Pten led to 5.6-fold increase in phosphor-Ser473 Akt level confirming activation of the Akt pathway ( XREF_FIG ) .	Deletion of Pten led to 5.6-fold increase in phosphor-Ser473 Akt level confirming activation of the Akt pathway (XREF_FIG).	0	16	led	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	2	3	15	16
Adenovirus mediated expression of PTEN completely suppressed constitutive Akt activation in LNCaP prostate cancer cells and enhanced apoptosis induced by a broad range of apoptotic stimuli .	Adenovirus mediated expression of PTEN completely suppressed constitutive Akt activation in LNCaP prostate cancer cells and enhanced apoptosis induced by a broad range of apoptotic stimuli.	2	9	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	4	5	8	9
Functional correlation between Akt activation and the activation of NFkappaB was confirmed in U251MG GBM cells in which inhibition of Akt activation either by stable expression of PTEN or by the PI3-kinase inhibitors , wortmannin and LY294002 , led to a concomitant decrease in NFkappaB binding activity .	Functional correlation between Akt activation and the activation of NFkappaB was confirmed in U251MG GBM cells in which inhibition of Akt activation either by stable expression of PTEN or by the PI3-kinase inhibitors, wortmannin and LY294002, led to a concomitant decrease in NFkappaB binding activity.	18	28	inhibition	Negative_activation_syntax_1_noun	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	27	28	20	21
In an attempt to explain this , we hypothesized that progressive decrease or loss of PTEN expression in the presence of PI3K p110alpha inhibition might restore PI3K and AKT signalling through PI3K p110beta activity .	In an attempt to explain this, we hypothesized that progressive decrease or loss of PTEN expression in the presence of PI3K p110alpha inhibition might restore PI3K and AKT signalling through PI3K p110beta activity.	15	29	restore	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	15	16	28	29
As the PIP3 phosphatase PTEN inhibits Akt activation , we determined the expression of PTEN and p-PTEN ( the unstable form of PTEN ) in HUVEC after DDAH1 overexpression .	As the PIP3 phosphatase PTEN inhibits Akt activation, we determined the expression of PTEN and p-PTEN (the unstable form of PTEN) in HUVEC after DDAH1 overexpression.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	6	7
Given that PTEN negatively regulates AKT signaling , we concluded that PTEN is unlikely to contribute to the observed decrease in AKT activity in mitotically arrested ovarian cancer cells .	Given that PTEN negatively regulates AKT signaling, we concluded that PTEN is unlikely to contribute to the observed decrease in AKT activity in mitotically arrested ovarian cancer cells.	2	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	5	6
The principal function of PTEN is dephosphorylating Phosphotidylinositol ( 3,4,5 ) phosphate ( PIP3 ) to Phosphotidylinositol ( 4,5 ) phosphate ( PIP2 ) and thus inhibits the activation of Phosphoinositide dependent kinase 1 ( PDK1 ) and then Akt ( XREF_FIG ) .	The principal function of PTEN is dephosphorylating Phosphotidylinositol (3,4,5) phosphate (PIP3) to Phosphotidylinositol (4,5) phosphate (PIP2) and thus inhibits the activation of Phosphoinositide dependent kinase 1 (PDK1) and then Akt (XREF_FIG).	2	41	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	39	40
The loss of PTEN , observed in miR-21 over-expressing colon cancer cells could partly be responsible for activation of Akt , as evidenced by the increased levels of pAkt in colonospheres .	The loss of PTEN, observed in miR-21 over-expressing colon cancer cells could partly be responsible for activation of Akt, as evidenced by the increased levels of pAkt in colonospheres.	1	20	be responsible for activation	Positive_activation_copula_1	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	3	4	19	20
Loss of PTEN and consequent elevation of AKT activity can promote both mTOR as well as AR dependent proliferation .	Loss of PTEN and consequent elevation of AKT activity can promote both mTOR as well as AR dependent proliferation.	2	8	elevation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	7	8
In hepatocellular carcinoma , miR-1236-3p down-regulates alpha-fetoprotein ( AFP ) , thus causing PTEN accumulation , which inhibits the PI3K and Akt pathway [ XREF_BIBR ] .	In hepatocellular carcinoma, miR-1236-3p down-regulates alpha-fetoprotein (AFP), thus causing PTEN accumulation, which inhibits the PI3K and Akt pathway [XREF_BIBR].	13	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	21	22
Loss of PTEN and subsequent activation of AKT impair Chk1 through phosphorylation , ubiquitination , and reduced nuclear localization to promote genomic instability in tumor cells [ XREF_BIBR ] .	Loss of PTEN and subsequent activation of AKT impair Chk1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells [XREF_BIBR].	2	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	7	8
AKT3 activation is found in about 60 % of sporadic melanomas subsequent to gene amplification ( 35 % of the cases ) or to inactivation of PTEN ( 40-60 % of the cases ) , which negatively regulates the PI3K and AKT pathway [ XREF_BIBR - XREF_BIBR ] .	AKT3 activation is found in about 60% of sporadic melanomas subsequent to gene amplification (35% of the cases) or to inactivation of PTEN (40-60% of the cases), which negatively regulates the PI3K and AKT pathway [XREF_BIBR - XREF_BIBR].	24	46	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	26	27	41	42
Several subsequent studies demonstrated that nuclear PTEN alone can elicit G1 arrest independent of AKT inhibition [ XREF_BIBR - XREF_BIBR ] .	Several subsequent studies demonstrated that nuclear PTEN alone can elicit G1 arrest independent of AKT inhibition [XREF_BIBR - XREF_BIBR].	5	17	elicit	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	14	15
It was reported that PTEN is a substrate of tankyrase , and PARylation of PTEN by tankyrase promotes PTEN degradation and activation of downstream AKT [ XREF_BIBR ] .	It was reported that PTEN is a substrate of tankyrase, and PARylation of PTEN by tankyrase promotes PTEN degradation and activation of downstream AKT [XREF_BIBR].	12	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	24	25
Through its ability to catalyze the hydrolysis of the 3 ' position phosphate on PIP 3 , PTEN negatively regulates Akt activation and insulin signaling [ XREF_BIBR ] .	Through its ability to catalyze the hydrolysis of the 3 ' position phosphate on PIP 3, PTEN negatively regulates Akt activation and insulin signaling [XREF_BIBR].	17	21	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	17	18	20	21
Thus , PTEN mediated Akt might directly inhibit Foxo1 signaling via Akt mediated phosphorylation of Foxo1 in IR triggered liver inflammation .	Thus, PTEN mediated Akt might directly inhibit Foxo1 signaling via Akt mediated phosphorylation of Foxo1 in IR triggered liver inflammation.	2	7	mediated	Positive_early_activation	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	4	5
PTEN is inactivated in some malignant tumors , resulting in Akt hyper-activation , thereby promoting cell proliferation , inhibition of apoptosis , and enhanced cell invasion and radioresistance [ XREF_BIBR - XREF_BIBR ] .	PTEN is inactivated in some malignant tumors, resulting in Akt hyper-activation, thereby promoting cell proliferation, inhibition of apoptosis, and enhanced cell invasion and radioresistance [XREF_BIBR - XREF_BIBR].	0	23	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	10	11
The PI3K and Akt pathway is negatively regulated by phosphatase and tensin homolog ( PTEN ) .	The PI3K and Akt pathway is negatively regulated by phosphatase and tensin homolog (PTEN).	1	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	9	13	3	4
It has been recently reported that PTEN is critical for CSCs maintenance , in that PTEN loss results in activation of Akt with subsequent development of CSCs and ultimately tumorigenesis [ XREF_BIBR ] .	It has been recently reported that PTEN is critical for CSCs maintenance, in that PTEN loss results in activation of Akt with subsequent development of CSCs and ultimately tumorigenesis [XREF_BIBR].	15	22	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	15	16	21	22
Among the predicted targets of SOX11 are POU3F2 ( BRN2 ) , which can drive a neuroendocrine phenotype in prostate cancer xenografts , as well as MYCN , which promotes the formation of a CRPC-NE phenotype in relevant human and mouse models in collaboration with Pten loss-of-function or activation of AKT kinase activity .	Among the predicted targets of SOX11 are POU3F2 (BRN2), which can drive a neuroendocrine phenotype in prostate cancer xenografts, as well as MYCN, which promotes the formation of a CRPC-NE phenotype in relevant human and mouse models in collaboration with Pten loss-of-function or activation of AKT kinase activity.	45	52	loss-of-function	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	45	46	50	51
Consistent with this function , deletion of PTEN activates Akt and PKB dependent cell signaling pathways [ XREF_BIBR ] .	Consistent with this function, deletion of PTEN activates Akt and PKB dependent cell signaling pathways [XREF_BIBR].	5	11	activates	Positive_activation_token_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	9	10
[ XREF_BIBR ] In our study , vimentin was up-regulated in KYSE-150/RR cells ( XREF_FIG ) and overexpression of PTEN inactivated PI3K and Akt signaling leading to downregulation of vimentin expression in these cells ( XREF_FIG ) .	[XREF_BIBR] In our study, vimentin was up-regulated in KYSE-150/RR cells (XREF_FIG) and overexpression of PTEN inactivated PI3K and Akt signaling leading to downregulation of vimentin expression in these cells (XREF_FIG).	17	24	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	overexpression of PTEN	pten	Akt	Akt	akt	19	20	23	24
It has been reported that liver specific deletion of PTEN expression activates Akt and enhances the development of fatty liver [ XREF_BIBR ] .	It has been reported that liver specific deletion of PTEN expression activates Akt and enhances the development of fatty liver [XREF_BIBR].	9	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	9	10	12	13
Interestingly , under the same conditions , XIP-NLS significantly increase the expression of the negative regulator of PI3K and Akt pathway , phosphatase and tensin homolog ( PTEN ) , mainly involved in axonal growth modulation 24 .	Interestingly, under the same conditions, XIP-NLS significantly increase the expression of the negative regulator of PI3K and Akt pathway, phosphatase and tensin homolog (PTEN), mainly involved in axonal growth modulation 24.	9	28	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	27	28	19	20
PTEN is inactivated in some malignant tumors , resulting in Akt hyper-activation , thereby promoting cell proliferation , inhibition of apoptosis , and enhancing cell invasion and radioresistance XREF_BIBR - XREF_BIBR .	PTEN is inactivated in some malignant tumors, resulting in Akt hyper-activation, thereby promoting cell proliferation, inhibition of apoptosis, and enhancing cell invasion and radioresistance XREF_BIBR - XREF_BIBR.	0	11	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	10	11
Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC , confirmed by a PTEN loss and activation of the PI3K and AKT pathway in immunohistochemistry .	Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K and AKT pathway in immunohistochemistry.	20	29	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	20	21	28	29
To support this , decreased cellular uptake of CNPs was also found when PI3K and Akt was suppressed by PTEN overexpression in IPF fibroblasts ( XREF_SUPPLEMENTARY ) .	To support this, decreased cellular uptake of CNPs was also found when PI3K and Akt was suppressed by PTEN overexpression in IPF fibroblasts (XREF_SUPPLEMENTARY).	13	21	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN overexpression	pten	Akt	Akt	akt	19	20	15	16
PTEN negatively regulates Akt activation through its ability to dephosphorylate the 3-position phosphate from phosphatidylinositol ( 3,4,5 ) trisphosphate to produce phosphatidylinositol ( 4,5 ) bisphosphate .	PTEN negatively regulates Akt activation through its ability to dephosphorylate the 3-position phosphate from phosphatidylinositol (3,4,5) trisphosphate to produce phosphatidylinositol (4,5) bisphosphate.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
As expected , the loss of both Lkb1 and Pten in these tumors activated the AKT and mTOR pathways , likely driving cellular proliferation and tumorigenesis .	As expected, the loss of both Lkb1 and Pten in these tumors activated the AKT and mTOR pathways, likely driving cellular proliferation and tumorigenesis.	4	18	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	loss of both Lkb1 and Pten	pten	AKT	AKT	akt	9	10	15	16
PTEN inhibits AKT activation and we have previously observed that within 15-30 min following PDGF-BB treatment of medulloblastoma cells there is a significant decrease in the level of PTEN protein expression , presumably through activation of proteosomal degradation .	PTEN inhibits AKT activation and we have previously observed that within 15-30 min following PDGF-BB treatment of medulloblastoma cells there is a significant decrease in the level of PTEN protein expression, presumably through activation of proteosomal degradation.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	2	3
miR-205 negatively regulates PTEN expression and leads to activation of the AKT pathway .	miR-205 negatively regulates PTEN expression and leads to activation of the AKT pathway.	0	12	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	miR-205 negatively regulates PTEN expression	pten	AKT	AKT	akt	3	4	11	12
PTEN functions as a tumor suppressor gene , specifically by negatively regulating the PI3K and Akt signaling pathway XREF_BIBR .	PTEN functions as a tumor suppressor gene, specifically by negatively regulating the PI3K and Akt signaling pathway XREF_BIBR.	0	18	negatively regulating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	15	16
Among many functions , PTEN negatively regulates the AKT anti-apoptotic signaling pathway , while nuclear PTEN affects the cell cycle by repressing the mitogen activated protein kinase pathway .	Among many functions, PTEN negatively regulates the AKT anti-apoptotic signaling pathway, while nuclear PTEN affects the cell cycle by repressing the mitogen activated protein kinase pathway.	4	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	8	9
This is further supported by the tumour suppressor PTEN , which is frequently mutated or deleted in a large number of human cancers , inactivating the PI3-K and Akt pathway [ XREF_BIBR - XREF_BIBR ] .	This is further supported by the tumour suppressor PTEN, which is frequently mutated or deleted in a large number of human cancers, inactivating the PI3-K and Akt pathway [XREF_BIBR - XREF_BIBR].	3	33	inactivating	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	28	29
PTEN blocks the activation of Akt , affecting cell cycling , translation , and apoptosis XREF_BIBR .	PTEN blocks the activation of Akt, affecting cell cycling, translation, and apoptosis XREF_BIBR.	0	6	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
Pten and Inpp4b suppress the PI3K and AKT pathway by degrading PI ( 3,4,5 ) P 3 and PI ( 3,4 ) P 2 respectively , the chief activators of AKT .	Pten and Inpp4b suppress the PI3K and AKT pathway by degrading PI (3,4,5) P 3 and PI (3,4) P 2 respectively, the chief activators of AKT.	0	8	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	0	1	7	8
Loss of PTENP1 leads to increased PTEN microRNA targeting and decreased PTEN expression , and subsequently leads to the activation of the PI3K and Akt pathway .	Loss of PTENP1 leads to increased PTEN microRNA targeting and decreased PTEN expression, and subsequently leads to the activation of the PI3K and Akt pathway.	0	25	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of PTENP1 leads to increased PTEN microRNA targeting and decreased PTEN expression	pten	Akt	Akt	akt	11	12	24	25
Selenium is an antioxidant nutrient reported to inhibit oncogenic Akt and NFkB pathways as well as inducing the expression of tumor suppressors PTEN , p53 and KLF-4 to mediate apoptotic cell death .	Selenium is an antioxidant nutrient reported to inhibit oncogenic Akt and NFkB pathways as well as inducing the expression of tumor suppressors PTEN, p53 and KLF-4 to mediate apoptotic cell death.	5	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	22	23	9	10
These data highlight the fact that PI3K and AKT is inhibited by wild-type PTEN but not by a phosphatase dead mutant PTEN in these lung adenocarcinoma cells .	These data highlight the fact that PI3K and AKT is inhibited by wild-type PTEN but not by a phosphatase dead mutant PTEN in these lung adenocarcinoma cells.	6	26	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	13	14	8	9
Although it has been reported that in murine ESCs , inhibition of PI3K suppresses and knockout of Pten increases Akt activity and cell proliferation , the functional correlation between direct inhibition of specific Akt isoforms and ESC growth is not understood .	Although it has been reported that in murine ESCs, inhibition of PI3K suppresses and knockout of Pten increases Akt activity and cell proliferation, the functional correlation between direct inhibition of specific Akt isoforms and ESC growth is not understood.	15	20	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	17	18	19	20
The PI3K and Akt signaling pathway is negatively regulated by PTEN , a tumor suppressor protein .	The PI3K and Akt signaling pathway is negatively regulated by PTEN, a tumor suppressor protein.	3	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	3	4
Restoration of p53 or inactivation of Akt by PTEN ( phosphatase and tensin homolog ) gene delivery inhibited lung tumorigenesis [ XREF_BIBR ] and suppression of Akt by programmed cell death 4 ( PDCD4 ) induced apoptosis in a mouse model of lung cancer [ XREF_BIBR ] .	Restoration of p53 or inactivation of Akt by PTEN (phosphatase and tensin homolog) gene delivery inhibited lung tumorigenesis [XREF_BIBR] and suppression of Akt by programmed cell death 4 (PDCD4) induced apoptosis in a mouse model of lung cancer [XREF_BIBR].	0	13	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	6	7
Overexpression of PTEN in brain seeking MDA-MB-231 BR cells in vitro reduced activation of the AKT pathway , notably by suppression of Akt1 kinase activity .	Overexpression of PTEN in brain seeking MDA-MB-231 BR cells in vitro reduced activation of the AKT pathway, notably by suppression of Akt1 kinase activity.	0	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Overexpression of PTEN	pten	AKT	AKT	akt	2	3	15	16
Then , we showed that PTEN could suppress AKT activity by its lipid phosphatase domain .	Then, we showed that PTEN could suppress AKT activity by its lipid phosphatase domain.	5	9	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	8	9
As an antagonist of the PI3Kinase , PTEN inhibits the activation of AKT and thereby down-regulates cell proliferation and migration [ XREF_BIBR - XREF_BIBR ] .	As an antagonist of the PI3Kinase, PTEN inhibits the activation of AKT and thereby down-regulates cell proliferation and migration [XREF_BIBR - XREF_BIBR].	7	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	12	13
PTEN promoter methylation correlates with decreased PTEN protein expression , which often increases AKT and mTOR pathway activation in tumor progression [ XREF_BIBR ] .	PTEN promoter methylation correlates with decreased PTEN protein expression, which often increases AKT and mTOR pathway activation in tumor progression [XREF_BIBR].	6	17	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN protein expression	pten	AKT	AKT	akt	6	7	13	14
It has been described in a number of human cancers that genetic inhibition of PTEN enhances cell survival by facilitating the activation of the PI3K and Akt pathway [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	It has been described in a number of human cancers that genetic inhibition of PTEN enhances cell survival by facilitating the activation of the PI3K and Akt pathway [XREF_BIBR, XREF_BIBR - XREF_BIBR].	12	27	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	26	27
PTEN , a tumor suppressor gene located in 10q23 , encodes a lipid phosphatase inhibiting PI3K-AKT pathway and loss of PTEN activates PI3K-AKT signaling ( XREF_FIG ) XREF_BIBR .	PTEN, a tumor suppressor gene located in 10q23, encodes a lipid phosphatase inhibiting PI3K-AKT pathway and loss of PTEN activates PI3K-AKT signaling (XREF_FIG) XREF_BIBR.	16	23	activates	Positive_activation_token_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	20	21	22	23
The PI3K and Akt signaling pathway may be blocked by phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) through dephosphorylating the signaling lipid , phosphatidylinositol 3,4,5-triphosphate .	The PI3K and Akt signaling pathway may be blocked by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through dephosphorylating the signaling lipid, phosphatidylinositol 3,4,5-triphosphate.	3	14	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	10	14	3	4
Rapamycin treatment and Pten deletion both increased Akt activation in bone marrow cells and in HSCs based on Western blots performed in c-kit + Flk-2 - Lin - Sca-1 + CD48 - cells , a population highly enriched for HSCs ( XREF_FIG ) .	Rapamycin treatment and Pten deletion both increased Akt activation in bone marrow cells and in HSCs based on Western blots performed in c-kit + Flk-2 - Lin - Sca-1 + CD48 - cells, a population highly enriched for HSCs (XREF_FIG).	3	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	3	4	7	8
Since lapatinib blocks AKT phosphorylation by inhibiting both EGFR and HER2 , its activity does not depend on phosphatase and tensin homolog ( PTEN ) , the phosphatase that negatively regulates AKT and is required for trastuzumab anti-tumor activity .	Since lapatinib blocks AKT phosphorylation by inhibiting both EGFR and HER2, its activity does not depend on phosphatase and tensin homolog (PTEN), the phosphatase that negatively regulates AKT and is required for trastuzumab anti-tumor activity.	21	32	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	23	24	31	32
In these tumors , PTEN loss caused activation of Akt , which may , like Bax deletion , effectively block apoptosis [ XREF_BIBR ] .	In these tumors, PTEN loss caused activation of Akt, which may, like Bax deletion, effectively block apoptosis [XREF_BIBR].	4	19	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	9	10
AKT activity is negatively regulated by PTEN [ XREF_BIBR - XREF_BIBR ] and PHLPP1 [ XREF_BIBR ] .	AKT activity is negatively regulated by PTEN [XREF_BIBR - XREF_BIBR] and PHLPP1 [XREF_BIBR].	0	8	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	0	1
More importantly , restoration of PTEN decreased Akt activation induced by miR-3142 ( XREF_FIG ) .	More importantly, restoration of PTEN decreased Akt activation induced by miR-3142 (XREF_FIG).	3	8	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	7	8
Apart from loss of TRAIL receptor expression , resistance can be acquired by different mechanisms , including up-regulation of TRAIL decoy receptors , increased expression of the caspase-8 inhibitor cFLIP , loss of caspase-8 , or enhanced AKT kinase activity caused by PTEN phosphatase deletion .	Apart from loss of TRAIL receptor expression, resistance can be acquired by different mechanisms, including up-regulation of TRAIL decoy receptors, increased expression of the caspase-8 inhibitor cFLIP, loss of caspase-8, or enhanced AKT kinase activity caused by PTEN phosphatase deletion.	37	44	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	42	43	37	38
As expected , PTEN knockdown further increased PI3K and AKT signaling , as indicated by enhanced basal levels of pAKT Ser473 , pAKT Thr308 , and pPRAS40 ( although consistently observed , this effect was modest , as might be expected in cell lines that already harbor PI3K subunit mutations ) ( XREF_FIG ) .	As expected, PTEN knockdown further increased PI3K and AKT signaling, as indicated by enhanced basal levels of pAKT Ser473, pAKT Thr308, and pPRAS40 (although consistently observed, this effect was modest, as might be expected in cell lines that already harbor PI3K subunit mutations) (XREF_FIG).	3	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	9	10
In its normal state , the PI3K and Akt pathway is negatively regulated by PTEN ( phosphatase tensin homolog ) , which converts PIP3 to PIP2 [ XREF_BIBR ] .	In its normal state, the PI3K and Akt pathway is negatively regulated by PTEN (phosphatase tensin homolog), which converts PIP3 to PIP2 [XREF_BIBR].	6	22	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	8	9
PTEN loss , resulting in enhanced PI3K signal transduction , leads to hyper-active AKT ( Stambolic etal ., 1998 ) .	PTEN loss, resulting in enhanced PI3K signal transduction, leads to hyper-active AKT (Stambolic etal., 1998).	0	14	leads	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	13	14
PTEN negatively regulates the activity of PI3K and AKT signaling by converting PIP3 to PIP2 .	PTEN negatively regulates the activity of PI3K and AKT signaling by converting PIP3 to PIP2.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
Loss of function PTEN leads to Akt activation by PI3K phosphorylation and results in poor prognosis of GBM [ XREF_BIBR , XREF_BIBR ] .	Loss of function PTEN leads to Akt activation by PI3K phosphorylation and results in poor prognosis of GBM [XREF_BIBR, XREF_BIBR].	0	7	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of function PTEN	pten	Akt	Akt	akt	3	4	6	7
Importantly , homozygous deletion of Pten invariably induces AKT activation and prostate tumorigenesis in mice .	Importantly, homozygous deletion of Pten invariably induces AKT activation and prostate tumorigenesis in mice.	3	9	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	5	6	8	9
The activity of PI3K is negatively regulated by the tumor suppressor Phosphatase And Tensin Homolog ( PTEN ) , which is a PIP3 phosphatase , and therefore inhibits the PI3K and Akt signaling pathway .	The activity of PI3K is negatively regulated by the tumor suppressor Phosphatase And Tensin Homolog (PTEN), which is a PIP3 phosphatase, and therefore inhibits the PI3K and Akt signaling pathway.	6	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Phosphatase And Tensin Homolog	Phosphatase And Tensin Homolog	Phosphatase And Tensin Homolog	Akt	Akt	Akt	11	15	31	32
PTEN , a phosphatase converting PIP3 to inactive PIP2 antagonises PI3K function and negatively regulates Akt activities .	PTEN, a phosphatase converting PIP3 to inactive PIP2 antagonises PI3K function and negatively regulates Akt activities.	0	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	15	16
Moreover , PD-1 ligation can augment the activity of the protein phosphatase and tensin homolog ( PTEN ) , a cellular phosphatase that inhibits PI3K and AKT signaling and thus leads to impaired survival , proliferation , and IL-2 release .	Moreover, PD-1 ligation can augment the activity of the protein phosphatase and tensin homolog (PTEN), a cellular phosphatase that inhibits PI3K and AKT signaling and thus leads to impaired survival, proliferation, and IL-2 release.	11	27	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	16	17	26	27
Complete loss of PTEN leads to activated PI3K and AKT signaling , cell autonomous disease progression , and potential impacts on immunosuppression within the TME .	Complete loss of PTEN leads to activated PI3K and AKT signaling, cell autonomous disease progression, and potential impacts on immunosuppression within the TME.	1	10	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	3	4	9	10
It is well known that PTEN , a lipid phosphatase that dephosphorylates PtdIns ( 3,4,5 ) P3 , negatively regulates the PI3K and Akt signaling pathway , thus emphasizing the role of PTEN as a tumour suppressor in multiple tumour types [ XREF_BIBR ] .	It is well known that PTEN, a lipid phosphatase that dephosphorylates PtdIns (3,4,5) P3, negatively regulates the PI3K and Akt signaling pathway, thus emphasizing the role of PTEN as a tumour suppressor in multiple tumour types [XREF_BIBR].	5	25	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN, a lipid phosphatase that dephosphorylates PtdIns (3,4,5) P3	pten	Akt	Akt	akt	5	6	23	24
Physiologically , phosphatidylinositol 3,4,5-trisphosphate ( PIP3 ) is the substrate of PTEN , whereby PTEN dephosphosphorylates PIP3 , indirectly inhibiting AKT activation .	Physiologically, phosphatidylinositol 3,4,5-trisphosphate (PIP3) is the substrate of PTEN, whereby PTEN dephosphosphorylates PIP3, indirectly inhibiting AKT activation.	9	21	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	11	12	20	21
PI3K promotes while PTEN ( phosphatase and tensin homology ) inhibits the activities of downstream PDK1 ( 3-phosphoinositide-dependent protein kinase-1 ) and AKT ( or PKB , protein kinase B ) .	PI3K promotes while PTEN (phosphatase and tensin homology) inhibits the activities of downstream PDK1 (3-phosphoinositide-dependent protein kinase-1) and AKT (or PKB, protein kinase B).	3	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	3	4	25	26
Given that PTEN negatively mediates Akt activity by dephosphorylating phosphoinositide substrates , PTEN suppression is likely to increase axon growth by enhancing activity of PI3K and Akt signaling .	Given that PTEN negatively mediates Akt activity by dephosphorylating phosphoinositide substrates, PTEN suppression is likely to increase axon growth by enhancing activity of PI3K and Akt signaling.	2	6	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	5	6
Although it has been shown that PTEN antagonizes PI3K function and negatively regulates AKT signaling pathway , XREF_BIBR , XREF_BIBR we failed to observe a correlation between MHC Class I and PTEN expression in the present study ( data not shown ) .	Although it has been shown that PTEN antagonizes PI3K function and negatively regulates AKT signaling pathway, XREF_BIBR, XREF_BIBR we failed to observe a correlation between MHC Class I and PTEN expression in the present study (data not shown).	6	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	13	14
It has been reported that PTEN negatively regulates the PI3K and AKT signaling pathway , leading to substantially decreasing p-AKT , controlling cancer cell proliferation [ XREF_BIBR ] .	It has been reported that PTEN negatively regulates the PI3K and AKT signaling pathway, leading to substantially decreasing p-AKT, controlling cancer cell proliferation [XREF_BIBR].	5	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	11	12
Though protein phosphatase ( PP ) 2A , calcineurin ( PP2B ) and phosphatase and tensin homolog ( PTEN ) have been shown to inhibit Akt activity through regulating its upstream signaling or dephosphorylating Akt at Thr308 and/or Ser473 , they have poor substrate selectivity , eliciting de-phosphorylation of diverse target molecules [ XREF_BIBR - XREF_BIBR ] .	Though protein phosphatase (PP) 2A, calcineurin (PP2B) and phosphatase and tensin homolog (PTEN) have been shown to inhibit Akt activity through regulating its upstream signaling or dephosphorylating Akt at Thr308 and/or Ser473, they have poor substrate selectivity, eliciting de-phosphorylation of diverse target molecules [XREF_BIBR - XREF_BIBR].	13	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	13	17	25	26
Loss of PTEN protein is reportedly associated with myocardial and brain ischemia [ XREF_BIBR - XREF_BIBR ] , presumably as a cellular adaptive stress response to activate the pro survival PI3K and Akt signaling .	Loss of PTEN protein is reportedly associated with myocardial and brain ischemia [XREF_BIBR - XREF_BIBR], presumably as a cellular adaptive stress response to activate the pro survival PI3K and Akt signaling.	2	33	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	32	33
In addition to these positive regulators , Akt signaling can also be negatively regulated by the phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) XREF_BIBR , XREF_BIBR , S nitrosylation induced by increases in nitric oxide ( NO ) XREF_BIBR - XREF_BIBR and elevated extracellular glucose XREF_BIBR , XREF_BIBR .	In addition to these positive regulators, Akt signaling can also be negatively regulated by the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) XREF_BIBR, XREF_BIBR, S nitrosylation induced by increases in nitric oxide (NO) XREF_BIBR - XREF_BIBR and elevated extracellular glucose XREF_BIBR, XREF_BIBR.	7	20	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	16	20	7	8
Indeed , PTEN can inhibit the activation of AKT , thus preventing GLUT1 expression on the plasmamembrane [ XREF_BIBR ] .	Indeed, PTEN can inhibit the activation of AKT, thus preventing GLUT1 expression on the plasmamembrane [XREF_BIBR].	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	8	9
Akt activation is negatively regulated by phosphatase and tensin homolog deleted from chromosome 10 ( PTEN ) XREF_BIBR .	Akt activation is negatively regulated by phosphatase and tensin homolog deleted from chromosome 10 (PTEN) XREF_BIBR.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	6	10	0	1
PTEN also negatively regulates mTOR by turning off PI3K-AKT signaling .	PTEN also negatively regulates mTOR by turning off PI3K-AKT signaling.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	8	9
Downregulation of TET1 therefore may activate AKT and mTOR pathways that are suppressed by PTEN .	Downregulation of TET1 therefore may activate AKT and mTOR pathways that are suppressed by PTEN.	6	15	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	6	7
p-Akt , a downstream target inhibited by Pten , was overexpressed ( XREF_SUPPLEMENTARY ) , suggesting that , upon oral administration of Tam , inactivation of TGF-beta signaling by Tgfbr1 deletion and activation of PI3k and Akt signaling by Pten loss were localized in the oral epithelia .	p-Akt, a downstream target inhibited by Pten, was overexpressed (XREF_SUPPLEMENTARY), suggesting that, upon oral administration of Tam, inactivation of TGF-beta signaling by Tgfbr1 deletion and activation of PI3k and Akt signaling by Pten loss were localized in the oral epithelia.	34	40	signaling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	39	40	36	37
As PTEN attenuates PI3K and Akt signaling , through the dephosphorylation of PIP 3 , reduced levels can result in the hyper-activation of Akt signaling driving mTORC1 activity .	As PTEN attenuates PI3K and Akt signaling, through the dephosphorylation of PIP 3, reduced levels can result in the hyper-activation of Akt signaling driving mTORC1 activity.	1	6	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	5	6
Transfection of PTEN into the PTEN negative decreased the activation of Akt and the downstream p70 ( S6K ) and reversed the resistance to doxorubicin in these cells , indicating that changes in PTEN status and Akt activation modulate the cellular response to doxorubicin [ XREF_BIBR ] .	Transfection of PTEN into the PTEN negative decreased the activation of Akt and the downstream p70 (S6K) and reversed the resistance to doxorubicin in these cells, indicating that changes in PTEN status and Akt activation modulate the cellular response to doxorubicin [XREF_BIBR].	0	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	11	12
The new isoform PTEN long exists in neurons and also inhibits the PI3K and Akt pathway .	The new isoform PTEN long exists in neurons and also inhibits the PI3K and Akt pathway.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	14	15
We further demonstrate that PTEN acts cell-autonomously to suppress PI3K and Akt activation and control amacrine interneuron morphogenesis .	We further demonstrate that PTEN acts cell-autonomously to suppress PI3K and Akt activation and control amacrine interneuron morphogenesis.	4	12	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	11	12
The authors found that the suppressed AKT signaling in TSC1 deficient SCs undergoing development could be restored by co-ablation of PTEN ( in TSC1 fl/fl ; PTEN fl/fl ; P0 Cre mice ) , and this manipulation clearly exacerbated the hypomyelination phenotype seen in TSC1-SCKO nerves .	The authors found that the suppressed AKT signaling in TSC1 deficient SCs undergoing development could be restored by co-ablation of PTEN (in TSC1 fl/fl; PTEN fl/fl; P0 Cre mice), and this manipulation clearly exacerbated the hypomyelination phenotype seen in TSC1-SCKO nerves.	6	21	restored	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	20	21	6	7
The suppression of PDLIM2 results in direct activation of NF-kappaB , while the suppression of PTEN , results in activation of the AKT kinase , contributing to the phosphorylation of NF-kappaB .	The suppression of PDLIM2 results in direct activation of NF-kappaB, while the suppression of PTEN, results in activation of the AKT kinase, contributing to the phosphorylation of NF-kappaB.	13	23	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	15	16	22	23
These results support the synergetic role of FZR1 depletion induced ERK activation , and PTEN loss induced AKT activation in transforming primary melanocytes to drive melanomagenesis in vitro .	These results support the synergetic role of FZR1 depletion induced ERK activation, and PTEN loss induced AKT activation in transforming primary melanocytes to drive melanomagenesis in vitro.	14	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	17	18
Other potential modulators of Akt activity include ( i ) the tyrosine phosphatase Phosphatase and Tensin homolog ( PTEN ) which regulate Akt activity through dephosphorylation of phosphoinositide PIP 3 down-stream of PI3K XREF_BIBR , ( ii ) 3-phosphoinositide dependent protein kinase-1 ( PDK1 ) XREF_BIBR , and ( iii ) PH domain and leucine rich repeat protein phosphatases 2 ( PHLPPL or PHLPP2 ) and protein phosphatase 2 ( PP2A ) which dephosphorylate and inhibit Akt XREF_BIBR , XREF_BIBR .	Other potential modulators of Akt activity include (i) the tyrosine phosphatase Phosphatase and Tensin homolog (PTEN) which regulate Akt activity through dephosphorylation of phosphoinositide PIP 3 down-stream of PI3K XREF_BIBR, (ii) 3-phosphoinositide dependent protein kinase-1 (PDK1) XREF_BIBR, and (iii) PH domain and leucine rich repeat protein phosphatases 2 (PHLPPL or PHLPP2) and protein phosphatase 2 (PP2A) which dephosphorylate and inhibit Akt XREF_BIBR, XREF_BIBR.	6	77	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Phosphatase and Tensin homolog	Phosphatase and Tensin homolog	Phosphatase and Tensin homolog	Akt	Akt	Akt	13	17	76	77
BMP activation is also associated with expression of active ( non phosphorylated ) PTEN , which blocks PI3K-Akt signaling and thus decreases Wnt signaling due to stabilization of GSK3beta .	BMP activation is also associated with expression of active (non phosphorylated) PTEN, which blocks PI3K-Akt signaling and thus decreases Wnt signaling due to stabilization of GSK3beta.	6	21	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of active (non phosphorylated) PTEN	pten	PI3K-Akt	PI3K-Akt	pi3k-akt	13	14	17	18
Activation of AKT signaling by complete loss of PTEN ( H-score of 0 ) or by mutations of PIK3CA or AKT in the archival tumors also tended to correlate with stable radiographic criteria for patients treated with ipatasertib .	Activation of AKT signaling by complete loss of PTEN (H-score of 0) or by mutations of PIK3CA or AKT in the archival tumors also tended to correlate with stable radiographic criteria for patients treated with ipatasertib.	2	10	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	8	9	2	3
Thrombin Decreases PTEN Expression and Activates the PI3K and AKT Signaling Pathway in Glc-82 Cells .	Thrombin Decreases PTEN Expression and Activates the PI3K and AKT Signaling Pathway in Glc-82 Cells.	0	11	Activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Thrombin Decreases PTEN Expression	pten	AKT	AKT	akt	2	3	9	10
XREF_BIBR Phosphatase and tensin homolog ( PTEN ) , a lipid phosphatase , negatively regulates the PI3K and Akt pathway .	XREF_BIBR Phosphatase and tensin homolog (PTEN), a lipid phosphatase, negatively regulates the PI3K and Akt pathway.	0	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Akt	Akt	Akt	1	5	18	19
Akt signaling is activated by phosphoinositide 3-kinase and inhibited by the tumor suppressors p53 and phosphatase and tensin homolog .	Akt signaling is activated by phosphoinositide 3-kinase and inhibited by the tumor suppressors p53 and phosphatase and tensin homolog.	0	19	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	15	19	0	1
PTEN negatively regulates PI3K-AKT signaling , which controls in parallel mTOR and GSK3 pathways .	PTEN negatively regulates PI3K-AKT signaling, which controls in parallel mTOR and GSK3 pathways.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	3	4
Phosphorylation of NEP uncouples PTEN dependent inhibition of Akt .	Phosphorylation of NEP uncouples PTEN dependent inhibition of Akt.	4	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	8	9
PTEN inhibits the ability of PI3K to catalyze the production of phosphotidylinositol-3 ,4,5 triphosphate and thus antagonizes the Akt cascade [ XREF_BIBR ] .	PTEN inhibits the ability of PI3K to catalyze the production of phosphotidylinositol-3,4,5 triphosphate and thus antagonizes the Akt cascade [XREF_BIBR].	0	19	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	18	19
In contrast , PTEN is known to antagonize oncogenic PI3K and Akt signaling .	In contrast, PTEN is known to antagonize oncogenic PI3K and Akt signaling.	3	12	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	11	12
Conversely , loss of PTEN activity causes an increase in AKT activity leading to inhibition of FOXO protein activity through phosphorylation and cytoplasmic sequestration [ XREF_BIBR ] .	Conversely, loss of PTEN activity causes an increase in AKT activity leading to inhibition of FOXO protein activity through phosphorylation and cytoplasmic sequestration [XREF_BIBR].	4	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	10	11
XREF_BIBR PTEN is a negative regulator of PI3K and inhibits Akt and mTOR and MAPK signaling , leading to inhibition of cell growth and cell death .	XREF_BIBR PTEN is a negative regulator of PI3K and inhibits Akt and mTOR and MAPK signaling, leading to inhibition of cell growth and cell death.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	10	11
Our results indicate that calpain-2 cleaves PTEN , a phosphatase that inhibits Akt , and thus allows BDNF to trigger PI3K and Akt signaling .	Our results indicate that calpain-2 cleaves PTEN, a phosphatase that inhibits Akt, and thus allows BDNF to trigger PI3K and Akt signaling.	5	13	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	12	13
Functionally , the lipid phosphatase PTEN antagonizes the PI3K-AKT signalling pathway by catalysing phosphatidylinositol-3 ,4,5-trisphosphate ( PIP3 ) to phosphatidylinositol-4 ,5-bisphosphate ( PIP2 ) XREF_BIBR .	Functionally, the lipid phosphatase PTEN antagonizes the PI3K-AKT signalling pathway by catalysing phosphatidylinositol-3,4,5-trisphosphate (PIP3) to phosphatidylinositol-4,5-bisphosphate (PIP2) XREF_BIBR.	2	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	5	6	8	9
PTEN ( phosphatase and tensin homolog ) binds to and inhibits the function of PIP3 and AKT and PKB , which are responsible for proliferation and inhibition of apoptosis .	PTEN (phosphatase and tensin homolog) binds to and inhibits the function of PIP3 and AKT and PKB, which are responsible for proliferation and inhibition of apoptosis.	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	16	17
Akt is negatively regulated by the tumor suppressor , phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) .	Akt is negatively regulated by the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN).	0	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	9	13	0	1
XREF_BIBR Re-introduction and expression of PTEN inhibits activation of Akt and therefore results in suppression of cell cycle progression as well as apoptosis .	XREF_BIBR Re-introduction and expression of PTEN inhibits activation of Akt and therefore results in suppression of cell cycle progression as well as apoptosis.	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	9	10
P-Rex2 inhibits the activity of phosphatase and tensin homolog ( PTEN ) , which increases Akt activation XREF_BIBR .	P-Rex2 inhibits the activity of phosphatase and tensin homolog (PTEN), which increases Akt activation XREF_BIBR.	5	17	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	5	9	15	16
Meanwhile , it has been reported that p53 induces PTEN gene expression thus repressing AKT activation 52 .	Meanwhile, it has been reported that p53 induces PTEN gene expression thus repressing AKT activation 52.	7	15	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	p53 induces PTEN gene expression	pten	AKT	AKT	akt	9	10	14	15
Phosphatase and tensin homolog ( PTEN ) , a lipid phosphatase that negatively regulates the PI3-K and Akt pathway , is frequently inactivated in prostate cancer .	Phosphatase and tensin homolog (PTEN), a lipid phosphatase that negatively regulates the PI3-K and Akt pathway, is frequently inactivated in prostate cancer.	0	18	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Akt	Akt	Akt	0	4	17	18
XREF_BIBR , XREF_BIBR Normally the PI3K / AKT pathway is downregulated by PTEN .	XREF_BIBR, XREF_BIBR Normally the PI3K / AKT pathway is downregulated by PTEN.	7	13	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	12	13	7	8
This is a provocative concept which is supported by in vitro evidence that Akt phosphorylates Mdm2 , resulting in ubiquitination and degradation of p53 , and that when Pten is present to inhibit Akt , p53 remains functional in mediating sensitivity to DNA damaging agents .	This is a provocative concept which is supported by in vitro evidence that Akt phosphorylates Mdm2, resulting in ubiquitination and degradation of p53, and that when Pten is present to inhibit Akt, p53 remains functional in mediating sensitivity to DNA damaging agents.	28	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	28	29	33	34
Phosphatase and tensin homolog ( PTEN ) activation inhibits AKT and mTOR signaling , and current studies have confirmed that microRNA ( miRNA ) -21 targets PTEN to activate the AKT and mTOR pathway , which plays an important role in the key pathological damage observed in DN [ XREF_BIBR , XREF_BIBR ] .	Phosphatase and tensin homolog (PTEN) activation inhibits AKT and mTOR signaling, and current studies have confirmed that microRNA (miRNA) -21 targets PTEN to activate the AKT and mTOR pathway, which plays an important role in the key pathological damage observed in DN [XREF_BIBR, XREF_BIBR].	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	AKT	AKT	AKT	0	4	9	10
The knockdown ofINPP4A/B or deletion of PTEN augmented the activation of AKT , and this was further increased by combined knockdown and deletion of these two enzymes ( XREF_FIG A and 6B ) .	The knockdown ofINPP4A/B or deletion of PTEN augmented the activation of AKT, and this was further increased by combined knockdown and deletion of these two enzymes (XREF_FIG A and 6B).	2	12	augmented	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	11	12
EGCG induced the expression of PTEN and inhibited the phosphorylation / activation of AKT in in tumor tissues .	EGCG induced the expression of PTEN and inhibited the phosphorylation / activation of AKT in in tumor tissues.	0	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	EGCG induced the expression of PTEN	pten	AKT	AKT	akt	5	6	13	14
PI3K and AKT signaling is suppressed by the phosphatase activity of the Phosphatase and tensin homolog ( PTEN ) , which is likely the most important tumor suppressor gene in the prostate .	PI3K and AKT signaling is suppressed by the phosphatase activity of the Phosphatase and tensin homolog (PTEN), which is likely the most important tumor suppressor gene in the prostate.	0	16	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	AKT	AKT	AKT	12	16	2	3
Therefore PTEN loss results in the constitutive upregulation of PI3K and Akt .	Therefore PTEN loss results in the constitutive upregulation of PI3K and Akt.	1	12	upregulation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	11	12
As a novel tumor suppressor gene , PTEN can negatively regulate PI3K and AKT signal pathways , and decreased their regulatory roles in cell proliferation , cell cycle , migration , and invasion .	As a novel tumor suppressor gene, PTEN can negatively regulate PI3K and AKT signal pathways, and decreased their regulatory roles in cell proliferation, cell cycle, migration, and invasion.	7	18	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	13	14
In addition , SPOP mutation primarily affects readouts of mTOR activity , with less effect on Akt activation driven by Pten loss , consistent with parallel signaling rather than truly redundant pathways .	In addition, SPOP mutation primarily affects readouts of mTOR activity, with less effect on Akt activation driven by Pten loss, consistent with parallel signaling rather than truly redundant pathways.	16	21	driven	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	20	21	16	17
First , we found that IR insult promoted PTEN phosphorylation and downregulated Akt activation , whereas knockdown of PTEN activated Akt .	First, we found that IR insult promoted PTEN phosphorylation and downregulated Akt activation, whereas knockdown of PTEN activated Akt.	16	21	activated	Positive_activation_token_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	20	21
Recent studies indicate that activated Akt contributes to the acquired resistance to sorafenib , and miR-21 dysregulates phosphatase and tensin homolog ( PTEN ) , which inhibits Akt activation .	Recent studies indicate that activated Akt contributes to the acquired resistance to sorafenib, and miR-21 dysregulates phosphatase and tensin homolog (PTEN), which inhibits Akt activation.	6	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	17	21	27	28
Whereas loss of Pten indeed resulted in Akt activation , as evidenced by elevated Akt Ser473 and Thr308 phosphorylation levels , Atf3 deficiency dramatically increased Akt phosphorylation levels , indicating that ATF3 suppressed Akt activation in Pten inactivated prostate lesions .	Whereas loss of Pten indeed resulted in Akt activation, as evidenced by elevated Akt Ser473 and Thr308 phosphorylation levels, Atf3 deficiency dramatically increased Akt phosphorylation levels, indicating that ATF3 suppressed Akt activation in Pten inactivated prostate lesions.	1	9	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Pten	loss of Pten	pten	Akt	Akt	akt	3	4	7	8
A recent study demonstrated that BRAF induced OIS in melanocytes was enforced by PTEN acting to inhibit AKT [ XREF_BIBR ] .	A recent study demonstrated that BRAF induced OIS in melanocytes was enforced by PTEN acting to inhibit AKT [XREF_BIBR].	11	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	13	14	17	18
Reexpression of PTEN , however , repressed the constitutively elevated PI3K and Akt signaling present in CEM cells as determined by a decrease in active ( phosphorylated ) Akt ( XREF_FIG A ) , suggesting that PTEN-replete CEM cells may be rescued in their ability to regulate PIP 3 levels and would thus be responsive to treatment with PI3K inhibitors .	Reexpression of PTEN, however, repressed the constitutively elevated PI3K and Akt signaling present in CEM cells as determined by a decrease in active (phosphorylated) Akt (XREF_FIG A), suggesting that PTEN-replete CEM cells may be rescued in their ability to regulate PIP 3 levels and would thus be responsive to treatment with PI3K inhibitors.	0	13	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Reexpression of PTEN	pten	Akt	Akt	akt	2	3	12	13
Using western-blot assays , we showed Pten loss and activation of AKT and ERK in PC-9 GR cells compared with PC-9 cells , but did not show total AKT and total ERK expression difference between the two cell lines ( XREF_FIG ) .	Using western-blot assays, we showed Pten loss and activation of AKT and ERK in PC-9 GR cells compared with PC-9 cells, but did not show total AKT and total ERK expression difference between the two cell lines (XREF_FIG).	6	13	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	6	7	11	12
Resembling those of mice lacking PTEN ( inhibitor of AKT activation ) , these defects are consistent with the ability of AKT to phosphorylate and degrade FOXO proteins .	Resembling those of mice lacking PTEN (inhibitor of AKT activation), these defects are consistent with the ability of AKT to phosphorylate and degrade FOXO proteins.	4	10	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	9	10
One of the possible survival and proliferative pathways is the PI3K and Akt signaling pathway , which is negatively regulated by the phosphatase and tensin homolog ( PTEN ) tumor suppressor .	One of the possible survival and proliferative pathways is the PI3K and Akt signaling pathway, which is negatively regulated by the phosphatase and tensin homolog (PTEN) tumor suppressor.	12	26	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	22	26	12	13
Neuronal PTEN loss activate Akt and results in an increased expression and activation of GABA A signaling , which provides protective action against ischemic stroke at acute phase , but compromises long-term functional recovery and contribute to vascular cognitive impairment .	Neuronal PTEN loss activate Akt and results in an increased expression and activation of GABA A signaling, which provides protective action against ischemic stroke at acute phase, but compromises long-term functional recovery and contribute to vascular cognitive impairment.	1	5	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	4	5
Protein phosphatase and tensin homologue ( PTEN ) dephosphorylates focal adhesion kinase and suppresses the activation of Akt and hence suppresses adhesive signaling .	Protein phosphatase and tensin homologue (PTEN) dephosphorylates focal adhesion kinase and suppresses the activation of Akt and hence suppresses adhesive signaling.	1	18	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	17	18
Furthermore , protein kinase B/Akt inhibition induced by ONOO- or high glucose and apoptosis triggered by high glucose could be abolished by transfection of PTEN specific small interfering RNA , suggesting that PTEN mediated the Akt inhibition by ONOO-.	Furthermore, protein kinase B/Akt inhibition induced by ONOO- or high glucose and apoptosis triggered by high glucose could be abolished by transfection of PTEN specific small interfering RNA, suggesting that PTEN mediated the Akt inhibition by ONOO-.	32	36	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	32	33	35	36
PTEN is thought to function as a tumour suppressor due to its ability to block G 1 cell cycle progression , induce apoptosis , and negatively regulate the PI3-K and AKT cell survival pathway .	PTEN is thought to function as a tumour suppressor due to its ability to block G 1 cell cycle progression, induce apoptosis, and negatively regulate the PI3-K and AKT cell survival pathway.	0	33	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	30	31
During normal tissue repair , unwanted fibroblasts are eliminated during collagen-matrix contraction by a mechanism whereby high PTEN activity suppresses Akt .	During normal tissue repair, unwanted fibroblasts are eliminated during collagen-matrix contraction by a mechanism whereby high PTEN activity suppresses Akt.	17	21	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	17	18	20	21
Compared to the control shLuc cells , PTEN knockdown caused reduced inflammation response to LPS induction and enhanced activation of Akt .	Compared to the control shLuc cells, PTEN knockdown caused reduced inflammation response to LPS induction and enhanced activation of Akt.	7	21	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	20	21
A previous study demonstrated that PTEN inhibited the proliferation and migration of human airway smooth muscle mass cells by downregulating the activity of the Akt signaling pathway .	A previous study demonstrated that PTEN inhibited the proliferation and migration of human airway smooth muscle mass cells by downregulating the activity of the Akt signaling pathway.	5	26	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	24	25
Accordingly , PTEN and Foxo1a protein levels are reduced by miR-486 overexpression , which , in turn , enhances PI3K and Akt signaling .	Accordingly, PTEN and Foxo1a protein levels are reduced by miR-486 overexpression, which, in turn, enhances PI3K and Akt signaling.	2	22	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN and Foxo1a protein levels are reduced by miR-486 overexpression	pten	Akt	Akt	akt	2	3	21	22
Loss of PTEN results in Akt activation and a subsequent reduction in apoptosis .	Loss of PTEN results in Akt activation and a subsequent reduction in apoptosis.	0	7	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	5	6
The dual specificity tyrosine threonine and PI3-phosphatase tumor suppressor protein PTEN [ XREF_BIBR , XREF_BIBR ] prevents the accumulation of the PI3K products and , thus , attenuates PI3K and AKT signaling [ XREF_BIBR ] .	The dual specificity tyrosine-threonine and PI3-phosphatase tumor suppressor protein PTEN [XREF_BIBR, XREF_BIBR] prevents the accumulation of the PI3K products and, thus, attenuates PI3K and AKT signaling [XREF_BIBR].	10	33	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	30	31
In particular , LKB1 activates AMPK , which in turn activates FoxO3A , while PTEN inhibits Akt , which in turn inhibits FoxO3A [ XREF_BIBR ] .	In particular, LKB1 activates AMPK, which in turn activates FoxO3A, while PTEN inhibits Akt, which in turn inhibits FoxO3A [XREF_BIBR].	14	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	16	17
By dephosphorylation of PIP3 , PTEN negatively regulates PI3K and AKT leading to tumor suppression .	By dephosphorylation of PIP3, PTEN negatively regulates PI3K and AKT leading to tumor suppression.	5	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	10	11
24 PTEN negatively regulates the PI3-K and Akt pathway , 25 and therefore we determined the effect of AT-101 on phosphorylated PTEN and Akt levels .	24 PTEN negatively regulates the PI3-K and Akt pathway, 25 and therefore we determined the effect of AT-101 on phosphorylated PTEN and Akt levels.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	7	8
The loss of PTEN or its mutation activates the PI3-K and Akt signaling pathway , which contributes to the tumorigenesis , progression and invasiveness of prostate cancer [ XREF_BIBR - XREF_BIBR ] .	The loss of PTEN or its mutation activates the PI3-K and Akt signaling pathway, which contributes to the tumorigenesis, progression and invasiveness of prostate cancer [XREF_BIBR - XREF_BIBR].	1	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	3	4	11	12
Increased PTEN activity promotes tissue inflammation , while deletion of PTEN activates PI3K and Akt signaling and reduces inflammatory response .	Increased PTEN activity promotes tissue inflammation, while deletion of PTEN activates PI3K and Akt signaling and reduces inflammatory response.	8	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	14	15
The tumor suppressor phosphatase and tensin homolog ( PTEN ) inhibits AKT activation by dephosphorylation of PIP3 to PIP2 [ XREF_BIBR ] .	The tumor suppressor phosphatase and tensin homolog (PTEN) inhibits AKT activation by dephosphorylation of PIP3 to PIP2 [XREF_BIBR].	3	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	11	12
The direct correlation between AKT phosphorylation , membrane localization , and PI3K phospholipid products also suggested that PTEN activity might suppress AKT activation in some PIK3CA-mutant cells by constraining phosphatidylinositide accumulation .	The direct correlation between AKT phosphorylation, membrane localization, and PI3K phospholipid products also suggested that PTEN activity might suppress AKT activation in some PIK3CA-mutant cells by constraining phosphatidylinositide accumulation.	17	22	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	17	18	21	22
Endogenous phosphorylation of certain Pten residues , such as Serine 380 , can inhibit Pten activity and permit Akt driven proliferation XREF_BIBR XREF_BIBR .	Endogenous phosphorylation of certain Pten residues, such as Serine 380, can inhibit Pten activity and permit Akt driven proliferation XREF_BIBR XREF_BIBR.	1	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	phosphorylation of certain Pten residues, such as Serine 380	pten	Akt	Akt	akt	4	5	18	19
PTEN is well-known to negatively regulate Akt and mTOR pathway [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	PTEN is well-known to negatively regulate Akt and mTOR pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	15	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	6	7
Consistent with this idea , malignant tumors are very rare in TSC patients , whereas in Cowden ' s disease , where loss of PTEN activates Akt independently of growth factor signaling , the development of malignant tumors is much more common .	Consistent with this idea, malignant tumors are very rare in TSC patients, whereas in Cowden 's disease, where loss of PTEN activates Akt independently of growth factor signaling, the development of malignant tumors is much more common.	22	31	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	24	25	26	27
Interestingly , HDAC6 inhibitor treatment led to inactivating phosphorylation of PTEN ( P-PTEN Ser380 ) , which likely led to the increased P-AKT in cells that express PTEN .	Interestingly, HDAC6 inhibitor treatment led to inactivating phosphorylation of PTEN (P-PTEN Ser380), which likely led to the increased P-AKT in cells that express PTEN.	2	23	led	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	PTEN	HDAC6 inhibitor treatment led to inactivating phosphorylation of PTEN (P-PTEN Ser380	pten	P-AKT	P-AKT	p-akt	10	11	22	23
PTEN negatively regulates PI3K and Akt pathway ; loss of PTEN activity may lead to permanent PI3K and Akt activation .	PTEN negatively regulates PI3K and Akt pathway; loss of PTEN activity may lead to permanent PI3K and Akt activation.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
Meanwhile , Pten represses the AKT and PI3K signalling cascade , functioning as a regeneration suppressor 30 , 31 , 32 .	Meanwhile, Pten represses the AKT and PI3K signalling cascade, functioning as a regeneration suppressor 30, 31, 32.	2	9	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	2	3	5	6
PTEN functions as a tumor suppressor gene by negatively regulating the Akt pathway , and it is one of the most frequently inactivated tumor suppressor genes in human cancers [ XREF_BIBR ] .	PTEN functions as a tumor suppressor gene by negatively regulating the Akt pathway, and it is one of the most frequently inactivated tumor suppressor genes in human cancers [XREF_BIBR].	0	12	negatively regulating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	11	12
42 PTEN also negatively regulates the activation of AKT , which promotes tumor cell survival in combination with the phosphoinositide 3-kinase/mammalian target of rapamycin pathway .	42 PTEN also negatively regulates the activation of AKT, which promotes tumor cell survival in combination with the phosphoinositide 3-kinase/mammalian target of rapamycin pathway.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	8	9
Disruption of PTEN causing PI3Kinase and AKT activation and NRAS and BRAF mutations leading to constitutive activation of signaling via the MAPK pathway are considered two of the key drivers of melanomagenesis .	Disruption of PTEN causing PI3Kinase and AKT activation and NRAS and BRAF mutations leading to constitutive activation of signaling via the MAPK pathway are considered two of the key drivers of melanomagenesis.	0	7	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	6	7
PTEN negatively regulates Akt activity .	PTEN negatively regulates Akt activity.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
Loss of PTEN function through deletion , epigenetic modification , or mutation causes activation of the PI3K and AKT pathway , which is well documented to contribute to prostate cancer progression and metastasis .	Loss of PTEN function through deletion, epigenetic modification, or mutation causes activation of the PI3K and AKT pathway, which is well documented to contribute to prostate cancer progression and metastasis.	2	19	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	18	19
Often , RAS and ERK signaling is activated by mutation of the RAS or RAF oncogenes , and PI3K and AKT is activated by loss of the tumor suppressor PTEN .	Often, RAS and ERK signaling is activated by mutation of the RAS or RAF oncogenes, and PI3K and AKT is activated by loss of the tumor suppressor PTEN.	18	30	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of the tumor suppressor PTEN	pten	AKT	AKT	akt	29	30	20	21
Consistent with activation of the Ras and Akt signaling pathways by loss of Nf1 and Pten , respectively , some tumor regions showed robust pErk and pAkt expression ( XREF_SUPPLEMENTARY ) .	Consistent with activation of the Ras and Akt signaling pathways by loss of Nf1 and Pten, respectively, some tumor regions showed robust pErk and pAkt expression (XREF_SUPPLEMENTARY).	2	16	activation	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	Pten	loss of Nf1 and Pten	pten	Akt	Akt	akt	15	16	7	8
Moreover , Snail suppresses PTEN expression , thus potentiating the PI3K and Akt pathway .	Moreover, Snail suppresses PTEN expression, thus potentiating the PI3K and Akt pathway.	2	13	potentiating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Snail suppresses PTEN expression	pten	Akt	Akt	akt	4	5	12	13
PTEN ( phosphatase and tensin homolog deleted on chromosome 10 ) negatively regulates Akt activation .	PTEN (phosphatase and tensin homolog deleted on chromosome 10) negatively regulates Akt activation.	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	13	14
PI3K stimulates AKT resulting in a survival signal , thus PTEN silencing allows PI3K and AKT activation and inappropriate survival of cancer cells .	PI3K stimulates AKT resulting in a survival signal, thus PTEN silencing allows PI3K and AKT activation and inappropriate survival of cancer cells.	10	16	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	15	16
PTEN , acts as a phosphoinositide phosphatase to counteract the effect of PI3K and thus inhibit the PI3K and Akt pathway .	PTEN, acts as a phosphoinositide phosphatase to counteract the effect of PI3K and thus inhibit the PI3K and Akt pathway.	0	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	19	20
PTEN deletion results in Akt activation .	PTEN deletion results in Akt activation.	0	6	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	4	5
Phosphatase and tensin homolog ( PTEN ) , a tumor suppressor , negatively regulates PI3K and Akt signaling as a lipid phosphatase [ XREF_BIBR ] .	Phosphatase and tensin homolog (PTEN), a tumor suppressor, negatively regulates PI3K and Akt signaling as a lipid phosphatase [XREF_BIBR].	3	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	16	17
For example , loss of PTEN , which activates the PI3K-AKT pathway , correlates with significantly increased risk of brain metastasis in melanoma 3 .	For example, loss of PTEN, which activates the PI3K-AKT pathway, correlates with significantly increased risk of brain metastasis in melanoma 3.	3	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	5	6	10	11
Loss of PTEN function can activate the PI3k and Akt signaling pathway , thus participating in cancerogenesis .	Loss of PTEN function can activate the PI3k and Akt signaling pathway, thus participating in cancerogenesis.	2	11	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	9	10
These data support then the critical functions of the PTEN loss induced sustained PI3K and Akt activation in PC stem and progenitor cells in prostate carcinogenesis and treatment resistance .	These data support then the critical functions of the PTEN loss induced sustained PI3K and Akt activation in PC stem and progenitor cells in prostate carcinogenesis and treatment resistance.	9	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	15	16
PTEN acts as a phosphatase for PIP3 and negatively regulates the PI3K and AKT pathway , and p27 KIP1 is a cyclin dependent kinase inhibitor that regulates the G1 to S-phase transition by binding to and regulating the activity of cyclin dependent kinases .	PTEN acts as a phosphatase for PIP3 and negatively regulates the PI3K and AKT pathway, and p27 KIP1 is a cyclin dependent kinase inhibitor that regulates the G1 to S-phase transition by binding to and regulating the activity of cyclin dependent kinases.	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	13	14
Aberrations in PI3K and Akt signaling such as loss of PTEN , an Akt phosphorylation inhibitor and tumor suppressor , as well as overexpression and over-activation of Akt ( pAkt ) , have been identified as important mechanisms contributing to breast cell proliferation [ XREF_BIBR - XREF_BIBR ] .	Aberrations in PI3K and Akt signaling such as loss of PTEN, an Akt phosphorylation inhibitor and tumor suppressor, as well as overexpression and over-activation of Akt (pAkt), have been identified as important mechanisms contributing to breast cell proliferation [XREF_BIBR - XREF_BIBR].	2	11	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	10	11	4	5
PTEN loss in Ewing sarcoma augments AKT signaling .	PTEN loss in Ewing sarcoma augments AKT signaling.	0	7	augments	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
PTEN inactivates Akt , leading to the sequestration of Mdm2 in the cytoplasm and upregulation of nuclear p53 .	PTEN inactivates Akt, leading to the sequestration of Mdm2 in the cytoplasm and upregulation of nuclear p53.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	2	3
Conditional deletion of Pten in mouse prostate activates Akt signaling and causes focal prostate intraepithelial neoplasia ( PIN ) by 6 weeks and high grade PIN ( HGPIN ) by 8-9 weeks .	Conditional deletion of Pten in mouse prostate activates Akt signaling and causes focal prostate intraepithelial neoplasia (PIN) by 6 weeks and high grade PIN (HGPIN) by 8-9 weeks.	1	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	3	4	8	9
PTEN loss in other neoplasms , however , promotes AKT mediated cancer growth suggesting that downstream effectors such p53 activation critically regulates eventual cell growth and inhibitory and fibrotic phenotype .	PTEN loss in other neoplasms, however, promotes AKT mediated cancer growth suggesting that downstream effectors such p53 activation critically regulates eventual cell growth and inhibitory and fibrotic phenotype.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	9	10
Maternal HFD could increase the standard serum leptin level , inhibit the expression of PTEN protein , promote P-Akt protein expression , activate the PI3K and Akt pathway , and ultimately promote the development and progression of PCa in TRAMP offspring .	Maternal HFD could increase the standard serum leptin level, inhibit the expression of PTEN protein, promote P-Akt protein expression, activate the PI3K and Akt pathway, and ultimately promote the development and progression of PCa in TRAMP offspring.	1	27	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	HFD could increase the standard serum leptin level, inhibit the expression of PTEN	pten	Akt	Akt	akt	14	15	26	27
The tumour-suppressor gene phosphatase and tensin homologue ( PTEN ) directly antagonises the PI3K-AKT pathway by converting PIP3 back to PIP2 .	The tumour-suppressor gene phosphatase and tensin homologue (PTEN) directly antagonises the PI3K-AKT pathway by converting PIP3 back to PIP2.	3	14	antagonises	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	8	9	13	14
PTEN ( Phosphatase and TENsin homolog deleted on chromosome ten ) , a tumor-suppressorgene with dual lipid and protein phosphatase activity , antagonizes the PI3K and AKT signaling pathway and suppresses cell survival , as well as cell proliferation .	PTEN (Phosphatase and TENsin homolog deleted on chromosome ten), a tumor-suppressorgene with dual lipid and protein phosphatase activity, antagonizes the PI3K and AKT signaling pathway and suppresses cell survival, as well as cell proliferation.	0	30	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	26	27
Regardless of the NOTCH1 and FBW7 mutational status , loss of PTEN in these samples should result in increased AKT signaling and resistance to standard chemotherapy and GSIs .	Regardless of the NOTCH1 and FBW7 mutational status, loss of PTEN in these samples should result in increased AKT signaling and resistance to standard chemotherapy and GSIs.	9	21	signaling	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	11	12	19	20
The lipid protein phosphatase PTEN negatively regulates AKT activation and acts as tumor suppressor XREF_BIBR .	The lipid protein phosphatase PTEN negatively regulates AKT activation and acts as tumor suppressor XREF_BIBR.	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	7	8
PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12 and CXCR4 signaling .	PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12 and CXCR4 signaling.	0	4	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
Additionally , p53 activation also leads to upregulation of the phosphatidylinositol phosphatase PTEN ( an inhibitor of the PI3K and AKT signaling pathway ) and TSC2 at the transcriptional level , which may contribute to the long-term suppression of mTOR [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Additionally, p53 activation also leads to upregulation of the phosphatidylinositol phosphatase PTEN (an inhibitor of the PI3K and AKT signaling pathway) and TSC2 at the transcriptional level, which may contribute to the long-term suppression of mTOR [XREF_BIBR, XREF_BIBR - XREF_BIBR].	7	22	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	12	13	20	21
First , PTEN blocks the pathway leading to PI3K , phosphatidylinositol ( 3,4,5 )-trisphosphate ( PIP3 ) , and Akt , through which it inhibits cellular apoptosis and expression of cyclin D and , through mdm2 , suppresses the degradation of p53 to stop tumor formation XREF_BIBR .	First, PTEN blocks the pathway leading to PI3K, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), and Akt, through which it inhibits cellular apoptosis and expression of cyclin D and, through mdm2, suppresses the degradation of p53 to stop tumor formation XREF_BIBR.	2	37	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	19	20
MicroRNA-21-mediated suppression of PTEN thus promotes PI3K and AKT signaling , which downregulates nuclear forkhead box transcription factor ( FoxO ) activity ( XREF_FIG ) .	MicroRNA-21-mediated suppression of PTEN thus promotes PI3K and AKT signaling, which downregulates nuclear forkhead box transcription factor (FoxO) activity (XREF_FIG).	1	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	8	9
PTEN negatively regulates AKT activation via its lipid phosphatase activity .	PTEN negatively regulates AKT activation via its lipid phosphatase activity.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	3	4
Furthermore , we have observed an additive effect of FTY720 in killing gastric cancer cells when in combination with Cisplatin , partly through PTEN mediated Akt and MDM2 inhibition .	Furthermore, we have observed an additive effect of FTY720 in killing gastric cancer cells when in combination with Cisplatin, partly through PTEN mediated Akt and MDM2 inhibition.	21	28	mediated	Positive_early_activation	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	23	24	25	26
As a regulator of PI3K , while the phosphatase PTEN negatively regulates PI3K-Akt signaling , many studies have shown that this signaling is activated by KL-Kit in the hematopoietic , melanogenic , and gametogenic cell lineages , and also in mast cells [ XREF_BIBR ] .	As a regulator of PI3K, while the phosphatase PTEN negatively regulates PI3K-Akt signaling, many studies have shown that this signaling is activated by KL-Kit in the hematopoietic, melanogenic, and gametogenic cell lineages, and also in mast cells [XREF_BIBR].	7	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	9	10	12	13
Loss of PTEN results in constitutive activation of Akt and in alteration of downstream factors in Akt signaling .	Loss of PTEN results in constitutive activation of Akt and in alteration of downstream factors in Akt signaling.	0	9	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	8	9
The Akt activity is negatively regulated by PTEN ( phosphatase and tensin homolog deleted on chromosome 10 ) , a tumor suppressor gene that is suppressed , mutated , or deleted at high frequency in a large number of cancers [ XREF_BIBR ] .	The Akt activity is negatively regulated by PTEN (phosphatase and tensin homolog deleted on chromosome 10), a tumor suppressor gene that is suppressed, mutated, or deleted at high frequency in a large number of cancers [XREF_BIBR].	1	22	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	1	2
Expression of NICD2 increases levels of PTEN , which negatively regulates Akt activity , and p53 independent of radiation exposure , suggesting that the activities of these two proteins may not be directly involved in radioprotective functions of Notch .	Expression of NICD2 increases levels of PTEN, which negatively regulates Akt activity, and p53 independent of radiation exposure, suggesting that the activities of these two proteins may not be directly involved in radioprotective functions of Notch.	0	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Expression of NICD2 increases levels of PTEN	pten	Akt	Akt	akt	6	7	11	12
In this study , PTEN overexpression decreases IGF-I-induced Akt activity , enhances serum withdrawal induced apoptosis , and decreases IGF-I protection and cell growth in SHEP cells .	In this study, PTEN overexpression decreases IGF-I-induced Akt activity, enhances serum withdrawal induced apoptosis, and decreases IGF-I protection and cell growth in SHEP cells.	4	9	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN overexpression	pten	Akt	Akt	akt	4	5	8	9
Bmi1 inhibits PTEN expression in nasopharyngeal cancers , subsequently activating AKT .	Bmi1 inhibits PTEN expression in nasopharyngeal cancers, subsequently activating AKT.	0	11	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Bmi1 inhibits PTEN expression	pten	AKT	AKT	akt	2	3	10	11
In CRCs , an abnormal activation of Wnt signaling pathway leads to nuclear beta-catenin accumulation and subsequent abnormal CSCs proliferation ; moreover , BMPs signaling inhibition promotes nuclear beta-catenin activity through PTEN inactivation and activation of PI3K-Akt pathway [ XREF_BIBR ] .	In CRCs, an abnormal activation of Wnt signaling pathway leads to nuclear beta-catenin accumulation and subsequent abnormal CSCs proliferation; moreover, BMPs signaling inhibition promotes nuclear beta-catenin activity through PTEN inactivation and activation of PI3K-Akt pathway [XREF_BIBR].	31	39	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	31	32	36	37
Furthermore , we demonstrated suppression of AKT phosphorylation by SLE treatment in LNCaP cells , suggesting that PTEN inhibits the PI3K and AKT pathway and its downstream functions including cell survival and proliferation in SLE treated LNCaP cells .	Furthermore, we demonstrated suppression of AKT phosphorylation by SLE treatment in LNCaP cells, suggesting that PTEN inhibits the PI3K and AKT pathway and its downstream functions including cell survival and proliferation in SLE treated LNCaP cells.	17	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	17	18	22	23
It has also been noticed that the EGFR amplification is often accompanied by an upregulated expression of the deletion mutant EGFR variant III form , also designated as EGFRvIII or DeltaEGFR , as well as the PTEN loss induced Akt activation , and associated with a poor overall survival of GBM patients .	It has also been noticed that the EGFR amplification is often accompanied by an upregulated expression of the deletion mutant EGFR variant III form, also designated as EGFRvIII or DeltaEGFR, as well as the PTEN loss induced Akt activation, and associated with a poor overall survival of GBM patients.	36	40	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	36	37	39	40
Since PTEN inhibits AKT activation , we asked whether PTEN upregulation could be responsible for attenuation of AKT activation in GFP-Pfn1 expressing cells .	Since PTEN inhibits AKT activation, we asked whether PTEN upregulation could be responsible for attenuation of AKT activation in GFP-Pfn1 expressing cells.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	3	4
In addition , the upregulation of PTEN ( phosphatase and tensin homolog deleted on chromosome 10 ) , a tumor suppressor gene frequently deleted or mutated in many human cancers , has been demonstrated to reduce ROS generation by regulating the PI3K and AKT pathway [ XREF_BIBR ] .	In addition, the upregulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10), a tumor suppressor gene frequently deleted or mutated in many human cancers, has been demonstrated to reduce ROS generation by regulating the PI3K and AKT pathway [XREF_BIBR].	4	46	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	43	44
Conversely , the lipid phosphatase PTEN attenuates AKT activation by dephosphorylating the 3 ' position of phosphatidylinositols [ XREF_BIBR ] .	Conversely, the lipid phosphatase PTEN attenuates AKT activation by dephosphorylating the 3 ' position of phosphatidylinositols [XREF_BIBR].	2	8	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	7	8
However , deletion of PTEN , activates AKT and overrides V600E BRAF induced inhibition of AKT [ XREF_BIBR ] .	However, deletion of PTEN, activates AKT and overrides V600E BRAF induced inhibition of AKT [XREF_BIBR].	2	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	7	8
Expression of WT-PTEN also caused decreased activation of Akt , p70 S6K , and Erk signaling pathways .	Expression of WT-PTEN also caused decreased activation of Akt, p70 S6K, and Erk signaling pathways.	0	16	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WT-PTEN	Expression of WT-PTEN	wt-pten	Akt	Akt	akt	2	3	8	9
Ectopic expression of PTEN in breast cancer cell lines upregulates apoptosis machinery and decreases AKT activation , whereas a constitutively active AKT rescues these cells from PTEN mediated apoptosis .	Ectopic expression of PTEN in breast cancer cell lines upregulates apoptosis machinery and decreases AKT activation, whereas a constitutively active AKT rescues these cells from PTEN mediated apoptosis.	1	15	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	AKT	AKT	akt	3	4	14	15
PTEN mainly localizes to the cytoplasm and negatively regulates PI3K and AKT signaling .	PTEN mainly localizes to the cytoplasm and negatively regulates PI3K and AKT signaling.	0	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	11	12
The loss of PTEN results in increased accumulation of PIP 3 and AKT activation , which has been associated with poor clinical outcomes .	The loss of PTEN results in increased accumulation of PIP 3 and AKT activation, which has been associated with poor clinical outcomes.	1	14	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	3	4	12	13
The tumor suppressor gene PTEN negatively regulates the PI3K and Akt pathway .	The tumor suppressor gene PTEN negatively regulates the PI3K and Akt pathway.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	10	11
It has been reported that PTEN protein could contribute to drug sensitivity by suppressing the PI3K and Akt pathway , and serve as target gene of many miRNAs , such as miR-21 , miR-22 and miR-222 [ XREF_BIBR , XREF_BIBR ] .	It has been reported that PTEN protein could contribute to drug sensitivity by suppressing the PI3K and Akt pathway, and serve as target gene of many miRNAs, such as miR-21, miR-22 and miR-222 [XREF_BIBR, XREF_BIBR].	5	18	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	17	18
Since PTEN is known to inhibit AKT activation we wished to establish whether the elevated PTEN levels evident in ODAM expressing melanoma cells are responsible for the observed suppression of AKT activation .	Since PTEN is known to inhibit AKT activation we wished to establish whether the elevated PTEN levels evident in ODAM expressing melanoma cells are responsible for the observed suppression of AKT activation.	1	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	6	7
PTEN antagonizes PI3K function and negatively regulates AKT activity .	PTEN antagonizes PI3K function and negatively regulates AKT activity.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	7	8
Since PTEN inhibits PI3K and Akt , another possibility is that S6K2 knockdown increases PTEN level resulting in inhibition of Akt .	Since PTEN inhibits PI3K and Akt, another possibility is that S6K2 knockdown increases PTEN level resulting in inhibition of Akt.	1	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	5	6
Phosphatase and tensin homolog ( PTEN ) , commonly known as a tumor suppressor , inhibits ERK and AKT activation and initiates both apoptotic pathways , and cell cycle arrest .	Phosphatase and tensin homolog (PTEN), commonly known as a tumor suppressor, inhibits ERK and AKT activation and initiates both apoptotic pathways, and cell cycle arrest.	0	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	AKT	AKT	AKT	0	4	18	19
Loss of PTEN leads to the activation of the PI3K and AKT cascade and stimulates cell growth and survival .	Loss of PTEN leads to the activation of the PI3K and AKT cascade and stimulates cell growth and survival.	0	12	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	11	12
PTEN is inactivated in certain malignant tumors , resulting in Akt hyper-activation , thereby promoting cell proliferation , inhibiting of apoptosis and enhancing cell invasion and radio resistance XREF_BIBR , XREF_BIBR .	PTEN is inactivated in certain malignant tumors, resulting in Akt hyper-activation, thereby promoting cell proliferation, inhibiting of apoptosis and enhancing cell invasion and radio resistance XREF_BIBR, XREF_BIBR.	0	11	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	10	11
It was also demonstrated that the loss of PTEN contributed to the process of mitochondrial biogenesis , respiration and increased the mitochondrial volume and ROS production by activating the insulin activated PI3K and AKT pathway , a main anabolic pathway XREF_BIBR .	It was also demonstrated that the loss of PTEN contributed to the process of mitochondrial biogenesis, respiration and increased the mitochondrial volume and ROS production by activating the insulin activated PI3K and AKT pathway, a main anabolic pathway XREF_BIBR.	6	34	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	8	9	33	34
Two miR-200a targets , FOG-2 and PTEN negatively regulate PI3K and AKT pathway .	Two miR-200a targets, FOG-2 and PTEN negatively regulate PI3K and AKT pathway.	2	12	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	11	12
XREF_BIBR Akt can be also activated by loss of PTEN , a mechanism that has been associated with a poor prognosis and increased risk of relapse after treatment with tamoxifen .	XREF_BIBR Akt can be also activated by loss of PTEN, a mechanism that has been associated with a poor prognosis and increased risk of relapse after treatment with tamoxifen.	0	12	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	9	10	1	2
Loss of PTEN activates the PI3K-AKT pathway and promotes cell proliferation XREF_BIBR XREF_BIBR .	Loss of PTEN activates the PI3K-AKT pathway and promotes cell proliferation XREF_BIBR XREF_BIBR.	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	2	3	5	6
PTEN negatively regulates PI3K and AKT , making it and/or its signaling pathway a very likely candidate involved in RCC .	PTEN negatively regulates PI3K and AKT, making it and/or its signaling pathway a very likely candidate involved in RCC.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
Pten is known to inhibit the activation of Akt , while loss of Pten increases the expression of phospho-Akt ( p-Akt ) .	Pten is known to inhibit the activation of Akt, while loss of Pten increases the expression of phospho-Akt (p-Akt).	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	0	1	8	9
Furthermore , our data indicate that PTEN upregulation prevents cell proliferation showing that PTEN negatively regulates Akt activation and thus VSMC proliferation which is required for hyperplasia and restenosis .	Furthermore, our data indicate that PTEN upregulation prevents cell proliferation showing that PTEN negatively regulates Akt activation and thus VSMC proliferation which is required for hyperplasia and restenosis.	13	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	16	17
It has been well established that loss of PTEN results in Akt activation , which leads to phosphorylation and cytoplasmic localization of FOXO proteins .	It has been well established that loss of PTEN results in Akt activation, which leads to phosphorylation and cytoplasmic localization of FOXO proteins.	6	13	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	8	9	11	12
The PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo .	The PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo.	1	9	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	8	9
Recently we demonstrated that PTEN inhibits PI3K and Akt signaling by direct interaction between PTEN and the p85alpha regulatory subunit of PI3K contributing to alcohol induced insulin resistance [ XREF_BIBR ] .	Recently we demonstrated that PTEN inhibits PI3K and Akt signaling by direct interaction between PTEN and the p85alpha regulatory subunit of PI3K contributing to alcohol induced insulin resistance [XREF_BIBR].	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	8	9
Prenatal ethanol also increases hepatic and skeletal muscle expression of tribbles-3 and PTEN ( phosphatase and tensin homolog deleted on chromosome 10 ) , which are markers of cellular stress and can inhibit Akt activation .	Prenatal ethanol also increases hepatic and skeletal muscle expression of tribbles-3 and PTEN (phosphatase and tensin homolog deleted on chromosome 10), which are markers of cellular stress and can inhibit Akt activation.	1	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	ethanol also increases hepatic and skeletal muscle expression of tribbles-3 and PTEN	pten	Akt	Akt	akt	12	13	33	34
Although overexpression of PTEN ( phosphatase and tensin homolog ) , which acts as a lipid phosphatase to dephosphorylates PIP3 and therefore negatively regulates PI3K and AKT pathway , was found to suppress esophageal cancer cell growth [ XREF_BIBR ] , experimental data on direct targeting of PI3K and AKT in the preclinical setting are limited .	Although overexpression of PTEN (phosphatase and tensin homolog), which acts as a lipid phosphatase to dephosphorylates PIP3 and therefore negatively regulates PI3K and AKT pathway, was found to suppress esophageal cancer cell growth [XREF_BIBR], experimental data on direct targeting of PI3K and AKT in the preclinical setting are limited.	1	27	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	overexpression of PTEN	pten	AKT	AKT	akt	3	4	26	27
Low PTEN expression after nerve injury promotes Akt and mammalian target of rapamycin ( mTOR ) signaling pathway activity .	Low PTEN expression after nerve injury promotes Akt and mammalian target of rapamycin (mTOR) signaling pathway activity.	1	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	1	2	7	8
As for PTEN , Liang Deng et al reported that PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo [ XREF_BIBR ] .	As for PTEN, Liang Deng et al reported that PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo [XREF_BIBR].	10	18	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	17	18
The Akt survival pathway is positively and negatively regulated by PI3K and PTEN , respectively , through their opposing effects on phosphatidylinositol-3 '-phosphate ( PIP 3 ) generation .	The Akt survival pathway is positively and negatively regulated by PI3K and PTEN, respectively, through their opposing effects on phosphatidylinositol-3 '-phosphate (PIP 3) generation.	1	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	12	13	1	2
PDK1 associated phosphorylation of T308 is associated with full AKT activation and was only observed in the absence of PTEN suggesting that AKT activation is augmented by PTEN loss .	PDK1 associated phosphorylation of T308 is associated with full AKT activation and was only observed in the absence of PTEN suggesting that AKT activation is augmented by PTEN loss.	22	28	augmented	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	27	28	22	23
Finally , since PTEN antagonizes the PI3K and AKT signaling pathway by dephosphorylating phosphoinositides , and no change in total PTEN levels were observed by protein MS , we checked pPTEN Ser 380 status and found increased pPTEN Ser 380 phosphorylation ; a modification thought to stabilize PTEN and maintain its function .	Finally, since PTEN antagonizes the PI3K and AKT signaling pathway by dephosphorylating phosphoinositides, and no change in total PTEN levels were observed by protein MS, we checked pPTEN Ser 380 status and found increased pPTEN Ser 380 phosphorylation; a modification thought to stabilize PTEN and maintain its function.	3	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	8	9
Specifically , loss of PTEN leads to activation of AKT , which in turn promotes anti-apoptotic and pro cell cycle entry pathways believed to be essential in tumourigenesis .	Specifically, loss of PTEN leads to activation of AKT, which in turn promotes anti-apoptotic and pro cell cycle entry pathways believed to be essential in tumourigenesis.	2	14	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	4	5	9	10
It is well established that the tumor suppressor PTEN negatively regulates the oncogenic signaling pathway PI3K and AKT ; however , literature suggests that PTEN may also regulate the ERK1/2 pathway to combat neoplastic development .	It is well established that the tumor suppressor PTEN negatively regulates the oncogenic signaling pathway PI3K and AKT; however, literature suggests that PTEN may also regulate the ERK1/2 pathway to combat neoplastic development.	5	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	17	18
38 GHR suppression enhances the expression of tumor-suppressor PTEN and negatively regulates the PI3K and AKT signaling , which further increases the antitumor effect of GHR silencing in PDAC cell lines .	38 GHR suppression enhances the expression of tumor-suppressor PTEN and negatively regulates the PI3K and AKT signaling, which further increases the antitumor effect of GHR silencing in PDAC cell lines.	1	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	GHR suppression enhances the expression of tumor-suppressor PTEN	pten	AKT	AKT	akt	8	9	15	16
Gene transfer of PTEN to RVLM in SHR also abrogated the enhanced Akt activation and promoted antihypertension .	Gene transfer of PTEN to RVLM in SHR also abrogated the enhanced Akt activation and promoted antihypertension.	1	13	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	12	13
PTEN negatively regulates AKT , and therefore acts as a tumour suppressor .	PTEN negatively regulates AKT, and therefore acts as a tumour suppressor.	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	3	4
PTEN has been shown to suppress the PI3K and Akt pathway which activates a number of target proteins to promote nutrient uptake , protein synthesis , cell survival , cell proliferation , cell motility and angiogenesis [ XREF_BIBR ] .	PTEN has been shown to suppress the PI3K and Akt pathway which activates a number of target proteins to promote nutrient uptake, protein synthesis, cell survival, cell proliferation, cell motility and angiogenesis [XREF_BIBR].	0	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	9	10
We studied the regeneration capacity of beta-cells in mouse model where PI3K and AKT pathway downstream of insulin and IGF -1 signaling , is upregulated by genetic deletion of Pten ( phosphatase and tensin homologue deleted on chromosome 10 ) specifically in insulin producing cells .	We studied the regeneration capacity of beta-cells in mouse model where PI3K and AKT pathway downstream of insulin and IGF -1 signaling, is upregulated by genetic deletion of Pten (phosphatase and tensin homologue deleted on chromosome 10) specifically in insulin producing cells.	11	30	upregulated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	29	30	13	14
PTEN antagonizes the action of the PI3 kinase and Akt pathways , which mediates many of the downstream effects of neurotrophins and other growth factor receptors XREF_BIBR , XREF_BIBR .	PTEN antagonizes the action of the PI3 kinase and Akt pathways, which mediates many of the downstream effects of neurotrophins and other growth factor receptors XREF_BIBR, XREF_BIBR.	0	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	9	10
A genetic functional approach in ERBB2 overexpressing cell lines showed that PTEN loss or gain-of-function E545K and H1047R PIK3CA mutations resulted in sustained AKT activation despite the presence of the ERBB2 kinase inhibitor lapatinib ; yet combination with the dual PI3K and mTOR inhibitor NVP-BEZ235 was able to abrogate AKT phosphorylation and tumor growth .	A genetic functional approach in ERBB2 overexpressing cell lines showed that PTEN loss or gain-of-function E545K and H1047R PIK3CA mutations resulted in sustained AKT activation despite the presence of the ERBB2 kinase inhibitor lapatinib; yet combination with the dual PI3K and mTOR inhibitor NVP-BEZ235 was able to abrogate AKT phosphorylation and tumor growth.	11	25	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	11	12	23	24
The correlation between AKT activation and FoxO protein expression has been observed in T cells : it has been seen in two separate studies that AKT activation by PTEN deletion correlated with increased FoxO protein levels [ XREF_BIBR ] , while inhibition of AKT associated with decreased FoxO protein levels [ XREF_BIBR ] .	The correlation between AKT activation and FoxO protein expression has been observed in T cells : it has been seen in two separate studies that AKT activation by PTEN deletion correlated with increased FoxO protein levels [XREF_BIBR], while inhibition of AKT associated with decreased FoxO protein levels [XREF_BIBR].	25	29	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	28	29	25	26
Akt activation can be potentially inhibited by the Phosphatase and Tensin homolog ( PTEN ) , which is located on the chromosomal band 10q23 .	Akt activation can be potentially inhibited by the Phosphatase and Tensin homolog (PTEN), which is located on the chromosomal band 10q23.	0	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Phosphatase and Tensin homolog	Phosphatase and Tensin homolog	Phosphatase and Tensin homolog	Akt	Akt	Akt	8	12	0	1
PI3K and Akt pathway is negatively regulated by phosphatase and tensin homolog ( PTEN ) .	PI3K and Akt pathway is negatively regulated by phosphatase and tensin homolog (PTEN).	0	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	8	12	2	3
XREF_BIBR PTEN inhibits the AKT signaling pathway , thus glioblastoma cells that have mutations in PTEN show constant activation of EGFR/AKT/mTOR signaling pathway .	XREF_BIBR PTEN inhibits the AKT signaling pathway, thus glioblastoma cells that have mutations in PTEN show constant activation of EGFR/AKT/mTOR signaling pathway.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	4	5
The tumor suppressor PTEN negatively regulates AKT function ; however , mutation in ( or deletion of ) PTEN either in primary ( 30 % ) or metastatic ( 63 % ) prostate tumors is often responsible for AKT mediated survival signaling [ XREF_BIBR ] , resulting in downregulation of pro apoptotic signaling governed by FOXO3a and Par-4 [ XREF_BIBR - XREF_BIBR ] .	The tumor suppressor PTEN negatively regulates AKT function; however, mutation in (or deletion of) PTEN either in primary (30%) or metastatic (63%) prostate tumors is often responsible for AKT mediated survival signaling [XREF_BIBR], resulting in downregulation of pro apoptotic signaling governed by FOXO3a and Par-4 [XREF_BIBR - XREF_BIBR].	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	6	7
Because Pten functions upstream of mTOR and negatively regulates PI3K and Akt signaling as a haploinsufficient tumor suppressor XREF_BIBR , the loss of Pten is expected to result in the activation of mTOR .	Because Pten functions upstream of mTOR and negatively regulates PI3K and Akt signaling as a haploinsufficient tumor suppressor XREF_BIBR, the loss of Pten is expected to result in the activation of mTOR.	1	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	1	2	11	12
Our results are consistent with published data using mice harboring a deletion of Pten , a tumor suppressor gene that negatively regulates the Akt and mTOR pathway , since liver specific inactivation of Pten leads to steatosis and , eventually , HCC development .	Our results are consistent with published data using mice harboring a deletion of Pten, a tumor suppressor gene that negatively regulates the Akt and mTOR pathway, since liver specific inactivation of Pten leads to steatosis and, eventually, HCC development.	11	26	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	13	14	23	24
PTEN knockdown was also shown to lead to Jun-N-terminal kinase ( JNK ) pathway activation in an AKT independent manner [ XREF_BIBR ] .	PTEN knockdown was also shown to lead to Jun-N-terminal kinase (JNK) pathway activation in an AKT independent manner [XREF_BIBR].	0	19	lead	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	17	18
PTEN acts as a phosphatase for PI3P and negatively regulates the PI3K and Akt pathway .	PTEN acts as a phosphatase for PI3P and negatively regulates the PI3K and Akt pathway.	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	13	14
As an example , it has been reported that short-term treatment with Sunitinib induces the expression of the dual lipid and phosphatase PTEN that negatively regulates PI3K and AKT XREF_BIBR , whereas at long-term exposure induces epigenetic silencing of the PTEN gene XREF_BIBR .	As an example, it has been reported that short-term treatment with Sunitinib induces the expression of the dual lipid and phosphatase PTEN that negatively regulates PI3K and AKT XREF_BIBR, whereas at long-term exposure induces epigenetic silencing of the PTEN gene XREF_BIBR.	15	29	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of the dual lipid and phosphatase PTEN	pten	AKT	AKT	akt	22	23	28	29
Downregulation of circIBTK resulted in decreased expression of PTEN and thereby increased phosphorylation of AKT and knockdown of miR-29b significantly reversed the PTEN downregulation and activation of the AKT signaling pathway induced by circIBTK inhibition .	Downregulation of circIBTK resulted in decreased expression of PTEN and thereby increased phosphorylation of AKT and knockdown of miR-29b significantly reversed the PTEN downregulation and activation of the AKT signaling pathway induced by circIBTK inhibition.	22	30	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	22	23	28	29
High levels of PTEN antagonize Akt activity , which favors nuclear retention of FOXO3a and , consequently , activation of transcription of proapoptotic genes that are part of either the extrinsic pathway , such as FasL or TRAIL , or the intrinsic pathway , such as Bim , PUMA , and Noxa .	High levels of PTEN antagonize Akt activity, which favors nuclear retention of FOXO3a and, consequently, activation of transcription of proapoptotic genes that are part of either the extrinsic pathway, such as FasL or TRAIL, or the intrinsic pathway, such as Bim, PUMA, and Noxa.	1	6	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	levels of PTEN	pten	Akt	Akt	akt	3	4	5	6
This observation can be due to either the hyperactivation of other pathways that also activates 4EBP-1 or AKT - such as the RAS/RAF/MAPK , the IGF-1R and IRS-1 , and the mTOR pathways , or the loss of PTEN inhibition of AKT activation , or the existence of another PI3 kinase activating mutation that was not tested in this study - highlighting the limitation of this study as a genotyping study of particular mutations and underscoring the ultimate need for whole gene sequencing to comprehensively evaluate the mutation rate of PIK3CA in this cohort .	This observation can be due to either the hyperactivation of other pathways that also activates 4EBP-1 or AKT - such as the RAS/RAF/MAPK, the IGF-1R and IRS-1, and the mTOR pathways, or the loss of PTEN inhibition of AKT activation, or the existence of another PI3 kinase activating mutation that was not tested in this study - highlighting the limitation of this study as a genotyping study of particular mutations and underscoring the ultimate need for whole gene sequencing to comprehensively evaluate the mutation rate of PIK3CA in this cohort.	38	42	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	38	39	41	42
It is well established that loss of PTEN results in activation of the PI3K and AKT pathway and downstream effectors leading to cancer cell survival and expression of the malignant phenotype .	It is well established that loss of PTEN results in activation of the PI3K and AKT pathway and downstream effectors leading to cancer cell survival and expression of the malignant phenotype.	5	16	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	7	8	15	16
On the other hand , PTEN negatively regulates the activation of Akt , which occurs through phosphorylation of the Akt protein .	On the other hand, PTEN negatively regulates the activation of Akt, which occurs through phosphorylation of the Akt protein.	5	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	11	12
PTEN can negatively regulate AKT signaling and is also frequently mutated in several solid cancers .	PTEN can negatively regulate AKT signaling and is also frequently mutated in several solid cancers.	0	10	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	4	5
PTEN inhibit Akt signal transduction pathway and modulates its downstream cellular functions through lipid phosphatase activity .	PTEN inhibit Akt signal transduction pathway and modulates its downstream cellular functions through lipid phosphatase activity.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	2	3
Additionally , previous transcriptome analysis on LCM motor neurons from spinal cord motor neurons of SOD1-ALS patients showed that the PI3K and Akt signalling pathway , negatively regulated by PTEN , was increased in the surviving motor neurons , and may provide a therapeutic target .	Additionally, previous transcriptome analysis on LCM motor neurons from spinal cord motor neurons of SOD1-ALS patients showed that the PI3K and Akt signalling pathway, negatively regulated by PTEN, was increased in the surviving motor neurons, and may provide a therapeutic target.	22	30	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	29	30	22	23
Therefore , under normal physiological conditions , PTEN suppresses AKT activity to maintain activation of the RAF1 and ERK signaling pathway , which in turn maintains normal function of the initial segment and therefore , normal sperm maturation .	Therefore, under normal physiological conditions, PTEN suppresses AKT activity to maintain activation of the RAF1 and ERK signaling pathway, which in turn maintains normal function of the initial segment and therefore, normal sperm maturation.	7	10	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	9	10
Efficient PTEN knockdown resulted in a similar two-fold Akt activation ( XREF_FIG ) , indicating comparable patterns of Akt activation in cells lacking either PTEN or membrane NHERF1 .	Efficient PTEN knockdown resulted in a similar two-fold Akt activation (XREF_FIG), indicating comparable patterns of Akt activation in cells lacking either PTEN or membrane NHERF1.	1	10	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	8	9
We determined that heterozygous loss of PTEN in the non tumorigenic human mammary epithelial cell line , MCF-10A , was sufficient for activation of the PI3K and Akt and MAPK pathways , while the homozygous absence of PTEN expression led to a further increased activation of both pathways .	We determined that heterozygous loss of PTEN in the non tumorigenic human mammary epithelial cell line, MCF-10A, was sufficient for activation of the PI3K and Akt and MAPK pathways, while the homozygous absence of PTEN expression led to a further increased activation of both pathways.	4	28	was sufficient for activation	Positive_activation_copula_1	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	6	7	27	28
Loss of PTEN , PI3K mutation , AKT1 and AKT2 amplification may activate AKT kinase .	Loss of PTEN, PI3K mutation, AKT1 and AKT2 amplification may activate AKT kinase.	0	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	13	14
The hypoacetylated TRB3 and PTEN can inhibit the Akt activity in a rat model of prenatal alcohol exposure [ XREF_BIBR ] , which suggests that HDACI treatment could inhibit the activity of TRB3 and PTEN , and therefore enhance Akt signaling .	The hypoacetylated TRB3 and PTEN can inhibit the Akt activity in a rat model of prenatal alcohol exposure [XREF_BIBR], which suggests that HDACI treatment could inhibit the activity of TRB3 and PTEN, and therefore enhance Akt signaling.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	8	9
Collectively , these data in a mouse prostate cell system uncover for the first time a novel and complex relationship between PTEN loss mediated PI3K and AKT activation and posttranslational regulation of MT1-MMP , which may play a role in PC progression .	Collectively, these data in a mouse prostate cell system uncover for the first time a novel and complex relationship between PTEN loss mediated PI3K and AKT activation and posttranslational regulation of MT1-MMP, which may play a role in PC progression.	21	27	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	21	22	26	27
Since PTEN inhibits the PI3-kinase and AKT signaling pathway 76 , the increase in pAKT yet again indicates a reduction in PTEN activity .	Since PTEN inhibits the PI3-kinase and AKT signaling pathway 76, the increase in pAKT yet again indicates a reduction in PTEN activity.	1	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	6	7
While the lipid phosphatase and tumor suppressor PTEN antagonizes Akt signaling by dephosphorylating phosphoinositides , thereby preventing the activation of PDK1 and Akt , the mechanisms that directly terminate Akt signaling are not well characterized .	While the lipid phosphatase and tumor suppressor PTEN antagonizes Akt signaling by dephosphorylating phosphoinositides, thereby preventing the activation of PDK1 and Akt, the mechanisms that directly terminate Akt signaling are not well characterized.	3	10	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	9	10
GA enhanced PTEN expression and blocked the PI3K and Akt pathway .	GA enhanced PTEN expression and blocked the PI3K and Akt pathway.	0	10	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	GA enhanced PTEN expression	pten	Akt	Akt	akt	2	3	9	10
PI3K and AKT signaling is negatively regulated by the lipid phosphatase , phosphatase and tensin homolog deleted on chromosome ten ( PTEN ) , which serves as an antioncogene and is mutated in many types of cancer .	PI3K and AKT signaling is negatively regulated by the lipid phosphatase, phosphatase and tensin homolog deleted on chromosome ten (PTEN), which serves as an antioncogene and is mutated in many types of cancer.	0	16	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	12	16	2	3
Indeed , the anterior lobe of normal mice expresses the lowest level of all the lobes of the AKT antagonist PTEN , such that combining the Nkx3.1-/- mice with a Pten +/- background greatly accelerates neoplastic progression in the prostate , especially in the anterior lobe .	Indeed, the anterior lobe of normal mice expresses the lowest level of all the lobes of the AKT antagonist PTEN, such that combining the Nkx3.1-/- mice with a Pten +/- background greatly accelerates neoplastic progression in the prostate, especially in the anterior lobe.	15	21	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	20	21	18	19
The PI3K and AKT pathway is also negatively regulated by phosphatase and tensin homolog ( PTEN ) , a phosphatase that opposes PI3K activity to repress AKT activation [ XREF_BIBR ] .	The PI3K and AKT pathway is also negatively regulated by phosphatase and tensin homolog (PTEN), a phosphatase that opposes PI3K activity to repress AKT activation [XREF_BIBR].	1	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	10	14	3	4
While knockdown of PTEN enhanced AKT activation , this did not affect the generation of primary spheres and the propagation of secondary spheres .	While knockdown of PTEN enhanced AKT activation, this did not affect the generation of primary spheres and the propagation of secondary spheres.	1	6	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	5	6
Reciprocally , PTEN overexpression downregulates Akt activity and depresses cellular PtdIns-3 ,4,5-P 3 levels .	Reciprocally, PTEN overexpression downregulates Akt activity and depresses cellular PtdIns-3,4,5-P 3 levels.	2	6	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN overexpression	pten	Akt	Akt	akt	2	3	5	6
Given that Pten normally antagonizes PI3K and inhibits Akt signaling , we next investigated whether Pten was deactivated in these animals .	Given that Pten normally antagonizes PI3K and inhibits Akt signaling, we next investigated whether Pten was deactivated in these animals.	2	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	2	3	8	9
PTEN counteracts the effects of PI3K on AKT , and loss of PTEN expression mediates AKT activation [ XREF_BIBR ] .	PTEN counteracts the effects of PI3K on AKT, and loss of PTEN expression mediates AKT activation [XREF_BIBR].	12	16	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	12	13	15	16
In mouse endometrial and bladder cancers , loss of PTEN and LKB1 leads to activation of the AKT and mTOR pathway and results in tumors sensitivity to PI3K and mTOR inhibition .	In mouse endometrial and bladder cancers, loss of PTEN and LKB1 leads to activation of the AKT and mTOR pathway and results in tumors sensitivity to PI3K and mTOR inhibition.	7	20	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	9	10	17	18
Akt is inhibited by PP2A , PHLPP1/2 , and indirectly by PTEN .	Akt is inhibited by PP2A, PHLPP1/2, and indirectly by PTEN.	0	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	0	1
In addition , Akt may be negatively regulated by the carboxy-terminal modulator protein , CTMP , that binds to the C-terminal of Akt and inactivates it ) and/or the phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) that converts phosphoinositol 3,4,5-triphosphate to phosphoinositol 4,5-biphosphate , inhibiting Akt phosphorylation and activation .	In addition, Akt may be negatively regulated by the carboxy-terminal modulator protein, CTMP, that binds to the C-terminal of Akt and inactivates it) and/or the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) that converts phosphoinositol 3,4,5-triphosphate to phosphoinositol 4,5-biphosphate, inhibiting Akt phosphorylation and activation.	3	33	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	binds to the C-terminal of Akt and inactivates it) and/or the phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	29	33	3	4
IGFBP-2 knockdown led to decreased PTEN tyrosine phosphorylation and decreased AKT Ser473 activation .	IGFBP-2 knockdown led to decreased PTEN tyrosine phosphorylation and decreased AKT Ser473 activation.	0	12	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	IGFBP-2 knockdown led to decreased PTEN tyrosine phosphorylation	pten	AKT	AKT	akt	5	6	10	11
PTEN inhibits activation of Akt , the downstream effector of PI 3-kinase , which is integral to cell proliferation , migration , survival , and angiogenesis essential for tissue injury healing .	PTEN inhibits activation of Akt, the downstream effector of PI 3-kinase, which is integral to cell proliferation, migration, survival, and angiogenesis essential for tissue injury healing.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	4	5
XREF_BIBR , XREF_BIBR Interestingly , we found that activation of PI3K and Akt signaling by Pten gene deletion was unable to elevate the levels of Myc protein in hematopoietic cells .	XREF_BIBR, XREF_BIBR Interestingly, we found that activation of PI3K and Akt signaling by Pten gene deletion was unable to elevate the levels of Myc protein in hematopoietic cells.	10	17	signaling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	15	16	12	13
As shown ( XREF_FIG , left panel ) , deletion of Pten alone activated Akt and p53/p21/p16 signaling pathways , which cause the senescence phenotype ( XREF_SUPPLEMENTARY ) .	As shown (XREF_FIG, left panel), deletion of Pten alone activated Akt and p53/p21/p16 signaling pathways, which cause the senescence phenotype (XREF_SUPPLEMENTARY).	9	18	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	11	12	14	15
Moreover , shikonin increased the PTEN level and inactivated the PI3K and AKT signaling pathway , subsequently upregulating BAX in K562 cells .	Moreover, shikonin increased the PTEN level and inactivated the PI3K and AKT signaling pathway, subsequently upregulating BAX in K562 cells.	2	14	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	shikonin increased the PTEN level	pten	AKT	AKT	akt	5	6	12	13
The PTEN lipid phosphatase mutant G129E fails to inhibit IGF-I-stimulated Akt activity and protection from apoptosis .	The PTEN lipid phosphatase mutant G129E fails to inhibit IGF-I-stimulated Akt activity and protection from apoptosis.	1	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	10	11
The PI3K and AKT activity was decreased in cells treated with pten ( bpv ) after transfecting with SALL4-siRNA , whereby p-PI3K and p-AKT protein levels were significantly increased as compared to cells transfected with SALL4-siRNA only .	The PI3K and AKT activity was decreased in cells treated with pten (bpv) after transfecting with SALL4-siRNA, whereby p-PI3K and p-AKT protein levels were significantly increased as compared to cells transfected with SALL4-siRNA only.	1	13	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	pten	pten	pten	AKT	AKT	AKT	11	12	3	4
The observation that complete inactivation of Pten in mouse thyroid results mainly in follicular adenoma within 12 months of age and that Inpp4b loss does not accelerate the entire tumor spectrum of Pten +/- mice raised the possibility that loss of Inpp4b specifically cooperates with Pten loss for tumor progression and metastasis in thyroid , not through a generic elevation of PI3K and AKT signaling , but potentially by deregulating the PI3K pathway in a more selective manner .	The observation that complete inactivation of Pten in mouse thyroid results mainly in follicular adenoma within 12 months of age and that Inpp4b loss does not accelerate the entire tumor spectrum of Pten +/- mice raised the possibility that loss of Inpp4b specifically cooperates with Pten loss for tumor progression and metastasis in thyroid, not through a generic elevation of PI3K and AKT signaling, but potentially by deregulating the PI3K pathway in a more selective manner.	45	64	elevation	Positive_activation_syntax_7_noun	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	45	46	63	64
PTEN blocks PI3K and AKT signaling by dephosphorylation of PIP3 .	PTEN blocks PI3K and AKT signaling by dephosphorylation of PIP3.	0	5	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	4	5
In glioblastoma patients , this is reflected by the modest response towards mTOR inhibition in the presence of PTEN inactivating mutations and an enhanced AKT activity .	In glioblastoma patients, this is reflected by the modest response towards mTOR inhibition in the presence of PTEN inactivating mutations and an enhanced AKT activity.	16	25	inactivating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	18	19	24	25
In addition , morin increased the expression of PTEN , a target gene of PPARgamma that suppresses angiogenesis , and inhibited PI3K and Akt signaling .	In addition, morin increased the expression of PTEN, a target gene of PPARgamma that suppresses angiogenesis, and inhibited PI3K and Akt signaling.	3	24	inhibited	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	morin increased the expression of PTEN	pten	Akt	Akt	akt	8	9	23	24
We now show that reduced dosage of PTEN , a negative regulator of PI ( 3 ) K signaling , is sufficient to activate Akt , but has only a modest effect on lymphomagenesis in the same model .	We now show that reduced dosage of PTEN, a negative regulator of PI (3) K signaling, is sufficient to activate Akt, but has only a modest effect on lymphomagenesis in the same model.	5	25	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	24	25
Finally , recent reports have indicated that phosphatase and tensin homolog ( PTEN ) loss , which causes AKT activation , may affect PrCa progression .	Finally, recent reports have indicated that phosphatase and tensin homolog (PTEN) loss, which causes AKT activation, may affect PrCa progression.	7	19	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	7	11	18	19
The tumor suppressor gene PTEN negatively regulates Akt , a downstream mediator phosphoinositol 3-kinase .	The tumor suppressor gene PTEN negatively regulates Akt, a downstream mediator phosphoinositol 3-kinase.	0	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	7	8
PTEN dephosphorylates phosphatidylinositol triphosphate ( PIP ) -3 to PIP2 , inhibiting the activation of the oncogene AKT [ XREF_BIBR ] , and then negatively regulates the phosphatidylinositol 3-kinase ( PI3K )/Akt pathway .	PTEN dephosphorylates phosphatidylinositol triphosphate (PIP) -3 to PIP2, inhibiting the activation of the oncogene AKT [XREF_BIBR], and then negatively regulates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.	0	19	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN dephosphorylates phosphatidylinositol triphosphate	pten	AKT	AKT	akt	0	1	17	18
PI3K and AKT signaling is inhibited by the tumor suppressor phosphatase and tensin homolog ( PTEN ) , which is often mutated in many types of tumors .	PI3K and AKT signaling is inhibited by the tumor suppressor phosphatase and tensin homolog (PTEN), which is often mutated in many types of tumors.	0	21	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	10	14	2	3
For instance , the tumor suppressor PTEN negatively regulates the AKT pathway , thus affecting cellular uptake and use of glucose .	For instance, the tumor suppressor PTEN negatively regulates the AKT pathway, thus affecting cellular uptake and use of glucose.	3	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	10	11
Adenovirus mediated PTEN and MMAC1 expression in LNCaP cells reduced Akt activation , activated apoptosis , and sensitized cells to TNF but not to TRAIL .	Adenovirus mediated PTEN and MMAC1 expression in LNCaP cells reduced Akt activation, activated apoptosis, and sensitized cells to TNF but not to TRAIL.	4	11	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MMAC1	MMAC1 expression	mmac1	Akt	Akt	akt	4	5	10	11
PTEN antagonizes PI3K and negatively regulates AKT activity , which can affect migration and apoptosis as well as proliferation .	PTEN antagonizes PI3K and negatively regulates AKT activity, which can affect migration and apoptosis as well as proliferation.	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
PIK3CA and AKT is also negatively regulated by the lipid phosphatase PTEN , which is itself frequently mutated in human cancers .	PIK3CA and AKT is also negatively regulated by the lipid phosphatase PTEN, which is itself frequently mutated in human cancers.	0	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	11	12	2	3
miR-21 also plays an important role in hepatocytes , where it is induced by nuclear factor-kappaB , leading to the downregulation of phosphatase and tensin homolog ( PTEN ) , a protein that inhibits Akt activation .	miR-21 also plays an important role in hepatocytes, where it is induced by nuclear factor-kappaB, leading to the downregulation of phosphatase and tensin homolog (PTEN), a protein that inhibits Akt activation.	25	35	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	27	28	34	35
Phosphatase and tensin homologue ( PTEN ) negatively regulates PI3K and Akt signalling XREF_BIBR .	Phosphatase and tensin homologue (PTEN) negatively regulates PI3K and Akt signalling XREF_BIBR.	3	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	11	12
Both PTEN , which inhibits Akt , and LKB1 , which activates AMPK , are activated by nutrient depletion and induce a catabolic state in cells and , through downstream effects on mTOR , also inhibit cellular proliferation .	Both PTEN, which inhibits Akt, and LKB1, which activates AMPK, are activated by nutrient depletion and induce a catabolic state in cells and, through downstream effects on mTOR, also inhibit cellular proliferation.	0	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	5	6
Glucocorticoid up-regulates PTEN expression , which dephosphorylates the signal lipid PIP3 and down-regulates PIP3 and AKT actions in turn .	Glucocorticoid up-regulates PTEN expression, which dephosphorylates the signal lipid PIP3 and down-regulates PIP3 and AKT actions in turn.	2	16	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	2	3	15	16
The PTEN loss and activation of AKT signaling pathway contributed to Erlotinib resistance in EGFR-mutant NSCLC cell line H1650 .	The PTEN loss and activation of AKT signaling pathway contributed to Erlotinib resistance in EGFR-mutant NSCLC cell line H1650.	1	8	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	6	7
In this study we evaluated whether reintroducing P53 using non viral gene transfer enhances PTEN mediated inhibition of PI3K and AKT signaling by cetuximab in PC3 prostate adenocarcinoma cell line bearing p53 and pten mutations .	In this study we evaluated whether reintroducing P53 using non viral gene transfer enhances PTEN mediated inhibition of PI3K and AKT signaling by cetuximab in PC3 prostate adenocarcinoma cell line bearing p53 and pten mutations.	13	21	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	20	21
Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) and the presence of putative p63 binding sites in the pten promoter led us to investigate whether DeltaNp63alpha regulates PTEN expression .	Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63 binding sites in the pten promoter led us to investigate whether DeltaNp63alpha regulates PTEN expression.	2	9	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	5	9	2	3
PTEN acts as a tumor suppressor in most cells , and loss of PTEN leads to constitutive activation of AKT and resistance to apoptosis [ XREF_BIBR , XREF_BIBR ] .	PTEN acts as a tumor suppressor in most cells, and loss of PTEN leads to constitutive activation of AKT and resistance to apoptosis [XREF_BIBR, XREF_BIBR].	11	21	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	13	14	19	20
IGFBP2 has been shown to reduce PTEN expression and enhance AKT activation in response to IGF1 through its heparin binding domain [ XREF_BIBR ] .	IGFBP2 has been shown to reduce PTEN expression and enhance AKT activation in response to IGF1 through its heparin binding domain [XREF_BIBR].	0	11	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	IGFBP2 has been shown to reduce PTEN expression	pten	AKT	AKT	akt	6	7	10	11
The increase in ROS might activate PTEN , which in turn diminished AKT activation .	The increase in ROS might activate PTEN, which in turn diminished AKT activation.	5	13	diminished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	12	13
PTEN negatively regulates the activity of PI3K and AKT signaling by converting PIP3 to PIP2 ( phosphatidylinositol 4,5-bisphosphate ) .	PTEN negatively regulates the activity of PI3K and AKT signaling by converting PIP3 to PIP2 (phosphatidylinositol 4,5-bisphosphate).	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	8	9
PTEN , a dual specificity phosphatase , has the ability to dephosphorylate inositol phospholipids such as phosphatidylinositol-3 ,4,5-triphosphate ( PIP3 ) and , as a consequence , negatively regulates AKT activation .	PTEN, a dual specificity phosphatase, has the ability to dephosphorylate inositol phospholipids such as phosphatidylinositol-3,4,5-triphosphate (PIP3) and, as a consequence, negatively regulates AKT activation.	0	30	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	29	30
Ectopic PTEN overexpression in T24 cells blocked the Akt signal pathway which attenuated cell growth via upregualtion of BTG2 gene expression , while reverse effect was found in PTEN-knockdown RT-4 cells .	Ectopic PTEN overexpression in T24 cells blocked the Akt signal pathway which attenuated cell growth via upregualtion of BTG2 gene expression, while reverse effect was found in PTEN-knockdown RT-4 cells.	1	10	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN overexpression	pten	Akt	Akt	akt	1	2	8	9
The disruption of Pten and expression of mutant KRAS G12D are expected to increase the activity of the PI3K and AKT and RAS/MEK1/ERK1/2 pathways , respectively .	The disruption of Pten and expression of mutant KRAS G12D are expected to increase the activity of the PI3K and AKT and RAS/MEK1/ERK1/2 pathways, respectively.	1	21	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	3	4	20	21
PTEN antagonizes the phosphoinositol-3-kinase and AKT signaling pathway and suppresses cell survival as well as cell proliferation , thereby safeguards important cellular machineries against tumorigenesis XREF_BIBR .	PTEN antagonizes the phosphoinositol-3-kinase and AKT signaling pathway and suppresses cell survival as well as cell proliferation, thereby safeguards important cellular machineries against tumorigenesis XREF_BIBR.	0	9	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
Considering that Akt is negatively regulated by PTEN and essential not only for prevention of apoptosis but also for growth factor induced cell proliferation , we assessed the serum induced SMC proliferation following the overexpression of PTEN .	Considering that Akt is negatively regulated by PTEN and essential not only for prevention of apoptosis but also for growth factor induced cell proliferation, we assessed the serum induced SMC proliferation following the overexpression of PTEN.	0	26	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	2	3
The loss of PTEN leads to accumulation of PIP3 and increases PI3K-AKT signaling [ XREF_BIBR ] .	The loss of PTEN leads to accumulation of PIP3 and increases PI3K-AKT signaling [XREF_BIBR].	1	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	3	4	11	12
PTEN , a tumor suppressor protein , possesses alkaline phosphatase and protein phosphatase activities and can block PI3K and AKT signaling XREF_BIBR , XREF_BIBR .	PTEN, a tumor suppressor protein, possesses alkaline phosphatase and protein phosphatase activities and can block PI3K and AKT signaling XREF_BIBR, XREF_BIBR.	0	21	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	19	20
Because PTEN can negatively regulate the Akt cascade , we postulated that 1,4-NQ would activate the PTEN-Akt signaling pathway and that this activation could be modulated by polysulfides such as Na 2 S 4 .	Because PTEN can negatively regulate the Akt cascade, we postulated that 1,4-NQ would activate the PTEN-Akt signaling pathway and that this activation could be modulated by polysulfides such as Na 2 S 4.	1	7	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	6	7
In contrast , expression of PTEN attenuated Akt activation , thereby increasing sensitivity to apoptotic stimuli in cell culture and in vivo in animal models .	In contrast, expression of PTEN attenuated Akt activation, thereby increasing sensitivity to apoptotic stimuli in cell culture and in vivo in animal models.	3	8	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	5	6	7	8
p53 activates transcription of the PTEN gene and increased levels of PTEN protein in vitro can suppress AKT activation .	p53 activates transcription of the PTEN gene and increased levels of PTEN protein in vitro can suppress AKT activation.	11	18	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	11	12	17	18
The inhibition of PTEN enhances PI3K and Akt signaling and could prevent myocardium from ischemia-reperfusion injury XREF_BIBR .	The inhibition of PTEN enhances PI3K and Akt signaling and could prevent myocardium from ischemia-reperfusion injury XREF_BIBR.	1	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	7	8
Although neither cytoplasmic PTEN ( cPTEN ) expression ( main location for PTEN inhibiting Akt activation ) nor membrane Akt 473 ( mAkt 473 ) phosphorylation ( main location for Akt activation ) was associated with CSS alone , when considered together to make a cumulative prognostic score , were associated with CSS .	Although neither cytoplasmic PTEN (cPTEN) expression (main location for PTEN inhibiting Akt activation) nor membrane Akt 473 (mAkt 473) phosphorylation (main location for Akt activation) was associated with CSS alone, when considered together to make a cumulative prognostic score, were associated with CSS.	10	15	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	12	13	14	15
Both PI3-K amplification and PTEN deletion consistently activate Akt , which plays a central role in a number of cell signaling pathways that are important in cancer cell survival [ XREF_BIBR ] .	Both PI3-K amplification and PTEN deletion consistently activate Akt, which plays a central role in a number of cell signaling pathways that are important in cancer cell survival [XREF_BIBR].	4	11	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	8	9
Lipid phosphatases , PTEN [ XREF_BIBR ] and SHIP [ XREF_BIBR ] , have indirectly inhibited PI3K and AKT signal transduction through the enzymatic conversion of PIP3 .	Lipid phosphatases, PTEN [XREF_BIBR] and SHIP [XREF_BIBR], have indirectly inhibited PI3K and AKT signal transduction through the enzymatic conversion of PIP3.	3	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	18	19
Our results identify CK2 as a new target of PD-1 and reveal an unexpected mechanism by which PD-1 decreases PTEN protein expression while increasing PTEN activity , thereby inhibiting the PI3K and Akt signaling axis .	Our results identify CK2 as a new target of PD-1 and reveal an unexpected mechanism by which PD-1 decreases PTEN protein expression while increasing PTEN activity, thereby inhibiting the PI3K and Akt signaling axis.	17	34	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PD-1 decreases PTEN protein expression	pten	Akt	Akt	akt	19	20	32	33
PTEN inhibition results in Akt activation and induces cardioprotection in mice .	PTEN inhibition results in Akt activation and induces cardioprotection in mice.	0	6	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	4	5
Since the PTEN phosphatase is known to antagonize activation of Akt by PI 3 K , levels of PTEN in these BF neurons were determined with and without proNGF treatment .	Since the PTEN phosphatase is known to antagonize activation of Akt by PI 3 K, levels of PTEN in these BF neurons were determined with and without proNGF treatment.	2	11	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	10	11
To the best of our knowledge , PTEN is a natural inhibitor of PI3K at the 3-phosphate site and negatively regulates the AKT signalling pathway [ XREF_BIBR ] .	To the best of our knowledge, PTEN is a natural inhibitor of PI3K at the 3-phosphate site and negatively regulates the AKT signalling pathway [XREF_BIBR].	7	24	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	22	23
PD-1 engagement by PD-L1 dephosphorylates proximal signaling molecules and augments PTEN expression , inhibiting PI3K and AKT activation [ XREF_BIBR , XREF_BIBR ] .	PD-1 engagement by PD-L1 dephosphorylates proximal signaling molecules and augments PTEN expression, inhibiting PI3K and AKT activation [XREF_BIBR, XREF_BIBR].	0	21	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PD-1 engagement by PD-L1 dephosphorylates proximal signaling molecules and augments PTEN expression	pten	AKT	AKT	akt	10	11	16	17
PTEN negatively regulates PI3K and Akt pathway by metabolizing phosphatidylinositol 3,4,5-trisphosphate [ PtdIns ( 3,4,5 ) P ( 3 ) ] and acts in direct antagonism to PI3-kinases , leading to inactivation of Akt [ XREF_BIBR ] .	PTEN negatively regulates PI3K and Akt pathway by metabolizing phosphatidylinositol 3,4,5-trisphosphate [PtdIns (3,4,5) P (3)] and acts in direct antagonism to PI3-kinases, leading to inactivation of Akt [XREF_BIBR].	0	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
The role of PTEN loss and consecutive over-activation of the AKT pathway and its evaluation is still under investigation , as far as response to anti-EGFR moAbs is concerned .	The role of PTEN loss and consecutive over-activation of the AKT pathway and its evaluation is still under investigation, as far as response to anti-EGFR moAbs is concerned.	3	11	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	10	11
PTEN has been reported to downregulate PI3K and Akt dependent cell survival , and an obvious decrease in the expression of phospho-Akt ( ser473 ) was observed after BDE47 treatment , suggesting that the inhibition of Akt phosphorylation might be related to germ cell survival .	PTEN has been reported to downregulate PI3K and Akt dependent cell survival, and an obvious decrease in the expression of phospho-Akt (ser473) was observed after BDE47 treatment, suggesting that the inhibition of Akt phosphorylation might be related to germ cell survival.	0	11	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	8	9
PD-1 can target and inhibit CK2 mediated PTEN phosphorylation and promote its degradation while it induces PTEN phosphatase activity , thus repressing PI3K and Akt signaling [ XREF_BIBR - XREF_BIBR ] .	PD-1 can target and inhibit CK2 mediated PTEN phosphorylation and promote its degradation while it induces PTEN phosphatase activity, thus repressing PI3K and Akt signaling [XREF_BIBR - XREF_BIBR].	16	29	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	24	25
PTEN deficiency leads to PIP3 accumulation and thereby de-repression of the PI3K and AKT pathway , which in turn promotes cell growth , proliferation , angiogenesis , and other cellular processes XREF_BIBR .	PTEN deficiency leads to PIP3 accumulation and thereby de-repression of the PI3K and AKT pathway, which in turn promotes cell growth, proliferation, angiogenesis, and other cellular processes XREF_BIBR.	0	14	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	13	14
8 Loss of PTEN activates PI3K and AKT pathway , leading to cancer progression in a wide variety of human cancers .	8 Loss of PTEN activates PI3K and AKT pathway, leading to cancer progression in a wide variety of human cancers.	1	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	3	4	7	8
However , although PTEN deletion caused an immediate strong activation of PKB in T cell progenitors , the loss of PDK1 did not prevent expression of CD71 and CD98 in these cells .	However, although PTEN deletion caused an immediate strong activation of PKB in T cell progenitors, the loss of PDK1 did not prevent expression of CD71 and CD98 in these cells.	3	12	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	3	4	11	12
Recent findings from Hamamoto ' s group showed that SMYD2 mediated PTEN methylation at lysine 313 increased phosphorylation at serine 380 of PTEN , consequently inactivated PTEN and activated AKT activity and promoted cell growth and proliferation XREF_BIBR .	Recent findings from Hamamoto 's group showed that SMYD2 mediated PTEN methylation at lysine 313 increased phosphorylation at serine 380 of PTEN, consequently inactivated PTEN and activated AKT activity and promoted cell growth and proliferation XREF_BIBR.	9	30	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	SMYD2 mediated PTEN methylation at lysine 313 increased phosphorylation at serine 380 of PTEN	pten	AKT	AKT	akt	22	23	29	30
In contrast , deletion of the Pten ( phosphatase and tensin homolog ) gene , an antagonist of the PI3K-AKT pathway , enhances the PI3K-AKT signaling axis and enhances the electric field induced cellular responses [ XREF_BIBR ] .	In contrast, deletion of the Pten (phosphatase and tensin homolog) gene, an antagonist of the PI3K-AKT pathway, enhances the PI3K-AKT signaling axis and enhances the electric field induced cellular responses [XREF_BIBR].	6	26	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	PI3K-AKT	PI3K-AKT	PI3K-AKT	6	7	24	25
PTEN dephosphorylates phosphatidylinositol -trisphosphate ( PIP3 ) , inhibiting Akt recruitment to the plasma membrane and activation ; PTEN deletion leads to constitutively-active Akt .	PTEN dephosphorylates phosphatidylinositol -trisphosphate (PIP3), inhibiting Akt recruitment to the plasma membrane and activation; PTEN deletion leads to constitutively-active Akt.	18	24	leads	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	23	24
Significantly , functional loss of PTEN , which induces the development of prostate cancer in knockout mice , leads to activation of Akt , a critical component of the survival and oncogenic function of IGF-I .	Significantly, functional loss of PTEN, which induces the development of prostate cancer in knockout mice, leads to activation of Akt, a critical component of the survival and oncogenic function of IGF-I.	3	23	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	5	6	22	23
A recent study showed that the biological activity of TOB-1 is initiated by its interaction with the key tumor suppressor protein PTEN , which inhibits the PI3K and Akt signaling pathway and has a multifunctional role in cell proliferation , migration , and invasion .	A recent study showed that the biological activity of TOB-1 is initiated by its interaction with the key tumor suppressor protein PTEN, which inhibits the PI3K and Akt signaling pathway and has a multifunctional role in cell proliferation, migration, and invasion.	11	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	21	22	28	29
In several cancer models , loss of function mutations in the PTEN results in hyper-phosphorylated and activated Akt Our studies show that like PTEN , PPTR-1 acts to negatively regulate the insulin and IGF -1 signaling .	In several cancer models, loss of function mutations in the PTEN results in hyper-phosphorylated and activated Akt Our studies show that like PTEN, PPTR-1 acts to negatively regulate the insulin and IGF -1 signaling.	8	26	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	17	18
The reversible inactivation of phosphatases , such CDC25A and PTEN , by estrogen induced ROS may be a key component of AKT activation XREF_BIBR , XREF_BIBR .	The reversible inactivation of phosphatases, such CDC25A and PTEN, by estrogen induced ROS may be a key component of AKT activation XREF_BIBR, XREF_BIBR.	4	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	21	22
Liver specific PTEN knockout results in AKT activation and produces very similar pathology including hepatomegally , steatosis , and steatohepatitis .	Liver specific PTEN knockout results in AKT activation and produces very similar pathology including hepatomegally, steatosis, and steatohepatitis.	0	9	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	6	7
The downregulation of AKT pathway is accompanied with increased PTEN expression ( canonical inhibitor of AKT activation ) and its activated form pPTENs380 .	The downregulation of AKT pathway is accompanied with increased PTEN expression (canonical inhibitor of AKT activation) and its activated form pPTENs380.	9	16	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	9	10	15	16
Here , we found the over-expression of AFP decreased PTEN expression and thus promoted the PI3K and Akt pathway , but the knockdown of AFP increased PTEN levels and resulted in the inhibition of the PI3K and Akt pathway .	Here, we found the over-expression of AFP decreased PTEN expression and thus promoted the PI3K and Akt pathway, but the knockdown of AFP increased PTEN levels and resulted in the inhibition of the PI3K and Akt pathway.	5	18	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	over-expression of AFP decreased PTEN expression	pten	Akt	Akt	akt	9	10	17	18
We hypothesized that the activation of phosphorylated CREB ( pCREB ) and PTEN could inhibit the AKT signaling pathway to attenuate pulmonary arterial remodeling in rats with monocrotaline induced PAH .	We hypothesized that the activation of phosphorylated CREB (pCREB) and PTEN could inhibit the AKT signaling pathway to attenuate pulmonary arterial remodeling in rats with monocrotaline induced PAH.	7	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	12	13	16	17
Blocking PTEN may reactivate the PI3K and Akt pathway and attenuate photoreceptor apoptosis by suppressing the mitochondrial pathway .	Blocking PTEN may reactivate the PI3K and Akt pathway and attenuate photoreceptor apoptosis by suppressing the mitochondrial pathway.	0	10	reactivate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	7	8
PTEN inhibits the activation of Akt , a serine threonine kinase involved in proliferative metabolic and anti-apoptotic pathways , and has tumor suppressor properties .	PTEN inhibits the activation of Akt, a serine threonine kinase involved in proliferative metabolic and anti-apoptotic pathways, and has tumor suppressor properties.	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
The results showed that loss of PTEN and upregulation of Akt in and treatment with HO-3867 significantly restored PTEN levels and caused downregulation of Akt .	The results showed that loss of PTEN and upregulation of Akt in and treatment with HO-3867 significantly restored PTEN levels and caused downregulation of Akt.	4	25	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN and upregulation of Akt in and treatment with HO-3867 significantly restored PTEN levels	pten	Akt	Akt	akt	6	7	24	25
As PTEN directly opposes the actions of PI3-K and therefore inhibits Akt and PKB , the effect of PTEN expression on the phosphorylation of all putative eNOS regulatory sites was examined .	As PTEN directly opposes the actions of PI3-K and therefore inhibits Akt and PKB, the effect of PTEN expression on the phosphorylation of all putative eNOS regulatory sites was examined.	1	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	11	12
As a result , PTEN is upregulated to repress AKT and mTOR activity and then activates autophagy , sequentially reversing sorafenib resistance .	As a result, PTEN is upregulated to repress AKT and mTOR activity and then activates autophagy, sequentially reversing sorafenib resistance.	4	15	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	9	10
miR-29a targets phosphatase and tensin homolog ( PTEN ) mRNA , and it thereby increases the activity of the AKT signalling pathway .	miR-29a targets phosphatase and tensin homolog (PTEN) mRNA, and it thereby increases the activity of the AKT signalling pathway.	0	21	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	2	6	19	20
In a subset of EMPD , AKT is not activated by HER2 overexpression or by loss of PTEN , which is not the case in MPD .	In a subset of EMPD, AKT is not activated by HER2 overexpression or by loss of PTEN, which is not the case in MPD.	6	18	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	17	18	6	7
Loss of PTEN induced Akt activation has been shown to overcome a DNA damage induced G2/M checkpoint and facilitate further transition of colon cancer cells to G1 phase [ XREF_BIBR ] .	Loss of PTEN induced Akt activation has been shown to overcome a DNA damage induced G2/M checkpoint and facilitate further transition of colon cancer cells to G1 phase [XREF_BIBR].	0	5	induced	Positive_early_activation	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	4	5
The loss of PTEN constitutively activated Akt kinase activity and the mTORC1 pathway .	The loss of PTEN constitutively activated Akt kinase activity and the mTORC1 pathway.	1	8	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	3	4	6	7
PC-3 cells do not express a functional PTEN and loss of PTEN leads to Akt activation and cytoplasmic localization of FOXO1 .	PC-3 cells do not express a functional PTEN and loss of PTEN leads to Akt activation and cytoplasmic localization of FOXO1.	9	15	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	11	12	14	15
A mechanistic study showed that FGF21 induced antiapoptotic effect in T1DM mice is attributed to the activation of AMP activated protein kinase ( AMPK ) followed by inactivation of phosphatase and tensin homolog ( PTEN ) that negatively regulates AKT signaling 12 .	A mechanistic study showed that FGF21 induced antiapoptotic effect in T1DM mice is attributed to the activation of AMP activated protein kinase (AMPK) followed by inactivation of phosphatase and tensin homolog (PTEN) that negatively regulates AKT signaling 12.	21	40	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	34	35	39	40
We also observed that PDK1 , which is a kinase upstream of AKT , is down-regulated by 6.8 fold in MCF-7 cells and 3.2 fold in SKBr3 cells , whereas the tumor suppressor PTEN that also inhibits AKT is increased 54 fold in MDA-MB-468 cells ( XREF_FIG ) .	We also observed that PDK1, which is a kinase upstream of AKT, is down-regulated by 6.8 fold in MCF-7 cells and 3.2 fold in SKBr3 cells, whereas the tumor suppressor PTEN that also inhibits AKT is increased 54 fold in MDA-MB-468 cells (XREF_FIG).	30	41	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	33	34	37	38
Under the condition of hypoxia , Notch-1 could be activated by HIF1alpha ( hypoxia inducible factor 1-alpha ) in lung adenocarcinoma cells , then the activated Notch-1 could suppress the expression of PTEN ( phosphatase and tensin homolog ) and activate AKT [ XREF_BIBR ] .	Under the condition of hypoxia, Notch-1 could be activated by HIF1alpha (hypoxia inducible factor 1-alpha) in lung adenocarcinoma cells, then the activated Notch-1 could suppress the expression of PTEN (phosphatase and tensin homolog) and activate AKT [XREF_BIBR].	26	43	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Notch-1 could suppress the expression of PTEN	pten	AKT	AKT	akt	32	33	41	42
To determine whether PTEN inhibition increases Akt activity and induces cardioprotection , we pretreated mice with VO , considered as the most potent PTEN inhibitor , for 30 min .	To determine whether PTEN inhibition increases Akt activity and induces cardioprotection, we pretreated mice with VO, considered as the most potent PTEN inhibitor, for 30 min.	3	7	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	6	7
57 Sustained PTENP1 expression in HCC cells upregulates PTEN expression and suppresses the PI3K and AKT signaling cascade , which results in the induction of autophagy , as well as the inhibition of cell proliferation and migration and invasion .	57 Sustained PTENP1 expression in HCC cells upregulates PTEN expression and suppresses the PI3K and AKT signaling cascade, which results in the induction of autophagy, as well as the inhibition of cell proliferation and migration and invasion.	2	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTENP1 expression in HCC cells upregulates PTEN expression	pten	AKT	AKT	akt	8	9	15	16
Mechanistically , we found that FMG significantly promoted p-PTEN expression and subsequently inhibited PI3K and AKT signaling pathway .	Mechanistically, we found that FMG significantly promoted p-PTEN expression and subsequently inhibited PI3K and AKT signaling pathway.	5	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p-PTEN	FMG significantly promoted p-PTEN expression	p-pten	AKT	AKT	akt	8	9	15	16
Research on acquired resistance to EGFR inhibitory drugs in lung cancer has mainly focused on the PI3K-AKT pathway , activated by MET amplification or PTEN loss of function .	Research on acquired resistance to EGFR inhibitory drugs in lung cancer has mainly focused on the PI3K-AKT pathway, activated by MET amplification or PTEN loss of function.	16	25	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	24	25	16	17
Pten antagonizes PI3K signaling upstream of the Akt pathway and , consequently , loss of Pten leads to constitutive activation of Akt .	Pten antagonizes PI3K signaling upstream of the Akt pathway and, consequently, loss of Pten leads to constitutive activation of Akt.	13	22	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Pten	loss of Pten	pten	Akt	Akt	akt	15	16	21	22
PTEN , that negatively regulates Akt signalling , was also evaluated .	PTEN, that negatively regulates Akt signalling, was also evaluated.	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
MTDH could reduce the expression of PTEN , up-regulate AKT and BCL2 and inhibit the apoptosis induced by tamoxifen .	MTDH could reduce the expression of PTEN, up-regulate AKT and BCL2 and inhibit the apoptosis induced by tamoxifen.	0	11	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	MTDH could reduce the expression of PTEN	pten	AKT	AKT	akt	6	7	9	10
Here we demonstrate that PTEN loss is not sufficient to drive Akt activation and resistance to DR in tumors with low growth factor receptor levels .	Here we demonstrate that PTEN loss is not sufficient to drive Akt activation and resistance to DR in tumors with low growth factor receptor levels.	4	12	drive	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	11	12
As its lipid phosphatase activity by converting PIP3 to PIP2 , PTEN prevents AKT activation .	As its lipid phosphatase activity by converting PIP3 to PIP2, PTEN prevents AKT activation.	11	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	11	12	13	14
A key cell-intrinsic inhibitor of Akt signaling is phosphatase and tensin homolog ( Pten ) , a lipid phosphatase that prevents Akt activation by dephosphorylating PI3K generated inositol phospholipids .	A key cell-intrinsic inhibitor of Akt signaling is phosphatase and tensin homolog (Pten), a lipid phosphatase that prevents Akt activation by dephosphorylating PI3K generated inositol phospholipids.	11	22	prevents	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	13	14	21	22
The reversible inactivation of PTEN by E2 induced ROS may be a key component of AKT activation .	The reversible inactivation of PTEN by E2 induced ROS may be a key component of AKT activation.	2	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	15	16
The resulting activated PTEN downregulated Akt activity , which is essential for cell proliferation .	The resulting activated PTEN downregulated Akt activity, which is essential for cell proliferation.	0	6	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	5	6
The constitutive activation of NF kappa B- and beta-catenin-dependent transcription is inhibited by transiently transfecting either kinase dead ( KD ) IKK alpha , which blocks IKK alpha kinase activity , KD AKT , which blocks AKT activity , or wildtype ( WT ) PTEN , which inhibits PI3K and AKT activity .	The constitutive activation of NF kappa B- and beta-catenin-dependent transcription is inhibited by transiently transfecting either kinase dead (KD) IKK alpha, which blocks IKK alpha kinase activity, KD AKT, which blocks AKT activity, or wildtype (WT) PTEN, which inhibits PI3K and AKT activity.	29	47	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	44	45	36	37
PTEN antagonizes PI3K and negatively regulates the AKT signaling pathway .	PTEN antagonizes PI3K and negatively regulates the AKT signaling pathway.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	7	8
By itself , single PHLPP1 depletion was not sufficient to elevate Akt phosphorylation ( XREF_FIG and XREF_SUPPLEMENTARY ) , suggesting that PTEN effectively suppresses PI3K-Akt signaling .	By itself, single PHLPP1 depletion was not sufficient to elevate Akt phosphorylation (XREF_FIG and XREF_SUPPLEMENTARY), suggesting that PTEN effectively suppresses PI3K-Akt signaling.	21	25	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	21	22	24	25
Loss of PTEN activates the PI3K-AKT pathway , which is currently an attractive target for drug development .	Loss of PTEN activates the PI3K-AKT pathway, which is currently an attractive target for drug development.	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	2	3	5	6
Furthermore , we found that adenovirus mediated PTEN overexpression led to decreased AKT activation , and significantly reduced cell proliferation and collagen synthesis of HSFBs , while increased the apoptosis .	Furthermore, we found that adenovirus mediated PTEN overexpression led to decreased AKT activation, and significantly reduced cell proliferation and collagen synthesis of HSFBs, while increased the apoptosis.	7	13	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN overexpression	pten	AKT	AKT	akt	7	8	12	13
The expression of pAKT and pmTOR was also higher in CIN and tumours than in normal cells , whereas the expression of PTEN was decreased in CIN and tumour tissue compared with normal cells , suggesting a link between MKRN1 and the PI3K and AKT pathway ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	The expression of pAKT and pmTOR was also higher in CIN and tumours than in normal cells, whereas the expression of PTEN was decreased in CIN and tumour tissue compared with normal cells, suggesting a link between MKRN1 and the PI3K and AKT pathway (XREF_FIG; XREF_SUPPLEMENTARY).	20	45	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	AKT	AKT	akt	22	23	44	45
Loss of PTEN results in PI3 and AKT cascade activation , and tumor cells with constitutive AKT activation are reportedly resistant to chemo- and radiotherapy , a result attributed to AKT activating DNA protein kinase ( PK ) by phosphorylation , suppressing apoptosis and enhancing DNA repair .	Loss of PTEN results in PI3 and AKT cascade activation, and tumor cells with constitutive AKT activation are reportedly resistant to chemo- and radiotherapy, a result attributed to AKT activating DNA protein kinase (PK) by phosphorylation, suppressing apoptosis and enhancing DNA repair.	0	10	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	7	8
Mechanistically , increased basal lipolysis observed in Ecscr silenced 3T3-L1 cells could result from increased PTEN activity , which would reduce AKT activation leading to elevated HSL phosphorylation .	Mechanistically, increased basal lipolysis observed in Ecscr silenced 3T3-L1 cells could result from increased PTEN activity, which would reduce AKT activation leading to elevated HSL phosphorylation.	15	22	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	15	16	21	22
It is known that AKT activity can be positively regulated by PI3K and negatively regulated by PTEN .	It is known that AKT activity can be positively regulated by PI3K and negatively regulated by PTEN.	4	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	16	17	4	5
YAP activity leads to the expression of miR-29 which inhibits the translation of PTEN , a phosphatase , which in its active state inhibits Akt .	YAP activity leads to the expression of miR-29 which inhibits the translation of PTEN, a phosphatase, which in its active state inhibits Akt.	11	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	24	25
Loss of PTEN causes the P13K and Akt pathway to be hyperactive which contributes to cell survival and resistance to therapeutics in various cancers , including the liver cancer .	Loss of PTEN causes the P13K and Akt pathway to be hyperactive which contributes to cell survival and resistance to therapeutics in various cancers, including the liver cancer.	0	8	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	7	8
In summary , our data suggest that PTEN normally works to limit the NK cell ' s PI3K and AKT and MAPK pathway activation and the consequent mobilization of cytolytic mediators toward the target cell and suggest that PTEN is among the active regulatory components prior to human NK cells transitioning from the noncytolytic CD56 ( bright ) NK cell to the cytolytic CD56 ( dim ) NK cells .	In summary, our data suggest that PTEN normally works to limit the NK cell 's PI3K and AKT and MAPK pathway activation and the consequent mobilization of cytolytic mediators toward the target cell and suggest that PTEN is among the active regulatory components prior to human NK cells transitioning from the noncytolytic CD56 (bright) NK cell to the cytolytic CD56 (dim) NK cells.	7	36	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	19	20
This can be described as rare , but the PI3K and AKT pathway may also be deregulated by the mutations in phosphatase and tensin homolog ( PTEN ) ; a PI3K inhibitor .	This can be described as rare, but the PI3K and AKT pathway may also be deregulated by the mutations in phosphatase and tensin homolog (PTEN); a PI3K inhibitor.	9	25	deregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	21	25	11	12
Furthermore , PfnI overexpression has been reported to up-regulate PTEN expression , therefore indirectly suppressing Akt activity by controlling phosphoinositide production XREF_BIBR .	Furthermore, PfnI overexpression has been reported to up-regulate PTEN expression, therefore indirectly suppressing Akt activity by controlling phosphoinositide production XREF_BIBR.	2	16	suppressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PfnI overexpression has been reported to up-regulate PTEN expression	pten	Akt	Akt	akt	9	10	15	16
ROS inhibition of PTEN increases Akt signal transduction to regulate FoxO transcription factors .	ROS inhibition of PTEN increases Akt signal transduction to regulate FoxO transcription factors.	1	7	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	5	6
The changes in this pathway demonstrated that a decrease in PTEN could promote AKT activation to inhibit the FoxO signaling and lead to apoptosis resistance .	The changes in this pathway demonstrated that a decrease in PTEN could promote AKT activation to inhibit the FoxO signaling and lead to apoptosis resistance.	8	14	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	13	14
However , Pten +/-; Tsc2 +/- mice develop aggressive hemangiomas because Pten deletion overrides the negative feedback loop and activates Akt .	However, Pten +/-; Tsc2 +/- mice develop aggressive hemangiomas because Pten deletion overrides the negative feedback loop and activates Akt.	11	21	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	11	12	20	21
PTEN inhibits the activation of AKT by dephosphorylating phosphatidylinositols at the 3 ' position , thereby antagonizing PI3K mediated signaling [ XREF_FIG ] XREF_BIBR .	PTEN inhibits the activation of AKT by dephosphorylating phosphatidylinositols at the 3 ' position, thereby antagonizing PI3K mediated signaling [XREF_FIG] XREF_BIBR.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
A possible explanation is that pharmacological inhibition of PTEN only transiently increases PI3K and Akt signaling , due to degradation of the inhibitor , thereby affecting secretion but not gene transcription .	A possible explanation is that pharmacological inhibition of PTEN only transiently increases PI3K and Akt signaling, due to degradation of the inhibitor, thereby affecting secretion but not gene transcription.	6	15	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	14	15
XREF_BIBR PTEN , a dual-specificity phosphatase and tumor suppressor gene , inhibits Akt and mTOR and MAPK signaling , leading to cell death and growth regulation .	XREF_BIBR PTEN, a dual-specificity phosphatase and tumor suppressor gene, inhibits Akt and mTOR and MAPK signaling, leading to cell death and growth regulation.	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	12	13
Following this , PTEN might operate to reduce protein load by tempering Akt activity .	Following this, PTEN might operate to reduce protein load by tempering Akt activity.	3	13	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	12	13
PTEN , a 3 '-phosphoinositide phosphatase , antagonizes PKB , and has a stimulatory effect on autophagy .	PTEN, a 3 '-phosphoinositide phosphatase, antagonizes PKB, and has a stimulatory effect on autophagy.	0	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	0	1	8	9
Loss-of-function mutations in PTEN , which is a tumor suppressor and an antagonist of the PI3K and AKT pathway , induce AKT regulated metastasis in CRCs 54 .	Loss-of-function mutations in PTEN, which is a tumor suppressor and an antagonist of the PI3K and AKT pathway, induce AKT regulated metastasis in CRCs 54.	1	23	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	21	22
A loss of phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) function also activates Akt , which is then associated with a worse outcome among BC patients treated with endocrine therapy .	A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt, which is then associated with a worse outcome among BC patients treated with endocrine therapy.	1	22	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	loss of phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	3	7	17	18
The over-expression of miRNA-21 decreases PTEN expression and simultaneously activates the Akt and mTOR signaling pathway , thereby inducing mesangial cell hypertrophy and mesangial matrix expansion .	The over-expression of miRNA-21 decreases PTEN expression and simultaneously activates the Akt and mTOR signaling pathway, thereby inducing mesangial cell hypertrophy and mesangial matrix expansion.	1	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	over-expression of miRNA-21 decreases PTEN expression	pten	Akt	Akt	akt	5	6	11	12
However , in the absence of DJ-1 , excessive AKT inhibition by PTEN results in a buildup of HK1 in the cytosol where it must compete for extramitochondrial ATP .	However, in the absence of DJ-1, excessive AKT inhibition by PTEN results in a buildup of HK1 in the cytosol where it must compete for extramitochondrial ATP.	9	13	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	12	13	9	10
In contrast , AEG-1 overexpression retained S474 phosphorylation when PTEN and LY294002 inhibited PI3K-Akt activation .	In contrast, AEG-1 overexpression retained S474 phosphorylation when PTEN and LY294002 inhibited PI3K-Akt activation.	9	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	9	10	13	14
These factors act in concert in the pathway of carcinogenesis , and a loss of PTEN causes Akt activation .	These factors act in concert in the pathway of carcinogenesis, and a loss of PTEN causes Akt activation.	13	18	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	15	16	17	18
PTEN inhibits PI3K and negatively regulates the PI3K and Akt signalling pathway .	PTEN inhibits PI3K and negatively regulates the PI3K and Akt signalling pathway.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	9	10
Thus , we concluded ( 1 ) that it is the degree of PTEN localization to endosomes that dictates its efficiency rather than overall cytoplasmic PTEN expression levels and ( 2 ) that PI ( 3 ) P marked intracellular vesicles display a significant pool of PI ( 3,4,5 ) P 3 at steady state , which the FYVE fused or endogenous-vesicle-associated PTEN can inactivate to prevent AKT activation .	Thus, we concluded (1) that it is the degree of PTEN localization to endosomes that dictates its efficiency rather than overall cytoplasmic PTEN expression levels and (2) that PI (3) P marked intracellular vesicles display a significant pool of PI (3,4,5) P 3 at steady state, which the FYVE fused or endogenous-vesicle-associated PTEN can inactivate to prevent AKT activation.	58	68	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	62	63	67	68
We found that PTEN reconstitution , c-Met pathway inhibition or their combination significantly decreased Akt activation and glioma growth as assessed by immunoblot analysis and cell viability assays , respectively .	We found that PTEN reconstitution, c-Met pathway inhibition or their combination significantly decreased Akt activation and glioma growth as assessed by immunoblot analysis and cell viability assays, respectively.	3	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	14	15
In conclusion , our results show that silencing of PTEN separately does not potently activate Akt .	In conclusion, our results show that silencing of PTEN separately does not potently activate Akt.	7	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	15	16
PTEN negatively regulates Akt activation , and activated Akt phosphorylates and inactivates EZH2 [ XREF_BIBR ] .	PTEN negatively regulates Akt activation, and activated Akt phosphorylates and inactivates EZH2 [XREF_BIBR].	0	13	activated	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	PTEN	PTEN	pten	Akt	Akt phosphorylates and inactivates EZH2	akt	0	1	8	9
Overexpression or enhanced activation of PTEN induces apoptosis by blocking Akt activation , leading to increased Bad and caspase-9 activities .	Overexpression or enhanced activation of PTEN induces apoptosis by blocking Akt activation, leading to increased Bad and caspase-9 activities.	0	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Overexpression or enhanced activation of PTEN	pten	Akt	Akt	akt	5	6	10	11
Expression of PTEN can inhibit AKT , promote apoptosis and inhibit growth , tumorigenicity and metastatic potential of PTEN deficient melanoma cells [ XREF_BIBR - XREF_BIBR ] .	Expression of PTEN can inhibit AKT, promote apoptosis and inhibit growth, tumorigenicity and metastatic potential of PTEN deficient melanoma cells [XREF_BIBR - XREF_BIBR].	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Expression of PTEN	pten	AKT	AKT	akt	2	3	5	6
While loss of PTEN leads to increased PI3K and AKT signaling , targeting the PI3K and AKT signaling pathway alone utilizing PI3K inhibitors or rapamycin analogs has had suboptimal therapeutic efficacy .	While loss of PTEN leads to increased PI3K and AKT signaling, targeting the PI3K and AKT signaling pathway alone utilizing PI3K inhibitors or rapamycin analogs has had suboptimal therapeutic efficacy.	1	10	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	3	4	9	10
PTEN attenuates PI3K signaling and Akt activation leading to HIF1-alpha stabilization and VEGF production XREF_BIBR .	PTEN attenuates PI3K signaling and Akt activation leading to HIF1-alpha stabilization and VEGF production XREF_BIBR.	0	6	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
A tumor suppressor PTEN negatively regulates the PI3K and AKT pathways through its lipid phosphatase activity .	A tumor suppressor PTEN negatively regulates the PI3K and AKT pathways through its lipid phosphatase activity.	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	9	10
While wt PTEN can prevent the activation of AKT by limiting the availability of PIP3 in the cells exposed to growth factors , both the G129E and C124S mutants lack the lipid phosphatase activity .	While wt PTEN can prevent the activation of AKT by limiting the availability of PIP3 in the cells exposed to growth factors, both the G129E and C124S mutants lack the lipid phosphatase activity.	1	9	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	8	9
PI3K-Akt signaling is antagonized by the phosphatase activity of phosphatase and tensin homolog ( PTEN ) .	PI3K-Akt signaling is antagonized by the phosphatase activity of phosphatase and tensin homolog (PTEN).	0	13	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	PI3K-Akt	PI3K-Akt	PI3K-Akt	9	13	0	1
This data suggested that the increase in H 2 O 2 , ATP deficiency , and AMPK activation stimulated the PTEN pathway , which consequently inhibited AKT activation .	This data suggested that the increase in H 2 O 2, ATP deficiency, and AMPK activation stimulated the PTEN pathway, which consequently inhibited AKT activation.	20	27	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	20	21	26	27
Overexpression of miR-146b in thyroid cells significantly decreased PTEN expression and increased AKT activation , demonstrating that miR-146b activates PI3K signaling by silencing PTEN .	Overexpression of miR-146b in thyroid cells significantly decreased PTEN expression and increased AKT activation, demonstrating that miR-146b activates PI3K signaling by silencing PTEN.	0	13	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Overexpression of miR-146b in thyroid cells significantly decreased PTEN expression	pten	AKT	AKT	akt	8	9	12	13
PTEN reduced AKT signaling in both control and SPARC overexpressing cells , suggesting that PTEN signaling works as a downstream effector for SPARC overexpression in neuroblastoma cells .	PTEN reduced AKT signaling in both control and SPARC overexpressing cells, suggesting that PTEN signaling works as a downstream effector for SPARC overexpression in neuroblastoma cells.	0	3	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	2	3
PTEN counteracts the activation of AKT by catalysing the conversion of PIP3 to PIP2 and thereby negatively regulates the PI3K and AKT pathway .	PTEN counteracts the activation of AKT by catalysing the conversion of PIP3 to PIP2 and thereby negatively regulates the PI3K and AKT pathway.	0	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	21	22
This could be explained that SHARPIN has been shown to bind PTEN and inhibit PTEN function , since PTEN antagonizes AKT activity XREF_BIBR .	This could be explained that SHARPIN has been shown to bind PTEN and inhibit PTEN function, since PTEN antagonizes AKT activity XREF_BIBR.	18	22	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	18	19	20	21
Following UVB radiation , PTEN suppression promotes cell survival by enhancing AKT activation .	Following UVB radiation, PTEN suppression promotes cell survival by enhancing AKT activation.	4	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	11	12
Overexpression of miR-214 decreased the levels of PTEN and increased Akt activity similar to high glucose and lead to phosphorylation of its substrates glycogen synthase kinase-3beta , PRAS40 , and tuberin .	Overexpression of miR-214 decreased the levels of PTEN and increased Akt activity similar to high glucose and lead to phosphorylation of its substrates glycogen synthase kinase-3beta, PRAS40, and tuberin.	0	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Overexpression of miR-214 decreased the levels of PTEN	pten	Akt	Akt	akt	7	8	10	11
The AKT activation can be blocked by PTEN via inhibition of phosphorylation XREF_BIBR , XREF_BIBR .	The AKT activation can be blocked by PTEN via inhibition of phosphorylation XREF_BIBR, XREF_BIBR.	1	9	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	1	2
PTEN is a tumor suppressing gene and negatively regulates the PI3K and Akt signalling pathway .	PTEN is a tumor suppressing gene and negatively regulates the PI3K and Akt signalling pathway.	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	12	13
Lipid phosphatase and tensin homolog on chromosome 10 ( PTEN ) antagonizes PI3K activity by dephosphorylating Ptdins ( 3,4,5 ) P ( 3 ) ; therefore , the inhibition of PTEN enhances PI3K and Akt signaling and could prevent myocardium from ischemia-reperfusion ( I/R ) injury .	Lipid phosphatase and tensin homolog on chromosome 10 (PTEN) antagonizes PI3K activity by dephosphorylating Ptdins (3,4,5) P (3); therefore, the inhibition of PTEN enhances PI3K and Akt signaling and could prevent myocardium from ischemia-reperfusion (I/R) injury.	28	35	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	30	31	34	35
XREF_BIBR Suppression of PTEN by miR-21 upregulates phosphatidylinositide 3-kinases ( PI3 K ) and Akt activity , and subsequently induces matrix metalloproteinase ( MMP ) -2 expression .	XREF_BIBR Suppression of PTEN by miR-21 upregulates phosphatidylinositide 3-kinases (PI3 K) and Akt activity, and subsequently induces matrix metalloproteinase (MMP) -2 expression.	1	15	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	14	15
This glioma is deficient in PTEN and shows constitutive activation of Akt , which can be inactivated by re-introduction of PTEN [ XREF_BIBR ] .	This glioma is deficient in PTEN and shows constitutive activation of Akt, which can be inactivated by re-introduction of PTEN [XREF_BIBR].	9	22	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	20	21	11	12
Consistently , inducible cardiac specific deletion of PTEN activates AKT and protects the heart from ischemia and reperfusion injury .	Consistently, inducible cardiac specific deletion of PTEN activates AKT and protects the heart from ischemia and reperfusion injury.	5	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	9	10
These findings indicate that the decreased PTEN induced by SAHA led to activation of PI3K-AKT to drive cell cycle progression to promote thyroid tumor cell proliferation in Thrb PV/PV Pten +/- mice .	These findings indicate that the decreased PTEN induced by SAHA led to activation of PI3K-AKT to drive cell cycle progression to promote thyroid tumor cell proliferation in Thrb PV/PV Pten +/- mice.	4	16	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	6	7	14	15
Silencing PTEN expression in RVLM with small interfering RNA , on the other hand , augmented PI3K and Akt signaling and promoted long-term pressor response in normotensive WKY rats .	Silencing PTEN expression in RVLM with small interfering RNA, on the other hand, augmented PI3K and Akt signaling and promoted long-term pressor response in normotensive WKY rats.	1	19	augmented	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	1	2	18	19
FOG2 and PTEN both negatively regulate PI3K and AKT activation .	FOG2 and PTEN both negatively regulate PI3K and AKT activation.	0	9	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	8	9
Interestingly , the co-culture model also results in PTEN loss and activation of PI3K and AKT pathway that has been demonstrated as fundamental proliferative and survival pathways in clinical settings .	Interestingly, the co-culture model also results in PTEN loss and activation of PI3K and AKT pathway that has been demonstrated as fundamental proliferative and survival pathways in clinical settings.	8	16	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	15	16
Loss of PTEN leads to the activation of AKT through the PI-3K pathway , downstream of EGFR .	Loss of PTEN leads to the activation of AKT through the PI-3K pathway, downstream of EGFR.	0	9	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	8	9
The loss of the PI3K and AKT signaling antagonist gene Pten in GC rarely causes GCT , but concomitant activation of CTNNB1 and loss of Pten in the Ctnnb1 tm1Mmt/+ ; Pten tm1Hwu and tm1Hwu ; Amhr2 tm3 ( cre ) Bhr/+ ( CPA ) model results in the development of aggressive , metastatic GCT with 100 % penetrance XREF_BIBR .	The loss of the PI3K and AKT signaling antagonist gene Pten in GC rarely causes GCT, but concomitant activation of CTNNB1 and loss of Pten in the Ctnnb1 tm1Mmt/+; Pten tm1Hwu and tm1Hwu; Amhr2 tm3 (cre) Bhr/+ (CPA) model results in the development of aggressive, metastatic GCT with 100% penetrance XREF_BIBR.	0	14	loss	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	10	11	6	7
Thus , the Akt activation is usually up- and downregulated by tumor suppressor PTEN .	Thus, the Akt activation is usually up- and downregulated by tumor suppressor PTEN.	3	14	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	3	4
PTEN inhibits PI3K-AKT signaling pathway .	PTEN inhibits PI3K-AKT signaling pathway.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	2	3
By inhibiting the tumorigenic activity of PI3K and Akt signaling , PTEN may also contribute to the maintenance of the differentiated , secretory state of BON cells .	By inhibiting the tumorigenic activity of PI3K and Akt signaling, PTEN may also contribute to the maintenance of the differentiated, secretory state of BON cells.	6	15	contribute	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	8	9
Our results indicate that Pten deletion activates AKT , and AKT activation promotes both axon regeneration and RGC survival after optic nerve injury .	Our results indicate that Pten deletion activates AKT, and AKT activation promotes both axon regeneration and RGC survival after optic nerve injury.	4	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	AKT	AKT	AKT	4	5	7	8
Loss of PTEN results in constitutive activation of AKT in multiple cancer types , including melanoma XREF_BIBR .	Loss of PTEN results in constitutive activation of AKT in multiple cancer types, including melanoma XREF_BIBR.	0	12	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	8	9
Notably , forced expression of PTEN in GIST-T1R cells negatively regulated the Akt and mTOR pathways and sensitized these cells to sunitinib mediated growth arrest and apoptosis .	Notably, forced expression of PTEN in GIST-T1R cells negatively regulated the Akt and mTOR pathways and sensitized these cells to sunitinib mediated growth arrest and apoptosis.	3	15	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	5	6	12	13
In agreement with these observations , catalytically active form of PTEN has been shown to suppress basal activation of AKT [ XREF_BIBR , XREF_BIBR ] .	In agreement with these observations, catalytically active form of PTEN has been shown to suppress basal activation of AKT [XREF_BIBR, XREF_BIBR].	8	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	19	20
A loss of phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) function also activates Akt .	A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt.	1	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	loss of phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	3	7	17	18
We also found that Rawq01 up-regulated the expression of PTEN through mir-21 inhibition and therefore inhibited the PI3K-AKT pathway .	We also found that Rawq01 up-regulated the expression of PTEN through mir-21 inhibition and therefore inhibited the PI3K-AKT pathway.	4	18	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Rawq01 up-regulated the expression of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	9	10	17	18
Phosphatase and tensin homolog ( PTEN ) functionally antagonizes the PI3K-Akt pathway .	Phosphatase and tensin homolog (PTEN) functionally antagonizes the PI3K-Akt pathway.	0	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	4	10	11
In fact genetic experiment in Drosophila showed that loss of PTEN promotes translocation of Akt to the cell membrane to increase its kinase activity [ XREF_BIBR ] .	In fact genetic experiment in Drosophila showed that loss of PTEN promotes translocation of Akt to the cell membrane to increase its kinase activity [XREF_BIBR].	8	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	10	11	14	15
It was reported that selective down-regulation of MTA1 in breast cancer cells increased PTEN expression and inhibited stimulation of the PI3K and AKT signaling .	It was reported that selective down-regulation of MTA1 in breast cancer cells increased PTEN expression and inhibited stimulation of the PI3K and AKT signaling.	7	23	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	MTA1 in breast cancer cells increased PTEN expression	pten	AKT	AKT	akt	13	14	22	23
Overexpression of miR-486 will reduce PTEN and Foxo1a protein levels , which , in turn , enhances PI3K-Akt signaling .	Overexpression of miR-486 will reduce PTEN and Foxo1a protein levels, which, in turn, enhances PI3K-Akt signaling.	0	18	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Overexpression of miR-486 will reduce PTEN and Foxo1a protein levels	pten	PI3K-Akt	PI3K-Akt	pi3k-akt	5	6	17	18
In addition to amplification of the Akt1 gene locus , frequent monoallelic deletions of PTEN phosphatase antagonism of PI3K and Akt in 47 % of cases [ XREF_BIBR ] or of promoter methylation in 39 % of cases have been described [ XREF_BIBR ] .	In addition to amplification of the Akt1 gene locus, frequent monoallelic deletions of PTEN phosphatase antagonism of PI3K and Akt in 47% of cases [XREF_BIBR] or of promoter methylation in 39% of cases have been described [XREF_BIBR].	14	21	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	20	21
The phosphatase PTEN inactivates Akt , and loss of homozygosity or mutation of this gene has been noted in ovarian cancer and endometrioid ovarian cancer , respectively [ XREF_BIBR , XREF_BIBR ] .	The phosphatase PTEN inactivates Akt, and loss of homozygosity or mutation of this gene has been noted in ovarian cancer and endometrioid ovarian cancer, respectively [XREF_BIBR, XREF_BIBR].	0	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	4	5
Prostate specific deletion of Rictor was found to supress PTEN driven tumourigenesis downstream of Akt in mice and mTORC2 mediates Akt dependent chemotherapy resistance in PTEN null glioma patients [ XREF_BIBR ] , indicating the importance of mTORC2 as a PI3kinase effector pathway .	Prostate specific deletion of Rictor was found to supress PTEN driven tumourigenesis downstream of Akt in mice and mTORC2 mediates Akt dependent chemotherapy resistance in PTEN null glioma patients [XREF_BIBR], indicating the importance of mTORC2 as a PI3kinase effector pathway.	8	15	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	14	15
XREF_BIBR This is consistent with the result that PTEN suppresses the activation of AKT pathway induced by inhibition of PIP3 in tumor cells .	XREF_BIBR This is consistent with the result that PTEN suppresses the activation of AKT pathway induced by inhibition of PIP3 in tumor cells.	8	14	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	13	14
Inhibition of serine/threonine kinase Akt signaling by some pharmacological agents or by PTEN induces G ( 1 ) arrest , in part by up-regulating p27 ( Kip1 ) .	Inhibition of serine/threonine kinase Akt signaling by some pharmacological agents or by PTEN induces G (1) arrest, in part by up-regulating p27 (Kip1).	4	13	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	12	13	4	5
PTEN inhibition results in phosphatidylinositol ( 3,4,5 )-trisphosphate ( PIP3 ) accumulation , and thus activates Akt .	PTEN inhibition results in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) accumulation, and thus activates Akt.	0	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	16	17
It has been reported that loss of PTEN can lead to activation of the AKT signaling pathway .	It has been reported that loss of PTEN can lead to activation of the AKT signaling pathway.	5	16	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	7	8	14	15
Akt is negatively regulated by the phosphatase PTEN , and a lack of PTEN leads to increased resistance to apoptosis .	Akt is negatively regulated by the phosphatase PTEN, and a lack of PTEN leads to increased resistance to apoptosis.	0	8	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	0	1
The tumor suppressor PTEN , which antagonizes the PI3K and AKT pathway , has been recognized to play a key role in neural functions .	The tumor suppressor PTEN, which antagonizes the PI3K and AKT pathway, has been recognized to play a key role in neural functions.	0	17	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	10	11
PTEN overexpression in 3T3-L1 adipocytes inhibited serine threonine kinase protein kinase B ( Akt ) activation and glucose uptake .	PTEN overexpression in 3T3-L1 adipocytes inhibited serine threonine kinase protein kinase B (Akt) activation and glucose uptake.	0	15	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN overexpression	pten	Akt	Akt	akt	0	1	13	14
One such mechanism represents the action of the tumor suppressor protein PTEN , which negatively regulates Akt kinase activity .	One such mechanism represents the action of the tumor suppressor protein PTEN, which negatively regulates Akt kinase activity.	5	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	16	17
PTEN negatively regulates the PI3K and AKT signaling pathway , inhibiting proliferation and survival .	PTEN negatively regulates the PI3K and AKT signaling pathway, inhibiting proliferation and survival.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
Because PTEN inhibits activation of AKT kinase , PTEN deficiency leads to overactivation of the PI3K-AKT signaling pathway in the affected areas , resulting in increased cell proliferation and reduced apoptosis .	Because PTEN inhibits activation of AKT kinase, PTEN deficiency leads to overactivation of the PI3K-AKT signaling pathway in the affected areas, resulting in increased cell proliferation and reduced apoptosis.	1	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	5	6
miR-21 , a negative regulator of PTEN expression , was upregulated in skeletal muscle of MKP1-MKO mice , resulting in increased Akt activity consistent with enhanced insulin sensitivity .	miR-21, a negative regulator of PTEN expression, was upregulated in skeletal muscle of MKP1-MKO mice, resulting in increased Akt activity consistent with enhanced insulin sensitivity.	6	22	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	6	7	21	22
Akt activity is negatively regulated by phosphatase and tensin homolog ( PTEN ) through blocking the formation of PIP3 [ XREF_BIBR ] and by PH domain leucine rich repeat protein phosphatase ( PHLPP ) , a phosphatase that directly dephosphorylates Akt at Ser473 [ XREF_BIBR - XREF_BIBR ] .	Akt activity is negatively regulated by phosphatase and tensin homolog (PTEN) through blocking the formation of PIP3 [XREF_BIBR] and by PH domain leucine rich repeat protein phosphatase (PHLPP), a phosphatase that directly dephosphorylates Akt at Ser473 [XREF_BIBR - XREF_BIBR].	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	6	10	0	1
Thus UV mediated inhibition of PTEN function may further enhance AKT activation induced by UV radiation .	Thus UV mediated inhibition of PTEN function may further enhance AKT activation induced by UV radiation.	5	11	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	10	11
Adenoviral re-expression of PTEN in GBM cells inhibited Akt kinase activity , leading to tumor cell apoptosis [ XREF_BIBR ] .	Adenoviral re-expression of PTEN in GBM cells inhibited Akt kinase activity, leading to tumor cell apoptosis [XREF_BIBR].	1	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	re-expression of PTEN	pten	Akt	Akt	akt	3	4	8	9
Previous studies have demonstrated that PTEN negatively regulated AKT signaling pathway , which is important for EMT [ XREF_BIBR , XREF_BIBR ] .	Previous studies have demonstrated that PTEN negatively regulated AKT signaling pathway, which is important for EMT [XREF_BIBR, XREF_BIBR].	5	10	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	8	9
The p53 increases PTEN and PTEN decreases AKT activity .	The p53 increases PTEN and PTEN decreases AKT activity.	3	8	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	7	8
PD-1 inhibits PI3K activation , which is required for Akt activation , and leads to increased PTEN phosphatase activity , effectively inhibiting the PI3K Akt pathway .	PD-1 inhibits PI3K activation, which is required for Akt activation, and leads to increased PTEN phosphatase activity, effectively inhibiting the PI3K Akt pathway.	16	25	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	24	25
Loss of PTEN protein results in upregulation of the PI3K and AKT pathway , which appears dependent on the PI3Kbeta isoform .	Loss of PTEN protein results in upregulation of the PI3K and AKT pathway, which appears dependent on the PI3Kbeta isoform.	2	12	results in upregulation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	11	12
Moreover , PI3K inhibitors ( LY294002 or wortmannin ) did not inhibit SRC activation in PTEN-knockdown cells ( XREF_FIG and XREF_SUPPLEMENTARY ) , indicating that SRC activation is not due to PTEN loss mediated AKT activation .	Moreover, PI3K inhibitors (LY294002 or wortmannin) did not inhibit SRC activation in PTEN-knockdown cells (XREF_FIG and XREF_SUPPLEMENTARY), indicating that SRC activation is not due to PTEN loss mediated AKT activation.	31	35	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	31	32	34	35
In normal cells , PTEN has phosphatase activity , which can make PIP3 dephosphoric acid to PIP2 to lose the messenger function and thereby inhibit the PI3K and Akt signaling pathway , leading to apoptosis and inhibition of proliferation .	In normal cells, PTEN has phosphatase activity, which can make PIP3 dephosphoric acid to PIP2 to lose the messenger function and thereby inhibit the PI3K and Akt signaling pathway, leading to apoptosis and inhibition of proliferation.	4	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	28	29
By using PTEN null primary mouse embryonic fibroblasts and their isogenic controls as well as small interfering RNA against PTEN , we demonstrated that PTEN is necessary for hSPRY2 to inhibit Akt activation by epidermal growth factor as well as cell proliferation .	By using PTEN null primary mouse embryonic fibroblasts and their isogenic controls as well as small interfering RNA against PTEN, we demonstrated that PTEN is necessary for hSPRY2 to inhibit Akt activation by epidermal growth factor as well as cell proliferation.	24	32	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	24	25	31	32
Loss of PTEN would activate the PI3K and Akt pathway .	Loss of PTEN would activate the PI3K and Akt pathway.	0	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	8	9
In addition , suppression of PTEN by siRNA in EpCAM depleted cells rescued AKT signalling activities in NPC cells .	In addition, suppression of PTEN by siRNA in EpCAM depleted cells rescued AKT signalling activities in NPC cells.	3	15	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	13	14
Since PIP3 is the main cellular product of the class I phosphoinositide 3-kinases ( PI3K ) , PTEN is capable of antagonizing PI3K activity and negatively regulates the PI3K-Akt signaling pathway XREF_BIBR .	Since PIP3 is the main cellular product of the class I phosphoinositide 3-kinases (PI3K), PTEN is capable of antagonizing PI3K activity and negatively regulates the PI3K-Akt signaling pathway XREF_BIBR.	17	31	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	17	18	28	29
XREF_BIBR Loss of functional PTEN leads to increased activity of AKT and mammalian target of rapamycin kinase pathways , which can promote both cell survival and proliferation through phosphorylation and inactivation of several downstream mediators .	XREF_BIBR Loss of functional PTEN leads to increased activity of AKT and mammalian target of rapamycin kinase pathways, which can promote both cell survival and proliferation through phosphorylation and inactivation of several downstream mediators.	1	11	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of functional PTEN	pten	AKT	AKT	akt	4	5	10	11
It has been proposed that phosphorylation of the C-terminal sites keeps PTEN in an inactive form in the cytoplasm ; however , the dephosphorylation induces translocation of PTEN to the plasma membrane where the active PTEN antagonizes PI3K-AKT signalling XREF_BIBR .	It has been proposed that phosphorylation of the C-terminal sites keeps PTEN in an inactive form in the cytoplasm; however, the dephosphorylation induces translocation of PTEN to the plasma membrane where the active PTEN antagonizes PI3K-AKT signalling XREF_BIBR.	33	39	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	35	36	37	38
PTEN as a phosphatase catalyzes dephosphorylation of PIP3 to PIP2 and blocks activation of AKT XREF_BIBR , XREF_BIBR .	PTEN as a phosphatase catalyzes dephosphorylation of PIP3 to PIP2 and blocks activation of AKT XREF_BIBR, XREF_BIBR.	0	15	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	14	15
PTEN inhibits the PI3K and Akt signaling pathway .	PTEN inhibits the PI3K and Akt signaling pathway.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
In normal cells PTEN reduces Akt signaling which reduces the Akt mediated inhibition of GSK3 .	In normal cells PTEN reduces Akt signaling which reduces the Akt mediated inhibition of GSK3.	3	6	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	5	6
Another recurrent event found in non small cell lung cancers ( NSCLC ) and small cell lung cancers ( SCLC ) is activation of the PI3K and AKT pathway , which is frequently caused by loss of PTEN .	Another recurrent event found in non small cell lung cancers (NSCLC) and small cell lung cancers (SCLC) is activation of the PI3K and AKT pathway, which is frequently caused by loss of PTEN.	25	38	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	37	38	27	28
ICAM-1 knockdown in T1 cells resulted in increased phosphorylation of PTEN and the subsequent activation of AKT .	ICAM-1 knockdown in T1 cells resulted in increased phosphorylation of PTEN and the subsequent activation of AKT.	0	17	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	ICAM-1 knockdown in T1 cells resulted in increased phosphorylation of PTEN	pten	AKT	AKT	akt	10	11	16	17
PTEN , a dual-specificity phosphatase and tumor suppressor gene , inhibits Akt and mTOR and MAPK signaling pathways , leading to cell death and growth regulation .	PTEN, a dual-specificity phosphatase and tumor suppressor gene, inhibits Akt and mTOR and MAPK signaling pathways, leading to cell death and growth regulation.	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	11	12
PTEN expression rapidly reduced the activity of Akt , which was followed by a G ( 1 ) arrest and eventually apoptosis .	PTEN expression rapidly reduced the activity of Akt, which was followed by a G (1) arrest and eventually apoptosis.	0	11	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	0	1	7	8
Preclinical data have proposed a role for PTEN loss and activation of the PI3K and AKT pathway in regulating androgen receptor ( AR ) transcriptional output and in driving resistance XREF_BIBR .	Preclinical data have proposed a role for PTEN loss and activation of the PI3K and AKT pathway in regulating androgen receptor (AR) transcriptional output and in driving resistance XREF_BIBR.	7	16	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	15	16
The PI3K and Akt pathway that activates mTORC1 signaling which in turn promotes mRNA translation is negatively regulated by the PTEN tumor suppressor [ XREF_BIBR ] .	The PI3K and Akt pathway that activates mTORC1 signaling which in turn promotes mRNA translation is negatively regulated by the PTEN tumor suppressor [XREF_BIBR].	1	22	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	20	21	3	4
This suggested that PTEN directly inhibited Akt activation .	This suggested that PTEN directly inhibited Akt activation.	3	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	6	7
While mTORC1 activation by Akt can stimulate a negative feedback mechanism , the primary negative regulator of the PI3K pathway is Pten , a lipid phosphatase that converts PIP3 back to PIP2 and thus antagonizes Akt activity .	While mTORC1 activation by Akt can stimulate a negative feedback mechanism, the primary negative regulator of the PI3K pathway is Pten, a lipid phosphatase that converts PIP3 back to PIP2 and thus antagonizes Akt activity.	6	36	antagonizes	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt	Akt	Akt	21	22	35	36
Because PTEN inactivates the Akt protein , miR-486 increases the phosphorylation status of Akt with a decrease in PTEN and FoxO1 protein levels in mouse primary myotubes .	Because PTEN inactivates the Akt protein, miR-486 increases the phosphorylation status of Akt with a decrease in PTEN and FoxO1 protein levels in mouse primary myotubes.	1	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	4	5
PTEN is known to negatively regulate the PI3K and AKT pathway thus affecting cell growth and survival in different cell types XREF_BIBR .	PTEN is known to negatively regulate the PI3K and AKT pathway thus affecting cell growth and survival in different cell types XREF_BIBR.	0	10	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	9	10
Biochemical validation of SF1670 activity revealed that the PTEN small molecule inhibitor induced activation of AKT signaling in pre-B ALL cases carrying BCR-ABL1 or KRAS G12V oncogenes within one hour of treatment ( XREF_FIG ) .	Biochemical validation of SF1670 activity revealed that the PTEN small molecule inhibitor induced activation of AKT signaling in pre-B ALL cases carrying BCR-ABL1 or KRAS G12V oncogenes within one hour of treatment (XREF_FIG).	8	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	15	16
In normal prostate epithelium and primary tumors , Akt signaling is suppressed by inositol polyphosphate 4-phosphatase type II ( INPP4B ) and Phosphatase and Tensin homolog deleted on chromosome 10 ( PTEN ) , which are lost in 47 % and 42 % of metastases , respectively [ XREF_BIBR ] .	In normal prostate epithelium and primary tumors, Akt signaling is suppressed by inositol polyphosphate 4-phosphatase type II (INPP4B) and Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN), which are lost in 47% and 42% of metastases, respectively [XREF_BIBR].	8	26	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Phosphatase and Tensin homolog	Phosphatase and Tensin homolog	Phosphatase and Tensin homolog	Akt	Akt	Akt	22	26	8	9
PTEN , a tumor suppressor protein , acts as a lipid phosphatase on PIP3 , and prevents AKT activation XREF_BIBR , XREF_BIBR .	PTEN, a tumor suppressor protein, acts as a lipid phosphatase on PIP3, and prevents AKT activation XREF_BIBR, XREF_BIBR.	0	19	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	17	18
PTEN inhibits PI3K and Akt signaling , which is a central regulator of cell proliferation and apoptosis [ XREF_BIBR ] .	PTEN inhibits PI3K and Akt signaling, which is a central regulator of cell proliferation and apoptosis [XREF_BIBR].	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	4	5
In glioblastoma , PTEN loss results in AKT elevation , 60 a process that enhances the malignant characteristics of transformed cells .	In glioblastoma, PTEN loss results in AKT elevation, 60 a process that enhances the malignant characteristics of transformed cells.	3	9	elevation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	7	8
Through its lipid phosphatase activity PTEN suppresses the PI3K and AKT pathway to govern cell proliferation , growth , migration , energy metabolism and death .	Through its lipid phosphatase activity PTEN suppresses the PI3K and AKT pathway to govern cell proliferation, growth, migration, energy metabolism and death.	5	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	10	11
When normal lung fibroblasts attach to polymerized collagen , the PI3K and Akt pathway is suppressed by high PTEN activity , thereby inhibiting fibroblast proliferation and promoting apoptosis XREF_BIBR - XREF_BIBR .	When normal lung fibroblasts attach to polymerized collagen, the PI3K and Akt pathway is suppressed by high PTEN activity, thereby inhibiting fibroblast proliferation and promoting apoptosis XREF_BIBR - XREF_BIBR.	10	19	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	12	13
The inhibition of NF-kappaB , Snail and YY1 by NO results in the derepression of PTEN and its upregulation and , thus , resulting in PTEN mediated inhibition of the PI3K and AKT pathway and downstream target genes involved in both proliferation and anti-apoptosis XREF_BIBR .	The inhibition of NF-kappaB, Snail and YY1 by NO results in the derepression of PTEN and its upregulation and, thus, resulting in PTEN mediated inhibition of the PI3K and AKT pathway and downstream target genes involved in both proliferation and anti-apoptosis XREF_BIBR.	23	33	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	25	26	32	33
The lipid phosphatase activity of PTEN decreases intracellular PtdIns ( 3,4,5 ) P ( 3 ) level and downstream Akt activity .	The lipid phosphatase activity of PTEN decreases intracellular PtdIns (3,4,5) P (3) level and downstream Akt activity.	3	20	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	19	20
PTEN inhibits PI3K dependent activation of AKT , while activated AKT triggers downstream mTOR and p70 S6K1 signaling resulting in the induction of pro angiogenic factors , thereby inducing neovascularization to promote tumor growth .	PTEN inhibits PI3K dependent activation of AKT, while activated AKT triggers downstream mTOR and p70 S6K1 signaling resulting in the induction of pro angiogenic factors, thereby inducing neovascularization to promote tumor growth.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
All of our cell lines express PTEN , and because loss of PTEN can activate AKT signaling , we wanted to test whether reduction of PTEN would sensitize cells to PP242 .	All of our cell lines express PTEN, and because loss of PTEN can activate AKT signaling, we wanted to test whether reduction of PTEN would sensitize cells to PP242.	10	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	AKT	AKT	akt	12	13	15	16
Function as tumor suppressor [ XREF_BIBR - XREF_BIBR ] , PTEN could inhibit PI3K and Akt signaling through reversing the phosphorylation of PIP3 , returning it to PIP2 , result in antagonizing the function of PI3K [ XREF_BIBR ] .	Function as tumor suppressor [XREF_BIBR - XREF_BIBR], PTEN could inhibit PI3K and Akt signaling through reversing the phosphorylation of PIP3, returning it to PIP2, result in antagonizing the function of PI3K [XREF_BIBR].	10	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	15	16
Moreover , PI3K and Akt , as an important signaling pathway that regulates cell survival , is possibly negatively regulated by PTEN .	Moreover, PI3K and Akt, as an important signaling pathway that regulates cell survival, is possibly negatively regulated by PTEN.	2	22	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	21	22	4	5
We previously found that when IPF fibroblasts attach to collagen rich matrix , Akt activity is up-regulated by PTEN suppression , which subsequently increases cell proliferation XREF_BIBR , XREF_BIBR .	We previously found that when IPF fibroblasts attach to collagen rich matrix, Akt activity is up-regulated by PTEN suppression, which subsequently increases cell proliferation XREF_BIBR, XREF_BIBR.	13	19	up-regulated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	13	14
Loss of PTEN function leads to increased levels of PtdIns ( 3,4,5 ) P3 and activation of AKT XREF_BIBR - XREF_BIBR .	Loss of PTEN function leads to increased levels of PtdIns (3,4,5) P3 and activation of AKT XREF_BIBR - XREF_BIBR.	2	18	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	17	18
Although Rho and ROCK can inhibit endothelial NO activity through multiple mechanisms , a key inhibitory step appears to be activation of PTEN , which counteracts PI3K activity and reduces Akt activity .	Although Rho and ROCK can inhibit endothelial NO activity through multiple mechanisms, a key inhibitory step appears to be activation of PTEN, which counteracts PI3K activity and reduces Akt activity.	20	31	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	22	23	30	31
XREF_BIBR , XREF_BIBR , XREF_BIBR In normal tissues , the PI3K and AKT pathway is negatively regulated by the tumor suppressor phosphatase and tensin homolog ( Pten ) .	XREF_BIBR, XREF_BIBR, XREF_BIBR In normal tissues, the PI3K and AKT pathway is negatively regulated by the tumor suppressor phosphatase and tensin homolog (Pten).	10	26	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	21	25	12	13
Unphosphorylated PTEN is active and inhibits Akt activation ; phosphorylated PTEN is inactive leading to Akt activation .	Unphosphorylated PTEN is active and inhibits Akt activation; phosphorylated PTEN is inactive leading to Akt activation.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Unphosphorylated PTEN	pten	Akt	Akt	akt	1	2	6	7
PTEN loss and simultaneous activation of AKT and mTOR signaling is frequently observed in human ovarian carcinomas .	PTEN loss and simultaneous activation of AKT and mTOR signaling is frequently observed in human ovarian carcinomas.	0	9	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
PTEN loss and subsequent activation of the PI3K and Akt signaling promotes the activation of mTOR signaling , which is hyperactive in many cancers .	PTEN loss and subsequent activation of the PI3K and Akt signaling promotes the activation of mTOR signaling, which is hyperactive in many cancers.	0	10	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	9	10
Taken together , these in vitro data suggest that the combination of EGFR gene amplification and PTEN deletion in MIBC renders the cells sensitive to treatment with dasatinib and PKI-587 owing to upregulated SRC and AKT signaling pathways .	Taken together, these in vitro data suggest that the combination of EGFR gene amplification and PTEN deletion in MIBC renders the cells sensitive to treatment with dasatinib and PKI-587 owing to upregulated SRC and AKT signaling pathways.	16	37	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	16	17	35	36
A surprising result is that PTEN deletion results in strong activation of PDK1 and PKB , but bypasses the normal PDK1 requirement for cell growth and proliferation of T cells .	A surprising result is that PTEN deletion results in strong activation of PDK1 and PKB, but bypasses the normal PDK1 requirement for cell growth and proliferation of T cells.	5	15	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	5	6	14	15
Inhibition of the PI3K and Akt pathway , by overexpression of phosphatase and tensin homolog ( PTEN ) or a dominant negative isoform of Akt ( Akt dn ) induced sEng release from endothelial cells and prevented the inhibitory effect of VEGF-A .	Inhibition of the PI3K and Akt pathway, by overexpression of phosphatase and tensin homolog (PTEN) or a dominant negative isoform of Akt (Akt dn) induced sEng release from endothelial cells and prevented the inhibitory effect of VEGF-A.	0	15	Inhibition	Negative_activation_syntax_1_noun	Negative_activation	Negative_activation	phosphatase and tensin homolog	overexpression of phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	11	15	5	6
PTEN negatively regulates AKT signaling via a phosphatase activity dependent process .	PTEN negatively regulates AKT signaling via a phosphatase activity dependent process.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	3	4
This is in contrast to the nTregs development and also the notion that DJ-1 deficiency enhances PTEN expression , thus attenuating the PI3K and AKT pathway and iTregs development .	This is in contrast to the nTregs development and also the notion that DJ-1 deficiency enhances PTEN expression, thus attenuating the PI3K and AKT pathway and iTregs development.	13	25	attenuating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	DJ-1 deficiency enhances PTEN expression	pten	AKT	AKT	akt	16	17	24	25
PTEN down-regulates intracellular levels of PtdIns ( 3,4,5 ) P3 and thus negatively regulates the PI3K and Akt pathway .	PTEN down-regulates intracellular levels of PtdIns (3,4,5) P3 and thus negatively regulates the PI3K and Akt pathway.	0	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	17	18
The tumor suppressor PTEN negatively regulates the PI3K and AKT pathway by converting PIP3 to PIP2 , thus removing the signal that would activate AKT [ XREF_BIBR ] .	The tumor suppressor PTEN negatively regulates the PI3K and AKT pathway by converting PIP3 to PIP2, thus removing the signal that would activate AKT [XREF_BIBR].	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	9	10
RhoA and its effector kinase ROCK inhibit PI3K activity by enhancing the activity of PTEN , which negatively regulates PI3K and Akt signaling pathway [ XREF_BIBR ] .	RhoA and its effector kinase ROCK inhibit PI3K activity by enhancing the activity of PTEN, which negatively regulates PI3K and Akt signaling pathway [XREF_BIBR].	12	23	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	21	22
Many studies have shown that PTEN can negatively regulate Akt activity.29 , 30 In addition , one recent study showed that PRMT5 regulates the self-renewal capacity of primary glioblastoma neurosphere cells through modulation of the PTEN-Akt axis.31 We speculated that PRMT9 , like PRMT5 , which also belongs to the type II enzymes , may regulate Akt activity via modulation of PTEN .	Many studies have shown that PTEN can negatively regulate Akt activity.29, 30 In addition, one recent study showed that PRMT5 regulates the self-renewal capacity of primary glioblastoma neurosphere cells through modulation of the PTEN-Akt axis.31 We speculated that PRMT9, like PRMT5, which also belongs to the type II enzymes, may regulate Akt activity via modulation of PTEN.	5	10	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	9	10
PTEN also downregulates cell proliferation and promotes apoptosis by suppressing Akt activation .	PTEN also downregulates cell proliferation and promotes apoptosis by suppressing Akt activation.	0	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	10	11
Obviously , the overexpression of CDX2 induced PTEN expression and repressed Akt activation in MGC-803 cells .	Obviously, the overexpression of CDX2 induced PTEN expression and repressed Akt activation in MGC-803 cells.	3	12	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	overexpression of CDX2 induced PTEN expression	pten	Akt	Akt	akt	7	8	11	12
AKT activation is normally limited by the activity of PTEN [ XREF_BIBR ] , supporting the hypothesis that PTEN loss of function has an important role in the failure of BRAFi therapy .	AKT activation is normally limited by the activity of PTEN [XREF_BIBR], supporting the hypothesis that PTEN loss of function has an important role in the failure of BRAFi therapy.	0	11	limited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	0	1
The tumor suppressor phosphatase PTEN can promote apoptosis of mitotic cells by inhibiting activation of the cell survival kinase Akt .	The tumor suppressor phosphatase PTEN can promote apoptosis of mitotic cells by inhibiting activation of the cell survival kinase Akt.	0	20	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	19	20
Because PIP3 is the main cellular product of PI3K , PTEN is capable of antagonizing PI3K activity and negatively regulates the PI3K-AKT cell-survival signaling pathway XREF_BIBR .	Because PIP3 is the main cellular product of PI3K, PTEN is capable of antagonizing PI3K activity and negatively regulates the PI3K-AKT cell-survival signaling pathway XREF_BIBR.	10	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	10	11	21	22
PTEN loss and up-regulation of the AKT pathway have begun to emerge as potentially important players in prostate cancer biology [ XREF_BIBR , XREF_BIBR ] .	PTEN loss and up-regulation of the AKT pathway have begun to emerge as potentially important players in prostate cancer biology [XREF_BIBR, XREF_BIBR].	0	7	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
In immunoblot analysis , PTEN overexpression also reversed PGE 2 -induced Akt activation and hCSCs marker up-regulation in Huh7 cells .	In immunoblot analysis, PTEN overexpression also reversed PGE 2 -induced Akt activation and hCSCs marker up-regulation in Huh7 cells.	4	12	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN overexpression	pten	Akt	Akt	akt	4	5	11	12
In agreement with latter reports , we found that PTEN knockdown in MCF7 or SUM159 resulted in activation of PI3-K and Akt pathway .	In agreement with latter reports, we found that PTEN knockdown in MCF7 or SUM159 resulted in activation of PI3-K and Akt pathway.	9	22	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	21	22
Loss of PTEN upregulates Akt , especially Akt3 , in prostate epithelial cells , which is essential for PDGF D expression .	Loss of PTEN upregulates Akt, especially Akt3, in prostate epithelial cells, which is essential for PDGF D expression.	0	7	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Loss of PTEN	pten	Akt	Akt	akt	2	3	4	5
PTEN inhibits PI3K and AKT signaling and is frequently reduced or mutated in human cancers [ XREF_BIBR , XREF_BIBR ] .	PTEN inhibits PI3K and AKT signaling and is frequently reduced or mutated in human cancers [XREF_BIBR, XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	4	5
Levels of PTEN ( phosphatase and tensin homolog deleted on chromosome ten ) , a phosphatase that inactivates Akt , were decreased following BDNF treatment , and calpain inhibition reversed this effect .	Levels of PTEN (phosphatase and tensin homolog deleted on chromosome ten), a phosphatase that inactivates Akt, were decreased following BDNF treatment, and calpain inhibition reversed this effect.	0	19	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	Levels of PTEN	pten	Akt	Akt	akt	2	3	18	19
This activity may be self directed ( i.e ., via dephosphorylation of PTEN ) [ XREF_BIBR ] , and is likely distinct from its role in the PI3K and AKT pathway , which is antagonized by PTEN lipid phosphatase activity and regulates cell proliferation , survival , and motility [ XREF_BIBR ] .	This activity may be self directed (i.e., via dephosphorylation of PTEN) [XREF_BIBR], and is likely distinct from its role in the PI3K and AKT pathway, which is antagonized by PTEN lipid phosphatase activity and regulates cell proliferation, survival, and motility [XREF_BIBR].	27	39	antagonized	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	36	37	29	30
PTEN could block PI3K and Akt signaling pathway activation , resulting in the inhibition on the proliferation and survival of PC cells [ XREF_BIBR ] .	PTEN could block PI3K and Akt signaling pathway activation, resulting in the inhibition on the proliferation and survival of PC cells [XREF_BIBR].	0	8	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	5	6
Upon expression , PTEN-GFP significantly lowered PH AKT -RFP signals at the plasma membrane .	Upon expression, PTEN-GFP significantly lowered PH AKT -RFP signals at the plasma membrane.	3	9	lowered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN-GFP	PTEN-GFP	PTEN-GFP	AKT	AKT	AKT	3	4	7	8
Dephosphorylation of PIP 3 by phosphatase and tensin homolog ( PTEN ) , a tumor suppressor , prevents activation of Akt .	Dephosphorylation of PIP 3 by phosphatase and tensin homolog (PTEN), a tumor suppressor, prevents activation of Akt.	0	21	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Dephosphorylation of PIP 3 by phosphatase and tensin homolog (PTEN	pten	Akt	Akt	akt	10	11	20	21
In addition , PDZK1 enhanced the anti-oncogene activity through altering the activities of tumour associated TFs , including downstream molecules in the AKT signalling pathway that are suppressed by PTEN .	In addition, PDZK1 enhanced the anti-oncogene activity through altering the activities of tumour associated TFs, including downstream molecules in the AKT signalling pathway that are suppressed by PTEN.	22	30	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	29	30	22	23
Rapamycin binds to mTORC1 , one of the two protein complexes in which mTOR functions , and has been shown to inhibit cell proliferation in a variety of tumor models , including those in which PI3K and AKT signaling is deregulated by phosphatase and tensin homolog ( PTEN ) loss .	Rapamycin binds to mTORC1, one of the two protein complexes in which mTOR functions, and has been shown to inhibit cell proliferation in a variety of tumor models, including those in which PI3K and AKT signaling is deregulated by phosphatase and tensin homolog (PTEN) loss.	35	46	deregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	42	46	37	38
Instead , we identified a phosphatase network in which the phosphatase PH domain leucine rich repeat protein phosphatase ( PHLPP ) acts as an essential phosphatase downstream of PTEN , thereby preventing excessive AKT activation in Treg cells , and provides functional complementation for PTEN .	Instead, we identified a phosphatase network in which the phosphatase PH domain leucine rich repeat protein phosphatase (PHLPP) acts as an essential phosphatase downstream of PTEN, thereby preventing excessive AKT activation in Treg cells, and provides functional complementation for PTEN.	25	34	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	28	29	33	34
PTEN is classically known to inhibit the PI3K and AKT signalling axis , but here we show that it also remarkably controls the nuclear levels and transcriptional activity of beta-catenin in an alternative PI3K and AKT way .	PTEN is classically known to inhibit the PI3K and AKT signalling axis, but here we show that it also remarkably controls the nuclear levels and transcriptional activity of beta-catenin in an alternative PI3K and AKT way.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	9	10
PTEN inhibits the AKT pathway , thereby activating many cell survival and proliferative pathways .	PTEN inhibits the AKT pathway, thereby activating many cell survival and proliferative pathways.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	3	4
Examples of alternative regulation are widely known and include : PTEN deletion and deactivation to activate AKT , independent activation of RAS and MAP kinase pathways and upregulation of other membrane tyrosine kinase receptors such as MET , HER-2 , PDGFR .	Examples of alternative regulation are widely known and include : PTEN deletion and deactivation to activate AKT, independent activation of RAS and MAP kinase pathways and upregulation of other membrane tyrosine kinase receptors such as MET, HER-2, PDGFR.	10	27	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	16	17
The Phosphatase PTEN ( Phosphatase and tensin homolog ) physiologically inhibits the downstream activity of PI3K and AKT axis and is frequently deregulated in HCC ( 66 % of tumor incidence in PTEN deficient mice ) [ XREF_BIBR ] ; moreover , it is correlated with poor prognosis and more frequent metastasis [ XREF_BIBR ] .	The Phosphatase PTEN (Phosphatase and tensin homolog) physiologically inhibits the downstream activity of PI3K and AKT axis and is frequently deregulated in HCC (66% of tumor incidence in PTEN deficient mice) [XREF_BIBR]; moreover, it is correlated with poor prognosis and more frequent metastasis [XREF_BIBR].	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	17	18
However , treatment with celecoxib or another COX-2 selective inhibitor ( valdecoxib ) completely blocked radiation induced increase of PTEN phosphorylation , rescued radiation induced decrease in PTEN membrane translocation , and correspondingly inactivated AKT .	However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation induced increase of PTEN phosphorylation, rescued radiation induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT.	11	35	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	valdecoxib) completely blocked radiation induced increase of PTEN phosphorylation	pten	AKT	AKT	akt	19	20	34	35
HH pathway activation is initiated by binding of HH ligand to Patched ( PTCH ) , a twelve transmembrane domain protein that blocks Smoothened ( SMO ) in the absence of HH .	HH pathway activation is initiated by binding of HH ligand to Patched (PTCH), a twelve transmembrane domain protein that blocks Smoothened (SMO) in the absence of HH.	4	29	blocks	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	13	14	25	26
The mechanism by which Ptch represses Smo signaling is not yet known .	The mechanism by which Ptch represses Smo signaling is not yet known.	4	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	4	5	6	7
In each of these cases , Smo constitutive activity is strongly suppressed by substoichiometric amounts of Ptch1 , and Smo activity is restored by treatment with Hh protein , illustrating that the underlying inhibitory effects are dependent on Ptch1 activity rather than nonspecific consequences of protein over-expression .	In each of these cases, Smo constitutive activity is strongly suppressed by substoichiometric amounts of Ptch1, and Smo activity is restored by treatment with Hh protein, illustrating that the underlying inhibitory effects are dependent on Ptch1 activity rather than nonspecific consequences of protein over-expression.	6	17	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Ptch1	amounts of Ptch1	ptch1	Smo	Smo	smo	16	17	6	7
In the absence of the HH ligand , PTC1 prevents the ciliary entry of SMO .	In the absence of the HH ligand, PTC1 prevents the ciliary entry of SMO.	8	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTC1	PTC1	PTC1	SMO	SMO	SMO	8	9	14	15
In the mature stroma , it was hypothesized that PTCH1 inhibits SMO , while GLI2 and GLI3 act as repressors .	In the mature stroma, it was hypothesized that PTCH1 inhibits SMO, while GLI2 and GLI3 act as repressors.	9	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	9	10	11	12
PTCH inhibits SMO and acts as a cell cycle regulator , by blocking downstream events that result in transcriptional activation of target genes ( XREF_FIG ) .	PTCH inhibits SMO and acts as a cell cycle regulator, by blocking downstream events that result in transcriptional activation of target genes (XREF_FIG).	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	0	1	2	3
In the absence of HH , PTCH1 is localized in primary cilia and constitutively suppresses the activity of SMO , a seven-pass transmembrane spanning protein that is a member of the G-protein-coupled receptor superfamily [ XREF_BIBR ] .	In the absence of HH, PTCH1 is localized in primary cilia and constitutively suppresses the activity of SMO, a seven-pass transmembrane spanning protein that is a member of the G-protein-coupled receptor superfamily [XREF_BIBR].	6	22	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	6	7	18	19
The differences between these models suggests that Ptch1 loss increases proliferation independently of Smo .	The differences between these models suggests that Ptch1 loss increases proliferation independently of Smo.	7	14	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	13	14
Ptch1 appears to be the most directly impacted by Notch , as the addition of DAPT alone to fibroblasts promotes Ptch1 accumulation within primary cilia ( XREF_FIG F , 7G , and 7J ) , and Ptch1 is known to block Smo entry and downstream signaling events .	Ptch1 appears to be the most directly impacted by Notch, as the addition of DAPT alone to fibroblasts promotes Ptch1 accumulation within primary cilia (XREF_FIG F, 7G, and 7J), and Ptch1 is known to block Smo entry and downstream signaling events.	36	42	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	36	37	41	42
In the absence of Hh ligand , Ptch1 inhibits the activity of Smo , permitting the sequential phosphorylation of Gli2 and Gli3 by protein kinase A ( PKA ) , glycogen synthase kinase-3 ( GSK3 ) , and casein kinase 1 ( CK1 ) .	In the absence of Hh ligand, Ptch1 inhibits the activity of Smo, permitting the sequential phosphorylation of Gli2 and Gli3 by protein kinase A (PKA), glycogen synthase kinase-3 (GSK3), and casein kinase 1 (CK1).	7	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	12	13
In the absence of Shh ligand , Ptch1 inhibits the activity of Smoothened ( Smo ) , the 7-pass transmembrane protein .	In the absence of Shh ligand, Ptch1 inhibits the activity of Smoothened (Smo), the 7-pass transmembrane protein.	7	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	14	15
PTCH1 inhibition of SMO may also be due to PTCH1 mediated inhibition of phosphatidylinositol-4-phosphate , which promotes the association of SMO with the cell surface membrane [ XREF_BIBR ] .	PTCH1 inhibition of SMO may also be due to PTCH1 mediated inhibition of phosphatidylinositol-4-phosphate, which promotes the association of SMO with the cell surface membrane [XREF_BIBR].	0	4	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	0	1	3	4
Likewise the repressive role of Ptch1 is not clear , but Ptch1 may sequester ciliary Smo keeping it inactive .	Likewise the repressive role of Ptch1 is not clear, but Ptch1 may sequester ciliary Smo keeping it inactive.	11	16	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	11	12	15	16
In the absence of HH ligand , transmembrane receptor Patched1 ( PTCH1 ) suppresses the seven-pass transmembrane protein Smoothened ( SMO ) and Suppressor of Fused ( SUFU ) inhibits glioma associated oncogene ( GLI ) transcription factors that control HH pathway response .	In the absence of HH ligand, transmembrane receptor Patched1 (PTCH1) suppresses the seven-pass transmembrane protein Smoothened (SMO) and Suppressor of Fused (SUFU) inhibits glioma associated oncogene (GLI) transcription factors that control HH pathway response.	9	21	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	11	12	20	21
As a consequence , Ptch inhibition of Smo , a 7-pass transmembrane spanning protein , is relieved , and the Shh signaling cascade is initiated , which in turn activates the Gli transcription factors .	As a consequence, Ptch inhibition of Smo, a 7-pass transmembrane spanning protein, is relieved, and the Shh signaling cascade is initiated, which in turn activates the Gli transcription factors.	4	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	4	5	7	8
In the absence of Hh , the Ptch receptor inhibits the co-receptor Smoothened ( Smo ) , by preventing its localization to the primary cilium .	In the absence of Hh, the Ptch receptor inhibits the co-receptor Smoothened (Smo), by preventing its localization to the primary cilium.	7	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	7	8	14	15
In absence of stimulation , Ptch represses Smo , ensuring that Hh pathway is inhibited .	In absence of stimulation, Ptch represses Smo, ensuring that Hh pathway is inhibited.	5	8	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	5	6	7	8
In the absence of Shh , Ptch 1 inhibits the function of another membrane protein smoothened ( Smoh ) .	In the absence of Shh, Ptch 1 inhibits the function of another membrane protein smoothened (Smoh).	6	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smoh	Smoh	Smoh	6	7	17	18
In the presence of secreted Shh , inhibition of Smo by Ptch is removed and Smo promotes Gli1 and Gli2 dissociation from an inhibitory complex , leading to the up-regulation of multiple Gli transcriptional targets XREF_BIBR , XREF_BIBR .	In the presence of secreted Shh, inhibition of Smo by Ptch is removed and Smo promotes Gli1 and Gli2 dissociation from an inhibitory complex, leading to the up-regulation of multiple Gli transcriptional targets XREF_BIBR, XREF_BIBR.	7	12	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	11	12	9	10
SMO is normally suppressed by PTC1 , however , inactivating mechanisms , such as mutation of PTC1 or the binding of hedgehog proteins to PTC1 , lead to continuous SMO activation and transcriptional responses .	SMO is normally suppressed by PTC1, however, inactivating mechanisms, such as mutation of PTC1 or the binding of hedgehog proteins to PTC1, lead to continuous SMO activation and transcriptional responses.	0	6	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTC1	PTC1	PTC1	SMO	SMO	SMO	5	6	0	1
Despite such recent insights on lipophilic regulators of Smo activity , the mechanisms by which Ptch1 represses Smo and how Hh ligand removes this repression remain major questions in the field .	Despite such recent insights on lipophilic regulators of Smo activity, the mechanisms by which Ptch1 represses Smo and how Hh ligand removes this repression remain major questions in the field.	15	18	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	15	16	17	18
Fibroblasts derived from animals genetically incapable of synthesizing these 3beta-hydroxysteroids ( Sc5d -/-) do not sustain intercellular repression of Smo by Ptch1 , whereas fibroblasts that have a genetic defect leading to increased ( pro-) vitamin D3 production ( Dhcr7 -/-) show exaggerated intercellular repression of Smo by Ptch1 .	Fibroblasts derived from animals genetically incapable of synthesizing these 3beta-hydroxysteroids (Sc5d -/-) do not sustain intercellular repression of Smo by Ptch1, whereas fibroblasts that have a genetic defect leading to increased (pro-) vitamin D3 production (Dhcr7 -/-) show exaggerated intercellular repression of Smo by Ptch1.	42	49	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	48	49	46	47
Ptch1 blocks Smo localization to the cilia in the absence of Shh .	Ptch1 blocks Smo localization to the cilia in the absence of Shh.	0	3	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	0	1	2	3
Ptc1 also localizes to the ciliary membrane and appears to inhibit Smo by impeding its accumulation in the ciliary compartment , and Gli1 , Gli2 , and Gli3 also localize to the cilium .	Ptc1 also localizes to the ciliary membrane and appears to inhibit Smo by impeding its accumulation in the ciliary compartment, and Gli1, Gli2, and Gli3 also localize to the cilium.	0	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	0	1	11	12
In the absence of the Hh ligands , Sonic ( Shh ) , Indian ( Ihh ) or Desert ( Dhh ) Hh , Ptc1 inhibits Smoothened ( Smo ) , leading to processing of Gli2 and Gli3 to their repressor forms , which blocks target gene transcription .	In the absence of the Hh ligands, Sonic (Shh), Indian (Ihh) or Desert (Dhh) Hh, Ptc1 inhibits Smoothened (Smo), leading to processing of Gli2 and Gli3 to their repressor forms, which blocks target gene transcription.	24	48	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Ptc1	Ptc1	ptc1	Smo	Smo), leading to processing of Gli2 and Gli3 to their repressor forms, which blocks target gene transcription	smo	24	25	28	29
Under the prevailing model of Shh pathway activation , the binding of Shh to Ptch1 ( the key Shh receptor ) results in the release of Ptch1 mediated inhibition of Smo , leading to Smo activation and subsequent cell-autonomous activation of the Shh response .	Under the prevailing model of Shh pathway activation, the binding of Shh to Ptch1 (the key Shh receptor) results in the release of Ptch1 mediated inhibition of Smo, leading to Smo activation and subsequent cell-autonomous activation of the Shh response.	24	31	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	26	27	30	31
SMO is negatively regulated by the transmembrane receptor PTCH .	SMO is negatively regulated by the transmembrane receptor PTCH.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	8	9	0	1
Upon HH ligand binding , the PTCH inhibition of SMO is released and the signal is transduced to the terminal effectors , the GLI , Glioma associated oncogene , proteins ( GLI1 , GLI2 , GLI3 ) [ XREF_BIBR ] .	Upon HH ligand binding, the PTCH inhibition of SMO is released and the signal is transduced to the terminal effectors, the GLI, Glioma associated oncogene, proteins (GLI1, GLI2, GLI3) [XREF_BIBR].	6	10	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	6	7	9	10
When Hh ligands are absent , Ptch prevents the trafficking and localization of Smo to the primary cilia , in turn preventing activation of the signaling cascade ( XREF_FIG ) [ XREF_BIBR ] .	When Hh ligands are absent, Ptch prevents the trafficking and localization of Smo to the primary cilia, in turn preventing activation of the signaling cascade (XREF_FIG) [XREF_BIBR].	6	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	13	14
In the absence of the HH ligand , PTCH blocks this migration of SMO into the primary cilium .	In the absence of the HH ligand, PTCH blocks this migration of SMO into the primary cilium.	8	14	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	8	9	13	14
The interaction relieves the Smoothened ( Smo ) complex that is inhibited by Ptch in the absence of the ligand .	The interaction relieves the Smoothened (Smo) complex that is inhibited by Ptch in the absence of the ligand.	6	14	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	13	14	6	7
MbetaCD : cholesterol activated signaling in Ptch1 -/- cells treated with cyclopamine to partially suppress SMO activity , showing that cholesterol signaling activity did not depend on the presence of PTCH1 ( XREF_FIG ) .	MbetaCD : cholesterol activated signaling in Ptch1 -/- cells treated with cyclopamine to partially suppress SMO activity, showing that cholesterol signaling activity did not depend on the presence of PTCH1 (XREF_FIG).	6	16	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	SMO	SMO	SMO	6	7	15	16
In the absence of ligand , PTCH inhibits SMO .	In the absence of ligand, PTCH inhibits SMO.	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	6	7	8	9
In the absence of Hh , Ptch inhibits Smo .	In the absence of Hh, Ptch inhibits Smo.	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	8	9
However , upon bound by a ligand , PTCH1 no longer inhibits Smo , thus allowing the accumulation of Smo in the primary cilium .	However, upon bound by a ligand, PTCH1 no longer inhibits Smo, thus allowing the accumulation of Smo in the primary cilium.	8	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	Smo	Smo	Smo	8	9	12	13
In the absence of Hh ligand , Patched1 ( Ptch1 ) , the antagonizing receptor of Hh , inhibits the activity of the seven-pass transmembrane protein Smoothened ( Smo ) .	In the absence of Hh ligand, Patched1 (Ptch1), the antagonizing receptor of Hh, inhibits the activity of the seven-pass transmembrane protein Smoothened (Smo).	7	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	9	10	28	29
In the absence of a Hedgehog ligand , Ptch catalytically inhibits the activity of Smo .	In the absence of a Hedgehog ligand, Ptch catalytically inhibits the activity of Smo.	8	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	8	9	14	15
In response to Shh signaling , Ptch1 inhibition of Smo at the PC is abolished , when Ptch1 is internalized and degraded [ XREF_BIBR ] .	In response to Shh signaling, Ptch1 inhibition of Smo at the PC is abolished, when Ptch1 is internalized and degraded [XREF_BIBR].	6	12	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	6	7	9	10
In the absence of Shh , Ptch mediated Smo inhibition can be bypassed by direct Smo agonists such as 7TM binding SAG and CRD binding 20 ( S )-OHC .	In the absence of Shh, Ptch mediated Smo inhibition can be bypassed by direct Smo agonists such as 7TM binding SAG and CRD binding 20 (S)-OHC.	6	9	mediated	Positive_early_activation	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	8	9
In the absence of Hh ligand the transmembrane receptor Patched1 ( Ptc1 ) inhibits Smoothened ( Smo ) while Hh binding results in a release of the repression of Smo by Ptc1 and in a cascade of phosphorylation events [ XREF_BIBR , XREF_BIBR ] .	In the absence of Hh ligand the transmembrane receptor Patched1 (Ptc1) inhibits Smoothened (Smo) while Hh binding results in a release of the repression of Smo by Ptc1 and in a cascade of phosphorylation events [XREF_BIBR, XREF_BIBR].	21	32	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	31	32	29	30
XREF_BIBR , XREF_BIBR In mammals , the pathway is activated by three lipid modified Hh proteins , Sonic ( Shh ) , Indian ( Ihh ) and Desert ( Dhh ) Hedgehogs , which bind to the receptor Patched ( Ptch1 ) , which in turn acts to constitutively inhibit Smoothened ( Smo ) , the molecular target of the small molecule Hh inhibitors in clinical use for basal cell carcinoma and medulloblastoma .	XREF_BIBR, XREF_BIBR In mammals, the pathway is activated by three lipid modified Hh proteins, Sonic (Shh), Indian (Ihh) and Desert (Dhh) Hedgehogs, which bind to the receptor Patched (Ptch1), which in turn acts to constitutively inhibit Smoothened (Smo), the molecular target of the small molecule Hh inhibitors in clinical use for basal cell carcinoma and medulloblastoma.	34	72	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	40	41	52	53
In the present study , we investigated the molecular mode by which Ptch1 represses Smo activity .	In the present study, we investigated the molecular mode by which Ptch1 represses Smo activity.	12	15	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	12	13	14	15
The mechanism by which Ptch inhibits Smo is not fully elucidated , but it does not seem to require physical interaction between the two molecules .	The mechanism by which Ptch inhibits Smo is not fully elucidated, but it does not seem to require physical interaction between the two molecules.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	4	5	6	7
In the presence of Shh ligand , PTCH1 inhibition of SMO at the primary cilium is abrogated resulting in the nuclear localization of glioma associated ( GLI ) transcription factors , which are the terminal effectors of the Shh signaling ( XREF_FIG ) .	In the presence of Shh ligand, PTCH1 inhibition of SMO at the primary cilium is abrogated resulting in the nuclear localization of glioma associated (GLI) transcription factors, which are the terminal effectors of the Shh signaling (XREF_FIG).	7	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	7	8	10	11
Without presence of ligands , PTCH1 represses activation of the transmembrane protein Smoothened ( SMO ) .	Without presence of ligands, PTCH1 represses activation of the transmembrane protein Smoothened (SMO).	5	15	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	5	6	14	15
In the inactive state , PTC1 represses SMO , and an inactive complex is formed in the cytoplasm with assembly with Costal 2 ( Cos2 ) , Fused ( Fu ) , suppressor of Fu ( SuFu ) , and Cubitus interruptus ( Ci ) , all associated with microtubules .	In the inactive state, PTC1 represses SMO, and an inactive complex is formed in the cytoplasm with assembly with Costal 2 (Cos2), Fused (Fu), suppressor of Fu (SuFu), and Cubitus interruptus (Ci), all associated with microtubules.	5	8	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTC1	PTC1	PTC1	SMO	SMO	SMO	5	6	7	8
Given the SBE induced pervasive inhibition of SHH signaling especially including PTCH which is supposed to repress SMO in normal mammalian cells , PTCH in lung cancer cells is still functioning as a repressor of hedgehog cascade reaction chain and is overwhelmingly suppressed or neutralized by overexpressed SHH .	Given the SBE induced pervasive inhibition of SHH signaling especially including PTCH which is supposed to repress SMO in normal mammalian cells, PTCH in lung cancer cells is still functioning as a repressor of hedgehog cascade reaction chain and is overwhelmingly suppressed or neutralized by overexpressed SHH.	3	21	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	11	12	17	18
If ligands are not present , PTCH will block the entry of SMO .	If ligands are not present, PTCH will block the entry of SMO.	6	13	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	6	7	12	13
In the resting state , the Hh receptor Ptch inhibits the activity of Smo , a G protein coupled ( GPCR )-like molecule .	In the resting state, the Hh receptor Ptch inhibits the activity of Smo, a G protein coupled (GPCR)-like molecule.	5	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	8	9	13	14
Hh receiving cells are enriched with cilia where PTCH inhibits SMO activity by preventing its accumulation within cilia .	Hh receiving cells are enriched with cilia where PTCH inhibits SMO activity by preventing its accumulation within cilia.	8	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	8	9	10	11
Binding of any of 3 Hh ligands to PTCH1 relieves PTCH1 repression of SMO , leading to downstream pathway activation including modification of the 3 GLI family transcription factors ( GLI1-GLI3 ) , which in turn promote transcription of genes regulating cell growth and differentiation .	Binding of any of 3 Hh ligands to PTCH1 relieves PTCH1 repression of SMO, leading to downstream pathway activation including modification of the 3 GLI family transcription factors (GLI1-GLI3), which in turn promote transcription of genes regulating cell growth and differentiation.	10	14	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	10	11	13	14
As a consequence , Ptch1 inhibition of Smoothened ( Smo ) , a 7-pass transmembrane spanning protein , is relieved and the SHH signaling cascade is initiated , which in turn activates the Gli transcription factors XREF_BIBR .	As a consequence, Ptch1 inhibition of Smoothened (Smo), a 7-pass transmembrane spanning protein, is relieved and the SHH signaling cascade is initiated, which in turn activates the Gli transcription factors XREF_BIBR.	4	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	9	10
Upon binding of Hh ligand to PTCH1 , the inhibition of SMO by PTCH1 is alleviated , resulting in the activation of Gli transcription factors , capable of regulating expression of Hh target genes [ XREF_BIBR ] .	Upon binding of Hh ligand to PTCH1, the inhibition of SMO by PTCH1 is alleviated, resulting in the activation of Gli transcription factors, capable of regulating expression of Hh target genes [XREF_BIBR].	9	14	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	13	14	11	12
In the absence of ligand , PTCH1 is located at the base of the cilium and prevents ciliary entry of SMO .	In the absence of ligand, PTCH1 is located at the base of the cilium and prevents ciliary entry of SMO.	6	21	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	6	7	20	21
When SHH reaches its target cell , it binds to the Patched-1 ( PTCH1 ) receptor , which inhibits Smoothened ( SMO ) , a downstream protein in the pathway that determines the fate of vertebrate limb development .	When SHH reaches its target cell, it binds to the Patched-1 (PTCH1) receptor, which inhibits Smoothened (SMO), a downstream protein in the pathway that determines the fate of vertebrate limb development.	13	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	13	14	21	22
In so far as the function of Ptch1 is to inhibit Smo signaling , its loss in cells not expressing Smo should be of little consequence - activation of HH signaling by loss of Ptch1 function by ligand binding or by inactivating mutation requires expression of downstream components of the signaling machinery .	In so far as the function of Ptch1 is to inhibit Smo signaling, its loss in cells not expressing Smo should be of little consequence - activation of HH signaling by loss of Ptch1 function by ligand binding or by inactivating mutation requires expression of downstream components of the signaling machinery.	5	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	11	12
Thus , oxysterol binding may be required for maximal Smo activity but not for mediating Ptch1 dependent inhibition of Smo .	Thus, oxysterol binding may be required for maximal Smo activity but not for mediating Ptch1 dependent inhibition of Smo.	15	20	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	15	16	19	20
Mixing Ptch1-overexpression cells with cells expressing Smo and Gli reporter produced inhibition of Gli reporter activity to approximately the same extent as fusing these cells , showing that this non cell autonomous repression of Smo by Ptch1 is of roughly similar potency compared to intracellular Smo repression by Ptch1 .	Mixing Ptch1-overexpression cells with cells expressing Smo and Gli reporter produced inhibition of Gli reporter activity to approximately the same extent as fusing these cells, showing that this non cell autonomous repression of Smo by Ptch1 is of roughly similar potency compared to intracellular Smo repression by Ptch1.	32	37	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	36	37	34	35
The inhibition of Smo by Ptc1 is relieved by Shh , thus allowing for transcription of downstream target genes via the Gli zinc-finger transcription factor family .	The inhibition of Smo by Ptc1 is relieved by Shh, thus allowing for transcription of downstream target genes via the Gli zinc-finger transcription factor family.	1	6	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	5	6	3	4
In the absence of Hh ligand , its receptor , Patched ( Ptc1 ) inhibits Smo activity , presumptively through a small molecule mediator [ XREF_BIBR ; XREF_BIBR ] .	In the absence of Hh ligand, its receptor, Patched (Ptc1) inhibits Smo activity, presumptively through a small molecule mediator [XREF_BIBR; XREF_BIBR].	7	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	12	13	15	16
Given our finding that Ptch1 suppression of Smo activity required ciliary localization , clearance of Ptch1 from the cilium and its subsequent degradation may result in a higher degree of Hh responsiveness .	Given our finding that Ptch1 suppression of Smo activity required ciliary localization, clearance of Ptch1 from the cilium and its subsequent degradation may result in a higher degree of Hh responsiveness.	4	8	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	7	8
Because both cell lines share the inability to properly synthesize cholesterol , and because we find a differential inhibitory potential on Smo , we conclude that sterol content alone can not account for Ptch1 mediated Smo inhibition , and we suggest that the effects found by other groups take place elsewhere in the Hh signalling pathway .	Because both cell lines share the inability to properly synthesize cholesterol, and because we find a differential inhibitory potential on Smo, we conclude that sterol content alone can not account for Ptch1 mediated Smo inhibition, and we suggest that the effects found by other groups take place elsewhere in the Hh signalling pathway.	31	36	mediated	Positive_early_activation	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	33	34	35	36
Protein patched homolog 1 ( Ptch1 ) is known to repress smoothened ( Smo ) under unligated conditions and this inhibition is released when the ligand ( Shh , Ihh , or Dhh ) binds to Ptch-1 .	Protein patched homolog 1 (Ptch1) is known to repress smoothened (Smo) under unligated conditions and this inhibition is released when the ligand (Shh, Ihh, or Dhh) binds to Ptch-1.	2	17	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	5	6	13	14
A current model of ciliary Hh signaling posits that Hh-Ptch interactions relieve Ptch mediated inhibition of Smo , leading to ciliary Smo accumulation and to the activation of Gli processing and function .	A current model of ciliary Hh signaling posits that Hh-Ptch interactions relieve Ptch mediated inhibition of Smo, leading to ciliary Smo accumulation and to the activation of Gli processing and function.	12	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	12	13	16	17
In the absence of Hh ligand , Ptch-1 constitutively inhibits the seven-transmembrane protein Smoothened ( Smo ) , and renders the pathway inactive .	In the absence of Hh ligand, Ptch-1 constitutively inhibits the seven-transmembrane protein Smoothened (Smo), and renders the pathway inactive.	7	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch-1	Ptch-1	Ptch-1	Smo	Smo	Smo	7	8	15	16
Thus , our work supports a model where PTCH1 may inhibit SMO by reducing cholesterol content or cholesterol accessibility ( or chemical activity ) in a membrane compartment that also contains SMO , leading to alterations in SMO conformation or trafficking .	Thus, our work supports a model where PTCH1 may inhibit SMO by reducing cholesterol content or cholesterol accessibility (or chemical activity) in a membrane compartment that also contains SMO, leading to alterations in SMO conformation or trafficking.	8	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	8	9	11	12
In the unbound state , PTCH1 prevents SMO activation in the primary cilium , an organelle required for the transduction of various chemical and mechanical signals .	In the unbound state, PTCH1 prevents SMO activation in the primary cilium, an organelle required for the transduction of various chemical and mechanical signals.	5	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	5	6	7	8
15 Unlike many cellular pathways in which receptors function as signal transducers and directly induce pathway activity following ligand binding , Ptch represses Smo and inhibits pathway signaling in the absence of Hh ligand .	15 Unlike many cellular pathways in which receptors function as signal transducers and directly induce pathway activity following ligand binding, Ptch represses Smo and inhibits pathway signaling in the absence of Hh ligand.	21	25	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	21	22	23	24
In the absence of Shh , Ptch1 inhibits the transmembrane protein Smoothened ( Smo ) , but upon Shh binding to Ptch1 , Smo is released into the cytoplasm , initiating a signaling cascade that activates the glioma associated ( Gli ) family of transcription factors .	In the absence of Shh, Ptch1 inhibits the transmembrane protein Smoothened (Smo), but upon Shh binding to Ptch1, Smo is released into the cytoplasm, initiating a signaling cascade that activates the glioma associated (Gli) family of transcription factors.	6	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	6	7	13	14
In the absence of ligands , the transmembrane Ptc1 protein inhibits Smo to transduce the signal and Gli3 is constantly proteolytically cleaved into the repressor form Gli3R .	In the absence of ligands, the transmembrane Ptc1 protein inhibits Smo to transduce the signal and Gli3 is constantly proteolytically cleaved into the repressor form Gli3R.	8	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	8	9	11	12
In the absence of HH , PTCH1 prevents SMO from signaling .	In the absence of HH, PTCH1 prevents SMO from signaling.	6	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	6	7	8	9
Ptch1 with full cytoplasmic tail but lacking a segment of the TM7-TM8 extracellular loop fully suppressed Smo activity but did not respond to Hh ( Ptch1 DeltaL2 , XREF_FIG ) , consistent with loss of Hh binding .	Ptch1 with full cytoplasmic tail but lacking a segment of the TM7-TM8 extracellular loop fully suppressed Smo activity but did not respond to Hh (Ptch1 DeltaL2, XREF_FIG), consistent with loss of Hh binding.	0	23	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	0	1	16	17
In the absence of Hh ligand , Ptch receptor represses Smo and prevents the activation of Hh signaling .	In the absence of Hh ligand, Ptch receptor represses Smo and prevents the activation of Hh signaling.	7	11	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	7	8	10	11
In the absence of Hh ligand binding , the receptor Ptch localizes at the primary cilium and inhibits the co-receptor Smo , which is an essential positive mediator of the entire pathway , resulting in the phosphorylation and cleavage of transcription factors Gli2 and Gli3 .	In the absence of Hh ligand binding, the receptor Ptch localizes at the primary cilium and inhibits the co-receptor Smo, which is an essential positive mediator of the entire pathway, resulting in the phosphorylation and cleavage of transcription factors Gli2 and Gli3.	8	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	10	11	20	21
In normal cells , Shh signaling is initiated by the binding of the Shh ligand to PTCH , which relieves PTCH mediated repression of SMOH .	In normal cells, Shh signaling is initiated by the binding of the Shh ligand to PTCH, which relieves PTCH mediated repression of SMOH.	20	25	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMOH	SMOH	SMOH	20	21	24	25
When ligand binds and Ptch inhibition of Smo is released , Ptch moves out of the primary cilia and Smo moves in to facilitate interaction with Glis and associated proteins .	When ligand binds and Ptch inhibition of Smo is released, Ptch moves out of the primary cilia and Smo moves in to facilitate interaction with Glis and associated proteins.	4	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	4	5	7	8
In the absence of Hh , Ptch is on the PC and blocks Smo from entering the PC ) and hence , Smo localizes in intracytoplasmic vesicles .	In the absence of Hh, Ptch is on the PC and blocks Smo from entering the PC) and hence, Smo localizes in intracytoplasmic vesicles.	6	14	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	13	14
One molecule of PTCH can inhibit several molecules of SMO , suggesting that the inhibition of SMO by PTCH is in a catalytic way [ XREF_BIBR ] .	One molecule of PTCH can inhibit several molecules of SMO, suggesting that the inhibition of SMO by PTCH is in a catalytic way [XREF_BIBR].	14	19	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	18	19	16	17
In the absence of the ligand , the Patched ( PTCH ) receptor inhibits Smoothened ( SMO ) , a downstream protein in the pathway .	In the absence of the ligand, the Patched (PTCH) receptor inhibits Smoothened (SMO), a downstream protein in the pathway.	10	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	10	11	16	17
The exact mechanism behind Ptch1 inhibition of Smo , however , remains unclear [ XREF_BIBR ] .	The exact mechanism behind Ptch1 inhibition of Smo, however, remains unclear [XREF_BIBR].	4	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	7	8
Once HH ligand binds to Ptch , Ptch no longer inhibits Smo , resulting in translocation of GLI to the nucleus and subsequent activation of proliferative genes 50 .	Once HH ligand binds to Ptch, Ptch no longer inhibits Smo, resulting in translocation of GLI to the nucleus and subsequent activation of proliferative genes 50.	7	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	7	8	11	12
In the presence of HH ligand , Ptch repression of Smo is abolished , leading to downstream activation of the Gli family of transcription factors ( Gli1 , 2 , 3 ) .	In the presence of HH ligand, Ptch repression of Smo is abolished, leading to downstream activation of the Gli family of transcription factors (Gli1, 2, 3).	7	11	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	7	8	10	11
Numerous evidences indicate that PTC1 represses SMO in a cell autonomous fashion .	Numerous evidences indicate that PTC1 represses SMO in a cell autonomous fashion.	4	11	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTC1	PTC1	PTC1	SMO	SMO	SMO	4	5	6	7
In the absence of ligand , Ptch constitutively represses the activity of Smoothened ( Smo ) , a 7-pass transmembrane spanning protein with homology to G protein coupled receptors .	In the absence of ligand, Ptch constitutively represses the activity of Smoothened (Smo), a 7-pass transmembrane spanning protein with homology to G protein coupled receptors.	6	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	14	15
Binding the ligand releases Ptch1 mediated repression of Smo , activating its function at the cell surface that leads to transcriptional induction of the Hh signaling cascade .	Binding the ligand releases Ptch1 mediated repression of Smo, activating its function at the cell surface that leads to transcriptional induction of the Hh signaling cascade.	4	9	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	8	9
In the absence of Shh signaling , Ptc1 localizes to primary cilia and prevents Smo accumulation within cilia .	In the absence of Shh signaling, Ptc1 localizes to primary cilia and prevents Smo accumulation within cilia.	7	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	7	8	14	15
PTCH inhibits signaling by the membrane protein Smoothened ( Smo ) , and this inhibition is relieved by binding sonic hedgehog ( SHH ) to PTCH .	PTCH inhibits signaling by the membrane protein Smoothened (Smo), and this inhibition is relieved by binding sonic hedgehog (SHH) to PTCH.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	Smo	Smo	Smo	0	1	9	10
Binding of HH to its receptor PTCH revokes the repressive effect of PTCH thereby allowing SMO to enter the primary cilium and initiate signaling .	Binding of HH to its receptor PTCH revokes the repressive effect of PTCH thereby allowing SMO to enter the primary cilium and initiate signaling.	10	17	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	12	13	15	16
The mechanism by which PTCH1 ( or PTCH2 ) inhibits SMO is not known , but recent data suggest that PTCH1 inhibits SMO both cell autonomously and non autonomously by functioning as an efflux pump for an oxysterol [ XREF_BIBR ] .	The mechanism by which PTCH1 (or PTCH2) inhibits SMO is not known, but recent data suggest that PTCH1 inhibits SMO both cell autonomously and non autonomously by functioning as an efflux pump for an oxysterol [XREF_BIBR].	20	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	20	21	22	23
Canonical Hh signaling is activated when Hh ligand binds PTCH to relieve PTCH mediated SMO inhibition at the base of the primary cilium .	Canonical Hh signaling is activated when Hh ligand binds PTCH to relieve PTCH mediated SMO inhibition at the base of the primary cilium.	11	15	mediated	Positive_early_activation	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	12	13	14	15
One of the most frequently mutated seven transmembrane domain receptors in tumors is smoothened ( SMO ) , which is negatively regulated by the twelve-transmembrane receptor Patched ( PTCH ) [ XREF_BIBR , XREF_BIBR ] .	One of the most frequently mutated seven transmembrane domain receptors in tumors is smoothened (SMO), which is negatively regulated by the twelve-transmembrane receptor Patched (PTCH) [XREF_BIBR, XREF_BIBR].	13	31	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	28	29	15	16
In the absence of Hh ligands , PTCH inhibits Smoothened ( SMO ) , preventing nuclear localization of the Glioblastoma ( Gli ) family transcription factors that regulate Hh-target gene expression .	In the absence of Hh ligands, PTCH inhibits Smoothened (SMO), preventing nuclear localization of the Glioblastoma (Gli) family transcription factors that regulate Hh-target gene expression.	7	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	7	8	11	12
Binding of Hh ligand to its transmembrane receptor Ptch1 relieves Ptch1 inhibition of Smo and allows Smo to signal to a complex of proteins that includes the transcription factors Ci ( in Drosophila ) / Gli ( in vertebrates ) [ XREF_BIBR ] .	Binding of Hh ligand to its transmembrane receptor Ptch1 relieves Ptch1 inhibition of Smo and allows Smo to signal to a complex of proteins that includes the transcription factors Ci (in Drosophila) / Gli (in vertebrates) [XREF_BIBR].	10	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	10	11	13	14
At rest , Ptch1 inhibits Smo activity , but upon its binding to Shh , releases this inhibition , thus allowing Smo mediated activation followed by Shh related transcriptional responses [ XREF_BIBR ] .	At rest, Ptch1 inhibits Smo activity, but upon its binding to Shh, releases this inhibition, thus allowing Smo mediated activation followed by Shh related transcriptional responses [XREF_BIBR].	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	3	4	5	6
When an Hh ligand binds to the PTCH1 receptor , it relieves the PTCH1 mediated inhibition of SMO .	When an Hh ligand binds to the PTCH1 receptor, it relieves the PTCH1 mediated inhibition of SMO.	12	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	13	14	17	18
Inhibition of Smo by Ptch1 results in the maintenance of a cytoplasmic proteolytic complex containing Suppressor of Fused ( SuFu ) .	Inhibition of Smo by Ptch1 results in the maintenance of a cytoplasmic proteolytic complex containing Suppressor of Fused (SuFu).	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	2	3
In the absence of Hh signaling , both Ptch1 , the Hh receptor that inhibits Smo activity , and Gpr161 , a GPCR that antagonizes Hh signaling by activating PKA , are localized to cilia .	In the absence of Hh signaling, both Ptch1, the Hh receptor that inhibits Smo activity, and Gpr161, a GPCR that antagonizes Hh signaling by activating PKA, are localized to cilia.	7	32	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	8	9	15	16
Ptc-1 tonically inhibits Smo , but once Shh binds Ptc-1 , Smo is disinhibited and downstream signaling occurs , classically through activation of the glioma associated oncogene homolog ( Gli ) family of transcription factors .	Ptc-1 tonically inhibits Smo, but once Shh binds Ptc-1, Smo is disinhibited and downstream signaling occurs, classically through activation of the glioma associated oncogene homolog (Gli) family of transcription factors.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc-1	Ptc-1	Ptc-1	Smo	Smo	Smo	0	1	3	4
One model is that Ptch1 inhibits the pathway by excluding Smo from the cilium in resting cells and that Hh binding triggers removal of Ptch1 from the cilium , thus enabling Smo to enter and activate signaling .	One model is that Ptch1 inhibits the pathway by excluding Smo from the cilium in resting cells and that Hh binding triggers removal of Ptch1 from the cilium, thus enabling Smo to enter and activate signaling.	4	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	10	11
Binding of the Hedgehog ligand to PTCH1 prevents PTCH1 mediated inhibition of SMO , thereby allowing SMO to localize to cilia and promote downstream activation of transcription factors encoded by the GLI zinc-finger family .	Binding of the Hedgehog ligand to PTCH1 prevents PTCH1 mediated inhibition of SMO, thereby allowing SMO to localize to cilia and promote downstream activation of transcription factors encoded by the GLI zinc-finger family.	8	18	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	8	9	16	17
In the absence of Hh ligand , Ptch1 is found at the base of the primary cilium , preventing the association of Smo with the cell membrane .	In the absence of Hh ligand, Ptch1 is found at the base of the primary cilium, preventing the association of Smo with the cell membrane.	7	23	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	22	23
In the absence of Shh , Ptch1 inhibits Smo and causes repression of the pathway [ XREF_BIBR ] .	In the absence of Shh, Ptch1 inhibits Smo and causes repression of the pathway [XREF_BIBR].	6	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	6	7	8	9
Although the present study clearly demonstrates that Ptch1 can inhibit Smo in an intercellular fashion , we have not addressed whether such intercellular action of Ptch1 on Smo is relevant for Hh action in vivo .	Although the present study clearly demonstrates that Ptch1 can inhibit Smo in an intercellular fashion, we have not addressed whether such intercellular action of Ptch1 on Smo is relevant for Hh action in vivo.	7	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	10	11
Several functional studies support a model where Ptch prevents Smo activation eitherby removing Smo agonists such as oxysterols from the primary cilium or by increasing the influx of Smo antagonists into the cilium [ XREF_BIBR - XREF_BIBR ] .	Several functional studies support a model where Ptch prevents Smo activation eitherby removing Smo agonists such as oxysterols from the primary cilium or by increasing the influx of Smo antagonists into the cilium [XREF_BIBR - XREF_BIBR].	7	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	7	8	13	14
Despite these findings , the mechanisms by which Ptch1 suppresses Smo activity and by which Hh inactivates this inhibitory function of Ptch1 remain unclear .	Despite these findings, the mechanisms by which Ptch1 suppresses Smo activity and by which Hh inactivates this inhibitory function of Ptch1 remain unclear.	8	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	8	9	10	11
In the absence of Hh ligands , PTCH inhibits SMO and rejects its entry to the cilium where it is believed to inhibit various protein kinases like PKA , GSK-3b and CK1 [ XREF_BIBR ] .	In the absence of Hh ligands, PTCH inhibits SMO and rejects its entry to the cilium where it is believed to inhibit various protein kinases like PKA, GSK-3b and CK1 [XREF_BIBR].	7	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	7	8	9	10
Binding of Shh to Ptch1 alleviates the Ptch1 inhibition of Smo , allowing the signal to propagate to three Gli proteins , the transcriptional effectors of the pathway , and activate the expression of target genes , including pathway components Ptch1 and Gli1 themselves .	Binding of Shh to Ptch1 alleviates the Ptch1 inhibition of Smo, allowing the signal to propagate to three Gli proteins, the transcriptional effectors of the pathway, and activate the expression of target genes, including pathway components Ptch1 and Gli1 themselves.	7	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	10	11
Further studies confirmed that Ptch inhibits Smo activity when hedgehog ligands are absent .	Further studies confirmed that Ptch inhibits Smo activity when hedgehog ligands are absent.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	4	5	6	7
Moreover , a truncated Smo molecule lacking the CRD can still be repressed by over-produced Ptch1 and remains weakly responsive to Shh [ XREF_BIBR , XREF_BIBR ] .	Moreover, a truncated Smo molecule lacking the CRD can still be repressed by over-produced Ptch1 and remains weakly responsive to Shh [XREF_BIBR, XREF_BIBR].	4	16	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	15	16	4	5
When SHH protein is not present , PTCH 1 inhibits the activity of SMO , which is a key activator of the pathway , thus preventing expression of target genes , such as GLI-1 .	When SHH protein is not present, PTCH 1 inhibits the activity of SMO, which is a key activator of the pathway, thus preventing expression of target genes, such as GLI-1.	7	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	7	8	13	14
In the absence of the Hh ligand , PTCH1 inhibits SMO , causing cleavage of GLI1 to the N-terminal repressor form .	In the absence of the Hh ligand, PTCH1 inhibits SMO, causing cleavage of GLI1 to the N-terminal repressor form.	8	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	8	9	10	11
Upon Hh binding to PTCH1 , SMO repression by PTCH1 is alleviated , SMO translocates to the primary cilium and signaling is transduced , leading to activation and nuclear translocation of GLI transcription factors ( see XREF_FIG and ) .	Upon Hh binding to PTCH1, SMO repression by PTCH1 is alleviated, SMO translocates to the primary cilium and signaling is transduced, leading to activation and nuclear translocation of GLI transcription factors (see XREF_FIG and).	6	10	repression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	9	10	6	7
Once Ptch1 is bound to active Hh ligands , the inhibition of Smo by Ptch1 is released , allowing Smo to signal downstream , eventually leading to activation of Gli family transcription factors ( Gli2 and Gli3 ) to regulate target gene expression .	Once Ptch1 is bound to active Hh ligands, the inhibition of Smo by Ptch1 is released, allowing Smo to signal downstream, eventually leading to activation of Gli family transcription factors (Gli2 and Gli3) to regulate target gene expression.	10	15	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	14	15	12	13
Consistent with this notion it was proposed that PTC1 activity either increases the concentration of an inhibitor of SMO or decreases the level of a SMO agonist .	Consistent with this notion it was proposed that PTC1 activity either increases the concentration of an inhibitor of SMO or decreases the level of a SMO agonist.	8	19	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTC1	PTC1	PTC1	SMO	SMO	SMO	8	9	18	19
In absence of HH ligands , PTCH inhibits pathway activation by preventing SMO to enter the cilium .	In absence of HH ligands, PTCH inhibits pathway activation by preventing SMO to enter the cilium.	6	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	6	7	12	13
The precise molecular mechanism by which Ptch inhibits Smo has not been established , with data suggesting a range of possibilities from direct physical interactions of the two proteins , to formation of a membrane channel by Ptch via its sterol binding domain that is required for inhibition of Smo .	The precise molecular mechanism by which Ptch inhibits Smo has not been established, with data suggesting a range of possibilities from direct physical interactions of the two proteins, to formation of a membrane channel by Ptch via its sterol binding domain that is required for inhibition of Smo.	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	8	9
After SSH binding , PTCH inhibition of SMO is released , with resultant phosphorylation and nuclear translocation of the zinc finger ( ZF ) glioma associated transcription factors GLI1 , GLI2 , and GLI3 , which are terminal effectors of SHh signaling ( XREF_FIG ) .	After SSH binding, PTCH inhibition of SMO is released, with resultant phosphorylation and nuclear translocation of the zinc finger (ZF) glioma associated transcription factors GLI1, GLI2, and GLI3, which are terminal effectors of SHh signaling (XREF_FIG).	4	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	4	5	7	8
In the absence of ligand , Ptch1 inhibits Smoothened ( Smo ) , a potent pathway activator .	In the absence of ligand, Ptch1 inhibits Smoothened (Smo), a potent pathway activator.	6	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	6	7	10	11
In the unbound state , PTCH1 inhibits smoothened ( SMO ) , a G protein coupled phosphoprotein receptor , presumably by preventing its localization to the cell surface .	In the unbound state, PTCH1 inhibits smoothened (SMO), a G protein coupled phosphoprotein receptor, presumably by preventing its localization to the cell surface.	5	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	5	6	9	10
PTCH , when active , constitutively inhibits SMO and thus downstream transcription factors like GLI-1 , GLI-2 , GLI-3 , as well as other genes involved in cell proliferation or survival ( e.g ., BCL-2 , BCL-X L ) [ XREF_BIBR ] .	PTCH, when active, constitutively inhibits SMO and thus downstream transcription factors like GLI-1, GLI-2, GLI-3, as well as other genes involved in cell proliferation or survival (e.g., BCL-2, BCL-X L) [XREF_BIBR].	0	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	0	1	7	8
In the absence of an Hh ligand , PTCH causes suppression of SMO XREF_BIBR , XREF_BIBR ; however , upon ligand binding to PTCH , SMO protein translocates into the primary cilium , and leads to the activation of transcription factor GLI1 , which then translocates to the nucleus , leading to the expression of Hh target genes XREF_BIBR , XREF_BIBR .	In the absence of an Hh ligand, PTCH causes suppression of SMO XREF_BIBR, XREF_BIBR; however, upon ligand binding to PTCH, SMO protein translocates into the primary cilium, and leads to the activation of transcription factor GLI1, which then translocates to the nucleus, leading to the expression of Hh target genes XREF_BIBR, XREF_BIBR.	8	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	8	9	12	13
This 3beta-hydroxysteroid translocation seems important for the intercellular repression of Smo by Ptch1 , because in the presence of 3beta-hydroxysteroid synthesis inhibitors Ptch1 was no longer capable of repressing Smo , whereas artificial stimulation of 3beta-hydroxysteroid biosynthesis by using mevalonate supplementation enhanced the inhibitory potential of Ptch1 on Smo .	This 3beta-hydroxysteroid translocation seems important for the intercellular repression of Smo by Ptch1, because in the presence of 3beta-hydroxysteroid synthesis inhibitors Ptch1 was no longer capable of repressing Smo, whereas artificial stimulation of 3beta-hydroxysteroid biosynthesis by using mevalonate supplementation enhanced the inhibitory potential of Ptch1 on Smo.	8	13	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	12	13	10	11
In the absence of Hedgehog , the twelve-transmembrane protein Patched ( Ptch ) represses the activity of the seven-transmembrane protein Smoothened ( Smo ) .	In the absence of Hedgehog, the twelve-transmembrane protein Patched (Ptch) represses the activity of the seven-transmembrane protein Smoothened (Smo).	11	23	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	11	12	22	23
PTCH1 activity inhibits the function of the 7-transmembrane G-couple-receptor-like protein Smoothened ( SMOH ) .	PTCH1 activity inhibits the function of the 7-transmembrane G-couple-receptor-like protein Smoothened (SMOH).	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMOH	SMOH	SMOH	0	1	12	13
PTC1 acts catalytically to inhibit SMO through a mediator molecule , which was postulated to be a lipid given the homology of PTC1 with bacterial permeases of the resistance-nodulation-division ( RND ) family that transport lipophilic toxins [ XREF_BIBR , XREF_BIBR ] .	PTC1 acts catalytically to inhibit SMO through a mediator molecule, which was postulated to be a lipid given the homology of PTC1 with bacterial permeases of the resistance-nodulation-division (RND) family that transport lipophilic toxins [XREF_BIBR, XREF_BIBR].	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTC1	PTC1	PTC1	SMO	SMO	SMO	0	1	5	6
The similarities to the Fsp-Cre ; Ptch1 fl/fl phenotypes suggest that Ptch1 inhibits Smo to block abnormal histology [ XREF_BIBR ] .	The similarities to the Fsp-Cre; Ptch1 fl/fl phenotypes suggest that Ptch1 inhibits Smo to block abnormal histology [XREF_BIBR].	11	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	11	12	13	14
Although the underlying mechanism of Ptch mediated Smo inhibition remains unclear , an intermediary small molecule regulated by Ptch may modulate Smo activity .	Although the underlying mechanism of Ptch mediated Smo inhibition remains unclear, an intermediary small molecule regulated by Ptch may modulate Smo activity.	3	8	mediated	Positive_early_activation	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	5	6	7	8
Additionally , SMO inhibition by PTCH1 occurred through a nonstoichiometric , catalytic mechanism , indicating that this inhibition was less dependent on the dose of the PTCH1 protein .	Additionally, SMO inhibition by PTCH1 occurred through a nonstoichiometric, catalytic mechanism, indicating that this inhibition was less dependent on the dose of the PTCH1 protein.	2	6	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	5	6	2	3
The lack of PTCH repression allows SMO to initiate a series of intracellular events that culminate in the activation of the GLI ( Glioma ) family of zinc finger transcription factors , i.e ., GLI1 , GLI2 and GLI3 [ XREF_BIBR , XREF_BIBR ] .	The lack of PTCH repression allows SMO to initiate a series of intracellular events that culminate in the activation of the GLI (Glioma) family of zinc finger transcription factors, i.e., GLI1, GLI2 and GLI3 [XREF_BIBR, XREF_BIBR].	3	8	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	3	4	6	7
In the target cell , Shh signalling is regulated by Patched ( Ptch ) , a transmembrane protein that inhibits Smoothened ( Smo ) 10 .	In the target cell, Shh signalling is regulated by Patched (Ptch), a transmembrane protein that inhibits Smoothened (Smo) 10.	8	24	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	12	13	22	23
In the absence of Shh , Ptch1 inhibits Smo localisation in primary cilia .	In the absence of Shh, Ptch1 inhibits Smo localisation in primary cilia.	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	6	7	8	9
In the absence of HH , PTCH inhibits SMO .	In the absence of HH, PTCH inhibits SMO.	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	6	7	8	9
In the absence of SHH , PTCH inhibits SMO , whereas the binding of SHH to PTCH suspends this inhibition , thereby activating zinc finger DNA binding proteins GLI1 , GLI2 and GLI3 .	In the absence of SHH, PTCH inhibits SMO, whereas the binding of SHH to PTCH suspends this inhibition, thereby activating zinc finger DNA binding proteins GLI1, GLI2 and GLI3.	6	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	6	7	8	9
In the absence of Hh ligands , Ptch1 inhibits the signaling activity of Smoothened ( Smo ) , a seven trans-membrane protein that shares sequence homology with G protein coupled receptors .	In the absence of Hh ligands, Ptch1 inhibits the signaling activity of Smoothened (Smo), a seven trans-membrane protein that shares sequence homology with G protein coupled receptors.	7	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	15	16
Ptch1 suppresses Shh signaling by antagonizing the function of Smoothened ( Smo ) , a 7-pass transmembrane protein with an essential role in Hedgehog signal transduction .	Ptch1 suppresses Shh signaling by antagonizing the function of Smoothened (Smo), a 7-pass transmembrane protein with an essential role in Hedgehog signal transduction.	0	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	0	1	11	12
In the canonical Hh pathway , in the absence of the Hh ligand , Ptch inhibits Smo , causing cleavage of Gli to the N-terminal repressor form .	In the canonical Hh pathway, in the absence of the Hh ligand, Ptch inhibits Smo, causing cleavage of Gli to the N-terminal repressor form.	14	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	14	15	16	17
In the absence of Hh ligand , the receptor Ptch1 with coreceptor binding proteins Cdon , Boc , and Gas1 inhibits Smo ; but when secreted Hh binds to Ptch1 , the repression of Smo is released , and signal transduction is initiated .	In the absence of Hh ligand, the receptor Ptch1 with coreceptor binding proteins Cdon, Boc, and Gas1 inhibits Smo; but when secreted Hh binds to Ptch1, the repression of Smo is released, and signal transduction is initiated.	7	42	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	9	10	21	22
Upon Shh binding , Ptch1 no longer represses Smo .	Upon Shh binding, Ptch1 no longer represses Smo.	4	9	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	8	9
Ptc1 localized to cilia and inhibited Smoothened ( Smo ) by preventing its accumulation within cilia .	Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia.	0	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	0	1	8	9
Ptch1 suppresses the Hh pathway , at least in part , by preventing the trafficking of Smo into the primary cilium XREF_BIBR .	Ptch1 suppresses the Hh pathway, at least in part, by preventing the trafficking of Smo into the primary cilium XREF_BIBR.	0	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	0	1	16	17
In the absence of ligand , Ptch inhibits the migration of Smoothened ( Smo ) to the membrane , keeping Smo inactive inside the cell .	In the absence of ligand, Ptch inhibits the migration of Smoothened (Smo) to the membrane, keeping Smo inactive inside the cell.	6	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	13	14
9 PTCH1 , a 12-transmembrane domain protein , normally functions to block Shh signaling by antagonizing the activity of Smoothened ( SMO ) , a seven domain transmembrane protein , preventing its migration into the cilium .	9 PTCH1, a 12-transmembrane domain protein, normally functions to block Shh signaling by antagonizing the activity of Smoothened (SMO), a seven domain transmembrane protein, preventing its migration into the cilium.	0	28	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	1	2	21	22
The PTCH1 receptor negatively regulates signaling in the absence of Hh ligands by preventing the SMO receptor from activating downstream signaling .	The PTCH1 receptor negatively regulates signaling in the absence of Hh ligands by preventing the SMO receptor from activating downstream signaling.	1	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	1	2	15	16
In a resting state , PTCH is expressed on the plasma membrane and acts to repress Smo activity .	In a resting state, PTCH is expressed on the plasma membrane and acts to repress Smo activity.	5	17	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH is expressed	ptch	Smo	Smo	smo	5	6	16	17
When no ligand is bound , the Ptch receptor is thought to inhibit Smoothened ( Smo ) , the network ' s main signal transducer , catalytically .	When no ligand is bound, the Ptch receptor is thought to inhibit Smoothened (Smo), the network 's main signal transducer, catalytically.	7	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	7	8	15	16
In the presence of Hh , the repression of SMO by PTCH1 is however lifted , triggering activation of downstream Shh effectors , the glioma associated ( Gli ) family of transcription factors .	In the presence of Hh, the repression of SMO by PTCH1 is however lifted, triggering activation of downstream Shh effectors, the glioma associated (Gli) family of transcription factors.	7	12	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	11	12	9	10
Without HH ligand , PTCH1 represses the activity of smoothened ( SMO ) , a seven-pass G-protein-coupled membrane protein , through an unknown mechanism .	Without HH ligand, PTCH1 represses the activity of smoothened (SMO), a seven-pass G-protein-coupled membrane protein, through an unknown mechanism.	4	18	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	4	5	11	12
In the absence of hedgehog ligand , the PTCH receptor inhibits the activation of SMO and subsequent activation of downstream effector target molecules such as Gli-1 ( glioma associated oncogene homolog 1 ) , a zinc finger transcription factor regulating the expression of genes associated with proliferation , angiogenesis , stemness and metastasis .	In the absence of hedgehog ligand, the PTCH receptor inhibits the activation of SMO and subsequent activation of downstream effector target molecules such as Gli-1 (glioma associated oncogene homolog 1), a zinc finger transcription factor regulating the expression of genes associated with proliferation, angiogenesis, stemness and metastasis.	8	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	8	9	14	15
In the absence of ligand binding , PTCH inhibits smoothened ( Smo ) , a signal transducer protein .	In the absence of ligand binding, PTCH inhibits smoothened (Smo), a signal transducer protein.	7	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	Smo	Smo	Smo	7	8	11	12
In the absence of Hh ligands , PTCH represses the accumulation of SMO on the primary cilia , thus resulting in the inactivation of the downstream cascade .	In the absence of Hh ligands, PTCH represses the accumulation of SMO on the primary cilia, thus resulting in the inactivation of the downstream cascade.	7	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	7	8	12	13
In the absence of HH ligand , a membrane receptor protein called patched ( PTCH ) represses the activity of another transmembrane receptor smoothened ( SMO ) .	In the absence of HH ligand, a membrane receptor protein called patched (PTCH) represses the activity of another transmembrane receptor smoothened (SMO).	14	26	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	14	15	25	26
In these cells , pathway activity is high due to the absence of Ptch1 mediated inhibition of Smo .	In these cells, pathway activity is high due to the absence of Ptch1 mediated inhibition of Smo.	11	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	13	14	17	18
In the absence of Shh , Ptch1 normally represses the activity of Smoothened ( Smo ) , the seven-pass transmembrane spanning receptor which is the major signaling component and switch in this pathway .	In the absence of Shh, Ptch1 normally represses the activity of Smoothened (Smo), the seven-pass transmembrane spanning receptor which is the major signaling component and switch in this pathway.	6	21	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	6	7	14	15
In the absence of a hedgehog ligand , Ptch-1 constitutively inhibits the transmembrane protein smoothened ( Smo ) and renders the pathway inactive .	In the absence of a hedgehog ligand, Ptch-1 constitutively inhibits the transmembrane protein smoothened (Smo) and renders the pathway inactive.	8	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch-1	Ptch-1	Ptch-1	Smo	Smo	Smo	8	9	16	17
The pathway is activated when HH ligands bind PTCH1 to relieve PTCH mediated SMO inhibition at the base of primary cilium [ XREF_BIBR ] .	The pathway is activated when HH ligands bind PTCH1 to relieve PTCH mediated SMO inhibition at the base of primary cilium [XREF_BIBR].	11	14	mediated	Positive_early_activation	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	11	12	13	14
In the absence of hedgehog protein , Ptch inhibits the activity of Smo .	In the absence of hedgehog protein, Ptch inhibits the activity of Smo.	7	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	7	8	12	13
The hypothesis that one molecule of Ptch inhibits one molecule of Smo by direct binding has been ruled out .	The hypothesis that one molecule of Ptch inhibits one molecule of Smo by direct binding has been ruled out.	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	11	12
Shh binding relieves Ptch1 mediated inhibition of Smoothened homolog ( Smo ) .	Shh binding relieves Ptch1 mediated inhibition of Smoothened homolog (Smo).	3	9	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smoothened homolog	Smoothened homolog	Smoothened homolog	3	4	7	9
In the absence of Hh proteins , the 12-transmembrane receptor Ptc1 inhibits activity of smoothened ( Smo ) , a 7-transmembrane protein that regulates activation of the Glioma associated oncogene homologue ( Gli ) family of transcription factors ; Gli1 , Gli2 , and Gli3 [ XREF_BIBR ] .	In the absence of Hh proteins, the 12-transmembrane receptor Ptc1 inhibits activity of smoothened (Smo), a 7-transmembrane protein that regulates activation of the Glioma associated oncogene homologue (Gli) family of transcription factors; Gli1, Gli2, and Gli3 [XREF_BIBR].	7	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	10	11	16	17
In the absence of Hh signaling , the twelve-transmembrane receptor ( 12TMR ) Patched1 ( Ptch1 ) localizes to the PC and suppresses the activity of the 7TMR Smo [ XREF_BIBR ] .	In the absence of Hh signaling, the twelve-transmembrane receptor (12TMR) Patched1 (Ptch1) localizes to the PC and suppresses the activity of the 7TMR Smo [XREF_BIBR].	13	30	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	15	16	28	29
Under physiological conditions , the transmembrane protein Ptch1 inhibits the seven-span transmembrane protein Smoothened ( Smo ) .	Under physiological conditions, the transmembrane protein Ptch1 inhibits the seven-span transmembrane protein Smoothened (Smo).	4	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	15	16
In the absence of HH ligand , PTCH1 sits in the cilium and suppresses SMO activity and localization .	In the absence of HH ligand, PTCH1 sits in the cilium and suppresses SMO activity and localization.	7	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	7	8	14	15
Despite intense efforts to understand Ptch function , the detailed mechanisms of how Ptch represses Smo in the absence of ligand is still elusive .	Despite intense efforts to understand Ptch function, the detailed mechanisms of how Ptch represses Smo in the absence of ligand is still elusive.	13	18	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	13	14	15	16
53 In the absence of the hedgehog ligand , the Ptch receptor inhibits the Smo co-receptor , which remains in vesicles at the base of the primary cilium and , therefore , far from the transcription factors of Gli-1 , 2 , and 3 , which are abundant on the surface of this organelle .	53 In the absence of the hedgehog ligand, the Ptch receptor inhibits the Smo co-receptor, which remains in vesicles at the base of the primary cilium and, therefore, far from the transcription factors of Gli-1, 2, and 3, which are abundant on the surface of this organelle.	10	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	10	11	14	15
In the absence of SHH , the 12- transmembrane receptor Patched-1 ( PTCH1 ) represses the 7- transmembrane protein Smoothened ( SMO ) , which regulates activation of the GLI family of transcription factors ( GLI1 , GLI2 and GLI3 ) [ XREF_BIBR ] .	In the absence of SHH, the 12- transmembrane receptor Patched-1 (PTCH1) represses the 7- transmembrane protein Smoothened (SMO), which regulates activation of the GLI family of transcription factors (GLI1, GLI2 and GLI3) [XREF_BIBR].	10	42	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	12	13	21	22
Upon binding of the HH morphogen , Ptc1 undergoes a conformational change , and is no longer able to suppress Smo activity .	Upon binding of the HH morphogen, Ptc1 undergoes a conformational change, and is no longer able to suppress Smo activity.	7	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	7	8	20	21
Upon Hh ligand binding , Ptc1 undergoes a conformational change and no longer suppresses Smo , triggering a downstream signaling cascade culminating in the modulation of Hh target gene expression via the three vertebrate Gli transcription factors .	Upon Hh ligand binding, Ptc1 undergoes a conformational change and no longer suppresses Smo, triggering a downstream signaling cascade culminating in the modulation of Hh target gene expression via the three vertebrate Gli transcription factors.	5	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	5	6	14	15
Upon binding of a Hh ligand , Sonic , Indian or Desert Hedgehog ( Shh , Ihh , Dhh ) , Ptc1 is inactivated , unleashing Smo and allowing the Gli transcription factors to initiate target gene transcription XREF_BIBR , XREF_BIBR .	Upon binding of a Hh ligand, Sonic, Indian or Desert Hedgehog (Shh, Ihh, Dhh), Ptc1 is inactivated, unleashing Smo and allowing the Gli transcription factors to initiate target gene transcription XREF_BIBR, XREF_BIBR.	21	27	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	21	22	26	27
In the absence of HH ligands , the PTCH receptor inhibits the activity of the 7-pass transmembrane protein Smoothened ( SMO ) , which acts as a positive regulator of the pathway .	In the absence of HH ligands, the PTCH receptor inhibits the activity of the 7-pass transmembrane protein Smoothened (SMO), which acts as a positive regulator of the pathway.	8	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	8	9	20	21
In the absence of hedgehog ligands , Ptch1 represses the activity of Smoothened ( Smo ) which mediates all vertebrate signaling .	In the absence of hedgehog ligands, Ptch1 represses the activity of Smoothened (Smo) which mediates all vertebrate signaling.	7	17	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	14	15
To determine whether Ptch inhibits Smo strictly in the same cell or also mediates non-cell-autonomous Smo inhibition , we generated genetically mosaic neuralized embryoid bodies ( nEBs ) from mouse embryonic stem cells ( mESCs ) .	To determine whether Ptch inhibits Smo strictly in the same cell or also mediates non-cell-autonomous Smo inhibition, we generated genetically mosaic neuralized embryoid bodies (nEBs) from mouse embryonic stem cells (mESCs).	3	16	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	3	4	15	16
Substantial evidence in the literature suggests that Ptch1 inhibition of Smo occurs by way of small molecular intermediates that may be transported by Ptch1 through the membrane .	Substantial evidence in the literature suggests that Ptch1 inhibition of Smo occurs by way of small molecular intermediates that may be transported by Ptch1 through the membrane.	7	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	10	11
In the absence of ligand , Ptch-1 represses Smo , thereby silencing the Hh signaling pathway .	In the absence of ligand, Ptch-1 represses Smo, thereby silencing the Hh signaling pathway.	6	11	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch-1	Ptch-1	Ptch-1	Smo	Smo	Smo	6	7	8	9
The regulatory relationship between Ptch and Smo has been the subject of much study , resulting in the following model : ( 1 ) Ptch in its unbound state inhibits Smo cell autonomously ( 2 ) Hh ligand bound to Ptch releases this inhibition and ( 3 ) uninhibited Smo redistributes in the cell and activates transcription of target genes through downstream factors .	The regulatory relationship between Ptch and Smo has been the subject of much study, resulting in the following model : (1) Ptch in its unbound state inhibits Smo cell autonomously (2) Hh ligand bound to Ptch releases this inhibition and (3) uninhibited Smo redistributes in the cell and activates transcription of target genes through downstream factors.	24	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	24	25	30	31
Hh stimulation abrogates the inhibition of Smo by Ptc1 .	Hh stimulation abrogates the inhibition of Smo by Ptc1.	2	9	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	8	9	6	7
In the absence of Hh ligands , Ptch1 inhibits the function of Smo , a 7-pass TM protein that is encoded by a human oncogene .	In the absence of Hh ligands, Ptch1 inhibits the function of Smo, a 7-pass TM protein that is encoded by a human oncogene.	7	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	12	13
Ptch is a 12-pass membrane protein that binds directly to Shh ligands and inhibits Smo function .	Ptch is a 12-pass membrane protein that binds directly to Shh ligands and inhibits Smo function.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	0	1	14	15
How does Ptch1 inhibit Smo ?	How does Ptch1 inhibit Smo?	2	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	2	3	4	5
In the absence of HH ligand , PTCH is localized to primary cilia and constitutively suppresses the activity of Smoothened ( SMO ) , a 7-pass transmembrane spanning protein , which is a member of the G-protein-coupled receptor superfamily [ XREF_BIBR ] ( XREF_FIG ) .	In the absence of HH ligand, PTCH is localized to primary cilia and constitutively suppresses the activity of Smoothened (SMO), a 7-pass transmembrane spanning protein, which is a member of the G-protein-coupled receptor superfamily [XREF_BIBR] (XREF_FIG).	7	26	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	7	8	21	22
In the absence of Hh , Ptc1 suppresses the activity of Smoothened ( Smo ) , another transmembrane protein .	In the absence of Hh, Ptc1 suppresses the activity of Smoothened (Smo), another transmembrane protein.	6	18	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	6	7	13	14
In the absence of Hh ligands , the Hh receptor Patched ( Ptch ) locates to the cilia and prevents ciliary accumulation of Smo to repress the pathway .	In the absence of Hh ligands, the Hh receptor Patched (Ptch) locates to the cilia and prevents ciliary accumulation of Smo to repress the pathway.	9	24	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	12	13	23	24
PTCH1 normally inhibits the signaling activity of SMO .	PTCH1 normally inhibits the signaling activity of SMO.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	0	1	7	8
PTCH repression of SMOH is relieved upon binding of SHH to PTCH resulting in the activation of Gli1 and Gli2 and several other genes including , for example , TGF-beta , Wnt , BCL-2 ( Regl et al , 2002 ) , basonuclin ( Cui et al , 2004 ) and the forkhead transcription factors FOXMI ( Teh et al , 2002 ) and FOXE1 ( Eichberger et al , 2004 ) .	PTCH repression of SMOH is relieved upon binding of SHH to PTCH resulting in the activation of Gli1 and Gli2 and several other genes including, for example, TGF-beta, Wnt, BCL-2 (Regl et al, 2002), basonuclin (Cui et al, 2004) and the forkhead transcription factors FOXMI (Teh et al, 2002) and FOXE1 (Eichberger et al, 2004).	0	4	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMOH	SMOH	SMOH	0	1	3	4
This relieves the Ptc1 mediated suppression of Smoothened ( Smo ) , triggering a complex downstream signal cascade [ Reviewed in [ XREF_BIBR ] ] .	This relieves the Ptc1 mediated suppression of Smoothened (Smo), triggering a complex downstream signal cascade [Reviewed in [XREF_BIBR]].	2	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	3	4	9	10
When there is no ligand bound to Ptch , Ptch inhibits Smo and keeps the downstream pathway inactivated .	When there is no ligand bound to Ptch, Ptch inhibits Smo and keeps the downstream pathway inactivated.	9	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	9	10	11	12
In the absence of Hh ligand , Ptch inhibits the activity of the downstream effector Smoothened ( Smo ) .	In the absence of Hh ligand, Ptch inhibits the activity of the downstream effector Smoothened (Smo).	7	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	7	8	17	18
Furthermore , cholesterol synergizes with Shh to activate Smo , as expected for an endogenous Smo ligand that is negatively regulated by Ptch1 .	Furthermore, cholesterol synergizes with Shh to activate Smo, as expected for an endogenous Smo ligand that is negatively regulated by Ptch1.	15	23	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	22	23	15	16
The expression of Ptc1 is more extensive , as its function is to combine Hh and inhibit Smo .	The expression of Ptc1 is more extensive, as its function is to combine Hh and inhibit Smo.	1	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	expression of Ptc1	ptc1	Smo	Smo	smo	3	4	17	18
In the absence of Sonic Hedgehog , the role of normal Ptch1 is to inhibit Smo .	In the absence of Sonic Hedgehog, the role of normal Ptch1 is to inhibit Smo.	8	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	11	12	15	16
Without participation of Shh protein , Ptch1 ( a 12 transmembrane-helix receptor protein and target of Shh ) inhibits the Shh pathway by assembling in cilia and excluding Smo protein ( Marigo et al ., 1996 ) .	Without participation of Shh protein, Ptch1 (a 12 transmembrane-helix receptor protein and target of Shh) inhibits the Shh pathway by assembling in cilia and excluding Smo protein (Marigo et al., 1996).	6	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	6	7	28	29
In the absence of the Hh ligand , Ptch inhibits Smo through an unknown mechanism , ensuring that signals are not relayed to the cytoplasm .	In the absence of the Hh ligand, Ptch inhibits Smo through an unknown mechanism, ensuring that signals are not relayed to the cytoplasm.	8	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	8	9	10	11
Conversely , medium conditioned by cells transfected with Ptch1 siRNA ( so lacking endogenous Ptch1 expression ) elevated Gli reporter activity significantly above medium that was conditioned by control cells , demonstrating that Ptch1 overexpression is not a prerequisite for observing this cell non autonomous repression of Smo by Ptch1 .	Conversely, medium conditioned by cells transfected with Ptch1 siRNA (so lacking endogenous Ptch1 expression) elevated Gli reporter activity significantly above medium that was conditioned by control cells, demonstrating that Ptch1 overexpression is not a prerequisite for observing this cell non autonomous repression of Smo by Ptch1.	40	50	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	49	50	47	48
Binding of the Hh ligand to PTCH1 receptor ( or the presence of a mutation in either the PTCH1 or SMO signal transducer ) removes the suppression of SMO by PTCH1 .	Binding of the Hh ligand to PTCH1 receptor (or the presence of a mutation in either the PTCH1 or SMO signal transducer) removes the suppression of SMO by PTCH1.	24	31	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	30	31	28	29
The failure of SmoDeltaCRD to become fully activated in response to Hh may point instead to a more indirect facilitative CRD function in stabilizing an active Smo conformation induced by loss of Ptch1 mediated repression .	The failure of SmoDeltaCRD to become fully activated in response to Hh may point instead to a more indirect facilitative CRD function in stabilizing an active Smo conformation induced by loss of Ptch1 mediated repression.	26	33	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Ptch1	loss of Ptch1	ptch1	Smo	Smo	smo	32	33	26	27
A critical negative regulator of the Shh pathway is the tumor suppressor Ptch1 , which suppresses smoothened ( Smo ) dependent activation of Gli1 transcriptional activity .	A critical negative regulator of the Shh pathway is the tumor suppressor Ptch1, which suppresses smoothened (Smo) dependent activation of Gli1 transcriptional activity.	3	21	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	12	13	18	19
In the absence of the Hh ligand , PTCH represses the activity of Smoothened ( SMO ) , a G like protein coupled receptor , by preventing its localization to the primary cilium .	In the absence of the Hh ligand, PTCH represses the activity of Smoothened (SMO), a G like protein coupled receptor, by preventing its localization to the primary cilium.	8	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	8	9	15	16
Shh signaling is activated by binding between Shh and its receptor , Patched ( Ptch ) , which relieves the Ptch mediated repression of smoothened ( Smo ) , a downstream membrane protein related to G protein coupled receptors .	Shh signaling is activated by binding between Shh and its receptor, Patched (Ptch), which relieves the Ptch mediated repression of smoothened (Smo), a downstream membrane protein related to G protein coupled receptors.	10	32	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	14	15	26	27
In the absence of Hh , Ptc1 represses Smo activity .	In the absence of Hh, Ptc1 represses Smo activity.	6	9	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	6	7	8	9
In the absence of Hh ligand , Ptch1 inhibits Smoothened ( Smo ) , a seven-pass transmembrane protein that functions as a potent pathway activator .	In the absence of Hh ligand, Ptch1 inhibits Smoothened (Smo), a seven-pass transmembrane protein that functions as a potent pathway activator.	7	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	11	12
PTCH1 is localized to the primary cilia and inhibits the accumulation of the constitutively active transmembrane protein SMO within the cilia .	PTCH1 is localized to the primary cilia and inhibits the accumulation of the constitutively active transmembrane protein SMO within the cilia.	0	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	0	1	17	18
In the absence of ligand binding , PTCH1 inhibits SMO , a membrane bound G-protein-coupled receptor like molecule and a positive regulator of Hh signals .	In the absence of ligand binding, PTCH1 inhibits SMO, a membrane bound G-protein-coupled receptor like molecule and a positive regulator of Hh signals.	7	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	7	8	9	10
Upon binding of Shh to Ptc1 , the repression of Smo by Ptc1 is relieved , allowing Smo to enter the cilium and Ptc1 to leave the cilium .	Upon binding of Shh to Ptc1, the repression of Smo by Ptc1 is relieved, allowing Smo to enter the cilium and Ptc1 to leave the cilium.	8	13	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	12	13	10	11
In the absence of Hh signaling , Ptch1 localizes to the PC and suppresses Smo by unknown mechanisms .	In the absence of Hh signaling, Ptch1 localizes to the PC and suppresses Smo by unknown mechanisms.	7	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	14	15
In the absence of hedgehog ligands ( which includes Sonic Hedgehog , Indian Hedgehog and Desert Hedgehog ) , Ptch associates with Smoothened ( Smo ) and blocks Smo function [ XREF_BIBR ] .	In the absence of hedgehog ligands (which includes Sonic Hedgehog, Indian Hedgehog and Desert Hedgehog), Ptch associates with Smoothened (Smo) and blocks Smo function [XREF_BIBR].	19	29	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	19	20	28	29
Once Hh binds to its receptor , Ptch no longer represses Smo and consequently Gli2 and Gli3 are not cleaved , thus activating Hh target genes [ XREF_BIBR ] .	Once Hh binds to its receptor, Ptch no longer represses Smo and consequently Gli2 and Gli3 are not cleaved, thus activating Hh target genes [XREF_BIBR].	7	12	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	7	8	11	12
PTCH inhibits SMO , which activates Gli-1 , in turn establishing a negative feedback loop in the presence of SHH signaling [ XREF_BIBR - XREF_BIBR ] .	PTCH inhibits SMO, which activates Gli-1, in turn establishing a negative feedback loop in the presence of SHH signaling [XREF_BIBR - XREF_BIBR].	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	0	1	2	3
In the absence of Sonic Hedgehog ( Shh ) , the transmembrane protein Patched 1 ( Ptch1 ) inhibits Smoothened ( Smo ) in transducing the signal , and as a result , the full-length activator form of Gli3 ( Gli3 FL ) , a transcriptional effector of the Shh signaling pathway , is proteolytically cleaved into the repressor form Gli3 R.	In the absence of Sonic Hedgehog (Shh), the transmembrane protein Patched 1 (Ptch1) inhibits Smoothened (Smo) in transducing the signal, and as a result, the full-length activator form of Gli3 (Gli3 FL), a transcriptional effector of the Shh signaling pathway, is proteolytically cleaved into the repressor form Gli3 R.	14	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	16	17	21	22
The twelve-pass transmembrane receptor patched-1 ( PTCH1 ) inhibits the seven-pass transmembrane G coupled receptor like protein smoothened ( SMO ) .	The twelve-pass transmembrane receptor patched-1 (PTCH1) inhibits the seven-pass transmembrane G coupled receptor like protein smoothened (SMO).	4	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	6	7	19	20
In the absence of Hh ligands , Ptch1 suppresses the activity of Smo , which is released upon Hh binding to Ptch1 , allowing Smo to activate its downstream targets 1 .	In the absence of Hh ligands, Ptch1 suppresses the activity of Smo, which is released upon Hh binding to Ptch1, allowing Smo to activate its downstream targets 1.	7	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	12	13
To test whether Ptch1 mediates the inhibitory effects of DAPTon Smo , we measured the impact of DAPT addition to Ptch1 LacZ and LacZ mutant MEFs .	To test whether Ptch1 mediates the inhibitory effects of DAPTon Smo, we measured the impact of DAPT addition to Ptch1 LacZ and LacZ mutant MEFs.	3	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	3	4	10	11
In some way , Ptc1 prevents the enrichment of Smo within the ciliary membrane , which is required for signal propagation .	In some way, Ptc1 prevents the enrichment of Smo within the ciliary membrane, which is required for signal propagation.	4	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	4	5	9	10
Once bound by ligand , however , PTCH1 no longer inhibits SMO , allowing SMO to positively regulate mobilization of the otherwise latent zinc-finger transcription factor GLI2 , residing in the cilia , to the nucleus where GLI2 transactivates the GLI1 promoter XREF_BIBR - XREF_BIBR .	Once bound by ligand, however, PTCH1 no longer inhibits SMO, allowing SMO to positively regulate mobilization of the otherwise latent zinc-finger transcription factor GLI2, residing in the cilia, to the nucleus where GLI2 transactivates the GLI1 promoter XREF_BIBR - XREF_BIBR.	7	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	7	8	11	12
An essential part of hedgehog pathway activation involves release of Ptc1 repression of Smo .	An essential part of hedgehog pathway activation involves release of Ptc1 repression of Smo.	10	14	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	10	11	13	14
The correlation we observe in our data set between increased expression of the PTCH1 gene and association with lowered BMD is consistent with the mouse work ; increased levels of PTCH1 represses SMO and Hh signalling which in turn results in reduced bone mass .	The correlation we observe in our data set between increased expression of the PTCH1 gene and association with lowered BMD is consistent with the mouse work; increased levels of PTCH1 represses SMO and Hh signalling which in turn results in reduced bone mass.	28	35	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	levels of PTCH1	ptch1	SMO	SMO	smo	30	31	32	33
In the absence of HH ligands , PTCH inhibits SMO .	In the absence of HH ligands, PTCH inhibits SMO.	7	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	7	8	9	10
In the absence of Hhs , the heptahelical protein Smo is inhibited by the Ptch Hh receptors .	In the absence of Hhs, the heptahelical protein Smo is inhibited by the Ptch Hh receptors.	6	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	14	15	9	10
Subsequently , Smo ( a 7 transmembrane-helix receptor protein and target protein of Ptch1 ) can no longer be inhibited by Ptch1 and activate Gli1 , the downstream target of the Shh pathway ( van den Heuvel and Ingham , 1996 ) .	Subsequently, Smo (a 7 transmembrane-helix receptor protein and target protein of Ptch1) can no longer be inhibited by Ptch1 and activate Gli1, the downstream target of the Shh pathway (van den Heuvel and Ingham, 1996).	2	23	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	21	22	2	3
In the absence of the Hh ligand , its receptor PTCH inhibits the function of SMO , thereby inactivating the Hh signaling .	In the absence of the Hh ligand, its receptor PTCH inhibits the function of SMO, thereby inactivating the Hh signaling.	8	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	10	11	15	16
According to prevailing models , Ptch inhibits Smo sub-stoichiometrically rather than through a direct binding relationship , by regulating the localization of a Smo regulatory molecule .	According to prevailing models, Ptch inhibits Smo sub-stoichiometrically rather than through a direct binding relationship, by regulating the localization of a Smo regulatory molecule.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	5	6	7	8
In the absence of sonic hedgehog ligand ( Shh ) , the Patched receptor ( PTCH1 ) prevents activation of Smoothened ( SMO ) , allowing Gli proteins to be sequestered by suppressor of fused homolog ( SUFU ) and kinesin family member 7 ( Kif7 ) .	In the absence of sonic hedgehog ligand (Shh), the Patched receptor (PTCH1) prevents activation of Smoothened (SMO), allowing Gli proteins to be sequestered by suppressor of fused homolog (SUFU) and kinesin family member 7 (Kif7).	13	25	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	15	16	22	23
In the absence of Hedgehog ligands , PTC1 inhibits the positive signal transducer smoothened homolog ( SMO ) , allowing proteolytic processing of GLI transcription factors , which generates transcriptional corepressor forms of these proteins .	In the absence of Hedgehog ligands, PTC1 inhibits the positive signal transducer smoothened homolog (SMO), allowing proteolytic processing of GLI transcription factors, which generates transcriptional corepressor forms of these proteins.	7	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTC1	PTC1	PTC1	smoothened homolog	smoothened homolog	smoothened homolog	7	8	13	15
PTCH inhibits the physically separate 7-pass transmembrane receptor Smoothened ( SMO ) by gating the movement of SMO into cilia .	PTCH inhibits the physically separate 7-pass transmembrane receptor Smoothened (SMO) by gating the movement of SMO into cilia.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	0	1	10	11
Unlike traditional receptors , the Ptch receptor is a negative regulator of the pathway : in the absence of ligand , Ptch blocks the activation of another transmembrane protein Smoothened ( Smo ) .	Unlike traditional receptors, the Ptch receptor is a negative regulator of the pathway : in the absence of ligand, Ptch blocks the activation of another transmembrane protein Smoothened (Smo).	21	32	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	21	22	31	32
The mechanism by which Ptch1 represses Smo has been the subject of numerous studies .	The mechanism by which Ptch1 represses Smo has been the subject of numerous studies.	4	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	6	7
One previously published model [ XREF_BIBR ] postulated the following : in the TEB , DHH and IHH ligands abrogate PTCH1 inhibition of SMO , leading to SMO functioning possibly canonically , possibly non canonically as a GPCR coupling with G alphai proteins , whereas in the mature duct , hedgehog signaling is inactive , PTCH1 inhibits SMO , and GLI3 repressor is expressed .	One previously published model [XREF_BIBR] postulated the following : in the TEB, DHH and IHH ligands abrogate PTCH1 inhibition of SMO, leading to SMO functioning possibly canonically, possibly non canonically as a GPCR coupling with G alphai proteins, whereas in the mature duct, hedgehog signaling is inactive, PTCH1 inhibits SMO, and GLI3 repressor is expressed.	55	58	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	55	56	57	58
In the absence of ligand , SMO is inhibited by PTCH1 .	In the absence of ligand, SMO is inhibited by PTCH1.	6	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	10	11	6	7
In the absence of Hh ligand , ciliary Ptch1 suppresses Smo activity and entry into the cilium , allowing the negative regulator Suppressor of Fused ( Sufu ) to inhibit Gli activity ( XREF_FIG ) .	In the absence of Hh ligand, ciliary Ptch1 suppresses Smo activity and entry into the cilium, allowing the negative regulator Suppressor of Fused (Sufu) to inhibit Gli activity (XREF_FIG).	7	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	8	9	10	11
The intermediary Patched ( PTCH1 ) , a 12-pass receptor , antagonizes SMO action in the absence of Hh [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The intermediary Patched (PTCH1), a 12-pass receptor, antagonizes SMO action in the absence of Hh [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	13	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	4	5	12	13
In the absence of Shh , Ptch 1 inhibits the function of another membrane protein smoothened ( Smo ) .	In the absence of Shh, Ptch 1 inhibits the function of another membrane protein smoothened (Smo).	6	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	17	18
In the absence of SHH , the membrane receptor Patched ( PTCH ) inhibits the activity of Smoothened ( SMO ) , a 7-pass transmembrane protein .	In the absence of SHH, the membrane receptor Patched (PTCH) inhibits the activity of Smoothened (SMO), a 7-pass transmembrane protein.	8	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	11	12	19	20
While loss-of-function mutations in PTCH and gain-of-function mutations in SMO activate HH signaling [ XREF_BIBR ] , acquired mutations in SMO or non canonical GLI activation render cancer cells resistant to SMO antagonists .	While loss-of-function mutations in PTCH and gain-of-function mutations in SMO activate HH signaling [XREF_BIBR], acquired mutations in SMO or non canonical GLI activation render cancer cells resistant to SMO antagonists.	4	25	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	4	5	20	21
In the presence of Hh ligands , the repression of Smo by Ptch1 is relieved [ XREF_BIBR , XREF_BIBR ] , activated Smo accumulates in primary cilia and Hh signaling is initiated [ XREF_BIBR ] .	In the presence of Hh ligands, the repression of Smo by Ptch1 is relieved [XREF_BIBR, XREF_BIBR], activated Smo accumulates in primary cilia and Hh signaling is initiated [XREF_BIBR].	8	13	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	12	13	10	11
In the canonical pathway ( beta catenin dependent ) , a ligand will bind to PTCH1 ( a transmembrane receptor ) , which relieves SMO ( G protein coupled receptor like protein ) .	In the canonical pathway (beta catenin dependent), a ligand will bind to PTCH1 (a transmembrane receptor), which relieves SMO (G protein coupled receptor like protein).	13	27	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	15	16	24	25
It has been shown that Ptch , when localized to the cilium , is able to inhibit the entry of Smo into the organelle .	It has been shown that Ptch, when localized to the cilium, is able to inhibit the entry of Smo into the organelle.	5	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	5	6	20	21
In the absence of the hedgehog ligands ( Desert Hedgehog ( DHH ) , Indian Hedgehog ( IHH ) , and Sonic Hedgehog ( SHH ) ) , the Patched-1 ( PTCH1 ) and Patched-2 ( PTCH2 ) receptors , inhibit Smoothened ( SMO ) , the main effector of signaling , which is located in vesicles in the cytoplasm [ XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	In the absence of the hedgehog ligands (Desert Hedgehog (DHH), Indian Hedgehog (IHH), and Sonic Hedgehog (SHH)), the Patched-1 (PTCH1) and Patched-2 (PTCH2) receptors, inhibit Smoothened (SMO), the main effector of signaling, which is located in vesicles in the cytoplasm [XREF_BIBR, XREF_BIBR] (XREF_FIG).	29	54	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	31	32	43	44
In the absence of Hh ligand , its receptor , Patched ( Ptc1 ) inhibits Smo activity , presumptively through a small molecule mediator .	In the absence of Hh ligand, its receptor, Patched (Ptc1) inhibits Smo activity, presumptively through a small molecule mediator.	7	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	12	13	15	16
This conclusion has been derived from the following observations : Ptch1 can inhibit Smo catalytically rather than stoichiometrically [ XREF_BIBR ] , Ptch1 and Smo do not physically interact in conventional biochemical assays , and Ptch1 demonstrates distant homology to the bacterial Resistance , Nodulation , Division ( RND ) family of small-molecule pumps [ XREF_BIBR ] .	This conclusion has been derived from the following observations : Ptch1 can inhibit Smo catalytically rather than stoichiometrically [XREF_BIBR], Ptch1 and Smo do not physically interact in conventional biochemical assays, and Ptch1 demonstrates distant homology to the bacterial Resistance, Nodulation, Division (RND) family of small-molecule pumps [XREF_BIBR].	10	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	10	11	13	14
To determine the maximal inhibition Ptch1 confers in a cell-autonomous fashion -- that is , the extent to which Ptch1 can inhibit Smo on the same cell -- we mixed and fused the two previously described cell populations .	To determine the maximal inhibition Ptch1 confers in a cell-autonomous fashion -- that is, the extent to which Ptch1 can inhibit Smo on the same cell -- we mixed and fused the two previously described cell populations.	19	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	19	20	22	23
Cocultures with DHH expressing BM stromal cells reduced sensitivity of CLLs to SMO-inhibitor treatment by activation of noncanonical ERK phosphorylation directly downstream of the PTCH1 receptor without involvement of SMO and could be overcome by the HH blocking Ab 5E1 or a combination of SMO and ERK inhibitors .	Cocultures with DHH expressing BM stromal cells reduced sensitivity of CLLs to SMO-inhibitor treatment by activation of noncanonical ERK phosphorylation directly downstream of the PTCH1 receptor without involvement of SMO and could be overcome by the HH blocking Ab 5E1 or a combination of SMO and ERK inhibitors.	7	30	reduced	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	PTCH1	phosphorylation directly downstream of the PTCH1	ptch1	SMO	SMO	smo	24	25	29	30
In mammals , the binding of Hh ligand to its 12-transmembrane protein receptor Patched-1 ( Ptch-1 ) relieves Ptch1 mediated inhibition of Smoothened ( Smo ) , a seven-pass transmembrane protein with homology to G-protein-coupled receptors ( GPCRs ) .	In mammals, the binding of Hh ligand to its 12-transmembrane protein receptor Patched-1 (Ptch-1) relieves Ptch1 mediated inhibition of Smoothened (Smo), a seven-pass transmembrane protein with homology to G-protein-coupled receptors (GPCRs).	18	30	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	18	19	24	25
In the absence of Hh ligands , PTCH1 inhibits SMO , which results in phosphorylation dependent ubiquitination of glioma associated oncogene homolog ( GLI ) transcription factors , leading to degradation and clearance of GLI1 and GLI2 or partial proteolysis of GLI3 that represses transcription of Hh target genes .	In the absence of Hh ligands, PTCH1 inhibits SMO, which results in phosphorylation dependent ubiquitination of glioma associated oncogene homolog (GLI) transcription factors, leading to degradation and clearance of GLI1 and GLI2 or partial proteolysis of GLI3 that represses transcription of Hh target genes.	7	21	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	PTCH1	PTCH1	ptch1	SMO	SMO, which results in phosphorylation dependent ubiquitination of glioma associated oncogene	smo	7	8	9	10
Upon binding of Hh to its receptor Ptch , an inhibitory effect of Ptch on Smo is released , allowing Smo to trigger a signaling cascade activating the Gli transcription factors ( Gli1 , 2 and 3 ) , essential effectors for Hh mediated cellular effects .	Upon binding of Hh to its receptor Ptch, an inhibitory effect of Ptch on Smo is released, allowing Smo to trigger a signaling cascade activating the Gli transcription factors (Gli1, 2 and 3), essential effectors for Hh mediated cellular effects.	11	22	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	13	14	20	21
Regardless , in the absence of Hh signalling , Ptch1 acts to inhibit Smo activity , facilitating the conversion of the transcriptional effectors of the Hh pathway , Gli2 and Gli3 , to their repressor forms .	Regardless, in the absence of Hh signalling, Ptch1 acts to inhibit Smo activity, facilitating the conversion of the transcriptional effectors of the Hh pathway, Gli2 and Gli3, to their repressor forms.	9	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	9	10	13	14
In the absence of this ligand , Ptch1 actively represses Smo to keep the pathway inactive [ XREF_BIBR ] .	In the absence of this ligand, Ptch1 actively represses Smo to keep the pathway inactive [XREF_BIBR].	7	11	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	7	8	10	11
In the absence of HH ligands , a cell-surface transmembrane protein Patched ( PTCH ) inhibits the transmembrane protein Smoothened ( SMO ) , and full length GLI proteins are then proteolytically processed to generate the repressor GLI R to suppress HH signaling target gene expression ( XREF_FIG ) .	In the absence of HH ligands, a cell-surface transmembrane protein Patched (PTCH) inhibits the transmembrane protein Smoothened (SMO), and full length GLI proteins are then proteolytically processed to generate the repressor GLI R to suppress HH signaling target gene expression (XREF_FIG).	13	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	13	14	21	22
The precise mechanism by which Ptch inhibits Smo is not yet clear , but is thought to involve modulation of sterol or phospholipid availability to affect Smo membrane trafficking .	The precise mechanism by which Ptch inhibits Smo is not yet clear, but is thought to involve modulation of sterol or phospholipid availability to affect Smo membrane trafficking.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	5	6	7	8
In the absence of ligand , PTCH1 inhibits Smoothened ( SMO ) , the binding of IHH relieves SMO inhibition , leading to activation of the GLI transcription factors : the activators GLI1 and GLI2 and the repressor GLI3 .	In the absence of ligand, PTCH1 inhibits Smoothened (SMO), the binding of IHH relieves SMO inhibition, leading to activation of the GLI transcription factors : the activators GLI1 and GLI2 and the repressor GLI3.	6	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	6	7	10	11
In the SHH signaling , binding of SHH ligands to their transmembrane receptor Patched ( PTCH ) interrupts PTCH mediated inhibition of Smoothened ( SMO ) [ XREF_BIBR ] .	In the SHH signaling, binding of SHH ligands to their transmembrane receptor Patched (PTCH) interrupts PTCH mediated inhibition of Smoothened (SMO) [XREF_BIBR].	18	27	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	18	19	24	25
In the absence of ligand binding , PTCH inhibits smoothened ( Smo ) , a protein that transduces the signal downstream .	In the absence of ligand binding, PTCH inhibits smoothened (Smo), a protein that transduces the signal downstream.	7	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	Smo	Smo	Smo	7	8	11	12
In the absence of hedgehog ligand , PTCH located on the cell membrane at the base of primary cilia , a cellular structure found in most mammalian cells , suppresses the SMO from entering the cilium , thereby preventing the initiation of downstream signaling events .	In the absence of hedgehog ligand, PTCH located on the cell membrane at the base of primary cilia, a cellular structure found in most mammalian cells, suppresses the SMO from entering the cilium, thereby preventing the initiation of downstream signaling events.	7	32	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	7	8	31	32
In the absence of Shh , Ptch represses the function of Smoothened ( Smo ) , a seven transmembrane G-protein-coupled receptor like protein that activates the Gli1 and Gli2 transcription factors and inactivates the transcriptional repressor Gli3 that together regulate the transcriptional program in the cell nucleus .	In the absence of Shh, Ptch represses the function of Smoothened (Smo), a seven transmembrane G-protein-coupled receptor like protein that activates the Gli1 and Gli2 transcription factors and inactivates the transcriptional repressor Gli3 that together regulate the transcriptional program in the cell nucleus.	6	20	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	13	14
In the absence of Hh , Ptch localizes to the base of the primary cilium and prevents the movement of Smo from the plasma membrane and endoplasmic vesicles into the primary cilium .	In the absence of Hh, Ptch localizes to the base of the primary cilium and prevents the movement of Smo from the plasma membrane and endoplasmic vesicles into the primary cilium.	6	27	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	20	21
When a Hedgehog ligand binds PTCH1 , PTCH1 inhibition of SMO is prevented by a mechanism that remains to be fully characterized and SMO is able to accumulate at the base of the primary cilium ( in mammals ) [ XREF_BIBR ] .	When a Hedgehog ligand binds PTCH1, PTCH1 inhibition of SMO is prevented by a mechanism that remains to be fully characterized and SMO is able to accumulate at the base of the primary cilium (in mammals) [XREF_BIBR].	7	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	7	8	10	11
Because Ptch1 and Smo do not unambiguously show physical association and because Ptch1 can inhibit Smo substoichiometrically , direct binding of Ptch1 to Smo as shown in XREF_FIG B , columns 1 and 2 , seems an unlikely mechanism of inhibition [ XREF_BIBR ] .	Because Ptch1 and Smo do not unambiguously show physical association and because Ptch1 can inhibit Smo substoichiometrically, direct binding of Ptch1 to Smo as shown in XREF_FIG B, columns 1 and 2, seems an unlikely mechanism of inhibition [XREF_BIBR].	12	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	12	13	15	16
We found that Ptch1 PY introduced into Ptch1 -/- cells blocked the ciliary accumulation of Smo in a manner similar to wild-type Ptch1 ( XREF_FIG ) .	We found that Ptch1 PY introduced into Ptch1 -/- cells blocked the ciliary accumulation of Smo in a manner similar to wild-type Ptch1 (XREF_FIG).	3	16	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	3	4	15	16
Ptch1 Can Inhibit Smo in a Non Cell Autonomous Fashion .	Ptch1 Can Inhibit Smo in a Non Cell Autonomous Fashion.	0	4	Inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	0	1	3	4
After performing additional tests to eliminate alternative explanations , the team concluded that Ptch1 inhibits Smo through an intermediary , and that the intermediary molecule can exert its influence between individual cells .	After performing additional tests to eliminate alternative explanations, the team concluded that Ptch1 inhibits Smo through an intermediary, and that the intermediary molecule can exert its influence between individual cells.	13	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	13	14	15	16
In the absence of Hh , Ptch-1 inhibits Smoothened ( Smo ) , a G protein coupled receptor .	In the absence of Hh, Ptch-1 inhibits Smoothened (Smo), a G protein coupled receptor.	6	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch-1	Ptch-1	Ptch-1	Smo	Smo	Smo	6	7	10	11
According to the common understanding , the cell surface protein PTCH1 blocks the SMO receptor as long as SHH is absent .	According to the common understanding, the cell surface protein PTCH1 blocks the SMO receptor as long as SHH is absent.	6	14	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	10	11	13	14
Ordinarily , PTCH inhibits SMO , maintaining SMO at the base of primary cilia .	Ordinarily, PTCH inhibits SMO, maintaining SMO at the base of primary cilia.	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	2	3	4	5
Upon ligand binding , the inhibition of Smo by Ptch proteins is relieved , and the signal is transmitted via Smo to inhibit the phosphorylation and cleavage of Gli family transcription factors .	Upon ligand binding, the inhibition of Smo by Ptch proteins is relieved, and the signal is transmitted via Smo to inhibit the phosphorylation and cleavage of Gli family transcription factors.	5	10	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	9	10	7	8
In the absence of Shh , patched ( Ptch ) , a 12-transmembrane spanning protein , represses smoothened ( SMO ) thereby inhibiting Hh signaling .	In the absence of Shh, patched (Ptch), a 12-transmembrane spanning protein, represses smoothened (SMO) thereby inhibiting Hh signaling.	8	22	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	SMO	SMO	SMO	8	9	19	20
In the absence of the Hh binding agent , PTCH suppresses SMO activity , preventing trafficking and insertion into the cellular cilia .	In the absence of the Hh binding agent, PTCH suppresses SMO activity, preventing trafficking and insertion into the cellular cilia.	9	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	9	10	11	12
Ligand-free Ptch inhibits the activation of Smoothened ( Smo ) by an incompletely known mechanism .	Ligand-free Ptch inhibits the activation of Smoothened (Smo) by an incompletely known mechanism.	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	1	2	8	9
In the absence of a Hh signal , PTCH1 inhibits the activation of SMO and subsequent downstream signaling .	In the absence of a Hh signal, PTCH1 inhibits the activation of SMO and subsequent downstream signaling.	8	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	8	9	13	14
In the absence of Hh ligands , PTCH1 blocks the activity of the G-protein-coupled receptor ( GPCR )-family protein SMO , which transmits the Hh signal across the membrane .	In the absence of Hh ligands, PTCH1 blocks the activity of the G-protein-coupled receptor (GPCR)-family protein SMO, which transmits the Hh signal across the membrane.	7	22	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	7	8	19	20
Smoothened protein ( SMO ) , another component of the Hh pathway , is physiologically repressed by PTCH1 .	Smoothened protein (SMO), another component of the Hh pathway, is physiologically repressed by PTCH1.	0	18	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	Smoothened protein	Smoothened protein	Smoothened protein	17	18	0	2
In the absence of Hh ligands , Ptc1 , the receptor , inhibits the activity of Smo 3 .	In the absence of Hh ligands, Ptc1, the receptor, inhibits the activity of Smo 3.	7	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	7	8	16	17
In the absence of SHH , PTCH1 inhibits Smoothened ( SMO ) , a downstream protein in the HH pathway .	In the absence of SHH, PTCH1 inhibits Smoothened (SMO), a downstream protein in the HH pathway.	6	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	6	7	10	11
Taken together , our data supports a model in which cholesterol is endogenous ligand responsible for Smo activation during Hh signaling , and that Ptch1 inhibits Smo by counteracting its activation by cholesterol ( XREF_FIG ) .	Taken together, our data supports a model in which cholesterol is endogenous ligand responsible for Smo activation during Hh signaling, and that Ptch1 inhibits Smo by counteracting its activation by cholesterol (XREF_FIG).	24	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	24	25	26	27
However , in the absence of Hh , Smo is continuously repressed by Ptch1 .	However, in the absence of Hh, Smo is continuously repressed by Ptch1.	8	14	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	13	14	8	9
Because Ptch1 inhibits the activity of Smo , its transcriptional activation is suggested to reduce the levels of active Gli .	Because Ptch1 inhibits the activity of Smo, its transcriptional activation is suggested to reduce the levels of active Gli.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	1	2	6	7
In the absence of HH ligands , PTCH inhibits the signaling of the seven trans-membrane domain protein and proto-oncogene Smoothened ( SMO ) .	In the absence of HH ligands, PTCH inhibits the signaling of the seven trans-membrane domain protein and proto-oncogene Smoothened (SMO).	7	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	7	8	21	22
In the absence of the ligands ( Sonic Hh [ Shh ] , Indian Hh [ Ihh ] , or Dessert Hh [ Dhh ] ) , PTCH1 constitutively represses SMO , thus preventing its translocation to primary cilia and repressing Hh signaling .	In the absence of the ligands (Sonic Hh [Shh], Indian Hh [Ihh], or Dessert Hh [Dhh]), PTCH1 constitutively represses SMO, thus preventing its translocation to primary cilia and repressing Hh signaling.	27	31	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	27	28	30	31
Upon binding of Hh to its receptor , Ptch no longer represses Smo and consequently Gli2 and Gli3 are not cleaved and instead function as activators of Hh target genes [ XREF_BIBR ] [ XREF_FIG ] .	Upon binding of Hh to its receptor, Ptch no longer represses Smo and consequently Gli2 and Gli3 are not cleaved and instead function as activators of Hh target genes [XREF_BIBR] [XREF_FIG].	8	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	8	9	12	13
Under normal conditions , and mostly in adults , the hedgehog pathway is ligand dependent and actively repressed because PTCH-1 constantly inhibits SMO , the key activator of the GLI pathway .	Under normal conditions, and mostly in adults, the hedgehog pathway is ligand dependent and actively repressed because PTCH-1 constantly inhibits SMO, the key activator of the GLI pathway.	19	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH-1	PTCH-1	PTCH-1	SMO	SMO	SMO	19	20	22	23
PTCH1 inhibits SMO from translocating to the cell membrane , thereby enhancing degradation of SMO .	PTCH1 inhibits SMO from translocating to the cell membrane, thereby enhancing degradation of SMO.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	0	1	2	3
Our results may have implications for understanding how PTCH1 inhibits SMO , a longstanding mystery in Hh signaling .	Our results may have implications for understanding how PTCH1 inhibits SMO, a longstanding mystery in Hh signaling.	8	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	8	9	10	11
In the absence of Hh ligand , PTCH1 suppresses the activation of SMO .	In the absence of Hh ligand, PTCH1 suppresses the activation of SMO.	7	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	7	8	12	13
No solid evidence has been provided to support direct suppression of SMO by PTCH .	No solid evidence has been provided to support direct suppression of SMO by PTCH.	7	14	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	13	14	11	12
XREF_BIBR , XREF_BIBR During normal Hh signaling , Hh protein binds to PTCH1 , thereby alleviating PTCH mediated suppression of SMO , a distant relative of G protein coupled receptors .	XREF_BIBR, XREF_BIBR During normal Hh signaling, Hh protein binds to PTCH1, thereby alleviating PTCH mediated suppression of SMO, a distant relative of G protein coupled receptors.	16	27	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	16	17	20	21
Secreted Hh molecules bind to the predominant Hh receptor patched1 ( Ptch1 ) , alleviating the Ptch mediated suppression of smoothened ( Smo ) , which is a putative seven-transmembrane protein , and triggering a cascade of intracellular events including the nuclear translocation of the zinc finger protein glioma associated oncogene homologue 1 ( Gli-1 ; Nakano et al , 1989 ; Aza-Blanc et al , 1997 ; Ruiz i Altaba , 1999 ; Hooper and Scott , 2005 ) .	Secreted Hh molecules bind to the predominant Hh receptor patched1 (Ptch1), alleviating the Ptch mediated suppression of smoothened (Smo), which is a putative seven-transmembrane protein, and triggering a cascade of intracellular events including the nuclear translocation of the zinc finger protein glioma associated oncogene homologue 1 (Gli-1; Nakano et al, 1989; Aza-Blanc et al, 1997; Ruiz i Altaba, 1999; Hooper and Scott, 2005).	15	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	16	17	22	23
The mechanisms by which Ptch1 inhibits Smo are unknown .	The mechanisms by which Ptch1 inhibits Smo are unknown.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	6	7
It was experimentally proved that the Hedgehog Interacting Protein 1 ( HHIP ) represses the Hedgehog ligands by directly binding with them and the higher concentration of PTCH1 in membrane would help to repress further SMO activation XREF_BIBR - XREF_BIBR .	It was experimentally proved that the Hedgehog Interacting Protein 1 (HHIP) represses the Hedgehog ligands by directly binding with them and the higher concentration of PTCH1 in membrane would help to repress further SMO activation XREF_BIBR - XREF_BIBR.	25	37	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	27	28	35	36
In the absence of ligand , Ptch represses the activity of the 7 pass transmembrane protein Smoothened ( Smo ) .	In the absence of ligand, Ptch represses the activity of the 7 pass transmembrane protein Smoothened (Smo).	6	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	18	19
In the absence of Shh ligand , the tumor suppressor Ptch inhibits Smo , which possesses characteristics of a G protein coupled receptor XREF_BIBR .	In the absence of Shh ligand, the tumor suppressor Ptch inhibits Smo, which possesses characteristics of a G protein coupled receptor XREF_BIBR.	7	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	10	11	12	13
According to this model , Ptc1 localized to the base of primary cilia inhibits the lateral transport of Smo , and binding of Shh to Ptc1 activates signaling by reciprocal movement of Ptc1 out of the cilium and Smo into the cilium XREF_BIBR , XREF_BIBR .	According to this model, Ptc1 localized to the base of primary cilia inhibits the lateral transport of Smo, and binding of Shh to Ptc1 activates signaling by reciprocal movement of Ptc1 out of the cilium and Smo into the cilium XREF_BIBR, XREF_BIBR.	5	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	5	6	18	19
The intercellular Ptch1 mediated inhibition of Smo as identified in the mix-and-match experiments may be conferred by either an inhibitory molecule secreted or translocated by Ptch1 or by diffusion of a cytosolic mediator through tight junctions .	The intercellular Ptch1 mediated inhibition of Smo as identified in the mix-and-match experiments may be conferred by either an inhibitory molecule secreted or translocated by Ptch1 or by diffusion of a cytosolic mediator through tight junctions.	0	7	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	2	3	6	7
Shh binding to Ptch alleviates the Ptch mediated repression of Smo , allowing activation of Gli transcription factors and expression of target genes .	Shh binding to Ptch alleviates the Ptch mediated repression of Smo, allowing activation of Gli transcription factors and expression of target genes.	5	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	6	7	10	11
In the absence of ligand , the Shh receptor Ptch represses the activity of Smo , while binding of Shh to Ptch relieves this blockade .	In the absence of ligand, the Shh receptor Ptch represses the activity of Smo, while binding of Shh to Ptch relieves this blockade.	6	15	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	9	10	14	15
97 When HH is absent , HH receptor patched-1 ( PTCH1 ) is located at the base of primary cilia and inhibits SMO function .	97 When HH is absent, HH receptor patched-1 (PTCH1) is located at the base of primary cilia and inhibits SMO function.	8	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	10	11	22	23
XREF_BIBR - XREF_BIBR Studies have revealed additional mechanisms controlling signaling of this pathway , such as the role of cilium in Hh signaling , XREF_BIBR - XREF_BIBR co-receptors of Hh molecules , XREF_BIBR - XREF_BIBR potential molecules mediating PTCH1 mediated SMO suppression , XREF_BIBR and ways for Gli transcription factor regulation .	XREF_BIBR - XREF_BIBR Studies have revealed additional mechanisms controlling signaling of this pathway, such as the role of cilium in Hh signaling, XREF_BIBR - XREF_BIBR co-receptors of Hh molecules, XREF_BIBR - XREF_BIBR potential molecules mediating PTCH1 mediated SMO suppression, XREF_BIBR and ways for Gli transcription factor regulation.	37	41	mediated	Positive_early_activation	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	38	39	40	41
In absence of Hh ligands , PTCH inhibits the localization of SMO to the cilia cell surface and represses SMO activity , thereby suppressing signal transmission via the GLI transcription factors into the nucleus .	In absence of Hh ligands, PTCH inhibits the localization of SMO to the cilia cell surface and represses SMO activity, thereby suppressing signal transmission via the GLI transcription factors into the nucleus.	6	20	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	6	7	19	20
In the absence of Shh , the transmembrane protein Patched ( Ptch ) represses Smoothened ( Smo ) , a G protein coupled receptor resembling protein .	In the absence of Shh, the transmembrane protein Patched (Ptch) represses Smoothened (Smo), a G protein coupled receptor resembling protein.	11	21	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	11	12	16	17
The postulated stromal PTCH1 inhibition of SMO , and GLI2 repressor function supporting normal development still fit with the experimental data .	The postulated stromal PTCH1 inhibition of SMO, and GLI2 repressor function supporting normal development still fit with the experimental data.	3	7	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	3	4	6	7
Before this binding , PTCH1 inhibits a seven transmembrane receptor , smoothened ( SMO ) .	Before this binding, PTCH1 inhibits a seven transmembrane receptor, smoothened (SMO).	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	4	5	13	14
It is known that Shh causes activation of a 7-transmembrane domain ( 7-TM ) protein Smoothened ( Smo ) , which under basal conditions is suppressed by Ptch .	It is known that Shh causes activation of a 7-transmembrane domain (7-TM) protein Smoothened (Smo), which under basal conditions is suppressed by Ptch.	10	28	suppressed	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	27	28	17	18
Hh protein binding to the transporter like receptor Patched ( Ptch ) releases Ptch inhibition of Smoothened ( Smo ) allowing the transduction of the Hh signal to the primary cilium .	Hh protein binding to the transporter like receptor Patched (Ptch) releases Ptch inhibition of Smoothened (Smo) allowing the transduction of the Hh signal to the primary cilium.	13	20	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	13	14	18	19
In the absence of Shh , Ptc1 represses Shh signaling by keeping Smoothened ( Smo ) out of the primary cilium .	In the absence of Shh, Ptc1 represses Shh signaling by keeping Smoothened (Smo) out of the primary cilium.	6	20	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	6	7	14	15
Of note , these fibroblasts also express basal levels of Ptch1 , the 12-pass Hedgehog receptor that , in the absence of Hedgehog ligand , inhibits Smo .	Of note, these fibroblasts also express basal levels of Ptch1, the 12-pass Hedgehog receptor that, in the absence of Hedgehog ligand, inhibits Smo.	8	27	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Ptch1	levels of Ptch1	ptch1	Smo	Smo	smo	10	11	26	27
Thus , it will be interesting to investigate whether intercellular repression of Smo by Ptch1 actually contributes to tumour suppression in vivo .	Thus, it will be interesting to investigate whether intercellular repression of Smo by Ptch1 actually contributes to tumour suppression in vivo.	10	15	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	14	15	12	13
In the absence of Hh ligand , PTCH inhibits SMO and renders the pathway inactive .	In the absence of Hh ligand, PTCH inhibits SMO and renders the pathway inactive.	7	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	7	8	9	10
In the absence of the Hs ligands , Ptch1 inhibits the accumulation of Smo to the cilia , then at the bottom of cilia , protein kinase A ( PKA ) along with kinesin Kif7 promotes proteolytic conversion of Gli3 to its repressor form .	In the absence of the Hs ligands, Ptch1 inhibits the accumulation of Smo to the cilia, then at the bottom of cilia, protein kinase A (PKA) along with kinesin Kif7 promotes proteolytic conversion of Gli3 to its repressor form.	8	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	8	9	13	14
When a Hh ligand binds to PTCH1 , PTCH1 ceases to repress SMO , resulting in an active SMO signal .	When a Hh ligand binds to PTCH1, PTCH1 ceases to repress SMO, resulting in an active SMO signal.	8	13	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	8	9	12	13
The exact mechanism of how Ptch represses Smo is incompletely understood ; however , it may involve oxysterols [ XREF_BIBR ] .	The exact mechanism of how Ptch represses Smo is incompletely understood; however, it may involve oxysterols [XREF_BIBR].	5	8	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	5	6	7	8
Result also showed that CTN could increase expression levels of PTEN , and reduce the phosphorylated levels of Akt ( protein kinase B ) on Thr 308 and Ser 473 domain .	Result also showed that CTN could increase expression levels of PTEN, and reduce the phosphorylated levels of Akt (protein kinase B) on Thr 308 and Ser 473 domain.	4	23	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	CTN could increase expression levels of PTEN	pten	protein kinase B	protein kinase B	protein kinase b	10	11	20	23
By removing the D3 phosphate from D3 phosphorylated phosphoinositides , PTEN inhibits the activation of not only Akt2 , but also Akt1 and Akt3 .	By removing the D3 phosphate from D3 phosphorylated phosphoinositides, PTEN inhibits the activation of not only Akt2, but also Akt1 and Akt3.	10	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt1	Akt1	Akt1	10	11	21	22
PTEN is a natural inhibitor of AKT1 , an oncogenic kinase that acts downstream of PI3K to control proliferation and survival .	PTEN is a natural inhibitor of AKT1, an oncogenic kinase that acts downstream of PI3K to control proliferation and survival.	0	10	is a natural inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT1	AKT1	AKT1	0	1	6	7
In recent studies , there has been consensus that a high percentage of PTEN loss and presence of p-Akt1 in TNBC indicates poor disease-free survival [ XREF_BIBR ] .	In recent studies, there has been consensus that a high percentage of PTEN loss and presence of p-Akt1 in TNBC indicates poor disease-free survival [XREF_BIBR].	13	20	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	p-Akt1	p-Akt1	p-Akt1	13	14	18	19
Expression of PTEN in the MDAMB-231BR subline reduced the activity of Akt1 to the level observed in the less aggressive MDA-MB-231 WT cells .	Expression of PTEN in the MDAMB-231BR subline reduced the activity of Akt1 to the level observed in the less aggressive MDA-MB-231 WT cells.	0	12	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Expression of PTEN	pten	Akt1	Akt1	akt1	2	3	11	12
PTEN ( Phosphatase and Tensin Homologue ) normally restricts activity of the PI3 Kinase ( PI3K ) / Protein Kinase B ( PKB , also known as AKT ) signaling pathway [ XREF_BIBR , XREF_BIBR ] .	PTEN (Phosphatase and Tensin Homologue) normally restricts activity of the PI3 Kinase (PI3K) / Protein Kinase B (PKB, also known as AKT) signaling pathway [XREF_BIBR, XREF_BIBR].	0	21	restricts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Protein Kinase B	Protein Kinase B	Protein Kinase B	0	1	18	21
Constitutive activation of Akt1 kinase occurs in human cancer through deletion and mutation of the tumor suppressor gene PTEN , the phosphatase that negatively regulates Akt1 , through amplification of the Akt1 genes , or through amplification of the catalytic subunit of PI3 kinase .	Constitutive activation of Akt1 kinase occurs in human cancer through deletion and mutation of the tumor suppressor gene PTEN, the phosphatase that negatively regulates Akt1, through amplification of the Akt1 genes, or through amplification of the catalytic subunit of PI3 kinase.	10	26	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt1	Akt1	Akt1	18	19	25	26
Recent studies have shown that a loss of PTEN causes continuous activation of protein kinase B ( Akt ) , which is critical in the phosphoinositide 3-kinase ( PI3K )-Akt pathway that leads to cell proliferation.9 , 10 , 11 When NSCLC with low PTEN expression is treated with TKIs , resistance will occur.12 Therefore , TKI resistance could be reversed by upregulating PTEN expression levels .	Recent studies have shown that a loss of PTEN causes continuous activation of protein kinase B (Akt), which is critical in the phosphoinositide 3-kinase (PI3K)-Akt pathway that leads to cell proliferation.9, 10, 11 When NSCLC with low PTEN expression is treated with TKIs, resistance will occur.12 Therefore, TKI resistance could be reversed by upregulating PTEN expression levels.	6	16	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	protein kinase B	protein kinase B	protein kinase b	8	9	13	16
In addition , a different study demonstrated that loss of PTEN promoted melanoma cell metastasis via activating Akt2 but not Akt1 or Akt3 [ XREF_BIBR ] .	In addition, a different study demonstrated that loss of PTEN promoted melanoma cell metastasis via activating Akt2 but not Akt1 or Akt3 [XREF_BIBR].	8	24	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	Akt1	Akt1	akt1	10	11	20	21
Protein kinase B ( Akt ) activation can be negatively regulated by PTEN .	Protein kinase B (Akt) activation can be negatively regulated by PTEN.	0	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Protein kinase B	Protein kinase B	Protein kinase B	12	13	0	3
Thus , haplodeficiency of Pten was sufficient to reverse the type 2 diabetes phenotype of Akt1 +/- Akt2 -/- mice to a pre-diabetic , insulin resistant state , similar to that observed in Akt2 -/- mice [ XREF_BIBR ] .	Thus, haplodeficiency of Pten was sufficient to reverse the type 2 diabetes phenotype of Akt1 +/- Akt2 -/- mice to a pre-diabetic, insulin resistant state, similar to that observed in Akt2 -/- mice [XREF_BIBR].	2	16	reverse	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten	Pten	Akt1	Akt1	Akt1	4	5	15	16
It must be noted that PTEN , one of the genes mutated in familial breast cancer , is an antagonist of AKT1 .	It must be noted that PTEN, one of the genes mutated in familial breast cancer, is an antagonist of AKT1.	5	22	is an antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT1	AKT1	AKT1	5	6	21	22
On the other hand , AKT1 is negatively regulated by PTEN , a p53 response gene that is inactivated in a variety of cancers XREF_BIBR .	On the other hand, AKT1 is negatively regulated by PTEN, a p53 response gene that is inactivated in a variety of cancers XREF_BIBR.	5	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT1	AKT1	AKT1	10	11	5	6
Signaling through S1PR4 in myoblasts involved activation of ROCK2 , leading to phosphatase and tensin homolog ( PTEN ) phosphorylation and subsequent inhibition of protein kinase B ( PKB and AKT ) signaling .	Signaling through S1PR4 in myoblasts involved activation of ROCK2, leading to phosphatase and tensin homolog (PTEN) phosphorylation and subsequent inhibition of protein kinase B (PKB and AKT) signaling.	12	27	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog (PTEN) phosphorylation	phosphatase and tensin homolog	protein kinase B	protein kinase B	protein kinase b	12	16	24	27
PTEN , in turn , reduces the phosporylation of Akt1 , also observed in our experiments .	PTEN, in turn, reduces the phosporylation of Akt1, also observed in our experiments.	0	12	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt1	Akt1	Akt1	0	1	9	10
A previous study demonstrated that increased PTEN may decrease spermatogenesis , fertility , and sperm maturation , and fertilization in the Akt1-/- and Akt2-/- male mice XREF_BIBR .	A previous study demonstrated that increased PTEN may decrease spermatogenesis, fertility, and sperm maturation, and fertilization in the Akt1-/- and Akt2-/- male mice XREF_BIBR.	5	26	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt1-/-	Akt1-/-	Akt1-/-	6	7	21	22
Decreased AKT1 signaling mediated by increased PTEN downregulates both TGFB and canonical WNT signals , suggesting that this pathway may synergize in the observed increase in G0 and delayed time to first division .	Decreased AKT1 signaling mediated by increased PTEN downregulates both TGFB and canonical WNT signals, suggesting that this pathway may synergize in the observed increase in G0 and delayed time to first division.	1	7	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT1	AKT1	AKT1	6	7	1	2
By opposing PI3K signaling , PTEN inhibits the activation of the critical PI3K effector proteins Akt1-3 ( also known as protein kinase B or PKB ) .	By opposing PI3K signaling, PTEN inhibits the activation of the critical PI3K effector proteins Akt1-3 (also known as protein kinase B or PKB).	5	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt1-3	Akt1-3	Akt1-3	5	6	15	16
But perhaps under conditions of prolonged serum withdrawal ( 36 hrs ) , GSK-3 activity , localization , etc may be altered ( i.e. directed at tau for example ) such that PS1 still sequesters beta-catenin but can not bring together GSK-3 .	But perhaps under conditions of prolonged serum withdrawal (36 hrs), GSK-3 activity, localization, etc may be altered (i.e. directed at tau for example) such that PS1 still sequesters beta-catenin but can not bring together GSK-3.	32	39	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	32	33	35	36
Our data indicate that the processed and unprocessed PS1 forms decrease beta-catenin .	Our data indicate that the processed and unprocessed PS1 forms decrease beta-catenin.	8	12	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	8	9	11	12
Finally , FAD mutations in PS1 can not efficiently restore beta-catenin degradation in PS1 null primary fibroblasts .	Finally, FAD mutations in PS1 can not efficiently restore beta-catenin degradation in PS1 null primary fibroblasts.	3	11	restore	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
APC may not be required for PS1 mediated degradation of beta-catenin .	APC may not be required for PS1 mediated degradation of beta-catenin.	4	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	6	7	10	11
The loss of PS1 can stimulate the activation of EGFR and beta-catenin pathways , which can contribute to neurodegeneration and aberrant cell cycle re-entry .	The loss of PS1 can stimulate the activation of EGFR and beta-catenin pathways, which can contribute to neurodegeneration and aberrant cell cycle re-entry.	1	12	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PS1	loss of PS1	ps1	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
In support of this finding , the beta-catenin half-life was dramatically longer in fibroblasts deficient in PS1 , and this phenotype was completely rescued by replacement of PS1 , demonstrating that PS1 normally stimulates the degradation of beta-catenin .	In support of this finding, the beta-catenin half-life was dramatically longer in fibroblasts deficient in PS1, and this phenotype was completely rescued by replacement of PS1, demonstrating that PS1 normally stimulates the degradation of beta-catenin.	31	38	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	31	32	37	38
The expression of mutated PS1 inhibited the Wnt-3A-induced accumulation of beta-catenin .	The expression of mutated PS1 inhibited the Wnt-3A-induced accumulation of beta-catenin.	1	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	expression of mutated PS1	ps1	beta-catenin	beta-catenin	beta-catenin	4	5	10	11
KCNIP4 is particularly interesting , as it encodes a potassium channel interacting protein that regulates membrane excitability and has also been shown to inhibit WNT signaling by promoting presenilin ( PS1 ) mediated degradation of beta-catenin .	KCNIP4 is particularly interesting, as it encodes a potassium channel interacting protein that regulates membrane excitability and has also been shown to inhibit WNT signaling by promoting presenilin (PS1) mediated degradation of beta-catenin.	28	36	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	30	31	35	36
In agreement with the observed impairment of beta-catenin signaling by PS1 and gamma-secretase inhibition , we found that the differentiation of BMSCs down to the osteoblastic lineage was arrested and redirected towards the alternative adipogenic program .	In agreement with the observed impairment of beta-catenin signaling by PS1 and gamma-secretase inhibition, we found that the differentiation of BMSCs down to the osteoblastic lineage was arrested and redirected towards the alternative adipogenic program.	7	13	signaling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	10	11	7	8
Our data suggests that of the neurogenic signals examined , downregulation of PS1 in NPCs induced the most dramatic reduction in phospho-beta-catenin .	Our data suggests that of the neurogenic signals examined, downregulation of PS1 in NPCs induced the most dramatic reduction in phospho-beta-catenin.	10	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	phospho-beta-catenin	phospho-beta-catenin	phospho-beta-catenin	12	13	21	22
According to some authors , PS1 down-regulates beta-catenin activity by enhancing the stability of the E , cadherin , beta , and catenin complex XREF_BIBR , whereas other authors have not detected this effect XREF_BIBR - XREF_BIBR .	According to some authors, PS1 down-regulates beta-catenin activity by enhancing the stability of the E, cadherin, beta, and catenin complex XREF_BIBR, whereas other authors have not detected this effect XREF_BIBR - XREF_BIBR.	5	8	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	5	6	7	8
Consequently , according to our model , mutations in PS1 that prevent processing , such as those shown in XREF_FIG , C410Y and Deltae9 , will decrease the activity of the beta-catenin .	Consequently, according to our model, mutations in PS1 that prevent processing, such as those shown in XREF_FIG, C410Y and Deltae9, will decrease the activity of the beta-catenin.	7	32	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	9	10	31	32
It was reported that beta-catenin interacts with PSs , and that PS1 promotes beta-catenin degradation regulating phosphorylation by cyclin dependent kinase 5 ( CDK5 ) and GSK-3beta [ XREF_BIBR - XREF_BIBR ] .	It was reported that beta-catenin interacts with PSs, and that PS1 promotes beta-catenin degradation regulating phosphorylation by cyclin dependent kinase 5 (CDK5) and GSK-3beta [XREF_BIBR - XREF_BIBR].	11	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	11	12	13	14
Neither treatment overcame PS1 mediated inhibition of beta-catenin signaling , suggesting that regulation of beta-catenin by PS1 was not affected by the activity of GSK 3beta .	Neither treatment overcame PS1 mediated inhibition of beta-catenin signaling, suggesting that regulation of beta-catenin by PS1 was not affected by the activity of GSK 3beta.	3	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
Dysfunctional PS-1 has been reported to negatively regulate the stability of beta-catenin for regulating neuronal apoptosis or for preventing neuronal differentiation XREF_BIBR , XREF_BIBR .	Dysfunctional PS-1 has been reported to negatively regulate the stability of beta-catenin for regulating neuronal apoptosis or for preventing neuronal differentiation XREF_BIBR, XREF_BIBR.	0	12	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PS-1	PS-1	PS-1	beta-catenin	beta-catenin	beta-catenin	1	2	11	12
PS1 also inhibited the transcriptional activity of endogenous beta-catenin , and the PS1 mutants were again less inhibitory at the level of Dvl but showed a different pattern of inhibition toward transcription below Dvl .	PS1 also inhibited the transcriptional activity of endogenous beta-catenin, and the PS1 mutants were again less inhibitory at the level of Dvl but showed a different pattern of inhibition toward transcription below Dvl.	0	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	0	1	8	9
Second , PS1 negatively regulates Wnt signaling by interacting with beta-catenin to facilitate beta-catenin turnover in vitro [ XREF_BIBR - XREF_BIBR ] .	Second, PS1 negatively regulates Wnt signaling by interacting with beta-catenin to facilitate beta-catenin turnover in vitro [XREF_BIBR - XREF_BIBR].	2	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	2	3	13	14
Whereas non processed PS1 inhibits beta-catenin .	Whereas non processed PS1 inhibits beta-catenin.	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	3	4	5	6
PRL ( 500 ng/ml ) reduced the LPL activity in human adipose tissue to 31 +/- 7.7 % , compared with control .	PRL (500 ng/ml) reduced the LPL activity in human adipose tissue to 31 +/- 7.7%, compared with control.	0	8	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PRL	PRL	PRL	LPL	LPL	LPL	0	1	7	8
Previous studies demonstrated that prolactin could reduce the lipoprotein lipase activity in human white adipose tissues , which lead to increase in triglyceride ( TG ) levels .	Previous studies demonstrated that prolactin could reduce the lipoprotein lipase activity in human white adipose tissues, which lead to increase in triglyceride (TG) levels.	4	10	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	prolactin	prolactin	prolactin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	8	10
Furthermore , in human adipose tissue cultured in vitro , prolactin ( PRL ) inhibited lipoprotein lipase ( LPL ) activity via functional PRL receptors .	Furthermore, in human adipose tissue cultured in vitro, prolactin (PRL) inhibited lipoprotein lipase (LPL) activity via functional PRL receptors.	10	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PRL	PRL	PRL	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	12	13	15	17
Separately , it is noteworthy that prolactin inhibits lipoprotein lipase activity in breast adipose tissue [ XREF_BIBR ] , which may have implications for the release of lipid from local adipose stores in the mammary glands either during neonatal development or lactation .	Separately, it is noteworthy that prolactin inhibits lipoprotein lipase activity in breast adipose tissue [XREF_BIBR], which may have implications for the release of lipid from local adipose stores in the mammary glands either during neonatal development or lactation.	6	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	prolactin	prolactin	prolactin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	7	8	10
Prolactin prevented the increase in insulin receptors and lipid synthesis and significantly decreased LPL activity in adipose tissue .	Prolactin prevented the increase in insulin receptors and lipid synthesis and significantly decreased LPL activity in adipose tissue.	0	14	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Prolactin	Prolactin	Prolactin	LPL	LPL	LPL	0	1	13	14
In humans , PRL inhibits lipoprotein lipase activity , an enzyme that hydrolyzes lipids into fatty acids [ XREF_BIBR ] , and adiponectin , an adipokine involved in glucose regulation and fatty acid catabolism [ XREF_BIBR ] .	In humans, PRL inhibits lipoprotein lipase activity, an enzyme that hydrolyzes lipids into fatty acids [XREF_BIBR], and adiponectin, an adipokine involved in glucose regulation and fatty acid catabolism [XREF_BIBR].	3	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PRL	PRL	PRL	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	5	7
Prolactin was also shown to inhibit LPL activity in human adipose tissue , a physiologic mechanism to regulate adipose tissue metabolism during lactation .	Prolactin was also shown to inhibit LPL activity in human adipose tissue, a physiologic mechanism to regulate adipose tissue metabolism during lactation.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Prolactin	Prolactin	Prolactin	LPL	LPL	LPL	0	1	6	7
Hence , PKD negatively regulates the function of Snail and inhibits EMT .	Hence, PKD negatively regulates the function of Snail and inhibits EMT.	2	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKD	PKD	PKD	Snail	Snail	Snail	2	3	8	9
Moreover , we reported that TCPTP knockdown in PTP1B deficient MEFS further enhanced IR activation , consistent with the two PTPs acting in a coordinated manner to attenuate insulin signalling [ XREF_BIBR ] .	Moreover, we reported that TCPTP knockdown in PTP1B deficient MEFS further enhanced IR activation, consistent with the two PTPs acting in a coordinated manner to attenuate insulin signalling [XREF_BIBR].	8	14	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	IR	IR	IR	8	9	13	14
Enzyme studies done in vitro show that the bioactive compound ( s ) can stimulate autophosphorylation of a truncated form of the insulin receptor and can inhibit PTP-1 , a rat homolog of a tyrosine phosphatase ( PTP-1B ) that inactivates the insulin receptor .	Enzyme studies done in vitro show that the bioactive compound (s) can stimulate autophosphorylation of a truncated form of the insulin receptor and can inhibit PTP-1, a rat homolog of a tyrosine phosphatase (PTP-1B) that inactivates the insulin receptor.	27	44	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP-1B	PTP-1B	PTP-1B	insulin receptor	insulin receptor	insulin receptor	37	38	42	44
Protein tyrosine phosphatase 1B ( PTP1B ) negatively regulates the insulin receptor ( IR ) .	Protein tyrosine phosphatase 1B (PTP1B) negatively regulates the insulin receptor (IR).	3	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	5	6	10	12
For example , by dephosphorylating the phosphorylated tyrosine of the insulin receptor , PTP1B is able to block the activated insulin receptor pathway , as validated by PTP1B gene deficient mice showing enhanced insulin sensitivity and a decreased incidence of obesity and diabetes XREF_BIBR .	For example, by dephosphorylating the phosphorylated tyrosine of the insulin receptor, PTP1B is able to block the activated insulin receptor pathway, as validated by PTP1B gene deficient mice showing enhanced insulin sensitivity and a decreased incidence of obesity and diabetes XREF_BIBR.	4	22	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	dephosphorylating the phosphorylated tyrosine of the insulin receptor, PTP1B	ptp1b	insulin receptor	insulin receptor	insulin receptor	13	14	20	22
A conditional deletion of PTP1B in the retina was shown to enhance insulin receptor signalling and cell survival [ XREF_BIBR ] .	A conditional deletion of PTP1B in the retina was shown to enhance insulin receptor signalling and cell survival [XREF_BIBR].	2	14	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	4	5	12	14
Although PTP1B , SHP2 , TCPTP , and RPTPe have been shown to negatively regulate IR signaling in the periphery , these PTPs have not been specifically studied within the context of CNS insulin signaling .	Although PTP1B, SHP2, TCPTP, and RPTPe have been shown to negatively regulate IR signaling in the periphery, these PTPs have not been specifically studied within the context of CNS insulin signaling.	1	16	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	IR	IR	IR	1	2	15	16
Since PTP1B inactivates the insulin receptor , this provides a second mechanism by which resveratrol might act through SIRT1 to improve insulin sensitivity .	Since PTP1B inactivates the insulin receptor, this provides a second mechanism by which resveratrol might act through SIRT1 to improve insulin sensitivity.	1	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	1	2	4	6
Protein tyrosine phosphatase 1B ( PTP1B ) is primarily known to negatively regulate insulin receptor signaling , with Ptp1b -/- mice displaying hypersensitivity to insulin 1 .	Protein tyrosine phosphatase 1B (PTP1B) is primarily known to negatively regulate insulin receptor signaling, with Ptp1b -/- mice displaying hypersensitivity to insulin 1.	3	15	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	5	6	13	15
PTP1B forms a physical complex with the activated IR and dephosphorylates it at Y1162 and Y1163 , while expression of exogenous PTP1B in cells can inhibit IR signaling XREF_BIBR .	PTP1B forms a physical complex with the activated IR and dephosphorylates it at Y1162 and Y1163, while expression of exogenous PTP1B in cells can inhibit IR signaling XREF_BIBR.	18	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	expression of exogenous PTP1B	ptp1b	IR	IR	ir	21	22	26	27
PTP1B dephosphorylates and thereby inactivates insulin receptor kinase , and as a result elevated PTP1B activity is highly associated with decreased insulin sensitivity leading to diabetes and obesity [ XREF_BIBR ] .	PTP1B dephosphorylates and thereby inactivates insulin receptor kinase, and as a result elevated PTP1B activity is highly associated with decreased insulin sensitivity leading to diabetes and obesity [XREF_BIBR].	0	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	0	1	5	7
Although both PTP1B and TCPTP inhibit the activity of IR by dephosphorylation , the catalytic tyrosine sites might be different .	Although both PTP1B and TCPTP inhibit the activity of IR by dephosphorylation, the catalytic tyrosine sites might be different.	1	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	IR	IR	IR	2	3	9	10
It can be deduced that PTP1B , TCPTP and PTPRF crosstalk with each other to negatively regulate IR .	It can be deduced that PTP1B, TCPTP and PTPRF crosstalk with each other to negatively regulate IR.	5	18	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	IR	IR	IR	5	6	17	18
One of the most important phosphatases regulating the insulin signalling cascade is the protein tyrosine phosphatase 1B ( PTP1B ) which inhibits insulin receptor and insulin receptor substrate 1 by direct dephosphorylation XREF_BIBR .	One of the most important phosphatases regulating the insulin signalling cascade is the protein tyrosine phosphatase 1B (PTP1B) which inhibits insulin receptor and insulin receptor substrate 1 by direct dephosphorylation XREF_BIBR.	16	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	18	19	22	24
Localisation of PTP1B to the endoplasmic reticulum may be important to prevent insulin independent autonomous activity of the immature insulin receptor precursor .	Localisation of PTP1B to the endoplasmic reticulum may be important to prevent insulin independent autonomous activity of the immature insulin receptor precursor.	0	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	2	3	19	21
Therefore , the inhibition of PTPs such as PTP1B that attenuate IR activation and signalling might be particularly effective in alleviating insulin resistance .	Therefore, the inhibition of PTPs such as PTP1B that attenuate IR activation and signalling might be particularly effective in alleviating insulin resistance.	5	12	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	IR	IR	IR	8	9	11	12
These proteins interfere with different steps in insulin signaling : ENPP1/PC -1 and the phosphatases PTP1B and PTPRF and LAR inhibit the insulin receptor activation ; INPPL1 and SHIP -2 hydrolyzes PI3-kinase products , hampering the phosphoinositide mediated downstream signaling ; and TRIB3 binds the serine threonine kinase Akt , reducing its phosphorylation levels .	These proteins interfere with different steps in insulin signaling : ENPP1/PC -1 and the phosphatases PTP1B and PTPRF and LAR inhibit the insulin receptor activation; INPPL1 and SHIP -2 hydrolyzes PI3-kinase products, hampering the phosphoinositide mediated downstream signaling; and TRIB3 binds the serine threonine kinase Akt, reducing its phosphorylation levels.	10	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	15	16	22	24
PTEN is a known inhibitor of PIK3CA , explaining the observed exclusivity between PTEN deletion and PIK3CA mutation .	PTEN is a known inhibitor of PIK3CA, explaining the observed exclusivity between PTEN deletion and PIK3CA mutation.	0	7	is a known inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	0	1	6	7
The PIK3CA signalling pathway may also be activated by the loss of PTEN , which is found in 30 % of CRCs and associated with a lack of objective tumour response and worse OS in patients with KRAS WT tumours treated with a cetuximabbased regimen [ XREF_BIBR ] .	The PIK3CA signalling pathway may also be activated by the loss of PTEN, which is found in 30% of CRCs and associated with a lack of objective tumour response and worse OS in patients with KRAS WT tumours treated with a cetuximabbased regimen [XREF_BIBR].	1	13	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PIK3CA	PIK3CA	pik3ca	12	13	1	2
Generally pik3ca gene is deregulated by PTEN gene ( tumor suppressor gene ) .	Generally pik3ca gene is deregulated by PTEN gene (tumor suppressor gene).	1	7	deregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	pik3ca	pik3ca	pik3ca	6	7	1	2
To investigate further the roles of p110 isoforms in PTEN deficient tumors , we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras , which is known to activate p110alpha , and loss of PTEN .	To investigate further the roles of p110 isoforms in PTEN deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110alpha, and loss of PTEN.	37	44	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	p110alpha	p110alpha	p110alpha	43	44	38	39
In conclusion , here we demonstrate that PTEN and INPP4B loss of expression , PIK3CA hotspot mutations , and AKT1 mutations are found in a subset of pure high-grade DCIS and high-grade DCIS adjacent to IBC , that the prevalence of alterations affecting these genes vary more according to the ER/HER2 subtype of DCIS than to its association with synchronous IBC .	In conclusion, here we demonstrate that PTEN and INPP4B loss of expression, PIK3CA hotspot mutations, and AKT1 mutations are found in a subset of pure high-grade DCIS and high-grade DCIS adjacent to IBC, that the prevalence of alterations affecting these genes vary more according to the ER/HER2 subtype of DCIS than to its association with synchronous IBC.	7	16	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	7	8	14	15
Taken together , these data argue that PTEN downregulation is sufficient to drive the switch from p110alpha to p110beta in an ErbB2 mouse model mimicking p110alpha inhibition .	Taken together, these data argue that PTEN downregulation is sufficient to drive the switch from p110alpha to p110beta in an ErbB2 mouse model mimicking p110alpha inhibition.	7	26	drive	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	p110alpha	p110alpha	p110alpha	7	8	25	26
PTEN , PIK3CA , PIK3R1 , and AKT1 form the core of the PI ( 3 ) K/AKT signaling pathway , as annotated in XREF_BIBR ( ) : AKT1 is known to interact with PTEN , PIK3R1 , and PIK3CA , while PTEN inhibits PIK3CA and PIK3R1 .	PTEN, PIK3CA, PIK3R1, and AKT1 form the core of the PI (3) K/AKT signaling pathway, as annotated in XREF_BIBR () : AKT1 is known to interact with PTEN, PIK3R1, and PIK3CA, while PTEN inhibits PIK3CA and PIK3R1.	42	46	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	42	43	44	45
It should be noted that it is conceivable that some of the small group of patients without PIK3CA mutations who responded to PI3K/AKT/mTOR axis inhibitors had other aberrations in PIK3CA not detected by our assay or had other abnormalities such as PTEN loss , that are known to activate PIK3CA .	It should be noted that it is conceivable that some of the small group of patients without PIK3CA mutations who responded to PI3K/AKT/mTOR axis inhibitors had other aberrations in PIK3CA not detected by our assay or had other abnormalities such as PTEN loss, that are known to activate PIK3CA.	41	50	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	41	42	49	50
PI3K activation is influenced by multiple changes in endometrial cancer , including most frequently PTEN loss of function , PIK3CA mutations and PIK3CA amplification [ XREF_BIBR - XREF_BIBR ] .	PI3K activation is influenced by multiple changes in endometrial cancer, including most frequently PTEN loss of function, PIK3CA mutations and PIK3CA amplification [XREF_BIBR - XREF_BIBR].	14	23	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	14	15	22	23
The vast majority of cases ( 69 % of pure DCIS and 75 % of DCIS adjacent to IBC ) harboring PTEN or INPP4B loss of expression , or PIK3CA or AKT1 mutations , displayed pAKT expression , whereas pS6 expression was found in 6 % and 21 % of pure DCIS and DCIS adjacent to IBC harboring these molecular aberrations .	The vast majority of cases (69% of pure DCIS and 75% of DCIS adjacent to IBC) harboring PTEN or INPP4B loss of expression, or PIK3CA or AKT1 mutations, displayed pAKT expression, whereas pS6 expression was found in 6% and 21% of pure DCIS and DCIS adjacent to IBC harboring these molecular aberrations.	21	32	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	21	22	29	30
In the fifth driver pathway , PIK3CA and PTEN are the core members of the RTK/RAS/PI ( 3 ) K signaling pathway which is prominently altered in glioblastoma , and PTEN inhibits PIK3CA in the RTK/RAS/PI ( 3 ) K signaling pathway .	In the fifth driver pathway, PIK3CA and PTEN are the core members of the RTK/RAS/PI (3) K signaling pathway which is prominently altered in glioblastoma, and PTEN inhibits PIK3CA in the RTK/RAS/PI (3) K signaling pathway.	30	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	30	31	32	33
We also observed that INPP4B loss of expression was preferentially found in cases lacking PTEN loss of expression and/or PIK3CA hotspot mutations .	We also observed that INPP4B loss of expression was preferentially found in cases lacking PTEN loss of expression and/or PIK3CA hotspot mutations.	14	21	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	14	15	19	20
Furthermore , gene expression profiles resulting from Pten loss or activation of Pik3ca in primary mouse endometrial epithelial cells exhibit minimal overlap .	Furthermore, gene expression profiles resulting from Pten loss or activation of Pik3ca in primary mouse endometrial epithelial cells exhibit minimal overlap.	7	13	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Pten	Pten	Pten	Pik3ca	Pik3ca	Pik3ca	7	8	12	13
The loss of PTEN function induces an increase in PIP-3 concentration and PIK3CA pathway activation .	The loss of PTEN function induces an increase in PIP-3 concentration and PIK3CA pathway activation.	3	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	3	4	12	13
PTEN interacts with PIK3R1 ; PIK3R1 interacts with PIK3CA ; PTEN inhibits PIK3CA in the RTK/RAS/PI ( 3 ) K signaling pathway .	PTEN interacts with PIK3R1; PIK3R1 interacts with PIK3CA; PTEN inhibits PIK3CA in the RTK/RAS/PI (3) K signaling pathway.	10	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	10	11	12	13
The loss of PTEN expression , which was reported to occur in 19.0 % -42.0 % of Western and 30.0 % -64.0 % of Chinese CRC tumors XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , induces an increase in PIP-3 concentration and PIK3CA pathway activation XREF_BIBR .	The loss of PTEN expression, which was reported to occur in 19.0% -42.0% of Western and 30.0% -64.0% of Chinese CRC tumors XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, induces an increase in PIP-3 concentration and PIK3CA pathway activation XREF_BIBR.	3	49	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN expression	pten	PIK3CA	PIK3CA	pik3ca	3	4	46	47
While PTEN loss increases PIK3CA activity , LKB1 loss-of-function promotes mTOR signaling .	While PTEN loss increases PIK3CA activity, LKB1 loss-of-function promotes mTOR signaling.	1	5	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	1	2	4	5
Thus , Atg7 and SHP2 knockdown reactivated STAT1 under Pa infection ( XREF_FIG ) .	Thus, Atg7 and SHP2 knockdown reactivated STAT1 under Pa infection (XREF_FIG).	2	8	reactivated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	STAT1	STAT1	STAT1	4	5	7	8
For instance , HCMV infection leads to the production of the tyrosine phosphatase Shp2 , which inhibits IFN-gamma-induced STAT1 tyrosine phosphorylation [ XREF_BIBR ] .	For instance, HCMV infection leads to the production of the tyrosine phosphatase Shp2, which inhibits IFN-gamma-induced STAT1 tyrosine phosphorylation [XREF_BIBR].	8	21	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Shp2	Shp2	shp2	STAT1	STAT1 tyrosine phosphorylation	stat1	13	14	18	19
Additionally , STAT1 activation can be directly downregulated by SHP2 [ XREF_BIBR ] .	Additionally, STAT1 activation can be directly downregulated by SHP2 [XREF_BIBR].	2	11	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	STAT1	STAT1	STAT1	9	10	2	3
XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR Moreover , Shp2 also limited STAT1 activation by interferon gamma in response to viral infection .	XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR Moreover, Shp2 also limited STAT1 activation by interferon gamma in response to viral infection.	9	13	limited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Shp2	Shp2	Shp2	STAT1	STAT1	STAT1	9	10	12	13
SHP2 siRNA knockdown partially increased the expression of p-STAT1 Tyr701 but not total STAT1 , p-STAT3 Tyr705 , and total STAT3 in DU145 and PC3 cells .	SHP2 siRNA knockdown partially increased the expression of p-STAT1 Tyr701 but not total STAT1, p-STAT3 Tyr705, and total STAT3 in DU145 and PC3 cells.	0	20	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	STAT1	STAT1	STAT1	0	1	13	14
Likewise , SHP2 mediated pSTAT1 downregulation diminished the production of Th1 cytokines by tumor cells , since its inhibition induced increased secretion of interleukin-12 ( IL-12 ) p35 and p40 and IFNgamma dependent CXCR3 and CCR5 binding chemokines .	Likewise, SHP2 mediated pSTAT1 downregulation diminished the production of Th1 cytokines by tumor cells, since its inhibition induced increased secretion of interleukin-12 (IL-12) p35 and p40 and IFNgamma dependent CXCR3 and CCR5 binding chemokines.	2	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	pSTAT1	pSTAT1	pSTAT1	2	3	4	5
Shp2 knockdown enhances IFN-alpha2b-stimulated STAT1 activation and inhibits Erk activation in A375 melanoma cells .	Shp2 knockdown enhances IFN-alpha2b-stimulated STAT1 activation and inhibits Erk activation in A375 melanoma cells.	0	5	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Shp2	Shp2	Shp2	STAT1	STAT1	STAT1	0	1	4	5
Together , these results suggest that p-EphrinB2 sustains endothelial cell viability by recruiting SHP2 , which inactivates STAT1 .	Together, these results suggest that p-EphrinB2 sustains endothelial cell viability by recruiting SHP2, which inactivates STAT1.	7	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	STAT1	STAT1	STAT1	13	14	17	18
This observation reflects the fact that EGFR signaling in combination with p-STAT1 suppression by SHP2 have overwhelmingly negative effects on immunogenic TA-peptide presentation , abrogating the generation , loading and presentation on surface HLA class I : TA peptide complexes , which are necessary for CTL lysis .	This observation reflects the fact that EGFR signaling in combination with p-STAT1 suppression by SHP2 have overwhelmingly negative effects on immunogenic TA-peptide presentation, abrogating the generation, loading and presentation on surface HLA class I : TA peptide complexes, which are necessary for CTL lysis.	11	15	suppression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	p-STAT1	p-STAT1	p-STAT1	14	15	11	12
Furthermore , overexpression of wild type ( WT ) SHP2 in keratinocytes decreased both basal and IFN-gamma-induced STAT1 phosphorylation compared to dominant negative , mutant SHP2 demonstrating that SHP2 overexpression suppressed STAT1 activation in epithelial cells ( XREF_FIG ) .	Furthermore, overexpression of wild type (WT) SHP2 in keratinocytes decreased both basal and IFN-gamma-induced STAT1 phosphorylation compared to dominant negative, mutant SHP2 demonstrating that SHP2 overexpression suppressed STAT1 activation in epithelial cells (XREF_FIG).	2	19	decreased	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	SHP2	overexpression of wild type (WT) SHP2	shp2	STAT1	STAT1 phosphorylation	stat1	9	10	17	18
Shp2 knockdown alone did not induce pSTAT1 .	Shp2 knockdown alone did not induce pSTAT1.	0	7	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Shp2	Shp2	Shp2	pSTAT1	pSTAT1	pSTAT1	0	1	6	7
SHP2 downregulates Jak2 and STAT3 in the mouse forebrain [ XREF_BIBR ] and SHP2 inhibits STAT1 and STAT3 differentially .	SHP2 downregulates Jak2 and STAT3 in the mouse forebrain [XREF_BIBR] and SHP2 inhibits STAT1 and STAT3 differentially.	13	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	STAT1	STAT1	STAT1	13	14	15	16
SHP-2 activation by fusaruside suppresses p-STAT1 and T-bet and production of Th1 cytokines .	SHP-2 activation by fusaruside suppresses p-STAT1 and T-bet and production of Th1 cytokines.	0	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP-2	SHP-2	SHP-2	p-STAT1	p-STAT1	p-STAT1	0	1	5	6
SHP2 phosphatase depletion using siRNA enhanced cetuximab induced p-STAT1 ( Tyr701 ) , as well as total STAT1 , expression suggesting that high SHP2 expression downstream of EGFR in HNC cells prevents STAT1 mediated signaling .	SHP2 phosphatase depletion using siRNA enhanced cetuximab induced p-STAT1 (Tyr701), as well as total STAT1, expression suggesting that high SHP2 expression downstream of EGFR in HNC cells prevents STAT1 mediated signaling.	23	34	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2 expression	shp2	STAT1	STAT1	stat1	23	24	32	33
ROS generating mitochondria accumulates in MEFs with an autophagy deficiency , and ROS regulated SHP2 inhibits JAK2 and STAT1 signaling .	ROS generating mitochondria accumulates in MEFs with an autophagy deficiency, and ROS regulated SHP2 inhibits JAK2 and STAT1 signaling.	14	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	STAT1	STAT1	STAT1	14	15	18	19
The phosphorylation of the CagA protein activates SHP-2 ( protein tyrosine phosphatase ) , which then inhibits the FAK ( focal adhesion kinase ) , an enzyme that modulates adhesion , migration , and cell survival [ XREF_BIBR ] .	The phosphorylation of the CagA protein activates SHP-2 (protein tyrosine phosphatase), which then inhibits the FAK (focal adhesion kinase), an enzyme that modulates adhesion, migration, and cell survival [XREF_BIBR].	6	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP-2	SHP-2	SHP-2	FAK	FAK	FAK	7	8	18	19
SHP2 inactivates FAK by dephosphorylation and thereby induces and enhances cell scattering [ XREF_BIBR ] .	SHP2 inactivates FAK by dephosphorylation and thereby induces and enhances cell scattering [XREF_BIBR].	0	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	FAK	FAK	FAK	0	1	2	3
Activation of Shp-2 phosphatase activity has consequently been reported to inactivate FAK in cells that ectopically express CagA [ XREF_BIBR ] .	Activation of Shp-2 phosphatase activity has consequently been reported to inactivate FAK in cells that ectopically express CagA [XREF_BIBR].	2	12	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Shp-2	Shp-2	Shp-2	FAK	FAK	FAK	2	3	11	12
SHP2 inactivates FAK to promote lamellipodia persistence and cell migration .	SHP2 inactivates FAK to promote lamellipodia persistence and cell migration.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	FAK	FAK	FAK	0	1	2	3
Our data suggest that SHP2 attenuates FAK activity to promote EGF induced cell migration .	Our data suggest that SHP2 attenuates FAK activity to promote EGF induced cell migration.	4	7	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	FAK	FAK	FAK	4	5	6	7
However , treatment with the FAK inhibitor followed by EGF stimulation led to a partial restoration ( by 20-30 % ) of wound healing in the shRNA cells ( XREF_FIG ) , suggesting that inactivation of FAK by SHP2 contributes to EGF induced cell migration .	However, treatment with the FAK inhibitor followed by EGF stimulation led to a partial restoration (by 20-30%) of wound healing in the shRNA cells (XREF_FIG), suggesting that inactivation of FAK by SHP2 contributes to EGF induced cell migration.	34	39	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	FAK	FAK	FAK	38	39	36	37
Shp2 inhibition was sufficient to activate FAK , Src , and the Akt and mTORC1 pathway in the absence of stretch , and the consequent hypertrophy was sensitive to inhibitors of FAK and Src and to rapamycin XREF_BIBR .	Shp2 inhibition was sufficient to activate FAK, Src, and the Akt and mTORC1 pathway in the absence of stretch, and the consequent hypertrophy was sensitive to inhibitors of FAK and Src and to rapamycin XREF_BIBR.	0	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Shp2	Shp2	Shp2	FAK	FAK	FAK	0	1	6	7
In a series of elegant molecular studies , they demonstrate that Shp2 associates with , dephosphorylates , and inhibits FAK in unstretched myocytes , and that stretch relieves this inhibition , which subsequently activates the mammalian target of rapamycin complex 1 ( mTORC1 ) pathway ( XREF_FIG ) .	In a series of elegant molecular studies, they demonstrate that Shp2 associates with, dephosphorylates, and inhibits FAK in unstretched myocytes, and that stretch relieves this inhibition, which subsequently activates the mammalian target of rapamycin complex 1 (mTORC1) pathway (XREF_FIG).	11	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Shp2	Shp2	Shp2	FAK	FAK	FAK	11	12	19	20
LRRK2 Inhibits FAK Activity by Promoting FERM mediated Autoinhibition of FAK and Recruiting the Tyrosine Phosphatase , SHP-2 .	LRRK2 Inhibits FAK Activity by Promoting FERM mediated Autoinhibition of FAK and Recruiting the Tyrosine Phosphatase, SHP-2.	7	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP-2	SHP-2	SHP-2	FAK	FAK	FAK	17	18	10	11
These results indicate that inhibition of FAK by SHP-2 plays a crucial role in the morphogenetic activity of CagA .	These results indicate that inhibition of FAK by SHP-2 plays a crucial role in the morphogenetic activity of CagA.	4	9	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SHP-2	SHP-2	SHP-2	FAK	FAK	FAK	8	9	6	7
Given the essential role for the p110alpha catalytic subunit of PI3K in transducing oncogenic signals downstream of upregulated or mutated RTKs and oncogenes such as Ras in hematological malignancies [ XREF_BIBR ] , it seemed a likely candidate but it was also possible that p110beta which is known to be activated by PTEN loss or p110delta might also be contributing [ XREF_BIBR , XREF_BIBR ] .	Given the essential role for the p110alpha catalytic subunit of PI3K in transducing oncogenic signals downstream of upregulated or mutated RTKs and oncogenes such as Ras in hematological malignancies [XREF_BIBR], it seemed a likely candidate but it was also possible that p110beta which is known to be activated by PTEN loss or p110delta might also be contributing [XREF_BIBR, XREF_BIBR].	44	59	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	p110beta	p110beta	p110beta	52	53	44	45
In CRPC , there are recurrent mutations in PIK3CB and frequent loss of PTEN , which may activate PIK3CB over PIK3CA [ XREF_BIBR ] , emphasizing the need for these specific PI3K isoforms inhibitors [ XREF_BIBR , XREF_BIBR ] to effectively clinically target this pathway .	In CRPC, there are recurrent mutations in PIK3CB and frequent loss of PTEN, which may activate PIK3CB over PIK3CA [XREF_BIBR], emphasizing the need for these specific PI3K isoforms inhibitors [XREF_BIBR, XREF_BIBR] to effectively clinically target this pathway.	11	22	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PIK3CB	PIK3CB	pik3cb	13	14	18	19
These results indicate that a 2-fold decrease in Pten levels can induce p110beta driven tumors ( XREF_FIG ) .	These results indicate that a 2-fold decrease in Pten levels can induce p110beta driven tumors (XREF_FIG).	8	13	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	Pten levels	pten	p110beta	p110beta	p110beta	8	9	12	13
The implication of this result , given our data indicating p110beta is expressed in MCF10a cells and that is unchanged by loss of PTEN ( XREF_FIG ) , is that there are no hard wired molecular contacts that mean loss of PTEN will always lead to PI3Kbeta becoming functionally dominant .	The implication of this result, given our data indicating p110beta is expressed in MCF10a cells and that is unchanged by loss of PTEN (XREF_FIG), is that there are no hard wired molecular contacts that mean loss of PTEN will always lead to PI3Kbeta becoming functionally dominant.	39	47	lead	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PI3Kbeta	PI3Kbeta	pi3kbeta	41	42	46	47
PTEN loss promotes p110beta signaling [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	PTEN loss promotes p110beta signaling [XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR].	0	4	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	p110beta	p110beta	p110beta	0	1	3	4
Other recent studies have demonstrated that certain PTEN deficient human cancer cell lines are sensitive to inactivation of p110beta rather than p110alpha .	Other recent studies have demonstrated that certain PTEN deficient human cancer cell lines are sensitive to inactivation of p110beta rather than p110alpha.	6	19	are sensitive to inactivation	Negative_activation_copula_1	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	p110beta	p110beta	p110beta	7	8	18	19
A number of studies have described preferential roles for PI3Kbeta emerging in the absence of PTEN XREF_BIBR , XREF_BIBR , XREF_BIBR and molecular explanations for this , based on the apparent association between PTEN and p85 XREF_BIBR possibly occurring preferentially with p110beta containing p85 : p110 complexes XREF_BIBR , XREF_BIBR and leading to PTEN repressing PI3Kbeta function selectively , have been put forward .	A number of studies have described preferential roles for PI3Kbeta emerging in the absence of PTEN XREF_BIBR, XREF_BIBR, XREF_BIBR and molecular explanations for this, based on the apparent association between PTEN and p85 XREF_BIBR possibly occurring preferentially with p110beta containing p85 : p110 complexes XREF_BIBR, XREF_BIBR and leading to PTEN repressing PI3Kbeta function selectively, have been put forward.	49	56	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3Kbeta	PI3Kbeta	PI3Kbeta	53	54	55	56
Previous studies also showed that phosphatase and tensin homolog deleted on chromosome 10 prevented the metastasis of myeloma cells by downregulating the activity of the FAK and matrix metalloproteinase signaling pathway .	Previous studies also showed that phosphatase and tensin homolog deleted on chromosome 10 prevented the metastasis of myeloma cells by downregulating the activity of the FAK and matrix metalloproteinase signaling pathway.	5	30	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	FAK	FAK	FAK	5	9	25	26
These results indicated that wild type PTEN , which inhibited FAK , MMP-2 , and MMP-9 , could suppress the proliferation and invasion ability of multiple myeloma cells .	These results indicated that wild type PTEN, which inhibited FAK, MMP-2, and MMP-9, could suppress the proliferation and invasion ability of multiple myeloma cells.	4	18	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	FAK	FAK	FAK	6	7	10	11
Since PTEN is known to negatively regulate FAK , we sought to determine if there was an association within patient samples .	Since PTEN is known to negatively regulate FAK, we sought to determine if there was an association within patient samples.	1	8	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	FAK	FAK	FAK	1	2	7	8
PTEN , known as an anti-oncogene , could directly inhibit FAK related pathways through directly de-phosphorylation of FAK [ XREF_BIBR ] .	PTEN, known as an anti-oncogene, could directly inhibit FAK related pathways through directly de-phosphorylation of FAK [XREF_BIBR].	0	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	FAK	FAK	FAK	0	1	10	11
PTEN is known to negatively regulate FAK .	PTEN is known to negatively regulate FAK.	0	7	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	FAK	FAK	FAK	0	1	6	7
Further , PTP-PEST can negatively regulate CAKbeta signaling by inhibiting the catalytic activity of the kinase .	Further, PTP-PEST can negatively regulate CAKbeta signaling by inhibiting the catalytic activity of the kinase.	2	7	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP-PEST	PTP-PEST	PTP-PEST	CAKbeta	CAKbeta	CAKbeta	2	3	6	7
PTP-PEST antagonizes the effects of the tyrosine kinase Pyk2 .	PTP-PEST antagonizes the effects of the tyrosine kinase Pyk2.	0	9	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP-PEST	PTP-PEST	PTP-PEST	Pyk2	Pyk2	Pyk2	0	1	8	9
Overexpression of the phosphatase-inactive form of SHP-2 inhibited EGFRvIII pTyr by decreasing MAPK phosphorylation .	Overexpression of the phosphatase-inactive form of SHP-2 inhibited EGFRvIII pTyr by decreasing MAPK phosphorylation.	4	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP-2	SHP-2	SHP-2	EGFRvIII	EGFRvIII	EGFRvIII	6	7	8	9
To determine if the PTP defective Shp2CSDA inhibits Shp2 mediated EGFR signaling in the lungs of transgenic mice , we produced CCSP-rtTA and tetO-EGFR L858R ( C/EL858R ) bitransgenic mice and CCSP-rtTA and tetO-Shp 2CSDA/tetO-EGFR L858R ( C/Sdn/EL858R ) tritransgenic mice .	To determine if the PTP defective Shp2CSDA inhibits Shp2 mediated EGFR signaling in the lungs of transgenic mice, we produced CCSP-rtTA and tetO-EGFR L858R (C/EL858R) bitransgenic mice and CCSP-rtTA and tetO-Shp 2CSDA/tetO-EGFR L858R (C/Sdn/EL858R) tritransgenic mice.	7	11	mediated	Positive_early_activation	Negative_activation	Negative_activation	Shp2	Shp2	Shp2	EGFR	EGFR	EGFR	8	9	10	11
PTPase-inactive SHP-2 C459S and shp-2 siRNA inhibited cell proliferation and transformation of EGFRvIII cells by perturbing cell cycle progression .	PTPase-inactive SHP-2 C459S and shp-2 siRNA inhibited cell proliferation and transformation of EGFRvIII cells by perturbing cell cycle progression.	4	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	shp-2	shp-2	shp-2	EGFRvIII	EGFRvIII	EGFRvIII	4	5	12	13
In our studies , expression of dominant negative SHP2 downregulates EGFR ( Additional file 2 : Figure S2c ) .	In our studies, expression of dominant negative SHP2 downregulates EGFR (Additional file 2 : Figure S2c).	4	13	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	expression of dominant negative SHP2	shp2	EGFR	EGFR	egfr	8	9	10	11
In glioblastoma mutiforme ( GBM ) cells , Shp2 promotes EGFR and c-Met co-inhibition induced GBM cell death by inhibition of Stat3 activity [ XREF_BIBR ] .	In glioblastoma mutiforme (GBM) cells, Shp2 promotes EGFR and c-Met co-inhibition induced GBM cell death by inhibition of Stat3 activity [XREF_BIBR].	8	13	promotes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Shp2	Shp2	Shp2	EGFR	EGFR	EGFR	8	9	10	11
Intriguingly , although tyrosine phosphatase SHP2 negatively regulates IRS , GAB1 and PI3K and AKT signaling , it positively influences ERK activity , which is partly explained by dephosphorylation of the specific sites involved in RasGAP binding .	Intriguingly, although tyrosine phosphatase SHP2 negatively regulates IRS, GAB1 and PI3K and AKT signaling, it positively influences ERK activity, which is partly explained by dephosphorylation of the specific sites involved in RasGAP binding.	3	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	GAB1	GAB1	GAB1	5	6	10	11
Further genetic analysis suggests that ptp-2 and Shp2 mediates the negative function of soc-1 and Gab1 in PI3K mediated signaling , as well as the positive function in Ras and Map kinase signaling .	Further genetic analysis suggests that ptp-2 and Shp2 mediates the negative function of soc-1 and Gab1 in PI3K mediated signaling, as well as the positive function in Ras and Map kinase signaling.	5	16	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Shp2	Shp2	Shp2	Gab1	Gab1	Gab1	7	8	15	16
In parallel to changes in dynamin phosphorylation , we observed a corresponding increase in dynamin GTPase activity in the presence of Src , which was reversed by the addition of PTP-PEST .	In parallel to changes in dynamin phosphorylation, we observed a corresponding increase in dynamin GTPase activity in the presence of Src, which was reversed by the addition of PTP-PEST.	19	31	reversed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTP-PEST	PTP-PEST	PTP-PEST	Src	Src	Src	30	31	21	22
In keeping with this notion , it was reported that expression of the catalytic domain of PTP-PEST was able to suppress the lethal effect of Src in yeast cells , seemingly by dephosphorylating its substrates .	In keeping with this notion, it was reported that expression of the catalytic domain of PTP-PEST was able to suppress the lethal effect of Src in yeast cells, seemingly by dephosphorylating its substrates.	14	26	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP-PEST	PTP-PEST	PTP-PEST	Src	Src	Src	16	17	25	26
3.4 PTP-PEST reverses the effect of Src on dynamin phosphorylation and activity .	3.4 PTP-PEST reverses the effect of Src on dynamin phosphorylation and activity.	0	7	reverses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP-PEST	PTP-PEST	PTP-PEST	Src	Src	Src	1	2	6	7
MiR-200b suppresses a tumor suppressor gene ( PTPN12 ) which is thought to inactivate the common oncogenes Src and Ras XREF_BIBR , such that the downregulation of miR-200b in sensitive cell lines allows the resultant proliferating cells to be targeted by adriamycin , a Topoisomerase II inhibitor .	MiR-200b suppresses a tumor suppressor gene (PTPN12) which is thought to inactivate the common oncogenes Src and Ras XREF_BIBR, such that the downregulation of miR-200b in sensitive cell lines allows the resultant proliferating cells to be targeted by adriamycin, a Topoisomerase II inhibitor.	5	22	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN12	PTPN12	PTPN12	Src	Src	Src	7	8	17	18
As a potential mechanism for the effect of ROS on invadopodia and podosomes , Diaz , Shani , and colleagues demonstrate that knockdown of PTP-PEST dramatically increases the number of podosomes in Src transformed cells .	As a potential mechanism for the effect of ROS on invadopodia and podosomes, Diaz, Shani, and colleagues demonstrate that knockdown of PTP-PEST dramatically increases the number of podosomes in Src transformed cells.	22	33	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP-PEST	PTP-PEST	PTP-PEST	Src	Src	Src	24	25	32	33
PQQ inhibited protein tyrosine phosphatase 1B ( PTP1B ) , which negatively regulates the EGFR signaling by tyrosine dephosphorylation , to oxidatively modify the catalytic cysteine through its redox cycling activity to generate H ( 2 ) O ( 2 ) .	PQQ inhibited protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the EGFR signaling by tyrosine dephosphorylation, to oxidatively modify the catalytic cysteine through its redox cycling activity to generate H (2) O (2).	5	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	EGFR	EGFR	EGFR	7	8	14	15
One example is the phosphatase PTP1B that impairs EGFR activation .	One example is the phosphatase PTP1B that impairs EGFR activation.	1	9	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	EGFR	EGFR	EGFR	5	6	8	9
These data , combined with prior observation that Mena INV dysregulates PTP1B dependent attenuation of EGFR signaling , fit a model in which PTP1B facilitates alpha5beta1 and EGFR cross-talk observed during 2D haptotaxis .	These data, combined with prior observation that Mena INV dysregulates PTP1B dependent attenuation of EGFR signaling, fit a model in which PTP1B facilitates alpha5beta1 and EGFR cross-talk observed during 2D haptotaxis.	11	16	attenuation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	EGFR	EGFR	EGFR	11	12	15	16
Ang II and H 2 O 2 induce activation of endothelial PYK2 and phosphorylation of eNOS on Tyr657 , and decrease eNOS activity .	Ang II and H 2 O 2 induce activation of endothelial PYK2 and phosphorylation of eNOS on Tyr657, and decrease eNOS activity.	0	22	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PYK2	Ang II and H 2 O 2 induce activation of endothelial PYK2 and phosphorylation	pyk2	eNOS	eNOS	enos	11	12	21	22
We investigated the ability of H 2 S to relieve PYK2 mediated eNOS inhibition and evaluated the importance of the H 2 S/PYK2/eNOS axis on cardiomyocyte injury in vitro and in vivo .	We investigated the ability of H 2 S to relieve PYK2 mediated eNOS inhibition and evaluated the importance of the H 2 S/PYK2/eNOS axis on cardiomyocyte injury in vitro and in vivo.	9	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	PYK2	PYK2	PYK2	eNOS	eNOS	eNOS	10	11	12	13
In addition , PYK2 overexpression reduced eNOS activity in a H 2 S-reversible manner .	In addition, PYK2 overexpression reduced eNOS activity in a H 2 S-reversible manner.	3	7	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PYK2	PYK2 overexpression	pyk2	eNOS	eNOS	enos	3	4	6	7
In mouse carotid arteries , the overexpression of wild-type PYK2 , but not a dominant negative PYK2 , decreased eNOS activity ( approximately 50 % ) , whereas in murine lung endothelial cells , the downregulation of PYK2 ( small interfering RNA ) increased ionomycin induced NO production .	In mouse carotid arteries, the overexpression of wild-type PYK2, but not a dominant negative PYK2, decreased eNOS activity (approximately 50%), whereas in murine lung endothelial cells, the downregulation of PYK2 (small interfering RNA) increased ionomycin induced NO production.	6	20	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PYK2	overexpression of wild-type PYK2	pyk2	eNOS	eNOS	enos	9	10	19	20
Similarly , Fyn markedly enhances , whereas PTP-PEST in combination with PSTPIP1 impairs , WASp capacity to stimulate Arp2/3 actin polymerizing activity in vitro .	Similarly, Fyn markedly enhances, whereas PTP-PEST in combination with PSTPIP1 impairs, WASp capacity to stimulate Arp2/3 actin polymerizing activity in vitro.	7	15	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP-PEST	PTP-PEST	PTP-PEST	WASp	WASp	WASp	7	8	14	15
Knockout of PTP1B or use of a pharmacological PTP1B inhibitor delays the onset of mammary tumor formation and reduces lung metastasis in the MMTV Her2 and NeuT mouse model by reducing Ras-MAPK and Akt signaling .	Knockout of PTP1B or use of a pharmacological PTP1B inhibitor delays the onset of mammary tumor formation and reduces lung metastasis in the MMTV Her2 and NeuT mouse model by reducing Ras-MAPK and Akt signaling.	0	34	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Akt	Akt	Akt	2	3	33	34
PTP1B also suppresses Akt activity by dephosphorylation but , like PP2A , ROS inhibit PTP1B activity and increase Akt activity resulting in increased anchorage independent growth [ XREF_BIBR , XREF_BIBR ] .	PTP1B also suppresses Akt activity by dephosphorylation but, like PP2A, ROS inhibit PTP1B activity and increase Akt activity resulting in increased anchorage independent growth [XREF_BIBR, XREF_BIBR].	0	4	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	Akt	Akt	Akt	0	1	3	4
Inhibition of PTP1B activates MEK and Erk and PI3K and Akt signaling pathways in RPE cells .	Inhibition of PTP1B activates MEK and Erk and PI3K and Akt signaling pathways in RPE cells.	0	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	Akt	Akt	Akt	2	3	10	11
Moreover , deletion of PTPN1 in fibroblasts leads to suppression of Erk signaling and increased insulin growth factor-1 ( IGF-1 )-induced AKT protein kinase B activity ( AKT and PKB ) .	Moreover, deletion of PTPN1 in fibroblasts leads to suppression of Erk signaling and increased insulin growth factor-1 (IGF-1)-induced AKT protein kinase B activity (AKT and PKB).	2	25	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN1	PTPN1	PTPN1	AKT	AKT	AKT	4	5	21	22
Consistently , exogenous GLI1 activity was also repressed by PTEN , a major tumour suppressor and inhibitor of AKT ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	Consistently, exogenous GLI1 activity was also repressed by PTEN, a major tumour suppressor and inhibitor of AKT (XREF_FIG; XREF_SUPPLEMENTARY).	3	16	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	GLI1	GLI1	GLI1	9	10	3	4
Similarly , PTEN negatively regulates GLI1 activity in different human tumors that include melanomas XREF_BIBR .	Similarly, PTEN negatively regulates GLI1 activity in different human tumors that include melanomas XREF_BIBR.	2	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	GLI1	GLI1	GLI1	2	3	5	6
Of note , we reported previously that the protein tyrosine phosphatase PTP1B , encoded by the PTPN1 gene , served to inhibit IGF-1R signaling that was essential for ovarian cancer cell proliferation , migration , invasion and anchorage independent growth [ XREF_BIBR ] .	Of note, we reported previously that the protein tyrosine phosphatase PTP1B, encoded by the PTPN1 gene, served to inhibit IGF-1R signaling that was essential for ovarian cancer cell proliferation, migration, invasion and anchorage independent growth [XREF_BIBR].	7	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	IGF-1R	IGF-1R	IGF-1R	11	12	22	23
Protein tyrosine phosphatase 1B ( PTP1B ) , an endoplasmic reticulum-resident phosphatase , has been reported to down-regulate IGF-IR by dephosphorylation .	Protein tyrosine phosphatase 1B (PTP1B), an endoplasmic reticulum-resident phosphatase, has been reported to down-regulate IGF-IR by dephosphorylation.	3	19	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	IGF-IR	IGF-IR	IGF-IR	5	6	18	19
The phosphatase PTP1B also negatively regulates the IGF-1R [ XREF_BIBR ] , associating with it in a ligand dependent manner [ XREF_BIBR ] .	The phosphatase PTP1B also negatively regulates the IGF-1R [XREF_BIBR], associating with it in a ligand dependent manner [XREF_BIBR].	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	IGF-1R	IGF-1R	IGF-1R	2	3	7	8
For example , ERCC2 is involved in transcription coupled DNA repair , and the tyrosine phosphatase PTPN12 is known to dephosphorylate and thereby inactivate the proto-oncogene c-ABL XREF_BIBR .	For example, ERCC2 is involved in transcription coupled DNA repair, and the tyrosine phosphatase PTPN12 is known to dephosphorylate and thereby inactivate the proto-oncogene c-ABL XREF_BIBR.	13	27	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN12	PTPN12	PTPN12	proto-oncogene c-ABL	proto-oncogene c-ABL	proto-oncogene c-ABL	16	17	25	27
PTP1B activity has direct consequences on EphA3 receptor trafficking and downstream biological responses : PTP1B overexpression reduces EphA3 activation at the cell surface and in cytosolic compartments , thereby decreasing ephrinA5 induced cell contraction , whereas PTP1B silencing enhances EphA3 activation and ephrin induced cell contraction .	PTP1B activity has direct consequences on EphA3 receptor trafficking and downstream biological responses : PTP1B overexpression reduces EphA3 activation at the cell surface and in cytosolic compartments, thereby decreasing ephrinA5 induced cell contraction, whereas PTP1B silencing enhances EphA3 activation and ephrin induced cell contraction.	14	18	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B overexpression	ptp1b	EphA3	EphA3	epha3	14	15	17	18
Likewise , overexpression of w/t PTP1B also decreased the trafficking of endogenous EphA3 in 22Rv1 prostate carcinoma cells .	Likewise, overexpression of w/t PTP1B also decreased the trafficking of endogenous EphA3 in 22Rv1 prostate carcinoma cells.	2	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	overexpression of w/t PTP1B	ptp1b	EphA3	EphA3	epha3	5	6	12	13
PTK7 protein depletion inhibits embryonic Wnt and beta-catenin signaling by strongly reducing LRP6 protein levels .	PTK7 protein depletion inhibits embryonic Wnt and beta-catenin signaling by strongly reducing LRP6 protein levels.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTK7	PTK7	PTK7	beta-catenin	beta-catenin	beta-catenin	0	1	7	8
In contrast to c-Src , PTPL1 prevents TRIP6 turnover at the sites of adhesions .	In contrast to c-Src, PTPL1 prevents TRIP6 turnover at the sites of adhesions.	5	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPL1	PTPL1	PTPL1	TRIP6	TRIP6	TRIP6	5	6	7	8
PTPalpha dephosphorylates Tyr 531 and activates Fyn , while STEP ( STriatal Enriched protein tyrosine Phosphatase ) dephosphorylates Tyr 420 and inactivates Fyn .	PTPalpha dephosphorylates Tyr 531 and activates Fyn, while STEP (STriatal Enriched protein tyrosine Phosphatase) dephosphorylates Tyr 420 and inactivates Fyn.	9	23	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	9	10	22	23
As disease progresses , Abeta has been proposed toactivate the Fyn phosphatase , striatal enriched protein tyrosine phosphatase ( STEP ) , eventually inactivating Fyn , which leads to the loss of synapses and dendritic spine collapse [ XREF_BIBR , XREF_BIBR ] .	As disease progresses, Abeta has been proposed toactivate the Fyn phosphatase, striatal enriched protein tyrosine phosphatase (STEP), eventually inactivating Fyn, which leads to the loss of synapses and dendritic spine collapse [XREF_BIBR, XREF_BIBR].	17	27	inactivating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	19	20	24	25
In addition , STEP inactivates ERK1/2 , Fyn , and p38 kinases by dephosphorylating a regulatory tyrosine within their activation loops .	In addition, STEP inactivates ERK1/2, Fyn, and p38 kinases by dephosphorylating a regulatory tyrosine within their activation loops.	3	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	3	4	7	8
Thus , activation of Fyn by PrP could outcompete downregulation of Fyn by STEP .	Thus, activation of Fyn by PrP could outcompete downregulation of Fyn by STEP.	8	14	downregulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	13	14	11	12
As mentioned above , STEP inactivates ERK but also p38 MAPK , Fyn , and Pyk2 .	As mentioned above, STEP inactivates ERK but also p38 MAPK, Fyn, and Pyk2.	4	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	4	5	12	13
STEP reduces ERK1/2 activity by dephosphorylating one of its regulatory tyrosine residues , Tyr 204 , and inactivates the Src family tyrosine kinase ( SFK ) Fyn by dephosphorylating its regulatory site .	STEP reduces ERK1/2 activity by dephosphorylating one of its regulatory tyrosine residues, Tyr 204, and inactivates the Src family tyrosine kinase (SFK) Fyn by dephosphorylating its regulatory site.	0	28	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	0	1	26	27
A time- resolved model for how Abeta , via Fyn , ultimately causes neuronal demise , posits that Abeta in a first step activates Fyn causing downstream excitotoxicity , and that Abeta later in disease activates STEP , a Fyn-phosphatase that eventually inactivates Fyn , leading to the loss of synapses [ XREF_BIBR ] .	A time- resolved model for how Abeta, via Fyn, ultimately causes neuronal demise, posits that Abeta in a first step activates Fyn causing downstream excitotoxicity, and that Abeta later in disease activates STEP, a Fyn-phosphatase that eventually inactivates Fyn, leading to the loss of synapses [XREF_BIBR].	35	44	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	36	37	43	44
STEP also inhibits the activity of Fyn by dephosphorylating the regulatory tyr 420 .	STEP also inhibits the activity of Fyn by dephosphorylating the regulatory tyr 420.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	0	1	6	7
XREF_BIBR , XREF_BIBR Interestingly , recent studies suggest that tau may act as a scaffold for Fyn that is needed for the effects of Abeta XREF_BIBR , XREF_BIBR Activation of Fyn is achieved by intermolecular autophosphorylation of Y420 in its catalytic domain , and STEP can inactivate Fyn through dephosphorylation of Y420 .	XREF_BIBR, XREF_BIBR Interestingly, recent studies suggest that tau may act as a scaffold for Fyn that is needed for the effects of Abeta XREF_BIBR, XREF_BIBR Activation of Fyn is achieved by intermolecular autophosphorylation of Y420 in its catalytic domain, and STEP can inactivate Fyn through dephosphorylation of Y420.	44	48	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	44	45	47	48
Full activation of the kinase requires the autophosphorylation at Tyrosine 417 and Fyn is inactivated via the dephosphorylation of Tyr417 by STEP .	Full activation of the kinase requires the autophosphorylation at Tyrosine 417 and Fyn is inactivated via the dephosphorylation of Tyr417 by STEP.	12	22	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	21	22	12	13
35 Our data are in line with recently reported findings that suggest that a tonic level of STEP activity suppresses ERK1/2- and Fyn signaling pathways , thereby increasing the synaptic availability of GluN2B and promoting central sensitization .	35 Our data are in line with recently reported findings that suggest that a tonic level of STEP activity suppresses ERK1/2- and Fyn signaling pathways, thereby increasing the synaptic availability of GluN2B and promoting central sensitization.	17	24	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	17	18	22	23
STEP also promotes NMDA receptor endocytosis and inactivates ERK1/2 and Fyn , thereby opposing synaptic strengthening .	STEP also promotes NMDA receptor endocytosis and inactivates ERK1/2 and Fyn, thereby opposing synaptic strengthening.	0	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	0	1	10	11
STEP dephosphorylates and inactivates Fyn directly and we demonstrate a parallel pathway by which STEP dephosphorylates and suppresses PTPalpha function also leading to Fyn inactivation .	STEP dephosphorylates and inactivates Fyn directly and we demonstrate a parallel pathway by which STEP dephosphorylates and suppresses PTPalpha function also leading to Fyn inactivation.	0	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	0	1	4	5
PP1 dephosphorylates and activates STEP , which inhibits Fyn and promotes internalization of NMDARs and AMPARs from synaptosomal membrane surfaces .	PP1 dephosphorylates and activates STEP, which inhibits Fyn and promotes internalization of NMDARs and AMPARs from synaptosomal membrane surfaces.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	PP1 dephosphorylates and activates STEP	step	Fyn	Fyn	fyn	4	5	8	9
In contrast to STEP , which dephosphorylates the activation loop and thereby inactivates Fyn , PTP alpha dephosphorylates a distinct inhibitory pTyr residue in Fyn XREF_BIBR , XREF_BIBR .	In contrast to STEP, which dephosphorylates the activation loop and thereby inactivates Fyn, PTP alpha dephosphorylates a distinct inhibitory pTyr residue in Fyn XREF_BIBR, XREF_BIBR.	1	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	3	4	13	14
A time resolved model for how Abeta via Fyn ultimately causes neuronal demise has been presented by Jannic Boehm , integrating the effects of Abeta on Fyn and STEP , a Fyn-phosphatase that eventually inactivates Fyn .	A time resolved model for how Abeta via Fyn ultimately causes neuronal demise has been presented by Jannic Boehm, integrating the effects of Abeta on Fyn and STEP, a Fyn-phosphatase that eventually inactivates Fyn.	20	36	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	28	29	35	36
PTP1B also limits Toll like receptor signaling in macrophages and inhibits leptin receptor signaling by dephosphorylating the receptor associated kinase JAK2 .	PTP1B also limits Toll like receptor signaling in macrophages and inhibits leptin receptor signaling by dephosphorylating the receptor associated kinase JAK2.	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	JAK2	JAK2	JAK2	0	1	20	21
This is in keeping with previous studies that have shown that PTP1B and TCPTP can function in concert to attenuate hypothalamic JAK-2 and STAT-3 signaling in vivo .	This is in keeping with previous studies that have shown that PTP1B and TCPTP can function in concert to attenuate hypothalamic JAK-2 and STAT-3 signaling in vivo.	11	26	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	JAK-2	JAK-2	JAK-2	11	12	21	22
Protein tyrosine phosphatase 1B ( PTP1B ) dephosphorylates and thus deactivates Jak2 , acting upstream of Ob-Rb and Stat3 to negatively regulate leptin signal transduction [ XREF_BIBR , XREF_BIBR ] .	Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates and thus deactivates Jak2, acting upstream of Ob-Rb and Stat3 to negatively regulate leptin signal transduction [XREF_BIBR, XREF_BIBR].	3	12	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	Jak2	Jak2	Jak2	5	6	11	12
PTP1B gene silencing increases the activation of c-Met , demonstrating an inhibitory role of this phosphatase .	PTP1B gene silencing increases the activation of c-Met, demonstrating an inhibitory role of this phosphatase.	0	8	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	c-Met	c-Met	c-Met	0	1	7	8
Knockdown of PTP1B in GBM43 cells abolished downregulation of P-MET by VEGF ( XREF_FIG ) , supporting a role for PTP1B in VEGF dependent suppression of P-MET .	Knockdown of PTP1B in GBM43 cells abolished downregulation of P-MET by VEGF (XREF_FIG), supporting a role for PTP1B in VEGF dependent suppression of P-MET.	0	10	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	P-MET	P-MET	P-MET	2	3	9	10
PTP1B phosphorylation increased when the c-Met receptor was deactivated , and gene knockdown of PTP1B increased c-Met activation .	PTP1B phosphorylation increased when the c-Met receptor was deactivated, and gene knockdown of PTP1B increased c-Met activation.	12	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	c-Met	c-Met	c-Met	14	15	16	17
Furthermore , PTPN2 attenuates IL-21 and STAT3 signaling and CD4 + T cell expansion and the generation of T follicular helper cells .	Furthermore, PTPN2 attenuates IL-21 and STAT3 signaling and CD4 + T cell expansion and the generation of T follicular helper cells.	2	7	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN2	PTPN2	PTPN2	STAT3	STAT3	STAT3	2	3	6	7
Inhibition of TCPTP in C57BL/6 mice enhanced leptin induced hypothalamic STAT3 signaling and increased the effects of leptin on body weight and energy expenditure .	Inhibition of TCPTP in C57BL/6 mice enhanced leptin induced hypothalamic STAT3 signaling and increased the effects of leptin on body weight and energy expenditure.	0	11	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TCPTP	TCPTP	TCPTP	STAT3	STAT3	STAT3	2	3	10	11
PTPN2 inhibition in beta-cells results in an early and more intense STAT1 and STAT3 activation after IFN-gamma treatment , suggesting that this phosphatase plays an important role in the dephosphorylation and consequent inactivation of these transcription factors in beta-cells .	PTPN2 inhibition in beta-cells results in an early and more intense STAT1 and STAT3 activation after IFN-gamma treatment, suggesting that this phosphatase plays an important role in the dephosphorylation and consequent inactivation of these transcription factors in beta-cells.	0	15	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PTPN2	PTPN2	PTPN2	STAT3	STAT3	STAT3	0	1	13	14
Inhibition of SOCS3 and TC-PTP lead to prolonged and stable activated STAT3 , whereas inhibition of PIAS3 accelerates the rate of activated STAT3 decay by inducing accumulation of cytoplasmic STAT3 .	Inhibition of SOCS3 and TC-PTP lead to prolonged and stable activated STAT3, whereas inhibition of PIAS3 accelerates the rate of activated STAT3 decay by inducing accumulation of cytoplasmic STAT3.	0	30	lead	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TC-PTP	TC-PTP	TC-PTP	STAT3	STAT3	STAT3	4	5	29	30
XREF_BIBR Analysis of TC-PTP-null MEFs revealed impaired dephosphorylation of nuclear STAT1 and STAT3 , but not STAT5 or STAT6 , suggesting TC-PTP may negatively regulate STAT3 mediated signaling .	XREF_BIBR Analysis of TC-PTP-null MEFs revealed impaired dephosphorylation of nuclear STAT1 and STAT3, but not STAT5 or STAT6, suggesting TC-PTP may negatively regulate STAT3 mediated signaling.	21	27	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TC-PTP	TC-PTP	TC-PTP	STAT3	STAT3	STAT3	21	22	25	26
While the activation of LKB1 and AMPK by Sirt1 involves deacetylation of LKB1 , it remains to be determined whether the deacetylation of PTP1B , Syk , or another unknown component ( s ) underlies the Sirt1 inhibition of PTP1B and Syk .	While the activation of LKB1 and AMPK by Sirt1 involves deacetylation of LKB1, it remains to be determined whether the deacetylation of PTP1B, Syk, or another unknown component (s) underlies the Sirt1 inhibition of PTP1B and Syk.	21	41	underlies	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	deacetylation of PTP1B	ptp1b	PTP1B	PTP1B	ptp1b	23	24	39	40
Although the significance of these serine phosphorylations remain unclear , phosphorylation of PTP1B at S50 by AKT can decrease PTP1B activity and impair its ability to dephosphorylate the IR [ XREF_BIBR ] , perhaps as part of a positive feedback loop to regulate insulin signaling .	Although the significance of these serine phosphorylations remain unclear, phosphorylation of PTP1B at S50 by AKT can decrease PTP1B activity and impair its ability to dephosphorylate the IR [XREF_BIBR], perhaps as part of a positive feedback loop to regulate insulin signaling.	10	20	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	phosphorylation of PTP1B at S50	ptp1b	PTP1B	PTP1B	ptp1b	12	13	19	20
TCPTP activation by intracellular domain of alpha2beta1 diminishes the kinase activity of VEGFR2 and blocks its internalization from the cell surface .	TCPTP activation by intracellular domain of alpha2beta1 diminishes the kinase activity of VEGFR2 and blocks its internalization from the cell surface.	0	13	diminishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TCPTP	TCPTP	TCPTP	VEGFR2	VEGFR2	VEGFR2	0	1	12	13
Collectively , our findings indicate that TC-PTP negatively regulates Flk-1 and JNK signaling via direct dephosphorylation of Flk-1 on its Y1173 residue , which contributes to increased epidermal apoptosis in response to UVB exposure .	Collectively, our findings indicate that TC-PTP negatively regulates Flk-1 and JNK signaling via direct dephosphorylation of Flk-1 on its Y1173 residue, which contributes to increased epidermal apoptosis in response to UVB exposure.	6	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TC-PTP	TC-PTP	TC-PTP	Flk-1	Flk-1	Flk-1	6	7	9	10
PTPN22 downregulates this LCK action and thus TCR signaling , and its inhibition can lead to increased risks for autoimmunity [ XREF_BIBR ] .	PTPN22 downregulates this LCK action and thus TCR signaling, and its inhibition can lead to increased risks for autoimmunity [XREF_BIBR].	0	4	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN22	PTPN22	PTPN22	LCK	LCK	LCK	0	1	3	4
Of these , PTPN2 ( TC-PTP ) and PTPN22 ( PEP and Lyp ) have been shown to attenuate Lck and Zap70 signaling and set the threshold for T cell activation .	Of these, PTPN2 (TC-PTP) and PTPN22 (PEP and Lyp) have been shown to attenuate Lck and Zap70 signaling and set the threshold for T cell activation.	3	22	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN22	PTPN22	PTPN22	Lck	Lck	Lck	8	9	19	20
The tyrosine phosphatase LYP , which down-regulates LCK activity in T cell response , can become mutated as R620W which is highly correlated to type 1 diabetes .	The tyrosine phosphatase LYP, which down-regulates LCK activity in T cell response, can become mutated as R620W which is highly correlated to type 1 diabetes.	0	15	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LYP	LYP	LYP	LCK	LCK	LCK	3	4	7	8
In human glioma cells , it has been shown that troglitazone activates protein-tyrosine phosphatase-1B ( PTP-1B ) , which subsequently reduces phosphotyrosine 705 STAT3 ( pY705-STAT3 ) via a PPARgamma independent pathway [ XREF_BIBR ] .	In human glioma cells, it has been shown that troglitazone activates protein-tyrosine phosphatase-1B (PTP-1B), which subsequently reduces phosphotyrosine 705 STAT3 (pY705-STAT3) via a PPARgamma independent pathway [XREF_BIBR].	12	31	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	protein-tyrosine phosphatase-1B	protein-tyrosine phosphatase-1B	protein-tyrosine phosphatase-1B	STAT3	STAT3	STAT3	12	14	23	24
PTP1B is also known to inhibit STAT3 activity via JAK dephosphorylation , which activates STAT3 , and recent reports have indicated that PTP1B expression is upregulated in pancreatic beta-cells and liver in response to ER stress .	PTP1B is also known to inhibit STAT3 activity via JAK dephosphorylation, which activates STAT3, and recent reports have indicated that PTP1B expression is upregulated in pancreatic beta-cells and liver in response to ER stress.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	STAT3	STAT3	STAT3	0	1	6	7
Conversely , PTPN2 inhibited the activation of Src signaling though the dephosphorylation of the active phosphorylated site on Src family kinases in hematopoietic cells , but not in splenocytes [ XREF_BIBR ] .	Conversely, PTPN2 inhibited the activation of Src signaling though the dephosphorylation of the active phosphorylated site on Src family kinases in hematopoietic cells, but not in splenocytes [XREF_BIBR].	2	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN2	PTPN2	PTPN2	Src	Src	Src	2	3	7	8
Inhibition of PTP1B Restores IRS1 Mediated Hepatic Insulin Signaling in IRS2 Deficient Mice .	Inhibition of PTP1B Restores IRS1 Mediated Hepatic Insulin Signaling in IRS2 Deficient Mice.	0	5	Restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	IRS1	IRS1	IRS1	2	3	4	5
Here , it has been demonstrated that PTPN2 downregulates IFNgamma induced proinflammatory STAT1 signalling .	Here, it has been demonstrated that PTPN2 downregulates IFNgamma induced proinflammatory STAT1 signalling.	7	13	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN2	PTPN2	PTPN2	STAT1	STAT1	STAT1	7	8	12	13
The rs1893217 ( C ) risk allele in PTPN2 correlates with two measurable phenotypes : decreased PTPN2 expression and diminished pSTAT5 in response to IL-2 and IL-15 .	The rs1893217 (C) risk allele in PTPN2 correlates with two measurable phenotypes : decreased PTPN2 expression and diminished pSTAT5 in response to IL-2 and IL-15.	6	21	diminished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN2	PTPN2 correlates with two measurable phenotypes : decreased PTPN2 expression	ptpn2	pSTAT5	pSTAT5	pstat5	8	9	20	21
In contrast , siRNA targeting PTPN2 entirely rescued pSTAT5 generation in response to IL-2 even after provision of the otherwise suppressive TCR-signal ( XREF_FIG ) .	In contrast, siRNA targeting PTPN2 entirely rescued pSTAT5 generation in response to IL-2 even after provision of the otherwise suppressive TCR-signal (XREF_FIG).	3	9	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN2	PTPN2	PTPN2	pSTAT5	pSTAT5	pSTAT5	5	6	8	9
In our study , CD4 + T cells from subjects heterozygous for the rs1893217 ( C ) risk allele of PTPN2 display decreased pSTAT5 in response to both IL-2 and IL-15 , but not IL-7 , suggesting that altered IL-2R signaling occurs downstream of CD25 and , most likely , involves the IL-2Rbeta chain .	In our study, CD4 + T cells from subjects heterozygous for the rs1893217 (C) risk allele of PTPN2 display decreased pSTAT5 in response to both IL-2 and IL-15, but not IL-7, suggesting that altered IL-2R signaling occurs downstream of CD25 and, most likely, involves the IL-2Rbeta chain.	20	24	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN2	PTPN2	PTPN2	pSTAT5	pSTAT5	pSTAT5	20	21	23	24
Studies also have shown that TC-PTP negatively regulates AKT signaling .	Studies also have shown that TC-PTP negatively regulates AKT signaling.	5	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TC-PTP	TC-PTP	TC-PTP	AKT	AKT	AKT	5	6	8	9
Moreover , a 45kDa variant of TC-PTP ( TC45 ) exits in the nucleus upon EGFR activation and inhibits the EGFR dependent activation of JNK and consequent activation of PI3K and Akt pathway , but elicits no impact on activation of ERK2 XREF_BIBR .	Moreover, a 45kDa variant of TC-PTP (TC45) exits in the nucleus upon EGFR activation and inhibits the EGFR dependent activation of JNK and consequent activation of PI3K and Akt pathway, but elicits no impact on activation of ERK2 XREF_BIBR.	4	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TC-PTP	TC-PTP	TC-PTP	Akt	Akt	Akt	6	7	31	32
EGFR is another substrate of TC-PTP that has a major role in cell growth XREF_BIBR , consequently , TC-PTP negatively regulates PI3K and AKT and MAPK signaling pathways , which are downstream signaling pathways of EGFR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	EGFR is another substrate of TC-PTP that has a major role in cell growth XREF_BIBR, consequently, TC-PTP negatively regulates PI3K and AKT and MAPK signaling pathways, which are downstream signaling pathways of EGFR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	18	33	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TC-PTP	TC-PTP	TC-PTP	AKT	AKT	AKT	18	19	23	24
Dephosphorylation of tyrosine residues by PTP1B , a protein tyrosine phosphatase , reduced the enhanced PKCdelta activity .	Dephosphorylation of tyrosine residues by PTP1B, a protein tyrosine phosphatase, reduced the enhanced PKCdelta activity.	0	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	Dephosphorylation of tyrosine residues by PTP1B, a protein tyrosine	ptp1b	PKCdelta	PKCdelta	pkcdelta	5	6	15	16
Although loss of PTPN6 has been shown to enhance JAK3 and STAT3 signaling in ALK positive anaplastic large-cell lymphoma , 59 the roles of PTPN6 in TNBC are not yet understood .	Although loss of PTPN6 has been shown to enhance JAK3 and STAT3 signaling in ALK positive anaplastic large-cell lymphoma, 59 the roles of PTPN6 in TNBC are not yet understood.	1	12	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN6	loss of PTPN6	ptpn6	STAT3	STAT3	stat3	3	4	11	12
Aberrant activation of STAT3 pathway is critical for persistent inflammation in lung tissues , and it has been reported that STAT3 activation is negatively regulated by PTPN6 [ XREF_BIBR ] .	Aberrant activation of STAT3 pathway is critical for persistent inflammation in lung tissues, and it has been reported that STAT3 activation is negatively regulated by PTPN6 [XREF_BIBR].	20	28	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTPN6	PTPN6	PTPN6	STAT3	STAT3	STAT3	26	27	20	21
Loss-of-function mutations in PTPN6 promote STAT3 deregulation via JAK3 kinase in DLBCL [ XREF_BIBR ] .	Loss-of-function mutations in PTPN6 promote STAT3 deregulation via JAK3 kinase in DLBCL [XREF_BIBR].	1	6	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN6	PTPN6	PTPN6	STAT3	STAT3	STAT3	3	4	5	6
Loss of function mutations in PTPN6 promote STAT3 deregulation via JAK3 kinase in diffuse large B-cell lymphoma .	Loss of function mutations in PTPN6 promote STAT3 deregulation via JAK3 kinase in diffuse large B-cell lymphoma.	3	8	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN6	PTPN6	PTPN6	STAT3	STAT3	STAT3	5	6	7	8
CD45 can positively and negatively regulate Lck activity by its proximity to the lipid raft associated Lck .	CD45 can positively and negatively regulate Lck activity by its proximity to the lipid raft associated Lck.	0	7	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lck	Lck	Lck	0	1	6	7
Exclusion of CD45 inhibits activity of p56lck associated with glycolipid enriched membrane domains .	Exclusion of CD45 inhibits activity of p56lck associated with glycolipid enriched membrane domains.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	p56lck	p56lck	p56lck	2	3	6	7
Microdomain localized CD45 inactivates Lck and inhibits TCR signaling at the early immune synapse .	Microdomain localized CD45 inactivates Lck and inhibits TCR signaling at the early immune synapse.	2	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lck	Lck	Lck	2	3	4	5
Since high CD45 expression dampens inducible TCR signaling , we conclude that CD45 negatively regulates Lck activity through an alternate substrate , most likely the activation loop tyrosine Y394 .	Since high CD45 expression dampens inducible TCR signaling, we conclude that CD45 negatively regulates Lck activity through an alternate substrate, most likely the activation loop tyrosine Y394.	12	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lck	Lck	Lck	12	13	15	16
Tyr394 is also dephosphorylated by SH2 domain containing phosphatase-1 and CD45 , which can hence positively and negatively regulate Lck activity .	Tyr394 is also dephosphorylated by SH2 domain containing phosphatase-1 and CD45, which can hence positively and negatively regulate Lck activity.	7	20	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lck	Lck	Lck	10	11	19	20
However , it appears that the predominant effect of CD45 inhibition is to activate Lck via increases in Tyr 394 phosphorylation [ XREF_BIBR , XREF_BIBR ] .	However, it appears that the predominant effect of CD45 inhibition is to activate Lck via increases in Tyr 394 phosphorylation [XREF_BIBR, XREF_BIBR].	9	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lck	Lck	Lck	9	10	14	15
Thus , CD45 expression decreased Lck activation in conditions where AIS formation occurs .	Thus, CD45 expression decreased Lck activation in conditions where AIS formation occurs.	2	6	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45 expression	cd45	Lck	Lck	lck	2	3	5	6
CD45 also enriched in AISs , but to modulate Src kinase activity , since localization of CD45 at the cell interface reduced the activation of proximal Lck .	CD45 also enriched in AISs, but to modulate Src kinase activity, since localization of CD45 at the cell interface reduced the activation of proximal Lck.	14	27	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lck	Lck	Lck	16	17	26	27
Partitioning of CD45 to GEMs by the galectin-glycoprotein lattice inactivates Lck , suppressing basal TCR signaling .	Partitioning of CD45 to GEMs by the galectin-glycoprotein lattice inactivates Lck, suppressing basal TCR signaling.	0	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lck	Lck	Lck	2	3	10	11
CD45 , a phosphatase that downregulates Lck , was detected at higher levels in the cSMAC as compared to TCR MCs .	CD45, a phosphatase that downregulates Lck, was detected at higher levels in the cSMAC as compared to TCR MCs.	0	9	downregulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lck	Lck	Lck	0	1	6	7
Interestingly , CD45 can also limit lck activity by dephosphorylating its active site .	Interestingly, CD45 can also limit lck activity by dephosphorylating its active site.	2	7	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	lck	lck	lck	2	3	6	7
In CD45 +/+ cells , CD45 triggering by GalXM reduces the activation of Lck , ZAP70 and Erk1/2 .	In CD45 +/+ cells, CD45 triggering by GalXM reduces the activation of Lck, ZAP70 and Erk1/2.	5	17	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lck	Lck	Lck	5	6	13	14
Several molecules that inhibit this complex pathway at different levels have been described ; among them : ectonucleotide pyrophosphatase/phosphodiesterase ( ENPP1 ) , the phosphatases protein tyrosine phosphatase nonreceptor type 1 ( PTP1B ) , and protein tyrosine phosphatase receptor type F ( PTPRF ) inhibit the IR activation [ XREF_BIBR - XREF_BIBR ] ; inositol polyphosphate phosphatase like 1 ( INPPL1 ) hydrolyzes PI3-kinase products , hampering the phosphoinositide mediated downstream signaling [ XREF_BIBR ] ; and tribbles homolog 3 ( TRIB3 ) binds Akt , reducing its phosphorylation levels [ XREF_BIBR ] ( XREF_FIG ) .	Several molecules that inhibit this complex pathway at different levels have been described; among them : ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), the phosphatases protein tyrosine phosphatase nonreceptor type 1 (PTP1B), and protein tyrosine phosphatase receptor type F (PTPRF) inhibit the IR activation [XREF_BIBR - XREF_BIBR]; inositol polyphosphate phosphatase like 1 (INPPL1) hydrolyzes PI3-kinase products, hampering the phosphoinositide mediated downstream signaling [XREF_BIBR]; and tribbles homolog 3 (TRIB3) binds Akt, reducing its phosphorylation levels [XREF_BIBR] (XREF_FIG).	41	48	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPRF	PTPRF	PTPRF	IR	IR	IR	43	44	47	48
Supporting this hypothesis , antisense suppression of the PTPase LAR in McA-RH7777 hepatoma cells increased insulin receptor signaling ( Kulas et .	Supporting this hypothesis, antisense suppression of the PTPase LAR in McA-RH7777 hepatoma cells increased insulin receptor signaling (Kulas et.	5	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	LAR	LAR	LAR	insulin receptor	insulin receptor	insulin receptor	9	10	15	17
Therefore , our results suggested that in the quiescent state , STAT3 activation is similar in BCSCs and non BCSCs , while under IL-6 stimulation , lower expression of the negative-feedback regulator PTPRD leads to stronger STAT3 activation in BCSCs .	Therefore, our results suggested that in the quiescent state, STAT3 activation is similar in BCSCs and non BCSCs, while under IL-6 stimulation, lower expression of the negative-feedback regulator PTPRD leads to stronger STAT3 activation in BCSCs.	27	37	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Negative_activation	PTPRD	expression of the negative-feedback regulator PTPRD	ptprd	STAT3	STAT3	stat3	32	33	36	37
The present study showed that PTPRD knockdown significantly increased STAT3 activation in vitro , and promoted tumorigenesis in mice characterized also by high pSTAT3 expression in tumor cells in vivo .	The present study showed that PTPRD knockdown significantly increased STAT3 activation in vitro, and promoted tumorigenesis in mice characterized also by high pSTAT3 expression in tumor cells in vivo.	5	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPRD	PTPRD	PTPRD	STAT3	STAT3	STAT3	5	6	9	10
In gliomas , loss of PTPRD could cause aberrant activation of STAT3 and is closely associated with glioma progression [ XREF_BIBR ] .	In gliomas, loss of PTPRD could cause aberrant activation of STAT3 and is closely associated with glioma progression [XREF_BIBR].	3	12	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPRD	loss of PTPRD	ptprd	STAT3	STAT3	stat3	5	6	11	12
STAT3 , a well-known oncoprotein [ XREF_BIBR ] , was inactivated by PTPRD activation and STAT3 was overexpression while PTPRD was inhibited [ XREF_BIBR ] , our results showed that PTPRD was well functional in the pathway .	STAT3, a well-known oncoprotein [XREF_BIBR], was inactivated by PTPRD activation and STAT3 was overexpression while PTPRD was inhibited [XREF_BIBR], our results showed that PTPRD was well functional in the pathway.	0	13	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTPRD	PTPRD	PTPRD	STAT3	STAT3	STAT3	12	13	0	1
This loss of PTPRD led to increased STAT3 activation and protumorigenic macrophage infiltration .	This loss of PTPRD led to increased STAT3 activation and protumorigenic macrophage infiltration.	1	8	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTPRD	loss of PTPRD	ptprd	STAT3	STAT3	stat3	3	4	7	8
XREF_BIBR Those patients with the lowest 20 percentile of hepatic PTPRD expression in adjacent tissue showed a strong and marked enrichment ( NES = 1.75 , FDR = 0.009 ) of the STAT3 transcriptional programme compared with patients with the highest 20 percentile ( see XREF_FIG B , C and online XREF_SUPPLEMENTARY ) , which is testimony of a PTPRD mediated STAT3 deactivation in vivo .	XREF_BIBR Those patients with the lowest 20 percentile of hepatic PTPRD expression in adjacent tissue showed a strong and marked enrichment (NES = 1.75, FDR = 0.009) of the STAT3 transcriptional programme compared with patients with the highest 20 percentile (see XREF_FIG B, C and online XREF_SUPPLEMENTARY), which is testimony of a PTPRD mediated STAT3 deactivation in vivo.	56	62	mediated	Positive_early_activation	Negative_activation	Negative_activation	PTPRD	PTPRD	PTPRD	STAT3	STAT3	STAT3	59	60	61	62
We demonstrate that overexpression of wild-type PTPRD in HNSCC cells significantly inhibits growth and STAT3 activation while PTPRD mutants do not , suggesting that mutation may lead to loss of function and subsequent hyper-phosphorylation of PTPRD substrates , especially STAT3 .	We demonstrate that overexpression of wild-type PTPRD in HNSCC cells significantly inhibits growth and STAT3 activation while PTPRD mutants do not, suggesting that mutation may lead to loss of function and subsequent hyper-phosphorylation of PTPRD substrates, especially STAT3.	3	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPRD	overexpression of wild-type PTPRD	ptprd	STAT3	STAT3	stat3	6	7	14	15
Mutations in PTPRD abrogate the ability to regulate STAT3 XREF_BIBR .	Mutations in PTPRD abrogate the ability to regulate STAT3 XREF_BIBR.	0	9	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPRD	PTPRD	PTPRD	STAT3	STAT3	STAT3	2	3	8	9
PTPRD negatively regulates IL-6 and STAT3 signaling .	PTPRD negatively regulates IL-6 and STAT3 signaling.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPRD	PTPRD	PTPRD	STAT3	STAT3	STAT3	0	1	5	6
XREF_BIBR , XREF_BIBR Inhibition of PP2A phosphatase in non del ( 5q ) erythroid precursors by lenalidomide leads to enhancement of erythropoietin receptor signaling by relieving CD45 repression of ligand dependent signaling JAK2 and Lyn kinase mediated STAT5 activation .	XREF_BIBR, XREF_BIBR Inhibition of PP2A phosphatase in non del (5q) erythroid precursors by lenalidomide leads to enhancement of erythropoietin receptor signaling by relieving CD45 repression of ligand dependent signaling JAK2 and Lyn kinase mediated STAT5 activation.	26	33	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CD45	CD45	CD45	JAK2	JAK2	JAK2	26	27	32	33
Taken collectively , these results suggest that CD45 keeps both BCR associated and total cytoplasmic pools of Lyn in an inactive state , and a mechanism by which Lyn is activated by relative reduction of CD45 effect may be operative on BCR ligation .	Taken collectively, these results suggest that CD45 keeps both BCR associated and total cytoplasmic pools of Lyn in an inactive state, and a mechanism by which Lyn is activated by relative reduction of CD45 effect may be operative on BCR ligation.	28	36	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lyn	Lyn	Lyn	35	36	28	29
We previously demonstrated that CD45 negatively regulates Lyn in the WEHI-231 B-cell line .	We previously demonstrated that CD45 negatively regulates Lyn in the WEHI-231 B-cell line.	4	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lyn	Lyn	Lyn	4	5	7	8
These results indicate selective inactivation of Lyn by CD45 activated with NU-L ( PAN ) and could partly explain the inhibitory mechanism on erythropoiesis exhibited by EPO .	These results indicate selective inactivation of Lyn by CD45 activated with NU-L (PAN) and could partly explain the inhibitory mechanism on erythropoiesis exhibited by EPO.	4	18	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	CD45	CD45	CD45	Lyn	Lyn	Lyn	8	9	6	7
Together , these data identify ERK2 as a specific and direct target of HePTP and are consistent with a model in which HePTP negatively regulates ERK2 activity as part of a feedback mechanism .	Together, these data identify ERK2 as a specific and direct target of HePTP and are consistent with a model in which HePTP negatively regulates ERK2 activity as part of a feedback mechanism.	22	26	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HePTP	HePTP	HePTP	ERK2	ERK2	ERK2	22	23	25	26
For example , in the T cell receptor ( TCR ) signaling pathway , WT cells express protein tyrosine phosphatase non receptor type 7 ( PTPN7 ) , which negatively regulates MAPK1 and ERK2 and MAPK3 and ERK1 XREF_BIBR , XREF_BIBR ( XREF_TABLE ) , whereas HPRT-KD cells over-express MAPK3 .	For example, in the T cell receptor (TCR) signaling pathway, WT cells express protein tyrosine phosphatase non receptor type 7 (PTPN7), which negatively regulates MAPK1 and ERK2 and MAPK3 and ERK1 XREF_BIBR, XREF_BIBR (XREF_TABLE), whereas HPRT-KD cells over-express MAPK3.	16	40	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN7	PTPN7	PTPN7	MAPK1	MAPK1	MAPK1	25	26	31	32
Related to this discussion is the fact that PTPRE can inhibit ERK1 and ERK2 kinase activities and block ELK1 induced transcriptional activity [ XREF_BIBR ] in a fashion similar to the DUSPs [ XREF_BIBR ] .	Related to this discussion is the fact that PTPRE can inhibit ERK1 and ERK2 kinase activities and block ELK1 induced transcriptional activity [XREF_BIBR] in a fashion similar to the DUSPs [XREF_BIBR].	8	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPRE	PTPRE	PTPRE	ERK2	ERK2	ERK2	8	9	13	14
A recent study demonstrated that LAR overexpression decreased the oncogenic activity of a RET and MEN2A mutation when LAR and RET were cotransfected with a MEN2A or MEN2B mutation into an NIH3T3 cell line , possibly owing to interference with RET dimerisation ( Qiao et al , 2001 ) .	A recent study demonstrated that LAR overexpression decreased the oncogenic activity of a RET and MEN2A mutation when LAR and RET were cotransfected with a MEN2A or MEN2B mutation into an NIH3T3 cell line, possibly owing to interference with RET dimerisation (Qiao et al, 2001).	5	14	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LAR	LAR overexpression	lar	RET	RET	ret	5	6	13	14
RPTPbeta and zeta negatively regulates ALK signaling by dephosphorylating the receptor .	RPTPbeta and zeta negatively regulates ALK signaling by dephosphorylating the receptor.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RPTPbeta	RPTPbeta	RPTPbeta	ALK	ALK	ALK	0	1	5	6
Our findings indicate that RB induces autophagy by repressing E2F1 activity .	Our findings indicate that RB induces autophagy by repressing E2F1 activity.	4	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RB	RB	RB	E2F1	E2F1	E2F1	4	5	9	10
Indeed , mice carrying genetically modified alleles of the retinoblastoma ( Rb ) tumor-suppressor gene , causing an increase in the E2F1 activity , showed high predisposition to develop pituitary tumors , and this occurs also in mice with impaired function of p27 or p18 , both converging on pRB pathway .	Indeed, mice carrying genetically modified alleles of the retinoblastoma (Rb) tumor-suppressor gene, causing an increase in the E2F1 activity, showed high predisposition to develop pituitary tumors, and this occurs also in mice with impaired function of p27 or p18, both converging on pRB pathway.	11	22	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	11	12	21	22
More recently , a new mechanism of pRB mediated E2F1 repression has been suggested in addition to this one .	More recently, a new mechanism of pRB mediated E2F1 repression has been suggested in addition to this one.	5	10	mediated	Positive_early_activation	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	7	8	9	10
Using mouse studies and patient tumor analysis it was subsequently established that , in colon cancer , Rb represses E2F1 activity to allow aberrant beta-catenin and c-Myc activity .	Using mouse studies and patient tumor analysis it was subsequently established that, in colon cancer, Rb represses E2F1 activity to allow aberrant beta-catenin and c-Myc activity.	17	20	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	17	18	19	20
Unbound nuclear E2F1 is dependent on the phosphorylation state of retinoblastoma protein Rb , which sequesters E2F1 in its unphosphorylated state [ XREF_BIBR ] .	Unbound nuclear E2F1 is dependent on the phosphorylation state of retinoblastoma protein Rb, which sequesters E2F1 in its unphosphorylated state [XREF_BIBR].	10	22	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	E2F1	E2F1	E2F1	10	12	16	17
We have previously shown that Rb , the founding member of the pocket proteins family , represses E2F1 activity by recruiting the histone deacetylase HDAC1 .	We have previously shown that Rb, the founding member of the pocket proteins family, represses E2F1 activity by recruiting the histone deacetylase HDAC1.	5	18	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	5	6	17	18
Because the retinoblastoma protein ( RB ) is also known to repress E2F1 transcriptional activity by recruiting HDAC1 in a similar but independent fashion of TRIM28 , we used the RB negative cell line Saos2 to test the effect of TyrRS on E2F1-HDAC1 interaction .	Because the retinoblastoma protein (RB) is also known to repress E2F1 transcriptional activity by recruiting HDAC1 in a similar but independent fashion of TRIM28, we used the RB negative cell line Saos2 to test the effect of TyrRS on E2F1-HDAC1 interaction.	2	14	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	E2F1	E2F1	E2F1	2	4	12	13
SDF-1alpha , which is able to rescue these neurons from apoptosis , induces a time dependent increase of total Rb expression while decreasing the nuclear content of phosphorylated ( Ser780 and Ser795 ) Rb and the transcriptional activity of E2F-1 .	SDF-1alpha, which is able to rescue these neurons from apoptosis, induces a time dependent increase of total Rb expression while decreasing the nuclear content of phosphorylated (Ser780 and Ser795) Rb and the transcriptional activity of E2F-1.	0	40	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	SDF-1alpha, which is able to rescue these neurons from apoptosis, induces a time dependent increase of total Rb expression	rb	E2F-1	E2F-1	e2f-1	19	20	39	40
A pRb allele lacking a NLS , pRb delta NLS , also sequestered E2F1 in the cytoplasm .	A pRb allele lacking a NLS, pRb delta NLS, also sequestered E2F1 in the cytoplasm.	1	14	sequestered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	1	2	13	14
Further , a recent report shows that pRb phosphorylation at threonine356/373 inhibits E2F1 transactivation domain binding to the pRb pocket domain .	Further, a recent report shows that pRb phosphorylation at threonine356/373 inhibits E2F1 transactivation domain binding to the pRb pocket domain.	7	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb phosphorylation	prb	E2F1	E2F1	e2f1	7	8	12	13
In addition , it has been shown that RB inactivation and deregulation of E2F1 , but not E2F2 or E2F3 , leads to DNA double strand break ( DSB ) accumulation and cell cycle checkpoint signaling XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	In addition, it has been shown that RB inactivation and deregulation of E2F1, but not E2F2 or E2F3, leads to DNA double strand break (DSB) accumulation and cell cycle checkpoint signaling XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	8	14	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	8	9	13	14
On the other hand , pRb down-regulated c-myc by sequestering E2F1 [ XREF_BIBR , XREF_BIBR ] .	On the other hand, pRb down-regulated c-myc by sequestering E2F1 [XREF_BIBR, XREF_BIBR].	5	14	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	5	6	10	11
RB interacts with chromatin and histone modifying enzymes to repress E2F1 transcription activity .	RB interacts with chromatin and histone modifying enzymes to repress E2F1 transcription activity.	0	12	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	0	1	10	11
In turn , pRB inhibits itself as well as E2F1 .	In turn, pRB inhibits itself as well as E2F1.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	3	4	9	10
We demonstrate that ORC1 represses Cyclin E gene ( CCNE1 ) transcription , an E2F1 activated gene that is also repressed by the Retinoblastoma ( RB ) protein .	We demonstrate that ORC1 represses Cyclin E gene (CCNE1) transcription, an E2F1 activated gene that is also repressed by the Retinoblastoma (RB) protein.	14	27	repressed	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	25	26	14	15
As TIGAR induced RB de-phosphorylation and inhibited the release of E2F1 from its complex with RB protein , E2F1 could not promote the entry of cells into S phase of cell cycle .	As TIGAR induced RB de-phosphorylation and inhibited the release of E2F1 from its complex with RB protein, E2F1 could not promote the entry of cells into S phase of cell cycle.	1	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	TIGAR induced RB de-phosphorylation	rb	E2F1	E2F1	e2f1	3	4	10	11
Furthermore , E2F1 repression by an Rb phosphorylation mutant could not be reversed by Mdm2 overexpression .	Furthermore, E2F1 repression by an Rb phosphorylation mutant could not be reversed by Mdm2 overexpression.	2	8	repression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Rb	Rb phosphorylation	rb	E2F1	E2F1	e2f1	6	7	2	3
Given that Rb is known to inhibit the transcription factor E2F1 , this loss of Rb activity is a likely explanation for the observed increases in protein expression of E2F1 and E2F1-targets in SCLC .	Given that Rb is known to inhibit the transcription factor E2F1, this loss of Rb activity is a likely explanation for the observed increases in protein expression of E2F1 and E2F1-targets in SCLC.	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	transcription factor E2F1	transcription factor E2F1	transcription factor E2F1	2	3	8	11
One exception is the transcription factor E2F1 , which is normally inhibited by RB1 ; it is the only cell cycle regulator identifier by the TCGA study as being predominantly altered in HPV+ cases ( 19 % activated via amplification of chromosome 20q11 , seen in only in 2 % of HPV- HNSCC ; XREF_FIG ) .	One exception is the transcription factor E2F1, which is normally inhibited by RB1; it is the only cell cycle regulator identifier by the TCGA study as being predominantly altered in HPV+ cases (19% activated via amplification of chromosome 20q11, seen in only in 2% of HPV- HNSCC; XREF_FIG).	4	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RB1	RB1	RB1	transcription factor E2F1	transcription factor E2F1	transcription factor E2F1	13	14	4	7
XREF_BIBR When combined with Skp2 deletion , Rb1 deletion triggered the p53 independent apoptotic activity of E2F1 .	XREF_BIBR When combined with Skp2 deletion, Rb1 deletion triggered the p53 independent apoptotic activity of E2F1.	7	17	triggered	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb1	Rb1	Rb1	E2F1	E2F1	E2F1	7	8	16	17
The Rb/E2F pathway is deregulated in most human brain tumors , and the finding that loss of E2F1 reduced pituitary tumorigenesis in Rb ( +/-) mice suggests that loss of pRb induces brain tumors by activating E2F1 .	The Rb/E2F pathway is deregulated in most human brain tumors, and the finding that loss of E2F1 reduced pituitary tumorigenesis in Rb (+/-) mice suggests that loss of pRb induces brain tumors by activating E2F1.	28	37	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRb	loss of pRb	prb	E2F1	E2F1	e2f1	30	31	36	37
Because the transcriptional activity of E2F1 is under the control of the tumor suppressor Rb , loss of Rb leads to constitutive activation of E2F1 and cancer development [ XREF_BIBR ] .	Because the transcriptional activity of E2F1 is under the control of the tumor suppressor Rb, loss of Rb leads to constitutive activation of E2F1 and cancer development [XREF_BIBR].	16	29	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Rb	loss of Rb	rb	E2F1	E2F1	e2f1	18	19	24	25
48 Double deletion of Rb and p130 are required to synergistically upregulate Myc , E2F-1 , and G 1 cyclin dependent kinases and expand the compartment of myocytes in S-phase and mitosis ( XREF_TABLE ) .	48 Double deletion of Rb and p130 are required to synergistically upregulate Myc, E2F-1, and G 1 cyclin dependent kinases and expand the compartment of myocytes in S-phase and mitosis (XREF_TABLE).	2	15	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F-1	E2F-1	E2F-1	4	5	14	15
Further studies revealed that , upon syncytialization , human chorionic gonadotropin reduced the phosphorylation of retinoblastoma protein ( pRB ) via activation of the cAMP and PKA pathway , which sequesters E2F transcription factor 1 ( E2F1 ) , the transcription factor for EZH2 expression .	Further studies revealed that, upon syncytialization, human chorionic gonadotropin reduced the phosphorylation of retinoblastoma protein (pRB) via activation of the cAMP and PKA pathway, which sequesters E2F transcription factor 1 (E2F1), the transcription factor for EZH2 expression.	9	41	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRB	chorionic gonadotropin reduced the phosphorylation of retinoblastoma protein (pRB	prb	E2F1	E2F1	e2f1	18	19	36	37
Over-expression of either Hmga1 or Hmga2 resulted in the development of mixed somatotroph and lactotroph pituitary adenomas by 16 months of age , and Hmga2 has been reported to enhance E2F1 activity , which is usually repressed by Rb to prevent progression through the cell cycle .	Over-expression of either Hmga1 or Hmga2 resulted in the development of mixed somatotroph and lactotroph pituitary adenomas by 16 months of age, and Hmga2 has been reported to enhance E2F1 activity, which is usually repressed by Rb to prevent progression through the cell cycle.	30	39	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	38	39	30	31
Reduced levels of CDC25A and CDK6 decreases the phosphorylation of pRB and subsequently inhibits the release of E2F1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Reduced levels of CDC25A and CDK6 decreases the phosphorylation of pRB and subsequently inhibits the release of E2F1 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRB	levels of CDC25A and CDK6 decreases the phosphorylation of pRB	prb	E2F1	E2F1	e2f1	10	11	17	18
Rb inhibits apoptosis by keeping E2F1 dependent apoptosis in check [ XREF_BIBR ] .	Rb inhibits apoptosis by keeping E2F1 dependent apoptosis in check [XREF_BIBR].	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	0	1	5	6
Here , we show that repression of E2F1 by RB leads to down-modulation of Bcl-2 ( XREF_SUPPLEMENTARY ; XREF_FIG ) , contributing to the triggering of autophagy .	Here, we show that repression of E2F1 by RB leads to down-modulation of Bcl-2 (XREF_SUPPLEMENTARY; XREF_FIG), contributing to the triggering of autophagy.	5	10	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	9	10	7	8
The molecular mechanisms involved in these roles have been elucidated in some biological systems : Rb sequesters the transcription factors of E2F-1 to regulate entry of cell cycle , but enhances the activities of transcription factors such as C / EBPs to initiate terminal differentiation .	The molecular mechanisms involved in these roles have been elucidated in some biological systems : Rb sequesters the transcription factors of E2F-1 to regulate entry of cell cycle, but enhances the activities of transcription factors such as C / EBPs to initiate terminal differentiation.	15	30	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F-1	E2F-1	E2F-1	15	16	21	22
XREF_FIG showed pRB deficiency impairs the ability of E2F1 to occupy the Alpl and Bglap promoters .	XREF_FIG showed pRB deficiency impairs the ability of E2F1 to occupy the Alpl and Bglap promoters.	2	9	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	2	3	8	9
We noticed that E2F1 protein was not increased by Rb1 deletion ( XREF_FIG lanes 1,2 ) , suggesting that E2F1 could be under negative regulation by protein degradation XREF_BIBR - XREF_BIBR .	We noticed that E2F1 protein was not increased by Rb1 deletion (XREF_FIG lanes 1,2), suggesting that E2F1 could be under negative regulation by protein degradation XREF_BIBR - XREF_BIBR.	3	10	increased	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Rb1	Rb1	Rb1	E2F1	E2F1	E2F1	9	10	3	4
This results in hypophosphorylation and activation of RB , which , in turn , sequesters the transcription factor E2F1 that regulates expression of genes involved in replication .	This results in hypophosphorylation and activation of RB, which, in turn, sequesters the transcription factor E2F1 that regulates expression of genes involved in replication.	3	19	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	hypophosphorylation and activation of RB	rb	transcription factor E2F1	transcription factor E2F1	transcription factor e2f1	7	8	16	19
When studied in the context of cell cycle progression , pRB generally antagonizes E2F1 .	When studied in the context of cell cycle progression, pRB generally antagonizes E2F1.	10	14	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	10	11	13	14
Furthermore , RB and hbrm cooperate to repress E2F1 activity in transient transfection assays .	Furthermore, RB and hbrm cooperate to repress E2F1 activity in transient transfection assays.	2	9	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	2	3	8	9
However , they argue that the primary role of pRb in bone differentiation is to inhibit E2F1 and thereby facilitate cell cycle exit .	However, they argue that the primary role of pRb in bone differentiation is to inhibit E2F1 and thereby facilitate cell cycle exit.	7	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	9	10	16	17
CAT reporter assays have shown that E2F-1 in association with its partner DP-1 transactivates its own promoter , whereas p105Rb inhibits the E2F-1 promoter .	CAT reporter assays have shown that E2F-1 in association with its partner DP-1 transactivates its own promoter, whereas p105Rb inhibits the E2F-1 promoter.	19	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p105Rb	p105Rb	p105Rb	E2F-1	E2F-1	E2F-1	19	20	22	23
Although HPV1 E7 showed the same affinity in vitro and in vivo for Rb1 as the high risk HPV E7s , it did not have the ability to activate the E2F-1 transcription factor inhibited by Rb1 , nor did it have any transforming activity when coexpressed with activated ras in primary rodent cells .	Although HPV1 E7 showed the same affinity in vitro and in vivo for Rb1 as the high risk HPV E7s, it did not have the ability to activate the E2F-1 transcription factor inhibited by Rb1, nor did it have any transforming activity when coexpressed with activated ras in primary rodent cells.	30	36	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Rb1	Rb1	Rb1	E2F-1	E2F-1	E2F-1	35	36	30	31
The retinoblastoma gene product , pRb , negatively regulates cell proliferation by modulating the activity of the transcription factor E2F1 that controls expression of S-phase genes .	The retinoblastoma gene product, pRb, negatively regulates cell proliferation by modulating the activity of the transcription factor E2F1 that controls expression of S-phase genes.	3	20	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	transcription factor E2F1	transcription factor E2F1	transcription factor E2F1	5	6	17	20
Therefore , pRB family members may inhibit E2F-1 activity , resulting in repression of E2F-1 target genes .	Therefore, pRB family members may inhibit E2F-1 activity, resulting in repression of E2F-1 target genes.	2	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F-1	E2F-1	E2F-1	2	3	7	8
Consequently , the retinoblastoma protein is hypophosphorylated , producing a concomitant inhibition of the transcription factor E2F1 ( necessary for cell growth and loss of differentiation ) and DHFR ( necessary for DNA synthesis .	Consequently, the retinoblastoma protein is hypophosphorylated, producing a concomitant inhibition of the transcription factor E2F1 (necessary for cell growth and loss of differentiation) and DHFR (necessary for DNA synthesis.	3	17	producing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	retinoblastoma protein	retinoblastoma protein is hypophosphorylated	retinoblastoma protein	transcription factor E2F1	transcription factor E2F1	transcription factor e2f1	3	5	14	17
In the developing or adult uninjured state , E2f1 is sequestered and inhibited by Rb1 , and ARF is inactive .	In the developing or adult uninjured state, E2f1 is sequestered and inhibited by Rb1, and ARF is inactive.	8	15	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Rb1	Rb1	Rb1	E2f1	E2f1	E2f1	14	15	8	9
Immunohistochemical analyses of thyroid tissue revealed that E2F1 , but not E2F2/3 , was selectively inactivated , indicating that the mutant Rb protein ( pRb ) suppressed thyroid tumors by inactivating E2F1 .	Immunohistochemical analyses of thyroid tissue revealed that E2F1, but not E2F2/3, was selectively inactivated, indicating that the mutant Rb protein (pRb) suppressed thyroid tumors by inactivating E2F1.	22	32	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	24	25	31	32
XREF_BIBR E2F1 is negatively regulated by pRb ( XREF_FIG ) , XREF_BIBR which is an important effector of the senescence phenotype .	XREF_BIBR E2F1 is negatively regulated by pRb (XREF_FIG), XREF_BIBR which is an important effector of the senescence phenotype.	0	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	6	7	1	2
Furthermore , ectopically expressed E2F1 , which is primarily inhibited by Rb under serum starved condition , represses Bin1 promoter activity in a manner that is dependent on the DNA binding and transactivation domains of E2F1 .	Furthermore, ectopically expressed E2F1, which is primarily inhibited by Rb under serum starved condition, represses Bin1 promoter activity in a manner that is dependent on the DNA binding and transactivation domains of E2F1.	3	12	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	11	12	4	5
RB1 has been shown to inhibit the E2F1 and E2F2 transcriptional factors [ XREF_BIBR ] ; therefore , the allelic deletion of RB1 that was observed in 85 % of breast cancer patients in our study is likely to lead to the activation of E2F1 and E2F2 .	RB1 has been shown to inhibit the E2F1 and E2F2 transcriptional factors [XREF_BIBR]; therefore, the allelic deletion of RB1 that was observed in 85% of breast cancer patients in our study is likely to lead to the activation of E2F1 and E2F2.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB1	RB1	RB1	E2F1	E2F1	E2F1	0	1	7	8
Aforementioned immunofluorescence and quantitative data indicate that FOXF2 re-expression suppresses CDK2 activity and consequently leads to dephosphorylation of RB , suggesting that RB function is activated to inhibit its downstream E2F1 transcriptional activity in FOXF2-re-expressing breast cancer cells .	Aforementioned immunofluorescence and quantitative data indicate that FOXF2 re-expression suppresses CDK2 activity and consequently leads to dephosphorylation of RB, suggesting that RB function is activated to inhibit its downstream E2F1 transcriptional activity in FOXF2-re-expressing breast cancer cells.	22	32	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	22	23	30	31
Since Rb is known to inhibit the transcriptional activity of E2F1 , this indicates a reduction in the expression of Cdc25A and TS upon TNF-alpha treatment .	Since Rb is known to inhibit the transcriptional activity of E2F1, this indicates a reduction in the expression of Cdc25A and TS upon TNF-alpha treatment.	1	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	1	2	10	11
It was also shown that in some cases binding of pRB and other pocket proteins to E2F-1 does not simply inhibit E2F-1 activity .	It was also shown that in some cases binding of pRB and other pocket proteins to E2F-1 does not simply inhibit E2F-1 activity.	10	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F-1	E2F-1	E2F-1	10	11	21	22
This exaggerated lipogenesis is associated with high levels of proliferation as indicated by Ki67 immunofluorescence , and increased cdk activity , leading to Rb inactivation and induction of E2F1 .	This exaggerated lipogenesis is associated with high levels of proliferation as indicated by Ki67 immunofluorescence, and increased cdk activity, leading to Rb inactivation and induction of E2F1.	23	29	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	23	24	28	29
We investigated how co-deletion of Skp2 and Rb1 led to further increased expression of E2F1 target genes .	We investigated how co-deletion of Skp2 and Rb1 led to further increased expression of E2F1 target genes.	3	16	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb1	Rb1	Rb1	E2F1	E2F1	E2F1	7	8	14	15
Cyclin E and A1 expression may be further refined by Shh through the increased negative regulation of Rb1 , which limits E2f1 activity .	Cyclin E and A1 expression may be further refined by Shh through the increased negative regulation of Rb1, which limits E2f1 activity.	15	22	limits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb1	Rb1	Rb1	E2f1	E2f1	E2f1	17	18	21	22
Our results showed that combination of 4-HPR and GST enhanced the stability of Rb , which in turn repressed E2F1 , MAD2 , and survivin to differential levels resulting in cell cycle arrest ( XREF_FIG ) .	Our results showed that combination of 4-HPR and GST enhanced the stability of Rb, which in turn repressed E2F1, MAD2, and survivin to differential levels resulting in cell cycle arrest (XREF_FIG).	11	24	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	13	14	19	20
Previous studies have indicated that pRb blocks E2F1 transcriptional activity by forming a stable complex with E2F1 XREF_BIBR .	Previous studies have indicated that pRb blocks E2F1 transcriptional activity by forming a stable complex with E2F1 XREF_BIBR.	5	9	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	5	6	7	8
When cells are in the quiescent phase , E2F-1 is inhibited by Rb ; during the G1/S transition , phosphorylated Rb dissociates from E2F-1 to activate E2F-1 , and E2F-1 can then initiate the expression of a series of cell proliferation related proteins , including survivin [ XREF_BIBR ] .	When cells are in the quiescent phase, E2F-1 is inhibited by Rb; during the G1/S transition, phosphorylated Rb dissociates from E2F-1 to activate E2F-1, and E2F-1 can then initiate the expression of a series of cell proliferation related proteins, including survivin [XREF_BIBR].	19	27	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb	Rb	E2F-1	E2F-1	E2F-1	20	21	26	27
At the same time , like E1A or E7 , the binding of Raf-1 to Rb relieved the Rb mediated repression of E2F1 transcriptional activity .	At the same time, like E1A or E7, the binding of Raf-1 to Rb relieved the Rb mediated repression of E2F1 transcriptional activity.	17	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	18	19	22	23
E2F1 is a key transcriptional regulator of DNA replication and cell-cycle progression , and is negatively regulated by the RB1 tumor suppressor XREF_BIBR .	E2F1 is a key transcriptional regulator of DNA replication and cell-cycle progression, and is negatively regulated by the RB1 tumor suppressor XREF_BIBR.	0	22	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RB1	RB1	RB1	E2F1	E2F1	E2F1	19	20	0	1
XREF_BIBR These studies therefore highlight a complex interplay between E2F1 and pRB under DNA damage conditions , which deviates from the simplistic cell cycle regulated pRB mediated repression of E2F1 .	XREF_BIBR These studies therefore highlight a complex interplay between E2F1 and pRB under DNA damage conditions, which deviates from the simplistic cell cycle regulated pRB mediated repression of E2F1.	24	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	25	26	29	30
The first one involves Rb that associates with and represses E2F1 before S phase entry .	The first one involves Rb that associates with and represses E2F1 before S phase entry.	3	11	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	4	5	10	11
As shown in XREF_FIG , we found that pRb was significantly more potent than RIP140 to inhibit E2F1 activity on both reporters , except on the cyclin E promoter in the presence of E2F1 alone .	As shown in XREF_FIG, we found that pRb was significantly more potent than RIP140 to inhibit E2F1 activity on both reporters, except on the cyclin E promoter in the presence of E2F1 alone.	8	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	8	9	17	18
Here we report that two kinases involved in signal transduction have opposite effects on E2F function : the stress induced kinase JNK1 inhibits E2F1 activity whereas the related p38 kinase reverses Rb mediated repression of E2F1 .	Here we report that two kinases involved in signal transduction have opposite effects on E2F function : the stress induced kinase JNK1 inhibits E2F1 activity whereas the related p38 kinase reverses Rb mediated repression of E2F1.	31	36	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	31	32	35	36
This result may indicate that the RB expression was controlled by E2F-1 and pRB and E2F-1 was inhibited by pRB during S phase but not in G 0 / G 1 .	This result may indicate that the RB expression was controlled by E2F-1 and pRB and E2F-1 was inhibited by pRB during S phase but not in G 0 / G 1.	15	20	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F-1	E2F-1	E2F-1	19	20	15	16
Reduced RB abundance , in turn , impairs E2F1 transcriptional inhibition , leading to increased peptidyl-prolyl cis-trans isomerase never-in-mitosis A ( NIMA )-interacting 1 ( PIN1 ) levels , human keratinocyte neoplastic cell transformation , and melanoma tumorigenesis via enhanced rapidly accelerated fibrosarcoma 1 ( RAF1 )-MEK-ERK signaling pathway activation .	Reduced RB abundance, in turn, impairs E2F1 transcriptional inhibition, leading to increased peptidyl-prolyl cis-trans isomerase never-in-mitosis A (NIMA)-interacting 1 (PIN1) levels, human keratinocyte neoplastic cell transformation, and melanoma tumorigenesis via enhanced rapidly accelerated fibrosarcoma 1 (RAF1)-MEK-ERK signaling pathway activation.	1	10	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	1	2	8	9
Since cyclin A binding to E2F1 inhibits E2F1 activity , the cyclin A unbound E2F1 activated E2F target genes to a higher degree than by loss of pRb alone .	Since cyclin A binding to E2F1 inhibits E2F1 activity, the cyclin A unbound E2F1 activated E2F target genes to a higher degree than by loss of pRb alone.	12	28	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	pRb	loss of pRb	prb	E2F1	E2F1	e2f1	27	28	14	15
Thus , although E2F1 sensitive transcription is indeed suppressed by Rb expression , these results strongly argue that E2F1 mediated transcriptional control over the presence of these proteins does not acutely regulate G 1 -S progression .	Thus, although E2F1 sensitive transcription is indeed suppressed by Rb expression, these results strongly argue that E2F1 mediated transcriptional control over the presence of these proteins does not acutely regulate G 1 -S progression.	3	12	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Rb	Rb expression	rb	E2F1	E2F1	e2f1	10	11	3	4
Our data indicate that RB induces autophagy by repressing E2F1 activity , and E2F1 antagonizes RB activity to prevent autophagy .	Our data indicate that RB induces autophagy by repressing E2F1 activity, and E2F1 antagonizes RB activity to prevent autophagy.	4	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RB	RB	RB	E2F1	E2F1	E2F1	4	5	9	10
Rb phosphorylation at serines 780 , 807 , and 811 inhibits sequestering of the E2F1 transcription factor .	Rb phosphorylation at serines 780, 807, and 811 inhibits sequestering of the E2F1 transcription factor.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb phosphorylation	rb	E2F1	E2F1	e2f1	0	1	14	15
Unphosphorylated Rb sequesters E2F1 , a key transcription factor promoting S-phase cell cycle progression , while p16 INK4A and p21 CIP1 stimulates this event by inhibiting cyclin dependent kinases [ XREF_BIBR ] .	Unphosphorylated Rb sequesters E2F1, a key transcription factor promoting S-phase cell cycle progression, while p16 INK4A and p21 CIP1 stimulates this event by inhibiting cyclin dependent kinases [XREF_BIBR].	0	8	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Unphosphorylated Rb	rb	E2F1	E2F1	e2f1	1	2	3	4
Under normal conditions , cyclin E is transcriptionally induced in late G1 by E2F1 , which is activated by pRb de-repression ( XREF_FIG ) .	Under normal conditions, cyclin E is transcriptionally induced in late G1 by E2F1, which is activated by pRb de-repression (XREF_FIG).	8	20	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	19	20	13	14
It was found that co-transfection of E2F1 led to a significant induction of all the three promoters ( XREF_FIG ) ; further , co-transfection of the large pocket region of Rb ( Rb-LP ) or the full length Rb ( Rb-FL ) could repress the E2F1 mediated induction .	It was found that co-transfection of E2F1 led to a significant induction of all the three promoters (XREF_FIG); further, co-transfection of the large pocket region of Rb (Rb-LP) or the full length Rb (Rb-FL) could repress the E2F1 mediated induction.	28	46	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	30	31	45	46
Unphosphorylated pRb suppresses the cell cycle regulator E2f1 forcing cell cycle exit and preventing cell cycle re-entry .	Unphosphorylated pRb suppresses the cell cycle regulator E2f1 forcing cell cycle exit and preventing cell cycle re-entry.	0	13	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	Unphosphorylated pRb	prb	E2f1	E2f1	e2f1	1	2	7	8
It was found that co-transfection of E2F1 alone led to a significant induction of all the four promoters ( XREF_FIG ) ; further , co-transfection of the large pocket region of Rb ( Rb-LP ) could repress the E2F1 mediated induction .	It was found that co-transfection of E2F1 alone led to a significant induction of all the four promoters (XREF_FIG); further, co-transfection of the large pocket region of Rb (Rb-LP) could repress the E2F1 mediated induction.	29	39	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	31	32	38	39
In its active state , Rb is hypophosphorylated and inhibits the transcription factors E2F-DP ( E2F-1 , -2 , and -3 ) .	In its active state, Rb is hypophosphorylated and inhibits the transcription factors E2F-DP (E2F-1, -2, and -3).	5	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb is hypophosphorylated	rb	E2F-1	E2F-1	e2f-1	5	6	15	16
Here , we show that Rb1 deletion induces higher expression of E2F1 target genes in the absence of Skp2 .	Here, we show that Rb1 deletion induces higher expression of E2F1 target genes in the absence of Skp2.	5	13	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb1	Rb1	Rb1	E2F1	E2F1	E2F1	5	6	11	12
During most of the G1 phase , E2F1 and DP1 activity is repressed by the retinoblastoma gene product RB , which directly contacts the E2F1 activation domain and silences it .	During most of the G1 phase, E2F1 and DP1 activity is repressed by the retinoblastoma gene product RB, which directly contacts the E2F1 activation domain and silences it.	7	28	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	18	19	7	8
Despite this p21 inhibitory function , the inhibition of CDK activity determines the inactivation of the retinoblastoma tumor suppressor protein ( pRB ) that in turn sequesters E2F1 ( E2 Family Member 1 ) , thus leading to apoptosis induction XREF_BIBR .	Despite this p21 inhibitory function, the inhibition of CDK activity determines the inactivation of the retinoblastoma tumor suppressor protein (pRB) that in turn sequesters E2F1 (E2 Family Member 1), thus leading to apoptosis induction XREF_BIBR.	13	36	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	21	22	27	28
Skp2 and Rb1 co-deletion increases E2F1 on target promoters .	Skp2 and Rb1 co-deletion increases E2F1 on target promoters.	0	8	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb1	Rb1	Rb1	E2F1	E2F1	E2F1	2	3	5	6
In its hypo phosphorylated form , pRb binds to and inhibits the activity of E2F1 , a transcription factor whose target genes are necessary for cell cycle progression .	In its hypo phosphorylated form, pRb binds to and inhibits the activity of E2F1, a transcription factor whose target genes are necessary for cell cycle progression.	6	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	6	7	14	15
RB1 is a transcriptional repressor of E2F1 and , when active , leads to cell cycle arrest .	RB1 is a transcriptional repressor of E2F1 and, when active, leads to cell cycle arrest.	0	7	is a transcriptional repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	RB1	RB1	RB1	E2F1	E2F1	E2F1	0	1	6	7
The E2F1 transcription factor , which is negatively regulated by the pRB and p16 ( INK4a ) tumor suppressor pathway , was implicated in the up-regulation of survivin .	The E2F1 transcription factor, which is negatively regulated by the pRB and p16 (INK4a) tumor suppressor pathway, was implicated in the up-regulation of survivin.	1	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	11	12	1	2
Generally , E2F1 is bound to and functionally inactivated by pRB ; however , proliferative signals induce the phosphorylation of pRB by cyclinD/CDK4/6 complexes leading to the dissociation of pRB from E2F1 , and the subsequent activation of E2F1 target genes [ XREF_BIBR ] .	Generally, E2F1 is bound to and functionally inactivated by pRB; however, proliferative signals induce the phosphorylation of pRB by cyclinD/CDK4/6 complexes leading to the dissociation of pRB from E2F1, and the subsequent activation of E2F1 target genes [XREF_BIBR].	2	11	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	10	11	2	3
While pRb represses E2F1 ,2,3 , p53 represses expression of miR-17 ~ 92 ; and miR-17 ~ 92 is frequently overexpressed in human retinoblastoma .	While pRb represses E2F1,2,3, p53 represses expression of miR-17 ~ 92; and miR-17 ~ 92 is frequently overexpressed in human retinoblastoma.	1	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	1	2	3	4
This indicates that Rb is repressing E2F1 activity on this pro apoptotic promoter in AoSMCs ( XREF_FIG ) .	This indicates that Rb is repressing E2F1 activity on this pro apoptotic promoter in AoSMCs (XREF_FIG).	3	7	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	3	4	6	7
Given that E2F1 activity is stimulated by p300 and CBP acetylase and repressed by an RB associated deacetylase , we asked if E2F1 was subject to modification by acetylation .	Given that E2F1 activity is stimulated by p300 and CBP acetylase and repressed by an RB associated deacetylase, we asked if E2F1 was subject to modification by acetylation.	2	16	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	15	16	2	3
Both cyclin E and E2F1 , required for entry into S phase of the cell cycle , are repressed by active RB1 and are used as markers for RB regulated gene expression .	Both cyclin E and E2F1, required for entry into S phase of the cell cycle, are repressed by active RB1 and are used as markers for RB regulated gene expression.	2	22	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RB1	RB1	RB1	E2F1	E2F1	E2F1	21	22	4	5
This effect was associated with repression of the cyclin E promoter and was independent of known E2F-1 repressors , such as pRB family members .	This effect was associated with repression of the cyclin E promoter and was independent of known E2F-1 repressors, such as pRB family members.	16	23	repressors	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F-1	E2F-1	E2F-1	21	22	16	17
Therefore , MYC amplification and RB1 deletion , the genomic abnormalities that are frequently observed in a wide range of cancer types , may drive an EZH2 and E2F1 dependent transcriptional program for cancer progression .	Therefore, MYC amplification and RB1 deletion, the genomic abnormalities that are frequently observed in a wide range of cancer types, may drive an EZH2 and E2F1 dependent transcriptional program for cancer progression.	5	31	drive	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RB1	RB1	RB1	E2F1	E2F1	E2F1	5	6	28	29
Functional loss of RB1 causes accelerated E2F1 mediated transactivation , followed by uncontrolled cell cycle progression .	Functional loss of RB1 causes accelerated E2F1 mediated transactivation, followed by uncontrolled cell cycle progression.	1	8	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RB1	loss of RB1	rb1	E2F1	E2F1	e2f1	3	4	6	7
The data revealed that E2F1 activity was blocked by the binding of RB .	The data revealed that E2F1 activity was blocked by the binding of RB.	4	13	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	12	13	4	5
Co-deletion of Skp2 and Rb1 induced more E2F1 occupancy to these promoters than deletion of Rb1 ( green columns 1,2 ) .	Co-deletion of Skp2 and Rb1 induced more E2F1 occupancy to these promoters than deletion of Rb1 (green columns 1,2).	0	8	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb1	Rb1	Rb1	E2F1	E2F1	E2F1	4	5	7	8
Rb contributes to the assembly of repressor complexes and inhibits the pro apoptotic transcription factor E2F1 .	Rb contributes to the assembly of repressor complexes and inhibits the pro apoptotic transcription factor E2F1.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	transcription factor E2F1	transcription factor E2F1	transcription factor E2F1	0	1	13	16
Accordingly , the proportion of E2F1 sequestered by Rb was reduced in wildtype NPCs expressing caAMPK , where as dnAMPK caused significantly more E2F1 sequestration ( XREF_FIG ) .	Accordingly, the proportion of E2F1 sequestered by Rb was reduced in wildtype NPCs expressing caAMPK, where as dnAMPK caused significantly more E2F1 sequestration (XREF_FIG).	3	9	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	8	9	5	6
However , it is paradoxical that PAX8 also promotes RB protein stability , as it seems that PAX8 simultaneously regulates a function that opposes the facilitation of E2F1 expression in tumor cell lines , as RB is known to inhibit the role of E2F1 .	However, it is paradoxical that PAX8 also promotes RB protein stability, as it seems that PAX8 simultaneously regulates a function that opposes the facilitation of E2F1 expression in tumor cell lines, as RB is known to inhibit the role of E2F1.	35	44	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	35	36	43	44
In contrast , the leucine repeat element was not important for Rb- or p107 mediated inhibition of E2F1 activity .	In contrast, the leucine repeat element was not important for Rb- or p107 mediated inhibition of E2F1 activity.	11	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb-	Rb-	Rb-	E2F1	E2F1	E2F1	11	12	17	18
For example , MDM2 was shown to bind to and ubiquitinate Rb , resulting in Rb degradation and release of the E2F1 that promotes cell cycle progression .	For example, MDM2 was shown to bind to and ubiquitinate Rb, resulting in Rb degradation and release of the E2F1 that promotes cell cycle progression.	15	23	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	15	16	21	22
Moreover , H1.2 expression augmented the E2F1 transcriptional repression mediated by pRb in reporter based assays ( XREF_SUPPLEMENTARY C ) .	Moreover, H1.2 expression augmented the E2F1 transcriptional repression mediated by pRb in reporter based assays (XREF_SUPPLEMENTARY C).	6	12	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	11	12	6	7
While either RB loss of function or E2F1 gain of function may sensitize cells to apoptosis , the mechanisms underlying these effects are not well understood .	While either RB loss of function or E2F1 gain of function may sensitize cells to apoptosis, the mechanisms underlying these effects are not well understood.	2	8	loss	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	RB	RB	RB	E2F1	E2F1	E2F1	2	3	7	8
PRB protein , in its unphosphorylated state , inhibits the progression of the cell cycle from the G1 to the S phase by sequestering the transcription factor E2F1 .	PRB protein, in its unphosphorylated state, inhibits the progression of the cell cycle from the G1 to the S phase by sequestering the transcription factor E2F1.	0	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PRB	PRB	PRB	transcription factor E2F1	transcription factor E2F1	transcription factor E2F1	0	1	25	28
However , it is still unclear how TNF-alpha affects Rb mediated E2F1 repression and downstream pathways cause apoptotic response in endothelial cells .	However, it is still unclear how TNF-alpha affects Rb mediated E2F1 repression and downstream pathways cause apoptotic response in endothelial cells.	8	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	9	10	11	12
Loss of pRB specifically activates E2F1 to transcriptionally activate ARF through a novel response element that has activity in various tumor cells with defective pRB , but not in normally growing cells [ XREF_BIBR ] .	Loss of pRB specifically activates E2F1 to transcriptionally activate ARF through a novel response element that has activity in various tumor cells with defective pRB, but not in normally growing cells [XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRB	Loss of pRB	prb	E2F1	E2F1	e2f1	2	3	5	6
It should also be taken into account that pRB loss of function also leads to multiple E2F1 independent effects .	It should also be taken into account that pRB loss of function also leads to multiple E2F1 independent effects.	8	18	leads	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	8	9	16	17
In proliferating C2 myoblasts as well as in other cell types , it has often been suggested that E2F1 , which activates a number of S phase genes , is negatively regulated by Rb , and that this is one way in which Rb inhibits the progression of cells into S phase .	In proliferating C2 myoblasts as well as in other cell types, it has often been suggested that E2F1, which activates a number of S phase genes, is negatively regulated by Rb, and that this is one way in which Rb inhibits the progression of cells into S phase.	18	34	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	33	34	18	19
Since the Wnt signaling pathway promotes cell proliferation and survival in some cell types , inhibition of E2F1 by Rb is required for the proliferation of these cells .	Since the Wnt signaling pathway promotes cell proliferation and survival in some cell types, inhibition of E2F1 by Rb is required for the proliferation of these cells.	15	20	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	19	20	17	18
Notably the transcription of these genes , with the exception of PTEN and AURA , are dependent upon E2F1 , a transcription factor that is negatively regulated by Rb .	Notably the transcription of these genes, with the exception of PTEN and AURA, are dependent upon E2F1, a transcription factor that is negatively regulated by Rb.	16	29	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	28	29	18	19
Bypassing CDK2 inhibition requires an additional function of E1A : the mutant E1A Delta26-35 does not overcome p27 induced arrest , while it binds pRb family proteins , prevents p16 induced arrest , and alleviates pRb mediated repression of E2F-1 transcriptional activity ( although E1A Delta26-35 fails to restore expression of E2F regulated genes in p27 arrested cells ) .	Bypassing CDK2 inhibition requires an additional function of E1A : the mutant E1A Delta26-35 does not overcome p27 induced arrest, while it binds pRb family proteins, prevents p16 induced arrest, and alleviates pRb mediated repression of E2F-1 transcriptional activity (although E1A Delta26-35 fails to restore expression of E2F regulated genes in p27 arrested cells).	35	41	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F-1	E2F-1	E2F-1	35	36	39	40
By contrast , complete loss of RB1 caused increased activation of the E2F1 pathway resulting in embryonic lethality that was partially reversed by E2F1 deletion [ XREF_BIBR ] .	By contrast, complete loss of RB1 caused increased activation of the E2F1 pathway resulting in embryonic lethality that was partially reversed by E2F1 deletion [XREF_BIBR].	4	13	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RB1	loss of RB1	rb1	E2F1	E2F1	e2f1	6	7	12	13
Inactivation of the retinoblastoma tumor suppressor ( pRb ) gene that occurs in many tumor cells lines , can deregulate activity of E2F1 transcription factor , a mechanism which links to induction of DSBs .	Inactivation of the retinoblastoma tumor suppressor (pRb) gene that occurs in many tumor cells lines, can deregulate activity of E2F1 transcription factor, a mechanism which links to induction of DSBs.	0	24	deregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	7	8	22	23
Raf-1 has been shown to bind to and suppress MST2 by preventing MST2 dimerization in a kinase independent manner XREF_BIBR .	Raf-1 has been shown to bind to and suppress MST2 by preventing MST2 dimerization in a kinase independent manner XREF_BIBR.	0	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MST2	MST2	MST2	0	1	9	10
While Mst2 is negatively regulated by Raf-1 , conversely , Mst2 regulates Raf-1 [ XREF_BIBR , XREF_BIBR ] .	While Mst2 is negatively regulated by Raf-1, conversely, Mst2 regulates Raf-1 [XREF_BIBR, XREF_BIBR].	1	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	Mst2	Mst2	Mst2	6	7	1	2
Further examination revealed that Raf-1 inhibits Mst2 activation by two mechanisms : first , by preventing homodimerization of Mst2 , and second , by recruiting a phosphatase that removes activating phosphorylations on Mst2 [ XREF_BIBR , XREF_BIBR ] .	Further examination revealed that Raf-1 inhibits Mst2 activation by two mechanisms : first, by preventing homodimerization of Mst2, and second, by recruiting a phosphatase that removes activating phosphorylations on Mst2 [XREF_BIBR, XREF_BIBR].	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	Mst2	Mst2	Mst2	4	5	6	7
Recently , we showed that Raf-1 kinase sequesters and inhibits MST2 and that this event is critical for Raf mediated cell survival .	Recently, we showed that Raf-1 kinase sequesters and inhibits MST2 and that this event is critical for Raf mediated cell survival.	5	11	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MST2	MST2	MST2	5	6	10	11
The RAF-1 kinase also inhibits cell death pathways mediated by apoptosis signal regulating kinase 1 ( ASK1 ) as well as mammalian sterile 20 kinase 2 ( MST2 ) .	The RAF-1 kinase also inhibits cell death pathways mediated by apoptosis signal regulating kinase 1 (ASK1) as well as mammalian sterile 20 kinase 2 (MST2).	1	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RAF-1	RAF-1	RAF-1	MST2	MST2	MST2	1	2	27	28
Moreover , Raf1 inhibits MST2 activity thus preventing apoptosis XREF_BIBR .	Moreover, Raf1 inhibits MST2 activity thus preventing apoptosis XREF_BIBR.	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf1	Raf1	Raf1	MST2	MST2	MST2	2	3	4	5
Mst2 is negatively regulated by the proto-oncoprotein Raf-1 in a manner independent of the kinase activity of Raf-1 .	Mst2 is negatively regulated by the proto-oncoprotein Raf-1 in a manner independent of the kinase activity of Raf-1.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	Mst2	Mst2	Mst2	7	8	0	1
102 Raf1 ( and ARaf but not BRaf ) was shown to bind the MST2 SARAH domain , inhibiting MST2 homodimerization and activation ; this inhibition does not require Raf1 kinase activity , providing a mechanism by which a kinase-inactive cRaf1 could suppress apoptosis , i.e ., by binding and suppressing MST2 activation .	102 Raf1 (and ARaf but not BRaf) was shown to bind the MST2 SARAH domain, inhibiting MST2 homodimerization and activation; this inhibition does not require Raf1 kinase activity, providing a mechanism by which a kinase-inactive cRaf1 could suppress apoptosis, i.e., by binding and suppressing MST2 activation.	0	20	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf1	Raf1	Raf1	MST2	MST2	MST2	1	2	19	20
Further , Raf1 reconstitution abrogated Mst2 kinase activity , suggesting that Mst2 homodimerization is required for Mst2 activity [ XREF_BIBR ] .	Further, Raf1 reconstitution abrogated Mst2 kinase activity, suggesting that Mst2 homodimerization is required for Mst2 activity [XREF_BIBR].	2	7	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf1	Raf1	Raf1	Mst2	Mst2	Mst2	2	3	5	6
Finally , Raf-1 forms a complex with and inhibits the proapoptotic kinases ASK-1 and MST-2 .	Finally, Raf-1 forms a complex with and inhibits the proapoptotic kinases ASK-1 and MST-2.	2	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MST-2	MST-2	MST-2	2	3	14	15
Here , the RAF kinases CRAF and ARAF sequester and inhibit the pro apoptotic kinase MST2 independently of their own kinase activity .	Here, the RAF kinases CRAF and ARAF sequester and inhibit the pro apoptotic kinase MST2 independently of their own kinase activity.	2	16	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CRAF	CRAF	CRAF	MST2	MST2	MST2	5	6	15	16
Raf-1 competes with RASSF1A for MST2 binding , thus suppressing MST2 activation and apoptosis [ XREF_BIBR ] .	Raf-1 competes with RASSF1A for MST2 binding, thus suppressing MST2 activation and apoptosis [XREF_BIBR].	0	11	suppressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MST2	MST2	MST2	0	1	10	11
XREF_BIBR Interestingly , the inhibition of MST2 by Raf-1 does not require Raf kinase activity but only relies on binding .	XREF_BIBR Interestingly, the inhibition of MST2 by Raf-1 does not require Raf kinase activity but only relies on binding.	4	9	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MST2	MST2	MST2	8	9	6	7
Taken together , these results suggest that Raf-1 inhibits ASK1 in an MKK and ERK independent manner , and also suggest that B-Raf and A-Raf function in parallel with Raf-1 to promote ERK1/2 activation in heart .	Taken together, these results suggest that Raf-1 inhibits ASK1 in an MKK and ERK independent manner, and also suggest that B-Raf and A-Raf function in parallel with Raf-1 to promote ERK1/2 activation in heart.	7	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	ASK1	ASK1	ASK1	7	8	9	10
This demonstrates that the increased expression of RAF-1 might have antagonized and suppressed ASK-1 , with consequently reduced apoptosis and increased insulin contents .	This demonstrates that the increased expression of RAF-1 might have antagonized and suppressed ASK-1, with consequently reduced apoptosis and increased insulin contents.	5	14	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RAF-1	expression of RAF-1	raf-1	ASK-1	ASK-1	ask-1	7	8	13	14
First , Raf-1 overexpression has been shown to increase cell survival by inhibiting ASK-1 function in the presence of the Mek pharmacological inhibitors PD98059 and U0126 [ XREF_BIBR ] .	First, Raf-1 overexpression has been shown to increase cell survival by inhibiting ASK-1 function in the presence of the Mek pharmacological inhibitors PD98059 and U0126 [XREF_BIBR].	2	14	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Raf-1	Raf-1 overexpression	raf-1	ASK-1	ASK-1	ask-1	2	3	13	14
For example , Raf-1 is both a protein kinase and an ASK1 inhibitor : if the kinase function of Raf-1 is inhibited with a small molecule inhibitor , the ability of Raf-1 to bind to and inhibit ASK1 remains [ XREF_BIBR ] .	For example, Raf-1 is both a protein kinase and an ASK1 inhibitor : if the kinase function of Raf-1 is inhibited with a small molecule inhibitor, the ability of Raf-1 to bind to and inhibit ASK1 remains [XREF_BIBR].	17	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	ASK1	ASK1	ASK1	19	20	37	38
One example is ASK1 , which was shown to be suppressed by CRAF independent of MEK-ERK pathway XREF_BIBR .	One example is ASK1, which was shown to be suppressed by CRAF independent of MEK-ERK pathway XREF_BIBR.	1	17	suppressed	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	CRAF	CRAF	CRAF	ASK1	ASK1	ASK1	12	13	3	4
Inhibition of either Raf-1 or ALG-2 ( apoptosis linked gene 2 ) expression results in apoptosis signal regulating kinase 1/c-Jun N-terminal kinase ( ASK1 and JNK ) signaling activation , and cell sensitivity to chemotherapeutic reagents , indicating that inhibition of ASK1 and JNK apoptotic signaling by Raf-1 is mediated by ALG-2 .	Inhibition of either Raf-1 or ALG-2 (apoptosis linked gene 2) expression results in apoptosis signal regulating kinase 1/c-Jun N-terminal kinase (ASK1 and JNK) signaling activation, and cell sensitivity to chemotherapeutic reagents, indicating that inhibition of ASK1 and JNK apoptotic signaling by Raf-1 is mediated by ALG-2.	41	48	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Raf-1	Raf-1	Raf-1	ASK1	ASK1	ASK1	47	48	41	42
Although the direct mechanism of inhibition is not known yet , the pathophysiological relevance of ASK1 inhibition by Raf-1 was demonstrated in a mouse model of heart disease [ XREF_BIBR ] .	Although the direct mechanism of inhibition is not known yet, the pathophysiological relevance of ASK1 inhibition by Raf-1 was demonstrated in a mouse model of heart disease [XREF_BIBR].	15	19	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	ASK1	ASK1	ASK1	18	19	15	16
Rb inhibits the Abl tyrosine kinase .	Rb inhibits the Abl tyrosine kinase.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	Abl	Abl	Abl	0	1	3	4
RB negatively regulates the kinase activity of c-Abl .	RB negatively regulates the kinase activity of c-Abl.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	RB	RB	c-Abl	c-Abl	c-Abl	0	1	7	8
We also show that ectopic expression of Rb induces apoptosis in Abl dependent tumor cells by inhibiting the Abl tyrosine kinase activity , and that Rb induced apoptosis is compromised by Abl catalysed phosphorylation of Rb at Y805 .	We also show that ectopic expression of Rb induces apoptosis in Abl dependent tumor cells by inhibiting the Abl tyrosine kinase activity, and that Rb induced apoptosis is compromised by Abl catalysed phosphorylation of Rb at Y805.	5	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	expression of Rb	rb	Abl	Abl	abl	7	8	11	12
In the nucleus , c-Abl activity is negatively regulated by the retinoblastoma protein ( RB ) and positively regulated by DNA damage signals .	In the nucleus, c-Abl activity is negatively regulated by the retinoblastoma protein (RB) and positively regulated by DNA damage signals.	4	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	c-Abl	c-Abl	c-Abl	11	13	4	5
RB binds to the ATP binding lobe in the kinase domain and inhibits the nuclear pool of c-Abl in quiescent and G1 cells .	RB binds to the ATP binding lobe in the kinase domain and inhibits the nuclear pool of c-Abl in quiescent and G1 cells.	0	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	RB	RB	c-Abl	c-Abl	c-Abl	0	1	17	18
To determine the mechanism by which ecSOD enhances VEGFR2 autophosphorylation , we examined whether ecSOD derived H 2 O 2 may inactivate PTPs such as DEP-1 and PTP1B , which negatively regulate VEGFR2 activation XREF_BIBR , XREF_BIBR .	To determine the mechanism by which ecSOD enhances VEGFR2 autophosphorylation, we examined whether ecSOD derived H 2 O 2 may inactivate PTPs such as DEP-1 and PTP1B, which negatively regulate VEGFR2 activation XREF_BIBR, XREF_BIBR.	22	34	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEP-1	DEP-1	DEP-1	VEGFR2	VEGFR2	VEGFR2	25	26	32	33
In previous studies , we showed that the phosphatase DEP-1 and CD148 can reduce VEGFR-2 signaling .	In previous studies, we showed that the phosphatase DEP-1 and CD148 can reduce VEGFR-2 signaling.	7	15	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEP-1	DEP-1	DEP-1	VEGFR-2	VEGFR-2	VEGFR-2	9	10	14	15
We report that DEP-1 and CD148 could prevent VEGFR-2 internalization along with the reduction of receptor phosphorylation and signaling .	We report that DEP-1 and CD148 could prevent VEGFR-2 internalization along with the reduction of receptor phosphorylation and signaling.	3	9	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEP-1	DEP-1	DEP-1	VEGFR-2	VEGFR-2	VEGFR-2	3	4	8	9
Wild-type DEP-1 ( DEPwt ) and the scrambled oligonucleotides slightly , but not significantly , reduced VEGFR-2 activation .	Wild-type DEP-1 (DEPwt) and the scrambled oligonucleotides slightly, but not significantly, reduced VEGFR-2 activation.	0	17	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DEP-1	DEP-1	DEP-1	VEGFR-2	VEGFR-2	VEGFR-2	1	2	16	17
When rassf6 is bound to MST2 , rassf6 inhibits MST2 activity , thus , inhibiting its role in the Hippo pathway .	When rassf6 is bound to MST2, rassf6 inhibits MST2 activity, thus, inhibiting its role in the Hippo pathway.	7	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	rassf6	rassf6	rassf6	MST2	MST2	MST2	7	8	9	10
An exception is RASSF6 , which has been reported to inhibit Mst2 .	An exception is RASSF6, which has been reported to inhibit Mst2.	1	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RASSF6	RASSF6	RASSF6	Mst2	Mst2	Mst2	3	4	11	12
Importantly , RASSF2 , RASSF4 , and RASSF6 inhibit MST2 under the same condition , and the chimera construct harboring the N-terminal region of RASSF1A and the C-terminal region of RASSF6 activates MST2 , supporting that the activation of MST2 is specific for RASSF1A and is mediated by the N-terminal region of RASSF1A .	Importantly, RASSF2, RASSF4, and RASSF6 inhibit MST2 under the same condition, and the chimera construct harboring the N-terminal region of RASSF1A and the C-terminal region of RASSF6 activates MST2, supporting that the activation of MST2 is specific for RASSF1A and is mediated by the N-terminal region of RASSF1A.	28	33	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	RASSF6	RASSF6	RASSF6	MST2	MST2	MST2	30	31	32	33
RASSF6 inhibited MST2 and antagonized Hippo signaling in a manner similar to that of dRASSF [ XREF_BIBR ] .	RASSF6 inhibited MST2 and antagonized Hippo signaling in a manner similar to that of dRASSF [XREF_BIBR].	0	4	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RASSF6	RASSF6	RASSF6	MST2	MST2	MST2	0	1	2	3
In addition , RanBPM and HGF inhibited the function of Mirk as a transcriptional coactivator .	In addition, RanBPM and HGF inhibited the function of Mirk as a transcriptional coactivator.	3	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RanBPM	RanBPM	RanBPM	Mirk	Mirk	Mirk	3	4	10	11
Next we addressed the effect of RanBPM on Dyrk1B by co-expression of the two proteins in Neuro 2a cells for 16 h. Unexpectedly , we found that RanBPM significantly enhanced proteasomal degradation of Dyrk1B in a dose dependent manner , a phenomenon that was inhibited by MG132 ( XREF_FIG ) .	Next we addressed the effect of RanBPM on Dyrk1B by co-expression of the two proteins in Neuro 2a cells for 16 h. Unexpectedly, we found that RanBPM significantly enhanced proteasomal degradation of Dyrk1B in a dose dependent manner, a phenomenon that was inhibited by MG132 (XREF_FIG).	27	34	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RanBPM	RanBPM	RanBPM	Dyrk1B	Dyrk1B	Dyrk1B	27	28	33	34
As these results were obtained by in vitro kinase assays with GST-fusion proteins in the absence of a cellular context , the authors could not have observed a RanBPM induced proteasomal degradation of Dyrk1B .	As these results were obtained by in vitro kinase assays with GST-fusion proteins in the absence of a cellular context, the authors could not have observed a RanBPM induced proteasomal degradation of Dyrk1B.	27	34	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RanBPM	RanBPM	RanBPM	Dyrk1B	Dyrk1B	Dyrk1B	28	29	33	34
The RanBPM dependent degradation of Dyrk1B could be prevented by Cend1 , as shown here , resulting in segregation of Dyrk1B in the nucleus of triple transfected Neuro 2a cells co-expressing RanBPM , Dyrk1B and Cend1 ( XREF_FIG ) .	The RanBPM dependent degradation of Dyrk1B could be prevented by Cend1, as shown here, resulting in segregation of Dyrk1B in the nucleus of triple transfected Neuro 2a cells co-expressing RanBPM, Dyrk1B and Cend1 (XREF_FIG).	1	6	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	RanBPM	RanBPM	RanBPM	Dyrk1B	Dyrk1B	Dyrk1B	1	2	5	6
RanBPM inhibited the kinase activity of Mirk and Dyrk1B and Dyrk1A .	RanBPM inhibited the kinase activity of Mirk and Dyrk1B and Dyrk1A.	0	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RanBPM	RanBPM	RanBPM	Dyrk1B	Dyrk1B	Dyrk1B	0	1	8	9
Phosphorylation of both the Rb IDL and RbC N sites together dramatically reduces E2F2 TD .	Phosphorylation of both the Rb IDL and RbC N sites together dramatically reduces E2F2 TD.	0	14	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Phosphorylation of both the Rb	rb	E2F2	E2F2	e2f2	4	5	13	14
As expected the RB G mutation disrupts binding of the activator E2Fs , E2F2 and E2F3 .	As expected the RB G mutation disrupts binding of the activator E2Fs, E2F2 and E2F3.	3	14	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	RB	RB	E2F2	E2F2	E2F2	3	4	13	14
It has been reported that Rb mediated gene expression repression of E2F2 ( transcription factor 2 ) , by acting to tether Rb to specific E2F promoter sites , was crucial in T cells , and mutation of E2F2 in mice resulted in enhanced T lymphocyte proliferation leading to the development of autoimmunity .	It has been reported that Rb mediated gene expression repression of E2F2 (transcription factor 2), by acting to tether Rb to specific E2F promoter sites, was crucial in T cells, and mutation of E2F2 in mice resulted in enhanced T lymphocyte proliferation leading to the development of autoimmunity.	5	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F2	E2F2	E2F2	5	6	11	12
Depletion of RARalpha prevented the ATRA dependent increase in beta-catenin and VE-cadherin , confirming that RARalpha activation is key to cytodifferentiation ( XREF_FIG ) .	Depletion of RARalpha prevented the ATRA dependent increase in beta-catenin and VE-cadherin, confirming that RARalpha activation is key to cytodifferentiation (XREF_FIG).	0	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	RARalpha	RARalpha	RARalpha	beta-catenin	beta-catenin	beta-catenin	2	3	9	10
In the latter study , however , RARalpha was shown to inhibit the nuclear localization of beta-catenin without significantly affecting its total levels .	In the latter study, however, RARalpha was shown to inhibit the nuclear localization of beta-catenin without significantly affecting its total levels.	7	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RARalpha	RARalpha	RARalpha	beta-catenin	beta-catenin	beta-catenin	7	8	16	17
In summary , these data show that SSi targets beta-catenin and gamma-catenin more efficiently than SSo , an effect apparently not mediated by PML and RARalpha .	In summary, these data show that SSi targets beta-catenin and gamma-catenin more efficiently than SSo, an effect apparently not mediated by PML and RARalpha.	8	26	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	RARalpha	RARalpha	RARalpha	beta-catenin	beta-catenin	beta-catenin	25	26	9	10
As seen in XREF_FIG , indirect immunostaining of Smad3 revealed that overexpression of RanBP3 decreased the intensity of nuclear Smad3 by 55.3 % ( +/-4.2 % ) .	As seen in XREF_FIG, indirect immunostaining of Smad3 revealed that overexpression of RanBP3 decreased the intensity of nuclear Smad3 by 55.3% (+/-4.2%).	11	20	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RanBP3	overexpression of RanBP3	ranbp3	Smad3	Smad3	smad3	13	14	19	20
Previously , we demonstrated that ARNT , TRIP230 and Rb form a complex and that Rb represses the function of TRIP230 and the transcriptional response to hypoxia [ XREF_BIBR ] .	Previously, we demonstrated that ARNT, TRIP230 and Rb form a complex and that Rb represses the function of TRIP230 and the transcriptional response to hypoxia [XREF_BIBR].	15	21	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	TRIP230	TRIP230	TRIP230	15	16	20	21
We have demonstrated that Rb represses or attenuates the co-activation function of TRIP230 and thereby regulates the transcriptional response to hypoxia .	We have demonstrated that Rb represses or attenuates the co-activation function of TRIP230 and thereby regulates the transcriptional response to hypoxia.	4	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	TRIP230	TRIP230	TRIP230	4	5	12	13
Mitochondrially active Raf-1 is unable to activate extracellular signal related kinase 1 ( ERK1 ) and ERK2 but suppresses cell death by inactivating the proapoptotic Bcl-2 family member BAD .	Mitochondrially active Raf-1 is unable to activate extracellular signal related kinase 1 (ERK1) and ERK2 but suppresses cell death by inactivating the proapoptotic Bcl-2 family member BAD.	1	29	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	BAD	BAD	BAD	2	3	28	29
In accordance , RanBP3 represses activin and Smad2 , but not BMP-Smad1 signaling in Xenopus embryos .	In accordance, RanBP3 represses activin and Smad2, but not BMP-Smad1 signaling in Xenopus embryos.	3	8	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RanBP3	RanBP3	RanBP3	Smad2	Smad2	Smad2	3	4	7	8
We then constitutively expressed shRNAs that targeted against the canonical Notch transcription factor RBPJk , which efficiently inhibited Notch signaling as shown by Western blot ( XREF_SUPPLEMENTARY ) .	We then constitutively expressed shRNAs that targeted against the canonical Notch transcription factor RBPJk, which efficiently inhibited Notch signaling as shown by Western blot (XREF_SUPPLEMENTARY).	6	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPJk	RBPJk	RBPJk	Notch	Notch	Notch	13	14	18	19
Conditional deletion of CSL ( RBP-Jkappa ) , which abrogates all canonical Notch signaling in BM cells and DCs resulted in substantial reduction in the presence of conventional DCs in spleens of the knockout mice .	Conditional deletion of CSL (RBP-Jkappa), which abrogates all canonical Notch signaling in BM cells and DCs resulted in substantial reduction in the presence of conventional DCs in spleens of the knockout mice.	3	13	abrogates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	Notch	Notch	Notch	5	6	12	13
Conversely , Notch inhibition by a dominant RBPjk and CSL led to accelerated differentiation of HSCs in vitro , indicating that Notch is responsible for maintaining HSCs in an undifferentiated state [ XREF_BIBR ] .	Conversely, Notch inhibition by a dominant RBPjk and CSL led to accelerated differentiation of HSCs in vitro, indicating that Notch is responsible for maintaining HSCs in an undifferentiated state [XREF_BIBR].	2	9	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	RBPjk	RBPjk	RBPjk	Notch	Notch	Notch	7	8	2	3
Altogether , these data strongly support a role for L3MBTL3 in the RBPJ dependent repression of Notch target genes in mammalian cells .	Altogether, these data strongly support a role for L3MBTL3 in the RBPJ dependent repression of Notch target genes in mammalian cells.	12	18	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	12	13	16	17
Deletion of RBPjkappa causes a failure of canonical Notch signaling , and null mutants for RBPjkappa display phenotypes similar to other Notch loss of function mutants , such as Notch1 , Pofut1 and double mutants of Presenilin1 and 2 .	Deletion of RBPjkappa causes a failure of canonical Notch signaling, and null mutants for RBPjkappa display phenotypes similar to other Notch loss of function mutants, such as Notch1, Pofut1 and double mutants of Presenilin1 and 2.	0	9	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPjkappa	RBPjkappa	RBPjkappa	Notch	Notch	Notch	2	3	8	9
Because ablation of Rbpj impairs all canonical Notch signaling , it is possible that other Notch receptors are important .	Because ablation of Rbpj impairs all canonical Notch signaling, it is possible that other Notch receptors are important.	1	8	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	3	4	7	8
Thus , our data suggests that Zeb2 controls SC myelination by priming the transcriptional program that promotes SC differentiation , while attenuating the Rbpj mediated Notch inhibitory pathway .	Thus, our data suggests that Zeb2 controls SC myelination by priming the transcriptional program that promotes SC differentiation, while attenuating the Rbpj mediated Notch inhibitory pathway.	4	27	mediated	Positive_early_activation	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	23	24	25	26
RBP-Jkappa represses Notch target genes by recruiting transcriptional co-repressors , which include SMRT , SHARP , SKIP and CIR in mammals .	RBP-Jkappa represses Notch target genes by recruiting transcriptional co-repressors, which include SMRT, SHARP, SKIP and CIR in mammals.	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	Notch	Notch	Notch	0	1	2	3
To evaluate whether RBPJ loss produces a Notch like gene signature , we identified genes differentially expressed in 10 human T-ALL cell lines with Notch activating mutations treated with vehicle or a Notch inhibitor .	To evaluate whether RBPJ loss produces a Notch like gene signature, we identified genes differentially expressed in 10 human T-ALL cell lines with Notch activating mutations treated with vehicle or a Notch inhibitor.	3	10	produces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	3	4	7	8
In the absence of Notch , RBP-Jkappa represses Notch target genes by recruiting a corepressor complex .	In the absence of Notch, RBP-Jkappa represses Notch target genes by recruiting a corepressor complex.	6	10	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	Notch	Notch	Notch	6	7	8	9
Exons 6 and 7 encode the DNA binding and Notch binding domains , and loss of these exons results in the complete loss of Rbpj mediated Notch signaling .	Exons 6 and 7 encode the DNA binding and Notch binding domains, and loss of these exons results in the complete loss of Rbpj mediated Notch signaling.	22	27	mediated	Positive_early_activation	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	24	25	26	27
In our present study , we conditionally inactivated transcription factor RBP-J which integrates all Notch receptor signals in mouse retina , and found that RBP-J mediated Notch signaling inhibits ganglion cell and photoreceptor differentiation , and promotes Muller glial cell differentiation during retinogenesis .	In our present study, we conditionally inactivated transcription factor RBP-J which integrates all Notch receptor signals in mouse retina, and found that RBP-J mediated Notch signaling inhibits ganglion cell and photoreceptor differentiation, and promotes Muller glial cell differentiation during retinogenesis.	24	27	mediated	Positive_early_activation	Negative_activation	Negative_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	24	25	26	27
Ablation of RBPjkappa abolishes all canonical Notch signaling and RBPjkappa global knockout mice exhibit similar or more severe phenotypes than those of Notch1 null embryos [ XREF_BIBR ] .	Ablation of RBPjkappa abolishes all canonical Notch signaling and RBPjkappa global knockout mice exhibit similar or more severe phenotypes than those of Notch1 null embryos [XREF_BIBR].	0	7	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPjkappa	RBPjkappa	RBPjkappa	Notch	Notch	Notch	2	3	6	7
We propose that a corepressor complex containing CtIP and CtBP facilitates RBP-Jkappa and SHARP mediated repression of Notch target genes .	We propose that a corepressor complex containing CtIP and CtBP facilitates RBP-Jkappa and SHARP-mediated repression of Notch target genes.	11	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	Notch	Notch	Notch	11	12	17	18
Our results have demonstrated that blockade of Notch signaling by RBP-J deletion in myeloid cells alleviates hepatic I/R injury by compromised NF-kappaB activation through cylindromatosis ( CYLD ) up-regulation .	Our results have demonstrated that blockade of Notch signaling by RBP-J deletion in myeloid cells alleviates hepatic I/R injury by compromised NF-kappaB activation through cylindromatosis (CYLD) up-regulation.	7	11	signaling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	10	11	7	8
In the absence of activated Notch , RBP-J represses Notch target genes by recruiting a corepressor complex .	In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex.	7	11	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	7	8	9	10
In a study by Maillard et al ., Notch signalling was blocked by elimination of CBF1 and expression of dominant negative MAML mutants , and canonical Notch signalling was shown to be dispensable for the maintenance of long-term ( LT ) HSCs in vivo [ XREF_BIBR ] .	In a study by Maillard et al., Notch signalling was blocked by elimination of CBF1 and expression of dominant negative MAML mutants, and canonical Notch signalling was shown to be dispensable for the maintenance of long-term (LT) HSCs in vivo [XREF_BIBR].	8	22	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CBF1	CBF1	CBF1	Notch	Notch	Notch	15	16	8	9
Rather than constantly occupying Notch responsive enhancer elements , in many cases RBPjK is recruited alongside NICD , suggesting that RBPjK does not repress all Notch targets prior to Notch activation ( XREF_FIG ) [ XREF_BIBR ] .	Rather than constantly occupying Notch responsive enhancer elements, in many cases RBPjK is recruited alongside NICD, suggesting that RBPjK does not repress all Notch targets prior to Notch activation (XREF_FIG) [XREF_BIBR].	20	26	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPjK	RBPjK	RBPjK	Notch	Notch	Notch	20	21	25	26
Our main findings include ( i ) raised levels of DLL1 , which is a soluble Notch ligand with potential inhibiting effect on Notch signaling , ( ii ) down-regulation of PSEN1 and RBPJ ( SCZ ) , potentially impairing intracellular Notch signaling , and ( iii ) up-regulation of RFNG mRNA , which may inhibit ligand-receptor interactions , further impairing Notch signaling .	Our main findings include (i) raised levels of DLL1, which is a soluble Notch ligand with potential inhibiting effect on Notch signaling, (ii) down-regulation of PSEN1 and RBPJ (SCZ), potentially impairing intracellular Notch signaling, and (iii) up-regulation of RFNG mRNA, which may inhibit ligand-receptor interactions, further impairing Notch signaling.	29	42	impairing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	33	34	41	42
The transcription factor RBP-J is critical for the transcriptional output of Notch ( 1-4 ) receptor signaling and ablation of the Rbpj gene abolishes canonical Notch signaling within that cell .	The transcription factor RBP-J is critical for the transcriptional output of Notch (1-4) receptor signaling and ablation of the Rbpj gene abolishes canonical Notch signaling within that cell.	21	26	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	21	22	25	26
On the other hand , attenuation of Notch signaling by overexpression of a dominant negative RBP-J calledRBP-JR218H led to the increased proliferation of K562 cells .	On the other hand, attenuation of Notch signaling by overexpression of a dominant negative RBP-J calledRBP-JR218H led to the increased proliferation of K562 cells.	7	16	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	RBP-J	overexpression of a dominant negative RBP-J	rbp-j	Notch	Notch	notch	15	16	7	8
Disruption of Notch signaling by Rbpj depletion in satellite cells leads to precocious differentiation and depletion of satellite cells [ XREF_BIBR ] .	Disruption of Notch signaling by Rbpj depletion in satellite cells leads to precocious differentiation and depletion of satellite cells [XREF_BIBR].	2	6	signaling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	5	6	2	3
On the other hand , when Notch signaling was attenuated by over-expression of a dominant negative RBP-J , RBP-J ( R218H ) , in K562 cells , the proliferation of K562 was increased .	On the other hand, when Notch signaling was attenuated by over-expression of a dominant negative RBP-J, RBP-J (R218H), in K562 cells, the proliferation of K562 was increased.	6	17	attenuated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RBP-J	over-expression of a dominant negative RBP-J	rbp-j	Notch	Notch	notch	16	17	6	7
Our previous study have revealed that blockade of canonical Notch signaling by RBP-J deletion in hepatocytes increases ROS through JAK2 and STAT3 signal and aggravates hepatocyte death in hepatic I/R injury XREF_BIBR .	Our previous study have revealed that blockade of canonical Notch signaling by RBP-J deletion in hepatocytes increases ROS through JAK2 and STAT3 signal and aggravates hepatocyte death in hepatic I/R injury XREF_BIBR.	9	13	signaling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	12	13	9	10
This confirms that Cre mediated loss of RBPj in the excitatory neurons would eliminate all canonical Notch signaling .	This confirms that Cre mediated loss of RBPj in the excitatory neurons would eliminate all canonical Notch signaling.	3	17	eliminate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPj	Cre mediated loss of RBPj	rbpj	Notch	Notch	notch	7	8	16	17
Conversely , loss of Rbpj-kappa mediated Notch signaling leads to a premature burst of differentiation during early development , resulting in greater numbers of POMC and NPY neurons at e18.5 .	Conversely, loss of Rbpj-kappa mediated Notch signaling leads to a premature burst of differentiation during early development, resulting in greater numbers of POMC and NPY neurons at e18.5.	2	7	mediated	Positive_early_activation	Negative_activation	Negative_activation	Rbpj-kappa	Rbpj-kappa	Rbpj-kappa	Notch	Notch	Notch	4	5	6	7
In the absence of Notch signaling , CSL and RBPJ factors act alone to repress Notch target genes .	In the absence of Notch signaling, CSL and RBPJ factors act alone to repress Notch target genes.	7	17	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	9	10	15	16
Interestingly , conditional deletion of a downstream Notch effector ( Rbpj ) results in premature differentiation into neurons and depletion of the NSC pool in both embryonic and adult brain , further supporting the contribution of Notch signaling to NSC maintenance .	Interestingly, conditional deletion of a downstream Notch effector (Rbpj) results in premature differentiation into neurons and depletion of the NSC pool in both embryonic and adult brain, further supporting the contribution of Notch signaling to NSC maintenance.	10	37	supporting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	10	11	36	37
XREF_BIBR Removal of Rbpj largely reversed the Notch gain-of-function phenotype in the limbs and skull of Notch gain-of-function mutant .	XREF_BIBR Removal of Rbpj largely reversed the Notch gain-of-function phenotype in the limbs and skull of Notch gain-of-function mutant.	1	9	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	3	4	7	8
Importantly , inhibition of Notch signaling , through gamma-secretase inhibition or by Rbpj inactivation , interfered with the robust transcriptional induction at both the canonical and alternative promoters in leukemic cells but did not alter the increase in basal transcription observed in pre-leukemic thymocytes .	Importantly, inhibition of Notch signaling, through gamma-secretase inhibition or by Rbpj inactivation, interfered with the robust transcriptional induction at both the canonical and alternative promoters in leukemic cells but did not alter the increase in basal transcription observed in pre-leukemic thymocytes.	2	13	inhibition	Negative_activation_syntax_1_noun	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	12	13	4	5
Previous experiments in which global Notch signaling was eliminated by the removal of Pofut1 or RBP-Jkappa in oocytes suggest that Notch signaling is not required through any of the four mammalian Notch receptors until after gastrulation [ XREF_BIBR , XREF_BIBR ] .	Previous experiments in which global Notch signaling was eliminated by the removal of Pofut1 or RBP-Jkappa in oocytes suggest that Notch signaling is not required through any of the four mammalian Notch receptors until after gastrulation [XREF_BIBR, XREF_BIBR].	5	16	eliminated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	Notch	Notch	Notch	15	16	5	6
CSL and RBPJ , a transcriptional repressor that mediates Notch signaling , suppresses gene expression program ( s ) leading to stromal senescence and CAF activation .	CSL and RBPJ, a transcriptional repressor that mediates Notch signaling, suppresses gene expression program (s) leading to stromal senescence and CAF activation.	0	12	mediates	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	2	3	9	10
RBPJ is ubiquitously expressed , and can either activate genes by forming a complex with the Notch intracellular domain ( NICD ) when Notch is active XREF_BIBR , or silence an overlapping but non identical set of genes by recruiting co-repressors in the absence of Notch signalling XREF_BIBR XREF_BIBR XREF_BIBR .	RBPJ is ubiquitously expressed, and can either activate genes by forming a complex with the Notch intracellular domain (NICD) when Notch is active XREF_BIBR, or silence an overlapping but non identical set of genes by recruiting co-repressors in the absence of Notch signalling XREF_BIBR XREF_BIBR XREF_BIBR.	0	46	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJ	RBPJ is ubiquitously expressed	rbpj	Notch	Notch	notch	0	1	45	46
In the absence of Notch , RBP-Jkappa represses Notch target genes through the recruitment of a corepressor complex .	In the absence of Notch, RBP-Jkappa represses Notch target genes through the recruitment of a corepressor complex.	6	10	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	Notch	Notch	Notch	6	7	8	9
In conclusion , conditional Rbpj deficiency in mice disrupts canonical Notch and Rbpj signaling and produces severe renal hypoplasia , tubular cysts and rapidly progressive renal failure , features that resemble the kidney disease in humans with Alagille syndrome that is due to mutations in either JAGGED1 or NOTCH2 .	In conclusion, conditional Rbpj deficiency in mice disrupts canonical Notch and Rbpj signaling and produces severe renal hypoplasia, tubular cysts and rapidly progressive renal failure, features that resemble the kidney disease in humans with Alagille syndrome that is due to mutations in either JAGGED1 or NOTCH2.	4	13	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	4	5	10	11
Clearly , Rbpj H6shRNA inhibits Notch canonical signaling .	Clearly, Rbpj H6shRNA inhibits Notch canonical signaling.	2	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	2	3	5	6
After recruitment of additional co-activators , RBPJkappa induces canonical Notch targets such as hairy and enhancer of split ( HES ) and hairy and enhancer of split related ( HEY ) genes , which act as transcriptional repressors XREF_BIBR , XREF_BIBR .	After recruitment of additional co-activators, RBPJkappa induces canonical Notch targets such as hairy and enhancer of split (HES) and hairy and enhancer of split related (HEY) genes, which act as transcriptional repressors XREF_BIBR, XREF_BIBR.	6	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJkappa	RBPJkappa	RBPJkappa	Notch	Notch	Notch	6	7	9	10
We found that rbpj derepression stimulated the Notch pathway .	We found that rbpj derepression stimulated the Notch pathway.	3	8	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	rbpj	rbpj	rbpj	Notch	Notch	Notch	3	4	7	8
In the absence of Notch signaling , RBP-J forms a complex with transcriptional repressors and prevents opportunistic expression of the Notch target genes .	In the absence of Notch signaling, RBP-J forms a complex with transcriptional repressors and prevents opportunistic expression of the Notch target genes.	7	22	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	7	8	20	21
Loss of RBPJ acts to derepress target gene promoters , allowing Notch independent activation by alternate transcription factors that promote tumor growth .	Loss of RBPJ acts to derepress target gene promoters, allowing Notch independent activation by alternate transcription factors that promote tumor growth.	0	13	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJ	Loss of RBPJ	rbpj	Notch	Notch	notch	2	3	11	12
Second , ERK evoked RSK1 signaling has been shown to block TSC2 activity , and thereby stimulate mTOR1 signaling .	Second, ERK evoked RSK1 signaling has been shown to block TSC2 activity, and thereby stimulate mTOR1 signaling.	4	12	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RSK1	RSK1	RSK1	TSC2	TSC2	TSC2	4	5	11	12
RNA interference targeting nuclear factor ( NF )-kappaB p65 blocked the effects of IL-1beta or TNF-alpha on cell morphologic change , survival , migration , and collagen gel contraction .	RNA interference targeting nuclear factor (NF)-kappaB p65 blocked the effects of IL-1beta or TNF-alpha on cell morphologic change, survival, migration, and collagen gel contraction.	8	15	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p65	p65	p65	IL-1beta	IL-1beta	IL-1beta	8	9	13	14
This suggests that one mechanism of action of w3 fatty acids may be by blocking p65 NFkappabeta activation thereby inhibiting the IL-1beta signaling cascade .	This suggests that one mechanism of action of w3 fatty acids may be by blocking p65 NFkappabeta activation thereby inhibiting the IL-1beta signaling cascade.	15	23	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p65	p65	p65	IL-1beta	IL-1beta	IL-1beta	15	16	21	22
Chen showed that p65 specific siRNA could suppress the induction of IL-1beta and delay the cartilage degradation in OA model in early-phase 9 .	Chen showed that p65 specific siRNA could suppress the induction of IL-1beta and delay the cartilage degradation in OA model in early-phase 9.	3	12	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p65	p65	p65	IL-1beta	IL-1beta	IL-1beta	3	4	11	12
Similarly , IL-1beta , IL-6 and COX-2 transcripts were also induced in 231/Lap # 2 cells and were inhibited by p65 shRNA .	Similarly, IL-1beta, IL-6 and COX-2 transcripts were also induced in 231/Lap # 2 cells and were inhibited by p65 shRNA.	2	21	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	p65	p65	p65	IL-1beta	IL-1beta	IL-1beta	20	21	2	3
The results indicated that DFMG , CLI-095 and IL-1Ra significantly downregulated the expression levels of TLR4 , MyD88 and NF-kappaB p65 ( XREF_FIG ) in the HUVE-12 cells and decreased the secretion of IL-1beta ( XREF_FIG ) in the co-culture supernatant .	The results indicated that DFMG, CLI-095 and IL-1Ra significantly downregulated the expression levels of TLR4, MyD88 and NF-kappaB p65 (XREF_FIG) in the HUVE-12 cells and decreased the secretion of IL-1beta (XREF_FIG) in the co-culture supernatant.	4	34	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NF-kappaB p65	DFMG, CLI-095 and IL-1Ra significantly downregulated the expression levels of TLR4, MyD88 and NF-kappaB p65	nf-kappab p65	IL-1beta	IL-1beta	il-1beta	19	21	33	34
Serum induced DEPTOR degradation is blocked by inhibition of S6K1 and RSK1 kinases via small molecule inhibitors or siRNAs .	Serum induced DEPTOR degradation is blocked by inhibition of S6K1 and RSK1 kinases via small molecule inhibitors or siRNAs.	2	12	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RSK1	RSK1	RSK1	DEPTOR	DEPTOR	DEPTOR	11	12	2	3
Interestingly , neither ROCK1 nor ROCK2 depletion individually was able to strongly reduce pMYPT1 or pCofilin , and instead , concurrent depletion of both was required to reduce pMYPT1 and to a lesser extent pCofilin ( XREF_FIG ) .	Interestingly, neither ROCK1 nor ROCK2 depletion individually was able to strongly reduce pMYPT1 or pCofilin, and instead, concurrent depletion of both was required to reduce pMYPT1 and to a lesser extent pCofilin (XREF_FIG).	2	15	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ROCK1	ROCK1	ROCK1	pMYPT1	pMYPT1	pMYPT1	3	4	13	14
Inhibition of MYPT1 by ROCK1 activation is one of the mechanisms thought to be responsible for Ca 2+ sensitization of smooth-muscle contraction [ XREF_BIBR , XREF_BIBR ] ; even if other kinase activities , ( i.e. zipper interacting protein kinase , ZIP ; integrin linked kinase ; ILK ; dystrophia myotonica kinase ; DMK ) can inhibit MYPT1 [ XREF_BIBR - XREF_BIBR ] ) .	Inhibition of MYPT1 by ROCK1 activation is one of the mechanisms thought to be responsible for Ca 2+ sensitization of smooth-muscle contraction [XREF_BIBR, XREF_BIBR]; even if other kinase activities, (i.e. zipper interacting protein kinase, ZIP; integrin linked kinase; ILK; dystrophia myotonica kinase; DMK) can inhibit MYPT1 [XREF_BIBR - XREF_BIBR]).	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	ROCK1	ROCK1	ROCK1	MYPT1	MYPT1	MYPT1	4	5	2	3
Moreover , overexpression of Rheb also reduced the interaction of FKBP38 with mTOR in AA deprived cells , and the interaction was further diminished when AAs were restored .	Moreover, overexpression of Rheb also reduced the interaction of FKBP38 with mTOR in AA deprived cells, and the interaction was further diminished when AAs were restored.	2	11	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rheb	overexpression of Rheb	rheb	FKBP38	FKBP38	fkbp38	4	5	10	11
The same observations also support a signaling model in which Rheb activates mTORC1 by antagonizing the inhibitory effect of FKBP38 on mTOR ( XREF_FIG ) .	The same observations also support a signaling model in which Rheb activates mTORC1 by antagonizing the inhibitory effect of FKBP38 on mTOR (XREF_FIG).	10	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rheb	Rheb	Rheb	FKBP38	FKBP38	FKBP38	10	11	19	20
Together with our observations that ROCKII regulates E/R/M and paxillin phosphorylation and inactivates MYPT1 , we suggest that in untreated Eu-hESC , increased basal cell migration is due to activation of ROCKII signalling leading to enhanced levels of basal E/R/M , paxillin and MYPT1 phosphorylation .	Together with our observations that ROCKII regulates E/R/M and paxillin phosphorylation and inactivates MYPT1, we suggest that in untreated Eu-hESC, increased basal cell migration is due to activation of ROCKII signalling leading to enhanced levels of basal E/R/M, paxillin and MYPT1 phosphorylation.	5	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ROCKII	ROCKII	ROCKII	MYPT1	MYPT1	MYPT1	5	6	13	14
For example , mice lacking the ribosomal gene Rpl22 show no defects in translation owing to the upregulation of its paralogue , Rpl22l1 , the expression of which is normally inhibited by RPL22 [ XREF_BIBR ] .	For example, mice lacking the ribosomal gene Rpl22 show no defects in translation owing to the upregulation of its paralogue, Rpl22l1, the expression of which is normally inhibited by RPL22 [XREF_BIBR].	20	34	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	RPL22	RPL22	RPL22	Rpl22l1	Rpl22l1	Rpl22l1	32	33	22	23
Together , these observations support a model where both Rpl22 and Like1 bind smad1 mRNA , but have antagonistic effects on Smad1 protein levels , with Rpl22 acting to repress expression and Rpl22l1 acting to oppose that repression .	Together, these observations support a model where both Rpl22 and Like1 bind smad1 mRNA, but have antagonistic effects on Smad1 protein levels, with Rpl22 acting to repress expression and Rpl22l1 acting to oppose that repression.	4	33	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rpl22	Rpl22	Rpl22	Rpl22l1	Rpl22l1	Rpl22l1	26	27	32	33
NFAT also increases the expression of RCAN1 , which can bind to , and inhibit CnA ( XREF_FIG , ( 3 ) ) .	NFAT also increases the expression of RCAN1, which can bind to, and inhibit CnA (XREF_FIG, (3)).	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RCAN1	NFAT also increases the expression of RCAN1	rcan1	CnA	CnA	cna	6	7	15	16
As RPGRIP1 appears to link RPGR to the cilium , it is possible that RPGR ' s effect on RAB8A function may occur in distinct subcellular compartments of photoreceptors and that RPGRIP1 and other interacting proteins may modulate targeting of RPGR to such compartments .	As RPGRIP1 appears to link RPGR to the cilium, it is possible that RPGR 's effect on RAB8A function may occur in distinct subcellular compartments of photoreceptors and that RPGRIP1 and other interacting proteins may modulate targeting of RPGR to such compartments.	31	41	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RPGRIP1	RPGRIP1	RPGRIP1	RPGR	RPGR	RPGR	31	32	40	41
RPL10 can repress transcriptional activity of the proto-oncogene c-Jun in vitro , but these activities have not been verified in vivo [ XREF_BIBR - XREF_BIBR ] .	RPL10 can repress transcriptional activity of the proto-oncogene c-Jun in vitro, but these activities have not been verified in vivo [XREF_BIBR - XREF_BIBR].	0	9	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RPL10	RPL10	RPL10	proto-oncogene c-Jun	proto-oncogene c-Jun	proto-oncogene c-Jun	0	1	7	9
Upon TGF-beta treatment , RNF111 interacts with R-Smads , mediates degradation of the corepressors Ski and SnoN , and facilitates transcriptional regulation by the Smad complex .	Upon TGF-beta treatment, RNF111 interacts with R-Smads, mediates degradation of the corepressors Ski and SnoN, and facilitates transcriptional regulation by the Smad complex.	4	19	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RNF111	RNF111	RNF111	Ski	Ski	Ski	4	5	14	15
Chronic ET-1 treatment inhibited insulin stimulated tyrosine phosphorylation of G alpha q/11 and IRS-1 , as well as their association with PI3-kinase and blocked the activation of PI3-kinase activity and phosphorylation of AKT : In addition , chronic ET-1 treatment caused IRS-1 degradation , which could be blocked by inhibitors of PI3-kinase or p70 S6-kinase .	Chronic ET-1 treatment inhibited insulin stimulated tyrosine phosphorylation of G alpha q/11 and IRS-1, as well as their association with PI3-kinase and blocked the activation of PI3-kinase activity and phosphorylation of AKT : In addition, chronic ET-1 treatment caused IRS-1 degradation, which could be blocked by inhibitors of PI3-kinase or p70 S6-kinase.	41	54	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p70	p70	p70	IRS-1	IRS-1	IRS-1	53	54	41	42
The phosphorylation of S6K1 inactivates IRS-1 which is required for insulin signaling through PI3K .	The phosphorylation of S6K1 inactivates IRS-1 which is required for insulin signaling through PI3K.	1	8	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	phosphorylation of S6K1	s6k1	IRS-1	IRS-1	irs-1	3	4	5	6
Growth factor activation of this pathway promotes VSMC de-differentiation and proliferation , while mTORC1 inhibition promotes differentiation , by relieving the classical S6K1 mediated negative feedback regulation of insulin receptor substrate-1 ( IRS-1 ) signaling to PI3K and AKT XREF_BIBR .	Growth factor activation of this pathway promotes VSMC de-differentiation and proliferation, while mTORC1 inhibition promotes differentiation, by relieving the classical S6K1 mediated negative feedback regulation of insulin receptor substrate-1 (IRS-1) signaling to PI3K and AKT XREF_BIBR.	19	31	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	22	23	28	31
In culture , high levels of mTORC1 and S6K1 activity reduce IRS-1 protein and mRNA levels , diminish its function , and through serine phosphorylation targets it for proteasomal degradation .	In culture, high levels of mTORC1 and S6K1 activity reduce IRS-1 protein and mRNA levels, diminish its function, and through serine phosphorylation targets it for proteasomal degradation.	6	12	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	8	9	11	12
Mechanistically , a feedback loop has been established to indicate that S6K1 negatively regulates the stability of insulin receptor substrate 1 ( IRS1 ) through directly phosphorylating the S307 and S636 and S639 residues under nutrient deprivation conditions [ XREF_BIBR ] , as well as shuts down insulin or IGF-1 ( insulin like growth factor ) mediated activation of Akt by phosphorylating Grb10 ( growth factor receptor bound protein 10 ) [ XREF_BIBR , XREF_BIBR ] .	Mechanistically, a feedback loop has been established to indicate that S6K1 negatively regulates the stability of insulin receptor substrate 1 (IRS1) through directly phosphorylating the S307 and S636 and S639 residues under nutrient deprivation conditions [XREF_BIBR], as well as shuts down insulin or IGF-1 (insulin like growth factor) mediated activation of Akt by phosphorylating Grb10 (growth factor receptor bound protein 10) [XREF_BIBR, XREF_BIBR].	11	63	negatively regulates	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	S6K1	S6K1	s6k1	insulin receptor substrate 1	insulin receptor substrate 1 (IRS1) through directly phosphorylating the S307 and S636 and S639 residues under nutrient deprivation conditions [XREF_BIBR], as well as shuts down insulin or IGF-1 (insulin like growth factor) mediated activation of Akt by phosphorylating Grb10	insulin receptor substrate 1	11	12	17	21
mTORC1 activates S6K1 , which inhibits IRS-1 through phosphorylation in serine 302 42 .	mTORC1 activates S6K1, which inhibits IRS-1 through phosphorylation in serine 302 42.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	2	3	6	7
Lastly , S6K1 inhibits IRS-1 activity by phosphorylation at Ser318 XREF_BIBR .	Lastly, S6K1 inhibits IRS-1 activity by phosphorylation at Ser318 XREF_BIBR.	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	2	3	4	5
Thus , the inhibition of p70S6K can increase IRS-1 to feedback activate PI3K and AKT , which in turn drives tumor cells to acquire resistance to rapamycin .	Thus, the inhibition of p70S6K can increase IRS-1 to feedback activate PI3K and AKT, which in turn drives tumor cells to acquire resistance to rapamycin.	3	9	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p70S6K	p70S6K	p70S6K	IRS-1	IRS-1	IRS-1	5	6	8	9
This is mediated by relief of the classical feedback loop in which mTORC1 and its substrate S6K1 promote IRS-1 degradation to dampen signaling through insulin and insulin like growth factors .	This is mediated by relief of the classical feedback loop in which mTORC1 and its substrate S6K1 promote IRS-1 degradation to dampen signaling through insulin and insulin like growth factors.	12	19	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	16	17	18	19
We have previously found that the inhibition of mTORC1 and S6K1 by rapamycin or adiponectin relieves the feedback inhibition of IRS1 , resulting in increased PI3K and Akt2 activity .	We have previously found that the inhibition of mTORC1 and S6K1 by rapamycin or adiponectin relieves the feedback inhibition of IRS1, resulting in increased PI3K and Akt2 activity.	6	21	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS1	IRS1	IRS1	10	11	20	21
Suppression of either S6K1 or S6K2 mimics the effect of rapamycin treatment and restores IRS-1 mRNA to a level approaching that of TSC2 +/+ MEFs ( XREF_FIG ) .	Suppression of either S6K1 or S6K2 mimics the effect of rapamycin treatment and restores IRS-1 mRNA to a level approaching that of TSC2 +/+ MEFs (XREF_FIG).	0	15	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	3	4	14	15
One mechanism by which this occurs appears to be through p70S6K dependent downregulation of IRS1 .	One mechanism by which this occurs appears to be through p70S6K dependent downregulation of IRS1.	10	15	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p70S6K	p70S6K	p70S6K	IRS1	IRS1	IRS1	10	11	14	15
Persistent mTORC1 activation is generally postulated to inhibit AKT via its downstream kinase , S6K1 , which phosphorylates and inhibits either insulin receptor substrate-1 or members of the mTORC2 complex , rictor at Thr1135 and mSIN1 at Thr86 and Thr398 .	Persistent mTORC1 activation is generally postulated to inhibit AKT via its downstream kinase, S6K1, which phosphorylates and inhibits either insulin receptor substrate-1 or members of the mTORC2 complex, rictor at Thr1135 and mSIN1 at Thr86 and Thr398.	12	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	14	15	21	24
Normally , IGF stimulation results in activation of S6K1 , which negatively regulates adaptor protein insulin receptor substrate-1 ( IRS1 ) function by phosphorylation .	Normally, IGF stimulation results in activation of S6K1, which negatively regulates adaptor protein insulin receptor substrate-1 (IRS1) function by phosphorylation.	6	21	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS1	IRS1	IRS1	8	9	19	20
It is possible that that these two points of interaction complete a regulatory loop that permits crosstalk between the two pathways by allowing signals from the ERK and MAPK pathway to feedback onto PI3K/AKT/mTOR through the inhibition of IRS-1 by p70S6K .	It is possible that that these two points of interaction complete a regulatory loop that permits crosstalk between the two pathways by allowing signals from the ERK and MAPK pathway to feedback onto PI3K/AKT/mTOR through the inhibition of IRS-1 by p70S6K.	36	41	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p70S6K	p70S6K	p70S6K	IRS-1	IRS-1	IRS-1	40	41	38	39
The PI3K/AKT/mTOR signalling pathway is under the control of PTEN , but it may also be inactivated by a feedback loop in which S6K1 directly inhibits IRS1 .	The PI3K/AKT/mTOR signalling pathway is under the control of PTEN, but it may also be inactivated by a feedback loop in which S6K1 directly inhibits IRS1.	23	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS1	IRS1	IRS1	23	24	26	27
p70S6 kinase is known to negatively regulate IRS-1 through a feedback phosphorylation and inhibition of p70S6 kinase results in increased IGF receptor and PI3 kinase and AKT signaling [ XREF_BIBR ] .	p70S6 kinase is known to negatively regulate IRS-1 through a feedback phosphorylation and inhibition of p70S6 kinase results in increased IGF receptor and PI3 kinase and AKT signaling [XREF_BIBR].	0	8	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p70S6 kinase	p70S6 kinase	p70S6 kinase	IRS-1	IRS-1	IRS-1	0	2	7	8
Multiple mechanisms might contribute to such an augmented effect : ( i ) S6K1 has been shown to phosphorylate and negatively regulate IRS-1 signaling .	Multiple mechanisms might contribute to such an augmented effect : (i) S6K1 has been shown to phosphorylate and negatively regulate IRS-1 signaling.	3	23	negatively regulate	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	13	14	22	23
It has been reported that in solid tumor models , activation of mTORC1 drives p70S6K mediated degradation of the IR/IGF-1R adaptor protein IRS-1 , and is therefore a negative regulator of PI3K [ XREF_BIBR ] .	It has been reported that in solid tumor models, activation of mTORC1 drives p70S6K mediated degradation of the IR/IGF-1R adaptor protein IRS-1, and is therefore a negative regulator of PI3K [XREF_BIBR].	10	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p70S6K	p70S6K	p70S6K	IRS-1	IRS-1	IRS-1	14	15	22	23
Even though S6K1 activity increases throughout muscle cell differentiation and IRS-1 levels decrease over this period , siRNA suggests that S6K1 is not mediating the decrease in IRS-1 .	Even though S6K1 activity increases throughout muscle cell differentiation and IRS-1 levels decrease over this period, siRNA suggests that S6K1 is not mediating the decrease in IRS-1.	20	28	mediating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	20	21	27	28
Since growth factor mediated differentiation is thought to involve IGF-II signaling through IRS-1 to PI3K and PKB , we further hypothesized that decreasing S6K1 would increase IRS-1 protein and result in greater IGF-II signaling and myoblast differentiation .	Since growth factor mediated differentiation is thought to involve IGF-II signaling through IRS-1 to PI3K and PKB, we further hypothesized that decreasing S6K1 would increase IRS-1 protein and result in greater IGF-II signaling and myoblast differentiation.	22	27	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	23	24	26	27
Ethanol feeding suppressed beta-catenin signaling and led to less SGK1 expression which in turn promoted Foxo3A upregulation to induce hepatocyte apoptosis , whereas Wnt agonist administration reversed this process .	Ethanol feeding suppressed beta-catenin signaling and led to less SGK1 expression which in turn promoted Foxo3A upregulation to induce hepatocyte apoptosis, whereas Wnt agonist administration reversed this process.	0	16	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK1	Ethanol feeding suppressed beta-catenin signaling and led to less SGK1 expression	sgk1	Foxo3A	Foxo3A	foxo3a	9	10	15	16
Additionally , when metabolic stress was simulated by concomitant treatment with AMPK activating stimuli , rapid phosphorylation of FOXO3 by AMPK prevented the inactivation of FOXO3 by SGK-1 ( XREF_FIG ) .	Additionally, when metabolic stress was simulated by concomitant treatment with AMPK activating stimuli, rapid phosphorylation of FOXO3 by AMPK prevented the inactivation of FOXO3 by SGK-1 (XREF_FIG).	21	29	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SGK-1	SGK-1	SGK-1	FOXO3	FOXO3	FOXO3	27	28	25	26
Serum and glucocorticoid regulated kinase 1 ( SGK1 ) was used as a positive control in view of the known strong dependence of its transcript levels from serum availability ; furthermore , SGK1 is known to inhibit FOXO3a function via phosphorylation and it shows altered expression in the MPP + mouse model of PD [ XREF_BIBR , XREF_BIBR ] .	Serum and glucocorticoid regulated kinase 1 (SGK1) was used as a positive control in view of the known strong dependence of its transcript levels from serum availability; furthermore, SGK1 is known to inhibit FOXO3a function via phosphorylation and it shows altered expression in the MPP + mouse model of PD [XREF_BIBR, XREF_BIBR].	32	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	FOXO3a	FOXO3a	FOXO3a	32	33	37	38
In other words , SGK-1 can apparently only inactivate FOXO3 when intracellular energy levels were high , indicating a hierarchical order within the signalling network , in which low energy has the highest priority .	In other words, SGK-1 can apparently only inactivate FOXO3 when intracellular energy levels were high, indicating a hierarchical order within the signalling network, in which low energy has the highest priority.	4	15	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK-1	SGK-1	SGK-1	FOXO3	FOXO3	FOXO3	4	5	9	10
Either when FOXO3 proteins were post-translationally inhibited by SGK-1 after exclusive Dex treatment , or when cycloheximide inhibited de novo synthesis of FOXO3 proteins ( XREF_FIG ) , transcriptional induction of the FOXO3 gene was only half as pronounced as under the combined Dex and AICAR conditions , were FOXO3 was entirely post-translationally active ( XREF_FIG ; approx .	Either when FOXO3 proteins were post-translationally inhibited by SGK-1 after exclusive Dex treatment, or when cycloheximide inhibited de novo synthesis of FOXO3 proteins (XREF_FIG), transcriptional induction of the FOXO3 gene was only half as pronounced as under the combined Dex and AICAR conditions, were FOXO3 was entirely post-translationally active (XREF_FIG; approx.	2	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SGK-1	SGK-1	SGK-1	FOXO3	FOXO3	FOXO3	8	9	2	3
SGK1 negatively regulates the transcription factor FOXO3a via phosphorylation and exclusion from the nucleus , leading to FOXO3a degradation [ XREF_BIBR ] .	SGK1 negatively regulates the transcription factor FOXO3a via phosphorylation and exclusion from the nucleus, leading to FOXO3a degradation [XREF_BIBR].	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	FOXO3a	FOXO3a	FOXO3a	0	1	6	7
Similar to PKB , SGK is able to block Foxo3 , a member of the forkhead family of transcription factors that acts as a tumor suppressor , activity by phosphorylation .	Similar to PKB, SGK is able to block Foxo3, a member of the forkhead family of transcription factors that acts as a tumor suppressor, activity by phosphorylation.	4	12	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK	SGK	SGK	Foxo3	Foxo3	Foxo3	4	5	9	10
In mammalian cell culture , Sgk inhibits FoxO3 activity , and in C. elegans , SGK-1 is thought to limit lifespan by inhibiting DAF-16 and FoxO activity .	In mammalian cell culture, Sgk inhibits FoxO3 activity, and in C. elegans, SGK-1 is thought to limit lifespan by inhibiting DAF-16 and FoxO activity.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sgk	Sgk	Sgk	FoxO3	FoxO3	FoxO3	5	6	7	8
SGK1 also inhibits FOXO3A [ XREF_BIBR - XREF_BIBR ] , a transcription factor of autophagy genes [ XREF_BIBR ] .	SGK1 also inhibits FOXO3A [XREF_BIBR - XREF_BIBR], a transcription factor of autophagy genes [XREF_BIBR].	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	FOXO3A	FOXO3A	FOXO3A	0	1	3	4
FOXO3a , a pro apoptotic factor , is negatively regulated by SGK1 .	FOXO3a, a pro apoptotic factor, is negatively regulated by SGK1.	0	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	FOXO3a	FOXO3a	FOXO3a	11	12	0	1
As shown in XREF_FIG , SGK-1 mediated inhibition of the FOXO3 WT driven LKB1 reporter induction was accompanied by an increased phosphorylation of the threonine 32 residue ( T32 ) within the FOXO3 WT protein .	As shown in XREF_FIG, SGK-1 mediated inhibition of the FOXO3 WT driven LKB1 reporter induction was accompanied by an increased phosphorylation of the threonine 32 residue (T32) within the FOXO3 WT protein.	5	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK-1	SGK-1	SGK-1	FOXO3	FOXO3	FOXO3	5	6	10	11
Since SGK-1 is an immediate early response glucocorticoid receptor ( GR ) target gene XREF_BIBR and GR mediated SGK-1 induction can also inhibit FOXO3 activity by phosphorylation at T32 XREF_BIBR , we next analysed the impact of GR activation on LKB1 expression .	Since SGK-1 is an immediate early response glucocorticoid receptor (GR) target gene XREF_BIBR and GR mediated SGK-1 induction can also inhibit FOXO3 activity by phosphorylation at T32 XREF_BIBR, we next analysed the impact of GR activation on LKB1 expression.	16	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK-1	GR mediated SGK-1	sgk-1	FOXO3	FOXO3	foxo3	18	19	23	24
Furthermore , it was shown by expression of a SGK-1 short interfering RNA that glucocorticoid mediated induction of SGK-1 is sufficient to inactivate FOXO3 even in the absence of serum XREF_BIBR .	Furthermore, it was shown by expression of a SGK-1 short interfering RNA that glucocorticoid mediated induction of SGK-1 is sufficient to inactivate FOXO3 even in the absence of serum XREF_BIBR.	16	24	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK-1	SGK-1	SGK-1	FOXO3	FOXO3	FOXO3	18	19	23	24
Furthermore , Rubicon was found to decrease VPS34 kinase activity , and this inhibitory effect seems to be aborted with an excess of Beclin 1 11 .	Furthermore, Rubicon was found to decrease VPS34 kinase activity, and this inhibitory effect seems to be aborted with an excess of Beclin 1 11.	2	9	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rubicon	Rubicon	Rubicon	VPS34	VPS34	VPS34	2	3	7	8
These results suggest that S498 phosphorylation might play an important role in RUBICON mediated suppression of the Vps34 kinase activity .	These results suggest that S498 phosphorylation might play an important role in RUBICON mediated suppression of the Vps34 kinase activity.	10	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RUBICON	RUBICON	RUBICON	Vps34	Vps34	Vps34	12	13	17	18
These results indicate that although Rubicon WT , DeltaCCD , and DeltaSR suppress Vps34 activity under normal conditions , they show little or no suppressive effects on Vps34 activity under zymosan-treatment conditions .	These results indicate that although Rubicon WT, DeltaCCD, and DeltaSR suppress Vps34 activity under normal conditions, they show little or no suppressive effects on Vps34 activity under zymosan-treatment conditions.	5	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rubicon	Rubicon	Rubicon	Vps34	Vps34	Vps34	5	6	13	14
In contrast to Atg14L , Rubicon was found to reduce Vps34 activity and inhibit autophagy ; although depletion of Rubicon caused increased autophagy and endocytosis , ectopic expression of Rubicon resulted in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation .	In contrast to Atg14L, Rubicon was found to reduce Vps34 activity and inhibit autophagy; although depletion of Rubicon caused increased autophagy and endocytosis, ectopic expression of Rubicon resulted in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation.	5	13	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rubicon	Rubicon	Rubicon	Vps34	Vps34	Vps34	5	6	10	11
The phosphorylation dependent binding of UVRAG to RUBICON has a dual effect on UVRAG functions : first , the enhanced binding of RUBICON suppresses the ability of UVRAG to stimulate the kinase activity of Vps34 ; and second , RUBICON binding interferes with the interaction between UVRAG and the HOPS complex , thereby inhibiting the lysosomal fusion machinery .	The phosphorylation dependent binding of UVRAG to RUBICON has a dual effect on UVRAG functions : first, the enhanced binding of RUBICON suppresses the ability of UVRAG to stimulate the kinase activity of Vps34; and second, RUBICON binding interferes with the interaction between UVRAG and the HOPS complex, thereby inhibiting the lysosomal fusion machinery.	20	35	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RUBICON	RUBICON	RUBICON	Vps34	Vps34	Vps34	22	23	34	35
This result suggests that over-expression of Rubicon inhibits the Vps34 kinase activity , and this effect does not require Beclin 1 .	This result suggests that over-expression of Rubicon inhibits the Vps34 kinase activity, and this effect does not require Beclin 1.	4	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rubicon	over-expression of Rubicon	rubicon	Vps34	Vps34	vps34	6	7	9	10
By contrast , Rubicon , a newly identified Beclin1 interacting protein , reduces Vps34 lipid kinase activity and downregulates autophagy with aberrant expression in multiple types of cancer .	By contrast, Rubicon, a newly identified Beclin1 interacting protein, reduces Vps34 lipid kinase activity and downregulates autophagy with aberrant expression in multiple types of cancer.	3	18	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rubicon	Rubicon	Rubicon	Vps34	Vps34	Vps34	3	4	13	14
Rubicon reduces hVps34 activity and inhibits autophagy .	Rubicon reduces hVps34 activity and inhibits autophagy.	0	5	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rubicon	Rubicon	Rubicon	hVps34	hVps34	hVps34	0	1	2	3
These data indicate that while Rubicon inhibits VPS34 activity during canonical autophagy XREF_BIBR , XREF_BIBR , VPS34 activity on the LAPosome requires Rubicon .	These data indicate that while Rubicon inhibits VPS34 activity during canonical autophagy XREF_BIBR, XREF_BIBR, VPS34 activity on the LAPosome requires Rubicon.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rubicon	Rubicon	Rubicon	VPS34	VPS34	VPS34	5	6	7	8
: Rubicon has been suggested to suppress autophagosome maturation by negatively regulating PI3KC3 and Vps34 activity .	: Rubicon has been suggested to suppress autophagosome maturation by negatively regulating PI3KC3 and Vps34 activity.	1	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rubicon	Rubicon	Rubicon	Vps34	Vps34	Vps34	1	2	14	15
This result suggests that RUBICON might depend on S498 phosphorylation to suppress the Vps34 activity .	This result suggests that RUBICON might depend on S498 phosphorylation to suppress the Vps34 activity.	4	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RUBICON	RUBICON	RUBICON	Vps34	Vps34	Vps34	4	5	13	14
Instead , SARM was found to negatively regulate TRIF dependent TLR3 and TLR4 signaling in human cells through direct interaction with TRIF .	Instead, SARM was found to negatively regulate TRIF dependent TLR3 and TLR4 signaling in human cells through direct interaction with TRIF.	2	10	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	2	3	8	9
The fifth adaptor protein , SARM , has been suggested to negatively regulate TRIF [ XREF_BIBR ] .	The fifth adaptor protein, SARM, has been suggested to negatively regulate TRIF [XREF_BIBR].	3	15	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	5	6	13	14
We selected target genes based on their known function in suppressing innate immune responses : Toll interacting protein ( Tollip ) and IL-1 receptor associated kinase M ( IRAK-M ) negatively regulate TLR responses ; NLR family member XI ( NLRX1 ) inhibits both TLR and RLR signaling ; activating transcription factor 3 ( ATF3 ) is induced by TLR agonists and inhibits IL-6 and IL-12 production ; SARM1 negatively regulates TLR-adaptors TRIF and MyD88 ; and E3 ubiquitin ligase RBCC protein interacting with PKC1 ( RBCK1 ) modulates the activity of NFkappaB , IRF3 , and TNFalpha .	We selected target genes based on their known function in suppressing innate immune responses : Toll interacting protein (Tollip) and IL-1 receptor associated kinase M (IRAK-M) negatively regulate TLR responses; NLR family member XI (NLRX1) inhibits both TLR and RLR signaling; activating transcription factor 3 (ATF3) is induced by TLR agonists and inhibits IL-6 and IL-12 production; SARM1 negatively regulates TLR-adaptors TRIF and MyD88; and E3 ubiquitin ligase RBCC protein interacting with PKC1 (RBCK1) modulates the activity of NFkappaB, IRF3, and TNFalpha.	68	74	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM1	SARM1	SARM1	TRIF	TRIF	TRIF	68	69	72	73
SARM has been shown to associate with and inhibit TRIF [ XREF_BIBR ] .	SARM has been shown to associate with and inhibit TRIF [XREF_BIBR].	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	0	1	9	10
Inhibitors of TRIF signaling SARM and TAG have been identified but their role in TLR tolerance is incompletely understood .	Inhibitors of TRIF signaling SARM and TAG have been identified but their role in TLR tolerance is incompletely understood.	0	6	signaling	Positive_activation_token_1_noun	Negative_activation	Negative_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	4	5	2	3
A fifth adaptor protein , SARM , negatively regulates TRIF dependent signaling [ XREF_BIBR , XREF_BIBR ] .	A fifth adaptor protein, SARM, negatively regulates TRIF dependent signaling [XREF_BIBR, XREF_BIBR].	3	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	5	6	9	10
Sterile-alpha- and armadillo-motif-containing protein 1 ( SARM1 ) , was shown to inhibit TRIF and is also critical for TLR independent innate immunity .	Sterile-alpha- and armadillo-motif-containing protein 1 (SARM1), was shown to inhibit TRIF and is also critical for TLR independent innate immunity.	3	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM1	SARM1	SARM1	TRIF	TRIF	TRIF	6	7	13	14
However , the cells expressed increased levels of mRNA for SOCS1 , which promotes the degradation of MAL ( MyD88 adaptor like protein ) , and SARM , which inhibits TRIF signaling .	However, the cells expressed increased levels of mRNA for SOCS1, which promotes the degradation of MAL (MyD88 adaptor like protein), and SARM, which inhibits TRIF signaling.	6	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	26	27	30	31
SARM strongly inhibits TRIF mediated , but not MyD88 mediated , activation of NF-kappaB .	SARM strongly inhibits TRIF mediated, but not MyD88 mediated, activation of NF-kappaB.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	0	1	3	4
Indeed , in mammals XREF_BIBR XREF_BIBR XREF_BIBR ; protochordates XREF_BIBR XREF_BIBR and arthropods XREF_BIBR XREF_BIBR , SARM inhibits the TLR signaling pathways specifically via MyD88 and/or TRIF and/or TRAF6 .	Indeed, in mammals XREF_BIBR XREF_BIBR XREF_BIBR; protochordates XREF_BIBR XREF_BIBR and arthropods XREF_BIBR XREF_BIBR, SARM inhibits the TLR signaling pathways specifically via MyD88 and/or TRIF and/or TRAF6.	16	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	16	17	26	27
The fifth TIR adaptor SARM ( sterile-alpha and HEAT and Armadillo motifs containing protein ) has been shown to inhibit TRIF [ XREF_BIBR ] .	The fifth TIR adaptor SARM (sterile-alpha and HEAT and Armadillo motifs containing protein) has been shown to inhibit TRIF [XREF_BIBR].	0	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	4	5	20	21
While the first four adaptor proteins lead to downstream signalling , SARM1 has been found to inhibit TRIF [ XREF_BIBR ] .	While the first four adaptor proteins lead to downstream signalling, SARM1 has been found to inhibit TRIF [XREF_BIBR].	11	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM1	SARM1	SARM1	TRIF	TRIF	TRIF	11	12	17	18
SARM1 was shown to inhibit TRIF dependent TLR3 and TLR4 signaling in immune cells .	SARM1 was shown to inhibit TRIF dependent TLR3 and TLR4 signaling in immune cells.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM1	SARM1	SARM1	TRIF	TRIF	TRIF	0	1	5	6
Indeed , the isoform SGK1 phosphorylates and negatively regulates members of the FOXO family of transcription factors involved in promoting apoptosis [ XREF_BIBR , XREF_BIBR ] .	Indeed, the isoform SGK1 phosphorylates and negatively regulates members of the FOXO family of transcription factors involved in promoting apoptosis [XREF_BIBR, XREF_BIBR].	2	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	FOXO	FOXO	FOXO	4	5	12	13
Taken together , these results suggest that in contrast to existing paradigms of FoxO inhibition by Sgk , SGK-1 promotes C. elegans longevity in a DAF-16 and FoxO dependent manner .	Taken together, these results suggest that in contrast to existing paradigms of FoxO inhibition by Sgk, SGK-1 promotes C. elegans longevity in a DAF-16 and FoxO-dependent manner.	13	17	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Sgk	Sgk	Sgk	FoxO	FoxO	FoxO	16	17	13	14
SGK1 , in turn , suppresses the activity of Foxo1 , a repressor of IL-23 expression .	SGK1, in turn, suppresses the activity of Foxo1, a repressor of IL-23 expression.	0	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	Foxo1	Foxo1	Foxo1	0	1	9	10
Transfection of a Foxo1 luciferase reporter in the presence of Foxo1 led to increased luciferase activity ( XREF_SUPPLEMENTARY ) , while increasing expression of SGK1 in the presence of Foxo1 resulted in a dose dependent decrease in reporter activity , suggesting that SGK1 inhibited Foxo1 mediated transactivation of its own promoter ( XREF_FIG ) .	Transfection of a Foxo1 luciferase reporter in the presence of Foxo1 led to increased luciferase activity (XREF_SUPPLEMENTARY), while increasing expression of SGK1 in the presence of Foxo1 resulted in a dose dependent decrease in reporter activity, suggesting that SGK1 inhibited Foxo1 mediated transactivation of its own promoter (XREF_FIG).	42	46	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	Foxo1	Foxo1	Foxo1	42	43	44	45
While Foxo1 inhibited RORgammat mediated Il23r expression , co-expression of SGK1 together with RORgammat and Foxo1 abrogated the suppressive effects of Foxo1 and rescued Il23r promoter transcriptional activity ( XREF_FIG ) .	While Foxo1 inhibited RORgammat mediated Il23r expression, co-expression of SGK1 together with RORgammat and Foxo1 abrogated the suppressive effects of Foxo1 and rescued Il23r promoter transcriptional activity (XREF_FIG).	8	22	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK1	co-expression of SGK1	sgk1	Foxo1	Foxo1	foxo1	10	11	21	22
It is suggested that IL-23 induces SGK1 mediated inactivation of Foxo1 to enhance the induction and effector functions of pathogenic Th17 cells 18 .	It is suggested that IL-23 induces SGK1 mediated inactivation of Foxo1 to enhance the induction and effector functions of pathogenic Th17 cells 18.	6	11	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	Foxo1	Foxo1	Foxo1	6	7	10	11
SGK1 signaling blocks Foxo1 , which is a repressor of IL-23R .	SGK1 signaling blocks Foxo1, which is a repressor of IL-23R.	0	8	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	Foxo1	Foxo1	Foxo1	0	1	3	4
One action of SGK1 is to deactivate the transcription factor Foxo1 .	One action of SGK1 is to deactivate the transcription factor Foxo1.	1	11	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	Foxo1	Foxo1	Foxo1	3	4	10	11
SGK1 , in turn , promotes adipogenesis by phosphorylating and inhibiting transcription factor FOXO1 and , subsequently , activating the transcription of PPARgamma in adipocytes .	SGK1, in turn, promotes adipogenesis by phosphorylating and inhibiting transcription factor FOXO1 and, subsequently, activating the transcription of PPARgamma in adipocytes.	0	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK1	SGK1	SGK1	FOXO1	FOXO1	FOXO1	0	1	13	14
Expression of constitutively active p70S6K or siRNA mediated knockdown of both tuberous sclerosis complex tuberin ( TSC2 ) and Rictor to increase p70S6K activation leads to the differentiation of human embryonic stem cells .	Expression of constitutively active p70S6K or siRNA mediated knockdown of both tuberous sclerosis complex tuberin (TSC2) and Rictor to increase p70S6K activation leads to the differentiation of human embryonic stem cells.	0	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p70S6K	Expression of constitutively active p70S6K	p70s6k	Rictor	Rictor	rictor	4	5	19	20
XREF_BIBR As predicted , depletion of rictor by > 95 % had no effect on p70S6K , rpS6 or 4E-BP1 phosphorylation ; depletion of both raptor and rictor showed effects similar to depletion of rictor alone .	XREF_BIBR As predicted, depletion of rictor by> 95% had no effect on p70S6K, rpS6 or 4E-BP1 phosphorylation; depletion of both raptor and rictor showed effects similar to depletion of rictor alone.	15	28	depletion	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	p70S6K	p70S6K, rpS6 or 4E-BP1 phosphorylation	p70s6k	rictor	rictor	rictor	15	16	27	28
Thus , reduced mTORC2 activity in AS mice could be a consequence of either decreased stimulation from TSC2 or increased inhibition of rictor by S6K1 .	Thus, reduced mTORC2 activity in AS mice could be a consequence of either decreased stimulation from TSC2 or increased inhibition of rictor by S6K1.	20	25	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	rictor	rictor	rictor	24	25	22	23
In addition to PP2A , SET also inhibits Nm23-H1 , a nucleoside diphosphate kinase implicated in granzyme activated hydrolytic cleavage of DNA [ XREF_BIBR ] .	In addition to PP2A, SET also inhibits Nm23-H1, a nucleoside diphosphate kinase implicated in granzyme activated hydrolytic cleavage of DNA [XREF_BIBR].	5	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SET	SET	SET	Nm23-H1	Nm23-H1	Nm23-H1	5	6	8	9
The SET oncoprotein functions to inhibit the metastasis suppressor protein nm23-H1 by sequestering it in the cytosol .	The SET oncoprotein functions to inhibit the metastasis suppressor protein nm23-H1 by sequestering it in the cytosol.	1	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SET	SET	SET	nm23-H1	nm23-H1	nm23-H1	1	2	10	11
SET is a suppressor of PP2A and NM23 .	SET is a suppressor of PP2A and NM23.	0	8	is a suppressor	Negative_activation_copula_1	Negative_activation	Negative_activation	SET	SET	SET	NM23	NM23	NM23	0	1	7	8
SET also inhibits the GZMA activated DNase NME1 , a nucleotide diphosphate kinase involved in cytarabine activation .	SET also inhibits the GZMA activated DNase NME1, a nucleotide diphosphate kinase involved in cytarabine activation.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SET	SET	SET	NME1	NME1	NME1	0	1	7	8
This basal inhibition of p53 by MSK2 occurred independently of its kinase activity and of upstream mitogen activated protein kinase signaling to MSK2 .	This basal inhibition of p53 by MSK2 occurred independently of its kinase activity and of upstream mitogen activated protein kinase signaling to MSK2.	2	7	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	MSK2	MSK2	MSK2	p53	p53	p53	6	7	4	5
Mitogen- and stress activated kinase 2 ( MSK2 ) inhibits the transcription factor p53 , and we investigate here the mechanisms underlying this inhibition .	Mitogen- and stress activated kinase 2 (MSK2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MSK2	MSK2	MSK2	p53	p53	p53	7	8	13	14
Collectively , our study shows that alpha-LA suppresses colorectal tumor cell growth at least partially by preventing RPS6KA4 mediated p53 inhibition through blockade of NF-kappaB signaling .	Collectively, our study shows that alpha-LA suppresses colorectal tumor cell growth at least partially by preventing RPS6KA4 mediated p53 inhibition through blockade of NF-kappaB signaling.	16	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	RPS6KA4	RPS6KA4	RPS6KA4	p53	p53	p53	17	18	19	20
On the basis of our microarray data showing alpha-LA downregulation of the ribosomal protein p90S6K ( RPS6KA4 ) , which has been reported to inhibit p53 function , we tested whether alpha-LA regulation of RPS6KA4 is associated with its proapoptotic function .	On the basis of our microarray data showing alpha-LA downregulation of the ribosomal protein p90S6K (RPS6KA4), which has been reported to inhibit p53 function, we tested whether alpha-LA regulation of RPS6KA4 is associated with its proapoptotic function.	14	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RPS6KA4	RPS6KA4	RPS6KA4	p53	p53	p53	16	17	25	26
As downstream target of mTOR , S6K1 enhances protein synthesis upon activation by facilitating PDCD4 degradation via phosphorylation , which in turn releases elF4A helicase from the wind-up secondary structure in mRNA 5 ' untranslated region .	As downstream target of mTOR, S6K1 enhances protein synthesis upon activation by facilitating PDCD4 degradation via phosphorylation, which in turn releases elF4A helicase from the wind-up secondary structure in mRNA 5 ' untranslated region.	6	15	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	PDCD4	PDCD4	PDCD4	6	7	14	15
S6K1 also phosphorylates and promotes the degradation of PDCD4 , an inhibitor of eIF4B , and enhances the translation efficiency of spliced mRNAs via its interaction with SKAR , a component of exon-junction complexes .	S6K1 also phosphorylates and promotes the degradation of PDCD4, an inhibitor of eIF4B, and enhances the translation efficiency of spliced mRNAs via its interaction with SKAR, a component of exon-junction complexes.	0	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	PDCD4	PDCD4	PDCD4	0	1	8	9
The activity of AP-1 can be suppressed by PDCD4 , which in turn is negatively regulated by activation of the mTOR substrate p70 S6K1 [ XREF_BIBR , XREF_BIBR ] .	The activity of AP-1 can be suppressed by PDCD4, which in turn is negatively regulated by activation of the mTOR substrate p70 S6K1 [XREF_BIBR, XREF_BIBR].	6	24	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p70 S6K1	p70 S6K1	p70 S6K1	PDCD4	PDCD4	PDCD4	22	24	8	9
Sema3A treatment , for example , decreases the adhesion of human NRP1 + thymocytes on TEC monolayers .	Sema3A treatment, for example, decreases the adhesion of human NRP1 + thymocytes on TEC monolayers.	0	12	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sema3A	Sema3A	Sema3A	NRP1	NRP1	NRP1	0	1	11	12
Using gain-of-function and loss-of-function experiments , Moret and colleagues [ XREF_BIBR ] found that intrinsic Sema3A decreases the availability of neuropilin-1 at the growth cone membrane , thereby decreasing the sensitivity of motor growth cones to extrinsic Sema3A .	Using gain-of-function and loss-of-function experiments, Moret and colleagues [XREF_BIBR] found that intrinsic Sema3A decreases the availability of neuropilin-1 at the growth cone membrane, thereby decreasing the sensitivity of motor growth cones to extrinsic Sema3A.	14	21	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sema3A	Sema3A	Sema3A	neuropilin-1	neuropilin-1	neuropilin-1	15	16	20	21
Sema3A also reduced cell-surface Npn-1 in endothelial cells and promoted its internalization , but required a higher concentration than VEGF ( 165 ) .	Sema3A also reduced cell-surface Npn-1 in endothelial cells and promoted its internalization, but required a higher concentration than VEGF (165).	0	14	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sema3A	Sema3A	Sema3A	Npn-1	Npn-1	Npn-1	0	1	4	5
The activation of mTOR is supported by increased phosphorylation of upstream proteins including ERK and Akt , and mTOR then phosphorylates and activates the downstream protein p70S6K , which inhibits eEF2K , thereby decreasing the phosphorylation of eEF2 and effectively inhibiting eukaryotic initiation factor 4E ( eIF4E ) .	The activation of mTOR is supported by increased phosphorylation of upstream proteins including ERK and Akt, and mTOR then phosphorylates and activates the downstream protein p70S6K, which inhibits eEF2K, thereby decreasing the phosphorylation of eEF2 and effectively inhibiting eukaryotic initiation factor 4E (eIF4E).	18	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p70S6K	mTOR then phosphorylates and activates the downstream protein p70S6K	p70s6k	eEF2K	eEF2K	eef2k	26	27	30	31
Alternatively , Fzl1/2/7 signaling could activate a secreted modulator like sFRP-1 that blocks Wnt1 and Wnt8-Fzl 5/8-JNK signaling at the extracellular level .	Alternatively, Fzl1/2/7 signaling could activate a secreted modulator like sFRP-1 that blocks Wnt1 and Wnt8-Fzl 5/8-JNK signaling at the extracellular level.	5	17	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	sFRP-1	sFRP-1	sFRP-1	Wnt1	Wnt1	Wnt1	10	11	13	14
First , SFRP1 has been shown to bind canonical Wnt1 but is unable to bind Wnt5a XREF_BIBR and also antagonises Wnt1 function but not Wnt5a function in Xenopus development XREF_BIBR , suggesting that SFRP1 upregulation further represses canonical Wnt signalling .	First, SFRP1 has been shown to bind canonical Wnt1 but is unable to bind Wnt5a XREF_BIBR and also antagonises Wnt1 function but not Wnt5a function in Xenopus development XREF_BIBR, suggesting that SFRP1 upregulation further represses canonical Wnt signalling.	2	21	antagonises	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SFRP1	SFRP1	SFRP1	Wnt1	Wnt1	Wnt1	2	3	20	21
In the xenograft CRC tumors harvested on day 28 , tumors generated from SGK1 shRNA-stable-expression cell line displayed decreased SGK1 expression and increased p27 expression ( XREF_FIG ) , indicating that SGK1 could also repress p27 in vivo .	In the xenograft CRC tumors harvested on day 28, tumors generated from SGK1 shRNA-stable-expression cell line displayed decreased SGK1 expression and increased p27 expression (XREF_FIG), indicating that SGK1 could also repress p27 in vivo.	31	37	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK1	SGK1	SGK1	p27	p27	p27	31	32	35	36
BMPR-IB and Alk6 induced Runx2 proteins reduced Notch1 activity to a marked degree .	BMPR-IB and Alk6-induced Runx2 proteins reduced Notch1 activity to a marked degree.	2	8	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Runx2	Alk6-induced Runx2	runx2	Notch1	Notch1	notch1	4	5	7	8
In this process SFRP1 inhibits Wnt-4 signaling whereas SFRP2 promotes it [ XREF_BIBR ] .	In this process SFRP1 inhibits Wnt-4 signaling whereas SFRP2 promotes it [XREF_BIBR].	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SFRP1	SFRP1	SFRP1	Wnt-4	Wnt-4	Wnt-4	3	4	5	6
Interestingly , resveratrol , a substance that increases expression of SIRT1 ( Silent information regulator 1 ) , an enzyme that deacetylates and in consequence reduces the activity of p53 , delayed ALS onset and prolonged the lifetime of mice bearing the latter mutation .	Interestingly, resveratrol, a substance that increases expression of SIRT1 (Silent information regulator 1), an enzyme that deacetylates and in consequence reduces the activity of p53, delayed ALS onset and prolonged the lifetime of mice bearing the latter mutation.	2	31	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	resveratrol, a substance that increases expression of SIRT1	sirt1	p53	p53	p53	10	11	29	30
In addition , SIRT1 represses p53 via deacetylating p53 to facilitate cellular recovery from genotoxic stress [ XREF_BIBR ] .	In addition, SIRT1 represses p53 via deacetylating p53 to facilitate cellular recovery from genotoxic stress [XREF_BIBR].	3	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	5	6
Given that SIRT1 can negatively regulate p53 localization to the nucleus and its function as a transcription factor , it is worth considering if SIRT1 can have a role in the formation of cancers .	Given that SIRT1 can negatively regulate p53 localization to the nucleus and its function as a transcription factor, it is worth considering if SIRT1 can have a role in the formation of cancers.	2	7	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	6	7
SIRT1 also regulates inflammation by interfering with the NF-kB pathway ( Salminen etal ., 2008 ; Shinozaki etal ., 2014 ) and represses p53 activity to reduce apoptosis during stress ( Luo etal ., 2001 ; Cheng etal ., 2003 ) .	SIRT1 also regulates inflammation by interfering with the NF-kB pathway (Salminen etal., 2008; Shinozaki etal., 2014) and represses p53 activity to reduce apoptosis during stress (Luo etal., 2001; Cheng etal., 2003).	0	24	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	23	24
The results revealed that transfection of SIRT1 significantly inhibited the ability of Brca1 Co / Co ; MMTV-Cre ; p53 +/- cells to form tumors in nude mice ( XREF_FIG ) .	The results revealed that transfection of SIRT1 significantly inhibited the ability of Brca1 Co / Co; MMTV-Cre; p53 +/- cells to form tumors in nude mice (XREF_FIG).	4	29	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	19	20
XREF_BIBR , XREF_BIBR Inactivation of HIC1 alleviates repression of SIRT1 , which subsequently inactivates p53 .	XREF_BIBR, XREF_BIBR Inactivation of HIC1 alleviates repression of SIRT1, which subsequently inactivates p53.	7	15	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	14	15
Additionally , miR-34 induces apoptosis by repressing the Sirt1 deacetylase , which inactivates p53 through deacetylation of lysine 382 .	Additionally, miR-34 induces apoptosis by repressing the Sirt1 deacetylase, which inactivates p53 through deacetylation of lysine 382.	8	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	8	9	13	14
SIRT1 down-regulates AMPK through deacetylating the serine threonine kinase liver kinase B1 ( LKB1 ) , and antagonizes p53 activation by deacetylation [ XREF_BIBR , XREF_BIBR ] .	SIRT1 down-regulates AMPK through deacetylating the serine threonine kinase liver kinase B1 (LKB1), and antagonizes p53 activation by deacetylation [XREF_BIBR, XREF_BIBR].	0	19	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	18	19
XREF_BIBR miR-34a indirectly activates p53 by downregulating SIRT1 , which negatively regulates p53 through deacetylation , leading to induction of p21 and PUMA and ultimately apoptosis .	XREF_BIBR miR-34a indirectly activates p53 by downregulating SIRT1, which negatively regulates p53 through deacetylation, leading to induction of p21 and PUMA and ultimately apoptosis.	3	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	7	8	12	13
The inactivation of p53 by SIRT1 may retard apoptosis and render cells more resistant to oxidative stress [ XREF_BIBR , XREF_BIBR ] .	The inactivation of p53 by SIRT1 may retard apoptosis and render cells more resistant to oxidative stress [XREF_BIBR, XREF_BIBR].	1	6	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	5	6	3	4
XREF_BIBR , XREF_BIBR , XREF_BIBR For instance , SIRT1 inactivates the tumor suppressor p53 deacetylating the Lys382 residue .	XREF_BIBR, XREF_BIBR, XREF_BIBR For instance, SIRT1 inactivates the tumor suppressor p53 deacetylating the Lys382 residue.	8	14	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	8	9	11	14
Moreover , SIRT1 deacetylates and thus inactivates p53 and forkhead box O1 ( FOXO1 ) , two inducers of cell cycle arrest and apoptosis as well as inhibitors of proliferation [ XREF_BIBR ] .	Moreover, SIRT1 deacetylates and thus inactivates p53 and forkhead box O1 (FOXO1), two inducers of cell cycle arrest and apoptosis as well as inhibitors of proliferation [XREF_BIBR].	2	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	7	8
For instance , one study in rat liver , which was focusing on the apoptosis inducing effects of bile acids , reported a deoxycholic acid induced miRNA-34a expression that also blunted Sirt1 mediated downstream inactivation of p53 signaling [ XREF_BIBR ] .	For instance, one study in rat liver, which was focusing on the apoptosis inducing effects of bile acids, reported a deoxycholic acid induced miRNA-34a expression that also blunted Sirt1 mediated downstream inactivation of p53 signaling [XREF_BIBR].	31	39	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	31	32	36	37
Sirt1 inhibition of p53 function is well documented , while EZH2 has been noted to indirectly modulate p53 signaling and depletion of EZH2 leads to increased apoptosis in response to DNA damage .	Sirt1 inhibition of p53 function is well documented, while EZH2 has been noted to indirectly modulate p53 signaling and depletion of EZH2 leads to increased apoptosis in response to DNA damage.	0	4	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	0	1	3	4
Our result shows that SIRT1 silencing can induce cell senescence in p53 deficient or p16 deficient cells lines , suggesting that the p53-p21 axis or p16 alone can not be the only mediator of cell senescence after SIRT1 silencing .	Our result shows that SIRT1 silencing can induce cell senescence in p53 deficient or p16 deficient cells lines, suggesting that the p53-p21 axis or p16 alone can not be the only mediator of cell senescence after SIRT1 silencing.	4	12	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	11	12
SIRT1 inactivates p53 by deacetylation of p53 XREF_BIBR .	SIRT1 inactivates p53 by deacetylation of p53 XREF_BIBR.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	2	3
Moreover , activation of SIRT1 decreased the expression of miR-34a and the acylation of p53 .	Moreover, activation of SIRT1 decreased the expression of miR-34a and the acylation of p53.	2	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	14	15
Conversely , the class III histone deacetylase SIRT1 inhibits p53 transcriptional activation by deacetylating p53 following DNA damage .	Conversely, the class III histone deacetylase SIRT1 inhibits p53 transcriptional activation by deacetylating p53 following DNA damage.	2	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	7	8	9	10
Further , E2 treatment results in deacetylation of p53 , and SIRT1 knockdown abolishes this effect , suggesting that SIRT1 is necessary for the ability of ERalpha to suppress p53 signaling in breast cancer .	Further, E2 treatment results in deacetylation of p53, and SIRT1 knockdown abolishes this effect, suggesting that SIRT1 is necessary for the ability of ERalpha to suppress p53 signaling in breast cancer.	19	30	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	19	20	29	30
Sirt-1 down-regulates p53 activity , rising lifespan , and cell survival ; it also deacetylases peroxisome proliferator activated receptor-gamma ( PPAR-gamma ) and its coactivator 1 alpha ( PGC-1alpha ) , promoting lipid mobilization , positively regulating insulin secretion , and increasing mitochondrial dimension and number .	Sirt-1 down-regulates p53 activity, rising lifespan, and cell survival; it also deacetylases peroxisome proliferator activated receptor-gamma (PPAR-gamma) and its coactivator 1 alpha (PGC-1alpha), promoting lipid mobilization, positively regulating insulin secretion, and increasing mitochondrial dimension and number.	0	3	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt-1	Sirt-1	Sirt-1	p53	p53	p53	0	1	2	3
SIRT1 overexpression may be necessary to inhibit p53 activity and allow maintenance of AML cells in the setting of FLT3-ITD-induced oncogenic stress , similar to its potential role as an adaptive response to BCR-ABL-related oncogenic stress in CML cells .	SIRT1 overexpression may be necessary to inhibit p53 activity and allow maintenance of AML cells in the setting of FLT3-ITD-induced oncogenic stress, similar to its potential role as an adaptive response to BCR-ABL-related oncogenic stress in CML cells.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1 overexpression	sirt1	p53	p53	p53	0	1	7	8
Pharmacologic inhibition of SIRT1 or genetic depletion of p53 abolish the effects of ghrelin on AMPK and thereby blunt ghrelin induced effects on transcription factors , including pCREB , FoxO1 , and Bsx , and neuropeptides , such as NPY and AgRP , leading to a suppression of ghrelin induced food intake .	Pharmacologic inhibition of SIRT1 or genetic depletion of p53 abolish the effects of ghrelin on AMPK and thereby blunt ghrelin induced effects on transcription factors, including pCREB, FoxO1, and Bsx, and neuropeptides, such as NPY and AgRP, leading to a suppression of ghrelin induced food intake.	3	9	depletion	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	8	9
Increased SIRT1 activity represses p53 activity to prevent p53 dependent cellular senescence .	Increased SIRT1 activity represses p53 activity to prevent p53 dependent cellular senescence.	1	5	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	1	2	4	5
For example , the previous finding that activation of SIRT1 might reduce p53 activity and therefore , elevate the risk of cancer in mammals should not be a concern in our study as virtually all BRCA1 mutant cancer cells are p53 deficient .	For example, the previous finding that activation of SIRT1 might reduce p53 activity and therefore, elevate the risk of cancer in mammals should not be a concern in our study as virtually all BRCA1 mutant cancer cells are p53 deficient.	7	13	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	12	13
SIRT1 has been found to negatively regulate the tumor suppressor gene p53 through an NAD dependent deacetylating mechanism and therefore , SIRT1 has been considered as a tumorigenic factor [ XREF_BIBR ] .	SIRT1 has been found to negatively regulate the tumor suppressor gene p53 through an NAD dependent deacetylating mechanism and therefore, SIRT1 has been considered as a tumorigenic factor [XREF_BIBR].	0	12	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	11	12
Lots of researches supported that when myocardial ischemia happened , SIRT1 could reduce activity of P53 through deacetylation and suppress the cardiomyocyte apoptosis [ XREF_BIBR - XREF_BIBR ] .	Lots of researches supported that when myocardial ischemia happened, SIRT1 could reduce activity of P53 through deacetylation and suppress the cardiomyocyte apoptosis [XREF_BIBR - XREF_BIBR].	10	16	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	P53	P53	P53	10	11	15	16
SIRT1 , the main member of the sirtuin family , inactivates p53 by deacetylating a critical lysine residue .	SIRT1, the main member of the sirtuin family, inactivates p53 by deacetylating a critical lysine residue.	0	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	11	12
Since p53 is a known SIRT1 substrate we propose that elevated SIRT1 levels ( induced by HPV E7 ) attenuate p53 pro apoptotic capacity via its de-acetylation .	Since p53 is a known SIRT1 substrate we propose that elevated SIRT1 levels (induced by HPV E7) attenuate p53 pro apoptotic capacity via its de-acetylation.	11	23	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1 levels	sirt1	p53	p53	p53	11	12	20	21
p53 accumulation in Ampkalpha1 (-/-) MEFs was reversed by SIRT1 activation by resveratrol .	p53 accumulation in Ampkalpha1 (-/-) MEFs was reversed by SIRT1 activation by resveratrol.	0	10	reversed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	0	1
For example , downregulation of p53 by SIRT1 deacetylation may affect lifespan by inhibiting cellular apoptosis and replicative senescence processes [ XREF_BIBR - XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	For example, downregulation of p53 by SIRT1 deacetylation may affect lifespan by inhibiting cellular apoptosis and replicative senescence processes [XREF_BIBR - XREF_BIBR, XREF_BIBR - XREF_BIBR].	3	9	downregulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SIRT1	SIRT1 deacetylation	sirt1	p53	p53	p53	7	8	5	6
SIRT1 has been reported to downregulate TP53 activity by its deacetylation XREF_BIBR .	SIRT1 has been reported to downregulate TP53 activity by its deacetylation XREF_BIBR.	0	7	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	TP53	TP53	TP53	0	1	6	7
Thus , SIRT1 inhibition was proposed to upregulate several p53 dependent pro apoptotic factors in B-CLL cells , thereby promoting apoptosis .	Thus, SIRT1 inhibition was proposed to upregulate several p53 dependent pro apoptotic factors in B-CLL cells, thereby promoting apoptosis.	2	13	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	9	10
The decrease in SIRT1 expression leads to an increase in the acetylation of p53 , enhancing p53 transcriptional activity , through the positive feedback loop as shown in XREF_FIG .	The decrease in SIRT1 expression leads to an increase in the acetylation of p53, enhancing p53 transcriptional activity, through the positive feedback loop as shown in XREF_FIG.	3	18	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1 expression	sirt1	p53	p53	p53	3	4	16	17
Inhibition of SIRT1 may increase p53 activity and in-turn result in upregulation of miR-34a , to further induce SIRT1 silencing .	Inhibition of SIRT1 may increase p53 activity and in-turn result in upregulation of miR-34a, to further induce SIRT1 silencing.	0	6	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	5	6
Whereas wild-type SIRT1 and phosphorylation deficient SIRT1 S682A reduced p53 regulated transactivation of the PUMA promoter to a similar extend , phospho-mimetic SIRT1 S682D was less efficient in suppressing p53 dependent transcription ( XREF_FIG ) .	Whereas wild-type SIRT1 and phosphorylation deficient SIRT1 S682A reduced p53 regulated transactivation of the PUMA promoter to a similar extend, phospho-mimetic SIRT1 S682D was less efficient in suppressing p53 dependent transcription (XREF_FIG).	6	11	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	9	10
The available evidence indicated that SIRT1 reduces the activity of p53 by removing these acetyl groups that inhibits apoptosis and promotes cell survival [ XREF_BIBR , XREF_BIBR ] .	The available evidence indicated that SIRT1 reduces the activity of p53 by removing these acetyl groups that inhibits apoptosis and promotes cell survival [XREF_BIBR, XREF_BIBR].	5	11	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	5	6	10	11
It is interesting that SIRT1 inhibition did not effectively induce p53 activation or inhibit FLT3-WT AML cells , despite their having nonmutated p53 , whereas MDM2 inhibitors such as nutlin-3 could activate p53 in FLT3-WT AML cells and even normal cells .	It is interesting that SIRT1 inhibition did not effectively induce p53 activation or inhibit FLT3-WT AML cells, despite their having nonmutated p53, whereas MDM2 inhibitors such as nutlin-3 could activate p53 in FLT3-WT AML cells and even normal cells.	4	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	10	11
SIRT1 downregulates the activity of p53 , which has been shown to downregulate Wnt signaling by promoting beta-catenin phosphorylation and degradation XREF_BIBR .	SIRT1 downregulates the activity of p53, which has been shown to downregulate Wnt signaling by promoting beta-catenin phosphorylation and degradation XREF_BIBR.	0	19	downregulates	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	SIRT1	SIRT1	sirt1	p53	p53, which has been shown to downregulate Wnt signaling by promoting beta-catenin phosphorylation	p53	0	1	5	6
Based on the cell culture data showing that SIRT1 inactivates p53 , it was initially suspected that p53 hyperactivity was responsible for the embryonic lethality of SIRT1 -/- mice .	Based on the cell culture data showing that SIRT1 inactivates p53, it was initially suspected that p53 hyperactivity was responsible for the embryonic lethality of SIRT1 -/- mice.	8	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	8	9	10	11
SIRT1 null deletion activates p53 and promotes UVB induced apoptosis .	SIRT1 null deletion activates p53 and promotes UVB induced apoptosis.	0	5	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	4	5
To test whether the p53-p21 pathway may be involved in SIRT1 silencing mediated cell senescence in p53 wild-type cells , we checked the acetylated p53 and p21 levels in H460 cells .	To test whether the p53-p21 pathway may be involved in SIRT1 silencing mediated cell senescence in p53 wild-type cells, we checked the acetylated p53 and p21 levels in H460 cells.	10	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	10	11	16	17
Sirt1 represses p53 dependent apoptosis triggered by acute oxidative stress or DNA damage in fibroblasts and mesangial cells .	Sirt1 represses p53 dependent apoptosis triggered by acute oxidative stress or DNA damage in fibroblasts and mesangial cells.	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	0	1	2	3
However , during tumorigenesis , increased levels of SIRT1 will suppress p53 triggering further suppression of p53 downstream mir-34a in a feedback loop .	However, during tumorigenesis, increased levels of SIRT1 will suppress p53 triggering further suppression of p53 downstream mir-34a in a feedback loop.	6	12	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	levels of SIRT1	sirt1	p53	p53	p53	8	9	11	12
Sirt1 may inactivate the 382nd lysine residue of p53 , reduce the expression of the wild-type p53 protein combining with the DNA cis element to promote p53 mutation .	Sirt1 may inactivate the 382nd lysine residue of p53, reduce the expression of the wild-type p53 protein combining with the DNA cis element to promote p53 mutation.	0	9	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	0	1	8	9
SIRT1 deacetylates and inactivates p53 to antagonize RS and SIPS [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	SIRT1 deacetylates and inactivates p53 to antagonize RS and SIPS [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	4	5
In the presence of Cav-1 , the active oxidative phosphorylation in mitochondria increases the NAD + / NADH ratio and activates SIRT1 , which consequently deacetylates , destabilizes , and degrades p53 , inactivating a p53-p21 pathway and preventing premature senescence .	In the presence of Cav-1, the active oxidative phosphorylation in mitochondria increases the NAD + / NADH ratio and activates SIRT1, which consequently deacetylates, destabilizes, and degrades p53, inactivating a p53-p21 pathway and preventing premature senescence.	20	32	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	21	22	31	32
It was previously demonstrated that miR-34a targets Sirt1 and is regulated by p53 , which in turn , is activated by Sirt1 suppression [ XREF_BIBR ] .	It was previously demonstrated that miR-34a targets Sirt1 and is regulated by p53, which in turn, is activated by Sirt1 suppression [XREF_BIBR].	10	24	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	21	22	12	13
miR-449b and miR34 which block the p53 repressors SIRT1 and HDAC1 were down-regulated .	miR-449b and miR34 which block the p53 repressors SIRT1 and HDAC1 were down-regulated.	4	10	repressors	Negative_activation_token_1_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	8	9	6	7
In addition , SIRT1 silencing by RNAi or specific inhibitors did not affect cell viability and was not sufficient to induce activation of endogenous p53 in the absence of applied stress XREF_BIBR - XREF_BIBR .	In addition, SIRT1 silencing by RNAi or specific inhibitors did not affect cell viability and was not sufficient to induce activation of endogenous p53 in the absence of applied stress XREF_BIBR - XREF_BIBR.	3	25	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	24	25
SIRT1 inhibition could increase the transcriptional activity of p53 which results in the increased expression of several p53 target genes including Bax , Necdin and Gfi-1 in CML CD34 + cells .	SIRT1 inhibition could increase the transcriptional activity of p53 which results in the increased expression of several p53 target genes including Bax, Necdin and Gfi-1 in CML CD34 + cells.	0	9	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	8	9
SIRT1 inactivates p53 by deacetylating a specific lysine residue to target it degradation .	SIRT1 inactivates p53 by deacetylating a specific lysine residue to target it degradation.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	2	3
XREF_BIBR Other data showed that this optimizing of SIRT1 mediated p53 degradation by visfatin induces the extension of human cell life span , such as smooth muscle cells , and the resistance to oxidative stress .	XREF_BIBR Other data showed that this optimizing of SIRT1 mediated p53 degradation by visfatin induces the extension of human cell life span, such as smooth muscle cells, and the resistance to oxidative stress.	5	11	mediated	Positive_early_activation	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	8	9	10	11
SIRT1 represses the function of p53 , KU70 , and the FOXO family proteins through deacetylation , and SIRT1 downregulation induces cell cycle arrest and apoptosis in cancer cells [ XREF_BIBR ] .	SIRT1 represses the function of p53, KU70, and the FOXO family proteins through deacetylation, and SIRT1 downregulation induces cell cycle arrest and apoptosis in cancer cells [XREF_BIBR].	0	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	5	6
Sirt1 directly suppresses NF-kappaB and p53 activation , because its N-terminal domain promotes deacetylation of NF-kappaB p65 XREF_BIBR and p53 XREF_BIBR .	Sirt1 directly suppresses NF-kappaB and p53 activation, because its N-terminal domain promotes deacetylation of NF-kappaB p65 XREF_BIBR and p53 XREF_BIBR.	0	6	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	0	1	5	6
Additionally , SIRT1 represses p53 function via deacetylation , and so , promotes tumor growth [ XREF_BIBR ] .	Additionally, SIRT1 represses p53 function via deacetylation, and so, promotes tumor growth [XREF_BIBR].	2	12	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	4	5
In irradiated cells the SIRT1 protein acts as an antagonist of the post-translational modification of p53 and thus repressing the transcriptional activity of the p53 protein [ XREF_BIBR ] .	In irradiated cells the SIRT1 protein acts as an antagonist of the post-translational modification of p53 and thus repressing the transcriptional activity of the p53 protein [XREF_BIBR].	4	27	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	24	25
Besides MDM2 , a NAD dependent deacetylase , silent information regulator 1 ( SIRT1 ) , increases the level of deacetylated p53 and negatively regulates the p53 activity [ XREF_BIBR , XREF_BIBR ] .	Besides MDM2, a NAD dependent deacetylase, silent information regulator 1 (SIRT1), increases the level of deacetylated p53 and negatively regulates the p53 activity [XREF_BIBR, XREF_BIBR].	6	22	increases	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	SIRT1	SIRT1	sirt1	p53	level of deacetylated p53	p53	13	14	21	22
First , SIRT1 knockout mice exhibit p53 hyperacetylation and increased radiation induced apoptosis consistent with SIRT1 inhibition of p53 function .	First, SIRT1 knockout mice exhibit p53 hyperacetylation and increased radiation induced apoptosis consistent with SIRT1 inhibition of p53 function.	15	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	15	16	18	19
Additionally , SIRT1 inhibits p53 through deacetylation , thus increasing the possibility of neoplastic transformation [ XREF_BIBR ] , p53 regulates SIRT1 transcription through a negative feedback loop , decreasing SIRT1 activity , which , in turn , increases TP53 activity [ XREF_BIBR ] .	Additionally, SIRT1 inhibits p53 through deacetylation, thus increasing the possibility of neoplastic transformation [XREF_BIBR], p53 regulates SIRT1 transcription through a negative feedback loop, decreasing SIRT1 activity, which, in turn, increases TP53 activity [XREF_BIBR].	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	4	5
In addition , inhibition of SIRT1 activates p53 dependent apoptosis via deacetylation and stabilization of p53 .	In addition, inhibition of SIRT1 activates p53 dependent apoptosis via deacetylation and stabilization of p53.	3	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	5	6	7	8
SIRT1 has shown to inhibit apoptosis by regulating p53 , reducing oxidative stress by regulating antioxidant defences via FOXO family members , and regulates mitochondrial biogenesis mediated by PGC-1alpha [ XREF_BIBR ] .	SIRT1 has shown to inhibit apoptosis by regulating p53, reducing oxidative stress by regulating antioxidant defences via FOXO family members, and regulates mitochondrial biogenesis mediated by PGC-1alpha [XREF_BIBR].	0	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	8	9
Our results are in conflict with previous experiments , which showed that enforced SIRT1 expression in HCT116 cells abrogated p53 dependent apoptosis induced by miR-34a [ XREF_BIBR ] .	Our results are in conflict with previous experiments, which showed that enforced SIRT1 expression in HCT116 cells abrogated p53 dependent apoptosis induced by miR-34a [XREF_BIBR].	13	21	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1 expression	sirt1	p53	p53	p53	13	14	19	20
For example , SIRT1 negatively regulates p53 dependent apoptosis by deacetylating p53 in response to cellular damage .	For example, SIRT1 negatively regulates p53 dependent apoptosis by deacetylating p53 in response to cellular damage.	3	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	6	7
52 More importantly , SIRT1 inactivates p53 , leading to the downregulation of p53 mediated growth arrest and apoptosis , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR which results in an increased risk of cancer .	52 More importantly, SIRT1 inactivates p53, leading to the downregulation of p53 mediated growth arrest and apoptosis, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR which results in an increased risk of cancer.	4	7	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	6	7
miR-34a is the direct target gene of p53 , and one of the miR-34a targets is sirtuin 1 ( SIRT1 ) , which can inhibit p53 dependent apoptosis by deacetylating all major p53 acetylation sites [ XREF_BIBR , XREF_BIBR ] .	miR-34a is the direct target gene of p53, and one of the miR-34a targets is sirtuin 1 (SIRT1), which can inhibit p53 dependent apoptosis by deacetylating all major p53 acetylation sites [XREF_BIBR, XREF_BIBR].	16	34	inhibit	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	SIRT1	SIRT1	sirt1	p53	deacetylating all major p53	p53	19	20	32	33
Over-expression of SIRT1 attenuated the transcriptional activity of p53 in response to exogenous hydrogen peroxide treatment , which prevented the induction of a p53 mediated apoptosis program [ XREF_BIBR ] .	Over-expression of SIRT1 attenuated the transcriptional activity of p53 in response to exogenous hydrogen peroxide treatment, which prevented the induction of a p53 mediated apoptosis program [XREF_BIBR].	0	10	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	Over-expression of SIRT1	sirt1	p53	p53	p53	2	3	8	9
SIRT1 inhibition increases p53 transcriptional activity .	SIRT1 inhibition increases p53 transcriptional activity.	0	5	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	3	4
Visfatin even has been described as extending the lifespan of the cells in smooth muscles by augmenting SIRT1 mediated p53 degradation .	Visfatin even has been described as extending the lifespan of the cells in smooth muscles by augmenting SIRT1 mediated p53 degradation.	16	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	17	18	19	20
Furthermore , miR-34 suppression of SIRT1 ultimately leads to apoptosis in WT human colon cancer cells but not in human colon cancer cells lacking p53 .	Furthermore, miR-34 suppression of SIRT1 ultimately leads to apoptosis in WT human colon cancer cells but not in human colon cancer cells lacking p53.	3	25	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	5	6	24	25
Reduced Sirt1 activity induced by ICS in COPD lungs could be related to increased p53 acetylation , and could possibly enhance p53 associated COPD and emphysema [ XREF_BIBR ] .	Reduced Sirt1 activity induced by ICS in COPD lungs could be related to increased p53 acetylation, and could possibly enhance p53 associated COPD and emphysema [XREF_BIBR].	1	22	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	1	2	21	22
SIRT1 can negatively regulate p53 by deacetylating several lysine sites .	SIRT1 can negatively regulate p53 by deacetylating several lysine sites.	0	5	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	4	5
Importantly , Sirt1 overexpression attenuates the upregulation of the senescence markers p21 , p16 , and p53 in the lungs of SIRT1 heterozygous mice , thereby protecting against lung senescence in epithelial cells , but not in macrophages 23 .	Importantly, Sirt1 overexpression attenuates the upregulation of the senescence markers p21, p16, and p53 in the lungs of SIRT1 heterozygous mice, thereby protecting against lung senescence in epithelial cells, but not in macrophages 23.	2	17	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1 overexpression	sirt1	p53	p53	p53	2	3	16	17
miR-449 reduction by Hp in GC induces apoptosis by inhibiting SIRT1 , which represses the p53 pathway [ XREF_BIBR ] .	miR-449 reduction by Hp in GC induces apoptosis by inhibiting SIRT1, which represses the p53 pathway [XREF_BIBR].	6	16	represses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	10	11	15	16
In vitro , SIRT1 inhibits p53 , Bax , Ku70 , FOXO , and the retinoblastoma ( Rb ) protein , which may be anticipated to promote cell proliferation .	In vitro, SIRT1 inhibits p53, Bax, Ku70, FOXO, and the retinoblastoma (Rb) protein, which may be anticipated to promote cell proliferation.	1	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	5	6
miR-34a indirectly activates p53 by downregulating SIRT1 , which negativly regulates p53 through deacetylation .	miR-34a indirectly activates p53 by downregulating SIRT1, which negativly regulates p53 through deacetylation.	2	12	negativly regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	11	12
Overexpression of SirT1 disrupts p53 dependent pathways , resulting in a significant reduction in the cell ' s ability to respond to stress and DNA damage .	Overexpression of SirT1 disrupts p53 dependent pathways, resulting in a significant reduction in the cell 's ability to respond to stress and DNA damage.	0	6	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SirT1	Overexpression of SirT1	sirt1	p53	p53	p53	2	3	4	5
Most notably , SIRT1 could deactivate p53 and attenuate its ability as a transcription factor , thereby ameliorating apoptosis [ XREF_BIBR ] .	Most notably, SIRT1 could deactivate p53 and attenuate its ability as a transcription factor, thereby ameliorating apoptosis [XREF_BIBR].	3	8	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	6	7
In response to DNA damage or oxidative stress , Sirt1 is activated to repress p53 dependent apoptosis in mammalian cells , nuclear p53 mediated transactivation of proapoptotic genes in mouse cells , and FOXO3 induced cell death in human cells .	In response to DNA damage or oxidative stress, Sirt1 is activated to repress p53 dependent apoptosis in mammalian cells, nuclear p53 mediated transactivation of proapoptotic genes in mouse cells, and FOXO3 induced cell death in human cells.	9	16	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	9	10	14	15
Oxidative stress induced lens epithelial cultures were protected from apoptosis by SIRT1 inhibition of p53 pathway 41 .	Oxidative stress induced lens epithelial cultures were protected from apoptosis by SIRT1 inhibition of p53 pathway 41.	11	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	11	12	14	15
As Sirt-1 inactivates p53 , and p53 activity is essential for normal embryonic development through regulation of TGF-beta signaling [ XREF_BIBR , XREF_BIBR ] , Sirt-1 could be involved in regulating multiple pathways during gut development .	As Sirt-1 inactivates p53, and p53 activity is essential for normal embryonic development through regulation of TGF-beta signaling [XREF_BIBR, XREF_BIBR], Sirt-1 could be involved in regulating multiple pathways during gut development.	1	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt-1	Sirt-1	Sirt-1	p53	p53	p53	1	2	3	4
cDNA microarray data-set analysis between mESC and EB in wild and SIRT1 showed that SIRT1 inhibits p53 signaling pathway but not affect NF-kappaB signaling pathway .	cDNA microarray data-set analysis between mESC and EB in wild and SIRT1 showed that SIRT1 inhibits p53 signaling pathway but not affect NF-kappaB signaling pathway.	14	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	14	15	16	17
SirT1 haploinsufficiency promotes spontaneous tumor development in TP53 +/- mice , while overexpression of SirT1 in lymphocyte progenitors reduces the incidence of thymic lymphomas in TP53 +/- mice post gamma irradiation , consistent with a tumor-suppressor function of SirT1 .	SirT1 haploinsufficiency promotes spontaneous tumor development in TP53 +/- mice, while overexpression of SirT1 in lymphocyte progenitors reduces the incidence of thymic lymphomas in TP53 +/- mice post gamma irradiation, consistent with a tumor-suppressor function of SirT1.	0	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SirT1	SirT1	SirT1	TP53	TP53	TP53	0	1	7	8
First , SIRT1 knockdown , the catalytically inactive H363Y allele , or specific inhibition of SIRT1 in cells does not affect cell viability or cell growth and is not sufficient to induce activation of endogenous p53 .	First, SIRT1 knockdown, the catalytically inactive H363Y allele, or specific inhibition of SIRT1 in cells does not affect cell viability or cell growth and is not sufficient to induce activation of endogenous p53.	13	36	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	15	16	35	36
In turn , inactivation of p53 by SIRT1 dependent deacetylation is accompanied by AMPK activation .	In turn, inactivation of p53 by SIRT1 dependent deacetylation is accompanied by AMPK activation.	3	10	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SIRT1	SIRT1 dependent deacetylation	sirt1	p53	p53	p53	7	8	5	6
Recently , some studies have suggested that SIRT1 could be over-expressed in breast , prostate and colon cancers and up-regulated SIRT1 inactivates p53 by deacetylation .	Recently, some studies have suggested that SIRT1 could be over-expressed in breast, prostate and colon cancers and up-regulated SIRT1 inactivates p53 by deacetylation.	7	23	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	7	8	22	23
Moreover , SirT1 overexpression in cancer represses p53 dependent cell-cycle arrest and apoptosis in response to DNA damage and oxidative stress .	Moreover, SirT1 overexpression in cancer represses p53 dependent cell-cycle arrest and apoptosis in response to DNA damage and oxidative stress.	2	10	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SirT1	SirT1 overexpression	sirt1	p53	p53	p53	2	3	7	8
SIRT-1 inactivates p53 via deacetylation , which allows the proliferation of cells in the presence of damaged DNA , promoting tumor progression [ XREF_BIBR ] .	SIRT-1 inactivates p53 via deacetylation, which allows the proliferation of cells in the presence of damaged DNA, promoting tumor progression [XREF_BIBR].	0	4	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT-1	SIRT-1	SIRT-1	p53	p53	p53	0	1	2	3
For example , SIRT1 inhibits p53 , reducing its pro apoptotic effect .	For example, SIRT1 inhibits p53, reducing its pro apoptotic effect.	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	5	6
Taken together , our data suggest that inhibition of SIRT1 by MHY2256 causes increased activation of p53 by decreasing MDM2 expression .	Taken together, our data suggest that inhibition of SIRT1 by MHY2256 causes increased activation of p53 by decreasing MDM2 expression.	7	17	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	16	17
Thus , under these conditions , AROS does not appear to be required for p53 deacetylation , suggesting that SIRT1 is able to suppress p53 when AROS expression is reduced .	Thus, under these conditions, AROS does not appear to be required for p53 deacetylation, suggesting that SIRT1 is able to suppress p53 when AROS expression is reduced.	19	25	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	19	20	24	25
Sirt1 inactivates p53 and nuclear factor-kappaB subunit p65 and RelA , which are involved in cell death .	Sirt1 inactivates p53 and nuclear factor-kappaB subunit p65 and RelA, which are involved in cell death.	0	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	0	1	2	3
109 As p53 is inhibited by Sirt1 and it activates p66Shc , studies are needed to demonstrate the concerted action of these elements on vascular homeostasis ( XREF_FIG ) .	109 As p53 is inhibited by Sirt1 and it activates p66Shc, studies are needed to demonstrate the concerted action of these elements on vascular homeostasis (XREF_FIG).	2	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	6	7	2	3
Because SIRT1 has been identified to deactivate p53 through deacetylation , experiments in the human TK6 lymphoblastoid cell line were conducted to identify if DHC could induce a phenotype consistent with SIRT1 inhibition and p53 activation .	Because SIRT1 has been identified to deactivate p53 through deacetylation, experiments in the human TK6 lymphoblastoid cell line were conducted to identify if DHC could induce a phenotype consistent with SIRT1 inhibition and p53 activation.	1	8	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	1	2	7	8
These observations indicate that SIRT1 knockdown can activate p53 signaling in IM treated CML cells .	These observations indicate that SIRT1 knockdown can activate p53 signaling in IM treated CML cells.	4	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	8	9
However , overexpression of SIRT1 through resveratrol treatment or transfection clearly attenuated the NiONPs induced apoptosis and activation of p53 and Bax .	However, overexpression of SIRT1 through resveratrol treatment or transfection clearly attenuated the NiONPs induced apoptosis and activation of p53 and Bax.	2	21	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	overexpression of SIRT1	sirt1	p53	p53	p53	4	5	19	20
Specifically , SIRT1 decreases p53 activity .	Specifically, SIRT1 decreases p53 activity.	2	5	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	4	5
SIRT1 is expressed at a higher level in cancerous cells and promotes oncogenesis by suppressing p53 activity through deacetylation of lysine 382 XREF_BIBR , XREF_BIBR .	SIRT1 is expressed at a higher level in cancerous cells and promotes oncogenesis by suppressing p53 activity through deacetylation of lysine 382 XREF_BIBR, XREF_BIBR.	0	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1 is expressed	sirt1	p53	p53	p53	0	1	15	16
Therefore , p300 is a positive regulator of p53 activity , while SIRT1 negatively regulates p53 functions .	Therefore, p300 is a positive regulator of p53 activity, while SIRT1 negatively regulates p53 functions.	12	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	12	13	15	16
SIRT1 is markedly increased in malignant ovarian tumors ( especially , in serous carcinoma ) compared to corresponding normal tissues , and up-regulated SIRT1 inactivates p53 by deacetylation [ XREF_BIBR ] .	SIRT1 is markedly increased in malignant ovarian tumors (especially, in serous carcinoma) compared to corresponding normal tissues, and up-regulated SIRT1 inactivates p53 by deacetylation [XREF_BIBR].	0	26	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	25	26
SIRT1 could inhibit p53 activation induced by genotoxic stress XREF_BIBR .	SIRT1 could inhibit p53 activation induced by genotoxic stress XREF_BIBR.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	3	4
SIRT1 function as a deacetylase directly inhibits p53 dependent apoptosis in cortical neurons , and forkhead box ( Fox ) O3 dependent apoptosis in cerebellar granule neurons , when treated with DNA damaging , apoptosis promoting agents [ XREF_BIBR - XREF_BIBR ] .	SIRT1 function as a deacetylase directly inhibits p53 dependent apoptosis in cortical neurons, and forkhead box (Fox) O3 dependent apoptosis in cerebellar granule neurons, when treated with DNA damaging, apoptosis promoting agents [XREF_BIBR - XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	7	8
Sirt1 negatively regulates the tumor suppressor p53 and other tumor suppressors and inhibits the transcription activity of AP-1 by targeting c-JUN .	Sirt1 negatively regulates the tumor suppressor p53 and other tumor suppressors and inhibits the transcription activity of AP-1 by targeting c-JUN.	0	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	0	1	4	7
On the basis of the cell culture data showing that SIRT1 downregulates p53 , it was expected that the SIRT1 -/- p53 -/+ combination could delay the formation of cancer relative to p53 +/- mice .	On the basis of the cell culture data showing that SIRT1 downregulates p53, it was expected that the SIRT1 -/- p53 -/+ combination could delay the formation of cancer relative to p53 +/- mice.	10	13	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	10	11	12	13
SIRT1 deacetylates and thereby represses p53 activity to protect cells from p53 dependent anti-proliferative responses XREF_BIBR , XREF_BIBR .	SIRT1 deacetylates and thereby represses p53 activity to protect cells from p53 dependent anti-proliferative responses XREF_BIBR, XREF_BIBR.	0	6	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	5	6
Sirt1 inhibits p65 NF-kappaB and p53 by deacetylating these transcription factors .	Sirt1 inhibits p65 NF-kappaB and p53 by deacetylating these transcription factors.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	0	1	5	6
Unlike in macrophages , SIRT1 activation downregulated p53 in primary hepatocyte cultures ( data not shown ) .	Unlike in macrophages, SIRT1 activation downregulated p53 in primary hepatocyte cultures (data not shown).	4	11	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	7	8
Sirt1 inhibits p65 NF-kappaB and p53 by deacetylation , reducing inflammation and apoptosis [ XREF_BIBR - XREF_BIBR ] .	Sirt1 inhibits p65 NF-kappaB and p53 by deacetylation, reducing inflammation and apoptosis [XREF_BIBR - XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	0	1	5	6
SIRT1 deacetylates and decreases the transcriptional activity of pro apoptotic p53 and increases cell survival after DNA damage XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	SIRT1 deacetylates and decreases the transcriptional activity of pro apoptotic p53 and increases cell survival after DNA damage XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	11	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	10	11
Overexpression of SIRT1 strongly attenuates p53 dependent apoptosis upon DNA damage and oxidative stress .	Overexpression of SIRT1 strongly attenuates p53 dependent apoptosis upon DNA damage and oxidative stress.	0	7	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	Overexpression of SIRT1	sirt1	p53	p53	p53	2	3	5	6
Earlier studies indicated that SIRT1 promotes cell survival under oxidative stress by inhibiting p53 dependent apoptosis , due to inhibition of p53 transactivation through its deacetylation [ XREF_BIBR ] .	Earlier studies indicated that SIRT1 promotes cell survival under oxidative stress by inhibiting p53 dependent apoptosis, due to inhibition of p53 transactivation through its deacetylation [XREF_BIBR].	4	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	13	14
Although it remains to be investigated why INZ does not activate p53 in normal fibroblast cells , it is possible that in the absence of stress , SIRT1 might not be needed to inactivate p53 as p53 is not acetylated by p300 and CBP in normally growing cells .	Although it remains to be investigated why INZ does not activate p53 in normal fibroblast cells, it is possible that in the absence of stress, SIRT1 might not be needed to inactivate p53 as p53 is not acetylated by p300 and CBP in normally growing cells.	27	35	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	27	28	34	35
On the other hand , SIRT1 can inhibit p53 through the deacetylation of Lys382 , which deactivates downstream p53 signaling .	On the other hand, SIRT1 can inhibit p53 through the deacetylation of Lys382, which deactivates downstream p53 signaling.	5	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	5	6	8	9
Furthermore , Sirt1 also inhibits p53 transcriptional activity induced by HG , which may affect the p66Shc expression XREF_BIBR .	Furthermore, Sirt1 also inhibits p53 transcriptional activity induced by HG, which may affect the p66Shc expression XREF_BIBR.	2	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	2	3	5	6
In keeping with the evidence that SIRT1 inactivates TP53 by deacetylating a critical lysine residue at position 382 [ XREF_BIBR ] , we demonstrated a significant increase of TP53 acetylation at lys382 upon anti-IgM stimulation of CLL cells .	In keeping with the evidence that SIRT1 inactivates TP53 by deacetylating a critical lysine residue at position 382 [XREF_BIBR], we demonstrated a significant increase of TP53 acetylation at lys382 upon anti-IgM stimulation of CLL cells.	6	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	TP53	TP53	TP53	6	7	8	9
Several studies have mentioned the roles of SIRT1 as anti-apoptotic regulator that SIRT1 deacetylates the DNA repair factor , and also inhibits p53 and NF-kappaB signaling .	Several studies have mentioned the roles of SIRT1 as anti-apoptotic regulator that SIRT1 deacetylates the DNA repair factor, and also inhibits p53 and NF-kappaB signaling.	12	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	12	13	22	23
Recent studies reported that p53 activation and the stress response function can be inhibited by SIRT1 .	Recent studies reported that p53 activation and the stress response function can be inhibited by SIRT1.	4	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	15	16	4	5
Although SIRT1 , a p53 deacetylase , inhibits p53 mediated transactivation , how SIRT1 regulates these p53 multifunctions is unclear .	Although SIRT1, a p53 deacetylase, inhibits p53 mediated transactivation, how SIRT1 regulates these p53 multifunctions is unclear.	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	1	2	8	9
In the former study , Sirt1 induced renal epithelial cell proliferation by inhibiting the function of both Rb and p53 through the deacetylation of these molecules .	In the former study, Sirt1 induced renal epithelial cell proliferation by inhibiting the function of both Rb and p53 through the deacetylation of these molecules.	5	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	5	6	19	20
The overexpression of SIRT1 inhibits the p53 and p21 cip pathway and CEP cell senescence in oxidative stress .	The overexpression of SIRT1 inhibits the p53 and p21 cip pathway and CEP cell senescence in oxidative stress.	1	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	overexpression of SIRT1	sirt1	p53	p53	p53	3	4	6	7
In contrast , the inhibition of SIRT1 activity activates the p53 and p21 cip pathway and , thereby , CEP cell senescence by increasing the levels of acetylated p53 .	In contrast, the inhibition of SIRT1 activity activates the p53 and p21 cip pathway and, thereby, CEP cell senescence by increasing the levels of acetylated p53.	6	21	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	10	11
Recent studies have reported that epigenetic inactivation of HIC1 results in up-regulation of SIRT1 , which deacetylates p53 , and that SIRT1 down-regulates p53 through histone deacetylation .	Recent studies have reported that epigenetic inactivation of HIC1 results in up-regulation of SIRT1, which deacetylates p53, and that SIRT1 down-regulates p53 through histone deacetylation.	21	24	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	21	22	23	24
As a deacetylase , SIRT1 inhibits p53 activity via deacetylation at lysine 382 [ XREF_BIBR ] .	As a deacetylase, SIRT1 inhibits p53 activity via deacetylation at lysine 382 [XREF_BIBR].	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	6	7
Given that SIRT1 downregulates p53 in cell culture experiments , SIRT1 activity was expected to exacerbate the p53 +/- phenotype and shorten life span , but the opposite occurred .	Given that SIRT1 downregulates p53 in cell culture experiments, SIRT1 activity was expected to exacerbate the p53 +/- phenotype and shorten life span, but the opposite occurred.	2	8	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	4	5
Sirt1 is known to deacetylate p53 , preventing p53 from triggering cellular senescence and apoptosis in response to DNA damage and stress XREF_BIBR , XREF_BIBR .	Sirt1 is known to deacetylate p53, preventing p53 from triggering cellular senescence and apoptosis in response to DNA damage and stress XREF_BIBR, XREF_BIBR.	0	9	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1 is known to deacetylate p53	sirt1	p53	p53	p53	0	1	8	9
DBC1 may therefore promote the development of breast cancer through activation of SIRT1 , which then downregulates p53 and/or other tumor suppressor pathways .	DBC1 may therefore promote the development of breast cancer through activation of SIRT1, which then downregulates p53 and/or other tumor suppressor pathways.	10	19	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	12	13	17	18
Therefore , while increased SIRT1 expression following inhibition of miR-34a activity reduces p53 , this could have also reduced the direct inhibitory effect of miR-34a on TP53 , leading to further increase in p53 expression [ XREF_BIBR ] .	Therefore, while increased SIRT1 expression following inhibition of miR-34a activity reduces p53, this could have also reduced the direct inhibitory effect of miR-34a on TP53, leading to further increase in p53 expression [XREF_BIBR].	4	13	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1 expression	sirt1	p53	p53	p53	4	5	12	13
The class III histone deactylase ( HDAC ) , SIRT1 , has cancer relevance because it regulates lifespan in multiple organisms , down-regulates p53 function through deacetylation , and is linked to polycomb gene silencing in Drosophila .	The class III histone deactylase (HDAC), SIRT1, has cancer relevance because it regulates lifespan in multiple organisms, down-regulates p53 function through deacetylation, and is linked to polycomb gene silencing in Drosophila.	4	24	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	23	24
Overexpression of SIRT1 inactivates the p53 , and thus causing the low response of cancer cells carrying WT p53 to DNA damaging chemotherapeutic drugs .	Overexpression of SIRT1 inactivates the p53, and thus causing the low response of cancer cells carrying WT p53 to DNA damaging chemotherapeutic drugs.	0	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	Overexpression of SIRT1	sirt1	p53	p53	p53	2	3	5	6
Consistent with SIRT1 inhibition of p53 function , Sirt1 (-/-) knockout mice exhibit p53 hyperacetylation and increased radiation induced apoptosis , raising the possibility that SIRT1 can facilitate tumour growth by antagonism of p53 [ XREF_BIBR ] .	Consistent with SIRT1 inhibition of p53 function, Sirt1 (-/-) knockout mice exhibit p53 hyperacetylation and increased radiation induced apoptosis, raising the possibility that SIRT1 can facilitate tumour growth by antagonism of p53 [XREF_BIBR].	2	6	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	5	6
For example , in cells exposed to high concentrations of chemotherapeutic , overexpressed SIRT1 represses induction of p53 target genes and reduces apoptosis .	For example, in cells exposed to high concentrations of chemotherapeutic, overexpressed SIRT1 represses induction of p53 target genes and reduces apoptosis.	12	21	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	13	14	17	18
TP53 directly binds the mir-34a promoter inducing its expression , while miR-34a indirectly promotes p53 expression by targeting and repressing levels of the deacetylase SIRT1 , which negatively regulates TP53 .	TP53 directly binds the mir-34a promoter inducing its expression, while miR-34a indirectly promotes p53 expression by targeting and repressing levels of the deacetylase SIRT1, which negatively regulates TP53.	20	30	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	levels of the deacetylase SIRT1	sirt1	TP53	TP53	tp53	24	25	29	30
It has been further reported that p53 activation by SIRT1 inhibition , in combination with imatinib increased the killing of CML progenitor cells [ XREF_BIBR ] and that the combination of nutlin3a with imatinib enhanced CML apoptosis [ XREF_BIBR ] .	It has been further reported that p53 activation by SIRT1 inhibition, in combination with imatinib increased the killing of CML progenitor cells [XREF_BIBR] and that the combination of nutlin3a with imatinib enhanced CML apoptosis [XREF_BIBR].	6	10	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	6	7
Exemplifying the utility of small molecules to understand cellular events , our findings with tenovins have led us to complete previous experiments by showing that SirT1 inhibition by transient transfection of a SirT1 mutant with dominant negative activity leads to increased p53 transcriptional activity .	Exemplifying the utility of small molecules to understand cellular events, our findings with tenovins have led us to complete previous experiments by showing that SirT1 inhibition by transient transfection of a SirT1 mutant with dominant negative activity leads to increased p53 transcriptional activity.	25	43	leads	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	SirT1	SirT1	SirT1	p53	p53	p53	25	26	41	42
The first evidence of Sirt1 as a tumor promoter came from experiments showing that Sirt1 physically interacts with p53 and attenuates p53 mediated functions through deacetylation of p53 at its C-terminal Lys382 residue [ XREF_BIBR , XREF_BIBR ] .	The first evidence of Sirt1 as a tumor promoter came from experiments showing that Sirt1 physically interacts with p53 and attenuates p53 mediated functions through deacetylation of p53 at its C-terminal Lys382 residue [XREF_BIBR, XREF_BIBR].	2	23	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	4	5	21	22
Since p53 is a known SIRT1 target [ XREF_BIBR ] , this suggests that tumorigenesis and progression of these cancers may be due in part to SIRT1 inhibition of p53 activity through deacetylation .	Since p53 is a known SIRT1 target [XREF_BIBR], this suggests that tumorigenesis and progression of these cancers may be due in part to SIRT1 inhibition of p53 activity through deacetylation.	26	30	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	26	27	29	30
These above results indicated that O GlcNAcylation of SIRT1 attenuated the function of p53 during the stress response , suggesting that SIRT1 O GlcNAcylation might prevent stress induced apoptosis .	These above results indicated that O GlcNAcylation of SIRT1 attenuated the function of p53 during the stress response, suggesting that SIRT1 O GlcNAcylation might prevent stress induced apoptosis.	6	14	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	8	9	13	14
Loss of one allele of SIRT1 ( SIRT1 +/-) in mice accelerates tumor onset and incidence in the p53 +/- background , indicating that SIRT1 haplo-insufficiency facilities tumorigenesis [ XREF_BIBR ] , while overexpression of SIRT1 , specifically in the gut , reduces the number and size of intestinal tumors in APC min/+ mice [ XREF_BIBR ] .	Loss of one allele of SIRT1 (SIRT1 +/-) in mice accelerates tumor onset and incidence in the p53 +/- background, indicating that SIRT1 haplo-insufficiency facilities tumorigenesis [XREF_BIBR], while overexpression of SIRT1, specifically in the gut, reduces the number and size of intestinal tumors in APC min/+ mice [XREF_BIBR].	3	20	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	5	6	18	19
These data indicate that NAMPT is a longevity protein that can add stress resistant life to human smooth muscle cells by optimizing SIRT1 mediated p53 degradation .	These data indicate that NAMPT is a longevity protein that can add stress resistant life to human smooth muscle cells by optimizing SIRT1 mediated p53 degradation.	21	25	mediated	Positive_early_activation	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	22	23	24	25
Thus , NAMPT may also be a longevity protein that can add stress-resistance and extend the lifespan of human SMCs by optimizing SIRT1 mediated p53 degradation .	Thus, NAMPT may also be a longevity protein that can add stress-resistance and extend the lifespan of human SMCs by optimizing SIRT1 mediated p53 degradation.	21	25	mediated	Positive_early_activation	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	22	23	24	25
Increased SIRT1 activity has been previously shown to represses p53 activity to prevent p53 dependent cellular senescence .	Increased SIRT1 activity has been previously shown to represses p53 activity to prevent p53 dependent cellular senescence.	1	10	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	1	2	9	10
In contrast , the inhibition of SirT1 potentiates p53 dependent apoptosis .	In contrast, the inhibition of SirT1 potentiates p53 dependent apoptosis.	4	10	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SirT1	SirT1	SirT1	p53	p53	p53	6	7	8	9
These data indicate that Nampt is a longevity protein that can add stress resistant life to human SMCs by optimizing SIRT1 mediated p53 degradation .	These data indicate that Nampt is a longevity protein that can add stress resistant life to human SMCs by optimizing SIRT1 mediated p53 degradation.	19	23	mediated	Positive_early_activation	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	20	21	22	23
The studies implicate that Sirt1 inactivates p53 via deacetylation in tumor cells , leading to downregulation of the p53 target genes.17 , 18 To investigate whether upregulation of Sirt1 by catecholamines affects the p53 acetylation , we treated SiHa and CaSki cells , which express wildtype p53 , with 0.5 muM DOX , an inducer of DNA double-strand break , which causes p53 activation , for 18h .	The studies implicate that Sirt1 inactivates p53 via deacetylation in tumor cells, leading to downregulation of the p53 target genes.17, 18 To investigate whether upregulation of Sirt1 by catecholamines affects the p53 acetylation, we treated SiHa and CaSki cells, which express wildtype p53, with 0.5 muM DOX, an inducer of DNA double-strand break, which causes p53 activation, for 18h.	4	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	4	5	6	7
Previous studies have shown that Sirt1 negatively regulates p53 activity and protects ECs from H 2 O 2 -induced senescence [ XREF_BIBR ] .	Previous studies have shown that Sirt1 negatively regulates p53 activity and protects ECs from H 2 O 2 -induced senescence [XREF_BIBR].	5	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	5	6	8	9
In this context , SIRT1 deficient cells fail to normally upregulate either the p19 ( ARF ) senescence regulator or its downstream target p53 .	In this context, SIRT1 deficient cells fail to normally upregulate either the p19 (ARF) senescence regulator or its downstream target p53.	4	24	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	23	24
On the other hand , up regulation of SIRT1 inactivates p53 .	On the other hand, up regulation of SIRT1 inactivates p53.	6	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	8	9	10	11
Genotoxic stress activates p53 , the strongest inducer of miR-34a that inhibits SIRT1 expression , which in turn inactivates p53 by its deacetylation .	Genotoxic stress activates p53, the strongest inducer of miR-34a that inhibits SIRT1 expression, which in turn inactivates p53 by its deacetylation.	3	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	p53, the strongest inducer of miR-34a that inhibits SIRT1 expression	sirt1	p53	p53	p53	12	13	19	20
It seems that SIRT1 is able to deacetylase and inhibit p53 activity and suppress the induction of apoptosis and prolongs cellular survival in response to DNA damage in some cancer cells .	It seems that SIRT1 is able to deacetylase and inhibit p53 activity and suppress the induction of apoptosis and prolongs cellular survival in response to DNA damage in some cancer cells.	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	10	11
Thus , SIRT1 may inhibit p53 in prolonged fasting whereas in short-term fasting p53 is free to elicit its glucogenic activities .	Thus, SIRT1 may inhibit p53 in prolonged fasting whereas in short-term fasting p53 is free to elicit its glucogenic activities.	2	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	5	6
SIRT1 down-regulates p53 activity , increasing lifespan , cell survival , and neuroprotection ; it also deacetylates peroxisome proliferator activated receptor-gamma and its coactivator 1alpha , promoting fat mobilization , increasing mitochondrial size and number , and positively regulating insulin secretion .	SIRT1 down-regulates p53 activity, increasing lifespan, cell survival, and neuroprotection; it also deacetylates peroxisome proliferator activated receptor-gamma and its coactivator 1alpha, promoting fat mobilization, increasing mitochondrial size and number, and positively regulating insulin secretion.	0	3	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	2	3
Co-transfection of miR-34a-resistant SIRT1 , which increased SIRT1 protein , did not significantly reduce miR-34a-induced pG13-luc promoter activity or increase p53 target ( CDKN1A , PUMA and TP53INP ) mRNAs ( XREF_FIG ) .	Co-transfection of miR-34a-resistant SIRT1, which increased SIRT1 protein, did not significantly reduce miR-34a-induced pG13-luc promoter activity or increase p53 target (CDKN1A, PUMA and TP53INP) mRNAs (XREF_FIG).	0	29	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	20	21
Although previous studies indicated that the p53 inactivation by SIRT1 promotes cell survival during stress , other studies have suggested that small-molecule SIRT1 inhibitors do not affect cell survival , and that developmental defects in a SIRT1 knockout mouse strain are not rescued by crossing to p53 null mice .	Although previous studies indicated that the p53 inactivation by SIRT1 promotes cell survival during stress, other studies have suggested that small-molecule SIRT1 inhibitors do not affect cell survival, and that developmental defects in a SIRT1 knockout mouse strain are not rescued by crossing to p53 null mice.	6	10	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	6	7
HIC1 directly represses SIRT1 transcription to modulate the P53 dependent apoptotic response to non repairable double-strands breaks [ XREF_BIBR ] .	HIC1 directly represses SIRT1 transcription to modulate the P53 dependent apoptotic response to non repairable double-strands breaks [XREF_BIBR].	0	11	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	HIC1 directly represses SIRT1 transcription	sirt1	P53	P53	p53	3	4	8	9
Among these are the p53-p21 pathway via PI3K , 42 increased p53 stabilization and activation through SIRT1 inhibition , 43 and ERK activation , which also upregulates p53 and promotes its stability and activity .	Among these are the p53-p21 pathway via PI3K, 42 increased p53 stabilization and activation through SIRT1 inhibition, 43 and ERK activation, which also upregulates p53 and promotes its stability and activity.	16	28	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	16	17	27	28
The NAD dependent histone deacetylase Sirt1 antagonizes p53 transcriptional activity to regulate cell-cycle progression and apoptosis .	The NAD dependent histone deacetylase Sirt1 antagonizes p53 transcriptional activity to regulate cell-cycle progression and apoptosis.	0	9	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	5	6	7	8
In this manner , SIRT1 promotes cell survival under stress conditions by specifically repressing p53 dependent apoptosis .	In this manner, SIRT1 promotes cell survival under stress conditions by specifically repressing p53 dependent apoptosis.	4	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	14	15
In addition , the inhibition of SIRT1 activates p53 dependent apoptosis through deacetylation and stabilization of p53 .	In addition, the inhibition of SIRT1 activates p53 dependent apoptosis through deacetylation and stabilization of p53.	4	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	8	9
A speculative model therefore is , in normal state mir-34a , a known p53-miR , suppresses SIRT1 ( which is known to suppress p53 ) balancing the SIRT1 mediated transcriptional repression of p53 .	A speculative model therefore is, in normal state mir-34a, a known p53-miR, suppresses SIRT1 (which is known to suppress p53) balancing the SIRT1 mediated transcriptional repression of p53.	25	33	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	27	28	32	33
SIRT1 knockdown also increased the activity of endogenous p53 in 293 cells ( XREF_SUPPLEMENTARY ) .	SIRT1 knockdown also increased the activity of endogenous p53 in 293 cells (XREF_SUPPLEMENTARY).	0	9	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	8	9
In p25 transgenic mice , which overexpress the cdk5 activating human p25 protein and exhibit tau hyperphosphorylation and neurodegeneration , 37 injection of the Sirt1 activating polyphenol resveratrol resulted in less hippocampal degeneration , less cognitive deficit , and reduced acetylation of Sirt1 substrates PGC-1alpha and p53 .	In p25 transgenic mice, which overexpress the cdk5 activating human p25 protein and exhibit tau hyperphosphorylation and neurodegeneration, 37 injection of the Sirt1 activating polyphenol resveratrol resulted in less hippocampal degeneration, less cognitive deficit, and reduced acetylation of Sirt1 substrates PGC-1alpha and p53.	24	47	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	24	25	46	47
Expression of wild-type Sirt1 in human cells reduces the transcriptional activity of p53 .	Expression of wild-type Sirt1 in human cells reduces the transcriptional activity of p53.	0	13	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Expression of wild-type Sirt1	sirt1	p53	p53	p53	3	4	12	13
To further assess the role of p53 acetylation in cell death induction by PA-2 , we overexpressed in MDA-MB-231 cells SIRT1 , which negatively regulates p53 through its de-acetylation [ XREF_BIBR , XREF_BIBR ] .	To further assess the role of p53 acetylation in cell death induction by PA-2, we overexpressed in MDA-MB-231 cells SIRT1, which negatively regulates p53 through its de-acetylation [XREF_BIBR, XREF_BIBR].	16	26	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	20	21	25	26
SIRT1 normally functions to suppress p53 , thus , by targeting SIRT1 , miR-34 safeguards expression of p53 and thus its downstream targets .	SIRT1 normally functions to suppress p53, thus, by targeting SIRT1, miR-34 safeguards expression of p53 and thus its downstream targets.	0	6	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	5	6
Recently , it has been demonstrated that the endothelium specific overexpression of SIRT1 is able to inhibit the HG induced upregulation of the senescence associated markers , such as the CDK inhibitor p21 Waf1/Cip1/Sdi1 ( p21 ) , p53 , and the plasminogen activator inhibitor-1 ( PAI-1 ) [ XREF_BIBR ] .	Recently, it has been demonstrated that the endothelium specific overexpression of SIRT1 is able to inhibit the HG induced upregulation of the senescence associated markers, such as the CDK inhibitor p21 Waf1/Cip1/Sdi1 (p21), p53, and the plasminogen activator inhibitor-1 (PAI-1) [XREF_BIBR].	10	39	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	overexpression of SIRT1	sirt1	p53	p53	p53	12	13	38	39
Both human and mouse SIRT1 are thought to promote cell survival by deacetylating and thus deactivating the p53 proapoptotic gene XREF_BIBR - XREF_BIBR .	Both human and mouse SIRT1 are thought to promote cell survival by deacetylating and thus deactivating the p53 proapoptotic gene XREF_BIBR - XREF_BIBR.	1	20	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	17	18
Interestingly MST1 was shown to be able to activate p53 in response to cisplatin induced DNA damage by phosphorylating and inactivating Sirt1 , a deacetylase that inactivates p53 [ XREF_BIBR ] .	Interestingly MST1 was shown to be able to activate p53 in response to cisplatin induced DNA damage by phosphorylating and inactivating Sirt1, a deacetylase that inactivates p53 [XREF_BIBR].	14	29	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	21	22	27	28
Interestingly , CK2-Is downregulated SIRT1 activity and over-expression of SIRT1 decreased p53 transcriptional activity and rescued cells from CK2-I-induced apoptosis .	Interestingly, CK2-Is downregulated SIRT1 activity and over-expression of SIRT1 decreased p53 transcriptional activity and rescued cells from CK2-I-induced apoptosis.	4	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	11	12
Additionally , a member of the sirtuin family , silent information regulator type-1 ( SIRT1 ) , promotes cell survival by repressing p53- and non-p53-dependent apoptosis in response to DNA damage and oxidative stress .	Additionally, a member of the sirtuin family, silent information regulator type-1 (SIRT1), promotes cell survival by repressing p53- and non-p53-dependent apoptosis in response to DNA damage and oxidative stress.	12	25	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53-	p53-	p53-	14	15	22	23
We show that resveratrol activates p53 that is negatively regulated by SIRT1 deacetylation on Lys379 and positively by AMPK phosphorylation on Ser15 in mouse ESCs ( mESCs ) .	We show that resveratrol activates p53 that is negatively regulated by SIRT1 deacetylation on Lys379 and positively by AMPK phosphorylation on Ser15 in mouse ESCs (mESCs).	4	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SIRT1	SIRT1 deacetylation on Lys379	sirt1	p53	p53	p53	11	12	5	6
At the same time , SIRT1 can also deactivate transcriptional activity of p53 , thereby inhibiting its function .	At the same time, SIRT1 can also deactivate transcriptional activity of p53, thereby inhibiting its function.	5	13	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	5	6	12	13
XREF_BIBR , XREF_BIBR Interestingly , p53 , a well-known target of SIRT1 , accumulates in the cytoplasm of various cancer cells , functioning as a proapoptotic protein ; and SIRT1 might inhibit p53 dependent apoptosis in the cytoplasm of cancer cells .	XREF_BIBR, XREF_BIBR Interestingly, p53, a well-known target of SIRT1, accumulates in the cytoplasm of various cancer cells, functioning as a proapoptotic protein; and SIRT1 might inhibit p53 dependent apoptosis in the cytoplasm of cancer cells.	29	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	29	30	32	33
Among other targets , SIRT1 down-regulates the activity of the nuclear transcription factor p53 , being this related with an increase in lifespan and cell survival associated to stress resistance .	Among other targets, SIRT1 down-regulates the activity of the nuclear transcription factor p53, being this related with an increase in lifespan and cell survival associated to stress resistance.	4	14	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	13	14
The class III histone deacetylase sirtuin 1 ( SIRT1 ) represses p53 transcriptional activation by deacetylating p53 following DNA damage .	The class III histone deacetylase sirtuin 1 (SIRT1) represses p53 transcriptional activation by deacetylating p53 following DNA damage.	5	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	8	9	11	12
Since p53 is constitutively suppressed by SIRT1 in HCT116 cells , 20 this result is consistent with targeted SIRT1 silencing by each of the 3 '-DNA/siRNA constructs I-III .	Since p53 is constitutively suppressed by SIRT1 in HCT116 cells, 20 this result is consistent with targeted SIRT1 silencing by each of the 3 '-DNA/siRNA constructs I-III.	1	9	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	1	2
As a consequence , SIRT1 represses p53 dependent apoptosis in response to DNA damage and oxidative stress , and promotes cell survival under cellular stress induced by agents such as etoposide or irradiation .	As a consequence, SIRT1 represses p53 dependent apoptosis in response to DNA damage and oxidative stress, and promotes cell survival under cellular stress induced by agents such as etoposide or irradiation.	4	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	6	7
Additionally , SIRT1 represses p53 function via deacetylation , promoting tumor growth .	Additionally, SIRT1 represses p53 function via deacetylation, promoting tumor growth.	2	5	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	4	5
Although wild-type p53 is expressed in approximately 50 % of patients with cancer , it remains dysfunctional in these tumor cells because of abnormally elevated levels of p53 suppressors such as MDM2 , MDMX , SIRT1 , and HDACs [ XREF_BIBR - XREF_BIBR ] .	Although wild-type p53 is expressed in approximately 50% of patients with cancer, it remains dysfunctional in these tumor cells because of abnormally elevated levels of p53 suppressors such as MDM2, MDMX, SIRT1, and HDACs [XREF_BIBR - XREF_BIBR].	27	36	suppressors	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	35	36	27	28
Previous studies showed that SIRT1 repressed the activity of p53 by deacetylating the C-terminal Lys120 , Lys164 and Lys382 residues [ XREF_BIBR - XREF_BIBR ] .	Previous studies showed that SIRT1 repressed the activity of p53 by deacetylating the C-terminal Lys120, Lys164 and Lys382 residues [XREF_BIBR - XREF_BIBR].	4	10	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	9	10
Several proteins help to modify the interactions of SIRT1 with p53 , including p53 ( itself ) , DBC1 , AROS , and HIC1 , suggesting that it is a cellular imperative to control the inhibition of p53 by SIRT1 under certain conditions .	Several proteins help to modify the interactions of SIRT1 with p53, including p53 (itself), DBC1, AROS, and HIC1, suggesting that it is a cellular imperative to control the inhibition of p53 by SIRT1 under certain conditions.	33	40	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	39	40	37	38
LNAC only induced p-ATM ( S1981 ) in control cells and not after CM exposure , suggesting that the reduced oxidative stress levels might trigger a cell cycle progression and DNA damage response , presumably via SIRT1 mediated p53 and NBS1 activations respectively .	LNAC only induced p-ATM (S1981) in control cells and not after CM exposure, suggesting that the reduced oxidative stress levels might trigger a cell cycle progression and DNA damage response, presumably via SIRT1 mediated p53 and NBS1 activations respectively.	28	41	mediated	Positive_early_activation	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	36	37	38	39
Accordingly , the inactivation of HIC1 upregulates the transcription of SIRT1 , thereby inactivating p53 , which allows cells to bypass apoptosis after DNA damage .	Accordingly, the inactivation of HIC1 upregulates the transcription of SIRT1, thereby inactivating p53, which allows cells to bypass apoptosis after DNA damage.	5	17	inactivating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	HIC1 upregulates the transcription of SIRT1	sirt1	p53	p53	p53	10	11	14	15
Treatment with metformin attenuated the HG induced reduction of SIRT1 expression , modulated the SIRT1 downstream targets FoxO-1 and p53 and p21 , and protected endothelial cells from HG induced premature senescence .	Treatment with metformin attenuated the HG induced reduction of SIRT1 expression, modulated the SIRT1 downstream targets FoxO-1 and p53 and p21, and protected endothelial cells from HG induced premature senescence.	5	21	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	HG induced reduction of SIRT1 expression	sirt1	p53	p53	p53	9	10	19	20
SIRT1 , a mammalian homolog of Sir2 , has been reported to downregulate p53 activity and thereby prolong the lifespan of cells .	SIRT1, a mammalian homolog of Sir2, has been reported to downregulate p53 activity and thereby prolong the lifespan of cells.	0	17	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	13	14
In particular , SIRT1 acts on K382 and negatively regulates p53 action on pro apoptotic genes .	In particular, SIRT1 acts on K382 and negatively regulates p53 action on pro apoptotic genes.	3	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	10	11
XREF_BIBR Sirt1 also attenuates p53 and PTEN , promotes EMT , and increases cell migration , all of which promote carcinogenesis .	XREF_BIBR Sirt1 also attenuates p53 and PTEN, promotes EMT, and increases cell migration, all of which promote carcinogenesis.	0	12	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	1	2	4	5
More recently , AROS was also identified as a direct interactant of the NAD + -dependent deacetylase SIRT1 , promoting SIRT1 mediated suppression of p53 in human cancer cell lines .	More recently, AROS was also identified as a direct interactant of the NAD + -dependent deacetylase SIRT1, promoting SIRT1 mediated suppression of p53 in human cancer cell lines.	20	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	20	21	24	25
However , as reported previously , 19 SIRT1 silencing induces apoptosis in HCT116 p53 +/+ cancer cells , an effect specifically rescued by Forkhead box protein O4 ( Foxo4 ) cosilencing ( XREF_SUPPLEMENTARY ) .	However, as reported previously, 19 SIRT1 silencing induces apoptosis in HCT116 p53 +/+ cancer cells, an effect specifically rescued by Forkhead box protein O4 (Foxo4) cosilencing (XREF_SUPPLEMENTARY).	7	16	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	7	8	13	14
Furthermore , it has been reported that iNampt promotes cellular life span of SMCs through increasing Sirt1 mediated p53 degradation [ XREF_BIBR ] .	Furthermore, it has been reported that iNampt promotes cellular life span of SMCs through increasing Sirt1 mediated p53 degradation [XREF_BIBR].	16	21	mediated	Positive_early_activation	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	16	17	18	19
Thus overexpression of Sirt1 deactivates p53 and disrupts p53 dependent pathways and this results in a large reduction in the cell ' s ability to respond to stress and DNA damage [ XREF_BIBR , XREF_BIBR ] .	Thus overexpression of Sirt1 deactivates p53 and disrupts p53 dependent pathways and this results in a large reduction in the cell 's ability to respond to stress and DNA damage [XREF_BIBR, XREF_BIBR].	1	10	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	overexpression of Sirt1	sirt1	p53	p53	p53	3	4	8	9
XREF_BIBR Interestingly , AMPK has not only been shown to activate p53 by serine 15 phosphorylation , it also directly phosphorylatesand inactivates SIRT1 , leading to inhibition of SIRT1 mediated p53 repression , so the role of AMPK in this pathway requires further investigation .	XREF_BIBR Interestingly, AMPK has not only been shown to activate p53 by serine 15 phosphorylation, it also directly phosphorylatesand inactivates SIRT1, leading to inhibition of SIRT1 mediated p53 repression, so the role of AMPK in this pathway requires further investigation.	26	31	mediated	Positive_early_activation	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	28	29	30	31
It is noteworthy that this p53 activating effect elicited by SIRT1 inhibition was not seen in FLT3 non mutated AML cells or normal cells , underscoring the importance of identifying oncogene specific adaptive response in the face of chemotherapy and other targeted therapy .	It is noteworthy that this p53 activating effect elicited by SIRT1 inhibition was not seen in FLT3 non mutated AML cells or normal cells, underscoring the importance of identifying oncogene specific adaptive response in the face of chemotherapy and other targeted therapy.	5	11	elicited	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	10	11	5	6
In particular SIRT1 , the most widely studied sirtuin isoform , may operate as either tumour promoter or tumour suppressor : on the one hand , SIRT1 can repress p53 function via deacetylation , on the other hand , it can also facilitate DNA repair .	In particular SIRT1, the most widely studied sirtuin isoform, may operate as either tumour promoter or tumour suppressor : on the one hand, SIRT1 can repress p53 function via deacetylation, on the other hand, it can also facilitate DNA repair.	26	30	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	26	27	29	30
However , the Reactome gene sets alone showed that in all three datasets there was an upregulation of genes involved in cell proliferation and the control of mitosis , including G1-to-S transition , synthesis of DNA , SCF and skp2 mediated degradation of p27 and p21 , and p53 regulation , among others .	However, the Reactome gene sets alone showed that in all three datasets there was an upregulation of genes involved in cell proliferation and the control of mitosis, including G1-to-S transition, synthesis of DNA, SCF and skp2 mediated degradation of p27 and p21, and p53 regulation, among others.	33	49	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	skp2	skp2	skp2	p27	p27	p27	39	40	43	44
For example , the oncogenic F-box protein Skp2 is overexpressed in human tumors , and promotes p27 degradation , contributing to malignant progression , whereas the tumor suppressor F-box protein FBW7 , which degrades several proto-oncogenes ( such as MYC , Notch , JUN and Cyclin E ) , undergoes numerous cancer associated mutations , and loss of FBW7 function causes chromosomal instability and tumorigenesis .	For example, the oncogenic F-box protein Skp2 is overexpressed in human tumors, and promotes p27 degradation, contributing to malignant progression, whereas the tumor suppressor F-box protein FBW7, which degrades several proto-oncogenes (such as MYC, Notch, JUN and Cyclin E), undergoes numerous cancer associated mutations, and loss of FBW7 function causes chromosomal instability and tumorigenesis.	5	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	F-box protein Skp2	F-box protein Skp2 is overexpressed	f-box protein skp2	p27	p27	p27	5	8	16	17
In addition , a critical role for Skp2 dependent degradation of p27 in colon adenoma-carcinoma development was demonstrated using a Skp2 knock-in model [ XREF_BIBR ] .	In addition, a critical role for Skp2 dependent degradation of p27 in colon adenoma-carcinoma development was demonstrated using a Skp2 knock-in model [XREF_BIBR].	7	15	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	7	8	11	12
XREF_BIBR , XREF_BIBR Rb-E2F1 is controlled by CDKs , while Skp2 negatively regulates p27 , an inhibitor of CDKs .	XREF_BIBR, XREF_BIBR Rb-E2F1 is controlled by CDKs, while Skp2 negatively regulates p27, an inhibitor of CDKs.	10	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	10	11	13	14
Furthermore , how Skp2 mediates p27 degradation has actually not been clearly delineated since abolishing p27 phosphorylation at Thr187 prevented ubiquitination of the p27T187A mutant ( in which Thr187 is changed to Ala , which can not be phosphorylated ) in test tubes but not in p27 T187A and T187A mice [ XREF_BIBR ] .	Furthermore, how Skp2 mediates p27 degradation has actually not been clearly delineated since abolishing p27 phosphorylation at Thr187 prevented ubiquitination of the p27T187A mutant (in which Thr187 is changed to Ala, which can not be phosphorylated) in test tubes but not in p27 T187A and T187A mice [XREF_BIBR].	3	6	mediates	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	5	6
IL-7-induced p27 Kip1 degradation mediated by Skp2 dependent and Skp2 independent and PKC dependent pathways .	IL-7-induced p27 Kip1 degradation mediated by Skp2 dependent and Skp2-independent and PKC-dependent pathways.	1	7	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	6	7	1	3
Expression of p45SKP2 in quiescent fibroblasts promotes p27Kip1 degradation , allows the generation of cyclin-A-dependent kinase activity and induces S phase .	Expression of p45SKP2 in quiescent fibroblasts promotes p27Kip1 degradation, allows the generation of cyclin-A-dependent kinase activity and induces S phase.	0	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p45SKP2	Expression of p45SKP2	p45skp2	p27Kip1	p27Kip1	p27kip1	2	3	7	8
Therefore , this study seeks to determine the impact of AMPKalpha activation on bladder cancer proliferation and whether this is dependent on , or mediated in part by SKP2 mediated degradation and control of p27 protein .	Therefore, this study seeks to determine the impact of AMPKalpha activation on bladder cancer proliferation and whether this is dependent on, or mediated in part by SKP2 mediated degradation and control of p27 protein.	24	35	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	28	29	34	35
These results showed that Skp2 signaling positively regulates the activity of CDKs by decreasing p27 in A549 and NCI-H1975 cells , supporting the conclusion that Skp2 promotes cell cycle progression by degrading p27 .	These results showed that Skp2 signaling positively regulates the activity of CDKs by decreasing p27 in A549 and NCI-H1975 cells, supporting the conclusion that Skp2 promotes cell cycle progression by degrading p27.	25	33	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	25	26	32	33
We expected that Rb1 deletion in the absence of deregulated Skp2 would elevate p27 to inhibit melanotroph proliferation and , therefore , prevent tumorigenesis .	We expected that Rb1 deletion in the absence of deregulated Skp2 would elevate p27 to inhibit melanotroph proliferation and, therefore, prevent tumorigenesis.	7	14	elevate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	10	11	13	14
Simvastatin transcriptionally inhibits Skp2 expression and promotes p27 accumulation in HepG2 cells .	Simvastatin transcriptionally inhibits Skp2 expression and promotes p27 accumulation in HepG2 cells.	0	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Simvastatin transcriptionally inhibits Skp2 expression	skp2	p27	p27	p27	3	4	7	8
These results indicate that the Skp2 mediated degradation pathway regulating the cellular degradation of p27 is essential for establishing beta cell mass and to respond to increased metabolic demand associated with insulin resistance .	These results indicate that the Skp2 mediated degradation pathway regulating the cellular degradation of p27 is essential for establishing beta cell mass and to respond to increased metabolic demand associated with insulin resistance.	4	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	5	6	14	15
We conclude that miR-221/222 compensates for loss of Skp2 mediated p27 degradation during cell cycling , contributes to proteasome dependent G1 phase regulation of p27 , and accounts for the anti-mitogenic effect of cAMP during growth inhibition .	We conclude that miR-221/222 compensates for loss of Skp2 mediated p27 degradation during cell cycling, contributes to proteasome dependent G1 phase regulation of p27, and accounts for the anti-mitogenic effect of cAMP during growth inhibition.	6	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	8	9	10	11
Moreover , overexpression of Skp2 in MCF-7 cells prevented accumulation of p27Kip1 and promoted resistance to the antiproliferative effects of EGCG .	Moreover, overexpression of Skp2 in MCF-7 cells prevented accumulation of p27Kip1 and promoted resistance to the antiproliferative effects of EGCG.	2	12	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	overexpression of Skp2	skp2	p27Kip1	p27Kip1	p27kip1	4	5	11	12
Therefore , TNF-alpha is likely to participate in Skp2 and Cks1 dependent degradation of p27 as a precipitating factor of chronic nephropathy .	Therefore, TNF-alpha is likely to participate in Skp2 and Cks1 dependent degradation of p27 as a precipitating factor of chronic nephropathy.	8	15	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	8	9	14	15
Knockdown of Skp2 reversed the p27 induction and G1 arrest .	Knockdown of Skp2 reversed the p27 induction and G1 arrest.	0	6	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	2	3	5	6
Rosiglitazone attenuated Skp2 expression , thereby promoting p27 accumulation in H. pylori infected human gastric epithelial cells .	Rosiglitazone attenuated Skp2 expression, thereby promoting p27 accumulation in H. pylori infected human gastric epithelial cells.	0	8	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Rosiglitazone attenuated Skp2 expression	skp2	p27	p27	p27	2	3	7	8
These studies demonstrated that hypophosphorylated pRb associates with the APC/C specifically when activated by Cdh1 , thus promoting Skp2 degradation and accumulation of p27 Kip1 and p21 Cip1 .	These studies demonstrated that hypophosphorylated pRb associates with the APC/C specifically when activated by Cdh1, thus promoting Skp2 degradation and accumulation of p27 Kip1 and p21 Cip1.	18	25	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	18	19	23	25
The increased protein stability of p27 likely resulted from IBET mediated suppression of Skp2 , an E3 ligase that can mediate p27 degradation by increasing its ubiquitinylation .	The increased protein stability of p27 likely resulted from IBET mediated suppression of Skp2, an E3 ligase that can mediate p27 degradation by increasing its ubiquitinylation.	11	22	mediate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	13	14	21	22
Taken together , these data suggested that Skp2 acted as an oncogene in human gastric cancer , and that Skp2 mediated p27kip1 degradation contributed to the progression of gastric cancer .	Taken together, these data suggested that Skp2 acted as an oncogene in human gastric cancer, and that Skp2 mediated p27kip1 degradation contributed to the progression of gastric cancer.	19	22	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27kip1	p27kip1	p27kip1	19	20	21	22
The cullin RING ubiquitin ligase , CRL1 ( SKP2 ) , directing the degradation of the tumor suppressor p27 , is a well validated drug target in a wide variety of human cancers .	The cullin RING ubiquitin ligase, CRL1 (SKP2), directing the degradation of the tumor suppressor p27, is a well validated drug target in a wide variety of human cancers.	6	19	directing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	8	9	18	19
Not only did CAPE treatment suppressed Skp2 protein expression while increased protein abundance of p53 , p21 Cip1 and p27 Kip1 , but overexpression of Skp2 or siRNA knockdown of p53 , p21 Cip1 and p27 Kip1 also partially blocked the suppressive effect of CAPE on CRPC cells .	Not only did CAPE treatment suppressed Skp2 protein expression while increased protein abundance of p53, p21 Cip1 and p27 Kip1, but overexpression of Skp2 or siRNA knockdown of p53, p21 Cip1 and p27 Kip1 also partially blocked the suppressive effect of CAPE on CRPC cells.	23	37	knockdown	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	overexpression of Skp2	skp2	p27 Kip1	p27 Kip1	p27 kip1	25	26	35	37
XREF_BIBR , XREF_BIBR Skp2 , which can also be regulated by p52 , XREF_BIBR , XREF_BIBR promotes the degradation of the CDK inhibitor p27 , allowing cell cycle progression XREF_BIBR .	XREF_BIBR, XREF_BIBR Skp2, which can also be regulated by p52, XREF_BIBR, XREF_BIBR promotes the degradation of the CDK inhibitor p27, allowing cell cycle progression XREF_BIBR.	0	24	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	23	24
Both p21 and p27 proteins are degraded by Skp2 E3 ligase , and skp2 -/- cells in the presence of tumor suppressors exhibit increased cellular senescence .	Both p21 and p27 proteins are degraded by Skp2 E3 ligase, and skp2 -/- cells in the presence of tumor suppressors exhibit increased cellular senescence.	1	10	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	8	9	3	4
Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3 AR cells partially blocked accumulation of p27 Kip1 and increased Cdk2 activity under androgen treatment , which partially blocked the androgenic suppressive effects on proliferation and cell cycle .	Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3 AR cells partially blocked accumulation of p27 Kip1 and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle.	0	17	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Overexpression of Skp2	skp2	p27 Kip1	p27 Kip1	p27 kip1	2	3	15	17
CAPE treatment reduced protein expression of Skp2 but induced protein abundance of p21 Cip1 , p27 Kip1 , p53 , and ATF4 .	CAPE treatment reduced protein expression of Skp2 but induced protein abundance of p21 Cip1, p27 Kip1, p53, and ATF4.	0	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	CAPE treatment reduced protein expression of Skp2	skp2	p27 Kip1	p27 Kip1	p27 kip1	6	7	15	17
Furthermore , a knock-in mouse model showed a crucial role of Skp2 dependent degradation of p27 for the progress of colon adenomas to carcinoma [ XREF_BIBR ] .	Furthermore, a knock-in mouse model showed a crucial role of Skp2 dependent degradation of p27 for the progress of colon adenomas to carcinoma [XREF_BIBR].	11	16	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	11	12	15	16
Here , we demonstrate that galectin-3 increases the expression of Skp2 and induces degradation of p27 KIP1 protein , without influencing p27 KIP1 mRNA levels .	Here, we demonstrate that galectin-3 increases the expression of Skp2 and induces degradation of p27 KIP1 protein, without influencing p27 KIP1 mRNA levels.	5	17	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	galectin-3 increases the expression of Skp2	skp2	p27 KIP1	p27 KIP1	p27 kip1	10	11	15	17
Because the Skp2 autoinduction loop can function in mitogen deprived cells ( XREF_FIG ) , we reasoned that these results could be reconciled if Skp2 mediated p27 degradation was essential only for the transition to mitogen independence , also called the restriction point .	Because the Skp2 autoinduction loop can function in mitogen deprived cells (XREF_FIG), we reasoned that these results could be reconciled if Skp2 mediated p27 degradation was essential only for the transition to mitogen independence, also called the restriction point.	24	39	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	24	25	26	27
Treatment with other actin inhibitors , psychosine and cytochalasin D , also led to increases in p27 and Kip1 and Cyclin E ( XREF_FIG ) , indicating that actin damage leads to inhibition of Skp2 mediated p27 and Kip1 degradation .	Treatment with other actin inhibitors, psychosine and cytochalasin D, also led to increases in p27 and Kip1 and Cyclin E (XREF_FIG), indicating that actin damage leads to inhibition of Skp2 mediated p27 and Kip1 degradation.	32	39	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	34	35	36	37
SKP2 mediated p27 degradation .	SKP2 mediated p27 degradation.	0	3	mediated	Positive_early_activation	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	0	1	2	3
In conclusion , troglitazone attenuated Skp2 expression , thereby promoting p27 ( Kip1 ) accumulation in human hepatoma cells .	In conclusion, troglitazone attenuated Skp2 expression, thereby promoting p27 (Kip1) accumulation in human hepatoma cells.	3	14	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	troglitazone attenuated Skp2 expression	skp2	p27	p27	p27	5	6	10	11
This surprising finding has led to the notion that there must be mechanisms compensating for loss of Skp2 mediated p27 degradation .	This surprising finding has led to the notion that there must be mechanisms compensating for loss of Skp2 mediated p27 degradation.	15	20	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	17	18	19	20
Moreover , prostate specific expression of Skp2 downregulates p27 and consequently induces hyperplasia , dysplasia , and low-grade carcinoma 117 .	Moreover, prostate specific expression of Skp2 downregulates p27 and consequently induces hyperplasia, dysplasia, and low-grade carcinoma 117.	4	9	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	6	7	8	9
Conversely , adenovirus mediated overexpression of NOR1 induces Skp2 expression in VSMC and decreases protein abundance of its target p27 .	Conversely, adenovirus mediated overexpression of NOR1 induces Skp2 expression in VSMC and decreases protein abundance of its target p27.	4	20	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	overexpression of NOR1 induces Skp2 expression	skp2	p27	p27	p27	8	9	19	20
Interestingly , FaDu cells with reduced cortactin levels also exhibited a significant diminution in RhoA expression and activity , together with decreased expression of Skp2 , a critical component of the SCF ubiquitin ligase that targets p27 ( Kip1 ) and p57 ( Kip2 ) for degradation .	Interestingly, FaDu cells with reduced cortactin levels also exhibited a significant diminution in RhoA expression and activity, together with decreased expression of Skp2, a critical component of the SCF ubiquitin ligase that targets p27 (Kip1) and p57 (Kip2) for degradation.	22	41	targets	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	24	25	36	37
Together , these data suggest that SIRT2 suppression may increase NSCLC cell growth , possibly through Skp2 mediated p27 degradation .	Together, these data suggest that SIRT2 suppression may increase NSCLC cell growth, possibly through Skp2 mediated p27 degradation.	9	19	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	16	17	18	19
Amplification of SKP2 , which encodes a ubiquitin ligase that targets p27 Kip1 for proteasomal degradation , may also serve to inactivate p27 Kip1 .	Amplification of SKP2, which encodes a ubiquitin ligase that targets p27 Kip1 for proteasomal degradation, may also serve to inactivate p27 Kip1.	0	24	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27 Kip1	p27 Kip1	p27 Kip1	2	3	22	24
One of the potent CDK inhibitors is p27 , a protein which is degraded by the protein , SKP2 .	One of the potent CDK inhibitors is p27, a protein which is degraded by the protein, SKP2.	5	19	degraded	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	18	19	7	8
However , in the time since it became widely acknowledged that SKP2 mediates p27 degradation in G1 phase , several discrepancies have emerged .	However, in the time since it became widely acknowledged that SKP2 mediates p27 degradation in G1 phase, several discrepancies have emerged.	11	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	11	12	13	14
Indeed , overexpression of Skp2 in KO VSMC efficiently decreased both p21 cip1 and p27 kip1 ( XREF_SUPPLEMENTARY ) .	Indeed, overexpression of Skp2 in KO VSMC efficiently decreased both p21 cip1 and p27 kip1 (XREF_SUPPLEMENTARY).	2	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	overexpression of Skp2	skp2	p27 kip1	p27 kip1	p27 kip1	4	5	14	16
The lower endogenous level p27 Kip1 in Skp2 overexpressing LNCaP 104-R1 cells was consistent to the function of Skp2 as Skp2 target p27 Kip1 for degradation .	The lower endogenous level p27 Kip1 in Skp2 overexpressing LNCaP 104-R1 cells was consistent to the function of Skp2 as Skp2 target p27 Kip1 for degradation.	20	24	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	20	21	22	24
More studies are needed to determine the relative contributions of Skp2 mediated p27 degradation and Akt activation .	More studies are needed to determine the relative contributions of Skp2 mediated p27 degradation and Akt activation.	8	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	10	11	12	13
Meanwhile , the Skp2 , which is the substrate of APC/C and degrades p27 [ XREF_BIBR - XREF_BIBR ] , was increased .	Meanwhile, the Skp2, which is the substrate of APC/C and degrades p27 [XREF_BIBR - XREF_BIBR], was increased.	2	21	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	13	14
beta3 integrin was shown to be associated with inhibition of cell growth and promotion of apoptosis [ XREF_BIBR ] , and over-expression of beta1 integrin inhibits HCC cell proliferation by preventing Skp-2 dependent degradation of p27 via PI3K pathways [ XREF_BIBR ] .	beta3 integrin was shown to be associated with inhibition of cell growth and promotion of apoptosis [XREF_BIBR], and over-expression of beta1 integrin inhibits HCC cell proliferation by preventing Skp-2 dependent degradation of p27 via PI3K pathways [XREF_BIBR].	31	38	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp-2	Skp-2	Skp-2	p27	p27	p27	31	32	35	36
Expression of Skp2 protein may lead to decrease p27 ( kip1 ) level in human prostatic carcinoma , indicating its involvement in the development of human prostatic carcinoma .	Expression of Skp2 protein may lead to decrease p27 (kip1) level in human prostatic carcinoma, indicating its involvement in the development of human prostatic carcinoma.	0	11	lead	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Expression of Skp2	skp2	kip1	kip1	kip1	2	3	10	11
In human cancers , it was demonstrated that Skp2 overexpression stimulates the degradation of p27 , indicating that Skp2 overexpression facilitates accelerated tumor growth and malignant potential [ XREF_BIBR ] .	In human cancers, it was demonstrated that Skp2 overexpression stimulates the degradation of p27, indicating that Skp2 overexpression facilitates accelerated tumor growth and malignant potential [XREF_BIBR].	8	15	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2 overexpression	skp2	p27	p27	p27	8	9	14	15
Similar findings have been obtained for leukemia , with Skp2 knockdown in human CML cell lines resulting in upregulation of p27 and genetic ablation of Skp2 inducing a delay in disease progression in a mouse model of CML.43 Genetic ablation of Skp2 was also found to impair cell cycle progression in hematopoietic stem and progenitor cells ,44 suggesting that Skp2 inhibition might promote the dormancy of LSCs , although this possibility requires further validation .	Similar findings have been obtained for leukemia, with Skp2 knockdown in human CML cell lines resulting in upregulation of p27 and genetic ablation of Skp2 inducing a delay in disease progression in a mouse model of CML.43 Genetic ablation of Skp2 was also found to impair cell cycle progression in hematopoietic stem and progenitor cells,44 suggesting that Skp2 inhibition might promote the dormancy of LSCs, although this possibility requires further validation.	9	23	resulting in upregulation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	9	10	20	21
SKP2 promotes the degradation of the CDK inhibitor p27 Kip1 , which was implicated in cell migration through control of the RhoA pathway 136 ( Box 1 ) .	SKP2 promotes the degradation of the CDK inhibitor p27 Kip1, which was implicated in cell migration through control of the RhoA pathway 136 (Box 1).	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27 Kip1	p27 Kip1	p27 Kip1	0	1	8	10
The targeting of Skp2 by Cdh1-APC for destruction results in elevation of p21 and p27 , which are crucial for coordinating cellular division and differentiation .	The targeting of Skp2 by Cdh1-APC for destruction results in elevation of p21 and p27, which are crucial for coordinating cellular division and differentiation.	1	15	results in elevation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	14	15
Studies have also shown that p107 can decrease Skp2 levels and increase p27 KIP1 , delaying S-phase entry [ XREF_BIBR , XREF_BIBR ] .	Studies have also shown that p107 can decrease Skp2 levels and increase p27 KIP1, delaying S-phase entry [XREF_BIBR, XREF_BIBR].	5	14	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	p107 can decrease Skp2 levels	skp2	p27 KIP1	p27 KIP1	p27 kip1	8	9	12	14
If p27T187A KI prevented p27 ubiquitination by SCF Skp2 and Cks1 to accumulate p27 , knockdown of Skp2 in p27T187A KI cells would not further increase p27 , and this proved true ( XREF_FIG ) .	If p27T187A KI prevented p27 ubiquitination by SCF Skp2 and Cks1 to accumulate p27, knockdown of Skp2 in p27T187A KI cells would not further increase p27, and this proved true (XREF_FIG).	15	27	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	17	18	26	27
Loss of Brap resulted in elevated Skp2 , which increased p27 Kip1 destruction , leading to G1 phase truncation and premature S phase entry .	Loss of Brap resulted in elevated Skp2, which increased p27 Kip1 destruction, leading to G1 phase truncation and premature S phase entry.	3	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	6	7	10	12
The higher expression of Skp2 induces the degradation of p27 and promotes the entry of S phase from G phase , leading to induction of the immortalized cell proliferation .	The higher expression of Skp2 induces the degradation of p27 and promotes the entry of S phase from G phase, leading to induction of the immortalized cell proliferation.	2	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	4	5	9	10
Skp2 may promote cell proliferation of fibroblastic cells as well as epithelial cells by degrading p27 .	Skp2 may promote cell proliferation of fibroblastic cells as well as epithelial cells by degrading p27.	0	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	15	16
We show that miR221/222 redundantly regulate p27 levels post-transcriptionally , and this finding helps to explain why pronounced defects in p27 expression and cell cycling are not regularly observed in vitro or in vivo when Skp2 mediated p27 degradation is precluded by mutation of p27T187 .	We show that miR221/222 redundantly regulate p27 levels post-transcriptionally, and this finding helps to explain why pronounced defects in p27 expression and cell cycling are not regularly observed in vitro or in vivo when Skp2 mediated p27 degradation is precluded by mutation of p27T187.	35	38	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	35	36	37	38
Taken together , p27 Kip1 reduction in the absence of AMPKalpha2in VSMCs is mediated by Skp2 .	Taken together, p27 Kip1 reduction in the absence of AMPKalpha2in VSMCs is mediated by Skp2.	3	16	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	15	16	3	5
Although Skp2 has been thought to mediate the degradation of p27 at the G ( 1 )-S transition , Skp2 (-/-) cells exhibit accumulation of p27 in S-G ( 2 ) phase with overreplication .	Although Skp2 has been thought to mediate the degradation of p27 at the G (1)-S transition, Skp2 (-/-) cells exhibit accumulation of p27 in S-G (2) phase with overreplication.	1	11	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	1	2	10	11
Jag-1 and Notch2 signaling robustly decreased S-phase kinase associated protein ( Skp2 ) , an F-box protein that degrades p27 kip1 during G1 .	Jag-1 and Notch2 signaling robustly decreased S-phase kinase associated protein (Skp2), an F-box protein that degrades p27 kip1 during G1.	9	21	degrades	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 kip1	p27 kip1	p27 kip1	11	12	19	21
This gonadal hypoplasia was likely attributable to the lack of Skp2 dependent degradation of p27 by the proteasome [ XREF_BIBR , XREF_BIBR ] .	This gonadal hypoplasia was likely attributable to the lack of Skp2 dependent degradation of p27 by the proteasome [XREF_BIBR, XREF_BIBR].	10	15	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	10	11	14	15
These data indicate that Hippo-Skp2 signaling prevents genomic instability through two possible mechanisms : maintaining Skp2 mediated p27 degradation in the nuclei to limit polyploidy formation or preventing Skp2 mediated FoxO1/3 degradation in the cytosol to block polyploidy cell division , thereby limiting the risk of genomic instability , aneuploidy and tumorigenesis .	These data indicate that Hippo-Skp2 signaling prevents genomic instability through two possible mechanisms : maintaining Skp2 mediated p27 degradation in the nuclei to limit polyploidy formation or preventing Skp2 mediated FoxO1/3 degradation in the cytosol to block polyploidy cell division, thereby limiting the risk of genomic instability, aneuploidy and tumorigenesis.	14	18	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	15	16	17	18
Skp2 is a component of the SCF ubiquitin ligase and mediates the degradation of p27 .	Skp2 is a component of the SCF ubiquitin ligase and mediates the degradation of p27.	0	15	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	14	15
Furthermore , p210 Bcr-Abl also induces the expression of Skp2 and thus promotes the degradation of p27 kip1 [ XREF_BIBR , XREF_BIBR ] .	Furthermore, p210 Bcr-Abl also induces the expression of Skp2 and thus promotes the degradation of p27 kip1 [XREF_BIBR, XREF_BIBR].	2	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	p210 Bcr-Abl also induces the expression of Skp2	skp2	p27 kip1	p27 kip1	p27 kip1	9	10	16	18
We propose that the essential role for Skp2 dependent degradation of p27 is in the formation of an autoinduction loop that selectively controls the transition to mitogen-independence , and that Skp2 dependent proteolysis may be dispensable when pocket proteins are constitutively inactivated .	We propose that the essential role for Skp2 dependent degradation of p27 is in the formation of an autoinduction loop that selectively controls the transition to mitogen-independence, and that Skp2 dependent proteolysis may be dispensable when pocket proteins are constitutively inactivated.	7	12	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	7	8	11	12
SIRT2 regulates p27 levels through Skp2 mediated p27 degradation .	SIRT2 regulates p27 levels through Skp2 mediated p27 degradation.	1	8	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	5	6	7	8
Taken together , the results of this study identify p27 as the key mediator of 1,25 ( OH ) ( 2 ) D ( 3 )-induced growth suppression in G ( 1 ) and show that the hormone achieves this by decreasing the activity of CDK2 and reducing the abundance of Skp2 , which act together to degrade p27 .	Taken together, the results of this study identify p27 as the key mediator of 1,25 (OH) (2) D (3)-induced growth suppression in G (1) and show that the hormone achieves this by decreasing the activity of CDK2 and reducing the abundance of Skp2, which act together to degrade p27.	49	59	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	51	52	58	59
Although combined overexpression of Skp2 and Cks1 rescues p27 degradation in S phase , it can not override p27 accumulation in G ( 1 ) phase and cell cycle arrest by oncostatin M.	Although combined overexpression of Skp2 and Cks1 rescues p27 degradation in S phase, it can not override p27 accumulation in G (1) phase and cell cycle arrest by oncostatin M.	2	9	rescues	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	overexpression of Skp2	skp2	p27	p27	p27	4	5	8	9
In G 0 and during the G 1 phase of the cell cycle , Skp2 is degraded via the APC/C Cdh1 ubiquitin ligase to allow stabilization of p27 and inhibition of CDKs , facilitating the maintenance of the G 0 / G 1 state .	In G 0 and during the G 1 phase of the cell cycle, Skp2 is degraded via the APC/C Cdh1 ubiquitin ligase to allow stabilization of p27 and inhibition of CDKs, facilitating the maintenance of the G 0 / G 1 state.	14	29	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	14	15	27	28
For example , the anaphase promoting complex and cyclosome ( APC/C ) promotes the exit from mitosis via destruction of securin and mitotic cyclins , whereas CRL1 ( Skp2 ) allows entry into S phase by targeting the destruction of the cyclin dependent kinase ( CDK ) inhibitor p27 .	For example, the anaphase promoting complex and cyclosome (APC/C) promotes the exit from mitosis via destruction of securin and mitotic cyclins, whereas CRL1 (Skp2) allows entry into S phase by targeting the destruction of the cyclin dependent kinase (CDK) inhibitor p27.	26	49	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	28	29	48	49
Targeting Skp2 in experimental models resulted in up-regulation of p27 ( Kip1 ) and arrested cellular proliferation .	Targeting Skp2 in experimental models resulted in up-regulation of p27 (Kip1) and arrested cellular proliferation.	0	16	up-regulation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	1	2	9	10
Similarly , siRNA knockdown of SKP2 causes p27 accumulation and suppresses the growth of melanoma cells in monolayer culture and in nude mice .	Similarly, siRNA knockdown of SKP2 causes p27 accumulation and suppresses the growth of melanoma cells in monolayer culture and in nude mice.	3	8	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	5	6	7	8
The Skp2 component of the SCF ( SKP2 ) complex that degrades p27 ( Kip1 ) was increased in ErbB2 tumors correlating with earlier tumor onset .	The Skp2 component of the SCF (SKP2) complex that degrades p27 (Kip1) was increased in ErbB2 tumors correlating with earlier tumor onset.	1	13	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	1	2	12	13
Translation of mRNAs involved in cell growth , proliferation , and bioenergetics were selectively inhibited by reduction of eIF4GI , as was the mRNA encoding Skp2 that inhibits p27 , whereas catabolic pathway factors were increased .	Translation of mRNAs involved in cell growth, proliferation, and bioenergetics were selectively inhibited by reduction of eIF4GI, as was the mRNA encoding Skp2 that inhibits p27, whereas catabolic pathway factors were increased.	14	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	25	26	28	29
These compounds selectively inhibited Skp2 mediated p27 degradation by reducing p27 binding through key compound-receptor contacts .	These compounds selectively inhibited Skp2 mediated p27 degradation by reducing p27 binding through key compound-receptor contacts.	4	7	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	4	5	6	7
Thus , causes other than increased Skp2 mediate p27 loss in a majority of cases [ XREF_BIBR ] .	Thus, causes other than increased Skp2 mediate p27 loss in a majority of cases [XREF_BIBR].	5	9	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	6	7	8	9
Inhibition of Skp2 prevents p27 Kip1 degradation and suppresses proliferation of many cell types [ XREF_BIBR , XREF_BIBR ] .	Inhibition of Skp2 prevents p27 Kip1 degradation and suppresses proliferation of many cell types [XREF_BIBR, XREF_BIBR].	0	6	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	2	3	4	6
These results imply that p27 T187A MEFs ( which have gone through mouse development in the absence of wild-type p27 ) may have acquired a compensatory mechanism that bypasses the need for Skp2 mediated p27 degradation in mitogen bathed cells .	These results imply that p27 T187A MEFs (which have gone through mouse development in the absence of wild-type p27) may have acquired a compensatory mechanism that bypasses the need for Skp2 mediated p27 degradation in mitogen bathed cells.	30	35	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	32	33	34	35
103 In agreement with the requirement for phosphorylation by and association with cyclins and CDKs for Skp2 mediated p27 Kip1 degradation , the expression levels of p27 CK- in p27 CK- knock-in cells , which carry point mutations in protein interaction domains that abolish p27 Kip1 binding to cyclins and CDKs and consequently can not inhibit cyclins and CDKs , are increased in various tissues and mouse embryonic fibroblasts .	103 In agreement with the requirement for phosphorylation by and association with cyclins and CDKs for Skp2 mediated p27 Kip1 degradation, the expression levels of p27 CK- in p27 CK- knock-in cells, which carry point mutations in protein interaction domains that abolish p27 Kip1 binding to cyclins and CDKs and consequently can not inhibit cyclins and CDKs, are increased in various tissues and mouse embryonic fibroblasts.	12	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	16	17	18	20
Skp2 may mediate the degradation of p27 Kip1 in liver cancer .	Skp2 may mediate the degradation of p27 Kip1 in liver cancer.	0	8	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	0	1	6	8
In addition , we showed that inhibition of Skp2 is a critical step for the suppression of cell proliferation by Tubocapsanolide A because ectoexpression of Skp2 effectively reversed Tubocapsanolide A induced p27 up-regulation and growth inhibition in human lung cancer cells .	In addition, we showed that inhibition of Skp2 is a critical step for the suppression of cell proliferation by Tubocapsanolide A because ectoexpression of Skp2 effectively reversed Tubocapsanolide A induced p27 up-regulation and growth inhibition in human lung cancer cells.	23	32	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	ectoexpression of Skp2	skp2	p27	p27	p27	25	26	31	32
As reported previously , Skp2 overexpression is able to induce degradation of p27 [ XREF_BIBR , XREF_BIBR ] .	As reported previously, Skp2 overexpression is able to induce degradation of p27 [XREF_BIBR, XREF_BIBR].	4	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2 overexpression	skp2	p27	p27	p27	4	5	12	13
The recruitment of these axes , one inhibiting the transcription of p27 Kip1 and the other leading to the Skp2 mediated degradation of p27 Kip1 proteins , may have evolved for a rapid and sustained proliferative response of MG to injury .	The recruitment of these axes, one inhibiting the transcription of p27 Kip1 and the other leading to the Skp2 mediated degradation of p27 Kip1 proteins, may have evolved for a rapid and sustained proliferative response of MG to injury.	15	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	19	20	23	25
More recently it has been shown that the Skp2 mediated degradation of p27 occurs predominantly during the S phase XREF_BIBR in accord with the fact that it requires the activity of the CDK containing complexes XREF_BIBR and a direct phosphorylation on multiple tyrosine residues XREF_BIBR - XREF_BIBR .	More recently it has been shown that the Skp2 mediated degradation of p27 occurs predominantly during the S phase XREF_BIBR in accord with the fact that it requires the activity of the CDK containing complexes XREF_BIBR and a direct phosphorylation on multiple tyrosine residues XREF_BIBR - XREF_BIBR.	7	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	8	9	12	13
These data indicate that skp2 and c-myc mediate p27 loss and proliferation induced by PTHrP .	These data indicate that skp2 and c-myc mediate p27 loss and proliferation induced by PTHrP.	4	9	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	skp2	skp2	skp2	p27	p27	p27	4	5	8	9
Since phosphorylation of T187 is an event necessary for the Skp2 mediated degradation of p27 XREF_BIBR - XREF_BIBR , XREF_BIBR , our data pointed to a Skp2 independent pathway leading to p27 down-modulation .	Since phosphorylation of T187 is an event necessary for the Skp2 mediated degradation of p27 XREF_BIBR - XREF_BIBR, XREF_BIBR, our data pointed to a Skp2 independent pathway leading to p27 down-modulation.	7	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	10	11	14	15
Skp2 mediated p27 Degradation is Dispensable for VSMC Cycling in vivo .	Skp2 mediated p27 Degradation is Dispensable for VSMC Cycling in vivo.	0	3	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	2	3
SKP2 mediated p27 degradation is the paradigm for the development of SCF targeted inhibitors because of our extensive understanding of the biochemistry , a high quality crystal structure , and an established link to disease .	SKP2 mediated p27 degradation is the paradigm for the development of SCF targeted inhibitors because of our extensive understanding of the biochemistry, a high quality crystal structure, and an established link to disease.	0	3	mediated	Positive_early_activation	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	0	1	2	3
As expected , Skp2 knockdown induced accumulation of p27 in these human retinoblastoma cells ( XREF_FIG ) .	As expected, Skp2 knockdown induced accumulation of p27 in these human retinoblastoma cells (XREF_FIG).	3	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	8	9
Skp2 knockdown by siRNA further upregulated p27Kip1 and potentiated salinomycin induced G1 arrest , indicating that the Skp2-p27Kip1 pathway is an important pathway to cell growth inhibition by salinomycin .	Skp2 knockdown by siRNA further upregulated p27Kip1 and potentiated salinomycin induced G1 arrest, indicating that the Skp2-p27Kip1 pathway is an important pathway to cell growth inhibition by salinomycin.	0	7	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27Kip1	p27Kip1	p27Kip1	0	1	6	7
To explore this possibility , we inactivated pocket proteins by ectopic expression of E7 , knocked down Skp2 with siRNA , and determined the consequence of reduced Skp2 expression on S phase entry in serum deprived MEFs ( conditions where Skp2- mediated p27 degradation is required for the feedback loop and S phase entry ; XREF_FIG - XREF_FIG XREF_FIG ) .	To explore this possibility, we inactivated pocket proteins by ectopic expression of E7, knocked down Skp2 with siRNA, and determined the consequence of reduced Skp2 expression on S phase entry in serum deprived MEFs (conditions where Skp2- mediated p27 degradation is required for the feedback loop and S phase entry; XREF_FIG - XREF_FIG XREF_FIG).	40	43	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2-	Skp2-	Skp2-	p27	p27	p27	40	41	42	43
PTEN might inhibit p27 proteolysis through the repression of SKP2 , the F-box component of the SCF Skp2 ubiquitin ligase complex that mediates cyclin E-Cdk2-dependent p27 degradation .	PTEN might inhibit p27 proteolysis through the repression of SKP2, the F-box component of the SCF Skp2 ubiquitin ligase complex that mediates cyclin E-Cdk2-dependent p27 degradation.	7	26	mediates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	9	10	25	26
These experiments implicate Skp2 of the SCF-Skp2 and Cks1 as a direct mediator of E2 induced degradation of p27 .	These experiments implicate Skp2 of the SCF-Skp2 and Cks1 as a direct mediator of E2 induced degradation of p27.	3	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	18	19
In contrast , R1881 decreased the levels of MYC and SKP2 and increased p27kip1 in the more strongly androgen repressed LNCaP 104-R cell lines [ XREF_BIBR , XREF_BIBR ] .	In contrast, R1881 decreased the levels of MYC and SKP2 and increased p27kip1 in the more strongly androgen repressed LNCaP 104-R cell lines [XREF_BIBR, XREF_BIBR].	3	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	R1881 decreased the levels of MYC and SKP2	skp2	p27kip1	p27kip1	p27kip1	10	11	13	14
However , p27 is phosphorylated on threonine 187 in the presence of lovastatin [ XREF_BIBR ] and overexpression of Skp2 can rescue p27 degradation in lovastatin arrested cells .	However, p27 is phosphorylated on threonine 187 in the presence of lovastatin [XREF_BIBR] and overexpression of Skp2 can rescue p27 degradation in lovastatin arrested cells.	17	23	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	overexpression of Skp2	skp2	p27	p27	p27	19	20	22	23
These findings suggest that the increased Skp2 promoted the degradation of p27 , p21 , c-Myc , b-Myb and cyclin E in the UUO kidneys .	These findings suggest that the increased Skp2 promoted the degradation of p27, p21, c-Myc, b-Myb and cyclin E in the UUO kidneys.	4	20	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	6	7	11	12
The ubiquitylation and degradation of Skp2 and Cks1 by the E3 ligase APC and Cdh1 would prevent the degradation of p27 .	The ubiquitylation and degradation of Skp2 and Cks1 by the E3 ligase APC and Cdh1 would prevent the degradation of p27.	1	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	ubiquitylation and degradation of Skp2	skp2	p27	p27	p27	5	6	20	21
It recognizes Thr187 phosphorylated p27 and is essential for the rigid binding between p27 and Skp2 that results in Skp2 mediated degradation of p27 [ XREF_BIBR , XREF_BIBR ] .	It recognizes Thr187 phosphorylated p27 and is essential for the rigid binding between p27 and Skp2 that results in Skp2 mediated degradation of p27 [XREF_BIBR, XREF_BIBR].	19	27	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	19	20	23	24
Our results further indicated that inhibition of Skp2 by siRNA abolished AMPKalpha2 knockdown induced p27 Kip1 reduction and therefore suppressed PASMCs proliferation .	Our results further indicated that inhibition of Skp2 by siRNA abolished AMPKalpha2 knockdown induced p27 Kip1 reduction and therefore suppressed PASMCs proliferation.	5	16	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	7	8	14	16
Recent studies have clearly shown that Cks1 plays an essential role in Skp2 mediated degradation of p27 Kip1 .	Recent studies have clearly shown that Cks1 plays an essential role in Skp2 mediated degradation of p27 Kip1.	10	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	12	13	16	18
For instance , a new ubiquitin ligase for p27 Kip1 has recently been identified , which is a member for Skp2 independent down-regulation of p27 Kip1 at the G0-G1 transition [ XREF_BIBR ] .	For instance, a new ubiquitin ligase for p27 Kip1 has recently been identified, which is a member for Skp2 independent down-regulation of p27 Kip1 at the G0-G1 transition [XREF_BIBR].	20	26	down-regulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	20	21	24	26
These findings reveal that the cyclin A binding activity of Skp2 is important in providing survival support for Rb1 deficient pituitary tumorigenesis , but reaffirm that the major functional mechanism of Skp2 in promoting survival following Rb1 deletion is to mediate p27 degradation by the SCF Skp2 ubiquitin ligase .	These findings reveal that the cyclin A binding activity of Skp2 is important in providing survival support for Rb1 deficient pituitary tumorigenesis, but reaffirm that the major functional mechanism of Skp2 in promoting survival following Rb1 deletion is to mediate p27 degradation by the SCF Skp2 ubiquitin ligase.	29	42	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	31	32	41	42
CBP-null tumors show reduced levels of p27Kip1 and increased levels of cyclin E and Skp2 , two oncoproteins that can promote p27Kip1 proteolysis .	CBP-null tumors show reduced levels of p27Kip1 and increased levels of cyclin E and Skp2, two oncoproteins that can promote p27Kip1 proteolysis.	6	15	increased	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Skp2	levels of cyclin E and Skp2	skp2	p27Kip1	p27Kip1	p27kip1	14	15	6	7
Consequently , combined deletion of Trp53 ( mouse homolog of TP53 ) and Skp2 increased p27 protein to much higher levels than could be achieved by Skp2 deletion or Trp53 deletion alone .	Consequently, combined deletion of Trp53 (mouse homolog of TP53) and Skp2 increased p27 protein to much higher levels than could be achieved by Skp2 deletion or Trp53 deletion alone.	3	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	13	14	15	16
Compounds which inhibit Skp2 mediated p27 degradation promote cell-type specific blockage in the G1 or G2/M phases [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Compounds which inhibit Skp2 mediated p27 degradation promote cell-type specific blockage in the G1 or G2/M phases [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	6	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	5	6
Ki67 staining confirmed that in vivo VSMC cycling was increased by deletion of p27 but not reduced , relative to wild-type , when Skp2 dependent degradation of p27 was blocked by the T187A mutation ( XREF_SUPPLEMENTARY -D ) .	Ki67 staining confirmed that in vivo VSMC cycling was increased by deletion of p27 but not reduced, relative to wild-type, when Skp2 dependent degradation of p27 was blocked by the T187A mutation (XREF_SUPPLEMENTARY -D).	23	28	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	23	24	27	28
Overexpression of Skp2 blocks the effects of AZQ on senescence and p27 ( Kip1 ) induction .	Overexpression of Skp2 blocks the effects of AZQ on senescence and p27 (Kip1) induction.	0	15	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Overexpression of Skp2	skp2	p27	p27	p27	2	3	11	12
It was shown that Skp2 mediated p27 degradation is also involved in cell size regulation .	It was shown that Skp2 mediated p27 degradation is also involved in cell size regulation.	4	10	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	4	5	6	7
Cks1 also increases p27 degradation in the early stage of renal damage , and Skp2 and Cks1 promote p27 degradation selectively in a collaborative manner .	Cks1 also increases p27 degradation in the early stage of renal damage, and Skp2 and Cks1 promote p27 degradation selectively in a collaborative manner.	14	19	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	14	15	18	19
Moreover , knockdown of SKP2 resulted in elevation of p27 and downregulation of phosphorylation of Rb , whereas overexpression of SKP2 led to downregulation of p27 and upregulation of phosphorylation of Rb .	Moreover, knockdown of SKP2 resulted in elevation of p27 and downregulation of phosphorylation of Rb, whereas overexpression of SKP2 led to downregulation of p27 and upregulation of phosphorylation of Rb.	2	13	resulted in elevation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	4	5	9	10
The simultaneous inhibition of activated MAPK pathways and Skp2 dependent degradation of p27 reduced the melanoma malignant phenotype , suggesting that the combinatorial blockade of these pathways could be a useful therapeutic tool for cancer treatment .	The simultaneous inhibition of activated MAPK pathways and Skp2 dependent degradation of p27 reduced the melanoma malignant phenotype, suggesting that the combinatorial blockade of these pathways could be a useful therapeutic tool for cancer treatment.	8	13	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	8	9	12	13
In a number of cases , this decrease has been correlated with increased levels of Skp2 that mediates p27 degradation at S/G 2 .	In a number of cases, this decrease has been correlated with increased levels of Skp2 that mediates p27 degradation at S/G 2.	13	19	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	levels of Skp2	skp2	p27	p27	p27	15	16	18	19
However , binding of tuberin to p27 sequesters p27 from Skp2 accompanied by a stabilization of the p27 interaction with cdk2 , and hence , Skp2 induced p27 degradation and cell cycle progression is abolished by tuberin ' s protective binding to p27 .	However, binding of tuberin to p27 sequesters p27 from Skp2 accompanied by a stabilization of the p27 interaction with cdk2, and hence, Skp2 induced p27 degradation and cell cycle progression is abolished by tuberin 's protective binding to p27.	25	28	induced	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	25	26	27	28
Furthermore , knockdown of SKP2 with small interference RNA specific for SKP2 caused accumulation of p27Kip1 .	Furthermore, knockdown of SKP2 with small interference RNA specific for SKP2 caused accumulation of p27Kip1.	2	16	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27Kip1	p27Kip1	p27Kip1	4	5	15	16
Moreover , overexpression of p45Skp2 in DG75 cells prevents p27Kip1 protein accumulation and promotes resistance to the antiproliferative effects of RA .	Moreover, overexpression of p45Skp2 in DG75 cells prevents p27Kip1 protein accumulation and promotes resistance to the antiproliferative effects of RA.	2	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p45Skp2	overexpression of p45Skp2	p45skp2	p27Kip1	p27Kip1	p27kip1	4	5	9	10
p27T187A KI or Skp2 knockdown ( KD ) induced similar degrees of p27 protein accumulation in DKO prostate cells , and Skp2 KD did not further increase p27 protein in DKO prostate cells that contained p27T187A KI ( AADKO prostate cells ) .	p27T187A KI or Skp2 knockdown (KD) induced similar degrees of p27 protein accumulation in DKO prostate cells, and Skp2 KD did not further increase p27 protein in DKO prostate cells that contained p27T187A KI (AADKO prostate cells).	3	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	12	13
However , recent reports demonstrate a central role for the Skp2 mediated degradation of p27 Kip1 protein in the vascular response to injury .	However, recent reports demonstrate a central role for the Skp2 mediated degradation of p27 Kip1 protein in the vascular response to injury.	7	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	10	11	14	16
In vitro , GLP-1 treatment increases Skp2 levels , which accelerates p27 degradation , whereas in vivo , loss of Skp2 prevents glucoincretin induced beta-cell proliferation .	In vitro, GLP-1 treatment increases Skp2 levels, which accelerates p27 degradation, whereas in vivo, loss of Skp2 prevents glucoincretin induced beta-cell proliferation.	3	12	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	GLP-1 treatment increases Skp2 levels	skp2	p27	p27	p27	6	7	11	12
To assess whether Skp2 independent degradation of p27 detected in Cdk2 -/- Skp2 -/- cells involved any of the aforementioned ubiquitin ligase complexes , we performed knockdown of KPC1 , Pirh2 , and DDB1 .	To assess whether Skp2 independent degradation of p27 detected in Cdk2 -/- Skp2 -/- cells involved any of the aforementioned ubiquitin ligase complexes, we performed knockdown of KPC1, Pirh2, and DDB1.	3	8	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	7	8
The loss of Skp2 ( and possibly Cks1 ) in turn causes Tax expressing cells to accumulate p27 throughout S , G2 , and M , leading to rapid senescence .	The loss of Skp2 (and possibly Cks1) in turn causes Tax expressing cells to accumulate p27 throughout S, G2, and M, leading to rapid senescence.	1	18	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	loss of Skp2	skp2	p27	p27	p27	3	4	17	18
This type of chemical genetic approach would not be possible without the availability of inhibitors specifically blocking Skp2 mediated p27 degradation .	This type of chemical genetic approach would not be possible without the availability of inhibitors specifically blocking Skp2 mediated p27 degradation.	17	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	17	18	19	20
SCF Skp2 is the best studied regulator of p27 levels , but Skp2 mediated p27 degradation is not essential in vivo or in vitro .	SCF Skp2 is the best studied regulator of p27 levels, but Skp2 mediated p27 degradation is not essential in vivo or in vitro.	12	15	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	12	13	14	15
Together these data demonstrate that AMPKalpha2 functions to control bladder cancer growth through regulating SKP2 mediated degradation of p27 .	Together these data demonstrate that AMPKalpha2 functions to control bladder cancer growth through regulating SKP2 mediated degradation of p27.	13	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	14	15	18	19
Targeting Skp2 could induce cancer cell apoptosis and suppress tumorigenesis [ XREF_BIBR , XREF_BIBR ] , while inhibition of Skp2 mediated p27 and E-cadherin degradation leads to cell cycle blockage and migration inhibition [ XREF_BIBR , XREF_BIBR ] .	Targeting Skp2 could induce cancer cell apoptosis and suppress tumorigenesis [XREF_BIBR, XREF_BIBR], while inhibition of Skp2 mediated p27 and E-cadherin degradation leads to cell cycle blockage and migration inhibition [XREF_BIBR, XREF_BIBR].	17	24	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	19	20	21	22
Further , forced expression of Skp2 in ERK1/2 inhibited cells downregulated p27 ( Kip1 ) .	Further, forced expression of Skp2 in ERK1/2 inhibited cells downregulated p27 (Kip1).	3	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	5	6	11	12
p27 for example , is suppressed by elevated levels of the ubiquitin ligase SKP2 which presumably allows CDK2 activity to remain high in cycling hESCs [ XREF_BIBR ] .	p27 for example, is suppressed by elevated levels of the ubiquitin ligase SKP2 which presumably allows CDK2 activity to remain high in cycling hESCs [XREF_BIBR].	0	16	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SKP2	levels of the ubiquitin ligase SKP2	skp2	p27	p27	p27	13	14	0	1
In fact , overexpression of Skp2 in WT VSMC reduced both p21 cip1 and p27 kip1 .	In fact, overexpression of Skp2 in WT VSMC reduced both p21 cip1 and p27 kip1.	3	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	overexpression of Skp2	skp2	p27 kip1	p27 kip1	p27 kip1	5	6	14	16
Skp2 promotes ubiquitin dependent proteasome degradation of cell cycle inhibitor p27 .	Skp2 promotes ubiquitin dependent proteasome degradation of cell cycle inhibitor p27.	0	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	10	11
Skp2 can also stimulate p27 degradation and S phase entry in serum deprived cells .	Skp2 can also stimulate p27 degradation and S phase entry in serum deprived cells.	0	5	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	4	5
Skp2 dependent proteasomal degradation of p27 plays role in the malignant transformation of CCA .	Skp2 dependent proteasomal degradation of p27 plays role in the malignant transformation of CCA.	0	6	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	5	6
These effects of rosiglitazone were associated with decreased Skp2 expression , thereby promoting p27 accumulation in H. pylori infected gastric epithelial cells .	These effects of rosiglitazone were associated with decreased Skp2 expression, thereby promoting p27 accumulation in H. pylori infected gastric epithelial cells.	8	14	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2 expression	skp2	p27	p27	p27	8	9	13	14
Interestingly , Skp2 mediated p27 degradation was not essential for G1/S or S/G2 transition as preadipocytes shifted from quiescence to proliferation during adipocyte hyperplasia .	Interestingly, Skp2 mediated p27 degradation was not essential for G1/S or S/G2 transition as preadipocytes shifted from quiescence to proliferation during adipocyte hyperplasia.	2	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	2	3	4	5
In particular , the degradation of p27 Kip1 by SKP2 has been documented as a major factor in normal keratinocyte proliferation and skin homeostasis .	In particular, the degradation of p27 Kip1 by SKP2 has been documented as a major factor in normal keratinocyte proliferation and skin homeostasis.	4	10	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27 Kip1	p27 Kip1	p27 Kip1	9	10	6	8
To determine whether p27 degradation by Skp2 is required for BLM induced pulmonary fibrosis progression , further studies are required .	To determine whether p27 degradation by Skp2 is required for BLM induced pulmonary fibrosis progression, further studies are required.	3	7	degradation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	6	7	3	4
In addition , Skp2 , as induced by renal damage , promotes the proliferation of tubular epithelial cells and interstitial fibroblasts by enhancing the degradation of p27 and p21 .	In addition, Skp2, as induced by renal damage, promotes the proliferation of tubular epithelial cells and interstitial fibroblasts by enhancing the degradation of p27 and p21.	3	28	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	26	27
Using a structure based approach encompassing both in silico virtual ligand screening ( VLS ) and in vitro assays , we identified a diverse set of inhibitors of Skp2 mediated p27 degradation that reduce p27 ubiquitylation by specifically and competitively inhibiting the Skp2-p27 interaction .	Using a structure based approach encompassing both in silico virtual ligand screening (VLS) and in vitro assays, we identified a diverse set of inhibitors of Skp2 mediated p27 degradation that reduce p27 ubiquitylation by specifically and competitively inhibiting the Skp2-p27 interaction.	26	31	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	28	29	30	31
Therefore , we conclude that p27 is a main target for Skp2 and that degradation of p27 by Skp2 is required for the progression of renal injury mediated by UUO .	Therefore, we conclude that p27 is a main target for Skp2 and that degradation of p27 by Skp2 is required for the progression of renal injury mediated by UUO.	14	19	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	18	19	16	17
While it may surprise that SKP2 overexpression alone is sufficient to mediate p27 degradation in LNCaP cells , given the known requirement for p27 phosphorylation [ XREF_BIBR ] , similar observations were made in rat fibroblasts , human U87 cells , and primary rat hepatocytes [ XREF_BIBR - XREF_BIBR ] .	While it may surprise that SKP2 overexpression alone is sufficient to mediate p27 degradation in LNCaP cells, given the known requirement for p27 phosphorylation [XREF_BIBR], similar observations were made in rat fibroblasts, human U87 cells, and primary rat hepatocytes [XREF_BIBR - XREF_BIBR].	5	13	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2 overexpression	skp2	p27	p27	p27	5	6	12	13
We have shown recently that Tax stablizes p27 protein in part by causing APC/C mediated poly-ubiquitination and degradation of Skp2 , the substrate-recognition subunit of SCF Skp2 , the E3 ubiquitin ligase that targets p27 for destruction XREF_BIBR .	We have shown recently that Tax stablizes p27 protein in part by causing APC/C mediated poly-ubiquitination and degradation of Skp2, the substrate-recognition subunit of SCF Skp2, the E3 ubiquitin ligase that targets p27 for destruction XREF_BIBR.	13	37	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	APC/C mediated poly-ubiquitination and degradation of Skp2	skp2	p27	p27	p27	19	20	34	35
Consistent with these findings , we found that Skp2 overexpression significantly prevented simvastatin induced G0/G1 cell cycle arrest and p27 accumulation ( XREF_FIG ) .	Consistent with these findings, we found that Skp2 overexpression significantly prevented simvastatin induced G0/G1 cell cycle arrest and p27 accumulation (XREF_FIG).	8	20	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2 overexpression	skp2	p27	p27	p27	8	9	19	20
Recently , an in silico screen also identified small-molecule inhibitors , called ' skpins ' , that block SKP2 mediated p27 degradation , thereby leading to p27 accumulation and subsequently causing cell cycle arrest at G1 or G2/M in cancer cells 154 .	Recently, an in silico screen also identified small-molecule inhibitors, called ' skpins ', that block SKP2 mediated p27 degradation, thereby leading to p27 accumulation and subsequently causing cell cycle arrest at G1 or G2/M in cancer cells 154.	17	21	mediated	Positive_early_activation	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	18	19	20	21
XREF_FIG shows that specific depletion of Akt1 , but not Akt2 , markedly decreases Skp2 protein levels in HeLa cells , and induces its downstream target p27 .	XREF_FIG shows that specific depletion of Akt1, but not Akt2, markedly decreases Skp2 protein levels in HeLa cells, and induces its downstream target p27.	10	27	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Akt2, markedly decreases Skp2 protein levels	skp2	p27	p27	p27	14	15	26	27
Notably , maturing cone precursors had exceptionally high Thr187 phosphorylated p27 ( XREF_FIG ) , coincident with a maturation associated decrease in total p27 , suggesting that SKP2 mediated p27 degradation might enable cone precursor proliferation .	Notably, maturing cone precursors had exceptionally high Thr187 phosphorylated p27 (XREF_FIG), coincident with a maturation associated decrease in total p27, suggesting that SKP2 mediated p27 degradation might enable cone precursor proliferation.	27	32	mediated	Positive_early_activation	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	27	28	29	30
Second , enforced expression of Skp2 in p107 overexpressing cells restores normal p27 degradation and S phase entry .	Second, enforced expression of Skp2 in p107 overexpressing cells restores normal p27 degradation and S phase entry.	3	13	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	5	6	12	13
This summary is not complete , because several highly regulated genes , such as SKP2 , which inhibit CDKN1B , CYCE and CDKN1A were not connected in our filovirus infection network , probably because of missing information in the literature .	This summary is not complete, because several highly regulated genes, such as SKP2, which inhibit CDKN1B, CYCE and CDKN1A were not connected in our filovirus infection network, probably because of missing information in the literature.	10	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	CDKN1B	CDKN1B	CDKN1B	14	15	18	19
Collectively , these results suggest that Skp2 induced p27 Kip1 reduction mediates AMPKalpha2 knockdown stimulated PASMCs proliferation .	Collectively, these results suggest that Skp2 induced p27 Kip1 reduction mediates AMPKalpha2 knockdown stimulated PASMCs proliferation.	6	10	induced	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	6	7	8	10
In addition , EBNA-3C activates Skp2 , which is one of the two integral proteins of SCF Skp2 E3-ubiquitin ligase , leading to phosphorylation and subsequent ubiquitin dependent proteasomal degradation of another CDK inhibitor p27 KIP1 .	In addition, EBNA-3C activates Skp2, which is one of the two integral proteins of SCF Skp2 E3-ubiquitin ligase, leading to phosphorylation and subsequent ubiquitin dependent proteasomal degradation of another CDK inhibitor p27 KIP1.	5	36	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27 KIP1	p27 KIP1	p27 KIP1	5	6	34	36
However , we reasoned that the repeated autoinduction of cyclin E might also require Skp2 mediated p27 degradation to allow for the activation of cyclin E-Cdk2 .	However, we reasoned that the repeated autoinduction of cyclin E might also require Skp2 mediated p27 degradation to allow for the activation of cyclin E-Cdk2.	13	17	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	14	15	16	17
Fbxl proteins are thought to recruit substrates to the SCF complex through the interaction with their LRR domains , and substrates have been identified for several Fbxls such as Skp2 ( Fbxl1 ) , which degrades p27 .	Fbxl proteins are thought to recruit substrates to the SCF complex through the interaction with their LRR domains, and substrates have been identified for several Fbxls such as Skp2 (Fbxl1), which degrades p27.	26	37	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	29	30	36	37
These compounds ( such as C1 , C2 , C16 and C20 , XREF_TABLE ) selectively inhibited Skp2 mediated p27 degradation by reducing p27 binding to SCF Skp2 without affecting the stability of other Skp2 substrates .	These compounds (such as C1, C2, C16 and C20, XREF_TABLE) selectively inhibited Skp2 mediated p27 degradation by reducing p27 binding to SCF Skp2 without affecting the stability of other Skp2 substrates.	17	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	17	18	19	20
Based on the detailed analysis of p27 degradation by the skp2 dependent SCF complex it seems now possible to interfere with p27 degradation in a much more specific way .	Based on the detailed analysis of p27 degradation by the skp2 dependent SCF complex it seems now possible to interfere with p27 degradation in a much more specific way.	6	13	degradation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	skp2	skp2	skp2	p27	p27	p27	10	11	6	7
In such a scenario , cyclin E/CDK2 induced phosphorylation of p27 would be followed by SKP2 mediated degradation and loss of p27 from promoters .	In such a scenario, cyclin E/CDK2 induced phosphorylation of p27 would be followed by SKP2 mediated degradation and loss of p27 from promoters.	13	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	15	16	21	22
In the absence of cell adhesion , both the Skp2 message and protein disappear , but the enforced expression of Skp2 in nonadherent immortalized fibroblasts allows p27 degradation and cell cycle progression .	In the absence of cell adhesion, both the Skp2 message and protein disappear, but the enforced expression of Skp2 in nonadherent immortalized fibroblasts allows p27 degradation and cell cycle progression.	18	27	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	20	21	26	27
The molecular pathway that compensates for loss of Skp2 mediated p27 degradation has remained elusive .	The molecular pathway that compensates for loss of Skp2 mediated p27 degradation has remained elusive.	6	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	8	9	10	11
Several defects in p27 regulation have been described in BCR-ABL expressing cell lines , including reduced FoxO regulated p27 transcription , enhanced Jab1 mediated export and enhanced Skp2 mediated p27 degradation .	Several defects in p27 regulation have been described in BCR-ABL expressing cell lines, including reduced FoxO regulated p27 transcription, enhanced Jab1 mediated export and enhanced Skp2 mediated p27 degradation.	27	30	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	27	28	29	30
Taken together , our data highlight two anti-proliferative mechanisms for curcumin in 3T3-L1 PAs , where curcumin increased p27 protein stability by ( 1 ) inhibiting Skp2 mediated p27 proteolysis and ( 2 ) inhibiting proteasome mediated p27 degradation .	Taken together, our data highlight two anti-proliferative mechanisms for curcumin in 3T3-L1 PAs, where curcumin increased p27 protein stability by (1) inhibiting Skp2 mediated p27 proteolysis and (2) inhibiting proteasome mediated p27 degradation.	25	29	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	26	27	28	29
It is not surprising that downregulation of Skp2 expression by QC was associated with upregulation of cell cycle inhibitors such as p21 and p27 given that Skp2 has been shown to promote proteasomal degradation of p21 and p27 .	It is not surprising that downregulation of Skp2 expression by QC was associated with upregulation of cell cycle inhibitors such as p21 and p27 given that Skp2 has been shown to promote proteasomal degradation of p21 and p27.	26	38	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	26	27	37	38
SKP2 activates CDK2 and CDK1 by directing the degradation of CDKN1 ( p27 ) and CDKN1B ( p21 ) .	SKP2 activates CDK2 and CDK1 by directing the degradation of CDKN1 (p27) and CDKN1B (p21).	0	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	CDKN1B	CDKN1B	CDKN1B	0	1	15	16
Also , BCR-ABL stimulates cell cycle progression by promoting Skp2 mediated degradation of p27 28 ; and Skp2 is required for BCR-ABL induced myeloproliferative disease 35 .	Also, BCR-ABL stimulates cell cycle progression by promoting Skp2 mediated degradation of p27 28; and Skp2 is required for BCR-ABL induced myeloproliferative disease 35.	8	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	9	10	13	14
In the androgen sensitive LNCaP 104-S cells , R1881 increased levels of MYC and SKP2 expression and decreased levels of p27kip1 [ XREF_BIBR ] .	In the androgen sensitive LNCaP 104-S cells, R1881 increased levels of MYC and SKP2 expression and decreased levels of p27kip1 [XREF_BIBR].	8	22	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	R1881 increased levels of MYC and SKP2 expression	skp2	p27kip1	p27kip1	p27kip1	14	15	20	21
Increased Skp2 decreases the stability of p27 KIP1 , thereby promoting cell cycle progression and inhibiting premature senescence ( XREF_FIG ) .	Increased Skp2 decreases the stability of p27 KIP1, thereby promoting cell cycle progression and inhibiting premature senescence (XREF_FIG).	0	8	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 KIP1	p27 KIP1	p27 KIP1	1	2	6	8
Skp2 induced p27 degradation and cell cycle progression is abolished by tuberin ' s protective binding to p27 .	Skp2 induced p27 degradation and cell cycle progression is abolished by tuberin 's protective binding to p27.	0	3	induced	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	2	3
For example , RB cooperates with transcription factors such as MYOD or RUNX2 to regulate cell differentiation in an E2F independent manner.5 The RB protein suppresses the degradation of p27 by SKP2 through direct binding to SKP2 ; this allows RB to attenuate cell cycle progression in an E2F independent manner.6 , 7 The RB protein is located in the mitochondrial fraction , where it promotes BAX dependent apoptosis.8 , 9 Hyperphosphorylated RB is not simply inactivated , but rather contributes to suppression of the mTORC2-AKT pathway , leading to enhanced sensitivity to chemotherapy.10 In addition to genes involved in cell cycle control , the RB and E2F complex suppresses a number of genes involved in pluripotency , cellular metabolism , innate immunity , and cytokine signaling.11 , 12 , 13 , 14 , 15 The RB and E2F complex colocalizes with EZH2 at intronic and intergenic regions in the genome , and mediates silencing of repetitive DNA sequences.16 Conversely , in particular contexts , the RB and E2F complex positively regulates gene transcription by forming a complex with transcriptional activators.3 To date , more than 300 proteins have been identified as possible binding partners of RB .	For example, RB cooperates with transcription factors such as MYOD or RUNX2 to regulate cell differentiation in an E2F independent manner.5 The RB protein suppresses the degradation of p27 by SKP2 through direct binding to SKP2; this allows RB to attenuate cell cycle progression in an E2F independent manner.6, 7 The RB protein is located in the mitochondrial fraction, where it promotes BAX dependent apoptosis.8, 9 Hyperphosphorylated RB is not simply inactivated, but rather contributes to suppression of the mTORC2-AKT pathway, leading to enhanced sensitivity to chemotherapy.10 In addition to genes involved in cell cycle control, the RB and E2F complex suppresses a number of genes involved in pluripotency, cellular metabolism, innate immunity, and cytokine signaling.11, 12, 13, 14, 15 The RB and E2F complex colocalizes with EZH2 at intronic and intergenic regions in the genome, and mediates silencing of repetitive DNA sequences.16 Conversely, in particular contexts, the RB and E2F complex positively regulates gene transcription by forming a complex with transcriptional activators.3 To date, more than 300 proteins have been identified as possible binding partners of RB.	27	196	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	31	32	29	30
However , despite 20 years of investigation , a valid chemical inhibitor of Skp2 mediated degradation of p27 has not been identified .	However, despite 20 years of investigation, a valid chemical inhibitor of Skp2 mediated degradation of p27 has not been identified.	11	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	13	14	17	18
The degradation of p27 by Skp2 is reported to occur in the nucleus XREF_BIBR , XREF_BIBR .	The degradation of p27 by Skp2 is reported to occur in the nucleus XREF_BIBR, XREF_BIBR.	1	6	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	5	6	3	4
Overexpression of Skp2 in MCL decreased p27 ( Kip1 ) , whereas inhibition of Skp2 by siRNA increased p27 ( Kip1 ) and p21 levels .	Overexpression of Skp2 in MCL decreased p27 (Kip1), whereas inhibition of Skp2 by siRNA increased p27 (Kip1) and p21 levels.	0	8	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Overexpression of Skp2	skp2	p27	p27	p27	2	3	6	7
Although we do not yet know the reason for this observation , we postulate that in the presence of high Cks1 levels Skp2 degradation of p27 Kip1 is more efficient and that lower levels of Skp2 are therefore required to down-regulate p27 Kip1 .	Although we do not yet know the reason for this observation, we postulate that in the presence of high Cks1 levels Skp2 degradation of p27 Kip1 is more efficient and that lower levels of Skp2 are therefore required to down-regulate p27 Kip1.	22	27	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	22	23	25	27
In fact , the notion that Skp2 mediated degradation of p27 may not be required for tumor development is supported by the finding that the p27 T187A mutation does not delay tumorigenesis in mouse models of Ras dependent lung and colon cancer .	In fact, the notion that Skp2 mediated degradation of p27 may not be required for tumor development is supported by the finding that the p27 T187A mutation does not delay tumorigenesis in mouse models of Ras dependent lung and colon cancer.	6	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	6	7	10	11
miR-221/222 Compensates for Skp2 Mediated p27 Degradation and Is a Primary Target of Cell Cycle Regulation by Prostacyclin and cAMP .	miR-221/222 Compensates for Skp2 Mediated p27 Degradation and Is a Primary Target of Cell Cycle Regulation by Prostacyclin and cAMP.	1	6	Mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	5	6
Thus , Skp2 dependent degradation of p27 , and probably the Skp2 autoinduction loop , regulates progression through the restriction point .	Thus, Skp2 dependent degradation of p27, and probably the Skp2 autoinduction loop, regulates progression through the restriction point.	2	13	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	2	3	6	7
The search for an alternative mechanism of G 1 regulation by pRB led to the discovery that APC/C FZR1 and SKP2 simultaneously bind to pRB resulting in SKP2 degradation and accumulation of p27 KIP1 [ XREF_BIBR ] .	The search for an alternative mechanism of G 1 regulation by pRB led to the discovery that APC/C FZR1 and SKP2 simultaneously bind to pRB resulting in SKP2 degradation and accumulation of p27 KIP1 [XREF_BIBR].	27	35	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27 KIP1	p27 KIP1	p27 KIP1	27	28	32	34
In proliferating cells , p27 is degraded in the nucleus during S and G2 phases by Skp2 , the F-box protein component of the SCF ubiquitin ligase ( E3 ) complex [ XREF_BIBR ] .	In proliferating cells, p27 is degraded in the nucleus during S and G2 phases by Skp2, the F-box protein component of the SCF ubiquitin ligase (E3) complex [XREF_BIBR].	4	17	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	16	17	4	5
MiR-203-mediated Skp2 suppression likely enhanced the stability of p21 and p27 , leading to cell cycle arrest and increased senescence .	MiR-203-mediated Skp2 suppression likely enhanced the stability of p21 and p27, leading to cell cycle arrest and increased senescence.	1	11	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	1	2	10	11
These data suggest that SIRT2 indeed regulates p27 levels through Skp2 mediated p27 degradation .	These data suggest that SIRT2 indeed regulates p27 levels through Skp2 mediated p27 degradation.	6	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	10	11	12	13
Overexpression of SKP2 largely blocked p27 induction after silencing of TWIST1 but did not rescue loss of TWIST1 ( XREF_SUPPLEMENTARY ) .	Overexpression of SKP2 largely blocked p27 induction after silencing of TWIST1 but did not rescue loss of TWIST1 (XREF_SUPPLEMENTARY).	0	6	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	Overexpression of SKP2	skp2	p27	p27	p27	2	3	5	6
When treated with MLN8237 , p27 was degraded by calpain , rather than by Skp2 , a canonical p27 E3 ligase .	When treated with MLN8237, p27 was degraded by calpain, rather than by Skp2, a canonical p27 E3 ligase.	5	20	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	14	15	5	6
Thus , Skp2 mediated p27 degradation is dispensable for VSMC cycling in vivo .	Thus, Skp2 mediated p27 degradation is dispensable for VSMC cycling in vivo.	2	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	2	3	4	5
Furthermore , pre-depletion of Skp2 by siRNA also eliminated p27 Kip1 downregulation and PASMCs proliferation caused by AMPKalpha2 knockdown .	Furthermore, pre-depletion of Skp2 by siRNA also eliminated p27 Kip1 downregulation and PASMCs proliferation caused by AMPKalpha2 knockdown.	2	11	eliminated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	4	5	9	11
These findings suggest that Cks1 overexpression may play an important role for OSCC development through Skp2 mediated p27 degradation , and that Cks1 siRNA can be a novel modality of gene therapy .	These findings suggest that Cks1 overexpression may play an important role for OSCC development through Skp2 mediated p27 degradation, and that Cks1 siRNA can be a novel modality of gene therapy.	7	18	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	15	16	17	18
However , XREF_BIBR , using knockin of p27 T187A , reported that Skp2 mediated p27 degradation is not required for S phase entry in serum stimulated MEFs .	However, XREF_BIBR, using knockin of p27 T187A, reported that Skp2 mediated p27 degradation is not required for S phase entry in serum stimulated MEFs.	12	18	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	12	13	14	15
However , a potential mechanism may involve Skp2 , an E3 ligase that mediates p27 degradation and thereby regulate S-phase entry .	However, a potential mechanism may involve Skp2, an E3 ligase that mediates p27 degradation and thereby regulate S-phase entry.	6	15	mediates	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	7	8	14	15
c-Myc promotes Skp2 mediated degradation of p27 XREF_BIBR .	c-Myc promotes Skp2 mediated degradation of p27 XREF_BIBR.	1	7	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	2	3	6	7
However , RA also decreases Skp2 levels thus impairing the ability of p27 to be ubiquitinated .	However, RA also decreases Skp2 levels thus impairing the ability of p27 to be ubiquitinated.	2	13	impairing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	RA also decreases Skp2 levels	skp2	p27	p27	p27	5	6	12	13
Since miR221/222 and Skp2 must both be inhibited to prevent p27 down-regulation ( refer to XREF_FIG ) and since Skp2 is required in S phase , we propose that miR221/222 has a major role tranducing the effect of cicaprost on G1 phase p27 .	Since miR221/222 and Skp2 must both be inhibited to prevent p27 down-regulation (refer to XREF_FIG) and since Skp2 is required in S phase, we propose that miR221/222 has a major role tranducing the effect of cicaprost on G1 phase p27.	1	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	10	11
Genetic silencing of p62 downregulated Skp2 expression and caused upregulation of cell cycle inhibitors p21 and p27 .	Genetic silencing of p62 downregulated Skp2 expression and caused upregulation of cell cycle inhibitors p21 and p27.	3	17	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	p62 downregulated Skp2 expression	skp2	p27	p27	p27	5	6	16	17
Under normal conditions , the degradation of Skp2 promotes the stabilization of p27 , which is an inhibitor of cyclin dependent kinases , and that results in cell cycle exit .	Under normal conditions, the degradation of Skp2 promotes the stabilization of p27, which is an inhibitor of cyclin dependent kinases, and that results in cell cycle exit.	5	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	7	8	12	13
Together , these results suggested that overexpression of integrin beta1 inhibited cell proliferation by preventing the Skp2 dependent degradation of p27 ( Kip1 ) via PI3K pathway .	Together, these results suggested that overexpression of integrin beta1 inhibited cell proliferation by preventing the Skp2 dependent degradation of p27 (Kip1) via PI3K pathway.	16	26	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	16	17	20	21
miR-221/222 Compensates for Loss of Skp2 mediated p27 Degradation .	miR-221/222 Compensates for Loss of Skp2 mediated p27 Degradation.	3	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	5	6	7	8
In the vast majority of tumours , p27 is inactivated by SKP2 mediated degradation , not genetic deletion , and SKP2 overexpression correlates with high tumour grade and poor prognosis in a broad range of cancers 16 .	In the vast majority of tumours, p27 is inactivated by SKP2 mediated degradation, not genetic deletion, and SKP2 overexpression correlates with high tumour grade and poor prognosis in a broad range of cancers 16.	7	12	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	11	12	7	8
p21 and p27 did not accumulate in S-phase arrested cells , probably because Skp2 levels remain generally elevated and these remaining levels of Skp2 may be sufficient to promote p21 and p27 degradation .	p21 and p27 did not accumulate in S-phase arrested cells, probably because Skp2 levels remain generally elevated and these remaining levels of Skp2 may be sufficient to promote p21 and p27 degradation.	17	32	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	23	24	31	32
We showed here that expression of DN-Skp2 prevented downregulation of p27 Kip1 and resulted in significantly reduced levels of hyperphosphorylated Rb protein , a marker of G1-S transition , reduced rates of VSMC proliferation and smaller neointimal lesions .	We showed here that expression of DN-Skp2 prevented downregulation of p27 Kip1 and resulted in significantly reduced levels of hyperphosphorylated Rb protein, a marker of G1-S transition, reduced rates of VSMC proliferation and smaller neointimal lesions.	4	12	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DN-Skp2	expression of DN-Skp2	dn-skp2	p27 Kip1	p27 Kip1	p27 kip1	6	7	10	12
The effects of tanshinone IIA on PASMCs proliferation and cell cycle was at least due to its slowing down the hypoxia induced degradation of p27 protein via decreasing the phosphorylation of Akt then the production of Skp2 ( XREF_FIG ) .	The effects of tanshinone IIA on PASMCs proliferation and cell cycle was at least due to its slowing down the hypoxia induced degradation of p27 protein via decreasing the phosphorylation of Akt then the production of Skp2 (XREF_FIG).	21	38	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	36	37	24	25
Regulation of p27 in human cancers is predominantly through a mechanism involving Skp2 mediated proteosomal degradation of p27 ( Bloom and Pagano , 2003 ) .	Regulation of p27 in human cancers is predominantly through a mechanism involving Skp2 mediated proteosomal degradation of p27 (Bloom and Pagano, 2003).	12	21	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	12	13	17	18
Conversely , while wt Skp2 and Skp2 S72D promoted p27 degradation , Skp2 S72A markedly reduced this activity ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Conversely, while wt Skp2 and Skp2 S72D promoted p27 degradation, Skp2 S72A markedly reduced this activity (XREF_FIG and XREF_SUPPLEMENTARY).	3	10	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	4	5	9	10
The data implicates that preventing nuclear p27 degradation by blocking Skp2 and Cks1 mediated degradation of p27 or increasing Cdh1 to mediate degradation of Skp2-Cks1 are potential strategies for the prevention and treatment of ECA .	The data implicates that preventing nuclear p27 degradation by blocking Skp2 and Cks1 mediated degradation of p27 or increasing Cdh1 to mediate degradation of Skp2-Cks1 are potential strategies for the prevention and treatment of ECA.	9	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	10	11	16	17
Overexpression of Skp2 in LNCaP 104-R1 cells partially reduced the induction of p27 Kip1 ( XREF_FIG ) , growth inhibition ( XREF_FIG ) , and G1 cell cycle arrest ( XREF_FIG ) caused by androgen treatment .	Overexpression of Skp2 in LNCaP 104-R1 cells partially reduced the induction of p27 Kip1 (XREF_FIG), growth inhibition (XREF_FIG), and G1 cell cycle arrest (XREF_FIG) caused by androgen treatment.	0	14	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Overexpression of Skp2	skp2	p27 Kip1	p27 Kip1	p27 kip1	2	3	12	14
In contrast , the restriction point defect is clearly seen in p27 T187A MEFs , emphasizing that the role of Skp2 mediated p27 degradation in the transition to mitogen independence is essential .	In contrast, the restriction point defect is clearly seen in p27 T187A MEFs, emphasizing that the role of Skp2 mediated p27 degradation in the transition to mitogen independence is essential.	18	23	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	20	21	22	23
These results suggest that Skp2 and Cks1 collaboratively promote p27 degradation via the ubiquitin proteasome pathway and induce tubular epithelial cell proliferation in the early stages of renal damage , resulting in tubular dilation in chronic nephropathy .	These results suggest that Skp2 and Cks1 collaboratively promote p27 degradation via the ubiquitin proteasome pathway and induce tubular epithelial cell proliferation in the early stages of renal damage, resulting in tubular dilation in chronic nephropathy.	4	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	4	5	9	10
We interpret the reduced steady-state levels of p27 kip1 observed in CSN5 and JAB1 del and del DN cells as a further indication that they are arrested in S phase , as Skp2 mediated degradation of p27 kip1 is maximal in cells undergoing DNA replication .	We interpret the reduced steady-state levels of p27 kip1 observed in CSN5 and JAB1 del and del DN cells as a further indication that they are arrested in S phase, as Skp2 mediated degradation of p27 kip1 is maximal in cells undergoing DNA replication.	32	39	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 kip1	p27 kip1	p27 kip1	32	33	36	38
Strikingly , Skp2 silencing completely rescued p27 stability in Foxo3a knockdown cells ( XREF_FIG ) .	Strikingly, Skp2 silencing completely rescued p27 stability in Foxo3a knockdown cells (XREF_FIG).	2	7	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	2	3	6	7
In support of Skp2 mediated p27 degradation , we further showed that curcumin markedly increased p27 protein stability , as p27 half-life more than doubled in the presence of 20microM curcumin .	In support of Skp2 mediated p27 degradation, we further showed that curcumin markedly increased p27 protein stability, as p27 half-life more than doubled in the presence of 20microM curcumin.	1	6	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	5	6
S phase kinase associated protein 2 ( SKP2 ) promotes p27 degradation via the ubiquitin-proteasome system XREF_BIBR and p27 upregulation facilitated by a SKP2 inhibitor significantly suppresses the cell cycle and results in lower proliferation potency .	S phase kinase associated protein 2 (SKP2) promotes p27 degradation via the ubiquitin-proteasome system XREF_BIBR and p27 upregulation facilitated by a SKP2 inhibitor significantly suppresses the cell cycle and results in lower proliferation potency.	4	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	7	8	10	11
In some tissue culture cells , overexpression of SKP2 is sufficient to induce p27 degradation and S phase entry [ XREF_BIBR - XREF_BIBR ] , and can cooperate with ras in transformation [ XREF_BIBR , XREF_BIBR ] .	In some tissue culture cells, overexpression of SKP2 is sufficient to induce p27 degradation and S phase entry [XREF_BIBR - XREF_BIBR], and can cooperate with ras in transformation [XREF_BIBR, XREF_BIBR].	6	14	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	overexpression of SKP2	skp2	p27	p27	p27	8	9	13	14
To test whether SKP2 mediated p27 degradation is sufficient to overcome the MIB induced G1 cell cycle arrest , LNCaP cells were arrested with MIB for 72 h , followed by infection with SKP2 adenovirus .	To test whether SKP2 mediated p27 degradation is sufficient to overcome the MIB induced G1 cell cycle arrest, LNCaP cells were arrested with MIB for 72 h, followed by infection with SKP2 adenovirus.	3	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	3	4	5	6
In melanoma cells , mutation in BRAF constitutively activates BRAF signaling , which regulates Cks1 and Skp2 mediated p27 degradation and controls G1 cell cycle event XREF_BIBR , XREF_BIBR .	In melanoma cells, mutation in BRAF constitutively activates BRAF signaling, which regulates Cks1 and Skp2 mediated p27 degradation and controls G1 cell cycle event XREF_BIBR, XREF_BIBR.	14	19	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	16	17	18	19
We discovered that overexpression of Skp2 reduced the accumulation of p21 Cip1 and p27 Kip1 as well as lessen the decrease of Cdk2 and phospho-Cdk2 T160 caused by CAPE treatment .	We discovered that overexpression of Skp2 reduced the accumulation of p21 Cip1 and p27 Kip1 as well as lessen the decrease of Cdk2 and phospho-Cdk2 T160 caused by CAPE treatment.	3	15	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	overexpression of Skp2	skp2	p27 Kip1	p27 Kip1	p27 kip1	5	6	13	15
Moreover , overexpression of Skp2 in T-47D cells prevents accumulation of p27 and promotes resistance to ATRA .	Moreover, overexpression of Skp2 in T-47D cells prevents accumulation of p27 and promotes resistance to ATRA.	2	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	overexpression of Skp2	skp2	p27	p27	p27	4	5	11	12
Cks1 is an essential factor in facilitating Skp2 dependent degradation of p27 , but its role in salivary malignancies is unknown .	Cks1 is an essential factor in facilitating Skp2 dependent degradation of p27, but its role in salivary malignancies is unknown.	7	12	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	7	8	11	12
This hypothesis is consistent with the observations that SKP2 can be induced by activated STAT3 and that SKP2 negatively regulates p21 .	This hypothesis is consistent with the observations that SKP2 can be induced by activated STAT3 and that SKP2 negatively regulates p21.	17	21	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p21	p21	p21	17	18	20	21
However , the possible involvement of the Skp2 mediated degradation of p21 cip protein could not be excluded [ XREF_BIBR ] , and the transcriptional regulation of p21 cip expression by simvastatin still needs to be further elucidated [ XREF_BIBR ] .	However, the possible involvement of the Skp2 mediated degradation of p21 cip protein could not be excluded [XREF_BIBR], and the transcriptional regulation of p21 cip expression by simvastatin still needs to be further elucidated [XREF_BIBR].	4	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p21	p21	p21	7	8	11	12
Skp2 overexpression down-regulates p21 Cip1 , while overexpression of F-box deleted dominant negative Skp2 ( DN-Skp2 ) upregulates p21 Cip1 in rat VSMC in vitro .	Skp2 overexpression down-regulates p21 Cip1, while overexpression of F-box deleted dominant negative Skp2 (DN-Skp2) upregulates p21 Cip1 in rat VSMC in vitro.	0	5	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2 overexpression	skp2	p21 Cip1	p21 Cip1	p21 cip1	0	1	3	5
Furthermore , in vitro data suggest that hepatitis B virus ( HBV ) core promoter mutations might contribute to HBV associated liver cancer development by SKP2 dependent degradation of the p21 WAF1 tumor suppressor gene [ XREF_BIBR ] .	Furthermore, in vitro data suggest that hepatitis B virus (HBV) core promoter mutations might contribute to HBV associated liver cancer development by SKP2 dependent degradation of the p21 WAF1 tumor suppressor gene [XREF_BIBR].	25	34	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p21 WAF1	p21 WAF1	p21 WAF1	25	26	30	32
Notch signaling is known to induce skp2 expression and promote reduction of p21 and p27 cyclin dependent kinase inhibitors .	Notch signaling is known to induce skp2 expression and promote reduction of p21 and p27 cyclin dependent kinase inhibitors.	0	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	skp2	Notch signaling is known to induce skp2 expression	skp2	p21	p21	p21	6	7	12	13
Skp2 and Cdt2 degrade p21 with different rates and timings .	Skp2 and Cdt2 degrade p21 with different rates and timings.	0	5	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p21	p21	p21	0	1	4	5
Transfection of miR-7 mimics in NPC cells inhibited the expression of Skp2 and increased the abundance of p21 and p57 ( XREF_FIG ) .	Transfection of miR-7 mimics in NPC cells inhibited the expression of Skp2 and increased the abundance of p21 and p57 (XREF_FIG).	2	21	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	miR-7 mimics in NPC cells inhibited the expression of Skp2	skp2	p21	p21	p21	11	12	17	18
The downregulation of Skp2 further prevents the degradation of p27 Kip1 and p21 Cip1 proteins XREF_BIBR , XREF_BIBR .	The downregulation of Skp2 further prevents the degradation of p27 Kip1 and p21 Cip1 proteins XREF_BIBR, XREF_BIBR.	1	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p21 Cip1	p21 Cip1	p21 Cip1	3	4	12	14
In an earlier study , we showed that a combination of CP mutations typically seen at the time of HCC diagnosis ( TA plus T1753V and T1768A ) up-regulates SKP2 which in turn down-regulates cell cycle inhibitor p21 , leading to accelerated cell cycle progression , anchorage independent cell growth , and increased cellular proliferation .	In an earlier study, we showed that a combination of CP mutations typically seen at the time of HCC diagnosis (TA plus T1753V and T1768A) up-regulates SKP2 which in turn down-regulates cell cycle inhibitor p21, leading to accelerated cell cycle progression, anchorage independent cell growth, and increased cellular proliferation.	28	38	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p21	p21	p21	29	30	37	38
36 Ubiquitylation- and Skp2 independent proteasomal degradation of p21 Cip1 also occurs in response to ultraviolet irradiation , which is mediated by phosphorylation of p21 Cip1 at S114 via GSK3beta , a downstream effector of the ATR DNA damage signaling pathway .	36 Ubiquitylation- and Skp2 independent proteasomal degradation of p21 Cip1 also occurs in response to ultraviolet irradiation, which is mediated by phosphorylation of p21 Cip1 at S114 via GSK3beta, a downstream effector of the ATR DNA damage signaling pathway.	1	10	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Ubiquitylation- and Skp2	skp2	p21 Cip1	p21 Cip1	p21 cip1	3	4	8	10
It was previously reported that low doses , but not high doses , of UV trigger the Skp2 mediated proteasomal degradation of the cyclin dependent kinase inhibitor p21 in mammalian cells .	It was previously reported that low doses, but not high doses, of UV trigger the Skp2 mediated proteasomal degradation of the cyclin dependent kinase inhibitor p21 in mammalian cells.	16	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p21	p21	p21	17	18	27	28
It has been also identified that Cdc20 binds p21 in a D-box motif dependent manner to promote the timely degradation of p21 in prometaphase , whereas Skp2 degrades p21 during the G1/S transition .	It has been also identified that Cdc20 binds p21 in a D-box motif dependent manner to promote the timely degradation of p21 in prometaphase, whereas Skp2 degrades p21 during the G1/S transition.	26	29	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p21	p21	p21	26	27	28	29
Inhibition of SKP1 , CUL-1 or SKP2 induced the accumulation of cyclin D1 and p21 .	Inhibition of SKP1, CUL-1 or SKP2 induced the accumulation of cyclin D1 and p21.	0	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p21	p21	p21	6	7	14	15
SKP2 is a component of SKP2 , Cullin , F-box containing complex ( SKP2-SCF ) E3 ligase and has previously been reported to inhibit p21 and p27 expression in solid tumors [ XREF_BIBR , XREF_BIBR ] .	SKP2 is a component of SKP2, Cullin, F-box containing complex (SKP2-SCF) E3 ligase and has previously been reported to inhibit p21 and p27 expression in solid tumors [XREF_BIBR, XREF_BIBR].	0	28	inhibit	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	SKP2	SKP2	skp2	p21	p21 and p27 expression	p21	0	1	24	25
It showed that VPA reduced the expression of skp2 and upregulated p21 , p27 , which would inhibit the progress of cell proliferation .	It showed that VPA reduced the expression of skp2 and upregulated p21, p27, which would inhibit the progress of cell proliferation.	3	17	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	skp2	VPA reduced the expression of skp2	skp2	p21	p21	p21	8	9	11	12
During vertebrate Hh signaling , Shh inhibits Ptch1 , leading to Smo activation .	During vertebrate Hh signaling, Shh inhibits Ptch1, leading to Smo activation.	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	5	6	7	8
They indicate that administration of Shh inhibitor to mutant embryos caused Ptch1 upregulation at the expanded ZLI , where Shh levels were blocking Ptch1 production , while simultaneously reducing Ptch1 expression in cells outside the expanded ZLI , where lower levels of Shh were activating Ptch1 .	They indicate that administration of Shh inhibitor to mutant embryos caused Ptch1 upregulation at the expanded ZLI, where Shh levels were blocking Ptch1 production, while simultaneously reducing Ptch1 expression in cells outside the expanded ZLI, where lower levels of Shh were activating Ptch1.	40	46	activating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Shh	levels of Shh	shh	Ptch1	Ptch1	ptch1	42	43	45	46
By increasing the level of PTCH1 protein in responding cells , SHH signaling attenuates its own activity in a negative feedback loop XREF_BIBR .	By increasing the level of PTCH1 protein in responding cells, SHH signaling attenuates its own activity in a negative feedback loop XREF_BIBR.	5	14	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHH	SHH	SHH	PTCH1	PTCH1	PTCH1	11	12	5	6
Gli1 activates Ptc1 expression and thus counters , to some extent Shh repression of Ptc1 activity [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Gli1 activates Ptc1 expression and thus counters, to some extent Shh repression of Ptc1 activity [XREF_BIBR, XREF_BIBR, XREF_BIBR].	11	15	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	11	12	14	15
Upon Ptch1 inhibition by Shh , cholesterol activity in cilia increases , leading to Smo activation ; testing this hypothesis will require developing methods to image cholesterol in cilia .	Upon Ptch1 inhibition by Shh, cholesterol activity in cilia increases, leading to Smo activation; testing this hypothesis will require developing methods to image cholesterol in cilia.	1	5	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	4	5	1	2
When SMO ciliary accumulation is accompanied by SMO activation , GLI2 protein levels at the tips of cilia increase , as seen when PTCH1 is inactivated by SHH or genetically disrupted in Ptch1 -/- cells ( XREF_SUPPLEMENTARY E and S5F ) .	When SMO ciliary accumulation is accompanied by SMO activation, GLI2 protein levels at the tips of cilia increase, as seen when PTCH1 is inactivated by SHH or genetically disrupted in Ptch1 -/- cells (XREF_SUPPLEMENTARY E and S5F).	23	28	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SHH	SHH	SHH	PTCH1	PTCH1	PTCH1	27	28	23	24
The addition of 1 mug/ml recombinant Shh , which should inhibit Ptch1 present in these experiments , was able to abolish the inhibition conferred by Ptch1 .	The addition of 1 mug/ml recombinant Shh, which should inhibit Ptch1 present in these experiments, was able to abolish the inhibition conferred by Ptch1.	1	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	6	7	11	12
Notably , pharmacological inhibition of Shh and Notch signaling underlines different biological outcomes on GCPs and Ptch1 -/- MEFs , where Shh pathway shows a predominant effect in sustaining the proliferation compared with Notch signaling .	Notably, pharmacological inhibition of Shh and Notch signaling underlines different biological outcomes on GCPs and Ptch1 -/- MEFs, where Shh pathway shows a predominant effect in sustaining the proliferation compared with Notch signaling.	5	18	underlines	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	5	6	16	17
High Shh concentrations bind to and suppress more Ptc1 than lower Shh concentrations , thereby sustaining intracellular signal transduction for longer XREF_BIBR , XREF_BIBR .	High Shh concentrations bind to and suppress more Ptc1 than lower Shh concentrations, thereby sustaining intracellular signal transduction for longer XREF_BIBR, XREF_BIBR.	1	9	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	1	2	8	9
The inability of Shh to prevent Ptch1 conditioned , medium dependent inhibition of Smo activity is expected , because the transferred medium does not contain donor cells expressing Ptch1 on which Shh should exert its action , and the presence of the medium-borne factor in the Ptch1 conditioned medium shortcuts the function of endogenous Ptch1 in the reporter cells .	The inability of Shh to prevent Ptch1 conditioned, medium dependent inhibition of Smo activity is expected, because the transferred medium does not contain donor cells expressing Ptch1 on which Shh should exert its action, and the presence of the medium-borne factor in the Ptch1 conditioned medium shortcuts the function of endogenous Ptch1 in the reporter cells.	1	7	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	3	4	6	7
By increasing the level of PTCH1 protein in responding cells , SHH signaling attenuates its own activity in a negative feedback loop [ XREF_BIBR ] .	By increasing the level of PTCH1 protein in responding cells, SHH signaling attenuates its own activity in a negative feedback loop [XREF_BIBR].	5	14	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHH	SHH	SHH	PTCH1	PTCH1	PTCH1	11	12	5	6
In cell lines , it has been shown that the Shh pathways can activate the G2/M transition by inhibiting the interaction of Ptch-1 with cyclin B1 XREF_BIBR .	In cell lines, it has been shown that the Shh pathways can activate the G2/M transition by inhibiting the interaction of Ptch-1 with cyclin B1 XREF_BIBR.	10	23	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch-1	Ptch-1	Ptch-1	10	11	22	23
A decrease in SHH allows Ptch-1 to suppress Smo-Gli-1 signaling .	A decrease in SHH allows Ptch-1 to suppress Smo-Gli-1 signaling.	1	7	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHH	SHH	SHH	Ptch-1	Ptch-1	Ptch-1	3	4	5	6
These data suggest that inhibition of Ptch by Shh is able to induce nuclear localisation of Ccnb1 that mirrors the effect of Ptch inactivation 20 , independent of Smo signaling , consistent with activation of non canonical Hh signaling .	These data suggest that inhibition of Ptch by Shh is able to induce nuclear localisation of Ccnb1 that mirrors the effect of Ptch inactivation 20, independent of Smo signaling, consistent with activation of non canonical Hh signaling.	4	9	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptch	Ptch	Ptch	8	9	6	7
When the feedback loop is broken , as in figure XREF_FIG , Shh signalling causes rapid suppression of Ptc1 to low levels and growth of Smo and Gli1 to high levels .	When the feedback loop is broken, as in figure XREF_FIG, Shh signalling causes rapid suppression of Ptc1 to low levels and growth of Smo and Gli1 to high levels.	12	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	12	13	18	19
Furthermore , AMPK can activate Sirtuin 1 ( SIRT1 ) , an NAD dependent deacetylase that has been shown to deacetylate and thus inactivate p65 , a subunit of NFkappaB , in HEK 293T cells expressing p65 70 .	Furthermore, AMPK can activate Sirtuin 1 (SIRT1), an NAD dependent deacetylase that has been shown to deacetylate and thus inactivate p65, a subunit of NFkappaB, in HEK 293T cells expressing p65 70.	5	27	inactivate	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p65	p65	p65	8	9	24	25
SIRT1 negatively regulates the transcriptional activity of NF-kappaB p65 to modulate the immune response in macrophages 51 .	SIRT1 negatively regulates the transcriptional activity of NF-kappaB p65 to modulate the immune response in macrophages 51.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	0	1	7	9
Consistent with anti-inflammatory and chemopreventative actions , a key observation of this study is that APO10LA supplementation induced SIRT1 protein expression and increased deacetylation of SIRT1 targets ( NF-kappaB p65 and FoxO1 ; XREF_FIG ) .	Consistent with anti-inflammatory and chemopreventative actions, a key observation of this study is that APO10LA supplementation induced SIRT1 protein expression and increased deacetylation of SIRT1 targets (NF-kappaB p65 and FoxO1; XREF_FIG).	15	30	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	APO10LA supplementation induced SIRT1 protein expression	sirt1	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	18	19	28	30
The results showed that resveratrol , the activator of SIRT1 , inhibited the binding of NF-kappaB p65 to the MMP-13 promoter , and the situation was the opposite after being treated with the inhibitor of SIRT1 .	The results showed that resveratrol, the activator of SIRT1, inhibited the binding of NF-kappaB p65 to the MMP-13 promoter, and the situation was the opposite after being treated with the inhibitor of SIRT1.	7	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	9	10	15	17
HDAC1 , HDAC2 and HDAC3 can promote deacetylation of p65 at lysine 221 , stabilizing p65-IkappaBalpha interactions [ XREF_BIBR ] , while SIRT1 can inactivate p65 through deacetylation of lysine 310 [ XREF_BIBR ] .	HDAC1, HDAC2 and HDAC3 can promote deacetylation of p65 at lysine 221, stabilizing p65-IkappaBalpha interactions [XREF_BIBR], while SIRT1 can inactivate p65 through deacetylation of lysine 310 [XREF_BIBR].	22	26	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p65	p65	p65	22	23	25	26
To test whether RelA and p65 signaling is suppressed by SIRT1 in HAECs , we quantified DNA bound RelA and p65 in TNFalpha stimulated and unstimulated cells pretreated with the SIRT1 inhibitor splitomicin [ XREF_BIBR ] .	To test whether RelA and p65 signaling is suppressed by SIRT1 in HAECs, we quantified DNA bound RelA and p65 in TNFalpha stimulated and unstimulated cells pretreated with the SIRT1 inhibitor splitomicin [XREF_BIBR].	3	12	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p65	p65	p65	10	11	5	6
Notably , the NF-kappaB p65 signaling pathway is able to stimulate glycolytic energy flux in the context of chronic metabolic diseases , including diabetes , where as Sirt1 activation inhibits NF-kappaB p65 signaling to enhance oxidative metabolism and resolve inflammation .	Notably, the NF-kappaB p65 signaling pathway is able to stimulate glycolytic energy flux in the context of chronic metabolic diseases, including diabetes, where as Sirt1 activation inhibits NF-kappaB p65 signaling to enhance oxidative metabolism and resolve inflammation.	27	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	27	28	30	32
SIRT1 employs the strategy of post-translational modulation to suppress the NF-kappaB p65 transcriptional activity : it physically associates and directly deacetylates p65 at lysine 310 XREF_BIBR .	SIRT1 employs the strategy of post-translational modulation to suppress the NF-kappaB p65 transcriptional activity : it physically associates and directly deacetylates p65 at lysine 310 XREF_BIBR.	0	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	0	1	10	12
21 Selective deacetylation of Lys310 by sirtuin 1 ( SIRT1 ) , a class III histone deacetylase , inhibits the transcriptional activity of RelA 22 and prevents the beta-amyloid-induced release of neurotoxic factors from microglial cells .	21 Selective deacetylation of Lys310 by sirtuin 1 (SIRT1), a class III histone deacetylase, inhibits the transcriptional activity of RelA 22 and prevents the beta-amyloid-induced release of neurotoxic factors from microglial cells.	2	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	deacetylation of Lys310 by sirtuin 1 (SIRT1	sirt1	RelA	RelA	rela	9	10	23	24
SIRT1 , lying proximal in immunometabolic signaling , deacetylates and inactivates NF-kappaB p65 proimmune transcription factor function and supports a shift to supporting NF-kappaB RelB immune repressor functions by chromatin structural modifications [ XREF_BIBR ] .	SIRT1, lying proximal in immunometabolic signaling, deacetylates and inactivates NF-kappaB p65 proimmune transcription factor function and supports a shift to supporting NF-kappaB RelB immune repressor functions by chromatin structural modifications [XREF_BIBR].	0	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	0	1	11	13
Previous studies have suggested that Sirt1 inhibition disrupted oxidative energy metabolism and stimulated NF-kappaB p65 to induce the inflammatory response characteristic of various chronic metabolic and age associated diseases .	Previous studies have suggested that Sirt1 inhibition disrupted oxidative energy metabolism and stimulated NF-kappaB p65 to induce the inflammatory response characteristic of various chronic metabolic and age associated diseases.	5	15	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	5	6	13	15
Finally , SIRT1 inactivates the p65 subunit of NF-kB through direct deacetylation .	Finally, SIRT1 inactivates the p65 subunit of NF-kB through direct deacetylation.	2	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p65	p65	p65	2	3	5	6
However , our results suggest that SIRT1 physically interacts with and represses p300 transactivation in an NAD dependent manner .	However, our results suggest that SIRT1 physically interacts with and represses p300 transactivation in an NAD dependent manner.	6	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	6	7	12	13
Intriguingly , the Pestell group 36 demonstrated that p300 is repressed by the deacetylase SIRT1 .	Intriguingly, the Pestell group 36 demonstrated that p300 is repressed by the deacetylase SIRT1.	8	15	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	14	15	8	9
SIRT1 repression of p300 has been shown to occur via deacetylation of two lysine residues ( 1020 and 1024 ) within the p300 cysteine rich domain ( CRD1 ) XREF_BIBR .	SIRT1 repression of p300 has been shown to occur via deacetylation of two lysine residues (1020 and 1024) within the p300 cysteine rich domain (CRD1) XREF_BIBR.	0	4	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	0	1	3	4
19 In addition , SIRT1 could also inactivate p300 and CBP , critical co-activators of NF-kappaB , by deacetylation and facilitate the downregulation of NF-kappaB-dependent expression of inflammatory genes .	19 In addition, SIRT1 could also inactivate p300 and CBP, critical co-activators of NF-kappaB, by deacetylation and facilitate the downregulation of NF-kappaB-dependent expression of inflammatory genes.	4	20	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	4	5	8	9
Sirt1 has the opposite enzymatic activity to CBP and p300 , and is known to repress p300 activation of transcription in certain contexts XREF_BIBR .	Sirt1 has the opposite enzymatic activity to CBP and p300, and is known to repress p300 activation of transcription in certain contexts XREF_BIBR.	0	17	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p300	p300	p300	0	1	16	17
SIRT1 inhibits p300 activity by deacetylating K1020 and K1024 .	SIRT1 inhibits p300 activity by deacetylating K1020 and K1024.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	0	1	2	3
It has been shown that SIRT1 interacts with and impairs the activity of histone acetyltransferases ( HATs ) p300 and MOF that are responsible for H3k9 and H4k16 acetylation , [ XREF_BIBR , XREF_BIBR ] respectively .	It has been shown that SIRT1 interacts with and impairs the activity of histone acetyltransferases (HATs) p300 and MOF that are responsible for H3k9 and H4k16 acetylation, [XREF_BIBR, XREF_BIBR] respectively.	5	23	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	5	6	18	19
Since we evidenced in glioblastomas that the amounts of CD44 are high and that the amount of SIRT1 that inactivates EP300 is low , we can assume that this situation may facilitate activation of STAT3 by acetylation .	Since we evidenced in glioblastomas that the amounts of CD44 are high and that the amount of SIRT1 that inactivates EP300 is low, we can assume that this situation may facilitate activation of STAT3 by acetylation.	15	21	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	amount of SIRT1	sirt1	EP300	EP300	ep300	17	18	20	21
It was demonstrated that SIRT1 interacts with and represses p300 transactivation in a NAD dependent manner .	It was demonstrated that SIRT1 interacts with and represses p300 transactivation in a NAD dependent manner.	4	10	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	4	5	9	10
Herein , SIRT1 physically interacted with and repressed p300 transactivation , requiring the NAD dependent deacetylase activity of SIRT1 .	Herein, SIRT1 physically interacted with and repressed p300 transactivation, requiring the NAD dependent deacetylase activity of SIRT1.	2	9	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	2	3	8	9
Resveratrol activated SIRT-1 ( Deacetylase ) Inhibits p300 Acetyltransferase and NF-kappaB Signaling .	Resveratrol activated SIRT-1 (Deacetylase) Inhibits p300 Acetyltransferase and NF-kappaB Signaling.	2	8	Inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT-1	SIRT-1	SIRT-1	p300	p300	p300	2	3	7	8
The SIRT1 selective activator SA3 elicited comparable suppression of p300 .	The SIRT1 selective activator SA3 elicited comparable suppression of p300.	0	10	elicited	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	1	2	9	10
The SUMO specific protease SSP3 relieves SIRT1 repression of p300 , indicating that p300 serves as a deacetylase substrate for SIRT1 through a conserved SUMO consensus motif .	The SUMO specific protease SSP3 relieves SIRT1 repression of p300, indicating that p300 serves as a deacetylase substrate for SIRT1 through a conserved SUMO consensus motif.	6	10	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	6	7	9	10
Thus , the downregulation of p300 by SIRT1 may contribute to the suppression of Smad transcription factors .	Thus, the downregulation of p300 by SIRT1 may contribute to the suppression of Smad transcription factors.	3	8	downregulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	7	8	5	6
SIRT1 negatively regulates Notch1 intracellular domain ( N1IC ) and Notch1 target genes HEY1 and HEY2 in response to Delta like ligand 4 ( DLL4 ) stimulation .	SIRT1 negatively regulates Notch1 intracellular domain (N1IC) and Notch1 target genes HEY1 and HEY2 in response to Delta like ligand 4 (DLL4) stimulation.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	0	1	3	4
Of notes , SIRT1 negatively regulated Notch1 via deacetylation , thus changes at transcriptional level of Notch may also play a role in the reduction of Notch activity affected by SIRT1 .	Of notes, SIRT1 negatively regulated Notch1 via deacetylation, thus changes at transcriptional level of Notch may also play a role in the reduction of Notch activity affected by SIRT1.	3	8	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	3	4	6	7
In addition , SIRT1 negatively regulated the activity of Notch1 signaling in endothelium of lung cancer and inhibited N1IC expression which leading to endothelial cell proliferation and promoting the growth of lung cancer [ XREF_BIBR ] .	In addition, SIRT1 negatively regulated the activity of Notch1 signaling in endothelium of lung cancer and inhibited N1IC expression which leading to endothelial cell proliferation and promoting the growth of lung cancer [XREF_BIBR].	3	17	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	3	4	9	10
Loss of functional SIRT1 enhances Notch1 signaling in capillary endothelial cells following injury .	Loss of functional SIRT1 enhances Notch1 signaling in capillary endothelial cells following injury.	0	6	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	Loss of functional SIRT1	sirt1	Notch1	Notch1	notch1	3	4	5	6
SIRT1 directly represses Notch1 promoter activity [ XREF_BIBR ] .	SIRT1 directly represses Notch1 promoter activity [XREF_BIBR].	0	5	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	0	1	3	4
These results demonstrated that SIRT1 significantly inhibited Notch1 reporter activity when the SIRT1 binding site was present ( XREF_FIG +400 ) , which was not observed when the SIRT1 binding site was absent ( XREF_FIG +1750 ) .	These results demonstrated that SIRT1 significantly inhibited Notch1 reporter activity when the SIRT1 binding site was present (XREF_FIG +400), which was not observed when the SIRT1 binding site was absent (XREF_FIG +1750).	4	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	4	5	7	8
SIRT1 represses Notch1 signaling in retinal endothelial cells , which contributes to retinal angiogenesis [ XREF_BIBR ] .	SIRT1 represses Notch1 signaling in retinal endothelial cells, which contributes to retinal angiogenesis [XREF_BIBR].	0	3	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	0	1	2	3
CRTC2 activation , which is essential for StAR transcription , is suppressed by SIK1 and SIK2 in adrenal cells .	CRTC2 activation, which is essential for StAR transcription, is suppressed by SIK1 and SIK2 in adrenal cells.	0	15	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SIK1	SIK1	SIK1	CRTC2	CRTC2	CRTC2	13	14	0	1
Induced SIK1 attenuates the activity of CRTC2 , a key mediator of StAR transcription and splicing , but only as cAMP levels decline .	Induced SIK1 attenuates the activity of CRTC2, a key mediator of StAR transcription and splicing, but only as cAMP levels decline.	1	10	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIK1	SIK1	SIK1	CRTC2	CRTC2	CRTC2	1	2	6	7
When Br-cAMP is added to the cell , the loss of SIK activity causes TORC2-GFP to migrate slowly to the nucleus over the course of 1- to 6hr ( Lee , unpublished ) .	When Br-cAMP is added to the cell, the loss of SIK activity causes TORC2-GFP to migrate slowly to the nucleus over the course of 1- to 6hr (Lee, unpublished).	11	15	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIK	SIK	SIK	TORC2-GFP	TORC2-GFP	TORC2-GFP	11	12	14	15
In addition , these investigators demonstrated that the Foxl2 promoter is repressed by Sirt1 expression as part of a feedback mechanism of regulation in response to stress [ XREF_BIBR ] .	In addition, these investigators demonstrated that the Foxl2 promoter is repressed by Sirt1 expression as part of a feedback mechanism of regulation in response to stress [XREF_BIBR].	8	15	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Sirt1	Sirt1 expression	sirt1	Foxl2	Foxl2	foxl2	13	14	8	9
In line with this , we find that FOXL2 activity is repressed by the SIRT1 deacetylase .	In line with this, we find that FOXL2 activity is repressed by the SIRT1 deacetylase.	8	15	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	FOXL2	FOXL2	FOXL2	14	15	8	9
XREF_BIBR In granulosa cells , SIRT1 suppresses the activity of transcriptional factor FOXL2 on targets involved in cell cycle and DNA repair .	XREF_BIBR In granulosa cells, SIRT1 suppresses the activity of transcriptional factor FOXL2 on targets involved in cell cycle and DNA repair.	5	14	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	FOXL2	FOXL2	FOXL2	5	6	12	13
Finally , the SIRT1 deacetylase suppresses FOXL2 activity on targets linked to cell-cycle and DNA repair in a dose dependent manner .	Finally, the SIRT1 deacetylase suppresses FOXL2 activity on targets linked to cell-cycle and DNA repair in a dose dependent manner.	3	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	FOXL2	FOXL2	FOXL2	3	4	6	7
In a manner similar to that reported for dibenzoylmethane , a structural analog of curcumin , in mice fed a high-fat diet [ XREF_BIBR ] , APS reduced hyperglycemia and IR in KKay mice , in part through restoration of PKB phosphorylation and GLUT4 translocation [ XREF_BIBR ] .	In a manner similar to that reported for dibenzoylmethane, a structural analog of curcumin, in mice fed a high-fat diet [XREF_BIBR], APS reduced hyperglycemia and IR in KKay mice, in part through restoration of PKB phosphorylation and GLUT4 translocation [XREF_BIBR].	26	31	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APS	APS	APS	IR	IR	IR	26	27	30	31
In addition , APS attenuated IR in T2DM , likely through upregulating or maintaining the miR-203a-3p expression levels , decreasing GRP78 mRNA and protein expression levels and regulating the protein expression of the ERS signaling pathway .	In addition, APS attenuated IR in T2DM, likely through upregulating or maintaining the miR-203a-3p expression levels, decreasing GRP78 mRNA and protein expression levels and regulating the protein expression of the ERS signaling pathway.	3	7	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APS	APS	APS	IR	IR	IR	3	4	5	6
We propose that APS attenuates IR by upregulating the levels of particular miRNAs , such as miR-203a-3p , let-7i-5p , -miR-106b-5p and miR-23a-3p , miR-490-3p and miR-490-5p and downregulating miR-101a-3p , miR-103-3p , miR-181a-5p and miR-384-3p , etc ..	We propose that APS attenuates IR by upregulating the levels of particular miRNAs, such as miR-203a-3p, let-7i-5p, -miR-106b-5p and miR-23a-3p, miR-490-3p and miR-490-5p and downregulating miR-101a-3p, miR-103-3p, miR-181a-5p and miR-384-3p, etc..	3	6	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APS	APS	APS	IR	IR	IR	3	4	5	6
For the first time , we discovered that APS could attenuated IR probably through up-regulating or maintaining the miR-203a-3p levels , reducing GRP78 mRNA and protein and reducing the expression of CHOP , caspase-12 and phosphorylation of JNK1 protein of the ERS signaling pathway .	For the first time, we discovered that APS could attenuated IR probably through up-regulating or maintaining the miR-203a-3p levels, reducing GRP78 mRNA and protein and reducing the expression of CHOP, caspase-12 and phosphorylation of JNK1 protein of the ERS signaling pathway.	8	12	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APS	APS	APS	IR	IR	IR	8	9	11	12
We observed that cells expressing SLAP2 have a 30 to 90 % enhancement in FLT3 ubiquitination suggesting that SLAP2 expression decreases FLT3 stability through ubiquitination mediated degradation .	We observed that cells expressing SLAP2 have a 30 to 90% enhancement in FLT3 ubiquitination suggesting that SLAP2 expression decreases FLT3 stability through ubiquitination mediated degradation.	18	22	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SLAP2	SLAP2 expression	slap2	FLT3	FLT3	flt3	18	19	21	22
Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT , ERK , p38 and STAT5 .	Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT, ERK, p38 and STAT5.	0	7	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SLAP2	Expression of SLAP2	slap2	FLT3	FLT3	flt3	2	3	4	5
Src like adaptor protein 2 ( SLAP2 ) binds to and inhibits FLT3 signaling .	Src like adaptor protein 2 (SLAP2) binds to and inhibits FLT3 signaling.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SLAP2	SLAP2	SLAP2	FLT3	FLT3	FLT3	6	7	12	13
Finally , SLAP2 accelerated FLT3 degradation through enhanced ubiquitination .	Finally, SLAP2 accelerated FLT3 degradation through enhanced ubiquitination.	2	5	accelerated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SLAP2	SLAP2	SLAP2	FLT3	FLT3	FLT3	2	3	4	5
SLAP2 expression partially blocked FLT3 downstream signaling .	SLAP2 expression partially blocked FLT3 downstream signaling.	0	6	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SLAP2	SLAP2 expression	slap2	FLT3	FLT3	flt3	0	1	4	5
Moreover , SIRT7 decreased apoptosis and p53 response pathway [ XREF_BIBR ] .	Moreover, SIRT7 decreased apoptosis and p53 response pathway [XREF_BIBR].	2	8	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT7	SIRT7	SIRT7	p53	p53	p53	2	3	6	7
Moreover , knockdown of SIRT7 markedly increased the transcriptional activity of p53 toward apoptosis and activated the p53 mediated proapoptotic signaling pathway .	Moreover, knockdown of SIRT7 markedly increased the transcriptional activity of p53 toward apoptosis and activated the p53 mediated proapoptotic signaling pathway.	2	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT7	SIRT7	SIRT7	p53	p53	p53	4	5	11	12
As reported previously , CISK appeared to inhibit FKHRL1 activity in a dose dependent manner ( XREF_FIG ) .	As reported previously, CISK appeared to inhibit FKHRL1 activity in a dose dependent manner (XREF_FIG).	4	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CISK	CISK	CISK	FKHRL1	FKHRL1	FKHRL1	4	5	8	9
In contrast , the R90A mutation abolished the inhibition of FKHRL1 by CISK , suggesting that phosphoinositide binding may be crucial for CISK function in vivo .	In contrast, the R90A mutation abolished the inhibition of FKHRL1 by CISK, suggesting that phosphoinositide binding may be crucial for CISK function in vivo.	6	13	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	CISK	CISK	CISK	FKHRL1	FKHRL1	FKHRL1	12	13	10	11
Cytoplasmic localization of Ski prevents its associated protein Smad3 from translocation to the nucleus in response to TGF-beta .	Cytoplasmic localization of Ski prevents its associated protein Smad3 from translocation to the nucleus in response to TGF-beta.	1	9	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ski	Ski	Ski	Smad3	Smad3	Smad3	3	4	8	9
232 Ski also inhibits Smad3 activation but stimulates the p38 pathway to block TGF-beta-induced vascular smooth muscle cell proliferation after vascular injury .	232 Ski also inhibits Smad3 activation but stimulates the p38 pathway to block TGF-beta-induced vascular smooth muscle cell proliferation after vascular injury.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ski	Ski	Ski	Smad3	Smad3	Smad3	1	2	4	5
SKIL has been reported to inhibit SMAD4 function by repressing its transcriptional activity by recruitment of the transcriptional co-repressor N-CoR .	SKIL has been reported to inhibit SMAD4 function by repressing its transcriptional activity by recruitment of the transcriptional co-repressor N-CoR.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKIL	SKIL	SKIL	SMAD4	SMAD4	SMAD4	0	1	6	7
Since SKIL has been suggested to inhibit SMAD4 function , we tested the effect on suppression of SMAD4 in our system .	Since SKIL has been suggested to inhibit SMAD4 function, we tested the effect on suppression of SMAD4 in our system.	1	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKIL	SKIL	SKIL	SMAD4	SMAD4	SMAD4	1	2	7	8
SirT1 activity puts the clock in a transcriptional repressive state and simultaneously inhibits MyoD , a skeletal muscle specific transcription factor that regulates skeletal muscle growth and differentiation .	SirT1 activity puts the clock in a transcriptional repressive state and simultaneously inhibits MyoD, a skeletal muscle specific transcription factor that regulates skeletal muscle growth and differentiation.	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SirT1	SirT1	SirT1	MyoD	MyoD	MyoD	0	1	13	14
These observat- ions suggest that though Sirt1 might play a positive role in the proliferation of activated satellite cells , higher levels of nuclear Sirt1 in the activated muscle progenitor cells of old animals may inhibit MyoD activity and diminish their myogenic potential .	These observat- ions suggest that though Sirt1 might play a positive role in the proliferation of activated satellite cells, higher levels of nuclear Sirt1 in the activated muscle progenitor cells of old animals may inhibit MyoD activity and diminish their myogenic potential.	21	37	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	levels of nuclear Sirt1	sirt1	MyoD	MyoD	myod	24	25	36	37
Metabolic Reprogramming of Proliferating Muscle Cells to Oxidative Phosphorylation Leads to a SIRT1 Dependent Repression of MyoD .	Metabolic Reprogramming of Proliferating Muscle Cells to Oxidative Phosphorylation Leads to a SIRT1 Dependent Repression of MyoD.	12	17	Repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	MyoD	MyoD	MyoD	12	13	16	17
Sik3 anchors CRTC2 in the cytoplasm , preventing CRTC2 from co-activating CREB in nuclei XREF_BIBR .	Sik3 anchors CRTC2 in the cytoplasm, preventing CRTC2 from co-activating CREB in nuclei XREF_BIBR.	0	9	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sik3	Sik3	Sik3	CRTC2	CRTC2	CRTC2	0	1	8	9
To further confirm the negative effect of Sirt1 on Smad7 , IBD LPMC were treated with Cay10591 , a Sirt1 activator .	To further confirm the negative effect of Sirt1 on Smad7, IBD LPMC were treated with Cay10591, a Sirt1 activator.	7	20	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	Smad7	Smad7	Smad7	19	20	9	10
We report that Siah-1 interacts directly with and promotes the degradation of the cell fate regulator Numb .	We report that Siah-1 interacts directly with and promotes the degradation of the cell fate regulator Numb.	3	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Siah-1	Siah-1	Siah-1	Numb	Numb	Numb	3	4	16	17
Thus , Siah-1 may limit the availability of synphilin-1 to bind to alpha-synuclein and thereby attenuate the formation of Lewy bodies XREF_BIBR .	Thus, Siah-1 may limit the availability of synphilin-1 to bind to alpha-synuclein and thereby attenuate the formation of Lewy bodies XREF_BIBR.	2	9	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Siah-1	Siah-1	Siah-1	synphilin-1	synphilin-1	synphilin-1	2	3	8	9
Synphilin-1 inhibition can be relieved by co-expression of Siah-1 that targets synphilin-1 to degradation .	Synphilin-1 inhibition can be relieved by co-expression of Siah-1 that targets synphilin-1 to degradation.	0	9	relieved	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Siah-1	co-expression of Siah-1	siah-1	synphilin-1	Synphilin-1	synphilin-1	8	9	0	1
This included a dominant negative Eps15 construct and a molecule termed Transferrin receptor Trafficking Protein ( TTP ; SH3BP4 ) , overexpression of which has been show to inhibit TfR internalization .	This included a dominant negative Eps15 construct and a molecule termed Transferrin receptor Trafficking Protein (TTP; SH3BP4), overexpression of which has been show to inhibit TfR internalization.	11	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Transferrin receptor Trafficking Protein	Transferrin receptor Trafficking Protein (TTP; SH3BP4), overexpression	transferrin receptor trafficking protein	TfR	TfR	tfr	11	15	29	30
Additionally SMAD7 can inhibit SMAD2 and SMAD3 activity , thus blocking TGF-beta signaling and its effect on cancer promotion .	Additionally SMAD7 can inhibit SMAD2 and SMAD3 activity, thus blocking TGF-beta signaling and its effect on cancer promotion.	1	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	SMAD3	SMAD3	SMAD3	1	2	6	7
While transfection with siRNA to reduce Smad3 levels reversed SMC proliferation stimulated by AdSmad3 XREF_BIBR , adenoviral expression of Smad7 , which blocks Smad3 signaling , effectively inhibited intimal hyperplasia XREF_BIBR .	While transfection with siRNA to reduce Smad3 levels reversed SMC proliferation stimulated by AdSmad3 XREF_BIBR, adenoviral expression of Smad7, which blocks Smad3 signaling, effectively inhibited intimal hyperplasia XREF_BIBR.	17	24	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	expression of Smad7	smad7	Smad3	Smad3	smad3	19	20	23	24
XREF_BIBR In turn , both NF-kappaB and Smad3 can increase the expression of Smad7 , which competes for TGF-beta1 receptors and downregulates the TGF-beta1 and Smad3 pathway , providing negative feedback .	XREF_BIBR In turn, both NF-kappaB and Smad3 can increase the expression of Smad7, which competes for TGF-beta1 receptors and downregulates the TGF-beta1 and Smad3 pathway, providing negative feedback.	5	26	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	NF-kappaB and Smad3 can increase the expression of Smad7	smad7	Smad3	Smad3	smad3	13	14	25	26
In in vivo , deletion of Smad7 enhanced Smad3 signaling , thereby promoting miR-192 expression and fibrosis in obstructive kidney disease .	In in vivo, deletion of Smad7 enhanced Smad3 signaling, thereby promoting miR-192 expression and fibrosis in obstructive kidney disease.	4	9	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	6	7	8	9
Alternatively , Smad7 is an inhibitory Smad and negatively regulates Smad3 activation by its negative feedback mechanism .	Alternatively, Smad7 is an inhibitory Smad and negatively regulates Smad3 activation by its negative feedback mechanism.	2	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	2	3	10	11
In addition , IFN-gamma induces expression of Smad7 , an inhibitory Smad family member , and thus inhibits TGF-beta-induced activation of Smad3 [ XREF_BIBR ] .	In addition, IFN-gamma induces expression of Smad7, an inhibitory Smad family member, and thus inhibits TGF-beta-induced activation of Smad3 [XREF_BIBR].	3	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	IFN-gamma induces expression of Smad7	smad7	Smad3	Smad3	smad3	7	8	21	22
While Smad7 represses Smad3 activation by TGF-beta , it does not reverse the inhibitory effect of TGF-beta on myogenesis , suggesting a different function in myogenic cells .	While Smad7 represses Smad3 activation by TGF-beta, it does not reverse the inhibitory effect of TGF-beta on myogenesis, suggesting a different function in myogenic cells.	1	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	1	2	3	4
In inflamed mucosal tissue explants from patients with CD , inhibition of Smad7 also restores p-Smad3 and decreases proinflammatory cytokine production , an effect that is partially blocked by anti-TGF-beta1 .	In inflamed mucosal tissue explants from patients with CD, inhibition of Smad7 also restores p-Smad3 and decreases proinflammatory cytokine production, an effect that is partially blocked by anti-TGF-beta1.	10	16	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	p-Smad3	p-Smad3	p-Smad3	12	13	15	16
Smad6 and Smad7 inhibit Smad2 and Smad3 activation by competing with Smad2 and Smad3 for binding to the TGF-beta receptors [ XREF_BIBR ] .	Smad6 and Smad7 inhibit Smad2 and Smad3 activation by competing with Smad2 and Smad3 for binding to the TGF-beta receptors [XREF_BIBR].	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	2	3	6	7
Because Smad7 can abrogate both Smad2- and Smad3 dependent responses , we sought to clarify the specific role of cellular Smad3 in PPAR-gamma suppression using mouse fibroblasts deficient in Smad3 XREF_BIBR .	Because Smad7 can abrogate both Smad2- and Smad3 dependent responses, we sought to clarify the specific role of cellular Smad3 in PPAR-gamma suppression using mouse fibroblasts deficient in Smad3 XREF_BIBR.	1	9	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	1	2	7	8
Smad7 was recently shown to antagonize TGF-beta-induced activation of signal transducing Smad2 and Smad3 proteins .	Smad7 was recently shown to antagonize TGF-beta-induced activation of signal transducing Smad2 and Smad3 proteins.	0	14	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	0	1	13	14
Smad7 inhibits TGF-beta signaling by preventing activation of Smad2 or Smad3 , whereas Smad6 inhibits TGF-beta signaling by preventing activation of Smad1 , Smad5 , or Smad8 .	Smad7 inhibits TGF-beta signaling by preventing activation of Smad2 or Smad3, whereas Smad6 inhibits TGF-beta signaling by preventing activation of Smad1, Smad5, or Smad8.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	0	1	10	11
Increased expression of Smad7 , an inhibitory Smad that binds TbetaRI , that can be induced by Jak and STAT signaling might also inhibit TGF-beta-induced Smad3 activation ; however , TpIC decreased Smad7 mRNA expression ( XREF_FIG ) .	Increased expression of Smad7, an inhibitory Smad that binds TbetaRI, that can be induced by Jak and STAT signaling might also inhibit TGF-beta-induced Smad3 activation; however, TpIC decreased Smad7 mRNA expression (XREF_FIG).	1	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	expression of Smad7	smad7	Smad3	Smad3	smad3	3	4	25	26
This is of particular interest when keeping in mind that Smad7 negatively regulates Smad3 .	This is of particular interest when keeping in mind that Smad7 negatively regulates Smad3.	10	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	10	11	13	14
SAHA induced higher Smad7 levels and inhibited translocation of Smad3 to the nucleus , also when combined with IGF-1 .	SAHA induced higher Smad7 levels and inhibited translocation of Smad3 to the nucleus, also when combined with IGF-1.	0	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	SAHA induced higher Smad7 levels	smad7	Smad3	Smad3	smad3	3	4	9	10
It is known that Smad7 , a negative regulator of TGF-receptor I ( TBRI ) kinase , disrupts the activation of Smad2 and Smad3 and restrains TGF-beta-mediated Smad signaling XREF_BIBR - XREF_BIBR .	It is known that Smad7, a negative regulator of TGF-receptor I (TBRI) kinase, disrupts the activation of Smad2 and Smad3 and restrains TGF-beta-mediated Smad signaling XREF_BIBR - XREF_BIBR.	4	25	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	4	5	23	24
Briefly , smad3 has been proven to play a pivotal pathogenic role ; while smad7 , as an inhibitory member of the smad superfamily , antagonizes the action of smad3 XREF_BIBR XREF_BIBR .	Briefly, smad3 has been proven to play a pivotal pathogenic role; while smad7, as an inhibitory member of the smad superfamily, antagonizes the action of smad3 XREF_BIBR XREF_BIBR.	14	31	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	smad7	smad7	smad7	smad3	smad3	smad3	14	15	29	30
Inhibiting Smad7 can restore the TGF-beta1 and Smad3 signaling and result in the suppression of inflammatory cytokine production in patients with inflammatory bowel diseases [ XREF_BIBR , XREF_BIBR ] .	Inhibiting Smad7 can restore the TGF-beta1 and Smad3 signaling and result in the suppression of inflammatory cytokine production in patients with inflammatory bowel diseases [XREF_BIBR, XREF_BIBR].	0	8	restore	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	1	2	7	8
Similar results were evident following induction of the intracellular Smad2 and Smad3 antagonist Smad7 by hepatocyte growth factor in RLE-6TN cells [ XREF_BIBR ] .	Similar results were evident following induction of the intracellular Smad2 and Smad3 antagonist Smad7 by hepatocyte growth factor in RLE-6TN cells [XREF_BIBR].	5	14	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	13	14	11	12
Hypoxic ECs and SMCs have decreased expression of the inhibitory factor SMAD7 , upregulation of TGFbeta1 , increased SMAD3 activation , and ultimately upregulation of the focal adhesion molecule TGFbeta1i1 .	Hypoxic ECs and SMCs have decreased expression of the inhibitory factor SMAD7, upregulation of TGFbeta1, increased SMAD3 activation, and ultimately upregulation of the focal adhesion molecule TGFbeta1i1.	6	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAD7	expression of the inhibitory factor SMAD7	smad7	SMAD3	SMAD3	smad3	11	12	18	19
Interestingly , in inflammatory bowel disease , silencing of SMAD7 with anti-sense oligonucleotide treatment restored SMAD3 activation and reduced synthesis of inflammatory cytokines by endogenous TGFbeta [ XREF_BIBR ] .	Interestingly, in inflammatory bowel disease, silencing of SMAD7 with anti-sense oligonucleotide treatment restored SMAD3 activation and reduced synthesis of inflammatory cytokines by endogenous TGFbeta [XREF_BIBR].	7	16	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	SMAD3	SMAD3	SMAD3	9	10	15	16
In line with the hypothesis that Smad2/3 signaling is responsible for the induction of SBE containing promoters by DeltaNp73 , Smad7 which inhibits Smad2 and Smad3 activation XREF_BIBR , already at a very low concentration effectively prevented the DeltaNp73 stimulated increase in TGF-beta signaling in Hep3B cells ( XREF_FIG ) .	In line with the hypothesis that Smad2/3 signaling is responsible for the induction of SBE containing promoters by DeltaNp73, Smad7 which inhibits Smad2 and Smad3 activation XREF_BIBR, already at a very low concentration effectively prevented the DeltaNp73 stimulated increase in TGF-beta signaling in Hep3B cells (XREF_FIG).	20	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	20	21	25	26
Silencing SMAD7 can restore TGFbeta and SMAD3 signaling and result in the suppression of inflammatory cytokine production in patients with inflammatory bowel diseases [ XREF_BIBR ] .	Silencing SMAD7 can restore TGFbeta and SMAD3 signaling and result in the suppression of inflammatory cytokine production in patients with inflammatory bowel diseases [XREF_BIBR].	0	7	restore	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	SMAD3	SMAD3	SMAD3	1	2	6	7
SMAD7 can block the activation of SMAD2 and SMAD3 , while the SMAD anchor for receptor activation ( SARA , also known as ZFYVE9 ) stabilizes the SMAD4-TGFBR1 interaction .	SMAD7 can block the activation of SMAD2 and SMAD3, while the SMAD anchor for receptor activation (SARA, also known as ZFYVE9) stabilizes the SMAD4-TGFBR1 interaction.	0	9	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	SMAD3	SMAD3	SMAD3	0	1	8	9
The present finding that disrupted Smad7 enhanced Smad3 mediated renal fibrosis added a new evidence for a protective role of Smad7 in ANG II mediated hypertensive nephropathy .	The present finding that disrupted Smad7 enhanced Smad3 mediated renal fibrosis added a new evidence for a protective role of Smad7 in ANG II mediated hypertensive nephropathy.	4	11	enhanced	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	5	6	7	8
Inhibition of Smad7 with a specific antisense oligonucleotide restores TGF-beta1 and Smad3 signaling , resulting in a marked suppression of inflammatory cytokine production .	Inhibition of Smad7 with a specific antisense oligonucleotide restores TGF-beta1 and Smad3 signaling, resulting in a marked suppression of inflammatory cytokine production.	0	12	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	2	3	11	12
Smad7 is an inhibitor of Smad2 and Smad3 , and it had confirmed the role of Smad7 and NF-kappaB crosstalk pathway in renal inflammation ; In contrast , overexpression of Smad7 can inhibit the activation of NF-kappaB .	Smad7 is an inhibitor of Smad2 and Smad3, and it had confirmed the role of Smad7 and NF-kappaB crosstalk pathway in renal inflammation; In contrast, overexpression of Smad7 can inhibit the activation of NF-kappaB.	0	8	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	0	1	7	8
Most importantly , Smad7 is an inhibitor of both Smad3 mediated renal fibrosis and NF-kappaB-driven renal inflammation .	Most importantly, Smad7 is an inhibitor of both Smad3 mediated renal fibrosis and NF-kappaB-driven renal inflammation.	3	10	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	3	4	9	10
XREF_BIBR Although activated TGF-beta1 was abundant in the mucus , H. pylori infection results in increased expression of Smad7 , which inhibits Smad3 functions .	XREF_BIBR Although activated TGF-beta1 was abundant in the mucus, H. pylori infection results in increased expression of Smad7, which inhibits Smad3 functions.	16	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	expression of Smad7	smad7	Smad3	Smad3	smad3	18	19	22	23
Additionally , inhibition of Smad3 by overexpression of the inhibitory Smad7 protein or by treatment with the small molecule , halofuginone , dramatically reduces responses in animal models of kidney , lung , liver and radiation induced fibrosis .	Additionally, inhibition of Smad3 by overexpression of the inhibitory Smad7 protein or by treatment with the small molecule, halofuginone, dramatically reduces responses in animal models of kidney, lung, liver and radiation induced fibrosis.	2	14	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Smad7	overexpression of the inhibitory Smad7	smad7	Smad3	Smad3	smad3	10	11	4	5
Overexpression of Smad7 not only inhibits Smad3 mediated renal fibrosis such as collagen matrix expression including epithelial-mesenchymal transition , but also blocks NF-kappaB-driven renal inflammation including accumulation of macrophages and T cells in both glomeruli and tubulointerstitium and upregulation of renal IL-1 , TNFalpha , ICAM-1 , and iNOS .	Overexpression of Smad7 not only inhibits Smad3 mediated renal fibrosis such as collagen matrix expression including epithelial-mesenchymal transition, but also blocks NF-kappaB-driven renal inflammation including accumulation of macrophages and T cells in both glomeruli and tubulointerstitium and upregulation of renal IL-1, TNFalpha, ICAM-1, and iNOS.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Overexpression of Smad7	smad7	Smad3	Smad3	smad3	2	3	6	7
In vivo , deletion of Smad7 enhanced Smad3 signaling , thereby promoting miR-192 expression and fibrosis in obstructive kidney disease .	In vivo, deletion of Smad7 enhanced Smad3 signaling, thereby promoting miR-192 expression and fibrosis in obstructive kidney disease.	3	8	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	5	6	7	8
Phosphorylated SMAD3 binds to SMAD4 and is translocated to the nucleus , where , along with other transcription factors , it promotes transcription of genes encoding matrix proteins ; SMAD3 activity is inhibited by SMAD7 .	Phosphorylated SMAD3 binds to SMAD4 and is translocated to the nucleus, where, along with other transcription factors, it promotes transcription of genes encoding matrix proteins; SMAD3 activity is inhibited by SMAD7.	29	35	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	SMAD3	SMAD3	SMAD3	34	35	29	30
By contrast , Smad7 inhibits Smad2 and Smad3 activation by causing the degradation of TbetaRI and Smads via the ubiquitin-proteasome degradation mechanism XREF_BIBR , XREF_BIBR , XREF_BIBR .	By contrast, Smad7 inhibits Smad2 and Smad3 activation by causing the degradation of TbetaRI and Smads via the ubiquitin-proteasome degradation mechanism XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	3	4	7	8
Cumulatively , these findings support the concept that SMAD7 is a competitive inhibitor of SMAD3 .	Cumulatively, these findings support the concept that SMAD7 is a competitive inhibitor of SMAD3.	8	15	is a competitive inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	SMAD3	SMAD3	SMAD3	8	9	14	15
We show that IL1B induced Smad 7 inhibits the nuclear localization of Smad 3 , thereby bringing about transcriptional repression of Smad 3 dependent gastrin expression .	We show that IL1B induced Smad 7 inhibits the nuclear localization of Smad 3, thereby bringing about transcriptional repression of Smad 3 dependent gastrin expression.	3	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad 7	IL1B induced Smad 7	smad 7	Smad 3	Smad 3	smad 3	5	7	12	14
Overexpression of Smad7 inhibits both Smad3 mediated renal fibrosis and NF-kappaB-driven renal inflammation .	Overexpression of Smad7 inhibits both Smad3 mediated renal fibrosis and NF-kappaB-driven renal inflammation.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Overexpression of Smad7	smad7	Smad3	Smad3	smad3	2	3	5	6
Smad7 is an inhibitory Smad and negatively regulates Smad2 and Smad3 activation by its negative feed-back mechanism .	Smad7 is an inhibitory Smad and negatively regulates Smad2 and Smad3 activation by its negative feed-back mechanism.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	0	1	10	11
Smad7 inhibits renal fibrosis by negatively regulating Smad2 and Smad3 activation via its negative feedback mechanism .	Smad7 inhibits renal fibrosis by negatively regulating Smad2 and Smad3 activation via its negative feedback mechanism.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	0	1	9	10
Whereas SMAD7 inhibits both TGF-beta and SMAD3 and BMP and SMAD1 signaling , SMAD6 is a relatively specific inhibitor of BMP signaling .	Whereas SMAD7 inhibits both TGF-beta and SMAD3 and BMP and SMAD1 signaling, SMAD6 is a relatively specific inhibitor of BMP signaling.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	SMAD3	SMAD3	SMAD3	1	2	6	7
Adenovirus mediated Smad7 overexpression inhibited TGF-beta1-induced nuclear accumulation of Smad3 and Smad4 , and potentiated activated PSC proliferation .	Adenovirus mediated Smad7 overexpression inhibited TGF-beta1-induced nuclear accumulation of Smad3 and Smad4, and potentiated activated PSC proliferation.	2	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7 overexpression	smad7	Smad3	Smad3	smad3	2	3	9	10
And Smad7 negatively regulates the activation of Smad2 and Smad3 XREF_BIBR .	And Smad7 negatively regulates the activation of Smad2 and Smad3 XREF_BIBR.	1	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	1	2	9	10
It is known that Smad7 inhibits TGF-beta signaling by associating with its receptor and thus preventing Smad2 and Smad3 access for phosphorylation XREF_BIBR , XREF_BIBR .	It is known that Smad7 inhibits TGF-beta signaling by associating with its receptor and thus preventing Smad2 and Smad3 access for phosphorylation XREF_BIBR, XREF_BIBR.	4	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	4	5	18	19
Based on the identification of downstream events of TGF-beta signaling transduction over the past several years , TGF-beta1 has been shown to activate Smad2 and Smad3 , which are negatively regulated by Smad7 , an inhibitor of TGF-beta signaling , through the ubiquitin-proteasome degradation mechanism [ XREF_BIBR ] .	Based on the identification of downstream events of TGF-beta signaling transduction over the past several years, TGF-beta1 has been shown to activate Smad2 and Smad3, which are negatively regulated by Smad7, an inhibitor of TGF-beta signaling, through the ubiquitin-proteasome degradation mechanism [XREF_BIBR].	22	35	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	32	33	25	26
Consistently , silencing of Smad7 with a specific antisense oligonucleotide restores transforming growth factor-beta1 and Smad3 signalling , thereby leading to inhibition of inflammatory cytokine production and attenuation of experimental colitis in mice .	Consistently, silencing of Smad7 with a specific antisense oligonucleotide restores transforming growth factor-beta1 and Smad3 signalling, thereby leading to inhibition of inflammatory cytokine production and attenuation of experimental colitis in mice.	2	16	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	4	5	15	16
For example , Smurf1 promotes the proteasomal degradation of Smad1/5 , Runx2 , JunB and MEKK2 proteins , all of these proteins are positive osteoblast regulators .	For example, Smurf1 promotes the proteasomal degradation of Smad1/5, Runx2, JunB and MEKK2 proteins, all of these proteins are positive osteoblast regulators.	3	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	3	4	11	12
Recently we have found that Smurf1 mediates the protein degradation of the osteoblast specific transcription factor Runx2 and Cbfa1 .	Recently we have found that Smurf1 mediates the protein degradation of the osteoblast specific transcription factor Runx2 and Cbfa1.	5	19	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Cbfa1	Cbfa1	Cbfa1	5	6	18	19
We found that Smads 1 and 5 had no effect on Smurf1 induced Runx2 degradation .	We found that Smads 1 and 5 had no effect on Smurf1 induced Runx2 degradation.	9	14	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	11	12	13	14
It may because the Smurf1 mediated degradation of Runx2 does not fully require BMP-2 stimulation XREF_BIBR .	It may because the Smurf1 mediated degradation of Runx2 does not fully require BMP-2 stimulation XREF_BIBR.	3	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	4	5	8	9
38 The anabolic factor BMP2 stimulates Runx2 acetylation and thereby prevents Smurf1 induced Runx2 degradation .	38 The anabolic factor BMP2 stimulates Runx2 acetylation and thereby prevents Smurf1 induced Runx2 degradation.	10	14	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	11	12	13	14
Instead , our investigation shows that deleting a single E3 ubiquitin ligase implicated in Runx2 degradation Smurf1 , results in an increase in Runx2 accumulation leading to a premature osteoblast differentiation during embryonic development and increased bone formation post-natally .	Instead, our investigation shows that deleting a single E3 ubiquitin ligase implicated in Runx2 degradation Smurf1, results in an increase in Runx2 accumulation leading to a premature osteoblast differentiation during embryonic development and increased bone formation post-natally.	12	17	degradation	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	16	17	14	15
These results demonstrate that in addition to its interaction with the PY motif of Runx2 , Smurf1 induces Runx2 degradation in a Smad6 dependent manner [ XREF_BIBR ] .	These results demonstrate that in addition to its interaction with the PY motif of Runx2, Smurf1 induces Runx2 degradation in a Smad6 dependent manner [XREF_BIBR].	16	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	16	17	18	19
We demonstrated that overexpression of Smurf1 induces proteasomal degradation of Smad1 and Runx2 proteins in 2T3 osteoblast precursor cells and in C2C12 myoblast and osteoblast precursor cells .	We demonstrated that overexpression of Smurf1 induces proteasomal degradation of Smad1 and Runx2 proteins in 2T3 osteoblast precursor cells and in C2C12 myoblast and osteoblast precursor cells.	3	13	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	overexpression of Smurf1	smurf1	Runx2	Runx2	runx2	5	6	12	13
For example , the E3 ligases , Smurf1 , Itch and Wwp1 , promote degradation of Runx2 , JunB , and CXCR4 proteins to inhibit their functions .	For example, the E3 ligases, Smurf1, Itch and Wwp1, promote degradation of Runx2, JunB, and CXCR4 proteins to inhibit their functions.	5	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	7	8	16	17
These results indicate that AMPK favors Runx2 proteasomal degradation by phosphorylating Smurf1 .	These results indicate that AMPK favors Runx2 proteasomal degradation by phosphorylating Smurf1.	6	12	degradation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Smurf1	phosphorylating Smurf1	smurf1	Runx2	Runx2	runx2	11	12	6	7
Smad6 but not Smad7 , binds Runx2 , enhancing Smurf1 induced Runx2 degradation .	Smad6 but not Smad7, binds Runx2, enhancing Smurf1 induced Runx2 degradation.	8	12	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	9	10	11	12
BMP2 acetylates Runx2 by p300 to protect from Smurf1 mediated degradation of Runx2 .	BMP2 acetylates Runx2 by p300 to protect from Smurf1 mediated degradation of Runx2.	6	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	8	9	12	13
The unexpected result may attribute to two reasons : one , Smurf1 mediated Runx2 degradation may be induced by other stimulus independent of BMP-2 XREF_BIBR XREF_BIBR ; second , Runx2 has other ligases besides Smurf1 , as even full abolishment of Smurf1 can not entirely regulate Runx2 protein stability XREF_BIBR XREF_BIBR .	The unexpected result may attribute to two reasons : one, Smurf1 mediated Runx2 degradation may be induced by other stimulus independent of BMP-2 XREF_BIBR XREF_BIBR; second, Runx2 has other ligases besides Smurf1, as even full abolishment of Smurf1 can not entirely regulate Runx2 protein stability XREF_BIBR XREF_BIBR.	9	14	mediated	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	11	12	13	14
Moreover , Smurf1 also directly mediates Runx2 degradation in a ubiquitination dependent manner and thus acts as a bone formation suppressor XREF_BIBR - XREF_BIBR .	Moreover, Smurf1 also directly mediates Runx2 degradation in a ubiquitination dependent manner and thus acts as a bone formation suppressor XREF_BIBR - XREF_BIBR.	2	15	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	2	3	6	7
Smurf1 induced Runx2 degradation serves as a negative regulatory mechanism for the BMP-Smad-Runx2 signaling pathway .	Smurf1 induced Runx2 degradation serves as a negative regulatory mechanism for the BMP-Smad-Runx2 signaling pathway.	0	3	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	0	1	2	3
EGF decreased the transcriptional activity of Runx2 and Smurf1 , which was partially rescued by Smurf1 silencing .	EGF decreased the transcriptional activity of Runx2 and Smurf1, which was partially rescued by Smurf1 silencing.	4	16	rescued	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	15	16	6	7
Previous research has identified that Smad6 can interact with Runx2 and enhance Smurf1 induced Runx2 degradation in a ubiquitin-proteasome-dependent manner .	Previous research has identified that Smad6 can interact with Runx2 and enhance Smurf1 induced Runx2 degradation in a ubiquitin-proteasome-dependent manner.	12	15	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	12	13	14	15
For example , as PTH activates the osteoblast generation of cAMP and the enhanced expression of RUNX2 it simultaneously stimulates phosphodiesterase activity and Smurf1 mediated RUNX2 proteasomal degradation .	For example, as PTH activates the osteoblast generation of cAMP and the enhanced expression of RUNX2 it simultaneously stimulates phosphodiesterase activity and Smurf1 mediated RUNX2 proteasomal degradation.	21	27	mediated	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	RUNX2	RUNX2	RUNX2	23	24	25	26
Although the observed effects were mild , they might indicate the possibility that selective compounds act partly through blocking Smurf1 mediated Runx2 degradation .	Although the observed effects were mild, they might indicate the possibility that selective compounds act partly through blocking Smurf1 mediated Runx2 degradation.	19	22	mediated	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	19	20	21	22
To determine whether Smurf1 induces Runx2 degradation through the interaction with the PY motif of Runx2 , we created a mutant Runx2 with a PY motif deletion and found that Smurf1 retained some of its ability to induce the degradation of the mutant Runx2 , suggesting that Smurf1 could induce Runx2 degradation through an indirect mechanism .	To determine whether Smurf1 induces Runx2 degradation through the interaction with the PY motif of Runx2, we created a mutant Runx2 with a PY motif deletion and found that Smurf1 retained some of its ability to induce the degradation of the mutant Runx2, suggesting that Smurf1 could induce Runx2 degradation through an indirect mechanism.	3	6	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	3	4	5	6
In previous studies we discovered that E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 ( Smurf1 ) induces Runx2 degradation in a ubiquitin-proteasome-dependent manner , and Smurf1 plays an important role in osteoblast function and bone formation .	In previous studies we discovered that E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (Smurf1) induces Runx2 degradation in a ubiquitin-proteasome-dependent manner, and Smurf1 plays an important role in osteoblast function and bone formation.	12	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	15	16	18	19
In the presence of increased Runx2 protein levels , CHIP expression decreases , whereas the expression of other E3 ligases involved in Runx2 degradation , such as Smurf1 or WWP1 , remains constant or increases during osteoblast differentiation .	In the presence of increased Runx2 protein levels, CHIP expression decreases, whereas the expression of other E3 ligases involved in Runx2 degradation, such as Smurf1 or WWP1, remains constant or increases during osteoblast differentiation.	22	29	degradation	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	27	28	22	23
The forced expression of Smurf1 , an ubiquitin ligase responsible for Runx2 degradation , abrogated the collagen fibre induced increase of Runx2 .	The forced expression of Smurf1, an ubiquitin ligase responsible for Runx2 degradation, abrogated the collagen fibre induced increase of Runx2.	2	22	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	expression of Smurf1	smurf1	Runx2	Runx2	runx2	4	5	21	22
For example , PTH enhances osteoblast expression of Runx2 , which supports the anti-apoptotic phenotype while concomitantly inducing Smurf1 mediated Runx2 proteasomal degradation thus providing a self limiting response to the anabolic action of PTH .	For example, PTH enhances osteoblast expression of Runx2, which supports the anti-apoptotic phenotype while concomitantly inducing Smurf1 mediated Runx2 proteasomal degradation thus providing a self limiting response to the anabolic action of PTH.	17	22	mediated	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	18	19	20	21
Smurf1 promotes the degradation of Smad1/5 3 , Runx2 23 , JunB 6 and MEKK2 27 proteins .	Smurf1 promotes the degradation of Smad1/5 3, Runx2 23, JunB 6 and MEKK2 27 proteins.	0	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	0	1	8	9
Smurf1 induced Runx2 degradation can be enhanced by Smad6 and TNF , as Smad6 interacts with Runx2 and TNF promotes the expression of Smurf1 expression in osteoblasts .	Smurf1 induced Runx2 degradation can be enhanced by Smad6 and TNF, as Smad6 interacts with Runx2 and TNF promotes the expression of Smurf1 expression in osteoblasts.	0	3	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	0	1	2	3
Because Smurf1 has been reported to enhance Runx2 degradation , we compared whether CHIP and Smurf1 have a similar effect on turnover rates of the Runx2 protein .	Because Smurf1 has been reported to enhance Runx2 degradation, we compared whether CHIP and Smurf1 have a similar effect on turnover rates of the Runx2 protein.	1	8	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	1	2	7	8
In the present studies we investigated the molecular mechanism of Smurf1 induced Runx2 degradation .	In the present studies we investigated the molecular mechanism of Smurf1 induced Runx2 degradation.	8	13	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	10	11	12	13
Smad6 enhances Smurf1 induced Runx2 degradation in an ubiquitin-proteasome-dependent manner .	Smad6 enhances Smurf1 induced Runx2 degradation in an ubiquitin-proteasome-dependent manner.	2	5	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	2	3	4	5
In addition to transcriptional regulation , Runx2 and Cbfa1 is regulated at the post-translational level ; Runx2 protein is degraded by smurf1 , an E3 ubiquitin ligase , through the ubiquitin-proteasome pathway .	In addition to transcriptional regulation, Runx2 and Cbfa1 is regulated at the post-translational level; Runx2 protein is degraded by smurf1, an E3 ubiquitin ligase, through the ubiquitin-proteasome pathway.	16	26	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	smurf1	smurf1	smurf1	Runx2	Runx2	Runx2	21	22	16	17
162 Besides its role in BMP signaling , Smad6 and Smurf1 also induce Runx2 degradation in an ubiquitin-proteasome-dependent manner , which directly inhibits osteoblast differentiation .	162 Besides its role in BMP signaling, Smad6 and Smurf1 also induce Runx2 degradation in an ubiquitin-proteasome-dependent manner, which directly inhibits osteoblast differentiation.	8	14	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	10	11	13	14
SMAD specific E3 ubiquitin protein ligase 1 ( Smurf1 ) , a HECT domain E3 ubiquitin ligase mediates degradation of Runx2 , type1 BMP receptor and BMP activated Smad1 and smad5 proteins .	SMAD specific E3 ubiquitin protein ligase 1 (Smurf1), a HECT domain E3 ubiquitin ligase mediates degradation of Runx2, type1 BMP receptor and BMP activated Smad1 and smad5 proteins.	1	26	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	8	9	20	21
These results demonstrate that in addition to its interaction with the PY motif of Runx2 , Smurf1 induces Runx2 degradation in a Smad6 dependent manner .	These results demonstrate that in addition to its interaction with the PY motif of Runx2, Smurf1 induces Runx2 degradation in a Smad6 dependent manner.	16	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	16	17	18	19
Since we already identified that miR-15b targets Smurf1 ( XREF_FIG ) and it is evident that Smurf1 degrades Runx2 protein by interacting with it , followed by ubiquitination and proteasomal pathway , we next determined expression of Smurf1 protein .	Since we already identified that miR-15b targets Smurf1 (XREF_FIG) and it is evident that Smurf1 degrades Runx2 protein by interacting with it, followed by ubiquitination and proteasomal pathway, we next determined expression of Smurf1 protein.	16	19	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	16	17	18	19
We conclude that in chronic inflammatory disorders where TNF is increased , TNF induces the expression of ubiquitin ligase Smurf1 and promotes ubiquitination and proteasomal degradation of Smad1 and Runx2 , leading to systemic bone loss .	We conclude that in chronic inflammatory disorders where TNF is increased, TNF induces the expression of ubiquitin ligase Smurf1 and promotes ubiquitination and proteasomal degradation of Smad1 and Runx2, leading to systemic bone loss.	12	30	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	TNF induces the expression of ubiquitin ligase Smurf1	smurf1	Runx2	Runx2	runx2	19	20	29	30
In the present studies we found that Smads 1 and 5 had no effect on Smurf1 induced Runx2 degradation .	In the present studies we found that Smads 1 and 5 had no effect on Smurf1 induced Runx2 degradation.	13	18	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	15	16	17	18
Acetylation inhibited Smurf1 mediated degradation of Runx2 and also stimulated Runx2 transcriptional activity .	Acetylation inhibited Smurf1 mediated degradation of Runx2 and also stimulated Runx2 transcriptional activity.	1	7	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	2	3	6	7
Similarly , Smad6 could also serve as an adaptor to mediate Smurf1 induced Runx2 degradation [ XREF_BIBR ] .	Similarly, Smad6 could also serve as an adaptor to mediate Smurf1 induced Runx2 degradation [XREF_BIBR].	10	14	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	11	12	13	14
To determine whether Smurf1 induces Runx2 degradation through the interaction with the PY motif of Runx2 , we created a mutant Runx2 with a PY motif deletion and found that Smurf1 retained some of its ability to induce the degradation of the mutant Runx2 , suggesting that Smurf1 could also induce Runx2 degradation through an indirect mechanism .	To determine whether Smurf1 induces Runx2 degradation through the interaction with the PY motif of Runx2, we created a mutant Runx2 with a PY motif deletion and found that Smurf1 retained some of its ability to induce the degradation of the mutant Runx2, suggesting that Smurf1 could also induce Runx2 degradation through an indirect mechanism.	3	6	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	3	4	5	6
TNF-alpha also induces the expression of E3 ubiquitin ligase protein Smurf1 and Smurf2 and promotes degradation of Runx2 , another key transcription factor regulating osteoblast differentiation and bone formation .	TNF-alpha also induces the expression of E3 ubiquitin ligase protein Smurf1 and Smurf2 and promotes degradation of Runx2, another key transcription factor regulating osteoblast differentiation and bone formation.	0	22	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	TNF-alpha also induces the expression of E3 ubiquitin ligase protein Smurf1	smurf1	Runx2	Runx2	runx2	10	11	17	18
Smad1 degradation is mediated by the E3 ubiquitin ligase Smurf1 ( Smad ubiquitin regulatory factor 1 ) , but the specific E3 ligase responsible for Cbfa1 degradation has not been identified .	Smad1 degradation is mediated by the E3 ubiquitin ligase Smurf1 (Smad ubiquitin regulatory factor 1), but the specific E3 ligase responsible for Cbfa1 degradation has not been identified.	0	12	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	9	10	0	1
It has also been revealed that CREBH induces the expression of SMAD ubiquitination regulatory factor 1 ( Smurf1 ) , which in turn degrades SMAD1 via ubiquitination .	It has also been revealed that CREBH induces the expression of SMAD ubiquitination regulatory factor 1 (Smurf1), which in turn degrades SMAD1 via ubiquitination.	6	26	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD ubiquitination regulatory factor 1	CREBH induces the expression of SMAD ubiquitination regulatory factor 1	smad ubiquitination regulatory factor 1	SMAD1	SMAD1	smad1	11	16	24	25
Although extracellular inhibitors may contribute to this inhibition , SMURF1 directly inhibits the activation of SMAD1 , 5 , and 8 and blocks the downstream BMP signaling cascade [ XREF_BIBR , XREF_BIBR ] .	Although extracellular inhibitors may contribute to this inhibition, SMURF1 directly inhibits the activation of SMAD1, 5, and 8 and blocks the downstream BMP signaling cascade [XREF_BIBR, XREF_BIBR].	9	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMURF1	SMURF1	SMURF1	SMAD1	SMAD1	SMAD1	9	10	15	16
Further studies found that overexpression of Smurf1 reduced BMP specific Smad1 and Smad5 , but not Smad8 , protein levels .	Further studies found that overexpression of Smurf1 reduced BMP specific Smad1 and Smad5, but not Smad8, protein levels.	4	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	overexpression of Smurf1	smurf1	Smad1	Smad1	smad1	6	7	10	11
Uev1A promotes Smurf1 mediated Smad1 degradation .	Uev1A promotes Smurf1 mediated Smad1 degradation.	1	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	2	3	4	5
Smurf1 induced Smad1 and Runx2 degradation is prevented by treating cells with proteasome inhibitor .	Smurf1 induced Smad1 and Runx2 degradation is prevented by treating cells with proteasome inhibitor.	0	5	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	0	1	2	3
In Smad1 , linker phosphorylation creates a binding site for Smurf1 , which triggers Smad1 degradation .	In Smad1, linker phosphorylation creates a binding site for Smurf1, which triggers Smad1 degradation.	5	15	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	10	11	14	15
These results are compatible with the idea that Smurf1 promotes degradation of Smad1 but not Smad2 and suggest that Smurf1 can function differently from Smurf2 in regulation of early frog embryogenesis .	These results are compatible with the idea that Smurf1 promotes degradation of Smad1 but not Smad2 and suggest that Smurf1 can function differently from Smurf2 in regulation of early frog embryogenesis.	8	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	8	9	12	13
Mechanistic studies revealed that CREBH increased the expression of Smad ubiquitination regulatory factor 1 ( Smurf1 ) , leading to ubiquitin dependent degradation of Smad1 , whereas knockdown of CREBH inhibited TNFalpha mediated degradation of Smad1 by Smurf1 .	Mechanistic studies revealed that CREBH increased the expression of Smad ubiquitination regulatory factor 1 (Smurf1), leading to ubiquitin dependent degradation of Smad1, whereas knockdown of CREBH inhibited TNFalpha mediated degradation of Smad1 by Smurf1.	32	38	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	37	38	35	36
39 In addition to regulating Runx2 degradation , Smurf1 mediates the degradation of Smad1 , a downstream mediator of BMP receptors , and thereby inhibits BMP induced osteoblast differentiation .	39 In addition to regulating Runx2 degradation, Smurf1 mediates the degradation of Smad1, a downstream mediator of BMP receptors, and thereby inhibits BMP induced osteoblast differentiation.	8	24	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	8	9	13	14
For example , in bone , Smad3 represses the transcriptional activity of the osteogenic transcription factor Runx2 , which in turn regulates osteoblast differentiation and bone matrix material properties .	For example, in bone, Smad3 represses the transcriptional activity of the osteogenic transcription factor Runx2, which in turn regulates osteoblast differentiation and bone matrix material properties.	6	21	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Runx2	Runx2	Runx2	6	7	16	17
SMAD3 directly inhibits RUNX2 activity and furthermore activates CCND1 , another inhibitor of RUNX2 .	SMAD3 directly inhibits RUNX2 activity and furthermore activates CCND1, another inhibitor of RUNX2.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD3	SMAD3	SMAD3	RUNX2	RUNX2	RUNX2	0	1	3	4
Interaction of Runx2 with Smad1 facilitates the function of Runx2 in stimulating terminal differentiation , while Smad3 blocks Runx2 function [ XREF_BIBR - XREF_BIBR ] .	Interaction of Runx2 with Smad1 facilitates the function of Runx2 in stimulating terminal differentiation, while Smad3 blocks Runx2 function [XREF_BIBR - XREF_BIBR].	16	19	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Runx2	Runx2	Runx2	16	17	18	19
Complex formation of Runx2 with Smad1 is vital for the function of Runx2 , whereas the interaction of Smad3 with Runx2 inhibits Runx2 functioning .	Complex formation of Runx2 with Smad1 is vital for the function of Runx2, whereas the interaction of Smad3 with Runx2 inhibits Runx2 functioning.	16	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Runx2	Runx2	Runx2	18	19	22	23
To explain these findings , it should be borne in mind that variants in the intronic region of HDAC5 were previously found to be highly associated with alterations in the bone mineral remodeling process , where HDAC5 is needed for TGF-beta-mediated osteoblast differentiation , which occurs when Smad3 inhibits the function of Runx2 .	To explain these findings, it should be borne in mind that variants in the intronic region of HDAC5 were previously found to be highly associated with alterations in the bone mineral remodeling process, where HDAC5 is needed for TGF-beta-mediated osteoblast differentiation, which occurs when Smad3 inhibits the function of Runx2.	47	53	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Runx2	Runx2	Runx2	47	48	52	53
The mechanism through which TGF-beta and Smad3 inhibits Runx2 function has not been characterized .	The mechanism through which TGF-beta and Smad3 inhibits Runx2 function has not been characterized.	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Runx2	Runx2	Runx2	6	7	8	9
Smad3 acts as a key component of TGF-beta-induced repression of adipocyte differentiation , and represses CBFA1 activity to inhibit osteoblastic differentiation by TGF-beta .	Smad3 acts as a key component of TGF-beta-induced repression of adipocyte differentiation, and represses CBFA1 activity to inhibit osteoblastic differentiation by TGF-beta.	0	16	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	CBFA1	CBFA1	CBFA1	0	1	15	16
TGF-beta-activated Smad3 represses Runx2 function in chondrocytes .	TGF-beta-activated Smad3 represses Runx2 function in chondrocytes.	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Runx2	Runx2	Runx2	1	2	3	4
Therefore , TGF-beta-activated Smad3 represses Runx2 function to rapidly inhibit MMP-13 expression .	Therefore, TGF-beta-activated Smad3 represses Runx2 function to rapidly inhibit MMP-13 expression.	2	6	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Runx2	Runx2	Runx2	3	4	5	6
These results demonstrate that in chondrocytes , TGF-beta-activated Smad3 is sufficient to repress Runx2 inducible transactivation , specifically of an MMP-13 promoter reporter construct .	These results demonstrate that in chondrocytes, TGF-beta-activated Smad3 is sufficient to repress Runx2 inducible transactivation, specifically of an MMP-13 promoter reporter construct.	7	23	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Runx2	Runx2	Runx2	8	9	13	14
In contrast , the MH2 domains of Smad6 and Smad7 ( Smad6C and Smad7C ) repressed the transcriptional activity of TbetaR-I ( TD ) to extents similar to that induced by the full-length Smad6 , but were less potent than the full-length Smad7 .	In contrast, the MH2 domains of Smad6 and Smad7 (Smad6C and Smad7C) repressed the transcriptional activity of TbetaR-I (TD) to extents similar to that induced by the full-length Smad6, but were less potent than the full-length Smad7.	5	22	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	TbetaR-I	TbetaR-I	TbetaR-I	9	10	20	21
Here , we demonstrate that CD109 enhances SMAD7 and Smurf2 mediated degradation of TGFBR1 in a ligand dependent manner .	Here, we demonstrate that CD109 enhances SMAD7 and Smurf2 mediated degradation of TGFBR1 in a ligand dependent manner.	6	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	TGFBR1	TGFBR1	TGFBR1	7	8	13	14
SARA ' s key role in TGFbeta signalling is not limited to SMAD activation ; SARA may also modulate the outcome and duration of the signal by regulating the balance between SMAD2 and SMAD3 and facilitating SMAD7 mediated TbetaRI dephoshorylation [ XREF_BIBR ] .	SARA 's key role in TGFbeta signalling is not limited to SMAD activation; SARA may also modulate the outcome and duration of the signal by regulating the balance between SMAD2 and SMAD3 and facilitating SMAD7 mediated TbetaRI dephoshorylation [XREF_BIBR].	35	39	mediated	Positive_early_activation	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	TbetaRI	TbetaRI	TbetaRI	36	37	38	39
In addition to interacting stably with the activated TGF-beta type I receptor ( TbetaRI ) to prevent phosphorylation of the receptor regulated Smads ( Smad2 and Smad3 ) , Smad7 also induces degradation of the activated TbetaRI through association with different E3 ubiquitin ligases .	In addition to interacting stably with the activated TGF-beta type I receptor (TbetaRI) to prevent phosphorylation of the receptor regulated Smads (Smad2 and Smad3), Smad7 also induces degradation of the activated TbetaRI through association with different E3 ubiquitin ligases.	29	37	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	TbetaRI	TbetaRI	TbetaRI	29	30	36	37
Whilst SMAD6 appears to selectively inhibit BMP and ALK1 signalling , SMAD7 inhibits both BMP and ALK1 and TGFbeta and ALK5 signalling .	Whilst SMAD6 appears to selectively inhibit BMP and ALK1 signalling, SMAD7 inhibits both BMP and ALK1 and TGFbeta and ALK5 signalling.	11	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	ALK5	ALK5	ALK5	11	12	20	21
Taken together , these results suggest that CD109 is an important regulator of SMAD7 and Smurf2 mediated degradation of TGFBR1 .	Taken together, these results suggest that CD109 is an important regulator of SMAD7 and Smurf2 mediated degradation of TGFBR1.	11	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	TGFBR1	TGFBR1	TGFBR1	13	14	19	20
Ubiquitin promotes association of SIK to Smad7 , which down-regulates ALK5 .	Ubiquitin promotes association of SIK to Smad7, which down-regulates ALK5.	1	11	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	ALK5	ALK5	ALK5	6	7	10	11
In this study , we showed that SMAD7 attenuated the TGF-beta signaling pathway in ovarian granulosa cells ( GCs ) by regulating TGFBR1 transcriptional activity .	In this study, we showed that SMAD7 attenuated the TGF-beta signaling pathway in ovarian granulosa cells (GCs) by regulating TGFBR1 transcriptional activity.	7	24	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	TGFBR1	TGFBR1	TGFBR1	7	8	22	23
It has previously been reported that SMAD7 inhibits TGFbeta signaling by recruiting the E3 ubiquitin ligase AIP4 and TGFBR1 but without SMAD7 degradation .	It has previously been reported that SMAD7 inhibits TGFbeta signaling by recruiting the E3 ubiquitin ligase AIP4 and TGFBR1 but without SMAD7 degradation.	6	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD7	SMAD7	SMAD7	TGFBR1	TGFBR1	TGFBR1	6	7	18	19
Smad3 has previously been demonstrated to inhibit the activity of C/EBPbeta on transcribing monocyte chemoattractant protein-1 , inducible nitric oxide synthase and haptoglobin promoter by interacting with C/EBPbeta .	Smad3 has previously been demonstrated to inhibit the activity of C/EBPbeta on transcribing monocyte chemoattractant protein-1, inducible nitric oxide synthase and haptoglobin promoter by interacting with C/EBPbeta.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	C/EBPbeta	C/EBPbeta	C/EBPbeta	0	1	10	11
Smad3 mediates this effect in part by inhibiting C/EBP-beta and C/EBP-delta through distinct mechanisms .	Smad3 mediates this effect in part by inhibiting C/EBP-beta and C/EBP-delta through distinct mechanisms.	0	10	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad3	Smad3	Smad3	C/EBP-beta	C/EBP-beta	C/EBP-beta	0	1	8	9
Additionally , the MH2 domain of Smad3 has been shown to combine with C/EBPbeta , and subsequently decrease the association between C/EBPbeta and TGF-beta1 promoter , suggesting that the increased expression of Smad3 inhibited the activity of C/EBPbeta on the TGF-beta1 promoter .	Additionally, the MH2 domain of Smad3 has been shown to combine with C/EBPbeta, and subsequently decrease the association between C/EBPbeta and TGF-beta1 promoter, suggesting that the increased expression of Smad3 inhibited the activity of C/EBPbeta on the TGF-beta1 promoter.	30	38	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	expression of Smad3	smad3	C/EBPbeta	C/EBPbeta	c/ebpbeta	32	33	37	38
During adipogenesis , RA treatment and the consequent increase in Smad3 expression prevents interaction of C/EBPbeta with the C/EBPalpha promoter , decreasing expression of the master regulator resulting in the inhibition of differentiation .	During adipogenesis, RA treatment and the consequent increase in Smad3 expression prevents interaction of C/EBPbeta with the C/EBPalpha promoter, decreasing expression of the master regulator resulting in the inhibition of differentiation.	10	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3 expression	smad3	C/EBPbeta	C/EBPbeta	c/ebpbeta	10	11	15	16
Interestingly , expression of Smad3 and Smad4 , the downstream regulators of the TGF-beta1-signaling pathway , impairs the activity of C/EBPbeta on the TGF-beta1 promoter .	Interestingly, expression of Smad3 and Smad4, the downstream regulators of the TGF-beta1-signaling pathway, impairs the activity of C/EBPbeta on the TGF-beta1 promoter.	2	21	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	expression of Smad3	smad3	C/EBPbeta	C/EBPbeta	c/ebpbeta	4	5	20	21
Functionally , Smad-3 does not affect C/EBPbeta transactivation , whereas Smad-3 and Smad-4 together significantly decrease C/EBPbeta transactivation .	Functionally, Smad-3 does not affect C/EBPbeta transactivation, whereas Smad-3 and Smad-4 together significantly decrease C/EBPbeta transactivation.	10	17	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad-3	Smad-3	Smad-3	C/EBPbeta	C/EBPbeta	C/EBPbeta	10	11	16	17
As such , increased Smad3 levels can abrogate C/EBPbeta mediated transcriptional responses [ XREF_BIBR ] .	As such, increased Smad3 levels can abrogate C/EBPbeta mediated transcriptional responses [XREF_BIBR].	4	9	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3 levels	smad3	C/EBPbeta	C/EBPbeta	c/ebpbeta	4	5	8	9
Smad3 Represses C/EBP-beta Transactivation .	Smad3 Represses C/EBP-beta Transactivation.	0	3	Represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	C/EBP-beta	C/EBP-beta	C/EBP-beta	0	1	2	3
Smad3 proteins have been shown to complex with and repress C/EBP-beta transcriptional activity in astrocytes , 3T3 fibroblasts and adipocytes .	Smad3 proteins have been shown to complex with and repress C/EBP-beta transcriptional activity in astrocytes, 3T3 fibroblasts and adipocytes.	0	12	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	C/EBP-beta	C/EBP-beta	C/EBP-beta	0	1	10	11
Smad-3 and -4 , either alone or together , inhibit the interaction of C/EBPbeta with DNA binding sites through protein protein interactions .	Smad-3 and -4, either alone or together, inhibit the interaction of C/EBPbeta with DNA binding sites through protein protein interactions.	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad-3	Smad-3	Smad-3	C/EBPbeta	C/EBPbeta	C/EBPbeta	0	1	13	14
In addition , Smad3 represses MyoD activity through direct interaction .	In addition, Smad3 represses MyoD activity through direct interaction.	3	6	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	MyoD	MyoD	MyoD	3	4	5	6
Although Smad3 has been shown to repress the activity of MyoD through direct protein protein interactions , the results presented here highlight a more upstream point of convergence between the two pathways .	Although Smad3 has been shown to repress the activity of MyoD through direct protein protein interactions, the results presented here highlight a more upstream point of convergence between the two pathways.	1	11	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	MyoD	MyoD	MyoD	1	2	10	11
Ectopic expression of MyoD , on the other hand , strongly trans-activated the reporter , and this activation was repressed by Smad3 co-expression at a dose dependent manner ( XREF_FIG ) , suggesting Smad3 inhibits MyoD activation .	Ectopic expression of MyoD, on the other hand, strongly trans-activated the reporter, and this activation was repressed by Smad3 co-expression at a dose dependent manner (XREF_FIG), suggesting Smad3 inhibits MyoD activation.	33	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	MyoD	MyoD	MyoD	33	34	35	36
Previously , Liu et al demonstrated that Smad3 acts downstream of TGF-beta to repress MyoD dependent activation through physically interacting with MyoD thus interfering with its formation of an active MyoD/E protein complex and its subsequent binding to multimerized E-box sequence XREF_BIBR , XREF_BIBR .	Previously, Liu et al demonstrated that Smad3 acts downstream of TGF-beta to repress MyoD dependent activation through physically interacting with MyoD thus interfering with its formation of an active MyoD/E protein complex and its subsequent binding to multimerized E-box sequence XREF_BIBR, XREF_BIBR.	7	16	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	MyoD	MyoD	MyoD	7	8	14	15
TGF-beta-activated Smad3 directly suppresses the transcriptional activity of MyoD and myogenin .	TGF-beta-activated Smad3 directly suppresses the transcriptional activity of MyoD and myogenin.	0	10	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	MyoD	MyoD	MyoD	1	2	8	9
In particular , Smad3 , but not Smad2 , blocks MyoD mediated transcriptional activation by associating with bHLH region of MyoD .	In particular, Smad3, but not Smad2, blocks MyoD mediated transcriptional activation by associating with bHLH region of MyoD.	3	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	MyoD	MyoD	MyoD	3	4	10	11
XREF_BIBR first reported that the TGF-beta1 effector Smad3 , but not Smad2 , mediates the inhibition of myogenic differentiation mainly by repressing the activity of the transcriptional factor MyoD .	XREF_BIBR first reported that the TGF-beta1 effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation mainly by repressing the activity of the transcriptional factor MyoD.	4	29	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad3	Smad3	Smad3	MyoD	MyoD	MyoD	7	8	28	29
MyoD and myogenin are both downregulated by SmaD3 and myostatin expression [ XREF_BIBR ] .	MyoD and myogenin are both downregulated by SmaD3 and myostatin expression [XREF_BIBR].	0	12	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SmaD3	SmaD3	SmaD3	MyoD	MyoD	MyoD	7	8	0	1
Smad6 can also inhibit R-Smad signaling in a phosphorylation independent manner by interacting with receptor activated Smad1 , thus forming an inactive Smad1 and Smad6 complex [ XREF_BIBR ] .	Smad6 can also inhibit R-Smad signaling in a phosphorylation independent manner by interacting with receptor activated Smad1, thus forming an inactive Smad1 and Smad6 complex [XREF_BIBR].	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	Smad1	Smad1	Smad1	0	1	16	17
SMAD6 inhibits BMP signaling by sequestering SMAD1 in an inactive SMAD1-6 complex [ XREF_BIBR ] , whereas SMAD7 can bind directly to the activated BMP type I receptor , competing with R-Smads .	SMAD6 inhibits BMP signaling by sequestering SMAD1 in an inactive SMAD1-6 complex [XREF_BIBR], whereas SMAD7 can bind directly to the activated BMP type I receptor, competing with R-Smads.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD6	SMAD6	SMAD6	SMAD1	SMAD1	SMAD1	0	1	6	7
Smad6 can also limit BMP signaling by associating with receptor activated Smad1 , thereby inhibiting its association with Smad4 .	Smad6 can also limit BMP signaling by associating with receptor activated Smad1, thereby inhibiting its association with Smad4.	0	12	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	Smad1	Smad1	Smad1	0	1	11	12
The signaling is highly regulated at different molecular levels , for example , Noggin blocks BMP signaling and Smad6 prevents activation of Smad1 , 5 , and 8 .	The signaling is highly regulated at different molecular levels, for example, Noggin blocks BMP signaling and Smad6 prevents activation of Smad1, 5, and 8.	18	27	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	Smad1	Smad1	Smad1	18	19	22	23
We also found that Smad6 inhibits BMPs and Smad1 signaling without interfering with receptor mediated phosphorylation of Smad1 ( XREF_SUPPLEMENTARY ) .	We also found that Smad6 inhibits BMPs and Smad1 signaling without interfering with receptor mediated phosphorylation of Smad1 (XREF_SUPPLEMENTARY).	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	Smad1	Smad1	Smad1	4	5	8	9
Previous studies have suggested that Smad6 directly inhibits the activity of Smad1 ( XREF_FIG ) , making it possible that Smad6 acts to terminate the role of Smad1 .	Previous studies have suggested that Smad6 directly inhibits the activity of Smad1 (XREF_FIG), making it possible that Smad6 acts to terminate the role of Smad1.	5	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	Smad1	Smad1	Smad1	5	6	11	12
Therefore , Smad6 selectively antagonizes BMP activated Smad1 by acting as a Smad4 decoy .	Therefore, Smad6 selectively antagonizes BMP activated Smad1 by acting as a Smad4 decoy.	2	9	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	Smad1	Smad1	Smad1	2	3	7	8
Smad6 inhibits BMP and Smad1 signaling without interfering with receptor mediated phosphorylation of Smad1 .	Smad6 inhibits BMP and Smad1 signaling without interfering with receptor mediated phosphorylation of Smad1.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	Smad1	Smad1	Smad1	0	1	4	5
In the absence of the HH ligand , SMO is not translocated into the cilium and thus can not antagonize SUFU .	In the absence of the HH ligand, SMO is not translocated into the cilium and thus can not antagonize SUFU.	8	21	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMO	SMO	SMO	SUFU	SUFU	SUFU	8	9	20	21
This simple model is consistent with at least two findings : ( 1 ) the Hh pathway is constitutively active in SuFu -/- cells independent of cilia , suggesting that active Smo at cilia might signal by inhibiting SuFu , and ( 2 ) activation of PKA by forskolin ( FSK ) inhibits signaling by active Smo in cells that have SuFu but can not block constitutive signaling caused by loss of SuFu , suggesting that Smo and PKA might exert their opposing effects on Hh signaling through SuFu .	This simple model is consistent with at least two findings : (1) the Hh pathway is constitutively active in SuFu -/- cells independent of cilia, suggesting that active Smo at cilia might signal by inhibiting SuFu, and (2) activation of PKA by forskolin (FSK) inhibits signaling by active Smo in cells that have SuFu but can not block constitutive signaling caused by loss of SuFu, suggesting that Smo and PKA might exert their opposing effects on Hh signaling through SuFu.	30	39	signal	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smo	Smo	Smo	SuFu	SuFu	SuFu	31	32	38	39
In the absence of the SHH ligand , SMO is not translocated into the cilium and thus can not antagonize SUFU .	In the absence of the SHH ligand, SMO is not translocated into the cilium and thus can not antagonize SUFU.	8	21	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMO	SMO	SMO	SUFU	SUFU	SUFU	8	9	20	21
It is unclear how Smo antagonizes Sufu function molecularly .	It is unclear how Smo antagonizes Sufu function molecularly.	4	7	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smo	Smo	Smo	Sufu	Sufu	Sufu	4	5	6	7
Removal of Sufu in both Smoothened ( Smo ) and Ift88 mutants , respectively , leads to full activation of Hh signaling , suggesting that Smo mediated repression of Sufu , but not the inhibitory function of Sufu , requires cilia .	Removal of Sufu in both Smoothened (Smo) and Ift88 mutants, respectively, leads to full activation of Hh signaling, suggesting that Smo mediated repression of Sufu, but not the inhibitory function of Sufu, requires cilia.	25	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smo	Smo	Smo	Sufu	Sufu	Sufu	25	26	29	30
A simple model for vertebrate Hh signaling is that active Smo at the cilium inhibits SuFu to allow Gli activation ; however , a major unanswered question has been if and how SuFu is regulated by Hh signaling .	A simple model for vertebrate Hh signaling is that active Smo at the cilium inhibits SuFu to allow Gli activation; however, a major unanswered question has been if and how SuFu is regulated by Hh signaling.	9	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smo	Smo	Smo	SuFu	SuFu	SuFu	10	11	15	16
Smo activates Hh signaling by antagonizing the inhibitory function of Sufu .	Smo activates Hh signaling by antagonizing the inhibitory function of Sufu.	0	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smo	Smo	Smo	Sufu	Sufu	Sufu	0	1	10	11
Smad3 prevents Pax6 paired domain from binding DNA .	Smad3 prevents Pax6 paired domain from binding DNA.	0	4	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Pax6	Pax6	Pax6	0	1	2	3
Finally , in DNA adsorption assays , activated Smad3 inhibited Pax6 from binding the consensus paired domain recognition sequence .	Finally, in DNA adsorption assays, activated Smad3 inhibited Pax6 from binding the consensus paired domain recognition sequence.	7	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Pax6	Pax6	Pax6	8	9	10	11
They do so by controlling Pax6 activity : although Smad3 may inhibit Pax6 protein function , its sustained downregulation requires transcriptional repression by Wnt initiated beta-catenin .	They do so by controlling Pax6 activity : although Smad3 may inhibit Pax6 protein function, its sustained downregulation requires transcriptional repression by Wnt initiated beta-catenin.	9	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Pax6	Pax6	Pax6	9	10	12	13
Although pSmad3 may sequester Pax6 protein to inhibit its function as a transcriptional activator XREF_BIBR , TGF-betas also function indirectly by inducing Wnt2b .	Although pSmad3 may sequester Pax6 protein to inhibit its function as a transcriptional activator XREF_BIBR, TGF-betas also function indirectly by inducing Wnt2b.	1	5	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pSmad3	pSmad3	pSmad3	Pax6	Pax6	Pax6	1	2	4	5
Prior studies have shown that TGF-beta1 effector molecules , Smad3 and Smad4 , can repress the function of c-Jun , c-Fos , and C/EBPalpha , all of which are putative activators of HO-1 .	Prior studies have shown that TGF-beta1 effector molecules, Smad3 and Smad4, can repress the function of c-Jun, c-Fos, and C/EBPalpha, all of which are putative activators of HO-1.	7	30	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	C/EBPalpha	C/EBPalpha	C/EBPalpha	9	10	23	24
In addition , when Smad3 expression was inhibited by siRNA , the HBZ mediated suppression of C/EBPalpha activity was partially restored , indicating that Smad3 functions to suppress C/EBPalpha signaling along with HBZ .	In addition, when Smad3 expression was inhibited by siRNA, the HBZ mediated suppression of C/EBPalpha activity was partially restored, indicating that Smad3 functions to suppress C/EBPalpha signaling along with HBZ.	24	29	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	C/EBPalpha	C/EBPalpha	C/EBPalpha	24	25	28	29
To determine whether Smad3 is required for HBZ to suppress C/EBPalpha , we analyzed the effect of SIS3 , an inhibitor of Smad3 , on the ability of HBZ to inhibit C/EBPalpha transcriptional activity .	To determine whether Smad3 is required for HBZ to suppress C/EBPalpha, we analyzed the effect of SIS3, an inhibitor of Smad3, on the ability of HBZ to inhibit C/EBPalpha transcriptional activity.	3	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	C/EBPalpha	C/EBPalpha	C/EBPalpha	3	4	10	11
have shown that SMAD3 disrupts the positive feedback loop between the adipogenic master regulators PPARgamma and C/EBPalpha in white adipocytes XREF_BIBR .	have shown that SMAD3 disrupts the positive feedback loop between the adipogenic master regulators PPARgamma and C/EBPalpha in white adipocytes XREF_BIBR.	3	20	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD3	SMAD3	SMAD3	C/EBPalpha	C/EBPalpha	C/EBPalpha	3	4	16	17
Smurf1 also induces the degradation of Smad5 , facilitating myogenic differentiation of C2C12 cells at the expense of reduced BMP induced osteogenic differentiation [ XREF_BIBR ] .	Smurf1 also induces the degradation of Smad5, facilitating myogenic differentiation of C2C12 cells at the expense of reduced BMP induced osteogenic differentiation [XREF_BIBR].	0	7	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Smad5	Smad5	Smad5	0	1	6	7
Increasing Smad6 also attenuated TGF-beta1-induced activation of p-PKC-delta and p-Smad3 in BMP-2 knock-down cardiomyocytes ( XREF_FIG C ) .	Increasing Smad6 also attenuated TGF-beta1-induced activation of p-PKC-delta and p-Smad3 in BMP-2 knock-down cardiomyocytes (XREF_FIG C).	0	10	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	p-Smad3	p-Smad3	p-Smad3	1	2	9	10
Smad6 overexpression attenuated TGF-beta1-induced activation of PKC-delta and Smad3 , promoted TGF-beta RI degradation in BMP-2 knock-down cardiomyocytes , and could be abolished after knocking-down Smurf-1 , in which Smad6 and Smurf1 complex formation was critically involved .	Smad6 overexpression attenuated TGF-beta1-induced activation of PKC-delta and Smad3, promoted TGF-beta RI degradation in BMP-2 knock-down cardiomyocytes, and could be abolished after knocking-down Smurf-1, in which Smad6 and Smurf1 complex formation was critically involved.	0	9	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6 overexpression	smad6	Smad3	Smad3	smad3	0	1	8	9
Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4 , but does not inhibit the activity of Smad3 .	Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3.	0	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	Smad3	Smad3	Smad3	0	1	21	22
Smad6 has been originally identified as one of the inhibitory Smads to inhibit transforming growth factor ( TGF )-beta/bone morphogenic protein ( BMP ) signaling through reduced phosphorylation of Smad2 and Smad5 , competition with Smad4 , and downregulation of Smad4 with Smurf1 .	Smad6 has been originally identified as one of the inhibitory Smads to inhibit transforming growth factor (TGF)-beta/bone morphogenic protein (BMP) signaling through reduced phosphorylation of Smad2 and Smad5, competition with Smad4, and downregulation of Smad4 with Smurf1.	0	42	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	Smad4	Smad4	Smad4	0	1	40	41
The I-Smad Smad6 has indeed been reported to inhibit TGF-beta signaling by sequestering the Co-Smad Smad4 in an inactive complex [ XREF_BIBR ] .	The I-Smad Smad6 has indeed been reported to inhibit TGF-beta signaling by sequestering the Co-Smad Smad4 in an inactive complex [XREF_BIBR].	0	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	Smad4	Smad4	Smad4	2	3	15	16
Results from experiments tracking the dynamics of R-Smad phosphorylation XREF_BIBR and from computational modeling of the signaling behavior in these cells XREF_BIBR suggest that Smad7 primarily inhibits activation of the Smad1 channel .	Results from experiments tracking the dynamics of R-Smad phosphorylation XREF_BIBR and from computational modeling of the signaling behavior in these cells XREF_BIBR suggest that Smad7 primarily inhibits activation of the Smad1 channel.	24	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad1	Smad1	Smad1	24	25	30	31
This Smad7 inhibition is enhanced by co-expression of Smurf1 .	This Smad7 inhibition is enhanced by co-expression of Smurf1.	1	9	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Smurf1	co-expression of Smurf1	smurf1	Smad7	Smad7	smad7	8	9	1	2
Smurf1 and Smurf2 also promote degradation of Smad7 in the ternary complex with the TGF-beta receptors .	Smurf1 and Smurf2 also promote degradation of Smad7 in the ternary complex with the TGF-beta receptors.	0	8	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Smad7	Smad7	Smad7	0	1	7	8
However , SMCR8 overexpression or depletion does not disrupt association of ULK1 and ATG13 or induce changes in the ULK1 complex fractionation pattern .	However, SMCR8 overexpression or depletion does not disrupt association of ULK1 and ATG13 or induce changes in the ULK1 complex fractionation pattern.	2	13	disrupt	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMCR8	SMCR8 overexpression	smcr8	ULK1	ULK1	ulk1	2	3	11	12
Furthermore , SMCR8 depletion decreased phosphorylation of mTORC1 substrates but markedly enhanced ULK1 kinase activity .	Furthermore, SMCR8 depletion decreased phosphorylation of mTORC1 substrates but markedly enhanced ULK1 kinase activity.	2	14	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SMCR8	SMCR8	SMCR8	ULK1	ULK1	ULK1	2	3	12	13
We reported that Smad6 inhibited BMPR1A and BMPR1B preferentially to ACVR1 and ACVRL1 , and inhibited BMP2 induced Smad1/5 phosphorylation more prominently than BMP6 induced Smad1/5 phosphorylation XREF_BIBR .	We reported that Smad6 inhibited BMPR1A and BMPR1B preferentially to ACVR1 and ACVRL1, and inhibited BMP2 induced Smad1/5 phosphorylation more prominently than BMP6 induced Smad1/5 phosphorylation XREF_BIBR.	3	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	BMPR1A	BMPR1A	BMPR1A	3	4	5	6
SMAD6 has been reported to preferentially inhibit BMPR1A signaling [ XREF_BIBR ] ; therefore , caBMPR1A was selected as the signal transducer in the cell system .	SMAD6 has been reported to preferentially inhibit BMPR1A signaling [XREF_BIBR]; therefore, caBMPR1A was selected as the signal transducer in the cell system.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD6	SMAD6	SMAD6	BMPR1A	BMPR1A	BMPR1A	0	1	7	8
SMAD4 can be proteasomally degraded after polyubiquitination by SMURF1 and SMURF2 E3 ligase complexes , which possess the WW domain ( Moren et al , 2003 , 2005 ) .	SMAD4 can be proteasomally degraded after polyubiquitination by SMURF1 and SMURF2 E3 ligase complexes, which possess the WW domain (Moren et al, 2003, 2005).	0	13	degraded	Negative_activation_syntax_4_verb	Negative_activation	Negative_activation	SMURF1	SMURF1	SMURF1	SMAD4	SMAD4	SMAD4	8	9	0	1
Smad6 and Smad7 have been shown to reversely inhibit TAK1 activation in certain cell types , such as rat pheochromocytoma PC12 cells XREF_BIBR and mouse hybridoma MH60 cells XREF_BIBR .	Smad6 and Smad7 have been shown to reversely inhibit TAK1 activation in certain cell types, such as rat pheochromocytoma PC12 cells XREF_BIBR and mouse hybridoma MH60 cells XREF_BIBR.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad6	Smad6	Smad6	TAK1	TAK1	TAK1	0	1	9	10
SOCS3 can inhibit STAT3 by three main mechanisms : direct inhibition of JAK proteins , competition with STAT3 for binding to pY sites on activated receptors , and recruitment and ubiquitylation of signaling proteins and their consequent degradation by the proteasome system [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	SOCS3 can inhibit STAT3 by three main mechanisms : direct inhibition of JAK proteins, competition with STAT3 for binding to pY sites on activated receptors, and recruitment and ubiquitylation of signaling proteins and their consequent degradation by the proteasome system [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	3	4
Consistently , increased SOCS3 expression in POMC neurons results in impaired STAT3 signaling with subsequent leptin resistance and obesity .	Consistently, increased SOCS3 expression in POMC neurons results in impaired STAT3 signaling with subsequent leptin resistance and obesity.	3	13	signaling	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	3	4	11	12
The key molecule that determines the half-life of STAT3 phosphorylation is suppressor of cytokine signaling-3 ( SOCS3 ) , which inactivates and degrades STAT3 XREF_BIBR .	The key molecule that determines the half-life of STAT3 phosphorylation is suppressor of cytokine signaling-3 (SOCS3), which inactivates and degrades STAT3 XREF_BIBR.	14	24	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	16	17	23	24
A critical role of STAT3 signaling in regulating astrocyte function is also supported by spinal cord injury in mice in which SOCS3 , which inhibits STAT3 signaling , was specifically ablated in astrocytes .	A critical role of STAT3 signaling in regulating astrocyte function is also supported by spinal cord injury in mice in which SOCS3, which inhibits STAT3 signaling, was specifically ablated in astrocytes.	21	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	21	22	25	26
SOCS3 is an inhibitor of STAT3 that is essential for induction of the orphan nuclear receptor RORt , Th17 polarization and EAE development .	SOCS3 is an inhibitor of STAT3 that is essential for induction of the orphan nuclear receptor RORt, Th17 polarization and EAE development.	0	6	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	5	6
As SOCS3 suppression of STAT3 activity is an important mechanism during muscle differentiation XREF_BIBR , we assessed in the current study whether there was a difference in differentiation capacity of the different cell groups .	As SOCS3 suppression of STAT3 activity is an important mechanism during muscle differentiation XREF_BIBR, we assessed in the current study whether there was a difference in differentiation capacity of the different cell groups.	1	5	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	1	2	4	5
In addition , SOCS3 blocks STAT3 signaling and inhibits T H 17 polarization XREF_BIBR , XREF_BIBR .	In addition, SOCS3 blocks STAT3 signaling and inhibits T H 17 polarization XREF_BIBR, XREF_BIBR.	3	8	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	3	4	5	6
SOCS-3 has been shown to inhibit not only the STAT3 pathway , but also the extracellular signal related kinase ( Erk ) 1/2 and NF-kB pathways [ XREF_BIBR , XREF_BIBR ] , providing a possible mechanistic explanation for how leptin induced responses could be modulated by SOCS-3 in chondrocytes .	SOCS-3 has been shown to inhibit not only the STAT3 pathway, but also the extracellular signal related kinase (Erk) 1/2 and NF-kB pathways [XREF_BIBR, XREF_BIBR], providing a possible mechanistic explanation for how leptin induced responses could be modulated by SOCS-3 in chondrocytes.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	STAT3	STAT3	STAT3	0	1	9	10
If this was correct , it seemed likely that SOCS3 inhibited STAT3 activation in the photoreceptor cells to avoid the decrease in rhodopsin .	If this was correct, it seemed likely that SOCS3 inhibited STAT3 activation in the photoreceptor cells to avoid the decrease in rhodopsin.	9	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	9	10	11	12
Contrary to miR-185 ' s protective effects , SOCS3 significantly suppressed functions of beta-cell and inactivated STAT3 pathway .	Contrary to miR-185 's protective effects, SOCS3 significantly suppressed functions of beta-cell and inactivated STAT3 pathway.	4	17	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	8	9	16	17
The pSTAT3 then directly and indirectly activates downstream genes , including Myod1 , which is the master regulator of myogenesis , and SOCS3 , which negatively regulate STAT3 .	The pSTAT3 then directly and indirectly activates downstream genes, including Myod1, which is the master regulator of myogenesis, and SOCS3, which negatively regulate STAT3.	6	28	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	22	23	27	28
LPS induced SOCS3 blocks activation of STAT3 , a transcriptionfactor inhibitory to proinflammatory mediator production .	LPS induced SOCS3 blocks activation of STAT3, a transcriptionfactor inhibitory to proinflammatory mediator production.	0	7	blocks activation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SOCS3	LPS induced SOCS3	socs3	STAT3	STAT3	stat3	2	3	6	7
SOCS3 inhibits STAT3 mediated signalling by binding to the IL-6 receptor family subunit gp130 , G-CSF , leptin and the IL-12 receptor XREF_BIBR .	SOCS3 inhibits STAT3 mediated signalling by binding to the IL-6 receptor family subunit gp130, G-CSF, leptin and the IL-12 receptor XREF_BIBR.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	2	3
Finally , the repressor SOCS3 can directly compete with Shp2 for gp130 binding , preventing activation of STAT3 , ERKs and Akt .	Finally, the repressor SOCS3 can directly compete with Shp2 for gp130 binding, preventing activation of STAT3, ERKs and Akt.	2	21	preventing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	4	5	17	18
In the case of IL-6 signaling , Jak2 activation induces Stat3 mediated SOCS3 gene expression , which in turn , inhibits Jak2 and Stat3 signaling .	In the case of IL-6 signaling, Jak2 activation induces Stat3 mediated SOCS3 gene expression, which in turn, inhibits Jak2 and Stat3 signaling.	7	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	Jak2 activation induces Stat3 mediated SOCS3 gene expression	socs3	Stat3	Stat3	stat3	12	13	23	24
Feedback regulation of STAT3 activation is a complex process and the two major players are the SHP2 phosphatase and the product of the STAT3 inducible gene SOCS3 ( suppressor of cytokine signaling ) , which blocks STAT3 activation by gp130 receptor .	Feedback regulation of STAT3 activation is a complex process and the two major players are the SHP2 phosphatase and the product of the STAT3 inducible gene SOCS3 (suppressor of cytokine signaling), which blocks STAT3 activation by gp130 receptor.	17	37	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	26	27	36	37
These data suggest that CIS3 is induced via STAT3 and that CIS3 suppresses STAT3 activation in a colon derived cell line .	These data suggest that CIS3 is induced via STAT3 and that CIS3 suppresses STAT3 activation in a colon derived cell line.	11	14	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIS3	CIS3	CIS3	STAT3	STAT3	STAT3	11	12	13	14
The enforced overexpression of SOCS3 abolished the hypoxia induced STAT3 activation and the STAT3 mediated transcriptional upregulation of the VEGF gene .	The enforced overexpression of SOCS3 abolished the hypoxia induced STAT3 activation and the STAT3 mediated transcriptional upregulation of the VEGF gene.	2	10	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	overexpression of SOCS3	socs3	STAT3	STAT3	stat3	4	5	9	10
Similarly , SOCS3 overexpression significantly inhibited HG induced tyrosine phosphorylation JAK2 and STAT3 .	Similarly, SOCS3 overexpression significantly inhibited HG induced tyrosine phosphorylation JAK2 and STAT3.	2	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 overexpression	socs3	STAT3	STAT3	stat3	2	3	12	13
A SOCS3 derived peptide prevents IL-22-induced STAT3 and Erk activation in transformed keratinocytes .	A SOCS3 derived peptide prevents IL-22-induced STAT3 and Erk activation in transformed keratinocytes.	0	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	1	2	6	7
Collectively , these results suggest that IL-6 cytokine induced SOCS3 expression contributes to neuronal death by inhibiting the protective effect of activated STAT3 .	Collectively, these results suggest that IL-6 cytokine induced SOCS3 expression contributes to neuronal death by inhibiting the protective effect of activated STAT3.	9	23	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	9	10	22	23
Therefore , we propose that SOCS3 may negatively regulate STAT3 activation by complexing with receptor dissociated pJAK1 and targeting it for proteasomal degradation , thus ensuring kinase active JAK1 is separated from its STAT3 substrate .	Therefore, we propose that SOCS3 may negatively regulate STAT3 activation by complexing with receptor dissociated pJAK1 and targeting it for proteasomal degradation, thus ensuring kinase active JAK1 is separated from its STAT3 substrate.	5	10	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	5	6	9	10
SOCS3 homozygous deletion in the pancreas accelerates development of pancreatic intraepithelial neoplasia ( PanIN ) and pancreatic cancer by activating Stat3 and NF-kappaB signaling in mouse models .	SOCS3 homozygous deletion in the pancreas accelerates development of pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer by activating Stat3 and NF-kappaB signaling in mouse models.	0	23	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	Stat3	Stat3	Stat3	0	1	20	21
Loss of Socs3 led to enhanced and precocious Stat3 activation .	Loss of Socs3 led to enhanced and precocious Stat3 activation.	0	9	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Socs3	Loss of Socs3	socs3	Stat3	Stat3	stat3	2	3	8	9
Furthermore , the endogenous SOCS3 in wild-type mice contributed to the recovery of visual function but failed to prevent the effects of activated STAT3 at its peak levels .	Furthermore, the endogenous SOCS3 in wild-type mice contributed to the recovery of visual function but failed to prevent the effects of activated STAT3 at its peak levels.	2	27	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	4	5	23	24
SOCS3 works in a classic negative feedback loop to attenuate STAT3 activity by suppressive binding with phosphorylated JAK [ XREF_BIBR ] and/or facilitating ubiqitination of JAK in the cytoplasm [ XREF_BIBR ] .	SOCS3 works in a classic negative feedback loop to attenuate STAT3 activity by suppressive binding with phosphorylated JAK [XREF_BIBR] and/or facilitating ubiqitination of JAK in the cytoplasm [XREF_BIBR].	0	11	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	10	11
The constitutive STAT3 activation in nAMD is not caused by the abnormalities of the IL-6R and gp130 receptor or the negative regulator SOCS3 as their expression levels were comparable between nAMD patients and controls .	The constitutive STAT3 activation in nAMD is not caused by the abnormalities of the IL-6R and gp130 receptor or the negative regulator SOCS3 as their expression levels were comparable between nAMD patients and controls.	2	23	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	22	23	2	3
Localized overexpression of SOCS3 in the tibialis muscle inhibited STAT3 activation and prevented muscle wasting in C26 and burn cachexia .	Localized overexpression of SOCS3 in the tibialis muscle inhibited STAT3 activation and prevented muscle wasting in C26 and burn cachexia.	1	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	overexpression of SOCS3	socs3	STAT3	STAT3	stat3	3	4	9	10
SOCS3 an inhibitor of STAT3 [ XREF_BIBR ] was significantly downregulated in the female beta2GPI-/- mice fed a NC diet when compared to female WT mice fed a NC diet .	SOCS3 an inhibitor of STAT3 [XREF_BIBR] was significantly downregulated in the female beta2GPI-/- mice fed a NC diet when compared to female WT mice fed a NC diet.	0	6	inhibitor	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	4	5
The level of SOCS3 , an anti-inflammatory mediator that decreases pSTAT3 signaling , was significantly decreased in the BAL fluid of SPC-TK and SPC-KO mice .	The level of SOCS3, an anti-inflammatory mediator that decreases pSTAT3 signaling, was significantly decreased in the BAL fluid of SPC-TK and SPC-KO mice.	1	11	decreases	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	SOCS3	level of SOCS3	socs3	pSTAT3	pSTAT3	pstat3	3	4	10	11
These data suggest that over-expression of SOCS3 following EPA-FFA supplementation , probably as a downstream effect of IL-10 induction , reduces STAT3 activation , in particular in patients with highest percentage of EPA in RBC membranes .	These data suggest that over-expression of SOCS3 following EPA-FFA supplementation, probably as a downstream effect of IL-10 induction, reduces STAT3 activation, in particular in patients with highest percentage of EPA in RBC membranes.	4	22	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	over-expression of SOCS3	socs3	STAT3	STAT3	stat3	6	7	21	22
Thus SOCS3 can suppress both STAT3 and STAT1 signaling by IL-6 but does not affect STAT3 signaling by IL-10 or STAT1 signaling by interferons .	Thus SOCS3 can suppress both STAT3 and STAT1 signaling by IL-6 but does not affect STAT3 signaling by IL-10 or STAT1 signaling by interferons.	1	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	1	2	5	6
By comparing Figure XREF_FIG and XREF_FIG , in which we run the simulation in the absence of SOCS3 , we observe that the effect of SOCS3 expression in response to STAT3 activation is to activate the slow attenuation process observed in the full model : removal of SOCS3 suppresses the delayed re-appearance of cytoplasmic STAT3 and the pathway exhibits prolonged and stable nuclear occupancy of STAT3 .	By comparing Figure XREF_FIG and XREF_FIG, in which we run the simulation in the absence of SOCS3, we observe that the effect of SOCS3 expression in response to STAT3 activation is to activate the slow attenuation process observed in the full model : removal of SOCS3 suppresses the delayed re-appearance of cytoplasmic STAT3 and the pathway exhibits prolonged and stable nuclear occupancy of STAT3.	45	55	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	47	48	54	55
SOCS3 functionally suppresses STAT3 activation and negatively regulate tumor development .	SOCS3 functionally suppresses STAT3 activation and negatively regulate tumor development.	0	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	3	4
Of note , SOCS3 inhibits pSTAT3 and LIFR signaling , suggesting a complex interplay among these components that in the context of B cells takes place solely within a minor subset of B1a cells that expresses CD25 .	Of note, SOCS3 inhibits pSTAT3 and LIFR signaling, suggesting a complex interplay among these components that in the context of B cells takes place solely within a minor subset of B1a cells that expresses CD25.	3	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	pSTAT3	pSTAT3	pSTAT3	3	4	5	6
To determine whether the effect of TGF-beta on STAT3 activation could be due to reduced numbers of effector T cells , CD4 + CD25 - T cells were cultured with anti-CD3 and anti-CD28 in the presence of IL-6 , TGF-beta , or IL-6 plus TGF-beta , and SOCS3 expression and STAT3 activation was determined at different time points from 0.5 to 4 h. IL-6 induced both SOCS3 expression and STAT3 activation , whereas TGF-beta inhibited SOCS3 expression and enhanced STAT3 activation ( data not shown ) , similar to that of unseparated CD4 + T cells .	To determine whether the effect of TGF-beta on STAT3 activation could be due to reduced numbers of effector T cells, CD4 + CD25 - T cells were cultured with anti-CD3 and anti-CD28 in the presence of IL-6, TGF-beta, or IL-6 plus TGF-beta, and SOCS3 expression and STAT3 activation was determined at different time points from 0.5 to 4 h. IL-6 induced both SOCS3 expression and STAT3 activation, whereas TGF-beta inhibited SOCS3 expression and enhanced STAT3 activation (data not shown), similar to that of unseparated CD4 + T cells.	73	80	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	TGF-beta inhibited SOCS3 expression	socs3	STAT3	STAT3	stat3	75	76	79	80
SOCS3 binds to the SHP2 site on the shared receptor gp130 , blocking the IL-6-induced STAT3 response .	SOCS3 binds to the SHP2 site on the shared receptor gp130, blocking the IL-6-induced STAT3 response.	0	16	blocking	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	15	16
To investigate the mechanisms maintaining STAT3 aberrantly phosphorylated using transcriptional protein and functional assays , we analyzed interleukin ( IL ) -6 and suppressor of cytokine signaling-3 ( SOCS3 ) , 2 key factors of the JAK and STAT pathway that induce and inhibit STAT3 activation , respectively .	To investigate the mechanisms maintaining STAT3 aberrantly phosphorylated using transcriptional protein and functional assays, we analyzed interleukin (IL) -6 and suppressor of cytokine signaling-3 (SOCS3), 2 key factors of the JAK and STAT pathway that induce and inhibit STAT3 activation, respectively.	16	45	induce	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	suppressor of cytokine signaling-3	suppressor of cytokine signaling-3	suppressor of cytokine signaling-3	STAT3	STAT3	STAT3	23	27	44	45
Recent work has demonstrated that SOCS3 expressed in primary sensory neurons can suppress STAT3 mediated neurite growth in vitro .	Recent work has demonstrated that SOCS3 expressed in primary sensory neurons can suppress STAT3 mediated neurite growth in vitro.	5	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 expressed	socs3	STAT3	STAT3	stat3	5	6	13	14
Finally , one group demonstrated that overexpression of SOCS-3 in neural stem cells decreased STAT-3 activation , promoted the maintenance of the neural stem cell phenotype and inhibited astrogliogenesis .	Finally, one group demonstrated that overexpression of SOCS-3 in neural stem cells decreased STAT-3 activation, promoted the maintenance of the neural stem cell phenotype and inhibited astrogliogenesis.	6	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	overexpression of SOCS-3	socs-3	STAT-3	STAT-3	stat-3	8	9	14	15
Pre-treating cerulein stimulated AR42J cells or rats with the peroxisome proliferator activated receptor-gamma ( PPAR-gamma ) ligands , 15d-PGJ2 and troglitazone , induced SOCS 3 expression and inhibited JAK2 and STAT3 activation .	Pre-treating cerulein stimulated AR42J cells or rats with the peroxisome proliferator activated receptor-gamma (PPAR-gamma) ligands, 15d-PGJ2 and troglitazone, induced SOCS 3 expression and inhibited JAK2 and STAT3 activation.	1	31	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS 3	cerulein stimulated AR42J cells or rats with the peroxisome proliferator activated receptor-gamma (PPAR-gamma) ligands, 15d-PGJ2 and troglitazone, induced SOCS 3 expression	socs 3	STAT3	STAT3	stat3	23	25	30	31
Our results implies that aberrant STAT3 signaling may be inhibited by EV release and transfer of SOCS3 or regulators of STAT3 signaling network .	Our results implies that aberrant STAT3 signaling may be inhibited by EV release and transfer of SOCS3 or regulators of STAT3 signaling network.	5	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	16	17	5	6
SOCS3 inhibits STAT3 activation and thus represents a classic feedback inhibitor of cytokine signaling .	SOCS3 inhibits STAT3 activation and thus represents a classic feedback inhibitor of cytokine signaling.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	2	3
SOCS3 effectively inhibited STAT3 activation and blocked further photoreceptor cell dysfunction .	SOCS3 effectively inhibited STAT3 activation and blocked further photoreceptor cell dysfunction.	0	6	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	3	4
Since SOCS3 can bind to interleukin ( IL ) -12 receptor , which can activate STAT3 , SOCS3 can inhibit the IL-12-mediated activation of STAT3 .	Since SOCS3 can bind to interleukin (IL) -12 receptor, which can activate STAT3, SOCS3 can inhibit the IL-12-mediated activation of STAT3.	17	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	17	18	24	25
One well studied example involves STAT3 , which upregulates the expression of SOCS3 , which in turn represses STAT3 activity .	One well studied example involves STAT3, which upregulates the expression of SOCS3, which in turn represses STAT3 activity.	5	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	STAT3, which upregulates the expression of SOCS3	socs3	STAT3	STAT3	stat3	12	13	18	19
This indicates that loss of SOCS3 prolongs STAT3 activation in response to GCM .	This indicates that loss of SOCS3 prolongs STAT3 activation in response to GCM.	3	8	prolongs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	loss of SOCS3	socs3	STAT3	STAT3	stat3	5	6	7	8
On the other hand , SOCS3 has been shown to down-regulate STAT1 , STAT3 and STAT5 activity upon cytokine stimulation [ XREF_BIBR ] .	On the other hand, SOCS3 has been shown to down-regulate STAT1, STAT3 and STAT5 activity upon cytokine stimulation [XREF_BIBR].	5	16	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	5	6	13	14
SOCS3 strongly suppresses STAT3 activity through IL-6 signaling XREF_BIBR .	SOCS3 strongly suppresses STAT3 activity through IL-6 signaling XREF_BIBR.	0	4	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	3	4
XREF_BIBR SOCS3 inhibits STAT3 activation and cytokine signaling in macrophages and microglia .	XREF_BIBR SOCS3 inhibits STAT3 activation and cytokine signaling in macrophages and microglia.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	1	2	3	4
SOCS3 another member of SOCS family , inhibits STAT3 activation by gp130 , a receptor chain of IL-6R family molecules , amongst other receptors .	SOCS3 another member of SOCS family, inhibits STAT3 activation by gp130, a receptor chain of IL-6R family molecules, amongst other receptors.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	8	9
As SOCS3 inhibits STAT3 signaling , the critical signaling pathway in Th17 cell differentiation , deletion of SOCS3 promotes Th17 cell generation .	As SOCS3 inhibits STAT3 signaling, the critical signaling pathway in Th17 cell differentiation, deletion of SOCS3 promotes Th17 cell generation.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	1	2	3	4
SOCS3 is known to block STAT3 signaling and inhibit Th17 differentiation .	SOCS3 is known to block STAT3 signaling and inhibit Th17 differentiation.	0	8	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	5	6
We hypothesized that following ischemia and reperfusion ( I/R ) : 1 ) endogenous testosterone decreases myocardial STAT3 and SOCS3 in males ; 2 ) administration of exogenous testosterone reduces myocardial STAT3 and SOCS3 in female and castrated male hearts .	We hypothesized that following ischemia and reperfusion (I/R) : 1) endogenous testosterone decreases myocardial STAT3 and SOCS3 in males; 2) administration of exogenous testosterone reduces myocardial STAT3 and SOCS3 in female and castrated male hearts.	15	33	reduces	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	19	20	31	32
STAT3 activation was suppressed by SOCS3 overexpression .	STAT3 activation was suppressed by SOCS3 overexpression.	0	7	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 overexpression	socs3	STAT3	STAT3	stat3	5	6	0	1
Transfection of these cells with the STAT3 UTR sequences fused with luciferase reporter gene showed about 40 % reduction in the luciferase activity , and since SOCS3 is a feedback inhibitor of STAT3 , these results imply that miR-125b affects SOCS3 expression by inhibiting STAT3 [ XREF_BIBR ] .	Transfection of these cells with the STAT3 UTR sequences fused with luciferase reporter gene showed about 40% reduction in the luciferase activity, and since SOCS3 is a feedback inhibitor of STAT3, these results imply that miR-125b affects SOCS3 expression by inhibiting STAT3 [XREF_BIBR].	26	33	is a feedback inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	26	27	32	33
Uptake of SOCS3 containing MPs by AECs inhibits target cell STAT3 activation .	Uptake of SOCS3 containing MPs by AECs inhibits target cell STAT3 activation.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	2	3	10	11
In addition , separate silencing of SOCS1 and SOCS3 rescued the STAT3 activity repressed by miR-196b-5p knockdown , which was more obvious when SOCS1 and SOCS3 were simultaneously silenced ( XREF_SUPPLEMENTARY ) , demonstrating that SOCS1 and SOCS3 were functional effectors of miR-196b-5p on regulating STAT3 signaling .	In addition, separate silencing of SOCS1 and SOCS3 rescued the STAT3 activity repressed by miR-196b-5p knockdown, which was more obvious when SOCS1 and SOCS3 were simultaneously silenced (XREF_SUPPLEMENTARY), demonstrating that SOCS1 and SOCS3 were functional effectors of miR-196b-5p on regulating STAT3 signaling.	4	12	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	8	9	11	12
SOCS3 specifically inhibits IL-6-induced STAT3 activation by binding to the STAT3 docking site ( Tyr759 ) in one of the components of the IL-6 receptor , gp130 XREF_BIBR , XREF_BIBR .	SOCS3 specifically inhibits IL-6-induced STAT3 activation by binding to the STAT3 docking site (Tyr759) in one of the components of the IL-6 receptor, gp130 XREF_BIBR, XREF_BIBR.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	4	5
These studies , including our recent study [ XREF_BIBR ] , have demonstrated that cytokine- or nerve injury induced SOCS3 expression negatively regulates the activity of STAT3 , consequently leading to reductions in neuroprotection and neurite outgrowth .	These studies, including our recent study [XREF_BIBR], have demonstrated that cytokine- or nerve injury induced SOCS3 expression negatively regulates the activity of STAT3, consequently leading to reductions in neuroprotection and neurite outgrowth.	19	27	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	19	20	26	27
However , it is very unlikely that this kinase is involved , as SOCS3 adenovirus did not inhibit STAT3 activation by the core ( see XREF_FIG D ) .	However, it is very unlikely that this kinase is involved, as SOCS3 adenovirus did not inhibit STAT3 activation by the core (see XREF_FIG D).	13	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	13	14	18	19
High levels of SOCS3 inhibit STAT3 activation and reduce the generation of Th17 cells while the absence of SOCS3 enhances STAT3 phosphorylation and Th17 development XREF_BIBR , XREF_BIBR .	High levels of SOCS3 inhibit STAT3 activation and reduce the generation of Th17 cells while the absence of SOCS3 enhances STAT3 phosphorylation and Th17 development XREF_BIBR, XREF_BIBR.	16	22	enhances	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	SOCS3	SOCS3	socs3	STAT3	STAT3 phosphorylation	stat3	18	19	20	21
We have previously analysed the role of SOCS3 , a molecule that inhibits STAT3 activation after triggering of several cytokine and growth factor receptors , and found that mice devoid in SOCS3 in myeloid or lymphoid cells showed increased susceptibility to M. tuberculosis [ XREF_BIBR ] .	We have previously analysed the role of SOCS3, a molecule that inhibits STAT3 activation after triggering of several cytokine and growth factor receptors, and found that mice devoid in SOCS3 in myeloid or lymphoid cells showed increased susceptibility to M. tuberculosis [XREF_BIBR].	5	14	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	7	8	13	14
Because the overexpression of SOCS3 inhibits leptin induced activation of both STAT3 and AMPK in skeletal muscle myotubes , and because muscle specific SOCS3 transgenic mice are obese , we hypothesized that SOCS3 MKO mice might have increased muscle AMPK , elevated rates of fatty acid oxidation , and increased energy expenditure .	Because the overexpression of SOCS3 inhibits leptin induced activation of both STAT3 and AMPK in skeletal muscle myotubes, and because muscle specific SOCS3 transgenic mice are obese, we hypothesized that SOCS3 MKO mice might have increased muscle AMPK, elevated rates of fatty acid oxidation, and increased energy expenditure.	2	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	overexpression of SOCS3	socs3	STAT3	STAT3	stat3	4	5	11	12
The accumulation of SOCS3 protein has been shown to enhance SOCS3 association with JAK2 , which then promotes the ubiquitination and degradation of JAK2 , resulting in a loss of STAT3 phosphorylation and function 50 , indicating that Wwox and SOCS3 negatively regulate STAT3 activity by distinct regulatory mechanisms .	The accumulation of SOCS3 protein has been shown to enhance SOCS3 association with JAK2, which then promotes the ubiquitination and degradation of JAK2, resulting in a loss of STAT3 phosphorylation and function 50, indicating that Wwox and SOCS3 negatively regulate STAT3 activity by distinct regulatory mechanisms.	38	44	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	40	41	43	44
SOCS3 might partially mediate this effect by suppressing STAT3 activation and blocking IL-6 and IL-23 induction [ XREF_BIBR ] .	SOCS3 might partially mediate this effect by suppressing STAT3 activation and blocking IL-6 and IL-23 induction [XREF_BIBR].	0	9	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	8	9
Nonetheless , together with enhanced IL-10 gene and protein expression upon treatment with STAT3 inhibitors , our data clearly indicate that PMA induced SOCS3 expression negatively regulates STAT3 , leading to increased production of IL-10 .	Nonetheless, together with enhanced IL-10 gene and protein expression upon treatment with STAT3 inhibitors, our data clearly indicate that PMA induced SOCS3 expression negatively regulates STAT3, leading to increased production of IL-10.	23	28	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	23	24	27	28
Taken together , these data show that SOCS-3 does not inhibit Stat3 activation , growth , and survival in CTCL .	Taken together, these data show that SOCS-3 does not inhibit Stat3 activation, growth, and survival in CTCL.	7	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	Stat3	Stat3	Stat3	7	8	11	12
Therefore , it is likely that curcumin increased the expression level of SOCS1 and SOCS3 , thus inhibiting the activity of STAT3 which resulted in change of FOXA2 expression .	Therefore, it is likely that curcumin increased the expression level of SOCS1 and SOCS3, thus inhibiting the activity of STAT3 which resulted in change of FOXA2 expression.	6	22	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	curcumin increased the expression level of SOCS1 and SOCS3	socs3	STAT3	STAT3	stat3	14	15	21	22
Consistent with its role in suppressing STAT3 activation by IL-6 , SOCS3 over-expression inhibited STAT3 but not NF-kappaB activation induced by miR-K12-1 ( XREF_SUPPLEMENTARY ) .	Consistent with its role in suppressing STAT3 activation by IL-6, SOCS3 over-expression inhibited STAT3 but not NF-kappaB activation induced by miR-K12-1 (XREF_SUPPLEMENTARY).	11	18	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 over-expression	socs3	STAT3	STAT3	stat3	11	12	14	15
Collectively , these data indicate that TGF-beta inhibition of SOCS3 mainly enhances the function of IL-6 and STAT3 pathway on inhibition of Foxp3 expression .	Collectively, these data indicate that TGF-beta inhibition of SOCS3 mainly enhances the function of IL-6 and STAT3 pathway on inhibition of Foxp3 expression.	7	18	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	9	10	17	18
Results from Lentivirus mediated modulation of SOCS3 levels demonstrated that STAT3 activation , in particular of P-STAT3 Ser levels , was negatively regulated by expression of SOCS3 .	Results from Lentivirus mediated modulation of SOCS3 levels demonstrated that STAT3 activation, in particular of P-STAT3 Ser levels, was negatively regulated by expression of SOCS3.	10	27	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	expression of SOCS3	socs3	STAT3	STAT3	stat3	26	27	10	11
Moreover , the NF-kappaB driven SOCS3 expression acts as a negative regulator of STAT3 , abrogating any subsequent STAT3 activation and provides a mechanism of STAT3 inhibition following JSI-124 treatment .	Moreover, the NF-kappaB driven SOCS3 expression acts as a negative regulator of STAT3, abrogating any subsequent STAT3 activation and provides a mechanism of STAT3 inhibition following JSI-124 treatment.	3	19	abrogating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	NF-kappaB driven SOCS3 expression	socs3	STAT3	STAT3	stat3	5	6	18	19
Three independent signaling pathways , STAT3 , MEK1-ERK1/2 , and AKT activation , that are coinduced by LIF stimulation were completely suppressed by SOCS3 overexpression .	Three independent signaling pathways, STAT3, MEK1-ERK1/2, and AKT activation, that are coinduced by LIF stimulation were completely suppressed by SOCS3 overexpression.	3	25	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 overexpression	socs3	STAT3	STAT3	stat3	23	24	5	6
These modifications and rapid degradation by proteasome could be reasons for the incomplete suppression of STAT3 by CIS3 in chronic inflammation .	These modifications and rapid degradation by proteasome could be reasons for the incomplete suppression of STAT3 by CIS3 in chronic inflammation.	9	20	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	CIS3	CIS3	CIS3	STAT3	STAT3	STAT3	17	18	15	16
Furthermore , the decrease of SOCS3 increased activation of STAT3 .	Furthermore, the decrease of SOCS3 increased activation of STAT3.	3	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	5	6	9	10
Consequently , we determined whether SOCS3 also inhibited STAT3 mediated induction of Arg1 expression after infection with BCG .	Consequently, we determined whether SOCS3 also inhibited STAT3 mediated induction of Arg1 expression after infection with BCG.	5	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	5	6	8	9
SOCS3 negatively regulates STAT3 activation , which in turn inhibits IL-6-induced neuritic outgrowth in vitro .	SOCS3 negatively regulates STAT3 activation, which in turn inhibits IL-6-induced neuritic outgrowth in vitro.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	3	4
On the other hand , to confirm our finding that human SOCS-3 was an interacting protein of DP-1 , approaching the question from another angle , we investigated whether DP-1 could eliminate the inhibitory action of SOCS-3 toward LIF stimulated STAT3 transcriptional activity in JAK-STAT signaling .	On the other hand, to confirm our finding that human SOCS-3 was an interacting protein of DP-1, approaching the question from another angle, we investigated whether DP-1 could eliminate the inhibitory action of SOCS-3 toward LIF stimulated STAT3 transcriptional activity in JAK-STAT signaling.	34	42	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	STAT3	STAT3	STAT3	36	37	40	41
Therefore , following JSI-124 treatment , the NF-kappaB driven SOCS3 expression acts as a negative regulator of STAT3 , abrogating any subsequent STAT3 activation and provides a mechanism of STAT3 inhibition ( XREF_FIG ) .	Therefore, following JSI-124 treatment, the NF-kappaB driven SOCS3 expression acts as a negative regulator of STAT3, abrogating any subsequent STAT3 activation and provides a mechanism of STAT3 inhibition (XREF_FIG).	7	23	abrogating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	NF-kappaB driven SOCS3 expression	socs3	STAT3	STAT3	stat3	9	10	22	23
SOCS3 Preserves Rhodopsin and Inhibits STAT3 Activation following IL-6 Exposure in Adult Retinal Explants -- To investigate the mechanism of decrease in rhodopsin during inflammation , we utilized retinal explants derived from adult retinas ( adult retinal explants ) .	SOCS3 Preserves Rhodopsin and Inhibits STAT3 Activation following IL-6 Exposure in Adult Retinal Explants -- To investigate the mechanism of decrease in rhodopsin during inflammation, we utilized retinal explants derived from adult retinas (adult retinal explants).	0	6	Inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	5	6
Particularly , SOCS3 , whose expression is induced by both NF-kappaB and STAT3 , binds to the gp130 receptor subunit and prevents further cytokine dependent activation of STAT3 .	Particularly, SOCS3, whose expression is induced by both NF-kappaB and STAT3, binds to the gp130 receptor subunit and prevents further cytokine dependent activation of STAT3.	2	28	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	2	3	27	28
Therefore we initially hypothesized that SOCS3 is likely to directly impact on flagellin induced transcription factor binding ; however , SOCS3 does not appear to be limiting NF-kappaB or STAT3 activation in response to TLR5 ligation .	Therefore we initially hypothesized that SOCS3 is likely to directly impact on flagellin induced transcription factor binding; however, SOCS3 does not appear to be limiting NF-kappaB or STAT3 activation in response to TLR5 ligation.	20	30	limiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	20	21	29	30
STAT3 activates the transcription of SOCS3 which can block STAT3 signalling either by direct binding and inhibition of JAKs , by competing with STAT3 for pY binding sites on activated receptor chains , or by binding signalling proteins and targeting them for proteasomal degradation [ XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	STAT3 activates the transcription of SOCS3 which can block STAT3 signalling either by direct binding and inhibition of JAKs, by competing with STAT3 for pY binding sites on activated receptor chains, or by binding signalling proteins and targeting them for proteasomal degradation [XREF_BIBR, XREF_BIBR] (XREF_FIG).	0	10	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	STAT3 activates the transcription of SOCS3	socs3	STAT3	STAT3	stat3	5	6	9	10
Similarly , deletion of Socs3 using T3b-Cre also led to gastric tumor development , mediated via enhanced leptin induced STAT3 activation .	Similarly, deletion of Socs3 using T3b-Cre also led to gastric tumor development, mediated via enhanced leptin induced STAT3 activation.	2	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	4	5	19	20
Quercetin treatment for 24h dose-dependently upregulated the decreased p-Jak2 and p-Stat3 ( XREF_FIG ) , as well as reduced Socs3 expression ( XREF_FIG ) in fructose incubated INS-1 beta-cells .	Quercetin treatment for 24h dose-dependently upregulated the decreased p-Jak2 and p-Stat3 (XREF_FIG), as well as reduced Socs3 expression (XREF_FIG) in fructose incubated INS-1 beta-cells.	5	21	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3 expression	socs3	p-Stat3	p-Stat3	p-stat3	19	20	10	11
Under physiological conditions , suppressor of cytokine signaling 3 ( SOCS3 ) , which modulates activated STAT3 via a feedback loop , fine-tunes this signal [ XREF_BIBR , XREF_BIBR ] .	Under physiological conditions, suppressor of cytokine signaling 3 (SOCS3), which modulates activated STAT3 via a feedback loop, fine-tunes this signal [XREF_BIBR, XREF_BIBR].	4	20	modulates activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	10	11	16	17
SOCS3 has been shown to block STAT3 signaling and its deletion results in enhanced generation of Th17 cells [ XREF_BIBR , XREF_BIBR ] .	SOCS3 has been shown to block STAT3 signaling and its deletion results in enhanced generation of Th17 cells [XREF_BIBR, XREF_BIBR].	0	7	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	6	7
Together these observations form the first endogenous study to demonstrate that the SOCS3 SOCS box targets phosphorylated JAK1 for proteasomal degradation and that SOCS3 negatively regulates JAK1 and STAT3 signaling by sequestering phosphorylated JAK1 from the receptor as a means of terminating STAT3 activation .	Together these observations form the first endogenous study to demonstrate that the SOCS3 SOCS box targets phosphorylated JAK1 for proteasomal degradation and that SOCS3 negatively regulates JAK1 and STAT3 signaling by sequestering phosphorylated JAK1 from the receptor as a means of terminating STAT3 activation.	23	29	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	23	24	28	29
These results suggested that SOCS3 may inhibit the HG induced upregulation of JAK2 and STAT3 proteins , adhesion molecules and cytokines in the lungs , thus suggesting a critical role for the SOCS3/JAK2/STAT3 pathway during the inflammatory responses to hyperglycemia .	These results suggested that SOCS3 may inhibit the HG induced upregulation of JAK2 and STAT3 proteins, adhesion molecules and cytokines in the lungs, thus suggesting a critical role for the SOCS3/JAK2/STAT3 pathway during the inflammatory responses to hyperglycemia.	4	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	4	5	14	15
Overexpression of SOCS3 blocks nuclear translocation of STAT3 and neurite outgrowth , and inhibition of endogenous SOCS3 through overexpression of a dominant negative mutant SOCS3 stimulates neurite outgrowth .	Overexpression of SOCS3 blocks nuclear translocation of STAT3 and neurite outgrowth, and inhibition of endogenous SOCS3 through overexpression of a dominant negative mutant SOCS3 stimulates neurite outgrowth.	0	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	Overexpression of SOCS3	socs3	STAT3	STAT3	stat3	2	3	7	8
SOCS3 , which primarily inhibits STAT3 signaling , was significantly 14-fold higher in aUC and 6-fold higher in aCD compared to NS ( XREF_FIG ) .	SOCS3, which primarily inhibits STAT3 signaling, was significantly 14-fold higher in aUC and 6-fold higher in aCD compared to NS (XREF_FIG).	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	5	6
Previously , we demonstrated that the SOCS3 lentivirus can efficiently suppress activation of STAT3 .	Previously, we demonstrated that the SOCS3 lentivirus can efficiently suppress activation of STAT3.	6	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	6	7	13	14
This finding was interpreted as a JAK and STAT driven increase in proteolytic degradation of SOCS3 , which would in turn lead to persistent STAT3 signaling in the muscle because SOCS3 inhibits STAT3 .	This finding was interpreted as a JAK and STAT driven increase in proteolytic degradation of SOCS3, which would in turn lead to persistent STAT3 signaling in the muscle because SOCS3 inhibits STAT3.	30	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	30	31	32	33
Taken together , these observations suggest that SOCS3 may not be present in sufficient quantities to inhibit STAT3 activation in cachectic muscle .	Taken together, these observations suggest that SOCS3 may not be present in sufficient quantities to inhibit STAT3 activation in cachectic muscle.	7	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	7	8	17	18
In Teffs , Socs3 inhibited STAT4 and STAT3 signaling thereby suppressing Th1 and Th17 responses and favoring Th2 differentiation XREF_BIBR .	In Teffs, Socs3 inhibited STAT4 and STAT3 signaling thereby suppressing Th1 and Th17 responses and favoring Th2 differentiation XREF_BIBR.	3	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	3	4	7	8
STAT3 activation is essential for the differentiation and polarization of M2 macrophages [ XREF_BIBR , XREF_BIBR ] and SOCS3 inhibits the activation of the STAT3 pathway .	STAT3 activation is essential for the differentiation and polarization of M2 macrophages [XREF_BIBR, XREF_BIBR] and SOCS3 inhibits the activation of the STAT3 pathway.	13	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	18	19	24	25
SOCS3 overexpression prevented the nuclear accumulation of STAT3 and GFAP upregulation in mouse models of ND .	SOCS3 overexpression prevented the nuclear accumulation of STAT3 and GFAP upregulation in mouse models of ND.	0	10	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 overexpression	socs3	STAT3	STAT3	stat3	0	1	7	8
To explore the importance of this feedback loop in neovascularization , we broke down the positive feedback loop through subretinal injection of lentivirus expressing SOCS3 , which inhibited STAT3 activation in Vldlr -/- retinas .	To explore the importance of this feedback loop in neovascularization, we broke down the positive feedback loop through subretinal injection of lentivirus expressing SOCS3, which inhibited STAT3 activation in Vldlr -/- retinas.	23	29	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	24	25	28	29
9 However , SOCS3 does not directly inhibit STAT3 but acts in a receptor specific manner , through interference between gp130 and JAK activation .	9 However, SOCS3 does not directly inhibit STAT3 but acts in a receptor specific manner, through interference between gp130 and JAK activation.	3	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	3	4	8	9
On the one hand , when expressed in cancer cells and MDSC precursors , SOCS3 can promote antitumor immunity by blocking the effects of STAT3 inducing , immunosuppressive cytokines .	On the one hand, when expressed in cancer cells and MDSC precursors, SOCS3 can promote antitumor immunity by blocking the effects of STAT3 inducing, immunosuppressive cytokines.	14	28	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	14	15	24	25
Conversely , Stat3 can be inhibited by Socs3 , as a result of IFN and TLR signaling and Notch activation .	Conversely, Stat3 can be inhibited by Socs3, as a result of IFN and TLR signaling and Notch activation.	2	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Socs3	Socs3	Socs3	Stat3	Stat3	Stat3	7	8	2	3
Our analysis shows that SOCS3 inhibits STAT3 activation via JAK1 [ XREF_BIBR ] .	Our analysis shows that SOCS3 inhibits STAT3 activation via JAK1 [XREF_BIBR].	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	4	5	6	7
We found that CIS3 was induced as colitis developed , whereas a high level of CIS3 expression rather suppressed STAT3 activation .	We found that CIS3 was induced as colitis developed, whereas a high level of CIS3 expression rather suppressed STAT3 activation.	15	20	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIS3	CIS3 expression	cis3	STAT3	STAT3	stat3	15	16	19	20
XREF_BIBR Deletion of Socs3 using mb1-Cre was found to prolong IL-6-induced STAT3 activation in plasma cells and alter germinal center function following T cell dependent immunization .	XREF_BIBR Deletion of Socs3 using mb1-Cre was found to prolong IL-6-induced STAT3 activation in plasma cells and alter germinal center function following T cell dependent immunization.	1	12	prolong	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	3	4	11	12
SOCS3 negatively regulates the STAT3 pathway [ XREF_BIBR ] .	SOCS3 negatively regulates the STAT3 pathway [XREF_BIBR].	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	4	5
In naive CD45RA T-cells , IFNbeta also induces SOCS3 which inhibits STAT3 cell signaling and a subsequent expression of the Th17-cell master regulatory transcription factor RORc .	In naive CD45RA T-cells, IFNbeta also induces SOCS3 which inhibits STAT3 cell signaling and a subsequent expression of the Th17-cell master regulatory transcription factor RORc.	7	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	8	9	11	12
Additionally , the transcription and translation of the STAT3 target gene SOCS3 was attenuated by CK2 inhibition , supporting the functional consequences of STAT3 inhibition .	Additionally, the transcription and translation of the STAT3 target gene SOCS3 was attenuated by CK2 inhibition, supporting the functional consequences of STAT3 inhibition.	3	24	supporting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	transcription and translation of the STAT3 target gene SOCS3	socs3	STAT3	STAT3	stat3	11	12	23	24
In addition , SOCS3 in neurons has been reported to inhibit cytokine induced STAT3 activation and the inducible gene , Bcl-xL , while inhibition of SOCS3 enhances STAT3 activation .	In addition, SOCS3 in neurons has been reported to inhibit cytokine induced STAT3 activation and the inducible gene, Bcl-xL, while inhibition of SOCS3 enhances STAT3 activation.	23	28	enhances	Positive_activation_syntax_3a_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	25	26	27	28
TGF-beta inhibits IL-6-induced SOCS3 expression and enhances STAT3 activation .	TGF-beta inhibits IL-6-induced SOCS3 expression and enhances STAT3 activation.	0	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	TGF-beta inhibits IL-6-induced SOCS3 expression	socs3	STAT3	STAT3	stat3	3	4	7	8
Socs3 protein antagonizes the activation of stat3 in the cytosol as a negative feedback .	Socs3 protein antagonizes the activation of stat3 in the cytosol as a negative feedback.	0	7	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3	Socs3	stat3	stat3	stat3	0	1	6	7
Consistent with a role for the JAK and STAT pathway , loss of Socs1 and Socs3 ( suppressors of cytokine signaling ) expression results in increased activation of STAT1 , STAT3 and NFKB and development of colorectal tumors .	Consistent with a role for the JAK and STAT pathway, loss of Socs1 and Socs3 (suppressors of cytokine signaling) expression results in increased activation of STAT1, STAT3 and NFKB and development of colorectal tumors.	11	31	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Socs3	loss of Socs1 and Socs3	socs3	STAT3	STAT3	stat3	15	16	30	31
This has led to the concept that differential SOCS3 sensitivity restricts pSTAT3 signaling by IL-6 and distinguishes the pro- and anti-inflammatory effects of IL-6 and IL-10 respectively .	This has led to the concept that differential SOCS3 sensitivity restricts pSTAT3 signaling by IL-6 and distinguishes the pro- and anti-inflammatory effects of IL-6 and IL-10 respectively.	8	12	restricts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	pSTAT3	pSTAT3	pSTAT3	8	9	11	12
We show that upregulation of Socs3 in POMC neurons inhibits pSTAT3 and mTOR pathways concurrently , which precedes the onset of weight gain .	We show that upregulation of Socs3 in POMC neurons inhibits pSTAT3 and mTOR pathways concurrently, which precedes the onset of weight gain.	3	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3	Socs3	pSTAT3	pSTAT3	pSTAT3	5	6	10	11
IFN-gamma and the TLR4 ligands activate the synthesis of SOCS3 , which blocks STAT3 , thereby preventing formation of the M2 phenotype [ XREF_BIBR ] ( XREF_FIG ) .	IFN-gamma and the TLR4 ligands activate the synthesis of SOCS3, which blocks STAT3, thereby preventing formation of the M2 phenotype [XREF_BIBR] (XREF_FIG).	7	14	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	9	10	13	14
Notably , SOCS3 overexpression was demonstrated to attenuate the HG induced increases in p-JAK2 and p-STAT3 , showing that SOCS3 , which are negative regulators of the JAK2 and STAT3 signaling pathway , are involved in hyperglycemia induced cell responses during the development of diabetic lung injury .	Notably, SOCS3 overexpression was demonstrated to attenuate the HG induced increases in p-JAK2 and p-STAT3, showing that SOCS3, which are negative regulators of the JAK2 and STAT3 signaling pathway, are involved in hyperglycemia induced cell responses during the development of diabetic lung injury.	2	16	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 overexpression	socs3	p-STAT3	p-STAT3	p-stat3	2	3	15	16
Taken together , all the results indicated that SOCS3 promoted lipid synthesis in mice liver and promoted hepatocyte apoptosis by inhibiting the activation of the JAK2 and STAT3 signaling pathway , however the detailed regulation mechanism had not yet been fully understood and needs further study .	Taken together, all the results indicated that SOCS3 promoted lipid synthesis in mice liver and promoted hepatocyte apoptosis by inhibiting the activation of the JAK2 and STAT3 signaling pathway, however the detailed regulation mechanism had not yet been fully understood and needs further study.	8	29	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	8	9	27	28
In vitro , SOCS3 overexpression abrogated IL-6-induced activation of STAT3 in lung epithelial cells .	In vitro, SOCS3 overexpression abrogated IL-6-induced activation of STAT3 in lung epithelial cells.	3	10	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 overexpression	socs3	STAT3	STAT3	stat3	3	4	9	10
Interestingly , activation of STAT3 can upregulate the gene expression of Socs3 , which can in turn inhibit STAT3 activity and impede axonal sprouting and regeneration XREF_BIBR , possibly serving as a negative feedback to STAT3 activation to fine-tune its regulation in astrogliosis and axon regrowth after injury .	Interestingly, activation of STAT3 can upregulate the gene expression of Socs3, which can in turn inhibit STAT3 activity and impede axonal sprouting and regeneration XREF_BIBR, possibly serving as a negative feedback to STAT3 activation to fine-tune its regulation in astrogliosis and axon regrowth after injury.	9	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	expression of Socs3	socs3	STAT3	STAT3	stat3	11	12	18	19
In rats with streptozotocin induced diabetes , SOCS1 and SOCS3 gene overexpression via adenovirus injection have been shown to decrease the activation of STAT1 and STAT3 in the kidney and expression of proinflammatory and profibrotic cytokines [ XREF_BIBR ] .	In rats with streptozotocin induced diabetes, SOCS1 and SOCS3 gene overexpression via adenovirus injection have been shown to decrease the activation of STAT1 and STAT3 in the kidney and expression of proinflammatory and profibrotic cytokines [XREF_BIBR].	7	26	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 gene overexpression	socs3	STAT3	STAT3	stat3	9	10	25	26
After activation , the repressor protein SOCS3 can block any further activation of STAT-3 through negative regulation .	After activation, the repressor protein SOCS3 can block any further activation of STAT-3 through negative regulation.	3	14	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT-3	STAT-3	STAT-3	6	7	13	14
We observed decreased STAT3 and suppressor of cytokine signaling 3 ( SOCS3 ) in male hearts , which was associated with worse post-ischemic myocardial function compared to females .	We observed decreased STAT3 and suppressor of cytokine signaling 3 (SOCS3) in male hearts, which was associated with worse post-ischemic myocardial function compared to females.	2	10	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	STAT3	5	10	3	4
Recent studies have revealed that SOCS3 determines the gene program activated by IL-6 , and upregulated SOCS3 may help enhance a blockade of STAT3 signaling [ XREF_BIBR ] .	Recent studies have revealed that SOCS3 determines the gene program activated by IL-6, and upregulated SOCS3 may help enhance a blockade of STAT3 signaling [XREF_BIBR].	16	26	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	16	17	23	24
To further examine the possibility that TGF-beta inhibits SOCS3 expression and thus enhances STAT3 activation , we determined SOCS3 expression and STAT3 activation in CD4 + T cells from TGFbetaRII dominant negative transgenic ( TGFbetaRII DN ) mice , whose TGF-beta signaling is greatly impaired .	To further examine the possibility that TGF-beta inhibits SOCS3 expression and thus enhances STAT3 activation, we determined SOCS3 expression and STAT3 activation in CD4 + T cells from TGFbetaRII dominant negative transgenic (TGFbetaRII DN) mice, whose TGF-beta signaling is greatly impaired.	6	14	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	TGF-beta inhibits SOCS3 expression	socs3	STAT3	STAT3	stat3	8	9	13	14
Overexpression of SOCS3 nearly abolished IL-22-induced activation of STAT3 .	Overexpression of SOCS3 nearly abolished IL-22-induced activation of STAT3.	0	9	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	Overexpression of SOCS3	socs3	STAT3	STAT3	stat3	2	3	8	9
SOCS3 is known to negatively regulate STAT3 activity [ XREF_BIBR ] .	SOCS3 is known to negatively regulate STAT3 activity [XREF_BIBR].	0	7	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	6	7
TGF-beta inhibits IL-21-induced SOCS3 expression and enhances STAT3 activation .	TGF-beta inhibits IL-21-induced SOCS3 expression and enhances STAT3 activation.	0	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	TGF-beta inhibits IL-21-induced SOCS3 expression	socs3	STAT3	STAT3	stat3	3	4	7	8
Consistent with this finding , Qin et al demonstrated that TGF beta mediated inhibition of SOCS3 prolongs STAT3 activation and may promote Th17 differentiation XREF_BIBR .	Consistent with this finding, Qin et al demonstrated that TGF beta mediated inhibition of SOCS3 prolongs STAT3 activation and may promote Th17 differentiation XREF_BIBR.	13	18	prolongs	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	15	16	17	18
Cell lines constitutively overexpressing SOCS proteins demonstrated that SOCS1 and SOCS3 , but not SOCS2 , are able to partially inhibit IL-10-mediated STAT3 activation and proliferative responses .	Cell lines constitutively overexpressing SOCS proteins demonstrated that SOCS1 and SOCS3, but not SOCS2, are able to partially inhibit IL-10-mediated STAT3 activation and proliferative responses.	8	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	10	11	22	23
To explore this , we examined whether DP-1 could block the SOCS-3 inhibition of LIF stimulated STAT3 transcriptional activity by conducting a luciferase assay with a reporter plasmid bearing the APRE promoter and luciferase gene .	To explore this, we examined whether DP-1 could block the SOCS-3 inhibition of LIF stimulated STAT3 transcriptional activity by conducting a luciferase assay with a reporter plasmid bearing the APRE promoter and luciferase gene.	11	18	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	STAT3	STAT3	STAT3	11	12	16	17
The overexpressed SOCS3 , upregulated by STAT3 activation , then negatively regulates activation of STAT3 , which in turn decreases levels of both P-STAT3 Tyr in the cytosol and P-STAT3 Ser in mitochondria ( XREF_FIG ) .	The overexpressed SOCS3, upregulated by STAT3 activation, then negatively regulates activation of STAT3, which in turn decreases levels of both P-STAT3 Tyr in the cytosol and P-STAT3 Ser in mitochondria (XREF_FIG).	0	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	2	3	14	15
In contrast , DP-1 almost completely eliminated the inhibitory action of SOCS-3 on LIF stimulated STAT-3 transcriptional activity in JAK-STAT signaling .	In contrast, DP-1 almost completely eliminated the inhibitory action of SOCS-3 on LIF stimulated STAT-3 transcriptional activity in JAK-STAT signaling.	9	17	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	STAT-3	STAT-3	STAT-3	11	12	15	16
In mammals , there is a self-restrictive feedback mechanism between stat3 and socs3 : stat3 activates the transcription of socs3 , which in turn , antagonizes stat3 activation .	In mammals, there is a self-restrictive feedback mechanism between stat3 and socs3 : stat3 activates the transcription of socs3, which in turn, antagonizes stat3 activation.	14	27	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	socs3	stat3 activates the transcription of socs3	socs3	stat3	stat3	stat3	19	20	26	27
Therefore , SOCS3 enhances degradation of all receptor states and inhibits the STAT3 activating reaction converting STAT3 to pSTAT3 .	Therefore, SOCS3 enhances degradation of all receptor states and inhibits the STAT3 activating reaction converting STAT3 to pSTAT3.	2	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	2	3	12	13
Socs3 expression is induced by Stat3 signaling and binds to the leptin receptor , blocking Stat3 activation [ XREF_BIBR ; XREF_BIBR ] .	Socs3 expression is induced by Stat3 signaling and binds to the leptin receptor, blocking Stat3 activation [XREF_BIBR; XREF_BIBR].	0	16	blocking	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3 expression is induced by Stat3 signaling and binds to the leptin receptor	socs3	Stat3	Stat3	stat3	0	1	15	16
Exogenous expression of SOCS1 , SOCS3 , and SOCS5 in the highly aggressive anaplastic thyroid cancer cells abolished the activation of STAT3 signaling pathway activation resulting in alteration in the balance of proapoptotic and antiapoptotic molecules and sensitization to chemotherapeutic drugs in vitro [ XREF_BIBR ] .	Exogenous expression of SOCS1, SOCS3, and SOCS5 in the highly aggressive anaplastic thyroid cancer cells abolished the activation of STAT3 signaling pathway activation resulting in alteration in the balance of proapoptotic and antiapoptotic molecules and sensitization to chemotherapeutic drugs in vitro [XREF_BIBR].	1	24	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	expression of SOCS1, SOCS3	socs3	STAT3	STAT3	stat3	5	6	21	22
In another study , periarticular injection of the SOCS3 adenovirus into the ankle joints of mice with arthritis drastically suppressed STAT3 activation and reduced the severity of arthritis and joint swelling compared with control groups .	In another study, periarticular injection of the SOCS3 adenovirus into the ankle joints of mice with arthritis drastically suppressed STAT3 activation and reduced the severity of arthritis and joint swelling compared with control groups.	8	21	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	8	9	20	21
ROP16 activated STAT3 , which stimulated SOCS3 expression that in turn diminished STAT3 activation .	ROP16 activated STAT3, which stimulated SOCS3 expression that in turn diminished STAT3 activation.	0	13	diminished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	ROP16 activated STAT3, which stimulated SOCS3 expression	socs3	STAT3	STAT3	stat3	6	7	12	13
On the contrary to miR-185 ' s protective effects , SOCS3 significantly suppressed functions of beta-cell and inactivated Stat3 pathway .	On the contrary to miR-185 's protective effects, SOCS3 significantly suppressed functions of beta-cell and inactivated Stat3 pathway.	10	19	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	Stat3	Stat3	Stat3	10	11	18	19
Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury .	Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury.	0	8	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	6	7	1	2
Thus , elevated expression of SOCS3 blocks the JAK and STAT3 pathway and thereby limits some of the physiological consequences of STAT3 mediated signalling [ XREF_BIBR , XREF_BIBR ] .	Thus, elevated expression of SOCS3 blocks the JAK and STAT3 pathway and thereby limits some of the physiological consequences of STAT3 mediated signalling [XREF_BIBR, XREF_BIBR].	3	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	expression of SOCS3	socs3	STAT3	STAT3	stat3	5	6	10	11
However , such elimination was not observed for SOCS-3 ( Delta156-172 )-mediated inhibition of the STAT3 transcriptional activity , because SOCS-3 ( Delta156-172 ) is not able to bind to DP-1 ( XREF_FIG , lane 18 ) .	However, such elimination was not observed for SOCS-3 (Delta156-172)-mediated inhibition of the STAT3 transcriptional activity, because SOCS-3 (Delta156-172) is not able to bind to DP-1 (XREF_FIG, lane 18).	6	26	inhibition	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	STAT3	STAT3	STAT3	8	9	15	16
Because deletion of SOCS3 has been shown to prolong activation of STAT1 and STAT3 following IL-6 stimulation , thereby enhancing inflammatory responses , we wondered whether a similar mechanism was operating in our cocultures .	Because deletion of SOCS3 has been shown to prolong activation of STAT1 and STAT3 following IL-6 stimulation, thereby enhancing inflammatory responses, we wondered whether a similar mechanism was operating in our cocultures.	1	14	prolong	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	3	4	13	14
Our data demonstrated that restoration of SOCS3 , which inhibits the JAK and STAT3 pathway , by AFP-D55-SOCS3 not only could antagonize HCC therapeutic resistance to TRAIL and adenoviruses , but could also induce cell cycle arrest in HCC cell lines .	Our data demonstrated that restoration of SOCS3, which inhibits the JAK and STAT3 pathway, by AFP-D55-SOCS3 not only could antagonize HCC therapeutic resistance to TRAIL and adenoviruses, but could also induce cell cycle arrest in HCC cell lines.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	6	7	13	14
Activated STAT3 has been reported to directly upregulate TGF-beta1 promoter activity , and SOCS3 is known to negatively regulate STAT3 activation .	Activated STAT3 has been reported to directly upregulate TGF-beta1 promoter activity, and SOCS3 is known to negatively regulate STAT3 activation.	13	20	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	13	14	19	20
Biological relevance is shown by the observation that overexpression of SOCS3 when K140 can not be methylated blocks the ability of cells to activate STAT3 in response to IL-6 .	Biological relevance is shown by the observation that overexpression of SOCS3 when K140 can not be methylated blocks the ability of cells to activate STAT3 in response to IL-6.	8	26	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	overexpression of SOCS3	socs3	STAT3	STAT3	stat3	10	11	24	25
Transgenic upregulation of SOCS3 in POMC neurons not only inhibits STAT3 signaling but also suppresses other signaling pathways , including mTOR signaling [ XREF_BIBR ] .	Transgenic upregulation of SOCS3 in POMC neurons not only inhibits STAT3 signaling but also suppresses other signaling pathways, including mTOR signaling [XREF_BIBR].	1	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	3	4	10	11
STAT3 , SOCS3 ( repressor of STAT3 ) , and nuclear factor kappaB ( NF-kappaB ) are among the key molecules previously shown to regulate astrogliosis and lesion size after spinal cord injury .	STAT3, SOCS3 (repressor of STAT3), and nuclear factor kappaB (NF-kappaB) are among the key molecules previously shown to regulate astrogliosis and lesion size after spinal cord injury.	0	7	repressor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	2	3	6	7
We show that Socs3 upregulation in POMC neurons antagonizes pSTAT3 and mTOR-S6K signaling with subsequent leptin resistance and obesity .	We show that Socs3 upregulation in POMC neurons antagonizes pSTAT3 and mTOR-S6K signaling with subsequent leptin resistance and obesity.	3	12	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3	Socs3	pSTAT3	pSTAT3	pSTAT3	3	4	9	10
Therefore , in this study , we hypothesized that : 1 ) endogenous testosterone will decrease myocardial STAT3 activation and SOCS3 expression in male hearts following I/R ; 2 ) administration of exogenous testosterone will reduce myocardial STAT3 and SOCS3 in female and castrated male hearts in response to acute I/R .	Therefore, in this study, we hypothesized that : 1) endogenous testosterone will decrease myocardial STAT3 activation and SOCS3 expression in male hearts following I/R; 2) administration of exogenous testosterone will reduce myocardial STAT3 and SOCS3 in female and castrated male hearts in response to acute I/R.	20	39	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	20	21	37	38
Based on the evidence that forced expression of CIS3 can inhibit IL-6-mediated STAT3 activation , CIS3 , which is induced by STAT3 activation , acts as a negative feedback regulator of STAT3 .	Based on the evidence that forced expression of CIS3 can inhibit IL-6-mediated STAT3 activation, CIS3, which is induced by STAT3 activation, acts as a negative feedback regulator of STAT3.	6	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIS3	expression of CIS3	cis3	STAT3	STAT3	stat3	8	9	12	13
SOCS1 and SOCS3 reciprocally inhibit STAT1 and STAT3 signaling with SOCS1 preferential inhibition of IFN-gamma signaling and SOCS3 preferential inhibition of IL-6 signaling in the liver [ XREF_BIBR ] .	SOCS1 and SOCS3 reciprocally inhibit STAT1 and STAT3 signaling with SOCS1 preferential inhibition of IFN-gamma signaling and SOCS3 preferential inhibition of IL-6 signaling in the liver [XREF_BIBR].	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	2	3	7	8
In addition , SOCS3 blocks STAT3 signaling and consequently inhibits Th17 polarization [ XREF_BIBR ] .	In addition, SOCS3 blocks STAT3 signaling and consequently inhibits Th17 polarization [XREF_BIBR].	3	9	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	3	4	5	6
SOCS3 efficiently suppressed STAT3 and STAT5 activation by WT G-CSF-R in luciferase reporter assays .	SOCS3 efficiently suppressed STAT3 and STAT5 activation by WT G-CSF-R in luciferase reporter assays.	0	6	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	3	4
First , the cytokine inducible SOCS1 and SOCS3 that inhibits STAT1 and STAT3 activation through direct binding to signaling complexes were elevated in UC and CD thus establishing potential feedback inhibition to signal transduction .	First, the cytokine inducible SOCS1 and SOCS3 that inhibits STAT1 and STAT3 activation through direct binding to signaling complexes were elevated in UC and CD thus establishing potential feedback inhibition to signal transduction.	5	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	7	8	12	13
Socs3 , suppressor of cytokine signaling-3 , is preferentially expressed in Th2 cells XREF_BIBR and inhibits Th1 and Th17 differentiation by suppressing STAT4 and STAT3 activation , respectively XREF_BIBR XREF_BIBR .	Socs3, suppressor of cytokine signaling-3, is preferentially expressed in Th2 cells XREF_BIBR and inhibits Th1 and Th17 differentiation by suppressing STAT4 and STAT3 activation, respectively XREF_BIBR XREF_BIBR.	0	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3, suppressor of cytokine signaling-3, is preferentially expressed	socs3	STAT3	STAT3	stat3	0	1	24	25
In addition , overexpression of SOCS-3 in the pro B cell line effectively blocked STAT3 activation induced by IL-11 .	In addition, overexpression of SOCS-3 in the pro B cell line effectively blocked STAT3 activation induced by IL-11.	3	15	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	overexpression of SOCS-3	socs-3	STAT3	STAT3	stat3	5	6	14	15
Thus , it is highly possible that expression of CIS3 negatively regulates the pathogenesis of inflammation by modulating STAT3 activity .	Thus, it is highly possible that expression of CIS3 negatively regulates the pathogenesis of inflammation by modulating STAT3 activity.	7	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIS3	expression of CIS3	cis3	STAT3	STAT3	stat3	9	10	18	19
SOCS3 and PTB1B inhibit STAT3 using feedback inhibition .	SOCS3 and PTB1B inhibit STAT3 using feedback inhibition.	0	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	4	5
Consistent with previous reports , we show here that the cardiac specific deletion of SOCS3 induced a sustained activation of STAT3 and reduced myocardial apoptosis that prevented IRI in mice .	Consistent with previous reports, we show here that the cardiac specific deletion of SOCS3 induced a sustained activation of STAT3 and reduced myocardial apoptosis that prevented IRI in mice.	12	21	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	14	15	20	21
On the basis of the evidence that forced expression of SOCS3 can inhibit IL-6-mediated STAT3 activation , we propose that SOCS3 is a negative regulator of inflammatory diseases in synovial fibroblasts , especially in those in which IL-6 levels are very high .	On the basis of the evidence that forced expression of SOCS3 can inhibit IL-6-mediated STAT3 activation, we propose that SOCS3 is a negative regulator of inflammatory diseases in synovial fibroblasts, especially in those in which IL-6 levels are very high.	8	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	expression of SOCS3	socs3	STAT3	STAT3	stat3	10	11	14	15
It is well established that STAT3 activation in leptin signaling is attenuated by SOCS3 , and decrease in STAT3 activation has been considered as an indicator of leptin resistance .	It is well established that STAT3 activation in leptin signaling is attenuated by SOCS3, and decrease in STAT3 activation has been considered as an indicator of leptin resistance.	5	14	attenuated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	13	14	5	6
Loss of SOCS3 prolongs STAT3 activation in response to GL261 tumor cell conditioned medium .	Loss of SOCS3 prolongs STAT3 activation in response to GL261 tumor cell conditioned medium.	0	5	prolongs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	Loss of SOCS3	socs3	STAT3	STAT3	stat3	2	3	4	5
SOCS3 is normally increased at sites of both acute and chronic inflammation [ XREF_BIBR ] and has been shown to specifically suppress STAT3 activation [ XREF_BIBR ] .	SOCS3 is normally increased at sites of both acute and chronic inflammation [XREF_BIBR] and has been shown to specifically suppress STAT3 activation [XREF_BIBR].	0	23	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	22	23
XREF_BIBR However , our studies demonstrated that STAT3 , a transcription factor that can increase cyclin D1 levels , was not phosphorylated in older PiZ mice , although SOCS3 , a protein that can reduce STAT3 activation , had slightly lower mRNA levels in older PiZ mice than in Wt .	XREF_BIBR However, our studies demonstrated that STAT3, a transcription factor that can increase cyclin D1 levels, was not phosphorylated in older PiZ mice, although SOCS3, a protein that can reduce STAT3 activation, had slightly lower mRNA levels in older PiZ mice than in Wt.	28	38	reduce	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	28	29	35	36
SOCS3 has been shown to limit the actions of both of these cytokines as well as their downstream targets STAT3 and NFkappaB , which are frequently activated in humans and mouse models of CRC [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	SOCS3 has been shown to limit the actions of both of these cytokines as well as their downstream targets STAT3 and NFkappaB, which are frequently activated in humans and mouse models of CRC [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	26	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	19	20
SOCS3 normally serves to inhibit STAT3 however if a homozygous deletion occur in the SOCS3 gene then its normally inhibitory function is reversed leading to increased levels of SOCS3 an observed progression to PC is observed .	SOCS3 normally serves to inhibit STAT3 however if a homozygous deletion occur in the SOCS3 gene then its normally inhibitory function is reversed leading to increased levels of SOCS3 an observed progression to PC is observed.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	5	6
SOCS3 also negatively regulates JAK and STAT3 pathway [ XREF_BIBR ] and is regarded as a common target for neuronal protection and axon regeneration after SCI [ XREF_BIBR ] .	SOCS3 also negatively regulates JAK and STAT3 pathway [XREF_BIBR] and is regarded as a common target for neuronal protection and axon regeneration after SCI [XREF_BIBR].	0	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	6	7
Recently , it has been demonstrated that TNF-alpha and LPS induce the expression of suppressor of cytokine signaling 3 ( SOCS3 ) and inhibit IL-6-induced STAT3 activation in macrophages .	Recently, it has been demonstrated that TNF-alpha and LPS induce the expression of suppressor of cytokine signaling 3 (SOCS3) and inhibit IL-6-induced STAT3 activation in macrophages.	7	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	TNF-alpha and LPS induce the expression of suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	stat3	14	19	25	26
Our data suggest that STAT3 is inhibited by SOCS3 in control mucosa , but it is constantly activated in the LPL-T of IBD patients due to the low expression of SOCS3 , indicating that anti-CD3-stimulated LPL-T of IBD patients are more sensitive to leptin and APN than those of controls .	Our data suggest that STAT3 is inhibited by SOCS3 in control mucosa, but it is constantly activated in the LPL-T of IBD patients due to the low expression of SOCS3, indicating that anti-CD3-stimulated LPL-T of IBD patients are more sensitive to leptin and APN than those of controls.	4	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	8	9	4	5
SOCS3 inhibits STAT6 and STAT3 and mitigates Th1 and Th17 differentiation , and indeed , we found an increase in the levels of SOCS3 in RHEB -/- T cells .	SOCS3 inhibits STAT6 and STAT3 and mitigates Th1 and Th17 differentiation, and indeed, we found an increase in the levels of SOCS3 in RHEB -/- T cells.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	4	5
A large amount of IFN-gamma in SOCS1 deficient T cells suppresses Th17 differentiation , which can be explained by the SOCS3 induced STAT3 suppression after STAT1 activation in SOCS1 deficient T cells .	A large amount of IFN-gamma in SOCS1 deficient T cells suppresses Th17 differentiation, which can be explained by the SOCS3 induced STAT3 suppression after STAT1 activation in SOCS1 deficient T cells.	17	23	induced	Positive_early_activation	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	20	21	22	23
We postulated that TGF-beta might inhibit SOCS3 expression induced by IL-6 and IL-21 , thus enhancing STAT3 activation and Th17 cell development .	We postulated that TGF-beta might inhibit SOCS3 expression induced by IL-6 and IL-21, thus enhancing STAT3 activation and Th17 cell development.	3	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	TGF-beta might inhibit SOCS3 expression	socs3	STAT3	STAT3	stat3	6	7	16	17
These data confirm the observation that SOCS3 acts in a negative feedback loop to arrest STAT3 activation in hepatocytes during liver regeneration .	These data confirm the observation that SOCS3 acts in a negative feedback loop to arrest STAT3 activation in hepatocytes during liver regeneration.	6	16	arrest	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	6	7	15	16
In addition , SOCS 1 and SOCS 3 inhibit JAK and STAT3 signaling through direct binding and suppression of the gp130 receptor and their associated JAKs [ XREF_BIBR , XREF_BIBR ] .	In addition, SOCS 1 and SOCS 3 inhibit JAK and STAT3 signaling through direct binding and suppression of the gp130 receptor and their associated JAKs [XREF_BIBR, XREF_BIBR].	3	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS 3	SOCS 3	SOCS 3	STAT3	STAT3	STAT3	6	8	11	12
The role of SOCS3 in neurons is detrimental for STAT3 induced neuroprotection , as OSM or IL-6 + IL-6R-induced SOCS3 expression in neurons was reported to inhibit STAT3 induced protective effects on neurons in vitro .	The role of SOCS3 in neurons is detrimental for STAT3 induced neuroprotection, as OSM or IL-6 + IL-6R-induced SOCS3 expression in neurons was reported to inhibit STAT3 induced protective effects on neurons in vitro.	19	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	19	20	27	28
Socs3 upregulation impairs both STAT3 and mTOR signaling before the onset of obesity .	Socs3 upregulation impairs both STAT3 and mTOR signaling before the onset of obesity.	0	7	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	0	1	4	5
SOCS3 inhibits JAK2 and STAT3 signaling , providing a negative feedback mechanism .	SOCS3 inhibits JAK2 and STAT3 signaling, providing a negative feedback mechanism.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	4	5
Reactivation could be a plausible explanation for why , even though IL6 message levels are low , SOCS3 levels are elevated , enabling SOCS3 to inhibit JAK activity and thus reduce STAT3 signaling in prostate cancer cells treated with ASC-PEDF CCM .	Reactivation could be a plausible explanation for why, even though IL6 message levels are low, SOCS3 levels are elevated, enabling SOCS3 to inhibit JAK activity and thus reduce STAT3 signaling in prostate cancer cells treated with ASC-PEDF CCM.	17	32	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 levels	socs3	STAT3	STAT3	stat3	17	18	31	32
Since SOCS3 is one of the inhibitors of the IL-6 and STAT3 signaling , here we aim at investigating whether SOCS3 can antagonize the IL-6 and STAT3 pathway , thus improving muscle wasting in cancer- and burn associated cachexia .	Since SOCS3 is one of the inhibitors of the IL-6 and STAT3 signaling, here we aim at investigating whether SOCS3 can antagonize the IL-6 and STAT3 pathway, thus improving muscle wasting in cancer- and burn associated cachexia.	20	27	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	20	21	26	27
Following DNA damage in WT cells , STAT3 signaling is repressed by SOCS3 , which favors cell cycle arrest through induction of p21 , among other genes .	Following DNA damage in WT cells, STAT3 signaling is repressed by SOCS3, which favors cell cycle arrest through induction of p21, among other genes.	7	15	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	12	13	7	8
We also considered that although the usual role of SOCS3 is to inhibit STAT3 activation , SOCS3 also binds to RasGAP , activating Ras and maintaining ERK activation ( XREF_FIG ) .	We also considered that although the usual role of SOCS3 is to inhibit STAT3 activation, SOCS3 also binds to RasGAP, activating Ras and maintaining ERK activation (XREF_FIG).	7	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	9	10	13	14
Thus high levels of SOCS3 protein should inhibit STAT3 activation .	Thus high levels of SOCS3 protein should inhibit STAT3 activation.	4	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	4	5	8	9
Previous studies showed that SOCS3 acts as a negative regulator of STAT3 phosphorylation in Th cells , and that inhibiting SOCS3 prolongs STAT3 activation during Th17 cell differentiation XREF_BIBR , XREF_BIBR .	Previous studies showed that SOCS3 acts as a negative regulator of STAT3 phosphorylation in Th cells, and that inhibiting SOCS3 prolongs STAT3 activation during Th17 cell differentiation XREF_BIBR, XREF_BIBR.	19	23	prolongs	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	20	21	22	23
EPA-FFA supplementation induces both IL-10 and SOCS3 expression reducing STAT3 activation .	EPA-FFA supplementation induces both IL-10 and SOCS3 expression reducing STAT3 activation.	6	10	reducing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	6	7	9	10
In a dose dependent way , SOCS-3 inhibited GH induced DNA binding of both STAT3 and STAT5 in RIN-5AH cells stably transfected with a ponasterone inducible SOCS-3 expression system .	In a dose dependent way, SOCS-3 inhibited GH induced DNA binding of both STAT3 and STAT5 in RIN-5AH cells stably transfected with a ponasterone inducible SOCS-3 expression system.	6	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	STAT3	STAT3	STAT3	6	7	14	15
In contrast , while SOCS3 still inhibited STAT3 activation by G-CSF-R-d715 , STAT5 activation was no longer affected .	In contrast, while SOCS3 still inhibited STAT3 activation by G-CSF-R-d715, STAT5 activation was no longer affected.	4	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	4	5	7	8
SOCS3 is an inhibitor of IL-6 and STAT3 , regulated by DNA methylation .	SOCS3 is an inhibitor of IL-6 and STAT3, regulated by DNA methylation.	0	8	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	7	8
199 Conversely , SOCS3 overexpression in POMC neurons impairs STAT3 signaling .	199 Conversely, SOCS3 overexpression in POMC neurons impairs STAT3 signaling.	3	10	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 overexpression	socs3	STAT3	STAT3	stat3	3	4	9	10
SOCS3 is known to inhibit IL-6 and STAT3 signaling .	SOCS3 is known to inhibit IL-6 and STAT3 signaling.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	7	8
The cytokine signaling suppressor SOCS-3 can reduce STAT3 driven cell proliferation in a physiological context and is frequently found silenced by hypermethylation in human lung cancer cells XREF_BIBR .	The cytokine signaling suppressor SOCS-3 can reduce STAT3 driven cell proliferation in a physiological context and is frequently found silenced by hypermethylation in human lung cancer cells XREF_BIBR.	0	18	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS-3	SOCS-3	SOCS-3	STAT3	STAT3	STAT3	4	5	7	8
Activation of suppressor of cytokine signaling 3 ( SOCS3 ) , a negative regulator of STAT3 signaling , inhibits STAT3 signaling pathway to suppress the proliferation of OSCC [ XREF_BIBR ] .	Activation of suppressor of cytokine signaling 3 (SOCS3), a negative regulator of STAT3 signaling, inhibits STAT3 signaling pathway to suppress the proliferation of OSCC [XREF_BIBR].	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	8	9	19	20
In vitro , overexpression of SOCS3 reduced IL-6-dependent STAT3 activation .	In vitro, overexpression of SOCS3 reduced IL-6-dependent STAT3 activation.	3	9	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	overexpression of SOCS3	socs3	STAT3	STAT3	stat3	5	6	8	9
Since SOCS3 inhibits STAT3 signaling in a number of cells , it is not surprising that SOCS3 was also shown to negatively regulate innate and adaptive immunity in both antigen induced arthritis ( AIA ) and CIA .	Since SOCS3 inhibits STAT3 signaling in a number of cells, it is not surprising that SOCS3 was also shown to negatively regulate innate and adaptive immunity in both antigen induced arthritis (AIA) and CIA.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	1	2	3	4
Stat3 and Socs3 act in a negative feedback loop in which Stat3 induces socs3 , which then inhibits Stat3 activation .	Stat3 and Socs3 act in a negative feedback loop in which Stat3 induces socs3, which then inhibits Stat3 activation.	12	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	socs3	socs3	socs3	Stat3	Stat3	Stat3	13	14	18	19
XREF_BIBR , XREF_BIBR It is also reported that TGFbeta inhibits SOCS3 gene transcription and prolongs STAT3 activation during Th17 cell differentiation .	XREF_BIBR, XREF_BIBR It is also reported that TGFbeta inhibits SOCS3 gene transcription and prolongs STAT3 activation during Th17 cell differentiation.	8	16	prolongs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	TGFbeta inhibits SOCS3 gene transcription	socs3	STAT3	STAT3	stat3	10	11	15	16
The role of SOCS3 as a negative feedback inhibitor of STAT3 signaling often targets it for CpG island methylation in cells that are addicted to STAT3 signaling and , as an additional selective advantage , may induce or enhance the immunosuppressive potential of STAT3 addicted tumors .	The role of SOCS3 as a negative feedback inhibitor of STAT3 signaling often targets it for CpG island methylation in cells that are addicted to STAT3 signaling and, as an additional selective advantage, may induce or enhance the immunosuppressive potential of STAT3 addicted tumors.	1	45	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	3	4	43	44
In particular , Socs3 is induced and degraded rapidly and is known to block the activation of STAT3 in response to IL-6 , by binding to the IL-6 gp130 receptor complex and mediating its degradation [ XREF_BIBR , XREF_BIBR ] .	In particular, Socs3 is induced and degraded rapidly and is known to block the activation of STAT3 in response to IL-6, by binding to the IL-6 gp130 receptor complex and mediating its degradation [XREF_BIBR, XREF_BIBR].	3	19	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	3	4	17	18
SOCS-3 has been found to negatively regulate STAT-3 activation 21 and given that STAT-3 has been shown to mediate epithelial cell apoptosis 22 , SOCS-3 may hold the potential to regulate epithelial cell growth .	SOCS-3 has been found to negatively regulate STAT-3 activation 21 and given that STAT-3 has been shown to mediate epithelial cell apoptosis 22, SOCS-3 may hold the potential to regulate epithelial cell growth.	0	11	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	STAT-3	STAT-3	STAT-3	0	1	7	8
Accumulating studies support that inhibition of SOCS3 expression promoted STAT3 activation , enhanced hepatic fibrosis , increased proliferation and tumor aggressiveness [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Accumulating studies support that inhibition of SOCS3 expression promoted STAT3 activation, enhanced hepatic fibrosis, increased proliferation and tumor aggressiveness [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	10	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	6	7	9	10
In line with these findings , we demonstrated that loss of SOCS3 protein expression in MCF10A-p53 - PTEN - cells plays crucial role in tumor development and progression via activating IL6 mediated Stat3 and NF-kappaB pathway .	In line with these findings, we demonstrated that loss of SOCS3 protein expression in MCF10A-p53 - PTEN - cells plays crucial role in tumor development and progression via activating IL6 mediated Stat3 and NF-kappaB pathway.	11	35	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 protein expression	socs3	Stat3	Stat3	stat3	11	12	32	33
Given that SOCS3 inhibits the STAT3 signaling that is responsible for the inflammatory cytokine section of macrophage and that STAT3 signaling is highly activated in M1 macrophages , the expression of SOCS3 significantly regulates the macrophage differentiation and its proinflammatory properties .	Given that SOCS3 inhibits the STAT3 signaling that is responsible for the inflammatory cytokine section of macrophage and that STAT3 signaling is highly activated in M1 macrophages, the expression of SOCS3 significantly regulates the macrophage differentiation and its proinflammatory properties.	2	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	2	3	5	6
Expression of SOCS3 in YAP -/- astrocytes prevented the hyperactivation of STAT3 and partially restored the astrocytic activation .	Expression of SOCS3 in YAP -/- astrocytes prevented the hyperactivation of STAT3 and partially restored the astrocytic activation.	0	12	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	Expression of SOCS3	socs3	STAT3	STAT3	stat3	2	3	11	12
In addition , restoration of SOCS3 expression attenuated STAT3 activation , induced apoptosis , and suppressed tumor cell growth in lung cancer [ XREF_BIBR ] .	In addition, restoration of SOCS3 expression attenuated STAT3 activation, induced apoptosis, and suppressed tumor cell growth in lung cancer [XREF_BIBR].	5	9	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	5	6	8	9
Overexpression of SOCS3 has been shown to block nuclear translocation of signal transducer and activator of transcription 3 ( STAT3 ) and neurite outgrowth of dorsal root ganglia ( DRG ) neurons .	Overexpression of SOCS3 has been shown to block nuclear translocation of signal transducer and activator of transcription 3 (STAT3) and neurite outgrowth of dorsal root ganglia (DRG) neurons.	0	20	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	Overexpression of SOCS3	socs3	STAT3	STAT3	stat3	2	3	19	20
Overall our structural and biochemical data strongly imply that SOCS3 inhibits JAK by blocking substrate binding although one interesting conundrum remains : a steady-state analysis of SOCS3 inhibition of JAK2 revealed that SOCS3 displays non competitive inhibitory kinetics both as regards ATP and substrate [ XREF_BIBR ] .	Overall our structural and biochemical data strongly imply that SOCS3 inhibits JAK by blocking substrate binding although one interesting conundrum remains : a steady-state analysis of SOCS3 inhibition of JAK2 revealed that SOCS3 displays non competitive inhibitory kinetics both as regards ATP and substrate [XREF_BIBR].	26	30	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	26	27	29	30
Although the effect of JAK2 inhibition by transcriptional feedback regulators was not significant as shown in XREF_FIG , we included the inhibition of JAK2 by SOCS3 since the effect could be obscured by other attenuation mechanisms , i.e ., deactivation of JAK2 by SHP-1 .	Although the effect of JAK2 inhibition by transcriptional feedback regulators was not significant as shown in XREF_FIG, we included the inhibition of JAK2 by SOCS3 since the effect could be obscured by other attenuation mechanisms, i.e., deactivation of JAK2 by SHP-1.	19	26	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	25	26	23	24
As shown in XREF_FIG , SOCS3 inhibited all JAK2 JH1 JH2 mutant proteins with a similar inhibitory concentration for 50 % maximal activity ( IC 50 ) to wild-type JAK2 JH1-JH2 .	As shown in XREF_FIG, SOCS3 inhibited all JAK2 JH1 JH2 mutant proteins with a similar inhibitory concentration for 50% maximal activity (IC 50) to wild-type JAK2 JH1-JH2.	5	12	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	5	6	8	9
SOCS3 inhibits JAK1 , JAK2 and TYK2 but not JAK3 .	SOCS3 inhibits JAK1, JAK2 and TYK2 but not JAK3.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	4	5
First , SOCS3 is able to directly inhibit the catalytic activity of JAK1 , JAK2 or TYK2 whilst remaining bound to the cytokine receptor .	First, SOCS3 is able to directly inhibit the catalytic activity of JAK1, JAK2 or TYK2 whilst remaining bound to the cytokine receptor.	2	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	2	3	14	15
There are four mammalian JAKs ( JAK1-3 and TYK2 ) ; recently it has been shown that SOCS3 directly inhibits JAK1 , JAK2 and TYK2 but does not inhibit JAK3 17 .	There are four mammalian JAKs (JAK1-3 and TYK2); recently it has been shown that SOCS3 directly inhibits JAK1, JAK2 and TYK2 but does not inhibit JAK3 17.	17	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	17	18	22	23
In vitro inhibition assays have shown that SOCS3 can only directly inhibit JAK1 , JAK2 and TYK2 and that the GQM motif is responsible for this specificity [ XREF_BIBR ] .	In vitro inhibition assays have shown that SOCS3 can only directly inhibit JAK1, JAK2 and TYK2 and that the GQM motif is responsible for this specificity [XREF_BIBR].	7	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	7	8	14	15
SOCS3 inhibited JAK1 , JAK2 and TYK2 with IC 50 values of 2muM , 1.5 muM and 7muM respectively but had no inhibitory effect on JAK3 ( XREF_FIG ) .	SOCS3 inhibited JAK1, JAK2 and TYK2 with IC 50 values of 2muM, 1.5 muM and 7muM respectively but had no inhibitory effect on JAK3 (XREF_FIG).	0	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	4	5
IL-6 can stimulate production of suppressor of cytokine signaling protein 3 ( SOCS-3 ) , which negatively regulates the GH receptor and Jak2 , potentially explaining how IL-6 reduces IGF-I gene expression [ XREF_BIBR ] .	IL-6 can stimulate production of suppressor of cytokine signaling protein 3 (SOCS-3), which negatively regulates the GH receptor and Jak2, potentially explaining how IL-6 reduces IGF-I gene expression [XREF_BIBR].	5	23	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	SOCS-3	SOCS-3	SOCS-3	Jak2	Jak2	Jak2	12	13	22	23
XREF_BIBR Therefore , inhibition of JAK2 by SOCS3 could result in decreased proliferation .	XREF_BIBR Therefore, inhibition of JAK2 by SOCS3 could result in decreased proliferation.	3	8	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	7	8	5	6
CIS3 inhibits JAK2 kinase activity by binding to the activation loop through the SH2 domain , and KIR is necessary for kinase inhibition .	CIS3 inhibits JAK2 kinase activity by binding to the activation loop through the SH2 domain, and KIR is necessary for kinase inhibition.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIS3	CIS3	CIS3	JAK2	JAK2	JAK2	0	1	2	3
However , Socs3 overexpression primarily blocks the activity of Jak2 and not on Stat3 XREF_BIBR .	However, Socs3 overexpression primarily blocks the activity of Jak2 and not on Stat3 XREF_BIBR.	2	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3 overexpression	socs3	Jak2	Jak2	jak2	2	3	9	10
Importantly , we show that whilst SOCS3 can inhibit JAK1 , JAK2 and TYK2 in the absence of receptor , it does so with relatively poor ( micromolar ) affinity .	Importantly, we show that whilst SOCS3 can inhibit JAK1, JAK2 and TYK2 in the absence of receptor, it does so with relatively poor (micromolar) affinity.	6	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	6	7	11	12
In particular , SOCS-3 and and/or CIS may inhibit JAK2 [ XREF_BIBR - XREF_BIBR ] , and SOCS-3 and -2 further have been proposed to cross-regulate [ XREF_BIBR ] .	In particular, SOCS-3 and and/or CIS may inhibit JAK2 [XREF_BIBR - XREF_BIBR], and SOCS-3 and -2 further have been proposed to cross-regulate [XREF_BIBR].	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	JAK2	JAK2	JAK2	3	4	9	10
SOCS3 can inhibit JAK1 , JAK2 and TYK2 but not JAK3 .	SOCS3 can inhibit JAK1, JAK2 and TYK2 but not JAK3.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	5	6
Further consistent with inhibitory activity of SOCS3 , LPS also inhibited the JAK2 dependent activation of Stat5 by GM-CSF .	Further consistent with inhibitory activity of SOCS3, LPS also inhibited the JAK2 dependent activation of Stat5 by GM-CSF.	4	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	6	7	12	13
Furthermore , TrkB in the absence of c-Src binds directly to JAK2 and inhibits SOCS3 mediated JAK2 degradation , resulting in increased total JAK2 and STAT3 levels , which subsequently leads to JAK2 and STAT3 activation and Twist-1 upregulation .	Furthermore, TrkB in the absence of c-Src binds directly to JAK2 and inhibits SOCS3 mediated JAK2 degradation, resulting in increased total JAK2 and STAT3 levels, which subsequently leads to JAK2 and STAT3 activation and Twist-1 upregulation.	13	19	mediated	Positive_early_activation	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	14	15	16	17
We also show that Huh7 cells expressing OBRb and SOCS3 ( inhibitor of JAK2 ) resulted in a marked reduction of AMPK activation in response to leptin .	We also show that Huh7 cells expressing OBRb and SOCS3 (inhibitor of JAK2) resulted in a marked reduction of AMPK activation in response to leptin.	6	14	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	9	10	13	14
Jak2 activates Stat3 by phosphorylation , and phosphorylated Stat3 ( pStat3 ) induces Socs3 expression , which in turn inhibits Jak2 .	Jak2 activates Stat3 by phosphorylation, and phosphorylated Stat3 (pStat3) induces Socs3 expression, which in turn inhibits Jak2.	7	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	phosphorylated Stat3 (pStat3) induces Socs3	socs3	Jak2	Jak2	jak2	13	14	20	21
In addition , the upregulation of SOCS3 by ERK downregulates the JAK2 and TAT3 pathway and causes the arrest of cells in G1 phase .	In addition, the upregulation of SOCS3 by ERK downregulates the JAK2 and TAT3 pathway and causes the arrest of cells in G1 phase.	4	14	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	6	7	11	12
XREF_BIBR SOCS3 binds to Tyr 985 to mediate inhibition of Jak2 tyrosine kinase activity through the N-terminal kinase inhibitory region .	XREF_BIBR SOCS3 binds to Tyr 985 to mediate inhibition of Jak2 tyrosine kinase activity through the N-terminal kinase inhibitory region.	0	13	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	Jak2	Jak2	Jak2	1	2	10	11
Here , we found that TrkC was sufficient for direct interaction with JAK2 and blocked SOCS3 induced JAK2 degradation , which resulted in stabilization of JAK2 expression and induction of STAT3 , as well as the upregulation of Twist-1 gene expression .	Here, we found that TrkC was sufficient for direct interaction with JAK2 and blocked SOCS3 induced JAK2 degradation, which resulted in stabilization of JAK2 expression and induction of STAT3, as well as the upregulation of Twist-1 gene expression.	15	18	induced	Positive_early_activation	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	15	16	17	18
SOCS3 was recently shown to directly inhibit JAK1 , JAK2 and TYK2 via a conserved three-residue motif .	SOCS3 was recently shown to directly inhibit JAK1, JAK2 and TYK2 via a conserved three-residue motif.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	9	10
SOCS3 binds to LepRb Tyr 985 and mediates negative feedback by directly inhibiting JAK2 activity and/or targeting the receptor and JAK2 complex for proteasomal degradation .	SOCS3 binds to LepRb Tyr 985 and mediates negative feedback by directly inhibiting JAK2 activity and/or targeting the receptor and JAK2 complex for proteasomal degradation.	0	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	13	14
After induction , SOCS3 associates with JAK2 and impairs further activation of the JAK2 and STAT1 pathway .	After induction, SOCS3 associates with JAK2 and impairs further activation of the JAK2 and STAT1 pathway.	3	16	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	3	4	13	14
Therefore , CIS3 and JAB inhibit JAK2 tyrosine kinase activity by an essentially similar mechanism .	Therefore, CIS3 and JAB inhibit JAK2 tyrosine kinase activity by an essentially similar mechanism.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CIS3	CIS3	CIS3	JAK2	JAK2	JAK2	2	3	6	7
Both SOCS1 and SOCS3 coimmunoprecipitate with JAK2 , but only SOCS1 significantly inhibited the in vitro kinase activity of JAK2 [ XREF_BIBR ] .	Both SOCS1 and SOCS3 coimmunoprecipitate with JAK2, but only SOCS1 significantly inhibited the in vitro kinase activity of JAK2 [XREF_BIBR].	1	21	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	3	4	19	20
Moreover , SOCS-3 inhibits JAK2 through a different mechanism that requires the presence of GHR [ XREF_BIBR ] .	Moreover, SOCS-3 inhibits JAK2 through a different mechanism that requires the presence of GHR [XREF_BIBR].	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	JAK2	JAK2	JAK2	2	3	4	5
SOCS-1 inhibited the tyrosine kinase activity of Janus kinase 2 ( JAK2 ) directly , while SOCS-3 only inhibited JAK2 when stimulated by the GH receptor .	SOCS-1 inhibited the tyrosine kinase activity of Janus kinase 2 (JAK2) directly, while SOCS-3 only inhibited JAK2 when stimulated by the GH receptor.	16	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	JAK2	JAK2	JAK2	16	17	19	20
SOCS3 1-225 inhibited JAK2 with an identical IC 50 to SOCS3 22-225 and was also apparently non competitive as regards substrate ( XREF_FIG ) .	SOCS3 1-225 inhibited JAK2 with an identical IC 50 to SOCS3 22-225 and was also apparently non competitive as regards substrate (XREF_FIG).	0	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	3	4
XREF_BIBR SOCS3 directly inhibits JAK1 , JAK2 , and TYK2 by binding to a conserved glycine-glutamine-methionine ( GQM ) motif in a unique insertion loop in JAKs , and is unable to inhibit JAK3 due to the absence of this motif .	XREF_BIBR SOCS3 directly inhibits JAK1, JAK2, and TYK2 by binding to a conserved glycine-glutamine-methionine (GQM) motif in a unique insertion loop in JAKs, and is unable to inhibit JAK3 due to the absence of this motif.	0	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	1	2	6	7
SOCS3 binds and directly inhibits the catalytic domains of JAK1 , JAK2 , and TYK2 , but not JAK3 .	SOCS3 binds and directly inhibits the catalytic domains of JAK1, JAK2, and TYK2, but not JAK3.	0	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	11	12
SOCS3 inhibits JAK2 kinase activity by directly binding to JAK2 [ XREF_BIBR ] .	SOCS3 inhibits JAK2 kinase activity by directly binding to JAK2 [XREF_BIBR].	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	2	3
Since SOCS3 can inhibit JAK2 directly via its KIR domain to attenuate downstream STAT5 activation , SOCS3 becomes more effective with the relative increase of JAK2 activation .	Since SOCS3 can inhibit JAK2 directly via its KIR domain to attenuate downstream STAT5 activation, SOCS3 becomes more effective with the relative increase of JAK2 activation.	1	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	1	2	4	5
As shown in XREF_FIG , this effect may have been caused by a direct inhibition of STAT6 transcription , by inhibition of JAK2 transcription , and/or by upregulation of SOCS3 , which may inhibit Jak2 function .	As shown in XREF_FIG, this effect may have been caused by a direct inhibition of STAT6 transcription, by inhibition of JAK2 transcription, and/or by upregulation of SOCS3, which may inhibit Jak2 function.	27	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	Jak2	Jak2	Jak2	29	30	34	35
SOCS3 has been shown to inhibit JAK1 , JAK2 , and TYK2 but not JAK3 .	SOCS3 has been shown to inhibit JAK1, JAK2, and TYK2 but not JAK3.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	8	9
For example , LepRb --> STAT3 signaling induces SOCS3 transcription , which attenuates LepRb and Jak2 mediated intracellular signaling and the ablation of LepRb --> STAT3 signaling prevents SOCS3 mediated feedback inhibition of LepRb .	For example, LepRb --> STAT3 signaling induces SOCS3 transcription, which attenuates LepRb and Jak2 mediated intracellular signaling and the ablation of LepRb --> STAT3 signaling prevents SOCS3 mediated feedback inhibition of LepRb.	3	16	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	LepRb --> STAT3 signaling induces SOCS3 transcription	socs3	Jak2	Jak2	jak2	8	9	15	16
SOCS3 inhibits the catalytic domain of JAK2 ( in addition to JAK1 and TYK2 ) by binding near the active site and preventing substrate access .	SOCS3 inhibits the catalytic domain of JAK2 (in addition to JAK1 and TYK2) by binding near the active site and preventing substrate access.	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	6	7
In addition , the structure provides insights into the possible mechanisms by which SOCS3 and SOCS1 inhibit JAK2 kinase activity .	In addition, the structure provides insights into the possible mechanisms by which SOCS3 and SOCS1 inhibit JAK2 kinase activity.	13	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	13	14	17	18
In addition , both SOCS-3 and PTP-1B suppress signaling through receptor associated Janus kinase 2 ( JAK2 ) and tyrosine kinase receptors , although they have different modes of action : SOCS-3 can interact with and block JAK2 activity , promote degradation of insulin receptor substrate proteins and receptor complex via its SOCS box , and block access to specific cytokine receptor tyrosine residues , whereas PTP-1B is an endoplasmic reticulum associated enzyme that dephosphorylates and inactivates these same partners , probably following endocytosis of the ligand receptor complex .	In addition, both SOCS-3 and PTP-1B suppress signaling through receptor associated Janus kinase 2 (JAK2) and tyrosine kinase receptors, although they have different modes of action : SOCS-3 can interact with and block JAK2 activity, promote degradation of insulin receptor substrate proteins and receptor complex via its SOCS box, and block access to specific cytokine receptor tyrosine residues, whereas PTP-1B is an endoplasmic reticulum associated enzyme that dephosphorylates and inactivates these same partners, probably following endocytosis of the ligand receptor complex.	31	38	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	JAK2	JAK2	JAK2	31	32	37	38
SOCS3 inhibits JAK1 , JAK2 and TYK2 but not JAK3 due to the presence of a three-residue ( GQM ) motif in the JAK insertion loop .	SOCS3 inhibits JAK1, JAK2 and TYK2 but not JAK3 due to the presence of a three-residue (GQM) motif in the JAK insertion loop.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	4	5
Based on our previous characterisation of JAK2 JH1 inhibition by the SOCS3 SH2 domain [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] and the JAK2 JH1-JH2 inhibition studies described above , we predicted that the SOCS3 SH2 domain would engage the JH1 domain within the JAK2 JH1-JH2 construct via an analogous , phospho independent binding mode .	Based on our previous characterisation of JAK2 JH1 inhibition by the SOCS3 SH2 domain [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] and the JAK2 JH1-JH2 inhibition studies described above, we predicted that the SOCS3 SH2 domain would engage the JH1 domain within the JAK2 JH1-JH2 construct via an analogous, phospho independent binding mode.	6	21	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	11	12	6	7
Our data suggest that GH induces refractoriness to the insulin like effects in a negative-feedback manner by inhibiting GH induced GHR/Jak2/IRS-1/IRS-2 phosphorylation through upregulation of SOCS-3 , which almost completely blocks Jak2 activation .	Our data suggest that GH induces refractoriness to the insulin like effects in a negative-feedback manner by inhibiting GH induced GHR/Jak2/IRS-1/IRS-2 phosphorylation through upregulation of SOCS-3, which almost completely blocks Jak2 activation.	23	32	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	Jak2	Jak2	Jak2	25	26	31	32
SOCS3 can inhibit JAK1 , JAK2 and TYK2 via its KIR , but not JAK3 .	SOCS3 can inhibit JAK1, JAK2 and TYK2 via its KIR, but not JAK3.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	5	6
SOCS3 can inhibit JAK1 , JAK2 and TYK2 however it does so effectively only when they are already bound to a cytokine receptor that contains a SOCS3 binding site such as gp130 , G-CSFR and lepR .	SOCS3 can inhibit JAK1, JAK2 and TYK2 however it does so effectively only when they are already bound to a cytokine receptor that contains a SOCS3 binding site such as gp130, G-CSFR and lepR.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	5	6
Seminal work by Yoshimura and colleagues showed that both SOCS3 and SOCS1 can directly inhibit the catalytic activity of JAK1 and JAK2 and that this ability requires a short ( approximately 12 residue ) motif immediately N-terminal to the ESS .	Seminal work by Yoshimura and colleagues showed that both SOCS3 and SOCS1 can directly inhibit the catalytic activity of JAK1 and JAK2 and that this ability requires a short (approximately 12 residue) motif immediately N-terminal to the ESS.	8	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	9	10	21	22
Interestingly , SOCS3 can inhibit JAK1 , JAK2 and TYK2 , but not JAK3 XREF_BIBR , providing further specificity in the regulation of the JAK and STAT system .	Interestingly, SOCS3 can inhibit JAK1, JAK2 and TYK2, but not JAK3 XREF_BIBR, providing further specificity in the regulation of the JAK and STAT system.	2	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	2	3	7	8
The SOCS3 protein is known to bind to JAK2 and suppress JAK2 activity through direct binding to the JAK2 catalytic center and promotion of the proteasomal degradation of JAK2 [ XREF_BIBR ] .	The SOCS3 protein is known to bind to JAK2 and suppress JAK2 activity through direct binding to the JAK2 catalytic center and promotion of the proteasomal degradation of JAK2 [XREF_BIBR].	1	12	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	1	2	11	12
Further supporting the role of the KIR in this process , deletion of the first 3 residues in the KIR results a ten-fold increase in the IC 50 value for SOCS3 inhibition of JAK2 activity .	Further supporting the role of the KIR in this process, deletion of the first 3 residues in the KIR results a ten-fold increase in the IC 50 value for SOCS3 inhibition of JAK2 activity.	30	34	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	30	31	33	34
All JAK2 JH1 JH2 mutants were inhibited by SOCS3 with similar affinity .	All JAK2 JH1 JH2 mutants were inhibited by SOCS3 with similar affinity.	1	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	8	9	1	2
A limiting feature of these assays was that the concentration of SOCS3 required to inhibit JAK2 JH1 was similar to the concentration of substrate .	A limiting feature of these assays was that the concentration of SOCS3 required to inhibit JAK2 JH1 was similar to the concentration of substrate.	9	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	11	12	15	16
However , SOCS3 can inhibit the activation of JAK2 in response to GH stimulation when both SOCS3 and the GH receptor are coexpressed in HEK 293 cells .	However, SOCS3 can inhibit the activation of JAK2 in response to GH stimulation when both SOCS3 and the GH receptor are coexpressed in HEK 293 cells.	2	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	2	3	8	9
Additionally , a chimera of SOCS3 , in which the KIR was replaced by the equivalent SOCS5 region , did not inhibit JAK2 kinase activity in vitro XREF_BIBR .	Additionally, a chimera of SOCS3, in which the KIR was replaced by the equivalent SOCS5 region, did not inhibit JAK2 kinase activity in vitro XREF_BIBR.	3	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	5	6	22	23
Dose response experiments were conducted in 293 cells and SOCS-1 and SOCS-3 were shown to inhibit the transcriptional activation of a GH responsive element and suppressed Jak2 tyrosine kinase activity .	Dose response experiments were conducted in 293 cells and SOCS-1 and SOCS-3 were shown to inhibit the transcriptional activation of a GH responsive element and suppressed Jak2 tyrosine kinase activity.	9	29	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	Jak2	Jak2	Jak2	11	12	26	27
Given that our previous data had shown that SOCS3 inhibits JAK2 with non competitive kinetics towards substrate 17 , the above model required further validation .	Given that our previous data had shown that SOCS3 inhibits JAK2 with non competitive kinetics towards substrate 17, the above model required further validation.	8	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	8	9	10	11
Both SOCS1 and SOCS3 directly inhibit JAK1 , JAK2 , and TYK2 .	Both SOCS1 and SOCS3 directly inhibit JAK1, JAK2, and TYK2.	1	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	3	4	8	9
To further confirm the inhibition of the IL-6 and STAT3 signalling pathway by OCA and whether the increase in SOCS3 had subsequently caused an inhibition of Jak-2 , the relative mRNA level of Jak-2 in OCA treated cells was determined .	To further confirm the inhibition of the IL-6 and STAT3 signalling pathway by OCA and whether the increase in SOCS3 had subsequently caused an inhibition of Jak-2, the relative mRNA level of Jak-2 in OCA treated cells was determined.	17	27	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	Jak-2	Jak-2	Jak-2	19	20	26	27
SOCS and CIS proteins can thus inhibit GH signaling to STAT5b by three distinct mechanisms , distinguished by their molecular targets within the GHR-JAK2 signaling complex , as exemplified by SOCS-1 ( direct JAK2 kinase inhibition ) , SOCS-3 ( inhibition of JAK2 signaling via membrane proximal GHR tyrosines 333 and 338 ) , and CIS and SOCS-2 ( inhibition via membrane-distal tyrosine ( s ) ) .	SOCS and CIS proteins can thus inhibit GH signaling to STAT5b by three distinct mechanisms, distinguished by their molecular targets within the GHR-JAK2 signaling complex, as exemplified by SOCS-1 (direct JAK2 kinase inhibition), SOCS-3 (inhibition of JAK2 signaling via membrane proximal GHR tyrosines 333 and 338), and CIS and SOCS-2 (inhibition via membrane-distal tyrosine (s)).	28	43	inhibition	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	JAK2	JAK2	JAK2	38	39	42	43
We show that SOCS3 directly inhibits JAK1 , JAK2 and TYK2 but not JAK3 due to the presence of a conserved three-residue motif on the former three JAK family members .	We show that SOCS3 directly inhibits JAK1, JAK2 and TYK2 but not JAK3 due to the presence of a conserved three-residue motif on the former three JAK family members.	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	3	4	8	9
A secondary level of specificity is present in that SOCS3 can only inhibit JAK1 , JAK2 and TYK2 but not JAK3 ( See XREF_FIG ) .	A secondary level of specificity is present in that SOCS3 can only inhibit JAK1, JAK2 and TYK2 but not JAK3 (See XREF_FIG).	6	20	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	9	10	15	16
21 Another member of the same protein family , SOCS3 , binds and directly inhibits the catalytic domains of JAK1 and JAK2 proteins , 22 and reduced expression of SOCS3 has been reported in various human cancers associated with constitutive STAT3 activation .	21 Another member of the same protein family, SOCS3, binds and directly inhibits the catalytic domains of JAK1 and JAK2 proteins, 22 and reduced expression of SOCS3 has been reported in various human cancers associated with constitutive STAT3 activation.	7	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	9	10	21	22
SOCS3 can inhibit JAK1 , JAK2 and TYK2 via its kinase inhibitory region , but not JAK3 [ XREF_BIBR ] .	SOCS3 can inhibit JAK1, JAK2 and TYK2 via its kinase inhibitory region, but not JAK3 [XREF_BIBR].	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	5	6
SOCS3 can inhibit the activity of JAK2 kinase and negatively regulate cytokine signaling through the JAK and STAT pathway .	SOCS3 can inhibit the activity of JAK2 kinase and negatively regulate cytokine signaling through the JAK and STAT pathway.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	6	7
Tyr 985 recruits the tyrosine phosphatase PTPN11 ( a.k.a ., SHP2 ; which controls ERK activation ) , and also binds the suppressor of cytokine signaling-3 ( SOCS3 ; an inhibitor of LepRb and Jak2 signaling ) .	Tyr 985 recruits the tyrosine phosphatase PTPN11 (a.k.a., SHP2; which controls ERK activation), and also binds the suppressor of cytokine signaling-3 (SOCS3; an inhibitor of LepRb and Jak2 signaling).	25	35	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	Jak2	Jak2	Jak2	27	28	34	35
SOCS3 , which has extensive interactions with IL-12p40 , IL-12p35 , IL-23p19 , and IL-6 , is a cytokine inducible negative regulator of cytokine signaling and can inhibit the activity of JAK2 kinase .	SOCS3, which has extensive interactions with IL-12p40, IL-12p35, IL-23p19, and IL-6, is a cytokine inducible negative regulator of cytokine signaling and can inhibit the activity of JAK2 kinase.	0	32	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	31	32
Using an in vitro kinase assay system consisting of purified recombinant enzyme ( JAK2 kinase domain ) , substrate ( gp130 cytoplasmic domain ) and inhibitor ( SOCS3 ) we demonstrated that SOCS3 inhibits the catalytic ( JH1 ) domain of JAK2 with an IC 50 of approximately 1 muM [ XREF_BIBR ] .	Using an in vitro kinase assay system consisting of purified recombinant enzyme (JAK2 kinase domain), substrate (gp130 cytoplasmic domain) and inhibitor (SOCS3) we demonstrated that SOCS3 inhibits the catalytic (JH1) domain of JAK2 with an IC 50 of approximately 1 muM [XREF_BIBR].	32	51	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	32	33	41	42
When IFN-gamma is excessively expressed , IL-4 signaling through STAT6 can be blocked by SOCS1 ; however , when IL-4 is highly expressed , IFN-gamma signaling through STAT1 is blocked by SOCS1 .	When IFN-gamma is excessively expressed, IL-4 signaling through STAT6 can be blocked by SOCS1; however, when IL-4 is highly expressed, IFN-gamma signaling through STAT1 is blocked by SOCS1.	24	32	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	31	32	24	25
IL-12-mediated IFN-gamma production in Xiap -/- tTreg cells was similarly inhibited by SOCS1 re-introduction .	IL-12-mediated IFN-gamma production in Xiap -/- tTreg cells was similarly inhibited by SOCS1 re-introduction.	1	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	12	13	1	2
For example SOCS1 inhibits interferon gamma signaling without affecting IL-6 signaling while the converse is true for SOCS3 , yet both cytokine receptor systems utilize the same JAKs ( JAK1 and JAK2 ) .	For example SOCS1 inhibits interferon gamma signaling without affecting IL-6 signaling while the converse is true for SOCS3, yet both cytokine receptor systems utilize the same JAKs (JAK1 and JAK2).	2	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	interferon gamma	interferon gamma	interferon gamma	2	3	4	6
SOCS1 negatively regulates IFNgamma , TNFalpha and IL-1beta while SOCS3 negatively regulates LIF and IL-6 .	SOCS1 negatively regulates IFNgamma, TNFalpha and IL-1beta while SOCS3 negatively regulates LIF and IL-6.	0	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	0	1	3	4
In such case inhibition turned out not to be effective , and available experimental data clearly show that SOCS-1 expression is induced by IFN-gamma and overexpression of SOCS-1 inhibits IFN-gamma signaling .	In such case inhibition turned out not to be effective, and available experimental data clearly show that SOCS-1 expression is induced by IFN-gamma and overexpression of SOCS-1 inhibits IFN-gamma signaling.	25	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	overexpression of SOCS-1	socs-1	IFN-gamma	IFN-gamma	ifn-gamma	27	28	29	30
Importantly , SOCS1 coexpression inhibited interferon-alpha and interferon-gamma signaling and protected FLT3-ITD hematopoietic cells from interferon mediated growth inhibitory effects .	Importantly, SOCS1 coexpression inhibited interferon-alpha and interferon-gamma signaling and protected FLT3-ITD hematopoietic cells from interferon mediated growth inhibitory effects.	2	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1 coexpression	socs1	interferon-gamma	interferon-gamma	interferon-gamma	2	3	7	8
The increased levels of SOCS1 protein thus inhibited IL-12 and IFN-gamma to block Th1 cell differentiation , but promoted Th2 cell differentiation .	The increased levels of SOCS1 protein thus inhibited IL-12 and IFN-gamma to block Th1 cell differentiation, but promoted Th2 cell differentiation.	4	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	4	5	10	11
SOCS1 inhibits IFN-gamma signaling via direct interaction with IFNGR1 or JAK kinases 40 , and represses type I IFN signaling via the interferon alpha receptor ( IFNAR1 )-associated TYK2 41 .	SOCS1 inhibits IFN-gamma signaling via direct interaction with IFNGR1 or JAK kinases 40, and represses type I IFN signaling via the interferon alpha receptor (IFNAR1)-associated TYK2 41.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	0	1	2	3
XREF_BIBR SOCS1 and SOCS3 KIR mimetics have been shown to inhibit STAT pathways XREF_BIBR and the small peptide mimetics of SOCS1 effectively inhibits IL-6 and IFN-gamma signaling in vitro and in vivo by targeting JAK-STAT pathway .	XREF_BIBR SOCS1 and SOCS3 KIR mimetics have been shown to inhibit STAT pathways XREF_BIBR and the small peptide mimetics of SOCS1 effectively inhibits IL-6 and IFN-gamma signaling in vitro and in vivo by targeting JAK-STAT pathway.	18	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	20	21	25	26
MiR-155 overexpression promoted expressions of major histocompatibility complex ( MHC ) I , MHC II , Chemokine ( C-X-C motif ) ligand ( CXCL ) 9 , CXCL10 , monocyte chemotactic protein 1 , and CXCL1 after IFN-gamma stimulation , which could be suppressed by SOCS1 overexpression .	MiR-155 overexpression promoted expressions of major histocompatibility complex (MHC) I, MHC II, Chemokine (C-X-C motif) ligand (CXCL) 9, CXCL10, monocyte chemotactic protein 1, and CXCL1 after IFN-gamma stimulation, which could be suppressed by SOCS1 overexpression.	37	47	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS1	SOCS1 overexpression	socs1	IFN-gamma	IFN-gamma	ifn-gamma	45	46	37	38
While SOCS1 inhibits STAT1 activation in the IFN-gamma signaling cascade , SOCS3 is a major negative regulator of the IL-6-STAT3 signaling pathway .	While SOCS1 inhibits STAT1 activation in the IFN-gamma signaling cascade, SOCS3 is a major negative regulator of the IL-6-STAT3 signaling pathway.	1	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	1	2	7	8
SOCS1 is a potent inhibitor of interferon gamma ( IFN-y )/STAT1 signaling .	SOCS1 is a potent inhibitor of interferon gamma (IFN-y)/STAT1 signaling.	0	8	is a potent inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	interferon gamma	interferon gamma	interferon gamma	0	1	6	8
The impairment of SOCS1 induction would prevent the negative feedback regulation of IL-2-mediated IFN-gamma production , which is observed as elevated IFN-gamma levels in primary T-LGLL patient samples and the TL-1 cell line .	The impairment of SOCS1 induction would prevent the negative feedback regulation of IL-2-mediated IFN-gamma production, which is observed as elevated IFN-gamma levels in primary T-LGLL patient samples and the TL-1 cell line.	3	14	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	3	4	13	14
The intracellular parasite Toxoplasma gondii that survives and multiplies in professional phagocytes such as macrophages induces SOCS1 expression that inhibits IFN-gamma receptor signaling [ XREF_BIBR ] .	The intracellular parasite Toxoplasma gondii that survives and multiplies in professional phagocytes such as macrophages induces SOCS1 expression that inhibits IFN-gamma receptor signaling [XREF_BIBR].	16	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1 expression	socs1	IFN-gamma	IFN-gamma	ifn-gamma	16	17	20	21
We next sought to determine how SOCS1 may inhibit viral clearance by investigating protective antiviral immune responses in SOCS1 -/- IFN-gamma -/- mice .	We next sought to determine how SOCS1 may inhibit viral clearance by investigating protective antiviral immune responses in SOCS1 -/- IFN-gamma -/- mice.	6	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	6	7	20	21
SOCS1 negatively regulates IFNgamma signaling pathway ( and other pathways ) by directly inhibiting JAKs .	SOCS1 negatively regulates IFNgamma signaling pathway (and other pathways) by directly inhibiting JAKs.	0	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	0	1	3	4
As both SOCS1 and 3 downregulate IFN-gamma signaling , their upregulation may represent an evasion strategy of T. bryosalmonae to dampen IFN-gamma signaling and host immune defense .	As both SOCS1 and 3 downregulate IFN-gamma signaling, their upregulation may represent an evasion strategy of T. bryosalmonae to dampen IFN-gamma signaling and host immune defense.	1	7	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	2	3	6	7
HIV-1 infected progressor patients demonstrated elevated levels of SOCS-1 mRNA and reduced IRF-1 mRNA in response to IFN-gamma signaling , suggesting that elevated SOCS-1 also inhibits IFN-gamma induced responses in this group of patients relative to uninfected controls or NVS patients .	HIV-1 infected progressor patients demonstrated elevated levels of SOCS-1 mRNA and reduced IRF-1 mRNA in response to IFN-gamma signaling, suggesting that elevated SOCS-1 also inhibits IFN-gamma induced responses in this group of patients relative to uninfected controls or NVS patients.	22	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	IFN-gamma	IFN-gamma	IFN-gamma	23	24	26	27
SOCS1 overexpression in oligodendrocytes suppresses the early , protective effects of IFN-gamma on oligodendrocytes , but also blocks its later , deleterious actions in EAE [ XREF_BIBR ] .	SOCS1 overexpression in oligodendrocytes suppresses the early, protective effects of IFN-gamma on oligodendrocytes, but also blocks its later, deleterious actions in EAE [XREF_BIBR].	0	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1 overexpression	socs1	IFN-gamma	IFN-gamma	ifn-gamma	0	1	11	12
Suppressor of cytokine signaling 1 ( SOCS1 ) and protein tyrosine phosphatases can negatively modulate IFN-gamma signaling .	Suppressor of cytokine signaling 1 (SOCS1) and protein tyrosine phosphatases can negatively modulate IFN-gamma signaling.	0	16	modulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	6	7	15	16
SOCS-1 has been shown to be critical for preventing interferon gamma ( IFNgamma )-mediated growth arrest of M-1 myeloid cells ( Sakamoto et al , 1998 ) , and overexpression of SOCS-1 or SOCS-3 in breast cancer lines inhibits the antiviral and antiproliferative ability of IFNgamma ( Song and Shuai , 1998 ) .	SOCS-1 has been shown to be critical for preventing interferon gamma (IFNgamma)-mediated growth arrest of M-1 myeloid cells (Sakamoto et al, 1998), and overexpression of SOCS-1 or SOCS-3 in breast cancer lines inhibits the antiviral and antiproliferative ability of IFNgamma (Song and Shuai, 1998).	29	51	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	overexpression of SOCS-1	socs-1	IFNgamma	IFNgamma	ifngamma	31	32	45	46
We next asked whether SOCS1 silencing could enhance HIV Env specific CTL responses by using IFN-gamma ELISPOT , intracellular cytokine staining , and CTL assays to test the functional status of CD8 + T cells in the immunized mice .	We next asked whether SOCS1 silencing could enhance HIV Env specific CTL responses by using IFN-gamma ELISPOT, intracellular cytokine staining, and CTL assays to test the functional status of CD8 + T cells in the immunized mice.	4	16	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	4	5	15	16
XREF_BIBR , XREF_BIBR Since SOCS1 suppresses both IFNgamma- and IL-4-mediated Th1 and Th2 cell differentiation , genetic ablation of SOCS1 results in unconditional hyperactivation of T cells .	XREF_BIBR, XREF_BIBR Since SOCS1 suppresses both IFNgamma- and IL-4-mediated Th1 and Th2 cell differentiation, genetic ablation of SOCS1 results in unconditional hyperactivation of T cells.	4	14	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFNgamma-	IFNgamma-	IFNgamma-	4	5	7	8
Indeed , expression of SOCS1 reduced IFN-gamma production in Egr2- and Egr3 deficient CD4 + Tcells , whereas SOCS3 suppressed STAT3 activation and production of IL-17A ( XREF_FIG D and 4E ) .	Indeed, expression of SOCS1 reduced IFN-gamma production in Egr2- and Egr3 deficient CD4 + Tcells, whereas SOCS3 suppressed STAT3 activation and production of IL-17A (XREF_FIG D and 4E).	2	7	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	expression of SOCS1	socs1	IFN-gamma	IFN-gamma	ifn-gamma	4	5	6	7
In addition , IFN-gamma may mediate its effects via the upregulation of suppressor of cytokine signaling 1 ( SOCS1 , a regulatory protein that attenuates IFN-gamma signaling ) [ XREF_BIBR ] , the inhibition of proliferation of T cells and macrophages [ XREF_BIBR , XREF_BIBR ] , and the induction of inducible nitric oxide synthase ( iNOS ) and nitric oxide ( NO ) [ XREF_BIBR , XREF_BIBR ] .	In addition, IFN-gamma may mediate its effects via the upregulation of suppressor of cytokine signaling 1 (SOCS1, a regulatory protein that attenuates IFN-gamma signaling) [XREF_BIBR], the inhibition of proliferation of T cells and macrophages [XREF_BIBR, XREF_BIBR], and the induction of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) [XREF_BIBR, XREF_BIBR].	7	26	attenuates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	18	19	25	26
To determine whether the reduced SOCS1 expression in Ubc13 deficient T reg cells contributed to their functional abnormality , we used a SOCS1 mimetic peptide that spans the kinase inhibitory region ( KIR ) of SOCS1 and is known to effectively inhibit IL-6 and IFN-gamma signaling in vitro and partially rescue SOCS1 function in vivo XREF_BIBR , XREF_BIBR - XREF_BIBR .	To determine whether the reduced SOCS1 expression in Ubc13 deficient T reg cells contributed to their functional abnormality, we used a SOCS1 mimetic peptide that spans the kinase inhibitory region (KIR) of SOCS1 and is known to effectively inhibit IL-6 and IFN-gamma signaling in vitro and partially rescue SOCS1 function in vivo XREF_BIBR, XREF_BIBR - XREF_BIBR.	22	45	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	22	23	44	45
As SOCS1 suppresses both IFN-gamma and IL-4 signaling , SOCS1 upregulation may be an approach for the reciprocal inhibition of Th1 and Th2 cells .	As SOCS1 suppresses both IFN-gamma and IL-4 signaling, SOCS1 upregulation may be an approach for the reciprocal inhibition of Th1 and Th2 cells.	1	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	1	2	4	5
Overexpression of SOCS-1 and , to a lesser extend , of SOCS-3 and CIS inhibited IFN-gamma signaling as measured by activation of STAT1 .	Overexpression of SOCS-1 and, to a lesser extend, of SOCS-3 and CIS inhibited IFN-gamma signaling as measured by activation of STAT1.	0	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	Overexpression of SOCS-1	socs-1	IFN-gamma	IFN-gamma	ifn-gamma	2	3	15	16
These data suggest that higher SOCS-1 levels in CD4+ T cells from untreated persons with progressive HIV-1 abrogate IFN-gamma induction of IRF-1 .	These data suggest that higher SOCS-1 levels in CD4+ T cells from untreated persons with progressive HIV-1 abrogate IFN-gamma induction of IRF-1.	5	19	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1 levels	socs-1	IFN-gamma	IFN-gamma	ifn-gamma	5	6	18	19
In this model , IL-10 induction of SOCS-1 by CD4+ T cells and dendritic cells inhibits both LPS and IFN-gamma signaling .	In this model, IL-10 induction of SOCS-1 by CD4+ T cells and dendritic cells inhibits both LPS and IFN-gamma signaling.	5	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	IFN-gamma	IFN-gamma	IFN-gamma	7	8	19	20
IL-6 is classically described to promote Th17 differentiation and oppose Th1 differentiation via upregulation of SOCS1 , which inhibits IFNgamma signaling during T cell activation XREF_BIBR , XREF_BIBR .	IL-6 is classically described to promote Th17 differentiation and oppose Th1 differentiation via upregulation of SOCS1, which inhibits IFNgamma signaling during T cell activation XREF_BIBR, XREF_BIBR.	13	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	15	16	19	20
SOCS1 inhibits STAT1 activation in the IFN-gamma signaling cascade , while SOCS3 is a major negative regulator of IL-6-STAT3 signaling XREF_BIBR , XREF_BIBR .	SOCS1 inhibits STAT1 activation in the IFN-gamma signaling cascade, while SOCS3 is a major negative regulator of IL-6-STAT3 signaling XREF_BIBR, XREF_BIBR.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	0	1	6	7
In the human THP-1 monocytic cell line , PTPN22 co-immunoprecipitates with SOCS1 and inhibits SOCS1 tyrosine phosphorylation to enhance IFN-gamma signaling .	In the human THP-1 monocytic cell line, PTPN22 co-immunoprecipitates with SOCS1 and inhibits SOCS1 tyrosine phosphorylation to enhance IFN-gamma signaling.	8	20	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	PTPN22 co-immunoprecipitates with SOCS1 and inhibits SOCS1 tyrosine phosphorylation	socs1	IFN-gamma	IFN-gamma	ifn-gamma	14	15	19	20
SOCS-1 inhibits IFN-gamma function by binding to the autophosphorylation site of the tyrosine kinase Janus kinase ( JAK ) 2 .	SOCS-1 inhibits IFN-gamma function by binding to the autophosphorylation site of the tyrosine kinase Janus kinase (JAK) 2.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	IFN-gamma	IFN-gamma	IFN-gamma	0	1	2	3
Therefore , we propose that elevated SOCS-1 expression by OCP abrogates IFN-gamma mediated control of osteoclastogenesis in the HIV-1 Tg rat and hypothesize that overproduction of SOCS-1 during HIV-1 infection is an important mechanism by which osteoclastogenesis is augmented , leading to an increase in bone loss .	Therefore, we propose that elevated SOCS-1 expression by OCP abrogates IFN-gamma mediated control of osteoclastogenesis in the HIV-1 Tg rat and hypothesize that overproduction of SOCS-1 during HIV-1 infection is an important mechanism by which osteoclastogenesis is augmented, leading to an increase in bone loss.	6	13	abrogates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1 expression	socs-1	IFN-gamma	IFN-gamma	ifn-gamma	6	7	11	12
SOCS-1 inhibited IFN-gamma induction of MHC-II protein , while SOCS-3 inhibited insulin growth factor-1 ( IGF-1 )-induced neurite outgrowth .	SOCS-1 inhibited IFN-gamma induction of MHC-II protein, while SOCS-3 inhibited insulin growth factor-1 (IGF-1)-induced neurite outgrowth.	0	3	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	IFN-gamma	IFN-gamma	IFN-gamma	0	1	2	3
Clearly , the main role of SOCS-1 , therefore , is to prevent uncontrolled and lethal IFN-gamma signaling .	Clearly, the main role of SOCS-1, therefore, is to prevent uncontrolled and lethal IFN-gamma signaling.	4	17	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	IFN-gamma	IFN-gamma	IFN-gamma	6	7	16	17
Our data shows down-regulation of IFN-gamma / SOCS1 expression to be induced only in active TB cases , distinguishing them from healthy individuals likely to have latent TB .	Our data shows down-regulation of IFN-gamma / SOCS1 expression to be induced only in active TB cases, distinguishing them from healthy individuals likely to have latent TB.	3	9	down-regulation	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	SOCS1	SOCS1 expression	socs1	IFN-gamma	IFN-gamma	ifn-gamma	7	8	5	6
Together , these data indicate a specific change in SOCS1 levels in sJIA monocytes and suggest that SOCS1 inhibits IFNgamma signaling in these cells .	Together, these data indicate a specific change in SOCS1 levels in sJIA monocytes and suggest that SOCS1 inhibits IFNgamma signaling in these cells.	17	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	17	18	19	20
Compared with Socs3 mRNA , Socs1 mRNA was induced relatively slowly , and SOCS1 simply attenuated the duration of IFNgamma signaling .	Compared with Socs3 mRNA, Socs1 mRNA was induced relatively slowly, and SOCS1 simply attenuated the duration of IFNgamma signaling.	13	20	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	13	14	19	20
SOCS1 is now considered to be an immune checkpoint molecule for anti-tumor immunity , because SOCS1 negatively regulates signaling of IFN-gamma and IL-12 , essential cytokines for anti-tumor immunity .	SOCS1 is now considered to be an immune checkpoint molecule for anti-tumor immunity, because SOCS1 negatively regulates signaling of IFN-gamma and IL-12, essential cytokines for anti-tumor immunity.	15	25	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	15	16	20	21
Higher amounts of SOCS1 protein suppress IL-12 and IFNgamma signaling leading to a Th1 cell differentiation blockade , while promoting Th2 cell induction .	Higher amounts of SOCS1 protein suppress IL-12 and IFNgamma signaling leading to a Th1 cell differentiation blockade, while promoting Th2 cell induction.	3	9	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	3	4	8	9
IFN-alpha and IFN-gamma responsiveness was most inhibited by over-expression of SOCS1 as compared to SOCS3 .	IFN-alpha and IFN-gamma responsiveness was most inhibited by over-expression of SOCS1 as compared to SOCS3.	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS1	over-expression of SOCS1	socs1	IFN-gamma	IFN-gamma	ifn-gamma	10	11	2	3
It has been recently shown that small peptide mimetics of SOCS1 possessing the kinase inhibitory region of SOCS1 , but not the SOCS box , can effectively inhibit IL6 and IFNgamma signaling in vitro .	It has been recently shown that small peptide mimetics of SOCS1 possessing the kinase inhibitory region of SOCS1, but not the SOCS box, can effectively inhibit IL6 and IFNgamma signaling in vitro.	8	31	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	10	11	30	31
SOCS 1 ( M2 phenotype ) inhibits the proinflammatory signalling pathways downstream of IFN-gamma and Toll like receptor 4 , whilst SOCS 3 ( M1 phenotype ) inhibits signal transduction and activation of transcription 3 ( STAT 3 ) signalling .	SOCS 1 (M2 phenotype) inhibits the proinflammatory signalling pathways downstream of IFN-gamma and Toll like receptor 4, whilst SOCS 3 (M1 phenotype) inhibits signal transduction and activation of transcription 3 (STAT 3) signalling.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS 1	SOCS 1	SOCS 1	IFN-gamma	IFN-gamma	IFN-gamma	0	2	13	14
SOCS-1 binds to and inhibits the IFNgamma receptor associated kinase Janus activated kinase ( JAK ) 2 and inhibits its function in vitro , but the mechanism by which SOCS-1 inhibits IFNgamma dependent signaling in vivo is not clear .	SOCS-1 binds to and inhibits the IFNgamma receptor associated kinase Janus activated kinase (JAK) 2 and inhibits its function in vitro, but the mechanism by which SOCS-1 inhibits IFNgamma dependent signaling in vivo is not clear.	29	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	IFNgamma	IFNgamma	IFNgamma	29	30	31	32
SOCS-1 negatively regulates the action of both IL-4 and IFN-gamma , thus the lower IgE level observed with the SOCS1-820T variant might suggest that SOCS-1 has a more pronounced effect on the IL-4 pathway .	SOCS-1 negatively regulates the action of both IL-4 and IFN-gamma, thus the lower IgE level observed with the SOCS1-820T variant might suggest that SOCS-1 has a more pronounced effect on the IL-4 pathway.	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	IFN-gamma	IFN-gamma	IFN-gamma	0	1	9	10
Inhibition of SOCS1 restores the antiviral effect of IFN-gamma during MHV-68 infection in BMMs .	Inhibition of SOCS1 restores the antiviral effect of IFN-gamma during MHV-68 infection in BMMs.	0	9	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	2	3	8	9
SOCS1 inhibits the Janus kinase and signal transducers and activators of transcription signaling pathway as part of a negative feedback loop and can suppresses the function of IFN-gamma , inhibits Th1 responses , DC activation , and negatively regulates the TLR-NF-kappaB pathway [ XREF_BIBR ] .	SOCS1 inhibits the Janus kinase and signal transducers and activators of transcription signaling pathway as part of a negative feedback loop and can suppresses the function of IFN-gamma, inhibits Th1 responses, DC activation, and negatively regulates the TLR-NF-kappaB pathway [XREF_BIBR].	0	38	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	0	1	27	28
SOCS1 also promotes mycobacterial growth in macrophages by blocking IFN-gamma secretion in response to IL-12 induced by the infection .	SOCS1 also promotes mycobacterial growth in macrophages by blocking IFN-gamma secretion in response to IL-12 induced by the infection.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	0	1	9	10
Further , overexpression of SOCS1 , a JAK inhibitor , diminished the antagonistic effect of IFN-gamma on TGF-beta1-induced GL alpha transcription and IgA secretion .	Further, overexpression of SOCS1, a JAK inhibitor, diminished the antagonistic effect of IFN-gamma on TGF-beta1-induced GL alpha transcription and IgA secretion.	2	16	diminished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	overexpression of SOCS1	socs1	IFN-gamma	IFN-gamma	ifn-gamma	4	5	15	16
We reasoned that pJAK2 ( 1001-1013 ) with a palmitate group for cell penetration would compete with JAK2 for SOCS-1 and thus block SOCS-1 inhibition of IFNgamma activity in HSV-1 infected keratinocytes .	We reasoned that pJAK2 (1001-1013) with a palmitate group for cell penetration would compete with JAK2 for SOCS-1 and thus block SOCS-1 inhibition of IFNgamma activity in HSV-1 infected keratinocytes.	23	27	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	IFNgamma	IFNgamma	IFNgamma	23	24	26	27
By identifying the cellular factors that negatively regulate JAK-STAT1 signaling , we revealed that the infection of BMMs by MHV-68 induces the expression of suppressor of cytokine signaling 1 ( SOCS1 ) and that depletion of SOCS1 restores the inhibitory effect of IFN-gamma on virus replication .	By identifying the cellular factors that negatively regulate JAK-STAT1 signaling, we revealed that the infection of BMMs by MHV-68 induces the expression of suppressor of cytokine signaling 1 (SOCS1) and that depletion of SOCS1 restores the inhibitory effect of IFN-gamma on virus replication.	34	43	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	36	37	42	43
IFN-gamma also upregulates expression of proteins , such as SOCS-1 , that attenuate the IFN-gamma response [ XREF_BIBR ] .	IFN-gamma also upregulates expression of proteins, such as SOCS-1, that attenuate the IFN-gamma response [XREF_BIBR].	3	15	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	IFN-gamma	IFN-gamma	IFN-gamma	9	10	14	15
Likewise , it has been shown that IFN-gamma signaling is only poorly suppressed by SOCS1 when its binding site on the IFN-gamma receptor ( pTyr441 ) has been mutated ( Starr et al ., 2009 ) and we suggest that SOCS1 and SOCS3 both share this mechanism of receptor dependence to gain high specificity and efficacy towards particular cytokines .	Likewise, it has been shown that IFN-gamma signaling is only poorly suppressed by SOCS1 when its binding site on the IFN-gamma receptor (pTyr441) has been mutated (Starr et al., 2009) and we suggest that SOCS1 and SOCS3 both share this mechanism of receptor dependence to gain high specificity and efficacy towards particular cytokines.	7	15	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	14	15	7	8
Importantly , SOCS1 and/or SOCS3 are upregulated in macrophages by several intracellular pathogens , including L. monocytogenes , Toxoplasma gondii , Leishmania major , and Mycobacterium avium , and inhibit the ability of IFN-gamma to activate macrophages and kill intracellular organisms .	Importantly, SOCS1 and/or SOCS3 are upregulated in macrophages by several intracellular pathogens, including L. monocytogenes, Toxoplasma gondii, Leishmania major, and Mycobacterium avium, and inhibit the ability of IFN-gamma to activate macrophages and kill intracellular organisms.	2	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	2	3	33	34
XREF_BIBR The increase in SOCS1 blocks an IFNgamma feedback loop , which under normal conditions further increases IFNgamma production .	XREF_BIBR The increase in SOCS1 blocks an IFNgamma feedback loop, which under normal conditions further increases IFNgamma production.	0	18	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	4	5	17	18
The essential physiological function of SOCS1 is to attenuate interferon gamma signaling in immune cells .	The essential physiological function of SOCS1 is to attenuate interferon gamma signaling in immune cells.	3	11	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	interferon gamma	interferon gamma	interferon gamma	5	6	9	11
However , SOCS1 suppresses the effect of IFN-gamma on keratinocytes by inhibiting the JAK2 and STAT1 pathway .	However, SOCS1 suppresses the effect of IFN-gamma on keratinocytes by inhibiting the JAK2 and STAT1 pathway.	2	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	2	3	7	8
Firstly , we demonstrated that SOCS1 and SOCS3 molecules , both abundantly expressed in psoriatic epidermis , suppress the IFN-gamma and TNF-alpha-induced apoptosis in human keratinocytes by specifically sustaining the activation of the anti-apoptotic PI3K and AKT pathway .	Firstly, we demonstrated that SOCS1 and SOCS3 molecules, both abundantly expressed in psoriatic epidermis, suppress the IFN-gamma and TNF-alpha-induced apoptosis in human keratinocytes by specifically sustaining the activation of the anti-apoptotic PI3K and AKT pathway.	5	22	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	5	6	19	20
It is possible that since IL-6 has been shown to upregulate SOCS-1 expression in activated T cells [ XREF_BIBR ] , the elevated SOCS-1 level in CD8 T cells lowered the intensity or duration of IL-2 and IFN-gamma signaling , thereby impairing IFN-gamma expression .	It is possible that since IL-6 has been shown to upregulate SOCS-1 expression in activated T cells [XREF_BIBR], the elevated SOCS-1 level in CD8 T cells lowered the intensity or duration of IL-2 and IFN-gamma signaling, thereby impairing IFN-gamma expression.	23	38	lowered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1 level	socs-1	IFN-gamma	IFN-gamma	ifn-gamma	23	24	37	38
SOCS1 could be induced by ( STAT1N ) * 2 after IL-6 stimulation , but SOCS1 induction by IL-6 is not sufficient to inhibit IFN-gamma signalling .	SOCS1 could be induced by (STAT1N) * 2 after IL-6 stimulation, but SOCS1 induction by IL-6 is not sufficient to inhibit IFN-gamma signalling.	15	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	15	16	24	25
Interestingly , in a report of Reddy et al ., 36 it was shown that co-expression of SOCS1 with FLT3 and ITD inhibited interferon-gamma signaling and protected FLT3 and ITD hematopoietic cells from interferon mediated growth inhibitory effects .	Interestingly, in a report of Reddy et al., 36 it was shown that co-expression of SOCS1 with FLT3 and ITD inhibited interferon-gamma signaling and protected FLT3 and ITD hematopoietic cells from interferon mediated growth inhibitory effects.	15	24	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	co-expression of SOCS1	socs1	interferon-gamma	interferon-gamma	interferon-gamma	17	18	23	24
Thus , SOCS1 mediated inhibition can explain the suppressive properties of IFN-gamma on Th2 differentiation ( XREF_FIG and XREF_FIG ) .	Thus, SOCS1 mediated inhibition can explain the suppressive properties of IFN-gamma on Th2 differentiation (XREF_FIG and XREF_FIG).	2	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	2	3	11	12
XREF_BIBR , XREF_BIBR Among these , SOCS1 negatively regulates IFN-gamma signaling by binding and inactivating Jak2 protein and , in turn , impeding the activation of STAT1 transcription factor .	XREF_BIBR, XREF_BIBR Among these, SOCS1 negatively regulates IFN-gamma signaling by binding and inactivating Jak2 protein and, in turn, impeding the activation of STAT1 transcription factor.	6	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	6	7	9	10
SOCS3 , which is a major suppressor of JAK-STAT signaling , is reported to inhibit JAK1 and TYK2 XREF_BIBR .	SOCS3, which is a major suppressor of JAK-STAT signaling, is reported to inhibit JAK1 and TYK2 XREF_BIBR.	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK1	JAK1	JAK1	0	1	15	16
Induction of SOCS1 or SOCS3 could therefore lead to diminished JAK1 activity during the second wave , and hence , a greater reliance on JAK3 activity .	Induction of SOCS1 or SOCS3 could therefore lead to diminished JAK1 activity during the second wave, and hence, a greater reliance on JAK3 activity.	0	11	lead	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK1	JAK1	JAK1	4	5	10	11
The overexpression of SOCS3 induces apoptosis and partial G0/G1 arrest by inhibiting JAK1 , ERK , and FAK signaling pathways in malignant pleural mesothelioma EHMES-1 and H226 cell lines .	The overexpression of SOCS3 induces apoptosis and partial G0/G1 arrest by inhibiting JAK1, ERK, and FAK signaling pathways in malignant pleural mesothelioma EHMES-1 and H226 cell lines.	1	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	overexpression of SOCS3	socs3	JAK1	JAK1	jak1	3	4	12	13
SOCS3 , itself inducible by STAT3 , inhibits JAK1 activity through an unknown mechanism involving its kinase inhibitor domain [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	SOCS3, itself inducible by STAT3, inhibits JAK1 activity through an unknown mechanism involving its kinase inhibitor domain [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK1	JAK1	JAK1	0	1	8	9
Using in vitro inhibition assays we showed that SOCS3 directly inhibits JAK1 , JAK2 and TYK2 , with similar affinity , but does not inhibit JAK3 [ XREF_BIBR ] and that this inhibition requires the presence of this GQM motif .	Using in vitro inhibition assays we showed that SOCS3 directly inhibits JAK1, JAK2 and TYK2, with similar affinity, but does not inhibit JAK3 [XREF_BIBR] and that this inhibition requires the presence of this GQM motif.	8	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK1	JAK1	JAK1	8	9	11	12
A recent study showed that SOCS1 and SOCS3 can promote myogenic differentiation by inhibiting JAK1 and gp130 , respectively XREF_BIBR .	A recent study showed that SOCS1 and SOCS3 can promote myogenic differentiation by inhibiting JAK1 and gp130, respectively XREF_BIBR.	5	19	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	JAK1	JAK1	JAK1	7	8	14	15
Once bound , SOCS3 is thought to inhibit G-CSFR signalling by at least two distinct mechanisms : the first is through interaction of its KIR with receptor bound JAKs via a process similar to that described for SOCS3 inhibition of gp130 [ XREF_BIBR , XREF_BIBR ] .	Once bound, SOCS3 is thought to inhibit G-CSFR signalling by at least two distinct mechanisms : the first is through interaction of its KIR with receptor bound JAKs via a process similar to that described for SOCS3 inhibition of gp130 [XREF_BIBR, XREF_BIBR].	37	44	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	37	38	40	41
XREF_BIBR By contrast , SOCS3 attenuates gp130 signalling , limiting IL-6-induced STAT1 gene expression and inhibiting IL-6-induced STAT3 anti-inflammatory effects .	XREF_BIBR By contrast, SOCS3 attenuates gp130 signalling, limiting IL-6-induced STAT1 gene expression and inhibiting IL-6-induced STAT3 anti-inflammatory effects.	4	7	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	4	5	6	7
The molecular rationale underpinning the reciprocal relationship between activation of the Stat1/3 and Erk1/2 signalling arises from the observation that the negative regulatory Socs3 protein is transcriptionally induced by Stat3 and requires binding to the phosphorylated tyrosine residue in position 757 in mouse ( 759 in human ) gp130 .	The molecular rationale underpinning the reciprocal relationship between activation of the Stat1/3 and Erk1/2 signalling arises from the observation that the negative regulatory Socs3 protein is transcriptionally induced by Stat3 and requires binding to the phosphorylated tyrosine residue in position 757 in mouse (759 in human) gp130.	23	49	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	Socs3	Socs3	gp130	gp130	gp130	23	24	48	49
XREF_BIBR Gp130 downstream signaling pathways , STAT3 , extracellular-signal-regulated kinases 1 and 2 ( ERK1/2 ) , and AKT activation , which are coinduced by LIF stimulation , were completely suppressed by SOCS3 overexpression .	XREF_BIBR Gp130 downstream signaling pathways, STAT3, extracellular-signal-regulated kinases 1 and 2 (ERK1/2), and AKT activation, which are coinduced by LIF stimulation, were completely suppressed by SOCS3 overexpression.	0	34	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 overexpression	socs3	Gp130	Gp130	gp130	32	33	1	2
This mechanism explains the contrasting effects of STAT3 mediated IL-6 vs. IL-10 gene transcription ; the transient nature of IL-6 signaling is controlled by rapid SOCS3 inhibition of the gp130 subunit of the IL-6 receptor .	This mechanism explains the contrasting effects of STAT3 mediated IL-6 vs. IL-10 gene transcription; the transient nature of IL-6 signaling is controlled by rapid SOCS3 inhibition of the gp130 subunit of the IL-6 receptor.	25	30	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	25	26	29	30
SOCS3 siRNA knockdown and SOCS3 deletion in astrocytes enhanced the synergistic effect of IL-6/R and IL-17 on IL-6 gene expression , which was due to enhanced activation of the NF-kappaB and MAPK pathways ( XREF_FIG ) .	SOCS3 siRNA knockdown and SOCS3 deletion in astrocytes enhanced the synergistic effect of IL-6/R and IL-17 on IL-6 gene expression, which was due to enhanced activation of the NF-kappaB and MAPK pathways (XREF_FIG).	0	15	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IL-6/R	IL-6/R	IL-6/R	0	1	13	14
It has been shown that SOCS3 predominantly inhibits the gp130 subunit of the IL-6 receptor .	It has been shown that SOCS3 predominantly inhibits the gp130 subunit of the IL-6 receptor.	5	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	5	6	9	10
We observed that reduced SOCS3 expression by Lenti-shSOCS3 enhanced basal expression of Bcl-xL expression ( XREF_FIG , lanes 1 and 5 ) , and enhanced IL-6/R up-regulation of Bcl-xL , compared to pGipz infected cells ( lanes 2-4 compared to lanes 6-8 ) .	We observed that reduced SOCS3 expression by Lenti-shSOCS3 enhanced basal expression of Bcl-xL expression (XREF_FIG, lanes 1 and 5), and enhanced IL-6/R up-regulation of Bcl-xL, compared to pGipz infected cells (lanes 2-4 compared to lanes 6-8).	4	26	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 expression	socs3	IL-6/R	IL-6/R	il-6/r	4	5	25	26
Interestingly , knockdown of SOCS3 expression in astrocytes by siRNA enhanced IL-6/R plus IL-17 induction of IL-6 .	Interestingly, knockdown of SOCS3 expression in astrocytes by siRNA enhanced IL-6/R plus IL-17 induction of IL-6.	4	14	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 expression	socs3	IL-6/R	IL-6/R	il-6/r	4	5	11	12
Although structurally similar to SOCS3 , SOCS1 inhibits cytokine signaling by binding directly to JAK , whereas SOCS3 inhibits JAK only in the presence of gp130 ( glycoprotein 130 ) .	Although structurally similar to SOCS3, SOCS1 inhibits cytokine signaling by binding directly to JAK, whereas SOCS3 inhibits JAK only in the presence of gp130 (glycoprotein 130).	17	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	17	18	25	26
Taken together , these data suggest that the mechanism by which SOCS-3 inhibits the gp130 signaling pathway depends on recruitment to the phosphorylated gp130 receptor , and that some of the negative regulatory roles previously attributed to the phosphatase SHP-2 might in fact be caused by the action of SOCS-3 .	Taken together, these data suggest that the mechanism by which SOCS-3 inhibits the gp130 signaling pathway depends on recruitment to the phosphorylated gp130 receptor, and that some of the negative regulatory roles previously attributed to the phosphatase SHP-2 might in fact be caused by the action of SOCS-3.	11	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	gp130	gp130	gp130	11	12	14	15
A recent study has revealed that the feedback inhibition of the oncostatin M receptor by SOCS3 was independent of phosphotyrosine motifs in the receptor chain , whereas the same levels SOCS3 did not inhibit gp130 in the absence of Tyr759 [ XREF_BIBR ] .	A recent study has revealed that the feedback inhibition of the oncostatin M receptor by SOCS3 was independent of phosphotyrosine motifs in the receptor chain, whereas the same levels SOCS3 did not inhibit gp130 in the absence of Tyr759 [XREF_BIBR].	27	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	30	31	34	35
One such inhibitor of the IL-6 and gp130 pathway is SOCS3 which inhibits gp130 signaling .	One such inhibitor of the IL-6 and gp130 pathway is SOCS3 which inhibits gp130 signaling.	2	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	10	11	13	14
SOCS3 attenuates cell signaling via binding directly to the cytokine receptor subunit gp130 42 .	SOCS3 attenuates cell signaling via binding directly to the cytokine receptor subunit gp130 42.	0	13	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	0	1	12	13
While STAT3 is a required transcription factor for Th17 differentiation and cytokine production , IL-10 negatively regulates Th17 cytokine production by increasing SOCS3 expression which downregulates IL-6 and gp130 signaling .	While STAT3 is a required transcription factor for Th17 differentiation and cytokine production, IL-10 negatively regulates Th17 cytokine production by increasing SOCS3 expression which downregulates IL-6 and gp130 signaling.	14	29	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	IL-10 negatively regulates Th17 cytokine production by increasing SOCS3 expression	socs3	gp130	gp130	gp130	22	23	28	29
Indeed , His54 occupies the substrate binding site 25 , mimicking a substrate tyrosine and indicating that SOCS1 inhibits JAK1 by blocking peptide substrate ( but not ATP ) access .	Indeed, His54 occupies the substrate binding site 25, mimicking a substrate tyrosine and indicating that SOCS1 inhibits JAK1 by blocking peptide substrate (but not ATP) access.	17	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	JAK1	JAK1	JAK1	17	18	19	20
A similar feedback loop exists in the T-bet attractor but it is rendered inactive by the inhibition of JAK1 by SOCS1 .	A similar feedback loop exists in the T-bet attractor but it is rendered inactive by the inhibition of JAK1 by SOCS1.	12	21	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	JAK1	JAK1	JAK1	20	21	18	19
SOCS1 is a potent inhibitor of JAK1 and JAK2 .	SOCS1 is a potent inhibitor of JAK1 and JAK2.	0	8	is a potent inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	JAK1	JAK1	JAK1	0	1	6	7
We have examined the ability of SOCS family members to suppress IL-4 signaling , and we have found that SOCS-1 potently inhibits the activation of JAK1 kinase and Stat6 in response to IL-4 .	We have examined the ability of SOCS family members to suppress IL-4 signaling, and we have found that SOCS-1 potently inhibits the activation of JAK1 kinase and Stat6 in response to IL-4.	19	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	JAK1	JAK1	JAK1	19	20	25	26
showed that a prolonged activity of JAK1 and reduced levels of SOCS1 associated with the delayed kinetics of STAT2 activation .	showed that a prolonged activity of JAK1 and reduced levels of SOCS1 associated with the delayed kinetics of STAT2 activation.	6	12	reduced	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	SOCS1	levels of SOCS1	socs1	JAK1	JAK1	jak1	11	12	6	7
Furthermore , in vitro kinase assay indicated that JAB suppressed hyperactivation of JAK1 and JAK2 and JAK1 induced by IFNgamma and IL-6 plus sIL-6R respectively , but not v-Src-induced basal JAK1 and JAK2 activity .	Furthermore, in vitro kinase assay indicated that JAB suppressed hyperactivation of JAK1 and JAK2 and JAK1 induced by IFNgamma and IL-6 plus sIL-6R respectively, but not v-Src-induced basal JAK1 and JAK2 activity.	8	16	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	JAB	JAB	JAB	JAK1	JAK1	JAK1	8	9	12	13
SOCS1 from all three species could directly inhibit the catalytic activity of JAK1 , JAK2 and TYK2 but not JAK3 .	SOCS1 from all three species could directly inhibit the catalytic activity of JAK1, JAK2 and TYK2 but not JAK3.	0	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	JAK1	JAK1	JAK1	0	1	12	13
In miR-322-silenced cells , increased Smurf2 suppressed TGF-beta-induced Smad2 activation by enhancing p-Smad2 degradation ( XREF_FIG ) .	In miR-322-silenced cells, increased Smurf2 suppressed TGF-beta-induced Smad2 activation by enhancing p-Smad2 degradation (XREF_FIG).	5	9	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad2	Smad2	Smad2	5	6	8	9
In this study , we have identified a novel HECT class ubiquitin E3 ligase , designated Smurf2 , that negatively regulates Smad2 signaling .	In this study, we have identified a novel HECT class ubiquitin E3 ligase, designated Smurf2, that negatively regulates Smad2 signaling.	6	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ligase	ligase	ligase	Smad2	Smad2	Smad2	13	14	21	22
Inhibition of Smurf2 translation by miR-322/503 modulates TGF-beta and Smad2 signaling and intestinal epithelial homeostasis .	Inhibition of Smurf2 translation by miR-322/503 modulates TGF-beta and Smad2 signaling and intestinal epithelial homeostasis.	2	10	modulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad2	Smad2	Smad2	2	3	9	10
SARA prevents Smurf2 induced Smad2 degradation .	SARA prevents Smurf2 induced Smad2 degradation.	2	5	induced	Positive_early_activation	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad2	Smad2	Smad2	2	3	4	5
We demonstrated that high-level expression of Smurf2 appears to correlate with tumor development and poor prognosis in patients with esophageal SCC and that alteration of Smad2 expression in the TGF-beta signaling pathway may be induced by enhancement of Smad2 degradation mediated by high-level expression of Smurf2 .	We demonstrated that high-level expression of Smurf2 appears to correlate with tumor development and poor prognosis in patients with esophageal SCC and that alteration of Smad2 expression in the TGF-beta signaling pathway may be induced by enhancement of Smad2 degradation mediated by high-level expression of Smurf2.	38	46	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Smurf2	expression of Smurf2	smurf2	Smad2	Smad2	smad2	45	46	38	39
Overall , Aza treated ACs represent a novel model for the study of mechanisms that regulate maturational potential of articular cartilage , with the data suggesting that maturation of these cells may be due to up-regulation of Smad1 and 5 coupled with a Smurf2 dependent degradation of Smad2 and 3 and loss of TGF-beta signaling .	Overall, Aza treated ACs represent a novel model for the study of mechanisms that regulate maturational potential of articular cartilage, with the data suggesting that maturation of these cells may be due to up-regulation of Smad1 and 5 coupled with a Smurf2 dependent degradation of Smad2 and 3 and loss of TGF-beta signaling.	43	49	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad2	Smad2	Smad2	43	44	47	48
Inhibition of the proteasomal pathway prevented Smurf2 mediated downregulation of Smad2 and Smad corepressors .	Inhibition of the proteasomal pathway prevented Smurf2 mediated downregulation of Smad2 and Smad corepressors.	6	13	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad2	Smad2	Smad2	6	7	10	11
Notably , the knockdown of Smurf1 or of the closely related Smurf2 ( XREF_SUPPLEMENTARY ) did not prolong the accumulation of activated Smad2 following TGFbeta stimulation ( XREF_FIG ) , though addition of proteasome inhibitor MG132 did ( refer to XREF_FIG below ) .	Notably, the knockdown of Smurf1 or of the closely related Smurf2 (XREF_SUPPLEMENTARY) did not prolong the accumulation of activated Smad2 following TGFbeta stimulation (XREF_FIG), though addition of proteasome inhibitor MG132 did (refer to XREF_FIG below).	3	25	prolong	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad2	Smad2	Smad2	11	12	22	23
Increased levels of endogenous Smurf2 by antagonization of miR-503/322 inhibit TGF-beta-induced Smad2 activation by increasing the degradation of phosphorylated Smad2 .	Increased levels of endogenous Smurf2 by antagonization of miR-503/322 inhibit TGF-beta-induced Smad2 activation by increasing the degradation of phosphorylated Smad2.	1	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	levels of endogenous Smurf2	smurf2	Smad2	Smad2	smad2	4	5	11	12
Increased levels of endogenous Smurf2 by decreasing miR-503 and miR-322 abundances inhibit TGF-beta-induced Smad2 activation by enhancing phosphorylated Smad2 degradation .	Increased levels of endogenous Smurf2 by decreasing miR-503 and miR-322 abundances inhibit TGF-beta-induced Smad2 activation by enhancing phosphorylated Smad2 degradation.	1	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	levels of endogenous Smurf2	smurf2	Smad2	Smad2	smad2	4	5	13	14
Although Smurf2 has been shown to cause the degradation of TbetaRI , the Smad2 and Smad3 in vitro [ XREF_BIBR - XREF_BIBR ] and in vivo study of Smurf2 knockout mice reveals that Smurf2 does not cause the degradation of Smad2 , Smad3 or the TGF-beta type I receptor .	Although Smurf2 has been shown to cause the degradation of TbetaRI, the Smad2 and Smad3 in vitro [XREF_BIBR - XREF_BIBR] and in vivo study of Smurf2 knockout mice reveals that Smurf2 does not cause the degradation of Smad2, Smad3 or the TGF-beta type I receptor.	33	46	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad2	Smad2	Smad2	33	34	40	41
These results indicate that increased Smurf2 by miR-322/503 silencing inhibits TGF-beta and Smad2 activation by enhancing p-Smad2 degradation .	These results indicate that increased Smurf2 by miR-322/503 silencing inhibits TGF-beta and Smad2 activation by enhancing p-Smad2 degradation.	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad2	Smad2	Smad2	5	6	12	13
This indicates that JAK3 , which lacks GQM , will not be inhibited by SOCS3 even if they were to be bound to the same receptor complex .	This indicates that JAK3, which lacks GQM, will not be inhibited by SOCS3 even if they were to be bound to the same receptor complex.	3	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	JAK3	JAK3	JAK3	14	15	3	4
Thus , the deletion of SOCS3 enhances IRS1 activation without altering expression levels .	Thus, the deletion of SOCS3 enhances IRS1 activation without altering expression levels.	3	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IRS1	IRS1	IRS1	5	6	7	8
HBx enhances SOCS3 induced IRS1 protein degradation .	HBx enhances SOCS3 induced IRS1 protein degradation.	2	6	induced	Positive_early_activation	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IRS1	IRS1	IRS1	2	3	4	5
In conclusion , our data indicate that HBx proteins are able to augment SOCS3 expression and decrease IRS1 proteins , thereby causing impairments of hepatic insulin signaling and inhibition of hepatic insulin action .	In conclusion, our data indicate that HBx proteins are able to augment SOCS3 expression and decrease IRS1 proteins, thereby causing impairments of hepatic insulin signaling and inhibition of hepatic insulin action.	7	18	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	HBx proteins are able to augment SOCS3 expression	socs3	IRS1	IRS1	irs1	13	14	17	18
A possible mechanism is that HCV core induced SOCS3 promotes proteosomal degradation of IRS1 and IRS2 through ubiquitination .	A possible mechanism is that HCV core induced SOCS3 promotes proteosomal degradation of IRS1 and IRS2 through ubiquitination.	8	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IRS1	IRS1	IRS1	8	9	13	14
SOCS1 , SOCS3 , and SOCS6 have been shown to inhibit IRS1 and IRS2 , and block insulin signaling [ XREF_BIBR , XREF_BIBR ] .	SOCS1, SOCS3, and SOCS6 have been shown to inhibit IRS1 and IRS2, and block insulin signaling [XREF_BIBR, XREF_BIBR].	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IRS1	IRS1	IRS1	2	3	11	12
TNF-alpha and IL-6 cause insulin resistance through activation of MAPK , PKC , mTOR and S6K1 and SOCS-3 mediated proteasomal degradation of IRS-1 .	TNF-alpha and IL-6 cause insulin resistance through activation of MAPK, PKC, mTOR and S6K1 and SOCS-3 mediated proteasomal degradation of IRS-1.	17	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-3	SOCS-3	SOCS-3	IRS-1	IRS-1	IRS-1	17	18	22	23
The underlying mechanism involves an IL-6-induced increase in SOCS3 and SOCS3 mediated degradation of IRS-1 and possibly AMPK in heart .	The underlying mechanism involves an IL-6-induced increase in SOCS3 and SOCS3 mediated degradation of IRS-1 and possibly AMPK in heart.	6	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IRS-1	IRS-1	IRS-1	8	9	14	15
A proposed mechanism was that CORE induced SOCS3 promotes proteasomal degradation of IRS1 and IRS2 through ubiquitination .	A proposed mechanism was that CORE induced SOCS3 promotes proteasomal degradation of IRS1 and IRS2 through ubiquitination.	5	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	CORE induced SOCS3	socs3	IRS1	IRS1	irs1	7	8	12	13
As shown in XREF_FIG , robust overexpression levels of SOCS1 , SOCS3 , and SOCS6 did not induce the degradation of IRS1 protein .	As shown in XREF_FIG, robust overexpression levels of SOCS1, SOCS3, and SOCS6 did not induce the degradation of IRS1 protein.	7	22	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	levels of SOCS1, SOCS3	socs3	IRS1	IRS1	irs1	11	12	21	22
As previously discussed , SOCS3 causes insulin resistance by directly inhibiting IR and IRS-1 and IRS-2 , which consequently causes decreased activity of downstream components in the insulin signaling pathway .	As previously discussed, SOCS3 causes insulin resistance by directly inhibiting IR and IRS-1 and IRS-2, which consequently causes decreased activity of downstream components in the insulin signaling pathway.	4	19	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	IRS-1	IRS-1	IRS-1	4	5	13	14
As noted above , the SOCS3 proteins have been previously reported to induce the proteasome dependent degradation of IRS1 , and HBx may result in the induction of SOCS3 mRNA and protein expression .	As noted above, the SOCS3 proteins have been previously reported to induce the proteasome dependent degradation of IRS1, and HBx may result in the induction of SOCS3 mRNA and protein expression.	5	19	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IRS1	IRS1	IRS1	5	6	18	19
Activation of Smads by Ang II was attributed to degradation of an inhibitory Smad7 , which was mediated by the AT1-Smurf2-dependent ubiquitin degradation mechanism because blockade of AT1 receptor or knockdown of Smurf2 inhibited Smad7 loss , thereby reducing Smad2/3 activation and EMT in response to Ang II.	Activation of Smads by Ang II was attributed to degradation of an inhibitory Smad7, which was mediated by the AT1-Smurf2-dependent ubiquitin degradation mechanism because blockade of AT1 receptor or knockdown of Smurf2 inhibited Smad7 loss, thereby reducing Smad2/3 activation and EMT in response to Ang II.	28	35	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad7	Smad7	Smad7	32	33	34	35
Thus , we hypothesized that activation of Akt by TGF-beta1 increases Smurf2 expression which would inhibit Smad7 , and thus Akt could participate in TGF-beta1-induced MMT and peritoneal fibrosis in mice undergoing PD .	Thus, we hypothesized that activation of Akt by TGF-beta1 increases Smurf2 expression which would inhibit Smad7, and thus Akt could participate in TGF-beta1-induced MMT and peritoneal fibrosis in mice undergoing PD.	7	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Akt by TGF-beta1 increases Smurf2 expression	smurf2	Smad7	Smad7	smad7	11	12	16	17
Blockade of NF-kappaB-driven renal inflammation and TGF-beta and Smad3 mediated renal fibrosis by preventing the Smurf2 mediated Smad7 degradation pathway may be mechanisms through which TSF inhibits type 2 DN .	Blockade of NF-kappaB-driven renal inflammation and TGF-beta and Smad3-mediated renal fibrosis by preventing the Smurf2 mediated Smad7 degradation pathway may be mechanisms through which TSF inhibits type 2 DN.	14	19	mediated	Positive_early_activation	Negative_activation	Positive_activation	Smurf2	Smurf2	Smurf2	Smad7	Smad7	Smad7	15	16	17	18
This is clearly demonstrated by the recent finding that upregulation of renal Smurf2 causes an ubiquitin dependent degradation of renal Smad7 , resulting in enhanced TGF-beta and Smad signaling and progressive renal fibrosis XREF_BIBR .	This is clearly demonstrated by the recent finding that upregulation of renal Smurf2 causes an ubiquitin dependent degradation of renal Smad7, resulting in enhanced TGF-beta and Smad signaling and progressive renal fibrosis XREF_BIBR.	9	21	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad7	Smad7	Smad7	12	13	20	21
Whether Akt induces Smurf2 expression and then inhibits Smad7 participation in MMT transformation during PD and the relevant mechanism ( s ) involved have not been thoroughly explored .	Whether Akt induces Smurf2 expression and then inhibits Smad7 participation in MMT transformation during PD and the relevant mechanism (s) involved have not been thoroughly explored.	1	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Akt induces Smurf2 expression	smurf2	Smad7	Smad7	smad7	3	4	8	9
This is clearly demonstrated by the recent finding that up-regulation of renal Smurf2 causes an ubiquitin dependent degradation of renal Smad7 , resulting in enhanced TGF-beta and Smad signaling and progressive renal fibrosis XREF_BIBR .	This is clearly demonstrated by the recent finding that up-regulation of renal Smurf2 causes an ubiquitin dependent degradation of renal Smad7, resulting in enhanced TGF-beta and Smad signaling and progressive renal fibrosis XREF_BIBR.	9	21	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad7	Smad7	Smad7	12	13	20	21
Previously , we have demonstrated that the bone morphogenetic protein ( BMP ) antagonist uterine sensitization associated gene-1 ( USAG-1 ) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure .	Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure.	15	31	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	USAG-1	USAG-1	USAG-1	BMP-7	BMP-7	BMP-7	19	20	27	28
Using this model , we demonstrated that USAG-1 inhibits BMP7 signaling , leading to apoptosis and degeneration of rudimentary tooth germs in maxillary supernumerary incisor formation [ XREF_BIBR ] .	Using this model, we demonstrated that USAG-1 inhibits BMP7 signaling, leading to apoptosis and degeneration of rudimentary tooth germs in maxillary supernumerary incisor formation [XREF_BIBR].	7	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	USAG-1	USAG-1	USAG-1	BMP7	BMP7	BMP7	7	8	9	10
Previously we identified the product of uterine sensitization associated gene-1 ( USAG-1 ) as a Bmp antagonist , which is by far the most abundantly expressed in the kidney , and demonstrated that USAG-1 negatively regulates the renoprotective activity of Bmp7 in many types of kidney disease XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Previously we identified the product of uterine sensitization associated gene-1 (USAG-1) as a Bmp antagonist, which is by far the most abundantly expressed in the kidney, and demonstrated that USAG-1 negatively regulates the renoprotective activity of Bmp7 in many types of kidney disease XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	33	41	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	USAG-1	USAG-1	USAG-1	Bmp7	Bmp7	Bmp7	33	34	40	41
In breast cancer cells , SOSTDC1 modestly increases Wnt3a signaling , decreases BMP-7 signaling , and does not affect BMP-2-induced signaling .	In breast cancer cells, SOSTDC1 modestly increases Wnt3a signaling, decreases BMP-7 signaling, and does not affect BMP-2-induced signaling.	5	18	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOSTDC1	SOSTDC1	SOSTDC1	BMP-7	BMP-7	BMP-7	5	6	12	13
The mechanism for suppressing deciduous incisors in mice is expression of USAG-1 , which inhibits BMP-7 signaling , leading to apoptosis and degeneration of rudimentary tooth germs .	The mechanism for suppressing deciduous incisors in mice is expression of USAG-1, which inhibits BMP-7 signaling, leading to apoptosis and degeneration of rudimentary tooth germs.	9	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	USAG-1	expression of USAG-1	usag-1	BMP-7	BMP-7	bmp-7	11	12	15	16
In line with previous results , Lys734 partially attenuated SMURF2 mediated degradation of TbetaRI .	In line with previous results, Lys734 partially attenuated SMURF2 mediated degradation of TbetaRI.	8	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SMURF2	SMURF2	SMURF2	TbetaRI	TbetaRI	TbetaRI	9	10	13	14
This showed an IL-2-reminiscent inductive effect on gene expression through SOCS1 knockdown in MAC-1 cells , suggesting that SOCS1 mediates inhibition of IL-2 - JAK3 - STAT5 signaling .	This showed an IL-2-reminiscent inductive effect on gene expression through SOCS1 knockdown in MAC-1 cells, suggesting that SOCS1 mediates inhibition of IL-2 - JAK3 - STAT5 signaling.	18	25	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	JAK3	JAK3	JAK3	18	19	24	25
Subsequently , WNT5A responsive protein inhibitors of activated STAT ( PIAS-1 ) and suppressor of cytokine signaling 1 ( SOCS-1 ) mediate the downregulation of IRAK-1 , IRAK-4 , and MyD88 , resulting in decreased expression of interleukin 12 ( IL-12 ) , IL-1beta , and tumor necrosis factor alpha ( TNF-alpha ) .	Subsequently, WNT5A responsive protein inhibitors of activated STAT (PIAS-1) and suppressor of cytokine signaling 1 (SOCS-1) mediate the downregulation of IRAK-1, IRAK-4, and MyD88, resulting in decreased expression of interleukin 12 (IL-12), IL-1beta, and tumor necrosis factor alpha (TNF-alpha).	5	27	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	SOCS-1	SOCS-1	IRAK-1	IRAK-1	IRAK-1	19	20	25	26
In Xenopus embryos , ectopic Smurf2 expression specifically inhibits Smad1 responses and thereby affects embryonic patterning by bone morphogenetic protein signals .	In Xenopus embryos, ectopic Smurf2 expression specifically inhibits Smad1 responses and thereby affects embryonic patterning by bone morphogenetic protein signals.	5	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf2	Smurf2 expression	smurf2	Smad1	Smad1	smad1	5	6	9	10
Furthermore , constitutive overexpression of SOCS-1 inhibited IFNgamma dependent signaling only in cells expressing IFNGR1 variants that included the Tyr ( 441 ) mutation .	Furthermore, constitutive overexpression of SOCS-1 inhibited IFNgamma dependent signaling only in cells expressing IFNGR1 variants that included the Tyr (441) mutation.	3	15	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS-1	overexpression of SOCS-1	socs-1	IFNGR1	IFNGR1	ifngr1	5	6	14	15
These data are insufficient to conclude that SOX17 suppresses the activity of the Wnt and beta-catenin signaling pathway .	These data are insufficient to conclude that SOX17 suppresses the activity of the Wnt and beta-catenin signaling pathway.	7	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	7	8	15	16
Sox17 promotes proteasomal degradation of beta-catenin .	Sox17 promotes proteasomal degradation of beta-catenin.	0	6	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	0	1	5	6
Because of its nuclear localization ( XREF_FIG ) , it would be reasonable to predict that depletion of beta-catenin by Sox17 occurs primarily from the nucleus .	Because of its nuclear localization (XREF_FIG), it would be reasonable to predict that depletion of beta-catenin by Sox17 occurs primarily from the nucleus.	16	21	depletion	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	20	21	18	19
Developmental studies in cultured cells and transgenic mice in vivo demonstrated that Sox17 promotes OPC differentiation by inhibiting the Wnt and beta-catenin pathway .	Developmental studies in cultured cells and transgenic mice in vivo demonstrated that Sox17 promotes OPC differentiation by inhibiting the Wnt and beta-catenin pathway.	12	22	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	12	13	21	22
Since Sox17 promotes cell cycle exit and antagonizes Wnt and beta-catenin signaling , we hypothesized that Sox17 interaction with beta-catenin may distinguish the two proliferative conditions .	Since Sox17 promotes cell cycle exit and antagonizes Wnt and beta-catenin signaling, we hypothesized that Sox17 interaction with beta-catenin may distinguish the two proliferative conditions.	1	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	1	2	10	11
This suggests that SOX4 stabilizes beta-catenin by antagonizing the same pathway that SOX17 and SOX7 use to promote beta-catenin degradation .	This suggests that SOX4 stabilizes beta-catenin by antagonizing the same pathway that SOX17 and SOX7 use to promote beta-catenin degradation.	12	19	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	12	13	18	19
When recombinant Sox17 is co-transfected with MEK , the increase in reporter activity is abolished ( XREF_FIG ) , indicating that Sox17 antagonizes the transcriptional response of beta-catenin and TCF to MEK activation .	When recombinant Sox17 is co-transfected with MEK, the increase in reporter activity is abolished (XREF_FIG), indicating that Sox17 antagonizes the transcriptional response of beta-catenin and TCF to MEK activation.	21	29	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	21	22	27	28
Sox17 , a transcription factor , was considered as an antagonist to inhibit canonical Wnt and beta-catenin signaling in several malignant tumors .	Sox17, a transcription factor, was considered as an antagonist to inhibit canonical Wnt and beta-catenin signaling in several malignant tumors.	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	0	1	16	17
In this study , we define signaling pathways regulated by Sox17 in OPCs , and show that Sox17 antagonizes the Wnt and beta-catenin pathway , which is also stimulated by the mitogen PDGF .	In this study, we define signaling pathways regulated by Sox17 in OPCs, and show that Sox17 antagonizes the Wnt and beta-catenin pathway, which is also stimulated by the mitogen PDGF.	17	23	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	17	18	22	23
Together , these results indicated that SOX17 suppresses beta-catenin and TCF transcription activity by down-regulating MAML3 .	Together, these results indicated that SOX17 suppresses beta-catenin and TCF transcription activity by down-regulating MAML3.	6	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
In this assay , co-transfection of Xenopus SOX17 or SOX3 suppressed the ability of beta-catenin to stimulate transcription of the TOP : flash reporter .	In this assay, co-transfection of Xenopus SOX17 or SOX3 suppressed the ability of beta-catenin to stimulate transcription of the TOP : flash reporter.	4	15	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	7	8	14	15
We speculate that there is a fine balance between SOX17 ' s activation and repression of pBAR that is influenced by multiple factors including : the induction of SOX17 by beta-catenin [ XREF_BIBR ] , the GSK3beta independent downregulation of beta-catenin by SOX17 [ XREF_BIBR , XREF_BIBR ] , the direct interaction of SOX17 , TCF and beta-catenin [ XREF_BIBR , XREF_BIBR ] , the similarity between TCF and SOX17 binding motifs [ XREF_BIBR ] , the possibility that SOX17 mediated repression of TCF promoter sites involves additional WNT induced factors other than beta-catenin [ XREF_BIBR ] , and the positive feedback loop mediated by TCF-4 sites within the beta-catenin promoter [ XREF_BIBR ] .	We speculate that there is a fine balance between SOX17 's activation and repression of pBAR that is influenced by multiple factors including : the induction of SOX17 by beta-catenin [XREF_BIBR], the GSK3beta independent downregulation of beta-catenin by SOX17 [XREF_BIBR, XREF_BIBR], the direct interaction of SOX17, TCF and beta-catenin [XREF_BIBR, XREF_BIBR], the similarity between TCF and SOX17 binding motifs [XREF_BIBR], the possibility that SOX17 mediated repression of TCF promoter sites involves additional WNT induced factors other than beta-catenin [XREF_BIBR], and the positive feedback loop mediated by TCF-4 sites within the beta-catenin promoter [XREF_BIBR].	38	112	downregulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	42	43	40	41
The TOP and FOP-Flash reporter assay and Western blotting showed SOX17 inhibited the activity of the Wnt and beta-catenin signaling pathway in cervical cancer .	The TOP and FOP-Flash reporter assay and Western blotting showed SOX17 inhibited the activity of the Wnt and beta-catenin signaling pathway in cervical cancer.	10	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	10	11	18	19
SOX17 inhibits the activity of Wnt and beta-catenin pathway through directly binding to the promoter of beta-catenin in cervical cancer cells .	SOX17 inhibits the activity of Wnt and beta-catenin pathway through directly binding to the promoter of beta-catenin in cervical cancer cells.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	0	1	7	8
However , SOX17 inhibits canonical Wnt and beta-catenin signaling and suppresses tumor growth in papillary thyroid carcinoma .	However, SOX17 inhibits canonical Wnt and beta-catenin signaling and suppresses tumor growth in papillary thyroid carcinoma.	2	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
We have shown that that overexpressing recombinant Sox17 and interference with Sox17 mediated beta-catenin degradation regulates CNPase levels .	We have shown that that overexpressing recombinant Sox17 and interference with Sox17 mediated beta-catenin degradation regulates CNPase levels.	5	14	mediated	Positive_early_activation	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	11	12	13	14
Based on our previous observation of beta-catenin antagonism by Sox17 in primary rodent OPCs , we wanted to determine how recombinant Sox17 affected beta-catenin in HOG cells .	Based on our previous observation of beta-catenin antagonism by Sox17 in primary rodent OPCs, we wanted to determine how recombinant Sox17 affected beta-catenin in HOG cells.	6	13	antagonism	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	9	10	6	7
These findings suggest that Sox17 knockdown could relieve repression of the canonical beta-catenin arm of the Wnt signaling pathway .	These findings suggest that Sox17 knockdown could relieve repression of the canonical beta-catenin arm of the Wnt signaling pathway.	4	13	relieve	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	4	5	12	13
Sox17 knockdown increased the levels of cyclin D1 , Axin2 , and activated beta-catenin .	Sox17 knockdown increased the levels of cyclin D1, Axin2, and activated beta-catenin.	0	14	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	0	1	13	14
Our experiments with MG132 demonstrate that Sox17 promotes proteasomal degradation of beta-catenin in proliferating OPCs .	Our experiments with MG132 demonstrate that Sox17 promotes proteasomal degradation of beta-catenin in proliferating OPCs.	6	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	6	7	11	12
This is believed to be independent of GSK3beta activity , as Sox17 mediated degradation of beta-catenin was unaffected by lithium chloride .	This is believed to be independent of GSK3beta activity, as Sox17 mediated degradation of beta-catenin was unaffected by lithium chloride.	11	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	11	12	15	16
Our results showed that SOX17 was sufficient to suppress CRC cell proliferation , stemness and EMT by regulating beta-catenin and TCF activity .	Our results showed that SOX17 was sufficient to suppress CRC cell proliferation, stemness and EMT by regulating beta-catenin and TCF activity.	4	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	4	5	18	19
The SRY-box 17 ( Sox17 ) transcription factor is a regulator of oligodendrocyte differentiation , which was found to affect Wnt signaling at multiple levels , including Sox17 mediated proteasomal degradation of beta-catenin .	The SRY-box 17 (Sox17) transcription factor is a regulator of oligodendrocyte differentiation, which was found to affect Wnt signaling at multiple levels, including Sox17 mediated proteasomal degradation of beta-catenin.	0	33	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	4	5	32	33
Taken together , our findings suggested that SOX17 inhibited the tumor formation , proliferation and activity of the Wnt and beta-catenin signaling pathway by directly binding to the region between the -1756 and -1473 nucleotides in the beta-catenin promoter in cervical cancer cells .	Taken together, our findings suggested that SOX17 inhibited the tumor formation, proliferation and activity of the Wnt and beta-catenin signaling pathway by directly binding to the region between the -1756 and -1473 nucleotides in the beta-catenin promoter in cervical cancer cells.	7	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	7	8	20	21
The present study demonstrated that SOX17 was down-regulated during the progression of cervical cancer and that SOX17 expression inhibited the proliferation , tumor formation and activity of the Wnt and beta-catenin signaling pathway by directly binding to the promoter region of beta-catenin in cervical cancer cells .	The present study demonstrated that SOX17 was down-regulated during the progression of cervical cancer and that SOX17 expression inhibited the proliferation, tumor formation and activity of the Wnt and beta-catenin signaling pathway by directly binding to the promoter region of beta-catenin in cervical cancer cells.	16	32	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17 expression	sox17	beta-catenin	beta-catenin	beta-catenin	16	17	30	31
In particular , Sox17 promotes the degradation of both beta-catenin and TCF proteins via a noncanonical , glycogen synthase kinase 3beta independent mechanism that can be blocked by proteasome inhibitors .	In particular, Sox17 promotes the degradation of both beta-catenin and TCF proteins via a noncanonical, glycogen synthase kinase 3beta independent mechanism that can be blocked by proteasome inhibitors.	3	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	3	4	9	10
These results revealed that beta-catenin might be the key molecule , by which SOX17 attenuate the activity of Wnt and beta-catenin signaling pathway .	These results revealed that beta-catenin might be the key molecule, by which SOX17 attenuate the activity of Wnt and beta-catenin signaling pathway.	13	22	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	13	14	20	21
Sox17 promotes the degradation of beta-catenin , thus relieving the Wnt and beta-catenin / Tcf7l2 brake on differentiation .	Sox17 promotes the degradation of beta-catenin, thus relieving the Wnt and beta-catenin / Tcf7l2 brake on differentiation.	0	6	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	0	1	5	6
In the present study , the TOP and FOP flash luciferase reporter assay revealed that the Wnt and beta-catenin signaling activity was attenuated by SOX17 in cervical cancer .	In the present study, the TOP and FOP flash luciferase reporter assay revealed that the Wnt and beta-catenin signaling activity was attenuated by SOX17 in cervical cancer.	18	27	attenuated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	24	25	18	19
Consistent with SOX17 acting to inhibit the Wnt and beta-catenin pathway , our data showed that elevated SOX17 p.Y259N protein inappropriately suppressed the Wnt signaling pathway in renal cells .	Consistent with SOX17 acting to inhibit the Wnt and beta-catenin pathway, our data showed that elevated SOX17 p.Y259N protein inappropriately suppressed the Wnt signaling pathway in renal cells.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	2	3	9	10
This observation provides in vivo evidence that loss of Sox17 in the developing white matter upregulates canonical Wnt and beta-catenin signaling and supports our findings in PDGF treated cultured OPCs .	This observation provides in vivo evidence that loss of Sox17 in the developing white matter upregulates canonical Wnt and beta-catenin signaling and supports our findings in PDGF treated cultured OPCs.	7	20	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sox17	loss of Sox17	sox17	beta-catenin	beta-catenin	beta-catenin	9	10	19	20
When overexpressed in SW480 colon carcinoma cells , Sox17 represses beta-catenin and TCF activity in a dose dependent manner and inhibits proliferation .	When overexpressed in SW480 colon carcinoma cells, Sox17 represses beta-catenin and TCF activity in a dose dependent manner and inhibits proliferation.	8	20	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	8	9	10	11
Based on evidence that PDGF signaling is associated with beta-catenin accumulation in liver carcinoma and that the activity of PDGF as a mitogen and migratory signal in smooth muscle as been shown to be mediated by GSK3beta inhibition , we hypothesized that Wnt and beta-catenin activation by Sox17 knockdown in our culture system may involve PDGF .	Based on evidence that PDGF signaling is associated with beta-catenin accumulation in liver carcinoma and that the activity of PDGF as a mitogen and migratory signal in smooth muscle as been shown to be mediated by GSK3beta inhibition, we hypothesized that Wnt and beta-catenin activation by Sox17 knockdown in our culture system may involve PDGF.	42	48	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	47	48	44	45
Although beta-catenin , cyclin D1 , and c-Myc were markedly inhibited by SOX17 , p-GSK3beta failed to show significant expression change .	Although beta-catenin, cyclin D1, and c-Myc were markedly inhibited by SOX17, p-GSK3beta failed to show significant expression change.	1	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	12	13	1	2
Our results above demonstrated that SOX17 inhibited the activity of Wnt and beta-catenin signaling pathway through trans-suppressing the key molecule , beta-catenin .	Our results above demonstrated that SOX17 inhibited the activity of Wnt and beta-catenin signaling pathway through trans-suppressing the key molecule, beta-catenin.	5	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	5	6	12	13
While SOX17 promotes degradation of both beta-catenin and TCF proteins through a GSK3beta independent mechanism , SOX4 may function to stabilize beta-catenin protein .	While SOX17 promotes degradation of both beta-catenin and TCF proteins through a GSK3beta independent mechanism, SOX4 may function to stabilize beta-catenin protein.	1	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
SOX17 has been reported to promote the degradation of beta-catenin and TCF via a GSK3beta independent mechanism in the Wnt signaling pathway , and has been recognized as an important antagonist and inhibitor of the canonical Wnt signaling pathway .	SOX17 has been reported to promote the degradation of beta-catenin and TCF via a GSK3beta independent mechanism in the Wnt signaling pathway, and has been recognized as an important antagonist and inhibitor of the canonical Wnt signaling pathway.	0	26	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	0	1	9	10
SOX17 induces cell cycle arrest by trans-suppressing the Wnt and beta-catenin pathway in cervical cancer cells .	SOX17 induces cell cycle arrest by trans-suppressing the Wnt and beta-catenin pathway in cervical cancer cells.	0	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	0	1	10	11
In conclusion , SOX17 negatively regulates canonical WNT and beta-catenin signaling pathway and inhibits human HCC cells growth , providing an explanation for the loss of expression by epigenetic mechanisms in these tumors .	In conclusion, SOX17 negatively regulates canonical WNT and beta-catenin signaling pathway and inhibits human HCC cells growth, providing an explanation for the loss of expression by epigenetic mechanisms in these tumors.	3	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	3	4	9	10
Since a more than 20-fold higher Sclerostin concentration is necessary to antagonize Wnt3a in comparison to Wnt1 , this might question whether Sclerostin is a physiologically relevant Wnt3a inhibitor in vivo .	Since a more than 20-fold higher Sclerostin concentration is necessary to antagonize Wnt3a in comparison to Wnt1, this might question whether Sclerostin is a physiologically relevant Wnt3a inhibitor in vivo.	6	14	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	6	7	12	13
Several reports nevertheless showed that Sclerostin could attenuate Wnt3a activity XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , although the required concentrations to efficiently antagonize Wnt3a question the physiological relevance of Sclerostin as Wnt3a inhibitor .	Several reports nevertheless showed that Sclerostin could attenuate Wnt3a activity XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, although the required concentrations to efficiently antagonize Wnt3a question the physiological relevance of Sclerostin as Wnt3a inhibitor.	5	18	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	5	6	8	9
We could detect clear differences in the inhibition of these proteins , suggesting that the mechanism by which Sclerostin antagonizes Wnt1 and Wnt3a is fundamentally different .	We could detect clear differences in the inhibition of these proteins, suggesting that the mechanism by which Sclerostin antagonizes Wnt1 and Wnt3a is fundamentally different.	18	23	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	18	19	22	23
Moreover , sclerostin prevented Wnt3a mediated osteoblastogenesis without affecting LRP5/6 phosphorylation or beta-catenin transcriptional activity .	Moreover, sclerostin prevented Wnt3a mediated osteoblastogenesis without affecting LRP5/6 phosphorylation or beta-catenin transcriptional activity.	2	6	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	sclerostin	sclerostin	sclerostin	Wnt3a	Wnt3a	Wnt3a	2	3	4	5
This epitope was later confirmed by deletion studies of LRP5 , showing that Sclerostin mediated Wnt3a inhibition depends on the presence of the first two beta-propeller domains XREF_BIBR .	This epitope was later confirmed by deletion studies of LRP5, showing that Sclerostin mediated Wnt3a inhibition depends on the presence of the first two beta-propeller domains XREF_BIBR.	13	16	mediated	Positive_early_activation	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	13	14	15	16
Thus activation by Wnt factors as well as their inhibition by Sclerostin or Dkk family members might involve an allosteric conformational switch in the LRP ectodomain as suggested XREF_BIBR , XREF_BIBR , XREF_BIBR possibly explaining how Sclerostin can inhibit Wnt3a without sharing common binding epitopes on LRP6 .	Thus activation by Wnt factors as well as their inhibition by Sclerostin or Dkk family members might involve an allosteric conformational switch in the LRP ectodomain as suggested XREF_BIBR, XREF_BIBR, XREF_BIBR possibly explaining how Sclerostin can inhibit Wnt3a without sharing common binding epitopes on LRP6.	36	40	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	36	37	39	40
As other studies have also shown that Sclerostin can inhibit Wnt3a in vitro XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR we have to accept that Sclerostin is ( at least from a mechanistic point of view ) a Wnt3a inhibitor even though Sclerostin and Wnt3a do not exhibit overlapping binding sites on LRP6 XREF_BIBR , XREF_BIBR and thus the inhibition can not be explained by a pure competition mechanism .	As other studies have also shown that Sclerostin can inhibit Wnt3a in vitro XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR we have to accept that Sclerostin is (at least from a mechanistic point of view) a Wnt3a inhibitor even though Sclerostin and Wnt3a do not exhibit overlapping binding sites on LRP6 XREF_BIBR, XREF_BIBR and thus the inhibition can not be explained by a pure competition mechanism.	7	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	7	8	10	11
Importantly , SOST treatment inhibited canonical Wnt3a activity in combined treatments , and also reduced transcriptional coactivator with PDZ motif ( TAZ )-responsive transcriptional activity and gene expression .	Importantly, SOST treatment inhibited canonical Wnt3a activity in combined treatments, and also reduced transcriptional coactivator with PDZ motif (TAZ)-responsive transcriptional activity and gene expression.	2	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOST	SOST	SOST	Wnt3a	Wnt3a	Wnt3a	2	3	6	7
Together with the variants DeltaLoop and Alaloop of Sclerostin showing a 2.6- and 4.5-fold lower efficiency to antagonize Wnt3a ( IC 50 DeltaLoop 655 +/-143 nM , IC 50 Alaloop 1114 +/-475 nM , XREF_FIG ) these observations suggest that the inhibition of Wnt3a by Sclerostin is specific .	Together with the variants DeltaLoop and Alaloop of Sclerostin showing a 2.6- and 4.5-fold lower efficiency to antagonize Wnt3a (IC 50 DeltaLoop 655 +/-143 nM, IC 50 Alaloop 1114 +/-475 nM, XREF_FIG) these observations suggest that the inhibition of Wnt3a by Sclerostin is specific.	41	46	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	45	46	43	44
Sclerostin can inhibit Wnt3a by a mechanism different from Wnt1 inhibition .	Sclerostin can inhibit Wnt3a by a mechanism different from Wnt1 inhibition.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	0	1	3	4
Using the same in vitro binding and Xenopus assays employed to investigate the relationship between Wise and Wnt signaling XREF_BIBR , we and others have found that Sost is also able to inhibit various Wnt signaling ligands ( Wnt1 and Wnt3a ) through interactions with Lrp1 , Lrp4 , Lrp5 or Lrp6 XREF_BIBR , XREF_BIBR , XREF_BIBR .	Using the same in vitro binding and Xenopus assays employed to investigate the relationship between Wise and Wnt signaling XREF_BIBR, we and others have found that Sost is also able to inhibit various Wnt signaling ligands (Wnt1 and Wnt3a) through interactions with Lrp1, Lrp4, Lrp5 or Lrp6 XREF_BIBR, XREF_BIBR, XREF_BIBR.	27	41	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sost	Sost	Sost	Wnt3a	Wnt3a	Wnt3a	27	28	40	41
Sclerostin ( 100ng/mL ) inhibited both the effects of MLO-Y4 CM and WNT3a on C2C12 cell differentiation .	Sclerostin (100ng/mL) inhibited both the effects of MLO-Y4 CM and WNT3a on C2C12 cell differentiation.	0	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	WNT3a	WNT3a	WNT3a	0	1	12	13
In this regard , the Wnt and beta-catenin signaling pathway is anabolic in skeletal muscle [ XREF_BIBR ] and sclerostin co-incubation has been shown to abolish Wnt3a mediated C2C12 differentiation in culture , demonstrating that sclerostin antagonizes Wnt signaling in an isolated murine muscle cell line [ XREF_BIBR ] .	In this regard, the Wnt and beta-catenin signaling pathway is anabolic in skeletal muscle [XREF_BIBR] and sclerostin co-incubation has been shown to abolish Wnt3a mediated C2C12 differentiation in culture, demonstrating that sclerostin antagonizes Wnt signaling in an isolated murine muscle cell line [XREF_BIBR].	19	27	abolish	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	sclerostin	sclerostin	sclerostin	Wnt3a	Wnt3a	Wnt3a	19	20	26	27
Furthermore the Hill coefficient of the dose dependent inhibition of Wnt3a by Sclerostin clearly deviates from the expected slope being a further hint that the inhibition of Wnt3a by Sclerostin follows a different mechanism than Wnt1 ( XREF_FIG ) .	Furthermore the Hill coefficient of the dose dependent inhibition of Wnt3a by Sclerostin clearly deviates from the expected slope being a further hint that the inhibition of Wnt3a by Sclerostin follows a different mechanism than Wnt1 (XREF_FIG).	25	30	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	29	30	27	28
Finally , a direct hint that the mechanism by which Sclerostin inhibits Wnt1 and Wnt3a differs mechanistically is seen from the measurements of cytoplasmic beta-Catenin levels via in cell Western analysis .	Finally, a direct hint that the mechanism by which Sclerostin inhibits Wnt1 and Wnt3a differs mechanistically is seen from the measurements of cytoplasmic beta-Catenin levels via in cell Western analysis.	10	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	10	11	14	15
Consistent with previous reports XREF_BIBR we found that Sclerostin attenuated Wnt3a induced responses , but full inhibition was never achieved .	Consistent with previous reports XREF_BIBR we found that Sclerostin attenuated Wnt3a induced responses, but full inhibition was never achieved.	8	12	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	8	9	10	11
However , the Sclerostin neutralizing Fab antibody AbD09097 XREF_BIBR rescues Sclerostin mediated Wnt3a inhibition ( XREF_FIG ) .	However, the Sclerostin neutralizing Fab antibody AbD09097 XREF_BIBR rescues Sclerostin mediated Wnt3a inhibition (XREF_FIG).	9	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	10	11	12	13
Using peptides identical to a short connexin ( Cx ) amino acid sequence to specifically block hemichannels , we found that protein kinase C , Src , and lysophosphatidic acid ( LPA ) inhibited GJs and hemichannel mediated ATP release in Cx43 expressing C6 glioma cells ( C6-Cx43 ) .	Using peptides identical to a short connexin (Cx) amino acid sequence to specifically block hemichannels, we found that protein kinase C, Src, and lysophosphatidic acid (LPA) inhibited GJs and hemichannel mediated ATP release in Cx43 expressing C6 glioma cells (C6-Cx43).	23	42	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	Cx43	Cx43	Cx43	25	26	41	42
Tyrosine phosphorylation was found to be a hallmark of Src mediated Cx43 inhibition , and it was demonstrated that Src phosphorylates the Cx43 CT on residues Y247 and Y265 [ XREF_BIBR ] .	Tyrosine phosphorylation was found to be a hallmark of Src mediated Cx43 inhibition, and it was demonstrated that Src phosphorylates the Cx43 CT on residues Y247 and Y265 [XREF_BIBR].	7	12	mediated	Positive_early_activation	Negative_activation	Negative_activation	Src	Src	Src	Cx43	Cx43	Cx43	9	10	11	12
Since oxidative stress activates c-Src , c-Src downregulates Cx43 , and Cx43 levels are inversely related to arrhythmic risk , this represents another ROS dependent mechanism that may increase arrhythmic risk .	Since oxidative stress activates c-Src, c-Src downregulates Cx43, and Cx43 levels are inversely related to arrhythmic risk, this represents another ROS dependent mechanism that may increase arrhythmic risk.	6	9	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	Cx43	Cx43	Cx43	6	7	8	9
Inhibition of c-Src following MI increases Cx43 , improves CV , reduces arrhythmia inducibility , and may represent a new approach to arrhythmia reduction in ischemic cardiomyopathy .	Inhibition of c-Src following MI increases Cx43, improves CV, reduces arrhythmia inducibility, and may represent a new approach to arrhythmia reduction in ischemic cardiomyopathy.	0	7	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	Cx43	Cx43	Cx43	2	3	6	7
PP1 reduced total and phospho c-Src levels , increased the Cx43 level by 2.1-fold ( P < 0.005 ) , increased Cx43 at the gap junctions ( immunostaining ) , improved gap junctional communication ( dye spread ) , and reduced ventricular tachycardia inducibility and sudden cardiac death .	PP1 reduced total and phospho c-Src levels, increased the Cx43 level by 2.1-fold (P < 0.005), increased Cx43 at the gap junctions (immunostaining), improved gap junctional communication (dye spread), and reduced ventricular tachycardia inducibility and sudden cardiac death.	0	12	increased	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	c-Src	PP1 reduced total and phospho c-Src levels	c-src	Cx43	Cx43 level	cx43	5	6	10	11
CK1 phosphorylation is shown to promote cell communication , while the effects of Src and MAPK appear to inhibit Cx43 channel gating by affecting channel closure .	CK1 phosphorylation is shown to promote cell communication, while the effects of Src and MAPK appear to inhibit Cx43 channel gating by affecting channel closure.	11	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	Cx43	Cx43	Cx43	13	14	19	20
We postulated that a cause of Cx43 reduction and sudden death in ACE8/8 mice was an increased level of c-Src and that the inhibition of c-Src would increase Cx43 and improve survival in ACE8/8 mice .	We postulated that a cause of Cx43 reduction and sudden death in ACE8/8 mice was an increased level of c-Src and that the inhibition of c-Src would increase Cx43 and improve survival in ACE8/8 mice.	23	29	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	Cx43	Cx43	Cx43	25	26	28	29
RAS activation is associated with c-Src upregulation , Cx43 loss , reduced myocyte coupling , and arrhythmic sudden death , which can be prevented by c-Src inhibition .	RAS activation is associated with c-Src upregulation, Cx43 loss, reduced myocyte coupling, and arrhythmic sudden death, which can be prevented by c-Src inhibition.	8	26	prevented	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	Cx43	Cx43	Cx43	25	26	8	9
Conversely , Src phosphorylation of S279 and S282 have been shown to mediate Cx43 endocytosis [ XREF_BIBR , XREF_BIBR ] , indicating that targeting of Src mediated Cx43 phosphorlation may prevent injury mediated endocytosis of GJs .	Conversely, Src phosphorylation of S279 and S282 have been shown to mediate Cx43 endocytosis [XREF_BIBR, XREF_BIBR], indicating that targeting of Src mediated Cx43 phosphorlation may prevent injury mediated endocytosis of GJs.	23	28	mediated	Positive_early_activation	Negative_activation	Positive_activation	Src	Src	Src	Cx43	Cx43	Cx43	25	26	27	28
Constitutively active c-Src also inhibited interactions of Cx43 with ZO-1 , although the molecular mechanisms by which this occurred were not explored .	Constitutively active c-Src also inhibited interactions of Cx43 with ZO-1, although the molecular mechanisms by which this occurred were not explored.	1	8	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	Cx43	Cx43	Cx43	2	3	7	8
Cell surface biotinylation revealed that , by phosphorylating Tyr265 , constitutively active c-Src reduces total and cell surface connexin-43 down to the levels seen in cells expressing a mutant connexin-43 lacking the ZO-1 binding domain .	Cell surface biotinylation revealed that, by phosphorylating Tyr265, constitutively active c-Src reduces total and cell surface connexin-43 down to the levels seen in cells expressing a mutant connexin-43 lacking the ZO-1 binding domain.	11	19	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	connexin-43	connexin-43	connexin-43	12	13	18	19
Taken together , the data indicate that activated Src inhibits PTEN function leading to alterations in signaling through the PI3K and AKT pathway .	Taken together, the data indicate that activated Src inhibits PTEN function leading to alterations in signaling through the PI3K and AKT pathway.	7	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	PTEN	PTEN	PTEN	8	9	10	11
In particular , enhanced Src activity diminishes PTEN stability and therefore facilities an increase in AKT activation [ XREF_BIBR ] .	In particular, enhanced Src activity diminishes PTEN stability and therefore facilities an increase in AKT activation [XREF_BIBR].	4	8	diminishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	PTEN	PTEN	PTEN	4	5	7	8
The action of trastuzumab is dependent on HER-2 signaling through Src hyperactivation , which further inhibits PTEN and its downstream PI3K and AKT signaling in cell proliferation .	The action of trastuzumab is dependent on HER-2 signaling through Src hyperactivation, which further inhibits PTEN and its downstream PI3K and AKT signaling in cell proliferation.	10	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	PTEN	PTEN	PTEN	10	11	16	17
Src was shown to interact with and reduce the stability of PTEN resulting in an increase in the PI3K and Akt pathway [ XREF_BIBR ] .	Src was shown to interact with and reduce the stability of PTEN resulting in an increase in the PI3K and Akt pathway [XREF_BIBR].	0	12	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	PTEN	PTEN	PTEN	0	1	11	12
However , in the presence of functional PTEN , Src reverses the activity of PTEN , resulting in an increase in AKT phosphorylation .	However, in the presence of functional PTEN, Src reverses the activity of PTEN, resulting in an increase in AKT phosphorylation.	9	15	reverses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	PTEN	PTEN	PTEN	9	10	14	15
Because the activity of c-Src promotes PTEN degradation and reduces its ability to inhibit the PI3K and Akt pathway [ XREF_BIBR ] , we analyzed the involvement of c-Src in the effect of Cx43 on PTEN .	Because the activity of c-Src promotes PTEN degradation and reduces its ability to inhibit the PI3K and Akt pathway [XREF_BIBR], we analyzed the involvement of c-Src in the effect of Cx43 on PTEN.	2	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	PTEN	PTEN	PTEN	4	5	6	7
Because Src inhibitors can reverse Src induced suppression of PTEN function XREF_BIBR , the ineffectiveness of bosutinib on these cells actually suggested a stronger LOF effect of nonsense mutations over missense mutations .	Because Src inhibitors can reverse Src induced suppression of PTEN function XREF_BIBR, the ineffectiveness of bosutinib on these cells actually suggested a stronger LOF effect of nonsense mutations over missense mutations.	4	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	PTEN	PTEN	PTEN	5	6	9	10
For instance , greater activity of Src reduces the stability of PTEN , resulting in an increase in the Akt pathway .	For instance, greater activity of Src reduces the stability of PTEN, resulting in an increase in the Akt pathway.	4	12	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	PTEN	PTEN	PTEN	6	7	11	12
Src does not only transactivate EGFR , but also inhibits PTEN by phosphorylation thus playing a crucial role in apelin induced cardioprotection .	Src does not only transactivate EGFR, but also inhibits PTEN by phosphorylation thus playing a crucial role in apelin induced cardioprotection.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	PTEN	PTEN	PTEN	0	1	10	11
To investigate how MSCs mediated activation of Src regulates phosphatase and tension homolog ( PTEN ) , we examined whether breast cancer cells in co-culture with MSCs may inhibit PTEN , since Src activation has recently been reported to promote loss of PTEN XREF_BIBR .	To investigate how MSCs mediated activation of Src regulates phosphatase and tension homolog (PTEN), we examined whether breast cancer cells in co-culture with MSCs may inhibit PTEN, since Src activation has recently been reported to promote loss of PTEN XREF_BIBR.	32	43	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	PTEN	PTEN	PTEN	32	33	42	43
Furthermore , we find that Src activated breast cancer lines show reduced p27 and observe a correlation between Src activation and reduced nuclear p27 in 482 primary human breast cancers .	Furthermore, we find that Src activated breast cancer lines show reduced p27 and observe a correlation between Src activation and reduced nuclear p27 in 482 primary human breast cancers.	5	24	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	p27	p27	p27	5	6	23	24
Src activated breast cancer cell lines display reduced p27 .	Src activated breast cancer cell lines display reduced p27.	0	9	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	p27	p27	p27	0	1	8	9
Finally , SRC was shown to phosphorylate p27 at Tyr74 and Tyr88 , resulting in less nuclear p27 due to an accumulation of cytoplasmic p27 ; pharmacological inhibition of SRC subsequently restored p27 function ( see also section ' Drug resistance ' ) As mentioned previously , p21 and p27 inactivation can also occur through binding and subsequent sequestration by cyclin-D-CDK4/6 .	Finally, SRC was shown to phosphorylate p27 at Tyr74 and Tyr88, resulting in less nuclear p27 due to an accumulation of cytoplasmic p27; pharmacological inhibition of SRC subsequently restored p27 function (see also section ' Drug resistance ') As mentioned previously, p21 and p27 inactivation can also occur through binding and subsequent sequestration by cyclin-D-CDK4/6.	27	33	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SRC	SRC	SRC	p27	p27	p27	29	30	32	33
It has been reported that the oncogenic activation of RTK , PI3K , SRC , or Ras-MAPK pathways cooperate to inactivate p27Kip1 , accelerate its proteolysis or change its intracellular localization in human cancers through modifications in p27Kip1 phosphorylation XREF_BIBR .	It has been reported that the oncogenic activation of RTK, PI3K, SRC, or Ras-MAPK pathways cooperate to inactivate p27Kip1, accelerate its proteolysis or change its intracellular localization in human cancers through modifications in p27Kip1 phosphorylation XREF_BIBR.	7	22	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SRC	SRC	SRC	p27Kip1	p27Kip1	p27Kip1	13	14	21	22
Src inhibitors increase cellular p27 stability , whereas Src overexpression accelerates p27 proteolysis [ XREF_BIBR ] .	Src inhibitors increase cellular p27 stability, whereas Src overexpression accelerates p27 proteolysis [XREF_BIBR].	8	12	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src overexpression	src	p27	p27	p27	8	9	11	12
c-src plays an important role in cell cycle progression in many tumor cells , and suppressing c-src downregulates cyclin D1 and cyclin E and upregulates p27 Kip1 [ XREF_BIBR ] .	c-src plays an important role in cell cycle progression in many tumor cells, and suppressing c-src downregulates cyclin D1 and cyclin E and upregulates p27 Kip1 [XREF_BIBR].	15	27	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-src	c-src	c-src	p27 Kip1	p27 Kip1	p27 Kip1	16	17	25	27
Furthermore , Src inhibition decreased expression of cell proliferation marker ( PCNA ) and inhibited expression of positive regulators of cell cycle progression ( cyclin D and cyclin E ) , and conversely , increased expression levels of cell cycle suppressors ( p21 and p27 ) .	Furthermore, Src inhibition decreased expression of cell proliferation marker (PCNA) and inhibited expression of positive regulators of cell cycle progression (cyclin D and cyclin E), and conversely, increased expression levels of cell cycle suppressors (p21 and p27).	2	45	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	p27	p27	p27	2	3	44	45
Src inhibitors increase cellular p27 stability , and Src overexpression accelerates p27 proteolysis .	Src inhibitors increase cellular p27 stability, and Src overexpression accelerates p27 proteolysis.	8	12	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src overexpression	src	p27	p27	p27	8	9	11	12
In fact , cortactin is inhibited by Src phosphorylation , and p140Cap directly binds Src and suppresses its activation through binding to the C-terminal Src kinase ( Csk ) .	In fact, cortactin is inhibited by Src phosphorylation, and p140Cap directly binds Src and suppresses its activation through binding to the C-terminal Src kinase (Csk).	3	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Src	Src phosphorylation	src	cortactin	cortactin	cortactin	7	8	3	4
The catalytic activity of Src is inhibited by phosphorylated-CagA , leading to tyrosine dephosphorylation of the actin binding proteins cortactin , ezrin , and vinculin , which ultimately results in cellular rearrangements and elongation .	The catalytic activity of Src is inhibited by phosphorylated-CagA, leading to tyrosine dephosphorylation of the actin binding proteins cortactin, ezrin, and vinculin, which ultimately results in cellular rearrangements and elongation.	2	21	leading	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	cortactin	cortactin	cortactin	4	5	19	20
55 By suppressing cellular levels of PTPdelta , MTSS1 inhibits the dephosphorylation and activation of Src , thereby blocking the activation of CTTN .	55 By suppressing cellular levels of PTPdelta, MTSS1 inhibits the dephosphorylation and activation of Src, thereby blocking the activation of CTTN.	8	23	blocking	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	MTSS1 inhibits the dephosphorylation and activation of Src	src	CTTN	CTTN	cttn	15	16	22	23
Additionally , tyrosine phosphorylation of cortactin in MKN45 cells treated with inhibitors of Src , Abl or Met , correlate with the ability of treated cells to form invadopodia , with Met inhibition exerting the strongest impact ( XREF_FIG ) .	Additionally, tyrosine phosphorylation of cortactin in MKN45 cells treated with inhibitors of Src, Abl or Met, correlate with the ability of treated cells to form invadopodia, with Met inhibition exerting the strongest impact (XREF_FIG).	3	17	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	Src	Src	Src	cortactin	cortactin	cortactin	13	14	5	6
SRGAP3 has been proposed to locally deactivate RAC1 activity at the leading edge of migrating cells through its interactions with lamellipodium associated components ( XREF_FIG ) .	SRGAP3 has been proposed to locally deactivate RAC1 activity at the leading edge of migrating cells through its interactions with lamellipodium associated components (XREF_FIG).	0	8	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SRGAP3	SRGAP3	SRGAP3	RAC1	RAC1	RAC1	0	1	7	8
For example , SRGAP3 attenuates RAC1 mediated neurite outgrowth by binding to the WASF1 ( WAVE1 and Scar ) complex , which is itself a RAC1 effector .	For example, SRGAP3 attenuates RAC1 mediated neurite outgrowth by binding to the WASF1 (WAVE1 and Scar) complex, which is itself a RAC1 effector.	3	26	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SRGAP3	SRGAP3	SRGAP3	RAC1	RAC1	RAC1	3	4	25	26
Among these members , srGAP1 preferentially inhibits Cdc42 , whereas srGAP2 and srGAP3 downregulate Rac1 .	Among these members, srGAP1 preferentially inhibits Cdc42, whereas srGAP2 and srGAP3 downregulate Rac1.	10	15	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	srGAP3	srGAP3	srGAP3	Rac1	Rac1	Rac1	12	13	14	15
Since srGAP2 integrates both membrane topology and Slit-Robo repulsive signals , this mechanism ensures that srGAP2 inactivates Rac1 at the right subcellular region and in a specific morphodynamic phase .	Since srGAP2 integrates both membrane topology and Slit-Robo repulsive signals, this mechanism ensures that srGAP2 inactivates Rac1 at the right subcellular region and in a specific morphodynamic phase.	15	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	srGAP2	srGAP2	srGAP2	Rac1	Rac1	Rac1	15	16	17	18
Furthermore , the concept that Spi-1 could inhibit the function of GATA-1 in erythroleukemic cells is supported by the reversal of tumorigenicity and the re-initiation of a differentiation program when GATA-1 expression is ectopically imposed in a Friend tumor cell line [ XREF_BIBR ] .	Furthermore, the concept that Spi-1 could inhibit the function of GATA-1 in erythroleukemic cells is supported by the reversal of tumorigenicity and the re-initiation of a differentiation program when GATA-1 expression is ectopically imposed in a Friend tumor cell line [XREF_BIBR].	5	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Spi-1	Spi-1	Spi-1	GATA-1	GATA-1	GATA-1	5	6	11	12
Nonetheless , target genes for GATA-1 , such as EKLF , NF-E2 , beta globin , EpoR and GATA-1-itself are expressed in both Friend and spi-1 transgenic cells [ XREF_BIBR ] ( our unpublished data ) indicating that some GATA-1 functions are not abolished by Spi-1 overexpression .	Nonetheless, target genes for GATA-1, such as EKLF, NF-E2, beta globin, EpoR and GATA-1-itself are expressed in both Friend and spi-1 transgenic cells [XREF_BIBR] (our unpublished data) indicating that some GATA-1 functions are not abolished by Spi-1 overexpression.	39	47	abolished	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Spi-1	Spi-1 overexpression	spi-1	GATA-1	GATA-1	gata-1	45	46	39	40
Radicicol further reduced c-Src protein abundance , increased the ubiquitination of caspase-8 and c-Src , and enhanced the cleavage of caspase-8 and -3 .	Radicicol further reduced c-Src protein abundance, increased the ubiquitination of caspase-8 and c-Src, and enhanced the cleavage of caspase-8 and -3.	0	22	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-Src	Radicicol further reduced c-Src protein abundance, increased the ubiquitination of caspase-8 and c-Src	c-src	caspase-8	caspase-8	caspase-8	13	14	20	21
The endometriotic 70-kDa SRC-1 isoform also interacts with caspase 8 to inhibit caspase 8 activation in ectopic lesions to promote their survival .	The endometriotic 70-kDa SRC-1 isoform also interacts with caspase 8 to inhibit caspase 8 activation in ectopic lesions to promote their survival.	3	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SRC-1	SRC-1	SRC-1	caspase 8	caspase 8	caspase 8	3	4	12	14
The Src family tyrosine kinases Src , Fyn , and Lyn phosphorylate tyrosine 380 ( Y380 ) and suppress caspase-8 activation .	The Src family tyrosine kinases Src, Fyn, and Lyn phosphorylate tyrosine 380 (Y380) and suppress caspase-8 activation.	1	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	caspase-8	caspase-8	caspase-8	1	2	19	20
In contrast , inhibition of c-Src still increased the numbers of surface ROMK1 in cells treated with boiled tetanus toxin .	In contrast, inhibition of c-Src still increased the numbers of surface ROMK1 in cells treated with boiled tetanus toxin.	3	13	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	ROMK1	ROMK1	ROMK1	5	6	12	13
To determine whether SNARE proteins are involved in mediating exocytosis of ROMK1 induced by the inhibition of c-Src , we examined the effect of herbimycin A on ROMK1 trafficking in cells treated with tetanus toxin .	To determine whether SNARE proteins are involved in mediating exocytosis of ROMK1 induced by the inhibition of c-Src, we examined the effect of herbimycin A on ROMK1 trafficking in cells treated with tetanus toxin.	9	18	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	ROMK1	ROMK1	ROMK1	17	18	11	12
The biotin labeling technique demonstrated that the inhibition of c-Src increased surface ROMK1 by 110 % .	The biotin labeling technique demonstrated that the inhibition of c-Src increased surface ROMK1 by 110%.	7	13	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	ROMK1	ROMK1	ROMK1	9	10	12	13
It was found that constitutively active c-Src diminished propagation of Ca ( 2+ ) waves in HEK293 cells and reduced gap junctional conductance between pairs of cardiac myocytes .	It was found that constitutively active c-Src diminished propagation of Ca (2+) waves in HEK293 cells and reduced gap junctional conductance between pairs of cardiac myocytes.	5	22	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	gap	gap	gap	6	7	20	21
Since Src is known to suppress gap junctional communication in cultured cells such as rodent fibroblasts and epithelial cells , it is tempting to speculate that Src may be responsible , at least in part , for gap junction closure in these lines .	Since Src is known to suppress gap junctional communication in cultured cells such as rodent fibroblasts and epithelial cells, it is tempting to speculate that Src may be responsible, at least in part, for gap junction closure in these lines.	1	8	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	gap	gap	gap	1	2	6	7
In addition , Src activation blocks the activity of Rasa1 [ XREF_BIBR ] , while stimulating Pak2 and Pak4 activation and Raf activation [ XREF_BIBR ] .	In addition, Src activation blocks the activity of Rasa1 [XREF_BIBR], while stimulating Pak2 and Pak4 activation and Raf activation [XREF_BIBR].	3	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	Rasa1	Rasa1	Rasa1	3	4	9	10
Since Src is known to suppress gap junctional communication it is tempting to speculate that Src may be responsible , at least in part , for gap junction closure in these lines .	Since Src is known to suppress gap junctional communication it is tempting to speculate that Src may be responsible, at least in part, for gap junction closure in these lines.	1	8	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	gap	gap	gap	1	2	6	7
SPEN is a co-repressor of RBPJ , the nuclear effector of the NOTCH1 pathway , and a putative negative regulator of NOTCH1 signaling .	SPEN is a co-repressor of RBPJ, the nuclear effector of the NOTCH1 pathway, and a putative negative regulator of NOTCH1 signaling.	0	6	is a co-repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	SPEN	SPEN	SPEN	RBPJ	RBPJ	RBPJ	0	1	5	6
SPEN is a co-repressor of RBPJ and a putative negative regulator of NOTCH1 signaling .	SPEN is a co-repressor of RBPJ and a putative negative regulator of NOTCH1 signaling.	0	6	is a co-repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	SPEN	SPEN	SPEN	RBPJ	RBPJ	RBPJ	0	1	5	6
ACCs can harbor activating mutations in NOTCH1 or loss of function mutations in the RBPJ repressor SPEN XREF_BIBR , XREF_BIBR , XREF_BIBR .	ACCs can harbor activating mutations in NOTCH1 or loss of function mutations in the RBPJ repressor SPEN XREF_BIBR, XREF_BIBR, XREF_BIBR.	14	21	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	SPEN	SPEN	SPEN	RBPJ	RBPJ	RBPJ	16	17	14	15
Gas6 treated endothelial cells were transfected with small interfering RNA ( siRNA ) for Axl , caveolin-1 , c-Src , and Akt or treated with pharmacological inhibitors of c-Src and ERK1/2 .	Gas6 treated endothelial cells were transfected with small interfering RNA (siRNA) for Axl, caveolin-1, c-Src, and Akt or treated with pharmacological inhibitors of c-Src and ERK1/2.	14	30	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	caveolin-1	caveolin-1	caveolin-1	28	29	16	17
Moreover , knockdown of the Na/K-ATPase increases basal levels of active Src and stimulates endocytosis of Cav1 from the plasma membrane .	Moreover, knockdown of the Na/K-ATPase increases basal levels of active Src and stimulates endocytosis of Cav1 from the plasma membrane.	5	17	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Na/K-ATPase increases basal levels of active Src	src	Cav1	Cav1	cav1	11	12	16	17
As expected , inhibition of Src or NOX1 increased TGF-beta-induced cell death in Cav1 ( +/+ ) cells .	As expected, inhibition of Src or NOX1 increased TGF-beta-induced cell death in Cav1 (+/+) cells.	3	15	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Src	Src	Src	Cav1	Cav1	Cav1	5	6	13	14
Another possible mechanism by which SOX6 may antagonize Wnt and beta-catenin activity is by repressing WISP3 , an activator of this pathway [ XREF_BIBR ] .	Another possible mechanism by which SOX6 may antagonize Wnt and beta-catenin activity is by repressing WISP3, an activator of this pathway [XREF_BIBR].	5	11	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX6	SOX6	SOX6	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
Sox6 also has been reported to interact with HDAC1 and can inhibit beta-catenin dependent transcriptional activation via direct interaction .	Sox6 also has been reported to interact with HDAC1 and can inhibit beta-catenin dependent transcriptional activation via direct interaction.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sox6	Sox6	Sox6	beta-catenin	beta-catenin	beta-catenin	0	1	12	13
In pancreatic beta-cells , SOX6 inhibited cyclin D1 promoter activity and negatively regulated cell proliferation by interacting with histone deacetylase 1 ( HDAC1 ) and beta-catenin [ XREF_BIBR ] .	In pancreatic beta-cells, SOX6 inhibited cyclin D1 promoter activity and negatively regulated cell proliferation by interacting with histone deacetylase 1 (HDAC1) and beta-catenin [XREF_BIBR].	4	27	negatively regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX6	SOX6	SOX6	beta-catenin	beta-catenin	beta-catenin	4	5	25	26
Importantly , the beneficial effects of rapamycin on mitochondrial function were absent in brains and fibroblasts from first generation TERT -/- mice , and when TERT shuttling was inhibited by the Src kinase inhibitor bosutinib .	Importantly, the beneficial effects of rapamycin on mitochondrial function were absent in brains and fibroblasts from first generation TERT -/- mice, and when TERT shuttling was inhibited by the Src kinase inhibitor bosutinib.	25	34	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Src	Src	Src	TERT	TERT	TERT	31	32	25	26
TERT is required for proper endothelial cell function and is inactivated by Src kinase under conditions of oxidative stress .	TERT is required for proper endothelial cell function and is inactivated by Src kinase under conditions of oxidative stress.	0	13	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Src	Src	Src	TERT	TERT	TERT	12	13	0	1
Spry4 reduces migration and invasion in NSCLC and reduces MMP-9 activity .	Spry4 reduces migration and invasion in NSCLC and reduces MMP-9 activity.	0	10	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Spry4	Spry4	Spry4	MMP-9	MMP-9	MMP-9	0	1	9	10
Sufu physically interacts with and represses the transcriptional activities of Gli proteins in the absence of cilia , raising the possibility that these proteins may form a complex prior to their ciliary localization XREF_BIBR , XREF_BIBR .	Sufu physically interacts with and represses the transcriptional activities of Gli proteins in the absence of cilia, raising the possibility that these proteins may form a complex prior to their ciliary localization XREF_BIBR, XREF_BIBR.	0	11	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	0	1	10	11
The greater abundance of GLI1 130 over GLI1 FL is consistent with the deduced absence in GLI1 130 of two inhibitory sites in the N-terminus of GLI1 FL : an N ' degron and a key binding site for the GLI1 antagonist SUFUH .	The greater abundance of GLI1 130 over GLI1 FL is consistent with the deduced absence in GLI1 130 of two inhibitory sites in the N-terminus of GLI1 FL : an N ' degron and a key binding site for the GLI1 antagonist SUFUH.	37	43	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	SUFUH	SUFUH	SUFUH	GLI1	GLI1	GLI1	42	43	40	41
The demonstration that deficiency of Sufu can lead to full activation of Hh signaling even in the absence of cilia ( Ift88 mutant cells ) indicated that a primary function of cilia is to remove Sufu inhibition of Gli activity [ XREF_BIBR ] .	The demonstration that deficiency of Sufu can lead to full activation of Hh signaling even in the absence of cilia (Ift88 mutant cells) indicated that a primary function of cilia is to remove Sufu inhibition of Gli activity [XREF_BIBR].	35	41	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	35	36	38	39
It has been reported that without HH ligand stimulation , Gli1 function is inhibited by SuFu .	It has been reported that without HH ligand stimulation, Gli1 function is inhibited by SuFu.	10	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Gli1	Gli1	Gli1	15	16	10	11
SUFU suppresses GLI activity by sequestering GLI in the cytoplasm [ XREF_BIBR ] .	SUFU suppresses GLI activity by sequestering GLI in the cytoplasm [XREF_BIBR].	0	3	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	0	1	2	3
Despite co-localization of Sufu and Gli proteins at the tips of primary cilia , Sufu inhibits Gli activator function in the absence of cilia XREF_BIBR , XREF_BIBR , XREF_BIBR .	Despite co-localization of Sufu and Gli proteins at the tips of primary cilia, Sufu inhibits Gli activator function in the absence of cilia XREF_BIBR, XREF_BIBR, XREF_BIBR.	14	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	14	15	16	17
Furthermore , Sufu overexpression decreased the binding between Numb and Gli1 ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	Furthermore, Sufu overexpression decreased the binding between Numb and Gli1 (XREF_FIG; XREF_SUPPLEMENTARY).	2	12	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu overexpression	sufu	Gli1	Gli1	gli1	2	3	10	11
SUFU suppresses GLI1 activity through direct binding to its N- and C-domains , sequestering it in the cytoplasm , and scaffolding GLI1 to transcriptional co-repressors [ XREF_BIBR , XREF_BIBR ] .	SUFU suppresses GLI1 activity through direct binding to its N- and C-domains, sequestering it in the cytoplasm, and scaffolding GLI1 to transcriptional co-repressors [XREF_BIBR, XREF_BIBR].	0	3	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI1	GLI1	GLI1	0	1	2	3
SuFu also acts to inhibit the activation of Gli [ XREF_BIBR , XREF_BIBR ] .	SuFu also acts to inhibit the activation of Gli [XREF_BIBR, XREF_BIBR].	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Gli	Gli	Gli	0	1	8	9
This pathway is ultimately transmitted by the zinc-finger transcriptional factor Gli , of which activity is suppressed by Sufu , a negative regulator of this signaling .	This pathway is ultimately transmitted by the zinc-finger transcriptional factor Gli, of which activity is suppressed by Sufu, a negative regulator of this signaling.	4	22	suppressed	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	18	19	10	11
Sufu directly interacts with , and appears to sequester Gli proteins in the cytoplasm XREF_BIBR , XREF_BIBR , XREF_BIBR .	Sufu directly interacts with, and appears to sequester Gli proteins in the cytoplasm XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	10	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	0	1	9	10
Gli1 binds to and is inhibited by SuFu .	Gli1 binds to and is inhibited by SuFu.	0	8	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Gli1	Gli1	Gli1	7	8	0	1
While SUFU negatively regulates GLI1 , the dual specificity Yak1 related kinase Dyrk1 appears to potentiate GLI1 activity .	While SUFU negatively regulates GLI1, the dual specificity Yak1 related kinase Dyrk1 appears to potentiate GLI1 activity.	1	5	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI1	GLI1	GLI1	1	2	4	5
Alternatively , as Sufu antagonizes Gli activity in the nucleus , our data may be an indication that cilia localization of Sufu is not a prerequisite for its nuclear function .	Alternatively, as Sufu antagonizes Gli activity in the nucleus, our data may be an indication that cilia localization of Sufu is not a prerequisite for its nuclear function.	3	6	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	3	4	5	6
Transfection of a SUFU cDNA harboring the T411M missense mutation suppressed Gli reporter gene downregulation as observed with wild-type SUFU [ XREF_BIBR ] , although it is unclear whether such results were observed with similar levels of SUFU protein expressed .	Transfection of a SUFU cDNA harboring the T411M missense mutation suppressed Gli reporter gene downregulation as observed with wild-type SUFU [XREF_BIBR], although it is unclear whether such results were observed with similar levels of SUFU protein expressed.	3	14	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	Gli	Gli	Gli	3	4	11	12
Interestingly , SUFU overexpression , which is expected to inhibit GLI1 , also produced similar effects in NIH3T3 cells .	Interestingly, SUFU overexpression, which is expected to inhibit GLI1, also produced similar effects in NIH3T3 cells.	2	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU overexpression	sufu	GLI1	GLI1	gli1	2	3	10	11
In vertebrates , Sufu inhibits Gli mediated transcriptional activation in the nucleus by recruiting a histone deacetylation complex to Gli target genes .	In vertebrates, Sufu inhibits Gli mediated transcriptional activation in the nucleus by recruiting a histone deacetylation complex to Gli target genes.	3	17	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Sufu	Sufu	sufu	Gli	Gli mediated transcriptional activation in the nucleus by recruiting a histone deacetylation	gli	3	4	5	6
Sufu not only negatively regulates the activity of Gli , but also protects its protein expression level from being downregulated by the Spop mediated ubiquitination and degradation XREF_BIBR - XREF_BIBR .	Sufu not only negatively regulates the activity of Gli, but also protects its protein expression level from being downregulated by the Spop mediated ubiquitination and degradation XREF_BIBR - XREF_BIBR.	0	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	0	1	8	9
In steps 9-14 spermatids ( stages IX-XIV ) Hh signalling is turned off by SUFU that sequesters GLI1 in the cytoplasm .	In steps 9-14 spermatids (stages IX-XIV) Hh signalling is turned off by SUFU that sequesters GLI1 in the cytoplasm.	11	20	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI1	GLI1	GLI1	14	15	17	18
This is a critical transduction step between SMO and PKA and SuFu ( suppression of Gli proteolytic processing ) , and results in the inhibition of Gli3 repressor formation ( recruitment of Gli proteins and SuFu to the tips of cilia ) and the induction of activated Gli2 and Gli3 .	This is a critical transduction step between SMO and PKA and SuFu (suppression of Gli proteolytic processing), and results in the inhibition of Gli3 repressor formation (recruitment of Gli proteins and SuFu to the tips of cilia) and the induction of activated Gli2 and Gli3.	5	17	suppression	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Gli	Gli	Gli	11	12	15	16
Sufu can sequester Gli proteins in the cytoplasm , but can also interact with Gli bound to DNA .	Sufu can sequester Gli proteins in the cytoplasm, but can also interact with Gli bound to DNA.	0	12	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	0	1	3	4
In addition to be regulated by ubiquitination , Gli1 can also be modulated by SUFU , which interacts with and inhibits Gli1 activation by sequestering it in the cytosol .	In addition to be regulated by ubiquitination, Gli1 can also be modulated by SUFU, which interacts with and inhibits Gli1 activation by sequestering it in the cytosol.	12	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	Gli1	Gli1	Gli1	14	15	21	22
Furthermore , clinical trials on colorectal , ovarian and pancreatic cancer failed to demonstrate therapeutic efficacy of SMO inhibition [ XREF_BIBR ] , which may at least in part be due to SMO independent activation of oncogenic GLI activity by for instance TGFbeta , RAS , PI3K/AKT/S6K or genetic deletion of the GLI repressor SUFU .	Furthermore, clinical trials on colorectal, ovarian and pancreatic cancer failed to demonstrate therapeutic efficacy of SMO inhibition [XREF_BIBR], which may at least in part be due to SMO independent activation of oncogenic GLI activity by for instance TGFbeta, RAS, PI3K/AKT/S6K or genetic deletion of the GLI repressor SUFU.	49	55	repressor	Negative_activation_token_1_noun	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	54	55	52	53
Ras can regulate the nuclear localization of GLI1 via SUFU based on the report that enhanced levels of SUFU prevented nuclear localization of GLI induced by oncogenic Ras .	Ras can regulate the nuclear localization of GLI1 via SUFU based on the report that enhanced levels of SUFU prevented nuclear localization of GLI induced by oncogenic Ras.	16	24	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	levels of SUFU	sufu	GLI	GLI	gli	18	19	23	24
At the same time , we also determined the ability of the various mutant MCL-1 proteins to overcome SUFU mediated GLI inhibition using the GLI-BS reporter ( XREF_SUPPLEMENTARY ) .	At the same time, we also determined the ability of the various mutant MCL-1 proteins to overcome SUFU mediated GLI inhibition using the GLI-BS reporter (XREF_SUPPLEMENTARY).	18	21	mediated	Positive_early_activation	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	18	19	20	21
Sufu inhibits Gli activated reporter expression in the absence of cilia .	Sufu inhibits Gli activated reporter expression in the absence of cilia.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	0	1	2	3
Dissociation of GLI and SUFU blocks GLI processing to give repressor forms and results in accumulation of GLI in cilia .	Dissociation of GLI and SUFU blocks GLI processing to give repressor forms and results in accumulation of GLI in cilia.	0	7	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	4	5	6	7
SUFU inhibits GLI mediated transcriptional activation in the nucleus by recruiting a histone deacetylation complex to GLI target genes XREF_BIBR , XREF_BIBR .	SUFU inhibits GLI mediated transcriptional activation in the nucleus by recruiting a histone deacetylation complex to GLI target genes XREF_BIBR, XREF_BIBR.	0	14	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	SUFU	SUFU	sufu	GLI	GLI mediated transcriptional activation in the nucleus by recruiting a histone deacetylation	gli	0	1	2	3
This implies that Sufu also attenuates Gli1 activity and that Kif7 acts in concert with Sufu to restrain Gli1 activity in the myotome .	This implies that Sufu also attenuates Gli1 activity and that Kif7 acts in concert with Sufu to restrain Gli1 activity in the myotome.	3	7	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli1	Gli1	Gli1	3	4	6	7
It has been shown by several groups that SUFU inhibits both GLI1 and GLI2 transcriptional activity and has major effects on the shuttling between cytosol and nucleus [ XREF_BIBR - XREF_BIBR ] .	It has been shown by several groups that SUFU inhibits both GLI1 and GLI2 transcriptional activity and has major effects on the shuttling between cytosol and nucleus [XREF_BIBR - XREF_BIBR].	8	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI1	GLI1	GLI1	8	9	11	12
In order to unambiguously address whether Sufu requires cilia to inhibit Gli activity and Hh signaling , it is critical to establish a tissue culture system in which cilia formation is completely disrupted .	In order to unambiguously address whether Sufu requires cilia to inhibit Gli activity and Hh signaling, it is critical to establish a tissue culture system in which cilia formation is completely disrupted.	6	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	6	7	11	12
Sufu also sequesters Gli in the cytoplasm in the absence of Hh , but the molecular mechanism underlying this sequestration remains elusive .	Sufu also sequesters Gli in the cytoplasm in the absence of Hh, but the molecular mechanism underlying this sequestration remains elusive.	0	6	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	0	1	3	4
Moreover , GLI transcription factors are inhibited by suppressor of fused ( SUFU ) , XREF_BIBR which sequesters GLI proteins in the cytoplasm and abolishes their nuclear entry and transcriptional effects .	Moreover, GLI transcription factors are inhibited by suppressor of fused (SUFU), XREF_BIBR which sequesters GLI proteins in the cytoplasm and abolishes their nuclear entry and transcriptional effects.	10	19	sequesters	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	12	13	18	19
Sufu inhibited Gli1 nuclear localization and promoted Gli1 proteolysis .	Sufu inhibited Gli1 nuclear localization and promoted Gli1 proteolysis.	0	6	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli1	Gli1	Gli1	0	1	2	3
Sufu represses Gli transcription factors by sequestering Gli proteins in the cytoplasm or by directly inhibiting Gli mediated transactivation .	Sufu represses Gli transcription factors by sequestering Gli proteins in the cytoplasm or by directly inhibiting Gli mediated transactivation.	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	0	1	2	3
Consequently , Sufu overexpression inhibits Gli1 and Gli2 trafficking into the nucleus and transcriptional activity .	Consequently, Sufu overexpression inhibits Gli1 and Gli2 trafficking into the nucleus and transcriptional activity.	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu overexpression	sufu	Gli1	Gli1	gli1	2	3	5	6
Finally , it is known that Sufu normally sequesters Gli1 and Gli2 to the cytoplasm [ XREF_BIBR - XREF_BIBR ] .	Finally, it is known that Sufu normally sequesters Gli1 and Gli2 to the cytoplasm [XREF_BIBR - XREF_BIBR].	6	11	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli1	Gli1	Gli1	6	7	9	10
Sufu can sequester Gli proteins , regulate Gli2/3 protein levels , facilitate the production of Gli repressor and inhibit the generation of Gli activators .	Sufu can sequester Gli proteins, regulate Gli2/3 protein levels, facilitate the production of Gli repressor and inhibit the generation of Gli activators.	0	4	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	0	1	3	4
When SMO is inactivated , SuFu binds to and inhibits Gli1 function .	When SMO is inactivated, SuFu binds to and inhibits Gli1 function.	5	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Gli1	Gli1	Gli1	5	6	10	11
Since Gli1 function is inhibited by SuFu , we also examined whether there are any interactions between mTOR pathway components and SuFu .	Since Gli1 function is inhibited by SuFu, we also examined whether there are any interactions between mTOR pathway components and SuFu.	1	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Gli1	Gli1	Gli1	6	7	1	2
An activator form of GLI2 ( GLI2DeltaN ) , but not constitutively active SMO-M2 , activated the pathway in Ift27-/- cells , and cells null for both Ift27 and Suppressor of Fused ( Sufu ) , which suppresses GLI activation , showed greater activation of the pathway , than Sufu-null cells alone .	An activator form of GLI2 (GLI2DeltaN), but not constitutively active SMO-M2, activated the pathway in Ift27-/- cells, and cells null for both Ift27 and Suppressor of Fused (Sufu), which suppresses GLI activation, showed greater activation of the pathway, than Sufu-null cells alone.	27	39	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	GLI	GLI	GLI	33	34	38	39
In addition , mammalian Sufu functions in the nucleus to repress Gli dependent transcription by interacting with the SAP18-mSin3 HDAC ( histone deacetylase ) complex .	In addition, mammalian Sufu functions in the nucleus to repress Gli dependent transcription by interacting with the SAP18-mSin3 HDAC (histone deacetylase) complex.	4	13	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	4	5	11	12
These data revealed that Sufu suppressed Gli1 activation .	These data revealed that Sufu suppressed Gli1 activation.	4	7	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli1	Gli1	Gli1	4	5	6	7
Taken together , we identified a novel motif in the Gli/Ci family of proteins that is essential both for protein protein interaction with SUFU and for functional repression of GLI1 by SUFU .	Taken together, we identified a novel motif in the Gli/Ci family of proteins that is essential both for protein protein interaction with SUFU and for functional repression of GLI1 by SUFU.	16	32	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI1	GLI1	GLI1	31	32	29	30
Sufu can inhibit the transcriptional activator function of Gli1 and Gli2 , independently of cytoplasmic sequestration .	Sufu can inhibit the transcriptional activator function of Gli1 and Gli2, independently of cytoplasmic sequestration.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli1	Gli1	Gli1	0	1	8	9
In addition , overexpression of Sufu reduced Gli reporter gene transcription activity and prevented Gli1 nuclear accumulation , whereas knockdown of Sufu reversed these effects .	In addition, overexpression of Sufu reduced Gli reporter gene transcription activity and prevented Gli1 nuclear accumulation, whereas knockdown of Sufu reversed these effects.	3	16	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	overexpression of Sufu	sufu	Gli1	Gli1	gli1	5	6	14	15
The SUFU protein interacts with GLI1 , and consequently sequesters GLI1 in the cytoplasm and prevents GLI1 from regulating gene transcription .	The SUFU protein interacts with GLI1, and consequently sequesters GLI1 in the cytoplasm and prevents GLI1 from regulating gene transcription.	1	11	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI1	GLI1	GLI1	1	2	10	11
Prosurvival BCL-2 proteins disrupt SUFU repression of GLI activity .	Prosurvival BCL-2 proteins disrupt SUFU repression of GLI activity.	4	8	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	4	5	7	8
We favor a model in which Gli enters the nucleus without SuFu for the following reasons : ( a ) SuFu blocks nuclear localization of overexpressed Gli , whereas Gli proteins are nuclear in the absence of SuFu , ( b ) Hh stimulation causes the rapid dissociation of SuFu-Gli complexes , indicating that a critical step in generating active Gli is the removal of bound SuFu , and ( c ) SuFu is not required in the nucleus , as the transcriptional output of the Hh pathway is maximal in SuFu -/- cells .	We favor a model in which Gli enters the nucleus without SuFu for the following reasons : (a) SuFu blocks nuclear localization of overexpressed Gli, whereas Gli proteins are nuclear in the absence of SuFu, (b) Hh stimulation causes the rapid dissociation of SuFu-Gli complexes, indicating that a critical step in generating active Gli is the removal of bound SuFu, and (c) SuFu is not required in the nucleus, as the transcriptional output of the Hh pathway is maximal in SuFu -/- cells.	20	27	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Gli	Gli	Gli	20	21	26	27
As SuFu blocks nuclear import of Gli proteins , the major mechanistic question is how active Smo at the cilium modifies the SuFu and Gli complex to allow Gli activation and nuclear entry .	As SuFu blocks nuclear import of Gli proteins, the major mechanistic question is how active Smo at the cilium modifies the SuFu and Gli complex to allow Gli activation and nuclear entry.	1	7	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Gli	Gli	Gli	1	2	6	7
XREF_BIBR , XREF_BIBR An important regulator of Gli1 activities is the inhibitor Sufu , which sequesters Gli1 in the cytoplasm and also inhibits Gli1 activities in the nucleus .	XREF_BIBR, XREF_BIBR An important regulator of Gli1 activities is the inhibitor Sufu, which sequesters Gli1 in the cytoplasm and also inhibits Gli1 activities in the nucleus.	0	22	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli1	Gli1	Gli1	12	13	16	17
Taken together , TNFalpha and S6K1 induced phosphorylation of Gli1Ser84 attenuates SuFu mediated Gli1 inhibition .	Taken together, TNFalpha and S6K1 induced phosphorylation of Gli1Ser84 attenuates SuFu mediated Gli1 inhibition.	10	14	mediated	Positive_early_activation	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Gli1	Gli1	Gli1	11	12	13	14
To determine whether Sufu suppression of Gli activity is required for Hh induced activation of gene targets , we focused on Gli2 , the major mediator of Hh positive transcriptional response [ XREF_BIBR ] , and began by mapping determinants in Gli2 that mediate Sufu binding .	To determine whether Sufu suppression of Gli activity is required for Hh induced activation of gene targets, we focused on Gli2, the major mediator of Hh positive transcriptional response [XREF_BIBR], and began by mapping determinants in Gli2 that mediate Sufu binding.	3	7	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	3	4	6	7
Current data suggest that SUFU , being a part of a multiprotein complex that also includes beta-arrestin , KIF3a and IFT88 , impedes the nuclear localization of GLI proteins XREF_BIBR , XREF_BIBR , XREF_BIBR .	Current data suggest that SUFU, being a part of a multiprotein complex that also includes beta-arrestin, KIF3a and IFT88, impedes the nuclear localization of GLI proteins XREF_BIBR, XREF_BIBR, XREF_BIBR.	4	29	impedes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	4	5	27	28
An implication from the above findings is that additional mechanisms may be involved in MST1 mediated AR inhibition .	An implication from the above findings is that additional mechanisms may be involved in MST1 mediated AR inhibition.	12	17	mediated	Positive_early_activation	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	14	15	16	17
This indicates that MST1 attenuates AR signaling by a distinct mechanism apart from JNK or p38 MAP kinase activation .	This indicates that MST1 attenuates AR signaling by a distinct mechanism apart from JNK or p38 MAP kinase activation.	3	6	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	3	4	5	6
MST1 was shown previously to inhibit AR transcriptional activity .	MST1 was shown previously to inhibit AR transcriptional activity.	0	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	0	1	6	7
Co-IP experiments further revealed that MST1 , AR , and AKT1 form a tri and partite complex in vivo ( XREF_FIG , right panel ) , indicating that MST1 also intersects with AKT signaling to attenuate AR activity .	Co-IP experiments further revealed that MST1, AR, and AKT1 form a tri and partite complex in vivo (XREF_FIG, right panel), indicating that MST1 also intersects with AKT signaling to attenuate AR activity.	28	37	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	28	29	36	37
15 MST1 localizes to chromatin , phosphorylates and negatively regulates AR and suppresses PCa tumor growth independently of its pro apoptotic role .	15 MST1 localizes to chromatin, phosphorylates and negatively regulates AR and suppresses PCa tumor growth independently of its pro apoptotic role.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	1	2	10	11
MST1 knockdown by a gene specific small interfering RNA ( siRNA ) resulted in the upregulation of basal and androgen stimulated AR responsive PSA promoter reporter activation , by at least 2-fold in comparison to siRNA control ( XREF_FIG , upper panel ) .	MST1 knockdown by a gene specific small interfering RNA (siRNA) resulted in the upregulation of basal and androgen stimulated AR responsive PSA promoter reporter activation, by at least 2-fold in comparison to siRNA control (XREF_FIG, upper panel).	0	22	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	0	1	21	22
Here we found that the induction of MST1 expression is sufficient to antagonize AR driven gene expression and suppress PCa cell growth .	Here we found that the induction of MST1 expression is sufficient to antagonize AR driven gene expression and suppress PCa cell growth.	7	14	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1 expression	mst1	AR	AR	ar	7	8	13	14
We selected these genes because ( i ) their expressions were differentially regulated by STK4 in all three conditions ( XREF_SUPPLEMENTARY ) , ( ii ) KLK3 and FKBP5 are well-known targets of AR that is also negatively regulated by STK4 [ XREF_BIBR ] and ( iii ) MYC is a YAP and TEAD target and it intersected with STK4 signaling in PC cells [ XREF_BIBR ] .	We selected these genes because (i) their expressions were differentially regulated by STK4 in all three conditions (XREF_SUPPLEMENTARY), (ii) KLK3 and FKBP5 are well-known targets of AR that is also negatively regulated by STK4 [XREF_BIBR] and (iii) MYC is a YAP and TEAD target and it intersected with STK4 signaling in PC cells [XREF_BIBR].	31	42	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	STK4	STK4	STK4	AR	AR	AR	40	41	33	34
Although both the full-length MST1 and the cleaved MST1-N forms bound and inhibited AR activity , caspase resistant MST1 was the most potent AR inhibitor .	Although both the full-length MST1 and the cleaved MST1-N forms bound and inhibited AR activity, caspase resistant MST1 was the most potent AR inhibitor.	1	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	4	5	13	14
Taken together , these data suggest that SAFB1 and MST1 cooperate to repress the AR .	Taken together, these data suggest that SAFB1 and MST1 cooperate to repress the AR.	7	15	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	9	10	14	15
MST1 attenuates AR activity in a Ser 650 phosphorylation independent manner .	MST1 attenuates AR activity in a Ser 650 phosphorylation independent manner.	0	3	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	0	1	2	3
The MST1 serine threonine kinase also interacts with the AR DBD and inhibits AR activity , but by a mechanism that involves decreases in DNA binding [ XREF_BIBR ] .	The MST1 serine threonine kinase also interacts with the AR DBD and inhibits AR activity, but by a mechanism that involves decreases in DNA binding [XREF_BIBR].	1	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	1	2	13	14
We also showed that STK4 signaling depending on its subcellular locations suppressed AR transcript with varying degrees .	We also showed that STK4 signaling depending on its subcellular locations suppressed AR transcript with varying degrees.	4	13	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STK4	STK4	STK4	AR	AR	AR	4	5	12	13
Our data suggest that MST1 attenuates AR activity via a mechanism that involves protein complex formation between AR and MST1 in a manner that is independent of its kinase activity .	Our data suggest that MST1 attenuates AR activity via a mechanism that involves protein complex formation between AR and MST1 in a manner that is independent of its kinase activity.	4	7	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	4	5	6	7
MST1 was also found in AR-chromatin complexes , and enforced expression of MST1 reduced the binding of AR to a well characterized , androgen responsive region within the prostate specific antigen ( PSA ) promoter .	MST1 was also found in AR-chromatin complexes, and enforced expression of MST1 reduced the binding of AR to a well characterized, androgen responsive region within the prostate specific antigen (PSA) promoter.	10	18	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	expression of MST1	mst1	AR	AR	ar	12	13	17	18
MST1 suppresses AR activity by intersecting with AKT1 signaling and antagonizing formation of AR-chromatin complexes .	MST1 suppresses AR activity by intersecting with AKT1 signaling and antagonizing formation of AR-chromatin complexes.	0	3	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	0	1	2	3
These findings suggest that loss of MST1 signaling may promote hyperactivation of AR and may be associated with the emergence of the castration resistant phenotype .	These findings suggest that loss of MST1 signaling may promote hyperactivation of AR and may be associated with the emergence of the castration resistant phenotype.	6	13	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	6	7	12	13
Given that MST1 attenuates AR activity by forming protein complexes , the localization of MST1 into the holo-AR transcriptional complex could also attenuate the AR .	Given that MST1 attenuates AR activity by forming protein complexes, the localization of MST1 into the holo-AR transcriptional complex could also attenuate the AR.	12	25	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1	MST1	AR	AR	AR	14	15	24	25
To test whether MST1 induction could suppress AR activation mediated by AKT1 signaling , we performed promoter reporter assays and showed that enforced MST1 expression antagonized AKT1 mediated androgen dependent and - independent AR activation ( XREF_FIG , left panel ) .	To test whether MST1 induction could suppress AR activation mediated by AKT1 signaling, we performed promoter reporter assays and showed that enforced MST1 expression antagonized AKT1 mediated androgen dependent and - independent AR activation (XREF_FIG, left panel).	23	34	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MST1	MST1 expression	mst1	AR	AR	ar	23	24	33	34
Sufu restricts the activity of Gli2 through cytoplasmic sequestration .	Sufu restricts the activity of Gli2 through cytoplasmic sequestration.	0	6	restricts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli2	Gli2	Gli2	0	1	5	6
Therefore Sufu prevents the processing of the full-length Gli2 and Gli3 proteins so that they are available for processing in a cilia independent manner [ XREF_BIBR , XREF_BIBR ] .	Therefore Sufu prevents the processing of the full-length Gli2 and Gli3 proteins so that they are available for processing in a cilia independent manner [XREF_BIBR, XREF_BIBR].	1	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli2	Gli2	Gli2	1	2	8	9
In our analysis of mammalian Sufu function we first excluded the general inactivation of Sufu as a mechanism for pathway activation by demonstrating that a Gli2 protein with a GAL4 DNA binding domain , although it is an artificial synthetic protein , can be inactivated by Sufu , even when stimulated by ShhN .	In our analysis of mammalian Sufu function we first excluded the general inactivation of Sufu as a mechanism for pathway activation by demonstrating that a Gli2 protein with a GAL4 DNA binding domain, although it is an artificial synthetic protein, can be inactivated by Sufu, even when stimulated by ShhN.	25	47	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli2	Gli2	Gli2	46	47	25	26
In basal cell carcinoma ( BCC ) , Sufu restricts the activity of Gli2 through cytoplasmic sequestration and Sufu and kif7 simultaneous deletion induces BCC [ XREF_BIBR ] .	In basal cell carcinoma (BCC), Sufu restricts the activity of Gli2 through cytoplasmic sequestration and Sufu and kif7 simultaneous deletion induces BCC [XREF_BIBR].	8	14	restricts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli2	Gli2	Gli2	8	9	13	14
Kif7 alleviates Sufu inhibition of Gli2 dependent FP development .	Kif7 alleviates Sufu inhibition of Gli2 dependent FP development.	2	8	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli2	Gli2	Gli2	2	3	5	6
These observations are in line with an earlier study , which showed that a SUFU deletion construct lacking the amino acids 389-485 was fully capable to repress GLI2 , but to a lesser extent GLI1 XREF_BIBR .	These observations are in line with an earlier study, which showed that a SUFU deletion construct lacking the amino acids 389-485 was fully capable to repress GLI2, but to a lesser extent GLI1 XREF_BIBR.	14	28	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI2	GLI2	GLI2	14	15	27	28
In this repressed state , the negative pathway regulator suppressor of fused ( SUFU ) sequesters the first-line effector proteins , glioblastoma-associated-protein 2 and 3 ( GLI2 , GLI3 ) in the cytoplasm at the base of the primary cilium .	In this repressed state, the negative pathway regulator suppressor of fused (SUFU) sequesters the first-line effector proteins, glioblastoma-associated-protein 2 and 3 (GLI2, GLI3) in the cytoplasm at the base of the primary cilium.	9	28	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	GLI2	GLI2	GLI2	13	14	26	27
In resting cells the Rab-GAP activity of AS160 prevents the Rab dependent trafficking of GLUT4 to the cell surface .	In resting cells the Rab-GAP activity of AS160 prevents the Rab dependent trafficking of GLUT4 to the cell surface.	5	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	7	8	14	15
Indeed , studies have shown that knockdown of AS160 increases the localization of GLUT4 at the PM of unstimulated cells , which impairs insulin stimulated GLUT4 translocation [ XREF_BIBR , XREF_BIBR ] .	Indeed, studies have shown that knockdown of AS160 increases the localization of GLUT4 at the PM of unstimulated cells, which impairs insulin stimulated GLUT4 translocation [XREF_BIBR, XREF_BIBR].	6	14	increases	Positive_activation_syntax_3a_verb	Negative_activation	Negative_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	8	9	13	14
The inactivation of RabGAP of AS160 promotes lysosomal degradation of GLUT4 , and the inhibition of lysosome function could restore GLUT4 protein levels .	The inactivation of RabGAP of AS160 promotes lysosomal degradation of GLUT4, and the inhibition of lysosome function could restore GLUT4 protein levels.	3	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	5	6	10	11
In adipocytes , GLUT4 transporter is carried in specialized vesicles ( GLUT4 vesicles ) whose trafficking to plasma membrane can be inhibited by AS160 in resting cells .	In adipocytes, GLUT4 transporter is carried in specialized vesicles (GLUT4 vesicles) whose trafficking to plasma membrane can be inhibited by AS160 in resting cells.	11	26	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	23	24	11	12
The suppression of AS160 phosphorylation by the siRNA mediated AMPKalpha1 subunit knockdown promoted GLUT4 vesicle retention in intracellular compartments .	The suppression of AS160 phosphorylation by the siRNA mediated AMPKalpha1 subunit knockdown promoted GLUT4 vesicle retention in intracellular compartments.	3	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AS160	AS160 phosphorylation	as160	GLUT4	GLUT4	glut4	3	4	13	14
In addition , insulin stimulated glucose transport and cell surface GLUT4 content are reduced in isolated muscles of mice with Tbc1d4-Thr649Ala knockin mutation , but not in adipocytes XREF_BIBR , while inhibition of Tbc1d4 in 3T3-L1 adipocytes increases the content of GLUT4 in the plasma membrane XREF_BIBR .	In addition, insulin stimulated glucose transport and cell surface GLUT4 content are reduced in isolated muscles of mice with Tbc1d4-Thr649Ala knockin mutation, but not in adipocytes XREF_BIBR, while inhibition of Tbc1d4 in 3T3-L1 adipocytes increases the content of GLUT4 in the plasma membrane XREF_BIBR.	31	46	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Tbc1d4	Tbc1d4	Tbc1d4	GLUT4	GLUT4	GLUT4	33	34	41	42
In basal adipocytes , AS160 inhibits GLUT4 insertion into the PM by specifically inhibiting a prefusion step of GSV with the PM .	In basal adipocytes, AS160 inhibits GLUT4 insertion into the PM by specifically inhibiting a prefusion step of GSV with the PM.	4	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	4	5	6	7
First , knockdown of AS160 in 3T3-L1 adipocytes caused only 30 % of the increase in cell surface GLUT4 as that caused by insulin [ XREF_BIBR ] .	First, knockdown of AS160 in 3T3-L1 adipocytes caused only 30% of the increase in cell surface GLUT4 as that caused by insulin [XREF_BIBR].	2	19	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	4	5	18	19
The Akt substrate AS160 ( TCB1D4 ) regulates Glut4 exocytosis ; shRNA knockdown of AS160 increases surface Glut4 in basal adipocytes .	The Akt substrate AS160 (TCB1D4) regulates Glut4 exocytosis; shRNA knockdown of AS160 increases surface Glut4 in basal adipocytes.	12	20	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AS160	AS160	AS160	Glut4	Glut4	Glut4	14	15	17	18
The transcription factor TBET , a master regulator of Th1 cell differentiation , represses the Gata3 gene .	The transcription factor TBET, a master regulator of Th1 cell differentiation, represses the Gata3 gene.	0	16	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TBET	TBET	TBET	Gata3	Gata3	Gata3	3	4	15	16
In addition to activating Th1 , T-bet also represses GATA-3 and ROR-gammat transcription programs .	In addition to activating Th1, T-bet also represses GATA-3 and ROR-gammat transcription programs.	6	13	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	T-bet	T-bet	T-bet	GATA-3	GATA-3	GATA-3	6	7	9	10
Additionally , T-bet suppresses GATA3 , a transcription factor that aids in regulation of Th2-type immune responses .	Additionally, T-bet suppresses GATA3, a transcription factor that aids in regulation of Th2-type immune responses.	2	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	T-bet	T-bet	T-bet	GATA3	GATA3	GATA3	2	3	4	5
However , T-bet suppresses GATA3 and in the presence of a Th2 skewing micro-environment , such as the skin , impaired expression of T-bet in the absence of RA signaling renders cells susceptible to Th2 deviation .	However, T-bet suppresses GATA3 and in the presence of a Th2 skewing micro-environment, such as the skin, impaired expression of T-bet in the absence of RA signaling renders cells susceptible to Th2 deviation.	2	5	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	T-bet	T-bet	T-bet	GATA3	GATA3	GATA3	2	3	4	5
Concurrently , T-bet is required to suppress GATA3 and RORgammat whilst driving IFNgamma and Eomes expression ultimately leading to a T-bet lo Eomes hi phenotype , which can reliably identify T R 1 cells after BMT as well as in steady state in mouse and man .	Concurrently, T-bet is required to suppress GATA3 and RORgammat whilst driving IFNgamma and Eomes expression ultimately leading to a T-bet lo Eomes hi phenotype, which can reliably identify T R 1 cells after BMT as well as in steady state in mouse and man.	2	9	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	T-bet	T-bet	T-bet	GATA3	GATA3	GATA3	2	3	7	8
These results suggest that T-bet suppresses GATA-3 at a transcriptional level rather than at a posttranscriptional level .	These results suggest that T-bet suppresses GATA-3 at a transcriptional level rather than at a posttranscriptional level.	4	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	T-bet	T-bet	T-bet	GATA-3	GATA-3	GATA-3	4	5	6	7
Meanwhile , activated T-bet and Runx3 can suppress GATA3 signaling , causing the expression of the Th2 specific IL-4 gene to be inhibited .	Meanwhile, activated T-bet and Runx3 can suppress GATA3 signaling, causing the expression of the Th2 specific IL-4 gene to be inhibited.	2	9	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	T-bet	T-bet	T-bet	GATA3	GATA3	GATA3	3	4	8	9
Consequently , p21 induction in early G ( 1 ) is critical for TGF-beta 1 inhibition of CDK2 kinase activity .	Consequently, p21 induction in early G (1) is critical for TGF-beta 1 inhibition of CDK2 kinase activity.	13	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TGF-beta 1	TGF-beta 1	TGF-beta 1	CDK2	CDK2	CDK2	13	15	17	18
Finally , we show that TGFbeta1 reduces both CDK4 and CDK2 enzymatic activities .	Finally, we show that TGFbeta1 reduces both CDK4 and CDK2 enzymatic activities.	5	12	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TGFbeta1	TGFbeta1	TGFbeta1	CDK2	CDK2	CDK2	5	6	10	11
Taken together , these results suggest that TGF-beta1 and rapamycin cooperate to inhibit the activity of nuclear Cdk2 through several mechanisms including decreasing the total concentration of nuclear Cdk2 , increasing the stoichiometry of phosphorylation of nuclear Cdk2 on the inhibitory site , Tyr 15 , and increasing the stoichiometry of binding of p27 to nuclear Cdk2 .	Taken together, these results suggest that TGF-beta1 and rapamycin cooperate to inhibit the activity of nuclear Cdk2 through several mechanisms including decreasing the total concentration of nuclear Cdk2, increasing the stoichiometry of phosphorylation of nuclear Cdk2 on the inhibitory site, Tyr 15, and increasing the stoichiometry of binding of p27 to nuclear Cdk2.	7	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	Cdk2	Cdk2	Cdk2	7	8	17	18
Furthermore , TGF-beta1 inhibits cdk2-cyclin through p27 Kip1 .	Furthermore, TGF-beta1 inhibits cdk2-cyclin through p27 Kip1.	2	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	cdk2-cyclin	cdk2-cyclin	cdk2-cyclin	2	3	4	5
To verify that TGF-beta1 and rapamycin cooperate to inhibit nuclear Cdk2 activity specifically , we prepared nuclear and cytoplasmic extracts from NMuMG cells treated as in Fig .	To verify that TGF-beta1 and rapamycin cooperate to inhibit nuclear Cdk2 activity specifically, we prepared nuclear and cytoplasmic extracts from NMuMG cells treated as in Fig.	3	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	Cdk2	Cdk2	Cdk2	3	4	10	11
( 2 ) 2 ng/ml TGF-beta1 could significantly inhibit the production of cyclin A , cyclin D1 , CDK2 and CDK4 , the protein levels were significantly lower than control group .	(2) 2 ng/ml TGF-beta1 could significantly inhibit the production of cyclin A, cyclin D1, CDK2 and CDK4, the protein levels were significantly lower than control group.	3	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	CDK2	CDK2	CDK2	5	6	18	19
Our results show that shRNA knockdown of Cripto and/or GRP78 or antibody blockade of GRP78 in NCCIT cells enhances activin-A , activin-B and TGF-beta1 signaling while inhibiting Nodal signaling .	Our results show that shRNA knockdown of Cripto and/or GRP78 or antibody blockade of GRP78 in NCCIT cells enhances activin-A, activin-B and TGF-beta1 signaling while inhibiting Nodal signaling.	5	24	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cripto	Cripto	Cripto	TGF-beta1	TGF-beta1	TGF-beta1	7	8	23	24
Cripto knockdown in HeLa cells enhances TGF-beta1 signaling indicating a role for endogenous Cripto as a TGF-beta antagonist [ XREF_BIBR ] .	Cripto knockdown in HeLa cells enhances TGF-beta1 signaling indicating a role for endogenous Cripto as a TGF-beta antagonist [XREF_BIBR].	0	7	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cripto	Cripto	Cripto	TGF-beta1	TGF-beta1	TGF-beta1	0	1	6	7
Cripto knockdown or GRP78 knockdown similarly enhanced activin-A , activin-B and TGF-beta1 signaling while inhibiting Nodal signaling and knockdown of both proteins had a more pronounced effect than knockdown of either alone [ XREF_BIBR ] .	Cripto knockdown or GRP78 knockdown similarly enhanced activin-A, activin-B and TGF-beta1 signaling while inhibiting Nodal signaling and knockdown of both proteins had a more pronounced effect than knockdown of either alone [XREF_BIBR].	0	12	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cripto	Cripto	Cripto	TGF-beta1	TGF-beta1	TGF-beta1	0	1	11	12
In contrast to its role as a Nodal co-receptor , Cripto inhibits activin signaling and cytostatic TGF-beta1 effects .	In contrast to its role as a Nodal co-receptor, Cripto inhibits activin signaling and cytostatic TGF-beta1 effects.	10	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cripto	Cripto	Cripto	TGF-beta1	TGF-beta1	TGF-beta1	10	11	16	17
In contrast , anti-inflammatory cytokines ( e.g ., IL-4 , IL-10 , IL-13 ) activate Stat3 and Stat6 , which are needed to induce anti-inflammatory gene expression ( e.g ., arginase-1 , suppressor of cytokine signaling 3 - SOCS-3 ) , and inhibit Stat1 and NF-kappaB .	In contrast, anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-13) activate Stat3 and Stat6, which are needed to induce anti-inflammatory gene expression (e.g., arginase-1, suppressor of cytokine signaling 3 - SOCS-3), and inhibit Stat1 and NF-kappaB.	14	45	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Stat6	Stat6	Stat6	Stat1	Stat1	Stat1	17	18	43	44
In STAT3 deficient cells XREF_BIBR or cells with STAT6 knocked down XREF_BIBR , increased transcription of STAT1 target genes has been found , suggesting that STAT3 and STAT6 can antagonize STAT1 activity .	In STAT3 deficient cells XREF_BIBR or cells with STAT6 knocked down XREF_BIBR, increased transcription of STAT1 target genes has been found, suggesting that STAT3 and STAT6 can antagonize STAT1 activity.	25	31	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STAT6	STAT6	STAT6	STAT1	STAT1	STAT1	27	28	30	31
Because Stat6 antagonizes Stat1 , we tested whether IL-4 promoted virus replication in the absence of Stat1 .	Because Stat6 antagonizes Stat1, we tested whether IL-4 promoted virus replication in the absence of Stat1.	1	4	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Stat6	Stat6	Stat6	Stat1	Stat1	Stat1	1	2	3	4
Stat6 mediates responses to IL-4 and antagonizes Stat1 activated by IFN-gamma .	Stat6 mediates responses to IL-4 and antagonizes Stat1 activated by IFN-gamma.	0	8	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Stat6	Stat6	Stat6	Stat1	Stat1	Stat1	0	1	7	8
This was probably because P6 strongly inhibited STAT1 , STAT5 , and STAT6 phosphorylation , whereas STAT3 phosphorylation was less efficiently suppressed by P6 at the same concentration .	This was probably because P6 strongly inhibited STAT1, STAT5, and STAT6 phosphorylation, whereas STAT3 phosphorylation was less efficiently suppressed by P6 at the same concentration.	6	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STAT6	STAT6 phosphorylation	stat6	STAT1	STAT1	stat1	12	13	7	8
NF-kappaB and STAT1 signaling suppresses the activation of STAT3 and STAT6 , while activations of STAT3 and STAT6 inhibit NF-kappaB and STAT1 signaling .	NF-kappaB and STAT1 signaling suppresses the activation of STAT3 and STAT6, while activations of STAT3 and STAT6 inhibit NF-kappaB and STAT1 signaling.	13	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STAT6	STAT6	STAT6	STAT1	STAT1	STAT1	17	18	21	22
In this model , the presence of an LKB1 and STK11 mutation may potentially explain these results : indeed , loss of LKB1 may lead to mTOR hyperactivation XREF_BIBR XREF_BIBR , bypassing PTEN effects ; moreover LKB1 and STK11 and PTEN may interact with each other , resulting in LKB1 cytoplasmic retention and PTEN phosphorylation , although the biological significance of these modifications has not yet been defined XREF_BIBR .	In this model, the presence of an LKB1 and STK11 mutation may potentially explain these results : indeed, loss of LKB1 may lead to mTOR hyperactivation XREF_BIBR XREF_BIBR, bypassing PTEN effects; moreover LKB1 and STK11 and PTEN may interact with each other, resulting in LKB1 cytoplasmic retention and PTEN phosphorylation, although the biological significance of these modifications has not yet been defined XREF_BIBR.	20	33	lead	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LKB1	loss of LKB1	lkb1	PTEN	PTEN	pten	22	23	32	33
In particular , GNA11 can act as an oncoprotein by activating mTOR signaling , whereas STK11 inhibits mTOR activity downstream of PTEN .	In particular, GNA11 can act as an oncoprotein by activating mTOR signaling, whereas STK11 inhibits mTOR activity downstream of PTEN.	15	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STK11	STK11	STK11	PTEN	PTEN	PTEN	15	16	21	22
Distinct regulation of Gli activator and Gli3 repressor by Sufu .	Distinct regulation of Gli activator and Gli3 repressor by Sufu.	4	10	activator	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli3	Gli3	Gli3	9	10	6	7
Suppression of PAK1 by LKB1 is mediated by its phosphorylation at Thr 109 , XREF_BIBR suggesting the role of LKB1 in suppression of cell migration through inhibition of PAK1 .	Suppression of PAK1 by LKB1 is mediated by its phosphorylation at Thr 109, XREF_BIBR suggesting the role of LKB1 in suppression of cell migration through inhibition of PAK1.	0	5	Suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	LKB1	LKB1	LKB1	PAK1	PAK1	PAK1	4	5	2	3
Similarly , the serine/threonine protein kinase LKB1 , a tumor suppressor gene that is implicated in suppression of cell growth and metastasis , suppresses PAK1 by phosphorylation of Thr109 in the PBD .	Similarly, the serine/threonine protein kinase LKB1, a tumor suppressor gene that is implicated in suppression of cell growth and metastasis, suppresses PAK1 by phosphorylation of Thr109 in the PBD.	2	25	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LKB1	LKB1	LKB1	PAK1	PAK1	PAK1	6	7	24	25
Interestingly , another study in human colon cancer cell lines and MEFs shows that LKB1 represses PAK1 via phosphorylation at a newly described Thr 109 site XREF_BIBR .	Interestingly, another study in human colon cancer cell lines and MEFs shows that LKB1 represses PAK1 via phosphorylation at a newly described Thr 109 site XREF_BIBR.	14	26	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LKB1	LKB1	LKB1	PAK1	PAK1	PAK1	14	15	16	17
Moreover , TAF1 has been shown to block p53 activity , 27 and inactivation of TAF1 triggers a DNA damage response .	Moreover, TAF1 has been shown to block p53 activity, 27 and inactivation of TAF1 triggers a DNA damage response.	2	9	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TAF1	TAF1	TAF1	p53	p53	p53	2	3	8	9
However , our ChIP-Seq analysis also reveals reduction of p53 activation of apoptosis genes ( such as PIG1 ) and metabolism genes ( such as TIGAR , XREF_SUPPLEMENTARY ) at 16 h after DNA damage , suggesting ATP dependent TAF1 phosphorylation may inhibit overall p53 tumor suppressor activity .	However, our ChIP-Seq analysis also reveals reduction of p53 activation of apoptosis genes (such as PIG1) and metabolism genes (such as TIGAR, XREF_SUPPLEMENTARY) at 16 h after DNA damage, suggesting ATP dependent TAF1 phosphorylation may inhibit overall p53 tumor suppressor activity.	39	47	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TAF1	TAF1 phosphorylation	taf1	p53	p53	p53	39	40	44	45
In nutrition rich conditions ( or higher cellular ATP levels ) , however , p53 is inactivated by ATP dependent TAF1 phosphorylation , so cells can undergo G1 progression .	In nutrition rich conditions (or higher cellular ATP levels), however, p53 is inactivated by ATP dependent TAF1 phosphorylation, so cells can undergo G1 progression.	14	22	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TAF1	TAF1 phosphorylation	taf1	p53	p53	p53	20	21	14	15
Consistent with the observation that CHIP induces Smad1 degradation , we further show that the expression of CHIP can inhibit the transcriptional activities of the Smad1 and Smad4 complex induced by BMP signals .	Consistent with the observation that CHIP induces Smad1 degradation, we further show that the expression of CHIP can inhibit the transcriptional activities of the Smad1 and Smad4 complex induced by BMP signals.	5	8	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CHIP	CHIP	CHIP	Smad1	Smad1	Smad1	5	6	7	8
TBX2 inhibits the activity of MyoD and myogenin .	TBX2 inhibits the activity of MyoD and myogenin.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TBX2	TBX2	TBX2	myogenin	myogenin	myogenin	0	1	7	8
TBX2 inhibited the regulatory factors myogenic differentiation 1 and myogenin , leading to the promotion of proliferation .	TBX2 inhibited the regulatory factors myogenic differentiation 1 and myogenin, leading to the promotion of proliferation.	0	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TBX2	TBX2	TBX2	myogenin	myogenin	myogenin	0	1	9	10
STAT1 knockdown by siRNA caused downregulation of p53 and Fbxw7 , and upregulation of cyclin A , cyclin D1 , cyclin E , CDK2 , Hes-1 and NF-kappaB p65 .	STAT1 knockdown by siRNA caused downregulation of p53 and Fbxw7, and upregulation of cyclin A, cyclin D1, cyclin E, CDK2, Hes-1 and NF-kappaB p65.	0	29	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	STAT1	STAT1	STAT1	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	0	1	27	29
XREF_FIG b. Among the elevated decisive genes of the interferon pathway is the transcription factor STAT1 , which in turn induces the STAT1 dependent protein IRF1 thereby inhibiting NFkappaBp65 .	XREF_FIG b. Among the elevated decisive genes of the interferon pathway is the transcription factor STAT1, which in turn induces the STAT1 dependent protein IRF1 thereby inhibiting NFkappaBp65.	22	29	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STAT1	STAT1	STAT1	NFkappaBp65	NFkappaBp65	NFkappaBp65	22	23	28	29
TGFbeta1 significantly reduced Skp2 after 14 h of administration ( P < 0.05 ) .	TGFbeta1 significantly reduced Skp2 after 14 h of administration (P < 0.05).	0	4	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TGFbeta1	TGFbeta1	TGFbeta1	Skp2	Skp2	Skp2	0	1	3	4
The pseudophosphatase STYX prevents the substrate recognition subunit FBXW7 from binding the catalytic E3 ubiquitin ligase complex .	The pseudophosphatase STYX prevents the substrate recognition subunit FBXW7 from binding the catalytic E3 ubiquitin ligase complex.	0	9	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STYX	STYX	STYX	FBXW7	FBXW7	FBXW7	2	3	8	9
The E3 ubiquitin ligase scaffolding protein Cullin 3 recognizes the N-terminus of Glis3 , and facilitates Glis3 polyubiquitination , while the Hedgehog regulator Suppressor of Fused ( SuFu ) interferes with the Cullin 3/Glis3 interaction , promoting the accumulation of Glis3 [ XREF_BIBR ] .	The E3 ubiquitin ligase scaffolding protein Cullin 3 recognizes the N-terminus of Glis3, and facilitates Glis3 polyubiquitination, while the Hedgehog regulator Suppressor of Fused (SuFu) interferes with the Cullin 3/Glis3 interaction, promoting the accumulation of Glis3 [XREF_BIBR].	25	42	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Glis3	Glis3	Glis3	27	28	40	41
It is known that TSC2 complex inhibits mTOR activation to promote autophagy through its GTPase protein ( GAP ) activity toward small GTPase Rheb [ XREF_BIBR , XREF_BIBR ] .	It is known that TSC2 complex inhibits mTOR activation to promote autophagy through its GTPase protein (GAP) activity toward small GTPase Rheb [XREF_BIBR, XREF_BIBR].	4	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	4	5	7	8
Immunohistochemical analyses were used to examine the status of the lycopene sensitive mTOR pathway , which is negatively regulated by the Tsc2 complex .	Immunohistochemical analyses were used to examine the status of the lycopene sensitive mTOR pathway, which is negatively regulated by the Tsc2 complex.	12	22	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	21	22	12	13
In the majority of cells under stress conditions , activation of AMPK phosphorylates TSC2 leading to TSC1 and TSC2 dependent suppression of mTOR to inhibit cell proliferation [ XREF_BIBR , XREF_BIBR ] .	In the majority of cells under stress conditions, activation of AMPK phosphorylates TSC2 leading to TSC1 and TSC2 dependent suppression of mTOR to inhibit cell proliferation [XREF_BIBR, XREF_BIBR].	16	23	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	18	19	22	23
Subsequently , activation of TSC1 and TSC2 suppresses mTOR activity by deactivating the mTORC1 interacting protein , Rheb , inducing autophagy [ XREF_BIBR - XREF_BIBR ] .	Subsequently, activation of TSC1 and TSC2 suppresses mTOR activity by deactivating the mTORC1 interacting protein, Rheb, inducing autophagy [XREF_BIBR - XREF_BIBR].	2	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	6	7	8	9
Under periods of starvation , serum withdrawal , or other stresses , the GTPase activating protein TSC2 inhibiting Rheb and mTOR activity , and consequentially activating the serine/threonine kinase Atg1 .	Under periods of starvation, serum withdrawal, or other stresses, the GTPase activating protein TSC2 inhibiting Rheb and mTOR activity, and consequentially activating the serine/threonine kinase Atg1.	14	21	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	16	17	20	21
The loss of TSC2 , which is upstream of mTOR , activates S6K1 , promotes cell growth and survival , activates mTOR kinase activities , inhibits mTORC1 and mTORC2 via mTOR inhibitors , and suppresses S6K1 and Akt .	The loss of TSC2, which is upstream of mTOR, activates S6K1, promotes cell growth and survival, activates mTOR kinase activities, inhibits mTORC1 and mTORC2 via mTOR inhibitors, and suppresses S6K1 and Akt.	1	23	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	loss of TSC2	tsc2	mTOR	mTOR	mtor	3	4	21	22
XREF_BIBR , XREF_BIBR The products of two p53 target genes , Sestrin 1 and 2 activate AMPK , which phosphorylates TSC2 and stimulates its GAP activity enabling mTOR inhibition .	XREF_BIBR, XREF_BIBR The products of two p53 target genes, Sestrin 1 and 2 activate AMPK, which phosphorylates TSC2 and stimulates its GAP activity enabling mTOR inhibition.	16	28	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK, which phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	20	21	27	28
Together , our data suggest that loss of tuberin , which causes mTOR activation , leads to a novel cellular growth promoting pathway involving mitochondrial oxidant dependent p42/44 MAPK activation and mitogenic growth responses to PDGF .	Together, our data suggest that loss of tuberin, which causes mTOR activation, leads to a novel cellular growth promoting pathway involving mitochondrial oxidant dependent p42/44 MAPK activation and mitogenic growth responses to PDGF.	6	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	loss of tuberin	tuberin	mTOR	mTOR	mtor	8	9	12	13
AMPK regulates autophagy by inhibition of mTOR by phosphorylation of TSC2 and Raptor .	AMPK regulates autophagy by inhibition of mTOR by phosphorylation of TSC2 and Raptor.	4	12	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	TSC2	phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	10	11	6	7
Besides controlling carbohydrate and lipid metabolism , AMPK phosphorylates major mTOR signaling regulators like TSC2 , thus functioning to suppress mTOR signaling that governs anabolic responses , such as protein synthesis .	Besides controlling carbohydrate and lipid metabolism, AMPK phosphorylates major mTOR signaling regulators like TSC2, thus functioning to suppress mTOR signaling that governs anabolic responses, such as protein synthesis.	8	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylates major mTOR signaling regulators like TSC2	tsc2	mTOR	mTOR	mtor	14	15	20	21
Silencing of TSC2 enhanced mTOR activity in stimulated T cells cultured alone and completely restored mTOR activity in T cells co-cultured with MDSC .	Silencing of TSC2 enhanced mTOR activity in stimulated T cells cultured alone and completely restored mTOR activity in T cells co-cultured with MDSC.	0	16	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	15	16
Indeed , Myc inhibits the mTOR repressor TSC2 , thereby increasing mTOR activity to facilitate translation through S6K and 4E-BP phosphorylation [ XREF_BIBR ] .	Indeed, Myc inhibits the mTOR repressor TSC2, thereby increasing mTOR activity to facilitate translation through S6K and 4E-BP phosphorylation [XREF_BIBR].	3	8	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	7	8	5	6
The PTEN and TSC2 tumor suppressors function to antagonize mTOR ( mammalian target of rapamycin ) activation by Akt ; hence , compound heterozygous inactivation of Pten and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner .	The PTEN and TSC2 tumor suppressors function to antagonize mTOR (mammalian target of rapamycin) activation by Akt; hence, compound heterozygous inactivation of Pten and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner.	3	15	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	3	4	11	15
These data suggest that PC1 functions by inducing the formation of a complex with tuberin and the Ser/Thr kinase mTOR thereby inhibiting mTOR activity .	These data suggest that PC1 functions by inducing the formation of a complex with tuberin and the Ser/Thr kinase mTOR thereby inhibiting mTOR activity.	14	23	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	14	15	22	23
In normal conditions , mTOR activity is inhibited by proteins hamartin and tuberin that are encoded by TISC1 and TISC2 genes .	In normal conditions, mTOR activity is inhibited by proteins hamartin and tuberin that are encoded by TISC1 and TISC2 genes.	4	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	12	13	4	5
In human peripheral monocytes stimulated by lipopolysaccharide , mTOR was inhibited by rapamycin or activated by RNA interference mediated knockdown of the mTOR repressor tuberous sclerosis complex 2 ( TSC2 ) .	In human peripheral monocytes stimulated by lipopolysaccharide, mTOR was inhibited by rapamycin or activated by RNA interference mediated knockdown of the mTOR repressor tuberous sclerosis complex 2 (TSC2).	18	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	29	30	22	23
It is caused by mutations in the genes encoding hamartin ( TSC1 ) and tuberin ( TSC2 ) that are involved in the regulation of cell proliferation and differentiation and inhibit the mTOR pathway [ XREF_BIBR ] .	It is caused by mutations in the genes encoding hamartin (TSC1) and tuberin (TSC2) that are involved in the regulation of cell proliferation and differentiation and inhibit the mTOR pathway [XREF_BIBR].	2	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	14	15	32	33
One of the major downstream substrates of Akt is TSC2 , which is phosphorylated to activate the mammalian target of Rapamycin ( mTOR ) , another important tumorigenesis promoting kinase .	One of the major downstream substrates of Akt is TSC2, which is phosphorylated to activate the mammalian target of Rapamycin (mTOR), another important tumorigenesis promoting kinase.	5	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2, which is phosphorylated	tsc2	mammalian target of Rapamycin	mammalian target of Rapamycin	mammalian target of rapamycin	9	10	17	21
Among the 4 patients who had PR or SD > 12 months , 1 patient with Hodgkin lymphoma had TSC2 loss , a molecular aberration that putatively activates the mTOR pathway .	Among the 4 patients who had PR or SD> 12 months, 1 patient with Hodgkin lymphoma had TSC2 loss, a molecular aberration that putatively activates the mTOR pathway.	19	30	activates	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	19	20	29	30
However , mTOR is negatively regulated by complex of tuberin and hamartin [ XREF_BIBR ] .	However, mTOR is negatively regulated by complex of tuberin and hamartin [XREF_BIBR].	2	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	9	10	2	3
One study revealed that a coordinated phosphorylation of TSC2 by GSK-3beta and AMPK suppresses mTOR activity 53 .	One study revealed that a coordinated phosphorylation of TSC2 by GSK-3beta and AMPK suppresses mTOR activity 53.	6	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	8	9	14	15
Our data support that RTP801 and RTP801L work downstream of AKT and upstream of TSC2 to inhibit mTOR functions .	Our data support that RTP801 and RTP801L work downstream of AKT and upstream of TSC2 to inhibit mTOR functions.	12	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	14	15	17	18
mTOR is inhibited , in part , by two tumor-suppressor proteins , TSC2 and PTEN .	mTOR is inhibited, in part, by two tumor-suppressor proteins, TSC2 and PTEN.	0	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	12	13	0	1
Full-length TSC2 protein interacts with TSC1 to inhibit the activation of mTOR by Rheb .	Full-length TSC2 protein interacts with TSC1 to inhibit the activation of mTOR by Rheb.	1	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	1	2	11	12
Since hamartin and tuberin negatively regulate mTOR activity , which in turn phosphorylates and thereby activates important translation factors such as p70 S6 kinase 1 ( S6K1 ) and eukaryote initiation factor 4E binding protein ( eIF4E-BP ) , a major role of the TSC-mTOR signaling pathway has been suggested for tumorigenesis , and both genes were initially recognized as tumor suppressors [ XREF_BIBR ] .	Since hamartin and tuberin negatively regulate mTOR activity, which in turn phosphorylates and thereby activates important translation factors such as p70 S6 kinase 1 (S6K1) and eukaryote initiation factor 4E binding protein (eIF4E-BP), a major role of the TSC-mTOR signaling pathway has been suggested for tumorigenesis, and both genes were initially recognized as tumor suppressors [XREF_BIBR].	1	7	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	3	4	6	7
These data imply that TSC2 can inhibit mTOR while simultaneously induce Akt and NF-kappaB in the EEF cells .	These data imply that TSC2 can inhibit mTOR while simultaneously induce Akt and NF-kappaB in the EEF cells.	4	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	4	5	7	8
TSC2 can inhibit mTOR signaling , which can be reversed by AKT phosphorylation .	TSC2 can inhibit mTOR signaling, which can be reversed by AKT phosphorylation.	0	4	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	0	1	3	4
Tuberin is a suppressor of mTOR , and phosphorylated tuberin loses its suppressive effect against mTOR [ XREF_BIBR ] .	Tuberin is a suppressor of mTOR, and phosphorylated tuberin loses its suppressive effect against mTOR [XREF_BIBR].	0	6	is a suppressor	Negative_activation_copula_1	Negative_activation	Negative_activation	Tuberin	Tuberin	Tuberin	mTOR	mTOR	mTOR	0	1	5	6
Silencing of TSC2 restored mTOR activity in T cells cultured with MDSC , but it also led to T cell apoptosis , suggesting the key role of this inhibition in the survival of T cells to MDSC .	Silencing of TSC2 restored mTOR activity in T cells cultured with MDSC, but it also led to T cell apoptosis, suggesting the key role of this inhibition in the survival of T cells to MDSC.	0	5	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	4	5
Surprisingly , rapamycin treatment also rescues lamination defects in tuberous sclerosis complex ( TSC ) 2 deficient mice , in which loss of TSC2 leads to activation of mTOR signaling and aberrant regulation of Reelin-Dab1 signaling .	Surprisingly, rapamycin treatment also rescues lamination defects in tuberous sclerosis complex (TSC) 2 deficient mice, in which loss of TSC2 leads to activation of mTOR signaling and aberrant regulation of Reelin-Dab1 signaling.	21	29	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	loss of TSC2	tsc2	mTOR	mTOR	mtor	23	24	28	29
Both proteins TSC1 and TSC2 downregulate mTOR , which eventually lead to the promotion of autophagy [ XREF_BIBR - XREF_BIBR ] .	Both proteins TSC1 and TSC2 downregulate mTOR, which eventually lead to the promotion of autophagy [XREF_BIBR - XREF_BIBR].	2	10	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	4	5	6	7
ERK dependent phosphorylation on serine 664 of TSC2 leads to the dissociation of TSC1-TSC2 and impairment of TSC2 to inhibit mTOR signaling .	ERK dependent phosphorylation on serine 664 of TSC2 leads to the dissociation of TSC1-TSC2 and impairment of TSC2 to inhibit mTOR signaling.	2	21	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation on serine 664 of TSC2	tsc2	mTOR	mTOR	mtor	7	8	20	21
Fisetin also activated the mTOR repressor TSC2 through inhibition of Akt and activation of AMPK .	Fisetin also activated the mTOR repressor TSC2 through inhibition of Akt and activation of AMPK.	2	7	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	6	7	4	5
Other downstream targets of AMPK include TSC2 , which inhibits mammalian target of rapamycin complex 1 ( mTORC1 ) and protein synthesis ; XREF_BIBR HMG-CoA reductase , which leads to the inhibition of cholesterol synthesis ; XREF_BIBR peroxisome proliferator activated receptor-gamma coactivator ( PPARalpha ) 1alpha , which stimulates mitochondrial biogenesis , XREF_BIBR , XREF_BIBR and many others .	Other downstream targets of AMPK include TSC2, which inhibits mammalian target of rapamycin complex 1 (mTORC1) and protein synthesis; XREF_BIBR HMG-CoA reductase, which leads to the inhibition of cholesterol synthesis; XREF_BIBR peroxisome proliferator activated receptor-gamma coactivator (PPARalpha) 1alpha, which stimulates mitochondrial biogenesis, XREF_BIBR, XREF_BIBR and many others.	5	48	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	6	7	10	14
Therefore , homozygous loss of TSC1 or TSC2 leads to high constitutive activation of mTOR signaling , as detected in mouse embryonic fibroblasts , in the tumors of rodent models of TSC , and in human TSC cells and tumors .	Therefore, homozygous loss of TSC1 or TSC2 leads to high constitutive activation of mTOR signaling, as detected in mouse embryonic fibroblasts, in the tumors of rodent models of TSC, and in human TSC cells and tumors.	3	15	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	loss of TSC1 or TSC2	tsc2	mTOR	mTOR	mtor	7	8	14	15
ERK dependent phosphorylation of TSC2 , particularly at Ser664 , leads to TSC1-TSC2 dissociation and markedly impairs the ability of TSC2 to inhibit mTOR signaling .	ERK dependent phosphorylation of TSC2, particularly at Ser664, leads to TSC1-TSC2 dissociation and markedly impairs the ability of TSC2 to inhibit mTOR signaling.	0	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	ERK dependent phosphorylation of TSC2, particularly at Ser664	tsc2	mTOR	mTOR	mtor	4	5	23	24
It has to be pointed out that pAkt is an upstream positive regulator of mTOR through TSC2 inhibition expected to increase mTOR signaling .	It has to be pointed out that pAkt is an upstream positive regulator of mTOR through TSC2 inhibition expected to increase mTOR signaling.	16	22	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	16	17	21	22
In the setting of low concentrations of adenosine triphosphate ( and high AMP ) , AMPK activates TSC2 , which inhibits mTOR .	In the setting of low concentrations of adenosine triphosphate (and high AMP), AMPK activates TSC2, which inhibits mTOR.	16	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	17	18	21	22
The activated AMPK can phosphorylate and activate TSC2 , and sequentially inhibit mTOR and activate autophagy XREF_BIBR .	The activated AMPK can phosphorylate and activate TSC2, and sequentially inhibit mTOR and activate autophagy XREF_BIBR.	2	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK can phosphorylate and activate TSC2	tsc2	mTOR	mTOR	mtor	7	8	12	13
Recent studies have revealed that TSC2 plays an important role in the cell growth and proliferation pathway , in which TSC2 forms a functional complex with TSC1 and negatively regulates both growth factor and nutrient dependent activation of mTOR signalling to its downstream targets S6 kinase and 4EBP1 ( Gao et al , 2002 ; Manning and Cantley , 2003 ; Saucedo et al , 2003 ; Stocker et al , 2003 ; Hay and Sonenberg , 2004 ) .	Recent studies have revealed that TSC2 plays an important role in the cell growth and proliferation pathway, in which TSC2 forms a functional complex with TSC1 and negatively regulates both growth factor and nutrient dependent activation of mTOR signalling to its downstream targets S6 kinase and 4EBP1 (Gao et al, 2002; Manning and Cantley, 2003; Saucedo et al, 2003; Stocker et al, 2003; Hay and Sonenberg, 2004).	20	39	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	20	21	38	39
Activation of AMPK leads to suppression of mammalian target of rapamycin ( mTOR ) signaling , and the molecular mechanisms involve phosphorylation of tuberous sclerosis complex protein TSC2 at Thr 1227 and Ser 1345 that increases the activity of the TSC1 and TSC2 complex to inhibit mTOR [ XREF_BIBR , XREF_BIBR ] .	Activation of AMPK leads to suppression of mammalian target of rapamycin (mTOR) signaling, and the molecular mechanisms involve phosphorylation of tuberous sclerosis complex protein TSC2 at Thr 1227 and Ser 1345 that increases the activity of the TSC1 and TSC2 complex to inhibit mTOR [XREF_BIBR, XREF_BIBR].	21	50	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation of tuberous sclerosis complex protein TSC2 at Thr 1227 and Ser 1345	tsc2	mTOR	mTOR	mtor	27	28	46	47
We found that PPARgamma ligands activate TSC2 , which , in turn , inhibits mTOR signaling in NSCLC cells through PPARgamma independent pathways .	We found that PPARgamma ligands activate TSC2, which, in turn, inhibits mTOR signaling in NSCLC cells through PPARgamma independent pathways.	5	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	6	7	14	15
As such , loss of either TSC1 or TSC2 leads to mTOR activation .	As such, loss of either TSC1 or TSC2 leads to mTOR activation.	3	12	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	loss of either TSC1 or TSC2	tsc2	mTOR	mTOR	mtor	8	9	11	12
During nutrient stress AMPK phosphorylates TSC2 on S and T to increase the GTPase activating protein ( GAP ) activity of TSC2 toward Rheb , thereby inhibiting mTOR activity XREF_BIBR .	During nutrient stress AMPK phosphorylates TSC2 on S and T to increase the GTPase activating protein (GAP) activity of TSC2 toward Rheb, thereby inhibiting mTOR activity XREF_BIBR.	4	29	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	5	6	27	28
Activation of AMPK , a target of several glucose lowering agents used in diabetes treatment , including metformin and the thiazolidenediones , stimulates insulin action in peripheral tissues , acting to phosphorylate and stimulate the TSC1 : TSC2 complex , which subsequently inactivates mammalian target of rapamycin and regulatory associated protein of mTOR ( mTOR and Raptor ) .	Activation of AMPK, a target of several glucose lowering agents used in diabetes treatment, including metformin and the thiazolidenediones, stimulates insulin action in peripheral tissues, acting to phosphorylate and stimulate the TSC1 : TSC2 complex, which subsequently inactivates mammalian target of rapamycin and regulatory associated protein of mTOR (mTOR and Raptor).	31	47	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylate and stimulate the TSC1 : TSC2	tsc2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	37	38	43	47
In such cases loss of TSC1 and TSC2 would be required to activate mTOR .	In such cases loss of TSC1 and TSC2 would be required to activate mTOR.	3	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	loss of TSC1 and TSC2	tsc2	mTOR	mTOR	mtor	7	8	13	14
In contrast , under ATP privation , the AMPK phosphorylates and potentiates tuberous sclerosis protein 2 ( TSC2 ) , which inhibits mTOR in combination with TSC1 ( hamartin ) [ XREF_BIBR ] ( XREF_FIG ) .	In contrast, under ATP privation, the AMPK phosphorylates and potentiates tuberous sclerosis protein 2 (TSC2), which inhibits mTOR in combination with TSC1 (hamartin) [XREF_BIBR] (XREF_FIG).	8	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK phosphorylates and potentiates tuberous sclerosis protein 2 (TSC2	tsc2	mTOR	mTOR	mtor	17	18	22	23
In sestrin over expressing cells , siRNA knockdown of TSC2 restores the activation of mTOR by upstream signals , suggesting the TSC complex is necessary for sestrin ' s inhibitory activity .	In sestrin over expressing cells, siRNA knockdown of TSC2 restores the activation of mTOR by upstream signals, suggesting the TSC complex is necessary for sestrin 's inhibitory activity.	7	15	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	9	10	14	15
Loss of TSC2 leads to activation of MTOR and downstream signaling elements , causes endoplasmic reticulum ( ER ) stress , activates the unfolded protein response , and results in tumor development [ XREF_BIBR ] .	Loss of TSC2 leads to activation of MTOR and downstream signaling elements, causes endoplasmic reticulum (ER) stress, activates the unfolded protein response, and results in tumor development [XREF_BIBR].	0	11	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	Loss of TSC2	tsc2	MTOR	MTOR	mtor	2	3	7	8
The mutations of either TSC1 or TSC2 gene activate the mammalian target of rapamycin ( mTOR ) signaling pathway , resulting in cellular aberrant function and tumor growth [ XREF_BIBR , XREF_BIBR ] .	The mutations of either TSC1 or TSC2 gene activate the mammalian target of rapamycin (mTOR) signaling pathway, resulting in cellular aberrant function and tumor growth [XREF_BIBR, XREF_BIBR].	6	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	6	7	10	14
We set out to test the hypothesis that PPARgamma ligands activate tuberous sclerosis complex-2 ( TSC2 ) , a tumor suppressor gene that inhibits mTOR signaling .	We set out to test the hypothesis that PPARgamma ligands activate tuberous sclerosis complex-2 (TSC2), a tumor suppressor gene that inhibits mTOR signaling.	13	25	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	15	16	24	25
The tumor suppressor tuberin , the TSC2 gene product , negatively regulates the mammalian target of rapamycin ( mTOR ) pathway , which is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human chronic diseases , including cancer [ XREF_BIBR ] .	The tumor suppressor tuberin, the TSC2 gene product, negatively regulates the mammalian target of rapamycin (mTOR) pathway, which is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human chronic diseases, including cancer [XREF_BIBR].	6	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	6	7	13	17
We investigated the effect of the signaling molecule tuberin , which modulates the mammalian target of rapamycin pathway , on renal hypertrophy and fibronectin expression .	We investigated the effect of the signaling molecule tuberin, which modulates the mammalian target of rapamycin pathway, on renal hypertrophy and fibronectin expression.	3	17	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	8	9	13	17
mTOR is inhibited upon withdrawal of growth factors , such as insulin or insulin like growth factors , by a cascade of phosphorylation reactions involving Class I PI3K , Akt , TSC1 and TSC2 , and Rheb .	mTOR is inhibited upon withdrawal of growth factors, such as insulin or insulin like growth factors, by a cascade of phosphorylation reactions involving Class I PI3K, Akt, TSC1 and TSC2, and Rheb.	0	34	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	phosphorylation reactions involving Class I PI3K, Akt, TSC1 and TSC2	tsc2	mTOR	mTOR	mtor	33	34	0	1
AKT inhibits TSC2 mediated inhibition of the mammalian target of rapamycin , or mTOR , functionality .	AKT inhibits TSC2 mediated inhibition of the mammalian target of rapamycin, or mTOR, functionality.	2	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	2	3	7	11
Phosphorylation of tuberin by AMPK enhances tuberin repression of mTOR signaling , and tuberin is essential for altered cell growth in response to energy deprivation .	Phosphorylation of tuberin by AMPK enhances tuberin repression of mTOR signaling, and tuberin is essential for altered cell growth in response to energy deprivation.	6	10	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	6	7	9	10
XREF_BIBR Both sestrins can trigger the AMPK and target it to phosphorylate and activate TSC1 and TSC2 complex , thereby inhibiting the signaling of mTOR , a critical autophagy inhibitor of cells , XREF_BIBR , XREF_BIBR and so CX-5461-induced autophagy through AMPK and mTOR signaling pathway in U2-OS cells might arise from the upregulation of Sesn1/2 by p53 .	XREF_BIBR Both sestrins can trigger the AMPK and target it to phosphorylate and activate TSC1 and TSC2 complex, thereby inhibiting the signaling of mTOR, a critical autophagy inhibitor of cells, XREF_BIBR, XREF_BIBR and so CX-5461-induced autophagy through AMPK and mTOR signaling pathway in U2-OS cells might arise from the upregulation of Sesn1/2 by p53.	11	25	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylate and activate TSC1 and TSC2	tsc2	mTOR	mTOR	mtor	16	17	24	25
XREF_BIBR TSC1 or TSC2 depleted cells fail to attenuate downstream mTOR signaling in response to amino acid depletion , serum starvation or growth factor withdrawal .	XREF_BIBR TSC1 or TSC2 depleted cells fail to attenuate downstream mTOR signaling in response to amino acid depletion, serum starvation or growth factor withdrawal.	1	11	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	3	4	10	11
Tuberous sclerosis is a genetic condition resulting from mutations in the TSC1 or TSC2 gene , which negatively regulate mTOR activity .	Tuberous sclerosis is a genetic condition resulting from mutations in the TSC1 or TSC2 gene, which negatively regulate mTOR activity.	11	20	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	13	14	19	20
To validate whether Rheb was involved in PRL-3-mediated TSC2 suppression and activation of mTOR , we used a Rheb activation assay to directly study the levels of active Rheb ( Rheb-GTP ) in PRL-3-overexpressing cells .	To validate whether Rheb was involved in PRL-3-mediated TSC2 suppression and activation of mTOR, we used a Rheb activation assay to directly study the levels of active Rheb (Rheb-GTP) in PRL-3-overexpressing cells.	8	14	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	8	9	13	14
In the presence of growth factors such as insulin or insulin like growth factors , stimulated Akt and extracellular signal regulated protein kinases 1 and 2 ( ERK1/2 ) can phosphorylate and disrupt the tuberous sclerosis complex 1/2 ( TSC1 and TSC2 ) , which activates mTOR inhibition and thus inhibiting autophagy [ XREF_BIBR ] .	In the presence of growth factors such as insulin or insulin like growth factors, stimulated Akt and extracellular signal regulated protein kinases 1 and 2 (ERK1/2) can phosphorylate and disrupt the tuberous sclerosis complex 1/2 (TSC1 and TSC2), which activates mTOR inhibition and thus inhibiting autophagy [XREF_BIBR].	18	47	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	extracellular signal regulated protein kinases 1 and 2 (ERK1/2) can phosphorylate and disrupt the tuberous sclerosis complex 1/2 (TSC1 and TSC2	tsc2	mTOR	mTOR	mtor	41	42	46	47
Akt activates mTOR through ( i ) phosphorylation and inhibition of tuberous sclerosis complex 2 ( TSC2 ) , which inactivates the mTOR activating GTP binding protein Rheb , and/or ( ii ) phosphorylation of PRAS40 a member of mTORC1 , one of the two functional complexes of mTOR , which includes mLST8 and Gbl and the scaffold protein Raptor .	Akt activates mTOR through (i) phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which inactivates the mTOR activating GTP binding protein Rheb, and/or (ii) phosphorylation of PRAS40 a member of mTORC1, one of the two functional complexes of mTOR, which includes mLST8 and Gbl and the scaffold protein Raptor.	2	31	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	16	17	22	23
Identification of mutations in the tuberous sclerosis 1 ( TSC1 ) and TSC2 genes producing constitutive activation of the mammalian target of rapamycin ( mTOR ) pathway presents an opportunity for targeted therapy .	Identification of mutations in the tuberous sclerosis 1 (TSC1) and TSC2 genes producing constitutive activation of the mammalian target of rapamycin (mTOR) pathway presents an opportunity for targeted therapy.	12	23	producing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	12	13	19	23
The inactivation of TSC2 leads to proteasomal degradation of the TSC1 and TSC2 protein complex which in turn activates the mammalian target of rapamycin ( mTOR ) activation .	The inactivation of TSC2 leads to proteasomal degradation of the TSC1 and TSC2 protein complex which in turn activates the mammalian target of rapamycin (mTOR) activation.	12	24	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	12	13	20	24
In addition , the activation of AMPK can phosphorylate TSC2 and the activated TSC2 can suppress mTOR complex 1 ( mTORC1 ) to induce autophagy XREF_BIBR , XREF_BIBR .	In addition, the activation of AMPK can phosphorylate TSC2 and the activated TSC2 can suppress mTOR complex 1 (mTORC1) to induce autophagy XREF_BIBR, XREF_BIBR.	11	17	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	13	14	16	17
GSK-3beta phosphorylates and activates TSC2 , which in turn inhibits mTOR 11 , where GSK-3beta is required for mTOR regulation by energy starvation 11 .	GSK-3beta phosphorylates and activates TSC2, which in turn inhibits mTOR 11, where GSK-3beta is required for mTOR regulation by energy starvation 11.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	GSK-3beta phosphorylates and activates TSC2	tsc2	mTOR	mTOR	mtor	4	5	10	11
To investigate whether the suppressed AKT and mTOR pathway contributes to the reversibility of contact inhibition , they designed shRNA that silenced the expression of TSC2 , an AKT substrate that inhibits mTOR activity by suppressing the mTOR activating small GTP binding protein Rheb .	To investigate whether the suppressed AKT and mTOR pathway contributes to the reversibility of contact inhibition, they designed shRNA that silenced the expression of TSC2, an AKT substrate that inhibits mTOR activity by suppressing the mTOR activating small GTP binding protein Rheb.	23	33	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC2	expression of TSC2	tsc2	mTOR	mTOR	mtor	25	26	32	33
Under metabolic stresses , such as hypoxia and energy deprivation , LKB1-AMPK signaling can be activated , and subsequently phosphorylates and activates tuberous sclerosis complex 2 ( TSC2 ) , which next inhibits mTOR and mTORC1 , leading to the activation of autophagy [ XREF_BIBR ] .	Under metabolic stresses, such as hypoxia and energy deprivation, LKB1-AMPK signaling can be activated, and subsequently phosphorylates and activates tuberous sclerosis complex 2 (TSC2), which next inhibits mTOR and mTORC1, leading to the activation of autophagy [XREF_BIBR].	19	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylates and activates tuberous sclerosis complex 2 (TSC2	tsc2	mTOR	mTOR	mtor	27	28	33	34
Once activated , AMP kinase phosphorylates TSC2 which then suppresses mTOR .	Once activated, AMP kinase phosphorylates TSC2 which then suppresses mTOR.	3	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMP kinase phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	6	7	10	11
On the contrary , the anti-oncogene phosphatase and tensin homology deleted on chromosome 10 ( PTEN ) , TSC complex subunit 1 ( TSC1 ) , and TSC complex subunit 2 ( TSC2 ) can inhibit the progress of the mTOR pathway .	On the contrary, the anti-oncogene phosphatase and tensin homology deleted on chromosome 10 (PTEN), TSC complex subunit 1 (TSC1), and TSC complex subunit 2 (TSC2) can inhibit the progress of the mTOR pathway.	6	41	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	32	33	40	41
Activated AMPK could phosphorylate tumor suppressor tuberous sclerosis complex 2 ( TSC2 ) to inhibit mTOR activity , which plays a critical role in cancer progression [ XREF_BIBR ] .	Activated AMPK could phosphorylate tumor suppressor tuberous sclerosis complex 2 (TSC2) to inhibit mTOR activity, which plays a critical role in cancer progression [XREF_BIBR].	1	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK could phosphorylate tumor suppressor tuberous sclerosis complex 2 (TSC2	tsc2	mTOR	mTOR	mtor	11	12	15	16
mTOR , on the other hand , is activated indirectly by Akt through phosphorylation of TSC2 in the TSC1 and TSC2 ( hamartin and tuberin ) heterodimer that inhibits mTOR signaling .	mTOR, on the other hand, is activated indirectly by Akt through phosphorylation of TSC2 in the TSC1 and TSC2 (hamartin and tuberin) heterodimer that inhibits mTOR signaling.	13	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	15	16	29	30
We next determined whether TSC2 was required for the ability of apicidin to inhibit the mTOR pathway .	We next determined whether TSC2 was required for the ability of apicidin to inhibit the mTOR pathway.	4	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	4	5	15	16
The relevance of the mTOR pathway in the pathophysiology of TSC was first suggested in simplified biological systems , such as drosophila and yeast , in which hamartin and tuberin were shown to inhibit mTOR signaling .	The relevance of the mTOR pathway in the pathophysiology of TSC was first suggested in simplified biological systems, such as drosophila and yeast, in which hamartin and tuberin were shown to inhibit mTOR signaling.	27	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	29	30	34	35
The tumor suppressor tuberin , encoded by the Tuberous Sclerosis Complex ( TSC ) gene TSC2 , negatively regulates the mammalian target of rapamycin ( mTOR ) pathway , which plays a key role in the control of cell growth and proliferation .	The tumor suppressor tuberin, encoded by the Tuberous Sclerosis Complex (TSC) gene TSC2, negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in the control of cell growth and proliferation.	0	24	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	3	4	20	24
In HT29 colon tumoral cells XREF_BIBR , AMPK activation by synthetic molecules or polyphenolic compounds was shown to activate TSC2 , which in turn inhibits TORC1 and mTOR and p70S6K .	In HT29 colon tumoral cells XREF_BIBR, AMPK activation by synthetic molecules or polyphenolic compounds was shown to activate TSC2, which in turn inhibits TORC1 and mTOR and p70S6K.	18	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	19	20	27	28
Upon stimuli , AMPK ca activate autophagy by directly phosphorylating and activating ULK1 or indirectly activating ULK1 with TSC2 mediated mTOR inhibition .	Upon stimuli, AMPK ca activate autophagy by directly phosphorylating and activating ULK1 or indirectly activating ULK1 with TSC2 mediated mTOR inhibition.	15	21	mediated	Positive_early_activation	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	18	19	20	21
LKB1 is linked to mTOR regulation through the sequential activation of AMP activated protein kinase ( AMPK ) and the tumor suppressor TSC2 , a GTPase activating protein that negatively regulates mTOR through the small G protein Rheb .	LKB1 is linked to mTOR regulation through the sequential activation of AMP activated protein kinase (AMPK) and the tumor suppressor TSC2, a GTPase activating protein that negatively regulates mTOR through the small G protein Rheb.	2	32	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	22	23	31	32
Interestingly , loss of either TSC1 or TSC2 , which leads to hyperactive mTOR , also triggers ER stress and the UPR - indicating that hyperactive mTOR leads to the activation of PERK and generates the PA to support increased mTOR activity .	Interestingly, loss of either TSC1 or TSC2, which leads to hyperactive mTOR, also triggers ER stress and the UPR - indicating that hyperactive mTOR leads to the activation of PERK and generates the PA to support increased mTOR activity.	2	14	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	TSC2	loss of either TSC1 or TSC2	tsc2	mTOR	mTOR	mtor	7	8	13	14
The TSC2 inhibited mTOR and other substrates , including S6K , 4EBP-1 and EIF2 , which resulted in reduced cell size and growth rates .	The TSC2 inhibited mTOR and other substrates, including S6K, 4EBP-1 and EIF2, which resulted in reduced cell size and growth rates.	0	6	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	1	2	3	4
We also analyzed REDD1 ( RTP801 ) , which has been shown to be strongly induced under hypoxic conditions in a HIF-1alpha dependent manner XREF_BIBR and recent studies also suggest that REDD1 plays a role in the TSC1 and TSC2 mediated inhibition of mTOR XREF_BIBR .	We also analyzed REDD1 (RTP801), which has been shown to be strongly induced under hypoxic conditions in a HIF-1alpha dependent manner XREF_BIBR and recent studies also suggest that REDD1 plays a role in the TSC1 and TSC2 mediated inhibition of mTOR XREF_BIBR.	34	44	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	39	40	43	44
Our study demonstrates that IFNbeta dependent activation of STATs and p38 MAPK is not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and that TSC2 dependent inhibition of mTOR and S6K1 cooperates with IFNbeta in inhibiting human LAM and TSC2-null ELT3 cell proliferation .	Our study demonstrates that IFNbeta dependent activation of STATs and p38 MAPK is not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and that TSC2 dependent inhibition of mTOR and S6K1 cooperates with IFNbeta in inhibiting human LAM and TSC2-null ELT3 cell proliferation.	26	32	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	26	27	30	31
Rapamycin and FKBP12 destabilizes the mTOR complex [ XREF_BIBR ] while p53 induces transcription of Sestrin 1 and 2 to activate AMPK and TSC2 inhibition of mTOR [ XREF_BIBR ] .	Rapamycin and FKBP12 destabilizes the mTOR complex [XREF_BIBR] while p53 induces transcription of Sestrin 1 and 2 to activate AMPK and TSC2 inhibition of mTOR [XREF_BIBR].	21	28	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	23	24	26	27
Recently , the TSC1 and TSC2 protein complex was shown to inhibit the kinase mTOR ( mammalian target of rapamycin ) .	Recently, the TSC1 and TSC2 protein complex was shown to inhibit the kinase mTOR (mammalian target of rapamycin).	5	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	5	6	14	15
In the presence of a functional membrane bound PC1 C-terminal tail , phosphorylation of tuberin by PI3K and AKT is inhibited and TSC2 becomes tethered to the membrane , repressing mTOR signaling .	In the presence of a functional membrane bound PC1 C-terminal tail, phosphorylation of tuberin by PI3K and AKT is inhibited and TSC2 becomes tethered to the membrane, repressing mTOR signaling.	22	31	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	22	23	30	31
Here , we show that loss of Tsc2 in osteoblasts constitutively activates mTOR and destabilizes Irs1 , causing osteoblasts to differentiate poorly and become resistant to insulin .	Here, we show that loss of Tsc2 in osteoblasts constitutively activates mTOR and destabilizes Irs1, causing osteoblasts to differentiate poorly and become resistant to insulin.	5	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tsc2	loss of Tsc2	tsc2	mTOR	mTOR	mtor	7	8	12	13
Loss of TSC1 or TSC2 leads to hyperactive mTOR signaling , which is the main cause of tumor growth in TSC patients , and the decreased AKT1 activity due to the negative feedback regulation of mTOR may account for the benign nature of TSC tumors .	Loss of TSC1 or TSC2 leads to hyperactive mTOR signaling, which is the main cause of tumor growth in TSC patients, and the decreased AKT1 activity due to the negative feedback regulation of mTOR may account for the benign nature of TSC tumors.	0	9	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	Loss of TSC1 or TSC2	tsc2	mTOR	mTOR	mtor	4	5	8	9
Mutations in the TSC1 or TSC2 genes lead to disruption of the TSC1-TSC2 intracellular protein complex , causing overactivation of the mammalian target of rapamycin ( mTOR ) protein complex .	Mutations in the TSC1 or TSC2 genes lead to disruption of the TSC1-TSC2 intracellular protein complex, causing overactivation of the mammalian target of rapamycin (mTOR) protein complex.	3	25	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	5	6	21	25
For example , hypoxia suppresses energy-costly mRNA translation and protein synthesis via AMPK and TSC2 mediated mTOR inhibition XREF_BIBR or other mechanisms XREF_BIBR , XREF_BIBR .	For example, hypoxia suppresses energy-costly mRNA translation and protein synthesis via AMPK and TSC2 mediated mTOR inhibition XREF_BIBR or other mechanisms XREF_BIBR, XREF_BIBR.	7	18	mediated	Positive_early_activation	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	14	15	16	17
Moreover , AMPK can inhibit the activity of the mTOR complex 1 ( mTORC1 ) , either phosphorylating the regulatory Raptor component or activating TSC2 which subsequently inhibit mTOR activity [ XREF_BIBR ] .	Moreover, AMPK can inhibit the activity of the mTOR complex 1 (mTORC1), either phosphorylating the regulatory Raptor component or activating TSC2 which subsequently inhibit mTOR activity [XREF_BIBR].	23	29	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	24	25	28	29
It is now generally recognized that the primary function of the TSC1 and TSC2 protein complex is to inhibit mTOR signaling .	It is now generally recognized that the primary function of the TSC1 and TSC2 protein complex is to inhibit mTOR signaling.	13	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	13	14	19	20
TSC1 and TSC2 , which inhibit mTOR signaling , are known as important regulators of cell size and growth [ XREF_BIBR , XREF_BIBR ] .	TSC1 and TSC2, which inhibit mTOR signaling, are known as important regulators of cell size and growth [XREF_BIBR, XREF_BIBR].	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	6	7
First , in the nucleus , p53 has been reported to promote autophagy by transactivating genes encoding : DRAM1 , which is induced by DNA damage and localized to lysosomes with autophagosome accumulation ; and sestrin 1 and 2 , AMPK beta1 and beta2 , and TSC2 , which act on the AMPK pathway to inhibit the autophagy suppressor mTOR , thus activating autophagy [ XREF_BIBR , XREF_BIBR ] .	First, in the nucleus, p53 has been reported to promote autophagy by transactivating genes encoding : DRAM1, which is induced by DNA damage and localized to lysosomes with autophagosome accumulation; and sestrin 1 and 2, AMPK beta1 and beta2, and TSC2, which act on the AMPK pathway to inhibit the autophagy suppressor mTOR, thus activating autophagy [XREF_BIBR, XREF_BIBR].	35	60	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	46	47	59	60
In fact , Myc inhibits mTOR repressor TSC2 , thus increasing mTOR activity to facilitate cap dependent translation through S6K and 4E-BP phosphorylation [ XREF_BIBR ] .	In fact, Myc inhibits mTOR repressor TSC2, thus increasing mTOR activity to facilitate cap dependent translation through S6K and 4E-BP phosphorylation [XREF_BIBR].	4	10	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	7	8	5	6
We have demonstrated that the short intracellular C-terminal tail of polycystin-1 ( CP1 ) when membrane bound , enhances TSC2 mediated repression of mTOR signaling in human cells .	We have demonstrated that the short intracellular C-terminal tail of polycystin-1 (CP1) when membrane bound, enhances TSC2 mediated repression of mTOR signaling in human cells.	19	24	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	19	20	23	24
Specifically AMPK phosphorylates the Tuberous Sclerosis 2 ( TSC2 ) protein that inhibits mTOR and activates autophagy in an analogous mechanism to that seen during starvation [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Specifically AMPK phosphorylates the Tuberous Sclerosis 2 (TSC2) protein that inhibits mTOR and activates autophagy in an analogous mechanism to that seen during starvation [XREF_BIBR, XREF_BIBR - XREF_BIBR].	1	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK phosphorylates the Tuberous Sclerosis 2 (TSC2	tsc2	mTOR	mTOR	mtor	8	9	13	14
Local cap dependent mRNA translation is also controlled by mammalian target of rapamycin ( mTOR ) , which in turn is negatively regulated by the tuberous sclerosis complex proteins TSC1 and TSC2 .	Local cap dependent mRNA translation is also controlled by mammalian target of rapamycin (mTOR), which in turn is negatively regulated by the tuberous sclerosis complex proteins TSC1 and TSC2.	12	32	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	31	32	14	15
To downregulate protein synthesis , AMPK phosphorylates TSC2 , which in turn inhibits mTOR pathway , leading to dephosphorylation of ribosomal subunit component RPS6 ( S6 ) and sequestration of translation initiation factor 4E ( eIF4E ) .	To downregulate protein synthesis, AMPK phosphorylates TSC2, which in turn inhibits mTOR pathway, leading to dephosphorylation of ribosomal subunit component RPS6 (S6) and sequestration of translation initiation factor 4E (eIF4E).	5	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	7	8	13	14
In normal and adult kidney , PC1 functions by inducing the formation of PC1 , tuberin , and mTOR complex thereby inhibiting mTOR activity XREF_BIBR , yet in human ADPKD patients and mouse models , null of PC1 leads to the inability to assemble this inhibitory complex thereby causing mTOR pathway inappropriately activated XREF_BIBR , XREF_BIBR .	In normal and adult kidney, PC1 functions by inducing the formation of PC1, tuberin, and mTOR complex thereby inhibiting mTOR activity XREF_BIBR, yet in human ADPKD patients and mouse models, null of PC1 leads to the inability to assemble this inhibitory complex thereby causing mTOR pathway inappropriately activated XREF_BIBR, XREF_BIBR.	11	24	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	15	16	22	23
The TSC1 and TSC2 proteins negatively regulate mTOR Complex 1 ( mTORC1 ) by inhibiting Rheb activity [ XREF_BIBR ] .	The TSC1 and TSC2 proteins negatively regulate mTOR Complex 1 (mTORC1) by inhibiting Rheb activity [XREF_BIBR].	1	8	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	3	4	7	8
The tuberous sclerosis 1 ( TSC1 ) and TSC2 complex negatively regulates the activity of an mTOR containing multiprotein complex called mTOR complex 1 .	The tuberous sclerosis 1 (TSC1) and TSC2 complex negatively regulates the activity of an mTOR containing multiprotein complex called mTOR complex 1.	8	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	8	9	16	17
Loss of tuberin results in a constitutively activated mTOR signalling leading to increased cell growth [ XREF_BIBR ] .	Loss of tuberin results in a constitutively activated mTOR signalling leading to increased cell growth [XREF_BIBR].	0	10	signalling	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	tuberin	Loss of tuberin	tuberin	mTOR	mTOR	mtor	2	3	8	9
Indeed , genetically reducing TSC2 causes mTOR hyperactivity in people and rodents .	Indeed, genetically reducing TSC2 causes mTOR hyperactivity in people and rodents.	3	7	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	4	5	6	7
This membrane retention of TSC2 enhances TSC2 repression of mTOR signaling in human cells .	This membrane retention of TSC2 enhances TSC2 repression of mTOR signaling in human cells.	6	10	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	6	7	9	10
mTOR is inhibited by activation of upstream repressors TSC1 and TSC2 while AMPK activity is high .	mTOR is inhibited by activation of upstream repressors TSC1 and TSC2 while AMPK activity is high.	0	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	10	11	0	1
In turn , elevated AKT activity increased phosphorylation and degradation of the downstream target TSC2 , activating mTOR signaling , a key integrator coordinating proliferative and metabolic signals required for cell growth and survival ( XREF_FIG ) .	In turn, elevated AKT activity increased phosphorylation and degradation of the downstream target TSC2, activating mTOR signaling, a key integrator coordinating proliferative and metabolic signals required for cell growth and survival (XREF_FIG).	4	18	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	AKT activity increased phosphorylation and degradation of the downstream target TSC2	tsc2	mTOR	mTOR	mtor	14	15	17	18
The Tsc1 and Tsc2 complex interacts with PI3K and Akt signaling such that inhibition of TSC1 and TSC2 activates mTOR and disrupts PI3K-Akt signaling .	The Tsc1 and Tsc2 complex interacts with PI3K and Akt signaling such that inhibition of TSC1 and TSC2 activates mTOR and disrupts PI3K-Akt signaling.	13	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	17	18	19	20
Loss of TSC2 leads to activation of mTOR ( mammalian target of rapamycin ) , which , in addition to activating protein synthesis and cell growth , also potently inhibits autophagy [ XREF_BIBR ] .	Loss of TSC2 leads to activation of mTOR (mammalian target of rapamycin), which, in addition to activating protein synthesis and cell growth, also potently inhibits autophagy [XREF_BIBR].	0	29	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	Loss of TSC2	tsc2	mTOR	mTOR	mtor	2	3	7	8
The protein TSC2 negatively regulates the mTOR pathway by binding and blocking the GTPase activity of Rheb , a positive regulator of mTORC1 activity [ XREF_BIBR ] .	The protein TSC2 negatively regulates the mTOR pathway by binding and blocking the GTPase activity of Rheb, a positive regulator of mTORC1 activity [XREF_BIBR].	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	6	7
Our data corroborates the transgenic mouse data by showing that knockdown of TSC2 increases mTOR and NF-kappaB activity in PTEN null cells , suggesting that loss of TSC2 function coupled with loss of PTEN function activates mTOR and NF-kappaB which may promote tumorigenesis .	Our data corroborates the transgenic mouse data by showing that knockdown of TSC2 increases mTOR and NF-kappaB activity in PTEN null cells, suggesting that loss of TSC2 function coupled with loss of PTEN function activates mTOR and NF-kappaB which may promote tumorigenesis.	10	17	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	12	13	14	15
Phosphorylation of TSC2 by ERK promoted dissociation of the tuberous sclerosis complex and attenuated TSC2 mediated inhibition of mTOR in cells .	Phosphorylation of TSC2 by ERK promoted dissociation of the tuberous sclerosis complex and attenuated TSC2 mediated inhibition of mTOR in cells.	14	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	14	15	18	19
In contrast , phosphorylation and activation of TSC2 by several kinases inhibits mTOR signaling .	In contrast, phosphorylation and activation of TSC2 by several kinases inhibits mTOR signaling.	3	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation and activation of TSC2	tsc2	mTOR	mTOR	mtor	7	8	12	13
TSC derives from inactivating mutations of either the TSC1 or TSC2 tumor suppressor gene , and the resulting inactivation of the TSC1 and TSC2 protein complex causes hyperactivation of the mammalian target of rapamycin ( mTOR ) , leading to uncontrolled cell growth and proliferation .	TSC derives from inactivating mutations of either the TSC1 or TSC2 tumor suppressor gene, and the resulting inactivation of the TSC1 and TSC2 protein complex causes hyperactivation of the mammalian target of rapamycin (mTOR), leading to uncontrolled cell growth and proliferation.	23	34	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	23	24	30	34
Signaling through mTOR is also controlled by upstream members of the pathway such as the Ras homolog enriched in brain ( Rheb ) , a GTPase that activates mTOR , and tuberin ( also known as TSC2 ) , a GTPase activating protein , which , with its binding partner hamartin ( also known as TSC1 ) , acts to repress mTOR .	Signaling through mTOR is also controlled by upstream members of the pathway such as the Ras homolog enriched in brain (Rheb), a GTPase that activates mTOR, and tuberin (also known as TSC2), a GTPase activating protein, which, with its binding partner hamartin (also known as TSC1), acts to repress mTOR.	8	62	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	31	32	61	62
Suppression of mTOR by tuberin takes place only when tuberin is tethered to the membrane .	Suppression of mTOR by tuberin takes place only when tuberin is tethered to the membrane.	0	5	Suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	4	5	2	3
AMPK activation phosphorylates tuberous sclerosis complex 2 ( TSC2 ) , which inhibits mTOR and induces autophagy [ XREF_BIBR ] .	AMPK activation phosphorylates tuberous sclerosis complex 2 (TSC2), which inhibits mTOR and induces autophagy [XREF_BIBR].	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK activation phosphorylates tuberous sclerosis complex 2 (TSC2	tsc2	mTOR	mTOR	mtor	8	9	13	14
In evaluating the mechanism of increased mTOR activity documented in gliomas , we asked whether decreased expression levels of hamartin and tuberin may relieve the inhibitory control of mTOR and lead to elevated mTOR activity .	In evaluating the mechanism of increased mTOR activity documented in gliomas, we asked whether decreased expression levels of hamartin and tuberin may relieve the inhibitory control of mTOR and lead to elevated mTOR activity.	17	29	relieve	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	levels of hamartin and tuberin	tuberin	mTOR	mTOR	mtor	21	22	28	29
In a second phase , we postulate that calpain activation , through PTEN , hamartin and tuberin degradation relieves mTOR inhibition and stimulates protein synthesis , which might be critical for providing long-term consolidation of modified spine structures .	In a second phase, we postulate that calpain activation, through PTEN, hamartin and tuberin degradation relieves mTOR inhibition and stimulates protein synthesis, which might be critical for providing long-term consolidation of modified spine structures.	16	20	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	16	17	19	20
TSC1 and TSC2 are downstream of AMPK and negatively regulate mTOR in response to cellular energy deficit .	TSC1 and TSC2 are downstream of AMPK and negatively regulate mTOR in response to cellular energy deficit.	0	12	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	10	11
Because loss of TSC2 upregulates mTOR activity , we examined whether TSC2 dependent stress fiber remodeling and migration is mediated by mTOR .	Because loss of TSC2 upregulates mTOR activity, we examined whether TSC2 dependent stress fiber remodeling and migration is mediated by mTOR.	1	6	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	loss of TSC2	tsc2	mTOR	mTOR	mtor	3	4	5	6
It is possible that they express negative mTOR regulators such as TSC2 , which limits mTOR signalling in Drosophila intestinal stem cells but not progenitors , or that stem cells are more adept than progenitors at using low levels of nutrients for proliferation , perhaps because of their slower cycling .	It is possible that they express negative mTOR regulators such as TSC2, which limits mTOR signalling in Drosophila intestinal stem cells but not progenitors, or that stem cells are more adept than progenitors at using low levels of nutrients for proliferation, perhaps because of their slower cycling.	8	16	limits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	11	12	15	16
Hamartin and tuberin act as a complex upstream of mTOR and inhibit the mTOR pathway via inhibition of Rheb ( Ras homolog enriched in brain ) ( XREF_FIG ) .	Hamartin and tuberin act as a complex upstream of mTOR and inhibit the mTOR pathway via inhibition of Rheb (Ras homolog enriched in brain) (XREF_FIG).	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	2	3	13	14
These results were inconsistent when considering that mTOR was negatively regulated by TSC2 .	These results were inconsistent when considering that mTOR was negatively regulated by TSC2.	7	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	12	13	7	8
TSC2 ( 16p13.3 ) inhibits mTOR protein and regulates cell growth .	TSC2 (16p13.3) inhibits mTOR protein and regulates cell growth.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	0	1	5	6
Although iron chelation may affect multiple signaling pathways related to cell survival , our data support the conclusion that REDD1 functions up-stream of tuberin to down-regulate the mTOR pathway in response to deferasirox .	Although iron chelation may affect multiple signaling pathways related to cell survival, our data support the conclusion that REDD1 functions up-stream of tuberin to down-regulate the mTOR pathway in response to deferasirox.	21	28	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	23	24	27	28
RSK1 phosphorylation and inactivation of the tumor suppressor Tuberin at Ser 1798 led to activation of mTOR and enhanced proliferation [ XREF_BIBR ] .	RSK1 phosphorylation and inactivation of the tumor suppressor Tuberin at Ser 1798 led to activation of mTOR and enhanced proliferation [XREF_BIBR].	0	17	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Tuberin	RSK1 phosphorylation and inactivation of the tumor suppressor Tuberin at Ser 1798	tuberin	mTOR	mTOR	mtor	8	9	16	17
It is generally believed that activation of PI3K and Akt stimulates the mTOR pathway by phosphorylating and inactivating the tumor suppressor protein tuberous sclerosis complex 2 ( TSC2 ) , which negatively regulates mTOR activity .	It is generally believed that activation of PI3K and Akt stimulates the mTOR pathway by phosphorylating and inactivating the tumor suppressor protein tuberous sclerosis complex 2 (TSC2), which negatively regulates mTOR activity.	17	34	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	27	28	33	34
Akt phosphorylates several substrates , including TSC2 ( tuberous sclerosis complex , tuberin ) , which finally activates the mammalian target of rapamycin ( mTOR ) and provides a direct link between insulin signaling and nutrient sensing .	Akt phosphorylates several substrates, including TSC2 (tuberous sclerosis complex, tuberin), which finally activates the mammalian target of rapamycin (mTOR) and provides a direct link between insulin signaling and nutrient sensing.	3	27	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	6	7	19	23
FST also activated the mTOR repressor TSC2 ( tuberous sclerosis 2 ) , commonly associated with inhibition of Akt and activation of AMPK [ XREF_BIBR ] .	FST also activated the mTOR repressor TSC2 (tuberous sclerosis 2), commonly associated with inhibition of Akt and activation of AMPK [XREF_BIBR].	2	14	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	6	7	4	5
This proliferation of smooth muscle like cells is reported to be due to the activation of mammalian target of rapamycin ( mTOR ) caused by mutations in the tuberous sclerosis complex 1 ( TSC1 ) or TSC2 genes .	This proliferation of smooth muscle like cells is reported to be due to the activation of mammalian target of rapamycin (mTOR) caused by mutations in the tuberous sclerosis complex 1 (TSC1) or TSC2 genes.	16	37	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	36	37	16	20
HERC1 is a ubiquitin ligase that destabilizes TSC2 24 , and TSC2 in complex with TSC1 inhibits FRAP1 function XREF_BIBR , XREF_BIBR .	HERC1 is a ubiquitin ligase that destabilizes TSC2 24, and TSC2 in complex with TSC1 inhibits FRAP1 function XREF_BIBR, XREF_BIBR.	11	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	FRAP1	FRAP1	FRAP1	11	12	17	18
Recent studies demonstrate that activation of AMPK phosphorylate and activates TSC2 that negatively regulates mTOR XREF_BIBR .	Recent studies demonstrate that activation of AMPK phosphorylate and activates TSC2 that negatively regulates mTOR XREF_BIBR.	9	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	10	11	14	15
The Tsc2 product , tuberin , negatively regulates the mTOR pathway .	The Tsc2 product, tuberin, negatively regulates the mTOR pathway.	2	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	4	5	9	10
AMPK promotes autophagy by at least the following ways : phosphorylating the tuberous sclerosis ( TSC ) complex proteins TSC1 and TSC2 , which in turn downregulate mTOR activity and induce autophagy 59 , phosphorylating FOXO3 , phosphorylating ULK1 , and dissociating Beclin1 and Bcl-2 by stimulating JNK1-Bcl-2 signaling XREF_BIBR - XREF_BIBR .	AMPK promotes autophagy by at least the following ways : phosphorylating the tuberous sclerosis (TSC) complex proteins TSC1 and TSC2, which in turn downregulate mTOR activity and induce autophagy 59, phosphorylating FOXO3, phosphorylating ULK1, and dissociating Beclin1 and Bcl-2 by stimulating JNK1-Bcl-2 signaling XREF_BIBR - XREF_BIBR.	18	28	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	21	22	27	28
Our data demonstrate that TSC1 and TSC2 differentially regulate actin stress fiber formation and cell migration , and that only TSC2 loss promotes mTOR- and mTORC2 dependent pro migratory cell phenotype .	Our data demonstrate that TSC1 and TSC2 differentially regulate actin stress fiber formation and cell migration, and that only TSC2 loss promotes mTOR- and mTORC2 dependent pro migratory cell phenotype.	20	30	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR-	mTOR-	mTOR-	20	21	23	24
Supporting an increased protein degradation relative to synthesis due to food deprivation , starved trout muscle contained high levels of the transcript for tuberous sclerosis component 2 ( TSC2 ) which has been shown , in mammals , to inhibit mTOR a positive regulator of cell growth and proliferation [ XREF_BIBR ] , and of the transcript encoding the translational repressor 4E-BP1 , which presumably reinforces the inhibition of cap dependent translation resulting from inactivation of Akt and mTOR [ XREF_BIBR ] .	Supporting an increased protein degradation relative to synthesis due to food deprivation, starved trout muscle contained high levels of the transcript for tuberous sclerosis component 2 (TSC2) which has been shown, in mammals, to inhibit mTOR a positive regulator of cell growth and proliferation [XREF_BIBR], and of the transcript encoding the translational repressor 4E-BP1, which presumably reinforces the inhibition of cap dependent translation resulting from inactivation of Akt and mTOR [XREF_BIBR].	16	41	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	28	29	40	41
In tumors that retained TSC2 expression , phosphorylation of tuberin at S939 was observed with a high frequency , indicating that mTOR repression by TSC2 had been relieved via AKT phosphorylation of this tumor suppressor .	In tumors that retained TSC2 expression, phosphorylation of tuberin at S939 was observed with a high frequency, indicating that mTOR repression by TSC2 had been relieved via AKT phosphorylation of this tumor suppressor.	21	25	repression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	24	25	21	22
Growth factor signals and energy status are transmitted to mTOR C1 via TSC a complex of TSC1 and TSC2 proteins , which bind to Rheb and inhibit mTOR C1 activation .	Growth factor signals and energy status are transmitted to mTOR C1 via TSC a complex of TSC1 and TSC2 proteins, which bind to Rheb and inhibit mTOR C1 activation.	16	29	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2 proteins, which bind to Rheb	tsc2	mTOR	mTOR	mtor	18	19	27	28
TSC2 usually inhibits mTOR via Rheb ( Ras homolog enriched in brain ) , a GTP binding protein .	TSC2 usually inhibits mTOR via Rheb (Ras homolog enriched in brain), a GTP binding protein.	0	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	0	1	3	4
[ XREF_BIBR ] Finally , phosphorylation of TSC2 by AMPK suppresses mTOR and promotes energy producing autophagy .	[XREF_BIBR] Finally, phosphorylation of TSC2 by AMPK suppresses mTOR and promotes energy producing autophagy.	5	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	7	8	11	12
Although loss of tuberin promotes cell growth and tumorigenesis , cells expressing tuberin must also be able to relieve tuberin repression of mammalian TOR ( mTOR ) signaling during conditions of mitogenic sufficiency .	Although loss of tuberin promotes cell growth and tumorigenesis, cells expressing tuberin must also be able to relieve tuberin repression of mammalian TOR (mTOR) signaling during conditions of mitogenic sufficiency.	19	27	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	19	20	25	26
Activation of AMPK modulates insulin signalling downstream of the insulin receptor [ XREF_BIBR ] , most notably via differentially phosphorylating the tuberous sclerosis complex TSC1 and TSC2 to inactivate mTOR [ XREF_BIBR , XREF_BIBR ] .	Activation of AMPK modulates insulin signalling downstream of the insulin receptor [XREF_BIBR], most notably via differentially phosphorylating the tuberous sclerosis complex TSC1 and TSC2 to inactivate mTOR [XREF_BIBR, XREF_BIBR].	19	33	inactivate	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC2	phosphorylating the tuberous sclerosis complex TSC1 and TSC2	tsc2	mTOR	mTOR	mtor	26	27	29	30
At the molecular level , TSC is caused by either the loss or malfunction of either hamartin ( TSC1 ) or tuberin ( TSC2 ) , which interact in a heterodimer known as the TSC1 and TSC2 complex , to negatively regulate mammalian target of rapamycin complex 1 ( mTORC1 ) .	At the molecular level, TSC is caused by either the loss or malfunction of either hamartin (TSC1) or tuberin (TSC2), which interact in a heterodimer known as the TSC1 and TSC2 complex, to negatively regulate mammalian target of rapamycin complex 1 (mTORC1).	11	46	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	loss or malfunction of either hamartin (TSC1) or tuberin	tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	21	22	42	46
Taken together , these data indicate that 1 ) TSC2 inhibits mTOR activity and induces Akt activity through mTOR inhibition , and 2 ) TSC2 mediated induction of Akt enhances NF-kappaB activity .	Taken together, these data indicate that 1) TSC2 inhibits mTOR activity and induces Akt activity through mTOR inhibition, and 2) TSC2 mediated induction of Akt enhances NF-kappaB activity.	9	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	9	10	11	12
It is caused by mutations in the TSC1 or TSC2 tumor suppressor genes , resulting in hyperactivation of the mechanistic target of rapamycin ( mTOR ) signaling pathway and subsequent cell cycle dysregulation .	It is caused by mutations in the TSC1 or TSC2 tumor suppressor genes, resulting in hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway and subsequent cell cycle dysregulation.	2	23	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	9	10	19	23
Dephosphorylation of TSC2 inhibits mTOR and activates autophagy .	Dephosphorylation of TSC2 inhibits mTOR and activates autophagy.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Dephosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	2	3	4	5
Since TSC2 inhibits mTOR by inactivating the small GTPase Rheb ( Inoki etal , 2003 ) , increased levels of AMPK activated TSC2 at the lysosomal surface may explain diminished basal mTOR activity in KO cells .	Since TSC2 inhibits mTOR by inactivating the small GTPase Rheb (Inoki etal, 2003), increased levels of AMPK activated TSC2 at the lysosomal surface may explain diminished basal mTOR activity in KO cells.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	1	2	3	4
TSC2 negatively regulates the activity of the GTPase Rheb and thereby inhibits mammalian target of rapamycin complex 1 ( mTORC1 ) signaling .	TSC2 negatively regulates the activity of the GTPase Rheb and thereby inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	12	16
TSC2 negatively regulates Notch1 signaling in an mTOR dependent and -independent fashion .	TSC2 negatively regulates Notch1 signaling in an mTOR dependent and -independent fashion.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	0	1	7	8
Loss of TSC2 results in constitutive activation of RHEB and its target mTOR .	Loss of TSC2 results in constitutive activation of RHEB and its target mTOR.	0	13	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	TSC2	Loss of TSC2	tsc2	mTOR	mTOR	mtor	2	3	12	13
Moreover , since this phosphorylation is known to relieve TSC2 mediated inhibition of mTOR , the implication is that this is a mechanism by which KSHV ORF45 activated RSK regulates Akt/mTOR/S6K activity [ XREF_BIBR ] .	Moreover, since this phosphorylation is known to relieve TSC2 mediated inhibition of mTOR, the implication is that this is a mechanism by which KSHV ORF45 activated RSK regulates Akt/mTOR/S6K activity [XREF_BIBR].	9	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	9	10	13	14
As unphosphorylated Tsc2 is known to inhibit mTOR [ XREF_BIBR ] , our observed reduction in phosphorylated Tsc2 will result in increased inhibition of mTOR .	As unphosphorylated Tsc2 is known to inhibit mTOR [XREF_BIBR], our observed reduction in phosphorylated Tsc2 will result in increased inhibition of mTOR.	1	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc2	unphosphorylated Tsc2	tsc2	mTOR	mTOR	mtor	2	3	7	8
AMPK is known to phosphorylate and enhance TSC2 , which inhibits the mTOR pathway , promoting autophagy [ XREF_BIBR , XREF_BIBR ] .	AMPK is known to phosphorylate and enhance TSC2, which inhibits the mTOR pathway, promoting autophagy [XREF_BIBR, XREF_BIBR].	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK is known to phosphorylate and enhance TSC2	tsc2	mTOR	mTOR	mtor	7	8	12	13
Silencing TSC2 restored the mTOR related signal and partially blocked the effect of rosiglitazone on cell growth inhibition .	Silencing TSC2 restored the mTOR related signal and partially blocked the effect of rosiglitazone on cell growth inhibition.	0	9	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	1	2	4	5
Constitutive mTOR activation by loss of TSC1 and TSC2 rapidly stimulates the targets of both PERK and IRE1 , which UPR activation could not be observed in combined treatment of TSC1 and TSC2 depletion and rapamycin addition .	Constitutive mTOR activation by loss of TSC1 and TSC2 rapidly stimulates the targets of both PERK and IRE1, which UPR activation could not be observed in combined treatment of TSC1 and TSC2 depletion and rapamycin addition.	1	9	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	TSC2	loss of TSC1 and TSC2	tsc2	mTOR	mTOR	mtor	8	9	1	2
Because mTOR can be alternatively downregulated by tuberous sclerosis complex 2 ( TSC2 ) activation mediated by 5 ' adenosine monophosphate activated protein kinase ( AMPK ) , we proposed that the activation of AMPK alpha1/2 by LKB1 and/or by calmodulin dependent protein kinase kinase ( CaMKK ) would also block the nuclear export of PTEN in a manner similar to that of inhibitors of PI3K , mTOR , and S6K .	Because mTOR can be alternatively downregulated by tuberous sclerosis complex 2 (TSC2) activation mediated by 5 ' adenosine monophosphate activated protein kinase (AMPK), we proposed that the activation of AMPK alpha1/2 by LKB1 and/or by calmodulin dependent protein kinase kinase (CaMKK) would also block the nuclear export of PTEN in a manner similar to that of inhibitors of PI3K, mTOR, and S6K.	1	14	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	12	13	1	2
TSC1/2 form a protein complex that negatively regulates mTOR signaling , and loss of either TSC1 or TSC2 leads to constitutive activation of the mTOR pathway .	TSC1/2 form a protein complex that negatively regulates mTOR signaling, and loss of either TSC1 or TSC2 leads to constitutive activation of the mTOR pathway.	12	25	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	loss of either TSC1 or TSC2	tsc2	mTOR	mTOR	mtor	17	18	24	25
AMPK also phosphorylates TSC2 ( Ser1387 ) and RAPTOR ( Ser792 ) to inhibit mTOR .	AMPK also phosphorylates TSC2 (Ser1387) and RAPTOR (Ser792) to inhibit mTOR.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK also phosphorylates TSC2 (Ser1387	tsc2	mTOR	mTOR	mtor	3	4	14	15
Activation of AMPK suppresses mammalian target of rapamycin ( mTOR ) signaling and the molecular mechanism involves phosphorylation of tuberous sclerosis complex protein TSC2 at Thr1227 and Ser1345 that increases the activity of TSC1 and TSC2 complex to inhibit mTOR .	Activation of AMPK suppresses mammalian target of rapamycin (mTOR) signaling and the molecular mechanism involves phosphorylation of tuberous sclerosis complex protein TSC2 at Thr1227 and Ser1345 that increases the activity of TSC1 and TSC2 complex to inhibit mTOR.	17	40	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation of tuberous sclerosis complex protein TSC2 at Thr1227 and Ser1345	tsc2	mTOR	mTOR	mtor	23	24	39	40
Therefore , loss-of-function mutations or removal of PTEN , which leads to hyperactivation of Akt , or loss of TSC1 and TSC2 , which leads to increased unbound RHEB , can cause an upregulation of mTOR signaling .	Therefore, loss-of-function mutations or removal of PTEN, which leads to hyperactivation of Akt, or loss of TSC1 and TSC2, which leads to increased unbound RHEB, can cause an upregulation of mTOR signaling.	7	36	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	PTEN, which leads to hyperactivation of Akt, or loss of TSC1 and TSC2	tsc2	mTOR	mTOR	mtor	21	22	35	36
mTOR activity is negatively regulated by the heterodimer TSC1 ( hamartin ) and TSC2 ( tuberin ) .	mTOR activity is negatively regulated by the heterodimer TSC1 (hamartin) and TSC2 (tuberin).	0	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	13	14	0	1
Higher level or activation of Tuberin , which is a product of the tumor suppressor gene TSC-2 and inhibits Rheb , can inhibit activation of the mTOR signaling pathway [ XREF_BIBR - XREF_BIBR ] .	Higher level or activation of Tuberin, which is a product of the tumor suppressor gene TSC-2 and inhibits Rheb, can inhibit activation of the mTOR signaling pathway [XREF_BIBR - XREF_BIBR].	1	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tuberin	level or activation of Tuberin	tuberin	mTOR	mTOR	mtor	5	6	26	27
These data identify a unique mechanism for modulation of TSC2 repression of mTOR signaling via membrane retention of this tumor suppressor , and identify PC-1 as a regulator of this downstream component of the PI3K signaling cascade .	These data identify a unique mechanism for modulation of TSC2 repression of mTOR signaling via membrane retention of this tumor suppressor, and identify PC-1 as a regulator of this downstream component of the PI3K signaling cascade.	9	13	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	9	10	12	13
Thus , as shown in XREF_FIG , membrane tethered CP1 enhanced TSC2 retention at the membrane and protected this tumor suppressor from AKT phosphorylation to enhance TSC2 repression of mTOR .	Thus, as shown in XREF_FIG, membrane tethered CP1 enhanced TSC2 retention at the membrane and protected this tumor suppressor from AKT phosphorylation to enhance TSC2 repression of mTOR.	26	30	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	26	27	29	30
Phosphorylation of TSC2 by GSK-3 enhances the suppression of mTOR signaling in cultured cells and GSK-3 suppresses mTOR signaling in hippocampal tissue .	Phosphorylation of TSC2 by GSK-3 enhances the suppression of mTOR signaling in cultured cells and GSK-3 suppresses mTOR signaling in hippocampal tissue.	0	18	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	2	3	17	18
We show by biotin switch assay that TSC2 , which in the activated state acts to suppress mTOR activation , by forming a Rheb inactivating complex with TSC1 , is constitutively nitrosylated in melanoma cells .	We show by biotin switch assay that TSC2, which in the activated state acts to suppress mTOR activation, by forming a Rheb inactivating complex with TSC1, is constitutively nitrosylated in melanoma cells.	7	31	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	7	8	17	18
Both increased TSC2 phosphorylation and enhanced formation of the TSC1.TSC2 heterodimer can negatively regulate mTOR activity .	Both increased TSC2 phosphorylation and enhanced formation of the TSC1.TSC2 heterodimer can negatively regulate mTOR activity.	2	15	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2 phosphorylation and enhanced formation of the TSC1.TSC2	tsc2	mTOR	mTOR	mtor	2	3	14	15
These effects are dependent on TSC2 mediated mechanistic target of rapamycin inactivation .	These effects are dependent on TSC2 mediated mechanistic target of rapamycin inactivation.	3	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	5	6	7	11
Phosphorylation of the tumor suppressor TSC2 by Akt results in its inactivation , thereby promoting the accumulation of ( active ) Rheb-GTP and the induction of mTOR activity .	Phosphorylation of the tumor suppressor TSC2 by Akt results in its inactivation, thereby promoting the accumulation of (active) Rheb-GTP and the induction of mTOR activity.	0	27	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of the tumor suppressor TSC2	tsc2	mTOR	mTOR	mtor	5	6	26	27
Akt can directly phosphorylate and activate mTOR , as well as indirectly activating it by phosphorylating and inactivate tuberous sclerosis complex 2 ( TSC2 ) , also called tuberin , which normally inhibits mTOR through the GTP binding protein Ras homolog enriched in brain ( Rheb ) [ XREF_BIBR ] .	Akt can directly phosphorylate and activate mTOR, as well as indirectly activating it by phosphorylating and inactivate tuberous sclerosis complex 2 (TSC2), also called tuberin, which normally inhibits mTOR through the GTP binding protein Ras homolog enriched in brain (Rheb) [XREF_BIBR].	17	34	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	23	24	33	34
Upon Akt activation , growth factors ( PDGF , VEGF and IGF-1 ) and insulin block the TSC2 ( tuberous sclerosis complex 2 ) complex , which in turn inhibits the mTOR protein ( mammalian target of rapamycin ) .	Upon Akt activation, growth factors (PDGF, VEGF and IGF-1) and insulin block the TSC2 (tuberous sclerosis complex 2) complex, which in turn inhibits the mTOR protein (mammalian target of rapamycin).	17	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	17	18	31	32
Polycystin-1 and the TSC1 and TSC2 tumor suppressor complex both act to suppress the activity of mTOR .	Polycystin-1 and the TSC1 and TSC2 tumor suppressor complex both act to suppress the activity of mTOR.	5	17	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	5	6	16	17
TSC2 is an inhibitor of ras homologue enriched in brain ( RHEB ) and hence the loss of TSC2 leads to activation of mTOR and S6K .	TSC2 is an inhibitor of ras homologue enriched in brain (RHEB) and hence the loss of TSC2 leads to activation of mTOR and S6K.	16	25	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	loss of TSC2	tsc2	mTOR	mTOR	mtor	18	19	23	24
Tsc2 negatively regulates mTOR through inhibition of Rheb , a small GTPase protein , by its GAP ( GTPase activating protein ) activity , so that the removal of Tsc2 activates mTORC1 by Rheb activation ( XREF_FIG ) .	Tsc2 negatively regulates mTOR through inhibition of Rheb, a small GTPase protein, by its GAP (GTPase activating protein) activity, so that the removal of Tsc2 activates mTORC1 by Rheb activation (XREF_FIG).	0	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	0	1	3	4
In response to energy deficit in the cell , AMPK phosphorylates TSC2 which then complexes with TSC1 and negatively regulates the mTOR pathway .	In response to energy deficit in the cell, AMPK phosphorylates TSC2 which then complexes with TSC1 and negatively regulates the mTOR pathway.	9	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	11	12	21	22
First , AMPK activates TSC2 , which inhibits mTOR , thus reducing activity of ribosomal S6 kinase and eukaryotic initiation factor-4 ( eIF4 ) .	First, AMPK activates TSC2, which inhibits mTOR, thus reducing activity of ribosomal S6 kinase and eukaryotic initiation factor-4 (eIF4).	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	4	5	8	9
XREF_BIBR , XREF_BIBR It is known that 3 induced activation of AMPK leads to TSC2 phosphorylation mediated mTOR inhibition .	XREF_BIBR, XREF_BIBR It is known that 3 induced activation of AMPK leads to TSC2 phosphorylation mediated mTOR inhibition.	14	18	mediated	Positive_activation_token_1_verb	Negative_activation	Negative_activation	TSC2	TSC2 phosphorylation	tsc2	mTOR	mTOR	mtor	14	15	17	18
In the absence of an upstream Wnt signal , GSK3 phosphorylates TSC2 , which normally acts to inhibit cell growth by activating the GTPase activity of Rheb , causing inhibition of mTOR .	In the absence of an upstream Wnt signal, GSK3 phosphorylates TSC2, which normally acts to inhibit cell growth by activating the GTPase activity of Rheb, causing inhibition of mTOR.	10	32	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	11	12	31	32
15 ATM is exported to the cytoplasm in response to high concentration of ROS and reactive nitrogen species ( RNS ) like nitric oxide ( NO ) , and deactivates mTOR through a series of phosphorylation dependent activation processes involving liver kinase B1 ( LKB1 ) , AMPK and the tumor suppressor tuberous sclerosis 2 ( TSC2 ) .	15 ATM is exported to the cytoplasm in response to high concentration of ROS and reactive nitrogen species (RNS) like nitric oxide (NO), and deactivates mTOR through a series of phosphorylation dependent activation processes involving liver kinase B1 (LKB1), AMPK and the tumor suppressor tuberous sclerosis 2 (TSC2).	29	57	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	56	57	30	31
We can not exclude that Tsc2 might have additional unidentified functions that compensate Tsc1-mutant phenotypes ; however , since the loss of either Tsc1 or Tsc2 abolishes the Rheb-GTPase-activating activity , resulting in constitutively activated mTOR , it is unlikely that Tsc2 alone can suppress mTOR activation in the absence of Tsc1 .	We can not exclude that Tsc2 might have additional unidentified functions that compensate Tsc1-mutant phenotypes; however, since the loss of either Tsc1 or Tsc2 abolishes the Rheb-GTPase-activating activity, resulting in constitutively activated mTOR, it is unlikely that Tsc2 alone can suppress mTOR activation in the absence of Tsc1.	41	46	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	41	42	45	46
Two of these genes , TSC1 and TSC2 , are downstream of AMPK and negatively regulate mTOR in response to cellular energy deficits .	Two of these genes, TSC1 and TSC2, are downstream of AMPK and negatively regulate mTOR in response to cellular energy deficits.	3	18	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	7	8	16	17
Then , TSC2 in PKR gene silencing conditions can be blocked by sequestration with 14-3-3 proteins to prevent the inhibitory effect of TSC2 in the mTOR signalling pathway .	Then, TSC2 in PKR gene silencing conditions can be blocked by sequestration with 14-3-3 proteins to prevent the inhibitory effect of TSC2 in the mTOR signalling pathway.	2	27	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	25	26
Firstly , AMPK phosphorylates TSC2 and RAPTOR , two essential regulators of mTOR , to suppress mTOR .	Firstly, AMPK phosphorylates TSC2 and RAPTOR, two essential regulators of mTOR, to suppress mTOR.	2	17	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	4	5	16	17
AMPK activates TSC2 phosphorylation to catalyze the conversion of Rheb-GTP to Rheb-GDP and thus inhibits mTOR XREF_BIBR .	AMPK activates TSC2 phosphorylation to catalyze the conversion of Rheb-GTP to Rheb-GDP and thus inhibits mTOR XREF_BIBR.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK activates TSC2 phosphorylation	tsc2	mTOR	mTOR	mtor	2	3	15	16
Furthermore , mTOR signaling could be further repressed by CP1 under conditions in which AMPK was activated and mTOR was repressed by TSC2 .	Furthermore, mTOR signaling could be further repressed by CP1 under conditions in which AMPK was activated and mTOR was repressed by TSC2.	18	23	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	22	23	18	19
Furthermore , because glucose restriction in skeletal muscle cells has been shown to increase activity of AMPK [ XREF_BIBR ] and can suppress growth related signalling of P70S6K via TSC2 inhibition of mTOR [ XREF_BIBR ] , we also investigated AMPK signalling at the same time points .	Furthermore, because glucose restriction in skeletal muscle cells has been shown to increase activity of AMPK [XREF_BIBR] and can suppress growth related signalling of P70S6K via TSC2 inhibition of mTOR [XREF_BIBR], we also investigated AMPK signalling at the same time points.	29	34	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	29	30	32	33
Loss of TSC1 or TSC2 function therefore causes activation of mTOR Complex 1 ( mTORC1 ) .	Loss of TSC1 or TSC2 function therefore causes activation of mTOR Complex 1 (mTORC1).	2	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	4	5	10	11
Activated Akt can phosphorylate and inactivate tuberous sclerosis complex 2 ( TSC2 ) , which negatively regulates mTOR .	Activated Akt can phosphorylate and inactivate tuberous sclerosis complex 2 (TSC2), which negatively regulates mTOR.	9	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	11	12	17	18
AMP activated protein kinase ( AMPK ) , which is responsive to cellular energy depletion , can inhibit cell growth through TSC2 dependent suppression of mTOR signaling XREF_BIBR , XREF_BIBR .	AMP activated protein kinase (AMPK), which is responsive to cellular energy depletion, can inhibit cell growth through TSC2 dependent suppression of mTOR signaling XREF_BIBR, XREF_BIBR.	21	27	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	21	22	25	26
Phosphorylation of TSC2 and Raptor by AMPK inhibits mTOR anabolic activity XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Phosphorylation of TSC2 and Raptor by AMPK inhibits mTOR anabolic activity XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	2	3	8	9
Abrogation of REDD1 mediated suppression of mTOR by TSC2 RNAi protected FASN inhibitor sensitive ovarian cancer cells ( OVCA 420 cells ) from orlistat induced death .	Abrogation of REDD1 mediated suppression of mTOR by TSC2 RNAi protected FASN inhibitor sensitive ovarian cancer cells (OVCA 420 cells) from orlistat induced death.	4	9	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	8	9	6	7
At least part of this inhibition is mediated through a REDD1 and TSC1 and TSC2 dependent inhibition of the mTOR kinase .	At least part of this inhibition is mediated through a REDD1 and TSC1 and TSC2 dependent inhibition of the mTOR kinase.	14	20	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	14	15	19	20
Notably , this increase in mTOR activity induced by TSC2 inhibition completely rescued Bmpr1a -/- apoptotic cell elimination during cell competition .	Notably, this increase in mTOR activity induced by TSC2 inhibition completely rescued Bmpr1a -/- apoptotic cell elimination during cell competition.	5	10	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	9	10	5	6
Inactivation of Tuberin allows GTP bound-Rheb to accumulate and activate the mammalian target of rapamycin ( mTOR )/Raptor ( TORC1 ) complex , which ultimately regulates protein synthesis and cell growth [ XREF_BIBR ] .	Inactivation of Tuberin allows GTP bound-Rheb to accumulate and activate the mammalian target of rapamycin (mTOR)/Raptor (TORC1) complex, which ultimately regulates protein synthesis and cell growth [XREF_BIBR].	0	15	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tuberin	Tuberin	Tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	2	3	11	15
Therefore , in both assays , the TSC2 I820del and L1511H variants were unable to inhibit mTOR , indicating that both these variants are pathogenic , while the TSC2 R1772C and T993M variants were just as active as wild-type TSC2 and are therefore not pathogenic amino acid substitutions .	Therefore, in both assays, the TSC2 I820del and L1511H variants were unable to inhibit mTOR, indicating that both these variants are pathogenic, while the TSC2 R1772C and T993M variants were just as active as wild-type TSC2 and are therefore not pathogenic amino acid substitutions.	7	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	7	8	16	17
TSC2 protein complexes with TSC1 and blocks the ability of the Rheb ( Ras homolog enriched in brain ) GTPase to activate mTOR ( mammalian target of rapamycin ) , a crucial signal transducer which regulates protein synthesis and cell growth .	TSC2 protein complexes with TSC1 and blocks the ability of the Rheb (Ras homolog enriched in brain) GTPase to activate mTOR (mammalian target of rapamycin), a crucial signal transducer which regulates protein synthesis and cell growth.	0	33	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	0	1	22	23
ERK dependent phosphorylation on serine 664 of TSC2 leads to TSC1-TSC2 dissociation and impairment of TSC2 ability to inhibit mTOR signaling , suggesting that the Ras and MAPK pathway upstream of the TSC complex and that ERK may modulate mTOR signaling pathway and contribute to disease progression through phosphorylation and inactivation of TSC2 [ XREF_BIBR ] .	ERK dependent phosphorylation on serine 664 of TSC2 leads to TSC1-TSC2 dissociation and impairment of TSC2 ability to inhibit mTOR signaling, suggesting that the Ras and MAPK pathway upstream of the TSC complex and that ERK may modulate mTOR signaling pathway and contribute to disease progression through phosphorylation and inactivation of TSC2 [XREF_BIBR].	2	20	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation on serine 664 of TSC2	tsc2	mTOR	mTOR	mtor	7	8	19	20
Interestingly , while we previously showed activation of AMPKalpha and downstream tumor suppressor TSC2 which act to inhibit mTOR in both U251 and U87 parental cells [ XREF_BIBR ] , U87TMZ appears to have lost the ability to act through this pathway which suggests direct inhibition of the Akt and mTOR axis .	Interestingly, while we previously showed activation of AMPKalpha and downstream tumor suppressor TSC2 which act to inhibit mTOR in both U251 and U87 parental cells [XREF_BIBR], U87TMZ appears to have lost the ability to act through this pathway which suggests direct inhibition of the Akt and mTOR axis.	5	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	13	14	18	19
Under energy depletion conditions , AMPK phosphorylates TSC2 and RAPTOR , two essential regulators of mTOR , to suppress mTOR resulting in autophagy induction [ XREF_BIBR , XREF_BIBR ] .	Under energy depletion conditions, AMPK phosphorylates TSC2 and RAPTOR, two essential regulators of mTOR, to suppress mTOR resulting in autophagy induction [XREF_BIBR, XREF_BIBR].	5	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	7	8	19	20
In contrast , AMPK activation stimulates TSC by phosphorylating tuberin at different sites from Akt and thereby inhibits mTOR and slows growth .	In contrast, AMPK activation stimulates TSC by phosphorylating tuberin at different sites from Akt and thereby inhibits mTOR and slows growth.	3	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	AMPK activation stimulates TSC by phosphorylating tuberin	tuberin	mTOR	mTOR	mtor	9	10	18	19
When HDAC activity is suppressed , either pharmacologically or through genetic ablation , TSC2 abundance increases , thereby inhibiting mTOR activity .	When HDAC activity is suppressed, either pharmacologically or through genetic ablation, TSC2 abundance increases, thereby inhibiting mTOR activity.	13	20	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	13	14	19	20
Under the condition of starvation , AMPK phosphorylates tuberous sclerosis 2 ( TSC2 ) , which inhibits mTOR and S6K1 pathway [ XREF_BIBR ] : phosphorylation of TSC2 by AMPK is critical in the process of mRNA translation and cell size regulation during energy deficiency ( XREF_FIG ) .	Under the condition of starvation, AMPK phosphorylates tuberous sclerosis 2 (TSC2), which inhibits mTOR and S6K1 pathway [XREF_BIBR] : phosphorylation of TSC2 by AMPK is critical in the process of mRNA translation and cell size regulation during energy deficiency (XREF_FIG).	6	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK phosphorylates tuberous sclerosis 2 (TSC2	tsc2	mTOR	mTOR	mtor	12	13	17	18
We found that loss of Tsc2 potentiated store operated Ca 2+ entry ( SOCE ) in an mTOR complex 1 ( mTORC1 )-dependent way .	We found that loss of Tsc2 potentiated store operated Ca 2+ entry (SOCE) in an mTOR complex 1 (mTORC1)-dependent way.	3	18	potentiated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tsc2	loss of Tsc2	tsc2	mTOR	mTOR	mtor	5	6	17	18
The canonical pathway for mTOR regulation is independent of erk1/2 and involves PI3K-PDK1-Akt-dependent inactivation of the mTOR suppressor TSC2 , which then leads to mTOR-p70S6K dependent translation of mRNAs and de novo protein synthesis at active synapses ( Hoeffer and Klann , 2010 ) .	The canonical pathway for mTOR regulation is independent of erk1/2 and involves PI3K-PDK1-Akt-dependent inactivation of the mTOR suppressor TSC2, which then leads to mTOR-p70S6K dependent translation of mRNAs and de novo protein synthesis at active synapses (Hoeffer and Klann, 2010).	13	22	suppressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	18	19	16	17
Furthermore , phosphorylation and activation of TSC2 by GSK3beta inhibits mTOR signaling .	Furthermore, phosphorylation and activation of TSC2 by GSK3beta inhibits mTOR signaling.	2	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation and activation of TSC2	tsc2	mTOR	mTOR	mtor	6	7	10	11
Mutations in either TSC1 or TSC2 , which encode hamartin and tuberin , respectively , cause the abnormal activation of mammalian target of rapamycin ( mTOR ) .	Mutations in either TSC1 or TSC2, which encode hamartin and tuberin, respectively, cause the abnormal activation of mammalian target of rapamycin (mTOR).	0	24	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	5	6	20	24
GTP bound Ras homolog enriched in brain ( Rheb ) is a necessary mTOR activator that is inhibited by tuberous sclerosis complex 1 ( TSC1 ) and tuberous sclerosis complex 2 ( TSC2 ) .	GTP bound Ras homolog enriched in brain (Rheb) is a necessary mTOR activator that is inhibited by tuberous sclerosis complex 1 (TSC1) and tuberous sclerosis complex 2 (TSC2).	13	33	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	32	33	13	14
TSC2 is able to form a complex with TSC1 and inhibits mTOR activity , which is usually assessed in terms of the phosphorylation status of the downstream substrate 4E-BP1 XREF_BIBR , XREF_BIBR .	TSC2 is able to form a complex with TSC1 and inhibits mTOR activity, which is usually assessed in terms of the phosphorylation status of the downstream substrate 4E-BP1 XREF_BIBR, XREF_BIBR.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	0	1	11	12
These results may be generalizable and applicable to humans because TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling [ XREF_BIBR ] .	These results may be generalizable and applicable to humans because TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling [XREF_BIBR].	10	20	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2 is phosphorylated	tsc2	mTOR	mTOR	mtor	10	11	19	20
Nuclear p53 transactivates TSC2 ( tuberous sclerosis ) and AMPK ( AMP activated protein kinase ) , both of which downregulate mTOR activity , thus indirectly promoting autophagy ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	Nuclear p53 transactivates TSC2 (tuberous sclerosis) and AMPK (AMP activated protein kinase), both of which downregulate mTOR activity, thus indirectly promoting autophagy (XREF_FIG) [XREF_BIBR, XREF_BIBR].	2	22	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	3	4	21	22
TSC2 isoform A does not inhibit mTOR activation .	TSC2 isoform A does not inhibit mTOR activation.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	0	1	6	7
TSC2 functions in complex with TSC1 , and negatively regulates the Rheb and mTOR pathway and cell growth [ XREF_BIBR ] .	TSC2 functions in complex with TSC1, and negatively regulates the Rheb and mTOR pathway and cell growth [XREF_BIBR].	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	0	1	13	14
In neonatal rat cardiomyocytes , loss of TSC2 abolished HDAC dependent inhibition of mTOR activity , and increased expression of TSC2 was sufficient to reduce hypertrophy in response to phenylephrine .	In neonatal rat cardiomyocytes, loss of TSC2 abolished HDAC dependent inhibition of mTOR activity, and increased expression of TSC2 was sufficient to reduce hypertrophy in response to phenylephrine.	5	14	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	loss of TSC2	tsc2	mTOR	mTOR	mtor	7	8	13	14
Deletion of Tsc2 in mouse oocytes caused increased mTOR activity followed by accelerated recruitment of the OR starting by P23 and follicle depletion by 4 months .	Deletion of Tsc2 in mouse oocytes caused increased mTOR activity followed by accelerated recruitment of the OR starting by P23 and follicle depletion by 4 months.	0	9	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	2	3	8	9
The activation of AMPK by LKB1 leads to phosphorylation of tuberous sclerosis complex 2 ( TSC-2 ) , which in turn inhibits the mTOR protein ( mammalian target of rapamycin ) , a key protein which regulates processes of cell growth and angiogenesis , and promotes cell division and protein synthesis .	The activation of AMPK by LKB1 leads to phosphorylation of tuberous sclerosis complex 2 (TSC-2), which in turn inhibits the mTOR protein (mammalian target of rapamycin), a key protein which regulates processes of cell growth and angiogenesis, and promotes cell division and protein synthesis.	8	45	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC-2	phosphorylation of tuberous sclerosis complex 2 (TSC-2	tsc-2	mTOR	mTOR	mtor	15	16	23	24
Moreover , p53 knockdown markedly increased Bcl-2 and cleaved caspase-12 in tumor cells ( XREF_FIG ) .	Moreover, p53 knockdown markedly increased Bcl-2 and cleaved caspase-12 in tumor cells (XREF_FIG).	2	7	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	6	7
The inhibition of p53 expression can up-regulate Bcl-2 proteins in a rat model of cholestasis [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The inhibition of p53 expression can up-regulate Bcl-2 proteins in a rat model of cholestasis [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	8	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53 expression	p53	Bcl-2	Bcl-2	bcl-2	3	4	7	8
In addition , PCR results indicated that the two compounds 5a and 5b induced the expression of p53 gene and decreased induction of BCL2 ( anti-apoptotic gene ) , while the two compounds have no effect on the protein expression of Caspase-9 .	In addition, PCR results indicated that the two compounds 5a and 5b induced the expression of p53 gene and decreased induction of BCL2 (anti-apoptotic gene), while the two compounds have no effect on the protein expression of Caspase-9.	12	26	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	5b induced the expression of p53	p53	BCL2	BCL2	bcl2	17	18	23	24
p53 may downregulate bcl-2 and P-glycoprotein to induce apoptosis in melanoma cells after chemotherapy .	p53 may downregulate bcl-2 and P-glycoprotein to induce apoptosis in melanoma cells after chemotherapy.	0	5	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	0	1	3	4
IFNalpha markedly upregulated p53 , Bax , Mdm2 , and p21 , downregulated Bcl-2 , and activated caspase-3 and PARP cleavage in response to doxorubicin in U2OS cells .	IFNalpha markedly upregulated p53, Bax, Mdm2, and p21, downregulated Bcl-2, and activated caspase-3 and PARP cleavage in response to doxorubicin in U2OS cells.	3	14	downregulated	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	13	14
Furthermore , JNK2 activated the expression of p53 and inhibited Bcl-2 .	Furthermore, JNK2 activated the expression of p53 and inhibited Bcl-2.	2	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	JNK2 activated the expression of p53	p53	Bcl-2	Bcl-2	bcl-2	7	8	10	11
However , the absence of p53 could not prevent Bcl-2 deficient mice from polycystic kidney disease and thymus degeneration , indicating that Bcl-2 deficiency induced phenotype is p53 independent in kidney and thymus .	However, the absence of p53 could not prevent Bcl-2 deficient mice from polycystic kidney disease and thymus degeneration, indicating that Bcl-2 deficiency induced phenotype is p53 independent in kidney and thymus.	3	11	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	5	6	9	10
In agreement with this finding , endogenous or ectopic expression of wild-type , but not mutant , p53 increased miR-124 levels and suppressed p65 , MYC and BCL2 .	In agreement with this finding, endogenous or ectopic expression of wild-type, but not mutant, p53 increased miR-124 levels and suppressed p65, MYC and BCL2.	9	28	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	expression of wild-type, but not mutant, p53	p53	BCL2	BCL2	bcl2	17	18	27	28
Molecular pathological analysis showed that amitriptyline induced p53 , activated caspase-3 , and decreased antiapoptotic Bcl-2 and Mcl-1 in tumor tissues .	Molecular pathological analysis showed that amitriptyline induced p53, activated caspase-3, and decreased antiapoptotic Bcl-2 and Mcl-1 in tumor tissues.	5	17	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	amitriptyline induced p53	p53	Bcl-2	Bcl-2	bcl-2	7	8	15	16
The interaction of p53 with the 5 ' UTR suggested that the P2 region is responsible for the p53 dependent degradation of bcl-2 mRNA .	The interaction of p53 with the 5 ' UTR suggested that the P2 region is responsible for the p53 dependent degradation of bcl-2 mRNA.	18	23	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	18	19	22	23
In this model , p53 dependent signals , like the induction of Bax and direct inhibition of Bcl2 , may synergize with p53 independent signals including the induction of Bim to antagonize Bcl2 function and promote apoptosis .	In this model, p53 dependent signals, like the induction of Bax and direct inhibition of Bcl2, may synergize with p53 independent signals including the induction of Bim to antagonize Bcl2 function and promote apoptosis.	4	33	synergize	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	4	5	32	33
p53 not only transactivates several genes encoding Bcl-2 family proteins but also antagonizes Bcl-2 and Bcl-xL and activates Bax and Bak through protein protein interactions .	p53 not only transactivates several genes encoding Bcl-2 family proteins but also antagonizes Bcl-2 and Bcl-xL and activates Bax and Bak through protein protein interactions.	0	15	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	13	14
Moreover , western blotting analysis revealed that knockdown of TRIM24 increased the protein levels of p53 , Bax , and Caspase-8 , and decreased Bcl-2 , Survivin , Cyclin D1 , and CDK4 .	Moreover, western blotting analysis revealed that knockdown of TRIM24 increased the protein levels of p53, Bax, and Caspase-8, and decreased Bcl-2, Survivin, Cyclin D1, and CDK4.	9	32	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	TRIM24 increased the protein levels of p53	p53	Bcl-2	Bcl-2	bcl-2	15	16	24	25
p53 represses the activity of BCL2 , an anti-apoptotic protein involved in retaining the mitochondrial permeability , as well as survivin .	p53 represses the activity of BCL2, an anti-apoptotic protein involved in retaining the mitochondrial permeability, as well as survivin.	0	9	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL2	BCL2	BCL2	0	1	5	6
However , p53 may enhance not only transcription of bax and repress bcl-2 , but also may upregulate the local renin-angiotensin system , inducing the formation and secretion of angiotensin II from the cells .	However, p53 may enhance not only transcription of bax and repress bcl-2, but also may upregulate the local renin-angiotensin system, inducing the formation and secretion of angiotensin II from the cells.	2	17	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53 may enhance not only transcription	p53	bcl-2	bcl-2	bcl-2	2	3	12	13
In addition , ASA could led to a loss in the mitochondrial out membrane potential , up-regulate p53 , phosphorylated p53 and Bax , down-regulate Bcl-2 , release cytochrome c from the mitochondria to the cytoplasm , and activate caspase-9 and caspase-3 in A549 cells , which revealed that ASA could also induce apoptosis through the mitochondria mediated pathway .	In addition, ASA could led to a loss in the mitochondrial out membrane potential, up-regulate p53, phosphorylated p53 and Bax, down-regulate Bcl-2, release cytochrome c from the mitochondria to the cytoplasm, and activate caspase-9 and caspase-3 in A549 cells, which revealed that ASA could also induce apoptosis through the mitochondria mediated pathway.	17	29	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	17	18	25	26
Carcinosinum 200C increased apoptotic gene p53 and Ruta 200C decreased antiapoptotic gene Bcl2 .	Carcinosinum 200C increased apoptotic gene p53 and Ruta 200C decreased antiapoptotic gene Bcl2.	3	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	5	6	12	13
Despite the previous reports that interaction of p53 with the P2 promoter region suppresses P2 promoter activity in primary airway and lung cancer cell lines XREF_BIBR , XREF_BIBR , we first suspected that p53 does not suppress bcl-2 promoter activity when we noticed that within the context of the full-length P1-M-P2 promoter .	Despite the previous reports that interaction of p53 with the P2 promoter region suppresses P2 promoter activity in primary airway and lung cancer cell lines XREF_BIBR, XREF_BIBR, we first suspected that p53 does not suppress bcl-2 promoter activity when we noticed that within the context of the full-length P1-M-P2 promoter.	33	39	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	33	34	37	38
p53 can down-regulate Bcl-2 which protects cells from apoptosis ( Sano et al ., 1995 ; Kane et al ., 1994 ) .	p53 can down-regulate Bcl-2 which protects cells from apoptosis (Sano et al., 1995; Kane et al., 1994).	0	5	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	3	4
The results obtained by Basu and Haldar indicated that a loss of p53 function may substitute for elevated Bcl-2 activity in breast cancer cells as well as suggesting that p53 may be able to downregulate Bcl-2 .	The results obtained by Basu and Haldar indicated that a loss of p53 function may substitute for elevated Bcl-2 activity in breast cancer cells as well as suggesting that p53 may be able to downregulate Bcl-2.	29	36	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	29	30	35	36
ERalpha induces Bcl-2 , an anti-apoptotic gene , while p53 inhibits Bcl-2 through Noxa [ XREF_BIBR , XREF_BIBR ] .	ERalpha induces Bcl-2, an anti-apoptotic gene, while p53 inhibits Bcl-2 through Noxa [XREF_BIBR, XREF_BIBR].	9	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	9	10	11	12
Validated targets of miR-34a include CDK4 , Cyclin E2 , Bcl2 and c-Met , all of which are also transcriptionally repressed by p53 ( XREF_FIG ) .	Validated targets of miR-34a include CDK4, Cyclin E2, Bcl2 and c-Met, all of which are also transcriptionally repressed by p53 (XREF_FIG).	8	24	repressed	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	22	23	10	11
P53 can down-regulate BCL-2 and BAX to promote apoptosis .	P53 can down-regulate BCL-2 and BAX to promote apoptosis.	0	5	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P53	P53	P53	BCL-2	BCL-2	BCL-2	0	1	3	4
For up-stream mechanism , CIN-RM mediated apoptosis through a p53 dependent mechanism , that consequently down-regulated anti-apoptotic B-cell lymphoma 2 ( BCL2 ) , while increasing the level of pro apoptotic BCL2 associated X ( BAX ) .	For up-stream mechanism, CIN-RM mediated apoptosis through a p53 dependent mechanism, that consequently down-regulated anti-apoptotic B-cell lymphoma 2 (BCL2), while increasing the level of pro apoptotic BCL2 associated X (BAX).	9	32	down-regulated	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	p53	p53	p53	BCL2	level of pro apoptotic BCL2	bcl2	9	10	31	32
Renieramycin M treatment caused p53 activation , which subsequently down-regulated anti-apoptotic MCL-1 and BCL-2 proteins , while the level of pro apoptotic BAX protein was not altered .	Renieramycin M treatment caused p53 activation, which subsequently down-regulated anti-apoptotic MCL-1 and BCL-2 proteins, while the level of pro apoptotic BAX protein was not altered.	4	14	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	4	5	13	14
STS increased the expression of p53 and decreased that of Bcl-2 .	STS increased the expression of p53 and decreased that of Bcl-2.	0	11	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	STS increased the expression of p53	p53	Bcl-2	Bcl-2	bcl-2	5	6	10	11
Inhibition of PP1 only slightly increased p53 levels but dramatically increased p53 phosphorylation at S15 and S37 which enhanced regulation of p53 targets Bcl2 and Bax .	Inhibition of PP1 only slightly increased p53 levels but dramatically increased p53 phosphorylation at S15 and S37 which enhanced regulation of p53 targets Bcl2 and Bax.	2	25	increased	Positive_regulation_syntax_1_verb	Negative_activation	Negative_regulation	p53	PP1 only slightly increased p53 levels	p53	Bcl2	phosphorylation at S15 and S37 which enhanced regulation of p53 targets Bcl2	bcl2	6	7	23	24
The results indicated that iASPP significantly inhibited p53 expression and up-regulated anti-apoptotic protein bcl-2 , but obviously down-regulated pro apoptotic proteins bax and caspase-3 .	The results indicated that iASPP significantly inhibited p53 expression and up-regulated anti-apoptotic protein bcl-2, but obviously down-regulated pro apoptotic proteins bax and caspase-3.	4	14	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	iASPP significantly inhibited p53 expression	p53	bcl-2	bcl-2	bcl-2	7	8	13	14
After prolonged culturing periods of four months , we observed massive cell death of c-Myc transduced astrocytes which might be due to p53 independent suppression of Bcl-2 and induction of pro apoptotic proteins like Bax and Bak XREF_BIBR .	After prolonged culturing periods of four months, we observed massive cell death of c-Myc transduced astrocytes which might be due to p53 independent suppression of Bcl-2 and induction of pro apoptotic proteins like Bax and Bak XREF_BIBR.	22	32	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	22	23	26	27
The promoter activity assays repeatedly showed that p53 minimally suppressed bcl-2 promoter activity , and removal of the entire P2 region affected promoter activity only by a factor of 2-3 .	The promoter activity assays repeatedly showed that p53 minimally suppressed bcl-2 promoter activity, and removal of the entire P2 region affected promoter activity only by a factor of 2-3.	7	12	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	7	8	10	11
p53 binds to and inhibits antiapoptotic members of the Bcl-2 family that reside in the mitochondrial surface , such as Bcl-2 or Bcl-xL , resulting in increased mitochondrial membrane permeability , the release of mitochondrial cytochrome c into the cytosol , and the initiation of the apoptotic caspase cascade .	p53 binds to and inhibits antiapoptotic members of the Bcl-2 family that reside in the mitochondrial surface, such as Bcl-2 or Bcl-xL, resulting in increased mitochondrial membrane permeability, the release of mitochondrial cytochrome c into the cytosol, and the initiation of the apoptotic caspase cascade.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	9	10
p53 , as a tumor suppressor gene , downregulates Bcl-2 transcription activity and plays a duplicate role in autophagy regulation , depending on its subcellular location , and the mutation of p53 is one of the most common genetic events described in human cancers .	p53, as a tumor suppressor gene, downregulates Bcl-2 transcription activity and plays a duplicate role in autophagy regulation, depending on its subcellular location, and the mutation of p53 is one of the most common genetic events described in human cancers.	0	13	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	9	10
Stimulation of p53 can initiate apoptosis by activating proapoptotic Bcl-2 family member , such as Bax , and repressing antiapoptotic Bcl-2 proteins , such as Bcl-2 and Bcl-xl .	Stimulation of p53 can initiate apoptosis by activating proapoptotic Bcl-2 family member, such as Bax, and repressing antiapoptotic Bcl-2 proteins, such as Bcl-2 and Bcl-xl.	0	11	initiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	9	10
It was shown in cancer cells that the tumor suppressor p53 induces apoptosis by inhibiting the anti-apoptotic bcl-2 [ XREF_BIBR ] as well as the pro apoptotic bax protein [ XREF_BIBR ] .	It was shown in cancer cells that the tumor suppressor p53 induces apoptosis by inhibiting the anti-apoptotic bcl-2 [XREF_BIBR] as well as the pro apoptotic bax protein [XREF_BIBR].	8	28	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	bcl-2	bcl-2	bcl-2	8	11	17	18
Interestingly , we have recently demonstrated that p53 may up-regulate bax and down-regulate Bcl-2 protein resulting in apoptosis [ XREF_BIBR ] and that Fas and Fas-ligand pathway is essential for UV induced apoptosis [ XREF_BIBR ] .	Interestingly, we have recently demonstrated that p53 may up-regulate bax and down-regulate Bcl-2 protein resulting in apoptosis [XREF_BIBR] and that Fas and Fas-ligand pathway is essential for UV induced apoptosis [XREF_BIBR].	7	14	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	7	8	13	14
Knockdown of p53 significantly reversed the induction of Bax and Bak as well as the downregulation of Bcl-2 caused by LL-37 ( XREF_FIG ) .	Knockdown of p53 significantly reversed the induction of Bax and Bak as well as the downregulation of Bcl-2 caused by LL-37 (XREF_FIG).	0	18	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	17	18
Finally , it was observed that a spectrum of p53 target genes implicated in p53 induced growth suppression and apoptosis were similarly regulated , either induced ( gadd45 , waf1 , mdm2 , and bax ) or suppressed ( c-myc and bcl-2 ) , after activation of wt p53 function in M1p53 and M1p53 and bcl -2 cells .	Finally, it was observed that a spectrum of p53 target genes implicated in p53 induced growth suppression and apoptosis were similarly regulated, either induced (gadd45, waf1, mdm2, and bax) or suppressed (c-myc and bcl-2), after activation of wt p53 function in M1p53 and M1p53 and bcl -2 cells.	9	42	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	9	10	41	42
Moreover , BCL2 and BIRC5 ( Survivin ) are repressed by stabilization of p53 following DNA damage resulting from doxorubicin treatment in acute myeloblastic leukemia [ XREF_BIBR , XREF_BIBR ] .	Moreover, BCL2 and BIRC5 (Survivin) are repressed by stabilization of p53 following DNA damage resulting from doxorubicin treatment in acute myeloblastic leukemia [XREF_BIBR, XREF_BIBR].	2	14	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL2	BCL2	BCL2	13	14	2	3
The decrease in the Bcl-2 : Bax ratio and upregulation of the cellular renin-angiotensin system , by the activation of p53 , is thought to trigger myocyte apoptosis .	The decrease in the Bcl-2 : Bax ratio and upregulation of the cellular renin-angiotensin system, by the activation of p53, is thought to trigger myocyte apoptosis.	1	21	decrease	Negative_activation_syntax_1_noun	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	20	21	4	5
Troglitazone induced p53 protein expression and decreased bcl-2 mRNA , suggesting possible mechanisms for troglitazone induced apoptosis .	Troglitazone induced p53 protein expression and decreased bcl-2 mRNA, suggesting possible mechanisms for troglitazone induced apoptosis.	0	8	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	Troglitazone induced p53 protein expression	p53	bcl-2	bcl-2	bcl-2	2	3	7	8
Depending on a particular set of these downstream effectors , activated p53 is known to initiate apoptosis by targeting BH3-only Bcl-2 subfamily , and antagonists of the inhibitor of apoptosis ( anti-IAP ) to promote DNA repair by targeting DNA mismatch-repair protein MSH2 , ribonucleotide reductase ( RNR ) and ssDNA dependent ATP dependent helicase Ku70/Ku80 , and to mediate cell cycle arrest by targeting cyclin E and cyclin dependent kinase inhibitor 1 ( or protein p21 ) .	Depending on a particular set of these downstream effectors, activated p53 is known to initiate apoptosis by targeting BH3-only Bcl-2 subfamily, and antagonists of the inhibitor of apoptosis (anti-IAP) to promote DNA repair by targeting DNA mismatch-repair protein MSH2, ribonucleotide reductase (RNR) and ssDNA dependent ATP dependent helicase Ku70/Ku80, and to mediate cell cycle arrest by targeting cyclin E and cyclin dependent kinase inhibitor 1 (or protein p21).	10	21	initiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	11	12	20	21
Moreover , 10 and 20 mug/mL Sal B reduced the expression levels of p53 , increased the Bcl-2 and Bax ratio and inhibited the caspase-3 activity in ox-LDL-treated HUVECs ( P < 0.05 ) .	Moreover, 10 and 20 mug/mL Sal B reduced the expression levels of p53, increased the Bcl-2 and Bax ratio and inhibited the caspase-3 activity in ox-LDL-treated HUVECs (P < 0.05).	6	20	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	Sal B reduced the expression levels of p53	p53	Bcl-2	Bcl-2	bcl-2	13	14	17	18
Transient transfection analyses revealed that wild-type p53 repressed the bcl-2 full-length promoter .	Transient transfection analyses revealed that wild-type p53 repressed the bcl-2 full-length promoter.	5	11	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	6	7	9	10
First , the Bcl2 promoter is down-regulated by p53 in human B-cell lymphoma cell lines [ XREF_BIBR ] and mice that lack functional p53 exhibit increased expression of Bcl2 in lymphocytes [ XREF_BIBR , XREF_BIBR ] .	First, the Bcl2 promoter is down-regulated by p53 in human B-cell lymphoma cell lines [XREF_BIBR] and mice that lack functional p53 exhibit increased expression of Bcl2 in lymphocytes [XREF_BIBR, XREF_BIBR].	3	21	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	8	9	3	4
Recent evidence also indicates that p53 itself may also behave as a BH3-only proapoptotic protein to antagonize antiapoptotic Bcl-2 proteins as well as causing transrepression of antiapoptotic Bcl-2 gene transcription XREF_BIBR - XREF_BIBR .	Recent evidence also indicates that p53 itself may also behave as a BH3-only proapoptotic protein to antagonize antiapoptotic Bcl-2 proteins as well as causing transrepression of antiapoptotic Bcl-2 gene transcription XREF_BIBR - XREF_BIBR.	5	30	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	5	6	27	28
TQ induces a G1 cell cycle arrest , increases p53 and p21WAF1 protein levels , induces apoptosis in a dose- and time dependent manner , and reduces Bcl-2 protein in HCT116 .	TQ induces a G1 cell cycle arrest, increases p53 and p21WAF1 protein levels, induces apoptosis in a dose- and time dependent manner, and reduces Bcl-2 protein in HCT116.	0	28	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	TQ induces a G1 cell cycle arrest, increases p53 and p21WAF1 protein levels	p53	Bcl-2	Bcl-2	bcl-2	9	10	27	28
XREF_BIBR Conversely , p53 transcriptionally represses bcl-2 , PCNA , and Arf .	XREF_BIBR Conversely, p53 transcriptionally represses bcl-2, PCNA, and Arf.	3	11	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	3	4	6	7
As p53 can antagonize the anti-apoptotic effects of Bcl-2 and Bcl-xL [ XREF_BIBR ] , USP7 may inhibit the Bcl-2 and Bcl-xL anti-apoptotic effect by negatively regulating p53 .	As p53 can antagonize the anti-apoptotic effects of Bcl-2 and Bcl-xL [XREF_BIBR], USP7 may inhibit the Bcl-2 and Bcl-xL anti-apoptotic effect by negatively regulating p53.	1	12	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	1	2	8	9
p53 induces a number of mitochondria mediated apoptotic genes , such as Bax , Noxa , PUMA , and BID , and represses the anti-apoptotic Bcl2 and CIAPs .	p53 induces a number of mitochondria mediated apoptotic genes, such as Bax, Noxa, PUMA, and BID, and represses the anti-apoptotic Bcl2 and CIAPs.	0	27	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	0	1	25	26
Thus , we consider the following carcinogenesis mechanism in this case : the degradation of p53 by HPV infection induced cell-cycle dysfunction and caused bcl-2 gene activation , apoptosis suppression , and carcinogenesis .	Thus, we consider the following carcinogenesis mechanism in this case : the degradation of p53 by HPV infection induced cell-cycle dysfunction and caused bcl-2 gene activation, apoptosis suppression, and carcinogenesis.	13	26	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	15	16	24	25
Bcl-2 promotor contains a p53 negative response element , which may account for p53 mediated transrepression of Bcl-2 XREF_BIBR .	Bcl-2 promotor contains a p53 negative response element, which may account for p53 mediated transrepression of Bcl-2 XREF_BIBR.	13	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	13	14	17	18
Ciprofloxacin inhibited gamma-irradiation-induced p53 phosphorylation and increased Bcl-2 production and reduced cell death in PBMCs .	Ciprofloxacin inhibited gamma-irradiation-induced p53 phosphorylation and increased Bcl-2 production and reduced cell death in PBMCs.	0	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	Ciprofloxacin inhibited gamma-irradiation-induced p53 phosphorylation	p53	Bcl-2	Bcl-2	bcl-2	3	4	7	8
Thus , p53 enhances the myocyte renin-angiotensin-system and decreases the Bcl-2 and Bax ratio in the cells , triggering apoptosis .	Thus, p53 enhances the myocyte renin-angiotensin-system and decreases the Bcl-2 and Bax ratio in the cells, triggering apoptosis.	2	13	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	10	11
The number of p53 pulses needed to deplete BCL-2 below the apoptotic threshold level is determined .	The number of p53 pulses needed to deplete BCL-2 below the apoptotic threshold level is determined.	3	9	deplete	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	3	4	8	9
p53 inhibits Bcl-2 via promoting its antagonists or via repressing Bcl-2 transcription in some settings [ XREF_BIBR ] .	p53 inhibits Bcl-2 via promoting its antagonists or via repressing Bcl-2 transcription in some settings [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	2	3
However , the developmental defects caused by survivin deficiency can not be rescued by p53 inactivation or introduction of Bcl-2 .	However, the developmental defects caused by survivin deficiency can not be rescued by p53 inactivation or introduction of Bcl-2.	14	20	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	14	15	19	20
This might not result from the regulation by Cg-Bcl-2 or Cg-Bcl-xl , as the anti-apoptotic Bcl-2 family members were both negatively regulated by Cg-p53 .	This might not result from the regulation by Cg-Bcl-2 or Cg-Bcl-xl, as the anti-apoptotic Bcl-2 family members were both negatively regulated by Cg-p53.	15	24	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Cg-p53	Cg-p53	Cg-p53	Bcl-2	Bcl-2	Bcl-2	23	24	15	16
Furthermore , p53 has been shown to repress BCL2 at the transcriptional level though binding the proximal BCL2 promoter region in hematopoietic cells .	Furthermore, p53 has been shown to repress BCL2 at the transcriptional level though binding the proximal BCL2 promoter region in hematopoietic cells.	2	9	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL2	BCL2	BCL2	2	3	8	9
The aim of these therapies is to restore p53 activity , downregulate anti-apoptotic Bcl-2 proteins or NF-kappaB activity , and to upregulate extrinsic , death receptor mediated pathways .	The aim of these therapies is to restore p53 activity, downregulate anti-apoptotic Bcl-2 proteins or NF-kappaB activity, and to upregulate extrinsic, death receptor mediated pathways.	8	14	downregulate	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	8	9	13	14
44 Moreover , we identified the p53 independent downregulation of BCL2 to be a crucial factor in the apoptotic phenotype of CITED2-knockdown cells .	44 Moreover, we identified the p53 independent downregulation of BCL2 to be a crucial factor in the apoptotic phenotype of CITED2-knockdown cells.	6	11	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	BCL2	BCL2	BCL2	6	7	10	11
p53 induces apoptosis by transactivating proapoptotic genes such as BAX , PUMA , SCOTIN , and FAS , and inhibiting the antiapoptotic gene BCL-2 .	p53 induces apoptosis by transactivating proapoptotic genes such as BAX, PUMA, SCOTIN, and FAS, and inhibiting the antiapoptotic gene BCL-2.	0	24	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	0	1	23	24
As shown in XREF_FIG , LHX6 increased expression of the pro apoptotic gene p53 and downregulated the anti-apoptotic gene Bcl-2 .	As shown in XREF_FIG, LHX6 increased expression of the pro apoptotic gene p53 and downregulated the anti-apoptotic gene Bcl-2.	5	20	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	LHX6 increased expression of the pro apoptotic gene p53	p53	Bcl-2	Bcl-2	bcl-2	13	14	19	20
Therefore , we demonstrated that p53 and the histone deacetylases repress the bcl-2 promoter independently .	Therefore, we demonstrated that p53 and the histone deacetylases repress the bcl-2 promoter independently.	5	13	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	5	6	12	13
Bcl-2 is negatively regulated by the tumor suppressor p53 in response to DNA damage during apoptotic cell death .	Bcl-2 is negatively regulated by the tumor suppressor p53 in response to DNA damage during apoptotic cell death.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	Bcl-2	Bcl-2	Bcl-2	6	9	0	1
We found that Bcl-2 expression , an antiapoptotic protein , is inversely related to p53 expression , indicating that the increase of p53 may decrease the Bcl-2 protein , which corroborate with previous studies [ XREF_BIBR ] .	We found that Bcl-2 expression, an antiapoptotic protein, is inversely related to p53 expression, indicating that the increase of p53 may decrease the Bcl-2 protein, which corroborate with previous studies [XREF_BIBR].	20	27	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	22	23	26	27
The combination treatment induced multiple apoptotic molecules co-action and intracellular drug accumulation contributed to the synergistic cytotoxicity , including caspase activation , PARP cleavage , XIAP downregulation , p53 dependent suppression of Bcl-2 and MRP1 expression via the inhibition of phosphoinositide 3-kinase ( PI3K )/Akt/nuclear factor-kappaB ( NF-kappaB ) signaling pathway .	The combination treatment induced multiple apoptotic molecules co-action and intracellular drug accumulation contributed to the synergistic cytotoxicity, including caspase activation, PARP cleavage, XIAP downregulation, p53 dependent suppression of Bcl-2 and MRP1 expression via the inhibition of phosphoinositide 3-kinase (PI3K)/Akt/nuclear factor-kappaB (NF-kappaB) signaling pathway.	28	33	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	28	29	32	33
This subexpression of Bcl-2 could be induced by the above described activation of p53 , since p53 has been shown to block Bcl-2 transcription XREF_BIBR , XREF_BIBR , XREF_BIBR ( XREF_FIG ) .	This subexpression of Bcl-2 could be induced by the above described activation of p53, since p53 has been shown to block Bcl-2 transcription XREF_BIBR, XREF_BIBR, XREF_BIBR (XREF_FIG).	16	24	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	16	17	22	23
These results indicate that NF-kappaB-dependent and p53 independent down-regulation of Bcl-2 may be involved in galangin plus TRAIL mediated apoptosis .	These results indicate that NF-kappaB-dependent and p53 independent down-regulation of Bcl-2 may be involved in galangin plus TRAIL mediated apoptosis.	6	11	down-regulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	6	7	10	11
Ad-E2F1 in combination with AS-MDM2 enhances phospho-p53 levels , increases p53 transactivation leading to upregulation of p53 targets , increases levels of phospho-gammaH2AX and down-regulates Bcl-2 and AR in LNCaP and LNCaP-Res cells .	Ad-E2F1 in combination with AS-MDM2 enhances phospho-p53 levels, increases p53 transactivation leading to upregulation of p53 targets, increases levels of phospho-gammaH2AX and down-regulates Bcl-2 and AR in LNCaP and LNCaP-Res cells.	0	27	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phospho-p53	Ad-E2F1 in combination with AS-MDM2 enhances phospho-p53 levels	phospho-p53	Bcl-2	Bcl-2	bcl-2	6	7	25	26
Reverse transcription-polymerase chain reaction and western blot analysis were used to detect the levels of mRNA and proteins of p53 upregulated modulator of apoptosis ( PUMA ) , Bax and Bcl-2 .	Reverse transcription-polymerase chain reaction and western blot analysis were used to detect the levels of mRNA and proteins of p53 upregulated modulator of apoptosis (PUMA), Bax and Bcl-2.	17	31	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	19	20	30	31
Recently , it was shown that during apoptosis p53 can specifically translocate to mitochondria , where it physically interacts with and inactivates prosurvival Bcl-2 proteins .	Recently, it was shown that during apoptosis p53 can specifically translocate to mitochondria, where it physically interacts with and inactivates prosurvival Bcl-2 proteins.	8	24	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	p53	p53 can specifically translocate to mitochondria	p53	Bcl-2	Bcl-2	bcl-2	8	9	23	24
Another study has also showed that simultaneous treatment with EGCG and erlotinib , an inhibitor of EGFR-tyrosine kinase , strongly induced cell cycle arrest and apoptosis via p53 dependent induction of p21 , p27 , and Bim , and p53 dependent inhibition of NF-kappaB and its antiapoptotic target , Bcl-2 in squamous cell carcinoma of the head and neck cells ( SCCHN ) [ XREF_BIBR ] .	Another study has also showed that simultaneous treatment with EGCG and erlotinib, an inhibitor of EGFR-tyrosine kinase, strongly induced cell cycle arrest and apoptosis via p53 dependent induction of p21, p27, and Bim, and p53 dependent inhibition of NF-kappaB and its antiapoptotic target, Bcl-2 in squamous cell carcinoma of the head and neck cells (SCCHN) [XREF_BIBR].	39	53	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	39	40	49	50
Upregulation of P53 significantly decreased the Bcl-2 and Bax ratio that induced the release of cytochrome C from the mitochondria which in turn caused upregulation of caspase-3 .	Upregulation of P53 significantly decreased the Bcl-2 and Bax ratio that induced the release of cytochrome C from the mitochondria which in turn caused upregulation of caspase-3.	0	9	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P53	P53	P53	Bcl-2	Bcl-2	Bcl-2	2	3	6	7
XREF_FIG depicts expression of Bax , a pro apoptotic protein that can be induced by p53 , and Bcl-2 , an anti-apoptotic protein that can be repressed by p53 [ XREF_BIBR ] .	XREF_FIG depicts expression of Bax, a pro apoptotic protein that can be induced by p53, and Bcl-2, an anti-apoptotic protein that can be repressed by p53 [XREF_BIBR].	1	30	repressed	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	28	29	18	19
In addition , p53 has been shown to suppress survivin [ XREF_BIBR ] and Bcl-2 [ XREF_BIBR ] expression .	In addition, p53 has been shown to suppress survivin [XREF_BIBR] and Bcl-2 [XREF_BIBR] expression.	3	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	14	15
The p53 protein was decreased pro survival Bcl-2 proteins and elevated pro apoptosis Bax protein expression [ XREF_BIBR , XREF_BIBR ] .	The p53 protein was decreased pro survival Bcl-2 proteins and elevated pro apoptosis Bax protein expression [XREF_BIBR, XREF_BIBR].	1	8	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	1	2	7	8
We found that BRP can promote the expression of p53 and the further activation of Caspase-3 , and down-regulate Bcl-2 and Bax ratio as shown by Western blot analysis .	We found that BRP can promote the expression of p53 and the further activation of Caspase-3, and down-regulate Bcl-2 and Bax ratio as shown by Western blot analysis.	3	22	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	BRP can promote the expression of p53	p53	Bcl-2	Bcl-2	bcl-2	9	10	19	20
Blocking p53 activity with mutant p53 did not abrogate E2F-1-induced suppression of Bcl-2 .	Blocking p53 activity with mutant p53 did not abrogate E2F-1-induced suppression of Bcl-2.	1	13	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	1	2	12	13
Although well known as a transcriptional activator , p53 also represses genes that are involved in various signaling pathways such as cell proliferation ( c-myc , cyclin B ) and apoptosis ( Bcl2 , surviving ) XREF_BIBR , XREF_BIBR .	Although well known as a transcriptional activator, p53 also represses genes that are involved in various signaling pathways such as cell proliferation (c-myc, cyclin B) and apoptosis (Bcl2, surviving) XREF_BIBR, XREF_BIBR.	8	34	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	8	9	32	33
Likewise , results from a mouse knock-in model showed that acetylation of murine p53 at K317 ( equivalent to K320 in humans ) normally prevents p53 dependent induction of apoptotic genes , Noxa ( Bcl-2 homology 3-only apoptotic protein ) and Pidd ( p53 Induced protein with a Death Domain ) , and inhibits apoptosis following DNA damage [ XREF_BIBR ] .	Likewise, results from a mouse knock-in model showed that acetylation of murine p53 at K317 (equivalent to K320 in humans) normally prevents p53 dependent induction of apoptotic genes, Noxa (Bcl-2 homology 3-only apoptotic protein) and Pidd (p53 Induced protein with a Death Domain), and inhibits apoptosis following DNA damage [XREF_BIBR].	10	35	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	acetylation of murine p53 at K317	p53	Bcl-2	Bcl-2	bcl-2	13	14	34	35
Meanwhile , the activated P53 up-regulates the apoptotic receptor and ligand ( Fas and Fasl ) , pro apoptotic proteins ( Bax , Bok ) and apoptotic enzymes ( caspases 8 , 9 and 3 ) but down-regulates anti-apoptotic proteins ( Bcl-2 , Mcl-1 ) .	Meanwhile, the activated P53 up-regulates the apoptotic receptor and ligand (Fas and Fasl), pro apoptotic proteins (Bax, Bok) and apoptotic enzymes (caspases 8, 9 and 3) but down-regulates anti-apoptotic proteins (Bcl-2, Mcl-1).	2	43	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P53	P53	P53	Bcl-2	Bcl-2	Bcl-2	4	5	41	42
Interestingly , p53 can repress BCL2 both directly via promoter binding , and indirectly via miR-34a ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	Interestingly, p53 can repress BCL2 both directly via promoter binding, and indirectly via miR-34a (XREF_FIG) [XREF_BIBR, XREF_BIBR].	2	15	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL2	BCL2	BCL2	2	3	5	6
Under some conditions , cytoplasmic p53 inactivates Bcl-2 like proteins at the mitochondria , though the significance and mechanisms are not well understood .	Under some conditions, cytoplasmic p53 inactivates Bcl-2 like proteins at the mitochondria, though the significance and mechanisms are not well understood.	4	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	5	6	7	8
MAPK and p53 inhibition abolished the BCL-2 suppression and p21 Cip1 elevation that was induced by DDIT4 downregulation .	MAPK and p53 inhibition abolished the BCL-2 suppression and p21 Cip1 elevation that was induced by DDIT4 downregulation.	0	7	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	2	3	6	7
Thus , we retested 18 genes for binding and regulation by p53 that were described to be directly repressed by p53 , namely ABCB1 ( MDR1 ) , XREF_BIBR BCL2 , XREF_BIBR BNIP3 , XREF_BIBR CCNB1 , XREF_BIBR CD44 , XREF_BIBR CDC20 , XREF_BIBR CDK1 ( CDC2 ) , XREF_BIBR CRYZ , XREF_BIBR HSPA8 , XREF_BIBR ID2 , XREF_BIBR LASP1 , XREF_BIBR MAD1L1 ( MAD1 ) , XREF_BIBR ME1 , ME2 , ME3 , XREF_BIBR NEK2 , XREF_BIBR PTK2 ( FAK ) , XREF_BIBR and TPT1 ( TCTP ) .	Thus, we retested 18 genes for binding and regulation by p53 that were described to be directly repressed by p53, namely ABCB1 (MDR1), XREF_BIBR BCL2, XREF_BIBR BNIP3, XREF_BIBR CCNB1, XREF_BIBR CD44, XREF_BIBR CDC20, XREF_BIBR CDK1 (CDC2), XREF_BIBR CRYZ, XREF_BIBR HSPA8, XREF_BIBR ID2, XREF_BIBR LASP1, XREF_BIBR MAD1L1 (MAD1), XREF_BIBR ME1, ME2, ME3, XREF_BIBR NEK2, XREF_BIBR PTK2 (FAK), XREF_BIBR and TPT1 (TCTP).	3	87	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL2	BCL2	BCL2	11	12	29	30
Here we show that p53 decreases bcl-2 mRNA half-life by interacting with the 5 ' untranslated region ( UTR ) .	Here we show that p53 decreases bcl-2 mRNA half-life by interacting with the 5 ' untranslated region (UTR).	4	8	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	4	5	6	7
p53 may elicit this synergistic pro apoptotic effects by enhancing caspase 3 activation and diminishing Bcl-2 ( anti-apoptotic ) levels .	p53 may elicit this synergistic pro apoptotic effects by enhancing caspase 3 activation and diminishing Bcl-2 (anti-apoptotic) levels.	0	16	elicit	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	15	16
p53 has been reported to bind to the outer mitochondrial membrane and antagonize the anti-apoptotic function of BCL2 and BCL-XL .	p53 has been reported to bind to the outer mitochondrial membrane and antagonize the anti-apoptotic function of BCL2 and BCL-XL.	0	19	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL2	BCL2	BCL2	0	1	17	18
Ciprofloxacin potentiated gamma-irradiation-induced p53 phosphorylation , reduced Bcl-2 production and increased cell death in TK6 cells .	Ciprofloxacin potentiated gamma-irradiation-induced p53 phosphorylation, reduced Bcl-2 production and increased cell death in TK6 cells.	0	8	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	Ciprofloxacin potentiated gamma-irradiation-induced p53 phosphorylation	p53	Bcl-2	Bcl-2	bcl-2	3	4	7	8
E2F1 is known to enhance apoptosis induced by p53 and cooperate with p53 in activation of several genes ; moreover , E2F and p53 have been shown to repress two anti-apoptotic genes Bcl-2 and Mcl-1 .	E2F1 is known to enhance apoptosis induced by p53 and cooperate with p53 in activation of several genes; moreover, E2F and p53 have been shown to repress two anti-apoptotic genes Bcl-2 and Mcl-1.	21	34	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	23	24	32	33
For example , the pro apoptotic Bax and Bid are transcriptional targets of p53 [ XREF_BIBR - XREF_BIBR ] whereas Bcl-2 is negatively regulated by p53 [ XREF_BIBR - XREF_BIBR ] .	For example, the pro apoptotic Bax and Bid are transcriptional targets of p53 [XREF_BIBR - XREF_BIBR] whereas Bcl-2 is negatively regulated by p53 [XREF_BIBR - XREF_BIBR].	20	27	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	25	26	20	21
The apoptotic module of the p53 response involves numerous factors , including the BCL2-homology domain 3 ( BH3 )-only proteins PUMA and NOXA , which are both p53 target genes that inhibit pro survival BCL2 family members such as BCL2 , BCL2L1 ( BCL-xL ) and MCL1 , thus activating the intrinsic apoptotic pathway [ XREF_BIBR - XREF_BIBR ] .	The apoptotic module of the p53 response involves numerous factors, including the BCL2-homology domain 3 (BH3)-only proteins PUMA and NOXA, which are both p53 target genes that inhibit pro survival BCL2 family members such as BCL2, BCL2L1 (BCL-xL) and MCL1, thus activating the intrinsic apoptotic pathway [XREF_BIBR - XREF_BIBR].	27	36	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL2	BCL2	BCL2	27	28	34	35
However , in many cases where an anti-apoptotic lesion is also present ( loss of p53 and p19ARF ; upregulation of antiapoptotic Bcl2 family members etc ) , or potentially the microenvironment continues to prevent apoptosis , sustained inactivation would be essential for tumour regression .	However, in many cases where an anti-apoptotic lesion is also present (loss of p53 and p19ARF; upregulation of antiapoptotic Bcl2 family members etc), or potentially the microenvironment continues to prevent apoptosis, sustained inactivation would be essential for tumour regression.	13	25	upregulation	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	p53	loss of p53	p53	Bcl2	Bcl2	bcl2	15	16	22	23
However , the present studies show that the PRD of p53 also enhances cell death by reducing bcl-2 mRNA half-life through interactions with the 5 ' UTR region and suppressing expression of this central inhibitor of apoptosis .	However, the present studies show that the PRD of p53 also enhances cell death by reducing bcl-2 mRNA half-life through interactions with the 5 ' UTR region and suppressing expression of this central inhibitor of apoptosis.	8	19	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	10	11	17	18
Tumor protein 53 ( TP53 ) , a transcriptional factor , induces expression of the B-cell lymphoma 2 associated X protein ( BAX ) gene by directly binding to the TP53 binding element in the BAX promoter but inhibits B-cell lymphoma 2 ( BCL2 ) promoter driven transcription through a responsive region in the BCL2 promoter .	Tumor protein 53 (TP53), a transcriptional factor, induces expression of the B-cell lymphoma 2 associated X protein (BAX) gene by directly binding to the TP53 binding element in the BAX promoter but inhibits B-cell lymphoma 2 (BCL2) promoter driven transcription through a responsive region in the BCL2 promoter.	0	45	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tumor protein 53	Tumor protein 53	Tumor protein 53	BCL2	BCL2	BCL2	0	3	43	44
XREF_BIBR p53 upregulated modulator of apoptosis ( PUMA ) is a downstream target of p53 and a BH3-only Bcl-2 family member .	XREF_BIBR p53 upregulated modulator of apoptosis (PUMA) is a downstream target of p53 and a BH3-only Bcl-2 family member.	0	20	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	1	2	18	19
Interestingly , one of the regulated targets is Bcl2 , a well-known p53 inhibited gene .	Interestingly, one of the regulated targets is Bcl2, a well-known p53 inhibited gene.	0	14	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	12	13	8	9
Curcumin significantly induces apoptosis in NVPBEZ235 treated cells through p53 dependent downregulation of MCL-1 and BCL-2 protein expression [ XREF_BIBR ] .	Curcumin significantly induces apoptosis in NVPBEZ235 treated cells through p53 dependent downregulation of MCL-1 and BCL-2 protein expression [XREF_BIBR].	9	19	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	9	10	15	16
p53 blocks the functions of the anti-apoptotic Bcl-2 family members and activates some pro apoptotic factors , while caspase 9 , which initiates the executioner apoptotic caspase 3 and caspase 7 , can be further activated by Bak or Bax [ XREF_BIBR ] .	p53 blocks the functions of the anti-apoptotic Bcl-2 family members and activates some pro apoptotic factors, while caspase 9, which initiates the executioner apoptotic caspase 3 and caspase 7, can be further activated by Bak or Bax [XREF_BIBR].	0	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	7	8
This effect is opposed by the pro apoptotic p53 protein which completely inhibits the ability of Brn-3a to activate the Bcl-2 and Bcl-x promoters .	This effect is opposed by the pro apoptotic p53 protein which completely inhibits the ability of Brn-3a to activate the Bcl-2 and Bcl-x promoters.	8	23	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	8	9	20	21
Indeed , miR-34a expression levels were correlated with the rate of apoptosis in HepG2 cells , in which tumor suppressor p53 activated miR-34a and down-regulated Bcl2 .	Indeed, miR-34a expression levels were correlated with the rate of apoptosis in HepG2 cells, in which tumor suppressor p53 activated miR-34a and down-regulated Bcl2.	18	26	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	Bcl2	Bcl2	Bcl2	18	21	25	26
This appeared to be due to the down-regulation of Bcl-2 by p53 .	This appeared to be due to the down-regulation of Bcl-2 by p53.	4	12	down-regulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	11	12	9	10
Two re-ports demonstrated an inverse correlation among p53 and bcl-2 expression in OSCC suggesting that one of these proteins could substitute the other during carcinogenesis and that TP53 gene can downregulate the bcl-2 gene during the apoptotic process .	Two re-ports demonstrated an inverse correlation among p53 and bcl-2 expression in OSCC suggesting that one of these proteins could substitute the other during carcinogenesis and that TP53 gene can downregulate the bcl-2 gene during the apoptotic process.	27	33	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TP53	TP53	TP53	bcl-2	bcl-2	bcl-2	27	28	32	33
Because wild-type p53 can transcriptionally down-regulate bcl-2 , we speculate that p53 mutations may contribute to the association of t ( 8 ; 21 ) chromosomal abnormalities with higher Bcl-2 expression levels in leukemia cell lines .	Because wild-type p53 can transcriptionally down-regulate bcl-2, we speculate that p53 mutations may contribute to the association of t (8; 21) chromosomal abnormalities with higher Bcl-2 expression levels in leukemia cell lines.	1	7	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	2	3	6	7
p53 can further function outside its role as a nuclear transcription factor and has been shown to cause caspase activation , Bcl-2 inhibition , and MPT in the cytoplasm .	p53 can further function outside its role as a nuclear transcription factor and has been shown to cause caspase activation, Bcl-2 inhibition, and MPT in the cytoplasm.	0	22	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	21	22
The anti-apoptotic Mcl-1 and BCl-2 genes are downregulated via direct transcriptional repression by E2F1 in a p53 independent manner .	The anti-apoptotic Mcl-1 and BCl-2 genes are downregulated via direct transcriptional repression by E2F1 in a p53 independent manner.	4	18	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	BCl-2	BCl-2	BCl-2	16	17	4	5
Because p53 Pro drastically reduced bcl-2 mRNA stability , we investigated whether cell death is enhanced in p53 Pro -expressing cells that are grown in the presence of mRNA synthesis inhibitors and various cell death stimuli .	Because p53 Pro drastically reduced bcl-2 mRNA stability, we investigated whether cell death is enhanced in p53 Pro -expressing cells that are grown in the presence of mRNA synthesis inhibitors and various cell death stimuli.	1	7	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	1	2	5	6
Downregulation of miR-214 increased p53 protein expression and decreased the Bcl-2 and Bax signaling pathway of TSCC Tca8113 cells .	Downregulation of miR-214 increased p53 protein expression and decreased the Bcl-2 and Bax signaling pathway of TSCC Tca8113 cells.	2	18	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	miR-214 increased p53 protein expression	p53	Bcl-2	Bcl-2	bcl-2	4	5	10	11
Since bcl-2 is negatively regulated by p53 , it could be presumed that the p53 detected in the tumour cells may be non functional or inactive possibly because of interaction with proteins such as E6 or mdm-2 .	Since bcl-2 is negatively regulated by p53, it could be presumed that the p53 detected in the tumour cells may be non functional or inactive possibly because of interaction with proteins such as E6 or mdm-2.	1	7	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	6	7	1	2
Together , these results showed that p53 enhances the degradation of bcl-2 mRNA .	Together, these results showed that p53 enhances the degradation of bcl-2 mRNA.	6	12	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	6	7	11	12
In this model , p53 inhibits the Bcl-2 synthesis process , which normally suppresses the induction of apoptosis .	In this model, p53 inhibits the Bcl-2 synthesis process, which normally suppresses the induction of apoptosis.	4	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	4	5	7	8
In addition , Bcl-2 is also negatively regulated by pi1 XREF_BIBR , WT1 XREF_BIBR , and p53 XREF_BIBR .	In addition, Bcl-2 is also negatively regulated by pi1 XREF_BIBR, WT1 XREF_BIBR, and p53 XREF_BIBR.	3	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	16	17	3	4
Bcl2 , encoded by the gene BCL2 , as a critical pro survival member of Bcl2 protein family which regulates apoptosis , is usually considered to be a downstream target of p53 and can be negatively regulated by p53 .	Bcl2, encoded by the gene BCL2, as a critical pro survival member of Bcl2 protein family which regulates apoptosis, is usually considered to be a downstream target of p53 and can be negatively regulated by p53.	0	39	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	38	39	0	1
Moreover , PX-478 alone upregulated p53 expression and reduced the bcl2 and BAX ratio under hypoxia , but not under oxia .	Moreover, PX-478 alone upregulated p53 expression and reduced the bcl2 and BAX ratio under hypoxia, but not under oxia.	2	13	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	PX-478 alone upregulated p53 expression	p53	bcl2	bcl2	bcl2	5	6	10	11
Besides , Bcl-2 is also repressed by p53 [ XREF_BIBR ] .	Besides, Bcl-2 is also repressed by p53 [XREF_BIBR].	2	9	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	7	8	2	3
Inhibition of p53 and TG2 increased ROS and Bcl-2 production under glucose starvation conditions .	Inhibition of p53 and TG2 increased ROS and Bcl-2 production under glucose starvation conditions.	0	9	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	8	9
Overexpression of PrP C in SGC7901 cells demonstrated decreased drug accumulation and increased drug release through upregulating P-glycoprotein , Bcl-2 and downregulating p53 and Bax , [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Overexpression of PrP C in SGC7901 cells demonstrated decreased drug accumulation and increased drug release through upregulating P-glycoprotein, Bcl-2 and downregulating p53 and Bax, [XREF_BIBR, XREF_BIBR, XREF_BIBR].	14	24	downregulating	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	22	23	19	20
The p53 can downregulate Bcl-2 which protects cells from apoptosis .	The p53 can downregulate Bcl-2 which protects cells from apoptosis.	0	6	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	1	2	4	5
In addition , p53 inactivation or introduction of Bcl-2 failed to rescue the thymocyte developmental defects caused by survivin deficiency .	In addition, p53 inactivation or introduction of Bcl-2 failed to rescue the thymocyte developmental defects caused by survivin deficiency.	3	9	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	8	9
If TSC2 can inactivate Rheb by an additional , GAP independent mechanism then TSC2 should still be able to inhibit mTORC1 activity driven by constitutively GTP loaded Rheb mutants .	If TSC2 can inactivate Rheb by an additional, GAP independent mechanism then TSC2 should still be able to inhibit mTORC1 activity driven by constitutively GTP loaded Rheb mutants.	1	5	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	1	2	4	5
Once sequestered , TSC2 can not suppress Rheb and this leads to the activation of Rheb and mTORC1 .	Once sequestered, TSC2 can not suppress Rheb and this leads to the activation of Rheb and mTORC1.	3	8	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	3	4	7	8
As described above , TSC1 and TSC2 coordinate to inhibit downstream Rheb and mTORC1 .	As described above, TSC1 and TSC2 coordinate to inhibit downstream Rheb and mTORC1.	4	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	6	7	11	12
TSC1- TSC2 negatively regulates mTORC1 activity by converting Rheb into its inactive GDP bound state .	TSC1- TSC2 negatively regulates mTORC1 activity by converting Rheb into its inactive GDP bound state.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	1	2	8	9
For example , REDD1 , which is a negative regulator of mTORC1 via TSC2 dependent inactivation of Rheb is increased in septic muscle .	For example, REDD1, which is a negative regulator of mTORC1 via TSC2 dependent inactivation of Rheb is increased in septic muscle.	13	18	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	13	14	17	18
This leads to activation of TSC2 , which inhibits Rheb .	This leads to activation of TSC2, which inhibits Rheb.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	5	6	9	10
Transfection of TSC2 into p53 null cells replaced TSC2 and diminished Rheb at the lysosome , recapitulating cells with wt p53 .	Transfection of TSC2 into p53 null cells replaced TSC2 and diminished Rheb at the lysosome, recapitulating cells with wt p53.	0	12	diminished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	2	3	11	12
Normally , TSC2 negatively regulates Rheb , which is immediately upstream of mTORC1 .	Normally, TSC2 negatively regulates Rheb, which is immediately upstream of mTORC1.	2	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	2	3	5	6
Akt then negatively regulates the GTPase activating proteins TSC1 and TSC2 , which negatively regulate Rheb .	Akt then negatively regulates the GTPase activating proteins TSC1 and TSC2, which negatively regulate Rheb.	6	16	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	10	11	15	16
Within the TSC1/2 complex , the TSC1 subunit stabilizes and regulates the GAP activity of TSC2 , which inactivates Rheb .	Within the TSC1/2 complex, the TSC1 subunit stabilizes and regulates the GAP activity of TSC2, which inactivates Rheb.	13	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	15	16	19	20
Activation of IIS inhibits TSC1 and TSC2 , a heterodimer that negatively regulates Rheb , an activator of the TOR complex .	Activation of IIS inhibits TSC1 and TSC2, a heterodimer that negatively regulates Rheb, an activator of the TOR complex.	3	16	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	6	7	13	14
Therefore , Wnt mediated inactivation of Gsk3 alleviates Tsc2 driven inhibition of Rheb and results in TOR activation .	Therefore, Wnt mediated inactivation of Gsk3 alleviates Tsc2 driven inhibition of Rheb and results in TOR activation.	8	13	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	Rheb	Rheb	Rheb	8	9	12	13
Of relevance for our current work , RHEB is negatively regulated by the GTPase activating protein TSC2 .	Of relevance for our current work, RHEB is negatively regulated by the GTPase activating protein TSC2.	7	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	RHEB	RHEB	RHEB	16	17	7	8
This process is antagonized by the GAP activity of TSC2 , which , when associated with lysosomes in the absence of PI3K-Akt signaling , inactivates RHEB .	This process is antagonized by the GAP activity of TSC2, which, when associated with lysosomes in the absence of PI3K-Akt signaling, inactivates RHEB.	7	26	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	RHEB	RHEB	RHEB	9	10	25	26
mTOR function can be decreased by three mechanisms : 1 ) TSC2 phosphorylation by AMPK deactivates Rheb GTPase and , consequently , inhibits TORC1 ; 2 ) inhibition of Raptor and RPTOR , a component of TORC1 , results in TORC1 recruitment to 14-3-3 proteins , and 3 ) amino acid starvation can decrease mTOR activity through Rag GTPases .	mTOR function can be decreased by three mechanisms : 1) TSC2 phosphorylation by AMPK deactivates Rheb GTPase and, consequently, inhibits TORC1; 2) inhibition of Raptor and RPTOR, a component of TORC1, results in TORC1 recruitment to 14-3-3 proteins, and 3) amino acid starvation can decrease mTOR activity through Rag GTPases.	11	17	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2 phosphorylation	tsc2	Rheb	Rheb	rheb	11	12	16	17
Thus , in this particular example , it seems reasonable to consider that in the EGFR pathway Rheb is inhibited by Tsc2 .	Thus, in this particular example, it seems reasonable to consider that in the EGFR pathway Rheb is inhibited by Tsc2.	17	22	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	Rheb	Rheb	Rheb	21	22	17	18
Activation of TSC1 and TSC2 suppresses both Rheb and mTORC1 activity , inducing autophagy [ XREF_BIBR - XREF_BIBR ] .	Activation of TSC1 and TSC2 suppresses both Rheb and mTORC1 activity, inducing autophagy [XREF_BIBR - XREF_BIBR].	0	10	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	4	5	7	8
TSC2 phosphorylation by Akt represses GAP activity of the TSC1 and TSC2 complex , allowing Rheb to accumulate in a GTP bound state .	TSC2 phosphorylation by Akt represses GAP activity of the TSC1 and TSC2 complex, allowing Rheb to accumulate in a GTP bound state.	0	17	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2 phosphorylation by Akt represses GAP activity of the TSC1 and TSC2 complex	tsc2	Rheb	Rheb	rheb	0	1	15	16
Subsequently , lysosomal mTORC1 is directly activated by Rheb , which is inhibited by TSC2 , a specific GAP for Rheb .	Subsequently, lysosomal mTORC1 is directly activated by Rheb, which is inhibited by TSC2, a specific GAP for Rheb.	6	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	14	15	8	9
This mechanism is independent of TSC1 and TSC2 mediated inhibition of Rheb .	This mechanism is independent of TSC1 and TSC2 mediated inhibition of Rheb.	1	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	7	8	11	12
TSC2 inhibits RheB through its GAP activity and thus functions as negative regulator of mTORC1 signaling .	TSC2 inhibits RheB through its GAP activity and thus functions as negative regulator of mTORC1 signaling.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	RheB	RheB	RheB	0	1	2	3
Thus alpha 2 M *-induced increase in RAS-MAPK and Akt activation would promote phosphorylation of TSC2 and inhibit its activity towards the GTP * Rheb causing an increase in the Rheb pool which would promote mTORC1 activation as seen in p-mTOR S2481 levels ( XREF_FIG ) .	Thus alpha 2 M *-induced increase in RAS-MAPK and Akt activation would promote phosphorylation of TSC2 and inhibit its activity towards the GTP * Rheb causing an increase in the Rheb pool which would promote mTORC1 activation as seen in p-mTOR S2481 levels (XREF_FIG).	1	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	alpha 2 M *-induced increase in RAS-MAPK and Akt activation would promote phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	15	16	24	25
Interestingly , adiponectin inhibits mTORC1 to a lesser degree than rapamycin in both VSMC and EC , perhaps because adiponectin inhibits mTORC1 indirectly via AMPK : AMPK phosphorylates TSC2 , which , in turn , inhibits Rheb , a requisite mTORC1 activator .	Interestingly, adiponectin inhibits mTORC1 to a lesser degree than rapamycin in both VSMC and EC, perhaps because adiponectin inhibits mTORC1 indirectly via AMPK : AMPK phosphorylates TSC2, which, in turn, inhibits Rheb, a requisite mTORC1 activator.	26	41	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK phosphorylates TSC2	tsc2	Rheb	Rheb	rheb	28	29	36	37
As stated previously , GSK-3 phosphorylates TSC2 which in turn inhibits Rheb and mTORC1 activity .	As stated previously, GSK-3 phosphorylates TSC2 which in turn inhibits Rheb and mTORC1 activity.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	GSK-3 phosphorylates TSC2	tsc2	Rheb	Rheb	rheb	6	7	11	12
Elevated TSC2 phosphorylation at S1387 decreases the association of Rheb and Rag with mTOR This , in turn , inhibits the ability of mTORC1 to regulate the downstream proteins 4E-BP1 and S6K1 , which play a central role in regulating protein synthesis .	Elevated TSC2 phosphorylation at S1387 decreases the association of Rheb and Rag with mTOR This, in turn, inhibits the ability of mTORC1 to regulate the downstream proteins 4E-BP1 and S6K1, which play a central role in regulating protein synthesis.	1	10	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2 phosphorylation at S1387	tsc2	Rheb	Rheb	rheb	1	2	9	10
64 TSC2 phosphorylation by Akt represses GAP activity of the TSC1 and TSC2 complex , allowing Rheb to accumulate in a guanosine-5 '-triphosphate ( GTP )-bound state .	64 TSC2 phosphorylation by Akt represses GAP activity of the TSC1 and TSC2 complex, allowing Rheb to accumulate in a guanosine-5 '-triphosphate (GTP)-bound state.	1	18	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2 phosphorylation by Akt represses GAP activity of the TSC1 and TSC2 complex	tsc2	Rheb	Rheb	rheb	1	2	16	17
The activation of mTOR could occur through a number of mechanisms including direct interactions with p-AKT itself [ XREF_BIBR ] , or p-AKT-mediated inhibition of tuberous sclerosis 2 ( TSC2 ) , which then inhibits Rheb and leads to activation of mTOR [ XREF_BIBR - XREF_BIBR ] .	The activation of mTOR could occur through a number of mechanisms including direct interactions with p-AKT itself [XREF_BIBR], or p-AKT-mediated inhibition of tuberous sclerosis 2 (TSC2), which then inhibits Rheb and leads to activation of mTOR [XREF_BIBR - XREF_BIBR].	26	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	29	30	35	36
Loss of TSC1 or TSC2 activity stimulates mTORC1 by enhancing Rheb activity , which also impairs basal autophagy .	Loss of TSC1 or TSC2 activity stimulates mTORC1 by enhancing Rheb activity, which also impairs basal autophagy.	2	11	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	4	5	10	11
TSC2 inhibits RheB and , thus , mTORC1 via its GTPase activity [ XREF_BIBR - XREF_BIBR ] .	TSC2 inhibits RheB and, thus, mTORC1 via its GTPase activity [XREF_BIBR - XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	RheB	RheB	RheB	0	1	2	3
Second , AKT phosphorylates and inhibits TSC2 resulting in activation of mTORC1 by the RHEB GTPase negatively regulated by TSC2 .	Second, AKT phosphorylates and inhibits TSC2 resulting in activation of mTORC1 by the RHEB GTPase negatively regulated by TSC2.	14	20	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	RHEB	RHEB	RHEB	19	20	14	15
For example , activated Akt phosphorylates and inhibits the GTPase activating protein tuberous sclerosis complex-2 ( TSC2 ) , a molecule that constitutively represses the Ras homolog enriched in brain ( Rheb ) protein .	For example, activated Akt phosphorylates and inhibits the GTPase activating protein tuberous sclerosis complex-2 (TSC2), a molecule that constitutively represses the Ras homolog enriched in brain (Rheb) protein.	14	30	represses	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	16	17	25	30
AMPK can phosphorylate Raptor ( regulatory associated protein of mTOR ) , an essential component of mTOR complex 1 ( mTORC1 ) , the activity of which blocks autophagy or can phosphorylate TSC2 ( tuberous sclerosis complex 2 ) that directly inhibits Ras homolog enriched in brain ( Rheb )-mediated mTORC1activation .	AMPK can phosphorylate Raptor (regulatory associated protein of mTOR), an essential component of mTOR complex 1 (mTORC1), the activity of which blocks autophagy or can phosphorylate TSC2 (tuberous sclerosis complex 2) that directly inhibits Ras homolog enriched in brain (Rheb)-mediated mTORC1activation.	3	47	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Raptor (regulatory associated protein of mTOR), an essential component of mTOR complex 1 (mTORC1), the activity of which blocks autophagy or can phosphorylate TSC2	tsc2	Ras homolog enriched in brain	Ras homolog enriched in brain	ras homolog enriched in brain	32	33	42	47
In its unphosphorylated state , Tsc2 , in complex with Tsc1 and Melted , inhibits the activity of the small GTPase Rheb by stimulating the turnover of Rheb associated GTP to GDP .	In its unphosphorylated state, Tsc2, in complex with Tsc1 and Melted, inhibits the activity of the small GTPase Rheb by stimulating the turnover of Rheb associated GTP to GDP.	5	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	Rheb	Rheb	Rheb	5	6	21	22
In contrast , phosphorylation of TSC2 by AMPK increases its GTPase activity , stabilizes the TSC2 and TSC1 complex , and inactivates Rheb , leading to inactivation of mTORC1 and thus triggering autophagy [ XREF_BIBR ] .	In contrast, phosphorylation of TSC2 by AMPK increases its GTPase activity, stabilizes the TSC2 and TSC1 complex, and inactivates Rheb, leading to inactivation of mTORC1 and thus triggering autophagy [XREF_BIBR].	3	23	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	5	6	22	23
Tuberin is also phosphorylated by the AMP activated protein kinase ( AMPK ) , which in contrast to AKT , activates tuberin suppression of Rheb and inhibits mTOR signaling [ XREF_BIBR ] .	Tuberin is also phosphorylated by the AMP activated protein kinase (AMPK), which in contrast to AKT, activates tuberin suppression of Rheb and inhibits mTOR signaling [XREF_BIBR].	21	25	suppression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	Rheb	Rheb	Rheb	21	22	24	25
Normally when TSC1 and TSC2 are dimerized , the complex binds to RAS homolog enriched in brain ( RHEB ) ; however , activated Akt phosphorylates TSC2 and prevents RHEB from binding .	Normally when TSC1 and TSC2 are dimerized, the complex binds to RAS homolog enriched in brain (RHEB); however, activated Akt phosphorylates TSC2 and prevents RHEB from binding.	24	30	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Akt phosphorylates TSC2	tsc2	RHEB	RHEB	rheb	26	27	29	30
Activation of TORC1 by Akt is mediated by inhibition of the tuberous sclerosis complex 2 ( TSC2 ) , which inhibits the TORC1-activator Rheb [ XREF_BIBR - XREF_BIBR ] .	Activation of TORC1 by Akt is mediated by inhibition of the tuberous sclerosis complex 2 (TSC2), which inhibits the TORC1-activator Rheb [XREF_BIBR - XREF_BIBR].	8	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	16	17	23	24
This reciprocal relationship between binding of TSC2 at the lysosome and the levels of Rheb at this location suggests that higher TSC2 at the lysosome downregulates lysosomal Rheb .	This reciprocal relationship between binding of TSC2 at the lysosome and the levels of Rheb at this location suggests that higher TSC2 at the lysosome downregulates lysosomal Rheb.	20	28	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	21	22	27	28
TSC1 and TSC2 proteins together act to negatively regulate Rheb , thereby inhibiting protein synthesis .	TSC1 and TSC2 proteins together act to negatively regulate Rheb, thereby inhibiting protein synthesis.	0	10	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	2	3	9	10
TSC1 and TSC2 suppress the activity of RHEB ( Ras like GTPase ) , which are needed to activate mTORC1 [ XREF_BIBR ] .	TSC1 and TSC2 suppress the activity of RHEB (Ras like GTPase), which are needed to activate mTORC1 [XREF_BIBR].	0	18	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	RHEB	RHEB	RHEB	2	3	7	8
Indeed , in the scientific paper corpus we have used , this inhibition of Rheb by Tsc2 was not demonstrated .	Indeed, in the scientific paper corpus we have used, this inhibition of Rheb by Tsc2 was not demonstrated.	12	17	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	Rheb	Rheb	Rheb	16	17	14	15
Phosphorylation of TSC2 by AKT at T1462 disrupts the ability of TSC2 to regulate Rheb , resulting in enhanced mTORC1 function .	Phosphorylation of TSC2 by AKT at T1462 disrupts the ability of TSC2 to regulate Rheb, resulting in enhanced mTORC1 function.	0	16	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Phosphorylation of TSC2 by AKT at T1462	tsc2	Rheb	Rheb	rheb	2	3	14	15
TSC2-null cell proliferation was inhibited not only by reexpression of TSC2 or small interfering RNA ( siRNA )-induced downregulation of Rheb , mTOR , or raptor , but also by siRNA for rictor .	TSC2-null cell proliferation was inhibited not only by reexpression of TSC2 or small interfering RNA (siRNA)-induced downregulation of Rheb, mTOR, or raptor, but also by siRNA for rictor.	8	21	downregulation	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	TSC2	reexpression of TSC2	tsc2	Rheb	Rheb	rheb	10	11	20	21
Akt , in turn , phosphorylates TSC2 , thereby eliminating TSC2 ' s inactivation of Rheb , and the release of Rheb inhibition leads to stimulation of mTORC1 .	Akt, in turn, phosphorylates TSC2, thereby eliminating TSC2 's inactivation of Rheb, and the release of Rheb inhibition leads to stimulation of mTORC1.	0	16	eliminating	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Akt, in turn, phosphorylates TSC2	tsc2	Rheb	Rheb	rheb	6	7	15	16
It has been shown that TSC2 can repress the activity of the Ras related GTPase Rheb via its associated GAP domain ( GTPase activating protein ) , resulting in the inactivation of TOR .	It has been shown that TSC2 can repress the activity of the Ras related GTPase Rheb via its associated GAP domain (GTPase activating protein), resulting in the inactivation of TOR.	5	20	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	5	6	15	16
Functional assays in cells expressing Flag tagged WT-TSC2 or PxBS TSC2 mutants ( RQ , RW , and RG ) co-transfected with Flag-TSC1 , myc-Rheb and either HA-S6K ( XREF_FIG , left panel ) or HA-4E-BP1 ( XREF_FIG , right panel ) showed that while WT-TSC2 suppressed Rheb activation of mTORC1 ( evidenced by decreased phosphorylation of S6K1 and 4E-BP1 and [ 32 P ]-radiolabeled-S6 ) , all three pathogenic PxBS TSC2 mutants were deficient in mTORC1 repression ( XREF_FIG ) .	Functional assays in cells expressing Flag tagged WT-TSC2 or PxBS TSC2 mutants (RQ, RW, and RG) co-transfected with Flag-TSC1, myc-Rheb and either HA-S6K (XREF_FIG, left panel) or HA-4E-BP1 (XREF_FIG, right panel) showed that while WT-TSC2 suppressed Rheb activation of mTORC1 (evidenced by decreased phosphorylation of S6K1 and 4E-BP1 and [32 P]-radiolabeled-S6), all three pathogenic PxBS TSC2 mutants were deficient in mTORC1 repression (XREF_FIG).	45	48	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WT-TSC2	WT-TSC2	WT-TSC2	Rheb	Rheb	Rheb	45	46	47	48
TSC2 then inactivates Rheb , which impairs the interaction of mTOR with Rheb and Rag proteins .	TSC2 then inactivates Rheb, which impairs the interaction of mTOR with Rheb and Rag proteins.	0	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	0	1	3	4
TSC2 inactivates RheB through its GAP activity , and TSC1 is crucial for TSC2 stability in many cell types including immune cells .	TSC2 inactivates RheB through its GAP activity, and TSC1 is crucial for TSC2 stability in many cell types including immune cells.	0	3	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	RheB	RheB	RheB	0	1	2	3
AMPK can directly phosphorylate TSC2 on S1387 , thereby promoting its inhibition of Rheb and mTORC1 .	AMPK can directly phosphorylate TSC2 on S1387, thereby promoting its inhibition of Rheb and mTORC1.	0	15	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK can directly phosphorylate TSC2 on S1387	tsc2	Rheb	Rheb	rheb	4	5	13	14
These phosphorylation events release TSC2 mediated inhibition of the GTPase Ras homolog enriched in brain ( RHEB ) , thus allowing RHEB to activate mTORC1 [ XREF_BIBR ] .	These phosphorylation events release TSC2 mediated inhibition of the GTPase Ras homolog enriched in brain (RHEB), thus allowing RHEB to activate mTORC1 [XREF_BIBR].	4	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	4	5	10	15
TSC2 loss might also promote the association of Rheb and mTORC1 on a non lysosomal membrane .	TSC2 loss might also promote the association of Rheb and mTORC1 on a non lysosomal membrane.	0	9	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	0	1	8	9
When active , TSC2 inhibits Ras family GTPase Rheb by stimulating the conversion of Rheb-GTP to Rheb-GDP .	When active, TSC2 inhibits Ras family GTPase Rheb by stimulating the conversion of Rheb-GTP to Rheb-GDP.	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	3	4	8	9
Polycystin-1 has been shown to interact with tuberin ( TSC2 ) , which inhibits Rheb , an activator of mTOR ( XREF_FIG ) .	Polycystin-1 has been shown to interact with tuberin (TSC2), which inhibits Rheb, an activator of mTOR (XREF_FIG).	5	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	Rheb	Rheb	Rheb	7	8	14	15
Loss-of-function germline mutations in TSC1 or TSC2 cause Rheb hyperactivation and tuberous sclerosis complex disease which is characterized by the formation of hamartomas in a variety of organs .	Loss-of-function germline mutations in TSC1 or TSC2 cause Rheb hyperactivation and tuberous sclerosis complex disease which is characterized by the formation of hamartomas in a variety of organs.	2	9	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	6	7	8	9
Since TSC2 is known to repress mTOR1 signaling by regulating Rheb GTPase 26 , we examined whether PEX5 affects TSC2 expression .	Since TSC2 is known to repress mTOR1 signaling by regulating Rheb GTPase 26, we examined whether PEX5 affects TSC2 expression.	1	11	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	1	2	10	11
The Rheb is inactivated by TSC2 with GAP activity responsible for hydrolysis of RHEB , resulting in mTOR signaling inhibition [ XREF_BIBR , XREF_BIBR ] .	The Rheb is inactivated by TSC2 with GAP activity responsible for hydrolysis of RHEB, resulting in mTOR signaling inhibition [XREF_BIBR, XREF_BIBR].	0	6	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	5	6	1	2
Phosphorylation of TSC2 by AKT inhibits inactivation of rheb through the rheb-GTPase function of the TSC1 and TSC2 complex .	Phosphorylation of TSC2 by AKT inhibits inactivation of rheb through the rheb-GTPase function of the TSC1 and TSC2 complex.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Phosphorylation of TSC2	tsc2	rheb	rheb	rheb	2	3	8	9
AMPK is known to be phosphorylated by the serine/threonine kinase LKB1 ( Liver kinase B1 ) and to phosphorylate TSC2 ( Tuberous Sclerosis Complex 2 ) , a GAP ( GTPase activating protein ) domain containing protein , which inactivates the Rheb GTPase , a direct activator of MTORC1 ( XREF_FIG ) .	AMPK is known to be phosphorylated by the serine/threonine kinase LKB1 (Liver kinase B1) and to phosphorylate TSC2 (Tuberous Sclerosis Complex 2), a GAP (GTPase activating protein) domain containing protein, which inactivates the Rheb GTPase, a direct activator of MTORC1 (XREF_FIG).	18	42	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylate TSC2	tsc2	Rheb	Rheb	rheb	19	20	41	42
Tuberin has been shown to inactivate Rheb , a protein involved in the mTOR signalling pathway .	Tuberin has been shown to inactivate Rheb, a protein involved in the mTOR signalling pathway.	0	9	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tuberin	Tuberin	Tuberin	Rheb	Rheb	Rheb	0	1	6	7
We then searched the literature for such a demonstration , but we could not find an experiment demonstrating that EGF activated Tsc2 inhibits Rheb .	We then searched the literature for such a demonstration, but we could not find an experiment demonstrating that EGF activated Tsc2 inhibits Rheb.	21	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	Rheb	Rheb	Rheb	21	22	23	24
TSC2 phosphorylated by Akt ceases to inhibit the Ras homolog enriched in brain ( Rheb ) protein that is required for activation of mammalian target of rapamycin ( mTOR ) activation [ XREF_BIBR ] .	TSC2 phosphorylated by Akt ceases to inhibit the Ras homolog enriched in brain (Rheb) protein that is required for activation of mammalian target of rapamycin (mTOR) activation [XREF_BIBR].	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2 phosphorylated	tsc2	Ras homolog enriched in brain	Ras homolog enriched in brain	ras homolog enriched in brain	0	1	8	13
Therefore , Wnt mediated inactivation of Gsk3 alleviates Tsc2 driven inhibition of Rheb and results in TORC1 activation .	Therefore, Wnt mediated inactivation of Gsk3 alleviates Tsc2 driven inhibition of Rheb and results in TORC1 activation.	8	13	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	Rheb	Rheb	Rheb	8	9	12	13
Phosphorylation of TSC2 by AKT inactivates its Rheb GTPase activity , leading to activation of mTOR Complex 1 ( mTORC1 ) .	Phosphorylation of TSC2 by AKT inactivates its Rheb GTPase activity, leading to activation of mTOR Complex 1 (mTORC1).	0	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	2	3	7	8
Rheb directly binds to mTORC1 and potently stimulates its activity , but Tsc1 and Tsc2 negatively regulates mTORC1 by converting Rheb into its inactive GDP bound form XREF_BIBR , XREF_BIBR .	Rheb directly binds to mTORC1 and potently stimulates its activity, but Tsc1 and Tsc2 negatively regulates mTORC1 by converting Rheb into its inactive GDP bound form XREF_BIBR, XREF_BIBR.	12	21	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	Rheb	Rheb	Rheb	14	15	20	21
Rheb is inhibited by the heterodimer of tuberous sclerosis proteins TSC1 and TSC2 ( TSC1/2 ) , which convert Rheb into an inactive GDP bound state .	Rheb is inhibited by the heterodimer of tuberous sclerosis proteins TSC1 and TSC2 (TSC1/2), which convert Rheb into an inactive GDP bound state.	0	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	12	13	0	1
RHEB is tightly regulated by the tuberous sclerosis 1 ( TSC1 ) and TSC2 complex , which , through its GTPase activating protein ( GAP ) activity toward RHEB , inactivates RHEB and mTORC1 .	RHEB is tightly regulated by the tuberous sclerosis 1 (TSC1) and TSC2 complex, which, through its GTPase activating protein (GAP) activity toward RHEB, inactivates RHEB and mTORC1.	13	33	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	RHEB	RHEB	RHEB	13	14	31	32
Active TSC2 inhibits Ras family GTPase Rheb , which in turn positively regulates the serine threonine kinase mammalian target of rapamycin ( mTOR ) , a central regulator of protein synthesis .	Active TSC2 inhibits Ras family GTPase Rheb, which in turn positively regulates the serine threonine kinase mammalian target of rapamycin (mTOR), a central regulator of protein synthesis.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	1	2	6	7
Rheb activity is inhibited by binding of the TSC1 and TSC2 ( tuberous sclerosis ) complex , as TSC2 is a GTPase activating protein ( GAP ) for Rheb .	Rheb activity is inhibited by binding of the TSC1 and TSC2 (tuberous sclerosis) complex, as TSC2 is a GTPase activating protein (GAP) for Rheb.	0	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	10	11	0	1
Once activated by upstream signals , Akt phosphorylates and inhibits the negative regulators Tsc2 and PRAS40 , which then activates the GTPase Rheb and releases TORC1 from inhibition .	Once activated by upstream signals, Akt phosphorylates and inhibits the negative regulators Tsc2 and PRAS40, which then activates the GTPase Rheb and releases TORC1 from inhibition.	6	24	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tsc2	Akt phosphorylates and inhibits the negative regulators Tsc2	tsc2	Rheb	Rheb	rheb	13	14	22	23
Due to this high similarity , the presence of the ' Asn thumb ' in Tuberin and its mutation in TSC patients , it has been assumed that Rheb inactivation by Tuberin follows the same mechanism as in Rap-Rap1GAP .	Due to this high similarity, the presence of the ' Asn thumb ' in Tuberin and its mutation in TSC patients, it has been assumed that Rheb inactivation by Tuberin follows the same mechanism as in Rap-Rap1GAP.	28	32	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Tuberin	Tuberin	Tuberin	Rheb	Rheb	Rheb	31	32	28	29
Phosphorylation of TSC2 by AMPK can increase the GAP activity of TSC2 , stabilize the TSC2 and TSC1 complex , and inactivate Rheb , resulting in the inactivation of mTORC1 and the initiation of autophagy XREF_BIBR .	Phosphorylation of TSC2 by AMPK can increase the GAP activity of TSC2, stabilize the TSC2 and TSC1 complex, and inactivate Rheb, resulting in the inactivation of mTORC1 and the initiation of autophagy XREF_BIBR.	0	23	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	2	3	22	23
In the absence of growth factors , Rheb is inactivated by a GTPase activating protein ( GAP ) complex consisting of TSC1 and TSC2 [ XREF_BIBR ] .	In the absence of growth factors, Rheb is inactivated by a GTPase activating protein (GAP) complex consisting of TSC1 and TSC2 [XREF_BIBR].	7	25	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	23	24	7	8
Key amongst these regulatory factors are the small GTPase Rheb , which directly associates with TOR to stimulate its signaling activity , and the TSC1 and TSC2 proteins , which together inhibit Rheb through the GAP activity of TSC2 .	Key amongst these regulatory factors are the small GTPase Rheb, which directly associates with TOR to stimulate its signaling activity, and the TSC1 and TSC2 proteins, which together inhibit Rheb through the GAP activity of TSC2.	13	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	associates with TOR to stimulate its signaling activity, and the TSC1 and TSC2	tsc2	Rheb	Rheb	rheb	26	27	32	33
Based on these results and as the catalytic Asn ( Asn1643 ) is conserved in Tuberin and mutated in TSC patients , we assume that Gln64 is not involved in catalysis and that Rheb downregulation by Tuberin is achieved by a mechanism that is identical to the Rap-RapGAP reaction .	Based on these results and as the catalytic Asn (Asn1643) is conserved in Tuberin and mutated in TSC patients, we assume that Gln64 is not involved in catalysis and that Rheb downregulation by Tuberin is achieved by a mechanism that is identical to the Rap-RapGAP reaction.	33	37	downregulation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Tuberin	Tuberin	Tuberin	Rheb	Rheb	Rheb	36	37	33	34
AKT phosphorylation of TSC2 releases TSC inhibition of the GTPase RHEB ( Ras homolog enriched in brain ) .	AKT phosphorylation of TSC2 releases TSC inhibition of the GTPase RHEB (Ras homolog enriched in brain).	0	11	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	AKT phosphorylation of TSC2	tsc2	RHEB	RHEB	rheb	3	4	10	11
As TSC1 inhibits mTOR activity in naive T cells through the tuberous sclerosis complex , AMPK restricts the engagement of metabolic programs associated with clonal expansion .	As TSC1 inhibits mTOR activity in naive T cells through the tuberous sclerosis complex, AMPK restricts the engagement of metabolic programs associated with clonal expansion.	1	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	1	2	3	4
However , only four were observed to be differentially regulated during the first 120 hpf : rps6ka1 , mapk1 and the mTORC2 complex member rictora , all of which encode molecules that promote mTOR signaling , and tsc1a , which encodes the tumor sclerosis complex protein , hamartin that inhibits mTOR signaling .	However, only four were observed to be differentially regulated during the first 120 hpf : rps6ka1, mapk1 and the mTORC2 complex member rictora, all of which encode molecules that promote mTOR signaling, and tsc1a, which encodes the tumor sclerosis complex protein, hamartin that inhibits mTOR signaling.	45	51	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	hamartin	hamartin	hamartin	mTOR	mTOR	mTOR	47	48	50	51
Moreover , in at least some experimental conditions , TSC1 , a component of the TSC1/2 ( hamartin and tuberin ) complex that negatively regulates mTOR pathway , has been shown to localize to the basal body , and loss of either TSC1 or TSC2 upregulates ciliogenesis XREF_BIBR , XREF_BIBR , XREF_BIBR .	Moreover, in at least some experimental conditions, TSC1, a component of the TSC1/2 (hamartin and tuberin) complex that negatively regulates mTOR pathway, has been shown to localize to the basal body, and loss of either TSC1 or TSC2 upregulates ciliogenesis XREF_BIBR, XREF_BIBR, XREF_BIBR.	9	32	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	9	10	25	26
One possibility was that forebrain Tsc1 deletion was driving an increase in mTOR activity .	One possibility was that forebrain Tsc1 deletion was driving an increase in mTOR activity.	5	13	driving	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	5	6	12	13
Surprisingly , however , deletion of TSC1 , also expected to enhance mTOR signaling in the same neuronal population , led to hyperphagia and obesity , suggesting that LKB1 may engage other signaling pathways to influence the activity of these and associated neurons in the melanocortin network .	Surprisingly, however, deletion of TSC1, also expected to enhance mTOR signaling in the same neuronal population, led to hyperphagia and obesity, suggesting that LKB1 may engage other signaling pathways to influence the activity of these and associated neurons in the melanocortin network.	4	13	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	6	7	12	13
Loss of a functional hamartin and tuberin complex leads to increased activation of mTOR signaling and subsequent unregulated cell growth and proliferation .	Loss of a functional hamartin and tuberin complex leads to increased activation of mTOR signaling and subsequent unregulated cell growth and proliferation.	0	14	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	hamartin	Loss of a functional hamartin	hamartin	mTOR	mTOR	mtor	4	5	13	14
While transcripts for Tsc1 that is an upstream negative regulator of mTOR signaling [ XREF_BIBR ] were highly reduced in Foxo3 mutant erythroblasts ( XREF_FIG ) , TSC1 protein was not significantly altered ( XREF_FIG , quantification in the right panel ) suggesting that reduction of TSC1 transcript expression was unlikely to mediate activation of mTOR in Foxo3 mutant erythroblasts .	While transcripts for Tsc1 that is an upstream negative regulator of mTOR signaling [XREF_BIBR] were highly reduced in Foxo3 mutant erythroblasts (XREF_FIG), TSC1 protein was not significantly altered (XREF_FIG, quantification in the right panel) suggesting that reduction of TSC1 transcript expression was unlikely to mediate activation of mTOR in Foxo3 mutant erythroblasts.	46	56	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 transcript expression	tsc1	mTOR	mTOR	mtor	46	47	55	56
XREF_BIBR TSC2 : TSC1 inhibits mTOR activity by stimulating the conversion of active Rheb-GTP to the inactive form , Rheb-GDP .	XREF_BIBR TSC2 : TSC1 inhibits mTOR activity by stimulating the conversion of active Rheb-GTP to the inactive form, Rheb-GDP.	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	3	4	5	6
In addition , loss of chromosome 9 is frequent , targeting CDKN2A at 9p21 ( encoding the cell cycle regulator p16 INK4A and the activator of p53 p14 ARF ) and various genes on 9q , such as TSC1 ( an inhibitor of mTOR ) .	In addition, loss of chromosome 9 is frequent, targeting CDKN2A at 9p21 (encoding the cell cycle regulator p16 INK4A and the activator of p53 p14 ARF) and various genes on 9q, such as TSC1 (an inhibitor of mTOR).	32	44	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	38	39	43	44
The distinguished role of PTEN for neuronal cell survival was underlined in studies where a conditional deletion of PTEN or Tsc1 was used to increase mTOR activity in RGC after ON lesion .	The distinguished role of PTEN for neuronal cell survival was underlined in studies where a conditional deletion of PTEN or Tsc1 was used to increase mTOR activity in RGC after ON lesion.	16	26	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	20	21	25	26
We confirmed that conditional loss of Tsc1 resulted in upregulation of the mTOR pathway in hippocampal neurons .	We confirmed that conditional loss of Tsc1 resulted in upregulation of the mTOR pathway in hippocampal neurons.	4	13	resulted in upregulation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Tsc1	loss of Tsc1	tsc1	mTOR	mTOR	mtor	6	7	12	13
Tsc1 deletion should be sufficient to activate the mTOR pathway .	Tsc1 deletion should be sufficient to activate the mTOR pathway.	0	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	0	1	8	9
The mTOR pathway is negatively regulated by tumor suppressor genes TSC1 and TSC2 , as well as by their upstream regulators including phosphatase and tensin homolog ( PTEN ) , the STE20 related kinase adaptor alpha ( STRADalpha and neurofibromin 1 ( NF1 ) ( XREF_FIG ) .	The mTOR pathway is negatively regulated by tumor suppressor genes TSC1 and TSC2, as well as by their upstream regulators including phosphatase and tensin homolog (PTEN), the STE20 related kinase adaptor alpha (STRADalpha and neurofibromin 1 (NF1) (XREF_FIG).	1	12	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	10	11	1	2
Using this approach , we propose a network model illustrating the linkage between hyperactivated mTOR signaling caused by TSC1 deletion and morphological and developmental defects in the telencephalon .	Using this approach, we propose a network model illustrating the linkage between hyperactivated mTOR signaling caused by TSC1 deletion and morphological and developmental defects in the telencephalon.	14	19	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	18	19	14	15
TSC2 is a GTPase activating protein towards Rheb and forms a functional complex with TSC1 that downregulates mTOR ( mechanistic target of rapamycin ) XREF_BIBR .	TSC2 is a GTPase activating protein towards Rheb and forms a functional complex with TSC1 that downregulates mTOR (mechanistic target of rapamycin) XREF_BIBR.	9	20	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	14	15	17	18
Tsc1 deletion can result in activation of the mTOR signaling pathway [ XREF_BIBR , XREF_BIBR ] .	Tsc1 deletion can result in activation of the mTOR signaling pathway [XREF_BIBR, XREF_BIBR].	0	10	result in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	0	1	8	9
Recently , mTOR activation by Pten or Tsc1 knockout was shown to promote the regenerative capacity of injured axons XREF_BIBR .	Recently, mTOR activation by Pten or Tsc1 knockout was shown to promote the regenerative capacity of injured axons XREF_BIBR.	2	8	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	7	8	2	3
In particular , conditional deletion of Tsc1 in interneuron progenitors increased mTOR signaling in GABAergic interneurons , leading to loss of interneuron subtypes , lower convulsant induced seizure threshold , and early mortality [ XREF_BIBR ] .	In particular, conditional deletion of Tsc1 in interneuron progenitors increased mTOR signaling in GABAergic interneurons, leading to loss of interneuron subtypes, lower convulsant induced seizure threshold, and early mortality [XREF_BIBR].	4	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	6	7	11	12
TSC1 and hamartin is an upstream inhibitor of mTOR , which regulates cell growth and protein degradation [ XREF_BIBR ] .	TSC1 and hamartin is an upstream inhibitor of mTOR, which regulates cell growth and protein degradation [XREF_BIBR].	0	11	is an upstream inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	hamartin	hamartin	hamartin	mTOR	mTOR	mTOR	2	3	8	9
While we observed no change in total tuberin expression , there was increased hamartin expression in both Nf1-/- TVZ NSCs and o-GSCs , and a decrease in phosphorylation mediated tuberin inactivation ( Ser 939 and Thr 1462 ) , excluding tuberin and hamartin mediated mTOR activation as the mechanism underlying the increased mTOR activity in o-GSCs ( XREF_SUPPLEMENTARY ) .	While we observed no change in total tuberin expression, there was increased hamartin expression in both Nf1-/- TVZ NSCs and o-GSCs, and a decrease in phosphorylation mediated tuberin inactivation (Ser 939 and Thr 1462), excluding tuberin and hamartin mediated mTOR activation as the mechanism underlying the increased mTOR activity in o-GSCs (XREF_SUPPLEMENTARY).	30	45	mediated	Positive_early_activation	Negative_activation	Negative_activation	hamartin	hamartin	hamartin	mTOR	mTOR	mTOR	42	43	44	45
Activation of mTOR by loss of the inhibitory TSC1 and TSC2 function resulted in decreased NF-kappaB activity in mouse embryonic fibroblasts .	Activation of mTOR by loss of the inhibitory TSC1 and TSC2 function resulted in decreased NF-kappaB activity in mouse embryonic fibroblasts.	0	11	Activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	TSC1	loss of the inhibitory TSC1	tsc1	mTOR	mTOR	mtor	8	9	2	3
Because TSC1 functions as a complex with TSC2 to inhibit mTOR signaling by preventing the degradation of TSC2 28 , we first investigated whether overexpression of TSC1 leads to stabilization of TSC2 in Tsc1 tg mice .	Because TSC1 functions as a complex with TSC2 to inhibit mTOR signaling by preventing the degradation of TSC2 28, we first investigated whether overexpression of TSC1 leads to stabilization of TSC2 in Tsc1 tg mice.	1	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	1	2	10	11
These results suggest that the selective deletion of Tsc1 in OLs resulted in activation of the mTOR pathway .	These results suggest that the selective deletion of Tsc1 in OLs resulted in activation of the mTOR pathway.	6	17	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	8	9	16	17
Moreover , neuronal loss-of-function of Tsc1 led to an mTOR dependent increase in AMPA receptor surface expression , possibly mediated by an mTOR dependent increase in local dendritic synthesis of AMPA receptors .	Moreover, neuronal loss-of-function of Tsc1 led to an mTOR dependent increase in AMPA receptor surface expression, possibly mediated by an mTOR dependent increase in local dendritic synthesis of AMPA receptors.	3	11	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Tsc1	loss-of-function of Tsc1	tsc1	mTOR	mTOR	mtor	5	6	9	10
To ensure that lack of competitiveness was not a result of the supra-physiological activation of mTOR driven by deletion of Tsc1 , we performed a similar set of experiments using mice engineered to express a constitutively active allele of the RagA ( Rraga ) GTPase , Rraga Q66L ( referred to hereafter as Rraga GTP ) .	To ensure that lack of competitiveness was not a result of the supra-physiological activation of mTOR driven by deletion of Tsc1, we performed a similar set of experiments using mice engineered to express a constitutively active allele of the RagA (Rraga) GTPase, Rraga Q66L (referred to hereafter as Rraga GTP).	13	21	driven	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	20	21	15	16
Loss of TSC1 leads to mTOR mediated inhibition of PI3K-AKT in naive CD8 + T cells .	Loss of TSC1 leads to mTOR mediated inhibition of PI3K-AKT in naive CD8 + T cells.	0	6	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	TSC1	Loss of TSC1	tsc1	mTOR	mTOR	mtor	2	3	5	6
They performed whole genome sequencing on the patient ' s archival tumor and identified a point mutation in TSC1 , a tumor suppressor gene that negatively regulates MTOR signaling .	They performed whole genome sequencing on the patient 's archival tumor and identified a point mutation in TSC1, a tumor suppressor gene that negatively regulates MTOR signaling.	13	28	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	MTOR	MTOR	MTOR	18	19	27	28
Here we report that , unexpectedly , constitutive activation of mTOR signalling by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death in mice , despite an initial increase of oligodendrocyte precursors during early development .	Here we report that, unexpectedly, constitutive activation of mTOR signalling by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death in mice, despite an initial increase of oligodendrocyte precursors during early development.	10	14	signalling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	13	14	10	11
These results indicate that the mTOR signaling pathway activated by Tsc1-deficiency in CACL1-111 cells was suppressed by restoration of TSC1 expression XREF_BIBR .	These results indicate that the mTOR signaling pathway activated by Tsc1-deficiency in CACL1-111 cells was suppressed by restoration of TSC1 expression XREF_BIBR.	5	21	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	19	20	5	6
Taken together , we showed both spontaneous activation and loss of cellularity of naive T cells after activation of mTOR by Tsc1 deletion .	Taken together, we showed both spontaneous activation and loss of cellularity of naive T cells after activation of mTOR by Tsc1 deletion.	17	22	activation	Positive_activation_token_2_noun	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	21	22	19	20
TSC2 : TSC1 is also inhibited by the binding of forkhead transcription factor ( FoxO1 ) to TSC2 , ultimately activating the mTOR signaling cascade .	TSC2 : TSC1 is also inhibited by the binding of forkhead transcription factor (FoxO1) to TSC2, ultimately activating the mTOR signaling cascade.	2	24	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	2	3	22	23
This can stimulate autophagy by activating AMPK or by upregulating phosphatase and tensin homologue ( PTEN , a PIP 3 3 ' phosphatase ) and TSC1 which inhibits mTOR .	This can stimulate autophagy by activating AMPK or by upregulating phosphatase and tensin homologue (PTEN, a PIP 3 3 ' phosphatase) and TSC1 which inhibits mTOR.	9	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	25	26	28	29
It is also possible that loss of Tsc1 causes mTOR independent alterations in neurons that could affect the actin cytoskeleton or receptor trafficking resulting in disruption of mGluR-LTD .	It is also possible that loss of Tsc1 causes mTOR independent alterations in neurons that could affect the actin cytoskeleton or receptor trafficking resulting in disruption of mGluR-LTD.	5	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tsc1	loss of Tsc1	tsc1	mTOR	mTOR	mtor	7	8	9	10
Also , TSC1 , in coordination with TSC2 , inhibits MTOR , which promotes cell growth and cell cycle progression [ XREF_BIBR ] .	Also, TSC1, in coordination with TSC2, inhibits MTOR, which promotes cell growth and cell cycle progression [XREF_BIBR].	2	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	MTOR	MTOR	MTOR	2	3	10	11
Interestingly , mice with B cells that overexpress mTOR because of a TSC1 deletion ( TSC1 normally inhibits mTOR , _ FIG ) also demonstrate similar defects in B-cell differentiation and antibody production [ XREF_BIBR ] .	Interestingly, mice with B cells that overexpress mTOR because of a TSC1 deletion (TSC1 normally inhibits mTOR, _ FIG) also demonstrate similar defects in B-cell differentiation and antibody production [XREF_BIBR].	15	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	15	16	18	19
Two tumor suppressors in the PI3K-mTOR pathway altered in the majority of human gliomas XREF_BIBR - XREF_BIBR , PI3K regulatory subunit pi3kr1 and the tsc1 repressor of mTOR , were decreased in expression level in the Tg ( flk1 : RFP ) is18 tumors ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Two tumor suppressors in the PI3K-mTOR pathway altered in the majority of human gliomas XREF_BIBR - XREF_BIBR, PI3K regulatory subunit pi3kr1 and the tsc1 repressor of mTOR, were decreased in expression level in the Tg (flk1 : RFP) is18 tumors (XREF_FIG and XREF_SUPPLEMENTARY).	24	28	repressor	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	tsc1	tsc1	tsc1	mTOR	mTOR	mTOR	24	25	27	28
Conversely , mTOR hyper activation by Tsc1 deletion results in a rapid exit from quiescence and cell cycle entry , which is accompanied by an increase in mitochondrial biogenesis and ROS levels .	Conversely, mTOR hyper activation by Tsc1 deletion results in a rapid exit from quiescence and cell cycle entry, which is accompanied by an increase in mitochondrial biogenesis and ROS levels.	2	7	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	6	7	2	3
When either PTEN or TSC1 were silenced in order to reactivate the mTOR pathway , it led to induction of extensive axon regeneration in adult neurons .	When either PTEN or TSC1 were silenced in order to reactivate the mTOR pathway, it led to induction of extensive axon regeneration in adult neurons.	2	13	reactivate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	4	5	12	13
These data indicate that deletion of TSC1 results in activation of mTOR signaling in the pancreas of Neurog3-Tsc1-/-( TN ) mice .	These data indicate that deletion of TSC1 results in activation of mTOR signaling in the pancreas of Neurog3-Tsc1-/-(TN) mice.	4	12	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	6	7	11	12
In wild-type adult mice , the regeneration failure may be contributable to the suppression of mTOR activity and new protein synthesis in axotomized RGCs , since reactivating this pathway by conditional knockout of TSC1 , which negatively regulate the mTOR pathway , leads to axon regeneration [ XREF_BIBR ] .	In wild-type adult mice, the regeneration failure may be contributable to the suppression of mTOR activity and new protein synthesis in axotomized RGCs, since reactivating this pathway by conditional knockout of TSC1, which negatively regulate the mTOR pathway, leads to axon regeneration [XREF_BIBR].	31	40	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	33	34	39	40
Deletion of tuberous sclerosis complex 1 ( TSC1 ) , a negative regulator of mTOR , also activated mTOR and enhanced axon regeneration principally by mimicking the effect of PTEN deficiency [ XREF_BIBR ] .	Deletion of tuberous sclerosis complex 1 (TSC1), a negative regulator of mTOR, also activated mTOR and enhanced axon regeneration principally by mimicking the effect of PTEN deficiency [XREF_BIBR].	0	19	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	7	8	18	19
XREF_BIBR TSC1 and TSC2 mutations impair regulation of the mTOR pathway and cause tuberous sclerosis .	XREF_BIBR TSC1 and TSC2 mutations impair regulation of the mTOR pathway and cause tuberous sclerosis.	0	12	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	1	2	9	10
This network model shows that mTOR complex 1 ( mTORC1 ) , unlike the mTORC2 , would be activated by TSC1 deletion .	This network model shows that mTOR complex 1 (mTORC1), unlike the mTORC2, would be activated by TSC1 deletion.	5	21	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	20	21	5	6
Tuberous sclerosis complex 1 ( Tsc1 ) suppresses mTOR signaling , and loss of function mutations of Tsc1 cause tumors and a variety of neurological symptoms including intellectual disability , seizures , and autism .	Tuberous sclerosis complex 1 (Tsc1) suppresses mTOR signaling, and loss of function mutations of Tsc1 cause tumors and a variety of neurological symptoms including intellectual disability, seizures, and autism.	2	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	5	6	8	9
TRB3 has been reported to inhibit the activity of Akt protein kinases .	TRB3 has been reported to inhibit the activity of Akt protein kinases.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	0	1	9	10
Overexpression of Trib3 decreases Akt protein activation in the liver and muscle , whereas knockdown of Trib3 expression increases Akt in these tissues .	Overexpression of Trib3 decreases Akt protein activation in the liver and muscle, whereas knockdown of Trib3 expression increases Akt in these tissues.	16	22	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Trib3	Trib3 expression	trib3	Akt	Akt	akt	16	17	19	20
A mouse Trib3 R variant robustly blocks Akt activation in the fly model , consistent with the conserved function of this site .	A mouse Trib3 R variant robustly blocks Akt activation in the fly model, consistent with the conserved function of this site.	2	8	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Trib3	Trib3	Trib3	Akt	Akt	Akt	2	3	7	8
ER stress induces translation of activating transcription factor 4 ( ATF4 ) ; this induces apoptosis by transcriptional activation of stress related proteins , including tribbles homolog 3 ( TRB3 ) , XREF_BIBR which inhibits Akt .	ER stress induces translation of activating transcription factor 4 (ATF4); this induces apoptosis by transcriptional activation of stress related proteins, including tribbles homolog 3 (TRB3), XREF_BIBR which inhibits Akt.	18	36	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	tribbles homolog 3	tribbles homolog 3	tribbles homolog 3	Akt	Akt	Akt	25	28	35	36
TRB3 directly binds to and inhibits the kinase activity of PKB XREF_BIBR .	TRB3 directly binds to and inhibits the kinase activity of PKB XREF_BIBR.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	PKB	PKB	PKB	0	1	10	11
XREF_BIBR - XREF_BIBR TRB3 binds to and inhibits the kinase activity of Akt family members , and Akt proteins are well described activators of protein translation via TOR .	XREF_BIBR - XREF_BIBR TRB3 binds to and inhibits the kinase activity of Akt family members, and Akt proteins are well described activators of protein translation via TOR.	2	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	3	4	12	13
Overexpression of TRB3 causes chondrocyte cell death by inhibiting the PI-3 kinase and Akt pathway in culture conditions where this pathway is important for chondrocyte survival .	Overexpression of TRB3 causes chondrocyte cell death by inhibiting the PI-3 kinase and Akt pathway in culture conditions where this pathway is important for chondrocyte survival.	0	14	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TRB3	Overexpression of TRB3	trb3	Akt	Akt	akt	2	3	13	14
We also detected a downregulation of Trib3 , which regulates the activation of MAP kinases [ XREF_BIBR ] and blocks Akt kinases promoting cell proliferation and survival [ XREF_BIBR ] .	We also detected a downregulation of Trib3, which regulates the activation of MAP kinases [XREF_BIBR] and blocks Akt kinases promoting cell proliferation and survival [XREF_BIBR].	4	21	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Trib3	Trib3	Trib3	Akt	Akt	Akt	6	7	20	21
TRIB3 impairs IRS-1 and Akt signalling in endothelial cells mediated by insulin [ XREF_BIBR ] , leading to reduced endothelial nitric oxide synthase ( eNOS ) and NO bioavailability [ XREF_BIBR ] , which is associated with endothelial dysfunction and increased leukocyte adhesion to endothelial cells , important steps for atherosclerotic lesion formation ( XREF_FIG ) [ XREF_BIBR ] .	TRIB3 impairs IRS-1 and Akt signalling in endothelial cells mediated by insulin [XREF_BIBR], leading to reduced endothelial nitric oxide synthase (eNOS) and NO bioavailability [XREF_BIBR], which is associated with endothelial dysfunction and increased leukocyte adhesion to endothelial cells, important steps for atherosclerotic lesion formation (XREF_FIG) [XREF_BIBR].	0	40	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIB3	TRIB3	TRIB3	Akt	Akt	Akt	0	1	4	5
Therefore , we assume that due to down-regulation of Nrf2 function , less transcriptional expression of multiple antioxidants would result in a further increase in diabetic oxidative stress , which directly or indirectly via ER stress up-regulates TRB3 that directly inhibits Akt function , as illustrated in XREF_FIG .	Therefore, we assume that due to down-regulation of Nrf2 function, less transcriptional expression of multiple antioxidants would result in a further increase in diabetic oxidative stress, which directly or indirectly via ER stress up-regulates TRB3 that directly inhibits Akt function, as illustrated in XREF_FIG.	36	42	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	37	38	41	42
Akt activation is a key event in adipogenesis and was severely inhibited by TRB3 in 3T3-L1 cells .	Akt activation is a key event in adipogenesis and was severely inhibited by TRB3 in 3T3-L1 cells.	0	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	13	14	0	1
XREF_BIBR , XREF_BIBR Further , the factor TRB3 ( tribbles homolog 3 ) inhibits Akt activity by sequestering the unphosphorylated form , thereby blocking its phosphorylation and activation .	XREF_BIBR, XREF_BIBR Further, the factor TRB3 (tribbles homolog 3) inhibits Akt activity by sequestering the unphosphorylated form, thereby blocking its phosphorylation and activation.	5	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	7	8	14	15
TRB3 is expressed during fasting in the liver through the activation of the PPAR-alpha and PGC-1alpha pathway and causes insulin resistance by suppressing Akt and PKB activity [ XREF_BIBR , XREF_BIBR ] .	TRB3 is expressed during fasting in the liver through the activation of the PPAR-alpha and PGC-1alpha pathway and causes insulin resistance by suppressing Akt and PKB activity [XREF_BIBR, XREF_BIBR].	0	30	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TRB3	TRB3 is expressed	trb3	Akt	Akt	akt	0	1	23	24
Studies have shown that upregulation of the expression of Trib3 can promote the inhibitory interaction of AKT with its upsteam kinases and lead to inhibition of AKT and mTORC1 axis and autophagy mediated cell death .	Studies have shown that upregulation of the expression of Trib3 can promote the inhibitory interaction of AKT with its upsteam kinases and lead to inhibition of AKT and mTORC1 axis and autophagy mediated cell death.	7	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Trib3	expression of Trib3	trib3	AKT	AKT	akt	9	10	16	17
Combining our results and a previous report that TRB3 is a direct inhibitor of Akt , it appears that ERK induced TRB3 suppresses Akt activity via direct binding and indirectly by further promoting ERK signaling as part of a positive feedback switch that inhibits PERK and Akt ( XREF_FIG ) .	Combining our results and a previous report that TRB3 is a direct inhibitor of Akt, it appears that ERK induced TRB3 suppresses Akt activity via direct binding and indirectly by further promoting ERK signaling as part of a positive feedback switch that inhibits PERK and Akt (XREF_FIG).	8	15	is a direct inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	8	9	14	15
Our data support the idea that THC induced TRIB3 up-regulation inhibits AKT phosphorylation by regulating the accessibility of AKT to its upstream activatory kinase ( the mammalian target of rapamycin complex 2 ; mTORC2 ) .	Our data support the idea that THC induced TRIB3 up-regulation inhibits AKT phosphorylation by regulating the accessibility of AKT to its upstream activatory kinase (the mammalian target of rapamycin complex 2; mTORC2).	6	13	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	TRIB3	THC induced TRIB3	trib3	AKT	AKT phosphorylation	akt	8	9	11	12
This TRIB3 variant was recently shown to reduce Akt and eNOS activation in endothelial cells , with consequent reduction in vascular NO concentrations [ XREF_BIBR ] .	This TRIB3 variant was recently shown to reduce Akt and eNOS activation in endothelial cells, with consequent reduction in vascular NO concentrations [XREF_BIBR].	1	11	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIB3	TRIB3	TRIB3	Akt	Akt	Akt	1	2	8	9
Upregulation of TRB3 ( an inhibitor of Akt and protein kinase B and a positive regulator of the cellular response to insulin ) by the direct transcriptional control of PPARalpha has a negative effect on insulin signaling .	Upregulation of TRB3 (an inhibitor of Akt and protein kinase B and a positive regulator of the cellular response to insulin) by the direct transcriptional control of PPARalpha has a negative effect on insulin signaling.	0	27	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	2	3	7	8
120 Trib3 inhibits Akt activity and thereby activates FOXO3a , which in turn binds to and activates the trib3 promoter .	120 Trib3 inhibits Akt activity and thereby activates FOXO3a, which in turn binds to and activates the trib3 promoter.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Trib3	Trib3	Trib3	Akt	Akt	Akt	1	2	3	4
TRB3 , which inhibits Akt and PKB signaling , is upregulated in hyperglycemic Goto-Kakizaki rat islets and has been implicated in ER stress induced apoptosis , as well as negative regulation of insulin exocytosis [ XREF_BIBR , XREF_BIBR ] .	TRB3, which inhibits Akt and PKB signaling, is upregulated in hyperglycemic Goto-Kakizaki rat islets and has been implicated in ER stress induced apoptosis, as well as negative regulation of insulin exocytosis [XREF_BIBR, XREF_BIBR].	0	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	PKB	PKB	PKB	0	1	6	7
For example , Trib3 activation is known to block the Akt pathway thereby inhibiting insulin responses in liver 66 .	For example, Trib3 activation is known to block the Akt pathway thereby inhibiting insulin responses in liver 66.	3	11	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Trib3	Trib3	Trib3	Akt	Akt	Akt	3	4	10	11
TRB3 negatively regulates Akt activation and noticeably , TRB3 expression is induced by insulin .	TRB3 negatively regulates Akt activation and noticeably, TRB3 expression is induced by insulin.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	0	1	3	4
As Trib3 is an inhibitor of Akt , and Akt can act as a pro survival kinase XREF_BIBR , it may be expected that some increases in cell death may occur with increased Trib3 expression .	As Trib3 is an inhibitor of Akt, and Akt can act as a pro survival kinase XREF_BIBR, it may be expected that some increases in cell death may occur with increased Trib3 expression.	1	7	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Trib3	Trib3	Trib3	Akt	Akt	Akt	1	2	6	7
TRB3 inhibits the kinase activity of AKT and regulate mitogen activated protein kinase ( MAPK ) family members .	TRB3 inhibits the kinase activity of AKT and regulate mitogen activated protein kinase (MAPK) family members.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	AKT	AKT	AKT	0	1	6	7
Mirn23a miRNA miR-24 targets Trib3 , which represses Akt kinase and Smurf1 E3 ubiquitinase activity [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Mirn23a miRNA miR-24 targets Trib3, which represses Akt kinase and Smurf1 E3 ubiquitinase activity [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	9	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Trib3	Trib3	Trib3	Akt	Akt	Akt	4	5	8	9
Previous studies indicate that TRB3 inhibits the transmission of the Akt signal XREF_BIBR , XREF_BIBR .	Previous studies indicate that TRB3 inhibits the transmission of the Akt signal XREF_BIBR, XREF_BIBR.	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	4	5	10	11
AKT signaling , which is negatively regulated by TRB3 , was enhanced by miR-124 overexpression .	AKT signaling, which is negatively regulated by TRB3, was enhanced by miR-124 overexpression.	0	9	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	AKT	AKT	AKT	8	9	0	1
Additionally , according to Koo et al ., PPARalpha impairs liver insulin signaling by activating TRB3 , which inhibits Akt activation .	Additionally, according to Koo et al., PPARalpha impairs liver insulin signaling by activating TRB3, which inhibits Akt activation.	9	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	15	16	19	20
TRB3 is known to inhibit cancer cell proliferation by inactivating AKT / mammalian target of the rapamycin complex 1 ( mTORC ) signal transduction .	TRB3 is known to inhibit cancer cell proliferation by inactivating AKT / mammalian target of the rapamycin complex 1 (mTORC) signal transduction.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	AKT	AKT	AKT	0	1	10	11
Here , we report that , upon Abeta treatment , tribbles pseudokinase 3 ( Trib3 , an ortholog of Drosophila Tribbles ) is up-regulated in neurons both in vivo and in vitro Increased Trib3 levels inhibited the activity of the kinase Akt by interacting with it .	Here, we report that, upon Abeta treatment, tribbles pseudokinase 3 (Trib3, an ortholog of Drosophila Tribbles) is up-regulated in neurons both in vivo and in vitro Increased Trib3 levels inhibited the activity of the kinase Akt by interacting with it.	33	42	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Trib3	Trib3 levels	trib3	Akt	Akt	akt	33	34	41	42
TRB3 , a tribbles homolog , has been shown to inhibit IGF-1 activation of Akt in HEK293 cells .	TRB3, a tribbles homolog, has been shown to inhibit IGF-1 activation of Akt in HEK293 cells.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	0	1	14	15
Addition of TRB3 siRNA 24 h prior to stretch reversed the decline of phospho Akt .	Addition of TRB3 siRNA 24 h prior to stretch reversed the decline of phospho Akt.	2	15	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	2	3	14	15
TRIB3 has been shown to inhibit activation of AKT and by extension insulin signalling in vitro .	TRIB3 has been shown to inhibit activation of AKT and by extension insulin signalling in vitro.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIB3	TRIB3	TRIB3	AKT	AKT	AKT	0	1	8	9
Following activation of the IRE1/ASK1/JNK and TRB3 pathways via BRAF V600E mediated p38 activation , Bcl-XL and Bcl -2 phosphorylation , induced by active JNK , and Akt and mTOR axis inhibition , mediated by TRB3 , lead to increased autophagic activity [ XREF_BIBR ] .	Following activation of the IRE1/ASK1/JNK and TRB3 pathways via BRAF V600E mediated p38 activation, Bcl-XL and Bcl -2 phosphorylation, induced by active JNK, and Akt and mTOR axis inhibition, mediated by TRB3, lead to increased autophagic activity [XREF_BIBR].	27	36	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	35	36	27	28
TRIB3 is a pseudo-kinase inhibitor of AKT , which is the direct upstream activator of eNOS and has been shown to be relevant to insulin resistance .	TRIB3 is a pseudo-kinase inhibitor of AKT, which is the direct upstream activator of eNOS and has been shown to be relevant to insulin resistance.	0	22	is a pseudo-kinase inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	TRIB3	TRIB3	TRIB3	AKT	AKT	AKT	0	1	6	7
Finally , augmented TRB3 promotes the inhibition of AKT activation and G1/S transition .	Finally, augmented TRB3 promotes the inhibition of AKT activation and G1/S transition.	3	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	AKT	AKT	AKT	3	4	8	9
Among the molecular mechanisms involved , we emphasize in this review the participation of TRB3 protein ( a mammalian homolog of Drosophila tribbles ) , which is able to inhibit Akt activity and , thereby , maintain Foxo1 activity in the nucleus of hepatocytes , inducing hyperglycemia .	Among the molecular mechanisms involved, we emphasize in this review the participation of TRB3 protein (a mammalian homolog of Drosophila tribbles), which is able to inhibit Akt activity and, thereby, maintain Foxo1 activity in the nucleus of hepatocytes, inducing hyperglycemia.	14	31	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	14	15	30	31
For example , TRB3 has been shown to inhibit AKT activation 26 , which could potentially explain how rd16 mice have reduced p-AKT levels accompanied by an elevation in TRB3 levels at P15 .	For example, TRB3 has been shown to inhibit AKT activation 26, which could potentially explain how rd16 mice have reduced p-AKT levels accompanied by an elevation in TRB3 levels at P15.	3	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	AKT	AKT	AKT	3	4	9	10
Trb3 , in turn , has been shown to inhibit Akt activity ( without affecting mTORC1 ) 42 .	Trb3, in turn, has been shown to inhibit Akt activity (without affecting mTORC1) 42.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Trb3	Trb3	Trb3	Akt	Akt	Akt	0	1	10	11
TRB3 inhibits the activity of Akt , an insulin sensitizing kinase which mediates insulin signaling in hepatocytes .	TRB3 inhibits the activity of Akt, an insulin sensitizing kinase which mediates insulin signaling in hepatocytes.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	0	1	5	6
Combined with unphosphorylated Akt , TRB3 can prevent Akt activity and negatively regulate the insulin signaling pathway [ XREF_BIBR ] .	Combined with unphosphorylated Akt, TRB3 can prevent Akt activity and negatively regulate the insulin signaling pathway [XREF_BIBR].	5	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	5	6	8	9
Taken together with our previous study showing Akt binding to TRB3 in muscle 6 , these data suggest that TRB3 inhibits IRS1 and Akt signaling presumably by direct or indirect association with these proteins .	Taken together with our previous study showing Akt binding to TRB3 in muscle 6, these data suggest that TRB3 inhibits IRS1 and Akt signaling presumably by direct or indirect association with these proteins.	19	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	19	20	23	24
ER stress can promote autophagy via Trib3 dependent inhibition of the AKT and mTORC1 axis in cannabinoid induced human and mouse cancer cell death .	ER stress can promote autophagy via Trib3 dependent inhibition of the AKT and mTORC1 axis in cannabinoid induced human and mouse cancer cell death.	6	12	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Trib3	Trib3	Trib3	AKT	AKT	AKT	6	7	11	12
Our data indicated that the expression of TRB3 is downregulated during C2C12 cells undergoing muscle differentiation and that overexpression of TRB3 inhibits Akt activation during differentiation .	Our data indicated that the expression of TRB3 is downregulated during C2C12 cells undergoing muscle differentiation and that overexpression of TRB3 inhibits Akt activation during differentiation.	18	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	overexpression of TRB3	trb3	Akt	Akt	akt	20	21	22	23
So MAG , a PPARgamma agonist , as evidenced by increased PPARgamma expressions and activation , inhibits its downstream TRB3 expressions , enhances Akt and eNOS activations , and finally decreases blood pressure .	So MAG, a PPARgamma agonist, as evidenced by increased PPARgamma expressions and activation, inhibits its downstream TRB3 expressions, enhances Akt and eNOS activations, and finally decreases blood pressure.	1	26	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TRB3	MAG, a PPARgamma agonist, as evidenced by increased PPARgamma expressions and activation, inhibits its downstream TRB3 expressions	trb3	Akt	Akt	akt	19	20	23	24
Inhibition of Akt activation by TRB3 was associated with reduced chondrocyte survival in low-density serum free alginate cultures , a condition in which we previously demonstrated that IGF-1 autocrine signaling promoted survival .	Inhibition of Akt activation by TRB3 was associated with reduced chondrocyte survival in low-density serum free alginate cultures, a condition in which we previously demonstrated that IGF-1 autocrine signaling promoted survival.	2	6	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	5	6	2	3
TRIB3 can inhibit AKT kinase activity and increased TRIB3 gene expression is associated with systemic insulin resistance in humans ( Oberkofler etal .	TRIB3 can inhibit AKT kinase activity and increased TRIB3 gene expression is associated with systemic insulin resistance in humans (Oberkofler etal.	0	7	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIB3	TRIB3	TRIB3	AKT	AKT	AKT	0	1	3	4
We conclude that MLKs compromise mitochondrial integrity and suppress cellular survival mechanisms via TRB3 dependent inhibition of Akt .	We conclude that MLKs compromise mitochondrial integrity and suppress cellular survival mechanisms via TRB3 dependent inhibition of Akt.	13	18	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	13	14	17	18
In the absence of mirn23a , Trib3 levels rise repressing AKT activity leading to accumulation of FoxO1 in the nucleus .	In the absence of mirn23a, Trib3 levels rise repressing AKT activity leading to accumulation of FoxO1 in the nucleus.	6	11	repressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Trib3	Trib3 levels	trib3	AKT	AKT	akt	6	7	10	11
It was reported that the pseudokinase tribble 3 ( Trb3 ) inhibits Akt activity , and that FoxO1 may elevate Akt activity by suppressing Trb3 expression .	It was reported that the pseudokinase tribble 3 (Trb3) inhibits Akt activity, and that FoxO1 may elevate Akt activity by suppressing Trb3 expression.	6	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Trb3	Trb3	Trb3	Akt	Akt	Akt	9	10	12	13
In accordance with this hypothesis , we found that TRB3 , whose gene transcription is induced by aminoacids deprivation , 25 and which is known to inhibit AKT activation , XREF_BIBR , XREF_BIBR is upregulated in cancer cells depleted of CCAR2 , but not in normal cells .	In accordance with this hypothesis, we found that TRB3, whose gene transcription is induced by aminoacids deprivation, 25 and which is known to inhibit AKT activation, XREF_BIBR, XREF_BIBR is upregulated in cancer cells depleted of CCAR2, but not in normal cells.	9	34	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	AKT	AKT	AKT	9	10	27	28
For example , Trb3 inhibits Akt activity and impairs insulin signaling in hepatic cells and in C2C12 muscle cells [ XREF_BIBR , XREF_BIBR ] .	For example, Trb3 inhibits Akt activity and impairs insulin signaling in hepatic cells and in C2C12 muscle cells [XREF_BIBR, XREF_BIBR].	3	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Trb3	Trb3	Trb3	Akt	Akt	Akt	3	4	5	6
Taken together , our results suggest that p53 dependent downregulation of Survivin , CDC25C , and PLK1 upon doxorubicin induced DNA damage requires the CDE and CHR elements and a p53- and p21 dependent shift from MMB to DREAM complexes binding to the promoters .	Taken together, our results suggest that p53 dependent downregulation of Survivin, CDC25C, and PLK1 upon doxorubicin induced DNA damage requires the CDE and CHR elements and a p53- and p21 dependent shift from MMB to DREAM complexes binding to the promoters.	7	16	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	7	8	11	12
In summary , we conclude that the phylogenetically conserved CDE and CHR elements mediate p53 dependent repression of Survivin , CDC25C , and PLK1 , while CCAAT-boxes as well as the proposed p53 consensus sites are not involved .	In summary, we conclude that the phylogenetically conserved CDE and CHR elements mediate p53 dependent repression of Survivin, CDC25C, and PLK1, while CCAAT-boxes as well as the proposed p53 consensus sites are not involved.	14	23	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	14	15	18	19
Third , mutation of proposed p53 binding sites essentially does not impair p53 dependent repression of Survivin , CDC25C , and PLK1 promoters .	Third, mutation of proposed p53 binding sites essentially does not impair p53 dependent repression of Survivin, CDC25C, and PLK1 promoters.	12	22	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	12	13	16	17
In certain cases , the co-repressive function of DNMT1 is accompanied by DNA methylation : for instance , upon doxorubicin treatment , TP53 recruits DNMT1 , which methylates the p53 repressed promoters of Survivin and Cdc25c .	In certain cases, the co-repressive function of DNMT1 is accompanied by DNA methylation : for instance, upon doxorubicin treatment, TP53 recruits DNMT1, which methylates the p53 repressed promoters of Survivin and Cdc25c.	28	35	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	29	30	33	34
More importantly , p53 dependent repression of the Survivin , Cdc25C , and Plk1 mouse orthologs was shown to depend on the pocket proteins p107 and p130 [ XREF_BIBR ] , which were later identified as components of the DREAM complex [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	More importantly, p53 dependent repression of the Survivin, Cdc25C, and Plk1 mouse orthologs was shown to depend on the pocket proteins p107 and p130 [XREF_BIBR], which were later identified as components of the DREAM complex [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	15	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	3	4	8	9
Notably , Survivin repression by p53 is shown to be distinct from p53 dependent growth arrest .	Notably, Survivin repression by p53 is shown to be distinct from p53 dependent growth arrest.	2	6	repression	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	5	6	2	3
Furthermore , p53 dependent repression of Survivin , CDC25C and many other factors controlling cell division appears to serve the same purpose [ XREF_BIBR ] .	Furthermore, p53 dependent repression of Survivin, CDC25C and many other factors controlling cell division appears to serve the same purpose [XREF_BIBR].	2	12	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	2	3	6	7
Further analyses via chromatin deacetylation of the survivin promoter suggest that modification of chromatin may contribute to survivin expression silencing by p53 XREF_BIBR , XREF_BIBR .	Further analyses via chromatin deacetylation of the survivin promoter suggest that modification of chromatin may contribute to survivin expression silencing by p53 XREF_BIBR, XREF_BIBR.	15	22	contribute	Positive_activation_syntax_3_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	21	22	17	18
Additionally , p53 significantly down-regulates survivin in lung cancer cells by binding to the promoter of survivin for transcriptional suppression , which causes Caspase-3 activation and a decline in cell proliferation with response to adriamycin [ XREF_BIBR ] .	Additionally, p53 significantly down-regulates survivin in lung cancer cells by binding to the promoter of survivin for transcriptional suppression, which causes Caspase-3 activation and a decline in cell proliferation with response to adriamycin [XREF_BIBR].	2	9	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	2	3	5	6
Furthermore , we demonstrated that KLF5 protein is able to bind to p53 and abrogate the p53 regulated repression of survivin .	Furthermore, we demonstrated that KLF5 protein is able to bind to p53 and abrogate the p53 regulated repression of survivin.	16	21	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	16	17	20	21
First , we find p53 dependent repression of Survivin , CDC25C , and PLK1 to be essentially lost in HCT116 cells lacking p21 compared to wild-type cells .	First, we find p53 dependent repression of Survivin, CDC25C, and PLK1 to be essentially lost in HCT116 cells lacking p21 compared to wild-type cells.	4	13	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	4	5	8	9
When testing promoter elements necessary for repression , we observed that both the CDE and the CHR sites are required for p53 dependent repression of Survivin , CDC25C , and PLK1 .	When testing promoter elements necessary for repression, we observed that both the CDE and the CHR sites are required for p53 dependent repression of Survivin, CDC25C, and PLK1.	21	30	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	21	22	25	26
We find that p21 is essential for p53 dependent repression of Survivin , CDC25C , and PLK1 .	We find that p21 is essential for p53 dependent repression of Survivin, CDC25C, and PLK1.	7	16	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	7	8	11	12
p53 dependent downregulation of Survivin , CDC25C , and PLK1 requires p21 .	p53 dependent downregulation of Survivin, CDC25C, and PLK1 requires p21.	0	9	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	0	1	4	5
This mechanism is consistent with the repression of Survivin by p53 , which involves recruitment of HDACs to the Survivin promoter region leading to chromatin condensation [ XREF_BIBR ]-[ XREF_BIBR ] .	This mechanism is consistent with the repression of Survivin by p53, which involves recruitment of HDACs to the Survivin promoter region leading to chromatin condensation [XREF_BIBR]-[XREF_BIBR].	3	13	repression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	10	11	8	9
p53 inhibition enhances MGMT and survivin expressions .	p53 inhibition enhances MGMT and survivin expressions.	0	6	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	0	1	5	6
BIRC5 , also repressed by TP53 protein XREF_BIBR , XREF_BIBR , encodes survivin , which is regarded as one of the most cancer specific proteins identified , inhibiting apoptosis and promoting cell proliferation XREF_BIBR - XREF_BIBR .	BIRC5, also repressed by TP53 protein XREF_BIBR, XREF_BIBR, encodes survivin, which is regarded as one of the most cancer specific proteins identified, inhibiting apoptosis and promoting cell proliferation XREF_BIBR - XREF_BIBR.	0	11	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TP53	TP53	TP53	BIRC5	BIRC5	BIRC5	5	6	0	1
In summary , we have demonstrated in this study that WMJ-S-001 exhibits anti-angiogenic effects through at least two signaling pathways : SHP-1-mediated suppression of VEGF-A-VEGFR2 signaling and p53 mediated alterations of p21 and survivin in HUVECs .	In summary, we have demonstrated in this study that WMJ-S-001 exhibits anti-angiogenic effects through at least two signaling pathways : SHP-1-mediated suppression of VEGF-A-VEGFR2 signaling and p53 mediated alterations of p21 and survivin in HUVECs.	22	34	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	27	28	33	34
This may also be the case with survivin , which is down-regulated by the wild-type TP53 [ XREF_BIBR , XREF_BIBR ] .	This may also be the case with survivin, which is down-regulated by the wild-type TP53 [XREF_BIBR, XREF_BIBR].	5	17	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TP53	TP53	TP53	survivin	survivin	survivin	15	16	7	8
Studies on cancer cell lines have shown that the wild-type TP53 repressed survivin at both mRNA and protein levels , by binding to its promoter [ XREF_BIBR , XREF_BIBR ] .	Studies on cancer cell lines have shown that the wild-type TP53 repressed survivin at both mRNA and protein levels, by binding to its promoter [XREF_BIBR, XREF_BIBR].	8	13	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TP53	TP53	TP53	survivin	survivin	survivin	10	11	12	13
Interestingly , BIRC5 , the gene encoding Survivin is transcriptionally repressed by p53 [ XREF_BIBR , XREF_BIBR ] .	Interestingly, BIRC5, the gene encoding Survivin is transcriptionally repressed by p53 [XREF_BIBR, XREF_BIBR].	2	16	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	BIRC5	BIRC5	BIRC5	12	13	2	3
41 To investigate the role of these E2Fs in the p53 dependent repression of survivin and CDC25C , we located putative E2F binding sites on their promoters , 42 and analyzed the relative occupancy of each of these E2Fs on their binding sites in EJp53 cells .	41 To investigate the role of these E2Fs in the p53 dependent repression of survivin and CDC25C, we located putative E2F binding sites on their promoters, 42 and analyzed the relative occupancy of each of these E2Fs on their binding sites in EJp53 cells.	10	16	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	10	11	14	15
Survivin is negatively regulated by p53 , both at the mRNA and protein [ XREF_BIBR ] .	Survivin is negatively regulated by p53, both at the mRNA and protein [XREF_BIBR].	0	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	5	6	0	1
It has been reported that accumulation of wild-type p53 in human ovarian cancer cells induced survivin transcriptional repression which did not require direct sequence specific DNA binding to survivin promoter .	It has been reported that accumulation of wild-type p53 in human ovarian cancer cells induced survivin transcriptional repression which did not require direct sequence specific DNA binding to survivin promoter.	5	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	8	9	15	16
Our results demonstrate that survivin is downregulated by p53 , and that siRNA targeting of survivin increases cell sensitivity to adriamycin and promotes apoptosis .	Our results demonstrate that survivin is downregulated by p53, and that siRNA targeting of survivin increases cell sensitivity to adriamycin and promotes apoptosis.	4	9	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	8	9	4	5
Survivin , a member of the inhibitor of apoptosis family of proteins , is negatively regulated by wild type p53 and plays an important role in regulation of both apoptosis and cell division XREF_BIBR .	Survivin, a member of the inhibitor of apoptosis family of proteins, is negatively regulated by wild type p53 and plays an important role in regulation of both apoptosis and cell division XREF_BIBR.	0	21	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	19	20	0	1
For example , survivin is negatively regulated by PTEN , p53 , BRCA1 and Rb , which are often mutated and inactivated in a variety of cancers , and upregulated by Notch signaling , WNT and beta - catenin , STAT3 and NF-kappaB .	For example, survivin is negatively regulated by PTEN, p53, BRCA1 and Rb, which are often mutated and inactivated in a variety of cancers, and upregulated by Notch signaling, WNT and beta - catenin, STAT3 and NF-kappaB.	3	29	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	10	11	3	4
As a mechanism of action , KLF5 binds directly to p53 and blocks p53 regulated repression of survivin .	As a mechanism of action, KLF5 binds directly to p53 and blocks p53 regulated repression of survivin.	13	18	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	13	14	17	18
Our data indicated that survivin was inhibited by overexpression of p53 in chemoresistant AML cells treated by decitabine .	Our data indicated that survivin was inhibited by overexpression of p53 in chemoresistant AML cells treated by decitabine.	4	11	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	overexpression of p53	p53	survivin	survivin	survivin	10	11	4	5
Here , we provide evidence that Survivin , CDC25C , and PLK1 are not directly repressed by p53 .	Here, we provide evidence that Survivin, CDC25C, and PLK1 are not directly repressed by p53.	6	18	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	17	18	6	7
Several studies demonstrate suppression of BIRC5 by TP53 [ XREF_BIBR ] .	Several studies demonstrate suppression of BIRC5 by TP53 [XREF_BIBR].	3	9	suppression	Negative_activation_token_2_noun	Negative_activation	Negative_activation	TP53	TP53	TP53	BIRC5	BIRC5	BIRC5	7	8	5	6
It has also been shown that BIRC5 is transcriptionally repressed upon DNA damage by wild type p53 .	It has also been shown that BIRC5 is transcriptionally repressed upon DNA damage by wild type p53.	6	17	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	BIRC5	BIRC5	BIRC5	16	17	6	7
Survivin is normally repressed by P53 in human melanocytes [ XREF_BIBR ] as shown in the current study , but was shown to be down-regulated in melanoma cell lines with null and mutant P53 when compared to those with wild-type P53 and was not altered by inhibition of P53 expression in melanoma , further suggesting aberrant transcriptional regulation of this target gene by P53 in melanoma .	Survivin is normally repressed by P53 in human melanocytes [XREF_BIBR] as shown in the current study, but was shown to be down-regulated in melanoma cell lines with null and mutant P53 when compared to those with wild-type P53 and was not altered by inhibition of P53 expression in melanoma, further suggesting aberrant transcriptional regulation of this target gene by P53 in melanoma.	0	44	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	P53	P53	P53	Survivin	Survivin	Survivin	5	6	0	1
However , while the coding region of survivin decreased 90 % , the 3 '-UTR proximal region also decreased 80 % , which implies that transcriptional suppression by p53 ( a transcriptional repressor of survivin ) , [ XREF_BIBR ] not miR-34b/c up-regulation , is the major contributor to survivin down-regulation .	However, while the coding region of survivin decreased 90%, the 3 '-UTR proximal region also decreased 80%, which implies that transcriptional suppression by p53 (a transcriptional repressor of survivin), [XREF_BIBR] not miR-34b/c up-regulation, is the major contributor to survivin down-regulation.	26	35	repressor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	28	29	34	35
In conclusion , the presented data suggest that the p53-p21-DREAM-CDE and CHR pathway regulates p53 dependent repression of Survivin , CDC25C , and PLK1 .	In conclusion, the presented data suggest that the p53-p21-DREAM-CDE and CHR pathway regulates p53 dependent repression of Survivin, CDC25C, and PLK1.	14	23	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	14	15	18	19
Our results are consistent with prior studies which document suppression and induction of survivin by p53 ) and MAPK stimulation , respectively .	Our results are consistent with prior studies which document suppression and induction of survivin by p53) and MAPK stimulation, respectively.	9	16	induction	Positive_activation_token_2_noun	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	15	16	13	14
While p53 and p21 suppress survivin in resting cells , drug induced replicative stress and DNA damage activate survivin and further NF-kappaB-activated genes dependent on p53 and NF-kappaB p65 [ XREF_BIBR ] .	While p53 and p21 suppress survivin in resting cells, drug induced replicative stress and DNA damage activate survivin and further NF-kappaB-activated genes dependent on p53 and NF-kappaB p65 [XREF_BIBR].	1	8	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	1	2	5	6
These results stand in contrast to several observations reported on the p53 dependent downregulation of Survivin , CDC25C , and PLK1 .	These results stand in contrast to several observations reported on the p53 dependent downregulation of Survivin, CDC25C, and PLK1.	11	20	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	11	12	15	16
Importantly , the p53 dependent downregulation of Survivin , CDC25C , and PLK1 is essentially lost in HCT116 p21 -/- cells in contrast to activation of MDM2 .	Importantly, the p53 dependent downregulation of Survivin, CDC25C, and PLK1 is essentially lost in HCT116 p21 -/- cells in contrast to activation of MDM2.	3	12	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	3	4	7	8
However , HU induced p53 does not trigger a repression of survivin .	However, HU induced p53 does not trigger a repression of survivin.	4	12	trigger	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	4	5	11	12
The mechanism may be modulated through the induction of apoptosis due to the p53 dependent down-regulation of survivin .	The mechanism may be modulated through the induction of apoptosis due to the p53 dependent down-regulation of survivin.	13	18	down-regulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	13	14	17	18
XREF_BIBR Moreover , megakaryocytic p53 is potentially increased to directly abrogate the antideath effects of survivin .	XREF_BIBR Moreover, megakaryocytic p53 is potentially increased to directly abrogate the antideath effects of survivin.	3	16	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	4	5	15	16
Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin .	Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin.	2	10	targeting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	2	3	9	10
Thus , p53 dependent repression of Survivin and PLK1 resembles that of the CCNB2 and KIF23 promoters [ XREF_BIBR , XREF_BIBR ] , whereas CDC25C displays CDE and CHR mediated downregulation similar to the PLK4 promoter [ XREF_BIBR ] .	Thus, p53 dependent repression of Survivin and PLK1 resembles that of the CCNB2 and KIF23 promoters [XREF_BIBR, XREF_BIBR], whereas CDC25C displays CDE and CHR mediated downregulation similar to the PLK4 promoter [XREF_BIBR].	2	8	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	p53	p53	p53	Survivin	Survivin	Survivin	2	3	6	7
64 TSC2 is a GTPase activating protein ( GAP ) that functions in association with tuberous sclerosis complex 1 ( TSC1 ; hamartin ) to inactivate the small G protein Rheb ( Ras homolog enriched in brain ) .	64 TSC2 is a GTPase activating protein (GAP) that functions in association with tuberous sclerosis complex 1 (TSC1; hamartin) to inactivate the small G protein Rheb (Ras homolog enriched in brain).	18	37	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	20	21	32	37
Hamartin and tuberin were shown to form a complex , with hamartin functioning as a stabilizing scaffold , to suppress the activity of Rheb through the GAP domain of tuberin .	Hamartin and tuberin were shown to form a complex, with hamartin functioning as a stabilizing scaffold, to suppress the activity of Rheb through the GAP domain of tuberin.	4	24	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	hamartin	hamartin	hamartin	Rheb	Rheb	Rheb	11	12	23	24
Rheb is negatively regulated by the tumor suppressor TSC1 ( hamartin )-TSC2 ( tuberin ) complex which functions as a GTPase activating protein ( GAP ) towards Rheb .	Rheb is negatively regulated by the tumor suppressor TSC1 (hamartin)-TSC2 (tuberin) complex which functions as a GTPase activating protein (GAP) towards Rheb.	0	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	Rheb	Rheb	Rheb	8	9	0	1
CTMP miRNA-1/2 reduced CTMP expression ( 115 % of control ; n = 4-6 ; P < 0.01 vs. nontargeting miRNA animals ; XREF_SUPPLEMENTARY ) and increased Akt kinase activity in the ipsilateral vs. contralateral CA1 of ischemic animals ( to 117 +/- 7 % of control ; P < 0.01 vs. nontargeting miRNA animals ; XREF_SUPPLEMENTARY ) .	CTMP miRNA-1/2 reduced CTMP expression (115% of control; n = 4-6; P < 0.01 vs. nontargeting miRNA animals; XREF_SUPPLEMENTARY) and increased Akt kinase activity in the ipsilateral vs. contralateral CA1 of ischemic animals (to 117 +/- 7% of control; P < 0.01 vs. nontargeting miRNA animals; XREF_SUPPLEMENTARY).	0	29	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CTMP	CTMP miRNA-1/2 reduced CTMP expression	ctmp	Akt	Akt	akt	0	1	27	28
Thus , ischemia promotes expression of CTMP , which binds Akt and inhibits Akt activity in neurons destined to die ; preconditioning modestly enhances CTMP expression , but attenuates ischemia induced CTMP upregulation and assembly with p-Akt .	Thus, ischemia promotes expression of CTMP, which binds Akt and inhibits Akt activity in neurons destined to die; preconditioning modestly enhances CTMP expression, but attenuates ischemia induced CTMP upregulation and assembly with p-Akt.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTMP	expression of CTMP	ctmp	Akt	Akt	akt	6	7	13	14
These findings demonstrate that CTMP silencing rescues Akt kinase activity and promotes survival of neurons destined to die and implicate CTMP as causally related to the neuronal death associated with ischemic stroke .	These findings demonstrate that CTMP silencing rescues Akt kinase activity and promotes survival of neurons destined to die and implicate CTMP as causally related to the neuronal death associated with ischemic stroke.	4	9	rescues	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CTMP	CTMP	CTMP	Akt	Akt	Akt	4	5	7	8
Evidence suggest that CTMP negatively regulates PKB activity in v-Akt transformed cells [ XREF_BIBR ] , ciliary ganglion neurons [ XREF_BIBR ] , and K-ras-induced lung cancer model [ XREF_BIBR ] .	Evidence suggest that CTMP negatively regulates PKB activity in v-Akt transformed cells [XREF_BIBR], ciliary ganglion neurons [XREF_BIBR], and K-ras-induced lung cancer model [XREF_BIBR].	3	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTMP	CTMP	CTMP	PKB	PKB	PKB	3	4	6	7
CTMP abolishes AKT kinase activity and promotes neuronal death [ XREF_BIBR ] .	CTMP abolishes AKT kinase activity and promotes neuronal death [XREF_BIBR].	0	6	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTMP	CTMP	CTMP	AKT	AKT	AKT	0	1	2	3
As well , the protective effect of ATF3 was mediated by downregulation of carboxyl-terminal modulator protein ( CTMP ) , a pro apoptotic factor that inhibits the anti-apoptotic Akt and PKB cascade .	As well, the protective effect of ATF3 was mediated by downregulation of carboxyl-terminal modulator protein (CTMP), a pro apoptotic factor that inhibits the anti-apoptotic Akt and PKB cascade.	15	31	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	CTMP	CTMP	CTMP	PKB	PKB	PKB	17	18	30	31
CTMP is an endogenous inhibitor of Akt , a key mediator of insulin signals , and insulin signals mediate autophagy pathway .	CTMP is an endogenous inhibitor of Akt, a key mediator of insulin signals, and insulin signals mediate autophagy pathway.	0	10	is an endogenous inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	CTMP	CTMP	CTMP	Akt	Akt	Akt	0	1	6	7
Overexpression of CTMP markedly reduced Akt kinase activity ( XREF_SUPPLEMENTARY .	Overexpression of CTMP markedly reduced Akt kinase activity (XREF_SUPPLEMENTARY.	0	7	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTMP	Overexpression of CTMP	ctmp	Akt	Akt	akt	2	3	5	6
CTMP eliminates AKT kinase activity , resulting in FoxO ( Ser256 ) dephosphorylation and neuronal apoptosis [ XREF_BIBR ] .	CTMP eliminates AKT kinase activity, resulting in FoxO (Ser256) dephosphorylation and neuronal apoptosis [XREF_BIBR].	0	4	eliminates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTMP	CTMP	CTMP	AKT	AKT	AKT	0	1	2	3
These results suggest that elevation of CTMP in the astrocytes may suppress Akt activity and ultimately negatively affect the outcome of astrocyte activation ( astroglisiois ) .	These results suggest that elevation of CTMP in the astrocytes may suppress Akt activity and ultimately negatively affect the outcome of astrocyte activation (astroglisiois).	4	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTMP	CTMP	CTMP	Akt	Akt	Akt	6	7	12	13
CTMP overexpression inactivates PKB in v-Akt-transformed cells transplanted into mice [ XREF_BIBR ] , in cultured cells [ XREF_BIBR ] , and in a K-ras-induced lung cancer model [ XREF_BIBR ] .	CTMP overexpression inactivates PKB in v-Akt-transformed cells transplanted into mice [XREF_BIBR], in cultured cells [XREF_BIBR], and in a K-ras-induced lung cancer model [XREF_BIBR].	0	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTMP	CTMP overexpression	ctmp	PKB	PKB	pkb	0	1	3	4
These results suggest that elevation of CTMP in diabetic mice suppresses Akt activity and ultimately negatively affects the outcome of ischemia .	These results suggest that elevation of CTMP in diabetic mice suppresses Akt activity and ultimately negatively affects the outcome of ischemia.	4	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTMP	CTMP	CTMP	Akt	Akt	Akt	6	7	11	12
This suggests a mechanism of Akt being positively regulated by PI3K , and negatively regulated by CTMP in the neuroprotective effects of volatile anesthetics ( see XREF_FIG ) .	This suggests a mechanism of Akt being positively regulated by PI3K, and negatively regulated by CTMP in the neuroprotective effects of volatile anesthetics (see XREF_FIG).	3	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	CTMP	CTMP	CTMP	Akt	Akt	Akt	16	17	5	6
XREF_BIBR In this study , binding of Them4 at the plasma membrane was shown to reduce Akt activity , as evidenced by decreases in phosphorylation at S473 and T308 .	XREF_BIBR In this study, binding of Them4 at the plasma membrane was shown to reduce Akt activity, as evidenced by decreases in phosphorylation at S473 and T308.	5	17	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Them4	Them4	Them4	Akt	Akt	Akt	7	8	16	17
The TSC1 and TSC2 complex persistently activates the mammalian target of rapamycin ( mTOR ) signaling pathway , which regulates cellular metabolism , growth and survival .	The TSC1 and TSC2 complex persistently activates the mammalian target of rapamycin (mTOR) signaling pathway, which regulates cellular metabolism, growth and survival.	1	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1 and TSC2 complex	tsc1	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	1	2	8	12
TSC1 and TSC2 complex inhibits mTOR activity by activating the GTPase activity of Rheb , and both Akt and AMPK converged at TSC1 and TSC2 to regulate mTOR activity .	TSC1 and TSC2 complex inhibits mTOR activity by activating the GTPase activity of Rheb, and both Akt and AMPK converged at TSC1 and TSC2 to regulate mTOR activity.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	0	1	5	6
The TSC1 and TSC2 heterodimer inhibits mTOR function through Rheb inactivation .	The TSC1 and TSC2 heterodimer inhibits mTOR function through Rheb inactivation.	1	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 heterodimer	tsc1	mTOR	mTOR	mtor	1	2	6	7
The mTOR is negatively regulated by TSC1 and TSC2 complex .	The mTOR is negatively regulated by TSC1 and TSC2 complex.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	6	7	1	2
The TSC1 and TSC2 complex is the only known GTPase for Rheb , serving to reduce Rheb-GTP levels , and thereby inhibit the activation of mTOR .	The TSC1 and TSC2 complex is the only known GTPase for Rheb, serving to reduce Rheb-GTP levels, and thereby inhibit the activation of mTOR.	1	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	1	2	25	26
However , when growth factors are depleted , the active TSC1 and TSC2 complex suppresses mTOR activity , followed by induction of autophagy .	However, when growth factors are depleted, the active TSC1 and TSC2 complex suppresses mTOR activity, followed by induction of autophagy.	8	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	10	11	15	16
The tuberous sclerosis 1 and 2 complex ( Tsc1 and Tsc2 complex ) negatively regulates mTOR activity [ XREF_BIBR - XREF_BIBR ] .	The tuberous sclerosis 1 and 2 complex (Tsc1 and Tsc2 complex) negatively regulates mTOR activity [XREF_BIBR - XREF_BIBR].	8	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc1	Tsc1 and Tsc2 complex	tsc1	mTOR	mTOR	mtor	8	9	15	16
mTOR is downregulated by the upstream TSC1 and TSC2 complex .	mTOR is downregulated by the upstream TSC1 and TSC2 complex.	0	10	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	6	7	0	1
The TSC1 and TSC2 complex inactivates Rheb to inhibit mTOR signaling XREF_BIBR , XREF_BIBR .	The TSC1 and TSC2 complex inactivates Rheb to inhibit mTOR signaling XREF_BIBR, XREF_BIBR.	1	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	1	2	9	10
The TSC1 and TSC2 proteins form a heterodimer that negatively regulates the mTOR pathway , which in turn modulates a wide array of cellular processes .	The TSC1 and TSC2 proteins form a heterodimer that negatively regulates the mTOR pathway, which in turn modulates a wide array of cellular processes.	1	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 proteins form a heterodimer	tsc1	mTOR	mTOR	mtor	1	2	12	13
TSC1 ( hamartin ) forms a complex with TSC2 ( tuberin ) that negatively regulates mTOR through Rheb inhibition , thus Tsc1 loss results in increased mTORC1 activity ( XREF_FIG ) .	TSC1 (hamartin) forms a complex with TSC2 (tuberin) that negatively regulates mTOR through Rheb inhibition, thus Tsc1 loss results in increased mTORC1 activity (XREF_FIG).	0	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 (hamartin) forms a complex with TSC2	tsc1	mTOR	mTOR	mtor	0	1	15	16
Inactivation of the TSC1 and TSC2 complex stimulates activity of mammalian target of rapamycin ( mTOR ) , a kinase that promotes the uptake of nutrients necessary for cellular growth .	Inactivation of the TSC1 and TSC2 complex stimulates activity of mammalian target of rapamycin (mTOR), a kinase that promotes the uptake of nutrients necessary for cellular growth.	3	14	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1 and TSC2 complex	tsc1	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	3	4	10	14
40 TSC1 and TSC2 complex inhibits mTOR activity by activating the GTPase activity of Ras homologue enriched in brain , and both Akt and AMPK converged at TSC1 and TSC2 to regulate mTOR activity .	40 TSC1 and TSC2 complex inhibits mTOR activity by activating the GTPase activity of Ras homologue enriched in brain, and both Akt and AMPK converged at TSC1 and TSC2 to regulate mTOR activity.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	1	2	6	7
Once activated , AKT mediated phosphorylation of TSC2 ( tuberous sclerosis complex 2 ) inhibits the TSC1 and TSC2 complex function , and thus activates mTOR signaling .	Once activated, AKT mediated phosphorylation of TSC2 (tuberous sclerosis complex 2) inhibits the TSC1 and TSC2 complex function, and thus activates mTOR signaling.	3	26	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	AKT mediated phosphorylation of TSC2 (tuberous sclerosis complex 2) inhibits the TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	16	17	25	26
For example , the TSC1 and TSC2 complex inhibits mTOR functions by inactivating Rheb ; Rheb binds and activates mTOR only when the former is in its GTP bound form .	For example, the TSC1 and TSC2 complex inhibits mTOR functions by inactivating Rheb; Rheb binds and activates mTOR only when the former is in its GTP bound form.	4	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	4	5	9	10
The TSC1 and TSC2 complex normally inhibits mTOR activity , with loss of function mutations resulting in overactive mTOR and consequential increased protein synthesis and decreased protein degradation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The TSC1 and TSC2 complex normally inhibits mTOR activity, with loss of function mutations resulting in overactive mTOR and consequential increased protein synthesis and decreased protein degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	1	2	7	8
TSC2 is phosphorylated and inactivated by Akt and the TSC1 and TSC2 complex negatively regulates the kinase mTOR .	TSC2 is phosphorylated and inactivated by Akt and the TSC1 and TSC2 complex negatively regulates the kinase mTOR.	9	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	9	10	17	18
Recent studies suggested that TSC2 functions as the GTPase activating protein of the small G protein Rheb , an upstream activator of mTOR , and that the TSC1 and TSC2 complex antagonizes the mTOR signaling pathway via stimulation of GTP hydrolysis of Rheb .	Recent studies suggested that TSC2 functions as the GTPase activating protein of the small G protein Rheb, an upstream activator of mTOR, and that the TSC1 and TSC2 complex antagonizes the mTOR signaling pathway via stimulation of GTP hydrolysis of Rheb.	27	35	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	27	28	33	34
Loss of function of the hamartin and tuberin complex in TSC tumors enhances mTOR signaling leading to increased cell numbers and cell size .	Loss of function of the hamartin and tuberin complex in TSC tumors enhances mTOR signaling leading to increased cell numbers and cell size.	5	14	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	hamartin	hamartin and tuberin complex	hamartin	mTOR	mTOR	mtor	5	6	13	14
153 One of the factors identified for the induction of insulin resistance is TNF-alpha , which directly impairs insulin signaling and IRS-1 activation .	153 One of the factors identified for the induction of insulin resistance is TNF-alpha, which directly impairs insulin signaling and IRS-1 activation.	4	22	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	IRS-1	IRS-1	IRS-1	13	14	21	22
TNFalpha increased suppressor of cytokine signaling 3 ( SOCS3 ) signaling , as well as insulin receptor substrate 1 ( IRS-1 ) Ser307 and insulin receptor ( IR ) Tyr960 phosphorylation , leading to inhibition of normal insulin signaling under high-glucose conditions [ XREF_BIBR ] .	TNFalpha increased suppressor of cytokine signaling 3 (SOCS3) signaling, as well as insulin receptor substrate 1 (IRS-1) Ser307 and insulin receptor (IR) Tyr960 phosphorylation, leading to inhibition of normal insulin signaling under high-glucose conditions [XREF_BIBR].	0	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	0	1	15	19
Also , TNFalpha and IL6 inhibit the activation of insulin receptor substrate-1 ( IRS-1 ) through induction of suppressors of cytokine signaling ( SOCS3 ) disrupting insulin action [ XREF_BIBR ] .	Also, TNFalpha and IL6 inhibit the activation of insulin receptor substrate-1 (IRS-1) through induction of suppressors of cytokine signaling (SOCS3) disrupting insulin action [XREF_BIBR].	2	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	2	3	9	12
In cultured cells , mutation of Ser307 was shown to protect against tumor necrosis factor alpha ( TNFalpha )-induced inhibition of Irs1 tyrosine ( Tyr ) phosphorylation via the Jnk kinase pathway ; thus , Ser307 phosphorylation is frequently cited as a cause of stress induced insulin resistance .	In cultured cells, mutation of Ser307 was shown to protect against tumor necrosis factor alpha (TNFalpha)-induced inhibition of Irs1 tyrosine (Tyr) phosphorylation via the Jnk kinase pathway; thus, Ser307 phosphorylation is frequently cited as a cause of stress induced insulin resistance.	12	22	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	Irs1	Irs1	Irs1	12	15	21	22
In contrast , work in 3T3-L1 adipocytes showed that TNFalpha induced increases in SOCS3 levels were not sufficient to induce IRS-1 degradation [ XREF_BIBR ] ; however in this study , the authors find that TNFalpha stimulation caused IRS-1 degradation at a high level , with only minimal increases in SOCS3 mRNA and protein levels [ XREF_BIBR ] .	In contrast, work in 3T3-L1 adipocytes showed that TNFalpha induced increases in SOCS3 levels were not sufficient to induce IRS-1 degradation [XREF_BIBR]; however in this study, the authors find that TNFalpha stimulation caused IRS-1 degradation at a high level, with only minimal increases in SOCS3 mRNA and protein levels [XREF_BIBR].	35	39	caused	Positive_activation_syntax_3a_verb	Negative_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	IRS-1	IRS-1	IRS-1	35	36	38	39
TNFalpha reduces IRS1 protein by activation of JNK or S6K , resulting in insulin resistance .	TNFalpha reduces IRS1 protein by activation of JNK or S6K, resulting in insulin resistance.	0	3	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	IRS1	IRS1	IRS1	0	1	2	3
It should be noted that TNF-alpha does not directly inhibit IRS-1 .	It should be noted that TNF-alpha does not directly inhibit IRS-1.	5	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	IRS-1	IRS-1	IRS-1	5	6	10	11
TNF-alpha acts through its p55 receptor to inhibit IRS-1 in the insulin signaling pathway [ XREF_BIBR ] .	TNF-alpha acts through its p55 receptor to inhibit IRS-1 in the insulin signaling pathway [XREF_BIBR].	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	IRS-1	IRS-1	IRS-1	0	1	8	9
TNF-alpha inhibits IRS-1 , GLUT4 and adiponectin in TNF-alpha-treated control cells , however , infection with Ad : IGFBP-3 restored IRS-1 , GLUT4 and adiponectin mRNA ( XREF_FIG ) and protein levels ( XREF_FIG ) .	TNF-alpha inhibits IRS-1, GLUT4 and adiponectin in TNF-alpha-treated control cells, however, infection with Ad : IGFBP-3 restored IRS-1, GLUT4 and adiponectin mRNA (XREF_FIG) and protein levels (XREF_FIG).	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	IRS-1	IRS-1	IRS-1	0	1	2	3
Several studies have suggested that IKKbeta and JNK are central coordinators in the regulation of TNFalpha induced insulin resistance , whereas the cellular and molecular mechanisms , by which TNFalpha impairs IRS1 function , are not fully elucidated .	Several studies have suggested that IKKbeta and JNK are central coordinators in the regulation of TNFalpha induced insulin resistance, whereas the cellular and molecular mechanisms, by which TNFalpha impairs IRS1 function, are not fully elucidated.	29	32	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	IRS1	IRS1	IRS1	29	30	31	32
TNF-alpha is known to contribute to insulin resistance both through activation of mitogen activated protein kinase ( MAPK ) and inhibitor of kappa B kinase ( IKK ) resulting in serine phosphorylation of IRS-1 and through activation of protein tyrosine phosphorylase b which leads to dephosphorylation and inactivation of the insulin receptor and IRS-1 [ XREF_BIBR ] .	TNF-alpha is known to contribute to insulin resistance both through activation of mitogen activated protein kinase (MAPK) and inhibitor of kappa B kinase (IKK) resulting in serine phosphorylation of IRS-1 and through activation of protein tyrosine phosphorylase b which leads to dephosphorylation and inactivation of the insulin receptor and IRS-1 [XREF_BIBR].	0	55	contribute	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	IRS-1	IRS-1	IRS-1	0	1	53	54
Although mechanisms involved in TNFalpha induced insulin resistance are not completely understood , compelling evidence indicates that TNFalpha inhibits IRS-1- and IRS-2-mediated PI3-kinase activation , leading to insulin resistance [ XREF_BIBR ] .	Although mechanisms involved in TNFalpha induced insulin resistance are not completely understood, compelling evidence indicates that TNFalpha inhibits IRS-1- and IRS-2-mediated PI3-kinase activation, leading to insulin resistance [XREF_BIBR].	17	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	IRS-1-	IRS-1-	IRS-1-	17	18	19	20
Hh signaling through FAP cilia regulated the expression of TIMP3 , a secreted metalloproteinase inhibitor , that inhibited MMP14 to block adipogenesis .	Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis.	7	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP3	expression of TIMP3	timp3	MMP14	MMP14	mmp14	9	10	18	19
TIMP-3 is able to inhibit the membrane type 1 MMP ( MT1-MMP or MMP14 ) unlike TIMP-1 which can not act on MT1-MMP .	TIMP-3 is able to inhibit the membrane type 1 MMP (MT1-MMP or MMP14) unlike TIMP-1 which can not act on MT1-MMP.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MT1-MMP	MT1-MMP	MT1-MMP	0	1	11	12
TIMP-2 , TIMP-3 and TIMP-4 are highly potent inhibitors of MT1-MMP .	TIMP-2, TIMP-3 and TIMP-4 are highly potent inhibitors of MT1-MMP.	0	11	are highly potent inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MT1-MMP	MT1-MMP	MT1-MMP	2	3	10	11
Specifically , TIMP-3 inhibits MT1-MMP , MMP-3 and TNFalpha converting enzyme ( TACE ) , which in turn suppresses the release of MMP-2 , MMP-9 and TNFalpha respectively ( XREF_FIG ) .	Specifically, TIMP-3 inhibits MT1-MMP, MMP-3 and TNFalpha converting enzyme (TACE), which in turn suppresses the release of MMP-2, MMP-9 and TNFalpha respectively (XREF_FIG).	2	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MT1-MMP	MT1-MMP	MT1-MMP	2	3	4	5
TIMP-2 , TIMP-3 , and TIMP-4 are highly potent inhibitors of MT1-MMP .	TIMP-2, TIMP-3, and TIMP-4 are highly potent inhibitors of MT1-MMP.	0	12	are highly potent inhibitors	Negative_activation_copula_1	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MT1-MMP	MT1-MMP	MT1-MMP	2	3	11	12
TIMP3 is known to inhibit ADAM17 ( DLK1 sheddase ) and MMP14 ( implicated in extracellular matrix turnover ) .	TIMP3 is known to inhibit ADAM17 (DLK1 sheddase) and MMP14 (implicated in extracellular matrix turnover).	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP3	TIMP3	TIMP3	MMP14	MMP14	MMP14	0	1	11	12
Both TIMP3 and batimastat inhibit MMP14 , and we found that inhibiting MMP14 function by either knockdown or pharmacological inhibitor blocked adipogenesis , consistent with previous data .	Both TIMP3 and batimastat inhibit MMP14, and we found that inhibiting MMP14 function by either knockdown or pharmacological inhibitor blocked adipogenesis, consistent with previous data.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP3	TIMP3	TIMP3	MMP14	MMP14	MMP14	1	2	5	6
TIMP-2 and TIMP-3 can block MT1-MMP activity to interfere with further tube morphogenesis ( by inhibiting sprouting and lumen formation ) and also inhibit tube regression mediated by MMP-1 and MMP-10 .	TIMP-2 and TIMP-3 can block MT1-MMP activity to interfere with further tube morphogenesis (by inhibiting sprouting and lumen formation) and also inhibit tube regression mediated by MMP-1 and MMP-10.	0	6	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MT1-MMP	MT1-MMP	MT1-MMP	2	3	5	6
Because TIMP-3 , for instance , both inhibits MT1-MMP ( which can activate other MMPs ) and inhibits the shedding of TNF-alpha converting enzyme and IL-6 , therapeutic application of a TIMP-3-like molecule could potentially prevent both the cytokine driven activation of synovial cells and cytokine independent activation of RA synovial fibroblasts [ XREF_BIBR ] .	Because TIMP-3, for instance, both inhibits MT1-MMP (which can activate other MMPs) and inhibits the shedding of TNF-alpha converting enzyme and IL-6, therapeutic application of a TIMP-3-like molecule could potentially prevent both the cytokine driven activation of synovial cells and cytokine independent activation of RA synovial fibroblasts [XREF_BIBR].	1	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MT1-MMP	MT1-MMP	MT1-MMP	1	2	8	9
In particular , TIMP-3 inhibits MT1-MMP , which is essential to proMMP-13 activation [ XREF_BIBR ] .	In particular, TIMP-3 inhibits MT1-MMP, which is essential to proMMP-13 activation [XREF_BIBR].	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MT1-MMP	MT1-MMP	MT1-MMP	3	4	5	6
Recently oxysterols , which activate the Liver X Receptor ( LXR ) , have been implicated in producing sEng , by upregulating matrix metalloproteinase-14 ( MMP14 ; cleaves endoglin to produce sEng ) and down-regulating tissue inhibitor of metalloproteinase-3 ( TIMP-3 ; inhibitor of MMP14 ) .	Recently oxysterols, which activate the Liver X Receptor (LXR), have been implicated in producing sEng, by upregulating matrix metalloproteinase-14 (MMP14; cleaves endoglin to produce sEng) and down-regulating tissue inhibitor of metalloproteinase-3 (TIMP-3; inhibitor of MMP14).	38	45	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MMP14	MMP14	MMP14	40	41	44	45
TIMP-1 has high affinity and rate of MMP-9 inhibition , while TIMP-3 effectively inhibits MMP-9 , MMP-2 , and MT1-MMP .	TIMP-1 has high affinity and rate of MMP-9 inhibition, while TIMP-3 effectively inhibits MMP-9, MMP-2, and MT1-MMP.	11	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MT1-MMP	MT1-MMP	MT1-MMP	11	12	19	20
TIMP-1 and TIMP-4 act as inhibitors against most types of MMPs , whereas they do not fully work as MMP-14 inhibitors ; MMP-14 activity is suppressed by TIMP-2 and TIMP-3 XREF_BIBR , XREF_BIBR , XREF_BIBR .	TIMP-1 and TIMP-4 act as inhibitors against most types of MMPs, whereas they do not fully work as MMP-14 inhibitors; MMP-14 activity is suppressed by TIMP-2 and TIMP-3 XREF_BIBR, XREF_BIBR, XREF_BIBR.	22	30	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MMP-14	MMP-14	MMP-14	29	30	22	23
To test whether TIMP3 , which can block MMP14 activity and accumulated in RDEB samples , was involved in MMP14 inactivation recombinant TIMP3 was also added to control cells and indeed blocked collagen I degradation ( XREF_FIG ) .	To test whether TIMP3, which can block MMP14 activity and accumulated in RDEB samples, was involved in MMP14 inactivation recombinant TIMP3 was also added to control cells and indeed blocked collagen I degradation (XREF_FIG).	3	17	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP3	TIMP3	TIMP3	MMP14	MMP14	MMP14	3	4	8	9
A Hh regulated secreted factor , TIMP3 , inhibits MMP14 and restrains adipogenesis , pointing to a strategy for reducing fatty degeneration and improving the regeneration of skeletal muscle following injury .	A Hh regulated secreted factor, TIMP3, inhibits MMP14 and restrains adipogenesis, pointing to a strategy for reducing fatty degeneration and improving the regeneration of skeletal muscle following injury.	1	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP3	TIMP3	TIMP3	MMP14	MMP14	MMP14	6	7	9	10
The hamartin and tuberin complex suppresses the activation of the small GTPase Rheb ( ras homolog enriched in brain ) , through a GTPase activating domain near the C-terminus of tuberin .	The hamartin and tuberin complex suppresses the activation of the small GTPase Rheb (ras homolog enriched in brain), through a GTPase activating domain near the C-terminus of tuberin.	1	19	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	hamartin	hamartin and tuberin complex	hamartin	ras homolog enriched in brain	ras homolog enriched in brain	ras homolog enriched in brain	1	2	14	19
The Tsc1 and Tsc2 complex inhibits the activity of Rheb via the GAP function of Tsc2 .	The Tsc1 and Tsc2 complex inhibits the activity of Rheb via the GAP function of Tsc2.	1	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc1	Tsc1 and Tsc2 complex	tsc1	Rheb	Rheb	rheb	1	2	9	10
The tuberous sclerosis 1 ( TSC1 ) and TSC2 form a complex that inactivates RHEB through its GAP ( GTPase activating protein ) activity , thereby suppressing mTORC1 activity .	The tuberous sclerosis 1 (TSC1) and TSC2 form a complex that inactivates RHEB through its GAP (GTPase activating protein) activity, thereby suppressing mTORC1 activity.	0	15	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1) and TSC2 form a complex	tsc1	RHEB	RHEB	rheb	5	6	14	15
Therefore , Akt mediated inhibition of the TSC1 and TSC2 complex serves to activate Rheb and mTORC1 .	Therefore, Akt mediated inhibition of the TSC1 and TSC2 complex serves to activate Rheb and mTORC1.	7	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	Rheb	Rheb	rheb	7	8	14	15
TSC1 and TSC2 complex inhibits Rheb ( Ras homolog enriched in brain ) GTPase , which activates mTORC1 .	TSC1 and TSC2 complex inhibits Rheb (Ras homolog enriched in brain) GTPase, which activates mTORC1.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	Rheb	Rheb	rheb	0	1	5	6
In a normal situation , the TSC1 and TSC2 complex inactivates RHEB by stimulating the conversion of RHEB-GTP to RHEB-GDP , which subsequently downregulates the mammallian target of rapamycin ( mTOR ) signaling pathway XREF_BIBR .	In a normal situation, the TSC1 and TSC2 complex inactivates RHEB by stimulating the conversion of RHEB-GTP to RHEB-GDP, which subsequently downregulates the mammallian target of rapamycin (mTOR) signaling pathway XREF_BIBR.	6	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	RHEB	RHEB	rheb	6	7	11	12
Rheb is inhibited by the TSC1 and TSC2 complex , which integrates energetic and growth factor signals through its phosphorylation by AMPK and Akt and PKB , respectively [ XREF_BIBR ] ( XREF_FIG ) .	Rheb is inhibited by the TSC1 and TSC2 complex, which integrates energetic and growth factor signals through its phosphorylation by AMPK and Akt and PKB, respectively [XREF_BIBR] (XREF_FIG).	0	9	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	Rheb	Rheb	rheb	5	6	0	1
This makes the TSC1 and TSC2 complex unable to inactivate Rheb , promoting mTORC1 activation .	This makes the TSC1 and TSC2 complex unable to inactivate Rheb, promoting mTORC1 activation.	3	11	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	Rheb	Rheb	rheb	3	4	10	11
Therefore , the TSC1 and TSC2 complex inhibits mTORC1 activation by stimulating the intrinsic GTPase activity of Rheb , leading to conversion of active GTP bound Rheb to the inactive GDP bound form .	Therefore, the TSC1 and TSC2 complex inhibits mTORC1 activation by stimulating the intrinsic GTPase activity of Rheb, leading to conversion of active GTP bound Rheb to the inactive GDP bound form.	3	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	Rheb	Rheb	rheb	3	4	17	18
On the other hand , it has been found that TORC1 is activated by the Ras family Rheb GTPase , which is negatively regulated by the Tsc1 and Tsc2 complex that acts as Rheb GTPase activating protein ( GAP ) [ XREF_BIBR ] .	On the other hand, it has been found that TORC1 is activated by the Ras family Rheb GTPase, which is negatively regulated by the Tsc1 and Tsc2 complex that acts as Rheb GTPase activating protein (GAP) [XREF_BIBR].	17	30	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Tsc1	Tsc1 and Tsc2 complex	tsc1	Rheb	Rheb	rheb	26	27	17	18
Rheb is inhibited by the GAP activity of the TSC1 and TSC2 complex , which promotes the turnover of GTP to GDP .	Rheb is inhibited by the GAP activity of the TSC1 and TSC2 complex, which promotes the turnover of GTP to GDP.	0	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	Rheb	Rheb	rheb	9	10	0	1
Therefore , inhibition of TSC1 and TSC2 heterodimer increases the activity of Rheb which subsequently leads to activation of mTORC1 .	Therefore, inhibition of TSC1 and TSC2 heterodimer increases the activity of Rheb which subsequently leads to activation of mTORC1.	4	13	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 heterodimer	tsc1	Rheb	Rheb	rheb	4	5	12	13
mTORC1 is activated by the Rheb GTPase , which , in turn , is inhibited by the TSC1 and TSC2 complex .	mTORC1 is activated by the Rheb GTPase, which, in turn, is inhibited by the TSC1 and TSC2 complex.	5	21	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	Rheb	Rheb	rheb	17	18	5	6
Greater modulation among HNSCC lines expressing low wt p53 than those over-expressing mt p53 protein suggested that decreased p53 expression might enhance activation of NF-kappaB , STAT3 and BCL-XL .	Greater modulation among HNSCC lines expressing low wt p53 than those over-expressing mt p53 protein suggested that decreased p53 expression might enhance activation of NF-kappaB, STAT3 and BCL-XL.	18	29	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53 expression	p53	BCL-XL	BCL-XL	bcl-xl	18	19	28	29
However , the R103E Bcl-xL mutation was previously shown to disrupt binding to p53 in vitro 8 , and was associated with reduced sequestration of p53 in UV treated cells ( XREF_FIG ) , while in vitro it only modestly reduced Bcl-xL binding to pro apoptotic BH3 domains ( XREF_FIG , XREF_FIG , XREF_SUPPLEMENTARY ) .	However, the R103E Bcl-xL mutation was previously shown to disrupt binding to p53 in vitro 8, and was associated with reduced sequestration of p53 in UV treated cells (XREF_FIG), while in vitro it only modestly reduced Bcl-xL binding to pro apoptotic BH3 domains (XREF_FIG, XREF_FIG, XREF_SUPPLEMENTARY).	23	47	reduced	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-xL	Bcl-xL	Bcl-xL	25	26	41	42
Knockout of p53 in addition to EAF2 in the murine model further increased p-STAT3 ( Tyr705 ) staining and increased Bcl-XL staining , indicating the importance of p53 in STAT3 signaling regulation when EAF2 is absent ( see XREF_FIG ) .	Knockout of p53 in addition to EAF2 in the murine model further increased p-STAT3 (Tyr705) staining and increased Bcl-XL staining, indicating the importance of p53 in STAT3 signaling regulation when EAF2 is absent (see XREF_FIG).	0	21	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-XL	Bcl-XL	Bcl-XL	2	3	20	21
MCD feeding enhanced hepatic p53 expression , corresponding to approximately 50 % fall in serum IGF-1 , decreased Bcl-XL , enhanced Bid cleavage to tBid , and up-regulation of p21 .	MCD feeding enhanced hepatic p53 expression, corresponding to approximately 50% fall in serum IGF-1, decreased Bcl-XL, enhanced Bid cleavage to tBid, and up-regulation of p21.	4	19	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53 expression	p53	Bcl-XL	Bcl-XL	bcl-xl	4	5	18	19
p53 modulates both the inhibition of BCL-xL by ABT-737 and death signals downstream of BCL-xL .	p53 modulates both the inhibition of BCL-xL by ABT-737 and death signals downstream of BCL-xL.	0	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL-xL	BCL-xL	BCL-xL	0	1	6	7
Apoptosis was associated with downregulated Bcl-xL ( anti-apoptotic protein ) , downregulated GATA4 ( transcriptional regulator of Bcl-xL ) , and upregulated p53 ( negative regulator of GATA4 gene transcription ) .	Apoptosis was associated with downregulated Bcl-xL (anti-apoptotic protein), downregulated GATA4 (transcriptional regulator of Bcl-xL), and upregulated p53 (negative regulator of GATA4 gene transcription).	11	25	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-xL	Bcl-xL	Bcl-xL	22	23	17	18
Bcl-XL had a significant effect on reducing 7-AAD positive cells treated with EGFP-p53 fused to TOM , XL , and OTC ( XREF_FIG ) .	Bcl-XL had a significant effect on reducing 7-AAD positive cells treated with EGFP-p53 fused to TOM, XL, and OTC (XREF_FIG).	0	13	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	EGFP-p53	EGFP-p53	EGFP-p53	Bcl-XL	Bcl-XL	Bcl-XL	12	13	0	1
[ XREF_BIBR ] It has been suggested that tumor cells might escape from tumor necrosis factor receptor mediated-apoptosis by expressing DcR3 , which blocks FasL function .	[XREF_BIBR] It has been suggested that tumor cells might escape from tumor necrosis factor receptor mediated-apoptosis by expressing DcR3, which blocks FasL function.	19	25	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	20	21	24	25
Certain tumours may escape FasL dependent immune-cytotoxic attack by expressing DcR3 , which blocks FasL function .	Certain tumours may escape FasL dependent immune-cytotoxic attack by expressing DcR3, which blocks FasL function.	9	15	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	10	11	14	15
Our data revealed that DcR3 pretreatment decreased FasL induced peripheral lymphocyte apoptosis .	Our data revealed that DcR3 pretreatment decreased FasL induced peripheral lymphocyte apoptosis.	4	8	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	4	5	7	8
In this study , we demonstrated that siRNA knockdown of DcR3 enhanced FasL induced apoptotic activity in human MFH cell lines and that FasL treatment with DcR3 inhibition significantly suppressed MFH cell proliferation .	In this study, we demonstrated that siRNA knockdown of DcR3 enhanced FasL induced apoptotic activity in human MFH cell lines and that FasL treatment with DcR3 inhibition significantly suppressed MFH cell proliferation.	8	13	enhanced	Positive_activation_token_1_verb	Negative_activation	Negative_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	10	11	12	13
Consequently , DcR3 suppression reduces competitive FasL suppression .	Consequently, DcR3 suppression reduces competitive FasL suppression.	2	7	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	2	3	6	7
DcR3 competes with Fas receptor for binding to FasL and inhibits the FasL and Fas apoptotic pathway .	DcR3 competes with Fas receptor for binding to FasL and inhibits the FasL and Fas apoptotic pathway.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	0	1	12	13
On the other hand , even without specific target cell delivery systems , animal studies modeling ARDS have shown promising beneficial effects on survival and histopathological changes by using a number of systemic or intratracheal apoptosis based treatments , including blockade of FasL by decoy receptor-3 [ XREF_BIBR ] , Fas : Ig fusion protein [ XREF_BIBR ] or Fas-siRNA [ XREF_BIBR ] and pan-caspase inhibition by z-VAD-fmk [ XREF_BIBR ] .	On the other hand, even without specific target cell delivery systems, animal studies modeling ARDS have shown promising beneficial effects on survival and histopathological changes by using a number of systemic or intratracheal apoptosis based treatments, including blockade of FasL by decoy receptor-3 [XREF_BIBR], Fas : Ig fusion protein [XREF_BIBR] or Fas-siRNA [XREF_BIBR] and pan-caspase inhibition by z-VAD-fmk [XREF_BIBR].	40	65	blockade	Negative_activation_token_2_noun	Negative_activation	Negative_activation	decoy receptor-3	decoy receptor-3	decoy receptor-3	FasL	FasL	FasL	44	46	42	43
In the current study , we demonstrate that TR6 can block the lethal activity of FasL in multiple in vitro systems , and extend this finding to an in vivo model of hepatitis .	In the current study, we demonstrate that TR6 can block the lethal activity of FasL in multiple in vitro systems, and extend this finding to an in vivo model of hepatitis.	8	23	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TR6	TR6	TR6	FasL	FasL	FasL	8	9	15	16
By competing with Fas and blocking FasL signaling , DcR3 might accelerate overactive immune responses and contribute to the development of autoimmune disorders .	By competing with Fas and blocking FasL signaling, DcR3 might accelerate overactive immune responses and contribute to the development of autoimmune disorders.	6	16	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	9	10	6	7
Human primary hepatocytes , HT-29 cells and Jurkat cells were assayed for viability to demonstrate TR6 inhibition of FasL mediated cytotoxicity in vitro .	Human primary hepatocytes, HT-29 cells and Jurkat cells were assayed for viability to demonstrate TR6 inhibition of FasL mediated cytotoxicity in vitro.	15	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TR6	TR6	TR6	FasL	FasL	FasL	15	16	18	19
These results indicate that DcR3 pretreatment decreases FasL induced peripheral lymphocyte apoptosis .	These results indicate that DcR3 pretreatment decreases FasL induced peripheral lymphocyte apoptosis.	4	8	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	4	5	7	8
DcR3 has been considered to potentially have therapeutic value in treating fulminant hepatic failure , because recombinant soluble DcR3 could block exogenous FasL mediated hepatocyte apoptosis in rodent hepatitis models .	DcR3 has been considered to potentially have therapeutic value in treating fulminant hepatic failure, because recombinant soluble DcR3 could block exogenous FasL mediated hepatocyte apoptosis in rodent hepatitis models.	16	23	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	18	19	22	23
FasL is inhibited by decoy receptor-3 ( DcR3 ) , a naturally occurring decoy receptor .	FasL is inhibited by decoy receptor-3 (DcR3), a naturally occurring decoy receptor.	0	6	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	decoy receptor-3	decoy receptor-3	decoy receptor-3	FasL	FasL	FasL	4	6	0	1
Importantly , TRAIL-R4 expression prevents TRAIL induced tumor regression in nude mice , but tumor regression induced by TRAIL can be restored with chemotherapy .	Importantly, TRAIL-R4 expression prevents TRAIL induced tumor regression in nude mice, but tumor regression induced by TRAIL can be restored with chemotherapy.	2	6	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAIL-R4	TRAIL-R4 expression	trail-r4	TRAIL	TRAIL	trail	2	3	5	6
Therefore , the decoy receptors TRAIL receptor-3 and TRAIL receptor-4 were initially proposed to negatively regulate TRAIL signaling by competing with TRAIL receptor-1 and TRAIL receptor-2 for TRAIL binding .	Therefore, the decoy receptors TRAIL receptor-3 and TRAIL receptor-4 were initially proposed to negatively regulate TRAIL signaling by competing with TRAIL receptor-1 and TRAIL receptor-2 for TRAIL binding.	8	17	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAIL receptor-4	TRAIL receptor-4	TRAIL receptor-4	TRAIL	TRAIL	TRAIL	8	10	16	17
TRAIL-R3 and TRAIL-R4 seem to block apoptotic signaling of TRAIL .	TRAIL-R3 and TRAIL-R4 seem to block apoptotic signaling of TRAIL.	0	10	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAIL-R4	TRAIL-R4	TRAIL-R4	TRAIL	TRAIL	TRAIL	2	3	9	10
XREF_BIBR concluded that increased expression of DcR2 , which is a decoy receptor that selectively inhibits TRAIL signaling , reduced in vitro chemosensitivity to doxorubicin and etoposide , while Wang and El-Deiry concluded that knockdown of the TRAIL receptor DR5 conferred resistance to 5-fluorouracil XREF_BIBR .	XREF_BIBR concluded that increased expression of DcR2, which is a decoy receptor that selectively inhibits TRAIL signaling, reduced in vitro chemosensitivity to doxorubicin and etoposide, while Wang and El-Deiry concluded that knockdown of the TRAIL receptor DR5 conferred resistance to 5-fluorouracil XREF_BIBR.	4	17	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	DcR2	expression of DcR2	dcr2	TRAIL	TRAIL	trail	6	7	16	17
TRAILR4 is incapable of signaling apoptosis upon TRAIL binding and sequesters TRAIL from binding to TRAILR1 and R2 , inhibiting apoptotic signaling .	TRAILR4 is incapable of signaling apoptosis upon TRAIL binding and sequesters TRAIL from binding to TRAILR1 and R2, inhibiting apoptotic signaling.	0	12	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAILR4	TRAILR4	TRAILR4	TRAIL	TRAIL	TRAIL	0	1	11	12
The specificity of DcR1- and DcR2 mediated TRAIL inhibition reveals an additional level of complexity for the regulation of TRAIL signaling .	The specificity of DcR1- and DcR2 mediated TRAIL inhibition reveals an additional level of complexity for the regulation of TRAIL signaling.	1	8	mediated	Positive_early_activation	Negative_activation	Negative_activation	DcR2	DcR2	DcR2	TRAIL	TRAIL	TRAIL	5	6	7	8
TRAILR4 is unable to induce cell death upon TRAIL binding , but rather sequesters TRAIL away from the proapoptotic TRAIL receptors .	TRAILR4 is unable to induce cell death upon TRAIL binding, but rather sequesters TRAIL away from the proapoptotic TRAIL receptors.	0	15	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAILR4	TRAILR4	TRAILR4	TRAIL	TRAIL	TRAIL	0	1	14	15
TRAIL-R3 ( DcR1 ) and TRAIL-R4 ( DcR2 ) can specifically inhibit TRAIL signaling at the membrane level [ XREF_BIBR , XREF_BIBR ] .	TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2) can specifically inhibit TRAIL signaling at the membrane level [XREF_BIBR, XREF_BIBR].	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAIL-R4	TRAIL-R4	TRAIL-R4	TRAIL	TRAIL	TRAIL	5	6	12	13
As mentioned above , we have previously shown that full-length TRAP150 inhibits the binding of full-length PSF to its target sequence on the CD45 pre-mRNA .	As mentioned above, we have previously shown that full-length TRAP150 inhibits the binding of full-length PSF to its target sequence on the CD45 pre-mRNA.	9	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAP150	TRAP150	TRAP150	PSF	PSF	PSF	10	11	16	17
TRAP150 directly blocks the binding of PSF RRMs to RNA , not protein .	TRAP150 directly blocks the binding of PSF RRMs to RNA, not protein.	0	7	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAP150	TRAP150	TRAP150	PSF	PSF	PSF	0	1	6	7
Similarly , TRAP150 antagonizes the effect of PSF on transcription coupled splicing of a CD44 derived minigene ,111 although it is unclear whether the primary activity of PSF in this assay is regulation of transcription or splicing .	Similarly, TRAP150 antagonizes the effect of PSF on transcription coupled splicing of a CD44 derived minigene,111 although it is unclear whether the primary activity of PSF in this assay is regulation of transcription or splicing.	2	8	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAP150	TRAP150	TRAP150	PSF	PSF	PSF	2	3	7	8
TRAP150 , in turn , blocks the binding of PSF to RNA .	TRAP150, in turn, blocks the binding of PSF to RNA.	0	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAP150	TRAP150	TRAP150	PSF	PSF	PSF	0	1	9	10
Here we demonstrate that in resting T cells PSF is directly phosphorylated by GSK3 thus promoting interaction of PSF with TRAP150 which prevents PSF from binding CD45 pre-mRNA .	Here we demonstrate that in resting T cells PSF is directly phosphorylated by GSK3 thus promoting interaction of PSF with TRAP150 which prevents PSF from binding CD45 pre-mRNA.	15	24	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAP150	TRAP150	TRAP150	PSF	PSF	PSF	20	21	23	24
In our model , the crucial regulatory point is the phosphorylation dependent interaction of PSF with TRAP150 , which prevents PSF from binding to the ESS1 RNA .	In our model, the crucial regulatory point is the phosphorylation dependent interaction of PSF with TRAP150, which prevents PSF from binding to the ESS1 RNA.	14	21	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAP150	TRAP150	TRAP150	PSF	PSF	PSF	16	17	20	21
Importantly , regardless of the actual mechanism of TRAP150 inhibition of PSF , our results add to a growing body of evidence that suggests that PSF function is regulated through cell state specific competition among protein , RNA and DNA interactors .	Importantly, regardless of the actual mechanism of TRAP150 inhibition of PSF, our results add to a growing body of evidence that suggests that PSF function is regulated through cell state specific competition among protein, RNA and DNA interactors.	8	12	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TRAP150	TRAP150	TRAP150	PSF	PSF	PSF	8	9	11	12
However , the addition of purified TRAP150 specifically inhibits the RNA binding capability of PSF purified from resting cells ( XREF_FIG , top ) with little impact on the RNA binding of PSF purified from stimulated cells ( XREF_FIG , bottom ) .	However, the addition of purified TRAP150 specifically inhibits the RNA binding capability of PSF purified from resting cells (XREF_FIG, top) with little impact on the RNA binding of PSF purified from stimulated cells (XREF_FIG, bottom).	3	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAP150	TRAP150	TRAP150	PSF	PSF	PSF	6	7	14	15
TRAP150 directly inhibits binding of PSF to the ESS1 RNA .	TRAP150 directly inhibits binding of PSF to the ESS1 RNA.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAP150	TRAP150	TRAP150	PSF	PSF	PSF	0	1	5	6
Three closely related receptors bind Apo2L : DR4 and DR5 , which contain cytoplasmic death domains and signal apoptosis , and DcR1 , a decoy receptor that lacks a cytoplasmic tail and inhibits Apo2L function [ 3-5 ] .	Three closely related receptors bind Apo2L : DR4 and DR5, which contain cytoplasmic death domains and signal apoptosis, and DcR1, a decoy receptor that lacks a cytoplasmic tail and inhibits Apo2L function [3-5].	4	34	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	DcR1	DcR1	DcR1	Apo2L	Apo2L	Apo2L	21	22	33	34
This tendency might be also affected by the constitutive expression of the decoy receptor for TRAIL , TRAIL-R3 ( XREF_FIG ) , which inhibits TRAIL signaling XREF_BIBR , or by the different sensitivity to soluble TRAIL ( XREF_SUPPLEMENTARY ) .	This tendency might be also affected by the constitutive expression of the decoy receptor for TRAIL, TRAIL-R3 (XREF_FIG), which inhibits TRAIL signaling XREF_BIBR, or by the different sensitivity to soluble TRAIL (XREF_SUPPLEMENTARY).	15	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAIL-R3	TRAIL-R3	TRAIL-R3	TRAIL	TRAIL	TRAIL	17	18	24	25
Thus , TRAIL receptor-3 may function as an antagonistic decoy receptor to attenuate the cytotoxic effect of TRAIL in most tissues that are TRAIL+ , DR4+ , and DR5+ .	Thus, TRAIL receptor-3 may function as an antagonistic decoy receptor to attenuate the cytotoxic effect of TRAIL in most tissues that are TRAIL+, DR4+, and DR5+.	2	18	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRAIL receptor-3	TRAIL receptor-3	TRAIL receptor-3	TRAIL	TRAIL	TRAIL	2	4	17	18
According to the combination of the reported and our tests , we deemed that in HNSCC TRIM24 may degrade the p53 protein as a E3-ubiquitin ligase but may not be a drive factor resposible for p53 degradation and not directly influence the p53 protein stability .	According to the combination of the reported and our tests, we deemed that in HNSCC TRIM24 may degrade the p53 protein as a E3-ubiquitin ligase but may not be a drive factor resposible for p53 degradation and not directly influence the p53 protein stability.	16	21	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	16	17	20	21
TRIM24 deletion in human breast cancers leads to p53 dependent apoptosis 14 .	TRIM24 deletion in human breast cancers leads to p53 dependent apoptosis 14.	0	9	leads	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	0	1	8	9
As a member of the tripartite motif ( TRIM ) protein family , which is defined as E3 ubiquitin ligases , TRIM24 can ubiquitylate and negatively regulates the level of p53 [ XREF_BIBR , XREF_BIBR ] .	As a member of the tripartite motif (TRIM) protein family, which is defined as E3 ubiquitin ligases, TRIM24 can ubiquitylate and negatively regulates the level of p53 [XREF_BIBR, XREF_BIBR].	21	34	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	21	22	30	31
For example , TRIM13 and TRIM19 have tumor suppressive activity through a direct effect on the p53 regulatory protein , MDM2 , while TRIM24 and TRIM28 suppress p53 stability and expression [ XREF_BIBR ] .	For example, TRIM13 and TRIM19 have tumor suppressive activity through a direct effect on the p53 regulatory protein, MDM2, while TRIM24 and TRIM28 suppress p53 stability and expression [XREF_BIBR].	23	28	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	23	24	27	28
TRIM24 , TRIM28 , TRIM29 ( also known as ataxia-telangiectasia group D complementing , or ATDC ) and TRIM39 all inhibit p53 activity by increasing p53 degradation and/or nuclear export , largely by controlling p53 ubiquitylation .	TRIM24, TRIM28, TRIM29 (also known as ataxia-telangiectasia group D complementing, or ATDC) and TRIM39 all inhibit p53 activity by increasing p53 degradation and/or nuclear export, largely by controlling p53 ubiquitylation.	0	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	0	1	21	22
Tollip inhibits Irak signaling by targeting it for ubiquitination [ XREF_BIBR ] .	Tollip inhibits Irak signaling by targeting it for ubiquitination [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tollip	Tollip	Tollip	Irak	Irak	Irak	0	1	2	3
IRAK-M acts by preventing dissociation of IRAK-1 from MyD88 or inducing other negative regulators A20 , SHIP-1 , inhibitor of NF-kappaB-alpha [ XREF_BIBR , XREF_BIBR ] , whereas Tollip suppresses IRAK1 activation [ XREF_BIBR ] .	IRAK-M acts by preventing dissociation of IRAK-1 from MyD88 or inducing other negative regulators A20, SHIP-1, inhibitor of NF-kappaB-alpha [XREF_BIBR, XREF_BIBR], whereas Tollip suppresses IRAK1 activation [XREF_BIBR].	28	31	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tollip	Tollip	Tollip	IRAK1	IRAK1	IRAK1	28	29	30	31
Toll interacting protein ( TOLLIP ) interacts with many types of TLR signaling downstream pathways and potently inhibits the activity of IRAK after TLR activation .	Toll interacting protein (TOLLIP) interacts with many types of TLR signaling downstream pathways and potently inhibits the activity of IRAK after TLR activation.	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Toll interacting protein	Toll interacting protein	Toll interacting protein	IRAK	IRAK	IRAK	0	3	21	22
In fact , Tollip overexpression dramatically inhibits IRAK1 kinase activity [ XREF_BIBR ] and suppresses NF-kappaB activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In fact, Tollip overexpression dramatically inhibits IRAK1 kinase activity [XREF_BIBR] and suppresses NF-kappaB activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tollip	Tollip overexpression	tollip	IRAK1	IRAK1	irak1	3	4	7	8
Tollip also negatively regulates IRAK-1 and IRAK-2 by directly binding to these proteins via the CUE domain and inhibiting auto-phosphorylation .	Tollip also negatively regulates IRAK-1 and IRAK-2 by directly binding to these proteins via the CUE domain and inhibiting auto-phosphorylation.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tollip	Tollip	Tollip	IRAK-1	IRAK-1	IRAK-1	0	1	4	5
TOLLIP inhibits the activation of IRAK1 by IRAK 4 .	TOLLIP inhibits the activation of IRAK1 by IRAK 4.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TOLLIP	TOLLIP	TOLLIP	IRAK1	IRAK1	IRAK1	0	1	5	6
Taken together , we speculate that salinomycin upregulates DDIT3 due to an ER stress response and , in turn , induces TRIB3 expression , which consequently inhibits AKT1 activation and MTORC1 , leading to autophagy .	Taken together, we speculate that salinomycin upregulates DDIT3 due to an ER stress response and, in turn, induces TRIB3 expression, which consequently inhibits AKT1 activation and MTORC1, leading to autophagy.	21	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIB3	TRIB3 expression	trib3	AKT1	AKT1	akt1	21	22	27	28
In addition , TRB-3 can inhibit serine threonine kinase AKT1 and , therefore , can negatively regulate cell survival XREF_BIBR .	In addition, TRB-3 can inhibit serine threonine kinase AKT1 and, therefore, can negatively regulate cell survival XREF_BIBR.	3	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB-3	TRB-3	TRB-3	AKT1	AKT1	AKT1	3	4	9	10
TRIB3 is a negative regulator of NF-kappaB and can also negatively regulate the cell survival serine threonine kinase AKT1 [ XREF_BIBR ] .	TRIB3 is a negative regulator of NF-kappaB and can also negatively regulate the cell survival serine threonine kinase AKT1 [XREF_BIBR].	0	20	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIB3	TRIB3	TRIB3	AKT1	AKT1	AKT1	0	1	18	19
GILZ expression was low in dormant cell derived cultures , and re-expression of GILZ inactivated FOXO3A and its downstream target , p21CIP1 .	GILZ expression was low in dormant cell derived cultures, and re-expression of GILZ inactivated FOXO3A and its downstream target, p21CIP1.	11	19	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GILZ	re-expression of GILZ	gilz	FOXO3A	FOXO3A	foxo3a	13	14	15	16
Thus , GILZ KD should prevent the nuclear exclusion of FOXO3A in dormant DMC derived cells but not in maternal cells .	Thus, GILZ KD should prevent the nuclear exclusion of FOXO3A in dormant DMC derived cells but not in maternal cells.	2	11	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GILZ	GILZ	GILZ	FOXO3A	FOXO3A	FOXO3A	2	3	10	11
On the other hand , GILZ inhibits FOXO3 transcriptional activity via CRM1 ( a nuclear transport receptor )-dependent nuclear exclusion of FOXO3 , leading to decreased expression of itself and BIM , a pro apoptotic member of the Bcl-2 family .	On the other hand, GILZ inhibits FOXO3 transcriptional activity via CRM1 (a nuclear transport receptor)-dependent nuclear exclusion of FOXO3, leading to decreased expression of itself and BIM, a pro apoptotic member of the Bcl-2 family.	5	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GILZ	GILZ	GILZ	FOXO3	FOXO3	FOXO3	5	6	7	8
Furthermore , GILZ inhibits FoxO3 transcriptional activity that leads to inhibition of Bim expression but also to down-regulation of GILZ itself .	Furthermore, GILZ inhibits FoxO3 transcriptional activity that leads to inhibition of Bim expression but also to down-regulation of GILZ itself.	2	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GILZ	GILZ	GILZ	FoxO3	FoxO3	FoxO3	2	3	4	5
GILZ inhibits FOXO1 , FOXO3 , and FOXO4 transcriptional activities measured with natural or synthetic FOXO responsive promoters in HL-60 cells .	GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO responsive promoters in HL-60 cells.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GILZ	GILZ	GILZ	FOXO3	FOXO3	FOXO3	0	1	4	5
In regards to down-regulation of Akt activity , the carboxyl-terminal modulator protein ( CTMP ) binds to the carboxyl-terminal regulatory domain of Akt1 at the plasma membrane to prevent Akt1 from phosphorylation .	In regards to down-regulation of Akt activity, the carboxyl-terminal modulator protein (CTMP) binds to the carboxyl-terminal regulatory domain of Akt1 at the plasma membrane to prevent Akt1 from phosphorylation.	9	30	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	carboxyl-terminal modulator protein	carboxyl-terminal modulator protein	carboxyl-terminal modulator protein	Akt1	Akt1	Akt1	9	12	29	30
In addition , the protective effect of ATF3 was mediated by the downregulation of carboxyl-terminal modulator protein ( CTMP ) , a proapoptotic factor that inhibits the antiapoptotic protein kinase B cascade [ XREF_BIBR ] .	In addition, the protective effect of ATF3 was mediated by the downregulation of carboxyl-terminal modulator protein (CTMP), a proapoptotic factor that inhibits the antiapoptotic protein kinase B cascade [XREF_BIBR].	14	31	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	carboxyl-terminal modulator protein	carboxyl-terminal modulator protein	carboxyl-terminal modulator protein	protein kinase B	protein kinase B	protein kinase B	14	17	28	31
Carboxyl-terminal modulator protein ( CTMP ) binds specifically to the carboxyl-terminal regulatory domain of Akt1 at the plasma membrane to prevent Akt1 from phosphorylation .	Carboxyl-terminal modulator protein (CTMP) binds specifically to the carboxyl-terminal regulatory domain of Akt1 at the plasma membrane to prevent Akt1 from phosphorylation.	0	22	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Carboxyl-terminal modulator protein	Carboxyl-terminal modulator protein	Carboxyl-terminal modulator protein	Akt1	Akt1	Akt1	0	3	21	22
Interestingly , it was reported that p53 downregulates Ets1 and Ets2 at transcriptional level , although the molecular mechanism for this downregulation has not been elucidated .	Interestingly, it was reported that p53 downregulates Ets1 and Ets2 at transcriptional level, although the molecular mechanism for this downregulation has not been elucidated.	6	13	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Ets1	Ets1	Ets1	6	7	8	9
In addition to Sp1 , p53 has been shown to directly interact with ETS1 and repress ETS1 mediated activation of target genes , such as IKKalpha XREF_BIBR and TXSA XREF_BIBR .	In addition to Sp1, p53 has been shown to directly interact with ETS1 and repress ETS1 mediated activation of target genes, such as IKKalpha XREF_BIBR and TXSA XREF_BIBR.	5	18	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	ETS1	ETS1	ETS1	5	6	16	17
Wildtype p53 , but not mutant p53 , was found to repress the Ets1 promoter [ XREF_BIBR ] and , in endothelial cells , retinoic acid negatively modulates Ets1 expression [ XREF_BIBR ] .	Wildtype p53, but not mutant p53, was found to repress the Ets1 promoter [XREF_BIBR] and, in endothelial cells, retinoic acid negatively modulates Ets1 expression [XREF_BIBR].	0	14	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Ets1	Ets1	Ets1	1	2	13	14
21 Given our findings that c-Abl and TTK expression are correlated with that of p53 , we next hypothesized that heterologous TTK expression in MCF-7 cells would enhance their oncogenic potential by circumventing the tumor suppressive activity of c-Abl , whereas functional disruption of TTK in MDA-MB-231 cells would restore the anti-tumor activities of c-Abl .	21 Given our findings that c-Abl and TTK expression are correlated with that of p53, we next hypothesized that heterologous TTK expression in MCF-7 cells would enhance their oncogenic potential by circumventing the tumor suppressive activity of c-Abl, whereas functional disruption of TTK in MDA-MB-231 cells would restore the anti-tumor activities of c-Abl.	42	55	restore	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TTK	TTK	TTK	c-Abl	c-Abl	c-Abl	44	45	54	55
Conversely , depleting TTK expression in MDA-MB-231 cells not only inhibited their organoid growth in 3D-cultures , but also sensitized them to the tumor suppressing activities of c-Abl independent of its subcellular localization .	Conversely, depleting TTK expression in MDA-MB-231 cells not only inhibited their organoid growth in 3D-cultures, but also sensitized them to the tumor suppressing activities of c-Abl independent of its subcellular localization.	3	32	suppressing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TTK	TTK expression	ttk	c-Abl	c-Abl	c-abl	3	4	27	28
MSH receptor ( MSH-R ) binding activity was upregulated by UVB , IL-1alpha , -1 beta and ET-1 , but was downregulated by TNF-alpha .	MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1 beta and ET-1, but was downregulated by TNF-alpha.	0	24	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	MSH receptor	MSH receptor	MSH receptor	23	24	0	2
Remarkably , TRIM21 knockdown is sufficient to elicit GMPS accumulation in the nucleus and p53 stabilization .	Remarkably, TRIM21 knockdown is sufficient to elicit GMPS accumulation in the nucleus and p53 stabilization.	2	9	elicit	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIM21	TRIM21	TRIM21	GMPS	GMPS	GMPS	2	3	8	9
The most well studied , XIAP , inhibits caspase-3 and -7 , caspase-6 ' s closest homologs , by binding to the active site .	The most well studied, XIAP, inhibits caspase-3 and -7, caspase-6 's closest homologs, by binding to the active site.	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	5	6	8	9
To analyze if the ubiquitin ligase activity of XIAP mediates degradation of the caspase-3 subunits we knocked down XIAP .	To analyze if the ubiquitin ligase activity of XIAP mediates degradation of the caspase-3 subunits we knocked down XIAP.	6	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	8	9	13	14
The modulating effects of EA-5Hz and EA-25Hz on Bax mediated apoptosis are possibly due to the activation of p38 MAPK/CREB/Bcl-xL and p38 MAPK/CREB/Bcl -2 signaling , respectively , thereby preventing Smac/DIABLO translocation and restoring XIAP mediated caspase-3 inhibition in the ischemic cortical penumbra 7 days after reperfusion .	The modulating effects of EA-5Hz and EA-25Hz on Bax mediated apoptosis are possibly due to the activation of p38 MAPK/CREB/Bcl-xL and p38 MAPK/CREB/Bcl -2 signaling, respectively, thereby preventing Smac/DIABLO translocation and restoring XIAP mediated caspase-3 inhibition in the ischemic cortical penumbra 7 days after reperfusion.	33	37	mediated	Positive_early_activation	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	34	35	36	37
HtrA2 can , like DIABLO and Smac , prevent XIAP inhibition of active caspase 3 in vitro and is able to counteract XIAP protection of mammalian NT2 cells against UV induced cell death .	HtrA2 can, like DIABLO and Smac, prevent XIAP inhibition of active caspase 3 in vitro and is able to counteract XIAP protection of mammalian NT2 cells against UV induced cell death.	9	15	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	9	10	13	15
XIAP simultaneously inhibits caspases-9 and caspase-3 .	XIAP simultaneously inhibits caspases-9 and caspase-3.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	5	6
For instance , the x linked IAP ( XIAP ) inhibits caspase-3 and -9 and is inversely inhibited by Smac .	For instance, the x linked IAP (XIAP) inhibits caspase-3 and -9 and is inversely inhibited by Smac.	6	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	8	9	11	12
This indicates that caspase-8 activity triggered by TRAIL is sufficient to cleave pro-caspase-3 while caspase-3 activation is prevented by XIAP mediated degradation of processed caspase-3 .	This indicates that caspase-8 activity triggered by TRAIL is sufficient to cleave pro-caspase-3 while caspase-3 activation is prevented by XIAP mediated degradation of processed caspase-3.	17	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	19	20	24	25
The results indicate that XIAP normally acts to decrease caspase-3 activation and hair cell loss during gentamicin ototoxicity , as part of a protective response to potentially damaging stimuli .	The results indicate that XIAP normally acts to decrease caspase-3 activation and hair cell loss during gentamicin ototoxicity, as part of a protective response to potentially damaging stimuli.	4	10	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	4	5	9	10
44 Removal of XIAP inhibition of caspase-3 would allow ( a second ) auto-cleavage of caspase-3 to remove its pro domain and make it fully active .	44 Removal of XIAP inhibition of caspase-3 would allow (a second) auto-cleavage of caspase-3 to remove its pro domain and make it fully active.	3	7	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	3	4	6	7
XIAP also inhibits the caspase-3 and 7 , but the mechanism of action was found to be different .	XIAP also inhibits the caspase-3 and 7, but the mechanism of action was found to be different.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	4	5
We found that knockdown of XIAP in U2OS cells by small interfering RNA ( siRNA ) promoted the cleavage and activation of caspase-3 , a major effector of apoptosis ( XREF_FIG A , B ; Fig.S1A ) , and caused sub-G1 apoptotic fragmentation of DNA ( XREF_FIG C ; Fig.S1B ) after prolonged treatment of the cells with nocodazole , a microtubule poison that prevents mitotic spindle assembly and arrests cells in mitosis .	We found that knockdown of XIAP in U2OS cells by small interfering RNA (siRNA) promoted the cleavage and activation of caspase-3, a major effector of apoptosis (XREF_FIG A, B; Fig.S1A), and caused sub-G1 apoptotic fragmentation of DNA (XREF_FIG C; Fig.S1B) after prolonged treatment of the cells with nocodazole, a microtubule poison that prevents mitotic spindle assembly and arrests cells in mitosis.	3	26	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	5	6	22	23
The modulating effects of EA-5Hz and EA-25Hz on Bax mediated apoptosis are possibly due to the activation of p38 MAPK/CREB/Bcl-xL and p38 MAPK/CREB/Bcl -2 signaling pathways , respectively , and eventually contribute to the prevention of Smac/DIABLO translocation and subsequent restoration of XIAP mediated suppression of caspase-3 in the cortical periinfarct area 7 days after reperfusion .	The modulating effects of EA-5Hz and EA-25Hz on Bax mediated apoptosis are possibly due to the activation of p38 MAPK/CREB/Bcl-xL and p38 MAPK/CREB/Bcl -2 signaling pathways, respectively, and eventually contribute to the prevention of Smac/DIABLO translocation and subsequent restoration of XIAP mediated suppression of caspase-3 in the cortical periinfarct area 7 days after reperfusion.	40	53	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	42	43	46	47
Analysis in acute brain slices and in cultured hippocampal neurons revealed that XIAP deletion increases CASP-3 activity , enhances alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ( AMPA ) receptor internalization , sharply increases LTD , and significantly reduces synapse density .	Analysis in acute brain slices and in cultured hippocampal neurons revealed that XIAP deletion increases CASP-3 activity, enhances alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization, sharply increases LTD, and significantly reduces synapse density.	12	16	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	CASP-3	CASP-3	CASP-3	12	13	15	16
XIAP has recently been shown to inhibit the apoptotic executioners caspase-3 and -7 .	XIAP has recently been shown to inhibit the apoptotic executioners caspase-3 and -7.	0	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	10	11
Caspase-3 is responsible for executing the apoptotic process and can be inhibited by the anti-apoptotic XIAP XREF_BIBR .	Caspase-3 is responsible for executing the apoptotic process and can be inhibited by the anti-apoptotic XIAP XREF_BIBR.	0	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	Caspase-3	Caspase-3	Caspase-3	15	16	0	1
XIAP , a ubiquitous IAP , can inhibit both caspase-9 , the initiator caspase of the mitochondrial apoptotic pathway , and the downstream effector caspases , caspase-3 and caspase-7 .	XIAP, a ubiquitous IAP, can inhibit both caspase-9, the initiator caspase of the mitochondrial apoptotic pathway, and the downstream effector caspases, caspase-3 and caspase-7.	0	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	26	27
The BIR1 and TAB1 interaction is crucial for XIAP induced TAK1 and NF-kappaB ( RelA and p65 and p50 subunits ) activation , since the BIR2 domain of XIAP directly blocks the active sites of caspase-3 and caspase-7 , while the BIR1 domain directly binds to TAB1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The BIR1 and TAB1 interaction is crucial for XIAP induced TAK1 and NF-kappaB (RelA and p65 and p50 subunits) activation, since the BIR2 domain of XIAP directly blocks the active sites of caspase-3 and caspase-7, while the BIR1 domain directly binds to TAB1 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	26	37	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	28	29	35	36
XIAP can inhibit procaspase-9 as well as activated molecules of caspase-9 and caspase-3 .	XIAP can inhibit procaspase-9 as well as activated molecules of caspase-9 and caspase-3.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	12	13
In this study , using constitutively active mutants of caspase-3 , we found that XIAP promotes the degradation of active-form caspase-3 , but not procaspase-3 , in living cells .	In this study, using constitutively active mutants of caspase-3, we found that XIAP promotes the degradation of active-form caspase-3, but not procaspase-3, in living cells.	14	28	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	14	15	20	21
61 XIAP counteracts apoptosis induction by directly inhibiting caspase-3 , 62 and in type-II cells a high XIAP and caspase -3 ratio prevents full caspase-3 activation by caspase-8 .	61 XIAP counteracts apoptosis induction by directly inhibiting caspase-3, 62 and in type-II cells a high XIAP and caspase -3 ratio prevents full caspase-3 activation by caspase-8.	15	25	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	17	18	24	25
The XIAP overexpression could simultaneously reduce the activation of caspase-3 , -7 , and -9 induced by NaBu addition .	The XIAP overexpression could simultaneously reduce the activation of caspase-3, -7, and -9 induced by NaBu addition.	1	15	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP overexpression	xiap	caspase-3	caspase-3	caspase-3	1	2	9	10
The XIAP is a direct inhibitor of executioner caspase-3 and initiator caspase-7 .	The XIAP is a direct inhibitor of executioner caspase-3 and initiator caspase-7.	0	11	is a direct inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	1	2	8	9
Amongst these , XIAP is known to inhibit the autocatalytic activation of caspase-3 , therefore preventing a further transmission of the death signal and consequently apoptosis .	Amongst these, XIAP is known to inhibit the autocatalytic activation of caspase-3, therefore preventing a further transmission of the death signal and consequently apoptosis.	3	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	3	4	12	13
XIAP , c-IAP1 , and c-IAP2 can directly or indirectly inhibit the activity of caspase-3 , -8 , and -9 .	XIAP, c-IAP1, and c-IAP2 can directly or indirectly inhibit the activity of caspase-3, -8, and -9.	0	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	14	15
Our results thus strongly suggest that EA-5Hz and EA-25Hz are neuroprotective against Bax mediated apoptosis by inhibiting the translocation of Smac/DIABLO from mitochondria to the cytosol , thereby restoring XIAP mediated suppression of caspase-3 activity in the ischemic cortical penumbra 7 days after reperfusion .	Our results thus strongly suggest that EA-5Hz and EA-25Hz are neuroprotective against Bax mediated apoptosis by inhibiting the translocation of Smac/DIABLO from mitochondria to the cytosol, thereby restoring XIAP mediated suppression of caspase-3 activity in the ischemic cortical penumbra 7 days after reperfusion.	29	34	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	29	30	33	34
Interestingly , CASP3 is able to degrade its own inhibitor ( XIAP ) which again enhances CASP3 activity and consequently induces apoptosis [ XREF_BIBR ] .	Interestingly, CASP3 is able to degrade its own inhibitor (XIAP) which again enhances CASP3 activity and consequently induces apoptosis [XREF_BIBR].	9	17	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	CASP3	CASP3	CASP3	11	12	16	17
Susuki et al proposed that active caspase-3 could be degraded by the proteasome after ubiquitination by XIAP [ XREF_BIBR ] , and a study by Ares et al proposed that the incubation of HMEC-1 cells with oxLDL results in the polyubiquitination of caspase-3 and inactivation of this protease .	Susuki et al proposed that active caspase-3 could be degraded by the proteasome after ubiquitination by XIAP [XREF_BIBR], and a study by Ares et al proposed that the incubation of HMEC-1 cells with oxLDL results in the polyubiquitination of caspase-3 and inactivation of this protease.	5	18	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	16	17	6	7
XREF_BIBR X linked IAP ( XIAP ) directly inhibits caspase-3 , -7 and -9 XREF_BIBR and inhibition of cIAPs and XIAP causes complex II ( the ' ripoptosome ' ; ( RIPK1-RIPK3-FADD-caspase-8-cFLIP ) , XREF_BIBR , XREF_BIBR which drives caspase-8-mediated apoptosis or caspase independent necroptosis without the need for receptor ligation .	XREF_BIBR X linked IAP (XIAP) directly inhibits caspase-3, -7 and -9 XREF_BIBR and inhibition of cIAPs and XIAP causes complex II (the ' ripoptosome '; (RIPK1-RIPK3-FADD-caspase-8-cFLIP), XREF_BIBR, XREF_BIBR which drives caspase-8-mediated apoptosis or caspase independent necroptosis without the need for receptor ligation.	3	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	5	6	9	10
XIAP is known to inhibit both the caspase-3 and 7 .	XIAP is known to inhibit both the caspase-3 and 7.	0	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	7	8
Once released into the cytosol , SMAC interacts with XIAP to release XIAP mediated inhibition of casp-3 .	Once released into the cytosol, SMAC interacts with XIAP to release XIAP mediated inhibition of casp-3.	12	17	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	casp-3	casp-3	casp-3	12	13	16	17
Accordingly , decreasing cellular XIAP levels in HCT116 PIK3CA-mut , LS-174T and DLD-1 cells using the SMAC-mimetic BV6 21 potently enhanced TRAIL sensitivity ( XREF_FIG ) and was accompanied by complete TRAIL induced caspase-3 activation ( XREF_FIG ) .	Accordingly, decreasing cellular XIAP levels in HCT116 PIK3CA-mut, LS-174T and DLD-1 cells using the SMAC-mimetic BV6 21 potently enhanced TRAIL sensitivity (XREF_FIG) and was accompanied by complete TRAIL induced caspase-3 activation (XREF_FIG).	4	34	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP levels	xiap	caspase-3	caspase-3	caspase-3	4	5	33	34
Inhibition of RING domain stabilizes XIAP causing TNF sensitivity as a result of increased retention of DISC mediated active caspase-3 , which ultimately overcomes the caspase-inhibitory function of XIAP [ XREF_BIBR ] .	Inhibition of RING domain stabilizes XIAP causing TNF sensitivity as a result of increased retention of DISC mediated active caspase-3, which ultimately overcomes the caspase-inhibitory function of XIAP [XREF_BIBR].	5	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	5	6	19	20
In addition , XIAP and other IAP proteins can directly inhibit caspase-3 and caspase-7 activity [ XREF_BIBR ] as well as modulate the Bax and cytochrome C apoptosis pathway via XIAP mediated inhibition of caspase-9 [ XREF_BIBR ] .	In addition, XIAP and other IAP proteins can directly inhibit caspase-3 and caspase-7 activity [XREF_BIBR] as well as modulate the Bax and cytochrome C apoptosis pathway via XIAP mediated inhibition of caspase-9 [XREF_BIBR].	3	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	3	4	11	12
Modeling suggests that XIAP mediated caspase-3 degradation is important for maintaining a pre-MOMP delay in type II cells .	Modeling suggests that XIAP mediated caspase-3 degradation is important for maintaining a pre-MOMP delay in type II cells.	3	6	mediated	Positive_early_activation	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	3	4	5	6
XIAP ( X linked inhibitor of apoptosis ) directly inhibits the upstream caspase-9 and the downstream caspase-3 and caspase-7 , and therefore controls critical apoptotic checkpoints .	XIAP (X linked inhibitor of apoptosis) directly inhibits the upstream caspase-9 and the downstream caspase-3 and caspase-7, and therefore controls critical apoptotic checkpoints.	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	16	17
Besides regulation of TGF-beta signaling , NF-kappaB pathway , autophagy and inflammatory responses formation , the most important function of XIAP is to inhibit caspase-9 , caspase-3 and caspase-7 through protein degradation mechanism .	Besides regulation of TGF-beta signaling, NF-kappaB pathway, autophagy and inflammatory responses formation, the most important function of XIAP is to inhibit caspase-9, caspase-3 and caspase-7 through protein degradation mechanism.	18	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	20	21	26	27
Furthermore , the expression of proapototic protein XAF1 , which blocks the XIAP mediated inhibition of caspase-3 ( Liston et al , 2001 ) , is also reduced in human melanomas ( Ng et al , 2004 ) .	Furthermore, the expression of proapototic protein XAF1, which blocks the XIAP mediated inhibition of caspase-3 (Liston et al, 2001), is also reduced in human melanomas (Ng et al, 2004).	11	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	12	13	16	17
The X linked inhibitor of apoptosis protein ( XIAP ) uses its second baculovirus IAP repeat domain ( BIR2 ) to inhibit the apoptotic executioner caspase-3 and -7 .	The X linked inhibitor of apoptosis protein (XIAP) uses its second baculovirus IAP repeat domain (BIR2) to inhibit the apoptotic executioner caspase-3 and -7.	1	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	8	9	25	26
10 Caspase-3 , -7 , and -9 are inhibited by XIAP , an IAP family member XREF_BIBR , XREF_BIBR that directly binds to and inactivates caspase-3 or caspase-9 to inhibit their degradation , resulting in suppression of apoptosis .	10 Caspase-3, -7, and -9 are inhibited by XIAP, an IAP family member XREF_BIBR, XREF_BIBR that directly binds to and inactivates caspase-3 or caspase-9 to inhibit their degradation, resulting in suppression of apoptosis.	8	33	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	10	11	25	26
The inhibitor of apoptosis XIAP that inhibits its downstream targets CASP3 and CASP7 are also part of the subgraph .	The inhibitor of apoptosis XIAP that inhibits its downstream targets CASP3 and CASP7 are also part of the subgraph.	1	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	CASP3	CASP3	CASP3	4	5	10	11
Xiap directly inhibits the initiator caspase-9 and execution caspase-3 and -7 .	Xiap directly inhibits the initiator caspase-9 and execution caspase-3 and -7.	0	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Xiap	Xiap	Xiap	caspase-3	caspase-3	caspase-3	0	1	8	9
Downstream of mitochondria , XIAP and PCNA inhibit caspase-9 and caspase-3 by direct binding .	Downstream of mitochondria, XIAP and PCNA inhibit caspase-9 and caspase-3 by direct binding.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	4	5	10	11
XIAP binds and directly inhibits apoptotic caspase activity ( caspase-3 , -7 and -9 ) .	XIAP binds and directly inhibits apoptotic caspase activity (caspase-3, -7 and -9).	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	9	10
These results demonstrate that the ubiquitin protein ligase activity of XIAP promotes the degradation of caspase-3 , which enhances its anti-apoptotic effect .	These results demonstrate that the ubiquitin protein ligase activity of XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect.	8	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	10	11	15	16
NIAP directly inhibits caspase-3 , -7 , and -9 and XIAP directly inhibits also caspase-3 and caspase-7 .	NIAP directly inhibits caspase-3, -7, and -9 and XIAP directly inhibits also caspase-3 and caspase-7.	3	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	10	11	14	15
The BIR2 domain of XIAP inhibits caspase 3 and caspase 7 , while BIR3 domain inhibits caspase 9 .	The BIR2 domain of XIAP inhibits caspase 3 and caspase 7, while BIR3 domain inhibits caspase 9.	2	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	4	5	6	8
EGCG inhibits the expression of XIAP and Bcl-2 and induces caspase-3 activation in human prostate cancer stem cells .	EGCG inhibits the expression of XIAP and Bcl-2 and induces caspase-3 activation in human prostate cancer stem cells.	0	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	EGCG inhibits the expression of XIAP	xiap	caspase-3	caspase-3	caspase-3	5	6	10	11
These results suggest that XIAP inhibits caspase-3 and caspase-9 in a different manner .	These results suggest that XIAP inhibits caspase-3 and caspase-9 in a different manner.	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	4	5	6	7
It functions as an antagonist of XIAP by rescuing XIAP suppressed caspase-3 activity , thus promoting cellular apoptosis .	It functions as an antagonist of XIAP by rescuing XIAP suppressed caspase-3 activity, thus promoting cellular apoptosis.	4	12	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	6	7	11	12
The results also demonstrate that ara-C induces cleavage of procaspase-3 by a caspase-8-dependent mechanism and that XIAP inhibits caspase-3 activity .	The results also demonstrate that ara-C induces cleavage of procaspase-3 by a caspase-8-dependent mechanism and that XIAP inhibits caspase-3 activity.	16	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	16	17	18	19
XIAP is a potent inhibitor of active caspase-3 , and the high expression of XIAP XREF_BIBR , XREF_BIBR , XREF_BIBR in MET cells prompted us to study whether XIAP is the decisive protein protecting MET cells from ABT737 induced cell death .	XIAP is a potent inhibitor of active caspase-3, and the high expression of XIAP XREF_BIBR, XREF_BIBR, XREF_BIBR in MET cells prompted us to study whether XIAP is the decisive protein protecting MET cells from ABT737 induced cell death.	0	8	is a potent inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	7	8
XIAP inhibits active caspase-3 by directly blocking downstream events such as further activation of caspases [ XREF_BIBR , XREF_BIBR ] .	XIAP inhibits active caspase-3 by directly blocking downstream events such as further activation of caspases [XREF_BIBR, XREF_BIBR].	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	3	4
Indeed , in the presence of Smac , a mitochondrial inhibitor of XIAP , the ability of cytochrome c was restored to trigger processing and activation of caspase-3 in HL derived B cells ( XREF_FIG ) .	Indeed, in the presence of Smac, a mitochondrial inhibitor of XIAP, the ability of cytochrome c was restored to trigger processing and activation of caspase-3 in HL derived B cells (XREF_FIG).	10	28	trigger	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	12	13	27	28
Thus , it is possible that the oxycodone triggered integrated stress response affects local translation in axons leading to decreased level of XIAP that promotes caspase 3 proteolytic activation and , thus , axonal degeneration .	Thus, it is possible that the oxycodone triggered integrated stress response affects local translation in axons leading to decreased level of XIAP that promotes caspase 3 proteolytic activation and, thus, axonal degeneration.	20	34	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	level of XIAP	xiap	caspase 3	caspase 3	caspase 3	22	23	25	27
In addition , to inhibit caspase 9 cleavage of caspase 3 , XIAP can also inhibit caspase 3 directly .	In addition, to inhibit caspase 9 cleavage of caspase 3, XIAP can also inhibit caspase 3 directly.	12	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	12	13	16	18
We show here that AFP cancels XIAP mediated inhibition of endogenous active caspases in cytosolic lysates of tumor cells , as well as XIAP induced blockage of active recombinant caspase 3 in a reconstituted cell-free system .	We show here that AFP cancels XIAP mediated inhibition of endogenous active caspases in cytosolic lysates of tumor cells, as well as XIAP induced blockage of active recombinant caspase 3 in a reconstituted cell-free system.	8	33	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	23	24	29	31
Furthermore , these mutants retained full ability to inhibit apoptosis in transfected cells , demonstrating that although XIAP is able to inhibit caspase 3 , this activity is dispensable for inhibition of apoptosis by XIAP in vivo .	Furthermore, these mutants retained full ability to inhibit apoptosis in transfected cells, demonstrating that although XIAP is able to inhibit caspase 3, this activity is dispensable for inhibition of apoptosis by XIAP in vivo.	17	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	17	18	22	24
XIAP can inhibit caspase 3 and 7 , and it is also involved in the suppression of the pro apoptotic JNK activity .	XIAP can inhibit caspase 3 and 7, and it is also involved in the suppression of the pro apoptotic JNK activity.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	0	1	3	5
Both carotenoids induced apoptosis in HTLV-1-infected T-cell lines , which was associated with the activation of caspases-3 , -8 and -9 , as well as down-regulation of the expression of the anti-apoptotic proteins , XIAP , cIAP2 , Bcl-2 and survivin ; XIAP and cIAP2 inhibit caspase-3 and 9 activities , respectively [ XREF_BIBR ] ( XREF_FIG ) .	Both carotenoids induced apoptosis in HTLV-1-infected T-cell lines, which was associated with the activation of caspases-3, -8 and -9, as well as down-regulation of the expression of the anti-apoptotic proteins, XIAP, cIAP2, Bcl-2 and survivin; XIAP and cIAP2 inhibit caspase-3 and 9 activities, respectively [XREF_BIBR] (XREF_FIG).	42	49	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	42	43	46	47
XIAP in particular is noted to inhibit caspase-3 , -7 , and -9 , while some contention exists whether cIAP1 and cIAP2 inhibit caspases directly .	XIAP in particular is noted to inhibit caspase-3, -7, and -9, while some contention exists whether cIAP1 and cIAP2 inhibit caspases directly.	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	7	8
For example , overexpression of XIAP failed to decrease caspase 3 after FL118 treatment .	For example, overexpression of XIAP failed to decrease caspase 3 after FL118 treatment.	3	11	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	overexpression of XIAP	xiap	caspase 3	caspase 3	caspase 3	5	6	9	11
A likely explanation for this result argues that XIAP is capable to effectively inhibit caspase-3 maturation in NCI-H460 and Bcl-2 cells , whereas the initial caspase-3 cleavage step can occur unhampered in the DISC .	A likely explanation for this result argues that XIAP is capable to effectively inhibit caspase-3 maturation in NCI-H460 and Bcl-2 cells, whereas the initial caspase-3 cleavage step can occur unhampered in the DISC.	8	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	8	9	14	15
Overexpression of XIAP markedly inhibited the cell death and caspase-3 activity in the neuro2a cells expressing mutant SOD1 .	Overexpression of XIAP markedly inhibited the cell death and caspase-3 activity in the neuro2a cells expressing mutant SOD1.	0	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	Overexpression of XIAP	xiap	caspase-3	caspase-3	caspase-3	2	3	9	10
Although the E3-ubiquitin ligase activity of XIAP seems dispensable , the analysis of cells from XIAPincrementRING transgenic mice revealed the influence of the RING dependent post-traductional modifications on XIAP mediated caspase-3 inhibition [ XREF_BIBR ] .	Although the E3-ubiquitin ligase activity of XIAP seems dispensable, the analysis of cells from XIAPincrementRING transgenic mice revealed the influence of the RING dependent post-traductional modifications on XIAP mediated caspase-3 inhibition [XREF_BIBR].	26	31	mediated	Positive_early_activation	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	28	29	30	31
Through this interaction , many are able to antagonise XIAP inhibition of caspase 3 in vitro .	Through this interaction, many are able to antagonise XIAP inhibition of caspase 3 in vitro.	9	14	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	9	10	12	14
Resistance of tumor cells to NK cell mediated death is associated with endogenous XIAP inhibiting the caspase-3 triggered by immune cell attack .	Resistance of tumor cells to NK cell mediated death is associated with endogenous XIAP inhibiting the caspase-3 triggered by immune cell attack.	10	17	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	13	14	16	17
XIAP could inhibit the function of caspase-3 , 7 and 9 , and thus prevent cell apoptosis [ XREF_BIBR - XREF_BIBR ] .	XIAP could inhibit the function of caspase-3, 7 and 9, and thus prevent cell apoptosis [XREF_BIBR - XREF_BIBR].	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	6	7
In CRC , XIAP inhibits caspase-3 activity by ubiquitining active p17 and mediating its degradation via proteasome in HCT-116 cells harboring PIK3CA mutations .	In CRC, XIAP inhibits caspase-3 activity by ubiquitining active p17 and mediating its degradation via proteasome in HCT-116 cells harboring PIK3CA mutations.	3	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	3	4	5	6
XREF_BIBR - XREF_BIBR The third BIR domain ( BIR3 ) of XIAP binds to the processed caspase-9 and inhibits its activity , and the BIR2 domain of XIAP , together with the linker preceding it , binds to and inhibits both caspase-3 and caspase-7 .	XREF_BIBR - XREF_BIBR The third BIR domain (BIR3) of XIAP binds to the processed caspase-9 and inhibits its activity, and the BIR2 domain of XIAP, together with the linker preceding it, binds to and inhibits both caspase-3 and caspase-7.	25	43	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	27	28	41	42
Western blot analysis showed that the combination of BNTX with TRAIL reduced XIAP expression and increased caspase-3 and PARP cleavage in tumor tissue extracts after 20 days of treatment .	Western blot analysis showed that the combination of BNTX with TRAIL reduced XIAP expression and increased caspase-3 and PARP cleavage in tumor tissue extracts after 20 days of treatment.	8	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	BNTX with TRAIL reduced XIAP expression	xiap	caspase-3	caspase-3	caspase-3	12	13	16	17
Using this library , we discovered an XIAP inhibitor , C38OX6 , which restored XIAP suppressed enzymatic activity of caspase-3 in vitro .	Using this library, we discovered an XIAP inhibitor, C38OX6, which restored XIAP suppressed enzymatic activity of caspase-3 in vitro.	14	20	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	14	15	19	20
XIAP , as an important member of the IAP family , can specifically inhibit the activity of caspase-3 , -7 and -9 , and inhibit the apoptosis of tumor cells .	XIAP, as an important member of the IAP family, can specifically inhibit the activity of caspase-3, -7 and -9, and inhibit the apoptosis of tumor cells.	0	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	17	18
Recombinant XIAP containing linker-BIR2-BIR3 ( residues 120-356 ) effectively inhibited the activity of caspase-3 and caspase-7 in a dose dependent manner and achieved complete inhibition at 50 nmol/L ( XREF_FIG ) .	Recombinant XIAP containing linker-BIR2-BIR3 (residues 120-356) effectively inhibited the activity of caspase-3 and caspase-7 in a dose dependent manner and achieved complete inhibition at 50 nmol/L (XREF_FIG).	0	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	1	2	13	14
Western blot analysis reveals that XIAP-KO mice have increased levels of both the 17 and 19 kDa forms of cleaved activated caspase 3 , suggesting that XIAP is normally reducing the amount of caspase 3 cleavage that occurs in wild-type mice following H-I and thus has an effect upstream of caspase 3 activation .	Western blot analysis reveals that XIAP-KO mice have increased levels of both the 17 and 19 kDa forms of cleaved activated caspase 3, suggesting that XIAP is normally reducing the amount of caspase 3 cleavage that occurs in wild-type mice following H-I and thus has an effect upstream of caspase 3 activation.	26	45	reducing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	26	27	33	35
Based on a report demonstrating that XIAP directly inhibits active caspase-3 [ XREF_BIBR ] , we investigated the inhibitory effect of AZD5582 on XIAP .	Based on a report demonstrating that XIAP directly inhibits active caspase-3 [XREF_BIBR], we investigated the inhibitory effect of AZD5582 on XIAP.	6	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	6	7	10	11
However , the triple combination of BNTX with TRAIL in cells that had been pretreated with the PI3K inhibitor most significantly downregulated XIAP expression and increased the cleavage of caspase-3 and PARP .	However, the triple combination of BNTX with TRAIL in cells that had been pretreated with the PI3K inhibitor most significantly downregulated XIAP expression and increased the cleavage of caspase-3 and PARP.	6	31	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	BNTX with TRAIL in cells that had been pretreated with the PI3K inhibitor most significantly downregulated XIAP expression	xiap	caspase-3	caspase-3	caspase-3	22	23	29	30
For example , XIAP inhibits initiator caspase-9 and executioner caspase-3 and -7 via direct physical interaction , whereas c-IAP1 and c-IAP2 bind caspase-3 and -7 but the inhibition of caspase activity is not efficient , instead these two proteins favor proteasomal degradation of caspases .	For example, XIAP inhibits initiator caspase-9 and executioner caspase-3 and -7 via direct physical interaction, whereas c-IAP1 and c-IAP2 bind caspase-3 and -7 but the inhibition of caspase activity is not efficient, instead these two proteins favor proteasomal degradation of caspases.	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	3	4	9	10
XIAP also inhibits caspase-3 and caspase-7 .	XIAP also inhibits caspase-3 and caspase-7.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	3	4
Finally , XIAP is reported to inhibit the activation of caspase-3 and caspase-7 via the baculovirus inhibitor of apoptosis protein repeat domain to inhibit apoptosis .	Finally, XIAP is reported to inhibit the activation of caspase-3 and caspase-7 via the baculovirus inhibitor of apoptosis protein repeat domain to inhibit apoptosis.	2	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	2	3	10	11
AEG35156 is an antisense oligonucleotide designed to selectively target XIAP , the only IAP family member that directly inhibits caspase-3 , -7 , and -9 .	AEG35156 is an antisense oligonucleotide designed to selectively target XIAP, the only IAP family member that directly inhibits caspase-3, -7, and -9.	8	24	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	9	10	19	20
In particular , XIAP knockdown in combination with TRAIL allowed the final cleavage step of caspase-3 to generate the catalytically active p17 fragment , whose production was otherwise blocked in Bcl-2 overexpressing cells .	In particular, XIAP knockdown in combination with TRAIL allowed the final cleavage step of caspase-3 to generate the catalytically active p17 fragment, whose production was otherwise blocked in Bcl-2 overexpressing cells.	3	16	allowed	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	3	4	15	16
Critically , mutation of Cys450 in XIAP prevented accumulation of caspase-3 and enhanced neuronal survival .	Critically, mutation of Cys450 in XIAP prevented accumulation of caspase-3 and enhanced neuronal survival.	4	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	6	7	10	11
Caspase-8-generated cleavage fragments of XIAP inhibit further processing of caspase-3 intermediates 36 by competitive binding of BIR1 and BIR2 ( BIR1-2 ) to a neo-epitope in the caspase-3 p19 fragment .	Caspase-8-generated cleavage fragments of XIAP inhibit further processing of caspase-3 intermediates 36 by competitive binding of BIR1 and BIR2 (BIR1-2) to a neo-epitope in the caspase-3 p19 fragment.	2	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	4	5	9	10
Inhibition of XIAP triggers intrinsic apoptosis by activating the caspase-9 , caspase-7 and caspase-3 , we then investigated the effects of combination treatment DOX+ anti-miR-24 on the caspase activation .	Inhibition of XIAP triggers intrinsic apoptosis by activating the caspase-9, caspase-7 and caspase-3, we then investigated the effects of combination treatment DOX+ anti-miR-24 on the caspase activation.	0	14	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	2	3	13	14
XIAP is degraded by the UPS , thus releasing caspase-3 and allowing induction of the axonal apoptotic cascade [ XREF_BIBR , XREF_BIBR ] and activation of calpain [ XREF_BIBR ] .	XIAP is degraded by the UPS, thus releasing caspase-3 and allowing induction of the axonal apoptotic cascade [XREF_BIBR, XREF_BIBR] and activation of calpain [XREF_BIBR].	0	10	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	9	10
XIAP ( X-chromosome-linked inhibitory apoptosis protein ) is an inhibitor of caspase-3 , -7 and -9 .	XIAP (X-chromosome-linked inhibitory apoptosis protein) is an inhibitor of caspase-3, -7 and -9.	0	15	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	11	12
Re-expression of ARHI further increased the cisplatin mediated suppression of Bcl-2 and XIAP expression and enhanced the accumulation of activated caspase-3 and cleaved PARP .	Re-expression of ARHI further increased the cisplatin mediated suppression of Bcl-2 and XIAP expression and enhanced the accumulation of activated caspase-3 and cleaved PARP.	0	21	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	Re-expression of ARHI further increased the cisplatin mediated suppression of Bcl-2 and XIAP expression	xiap	caspase-3	caspase-3	caspase-3	12	13	20	21
It has been previously revealed that XIAP could inhibit CASP3 activation .	It has been previously revealed that XIAP could inhibit CASP3 activation.	6	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	CASP3	CASP3	CASP3	6	7	9	10
By contrast , the levels of XIAP were not reduced by DOX in siCCN1-cells , thereby hindering the activation of caspase-3 .	By contrast, the levels of XIAP were not reduced by DOX in siCCN1-cells, thereby hindering the activation of caspase-3.	4	21	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	levels of XIAP	xiap	caspase-3	caspase-3	caspase-3	6	7	20	21
Tan IIA was also demonstrated to suppress IAP3 expression , which in turn activated Caspase 3 and Caspase 9 , as well as induction of cell apoptosis .	Tan IIA was also demonstrated to suppress IAP3 expression, which in turn activated Caspase 3 and Caspase 9, as well as induction of cell apoptosis.	0	23	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IAP3	Tan IIA was also demonstrated to suppress IAP3 expression	iap3	Caspase 3	Caspase 3	caspase 3	7	8	14	16
Interestingly , X linked inhibitor of apoptosis protein ( XIAP ) protein levels decreased in myocytes subjected to reoxygenation , and ERK phosphorylation can improve XIAP expression , which involved inhibiting caspase-3 , -7 and -9 activities .	Interestingly, X linked inhibitor of apoptosis protein (XIAP) protein levels decreased in myocytes subjected to reoxygenation, and ERK phosphorylation can improve XIAP expression, which involved inhibiting caspase-3, -7 and -9 activities.	25	36	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP expression	xiap	caspase-3	caspase-3	caspase-3	25	26	31	32
The XIAP protein has been shown to bind specifically to and inhibit the activated forms of caspase-3 , -7 and -9 , which are the enzymes that induce the intrinsic ( mitochondrial ) pathway of apoptosis [ XREF_BIBR ] .	The XIAP protein has been shown to bind specifically to and inhibit the activated forms of caspase-3, -7 and -9, which are the enzymes that induce the intrinsic (mitochondrial) pathway of apoptosis [XREF_BIBR].	1	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	1	2	16	17
The BIR2 domain of XIAP inhibits active caspase-3 and caspase-7 [ XREF_BIBR ] .	The BIR2 domain of XIAP inhibits active caspase-3 and caspase-7 [XREF_BIBR].	2	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	4	5	7	8
XIAP could suppress the activation of an initiator caspase , caspase-9 and the effector caspases ( caspase-3 , and -7 ) via its interaction through the BIR3 and BIR2 domains .	XIAP could suppress the activation of an initiator caspase, caspase-9 and the effector caspases (caspase-3, and -7) via its interaction through the BIR3 and BIR2 domains.	0	19	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	16	17
Since XIAP was able to inhibit activation of caspase-3 to protect cells from apoptosis , downregulation of XIAP provided an additional indication that YQ36 exerted antitumor effect was related to the activation of caspase cascade .	Since XIAP was able to inhibit activation of caspase-3 to protect cells from apoptosis, downregulation of XIAP provided an additional indication that YQ36 exerted antitumor effect was related to the activation of caspase cascade.	1	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	1	2	8	9
XIAP has been described to inhibit caspase-3 , -7 and -9 via its BIR2 and BIR3 domain and is therefore considered mediating the anti-apoptotic effect via this mechanism [ XREF_BIBR ] .	XIAP has been described to inhibit caspase-3, -7 and -9 via its BIR2 and BIR3 domain and is therefore considered mediating the anti-apoptotic effect via this mechanism [XREF_BIBR].	0	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	6	7
XIAP is a direct inhibitor of caspase-3 , -7 and -9 .	XIAP is a direct inhibitor of caspase-3, -7 and -9.	0	10	is a direct inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	6	7
Although XIAP mediated degradation of active caspase-3 is necessary , raising this degradation rate too much compromises the switch like activation of effector caspase substrate cleavage post-MOMP .	Although XIAP mediated degradation of active caspase-3 is necessary, raising this degradation rate too much compromises the switch like activation of effector caspase substrate cleavage post-MOMP.	1	7	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	1	2	6	7
XIAP can bind to and suppress the activities of caspase 3 in H460 cells and lead to apoptosis inhibition of these cells .	XIAP can bind to and suppress the activities of caspase 3 in H460 cells and lead to apoptosis inhibition of these cells.	0	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	0	1	9	11
Binding assays revealed that the inhibition of caspase-3 by XIAP was totally dependent on the interaction between the active site of caspase-3 and the linker region between the BIR1 and BIR2 domains of XIAP .	Binding assays revealed that the inhibition of caspase-3 by XIAP was totally dependent on the interaction between the active site of caspase-3 and the linker region between the BIR1 and BIR2 domains of XIAP.	5	10	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	9	10	7	8
XIAP can inhibit caspase-3 and caspase-7 by directly binding to them [ XREF_BIBR ] .	XIAP can inhibit caspase-3 and caspase-7 by directly binding to them [XREF_BIBR].	0	5	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	3	4
Virally mediated overexpression of the anti-apoptotic gene X chromosome linked inhibitor of apoptosis protein ( XIAP ) prevented both the production of catalytically active caspase-3 and degeneration of CA1 neurons after transient forebrain ischemia .	Virally mediated overexpression of the anti-apoptotic gene X chromosome linked inhibitor of apoptosis protein (XIAP) prevented both the production of catalytically active caspase-3 and degeneration of CA1 neurons after transient forebrain ischemia.	13	25	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	15	16	24	25
XIAP phosphorylated by AKT can prevent XIAP degradation and thus inhibit caspase 3 activation confer resistance to apoptosis XREF_BIBR .	XIAP phosphorylated by AKT can prevent XIAP degradation and thus inhibit caspase 3 activation confer resistance to apoptosis XREF_BIBR.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP phosphorylated	xiap	caspase 3	caspase 3	caspase 3	0	1	11	13
In addition , this amplification might occur by sequestration of XIAP by SMAC , thus removing XIAP inhibition of caspase-3 ( and caspases-7 and -9 ) .	In addition, this amplification might occur by sequestration of XIAP by SMAC, thus removing XIAP inhibition of caspase-3 (and caspases-7 and -9).	16	24	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	16	17	19	20
For instance , XIAP ( an inhibitor of caspase-3 ) is a well known anti-apoptotic player , and the sensitivity of PARP cleavage with respect to XIAP was correctly shown to be negative .	For instance, XIAP (an inhibitor of caspase-3) is a well known anti-apoptotic player, and the sensitivity of PARP cleavage with respect to XIAP was correctly shown to be negative.	3	15	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	3	4	8	9
TrkB ligand signaling , specifically from the target , may mediate neuronal survival by up-regulating XIAP , which blocks caspase-3 activation .	TrkB ligand signaling, specifically from the target, may mediate neuronal survival by up-regulating XIAP, which blocks caspase-3 activation.	14	20	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	15	16	19	20
XIAP can inhibit the initiator caspase-9 , as well as the effectors caspase-3 and -7 .	XIAP can inhibit the initiator caspase-9, as well as the effectors caspase-3 and -7.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	12	13
38 Treatment of hFb with BV6 where cFLIP has been knocked down resulted in a profound sensitisation to TRAIL ( XREF_FIG ) , showing that induction of TRAIL sensitivity in non transformed hFb would require Smac and DIABLO-release from the mitochondria as a mechanism to overcome XIAP mediated inhibition of caspase-3 , and not only of caspase-9 .	38 Treatment of hFb with BV6 where cFLIP has been knocked down resulted in a profound sensitisation to TRAIL (XREF_FIG), showing that induction of TRAIL sensitivity in non transformed hFb would require Smac and DIABLO-release from the mitochondria as a mechanism to overcome XIAP mediated inhibition of caspase-3, and not only of caspase-9.	46	51	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	46	47	50	51
In cytosolic extracts , inhibition of XIAP by the second mitochondria derived activator of caspases ( Smac )/DIABLO , or immunodepletion of XIAP restores cytochrome c triggered processing and activation of caspase-3 .	In cytosolic extracts, inhibition of XIAP by the second mitochondria derived activator of caspases (Smac)/DIABLO, or immunodepletion of XIAP restores cytochrome c triggered processing and activation of caspase-3.	4	32	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	6	7	31	32
18 XIAP prevents the activation of caspase-3 and -9 at different levels , including inhibition of substrate binding and proteasomal degradation of processed caspase-3 forms .	18 XIAP prevents the activation of caspase-3 and -9 at different levels, including inhibition of substrate binding and proteasomal degradation of processed caspase-3 forms.	0	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	1	2	6	7
Furthermore , small-molecule derivatives of polyphenylurea , screened for efficacy in overcoming XIAP inhibition of caspase 3 , have demonstrated in vivo antitumour activity against human prostate and colon cancer xenografts in the absence of significant toxicity to normal tissues ( Schimmer et al , 2004 ) .	Furthermore, small-molecule derivatives of polyphenylurea, screened for efficacy in overcoming XIAP inhibition of caspase 3, have demonstrated in vivo antitumour activity against human prostate and colon cancer xenografts in the absence of significant toxicity to normal tissues (Schimmer et al, 2004).	12	17	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	12	13	15	17
However , some tumors have mechanism of TRAIL resistance through overexpression of X linked inhibitory of apoptosis protein ( XIAP ) , which inhibits caspase 3 and 9 activation .	However, some tumors have mechanism of TRAIL resistance through overexpression of X linked inhibitory of apoptosis protein (XIAP), which inhibits caspase 3 and 9 activation.	17	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	19	20	24	26
In addition to competitive caspase inhibition , the E3-ligase activity of XIAP inhibits caspase-3 activation by ubiquitination of the active p17 fragment with subsequent proteasomal degradation .	In addition to competitive caspase inhibition, the E3-ligase activity of XIAP inhibits caspase-3 activation by ubiquitination of the active p17 fragment with subsequent proteasomal degradation.	9	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	11	12	13	14
Whether or not a BIR2 selective antagonist that inhibits the XIAP dependent repression of the downstream executioner caspases caspase-3 and caspase-7 can be efficacious either alone or in combination with known therapies remains to be seen .	Whether or not a BIR2 selective antagonist that inhibits the XIAP dependent repression of the downstream executioner caspases caspase-3 and caspase-7 can be efficacious either alone or in combination with known therapies remains to be seen.	10	20	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	10	11	18	19
Deletion of XIAP relieves the inhibition of caspase 9 cleavage of caspase 3 in response to cytochrome c release .	Deletion of XIAP relieves the inhibition of caspase 9 cleavage of caspase 3 in response to cytochrome c release.	0	14	relieves	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	2	3	11	13
XIAP suppresses caspase-3 and caspase-7 activities .	XIAP suppresses caspase-3 and caspase-7 activities.	0	5	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	2	3
To determine the role of X linked inhibitor of apoptosis protein ( XIAP ) , which suppresses caspase-3 , -7 and -9 activities and acts as an endogenous inhibitor of apoptotic cell death , in the regulation of granulosa cell apoptosis during follicular atresia , we examined the changes in the expression level and localization of XIAP mRNA and protein in granulosa cells during follicular atresia using reverse transcription-polymerase chain reaction ( RT-PCR ) , in situ hybridization , Western blotting and immunohistochemistry , respectively .	To determine the role of X linked inhibitor of apoptosis protein (XIAP), which suppresses caspase-3, -7 and -9 activities and acts as an endogenous inhibitor of apoptotic cell death, in the regulation of granulosa cell apoptosis during follicular atresia, we examined the changes in the expression level and localization of XIAP mRNA and protein in granulosa cells during follicular atresia using reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization, Western blotting and immunohistochemistry, respectively.	10	22	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	12	13	17	18
In a caspase de-repression assay , JP1400 was slightly better than JP1010 in relieving XIAP mediated caspase-3 and -9 inhibitions ( XREF_FIG ) .	In a caspase de-repression assay, JP1400 was slightly better than JP1010 in relieving XIAP mediated caspase-3 and -9 inhibitions (XREF_FIG).	11	19	mediated	Positive_early_activation	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	14	15	16	17
Our results suggest that caspase-3 could be inhibited in the cell by XIAP and that the mRIPA buffer ( lysate preparation ) and subsequent dilution into caspase assay buffer released XIAP from the active caspase-3 , making measurement of the DEVD-ase activity possible .	Our results suggest that caspase-3 could be inhibited in the cell by XIAP and that the mRIPA buffer (lysate preparation) and subsequent dilution into caspase assay buffer released XIAP from the active caspase-3, making measurement of the DEVD-ase activity possible.	4	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	12	13	4	5
Because XIAP binds to and inhibits caspase-3 , we reasoned that the inhibition of caspase-3 by XIAP must be relieved for efficient apoptosis induction by Smac mimetics and XIAP is a critical cellular target for Smac mimetics .	Because XIAP binds to and inhibits caspase-3, we reasoned that the inhibition of caspase-3 by XIAP must be relieved for efficient apoptosis induction by Smac mimetics and XIAP is a critical cellular target for Smac mimetics.	12	17	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	16	17	14	15
Ectopically expressed Siva1 increased caspase-3 activity , which was inhibited by XIAP in a ubiquitin-ligase-dependent manner .	Ectopically expressed Siva1 increased caspase-3 activity, which was inhibited by XIAP in a ubiquitin-ligase-dependent manner.	4	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	11	12	4	5
FLIP , which contains a catalytically inactive caspase like domain , interferes with the activation of caspase8 [ XREF_BIBR ] , an apoptotic initiator caspase ; while XIAP inhibits caspase3 , an apoptotic executioner caspase , through its second baculoviral IAP repeat ( BIR ) domain and NH 2 -linker [ XREF_BIBR ] .	FLIP, which contains a catalytically inactive caspase like domain, interferes with the activation of caspase8 [XREF_BIBR], an apoptotic initiator caspase; while XIAP inhibits caspase3, an apoptotic executioner caspase, through its second baculoviral IAP repeat (BIR) domain and NH 2 -linker [XREF_BIBR].	27	34	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase3	caspase3	caspase3	27	28	29	30
Relevant downstream targets of this pathway likely include the antiapoptosis factors MCL-1 and XIAP , which sustain mitochondrial integrity and directly prevent caspase 3 activation , respectively ( McCracken & Allen , 2014 ) .	Relevant downstream targets of this pathway likely include the antiapoptosis factors MCL-1 and XIAP, which sustain mitochondrial integrity and directly prevent caspase 3 activation, respectively (McCracken & Allen, 2014).	7	30	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	13	14	22	24
These results suggest high XIAP may prevent activation of caspase-3 , thereby regulating follicular atresia in antral follicles and could potentially be utilized as a marker of follicular health .	These results suggest high XIAP may prevent activation of caspase-3, thereby regulating follicular atresia in antral follicles and could potentially be utilized as a marker of follicular health.	3	22	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	4	5	9	10
XIAP appears to be one of the strongest inhibitors of the apoptotic machinery and suppresses apoptosis by preventing activation of caspase-3 and caspase-9 [ XREF_BIBR ] .	XIAP appears to be one of the strongest inhibitors of the apoptotic machinery and suppresses apoptosis by preventing activation of caspase-3 and caspase-9 [XREF_BIBR].	0	24	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	20	21
Abundance of anti-apoptotic proteins of IAP protein family , including cIAP1 , cIAP2and XIAP , which directly inhibit caspase 3 and 9 activation , was increased in DKO cells , adding to the protection from apoptosis provided by the decrease in Bax and increase in Bcl-2 and Bcl-xL .	Abundance of anti-apoptotic proteins of IAP protein family, including cIAP1, cIAP2and XIAP, which directly inhibit caspase 3 and 9 activation, was increased in DKO cells, adding to the protection from apoptosis provided by the decrease in Bax and increase in Bcl-2 and Bcl-xL.	12	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	13	14	18	20
In determining the influence of caspase-3 on muscle protein metabolism in rodent models of diabetes and CKD , we found that increased XIAP expression not only attenuates caspase-3 activity but also reduces muscle protein loss .	In determining the influence of caspase-3 on muscle protein metabolism in rodent models of diabetes and CKD, we found that increased XIAP expression not only attenuates caspase-3 activity but also reduces muscle protein loss.	22	28	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP expression	xiap	caspase-3	caspase-3	caspase-3	22	23	27	28
Specific inhibition of XIAP expression using an antisense XIAP phosphorodiamidate morpholino oligomer induced apoptosis and increased caspase-3 activity .	Specific inhibition of XIAP expression using an antisense XIAP phosphorodiamidate morpholino oligomer induced apoptosis and increased caspase-3 activity.	3	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP expression	xiap	caspase-3	caspase-3	caspase-3	3	4	16	17
5 XIAP is a known inhibitor of caspase-3 , caspase-7 and caspase-9 .	5 XIAP is a known inhibitor of caspase-3, caspase-7 and caspase-9.	0	11	is a known inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	1	2	7	8
Deletion of XIAP in the mouse or truncation of the ubiquitination promoting RING domain also caused elevated caspase-3 activity and sensitivity to apoptosis , demonstrating a critical role for XIAP mediated ubiquitination of caspase-3 in vivo .	Deletion of XIAP in the mouse or truncation of the ubiquitination promoting RING domain also caused elevated caspase-3 activity and sensitivity to apoptosis, demonstrating a critical role for XIAP mediated ubiquitination of caspase-3 in vivo.	0	18	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	2	3	17	18
Caspase-8 and Granzyme-B Partially Bypass the XIAP mediated Inhibition of Caspase-3 in HL derived B Cell Lines .	Caspase-8 and Granzyme-B Partially Bypass the XIAP mediated Inhibition of Caspase-3 in HL derived B Cell Lines.	5	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	Caspase-3	Caspase-3	Caspase-3	6	7	10	11
LTD is also blocked by overexpression of Bcl-xl ( an anti-apoptotic member of the Bcl2 family ) or XIAP ( a direct protein inhibitor of caspase-9 and caspase-3 ) [ XREF_BIBR ] .	LTD is also blocked by overexpression of Bcl-xl (an anti-apoptotic member of the Bcl2 family) or XIAP (a direct protein inhibitor of caspase-9 and caspase-3) [XREF_BIBR].	5	28	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	XIAP	overexpression of Bcl-xl (an anti-apoptotic member of the Bcl2 family) or XIAP	xiap	caspase-3	caspase-3	caspase-3	18	19	27	28
No differences were observed between groups in the levels of procaspase-7 or -12 or in XIAP ( an endogenous inhibitor of apoptosis , particularly of caspase-3 and -7 ) in any tissue .	No differences were observed between groups in the levels of procaspase-7 or -12 or in XIAP (an endogenous inhibitor of apoptosis, particularly of caspase-3 and -7) in any tissue.	3	31	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	15	16	25	26
Based on the first interrogation of the mechanism of IAPs in the laboratory of John Reeds , 106 XIAP was found to prevent caspase-3 processing in response to caspase-8 activation , thereby inhibit the extrinsic apoptotic signalling by blocking the activity of the downstream effector caspases , as opposed to interfering directly with caspase-8 activation .	Based on the first interrogation of the mechanism of IAPs in the laboratory of John Reeds, 106 XIAP was found to prevent caspase-3 processing in response to caspase-8 activation, thereby inhibit the extrinsic apoptotic signalling by blocking the activity of the downstream effector caspases, as opposed to interfering directly with caspase-8 activation.	17	24	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	18	19	23	24
XIAP is a direct inhibitor of execution caspase 3 and caspase 7 and suppresses the Bax and cytochrome c pathway by inhibiting caspase 9 [ XREF_BIBR , XREF_BIBR ] .	XIAP is a direct inhibitor of execution caspase 3 and caspase 7 and suppresses the Bax and cytochrome c pathway by inhibiting caspase 9 [XREF_BIBR, XREF_BIBR].	0	13	is a direct inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	0	1	7	9
In a caspase-3 functional assay , 20 nM of XIAP protein containing linker-BIR2-BIR3 can inhibit 90 % of the enzymatic activity of caspase-3 ( XREF_FIG ) .	In a caspase-3 functional assay, 20 nM of XIAP protein containing linker-BIR2-BIR3 can inhibit 90% of the enzymatic activity of caspase-3 (XREF_FIG).	9	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	9	10	22	23
The consequence of these effects could be an early attempt of fetal rhombencephalic neurons to defend themselves against the pro apoptotic effects of ethanol , because XIAP inhibits the activity of caspase-3 and increased Bcl-XL stabilizes the mitochondria from releasing cytochrome C. Moreover , increased catalase would attenuate ethanol associated oxidative stress and the associated apoptosis by catalyzing the conversion of hydrogen peroxide to water .	The consequence of these effects could be an early attempt of fetal rhombencephalic neurons to defend themselves against the pro apoptotic effects of ethanol, because XIAP inhibits the activity of caspase-3 and increased Bcl-XL stabilizes the mitochondria from releasing cytochrome C. Moreover, increased catalase would attenuate ethanol associated oxidative stress and the associated apoptosis by catalyzing the conversion of hydrogen peroxide to water.	26	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	26	27	31	32
Therefore , loss of XIAP does not lead to any further increase of caspase-3 activation as it is observed in type I pathway .	Therefore, loss of XIAP does not lead to any further increase of caspase-3 activation as it is observed in type I pathway.	2	14	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	XIAP	loss of XIAP	xiap	caspase-3	caspase-3	caspase-3	4	5	13	14
Detailed analysis of cellular localization of XIAP revealed that in the striatum of oxycodone exposed animals , the level of XIAP decreased in axonal bundles that coincided with increase in phospho-eIF2alpha , ATF4 , Bax and activated caspase 3 suggesting activation pro apoptotic signaling in axons .	Detailed analysis of cellular localization of XIAP revealed that in the striatum of oxycodone exposed animals, the level of XIAP decreased in axonal bundles that coincided with increase in phospho-eIF2alpha, ATF4, Bax and activated caspase 3 suggesting activation pro apoptotic signaling in axons.	18	39	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	level of XIAP	xiap	caspase 3	caspase 3	caspase 3	20	21	37	39
Surprisingly , we show here that binding of a dimeric Smac N-terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase-3 by XIAP .	Surprisingly, we show here that binding of a dimeric Smac N-terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase-3 by XIAP.	20	26	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	25	26	23	24
The resulting lack of X linked inhibitor of apoptosis ( XIAP ) inhibition by cytosolic Smac/DIABLO most likely caused the TRAIL resistance as RNAi against XIAP rescued caspase-3 activity and TRAIL sensitivity .	The resulting lack of X linked inhibitor of apoptosis (XIAP) inhibition by cytosolic Smac/DIABLO most likely caused the TRAIL resistance as RNAi against XIAP rescued caspase-3 activity and TRAIL sensitivity.	18	28	rescued	Positive_activation_token_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	25	26	27	28
XIAP inhibits the activation of caspase-3 and caspase-9 by binding to their BIR2 and BIR3 domains , respectively [ XREF_BIBR ] .	XIAP inhibits the activation of caspase-3 and caspase-9 by binding to their BIR2 and BIR3 domains, respectively [XREF_BIBR].	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	5	6
Consequently , a high HGF level activated the PI3K-Akt pathway and a high XIAP level suppressed caspase 3 activity in the first 14 days after Adv transduction ( XREF_FIG ) .	Consequently, a high HGF level activated the PI3K-Akt pathway and a high XIAP level suppressed caspase 3 activity in the first 14 days after Adv transduction (XREF_FIG).	13	18	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP level	xiap	caspase 3	caspase 3	caspase 3	13	14	16	18
The most well characterized mammalian inhibitor of apoptosis ( IAP ) is XIAP which can inhibit Caspase-3 and -7 by binding to their active catalytic sites with low nanomolar efficiency XREF_BIBR - XREF_BIBR .	The most well characterized mammalian inhibitor of apoptosis (IAP) is XIAP which can inhibit Caspase-3 and -7 by binding to their active catalytic sites with low nanomolar efficiency XREF_BIBR - XREF_BIBR.	5	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	Caspase-3	Caspase-3	Caspase-3	12	13	16	17
1 ) Overexpression of XIAP abolishes apoptosis and Casp3 activation in response to microinjection of cyto c ( type MN ) [ XREF_BIBR ] .	1) Overexpression of XIAP abolishes apoptosis and Casp3 activation in response to microinjection of cyto c (type MN) [XREF_BIBR].	2	9	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	Overexpression of XIAP	xiap	Casp3	Casp3	casp3	4	5	8	9
Similarly , the inhibition of XIAP expression with specific oligomers has been shown to induce caspase-3 activity , boosting the apoptotic effect of cisplatin and TRAIL in human prostate androgen-insensitive cancer cells [ XREF_BIBR ] .	Similarly, the inhibition of XIAP expression with specific oligomers has been shown to induce caspase-3 activity, boosting the apoptotic effect of cisplatin and TRAIL in human prostate androgen-insensitive cancer cells [XREF_BIBR].	5	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP expression	xiap	caspase-3	caspase-3	caspase-3	5	6	15	16
The other version of this motif is exemplified by XIAP ( X ) , which inhibits both Casp9 ( Y ) and Casp3 ( Z ) , two species coupled by a positive FBL .	The other version of this motif is exemplified by XIAP (X), which inhibits both Casp9 (Y) and Casp3 (Z), two species coupled by a positive FBL.	7	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	Casp3	Casp3	Casp3	9	10	22	23
CTSB mediated degradation of XIAP subsequently induced activation of caspase-3 and its nuclear entry to execute apoptosis .	CTSB mediated degradation of XIAP subsequently induced activation of caspase-3 and its nuclear entry to execute apoptosis.	2	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	4	5	9	10
This pseudoactivated caspase-3 was not inhibited by XIAP ( X linked inhibitor of apoptosis protein ) and rapidly killed cells at low concentrations .	This pseudoactivated caspase-3 was not inhibited by XIAP (X linked inhibitor of apoptosis protein) and rapidly killed cells at low concentrations.	0	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	7	8	2	3
It was observed that XIAP could inhibit both p17 and p12 and p20 and p12 forms of active caspase 3 .	It was observed that XIAP could inhibit both p17 and p12 and p20 and p12 forms of active caspase 3.	4	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	4	5	18	20
XIAP inhibits caspase-3 by the degradation of caspase-3 ( ( 4 ) in XREF_FIG ) , and caspase-3 inhibits XIAP through ubiquitination and degradation , ( 5 ) in XREF_FIG .	XIAP inhibits caspase-3 by the degradation of caspase-3 ((4) in XREF_FIG), and caspase-3 inhibits XIAP through ubiquitination and degradation, (5) in XREF_FIG.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	2	3
XREF_BIBR - XREF_BIBR While monovalent Smac mimetics can effectively and potently antagonize the inhibition by XIAP BIR3 protein of caspase-9 activity , they are less effective in antagonizing the inhibition of caspase-3 by XIAP protein containing both BIR2 and BIR3 domains .	XREF_BIBR - XREF_BIBR While monovalent Smac mimetics can effectively and potently antagonize the inhibition by XIAP BIR3 protein of caspase-9 activity, they are less effective in antagonizing the inhibition of caspase-3 by XIAP protein containing both BIR2 and BIR3 domains.	29	34	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	33	34	31	32
Even after stimulation with exogenous cytochrome c and dATP , XIAP impairs the proteolytic processing and activation of caspase-3 .	Even after stimulation with exogenous cytochrome c and dATP, XIAP impairs the proteolytic processing and activation of caspase-3.	10	19	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	10	11	18	19
Our results suggest that reinforcement of the positive feedback by XIAP , which relieves XIAP mediated caspase-3 inhibition , might favor a pro apoptotic cellular fate .	Our results suggest that reinforcement of the positive feedback by XIAP, which relieves XIAP mediated caspase-3 inhibition, might favor a pro apoptotic cellular fate.	13	17	mediated	Positive_early_activation	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	14	15	16	17
In the absence of MMP , caspase-3 subunits were degraded by the XIAP and proteasome pathway .	In the absence of MMP, caspase-3 subunits were degraded by the XIAP and proteasome pathway.	6	15	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	12	13	6	7
The efficacy of NK cell killing was attenuated by upregulation of XIAP to bind caspase-3 in tumor cells to escape apoptosis .	The efficacy of NK cell killing was attenuated by upregulation of XIAP to bind caspase-3 in tumor cells to escape apoptosis.	7	17	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	11	12	14	15
According to this model , the hyperactivation of CDK1 caused by WEE1 inhibition leads to futile cycles of increased replication origin firing , nucleotide depletion , and decreased replication fork progression XREF_BIBR , XREF_BIBR .	According to this model, the hyperactivation of CDK1 caused by WEE1 inhibition leads to futile cycles of increased replication origin firing, nucleotide depletion, and decreased replication fork progression XREF_BIBR, XREF_BIBR.	6	12	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	11	12	8	9
Current evidence demonstrates that CDK1 , which triggers mitotic entry by binding cyclin B , is inactivated by WEE1 .	Current evidence demonstrates that CDK1, which triggers mitotic entry by binding cyclin B, is inactivated by WEE1.	4	19	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	18	19	4	5
In contrast , during morphogenesis checkpoint activation , which monitors cell size and triggers Wee1 dependent inhibition of Cdk1 , pds1Delta cells remain arrested in metaphase , despite the assembly of a mitotic spindle and the generation of pulling forces on sister chromatids [ XREF_BIBR , XREF_BIBR ] .	In contrast, during morphogenesis checkpoint activation, which monitors cell size and triggers Wee1 dependent inhibition of Cdk1, pds1Delta cells remain arrested in metaphase, despite the assembly of a mitotic spindle and the generation of pulling forces on sister chromatids [XREF_BIBR, XREF_BIBR].	14	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	14	15	18	19
In summary , miR-129 suppressed lung cancer cell proliferation by arresting cell cycle at G2/M phase through inactivation of CDK1 by Wee1 , and reduced cell migration and invasion in lung cancer through controlling the protein levels of NF-kappaB and MMP-2 .	In summary, miR-129 suppressed lung cancer cell proliferation by arresting cell cycle at G2/M phase through inactivation of CDK1 by Wee1, and reduced cell migration and invasion in lung cancer through controlling the protein levels of NF-kappaB and MMP-2.	10	22	arresting	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	21	22	19	20
Cdk1 is regulated positively by Cdc25 and negatively regulated by Wee1 .	Cdk1 is regulated positively by Cdc25 and negatively regulated by Wee1.	0	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	10	11	0	1
Before the G2/M transition leading to cell division , Wee1 reversibly arrests the cell cycle by inactivating cdc2 through phosphorylation at Tyr 15 .	Before the G2/M transition leading to cell division, Wee1 reversibly arrests the cell cycle by inactivating cdc2 through phosphorylation at Tyr 15.	9	18	arrests	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	cdc2	cdc2	cdc2	9	10	17	18
The WEE1 kinase inactivates CDK1 by phosphorylating Tyr15 .	The WEE1 kinase inactivates CDK1 by phosphorylating Tyr15.	1	5	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	1	2	4	5
Thus , after the activation of the G2/M checkpoint , CHK1 , CHK2 , and WEE1 cooperate to negatively regulate CDK1 to prevent the formation of the complex with the cyclin B [ XREF_BIBR ] .	Thus, after the activation of the G2/M checkpoint, CHK1, CHK2, and WEE1 cooperate to negatively regulate CDK1 to prevent the formation of the complex with the cyclin B [XREF_BIBR].	10	21	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	15	16	20	21
MYC-SL genes involved in DNA repair processes were polymerases with roles in translesion DNA synthesis ( POLH and REV1L ) , an endonuclease ( NEIL ) , mitotic checkpoint genes activated in response to DNA damage ( the WEE1 and WEE2 that inhibit CDK2 and CDK1 activity ) , regulators of the mitotic spindle ( PRC1 ) , and components of the cohesin complex ( RAD21 ) .	MYC-SL genes involved in DNA repair processes were polymerases with roles in translesion DNA synthesis (POLH and REV1L), an endonuclease (NEIL), mitotic checkpoint genes activated in response to DNA damage (the WEE1 and WEE2 that inhibit CDK2 and CDK1 activity), regulators of the mitotic spindle (PRC1), and components of the cohesin complex (RAD21).	29	46	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	38	39	45	46
During AMCD induced prolonged mitosis , Fcp1 dependent Wee1 reactivation lowered cdk1 activity , weakening SAC dependent mitotic arrest and leading to mitosis exit and survival .	During AMCD induced prolonged mitosis, Fcp1 dependent Wee1 reactivation lowered cdk1 activity, weakening SAC dependent mitotic arrest and leading to mitosis exit and survival.	8	12	lowered	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	cdk1	cdk1	cdk1	8	9	11	12
To generate active cyclin B-CDK1 complexes , we coexpressed cyclin B1 or B2 with a mutant form of CDK1 , CDK1 T14A , Y15F ( hereafter referred to as CDK1 AF ) that can not be inactivated by either the Wee1 or Myt1 kinases ( Morgan 1995 ) .	To generate active cyclin B-CDK1 complexes, we coexpressed cyclin B1 or B2 with a mutant form of CDK1, CDK1 T14A, Y15F (hereafter referred to as CDK1 AF) that can not be inactivated by either the Wee1 or Myt1 kinases (Morgan 1995).	10	43	inactivated	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	40	41	18	19
Thus , inhibition of Wee1 after the gemcitabine treatment increases Cdk1 activity , which impairs DNA resection by CtIP and weakens the activation of ATR .	Thus, inhibition of Wee1 after the gemcitabine treatment increases Cdk1 activity, which impairs DNA resection by CtIP and weakens the activation of ATR.	2	11	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	4	5	10	11
A critical component of this DNA checkpoint is Wee1 , a tyrosine kinase that inactivates CDC2 through selective phosphorylation of its Tyr15 residue .	A critical component of this DNA checkpoint is Wee1, a tyrosine kinase that inactivates CDC2 through selective phosphorylation of its Tyr15 residue.	2	16	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDC2	CDC2	CDC2	8	9	15	16
The activity of p34cdc2 is controlled , in part , by the wee1 protein kinase , which inactivates cdc2 through phosphorylation at tyrosine 15 ( ref .	The activity of p34cdc2 is controlled, in part, by the wee1 protein kinase, which inactivates cdc2 through phosphorylation at tyrosine 15 (ref.	12	19	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	wee1	wee1	wee1	cdc2	cdc2	cdc2	12	13	18	19
WEE1 also negatively regulates CDK1 dependent replication origin firing and thus acts to prevent aberrant origin firing leading to nucleotide pool depletion and replication stress XREF_BIBR .	WEE1 also negatively regulates CDK1 dependent replication origin firing and thus acts to prevent aberrant origin firing leading to nucleotide pool depletion and replication stress XREF_BIBR.	0	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	0	1	4	5
Bortezomib also increased the ubiquitination of cyclin B1 and wee1 , but inhibited the kinase activity of the cdc2 and cyclin B complex .	Bortezomib also increased the ubiquitination of cyclin B1 and wee1, but inhibited the kinase activity of the cdc2 and cyclin B complex.	0	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	wee1	Bortezomib also increased the ubiquitination of cyclin B1 and wee1	wee1	cdc2	cdc2	cdc2	9	10	18	19
On the other hand , IndOH-LNC treatment increased the levels of Wee1 ( XREF_FIG ) , a component of the G2/M checkpoint that inhibits cdc2 .	On the other hand, IndOH-LNC treatment increased the levels of Wee1 (XREF_FIG), a component of the G2/M checkpoint that inhibits cdc2.	9	25	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Wee1	levels of Wee1	wee1	cdc2	cdc2	cdc2	11	12	24	25
Inhibition of Cdk1 by Wee1 has been well characterized in X. laevis and other systems [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Inhibition of Cdk1 by Wee1 has been well characterized in X. laevis and other systems [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	5	Inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	4	5	2	3
Inhibition of Wee1 thereby activates CDK1 , facilitating cells to enter the mitotic phase .	Inhibition of Wee1 thereby activates CDK1, facilitating cells to enter the mitotic phase.	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	2	3	5	6
Also , inhibition of a double positive feedback loop can be seen in G1 and S phases of the yeast cell cycle system in which Wee1 and Myt1 kinases inhibit Cdk1 which is activated by a double positive feedback loop with Cdc25 XREF_BIBR XREF_BIBR .	Also, inhibition of a double positive feedback loop can be seen in G1 and S phases of the yeast cell cycle system in which Wee1 and Myt1 kinases inhibit Cdk1 which is activated by a double positive feedback loop with Cdc25 XREF_BIBR XREF_BIBR.	25	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	25	26	30	31
On DNA damage , Chk1 and Wee1 phosphorylate and inhibit cdk1 , thus preventing entry into mitosis .	On DNA damage, Chk1 and Wee1 phosphorylate and inhibit cdk1, thus preventing entry into mitosis.	4	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	cdk1	cdk1	cdk1	6	7	10	11
In Xenopus , Drosophila or Zebrafish embryos early embryonic cell cycles are regulated by a balance of the two cell cycle regulators Wee1 and Cdc25 which inhibit or activate cdk1 respectively to set interphase length .	In Xenopus, Drosophila or Zebrafish embryos early embryonic cell cycles are regulated by a balance of the two cell cycle regulators Wee1 and Cdc25 which inhibit or activate cdk1 respectively to set interphase length.	12	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	cdk1	cdk1	cdk1	22	23	29	30
Wee1 inactivates the mitotic cyclin dependent kinase CDK1 during interphase through phosphorylation on tyrosine 15 .	Wee1 inactivates the mitotic cyclin dependent kinase CDK1 during interphase through phosphorylation on tyrosine 15.	0	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	0	1	7	8
In the detailed model for the mammalian cell cycle , the kinase Wee1 can inhibit Cdk1 and to a lesser extent Cdk2 .	In the detailed model for the mammalian cell cycle, the kinase Wee1 can inhibit Cdk1 and to a lesser extent Cdk2.	10	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	12	13	15	16
Moreover , Wee1 , a tyrosine kinase repressor of CDK1 and CDK2 , is targeted by small molecules to prevent repression of CDK1 and CDK2 in response to DNA damage and thus enhance genetic instability and apoptosis [ XREF_BIBR ] .	Moreover, Wee1, a tyrosine kinase repressor of CDK1 and CDK2, is targeted by small molecules to prevent repression of CDK1 and CDK2 in response to DNA damage and thus enhance genetic instability and apoptosis [XREF_BIBR].	2	32	targeted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	2	3	22	23
Thus , inhibition either of Wee1 , Chk1 , or ATR leads to decreased inhibitory phosphorylation of Cdk1 and thereby increased Cdk1 activity and G2 checkpoint abrogation .	Thus, inhibition either of Wee1, Chk1, or ATR leads to decreased inhibitory phosphorylation of Cdk1 and thereby increased Cdk1 activity and G2 checkpoint abrogation.	2	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	5	6	21	22
Since Wee1 inactivates CDK1 and Cyclin B during the S and G2 phases , its activity must be down-regulated for mitotic progression to occur [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Since Wee1 inactivates CDK1 and Cyclin B during the S and G2 phases, its activity must be down-regulated for mitotic progression to occur [XREF_BIBR, XREF_BIBR - XREF_BIBR].	1	6	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	1	2	3	4
One strategy to achieve this objective is via the inhibition of WEE1 , a cell cycle kinase that normally inactivates CDK1 by phosphorylating Tyr15 .	One strategy to achieve this objective is via the inhibition of WEE1, a cell cycle kinase that normally inactivates CDK1 by phosphorylating Tyr15.	9	21	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	11	12	20	21
In uninfected cells the G ( 2 )/M transition is regulated by cyclin kinase complex containing cdc2 and , initially , cyclin A , followed by cyclin B. cdc2 is downregulated through phosphorylation by wee-1 and myt-1 and upregulated by cdc-25C phosphatase .	In uninfected cells the G (2)/M transition is regulated by cyclin kinase complex containing cdc2 and, initially, cyclin A, followed by cyclin B. cdc2 is downregulated through phosphorylation by wee-1 and myt-1 and upregulated by cdc-25C phosphatase.	27	36	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	wee-1	wee-1	wee-1	cdc2	cdc2	cdc2	34	35	28	29
The cdc2 +/cyclin B kinase is positively regulated by cdc25+ tyrosine phosphatase and negatively regulated by wee1 +/mik1+ tyrosine kinases .	The cdc2 +/cyclin B kinase is positively regulated by cdc25+ tyrosine phosphatase and negatively regulated by wee1 +/mik1+ tyrosine kinases.	1	19	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	wee1	wee1	wee1	cdc2	cdc2	cdc2	16	17	1	2
The kinases Wee1 and Myt1 phosphorylate Thr 14 and Tyr 15 and thereby inactivate Cdk1 XREF_BIBR - XREF_BIBR .	The kinases Wee1 and Myt1 phosphorylate Thr 14 and Tyr 15 and thereby inactivate Cdk1 XREF_BIBR - XREF_BIBR.	0	15	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	2	3	14	15
It is known that Wee1 kinase , which phosphorylates and thereby inactivates the CDC2 and Cyclin B1 complex to inhibit G2/M transition , is regulated by the clock XREF_BIBR , XREF_BIBR , and is activated at dawn .	It is known that Wee1 kinase, which phosphorylates and thereby inactivates the CDC2 and Cyclin B1 complex to inhibit G2/M transition, is regulated by the clock XREF_BIBR, XREF_BIBR, and is activated at dawn.	4	19	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDC2	CDC2	CDC2	4	5	13	14
The Wee1 kinase inhibits Cdk1 via phosphorylation of a conserved tyrosine , which restrains entry into mitosis .	The Wee1 kinase inhibits Cdk1 via phosphorylation of a conserved tyrosine, which restrains entry into mitosis.	1	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	1	2	4	5
For example , Wee1 and Myt1 kinases inhibit Cdk1 activity through phosphorylation of threonine and tyrosine residues , while Cdc25 phosphatases restore activity by dephosphorylation of these residues .	For example, Wee1 and Myt1 kinases inhibit Cdk1 activity through phosphorylation of threonine and tyrosine residues, while Cdc25 phosphatases restore activity by dephosphorylation of these residues.	3	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	3	4	8	9
Cds1 is proposed to regulate Wee1 and Mik1 , two tyrosine kinases that inhibit the mitotic kinase Cdc2 .	Cds1 is proposed to regulate Wee1 and Mik1, two tyrosine kinases that inhibit the mitotic kinase Cdc2.	4	18	inhibit	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	5	6	17	18
We demonstrate that the S-phase checkpoint protects the nucleus from active cytoplasmic CDK1-CycB via two distinct mechanisms involving Grapes ( Chk1 )-dependent control of CycB nuclear localization and Wee1 dependent inhibition of nuclear CDK1 .	We demonstrate that the S-phase checkpoint protects the nucleus from active cytoplasmic CDK1-CycB via two distinct mechanisms involving Grapes (Chk1)-dependent control of CycB nuclear localization and Wee1 dependent inhibition of nuclear CDK1.	28	34	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	28	29	33	34
In the model , Wee1 suppresses cycB and Cdk1 more strongly than it suppresses cycA and Cdk1 .	In the model, Wee1 suppresses cycB and Cdk1 more strongly than it suppresses cycA and Cdk1.	4	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	4	5	8	9
Here we demonstrate that Wee1 inhibition by MK1775 results in activation of CDC2 , as assessed by decreased Tyr15 phosphorylation , unscheduled mitotic entry and significant cell death in sarcoma cell lines as well as in patient derived sarcoma tumors .	Here we demonstrate that Wee1 inhibition by MK1775 results in activation of CDC2, as assessed by decreased Tyr15 phosphorylation, unscheduled mitotic entry and significant cell death in sarcoma cell lines as well as in patient derived sarcoma tumors.	4	13	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDC2	CDC2	CDC2	4	5	12	13
During interphase , Cdk1 activity is downregulated by Wee1- and Myt1 dependent phosphorylation of conserved threonine T14 and tyrosine Y15 residues in the ATP binding domain of Cdk1 XREF_BIBR .	During interphase, Cdk1 activity is downregulated by Wee1- and Myt1 dependent phosphorylation of conserved threonine T14 and tyrosine Y15 residues in the ATP binding domain of Cdk1 XREF_BIBR.	3	13	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Wee1-	Wee1- and Myt1 dependent phosphorylation	wee1-	Cdk1	Cdk1	cdk1	8	9	3	4
Wee1 , a kind of tyrosine kinases , can inactivate Cdc2 and Cdc13 ( MPF ) in this way .	Wee1, a kind of tyrosine kinases, can inactivate Cdc2 and Cdc13 (MPF) in this way.	0	18	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	0	1	10	11
The other target for CDC2 mediated inactivation by phosphorylation is WEE1 , which can also reciprocally inhibit CDC2 function by phosphorylation XREF_BIBR .	The other target for CDC2 mediated inactivation by phosphorylation is WEE1, which can also reciprocally inhibit CDC2 function by phosphorylation XREF_BIBR.	5	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDC2	CDC2	CDC2	10	11	17	18
In response to DNA damage , WEE1 inactivates CDK1 through an inhibitory phosphorylation of its tyrosine 15 residue ( pCDK1-Y15 ) .	In response to DNA damage, WEE1 inactivates CDK1 through an inhibitory phosphorylation of its tyrosine 15 residue (pCDK1-Y15).	6	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	6	7	8	9
In the canonical pathway , cyclic AMP activated protein kinase A ( PKA ) activates WEE1 , which inhibits Cdk1 and CycB and thereby prevents meiotic resumption .	In the canonical pathway, cyclic AMP activated protein kinase A (PKA) activates WEE1, which inhibits Cdk1 and CycB and thereby prevents meiotic resumption.	14	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	Cdk1	Cdk1	Cdk1	15	16	19	20
This effect could be related to decreased cdc25c mediated cdk1 activation or to Wee1 inactivation of cdk1 as suggested by Tyr15 phosphorylation [ XREF_BIBR ] .	This effect could be related to decreased cdc25c mediated cdk1 activation or to Wee1 inactivation of cdk1 as suggested by Tyr15 phosphorylation [XREF_BIBR].	13	17	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	cdk1	cdk1	cdk1	13	14	16	17
Wee1 , the Cdc2 inhibitory kinase , needs to be down-regulated at the onset of mitosis to ensure rapid activation of Cdc2 .	Wee1, the Cdc2 inhibitory kinase, needs to be down-regulated at the onset of mitosis to ensure rapid activation of Cdc2.	0	22	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	0	1	21	22
For example , the wee1 kinase inhibits CDK1 by phosphorylating the Tyrosine 15 in the N-terminal glycine rich loop and obstructing access of the substrate to the kinase active site .	For example, the wee1 kinase inhibits CDK1 by phosphorylating the Tyrosine 15 in the N-terminal glycine rich loop and obstructing access of the substrate to the kinase active site.	4	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	wee1	wee1	wee1	CDK1	CDK1	CDK1	4	5	7	8
Cdc25C , Wee1 and Myt1 then decrease the activity of the CDK1 and cyclin B1 complex , resulting in an arrest of the cell cycle at the G2/M phase .	Cdc25C, Wee1 and Myt1 then decrease the activity of the CDK1 and cyclin B1 complex, resulting in an arrest of the cell cycle at the G2/M phase.	0	15	decrease	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	2	3	11	12
The expression of Vpr correlates with inactivation of the p34 and cdc2 CDK1 kinase associated with cyclin B. Cdc2 is normally activated by the cdc5 phosphatase which is inactive in its hypophosphorylated form in Vpr expressing cells , whereas Wee1 inhibits the cdc2 kinases .	The expression of Vpr correlates with inactivation of the p34 and cdc2 CDK1 kinase associated with cyclin B. Cdc2 is normally activated by the cdc5 phosphatase which is inactive in its hypophosphorylated form in Vpr expressing cells, whereas Wee1 inhibits the cdc2 kinases.	39	43	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	cdc2	cdc2	cdc2	39	40	42	43
A key player is Wee1 , which negatively regulates CDK1 to prevent mitosis , and Wee1 levels are diminished in Roma -/- mammary glands ( XREF_FIG E ) .	A key player is Wee1, which negatively regulates CDK1 to prevent mitosis, and Wee1 levels are diminished in Roma -/- mammary glands (XREF_FIG E).	2	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	4	5	9	10
WEE1 has a well defined role in cell cycle checkpoint control , with WEE1 activity limiting the pro mitotic effects of CDC2 ( aka CDK1 ) XREF_BIBR .	WEE1 has a well defined role in cell cycle checkpoint control, with WEE1 activity limiting the pro mitotic effects of CDC2 (aka CDK1) XREF_BIBR.	13	24	limiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDC2	CDC2	CDC2	13	14	21	22
The activated WEE1 and inactivated Cdc25c coordinay prevented Cdc2 and cyclin B activation and mitotic entry in cancer cells .	The activated WEE1 and inactivated Cdc25c coordinay prevented Cdc2 and cyclin B activation and mitotic entry in cancer cells.	0	12	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	Cdc2	Cdc2	Cdc2	2	3	8	9
The approach was investigated by inhibiting the WEE1 kinase , a cell cycle kinase that negatively regulates CDK1 activity .	The approach was investigated by inhibiting the WEE1 kinase, a cell cycle kinase that negatively regulates CDK1 activity.	7	18	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	7	8	17	18
Importantly , cdc2 ( CDK1 ) , a direct substrate of Wee1 that is inhibited by Wee1 , has been described as a proapoptotic mediator 39 .	Importantly, cdc2 (CDK1), a direct substrate of Wee1 that is inhibited by Wee1, has been described as a proapoptotic mediator 39.	2	20	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	cdc2	cdc2	cdc2	16	17	2	3
Progression from the S to the G2/M phase is a complex process , and involves cdc2 and cyclinB which are regulated positively by cdc25 phosphatase and negatively by Wee1 kinase .	Progression from the S to the G2/M phase is a complex process, and involves cdc2 and cyclinB which are regulated positively by cdc25 phosphatase and negatively by Wee1 kinase.	14	29	negatively	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	cdc2	cdc2	cdc2	28	29	15	16
Prior to the MBT in X. laevis embryos , Wee1 and Myt1 act in opposition to Cdc25C , inhibiting Cdk1 [ XREF_BIBR , XREF_BIBR ] .	Prior to the MBT in X. laevis embryos, Wee1 and Myt1 act in opposition to Cdc25C, inhibiting Cdk1 [XREF_BIBR, XREF_BIBR].	9	23	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	9	10	19	20
Eukaryotic mitotic entry is controlled by Cdk1 , which is activated by the Cdc25 phosphatase and inhibited by Wee1 tyrosine kinase , a target of the ubiquitin proteasome pathway .	Eukaryotic mitotic entry is controlled by Cdk1, which is activated by the Cdc25 phosphatase and inhibited by Wee1 tyrosine kinase, a target of the ubiquitin proteasome pathway.	4	20	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	18	19	6	7
Wee1 inhibits cdc2 activity through tyrosine phosphorylation , while dephosphorylation of cdc2 by the phosphatase cdc25 promotes cdc2-cyclinB activation that drives cells into mitosis .	Wee1 inhibits cdc2 activity through tyrosine phosphorylation, while dephosphorylation of cdc2 by the phosphatase cdc25 promotes cdc2-cyclinB activation that drives cells into mitosis.	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	cdc2	cdc2	cdc2	0	1	2	3
A key component of the eukaryotic cell cycle is the protein kinase Wee1 , which inhibits the cyclin dependent kinase Cdk1 in yeast through human cells .	A key component of the eukaryotic cell cycle is the protein kinase Wee1, which inhibits the cyclin dependent kinase Cdk1 in yeast through human cells.	2	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	12	13	20	21
CDK1 activity in turn is negatively regulated by the tyrosine kinase WEE1 and treatment with MK1775 , a selective WEE1 inhibitor , forces CDK1 activation .	CDK1 activity in turn is negatively regulated by the tyrosine kinase WEE1 and treatment with MK1775, a selective WEE1 inhibitor, forces CDK1 activation.	0	13	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	11	12	0	1
Indeed , Wee1 kinases inhibit Cdk1 activity by phosphorylation in the ATP binding domain [ XREF_BIBR ] .	Indeed, Wee1 kinases inhibit Cdk1 activity by phosphorylation in the ATP binding domain [XREF_BIBR].	2	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	2	3	5	6
Cdc2 is negatively regulated by the Wee1 kinase through an inhibitory phosphorylation on Y15 and is positively regulated by the cdc25C phosphatase via dephosphorylation at this same residue .	Cdc2 is negatively regulated by the Wee1 kinase through an inhibitory phosphorylation on Y15 and is positively regulated by the cdc25C phosphatase via dephosphorylation at this same residue.	0	17	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	6	7	0	1
In addition , Cks1B might also regulate Cdk1 activation , by functioning as the link between the cyclin B and Cdk1 complex and either Wee1 and Myt1 kinases ( inactivator of Cdk1 ) or Cdc25 phosphatase ( activator of Cdk1 ) .	In addition, Cks1B might also regulate Cdk1 activation, by functioning as the link between the cyclin B and Cdk1 complex and either Wee1 and Myt1 kinases (inactivator of Cdk1) or Cdc25 phosphatase (activator of Cdk1).	24	32	inactivator	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	24	25	31	32
This post-translational stabilization is negatively controlled by the Wee1 kinase , which can inhibit Cyclin-B and Cdk1 activity .	This post-translational stabilization is negatively controlled by the Wee1 kinase, which can inhibit Cyclin-B and Cdk1 activity.	8	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	8	9	16	17
In response to DNA damage , such as that induced in tumor cells by cytotoxic agents , Wee1 inactivates Cdc2 through phosphorylation of its Tyr15 residue , thus leading to G2 arrest ; this allows transformed cells the time needed for repair of damaged DNA and thus confers a survival advantage XREF_BIBR - XREF_BIBR .	In response to DNA damage, such as that induced in tumor cells by cytotoxic agents, Wee1 inactivates Cdc2 through phosphorylation of its Tyr15 residue, thus leading to G2 arrest; this allows transformed cells the time needed for repair of damaged DNA and thus confers a survival advantage XREF_BIBR - XREF_BIBR.	17	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	17	18	19	20
These seemingly paradoxical findings suggest that Wee1 does not act in a simple all-or-nothing manner to inhibit Cdk1 .	These seemingly paradoxical findings suggest that Wee1 does not act in a simple all-or-nothing manner to inhibit Cdk1.	6	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	6	7	17	18
Another example is the eukaryotic cyclin dependent kinase CDK1 , which is inactivated by the Wee1 and Myt1 protein kinases through the phosphorylation of two residues , Thr 14 and Tyr 15 , in its catalytic cleft .	Another example is the eukaryotic cyclin dependent kinase CDK1, which is inactivated by the Wee1 and Myt1 protein kinases through the phosphorylation of two residues, Thr 14 and Tyr 15, in its catalytic cleft.	1	19	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	15	16	8	9
In r5 , although it is not explicitly modeled , the Wee1 kinase deactivates Cdc2 by adding the inhibitory phosphate group to Cdc2 .	In r5, although it is not explicitly modeled, the Wee1 kinase deactivates Cdc2 by adding the inhibitory phosphate group to Cdc2.	11	15	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	11	12	14	15
Thus , it is speculated that elevated Wee1 expression inhibited CDK1 activity more by phosphorylation , which in turn caused the lower expression of survivin and consequently more activated Caspase-3 in the 14-HALO group .	Thus, it is speculated that elevated Wee1 expression inhibited CDK1 activity more by phosphorylation, which in turn caused the lower expression of survivin and consequently more activated Caspase-3 in the 14-HALO group.	7	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1 expression	wee1	CDK1	CDK1	cdk1	7	8	10	11
XREF_BIBR , XREF_BIBR WEE1 can inhibit the activity of CDK1 , thus delaying the cell cycle in M phase or arresting the cell cycle in G2/M phase .	XREF_BIBR, XREF_BIBR WEE1 can inhibit the activity of CDK1, thus delaying the cell cycle in M phase or arresting the cell cycle in G2/M phase.	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	3	4	9	10
The kinases Wee1 and cdc25 inhibit and activate , respectively , the p34 cdc2 -cyclin B 1 complex .	The kinases Wee1 and cdc25 inhibit and activate, respectively, the p34 cdc2 -cyclin B 1 complex.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	p34 cdc2	p34 cdc2	p34 cdc2	2	3	12	14
Thus , we consider that the activity of Cdk4-6 is activated by phosphorylation by the cyclin activated kinase protein , while Cdk2 and Cdk1 are activated by the phosphatase Cdc25 and inhibited by the kinase Wee1 .	Thus, we consider that the activity of Cdk4-6 is activated by phosphorylation by the cyclin activated kinase protein, while Cdk2 and Cdk1 are activated by the phosphatase Cdc25 and inhibited by the kinase Wee1.	21	36	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	35	36	23	24
However , Wee1 , supposed to inactivate CDK1 by phosphorylations at Thr14 and Tyr15 , increased by 1.80-fold at mRNA level .	However, Wee1, supposed to inactivate CDK1 by phosphorylations at Thr14 and Tyr15, increased by 1.80-fold at mRNA level.	2	15	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	2	3	7	8
In normal cells , WEE1 phosphorylates , and inactivates cyclin dependent kinase CDK1 preventing premature entry into mitosis while DNA integrity is ensured .	In normal cells, WEE1 phosphorylates, and inactivates cyclin dependent kinase CDK1 preventing premature entry into mitosis while DNA integrity is ensured.	4	13	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	4	5	12	13
Wee1 needs to be down-regulated at the onset of mitosis to ensure rapid activation of Cdk1 .	Wee1 needs to be down-regulated at the onset of mitosis to ensure rapid activation of Cdk1.	0	16	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	0	1	15	16
We therefore concluded that untimely nucleolar disruption during interphase induced improper stabilization of Wee1 , which suppressed Cdk1 activation and delayed mitotic entry .	We therefore concluded that untimely nucleolar disruption during interphase induced improper stabilization of Wee1, which suppressed Cdk1 activation and delayed mitotic entry.	11	18	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	13	14	17	18
Phosphorylation of cdc25A results in inhibition of CDK2 resulting in S-phase arrest , and phosphorylation of cdc25C and Wee1 causes inhibition of CDK1 , resulting in G2/M arrest [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] and it is through this function that the ATR-CHK1 pathway exerts cell cycle control at the G2/M and intra-S cell cycle checkpoints [ XREF_BIBR ] , preventing entry to mitosis via inhibition of CDK1 thereby preventing immediate mitotic catastrophe or permanent loss of genetic material .	Phosphorylation of cdc25A results in inhibition of CDK2 resulting in S-phase arrest, and phosphorylation of cdc25C and Wee1 causes inhibition of CDK1, resulting in G2/M arrest [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] and it is through this function that the ATR-CHK1 pathway exerts cell cycle control at the G2/M and intra-S cell cycle checkpoints [XREF_BIBR], preventing entry to mitosis via inhibition of CDK1 thereby preventing immediate mitotic catastrophe or permanent loss of genetic material.	14	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	phosphorylation of cdc25C and Wee1	wee1	CDK1	CDK1	cdk1	18	19	22	23
Our results indicate that Wee1 is a substrate of Cdc14 phosphatases in human cells and that by reversing specific Cdk1 phosphorylation , the Cdc14A isoform induces Wee1 stability , which in turn directly inhibits Cdk1 activity .	Our results indicate that Wee1 is a substrate of Cdc14 phosphatases in human cells and that by reversing specific Cdk1 phosphorylation, the Cdc14A isoform induces Wee1 stability, which in turn directly inhibits Cdk1 activity.	26	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	26	27	34	35
Wee1 reversibly arrests the cell cycle by inactivating Cdc2 through phosphorylation at Tyr 15 .	Wee1 reversibly arrests the cell cycle by inactivating Cdc2 through phosphorylation at Tyr 15.	0	9	arrests	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	0	1	8	9
This in turn leads to dephosphorylation of Cdk1 on T14 and Y15 , thereby alleviating Wee1 mediated inhibition of Cdk1 and Cyclin B1 .	This in turn leads to dephosphorylation of Cdk1 on T14 and Y15, thereby alleviating Wee1 mediated inhibition of Cdk1 and Cyclin B1.	15	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	15	16	19	20
Entry into mitosis depends on the activity of Cdk1 , which is inhibited by the Wee1 kinase and activated by the Cdc25 phosphatase .	Entry into mitosis depends on the activity of Cdk1, which is inhibited by the Wee1 kinase and activated by the Cdc25 phosphatase.	6	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	15	16	8	9
In human MCF-7 cell lines , inhibition of Wee1 increases Cdk1 activity and results in the inactivation of DNA repair 38 .	In human MCF-7 cell lines, inhibition of Wee1 increases Cdk1 activity and results in the inactivation of DNA repair 38.	6	11	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	8	9	10	11
Wee1 directly phosphorylates and inhibits Cdk1 and Cdk2 at the conserved Tyr15 residue [ XREF_BIBR ] .	Wee1 directly phosphorylates and inhibits Cdk1 and Cdk2 at the conserved Tyr15 residue [XREF_BIBR].	0	12	directly	Positive_regulation_token_1_verb	Negative_activation	Positive_regulation	Wee1	Wee1	wee1	Cdk1	phosphorylates and inhibits Cdk1 and Cdk2 at the conserved Tyr15	cdk1	0	1	5	6
275 WEE1 inhibition leads to unregulated CDK1 ( and 2 ) activity , overriding S/G2 checkpoints leading to mitotic catastrophe and cell death in DNA damaged cells .	275 WEE1 inhibition leads to unregulated CDK1 (and 2) activity, overriding S/G2 checkpoints leading to mitotic catastrophe and cell death in DNA damaged cells.	1	9	leads	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	1	2	6	7
CHK1 has a double role in CDK1 inactivation , by directly inhibiting Cdc25 and activating the tyrosine kinase Wee1 , which specifically inhibits CDK1 .	CHK1 has a double role in CDK1 inactivation, by directly inhibiting Cdc25 and activating the tyrosine kinase Wee1, which specifically inhibits CDK1.	14	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	18	19	23	24
Both Chk1 and Wee1 promote inhibition of the Cdk1 mitotic kinase that coordinates early mitotic events , including chromosome condensation .	Both Chk1 and Wee1 promote inhibition of the Cdk1 mitotic kinase that coordinates early mitotic events, including chromosome condensation.	1	10	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	3	4	8	9
Swe1 is the S. cerevisiae homolog of Wee1 , which inhibits Cdk1 by phosphorylation on a conserved tyrosine residue [ XREF_BIBR ] .	Swe1 is the S. cerevisiae homolog of Wee1, which inhibits Cdk1 by phosphorylation on a conserved tyrosine residue [XREF_BIBR].	5	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	7	8	11	12
In fission yeast the onset of mitosis is brought about by Cdc2 and Cdc13 kinase , which is inhibited by the Wee1 and Mik1 tyrosine kinases and activated by Cdc25 tyrosine phosphatase .	In fission yeast the onset of mitosis is brought about by Cdc2 and Cdc13 kinase, which is inhibited by the Wee1 and Mik1 tyrosine kinases and activated by Cdc25 tyrosine phosphatase.	11	25	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	21	22	11	12
Interestingly , Wee1 bearing mutations at these sites inhibited the mitotic activation of Cdc2 and Cyclin B more effectively than wild-type Wee1 .	Interestingly, Wee1 bearing mutations at these sites inhibited the mitotic activation of Cdc2 and Cyclin B more effectively than wild-type Wee1.	2	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	2	3	13	14
While PARP1/2 plays an essential role in the repair of single stranded DNA breaks , Wee1 inhibits Cdc2 kinase by phosphorylation of the Y15 residue of Cdc2 [ XREF_BIBR , XREF_BIBR ] .	While PARP1/2 plays an essential role in the repair of single stranded DNA breaks, Wee1 inhibits Cdc2 kinase by phosphorylation of the Y15 residue of Cdc2 [XREF_BIBR, XREF_BIBR].	15	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	15	16	17	18
YM155 probably abrogates G2 checkpoint by inhibiting the Wee1 and Mik1 kinases that suppress Cdc2 activation or by activating the Cdc25C phosphatase that , in turn , activates Cdc2 [ XREF_BIBR ] .	YM155 probably abrogates G2 checkpoint by inhibiting the Wee1 and Mik1 kinases that suppress Cdc2 activation or by activating the Cdc25C phosphatase that, in turn, activates Cdc2 [XREF_BIBR].	8	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	8	9	14	15
Wee1 protein kinase represses CDK1 required for G ( 2 )/M transition .	Wee1 protein kinase represses CDK1 required for G (2)/M transition.	0	5	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	0	1	4	5
In response to DNA damage , Wee1 inactivates CDK1 through phosphorylation at Tyr15 , thereby preventing cells from proceeding through mitosis by maintaining G2 arrest .	In response to DNA damage, Wee1 inactivates CDK1 through phosphorylation at Tyr15, thereby preventing cells from proceeding through mitosis by maintaining G2 arrest.	6	9	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	6	7	8	9
These findings indicate that Wee1 and Rum1 act jointly to inhibit Cdc2 and promote sexual development in nitrogen starved cells .	These findings indicate that Wee1 and Rum1 act jointly to inhibit Cdc2 and promote sexual development in nitrogen starved cells.	4	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdc2	Cdc2	Cdc2	4	5	11	12
Other significantly up-regulated genes in livers of A2M *-treated animals are WEE1 , which blocks CDK1 and CIART , PER2 and PER3 involved in the circadian rhythm [ XREF_BIBR , XREF_BIBR ] .	Other significantly up-regulated genes in livers of A2M *-treated animals are WEE1, which blocks CDK1 and CIART, PER2 and PER3 involved in the circadian rhythm [XREF_BIBR, XREF_BIBR].	0	21	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	11	12	15	16
During S phase , CDC2 activity is inhibited through phosphorylation by the MYT1 and MIK1 and WEE1 kinases at Thr 14 and Tyr 15 .	During S phase, CDC2 activity is inhibited through phosphorylation by the MYT1 and MIK1 and WEE1 kinases at Thr 14 and Tyr 15.	4	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDC2	CDC2	CDC2	16	17	4	5
Elevated CDK1 activity in G2 and in early mitosis is enhanced by the targeted ubiquitylation and degradation of the CDK1 tyrosine kinase and inhibitor Wee1 via the activity of an SCF ligase , which utilizes the beta-transducin repeat containing protein 1 ( betaTRCP1 ) as substrate recognition subunits ( SCF betaTRCP1 ) .	Elevated CDK1 activity in G2 and in early mitosis is enhanced by the targeted ubiquitylation and degradation of the CDK1 tyrosine kinase and inhibitor Wee1 via the activity of an SCF ligase, which utilizes the beta-transducin repeat containing protein 1 (betaTRCP1) as substrate recognition subunits (SCF betaTRCP1).	1	25	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Wee1	ubiquitylation and degradation of the CDK1 tyrosine kinase and inhibitor Wee1	wee1	CDK1	CDK1	cdk1	24	25	1	2
PLD2 promotes VHL mediated HIF-1alpha degradation through interaction of VHL with HIF-1alpha .	PLD2 promotes VHL mediated HIF-1alpha degradation through interaction of VHL with HIF-1alpha.	1	5	mediated	Positive_early_activation	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	2	3	4	5
Activity of prolyl-4-droxylases requires oxygen and therefore , under hypoxic conditions , the enzymes are inactivated , leading to HIF1alpha accumulation [ XREF_BIBR ] , Consistently , HIF1alpha accumulation can also be caused by mutational inactivation of VHL tumor suppressor , which is responsible for the development of von Hippel-Lindau disease , an inherited human cancer syndrome with high Incidence of tumors in eye , brain , kidney , lung and liver in affected individuals [ XREF_BIBR ] .	Activity of prolyl-4-droxylases requires oxygen and therefore, under hypoxic conditions, the enzymes are inactivated, leading to HIF1alpha accumulation [XREF_BIBR], Consistently, HIF1alpha accumulation can also be caused by mutational inactivation of VHL tumor suppressor, which is responsible for the development of von Hippel-Lindau disease, an inherited human cancer syndrome with high Incidence of tumors in eye, brain, kidney, lung and liver in affected individuals [XREF_BIBR].	27	39	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	37	38	27	28
Hydroxylation of HIF-1alpha allows recognition by the von Hippel-Lindau ( VHL ) tumor suppressor , which targets HIF-1alpha for proteosomal destruction .	Hydroxylation of HIF-1alpha allows recognition by the von Hippel-Lindau (VHL) tumor suppressor, which targets HIF-1alpha for proteosomal destruction.	10	20	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	10	11	17	18
Likewise , SAG siRNA silencing inhibits VHL induced HIF-1alpha degradation and promotes HIF-1alpha accumulation upon hypoxia .	Likewise, SAG siRNA silencing inhibits VHL induced HIF-1alpha degradation and promotes HIF-1alpha accumulation upon hypoxia.	6	11	induced	Positive_early_activation	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	6	7	8	9
These results demonstrated the effectiveness of the tamoxifen inducible VHL conditional knockout mouse system , which causes VHL inactivation and stabilization of HIF-1alpha and HIF-2alpha protein , following tamoxifen injection .	These results demonstrated the effectiveness of the tamoxifen inducible VHL conditional knockout mouse system, which causes VHL inactivation and stabilization of HIF-1alpha and HIF-2alpha protein, following tamoxifen injection.	17	25	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	17	18	22	23
Finally , we demonstrate that pVHL , VHLaK and KAP1 and TIF-1beta can be recruited into a single complex , indicating that KAP1 and TIF-1beta may participate in pVHL mediated transcriptional repression of HIF-1alpha .	Finally, we demonstrate that pVHL, VHLaK and KAP1 and TIF-1beta can be recruited into a single complex, indicating that KAP1 and TIF-1beta may participate in pVHL mediated transcriptional repression of HIF-1alpha.	26	34	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	28	29	33	34
There has been growing evidence for VHL independent degradation of HIF-1alpha through histone deacetylases ( HDACs ) inhibition [ XREF_BIBR , XREF_BIBR ] , heat shock protein 90 ( HSP90 ) [ XREF_BIBR , XREF_BIBR ] , the hypoxia associated factor ( HAF ) [ XREF_BIBR ] and an undescribed cullin independent proteasome degradation pathway [ XREF_BIBR , XREF_BIBR ] .	There has been growing evidence for VHL independent degradation of HIF-1alpha through histone deacetylases (HDACs) inhibition [XREF_BIBR, XREF_BIBR], heat shock protein 90 (HSP90) [XREF_BIBR, XREF_BIBR], the hypoxia associated factor (HAF) [XREF_BIBR] and an undescribed cullin independent proteasome degradation pathway [XREF_BIBR, XREF_BIBR].	6	13	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	6	7	10	11
Under normoxic conditions , HIF-1alpha is rapidly degraded by VHL in cells XREF_BIBR , XREF_BIBR .	Under normoxic conditions, HIF-1alpha is rapidly degraded by VHL in cells XREF_BIBR, XREF_BIBR.	4	10	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	9	10	4	5
Although pVHL mediated degradation of HIF-1alpha is an important pathway , phosphorylation of HIF-1alpha also plays a role by increasing the transcriptional activity of HIF-1alpha XREF_BIBR , XREF_BIBR .	Although pVHL mediated degradation of HIF-1alpha is an important pathway, phosphorylation of HIF-1alpha also plays a role by increasing the transcriptional activity of HIF-1alpha XREF_BIBR, XREF_BIBR.	1	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	1	2	5	6
Furthermore , we have confirmed VHL independent degradation of HIF-1alpha by silencing of VHL with siRNA in VHL positive FaDu cells .	Furthermore, we have confirmed VHL independent degradation of HIF-1alpha by silencing of VHL with siRNA in VHL positive FaDu cells.	5	10	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	5	6	9	10
HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene , VHL , which targets HIF-1alpha degradation .	HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene, VHL, which targets HIF-1alpha degradation.	12	19	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	14	15	18	19
Loss of pVHL , therefore , leads to the constitutive activation of HIF1alpha and its target genes , mimicking a state of constant hypoxia despite normal O 2 content .	Loss of pVHL, therefore, leads to the constitutive activation of HIF1alpha and its target genes, mimicking a state of constant hypoxia despite normal O 2 content.	0	16	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	pVHL	Loss of pVHL	pvhl	HIF1alpha	HIF1alpha	hif1alpha	2	3	12	13
VHL was shown to mediate HIF-1alpha degradation , which explains the angiogenic phenotype of many VHL-null tumors [ XREF_BIBR ] .	VHL was shown to mediate HIF-1alpha degradation, which explains the angiogenic phenotype of many VHL-null tumors [XREF_BIBR].	0	6	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	5	6
As a result , it was suggested that everolimus administration would be helpful as an anti-tumor therapy for CCA not only via down-regulation of p-mTOR but also degradation of HIF-1alpha by VHL and induction of apoptosis by cleaved caspase-3 .	As a result, it was suggested that everolimus administration would be helpful as an anti-tumor therapy for CCA not only via down-regulation of p-mTOR but also degradation of HIF-1alpha by VHL and induction of apoptosis by cleaved caspase-3.	12	35	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	31	32	29	30
In normoxia , VHL suppresses HIF1a mediated transcriptional response , which is characteristic to hypoxia .	In normoxia, VHL suppresses HIF1a mediated transcriptional response, which is characteristic to hypoxia.	3	6	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1a	HIF1a	HIF1a	3	4	5	6
The pVHL dependent degradation of HIF-1alpha is always present ( transitions t_116 to t_119 ) .	The pVHL dependent degradation of HIF-1alpha is always present (transitions t_116 to t_119).	1	6	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	1	2	5	6
Taken together , this study provides new insight into the mechanisms underlying VHL mediated HIF-1alpha degradation and transcriptional activation , and a molecular basis for drug targeting .	Taken together, this study provides new insight into the mechanisms underlying VHL mediated HIF-1alpha degradation and transcriptional activation, and a molecular basis for drug targeting.	11	15	mediated	Positive_early_activation	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	12	13	14	15
Taken together , we suggest that Trx plays an important role in angiogenesis and , therefore , antisense-Trx might be applicable to the inhibition of tumor angiogenesis through the induction of pVHL mediated HIF-1alpha degradation .	Taken together, we suggest that Trx plays an important role in angiogenesis and, therefore, antisense-Trx might be applicable to the inhibition of tumor angiogenesis through the induction of pVHL mediated HIF-1alpha degradation.	29	34	mediated	Positive_early_activation	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	31	32	33	34
Under hypoxic conditions as well as in case of VHL gene inactivation , the pVHL elonginC and B-Cul 2 complex does not degrade HIF-1alpha , which is stabilized and accumulates in the nucleus leading to subsequent over-expression of genes which are critical for tumor angiogenesis ( VEGF ) , glucose transport ( GLUT1 , GLUT3 ) , glycolysis , pH control ( CAIX , CAXII ) , epithelial proliferation ( PDGF , TGF-alpha ) , cell migration and homing ( CXCR4 ) .	Under hypoxic conditions as well as in case of VHL gene inactivation, the pVHL elonginC and B-Cul 2 complex does not degrade HIF-1alpha, which is stabilized and accumulates in the nucleus leading to subsequent over-expression of genes which are critical for tumor angiogenesis (VEGF), glucose transport (GLUT1, GLUT3), glycolysis, pH control (CAIX, CAXII), epithelial proliferation (PDGF, TGF-alpha), cell migration and homing (CXCR4).	14	29	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	14	15	23	24
However , the role of VBP1 in pVHL mediated degradation of HIF-1alpha is not yet known .	However, the role of VBP1 in pVHL mediated degradation of HIF-1alpha is not yet known.	5	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	11	12
Normoxic induction of HIF-1alpha by reactive oxygen species 29 , PLC and PKC 30 , and succinate XREF_BIBR , XREF_BIBR has been previously reported , and these agents inhibit protein hydroxylation thereby preventing recognition and degradation of HIF-1alpha by VHL .	Normoxic induction of HIF-1alpha by reactive oxygen species 29, PLC and PKC 30, and succinate XREF_BIBR, XREF_BIBR has been previously reported, and these agents inhibit protein hydroxylation thereby preventing recognition and degradation of HIF-1alpha by VHL.	32	40	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	39	40	37	38
Since mitochondrial metabolism and mROS production regulate HIF activity upstream of recognition by the VHL containing ubiquitin ligase , we sought to determine if epidermal deletion of VHL could rescue HIF-1alpha activity in the epidermal keratinocytes of TFAM EpiKO mice .	Since mitochondrial metabolism and mROS production regulate HIF activity upstream of recognition by the VHL containing ubiquitin ligase, we sought to determine if epidermal deletion of VHL could rescue HIF-1alpha activity in the epidermal keratinocytes of TFAM EpiKO mice.	25	31	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	27	28	30	31
VHL is known to direct poly-ubiquitylation and further degradation of HIF1a , a transcription factor which activates hypoxia associated genes XREF_BIBR , XREF_BIBR .	VHL is known to direct poly-ubiquitylation and further degradation of HIF1a, a transcription factor which activates hypoxia associated genes XREF_BIBR, XREF_BIBR.	0	14	direct	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1a	HIF1a	HIF1a	0	1	10	11
The current concept on the adaptive responses to changes in tissue oxygenation is mainly formed from the study on pVHL mediated degradation of HIF-1alpha .	The current concept on the adaptive responses to changes in tissue oxygenation is mainly formed from the study on pVHL mediated degradation of HIF-1alpha.	17	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	19	20	23	24
Several recent studies have shown that Vhl deletion in beta-cells results in Hif1alpha activation , impaired glucose stimulated insulin secretion ( GSIS ) and glucose intolerance .	Several recent studies have shown that Vhl deletion in beta-cells results in Hif1alpha activation, impaired glucose stimulated insulin secretion (GSIS) and glucose intolerance.	6	14	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	Vhl	Vhl	Vhl	Hif1alpha	Hif1alpha	Hif1alpha	6	7	12	13
IP5 promotes HIF-1alpha prolyl hydroxylation and thus pVHL dependent degradation of HIF-1alpha .	IP5 promotes HIF-1alpha prolyl hydroxylation and thus pVHL dependent degradation of HIF-1alpha.	7	12	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	11	12
Moreover , both p53 and VHL can promote the degradation of HIF-1alpha to indirectly suppress VEGF expression XREF_BIBR , XREF_BIBR , XREF_BIBR .	Moreover, both p53 and VHL can promote the degradation of HIF-1alpha to indirectly suppress VEGF expression XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	12	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	5	6	11	12
A murine model was used to demonstrate that when the HIF-1alpha protein was constitutively activated in osteoblasts by conditional deletion of the Vhl gene , the result was higher vascularity in long bones with complementary increases in bone volumes XREF_BIBR .	A murine model was used to demonstrate that when the HIF-1alpha protein was constitutively activated in osteoblasts by conditional deletion of the Vhl gene, the result was higher vascularity in long bones with complementary increases in bone volumes XREF_BIBR.	10	23	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Vhl	Vhl	Vhl	HIF-1alpha protein	HIF-1alpha protein	HIF-1alpha protein	22	23	10	12
VHL dependent degradation of HIF-1alpha is known to require the presence of Fe 2+ as a cofactor for the prolyl hydroxylases ( PHDs ) , which hydroxylate HIF-1alpha at conserved proline residues , mediating proteasomal degradation .	VHL dependent degradation of HIF-1alpha is known to require the presence of Fe 2+ as a cofactor for the prolyl hydroxylases (PHDs), which hydroxylate HIF-1alpha at conserved proline residues, mediating proteasomal degradation.	0	5	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	4	5
However it is also thought that a ternary complex between p53 , HIF-1alpha and Mdm2 may promote pVHL independent degradation of HIF-1alpha and modulation of p53 activity XREF_BIBR .	However it is also thought that a ternary complex between p53, HIF-1alpha and Mdm2 may promote pVHL independent degradation of HIF-1alpha and modulation of p53 activity XREF_BIBR.	17	23	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	17	18	21	22
Because VHL is responsible for the degradation of HIF-1alpha via its interaction with HIF-1alpha , we investigated whether PLD2 had any effect on the VHL mediated degradation of HIF-1alpha .	Because VHL is responsible for the degradation of HIF-1alpha via its interaction with HIF-1alpha, we investigated whether PLD2 had any effect on the VHL mediated degradation of HIF-1alpha.	21	29	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	24	25	28	29
Therefore , by promoting degradation of HIF-1alpha , pVHL can suppress HIF-1alpha stimulated transcription and function as a key tumor suppressor [ XREF_BIBR ] .	Therefore, by promoting degradation of HIF-1alpha, pVHL can suppress HIF-1alpha stimulated transcription and function as a key tumor suppressor [XREF_BIBR].	4	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	8	9	6	7
Hif-1alpha stabilisation is also typical of VHL related PCC , where pVHL deficiency reduces the clearance of Hif-1alpha through the ubiquitin-proteasome pathway .	Hif-1alpha stabilisation is also typical of VHL related PCC, where pVHL deficiency reduces the clearance of Hif-1alpha through the ubiquitin-proteasome pathway.	11	18	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	Hif-1alpha	Hif-1alpha	Hif-1alpha	11	12	17	18
In renal carcinoma , loss of VHL can lead to sustained up-regulation of both HIF-1alpha and HIF-2alpha isoforms in some tumors or only HIF-2alpha in other tumors , but not solely HIF-1alpha [ XREF_BIBR ] .	In renal carcinoma, loss of VHL can lead to sustained up-regulation of both HIF-1alpha and HIF-2alpha isoforms in some tumors or only HIF-2alpha in other tumors, but not solely HIF-1alpha [XREF_BIBR].	4	17	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	VHL	loss of VHL	vhl	HIF-1alpha	HIF-1alpha	hif-1alpha	6	7	14	15
Since VHL degradation failed to restore HIF-1alpha accumulation as seen in XREF_FIG , we investigated the possibility of a direct involvement of viral proteins in the degradation of VHL protein .	Since VHL degradation failed to restore HIF-1alpha accumulation as seen in XREF_FIG, we investigated the possibility of a direct involvement of viral proteins in the degradation of VHL protein.	1	7	restore	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	1	2	6	7
In 1999 , the Ratcliffe group discovered that pVHL deficient renal-cancer cells fail to degrade HIF-1alpha and also HIF-2alpha , a closely related alpha subunit .	In 1999, the Ratcliffe group discovered that pVHL deficient renal-cancer cells fail to degrade HIF-1alpha and also HIF-2alpha, a closely related alpha subunit.	8	18	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	8	9	15	16
The oxygen dependent degradation of HIF-1alpha by pVHL can also be mediated by hypoxia induced HIF-1alpha small ubiquitin like modifier ( SUMO ) ylation .	The oxygen dependent degradation of HIF-1alpha by pVHL can also be mediated by hypoxia induced HIF-1alpha small ubiquitin like modifier (SUMO) ylation.	3	8	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	5	6
We also noted that in VHL expressing UOK121 cells , there was no HIF1a expression , even under hypoxic conditions , most likely because the over-expressed VHL degrades HIF1a , even under hypoxic conditions [ XREF_BIBR ] .	We also noted that in VHL expressing UOK121 cells, there was no HIF1a expression, even under hypoxic conditions, most likely because the over-expressed VHL degrades HIF1a, even under hypoxic conditions [XREF_BIBR].	24	29	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1a	HIF1a	HIF1a	26	27	28	29
Although loss of VHL can lead to up-regulation of both HIF-1alpha and HIF-2alpha isoforms , there are some functional differences that exist between these two isoforms .	Although loss of VHL can lead to up-regulation of both HIF-1alpha and HIF-2alpha isoforms, there are some functional differences that exist between these two isoforms.	1	13	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	VHL	loss of VHL	vhl	HIF-1alpha	HIF-1alpha	hif-1alpha	3	4	10	11
pVHL also directly inhibits HIF-1alpha transactivation by recruiting histone deacetylases .	pVHL also directly inhibits HIF-1alpha transactivation by recruiting histone deacetylases.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	4	5
For example , Bento and colleagues discovered that in the presence of high glucose concentrations , the accumulation of methylglyoxal results in the O 2 / PHD and VHL independent degradation of HIF1A by Hsp70 associated recruitment of CHIP .	For example, Bento and colleagues discovered that in the presence of high glucose concentrations, the accumulation of methylglyoxal results in the O 2 / PHD and VHL independent degradation of HIF1A by Hsp70 associated recruitment of CHIP.	26	34	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1A	HIF1A	HIF1A	28	29	32	33
Since VHL is unable to degrade HIF-1alpha under hypoxic conditions , it is possible that HAF , as an oxygen independent ubiquitin ligase , may play a more central role in attenuating inappropriate HIF-1alpha upregulation under hypoxic , inflammatory conditions .	Since VHL is unable to degrade HIF-1alpha under hypoxic conditions, it is possible that HAF, as an oxygen independent ubiquitin ligase, may play a more central role in attenuating inappropriate HIF-1alpha upregulation under hypoxic, inflammatory conditions.	1	7	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	1	2	6	7
Loss of pVHL caused by mutation leads to constitutive activation of HIF-1alpha and HIF-2alpha , which contributes to the progression and development of neoplasms through up-regulation of their target genes such as VEGF and GLUT1 [ XREF_BIBR ] .	Loss of pVHL caused by mutation leads to constitutive activation of HIF-1alpha and HIF-2alpha, which contributes to the progression and development of neoplasms through up-regulation of their target genes such as VEGF and GLUT1 [XREF_BIBR].	0	13	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	pVHL	Loss of pVHL	pvhl	HIF-1alpha	HIF-1alpha	hif-1alpha	2	3	11	12
The most extensively studied patients are those with Chuvash polycythemia , who are homozygous for a hypomorphic allele of the VHL tumor suppressor , which impairs HIF-1alpha and HIF-2alpha degradation .	The most extensively studied patients are those with Chuvash polycythemia, who are homozygous for a hypomorphic allele of the VHL tumor suppressor, which impairs HIF-1alpha and HIF-2alpha degradation.	20	29	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	20	21	26	27
Formation of p97-UBXD7-HIF-1alpha-CUL2 and VHL E3 ubiquitin ligase complex initiates proteasomal degradation of HIF-1alpha .	Formation of p97-UBXD7-HIF-1alpha-CUL2 and VHL E3 ubiquitin ligase complex initiates proteasomal degradation of HIF-1alpha.	4	14	initiates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	4	5	13	14
As reported in the literature , VHL knockdown did not lead an increase of HIF-1alpha in FaDu cells under hypoxic conditions [ XREF_BIBR ] .	As reported in the literature, VHL knockdown did not lead an increase of HIF-1alpha in FaDu cells under hypoxic conditions [XREF_BIBR].	6	15	lead	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	6	7	14	15
VHL normally suppresses the HIF1alpha and HIF2alpha transcription factors , and aberrant or deleted VHL leads to HIF hyperactivation XREF_BIBR .	VHL normally suppresses the HIF1alpha and HIF2alpha transcription factors, and aberrant or deleted VHL leads to HIF hyperactivation XREF_BIBR.	0	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	0	1	4	5
Meanwhile , microtubule network breakdown also promotes pVHL mediated HIF-1alpha degradation in hypoxic CMs XREF_BIBR .	Meanwhile, microtubule network breakdown also promotes pVHL mediated HIF-1alpha degradation in hypoxic CMs XREF_BIBR.	6	10	mediated	Positive_early_activation	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	9	10
Hypoxia inducible factor-1alpha is scarce in normoxia , although it is constitutively transcribed , translated and rapidly degraded through hydroxylation at proline 402 and 564 residues by prolyl-4-hydroxylase ( PHD ) , targeting HIF-1alpha for proteosomal degradation mediated by the VHL protein .	Hypoxia inducible factor-1alpha is scarce in normoxia, although it is constitutively transcribed, translated and rapidly degraded through hydroxylation at proline 402 and 564 residues by prolyl-4-hydroxylase (PHD), targeting HIF-1alpha for proteosomal degradation mediated by the VHL protein.	27	41	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	40	41	33	34
Loss of vhl prevents Hif-1alpha degradation and augments vegfaa expression XREF_BIBR XREF_BIBR .	Loss of vhl prevents Hif-1alpha degradation and augments vegfaa expression XREF_BIBR XREF_BIBR.	0	5	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	vhl	Loss of vhl	vhl	Hif-1alpha	Hif-1alpha	hif-1alpha	2	3	4	5
These data indicate that Lys 63 -linked polyubiquitination dependent nuclear retention of HIF1alpha does not result from effects on VHL mediated HIF1alpha degradation .	These data indicate that Lys 63 -linked polyubiquitination dependent nuclear retention of HIF1alpha does not result from effects on VHL mediated HIF1alpha degradation.	17	22	mediated	Positive_early_activation	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	19	20	21	22
A loss of pVHL allows HIF-1alpha to dimerise with HIF-1beta and to activate the transcription of a number of proangiogenic genes , including VEGF .	A loss of pVHL allows HIF-1alpha to dimerise with HIF-1beta and to activate the transcription of a number of proangiogenic genes, including VEGF.	1	6	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	loss of pVHL	pvhl	HIF-1alpha	HIF-1alpha	hif-1alpha	3	4	5	6
Loss of VHL function upregulates HIF-1alpha , a transcription factor that leads to an overexpression of VEGF and drives tumor angiogenesis XREF_BIBR .	Loss of VHL function upregulates HIF-1alpha, a transcription factor that leads to an overexpression of VEGF and drives tumor angiogenesis XREF_BIBR.	2	9	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	2	3	5	6
However , pVHL , as the E3 ligase , promotes HIF-1alpha degradation , sensing the oxygen level XREF_BIBR , XREF_BIBR , XREF_BIBR , suggesting that there would be additional pVHL role in tumor initiation , because HIF-1alpha-mediated angiogenesis is required at late stage .	However, pVHL, as the E3 ligase, promotes HIF-1alpha degradation, sensing the oxygen level XREF_BIBR, XREF_BIBR, XREF_BIBR, suggesting that there would be additional pVHL role in tumor initiation, because HIF-1alpha-mediated angiogenesis is required at late stage.	2	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	2	3	10	11
It is well documented that VHL mediates proteasomal degradation of HIF-1alpha under normoxia .	It is well documented that VHL mediates proteasomal degradation of HIF-1alpha under normoxia.	5	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	5	6	10	11
For example , TBP1 specifically interacts with von Hippel-Lindau ( VHL ) and Hif1alpha and promotes the VHL dependent degradation of Hif1alpha in an ubiquitin dependent manner under conditions of normoxia XREF_BIBR .	For example, TBP1 specifically interacts with von Hippel-Lindau (VHL) and Hif1alpha and promotes the VHL dependent degradation of Hif1alpha in an ubiquitin dependent manner under conditions of normoxia XREF_BIBR.	17	26	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	Hif1alpha	Hif1alpha	Hif1alpha	17	18	21	22
However , mutation of P402 residue in human HIF-1alpha did not result in inhibition of HIF degradation , showing that HIF-1alpha may be degraded by a pVHL dependent mechanism that is independent of PHDs [ XREF_BIBR ] .	However, mutation of P402 residue in human HIF-1alpha did not result in inhibition of HIF degradation, showing that HIF-1alpha may be degraded by a pVHL dependent mechanism that is independent of PHDs [XREF_BIBR].	20	28	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	26	27	20	21
Under normal oxygen conditions , HIF1-alpha degradation is promoted by the E3 ubiquitin ligase pVHL ( von Hippel Lindau factor ) .	Under normal oxygen conditions, HIF1-alpha degradation is promoted by the E3 ubiquitin ligase pVHL (von Hippel Lindau factor).	5	18	promoted	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF1-alpha	HIF1-alpha	HIF1-alpha	14	15	5	6
Levels of HIF-1alpha protein were greatly increased in the RVN cells , a change that is expected given that VHL degrades HIF-1alpha .	Levels of HIF-1alpha protein were greatly increased in the RVN cells, a change that is expected given that VHL degrades HIF-1alpha.	19	22	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	19	20	21	22
In normoxia , VHL mediates ubiquitin dependent degradation of HIF1alpha .	In normoxia, VHL mediates ubiquitin dependent degradation of HIF1alpha.	3	10	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	3	4	9	10
HIF-1alpha hydroxylation allows recognition by the von Hippel-Lindau ( VHL ) tumor suppressor , which targets HIF-1alpha to the proteasome for degradation .	HIF-1alpha hydroxylation allows recognition by the von Hippel-Lindau (VHL) tumor suppressor, which targets HIF-1alpha to the proteasome for degradation.	9	17	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	9	10	16	17
Third , Vhl loss in primary cells directly results in upregulation of both HIF-1alpha and HIF-2alpha and recapitulates many features of RCC .	Third, Vhl loss in primary cells directly results in upregulation of both HIF-1alpha and HIF-2alpha and recapitulates many features of RCC.	2	15	results in upregulation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	Vhl	Vhl	Vhl	HIF-1alpha	HIF-1alpha	HIF-1alpha	2	3	13	14
This suggests that activation of the ATM-Chk2-E2F1 signaling axis contributes , at least in part , to the enhancing effect of OMA on pVHL mediated HIF-1alpha degradation , and is reflected in the suppression of VEGF expression .	This suggests that activation of the ATM-Chk2-E2F1 signaling axis contributes, at least in part, to the enhancing effect of OMA on pVHL mediated HIF-1alpha degradation, and is reflected in the suppression of VEGF expression.	21	26	mediated	Positive_early_activation	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	23	24	25	26
XREF_FIG F shows that administration of OMA drastically inhibited the expression of VEGF via activation of pVHL mediated HIF-1alpha degradation compared to that in the control samples , which is in agreement with data presented in XREF_FIG E.	XREF_FIG F shows that administration of OMA drastically inhibited the expression of VEGF via activation of pVHL mediated HIF-1alpha degradation compared to that in the control samples, which is in agreement with data presented in XREF_FIG E.	14	19	mediated	Positive_early_activation	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	16	17	18	19
Hypoxia slightly reduces expression of tumor suppressor VHL which targets HIF-1alpha for ubiquitination .	Hypoxia slightly reduces expression of tumor suppressor VHL which targets HIF-1alpha for ubiquitination.	3	12	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	expression of tumor suppressor VHL	vhl	HIF-1alpha	HIF-1alpha	hif-1alpha	7	8	10	11
BHLHE41 ( also known as SHARP1 ) binds to , and promotes VHL independent proteasomal degradation of HIF-1alpha and HIF-2alpha [ XREF_BIBR ] .	BHLHE41 (also known as SHARP1) binds to, and promotes VHL independent proteasomal degradation of HIF-1alpha and HIF-2alpha [XREF_BIBR].	12	21	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	12	13	17	18
The data in Figure XREF_FIG C demonstrated that inhibition of VHL by siRNA did not prevent HIF-1alpha degradation by MSA in FaDu cells expressing functional VHL .	The data in Figure XREF_FIG C demonstrated that inhibition of VHL by siRNA did not prevent HIF-1alpha degradation by MSA in FaDu cells expressing functional VHL.	8	17	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	10	11	16	17
Conversely , microtubule network breakdown upregulated pVHL mediated degradation of HIF-1alpha through activation of the p38 and MAPK pathway .	Conversely, microtubule network breakdown upregulated pVHL mediated degradation of HIF-1alpha through activation of the p38 and MAPK pathway.	5	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	6	7	10	11
Under normal oxygen levels , HIF-1alpha is hydroxylated at key proline residues facilitating interaction to von Hippel-Lindau protein ( pVHL ) which allows HIF-1alpha proteasomal degradation .	Under normal oxygen levels, HIF-1alpha is hydroxylated at key proline residues facilitating interaction to von Hippel-Lindau protein (pVHL) which allows HIF-1alpha proteasomal degradation.	17	25	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	19	20	23	24
Due to mutation , pVHL can not degrade HIF-1alpha , causing it to accumulate .	Due to mutation, pVHL can not degrade HIF-1alpha, causing it to accumulate.	4	9	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	4	5	8	9
Although we demonstrated the association of PLD1 with VHL , it was still not clear how PLD1 and VHL cooperate to degrade HIF-1alpha .	Although we demonstrated the association of PLD1 with VHL, it was still not clear how PLD1 and VHL cooperate to degrade HIF-1alpha.	16	23	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	18	19	22	23
In conclusion , our findings demonstrate that OMA is able to reduce the expression and secretion of VEGF in RPE cells through the subsequent regulation of multiple mechanisms as follows : ( 1 ) modulation of the intracellular ROS through inhibition of IDH enzymes ; ( 2 ) promotion of the ROS dependent ATM-Chk2-E2F1 signaling axis ; ( 3 ) activation of pVHL mediated HIF-1alpha degradation .	In conclusion, our findings demonstrate that OMA is able to reduce the expression and secretion of VEGF in RPE cells through the subsequent regulation of multiple mechanisms as follows : (1) modulation of the intracellular ROS through inhibition of IDH enzymes; (2) promotion of the ROS dependent ATM-Chk2-E2F1 signaling axis; (3) activation of pVHL mediated HIF-1alpha degradation.	60	65	mediated	Positive_early_activation	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	62	63	64	65
The VHL gene which inhibits the hypoxia inducible factors HIF1alpha and HIF2alpha , is well known to be a major target of 3p loss .	The VHL gene which inhibits the hypoxia inducible factors HIF1alpha and HIF2alpha, is well known to be a major target of 3p loss.	1	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	1	2	9	10
The reason for this may be the differential expression of VHL protein in these cells , given that wild-type VHL protein acts to prevent HIF-1alpha accumulation .	The reason for this may be the differential expression of VHL protein in these cells, given that wild-type VHL protein acts to prevent HIF-1alpha accumulation.	19	25	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	19	20	24	25
Two proline residues of HIF-1alpha are subjected to O 2 -dependent hydroxylation , which is required for binding of the von Hippel-Lindau tumor-suppressor protein ( VHL ) , which is the recognition component of a ubiquitin protein ligase that targets HIF-1alpha for rapid proteasomal degradation in non hypoxic cells XREF_BIBR .	Two proline residues of HIF-1alpha are subjected to O 2 -dependent hydroxylation, which is required for binding of the von Hippel-Lindau tumor-suppressor protein (VHL), which is the recognition component of a ubiquitin protein ligase that targets HIF-1alpha for rapid proteasomal degradation in non hypoxic cells XREF_BIBR.	23	44	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	25	26	40	41
Therefore , in a hypoxic condition , VHL mediated degradation of HIF-1alpha is prevented and HIF-1alpha accumulates , which leads to upregulation of HIF-1 target genes ( XREF_FIG ) .	Therefore, in a hypoxic condition, VHL mediated degradation of HIF-1alpha is prevented and HIF-1alpha accumulates, which leads to upregulation of HIF-1 target genes (XREF_FIG).	7	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	11	12
VHL is a tumor suppressor and degrades HIF-1alpha .	VHL is a tumor suppressor and degrades HIF-1alpha.	0	8	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	7	8
This is apparently the opposite of the observation from breast cancers , where DEC2 promoted VHL independent degradation of HIF-1alpha .	This is apparently the opposite of the observation from breast cancers, where DEC2 promoted VHL independent degradation of HIF-1alpha.	15	20	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	15	16	19	20
Since VHL mediates the degradation of HIF-1alpha and HIF-2alpha and thus inhibits the hypoxia pathways , the relative abundance of transcripts in the VHL-mutant A498 cells versus VHL reconstituted derivatives [ XREF_BIBR ] was compared to the changes in transcript levels of the same set of genes in RPTEC ( # 1 ) in response to hypoxia ( XREF_FIG D , detailed at : http://microarray-pubs.stanford.edu/hypoxia ) .	Since VHL mediates the degradation of HIF-1alpha and HIF-2alpha and thus inhibits the hypoxia pathways, the relative abundance of transcripts in the VHL-mutant A498 cells versus VHL reconstituted derivatives [XREF_BIBR] was compared to the changes in transcript levels of the same set of genes in RPTEC (# 1) in response to hypoxia (XREF_FIG D, detailed at : http://microarray-pubs.stanford.edu/hypoxia).	1	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	1	2	6	7
Under reoxygenation conditions in the presence of CHX , PLD2 promoted degradation of endogenous HIF-1alpha , which was further potentiated by VHL ( XREF_FIG ) , indicating that PLD2 cooperates with VHL to enhance VHL mediated HIF-1alpha degradation .	Under reoxygenation conditions in the presence of CHX, PLD2 promoted degradation of endogenous HIF-1alpha, which was further potentiated by VHL (XREF_FIG), indicating that PLD2 cooperates with VHL to enhance VHL mediated HIF-1alpha degradation.	33	37	mediated	Positive_early_activation	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	34	35	36	37
These novel observations may indicate that KAI1 exerts profound metastasis-suppressor activity in the tumor malignancy process via inhibition of CDCP1 mediated Src activation , followed by VHL induced HIF-1alpha degradation and , ultimately , decreased VEGF expression .	These novel observations may indicate that KAI1 exerts profound metastasis-suppressor activity in the tumor malignancy process via inhibition of CDCP1 mediated Src activation, followed by VHL induced HIF-1alpha degradation and, ultimately, decreased VEGF expression.	24	29	induced	Positive_early_activation	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	26	27	28	29
Loss of Vhl causes Hif1a dependent non obstructive hydronephrosis .	Loss of Vhl causes Hif1a dependent non obstructive hydronephrosis.	0	7	causes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Vhl	Loss of Vhl	vhl	Hif1a	Hif1a	hif1a	2	3	4	5
Notably , loss of both VHL and HIF-1alpha in chondrocytes causes a growth plate phenotype identical to the one described in HIF-1alpha null animals [ XREF_BIBR ] ; HIF-1alpha is thus epistatic to VHL .	Notably, loss of both VHL and HIF-1alpha in chondrocytes causes a growth plate phenotype identical to the one described in HIF-1alpha null animals [XREF_BIBR]; HIF-1alpha is thus epistatic to VHL.	2	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	loss of both VHL	vhl	HIF-1alpha	HIF-1alpha	hif-1alpha	5	6	21	22
VHL also directly inhibits HIF1alpha transactivation by recruiting several proteins , including VHLaK [ XREF_BIBR ] .	VHL also directly inhibits HIF1alpha transactivation by recruiting several proteins, including VHLaK [XREF_BIBR].	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	0	1	4	5
Western blot analysis revealed that HIF1alpha is efficiently degraded upon transfection of wild type or missense VHL indicating that missense pVHL can effectively degrade HIF1alpha in non hypoxic conditions .	Western blot analysis revealed that HIF1alpha is efficiently degraded upon transfection of wild type or missense VHL indicating that missense pVHL can effectively degrade HIF1alpha in non hypoxic conditions.	19	25	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF1alpha	HIF1alpha	HIF1alpha	20	21	24	25
Since HIF1alpha is normally degraded under normoxia by a VHL dependent mechanism , we also tested the expression of Vhl in the CSC .	Since HIF1alpha is normally degraded under normoxia by a VHL dependent mechanism, we also tested the expression of Vhl in the CSC.	1	11	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	9	10	1	2
These data suggest that PLD1 cooperates with VHL to enhance VHL mediated HIF-1alpha degradation .	These data suggest that PLD1 cooperates with VHL to enhance VHL mediated HIF-1alpha degradation.	9	13	mediated	Positive_early_activation	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	10	11	12	13
Under hypoxic conditions , pVHL mediated Hif-1alpha degradation is abolished , causing Hif-1alpha to accumulate and translocate to the nucleus where it forms a heterodimer with HIF-beta , which can bind to hypoxia responsive elements ( HREs ) in the promoters of hypoxia regulated genes XREF_BIBR .	Under hypoxic conditions, pVHL mediated Hif-1alpha degradation is abolished, causing Hif-1alpha to accumulate and translocate to the nucleus where it forms a heterodimer with HIF-beta, which can bind to hypoxia responsive elements (HREs) in the promoters of hypoxia regulated genes XREF_BIBR.	4	7	mediated	Positive_early_activation	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	Hif-1alpha	Hif-1alpha	Hif-1alpha	4	5	6	7
The degradation of HIF-1alpha by pVHL is known to be regulated through prolyl hydroxylase domain ( PHD ) proteins [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The degradation of HIF-1alpha by pVHL is known to be regulated through prolyl hydroxylase domain (PHD) proteins [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	6	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	5	6	3	4
The reduced HIF1alpha protein half-life was associated with an increase in the von Hippel-Lindau ( pVHL )-dependent proteasomal degradation of HIF1alpha .	The reduced HIF1alpha protein half-life was associated with an increase in the von Hippel-Lindau (pVHL)-dependent proteasomal degradation of HIF1alpha.	15	21	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF1alpha	HIF1alpha	HIF1alpha	15	16	20	21
One mechanism is the proteosomal degradation of HIF-1alpha by pVHL following hydroxylation of proline residues 564 and 402 by prolyl hydroxylase that enables the recognition of HIF-1alpha [ XREF_BIBR ] .	One mechanism is the proteosomal degradation of HIF-1alpha by pVHL following hydroxylation of proline residues 564 and 402 by prolyl hydroxylase that enables the recognition of HIF-1alpha [XREF_BIBR].	5	11	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	9	10	7	8
HA-HIF-1alpha will then accumulate under these normoxic conditions probably due to saturation of VHL mediated degradation of HIF-1alpha .	HA-HIF-1alpha will then accumulate under these normoxic conditions probably due to saturation of VHL mediated degradation of HIF-1alpha.	11	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	13	14	17	18
One is its modification and degradation by Mdm2 and the other is the pVHL independent degradation of HIF-1alpha .	One is its modification and degradation by Mdm2 and the other is the pVHL independent degradation of HIF-1alpha.	13	18	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	13	14	17	18
In normoxia , VHL prevents this stimulation by removing HIF-1alpha before it enters the nucleus .	In normoxia, VHL prevents this stimulation by removing HIF-1alpha before it enters the nucleus.	3	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	3	4	9	10
Given our finding that U19 and Eaf2 binds to and stabilizes pVHL , we investigated whether U19 and Eaf2 had any effect on the pVHL mediated degradation of HIF1alpha in immortalized U19 +/+ and U19 -/- MEFs .	Given our finding that U19 and Eaf2 binds to and stabilizes pVHL, we investigated whether U19 and Eaf2 had any effect on the pVHL mediated degradation of HIF1alpha in immortalized U19 +/+ and U19 -/- MEFs.	21	29	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF1alpha	HIF1alpha	HIF1alpha	24	25	28	29
IP5 acts by enhancing HIF-1alpha hydroxylation and thus pVHL dependent degradation of HIF-1alpha .	IP5 acts by enhancing HIF-1alpha hydroxylation and thus pVHL dependent degradation of HIF-1alpha.	8	13	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	8	9	12	13
Last two decades , molecular role of VHL has been reported to be E3 ligase and inhibit HIF-1alpha that induces VEGF , EPO and vascular neo-genesis related genes through its transcription ability XREF_BIBR , XREF_BIBR , XREF_BIBR .	Last two decades, molecular role of VHL has been reported to be E3 ligase and inhibit HIF-1alpha that induces VEGF, EPO and vascular neo-genesis related genes through its transcription ability XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	17	18
Under normoxic conditions , PPM1G downregulated HIF-1alpha expression in the absence ( lane 1 vs. lane 2 ) and presence ( lane 3 vs. lane 4 ) of VHL ( XREF_FIG C ) , suggesting that VHL does not mediate PPM1G dependent HIF-1alpha degradation .	Under normoxic conditions, PPM1G downregulated HIF-1alpha expression in the absence (lane 1 vs. lane 2) and presence (lane 3 vs. lane 4) of VHL (XREF_FIG C), suggesting that VHL does not mediate PPM1G dependent HIF-1alpha degradation.	36	43	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	36	37	42	43
1 Loss of VHL function leads to accumulation of the alpha-subunits of hypoxia inducible factor ( HIF ) transcription factors ( HIF-1alpha and HIF-2alpha ) that dimerize with HIF-1beta and transactivate HIF target genes such as vascular endothelial growth factor ( VEGF ) .	1 Loss of VHL function leads to accumulation of the alpha-subunits of hypoxia inducible factor (HIF) transcription factors (HIF-1alpha and HIF-2alpha) that dimerize with HIF-1beta and transactivate HIF target genes such as vascular endothelial growth factor (VEGF).	3	23	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	3	4	21	22
VEGF expression , in turn , is normally up-regulated by HIF-1alpha in response to decreases in oxygen concentration ; in normoxia , VHL proteins ubiquitinate and promote the proteasome dependent degradation of HIF-1alpha , thereby keeping HIF-1alpha levels and VEGF expression low [ XREF_BIBR ] .	VEGF expression, in turn, is normally up-regulated by HIF-1alpha in response to decreases in oxygen concentration; in normoxia, VHL proteins ubiquitinate and promote the proteasome dependent degradation of HIF-1alpha, thereby keeping HIF-1alpha levels and VEGF expression low [XREF_BIBR].	22	33	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	22	23	32	33
We further examined whether PLD1 modulated VHL mediated HIF-1alpha degradation .	We further examined whether PLD1 modulated VHL mediated HIF-1alpha degradation.	5	9	mediated	Positive_early_activation	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	6	7	8	9
We recently demonstrated that PLD1 protein itself destabilizes HIF-1alpha protein by interacting directly with the components involved in VHL dependent degradation of HIF-1alpha , independent of PLD activity .	We recently demonstrated that PLD1 protein itself destabilizes HIF-1alpha protein by interacting directly with the components involved in VHL dependent degradation of HIF-1alpha, independent of PLD activity.	18	23	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	18	19	22	23
During elaboration of PLD1 mediated HIF-1alpha regulation , we found that , while the enzymatic activity of PLD1 is responsible for the increased level of HIF-1alpha via promotion of translation , PLD1 protein itself destabilizes HIF-1alpha protein by interacting directly with the components involved in VHL dependent degradation of HIF-1alpha , independent of PLD activity .	During elaboration of PLD1 mediated HIF-1alpha regulation, we found that, while the enzymatic activity of PLD1 is responsible for the increased level of HIF-1alpha via promotion of translation, PLD1 protein itself destabilizes HIF-1alpha protein by interacting directly with the components involved in VHL dependent degradation of HIF-1alpha, independent of PLD activity.	45	51	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	45	46	49	50
Thus , these results support the conclusion that OMA suppresses VEGF expression by intervening with pVHL mediated activation of HIF-1alpha degradation .	Thus, these results support the conclusion that OMA suppresses VEGF expression by intervening with pVHL mediated activation of HIF-1alpha degradation.	15	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	15	16	19	20
Under normoxic conditions , HIF-1alpha is actively degraded by E3 ligase VHL in a proteosome dependent manner .	Under normoxic conditions, HIF-1alpha is actively degraded by E3 ligase VHL in a proteosome dependent manner.	4	16	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	11	12	4	5
The Von Hippel-Lindau protein ( pVHL ) regulates the hypoxia inducible factor ( HIF ) , and the loss of the pVHL function causes constitutive stabilization of HIF-1alpha and HIF-2alpha , resulting in the induction of HIF-transcriptional targets [ XREF_BIBR ] .	The Von Hippel-Lindau protein (pVHL) regulates the hypoxia inducible factor (HIF), and the loss of the pVHL function causes constitutive stabilization of HIF-1alpha and HIF-2alpha, resulting in the induction of HIF-transcriptional targets [XREF_BIBR].	21	29	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	21	22	27	28
VHL dependent degradation of HIF-1alpha is influenced by multiple proteins that are engaged in various biological functions , suggesting cross-talk between the HIF pathway and numerous signaling pathways .	VHL dependent degradation of HIF-1alpha is influenced by multiple proteins that are engaged in various biological functions, suggesting cross-talk between the HIF pathway and numerous signaling pathways.	0	5	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	4	5
In contrast , HIF1a downregulation by VHL over-expression , anti-miR-101 oligo administration or 2-MeOE2 treatment rescued cells from miR-101-mediated apoptosis and cell cycle arrest in breast cancer cells .	In contrast, HIF1a downregulation by VHL over-expression, anti-miR-101 oligo administration or 2-MeOE2 treatment rescued cells from miR-101-mediated apoptosis and cell cycle arrest in breast cancer cells.	3	8	downregulation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	VHL	VHL over-expression	vhl	HIF1a	HIF1a	hif1a	6	7	3	4
Together , these results reveal a non canonical , hypoxia independent mechanism for HIF-1alpha induction , by which phospho-Pfn-1-Tyr 129 binds VHL and prevents VHL mediated HIF-1alpha degradation , leading to accumulation of Pro hydroxylated HIF-1alpha in EC in culture and in vivo , even in normoxia .	Together, these results reveal a non canonical, hypoxia independent mechanism for HIF-1alpha induction, by which phospho-Pfn-1-Tyr 129 binds VHL and prevents VHL mediated HIF-1alpha degradation, leading to accumulation of Pro hydroxylated HIF-1alpha in EC in culture and in vivo, even in normoxia.	23	29	mediated	Positive_early_activation	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	24	25	26	27
In the normoxic state , HIF-1alpha is inactivated by proline hydroxylases ( PHDs ) and VHL within the cytosol .	In the normoxic state, HIF-1alpha is inactivated by proline hydroxylases (PHDs) and VHL within the cytosol.	5	18	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	15	16	5	6
Alternatively , loss-of-function mutations in pVHL or the enzymes involved in the metabolism of PHD cofactors cause the accumulation of HIF-1alpha in cancers .	Alternatively, loss-of-function mutations in pVHL or the enzymes involved in the metabolism of PHD cofactors cause the accumulation of HIF-1alpha in cancers.	3	22	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	5	6	20	21
This VHL independent degradation of HIF1alpha has shown to be RACK1 dependent XREF_BIBR .	This VHL independent degradation of HIF1alpha has shown to be RACK1 dependent XREF_BIBR.	1	6	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	1	2	5	6
VHL protein ( pVHL ) , an E3 ubiquitin ligase from the Vhl gene , inhibits the transcriptional activity of HIF-1alpha in cells .	VHL protein (pVHL), an E3 ubiquitin ligase from the Vhl gene, inhibits the transcriptional activity of HIF-1alpha in cells.	1	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	3	4	20	21
Treatment of a VHL deficient human RCC line with the HDAC inhibitor LAQ824 causes a dose dependent inhibition of HIF-1-alpha .	Treatment of a VHL deficient human RCC line with the HDAC inhibitor LAQ824 causes a dose dependent inhibition of HIF-1-alpha.	0	20	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1-alpha	HIF-1-alpha	HIF-1-alpha	3	4	19	20
This function of OMA was linked to its capacity to activate the pVHL mediated HIF-1alpha degradation in these cells , partly via a ROS dependent ATM signaling axis , through inhibition of IDH enzymes .	This function of OMA was linked to its capacity to activate the pVHL mediated HIF-1alpha degradation in these cells, partly via a ROS dependent ATM signaling axis, through inhibition of IDH enzymes.	11	15	mediated	Positive_early_activation	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	12	13	14	15
We found that siRNA mediated knockdown of VHL increased expression of both piRNAs , and that this induction was inhibited when VHL knockdown was combined with siRNA mediated knockdown of HIF-1alpha , indicating that HIF-1alpha stabilization induced by VHL knockdown was responsible for the increase in piRNA expression .	We found that siRNA mediated knockdown of VHL increased expression of both piRNAs, and that this induction was inhibited when VHL knockdown was combined with siRNA mediated knockdown of HIF-1alpha, indicating that HIF-1alpha stabilization induced by VHL knockdown was responsible for the increase in piRNA expression.	34	39	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	38	39	34	35
The ( CREG ) BMSC transplantation , directly or indirectly , may promote VEGF ' s anti-apoptosis and angiogenesis via the inhibition of VHL mediated HIF-1alpha degradation , consequently protecting against myocardial infarction .	The (CREG) BMSC transplantation, directly or indirectly, may promote VEGF 's anti-apoptosis and angiogenesis via the inhibition of VHL mediated HIF-1alpha degradation, consequently protecting against myocardial infarction.	21	26	mediated	Positive_early_activation	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	23	24	25	26
HIF-1alpha hydroxylation is a prerequisite for pVHL mediated HIF-1alpha degradation via the proteasome .	HIF-1alpha hydroxylation is a prerequisite for pVHL mediated HIF-1alpha degradation via the proteasome.	4	9	mediated	Positive_early_activation	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	6	7	8	9
In support of these findings , hydroxylation and VHL independent degradation of HIF-1alpha has been previously reported .	In support of these findings, hydroxylation and VHL independent degradation of HIF-1alpha has been previously reported.	6	13	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	hydroxylation and VHL	vhl	HIF-1alpha	HIF-1alpha	hif-1alpha	8	9	12	13
Under normoxia , HIF-1alpha is degraded by VHL , which recognizes HIF-1alpha when it is hydroxylated at Pro402 and/or Pro562 by the prolyl hydroxylase domain protein ( PHD ) [ XREF_BIBR ] .	Under normoxia, HIF-1alpha is degraded by VHL, which recognizes HIF-1alpha when it is hydroxylated at Pro402 and/or Pro562 by the prolyl hydroxylase domain protein (PHD) [XREF_BIBR].	3	19	degraded	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	3	4
PIASy is upregulated by hypoxia stress to block VHL mediated degradation of HIF1alpha .	PIASy is upregulated by hypoxia stress to block VHL mediated degradation of HIF1alpha.	7	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	8	9	12	13
In renal cell carcinoma , loss of the VHL ( von Hippel-Lindau syndrome ) gene that normally inhibits HIF1A ( hypoxia induced factor 1 , alpha subunit ) leads to enhanced vascularization , and sensitizes cancer cells to the mTOR inhibitor CCI-779 132 .	In renal cell carcinoma, loss of the VHL (von Hippel-Lindau syndrome) gene that normally inhibits HIF1A (hypoxia induced factor 1, alpha subunit) leads to enhanced vascularization, and sensitizes cancer cells to the mTOR inhibitor CCI-779 132.	8	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF1A	HIF1A	HIF1A	8	9	18	19
XREF_BIBR Our results suggested that the expression of KAI1 was significantly negatively correlated with VEGF level in HCC patients ( data not shown ) , which further supported the theory that KAI1 exerted profound metastasis-suppressor activity in the tumor malignancy process via inhibition of CDCP1 mediated Src activation , followed by VHL induced HIF-1a degradation and , ultimately , decreased VEGF expression .	XREF_BIBR Our results suggested that the expression of KAI1 was significantly negatively correlated with VEGF level in HCC patients (data not shown), which further supported the theory that KAI1 exerted profound metastasis-suppressor activity in the tumor malignancy process via inhibition of CDCP1 mediated Src activation, followed by VHL induced HIF-1a degradation and, ultimately, decreased VEGF expression.	49	54	induced	Positive_early_activation	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1a	HIF-1a	HIF-1a	51	52	53	54
This sensitization is in part achieved through XAF1 inhibition of XIAP anti-caspase activity .	This sensitization is in part achieved through XAF1 inhibition of XIAP anti-caspase activity.	7	12	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	7	8	10	11
XAF1 is a potent antagonist of anti-apoptotic XIAP and Survivin whereby Survivin is associated with high-risk neuroblastoma [ XREF_BIBR , XREF_BIBR ] .	XAF1 is a potent antagonist of anti-apoptotic XIAP and Survivin whereby Survivin is associated with high-risk neuroblastoma [XREF_BIBR, XREF_BIBR].	0	9	is a potent antagonist	Negative_activation_copula_1	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	0	1	7	8
The mechanism by which XAF1 antagonises the effects of XIAP is not very well known , but might affect the redistribution of XIAP from the cytoplasm to the nucleus ( Liston et al , 2001 ) .	The mechanism by which XAF1 antagonises the effects of XIAP is not very well known, but might affect the redistribution of XIAP from the cytoplasm to the nucleus (Liston et al, 2001).	4	10	antagonises	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	4	5	9	10
In recent years , XAF1 being a potent antagonist of XIAP , has been studied with interest for its involvement in tumor suppression .	In recent years, XAF1 being a potent antagonist of XIAP, has been studied with interest for its involvement in tumor suppression.	4	14	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	4	5	10	11
XAF1 is identified as XIAP binding protein and inhibits the function of XIAP anti-apoptosis .	XAF1 is identified as XIAP binding protein and inhibits the function of XIAP anti-apoptosis.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	0	1	12	13
Moreover , XIAP associated factor 1 ( XAF1 ) negatively regulates the antiapoptotic function of XIAP .	Moreover, XIAP associated factor 1 (XAF1) negatively regulates the antiapoptotic function of XIAP.	2	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP associated factor 1	XIAP associated factor 1	XIAP associated factor 1	XIAP	XIAP	XIAP	2	6	15	16
The finding of upregulated XAF1 mRNA expression in drug resistant UC cell variants was unexpected considering that XAF1 is known to inhibit the anti-apoptotic factor XIAP , and hence is anticipated to promote cell death [ XREF_BIBR ] .	The finding of upregulated XAF1 mRNA expression in drug resistant UC cell variants was unexpected considering that XAF1 is known to inhibit the anti-apoptotic factor XIAP, and hence is anticipated to promote cell death [XREF_BIBR].	17	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	17	18	25	26
XAF1 is an inhibitor of XIAP , a transducer of cell survival signaling .	XAF1 is an inhibitor of XIAP, a transducer of cell survival signaling.	0	8	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	0	1	5	6
XAF1 is a direct inhibitor of XIAP , so this decrease could be also be increasing the apoptotic threshold of these tumors [ XREF_BIBR ] .	XAF1 is a direct inhibitor of XIAP, so this decrease could be also be increasing the apoptotic threshold of these tumors [XREF_BIBR].	0	7	is a direct inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	0	1	6	7
XAF-1 negatively regulates X linked inhibitor of apoptotsis ( XIAP ) , a member of the IAP family ( XIAP , c-IAP-1 and c-IAP-2 ) , which are potent inhibitors of caspase-3 , -7 and -9 .	XAF-1 negatively regulates X linked inhibitor of apoptotsis (XIAP), a member of the IAP family (XIAP, c-IAP-1 and c-IAP-2), which are potent inhibitors of caspase-3, -7 and -9.	0	23	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF-1	XAF-1	XAF-1	XIAP	XIAP	XIAP	0	1	19	20
In particular , XAF1 reverses the anti-caspase activity of XIAP , a physiological inhibitor of apoptosis .	In particular, XAF1 reverses the anti-caspase activity of XIAP, a physiological inhibitor of apoptosis.	3	13	reverses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	3	4	9	10
The mechanism by which XAF1 antagonizes XIAP is not completely explained , although recent studies showed that XAF1 is able to sequestrate XIAP from the cytoplasm into the nucleus .	The mechanism by which XAF1 antagonizes XIAP is not completely explained, although recent studies showed that XAF1 is able to sequestrate XIAP from the cytoplasm into the nucleus.	4	7	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	4	5	6	7
In cancerization of oral mucosa , XIAP protein could play an important antiapoptotic role by overexpression , while XAF1 protein does not appear to antagonize effectively the role of XIAP .	In cancerization of oral mucosa, XIAP protein could play an important antiapoptotic role by overexpression, while XAF1 protein does not appear to antagonize effectively the role of XIAP.	18	30	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	18	19	29	30
XAF1 was previously shown to induce apoptosis independent of XIAP inhibition .	XAF1 was previously shown to induce apoptosis independent of XIAP inhibition.	0	10	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	0	1	9	10
HSF1 represses the expression of XAF1 ( XIAP associated factor ) in gastrointestinal cancers and relieves the inhibition of activity of the anti-apoptotic mediator XIAP [ XREF_BIBR ] .	HSF1 represses the expression of XAF1 (XIAP associated factor) in gastrointestinal cancers and relieves the inhibition of activity of the anti-apoptotic mediator XIAP [XREF_BIBR].	0	26	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	XAF1	HSF1 represses the expression of XAF1	xaf1	XIAP	XIAP	xiap	5	6	24	25
XAF1 antagonizes XIAP activities , thereby promoting apoptosis [ XREF_BIBR ] .	XAF1 antagonizes XIAP activities, thereby promoting apoptosis [XREF_BIBR].	0	3	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	0	1	2	3
XIAP suppresses caspase activation and cell death in vitro , and XAF1 antagonizes these XIAP activities .	XIAP suppresses caspase activation and cell death in vitro, and XAF1 antagonizes these XIAP activities.	11	15	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	11	12	14	15
However , it was shown that XIAP antagonist XAF1 can displace survivin to improve tumor cell death [ XREF_BIBR ] .	However, it was shown that XIAP antagonist XAF1 can displace survivin to improve tumor cell death [XREF_BIBR].	6	10	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	8	9	6	7
Stable overexpression of XAF1 sensitized colon cancer cells to TRAIL induced apoptosis significantly increased the activity of caspase 3 , 7 , 8 , and 9 ; released cytochrome c ; and down-regulated XIAP , survivin , and c-IAP-2 .	Stable overexpression of XAF1 sensitized colon cancer cells to TRAIL induced apoptosis significantly increased the activity of caspase 3, 7, 8, and 9; released cytochrome c; and down-regulated XIAP, survivin, and c-IAP-2.	1	38	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	overexpression of XAF1	xaf1	XIAP	XIAP	xiap	3	4	33	34
XAF-1 is known to antagonize XIAP and promote caspase dependent apoptosis .	XAF-1 is known to antagonize XIAP and promote caspase dependent apoptosis.	0	7	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF-1	XAF-1	XAF-1	XIAP	XIAP	XIAP	0	1	5	6
X linked inhibitor of apoptosis protein ( XIAP ) suppresses apoptotic cell death by binding to caspases and inhibiting their functions , while the XIAP associated factor1 ( XAF1 ) , a zinc finger protein , antagonizes XIAP activities , thereby promoting apoptosis .	X linked inhibitor of apoptosis protein (XIAP) suppresses apoptotic cell death by binding to caspases and inhibiting their functions, while the XIAP associated factor1 (XAF1), a zinc finger protein, antagonizes XIAP activities, thereby promoting apoptosis.	26	38	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	28	29	37	38
CDK2 mediates the replication origin during S phase and WEE1 inhibition is supposed to increase CDK2 activity , inducing uncontrolled replication fork and promoting more cells into S phase XREF_BIBR , XREF_BIBR .	CDK2 mediates the replication origin during S phase and WEE1 inhibition is supposed to increase CDK2 activity, inducing uncontrolled replication fork and promoting more cells into S phase XREF_BIBR, XREF_BIBR.	9	16	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK2	CDK2	CDK2	9	10	15	16
In order to determine whether Wee1 inhibits Cdk2 in early X. laevis embryos , cyclin E was immunoprecipitated from embryos overexpressing Wee1 , and Western analysis was performed on the immunoprecipitates to detect inhibitory tyrosine phosphorylation on Cdk2 .	In order to determine whether Wee1 inhibits Cdk2 in early X. laevis embryos, cyclin E was immunoprecipitated from embryos overexpressing Wee1, and Western analysis was performed on the immunoprecipitates to detect inhibitory tyrosine phosphorylation on Cdk2.	5	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk2	Cdk2	Cdk2	5	6	7	8
Additionally , inhibition of Wee1 causes aberrantly high CDK2 activity in S-phase cells , leading to unstable DNA replication structures and , ultimately , DNA damage .	Additionally, inhibition of Wee1 causes aberrantly high CDK2 activity in S-phase cells, leading to unstable DNA replication structures and, ultimately, DNA damage.	2	9	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK2	CDK2	CDK2	4	5	8	9
Because Wee1 kinase has been reported to inhibit Cdk2 41 , RDF/PD166285/2i treatment might up-regulate Cdk2 through inhibiting Wee1 kinase by PD166285 .	Because Wee1 kinase has been reported to inhibit Cdk2 41, RDF/PD166285/2i treatment might up-regulate Cdk2 through inhibiting Wee1 kinase by PD166285.	1	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk2	Cdk2	Cdk2	1	2	8	9
In this scenario Wee1 might inactivate Cdk2 in an unperturbed S phase thereby keeping Mus81 and Eme1 inactive , likely as a consequence of its non phosphorylation by Cdk2 .	In this scenario Wee1 might inactivate Cdk2 in an unperturbed S phase thereby keeping Mus81 and Eme1 inactive, likely as a consequence of its non phosphorylation by Cdk2.	3	7	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk2	Cdk2	Cdk2	3	4	6	7
15 Cables1 also connects Cdk2 and Wee1 , resulting in increased Cdk2 Y15 phosphorylation , decreased Cdk2 kinase activity and reduced cell growth in proliferating cells .	15 Cables1 also connects Cdk2 and Wee1, resulting in increased Cdk2 Y15 phosphorylation, decreased Cdk2 kinase activity and reduced cell growth in proliferating cells.	4	18	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk2	Cdk2	Cdk2	6	7	16	17
Extracts of ET treated cells phosphorylate the N terminus of WEE1 , an inhibitory kinase , which negatively regulates CDK2 activity through phosphorylation at Tyr ( 15 ) , leading to a decrease in WEE1 activity and a reduction in levels of phospho-Tyr ( 15 ) in the CDK2 protein .	Extracts of ET treated cells phosphorylate the N terminus of WEE1, an inhibitory kinase, which negatively regulates CDK2 activity through phosphorylation at Tyr (15), leading to a decrease in WEE1 activity and a reduction in levels of phospho-Tyr (15) in the CDK2 protein.	5	20	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	phosphorylate the N terminus of WEE1	wee1	CDK2	CDK2	cdk2	10	11	19	20
Embryos overexpressing Wee1 expressed higher levels of phosphorylated Cdk2 ( PCdk ) indicating inhibition of Cdk2 by Wee1 .	Embryos overexpressing Wee1 expressed higher levels of phosphorylated Cdk2 (PCdk) indicating inhibition of Cdk2 by Wee1.	12	18	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk2	Cdk2	Cdk2	17	18	15	16
The knockdown of endogenous WSB-1 with the expression of short hairpin RNA against WSB-1 increases the stability of endogenous HIPK2 and resulted in the accumulation of HIPK2 .	The knockdown of endogenous WSB-1 with the expression of short hairpin RNA against WSB-1 increases the stability of endogenous HIPK2 and resulted in the accumulation of HIPK2.	1	20	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WSB-1	WSB-1	WSB-1	HIPK2	HIPK2	HIPK2	4	5	19	20
HIPK2 degradation by WSB-1 is terminated in DNA damage conditions , and autophosphorylation of HIPK2 is markedly increased .	HIPK2 degradation by WSB-1 is terminated in DNA damage conditions, and autophosphorylation of HIPK2 is markedly increased.	0	4	degradation	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	WSB-1	WSB-1	WSB-1	HIPK2	HIPK2	HIPK2	3	4	0	1
Hypoxia induced HIPK2 degradation is reversed by WSB-1 loss .	Hypoxia induced HIPK2 degradation is reversed by WSB-1 loss.	2	8	reversed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	WSB-1	WSB-1	WSB-1	HIPK2	HIPK2	HIPK2	7	8	2	3
In unstressed conditions , SIAH1 , WSB1 and SCF and Fbx3 promote the steady-state degradation of HIPK2 to prevent cell cycle arrest or apoptosis .	In unstressed conditions, SIAH1, WSB1 and SCF and Fbx3 promote the steady-state degradation of HIPK2 to prevent cell cycle arrest or apoptosis.	4	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WSB1	WSB1	WSB1	HIPK2	HIPK2	HIPK2	6	7	16	17
wsb1 silencing through RNA interference in hypoxic HCC cell lines , rescued HIPK2 .	wsb1 silencing through RNA interference in hypoxic HCC cell lines, rescued HIPK2.	0	13	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	wsb1	wsb1	wsb1	HIPK2	HIPK2	HIPK2	0	1	12	13
DNA damaging agents such as adriamycin or cisplatin prevent the WSB1 mediated degradation of HIPK2 , which thereby remains active and stable for the induction of apoptosis [ XREF_BIBR ] .	DNA damaging agents such as adriamycin or cisplatin prevent the WSB1 mediated degradation of HIPK2, which thereby remains active and stable for the induction of apoptosis [XREF_BIBR].	8	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WSB1	WSB1	WSB1	HIPK2	HIPK2	HIPK2	10	11	14	15
Coexpression of VRK1 and GFP-BAF greatly diminishes the association of BAF with the nuclear chromatin and matrix and leads to its dispersal throughout the cell .	Coexpression of VRK1 and GFP-BAF greatly diminishes the association of BAF with the nuclear chromatin and matrix and leads to its dispersal throughout the cell.	0	11	diminishes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	VRK1	Coexpression of VRK1	vrk1	BAF	BAF	baf	2	3	10	11
Indeed , YAP1 was reported to inhibit RUNX2 function by sequestering its transcriptional activity , and unlike TAZ , YAP1 did not bind PPARgamma .	Indeed, YAP1 was reported to inhibit RUNX2 function by sequestering its transcriptional activity, and unlike TAZ, YAP1 did not bind PPARgamma.	2	8	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	YAP1	YAP1	YAP1	RUNX2	RUNX2	RUNX2	2	3	7	8
A complex interplay between YAP1 and/or lamin-A might reconcile past observations that YAP1 promotes osteogenesis but also inhibits RUNX2 ; switching between YAP1 and TAZ ( WWTR1 ) activities is also possible , because TAZ can promote osteoblast differentiation of MSCs by enhancing RUNX2 dependent transcriptional activation , and the IP-MS data suggested a YAP1-TAZ interaction .	A complex interplay between YAP1 and/or lamin-A might reconcile past observations that YAP1 promotes osteogenesis but also inhibits RUNX2; switching between YAP1 and TAZ (WWTR1) activities is also possible, because TAZ can promote osteoblast differentiation of MSCs by enhancing RUNX2 dependent transcriptional activation, and the IP-MS data suggested a YAP1-TAZ interaction.	12	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	YAP1	YAP1	YAP1	RUNX2	RUNX2	RUNX2	12	13	18	19
Overexpression of YAP65 prevented RUNX2 dependent downregulation of p21 ( CIP1 ) protein expression while promoting cell transformation .	Overexpression of YAP65 prevented RUNX2 dependent downregulation of p21 (CIP1) protein expression while promoting cell transformation.	0	6	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	YAP65	Overexpression of YAP65	yap65	RUNX2	RUNX2	runx2	2	3	4	5
STS1 and STS2 have been shown to constitutively interact with CBL and inhibit CBL mediated degradation of the epidermal growth factor ( EGF ) receptor .	STS1 and STS2 have been shown to constitutively interact with CBL and inhibit CBL mediated degradation of the epidermal growth factor (EGF) receptor.	0	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	STS1	STS1	STS1	CBL	CBL	CBL	0	1	13	14
A mutation in the N-terminal motif of FOG-2 abrogates FOG-2 mediated repression of GATA- 4 induced transcriptional activity .	A mutation in the N-terminal motif of FOG-2 abrogates FOG-2 mediated repression of GATA- 4 induced transcriptional activity.	9	15	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	FOG-2	FOG-2	FOG-2	GATA- 4	GATA- 4	GATA- 4	9	10	13	15
While both mutant ZFPM2 and FOG2 proteins , E30G ( c. 88A > G ) and S657G ( c. 1968A > G ) , retain the ability to bind the partner protein GATA4 and repress GATA4 mediated gene activation , the S657G , but not the E30G , mutation is subtly impaired in this function .	While both mutant ZFPM2 and FOG2 proteins, E30G (c. 88A> G) and S657G (c. 1968A> G), retain the ability to bind the partner protein GATA4 and repress GATA4 mediated gene activation, the S657G, but not the E30G, mutation is subtly impaired in this function.	5	36	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FOG2	FOG2	FOG2	GATA4	GATA4	GATA4	5	6	35	36
The functional result of this interaction was also identified by the predictive network as Zfpm2 mediated inhibition of Gata4 .	The functional result of this interaction was also identified by the predictive network as Zfpm2 mediated inhibition of Gata4.	14	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Zfpm2	Zfpm2	Zfpm2	Gata4	Gata4	Gata4	14	15	18	19
In vitro , FOG2 represses GATA4 dependent trans-activation of AMH in primary Sertoli cell cultures .	In vitro, FOG2 represses GATA4 dependent trans-activation of AMH in primary Sertoli cell cultures.	1	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FOG2	FOG2	FOG2	GATA4	GATA4	GATA4	3	4	5	6
As shown in XREF_FIG , GATA4 is able to directly activate this promoter , and FOG-2 effectively represses GATA4 mediated transcriptional activation .	As shown in XREF_FIG, GATA4 is able to directly activate this promoter, and FOG-2 effectively represses GATA4 mediated transcriptional activation.	15	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FOG-2	FOG-2	FOG-2	GATA4	GATA4	GATA4	15	16	18	19
The in vitro study revealed that the novel variants of ZFPM2 attenuated the transcription activity of GATA4 .	The in vitro study revealed that the novel variants of ZFPM2 attenuated the transcription activity of GATA4.	8	17	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ZFPM2	ZFPM2	ZFPM2	GATA4	GATA4	GATA4	10	11	16	17
Similarly , the N-terminal region of FOG2 represses GATA-4 activity XREF_BIBR , although the possibility remains open that other regions might contribute to repression .	Similarly, the N-terminal region of FOG2 represses GATA-4 activity XREF_BIBR, although the possibility remains open that other regions might contribute to repression.	4	10	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FOG2	FOG2	FOG2	GATA-4	GATA-4	GATA-4	6	7	8	9
The novel variants of ZFPM2 attenuated the transcriptional activation of GATA4 .	The novel variants of ZFPM2 attenuated the transcriptional activation of GATA4.	2	11	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ZFPM2	ZFPM2	ZFPM2	GATA4	GATA4	GATA4	4	5	10	11
While neither FOG2 , GATA2 , or GATA4 alone have a significant effect in regulating expression from the Ctip2 upstream region , FOG2 in combination with GATA2 , or GATA4 strongly reduces luciferase activity ( 49.6 % and 59.2 % reduction of the activity yielded by GATA2 and GATA4 alone , respectively ; XREF_FIG ) .	While neither FOG2, GATA2, or GATA4 alone have a significant effect in regulating expression from the Ctip2 upstream region, FOG2 in combination with GATA2, or GATA4 strongly reduces luciferase activity (49.6% and 59.2% reduction of the activity yielded by GATA2 and GATA4 alone, respectively; XREF_FIG).	22	53	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FOG2	FOG2	FOG2	GATA4	GATA4	GATA4	22	23	48	49
The luciferase reporter gene assays revealed that the wild-type ZFPM2 protein could inhibit the transcriptional activation of GATA4 on the promoter of ANF .	The luciferase reporter gene assays revealed that the wild-type ZFPM2 protein could inhibit the transcriptional activation of GATA4 on the promoter of ANF.	9	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ZFPM2	ZFPM2	ZFPM2	GATA4	GATA4	GATA4	9	10	17	18
The GATA repressor protein friend of GATA 2 ( FOG-2 ) , also known as zinc finger protein multitype-2 , attenuates the effect of GATA-4 and may also have a role to play in the regulation of CYP2C19 transcription .	The GATA repressor protein friend of GATA 2 (FOG-2), also known as zinc finger protein multitype-2, attenuates the effect of GATA-4 and may also have a role to play in the regulation of CYP2C19 transcription.	4	25	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FOG-2	FOG-2	FOG-2	GATA-4	GATA-4	GATA-4	9	10	24	25
We show that miRNA106a and to a lesser extent miR17 and 93 target the cardiac suppressor gene Fog2 , which specifically suppress Gata-4 and Coup-TF2 .	We show that miRNA106a and to a lesser extent miR17 and 93 target the cardiac suppressor gene Fog2, which specifically suppress Gata-4 and Coup-TF2.	1	24	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Fog2	Fog2	Fog2	Gata-4	Gata-4	Gata-4	17	18	22	23
In contrast , expression of the FOG-2 R3K5A protein was unable to significantly repress GATA-4 activated transcription of the ANF promoter in NIH3T3 cells in this transient transfection assay .	In contrast, expression of the FOG-2 R3K5A protein was unable to significantly repress GATA-4 activated transcription of the ANF promoter in NIH3T3 cells in this transient transfection assay.	3	16	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FOG-2	expression of the FOG-2	fog-2	GATA-4	GATA-4	gata-4	6	7	14	15
FOG-2 is a powerful repressor of GATA4 mediated gene expression XREF_BIBR and of cardiac myocyte hypertrophy in vitro XREF_BIBR .	FOG-2 is a powerful repressor of GATA4 mediated gene expression XREF_BIBR and of cardiac myocyte hypertrophy in vitro XREF_BIBR.	0	15	is a powerful repressor	Negative_activation_copula_1	Negative_activation	Negative_activation	FOG-2	FOG-2	FOG-2	GATA4	GATA4	GATA4	0	1	6	7
In vitro transfection assays verified that FOG-2 is able to repress the effect of GATA-4 on MIS transactivation in granulosa cells .	In vitro transfection assays verified that FOG-2 is able to repress the effect of GATA-4 on MIS transactivation in granulosa cells.	6	15	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FOG-2	FOG-2	FOG-2	GATA-4	GATA-4	GATA-4	6	7	14	15
We show that FOG-2-mediated repression is not blocked by the histone deacetylase inhibitor tricostatin A , suggesting that FOG-2 repression of GATA4 occurs via a histone deacetylase independent mechanism .	We show that FOG-2-mediated repression is not blocked by the histone deacetylase inhibitor tricostatin A, suggesting that FOG-2 repression of GATA4 occurs via a histone deacetylase independent mechanism.	18	22	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	FOG-2	FOG-2	FOG-2	GATA4	GATA4	GATA4	18	19	21	22
59 Phosphorylation of Bad inactivates Bad at Ser 136 by promoting its binding with cytosolic 14-3-3 proteins , which prevents Bad from inhibiting the anti-apoptotic factor BCL-XL .	59 Phosphorylation of Bad inactivates Bad at Ser 136 by promoting its binding with cytosolic 14-3-3 proteins, which prevents Bad from inhibiting the anti-apoptotic factor BCL-XL.	15	21	prevents	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	14-3-3 proteins	14-3-3 proteins	14-3-3 proteins	Bad	Bad	Bad	15	17	20	21
When phosphorylated , BAD is unable to heterodimerize with Bcl-2 or Bcl-xL and is sequestered into the cytosol by 14-3-3 protein .	When phosphorylated, BAD is unable to heterodimerize with Bcl-2 or Bcl-xL and is sequestered into the cytosol by 14-3-3 protein.	3	21	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	14-3-3 protein	14-3-3 protein	14-3-3 protein	BAD	BAD	BAD	19	21	3	4
Overexpression of 14-3-3 protein significantly increased the cellular level of Bcl-2 protein and decreased that of BAD protein .	Overexpression of 14-3-3 protein significantly increased the cellular level of Bcl-2 protein and decreased that of BAD protein.	0	18	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 protein	Overexpression of 14-3-3 protein	14-3-3 protein	BAD protein	BAD protein	bad protein	2	4	16	18
Phosphorylated BAD associates with 14-3-3 proteins in the cytoplasm , preventing translocation of BAD to the mitochondria and its interaction with the anti-apoptotic proteins Bcl-xL and Bcl-2 .	Phosphorylated BAD associates with 14-3-3 proteins in the cytoplasm, preventing translocation of BAD to the mitochondria and its interaction with the anti-apoptotic proteins Bcl-xL and Bcl-2.	0	14	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 proteins	Phosphorylated BAD associates with 14-3-3 proteins	14-3-3 proteins	BAD	BAD	bad	4	6	13	14
Akt phosphorylates Bad and subsequently the phosphorylated forms of Bad bind with 14-3-3 protein , which in turn prevents Bad from associating with BCL-XL or BCL-2 [ XREF_BIBR ] .	Akt phosphorylates Bad and subsequently the phosphorylated forms of Bad bind with 14-3-3 protein, which in turn prevents Bad from associating with BCL-XL or BCL-2 [XREF_BIBR].	1	20	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 protein	phosphorylates Bad and subsequently the phosphorylated forms of Bad bind with 14-3-3 protein	14-3-3 protein	Bad	Bad	bad	12	14	19	20
Phosphorylated Bad associates with 14-3-3 proteins in the cytoplasm , preventing translocation of Bad to the mitochondria XREF_BIBR and interaction with the anti-apoptotic proteins Bcl-2 and Bcl-xl XREF_BIBR , XREF_BIBR .	Phosphorylated Bad associates with 14-3-3 proteins in the cytoplasm, preventing translocation of Bad to the mitochondria XREF_BIBR and interaction with the anti-apoptotic proteins Bcl-2 and Bcl-xl XREF_BIBR, XREF_BIBR.	0	14	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 proteins	Phosphorylated Bad associates with 14-3-3 proteins	14-3-3 proteins	Bad	Bad	bad	4	6	13	14
Phosphorylation of BAD promotes its interaction with 14-3-3 proteins , which sequesters BAD in the cytosol .	Phosphorylation of BAD promotes its interaction with 14-3-3 proteins, which sequesters BAD in the cytosol.	7	15	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 proteins	14-3-3 proteins	14-3-3 proteins	BAD	BAD	BAD	7	9	12	13
14-3-3 sequesters BAD in the cytoplasm under physiologically normal conditions .	14-3-3 sequesters BAD in the cytoplasm under physiologically normal conditions.	0	5	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3	14-3-3	14-3-3	BAD	BAD	BAD	0	1	2	3
Once in the cytosol , FoxO is then sequestered by 14-3-3 proteins and is rendered inactive .	Once in the cytosol, FoxO is then sequestered by 14-3-3 proteins and is rendered inactive.	5	14	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	14-3-3 proteins	14-3-3 proteins	14-3-3 proteins	FoxO	FoxO	FoxO	10	12	5	6
DAF-16 and FOXO receives phosphorylation from the direct upstream AKT kinases mediated signal transduction response to insulin or IGF and is subsequently sequestered in the cytoplasm by 14-3-3 proteins , which antagonizes FoxO and negatively regulates longevity .	DAF-16 and FOXO receives phosphorylation from the direct upstream AKT kinases mediated signal transduction response to insulin or IGF and is subsequently sequestered in the cytoplasm by 14-3-3 proteins, which antagonizes FoxO and negatively regulates longevity.	0	29	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	14-3-3 proteins	14-3-3 proteins	14-3-3 proteins	FOXO	FOXO	FOXO	27	29	2	3
72 Phosphorylation of FOXO by AKT at specific sites promotes FOXO translocation from the nucleus to the cytosol , where 14-3-3 proteins sequester FOXO proteins to inhibit their nuclear transcription activity 73 ( XREF_FIG ) .	72 Phosphorylation of FOXO by AKT at specific sites promotes FOXO translocation from the nucleus to the cytosol, where 14-3-3 proteins sequester FOXO proteins to inhibit their nuclear transcription activity 73 (XREF_FIG).	20	24	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 proteins	14-3-3 proteins	14-3-3 proteins	FOXO	FOXO	FOXO	20	22	23	24
PKB induced phosphorylation at Ser253 and the sequential binding of 14-3-3 proteins have been suggested to prevent the interaction of FOXO with its target genes .	PKB induced phosphorylation at Ser253 and the sequential binding of 14-3-3 proteins have been suggested to prevent the interaction of FOXO with its target genes.	10	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 proteins	14-3-3 proteins	14-3-3 proteins	FOXO	FOXO	FOXO	10	12	20	21
It has also been suggested that the 14-3-3 protein may prevent nuclear re-import of FOXO proteins by masking their nuclear localization signal .	It has also been suggested that the 14-3-3 protein may prevent nuclear re-import of FOXO proteins by masking their nuclear localization signal.	7	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 protein	14-3-3 protein	14-3-3 protein	FOXO	FOXO	FOXO	7	9	14	15
Second , the 14-3-3 proteins prevent nuclear reimport of FOXO factors by masking their nuclear localization signal .	Second, the 14-3-3 proteins prevent nuclear reimport of FOXO factors by masking their nuclear localization signal.	3	10	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 proteins	14-3-3 proteins	14-3-3 proteins	FOXO	FOXO	FOXO	3	5	9	10
Importantly , pX dependent activation of p38 MAPK inactivates Cdc25C by phosphorylation of Ser216 , thus initiating activation of the G ( 2 )/M checkpoint , resulting in 4pX-1 cell growth retardation .	Importantly, pX dependent activation of p38 MAPK inactivates Cdc25C by phosphorylation of Ser216, thus initiating activation of the G (2)/M checkpoint, resulting in 4pX-1 cell growth retardation.	6	10	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p38 MAPK	p38 MAPK	p38 MAPK	Cdc25C	Cdc25C	Cdc25C	6	8	9	10
Lastly , p38 induces CDC25C cytoplasmic sequestration in response to DNA damage thereby inactivating CDC25C indirectly via MK2 kinase [ XREF_BIBR ] .	Lastly, p38 induces CDC25C cytoplasmic sequestration in response to DNA damage thereby inactivating CDC25C indirectly via MK2 kinase [XREF_BIBR].	2	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p38	p38	p38	CDC25C	CDC25C	CDC25C	2	3	14	15
CDC25C is also inhibited by p38 MAPK through the downstream kinase MK2 [ XREF_BIBR , XREF_BIBR ] .	CDC25C is also inhibited by p38 MAPK through the downstream kinase MK2 [XREF_BIBR, XREF_BIBR].	0	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p38 MAPK	p38 MAPK	p38 MAPK	CDC25C	CDC25C	CDC25C	5	7	0	1
Phosphorylation of p38 was inhibited by gefitinib and paclitaxel in combination , or by BI2536 alone , thereby relieving the inhibition of CDC25C and enhancing progression into mitosis .	Phosphorylation of p38 was inhibited by gefitinib and paclitaxel in combination, or by BI2536 alone, thereby relieving the inhibition of CDC25C and enhancing progression into mitosis.	0	23	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p38	Phosphorylation of p38	p38	CDC25C	CDC25C	cdc25c	2	3	22	23
Chemotherapeutic methylating agent temozolomide induces p38 MAPK activation which in turn inactivates Cdc25C and its downstream target Cdc2 , suggesting p38 MAPK is involved in the regulation of chemotherapeutic methylating agent induced G2 checkpoint bypass [ XREF_BIBR ] .	Chemotherapeutic methylating agent temozolomide induces p38 MAPK activation which in turn inactivates Cdc25C and its downstream target Cdc2, suggesting p38 MAPK is involved in the regulation of chemotherapeutic methylating agent induced G2 checkpoint bypass [XREF_BIBR].	5	17	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p38 MAPK	p38 MAPK	p38 MAPK	Cdc25C	Cdc25C	Cdc25C	5	7	12	13
In particular , our data demonstrate that : ( 1 ) ZNF521 binds to EBF1 via its carboxyl-terminal portion and this interaction is required for EBF1 inhibition ; ( 2 ) NuRD complex recruitment by ZNF521 is not essential for the inhibition of transactivation of EBF1 dependent promoters ; ( 3 ) ZNF521 represses EBF1 target genes in a human B-lymphoid molecular context ; and ( 4 ) RNAi mediated silencing of ZNF521 and Zfp521 in primary human and murine hematopoietic progenitors strongly enhances the generation of B-lymphocytes in vitro .	In particular, our data demonstrate that : (1) ZNF521 binds to EBF1 via its carboxyl-terminal portion and this interaction is required for EBF1 inhibition; (2) NuRD complex recruitment by ZNF521 is not essential for the inhibition of transactivation of EBF1 dependent promoters; (3) ZNF521 represses EBF1 target genes in a human B-lymphoid molecular context; and (4) RNAi mediated silencing of ZNF521 and Zfp521 in primary human and murine hematopoietic progenitors strongly enhances the generation of B-lymphocytes in vitro.	52	56	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ZNF521	ZNF521	ZNF521	EBF1	EBF1	EBF1	52	53	54	55
Finally , the zinc finger proteins ZNF423 and ZNF521 have been shown to interact directly with EBF1 and suppress EBF1 function XREF_BIBR , XREF_BIBR .	Finally, the zinc finger proteins ZNF423 and ZNF521 have been shown to interact directly with EBF1 and suppress EBF1 function XREF_BIBR, XREF_BIBR.	6	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ZNF521	ZNF521	ZNF521	EBF1	EBF1	EBF1	8	9	19	20
Here we show that ( 1 ) EHZF expression is abundant in human CD34+ progenitors and declines rapidly during cytokine driven differentiation ; ( 2 ) significant mRNA levels are found in most acute myelogenous leukemias ; ( 3 ) in response to BMPs EHZF complexes SMADs 1 and 4 , binds to , and enhances the transcriptional activity of , a BMP2/4 responsive element ; ( 4 ) EHZF inhibits the transcriptional activity of early B-cell factor ( EBF ) , a transcription factor essential for specification of the B-cell lineage .	Here we show that (1) EHZF expression is abundant in human CD34+ progenitors and declines rapidly during cytokine driven differentiation; (2) significant mRNA levels are found in most acute myelogenous leukemias; (3) in response to BMPs EHZF complexes SMADs 1 and 4, binds to, and enhances the transcriptional activity of, a BMP2/4 responsive element; (4) EHZF inhibits the transcriptional activity of early B-cell factor (EBF), a transcription factor essential for specification of the B-cell lineage.	69	78	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	EHZF	EHZF	EHZF	early B-cell factor	early B-cell factor	early B-cell factor	69	70	75	78
In addition , two multi-zinc finger proteins , ZNF423 and ZNF521 , antagonize the biological activity of EBF1 and thereby might promote tumorigenesis [ XREF_BIBR ] .	In addition, two multi-zinc finger proteins, ZNF423 and ZNF521, antagonize the biological activity of EBF1 and thereby might promote tumorigenesis [XREF_BIBR].	6	18	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ZNF521	ZNF521	ZNF521	EBF1	EBF1	EBF1	10	11	17	18
Stress induced phosphorylation of 14-3-3 by c-Jun N-terminal kinase ( JNK ) reduces 14-3-3 protein-FOXO3a binding capacity and directly inhibits nuclear export of FOXO3a thereby increasing transcriptional activity of FOXO3a [ XREF_BIBR ] .	Stress induced phosphorylation of 14-3-3 by c-Jun N-terminal kinase (JNK) reduces 14-3-3 protein-FOXO3a binding capacity and directly inhibits nuclear export of FOXO3a thereby increasing transcriptional activity of FOXO3a [XREF_BIBR].	2	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3	phosphorylation of 14-3-3	14-3-3	FOXO3a	FOXO3a	foxo3a	4	5	23	24
For example , p38 activates CHOP , a negative regulator of C/EBPbeta , and also blocks NFATc4 , which is a transcription factor for Pparg .	For example, p38 activates CHOP, a negative regulator of C/EBPbeta, and also blocks NFATc4, which is a transcription factor for Pparg.	3	22	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p38	p38	p38	NFATc4	NFATc4	NFATc4	3	4	16	17
In adipocytes , p38 MAPK negatively regulate transcriptional activity of NFATc4 that promote adipogenesis .	In adipocytes, p38 MAPK negatively regulate transcriptional activity of NFATc4 that promote adipogenesis.	3	11	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p38 MAPK	p38 MAPK	p38 MAPK	NFATc4	NFATc4	NFATc4	3	5	10	11
Given that Yap1 is well known for its oncogenic function , and 14-3-3 proteins inhibit Yap1 transcriptional functions by retaining it in the cytoplasm , we then asked whether the skin tumors induced in Er mice have increased Yap1 nuclear localization .	Given that Yap1 is well known for its oncogenic function, and 14-3-3 proteins inhibit Yap1 transcriptional functions by retaining it in the cytoplasm, we then asked whether the skin tumors induced in Er mice have increased Yap1 nuclear localization.	12	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 proteins	14-3-3 proteins	14-3-3 proteins	Yap1	Yap1	Yap1	12	14	15	16
Phosphorylation at Ser 967 is essential for ASK1 association with 14-3-3 protein , which attenuates ASK1 activity XREF_BIBR .	Phosphorylation at Ser 967 is essential for ASK1 association with 14-3-3 protein, which attenuates ASK1 activity XREF_BIBR.	10	17	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 protein	14-3-3 protein	14-3-3 protein	ASK1	ASK1	ASK1	10	12	15	16
14-3-3 antagonizes the pro apoptotic activity of Ask1 , suppressing cell death .	14-3-3 antagonizes the pro apoptotic activity of Ask1, suppressing cell death.	0	8	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3	14-3-3	14-3-3	Ask1	Ask1	Ask1	0	1	7	8
14-3-3 is an inhibitor of ASK1 .	14-3-3 is an inhibitor of ASK1.	0	6	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	14-3-3	14-3-3	14-3-3	ASK1	ASK1	ASK1	0	1	5	6
UV irradiation is known to induce a G2/M arrest through p38 MAP kinase mediated inhibition of cdc25B activity .	UV irradiation is known to induce a G2/M arrest through p38 MAP kinase mediated inhibition of cdc25B activity.	10	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p38	p38	p38	cdc25B	cdc25B	cdc25B	10	11	16	17
p38 activates the p53/GADD45alpha/14.3.3 pathway leading to inhibition of Cdc2 and cyclinB but can also inhibit the phosphatase Cdc25B via MK2 , impairing in both cases the G2/M transition .	p38 activates the p53/GADD45alpha/14.3.3 pathway leading to inhibition of Cdc2 and cyclinB but can also inhibit the phosphatase Cdc25B via MK2, impairing in both cases the G2/M transition.	0	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p38	p38	p38	Cdc25B	Cdc25B	Cdc25B	0	1	18	19
ZNRF3 is associated with the Wnt receptor complex , and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6 .	ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ZNRF3	ZNRF3	ZNRF3	LRP6	LRP6	LRP6	0	1	20	21
Furthermore , ACP1 reduced the proteins expression of NOX1 , NOX2 and NOX4 , as well as phosphorylation of ERK , p38 and Akt .	Furthermore, ACP1 reduced the proteins expression of NOX1, NOX2 and NOX4, as well as phosphorylation of ERK, p38 and Akt.	2	24	reduced	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	ACP1	ACP1	acp1	Akt	phosphorylation of ERK, p38 and Akt	akt	2	3	23	24
Concomitantly , active AKT phosphorylates PRAS40 causing it to release and bind to 14-3-3 proteins which prevent PRAS40 from inhibiting mTORC1 [ XREF_BIBR , XREF_BIBR ] .	Concomitantly, active AKT phosphorylates PRAS40 causing it to release and bind to 14-3-3 proteins which prevent PRAS40 from inhibiting mTORC1 [XREF_BIBR, XREF_BIBR].	13	18	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	14-3-3 proteins	14-3-3 proteins	14-3-3 proteins	PRAS40	PRAS40	PRAS40	13	15	17	18
Chromatin immunoprecipitation experiments suggest that ZNF76 prevents TBP from occupying the endogenous p21 promoter .	Chromatin immunoprecipitation experiments suggest that ZNF76 prevents TBP from occupying the endogenous p21 promoter.	5	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ZNF76	ZNF76	ZNF76	TBP	TBP	TBP	5	6	7	8
The direct binding of the N-terminal half of ABL-1 to ABI-1 strengthens the hypothesis that a direct interaction between these proteins exists in vivo and suggests that ABL-1 directly inhibits ABI-1 in its roles in the engulfment of apoptotic cells and DTC migration .	The direct binding of the N-terminal half of ABL-1 to ABI-1 strengthens the hypothesis that a direct interaction between these proteins exists in vivo and suggests that ABL-1 directly inhibits ABI-1 in its roles in the engulfment of apoptotic cells and DTC migration.	27	33	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABL-1	ABL-1	ABL-1	ABI-1	ABI-1	ABI-1	27	28	30	31
First , ABL-1 might directly inhibit ABI-1 from promoting engulfment of apoptotic cells and inappropriate DTC migration through a molecular pathway that acts in parallel to the known engulfment gene pathways ( XREF_FIG ) .	First, ABL-1 might directly inhibit ABI-1 from promoting engulfment of apoptotic cells and inappropriate DTC migration through a molecular pathway that acts in parallel to the known engulfment gene pathways (XREF_FIG).	2	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABL-1	ABL-1	ABL-1	ABI-1	ABI-1	ABI-1	2	3	6	7
We propose that ABL-1 inhibits ABI-1 and that these two proteins define a new molecular pathway required for cell-corpse engulfment and DTC migration .	We propose that ABL-1 inhibits ABI-1 and that these two proteins define a new molecular pathway required for cell-corpse engulfment and DTC migration.	3	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABL-1	ABL-1	ABL-1	ABI-1	ABI-1	ABI-1	3	4	5	6
Instead , abl-1 negatively regulates the engulfment gene abi-1 to inhibit cell death clearance ( See XREF_SUPPLEMENTARY ) .	Instead, abl-1 negatively regulates the engulfment gene abi-1 to inhibit cell death clearance (See XREF_SUPPLEMENTARY).	2	9	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	abl-1	abl-1	abl-1	abi-1	abi-1	abi-1	2	3	8	9
Although the mammalian Abl inhibits cell migrations via phosphorylation of CrkII , in C. elegans the mechanism is different : ABL-1 inhibits ABI-1 ( both interact physically in vitro ) , which acts to promote engulfment .	Although the mammalian Abl inhibits cell migrations via phosphorylation of CrkII, in C. elegans the mechanism is different : ABL-1 inhibits ABI-1 (both interact physically in vitro), which acts to promote engulfment.	20	34	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABL-1	ABL-1	ABL-1	ABI-1	ABI-1	ABI-1	20	21	22	23
By contrast , we found that ABL-1 inhibits ABI-1 .	By contrast, we found that ABL-1 inhibits ABI-1.	6	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABL-1	ABL-1	ABL-1	ABI-1	ABI-1	ABI-1	6	7	8	9
Knockdown of c-Abl and CAS attenuated the activation of Abi1 during contractile activation .	Knockdown of c-Abl and CAS attenuated the activation of Abi1 during contractile activation.	0	10	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	Abi1	Abi1	Abi1	2	3	9	10
Knockdown of Abl and CAS attenuates the activation of Abi1 during contractile activation .	Knockdown of Abl and CAS attenuates the activation of Abi1 during contractile activation.	0	10	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Abl	Abl	Abl	Abi1	Abi1	Abi1	2	3	9	10
Genetic and biochemical data indicate that ABL-1 inhibits ABI-1 in parallel to the CED-10 Rac pathway XREF_BIBR .	Genetic and biochemical data indicate that ABL-1 inhibits ABI-1 in parallel to the CED-10 Rac pathway XREF_BIBR.	6	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABL-1	ABL-1	ABL-1	ABI-1	ABI-1	ABI-1	6	7	8	9
PIP5Kalpha knockdown significantly decreased ABCA1 mediated apoA1 binding and cholesterol efflux in both RAW264.7 and HEK293 cells ( XREF_FIG , XREF_SUPPLEMENTARY ) .	PIP5Kalpha knockdown significantly decreased ABCA1 mediated apoA1 binding and cholesterol efflux in both RAW264.7 and HEK293 cells (XREF_FIG, XREF_SUPPLEMENTARY).	4	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA1	apoA1	apoA1	4	5	6	7
Percentage of probucol-inhibitable , ABCA1 specific cholesterol efflux and peptide mediated total efflux were measured in FAMP5 and another apoA-I mimetic L-4F peptide ( XREF_FIG A and XREF_FIG B ) .	Percentage of probucol-inhibitable, ABCA1 specific cholesterol efflux and peptide mediated total efflux were measured in FAMP5 and another apoA-I mimetic L-4F peptide (XREF_FIG A and XREF_FIG B).	4	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	4	5	19	20
SNTA delays the degradation of ABCA1 , and thereby , stimulates apolipoprotein A-I ( ApoA-I ) mediated release of cholesterol .	SNTA delays the degradation of ABCA1, and thereby, stimulates apolipoprotein A-I (ApoA-I) mediated release of cholesterol.	3	13	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ABCA1	ABCA1	ABCA1	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	5	6	11	13
Because paraoxon ' s ability to attenuate macrophage cholesterol efflux was dependent on the type of cholesterol acceptor used , we speculated that paraoxon might reduce the expression of the cholesterol transporter ABCA1 that mediates cholesterol efflux to ApoA1 because efflux to this acceptor was the most reduced following paraoxon treatment of THP-1 foam cells .	Because paraoxon 's ability to attenuate macrophage cholesterol efflux was dependent on the type of cholesterol acceptor used, we speculated that paraoxon might reduce the expression of the cholesterol transporter ABCA1 that mediates cholesterol efflux to ApoA1 because efflux to this acceptor was the most reduced following paraoxon treatment of THP-1 foam cells.	23	39	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ABCA1	paraoxon might reduce the expression of the cholesterol transporter ABCA1	abca1	ApoA1	ApoA1	apoa1	32	33	38	39
In Tangier disease , mutations in both alleles and the absence of ABCA1 activity reduce plasma HDL cholesterol and apoAI by 40 % to 50 % and decrease apoAI HDL lipidation XREF_BIBR , XREF_BIBR ; plasma apoE levels are unchanged or increased .	In Tangier disease, mutations in both alleles and the absence of ABCA1 activity reduce plasma HDL cholesterol and apoAI by 40% to 50% and decrease apoAI HDL lipidation XREF_BIBR, XREF_BIBR; plasma apoE levels are unchanged or increased.	12	25	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABCA1	ABCA1	ABCA1	apoAI	apoAI	apoAI	12	13	19	20
ABCA1 deficiency decreased apoA-I phospholipidation by 80 % , but acquisition of de novo synthesized and exogenous cholesterol only decreased by 40-60 % .	ABCA1 deficiency decreased apoA-I phospholipidation by 80%, but acquisition of de novo synthesized and exogenous cholesterol only decreased by 40-60%.	0	4	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	0	1	3	4
ABCA1 upregulation depletes lipid-poor ApoA-I by driving its conversion to alpha-HDL particles ; whereas , increasing the synthesis of new ApoA-I protein results in a parallel increase in lipid-poor ApoA-I .	ABCA1 upregulation depletes lipid-poor ApoA-I by driving its conversion to alpha-HDL particles; whereas, increasing the synthesis of new ApoA-I protein results in a parallel increase in lipid-poor ApoA-I.	0	5	depletes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABCA1	ABCA1	ABCA1	ApoA-I	ApoA-I	ApoA-I	0	1	4	5
The knock-down of the ATP binding cassette transporters A1 ( ABCA1 ) , G1 ( ABCG1 ) , and of the scavenger receptor-BI ( SR-BI ) diminishes but does not completely block the transport of apoA-I or HDL , so that other receptors appear to be involved .	The knock-down of the ATP binding cassette transporters A1 (ABCA1), G1 (ABCG1), and of the scavenger receptor-BI (SR-BI) diminishes but does not completely block the transport of apoA-I or HDL, so that other receptors appear to be involved.	4	37	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	10	11	35	36
Recently , new research has shown that knock-down of ABCA1 , ABCG1 , and SR-BI diminishes , but does not completely block , the transport of apoA-I or HDL through the endothelium [ XREF_BIBR , XREF_BIBR ] .	Recently, new research has shown that knock-down of ABCA1, ABCG1, and SR-BI diminishes, but does not completely block, the transport of apoA-I or HDL through the endothelium [XREF_BIBR, XREF_BIBR].	7	33	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABCA1	ABCA1	ABCA1	apoA-I	apoA-I	apoA-I	9	10	26	27
abl-1 expression almost completely abrogated the effect of the abl-1 ( n1963 ) mutation , whereas expression of a gfp-only control transgene had minimal effects on the engulfment defect of ced-10 ( n1993 ) ; abl-1 ( n1963 ) animals ( XREF_TABLE ) .	abl-1 expression almost completely abrogated the effect of the abl-1 (n1963) mutation, whereas expression of a gfp-only control transgene had minimal effects on the engulfment defect of ced-10 (n1993); abl-1 (n1963) animals (XREF_TABLE).	0	13	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	abl-1	abl-1 expression	abl-1	abl-1	abl-1	abl-1	0	1	9	10
c-Abl overexpression decreased ADCC sensitivity and rescued the effects of ABL1 knockdown .	c-Abl overexpression decreased ADCC sensitivity and rescued the effects of ABL1 knockdown.	0	11	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Abl	c-Abl overexpression	c-abl	ABL1	ABL1	abl1	0	1	10	11
We hypothesized that c-Abl expression could rescue the effects of ABL1 knockdown .	We hypothesized that c-Abl expression could rescue the effects of ABL1 knockdown.	3	11	rescue	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Abl	c-Abl expression	c-abl	ABL1	ABL1	abl1	3	4	10	11
Western blotting revealed that c-Abl plasmid co-transfection partially rescued endogenous c-Abl knockdown by ABL1 siRNA to ~ 80 % of the endogenous c-Abl levels ( XREF_FIG ) .	Western blotting revealed that c-Abl plasmid co-transfection partially rescued endogenous c-Abl knockdown by ABL1 siRNA to ~ 80% of the endogenous c-Abl levels (XREF_FIG).	11	24	knockdown	Negative_regulation_syntax_3_verb	Positive_activation	Positive_regulation	ABL1	ABL1	abl1	c-Abl	c-Abl levels	c-abl	13	14	22	23
These data indicate that imatinib impairment of Abl family kinase activity in HNSCC relieves the inhibitory effect of Abl on invadopodia function , promoting ECM degradation .	These data indicate that imatinib impairment of Abl family kinase activity in HNSCC relieves the inhibitory effect of Abl on invadopodia function, promoting ECM degradation.	7	21	relieves	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Abl	Abl	Abl	Abl	Abl	Abl	7	8	18	19
Consistent with the widespread expression of Abl , targeted disruption of the Abl1 gene in mice resulted in pleiotropic phenotypes including runtedness , high perinatal lethality , susceptibility to infections , and immune deficiencies in homozygous null Abl mice .	Consistent with the widespread expression of Abl, targeted disruption of the Abl1 gene in mice resulted in pleiotropic phenotypes including runtedness, high perinatal lethality, susceptibility to infections, and immune deficiencies in homozygous null Abl mice.	4	13	targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Abl	expression of Abl	abl	Abl1	Abl1	abl1	6	7	12	13
abi-1 ( tm494 ) abolishes the ability of abl-1 null mutations to suppress defects in engulfment and DTC migration XREF_BIBR .	abi-1 (tm494) abolishes the ability of abl-1 null mutations to suppress defects in engulfment and DTC migration XREF_BIBR.	0	10	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	abi-1	abi-1	abi-1	abl-1	abl-1	abl-1	0	1	8	9
In the present study , we show that Crk and Abi1 have reciprocal and opposing effects on Abl kinase activity , whereby Abl is affirmatively regulated by pTyr251 Crk phosphorylation , and negatively regulated by Abi1 isoform 2 .	In the present study, we show that Crk and Abi1 have reciprocal and opposing effects on Abl kinase activity, whereby Abl is affirmatively regulated by pTyr251 Crk phosphorylation, and negatively regulated by Abi1 isoform 2.	17	36	negatively regulated	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	Abi1	Abi1	Abi1	Abl	Abl	Abl	35	36	17	18
ABI1 can inhibit the transforming activity of v-Abl , and ABI1 derived phosphopeptides can inhibit ABL1 activity through an apparent allosteric effect .	ABI1 can inhibit the transforming activity of v-Abl, and ABI1 derived phosphopeptides can inhibit ABL1 activity through an apparent allosteric effect.	10	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ABI1	ABI1	ABI1	ABL1	ABL1	ABL1	10	11	15	16
In prostate cancer LnCap cells , overexpression of Abi1 Isoform 2 abrogates Abl kinase activity and decreases Tyr412 in the activation loop of kinase domain [ XREF_BIBR ] .	In prostate cancer LnCap cells, overexpression of Abi1 Isoform 2 abrogates Abl kinase activity and decreases Tyr412 in the activation loop of kinase domain [XREF_BIBR].	6	14	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Abi1	overexpression of Abi1	abi1	Abl	Abl	abl	8	9	12	13
As with phosphorylation by the DNA-PK complex , c-Abl phosphorylation inhibits WRN helicase and exonuclease activities .	As with phosphorylation by the DNA-PK complex, c-Abl phosphorylation inhibits WRN helicase and exonuclease activities.	8	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Abl	c-Abl phosphorylation	c-abl	WRN	WRN	wrn	8	9	11	12
We show that activated Abl impairs EGFR internalization .	We show that activated Abl impairs EGFR internalization.	3	7	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Abl	Abl	Abl	EGFR	EGFR	EGFR	4	5	6	7
These findings indicate that , in addition to stimulating catalase activity , c-Abl and Arg promote catalase degradation in the oxidative stress response .	These findings indicate that, in addition to stimulating catalase activity, c-Abl and Arg promote catalase degradation in the oxidative stress response.	12	17	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Abl	c-Abl	c-Abl	catalase	catalase	catalase	12	13	16	17
Likewise , we found that abl-1 ( n1963 ) mutations reduced the level of ER stress resistance conferred by ced-1 ( n2091 ) and ced-6 ( n2095 ) mutations ( XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY ) .	Likewise, we found that abl-1 (n1963) mutations reduced the level of ER stress resistance conferred by ced-1 (n2091) and ced-6 (n2095) mutations (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).	5	16	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	abl-1	abl-1	abl-1	ER	ER	ER	5	6	14	15
In apoptotic cells , activation of c-Abl prevented localization of LASP1 to focal contacts and that possibly disrupted survival signals emanating from these structures .	In apoptotic cells, activation of c-Abl prevented localization of LASP1 to focal contacts and that possibly disrupted survival signals emanating from these structures.	4	17	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Abl	c-Abl	c-Abl	LASP1	LASP1	LASP1	6	7	10	11
Protein analysis showed that c-Abl depletion obviously decreased the accumulation of p73 protein in irradiated cells at 0 and 4hpi , but not at 24hpi .	Protein analysis showed that c-Abl depletion obviously decreased the accumulation of p73 protein in irradiated cells at 0 and 4hpi, but not at 24hpi.	4	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Abl	c-Abl	c-Abl	p73	p73	p73	4	5	11	12
Here we report that genetic ablation of c-Abl accelerated c-Jun degradation .	Here we report that genetic ablation of c-Abl accelerated c-Jun degradation.	5	10	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Abl	c-Abl	c-Abl	c-Jun	c-Jun	c-Jun	7	8	9	10
Moreover , transfected AAK1 increases the localization of activated Notch to Rab5 positive endocytic vesicles , while AAK1 depletion or overexpression of Numb , an inhibitor of the pathway , interferes with this localization .	Moreover, transfected AAK1 increases the localization of activated Notch to Rab5 positive endocytic vesicles, while AAK1 depletion or overexpression of Numb, an inhibitor of the pathway, interferes with this localization.	17	23	depletion	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	AAK1	AAK1	AAK1	Numb	Numb	Numb	17	18	22	23
These findings suggest a new hypothesis that c-Abl signaling might be implicated in striatal function and raise the possibility that a c-Abl inhibitor might inhibit Cdk5 and DARPP-32-pThr75 signaling , thereby serving as a tool in treating PD symptoms .	These findings suggest a new hypothesis that c-Abl signaling might be implicated in striatal function and raise the possibility that a c-Abl inhibitor might inhibit Cdk5 and DARPP-32-pThr75 signaling, thereby serving as a tool in treating PD symptoms.	7	28	raise	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Abl	c-Abl	c-Abl	Cdk5	Cdk5	Cdk5	7	8	25	26
Therefore , PPARgamma not only downregulates the expression of ACE and AT1R , but also blocks the action of Ang II and ultimately inhibits adrenal aldosterone synthesis and secretion .	Therefore, PPARgamma not only downregulates the expression of ACE and AT1R, but also blocks the action of Ang II and ultimately inhibits adrenal aldosterone synthesis and secretion.	2	21	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	PPARgamma not only downregulates the expression of ACE	ace	Ang II	Ang II	ang ii	9	10	19	21
Although ACE inhibitors have a similar mechanism of action -- namely , inhibition of circulatory ACE , thereby decreasing the formation of angiotensin II -- individual members differ in their physicochemical properties , enzyme binding kinetics , pharmacokinetic profile , organ specific affinity and selectivity , as well as in their bradykinin potentiating effect .	Although ACE inhibitors have a similar mechanism of action -- namely, inhibition of circulatory ACE, thereby decreasing the formation of angiotensin II -- individual members differ in their physicochemical properties, enzyme binding kinetics, pharmacokinetic profile, organ specific affinity and selectivity, as well as in their bradykinin potentiating effect.	12	24	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	15	16	22	24
Collectively , we conclude that TERT decreased the cardiac expression of ACE but increased the expression of ACE 2 and Ang II in CIH mouse hearts .	Collectively, we conclude that TERT decreased the cardiac expression of ACE but increased the expression of ACE 2 and Ang II in CIH mouse hearts.	5	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	TERT decreased the cardiac expression of ACE	ace	Ang II	Ang II	ang ii	11	12	20	22
32 Inhibition of ACE alone prevents increased ACE protein expression , enhanced formation of ANG II and increased BP during systemic ANGII infusion .	32 Inhibition of ACE alone prevents increased ACE protein expression, enhanced formation of ANG II and increased BP during systemic ANGII infusion.	7	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE protein expression	ace	ANG II	ANG II	ang ii	7	8	14	16
By contrast , Ace KO mice have modestly reduced circulating Ang II , while tissue levels are not significantly modified , possibly as substantial amounts of Ang II are generated by non ACE pathways , while degradation pathways for Ang II are more limited [ XREF_BIBR ] .	By contrast, Ace KO mice have modestly reduced circulating Ang II, while tissue levels are not significantly modified, possibly as substantial amounts of Ang II are generated by non ACE pathways, while degradation pathways for Ang II are more limited [XREF_BIBR].	3	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ace	Ace	Ace	Ang II	Ang II	Ang II	3	4	10	12
These results suggest that decreased affinity of ACE to the substrate ANG-I ( so called ACE dysfunction syndrome ) produced the reninism and high concentration of plasma ANG-I , and that the latter induced an increase in the glomerular filtration rate of the kidneys with sequential occurrence of secondary hypokalemic periodic paralysis .	These results suggest that decreased affinity of ACE to the substrate ANG-I (so called ACE dysfunction syndrome) produced the reninism and high concentration of plasma ANG-I, and that the latter induced an increase in the glomerular filtration rate of the kidneys with sequential occurrence of secondary hypokalemic periodic paralysis.	5	28	produced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	ANG-I	ANG-I	ANG-I	7	8	27	28
Chronic ACE inhibition therapy restored previously reduced IGF1 plasma levels in patients with CHF , most likely by reducing angiotensin II activity .	Chronic ACE inhibition therapy restored previously reduced IGF1 plasma levels in patients with CHF, most likely by reducing angiotensin II activity.	1	21	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	1	2	19	21
The aim of the present study was to assess coronary blood flow regulation during tachycardia in the presence of elevated coronary plasma levels of angiotensin II , and the changes induced by ACE inhibition and blockade of angiotensin II and endothelin-A receptors .	The aim of the present study was to assess coronary blood flow regulation during tachycardia in the presence of elevated coronary plasma levels of angiotensin II, and the changes induced by ACE inhibition and blockade of angiotensin II and endothelin-A receptors.	32	41	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	32	33	37	39
Inhibition of kininase II with captopril significantly potentiates the vasodilator effect of bradykinin ( BK ) and Ang II in the rat MVB .	Inhibition of kininase II with captopril significantly potentiates the vasodilator effect of bradykinin (BK) and Ang II in the rat MVB.	0	19	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	kininase II	kininase II	kininase II	Ang II	Ang II	Ang II	2	4	17	19
The ACE homologue ACE2 metabolises AngII to Ang1-7 , decreasing AngII and increasing Ang1-7 , which counteracts AngII activity via the Mas receptor .	The ACE homologue ACE2 metabolises AngII to Ang1-7, decreasing AngII and increasing Ang1-7, which counteracts AngII activity via the Mas receptor.	1	11	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	AngII	AngII	AngII	1	2	10	11
These data suggest that angiotensin I conversion is limited by low physiological ACE activities , in vivo .	These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo.	4	13	limited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	12	13	4	6
In contrast , ACE inhibition by captopril did not inhibit ANG-I degradation .	In contrast, ACE inhibition by captopril did not inhibit ANG-I degradation.	3	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	ANG-I	ANG-I	ANG-I	3	4	10	11
Ang II inhibition by angiotensin converting enzyme ( ACE ) inhibitor in the developing rat kidney decreases the cellular proliferation and increases apoptosis , and this may account for neonatal renal growth impairment .	Ang II inhibition by angiotensin converting enzyme (ACE) inhibitor in the developing rat kidney decreases the cellular proliferation and increases apoptosis, and this may account for neonatal renal growth impairment.	0	7	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Ang II	Ang II	Ang II	4	7	0	2
His angiotensin converting enzyme ( ACE ) activities were normal , and administration of captopril inhibited the production of Ang II and aldosterone .	His angiotensin converting enzyme (ACE) activities were normal, and administration of captopril inhibited the production of Ang II and aldosterone.	0	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Ang II	Ang II	Ang II	1	4	19	21
Although there are theories postulating why blocking the harmful effects of Ang II at this receptor would be more effective than inhibiting ACE mediated conversion from inactive Ang I to Ang II , extrapolation to the clinical setting remains highly speculative .	Although there are theories postulating why blocking the harmful effects of Ang II at this receptor would be more effective than inhibiting ACE mediated conversion from inactive Ang I to Ang II, extrapolation to the clinical setting remains highly speculative.	21	32	mediated	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	22	23	30	32
The efficacy of angiotensin converting enzyme ( ACE ) inhibitors is well known to prevent the formation of angiotensin II ( Ang II ) by these agents .	The efficacy of angiotensin converting enzyme (ACE) inhibitors is well known to prevent the formation of angiotensin II (Ang II) by these agents.	1	22	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	3	6	18	20
XREF_BIBR In the kidneys , where angiotensinogen is available and renin activity is much higher , XREF_BIBR ACE inhibition increased Ang I in controls .	XREF_BIBR In the kidneys, where angiotensinogen is available and renin activity is much higher, XREF_BIBR ACE inhibition increased Ang I in controls.	17	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	17	18	20	22
Although angiotensin converting enzyme inhibition has been shown to prevent progression of the disease in postmenopausal women , the interaction of angiotensin II and estrogen in this process before and after the menopause is poorly understood .	Although angiotensin converting enzyme inhibition has been shown to prevent progression of the disease in postmenopausal women, the interaction of angiotensin II and estrogen in this process before and after the menopause is poorly understood.	1	23	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	1	4	21	23
ACE inhibition significantly increased Ang I in controls ( intrarenal Ang I in the ACEi group was 124 +/-14 fmol/g of KW ) but not in mice cotreated with Ang II ( Ang II+ ACE i : 76 +/-12.3 fmol/g of KW ) .	ACE inhibition significantly increased Ang I in controls (intrarenal Ang I in the ACEi group was 124 +/-14 fmol/g of KW) but not in mice cotreated with Ang II (Ang II+ACE i : 76 +/-12.3 fmol/g of KW).	0	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	0	1	4	6
The discovery that ACE inhibitors do not block the formation of all Ang II , such as that from Ang I via chymase and other non ACE enzymes , and/or that from angiotensinogen via non renin pathways , and Ang II levels persist during long-term ACE inhibitor therapy , fueled the concept that the combination of ACE inhibition and AT 1 receptor blockade may produce more complete blockade of the deleterious effects of Ang II and produce greater benefits .	The discovery that ACE inhibitors do not block the formation of all Ang II, such as that from Ang I via chymase and other non ACE enzymes, and/or that from angiotensinogen via non renin pathways, and Ang II levels persist during long-term ACE inhibitor therapy, fueled the concept that the combination of ACE inhibition and AT 1 receptor blockade may produce more complete blockade of the deleterious effects of Ang II and produce greater benefits.	56	75	produce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	56	57	73	75
Angiotensin Converting Enzyme 2 ( ACE2 ) , an ACE homologue XREF_BIBR , XREF_BIBR , degrades AngII into Ang-( 1-7 ) .	Angiotensin Converting Enzyme 2 (ACE2), an ACE homologue XREF_BIBR, XREF_BIBR, degrades AngII into Ang-(1-7).	9	17	degrades	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	AngII	AngII	AngII	9	10	16	17
Importantly , the absence of hypertension in ACE 10/10 mice implies that the lack of kidney ACE prevents angiotensin II infusion from shifting the pressure-natriuresis relationship , a major mechanism in establishing hypertension according to Guyton ' s kidney-fluids hypothesis [ XREF_BIBR ] .	Importantly, the absence of hypertension in ACE 10/10 mice implies that the lack of kidney ACE prevents angiotensin II infusion from shifting the pressure-natriuresis relationship, a major mechanism in establishing hypertension according to Guyton 's kidney-fluids hypothesis [XREF_BIBR].	13	20	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	16	17	18	20
The downstream target angiotensin converting enzyme ( ACE ) then modulates the concentration of angiotensin II , the key player of the RAAS system , and bradykinin , a component of the kallikrein-kinin system in opposite direction , therefore establishing a direct interaction between kallikrein-kinin and renin-angiotensin system [ XREF_BIBR , XREF_BIBR ] .	The downstream target angiotensin converting enzyme (ACE) then modulates the concentration of angiotensin II, the key player of the RAAS system, and bradykinin, a component of the kallikrein-kinin system in opposite direction, therefore establishing a direct interaction between kallikrein-kinin and renin-angiotensin system [XREF_BIBR, XREF_BIBR].	0	16	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	3	6	14	16
It is well established that angiotensin converting enzyme ( ACE ) inhibitors and angiotensin II receptor blockers ( ARBs ) reduce the effects of angiotensin II Fig .	It is well established that angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) reduce the effects of angiotensin II Fig.	5	26	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	5	8	24	26
The absence of renal ACE prevents local Ang II accumulation .	The absence of renal ACE prevents local Ang II accumulation.	1	9	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	4	5	7	9
In this study we demonstrate that blockade of ACE or chymase mediated endogenous production of Ang II , by captopril and chymostatin respectively , alleviates I/R injury .	In this study we demonstrate that blockade of ACE or chymase mediated endogenous production of Ang II, by captopril and chymostatin respectively, alleviates I/R injury.	6	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	8	9	15	17
Apple flavonoids inhibited angiotensin converting enzyme , which is a key enzyme that produce angiotensinogen II , a known vasoconstriction factor associated with hypertension .	Apple flavonoids inhibited angiotensin converting enzyme, which is a key enzyme that produce angiotensinogen II, a known vasoconstriction factor associated with hypertension.	2	20	produce	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensinogen	angiotensinogen	angiotensinogen	3	6	14	15
ACE inhibitors can block Ang-II synthesis catalyzed by ACE in cardiac fibroblasts but not that catalyzed by chymase in cardiac myocytes XREF_BIBR XREF_BIBR .	ACE inhibitors can block Ang-II synthesis catalyzed by ACE in cardiac fibroblasts but not that catalyzed by chymase in cardiac myocytes XREF_BIBR XREF_BIBR.	4	11	catalyzed	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ACE	ACE	ACE	Ang-II	Ang-II	Ang-II	8	9	4	5
ACE negatively regulates muscle growth by proteolytically converting inactive angiotensin I to the active form , angiotensin II.	ACE negatively regulates muscle growth by proteolytically converting inactive angiotensin I to the active form, angiotensin II.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	0	1	9	11
XREF_BIBR , XREF_BIBR Moreover , inhibition of ACE causes an increase in angiotensin I , which is then available for conversion to angiotensin II by ACE independent pathways not blocked by ACEIs , namely cathepsins and tonins .	XREF_BIBR, XREF_BIBR Moreover, inhibition of ACE causes an increase in angiotensin I, which is then available for conversion to angiotensin II by ACE independent pathways not blocked by ACEIs, namely cathepsins and tonins.	5	18	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	7	8	12	14
It is known that angiotensin converting enzyme ( ACE ) inhibitors not only prevent the formation of angiotensin II , but also potentiate the activity of bradykinin .	It is known that angiotensin converting enzyme (ACE) inhibitors not only prevent the formation of angiotensin II, but also potentiate the activity of bradykinin.	4	19	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	4	7	17	19
ACE can degrade angiotensin-I ( AT-I ) to generate AT-II , which results in hypertension .	ACE can degrade angiotensin-I (AT-I) to generate AT-II, which results in hypertension.	0	8	degrade	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin-I	angiotensin-I	angiotensin-I	0	1	3	4
In order to reduce the side effects during ACE inhibitor therapy , it is desirable to block the conversion of angiotensin I to angiotensin II by ACE ( known to be performed invivo mainly by C-ACE ) without interfering with the degradation of bradykinin 2 .	In order to reduce the side effects during ACE inhibitor therapy, it is desirable to block the conversion of angiotensin I to angiotensin II by ACE (known to be performed invivo mainly by C-ACE) without interfering with the degradation of bradykinin 2.	16	27	block	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	26	27	23	25
These studies provided evidence that the vascular compartment is the main site of Ang I formation and conversion to Ang II in the normal heart , and that vascular ACE may limit Ang I entry to the extravascular compartment .	These studies provided evidence that the vascular compartment is the main site of Ang I formation and conversion to Ang II in the normal heart, and that vascular ACE may limit Ang I entry to the extravascular compartment.	28	34	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	29	30	32	34
Under the conditions of this study , ACE inhibition led to nonuniform changes in the response to exogenous Ang I , suggesting intrarenal conversion of Ang I to Ang II.	Under the conditions of this study, ACE inhibition led to nonuniform changes in the response to exogenous Ang I, suggesting intrarenal conversion of Ang I to Ang II.	7	20	led	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	7	8	18	20
Consistently , angiotensin converting enzyme expression was reduced , implying a decrease in angiotensin II synthesis .	Consistently, angiotensin converting enzyme expression was reduced, implying a decrease in angiotensin II synthesis.	2	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme expression	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin ii	2	5	13	15
It acts as a competitive inhibitor for ACE preventing conversion of angiotensin I to angiotensin II which acts as a vasoconstrictor material and stimulates the secretion of aldosterone .	It acts as a competitive inhibitor for ACE preventing conversion of angiotensin I to angiotensin II which acts as a vasoconstrictor material and stimulates the secretion of aldosterone.	5	13	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	7	8	11	13
The results indicate that ( a ) the SFO mediates drinking caused by peripheral ACE inhibition ; ( b ) the ACE located within the SFO may locally convert ANG I to ANG II , which then stimulates thirst ; and ( c ) central ANG II receptors mediate thirst caused by peripheral ACE inhibition .	The results indicate that (a) the SFO mediates drinking caused by peripheral ACE inhibition; (b) the ACE located within the SFO may locally convert ANG I to ANG II, which then stimulates thirst; and (c) central ANG II receptors mediate thirst caused by peripheral ACE inhibition.	9	47	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	ANG II	ANG II	ANG II	14	15	45	47
The aims were to determine : ( 1 ) if angiotensin converting enzyme ( ACE ) inhibition and angiotensin II receptor blockade can prevent angiotensin II induced coronary vascular damage ; ( 2 ) if the cardioprotective properties of ACE inhibition are dose dependent ; and ( 3 ) if the cardioprotective properties of ACE inhibition are independent of its ability to prevent the conversion of angiotensin I to angiotensin II.	The aims were to determine : (1) if angiotensin converting enzyme (ACE) inhibition and angiotensin II receptor blockade can prevent angiotensin II induced coronary vascular damage; (2) if the cardioprotective properties of ACE inhibition are dose dependent; and (3) if the cardioprotective properties of ACE inhibition are independent of its ability to prevent the conversion of angiotensin I to angiotensin II.	12	26	prevent	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	14	15	24	26
Inhibitors of the ACE block the formation of Ang II but also cause a respective increase in the concentrations of Ang I that can subsequently be converted to Ang II by other pathways , such as the chymase system .	Inhibitors of the ACE block the formation of Ang II but also cause a respective increase in the concentrations of Ang I that can subsequently be converted to Ang II by other pathways, such as the chymase system.	0	38	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang I	Ang I	Ang I	3	4	20	22
While synthetic ACE inhibitors , such as Captopril function by directly blocking the action of ACE , ACE inhibitory peptides function by reacting with ACE , thus ACE is unavailable to cleave Ang I and prevent the production of the vasoconstrictor Ang II [ XREF_BIBR ] .	While synthetic ACE inhibitors, such as Captopril function by directly blocking the action of ACE, ACE inhibitory peptides function by reacting with ACE, thus ACE is unavailable to cleave Ang I and prevent the production of the vasoconstrictor Ang II [XREF_BIBR].	26	43	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	27	28	41	43
TERT decreased the cardiac expression of ACE but increased the expression of ACE 2 and Ang II in CIH .	TERT decreased the cardiac expression of ACE but increased the expression of ACE 2 and Ang II in CIH.	0	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ACE	TERT decreased the cardiac expression of ACE	ace	Ang II	Ang II	ang ii	6	7	15	17
Angiotensin converting enzyme ( ACE ) inhibitors and angiotensin receptor blocking drugs ( ARB ) block the effect of angiotensin II by different mechanisms .	Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blocking drugs (ARB) block the effect of angiotensin II by different mechanisms.	2	21	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	4	5	19	21
Angiotensin Converting Enzyme ( ACE ) inhibitors prevent the production of angiotensin II , which has been shown to reduce mortality in patients with congestive heart failure .	Angiotensin Converting Enzyme (ACE) inhibitors prevent the production of angiotensin II, which has been shown to reduce mortality in patients with congestive heart failure.	0	19	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angiotensin Converting Enzyme	Angiotensin Converting Enzyme	Angiotensin Converting Enzyme	angiotensin II	angiotensin II	angiotensin II	0	3	11	13
These data suggest the vascular compartment is the main site of angiotensin I and bradykinin-( 1-9 ) formation and metabolism , and vascular ACE may limit angiotensin I entry to the extravascular compartment of WT mice .	These data suggest the vascular compartment is the main site of angiotensin I and bradykinin-(1-9) formation and metabolism, and vascular ACE may limit angiotensin I entry to the extravascular compartment of WT mice.	22	28	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	23	24	26	28
Acute angiotensin converting enzyme inhibition reduced angiotensin I induced vasoconstriction by 78 % in the hearts of normotensive rats and by 82 % in the hypertensive rats ( p < 0.05 ) , whereas in vivo angiotensin converting enzyme inhibition potentiated angiotensin I induced vasoconstriction in the hearts of normotensive and hipertensive rats ( p < 0.05 ) .	Acute angiotensin converting enzyme inhibition reduced angiotensin I induced vasoconstriction by 78% in the hearts of normotensive rats and by 82% in the hypertensive rats (p < 0.05), whereas in vivo angiotensin converting enzyme inhibition potentiated angiotensin I induced vasoconstriction in the hearts of normotensive and hipertensive rats (p < 0.05).	0	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin I	angiotensin I	angiotensin I	1	4	6	8
Angiotensin converting enzyme ( ACE ) inhibitors not only reduce angiotensin II , but also increase bradykinin levels , since the angiotensin converting enzyme is identical to kininase II , an enzyme that degrades bradykinin .	Angiotensin converting enzyme (ACE) inhibitors not only reduce angiotensin II, but also increase bradykinin levels, since the angiotensin converting enzyme is identical to kininase II, an enzyme that degrades bradykinin.	0	15	reduce	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Angiotensin converting enzyme	Angiotensin converting enzyme	Angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	0	3	10	12
Mutations in the RAS genes ACE , AGT , AGTR1 and REN have all been reported to impair the production or function of angiotensin II , leading to RTD [ XREF_BIBR ] .	Mutations in the RAS genes ACE, AGT, AGTR1 and REN have all been reported to impair the production or function of angiotensin II, leading to RTD [XREF_BIBR].	0	25	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	5	6	23	25
The long standing classical model of sodium balance regulation in the distal nephron postulates that decreases in effective circulation volume or reduced dietary sodium intake lead to production of the potent antinatriuretic hormone Ang II from its inactive precursor Angiotensinogen ( AGT ) via subsequent cleavages by renin and angiotensin converting enzyme ( ACE ) [ XREF_BIBR ] .	The long standing classical model of sodium balance regulation in the distal nephron postulates that decreases in effective circulation volume or reduced dietary sodium intake lead to production of the potent antinatriuretic hormone Ang II from its inactive precursor Angiotensinogen (AGT) via subsequent cleavages by renin and angiotensin converting enzyme (ACE) [XREF_BIBR].	21	52	reduced	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Angiotensinogen	Angiotensinogen	Angiotensinogen	49	52	39	40
These peptides are capable of inhibiting angiotensin converting enzyme ( ACE ) , preventing the formation of Angiotensin II ( Ang II ) , a stimulator of OC resorption , from Angiotensin I ( Ang I ) .	These peptides are capable of inhibiting angiotensin converting enzyme (ACE), preventing the formation of Angiotensin II (Ang II), a stimulator of OC resorption, from Angiotensin I (Ang I).	8	33	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Angiotensin I	Angiotensin I	Angiotensin I	10	11	31	33
Angiotensin converting enzyme ( ACE ) 2 , a new component of RAS , can degrade Ang II to attenuate its subsequent physiological actions .	Angiotensin converting enzyme (ACE) 2, a new component of RAS, can degrade Ang II to attenuate its subsequent physiological actions.	2	18	degrade	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	4	5	16	18
The selective augmentation of angiotensin II effects by ACE inhibition and cyclosporin A suggests upregulation of angiotensin receptors in the aortic smooth muscle by these treatments .	The selective augmentation of angiotensin II effects by ACE inhibition and cyclosporin A suggests upregulation of angiotensin receptors in the aortic smooth muscle by these treatments.	2	9	augmentation	Positive_activation_syntax_1_noun	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	8	9	4	6
In addition , both heart ACE- and IF ACE mediated Ang II formation were strongly inhibited .	In addition, both heart ACE- and IF ACE mediated Ang II formation were strongly inhibited.	8	12	mediated	Positive_early_activation	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	8	9	10	12
The peptidic fractions that inhibited angiotensin I converting enzyme ( ACE ) were separated from the peptic digests of 2 microalgae , Chlorella vulgaris and Spirulina platensis , by ion exchange chromatography and gel filtration .	The peptidic fractions that inhibited angiotensin I converting enzyme (ACE) were separated from the peptic digests of 2 microalgae, Chlorella vulgaris and Spirulina platensis, by ion exchange chromatography and gel filtration.	2	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin I	angiotensin I	angiotensin I	10	11	5	7
Because Ang II induced eNOS glutathionylation impaired endothelium dependent vasorelaxation in aortic rings ex vivo , we examined whether attenuation of Ang II signaling by ACE inhibition could reduce baseline redox signaling within critical microdomains by reversing eNOS glutathionylation , thereby improving endothelial function in an in vivo setting .	Because Ang II induced eNOS glutathionylation impaired endothelium dependent vasorelaxation in aortic rings ex vivo, we examined whether attenuation of Ang II signaling by ACE inhibition could reduce baseline redox signaling within critical microdomains by reversing eNOS glutathionylation, thereby improving endothelial function in an in vivo setting.	21	26	signaling	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	25	26	21	23
Our study on intracellular effects of angiotensin II in human platelets showed that : ( 1 ) angiotensin II increases intracellular free calcium in platelets via a receptor operated mechanism and this increase is dose dependent ; ( 2 ) the effect on platelet intracellular free calcium depends on the extracellular calcium concentration ; ( 3 ) ACE inhibition leads to an increased sensitivity of intracellular free calcium to angiotensin II but does not alter epinephrine induced calcium increase ; ( 4 ) nifedipine reduces the susceptibility of platelet intracellular free calcium for angiotensin II.	Our study on intracellular effects of angiotensin II in human platelets showed that : (1) angiotensin II increases intracellular free calcium in platelets via a receptor operated mechanism and this increase is dose dependent; (2) the effect on platelet intracellular free calcium depends on the extracellular calcium concentration; (3) ACE inhibition leads to an increased sensitivity of intracellular free calcium to angiotensin II but does not alter epinephrine induced calcium increase; (4) nifedipine reduces the susceptibility of platelet intracellular free calcium for angiotensin II.	57	71	leads	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	57	58	69	71
In contrast , in the non modulators , short-term ACE inhibition significantly enhanced the angiotensin II dose response curve ( P less than 0.01 ) .	In contrast, in the non modulators, short-term ACE inhibition significantly enhanced the angiotensin II dose response curve (P less than 0.01).	9	18	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	9	10	14	16
In the present study , we determined whether hyperglycemia activates the cardiac intracellular renin-Ang system ( RAS ) in vivo and whether ARBs , ACE , or renin inhibitors block synthesis and effects of intracellular Ang II ( iAng II ) .	In the present study, we determined whether hyperglycemia activates the cardiac intracellular renin-Ang system (RAS) in vivo and whether ARBs, ACE, or renin inhibitors block synthesis and effects of intracellular Ang II (iAng II).	22	37	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	24	25	35	37
Angiotensin converting enzyme ( ACE ) inhibitors and angiotensin type I ( AT ( 1 ) ) receptor blocking drugs block the effects of angiotensin II by different mechanisms .	Angiotensin converting enzyme (ACE) inhibitors and angiotensin type I (AT (1)) receptor blocking drugs block the effects of angiotensin II by different mechanisms.	0	26	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angiotensin converting enzyme	Angiotensin converting enzyme	Angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	0	3	24	26
Although ACE inhibition increased the response to angiotensin II , the difference in the response to angiotensin II , between CC and AA+ AC patients remained intact in ACE inhibitor treated patients .	Although ACE inhibition increased the response to angiotensin II, the difference in the response to angiotensin II, between CC and AA+AC patients remained intact in ACE inhibitor treated patients.	1	9	increased	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	angiotensin II	angiotensin II	angiotensin II	1	2	7	9
Consistently , sympatho facilitation by Ang I , which could be abolished by the angiotensin converting enzyme ( ACE ) inhibitor imidaprilat , was apparently greater than that of Ang II in SHR , despite no difference in WKY .	Consistently, sympatho facilitation by Ang I, which could be abolished by the angiotensin converting enzyme (ACE) inhibitor imidaprilat, was apparently greater than that of Ang II in SHR, despite no difference in WKY.	4	25	abolished	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Ang I	Ang I	Ang I	14	17	5	7
Angiotensin converting enzyme ( ACE2 ) inhibits RAS activity by converting angiotensin II , the effector peptide of RAS , to angiotensin-( 1-7 ) , which activates Mas receptors ( MasR ) .	Angiotensin converting enzyme (ACE2) inhibits RAS activity by converting angiotensin II, the effector peptide of RAS, to angiotensin-(1-7), which activates Mas receptors (MasR).	0	26	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angiotensin converting enzyme	Angiotensin converting enzyme	Angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	0	3	11	13
The unique ability of angiotensin converting enzyme ( ACE ) inhibitors to inhibit the generation of angiotensin II has made them very useful agents for treating patients with renovascular hypertension .	The unique ability of angiotensin converting enzyme (ACE) inhibitors to inhibit the generation of angiotensin II has made them very useful agents for treating patients with renovascular hypertension.	2	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	4	7	16	18
Vascular reactivity is also modulated by inhibitors of angiotensin converting enzyme ( lisinopril ) and inhibitors of angiotensin II ( telmisartan , candesartan ) .	Vascular reactivity is also modulated by inhibitors of angiotensin converting enzyme (lisinopril) and inhibitors of angiotensin II (telmisartan, candesartan).	4	20	modulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin II	angiotensin II	angiotensin II	8	11	17	19
Therefore , our study concentrated on the presumed modulation by ACE inhibition of local AngII mediated inflammatory actions by a mechanism independent of blockage of AngII formation .	Therefore, our study concentrated on the presumed modulation by ACE inhibition of local AngII mediated inflammatory actions by a mechanism independent of blockage of AngII formation.	10	15	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ACE	ACE	ACE	AngII	AngII	AngII	10	11	14	15
Both ACE inhibition and application of an AngII antagonist affect the b-wave of the electroretinogram .	Both ACE inhibition and application of an AngII antagonist affect the b-wave of the electroretinogram.	1	8	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ACE	ACE	ACE	AngII	AngII	AngII	1	2	7	8
Chronic ACE inhibition restores the vasodilator response of MBF to Ang II in LH rats .	Chronic ACE inhibition restores the vasodilator response of MBF to Ang II in LH rats.	1	12	restores	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	ACE	ACE	ACE	Ang II	Ang II	Ang II	1	2	10	12
Ang-( 1-7 ) is produced via degradation of Ang II by the human angiotensin converting enzyme , also known as ACE2 .	Ang-(1-7) is produced via degradation of Ang II by the human angiotensin converting enzyme, also known as ACE2.	4	16	degradation	Negative_activation_syntax_6_noun	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	Ang II	Ang II	Ang II	13	16	8	10
Inhibition of ACE and AngII-receptor signalling and AT1R-blockage in AngII treated THP-1 monocytes led to decreased adhesion to endothelial monolayers .	Inhibition of ACE and AngII-receptor signalling and AT1R-blockage in AngII treated THP-1 monocytes led to decreased adhesion to endothelial monolayers.	2	10	signalling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ACE	ACE	ACE	AngII	AngII	AngII	2	3	9	10
Systemic inhibition of angiotensin converting enzyme with enalapril ( 25 mg/kg , per os for 14 days ) produces a large decrease in ANG II receptors localized exclusively in the subfornical organ ( SFO ) of the SHR , and no alterations in ANG II receptors in the normotensive WKY rats .	Systemic inhibition of angiotensin converting enzyme with enalapril (25 mg/kg, per os for 14 days) produces a large decrease in ANG II receptors localized exclusively in the subfornical organ (SFO) of the SHR, and no alterations in ANG II receptors in the normotensive WKY rats.	1	45	produces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	angiotensin converting enzyme	angiotensin converting enzyme	angiotensin converting enzyme	ANG II	ANG II	ANG II	3	6	43	45
ADAM17 RNAi decreased EMMPRIN , p-EGFR , p-ERK , MMP-2 , and MMP-9 proteins in SiHa and HeLa cells .	ADAM17 RNAi decreased EMMPRIN, p-EGFR, p-ERK, MMP-2, and MMP-9 proteins in SiHa and HeLa cells.	0	6	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ADAM17	ADAM17	ADAM17	p-EGFR	p-EGFR	p-EGFR	0	1	5	6
3.6 ADAM17 Knockdown Reduces EGFR Signaling in Colonic Epithelial Cells .	3.6 ADAM17 Knockdown Reduces EGFR Signaling in Colonic Epithelial Cells.	0	5	Reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ADAM17	ADAM17	ADAM17	EGFR	EGFR	EGFR	1	2	4	5
In KRAS induced pancreatic tumorigenesis and pancreatitis induced acinar-to-ductal metaplasia mouse models , Adam17 ablation blocks ligand dependent EGFR activation , preventing acinar-to-ductal metaplasia and KRAS driven tumorigenesis ( XREF_TABLE ) .	In KRAS induced pancreatic tumorigenesis and pancreatitis induced acinar-to-ductal metaplasia mouse models, Adam17 ablation blocks ligand dependent EGFR activation, preventing acinar-to-ductal metaplasia and KRAS driven tumorigenesis (XREF_TABLE).	13	19	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Adam17	Adam17	Adam17	EGFR	EGFR	EGFR	13	14	18	19
Analysis of EGFR signalling in Adam17 -/- keratinocytes by Western blot ( WB ) revealed about 80 % reduced EGFR activation ( XREF_FIG ) .	Analysis of EGFR signalling in Adam17 -/- keratinocytes by Western blot (WB) revealed about 80% reduced EGFR activation (XREF_FIG).	3	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Adam17	Adam17	Adam17	EGFR	EGFR	EGFR	5	6	19	20
In the IB3 cells , an EGFR neutralizing antibody ( XREF_FIG ) , TAPI-1 ( XREF_FIG ) , or TACE siRNA knockdown ( XREF_FIG ) inhibited EGFR-P markedly , whereas , in the C38 cells , these treatments inhibited EGFR-P only slightly ( XREF_FIG ) .	In the IB3 cells, an EGFR neutralizing antibody (XREF_FIG), TAPI-1 (XREF_FIG), or TACE siRNA knockdown (XREF_FIG) inhibited EGFR-P markedly, whereas, in the C38 cells, these treatments inhibited EGFR-P only slightly (XREF_FIG).	19	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TACE	TACE	TACE	EGFR-P	EGFR-P	EGFR-P	19	20	26	27
TACE and ADAM17 protein and protease activity were up-regulated markedly at 10 h and maintained to 40 h. Treatment of COCs with the TACE and ADAM17 selective inhibitor TNFalpha processing inhibitor-2 ( TAPI-2 ) significantly suppressed in a time dependent manner downstream targets of EGF receptor activation such as ERK1/2 phosphorylation , Ptgs2 , Has2 , and Tnfaip6 mRNA expression , hormone induced COC expansion , and meiotic maturation of the oocytes .	TACE and ADAM17 protein and protease activity were up-regulated markedly at 10 h and maintained to 40 h. Treatment of COCs with the TACE and ADAM17 selective inhibitor TNFalpha processing inhibitor-2 (TAPI-2) significantly suppressed in a time dependent manner downstream targets of EGF receptor activation such as ERK1/2 phosphorylation, Ptgs2, Has2, and Tnfaip6 mRNA expression, hormone induced COC expansion, and meiotic maturation of the oocytes.	0	46	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGF receptor	EGF receptor	EGF receptor	0	1	44	46
TACE genetic depletion in OPs abrogates EGFR activation in OL lineage cells , and perturbs cell expansion and survival , blunting the process of CNS remyelination .	TACE genetic depletion in OPs abrogates EGFR activation in OL lineage cells, and perturbs cell expansion and survival, blunting the process of CNS remyelination.	0	7	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TACE	TACE	TACE	EGFR	EGFR	EGFR	0	1	6	7
Therefore , TIMP-3-mediated ADAM17 inhibition is expected to relieve the block on Nrg1 activity and enhances erbB receptor signaling in Schwann cells .	Therefore, TIMP-3-mediated ADAM17 inhibition is expected to relieve the block on Nrg1 activity and enhances erbB receptor signaling in Schwann cells.	3	18	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ADAM17	ADAM17	ADAM17	erbB	erbB	erbB	3	4	16	17
Ang II induced contractile response was blocked by valsartan ( 100 microM , selective AT1 receptor antagonist ) but not PD 123,319 ( 100 microM , selective and potent AT2 receptor antagonist ) .	Ang II induced contractile response was blocked by valsartan (100 microM, selective AT1 receptor antagonist) but not PD 123,319 (100 microM, selective and potent AT2 receptor antagonist).	0	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	0	2	29	30
Contractile responses to ANG III , ANG IV , ANG II and ANG I were significantly inhibited by type 1 ANG II ( AT 1 ) receptor antagonist Dup 753 but not by type 2 ANG II ( AT2 ) receptor antagonist PD 123,319 .	Contractile responses to ANG III, ANG IV, ANG II and ANG I were significantly inhibited by type 1 ANG II (AT 1) receptor antagonist Dup 753 but not by type 2 ANG II (AT2) receptor antagonist PD 123,319.	1	39	inhibited	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	ANG II	ANG II	ANG II	AT2	AT2	AT2	35	37	38	39
Angiotensin converting enzyme inhibitors abolish the formation of Ang II , preventing thereby activation of both AT1 and AT2 receptors , while AT1RB selectively interferes with the stimulation of AT1 receptors .	Angiotensin converting enzyme inhibitors abolish the formation of Ang II, preventing thereby activation of both AT1 and AT2 receptors, while AT1RB selectively interferes with the stimulation of AT1 receptors.	8	19	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	8	10	18	19
Ang II , ang IV , and ang 5-8 decrease the cell number and proliferation in GH3 cell culture independently of the AT1 , AT2 , and AT4 receptors .	Ang II, ang IV, and ang 5-8 decrease the cell number and proliferation in GH3 cell culture independently of the AT1, AT2, and AT4 receptors.	0	25	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	0	2	24	25
Thus , 24-h infusions of Ang II selectively down-regulated AT2 receptors in the uterine artery , resulting in heightened Ang II reactivity .	Thus, 24-h infusions of Ang II selectively down-regulated AT2 receptors in the uterine artery, resulting in heightened Ang II reactivity.	5	10	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang II	Ang II	Ang II	AT2	AT2	AT2	5	7	9	10
These results indicate that AngII , through the AT1 receptor , down-regulates both AT1 and AT2 , but by different mechanisms ; AT1 receptor is regulated through internalization degradation of the occupied receptor and inhibition of transcription , whereas AT2 receptor is regulated mainly by decreasing the stability of its mRNA .	These results indicate that AngII, through the AT1 receptor, down-regulates both AT1 and AT2, but by different mechanisms; AT1 receptor is regulated through internalization degradation of the occupied receptor and inhibition of transcription, whereas AT2 receptor is regulated mainly by decreasing the stability of its mRNA.	4	16	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AngII	AngII	AngII	AT2	AT2	AT2	4	5	15	16
Angiotensin 1-7 and its receptor Mas ( Ang 1-7/Mas ) were described later and antagonize the effect of AT2 ; therefore , they could represent a target for therapeutical strategies .	Angiotensin 1-7 and its receptor Mas (Ang 1-7/Mas) were described later and antagonize the effect of AT2; therefore, they could represent a target for therapeutical strategies.	0	19	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angiotensin 1-7	Angiotensin 1-7	Angiotensin 1-7	AT2	AT2	AT2	0	2	18	19
XREF_BIBR Adiponectin reduces hepatic lipogenesis and increases beta oxidation through adiponectin receptor 1 ( adipoR1 )-mediated activation of adenosine monophosphate kinase ( AMPK ) and peroxisome proliferator activated receptor alpha ( PPAR alpha ) .	XREF_BIBR Adiponectin reduces hepatic lipogenesis and increases beta oxidation through adiponectin receptor 1 (adipoR1)-mediated activation of adenosine monophosphate kinase (AMPK) and peroxisome proliferator activated receptor alpha (PPAR alpha).	0	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Adiponectin	Adiponectin	Adiponectin	adipoR1	adipoR1	adipoR1	1	2	14	15
Third , adiponectin inhibition of PDGF induced VSMC proliferation does not require adiponectin receptors ( AdipoR1 and/or AdipoR2 ) , as evidenced in studies involving target specific downregulation of AdipoR1/R2 [ XREF_BIBR ] .	Third, adiponectin inhibition of PDGF induced VSMC proliferation does not require adiponectin receptors (AdipoR1 and/or AdipoR2), as evidenced in studies involving target specific downregulation of AdipoR1/R2 [XREF_BIBR].	2	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	adiponectin	adiponectin	adiponectin	AdipoR1	AdipoR1	AdipoR1	2	3	15	16
Based on our results , Acrp30 attenuated PPAR-gamma signaling in microglia by mediating AdipoR1 .	Based on our results, Acrp30 attenuated PPAR-gamma signaling in microglia by mediating AdipoR1.	5	14	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Acrp30	Acrp30	Acrp30	AdipoR1	AdipoR1	AdipoR1	5	6	13	14
Our data also confirmed that adiponectin reduced early apoptotic cells and blocked the mitochondrial apoptosis pathway by activating the AdipoR1 and AMP activated protein kinase ( AMPK ) signal pathway .	Our data also confirmed that adiponectin reduced early apoptotic cells and blocked the mitochondrial apoptosis pathway by activating the AdipoR1 and AMP activated protein kinase (AMPK) signal pathway.	5	24	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	adiponectin	adiponectin	adiponectin	AdipoR1	AdipoR1	AdipoR1	5	6	19	20
The inhibitory effect of adiponectin on androgen synthesis may be due to decreased thecal-interstitial cells differentiation in stroma by suppressing adiponectin receptor type 1 ( AdipoR1 ) , luteinizing hormone ( LH ) and insulin receptors in the ovary of S. heathi .	The inhibitory effect of adiponectin on androgen synthesis may be due to decreased thecal-interstitial cells differentiation in stroma by suppressing adiponectin receptor type 1 (AdipoR1), luteinizing hormone (LH) and insulin receptors in the ovary of S. heathi.	2	35	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	adiponectin	adiponectin	adiponectin	AdipoR1	AdipoR1	AdipoR1	4	5	25	26
To our knowledge , this study is the first to consider both adiponectin deficiency ( decrease of serum adiponectin levels and downregulation of AdipoR1 ) and BPH in an HFD mouse model .	To our knowledge, this study is the first to consider both adiponectin deficiency (decrease of serum adiponectin levels and downregulation of AdipoR1) and BPH in an HFD mouse model.	12	24	downregulation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	adiponectin	adiponectin deficiency (decrease of serum adiponectin levels	adiponectin	AdipoR1	AdipoR1	adipor1	12	13	23	24
Adiponectin rescued the decrease of adipoR1 induced by ox-LDL .	Adiponectin rescued the decrease of adipoR1 induced by ox-LDL.	0	6	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Adiponectin	Adiponectin	Adiponectin	adipoR1	adipoR1	adipoR1	0	1	5	6
Our results support a notion that Akt1 can not simply suppress HR by sequestering Brca1 to the cytoplasm because depletion of Akt1 can restore HR to Brca1 deficient cells .	Our results support a notion that Akt1 can not simply suppress HR by sequestering Brca1 to the cytoplasm because depletion of Akt1 can restore HR to Brca1 deficient cells.	6	15	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt1	Akt1	Akt1	Brca1	Brca1	Brca1	6	7	14	15
Previous work has shown that Akt1 inhibits HR by inducing cytoplasmic retention of Brca1 and Rad51 in Brca1-proficient cells .	Previous work has shown that Akt1 inhibits HR by inducing cytoplasmic retention of Brca1 and Rad51 in Brca1-proficient cells.	5	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt1	Akt1	Akt1	Brca1	Brca1	Brca1	5	6	13	14
Akt1 inhibits homologous recombination in Brca1 deficient cells by blocking the Chk1-Rad51 pathway .	Akt1 inhibits homologous recombination in Brca1 deficient cells by blocking the Chk1-Rad51 pathway.	0	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt1	Akt1	Akt1	Brca1	Brca1	Brca1	0	1	5	6
Akt1 has been reported to impair the nuclear localization and foci formation of BRCA1 and Rad51 as well as HR repair in normal tissue and breast cancer cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Akt1 has been reported to impair the nuclear localization and foci formation of BRCA1 and Rad51 as well as HR repair in normal tissue and breast cancer cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	15	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt1	Akt1	Akt1	BRCA1	BRCA1	BRCA1	0	1	13	14
Specifically , AKT1 inhibits HR by sequestering BRCA1 and RAD51 in the cytoplasm .	Specifically, AKT1 inhibits HR by sequestering BRCA1 and RAD51 in the cytoplasm.	2	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT1	AKT1	AKT1	BRCA1	BRCA1	BRCA1	2	3	7	8
Therefore , our data demonstrate that ZLDI-8 enhances chemotherapy effects on tumor cell proliferation blockage , induction of apoptosis and cell-cycle arrest by inhibiting Notch pathway and blocking chemical resistance .	Therefore, our data demonstrate that ZLDI-8 enhances chemotherapy effects on tumor cell proliferation blockage, induction of apoptosis and cell-cycle arrest by inhibiting Notch pathway and blocking chemical resistance.	6	25	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ZLDI-8	ZLDI-8	ZLDI-8	Notch	Notch	Notch	6	7	24	25
ZLDI-8 inhibits the activity of Notch signaling pathway .	ZLDI-8 inhibits the activity of Notch signaling pathway.	0	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ZLDI-8	ZLDI-8	ZLDI-8	Notch	Notch	Notch	0	1	5	6
Treatment of ZLDI-8 significantly disrupted the activity of Notch pathway in HCC cells and inhibited the epithelial-mesenchymal transition ( EMT ) process of HCC cells .	Treatment of ZLDI-8 significantly disrupted the activity of Notch pathway in HCC cells and inhibited the epithelial-mesenchymal transition (EMT) process of HCC cells.	0	9	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ZLDI-8	ZLDI-8	ZLDI-8	Notch	Notch	Notch	2	3	8	9
We further tested whether Notch signaling blockage by ZLDI-8 can also facilitate Sorafenib ' s effect .	We further tested whether Notch signaling blockage by ZLDI-8 can also facilitate Sorafenib 's effect.	4	9	blockage	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	ZLDI-8	ZLDI-8	ZLDI-8	Notch	Notch	Notch	8	9	4	5
By Murthy ' s research , it was demonstrated that ADAM-17 could suppress the activation of the Notch signal system [ XREF_BIBR ] .	By Murthy 's research, it was demonstrated that ADAM-17 could suppress the activation of the Notch signal system [XREF_BIBR].	10	19	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ADAM-17	ADAM-17	ADAM-17	Notch	Notch	Notch	10	11	17	18
These data reveal that PKG activation strategies , including PDE5 inhibition , ameliorate ANG II induced podocyte dysmotility by targeting TRPC6 in podocytes , highlighting the potential therapeutic utility of these approaches to treat hyperactive TRPC6 dependent glomerular disease .	These data reveal that PKG activation strategies, including PDE5 inhibition, ameliorate ANG II induced podocyte dysmotility by targeting TRPC6 in podocytes, highlighting the potential therapeutic utility of these approaches to treat hyperactive TRPC6 dependent glomerular disease.	13	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ANG II	ANG II	ANG II	TRPC6	TRPC6	TRPC6	13	15	20	21
XREF_FIG , the Ang II induced contractile response was significantly lower in TRPC6 deficient cells .	XREF_FIG, the Ang II induced contractile response was significantly lower in TRPC6 deficient cells.	3	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	3	5	12	13
In the continued presence of anti-PIP 2 antibodies , Ang II induced TRPC6 activity was greatly reduced , which presumably reflects a reduction in PIP 2 required to produce endogenous PLC mediated DAG production and TRPC6 opening .	In the continued presence of anti-PIP 2 antibodies, Ang II induced TRPC6 activity was greatly reduced, which presumably reflects a reduction in PIP 2 required to produce endogenous PLC mediated DAG production and TRPC6 opening.	9	13	induced	Positive_early_activation	Positive_activation	Negative_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	9	11	12	13
Wortmannin reduced Ang II evoked TRPC6 activity by over 75 % but increased OAG induced TRPC6 activity by over 50-fold .	Wortmannin reduced Ang II evoked TRPC6 activity by over 75% but increased OAG induced TRPC6 activity by over 50-fold.	2	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang II	Ang II	Ang II	TRPC6	TRPC6	TRPC6	2	4	15	16
Angiotensin II decreased ABCA1 protein and mRNA ; angiotensin II type-1 receptor ( AT1R ) blockade rescued this ABCA1 repression .	Angiotensin II decreased ABCA1 protein and mRNA; angiotensin II type-1 receptor (AT1R) blockade rescued this ABCA1 repression.	0	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angiotensin II	Angiotensin II	Angiotensin II	angiotensin II type-1 receptor	angiotensin II type-1 receptor	angiotensin II type-1 receptor	0	2	8	12
In the new S-D line intravenous infusion of angiotensin II ( Ang II ; 10 microg kg (-1) h (-1) ) over 120 min significantly lowered the duodenal AT1aR to AT2R RNA ratio .	In the new S-D line intravenous infusion of angiotensin II (Ang II; 10 microg kg (-1) h (-1)) over 120 min significantly lowered the duodenal AT1aR to AT2R RNA ratio.	6	29	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	angiotensin II	angiotensin II	angiotensin II	AT1aR	AT1aR	AT1aR	8	10	28	29
These studies , in conjunction with our results , suggest that central augmentation of the ACE2/Ang-( 1-7 )/MasR axis may complement therapuetic strategies that limit Ang-II induced activation of AT1aR to alleviate stress related diseases , like anxiety disorders .	These studies, in conjunction with our results, suggest that central augmentation of the ACE2/Ang-(1-7)/MasR axis may complement therapuetic strategies that limit Ang-II induced activation of AT1aR to alleviate stress related diseases, like anxiety disorders.	25	30	induced	Positive_early_activation	Positive_activation	Positive_activation	Ang-II	Ang-II	Ang-II	AT1aR	AT1aR	AT1aR	25	26	29	30
However , adiponectin partially suppressed the forskolin induced increase in Adipor2 in granulosa cells .	However, adiponectin partially suppressed the forskolin induced increase in Adipor2 in granulosa cells.	2	11	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	adiponectin	adiponectin	adiponectin	Adipor2	Adipor2	Adipor2	2	3	10	11
Elevated blood adiponectin induced by T-cad deficiency may act to inhibit allergic responses via AdipoR1 and/or AdipoR2 , which have been shown to mediate the insulin sensitizing and anti-apoptotic effects of adiponectin XREF_BIBR , XREF_BIBR .	Elevated blood adiponectin induced by T-cad deficiency may act to inhibit allergic responses via AdipoR1 and/or AdipoR2, which have been shown to mediate the insulin sensitizing and anti-apoptotic effects of adiponectin XREF_BIBR, XREF_BIBR.	0	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	adiponectin	adiponectin	adiponectin	AdipoR2	AdipoR2	AdipoR2	2	3	16	17
However , despite enriched expression in HSPCs , reduced expression of GPR56 in gene targeted Gpr56 deficient mice , revealed only subtle alterations in the hematopoietic compartment , with normal HSPC functions in both steady-state and regenerative hematopoiesis .	However, despite enriched expression in HSPCs, reduced expression of GPR56 in gene targeted Gpr56 deficient mice, revealed only subtle alterations in the hematopoietic compartment, with normal HSPC functions in both steady-state and regenerative hematopoiesis.	9	17	targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GPR56	expression of GPR56	gpr56	Gpr56	Gpr56	gpr56	11	12	15	16
Compromise of GPR56 expression failed to alter the c-Fos response to neuronostatin , thus eliminating GPR56 from our list of candidates .	Compromise of GPR56 expression failed to alter the c-Fos response to neuronostatin, thus eliminating GPR56 from our list of candidates.	2	16	eliminating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GPR56	GPR56 expression	gpr56	GPR56	GPR56	gpr56	2	3	15	16
Since ALK2 activates Smad1 and Smad6 blocks Smad1 signaling [ XREF_BIBR ] , these data are consistent with the known role of ALK2 XREF_BIBR , XREF_BIBR and Smad1 [ XREF_BIBR ] in endocardial cell EMT [ XREF_BIBR , XREF_BIBR ] .	Since ALK2 activates Smad1 and Smad6 blocks Smad1 signaling [XREF_BIBR], these data are consistent with the known role of ALK2 XREF_BIBR, XREF_BIBR and Smad1 [XREF_BIBR] in endocardial cell EMT [XREF_BIBR, XREF_BIBR].	1	6	activates	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ALK2	ALK2	ALK2	Smad1	Smad1	Smad1	1	2	3	4
Treatment of ZLDI-8 could inhibit the activation of ADAM-17 , and disrupts the accumulation of NICD in HCC cells , especially in the nucleus .	Treatment of ZLDI-8 could inhibit the activation of ADAM-17, and disrupts the accumulation of NICD in HCC cells, especially in the nucleus.	0	16	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ZLDI-8	ZLDI-8	ZLDI-8	NICD	NICD	NICD	2	3	15	16
MIS induces expression of Alk2 , Alk3 and Smad8 , but downregulates Smad5 in the urogenital ridge .	MIS induces expression of Alk2, Alk3 and Smad8, but downregulates Smad5 in the urogenital ridge.	0	13	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Alk2	MIS induces expression of Alk2	alk2	Smad5	Smad5	smad5	4	5	12	13
For example , expression of an endothelial cell specific constitutively active Akt1 transgene significantly attenuated neointima formation in carotid arteries after ligation XREF_BIBR , mediated through inhibition of neointimal cell apoptosis and Akt1 mediated eNOS activation in ECs .	For example, expression of an endothelial cell specific constitutively active Akt1 transgene significantly attenuated neointima formation in carotid arteries after ligation XREF_BIBR, mediated through inhibition of neointimal cell apoptosis and Akt1 mediated eNOS activation in ECs.	26	35	mediated	Positive_early_activation	Positive_activation	Negative_activation	Akt1	Akt1	Akt1	eNOS	eNOS	eNOS	32	33	34	35
H2S donor induced NOS3 activation was blocked by AKT1 but not MAPK3/1 inhibition .	H2S donor induced NOS3 activation was blocked by AKT1 but not MAPK3/1 inhibition.	3	12	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	AKT1	AKT1	AKT1	NOS3	NOS3	NOS3	8	9	3	4
Indeed , lack of Akt1 on the ApoE -/- background disrupts this protective eNOS regulated mechanism , leading to increased endothelial apoptosis , which , in turn , results in exacerbated atherosclerosis in ApoE -/- Akt1 -/- mice .	Indeed, lack of Akt1 on the ApoE -/- background disrupts this protective eNOS regulated mechanism, leading to increased endothelial apoptosis, which, in turn, results in exacerbated atherosclerosis in ApoE -/- Akt1 -/- mice.	2	14	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt1	Akt1	Akt1	eNOS	eNOS	eNOS	4	5	13	14
Cortisol infusion significantly increased muscle protein levels of Akt2 and phosphorylated Akt at Ser473 , and decreased protein levels of phosphorylated forms of mTOR at Ser2448 and S6K at Thr389 .	Cortisol infusion significantly increased muscle protein levels of Akt2 and phosphorylated Akt at Ser473, and decreased protein levels of phosphorylated forms of mTOR at Ser2448 and S6K at Thr389.	0	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt2	Cortisol infusion significantly increased muscle protein levels of Akt2	akt2	mTOR	mTOR	mtor	8	9	23	24
Reduced Akt1 activity significantly inhibited expression and activation of the mTOR pathway , while Akt2 ablation resulted in enhanced mTOR signaling .	Reduced Akt1 activity significantly inhibited expression and activation of the mTOR pathway, while Akt2 ablation resulted in enhanced mTOR signaling.	14	21	signaling	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Akt2	Akt2	Akt2	mTOR	mTOR	mTOR	14	15	19	20
AKT1/2i selectively inhibits Akt1 and Akt2 XREF_BIBR , XREF_BIBR , while mTOR1/2i is a selective inhibitor of mTOR kinase , thus blocks the signaling of both TORC1 and TORC2 complexes XREF_BIBR , XREF_BIBR .	AKT1/2i selectively inhibits Akt1 and Akt2 XREF_BIBR, XREF_BIBR, while mTOR1/2i is a selective inhibitor of mTOR kinase, thus blocks the signaling of both TORC1 and TORC2 complexes XREF_BIBR, XREF_BIBR.	3	18	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	Akt2	Akt2	Akt2	mTOR	mTOR	mTOR	5	6	17	18
In addition , co-expression of beta-TrCP facilitated AKT1 mediated Twist1 degradation ( XREF_FIG ) .	In addition, co-expression of beta-TrCP facilitated AKT1 mediated Twist1 degradation (XREF_FIG).	7	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	AKT1	AKT1	AKT1	Twist1	Twist1	Twist1	7	8	9	10
Inhibition of AKT1 induces Twist1 upregulation and metastatic potential .	Inhibition of AKT1 induces Twist1 upregulation and metastatic potential.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT1	AKT1	AKT1	Twist1	Twist1	Twist1	2	3	4	5
AKT1 modulates beta-TrCP-mediated Twist1 degradation .	AKT1 modulates beta-TrCP-mediated Twist1 degradation.	0	4	modulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT1	AKT1	AKT1	Twist1	Twist1	Twist1	0	1	3	4
In contrast , GLI1 function is inhibited by PI3K and AKT2 signalling in neuroblastoma ; AKT2 phosphorylates GSK3beta and prevents the destabilisation of SUFU , resulting in reduced GLI1 nuclear localisation and transcriptional activity .	In contrast, GLI1 function is inhibited by PI3K and AKT2 signalling in neuroblastoma; AKT2 phosphorylates GSK3beta and prevents the destabilisation of SUFU, resulting in reduced GLI1 nuclear localisation and transcriptional activity.	3	11	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	AKT2	AKT2	AKT2	GLI1	GLI1	GLI1	10	11	3	4
Specifically , the AKT2 isoform inhibited Gli1 luciferase activity .	Specifically, the AKT2 isoform inhibited Gli1 luciferase activity.	3	8	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT2	AKT2	AKT2	Gli1	Gli1	Gli1	3	4	6	7
Nuclear Akt1 phosphorylates 14.3.3 zeta at serine 58 to inhibit beta-catenin transactivation .	Nuclear Akt1 phosphorylates 14.3.3 zeta at serine 58 to inhibit beta-catenin transactivation.	0	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt1	Akt1	Akt1	beta-catenin	beta-catenin	beta-catenin	1	2	10	11
The results in this study can not exclude the possibility that increasing Akt1 protein levels by IFNgamma could inhibit beta-catenin signaling via other mechanisms .	The results in this study can not exclude the possibility that increasing Akt1 protein levels by IFNgamma could inhibit beta-catenin signaling via other mechanisms.	12	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt1	Akt1 protein levels	akt1	beta-catenin	beta-catenin	beta-catenin	12	13	19	20
Also , TSC-mutant cells are increasingly susceptible to ER stress , which is reversed by AKT1 reconstitution .	Also, TSC-mutant cells are increasingly susceptible to ER stress, which is reversed by AKT1 reconstitution.	8	16	reversed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	AKT1	AKT1	AKT1	ER	ER	ER	15	16	8	9
Paradoxically , co-expression of Akt1 could down-regulate transcriptional activity of ERalpha .	Paradoxically, co-expression of Akt1 could down-regulate transcriptional activity of ERalpha.	2	11	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt1	co-expression of Akt1	akt1	ERalpha	ERalpha	eralpha	4	5	10	11
In summary , our study suggested that Akt2 knockout may induce cardiac functional and geometric anomalies via inhibition of autophagy as well as activation of apoptosis and ER stress .	In summary, our study suggested that Akt2 knockout may induce cardiac functional and geometric anomalies via inhibition of autophagy as well as activation of apoptosis and ER stress.	7	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt2	Akt2	Akt2	ER	ER	ER	7	8	27	28
In this study , we observed that Akt2 knockout induced overt apoptosis and ER stress as evidenced by protein markers of apoptosis and ER stress , Caspase 3 activity and TUNEL staining , supporting a likely role for apoptosis and ER stress in cardiac contractile and geometric ( hypertrophic remodeling ) anomalies in Akt2 ablation induced insulin resistance .	In this study, we observed that Akt2 knockout induced overt apoptosis and ER stress as evidenced by protein markers of apoptosis and ER stress, Caspase 3 activity and TUNEL staining, supporting a likely role for apoptosis and ER stress in cardiac contractile and geometric (hypertrophic remodeling) anomalies in Akt2 ablation induced insulin resistance.	7	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt2	Akt2	Akt2	ER	ER	ER	7	8	13	14
In addition , Si-Akt2 transfection partially prevented the TM induced decrease in nuclear localization of beta-catenin .	In addition, Si-Akt2 transfection partially prevented the TM induced decrease in nuclear localization of beta-catenin.	3	16	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Si-Akt2	Si-Akt2	Si-Akt2	beta-catenin	beta-catenin	beta-catenin	3	4	15	16
VPA treatment increased the levels of activated Akt , deactivated glycogen synthase kinase-3beta ( GSK-3beta ) , beta-catenin , and Bcl-2 significantly when compared to FWB and saline control groups .	VPA treatment increased the levels of activated Akt, deactivated glycogen synthase kinase-3beta (GSK-3beta), beta-catenin, and Bcl-2 significantly when compared to FWB and saline control groups.	0	18	deactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	VPA treatment increased the levels of activated Akt	akt	beta-catenin	beta-catenin	beta-catenin	7	8	17	18
VPA treatment increased the levels of activated Akt , deactivated glycogen synthase kinase-3beta ( GSK-3beta ) , beta-catenin and Bcl-2 significantly when compared to FWB and saline control groups ( without an alteration in the total Akt and GSK-3beta levels ) .	VPA treatment increased the levels of activated Akt, deactivated glycogen synthase kinase-3beta (GSK-3beta), beta-catenin and Bcl-2 significantly when compared to FWB and saline control groups (without an alteration in the total Akt and GSK-3beta levels).	0	18	deactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	VPA treatment increased the levels of activated Akt	akt	beta-catenin	beta-catenin	beta-catenin	7	8	17	18
The AKT inhibitor , LY294002 , and the knockdown of AKT expression reversed the rIL-17B-induced upregulation of beta-catenin and some stemness markers .	The AKT inhibitor, LY294002, and the knockdown of AKT expression reversed the rIL-17B-induced upregulation of beta-catenin and some stemness markers.	10	21	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT expression	akt	beta-catenin	beta-catenin	beta-catenin	10	11	17	18
Several studies have shown that AM acts through PI3K , Akt , MAPK , FAK and other components of the cell-cell adhesion machinery [ XREF_BIBR - XREF_BIBR ] , suggesting that the PI3K and Akt signalling pathway might be inhibited by AM blockade to produce phospho-Ser 33 / Ser 37 / Thr 41 beta-catenin .	Several studies have shown that AM acts through PI3K, Akt, MAPK, FAK and other components of the cell-cell adhesion machinery [XREF_BIBR - XREF_BIBR], suggesting that the PI3K and Akt signalling pathway might be inhibited by AM blockade to produce phospho-Ser 33 / Ser 37 / Thr 41 beta-catenin.	34	54	produce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	34	35	53	54
In human tongue cancer cell lines as well as pancreatic cell lines , the reduction of migration and invasion leads to a decrease in beta-catenin , phospho-Akt , GSK-3beta , and some MMP levels , indicating that galectin-3-mediated migration and invasion involves beta-catenin degradation initiated by Akt phosphorylation in this model .	In human tongue cancer cell lines as well as pancreatic cell lines, the reduction of migration and invasion leads to a decrease in beta-catenin, phospho-Akt, GSK-3beta, and some MMP levels, indicating that galectin-3-mediated migration and invasion involves beta-catenin degradation initiated by Akt phosphorylation in this model.	42	48	initiated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Akt	Akt phosphorylation	akt	beta-catenin	beta-catenin	beta-catenin	46	47	42	43
Reduced PI3K and Akt signaling and expression of beta-catenin target genes in 5-ASA-treated CUC patients additionally suggests enhanced PTEN activity as well .	Reduced PI3K and Akt signaling and expression of beta-catenin target genes in 5-ASA-treated CUC patients additionally suggests enhanced PTEN activity as well.	3	10	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
Introduction of RONdelta170 into HCT116 cells blocked MSP induced Erkl/2 and AKT phosphorylation , reduced cytoplasmic beta-catenin accumulation , restored glycogen synthase kinase-beta activity , and attenuated various tumorigenic activities .	Introduction of RONdelta170 into HCT116 cells blocked MSP induced Erkl/2 and AKT phosphorylation, reduced cytoplasmic beta-catenin accumulation, restored glycogen synthase kinase-beta activity, and attenuated various tumorigenic activities.	2	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	RONdelta170 into HCT116 cells blocked MSP induced Erkl/2 and AKT phosphorylation	akt	beta-catenin	beta-catenin	beta-catenin	11	12	16	17
Concomitantly , Gbetagamma stimulates PI3K-AKT , which functions together with PKA to inhibit the beta-catenin degradation complex , stabilize beta-catenin and initiate downstream gene expression [ XREF_BIBR ] .	Concomitantly, Gbetagamma stimulates PI3K-AKT, which functions together with PKA to inhibit the beta-catenin degradation complex, stabilize beta-catenin and initiate downstream gene expression [XREF_BIBR].	3	21	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	beta-catenin	beta-catenin	beta-catenin	4	5	14	15
Slit2 knockdown increased AKT phosphorylation , activated anti-apoptotic signaling , suppressed GSK3beta activity and induced beta-catenin activation .	Slit2 knockdown increased AKT phosphorylation, activated anti-apoptotic signaling, suppressed GSK3beta activity and induced beta-catenin activation.	3	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT phosphorylation	akt	beta-catenin	beta-catenin	beta-catenin	3	4	15	16
Indeed , PI3K and Akt inhibition enhanced the transcriptional activity of beta-catenin , and this effect could be blocked by inhibition of ERK activity .	Indeed, PI3K and Akt inhibition enhanced the transcriptional activity of beta-catenin, and this effect could be blocked by inhibition of ERK activity.	2	12	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	4	5	11	12
Activation of the beta-catenin pathway is known to play a significant role in the development of colorectal cancer.18 ,20 Moreover , the PI3K and AKT pathway can positively regulate beta-catenin-dependent transcription , XREF_BIBR , XREF_BIBR and pharmacologic or genetic inhibition of PI3K and AKT activity allows suppression of beta-catenin activation .	Activation of the beta-catenin pathway is known to play a significant role in the development of colorectal cancer.18,20 Moreover, the PI3K and AKT pathway can positively regulate beta-catenin-dependent transcription, XREF_BIBR, XREF_BIBR and pharmacologic or genetic inhibition of PI3K and AKT activity allows suppression of beta-catenin activation.	43	49	allows	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	43	44	48	49
5-ASA reduces Akt mediated beta-catenin signaling in IL-10 -/- CAC .	5-ASA reduces Akt mediated beta-catenin signaling in IL-10 -/- CAC.	1	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
For example , EGFR activated PI3K and AKT leads to phosphorylation and subsequently inhibition of the beta-catenin suppressor GSK3beta , resulting in nuclear accumulation of beta-catenin [ XREF_BIBR ] .	For example, EGFR activated PI3K and AKT leads to phosphorylation and subsequently inhibition of the beta-catenin suppressor GSK3beta, resulting in nuclear accumulation of beta-catenin [XREF_BIBR].	5	18	leads	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	7	8	16	17
Since ethanol induced Akt deactivation results in the activation of downstream kinase GSK3beta and subsequent decreased beta-catenin , we used two inhibitors of GSK3beta , CHIR-98014 and TWS119 , to abolish this inhibitory effect of ethanol .	Since ethanol induced Akt deactivation results in the activation of downstream kinase GSK3beta and subsequent decreased beta-catenin, we used two inhibitors of GSK3beta, CHIR-98014 and TWS119, to abolish this inhibitory effect of ethanol.	1	17	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Akt	ethanol induced Akt	akt	beta-catenin	beta-catenin	beta-catenin	3	4	16	17
Furthermore , we observed that Akt inhibition enhanced the membrane staining of beta-catenin in control cells , an effect that was not seen in shDsc2 knockdown cells ( Supplemental Figure 5A ) .	Furthermore, we observed that Akt inhibition enhanced the membrane staining of beta-catenin in control cells, an effect that was not seen in shDsc2 knockdown cells (Supplemental Figure 5A).	5	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	5	6	12	13
Moreover , simultaneous Wnt-beta-catenin pathway hyperactivation and PI3K-AKT signaling inhibition promote nuclear accumulation of beta-catenin and FOXO3a , and eventual metastasis [ XREF_BIBR ] .	Moreover, simultaneous Wnt-beta-catenin pathway hyperactivation and PI3K-AKT signaling inhibition promote nuclear accumulation of beta-catenin and FOXO3a, and eventual metastasis [XREF_BIBR].	7	16	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	beta-catenin	beta-catenin	beta-catenin	7	8	14	15
The current data are consistent with the notion that 5-ASA inhibition of epithelial proliferation and progenitor cell activation result from reduced PI3K and Akt mediated beta-catenin activation .	The current data are consistent with the notion that 5-ASA inhibition of epithelial proliferation and progenitor cell activation result from reduced PI3K and Akt mediated beta-catenin activation.	18	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	23	24	25	26
Low AKT activity in osteoblasts correlates broadly with lower bone mass , higher levels of osteoblast apoptosis , and attenuated beta-catenin signaling .	Low AKT activity in osteoblasts correlates broadly with lower bone mass, higher levels of osteoblast apoptosis, and attenuated beta-catenin signaling.	1	21	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	1	2	20	21
The dual function of Akt in both inactivating phosphorylation of GSK-3beta at Ser 9 [ XREF_BIBR ] and activating phosphorylation of NHE-1 at Ser 648 [ XREF_BIBR ] suggests that Akt reduced activity could be a common molecular event underlying the ANP induced inhibition of both Wnt and beta-catenin signaling cascade and NHE-1 activity .	The dual function of Akt in both inactivating phosphorylation of GSK-3beta at Ser 9 [XREF_BIBR] and activating phosphorylation of NHE-1 at Ser 648 [XREF_BIBR] suggests that Akt reduced activity could be a common molecular event underlying the ANP induced inhibition of both Wnt and beta-catenin signaling cascade and NHE-1 activity.	2	50	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	4	5	48	49
In accordance with the observed morphologic change , inhibition of Akt activity induced the expression in immunoblotting and RT-PCR and localization of E-cadherin and beta-catenin as seen in the immunofluorescence analysis .	In accordance with the observed morphologic change, inhibition of Akt activity induced the expression in immunoblotting and RT-PCR and localization of E-cadherin and beta-catenin as seen in the immunofluorescence analysis.	10	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	10	11	24	25
The signaling proteins related to Wnt and beta-catenin including activated Akt ( phosphorylated Akt at Ser 473 ) , total Akt , inactivated glycogen synthase kinase3beta ( phosphorylated GSK3beta at Ser 9 ) , parental GSK3beta , and beta-catenin were determined by western blot analysis .	The signaling proteins related to Wnt and beta-catenin including activated Akt (phosphorylated Akt at Ser 473), total Akt, inactivated glycogen synthase kinase3beta (phosphorylated GSK3beta at Ser 9), parental GSK3beta, and beta-catenin were determined by western blot analysis.	2	40	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	20	21	38	39
We have previously shown that strain prevents adipogenesis in marrow derived stem cells in a signaling process that culminates in increased nuclear beta-catenin , whereby GSK3beta is inactivated through phosphorylation by Akt .	We have previously shown that strain prevents adipogenesis in marrow derived stem cells in a signaling process that culminates in increased nuclear beta-catenin, whereby GSK3beta is inactivated through phosphorylation by Akt.	18	32	inactivated	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	31	32	22	23
XREF_FIG shows that treatment of the cells with CIP significantly increased the level of activated Akt level , inactivated GSK3beta , and beta-catenin .	XREF_FIG shows that treatment of the cells with CIP significantly increased the level of activated Akt level, inactivated GSK3beta, and beta-catenin.	15	23	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt level	akt	beta-catenin	beta-catenin	beta-catenin	15	16	22	23
beta-catenin signaling , which is enhanced by TGFbeta [ XREF_BIBR ] and inhibited by Akt [ XREF_BIBR ] , can mediate the binding of E-cadherin to the actin cytoskeleton and regulate the expression of Snail and Slug [ XREF_BIBR ] .	beta-catenin signaling, which is enhanced by TGFbeta [XREF_BIBR] and inhibited by Akt [XREF_BIBR], can mediate the binding of E-cadherin to the actin cytoskeleton and regulate the expression of Snail and Slug [XREF_BIBR].	0	16	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	beta-catenin	beta-catenin	beta-catenin	14	15	0	1
We therefore investigated the role of the AKT and mTOR signaling pathway in apigenin induced autolysosomal degradation of beta-catenin .	We therefore investigated the role of the AKT and mTOR signaling pathway in apigenin induced autolysosomal degradation of beta-catenin.	4	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	7	8	18	19
Downregulation of AKT activation suppresses the activity of beta-catenin to inhibit thyroid growth in Thrb PV/PV mice .	Downregulation of AKT activation suppresses the activity of beta-catenin to inhibit thyroid growth in Thrb PV/PV mice.	2	9	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
Similar to the results with GSK2334470 , addition of alpelisib markedly increased the anti-tumor effect of fulvestrant and ribociclib against established MCF-7 xenografts and inhibited ER , PR , and S473 P-AKT ( XREF_FIG ) .	Similar to the results with GSK2334470, addition of alpelisib markedly increased the anti-tumor effect of fulvestrant and ribociclib against established MCF-7 xenografts and inhibited ER, PR, and S473 P-AKT (XREF_FIG).	11	33	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	P-AKT	P-AKT	P-AKT	ER	ER	ER	31	32	25	26
Chronic Akt activation and SB216763 significantly attenuated LPS induced changes in these ER stress markers without eliciting any notable effect by themselves .	Chronic Akt activation and SB216763 significantly attenuated LPS induced changes in these ER stress markers without eliciting any notable effect by themselves.	1	14	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	1	2	12	13
Importantly , TAS-117 enhances cytotoxicity induced by proteasome inhibitors ( bortezomib and carfilzomib ) by inhibition of proteasome inhibitor induced Akt activation and induction of fatal ER stress , associated with increased CHOP expression .	Importantly, TAS-117 enhances cytotoxicity induced by proteasome inhibitors (bortezomib and carfilzomib) by inhibition of proteasome inhibitor induced Akt activation and induction of fatal ER stress, associated with increased CHOP expression.	17	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	Akt	proteasome inhibitor induced Akt	akt	ER	ER	er	20	21	26	27
Similarly , another study demonstrated that Akt activation attenuated lipopolysaccharide induced cardiac dysfunction via Akt and GSK3beta dependent inhibition of apoptosis and ER stress [ XREF_BIBR ] .	Similarly, another study demonstrated that Akt activation attenuated lipopolysaccharide induced cardiac dysfunction via Akt and GSK3beta dependent inhibition of apoptosis and ER stress [XREF_BIBR].	14	25	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	14	15	22	23
Second , PI3K and Akt signaling , which impairs ER function , plays an important role in stress condition .	Second, PI3K and Akt signaling, which impairs ER function, plays an important role in stress condition.	2	10	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	4	5	9	10
Consistent with these finding we observed activation of Akt following treatment with EerI and more interestingly , we observed inhibiting Akt can partially blocks ER stress and its associated EMT in lung adenocarcinoma cells providing further evidence that Akt may contribute towards EMT by activating proliferation and survival pathways in cellular system .	Consistent with these finding we observed activation of Akt following treatment with EerI and more interestingly, we observed inhibiting Akt can partially blocks ER stress and its associated EMT in lung adenocarcinoma cells providing further evidence that Akt may contribute towards EMT by activating proliferation and survival pathways in cellular system.	20	25	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	20	21	24	25
Akt DN also inhibited the ATP stimulated Panx3 ER Ca 2+ release , but not IP3R ER Ca 2+ release ( XREF_FIG , b ) .	Akt DN also inhibited the ATP stimulated Panx3 ER Ca 2+ release, but not IP3R ER Ca 2+ release (XREF_FIG, b).	0	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	0	1	16	17
E2 increased the phosphorylation of Akt and eNOS that was not reversed by ICI 182,780 , supporting an ER independent mechanism .	E2 increased the phosphorylation of Akt and eNOS that was not reversed by ICI 182,780, supporting an ER independent mechanism.	0	20	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	E2 increased the phosphorylation of Akt	akt	ER	ER	er	5	6	18	19
Chronic Akt Activation Attenuated Lipopolysaccharide Induced Cardiac Dysfunction via Akt and GSK3beta Dependent Inhibition of Apoptosis and ER Stress .	Chronic Akt Activation Attenuated Lipopolysaccharide Induced Cardiac Dysfunction via Akt and GSK3beta Dependent Inhibition of Apoptosis and ER Stress.	9	18	Inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	9	10	17	18
Given the link between PHLDA3 and Akt as core signalling nodes in the network of proapoptotic molecules ( XREF_FIG A ) and the effect of PHLDA3 on Akt activity for anti-tumour effect , XREF_BIBR we hypothesised whether PHLDA3 inhibition of Akt mediates ER stress induced cell death .	Given the link between PHLDA3 and Akt as core signalling nodes in the network of proapoptotic molecules (XREF_FIG A) and the effect of PHLDA3 on Akt activity for anti-tumour effect, XREF_BIBR we hypothesised whether PHLDA3 inhibition of Akt mediates ER stress induced cell death.	38	43	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	40	41	42	43
In addition , melatonin pre-treatment also increased the phosphorylation of Akt , GSK-3beta , ERK1/2 and STAT3 and reduced PERK-eIF2alpha-ATF4-mediated ER stress .	In addition, melatonin pre-treatment also increased the phosphorylation of Akt, GSK-3beta, ERK1/2 and STAT3 and reduced PERK-eIF2alpha-ATF4-mediated ER stress.	3	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	melatonin pre-treatment also increased the phosphorylation of Akt	akt	ER	ER	er	10	11	20	21
Overall these results show that in MCF-7 cells , DynII depletion increases the basal AKT phosphorylation state , abolishes the ability of E2 to increase ERalpha S118 phosphorylation and AKT activation , alters the basal and E2 induced mechanism of ERalpha : IGF-1R interaction , deregulates ERalpha transcriptional activity and prevents E2 proliferative stimuli .	Overall these results show that in MCF-7 cells, DynII depletion increases the basal AKT phosphorylation state, abolishes the ability of E2 to increase ERalpha S118 phosphorylation and AKT activation, alters the basal and E2 induced mechanism of ERalpha : IGF-1R interaction, deregulates ERalpha transcriptional activity and prevents E2 proliferative stimuli.	9	48	deregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	DynII depletion increases the basal AKT phosphorylation	akt	ERalpha	ERalpha	eralpha	14	15	46	47
In vitro and in vivo studies have found that AKT inhibits ER calcium channel IP3R activity via direct phosphorylation , thereby limiting calcium release from the ER [ XREF_BIBR , XREF_BIBR ] .	In vitro and in vivo studies have found that AKT inhibits ER calcium channel IP3R activity via direct phosphorylation, thereby limiting calcium release from the ER [XREF_BIBR, XREF_BIBR].	9	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	ER	ER	ER	9	10	11	12
These findings suggest that BRCA1 regulates Akt signaling and the PI3K and Akt pathway modulates the ability of BRCA1 to repress ER-alpha , in part through serine phosphorylation events in the activation function-1 domain of ER-alpha .	These findings suggest that BRCA1 regulates Akt signaling and the PI3K and Akt pathway modulates the ability of BRCA1 to repress ER-alpha, in part through serine phosphorylation events in the activation function-1 domain of ER-alpha.	6	24	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ER-alpha	ER-alpha	ER-alpha	6	7	21	22
Furthermore , overexpression of AKT attenuated the NCTD induced apoptosis and ER stress in 786-O cells .	Furthermore, overexpression of AKT attenuated the NCTD induced apoptosis and ER stress in 786-O cells.	2	12	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	overexpression of AKT	akt	ER	ER	er	4	5	11	12
In this apoptotic process , PI3K and Akt perturbs the intracellular redox equilibration following PKC suppression and further induces ER stress , leading to apoptosis via activating the UPR ( XREF_FIG ) .	In this apoptotic process, PI3K and Akt perturbs the intracellular redox equilibration following PKC suppression and further induces ER stress, leading to apoptosis via activating the UPR (XREF_FIG).	5	20	perturbs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	7	8	19	20
Increased eIF2alphaP is an evolutionary conserved process that involves the endoplasmic reticulum ( ER )-resident protein kinase PERK , which is negatively regulated by Akt dependent phosphorylation at threonine 799 .	Increased eIF2alphaP is an evolutionary conserved process that involves the endoplasmic reticulum (ER)-resident protein kinase PERK, which is negatively regulated by Akt dependent phosphorylation at threonine 799.	13	30	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Akt	Akt dependent phosphorylation at threonine 799	akt	ER	ER	er	24	25	13	14
In addition , metformin treatment attenuated the albumin induced phosphorylation of AKT and the downstream targets of mTOR , and prevented albumin mediated inductions of EMT marker ( alpha-SMA ) , pro apoptotic ER stress marker CHOP , and apoptotic caspases -12 and -3 in renal cells .	In addition, metformin treatment attenuated the albumin induced phosphorylation of AKT and the downstream targets of mTOR, and prevented albumin mediated inductions of EMT marker (alpha-SMA), pro apoptotic ER stress marker CHOP, and apoptotic caspases -12 and -3 in renal cells.	3	36	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	metformin treatment attenuated the albumin induced phosphorylation of AKT	akt	ER	ER	er	11	12	33	34
In addition , inhibition of Akt enhanced ER stress induced macrophage apoptosis , and expression of a constitutively active myristoylated Akt blocked the enhancement of ER stress induced apoptosis that occurred with p38 inhibition in cultured cells .	In addition, inhibition of Akt enhanced ER stress induced macrophage apoptosis, and expression of a constitutively active myristoylated Akt blocked the enhancement of ER stress induced apoptosis that occurred with p38 inhibition in cultured cells.	3	8	enhanced	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	5	6	7	8
Furthermore , constitutive activation of AKT induced by adenoviral vectors inhibited the pro apoptotic effects and ER stress induced by wogonin in the HL-60 cells .	Furthermore, constitutive activation of AKT induced by adenoviral vectors inhibited the pro apoptotic effects and ER stress induced by wogonin in the HL-60 cells.	3	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	ER	ER	ER	5	6	16	17
Our data further demonstrate that both PERK and IRE1alpha pathways are activated by Akt inhibition in MM cells , indicating global ER stress triggered by TAS-117 .	Our data further demonstrate that both PERK and IRE1alpha pathways are activated by Akt inhibition in MM cells, indicating global ER stress triggered by TAS-117.	11	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	13	14	21	22
These results suggest that PPAR-delta agonist rescue of chronic alcoholic liver disease is mediated by enhancement of insulin signaling through Akt and metabolic pathways that reduce lipotoxicity and ER stress .	These results suggest that PPAR-delta agonist rescue of chronic alcoholic liver disease is mediated by enhancement of insulin signaling through Akt and metabolic pathways that reduce lipotoxicity and ER stress.	20	29	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	20	21	28	29
We found that NOS2 expression was associated with Akt activation in both ER positive and ER negative tumors XREF_BIBR .	We found that NOS2 expression was associated with Akt activation in both ER positive and ER negative tumors XREF_BIBR.	8	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Akt	Akt	Akt	ER	ER	ER	8	9	12	13
Loss of PTEN and subsequent AKT activation stimulate ERalpha dependent pathways that play an important role in endometrial tumorigenesis .	Loss of PTEN and subsequent AKT activation stimulate ERalpha dependent pathways that play an important role in endometrial tumorigenesis.	5	10	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	ERalpha	ERalpha	ERalpha	5	6	8	9
Palmitic acid ( PA ) not only reduced insulin stimulated phosphorylation of Akt but also induced endoplasmic reticulum ( ER ) expansion and ER stress .	Palmitic acid (PA) not only reduced insulin stimulated phosphorylation of Akt but also induced endoplasmic reticulum (ER) expansion and ER stress.	0	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Palmitic acid (PA) not only reduced insulin stimulated phosphorylation of Akt	akt	ER	ER	er	12	13	23	24
This effect probably contributes to the physiological stress response with Akt inhibition and activation of ER stress .	This effect probably contributes to the physiological stress response with Akt inhibition and activation of ER stress.	10	16	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Akt	Akt	Akt	ER	ER	ER	10	11	15	16
AKT inhibits ER signaling through downregulating the histone methyltransferase KMTD and by its inhibition of FOXO3 , which would otherwise activate ER .	AKT inhibits ER signaling through downregulating the histone methyltransferase KMTD and by its inhibition of FOXO3, which would otherwise activate ER.	0	3	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	ER	ER	ER	0	1	2	3
Nuclear FOXO3A , for example , can be phosphorylated followed by Ub dependent degradation by either AKT and the E3 SCF [ XREF_BIBR ] , or Erk and the E3 Mdm2 [ XREF_BIBR ] .	Nuclear FOXO3A, for example, can be phosphorylated followed by Ub dependent degradation by either AKT and the E3 SCF [XREF_BIBR], or Erk and the E3 Mdm2 [XREF_BIBR].	13	32	degradation	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	AKT	AKT	AKT	Mdm2	Mdm2	Mdm2	16	17	30	31
Disruption of CK1alpha function in myeloma cells resulted in decreased Mdm2 , increased p53 and p21 and reduced expression of beta-catenin and AKT .	Disruption of CK1alpha function in myeloma cells resulted in decreased Mdm2, increased p53 and p21 and reduced expression of beta-catenin and AKT.	7	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	expression of beta-catenin and AKT	akt	Mdm2	Mdm2	mdm2	22	23	10	11
These results are consistent with the following hypothesis : AKT inactivation causes a decrease of p-MDM2 and as a consequence , an increase of p53 .	These results are consistent with the following hypothesis : AKT inactivation causes a decrease of p-MDM2 and as a consequence, an increase of p53.	9	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	p-MDM2	p-MDM2	p-MDM2	9	10	15	16
AKT can also inactivate p53 by modulating subcellular localization of Mdm2 .	AKT can also inactivate p53 by modulating subcellular localization of Mdm2.	0	11	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	Mdm2	Mdm2	Mdm2	0	1	10	11
AKT1 and AKT2 knockdown by shRNA , whether singly or in combination , induced expression of p53 , MDM2 , and p21 ( XREF_FIG ) , consistent with AKT mediated MDM2 functional inactivation , with resultant p53 overexpression and transcriptional activation of MDM2 and p21 .	AKT1 and AKT2 knockdown by shRNA, whether singly or in combination, induced expression of p53, MDM2, and p21 (XREF_FIG), consistent with AKT mediated MDM2 functional inactivation, with resultant p53 overexpression and transcriptional activation of MDM2 and p21.	26	31	mediated	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	28	29	30	31
The activation of AMPK during low energy levels can lead to the induction of p53 activity [ XREF_BIBR ] and PI3K-Akt growth signaling can inhibit p53 by activating MDM2 to promote the degradation of p53 [ XREF_BIBR ] .	The activation of AMPK during low energy levels can lead to the induction of p53 activity [XREF_BIBR] and PI3K-Akt growth signaling can inhibit p53 by activating MDM2 to promote the degradation of p53 [XREF_BIBR].	20	29	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	MDM2	MDM2	MDM2	20	21	28	29
AKT promotes the inhibition of MDM2 through a nucleoplasmic NPM and ARF complex .	AKT promotes the inhibition of MDM2 through a nucleoplasmic NPM and ARF complex.	0	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	0	1	5	6
The results therefore show that E2/ERbeta acts through PI3K to activate Akt which in turn activates MDM2 and calcineurin degradation to suppress ISO induced apoptosis ( XREF_FIG B ) .	The results therefore show that E2/ERbeta acts through PI3K to activate Akt which in turn activates MDM2 and calcineurin degradation to suppress ISO induced apoptosis (XREF_FIG B).	10	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	11	12	16	17
Similarly , Akt can block p53 activation by potentiating Mdm2 , whereas activated p53 can tune down Akt in several different ways .	Similarly, Akt can block p53 activation by potentiating Mdm2, whereas activated p53 can tune down Akt in several different ways.	2	10	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	2	3	9	10
The Akt induced Mdm2 can suppress anti-tumor role of p53 followed by downregulation of cell cycle arrest protein p21 , a p53 transcriptional target gene , which in turn can prompt cell proliferation , faster cancer progression and finally higher mortality rate .	The Akt induced Mdm2 can suppress anti-tumor role of p53 followed by downregulation of cell cycle arrest protein p21, a p53 transcriptional target gene, which in turn can prompt cell proliferation, faster cancer progression and finally higher mortality rate.	0	5	induced	Positive_early_activation	Positive_activation	Negative_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	1	2	3	4
These results suggest that the cellular responses to AF are determined at least in part by Mdm2 and p21 ( CIP1 and WAF1 ) protein levels , as well as by Akt activity , leading either to cell cycle arrest when Mdm2 and p21 ( CIP1 and WAF1 ) are elevated , or to apoptosis when Mdm2 and p21 ( CIP1 and WAF1 ) are degraded by the proteasome and Akt insufficiently activated to protect against apoptosis .	These results suggest that the cellular responses to AF are determined at least in part by Mdm2 and p21 (CIP1 and WAF1) protein levels, as well as by Akt activity, leading either to cell cycle arrest when Mdm2 and p21 (CIP1 and WAF1) are elevated, or to apoptosis when Mdm2 and p21 (CIP1 and WAF1) are degraded by the proteasome and Akt insufficiently activated to protect against apoptosis.	56	71	degraded	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	70	71	56	57
Collectively , these results suggest that PPARbeta and delta inhibits AKT activity causing : 1 ) increased FOXO activity thereby preventing down-regulation of p27 and p21 caused by activation of HRAS , and 2 ) decreased p-MDM2 activity thereby preventing down-regulation of p53 mediated by activation of HRAS ( XREF_FIG ) .	Collectively, these results suggest that PPARbeta and delta inhibits AKT activity causing : 1) increased FOXO activity thereby preventing down-regulation of p27 and p21 caused by activation of HRAS, and 2) decreased p-MDM2 activity thereby preventing down-regulation of p53 mediated by activation of HRAS (XREF_FIG).	10	37	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	p-MDM2	p-MDM2	p-MDM2	10	11	36	37
Since inhibition of AKT promotes ARF localization to the nucleolus and enhanced MDM2 activity , we wished to address what effect increased MDM2 activity has on endogenous p53 .	Since inhibition of AKT promotes ARF localization to the nucleolus and enhanced MDM2 activity, we wished to address what effect increased MDM2 activity has on endogenous p53.	1	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	3	4	12	13
AKT can block p53 accumulation and apoptosis by augmenting ubiquitin ligase activity of MDM2 activity through phosphorylation [ XREF_BIBR ] .	AKT can block p53 accumulation and apoptosis by augmenting ubiquitin ligase activity of MDM2 activity through phosphorylation [XREF_BIBR].	0	14	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	0	1	13	14
AKT is somewhat controversial kinase of MDM2 because accumulating evidence suggests that AKT may both promote and inhibit the activity of MDM2 .	AKT is somewhat controversial kinase of MDM2 because accumulating evidence suggests that AKT may both promote and inhibit the activity of MDM2.	12	22	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	12	13	21	22
In another case , Akt prevented apoptosis via phosphorylation and translocation of MDM2 ( Murine double minute 2 ) into the nucleus [ XREF_BIBR , XREF_BIBR ] .	In another case, Akt prevented apoptosis via phosphorylation and translocation of MDM2 (Murine double minute 2) into the nucleus [XREF_BIBR, XREF_BIBR].	4	13	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	4	5	12	13
Thus , oncogenic Akt is able to functionally inactivate p53 by regulating Mdm2 and MdmX stability .	Thus, oncogenic Akt is able to functionally inactivate p53 by regulating Mdm2 and MdmX stability.	2	15	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	3	4	12	13
Mechanistically , mitochondrial fission induced redox activation of Akt promoted Mdm2 dependent ubiquitin-proteasomal degradation of p53 and IKK dependent NF-kappaB activation [ XREF_BIBR ] .	Mechanistically, mitochondrial fission induced redox activation of Akt promoted Mdm2 dependent ubiquitin-proteasomal degradation of p53 and IKK dependent NF-kappaB activation [XREF_BIBR].	6	13	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	8	9	10	11
Therefore AKT dephosphorylation observed during ribosomal stress could inhibit MDM2 import in the nucleus and as a consequence cause p53 stabilization .	Therefore AKT dephosphorylation observed during ribosomal stress could inhibit MDM2 import in the nucleus and as a consequence cause p53 stabilization.	1	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT dephosphorylation	akt	MDM2	MDM2	mdm2	1	2	9	10
Thus , PTEN alters Akt activation , which prevents Mdm2 nuclear localization .	Thus, PTEN alters Akt activation, which prevents Mdm2 nuclear localization.	4	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	Mdm2	Mdm2	Mdm2	4	5	9	10
14-3-3sigma negatively represses AKT induced MDM2 activation by promoting the cytoplasmic translocation of MDM2 and triggering its degradation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	14-3-3sigma negatively represses AKT induced MDM2 activation by promoting the cytoplasmic translocation of MDM2 and triggering its degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	AKT	AKT	AKT	MDM2	MDM2	MDM2	3	4	5	6
Furthermore , PKB dephosphorylation inactivated mdm2 ( murine double minute 2 ) , leading to an increase in p21 expression , and subsequent caspase initiation after G1/S phase arrest [ XREF_BIBR ] .	Furthermore, PKB dephosphorylation inactivated mdm2 (murine double minute 2), leading to an increase in p21 expression, and subsequent caspase initiation after G1/S phase arrest [XREF_BIBR].	2	24	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKB	PKB dephosphorylation	pkb	mdm2	mdm2	mdm2	2	3	5	6
In contrast , curcumin has a broader spectrum of activity , that possibly cause radiosensitization via multiple mechanisms including inhibition of TNF-alpha-mediated NF-kappaB activation ( XREF_SUPPLEMENTARY ) and Akt mediated inhibition of the MDM2 oncogene .	In contrast, curcumin has a broader spectrum of activity, that possibly cause radiosensitization via multiple mechanisms including inhibition of TNF-alpha-mediated NF-kappaB activation (XREF_SUPPLEMENTARY) and Akt mediated inhibition of the MDM2 oncogene.	28	34	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	28	29	33	34
From the Western blot , downstream phosphorylation of the Akt targets MDM2 and GSK3beta are clearly suppressed following 4-HNE pre-incubation .	From the Western blot, downstream phosphorylation of the Akt targets MDM2 and GSK3beta are clearly suppressed following 4-HNE pre-incubation.	6	16	targets	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Akt	phosphorylation of the Akt	akt	MDM2	MDM2	mdm2	9	10	11	12
The effects of NFAT1 on breast cancer cell invasion are countered by Akt which induces MDM2 mediated proteasomal degradation of NFAT1 [ XREF_BIBR ] .	The effects of NFAT1 on breast cancer cell invasion are countered by Akt which induces MDM2 mediated proteasomal degradation of NFAT1 [XREF_BIBR].	10	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	MDM2	MDM2	MDM2	12	13	15	16
In vitro , vandetanib decreased Akt phosphorylation and NO production , yet increased eNOS membrane content .	In vitro, vandetanib decreased Akt phosphorylation and NO production, yet increased eNOS membrane content.	3	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	vandetanib decreased Akt phosphorylation	akt	eNOS	eNOS	enos	5	6	13	14
PLTs induced Akt and eNOS inactivation and expression of eNOS .	PLTs induced Akt and eNOS inactivation and expression of eNOS.	2	10	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	9	10
Administration of wortmannin ( phosphatidylinositol 3-kinase , PI3 K , inhibitor ) attenuated the phosphorylation of Akt and eNOS and reduced eNOS activity .	Administration of wortmannin (phosphatidylinositol 3-kinase, PI3 K, inhibitor) attenuated the phosphorylation of Akt and eNOS and reduced eNOS activity.	4	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	phosphatidylinositol 3-kinase, PI3 K, inhibitor) attenuated the phosphorylation of Akt	akt	eNOS	eNOS	enos	16	17	21	22
At these concentrations , TSP1 can also inhibit the activation of eNOS by AKT via its interaction with the cell surface receptor CD36 .	At these concentrations, TSP1 can also inhibit the activation of eNOS by AKT via its interaction with the cell surface receptor CD36.	7	16	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	13	14	11	12
Treatment with oxLDL inactivated the Akt and endothelial nitric-oxide synthase ( eNOS ) pathway , induced eNOS degradation , and inhibited nitric oxide ( NO ) production in endothelial cells .	Treatment with oxLDL inactivated the Akt and endothelial nitric-oxide synthase (eNOS) pathway, induced eNOS degradation, and inhibited nitric oxide (NO) production in endothelial cells.	4	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	5	6	16	17
At higher concentrations of quercetin ( 30-100muM ) , eNOS activity was decreased in bovine aortic endothelial cells by decreasing Ser617 phosphorylation , and also ser473 Akt phosphorylation 126 .	At higher concentrations of quercetin (30-100muM), eNOS activity was decreased in bovine aortic endothelial cells by decreasing Ser617 phosphorylation, and also ser473 Akt phosphorylation 126.	9	27	decreased	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Akt	Ser617 phosphorylation, and also ser473 Akt	akt	eNOS	eNOS	enos	26	27	9	10
FFAs inhibit the PI3K and AKT pathway , which , aside from controlling insulin stimulated glucose uptake , is also needed to stimulate endothelial NOS ( e-NOS ) .	FFAs inhibit the PI3K and AKT pathway, which, aside from controlling insulin stimulated glucose uptake, is also needed to stimulate endothelial NOS (e-NOS).	3	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	endothelial NOS	endothelial NOS	endothelial NOS	5	6	23	25
Knockdown of Akt partially prevents eNOS upregulation promoted by nicorandil .	Knockdown of Akt partially prevents eNOS upregulation promoted by nicorandil.	0	6	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	5	6
Previous evidence indicates that in normal mice , HF feeding impedes the phosphorylation of eNOS ( a marker of eNOS activation ) in the thoracic aorta , and that this effect is accompanied by reduced phosphorylation of Akt 8 , ( the serine threonine kinase that phosphorylates and thereby activates eNOS ) .	Previous evidence indicates that in normal mice, HF feeding impedes the phosphorylation of eNOS (a marker of eNOS activation) in the thoracic aorta, and that this effect is accompanied by reduced phosphorylation of Akt 8, (the serine threonine kinase that phosphorylates and thereby activates eNOS).	35	51	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	phosphorylation of Akt 8, (the serine	akt	eNOS	eNOS	enos	37	38	50	51
rhACE2 may reduce the activity of Ang II inhibited endothelial cell eNOS , which can be blocked by PI3K and AKT pathway inhibitor LY294002 , suggesting PI3K and AKT signaling pathway plays an important role in rhACE2 ' s promotion of the activity of endothelial cell eNOS .	rhACE2 may reduce the activity of Ang II inhibited endothelial cell eNOS, which can be blocked by PI3K and AKT pathway inhibitor LY294002, suggesting PI3K and AKT signaling pathway plays an important role in rhACE2 's promotion of the activity of endothelial cell eNOS.	9	31	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	eNOS	eNOS	eNOS	20	21	11	12
CoPP increased adiponectin levels and phosphorylation of AKT and AMPK and reversed the eNOS and iNOS expression imbalance observed in the untreated diabetic heart .	CoPP increased adiponectin levels and phosphorylation of AKT and AMPK and reversed the eNOS and iNOS expression imbalance observed in the untreated diabetic heart.	0	18	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	CoPP increased adiponectin levels and phosphorylation of AKT	akt	eNOS	eNOS	enos	7	8	13	14
Additionally , Akt activation was found to reverse the eNOS and iNOS expression imbalance and reduce nitrative stress injury in the ischemic heart [ XREF_BIBR , XREF_BIBR ] .	Additionally, Akt activation was found to reverse the eNOS and iNOS expression imbalance and reduce nitrative stress injury in the ischemic heart [XREF_BIBR, XREF_BIBR].	2	13	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	eNOS	eNOS	eNOS	2	3	9	10
Interestingly , the level of Mre11 , a factor required for strand resection , was markedly reduced in PTEN -/- HCT116 cells compared with controls ( XREF_FIG ) , whereas constitutive Akt activity has been reported to inhibit recombination by inducing cytoplasmic sequestration of Rad51 and Brca1 .	Interestingly, the level of Mre11, a factor required for strand resection, was markedly reduced in PTEN -/- HCT116 cells compared with controls (XREF_FIG), whereas constitutive Akt activity has been reported to inhibit recombination by inducing cytoplasmic sequestration of Rad51 and Brca1.	31	47	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	Brca1	Brca1	Brca1	31	32	46	47
Alternatively , Akt and PKB can suppress BRCA1 signaling to disinhibit signal transducer and activator of transcription 3 ( STAT3 ) phosphorylation , regulating transcription [ XREF_BIBR ] .	Alternatively, Akt and PKB can suppress BRCA1 signaling to disinhibit signal transducer and activator of transcription 3 (STAT3) phosphorylation, regulating transcription [XREF_BIBR].	2	8	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKB	PKB	PKB	BRCA1	BRCA1	BRCA1	4	5	7	8
Previous studies demonstrated that BRCA1 is negatively regulated by the Akt signaling pathway XREF_BIBR , XREF_BIBR .	Previous studies demonstrated that BRCA1 is negatively regulated by the Akt signaling pathway XREF_BIBR, XREF_BIBR.	4	13	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	BRCA1	BRCA1	BRCA1	10	11	4	5
We show that Akt inhibits BRCA1 function that induces G2 cell cycle arrest .	We show that Akt inhibits BRCA1 function that induces G2 cell cycle arrest.	3	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	BRCA1	BRCA1	BRCA1	3	4	5	6
Strikingly , our results show that the inhibition of PI3K and AKT pathway with LY294002 restored not only BRCA1 but also FANCD2 foci in BCR and ABL transduced CD34+ cells .	Strikingly, our results show that the inhibition of PI3K and AKT pathway with LY294002 restored not only BRCA1 but also FANCD2 foci in BCR and ABL transduced CD34+ cells.	9	22	restored	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	BRCA1	BRCA1	BRCA1	11	12	18	19
Downregulating ERCC1 and BRCA1 significantly decreased PI3K and AKT phosphorylation levels ( P < 0.05 ) .	Downregulating ERCC1 and BRCA1 significantly decreased PI3K and AKT phosphorylation levels (P < 0.05).	0	10	Downregulating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT phosphorylation	akt	BRCA1	BRCA1	brca1	8	9	3	4
Conversely , AKT has also been shown to antagonize the activity of BRCA1 .	Conversely, AKT has also been shown to antagonize the activity of BRCA1.	2	13	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	BRCA1	BRCA1	BRCA1	2	3	12	13
Estrogen activated the AKT pathway in BRCA1 deficient tumor cells independent of ER , and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression .	Estrogen activated the AKT pathway in BRCA1 deficient tumor cells independent of ER, and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression.	18	29	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AKT	AKT	AKT	BRCA1	BRCA1	BRCA1	18	19	26	27
The inhibition of Akt was followed by the up-regulation of FOXO1/3 , GSK-3beta and p21 , inducing the dysregulation of CDK4/6 and CDK2 .	The inhibition of Akt was followed by the up-regulation of FOXO1/3, GSK-3beta and p21, inducing the dysregulation of CDK4/6 and CDK2.	1	23	inducing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	CDK2	CDK2	CDK2	3	4	22	23
While the PI3K and AKT and MEK and ERK pathways have both been implicated in regulating CDK2 , we found that AKT but not ERK inhibition was sufficient to inhibit CDK2 activation and block cell proliferation .	While the PI3K and AKT and MEK and ERK pathways have both been implicated in regulating CDK2, we found that AKT but not ERK inhibition was sufficient to inhibit CDK2 activation and block cell proliferation.	21	31	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	CDK2	CDK2	CDK2	21	22	30	31
The inhibition of Akt induced downstream dysregulation of CDK4/6 and CDK2 , thereby promoting cell entry from G1 to S phase .	The inhibition of Akt induced downstream dysregulation of CDK4/6 and CDK2, thereby promoting cell entry from G1 to S phase.	1	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	CDK2	CDK2	CDK2	3	4	10	11
Prevention of Akt activation by wortmannin and Ly294002 , two pharmacological PI 3 K inhibitors , strongly reduced Cdk2 activity .	Prevention of Akt activation by wortmannin and Ly294002, two pharmacological PI 3 K inhibitors, strongly reduced Cdk2 activity.	2	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	Cdk2	Cdk2	Cdk2	2	3	18	19
Inhibitors as well as dominant negative mutants of PI3-kinase and Akt not only inhibited CDK2 activation but also protected cells from apoptin induced cell death .	Inhibitors as well as dominant negative mutants of PI3-kinase and Akt not only inhibited CDK2 activation but also protected cells from apoptin induced cell death.	6	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt	Akt	CDK2	CDK2	CDK2	10	11	14	15
Moreover , PI3K-Akt signaling does not appear to disrupt the PRC1 complex itself or the nuclear localization of Bmi1 ( XREF_SUPPLEMENTARY ) .	Moreover, PI3K-Akt signaling does not appear to disrupt the PRC1 complex itself or the nuclear localization of Bmi1 (XREF_SUPPLEMENTARY).	2	20	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	Bmi1	Bmi1	Bmi1	2	3	18	19
The PI3K-Akt signaling pathway inhibits the association of Bmi1 with the Ink4a-Arf locus ( XREF_FIG ) and trimethylation of H3K27 ( XREF_FIG ) ; thus , it is possible that the dissociation of phosphorylated Bmi1 from chromatin may also relate to decreased trimethylation of H3K27 .	The PI3K-Akt signaling pathway inhibits the association of Bmi1 with the Ink4a-Arf locus (XREF_FIG) and trimethylation of H3K27 (XREF_FIG); thus, it is possible that the dissociation of phosphorylated Bmi1 from chromatin may also relate to decreased trimethylation of H3K27.	1	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	Bmi1	Bmi1	Bmi1	1	2	8	9
Indeed , we have recently demonstrated that lower ( more tolerated ) doses of AKT targeted therapy could target and radiosensitize glioblastoma TICs overexpressing BMI-1 .	Indeed, we have recently demonstrated that lower (more tolerated) doses of AKT targeted therapy could target and radiosensitize glioblastoma TICs overexpressing BMI-1.	12	25	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	BMI-1	BMI-1	BMI-1	14	15	24	25
PI3K and Akt signaling inhibits the association of Bmi1 with the Ink4a-Arf locus .	PI3K and Akt signaling inhibits the association of Bmi1 with the Ink4a-Arf locus.	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	Bmi1	Bmi1	Bmi1	2	3	8	9
The results demonstrated that 4-HIL suppressed the phosphorylation of both IRS-1 Ser 307 and Akt Ser 473 , but increased the expression GLUT4 at the tested total protein ( XREF_FIG ) .	The results demonstrated that 4-HIL suppressed the phosphorylation of both IRS-1 Ser 307 and Akt Ser 473, but increased the expression GLUT4 at the tested total protein (XREF_FIG).	4	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	4-HIL suppressed the phosphorylation of both IRS-1 Ser 307 and Akt	akt	GLUT4	GLUT4	glut4	14	15	22	23
Interestingly , although sarcolemmal GLUT1 was not significantly altered , chronic Akt activation actually decreased plasma membrane GLUT4 .	Interestingly, although sarcolemmal GLUT1 was not significantly altered, chronic Akt activation actually decreased plasma membrane GLUT4.	11	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	GLUT4	GLUT4	GLUT4	11	12	17	18
AKT2 was also shown to reduce sensitivity to the chemotherapeutic agent , cisplatin , by regulating XIAP , an inhibitor of execution of caspase 3 [ XREF_BIBR ] .	AKT2 was also shown to reduce sensitivity to the chemotherapeutic agent, cisplatin, by regulating XIAP, an inhibitor of execution of caspase 3 [XREF_BIBR].	0	19	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT2	AKT2	AKT2	XIAP	XIAP	XIAP	0	1	16	17
Expression of a constitutively active Akt2 prevented CDDP mediated down-regulation of Xiap and apoptosis in A2780s cells .	Expression of a constitutively active Akt2 prevented CDDP mediated down-regulation of Xiap and apoptosis in A2780s cells.	0	13	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt2	Expression of a constitutively active Akt2	akt2	Xiap	Xiap	xiap	5	6	11	12
MK2206 , a selective inhibitor of Akt , abolished the neuroprotective effects of MB , inhibited the phosphorylation of Akt and prevented the nuclear localization of MEF2D .	MK2206, a selective inhibitor of Akt, abolished the neuroprotective effects of MB, inhibited the phosphorylation of Akt and prevented the nuclear localization of MEF2D.	4	27	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt, abolished the neuroprotective effects of MB, inhibited the phosphorylation of Akt	akt	MEF2D	MEF2D	mef2d	6	7	26	27
p300 degradation is modulated by AKT activity .	p300 degradation is modulated by AKT activity.	0	6	modulated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	p300	p300	p300	5	6	0	1
Whereas AKT inactivation blocked PFKFB2 activation , suggesting that AKT activation is an important step in PFKFB2 activation .	Whereas AKT inactivation blocked PFKFB2 activation, suggesting that AKT activation is an important step in PFKFB2 activation.	1	5	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	PFKFB2	PFKFB2	PFKFB2	1	2	4	5
Interestingly , exogenous expression of a dominant negative AKT cDNA or of PED antisense in human breast cancer cells induced a significant down-regulation of PED and sensitized cells to chemotherapy induced cell death .	Interestingly, exogenous expression of a dominant negative AKT cDNA or of PED antisense in human breast cancer cells induced a significant down-regulation of PED and sensitized cells to chemotherapy induced cell death.	8	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	PED	PED	PED	8	9	24	25
Accordingly , both genetic and pharmacological simultaneous inhibition of these two isoforms result in reduced Akt mediated activation of PDE3B and enhanced cAMP accumulation within the hypothalamus and the intermediolateral nucleus , ultimately impinging on white adipose tissue lipolysis .	Accordingly, both genetic and pharmacological simultaneous inhibition of these two isoforms result in reduced Akt mediated activation of PDE3B and enhanced cAMP accumulation within the hypothalamus and the intermediolateral nucleus, ultimately impinging on white adipose tissue lipolysis.	15	20	mediated	Positive_early_activation	Positive_activation	Negative_activation	Akt	Akt	Akt	PDE3B	PDE3B	PDE3B	15	16	19	20
Blockade of the Akt and phosphoinositide 3-kinase ( PI3-kinase ) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce alpha-SMA , ezrin , paxillin , and moesin and to promote matrix contraction .	Blockade of the Akt and phosphoinositide 3-kinase (PI3-kinase) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce alpha-SMA, ezrin, paxillin, and moesin and to promote matrix contraction.	0	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	ezrin	ezrin	ezrin	3	4	24	25
These results confirm that kinase activity of Akt3 is required to inhibit mRNA cleavage activity of Ago2 .	These results confirm that kinase activity of Akt3 is required to inhibit mRNA cleavage activity of Ago2.	5	17	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt3	Akt3	Akt3	Ago2	Ago2	Ago2	7	8	16	17
ANGPT2 functions to antagonize the endothelial tyrosine kinase receptor TEK .	ANGPT2 functions to antagonize the endothelial tyrosine kinase receptor TEK.	0	10	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANGPT2	ANGPT2	ANGPT2	TEK	TEK	TEK	0	1	9	10
Angiopoietin-2 inactivates Tie2 to induce blood vessel instability , resulting in initiation of sprouting angiogenesis .	Angiopoietin-2 inactivates Tie2 to induce blood vessel instability, resulting in initiation of sprouting angiogenesis.	0	3	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angiopoietin-2	Angiopoietin-2	Angiopoietin-2	Tie2	Tie2	Tie2	0	1	2	3
Because Angpt-2 antagonizes Tie2 in the context of inflammation , a profound initial release of preformed Angpt-2 could initiate a feedback loop that sustains ( and perhaps amplifies ) the deleterious state of Tie2 signaling impairment .	Because Angpt-2 antagonizes Tie2 in the context of inflammation, a profound initial release of preformed Angpt-2 could initiate a feedback loop that sustains (and perhaps amplifies) the deleterious state of Tie2 signaling impairment.	13	35	initiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Angpt-2	Angpt-2	Angpt-2	Tie2	Tie2	Tie2	16	17	33	34
Binding of circulating Ang-1 to the Tie-2 receptor protects the vasculature from inflammation and leakage , whereas binding of Ang-2 antagonizes Tie-2 signaling and disrupts endothelial barrier function .	Binding of circulating Ang-1 to the Tie-2 receptor protects the vasculature from inflammation and leakage, whereas binding of Ang-2 antagonizes Tie-2 signaling and disrupts endothelial barrier function.	17	22	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	19	20	21	22
The rapid release of Ang-2 from endothelial cells upon activation of the endothelium by hypoxia , histamine , and thrombin would disrupt the protective , constitutive Ang-1 and Tie2 signaling by preventing Ang-1 from binding to the receptor XREF_BIBR , XREF_BIBR .	The rapid release of Ang-2 from endothelial cells upon activation of the endothelium by hypoxia, histamine, and thrombin would disrupt the protective, constitutive Ang-1 and Tie2 signaling by preventing Ang-1 from binding to the receptor XREF_BIBR, XREF_BIBR.	2	29	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	4	5	28	29
In contrast , Ang2 acts as a competitive antagonist of Ang1 and downregulates Tie2 signaling [ XREF_BIBR ] .	In contrast, Ang2 acts as a competitive antagonist of Ang1 and downregulates Tie2 signaling [XREF_BIBR].	3	14	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	3	4	13	14
Thus , protective Tie2 signaling in the ischemic pulmonary vasculature is probably inhibited by excess of locally released Ang-2 .	Thus, protective Tie2 signaling in the ischemic pulmonary vasculature is probably inhibited by excess of locally released Ang-2.	3	19	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	18	19	3	4
Ang2 acts as a TIE2 agonist in EPCs , which increases angiogenesis , but primarily antagonizes TIE2 in vascular endothelial cells , thereby reducing endothelial integrity , increasing vessel permeability , and inducing vessel destabilization and remodeling through , in part , the suppression of Ang1 mediated activity .	Ang2 acts as a TIE2 agonist in EPCs, which increases angiogenesis, but primarily antagonizes TIE2 in vascular endothelial cells, thereby reducing endothelial integrity, increasing vessel permeability, and inducing vessel destabilization and remodeling through, in part, the suppression of Ang1 mediated activity.	0	17	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	TIE2	TIE2	TIE2	0	1	16	17
Angiopoeitin-2 ( Ang-2 ) antagonizes Angiopeitin-1 ( Ang-1 ) -mediated Tie-2 signaling .	Angiopoeitin-2 (Ang-2) antagonizes Angiopeitin-1 (Ang-1) -mediated Tie-2 signaling.	0	11	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angiopoeitin-2	Angiopoeitin-2	Angiopoeitin-2	Tie-2	Tie-2	Tie-2	0	1	10	11
Ang-2 can disrupt Ang-1 and Tie2 signaling and destabilize EC homeostasis leading to an angiogenic response or vascular regression ( reviewed in Fagiani and Christofori 137 ) .	Ang-2 can disrupt Ang-1 and Tie2 signaling and destabilize EC homeostasis leading to an angiogenic response or vascular regression (reviewed in Fagiani and Christofori 137).	0	8	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	0	1	5	6
Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal , subretinal , and choroidal NV , with perturbation of Bruch ' s membrane also needed for the latter .	Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal, subretinal, and choroidal NV, with perturbation of Bruch 's membrane also needed for the latter.	3	12	suppression	Negative_activation_token_2_noun	Positive_activation	Negative_activation	angiopoietin 2	angiopoietin 2	angiopoietin 2	Tie2	Tie2	Tie2	9	11	7	8
Studies have shown that VEGFA inhibits ANGPT1-TIE-2 signalling via TIE-2 shedding , promoting , in concert with ANGPT2 mediated TIE-2 signalling inhibition , new vessel formation [ XREF_BIBR ] .	Studies have shown that VEGFA inhibits ANGPT1-TIE-2 signalling via TIE-2 shedding, promoting, in concert with ANGPT2 mediated TIE-2 signalling inhibition, new vessel formation [XREF_BIBR].	12	21	mediated	Positive_early_activation	Positive_activation	Negative_activation	ANGPT2	ANGPT2	ANGPT2	TIE-2	TIE-2	TIE-2	17	18	19	20
It has been believed that Ang-2 is thought to inactivate Tie2 and destabilize vessels by dissociating endothelial cells into endothelial cells and endothelial cells into mural cells [ XREF_BIBR ] .	It has been believed that Ang-2 is thought to inactivate Tie2 and destabilize vessels by dissociating endothelial cells into endothelial cells and endothelial cells into mural cells [XREF_BIBR].	5	12	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	5	6	10	11
Given that ANG1 activates the TIE2 receptor and ANG2 antagonizes TIE2 receptor activation XREF_BIBR , these data suggest that signaling through the TIE2 receptor is differentially required for embryonic and adult coronary vascular growth .	Given that ANG1 activates the TIE2 receptor and ANG2 antagonizes TIE2 receptor activation XREF_BIBR, these data suggest that signaling through the TIE2 receptor is differentially required for embryonic and adult coronary vascular growth.	6	13	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANG2	ANG2	ANG2	TIE2	TIE2	TIE2	8	9	10	11
Upon a variety of stimuli , Ang-2 is rapidly released by the activated endothelium from Weibel-Palade bodies XREF_BIBR , disrupts constitutive Ang-1 and Tie2 signalling by preventing Ang-1 from binding to Tie2 XREF_BIBR , XREF_BIBR , XREF_BIBR , and thereby promotes vascular permeability and leukocyte adhesion .	Upon a variety of stimuli, Ang-2 is rapidly released by the activated endothelium from Weibel-Palade bodies XREF_BIBR, disrupts constitutive Ang-1 and Tie2 signalling by preventing Ang-1 from binding to Tie2 XREF_BIBR, XREF_BIBR, XREF_BIBR, and thereby promotes vascular permeability and leukocyte adhesion.	6	40	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	6	7	23	24
Ang-2 has been reported to completely disrupt protective Tie-2 signaling in numerous studies9 , 10 , 11 .	Ang-2 has been reported to completely disrupt protective Tie-2 signaling in numerous studies9, 10, 11.	0	9	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	0	1	8	9
ANGPT2 is highly expressed by tumour endothelial cells , inhibits Tie2 activity and destabilises blood vessels , thereby facilitating VEGF dependent vessel growth .	ANGPT2 is highly expressed by tumour endothelial cells, inhibits Tie2 activity and destabilises blood vessels, thereby facilitating VEGF dependent vessel growth.	0	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANGPT2	ANGPT2 is highly expressed	angpt2	Tie2	Tie2	tie2	0	1	10	11
Ang1 signaling via Tie2 promotes vessel maturation and quiescence , whereas Ang2 blocks Ang1 and Tie2 signaling , and this leads to either angiogenesis or vessel regression and apoptosis , depending on the presence of VEGF or other angiogenic factors .	Ang1 signaling via Tie2 promotes vessel maturation and quiescence, whereas Ang2 blocks Ang1 and Tie2 signaling, and this leads to either angiogenesis or vessel regression and apoptosis, depending on the presence of VEGF or other angiogenic factors.	11	16	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	11	12	15	16
Inhibition of Tie-2 signaling by Angpt2 renders the endothelium more responsive to inflammatory stimuli [ XREF_BIBR ] , thereby activating the endothelium to facilitate TEM .	Inhibition of Tie-2 signaling by Angpt2 renders the endothelium more responsive to inflammatory stimuli [XREF_BIBR], thereby activating the endothelium to facilitate TEM.	2	6	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Angpt2	Angpt2	Angpt2	Tie-2	Tie-2	Tie-2	5	6	2	3
The antagonist Ang-2 is known to downregulate Tie2 signaling , thereby preparing vascular endothelial cells for enhanced responsiveness to factors that cause destabilization of the endothelial barrier XREF_BIBR .	The antagonist Ang-2 is known to downregulate Tie2 signaling, thereby preparing vascular endothelial cells for enhanced responsiveness to factors that cause destabilization of the endothelial barrier XREF_BIBR.	0	8	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	2	3	7	8
ANG-1 signalling through TIE-2 maintains vessel integrity through the recruitment of pericytes , while ANG-2 blocks ANG-1 and TIE-2 signalling , loosening the vascular structure and exposing the endothelium to inducers of angiogenesis such as VEGF [ XREF_BIBR ] .	ANG-1 signalling through TIE-2 maintains vessel integrity through the recruitment of pericytes, while ANG-2 blocks ANG-1 and TIE-2 signalling, loosening the vascular structure and exposing the endothelium to inducers of angiogenesis such as VEGF [XREF_BIBR].	14	19	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANG-2	ANG-2	ANG-2	TIE-2	TIE-2	TIE-2	14	15	18	19
ANG2 signaling is known to antagonize the effect of ANG1 mediated stimulation of TIE-2 under the condition of chronic inflammation leading to vessel destabilization and pericyte dropout by antagonizing the effect of ANG1 mediated stimulation of TIE-2 XREF_BIBR .	ANG2 signaling is known to antagonize the effect of ANG1 mediated stimulation of TIE-2 under the condition of chronic inflammation leading to vessel destabilization and pericyte dropout by antagonizing the effect of ANG1 mediated stimulation of TIE-2 XREF_BIBR.	0	14	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANG2	ANG2	ANG2	TIE-2	TIE-2	TIE-2	0	1	13	14
Together , these data indicate that ANG2 activation of Tie2 supports stable enlargement of normal nonleaky vessels , but reduction of Tie1 in inflammation leads to ANG2 antagonism of Tie2 and initiates a positive feedback loop wherein FOXO1 driven ANG2 expression promotes vascular remodeling and leakage .	Together, these data indicate that ANG2 activation of Tie2 supports stable enlargement of normal nonleaky vessels, but reduction of Tie1 in inflammation leads to ANG2 antagonism of Tie2 and initiates a positive feedback loop wherein FOXO1 driven ANG2 expression promotes vascular remodeling and leakage.	26	30	antagonism	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ANG2	ANG2	ANG2	Tie2	Tie2	Tie2	26	27	29	30
Stimulation of VEGF signaling and suppression of Tie-2 by Ang-2 are critical for developing retinal neovascularization and vascular leakage [ XREF_BIBR ] .	Stimulation of VEGF signaling and suppression of Tie-2 by Ang-2 are critical for developing retinal neovascularization and vascular leakage [XREF_BIBR].	3	10	suppression	Negative_activation_token_2_noun	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	9	10	7	8
The Tie2 antagonist Ang2 is a competitive antagonist of Ang1 produced by endothelial cells and is stored in Weibel-Palade bodies [ XREF_BIBR ] .	The Tie2 antagonist Ang2 is a competitive antagonist of Ang1 produced by endothelial cells and is stored in Weibel-Palade bodies [XREF_BIBR].	0	16	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	3	4	1	2
ANGPT1 , secreted from pericytes , activates TEK and TIE2 receptor to maintain endothelial quiescence or stabilization , whereas ANGPT2 , secreted from endothelial cells themselves by VEGF or hypoxia signaling , inhibits TEK to promote endothelial activation or sprouting .	ANGPT1, secreted from pericytes, activates TEK and TIE2 receptor to maintain endothelial quiescence or stabilization, whereas ANGPT2, secreted from endothelial cells themselves by VEGF or hypoxia signaling, inhibits TEK to promote endothelial activation or sprouting.	19	34	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANGPT2	ANGPT2	ANGPT2	TEK	TEK	TEK	19	20	33	34
Early experiments showed that Ang1 stabilizes newly formed vessels and reduces vascular permeability , with Ang2 blocking Ang1 activation of the Tie2 receptor .	Early experiments showed that Ang1 stabilizes newly formed vessels and reduces vascular permeability, with Ang2 blocking Ang1 activation of the Tie2 receptor.	5	22	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	15	16	21	22
In the presence of angiogenic stimulators , sprouting endothelial cells release ANG-2 , which antagonizes ANG-1 and TIE-2 signalling to enhance mural cell detachment , vascular perm eability and endothelial cell sprouting 47 .	In the presence of angiogenic stimulators, sprouting endothelial cells release ANG-2, which antagonizes ANG-1 and TIE-2 signalling to enhance mural cell detachment, vascular perm eability and endothelial cell sprouting 47.	10	18	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANG-2	ANG-2	ANG-2	TIE-2	TIE-2	TIE-2	11	12	17	18
Since Ang-2 blocks Tie2 signalling , this ultimately leads to vessel destabilization and regression [ XREF_BIBR ] .	Since Ang-2 blocks Tie2 signalling, this ultimately leads to vessel destabilization and regression [XREF_BIBR].	1	4	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	1	2	3	4
As previously described , Ang1 activated Tie2 and this was antagonized by Ang2 ( XREF_FIG ) .	As previously described, Ang1 activated Tie2 and this was antagonized by Ang2 (XREF_FIG).	6	14	antagonized	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	12	13	6	7
In the absence of VEGF , high concentrations of Ang-2 inhibit Tie-2 signaling as it displaces Ang-1 , the more active ligand , from the receptor [ XREF_BIBR , XREF_BIBR ] .	In the absence of VEGF, high concentrations of Ang-2 inhibit Tie-2 signaling as it displaces Ang-1, the more active ligand, from the receptor [XREF_BIBR, XREF_BIBR].	7	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	9	10	11	12
sTie2Fc inhibits Tie2 activation and Ang-2 can also inhibit Ang-1-mediated Tie2 activation .	sTie2Fc inhibits Tie2 activation and Ang-2 can also inhibit Ang-1-mediated Tie2 activation.	3	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	5	6	10	11
In contrast , angiopoietin-2 ( Ang-2 ) is an antagonist of Tie-2 that destabilizes existing vessels .	In contrast, angiopoietin-2 (Ang-2) is an antagonist of Tie-2 that destabilizes existing vessels.	3	12	is an antagonist	Negative_activation_copula_1	Positive_activation	Negative_activation	angiopoietin-2	angiopoietin-2	angiopoietin-2	Tie-2	Tie-2	Tie-2	3	4	11	12
While ANG2 competes with ANG1 to inhibit Tie2 , it can paradoxically also promote Tie2 phosphorylation ( p-Tie2 ) .	While ANG2 competes with ANG1 to inhibit Tie2, it can paradoxically also promote Tie2 phosphorylation (p-Tie2).	1	8	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANG2	ANG2	ANG2	Tie2	Tie2	Tie2	1	2	7	8
Ang-2 has been reported to completely disrupt protective Tie-2 signaling in numerous studies .	Ang-2 has been reported to completely disrupt protective Tie-2 signaling in numerous studies.	0	9	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	0	1	8	9
These results indicate that elevated Ang2 levels reduce junctional Tie2 localization and alter beta1-integrin activation and F-actin and VE-cadherin localization in the otherwise quiescent mouse aortic endothelium , recapitulating in vivo the effects of increased Ang2-beta1-integrin signalling observed in Tie2 silenced cultured endothelial cells .	These results indicate that elevated Ang2 levels reduce junctional Tie2 localization and alter beta1-integrin activation and F-actin and VE-cadherin localization in the otherwise quiescent mouse aortic endothelium, recapitulating in vivo the effects of increased Ang2-beta1-integrin signalling observed in Tie2 silenced cultured endothelial cells.	5	10	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2 levels	ang2	Tie2	Tie2	tie2	5	6	9	10
In sepsis , the endothelium releases high levels of pre-stored Angpt-2 - the natural antagonist of the Tie2 receptor - thereby inducing inflammation and vascular barrier breakdown actively contributing to multiple organ dysfunction and death XREF_BIBR XREF_BIBR .	In sepsis, the endothelium releases high levels of pre-stored Angpt-2 - the natural antagonist of the Tie2 receptor - thereby inducing inflammation and vascular barrier breakdown actively contributing to multiple organ dysfunction and death XREF_BIBR XREF_BIBR.	7	18	antagonist	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	Angpt-2	levels of pre-stored Angpt-2	angpt-2	Tie2	Tie2	tie2	10	11	17	18
Angiopoietin-2 ( Ang2 ) , as an antagonist for Ang1 , inhibits Ang1 promoted Tie2 signaling and decreases blood vessel maturation and stabilization .	Angiopoietin-2 (Ang2), as an antagonist for Ang1, inhibits Ang1 promoted Tie2 signaling and decreases blood vessel maturation and stabilization.	0	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	2	3	14	15
Inhibition of Tie2 signaling by Angpt2 interrupts survival and maintenance signals from surrounding cells and ECM , thereby making endothelial cells more responsive and more dependent upon soluble signals such as VEGF .	Inhibition of Tie2 signaling by Angpt2 interrupts survival and maintenance signals from surrounding cells and ECM, thereby making endothelial cells more responsive and more dependent upon soluble signals such as VEGF.	2	6	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Angpt2	Angpt2	Angpt2	Tie2	Tie2	Tie2	5	6	2	3
Ligation of Angpt-1 to Tie2 leads to its tyrosine phosphorylation , whereas Angpt-2 can antagonize Tie2 activation .	Ligation of Angpt-1 to Tie2 leads to its tyrosine phosphorylation, whereas Angpt-2 can antagonize Tie2 activation.	12	16	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angpt-2	Angpt-2	Angpt-2	Tie2	Tie2	Tie2	12	13	15	16
By blocking the stabilizing action of Ang-1 and Tie-2 signaling , Ang-2 initiates extensive angiogenesis , such as pericyte drop-off and extracellular matrix alteration XREF_BIBR , XREF_BIBR , which can facilitate microvessel sprouting .	By blocking the stabilizing action of Ang-1 and Tie-2 signaling, Ang-2 initiates extensive angiogenesis, such as pericyte drop-off and extracellular matrix alteration XREF_BIBR, XREF_BIBR, which can facilitate microvessel sprouting.	6	13	initiates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	11	12	8	9
XREF_BIBR Given that Ang-2 and Ang-1 are competing for the same endothelial bound receptor and that Ang-2 thereby inhibits Ang-1 and Tie-2 signaling related vessel stabilization , it is possible that high levels of Ang-2 serve as a surrogate marker for reduced Ang-1 and Tie-2 signaling XREF_BIBR , XREF_BIBR Several potential explanations can be invoked for the positive relations of Ang-2 to BP .	XREF_BIBR Given that Ang-2 and Ang-1 are competing for the same endothelial bound receptor and that Ang-2 thereby inhibits Ang-1 and Tie-2 signaling related vessel stabilization, it is possible that high levels of Ang-2 serve as a surrogate marker for reduced Ang-1 and Tie-2 signaling XREF_BIBR, XREF_BIBR Several potential explanations can be invoked for the positive relations of Ang-2 to BP.	16	25	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	16	17	21	22
In tumors , angiopoietin-2 ( Ang2 ) inhibits the activity of the receptor tyrosine kinase Tie2 and destabilizes blood vessels , thereby facilitating angiogenesis .	In tumors, angiopoietin-2 (Ang2) inhibits the activity of the receptor tyrosine kinase Tie2 and destabilizes blood vessels, thereby facilitating angiogenesis.	3	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	5	6	15	16
Ang1 affords maturation or stabilization of blood vessels through Tie2 , which can be blocked by Ang2 , while such inhibition by Ang2 results in the remodeling or initiation of vascular sprouts in the context of VEGF exposure [ XREF_BIBR ] .	Ang1 affords maturation or stabilization of blood vessels through Tie2, which can be blocked by Ang2, while such inhibition by Ang2 results in the remodeling or initiation of vascular sprouts in the context of VEGF exposure [XREF_BIBR].	1	17	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	16	17	9	10
Several drugs currently in pre-clinical development by Akebia Therapeutics specifically target ang2 mediated Tie-2 signaling inhibition , and have the potential to decrease pathogenic angiogenesis and permeability associated with DR/DME .	Several drugs currently in pre-clinical development by Akebia Therapeutics specifically target ang2 mediated Tie-2 signaling inhibition, and have the potential to decrease pathogenic angiogenesis and permeability associated with DR/DME.	5	15	mediated	Positive_early_activation	Positive_activation	Negative_activation	ang2	ang2	ang2	Tie-2	Tie-2	Tie-2	11	12	13	14
Importantly , Ang2 was still able to antagonize the elevated Ang1 activation of Tie2 that occurs on Tie1 ectodomain loss .	Importantly, Ang2 was still able to antagonize the elevated Ang1 activation of Tie2 that occurs on Tie1 ectodomain loss.	2	14	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	2	3	13	14
Ang-2 can inhibit the activation of Tie-2 by Ang-1 .	Ang-2 can inhibit the activation of Tie-2 by Ang-1.	0	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	0	1	6	7
Addition of Ang-2 blocks Tie-2 signaling , leading , in turn , to Rho-kinase activation and MLC-p , with the end result being EC contraction , gap formation , and disruption of barrier integrity .	Addition of Ang-2 blocks Tie-2 signaling, leading, in turn, to Rho-kinase activation and MLC-p, with the end result being EC contraction, gap formation, and disruption of barrier integrity.	0	5	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	2	3	4	5
In the presence of angiogenic stimulators , sprouting ECs release Ang-2 , which antagonizes Ang-1 and Tie-2 signaling to enhance mural cell detachment , vascular permeability and EC sprouting .	In the presence of angiogenic stimulators, sprouting ECs release Ang-2, which antagonizes Ang-1 and Tie-2 signaling to enhance mural cell detachment, vascular permeability and EC sprouting.	9	17	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	10	11	16	17
However , interestingly , Tie2 receptor activation was also attenuated by Angpt 2 antagonist treatment .	However, interestingly, Tie2 receptor activation was also attenuated by Angpt 2 antagonist treatment.	4	13	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Angpt 2	Angpt 2	Angpt 2	Tie2	Tie2	Tie2	11	13	4	5
Ang-2 , inducible in EC by VEGF , hypoxia , and inflammation [ XREF_BIBR - XREF_BIBR ] , antagonizes the Ang-1 and Tie2 pathway by competing with Ang-1 .	Ang-2, inducible in EC by VEGF, hypoxia, and inflammation [XREF_BIBR - XREF_BIBR], antagonizes the Ang-1 and Tie2 pathway by competing with Ang-1.	0	23	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	0	1	22	23
In addition to stimulation of VEGF signaling , the suppression of Tie-2 by Ang-2 is crucial for developing retinal neovascularization and vascular leakage [ XREF_BIBR ] .	In addition to stimulation of VEGF signaling, the suppression of Tie-2 by Ang-2 is crucial for developing retinal neovascularization and vascular leakage [XREF_BIBR].	9	14	suppression	Negative_activation_token_2_noun	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	13	14	11	12
Binding of circulating angiopoietin-1 ( Ang-1 ) to the Tie2 receptor protects the vasculature from inflammation and leakage , whereas binding of Ang-2 antagonizes Tie2 signaling and disrupts endothelial barrier function .	Binding of circulating angiopoietin-1 (Ang-1) to the Tie2 receptor protects the vasculature from inflammation and leakage, whereas binding of Ang-2 antagonizes Tie2 signaling and disrupts endothelial barrier function.	20	25	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	22	23	24	25
XREF_BIBR In our in vivo model , we found that Ang2 blocked Tie2 activation and that inhibiting Ang2 resulted in decreased ICAM-1 and VCAM-1 expression , most likely through the inhibition of the NF-kappaB pathway .	XREF_BIBR In our in vivo model, we found that Ang2 blocked Tie2 activation and that inhibiting Ang2 resulted in decreased ICAM-1 and VCAM-1 expression, most likely through the inhibition of the NF-kappaB pathway.	10	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	10	11	12	13
Angiopoietin 2 ( Ang-2 ) is an antagonist of Tie-2 that is expressed by endothelial cells at sites of angiogenesis .	Angiopoietin 2 (Ang-2) is an antagonist of Tie-2 that is expressed by endothelial cells at sites of angiogenesis.	0	10	is an antagonist	Negative_activation_copula_1	Positive_activation	Negative_activation	Angiopoietin 2	Angiopoietin 2	Angiopoietin 2	Tie-2	Tie-2	Tie-2	0	2	9	10
Based on proposed models of VEGF-A , ANGPT-1 and ANGPT-2 action in vascular development , the predominance of the endogenous Tie2 antagonist ANGPT-2 in the relative absence of VEGF-A would be expected to destabilize blood vessels .	Based on proposed models of VEGF-A, ANGPT-1 and ANGPT-2 action in vascular development, the predominance of the endogenous Tie2 antagonist ANGPT-2 in the relative absence of VEGF-A would be expected to destabilize blood vessels.	16	26	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	ANGPT-2	ANGPT-2	ANGPT-2	Tie2	Tie2	Tie2	22	23	20	21
Ang-2 inactivate Tie-2 , destabilizing the vasculature and increasing the response to VEGF .	Ang-2 inactivate Tie-2, destabilizing the vasculature and increasing the response to VEGF.	0	8	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	0	1	2	3
Both Ang1 and Ang2 attenuated TNF-alpha-induced Tie2 up-regulation .	Both Ang1 and Ang2 attenuated TNF-alpha-induced Tie2 up-regulation.	1	7	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	3	4	6	7
Angiopoietin-2 ( Ang-2 ) inhibits Tie-2 signaling by blocking the Tie-2 receptor leading to increased endothelial permeability [ XREF_BIBR ] .	Angiopoietin-2 (Ang-2) inhibits Tie-2 signaling by blocking the Tie-2 receptor leading to increased endothelial permeability [XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angiopoietin-2	Angiopoietin-2	Angiopoietin-2	Tie-2	Tie-2	Tie-2	0	1	5	6
In the presence of the Tie2 agonist Ang1 , Ang2 may act as an antagonist , blocking Tie2 signaling , although the actions of the angiopioetins are largely context dependent .	In the presence of the Tie2 agonist Ang1, Ang2 may act as an antagonist, blocking Tie2 signaling, although the actions of the angiopioetins are largely context dependent.	9	18	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	9	10	17	18
Ang2 competitively blocked activation of Tie-2 by Ang1 but Ang2 was equally as effective as Ang1 in activating Tie-2 phosphorylation in NIH 3T3 fibroblasts ectopically expressing Tie-2 [ XREF_BIBR ] .	Ang2 competitively blocked activation of Tie-2 by Ang1 but Ang2 was equally as effective as Ang1 in activating Tie-2 phosphorylation in NIH 3T3 fibroblasts ectopically expressing Tie-2 [XREF_BIBR].	0	6	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie-2	Tie-2	Tie-2	0	1	5	6
XREF_BIBR pointed out that increased glomerular expression of Ang-2 would tend to antagonize Ang-1-induced Tie-2 activation and destabilize capillaries and glomerular endothelia in podocin and Ang -2 transgene mice .	XREF_BIBR pointed out that increased glomerular expression of Ang-2 would tend to antagonize Ang-1-induced Tie-2 activation and destabilize capillaries and glomerular endothelia in podocin and Ang -2 transgene mice.	6	15	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	expression of Ang-2	ang-2	Tie-2	Tie-2	tie-2	8	9	14	15
In the presence of angiogenic stimuli , activated endothelial cells produce ANG2 that antagonizes ANG1 and TIE2 signaling enhancing mural cell detachment , vascular permeability , and endothelial cell sprouting .	In the presence of angiogenic stimuli, activated endothelial cells produce ANG2 that antagonizes ANG1 and TIE2 signaling enhancing mural cell detachment, vascular permeability, and endothelial cell sprouting.	10	17	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANG2	ANG2	ANG2	TIE2	TIE2	TIE2	11	12	16	17
In contrast , angiopoietin-2 ( Ang-2 ) is an antagonist of Tie-2 and destabilizes existing blood vessels [ XREF_BIBR , XREF_BIBR ] .	In contrast, angiopoietin-2 (Ang-2) is an antagonist of Tie-2 and destabilizes existing blood vessels [XREF_BIBR, XREF_BIBR].	3	13	is an antagonist	Negative_activation_copula_1	Positive_activation	Negative_activation	angiopoietin-2	angiopoietin-2	angiopoietin-2	Tie-2	Tie-2	Tie-2	3	4	11	12
Here we present an engineered synthetic Tie2 ligand that is not antagonised by Ang2 , easy to produce and more robust than Ang1 .	Here we present an engineered synthetic Tie2 ligand that is not antagonised by Ang2, easy to produce and more robust than Ang1.	6	14	antagonised	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	13	14	6	7
An excess of Ang-2 over Ang-1 - as herein observed on tissue and serum level - is known to induce vascular remodelling by blocking Tie2 signalling on EC [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	An excess of Ang-2 over Ang-1 - as herein observed on tissue and serum level - is known to induce vascular remodelling by blocking Tie2 signalling on EC [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	25	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	3	4	24	25
By blocking Tie-2 signaling , Ang-2 leads to a loosening of tight vascular structure XREF_BIBR ; XREF_BIBR ; XREF_BIBR .	By blocking Tie-2 signaling, Ang-2 leads to a loosening of tight vascular structure XREF_BIBR; XREF_BIBR; XREF_BIBR.	2	7	leads	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	5	6	2	3
Ang1 promotes Tie2 kinase activity and downstream intracellular signaling while Ang2 antagonizes Tie2 activation .	Ang1 promotes Tie2 kinase activity and downstream intracellular signaling while Ang2 antagonizes Tie2 activation.	10	13	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	10	11	12	13
However , the finding that Ang2 can still suppress Ang1 activation of Tie2 even when Tie1 ectodomain is cleaved , and therefore unable to restrict Ang1 access ( XREF_FIG ) , indicates Ang2 can act as a direct Ang1 antagonist without involvement of the Tie1 ectodomain .	However, the finding that Ang2 can still suppress Ang1 activation of Tie2 even when Tie1 ectodomain is cleaved, and therefore unable to restrict Ang1 access (XREF_FIG), indicates Ang2 can act as a direct Ang1 antagonist without involvement of the Tie1 ectodomain.	5	24	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	5	6	12	13
Each of these life threatening conditions also manifest alterations in Ang-2 : Ang-1 plasma concentrations favoring Ang-2 antagonism of Tie2 signaling .	Each of these life threatening conditions also manifest alterations in Ang-2 : Ang-1 plasma concentrations favoring Ang-2 antagonism of Tie2 signaling.	16	20	antagonism	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	16	17	19	20
Ang-2 is the naturally occurring antagonist to Ang-1 ; Ang-2 prevents Tie2 activation and results in vessel destabilisation ( Maisonpierre et al , 1997 ) .	Ang-2 is the naturally occurring antagonist to Ang-1; Ang-2 prevents Tie2 activation and results in vessel destabilisation (Maisonpierre et al, 1997).	9	14	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	9	10	11	12
Ang-2 interferes negatively with Ang-1 and Tie2 signaling , thereby antagonizing the Ang-1 and Tie2 axis .	Ang-2 interferes negatively with Ang-1 and Tie2 signaling, thereby antagonizing the Ang-1 and Tie2 axis.	0	15	antagonizing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	0	1	14	15
Ang2 , a naturally occurring antagonist of Ang1 , blocks the Tie2 receptor and induces vascular leak by disrupting AJs .	Ang2, a naturally occurring antagonist of Ang1, blocks the Tie2 receptor and induces vascular leak by disrupting AJs.	0	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	0	1	11	12
It is plausible that ANGPT2 antagonizes ANGPT1 in quiescent ECs to inhibit TIE2 activation while it synergizes ANGPT1 in TIE2 phosphorylation to promote angiogenesis .	It is plausible that ANGPT2 antagonizes ANGPT1 in quiescent ECs to inhibit TIE2 activation while it synergizes ANGPT1 in TIE2 phosphorylation to promote angiogenesis.	4	13	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ANGPT2	ANGPT2	ANGPT2	TIE2	TIE2	TIE2	4	5	12	13
In contrast , Ang2 , which is highly expressed by tumor endothelial cells , is thought to inhibit Tie2 activity and destabilize blood vessels , thereby facilitating VEGF dependent vessel growth .	In contrast, Ang2, which is highly expressed by tumor endothelial cells, is thought to inhibit Tie2 activity and destabilize blood vessels, thereby facilitating VEGF dependent vessel growth.	3	21	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang2	Ang2, which is highly expressed	ang2	Tie2	Tie2	tie2	3	4	18	19
Overexpression of Angpt-2 in the mouse endothelium attenuates physiological Tie2 signaling and thus increases vascular permeability , suggesting that Angpt-2 inhibits Tie2 signaling and counteract the Angpt-1 action [ XREF_BIBR ] .	Overexpression of Angpt-2 in the mouse endothelium attenuates physiological Tie2 signaling and thus increases vascular permeability, suggesting that Angpt-2 inhibits Tie2 signaling and counteract the Angpt-1 action [XREF_BIBR].	0	10	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angpt-2	Overexpression of Angpt-2	angpt-2	Tie2	Tie2	tie2	2	3	9	10
These data indicate that Ang2 mediated disruption of protective Ang1 and Tie2 signalling is operational in SLE .	These data indicate that Ang2 mediated disruption of protective Ang1 and Tie2 signalling is operational in SLE.	4	12	disruption	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	4	5	11	12
To elucidate the effects of the Ang2 blocking antibodies on this process , endothelial cells expressing Tie2 fluorescently tagged with GFP were treated with the Ang2 blocking or control antibodies .	To elucidate the effects of the Ang2 blocking antibodies on this process, endothelial cells expressing Tie2 fluorescently tagged with GFP were treated with the Ang2 blocking or control antibodies.	15	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Ang2	Ang2	Ang2	Tie2	Tie2	Tie2	25	26	16	17
The Tie2 antagonist angiopoietin-2 represents a promising target against sepsis associated multiple organ dysfunction .	The Tie2 antagonist angiopoietin-2 represents a promising target against sepsis associated multiple organ dysfunction.	0	4	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	angiopoietin-2	angiopoietin-2	angiopoietin-2	Tie2	Tie2	Tie2	3	4	1	2
In contrast , Ang-2 reversed the effects of Ang-1 and Tie2 signaling in the regulation of long-term HSCs .	In contrast, Ang-2 reversed the effects of Ang-1 and Tie2 signaling in the regulation of long-term HSCs.	3	11	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	3	4	10	11
ANG1 signaling is critical in the stabilization and maturation of vessels by recruiting mural cells , while ANG2 antagonizes the effect of ANG1 mediated stimulation of TIE-2 under the condition of chronic inflammation leading to vessel destabilization and pericyte dropout .	ANG1 signaling is critical in the stabilization and maturation of vessels by recruiting mural cells, while ANG2 antagonizes the effect of ANG1 mediated stimulation of TIE-2 under the condition of chronic inflammation leading to vessel destabilization and pericyte dropout.	17	27	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANG2	ANG2	ANG2	TIE-2	TIE-2	TIE-2	17	18	26	27
Both bind the tyrosine kinase with immunoglobulin like loop and epidermal growth factor homology domains ( Tie ) 2 receptor on endothelial cells , but angpt-1 is a Tie-2 agonist , whereas angpt-2 antagonizes Tie-2 signaling .	Both bind the tyrosine kinase with immunoglobulin like loop and epidermal growth factor homology domains (Tie) 2 receptor on endothelial cells, but angpt-1 is a Tie-2 agonist, whereas angpt-2 antagonizes Tie-2 signaling.	32	35	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	angpt-2	angpt-2	angpt-2	Tie-2	Tie-2	Tie-2	32	33	34	35
Ang-2 and Tie-1 downregulate Ang-1-induced Tie-2 signaling , and angiopoietin actions are further modified by vascular endothelial growth factor A and integrins .	Ang-2 and Tie-1 downregulate Ang-1-induced Tie-2 signaling, and angiopoietin actions are further modified by vascular endothelial growth factor A and integrins.	0	6	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie-2	Tie-2	Tie-2	0	1	5	6
In general , Ang-2 has been recognized as a naturally occurring antagonist to Ang-1 and prevents Tie2 activation [ XREF_BIBR , XREF_BIBR ] .	In general, Ang-2 has been recognized as a naturally occurring antagonist to Ang-1 and prevents Tie2 activation [XREF_BIBR, XREF_BIBR].	3	17	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ang-2	Ang-2	Ang-2	Tie2	Tie2	Tie2	3	4	16	17
In recent studies it was suggested that residue Tyr 166 in helix 7 is involved in the direct activation of LCAT , while oxidation of Met 148 in helix 6 was shown to impair the activation of LCAT by apo A-I .	In recent studies it was suggested that residue Tyr 166 in helix 7 is involved in the direct activation of LCAT, while oxidation of Met 148 in helix 6 was shown to impair the activation of LCAT by apo A-I.	35	41	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	apo A-I	apo A-I	apo A-I	LCAT	LCAT	LCAT	39	41	37	38
However , Shao and co-workers [ XREF_BIBR ] showed that apoA1 ceases to be a cofactor for LCAT , reducing the activity of LCAT to 20 % of normal activity in conditions of high levels of oxidative stress in vitro .	However, Shao and co-workers [XREF_BIBR] showed that apoA1 ceases to be a cofactor for LCAT, reducing the activity of LCAT to 20% of normal activity in conditions of high levels of oxidative stress in vitro.	10	26	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA1	apoA1	apoA1	LCAT	LCAT	LCAT	10	11	23	24
Since glycation of HDL significantly decreases its ability to inhibit oxidized LDL induced monocyte-endothelial cell interaction and infusion of reconstituted HDL obviously reduces atherosclerotic plaque volume and increases anti-inflammatory and cholesterol efflux properties of plasma HDL in patients with type 2 diabetes , we hypothesized that glycation of apoA-I might decrease LCAT activation and reverse cholesterol transport , leading to accelerated development of atherosclerotic lesions in diabetic patients .	Since glycation of HDL significantly decreases its ability to inhibit oxidized LDL induced monocyte-endothelial cell interaction and infusion of reconstituted HDL obviously reduces atherosclerotic plaque volume and increases anti-inflammatory and cholesterol efflux properties of plasma HDL in patients with type 2 diabetes, we hypothesized that glycation of apoA-I might decrease LCAT activation and reverse cholesterol transport, leading to accelerated development of atherosclerotic lesions in diabetic patients.	46	52	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	48	49	51	52
Further , ex vivo modification of apoAI to a comparable extent by the MPO pathway markedly inhibits cholesterol efflux and LCAT activity of the lipoprotein .	Further, ex vivo modification of apoAI to a comparable extent by the MPO pathway markedly inhibits cholesterol efflux and LCAT activity of the lipoprotein.	4	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoAI	apoAI	apoAI	LCAT	LCAT	LCAT	6	7	20	21
Removal of contaminating apo A-I , however , abolishes this LCAT activity which could be restored by addition of pure apo A-I .	Removal of contaminating apo A-I, however, abolishes this LCAT activity which could be restored by addition of pure apo A-I.	10	22	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	apo A-I	apo A-I	apo A-I	LCAT	LCAT	LCAT	20	22	10	11
In conclusion , although substitution of the Arg123-Tyr166 central or Ala190-Gln243 carboxyl-terminal pair of helices of apoA-I with the pair of helices of apoA-II yields chimeras with structure similar to that of native apoA-I , exchange of the central domain ( but not the carboxyl-terminal domain ) of apoA-I reduces the rate of LCAT activity that is independent of binding to rHDL .	In conclusion, although substitution of the Arg123-Tyr166 central or Ala190-Gln243 carboxyl-terminal pair of helices of apoA-I with the pair of helices of apoA-II yields chimeras with structure similar to that of native apoA-I, exchange of the central domain (but not the carboxyl-terminal domain) of apoA-I reduces the rate of LCAT activity that is independent of binding to rHDL.	39	54	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	48	49	53	54
Lipoprotein composition of apoAI , apoAIInonB , and apoCIIInonB in HDL particle and apoB : AII TRLs can contribute to decrease LCAT mass in Tx patients .	Lipoprotein composition of apoAI, apoAIInonB, and apoCIIInonB in HDL particle and apoB : AII TRLs can contribute to decrease LCAT mass in Tx patients.	1	22	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoAI	apoAI	apoAI	LCAT	LCAT	LCAT	3	4	21	22
The apoA-I M mouse serum had a higher FC/CE ratio compared to the WT apoA-I serum ( XREF_FIG ) because of the reduced LCAT activation by apoA-I M compared to WT apoA-I .	The apoA-I M mouse serum had a higher FC/CE ratio compared to the WT apoA-I serum (XREF_FIG) because of the reduced LCAT activation by apoA-I M compared to WT apoA-I.	23	27	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	26	27	23	24
Six heterozygous apoA-I missense mutations , namely Leu141Arg Pisa , Pro143Arg , Arg151Cys , Val156Arg , Arg160Leu Oslo , and Pro165Arg , have been associated with low HDL-C and decreased LCAT activity .	Six heterozygous apoA-I missense mutations, namely Leu141Arg Pisa, Pro143Arg, Arg151Cys, Val156Arg, Arg160Leu Oslo, and Pro165Arg, have been associated with low HDL-C and decreased LCAT activity.	2	31	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	2	3	30	31
ApoC and apoA-II were both found to inhibit the activation of LCAT by apoA-I .	ApoC and apoA-II were both found to inhibit the activation of LCAT by apoA-I.	7	14	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	13	14	11	12
These results support the concept that highly conserved negatively charged residues in apoA-I helix 6 interact directly and attenuate LCAT activation , independent of the overall particle charge .	These results support the concept that highly conserved negatively charged residues in apoA-I helix 6 interact directly and attenuate LCAT activation, independent of the overall particle charge.	12	20	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	12	13	19	20
44 Tyr166 undergoes chlorination and nitration in atheromas in vivo and this modification blocks the activation of LCAT by ApoA1 , which is an obligatory step in HDL particle maturation .	44 Tyr166 undergoes chlorination and nitration in atheromas in vivo and this modification blocks the activation of LCAT by ApoA1, which is an obligatory step in HDL particle maturation.	13	25	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	ApoA1	ApoA1	ApoA1	LCAT	LCAT	LCAT	19	20	17	18
Lipoprotein composition of apoAI , apoAIInonB , and apoCIIInonB in HDL particle and apoB : AII ( TRLs ) can contribute to decrease LCAT in Tx patients .	Lipoprotein composition of apoAI, apoAIInonB, and apoCIIInonB in HDL particle and apoB : AII (TRLs) can contribute to decrease LCAT in Tx patients.	1	26	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoAI	apoAI	apoAI	LCAT	LCAT	LCAT	3	4	23	24
5.1 Oxidation of a single methionine residue of apoA-I impairs LCAT activation .	5.1 Oxidation of a single methionine residue of apoA-I impairs LCAT activation.	6	11	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA-I	apoA-I	apoA-I	LCAT	LCAT	LCAT	8	9	10	11
In vitro investigation have exhibited that high levels of apoC-II have inhibited LPL activity rather than stimulated it [ XREF_BIBR ] .	In vitro investigation have exhibited that high levels of apoC-II have inhibited LPL activity rather than stimulated it [XREF_BIBR].	7	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoC-II	levels of apoC-II	apoc-ii	LPL	LPL	lpl	9	10	12	13
The reduction in absolute amounts of Apo C-II was also reflected in a reduction of the ratio Apo C-II and Apo C-III in very low density lipoproteins ( VLDL ) and in a reduction in the ability of the sera to activate skim milk lipoprotein lipase .	The reduction in absolute amounts of Apo C-II was also reflected in a reduction of the ratio Apo C-II and Apo C-III in very low density lipoproteins (VLDL) and in a reduction in the ability of the sera to activate skim milk lipoprotein lipase.	4	46	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Apo C-II	amounts of Apo C-II	apo c-ii	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	6	8	44	46
A high ratio of apoCII and apoCIII promotes LPL activity , whereas a low apoCII and apoCIII ratio inhibits LPL function .	A high ratio of apoCII and apoCIII promotes LPL activity, whereas a low apoCII and apoCIII ratio inhibits LPL function.	2	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoCII	apoCII	apoCII	LPL	LPL	LPL	4	5	8	9
Such liver derived LPL regulators include apoC3 and angiopietin like protein 3 ( ANGPTL3 ) , both of which inhibit LPL activity , and apoC2 , which is a potent activator of LPL .	Such liver derived LPL regulators include apoC3 and angiopietin like protein 3 (ANGPTL3), both of which inhibit LPL activity, and apoC2, which is a potent activator of LPL.	6	33	is a potent activator	Positive_activation_copula_1	Positive_activation	Positive_activation	apoC2	apoC2	apoC2	LPL	LPL	LPL	24	25	32	33
APOC2 deficiency is associated with marked elevation of plasma TG , VLDL and chylomicron levels and decreased LPL activity , LDL , IDL and HDL levels [ XREF_BIBR ] .	APOC2 deficiency is associated with marked elevation of plasma TG, VLDL and chylomicron levels and decreased LPL activity, LDL, IDL and HDL levels [XREF_BIBR].	0	26	decreased	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	APOC2	APOC2	apoc2	LPL	LPL activity, LDL, IDL and HDL levels	lpl	0	1	17	18
ApoC-I inhibits cholesterol ester transfer protein , apoC-II is a physiological activator of lipoprotein lipase , while apoC-III is its inhibitor and is also implicated in VLDL production .	ApoC-I inhibits cholesterol ester transfer protein, apoC-II is a physiological activator of lipoprotein lipase, while apoC-III is its inhibitor and is also implicated in VLDL production.	7	15	is a physiological activator	Positive_activation_copula_1	Positive_activation	Positive_activation	apoC-II	apoC-II	apoC-II	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	7	8	13	15
ApoC1 inhibits CETP ; ApoC2 activates lipoprotein lipase ; ApoC3 inhibits lipoprotein lipase [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	ApoC1 inhibits CETP; ApoC2 activates lipoprotein lipase; ApoC3 inhibits lipoprotein lipase [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ApoC2	ApoC2	ApoC2	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	6	8
However , both an excess and a lack of APO-CII inhibit LPL activity and thus result in hypertriglyceridemia .	However, both an excess and a lack of APO-CII inhibit LPL activity and thus result in hypertriglyceridemia.	7	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	APO-CII	APO-CII	APO-CII	LPL	LPL	LPL	9	10	11	12
For example , ApoC-II , a component of VLDL and chylomicrons , activates LPL , whereas ApoC-III inhibits LPL 33 .	For example, ApoC-II, a component of VLDL and chylomicrons, activates LPL, whereas ApoC-III inhibits LPL 33.	3	19	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ApoC-II	ApoC-II	ApoC-II	LPL	LPL	LPL	3	4	18	19
ApoCII prevented the inhibition by bis-ANS , and was also able to restore the activity of inhibited LPL in a competitive manner , but only with triacylglycerols with acyl chains longer than three carbons .	ApoCII prevented the inhibition by bis-ANS, and was also able to restore the activity of inhibited LPL in a competitive manner, but only with triacylglycerols with acyl chains longer than three carbons.	0	18	restore	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ApoCII	ApoCII	ApoCII	LPL	LPL	LPL	0	1	17	18
To determine the role of the apoptosome in PSAP induced apoptosis , we examined the effect of knockdown of Apaf-1 on PSAP induced caspase-9 activation .	To determine the role of the apoptosome in PSAP induced apoptosis, we examined the effect of knockdown of Apaf-1 on PSAP induced caspase-9 activation.	17	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	19	20	23	24
These results indicate that Apaf-1 overexpression lowers the apoptotic threshold by activating caspase-9 and caspase-3 .	These results indicate that Apaf-1 overexpression lowers the apoptotic threshold by activating caspase-9 and caspase-3.	4	14	lowers	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Apaf-1	Apaf-1 overexpression	apaf-1	caspase-9	caspase-9	caspase-9	4	5	12	13
Emodin increased Cytochome c , Apaf-1 but decreased Pro-caspase-9 in intrinsic mitochondrial pathway and increased Fas , FasL , FADD but decreased Pro-caspase-8 in extrinsic death receptor pathway in HeLa cells .	Emodin increased Cytochome c, Apaf-1 but decreased Pro-caspase-9 in intrinsic mitochondrial pathway and increased Fas, FasL, FADD but decreased Pro-caspase-8 in extrinsic death receptor pathway in HeLa cells.	5	14	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Apaf-1	Apaf-1	Apaf-1	Pro-caspase-9	Pro-caspase-9	Pro-caspase-9	5	6	8	9
Knockdown of Apaf-1 or the transcriptional regulatory proteins , E2F1 or p53 , by small interfering RNA ( siRNA ) duplexes inhibited the activation of caspase-9 and enhanced cell viability in AS-Core-expressing cells .	Knockdown of Apaf-1 or the transcriptional regulatory proteins, E2F1 or p53, by small interfering RNA (siRNA) duplexes inhibited the activation of caspase-9 and enhanced cell viability in AS-Core-expressing cells.	0	26	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	caspase-9	caspase-9	caspase-9	2	3	25	26
This protein inhibits the IAP , which are characterized by the blockage of caspase activity , while interacting with apoptotic protease activating factor 1 ( Apaf-1 ) enabling the catalytic activity of caspase-9 , the central protease mediator of the intrinsic pathway .	This protein inhibits the IAP, which are characterized by the blockage of caspase activity, while interacting with apoptotic protease activating factor 1 (Apaf-1) enabling the catalytic activity of caspase-9, the central protease mediator of the intrinsic pathway.	19	37	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	apoptotic protease activating factor 1	apoptotic protease activating factor 1	apoptotic protease activating factor 1	caspase-9	caspase-9	caspase-9	19	24	32	33
BCL-2 inhibits the mitochondrial apoptotic pathway inhibiting Cyc-C and Apaf-1 activation of Caspase 9 and inhibiting p53 induction of cell death .	BCL-2 inhibits the mitochondrial apoptotic pathway inhibiting Cyc-C and Apaf-1 activation of Caspase 9 and inhibiting p53 induction of cell death.	7	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Apaf-1	Apaf-1	Apaf-1	Caspase 9	Caspase 9	Caspase 9	9	10	12	14
Importantly , incubation of purified Apaf-1 and caspase 9 together with T. gondii extract dose-dependently prevented subsequent activation of caspase 9 triggered by cytochrome c and ATP .	Importantly, incubation of purified Apaf-1 and caspase 9 together with T. gondii extract dose-dependently prevented subsequent activation of caspase 9 triggered by cytochrome c and ATP.	2	21	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Apaf-1	Apaf-1	Apaf-1	caspase 9	caspase 9	caspase 9	5	6	19	21
After basal blood collection , control and ApoA5 ASO treated mice were injected intraperitoneally with poloxamer 407 ( 1 g/kg of body weight ; Sigma-Aldrich , USA ) to inhibit LPL activity .	After basal blood collection, control and ApoA5 ASO treated mice were injected intraperitoneally with poloxamer 407 (1 g/kg of body weight; Sigma-Aldrich, USA) to inhibit LPL activity.	5	31	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ApoA5	ApoA5	ApoA5	LPL	LPL	LPL	7	8	30	31
In the absence or presence apolipoprotein C-II , apoA-V marginally inhibited LPL activity .	In the absence or presence apolipoprotein C-II, apoA-V marginally inhibited LPL activity.	8	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA-V	apoA-V	apoA-V	LPL	LPL	LPL	8	9	11	12
APOA5 deficient mice have shown decreased LPL activity and the accumulation of larger very low density lipoprotein ( VLDL ) particles [ XREF_BIBR ] , which are precursors of small , dense LDL .	APOA5 deficient mice have shown decreased LPL activity and the accumulation of larger very low density lipoprotein (VLDL) particles [XREF_BIBR], which are precursors of small, dense LDL.	0	7	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	APOA5	APOA5	APOA5	LPL	LPL	LPL	0	1	6	7
APOA5 reduces plasma TG by inhibiting very low density lipoprotein-TG production and stimulating lipoprotein lipase mediated very low density lipoprotein-TG hydrolysis [ XREF_BIBR ] .	APOA5 reduces plasma TG by inhibiting very low density lipoprotein-TG production and stimulating lipoprotein lipase mediated very low density lipoprotein-TG hydrolysis [XREF_BIBR].	0	15	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	APOA5	APOA5	APOA5	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	13	15
By contrast , LPL activation and VLDL clearance were inhibited by the addition of apoA-V to rHDL .	By contrast, LPL activation and VLDL clearance were inhibited by the addition of apoA-V to rHDL.	3	15	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	apoA-V	apoA-V	apoA-V	LPL	LPL	LPL	14	15	3	4
in vivo studies have shown that apoA1 reduces free cholesterol accumulation in atherosclerotic lesions of ApoE deficient mice .	in vivo studies have shown that apoA1 reduces free cholesterol accumulation in atherosclerotic lesions of ApoE deficient mice.	6	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA1	apoA1	apoA1	ApoE	ApoE	ApoE	6	7	15	16
In this study , we tested whether a single high dose of recombinant apoA-I ( m ) could rapidly mobilize tissue cholesterol and reduce plaque lipid and macrophage content in apoE deficient mice .	In this study, we tested whether a single high dose of recombinant apoA-I (m) could rapidly mobilize tissue cholesterol and reduce plaque lipid and macrophage content in apoE deficient mice.	10	32	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	13	14	30	31
The PKC activator phorbol 12-myristate 13-acetate ( PMA ) stimulated apoE secretion , and both PMA induced and apoAI induced apoE secretion were inhibited by PKC inhibitors .	The PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated apoE secretion, and both PMA induced and apoAI induced apoE secretion were inhibited by PKC inhibitors.	18	21	induced	Positive_early_activation	Positive_activation	Negative_activation	apoAI	apoAI	apoAI	apoE	apoE	apoE	18	19	20	21
The major finding of the present study is that the apoA-I mimetic peptide D-4F prevented the acceleration of atherosclerosis in STZ induced diabetic apoE -/- mice .	The major finding of the present study is that the apoA-I mimetic peptide D-4F prevented the acceleration of atherosclerosis in STZ induced diabetic apoE -/- mice.	9	25	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoA-I	apoA-I	apoA-I	apoE	apoE	apoE	10	11	23	24
Lentiviral transduction of apoAI into HPCs reduces atherosclerosis in apoE (-/-) mice .	Lentiviral transduction of apoAI into HPCs reduces atherosclerosis in apoE (-/-) mice.	1	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	apoAI	apoAI	apoAI	apoE	apoE	apoE	3	4	9	10
Protein lysate extracted from cells after treatment with LY294002 or A563 exhibited differential migration of Vim on the isoelectric point axis compared to that of untreated cells , suggesting Vim post-translational modification ( most likely related to changes in phosphorylation state ) induced by AKT inhibition .	Protein lysate extracted from cells after treatment with LY294002 or A563 exhibited differential migration of Vim on the isoelectric point axis compared to that of untreated cells, suggesting Vim post-translational modification (most likely related to changes in phosphorylation state) induced by AKT inhibition.	29	45	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	Vim	Vim	Vim	44	45	29	30
AKT inhibition induces vimentin proteolysis .	AKT inhibition induces vimentin proteolysis.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AKT	AKT	AKT	vimentin	vimentin	vimentin	0	1	3	4
Moreover , Akt inhibition is known to induce caspase dependent vimentin proteolysis [ XREF_BIBR ] .	Moreover, Akt inhibition is known to induce caspase dependent vimentin proteolysis [XREF_BIBR].	2	11	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	vimentin	vimentin	vimentin	2	3	10	11
Another compelling finding in this study is that p17 functions as an inhibitor of the CDK2 and cyclin A2 complex , further enhancing inhibition of Akt phosphorylation at S473 , which reduces the interaction of Beclin 1 with 14-3-3 as well as Beclin 1 and vimentin .	Another compelling finding in this study is that p17 functions as an inhibitor of the CDK2 and cyclin A2 complex, further enhancing inhibition of Akt phosphorylation at S473, which reduces the interaction of Beclin 1 with 14-3-3 as well as Beclin 1 and vimentin.	25	46	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt phosphorylation at S473	akt	vimentin	vimentin	vimentin	25	26	45	46
Angpt 1 is known to activate the Tie2 receptor ; therefore , it was clear that Tie2 activation was attenuated by the Angpt 1 antagonist .	Angpt 1 is known to activate the Tie2 receptor; therefore, it was clear that Tie2 activation was attenuated by the Angpt 1 antagonist.	16	24	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Angpt 1	Angpt 1	Angpt 1	Tie2	Tie2	Tie2	22	24	16	17
Administration of Angpt 1 antagonist also attenuated , while the Angpt 2 antagonist tended to attenuate , whole kidney Tie2 receptor activation induced by uninephrectomy ( XREF_FIG ) .	Administration of Angpt 1 antagonist also attenuated, while the Angpt 2 antagonist tended to attenuate, whole kidney Tie2 receptor activation induced by uninephrectomy (XREF_FIG).	2	21	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Angpt 1	Angpt 1	Angpt 1	Tie2	Tie2	Tie2	2	4	19	20
XREF_BIBR The ability of the aptamer to selectively block ANGPT2 mediated TIE2 activation , but not ANGPT1 mediated TIE2 activation , was first confirmed in vitro using a TIE2 receptor phosphorylation assay ( XREF_FIG ) .	XREF_BIBR The ability of the aptamer to selectively block ANGPT2 mediated TIE2 activation, but not ANGPT1 mediated TIE2 activation, was first confirmed in vitro using a TIE2 receptor phosphorylation assay (XREF_FIG).	8	19	mediated	Positive_early_activation	Positive_activation	Negative_activation	ANGPT1	ANGPT1	ANGPT1	TIE2	TIE2	TIE2	16	17	18	19
A ten-fold decrease in cellular Tie2 caused the concentration of sTie2 required for 50 % inhibition of Angpt1 induced Tie2 tetramerization to fall to 57nM , a molar ratio of still more than 300:1 sTie2 : Angpt1 .	A ten-fold decrease in cellular Tie2 caused the concentration of sTie2 required for 50% inhibition of Angpt1 induced Tie2 tetramerization to fall to 57nM, a molar ratio of still more than 300:1 sTie2 : Angpt1.	15	20	induced	Positive_early_activation	Positive_activation	Negative_activation	Angpt1	Angpt1	Angpt1	Tie2	Tie2	Tie2	17	18	19	20
To compare the tissue radioactivity concentrations of LDLR -/- ApoB 100/100 mice to those of C57BL/6N and blocked LDLR -/- ApoB 100/100 mice in the in vivo PET and ex vivo biodistribution analyses , ANOVA with Dunnett ' s post hoc correction was performed .	To compare the tissue radioactivity concentrations of LDLR -/- ApoB 100/100 mice to those of C57BL/6N and blocked LDLR -/- ApoB 100/100 mice in the in vivo PET and ex vivo biodistribution analyses, ANOVA with Dunnett 's post hoc correction was performed.	5	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ApoB	ApoB	ApoB	LDLR	LDLR	LDLR	9	10	18	19
Related to LV dilatation , reduced thickness of both posterior and anterior LV wall was evident in both LDLR -/- ApoB 100/100 and IGF-II and LDLR -/- ApoB 100/100 mice .	Related to LV dilatation, reduced thickness of both posterior and anterior LV wall was evident in both LDLR -/- ApoB 100/100 and IGF-II and LDLR -/- ApoB 100/100 mice.	5	29	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ApoB	ApoB	ApoB	LDLR	LDLR	LDLR	27	28	18	19
Akt was shown to maintain telomerase activity by phosphorylation of its TERT subunit , and inactivating Akt reduced telomerase activity , leading to accelerated endothelial cell senescence .	Akt was shown to maintain telomerase activity by phosphorylation of its TERT subunit, and inactivating Akt reduced telomerase activity, leading to accelerated endothelial cell senescence.	15	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	16	17	18	19
Inactivation of Akt activity by a dominant negative mutant or wortmannin treatment attenuated nuclear localization of hTERT .	Inactivation of Akt activity by a dominant negative mutant or wortmannin treatment attenuated nuclear localization of hTERT.	2	17	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	hTERT	hTERT	hTERT	2	3	16	17
Instead , the defect was associated with decreased phosphorylation of the kinase Akt , that phosphorylates human telomerase reverse transcriptase to induce telomerase activity .	Instead, the defect was associated with decreased phosphorylation of the kinase Akt, that phosphorylates human telomerase reverse transcriptase to induce telomerase activity.	8	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Akt	Akt, that phosphorylates human telomerase reverse transcriptase	akt	telomerase	telomerase	telomerase	12	13	22	23
The authors also showed that Akt submitted to dephosphorylation at Ser473 by gambogic acid ( GA , a natural antitumor compound ) caused a decrease in TERT phosphorylation through Akt and subsequently decreased telomerase activity .	The authors also showed that Akt submitted to dephosphorylation at Ser473 by gambogic acid (GA, a natural antitumor compound) caused a decrease in TERT phosphorylation through Akt and subsequently decreased telomerase activity.	5	34	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	telomerase	telomerase	telomerase	5	6	33	34
To evaluate relevant targets of ALK activated Stat3 , we investigated the regulation of the anti-apoptotic protein Bcl-x ( L ) and its role in cell survival in NPM-ALK positive cells .	To evaluate relevant targets of ALK activated Stat3, we investigated the regulation of the anti-apoptotic protein Bcl-x (L) and its role in cell survival in NPM-ALK positive cells.	3	8	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ALK	ALK	ALK	Stat3	Stat3	Stat3	5	6	7	8
STAT3 activity was significantly induced by lone ALK inhibition in HSC3 cells and to a lower extent in Cal27 cells .	STAT3 activity was significantly induced by lone ALK inhibition in HSC3 cells and to a lower extent in Cal27 cells.	0	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	ALK	ALK	ALK	STAT3	STAT3	STAT3	7	8	0	1
A massive deregulation of key oncogenic molecules , such as TGFbeta1 , MYC , PI3K and AKT , pro metastatic and EMT SNAIL and Twist , NOTCH , WNT and beta-Catenin and MET , was observed in pHCC , suggesting that activation of prognostically adverse signaling pathways is a late event during hepatocarcinogenesis .	A massive deregulation of key oncogenic molecules, such as TGFbeta1, MYC, PI3K and AKT, pro metastatic and EMT SNAIL and Twist, NOTCH, WNT and beta-Catenin and MET, was observed in pHCC, suggesting that activation of prognostically adverse signaling pathways is a late event during hepatocarcinogenesis.	2	35	deregulation	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	AKT	AKT	AKT	Twist	Twist	Twist	16	17	24	25
In the present study , inhibition of Akt activity induced downregulation of EMT related Twist in OSCC cells .	In the present study, inhibition of Akt activity induced downregulation of EMT related Twist in OSCC cells.	7	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	Twist	Twist	Twist	7	8	14	15
MIS significantly suppressed growth of MISRII expressing MOVCAR cell line both in vitro and in vivo .	MIS significantly suppressed growth of MISRII expressing MOVCAR cell line both in vitro and in vivo.	0	6	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MIS	MIS	MIS	MISRII	MISRII	MISRII	0	1	5	6
In the present study , we show for the first time that MIS inhibits invasion in vitro and spontaneous migration to lung or posterior CAM in vivo of aggressive and invasive cancer cell lines which express MISRII and that this inhibition can occur at doses below those required to cause growth inhibition .	In the present study, we show for the first time that MIS inhibits invasion in vitro and spontaneous migration to lung or posterior CAM in vivo of aggressive and invasive cancer cell lines which express MISRII and that this inhibition can occur at doses below those required to cause growth inhibition.	12	37	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MIS	MIS	MIS	MISRII	MISRII	MISRII	12	13	36	37
For example , human angiopoietin-4 ( ANGPT4 ) , an important angiogenesis growth factor , has been shown to activate TEK ( tyrosine protein kinase receptor ) , while the mouse sequence-ortholog ( Angpt4 ) has been shown to inhibit TEK XREF_BIBR .	For example, human angiopoietin-4 (ANGPT4), an important angiogenesis growth factor, has been shown to activate TEK (tyrosine protein kinase receptor), while the mouse sequence-ortholog (Angpt4) has been shown to inhibit TEK XREF_BIBR.	4	23	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Angpt4	ANGPT4	ANGPT4	TEK	TEK	TEK	6	7	20	21
Direct targeting of YB-1 may not prove to be a promising approach when compared to the indirect targeting , as blocking of kinases PI3K , Akt , PDK-1 and RSK would cause blockage of YB-1 that may cause severely adverse side effects due to their vital role in cellular signalling pathways , making this therapy less feasible .	Direct targeting of YB-1 may not prove to be a promising approach when compared to the indirect targeting, as blocking of kinases PI3K, Akt, PDK-1 and RSK would cause blockage of YB-1 that may cause severely adverse side effects due to their vital role in cellular signalling pathways, making this therapy less feasible.	25	35	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Akt	Akt	Akt	YB-1	YB-1	YB-1	25	26	34	35
Likewise , down-regulation of AMBRA1 decreases the capacity of BECN1 to associate with PIK3C3 and reduces autophagy induction .	Likewise, down-regulation of AMBRA1 decreases the capacity of BECN1 to associate with PIK3C3 and reduces autophagy induction.	2	10	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AMBRA1	AMBRA1	AMBRA1	BECN1	BECN1	BECN1	4	5	9	10
Another group , however , showed that AR S213 phosphorylation by PIM-1S repressed AR function .	Another group, however, showed that AR S213 phosphorylation by PIM-1S repressed AR function.	7	14	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR S213 phosphorylation	ar	AR	AR	ar	7	8	13	14
Produced water effluents contain a complex mixture of substances which are known to bind to the estrogen receptor ( ER ) and antagonize the androgen receptor ( AR ) .	Produced water effluents contain a complex mixture of substances which are known to bind to the estrogen receptor (ER) and antagonize the androgen receptor (AR).	8	28	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	27	28	24	26
Targeted disruption of the p160 coactivator interface of androgen receptor ( AR ) selectively inhibits AR activity in both androgen dependent and castration resistant AR expressing prostate cancer cells .	Targeted disruption of the p160 coactivator interface of androgen receptor (AR) selectively inhibits AR activity in both androgen dependent and castration resistant AR expressing prostate cancer cells.	0	26	Targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR expressing	ar	androgen receptor	androgen receptor	androgen receptor	24	25	8	10
Interestingly , Ack1 or Src knockdown or dasatinib did not inhibit EGF induced AR Tyr 267 phosphorylation or EGF stimulated AR activity , suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr 267 .	Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF induced AR Tyr 267 phosphorylation or EGF stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr 267.	2	21	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	AR	Ack1 or Src knockdown or dasatinib did not inhibit EGF induced AR	ar	AR	AR	ar	13	14	20	21
To further verify the mechanism of HIF-2alpha-AR regulation , we checked the AR mRNA level when treated with sorafenib or under hypoxia condition and found AR mRNA levels were significantly decreased under sorafenib treatment or hypoxia condition ( XREF_FIG ) , suggesting AR might be transcriptional regulated by HIF-2alpha .	To further verify the mechanism of HIF-2alpha-AR regulation, we checked the AR mRNA level when treated with sorafenib or under hypoxia condition and found AR mRNA levels were significantly decreased under sorafenib treatment or hypoxia condition (XREF_FIG), suggesting AR might be transcriptional regulated by HIF-2alpha.	25	43	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR mRNA levels	ar	AR	AR	ar	25	26	42	43
Previous work has indeed demonstrated that Nutlin-3 treatment reduces AR protein levels and produces cell cycle arrest and apoptosis in prostate cancer cells expressing active AR and wild-type p53 [ XREF_BIBR , XREF_BIBR ] .	Previous work has indeed demonstrated that Nutlin-3 treatment reduces AR protein levels and produces cell cycle arrest and apoptosis in prostate cancer cells expressing active AR and wild-type p53 [XREF_BIBR, XREF_BIBR].	6	26	produces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Nutlin-3 treatment reduces AR protein levels	ar	AR	AR	ar	9	10	25	26
However , ectopic expression of wildtype AR in MDA-MB-231 ER negative cells restored the growth inhibitory effects of steroidal androgens and selective androgen receptor modulators ( SARMs ) , which could be partially reversed by AR antagonists [ XREF_BIBR ] .	However, ectopic expression of wildtype AR in MDA-MB-231 ER negative cells restored the growth inhibitory effects of steroidal androgens and selective androgen receptor modulators (SARMs), which could be partially reversed by AR antagonists [XREF_BIBR].	22	36	reversed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	35	36	22	24
It is important to point out that despite that this dose was expected to achieve a blood concentration of BBR 2 orders of magnitude lower than the doses used in the cell culture experiments , our in vitro findings that BBR reduced AR protein and the expression of AR regulated genes were confirmed by the animal experiment .	It is important to point out that despite that this dose was expected to achieve a blood concentration of BBR 2 orders of magnitude lower than the doses used in the cell culture experiments, our in vitro findings that BBR reduced AR protein and the expression of AR regulated genes were confirmed by the animal experiment.	41	49	reduced	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	AR	expression of AR	ar	AR	AR	ar	48	49	42	43
The findings presented in the current study expand upon our previous work describing the association of phosphorylated serine 213 in prostate cancer tumours and demonstrate that phosphorylation of AR can positively and negatively regulate AR actions .	The findings presented in the current study expand upon our previous work describing the association of phosphorylated serine 213 in prostate cancer tumours and demonstrate that phosphorylation of AR can positively and negatively regulate AR actions.	26	35	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	phosphorylation of AR	ar	AR	AR	ar	28	29	34	35
Additionally , AR overexpression resulted in acquired sunitinib resistance , and the AR antagonist enzalutamide induced AR degradation and attenuated AR downstream activity in sunitinib resistant cells , also indicated by decreased secretion of human kallikrein 2 ( KLK2 ) .	Additionally, AR overexpression resulted in acquired sunitinib resistance, and the AR antagonist enzalutamide induced AR degradation and attenuated AR downstream activity in sunitinib resistant cells, also indicated by decreased secretion of human kallikrein 2 (KLK2).	12	17	antagonist	Negative_activation_token_1_noun	Positive_activation	Positive_activation	AR	enzalutamide induced AR	ar	AR	AR	ar	16	17	12	13
The data suggest that SUMOylation of AR primarily at Lys 386 reduces the transcriptional activity of AR .	The data suggest that SUMOylation of AR primarily at Lys 386 reduces the transcriptional activity of AR.	4	17	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	SUMOylation of AR primarily at Lys 386	ar	AR	AR	ar	6	7	16	17
Conversely , depletion of USP22 dramatically down-regulates AR protein levels and abrogates basal and DHT stimulated AR activity in both ADT sensitive and CRPC cells .	Conversely, depletion of USP22 dramatically down-regulates AR protein levels and abrogates basal and DHT stimulated AR activity in both ADT sensitive and CRPC cells.	4	17	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	USP22 dramatically down-regulates AR protein levels	ar	AR	AR	ar	7	8	16	17
Previous data from our group showed that androgen receptor ( AR ) inhibits tumorigenic properties of the AR negative prostate cancer cell line , PC-3 XREF_BIBR .	Previous data from our group showed that androgen receptor (AR) inhibits tumorigenic properties of the AR negative prostate cancer cell line, PC-3 XREF_BIBR.	7	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	7	9	17	18
AR antagonist bicalutamide inhibited androgen induced AR reporter activity but did not inhibit heregulin- or EGF induced AR reporter activity ( XREF_SUPPLEMENTARY ) .	AR antagonist bicalutamide inhibited androgen induced AR reporter activity but did not inhibit heregulin- or EGF induced AR reporter activity (XREF_SUPPLEMENTARY).	0	19	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	AR	bicalutamide inhibited androgen induced AR reporter activity but did not inhibit heregulin- or EGF induced AR	ar	AR	AR	ar	17	18	0	1
While most CRPC still maintain AR mediated signaling activity , AR independent pathways are also involved in resistance to ADT , decreasing androgen receptor signaling inhibitors treatment effectiveness [ XREF_BIBR - XREF_BIBR ] .	While most CRPC still maintain AR mediated signaling activity, AR independent pathways are also involved in resistance to ADT, decreasing androgen receptor signaling inhibitors treatment effectiveness [XREF_BIBR - XREF_BIBR].	10	27	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	10	11	22	24
Over the years , pharmacological interventions that disrupt either androgen biosynthesis or the androgen receptor ( AR ) have been developed to treat PCa .	Over the years, pharmacological interventions that disrupt either androgen biosynthesis or the androgen receptor (AR) have been developed to treat PCa.	5	17	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	16	17	13	15
Based on our findings that deguelin inhibited mTORC1 signaling , decreased AR levels , and prevented androgen induced nuclear accumulation of AR , we hypothesized that the selectivity of deguelin emerged from combined inhibition of AR and mTOR .	Based on our findings that deguelin inhibited mTORC1 signaling, decreased AR levels, and prevented androgen induced nuclear accumulation of AR, we hypothesized that the selectivity of deguelin emerged from combined inhibition of AR and mTOR.	5	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	deguelin inhibited mTORC1 signaling, decreased AR levels	ar	AR	AR	ar	11	12	21	22
Our studies have shown that genetic ablation of inhibitor of differentiation 4 ( Id4 ) , a dominant negative helix loop helix protein , in mice results in prostatic intraepithelial neoplasia lesions and decreased Nkx3.1 expression without the loss of androgen receptor ( Ar ) expression .	Our studies have shown that genetic ablation of inhibitor of differentiation 4 (Id4), a dominant negative helix loop helix protein, in mice results in prostatic intraepithelial neoplasia lesions and decreased Nkx3.1 expression without the loss of androgen receptor (Ar) expression.	38	46	loss	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	androgen receptor	androgen receptor (Ar) expression	androgen receptor	androgen receptor	androgen receptor	androgen receptor	40	42	40	42
Since the loss of BMI1 decreased AR protein levels and inhibited AR signaling without downregulation of AR transcript levels , and our mass spectrometry analysis 9 indicated an interaction between BMI1 and AR , we hypothesized that BMI1 regulates the AR protein and its functions through a posttranslational modification .	Since the loss of BMI1 decreased AR protein levels and inhibited AR signaling without downregulation of AR transcript levels, and our mass spectrometry analysis 9 indicated an interaction between BMI1 and AR, we hypothesized that BMI1 regulates the AR protein and its functions through a posttranslational modification.	4	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	BMI1 decreased AR protein levels	ar	AR	AR	ar	6	7	11	12
Again , ciglitazone and rosiglitazone decreased DHT- induced AR transcriptional activation in the LNCaP cells , but did not decrease AR activation stimulated by DHT in the C4-2 cells .	Again, ciglitazone and rosiglitazone decreased DHT- induced AR transcriptional activation in the LNCaP cells, but did not decrease AR activation stimulated by DHT in the C4-2 cells.	2	21	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	ciglitazone and rosiglitazone decreased DHT- induced AR	ar	AR	AR	ar	8	9	20	21
qPCR assays also showed that miR-31 suppressed AR signaling , which was abrogated by overexpression of AR ( XREF_FIG ) .	qPCR assays also showed that miR-31 suppressed AR signaling, which was abrogated by overexpression of AR (XREF_FIG).	7	18	abrogated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	AR	overexpression of AR	ar	AR	AR	ar	16	17	7	8
In conclusion , the data presented here show that IGF-1 and Akt signaling promotes AR phosphorylation , reduces AR aggregation by stimulating protein clearance , and ameliorates disease manifestations in SBMA mice .	In conclusion, the data presented here show that IGF-1 and Akt signaling promotes AR phosphorylation, reduces AR aggregation by stimulating protein clearance, and ameliorates disease manifestations in SBMA mice.	9	19	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	IGF-1 and Akt signaling promotes AR phosphorylation	ar	AR	AR	ar	14	15	18	19
On the other hand , phosphorylation of AR at Ser 650 by JNK1 or p38 MAP kinase was demonstrated to inhibit AR activity .	On the other hand, phosphorylation of AR at Ser 650 by JNK1 or p38 MAP kinase was demonstrated to inhibit AR activity.	5	22	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	phosphorylation of AR at Ser 650	ar	AR	AR	ar	7	8	21	22
Ubiquitination of AR by RNF6 does not degrade AR , but increases its transcriptional activity .	Ubiquitination of AR by RNF6 does not degrade AR, but increases its transcriptional activity.	0	9	degrade	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	Ubiquitination of AR	ar	AR	AR	ar	2	3	8	9
Coexpression of AR and SRY caused marked repression of AR transcriptional activity on a series of androgen responsive reporter genes .	Coexpression of AR and SRY caused marked repression of AR transcriptional activity on a series of androgen responsive reporter genes.	0	11	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	Coexpression of AR	ar	AR	AR	ar	2	3	9	10
The androgen receptor ( AR ) surface directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer ( PC ) cells .	The androgen receptor (AR) surface directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC) cells.	1	12	directed	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	1	3	11	12
Testosterone induced expression of human kallikrein-3 mRNA and activation of androgen receptor ( AR ) were effectively inhibited by WKRG .	Testosterone induced expression of human kallikrein-3 mRNA and activation of androgen receptor (AR) were effectively inhibited by WKRG.	10	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	13	14	10	12
In particular , we showed that glycogen synthase kinase-3 beta phosphorylates the androgen receptor , thereby inhibiting androgen receptor driven transcription .	In particular, we showed that glycogen synthase kinase-3 beta phosphorylates the androgen receptor, thereby inhibiting androgen receptor driven transcription.	6	19	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	androgen receptor	glycogen synthase kinase-3 beta phosphorylates the androgen receptor	androgen receptor	androgen receptor	androgen receptor	androgen receptor	12	14	17	19
Intriguingly , each isoform regulates AR but yields opposing effects on receptor function ; cyclin D3/cdk11 p58 phosphorylates the AR N-terminus at Ser 308 , suppresses AR activity , and dampens prostate cell proliferation , whereas cdk11 p110 activates AR function and lacks the ability to phosphorylate AR .	Intriguingly, each isoform regulates AR but yields opposing effects on receptor function; cyclin D3/cdk11 p58 phosphorylates the AR N-terminus at Ser 308, suppresses AR activity, and dampens prostate cell proliferation, whereas cdk11 p110 activates AR function and lacks the ability to phosphorylate AR.	14	27	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	cyclin D3/cdk11 p58 phosphorylates the AR N-terminus at Ser 308	ar	AR	AR	ar	19	20	26	27
Concerning molecular targets and mechanisms of action , we demonstrated in vitro that SSA decreased AR level and suppressed AR dependent transactivation in prostate cancer cell culture models .	Concerning molecular targets and mechanisms of action, we demonstrated in vitro that SSA decreased AR level and suppressed AR dependent transactivation in prostate cancer cell culture models.	13	21	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	SSA decreased AR level	ar	AR	AR	ar	15	16	19	20
Here , we report that expression of a dominant negative AR associated protein 55 ( dARA55 ) coregulator , inhibits AR transcriptional activity and reduces the agonist activity of antiandrogens .	Here, we report that expression of a dominant negative AR associated protein 55 (dARA55) coregulator, inhibits AR transcriptional activity and reduces the agonist activity of antiandrogens.	5	22	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	expression of a dominant negative AR	ar	AR	AR	ar	10	11	20	21
Here the authors observed that only AR phosphorylation at serine 213 could inhibit AR transactivation thus inhibiting AR targets genes such as p21 , which modulates androgen/AR mediated apoptosis .	Here the authors observed that only AR phosphorylation at serine 213 could inhibit AR transactivation thus inhibiting AR targets genes such as p21, which modulates androgen/AR mediated apoptosis.	6	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR phosphorylation at serine 213	ar	AR	AR	ar	6	7	13	14
In vitro study has shown that inhibition of HSP27 phosphorylation or knockdown using the antisense drug OGX-427 , shifted the association of AR with HSP90 to murine double minute 2 , increased proteasome mediated AR degradation , decreased AR transcriptional activity and increased PCa LNCaP cell apoptotic rates .	In vitro study has shown that inhibition of HSP27 phosphorylation or knockdown using the antisense drug OGX-427, shifted the association of AR with HSP90 to murine double minute 2, increased proteasome mediated AR degradation, decreased AR transcriptional activity and increased PCa LNCaP cell apoptotic rates.	8	40	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	HSP27 phosphorylation or knockdown using the antisense drug OGX-427, shifted the association of AR with HSP90 to murine double minute 2, increased proteasome mediated AR	ar	AR	AR	ar	34	35	38	39
To confirm the target specificity , we used gene specific siRNAs for both CK2alpha and CK2alpha ' subunits , and the results suggested that both CK2 catalytic subunits are involved in androgen stimulated AR nuclear translocation and AR mediated gene expression in prostate cancer cells .	To confirm the target specificity, we used gene specific siRNAs for both CK2alpha and CK2alpha ' subunits, and the results suggested that both CK2 catalytic subunits are involved in androgen stimulated AR nuclear translocation and AR mediated gene expression in prostate cancer cells.	32	41	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR mediated gene expression	ar	AR	AR	ar	37	38	33	34
The ubiquitin/26S proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating NF-kappaB , and promotes AR activity by participating in the assembly of an AR transcription complex .	The ubiquitin/26S proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating NF-kappaB, and promotes AR activity by participating in the assembly of an AR transcription complex.	2	30	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression	ar	AR	AR	ar	21	22	29	30
Mechanisms contributing to this reactivation include increased intratumoral androgen accumulation and synthesis , AR overexpression , AR mutations ( in AR antagonist treated patients ) , and activation of kinase pathways that enhance AR activity .	Mechanisms contributing to this reactivation include increased intratumoral androgen accumulation and synthesis, AR overexpression, AR mutations (in AR antagonist treated patients), and activation of kinase pathways that enhance AR activity.	13	22	antagonist	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	AR	AR overexpression	ar	AR	AR	ar	13	14	20	21
Therapies that inhibit androgen receptor ( AR ) are needed for treatment of castration resistant prostate cancer ( CRPC ) .	Therapies that inhibit androgen receptor (AR) are needed for treatment of castration resistant prostate cancer (CRPC).	0	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	6	7	3	5
Tunicamycin ( TM ) , an agent that elicits ER stress by blocking N linked glycosylation , also stimulated AR protein expression and promoted aggregation of wild-type AR ( XREF_FIG ) .	Tunicamycin (TM), an agent that elicits ER stress by blocking N linked glycosylation, also stimulated AR protein expression and promoted aggregation of wild-type AR (XREF_FIG).	0	29	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	Tunicamycin (TM), an agent that elicits ER stress by blocking N linked glycosylation, also stimulated AR protein expression	ar	AR	AR	ar	19	20	27	28
In vivo experiments showed that silencing AR expression significantly suppressed AR positive bladder tumour growth with decreased cell proliferation .	In vivo experiments showed that silencing AR expression significantly suppressed AR positive bladder tumour growth with decreased cell proliferation.	6	11	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR expression	ar	AR	AR	ar	6	7	10	11
Moreover , the decrease of endogenous AR expression was only observed in LNCaP overexpressing AR-V7 but not in the presence of DHT activated AR-WT .	Moreover, the decrease of endogenous AR expression was only observed in LNCaP overexpressing AR-V7 but not in the presence of DHT activated AR-WT.	6	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR expression	ar	AR-WT	AR-WT	ar-wt	6	7	23	24
The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data that PI3K pathway signaling feedback inhibits the androgen receptor ( AR ) .	The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data that PI3K pathway signaling feedback inhibits the androgen receptor (AR).	14	26	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	25	26	22	24
MCF7 cells and the newly derived BCK4 cell line express both AR and ER and the new androgen receptor signaling inhibitor enzalutamide prevents ligand mediated stabilization of AR protein in MCF7 cells .	MCF7 cells and the newly derived BCK4 cell line express both AR and ER and the new androgen receptor signaling inhibitor enzalutamide prevents ligand mediated stabilization of AR protein in MCF7 cells.	17	28	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	17	19	27	28
In other studies , heparin binding EGF ( HB-EGF ) was found to decrease AR protein expression through activation of mTOR and decreased AR mRNA translation .	In other studies, heparin binding EGF (HB-EGF) was found to decrease AR protein expression through activation of mTOR and decreased AR mRNA translation.	6	25	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	EGF (HB-EGF) was found to decrease AR protein expression	ar	AR	AR	ar	14	15	23	24
Therefore , knocking down Skp2 will have impact on AR protein accumulation between an increase of AR caused by reduced ubiquitin mediated AR degradation and a decrease of AR contributed by Akt inactivation ( XREF_FIG ) .	Therefore, knocking down Skp2 will have impact on AR protein accumulation between an increase of AR caused by reduced ubiquitin mediated AR degradation and a decrease of AR contributed by Akt inactivation (XREF_FIG).	14	23	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	AR	ubiquitin mediated AR	ar	AR	AR	ar	22	23	16	17
Proteolysis targeting chimeric molecules ( Protacs ) target proteins for destruction by exploiting the ubiquitin dependent proteolytic system of eukaryotic cells.We designed two Protacs that contain the peptide ' degron ' from hypoxia inducible factor-1alpha , which binds to the Von -Hippel-Lindau ( VHL ) E3 ubiquitin ligase complex , linked to either dihydroxytestosterone that targets the androgen receptor ( AR ; Protac-A ) , or linked to estradiol ( E2 ) that targets the estrogen receptor-alpha ( ERalpha ; Protac-B ) .	Proteolysis targeting chimeric molecules (Protacs) target proteins for destruction by exploiting the ubiquitin dependent proteolytic system of eukaryotic cells.We designed two Protacs that contain the peptide ' degron ' from hypoxia inducible factor-1alpha, which binds to the Von -Hippel-Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone that targets the androgen receptor (AR; Protac-A), or linked to estradiol (E2) that targets the estrogen receptor-alpha (ERalpha; Protac-B).	53	62	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	60	61	57	59
The N-terminal 54 amino acid fragment of AR expressed in isolation reduced AR activity by 34 % .	The N-terminal 54 amino acid fragment of AR expressed in isolation reduced AR activity by 34%.	5	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR expressed	ar	AR	AR	ar	7	8	12	13
In contrast , expression of AR activated genes PSA , hK2 and NKX3.1 was largely downregulated and expression of the AR repressed gene MAS-PIN was upregulated by further knockdown of the majority of AR variants ( XREF_FIG , lanes 3 and 5 ) , supporting an important role of AR variants in regulation of these AR target genes in 22Rv1 cells .	In contrast, expression of AR activated genes PSA, hK2 and NKX3.1 was largely downregulated and expression of the AR repressed gene MAS-PIN was upregulated by further knockdown of the majority of AR variants (XREF_FIG, lanes 3 and 5), supporting an important role of AR variants in regulation of these AR target genes in 22Rv1 cells.	3	50	supporting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	expression of AR	ar	AR	AR	ar	5	6	49	50
Phosphorylation of the AR by Akt represses the AR activity through a ligand dependent manner , thus preventing androgen from activating the AR .	Phosphorylation of the AR by Akt represses the AR activity through a ligand dependent manner, thus preventing androgen from activating the AR.	0	9	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	Phosphorylation of the AR	ar	AR	AR	ar	3	4	8	9
We also found that in contrast to hormone dependent cells , HRG increased AR protein levels in control C81 cells , but slightly reduced AR protein in EBP1 transfectants .	We also found that in contrast to hormone dependent cells, HRG increased AR protein levels in control C81 cells, but slightly reduced AR protein in EBP1 transfectants.	11	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	HRG increased AR protein levels	ar	AR	AR	ar	13	14	24	25
Crucial findings of this study include the identification of ERG induced AR aggregation may have attenuated AR function .	Crucial findings of this study include the identification of ERG induced AR aggregation may have attenuated AR function.	9	17	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	ERG induced AR	ar	AR	AR	ar	11	12	16	17
We show that PTHrP induced transactivation of EGFR , Src and consequent AR tyrosine phosphorylation sequesters a subpopulation of AR protein from chaperone and CHIP complexes that normally regulate the proteasomal dependent degradation of the protein ( XREF_FIG ) .	We show that PTHrP induced transactivation of EGFR, Src and consequent AR tyrosine phosphorylation sequesters a subpopulation of AR protein from chaperone and CHIP complexes that normally regulate the proteasomal dependent degradation of the protein (XREF_FIG).	12	20	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR tyrosine phosphorylation	ar	AR	AR	ar	12	13	19	20
Silencing Ezh2 also increased AR expression , augmented AR activity , increased expression of the luminal lineage marker Krt8 , and decreased expression of neuroendocrine lineage markers ( XREF_FIG ) .	Silencing Ezh2 also increased AR expression, augmented AR activity, increased expression of the luminal lineage marker Krt8, and decreased expression of neuroendocrine lineage markers (XREF_FIG).	1	9	augmented	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	Ezh2 also increased AR expression	ar	AR	AR	ar	4	5	8	9
The authors claim that this finding is in accord with an emerging concept that reduced androgens in prostate tissues may , over time , lead to de-repression of AR expression , which , in turn , deregulates AR function and downstream de-repression of the AR target genes normally suppressed by androgens .	The authors claim that this finding is in accord with an emerging concept that reduced androgens in prostate tissues may, over time, lead to de-repression of AR expression, which, in turn, deregulates AR function and downstream de-repression of the AR target genes normally suppressed by androgens.	28	38	deregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR expression	ar	AR	AR	ar	28	29	37	38
Taken together , these data suggest that MKK4 and JNK and MKK6 and p38 directly phosphorylate the AR on S650 and negatively regulate AR transcription by facilitating AR nuclear export .	Taken together, these data suggest that MKK4 and JNK and MKK6 and p38 directly phosphorylate the AR on S650 and negatively regulate AR transcription by facilitating AR nuclear export.	7	25	negatively regulate	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	AR	MKK4 and JNK and MKK6 and p38 directly phosphorylate the AR on S650	ar	AR	AR transcription	ar	17	18	23	24
In contrast to the binding ability to Ubc9 , the sumoylation of AR via the association of SUMO-1 and PIAS1 is able to repress AR dependent transcription .	In contrast to the binding ability to Ubc9, the sumoylation of AR via the association of SUMO-1 and PIAS1 is able to repress AR dependent transcription.	10	26	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	sumoylation of AR	ar	AR	AR	ar	12	13	24	25
ICT was found to inhibit transcription of key AR regulated genes , such as KLK3 [ prostate specific antigen ( PSA ) ] and ARvs regulated genes , such as UBE2C and induce apoptosis in AR positive prostate cancer ( PC ) cells .	ICT was found to inhibit transcription of key AR regulated genes, such as KLK3 [prostate specific antigen (PSA)] and ARvs regulated genes, such as UBE2C and induce apoptosis in AR positive prostate cancer (PC) cells.	0	38	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	ICT was found to inhibit transcription of key AR	ar	AR	AR	ar	8	9	35	36
Particularly , in prostate cancer , the deacetylation of AR by SIRT1 represses androgen induced AR transcription and contributes to AR induced tumorigenesis [ XREF_BIBR ] .	Particularly, in prostate cancer, the deacetylation of AR by SIRT1 represses androgen induced AR transcription and contributes to AR induced tumorigenesis [XREF_BIBR].	7	17	represses	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	AR	deacetylation of AR by SIRT1	ar	AR	AR transcription	ar	9	10	15	16
AR SUMOylation is a dynamic process and is reversed by SENP1 , which promotes AR dependent transcription in PCa cells .	AR SUMOylation is a dynamic process and is reversed by SENP1, which promotes AR dependent transcription in PCa cells.	0	17	reversed	Negative_regulation_syntax_2_verb	Positive_activation	Negative_regulation	AR	SENP1, which promotes AR dependent transcription	ar	AR	AR SUMOylation	ar	14	15	0	1
PP1 inhibition enhanced proteasome mediated AR degradation , while PP1alpha overexpression increased AR expression and markedly enhanced AR transcriptional activity .	PP1 inhibition enhanced proteasome mediated AR degradation, while PP1alpha overexpression increased AR expression and markedly enhanced AR transcriptional activity.	0	19	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	PP1 inhibition enhanced proteasome mediated AR degradation, while PP1alpha overexpression increased AR expression	ar	AR	AR	ar	12	13	17	18
We concluded that a post-transcriptional impairment of AR protein expression is responsible for the inability of DHT to induce a transcriptional active form of the AR in vivo and therefore confirmed the clinical diagnosis of complete androgen insensitivity at the molecular level .	We concluded that a post-transcriptional impairment of AR protein expression is responsible for the inability of DHT to induce a transcriptional active form of the AR in vivo and therefore confirmed the clinical diagnosis of complete androgen insensitivity at the molecular level.	7	27	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR protein expression	ar	AR	AR	ar	7	8	25	26
Additionally , based on our analyses we can not make any conclusions as to why there is a loss of AR in some CHGA +/SYP+ metastases and not others .	Additionally, based on our analyses we can not make any conclusions as to why there is a loss of AR in some CHGA +/SYP+ metastases and not others.	16	28	is a loss	Negative_activation_copula_1	Positive_activation	Negative_activation	AR	loss of AR	ar	AR	AR	ar	20	21	20	21
VHL knockdown inhibits AR ubiquitination and decreases transcriptional activation of the AR .	VHL knockdown inhibits AR ubiquitination and decreases transcriptional activation of the AR.	0	12	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	VHL knockdown inhibits AR ubiquitination	ar	AR	AR	ar	3	4	11	12
Conversely , the glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta mediated phosphorylation of the androgen receptor , thereby enabling androgen receptor driven transcription to occur .	Conversely, the glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta mediated phosphorylation of the androgen receptor, thereby enabling androgen receptor driven transcription to occur.	3	27	enabling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	androgen receptor	glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta mediated phosphorylation of the androgen receptor	androgen receptor	androgen receptor	androgen receptor	androgen receptor	20	22	25	27
XREF_BIBR , XREF_BIBR Discovering the benefits of using androgen deprivation therapy and AR antagonists in bladder cancer has confirmed the essential role of AR in bladder cancer , 17 and downregulation of AR expression could inhibit the growth of bladder tumor .	XREF_BIBR, XREF_BIBR Discovering the benefits of using androgen deprivation therapy and AR antagonists in bladder cancer has confirmed the essential role of AR in bladder cancer, 17 and downregulation of AR expression could inhibit the growth of bladder tumor.	21	36	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR expression	ar	AR	AR	ar	32	33	23	24
Mutation of AR K845 abolishes RNF6 induced activation of AR mediated luciferase reporter activity , and attenuates the recruitment of AR to selective AR target genes .	Mutation of AR K845 abolishes RNF6 induced activation of AR mediated luciferase reporter activity, and attenuates the recruitment of AR to selective AR target genes.	2	13	abolishes	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	AR	AR	ar	AR	RNF6 induced activation of AR mediated luciferase reporter	ar	2	3	9	10
The expression of AR shRNA adenovirus 3 significantly reduced the activities of endogenous AR on PSA promoter and reporter in both LNCaP and LAPC4 cells .	The expression of AR shRNA adenovirus 3 significantly reduced the activities of endogenous AR on PSA promoter and reporter in both LNCaP and LAPC4 cells.	1	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	expression of AR	ar	AR	AR	ar	3	4	13	14
AR phosphorylation on S650 by stress kinases inhibits AR transcriptional activity by promoting its nuclear export .	AR phosphorylation on S650 by stress kinases inhibits AR transcriptional activity by promoting its nuclear export.	0	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR phosphorylation on S650	ar	AR	AR	ar	0	1	8	9
A similar study also demonstrated that high levels of AR inhibited the production of MUC1 and AR negative prostatic cancer cells expressed high level of MUC1 XREF_BIBR .	A similar study also demonstrated that high levels of AR inhibited the production of MUC1 and AR negative prostatic cancer cells expressed high level of MUC1 XREF_BIBR.	7	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	levels of AR	ar	AR	AR	ar	9	10	16	17
Through this competitive mechanism , HOTAIR expression inhibits AR ubiquitination , prevents AR protein degradation , and , thus , increases AR protein stability .	Through this competitive mechanism, HOTAIR expression inhibits AR ubiquitination, prevents AR protein degradation, and, thus, increases AR protein stability.	5	23	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	HOTAIR expression inhibits AR ubiquitination	ar	AR	AR	ar	8	9	21	22
Overexpression of AR in MDA-MB436 breast cancer cells decreased L1CAM expression at the protein and mRNA level and CHIP-analysis revealed binding of AR to the L1CAM promoter region .	Overexpression of AR in MDA-MB436 breast cancer cells decreased L1CAM expression at the protein and mRNA level and CHIP-analysis revealed binding of AR to the L1CAM promoter region.	0	23	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	Overexpression of AR	ar	AR	AR	ar	2	3	22	23
Enzalutamide , an androgen receptor antagonist and potent inhibitor of AR signaling , has been approved for the treatment of metastatic castration resistant prostate cancer .	Enzalutamide, an androgen receptor antagonist and potent inhibitor of AR signaling, has been approved for the treatment of metastatic castration resistant prostate cancer.	3	11	antagonist	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	3	5	10	11
In SBMA , chaperone enhanced ubiquitination of the AR increases AR degradation and ameliorates disease ( further discussed below ) [ XREF_BIBR ] .	In SBMA, chaperone enhanced ubiquitination of the AR increases AR degradation and ameliorates disease (further discussed below) [XREF_BIBR].	5	11	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	ubiquitination of the AR	ar	AR	AR	ar	8	9	10	11
Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR positive , but not AR negative , prostate cancer cells .	Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR positive, but not AR negative, prostate cancer cells.	6	23	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	PRMT5 by a specific inhibitor reduces the expression of AR	ar	AR	AR	ar	15	16	22	23
Inhibition of the PI3K pathway increases AR protein levels and partly restores AR signaling [ XREF_BIBR ] .	Inhibition of the PI3K pathway increases AR protein levels and partly restores AR signaling [XREF_BIBR].	3	13	restores	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	PI3K pathway increases AR protein levels	ar	AR	AR	ar	6	7	12	13
Mutation of the lysine residues involved in acetylation reduces ligand induced phosphorylation , while the point mutation of phosphorylation sites in the AR reduces HDAC mediated regulation of the AR [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Mutation of the lysine residues involved in acetylation reduces ligand induced phosphorylation, while the point mutation of phosphorylation sites in the AR reduces HDAC mediated regulation of the AR [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	18	43	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	phosphorylation sites in the AR	ar	AR	AR	ar	22	23	29	30
Similarly , inhibitors of histone deacetylase activity increase AR levels , promote corepressor/AR interaction on DNA , and augment AR activity and chromatin remodelling of integrated reporters in a receptor- and DHT dependent manner .	Similarly, inhibitors of histone deacetylase activity increase AR levels, promote corepressor/AR interaction on DNA, and augment AR activity and chromatin remodelling of integrated reporters in a receptor- and DHT dependent manner.	8	20	augment	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR levels	ar	AR	AR	ar	8	9	19	20
Furthermore , we observed that BR-DIM treatment suppressed the expression of AR , EZH2 and Lin28 , caused AR nuclear exclusion , and induced re-expression of let-7 and miR-34a in LNCaP and CWR22Rv1 cells [ XREF_BIBR , XREF_BIBR ] .	Furthermore, we observed that BR-DIM treatment suppressed the expression of AR, EZH2 and Lin28, caused AR nuclear exclusion, and induced re-expression of let-7 and miR-34a in LNCaP and CWR22Rv1 cells [XREF_BIBR, XREF_BIBR].	5	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	BR-DIM treatment suppressed the expression of AR	ar	AR	AR	ar	11	12	18	19
Androgen receptor ( AR ) antagonist bicalutamide was used to block AR .	Androgen receptor (AR) antagonist bicalutamide was used to block AR.	0	12	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Androgen receptor	Androgen receptor	Androgen receptor	AR	AR	AR	0	2	11	12
The phosphorylation of AR on Tyr534 reduced the interaction of AR with CHIP .	The phosphorylation of AR on Tyr534 reduced the interaction of AR with CHIP.	1	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	phosphorylation of AR on Tyr534	ar	AR	AR	ar	3	4	10	11
We therefore examined the role of AR Ser81 phosphorylation in the regulation of p300 and PTEN deficiency induced AR protein degradation .	We therefore examined the role of AR Ser81 phosphorylation in the regulation of p300 and PTEN deficiency induced AR protein degradation.	6	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR Ser81 phosphorylation	ar	AR	AR	ar	6	7	18	19
Interestingly , Baena et al ., demonstrated that ERG and ETV1 regulates androgen receptor ( AR ) target genes inversely , ERG negatively regulates the AR transcriptional program whereas ETV1 enhances AR signaling and activation of the AR transcriptional program 30 .	Interestingly, Baena et al., demonstrated that ERG and ETV1 regulates androgen receptor (AR) target genes inversely, ERG negatively regulates the AR transcriptional program whereas ETV1 enhances AR signaling and activation of the AR transcriptional program 30.	12	27	negatively regulates	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	12	14	25	26
However , the scopoletin treatment prevented AR expression in the lens epithelial cells and inhibited the extension of AR beneath the epithelial region ( XREF_FIG ) .	However, the scopoletin treatment prevented AR expression in the lens epithelial cells and inhibited the extension of AR beneath the epithelial region (XREF_FIG).	3	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	scopoletin treatment prevented AR expression	ar	AR	AR	ar	6	7	18	19
To examine whether Sp1 is required for flavokawain B mediated AR down-regulation , C4-2B cells were transiently transfected with Sp1 and then treated with flavokawain B. XREF_FIG shows that overexpression of Sp1 increased AR protein levels and attenuated the flavokawain B induced AR down-regulation .	To examine whether Sp1 is required for flavokawain B mediated AR down-regulation, C4-2B cells were transiently transfected with Sp1 and then treated with flavokawain B. XREF_FIG shows that overexpression of Sp1 increased AR protein levels and attenuated the flavokawain B induced AR down-regulation.	29	43	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	overexpression of Sp1 increased AR protein levels	ar	AR	AR	ar	33	34	42	43
The ectopic expression of a peptide mimic to the sequence on BAF57 that interacts with AR resulted in inhibited AR binding to chromatin , reduced AR stimulated transcription , and inhibited AR dependent prostate cancer cell proliferation .	The ectopic expression of a peptide mimic to the sequence on BAF57 that interacts with AR resulted in inhibited AR binding to chromatin, reduced AR stimulated transcription, and inhibited AR dependent prostate cancer cell proliferation.	25	32	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR stimulated transcription	ar	AR	AR	ar	25	26	31	32
AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy ' s Disease as a consequence of reduced ligand binding .	AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy 's Disease as a consequence of reduced ligand binding.	0	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR phosphorylation	ar	AR	AR	ar	0	1	9	10
In diabetic rats , AR expression was increased , and inhibiting AR ameliorated renal function [ XREF_BIBR ] .	In diabetic rats, AR expression was increased, and inhibiting AR ameliorated renal function [XREF_BIBR].	4	12	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR expression	ar	AR	AR	ar	4	5	11	12
3 Treatment typically includes the androgen receptor ( AR ) antagonist enzalutamide ( Xtandi ( R ) ) XREF_BIBR , XREF_BIBR that directly antagonizes the AR or abiraterone acetate ( Zytiga ( R ) ) , a molecule that blocks the synthesis of androgens .	3 Treatment typically includes the androgen receptor (AR) antagonist enzalutamide (Xtandi (R)) XREF_BIBR, XREF_BIBR that directly antagonizes the AR or abiraterone acetate (Zytiga (R)), a molecule that blocks the synthesis of androgens.	5	28	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	5	7	25	26
Co-transfection of PIM-1 kinase isoforms and the AR as well as the S213A mutant into 293T cells revealed that AR phosphorylation on S213 by PIM-1S , but not PIM-1L , decreased the AR half-life , and the phospho-mimetic T850D mutant was resistant to this S213 dependent PIM-1S-induced deregulation .	Co-transfection of PIM-1 kinase isoforms and the AR as well as the S213A mutant into 293T cells revealed that AR phosphorylation on S213 by PIM-1S, but not PIM-1L, decreased the AR half-life, and the phospho-mimetic T850D mutant was resistant to this S213 dependent PIM-1S-induced deregulation.	19	33	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR phosphorylation on S213	ar	AR	AR	ar	19	20	32	33
CNPY2 inhibited the MYLIP mediated ubiquitination of AR and suppressed AR protein degradation .	CNPY2 inhibited the MYLIP mediated ubiquitination of AR and suppressed AR protein degradation.	0	12	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AR	CNPY2 inhibited the MYLIP mediated ubiquitination of AR	ar	AR	AR	ar	7	8	10	11
Silencing of AMPKalpha resulted in an increased activation of AR by R1881 in both LNCaP and C4-2 cells and an increased androgen induced expression of the AR target genes CAMKK2 , KLK2 , KLK3 and TMPRSS2 .	Silencing of AMPKalpha resulted in an increased activation of AR by R1881 in both LNCaP and C4-2 cells and an increased androgen induced expression of the AR target genes CAMKK2, KLK2, KLK3 and TMPRSS2.	7	29	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	AR	R1881 in both LNCaP and C4-2 cells and an increased androgen induced expression of the AR	ar	AR	AR	ar	26	27	9	10
For men with locally advanced or metastatic disease , androgen deprivation therapy ( ADT ) that disrupts androgen receptor ( AR ) signaling is the accepted initial treatment .	For men with locally advanced or metastatic disease, androgen deprivation therapy (ADT) that disrupts androgen receptor (AR) signaling is the accepted initial treatment.	11	21	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR	AR	androgen receptor	androgen receptor	androgen receptor	20	21	17	19
Sumoylation of the wt AR at K388 and K521 in the NTD can inhibit AR transcriptional activity in a promoter context dependent manner .	Sumoylation of the wt AR at K388 and K521 in the NTD can inhibit AR transcriptional activity in a promoter context dependent manner.	0	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	Sumoylation of the wt AR at K388 and K521	ar	AR	AR	ar	4	5	14	15
Finally , our finding of lower AR expression in GG4 tumor areas after short-term finasteride exposure is in line with an emerging concept that reduced androgens in prostate tissues may over time lead to derepression of AR expression , which in turn deregulates AR function and downstream derepression of specific AR target genes normally repressed by androgens .	Finally, our finding of lower AR expression in GG4 tumor areas after short-term finasteride exposure is in line with an emerging concept that reduced androgens in prostate tissues may over time lead to derepression of AR expression, which in turn deregulates AR function and downstream derepression of specific AR target genes normally repressed by androgens.	36	44	deregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR expression	ar	AR	AR	ar	36	37	43	44
Interestingly , AR/p52 -02 also reduced cytoplasmic levels of pAR ser81 in C4-2 cells , but not in LNCaP , under the -R condition Inhibitor AR/p52 -02 induces ubiquitination of the AR , thereby reducing AR stability .	Interestingly, AR/p52 -02 also reduced cytoplasmic levels of pAR ser81 in C4-2 cells, but not in LNCaP, under the -R condition Inhibitor AR/p52 -02 induces ubiquitination of the AR, thereby reducing AR stability.	22	36	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	-R condition Inhibitor AR/p52 -02 induces ubiquitination of the AR	ar	AR	AR	ar	31	32	35	36
In both these cell lines , AR dependent expression including PSA , FKBP51 , and ARD1 was reversed by the antiandrogen Casodex , suggesting androgen dependent AR regulation .	In both these cell lines, AR dependent expression including PSA, FKBP51, and ARD1 was reversed by the antiandrogen Casodex, suggesting androgen dependent AR regulation.	6	27	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	AR dependent expression	ar	AR	AR	ar	6	7	26	27
The mechanisms by which androgen receptor ( AR ) antagonists inhibit AR activity , and how their antagonist activity may be abrogated in prostate cancer that progresses after androgen deprivation therapy , are not clear .	The mechanisms by which androgen receptor (AR) antagonists inhibit AR activity, and how their antagonist activity may be abrogated in prostate cancer that progresses after androgen deprivation therapy, are not clear.	4	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	androgen receptor	androgen receptor	androgen receptor	AR	AR	AR	4	6	11	12
Mithramycin down-regulates endogenous AR levels and inhibits AR transactivation of down stream targets .	Mithramycin down-regulates endogenous AR levels and inhibits AR transactivation of down stream targets.	0	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AR	Mithramycin down-regulates endogenous AR levels	ar	AR	AR	ar	3	4	7	8
Determining the exact mechanism of the inhibition of LARG stimulated RhoA nucleotide exchange is beyond the scope of the present study , however , we did determine whether the compounds inhibited GTP binding or LARG mediated exchange in the [ 35 S ] GTPgammaS guanine nucleotide binding assay .	Determining the exact mechanism of the inhibition of LARG stimulated RhoA nucleotide exchange is beyond the scope of the present study, however, we did determine whether the compounds inhibited GTP binding or LARG mediated exchange in the [35 S] GTPgammaS guanine nucleotide binding assay.	6	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	8	9	10	11
As a result , we describe here a fluorescence polarization high-throughput screen of a ChemBridge diverse chemical library for inhibitors of LARG mediated RhoA nucleotide exchange .	As a result, we describe here a fluorescence polarization high-throughput screen of a ChemBridge diverse chemical library for inhibitors of LARG mediated RhoA nucleotide exchange.	19	25	mediated	Positive_early_activation	Positive_activation	Negative_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	21	22	23	24
Similarly , Wnt-3a-induced RhoA activation was suppressed by p114-RhoGEF or Lfc shRNA , but not significantly by LARG shRNA ( XREF_FIG B ) .	Similarly, Wnt-3a-induced RhoA activation was suppressed by p114-RhoGEF or Lfc shRNA, but not significantly by LARG shRNA (XREF_FIG B).	3	18	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	17	18	3	4
Depletion of GEF-H1 and LARG with specific siRNAs attenuated RhoA activation and adaptive cellular stiffening in response to tensional forces on PECAM-1 ( XREF_FIG ) , further supporting a role for these GEFs in PECAM-1-dependent stiffening .	Depletion of GEF-H1 and LARG with specific siRNAs attenuated RhoA activation and adaptive cellular stiffening in response to tensional forces on PECAM-1 (XREF_FIG), further supporting a role for these GEFs in PECAM-1-dependent stiffening.	0	10	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	4	5	9	10
High-Throughput Screening for Small Molecule Inhibitors of LARG Stimulated RhoA Nucleotide Binding via a Novel Fluorescence Polarization Assay .	High-Throughput Screening for Small Molecule Inhibitors of LARG Stimulated RhoA Nucleotide Binding via a Novel Fluorescence Polarization Assay.	7	11	Stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	7	8	9	10
Therefore , in this study , we performed a ten-thousand compound high-throughput screen for small molecule inhibitors of LARG stimulated RhoA nucleotide exchange .	Therefore, in this study, we performed a ten-thousand compound high-throughput screen for small molecule inhibitors of LARG stimulated RhoA nucleotide exchange.	16	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	18	19	20	21
Inhibition of LARG stimulation of RhoA nucleotide exchange can occur by two primary mechanisms .	Inhibition of LARG stimulation of RhoA nucleotide exchange can occur by two primary mechanisms.	2	7	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	2	3	5	6
A ten-thousand diverse chemical compound collection from ChemBridge was used to screen for small molecule inhibitors of LARG stimulated RhoA nucleotide exchange .	A ten-thousand diverse chemical compound collection from ChemBridge was used to screen for small molecule inhibitors of LARG stimulated RhoA nucleotide exchange.	15	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	17	18	19	20
High-Throughput Screen for Inhibitors of LARG stimulated RhoA Nucleotide Exchange .	High-Throughput Screen for Inhibitors of LARG stimulated RhoA Nucleotide Exchange.	3	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	5	6	7	8
Knockdown of Lsc and LARG together significantly decreases RhoA activation and formation of stress fibers and focal adhesions downstream of fibronectin adhesion .	Knockdown of Lsc and LARG together significantly decreases RhoA activation and formation of stress fibers and focal adhesions downstream of fibronectin adhesion.	0	9	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	4	5	8	9
Knockdown of LARG expression inhibits RhoA activation downstream of ICAM-1 clustering .	Knockdown of LARG expression inhibits RhoA activation downstream of ICAM-1 clustering.	2	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG expression	larg	RhoA	RhoA	rhoa	2	3	5	6
Knockdown of LARG accelerated adipogenesis and repressed basal RhoA activity .	Knockdown of LARG accelerated adipogenesis and repressed basal RhoA activity.	0	9	repressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	2	3	8	9
Using a novel fluorescence polarization guanine nucleotide binding assay utilizing BODIPY-Texas Red-GTPgammaS ( BODIPY-TR-GTPgammaS ) , we performed a ten-thousand compound high-throughput screen for inhibitors of LARG stimulated RhoA nucleotide binding .	Using a novel fluorescence polarization guanine nucleotide binding assay utilizing BODIPY-Texas Red-GTPgammaS (BODIPY-TR-GTPgammaS), we performed a ten-thousand compound high-throughput screen for inhibitors of LARG stimulated RhoA nucleotide binding.	24	30	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	26	27	28	29
The five compounds identified in this study would be of interest for further development based on the multiple diseases and disorders that an inhibitor of LARG mediated RhoA nucleotide exchange may have a positive impact upon .	The five compounds identified in this study would be of interest for further development based on the multiple diseases and disorders that an inhibitor of LARG mediated RhoA nucleotide exchange may have a positive impact upon.	23	29	mediated	Positive_early_activation	Positive_activation	Negative_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	25	26	27	28
Therefore , a small molecule inhibitor of LARG mediated RhoA nucleotide exchange would be a useful tool to elucidate cancer mechanisms and as a potential cancer therapeutic .	Therefore, a small molecule inhibitor of LARG mediated RhoA nucleotide exchange would be a useful tool to elucidate cancer mechanisms and as a potential cancer therapeutic.	5	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	7	8	9	10
KD of LARG expression in ECs blocked ICAM-1-mediated activation of RhoA , confirming that LARG is critical for RhoA activation downstream of ICAM-1 .	KD of LARG expression in ECs blocked ICAM-1-mediated activation of RhoA, confirming that LARG is critical for RhoA activation downstream of ICAM-1.	2	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LARG	LARG expression	larg	RhoA	RhoA	rhoa	2	3	10	11
Therefore , small molecule inhibition of LARG mediated RhoA nucleotide exchange may prove to be useful in the development of pharmacological tools and therapeutics for better understanding of disease pathogenesis and treatment of diseases and disorders , including HIV , hypertension , and erectile dysfunction ( ED ) .	Therefore, small molecule inhibition of LARG mediated RhoA nucleotide exchange may prove to be useful in the development of pharmacological tools and therapeutics for better understanding of disease pathogenesis and treatment of diseases and disorders, including HIV, hypertension, and erectile dysfunction (ED).	4	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	6	7	8	9
Depletion of LARG or GEF-H1 significantly decreased RhoA activation in response to force , whereas knockdown of p115 did not affect the force induced RhoA activation ( XREF_FIG ) .	Depletion of LARG or GEF-H1 significantly decreased RhoA activation in response to force, whereas knockdown of p115 did not affect the force induced RhoA activation (XREF_FIG).	0	8	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LARG	LARG	LARG	RhoA	RhoA	RhoA	2	3	7	8
A single study has investigated the effect of Amphiregulin on endocytic EGFR downregulation , and found that Amphiregulin failed to induce EGFR degradation .	A single study has investigated the effect of Amphiregulin on endocytic EGFR downregulation, and found that Amphiregulin failed to induce EGFR degradation.	17	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Amphiregulin	Amphiregulin	Amphiregulin	EGFR	EGFR	EGFR	17	18	21	22
This finding suggested that AREG overexpression might antagonize some forms of EGFR signaling in the MDA-231 line .	This finding suggested that AREG overexpression might antagonize some forms of EGFR signaling in the MDA-231 line.	4	12	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AREG	AREG overexpression	areg	EGFR	EGFR	egfr	4	5	11	12
In accordance with previous researches , our data showed that EGFR was significantly inhibited by abundant miR-34a or defective AREG , besides which ErbB3 and ErbB4 were also remarkably activated by restoration of AREG in miR-34a over-expressed cells .	In accordance with previous researches, our data showed that EGFR was significantly inhibited by abundant miR-34a or defective AREG, besides which ErbB3 and ErbB4 were also remarkably activated by restoration of AREG in miR-34a over-expressed cells.	10	20	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	19	20	10	11
Using a phospho specific antibody that recognizes activated EGFR , we confirmed that depletion of AREG reduced EGFR activation in our primary cell model ( Fig XREF_FIG C ) .	Using a phospho specific antibody that recognizes activated EGFR, we confirmed that depletion of AREG reduced EGFR activation in our primary cell model (Fig XREF_FIG C).	13	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	15	16	17	18
This dependency on AREG-EGFR signaling conferred erlotinib sensitivity , while depletion of AREG reduced EGFR signaling and lead to decreased sensitivity to erlotinib in vitro and in vivo .	This dependency on AREG-EGFR signaling conferred erlotinib sensitivity, while depletion of AREG reduced EGFR signaling and lead to decreased sensitivity to erlotinib in vitro and in vivo.	10	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	12	13	14	15
As expected , neutralizing TGF-alpha and amphiregulin antibodies or EGFR antibodies prevented the autocrine EGFR activation ( XREF_FIG ) .	As expected, neutralizing TGF-alpha and amphiregulin antibodies or EGFR antibodies prevented the autocrine EGFR activation (XREF_FIG).	6	15	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	amphiregulin	amphiregulin	amphiregulin	EGFR	EGFR	EGFR	6	7	14	15
Amphiregulin promotes the immunosuppressive activity of EGFR positive Treg cells in vitro , so as to profoundly inhibit production of anti-viral components in CD8 + T cells .	Amphiregulin promotes the immunosuppressive activity of EGFR positive Treg cells in vitro, so as to profoundly inhibit production of anti-viral components in CD8 + T cells.	0	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Amphiregulin	Amphiregulin	Amphiregulin	EGFR	EGFR	EGFR	0	1	6	7
Indeed , earlier biochemical studies using epithelial cell lines have demonstrated that , compared to EGF , AREG induced signaling does not target EGFR for degradation but , instead , promotes EGFR recycling to the plasma membrane [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Indeed, earlier biochemical studies using epithelial cell lines have demonstrated that, compared to EGF, AREG induced signaling does not target EGFR for degradation but, instead, promotes EGFR recycling to the plasma membrane [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	17	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	17	18	23	24
Knockdown of AREG in HNSCC cells harboring MAPK1 E322K abrogated EGFR signaling and decreased sensitivity to erlotinib in vitro and in vivo .	Knockdown of AREG in HNSCC cells harboring MAPK1 E322K abrogated EGFR signaling and decreased sensitivity to erlotinib in vitro and in vivo.	0	11	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	2	3	10	11
Scatchard analysis of EGF binding shows that CRDGF induces a decrease in EGF receptor affinity .	Scatchard analysis of EGF binding shows that CRDGF induces a decrease in EGF receptor affinity.	7	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CRDGF	CRDGF	CRDGF	EGF receptor	EGF receptor	EGF receptor	7	8	12	14
Earlier studies have identified distinct EGFR trafficking patterns induced by EGF and AREG in various epithelial cell lines : whereas EGF targets EGFR for lysosomal degradation , AREG causes EGFR recycling , potentially relevant to different biological functions exerted by these growth factors [ XREF_BIBR , XREF_BIBR ] .	Earlier studies have identified distinct EGFR trafficking patterns induced by EGF and AREG in various epithelial cell lines : whereas EGF targets EGFR for lysosomal degradation, AREG causes EGFR recycling, potentially relevant to different biological functions exerted by these growth factors [XREF_BIBR, XREF_BIBR].	25	30	causes	Positive_activation_token_1_verb	Positive_activation	Negative_activation	AREG	AREG	AREG	EGFR	EGFR	EGFR	27	28	29	30
Additionally , Over-expressing miR-34a greatly reduced EGFR and uPA , which were reversed by re-expression of AREG .	Additionally, Over-expressing miR-34a greatly reduced EGFR and uPA, which were reversed by re-expression of AREG.	5	17	reversed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	AREG	re-expression of AREG	areg	EGFR	EGFR	egfr	16	17	6	7
An important difference between these two models is that ablation of Hif1beta not only inhibits Hif1alpha signaling , but also inhibits the actions of Hif2alpha and Ahr .	An important difference between these two models is that ablation of Hif1beta not only inhibits Hif1alpha signaling, but also inhibits the actions of Hif2alpha and Ahr.	9	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Hif1beta	Hif1beta	Hif1beta	Hif1alpha	Hif1alpha	Hif1alpha	11	12	15	16
We utilized a novel peptide ( Ainp1 ) to address whether the HIF-1alpha signaling could be suppressed by an ARNT mediated mechanism .	We utilized a novel peptide (Ainp1) to address whether the HIF-1alpha signaling could be suppressed by an ARNT mediated mechanism.	12	20	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ARNT	ARNT	ARNT	HIF-1alpha	HIF-1alpha	HIF-1alpha	19	20	12	13
Depletion of the constitutively expressed HIF-1alpha or HIF-1beta from breast cancer cells , MDA-MB-23 , completely blocked secretion of Hsp90alpha , which could be rescued by exogenously re-introduced the CA-HIF-1alpha , but not DN-HIF-1alpha ( 32 ) .	Depletion of the constitutively expressed HIF-1alpha or HIF-1beta from breast cancer cells, MDA-MB-23, completely blocked secretion of Hsp90alpha, which could be rescued by exogenously re-introduced the CA-HIF-1alpha, but not DN-HIF-1alpha (32).	0	35	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIF-1beta	HIF-1beta	HIF-1beta	DN-HIF-1alpha	DN-HIF-1alpha	DN-HIF-1alpha	7	8	33	34
Using this strategy , HIF1a TPM and ARNT protein are generated in a 1:1 ratio from a single mRNA transcript , thereby preventing HIF1a TPM from acting as a sink for endogenous ARNT protein , avoiding a possible dominant negative effect on endogenous HIF1a , EPAS1 and/or NEPAS function .	Using this strategy, HIF1a TPM and ARNT protein are generated in a 1:1 ratio from a single mRNA transcript, thereby preventing HIF1a TPM from acting as a sink for endogenous ARNT protein, avoiding a possible dominant negative effect on endogenous HIF1a, EPAS1 and/or NEPAS function.	7	24	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ARNT protein	ARNT protein	ARNT protein	HIF1a	HIF1a	HIF1a	7	9	23	24
The HIF3alpha and HIF1beta ( HIF3 ) and NEPAS and HIF1beta dimers suppress basal and hypoxia induced reporter gene activation , as well as HIF1 ( HIF1alpha and HIF1beta ) or HIF2 ( HIF2alpha and HIF1beta ) driven expression XREF_BIBR , XREF_BIBR .	The HIF3alpha and HIF1beta (HIF3) and NEPAS and HIF1beta dimers suppress basal and hypoxia induced reporter gene activation, as well as HIF1 (HIF1alpha and HIF1beta) or HIF2 (HIF2alpha and HIF1beta) driven expression XREF_BIBR, XREF_BIBR.	1	28	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HIF1beta	HIF1beta	HIF1beta	HIF1alpha	HIF1alpha	HIF1alpha	3	4	26	27
Given its relatively modest influence on AhR activation , we suspect that bilirubin is unlikely to regulate iNOS expression through ARNT dependent reciprocal inhibition of HIF-1alpha , at least under physiological conditions .	Given its relatively modest influence on AhR activation, we suspect that bilirubin is unlikely to regulate iNOS expression through ARNT dependent reciprocal inhibition of HIF-1alpha, at least under physiological conditions.	20	26	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ARNT	ARNT	ARNT	HIF-1alpha	HIF-1alpha	HIF-1alpha	20	21	25	26
For instance , P115RhoGEF , in addition to the aforementioned role , serves to reduce the metastatic phenotype by regulating the activity of Rho .	For instance, P115RhoGEF, in addition to the aforementioned role, serves to reduce the metastatic phenotype by regulating the activity of Rho.	3	24	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	P115RhoGEF	P115RhoGEF	P115RhoGEF	Rho	Rho	Rho	3	4	23	24
The down-regulation of P115RhoGEF inhibits the activity of Rho , which is critical for reducing cell migration .	The down-regulation of P115RhoGEF inhibits the activity of Rho, which is critical for reducing cell migration.	1	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	P115RhoGEF	P115RhoGEF	P115RhoGEF	Rho	Rho	Rho	3	4	8	9
The activity of RhoA was enhanced after LPS stimulation and pretreatment with p115RhoGEF siRNA or exoenzyme C3 transferase reduced RhoA activation significantly as shown by the pull-down assay .	The activity of RhoA was enhanced after LPS stimulation and pretreatment with p115RhoGEF siRNA or exoenzyme C3 transferase reduced RhoA activation significantly as shown by the pull-down assay.	12	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p115RhoGEF	p115RhoGEF	p115RhoGEF	RhoA	RhoA	RhoA	12	13	19	20
The effector loop of Rac1 mediates interactions with downstream effectors , whereas its C-terminus binds the exchange factor beta-Pix , which mediates Rac1 targeting and activation .	The effector loop of Rac1 mediates interactions with downstream effectors, whereas its C-terminus binds the exchange factor beta-Pix, which mediates Rac1 targeting and activation.	14	23	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	18	19	22	23
Our observation that beta-Pix binds specifically to Rac1 via its COOH terminus ( XREF_FIG ) suggests that beta-Pix mediates the targeting of Rac1 to the membrane .	Our observation that beta-Pix binds specifically to Rac1 via its COOH terminus (XREF_FIG) suggests that beta-Pix mediates the targeting of Rac1 to the membrane.	17	23	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	17	18	22	23
Furthermore , siRNA depletion of PLCgamma1 , beta-Pix , or GIT1 inhibited Cdc42 and Rac1 activation , while constitutively active forms of Cdc42 or Rac1 , but not RhoA , were able to rescue the elongation of these cells .	Furthermore, siRNA depletion of PLCgamma1, beta-Pix, or GIT1 inhibited Cdc42 and Rac1 activation, while constitutively active forms of Cdc42 or Rac1, but not RhoA, were able to rescue the elongation of these cells.	3	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-Pix	beta-Pix	beta-Pix	Rac1	Rac1	Rac1	7	8	14	15
Finally , betaPIX is shown to form a trimeric complex with smgGDS and Rac1 ; down-regulation of smgGDS expression by short interfering RNA causing significant inhibition of betaPIX mediated Rac1 activation and neurite outgrowth .	Finally, betaPIX is shown to form a trimeric complex with smgGDS and Rac1; down-regulation of smgGDS expression by short interfering RNA causing significant inhibition of betaPIX mediated Rac1 activation and neurite outgrowth.	25	30	mediated	Positive_early_activation	Positive_activation	Negative_activation	betaPIX	betaPIX	betaPIX	Rac1	Rac1	Rac1	27	28	29	30
mTOR1 also phosphorylates ATG14L , causing inhibition of the associated class 3 PI3 kinase VPS34 .	mTOR1 also phosphorylates ATG14L, causing inhibition of the associated class 3 PI3 kinase VPS34.	0	15	causing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATG14L	mTOR1 also phosphorylates ATG14L	atg14l	VPS34	VPS34	vps34	3	4	14	15
Further , mTORC1 phosphorylates Atg14L and inhibits the lipid kinase activity of Vps34 [ XREF_BIBR ] .	Further, mTORC1 phosphorylates Atg14L and inhibits the lipid kinase activity of Vps34 [XREF_BIBR].	2	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Atg14L	mTORC1 phosphorylates Atg14L	atg14l	Vps34	Vps34	vps34	4	5	12	13
Importantly , Atg14L immuno-depletion did not effectively reduce Vps34 or Beclin1 , indicating that the majority of Vps34 or Beclin1 is not associated with Atg14L .	Importantly, Atg14L immuno-depletion did not effectively reduce Vps34 or Beclin1, indicating that the majority of Vps34 or Beclin1 is not associated with Atg14L.	2	10	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Atg14L	Atg14L	Atg14L	Vps34	Vps34	Vps34	2	3	8	9
To further probe a mechanism by which LRS may regulate Vps34 , we performed in vitro kinase assays on Atg14L depleted Vps34 complex isolated from amino acid deprived cells .	To further probe a mechanism by which LRS may regulate Vps34, we performed in vitro kinase assays on Atg14L depleted Vps34 complex isolated from amino acid deprived cells.	13	22	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Atg14L	Atg14L	Atg14L	Vps34	Vps34	Vps34	19	20	21	22
Li et al ., [ XREF_BIBR ] reported that the synthetic steroidal glycoside SBF-1 decreased the expression level of ATF6 ( 90kDa ) , but increased that of ATF6alpha ( 50kDa ) .	Li et al., [XREF_BIBR] reported that the synthetic steroidal glycoside SBF-1 decreased the expression level of ATF6 (90kDa), but increased that of ATF6alpha (50kDa).	13	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATF6	SBF-1 decreased the expression level of ATF6	atf6	ATF6alpha	ATF6alpha	atf6alpha	19	20	28	29
To further study the effects of ATF6 on sEH expression , we examined the overexpression of ATF6 and siRNA knockdown of endogenous ATF6alpha , a potent transcriptional factor of ER stress response genes .	To further study the effects of ATF6 on sEH expression, we examined the overexpression of ATF6 and siRNA knockdown of endogenous ATF6alpha, a potent transcriptional factor of ER stress response genes.	14	27	knockdown	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ATF6	overexpression of ATF6	atf6	ATF6alpha	ATF6alpha	atf6alpha	16	17	22	23
XREF_BIBR - XREF_BIBR Here we show , in agreement with previous studies , 26 that MLK3 associates with p63RhoGEF , and inhibits p63RhoGEF induced RhoA activation measured by GST-Rhotekin pulldown assay .	XREF_BIBR - XREF_BIBR Here we show, in agreement with previous studies, 26 that MLK3 associates with p63RhoGEF, and inhibits p63RhoGEF induced RhoA activation measured by GST-Rhotekin pulldown assay.	21	25	induced	Positive_early_activation	Positive_activation	Negative_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	22	23	24	25
Knockdown of p63RhoGEF suppressed serum induced RhoA activation and chemotaxis and caused the aberrant formation of multiple lamellipodial protrusions after serum stimulation while control cells formed a single polarized lamellipodium .	Knockdown of p63RhoGEF suppressed serum induced RhoA activation and chemotaxis and caused the aberrant formation of multiple lamellipodial protrusions after serum stimulation while control cells formed a single polarized lamellipodium.	0	7	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p63RhoGEF	p63RhoGEF	p63RhoGEF	RhoA	RhoA	RhoA	2	3	6	7
We find that ArfGAP1 does not non specifically reduce LRRK2 kinase activity since MBP does not affect LRRK2 autophosphorylation and kinase activity ( XREF_FIG ) .	We find that ArfGAP1 does not non specifically reduce LRRK2 kinase activity since MBP does not affect LRRK2 autophosphorylation and kinase activity (XREF_FIG).	3	11	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ArfGAP1	ArfGAP1	ArfGAP1	LRRK2	LRRK2	LRRK2	3	4	9	10
These results strongly suggest that APP-BP1 modulates the cell cycle progression of fetal neural stem cells and that APP antagonistically regulates the function of APP-BP1 in cell cycle progression from G1 to S Phase .	These results strongly suggest that APP-BP1 modulates the cell cycle progression of fetal neural stem cells and that APP antagonistically regulates the function of APP-BP1 in cell cycle progression from G1 to S Phase.	18	28	antagonistically regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	APP	APP	APP	APP-BP1	APP-BP1	APP-BP1	18	19	24	25
mTOR phosphorylates Atg13 , ULK1 , and ULK2 , and inhibits ULK1 and ULK2 kinase activity to inhibit autophagy induction .	mTOR phosphorylates Atg13, ULK1, and ULK2, and inhibits ULK1 and ULK2 kinase activity to inhibit autophagy induction.	0	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Atg13	mTOR phosphorylates Atg13	atg13	ULK2	ULK2	ulk2	2	3	13	14
PI3-kinase inhibitors enhanced CSF-1-stimulated A-Raf and c-Raf-1 activities , and dominant negative A-Raf but not dominant negative c-Raf-1 reduced CSF-1-provoked ERK activation , suggesting that A-Raf mediates a part of the stimulatory signal from Ras to MEK and ERK , acting in parallel to PI3-kinase .	PI3-kinase inhibitors enhanced CSF-1-stimulated A-Raf and c-Raf-1 activities, and dominant negative A-Raf but not dominant negative c-Raf-1 reduced CSF-1-provoked ERK activation, suggesting that A-Raf mediates a part of the stimulatory signal from Ras to MEK and ERK, acting in parallel to PI3-kinase.	25	38	mediates	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	A-Raf	A-Raf	A-Raf	MEK	MEK	MEK	25	26	36	37
To that effect POT1 inhibits ATR mediated responses and TRF2 inhibits ATM .	To that effect POT1 inhibits ATR mediated responses and TRF2 inhibits ATM.	4	12	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	ATM	ATM	ATM	5	6	11	12
This is presumably associated with an essential role for ATR in rapidly proliferating cells and is consistent with reports that ATR kinase inhibitors induce ATM kinase activity in the absence of exogenous insult XREF_BIBR XREF_BIBR .	This is presumably associated with an essential role for ATR in rapidly proliferating cells and is consistent with reports that ATR kinase inhibitors induce ATM kinase activity in the absence of exogenous insult XREF_BIBR XREF_BIBR.	20	26	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	ATM	ATM	ATM	20	21	24	25
Thus , replication stress and DSB inducers activate NF-kappaB through a conserved pathway with opposite biologic outcomes , and ATR antagonizes ATM function at least in part by competing for NEMO association .	Thus, replication stress and DSB inducers activate NF-kappaB through a conserved pathway with opposite biologic outcomes, and ATR antagonizes ATM function at least in part by competing for NEMO association.	19	22	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	ATM	ATM	ATM	19	20	21	22
Thus , it is possible that the ATR pathway inhibitors target a non kinase component of the ATM and ATR pathways to suppress signal transduction .	Thus, it is possible that the ATR pathway inhibitors target a non kinase component of the ATM and ATR pathways to suppress signal transduction.	7	20	target	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	ATM	ATM	ATM	7	8	17	18
Increased ATM kinase activity in cells treated with ATR kinase inhibitors has been reported previously [ XREF_BIBR , XREF_BIBR ] .	Increased ATM kinase activity in cells treated with ATR kinase inhibitors has been reported previously [XREF_BIBR, XREF_BIBR].	1	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	ATR	ATR	ATR	ATM	ATM	ATM	8	9	1	2
Furthermore , cisplatin and ATR kinase inhibitors synergize to kill ATM deficient lung cancer cells in vitro and to resolve ATM deficient xenografts in vivo [ XREF_BIBR - XREF_BIBR ] .	Furthermore, cisplatin and ATR kinase inhibitors synergize to kill ATM deficient lung cancer cells in vitro and to resolve ATM deficient xenografts in vivo [XREF_BIBR - XREF_BIBR].	2	12	synergize	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	ATM	ATM	ATM	4	5	10	11
Thus the early events detected in Chk1- or ATR depleted cells treated with replication inhibitors are not evident in ATM depleted cells .	Thus the early events detected in Chk1- or ATR depleted cells treated with replication inhibitors are not evident in ATM depleted cells.	4	20	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	ATM	ATM	ATM	8	9	19	20
Our study shows that DNA-PKcs also phosphorylates ATM and inhibits ATM kinase activity .	Our study shows that DNA-PKcs also phosphorylates ATM and inhibits ATM kinase activity.	4	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	DNA-PKcs also phosphorylates ATM	atm	ATM	ATM	atm	7	8	10	11
The study demonstrated that ATM expression was diminished in ACC than in ACA , suggesting an important role of ATM in the tumorigenesis of ACC .	The study demonstrated that ATM expression was diminished in ACC than in ACA, suggesting an important role of ATM in the tumorigenesis of ACC.	4	20	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM expression	atm	ATM	ATM	atm	4	5	19	20
22 It is known to inhibit DNA dependent protein kinase ( DNA-PK ) , Ku-70 , Ku-80 , and ataxia telangiectasia mutated ( ATM ) proteins , XREF_BIBR - XREF_BIBR all of which are critically important to DNA double-strand repair .	22 It is known to inhibit DNA dependent protein kinase (DNA-PK), Ku-70, Ku-80, and ataxia telangiectasia mutated (ATM) proteins, XREF_BIBR - XREF_BIBR all of which are critically important to DNA double-strand repair.	0	24	inhibit	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	ataxia telangiectasia mutated	ataxia telangiectasia mutated	ataxia telangiectasia mutated	23	24	19	22
FOXO1 is a potential target of ATM , whereas FOXO3a can increase ATM expression in HSCs and directly interact with ATM to promote ATM activation in response to DNA damage .	FOXO1 is a potential target of ATM, whereas FOXO3a can increase ATM expression in HSCs and directly interact with ATM to promote ATM activation in response to DNA damage.	9	24	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	FOXO3a can increase ATM expression	atm	ATM	ATM	atm	12	13	23	24
31 A recent study found that DNA-PKcs directly phosphorylates ATM at multiple sites and inhibits ATM activity .	31 A recent study found that DNA-PKcs directly phosphorylates ATM at multiple sites and inhibits ATM activity.	6	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	DNA-PKcs directly phosphorylates ATM	atm	ATM	ATM	atm	9	10	15	16
Next , INPP4B knockdown can significantly downregulate ATM expression and subsequently inhibit the activation of ATM downstream targets of p-ATM , p-BRCA1 , p-ATR , and p-RAD51 .	Next, INPP4B knockdown can significantly downregulate ATM expression and subsequently inhibit the activation of ATM downstream targets of p-ATM, p-BRCA1, p-ATR, and p-RAD51.	2	17	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	INPP4B knockdown can significantly downregulate ATM expression	atm	ATM	ATM	atm	7	8	15	16
ATM ( Ataxia Telangiectasia Mutated ) kinase activity is a primary driving force for chromatin alterations emanating from DSB induction and these activities are in part thought to mediate ATM dependent suppression of genomic instability and carcinogenesis .	ATM (Ataxia Telangiectasia Mutated) kinase activity is a primary driving force for chromatin alterations emanating from DSB induction and these activities are in part thought to mediate ATM dependent suppression of genomic instability and carcinogenesis.	2	31	mediate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ataxia Telangiectasia Mutated	Ataxia Telangiectasia Mutated	Ataxia Telangiectasia Mutated	ATM	ATM	ATM	2	5	29	30
Loss of the ATM mediated signalling also does not alter the death response in ATR or Chk1 depleted cells .	Loss of the ATM mediated signalling also does not alter the death response in ATR or Chk1 depleted cells.	0	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	Loss of the ATM	atm	Chk1	Chk1	chk1	3	4	16	17
Moreover , depletion of ATM in SUM159-P2 cells significantly downregulated ZEB1 and CHK1 proteins ( XREF_FIG ) ; in contrast , neither knockdown of ATR or treatment with the ATR inhibitor ETP-46464 50 affected ZEB1 protein levels ( XREF_SUPPLEMENTARY ) .	Moreover, depletion of ATM in SUM159-P2 cells significantly downregulated ZEB1 and CHK1 proteins (XREF_FIG); in contrast, neither knockdown of ATR or treatment with the ATR inhibitor ETP-46464 50 affected ZEB1 protein levels (XREF_SUPPLEMENTARY).	2	13	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	CHK1	CHK1	CHK1	4	5	12	13
DNA-PKcs activity was depleted from ATM -/- immortalized MEFs either by treatment with PKi ( XREF_FIG ) , or by PKcs shRNA ( XREF_FIG ) , or by adenoviral CRE infection of ATM c/c DNA-PKcs -/- primary MEFs ( XREF_FIG ) .	DNA-PKcs activity was depleted from ATM -/- immortalized MEFs either by treatment with PKi (XREF_FIG), or by PKcs shRNA (XREF_FIG), or by adenoviral CRE infection of ATM c/c DNA-PKcs -/- primary MEFs (XREF_FIG).	0	33	depleted	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	DNA-PKcs	DNA-PKcs	DNA-PKcs	32	33	0	1
It is possible that the presence of an enzymatically inactive ATM protein might prevent DNA-PKcs , and potentially other phosphoinositide 3-kinase-related kinases , from phosphorylating shared substrates , thereby disrupting DNA repair to a greater extent than complete loss of ATM alone .	It is possible that the presence of an enzymatically inactive ATM protein might prevent DNA-PKcs, and potentially other phosphoinositide 3-kinase-related kinases, from phosphorylating shared substrates, thereby disrupting DNA repair to a greater extent than complete loss of ATM alone.	10	21	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	DNA-PKcs	DNA-PKcs	DNA-PKcs	10	11	14	15
Altogether , our results indicate that expression of kinase-inactive murine ATM does not abrogate DNA-PKcs or ATR function in B cells .	Altogether, our results indicate that expression of kinase-inactive murine ATM does not abrogate DNA-PKcs or ATR function in B cells.	6	17	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	expression of kinase-inactive murine ATM	atm	DNA-PKcs	DNA-PKcs	dna-pkcs	10	11	14	15
Therefore , the activation of Chk2 by ATM is counteracted by the ATM dependent deactivation of Chk2 by Wip1 .	Therefore, the activation of Chk2 by ATM is counteracted by the ATM dependent deactivation of Chk2 by Wip1.	12	17	deactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	12	13	16	17
As a positive control , ATM efficiently phosphorylated bacterially produced kinase-dead CHK2 , and pretreatment of the ATM immunocomplex with ATM specific inhibitor KU55933 essentially diminished the incorporation of 32 P-ATP into kinase-dead CHK2 by ATM ( XREF_FIG ) .	As a positive control, ATM efficiently phosphorylated bacterially produced kinase-dead CHK2, and pretreatment of the ATM immunocomplex with ATM specific inhibitor KU55933 essentially diminished the incorporation of 32 P-ATP into kinase-dead CHK2 by ATM (XREF_FIG).	25	37	diminished	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	35	36	33	34
ATM activated Chk2 primarily targets two critical effectors mediating the G 1 checkpoint , cdc25a and p53 [ XREF_BIBR ] .	ATM activated Chk2 primarily targets two critical effectors mediating the G 1 checkpoint, cdc25a and p53 [XREF_BIBR].	0	4	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	Chk2	Chk2	Chk2	0	1	2	3
Consistent with the effect of NSC23766 on the IR induced ATM and ATR , presence of 100 muM NSC23766 completely abrogated the IR induced Chk1 and Chk2 activation in CD18 and HPAF cells .	Consistent with the effect of NSC23766 on the IR induced ATM and ATR, presence of 100 muM NSC23766 completely abrogated the IR induced Chk1 and Chk2 activation in CD18 and HPAF cells.	8	27	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	IR induced ATM	atm	Chk2	Chk2	chk2	10	11	26	27
Upon IR , lineage negative ( Lin - ) Per2 -/- cells exhibited a diminished ATM kinase response that led to reduced p-CHK1 , p-CHK2 and p-p53 relative to wild type cells .	Upon IR, lineage negative (Lin -) Per2 -/- cells exhibited a diminished ATM kinase response that led to reduced p-CHK1, p-CHK2 and p-p53 relative to wild type cells.	15	25	led	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	p-CHK2	p-CHK2	p-CHK2	15	16	24	25
It seems that the ATM initiated signal transduction is partially impaired due to one of the main downstream effectors , CHK2 , which is decreased only in DHC tissue .	It seems that the ATM initiated signal transduction is partially impaired due to one of the main downstream effectors, CHK2, which is decreased only in DHC tissue.	3	24	initiated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	CHK2	CHK2	CHK2	4	5	20	21
ATM deficient cells showed no hyperphosphorylation and reduced foci formation of gamma-H2AX and 53BP1 in response to IR compared with cells expressing wild-type ATM , resulting low DNA repair efficiency XREF_BIBR , XREF_BIBR .	ATM deficient cells showed no hyperphosphorylation and reduced foci formation of gamma-H2AX and 53BP1 in response to IR compared with cells expressing wild-type ATM, resulting low DNA repair efficiency XREF_BIBR, XREF_BIBR.	0	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	0	1	13	14
Notably , inhibition of ATM or CtIP activity partially enhanced CSR in 53BP1 deficient B cells , suggesting that end resection is an important negative regulator of NHEJ that must be suppressed by 53BP1 to enable efficient CSR .	Notably, inhibition of ATM or CtIP activity partially enhanced CSR in 53BP1 deficient B cells, suggesting that end resection is an important negative regulator of NHEJ that must be suppressed by 53BP1 to enable efficient CSR.	2	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	4	5	12	13
Our cell cycle analysis showed that ATM inhibition or loss of 53BP1 clearly led to different defects in response to irradiation ( XREF_FIG ) .	Our cell cycle analysis showed that ATM inhibition or loss of 53BP1 clearly led to different defects in response to irradiation (XREF_FIG).	6	12	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	6	7	11	12
According to these data , a reduced ability of ATM to phosphorylate 53BP1 in this specific context , either caused by less ATM or less activity of mutated ATM , could promote faster 53BP1 repositioning and favor HR over NHEJ .	According to these data, a reduced ability of ATM to phosphorylate 53BP1 in this specific context, either caused by less ATM or less activity of mutated ATM, could promote faster 53BP1 repositioning and favor HR over NHEJ.	7	34	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	53BP1	53BP1	53BP1	9	10	33	34
These data suggest that impaired ATM activation in Mre11 ATLD1 and ATLD1 accounts for reduced p53 phosphorylation and may further account for the additive defects of Mre11 ATLD1 and ATLD1 and Chk2 -/- in apoptotic induction .	These data suggest that impaired ATM activation in Mre11 ATLD1 and ATLD1 accounts for reduced p53 phosphorylation and may further account for the additive defects of Mre11 ATLD1 and ATLD1 and Chk2 -/- in apoptotic induction.	5	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	ATM	ATM	ATM	Mre11	Mre11	Mre11	5	6	8	9
We reasoned that the attenuated ATM signaling in Mre11 and Nbs1 hypomorphic mutants might lead to elevated DSB numbers .	We reasoned that the attenuated ATM signaling in Mre11 and Nbs1 hypomorphic mutants might lead to elevated DSB numbers.	5	12	signaling	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	ATM	ATM	ATM	Mre11	Mre11	Mre11	5	6	8	9
MRE11 , but not ATM , is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of gammaH2AX foci in metaphase II.	MRE11, but not ATM, is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of gammaH2AX foci in metaphase II.	0	25	Inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	MRE11	MRE11	MRE11	4	5	24	25
The reason for this is that binding of ATM to the inner focus impedes the dissociation of MRN , so that the MRN concentration in the inner focus is increased when there is a high level of ATM activation .	The reason for this is that binding of ATM to the inner focus impedes the dissociation of MRN, so that the MRN concentration in the inner focus is increased when there is a high level of ATM activation.	6	18	impedes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	MRN	MRN	MRN	8	9	17	18
The nibrin DeltaAtm protein interacted with Mre11 and Rad50 ; however , Atm autophosphorylation was dramatically reduced after irradiation in NBS cells expressing the nibrin DeltaAtm transgenes relative to wild-type nibrin .	The nibrin DeltaAtm protein interacted with Mre11 and Rad50; however, Atm autophosphorylation was dramatically reduced after irradiation in NBS cells expressing the nibrin DeltaAtm transgenes relative to wild-type nibrin.	12	26	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Atm	Atm autophosphorylation	atm	nibrin	nibrin	nibrin	12	13	24	25
Concomitant inactivation of Atm induces premature apoptosis , suggesting that Atm may be required to promote DNA repair and prevent apoptosis in Nbn deficient damaged cells .	Concomitant inactivation of Atm induces premature apoptosis, suggesting that Atm may be required to promote DNA repair and prevent apoptosis in Nbn deficient damaged cells.	10	23	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Atm	Atm	Atm	Nbn	Nbn	Nbn	10	11	22	23
Atm prevents premature DSBs accumulation and apoptosis in Nbn deficient cerebellum and forebrain .	Atm prevents premature DSBs accumulation and apoptosis in Nbn deficient cerebellum and forebrain.	0	10	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Atm	Atm	Atm	Nbn	Nbn	Nbn	0	1	8	9
Deletion of ATM stimulates mNHEJ in H2AX -/- cells ( one-way Anova : P = 0.014 ; Figure XREF_FIG ) .	Deletion of ATM stimulates mNHEJ in H2AX -/- cells (one-way Anova : P = 0.014; Figure XREF_FIG).	0	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	2	3	6	7
This demonstrates that like DNA-PKcs , ATM suppresses H2AX independent mNHEJ .	This demonstrates that like DNA-PKcs, ATM suppresses H2AX independent mNHEJ.	6	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	6	7	8	9
The proportion of H2AX kinase that was inhibited by ATM antibodies was significantly higher in fraction 10 than in total extract ( compare columns 1 and 2 with columns 9 and 10 in XREF_FIG C ) .	The proportion of H2AX kinase that was inhibited by ATM antibodies was significantly higher in fraction 10 than in total extract (compare columns 1 and 2 with columns 9 and 10 in XREF_FIG C).	3	10	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	H2AX	H2AX	H2AX	9	10	3	4
ATM promotes HR by recruiting BRCA1 to DSBs but can also antagonize BRCA1 and promote NHEJ by recruiting p53 binding protein 1 ( 53BP1 ) , and these antagonistic functions are cell cycle regulated .	ATM promotes HR by recruiting BRCA1 to DSBs but can also antagonize BRCA1 and promote NHEJ by recruiting p53 binding protein 1 (53BP1), and these antagonistic functions are cell cycle regulated.	0	13	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	BRCA1	BRCA1	BRCA1	0	1	12	13
Some experts suggest surveillance in BRCA1 , ATM and TP53 mutation carriers should be limited to those with a first- or second-degree relative with PC [ XREF_BIBR ] .	Some experts suggest surveillance in BRCA1, ATM and TP53 mutation carriers should be limited to those with a first- or second-degree relative with PC [XREF_BIBR].	3	15	limited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	BRCA1	BRCA1	BRCA1	7	8	5	6
As revealed in qRT-PCR , activated prognostic factor ATM down-regulated tumor suppressor gene BRCA1 and prompted DNA repair genes hOGG1 and hMTH1 expression in lower concentrations of HBCD ( < 10 mg/L ) .	As revealed in qRT-PCR, activated prognostic factor ATM down-regulated tumor suppressor gene BRCA1 and prompted DNA repair genes hOGG1 and hMTH1 expression in lower concentrations of HBCD (< 10 mg/L).	8	15	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	ATM	ATM	BRCA1	BRCA1	BRCA1	8	9	13	14
Furthermore , haploid loss of ATM also rescued Brca1 deficiency associated embryonic lethality and premature aging .	Furthermore, haploid loss of ATM also rescued Brca1 deficiency associated embryonic lethality and premature aging.	3	9	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATM	loss of ATM	atm	Brca1	Brca1	brca1	5	6	8	9
Exo1 activity may be attenuated by ATM dependent phosphorylation following its role in resection to prevent the destruction of substrates required for HR .	Exo1 activity may be attenuated by ATM dependent phosphorylation following its role in resection to prevent the destruction of substrates required for HR.	0	9	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ATM	ATM dependent phosphorylation	atm	Exo1	Exo1	exo1	6	7	0	1
Given the inhibitory effect of resection on ATM activation , it is logical to assume that ATM might inhibit Exo1 to ensure that its own activation and retention at breaks is not prematurely terminated due to DSB to ssDNA conversion .	Given the inhibitory effect of resection on ATM activation, it is logical to assume that ATM might inhibit Exo1 to ensure that its own activation and retention at breaks is not prematurely terminated due to DSB to ssDNA conversion.	16	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	Exo1	Exo1	Exo1	16	17	19	20
Importantly , ATR depletion , but not ATM , abolished RPA1 depletion induced FANCD2-Ub , suggesting that ATR activation mediated FANCD2-Ub .	Importantly, ATR depletion, but not ATM, abolished RPA1 depletion induced FANCD2-Ub, suggesting that ATR activation mediated FANCD2-Ub.	3	14	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	FANCD2-Ub	FANCD2-Ub	FANCD2-Ub	7	8	13	14
Inhibiting ATM signaling or knockdown of Rad51 or FancD2 can block viral infection [ XREF_BIBR , XREF_BIBR ] .	Inhibiting ATM signaling or knockdown of Rad51 or FancD2 can block viral infection [XREF_BIBR, XREF_BIBR].	1	9	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ATM	ATM	ATM	FancD2	FancD2	FancD2	1	2	8	9
ChIP assays of pnr chromatin from XNP and dATRX overexpressing flies , show that in spite of XNP and dATRX increased levels , DREF still occupies the DRE-pnrbeta element , suggesting that XNP and dATRX did not prevent the association of DREF with this DRE site ( XREF_FIG A ) .	ChIP assays of pnr chromatin from XNP and dATRX overexpressing flies, show that in spite of XNP and dATRX increased levels, DREF still occupies the DRE-pnrbeta element, suggesting that XNP and dATRX did not prevent the association of DREF with this DRE site (XREF_FIG A).	32	47	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	XNP	XNP	XNP	DREF	DREF	DREF	32	33	41	42
In this situation , XNP and dATRX may be sequestering DREF and preventing it from interacting with DRE elements , thereby inhibiting transcription .	In this situation, XNP and dATRX may be sequestering DREF and preventing it from interacting with DRE elements, thereby inhibiting transcription.	4	12	sequestering	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	XNP	XNP	XNP	DREF	DREF	DREF	4	5	10	11
Interestingly , there was some decrease in ATM phosphorylation at a later time point , supporting a possible role of MDC1 in maintaining ATM phosphorylation ( XREF_FIG ) .	Interestingly, there was some decrease in ATM phosphorylation at a later time point, supporting a possible role of MDC1 in maintaining ATM phosphorylation (XREF_FIG).	7	21	supporting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM phosphorylation	atm	MDC1	MDC1	mdc1	7	8	20	21
Although subsequent studies have demonstrated that DNA-PK is an essential factor for Artemis activity [ XREF_BIBR ] , ATM dependent phosphorylation was suggested to inhibit regulation of Artemis by DNA-PK-dependent phosphorylation [ XREF_BIBR ] .	Although subsequent studies have demonstrated that DNA-PK is an essential factor for Artemis activity [XREF_BIBR], ATM dependent phosphorylation was suggested to inhibit regulation of Artemis by DNA-PK-dependent phosphorylation [XREF_BIBR].	18	28	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM dependent phosphorylation	atm	Artemis	Artemis	artemis	18	19	27	28
For example , ATM has been reported to repress the rapamycin sensitive mammalian target of rapamycin ( mTORC1 ) pathway by activating the serine/threonine kinase LKB1 and AMP activated protein kinase ( AMPK ) metabolic pathway ( Alexander et al ., 2010 ) .	For example, ATM has been reported to repress the rapamycin sensitive mammalian target of rapamycin (mTORC1) pathway by activating the serine/threonine kinase LKB1 and AMP activated protein kinase (AMPK) metabolic pathway (Alexander et al., 2010).	3	28	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATM	ATM	ATM	LKB1	LKB1	LKB1	3	4	25	26
In particular , VE-821 concentrations that sensitized to cisplatin , topotecan , or gemcitabine did not block ATR mediated Chk1 Ser 345 phosphorylation in ovarian cancer cells ( XREF_FIG ) even though VE-821 blocked this phosphorylation in U937 leukemia cells ( XREF_FIG ) .	In particular, VE-821 concentrations that sensitized to cisplatin, topotecan, or gemcitabine did not block ATR mediated Chk1 Ser 345 phosphorylation in ovarian cancer cells (XREF_FIG) even though VE-821 blocked this phosphorylation in U937 leukemia cells (XREF_FIG).	16	20	mediated	Positive_early_activation	Positive_activation	Negative_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	17	18	19	20
In agreement with previous reports XREF_BIBR , we observed that depletion of ATR or chemical inhibition of CHK1 almost completely prevents RAD51 from nuclear foci assembly after HU treatment .	In agreement with previous reports XREF_BIBR, we observed that depletion of ATR or chemical inhibition of CHK1 almost completely prevents RAD51 from nuclear foci assembly after HU treatment.	12	18	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	12	13	17	18
We also showed that ATR inhibition causes rapid Chk1 inactivation , which explains why this response to ATRi and Chk1i is similar .	We also showed that ATR inhibition causes rapid Chk1 inactivation, which explains why this response to ATRi and Chk1i is similar.	4	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	4	5	8	9
The observed G 2 / M cell cycle arrest involves the ATM and Rad3 related ( ATR ) kinase , as demonstrated by the ablation of ATR ( or inhibition of the ATR activated checkpoint kinase CHK1 ) attenuating the cell cycle arrest .	The observed G 2 / M cell cycle arrest involves the ATM and Rad3 related (ATR) kinase, as demonstrated by the ablation of ATR (or inhibition of the ATR activated checkpoint kinase CHK1) attenuating the cell cycle arrest.	29	37	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	32	33	36	37
Additionally , ATR can suppress origin firing and the intra-S checkpoint independent of CHK1 .	Additionally, ATR can suppress origin firing and the intra-S checkpoint independent of CHK1.	2	14	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	CHK1	CHK1	CHK1	2	3	13	14
Immunostaining with this phospho-antibody also demonstrated the presence of pChk1 in lysosomes ( XREF_FIG ) and confirmed that inhibition of the ATR kinase completely eliminated the signal of the Chk1 protein susceptible to lysosomal degradation ( XREF_FIG ) .	Immunostaining with this phospho-antibody also demonstrated the presence of pChk1 in lysosomes (XREF_FIG) and confirmed that inhibition of the ATR kinase completely eliminated the signal of the Chk1 protein susceptible to lysosomal degradation (XREF_FIG).	21	34	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	21	22	29	30
ATR targets Chk1 phosphorylation at S317 and S345 , stimulating the Chk1 kinase and releasing it from chromatin to carry out intra-S-phase checkpoint activities .	ATR targets Chk1 phosphorylation at S317 and S345, stimulating the Chk1 kinase and releasing it from chromatin to carry out intra-S-phase checkpoint activities.	0	12	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR targets Chk1 phosphorylation at S317	atr	Chk1	Chk1	chk1	0	1	11	12
Late replicating origins however , are inhibited by ATR and its substrate and checkpoint kinase 1 ( Chk1 ) .	Late replicating origins however, are inhibited by ATR and its substrate and checkpoint kinase 1 (Chk1).	6	16	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	checkpoint kinase 1	checkpoint kinase 1	checkpoint kinase 1	8	9	13	16
3.6 ATR dependent phosphorylation at Ser317 and Ser345 is not required for glucose deprivation induced Chk1 degradation .	3.6 ATR dependent phosphorylation at Ser317 and Ser345 is not required for glucose deprivation induced Chk1 degradation.	0	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	Chk1	Chk1	Chk1	1	2	15	16
Additionally , AURKA was found to suppress BRCA1 and BRCA2 , both play a major role in DNA damage response [ XREF_BIBR , XREF_BIBR ] .	Additionally, AURKA was found to suppress BRCA1 and BRCA2, both play a major role in DNA damage response [XREF_BIBR, XREF_BIBR].	2	9	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AURKA	AURKA	AURKA	BRCA1	BRCA1	BRCA1	2	3	7	8
The findings taken together indicate that Aurora kinase-A and -B antagonize the p53 and BRCA1 functions and thus tumors with elevated expression of the two kinases acquire loss of function phenotypes for these two critical tumor suppressor pathways even in the absence of any inactivating mutation in the respective tumor suppressor proteins .	The findings taken together indicate that Aurora kinase-A and -B antagonize the p53 and BRCA1 functions and thus tumors with elevated expression of the two kinases acquire loss of function phenotypes for these two critical tumor suppressor pathways even in the absence of any inactivating mutation in the respective tumor suppressor proteins.	6	15	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Aurora kinase-A	Aurora kinase-A	Aurora kinase-A	BRCA1	BRCA1	BRCA1	6	8	14	15
Furthermore , depletion of ATR was found to reduce FANCD2 containing APBs in HPV-16 E7 expressing cell populations .	Furthermore, depletion of ATR was found to reduce FANCD2 containing APBs in HPV-16 E7 expressing cell populations.	2	10	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ATR	ATR	ATR	FANCD2	FANCD2	FANCD2	4	5	9	10
The S phase checkpoint kinase Mec1 and ATR inhibits mitotic Cyclin Dependent Kinase activity through effector kinases Swe1 and Wee1 and Rad53 and Chk2 .	The S phase checkpoint kinase Mec1 and ATR inhibits mitotic Cyclin Dependent Kinase activity through effector kinases Swe1 and Wee1 and Rad53 and Chk2.	5	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	Rad53	Rad53	Rad53	7	8	21	22
In light of the abrogation of p53 stabilization , as well as the non disruptive ATR activation in Chk2 knockout cells , Chk2 is very likely to function as a mediator being responsible for p53 accumulation .	In light of the abrogation of p53 stabilization, as well as the non disruptive ATR activation in Chk2 knockout cells, Chk2 is very likely to function as a mediator being responsible for p53 accumulation.	15	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	ATR	ATR	ATR	Chk2	Chk2	Chk2	15	16	18	19
Here , we found that inhibition of the kinase ATR , which is the primary sensor of DNA replication stress , induced chromosomal breakage and death of mouse AML MLL cells ( with an MLL-ENL fusion and a constitutively active N-RAS ) independently of p53 .	Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML MLL cells (with an MLL-ENL fusion and a constitutively active N-RAS) independently of p53.	5	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	MLL	MLL	MLL	9	10	29	30
Deficiency in ATR greatly reduced the accumulation of MLL upon DNA damage ( XREF_FIG and XREF_SUPPLEMENTARY ) , identifying ATR as the principal kinase for the MLL induction .	Deficiency in ATR greatly reduced the accumulation of MLL upon DNA damage (XREF_FIG and XREF_SUPPLEMENTARY), identifying ATR as the principal kinase for the MLL induction.	0	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	MLL	MLL	MLL	2	3	8	9
Depletion of PrxII blocked PARsylation and ubiquitination of Axin1 without affecting total ubiquitination and caused the augmentation of functional Axin1 associated destruction complexes to degrade beta-catenin , hence reversing the oncogenic phenotype conferred by the APC mutation .	Depletion of PrxII blocked PARsylation and ubiquitination of Axin1 without affecting total ubiquitination and caused the augmentation of functional Axin1 associated destruction complexes to degrade beta-catenin, hence reversing the oncogenic phenotype conferred by the APC mutation.	2	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Axin1	PrxII blocked PARsylation and ubiquitination of Axin1	axin1	Axin1	Axin1	axin1	8	9	19	20
Transfection of Axin1 overexpressed vector and a specific sumatriptan dose were used to inhibit the activity of Axin1 mediated signaling pathway in LoVo cells .	Transfection of Axin1 overexpressed vector and a specific sumatriptan dose were used to inhibit the activity of Axin1 mediated signaling pathway in LoVo cells.	0	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Axin1	Axin1 overexpressed	axin1	Axin1	Axin1	axin1	2	3	17	18
Regulated Aurora-A is critical for maintenance of genomic integrity after DNA damage and the STK15 SNPs disrupt some physiologic functions of Aurora-A ; therefore , we hypothesized that the STK T91A and G169A SNPs would mediate CTXRT resistance and lead to adverse outcomes in patients with E/GEJC .	Regulated Aurora-A is critical for maintenance of genomic integrity after DNA damage and the STK15 SNPs disrupt some physiologic functions of Aurora-A; therefore, we hypothesized that the STK T91A and G169A SNPs would mediate CTXRT resistance and lead to adverse outcomes in patients with E/GEJC.	14	22	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STK15	STK15	STK15	Aurora-A	Aurora-A	Aurora-A	14	15	21	22
AurA depletion induces a proteasome dependent degradation of ASAP .	AurA depletion induces a proteasome dependent degradation of ASAP.	0	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	AurA	AurA	AurA	ASAP	ASAP	ASAP	0	1	8	9
Additionally , we note that inhibition of ATR kinase activity , by caffeine , seems to induce an enhanced association of Rad17 with damaged DNA .	Additionally, we note that inhibition of ATR kinase activity, by caffeine, seems to induce an enhanced association of Rad17 with damaged DNA.	7	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	Rad17	Rad17	Rad17	7	8	21	22
Given early indications of a role for tankyrase in APC regulated destabilization of AXIN , additional work is needed to decipher how APC limits AXIN abundance .	Given early indications of a role for tankyrase in APC regulated destabilization of AXIN, additional work is needed to decipher how APC limits AXIN abundance.	22	25	limits	Negative_activation_token_1_noun	Positive_activation	Negative_activation	AXIN	AXIN	AXIN	APC	APC	APC	24	25	22	23
Colchicine , a MT depolymerizing agent , abolished perinuclear accumulation of VP ( TMR ) , and Western blot analysis showed that VP induced V2R-GFP degradation is markedly retarded , but not abolished , by colchicine ( 10 muM ) .	Colchicine, a MT depolymerizing agent, abolished perinuclear accumulation of VP (TMR), and Western blot analysis showed that VP induced V2R-GFP degradation is markedly retarded, but not abolished, by colchicine (10 muM).	22	25	induced	Positive_early_activation	Positive_activation	Negative_activation	VP	VP	VP	V2R-GFP	V2R-GFP	V2R-GFP	22	23	24	25
As with chemical inhibition , immunodepletion of ATR abrogated CtIP dependent resection ( XREF_SUPPLEMENTARY ) .	As with chemical inhibition, immunodepletion of ATR abrogated CtIP dependent resection (XREF_SUPPLEMENTARY).	5	11	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ATR	ATR	ATR	CtIP	CtIP	CtIP	7	8	9	10
This is consistent with the observation that BACE1 deficiency almost abolishes the production of Abeta in mice .	This is consistent with the observation that BACE1 deficiency almost abolishes the production of Abeta in mice.	7	15	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	7	8	14	15
Heterozygous genetic depletion of BACE1 prevented the mitochondrial accumulation of both CTF99 and full length APP protein in an age dependent manner ( i.e. at 6 months of age , but not 12 months of age ) .	Heterozygous genetic depletion of BACE1 prevented the mitochondrial accumulation of both CTF99 and full length APP protein in an age dependent manner (i.e. at 6 months of age, but not 12 months of age).	2	16	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	4	5	15	16
These data further support the idea that endosomes are the most optimal compartments for BACE-1 enzymatic activities and that prevention of BACE-1 distribution into endosomes can reduce APP processing into Abeta .	These data further support the idea that endosomes are the most optimal compartments for BACE-1 enzymatic activities and that prevention of BACE-1 distribution into endosomes can reduce APP processing into Abeta.	21	28	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE-1	BACE-1	BACE-1	APP	APP	APP	21	22	27	28
Bace1 knockout ( Bace1 KO ) mice , which do not produce Abeta , show increased motor and cognitive deficits after TBI in the KO mice as compared to wild type controls .	Bace1 knockout (Bace1 KO) mice, which do not produce Abeta, show increased motor and cognitive deficits after TBI in the KO mice as compared to wild type controls.	0	13	produce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bace1	Bace1	Bace1	Abeta	Abeta	Abeta	0	1	12	13
Both pharmacological BACE1 inhibition and genetic loss of APP partially protected neurons from NMDA induced toxicity .	Both pharmacological BACE1 inhibition and genetic loss of APP partially protected neurons from NMDA induced toxicity.	2	9	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	2	3	8	9
Inhibition of beta-site amyloid precursor protein ( APP )-cleaving enzyme-1 ( BACE1 ) , the enzyme that initiates Abeta production , and other Abeta lowering strategies are commonly tested in transgenic mice overexpressing mutant APP .	Inhibition of beta-site amyloid precursor protein (APP)-cleaving enzyme-1 (BACE1), the enzyme that initiates Abeta production, and other Abeta lowering strategies are commonly tested in transgenic mice overexpressing mutant APP.	0	23	initiates	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	18	19
For example , we previously reported that nicotinamide riboside , a potent inducer of Fbx2 expression in neurons , significantly increased the binding of BACE1 to ubiquitin , enhanced BACE1 degradation by proteasome , and thus reduced Abeta toxicity .	For example, we previously reported that nicotinamide riboside, a potent inducer of Fbx2 expression in neurons, significantly increased the binding of BACE1 to ubiquitin, enhanced BACE1 degradation by proteasome, and thus reduced Abeta toxicity.	7	38	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	nicotinamide riboside, a potent inducer of Fbx2 expression in neurons, significantly increased the binding of BACE1	bace1	Abeta	Abeta	abeta	24	25	37	38
BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo .	BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo.	0	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE overexpression	bace	Abeta	Abeta	abeta	0	1	10	11
By inhibition of BACE1 mediated cleavage of APP , quercetin suppresses beta-amyloid synthesis in cell-free , cell based and in silico studies [ XREF_BIBR ] .	By inhibition of BACE1 mediated cleavage of APP, quercetin suppresses beta-amyloid synthesis in cell-free, cell based and in silico studies [XREF_BIBR].	1	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	7	8
Exploring the mechanisms of this effect , we obtained data that BRI2 decreases the cellular levels of BACE1 thus reducing the beta-cleavage of APP .	Exploring the mechanisms of this effect, we obtained data that BRI2 decreases the cellular levels of BACE1 thus reducing the beta-cleavage of APP.	11	24	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BRI2 decreases the cellular levels of BACE1	bace1	APP	APP	app	17	18	23	24
Genetic ablation of BACE-1 completely abolishes Abeta production , establishing BACE-1 as the major neuronal enzyme responsible for initiating the amyloidogenic processing of APP [ XREF_BIBR ] .	Genetic ablation of BACE-1 completely abolishes Abeta production, establishing BACE-1 as the major neuronal enzyme responsible for initiating the amyloidogenic processing of APP [XREF_BIBR].	1	7	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	3	4	6	7
The concentrations of sAPP-beta decreased and sAPP-alpha increased in response to treatment , further supporting that BACE1 inhibition induces a shift in APP processing pathways ( XREF_FIG ) .	The concentrations of sAPP-beta decreased and sAPP-alpha increased in response to treatment, further supporting that BACE1 inhibition induces a shift in APP processing pathways (XREF_FIG).	16	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	16	17	22	23
However , this coupling is not bidirectional since only BACE1 inhibition increased ADAM10-cleavage of APP , whereas the knock-out of ADAM10 did not raise beta-secretase cleavage of APP or Abeta generation .	However, this coupling is not bidirectional since only BACE1 inhibition increased ADAM10-cleavage of APP, whereas the knock-out of ADAM10 did not raise beta-secretase cleavage of APP or Abeta generation.	9	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	9	10	14	15
Overexpression or downregulation of BACE1 induces or inhibits cleavage of APP at the known beta-site locations , Asp1 and Glu11 , respectively .	Overexpression or downregulation of BACE1 induces or inhibits cleavage of APP at the known beta-site locations, Asp1 and Glu11, respectively.	0	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	Overexpression or downregulation of BACE1	bace1	APP	APP	app	4	5	10	11
Over expression of RTN proteins results in prolonged BACE1 retention in the ER with concomitant decrease in BACE1 mediated APP cleavage [ XREF_BIBR ] .	Over expression of RTN proteins results in prolonged BACE1 retention in the ER with concomitant decrease in BACE1 mediated APP cleavage [XREF_BIBR].	15	20	mediated	Positive_early_activation	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	17	18	19	20
Therefore , inhibition of BACE1 mediated beta processing of APP by regulating SNX12 might serve as an alternative strategy in developing an AD intervention .	Therefore, inhibition of BACE1 mediated beta processing of APP by regulating SNX12 might serve as an alternative strategy in developing an AD intervention.	2	10	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	4	5	9	10
Consequently , BACE1 inhibiting approaches can not reverse BACE1 or APP elevations associated with already existing Abeta plaques during advanced stages of AD , encountering their lesser efficacy in suppressing further plaque growth or ameliorating memory declines .	Consequently, BACE1 inhibiting approaches can not reverse BACE1 or APP elevations associated with already existing Abeta plaques during advanced stages of AD, encountering their lesser efficacy in suppressing further plaque growth or ameliorating memory declines.	2	11	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	2	3	10	11
Furthermore , BACE1 siRNA reduced APP betaCTF and Abeta production in primary cortical neurons derived from both wild-type and transgenic mice harboring the Swedish APP mutant .	Furthermore, BACE1 siRNA reduced APP betaCTF and Abeta production in primary cortical neurons derived from both wild-type and transgenic mice harboring the Swedish APP mutant.	2	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	8	9
This is in agreement with the previous findings that BACE1 haploinsufficiency can reduce Abeta concentrations and plaque load during earlier stages of progressive AD like pathology , whereas it has little or no effects on robust beta-amyloidosis at later stages in different APP transgenic mice .	This is in agreement with the previous findings that BACE1 haploinsufficiency can reduce Abeta concentrations and plaque load during earlier stages of progressive AD like pathology, whereas it has little or no effects on robust beta-amyloidosis at later stages in different APP transgenic mice.	9	14	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	9	10	13	14
Inhibition of gadd153 would therefore reduce NF-kappaB and BACE1 expression , prevent Abeta accumulation , and may have a translation potential for reducing the propgression of AD .	Inhibition of gadd153 would therefore reduce NF-kappaB and BACE1 expression, prevent Abeta accumulation, and may have a translation potential for reducing the propgression of AD.	2	13	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	gadd153 would therefore reduce NF-kappaB and BACE1 expression	bace1	Abeta	Abeta	abeta	8	9	12	13
Higher BACE expression inhibited Abeta deposition within both the cortex and the hippocampus .	Higher BACE expression inhibited Abeta deposition within both the cortex and the hippocampus.	0	5	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE expression	bace	Abeta	Abeta	abeta	1	2	4	5
This observation is consistent with the finding that the prodomain in BACE1 is less rigid than the other aspartic proteases and fails to block the entrance of APP into the BACE1 active cleft .	This observation is consistent with the finding that the prodomain in BACE1 is less rigid than the other aspartic proteases and fails to block the entrance of APP into the BACE1 active cleft.	9	28	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	11	12	27	28
Similarly , lentiviral delivery of BACE1 RNAi attenuated Abeta amyloidosis and rescued memory deficits in APP transgenics [ XREF_BIBR , XREF_BIBR ] .	Similarly, lentiviral delivery of BACE1 RNAi attenuated Abeta amyloidosis and rescued memory deficits in APP transgenics [XREF_BIBR, XREF_BIBR].	5	9	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	5	6	8	9
As BACE1 represents a favored target for AD intervention , inhibition of BACE1 mediated beta processing of APP by regulating SNX12 might provide an alternative strategy for developing AD therapeutics .	As BACE1 represents a favored target for AD intervention, inhibition of BACE1 mediated beta processing of APP by regulating SNX12 might provide an alternative strategy for developing AD therapeutics.	10	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	12	13	17	18
Elevation of endolysosome pH on one hand could lead to increased BACE-1 protein levels and enhanced BACE-1 activity that leads to amyloidogenic processing of AbetaPP , and on the other hand could reduce cathepsin activity thus impairing Abeta degradation in lysosomes , thus leading to intraneuronal Abeta accumulation ( XREF_FIG ) .	Elevation of endolysosome pH on one hand could lead to increased BACE-1 protein levels and enhanced BACE-1 activity that leads to amyloidogenic processing of AbetaPP, and on the other hand could reduce cathepsin activity thus impairing Abeta degradation in lysosomes, thus leading to intraneuronal Abeta accumulation (XREF_FIG).	16	38	impairing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE-1	BACE-1	BACE-1	Abeta	Abeta	Abeta	16	17	37	38
The knock-down of bace1 prevents Abeta generation and abolishes amyloid pathology in mice expressing the Swedish mutation of APP .	The knock-down of bace1 prevents Abeta generation and abolishes amyloid pathology in mice expressing the Swedish mutation of APP.	1	6	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	bace1	bace1	bace1	Abeta	Abeta	Abeta	3	4	5	6
The absence of BACE1 activity greatly attenuates Abeta production , XREF_BIBR - XREF_BIBR so the inhibition of this enzyme has come under a tremendous amount of scrutiny as a potential therapeutic mechanism for the treatment of AD .	The absence of BACE1 activity greatly attenuates Abeta production, XREF_BIBR - XREF_BIBR so the inhibition of this enzyme has come under a tremendous amount of scrutiny as a potential therapeutic mechanism for the treatment of AD.	3	8	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	3	4	7	8
That BACE1 expression levels regulate the trafficking and maturation of the APP family of proteins , but that BACE1 ablation did not prevent generation of APP , APLP1 and APLP2 ICDs .	That BACE1 expression levels regulate the trafficking and maturation of the APP family of proteins, but that BACE1 ablation did not prevent generation of APP, APLP1 and APLP2 ICDs.	18	30	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	18	19	25	26
While increased localization of BACE1 within the ER reduces generation of Abeta , intracellular trafficking of BACE1 to the more acidic endosomes clearly enhances Abeta production .	While increased localization of BACE1 within the ER reduces generation of Abeta, intracellular trafficking of BACE1 to the more acidic endosomes clearly enhances Abeta production.	14	25	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	16	17	24	25
Furthermore , BACE1 +/- deletion also reduced Abeta deposition in the insular cortex and basolateral amygdala of 5XFAD mice , two brain regions critically involved in the processing of CTA .	Furthermore, BACE1 +/- deletion also reduced Abeta deposition in the insular cortex and basolateral amygdala of 5XFAD mice, two brain regions critically involved in the processing of CTA.	2	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	7	8
Decreased metabolic activity increases beta secretase ( BACE ) which , in turn , increases Abeta deposition as a secondary response .	Decreased metabolic activity increases beta secretase (BACE) which, in turn, increases Abeta deposition as a secondary response.	5	16	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	7	8	15	16
Our data suggest that lacking BACE1 , which abolishes Abeta production [ XREF_BIBR , XREF_BIBR ] and several other BACE1 substrates [ XREF_BIBR - XREF_BIBR ] , results in basal potentiation of excitatory synaptic transmission in L2/3 of V1 and prevents homeostatic regulation by changes in sensory experience .	Our data suggest that lacking BACE1, which abolishes Abeta production [XREF_BIBR, XREF_BIBR] and several other BACE1 substrates [XREF_BIBR - XREF_BIBR], results in basal potentiation of excitatory synaptic transmission in L2/3 of V1 and prevents homeostatic regulation by changes in sensory experience.	4	10	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	5	6	9	10
It is interesting to note that elevated BACE1 activity induces impaired trafficking of APP along axons , similar to the impaired trafficking of Na v 1 alpha-subunits to the cell surface [ XREF_BIBR ] .	It is interesting to note that elevated BACE1 activity induces impaired trafficking of APP along axons, similar to the impaired trafficking of Na v 1 alpha-subunits to the cell surface [XREF_BIBR].	7	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	7	8	13	14
Finally , BACE1 has the correct cleavage specificity predicted for beta-secretase : BACE1 cleaves at Asp +1 and Glu +11 of the Abeta sequence ; BACE1 over-expression and knockdown increases and decreases sAPPbeta , C99 , and Abeta production , respectively ; BACE1 knockdown increases sAPPalpha and p3 production ; BACE1 sequence specificity at P1 is Leu > > Met > Val .	Finally, BACE1 has the correct cleavage specificity predicted for beta-secretase : BACE1 cleaves at Asp +1 and Glu +11 of the Abeta sequence; BACE1 over-expression and knockdown increases and decreases sAPPbeta, C99, and Abeta production, respectively; BACE1 knockdown increases sAPPalpha and p3 production; BACE1 sequence specificity at P1 is Leu>> Met> Val.	42	48	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	sAPPalpha	sAPPalpha	sAPPalpha	42	43	45	46
These studies showed that while BACE1 +/- deletion causes only a slight decrease ( ~ 12 % ) of soluble Abeta in younger APP mice at pre-pathological stages , it results in dramatic reductions ( ~ 30-90 % ) in Abeta levels and plaque load in older APP mice at moderate pathological stages .	These studies showed that while BACE1 +/- deletion causes only a slight decrease (~ 12%) of soluble Abeta in younger APP mice at pre-pathological stages, it results in dramatic reductions (~ 30-90%) in Abeta levels and plaque load in older APP mice at moderate pathological stages.	5	21	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	5	6	20	21
We also confirm the prior results of decreased BACE1 cleavage products of APP in the setting of anti-LRRTM3 siRNA treatment of SH-SY5Y-APP695wt cells XREF_BIBR .	We also confirm the prior results of decreased BACE1 cleavage products of APP in the setting of anti-LRRTM3 siRNA treatment of SH-SY5Y-APP695wt cells XREF_BIBR.	8	15	products	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	8	9	12	13
XREF_BIBR , XREF_BIBR Regardless of whether BACE1-AS is knocked down or overexpressed , both BACE1 mRNA and BACE1 protein are regulated in parallel , thereby reducing Abeta production and plaque deposition .	XREF_BIBR, XREF_BIBR Regardless of whether BACE1-AS is knocked down or overexpressed, both BACE1 mRNA and BACE1 protein are regulated in parallel, thereby reducing Abeta production and plaque deposition.	14	27	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	14	15	26	27
All the BACE1 peptide inhibitors was able to reduce the Abeta production ( XREF_FIG b ) .	All the BACE1 peptide inhibitors was able to reduce the Abeta production (XREF_FIG b).	0	11	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	10	11
Furthermore , we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Abeta production does lower amyloid deposition in 12-month-old Tg2576 mice .	Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Abeta production does lower amyloid deposition in 12-month-old Tg2576 mice.	11	15	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	14	15
Immunoblotting of the same nitrocellulose membrane showed that only fully glycosylated APP is phosphorylated , and that BACE overexpression selectively reduced mature APP within the optic nerve .	Immunoblotting of the same nitrocellulose membrane showed that only fully glycosylated APP is phosphorylated, and that BACE overexpression selectively reduced mature APP within the optic nerve.	17	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE overexpression	bace	APP	APP	app	17	18	22	23
However , higher levels of BACE expression dramatically decreased thioflavin S positive cortical deposition of Abeta amyloid .	However, higher levels of BACE expression dramatically decreased thioflavin S positive cortical deposition of Abeta amyloid.	5	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE expression	bace	Abeta	Abeta	abeta	5	6	15	16
beta-secretase ( BACE ) inhibition may also reduce Abeta , however , difficulties in drug delivery have limited its progress .	beta-secretase (BACE) inhibition may also reduce Abeta, however, difficulties in drug delivery have limited its progress.	0	9	reduce	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	2	3	8	9
Besides its antioxidant effect , curcumin was reported to inhibit BACE1 expression and reduce Abeta production [ XREF_BIBR ] .	Besides its antioxidant effect, curcumin was reported to inhibit BACE1 expression and reduce Abeta production [XREF_BIBR].	5	15	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	curcumin was reported to inhibit BACE1 expression	bace1	Abeta	Abeta	abeta	10	11	14	15
BACE overexpression in neuronal and nonneuronal cells increases Abeta generation , whereas genetic ablation of BACE eliminates Abeta production .	BACE overexpression in neuronal and nonneuronal cells increases Abeta generation, whereas genetic ablation of BACE eliminates Abeta production.	13	18	eliminates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	15	16	17	18
In fact , several studies unequivocally demonstrated that inhibition of BACE1 by RNAi mediated knock-down or genetic deletion ameliorates Abeta associated pathologies and cognitive deficits in mouse models of Abeta-amyloidosis .	In fact, several studies unequivocally demonstrated that inhibition of BACE1 by RNAi mediated knock-down or genetic deletion ameliorates Abeta associated pathologies and cognitive deficits in mouse models of Abeta-amyloidosis.	8	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	10	11	19	20
Subsequently , the decrease of BACE1 mediated APP processing may contribute to the improvement of hippocampal LTP and spatial learning and memory after low-frequency rTMS treatment in the present study .	Subsequently, the decrease of BACE1 mediated APP processing may contribute to the improvement of hippocampal LTP and spatial learning and memory after low-frequency rTMS treatment in the present study.	3	8	mediated	Positive_early_activation	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	7	8
Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid ( Abeta ) precursor protein cleaving enzyme 1 ( BACE1 ) that reduces Abeta production .	Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Abeta) precursor protein cleaving enzyme 1 (BACE1) that reduces Abeta production.	16	24	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	19	20	23	24
Ablation of BACE1 and BACE2 in a mouse model had reduced Abeta production compared to just a BACE1 knockout , suggesting BACE2 does , in fact , contribute to Abeta load [ XREF_BIBR ] .	Ablation of BACE1 and BACE2 in a mouse model had reduced Abeta production compared to just a BACE1 knockout, suggesting BACE2 does, in fact, contribute to Abeta load [XREF_BIBR].	0	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	11	12
Increased targeting of BACE1 to the lipid raft had been suggested to enhance beta-secretase processing of APP [ XREF_BIBR , XREF_BIBR ] .	Increased targeting of BACE1 to the lipid raft had been suggested to enhance beta-secretase processing of APP [XREF_BIBR, XREF_BIBR].	1	20	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	16	17
Therefore , overexpression of DSCR1 , a calcineurin inhibitor , might reduce BACE1 expression in neurons and thereby decrease Abeta generation , suggesting a negative role of calcineurin dependent BACE1 on the proteolytic cleavage of APP in Drosophila .	Therefore, overexpression of DSCR1, a calcineurin inhibitor, might reduce BACE1 expression in neurons and thereby decrease Abeta generation, suggesting a negative role of calcineurin dependent BACE1 on the proteolytic cleavage of APP in Drosophila.	2	20	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	overexpression of DSCR1, a calcineurin inhibitor, might reduce BACE1 expression	bace1	Abeta	Abeta	abeta	12	13	19	20
What is the ideal BACE inhibition strategy which decreases Abeta production while having a minimal impact on other BACE1 substrates ?	What is the ideal BACE inhibition strategy which decreases Abeta production while having a minimal impact on other BACE1 substrates?	4	10	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	4	5	9	10
Moreover , it is considered to be a better target than gamma-seretase for disease modifying drugs since the knockout mouse of BACE1 does not produce Abeta and shows only minor behavioral changes .	Moreover, it is considered to be a better target than gamma-seretase for disease modifying drugs since the knockout mouse of BACE1 does not produce Abeta and shows only minor behavioral changes.	19	26	produce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	21	22	25	26
Overexpression of reticulon proteins results in prolonged BACE1 retention in the endoplasmic reticulum with concomitant decrease in BACE1 mediated APP cleavage [ XREF_BIBR ] .	Overexpression of reticulon proteins results in prolonged BACE1 retention in the endoplasmic reticulum with concomitant decrease in BACE1 mediated APP cleavage [XREF_BIBR].	15	20	mediated	Positive_early_activation	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	17	18	19	20
Increased targeting of BACE1 to the lipid raft was suggested to enhance beta-secretase processing of APP [ XREF_BIBR , XREF_BIBR ] .	Increased targeting of BACE1 to the lipid raft was suggested to enhance beta-secretase processing of APP [XREF_BIBR, XREF_BIBR].	1	19	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	15	16
Using a human TfR knock-in mouse , we observed that anti-TfR and BACE1 antibodies could cross the BBB and reduce brain Abeta in a TfR affinity dependent fashion .	Using a human TfR knock-in mouse, we observed that anti-TfR and BACE1 antibodies could cross the BBB and reduce brain Abeta in a TfR affinity dependent fashion.	10	22	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	12	13	21	22
BACE inhibition increases sAPPalpha secretion from trans-Golgi network targeted APP .	BACE inhibition increases sAPPalpha secretion from trans-Golgi network targeted APP.	0	4	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE	BACE	sAPPalpha	sAPPalpha	sAPPalpha	0	1	3	4
Conversely , an alanine to threonine substitution two residues from the BACE1 cleavage site ( A673T ) reduces BACE1 mediated APP cleavage and results in a significant decrease in the risk of AD [ XREF_BIBR ] .	Conversely, an alanine to threonine substitution two residues from the BACE1 cleavage site (A673T) reduces BACE1 mediated APP cleavage and results in a significant decrease in the risk of AD [XREF_BIBR].	17	21	mediated	Positive_early_activation	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	18	19	20	21
Consequently , the lack of BACE1 prevents beta processing of the Amyloid Precursor Protein ( APP ) and Abeta production , which made it a promising target for drug development .	Consequently, the lack of BACE1 prevents beta processing of the Amyloid Precursor Protein (APP) and Abeta production, which made it a promising target for drug development.	3	14	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Amyloid Precursor Protein	Amyloid Precursor Protein	Amyloid Precursor Protein	5	6	11	14
BACE2 and BACE1 degrade Abeta in vitro .	BACE2 and BACE1 degrade Abeta in vitro.	0	5	degrade	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	4	5
Moreover , BACE inhibition in cells that expressed a TGN retained form of APP resulted in an elevation of sAPPalpha .	Moreover, BACE inhibition in cells that expressed a TGN retained form of APP resulted in an elevation of sAPPalpha.	2	20	elevation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	BACE	BACE	BACE	sAPPalpha	sAPPalpha	sAPPalpha	2	3	19	20
Similarly , binding of the BACE1 cleavage site in APP by an antibody also blocks BACE1 processing of APP .	Similarly, binding of the BACE1 cleavage site in APP by an antibody also blocks BACE1 processing of APP.	5	19	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	18	19
These physiological BACE1 functions cast a doubt on the safety of BACE1 inhibition therapy currently being developed to block Abeta generation in AD patients .	These physiological BACE1 functions cast a doubt on the safety of BACE1 inhibition therapy currently being developed to block Abeta generation in AD patients.	11	20	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	11	12	19	20
Lentiviral BACE1 siRNA delivered into the hippocampus has been found to effectively reduce Abeta production , neurodegeneration , and behavioral deficits in APP transgenic mice [ XREF_BIBR , XREF_BIBR ] .	Lentiviral BACE1 siRNA delivered into the hippocampus has been found to effectively reduce Abeta production, neurodegeneration, and behavioral deficits in APP transgenic mice [XREF_BIBR, XREF_BIBR].	1	24	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	1	2	22	23
Therefore we suggest that constitutive alpha-secretase activity maintains basal glucose uptake in muscle cells , whereas increased BACE1 activity inhibits this process by diverting APP down the amyloidogenic pathway .	Therefore we suggest that constitutive alpha-secretase activity maintains basal glucose uptake in muscle cells, whereas increased BACE1 activity inhibits this process by diverting APP down the amyloidogenic pathway.	17	25	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	17	18	24	25
TAT-APPsweBBP treatment reduced BACE1 mediated APP amyloidogenesis both in vitro ( XREF_FIG ) and in 5XFAD mice ( XREF_FIG ) , while also reducing cognitive impairments ( XREF_FIG ) .	TAT-APPsweBBP treatment reduced BACE1 mediated APP amyloidogenesis both in vitro (XREF_FIG) and in 5XFAD mice (XREF_FIG), while also reducing cognitive impairments (XREF_FIG).	2	6	mediated	Positive_early_activation	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	5	6
AD transgenic mouse models deficient in BACE1 abrogate the production of Abeta .	AD transgenic mouse models deficient in BACE1 abrogate the production of Abeta.	4	12	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	6	7	11	12
Furthermore , BACE1 heterozygous knockout mice have no reported abnormal phenotypes so far and heterozygous knockout of BACE1 still can reduce Abeta deposition in AD mice [ XREF_BIBR , XREF_BIBR ] .	Furthermore, BACE1 heterozygous knockout mice have no reported abnormal phenotypes so far and heterozygous knockout of BACE1 still can reduce Abeta deposition in AD mice [XREF_BIBR, XREF_BIBR].	15	22	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	17	18	21	22
BACE1 half-life was reduced in cells overexpressing UCHL1 and decreased APP C-terminal fragment C99 and Abeta levels were observed [ XREF_BIBR ] .	BACE1 half-life was reduced in cells overexpressing UCHL1 and decreased APP C-terminal fragment C99 and Abeta levels were observed [XREF_BIBR].	0	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	10	11
BACE1 deficiency almost abolishes the production of Abeta in mouse models , while mice deficient in BACE2 show no significant difference in Abeta generation [ XREF_BIBR ] .	BACE1 deficiency almost abolishes the production of Abeta in mouse models, while mice deficient in BACE2 show no significant difference in Abeta generation [XREF_BIBR].	0	10	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	7	8
Targeting of BACE1 to lipid rafts by adding an glycosylphosphatidylinositol ( GPI ) anchor at the place of transmembrane and C-terminal domain increased the production of sAPPbeta and Abeta [ XREF_BIBR ] .	Targeting of BACE1 to lipid rafts by adding an glycosylphosphatidylinositol (GPI) anchor at the place of transmembrane and C-terminal domain increased the production of sAPPbeta and Abeta [XREF_BIBR].	0	29	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	28	29
Double-transgenic APP and PS1 mice express altered APP and PS1 mRNAs and proteins , reduced beta-secretase 1 ( BACE1 ) mRNA and normal BACE1 protein , all of which suggest a particular mechanism of amyloidogenesis when compared with sporadic AD .	Double-transgenic APP and PS1 mice express altered APP and PS1 mRNAs and proteins, reduced beta-secretase 1 (BACE1) mRNA and normal BACE1 protein, all of which suggest a particular mechanism of amyloidogenesis when compared with sporadic AD.	5	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	23	24	7	8
Our results suggest that lentiviral vector delivery of BACE1 siRNA can specifically reduce the cleavage of APP and neurodegeneration in vivo and indicate that this approach could have potential therapeutic value for treatment of Alzheimer disease .	Our results suggest that lentiviral vector delivery of BACE1 siRNA can specifically reduce the cleavage of APP and neurodegeneration in vivo and indicate that this approach could have potential therapeutic value for treatment of Alzheimer disease.	8	18	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	8	9	16	17
In accordance with our previous findings [ XREF_BIBR , XREF_BIBR ] , we confirmed that BACE1 haploinsufficiency alone was not sufficient to reduce extensive Abeta deposition found in the hippocampus or cerebral cortex of 5XFAD mice at 12months of age ( n = 2 ) .	In accordance with our previous findings [XREF_BIBR, XREF_BIBR], we confirmed that BACE1 haploinsufficiency alone was not sufficient to reduce extensive Abeta deposition found in the hippocampus or cerebral cortex of 5XFAD mice at 12months of age (n = 2).	15	25	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	15	16	24	25
Furthermore , BACE1 haploinsufficiency significantly lowered direct beta-cleavage metabolites of APP ( C99 and sAPPbeta ) in 5XFAD mouse brains , changes that were also indistinguishable between males and females .	Furthermore, BACE1 haploinsufficiency significantly lowered direct beta-cleavage metabolites of APP (C99 and sAPPbeta) in 5XFAD mouse brains, changes that were also indistinguishable between males and females.	2	14	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	2	3	10	11
Increased targeting of BACE1 to the lipid raft had been suggested to enhance beta-secretase processing of APP .	Increased targeting of BACE1 to the lipid raft had been suggested to enhance beta-secretase processing of APP.	1	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	3	4	16	17
On the one hand , BACE1 and APP in vivo and in vitro partially localize to lipid raft domains enriched in cholesterol and sphingolipids , and enhanced targeting of BACE1 to these microdomains via addition of a GPI-anchor enhances Abeta production .	On the one hand, BACE1 and APP in vivo and in vitro partially localize to lipid raft domains enriched in cholesterol and sphingolipids, and enhanced targeting of BACE1 to these microdomains via addition of a GPI-anchor enhances Abeta production.	27	40	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	29	30	39	40
Therefore , we hypothesized that enhanced BACE expression leads to increased APP cleavage early in the secretory pathway , depleting APP before its transport to the presynaptic terminal .	Therefore, we hypothesized that enhanced BACE expression leads to increased APP cleavage early in the secretory pathway, depleting APP before its transport to the presynaptic terminal.	6	21	depleting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE expression	bace	APP	APP	app	6	7	20	21
This result supports the contention that the cells compensate for the enhanced p60TRP mediated PP2A activity ( compare with NSCs and PC12 cells , Figs 2D , 4D and 9C ) , resulting in the dephosphorylation of App ( XREF_FIG ) combined with reduced Bace1 mediated App processing [ XREF_BIBR ] .	This result supports the contention that the cells compensate for the enhanced p60TRP mediated PP2A activity (compare with NSCs and PC12 cells, Figs 2D, 4D and 9C), resulting in the dephosphorylation of App (XREF_FIG) combined with reduced Bace1 mediated App processing [XREF_BIBR].	44	49	mediated	Positive_early_activation	Positive_activation	Negative_activation	Bace1	Bace1	Bace1	App	App	App	44	45	46	47
As previously described , very high levels of BACE1 led to a paradoxical suppression of Abeta production , due to the generation , by the excess BACE1 enzyme , of abnormal APP derived intracellular cleavage products , that are not efficient substrates for GS ( XREF_SUPPLEMENTARY ) .	As previously described, very high levels of BACE1 led to a paradoxical suppression of Abeta production, due to the generation, by the excess BACE1 enzyme, of abnormal APP derived intracellular cleavage products, that are not efficient substrates for GS (XREF_SUPPLEMENTARY).	13	32	suppression	Negative_activation_syntax_1_noun	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	26	27	31	32
Rheb overexpression depletes BACE1 protein levels and reduces Abeta generation , whereas the RNAi knockdown of endogenous Rheb promotes BACE1 accumulation , and this effect by Rheb is independent of its mTOR signaling .	Rheb overexpression depletes BACE1 protein levels and reduces Abeta generation, whereas the RNAi knockdown of endogenous Rheb promotes BACE1 accumulation, and this effect by Rheb is independent of its mTOR signaling.	0	9	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	Rheb overexpression depletes BACE1 protein levels	bace1	Abeta	Abeta	abeta	3	4	8	9
Partial ablation of BACE1 reduces sAPPbeta , C99 and Abeta in 5XFAD mice .	Partial ablation of BACE1 reduces sAPPbeta, C99 and Abeta in 5XFAD mice.	1	9	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	sAPPbeta	sAPPbeta	sAPPbeta	3	4	5	6
Targeting BACE1 at the pre-mRNA level offers a very different alternative toward lowering BACE1 proteolytic production of Abeta .	Targeting BACE1 at the pre-mRNA level offers a very different alternative toward lowering BACE1 proteolytic production of Abeta.	13	18	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	13	14	17	18
For example , both the copatching of APP and BACE1 by cross linking antibodies [ XREF_BIBR ] and the exclusive targeting of BACE1 to lipid rafts by the addition of a GPI-anchor [ XREF_BIBR ] significantly increased APP cleavage at the beta-secretase site .	For example, both the copatching of APP and BACE1 by cross linking antibodies [XREF_BIBR] and the exclusive targeting of BACE1 to lipid rafts by the addition of a GPI-anchor [XREF_BIBR] significantly increased APP cleavage at the beta-secretase site.	5	38	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	9	10	37	38
BACE1 inhibition increases the ADAM10 cleavage of APP , such that total APP cleavage is only mildly reduced [ XREF_BIBR , XREF_BIBR ] .	BACE1 inhibition increases the ADAM10 cleavage of APP, such that total APP cleavage is only mildly reduced [XREF_BIBR, XREF_BIBR].	0	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	0	1	7	8
Furthermore , we have shown that BACE1 proteins translated from alternatively spliced transcripts have dramatically reduced beta-secretase activity and promotion of BACE1 alternative splicing reduces Abeta production .	Furthermore, we have shown that BACE1 proteins translated from alternatively spliced transcripts have dramatically reduced beta-secretase activity and promotion of BACE1 alternative splicing reduces Abeta production.	6	26	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	6	7	25	26
However , recent research also shows that partial inhibition of BACE1 can improve memory deficits and synaptic plasticity [ XREF_BIBR ] , suggesting that BACE1 may reduce or impair neuroplasticity by precluding the production of sAPPalpha , which is important in neuronal plasticity , survival , and protection [ XREF_BIBR ] .	However, recent research also shows that partial inhibition of BACE1 can improve memory deficits and synaptic plasticity [XREF_BIBR], suggesting that BACE1 may reduce or impair neuroplasticity by precluding the production of sAPPalpha, which is important in neuronal plasticity, survival, and protection [XREF_BIBR].	24	39	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	sAPPalpha	sAPPalpha	sAPPalpha	24	25	35	36
Knock-out of BACE1 in mice completely depleted neuronal Abeta secretion .	Knock-out of BACE1 in mice completely depleted neuronal Abeta secretion.	0	9	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	8	9
These concerns were further fueled by recent findings demonstrating that BACE inhibition upregulates non canonical APP processing and production of Aeta fragments that impair neuronal activity and LTP .	These concerns were further fueled by recent findings demonstrating that BACE inhibition upregulates non canonical APP processing and production of Aeta fragments that impair neuronal activity and LTP.	10	16	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE	BACE	APP	APP	APP	10	11	15	16
BACE inhibition does not increase sAPPalpha secretion in APP expressing CHO cells .	BACE inhibition does not increase sAPPalpha secretion in APP expressing CHO cells.	0	6	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE	BACE	sAPPalpha	sAPPalpha	sAPPalpha	0	1	5	6
Inhibition of BACE1 increased ADAM10 cleavage of APP , but a reduction of ADAM10 activity did not increase the BACE1 cleavage of APP in the neurons .	Inhibition of BACE1 increased ADAM10 cleavage of APP, but a reduction of ADAM10 activity did not increase the BACE1 cleavage of APP in the neurons.	0	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	2	3	7	8
PKCdelta knockdown reduces BACE1 expression , BACE1 mediated APP processing , and Abeta production .	PKCdelta knockdown reduces BACE1 expression, BACE1 mediated APP processing, and Abeta production.	6	9	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	6	7	8	9
MTT assay results showed that Abeta inhibited the viability of SH-SY5Y cells and downregulation of BACE1 enhanced the inhibitory effects of Abeta .	MTT assay results showed that Abeta inhibited the viability of SH-SY5Y cells and downregulation of BACE1 enhanced the inhibitory effects of Abeta.	11	22	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	15	16	21	22
Overexpression and RNA interference knockdown of CUTA can reduce and increase BACE1 mediated APP processing and Abeta secretion , respectively .	Overexpression and RNA interference knockdown of CUTA can reduce and increase BACE1 mediated APP processing and Abeta secretion, respectively.	8	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	11	12	13	14
BACE1 gene knock-out has been shown to prevent Abeta synthesis in mice , and studies have found that BACE1 activity levels are significantly increased in sporadic AD cases , particularly in neurons around Abeta plaques .	BACE1 gene knock-out has been shown to prevent Abeta synthesis in mice, and studies have found that BACE1 activity levels are significantly increased in sporadic AD cases, particularly in neurons around Abeta plaques.	0	9	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	8	9
BACE1 was also found to degrade Abeta , albeit ~ 150-fold less efficiently than BACE2 .	BACE1 was also found to degrade Abeta, albeit ~ 150-fold less efficiently than BACE2.	0	7	degrade	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	0	1	6	7
Genetic ablation of BACE1 in AD animals abolishes Abeta production and rescues AD like phenotypes .	Genetic ablation of BACE1 in AD animals abolishes Abeta production and rescues AD like phenotypes.	1	9	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	3	4	8	9
Cellular prion protein ( PrP C ) , another BACE1 partner , has been shown to bind the pro domain of BACE1 directly and inhibit BACE1 cleavage of wild type APP [ XREF_BIBR ] .	Cellular prion protein (PrP C), another BACE1 partner, has been shown to bind the pro domain of BACE1 directly and inhibit BACE1 cleavage of wild type APP [XREF_BIBR].	9	32	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	9	10	30	31
Decreased levels of GGA3 have recently been reported for brains of AD patients suggesting that altered compartmentalization of BACE in AD promotes the amyloidogenic processing of APP .	Decreased levels of GGA3 have recently been reported for brains of AD patients suggesting that altered compartmentalization of BACE in AD promotes the amyloidogenic processing of APP.	16	27	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE	BACE	BACE	APP	APP	APP	18	19	26	27
Delivery of BACE1 siRNA appears to specifically reduce the cleavage of APP by inhibiting BACE1 activity .	Delivery of BACE1 siRNA appears to specifically reduce the cleavage of APP by inhibiting BACE1 activity.	2	12	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	2	3	11	12
Alternatively , it has been reported that high expression levels of BACE1 suppress Abeta production both in vitro and in vivo .	Alternatively, it has been reported that high expression levels of BACE1 suppress Abeta production both in vitro and in vivo.	9	14	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	levels of BACE1	bace1	Abeta	Abeta	abeta	11	12	13	14
Interestingly , in the HEK293 heterologous cellular assay the BACE1 peptides completely inhibit the Abeta production while in vivo a maximum of 50 % reduction was achieved .	Interestingly, in the HEK293 heterologous cellular assay the BACE1 peptides completely inhibit the Abeta production while in vivo a maximum of 50% reduction was achieved.	9	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	9	10	14	15
Full-length APP , predominantly the N- and O glycosylated forms of APP detected by 4G8 ( anti-Abeta 17-24 ) , was reduced by BACE overexpression , which is consistent with increased APP proteolysis .	Full-length APP, predominantly the N- and O glycosylated forms of APP detected by 4G8 (anti-Abeta 17-24), was reduced by BACE overexpression, which is consistent with increased APP proteolysis.	0	25	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	BACE	BACE overexpression	bace	APP	APP	app	23	24	1	2
BACE1 peptide inhibitors and the BS conjugated constructs likely act in intracellular vesicles to inhibit BACE1 mediated processing of APP , an assumption based on previous studies that showed endocytosis as a necessary step in APP processing .	BACE1 peptide inhibitors and the BS conjugated constructs likely act in intracellular vesicles to inhibit BACE1 mediated processing of APP, an assumption based on previous studies that showed endocytosis as a necessary step in APP processing.	14	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	15	16	19	20
Furthermore , overexpression of BACE1 in cells or mice reduced APP alpha-secretase cleavage .	Furthermore, overexpression of BACE1 in cells or mice reduced APP alpha-secretase cleavage.	2	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	overexpression of BACE1	bace1	APP	APP	app	4	5	10	11
Mice completely deficient of BACE1 show abolished Abeta production , confirming that BACE1 is a critical and indispensable protease for Abeta release .	Mice completely deficient of BACE1 show abolished Abeta production, confirming that BACE1 is a critical and indispensable protease for Abeta release.	4	8	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	7	8
Since BACE1 acts on the first and rate limiting step in Abeta generation and BACE1 deficiency almost abolishes Abeta generation in mouse models , inhibition of BACE1 has received perhaps the most intensive efforts in academia and in industry .	Since BACE1 acts on the first and rate limiting step in Abeta generation and BACE1 deficiency almost abolishes Abeta generation in mouse models, inhibition of BACE1 has received perhaps the most intensive efforts in academia and in industry.	14	19	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	14	15	18	19
We showed previously that inhibition of monoacylglycerol lipase ( MAGL ) , the primary enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol ( 2-AG ) in the brain , robustly reduces Abeta by inhibiting beta-site amyloid precursor protein cleaving enzyme 1 ( BACE1 ) , a key enzyme responsible for Abeta formation .	We showed previously that inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, robustly reduces Abeta by inhibiting beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme responsible for Abeta formation.	28	45	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	40	41	29	30
In order to test whether sAPP-alpha suppresses BACE1 mediated APP processing in vivo , we further analyzed APP CTF expression ( XREF_FIG ) .	In order to test whether sAPP-alpha suppresses BACE1 mediated APP processing in vivo, we further analyzed APP CTF expression (XREF_FIG).	6	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	7	8	9	10
We may have to seriously consider shifting attention to therapeutic strategies other than BACE1 inhibition or reduction of Abeta alone and pay more attention to simultaneous clearance of tau and Abeta .	We may have to seriously consider shifting attention to therapeutic strategies other than BACE1 inhibition or reduction of Abeta alone and pay more attention to simultaneous clearance of tau and Abeta.	13	19	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	13	14	18	19
However , we discovered that high BACE overexpression paradoxically decreased Abeta deposition despite enhanced beta-cleavage of APP .	However, we discovered that high BACE overexpression paradoxically decreased Abeta deposition despite enhanced beta-cleavage of APP.	6	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE overexpression	bace	Abeta	Abeta	abeta	6	7	10	11
Notably , BACE1 haploinsufficiency did not reverse the upregulation of APP ( this study ) or BACE1 in 5XFAD mice at later age .	Notably, BACE1 haploinsufficiency did not reverse the upregulation of APP (this study) or BACE1 in 5XFAD mice at later age.	2	13	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	2	3	10	11
Additionally , modulation of BACE1 by sAPPalpha reduces generation of Abeta and plaques in cell culture and in a transgenic mouse model of AD .	Additionally, modulation of BACE1 by sAPPalpha reduces generation of Abeta and plaques in cell culture and in a transgenic mouse model of AD.	2	12	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	10	11
Together , these observations indicate that the balance of various BACE1 dependent processes appears to be important for both normal and abnormal performance , and future studies should be alert to potential mechanism based side effects that may occur with strong inhibition of BACE1 designed to attenuate Abeta amyloidosis in AD .	Together, these observations indicate that the balance of various BACE1 dependent processes appears to be important for both normal and abnormal performance, and future studies should be alert to potential mechanism based side effects that may occur with strong inhibition of BACE1 designed to attenuate Abeta amyloidosis in AD.	41	48	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	43	44	47	48
Genetic ablation of BACE1 prevents Abeta deposition and Abeta associated cognitive deficits in a mouse model of Abeta amyloidosis , but the discovery that homozygous BACE1 knockout ( BACE1 -/-) mice exhibit cognitive deficits , impairment of synaptic function , hypomyelination of axons of sciatic and optic nerves , and schizophrenia-relevant endophenotypes raised concerns about potential mechanism based toxicities associated with strong inhibition of BACE1 .	Genetic ablation of BACE1 prevents Abeta deposition and Abeta associated cognitive deficits in a mouse model of Abeta amyloidosis, but the discovery that homozygous BACE1 knockout (BACE1 -/-) mice exhibit cognitive deficits, impairment of synaptic function, hypomyelination of axons of sciatic and optic nerves, and schizophrenia-relevant endophenotypes raised concerns about potential mechanism based toxicities associated with strong inhibition of BACE1.	1	6	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	3	4	5	6
Selective targeting of BACE1 and gamma-secretase processing of APP in lipid rafts is considered as an elegant therapeutic strategy to modulate Abeta production .	Selective targeting of BACE1 and gamma-secretase processing of APP in lipid rafts is considered as an elegant therapeutic strategy to modulate Abeta production.	3	22	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	3	4	21	22
Combined activation of APP and BACE1 diminished the APP sgRNA mediated APP increase in either line ( XREF_FIG ) .	Combined activation of APP and BACE1 diminished the APP sgRNA mediated APP increase in either line (XREF_FIG).	1	12	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	11	12
BACE2 , a homologue of BACE1 located on chromosome 21 may impair the formation of amyloid-beta by cleaving APP within the amyloid-beta region .	BACE2, a homologue of BACE1 located on chromosome 21 may impair the formation of amyloid-beta by cleaving APP within the amyloid-beta region.	3	19	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	5	6	18	19
Overexpression of SorLA and LR11 in neurons causes redistribution of APP to the Golgi network and endosomes and decreased processing to Abeta by BACE1 ( XREF_FIG ) .	Overexpression of SorLA and LR11 in neurons causes redistribution of APP to the Golgi network and endosomes and decreased processing to Abeta by BACE1 (XREF_FIG).	18	25	decreased	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	23	24	21	22
Since PrP C inhibits BACE1 , PrP C level reduction may elevate Abeta production .	Since PrP C inhibits BACE1, PrP C level reduction may elevate Abeta production.	4	13	elevate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	12	13
Consistent with the histological results , cortical Abeta was slightly higher in APPxBACE-L mice in both soluble and insoluble fractions when compared with monogenic APP mice ( XREF_FIG ) , whereas higher BACE expression inhibited cortical Abeta accumulation .	Consistent with the histological results, cortical Abeta was slightly higher in APPxBACE-L mice in both soluble and insoluble fractions when compared with monogenic APP mice (XREF_FIG), whereas higher BACE expression inhibited cortical Abeta accumulation.	32	37	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE expression	bace	Abeta	Abeta	abeta	32	33	36	37
Redirection of BACE1 and APP into the endo-lysosomal pathway will reduce the proteolytic processing of APP by alpha-secretase .	Redirection of BACE1 and APP into the endo-lysosomal pathway will reduce the proteolytic processing of APP by alpha-secretase.	0	16	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	2	3	15	16
Some reports have indicated that down-regulation of BACE1 reduces Abeta loads effectively and BACE1 knockout mice are healthy , fertile and have no histological pathologies XREF_BIBR - XREF_BIBR .	Some reports have indicated that down-regulation of BACE1 reduces Abeta loads effectively and BACE1 knockout mice are healthy, fertile and have no histological pathologies XREF_BIBR - XREF_BIBR.	5	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	7	8	9	10
It has been reported that decreased BACE1 levels using lentiviral vectors expressing BACE1 siRNA reduce Abeta production and AD like alterations in APP transgenic mice [ XREF_BIBR ] .	It has been reported that decreased BACE1 levels using lentiviral vectors expressing BACE1 siRNA reduce Abeta production and AD like alterations in APP transgenic mice [XREF_BIBR].	6	16	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	BACE1 levels	bace1	Abeta	Abeta	abeta	6	7	15	16
Inhibition of BACE1 activity increased ADAM10 cleavage of APP , but a reduction of ADAM10 activity did not increase the BACE1 cleavage of APP .	Inhibition of BACE1 activity increased ADAM10 cleavage of APP, but a reduction of ADAM10 activity did not increase the BACE1 cleavage of APP.	2	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	2	3	8	9
Similarly , Abeta expression increases during the first 3 days after spinal cord injury , and if Abeta production is prevented by BACE1 knock-out or by treatment with a gamma-secretase inhibitor , the mice develop more white matter damage , and display impaired recovery from locomotor deficits .	Similarly, Abeta expression increases during the first 3 days after spinal cord injury, and if Abeta production is prevented by BACE1 knock-out or by treatment with a gamma-secretase inhibitor, the mice develop more white matter damage, and display impaired recovery from locomotor deficits.	17	23	prevented	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	22	23	17	18
Successful downregulation of BACE , full-length APP and APP c-terminal fragments by treatment with small interfering RNAs targeting these transcripts , attenuates the synthesis and accumulation of Abeta , and isoflurane induced activation of caspase-3 .	Successful downregulation of BACE, full-length APP and APP c-terminal fragments by treatment with small interfering RNAs targeting these transcripts, attenuates the synthesis and accumulation of Abeta, and isoflurane induced activation of caspase-3.	1	28	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE	BACE	BACE	Abeta	Abeta	Abeta	3	4	27	28
These results were supported by a significant reduction in the paired helical filament ( PHF ) , beta-amyloid ( betaA ) 1-40 and betaA 1-42 levels and a decrease in BACE1 mediated cleavage of APP ( into CTFbeta ) .	These results were supported by a significant reduction in the paired helical filament (PHF), beta-amyloid (betaA) 1-40 and betaA 1-42 levels and a decrease in BACE1 mediated cleavage of APP (into CTFbeta).	28	37	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	30	31	34	35
Thus , it is possible that the robust accumulation of BACE1 in Gga3 null mice following TBI produces a similar suppression of Abeta production .	Thus, it is possible that the robust accumulation of BACE1 in Gga3 null mice following TBI produces a similar suppression of Abeta production.	8	23	produces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	10	11	22	23
In primary rat , neurons and human neuronal cell lines NSAIDs strongly inhibit NF-kappaB-driven expression of BACE1 activity preventing the cleavage of Abeta from APP .	In primary rat, neurons and human neuronal cell lines NSAIDs strongly inhibit NF-kappaB-driven expression of BACE1 activity preventing the cleavage of Abeta from APP.	16	23	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	16	17	22	23
Se-Met Decreased the Production and Deposition of Abeta by Inhibiting Level of APP and BACE1 Mediated APP Processing .	Se-Met Decreased the Production and Deposition of Abeta by Inhibiting Level of APP and BACE1 Mediated APP Processing.	10	17	Mediated	Positive_early_activation	Positive_activation	Positive_activation	BACE1	BACE1	BACE1	APP	APP	APP	14	15	16	17
Engagement of BACE1 by the antibody reduces the production rate of Abeta .	Engagement of BACE1 by the antibody reduces the production rate of Abeta.	0	12	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	2	3	11	12
Together , biochemical analyses demonstrated that BACE1 +/- deletion significantly suppressed the beta-cleavage of APP in 5XFAD mice at 6 months of age resulting in reduced levels of C99 and Abeta42 ( by ~ 53 % and ~ 67 % , respectively ) , while it was no longer able to significantly influence levels of these beta-products in 15-18-month-old 5XFAD mouse brains ( ~ 18 % and ~ 20 % reductions , respectively ) .	Together, biochemical analyses demonstrated that BACE1 +/- deletion significantly suppressed the beta-cleavage of APP in 5XFAD mice at 6 months of age resulting in reduced levels of C99 and Abeta42 (by ~ 53% and ~ 67%, respectively), while it was no longer able to significantly influence levels of these beta-products in 15-18-month-old 5XFAD mouse brains (~ 18% and ~ 20% reductions, respectively).	6	15	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	APP	APP	APP	6	7	14	15
Human ( h ) BACE1 neurogenic knockout has recently been shown to induce Abeta accumulation , promotes brain inflammation and generates LOAD like phenotypes in mice in the absence of expression of mutant APP , suggesting that BACE1 represents a molecular risk factor for AD related to the aging process [ XREF_BIBR ] .	Human (h) BACE1 neurogenic knockout has recently been shown to induce Abeta accumulation, promotes brain inflammation and generates LOAD like phenotypes in mice in the absence of expression of mutant APP, suggesting that BACE1 represents a molecular risk factor for AD related to the aging process [XREF_BIBR].	4	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	13	14
In our study , Abeta inhibited the viability of SH-SY5Y cells and downregulation of BACE1 enhanced the inhibitory effects of Abeta .	In our study, Abeta inhibited the viability of SH-SY5Y cells and downregulation of BACE1 enhanced the inhibitory effects of Abeta.	10	21	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	14	15	20	21
The increased retention of BACE1 in the ER compartment would therefore also reduce Abeta production because of the near neutral pH environment in the ER .	The increased retention of BACE1 in the ER compartment would therefore also reduce Abeta production because of the near neutral pH environment in the ER.	2	14	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	BACE1	BACE1	Abeta	Abeta	Abeta	4	5	13	14
Moreover , overexpression of DISC1 in the hippocampus with an adeno associated virus reduced the levels of BACE1 , soluble Abeta40/42 , amyloid plaque density , and rescued cognitive deficits of APP and PS1 transgenic mice .	Moreover, overexpression of DISC1 in the hippocampus with an adeno associated virus reduced the levels of BACE1, soluble Abeta40/42, amyloid plaque density, and rescued cognitive deficits of APP and PS1 transgenic mice.	2	33	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BACE1	overexpression of DISC1 in the hippocampus with an adeno associated virus reduced the levels of BACE1	bace1	APP	APP	app	17	18	31	32
We have discovered that p75NTR mediates Abeta induced BACE1 upregulation , as both ECD-Fc and p75NTR knockout can block Abeta induced BACE1 upregulation and inhibit amyloidogenic APP processing .	We have discovered that p75NTR mediates Abeta induced BACE1 upregulation, as both ECD-Fc and p75NTR knockout can block Abeta induced BACE1 upregulation and inhibit amyloidogenic APP processing.	4	27	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BACE1	p75NTR mediates Abeta induced BACE1	bace1	APP	APP	app	8	9	26	27
Secondly , BACE1 protein levels were unaltered and degradation of Abeta was not enhanced as measured by a neprilysin activity assay .	Secondly, BACE1 protein levels were unaltered and degradation of Abeta was not enhanced as measured by a neprilysin activity assay.	2	11	were unaltered and degradation	Negative_activation_copula_1	Positive_activation	Negative_activation	BACE1	BACE1 protein levels	bace1	Abeta	Abeta	abeta	2	3	10	11
Baicalein induced apoptosis in a time dependent effect through the inhibition of Bcl-2 expression , increased the levels of Bax , reduced the level of deltapsim , and promoted the cytochrome c release and caspase-3 activation .	Baicalein induced apoptosis in a time dependent effect through the inhibition of Bcl-2 expression, increased the levels of Bax, reduced the level of deltapsim, and promoted the cytochrome c release and caspase-3 activation.	0	32	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Baicalein induced apoptosis in a time dependent effect through the inhibition of Bcl-2 expression, increased the levels of Bax	bax	cytochrome c	cytochrome c	cytochrome c	19	20	30	32
Moreover , SF up-regulated Bcl-2 and down-regulated Bax in cells and SF inhibited MPP + -induced activation of cytochrome c and caspase-3 , which suggests that SF effectively suppressed mitochondria dependent apoptosis in MPP + -treated SH-SY5Y cells .	Moreover, SF up-regulated Bcl-2 and down-regulated Bax in cells and SF inhibited MPP + -induced activation of cytochrome c and caspase-3, which suggests that SF effectively suppressed mitochondria dependent apoptosis in MPP + -treated SH-SY5Y cells.	7	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	18	20
Finally , the upregulation of Mrs2 has been shown to be responsible for the inhibition of the adriamycin induced apoptosis of a gastric cancer cell line , probably by suppressing Bax induced cytochrome c release from the mitochondria [ XREF_BIBR ] .	Finally, the upregulation of Mrs2 has been shown to be responsible for the inhibition of the adriamycin induced apoptosis of a gastric cancer cell line, probably by suppressing Bax induced cytochrome c release from the mitochondria [XREF_BIBR].	30	34	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	30	31	32	34
The inhibitor of cell death machinery is Bcl-2 also fails to prevent Bax induced cytochrome c release , activation of caspase-3 , membrane blebbing , nuclear fragmentation , and cell death .	The inhibitor of cell death machinery is Bcl-2 also fails to prevent Bax induced cytochrome c release, activation of caspase-3, membrane blebbing, nuclear fragmentation, and cell death.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	12	13	14	16
Bcl-2 inhibits the release of cytochrome C and ultimately inhibits apoptosis while activation of the Bax protein stimulates the release of cytochrome c from mitochondria and promotes apoptosis [ XREF_BIBR ] .	Bcl-2 inhibits the release of cytochrome C and ultimately inhibits apoptosis while activation of the Bax protein stimulates the release of cytochrome c from mitochondria and promotes apoptosis [XREF_BIBR].	15	23	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	21	23
In response to a variety of apoptosis stimuli , over-expression of Bcl-2 or Bax blocks cytochrome c release .	In response to a variety of apoptosis stimuli, over-expression of Bcl-2 or Bax blocks cytochrome c release.	9	17	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	over-expression of Bcl-2 or Bax	bax	cytochrome c	cytochrome c	cytochrome c	13	14	15	17
We now show that recombinant Bid and Bax cause complete cytochrome c loss from isolated mitochondria in vitro , but preserve the ultrastructure and protein import function of mitochondria , which depend on inner membrane polarization .	We now show that recombinant Bid and Bax cause complete cytochrome c loss from isolated mitochondria in vitro, but preserve the ultrastructure and protein import function of mitochondria, which depend on inner membrane polarization.	5	12	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	10	12
Translocation of Bax from the cytosol to mitochondria is thought to contribute to the pathogenesis of neurodegeneration by triggering the disruption of mitochondrial membrane potential , cytochrome c release , and caspase activation .	Translocation of Bax from the cytosol to mitochondria is thought to contribute to the pathogenesis of neurodegeneration by triggering the disruption of mitochondrial membrane potential, cytochrome c release, and caspase activation.	0	28	contribute	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Translocation of Bax from the cytosol to mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	2	3	26	28
To determine whether inhibition of Bax induced cytochrome c release by Ab # 20 and Ab # 25 was specific to PT associated cytochrome c release , we examined the effect of these antibodies on Bax induced cytochrome c release in the presence of a Ca 2+ chelator that completely inhibited the PT ( Zoratti and Szabo 1995 ; data not shown ) .	To determine whether inhibition of Bax induced cytochrome c release by Ab # 20 and Ab # 25 was specific to PT associated cytochrome c release, we examined the effect of these antibodies on Bax induced cytochrome c release in the presence of a Ca 2+ chelator that completely inhibited the PT (Zoratti and Szabo 1995; data not shown).	3	9	induced	Positive_early_activation	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	7	9
Therefore , it appears that ethanol induced neuroapoptosis is an intrinsic pathway mediated phenomenon involving Bax induced disruption of mitochondrial membranes and cytochrome c release as early events leading to caspase-3 activation .	Therefore, it appears that ethanol induced neuroapoptosis is an intrinsic pathway mediated phenomenon involving Bax induced disruption of mitochondrial membranes and cytochrome c release as early events leading to caspase-3 activation.	15	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	15	16	22	24
However , a staple position that replaced I148 and the highly conserved L152 , and localizes to the hydrophobic contact surface for BAX on the BIM BH3 alpha-helix ( XREF_FIG ) , markedly decreased BAX oligomerization ( XREF_FIG ) and BAX mediated cytochrome c release ( XREF_FIG , XREF_SUPPLEMENTARY ) , findings consistent with the near abrogation of BIM SAHB induced chemical shift perturbations of 15 N-BAX by BIM SAHB C ( XREF_SUPPLEMENTARY ) .	However, a staple position that replaced I148 and the highly conserved L152, and localizes to the hydrophobic contact surface for BAX on the BIM BH3 alpha-helix (XREF_FIG), markedly decreased BAX oligomerization (XREF_FIG) and BAX mediated cytochrome c release (XREF_FIG, XREF_SUPPLEMENTARY), findings consistent with the near abrogation of BIM SAHB induced chemical shift perturbations of 15 N-BAX by BIM SAHB C (XREF_SUPPLEMENTARY).	33	44	mediated	Positive_early_activation	Positive_activation	Negative_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	40	41	42	44
Developing neurons deprived of trophic support undergo apoptosis mediated by activation of c-Jun N-terminal kinases ( JNK ) and c-Jun , induction of the Bcl-2 homology 3-only protein Bim ( EL ) , Bax dependent loss of mitochondrial cytochrome c , and caspase activation .	Developing neurons deprived of trophic support undergo apoptosis mediated by activation of c-Jun N-terminal kinases (JNK) and c-Jun, induction of the Bcl-2 homology 3-only protein Bim (EL), Bax dependent loss of mitochondrial cytochrome c, and caspase activation.	33	40	loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	33	34	38	40
Mitochondrion bound HKII prevents apoptosis by both preventing mitochondrial permeability transition and inhibiting Bax mediated cytochrome c release [ XREF_BIBR ] .	Mitochondrion bound HKII prevents apoptosis by both preventing mitochondrial permeability transition and inhibiting Bax mediated cytochrome c release [XREF_BIBR].	12	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	13	14	15	17
The increased Bcl-2 and Bax ratio blocks the cytochrome C released from mitochondria , which inhibits the mitochondrial apoptotic pathways .	The increased Bcl-2 and Bax ratio blocks the cytochrome C released from mitochondria, which inhibits the mitochondrial apoptotic pathways.	4	10	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	4	5	8	10
ACS inhibition by Triacsin c markedly potentiated the Bax induced intrinsic apoptotic pathway by promoting cytochrome c release and subsequent caspase activation .	ACS inhibition by Triacsin c markedly potentiated the Bax induced intrinsic apoptotic pathway by promoting cytochrome c release and subsequent caspase activation.	7	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	8	9	15	17
Again , the specificity of PUMA SAHB A1 activity was confirmed by impairment of BAX mediated cytochrome c release upon SAHB mutagenesis .	Again, the specificity of PUMA SAHB A1 activity was confirmed by impairment of BAX mediated cytochrome c release upon SAHB mutagenesis.	12	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	14	15	16	18
Several target genes belong to the Bcl-2 family of proteins , which regulate whether the Bak and Bax proteins can cause mitochondrial outer membrane permeabilization and cytochrome c release as the trigger for intrinsic apoptosis induction .	Several target genes belong to the Bcl-2 family of proteins, which regulate whether the Bak and Bax proteins can cause mitochondrial outer membrane permeabilization and cytochrome c release as the trigger for intrinsic apoptosis induction.	15	28	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	17	18	26	28
These results indicate that NGF blocks TG induced Bax translocation to the mitochondria and in this way prevents cytochrome c release and subsequent caspase activation .	These results indicate that NGF blocks TG induced Bax translocation to the mitochondria and in this way prevents cytochrome c release and subsequent caspase activation.	4	20	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	NGF blocks TG induced Bax translocation to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	8	9	18	20
Inhibition of BAX by a representative Fab , 3G11 , prevented mitochondrial translocation of BAX and BAX mediated cytochrome c release .	Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX mediated cytochrome c release.	12	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	16	17	18	20
Caspase inhibitors failed to block cytochrome c and AK efflux induced by Bid , Bax and the pro apoptotic proteins in Xenopus cytosol .	Caspase inhibitors failed to block cytochrome c and AK efflux induced by Bid, Bax and the pro apoptotic proteins in Xenopus cytosol.	5	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	14	15	5	7
The prevailing view is that anti-apoptotic Bcl-2 family members such as BcL-x L prevent homo-oligomerization of pro apoptotic family members Bax and Bak in the outer mitochondrial membrane , thereby preventing the release of cytochrome c to promote caspase activation and apoptotic cell death .	The prevailing view is that anti-apoptotic Bcl-2 family members such as BcL-x L prevent homo-oligomerization of pro apoptotic family members Bax and Bak in the outer mitochondrial membrane, thereby preventing the release of cytochrome c to promote caspase activation and apoptotic cell death.	20	36	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	20	21	34	36
It is well established that Akt phosphorylates Bad and obviates its inhibitory effects on Bcl-X L , by blocking Bax associated channel formation ultimately inhibiting the release of cytochrome c on the mitochondrial membrane .	It is well established that Akt phosphorylates Bad and obviates its inhibitory effects on Bcl-X L, by blocking Bax associated channel formation ultimately inhibiting the release of cytochrome c on the mitochondrial membrane.	18	30	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	19	20	28	30
CM-12 and CM-24 induced the expresssions of Bax , cleaved-caspase 3 and cytochrome c , at the same time reduced Bcl-2 , hence , the Bcl-2 and Bax ratio was significantly decreased .	CM-12 and CM-24 induced the expresssions of Bax, cleaved-caspase 3 and cytochrome c, at the same time reduced Bcl-2, hence, the Bcl-2 and Bax ratio was significantly decreased.	12	32	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	27	28	12	14
As shown in XREF_FIG B ( bottom ) , PT independent cytochrome c release induced by Bax was also inhibited by both Ab # 20 and Ab # 25 , indicating an essential role of the VDAC in Bax induced cytochrome c release regardless of PT dependency .	As shown in XREF_FIG B (bottom), PT independent cytochrome c release induced by Bax was also inhibited by both Ab # 20 and Ab # 25, indicating an essential role of the VDAC in Bax induced cytochrome c release regardless of PT dependency.	36	42	induced	Positive_early_activation	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	38	39	40	42
They might stimulate ROS removal as described above for the ischaemic phase or they could reduce the Bax induced cytochrome c release .	They might stimulate ROS removal as described above for the ischaemic phase or they could reduce the Bax induced cytochrome c release.	15	21	induced	Positive_early_activation	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	17	18	19	21
Knockdown of HSP25 decreased the interaction between SIRT1 and p53 , leading to increased p53 acetylation on K379 , up-regulated pro apoptotic Bax protein expression , induced cytochrome c release , and triggered caspase-3 and caspase-9 activation .	Knockdown of HSP25 decreased the interaction between SIRT1 and p53, leading to increased p53 acetylation on K379, up-regulated pro apoptotic Bax protein expression, induced cytochrome c release, and triggered caspase-3 and caspase-9 activation.	2	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	HSP25 decreased the interaction between SIRT1 and p53, leading to increased p53 acetylation on K379, up-regulated pro apoptotic Bax protein expression	bax	cytochrome c	cytochrome c	cytochrome c	22	23	27	29
Blockade of AR activity in J774A.1 cells markedly augmented the acrolein- or hydrogen peroxide induced translocation of Bax to mitochondria along with reduced Bcl-2 and increased release of cytochrome c from the mitochodria .	Blockade of AR activity in J774A.1 cells markedly augmented the acrolein- or hydrogen peroxide induced translocation of Bax to mitochondria along with reduced Bcl-2 and increased release of cytochrome c from the mitochodria.	12	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	hydrogen peroxide induced translocation of Bax to mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	17	18	28	30
Up-regulation of pro apoptotic Bcl-X ( S ) and Bax contributed to cyanide induced cytochrome c release , because SN50 and a specific Bax antisense oligodeoxynucleotide significantly reduced release of cytochrome c from mitochondria as shown by western blot analysis .	Up-regulation of pro apoptotic Bcl-X (S) and Bax contributed to cyanide induced cytochrome c release, because SN50 and a specific Bax antisense oligodeoxynucleotide significantly reduced release of cytochrome c from mitochondria as shown by western blot analysis.	23	32	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	23	24	30	32
In addition , naloxone administration dose-dependently increased Bcl-2 levels , decreased Bax levels , stabilized the mitochondrial transmembrane potential , and inhibited cytochrome c release and caspase 3 and caspase 9 activation .	In addition, naloxone administration dose-dependently increased Bcl-2 levels, decreased Bax levels, stabilized the mitochondrial transmembrane potential, and inhibited cytochrome c release and caspase 3 and caspase 9 activation.	3	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	naloxone administration dose-dependently increased Bcl-2 levels, decreased Bax levels	bax	cytochrome c	cytochrome c	cytochrome c	11	12	22	24
Bax antisense oligodeoxynucleotide reduced PLC induced intimal cell apoptosis and cytochrome c release .	Bax antisense oligodeoxynucleotide reduced PLC induced intimal cell apoptosis and cytochrome c release.	0	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	10	12
However , Bax was able to induce pore formation and cytochrome c release in L. major mitochondria and ectopic expression of Bax caused loss of DeltaPsi m and cytochrome c release in T. brucei , suggesting functional homologues of this family may yet be discovered .	However, Bax was able to induce pore formation and cytochrome c release in L. major mitochondria and ectopic expression of Bax caused loss of DeltaPsi m and cytochrome c release in T. brucei, suggesting functional homologues of this family may yet be discovered.	19	30	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	21	22	28	30
Basically , the rise in Bcl-2 and drop in Bax would prevent cytochrome c to move outside from the mitochondria , reduce the increased levels of ROS , and thus attenuate programmed cell death in the renal tubule .	Basically, the rise in Bcl-2 and drop in Bax would prevent cytochrome c to move outside from the mitochondria, reduce the increased levels of ROS, and thus attenuate programmed cell death in the renal tubule.	5	14	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	9	10	12	14
Moreover , ISL increased the expression of pro apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2 , and Bcl-xl , thereby increasing cytochromec release .	Moreover, ISL increased the expression of pro apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2, and Bcl-xl, thereby increasing cytochromec release.	2	26	increasing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	ISL increased the expression of pro apoptotic protein Bax	bax	cytochromec	cytochromec	cytochromec	10	11	25	26
The Bax mediated cytochrome c release and cell death can be inhibited by Bcl-2 subfamily proteins .	The Bax mediated cytochrome c release and cell death can be inhibited by Bcl-2 subfamily proteins.	0	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	3	5
Another method to induce competence in sympathetic neurons , which does not include cycloheximide addition , is to deprive Bax deficient neurons of NGF for 24 h. Bax deficiency , like cycloheximide addition , blocks the cytochrome c release pathway specifically and therefore allows us to maintain the survival of NGF deprived neurons that develop competence .	Another method to induce competence in sympathetic neurons, which does not include cycloheximide addition, is to deprive Bax deficient neurons of NGF for 24 h. Bax deficiency, like cycloheximide addition, blocks the cytochrome c release pathway specifically and therefore allows us to maintain the survival of NGF deprived neurons that develop competence.	18	43	blocks	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	19	20	36	38
The reduction of Bcl-2 and Bax ratio triggered cytochrome c transferring from the mitochondria to the cytoplasm .	The reduction of Bcl-2 and Bax ratio triggered cytochrome c transferring from the mitochondria to the cytoplasm.	3	10	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	8	10
In conclusion , our data demonstrated that jaceosidin inhibited the growth of U87 glioblastoma cells and induced apoptosis through cell cycle arrest , upregulation of p53 and Bax , lowering MTP , release of cytochrome c , and cleavage of caspase 3 .	In conclusion, our data demonstrated that jaceosidin inhibited the growth of U87 glioblastoma cells and induced apoptosis through cell cycle arrest, upregulation of p53 and Bax, lowering MTP, release of cytochrome c, and cleavage of caspase 3.	23	36	lowering	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	27	28	34	36
These interactions result in the release of Bax and or Bak , promoting the loss of mitochondrial outer membrane potential and subsequent cytochrome c release .	These interactions result in the release of Bax and or Bak, promoting the loss of mitochondrial outer membrane potential and subsequent cytochrome c release.	7	24	promoting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	7	8	22	24
It was found recombinant Bax induced permeability in liposomes containing VDAC [ XREF_BIBR ] , and Bax activated cytochrome C release was blocked by intracellular microinjection of anti-VDAC antibodies [ XREF_BIBR ] .	It was found recombinant Bax induced permeability in liposomes containing VDAC [XREF_BIBR], and Bax activated cytochrome C release was blocked by intracellular microinjection of anti-VDAC antibodies [XREF_BIBR].	16	20	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	16	17	18	20
While Bax promotes the loss of DeltaPsi , cytochrome c release , and activation of caspases , overexpression of Bcl-2 in cells inhibits those changes prolonging cell survival [ XREF_BIBR - XREF_BIBR ] .	While Bax promotes the loss of DeltaPsi, cytochrome c release, and activation of caspases, overexpression of Bcl-2 in cells inhibits those changes prolonging cell survival [XREF_BIBR - XREF_BIBR].	1	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	1	2	8	10
The cytoplasmic Hsp70s regulate the apoptosis pathway at multiple levels , for example , Hsp70s have been shown to protect Bcl-2 from proteasomal degradation [ XREF_BIBR ] ; block Bax translocation to the mitochondria thereby preventing cytochrome c release [ XREF_BIBR ] ; bind Apaf-1 and prevent the recruitment of caspase-9 to the apoptosome [ XREF_BIBR , XREF_BIBR ] ; and to prevent AIF translocation to the nucleus to cause chromatin condensation and DNA degradation [ XREF_BIBR , XREF_BIBR ] .	The cytoplasmic Hsp70s regulate the apoptosis pathway at multiple levels, for example, Hsp70s have been shown to protect Bcl-2 from proteasomal degradation [XREF_BIBR]; block Bax translocation to the mitochondria thereby preventing cytochrome c release [XREF_BIBR]; bind Apaf-1 and prevent the recruitment of caspase-9 to the apoptosome [XREF_BIBR, XREF_BIBR]; and to prevent AIF translocation to the nucleus to cause chromatin condensation and DNA degradation [XREF_BIBR, XREF_BIBR].	29	38	preventing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax translocation to the mitochondria	bax	cytochrome c	cytochrome c	cytochrome c	29	30	36	38
[ XREF_BIBR XREF_BIBR - XREF_BIBR ] Similarly , a possibility exist that NLE induced overexpression of Bax may disrupt mitochondria membrane potential and increase cytochrome c release in granulosa cells .	[XREF_BIBR XREF_BIBR - XREF_BIBR] Similarly, a possibility exist that NLE induced overexpression of Bax may disrupt mitochondria membrane potential and increase cytochrome c release in granulosa cells.	12	26	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	NLE induced overexpression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	16	17	24	26
Sympathetic neurons undergoing programmed cell death after nerve growth factor ( NGF ) deprivation are shown to exhibit a protein synthesis dependent , BAX dependent loss of cytochrome c from the mitochondria .	Sympathetic neurons undergoing programmed cell death after nerve growth factor (NGF) deprivation are shown to exhibit a protein synthesis dependent, BAX dependent loss of cytochrome c from the mitochondria.	23	29	loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	23	24	27	29
Moreover , Rk3 induced the activation of caspase-8 , -9 , and -3 , promoted changes in mitochondrial membrane potential , decreased the expression of Bcl-2 , increased the expression of Bax , and caused the release of cytochrome c , which indicated that the apoptosis inducing effects of Rk3 were triggered via death receptor mediated mitochondria dependent pathways .	Moreover, Rk3 induced the activation of caspase-8, -9, and -3, promoted changes in mitochondrial membrane potential, decreased the expression of Bcl-2, increased the expression of Bax, and caused the release of cytochrome c, which indicated that the apoptosis inducing effects of Rk3 were triggered via death receptor mediated mitochondria dependent pathways.	2	40	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Rk3 induced the activation of caspase-8, -9, and -3, promoted changes in mitochondrial membrane potential, decreased the expression of Bcl-2, increased the expression of Bax	bax	cytochrome c	cytochrome c	cytochrome c	31	32	38	40
The activated survivin is able to inhibit the permeabilization of the mitochondrial outer membrane , and therefore prevents the release of cytochrome c , the activation of Bax and caspase-9 .	The activated survivin is able to inhibit the permeabilization of the mitochondrial outer membrane, and therefore prevents the release of cytochrome c, the activation of Bax and caspase-9.	17	29	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	27	28	21	23
Caspase inhibitors do not affect Bax induced cytochrome c release but block caspase-3 activation and nuclear fragmentation .	Caspase inhibitors do not affect Bax induced cytochrome c release but block caspase-3 activation and nuclear fragmentation.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	7	9
Bim deletion on the other hand could only transiently protect cells from neuronal apoptosis , as its pro apoptotic role was partially replaced by other BH-3 only members that functioned upstream of the Bax mediated cytochrome C release XREF_BIBR .	Bim deletion on the other hand could only transiently protect cells from neuronal apoptosis, as its pro apoptotic role was partially replaced by other BH-3 only members that functioned upstream of the Bax mediated cytochrome C release XREF_BIBR.	30	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	33	34	35	37
3G11 blocked BAX mitochondrial translocation and BAX mediated cytochrome c release consistent with a mechanism of BAX conformational suppression through extensive contacts with BAX , which prevent opening of the alpha1-alpha2 loop that is essential for BAX activation [ XREF_BIBR , XREF_BIBR ] .	3G11 blocked BAX mitochondrial translocation and BAX mediated cytochrome c release consistent with a mechanism of BAX conformational suppression through extensive contacts with BAX, which prevent opening of the alpha1-alpha2 loop that is essential for BAX activation [XREF_BIBR, XREF_BIBR].	4	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
When used jointly with vitamin C , vitamin E increases the Bcl-2 level in mitochondria and decreases the level of Bcl-2-like protein 4 , suppresses the release of cytochrome C , activates caspase-9 and caspase-3 , and thus , inhibits myocardial cell apoptosis .	When used jointly with vitamin C, vitamin E increases the Bcl-2 level in mitochondria and decreases the level of Bcl-2-like protein 4, suppresses the release of cytochrome C, activates caspase-9 and caspase-3, and thus, inhibits myocardial cell apoptosis.	7	30	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bcl-2-like protein 4	vitamin E increases the Bcl-2 level in mitochondria and decreases the level of Bcl-2-like protein 4	bcl-2-like protein 4	cytochrome C	cytochrome C	cytochrome c	20	23	28	30
Substituting the non natural amino acid at positions W147 , A149 , E151 , R153 , R154 , E158 , or Y162 did not disrupt BIM SAHB induced BAX oligomerization ( XREF_FIG ) or BAX mediated cytochrome c release ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Substituting the non natural amino acid at positions W147, A149, E151, R153, R154, E158, or Y162 did not disrupt BIM SAHB induced BAX oligomerization (XREF_FIG) or BAX mediated cytochrome c release (XREF_FIG, XREF_SUPPLEMENTARY).	29	38	mediated	Positive_early_activation	Positive_activation	Negative_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	34	35	36	38
CA also increased the number of sub-G1 hypodiploid cells ; increased mitochondrial dysfunction ( loss of MMP , cytochrome c release , and accompanied by Bcl-2 and Mcl-1 down-regulation and Bax up-regulation ) , and activated the caspase cascades activations , which displayed features of mitochondria dependent apoptosis pathway .	CA also increased the number of sub-G1 hypodiploid cells; increased mitochondrial dysfunction (loss of MMP, cytochrome c release, and accompanied by Bcl-2 and Mcl-1 down-regulation and Bax up-regulation), and activated the caspase cascades activations, which displayed features of mitochondria dependent apoptosis pathway.	14	31	loss	Negative_activation_syntax_1_noun	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	30	31	18	20
SCRT treatment increases the loss of MMP and translocalization of Bax to the mitochondria , and leads to cytochrome c release to the cytosol and activation of caspase-9 and -3 , resulting in the activation of the intrinsic apoptosis pathway .	SCRT treatment increases the loss of MMP and translocalization of Bax to the mitochondria, and leads to cytochrome c release to the cytosol and activation of caspase-9 and -3, resulting in the activation of the intrinsic apoptosis pathway.	0	20	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	Bax	SCRT treatment increases the loss of MMP and translocalization of Bax	bax	cytochrome c	cytochrome c	cytochrome c	10	11	18	20
A decrease in the Bcl-2 and Bax ratio and impairment of mitochondrial electron transport may cause release of cytochrome c involved in the control of cell apoptosis .	A decrease in the Bcl-2 and Bax ratio and impairment of mitochondrial electron transport may cause release of cytochrome c involved in the control of cell apoptosis.	4	20	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	18	20
Our previous study has shown that the H2-H3 peptide promotes apoptosis not only by directly activating Bax to release cytochrome c from mitochondria , but also by overcoming Bcl-2 ' s inhibition on Bax mediated cytochrome c release .	Our previous study has shown that the H2-H3 peptide promotes apoptosis not only by directly activating Bax to release cytochrome c from mitochondria, but also by overcoming Bcl-2 's inhibition on Bax mediated cytochrome c release.	31	37	mediated	Positive_early_activation	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	33	34	35	37
Blockers of the PTP including bongkrekic acid ( BKA ) , CsA , ADP , and EGTA were tested for their ability to inhibit Bax induced release of cytochrome C from isolated mitochondria .	Blockers of the PTP including bongkrekic acid (BKA), CsA, ADP, and EGTA were tested for their ability to inhibit Bax induced release of cytochrome C from isolated mitochondria.	23	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	24	25	28	30
The over-expression of Bcl2 not only prevents the development of cells apoptosis , but inhibits the release of cytochrome C , nevertheless , Bax may increase the membrane ' s permeability , which leads to the release of cytochrome C from mitochondria , activation of caspase-9 and initiation of the caspase activation pathway for apoptosis [ XREF_BIBR , XREF_BIBR ] .	The over-expression of Bcl2 not only prevents the development of cells apoptosis, but inhibits the release of cytochrome C, nevertheless, Bax may increase the membrane 's permeability, which leads to the release of cytochrome C from mitochondria, activation of caspase-9 and initiation of the caspase activation pathway for apoptosis [XREF_BIBR, XREF_BIBR].	18	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	23	24	18	20
Free Bad may cause a decrease in MMP via translocation from the cytosol to the mitochondrial membrane to displace pro apoptotic Bax ( Bcl-2-associated X protein ) from the anti-apoptotic Bcl-XL , and Bax subsequently translocates to the mitochondrion and induces cytochrome c release and caspase activation .	Free Bad may cause a decrease in MMP via translocation from the cytosol to the mitochondrial membrane to displace pro apoptotic Bax (Bcl-2-associated X protein) from the anti-apoptotic Bcl-XL, and Bax subsequently translocates to the mitochondrion and induces cytochrome c release and caspase activation.	33	43	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax subsequently translocates to the mitochondrion	bax	cytochrome c	cytochrome c	cytochrome c	33	34	41	43
Thirdly , P. gingivalis inhibits epithelial cell apoptosis by a number of mechanisms , including activation of Jak1/Akt/Stat3 [ XREF_BIBR , XREF_BIBR ] , enhancing the Bcl2 ( antiapoptotic ) : Bax ( proapoptotic ) ratio , blocking the release of the apoptosis effector cytochrome c , and the activation of downstream caspases [ XREF_BIBR ] .	Thirdly, P. gingivalis inhibits epithelial cell apoptosis by a number of mechanisms, including activation of Jak1/Akt/Stat3 [XREF_BIBR, XREF_BIBR], enhancing the Bcl2 (antiapoptotic) : Bax (proapoptotic) ratio, blocking the release of the apoptosis effector cytochrome c, and the activation of downstream caspases [XREF_BIBR].	31	46	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	31	32	44	46
Overexpression of mitochondrially located catalase ( MitoCatalase ) specifically increased basal Bcl-2 and decreased basal Bax expression , suppressed cytokine mediated reduction of Bcl-2 , and thereby prevented the release of cytochrome c , Smac/DIABLO and the activation of caspase-9 and -3 .	Overexpression of mitochondrially located catalase (MitoCatalase) specifically increased basal Bcl-2 and decreased basal Bax expression, suppressed cytokine mediated reduction of Bcl-2, and thereby prevented the release of cytochrome c, Smac/DIABLO and the activation of caspase-9 and -3.	0	33	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Overexpression of mitochondrially located catalase (MitoCatalase) specifically increased basal Bcl-2 and decreased basal Bax expression	bax	cytochrome c	cytochrome c	cytochrome c	15	16	31	33
BCL-2 and Bcl-xL are anti-apoptotic proteins and prevent the oligomerization of pro apoptotic proteins BAX and BAK , thus blocking the release of cytochrome c from mitochondria [ XREF_BIBR - XREF_BIBR ] .	BCL-2 and Bcl-xL are anti-apoptotic proteins and prevent the oligomerization of pro apoptotic proteins BAX and BAK, thus blocking the release of cytochrome c from mitochondria [XREF_BIBR - XREF_BIBR].	9	25	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	14	15	23	25
Western blot analysis of antiapoptotic proteins revealed an upregulation of Bcl-2 and Bcl-xL , well-known for their inhibitory role in Bak and Bax mediated cytochrome c release in the intrinsic apoptotic pathway , in docetaxel resistant cell lines compared with their chemonaive counterparts ( XREF_FIG B ) .	Western blot analysis of antiapoptotic proteins revealed an upregulation of Bcl-2 and Bcl-xL, well-known for their inhibitory role in Bak and Bax mediated cytochrome c release in the intrinsic apoptotic pathway, in docetaxel resistant cell lines compared with their chemonaive counterparts (XREF_FIG B).	18	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	22	23	24	26
If alpha9 is locked into its binding pocket ( the canonical BH3 binding groove ) by installation of a disulfide tether , the ligand induced allosteric changes in alpha9 are blocked , as are BIM SAHB induced BAX translocation to mitochondria and BAX mediated cytochrome c release 68 .	If alpha9 is locked into its binding pocket (the canonical BH3 binding groove) by installation of a disulfide tether, the ligand induced allosteric changes in alpha9 are blocked, as are BIM SAHB induced BAX translocation to mitochondria and BAX mediated cytochrome c release 68.	36	46	mediated	Positive_early_activation	Positive_activation	Negative_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	42	43	44	46
Propranolol reduces intracellular Ca ++ overload and attenuates mitochondrial dysfunction by its action on electron mitochondrial membrane transport , and also by inhibiting the Bax mediated cytochrome C release [ XREF_BIBR , XREF_BIBR ] .	Propranolol reduces intracellular Ca ++ overload and attenuates mitochondrial dysfunction by its action on electron mitochondrial membrane transport, and also by inhibiting the Bax mediated cytochrome C release [XREF_BIBR, XREF_BIBR].	22	28	mediated	Positive_early_activation	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	24	25	26	28
Decreased Bcl-2 and Bax ratios may trigger the release of cytochrome C from the mitochondria and activation of pro caspase 3 .	Decreased Bcl-2 and Bax ratios may trigger the release of cytochrome C from the mitochondria and activation of pro caspase 3.	1	12	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome C	cytochrome C	cytochrome C	3	4	10	12
Mechanism study showed that GQ triggered generation of reactive oxygen species ( ROS ) , then activated p38 and JNK signaling pathways , subsequently led to mitochondrial impairment by regulating the expression of Bcl-2 , Bcl-xl and Bax , and finally promoted the release of cytochrome c and the activation of caspases to induce apoptosis .	Mechanism study showed that GQ triggered generation of reactive oxygen species (ROS), then activated p38 and JNK signaling pathways, subsequently led to mitochondrial impairment by regulating the expression of Bcl-2, Bcl-xl and Bax, and finally promoted the release of cytochrome c and the activation of caspases to induce apoptosis.	4	47	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	GQ triggered generation of reactive oxygen species (ROS), then activated p38 and JNK signaling pathways, subsequently led to mitochondrial impairment by regulating the expression of Bcl-2, Bcl-xl and Bax	bax	cytochrome c	cytochrome c	cytochrome c	37	38	45	47
Most importantly , Bax specific small interfering RNAs partially inhibited cytochrome c release in RRV infected cells .	Most importantly, Bax specific small interfering RNAs partially inhibited cytochrome c release in RRV infected cells.	3	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	3	4	10	12
However , Bax KD significantly inhibited cytochrome c release by 42 % in Pdx1 KD cells ( XREF_FIG C ) .	However, Bax KD significantly inhibited cytochrome c release by 42% in Pdx1 KD cells (XREF_FIG C).	2	8	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	2	3	6	8
An inhibition of the mPT strongly attenuated cytochrome c release induced by BAX oligo in our experiments .	An inhibition of the mPT strongly attenuated cytochrome c release induced by BAX oligo in our experiments.	7	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	12	13	7	9
BAX and BAK , when released from protective BCL-2 proteins , can perturb the mitochondrial membrane forming pores that permit release of cytochrome c , leading to the activation of caspase 9 , and ultimately apoptosis .	BAX and BAK, when released from protective BCL-2 proteins, can perturb the mitochondrial membrane forming pores that permit release of cytochrome c, leading to the activation of caspase 9, and ultimately apoptosis.	0	24	perturb	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	0	1	22	24
Bcl-2 blocks the release of cytochrome c , whereas Bax localizes to mitochondria and enhances the release of cytochrome c , promotes nuclear fragmentation and induces cell death .	Bcl-2 blocks the release of cytochrome c, whereas Bax localizes to mitochondria and enhances the release of cytochrome c, promotes nuclear fragmentation and induces cell death.	9	25	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	9	10	18	20
Previous studies have also found that Bax interacts with the permeability transition pore to lower the mitochondrial membrane potential and release cytochrome c , inducing apoptosis [ XREF_BIBR ] .	Previous studies have also found that Bax interacts with the permeability transition pore to lower the mitochondrial membrane potential and release cytochrome c, inducing apoptosis [XREF_BIBR].	6	23	lower	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	6	7	21	23
This Bax overexpression induced cytochrome c release , a reduction of cytochrome c oxidase activity and mitochondrial membrane potential ( Delta ( Psi ) m ) .	This Bax overexpression induced cytochrome c release, a reduction of cytochrome c oxidase activity and mitochondrial membrane potential (Delta (Psi) m).	1	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax overexpression	bax	cytochrome c	cytochrome c	cytochrome c	1	2	4	6
These two pathways are distinct from each other because whereas cycloheximide addition and Bax deficiency block the cytochrome c release pathway , neither one blocks the development of the competence pathway .	These two pathways are distinct from each other because whereas cycloheximide addition and Bax deficiency block the cytochrome c release pathway, neither one blocks the development of the competence pathway.	13	19	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	13	14	17	19
Dexa alone increased cytosolic cytochrome c by 57 % ( p < 0.01 vs. control ) whereas Bax ablation with siRNAs completely prevented Dexa induced release of cytochrome c ( p < 0.01 vs. Dexa treated cells ) ( XREF_FIG ) .	Dexa alone increased cytosolic cytochrome c by 57% (p < 0.01 vs. control) whereas Bax ablation with siRNAs completely prevented Dexa induced release of cytochrome c (p < 0.01 vs. Dexa treated cells) (XREF_FIG).	17	29	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	17	18	27	29
Firstly , MCL1 binds to and suppresses the oligomerization of the pro apoptotic BCL-2 proteins , BAK and BAX , thus preventing mitochondrial outer membrane permeabilization , cytochrome c release , and activation of downstream caspases 1 .	Firstly, MCL1 binds to and suppresses the oligomerization of the pro apoptotic BCL-2 proteins, BAK and BAX, thus preventing mitochondrial outer membrane permeabilization, cytochrome c release, and activation of downstream caspases 1.	8	29	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	18	19	27	29
Bax KD inhibited the cytochrome c release induced by Pdx1 KD ( XREF_FIG C ) .	Bax KD inhibited the cytochrome c release induced by Pdx1 KD (XREF_FIG C).	0	6	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	0	1	4	6
It was recently reported that Bax targeting of OPA1 promoted cytochrome c release and apoptosis independently of MOMP [ XREF_BIBR ] .	It was recently reported that Bax targeting of OPA1 promoted cytochrome c release and apoptosis independently of MOMP [XREF_BIBR].	5	12	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	5	6	10	12
Furthermore , synergistic activity was detected in the presence of combinations of suboptimal doses of recombinant BAK and Bax , suggesting , that in the presence of a low dose of recombinant BAK , the resistance of these mitochondria to Bax mediated cytochrome c release was reversed [ XREF_BIBR ] .	Furthermore, synergistic activity was detected in the presence of combinations of suboptimal doses of recombinant BAK and Bax, suggesting, that in the presence of a low dose of recombinant BAK, the resistance of these mitochondria to Bax mediated cytochrome c release was reversed [XREF_BIBR].	38	44	mediated	Positive_early_activation	Positive_activation	Negative_activation	Bax	Bax	Bax	cytochrome c	cytochrome c	cytochrome c	40	41	42	44
It was found that E2 stabilizes the mitochondrial membrane potential , reduces intracellular ROS levels , up-regulates Bcl-2 expression , inhibits Bax expression , decreases the generation of cytochrome C , and finally reduces the apoptosis of RGC-5 cells in a high-glucose environment .	It was found that E2 stabilizes the mitochondrial membrane potential, reduces intracellular ROS levels, up-regulates Bcl-2 expression, inhibits Bax expression, decreases the generation of cytochrome C, and finally reduces the apoptosis of RGC-5 cells in a high-glucose environment.	4	30	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	E2 stabilizes the mitochondrial membrane potential, reduces intracellular ROS levels, up-regulates Bcl-2 expression, inhibits Bax expression	bax	cytochrome C	cytochrome C	cytochrome c	21	22	28	30
After phosphorylation , BAX inactivates mitochondrial cytochrome c , blocking the activation of caspases and inhibiting apoptosis .	After phosphorylation, BAX inactivates mitochondrial cytochrome c, blocking the activation of caspases and inhibiting apoptosis.	3	8	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAX	BAX	BAX	cytochrome c	cytochrome c	cytochrome c	3	4	6	8
In this study , we tested the hypothesis that the presence of endogenous truncated TrkB limits BDNF pro survival effects on diseased motoneurons .	In this study, we tested the hypothesis that the presence of endogenous truncated TrkB limits BDNF pro survival effects on diseased motoneurons.	13	19	limits	Negative_activation_token_1_noun	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	14	15
TrkB inhibition during IHH treatment also nullifies the IHH mediated enhancement of adult neurogenesis by significantly decreasing the number of DCX positive cells in DG region of hippocampus ( XREF_FIG ) Interestingly , our finding also showed that inhibition of BDNF mediated TrkB signalling , in reverse , reduces the expression of BDNF itself in hippocampus , even in the presence of IHH during UCMS exposure ( XREF_FIG ) .	TrkB inhibition during IHH treatment also nullifies the IHH mediated enhancement of adult neurogenesis by significantly decreasing the number of DCX positive cells in DG region of hippocampus (XREF_FIG) Interestingly, our finding also showed that inhibition of BDNF mediated TrkB signalling, in reverse, reduces the expression of BDNF itself in hippocampus, even in the presence of IHH during UCMS exposure (XREF_FIG).	38	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	40	41	42	43
Consistently , in neurons overexpressing RTLN-C1 , not only was endocytosis of BDNF activated TrkB impaired ( XREF_FIG , and Supplemental Figure S3 ) , but also dendrite outgrowth with or without BDNF was affected compared with that in control neurons ( XREF_FIG ) .	Consistently, in neurons overexpressing RTLN-C1, not only was endocytosis of BDNF activated TrkB impaired (XREF_FIG, and Supplemental Figure S3), but also dendrite outgrowth with or without BDNF was affected compared with that in control neurons (XREF_FIG).	10	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	12	13	14	15
Previous studies analyzing BDNF induced TrkB degradation in cerebellar neurons showed a t1/2 of 1-2 hours .	Previous studies analyzing BDNF induced TrkB degradation in cerebellar neurons showed a t1/2 of 1-2 hours.	2	6	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	5	6
Our results demonstrate that the BDNF system is affected at different levels in aged rats with global impairment including reduced transcription , impaired protein synthesis and processing , and decreased activation of the TrkB receptors .	Our results demonstrate that the BDNF system is affected at different levels in aged rats with global impairment including reduced transcription, impaired protein synthesis and processing, and decreased activation of the TrkB receptors.	5	34	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	33	34
Although TrkB positive innervation is dramatically reduced by inducible Bdnf removal from the epithelium , 45 % of TrkB positive innervation remained in the taste buds .	Although TrkB positive innervation is dramatically reduced by inducible Bdnf removal from the epithelium, 45% of TrkB positive innervation remained in the taste buds.	1	10	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Bdnf	Bdnf	Bdnf	TrkB	TrkB	TrkB	9	10	1	2
Loss of BDNF mediated activation of TrkB results in phenotypes reminiscent of BBS , included hyperphagia driven obesity XREF_BIBR , XREF_BIBR , XREF_BIBR .	Loss of BDNF mediated activation of TrkB results in phenotypes reminiscent of BBS, included hyperphagia driven obesity XREF_BIBR, XREF_BIBR, XREF_BIBR.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	6	7
BDNF induced TrkB activation down-regulates the K + -Cl - cotransporter KCC2 and impairs neuronal Cl - extrusion .	BDNF induced TrkB activation down-regulates the K + -Cl - cotransporter KCC2 and impairs neuronal Cl - extrusion.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
BDNF can also inactivate injury factors in cells by activating TrkB .	BDNF can also inactivate injury factors in cells by activating TrkB.	0	11	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	10	11
BDNF mediated TrkB retrograde transport is impaired in Tg2576 neurons .	BDNF mediated TrkB retrograde transport is impaired in Tg2576 neurons.	0	4	mediated	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
However , at physiological levels Trk.T1 negatively regulates full length TrkB ( TrkB.FL ) signaling so that it acts as a dominant and negative or BDNF sequestering trophic activity .	However, at physiological levels Trk.T1 negatively regulates full length TrkB (TrkB.FL) signaling so that it acts as a dominant and negative or BDNF sequestering trophic activity.	6	26	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	25	26	10	11
Furthermore , brain specific deletion of Bdnf , deletion of dendritic BDNF mRNA , shRNA mediated knockdown of BDNF using a viral vector , and a hypomorphic allele of Trkb that expresses only a quarter of TrkB all result in hyperphagia , obesity , and metabolic imbalances such as hyperglycemia .	Furthermore, brain specific deletion of Bdnf, deletion of dendritic BDNF mRNA, shRNA mediated knockdown of BDNF using a viral vector, and a hypomorphic allele of Trkb that expresses only a quarter of TrkB all result in hyperphagia, obesity, and metabolic imbalances such as hyperglycemia.	4	30	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bdnf	Bdnf	Bdnf	Trkb	Trkb	Trkb	6	7	29	30
Furthermore , we observed Fab inhibition of BDNF mediated TrkB activation with potency in the low micromolar range , perhaps indicating that the Fab fragment has much lower binding affinity compared to its bivalent IgG1 and F ( ab ' ) 2 counterparts .	Furthermore, we observed Fab inhibition of BDNF mediated TrkB activation with potency in the low micromolar range, perhaps indicating that the Fab fragment has much lower binding affinity compared to its bivalent IgG1 and F (ab ') 2 counterparts.	5	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	7	8	9	10
Consistently , treatment of these cells significantly impeded activation of TRKB by BDNF ( XREF_FIG ) .	Consistently, treatment of these cells significantly impeded activation of TRKB by BDNF (XREF_FIG).	7	14	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	12	13	10	11
Finally , ablation of KIF3A expression impaired axonemal extension and also reduced activation of TRKB by BDNF .	Finally, ablation of KIF3A expression impaired axonemal extension and also reduced activation of TRKB by BDNF.	11	17	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	16	17	14	15
In our study , scavenging extracellular BDNF , blocking trkB activation , postsynaptic shRNA mediated BDNF knockdown , and direct BDNF application all point to BDNF as a retrograde messenger linking postsynaptic consequences of AMPAR blockade with sustained enhancement of presynaptic neurotransmitter release .	In our study, scavenging extracellular BDNF, blocking trkB activation, postsynaptic shRNA mediated BDNF knockdown, and direct BDNF application all point to BDNF as a retrograde messenger linking postsynaptic consequences of AMPAR blockade with sustained enhancement of presynaptic neurotransmitter release.	2	10	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	trkB	trkB	trkB	6	7	9	10
Therapeutics mimicking BDNF or therapies that inhibit or potentiate TrkB signaling may lead to uncontrolled growth effects ( e.g ., axon sprouting , tumor growth , or cancer cell migration ) , epileptic seizures and excitotoxicity , or unwished stimulation of long-term changes in synaptic plasticity , for instance , in circuits underlying addiction , reward behavior , or fear and anxiety control .	Therapeutics mimicking BDNF or therapies that inhibit or potentiate TrkB signaling may lead to uncontrolled growth effects (e.g., axon sprouting, tumor growth, or cancer cell migration), epileptic seizures and excitotoxicity, or unwished stimulation of long-term changes in synaptic plasticity, for instance, in circuits underlying addiction, reward behavior, or fear and anxiety control.	1	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	9	10
Other important mechanisms contributing to the deficiency of BDNF and TrkB signalling in AD are the suppression of MAPK and ERK and PI3K and Akt pathways by sub-lethal concentrations of Abeta , without interference of TrkB-FL and PLCgamma activation [ XREF_BIBR ] , and the disruption of BDNF induced TrkB endocytosis .	Other important mechanisms contributing to the deficiency of BDNF and TrkB signalling in AD are the suppression of MAPK and ERK and PI3K and Akt pathways by sub-lethal concentrations of Abeta, without interference of TrkB-FL and PLCgamma activation [XREF_BIBR], and the disruption of BDNF induced TrkB endocytosis.	45	50	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	47	48	49	50
In the absence of BDNF the mobility of TrkB-mRFP puncta was greatly reduced in WT ( XREF_FIG ) , but not in AP-2 KO neurons ( XREF_SUPPLEMENTARY ) , suggesting that BDNF may induce the targeting of signalling-active TrkB to autophagosomes for AP-2/LC3/p150 Glued -mediated transport .	In the absence of BDNF the mobility of TrkB-mRFP puncta was greatly reduced in WT (XREF_FIG), but not in AP-2 KO neurons (XREF_SUPPLEMENTARY), suggesting that BDNF may induce the targeting of signalling-active TrkB to autophagosomes for AP-2/LC3/p150 Glued -mediated transport.	31	39	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	31	32	38	39
Although both BDNF collators effectively blocked the BDNF dependent TrkB activation ( XREF_SUPPLEMENTARY ) , neither had any significant impact on the activity dependent increase in CTB retrograde flux ( XREF_FIG ) .	Although both BDNF collators effectively blocked the BDNF dependent TrkB activation (XREF_SUPPLEMENTARY), neither had any significant impact on the activity dependent increase in CTB retrograde flux (XREF_FIG).	2	10	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	9	10
XREF_BIBR They concluded that BDNF limits its own long-term neuroprotective efficacy by initiating downregulation of its TrkB receptor .	XREF_BIBR They concluded that BDNF limits its own long-term neuroprotective efficacy by initiating downregulation of its TrkB receptor.	4	17	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	16	17
72 We assume that TrkB dependent tyrosine phosphorylation of SPRED2 might be preventive for protein degradation and might enable the suppression of Ras and ERK signaling stimulated by BDNF induced TrkB activation .	72 We assume that TrkB dependent tyrosine phosphorylation of SPRED2 might be preventive for protein degradation and might enable the suppression of Ras and ERK signaling stimulated by BDNF induced TrkB activation.	26	31	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	28	29	30	31
showed that TrkB activation in neurogenic regions , revealed by the intensity of pTrkB staining on total TrkB ( in SVZ and OB ) , was reduced by 30 % in Met BDNF brains .	showed that TrkB activation in neurogenic regions, revealed by the intensity of pTrkB staining on total TrkB (in SVZ and OB), was reduced by 30% in Met BDNF brains.	2	33	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	32	33	2	3
Dendritically localized BDNF and TrkB mRNAs are not translated unless that portion of the dendrite is stimulated , thus restricting BDNF and TrkB synthesis to synaptically active sites .	Dendritically localized BDNF and TrkB mRNAs are not translated unless that portion of the dendrite is stimulated, thus restricting BDNF and TrkB synthesis to synaptically active sites.	1	23	restricting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	2	3	22	23
Exogenous application of BDNF promotes the redistribution and stabilization of GABA A R and loss of BDNF and TrkB receptor signaling results in a reduction in the number of gephyrin and GABA A R clusters .	Exogenous application of BDNF promotes the redistribution and stabilization of GABA A R and loss of BDNF and TrkB receptor signaling results in a reduction in the number of gephyrin and GABA A R clusters.	1	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	18	19
Treatment of primary sympathetic neurons with NGF induced recycling of the TrkA receptor , however application of BDNF induced the degradation of the TrkB receptor .	Treatment of primary sympathetic neurons with NGF induced recycling of the TrkA receptor, however application of BDNF induced the degradation of the TrkB receptor.	15	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	17	18	23	24
In contrast , BDNF induced TrkB internalization was attenuated in GCPs infected with Numb shRNA lentivirus ( XREF_FIG , lanes 5 , 6 top panel ) .	In contrast, BDNF induced TrkB internalization was attenuated in GCPs infected with Numb shRNA lentivirus (XREF_FIG, lanes 5, 6 top panel).	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	5	6
A bridged cyclic peptide ( CN2097 ) , shown by nuclear magnetic resonance ( NMR ) studies to uniquely bind the PDZ1 domain of PSD-95 with high affinity , decreased the interaction of Arc with PSD-95 to restore BDNF induced TrkB and PSD -95 complex formation , signaling , and facilitate the induction of LTP in AS mice .	A bridged cyclic peptide (CN2097), shown by nuclear magnetic resonance (NMR) studies to uniquely bind the PDZ1 domain of PSD-95 with high affinity, decreased the interaction of Arc with PSD-95 to restore BDNF induced TrkB and PSD -95 complex formation, signaling, and facilitate the induction of LTP in AS mice.	37	50	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	38	39	40	41
Other studies have shown that infusing BDNF antisense cDNA into the hippocampus prevented the consolidation of contextual fear conditioning , an effect that was reversed by co-administration of BDNF In contrast , late-onset conditional forebrain TrkB knock-out mice were reported as having retarded acquisition of a freezing response to repeated foot shocks , and impaired freezing to tone in an altered context but normal freezing in the conditioned context at later times of testing .	Other studies have shown that infusing BDNF antisense cDNA into the hippocampus prevented the consolidation of contextual fear conditioning, an effect that was reversed by co-administration of BDNF In contrast, late-onset conditional forebrain TrkB knock-out mice were reported as having retarded acquisition of a freezing response to repeated foot shocks, and impaired freezing to tone in an altered context but normal freezing in the conditioned context at later times of testing.	18	39	reversed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	28	29	35	36
A surface biotinylation assay on lentivirus transduced hippocampal neurons indicated that , in agreement with the results from the neuronal morphology assay , depletion of either retrolinkin or WAVE1 , but not N-WASP , caused a block of BDNF triggered TrkB endocytosis ( XREF_FIG ) .	A surface biotinylation assay on lentivirus transduced hippocampal neurons indicated that, in agreement with the results from the neuronal morphology assay, depletion of either retrolinkin or WAVE1, but not N-WASP, caused a block of BDNF triggered TrkB endocytosis (XREF_FIG).	36	41	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	38	39	40	41
BDNF mediated TrkB signalling is an important downstream target for MC4R mediated signalling which participates in the regulation of energy balance and feeding behaviour [ XREF_BIBR ] .	BDNF mediated TrkB signalling is an important downstream target for MC4R mediated signalling which participates in the regulation of energy balance and feeding behaviour [XREF_BIBR].	0	3	mediated	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	2	3
Collectively , these data indicate that BDNF targeted photoablation selectively and effectively eliminates TrkB positive fibers .	Collectively, these data indicate that BDNF targeted photoablation selectively and effectively eliminates TrkB positive fibers.	6	15	eliminates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	13	14
This study reveals the following : ( 1 ) expression of trkB , BDNF , and NT-4 are not modulated by an excess of serotonin during barrel formation , ( 2 ) TrkB signaling limits branching of TCAs in inappropriate supragranular cortical layers , and ( 3 ) serotonin and TrkB signaling act together to cluster thalamocortical axons in layer IV .	This study reveals the following : (1) expression of trkB, BDNF, and NT-4 are not modulated by an excess of serotonin during barrel formation, (2) TrkB signaling limits branching of TCAs in inappropriate supragranular cortical layers, and (3) serotonin and TrkB signaling act together to cluster thalamocortical axons in layer IV.	9	34	modulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	expression of trkB, BDNF	bdnf	TrkB	TrkB	trkb	13	14	32	33
MG increased the cellular levels of BDNF but decreased the TrkB mRNA and protein expression significantly .	MG increased the cellular levels of BDNF but decreased the TrkB mRNA and protein expression significantly.	0	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	MG increased the cellular levels of BDNF	bdnf	TrkB	TrkB	trkb	6	7	10	11
Consistent with our findings that retrolinkin depletion blocks BDNF induced TrkB endocytosis ( XREF_FIG ) , knockdown of retrolinkin caused a decrease in colocalization of pTrk with APPL1 ( XREF_FIG ) .	Consistent with our findings that retrolinkin depletion blocks BDNF induced TrkB endocytosis (XREF_FIG), knockdown of retrolinkin caused a decrease in colocalization of pTrk with APPL1 (XREF_FIG).	7	11	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	8	9	10	11
To explain increased TrkB synaptic signaling in the Ts65Dn cortex , we envisioned several possibilities : increased expression of TrkB , increased expression or protein levels of BDNF , increased access of BDNF to TrkB , decreased retrograde trafficking of TrkB positive endosomes , or decreased downregulation of activated TrkB .	To explain increased TrkB synaptic signaling in the Ts65Dn cortex, we envisioned several possibilities : increased expression of TrkB, increased expression or protein levels of BDNF, increased access of BDNF to TrkB, decreased retrograde trafficking of TrkB positive endosomes, or decreased downregulation of activated TrkB.	22	50	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	expression or protein levels of BDNF	bdnf	TrkB	TrkB	trkb	27	28	49	50
Although we have provided evidences in the current study that the TrkB signaling defect is not caused by reduced BDNF concentration but an intrinsic impairment of the intracellular signaling component , we could not completely exclude the possibility that the change of energy metabolism in PIKE -/- brain , if any , contributes to the reduce brain mass , behavioral abnormalities and neuronal vulnerability to insults .	Although we have provided evidences in the current study that the TrkB signaling defect is not caused by reduced BDNF concentration but an intrinsic impairment of the intracellular signaling component, we could not completely exclude the possibility that the change of energy metabolism in PIKE -/- brain, if any, contributes to the reduce brain mass, behavioral abnormalities and neuronal vulnerability to insults.	11	20	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	19	20	11	12
These specific impairments are consistent with our observation that only a small percentage of AgRP or POMC neurons in the ARH express TrkB , because BDNF deficiency should only impair axonal growth of TrkB expressing neurons .	These specific impairments are consistent with our observation that only a small percentage of AgRP or POMC neurons in the ARH express TrkB, because BDNF deficiency should only impair axonal growth of TrkB expressing neurons.	25	34	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	25	26	33	34
A gradual increase in endogenous BDNF during incubation may elicit a slow activation of TrkB .	A gradual increase in endogenous BDNF during incubation may elicit a slow activation of TrkB.	2	15	elicit	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	14	15
These results demonstrate a dose dependent growth inhibition of BDNF activated TrkB by entrectinib in TrkB expressing NB cell lines .	These results demonstrate a dose dependent growth inhibition of BDNF activated TrkB by entrectinib in TrkB expressing NB cell lines.	7	12	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	9	10	11	12
demonstrated that androgen driven expression of the truncated TrkB.T1 in male mammary mesenchyme is required for inhibition of BDNF induced TrkB signaling in sensory axons .	demonstrated that androgen driven expression of the truncated TrkB.T1 in male mammary mesenchyme is required for inhibition of BDNF induced TrkB signaling in sensory axons.	16	21	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	18	19	20	21
Considering the role of ubiquitination in sorting cargo to the degradative pathway , we questioned whether BDNF and NT4 induced different rates of TrkB receptor degradation .	Considering the role of ubiquitination in sorting cargo to the degradative pathway, we questioned whether BDNF and NT4 induced different rates of TrkB receptor degradation.	16	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	16	17	23	24
alpha-Syn binds to the kinase domain on TrkB , which is negatively regulated by BDNF or Fyn tyrosine kinase .	alpha-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase.	5	18	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	14	15	7	8
Inhibition of the PI3K-AKT pathway blocked BDNF induced neurite outgrowth of PC12-GFP+ TrkB ( XREF_FIG , panel i , iii , v and vii ) .	Inhibition of the PI3K-AKT pathway blocked BDNF induced neurite outgrowth of PC12-GFP+ TrkB (XREF_FIG, panel i, iii, v and vii).	6	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	12	13
Studies with HNSCC cell lines reveal that in vitro stimulation with BDNF , the ligand for TrkB , upregulates the migration and invasion of HNSCC cells , and both transient and stable suppressions of TrkB result in significant abrogation of constitutive and ligand mediated migration and invasion .	Studies with HNSCC cell lines reveal that in vitro stimulation with BDNF, the ligand for TrkB, upregulates the migration and invasion of HNSCC cells, and both transient and stable suppressions of TrkB result in significant abrogation of constitutive and ligand mediated migration and invasion.	11	35	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	11	12	34	35
However , nonphysiological BDNF overexpression did not lead to a further decrease of TrkB protein caused by the lesion and did not downregulate TrkB transcripts XREF_BIBR .	However, nonphysiological BDNF overexpression did not lead to a further decrease of TrkB protein caused by the lesion and did not downregulate TrkB transcripts XREF_BIBR.	3	25	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF overexpression	bdnf	TrkB	TrkB	trkb	3	4	23	24
Deleting snapin Impairs BDNF Induced TrkB Retrograde Signaling .	Deleting snapin Impairs BDNF Induced TrkB Retrograde Signaling.	2	6	Induced	Positive_early_activation	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	3	4	5	6
For instance , disruption of BDNF induced TrkB signaling by perturbing snapin-Dynein interaction , which prevents their retrograde transport to the nucleus , was recently shown to reduce dendritic outgrowth .	For instance, disruption of BDNF induced TrkB signaling by perturbing snapin-Dynein interaction, which prevents their retrograde transport to the nucleus, was recently shown to reduce dendritic outgrowth.	3	8	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	7	8
BDNF does not increase the number of BrdU positive , TrkB negative cells or the overall number of TrkB negative cells .	BDNF does not increase the number of BrdU positive, TrkB negative cells or the overall number of TrkB negative cells.	0	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	0	1	10	11
Recent work has shown impairment of BDNF mediated TrkB retrograde transport in Tg2576 axons and in cultured neurons treated with Abeta [ XREF_BIBR ] .	Recent work has shown impairment of BDNF mediated TrkB retrograde transport in Tg2576 axons and in cultured neurons treated with Abeta [XREF_BIBR].	4	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	6	7	8	9
Decreased expression of the tyrosine receptor kinase B ( TRKB ) , which is activated by BDNF , in the PFC of depressed cases is also associated with an enrichment of H3K27me3 levels in the promoter of both TRKB and its astrocytic variant , TRKB.T1 XREF_BIBR ; XREF_BIBR .	Decreased expression of the tyrosine receptor kinase B (TRKB), which is activated by BDNF, in the PFC of depressed cases is also associated with an enrichment of H3K27me3 levels in the promoter of both TRKB and its astrocytic variant, TRKB.T1 XREF_BIBR; XREF_BIBR.	7	17	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	BDNF	BDNF	BDNF	TRKB	TRKB	TRKB	16	17	9	10
These data are in line with a previous report showing that chronic cocaine selectively increased BDNF mRNA levels in the NAc shell and decreased TrKB receptor mRNA in the NAc core .	These data are in line with a previous report showing that chronic cocaine selectively increased BDNF mRNA levels in the NAc shell and decreased TrKB receptor mRNA in the NAc core.	12	26	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	cocaine selectively increased BDNF mRNA levels	bdnf	TrKB	TrKB	trkb	15	16	24	25
Interestingly , there was a temporally inverse correlation between the appearance of the responsiveness of TrkB to systemic ADs and the marked developmental reduction of BDNF induced TrkB in brain microslices ex vivo .	Interestingly, there was a temporally inverse correlation between the appearance of the responsiveness of TrkB to systemic ADs and the marked developmental reduction of BDNF induced TrkB in brain microslices ex vivo.	23	28	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	25	26	27	28
Furthermore , removal of the Bdnf gene from the epithelium and taste buds caused a greater loss of TrkB positive innervation than total ( i.e ., P2X3 positive ) innervation ( p < 0.001 ) , suggesting that Bdnf gene removal primarily affects TrkB positive fibers .	Furthermore, removal of the Bdnf gene from the epithelium and taste buds caused a greater loss of TrkB positive innervation than total (i.e., P2X3 positive) innervation (p < 0.001), suggesting that Bdnf gene removal primarily affects TrkB positive fibers.	5	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bdnf	Bdnf	Bdnf	TrkB	TrkB	TrkB	5	6	18	19
Previous studies have suggested that BDNF induced TrkB degradation is proteasome dependent .	Previous studies have suggested that BDNF induced TrkB degradation is proteasome dependent.	5	8	induced	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	5	6	7	8
In contrast , infusion of BDNF antibodies into the CeA prevented p-TrkB elevation at 1 and 8 h after conditioning ( XREF_FIG ; ANOVA : F ( 4,10 ) = 9.377 , p = 0.002 ) .	In contrast, infusion of BDNF antibodies into the CeA prevented p-TrkB elevation at 1 and 8 h after conditioning (XREF_FIG; ANOVA : F (4,10) = 9.377, p = 0.002).	5	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	p-TrkB	p-TrkB	p-TrkB	5	6	11	12
We have found that BDNF treatment of WT cortical neurons significantly reduced cell surface TrkB but had no effect on cell surface TrkB in HAP1 KO cortical neurons .	We have found that BDNF treatment of WT cortical neurons significantly reduced cell surface TrkB but had no effect on cell surface TrkB in HAP1 KO cortical neurons.	4	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	TrkB	TrkB	TrkB	4	5	14	15
Moreover , this was associated with impaired BDNF mediated activation of phospho-TrkB despite normal expression of fl-TrkB in R6/2 cultures .	Moreover, this was associated with impaired BDNF mediated activation of phospho-TrkB despite normal expression of fl-TrkB in R6/2 cultures.	7	12	mediated	Positive_early_activation	Positive_activation	Negative_activation	BDNF	BDNF	BDNF	phospho-TrkB	phospho-TrkB	phospho-TrkB	7	8	11	12
When the cells were infected with Ad-PKG II and treated with 8-pCPT-cGMP before being stimulated with HGF , the HGF induced increase of Bcl-2 was abolished and an increase of Bax expression appeared , causing a decrease of the ratio of Bcl-2 and Bax .	When the cells were infected with Ad-PKG II and treated with 8-pCPT-cGMP before being stimulated with HGF, the HGF induced increase of Bcl-2 was abolished and an increase of Bax expression appeared, causing a decrease of the ratio of Bcl-2 and Bax.	30	44	causing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax expression	bax	Bax	Bax	bax	30	31	43	44
Our data showed that ING4 gene overexpression significantly increased the mRNA and protein levels of Bax in U-2OS cells , and decreased the Bcl-2 and Bax ratio at the mRNA level ( XREF_FIG ) .	Our data showed that ING4 gene overexpression significantly increased the mRNA and protein levels of Bax in U-2OS cells, and decreased the Bcl-2 and Bax ratio at the mRNA level (XREF_FIG).	4	26	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	ING4 gene overexpression significantly increased the mRNA and protein levels of Bax	bax	Bax	Bax	bax	15	16	25	26
The expressions of Bax and NF-KappaB were down-regulated obviously [ Bax ( A value ) : 12 529.2 +/-2 018.5 vs. 33 802.6 +/-5 778.0 , NF-KappaB ( A value ) : 1 843.1 +/-373.6 vs. 2 465.9 +/-664.8 , both P < 0.05 ] , and the change was more obvious in circular muscle layer .	The expressions of Bax and NF-KappaB were down-regulated obviously [Bax (A value) : 12 529.2 +/-2 018.5 vs. 33 802.6 +/-5 778.0, NF-KappaB (A value) : 1 843.1 +/-373.6 vs. 2 465.9 +/-664.8, both P < 0.05], and the change was more obvious in circular muscle layer.	1	41	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	expressions of Bax	bax	Bax	Bax	bax	3	4	10	11
Western blot analysis indicated that LDE markedly down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro apoptotic protein Bax , eventually leading the reduction of Bcl-2 and Bax protein ratios both in the cultured melanoma cells and in the tumors from melanoma bearing mice .	Western blot analysis indicated that LDE markedly down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro apoptotic protein Bax, eventually leading the reduction of Bcl-2 and Bax protein ratios both in the cultured melanoma cells and in the tumors from melanoma bearing mice.	5	33	leading	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	LDE markedly down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro apoptotic protein Bax	bax	Bax	Bax	bax	22	23	31	32
XREF_FIG illustrated that SI/R injury induced upregulation of Bax expression and downregulation of Bcl-2 expression , thereby decreasing the Bcl-2 and Bax ratio .	XREF_FIG illustrated that SI/R injury induced upregulation of Bax expression and downregulation of Bcl-2 expression, thereby decreasing the Bcl-2 and Bax ratio.	3	22	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	SI/R injury induced upregulation of Bax expression	bax	Bax	Bax	bax	8	9	21	22
Thermal trauma in burned animals , compared with the controls , increased the expression of pro apoptotic Bax protein ( 1.37 ( 0.94-1.47 ) ) , decreased anti-apoptotic Bcl-2 protein ( 1.16 ( 1.06-1.23 ) , p < 0.001 ) in epithelial cells , and elevated Bax and Bcl -2 ratios ( p < 0.05 ) .	Thermal trauma in burned animals, compared with the controls, increased the expression of pro apoptotic Bax protein (1.37 (0.94-1.47)), decreased anti-apoptotic Bcl-2 protein (1.16 (1.06-1.23), p < 0.001) in epithelial cells, and elevated Bax and Bcl -2 ratios (p < 0.05).	13	50	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	expression of pro apoptotic Bax	bax	Bax	Bax	bax	17	18	46	47
Moreover , MDD patients with a high risk for suicide had increased Bax and FAS mRNA expression and decreased Bcl-2 and Bcl-2 and Bax ratio when compared to patients without risk for suicide ( p < .001 ) .	Moreover, MDD patients with a high risk for suicide had increased Bax and FAS mRNA expression and decreased Bcl-2 and Bcl-2 and Bax ratio when compared to patients without risk for suicide (p <.001).	2	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	MDD patients with a high risk for suicide had increased Bax and FAS mRNA expression	bax	Bax	Bax	bax	12	13	23	24
We found that PLM reduced the expression level of Bax , increased the ratio of Bcl-2 and Bax and reduced active caspase 3 .	We found that PLM reduced the expression level of Bax, increased the ratio of Bcl-2 and Bax and reduced active caspase 3.	3	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	PLM reduced the expression level of Bax	bax	Bax	Bax	bax	9	10	17	18
The results of the present study indicated that ectopic miR-145 expression may decrease the expression of MMP-2 , MMP-9 and Bcl-2 , and increase the expression of Bax , thus increasing the Bax and Bcl -2 ratio .	The results of the present study indicated that ectopic miR-145 expression may decrease the expression of MMP-2, MMP-9 and Bcl-2, and increase the expression of Bax, thus increasing the Bax and Bcl -2 ratio.	9	36	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	miR-145 expression may decrease the expression of MMP-2, MMP-9 and Bcl-2, and increase the expression of Bax	bax	Bax	Bax	bax	27	28	32	33
XREF_BIBR As shown in XREF_FIG E-2H , compared with theCEL and Ctrl groups , hearts treated with siRNA-TR displayed increased Bcl-2 but decreased BAX protein expression and subsequently increased Bcl-2 and BAX ratios .	XREF_BIBR As shown in XREF_FIG E-2H, compared with theCEL and Ctrl groups, hearts treated with siRNA-TR displayed increased Bcl-2 but decreased BAX protein expression and subsequently increased Bcl-2 and BAX ratios.	20	32	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAX	Bcl-2 but decreased BAX protein expression	bax	BAX	BAX	bax	23	24	31	32
The present study also demonstrated that PD98059 , a specific ERK inhibitor , promoted HMC apoptosis , inhibited the expression levels of TGF-beta1 , Col-IV , Col-I and Bcl-2 , and upregulated the expression of Bax , therefore , decreasing the Bcl-2 and Bax ratio .	The present study also demonstrated that PD98059, a specific ERK inhibitor, promoted HMC apoptosis, inhibited the expression levels of TGF-beta1, Col-IV, Col-I and Bcl-2, and upregulated the expression of Bax, therefore, decreasing the Bcl-2 and Bax ratio.	10	44	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	ERK inhibitor, promoted HMC apoptosis, inhibited the expression levels of TGF-beta1, Col-IV, Col-I and Bcl-2, and upregulated the expression of Bax	bax	Bax	Bax	bax	35	36	43	44
Additionally , TRX significantly reduced the liver mRNA expressions of Bax ( P < 0.001 ) and increased the Bcl-2 and Bax ratio ( P < 0.001 ) compared with the control group .	Additionally, TRX significantly reduced the liver mRNA expressions of Bax (P < 0.001) and increased the Bcl-2 and Bax ratio (P < 0.001) compared with the control group.	2	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	TRX significantly reduced the liver mRNA expressions of Bax	bax	Bax	Bax	bax	10	11	21	22
Importantly , nicotine induced Bax phosphorylation potently blocks stress induced translocation of Bax from cytosol to mitochondria , impairs Bax insertion into mitochondrial membranes , and reduces the half-life of Bax protein ( i.e. from 9-12 h to < 6 h ) .	Importantly, nicotine induced Bax phosphorylation potently blocks stress induced translocation of Bax from cytosol to mitochondria, impairs Bax insertion into mitochondrial membranes, and reduces the half-life of Bax protein (i.e. from 9-12 h to < 6 h).	4	20	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax phosphorylation	bax	Bax	Bax	bax	4	5	19	20
To test whether SMBA induced inhibition of Bax phosphorylation promotes mitochondrial localization of Bax to initiate Cyt c release , A549 cells were treated with increasing concentrations of SMBA1 , 2 or 3 for 24 h. Bax and Cyt c were measured by immunofluorescence .	To test whether SMBA induced inhibition of Bax phosphorylation promotes mitochondrial localization of Bax to initiate Cyt c release, A549 cells were treated with increasing concentrations of SMBA1, 2 or 3 for 24 h. Bax and Cyt c were measured by immunofluorescence.	7	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax phosphorylation	bax	Bax	Bax	bax	7	8	13	14
The mechanisms are unclear , but could involve inhibition of MAPKs , or perhaps PI3K-Akt-dependent Bax phosphorylation at Ser184 , which would prevent Bax from heterodimerizing with Bcl-xL and other anti-apoptotic factors [ XREF_BIBR ] .	The mechanisms are unclear, but could involve inhibition of MAPKs, or perhaps PI3K-Akt-dependent Bax phosphorylation at Ser184, which would prevent Bax from heterodimerizing with Bcl-xL and other anti-apoptotic factors [XREF_BIBR].	15	24	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax phosphorylation at Ser184	bax	Bax	Bax	bax	15	16	23	24
Using a binary adenoviral system that can induce Bax gene expression , we showed that induction of the Bax gene expression via the hTERT promoter elicited tumor specific apoptosis in vitro , suppressed tumor growth in nude mice , and prevented the toxicity of the Bax gene in vitro and in vivo .	Using a binary adenoviral system that can induce Bax gene expression, we showed that induction of the Bax gene expression via the hTERT promoter elicited tumor specific apoptosis in vitro, suppressed tumor growth in nude mice, and prevented the toxicity of the Bax gene in vitro and in vivo.	18	46	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax gene expression	bax	Bax	Bax	bax	18	19	45	46
MS-275 increases the expression of apoptotic protein BAX , hence decreasing the BCL2 and BAX ratio , and coordinate with decrease in survival .	MS-275 increases the expression of apoptotic protein BAX, hence decreasing the BCL2 and BAX ratio, and coordinate with decrease in survival.	0	15	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAX	MS-275 increases the expression of apoptotic protein BAX	bax	BAX	BAX	bax	7	8	14	15
PRD treatment significantly reduced Bax and caspase-3 protein expression in diabetic rats , and significantly increased Bcl-2 protein expression and Bcl-2 and Bax ratio ( P < 0.01 ; XREF_FIG , XREF_TABLE ) .	PRD treatment significantly reduced Bax and caspase-3 protein expression in diabetic rats, and significantly increased Bcl-2 protein expression and Bcl-2 and Bax ratio (P < 0.01; XREF_FIG, XREF_TABLE).	0	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	PRD treatment significantly reduced Bax and caspase-3 protein expression	bax	Bax	Bax	bax	4	5	22	23
MA pretreatments decreased Bax expression , raised the Bcl-2 and Bax ratio , and increased cell viability .	MA pretreatments decreased Bax expression, raised the Bcl-2 and Bax ratio, and increased cell viability.	0	11	raised	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	MA pretreatments decreased Bax expression	bax	Bax	Bax	bax	3	4	10	11
Ubiquitination of Bax by parkin prevents stress induced translocation of Bax to the mitochondria [ XREF_BIBR , XREF_BIBR ] although Bcl-2 , whose C-terminus is directly bounded by parkin , is monoubiquitinated and is then steadily upregulated by parkin [ XREF_BIBR ] .	Ubiquitination of Bax by parkin prevents stress induced translocation of Bax to the mitochondria [XREF_BIBR, XREF_BIBR] although Bcl-2, whose C-terminus is directly bounded by parkin, is monoubiquitinated and is then steadily upregulated by parkin [XREF_BIBR].	0	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Ubiquitination of Bax	bax	Bax	Bax	bax	2	3	10	11
Control siRNA and 1 muM Gemcitabine treatment tended to suppress bcl-2 expression , but the expression of bax in this combinative treatment also decreased and did not lead to change the ratio of bax and bcl -2 towards proapoptosis ( 99 % of Control ) .	Control siRNA and 1 muM Gemcitabine treatment tended to suppress bcl-2 expression, but the expression of bax in this combinative treatment also decreased and did not lead to change the ratio of bax and bcl -2 towards proapoptosis (99% of Control).	15	34	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	bax	expression of bax	bax	bax	bax	bax	17	18	33	34
Results demonstrated that PLM treatment increases protein expression of Bcl-2 , significantly reduces Bax expression and increases ratio of Bcl-2 to Bax in the myocardium after myocardial IR injury when compared with control .	Results demonstrated that PLM treatment increases protein expression of Bcl-2, significantly reduces Bax expression and increases ratio of Bcl-2 to Bax in the myocardium after myocardial IR injury when compared with control.	3	24	increases	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	Bax	PLM treatment increases protein expression of Bcl-2, significantly reduces Bax expression	bax	Bax	Bax	bax	13	14	21	22
The impact of BTSA1 induced BAX activation in AML cells is regulated by the protein levels of BAX and availability of anti-apoptotic BCL-2 to sequester activated BAX .	The impact of BTSA1 induced BAX activation in AML cells is regulated by the protein levels of BAX and availability of anti-apoptotic BCL-2 to sequester activated BAX.	3	27	sequester activated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAX	BTSA1 induced BAX	bax	BAX	BAX	bax	5	6	26	27
Compared with the control group , the expression of Bcl-2 and Bax proteins were up-regulated significantly in Epi-CH group ( P < 0.05 and P < 0.01 , respectively ) , resulting in decreased ratio of Bcl-2 and Bax .	Compared with the control group, the expression of Bcl-2 and Bax proteins were up-regulated significantly in Epi-CH group (P < 0.05 and P < 0.01, respectively), resulting in decreased ratio of Bcl-2 and Bax.	7	39	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	expression of Bcl-2 and Bax	bax	Bax	Bax	bax	11	12	38	39
Here we discovered that the rapalog induced activation of AKT enhances Bax phosphorylation and inactivates the proapoptotic function of Bax .	Here we discovered that the rapalog induced activation of AKT enhances Bax phosphorylation and inactivates the proapoptotic function of Bax.	9	20	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	AKT enhances Bax phosphorylation	bax	Bax	Bax	bax	11	12	19	20
The pro apoptotic Bcl-2 member Bax can be regulated by ubiquitination indirectly ; the ubiquitin ligase Trim39 inhibits APC/C Cdh1 mediated ubiquitination and degradation of the Bax activator MOAP-1 , thus enhancing Bax activation and apoptosis XREF_BIBR .	The pro apoptotic Bcl-2 member Bax can be regulated by ubiquitination indirectly; the ubiquitin ligase Trim39 inhibits APC/C Cdh1 mediated ubiquitination and degradation of the Bax activator MOAP-1, thus enhancing Bax activation and apoptosis XREF_BIBR.	14	33	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	ubiquitin ligase Trim39 inhibits APC/C Cdh1 mediated ubiquitination and degradation of the Bax	bax	Bax	Bax	bax	26	27	32	33
Furthermore , Western blot analysis confirmed that BER dose-dependently down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro apoptotic protein Bax , eventually leading the reduction of Bcl-2 and Bax protein ratio in A549 cells .	Furthermore, Western blot analysis confirmed that BER dose-dependently down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro apoptotic protein Bax, eventually leading the reduction of Bcl-2 and Bax protein ratio in A549 cells.	19	35	leading	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	level of pro apoptotic protein Bax	bax	Bax	Bax	bax	24	25	33	34
Also , miR-138 overexpression followed by APG treatment dramatically increased Bax expression and decreased in Bcl-2 expression , resulting in the Bax : Bcl-2 ratio to trigger directly trigger intrinsic pathway of apoptosis such as mitochondrial release of Smac into the cytosol for down regulation and degradation of survivin and activation of caspase-3 .	Also, miR-138 overexpression followed by APG treatment dramatically increased Bax expression and decreased in Bcl-2 expression, resulting in the Bax : Bcl-2 ratio to trigger directly trigger intrinsic pathway of apoptosis such as mitochondrial release of Smac into the cytosol for down regulation and degradation of survivin and activation of caspase-3.	2	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	miR-138 overexpression followed by APG treatment dramatically increased Bax expression	bax	Bax	Bax	bax	10	11	21	22
Notably , the chronic administration of testosterone slightly reduced myocardial Akt activation compared to untreated males , but significantly decreased Bax protein levels and elevated the ratio of Bcl-2 and Bax .	Notably, the chronic administration of testosterone slightly reduced myocardial Akt activation compared to untreated males, but significantly decreased Bax protein levels and elevated the ratio of Bcl-2 and Bax.	6	31	elevated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	testosterone slightly reduced myocardial Akt activation compared to untreated males, but significantly decreased Bax protein levels	bax	Bax	Bax	bax	20	21	30	31
Consistent with the neuroprotective effect of E2 in females , E2 treatment significantly reduced the ischemia induced increase in Bax expression , reducing Bax in the penumbra from 199 +/-52% of non ischemic cortex to 130 +/-23% of corresponding E2 treated non ischemic cortex ( n = 6 ; P < 0.05 compared to vehicle ; XREF_FIG ) .	Consistent with the neuroprotective effect of E2 in females, E2 treatment significantly reduced the ischemia induced increase in Bax expression, reducing Bax in the penumbra from 199 +/-52% of non ischemic cortex to 130 +/-23% of corresponding E2 treated non ischemic cortex (n = 6; P < 0.05 compared to vehicle; XREF_FIG).	19	39	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax expression	bax	Bax	Bax	bax	19	20	23	24
When compared with those of OGD group , IL-10 treatment reduced Bax expression and increased Bcl-2 expression in OGD injured neurons ( Bax , 1.19 +/-0.05 vs. 2.16 +/-0.23 , p < 0.05 ; Bcl-2 , 0.77 +/-0.01 vs. 0.56 +/-0.01 , p < 0.001 ) ( XREF_FIG ) ; contrarily , IL-10NA treatment significantly increased Bax expression and decreased Bcl-2 expression ( Bax , 4.56 +/-0.38 vs. 2.16 +/-0.23 , p < 0.001 ; Bcl-2 , 0.38 +/-0.01 vs. 0.56 +/-0.01 , p < 0.01 ) ( XREF_FIG ) .	When compared with those of OGD group, IL-10 treatment reduced Bax expression and increased Bcl-2 expression in OGD injured neurons (Bax, 1.19 +/-0.05 vs. 2.16 +/-0.23, p < 0.05; Bcl-2, 0.77 +/-0.01 vs. 0.56 +/-0.01, p < 0.001) (XREF_FIG); contrarily, IL-10NA treatment significantly increased Bax expression and decreased Bcl-2 expression (Bax, 4.56 +/-0.38 vs. 2.16 +/-0.23, p < 0.001; Bcl-2, 0.38 +/-0.01 vs. 0.56 +/-0.01, p < 0.01) (XREF_FIG).	10	58	reduced	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	Bax	IL-10NA treatment significantly increased Bax expression	bax	Bax	Bax expression	bax	56	57	11	12
Because Bax was dominant , the increased expression of Bax significantly decreased the ratio of Bcl-2 and Bax .	Because Bax was dominant, the increased expression of Bax significantly decreased the ratio of Bcl-2 and Bax.	7	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	expression of Bax	bax	Bax	Bax	bax	9	10	17	18
EGb761 and alpha-tocopherol treatment reversed the increase in VCMs , decreased Bax expression , increased Bcl-2 expression , and decreased the Bax and Bcl -2 ratio .	EGb761 and alpha-tocopherol treatment reversed the increase in VCMs, decreased Bax expression, increased Bcl-2 expression, and decreased the Bax and Bcl -2 ratio.	0	25	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	EGb761 and alpha-tocopherol treatment reversed the increase in VCMs, decreased Bax expression	bax	Bax	Bax	bax	11	12	21	22
Additionally , it diminished the down-regulation of the anti-apoptotic proteins Mcl-1 ( 6 ) and Bcl-2 ( 7 ) , and decreased the expression level of the pro apoptotic protein Bax ( 8 ) , thus raising the ratio of Bcl-2 and Bax .	Additionally, it diminished the down-regulation of the anti-apoptotic proteins Mcl-1 (6) and Bcl-2 (7), and decreased the expression level of the pro apoptotic protein Bax (8), thus raising the ratio of Bcl-2 and Bax.	24	43	raising	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	level of the pro apoptotic protein Bax	bax	Bax	Bax	bax	30	31	42	43
120 Phosphorylation ( Ser184 ) of Bax inactivates its pro apoptotic function by maintaining Bax in the cytoplasm and heterodimerizing with anti-apoptotic Bcl-2 proteins , and thus contributes to increased survival and chemoresistance of human lung cancer cells .	120 Phosphorylation (Ser184) of Bax inactivates its pro apoptotic function by maintaining Bax in the cytoplasm and heterodimerizing with anti-apoptotic Bcl-2 proteins, and thus contributes to increased survival and chemoresistance of human lung cancer cells.	1	17	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Phosphorylation (Ser184) of Bax	bax	Bax	Bax	bax	6	7	14	15
Our results also showed that Bcl-2 protein expression decreased and Bax protein expression increased in fluoride treated liver and kidney of rats and MPPP can block Bcl-2 expression decrease and Bax expression increase .	Our results also showed that Bcl-2 protein expression decreased and Bax protein expression increased in fluoride treated liver and kidney of rats and MPPP can block Bcl-2 expression decrease and Bax expression increase.	10	32	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax protein expression	bax	Bax	Bax	bax	10	11	30	31
In the present study , we found that Bax and Bcl-2 levels were up- and downregulated , respectively , resulting in an increase in Bax and Bcl -2 ratio in oligoasthenospermia rats .	In the present study, we found that Bax and Bcl-2 levels were up- and downregulated, respectively, resulting in an increase in Bax and Bcl -2 ratio in oligoasthenospermia rats.	8	26	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax and Bcl-2 levels	bax	Bax	Bax	bax	8	9	24	25
In contrast , as Bax expression increases , the ratio of Bcl-2 and Bax decreases , resulting in cell death [ XREF_BIBR ] .	In contrast, as Bax expression increases, the ratio of Bcl-2 and Bax decreases, resulting in cell death [XREF_BIBR].	4	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	Bax expression	bax	Bax	Bax	bax	4	5	13	14
Both hAD-MSC and LIPUS pretreated hAD-MSC transplantation significantly reduced the Bax expression and significantly increased the Bcl-2 expression and the Bcl-2 and Bax ratio in the ovaries of POI rats .	Both hAD-MSC and LIPUS pretreated hAD-MSC transplantation significantly reduced the Bax expression and significantly increased the Bcl-2 expression and the Bcl-2 and Bax ratio in the ovaries of POI rats.	1	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	hAD-MSC and LIPUS pretreated hAD-MSC transplantation significantly reduced the Bax expression	bax	Bax	Bax	bax	10	11	22	23
We also found that DGLHD and active ingredients increased the expressions of the anti-apoptotic gene Bcl-2 and the proliferation related gene CyclinD1 , decreased the expression of the pro apoptosis gene Bax , and increased the ratio of Bcl-2 and Bax in NIT-1 cells , a model murine pancreatic beta cell line .	We also found that DGLHD and active ingredients increased the expressions of the anti-apoptotic gene Bcl-2 and the proliferation related gene CyclinD1, decreased the expression of the pro apoptosis gene Bax, and increased the ratio of Bcl-2 and Bax in NIT-1 cells, a model murine pancreatic beta cell line.	4	41	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	DGLHD and active ingredients increased the expressions of the anti-apoptotic gene Bcl-2 and the proliferation related gene CyclinD1, decreased the expression of the pro apoptosis gene Bax	bax	Bax	Bax	bax	31	32	40	41
Inhibition of NF-kappaB by JSH-23 or overexpression of AdIkappaBalphaDN restored the decreased expression of Bcl-2 and prevented the HG induced increase in Bax expression , thereby restoring the Bax and Bcl -2 ratio to control levels ( XREF_FIG ) .	Inhibition of NF-kappaB by JSH-23 or overexpression of AdIkappaBalphaDN restored the decreased expression of Bcl-2 and prevented the HG induced increase in Bax expression, thereby restoring the Bax and Bcl -2 ratio to control levels (XREF_FIG).	18	32	restoring	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	HG induced increase in Bax expression	bax	Bax	Bax	bax	22	23	28	29
In XREF_FIG , after limonin treatment , the expression of Bax in cytoplasm was decreased , while its expression in mitochondria was increased , suggesting a translocation of Bax from cytoplasm to mitochondria .	In XREF_FIG, after limonin treatment, the expression of Bax in cytoplasm was decreased, while its expression in mitochondria was increased, suggesting a translocation of Bax from cytoplasm to mitochondria.	8	29	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	expression of Bax	bax	Bax	Bax	bax	10	11	28	29
However , RDPS was demonstrated to significantly decrease the expression levels of caspase-3 and Bax , and increase the expression levels of Bcl-2 and the ratio of Bcl-2 : Bax .	However, RDPS was demonstrated to significantly decrease the expression levels of caspase-3 and Bax, and increase the expression levels of Bcl-2 and the ratio of Bcl-2 : Bax.	2	30	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	RDPS was demonstrated to significantly decrease the expression levels of caspase-3 and Bax	bax	Bax	Bax	bax	14	15	29	30
Yizhi jiannao granule can decrease the neuron apoptosis rate and the Bax level , increase the Bcl-2 level , and modulate the rate of Bcl-2 and Bax in SAMP/8 brain , which is probably part of the mechanisms of inhibiting the apoptosis and improving learning and memory .	Yizhi jiannao granule can decrease the neuron apoptosis rate and the Bax level, increase the Bcl-2 level, and modulate the rate of Bcl-2 and Bax in SAMP/8 brain, which is probably part of the mechanisms of inhibiting the apoptosis and improving learning and memory.	1	27	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	jiannao granule can decrease the neuron apoptosis rate and the Bax level	bax	Bax	Bax	bax	11	12	26	27
These findings support and extend our and others ' previous studies that phosphorylation of Bax at S184 can inactivate the proapoptotic function of Bax and that dephosphorylation of Bax at this site renders Bax more potent killing capacity XREF_BIBR - XREF_BIBR .	These findings support and extend our and others ' previous studies that phosphorylation of Bax at S184 can inactivate the proapoptotic function of Bax and that dephosphorylation of Bax at this site renders Bax more potent killing capacity XREF_BIBR - XREF_BIBR.	12	24	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	phosphorylation of Bax at S184	bax	Bax	Bax	bax	14	15	23	24
As phosphorylation events are known to modulate apoptosis , phosphorylation of Bax in Ser184 , probably by Akt , inhibits effects of Bax in mitochondria and prevents the induction of apoptosis .	As phosphorylation events are known to modulate apoptosis, phosphorylation of Bax in Ser184, probably by Akt, inhibits effects of Bax in mitochondria and prevents the induction of apoptosis.	9	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bax	phosphorylation of Bax in Ser184	bax	Bax	Bax	bax	11	12	22	23
Importantly , nicotine induced Bax phosphorylation potently blocks stress induced translocation of Bax from the cytosol to the mitochondria , impairs Bax insertion into mitochondrial membranes , and reduces the half-life of Bax protein [ XREF_BIBR ] .	Importantly, nicotine induced Bax phosphorylation potently blocks stress induced translocation of Bax from the cytosol to the mitochondria, impairs Bax insertion into mitochondrial membranes, and reduces the half-life of Bax protein [XREF_BIBR].	4	22	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bax	Bax phosphorylation	bax	Bax	Bax	bax	4	5	21	22
Thus far , our findings show that PUMA mediated de-repression of BIM promotes BAX activation in cells to initiate tUPR , therefore we biochemically modeled this de-repression scenario to determine a mitochondrial shape requirement .	Thus far, our findings show that PUMA mediated de-repression of BIM promotes BAX activation in cells to initiate tUPR, therefore we biochemically modeled this de-repression scenario to determine a mitochondrial shape requirement.	9	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	11	12	13	14
In the intrinsic pathway , RACK1 inhibits expression of anti-apoptotic Bcl-2 and Bcl-X ( L ) , induces expression of pro apoptotic Bim , targets Bim and Bax to the mitochondria , induces oligomerization of Bax ( which requires Bim and inhibition of Src ) , depolarizes mitochondria membranes , releases cytochrome c , and activates caspases-9 and -3 and death substrates .	In the intrinsic pathway, RACK1 inhibits expression of anti-apoptotic Bcl-2 and Bcl-X (L), induces expression of pro apoptotic Bim, targets Bim and Bax to the mitochondria, induces oligomerization of Bax (which requires Bim and inhibition of Src), depolarizes mitochondria membranes, releases cytochrome c, and activates caspases-9 and -3 and death substrates.	5	28	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	RACK1 inhibits expression of anti-apoptotic Bcl-2 and Bcl-X (L), induces expression of pro apoptotic Bim	bim	Bax	Bax	bax	22	23	27	28
The Bim accumulation in mitochondria enhances interaction of Bim with Bcl-2 , relieves Bax from Bcl-2-bound complexes , and subsequently results in release of cytochrome c into the cytoplasm .	The Bim accumulation in mitochondria enhances interaction of Bim with Bcl-2, relieves Bax from Bcl-2-bound complexes, and subsequently results in release of cytochrome c into the cytoplasm.	1	14	relieves	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bim	Bim	Bim	Bax	Bax	Bax	1	2	13	14
In contrast , the BH3-only protein Bim reduced the rate of Bax retrotranslocation more than 3 fold to 1.3 +/- 0.2 x 10 -3 s -1 in HCT116 Bax and Bak DKO cells that did not contain Bax foci .	In contrast, the BH3-only protein Bim reduced the rate of Bax retrotranslocation more than 3 fold to 1.3 +/- 0.2 x 10 -3 s -1 in HCT116 Bax and Bak DKO cells that did not contain Bax foci.	3	32	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bim	Bim	Bim	Bax	Bax	Bax	6	7	28	29
The observation that down-regulation of BIM by shRNA almost completely suppressed BAX and BAK activation , cytochrome c release , and cell death induced by Dex and MEK inhibitors co-treatment ( XREF_FIG ) strongly suggests that BIM is a central regulator in this regimen at least in CCRF-CEM T-ALL and RS4 ; 11 B-ALL cells .	The observation that down-regulation of BIM by shRNA almost completely suppressed BAX and BAK activation, cytochrome c release, and cell death induced by Dex and MEK inhibitors co-treatment (XREF_FIG) strongly suggests that BIM is a central regulator in this regimen at least in CCRF-CEM T-ALL and RS4; 11 B-ALL cells.	3	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BIM	BIM	BIM	BAX	BAX	BAX	5	6	11	12
Knockdown of BIM attenuated BAX , but not BAK , activation by cobimetinib plus A-1210477 .	Knockdown of BIM attenuated BAX, but not BAK, activation by cobimetinib plus A-1210477.	0	8	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	2	3	4	5
Pro apoptotic targets of JNK signaling include the BH3-only proteins BIM and BMF that can initiate BAK and BAX dependent apoptotic cell death .	Pro apoptotic targets of JNK signaling include the BH3-only proteins BIM and BMF that can initiate BAK and BAX dependent apoptotic cell death.	6	22	initiate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	10	11	18	19
In addition to interacting with Bak , F1 has also been reported to associate with the BH3-only protein Bim indirectly inhibiting the activation of the pro apoptotic protein Bax following an apoptotic stimulus XREF_BIBR , XREF_BIBR .	In addition to interacting with Bak, F1 has also been reported to associate with the BH3-only protein Bim indirectly inhibiting the activation of the pro apoptotic protein Bax following an apoptotic stimulus XREF_BIBR, XREF_BIBR.	13	33	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bim	Bim	Bim	Bax	Bax	Bax	18	19	28	29
Accordingly , deficiency of Bim and Puma impedes ER stress induced BAX and BAK activation and apoptosis .	Accordingly, deficiency of Bim and Puma impedes ER stress induced BAX and BAK activation and apoptosis.	2	14	impedes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bim	Bim	Bim	BAX	BAX	BAX	4	5	11	12
The Bim tumor-suppressor protein , an essential member of this family , induces apoptosis during lymphocyte maturation or when overexpressed through the regulatory activities of several prosurvival members of the Bcl-2 family , as well as the proapoptotic family member Bax [ XREF_BIBR ] .	The Bim tumor-suppressor protein, an essential member of this family, induces apoptosis during lymphocyte maturation or when overexpressed through the regulatory activities of several prosurvival members of the Bcl-2 family, as well as the proapoptotic family member Bax [XREF_BIBR].	1	42	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	1	2	40	41
Induction of CHOP , PUMA , and BIM by DEN was decreased in Bok -/- mice , as was the oligomerization of BAX , supporting a pro apoptotic role of BOK upstream of mitochondria .	Induction of CHOP, PUMA, and BIM by DEN was decreased in Bok -/- mice, as was the oligomerization of BAX, supporting a pro apoptotic role of BOK upstream of mitochondria.	0	23	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BIM	BIM	BIM	BAX	BAX	BAX	7	8	22	23
Down-regulation of BIM by short-hairpin RNA in ALL cells suppressed BAX and BAK activation , cytochrome c release , and cell death by Dex and PD184352 co-treatment .	Down-regulation of BIM by short-hairpin RNA in ALL cells suppressed BAX and BAK activation, cytochrome c release, and cell death by Dex and PD184352 co-treatment.	0	13	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BIM	BIM	BIM	BAX	BAX	BAX	2	3	10	11
As a further measure of specificity , we found that R153D mutagenesis of BIM SAHB , which eliminated its BAX activating capacity in the oligomerization and cytochrome c release assays ( XREF_FIG ) , likewise abolished BIM SAHB induced activation of BAX and BAX K21E in a cellular context ( XREF_FIG ) .	As a further measure of specificity, we found that R153D mutagenesis of BIM SAHB, which eliminated its BAX activating capacity in the oligomerization and cytochrome c release assays (XREF_FIG), likewise abolished BIM SAHB induced activation of BAX and BAX K21E in a cellular context (XREF_FIG).	36	44	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	36	37	41	42
Knockdown of Bim or Bmf also decreased the activation of Bax and Bak in response to paclitaxel treatment in MCF-7 cells , indicating that these BH3-only proteins act upstream of Bax and Bak activation as expected ( XREF_FIG ) .	Knockdown of Bim or Bmf also decreased the activation of Bax and Bak in response to paclitaxel treatment in MCF-7 cells, indicating that these BH3-only proteins act upstream of Bax and Bak activation as expected (XREF_FIG).	0	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	2	3	10	11
Depletion and inhibition of Rac-1 , JNK-1 , Bim , or Bmf prevented the activation of Bak and Bax and the subsequent activation of caspases .	Depletion and inhibition of Rac-1, JNK-1, Bim, or Bmf prevented the activation of Bak and Bax and the subsequent activation of caspases.	0	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	8	9	18	19
Accordingly , depletion and inhibition of JNK-1 , Bim or Bmf prevented the activation of Bax and Bak .	Accordingly, depletion and inhibition of JNK-1, Bim or Bmf prevented the activation of Bax and Bak.	2	17	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bim	Bim	Bim	Bax	Bax	Bax	8	9	15	16
We previously determined that a K21E point mutation in BAX impaired BIM SAHB binding and BH3 induced BAX activation in vitro and in cells XREF_BIBR , XREF_BIBR .	We previously determined that a K21E point mutation in BAX impaired BIM SAHB binding and BH3 induced BAX activation in vitro and in cells XREF_BIBR, XREF_BIBR.	11	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BIM	BIM	BIM	BAX	BAX	BAX	11	12	17	18
The ability of BIM to promote apoptosis induced by the drug combination was demonstrated using BIM shRNA that attenuated BAX , but not BAK , activation .	The ability of BIM to promote apoptosis induced by the drug combination was demonstrated using BIM shRNA that attenuated BAX, but not BAK, activation.	15	23	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BIM	BIM	BIM	BAX	BAX	BAX	15	16	19	20
BAX and BAK conformational changes were completely inhibited by down-regulation of BIM in clone 2 ( XREF_FIG ) .	BAX and BAK conformational changes were completely inhibited by down-regulation of BIM in clone 2 (XREF_FIG).	0	12	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	BIM	BIM	BIM	BAX	BAX	BAX	11	12	0	1
ERK also phosphorylates Mcl-1 and Bim which allows Bcl-2 , Bcl-xL and Mcl-1 to bind Bax and prevent Bax activation and the formation of Bax : Bax homodimers .	ERK also phosphorylates Mcl-1 and Bim which allows Bcl-2, Bcl-xL and Mcl-1 to bind Bax and prevent Bax activation and the formation of Bax : Bax homodimers.	0	19	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bim	ERK also phosphorylates Mcl-1 and Bim	bim	Bax	Bax	bax	5	6	18	19
On the other hand , downregulation of Bim by siRNA ( small interfering RNA ) significantly prevented HCV mediated activation of Bax and caspase 3 .	On the other hand, downregulation of Bim by siRNA (small interfering RNA) significantly prevented HCV mediated activation of Bax and caspase 3.	5	23	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bim	Bim	Bim	Bax	Bax	Bax	7	8	21	22
ERK phosphorylation also results in the phosphorylation of the pro apoptotic Bim protein , and then prevents Bax activation .	ERK phosphorylation also results in the phosphorylation of the pro apoptotic Bim protein, and then prevents Bax activation.	0	18	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bim	ERK phosphorylation also results in the phosphorylation of the pro apoptotic Bim	bim	Bax	Bax	bax	11	12	17	18
Bim knockdown by shRNA suppressed BAX and BAK conformational change and protected cells from dasatinib and PD184352 lethality .	Bim knockdown by shRNA suppressed BAX and BAK conformational change and protected cells from dasatinib and PD184352 lethality.	0	11	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bim	Bim	Bim	BAX	BAX	BAX	0	1	5	6
Both BIM and PUMA have been implicated as important contributors of FFA induced hepatocyte toxicity XREF_BIBR , XREF_BIBR ; and knockdown of BIM or PUMA in liver cells partially protects against FFA induced Bax activation , mitochondrial dysfunctions , caspase-3 activation and apoptosis .	Both BIM and PUMA have been implicated as important contributors of FFA induced hepatocyte toxicity XREF_BIBR, XREF_BIBR; and knockdown of BIM or PUMA in liver cells partially protects against FFA induced Bax activation, mitochondrial dysfunctions, caspase-3 activation and apoptosis.	20	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BIM	BIM	BIM	Bax	Bax	Bax	22	23	33	34
Killing was also observed in the constitutive absence of Bcl-x L because the only restraint left for controlling Bak , Mcl-1 , is now inactivated by Bim S 2A .	Killing was also observed in the constitutive absence of Bcl-x L because the only restraint left for controlling Bak, Mcl-1, is now inactivated by Bim S 2A.	17	28	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Bim	Bim	Bim	Bak	Bak	Bak	26	27	18	19
Thus , Mcl-1 may exert its antiapoptotic function via direct interaction with Bim leading to suppression of Bim triggered Bak activation .	Thus, Mcl-1 may exert its antiapoptotic function via direct interaction with Bim leading to suppression of Bim triggered Bak activation.	15	20	triggered	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Bim	Bim	Bim	Bak	Bak	Bak	17	18	19	20
Phosphorylation of Bad by JNK1 at Thr201 may reduce Bad association with Bcl-X L thus inhibiting the pro apoptotic activity of Bad .	Phosphorylation of Bad by JNK1 at Thr201 may reduce Bad association with Bcl-X L thus inhibiting the pro apoptotic activity of Bad.	12	22	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	Bad	Bad	Bad	12	14	21	22
Increased AIM2 expression can inhibit the expression of the anti-apoptotic protein Bcl-xL , increase the expression of the apoptosis proteins Bad and Bax , and activate caspases , resulting in cleavage of the DNA repair protein PARP .	Increased AIM2 expression can inhibit the expression of the anti-apoptotic protein Bcl-xL, increase the expression of the apoptosis proteins Bad and Bax, and activate caspases, resulting in cleavage of the DNA repair protein PARP.	1	22	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bcl-xL	AIM2 expression can inhibit the expression of the anti-apoptotic protein Bcl-xL	bcl-xl	Bad	Bad	bad	11	12	20	21
Our findings that the BAD-BAX-caspase-3 cascade is sufficient for LTD induction as demonstrated by infusion of active BAD or caspase-3 into hippocampal neurons and that overexpression of BCL-XL , which antagonizes BAD and BAX , inhibits LTD provide additional support for the importance of mitochondria to synaptic plasticity .	Our findings that the BAD-BAX-caspase-3 cascade is sufficient for LTD induction as demonstrated by infusion of active BAD or caspase-3 into hippocampal neurons and that overexpression of BCL-XL, which antagonizes BAD and BAX, inhibits LTD provide additional support for the importance of mitochondria to synaptic plasticity.	25	33	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BCL-XL	overexpression of BCL-XL	bcl-xl	BAD	BAD	bad	27	28	31	32
Work from the Danial group is consistent with an alternative indirect model whereby Bcl-2 and/or Bcl-x L might sequester Bad and limit its promotion of glucokinase activity .	Work from the Danial group is consistent with an alternative indirect model whereby Bcl-2 and/or Bcl-x L might sequester Bad and limit its promotion of glucokinase activity.	15	20	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bad	Bad	Bad	15	17	19	20
Calcitriol represses the expression of the anti-apoptotic , pro survival proteins Bcl-2 and Bcl-X L and may induce the expression of pro apoptotic proteins ( Bax , Bak and Bad ) .	Calcitriol represses the expression of the anti-apoptotic, pro survival proteins Bcl-2 and Bcl-X L and may induce the expression of pro apoptotic proteins (Bax, Bak and Bad).	0	30	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bcl-X L	Calcitriol represses the expression of the anti-apoptotic, pro survival proteins Bcl-2 and Bcl-X L	bcl-x l	Bad	Bad	bad	13	15	29	30
Here , we showed that purified HPU tested on three different gastric cancer epithelial cell lines increased their survival and inhibited apoptosis by modulation of the levels of Bcl-X L , an anti-apoptotic protein , and of BAD , a pro apoptotic protein .	Here, we showed that purified HPU tested on three different gastric cancer epithelial cell lines increased their survival and inhibited apoptosis by modulation of the levels of Bcl-X L, an anti-apoptotic protein, and of BAD, a pro apoptotic protein.	20	42	inhibited	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	Bcl-X L	levels of Bcl-X L	bcl-x l	BAD	BAD	bad	28	30	37	38
XREF_FIG shows that overexpression of bcl-xL almost completely inhibits BAD mediated radiosensitization , indicating that Bad radiosensitizes zebrafish neural tissue by engaging the mitochondrial apoptosis pathway .	XREF_FIG shows that overexpression of bcl-xL almost completely inhibits BAD mediated radiosensitization, indicating that Bad radiosensitizes zebrafish neural tissue by engaging the mitochondrial apoptosis pathway.	3	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	bcl-xL	overexpression of bcl-xL	bcl-xl	BAD	BAD	bad	5	6	9	10
XREF_BIBR , XREF_BIBR Bcl-2 and Bcl-X L sequester pro apoptotic tBid and Bad at the mitochondria , resulting in the prevention of Bax and Bak translocation and activation .	XREF_BIBR, XREF_BIBR Bcl-2 and Bcl-X L sequester pro apoptotic tBid and Bad at the mitochondria, resulting in the prevention of Bax and Bak translocation and activation.	5	13	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bcl-X L	Bcl-X L	Bcl-X L	Bad	Bad	Bad	5	7	12	13
For example , Bcl-xL sequesters BH3-only pro apoptotic molecules , Bim , Noxa , and Bad , and prevents the activation of downstream Bax and Bak .	For example, Bcl-xL sequesters BH3-only pro apoptotic molecules, Bim, Noxa, and Bad, and prevents the activation of downstream Bax and Bak.	3	18	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bad	Bad	Bad	3	4	15	16
On the other hand , the structurally most similar pro survival members , Bcl-2 , Bcl-xL , and Bcl-w , suppressed SNV induced apoptosis in the absence of Bad , whereas Mcl-1 and A1 did not .	On the other hand, the structurally most similar pro survival members, Bcl-2, Bcl-xL, and Bcl-w, suppressed SNV induced apoptosis in the absence of Bad, whereas Mcl-1 and A1 did not.	11	29	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bad	Bad	Bad	15	16	28	29
Bcl-xL prevents Bad from exerting metabolic functions as part of a mitochondrial multiprotein complex involving active glucokinase .	Bcl-xL prevents Bad from exerting metabolic functions as part of a mitochondrial multiprotein complex involving active glucokinase.	0	3	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bad	Bad	Bad	0	1	2	3
Activation of Bak appears to play an important role in NPM induced apoptosis in Jurkat cells , as downregulation of Bak increases the viability of NPM treated cells ( XREF_FIG ) and suppresses the loss of Deltapsim and the release of cytochrome C from mitochondria .	Activation of Bak appears to play an important role in NPM induced apoptosis in Jurkat cells, as downregulation of Bak increases the viability of NPM treated cells (XREF_FIG) and suppresses the loss of Deltapsim and the release of cytochrome C from mitochondria.	0	43	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bak	Bak	Bak	cytochrome C	cytochrome C	cytochrome C	2	3	41	43
These apoptotic mitochondrial events are regulated by members of B cell lymphoma 2 ( Bcl-2 ) family proteins , in which Bax and Bak trigger cytochrome c release and apoptosis , whereas Bcl2 , Bcl-xL and Bcl-w , inhibit apoptosis [ XREF_BIBR ] .	These apoptotic mitochondrial events are regulated by members of B cell lymphoma 2 (Bcl-2) family proteins, in which Bax and Bak trigger cytochrome c release and apoptosis, whereas Bcl2, Bcl-xL and Bcl-w, inhibit apoptosis [XREF_BIBR].	21	27	trigger	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	23	24	25	27
It blocks Bak mediated cytochrome c release and Bak dependent induction of apoptosis .	It blocks Bak mediated cytochrome c release and Bak dependent induction of apoptosis.	1	10	mediated	Positive_early_activation	Positive_activation	Positive_activation	Bak	Bak	Bak	cytochrome c	cytochrome c	cytochrome c	2	3	4	6
BAK is negatively regulated by BMX , a tyrosine kinase , which associates with and phosphorylates BAK , thereby contributing to its inactivation [ XREF_BIBR ] .	BAK is negatively regulated by BMX, a tyrosine kinase, which associates with and phosphorylates BAK, thereby contributing to its inactivation [XREF_BIBR].	0	17	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	BAK	BMX, a tyrosine kinase, which associates with and phosphorylates BAK	bak	BAK	BAK	bak	16	17	0	1
We next examined tyrosine phosphorylation specifically , as phosphorylation of Bak at Y108 was detected by mass spectroscopy , and proposed to block Bak activation .	We next examined tyrosine phosphorylation specifically, as phosphorylation of Bak at Y108 was detected by mass spectroscopy, and proposed to block Bak activation.	8	24	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bak	phosphorylation of Bak at Y108	bak	Bak	Bak	bak	10	11	23	24
VDAC2 has been suggested to inhibit Bak activation and mitochondrial apoptosis XREF_BIBR , but in contrast , VDAC2 mediated Bak recruitment has been proposed as precondition for tBID induced mitochondrial apoptosis XREF_BIBR .	VDAC2 has been suggested to inhibit Bak activation and mitochondrial apoptosis XREF_BIBR, but in contrast, VDAC2 mediated Bak recruitment has been proposed as precondition for tBID induced mitochondrial apoptosis XREF_BIBR.	5	20	inhibit	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Bak	VDAC2 mediated Bak	bak	Bak	Bak	bak	19	20	6	7
Co-expression of BAK and BI-1 reduced the interaction of BAK with IRE1alpha as compared with control ( XREF_SUPPLEMENTARY ) .	Co-expression of BAK and BI-1 reduced the interaction of BAK with IRE1alpha as compared with control (XREF_SUPPLEMENTARY).	0	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAK	Co-expression of BAK	bak	BAK	BAK	bak	2	3	9	10
Over-expression of BAK1 suppresses weak bri1 alleles , and bak1 knock out mutants are hypo sensitive to BR and resemble weak bri1 alleles XREF_BIBR , XREF_BIBR , XREF_BIBR .	Over-expression of BAK1 suppresses weak bri1 alleles, and bak1 knock out mutants are hypo sensitive to BR and resemble weak bri1 alleles XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAK1	Over-expression of BAK1	bak1	bak1	bak1	bak1	2	3	9	10
3.5 Knockdown of Bak expression prevented ZBP-89-mediated induction of Bak and apoptosis .	3.5 Knockdown of Bak expression prevented ZBP-89-mediated induction of Bak and apoptosis.	3	11	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak expression	bak	Bak	Bak	bak	3	4	9	10
We recently reported that phosphorylation of BAK at S117 blocks access of BH3 sequences of Bid and BAK to the hydrophobic pocket on BAK .	We recently reported that phosphorylation of BAK at S117 blocks access of BH3 sequences of Bid and BAK to the hydrophobic pocket on BAK.	4	18	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAK	phosphorylation of BAK at S117	bak	BAK	BAK	bak	6	7	17	18
We also found that inhibition of JNK and AP-1 function diminished basal expression of Bak and particularly Bax protein and caused complete blockade of Bak and Bax induction following CD40 ligation ( XREF_FIG ) , thus demonstrating that induction of Bak and Bax is fully dependent on the JNK/AP -1 pathway .	We also found that inhibition of JNK and AP-1 function diminished basal expression of Bak and particularly Bax protein and caused complete blockade of Bak and Bax induction following CD40 ligation (XREF_FIG), thus demonstrating that induction of Bak and Bax is fully dependent on the JNK/AP -1 pathway.	6	27	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	JNK and AP-1 function diminished basal expression of Bak	bak	Bak	Bak	bak	14	15	24	25
For instance , recent studies showed that in colon cancer , BARD1 splice variant , BARD1beta which has deletions of RING domain , can disrupt BRCA1 E3 ligase activity , and prevent BRCA1 nuclear localization XREF_BIBR .	For instance, recent studies showed that in colon cancer, BARD1 splice variant, BARD1beta which has deletions of RING domain, can disrupt BRCA1 E3 ligase activity, and prevent BRCA1 nuclear localization XREF_BIBR.	11	28	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	11	12	25	26
Thus , CRM1 , BARD1 and Aurora A promote the targeting and function of BRCA1 at centrosomes .	Thus, CRM1, BARD1 and Aurora A promote the targeting and function of BRCA1 at centrosomes.	2	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	4	5	14	15
We show that BARD1 promoted nuclear accumulation of BRCA1 , but repressed BRCA1 mediated transactivation by up to 75 % in transfected cells normalized for nuclear BRCA1 levels .	We show that BARD1 promoted nuclear accumulation of BRCA1, but repressed BRCA1 mediated transactivation by up to 75% in transfected cells normalized for nuclear BRCA1 levels.	3	14	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	3	4	12	13
We propose that BARD1 reduces BRCA1 transcriptional activity , and that this at least partly involves BRCA1 and BARD1 E3 ubiquitin ligase activity , which is disrupted by the C61G mutation .	We propose that BARD1 reduces BRCA1 transcriptional activity, and that this at least partly involves BRCA1 and BARD1 E3 ubiquitin ligase activity, which is disrupted by the C61G mutation.	3	22	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BARD1	BARD1	BARD1	BRCA1	BRCA1	BRCA1	3	4	5	6
7 BCOR ( BCL-6 interacting corepressor ) was first described to interact with BCL-6 POZ domain via its BCOR BCL6 binding domain and potentiate the transcriptional repression of BCL-6 .	7 BCOR (BCL-6 interacting corepressor) was first described to interact with BCL-6 POZ domain via its BCOR BCL6 binding domain and potentiate the transcriptional repression of BCL-6.	0	29	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BCOR	BCOR	BCOR	BCL-6	BCL-6	BCL-6	1	2	28	29
Given that BCOR , NCOR , and SMRT potentiate BCL6 repression , it was possible that one or several of these corepressors promotes Tfh formation .	Given that BCOR, NCOR, and SMRT potentiate BCL6 repression, it was possible that one or several of these corepressors promotes Tfh formation.	2	10	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BCOR	BCOR	BCOR	BCL6	BCL6	BCL6	2	3	9	10
BCoR can function as a corepressor when tethered to DNA and , when overexpressed , can potentiate BCL-6 repression .	BCoR can function as a corepressor when tethered to DNA and, when overexpressed, can potentiate BCL-6 repression.	0	18	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BCoR	BCoR	BCoR	BCL-6	BCL-6	BCL-6	0	1	17	18
Because BCOR is a known corepressor of BCL6 , an important regulator of germinal center formation in B-cell maturation , we hypothesized that Bcor Neo/Y and Bcor Gt/Y cell contribution to germinal center formation might be blocked or reduced in chimeras .	Because BCOR is a known corepressor of BCL6, an important regulator of germinal center formation in B-cell maturation, we hypothesized that Bcor Neo/Y and Bcor Gt/Y cell contribution to germinal center formation might be blocked or reduced in chimeras.	1	11	is a known corepressor	Negative_activation_copula_1	Positive_activation	Negative_activation	BCOR	BCOR	BCOR	BCL6	BCL6	BCL6	1	2	7	8
The lack of BCL-3 in the nucleus inhibits the transcriptional activity of NF-kappaB p50 and p52 , reduces the expression of cyclin-D1 , and delays G 1 / S transition of the cell cycle [ XREF_BIBR ] ( XREF_FIG ) .	The lack of BCL-3 in the nucleus inhibits the transcriptional activity of NF-kappaB p50 and p52, reduces the expression of cyclin-D1, and delays G 1 / S transition of the cell cycle [XREF_BIBR] (XREF_FIG).	1	22	inhibits	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	BCL-3	BCL-3	bcl-3	NF-kappaB p50	NF-kappaB p50 and p52, reduces the expression of cyclin-D1	nf-kappab p50	3	4	12	14
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Thus , Bcl3 specifically inhibits the DNA binding of homodimeric p50 or p52 .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Thus, Bcl3 specifically inhibits the DNA binding of homodimeric p50 or p52.	9	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bcl3	Bcl3	Bcl3	p50	p50	p50	9	10	17	18
Here we demonstrate that Bcl-3 can aid kappa B site dependent transcription in vivo by counteracting the inhibitory effects of p50 and NF-kappa B homodimers .	Here we demonstrate that Bcl-3 can aid kappa B site dependent transcription in vivo by counteracting the inhibitory effects of p50 and NF-kappa B homodimers.	4	24	aid	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bcl-3	Bcl-3	Bcl-3	p50	p50	p50	4	5	20	21
Together , these experiments demonstrate that Bcl-3 can inhibit the binding of p50 to promoters and sequences containing a NF-kappaB site and are important for Treg development and function .	Together, these experiments demonstrate that Bcl-3 can inhibit the binding of p50 to promoters and sequences containing a NF-kappaB site and are important for Treg development and function.	6	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bcl-3	Bcl-3	Bcl-3	p50	p50	p50	6	7	12	13
Thus HIP expression prevents the BAG-1 mediated slowing of the ATPase cycle of HSC70 and ensures optimal chaperoning of misfolded proteins .	Thus HIP expression prevents the BAG-1 mediated slowing of the ATPase cycle of HSC70 and ensures optimal chaperoning of misfolded proteins.	4	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BAG-1	BAG-1	BAG-1	HSC70	HSC70	HSC70	5	6	13	14
UPS inhibition is indeed a condition which occurs in motoneurons and muscle cells expressing mutSOD1 , and the increase in the BAG3 : BAG1 ratio allows BAG3 to more efficiently direct the HSC70 and CHIP associated substrates to autophagy for degradation .	UPS inhibition is indeed a condition which occurs in motoneurons and muscle cells expressing mutSOD1, and the increase in the BAG3 : BAG1 ratio allows BAG3 to more efficiently direct the HSC70 and CHIP associated substrates to autophagy for degradation.	23	35	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAG1	BAG1	BAG1	HSC70	HSC70	HSC70	23	24	32	33
Consistently , genetic depletion of Bcl9 , the mammalian homologue of the Wnt co-regulator in drosophila legless , in Pax7 positive cells abrogates nuclear localization of betacatenin and impairs injury mediated muscle regeneration .	Consistently, genetic depletion of Bcl9, the mammalian homologue of the Wnt co-regulator in drosophila legless, in Pax7 positive cells abrogates nuclear localization of betacatenin and impairs injury mediated muscle regeneration.	3	27	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bcl9	Bcl9	Bcl9	betacatenin	betacatenin	betacatenin	5	6	26	27
Importantly , BCL9 inactivation or pharmacological intervention of beta-catenin activity in vivo caused delayed myogenic differentiation but did not disturb progenitor proliferation during regeneration , evidence that the canonical pathway participates in the differentiation step XREF_BIBR , XREF_BIBR .	Importantly, BCL9 inactivation or pharmacological intervention of beta-catenin activity in vivo caused delayed myogenic differentiation but did not disturb progenitor proliferation during regeneration, evidence that the canonical pathway participates in the differentiation step XREF_BIBR, XREF_BIBR.	2	9	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	BCL9	BCL9	BCL9	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
In the presence of ROS , AXL ubiquitination is reduced , which results in an increased duration of pAXL .	In the presence of ROS, AXL ubiquitination is reduced, which results in an increased duration of pAXL.	6	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AXL	AXL ubiquitination	axl	pAXL	pAXL	paxl	6	7	18	19
We found that Axl expression was dramatically reduced in Axl-/- recipients : Axl-/- --> Axl-/- and Axl +/+ --> Axl-/- ( XREF_SUPPLEMENTARY ) .	We found that Axl expression was dramatically reduced in Axl-/- recipients : Axl-/- --> Axl-/- and Axl +/+ --> Axl-/- (XREF_SUPPLEMENTARY).	3	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Axl	Axl expression	axl	Axl	Axl	axl	3	4	16	17
can block intrinsic apoptosis through numerous mechanisms including the MDM2 mediated ubiquitylation and proteasomal degradation of the tumour suppressor p53 , the sequestration of pro apoptotic protein kinase Cdelta ( PKCdelta ) or BCL-2-associated agonist of cell death ( BAD ) to the inclusion membrane through diacylglcerol or 14-3-3beta-binding Incs , respectively XREF_BIBR , XREF_BIBR , and the upregulation or stabilization of anti-apoptotic proteins including BAG family molecular chaperone regulator 1 ( BAG1 ) , myeloid leukaemia cell differentiation protein 1 ( MCL1 ) or cIAP2 ( also known as BIRC3 ) XREF_BIBR , XREF_BIBR .	can block intrinsic apoptosis through numerous mechanisms including the MDM2 mediated ubiquitylation and proteasomal degradation of the tumour suppressor p53, the sequestration of pro apoptotic protein kinase Cdelta (PKCdelta) or BCL-2-associated agonist of cell death (BAD) to the inclusion membrane through diacylglcerol or 14-3-3beta-binding Incs, respectively XREF_BIBR, XREF_BIBR, and the upregulation or stabilization of anti-apoptotic proteins including BAG family molecular chaperone regulator 1 (BAG1), myeloid leukaemia cell differentiation protein 1 (MCL1) or cIAP2 (also known as BIRC3) XREF_BIBR, XREF_BIBR.	10	40	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BAD	BAD	BAD	p53	p53	p53	39	40	19	20
Simultaneously , cytosolic p53 is detained by the excessive Bad , thus preventing p53 from entering the nucleus for further transcription of DNA damage repair genes .	Simultaneously, cytosolic p53 is detained by the excessive Bad, thus preventing p53 from entering the nucleus for further transcription of DNA damage repair genes.	5	14	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bad	Bad	Bad	p53	p53	p53	9	10	13	14
Because BAG-1 attenuates glucocorticoid receptor ( GR ) nuclear translocation , activates ERK ( extracellular signal regulated kinase ) MAP ( mitogen activated protein ) kinases , and potentiates anti-apoptotic functions of BCL-2 , extensive additional studies were undertaken .	Because BAG-1 attenuates glucocorticoid receptor (GR) nuclear translocation, activates ERK (extracellular signal regulated kinase) MAP (mitogen activated protein) kinases, and potentiates anti-apoptotic functions of BCL-2, extensive additional studies were undertaken.	1	33	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAG-1	BAG-1	BAG-1	BCL-2	BCL-2	BCL-2	1	2	32	33
BAG-1 has previously been shown to augment the inhibitory effect of Bcl-2 on programmed cell death in cultured cell systems .	BAG-1 has previously been shown to augment the inhibitory effect of Bcl-2 on programmed cell death in cultured cell systems.	0	12	augment	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BAG-1	BAG-1	BAG-1	Bcl-2	Bcl-2	Bcl-2	0	1	11	12
However , in Ras transformed cells , detachment fails to induce Bcl-xL down regulation , but leads to Bak down-regulation , which subsequently blocks the release of Omi and HtrA2 resulting in anoikis resistance .	However, in Ras transformed cells, detachment fails to induce Bcl-xL down regulation, but leads to Bak down-regulation, which subsequently blocks the release of Omi and HtrA2 resulting in anoikis resistance.	18	30	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bak	Bak	Bak	HtrA2	HtrA2	HtrA2	18	19	29	30
Reduction in Axin2 via this mechanism was also reported to promote nuclear accumulation of GSK3beta , where it can phosphorylate to destabilize SNAIL1 .	Reduction in Axin2 via this mechanism was also reported to promote nuclear accumulation of GSK3beta, where it can phosphorylate to destabilize SNAIL1.	0	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Axin2	Axin2	Axin2	GSK3beta	GSK3beta	GSK3beta	2	3	14	15
BAG3 interacts with the ATPase domain of Hsc70 and Hsp70 , inhibits Hsc70 and Hsp70 chaperone activity in vitro and thus modulate the cellular responses to stress conditions .	BAG3 interacts with the ATPase domain of Hsc70 and Hsp70, inhibits Hsc70 and Hsp70 chaperone activity in vitro and thus modulate the cellular responses to stress conditions.	0	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAG3	BAG3	BAG3	Hsc70	Hsc70	Hsc70	0	1	12	13
The apoptosis protein cluster comprised the lowest number of proteins , of which both adapted cells markedly downregulated individual key proteins ( decreased BAX in AMO-CFZ , decreased CASP10 and DIABLO in AMO-BTZ ) .	The apoptosis protein cluster comprised the lowest number of proteins, of which both adapted cells markedly downregulated individual key proteins (decreased BAX in AMO-CFZ, decreased CASP10 and DIABLO in AMO-BTZ).	23	31	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAX	BAX	BAX	DIABLO	DIABLO	DIABLO	23	24	30	31
shRNA silencing of Bak , a target for E6 mediated proteolysis , demonstrated the requirement of Bak for UV induced AIF release and mitochondrial fragmentation .	shRNA silencing of Bak, a target for E6 mediated proteolysis, demonstrated the requirement of Bak for UV induced AIF release and mitochondrial fragmentation.	14	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bak	Bak	Bak	AIF	AIF	AIF	16	17	20	21
Bid activation decreased mitochondrial membrane potential and cytochrome-c release .	Bid activation decreased mitochondrial membrane potential and cytochrome-c release.	0	8	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bid	Bid	Bid	cytochrome-c	cytochrome-c	cytochrome-c	0	1	7	8
Treatment with THC induced caspase-2 , -8 , and -9 activation , cleavage of Bid , decreased mitochondrial membrane potential , and cytochrome c release , suggesting involvement of death-receptor and mitochondrial pathways .	Treatment with THC induced caspase-2, -8, and -9 activation, cleavage of Bid, decreased mitochondrial membrane potential, and cytochrome c release, suggesting involvement of death-receptor and mitochondrial pathways.	12	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	14	15	22	24
These data are consistent with those already published , indicating that the immunodepletion of Bid from TNF and cycloheximide treated cytosolic extracts prevented cytochrome c release 19 .	These data are consistent with those already published, indicating that the immunodepletion of Bid from TNF and cycloheximide treated cytosolic extracts prevented cytochrome c release 19.	12	25	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	14	15	23	25
The inhibitory effect of Bcl-2 on Bid induced cytochrome c release was further confirmed using mitochondria isolated from Bcl-2-overexpressing HeLa cells .	The inhibitory effect of Bcl-2 on Bid induced cytochrome c release was further confirmed using mitochondria isolated from Bcl-2-overexpressing HeLa cells.	4	10	induced	Positive_early_activation	Positive_activation	Negative_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
p15 BID within cytosol targeted normal mitochondria and released cytochrome c. Immunodepletion of p15 BID prevents cytochrome c release .	p15 BID within cytosol targeted normal mitochondria and released cytochrome c. Immunodepletion of p15 BID prevents cytochrome c release.	0	18	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p15 BID	p15 BID	p15 BID	cytochrome c	cytochrome c	cytochrome c	0	2	16	18
To test whether the inhibition of Bid induced cytochrome c release by Bcl-x L required its binding to Bax , we used a Bcl-x L mutant in which Gly 138 was replaced by an alanine ( Bcl-x L m : G 138 --> A ) .	To test whether the inhibition of Bid induced cytochrome c release by Bcl-x L required its binding to Bax, we used a Bcl-x L mutant in which Gly 138 was replaced by an alanine (Bcl-x L m : G 138 --> A).	4	10	induced	Positive_early_activation	Positive_activation	Negative_activation	Bid	Bid	Bid	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
Mdivi-1 attenuates mitochondrial division by blocking dynamin GTPase activity , impedes apoptosis by inhibiting mitochondrial outer membrane permeabilization and effectively hinders Bid activated Bax and Bak dependent cytochrome c release from mitochondria [ XREF_BIBR ] .	Mdivi-1 attenuates mitochondrial division by blocking dynamin GTPase activity, impedes apoptosis by inhibiting mitochondrial outer membrane permeabilization and effectively hinders Bid activated Bax and Bak dependent cytochrome c release from mitochondria [XREF_BIBR].	10	26	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Bid	Bid	Bid	Bax	Bax	Bax	21	22	23	24
In order for cell death to proceed , membrane targeted BID must still directly activate BAK and/or BAX to promote MOMP and apoptosis .	In order for cell death to proceed, membrane targeted BID must still directly activate BAK and/or BAX to promote MOMP and apoptosis.	9	19	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BID	BID	BID	BAX	BAX	BAX	10	11	17	18
Cell cycle arrest and apoptosis were induced in a dose dependent manner , and the expressions of p53 and p-14-3-3 were significantly up-regulated , whereas the expressions of c-Myc , p-AKT , p-BID were significantly down-regulated , furthermore , the ratio of BAX and BCL -2 were significantly increased in breast cancer cells after CD and VOSL treatment .	Cell cycle arrest and apoptosis were induced in a dose dependent manner, and the expressions of p53 and p-14-3-3 were significantly up-regulated, whereas the expressions of c-Myc, p-AKT, p-BID were significantly down-regulated, furthermore, the ratio of BAX and BCL -2 were significantly increased in breast cancer cells after CD and VOSL treatment.	26	43	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p-BID	expressions of c-Myc, p-AKT, p-BID	p-bid	BAX	BAX	bax	32	33	42	43
Therefore , even if PARP-1 and calpains are activated after MNNG treatment , BID genetic ablation abolishes both BAX activation and necroptosis .	Therefore, even if PARP-1 and calpains are activated after MNNG treatment, BID genetic ablation abolishes both BAX activation and necroptosis.	13	19	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BID	BID	BID	BAX	BAX	BAX	13	14	18	19
In the upstream , diosgenin increased the expression of Bax , decreased the expression of Bid and Bcl-2 , and augmented the Bax and Bcl -2 ratio .	In the upstream, diosgenin increased the expression of Bax, decreased the expression of Bid and Bcl-2, and augmented the Bax and Bcl -2 ratio.	4	26	augmented	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Bid	diosgenin increased the expression of Bax, decreased the expression of Bid	bid	Bax	Bax	bax	15	16	22	23
We find that cIAP1 represses RIPK1 kinase auto-activation via UBA dependent ubiquitylation of an expanded repertoire of Ub-acceptor lysines of RIPK1 .	We find that cIAP1 represses RIPK1 kinase auto-activation via UBA dependent ubiquitylation of an expanded repertoire of Ub-acceptor lysines of RIPK1.	3	7	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cIAP1	cIAP1	cIAP1	RIPK1	RIPK1	RIPK1	3	4	5	6
Although downregulation of c-IAP1 decreased the association of RIP1 with caspase-8 , c-IAP2 knockdown had no effect ( XREF_SUPPLEMENTARY ) .	Although downregulation of c-IAP1 decreased the association of RIP1 with caspase-8, c-IAP2 knockdown had no effect (XREF_SUPPLEMENTARY).	1	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-IAP1	c-IAP1	c-IAP1	RIP1	RIP1	RIP1	3	4	8	9
Thus , the primary function of TRAF2 RING domain mediated RIP1 ubiquitination might be to inhibit TNFalpha induced cell death by preventing cIAP1 dependent degradation of TRAF2 and RIP1 within the TNFR1 complex , rather than by activating the canonical IKK complex .	Thus, the primary function of TRAF2 RING domain mediated RIP1 ubiquitination might be to inhibit TNFalpha induced cell death by preventing cIAP1 dependent degradation of TRAF2 and RIP1 within the TNFR1 complex, rather than by activating the canonical IKK complex.	22	29	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	cIAP1	cIAP1	cIAP1	RIP1	RIP1	RIP1	22	23	28	29
Loss of cFLIP , cIAP1 , and TRAF2 could trigger apoptosis in NEMO deficient hepatocytes by promoting the association of RIPK1 with FADD and caspase-8 , as shown for ripoptosome formation in response to DNA damage .	Loss of cFLIP, cIAP1, and TRAF2 could trigger apoptosis in NEMO deficient hepatocytes by promoting the association of RIPK1 with FADD and caspase-8, as shown for ripoptosome formation in response to DNA damage.	0	21	trigger	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cIAP1	Loss of cFLIP, cIAP1	ciap1	RIPK1	RIPK1	ripk1	4	5	20	21
cIAP1 also prevents the assembly of secondary RIP1 containing cell death complexes after TRAILR , or CD95 stimulation [ XREF_BIBR ] .	cIAP1 also prevents the assembly of secondary RIP1 containing cell death complexes after TRAILR, or CD95 stimulation [XREF_BIBR].	0	8	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cIAP1	cIAP1	cIAP1	RIP1	RIP1	RIP1	0	1	7	8
Nevertheless , cIAP1 clearly also suppresses the cytotoxic potential of RIPK1 in a UBA independent manner .	Nevertheless, cIAP1 clearly also suppresses the cytotoxic potential of RIPK1 in a UBA independent manner.	2	15	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cIAP1	cIAP1	cIAP1	RIPK1	RIPK1	RIPK1	2	3	10	11
This treatment induced the pro apoptotic gene encoding caspase-8-associated protein , which is essential for FAS mediated apoptosis , and repressed cellular inhibitor of apoptosis protein 2 ( cIAP-2 ) , an apoptosis inhibitor .	This treatment induced the pro apoptotic gene encoding caspase-8-associated protein, which is essential for FAS mediated apoptosis, and repressed cellular inhibitor of apoptosis protein 2 (cIAP-2), an apoptosis inhibitor.	20	29	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cIAP-2	cIAP-2	cIAP-2	inhibitor of apoptosis protein 2	inhibitor of apoptosis protein 2	inhibitor of apoptosis protein 2	28	29	22	27
Induction of cIAP2 not only occurred after SM treatment but also in response to RNAi mediated knockdown of cIAP1 ( XREF_FIG ) .	Induction of cIAP2 not only occurred after SM treatment but also in response to RNAi mediated knockdown of cIAP1 (XREF_FIG).	0	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	cIAP2	cIAP2	cIAP2	cIAP1	cIAP1	cIAP1	2	3	18	19
Simultaneously with caspase-3 activation , there was loss of intact XIAP , cIAP-1 , and cIAP-2 and production of proteolytic products of each IAP protein .	Simultaneously with caspase-3 activation, there was loss of intact XIAP, cIAP-1, and cIAP-2 and production of proteolytic products of each IAP protein.	6	20	was loss	Negative_activation_copula_1	Positive_activation	Negative_activation	cIAP-2	loss of intact XIAP, cIAP-1, and cIAP-2	ciap-2	cIAP-1	cIAP-1	ciap-1	15	16	12	13
In contrast , AA modestly increased the level of phospho-SMAD2 ( 1.34-fold , p = 0.004 ) and phospho-SMAD1/5/8 ( 1.41-fold , p = 0.004 ) ( XREF_FIG ) , whereas BMP2 tended to non significantly reduce total SMAD1 .	In contrast, AA modestly increased the level of phospho-SMAD2 (1.34-fold, p = 0.004) and phospho-SMAD1/5/8 (1.41-fold, p = 0.004) (XREF_FIG), whereas BMP2 tended to non significantly reduce total SMAD1.	31	39	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP2	BMP2	BMP2	SMAD1	SMAD1	SMAD1	31	32	38	39
In summary , alcohol stimulates TGF-beta and BMP2 expression , and Smad2 phosphorylation but inhibits BMP receptor , and Smad1 and Smad5 activation .	In summary, alcohol stimulates TGF-beta and BMP2 expression, and Smad2 phosphorylation but inhibits BMP receptor, and Smad1 and Smad5 activation.	3	22	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP2	alcohol stimulates TGF-beta and BMP2 expression	bmp2	Smad1	Smad1	smad1	7	8	19	20
BMP-2 treatment increased OA mRNA and protein expression in a dose dependent manner and this upregulation was blocked in Smad1 siRNA transfected cultures .	BMP-2 treatment increased OA mRNA and protein expression in a dose dependent manner and this upregulation was blocked in Smad1 siRNA transfected cultures.	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-2	BMP-2	BMP-2	Smad1	Smad1	Smad1	0	1	19	20
In this study , we demonstrated that miRNA-30b attenuates bone morphogenetic protein 2 induced osteoblast differentiation by targeting Runx2 , Smad1 , and caspase-3 .	In this study, we demonstrated that miRNA-30b attenuates bone morphogenetic protein 2 induced osteoblast differentiation by targeting Runx2, Smad1, and caspase-3.	9	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	bone morphogenetic protein 2	bone morphogenetic protein 2	bone morphogenetic protein 2	Smad1	Smad1	Smad1	9	13	20	21
However , the BMP2 induced Smad1 nuclear migration was markedly inhibited by dnBMPR-II + dnActR-IIB double blockage ( XREF_FIG ) .	However, the BMP2 induced Smad1 nuclear migration was markedly inhibited by dnBMPR-II + dnActR-IIB double blockage (XREF_FIG).	2	7	induced	Positive_early_activation	Positive_activation	Negative_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	3	4	5	6
Overexpression of PPM1A dephosphorylates and thereby blocks the nuclear translocation of BMP2 induced Smad1 , a transcription factor that promotes skeletal and osteogenic development .	Overexpression of PPM1A dephosphorylates and thereby blocks the nuclear translocation of BMP2 induced Smad1, a transcription factor that promotes skeletal and osteogenic development.	9	17	induced	Positive_early_activation	Positive_activation	Negative_activation	BMP2	BMP2	BMP2	Smad1	Smad1	Smad1	11	12	13	14
In the developing mouse lung , Nkx2.1 and Bmp4 are co-expressed only in the distal branching epithelium , and decreased activity of either Nkx2.1 or Bmp4 results in similar defects in distal lung morphogenesis .	In the developing mouse lung, Nkx2.1 and Bmp4 are co-expressed only in the distal branching epithelium, and decreased activity of either Nkx2.1 or Bmp4 results in similar defects in distal lung morphogenesis.	6	26	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bmp4	Bmp4 are co-expressed	bmp4	Bmp4	Bmp4	bmp4	8	9	25	26
These findings suggest that Sox6 suppression induces transcription of BMP-4 and increases secretion of BMP-4 .	These findings suggest that Sox6 suppression induces transcription of BMP-4 and increases secretion of BMP-4.	4	15	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BMP-4	Sox6 suppression induces transcription of BMP-4	bmp-4	BMP-4	BMP-4	bmp-4	9	10	14	15
In order to establish the dorsal-ventral axis in BA1 , dorsally expressed Fgf in the ectoderm is restricted by Bone Morphogenetic Protein 4 ( BMP4 ) , expressed in the ventral ( distal ) portion of the BA1 ectoderm .	In order to establish the dorsal-ventral axis in BA1, dorsally expressed Fgf in the ectoderm is restricted by Bone Morphogenetic Protein 4 (BMP4), expressed in the ventral (distal) portion of the BA1 ectoderm.	17	28	restricted	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Bone Morphogenetic Protein 4	Bone Morphogenetic Protein 4 (BMP4), expressed	bone morphogenetic protein 4	Bone Morphogenetic Protein 4	Bone Morphogenetic Protein 4	bone morphogenetic protein 4	19	23	19	23
Previous studies show that overexpression of Bmp4 in the lung epithelium disrupts branching morphogenesis and inactivation of Bmp4 during lung budding leads to hypoplastic lungs .	Previous studies show that overexpression of Bmp4 in the lung epithelium disrupts branching morphogenesis and inactivation of Bmp4 during lung budding leads to hypoplastic lungs.	4	21	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bmp4	overexpression of Bmp4	bmp4	Bmp4	Bmp4	bmp4	6	7	17	18
In addition , the recruitment of BAX and BAK proteins to the mitochondria was reduced in NASH mice treated with Bid siRNA when compared to Neg siRNA ( BAX : P < 0.01 ) or control mice ( BAX : P < 0.05 , BAK : P < 0.001 ) ( XREF_FIG - XREF_FIG ) .	In addition, the recruitment of BAX and BAK proteins to the mitochondria was reduced in NASH mice treated with Bid siRNA when compared to Neg siRNA (BAX : P < 0.01) or control mice (BAX : P < 0.05, BAK : P < 0.001) (XREF_FIG - XREF_FIG).	6	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Bid	Bid	Bid	BAK	BAK	BAK	20	21	8	9
In response to the UV treatment , significantly ( P < 0.05 ) upregulated FDX1 , BAD and BID , downregulated FDXR , BAK1 , TNFSF10 , FAS , CASP6 , CASP3 and APAF1 , and insignificantly changed BCAP31 , BNIP1 , VDAC1 , BBC3 and CYCS were identified in UACC903 ( +6 ) cells .	In response to the UV treatment, significantly (P < 0.05) upregulated FDX1, BAD and BID, downregulated FDXR, BAK1, TNFSF10, FAS, CASP6, CASP3 and APAF1, and insignificantly changed BCAP31, BNIP1, VDAC1, BBC3 and CYCS were identified in UACC903 (+6) cells.	14	24	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BID	BID	BID	BAK1	BAK1	BAK1	18	19	23	24
Results with the Noxa peptide are consistent with reduced Bak activation by a Bid peptide in which truncation had removed the h0 region .	Results with the Noxa peptide are consistent with reduced Bak activation by a Bid peptide in which truncation had removed the h0 region.	9	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	Bid	Bid	Bid	Bak	Bak	Bak	13	14	9	10
Of major importance is the observation that the LPM cells in the vicinity of the liver primordium express bmp2a , and alterations in the relative position of the bmp2a expressing LPM and the liver primordium in the mypt1sq181 mutant prevent the close apposition of the Bmp2a producing cells and the liver primordium by 30 hpf .	Of major importance is the observation that the LPM cells in the vicinity of the liver primordium express bmp2a, and alterations in the relative position of the bmp2a expressing LPM and the liver primordium in the mypt1sq181 mutant prevent the close apposition of the Bmp2a producing cells and the liver primordium by 30 hpf.	25	46	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	bmp2a	bmp2a expressing	bmp2a	Bmp2a	Bmp2a	bmp2a	28	29	45	46
The expression of BMP-2 , BMP-4 and noggin ( the inducible antagonist of BMP-2 ) are known to affect proliferation and cell survival as a result of FGF9 activation in human tissue .	The expression of BMP-2, BMP-4 and noggin (the inducible antagonist of BMP-2) are known to affect proliferation and cell survival as a result of FGF9 activation in human tissue.	1	14	antagonist	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	BMP-2	expression of BMP-2	bmp-2	BMP-2	BMP-2	bmp-2	3	4	13	14
Inhibition of BMP2 signaling by overexpression of dominant negative BMP2 receptor did not attenuate aldosterone induced osteoblastic differentiation .	Inhibition of BMP2 signaling by overexpression of dominant negative BMP2 receptor did not attenuate aldosterone induced osteoblastic differentiation.	2	10	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	BMP2	overexpression of dominant negative BMP2	bmp2	BMP2	BMP2	bmp2	9	10	2	3
In the present study , we revealed that TGF-beta1-induced ROCK elevation suppressed the BMP-2 expression , constantly enhanced ROCK activity under pressure overload possibly blocked BMP-2 signal and strengthened TGF-beta biased fibrotic signalling .	In the present study, we revealed that TGF-beta1-induced ROCK elevation suppressed the BMP-2 expression, constantly enhanced ROCK activity under pressure overload possibly blocked BMP-2 signal and strengthened TGF-beta biased fibrotic signalling.	13	26	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP-2	BMP-2 expression	bmp-2	BMP-2	BMP-2	bmp-2	13	14	25	26
These results may be compared to the end point measurements of each of these mRNAs in cultures treated with both exogenous BMP7 , sh-BMP2 inhibition of BMP2 expression , and rescue of BMP2 inhibition with BMP7 treatment ( XREF_FIG , right panels ) .	These results may be compared to the end point measurements of each of these mRNAs in cultures treated with both exogenous BMP7, sh-BMP2 inhibition of BMP2 expression, and rescue of BMP2 inhibition with BMP7 treatment (XREF_FIG, right panels).	21	33	rescue	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	BMP2	BMP7, sh-BMP2 inhibition of BMP2 expression	bmp2	BMP2	BMP2	bmp2	26	27	32	33
Rather , studies support that a select pool of Survivin , released from mitochondria upon a death stimulus , inhibits apoptosis by binding to and stabilizing cytosolic XIAP XREF_BIBR and/or associating to and neutralizing the pro apoptotic protein Smac/DIABLO XREF_BIBR .	Rather, studies support that a select pool of Survivin, released from mitochondria upon a death stimulus, inhibits apoptosis by binding to and stabilizing cytosolic XIAP XREF_BIBR and/or associating to and neutralizing the pro apoptotic protein Smac/DIABLO XREF_BIBR.	7	28	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Survivin	Survivin	Survivin	XIAP	XIAP	XIAP	9	10	27	28
In S462 cells curcumin downregulated XIAP , survivin and BCL-2 , in ST88-14 cells survivin , MCL-1 and HIF1alpha and in NFS-1 cells survivin and HIF1alpha ( XREF_FIG ) .	In S462 cells curcumin downregulated XIAP, survivin and BCL-2, in ST88-14 cells survivin, MCL-1 and HIF1alpha and in NFS-1 cells survivin and HIF1alpha (XREF_FIG).	4	27	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	survivin	survivin	survivin	XIAP	XIAP	XIAP	23	24	5	6
These results indicate that the increased level of miR-17 family markedly contributes to the BMP2 mediated BMPRII repression .	These results indicate that the increased level of miR-17 family markedly contributes to the BMP2 mediated BMPRII repression.	11	17	mediated	Positive_early_activation	Positive_activation	Negative_activation	BMP2	BMP2	BMP2	BMPRII	BMPRII	BMPRII	14	15	16	17
Our data has demonstrated the relation between BMP , miR-17 family and BMPRII , in which up-regulated miR-17 family made great contribution to BMP2 mediated BMPRII repression , suggesting an important role of miR-17 family in the negative feedback loop of BMP signaling in primary neuron .	Our data has demonstrated the relation between BMP, miR-17 family and BMPRII, in which up-regulated miR-17 family made great contribution to BMP2 mediated BMPRII repression, suggesting an important role of miR-17 family in the negative feedback loop of BMP signaling in primary neuron.	21	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	BMP2	BMP2	BMP2	BMPRII	BMPRII	BMPRII	23	24	25	26
To further elucidate the role of miR-17 family in BMP2 mediated BMPRII repression , we conducted luciferase assay and found that BMP2 activation significantly reduced the expression of reporter gene tagged with 3 '-UTR of BMPRII while pretreatment with miR-17 family sponge blocked such effect ( XREF_FIG ) .	To further elucidate the role of miR-17 family in BMP2 mediated BMPRII repression, we conducted luciferase assay and found that BMP2 activation significantly reduced the expression of reporter gene tagged with 3 '-UTR of BMPRII while pretreatment with miR-17 family sponge blocked such effect (XREF_FIG).	7	12	mediated	Positive_early_activation	Positive_activation	Negative_activation	BMP2	BMP2	BMP2	BMPRII	BMPRII	BMPRII	9	10	11	12
agomiR-155 also reduced SMAD5 mRNA levels in MC3T3-E1 cells treated with BMP2 for 30 minutes ( P < 0.01 ; XREF_FIG ) .	agomiR-155 also reduced SMAD5 mRNA levels in MC3T3-E1 cells treated with BMP2 for 30 minutes (P < 0.01; XREF_FIG).	3	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	BMP2	BMP2	BMP2	SMAD5	SMAD5	SMAD5	11	12	3	4
We propose a model in which Bmp2 mediated Smad5 signalling suppresses the proliferative response to Shh by downregulation of the pathway , and allows granule cell precursor to enter their differentiation programme .	We propose a model in which Bmp2 mediated Smad5 signalling suppresses the proliferative response to Shh by downregulation of the pathway, and allows granule cell precursor to enter their differentiation programme.	6	9	mediated	Positive_early_activation	Positive_activation	Negative_activation	Bmp2	Bmp2	Bmp2	Smad5	Smad5	Smad5	6	7	8	9
In contrast , the BMP4 antagonist Gremlin , specifically up-regulated in MP cells , counteracts the stimulatory effects of BMP4 and inhibits proliferation of BMPR1a positive muscle cells .	In contrast, the BMP4 antagonist Gremlin, specifically up-regulated in MP cells, counteracts the stimulatory effects of BMP4 and inhibits proliferation of BMPR1a positive muscle cells.	4	27	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP4	BMP4	BMP4	BMPR1a	BMPR1a	BMPR1a	4	5	24	25
Finally , BMP4 induced nuclear translocation of NFATc1 was impaired in Bmpr1a depleted LuMECs ( XREF_FIG ) .	Finally, BMP4 induced nuclear translocation of NFATc1 was impaired in Bmpr1a depleted LuMECs (XREF_FIG).	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP4	BMP4	BMP4	Bmpr1a	Bmpr1a	Bmpr1a	2	3	11	12
Unlike BMP9 , BMP4 was unable to inhibit mitomycin C mediated BMPR2 and RAD51 depletion and gammaH2AX induction .	Unlike BMP9, BMP4 was unable to inhibit mitomycin C mediated BMPR2 and RAD51 depletion and gammaH2AX induction.	3	17	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP4	BMP4	BMP4	BMPR2	BMPR2	BMPR2	3	4	11	12
By contrast , BMP9 can activate through other type II receptors , but BMP4 can effectively inhibit such Bmpr2 independent BMP9 signaling .	By contrast, BMP9 can activate through other type II receptors, but BMP4 can effectively inhibit such Bmpr2 independent BMP9 signaling.	13	21	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP4	BMP4	BMP4	Bmpr2	Bmpr2	Bmpr2	13	14	18	19
Removing Bmpr1a from the lens cells did not eliminate pSmad1 staining .	Removing Bmpr1a from the lens cells did not eliminate pSmad1 staining.	0	10	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bmpr1a	Bmpr1a	Bmpr1a	pSmad1	pSmad1	pSmad1	1	2	9	10
Whereas TGFbeta induced loss of epithelial character and smooth muscle differentiation , BMP2 induced an ALK3 dependent loss of epithelial character and modestly inhibited TGFbeta stimulated differentiation .	Whereas TGFbeta induced loss of epithelial character and smooth muscle differentiation, BMP2 induced an ALK3 dependent loss of epithelial character and modestly inhibited TGFbeta stimulated differentiation.	12	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP2	BMP2	BMP2	ALK3	ALK3	ALK3	12	13	15	16
Treatment of V600E BRAF expressing cells with PLX4720 inhibited BRAF mediated MEK activation in cell lines harboring V600E BRAF as shown by a rapid and sustained decrease in the expression of phosphorylated MEK1/2 ( XREF_FIG ) .	Treatment of V600E BRAF expressing cells with PLX4720 inhibited BRAF mediated MEK activation in cell lines harboring V600E BRAF as shown by a rapid and sustained decrease in the expression of phosphorylated MEK1/2 (XREF_FIG).	8	12	mediated	Positive_early_activation	Positive_activation	Negative_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	9	10	11	12
It has become clear that ATP mimetic inhibitors of RAF drive dimerization of WT BRAF and CRAF , lead to phosphorylation of CRAF on serine 338 , potentiate the MEK and ERK pathway and thereby contribute to the observed increase in tumour growth XREF_BIBR XREF_BIBR XREF_BIBR .	It has become clear that ATP mimetic inhibitors of RAF drive dimerization of WT BRAF and CRAF, lead to phosphorylation of CRAF on serine 338, potentiate the MEK and ERK pathway and thereby contribute to the observed increase in tumour growth XREF_BIBR XREF_BIBR XREF_BIBR.	11	32	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	14	15	29	30
In cells expressing active mutant Ras , BRAF kinase inhibitors have been shown to paradoxically activate MEK and ERK , and have so far failed to show efficacy in tumors with mutant Ras .	In cells expressing active mutant Ras, BRAF kinase inhibitors have been shown to paradoxically activate MEK and ERK, and have so far failed to show efficacy in tumors with mutant Ras.	7	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	7	8	16	17
These data are consistent with previous reports that the majority of acquired resistance mechanisms to RAF or RAF and MEK inhibition in BRAF-mutant melanoma -- including NRAS alterations , BRAF amplification , MEK1 or MEK2 mutations , and BRAF splice isoforms -- also lead to reactivation of MAPK signaling , as opposed to activation of alternative parallel signaling pathways .	These data are consistent with previous reports that the majority of acquired resistance mechanisms to RAF or RAF and MEK inhibition in BRAF-mutant melanoma -- including NRAS alterations, BRAF amplification, MEK1 or MEK2 mutations, and BRAF splice isoforms -- also lead to reactivation of MAPK signaling, as opposed to activation of alternative parallel signaling pathways.	17	30	inhibition	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	29	30	19	20
It has been suggested that B-Raf inhibition in Ras-mutant cells causes c-Raf-dependent MEK and ERK activation XREF_BIBR XREF_BIBR .	It has been suggested that B-Raf inhibition in Ras-mutant cells causes c-Raf-dependent MEK and ERK activation XREF_BIBR XREF_BIBR.	5	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	B-Raf	B-Raf	B-Raf	MEK	MEK	MEK	5	6	12	13
Finally , E2F4 was found to be overexpressed , phosphorylated and nuclear localized in epithelial cells from human colorectal adenomas exhibiting mutations in APC and KRAS or BRAF genes , known to deregulate GSK3 and beta-catenin and MEK and ERK signaling , respectively .	Finally, E2F4 was found to be overexpressed, phosphorylated and nuclear localized in epithelial cells from human colorectal adenomas exhibiting mutations in APC and KRAS or BRAF genes, known to deregulate GSK3 and beta-catenin and MEK and ERK signaling, respectively.	27	40	deregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	27	28	37	38
Co-expression of kinase impaired BRAF and CRAF induces MEK and ERK pathway activation in HEK293T cells .	Co-expression of kinase impaired BRAF and CRAF induces MEK and ERK pathway activation in HEK293T cells.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BRAF	Co-expression of kinase impaired BRAF	braf	MEK	MEK	mek	4	5	8	9
BRAF inhibition promoted patient CLL proliferation in culture and in murine xenografts and activated MEK and ERK in primary CLL cells from additional patients .	BRAF inhibition promoted patient CLL proliferation in culture and in murine xenografts and activated MEK and ERK in primary CLL cells from additional patients.	0	23	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BRAF	BRAF	BRAF	MEK	MEK	MEK	0	1	14	15
We found that HB-EGF- and BTC induced EGFR internalization could not be fully inhibited by clathrin knockdown ( XREF_FIG ) .	We found that HB-EGF- and BTC induced EGFR internalization could not be fully inhibited by clathrin knockdown (XREF_FIG).	3	8	induced	Positive_early_activation	Positive_activation	Negative_activation	BTC	BTC	BTC	EGFR	EGFR	EGFR	5	6	7	8
BTC promotes the proliferation of RPCs by targeting the membrane receptors EGFR , ErbB2 and ErbB4 .	BTC promotes the proliferation of RPCs by targeting the membrane receptors EGFR, ErbB2 and ErbB4.	0	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BTC	BTC	BTC	EGFR	EGFR	EGFR	0	1	11	12
In contrast , pro proliferative betacellulin expression decreased an EGF receptor ligand as well as IGF1 while TGFbeta2 decreased mildly .	In contrast, pro proliferative betacellulin expression decreased an EGF receptor ligand as well as IGF1 while TGFbeta2 decreased mildly.	5	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	betacellulin	betacellulin expression	betacellulin	EGF receptor	EGF receptor	egf receptor	5	6	9	11
BTC stimulates EGFR degradation and in accordance with this , BTC leads to EGFR Tyr1045 phosphorylation , persistent c-Cbl recruitment , and EGFR ubiquitination .	BTC stimulates EGFR degradation and in accordance with this, BTC leads to EGFR Tyr1045 phosphorylation, persistent c-Cbl recruitment, and EGFR ubiquitination.	0	3	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	BTC	BTC	BTC	EGFR	EGFR	EGFR	0	1	2	3
In this case , EGF and BTC induced ErbB1 activation was reduced by ~ 30-40 % , whereas NDF induced ErbB3 and -4 activation was decreased by ~ 50 % ( XREF_FIG B ) .	In this case, EGF and BTC induced ErbB1 activation was reduced by ~ 30-40%, whereas NDF induced ErbB3 and -4 activation was decreased by ~ 50% (XREF_FIG B).	4	9	induced	Positive_early_activation	Positive_activation	Negative_activation	BTC	BTC	BTC	ErbB1	ErbB1	ErbB1	6	7	8	9
Consistent with a role for AKT in EGFR lysosomal trafficking , AKT inhibition reduced the rate of betacellulin induced EGFR degradation ( XREF_FIG ) .	Consistent with a role for AKT in EGFR lysosomal trafficking, AKT inhibition reduced the rate of betacellulin induced EGFR degradation (XREF_FIG).	15	20	induced	Positive_early_activation	Positive_activation	Negative_activation	betacellulin	betacellulin	betacellulin	EGFR	EGFR	EGFR	17	18	19	20
Immunodepletion of Bub1 abolishes the spindle checkpoint and the kinetochore binding of the checkpoint proteins Mad1 , Mad2 , Bub3 , and CENP-E .	Immunodepletion of Bub1 abolishes the spindle checkpoint and the kinetochore binding of the checkpoint proteins Mad1, Mad2, Bub3, and CENP-E.	0	22	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bub1	Bub1	Bub1	Mad1	Mad1	Mad1	2	3	15	16
In agreement with our previous result , we observed significant levels of kinetochore Mad1 in Bub1 depleted cells , but no detectable Mad1 after RZZ depletion and nocodazole treatment ( XREF_FIG f-h ) .	In agreement with our previous result, we observed significant levels of kinetochore Mad1 in Bub1 depleted cells, but no detectable Mad1 after RZZ depletion and nocodazole treatment (XREF_FIG f-h).	8	23	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bub1	Bub1	Bub1	Mad1	Mad1	Mad1	15	16	22	23
Here , we show that mutations in Bub1 and within the Mad1 C-terminal domain impair the kinetochore localization of Mad1 : Mad2 and abrogate checkpoint activity .	Here, we show that mutations in Bub1 and within the Mad1 C-terminal domain impair the kinetochore localization of Mad1 : Mad2 and abrogate checkpoint activity.	5	20	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bub1	Bub1	Bub1	Mad1	Mad1	Mad1	7	8	19	20
Depletion of BUB-1 eliminates the accumulation of MAD1 MDF-1 at the unattached kinetochore without interfering with the kinetochore localization of SPDL-1 , XREF_BIBR suggesting that MAD1 MDF-1 requires BUB-1 to interact with SPDL-1 .	Depletion of BUB-1 eliminates the accumulation of MAD1 MDF-1 at the unattached kinetochore without interfering with the kinetochore localization of SPDL-1, XREF_BIBR suggesting that MAD1 MDF-1 requires BUB-1 to interact with SPDL-1.	0	8	eliminates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BUB-1	BUB-1	BUB-1	MAD1	MAD1	MAD1	2	3	7	8
However , immunodepletion of Bub1 from Xenopus egg extracts prevents Mad1 and Mad2 localization at the kinetochore during establishment of the spindle assembly checkpoint , whereas we show here that only Mad1 is required for maintenance of CSF arrest , which does not require kinetochores .	However, immunodepletion of Bub1 from Xenopus egg extracts prevents Mad1 and Mad2 localization at the kinetochore during establishment of the spindle assembly checkpoint, whereas we show here that only Mad1 is required for maintenance of CSF arrest, which does not require kinetochores.	2	13	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bub1	Bub1	Bub1	Mad1	Mad1	Mad1	4	5	10	11
Cells from CLL patients undergoing treatment exhibited decreased expression of BCR target genes and decreased phosphorylation of Btk , a tyrosine kinase activated downstream of Syk [ XREF_BIBR ] .	Cells from CLL patients undergoing treatment exhibited decreased expression of BCR target genes and decreased phosphorylation of Btk, a tyrosine kinase activated downstream of Syk [XREF_BIBR].	15	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Btk	phosphorylation of Btk, a tyrosine	btk	Btk	Btk	btk	17	18	17	18
We propose that BMPR2 inhibits ALK2 mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B , necessary for ALK2 activation by activins and several BMPs .	We propose that BMPR2 inhibits ALK2 mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs.	3	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BMPR2	BMPR2	BMPR2	ALK2	ALK2	ALK2	3	4	5	6
Finally , we determined that the increased responsiveness of Bmpr2 Deltatd/+ PaSMCs to BMP7 relies on the presence of Alk2 , thus revealing that the tail domain of Bmpr2 inhibits Alk2 mediated signaling .	Finally, we determined that the increased responsiveness of Bmpr2 Deltatd/+ PaSMCs to BMP7 relies on the presence of Alk2, thus revealing that the tail domain of Bmpr2 inhibits Alk2 mediated signaling.	26	32	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bmpr2	Bmpr2	Bmpr2	Alk2	Alk2	Alk2	28	29	30	31
Taken together with our observations in Bmpr2 del and del PaSMC , these findings suggest that the tail domain of Bmpr2 suppresses Alk2 dependent BMP7 signaling by either Bmpr2-DeltaTD or Acvr2a and raise the possibility that the the tail domain of Bmpr2 directly inhibits Alk2 function .	Taken together with our observations in Bmpr2 del and del PaSMC, these findings suggest that the tail domain of Bmpr2 suppresses Alk2 dependent BMP7 signaling by either Bmpr2-DeltaTD or Acvr2a and raise the possibility that the the tail domain of Bmpr2 directly inhibits Alk2 function.	39	45	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bmpr2	Bmpr2	Bmpr2	Alk2	Alk2	Alk2	41	42	44	45
In the S-phase and the mitosis , beta-TrCP decreases the activity of Cdk1 by inducing Cdc25A and EMI1 degradation [ XREF_BIBR ] .	In the S-phase and the mitosis, beta-TrCP decreases the activity of Cdk1 by inducing Cdc25A and EMI1 degradation [XREF_BIBR].	7	20	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	Cdc25A	Cdc25A	Cdc25A	7	8	15	16
In response to DNA damage , beta-TrCP contributes to CDK1 dysfunction by mediating the degradation of CDC25A in collaboration with Chk1 ( checkpoint kinase 1 ) , thereby preventing cell cycle progression before the completion of DNA repair XREF_BIBR .	In response to DNA damage, beta-TrCP contributes to CDK1 dysfunction by mediating the degradation of CDC25A in collaboration with Chk1 (checkpoint kinase 1), thereby preventing cell cycle progression before the completion of DNA repair XREF_BIBR.	6	18	contributes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	CDC25A	CDC25A	CDC25A	6	7	16	17
Furthermore , inhibition or depletion of Bora by either anti-Bora antibody or Bora siRNA microinjection significantly reduced the rates of GVBD and inhibited first polar body extrusion ; caused morphologically defective spindles and misaligned chromosomes ; arrested maturing oocytes at prometaphase and metaphase-I stage , or left oocytes and their first polar bodies with severely misaligned chromosomes and defective spindles ; and/or caused the disappearance of Aurora A and Plk1 at the spindle .	Furthermore, inhibition or depletion of Bora by either anti-Bora antibody or Bora siRNA microinjection significantly reduced the rates of GVBD and inhibited first polar body extrusion; caused morphologically defective spindles and misaligned chromosomes; arrested maturing oocytes at prometaphase and metaphase-I stage, or left oocytes and their first polar bodies with severely misaligned chromosomes and defective spindles; and/or caused the disappearance of Aurora A and Plk1 at the spindle.	2	70	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	6	7	69	70
At the cellular level , expression of Bora at high levels also reduces microtubule growth during mitosis , possibly as a result of a perturbation of Aurora A and/or Plk1 ( XREF_FIG ) .	At the cellular level, expression of Bora at high levels also reduces microtubule growth during mitosis, possibly as a result of a perturbation of Aurora A and/or Plk1 (XREF_FIG).	5	31	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Bora	expression of Bora	bora	Plk1	Plk1	plk1	7	8	29	30
XREF_BIBR , XREF_BIBR We propose that disruption of the interaction of Aurora A with the Plk1 and Bora complex is used by the DDR to promote the initial inhibition of Plk1 , whereas disassembly of the Plk1 and Bora at later stages of the DDR helps to promote sustained inhibition of Plk1 activation .	XREF_BIBR, XREF_BIBR We propose that disruption of the interaction of Aurora A with the Plk1 and Bora complex is used by the DDR to promote the initial inhibition of Plk1, whereas disassembly of the Plk1 and Bora at later stages of the DDR helps to promote sustained inhibition of Plk1 activation.	33	52	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bora	Bora	Bora	Plk1	Plk1	Plk1	38	39	51	52
Both Bub1 mPheK and T609A failed to support Plk1 dependent inhibition of APC/C Cdc20 ( XREF_FIG ) .	Both Bub1 mPheK and T609A failed to support Plk1 dependent inhibition of APC/C Cdc20 (XREF_FIG).	1	10	support	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bub1	Bub1	Bub1	Plk1	Plk1	Plk1	1	2	8	9
Depletion of Bub1 in HeLa cells by RNA interference ( RNAi ) diminishes the kinetochore localization of Plk1 .	Depletion of Bub1 in HeLa cells by RNA interference (RNAi) diminishes the kinetochore localization of Plk1.	0	18	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Bub1	Bub1	Bub1	Plk1	Plk1	Plk1	2	3	17	18
Even though in vitro experiments supported this approach [ XREF_BIBR ] , the present studies using nucleofection of ITK-BTK ( SH3 ) into primary lymphoid cells showed a different outcome ; namely , the BTK SH3 domain substituted into the ITK protein does not maintain canonical ligand binding and thus results in diminished ITK signaling .	Even though in vitro experiments supported this approach [XREF_BIBR], the present studies using nucleofection of ITK-BTK (SH3) into primary lymphoid cells showed a different outcome; namely, the BTK SH3 domain substituted into the ITK protein does not maintain canonical ligand binding and thus results in diminished ITK signaling.	34	55	signaling	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	BTK	BTK	BTK	ITK	ITK	ITK	34	35	53	54
Ibrutinib , an irreversible inhibitor of ITK , and its homologue BTK , was used to pharmacologically inhibit ITK in primary TCL cells .	Ibrutinib, an irreversible inhibitor of ITK, and its homologue BTK, was used to pharmacologically inhibit ITK in primary TCL cells.	0	22	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BTK	BTK	BTK	ITK	ITK	ITK	11	12	18	19
Interestingly , melanoma cells carrying MEK1 T55delinsRT actually proliferated faster when treated with low levels of BRAF or ERK inhibitor , when compared to control treatment ( Fig XREF_FIG , Supplementary Figs S3 and S4 ) .	Interestingly, melanoma cells carrying MEK1 T55delinsRT actually proliferated faster when treated with low levels of BRAF or ERK inhibitor, when compared to control treatment (Fig XREF_FIG, Supplementary Figs S3 and S4).	5	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	BRAF	BRAF	BRAF	MEK1	MEK1	MEK1	16	17	5	6
For instance , BNIP-2 induces cell protrusions by targeting Cdc42 XREF_BIBR - XREF_BIBR and promotes muscle differentiation XREF_BIBR .	For instance, BNIP-2 induces cell protrusions by targeting Cdc42 XREF_BIBR - XREF_BIBR and promotes muscle differentiation XREF_BIBR.	3	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BNIP-2	BNIP-2	BNIP-2	Cdc42	Cdc42	Cdc42	3	4	9	10
For instance , the BCH domain of BNIP-2 induces cell protrusions by targeting Cdc42 and promotes muscle differentiation by coupling the myogenic Cdo receptor signaling to p38alpha and beta MAPK activation .	For instance, the BCH domain of BNIP-2 induces cell protrusions by targeting Cdc42 and promotes muscle differentiation by coupling the myogenic Cdo receptor signaling to p38alpha and beta MAPK activation.	5	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	BNIP-2	BNIP-2	BNIP-2	Cdc42	Cdc42	Cdc42	7	8	13	14
Since phosphorylation at S327 is critical for CtIP and BRCA1 association , we then tested whether overexpression of BRCA1 could reduce CtIP interacting with ZNF830 , and we detected a less level of CtIP bound to ZNF830 in presence of BRCA1 ( XREF_SUPPLEMENTARY ) .	Since phosphorylation at S327 is critical for CtIP and BRCA1 association, we then tested whether overexpression of BRCA1 could reduce CtIP interacting with ZNF830, and we detected a less level of CtIP bound to ZNF830 in presence of BRCA1 (XREF_SUPPLEMENTARY).	16	22	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BRCA1	overexpression of BRCA1	brca1	CtIP	CtIP	ctip	18	19	21	22
Accordingly , and consistent with increased histone acetylation at the BRCA1 promoter following estrogen induction , there is a dynamic loss of HDAC1 , p130 , BRCA1 , CtIP , CtBP , E2F-1 and E2F-4 from the BRCA1 proximal promoter following estrogen treatment ( XREF_FIG ) .	Accordingly, and consistent with increased histone acetylation at the BRCA1 promoter following estrogen induction, there is a dynamic loss of HDAC1, p130, BRCA1, CtIP, CtBP, E2F-1 and E2F-4 from the BRCA1 proximal promoter following estrogen treatment (XREF_FIG).	17	29	is a dynamic loss	Negative_activation_copula_1	Positive_activation	Negative_activation	BRCA1	loss of HDAC1, p130, BRCA1	brca1	CtIP	CtIP	ctip	26	27	28	29
Betacellulin , member of the EGF family , has recently been reported to induce proliferation of neural stem cells and prevent spontaneous differentiation in cell culture via both the EGF receptor ( EGFR ) located in NSCs and ErbB4 on neuroblasts XREF_BIBR .	Betacellulin, member of the EGF family, has recently been reported to induce proliferation of neural stem cells and prevent spontaneous differentiation in cell culture via both the EGF receptor (EGFR) located in NSCs and ErbB4 on neuroblasts XREF_BIBR.	0	39	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Betacellulin	Betacellulin	Betacellulin	ErbB4	ErbB4	ErbB4	0	1	38	39
Decreased TLR dependent cytokine production by Btk and Btk and Tec deficient resident peritoneal macrophages .	Decreased TLR dependent cytokine production by Btk and Btk and Tec deficient resident peritoneal macrophages.	0	14	production	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	Btk	Btk	Btk	Tec	Tec	Tec	6	7	10	11
One straightforward explanation for this observation is that Bub1 depletion , but not Bub1 inhibition , caused the displacement of CENP-E from KTs , a motor protein required for efficient chromosome congression .	One straightforward explanation for this observation is that Bub1 depletion, but not Bub1 inhibition, caused the displacement of CENP-E from KTs, a motor protein required for efficient chromosome congression.	8	21	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Bub1	Bub1	Bub1	CENP-E	CENP-E	CENP-E	8	9	20	21
Since the K193A mutation in CaMKKbeta disrupts binding to AMPK , but not CaMKIV we conclude that an active , closed ATP binding pocket and properly orientated alphaC helix could be required for CaMKKbeta association with AMPK , but not CaMKIV .	Since the K193A mutation in CaMKKbeta disrupts binding to AMPK, but not CaMKIV we conclude that an active, closed ATP binding pocket and properly orientated alphaC helix could be required for CaMKKbeta association with AMPK, but not CaMKIV.	3	14	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CaMKKbeta	CaMKKbeta	CaMKKbeta	CaMKIV	CaMKIV	CaMKIV	5	6	13	14
We found diminished STAT3 phosphorylation on both Tyr705 and Ser727 sites in AMPKalpha1-/- macrophages as well as AMPKalpha1 +/+ macrophages treated with an inhibitor of CaMKKbeta , an upstream activator of AMPK ( XREF_FIG and XREF_FIG ) .	We found diminished STAT3 phosphorylation on both Tyr705 and Ser727 sites in AMPKalpha1-/- macrophages as well as AMPKalpha1 +/+ macrophages treated with an inhibitor of CaMKKbeta, an upstream activator of AMPK (XREF_FIG and XREF_FIG).	17	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	CaMKKbeta	CaMKKbeta	CaMKKbeta	AMPKalpha1	AMPKalpha1	AMPKalpha1	25	26	17	18
It is known that Akt1 phosphorylates caspase-9 at Ser 196 , thereby blocking cytochrome c mediated caspas-9 activation and inactivation of caspase-3 leading to inhibition of proapoptotic signals XREF_BIBR .	It is known that Akt1 phosphorylates caspase-9 at Ser 196, thereby blocking cytochrome c mediated caspas-9 activation and inactivation of caspase-3 leading to inhibition of proapoptotic signals XREF_BIBR.	4	22	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-9	Akt1 phosphorylates caspase-9 at Ser 196	caspase-9	caspase-3	caspase-3	caspase-3	6	7	21	22
TCTP overexpression ( a ) reduced mitochondrial membrane damage thereby preventing cytochrome c release into the cytosol ; ( b ) inhibited apoptosome functions including caspase-9 activation , which in turn inhibited caspase-3 ; ( c ) perturbed the cleavage of the proteolytic targets including EGFR and PLC-gamma ; and ( d ) eventually inhibited cell death in etoposide treated HeLa cells .	TCTP overexpression (a) reduced mitochondrial membrane damage thereby preventing cytochrome c release into the cytosol; (b) inhibited apoptosome functions including caspase-9 activation, which in turn inhibited caspase-3; (c) perturbed the cleavage of the proteolytic targets including EGFR and PLC-gamma; and (d) eventually inhibited cell death in etoposide treated HeLa cells.	25	33	inhibited	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	25	26	32	33
But in hypoxic cultured neurons , we observed that application of DAF down-regulated the expression of caspase-9 and reduced caspase-3 activity .	But in hypoxic cultured neurons, we observed that application of DAF down-regulated the expression of caspase-9 and reduced caspase-3 activity.	11	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-9	DAF down-regulated the expression of caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	16	17	19	20
Caspase 9 inhibition blocked the TNP induced activation of caspase 3 significantly .	Caspase 9 inhibition blocked the TNP induced activation of caspase 3 significantly.	0	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Caspase 9	Caspase 9	Caspase 9	caspase 3	caspase 3	caspase 3	0	2	9	11
Interestingly , caspase-9 DN was not able to inhibit caspase-3 activity efficiently ( XREF_FIG ) .	Interestingly, caspase-9 DN was not able to inhibit caspase-3 activity efficiently (XREF_FIG).	2	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	9	10
High glucose also induces loss of the initiator caspase-9 and increases caspase-3 cleavage , effects blocked by IGF-I .	High glucose also induces loss of the initiator caspase-9 and increases caspase-3 cleavage, effects blocked by IGF-I.	1	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	glucose also induces loss of the initiator caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	11	12
In hypoxic human brain ECs treated with tPA , blockade of caspase-8 , but not MMP-9 , effectively inhibited caspase-3 activation , in contrast , in the absence of tPA , blockade of caspase-9 , but not MMP-8 , effectively inhibited caspase-3 activation .	In hypoxic human brain ECs treated with tPA, blockade of caspase-8, but not MMP-9, effectively inhibited caspase-3 activation, in contrast, in the absence of tPA, blockade of caspase-9, but not MMP-8, effectively inhibited caspase-3 activation.	31	42	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	33	34	41	42
Irreversible inhibition of caspase 9 blocked downstream caspase 3 activation and prevented apoptosis .	Irreversible inhibition of caspase 9 blocked downstream caspase 3 activation and prevented apoptosis.	1	9	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	3	5	7	9
Therefore , removal of the inhibition of caspase-9 by XIAP promotes activation of caspase-9 and the subsequent activation and apoptosis of caspase-3 .	Therefore, removal of the inhibition of caspase-9 by XIAP promotes activation of caspase-9 and the subsequent activation and apoptosis of caspase-3.	5	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	7	8	21	22
Furthermore , specific downregulation of either caspase-9 , Bax , or Bak by siRNA effectively reduced PARP cleavage and caspase-3 activation .	Furthermore, specific downregulation of either caspase-9, Bax, or Bak by siRNA effectively reduced PARP cleavage and caspase-3 activation.	3	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	6	7	19	20
Attenuation of incrementPsim can induce caspase9 activation , which subsequently induces the caspase3 cleavage .	Attenuation of incrementPsim can induce caspase9 activation, which subsequently induces the caspase3 cleavage.	5	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase9	caspase9	caspase9	caspase3	caspase3	caspase3	5	6	12	13
Caspase-9 activation is initiated by mitochondrial dysfunction signals , thus lead to PARP excitation , and finally induce caspase-3 degradation 47 .	Caspase-9 activation is initiated by mitochondrial dysfunction signals, thus lead to PARP excitation, and finally induce caspase-3 degradation 47.	0	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Caspase-9	Caspase-9	Caspase-9	caspase-3	caspase-3	caspase-3	0	1	18	19
These data indicate that LPA protects IEC-6 cells from camptothecin induced apoptosis through G ( i )-coupled inhibition of caspase-3 activation mediated by the attenuation of caspase-9 activation due to diminished cytochrome c release , involving upregulation of Bcl-2 protein expression and prevention of Bax translocation .	These data indicate that LPA protects IEC-6 cells from camptothecin induced apoptosis through G (i)-coupled inhibition of caspase-3 activation mediated by the attenuation of caspase-9 activation due to diminished cytochrome c release, involving upregulation of Bcl-2 protein expression and prevention of Bax translocation.	19	27	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	26	27	19	20
This pathway is activated by internalization of exogenous oxidatively truncated phospholipids because irreversible inhibition of caspase 9 blocks downstream caspase 3 activation and prevents apoptosis induced by truncated phospholipids .	This pathway is activated by internalization of exogenous oxidatively truncated phospholipids because irreversible inhibition of caspase 9 blocks downstream caspase 3 activation and prevents apoptosis induced by truncated phospholipids.	13	21	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	15	17	19	21
Akt also phosphorylates the initiator caspase-9 and in turn prevent activation of the effector caspase-3 , blocking apoptosis .	Akt also phosphorylates the initiator caspase-9 and in turn prevent activation of the effector caspase-3, blocking apoptosis.	0	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-9	Akt also phosphorylates the initiator caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	5	6	14	15
In vitro incubation experiments showed that MGO modified Hsp27 reduced the activity of caspase-9 , and MGO modified pHsp27 reduced activities of both caspase-9 and caspase-3 .	In vitro incubation experiments showed that MGO modified Hsp27 reduced the activity of caspase-9, and MGO modified pHsp27 reduced activities of both caspase-9 and caspase-3.	11	26	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	13	14	25	26
Phosphorylation of caspase-9 by phospho-Akt ( p-AKT ) impedes this process and thereby prevents downstream activation of caspase-3 [ XREF_BIBR ] .	Phosphorylation of caspase-9 by phospho-Akt (p-AKT) impedes this process and thereby prevents downstream activation of caspase-3 [XREF_BIBR].	0	19	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-9	Phosphorylation of caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	2	3	17	18
XREF_BIBR Akt ( acting via phosphorylation ) has been shown to inhibit the initiator caspase-9 , which in turn blocks the effector caspase-3 , suppressing apoptosis .	XREF_BIBR Akt (acting via phosphorylation) has been shown to inhibit the initiator caspase-9, which in turn blocks the effector caspase-3, suppressing apoptosis.	11	23	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-9	caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	14	15	22	23
p53 blocks the functions of the anti-apoptotic Bcl-2 family members and activates some pro apoptotic factors , while caspase 9 , which initiates the executioner apoptotic caspase 3 and caspase 7 , can be further activated by Bak or Bax [ XREF_BIBR ] .	p53 blocks the functions of the anti-apoptotic Bcl-2 family members and activates some pro apoptotic factors, while caspase 9, which initiates the executioner apoptotic caspase 3 and caspase 7, can be further activated by Bak or Bax [XREF_BIBR].	18	34	initiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	18	20	26	28
An example of how the MEK and ERK pathway might influence caspase-3 activity is demonstrated by ERK phosphorylation of caspase-9 at Thr 125 , which inhibits caspase-3 cleavage and activation [ XREF_BIBR ] .	An example of how the MEK and ERK pathway might influence caspase-3 activity is demonstrated by ERK phosphorylation of caspase-9 at Thr 125, which inhibits caspase-3 cleavage and activation [XREF_BIBR].	16	27	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-9	ERK phosphorylation of caspase-9 at Thr 125	caspase-9	caspase-3	caspase-3	caspase-3	19	20	26	27
Caspase 9 Processes Caspase 3 in Saccharomyces cerevisiae and MIHA Can Inhibit both Caspase 9 and Caspase 3 Processing .	Caspase 9 Processes Caspase 3 in Saccharomyces cerevisiae and MIHA Can Inhibit both Caspase 9 and Caspase 3 Processing.	0	18	Inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Caspase 9	Caspase 9	Caspase 9	Caspase 3	Caspase 3	Caspase 3	0	2	16	18
When 23A2 myoblasts are cultured in DM , caspase 9 activity is increased and pharmacological abrogation of caspase 9 activation impairs caspase 3 activation and apoptosis .	When 23A2 myoblasts are cultured in DM, caspase 9 activity is increased and pharmacological abrogation of caspase 9 activation impairs caspase 3 activation and apoptosis.	17	23	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase 9	caspase 9	caspase 9	caspase 3	caspase 3	caspase 3	17	19	21	23
As an apoptosis initiator , Caspase-9 inactivation may block the activation of the apoptosis executor Caspase-3 , which finally inhibits apoptosis , accelerates protein synthesis , increases the production of intracellular factors mediating protein synthesis and promotes cell division positively 19 .	As an apoptosis initiator, Caspase-9 inactivation may block the activation of the apoptosis executor Caspase-3, which finally inhibits apoptosis, accelerates protein synthesis, increases the production of intracellular factors mediating protein synthesis and promotes cell division positively 19.	5	36	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Caspase-9	Caspase-9	Caspase-9	Caspase-3	Caspase-3	Caspase-3	5	6	15	16
High glucose also induces loss of the initiator caspase-9 and increases caspase-3 cleavage , effects blocked by IGF-I , suggesting that IGF-I prevents apoptosis in DRG neurons by regulating PI3K and Akt pathway effectors , including GSK-3beta , CREB , and FKHR , and by blocking caspase activation .	High glucose also induces loss of the initiator caspase-9 and increases caspase-3 cleavage, effects blocked by IGF-I, suggesting that IGF-I prevents apoptosis in DRG neurons by regulating PI3K and Akt pathway effectors, including GSK-3beta, CREB, and FKHR, and by blocking caspase activation.	1	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-9	glucose also induces loss of the initiator caspase-9	caspase-9	caspase-3	caspase-3	caspase-3	8	9	11	12
These cells were then used to determine the effect of caspase-8 knockdown on UVB induced activation of caspase-3 .	These cells were then used to determine the effect of caspase-8 knockdown on UVB induced activation of caspase-3.	10	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	10	11	17	18
Inhibitors of caspase-8 , but not of caspase-9 , prevented endotoxin induced reductions in diaphragm force and caspase-3 activation ( P < 0.01 ) .	Inhibitors of caspase-8, but not of caspase-9, prevented endotoxin induced reductions in diaphragm force and caspase-3 activation (P < 0.01).	0	18	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	17	18
Interestingly , caspase 8 depletion reduced cleavage of caspase 3 and 9 ( XREF_SUPPLEMENTARY ) , suggesting crosstalk between these caspases .	Interestingly, caspase 8 depletion reduced cleavage of caspase 3 and 9 (XREF_SUPPLEMENTARY), suggesting crosstalk between these caspases.	2	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	2	4	8	10
APC inhibited tPA induced caspase-8 activation of caspase-3 in endothelium and caspase-3-dependent nuclear translocation of apoptosis inducing factor in NMDA treated neurons and reduced tPA mediated cerebral ischemic injury in mice .	APC inhibited tPA induced caspase-8 activation of caspase-3 in endothelium and caspase-3-dependent nuclear translocation of apoptosis inducing factor in NMDA treated neurons and reduced tPA mediated cerebral ischemic injury in mice.	0	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	caspase-8	APC inhibited tPA induced caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	4	5	7	8
We observed that the down-regulation of caspase 8 activity strongly repressed not only the execution phase caspase 3 dependent but also caspase 9 activity which suggests that in rNDV-B1 and Fas infected cells the strongest pro apoptotic stimuli comes from the extrinsic signaling pathway .	We observed that the down-regulation of caspase 8 activity strongly repressed not only the execution phase caspase 3 dependent but also caspase 9 activity which suggests that in rNDV-B1 and Fas infected cells the strongest pro apoptotic stimuli comes from the extrinsic signaling pathway.	6	23	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	6	8	16	18
In Poly ( I : C )-treated mice , cerebral I/R increased caspase-3 activity was reduced by 23.6 % and caspase-8 by 15.3 % , respectively , when compared with untreated I/R mice .	In Poly (I : C)-treated mice, cerebral I/R increased caspase-3 activity was reduced by 23.6% and caspase-8 by 15.3%, respectively, when compared with untreated I/R mice.	12	21	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	20	21	12	13
Knockdown of caspase-8 impaired induction of apoptosis , Bid cleavage and caspase-3 cleavage in the absence or presence of XIAP knockdown ( XREF_FIG ) .	Knockdown of caspase-8 impaired induction of apoptosis, Bid cleavage and caspase-3 cleavage in the absence or presence of XIAP knockdown (XREF_FIG).	2	12	induction	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	11	12
Knockdown of CASP8 prevents ER stress induced CASP3 activation and reduces the death of casp9 -/- cells .	Knockdown of CASP8 prevents ER stress induced CASP3 activation and reduces the death of casp9 -/- cells.	0	8	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CASP8	CASP8	CASP8	CASP3	CASP3	CASP3	2	3	7	8
As predicted by online tools , miR-24 may inhibit caspase 8 and miR-221 may inhibit Caspase 3 through targeting .	As predicted by online tools, miR-24 may inhibit caspase 8 and miR-221 may inhibit Caspase 3 through targeting.	9	17	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase 8	caspase 8	caspase 8	Caspase 3	Caspase 3	Caspase 3	9	11	15	17
Knockdown of caspase-8 in 089 and 090 cells ( knockdown efficiency 80-100 % ) markedly reduced processing of caspase-3 in response to the combination treatment ( XREF_FIG ) .	Knockdown of caspase-8 in 089 and 090 cells (knockdown efficiency 80-100%) markedly reduced processing of caspase-3 in response to the combination treatment (XREF_FIG).	0	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	2	3	18	19
Importantly , Caspase8 depletion significantly attenuated Caspase3 activity downstream of TNFalpha , especially when IKKbeta was inhibited ( XREF_FIG , P < 0.05 ) .	Importantly, Caspase8 depletion significantly attenuated Caspase3 activity downstream of TNFalpha, especially when IKKbeta was inhibited (XREF_FIG, P < 0.05).	2	7	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Caspase8	Caspase8	Caspase8	Caspase3	Caspase3	Caspase3	2	3	6	7
Moreover , activation of caspase-3 & -8 and cleavage of the effector caspase substrate , PARP , were almost completely suppressed by caspase-2 deficiency in orlistat treated 420 cells ( XREF_FIG , lane 2 vs. 4 ) , whereas downregulation of caspase-8 partially prevented caspase-3 activation , but failed to inhibit loss of full-length caspase-2 ( XREF_FIG , lane 2 vs. 6 ) .	Moreover, activation of caspase-3 & -8 and cleavage of the effector caspase substrate, PARP, were almost completely suppressed by caspase-2 deficiency in orlistat treated 420 cells (XREF_FIG, lane 2 vs. 4), whereas downregulation of caspase-8 partially prevented caspase-3 activation, but failed to inhibit loss of full-length caspase-2 (XREF_FIG, lane 2 vs. 6).	39	45	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	41	42	44	45
Furthermore , caspase 8 knockdown strongly inhibits activation of executioner caspase 3 , and cleavage of the caspase 3 substrate , PARP ( XREF_FIG ) .	Furthermore, caspase 8 knockdown strongly inhibits activation of executioner caspase 3, and cleavage of the caspase 3 substrate, PARP (XREF_FIG).	2	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	2	4	10	12
Silencing the NOS2-NO axis enhanced intracellular bacterial survival and attenuated caspase-8 mediated activation of caspase-3 in the infected HKM .	Silencing the NOS2-NO axis enhanced intracellular bacterial survival and attenuated caspase-8 mediated activation of caspase-3 in the infected HKM.	10	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	10	11	14	15
As observed for HCT116 cells , caspase 8 knockdown impairs BID cleavage , caspase 3 activation , PARP cleavage , and apoptosis in this cell line ( XREF_SUPPLEMENTARY ) .	As observed for HCT116 cells, caspase 8 knockdown impairs BID cleavage, caspase 3 activation, PARP cleavage, and apoptosis in this cell line (XREF_SUPPLEMENTARY).	6	15	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase 8	caspase 8	caspase 8	caspase 3	caspase 3	caspase 3	6	8	13	15
NAPS activated caspase-8 in a FADD independent manner , but the lack of caspase-8 did not suppress the activation of caspase-3 and -9 and cell death , indicating that caspase-8 activation does not play an important role in NAPS induced cell death .	NAPS activated caspase-8 in a FADD independent manner, but the lack of caspase-8 did not suppress the activation of caspase-3 and -9 and cell death, indicating that caspase-8 activation does not play an important role in NAPS induced cell death.	11	21	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	13	14	20	21
Impaired apoptosis of BMDN from iNOS KO mice was due to reduced caspase-8 activity which subsequently prevented caspase-3 and -9 activation .	Impaired apoptosis of BMDN from iNOS KO mice was due to reduced caspase-8 activity which subsequently prevented caspase-3 and -9 activation.	12	20	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-8	caspase-8	caspase-8	caspase-3	caspase-3	caspase-3	12	13	17	18
If the HPC induced neuronal and/or cerebral endothelial production of CCL2 acts as part of an autocrine and paracrine signaling mechanism , then preventing the CCL2 induced activation of CCR2 receptors should also inhibit HPC induced tolerance in a manner similar to the effects of CCL2 gene deletion .	If the HPC induced neuronal and/or cerebral endothelial production of CCL2 acts as part of an autocrine and paracrine signaling mechanism, then preventing the CCL2 induced activation of CCR2 receptors should also inhibit HPC induced tolerance in a manner similar to the effects of CCL2 gene deletion.	23	30	induced	Positive_early_activation	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	25	26	29	30
Subcutaneous PRP injection decreased CCL2 expression and increased CCR2 expression intensity in spinal cord dorsal horns in burn induced neuropathic pain model .	Subcutaneous PRP injection decreased CCL2 expression and increased CCR2 expression intensity in spinal cord dorsal horns in burn induced neuropathic pain model.	1	10	increased	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	CCL2	PRP injection decreased CCL2 expression	ccl2	CCR2	CCR2	ccr2	4	5	8	9
XREF_BIBR XREF_BIBR - XREF_BIBR For instance , exogenous spinal administration of CCL2 induces mechanical allodynia in wildtype but not CCR2 knockout mice , 37 and in a model of neuropathic pain the development of mechanical allodynia is totally abrogated in CCR2 knockout mice .	XREF_BIBR XREF_BIBR - XREF_BIBR For instance, exogenous spinal administration of CCL2 induces mechanical allodynia in wildtype but not CCR2 knockout mice, 37 and in a model of neuropathic pain the development of mechanical allodynia is totally abrogated in CCR2 knockout mice.	9	21	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	11	12	19	20
The finding that CCL2 blockade could inhibit T-reg recruitment is consistent with previous studies showing that : 1 ) CD4 + T-regs selectively over-express the CCL2 and CCL12 receptors CCR2 , and CCR4 , 2 ) CCL2 has been shown to specifically chemoattract T-regs in vitro , and 3 ) blocking CCR2 in vivo reduced the influx of T-regs to disease sites in a model of arthritis .	The finding that CCL2 blockade could inhibit T-reg recruitment is consistent with previous studies showing that : 1) CD4 + T-regs selectively over-express the CCL2 and CCL12 receptors CCR2, and CCR4, 2) CCL2 has been shown to specifically chemoattract T-regs in vitro, and 3) blocking CCR2 in vivo reduced the influx of T-regs to disease sites in a model of arthritis.	23	54	blocking	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	25	26	51	52
CCL2 loss of function as well as CCR2 gain of function or overexpression studies have collectively illustrated the fundamental role of CCR2 and CCL2 in recruitment and differentiation of macrophages with an M1 phenotype .	CCL2 loss of function as well as CCR2 gain of function or overexpression studies have collectively illustrated the fundamental role of CCR2 and CCL2 in recruitment and differentiation of macrophages with an M1 phenotype.	0	8	loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	0	1	7	8
Accordingly , depletion of CCL2 in these cells abolishes leaving of Ly6C high CCR2 + monocytes from the bone marrow 29 .	Accordingly, depletion of CCL2 in these cells abolishes leaving of Ly6C high CCR2 + monocytes from the bone marrow 29.	2	15	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	13	14
CCR2-knockout mice were shown to have significant defects in monocyte recruitment , suggesting that CCL2 mediated CCR2 activation is critically involved in the accumulation of monocytes at lesions [ XREF_BIBR ] .	CCR2-knockout mice were shown to have significant defects in monocyte recruitment, suggesting that CCL2 mediated CCR2 activation is critically involved in the accumulation of monocytes at lesions [XREF_BIBR].	14	17	mediated	Positive_early_activation	Positive_activation	Positive_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	14	15	16	17
Therefore , inhibition of CCL2 promoted CCR2 signaling is a promising approach towards a future therapy of neuropathic pain .	Therefore, inhibition of CCL2 promoted CCR2 signaling is a promising approach towards a future therapy of neuropathic pain.	2	7	promoted	Positive_activation_token_1_verb	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	6	7
In separate studies of PBMC migration in vitro under flow , we found that abluminal CCL2 induced lymphocyte and monocyte migration but selectively down-regulated monocyte CCR2 .	In separate studies of PBMC migration in vitro under flow, we found that abluminal CCL2 induced lymphocyte and monocyte migration but selectively down-regulated monocyte CCR2.	14	26	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	15	16	25	26
Similar results were obtained when CCR2 signalling was repressed by mutated CCL2 secreted from implanted mesenchymal stem cells [ XREF_BIBR ] .	Similar results were obtained when CCR2 signalling was repressed by mutated CCL2 secreted from implanted mesenchymal stem cells [XREF_BIBR].	5	12	repressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	11	12	5	6
We demonstrated that CCL2 reduced CCR2 from the monocyte cell surface .	We demonstrated that CCL2 reduced CCR2 from the monocyte cell surface.	3	6	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	3	4	5	6
MLN1202 is a humanized monoclonal antibody that blocks the activation of CCR2 by CCL2 .	MLN1202 is a humanized monoclonal antibody that blocks the activation of CCR2 by CCL2.	7	14	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	13	14	11	12
In vitro effects of CCL2 , which preferentially binds to CCR2 receptor [ XREF_BIBR , XREF_BIBR ] , were blocked by AZ889 suggesting a specific CCR2 excitatory mechanism .	In vitro effects of CCL2, which preferentially binds to CCR2 receptor [XREF_BIBR, XREF_BIBR], were blocked by AZ889 suggesting a specific CCR2 excitatory mechanism.	2	27	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL2	CCL2	CCL2	CCR2	CCR2	CCR2	4	5	25	26
Overexpression of caspase-8 significantly decreased cell number , caused caspase-8 and caspase-3 activation , decreased full-length Bid , caspase-9 , and caspase-7 , and significantly increased DNA fragmentation and M30 positive RPE cells .	Overexpression of caspase-8 significantly decreased cell number, caused caspase-8 and caspase-3 activation, decreased full-length Bid, caspase-9, and caspase-7, and significantly increased DNA fragmentation and M30 positive RPE cells.	0	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-8	Overexpression of caspase-8	caspase-8	caspase-9	caspase-9	caspase-9	2	3	18	19
In addition , after NADA treatment , caspase 8 and caspase 3 were decreased , cleaved-caspase 3 , cleaved caspase 9 and cleaved PARP ( C-PARP ) were increased .	In addition, after NADA treatment, caspase 8 and caspase 3 were decreased, cleaved-caspase 3, cleaved caspase 9 and cleaved PARP (C-PARP) were increased.	7	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase 8	caspase 8	caspase 8	caspase 9	caspase 9	caspase 9	7	9	19	21
Inhibition of caspase 9 prevented caspase 8 cleavage , while inhibition of caspase 8 did not diminish caspase 9 cleavage ( XREF_FIG ) .	Inhibition of caspase 9 prevented caspase 8 cleavage, while inhibition of caspase 8 did not diminish caspase 9 cleavage (XREF_FIG).	10	19	diminish	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 8	caspase 8	caspase 8	caspase 9	caspase 9	caspase 9	12	14	17	19
Addition of TFF1 ( 10 muM ) almost completely inhibited butyrate induced caspase-3 and -6 activities , and partially reduced caspase-9 activity , but had no effect on caspase-2 .	Addition of TFF1 (10 muM) almost completely inhibited butyrate induced caspase-3 and -6 activities, and partially reduced caspase-9 activity, but had no effect on caspase-2.	2	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-3	TFF1 (10 muM) almost completely inhibited butyrate induced caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	12	13	20	21
The physiological relevance of this positive feedback loop was confirmed in several studies , which showed that inhibition of Casp3 mediated cleavage of Casp9 prevented full activation of both Casp3 and Casp9 in response to cyto c [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The physiological relevance of this positive feedback loop was confirmed in several studies, which showed that inhibition of Casp3 mediated cleavage of Casp9 prevented full activation of both Casp3 and Casp9 in response to cyto c [XREF_BIBR, XREF_BIBR, XREF_BIBR].	17	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Casp3	Casp3	Casp3	Casp9	Casp9	Casp9	19	20	31	32
Glutathionylation of pro-caspase-3 inhibited proteolytic caspase-3 activation 16 and caspase-9 , whereas deglutathionylation of pro-caspase-3 by glutaredoxin induced apoptosis in endothelial cells .	Glutathionylation of pro-caspase-3 inhibited proteolytic caspase-3 activation 16 and caspase-9, whereas deglutathionylation of pro-caspase-3 by glutaredoxin induced apoptosis in endothelial cells.	0	10	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	pro-caspase-3	pro-caspase-3	pro-caspase-3	caspase-9	caspase-9	caspase-9	2	3	9	10
Knockdown of caspase-3 suppressed caspase-9-induced processing of the other caspases downstream of caspase-9 .	Knockdown of caspase-3 suppressed caspase-9-induced processing of the other caspases downstream of caspase-9.	0	13	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	caspase-9	caspase-9	caspase-9	2	3	12	13
Together , these data suggest that caspase-3 is the primary inactivator of DFF45 and ICAD and therefore the primary activator of apoptotic DNA fragmentation .	Together, these data suggest that caspase-3 is the primary inactivator of DFF45 and ICAD and therefore the primary activator of apoptotic DNA fragmentation.	6	14	is the primary inactivator	Negative_activation_copula_1	Positive_activation	Negative_activation	caspase-3	caspase-3	caspase-3	DFF45	DFF45	DFF45	6	7	12	13
19 However , in the presence of kosmotropic salt , ICAD degradation by caspase-3 was significantly suppressed compared with that by caspase-14 ( XREF_FIG ) .	19 However, in the presence of kosmotropic salt, ICAD degradation by caspase-3 was significantly suppressed compared with that by caspase-14 (XREF_FIG).	10	14	degradation	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	13	14	10	11
Increases in pro apoptotic protein ( calpain , and Bax ) , decrease in Bcl-2 expression , caspase-3 activationand ICAD degradation of treated samples confirmed apoptotic activation in DATS treated samples ( XREF_FIG ) .	Increases in pro apoptotic protein (calpain, and Bax), decrease in Bcl-2 expression, caspase-3 activationand ICAD degradation of treated samples confirmed apoptotic activation in DATS treated samples (XREF_FIG).	17	20	activationand	Positive_activation_token_1_verb	Positive_activation	Negative_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	17	18	19	20
When apoptosis occurs , CAD is released by the inhibitor of CAD , which is activated by caspase-3 .	When apoptosis occurs, CAD is released by the inhibitor of CAD, which is activated by caspase-3.	6	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	caspase-3	caspase-3	caspase-3	inhibitor of CAD	inhibitor of CAD	inhibitor of CAD	17	18	9	12
DEVD cleaving caspase-3 is the primary inactivator of ICAD and therefore the primary activator of apoptotic DNA fragmentation [ XREF_BIBR ] .	DEVD cleaving caspase-3 is the primary inactivator of ICAD and therefore the primary activator of apoptotic DNA fragmentation [XREF_BIBR].	0	9	is the primary inactivator	Negative_activation_copula_1	Positive_activation	Negative_activation	caspase-3	caspase-3	caspase-3	ICAD	ICAD	ICAD	2	3	8	9
Moreover , downregulation of Caspase 8 is expected to decrease the activation of pro apoptotic factors BID and BAX 38 .	Moreover, downregulation of Caspase 8 is expected to decrease the activation of pro apoptotic factors BID and BAX 38.	2	18	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Caspase 8	Caspase 8	Caspase 8	BID	BID	BID	4	6	16	17
Intact Bid protein is localized to the cytoplasm and inhibited by Bcl-2 , but upon cleavage by activated caspase-8 , truncated Bid ( tBid ) translocates to the mitochondria .	Intact Bid protein is localized to the cytoplasm and inhibited by Bcl-2, but upon cleavage by activated caspase-8, truncated Bid (tBid) translocates to the mitochondria.	1	20	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	caspase-8	caspase-8	caspase-8	Bid	Bid	Bid	18	19	1	2
To determine if deletion of Caspase-3 increases the activation of Caspase-6 and Caspase-7 after DEN treatment in mouse livers , we examined the expression of total and cleaved Caspase-6 and Caspase-7 in DEN treated mouse livers .	To determine if deletion of Caspase-3 increases the activation of Caspase-6 and Caspase-7 after DEN treatment in mouse livers, we examined the expression of total and cleaved Caspase-6 and Caspase-7 in DEN treated mouse livers.	3	12	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Caspase-3	Caspase-3	Caspase-3	Caspase-6	Caspase-6	Caspase-6	5	6	10	11
The most compelling experiments were those in which removal of individual caspases from the extracts blocked activation of other caspases , and it was particularly striking that depletion of caspase 3 abolished the ability of cytochrome c to trigger the processing of caspase 6 , placing caspase 3 upstream of caspase 6 .	The most compelling experiments were those in which removal of individual caspases from the extracts blocked activation of other caspases, and it was particularly striking that depletion of caspase 3 abolished the ability of cytochrome c to trigger the processing of caspase 6, placing caspase 3 upstream of caspase 6.	27	52	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	caspase 3	caspase 3	caspase 3	caspase 6	caspase 6	caspase 6	29	31	50	52
Indeed , overexpression of CARMA1 enhances PMA- and Bcl10 dependent NF-kappaB activation that is blocked by expression of CARMA1 lacking the Bcl10 interacting domain , demonstrating that CARMA1 acts upstream of Bcl10 .	Indeed, overexpression of CARMA1 enhances PMA- and Bcl10 dependent NF-kappaB activation that is blocked by expression of CARMA1 lacking the Bcl10 interacting domain, demonstrating that CARMA1 acts upstream of Bcl10.	6	19	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	CARMA1	expression of CARMA1	carma1	Bcl10	Bcl10	bcl10	18	19	8	9
Although CARMA1-BCL10 interaction was readily identified after BCL10 co-IP ( XREF_FIG ) , chronic activation of oncogenic CARMA1 induced BCL10 degradation , XREF_BIBR , XREF_BIBR which hampered a reliable BCL10 detection in mass spectrometry .	Although CARMA1-BCL10 interaction was readily identified after BCL10 co-IP (XREF_FIG), chronic activation of oncogenic CARMA1 induced BCL10 degradation, XREF_BIBR, XREF_BIBR which hampered a reliable BCL10 detection in mass spectrometry.	14	20	induced	Positive_early_activation	Positive_activation	Negative_activation	CARMA1	CARMA1	CARMA1	BCL10	BCL10	BCL10	17	18	19	20
Our data support a model that CARM1 promotes the silencing of EZH2 and BAF155 target genes by displacing BAF155 via methylation , which then permits the occupancy of the target gene promoters by EZH2 and their consequent repression by H3K27Me3 .	Our data support a model that CARM1 promotes the silencing of EZH2 and BAF155 target genes by displacing BAF155 via methylation, which then permits the occupancy of the target gene promoters by EZH2 and their consequent repression by H3K27Me3.	6	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CARM1	CARM1	CARM1	BAF155	BAF155	BAF155	6	7	13	14
CARM1 KO but not EZH2 inhibitor GSK126 treatment decreased the association of BAF155 , SNF5 , BRG1 , and Pol II with the TIMP3 promoter .	CARM1 KO but not EZH2 inhibitor GSK126 treatment decreased the association of BAF155, SNF5, BRG1, and Pol II with the TIMP3 promoter.	0	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CARM1	CARM1	CARM1	BAF155	BAF155	BAF155	0	1	12	13
Caspase-6 or -8 inhibition also decreased caspase-3 , -6 , and caspase-8 cleavage when assayed by western blot and reduced caspase-3 and -6 activities in colorimetric assays .	Caspase-6 or -8 inhibition also decreased caspase-3, -6, and caspase-8 cleavage when assayed by western blot and reduced caspase-3 and -6 activities in colorimetric assays.	0	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Caspase-6	Caspase-6	Caspase-6	caspase-8	caspase-8	caspase-8	0	1	11	12
Furthermore , it has been shown that CCK-8 reduces food intake in rats by activating the low affinity CCKAR .	Furthermore, it has been shown that CCK-8 reduces food intake in rats by activating the low affinity CCKAR.	7	19	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCK-8	CCK-8	CCK-8	CCKAR	CCKAR	CCKAR	7	8	18	19
Concordantly , antagonizing CCL25 was able to confine ConA induced liver damage and reduced the number of CCR9 + macrophages .	Concordantly, antagonizing CCL25 was able to confine ConA induced liver damage and reduced the number of CCR9 + macrophages.	2	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL25	CCL25	CCL25	CCR9	CCR9	CCR9	3	4	17	18
The CD69 and CXCR4 effects were driven by SDF-1 , while CCL21 downregulated CCR7 .	The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7.	11	14	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL21	CCL21	CCL21	CCR7	CCR7	CCR7	11	12	13	14
VEID-CHO at 10 nM added before caspase-8 selectively blocked the activity of caspase-6 with minimal effects on the activation of caspase-7 , caspase-3-p20 , or caspase-3-p17 ( data not shown ) .	VEID-CHO at 10 nM added before caspase-8 selectively blocked the activity of caspase-6 with minimal effects on the activation of caspase-7, caspase-3-p20, or caspase-3-p17 (data not shown).	6	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	caspase-8	caspase-8	caspase-8	caspase-6	caspase-6	caspase-6	6	7	12	13
Ouabain treatment induced cleavage of Rock-1 and Rock-2 , which was prevented by caspase-3 and caspase-2 specific inhibitors z-DEVD-fmk and z-VDVAD-fmk , respectively .	Ouabain treatment induced cleavage of Rock-1 and Rock-2, which was prevented by caspase-3 and caspase-2 specific inhibitors z-DEVD-fmk and z-VDVAD-fmk, respectively.	3	18	prevented	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	caspase-3	caspase-3	caspase-3	Rock-1	Rock-1	Rock-1	13	14	5	6
CCND1 downregulation is well characterized to decrease activation of cyclin dependent kinases Cdk4 and Cdk6 , that are not only required for G1 to S phase transition during cell cycle progression but also are major players in interaction with stromal cells that sustain tumor growth XREF_BIBR .	CCND1 downregulation is well characterized to decrease activation of cyclin dependent kinases Cdk4 and Cdk6, that are not only required for G1 to S phase transition during cell cycle progression but also are major players in interaction with stromal cells that sustain tumor growth XREF_BIBR.	0	35	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCND1	CCND1	CCND1	Cdk4	Cdk4	Cdk4	0	1	12	13
Thus , binding of AZ to CCND1 may inhibit the activation and reactivation of CDK4 by CCND1 and thereby cause G 1 arrest during the cell cycle [ XREF_BIBR ] .	Thus, binding of AZ to CCND1 may inhibit the activation and reactivation of CDK4 by CCND1 and thereby cause G 1 arrest during the cell cycle [XREF_BIBR].	8	17	reactivation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	CCND1	CCND1	CCND1	CDK4	CDK4	CDK4	16	17	14	15
Similarly , an acute and global ablation of Ccnd1 or pharmacological inhibition of CDK4 and CDK6 kinase activity in mice bearing Erbb2 V664E -driven mammary tumours blocked cancer progression and triggered tumour cell specific senescence without having any obvious effect on normal tissues 26 .	Similarly, an acute and global ablation of Ccnd1 or pharmacological inhibition of CDK4 and CDK6 kinase activity in mice bearing Erbb2 V664E -driven mammary tumours blocked cancer progression and triggered tumour cell specific senescence without having any obvious effect on normal tissues 26.	8	17	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Ccnd1	Ccnd1	Ccnd1	CDK4	CDK4	CDK4	8	9	13	14
Among these ligands , MCP-3 had the remarkable property of binding CCR5 with high affinity without eliciting a functional response , MCP-3 could also inhibit the activation of CCR5 by MIP-1beta and may therefore be considered as a natural antagonist for CCR5 .	Among these ligands, MCP-3 had the remarkable property of binding CCR5 with high affinity without eliciting a functional response, MCP-3 could also inhibit the activation of CCR5 by MIP-1beta and may therefore be considered as a natural antagonist for CCR5.	24	31	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	MIP-1beta	MIP-1beta	MIP-1beta	CCR5	CCR5	CCR5	30	31	28	29
These factors include the CD8 T cell derived anti-HIV factor ( CD8-SF ) [ XREF_BIBR ] and the beta-chemokines RANTES ( Regulated upon Activation , Normal T-cell Expressed , and Secreted ) , MIP-1alpha ( macrophage inflammatory protein-1alpha ) , and MIP-1beta [ XREF_BIBR ] , which block the CCR5 coreceptor , essential for virus entry into target leukocytes .	These factors include the CD8 T cell derived anti-HIV factor (CD8-SF) [XREF_BIBR] and the beta-chemokines RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted), MIP-1alpha (macrophage inflammatory protein-1alpha), and MIP-1beta [XREF_BIBR], which block the CCR5 coreceptor, essential for virus entry into target leukocytes.	41	50	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MIP-1beta	MIP-1beta	MIP-1beta	CCR5	CCR5	CCR5	41	42	49	50
CCL2 and CCL4 increased rapidly and significantly by Days 7 and 14 across all groups , suggesting potent CCR2 and CCR5 blockade ( all P < 0.05 vs. Day 1 [ predose ] ) .	CCL2 and CCL4 increased rapidly and significantly by Days 7 and 14 across all groups, suggesting potent CCR2 and CCR5 blockade (all P < 0.05 vs. Day 1 [predose]).	0	21	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL4	CCL4	CCL4	CCR5	CCR5	CCR5	2	3	20	21
Reversal of MIP-1alpha and MIP-1beta induced CCR5 down regulation was used to titer anti-MIP-1alpha and MIP-1beta antibody ( XREF_SUPPLEMENTARY ) .	Reversal of MIP-1alpha and MIP-1beta induced CCR5 down regulation was used to titer anti-MIP-1alpha and MIP-1beta antibody (XREF_SUPPLEMENTARY).	0	10	induced	Positive_early_activation	Positive_activation	Negative_activation	MIP-1beta	MIP-1beta	MIP-1beta	CCR5	CCR5	CCR5	4	5	6	7
Mutation of the basic 50s cluster of CCL5 , a coordinative site for CCL5 surface presentation , reduced CCR5- but not CCR1 mediated arrest and transmigration .	Mutation of the basic 50s cluster of CCL5, a coordinative site for CCL5 surface presentation, reduced CCR5- but not CCR1 mediated arrest and transmigration.	5	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	7	8	21	22
In comparison to CD133- non CSLCs , chemokine CCL5 and its receptors , CCR1 , CCR3 , and CCR5 , were consistently upregulated in CSLCs , and most importantly , blocking of CCL5 , CCR1 , or CCR3 effectively inhibits the invasive capacity of CSLCs .	In comparison to CD133- non CSLCs, chemokine CCL5 and its receptors, CCR1, CCR3, and CCR5, were consistently upregulated in CSLCs, and most importantly, blocking of CCL5, CCR1, or CCR3 effectively inhibits the invasive capacity of CSLCs.	7	35	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL5	CCL5	CCL5	CCR1	CCR1	CCR1	8	9	34	35
Recently , it has been demonstrated that Tax-1 and Tax-2 induce the expression of the CC-chemokines MIP1-alpha and CCL 3 MIP-1beta and CCL4 , and RANTES and CCL5 and that downregulate CCR5 in monocytes and PBMCs .	Recently, it has been demonstrated that Tax-1 and Tax-2 induce the expression of the CC-chemokines MIP1-alpha and CCL 3 MIP-1beta and CCL4, and RANTES and CCL5 and that downregulate CCR5 in monocytes and PBMCs.	7	35	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MIP1-alpha	Tax-1 and Tax-2 induce the expression of the CC-chemokines MIP1-alpha	mip1-alpha	CCR5	CCR5	ccr5	16	17	31	32
Maraviroc inhibited CCL5- or CCL3 driven internalization of CCR5 at concentrations as low as 10 nM ( XREF_FIG ) , an effect that was seen on effector CD8+ and CD4+ T cells but not on naive ( CCR5 negative ) CD8+ and CD4+ T cells .	Maraviroc inhibited CCL5- or CCL3 driven internalization of CCR5 at concentrations as low as 10 nM (XREF_FIG), an effect that was seen on effector CD8+ and CD4+ T cells but not on naive (CCR5 negative) CD8+ and CD4+ T cells.	1	38	driven	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CCL3	CCL3	CCL3	CCR5	CCR5	CCR5	4	5	37	38
Here , we report that decreasing the function of CCR5 increases MAPK and CREB signaling , long-term potentiation ( LTP ) , and hippocampus dependent memory in mice , while neuronal CCR5 overexpression caused memory deficits .	Here, we report that decreasing the function of CCR5 increases MAPK and CREB signaling, long-term potentiation (LTP), and hippocampus dependent memory in mice, while neuronal CCR5 overexpression caused memory deficits.	7	14	increases	Positive_activation_token_1_verb	Positive_activation	Negative_activation	CCR5	CCR5	CCR5	MAPK	MAPK	MAPK	9	10	11	12
In contrast , ectopic over-expression of CcnE2 in the liver inhibits S-phase progression and CcnE1 expression leading to the new hypothesis that CcnE2 has antagonistic cell cycle functions and is able to negatively control S-phase entry by down-regulating CcnE1 expression thereby restricting cdk2 kinase activity .	In contrast, ectopic over-expression of CcnE2 in the liver inhibits S-phase progression and CcnE1 expression leading to the new hypothesis that CcnE2 has antagonistic cell cycle functions and is able to negatively control S-phase entry by down-regulating CcnE1 expression thereby restricting cdk2 kinase activity.	38	44	restricting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CcnE1	CcnE1 expression	ccne1	cdk2	cdk2	cdk2	38	39	42	43
Additionally , we showed by Western blot that the CCR1 antagonist suppressed ERK1/2 and JNK activities in T cells stimulated with myosin and that IL-2 reversed this suppression .	Additionally, we showed by Western blot that the CCR1 antagonist suppressed ERK1/2 and JNK activities in T cells stimulated with myosin and that IL-2 reversed this suppression.	9	15	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CCR1	CCR1	CCR1	ERK1/2	ERK1/2	ERK1/2	9	10	12	13
Remarkably , CD19 deficiency suppressed the hyper-responsive phenotype of Lyn (-/-) B cells and autoimmunity characterized by serum autoantibodies and immune complex mediated glomerulonephritis in Lyn (-/-) mice .	Remarkably, CD19 deficiency suppressed the hyper-responsive phenotype of Lyn (-/-) B cells and autoimmunity characterized by serum autoantibodies and immune complex mediated glomerulonephritis in Lyn (-/-) mice.	2	12	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD19	CD19	CD19	Lyn	Lyn	Lyn	2	3	9	10
Phosphorylation of cdc25A results in inhibition of CDK2 resulting in S-phase arrest , and phosphorylation of cdc25C and Wee1 causes inhibition of CDK1 , resulting in G2/M arrest [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] and it is through this function that the ATR-CHK1 pathway exerts cell cycle control at the G2/M and intra-S cell cycle checkpoints [ XREF_BIBR ] , preventing entry to mitosis via inhibition of CDK1 thereby preventing immediate mitotic catastrophe or permanent loss of genetic material .	Phosphorylation of cdc25A results in inhibition of CDK2 resulting in S-phase arrest, and phosphorylation of cdc25C and Wee1 causes inhibition of CDK1, resulting in G2/M arrest [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] and it is through this function that the ATR-CHK1 pathway exerts cell cycle control at the G2/M and intra-S cell cycle checkpoints [XREF_BIBR], preventing entry to mitosis via inhibition of CDK1 thereby preventing immediate mitotic catastrophe or permanent loss of genetic material.	14	23	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	cdc25C	phosphorylation of cdc25C	cdc25c	CDK1	CDK1	cdk1	16	17	22	23
Cdc25C , Wee1 and Myt1 then decrease the activity of the CDK1 and cyclin B1 complex , resulting in an arrest of the cell cycle at the G2/M phase .	Cdc25C, Wee1 and Myt1 then decrease the activity of the CDK1 and cyclin B1 complex, resulting in an arrest of the cell cycle at the G2/M phase.	0	15	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25C	Cdc25C	Cdc25C	CDK1	CDK1	CDK1	0	1	11	12
In this study , CQ showed an inhibitory effect to cdc25C expression and stimulation of p21 that might inactivate cdc2 and cyclin B1 complex .	In this study, CQ showed an inhibitory effect to cdc25C expression and stimulation of p21 that might inactivate cdc2 and cyclin B1 complex.	10	23	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cdc25C	cdc25C expression	cdc25c	cdc2	cdc2	cdc2	10	11	19	20
Phosphorylation of cdc25c ( Thr48 ) suppressed cdc2 ( Tyr15 ) and cdc2 ( Tyr161 ) .	Phosphorylation of cdc25c (Thr48) suppressed cdc2 (Tyr15) and cdc2 (Tyr161).	0	12	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cdc25c	Phosphorylation of cdc25c (Thr48	cdc25c	cdc2	cdc2	cdc2	2	3	7	8
In these studies , PTX-2 increased phosphorylation of Cdc25C and decreased protein levels of Cdc2 ( Cdk1 , cyclin dependent kinase 1 ) , cyclin B1 ; and the M phase specific marker protein , phospho-histone 3 was markedly increased by PTX-2 [ XREF_BIBR ] .	In these studies, PTX-2 increased phosphorylation of Cdc25C and decreased protein levels of Cdc2 (Cdk1, cyclin dependent kinase 1), cyclin B1; and the M phase specific marker protein, phospho-histone 3 was markedly increased by PTX-2 [XREF_BIBR].	4	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25C	PTX-2 increased phosphorylation of Cdc25C	cdc25c	Cdk1	Cdk1	cdk1	8	9	16	17
The ATM kinase particularly senses DSBs , phosphorylating CHK2 , and subsequently inactivating CDC25c , which reduces the CDK1 activity to prevent the cell cycle process and repair DNA damage XREF_BIBR .	The ATM kinase particularly senses DSBs, phosphorylating CHK2, and subsequently inactivating CDC25c, which reduces the CDK1 activity to prevent the cell cycle process and repair DNA damage XREF_BIBR.	12	19	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDC25c	CDC25c	CDC25c	CDK1	CDK1	CDK1	13	14	18	19
The present results demonstrated that phospho-cdc25c was increased to inhibit the combination of cdc2 and cyclin B1 .	The present results demonstrated that phospho-cdc25c was increased to inhibit the combination of cdc2 and cyclin B1.	5	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	phospho-cdc25c	phospho-cdc25c	phospho-cdc25c	cdc2	cdc2	cdc2	5	6	13	14
Furthermore , Western blotting results showed that in p53 (-/-) cells vanadate caused cdc25C degradation and activation of phospho-cdc2 without alteration of the p21 level .	Furthermore, Western blotting results showed that in p53 (-/-) cells vanadate caused cdc25C degradation and activation of phospho-cdc2 without alteration of the p21 level.	13	19	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	cdc25C	cdc25C	cdc25C	phospho-cdc2	phospho-cdc2	phospho-cdc2	13	14	18	19
Cdc2 is a kind of cyclin dependent kinases ( CDKs ) and would be inactivated through phosphorylation by cdc25C [ XREF_BIBR ] .	Cdc2 is a kind of cyclin dependent kinases (CDKs) and would be inactivated through phosphorylation by cdc25C [XREF_BIBR].	0	20	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	cdc25C	cdc25C	cdc25C	Cdc2	Cdc2	Cdc2	18	19	0	1
This effect could be related to decreased cdc25c mediated cdk1 activation or to Wee1 inactivation of cdk1 as suggested by Tyr15 phosphorylation [ XREF_BIBR ] .	This effect could be related to decreased cdc25c mediated cdk1 activation or to Wee1 inactivation of cdk1 as suggested by Tyr15 phosphorylation [XREF_BIBR].	4	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	cdc25c	cdc25c	cdc25c	cdk1	cdk1	cdk1	7	8	9	10
Similarly , the dual-specificity phosphatase Cdc25C is down-regulated by p53 in response to DNA damage , preventing the activation of Cdc2 .	Similarly, the dual-specificity phosphatase Cdc25C is down-regulated by p53 in response to DNA damage, preventing the activation of Cdc2.	2	21	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	5	6	20	21
During G2 phase of the cell cycle JNK phosphorylates CDC25C at Ser168 and negatively regulates its phosphatase activity and thereby Cdk1 activation , thus controlling the onset of mitosis [ XREF_BIBR ] .	During G2 phase of the cell cycle JNK phosphorylates CDC25C at Ser168 and negatively regulates its phosphatase activity and thereby Cdk1 activation, thus controlling the onset of mitosis [XREF_BIBR].	7	21	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDC25C	JNK phosphorylates CDC25C at Ser168	cdc25c	Cdk1	Cdk1	cdk1	9	10	20	21
When the hyperactive Cdc25A catalytic fragment was added together with recombinant cyclin B to artificially dephosphorylate Cdc2 Tyr15 , M-phase induction was restored in apoptotic egg extracts , indicating that the blockage of cyclin B accumulation and the caspase mediated inactivation of Cdc25C dually inhibited Cdc2 activation .	When the hyperactive Cdc25A catalytic fragment was added together with recombinant cyclin B to artificially dephosphorylate Cdc2 Tyr15, M-phase induction was restored in apoptotic egg extracts, indicating that the blockage of cyclin B accumulation and the caspase mediated inactivation of Cdc25C dually inhibited Cdc2 activation.	40	46	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25C	Cdc25C	Cdc25C	Cdc2	Cdc2	Cdc2	42	43	45	46
It is known that both Cdc25C and Wee 1 phosphorylation cooperatively reduce Cdk1 and cyclin B1 activity leading to G 2 / M arrest [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It is known that both Cdc25C and Wee 1 phosphorylation cooperatively reduce Cdk1 and cyclin B1 activity leading to G 2 / M arrest [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	16	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25C	Cdc25C and Wee 1 phosphorylation	cdc25c	Cdk1	Cdk1	cdk1	5	6	12	13
The activated WEE1 and inactivated Cdc25c coordinay prevented Cdc2 and cyclin B activation and mitotic entry in cancer cells .	The activated WEE1 and inactivated Cdc25c coordinay prevented Cdc2 and cyclin B activation and mitotic entry in cancer cells.	5	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25c	Cdc25c	Cdc25c	Cdc2	Cdc2	Cdc2	5	6	8	9
Downregulation of CDC25C would block the activation of CDK1 , resulting in dissociation of cyclin B1 and prevention of cell cycle progression from G 2 to M phase .	Downregulation of CDC25C would block the activation of CDK1, resulting in dissociation of cyclin B1 and prevention of cell cycle progression from G 2 to M phase.	0	9	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDC25C	CDC25C	CDC25C	CDK1	CDK1	CDK1	2	3	8	9
As expected , we found TNFalpha mediated Cdc25A down-regulation to inhibit Cdk2 activity .	As expected, we found TNFalpha mediated Cdc25A down-regulation to inhibit Cdk2 activity.	5	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25A	TNFalpha mediated Cdc25A	cdc25a	Cdk2	Cdk2	cdk2	7	8	11	12
Inactivation of CDC25A by antisense oligonucleotides inhibited the enzymatic activity of Cdk2 enzyme , arresting the G1 phase of cell cycle in human breast carcinoma cells [ XREF_BIBR ] .	Inactivation of CDC25A by antisense oligonucleotides inhibited the enzymatic activity of Cdk2 enzyme, arresting the G1 phase of cell cycle in human breast carcinoma cells [XREF_BIBR].	0	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDC25A	CDC25A	CDC25A	Cdk2	Cdk2	Cdk2	2	3	11	12
We show that a metabolically stable analogue of anandamide , Met-F-AEA , induces an S phase growth arrest correlated with Chk1 activation , Cdc25A degradation and suppression of Cdk2 activity .	We show that a metabolically stable analogue of anandamide, Met-F-AEA, induces an S phase growth arrest correlated with Chk1 activation, Cdc25A degradation and suppression of Cdk2 activity.	23	29	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Cdc25A	Cdc25A	Cdc25A	Cdk2	Cdk2	Cdk2	23	24	28	29
After DNA damage in G1 phase , a rapid destruction of Cdc25A blocks the activation of cycE and Cdk2 ( the key complex in G1/S transitoin ) , inducing a transient cell cycle arrest that can only last for several hours ; A sustainable cell cycle arrest is realized by nuclear p53 inducing the transcription of p21 , a short lived protein that binds and inhibits both cycD and Cdk4 ( the key complex in cell cycle entry ) and cycE and ac-Cdk 2 ) .	After DNA damage in G1 phase, a rapid destruction of Cdc25A blocks the activation of cycE and Cdk2 (the key complex in G1/S transitoin), inducing a transient cell cycle arrest that can only last for several hours; A sustainable cell cycle arrest is realized by nuclear p53 inducing the transcription of p21, a short lived protein that binds and inhibits both cycD and Cdk4 (the key complex in cell cycle entry) and cycE and ac-Cdk 2).	9	19	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25A	Cdc25A	Cdc25A	Cdk2	Cdk2	Cdk2	11	12	18	19
Similarly , at the G1/S and intra-S-phase checkpoints , these kinases phosphorylate ( and thereby inhibit ) the CDC25A phosphatase in response to DNA damage , thus preventing CDK2 and cyclin E activation and temporarily halting the cell cycle .	Similarly, at the G1/S and intra-S-phase checkpoints, these kinases phosphorylate (and thereby inhibit) the CDC25A phosphatase in response to DNA damage, thus preventing CDK2 and cyclin E activation and temporarily halting the cell cycle.	18	32	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDC25A	CDC25A	CDC25A	CDK2	CDK2	CDK2	18	19	28	29
Chk2 , another checkpoint protein activated by ATM [ XREF_BIBR ] , can phosphorylate Cdc25A at S124 , which promotes Cdc25A degradation and downregulates CDK2 activity resulting in blockage of DNA synthesis [ XREF_BIBR ] .	Chk2, another checkpoint protein activated by ATM [XREF_BIBR], can phosphorylate Cdc25A at S124, which promotes Cdc25A degradation and downregulates CDK2 activity resulting in blockage of DNA synthesis [XREF_BIBR].	0	25	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25A	Chk2, another checkpoint protein activated by ATM [XREF_BIBR], can phosphorylate Cdc25A at S124	cdc25a	CDK2	CDK2	cdk2	14	15	24	25
In the presence of DNA damage , Cdk2 kinase activity is abrogated by a deficiency of Cdc25A phosphatase , which is marked by Chk1 and Chk2 for proteasomal degradation .	In the presence of DNA damage, Cdk2 kinase activity is abrogated by a deficiency of Cdc25A phosphatase, which is marked by Chk1 and Chk2 for proteasomal degradation.	7	17	abrogated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Cdc25A	Cdc25A	Cdc25A	Cdk2	Cdk2	Cdk2	16	17	7	8
Overall , CDK2 deregulation by both CycE and Cdc25A OE rapidly induces prolonged S phase and ATR activation , and accumulation of unusual replication intermediates .	Overall, CDK2 deregulation by both CycE and Cdc25A OE rapidly induces prolonged S phase and ATR activation, and accumulation of unusual replication intermediates.	2	9	deregulation	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	Cdc25A	Cdc25A	Cdc25A	CDK2	CDK2	CDK2	8	9	2	3
Chk2 , another checkpoint protein , was reported to be phosphorylated and activated by ATM upon ionizing radiation ( IR ) [ XREF_BIBR ] , and activated Chk2 phosphorylates Cdc25A at S123 , which promotes Cdc25A degradation and downregulates CDK2 activity resulting in blocking DNA synthesis and inducing S-phase checkpoint [ XREF_BIBR ] .	Chk2, another checkpoint protein, was reported to be phosphorylated and activated by ATM upon ionizing radiation (IR) [XREF_BIBR], and activated Chk2 phosphorylates Cdc25A at S123, which promotes Cdc25A degradation and downregulates CDK2 activity resulting in blocking DNA synthesis and inducing S-phase checkpoint [XREF_BIBR].	0	40	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25A	Chk2, another checkpoint protein, was reported to be phosphorylated and activated by ATM upon ionizing radiation (IR) [XREF_BIBR], and activated Chk2 phosphorylates Cdc25A at S123	cdc25a	CDK2	CDK2	cdk2	29	30	39	40
It has been known for some time that Cdc25A is important for the intra-S phase checkpoint response after genotoxic stress , which results in the phosphorylation of and degradation of Cdc25A and subsequent inactivation of cdk2 kinase .	It has been known for some time that Cdc25A is important for the intra-S phase checkpoint response after genotoxic stress, which results in the phosphorylation of and degradation of Cdc25A and subsequent inactivation of cdk2 kinase.	30	36	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Cdc25A	Cdc25A	Cdc25A	cdk2	cdk2	cdk2	30	31	35	36
Chk1 also regulates the S phase checkpoint by promoting proteolysis of Cdc25A , which in turn inhibits CDK2 activity , in response to some anticancer agents , such as infrared ray ( IR ) and ultraviolet ( UV ) light [ XREF_BIBR - XREF_BIBR ] .	Chk1 also regulates the S phase checkpoint by promoting proteolysis of Cdc25A, which in turn inhibits CDK2 activity, in response to some anticancer agents, such as infrared ray (IR) and ultraviolet (UV) light [XREF_BIBR - XREF_BIBR].	9	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25A	Cdc25A	Cdc25A	CDK2	CDK2	CDK2	11	12	17	18
Addition of the 26S proteasome inhibitor , MG132 , led to a partial block in TRAF2 and TRAF3 degradation induced by CD40 but had little effect on TRAF2 and TRAF3 levels in hCD40-LMP1-stimulated cells ( XREF_FIG and XREF_FIG ) .	Addition of the 26S proteasome inhibitor, MG132, led to a partial block in TRAF2 and TRAF3 degradation induced by CD40 but had little effect on TRAF2 and TRAF3 levels in hCD40-LMP1-stimulated cells (XREF_FIG and XREF_FIG).	15	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	21	22	17	18
This may be because CD40 mediated TRAF3 degradation requires close association with TRAF2 and the E3 ubiquitin ligase activity of the TRAF2 RING domain , and LMP1 exhibits much weaker TRAF2 binding than CD40 in B cells .	This may be because CD40 mediated TRAF3 degradation requires close association with TRAF2 and the E3 ubiquitin ligase activity of the TRAF2 RING domain, and LMP1 exhibits much weaker TRAF2 binding than CD40 in B cells.	4	7	mediated	Positive_early_activation	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	4	5	6	7
CD40 activation has been shown to induce rapid degradation of TRAF2 and TRAF3 , but not that of TRAF6 .	CD40 activation has been shown to induce rapid degradation of TRAF2 and TRAF3, but not that of TRAF6.	0	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	0	1	12	13
However , PG102 stimulated normal CD40 mediated TNFR associated factor ( TRAF ) 2 and TRAF3 degradation .	However, PG102 stimulated normal CD40 mediated TNFR associated factor (TRAF) 2 and TRAF3 degradation.	4	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	5	6	15	16
We have examined the impact of Ubc9 ablation on CD40 mediated TRAF3 degradation in EJ cells , a cell line that was fundamental in the discovery of CD40 XREF_BIBR and functionally responds to CD40 receptor occupancy XREF_BIBR .	We have examined the impact of Ubc9 ablation on CD40 mediated TRAF3 degradation in EJ cells, a cell line that was fundamental in the discovery of CD40 XREF_BIBR and functionally responds to CD40 receptor occupancy XREF_BIBR.	2	12	mediated	Positive_early_activation	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	9	10	11	12
We found that engagement of CD40 prevented the ability of TRAF2 and TRAF3 to coordinate assembly of the NIK and cIAPs complex ( XREF_SUPPLEMENTARY ) .	We found that engagement of CD40 prevented the ability of TRAF2 and TRAF3 to coordinate assembly of the NIK and cIAPs complex (XREF_SUPPLEMENTARY).	3	13	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	5	6	12	13
Increased CD40 expression binds more TRAF2 and TRAF3 and diminishes the pools of ' free ' TRAF2 and TRAF3 , leading to reduction of STING ubiquitination and degradation .	Increased CD40 expression binds more TRAF2 and TRAF3 and diminishes the pools of ' free ' TRAF2 and TRAF3, leading to reduction of STING ubiquitination and degradation.	1	19	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40	CD40 expression binds more TRAF2	cd40	TRAF3	TRAF3	traf3	1	2	18	19
However , LMP1 binds TRAF3 with markedly enhanced avidity , compared to CD40 , allowing LMP1 to sequester TRAF3 from the B-cell cytoplasm to the plasma membrane .	However, LMP1 binds TRAF3 with markedly enhanced avidity, compared to CD40, allowing LMP1 to sequester TRAF3 from the B-cell cytoplasm to the plasma membrane.	3	19	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	12	13	18	19
CD40 induced TRAF3 degradation was also dependent on TRAF2 , whose absence in B-cells and especially MEFs increased TRAF3 abundance ( XREF_FIG and XREF_SUPPLEMENTARY online ) .	CD40 induced TRAF3 degradation was also dependent on TRAF2, whose absence in B-cells and especially MEFs increased TRAF3 abundance (XREF_FIG and XREF_SUPPLEMENTARY online).	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	0	1	2	3
On the other hand , increased CD40 levels will bind more TRAF2 and TRAF3 and reduce the levels of ' free ' TRAF2 and TRAF3 , resulting in higher STING and IFN-beta levels because overexpression of TRAF3 led to STING degradation ( XREF_FIG ) .	On the other hand, increased CD40 levels will bind more TRAF2 and TRAF3 and reduce the levels of ' free ' TRAF2 and TRAF3, resulting in higher STING and IFN-beta levels because overexpression of TRAF3 led to STING degradation (XREF_FIG).	6	25	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40	CD40 levels will bind more TRAF2	cd40	TRAF3	TRAF3	traf3	6	7	24	25
However , CD40 mediated TRAF3 degradation is intact , and the single amino acid polymorphism occurs well outside of the TBS , and does not impact TRAF2 or TRAF6 binding .	However, CD40 mediated TRAF3 degradation is intact, and the single amino acid polymorphism occurs well outside of the TBS, and does not impact TRAF2 or TRAF6 binding.	2	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	2	3	4	5
The requirement of TRAF3 association with the TBS to observe BAFFR mediated TRAF3 degradation in the B cells line M12.4.1 suggests that , similar to CD40 mediated TRAF3 degradation , there is a requirement to associate with TRAF2 and its E3 ubiquitin ligase activity .	The requirement of TRAF3 association with the TBS to observe BAFFR mediated TRAF3 degradation in the B cells line M12.4.1 suggests that, similar to CD40 mediated TRAF3 degradation, there is a requirement to associate with TRAF2 and its E3 ubiquitin ligase activity.	23	28	mediated	Positive_early_activation	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	25	26	27	28
TRAF3 degradation is induced in B cells by CD40 or BAFF-R activation and its ablation in B cells prevents NIK degradation .	TRAF3 degradation is induced in B cells by CD40 or BAFF-R activation and its ablation in B cells prevents NIK degradation.	0	11	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	8	9	0	1
It has been previously shown that engagement of CD40 or BAFF-R induces rapid proteasome dependent degradation of TRAF3 in B lymphocytes .	It has been previously shown that engagement of CD40 or BAFF-R induces rapid proteasome dependent degradation of TRAF3 in B lymphocytes.	6	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF3	TRAF3	TRAF3	8	9	17	18
Finally , the same monoclonal antibodies against CD40 block CD40 ligand stimulation of chemokine production from HVECs ( data not shown ) .	Finally, the same monoclonal antibodies against CD40 block CD40 ligand stimulation of chemokine production from HVECs (data not shown).	7	11	block	Negative_activation_token_1_noun	Positive_activation	Negative_activation	CD40 ligand	CD40 ligand	CD40 ligand	CD40	CD40	CD40	9	11	7	8
TNFSF5 and TNFRSF5 gene defects , which impair CD40L and CD40 signaling in patients with hyper-IgM type-1 ( HIGM1 ) and HIGM3 syndromes XREF_BIBR respectively , led to a reduction of both circulating and follicular IgD + IgM - plasmablasts , but partially spared extrafollicular IgD + IgM - plasmablasts ( XREF_FIG and XREF_SUPPLEMENTARY online ) , suggesting that CD40L-CD40 interaction is indispensable for the generation of systemic but not mucosal IgD producing effector-memory B cells .	TNFSF5 and TNFRSF5 gene defects, which impair CD40L and CD40 signaling in patients with hyper-IgM type-1 (HIGM1) and HIGM3 syndromes XREF_BIBR respectively, led to a reduction of both circulating and follicular IgD + IgM - plasmablasts, but partially spared extrafollicular IgD + IgM - plasmablasts (XREF_FIG and XREF_SUPPLEMENTARY online), suggesting that CD40L-CD40 interaction is indispensable for the generation of systemic but not mucosal IgD producing effector-memory B cells.	0	11	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFSF5	TNFSF5	TNFSF5	CD40	CD40	CD40	0	1	10	11
Mutations in CD40 ligand ( CD40L ) that permit residual CD40L expression typically impair binding of CD40 .	Mutations in CD40 ligand (CD40L) that permit residual CD40L expression typically impair binding of CD40.	3	17	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	5	6	16	17
To determine whether CD40 is required for CD40L induced cell death in LGSC cells , we examined the effects of CD40L on cell viability following siRNA mediated knockdown of endogenous CD40 .	To determine whether CD40 is required for CD40L induced cell death in LGSC cells, we examined the effects of CD40L on cell viability following siRNA mediated knockdown of endogenous CD40.	18	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	20	21	30	31
CD40L null mice exhibited a blunted increase in T cell production of Wnt10b and abrogated CD40 signaling in SCs in response to iPTH treatment .	CD40L null mice exhibited a blunted increase in T cell production of Wnt10b and abrogated CD40 signaling in SCs in response to iPTH treatment.	0	16	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	0	1	15	16
Finally , systemic administration of FLT3L and/or CD40L reversed CD40 and IL-12 ( p40 ) deficiency of DCs in tumor bearing mice in vivo .	Finally, systemic administration of FLT3L and/or CD40L reversed CD40 and IL-12 (p40) deficiency of DCs in tumor bearing mice in vivo.	3	15	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	7	8	9	10
We hypothesized that scFv : CD40L fusion proteins would have reduced CD40 agonist activity similar to sCD40L but will be converted to a highly agonistic membrane CD40L like form of CD40L upon anchoring to cell surface exposed antigen via the scFv domain .	We hypothesized that scFv : CD40L fusion proteins would have reduced CD40 agonist activity similar to sCD40L but will be converted to a highly agonistic membrane CD40L like form of CD40L upon anchoring to cell surface exposed antigen via the scFv domain.	5	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	5	6	11	12
We suggest that this difference is because of reduced autocrine and paracrine CD40 activation by the lower level of CD40L expressed on plasmid transduced CLL cells and the shorter time - course of vaccine manufacture ( 5 h versus 3 days ) .	We suggest that this difference is because of reduced autocrine and paracrine CD40 activation by the lower level of CD40L expressed on plasmid transduced CLL cells and the shorter time - course of vaccine manufacture (5 h versus 3 days).	12	20	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	CD40L	level of CD40L	cd40l	CD40	CD40	cd40	19	20	12	13
Therefore , CD40L engagement clearly induces human NK effectors to recognize and kill CD40 negative resistant targets .	Therefore, CD40L engagement clearly induces human NK effectors to recognize and kill CD40 negative resistant targets.	2	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	2	3	13	14
CD40L may also inhibit growth of CD40 expressing tumors directly .	CD40L may also inhibit growth of CD40 expressing tumors directly.	0	8	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40L	CD40L	CD40L	CD40	CD40	CD40	0	1	6	7
Because neither toxin B nor DN Rac and Cdc42 inhibited the peak of PAK1 activation , which was induced upon cell adhesion in vector control cells , it appears that molecules other than Rac and Cdc42 ( for example CIB1 ) might contribute to the initial adhesion induced PAK1 activation .	Because neither toxin B nor DN Rac and Cdc42 inhibited the peak of PAK1 activation, which was induced upon cell adhesion in vector control cells, it appears that molecules other than Rac and Cdc42 (for example CIB1) might contribute to the initial adhesion induced PAK1 activation.	3	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	8	9	13	14
A similar non reversal of the PAK1 reduction by CDC42 was also observed when KLF2 expression was increased by vasoprotective simvastatin in HUVECs .	A similar non reversal of the PAK1 reduction by CDC42 was also observed when KLF2 expression was increased by vasoprotective simvastatin in HUVECs.	6	10	reduction	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	CDC42	CDC42	CDC42	PAK1	PAK1	PAK1	9	10	6	7
PAK1 activation induced by laminin-5 was suppressed by expression of a dominant negative Cdc42 .	PAK1 activation induced by laminin-5 was suppressed by expression of a dominant negative Cdc42.	0	14	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Cdc42	expression of a dominant negative Cdc42	cdc42	PAK1	PAK1	pak1	13	14	0	1
This may be related to the ability of E-Syt2 to suppress the activation of PAK1 by Cdc42 and Rac small GTPases .	This may be related to the ability of E-Syt2 to suppress the activation of PAK1 by Cdc42 and Rac small GTPases.	10	20	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	16	17	14	15
In agreement with our toxin B results , the coexpression of both dominant negative ( DN ) Rac and Cdc42 did not significantly inhibit PAK1 activation upon adhesion to FN but did attenuate PAK1 activation with prolonged adhesion to FN .	In agreement with our toxin B results, the coexpression of both dominant negative (DN) Rac and Cdc42 did not significantly inhibit PAK1 activation upon adhesion to FN but did attenuate PAK1 activation with prolonged adhesion to FN.	9	34	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc42	coexpression of both dominant negative (DN) Rac and Cdc42	cdc42	PAK1	PAK1	pak1	19	20	33	34
Third , adhesion induced PAK1 and cofilin activation were not inhibited by the coexpression of DN Rac and Cdc42 .	Third, adhesion induced PAK1 and cofilin activation were not inhibited by the coexpression of DN Rac and Cdc42.	4	19	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Cdc42	coexpression of DN Rac and Cdc42	cdc42	PAK1	PAK1	pak1	18	19	4	5
Dominant negative Ras , Rac , and Cdc42 suppressed PAK1 activation whereas activated Rac1 and Cdc42 were able to stimulate PAK1 even in the absence of any agonists [ XREF_BIBR ] .	Dominant negative Ras, Rac, and Cdc42 suppressed PAK1 activation whereas activated Rac1 and Cdc42 were able to stimulate PAK1 even in the absence of any agonists [XREF_BIBR].	13	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	15	16	20	21
Pak1 targets cytoskeletal organization by regulating the formation of motile structures modulated by small GTPases cdc42 and Rac1 .	Pak1 targets cytoskeletal organization by regulating the formation of motile structures modulated by small GTPases cdc42 and Rac1.	0	17	modulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cdc42	cdc42	cdc42	Pak1	Pak1	Pak1	15	16	0	1
This small-molecule PAK inhibitor was developed from a screen designed to detect an inhibition of Cdc42 mediated PAK1 activation rather than kinase activity [ XREF_BIBR ] .	This small-molecule PAK inhibitor was developed from a screen designed to detect an inhibition of Cdc42 mediated PAK1 activation rather than kinase activity [XREF_BIBR].	13	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	Cdc42	Cdc42	Cdc42	PAK1	PAK1	PAK1	15	16	17	18
PAK1 is the upstream kinase controlling the effector function of CDC42 and Rac1 functioning in the dissolution of stress fibers and reorganization of focal complexes [ XREF_BIBR ] and mutation of the putative residue in PAK1 phosphorylated by OSR1 reduced the activation of PAK1 by CDC42 .	PAK1 is the upstream kinase controlling the effector function of CDC42 and Rac1 functioning in the dissolution of stress fibers and reorganization of focal complexes [XREF_BIBR] and mutation of the putative residue in PAK1 phosphorylated by OSR1 reduced the activation of PAK1 by CDC42.	39	46	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	CDC42	CDC42	CDC42	PAK1	PAK1	PAK1	45	46	43	44
CD40 mediated TRAF2 degradation is highly associated with a RING domain of TRAF2 , although the RING domain of TRAF2 is not a site for ubiquitination by an E3 ligase 33 .	CD40 mediated TRAF2 degradation is highly associated with a RING domain of TRAF2, although the RING domain of TRAF2 is not a site for ubiquitination by an E3 ligase 33.	0	3	mediated	Positive_early_activation	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	0	1	2	3
CD40 , not LMP1 , signaling has been shown to degrade TRAF2 and 3 .	CD40, not LMP1, signaling has been shown to degrade TRAF2 and 3.	0	13	degrade	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	0	1	11	12
We show here that CD40 mediated TRAF2 degradation requires the zinc binding RING domain of TRAF2 and is preceded by TRAF2 ubiquitination , suggesting that the TRAF2 RING may promote ubiquitination although the RING itself is not a target of ubiquitination .	We show here that CD40 mediated TRAF2 degradation requires the zinc binding RING domain of TRAF2 and is preceded by TRAF2 ubiquitination, suggesting that the TRAF2 RING may promote ubiquitination although the RING itself is not a target of ubiquitination.	4	7	mediated	Positive_early_activation	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	4	5	6	7
It has also been shown that TRAF2 and TRAF3 translocation into the membrane rafts is consistently induced by CD40 activation , and CD40 dependent degradation of TRAF2 is believed to account for the negative feedback on activation .	It has also been shown that TRAF2 and TRAF3 translocation into the membrane rafts is consistently induced by CD40 activation, and CD40 dependent degradation of TRAF2 is believed to account for the negative feedback on activation.	22	27	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	CD40	CD40	CD40	TRAF2	TRAF2	TRAF2	22	23	26	27
Because dominant negative expression of Cdc42 results in DV abnormalities ( XREF_FIG ) and Cdc42 activates Pak , we speculated that expression of membrane tethered form of Pak ( UAS-PAK-myr ) , which acts as a dominant gain-of-function protein , might rescue the phenotype observed in Cdc42 mutants .	Because dominant negative expression of Cdc42 results in DV abnormalities (XREF_FIG) and Cdc42 activates Pak, we speculated that expression of membrane tethered form of Pak (UAS-PAK-myr), which acts as a dominant gain-of-function protein, might rescue the phenotype observed in Cdc42 mutants.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc42	Cdc42	Cdc42	Pak	Pak	Pak	5	6	16	17
As expected , Cdc42 promoted Pak activation leading to higher levels of MBP phosphorylation and this increased kinase activity was inhibited by IPA-3 ( XREF_FIG ; compare autoradiogram lanes 1-3 ) .	As expected, Cdc42 promoted Pak activation leading to higher levels of MBP phosphorylation and this increased kinase activity was inhibited by IPA-3 (XREF_FIG; compare autoradiogram lanes 1-3).	3	6	promoted	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Cdc42	Cdc42	Cdc42	Pak	Pak	Pak	3	4	5	6
Depletion of Cdc42 in HeLa cells decreased the entry of PAK , PAKDeltaSDeltaT , PAKDeltaS and PAKDeltaT to 60 +/-13% , 62 +/-2% , 71 +/-12% and 59 +/-1% , respectively ( XREF_FIG ) .	Depletion of Cdc42 in HeLa cells decreased the entry of PAK, PAKDeltaSDeltaT, PAKDeltaS and PAKDeltaT to 60 +/-13%, 62 +/-2%, 71 +/-12% and 59 +/-1%, respectively (XREF_FIG).	0	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	2	3	10	11
These results suggest targeting Cdc42 with the small molecule inhibitor AZA197 in colon cancer cells can effectively modulate PAK and ERK signaling interfering with Cyclin D1 expression to affect colon cancer cell proliferation .	These results suggest targeting Cdc42 with the small molecule inhibitor AZA197 in colon cancer cells can effectively modulate PAK and ERK signaling interfering with Cyclin D1 expression to affect colon cancer cell proliferation.	3	21	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdc42	Cdc42	Cdc42	PAK	PAK	PAK	4	5	18	19
We demonstrated that FK-3000 exerts an antiproliferative effect through two pathways : i ) G 2 / M phase arrest via downregulation of cyclin B and phospho-CDC2 by dephosphorylation of CDC25B and phosphorylation of p38 MAPK ; and ii ) p38 MAPK independent induction of apoptosis ( XREF_FIG ) .	We demonstrated that FK-3000 exerts an antiproliferative effect through two pathways : i) G 2 / M phase arrest via downregulation of cyclin B and phospho-CDC2 by dephosphorylation of CDC25B and phosphorylation of p38 MAPK; and ii) p38 MAPK independent induction of apoptosis (XREF_FIG).	21	31	downregulation	Negative_activation_syntax_6_noun	Positive_activation	Negative_activation	CDC25B	dephosphorylation of CDC25B	cdc25b	phospho-CDC2	phospho-CDC2	phospho-cdc2	30	31	26	27
When tsBN2 cells arrested in S phase were incubated at 40degreesC in the presence of cycloheximide , Cdc25B , but not Cdc25A and C , among a family of dual-specificity phosphatases , Cdc25 , was lost coincidentally with the lack of the activation of p34 cdc2 / cyclin B. Consistently , the immunodepletion of Cdc25B from the extract inhibited the activation of p34 cdc2 / cyclin B. Cdc25B was found to be unstable ( half-life < 30 min ) .	When tsBN2 cells arrested in S phase were incubated at 40degreesC in the presence of cycloheximide, Cdc25B, but not Cdc25A and C, among a family of dual-specificity phosphatases, Cdc25, was lost coincidentally with the lack of the activation of p34 cdc2 / cyclin B. Consistently, the immunodepletion of Cdc25B from the extract inhibited the activation of p34 cdc2 / cyclin B. Cdc25B was found to be unstable (half-life < 30 min).	52	64	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25B	Cdc25B	Cdc25B	p34 cdc2	p34 cdc2	p34 cdc2	54	55	62	64
Conclusively FK-3000 exerts its antiproliferative effect through two pathways : i ) G 2 / M cell cycle arrest via downregulation of cyclin B and phospho-CDC2 by p38 MAPK phosphorylation and CDC25B dephosphorylation , and ii ) p38 MAPK independent induction of apoptosis .	Conclusively FK-3000 exerts its antiproliferative effect through two pathways : i) G 2 / M cell cycle arrest via downregulation of cyclin B and phospho-CDC2 by p38 MAPK phosphorylation and CDC25B dephosphorylation, and ii) p38 MAPK independent induction of apoptosis.	20	32	downregulation	Negative_activation_syntax_6_noun	Positive_activation	Negative_activation	CDC25B	phosphorylation and CDC25B	cdc25b	phospho-CDC2	phospho-CDC2	phospho-cdc2	31	32	25	26
However , the addition of a CD70 mimicry protein ( FcCD70 ) greatly reduced the frequency of IL-17-producing cells in WT , but not Cd27 -/-, cultures .	However, the addition of a CD70 mimicry protein (FcCD70) greatly reduced the frequency of IL-17-producing cells in WT, but not Cd27 -/-, cultures.	6	26	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD70	CD70	CD70	Cd27	Cd27	Cd27	6	7	24	25
With a CD70 mAb blocking the CD70 and CD27 pathway , the antitumor activity of the anti-CD40 mAb was totally abolished , indicating the importance of CD27 in promoting antitumor immunity XREF_BIBR .	With a CD70 mAb blocking the CD70 and CD27 pathway, the antitumor activity of the anti-CD40 mAb was totally abolished, indicating the importance of CD27 in promoting antitumor immunity XREF_BIBR.	2	9	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD70	CD70	CD70	CD27	CD27	CD27	2	3	8	9
Moreover , the pathology related to chronic strains of LCMV can be diminished in CD27 deficient animals or animals treated with blocking antibody to CD70 , suggesting a prominent role of CD27-CD70 interaction in the infection with this virus .	Moreover, the pathology related to chronic strains of LCMV can be diminished in CD27 deficient animals or animals treated with blocking antibody to CD70, suggesting a prominent role of CD27-CD70 interaction in the infection with this virus.	14	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	CD70	CD70	CD70	CD27	CD27	CD27	24	25	14	15
The interaction between 14-3-3 and Cdc25A prevents Cdc25A from binding to cyclin B and CDK1 complex ; thus , phosphorylation of Cdc25A at T507 inactivates cyclin B and CDK1 complex and inhibits associated mitotic entry [ XREF_BIBR ] .	The interaction between 14-3-3 and Cdc25A prevents Cdc25A from binding to cyclin B and CDK1 complex; thus, phosphorylation of Cdc25A at T507 inactivates cyclin B and CDK1 complex and inhibits associated mitotic entry [XREF_BIBR].	19	29	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc25A	phosphorylation of Cdc25A at T507	cdc25a	CDK1	CDK1	cdk1	21	22	28	29
Increases in CDC73 repress beta-catenin activity , and CDC73 has been reported to be a tumor suppressor gene [ XREF_BIBR ] .	Increases in CDC73 repress beta-catenin activity, and CDC73 has been reported to be a tumor suppressor gene [XREF_BIBR].	0	5	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDC73	CDC73	CDC73	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
This strongly suggests that CDC73 may directly interact with and repress beta-catenin transcriptional activity in response to PKA stimulation within the adrenal cortex .	This strongly suggests that CDC73 may directly interact with and repress beta-catenin transcriptional activity in response to PKA stimulation within the adrenal cortex.	4	13	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDC73	CDC73	CDC73	beta-catenin	beta-catenin	beta-catenin	4	5	11	12
Unmodified MIF was shown to induce activation of ERK1/2 and AKT by binding its receptors CD74 and CXCR4 , which could be blocked by CXCR4 and CD74 neutralizing antibodies .	Unmodified MIF was shown to induce activation of ERK1/2 and AKT by binding its receptors CD74 and CXCR4, which could be blocked by CXCR4 and CD74 neutralizing antibodies.	12	28	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	CD74	CD74	CD74	CXCR4	CXCR4	CXCR4	26	27	17	18
In line with this , selective knock down of CDC2 inhibited BIRC5 abundance and suppressed its anti-apoptotic activities .	In line with this, selective knock down of CDC2 inhibited BIRC5 abundance and suppressed its anti-apoptotic activities.	5	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDC2	CDC2	CDC2	BIRC5	BIRC5	BIRC5	9	10	11	12
A previous study demonstrated that suppressive E-cadherin expression may stimulate Lrp5 and Lrp6 release from cell surface into cell cytosol and result in the stabilized cytoplastic beta-catenin level , as well as the enhanced osteogenic differentiation .	A previous study demonstrated that suppressive E-cadherin expression may stimulate Lrp5 and Lrp6 release from cell surface into cell cytosol and result in the stabilized cytoplastic beta-catenin level, as well as the enhanced osteogenic differentiation.	6	13	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	E-cadherin	E-cadherin expression	e-cadherin	Lrp6	Lrp6	lrp6	6	7	12	13
Finally , AR activity in G2/M is intricately modulated , as CDK1 can inhibit AR activity through phosphorylation on serine 308 , and the phosphatase Cdc25b enhances AR activity .	Finally, AR activity in G2/M is intricately modulated, as CDK1 can inhibit AR activity through phosphorylation on serine 308, and the phosphatase Cdc25b enhances AR activity.	11	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK1	CDK1	CDK1	AR	AR	AR	11	12	14	15
Furthermore , either inhibition of Cyclin B1 expression by siRNA interference or inhibition of CDK1 and Cyclin B1 activity by Roscovitine rescued the down-regulation of Mcl-1 .	Furthermore, either inhibition of Cyclin B1 expression by siRNA interference or inhibition of CDK1 and Cyclin B1 activity by Roscovitine rescued the down-regulation of Mcl-1.	7	26	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK1	expression by siRNA interference or inhibition of CDK1	cdk1	Mcl-1	Mcl-1	mcl-1	14	15	25	26
We therefore conclude that high MCL1 expression sensitizes hESCs to MCL1 deregulation , and CDK1 inhibition induces apoptosis in hESCs by negatively regulating MCL1 anti-apoptotic function .	We therefore conclude that high MCL1 expression sensitizes hESCs to MCL1 deregulation, and CDK1 inhibition induces apoptosis in hESCs by negatively regulating MCL1 anti-apoptotic function.	14	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK1	CDK1	CDK1	MCL1	MCL1	MCL1	14	15	23	24
Furthermore , either siRNA interference of Cyclin B1 or inhibition of the CDK1 and Cyclin B1 complex with Roscovitine rescued the decrease of Mcl-1 .	Furthermore, either siRNA interference of Cyclin B1 or inhibition of the CDK1 and Cyclin B1 complex with Roscovitine rescued the decrease of Mcl-1.	4	24	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK1	CDK1	CDK1	Mcl-1	Mcl-1	Mcl-1	12	13	23	24
However , given that there is less cyclin B1 to mediate Cdk1 degradation of Mcl-1 by Doc , it is not surprising that Mcl-1 levels are slightly higher in Doc + ABT-737 treated PC3 and shCyclin B1 compared to shGFP cells ( XREF_FIG ) .	However, given that there is less cyclin B1 to mediate Cdk1 degradation of Mcl-1 by Doc, it is not surprising that Mcl-1 levels are slightly higher in Doc + ABT-737 treated PC3 and shCyclin B1 compared to shGFP cells (XREF_FIG).	11	15	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Mcl-1	Mcl-1	Mcl-1	11	12	14	15
The inhibition of CDK1 and CDK9 caused the downregulation of the anti-apoptotic protein MCL-1 , by proteolytic degradation and by blockage of transcription respectively .	The inhibition of CDK1 and CDK9 caused the downregulation of the anti-apoptotic protein MCL-1, by proteolytic degradation and by blockage of transcription respectively.	1	14	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK1	CDK1	CDK1	MCL-1	MCL-1	MCL-1	3	4	13	14
Thus , Cdk1 does not block Chk1 activation , whereas it completely prevents association of Rad51 with damaged DNA ( XREF_FIG ) .	Thus, Cdk1 does not block Chk1 activation, whereas it completely prevents association of Rad51 with damaged DNA (XREF_FIG).	2	7	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Chk1	Chk1	Chk1	2	3	6	7
These observations suggest that Cdk1 negatively regulates Chk1 through its ability to promote completion of S-phase , removing the DNA replication checkpoint stimulus .	These observations suggest that Cdk1 negatively regulates Chk1 through its ability to promote completion of S-phase, removing the DNA replication checkpoint stimulus.	4	8	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Chk1	Chk1	Chk1	4	5	7	8
We then asked whether Cdk1 inhibits Rad51 loading and/or Chk1 activation .	We then asked whether Cdk1 inhibits Rad51 loading and/or Chk1 activation.	4	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Chk1	Chk1	Chk1	4	5	9	10
We previously found that siRNA mediated partial depletion of either CDK1 or CDK2 reduced the S-phase DNA damage upon Wee1 , as well as Chk1 , inhibition , suggesting that both CDK1 and CDK2 activities contribute to the effects [ XREF_BIBR ] .	We previously found that siRNA mediated partial depletion of either CDK1 or CDK2 reduced the S-phase DNA damage upon Wee1, as well as Chk1, inhibition, suggesting that both CDK1 and CDK2 activities contribute to the effects [XREF_BIBR].	7	26	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	Chk1	Chk1	Chk1	10	11	24	25
A second positive-feedback loop could also exist in the form of a double negative loop , postulated as APC activity on securin being first blocked by Cdk1 and Clb5 , followed by the continued destruction of securin by APC as Clb5 proteolysis continues [ XREF_BIBR ] .	A second positive-feedback loop could also exist in the form of a double negative loop, postulated as APC activity on securin being first blocked by Cdk1 and Clb5, followed by the continued destruction of securin by APC as Clb5 proteolysis continues [XREF_BIBR].	16	28	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Cdk1	Cdk1	Cdk1	securin	securin	securin	26	27	21	22
Importantly , Cdk1 inhibition also triggered rapid securin destruction in Mlh1 -/- oocytes ( XREF_FIG D and 2E ) .	Importantly, Cdk1 inhibition also triggered rapid securin destruction in Mlh1 -/- oocytes (XREF_FIG D and 2E).	2	8	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk1	Cdk1	Cdk1	securin	securin	securin	2	3	7	8
Cdk1 Depletion or Inhibition Reduces Formation of BRCA1 Foci .	Cdk1 Depletion or Inhibition Reduces Formation of BRCA1 Foci.	0	8	Reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1	Cdk1	BRCA1	BRCA1	BRCA1	0	1	7	8
As Cdk1 dependent phosphorylation stimulates Gwl activity not only towards Ensa and ARPP19 but also towards Gwl itself at autoactivatory sites , by reversing Cdk1 dependent phosphorylation Fcp1 could also reduce Gwl autoactivatory strength , favouring this way PP1 action to stably switch off Gwl autoactivation and , along with directly reducing Gwl activity towards Ensa and ARPP19 , allow PP1 and PP2A-B55 to shut Gwl activity offdefinitively .	As Cdk1 dependent phosphorylation stimulates Gwl activity not only towards Ensa and ARPP19 but also towards Gwl itself at autoactivatory sites, by reversing Cdk1 dependent phosphorylation Fcp1 could also reduce Gwl autoactivatory strength, favouring this way PP1 action to stably switch off Gwl autoactivation and, along with directly reducing Gwl activity towards Ensa and ARPP19, allow PP1 and PP2A-B55 to shut Gwl activity offdefinitively.	23	33	reduce	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Cdk1	Cdk1	Cdk1	Gwl	Gwl	Gwl	24	25	31	32
Inhibition of CDK2 expression by CDK2 specific RNAi significantly reduced CDK2 co-precipitated to Tat apparently due reduction of the expressed CDK2 .	Inhibition of CDK2 expression by CDK2 specific RNAi significantly reduced CDK2 co-precipitated to Tat apparently due reduction of the expressed CDK2.	0	7	Inhibition	Negative_regulation_syntax_1_noun	Positive_activation	Negative_regulation	CDK2	CDK2	cdk2	CDK2	CDK2 expression	cdk2	5	6	2	3
Also consistent with the microarray findings , in the cell culture setting mRNA levels of ATF3 , ID1 , ID2 , CDK2 ( cyclin dependent kinase 2 ) , and VEGFC ( Vascular endothelial growth factor C ) were up- ( ATF3 , ID1 and ID2 ) or down-regulated ( CDK2 and VEGFC ) in response to CDM treatment ( XREF_FIG ) .	Also consistent with the microarray findings, in the cell culture setting mRNA levels of ATF3, ID1, ID2, CDK2 (cyclin dependent kinase 2), and VEGFC (Vascular endothelial growth factor C) were up- (ATF3, ID1 and ID2) or down-regulated (CDK2 and VEGFC) in response to CDM treatment (XREF_FIG).	13	55	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK2	levels of ATF3, ID1, ID2, CDK2	cdk2	CDK2	CDK2	cdk2	21	22	50	51
The dual phosphorylation of cdk2 at Thr14 and Tyr15 , a modification which inhibits cdk2 kinase activity , increased robustly through 48 h of T-oligo exposure , but cdk2 was not modified in cells exposed to the control oligo .	The dual phosphorylation of cdk2 at Thr14 and Tyr15, a modification which inhibits cdk2 kinase activity, increased robustly through 48 h of T-oligo exposure, but cdk2 was not modified in cells exposed to the control oligo.	2	16	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	cdk2	phosphorylation of cdk2 at Thr14 and Tyr15	cdk2	cdk2	cdk2	cdk2	4	5	14	15
In vitro , BMS-387032 inhibits Cdk2 phosphorylation in the A2780 ovarian carcinoma cell line , inhibiting the phosphorylation of downstream targets of Cdk2 including pRb , histone H1 and DNA polymerase-alpha .	In vitro, BMS-387032 inhibits Cdk2 phosphorylation in the A2780 ovarian carcinoma cell line, inhibiting the phosphorylation of downstream targets of Cdk2 including pRb, histone H1 and DNA polymerase-alpha.	3	30	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk2	BMS-387032 inhibits Cdk2 phosphorylation	cdk2	Cdk2	Cdk2	cdk2	5	6	22	23
As shown in XREF_FIG , compared with WT , Cables1 AA showed greater interaction with Cdk2 , increased Cdk2 Y15 phosphorylation , and decreased Cdk2 kinase activity .	As shown in XREF_FIG, compared with WT, Cables1 AA showed greater interaction with Cdk2, increased Cdk2 Y15 phosphorylation, and decreased Cdk2 kinase activity.	9	26	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk2	Cables1 AA showed greater interaction with Cdk2, increased Cdk2 Y15 phosphorylation	cdk2	Cdk2	Cdk2	cdk2	18	19	24	25
In contrast , cell adhesion does not have pronounced effects on ( a ) the levels of cyclin E or cdk2 , ( b ) formation of the cyclin E and cdk2 complex , or ( c ) the positive and negative regulatory phosphorylations that modulate cdk2 activity .	In contrast, cell adhesion does not have pronounced effects on (a) the levels of cyclin E or cdk2, (b) formation of the cyclin E and cdk2 complex, or (c) the positive and negative regulatory phosphorylations that modulate cdk2 activity.	15	47	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdk2	levels of cyclin E or cdk2	cdk2	cdk2	cdk2	cdk2	20	21	46	47
We tested three different pairs of siRNA duplexes targeting CDK2 on the coding region and showed that all CDK2 siRNAs dramatically inhibited CDK2 expression without the detectable influence on the non targeted CDK4 in A549 cells ( XREF_FIG ) .	We tested three different pairs of siRNA duplexes targeting CDK2 on the coding region and showed that all CDK2 siRNAs dramatically inhibited CDK2 expression without the detectable influence on the non targeted CDK4 in A549 cells (XREF_FIG).	18	24	inhibited	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	CDK2	CDK2	cdk2	CDK2	CDK2 expression	cdk2	18	19	22	23
In the case of Cal-78 cells treatment with diacerein ( 100muM ) induced a small , but not significant change , for the expression of CDK1 , whereas the cyclin B1 and CDK2 levels were significantly down-regulated ( cyclin B1 : 0.612 +/-0.22 ( p = 0.039 ) ; CDK2 : 0.673 +/-0.16 ( p = 0.027 ) ) within the observation period .	In the case of Cal-78 cells treatment with diacerein (100muM) induced a small, but not significant change, for the expression of CDK1, whereas the cyclin B1 and CDK2 levels were significantly down-regulated (cyclin B1 : 0.612 +/-0.22 (p = 0.039); CDK2 : 0.673 +/-0.16 (p = 0.027)) within the observation period.	32	52	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK2	CDK2 levels	cdk2	CDK2	CDK2	cdk2	32	33	49	50
Western blotting confirmed that the reduced protein levels of Cdc25A attenuated the dephosphorylation of its downstream Cdk2 and thus reduced Cdk2 activity in the breast cancer cells without altering its expression ( XREF_FIG ) .	Western blotting confirmed that the reduced protein levels of Cdc25A attenuated the dephosphorylation of its downstream Cdk2 and thus reduced Cdk2 activity in the breast cancer cells without altering its expression (XREF_FIG).	7	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk2	levels of Cdc25A attenuated the dephosphorylation of its downstream Cdk2	cdk2	Cdk2	Cdk2	cdk2	16	17	20	21
We showed previously that the overexpression of cyclin A strongly activated Cdk2 in a dose dependent manner and that the overexpression of Cdk2-dn inhibited Cdk2 activity XREF_BIBR .	We showed previously that the overexpression of cyclin A strongly activated Cdk2 in a dose dependent manner and that the overexpression of Cdk2-dn inhibited Cdk2 activity XREF_BIBR.	20	26	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk2-dn	overexpression of Cdk2-dn	cdk2-dn	Cdk2	Cdk2	cdk2	22	23	24	25
Cdk2 kinase is inhibited by phosphorylation of thr14 and tyr15 of cdk2 by Wee1 and Myt1 kinase , which is reversed by Cdc25A phosphatase .	Cdk2 kinase is inhibited by phosphorylation of thr14 and tyr15 of cdk2 by Wee1 and Myt1 kinase, which is reversed by Cdc25A phosphatase.	0	12	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	cdk2	phosphorylation of thr14 and tyr15 of cdk2	cdk2	Cdk2	Cdk2	cdk2	11	12	0	1
We found that CDK1 inhibition by RO-3306 actively enhances downstream p53 signaling and that a combination strategy aimed at inhibiting CDK1 as well as activating p53 signaling deserves further investigation in AML .	We found that CDK1 inhibition by RO-3306 actively enhances downstream p53 signaling and that a combination strategy aimed at inhibiting CDK1 as well as activating p53 signaling deserves further investigation in AML.	3	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK1	CDK1	CDK1	p53	p53	p53	3	4	10	11
Concomitant inhibition of Cdk1 , 2 , and 9 activities in proliferating cells triggers DNA damage and p53 dependent apoptosis ( XREF_FIG ) .	Concomitant inhibition of Cdk1, 2, and 9 activities in proliferating cells triggers DNA damage and p53 dependent apoptosis (XREF_FIG).	1	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk1	Cdk1	Cdk1	p53	p53	p53	3	4	17	18
Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53 , suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways .	Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53, suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways.	0	14	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cdc2	Methyl sartortuoate treatment led to reduced expression of cdc2	cdc2	p53	p53	p53	8	9	13	14
Inhibition of cyclin dependent kinase 1 ( CDK1 ) can selectively induce the DNA damage response and P53 dependent apoptosis in hESCs , in contrast to only causing transient cell cycle arrest during DNA repair in differentiated cells [ XREF_BIBR ] .	Inhibition of cyclin dependent kinase 1 (CDK1) can selectively induce the DNA damage response and P53 dependent apoptosis in hESCs, in contrast to only causing transient cell cycle arrest during DNA repair in differentiated cells [XREF_BIBR].	2	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK1	CDK1	CDK1	P53	P53	P53	7	8	17	18
Our data demonstrate a novel pro survival signaling network initiated by radiation induced mitochondrial targeting of cyclin B1 , Cdk1 and p53 , and subsequent mitochondrial p53 Ser 315 phosphorylation causing enhanced mitochondrial ATP generation and mitochondrial membrane potential .	Our data demonstrate a novel pro survival signaling network initiated by radiation induced mitochondrial targeting of cyclin B1, Cdk1 and p53, and subsequent mitochondrial p53 Ser 315 phosphorylation causing enhanced mitochondrial ATP generation and mitochondrial membrane potential.	12	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk1	Cdk1 and p53, and subsequent mitochondrial p53 Ser 315 phosphorylation	cdk1	p53	p53	p53	19	20	21	22
Inhibition of CCNB1 and cdk1 reactivated and stabilized p53 in cells with functional loss of p53 [ XREF_BIBR ] .	Inhibition of CCNB1 and cdk1 reactivated and stabilized p53 in cells with functional loss of p53 [XREF_BIBR].	0	10	reactivated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	cdk1	cdk1	cdk1	p53	p53	p53	4	5	8	9
The mechanism by which p53 delays the G2/M transition is mediated by Cdc2 inhibition via three transcriptional targets of p53 , p21 , 14-3-3delta , and Gadd45 .	The mechanism by which p53 delays the G2/M transition is mediated by Cdc2 inhibition via three transcriptional targets of p53, p21, 14-3-3delta, and Gadd45.	4	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Cdc2	Cdc2	Cdc2	p53	p53	p53	12	13	4	5
In summary , our data suggest that p63 regulates GCTSC proliferation by binding to the CDC2 and CDC25C p53-REs , which may inhibit the p53 tumor suppressor activity and contribute to GCT tumorigenesis .	In summary, our data suggest that p63 regulates GCTSC proliferation by binding to the CDC2 and CDC25C p53-REs, which may inhibit the p53 tumor suppressor activity and contribute to GCT tumorigenesis.	15	27	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDC2	CDC2	CDC2	p53	p53	p53	15	16	24	25
Therefore , according to the current study , upregulated CDK1 may increase the growth of glioblastoma by promoting cell cycle pathways and inhibiting the p53 signaling pathway .	Therefore, according to the current study, upregulated CDK1 may increase the growth of glioblastoma by promoting cell cycle pathways and inhibiting the p53 signaling pathway.	9	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK1	CDK1	CDK1	p53	p53	p53	9	10	24	25
The expression levels of G2/M cell cycle regulating factors , cyclin B1 and Cdc2 , were significantly decreased , pp53 , p53 , and p21 were significantly increased in EF24 treated cells .	The expression levels of G2/M cell cycle regulating factors, cyclin B1 and Cdc2, were significantly decreased, pp53, p53, and p21 were significantly increased in EF24 treated cells.	8	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdc2	Cdc2	Cdc2	p53	p53	p53	13	14	21	22
Further analysis identified that CDC2 and cyclin B1 , key cell cycle regulators , were stably down-regulated following p53 stabilization by Nutlin-3 , consistent with direct interaction between p53 and the CDC2 and cyclin B1 promoters , leading to the repression of transcription by methylation .	Further analysis identified that CDC2 and cyclin B1, key cell cycle regulators, were stably down-regulated following p53 stabilization by Nutlin-3, consistent with direct interaction between p53 and the CDC2 and cyclin B1 promoters, leading to the repression of transcription by methylation.	4	19	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDC2	CDC2	CDC2	p53	p53	p53	4	5	18	19
Our data show that either pharmacologic inhibition of Cdk2 activity alone or inhibition of multiple Cdks is sufficient to induce p53 activation ( XREF_FIG ) .	Our data show that either pharmacologic inhibition of Cdk2 activity alone or inhibition of multiple Cdks is sufficient to induce p53 activation (XREF_FIG).	8	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk2	Cdk2	Cdk2	p53	p53	p53	8	9	20	21
By contrast , inhibition of Cdk2 ( with NU6140 ) increased p53 protein and activity , inhibited proliferation , but had no effect on apoptosis .	By contrast, inhibition of Cdk2 (with NU6140) increased p53 protein and activity, inhibited proliferation, but had no effect on apoptosis.	3	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk2	Cdk2	Cdk2	p53	p53	p53	5	6	11	12
Transient transfection assays were developed to show that the GFP-CDK2 docking site fusion protein ( GFP-CIP ) attenuates p53 activity in vivo and suppresses p21WAF1 induction which is similar to NU2058 but distinct from Roscovitine .	Transient transfection assays were developed to show that the GFP-CDK2 docking site fusion protein (GFP-CIP) attenuates p53 activity in vivo and suppresses p21WAF1 induction which is similar to NU2058 but distinct from Roscovitine.	9	19	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GFP-CDK2	GFP-CDK2	GFP-CDK2	p53	p53	p53	9	10	18	19
These results suggest that specific inhibition of Cdk2 promotes p53 and p21 signaling dependent cell cycle arrest without causing apoptosis .	These results suggest that specific inhibition of Cdk2 promotes p53 and p21 signaling dependent cell cycle arrest without causing apoptosis.	5	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk2	Cdk2	Cdk2	p53	p53	p53	7	8	9	10
Silencing of p53 increases Cdk2 activity by reducing p21 wAF1 and CIP1 expression , in turn Cdk2 phosphorylates Rb1 and dissociates E2F3 , which then promotes AURKA expression via binding to its gene promoter [ XREF_BIBR ] .	Silencing of p53 increases Cdk2 activity by reducing p21 wAF1 and CIP1 expression, in turn Cdk2 phosphorylates Rb1 and dissociates E2F3, which then promotes AURKA expression via binding to its gene promoter [XREF_BIBR].	2	5	increases	Positive_activation_token_1_noun	Positive_activation	Positive_activation	Cdk2	Cdk2	Cdk2	p53	p53	p53	4	5	2	3
In addition , as seen in exponentially growing cells , HBC decreased the expression of cell cycle regulatory proteins , viz ., cyclin A , cyclin E , cyclin D1 , and Cdk-2 , and increased the level of p53 and PARP cleavage in R1881 stimulated cells ( XREF_SUPPLEMENTARY ) .	In addition, as seen in exponentially growing cells, HBC decreased the expression of cell cycle regulatory proteins, viz., cyclin A, cyclin E, cyclin D1, and Cdk-2, and increased the level of p53 and PARP cleavage in R1881 stimulated cells (XREF_SUPPLEMENTARY).	10	42	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk-2	HBC decreased the expression of cell cycle regulatory proteins, viz., cyclin A, cyclin E, cyclin D1, and Cdk-2	cdk-2	p53	p53	p53	32	33	39	40
It has been reported that inhibition of Cdk2 by Roscovitine leads to blunted activation of Chk1 due to reduced phosphorylation [ XREF_BIBR , XREF_BIBR ] .	It has been reported that inhibition of Cdk2 by Roscovitine leads to blunted activation of Chk1 due to reduced phosphorylation [XREF_BIBR, XREF_BIBR].	5	16	leads	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk2	Cdk2	Cdk2	Chk1	Chk1	Chk1	7	8	15	16
Secondly , it has been demonstrated that Cyclin A-CDK2 complexes rapidly shuttle between the cytoplasm and the nucleus , allowing cytoplasmic targeting of CDC25C by CDK2 8 .	Secondly, it has been demonstrated that Cyclin A-CDK2 complexes rapidly shuttle between the cytoplasm and the nucleus, allowing cytoplasmic targeting of CDC25C by CDK2 8.	19	26	targeting	Positive_activation_token_2_noun	Positive_activation	Positive_activation	CDK2	CDK2	CDK2	CDC25C	CDC25C	CDC25C	25	26	23	24
Specifically , overexpression of CDK1 and CDK2 was found to repress the EZH2 target hoxA9 , an effect that was abrogated when EZH2 levels were reduced .	Specifically, overexpression of CDK1 and CDK2 was found to repress the EZH2 target hoxA9, an effect that was abrogated when EZH2 levels were reduced.	2	14	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK2	overexpression of CDK1 and CDK2	cdk2	EZH2	EZH2	ezh2	6	7	12	13
Individual loss of Cdk2 allowed normal CcnA2 and CcnE2 gene induction in liver after PH and in mitogen stimulated hepatocytes , whereas combined ablation of both factors resulted in a substantial inhibition of CcnA2 and CcnE2 .	Individual loss of Cdk2 allowed normal CcnA2 and CcnE2 gene induction in liver after PH and in mitogen stimulated hepatocytes, whereas combined ablation of both factors resulted in a substantial inhibition of CcnA2 and CcnE2.	1	12	allowed	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk2	loss of Cdk2	cdk2	CcnA2	CcnA2	ccna2	3	4	6	7
The activity cdk4 and cdk2 was also reduced , as consistent with cell cycle arrest in cells with activated DeltaRaf-1 : ER cells .	The activity cdk4 and cdk2 was also reduced, as consistent with cell cycle arrest in cells with activated DeltaRaf-1 : ER cells.	2	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cdk2	cdk2	cdk2	ER	ER	ER	4	5	21	22
Collectively , these results demonstrate that morin reduced cyclin D1 , cyclin E , CDK2 and CDK4 expression via the induction of p21WAF1 expression , increased ERK1/2 phosphorylation and decreased JNK , and AKT phosphorylation , and prevented MMP-9 expression via the inhibition of transcription factors AP-1 , Sp-1 , and NF-kappaB , thereby resulting in the inhibition of growth , migration , and invasion of bladder cancer EJ cells .	Collectively, these results demonstrate that morin reduced cyclin D1, cyclin E, CDK2 and CDK4 expression via the induction of p21WAF1 expression, increased ERK1/2 phosphorylation and decreased JNK, and AKT phosphorylation, and prevented MMP-9 expression via the inhibition of transcription factors AP-1, Sp-1, and NF-kappaB, thereby resulting in the inhibition of growth, migration, and invasion of bladder cancer EJ cells.	6	54	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK2	morin reduced cyclin D1, cyclin E, CDK2 and CDK4 expression via the induction of p21WAF1 expression, increased ERK1/2 phosphorylation	cdk2	Sp-1	Sp-1	sp-1	14	15	48	49
Inhibiting Cdk5 activity with olomoucine or a dominant negative construct , Cdk5T33 , increased the concentration of Src ( pY416 ) , shifted its subcellular localization to the cell periphery and enhanced wound closure .	Inhibiting Cdk5 activity with olomoucine or a dominant negative construct, Cdk5T33, increased the concentration of Src (pY416), shifted its subcellular localization to the cell periphery and enhanced wound closure.	1	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk5	Cdk5	Cdk5	Src	Src	Src	1	2	17	18
Thus , Cdk5 inhibition , like Src ( S75 ) mutation , produced no significant change in the ratio of kinase activity to Src ( pY419 ) ( XREF_FIG ) .	Thus, Cdk5 inhibition, like Src (S75) mutation, produced no significant change in the ratio of kinase activity to Src (pY419) (XREF_FIG).	2	28	produced	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	Cdk5	Cdk5	Cdk5	Src	Src	Src	2	3	23	24
Previous work from this laboratory showed that the 50-70 % increase in Src activity produced by Cdk5 inhibition is physiologically significant , as it results in Src dependent inactivation of Rho signaling and loss of central stress fibers [ XREF_BIBR , XREF_BIBR ] .	Previous work from this laboratory showed that the 50-70% increase in Src activity produced by Cdk5 inhibition is physiologically significant, as it results in Src dependent inactivation of Rho signaling and loss of central stress fibers [XREF_BIBR, XREF_BIBR].	12	17	produced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Cdk5	Cdk5	Cdk5	Src	Src	Src	16	17	12	13
This Cdk5 dependent suppression of active Src inhibits ROCK activity and results in cytoskeletal contraction and cell migration in lens epithelial cells 37 .	This Cdk5 dependent suppression of active Src inhibits ROCK activity and results in cytoskeletal contraction and cell migration in lens epithelial cells 37.	1	7	suppression	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Cdk5	Cdk5	Cdk5	Src	Src	Src	1	2	6	7
Cdk5 activity in this region was shown to limit the accumulation of active Src at the plasma membrane [ XREF_BIBR ] .	Cdk5 activity in this region was shown to limit the accumulation of active Src at the plasma membrane [XREF_BIBR].	0	14	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk5	Cdk5	Cdk5	Src	Src	Src	0	1	13	14
Previous work has shown that Src activity is also limited by Cdk5 , a proline directed kinase , which has been shown to phosphorylate Src ( S75 ) .	Previous work has shown that Src activity is also limited by Cdk5, a proline directed kinase, which has been shown to phosphorylate Src (S75).	5	12	limited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Cdk5	Cdk5	Cdk5	Src	Src	Src	11	12	5	6
CDK5 knockdown in HEY cells significantly prolonged the half-life of TP53 and p27 Kip1 proteins ( XREF_FIG ) .	CDK5 knockdown in HEY cells significantly prolonged the half-life of TP53 and p27 Kip1 proteins (XREF_FIG).	0	14	prolonged	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK5	CDK5	CDK5	TP53	TP53	TP53	0	1	10	11
In addition , CDK5 knockdown alone and in combination with paclitaxel induced G1 cell cycle arrest and caspase 3 dependent apoptotic cell death associated with post-translational upregulation and nuclear translocation of TP53 and p27 Kip1 as well as TP53 dependent transcriptional induction of p21 Cip1 in wild type TP53 cancer cells .	In addition, CDK5 knockdown alone and in combination with paclitaxel induced G1 cell cycle arrest and caspase 3 dependent apoptotic cell death associated with post-translational upregulation and nuclear translocation of TP53 and p27 Kip1 as well as TP53 dependent transcriptional induction of p21 Cip1 in wild type TP53 cancer cells.	3	41	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK5	CDK5	CDK5	TP53	TP53	TP53	3	4	38	39
Evidence has shown that CDK5 can downregulate the tumor suppressor DLC1 and target Dab1 and p53 in cancers , acting as a pro oncogenic factor [ XREF_BIBR - XREF_BIBR ] .	Evidence has shown that CDK5 can downregulate the tumor suppressor DLC1 and target Dab1 and p53 in cancers, acting as a pro oncogenic factor [XREF_BIBR - XREF_BIBR].	4	16	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK5	CDK5	CDK5	p53	p53	p53	4	5	15	16
CDK5 knockdown induces TP53 dependent growth inhibition , apoptosis and G1 arrest .	CDK5 knockdown induces TP53 dependent growth inhibition, apoptosis and G1 arrest.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK5	CDK5	CDK5	TP53	TP53	TP53	0	1	3	4
Thus , silencing of CDK5 produced post-translational upregulation of TP53 and p27 Kip1 associated with TP53 dependent transcriptional induction of p21 Cip1 .	Thus, silencing of CDK5 produced post-translational upregulation of TP53 and p27 Kip1 associated with TP53 dependent transcriptional induction of p21 Cip1.	2	12	produced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK5	CDK5	CDK5	TP53	TP53	TP53	4	5	9	10
In addition , Knockdown of CDK5 induced growth inhibition and knockdown of TP53 reduced silencing CDK5 mediated growth inhibition in the presence or absence of paclitaxel ( XREF_FIG ) .	In addition, Knockdown of CDK5 induced growth inhibition and knockdown of TP53 reduced silencing CDK5 mediated growth inhibition in the presence or absence of paclitaxel (XREF_FIG).	3	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	TP53	TP53	TP53	5	6	12	13
Flow cytometry studies showed that treatment of cells with ICEC-0782 for 24h increased the G2/M population at the lowest concentration tested , i.e ., 1muM ( from 28 % in untreated cells to 34 % ) , probably due to blockage of CDK7 induced activation of CDK1 .	Flow cytometry studies showed that treatment of cells with ICEC-0782 for 24h increased the G2/M population at the lowest concentration tested, i.e., 1muM (from 28% in untreated cells to 34%), probably due to blockage of CDK7 induced activation of CDK1.	40	47	induced	Positive_early_activation	Positive_activation	Negative_activation	CDK7	CDK7	CDK7	CDK1	CDK1	CDK1	42	43	46	47
For example , CAK normally prevents cyclin B pairing with Cdk2 by stabilizing intrinsically weak Cdk1 and cyclin B complexes XREF_BIBR , XREF_BIBR .	For example, CAK normally prevents cyclin B pairing with Cdk2 by stabilizing intrinsically weak Cdk1 and cyclin B complexes XREF_BIBR, XREF_BIBR.	3	20	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CAK	CAK	CAK	Cdk1	Cdk1	Cdk1	3	4	15	16
It is currently not clear how prolonged chromosomal CDK7 and CAK activity would prevent CDK1 inactivation , as this process depends mainly on CYCB degradation .	It is currently not clear how prolonged chromosomal CDK7 and CAK activity would prevent CDK1 inactivation, as this process depends mainly on CYCB degradation.	10	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CAK	CAK	CAK	CDK1	CDK1	CDK1	10	11	14	15
In support of this possibility , disruption of Cdk5 activity has no discernible effect on total Stat3 and the decrease in pStat3 ( S727 ) caused by disruption of Cdk5 activity does not alter the ability of Stat3 to translocate into the nucleus .	In support of this possibility, disruption of Cdk5 activity has no discernible effect on total Stat3 and the decrease in pStat3 (S727) caused by disruption of Cdk5 activity does not alter the ability of Stat3 to translocate into the nucleus.	19	30	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Cdk5	Cdk5	Cdk5	pStat3	pStat3	pStat3	29	30	21	22
Our results suggest that the miR-21 and CDK5 axis could partially mediate tumor cell mobility and EMT by targeting STAT3 in HNSCC .	Our results suggest that the miR-21 and CDK5 axis could partially mediate tumor cell mobility and EMT by targeting STAT3 in HNSCC.	5	20	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CDK5	CDK5	CDK5	STAT3	STAT3	STAT3	7	8	19	20
Interestingly , CPT also induces CDK5 activation and ROSC ( 25 muM ) blocked CDK5 , ATM activation and apoptosis ( as measured by caspase-3 activation ) .	Interestingly, CPT also induces CDK5 activation and ROSC (25 muM) blocked CDK5, ATM activation and apoptosis (as measured by caspase-3 activation).	5	17	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDK5	CDK5	CDK5	ATM	ATM	ATM	5	6	16	17
Results also indicated that siRNA directed against cdk3 ( si-cdk3 ) suppresses ATF1 activity , resulting in inhibition of cell proliferation and growth of human glioblastoma T98G cells in soft agar .	Results also indicated that siRNA directed against cdk3 (si-cdk3) suppresses ATF1 activity, resulting in inhibition of cell proliferation and growth of human glioblastoma T98G cells in soft agar.	4	13	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	si-cdk3	si-cdk3	si-cdk3	ATF1	ATF1	ATF1	9	10	12	13
As expected , silencing Cdk5 inhibited beta1 integrin activation in talin1 WT cells , but did not affect beta1 integrin activation in phospho mimicking talin1 S425D cells ( XREF_FIG ) .	As expected, silencing Cdk5 inhibited beta1 integrin activation in talin1 WT cells, but did not affect beta1 integrin activation in phospho mimicking talin1 S425D cells (XREF_FIG).	3	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Cdk5	Cdk5	Cdk5	talin1	talin1	talin1	4	5	10	11
In fact , inhibiting Cdk7 increased binding of Cdk2 to an unnatural partner , cyclin B , presumably because of impaired Cdk1 and cyclin B assembly and the resulting liberation of cyclin B XREF_BIBR .	In fact, inhibiting Cdk7 increased binding of Cdk2 to an unnatural partner, cyclin B, presumably because of impaired Cdk1 and cyclin B assembly and the resulting liberation of cyclin B XREF_BIBR.	3	9	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk7	Cdk7	Cdk7	Cdk2	Cdk2	Cdk2	4	5	8	9
Here we show that one of these proteins , called C42 , specifically inhibits the activation of Cdk5 by Nck5a .	Here we show that one of these proteins, called C42, specifically inhibits the activation of Cdk5 by Nck5a.	13	20	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Nck5a	Nck5a	Nck5a	Cdk5	Cdk5	Cdk5	19	20	17	18
Cdc25C is inactivated by chk1 , also a client protein , and chk2 [ XREF_BIBR ] .	Cdc25C is inactivated by chk1, also a client protein, and chk2 [XREF_BIBR].	0	14	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	chk2	chk2	chk2	Cdc25C	Cdc25C	Cdc25C	12	13	0	1
As CHK2 inactivates CDC25C via phosphorylation of CDC25C S216 , resulting in G2/M arrest [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , knockdown of either ERK1 or ERK2 reduced ETOP induced CDC25C S216 phosphorylation and significantly compromised ETOP induced G2/M arrest in MCF7 cells [ XREF_BIBR ] .	As CHK2 inactivates CDC25C via phosphorylation of CDC25C S216, resulting in G2/M arrest [XREF_BIBR, XREF_BIBR, XREF_BIBR], knockdown of either ERK1 or ERK2 reduced ETOP induced CDC25C S216 phosphorylation and significantly compromised ETOP induced G2/M arrest in MCF7 cells [XREF_BIBR].	1	5	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK2	CHK2	CHK2	CDC25C	CDC25C	CDC25C	1	2	3	4
DNA damage leads to the activation of CHK2 by phosphorylation , and the phosphor-CHK2 inhibits CDC25C phosphatase , preventing entry into mitosis , and has been shown to stabilize p53 , leading to cell cycle arrest in G1 phase [ XREF_BIBR ] .	DNA damage leads to the activation of CHK2 by phosphorylation, and the phosphor-CHK2 inhibits CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize p53, leading to cell cycle arrest in G1 phase [XREF_BIBR].	12	28	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	phosphor-CHK2	phosphor-CHK2	phosphor-CHK2	CDC25C	CDC25C	CDC25C	13	14	15	16
In turn , activated Chk2 phosphorylates and inactivates the Cdc25c phosphatase , maintaining CDC2 in its phosphorylated-inactive form and leading to G2/M arrest [ XREF_BIBR , XREF_BIBR ] .	In turn, activated Chk2 phosphorylates and inactivates the Cdc25c phosphatase, maintaining CDC2 in its phosphorylated-inactive form and leading to G2/M arrest [XREF_BIBR, XREF_BIBR].	3	10	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk2	Chk2	Chk2	Cdc25c	Cdc25c	Cdc25c	4	5	9	10
Cell cycle checkpoint kinase 2 ( CHK2 ) is known to inhibit CDC25C phosphatase and stabilize the p53 tumor suppressor protein , leading to cell cycle arrest in G1 XREF_BIBR .	Cell cycle checkpoint kinase 2 (CHK2) is known to inhibit CDC25C phosphatase and stabilize the p53 tumor suppressor protein, leading to cell cycle arrest in G1 XREF_BIBR.	3	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK2	CHK2	CHK2	CDC25C	CDC25C	CDC25C	6	7	12	13
Then , activated Chk2 phosphorylates and negatively regulates CDC25C , which is the positive regulators for the activity of cdc2 and cyclinB required for mitosis entry [ XREF_BIBR ] .	Then, activated Chk2 phosphorylates and negatively regulates CDC25C, which is the positive regulators for the activity of cdc2 and cyclinB required for mitosis entry [XREF_BIBR].	2	14	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk2	Chk2	Chk2	CDC25C	CDC25C	CDC25C	3	4	8	9
Next , we determined whether Cdc25C is downregulated by CPT induced Chk2 in LNCaP cells .	Next, we determined whether Cdc25C is downregulated by CPT induced Chk2 in LNCaP cells.	5	12	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Chk2	CPT induced Chk2	chk2	Cdc25C	Cdc25C	cdc25c	11	12	5	6
Cdc25C activity can also be inhibited via phosphorylation by checkpoint kinases Chk1 and Chk2 when there is a DNA damage , which will prevent cyclin B/cdk1 activation XREF_BIBR .	Cdc25C activity can also be inhibited via phosphorylation by checkpoint kinases Chk1 and Chk2 when there is a DNA damage, which will prevent cyclin B/cdk1 activation XREF_BIBR.	0	14	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Chk2	Chk2	Chk2	Cdc25C	Cdc25C	Cdc25C	13	14	0	1
ATM subsequently activates CHK2 by phosphorylating CHK2 threonine 68 ( T68 ) and CHK2 inactivates CDC25C via phosphorylation of its serine 216 ( S216 ) , resulting in G2/M arrest .	ATM subsequently activates CHK2 by phosphorylating CHK2 threonine 68 (T68) and CHK2 inactivates CDC25C via phosphorylation of its serine 216 (S216), resulting in G2/M arrest.	0	17	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK2	ATM subsequently activates CHK2 by phosphorylating CHK2 threonine 68 (T68	chk2	CDC25C	CDC25C	cdc25c	6	7	15	16
Genistein enhanced the activity of the checkpoint kinase , Chk2 , which phosphorylates and inactivates Cdc25C , induced accumulation of p53 , and activated the ataxia-telangiectasia-mutated ( ATM ) gene .	Genistein enhanced the activity of the checkpoint kinase, Chk2, which phosphorylates and inactivates Cdc25C, induced accumulation of p53, and activated the ataxia-telangiectasia-mutated (ATM) gene.	7	16	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk2	Chk2	Chk2	Cdc25C	Cdc25C	Cdc25C	9	10	15	16
Both CHK1 and CHK2 negatively regulate CDC25C via phosphorylation of a serine residue ( ser216 ) ; this event creates a site for the binding to 14-3-3 protein resulting in its cytoplasmic sequestration and G2/M checkpoint activation .	Both CHK1 and CHK2 negatively regulate CDC25C via phosphorylation of a serine residue (ser216); this event creates a site for the binding to 14-3-3 protein resulting in its cytoplasmic sequestration and G2/M checkpoint activation.	1	8	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK2	CHK2	CHK2	CDC25C	CDC25C	CDC25C	3	4	6	7
In turn , activated Chk2 phosphorylates downstream substrates , including Cdc25A on serine 123 and Cdc25C on Ser 215 , and inhibits Cdc25C phosphatase , preventing entry into mitosis , leading to cell cycle arrest in G1 phase .	In turn, activated Chk2 phosphorylates downstream substrates, including Cdc25A on serine 123 and Cdc25C on Ser 215, and inhibits Cdc25C phosphatase, preventing entry into mitosis, leading to cell cycle arrest in G1 phase.	3	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk2	Chk2	Chk2	Cdc25C	Cdc25C	Cdc25C	4	5	22	23
These kinases phosphorylate and activate Chk1 and Chk2 , which in turn phosphorylate and inactivate Cdc25C phosphatase resulting in blocking the activation of Cdk1 and transition into mitosis XREF_BIBR - XREF_BIBR .	These kinases phosphorylate and activate Chk1 and Chk2, which in turn phosphorylate and inactivate Cdc25C phosphatase resulting in blocking the activation of Cdk1 and transition into mitosis XREF_BIBR - XREF_BIBR.	4	16	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk2	Chk2	Chk2	Cdc25C	Cdc25C	Cdc25C	7	8	15	16
Chk1 and Chk2 in turn phosphorylate and inactivate CDC25C , targeting it for proteasomal degradation .	Chk1 and Chk2 in turn phosphorylate and inactivate CDC25C, targeting it for proteasomal degradation.	0	9	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk2	Chk2	Chk2	CDC25C	CDC25C	CDC25C	2	3	8	9
XREF_BIBR In the p53 independent pathway , CHK1 and CHK2 can inhibit the function of Cdc25C phosphatase through phosphorylation , leading to increase of p-CDK1 , an inactive form of CDK1 .	XREF_BIBR In the p53 independent pathway, CHK1 and CHK2 can inhibit the function of Cdc25C phosphatase through phosphorylation, leading to increase of p-CDK1, an inactive form of CDK1.	7	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK2	CHK2	CHK2	Cdc25C	Cdc25C	Cdc25C	9	10	15	16
After activation by ATM and ATR , both Chk1 and Cds1 phosphorylate and inactivate the vertebrate Cdc25 orthologue Cdc25C .	After activation by ATM and ATR, both Chk1 and Cds1 phosphorylate and inactivate the vertebrate Cdc25 orthologue Cdc25C.	8	19	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cds1	Cds1	Cds1	Cdc25C	Cdc25C	Cdc25C	10	11	18	19
CHK1 and CHK2 kinases are activated at G2-phase checkpoint by DNA damage or unreplicated chromosomal DNA , and inactivate Cdc25C through its phosphorylation .	CHK1 and CHK2 kinases are activated at G2-phase checkpoint by DNA damage or unreplicated chromosomal DNA, and inactivate Cdc25C through its phosphorylation.	0	20	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK2	CHK2	CHK2	Cdc25C	Cdc25C	Cdc25C	2	3	19	20
CHK2 negatively regulates CDC25C through S216 phosphorylation , which creates a binding site for 14-3-3 and results in cytoplasmic sequestration and proteasome degradation .	CHK2 negatively regulates CDC25C through S216 phosphorylation, which creates a binding site for 14-3-3 and results in cytoplasmic sequestration and proteasome degradation.	0	16	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK2	CHK2	CHK2	CDC25C	CDC25C	CDC25C	0	1	3	4
These data confirm that Chk2 induced Cdc25C degradation is required for CPT induced G 2 / M phase arrest by activating proteasome pathway .	These data confirm that Chk2 induced Cdc25C degradation is required for CPT induced G 2 / M phase arrest by activating proteasome pathway.	4	7	induced	Positive_early_activation	Positive_activation	Negative_activation	Chk2	Chk2	Chk2	Cdc25C	Cdc25C	Cdc25C	4	5	6	7
Chk1 inhibition augments p53 pathway activation and facilitates DNA DSBs formation in co-treatments with NAs .	Chk1 inhibition augments p53 pathway activation and facilitates DNA DSBs formation in co-treatments with NAs.	0	5	augments	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	0	1	3	4
Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53 mutated B-lymphoid cells .	Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53 mutated B-lymphoid cells.	0	10	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	TP53	TP53	TP53	0	1	9	10
As CK1delta and Chk1 are known to inhibit p53 via phosphorylation , pharmacological inhibition of both kinases resulted in activation of p53 similar to the effect of the MDM2 inhibitor nutlin-3 [ XREF_BIBR ] .	As CK1delta and Chk1 are known to inhibit p53 via phosphorylation, pharmacological inhibition of both kinases resulted in activation of p53 similar to the effect of the MDM2 inhibitor nutlin-3 [XREF_BIBR].	1	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	3	4	8	9
Following a 48 hour exposure of Chk1 depleted HCT116 p53-/- cells to thymidine , there was little change in the level of the cleaved caspase 2 relative to cells treated with the control siRNA while more robust levels of cleaved caspase 3 were evident ( XREF_FIG ) .	Following a 48 hour exposure of Chk1 depleted HCT116 p53-/- cells to thymidine, there was little change in the level of the cleaved caspase 2 relative to cells treated with the control siRNA while more robust levels of cleaved caspase 3 were evident (XREF_FIG).	4	10	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53-/-	p53-/-	p53-/-	6	7	9	10
Here we show that inhibition of Chk1 with GNE-783 following DNA damage induced with gemcitabine rapidly drives p53 defective cells into mitosis and enhances DNA damage , chromosome fragmentation , and cell death .	Here we show that inhibition of Chk1 with GNE-783 following DNA damage induced with gemcitabine rapidly drives p53 defective cells into mitosis and enhances DNA damage, chromosome fragmentation, and cell death.	4	19	drives	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	6	7	17	18
Altogether , our results demonstrate that , in tetraploid tumor cells , the inhibition of Chk1 sequentially triggers aberrant mitosis , p53 activation and Puma and BBC3 dependent mitochondrial apoptosis .	Altogether, our results demonstrate that, in tetraploid tumor cells, the inhibition of Chk1 sequentially triggers aberrant mitosis, p53 activation and Puma and BBC3 dependent mitochondrial apoptosis.	13	22	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	15	16	21	22
Chk1 inhibition significantly augments apoptosis in both p53-wt and p53 mutated cells .	Chk1 inhibition significantly augments apoptosis in both p53-wt and p53 mutated cells.	0	10	augments	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	0	1	9	10
The inhibition of the cell cycle checkpoint kinase CHK1 , which is activated by ATR in response to replication stress , impairs the ability of P53 knockdown to rescue the vascular defect promoted by TNFRSF1A in zebrafish embryos and further induces the expression of P21 in TNFalpha treated HUVECs , indicating that CHK1 might be downstream of P53 in the apoptotic signaling pathway triggered by TNFRSF1A in endothelial cells or , alternatively , it might inhibit a P53 independent apoptotic pathway in these cells .	The inhibition of the cell cycle checkpoint kinase CHK1, which is activated by ATR in response to replication stress, impairs the ability of P53 knockdown to rescue the vascular defect promoted by TNFRSF1A in zebrafish embryos and further induces the expression of P21 in TNFalpha treated HUVECs, indicating that CHK1 might be downstream of P53 in the apoptotic signaling pathway triggered by TNFRSF1A in endothelial cells or, alternatively, it might inhibit a P53 independent apoptotic pathway in these cells.	4	26	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cell cycle checkpoint kinase	cell cycle checkpoint kinase	cell cycle checkpoint kinase	P53	P53	P53	4	8	25	26
Moreover , Chk1 , but not Chk2 , also blocks a caspase-2-dependent apoptotic response independently of p53 , Bcl-2 , and caspase-3 .	Moreover, Chk1, but not Chk2, also blocks a caspase-2-dependent apoptotic response independently of p53, Bcl-2, and caspase-3.	2	21	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	2	3	16	17
Chk1 inhibition activated p53 regulated transcripts including Puma and BBC3 in tetraploid but not in diploid tumor cells .	Chk1 inhibition activated p53 regulated transcripts including Puma and BBC3 in tetraploid but not in diploid tumor cells.	0	5	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	0	1	3	4
Moreover , Chk1 inhibition alone induces only a slight p53 and p21 induction , while a strong induction of both proteins is observed by the combination with doxorubicin .	Moreover, Chk1 inhibition alone induces only a slight p53 and p21 induction, while a strong induction of both proteins is observed by the combination with doxorubicin.	2	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	2	3	9	10
Next , we downregulated a series of p53 target genes that were strongly induced by Chk1 inhibition in tetraploid cells ( XREF_SUPPLEMENTARY ) .	Next, we downregulated a series of p53 target genes that were strongly induced by Chk1 inhibition in tetraploid cells (XREF_SUPPLEMENTARY).	7	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	15	16	7	8
Strikingly , loss of Chk1 activated the checkpoint kinase Chk2 as well as the tumor suppressor p53 in these thymocytes .	Strikingly, loss of Chk1 activated the checkpoint kinase Chk2 as well as the tumor suppressor p53 in these thymocytes.	2	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk1	loss of Chk1	chk1	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	4	5	14	17
These data are consistent with the recent study showing that CHK1 loss can activate p53 [ XREF_BIBR ] and that CHK2 loss does not prevent Ser20 site phosphorylation [ XREF_BIBR ] .	These data are consistent with the recent study showing that CHK1 loss can activate p53 [XREF_BIBR] and that CHK2 loss does not prevent Ser20 site phosphorylation [XREF_BIBR].	10	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK1	CHK1	CHK1	p53	p53	p53	10	11	14	15
Although we have shown that the loss of Chk1 results in p53 upregulation and apoptosis , and previous work has demonstrated that only the p53 deficient DT-40 tumor cell line is able to tolerate Chk1 deletion , our results clearly show that the coincident deletion of p53 did not rescue the Chk1 null phenotype in the mouse small intestine , indicating that perhaps an alternative apoptotic pathway is activated by Chk1 loss .	Although we have shown that the loss of Chk1 results in p53 upregulation and apoptosis, and previous work has demonstrated that only the p53 deficient DT-40 tumor cell line is able to tolerate Chk1 deletion, our results clearly show that the coincident deletion of p53 did not rescue the Chk1 null phenotype in the mouse small intestine, indicating that perhaps an alternative apoptotic pathway is activated by Chk1 loss.	6	13	upregulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	Chk1	loss of Chk1	chk1	p53	p53	p53	8	9	11	12
Inhibitors of the G2-M regulatory proteins ATR , Wee1 and Chk1 have been shown to have increased activity when used as single agents , and also promote sensitization of p53 deficient cancer cells to DNA damaging agents .	Inhibitors of the G2-M regulatory proteins ATR, Wee1 and Chk1 have been shown to have increased activity when used as single agents, and also promote sensitization of p53 deficient cancer cells to DNA damaging agents.	0	32	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	10	11	29	30
Unlike the intrinsic pathway , the Chk1 suppressed response to replication inhibitors does not require p53 or Chk2 .	Unlike the intrinsic pathway, the Chk1 suppressed response to replication inhibitors does not require p53 or Chk2.	5	17	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	6	7	15	16
On the contrary , here we show that the inhibition of Chk1 can activate p53 , as indicated by an increased p53 phosphorylation and an increased transcription of p53 target genes .	On the contrary, here we show that the inhibition of Chk1 can activate p53, as indicated by an increased p53 phosphorylation and an increased transcription of p53 target genes.	9	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	11	12	14	15
In agreement with the previous report , cleaved caspase 2 was detected in Chk1 depleted HCT116 p53-/- cells exposed to 10 Gy IR while cleaved caspase 3 was not evident ( XREF_FIG ) .	In agreement with the previous report, cleaved caspase 2 was detected in Chk1 depleted HCT116 p53-/- cells exposed to 10 Gy IR while cleaved caspase 3 was not evident (XREF_FIG).	11	17	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53-/-	p53-/-	p53-/-	13	14	16	17
33 To determine whether the cells showing phosphorylation of Aurora B also showed phosphorylation of histone H3 , CHK1 depleted HCT116 p53-/- cells treated with thymidine for 24h were fixed and stained for pSer10-histone H3 and pThr232 Aurora B content using mouse anti-pSer10 histone H3 and rabbit anti-phospho Aurora kinase antibodies .	33 To determine whether the cells showing phosphorylation of Aurora B also showed phosphorylation of histone H3, CHK1 depleted HCT116 p53-/- cells treated with thymidine for 24h were fixed and stained for pSer10-histone H3 and pThr232 Aurora B content using mouse anti-pSer10 histone H3 and rabbit anti-phospho Aurora kinase antibodies.	13	22	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK1	phosphorylation of histone H3, CHK1	chk1	p53-/-	p53-/-	p53-/-	18	19	21	22
Furthermore , knockdown of Chk1 also increased LDM mediated apoptotic cell death in p53 knockout cells with activation of caspase-2 and caspase-3 .	Furthermore, knockdown of Chk1 also increased LDM mediated apoptotic cell death in p53 knockout cells with activation of caspase-2 and caspase-3.	2	15	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	4	5	13	14
These results thus support the hypothesis that inhibitors of ATR , Chk1 , or Wee1 can be used to selectively target p53 deficient lung cancer cells .	These results thus support the hypothesis that inhibitors of ATR, Chk1, or Wee1 can be used to selectively target p53 deficient lung cancer cells.	7	25	target	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	11	12	21	22
Cleaved caspase 2 was not detected in Chk1 depleted p53 +/+ HCT116 cells following thymidine treatment ( XREF_FIG ) .	Cleaved caspase 2 was not detected in Chk1 depleted p53 +/+ HCT116 cells following thymidine treatment (XREF_FIG).	5	10	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	p53	p53	p53	7	8	9	10
p21 WAF1 and/or p16 INK4A both inhibit the activity of cyclin dependent protein kinases ( CDKs ) that phosphorylate and inactivate the Retinoblastoma protein ( Rb ) , leading to accumulation of the hypo phosphorylated , active form of Rb that mediates cell-cycle arrest and other phenotypes of senescence .	p21 WAF1 and/or p16 INK4A both inhibit the activity of cyclin dependent protein kinases (CDKs) that phosphorylate and inactivate the Retinoblastoma protein (Rb), leading to accumulation of the hypo phosphorylated, active form of Rb that mediates cell-cycle arrest and other phenotypes of senescence.	0	40	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p21 WAF1	p21 WAF1	p21 WAF1	Rb	Rb	Rb	0	2	39	40
More recently another role for p21 waf1 and cip1 was suggested in that p21 waf1 and cip1 can activate retinoblastoma protein ( Rb ) via dephosphorylation and yet inactivate Rb via degradation , suggesting it can regulate cell cycle progression and/or arrest XREF_BIBR .	More recently another role for p21 waf1 and cip1 was suggested in that p21 waf1 and cip1 can activate retinoblastoma protein (Rb) via dephosphorylation and yet inactivate Rb via degradation, suggesting it can regulate cell cycle progression and/or arrest XREF_BIBR.	16	31	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cip1	cip1	cip1	Rb	Rb	Rb	16	17	29	30
Abundant intra-nuclear p21 expression underlies decreased pituitary tumor development in Pttg deficient Rb +/- mice .	Abundant intra-nuclear p21 expression underlies decreased pituitary tumor development in Pttg deficient Rb +/- mice.	2	14	underlies	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p21	p21 expression	p21	Rb	Rb	rb	2	3	12	13
Rb is inhibited by p21 , an important target gene of p53 .	Rb is inhibited by p21, an important target gene of p53.	0	9	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	p21	p21	p21	Rb	Rb	Rb	4	5	0	1
B7-H4 promoted the proliferation of SiHa and HeLa cells , and protected them from apoptosis , which was related to the upregulation of E7 , phosphorylated Rb ( pRb ) , E2F , P16 , P21 , Bcl-2 and the downregulation of Rb , cleaved PARP and cleaved caspase-3 as determined by western blotting .	B7-H4 promoted the proliferation of SiHa and HeLa cells, and protected them from apoptosis, which was related to the upregulation of E7, phosphorylated Rb (pRb), E2F, P16, P21, Bcl-2 and the downregulation of Rb, cleaved PARP and cleaved caspase-3 as determined by western blotting.	35	43	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	P21	P21	P21	Rb	Rb	Rb	35	36	42	43
In these cells , curcumin reversibly up-regulates Cip1 expressions and inactivates pRB and thus arrests them in G0 phase of cell cycle .	In these cells, curcumin reversibly up-regulates Cip1 expressions and inactivates pRB and thus arrests them in G0 phase of cell cycle.	4	12	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cip1	curcumin reversibly up-regulates Cip1 expressions	cip1	pRB	pRB	prb	7	8	11	12
H ( 2 ) O ( 2 ) and TGF-beta1 and -beta2 markedly enhanced the expression of p21 but downregulated pRb .	H (2) O (2) and TGF-beta1 and -beta2 markedly enhanced the expression of p21 but downregulated pRb.	9	21	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p21	TGF-beta1 and -beta2 markedly enhanced the expression of p21	p21	pRb	pRb	prb	17	18	20	21
This might be resulted from the up-regulation of p21 Cip1 and Waf1 because p21 Cip1 and Waf1 mediates pRb protein degradation .	This might be resulted from the up-regulation of p21 Cip1 and Waf1 because p21 Cip1 and Waf1 mediates pRb protein degradation.	13	20	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p21 Cip1	p21 Cip1	p21 Cip1	pRb	pRb	pRb	13	15	18	19
Collectively , p21 mediated suppression of cyclin and CDK functions , degradation of pRB , and inhibition of PCNA result in activation of G1/S and S-phase checkpoints .	Collectively, p21 mediated suppression of cyclin and CDK functions, degradation of pRB, and inhibition of PCNA result in activation of G1/S and S-phase checkpoints.	2	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p21	p21	p21	pRB	pRB	pRB	2	3	13	14
XREF_BIBR Independent of p21 , EGF-receptor stimulation has been shown to inactivate Rb directly by phosphorylation in cultured enterocytes .	XREF_BIBR Independent of p21, EGF-receptor stimulation has been shown to inactivate Rb directly by phosphorylation in cultured enterocytes.	1	13	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p21	p21	p21	Rb	Rb	Rb	3	4	12	13
Knockdown of ArhGAP11A caused CDKN1B and p27 mediated arrest in the G1 phase of the cell cycle , whereas depletion of RacGAP1 inhibited growth through the combined effects of cytokinesis failure , CDKN1A and p21 mediated RB1 inhibition , and the onset of senescence .	Knockdown of ArhGAP11A caused CDKN1B and p27 mediated arrest in the G1 phase of the cell cycle, whereas depletion of RacGAP1 inhibited growth through the combined effects of cytokinesis failure, CDKN1A and p21 mediated RB1 inhibition, and the onset of senescence.	32	37	mediated	Positive_early_activation	Positive_activation	Negative_activation	p21	p21	p21	RB1	RB1	RB1	34	35	36	37
We further determined that BMP4 mediates RPE senescence via activation of Smad and p38 pathways to activate p53 , and increase expression of p21 WAF1 / cip1 , and to decrease phospho-Rb .	We further determined that BMP4 mediates RPE senescence via activation of Smad and p38 pathways to activate p53, and increase expression of p21 WAF1 / cip1, and to decrease phospho-Rb.	4	32	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p21 WAF1	BMP4 mediates RPE senescence via activation of Smad and p38 pathways to activate p53, and increase expression of p21 WAF1	p21 waf1	phospho-Rb	phospho-Rb	phospho-rb	23	25	31	32
p21 also inactivates pRB through proteasome mediated degradation , independent of its effect on cyclin and CDK complexes [ XREF_BIBR ] .	p21 also inactivates pRB through proteasome mediated degradation, independent of its effect on cyclin and CDK complexes [XREF_BIBR].	0	4	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p21	p21	p21	pRB	pRB	pRB	0	1	3	4
p21 inhibits cyclin dependent kinases ( CDKs ) that phosphorylate and inactivate RB to allow progression from G1 to S phase of cell cycle .	p21 inhibits cyclin dependent kinases (CDKs) that phosphorylate and inactivate RB to allow progression from G1 to S phase of cell cycle.	0	13	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p21	p21	p21	RB	RB	RB	0	1	12	13
In addition , p21 competes with cyclin D1 in the combination with CDK4 to prevent Rb from being phosphorylated , leading to a block at the G1 phase .	In addition, p21 competes with cyclin D1 in the combination with CDK4 to prevent Rb from being phosphorylated, leading to a block at the G1 phase.	3	16	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p21	p21	p21	Rb	Rb	Rb	3	4	15	16
Instead , it involved increased p21 levels , decreased phospho-Rb and p63 .	Instead, it involved increased p21 levels, decreased phospho-Rb and p63.	5	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p21	p21 levels	p21	phospho-Rb	phospho-Rb	phospho-rb	5	6	9	10
Notably , middle aged wild-type lungs were abundant in senescent markers , with increased p53 and p21 cip , decreased Rb , and no change in p16 INK4A , compared to younger controls ( XREF_SUPPLEMENTARY ) .	Notably, middle aged wild-type lungs were abundant in senescent markers, with increased p53 and p21 cip, decreased Rb, and no change in p16 INK4A, compared to younger controls (XREF_SUPPLEMENTARY).	16	24	decreased	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	p21	p21	p21	Rb	Rb	Rb	16	17	20	21
Interestingly , these studies revealed that the phosphorylation of Chk1 at Ser 317 and Ser345 not only promotes full activation of Chk1 , but also induces degradation of Chk1 through the ubiquitin-proteasome pathway .	Interestingly, these studies revealed that the phosphorylation of Chk1 at Ser 317 and Ser345 not only promotes full activation of Chk1, but also induces degradation of Chk1 through the ubiquitin-proteasome pathway.	7	29	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	phosphorylation of Chk1 at Ser 317 and Ser345	chk1	Chk1	Chk1	chk1	9	10	28	29
Consistent with phosphorylation of Chk1 at S345 triggering ubiquitin mediated degradation of Chk1 , we observed a decrease in total Chk1 protein in response to treatment with gemcitabine and MK8776 ( with or without radiation ) .	Consistent with phosphorylation of Chk1 at S345 triggering ubiquitin mediated degradation of Chk1, we observed a decrease in total Chk1 protein in response to treatment with gemcitabine and MK8776 (with or without radiation).	2	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	phosphorylation of Chk1 at S345 triggering ubiquitin	chk1	Chk1	Chk1	chk1	4	5	12	13
Immunoblotting analysis demonstrated that UCN-01 alone or in combination with irinotecan affects the ATR mediated phosphorylation of Chk1 and PKC directly blocking the activation of the Chk1 target CDC25C , confirming the contribution of several targets in determining the response of CRC-SCs to UCN-01 .	Immunoblotting analysis demonstrated that UCN-01 alone or in combination with irinotecan affects the ATR mediated phosphorylation of Chk1 and PKC directly blocking the activation of the Chk1 target CDC25C, confirming the contribution of several targets in determining the response of CRC-SCs to UCN-01.	13	28	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	ATR mediated phosphorylation of Chk1	chk1	Chk1	Chk1	chk1	17	18	26	27
Further results show that Chk1 , a key regulator of the cell cycle arrest , is important for this since ablation of mTOR prevents DNA damage induced Chk1 phosphorylation and decreases Chk1 protein production .	Further results show that Chk1, a key regulator of the cell cycle arrest, is important for this since ablation of mTOR prevents DNA damage induced Chk1 phosphorylation and decreases Chk1 protein production.	22	33	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	mTOR prevents DNA damage induced Chk1 phosphorylation	chk1	Chk1	Chk1	chk1	27	28	31	32
The slightly increased phosphorylation of Chk1 in the Chk1-NP peptide treated cells may have triggered Chk1 degradation .	The slightly increased phosphorylation of Chk1 in the Chk1-NP peptide treated cells may have triggered Chk1 degradation.	3	16	triggered	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	Chk1	phosphorylation of Chk1	chk1	Chk1	Chk1	chk1	5	6	15	16
RP Sahu et al also found that silencing ATM or Chk1 expression abrogated ATM ( pSer-1981 ) and Chk1 ( pSer-345 ) activations in curcumin treated human pancreatic cancer cells and subsequently prevented the cells from undergoing G2/M cell cycle arrest XREF_BIBR .	RP Sahu et al also found that silencing ATM or Chk1 expression abrogated ATM (pSer-1981) and Chk1 (pSer-345) activations in curcumin treated human pancreatic cancer cells and subsequently prevented the cells from undergoing G2/M cell cycle arrest XREF_BIBR.	10	20	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1 expression	chk1	Chk1	Chk1	chk1	10	11	18	19
Impairment of CHK1 function has been described in PTEN-null contexts as a consequence of AKT phosphorylation of CHK1 on S280 promoting a partial delocalization of CHK1 from the nucleus to the cytoplasm .	Impairment of CHK1 function has been described in PTEN-null contexts as a consequence of AKT phosphorylation of CHK1 on S280 promoting a partial delocalization of CHK1 from the nucleus to the cytoplasm.	14	26	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	AKT phosphorylation of CHK1 on S280	chk1	CHK1	CHK1	chk1	17	18	25	26
Phosphorylation of Chk1 at serine 317 and 345 by ATR promotes Chk1 activation but also induces the ubiquitin-proteasome dependent degradation of Chk1 [ XREF_BIBR - XREF_BIBR ] .	Phosphorylation of Chk1 at serine 317 and 345 by ATR promotes Chk1 activation but also induces the ubiquitin-proteasome dependent degradation of Chk1 [XREF_BIBR - XREF_BIBR].	0	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Phosphorylation of Chk1 at serine 317 and 345	chk1	Chk1	Chk1	chk1	2	3	21	22
Examination of PLK1 and CHK1 phosphorylation in TMZ treated cells revealed elevated PLK1 activation and diminished CHK1 activation in the IDH1 mutant astrocytes .	Examination of PLK1 and CHK1 phosphorylation in TMZ treated cells revealed elevated PLK1 activation and diminished CHK1 activation in the IDH1 mutant astrocytes.	2	17	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK1	CHK1 phosphorylation	chk1	CHK1	CHK1	chk1	4	5	16	17
It was also reported that Akt induced phosphorylation of Chk1 on S280 in non hematopoietic cells , which prevented activation of Chk1 by inducing cytoplasmic translocation and ubiquitination XREF_BIBR , XREF_BIBR , although it has been later reported that Chk1 inhibition by Akt was not mediated by Chk1 phosphorylation on S280 XREF_BIBR , XREF_BIBR .	It was also reported that Akt induced phosphorylation of Chk1 on S280 in non hematopoietic cells, which prevented activation of Chk1 by inducing cytoplasmic translocation and ubiquitination XREF_BIBR, XREF_BIBR, although it has been later reported that Chk1 inhibition by Akt was not mediated by Chk1 phosphorylation on S280 XREF_BIBR, XREF_BIBR.	39	49	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Chk1	Chk1 phosphorylation	chk1	Chk1	Chk1	chk1	47	48	39	40
CBP-93872 decreased phospho-cdc2 Y15 by inhibiting phosphorylation of Chk1 , but did not suppress phospho-Chk2 or the kinase activities of either Chk1 or Chk2 in cellular or cell-free assays .	CBP-93872 decreased phospho-cdc2 Y15 by inhibiting phosphorylation of Chk1, but did not suppress phospho-Chk2 or the kinase activities of either Chk1 or Chk2 in cellular or cell-free assays.	0	23	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	CBP-93872 decreased phospho-cdc2 Y15 by inhibiting phosphorylation of Chk1	chk1	Chk1	Chk1	chk1	8	9	21	22
Recent studies suggest that at least three mechanisms inactivate Chk1 in vertebrate cells : ( 1 ) SCF beta-Trcp1 -mediated degradation of Claspin , an essential mediator during the ATR induced Chk1 phosphorylation ; ( 2 ) dephosphorylation of activated Chk1 by PP1 , PP2A , or PP2C type phosphatases ; and ( 3 ) Cul1 or Cul4A dependent degradation of Chk1 , as described in this paper and elsewhere .	Recent studies suggest that at least three mechanisms inactivate Chk1 in vertebrate cells : (1) SCF beta-Trcp1 -mediated degradation of Claspin, an essential mediator during the ATR induced Chk1 phosphorylation; (2) dephosphorylation of activated Chk1 by PP1, PP2A, or PP2C type phosphatases; and (3) Cul1 or Cul4A dependent degradation of Chk1, as described in this paper and elsewhere.	37	62	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Chk1	dephosphorylation of activated Chk1 by PP1, PP2A, or PP2C type phosphatases; and (3) Cul1	chk1	Chk1	Chk1	chk1	40	41	61	62
In our mathematical model , Chk1 inhibits Cdk1 by modulating the activities of Wee1 and Cdc25 ( bottom panel in XREF_FIG ) .	In our mathematical model, Chk1 inhibits Cdk1 by modulating the activities of Wee1 and Cdc25 (bottom panel in XREF_FIG).	5	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	5	6	13	14
The G2 DNA damage checkpoint inhibits Cdc2 and mitotic entry through the dual regulation of Wee1 and Cdc25 by the Chk1 effector kinase .	The G2 DNA damage checkpoint inhibits Cdc2 and mitotic entry through the dual regulation of Wee1 and Cdc25 by the Chk1 effector kinase.	5	22	inhibits	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	20	21	15	16
A well established role of Chk1 both in the response to DNA damage and also during the MBT in Drosophila is to inhibit Cdk1 by either activating Wee1 or inhibiting Cdc25 .	A well established role of Chk1 both in the response to DNA damage and also during the MBT in Drosophila is to inhibit Cdk1 by either activating Wee1 or inhibiting Cdc25.	3	28	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	5	6	27	28
Neuroblastoma is uniquely sensitive to single-agent inhibition of the DNA damage checkpoint kinase Chk1 , leading us to examine downstream effectors of this pathway and identify mitotic regulator Wee1 as an additional therapeutic target in this disease .	Neuroblastoma is uniquely sensitive to single-agent inhibition of the DNA damage checkpoint kinase Chk1, leading us to examine downstream effectors of this pathway and identify mitotic regulator Wee1 as an additional therapeutic target in this disease.	6	29	leading	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	13	14	28	29
Once activated , Chk1 inhibits the entry into mitosis by modulating Cdc25 and Wee1 , which coordinately regulate Cdc2-cyclin B , a critical inducer of mitosis .	Once activated, Chk1 inhibits the entry into mitosis by modulating Cdc25 and Wee1, which coordinately regulate Cdc2-cyclin B, a critical inducer of mitosis.	3	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Wee1	Wee1	Wee1	3	4	13	14
CHK1 depletion largely prevented the formation of RAD51 foci after HU .	CHK1 depletion largely prevented the formation of RAD51 foci after HU.	0	8	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	RAD51	RAD51	RAD51	0	1	7	8
Depletion of the damage response kinases 39 ataxia-telangiectasia mutated ( ATM ) , ATM-and-Rad53-like ( ATR ) , or CHK1 diminished the nuclear enrichment of RAD51 following MMC exposure , confirming that this response depends on the cellular pathways that sense and signal DNA damage ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Depletion of the damage response kinases 39 ataxia-telangiectasia mutated (ATM), ATM-and-Rad53-like (ATR), or CHK1 diminished the nuclear enrichment of RAD51 following MMC exposure, confirming that this response depends on the cellular pathways that sense and signal DNA damage (XREF_FIG, XREF_SUPPLEMENTARY).	7	28	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK1	CHK1	CHK1	RAD51	RAD51	RAD51	19	20	25	26
Our data suggest the inhibition of this Chk1 mediated Rad51 response to Gem induced replication stress is an important factor in determining Gem chemosensitization by Chk1 inhibition in pancreatic cancer cells .	Our data suggest the inhibition of this Chk1 mediated Rad51 response to Gem induced replication stress is an important factor in determining Gem chemosensitization by Chk1 inhibition in pancreatic cancer cells.	4	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Rad51	Rad51	Rad51	7	8	9	10
Inhibition of Chk1 mediated Rad51 responses to gemcitabine induced replication stress also contributes to chemosensitization by PD-321852 .	Inhibition of Chk1 mediated Rad51 responses to gemcitabine induced replication stress also contributes to chemosensitization by PD-321852.	0	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Rad51	Rad51	Rad51	2	3	4	5
Instead , our recent data demonstrate a stronger correlation between sensitization to gemcitabine by Chk1 inhibition and depletion of Rad51 protein , inhibition of Rad51 focus formation , and increased gamma-H2AX .	Instead, our recent data demonstrate a stronger correlation between sensitization to gemcitabine by Chk1 inhibition and depletion of Rad51 protein, inhibition of Rad51 focus formation, and increased gamma-H2AX.	14	20	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Rad51	Rad51	Rad51	14	15	19	20
Overexpression of CHK2 promoted pre-mRNA splicing and pre-mRNA splicing activity was decreased in CHK2 knockdown cells compared to control cells .	Overexpression of CHK2 promoted pre-mRNA splicing and pre-mRNA splicing activity was decreased in CHK2 knockdown cells compared to control cells.	0	15	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK2	Overexpression of CHK2	chk2	CHK2	CHK2	chk2	2	3	13	14
Blocking Chk2 activation by DN-Chk2 completely protected cells from DIM mediated G ( 2 )/M arrest .	Blocking Chk2 activation by DN-Chk2 completely protected cells from DIM mediated G (2)/M arrest.	1	5	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	DN-Chk2	DN-Chk2	DN-Chk2	Chk2	Chk2	Chk2	4	5	1	2
In response to DNA damage , ataxia telangiectasia mutated ( ATM ) phosphorylates the Chk2 tumour suppressor kinase at threonine 68 ( Thr68 ) , allowing Chk2 kinase dimerization and activation by autophosphorylations in the T-loop .	In response to DNA damage, ataxia telangiectasia mutated (ATM) phosphorylates the Chk2 tumour suppressor kinase at threonine 68 (Thr68), allowing Chk2 kinase dimerization and activation by autophosphorylations in the T-loop.	6	28	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Chk2	ataxia telangiectasia mutated (ATM) phosphorylates the Chk2 tumour suppressor kinase at threonine	chk2	Chk2	Chk2	chk2	14	15	26	27
Caffeine does not inhibit Chk2 and Cds1 activity directly , but rather , blocks the activation of Chk2 and Cds1 by inhibiting ATM kinase activity .	Caffeine does not inhibit Chk2 and Cds1 activity directly, but rather, blocks the activation of Chk2 and Cds1 by inhibiting ATM kinase activity.	6	19	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cds1	Cds1	Cds1	Chk2	Chk2	Chk2	6	7	17	18
Chk1 and 2 then inactivate Cdc25A , Cdc25B , and Cdc25C phosphatases via destruction or relocalization , resulting in elevated inhibitory phosphorylation of Cdk2 on Thr14 and Tyr15 .	Chk1 and 2 then inactivate Cdc25A, Cdc25B, and Cdc25C phosphatases via destruction or relocalization, resulting in elevated inhibitory phosphorylation of Cdk2 on Thr14 and Tyr15.	0	8	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25B	Cdc25B	Cdc25B	0	1	7	8
During interphase , the checkpoint kinase Chk1 negatively regulates CDC25B and prevents premature mitotic entry [ XREF_BIBR , XREF_BIBR ] .	During interphase, the checkpoint kinase Chk1 negatively regulates CDC25B and prevents premature mitotic entry [XREF_BIBR, XREF_BIBR].	3	11	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	CDC25B	CDC25B	CDC25B	6	7	9	10
Thus , CHK1 and MK2 mediate inactivation of CDC25B and induce a cell cycle arrest by blocking CDC25B dependent CDK activation [ XREF_BIBR ] .	Thus, CHK1 and MK2 mediate inactivation of CDC25B and induce a cell cycle arrest by blocking CDC25B dependent CDK activation [XREF_BIBR].	2	10	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CHK1	CHK1	CHK1	CDC25B	CDC25B	CDC25B	2	3	8	9
In addition , Chk1 phosphorylates and , thus , inhibits actions of Cdc25B and Cdc25C phosphatases .	In addition, Chk1 phosphorylates and, thus, inhibits actions of Cdc25B and Cdc25C phosphatases.	3	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25B	Cdc25B	Cdc25B	3	4	12	13
Genetic removal of both Cdo and Boc activity abrogates Shh signaling in the developing neural tube ; however , the loss of these components does not affect signaling in other Hh responsive tissues , including the developing limb .	Genetic removal of both Cdo and Boc activity abrogates Shh signaling in the developing neural tube; however, the loss of these components does not affect signaling in other Hh responsive tissues, including the developing limb.	1	10	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdo	Cdo	Cdo	Shh	Shh	Shh	4	5	9	10
Third , Shh signalling is not grossly affected in Cdo depleted P19 cells in the early stages of neurogenesis , a time point when Wnt signalling is upregulated as well as the modulation of Shh signalling by the treatment with an activator or inhibitor does not specifically affect Wnt signalling ( XREF_SUPPLEMENTARY ) .	Third, Shh signalling is not grossly affected in Cdo depleted P19 cells in the early stages of neurogenesis, a time point when Wnt signalling is upregulated as well as the modulation of Shh signalling by the treatment with an activator or inhibitor does not specifically affect Wnt signalling (XREF_SUPPLEMENTARY).	9	35	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdo	Cdo	Cdo	Shh	Shh	Shh	9	10	34	35
When expressed in a Ptc1-complementary pattern in optic vesicle , however , Cdo functions as a decoy receptor , negatively regulating Shh signaling to demarcate optic stalk and retina boundary .	When expressed in a Ptc1-complementary pattern in optic vesicle, however, Cdo functions as a decoy receptor, negatively regulating Shh signaling to demarcate optic stalk and retina boundary.	12	22	negatively regulating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdo	Cdo	Cdo	Shh	Shh	Shh	12	13	21	22
These data indicate that cdr2 normally sequesters c-Myc in the neuronal cytoplasm , thereby down-regulating c-Myc activity , and suggest a mechanism whereby inhibition of cdr2 function by autoantibodies in PCD may contribute to Purkinje neuronal death .	These data indicate that cdr2 normally sequesters c-Myc in the neuronal cytoplasm, thereby down-regulating c-Myc activity, and suggest a mechanism whereby inhibition of cdr2 function by autoantibodies in PCD may contribute to Purkinje neuronal death.	4	8	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cdr2	cdr2	cdr2	c-Myc	c-Myc	c-Myc	4	5	7	8
Cdr2 sequesters c-myc and prevents it from inducing transcription .	Cdr2 sequesters c-myc and prevents it from inducing transcription.	0	4	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdr2	Cdr2	Cdr2	c-myc	c-myc	c-myc	0	1	2	3
Studies suggest that CDR2 sequesters c-Myc in the neuronal cytoplasm and down regulates its activity .	Studies suggest that CDR2 sequesters c-Myc in the neuronal cytoplasm and down regulates its activity.	3	12	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDR2	CDR2	CDR2	c-Myc	c-Myc	c-Myc	3	4	5	6
Nevertheless , 3-MB-PP1 treatment of Cdk7 as/as cells caused a > 50 % decrease in Cdk4 and Cdk6 activity , relative to the matched , DMSO treated control , within 30 min , whereas Cdk2 retained the majority of its activity after 3 hr ( XREF_FIG ) .	Nevertheless, 3-MB-PP1 treatment of Cdk7 as/as cells caused a> 50% decrease in Cdk4 and Cdk6 activity, relative to the matched, DMSO treated control, within 30 min, whereas Cdk2 retained the majority of its activity after 3 hr (XREF_FIG).	5	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk7	Cdk7	Cdk7	Cdk4	Cdk4	Cdk4	5	6	15	16
Another study in Cdk7 as HCT116 cells showed that Cdk7 inhibition caused rapid inactivation of Cdk4 and Cdk6 ( in agreement with our results ) but loss of Cdk4 T-loop phosphorylation only in the population bound to the CDK inhibitor p21 .	Another study in Cdk7 as HCT116 cells showed that Cdk7 inhibition caused rapid inactivation of Cdk4 and Cdk6 (in agreement with our results) but loss of Cdk4 T-loop phosphorylation only in the population bound to the CDK inhibitor p21.	9	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk7	Cdk7	Cdk7	Cdk4	Cdk4	Cdk4	9	10	15	16
Here , we show that reduced expression and/or the absence of Chk2 allow Brca1 ( delta11 and delta11 ) mice to escape from embryonic lethality .	Here, we show that reduced expression and/or the absence of Chk2 allow Brca1 (delta11 and delta11) mice to escape from embryonic lethality.	9	17	allow	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Chk2	Chk2	Chk2	Brca1	Brca1	Brca1	11	12	13	14
As noted in XREF_FIG , although Chk2 deletion can rescue the Brca1 Delta11 / Delta11 embryonic lethality , Brca1 Delta11 / Delta11 Chk2 -/- MEFs appear to prematurely senesce at the same elevated rate as Brca1 Delta11 / Delta11 cells .	As noted in XREF_FIG, although Chk2 deletion can rescue the Brca1 Delta11 / Delta11 embryonic lethality, Brca1 Delta11 / Delta11 Chk2 -/- MEFs appear to prematurely senesce at the same elevated rate as Brca1 Delta11 / Delta11 cells.	6	12	rescue	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk2	Chk2	Chk2	Brca1	Brca1	Brca1	6	7	11	12
These results suggest that Chk1 prevents deleterious anaphase bridges by stabilising BLM .	These results suggest that Chk1 prevents deleterious anaphase bridges by stabilising BLM.	4	12	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	BLM	BLM	BLM	4	5	11	12
Conversely , the abrogation of endogenous Chk1 expression by Chk1 AS or Chk1 siRNA led to decreased BLM accumulation ( XREF_FIG ) .	Conversely, the abrogation of endogenous Chk1 expression by Chk1 AS or Chk1 siRNA led to decreased BLM accumulation (XREF_FIG).	3	18	led	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	Chk1	abrogation of endogenous Chk1 expression by Chk1 AS or Chk1 siRNA	chk1	BLM	BLM	blm	6	7	17	18
In Xenopus extracts , depletion of CENP-E prevents MAD2 localization to kinetochores , and thus the extracts fail to arrest in mitosis when spindle assembly is inhibited .	In Xenopus extracts, depletion of CENP-E prevents MAD2 localization to kinetochores, and thus the extracts fail to arrest in mitosis when spindle assembly is inhibited.	4	9	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CENP-E	CENP-E	CENP-E	MAD2	MAD2	MAD2	6	7	8	9
In contrast , Chk1 phosphorylation at Ser 345 was transiently reduced 6hs -but not 24hs- post-UV in FANCD2 depleted U2OS and in PD20 cells ( Figs XREF_FIG and XREF_SUPPLEMENTARY ) .	In contrast, Chk1 phosphorylation at Ser 345 was transiently reduced 6hs -but not 24hs- post-UV in FANCD2 depleted U2OS and in PD20 cells (Figs XREF_FIG and XREF_SUPPLEMENTARY).	3	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1 phosphorylation at Ser 345	chk1	FANCD2	FANCD2	fancd2	3	4	17	18
Since preliminary DNA damage had the same effects on unscheduled origin firing as Cdc7 kinase inhibitor , we propose that an ATR and Chk1 kinase dependent mechanism induced in cells prevents Cdc7 from phosphorylating its substrates at the pre-RC .	Since preliminary DNA damage had the same effects on unscheduled origin firing as Cdc7 kinase inhibitor, we propose that an ATR and Chk1 kinase dependent mechanism induced in cells prevents Cdc7 from phosphorylating its substrates at the pre-RC.	21	32	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc7	Cdc7	Cdc7	23	24	31	32
We found that the expression of Mib1 down-regulated the protein level of CDKL5 by ubiquitination , and antagonized CDKL5 function during the formation of dendritic spines .	We found that the expression of Mib1 down-regulated the protein level of CDKL5 by ubiquitination, and antagonized CDKL5 function during the formation of dendritic spines.	4	19	antagonized	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CDKL5	expression of Mib1 down-regulated the protein level of CDKL5	cdkl5	CDKL5	CDKL5	cdkl5	12	13	18	19
Inhibition of Mcs6 or Cdk9 Promotes Crosslinking of Spt5 to Chromatin .	Inhibition of Mcs6 or Cdk9 Promotes Crosslinking of Spt5 to Chromatin.	0	9	Promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cdk9	Cdk9	Cdk9	Spt5	Spt5	Spt5	4	5	8	9
Since kinase activity and the checkpoint are silenced following CENP-E-dependent microtubule attachment in extracts or binding of CENP-E antibodies that do not disrupt CENP-E association with BubR1 , CENP-E mediates silencing of BubR1 signaling .	Since kinase activity and the checkpoint are silenced following CENP-E-dependent microtubule attachment in extracts or binding of CENP-E antibodies that do not disrupt CENP-E association with BubR1, CENP-E mediates silencing of BubR1 signaling.	28	33	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CENP-E	CENP-E	CENP-E	BubR1	BubR1	BubR1	28	29	32	33
We further investigated the impact of CAK inhibition on UV induced transactivation of cellular p21 waf1 and DDB2 genes and their upstream regulator p53 using real-time RT-PCR .	We further investigated the impact of CAK inhibition on UV induced transactivation of cellular p21 waf1 and DDB2 genes and their upstream regulator p53 using real-time RT-PCR.	6	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CAK	CAK	CAK	p53	p53	p53	6	7	23	24
Depletion of CEP290 diminishes the localization of Rab8a to centrosomes and prevents its entry into the cilium .	Depletion of CEP290 diminishes the localization of Rab8a to centrosomes and prevents its entry into the cilium.	0	8	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CEP290	CEP290	CEP290	Rab8a	Rab8a	Rab8a	2	3	7	8
Taken together , these results suggest that Aurora-A modulates CHK1 activity through PLK1 triggered Claspin degradation .	Taken together, these results suggest that Aurora-A modulates CHK1 activity through PLK1 triggered Claspin degradation.	9	15	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CHK1	CHK1	CHK1	Claspin	Claspin	Claspin	9	10	14	15
Moreover , IKKalpha can attenuate IKKbeta initiated inflammatory responses .	Moreover, IKKalpha can attenuate IKKbeta initiated inflammatory responses.	2	6	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	2	3	5	6
While IKKalpha is known to inhibit IKKbeta and NF-kappaB in immune cells XREF_BIBR , this has not been reported for post-mitotic neurons .	While IKKalpha is known to inhibit IKKbeta and NF-kappaB in immune cells XREF_BIBR, this has not been reported for post-mitotic neurons.	1	8	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	1	2	6	7
Here we demonstrate that assembly of IKKalpha with IKKbeta in the heterodimeric signalsome serves two important functions : ( i ) in unstimulated cells , IKKalpha inhibits the constitutive IkappaB kinase activity of IKKbeta ; ( ii ) in activated cells , IKKalpha kinase activity is required for the induction of IKKbeta .	Here we demonstrate that assembly of IKKalpha with IKKbeta in the heterodimeric signalsome serves two important functions : (i) in unstimulated cells, IKKalpha inhibits the constitutive IkappaB kinase activity of IKKbeta; (ii) in activated cells, IKKalpha kinase activity is required for the induction of IKKbeta.	25	34	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	25	26	33	34
As shown in Figure XREF_FIG , oral intake of apigenin at doses of 20 and 50 mug resulted in marked reduction in the protein expression of IKKalpha and its phosphorylation , NF-kB and p65 whereas a modest decrease in p-IKKbeta in PC-3 and 22Rv1 tumor xenografts .	As shown in Figure XREF_FIG, oral intake of apigenin at doses of 20 and 50 mug resulted in marked reduction in the protein expression of IKKalpha and its phosphorylation, NF-kB and p65 whereas a modest decrease in p-IKKbeta in PC-3 and 22Rv1 tumor xenografts.	24	40	decrease	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	IKKalpha	expression of IKKalpha	ikkalpha	p-IKKbeta	p-IKKbeta	p-ikkbeta	26	27	39	40
In contrast , IKKalpha functions in the activation of a specific form of NF-kappaB in response to a subset of TNF family members and may also serve to attenuate IKKbeta driven NF-kappaB activation .	In contrast, IKKalpha functions in the activation of a specific form of NF-kappaB in response to a subset of TNF family members and may also serve to attenuate IKKbeta driven NF-kappaB activation.	3	30	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	3	4	29	30
In contrast , IKKalpha can repress IKKbeta activity and reduces the production of inflammatory cytokines XREF_BIBR .	In contrast, IKKalpha can repress IKKbeta activity and reduces the production of inflammatory cytokines XREF_BIBR.	3	9	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	3	4	6	7
Moreover , IKKalpha has anti-inflammatory properties and can inhibit the IKKbeta and NF-kappaB activity and lower the expression of inflammatory cytokines XREF_BIBR , XREF_BIBR .	Moreover, IKKalpha has anti-inflammatory properties and can inhibit the IKKbeta and NF-kappaB activity and lower the expression of inflammatory cytokines XREF_BIBR, XREF_BIBR.	2	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	2	3	10	11
Thus , IKKalpha may prevent Htt proteolysis independent of IKKbeta by modulating expression and/or activation of gene products that antagonize the toxic effects of DNA damage .	Thus, IKKalpha may prevent Htt proteolysis independent of IKKbeta by modulating expression and/or activation of gene products that antagonize the toxic effects of DNA damage.	2	10	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	2	3	9	10
IKKalpha , on the other hand , may act as a brake to suppress excessive IKKbeta activation and reduce neurotoxicity ( XREF_FIG ) .	IKKalpha, on the other hand, may act as a brake to suppress excessive IKKbeta activation and reduce neurotoxicity (XREF_FIG).	0	18	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	0	1	15	16
Importantly , in unstimulated cells , assembly of IKK1 with IKK2 into a heterodimeric complex inhibits the high intrinsic activity of IKK2 [ XREF_BIBR ] .	Importantly, in unstimulated cells, assembly of IKK1 with IKK2 into a heterodimeric complex inhibits the high intrinsic activity of IKK2 [XREF_BIBR].	6	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKK1	IKK1	IKK1	IKK2	IKK2	IKK2	8	9	21	22
Loss of IKK1 prolongs the activation of IKK2 and promotes inflammation [ XREF_BIBR ] .	Loss of IKK1 prolongs the activation of IKK2 and promotes inflammation [XREF_BIBR].	0	8	prolongs	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IKK1	Loss of IKK1	ikk1	IKK2	IKK2	ikk2	2	3	7	8
IKKalpha is known to inhibit the activity of IKKbeta in various models .	IKKalpha is known to inhibit the activity of IKKbeta in various models.	0	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	IKKbeta	IKKbeta	IKKbeta	0	1	8	9
Treatment of cells with or without siIKKalpha and beta and siRaf-1 demonstrated that phospho-NF-kB p65 S536 and COX-2 were selectively attenuated by IKKalpha and beta knockdown whereas Raf-1 knockdown diminished phosphorylation of ERK T185 and Y187 , MYPT1 T696 and MLC2 T18 and S19 but not COX-2 ( XREF_SUPPLEMENTARY ) .	Treatment of cells with or without siIKKalpha and beta and siRaf-1 demonstrated that phospho-NF-kB p65 S536 and COX-2 were selectively attenuated by IKKalpha and beta knockdown whereas Raf-1 knockdown diminished phosphorylation of ERK T185 and Y187, MYPT1 T696 and MLC2 T18 and S19 but not COX-2 (XREF_SUPPLEMENTARY).	14	24	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	p65	p65	p65	22	23	14	15
At basal levels , p65 is sequestered in the cytoplasm by its inhibitors IKKalpha and beta and IkappaB .	At basal levels, p65 is sequestered in the cytoplasm by its inhibitors IKKalpha and beta and IkappaB.	4	17	sequestered	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	p65	p65	p65	13	14	4	5
IKKalpha has been shown to suppress NF-kappaB activation by accelerating the turnover of RelA and C-Rel , and inactivation of IKKalpha , in contrast with inactivation of the canonical NF-kappaB pathway , can lead to enhanced inflammation .	IKKalpha has been shown to suppress NF-kappaB activation by accelerating the turnover of RelA and C-Rel, and inactivation of IKKalpha, in contrast with inactivation of the canonical NF-kappaB pathway, can lead to enhanced inflammation.	0	15	suppress	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	RelA	RelA	RelA	0	1	13	14
Consistent with this , we find that both GCN5 and the IkappaB Kinase ( IKK ) complex promote RelA degradation .	Consistent with this, we find that both GCN5 and the IkappaB Kinase (IKK) complex promote RelA degradation.	11	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB Kinase	IkappaB Kinase	IkappaB Kinase	RelA	RelA	RelA	11	13	18	19
As expected , either IKKalpha or beta partially attenuated canonical nuclear RELA and NF-kappaB reporter activity , while dual inhibition had the most potent effects ( XREF_FIG ) .	As expected, either IKKalpha or beta partially attenuated canonical nuclear RELA and NF-kappaB reporter activity, while dual inhibition had the most potent effects (XREF_FIG).	3	15	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	RELA	RELA	RELA	4	5	11	12
Previous work has shown that the other IKK catalytic subunit , IKKalpha , suppresses NF-kappaB activation by accelerating the turnover of NF-kappaB subunits RelA and c-Rel and thus their removal from proinflammatory gene promoters .	Previous work has shown that the other IKK catalytic subunit, IKKalpha, suppresses NF-kappaB activation by accelerating the turnover of NF-kappaB subunits RelA and c-Rel and thus their removal from proinflammatory gene promoters.	9	25	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	IKKalpha	IKKalpha	RelA	RelA	RelA	11	12	23	24
As shown in XREF_FIG , both PDTC and emodin inhibited the phosphorylations of IKKalpha and beta and IkappaBalpha and prevented IkappaBalpha degradation and disappearance of cytosolic p65 .	As shown in XREF_FIG, both PDTC and emodin inhibited the phosphorylations of IKKalpha and beta and IkappaBalpha and prevented IkappaBalpha degradation and disappearance of cytosolic p65.	8	27	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKalpha	emodin inhibited the phosphorylations of IKKalpha	ikkalpha	p65	p65	p65	13	14	26	27
Using small interfering RNA technology , we have shown that down-regulation of Claspin expression inhibits Chk1 activation in response to replication stress .	Using small interfering RNA technology, we have shown that down-regulation of Claspin expression inhibits Chk1 activation in response to replication stress.	12	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Claspin	Claspin expression	claspin	Chk1	Chk1	chk1	12	13	15	16
Yoo and colleagues showed that Xenopus Plx1 phosphorylates the checkpoint mediator protein Claspin at Ser934 to promote dissociation of Claspin from chromatin and thus inactivation of Chk1 .	Yoo and colleagues showed that Xenopus Plx1 phosphorylates the checkpoint mediator protein Claspin at Ser934 to promote dissociation of Claspin from chromatin and thus inactivation of Chk1.	5	27	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Claspin	Xenopus Plx1 phosphorylates the checkpoint mediator protein Claspin at Ser934	claspin	Chk1	Chk1	chk1	12	13	26	27
Significantly , removal of Claspin from egg extracts only partially abrogates the activation of Chk1 in response to chromatin with DSBs , whereas depletion of both Claspin and BRCA1 completely abolishes this activation .	Significantly, removal of Claspin from egg extracts only partially abrogates the activation of Chk1 in response to chromatin with DSBs, whereas depletion of both Claspin and BRCA1 completely abolishes this activation.	2	16	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Claspin	Claspin	Claspin	Chk1	Chk1	Chk1	4	5	14	15
Furthermore , the Mrc1 human homolog CLASPIN is targeted for degradation in response to HU treatment , thereby promoting CHK1 inactivation .	Furthermore, the Mrc1 human homolog CLASPIN is targeted for degradation in response to HU treatment, thereby promoting CHK1 inactivation.	2	20	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CLASPIN	CLASPIN	CLASPIN	CHK1	CHK1	CHK1	6	7	19	20
CHK1 is inhibited at the normal G2/M transition by Polo like kinase ( PLK ) 1 mediated phosphorylation and degradation of claspin XREF_BIBR , XREF_BIBR , a key regulator of CHK1 activity , as well as by CDK1 and CyclinB dependent inhibitory phosphorylation events in late G2 , triggering nuclear export of CHK1 and therefore limiting substrate accessibility 18 .	CHK1 is inhibited at the normal G2/M transition by Polo like kinase (PLK) 1 mediated phosphorylation and degradation of claspin XREF_BIBR, XREF_BIBR, a key regulator of CHK1 activity, as well as by CDK1 and CyclinB dependent inhibitory phosphorylation events in late G2, triggering nuclear export of CHK1 and therefore limiting substrate accessibility 18.	0	22	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	claspin	Polo like kinase (PLK) 1 mediated phosphorylation and degradation of claspin	claspin	CHK1	CHK1	chk1	21	22	0	1
Following a prolonged ATR activation , Plx1 mediated phosphorylation of Claspin induces attenuation of ATR- and Chk1 dependent signalling allowing mitosis onset .	Following a prolonged ATR activation, Plx1 mediated phosphorylation of Claspin induces attenuation of ATR- and Chk1 dependent signalling allowing mitosis onset.	6	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Claspin	Plx1 mediated phosphorylation of Claspin	claspin	Chk1	Chk1	chk1	10	11	16	17
We found that knockdown of IKKalpha enhanced nuclear accumulation of p52 and Rel B by an unknown mechanism .	We found that knockdown of IKKalpha enhanced nuclear accumulation of p52 and Rel B by an unknown mechanism.	3	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	p52	p52	p52	5	6	10	11
In the non canonical pathway , IKKalpha initiates processing of inhibitory p100 to functional p52 [ XREF_BIBR ] .	In the non canonical pathway, IKKalpha initiates processing of inhibitory p100 to functional p52 [XREF_BIBR].	6	12	initiates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	6	7	11	12
The noncanonical activation of p50 : RelA dimers by TNF related receptors appears to occur through NIK and IKKalpha mediated p100 degradation ( XREF_FIG ) [ XREF_BIBR ] .	The noncanonical activation of p50 : RelA dimers by TNF related receptors appears to occur through NIK and IKKalpha mediated p100 degradation (XREF_FIG) [XREF_BIBR].	14	21	mediated	Positive_early_activation	Positive_activation	Negative_activation	IKKalpha	IKKalpha	IKKalpha	p100	p100	p100	18	19	20	21
In addition to the canonical pathway of NF-kappaB activation mentioned above , in immune cells and under certain stimuli such as lymphtoxin-alpha and beta , CD40L , and B-cell activating factor belonging to the tumor necrosis factor ( TNF ) family ( BAFF ) , there exists an alternative pathway that requires NF-kappaB-interacting kinase ( NIK ) and IKK1 homodimer mediated slow processing of p100 into p52 followed by nuclear translocation of RelB and p52 dimer ( 4 , reviewed in Sun , this volume ) .	In addition to the canonical pathway of NF-kappaB activation mentioned above, in immune cells and under certain stimuli such as lymphtoxin-alpha and beta, CD40L, and B-cell activating factor belonging to the tumor necrosis factor (TNF) family (BAFF), there exists an alternative pathway that requires NF-kappaB-interacting kinase (NIK) and IKK1 homodimer mediated slow processing of p100 into p52 followed by nuclear translocation of RelB and p52 dimer (4, reviewed in Sun, this volume).	58	65	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKK1	IKK1	IKK1	p100	p100	p100	58	59	64	65
Notably , while NIK -/- and IKK1 AA ( see above ) mice both present strong impairments in p100 processing and associated defects in GC formation , defects in the follicular and MZ B-cell compartments in these mice are less severe than those observed in Baff and Baff-R -/- or Ikk1 -/- mice .	Notably, while NIK -/- and IKK1 AA (see above) mice both present strong impairments in p100 processing and associated defects in GC formation, defects in the follicular and MZ B-cell compartments in these mice are less severe than those observed in Baff and Baff-R -/- or Ikk1 -/- mice.	6	19	impairments	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	IKK1	IKK1	IKK1	p100	p100	p100	6	7	18	19
IKKalpha phosphorylation induces the polyubiquitination and proteasomal degradation of the NF-kappaB2 ( p100 ) precursor to the active form p52 ( Maruyama et al ., 2010 ) .	IKKalpha phosphorylation induces the polyubiquitination and proteasomal degradation of the NF-kappaB2 (p100) precursor to the active form p52 (Maruyama et al., 2010).	0	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKalpha	IKKalpha phosphorylation	ikkalpha	NF-kappaB2	NF-kappaB2	nf-kappab2	0	1	10	11
Chk2 phosphorylation of the pRB protein at Ser612 has been reported to activate its pro apoptotic function ( Inoue etal ., 2007 ) thus , the possibility exists that CHEK2 non sense mutations may inactivate pRB function in addition to inactivating the p53 pathway .	Chk2 phosphorylation of the pRB protein at Ser612 has been reported to activate its pro apoptotic function (Inoue etal., 2007) thus, the possibility exists that CHEK2 non sense mutations may inactivate pRB function in addition to inactivating the p53 pathway.	29	36	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CHEK2	CHEK2	CHEK2	pRB	pRB	pRB	29	30	35	36
CNK1 mediates AKT dependent inhibition of CRAF in EGF stimulated cells .	CNK1 mediates AKT dependent inhibition of CRAF in EGF stimulated cells.	0	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CNK1	CNK1	CNK1	CRAF	CRAF	CRAF	0	1	6	7
CSF-1 starvation of BMM produced an increase in primary Csf1r transcripts from the promoter and also from FIRE , paralleled by increased association of active RNA Pol II.	CSF-1 starvation of BMM produced an increase in primary Csf1r transcripts from the promoter and also from FIRE, paralleled by increased association of active RNA Pol II.	0	10	produced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CSF-1	CSF-1	CSF-1	Csf1r	Csf1r	Csf1r	0	1	9	10
Interestingly , and despite the fact that CSF1 signaling down-regulates Csf1r mRNA by acting on the anti-sense promoter activity of FIRE XREF_BIBR , XREF_BIBR a heterozygous knockout of Csf1r in mice 44 and rats ( CP , DAH , Manuscript in preparation ) is not dosage compensated and produces a 50 % reduction in Csf1r mRNA .	Interestingly, and despite the fact that CSF1 signaling down-regulates Csf1r mRNA by acting on the anti-sense promoter activity of FIRE XREF_BIBR, XREF_BIBR a heterozygous knockout of Csf1r in mice 44 and rats (CP, DAH, Manuscript in preparation) is not dosage compensated and produces a 50% reduction in Csf1r mRNA.	7	11	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CSF1	CSF1	CSF1	Csf1r	Csf1r	Csf1r	7	8	10	11
Since myeloid cells themselves control the circulating availability of CSF-1 depletion of CSF-1R expressing Ly6C + monocytes in Ccr2 -/- mice or MC21 treated animals could potentially alter the availability of the factor .	Since myeloid cells themselves control the circulating availability of CSF-1 depletion of CSF-1R expressing Ly6C + monocytes in Ccr2 -/- mice or MC21 treated animals could potentially alter the availability of the factor.	9	13	depletion	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	9	10	12	13
The wide expression of the CSF-1 and CSF-1R pair across breast cancer cell subtypes supports CSF-1 and CSF-1R targeting in breast cancer therapy .	The wide expression of the CSF-1 and CSF-1R pair across breast cancer cell subtypes supports CSF-1 and CSF-1R targeting in breast cancer therapy.	5	18	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	5	6	17	18
XREF_BIBR CSF1 signaling can be abrogated using inhibitors of the protein tyrosine kinase activity of the CSF1 receptor or by exogenous application of molecules that block CSF1 ligand-receptor binding .	XREF_BIBR CSF1 signaling can be abrogated using inhibitors of the protein tyrosine kinase activity of the CSF1 receptor or by exogenous application of molecules that block CSF1 ligand-receptor binding.	1	18	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CSF1	CSF1	CSF1	CSF1 receptor	CSF1 receptor	CSF1 receptor	1	2	16	18
The wide expression of CSF-1 and CSF-1R pair across breast cancer cell subtypes supports CSF-1 and CSF-1R targeting in breast cancer therapy .	The wide expression of CSF-1 and CSF-1R pair across breast cancer cell subtypes supports CSF-1 and CSF-1R targeting in breast cancer therapy.	4	17	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CSF-1	CSF-1	CSF-1	CSF-1R	CSF-1R	CSF-1R	4	5	16	17
In each case , addition of CSF1 down-regulated surface CSF1R ( XREF_FIG ) .	In each case, addition of CSF1 down-regulated surface CSF1R (XREF_FIG).	4	11	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CSF1	CSF1	CSF1	CSF1R	CSF1R	CSF1R	6	7	9	10
We used CRH receptor antagonists ( alpha-helical CRH 9-41 and astressin ) that block both CRH-R1 and CRH-R2 ( reviewed in ) to determine whether the CRH- and UCNI mediated increases in intracellular cAMP were specifically mediated by CRH receptors .	We used CRH receptor antagonists (alpha-helical CRH 9-41 and astressin) that block both CRH-R1 and CRH-R2 (reviewed in) to determine whether the CRH- and UCNI mediated increases in intracellular cAMP were specifically mediated by CRH receptors.	2	17	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CRH	CRH	CRH	CRH-R1	CRH-R1	CRH-R1	2	3	15	16
with CRH can down-regulate its own CRHR1 receptor .	with CRH can down-regulate its own CRHR1 receptor.	1	7	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CRH	CRH	CRH	CRHR1	CRHR1	CRHR1	1	2	6	7
Following the demonstration of Ucn mRNA production by C-20/A4 cells the presence of functional endogenous Ucn production was confirmed by CRFR receptor blockade ( by alpha-helical CRH ( 9-41 ) , a competitive inhibitor of both CRFR1 and CRFR2 receptor subclasses ) and the specific depletion of Ucn ligand released into the culture medium ( using an Ucn specific antibody ) .	Following the demonstration of Ucn mRNA production by C-20/A4 cells the presence of functional endogenous Ucn production was confirmed by CRFR receptor blockade (by alpha-helical CRH (9-41), a competitive inhibitor of both CRFR1 and CRFR2 receptor subclasses) and the specific depletion of Ucn ligand released into the culture medium (using an Ucn specific antibody).	20	33	blockade	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	CRH	CRH	CRH	CRFR	CRFR	CRFR	26	27	20	21
CBP treatment , however , can not reduce the NF-kappaB p65 content of the tissues .	CBP treatment, however, can not reduce the NF-kappaB p65 content of the tissues.	0	11	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CBP	CBP	CBP	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	0	1	9	11
Together , these experiments show that NSC-127102 suppresses the stimulation of p65 by CBP , but does not inhibit the stimulation of CREB by CBP .	Together, these experiments show that NSC-127102 suppresses the stimulation of p65 by CBP, but does not inhibit the stimulation of CREB by CBP.	7	14	stimulation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	CBP	CBP	CBP	p65	p65	p65	13	14	11	12
Past studies have demonstrated that an increased association of CREB and CBP suppresses NF-kappaB p65 activity .	Past studies have demonstrated that an increased association of CREB and CBP suppresses NF-kappaB p65 activity.	7	15	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CBP	CBP	CBP	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	11	12	13	15
The inhibitory effect of p65 on VDR transactivation was not due to recruitment of a histone deacetylase ( HDAC ) , since inhibition was not relieved by the HDAC inhibitors sodium butyrate or trichostatin A. Overexpression of SRC-1 or the general coactivators , Creb binding protein or SRC-3 , also failed to relieve p65 inhibition of transcription .	The inhibitory effect of p65 on VDR transactivation was not due to recruitment of a histone deacetylase (HDAC), since inhibition was not relieved by the HDAC inhibitors sodium butyrate or trichostatin A. Overexpression of SRC-1 or the general coactivators, Creb binding protein or SRC-3, also failed to relieve p65 inhibition of transcription.	43	54	relieve	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Creb binding protein	Creb binding protein	Creb binding protein	p65	p65	p65	43	46	53	54
However , c-Src activation ( pY418 ) did not change during this time period ( XREF_FIG ) , indicating that Cbp overexpression does not inhibit total c-Src kinase activity .	However, c-Src activation (pY418) did not change during this time period (XREF_FIG), indicating that Cbp overexpression does not inhibit total c-Src kinase activity.	20	28	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cbp	Cbp overexpression	cbp	c-Src kinase	c-Src kinase	c-src kinase	20	21	26	28
However , a recent study has shown that Cbp and Pag1 itself inhibits Src activity independently of Csk .	However, a recent study has shown that Cbp and Pag1 itself inhibits Src activity independently of Csk.	8	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cbp	Cbp	Cbp	Csk	Csk	Csk	8	9	17	18
Finally , RPTPalpha induced phosphorylation of Paxillin and Cbp and PAG induces recruitment of the SFK inhibitory kinase Csk , indicative of negative feedback loops limiting SFK activation by RPTPalpha .	Finally, RPTPalpha induced phosphorylation of Paxillin and Cbp and PAG induces recruitment of the SFK inhibitory kinase Csk, indicative of negative feedback loops limiting SFK activation by RPTPalpha.	2	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Cbp	RPTPalpha induced phosphorylation of Paxillin and Cbp	cbp	Csk	Csk	csk	8	9	18	19
CBP and PAG suppresses T cell receptor activation by recruiting CSK and it has been revealed that the phosphorylation of CBP and PAG Tyr314 creates a docking site for the CSK SH2 domain .	CBP and PAG suppresses T cell receptor activation by recruiting CSK and it has been revealed that the phosphorylation of CBP and PAG Tyr314 creates a docking site for the CSK SH2 domain.	0	11	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CBP	CBP	CBP	CSK	CSK	CSK	0	1	10	11
Certain proteins such as hPIP ( human PAK1 interacting protein 1 ) and CRIPAK ( Cys rich inhibitor of PAK1 ) may act to prevent such PAK kinase activation .	Certain proteins such as hPIP (human PAK1 interacting protein 1) and CRIPAK (Cys rich inhibitor of PAK1) may act to prevent such PAK kinase activation.	1	24	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	CRIPAK	CRIPAK	CRIPAK	PAK1	PAK1	PAK1	13	14	19	20
In vitro methylation of Creb3l1 promoter-luciferase constructs by CpG methyltransferase blocked activation of the Creb3l1 promoter by overexpression of Nr4a1 .	In vitro methylation of Creb3l1 promoter-luciferase constructs by CpG methyltransferase blocked activation of the Creb3l1 promoter by overexpression of Nr4a1.	2	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Creb3l1	methylation of Creb3l1	creb3l1	Creb3l1	Creb3l1	creb3l1	4	5	14	15
Absence of CORT not only prevented the obesity induced increase in ghrelin , In1-ghrelin and GHS-R transcripts but also caused a significant reduction in the expression of these transcripts ( black columns in XREF_FIG ) .	Absence of CORT not only prevented the obesity induced increase in ghrelin, In1-ghrelin and GHS-R transcripts but also caused a significant reduction in the expression of these transcripts (black columns in XREF_FIG).	0	16	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CORT	CORT	CORT	GHS-R	GHS-R	GHS-R	2	3	15	16
Finally , CSK protein expression was decreased 72 +/- 11 % in HAEC-hT using CSK targeted shRNA ( XREF_SUPPLEMENTARY ) .	Finally, CSK protein expression was decreased 72 +/- 11% in HAEC-hT using CSK targeted shRNA (XREF_SUPPLEMENTARY).	2	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CSK	CSK protein expression	csk	CSK	CSK	csk	2	3	14	15
Activation of mGluR2/3 couples to the inhibition of PKA and decreases phosphorylation of Ser364 on Csk , thereby inhibiting Csk activity .	Activation of mGluR2/3 couples to the inhibition of PKA and decreases phosphorylation of Ser364 on Csk, thereby inhibiting Csk activity.	2	20	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Csk	mGluR2/3 couples to the inhibition of PKA and decreases phosphorylation of Ser364 on Csk	csk	Csk	Csk	csk	15	16	19	20
Therefore we tested whether recombinant Csk could inhibit CfrSrc .	Therefore we tested whether recombinant Csk could inhibit CfrSrc.	4	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Csk	Csk	Csk	CfrSrc	CfrSrc	CfrSrc	5	6	8	9
Overexpression of Csk in these transformed cells caused reversion to normal phenotypes and also reduced the level of c-Src kinase activity .	Overexpression of Csk in these transformed cells caused reversion to normal phenotypes and also reduced the level of c-Src kinase activity.	0	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Csk	Overexpression of Csk	csk	c-Src kinase	c-Src kinase	c-src kinase	2	3	18	20
Longdaysin inhibited the CKIdelta mediated PER2-LUC degradation in a dose dependent manner ( XREF_SUPPLEMENTARY ) , suggesting its role in regulating both PER1 and PER2 stabilities through CKIdelta and/or CKIalpha .	Longdaysin inhibited the CKIdelta mediated PER2-LUC degradation in a dose dependent manner (XREF_SUPPLEMENTARY), suggesting its role in regulating both PER1 and PER2 stabilities through CKIdelta and/or CKIalpha.	1	6	mediated	Positive_early_activation	Positive_activation	Negative_activation	CKIdelta	CKIdelta	CKIdelta	PER2-LUC	PER2-LUC	PER2-LUC	3	4	5	6
The resulting reduction in SDF-1 in bone marrow promotes mobilization of CXCR4 + cells , including Treg cells , to peripheral blood .	The resulting reduction in SDF-1 in bone marrow promotes mobilization of CXCR4 + cells, including Treg cells, to peripheral blood.	2	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	4	5	11	12
Increased CXCL12 may then down-regulate CXCR4 [ XREF_BIBR ] .	Increased CXCL12 may then down-regulate CXCR4 [XREF_BIBR].	0	7	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	1	2	5	6
Since CXCR7 acts as a CXCL12 scavenger and CXCR4 protein expression recovered in telencephalic explants that were kept in CXCL12 free conditions , it is likely that excess CXCL12 downregulates the CXCR4 protein in the telencephalon of CXCR7 deficient mice XREF_BIBR .	Since CXCR7 acts as a CXCL12 scavenger and CXCR4 protein expression recovered in telencephalic explants that were kept in CXCL12 free conditions, it is likely that excess CXCL12 downregulates the CXCR4 protein in the telencephalon of CXCR7 deficient mice XREF_BIBR.	27	32	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	28	29	31	32
Importantly , CXCL12 2 also inhibited the growth of established CXCR4 expressing B16 lung metastatic tumors , suggesting that it may have utility in treating established metastasis in humans .	Importantly, CXCL12 2 also inhibited the growth of established CXCR4 expressing B16 lung metastatic tumors, suggesting that it may have utility in treating established metastasis in humans.	2	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	10	11
At the molecular level , we found that WWP1 negatively regulates CXCL12 induced CXCR4 lysosomal degradation , leading to increased breast cancer cell migration to the bone marrow cavity , a primary site for CXCL12 biosynthesis .	At the molecular level, we found that WWP1 negatively regulates CXCL12 induced CXCR4 lysosomal degradation, leading to increased breast cancer cell migration to the bone marrow cavity, a primary site for CXCL12 biosynthesis.	11	15	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	13	14
Furthermore , AMD3100 treatment in presence of CXCL12 significantly decreased invasiveness of MCF-7 CXCR4 WT cells ( 27.6 cells and field of view , p = 0.0004 ) and MDA-MB-231 cells ( 49.4 cells and field of view ) to CXCL12 but did not inhibit invasiveness of MCF-7 CXCR4DeltaCTD cells to CXCL12 ( 100 cells and field of view , p = 0.001 ; Supplemental Figure S2c ) .	Furthermore, AMD3100 treatment in presence of CXCL12 significantly decreased invasiveness of MCF-7 CXCR4 WT cells (27.6 cells and field of view, p = 0.0004) and MDA-MB-231 cells (49.4 cells and field of view) to CXCL12 but did not inhibit invasiveness of MCF-7 CXCR4DeltaCTD cells to CXCL12 (100 cells and field of view, p = 0.001; Supplemental Figure S2c).	5	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	13	14
While CTCE-9908 specifically targets CXCL12 and AMD3100 is inhibits CXCR4 , both compounds inhibited metastatic spread of various cancers in preclinical models , underscoring the importance of CXCL12 and CXCR4 signaling in metastatic disease .	While CTCE-9908 specifically targets CXCL12 and AMD3100 is inhibits CXCR4, both compounds inhibited metastatic spread of various cancers in preclinical models, underscoring the importance of CXCL12 and CXCR4 signaling in metastatic disease.	4	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	9	10
In summary , CXCL12 2 , but not wtCXCL12 , strongly inhibited CXCR4 expressing melanoma lung metastasis .	In summary, CXCL12 2, but not wtCXCL12, strongly inhibited CXCR4 expressing melanoma lung metastasis.	3	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	12	13
The observed decrease in mono-ubiquitination of CXCR4 in resting CD4 + T cells obtained from the elderly donors , prompted us to evaluate whether CXCL12 dependent degradation of CXCR4 was also impaired in CD4 + T cells from the elderly .	The observed decrease in mono-ubiquitination of CXCR4 in resting CD4 + T cells obtained from the elderly donors, prompted us to evaluate whether CXCL12 dependent degradation of CXCR4 was also impaired in CD4 + T cells from the elderly.	24	29	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	24	25	28	29
To verify this hypothesis , cultured degenerative NPCs were treated with SDF-1 following knockdown of CXCR4 using siRNA .	To verify this hypothesis, cultured degenerative NPCs were treated with SDF-1 following knockdown of CXCR4 using siRNA.	11	16	knockdown	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	11	12	15	16
However , investigating whether CXCL12 can prevent a CXCR4 using HIV-1 gp120 from inducing neuronal apoptosis , we observed that full-length CXCL12 itself is toxic to terminally differentiated cerebrocortical neurons via a pathway that depended on CXCR4 and implicated p38 mitogen activated protein kinase ( p38 MAPK ) [ XREF_BIBR , XREF_BIBR ] .	However, investigating whether CXCL12 can prevent a CXCR4 using HIV-1 gp120 from inducing neuronal apoptosis, we observed that full-length CXCL12 itself is toxic to terminally differentiated cerebrocortical neurons via a pathway that depended on CXCR4 and implicated p38 mitogen activated protein kinase (p38 MAPK) [XREF_BIBR, XREF_BIBR].	4	9	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	8	9
Due to enhanced serum stability , this dimeric CXCL12 variant was shown to inhibit pulmonary metastasis of CXCR4 expressing melanoma cells .	Due to enhanced serum stability, this dimeric CXCL12 variant was shown to inhibit pulmonary metastasis of CXCR4 expressing melanoma cells.	8	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	17	18
( 2 ) R1R2 promotes the cleavage of the fibrocyte chemoattractant CXCL12 , thus disrupting the CXCR4 and CXCL12 axis [ XREF_BIBR ] .	(2) R1R2 promotes the cleavage of the fibrocyte chemoattractant CXCL12, thus disrupting the CXCR4 and CXCL12 axis [XREF_BIBR].	6	19	disrupting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	16	17
It has been reported that extended CXCL12 stimulation ( > = 180 min ) causes CXCR4 degradation in HEK293 cells XREF_BIBR .	It has been reported that extended CXCL12 stimulation (> = 180 min) causes CXCR4 degradation in HEK293 cells XREF_BIBR.	6	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	15	16
Perissinotto ' s study showed that high SDF-1 concentration contributed to the osteosarcoma metastatic development into the lung and inhibiting the SDF-1 and CXCR4 pathway by small-molecule inhibitors or anti-CXCR4 antibodies , T134 peptide , might prevent the dissemination of osteosarcoma cells.17 Liao et al20 found that blocking CXCR4 by AMD3100 could reduce primary tumor growth and lung metastasis .	Perissinotto 's study showed that high SDF-1 concentration contributed to the osteosarcoma metastatic development into the lung and inhibiting the SDF-1 and CXCR4 pathway by small-molecule inhibitors or anti-CXCR4 antibodies, T134 peptide, might prevent the dissemination of osteosarcoma cells.17 Liao et al20 found that blocking CXCR4 by AMD3100 could reduce primary tumor growth and lung metastasis.	7	24	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	7	8	23	24
In contrast , cells that were incubated in the presence of SDF-1 clearly exhibited a loss in receptor signal , confirming that SDF-1 induces degradation of HA-CXCR4 .	In contrast, cells that were incubated in the presence of SDF-1 clearly exhibited a loss in receptor signal, confirming that SDF-1 induces degradation of HA-CXCR4.	22	27	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	HA-CXCR4	HA-CXCR4	HA-CXCR4	22	23	26	27
It is intriguing to hypothesize that exogenous SDF-1 blocked binding of CXCR4 on canine donor cells to SDF-1 in recipient mouse muscle .	It is intriguing to hypothesize that exogenous SDF-1 blocked binding of CXCR4 on canine donor cells to SDF-1 in recipient mouse muscle.	6	12	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	7	8	11	12
We speculate that during the late stages of the viral life cycle when mostly structural proteins such as Gag are expressed , SDF-1 induced CXCR4 downregulation is attenuated resulting in the accumulation of densensitized CXCR4 within intracellular compartments .	We speculate that during the late stages of the viral life cycle when mostly structural proteins such as Gag are expressed, SDF-1 induced CXCR4 downregulation is attenuated resulting in the accumulation of densensitized CXCR4 within intracellular compartments.	22	25	induced	Positive_early_activation	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	22	23	24	25
Deubiquitination of CXCR4 by USP14 Is Critical for Both CXCL12 induced CXCR4 Degradation and Chemotaxis but Not ERK Activation * .	Deubiquitination of CXCR4 by USP14 Is Critical for Both CXCL12 induced CXCR4 Degradation and Chemotaxis but Not ERK Activation *.	6	12	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	11	12
This is associated with decreased activation of CXCR4 by CXCL12 and decreased activation of downstream signals , including ERK1/2 and Akt .	This is associated with decreased activation of CXCR4 by CXCL12 and decreased activation of downstream signals, including ERK1/2 and Akt.	5	10	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	9	10	7	8
It is possible that hepatocytes or other liver cells take up 64 Cu-4 through CXCR4 independent pathways , which are blocked by excess cold 4 , but not by SDF-1 .	It is possible that hepatocytes or other liver cells take up 64 Cu-4 through CXCR4 independent pathways, which are blocked by excess cold 4, but not by SDF-1.	14	30	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	29	30	14	15
Although basal CXC chemokine receptor 4 ( CXCR4 ) expression was similar in EPCs from the 2 age groups , the stromal cell derived factor 1 induced CXCR4 and Janus kinase 2 phosphorylations were much lower in the elderly than in young EPCs .	Although basal CXC chemokine receptor 4 (CXCR4) expression was similar in EPCs from the 2 age groups, the stromal cell derived factor 1 induced CXCR4 and Janus kinase 2 phosphorylations were much lower in the elderly than in young EPCs.	21	30	induced	Positive_early_activation	Positive_activation	Negative_activation	stromal cell derived factor 1	stromal cell derived factor 1	stromal cell derived factor 1	CXCR4	CXCR4	CXCR4	21	26	27	28
The SDF-1 effect was blocked by a specific CXCR4 inhibitor , AMD3100 , or transfection of siRNA targeting CXCR4 .	The SDF-1 effect was blocked by a specific CXCR4 inhibitor, AMD3100, or transfection of siRNA targeting CXCR4.	1	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	1	2	18	19
Thus , we conclude that CXCR7 prevents downregulation of CXCR4 by CXCL12 stimulation .	Thus, we conclude that CXCR7 prevents downregulation of CXCR4 by CXCL12 stimulation.	7	12	downregulation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	11	12	9	10
CTCE-9908 , a peptide analog of SDF-1 and competitive inhibitor of CXCR4 , reduces the size of metastatic lesions derived from MDA-MB-231 human breast cancer cells , following injection into the left cardiac ventricle of nude mice [ XREF_BIBR ] .	CTCE-9908, a peptide analog of SDF-1 and competitive inhibitor of CXCR4, reduces the size of metastatic lesions derived from MDA-MB-231 human breast cancer cells, following injection into the left cardiac ventricle of nude mice [XREF_BIBR].	6	12	inhibitor	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	6	7	11	12
Both receptors were essential for responding to CXCL12 and for regulating interneuron migration , based on experiments that studied the effect of : 1 ) ectopic CXCL12 expression ; and 2 ) pharmacological blockade of CXCR4 in Cxcr7 -/- mutants .	Both receptors were essential for responding to CXCL12 and for regulating interneuron migration, based on experiments that studied the effect of : 1) ectopic CXCL12 expression; and 2) pharmacological blockade of CXCR4 in Cxcr7 -/- mutants.	25	36	blockade	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	CXCL12	CXCL12 expression	cxcl12	CXCR4	CXCR4	cxcr4	26	27	35	36
CXCR7 mediated depletion of CXCL12 reduces acute activation of CXCR4 and its downstream signaling pathways .	CXCR7 mediated depletion of CXCL12 reduces acute activation of CXCR4 and its downstream signaling pathways.	2	14	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	9	10
The fact that apical CXCL12 enhanced migration in all PBMC groups but down-regulated CXCR4 only on monocytes suggested that monocytes selectively respond to apical CXCL12 and that monocyte interactions with endothelium may have then facilitated T and B cell transmigration .	The fact that apical CXCL12 enhanced migration in all PBMC groups but down-regulated CXCR4 only on monocytes suggested that monocytes selectively respond to apical CXCL12 and that monocyte interactions with endothelium may have then facilitated T and B cell transmigration.	3	14	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	13	14
In addition , high levels of CXCL12 in the tumor microenvironment may disrupt the CXCR4 driven chemotactic response of tumor cells towards CXCL12 expressing tissues such as bone and lung .	In addition, high levels of CXCL12 in the tumor microenvironment may disrupt the CXCR4 driven chemotactic response of tumor cells towards CXCL12 expressing tissues such as bone and lung.	4	15	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	levels of CXCL12	cxcl12	CXCR4	CXCR4	cxcr4	6	7	14	15
These data establish that CXCR7 dependent depletion of CXCL12 from the extracellular space reduces acute CXCR4 signaling .	These data establish that CXCR7 dependent depletion of CXCL12 from the extracellular space reduces acute CXCR4 signaling.	6	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	15	16
We found that the expression of WWP1 shRNA in MDA-MB-231 cells prevented CXCL12 induced CXCR4 degradation and increased CXCL12 induced cell migration , which could be responsible for the increased bone metastasis of the WWP1 knockdown cells .	We found that the expression of WWP1 shRNA in MDA-MB-231 cells prevented CXCL12 induced CXCR4 degradation and increased CXCL12 induced cell migration, which could be responsible for the increased bone metastasis of the WWP1 knockdown cells.	12	17	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	12	13	14	15
CQ partially prevented CXCL12 induced CXCR4 degradation , but MG132 had no effect ( XREF_FIG ) .	CQ partially prevented CXCL12 induced CXCR4 degradation, but MG132 had no effect (XREF_FIG).	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	5	6
Apical CXCL12 down-regulates CXCR4 on transmigrating monocytes .	Apical CXCL12 down-regulates CXCR4 on transmigrating monocytes.	0	6	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	1	2	3	4
This suggests that high CXCL12 concentrations cause cellular degradation of CXCR4 receptors .	This suggests that high CXCL12 concentrations cause cellular degradation of CXCR4 receptors.	4	11	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	10	11
The present study demonstrates that fucose containing sulfated polysaccharides ( FCSP ) from brown algae interfere with the CXCL12 and CXCR4 axis in human Burkitt ' s lymphoma cells by binding CXCL12 and thereby blocking both CXCL12 induced CXCR4 receptor activation and downstream effects like migration and secretion of matrix metalloproteinase-9 .	The present study demonstrates that fucose containing sulfated polysaccharides (FCSP) from brown algae interfere with the CXCL12 and CXCR4 axis in human Burkitt 's lymphoma cells by binding CXCL12 and thereby blocking both CXCL12 induced CXCR4 receptor activation and downstream effects like migration and secretion of matrix metalloproteinase-9.	34	40	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	36	37	38	39
Similarly , AMD3100 acts as a potent allosteric inhibitor of CXCL12 induced CXCR4 activation but does not affect receptor mediated response to CXCL12 peptide fragments with agonistic properties .	Similarly, AMD3100 acts as a potent allosteric inhibitor of CXCL12 induced CXCR4 activation but does not affect receptor mediated response to CXCL12 peptide fragments with agonistic properties.	8	13	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	10	11	12	13
This form of SDF-1 is unable to trigger CXCR4 signalling and prevent the chemoattractant function of SDF-1alpha and CXCR4 in human progenitor cells 15 .	This form of SDF-1 is unable to trigger CXCR4 signalling and prevent the chemoattractant function of SDF-1alpha and CXCR4 in human progenitor cells 15.	1	19	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	3	4	18	19
To determine if CXCL12 induced CXCR4 degradation is through a proteasome or lysosome pathway , we treated cells with the proteasome inhibitor , MG132 , or the lysosome inhibitor , chloroquine ( CQ ) , in the presence of CXCL12 .	To determine if CXCL12 induced CXCR4 degradation is through a proteasome or lysosome pathway, we treated cells with the proteasome inhibitor, MG132, or the lysosome inhibitor, chloroquine (CQ), in the presence of CXCL12.	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	5	6
Some published literature states that CXCL12 alone will not increase the proliferation of mouse cerebellum granule cells , and blocking CXCR4 with a specific antagonist impairs the growth factor induced progression of NPCs through the cell cycle [ XREF_BIBR ] .	Some published literature states that CXCL12 alone will not increase the proliferation of mouse cerebellum granule cells, and blocking CXCR4 with a specific antagonist impairs the growth factor induced progression of NPCs through the cell cycle [XREF_BIBR].	5	21	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	20	21
We observed a significant inhibition of CXCL12 induced wound healing in MCF-7 and CXCR4 , SCP2 , and NT 2.5 after overnight pretreatment with JWH-015 ( 20 microM ) compared to the vehicle treated cells ( XREF_FIG ) .	We observed a significant inhibition of CXCL12 induced wound healing in MCF-7 and CXCR4, SCP2, and NT 2.5 after overnight pretreatment with JWH-015 (20 microM) compared to the vehicle treated cells (XREF_FIG).	4	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	13	14
Unexpectedly , CXCL12 selectively down-regulated CXCR4 on transmigrating monocytes , but not T cells .	Unexpectedly, CXCL12 selectively down-regulated CXCR4 on transmigrating monocytes, but not T cells.	2	13	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	5	6
Interestingly , itch promotes CXCL12 mediated CXCR4 degradation in Hela cells [ XREF_BIBR ] .	Interestingly, itch promotes CXCL12 mediated CXCR4 degradation in Hela cells [XREF_BIBR].	3	7	mediated	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	6	7
Second , overexpression of USP14 entirely eliminated CXCL12 induced CXCR4 degradation .	Second, overexpression of USP14 entirely eliminated CXCL12 induced CXCR4 degradation.	7	10	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	7	8	9	10
We also observed that ubiquitination of CXCR4 facilitated receptor degradation , whereas overexpression of USP14 or RNAi induced knockdown of USP14 blocked CXCL12 mediated CXCR4 degradation .	We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi induced knockdown of USP14 blocked CXCL12 mediated CXCR4 degradation.	21	25	mediated	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	22	23	24	25
XREF_BIBR first highlighted that DPPIV expression suppresses the malignant phenotype of melanocytes , and others have recently demonstrated that CXCL12 and CXCR4 signaling antagonists suppress CXCR4 + pulmonary metastases in preclinical models of melanoma .	XREF_BIBR first highlighted that DPPIV expression suppresses the malignant phenotype of melanocytes, and others have recently demonstrated that CXCL12 and CXCR4 signaling antagonists suppress CXCR4 + pulmonary metastases in preclinical models of melanoma.	19	28	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	25	26
Interestingly , genetic ablation of TNFR2 causes significant downregulation of CXCL12 expression in cuprizone induced lesions and decreases the number of CXCR4 expressing OPCs .	Interestingly, genetic ablation of TNFR2 causes significant downregulation of CXCL12 expression in cuprizone induced lesions and decreases the number of CXCR4 expressing OPCs.	5	22	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	TNFR2 causes significant downregulation of CXCL12 expression	cxcl12	CXCR4	CXCR4	cxcr4	10	11	21	22
ANGPTL2 suppression in MDA-MB231 cells attenuates CXCL12 activated CXCR4 signaling and expression .	ANGPTL2 suppression in MDA-MB231 cells attenuates CXCL12 activated CXCR4 signaling and expression.	5	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	8	9
Decreased CXCR4 resulted in disrupt lymphoma and host bone marrow derived stromal cells CXCR4 and CXCL12 axis , what resulted in stroma induced protection from immunotherapy infringement .	Decreased CXCR4 resulted in disrupt lymphoma and host bone marrow derived stromal cells CXCR4 and CXCL12 axis, what resulted in stroma induced protection from immunotherapy infringement.	0	16	Decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	15	16	1	2
We reported that Wwp1 regulates CXCL12 induced CXCR4 lysosomal degradation in breast cancer cells , thereby affecting cell migration .	We reported that Wwp1 regulates CXCL12 induced CXCR4 lysosomal degradation in breast cancer cells, thereby affecting cell migration.	5	9	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	7	8
Prior to testing the inhibitory activity of IL-24 on SDF-1 induced CXCR4 signaling , we determined whether H1299-IL24 cells responded to SDF-1 .	Prior to testing the inhibitory activity of IL-24 on SDF-1 induced CXCR4 signaling, we determined whether H1299-IL24 cells responded to SDF-1.	7	12	induced	Positive_early_activation	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	9	10	11	12
CXCL12 directly inhibited the cell cycle of WT , but not Cxcr4 -/-, primitive hematopoietic cells .	CXCL12 directly inhibited the cell cycle of WT, but not Cxcr4 -/-, primitive hematopoietic cells.	0	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	Cxcr4	Cxcr4	Cxcr4	0	1	11	12
Herein , we show that intravenous CXCL12 2 treatment inhibited initial pulmonary dissemination of CXCR4 expressing B16 more effectively than the FDA approved CXCR4 inhibitor , AMD3100 .	Herein, we show that intravenous CXCL12 2 treatment inhibited initial pulmonary dissemination of CXCR4 expressing B16 more effectively than the FDA approved CXCR4 inhibitor, AMD3100.	6	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	14	15
Thus , cleavage of CXCL12 not only impairs the normal neuroprotective function of CXCR4 , but also actively leads to neuronal injury via CXCR3 .	Thus, cleavage of CXCL12 not only impairs the normal neuroprotective function of CXCR4, but also actively leads to neuronal injury via CXCR3.	2	14	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	4	5	13	14
To determine if CXCL12 induced CXCR4 degradation is through proteasome or lysosome mechanism , we treated cells with lysosomes inhibitor Chloroquine or proteasome inhibitor MG132 in the presence of CXCR12 .	To determine if CXCL12 induced CXCR4 degradation is through proteasome or lysosome mechanism, we treated cells with lysosomes inhibitor Chloroquine or proteasome inhibitor MG132 in the presence of CXCR12.	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	5	6
By analogy , positive expression of CXCL12 at the primary tumor site presumably would suppress the metastasis of CXCR4 expressing cells , which has been shown in colon 30 and breast cancer models .	By analogy, positive expression of CXCL12 at the primary tumor site presumably would suppress the metastasis of CXCR4 expressing cells, which has been shown in colon 30 and breast cancer models.	4	20	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	expression of CXCL12	cxcl12	CXCR4	CXCR4	cxcr4	6	7	18	19
However , blocking of the CXCL12 induced CXCR4 mediated signaling was not able to completely suppress tumor growth or eliminate all cancer cells [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	However, blocking of the CXCL12 induced CXCR4 mediated signaling was not able to completely suppress tumor growth or eliminate all cancer cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	9	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	7	8
The observed absence of CXCR4 translocation and CXCL12 induced proliferation and invasion in HepG2 cells , confirms earlier data , indicating a loss of chemokine CXCL12 mediated CXCR4 signalling and receptor internalisation in HepG2 cells due to a receptor defect ( Mitra et al , 2001 ) .	The observed absence of CXCR4 translocation and CXCL12 induced proliferation and invasion in HepG2 cells, confirms earlier data, indicating a loss of chemokine CXCL12 mediated CXCR4 signalling and receptor internalisation in HepG2 cells due to a receptor defect (Mitra et al, 2001).	22	28	mediated	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	25	26	27	28
Interestingly , the administration of SDF-1 siRNA or neutralizing antibody against SDF-1alpha abolished high glucose induced up-regulation of CXCR4 .	Interestingly, the administration of SDF-1 siRNA or neutralizing antibody against SDF-1alpha abolished high glucose induced up-regulation of CXCR4.	5	19	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	18	19
However , CXCR7 knockdown lead to increase significantly in the levels of extracellular SDF-1 , which in turn triggered nearly 70 % CXCR4 endocytosis and degradation , which causes detect of CXCR4-mediate functions .	However, CXCR7 knockdown lead to increase significantly in the levels of extracellular SDF-1, which in turn triggered nearly 70% CXCR4 endocytosis and degradation, which causes detect of CXCR4-mediate functions.	10	23	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF-1	levels of extracellular SDF-1	sdf-1	CXCR4	CXCR4	cxcr4	13	14	22	23
However , 6-OHDA significantly increased the level of SDF-1 ( XREF_FIG ) and reduced the production of CXCR4 ( XREF_FIG ) , COX-2 ( XREF_FIG ) , PGE2 ( XREF_FIG ) , and Treg cells ( XREF_FIG ) in bone marrow ( n = 6 ; P < 0.05 ) .	However, 6-OHDA significantly increased the level of SDF-1 (XREF_FIG) and reduced the production of CXCR4 (XREF_FIG), COX-2 (XREF_FIG), PGE2 (XREF_FIG), and Treg cells (XREF_FIG) in bone marrow (n = 6; P < 0.05).	2	34	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	6-OHDA significantly increased the level of SDF-1	sdf-1	CXCR4	CXCR4	cxcr4	8	9	17	18
We chose to target USP14 , since previous studies have reported a critical role for USP14 in CXCR4 degradation and chemotaxis mediated by CXCL12 .	We chose to target USP14, since previous studies have reported a critical role for USP14 in CXCR4 degradation and chemotaxis mediated by CXCL12.	17	24	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	23	24	17	18
Unexpectedly , the constitutively dimeric SDF-1 protein , which was employed for structural studies , blocked CXCR4 mediated chemotaxis at low nanomolar concentrations .	Unexpectedly, the constitutively dimeric SDF-1 protein, which was employed for structural studies, blocked CXCR4 mediated chemotaxis at low nanomolar concentrations.	5	18	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	5	6	16	17
First , we examined if CXCL12 induced CXCR4 degradation occurs in MDA-MB-231 cells by Western blot analysis .	First, we examined if CXCL12 induced CXCR4 degradation occurs in MDA-MB-231 cells by Western blot analysis.	5	8	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	5	6	7	8
The addition of CXCL12 induced the survival and migration of serum starved CXCR4 + LM8 cells activating JNK and Akt pathways , which were abrogated by adding AMD3100 .	The addition of CXCL12 induced the survival and migration of serum starved CXCR4 + LM8 cells activating JNK and Akt pathways, which were abrogated by adding AMD3100.	1	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	12	13
Systemic treatment of mice with a CXCL12 blocking antibody or a CXCR4 antagonist reduced injury induced neointimal size and content of smooth muscle cells ( SMCs ) , which are a driving force of neointimal hyperplasia .	Systemic treatment of mice with a CXCL12 blocking antibody or a CXCR4 antagonist reduced injury induced neointimal size and content of smooth muscle cells (SMCs), which are a driving force of neointimal hyperplasia.	3	12	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	6	7	11	12
Recombinant NPM decreased GTP binding in membrane fractions after activation of CXCR4 by CXCL12 .	Recombinant NPM decreased GTP binding in membrane fractions after activation of CXCR4 by CXCL12.	2	14	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	13	14	11	12
CXCL12 significantly induced CXCR4 protein degradation , starting at 1 h and peaking at 3 h ( XREF_FIG ) .	CXCL12 significantly induced CXCR4 protein degradation, starting at 1 h and peaking at 3 h (XREF_FIG).	0	5	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	0	1	3	4
Interestingly , in mu-opioid receptor knockout glia , CXCL12 induced CXCR4 G protein coupling and other downstream signals are reduced , suggesting that regulatory mechanisms between these systems may differ depending on the cell type and the opioid receptor subtype .	Interestingly, in mu-opioid receptor knockout glia, CXCL12 induced CXCR4 G protein coupling and other downstream signals are reduced, suggesting that regulatory mechanisms between these systems may differ depending on the cell type and the opioid receptor subtype.	8	13	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	8	9	10	11
The CXCR4/7 ligand CXCL12 induced a reduction in surface expression of CXCR4 due to receptor internalization ( XREF_FIG ) thereby reduced the percentage of CXCR4 + monocytes .	The CXCR4/7 ligand CXCL12 induced a reduction in surface expression of CXCR4 due to receptor internalization (XREF_FIG) thereby reduced the percentage of CXCR4 + monocytes.	0	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	24	25
Finally , our finding that dormant cancer cells express a low level of CXCR4 suggests that treatments targeting the CXCL12 induced CXCR4 mediated signaling may be ineffective for cells at this stage .	Finally, our finding that dormant cancer cells express a low level of CXCR4 suggests that treatments targeting the CXCL12 induced CXCR4 mediated signaling may be ineffective for cells at this stage.	17	23	induced	Positive_early_activation	Positive_activation	Positive_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	21	22
By inhibition of CXCR4 and/or CXCR7 , we showed that CXCR7 participates in normal CD34 + and U937 cell migration and prevents downregulation of CXCR4 by CXCL12 stimulation .	By inhibition of CXCR4 and/or CXCR7, we showed that CXCR7 participates in normal CD34 + and U937 cell migration and prevents downregulation of CXCR4 by CXCL12 stimulation.	22	27	downregulation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	26	27	24	25
Our data strongly indicate that WWP1 may have a similar role to regulate cell migration through the regulation of CXCL12 induced CXCR4 degradation .	Our data strongly indicate that WWP1 may have a similar role to regulate cell migration through the regulation of CXCL12 induced CXCR4 degradation.	17	22	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	19	20	21	22
SDF-1 prevents entry of CXCR4 dependent ( X4 ) HIV viruses in T lymphocytes , by binding and internalizing CXCR4 .	SDF-1 prevents entry of CXCR4 dependent (X4) HIV viruses in T lymphocytes, by binding and internalizing CXCR4.	0	10	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	0	1	4	5
In conclusion , we demonstrated that MMP-2 inhibition suppressed SDF1 promoted hUCBSCs stem cells migration towards the tumor cells by blocking the SDF1 / CXCR4 mediated signaling .	In conclusion, we demonstrated that MMP-2 inhibition suppressed SDF1 promoted hUCBSCs stem cells migration towards the tumor cells by blocking the SDF1 / CXCR4 mediated signaling.	9	25	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SDF1	SDF1	SDF1	CXCR4	CXCR4	CXCR4	9	10	24	25
Indeed , in order to observe SDF-1 induced CXCR4 degradation in Jurkat cells , we needed to inhibit the synthesis of new receptors continuously with cycloheximide and incubate the cells with SDF-1 , PMA and ionomycin .	Indeed, in order to observe SDF-1 induced CXCR4 degradation in Jurkat cells, we needed to inhibit the synthesis of new receptors continuously with cycloheximide and incubate the cells with SDF-1, PMA and ionomycin.	5	9	induced	Positive_early_activation	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR4	CXCR4	CXCR4	6	7	8	9
As shown in XREF_FIG , JWH-015 ( 20 microM ) showed significant inhibition of CXCL12 induced migration of MCF-7 and CXCR4 and SCP2 cells .	As shown in XREF_FIG, JWH-015 (20 microM) showed significant inhibition of CXCL12 induced migration of MCF-7 and CXCR4 and SCP2 cells.	12	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	14	15	20	21
Interestingly , CXCL12 induced CXCR4 degradation was not observed in WWP1 shRNA cells ( XREF_FIG ) .	Interestingly, CXCL12 induced CXCR4 degradation was not observed in WWP1 shRNA cells (XREF_FIG).	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	4	5
In summary , we used the FAP system with flow cytometry and live cell imaging to show that cells co-expressing CXCR4 and HCMV US27 exhibit higher CXCR4 levels , greater CXCL12 induced internalization , and slower CXCR4 receptor recovery back to the cell surface .	In summary, we used the FAP system with flow cytometry and live cell imaging to show that cells co-expressing CXCR4 and HCMV US27 exhibit higher CXCR4 levels, greater CXCL12 induced internalization, and slower CXCR4 receptor recovery back to the cell surface.	29	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	30	31	36	37
However , since CXCL12 scavenging also prevents the downregulation of CXCR4 , ACKR3 could also well be beneficially influencing CXCR4 mediated effects .	However, since CXCL12 scavenging also prevents the downregulation of CXCR4, ACKR3 could also well be beneficially influencing CXCR4 mediated effects.	3	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	3	4	10	11
Inhibition of CXCL12 induced CXCR4 receptor internalization .	Inhibition of CXCL12 induced CXCR4 receptor internalization.	0	6	induced	Positive_early_activation	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR4	CXCR4	CXCR4	2	3	4	5
Importantly , IL8 treatment of the cells with reduced P53 levels resulted in an increase in cell number while the control cells showed reduced cell numbers in response to IL8 treatment , suggesting that P53 is critically important for the growth inhibition after activation of CXCR2 by IL8 .	Importantly, IL8 treatment of the cells with reduced P53 levels resulted in an increase in cell number while the control cells showed reduced cell numbers in response to IL8 treatment, suggesting that P53 is critically important for the growth inhibition after activation of CXCR2 by IL8.	37	48	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	47	48	45	46
CXCR2 and fMLPR were downregulated by IL-8 and fMLP , respectively .	CXCR2 and fMLPR were downregulated by IL-8 and fMLP, respectively.	0	8	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	6	7	0	1
Similarly , p53 may also be essential in the growth suppression after activation of CXCR2 by IL8 treatment in LNCaP and CXCR2 cells , as suggested by our microarray studies .	Similarly, p53 may also be essential in the growth suppression after activation of CXCR2 by IL8 treatment in LNCaP and CXCR2 cells, as suggested by our microarray studies.	12	17	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	16	17	14	15
Though SCH-N CXCR2 antagonism did not appreciably affect CS exposed mouse BALF IL-6 levels , mice treated with a nasal instillation of barn dust in conjunction with the dual CXCR1 and CXCR2 antagonist CXCL8 ( 3-74 ) K11R and G31P exhibited similar results to CXCR2 -/- mice BALF IL-6 levels .	Though SCH-N CXCR2 antagonism did not appreciably affect CS exposed mouse BALF IL-6 levels, mice treated with a nasal instillation of barn dust in conjunction with the dual CXCR1 and CXCR2 antagonist CXCL8 (3-74) K11R and G31P exhibited similar results to CXCR2 -/- mice BALF IL-6 levels.	16	34	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	33	34	31	32
Moreover , we demonstrated that interfering with IL-8 function by several complementary approaches , namely siRNA mediated silencing of IL-8 or its receptor CXCR2 , IL-8 blocking antibody , or pharmacological inhibition of endothelial CXCR2 , reduced the effects of U87-CM on hCMEC/D3 .	Moreover, we demonstrated that interfering with IL-8 function by several complementary approaches, namely siRNA mediated silencing of IL-8 or its receptor CXCR2, IL-8 blocking antibody, or pharmacological inhibition of endothelial CXCR2, reduced the effects of U87-CM on hCMEC/D3.	25	35	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	25	26	34	35
IL-8 and TNF-alpha down-regulate CXCR1 and CXCR2 from the neutrophil membrane .	IL-8 and TNF-alpha down-regulate CXCR1 and CXCR2 from the neutrophil membrane.	0	7	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-8	IL-8	IL-8	CXCR2	CXCR2	CXCR2	0	1	6	7
As shown in XREF_FIG , IL8 inhibited the proliferation of LNCaP and CXCR2 cells but not the parental LNCaP cells , a finding that supports our hypothesis .	As shown in XREF_FIG, IL8 inhibited the proliferation of LNCaP and CXCR2 cells but not the parental LNCaP cells, a finding that supports our hypothesis.	5	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL8	IL8	IL8	CXCR2	CXCR2	CXCR2	5	6	12	13
The former appears to be the case since DD-NAc-PGP dose dependently ( XREF_FIG ) and specifically ( XREF_FIG ) blocked the chemotactic activity of LL-NAc-PGP and CXCL8 ( XREF_FIG ) suggesting the DD- isomer may block the CXCR1 and/or CXCR2 receptors .	The former appears to be the case since DD-NAc-PGP dose dependently (XREF_FIG) and specifically (XREF_FIG) blocked the chemotactic activity of LL-NAc-PGP and CXCL8 (XREF_FIG) suggesting the DD- isomer may block the CXCR1 and/or CXCR2 receptors.	22	40	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	26	27	39	40
LL-37 , CXCL8 , and CXCL1 , but not ATP or BzATP , all down-regulate CXCR2 , similar to their effect on neutrophils ( XREF_SUPPLEMENTARY ) .	LL-37, CXCL8, and CXCL1, but not ATP or BzATP, all down-regulate CXCR2, similar to their effect on neutrophils (XREF_SUPPLEMENTARY).	0	17	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	2	3	15	16
The putative Ins ( 1,4,5 ) P3 receptor antagonist 2-aminoethoxydiphenyl borane reduced the response to CXCR2 activation by interleukin-8 , as did sustained inhibition of phosphatidylinositol 4-kinase with wortmannin , suggesting the involvement of phosphoinositides in the potentiation .	The putative Ins (1,4,5) P3 receptor antagonist 2-aminoethoxydiphenyl borane reduced the response to CXCR2 activation by interleukin-8, as did sustained inhibition of phosphatidylinositol 4-kinase with wortmannin, suggesting the involvement of phosphoinositides in the potentiation.	11	19	reduced	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	interleukin-8	interleukin-8	interleukin-8	CXCR2	CXCR2	CXCR2	18	19	15	16
CXCR1 and CXCR2 antagonist CXCL8 ( 3-74 ) K11R and G31P blocks lung inflammation in swine barn dust instilled mice .	CXCR1 and CXCR2 antagonist CXCL8 (3-74) K11R and G31P blocks lung inflammation in swine barn dust instilled mice.	0	11	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	CXCL8	CXCL8	CXCL8	CXCR2	CXCR2	CXCR2	4	5	2	3
Loss of functional APC results in the nuclear accumulation of beta-catenin , which activates the transcription factor Tcf-4 .	Loss of functional APC results in the nuclear accumulation of beta-catenin, which activates the transcription factor Tcf-4.	8	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Tcf-4	Tcf-4	Tcf-4	10	11	17	18
Because FoxOs can bind beta-catenin preventing the activation of TCF4 , we tested whether modulation of Foxo3a would cause any change to promoter activation induced by beta-catenin stabilization .	Because FoxOs can bind beta-catenin preventing the activation of TCF4, we tested whether modulation of Foxo3a would cause any change to promoter activation induced by beta-catenin stabilization.	3	10	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	4	5	9	10
Under activation of the Wnt pathway , beta-catenin relocates to the nucleus and induces the unhooking of TCF4 corepressors allowing the functional remodeling of TCF4 that becomes a transcriptional activator .	Under activation of the Wnt pathway, beta-catenin relocates to the nucleus and induces the unhooking of TCF4 corepressors allowing the functional remodeling of TCF4 that becomes a transcriptional activator.	7	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	7	8	17	18
In the HCC model , SIK would phosphorylate a transcriptional co-repressor protein of beta-catenin , inhibiting the beta , catenin , and TCF4 complex from inducing the EMT transcription factor Twist1 [ XREF_BIBR ] .	In the HCC model, SIK would phosphorylate a transcriptional co-repressor protein of beta-catenin, inhibiting the beta, catenin, and TCF4 complex from inducing the EMT transcription factor Twist1 [XREF_BIBR].	5	23	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	SIK would phosphorylate a transcriptional co-repressor protein of beta-catenin	beta-catenin	TCF4	TCF4	tcf4	13	14	22	23
Plakoglobin and beta-catenin bind to adjacent sites on Tcf-4 and plakoglobin inhibits binding of Tcf-4 to DNA ( Miravet et al , 2002 ) .	Plakoglobin and beta-catenin bind to adjacent sites on Tcf-4 and plakoglobin inhibits binding of Tcf-4 to DNA (Miravet et al, 2002).	0	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	Tcf-4	Tcf-4	Tcf-4	2	3	14	15
As vimentin is a target of beta-catenin and Tcf4 signaling , 43 cells treated with beta-catenin small interfering RNA failed to exhibit vimentin staining in response to CR infection , which paralleled the lack of vimentin staining in cells treated with Notch blocker dibenzazepine ( DBZ ) , 35 whereas E-cadherin staining was not detected under either condition ( XREF_FIG ) .	As vimentin is a target of beta-catenin and Tcf4 signaling, 43 cells treated with beta-catenin small interfering RNA failed to exhibit vimentin staining in response to CR infection, which paralleled the lack of vimentin staining in cells treated with Notch blocker dibenzazepine (DBZ), 35 whereas E-cadherin staining was not detected under either condition (XREF_FIG).	6	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	Tcf4	Tcf4	Tcf4	15	16	8	9
Silymarin induces GSK3beta dependent proteasomal degradation of beta-catenin and Axin dependent downregulation of TCF4 .	Silymarin induces GSK3beta dependent proteasomal degradation of beta-catenin and Axin dependent downregulation of TCF4.	7	14	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	7	8	13	14
Knocking down beta-catenin or inhibiting TCF4 , the key transcriptional factor of beta-catenin pathway , by TCF4-DN ( dominate negative TCF4 ) significantly decreased the transcriptional activity of beta-catenin in GSCs , as indicated by TOPflash activity ( XREF_FIG ) .	Knocking down beta-catenin or inhibiting TCF4, the key transcriptional factor of beta-catenin pathway, by TCF4-DN (dominate negative TCF4) significantly decreased the transcriptional activity of beta-catenin in GSCs, as indicated by TOPflash activity (XREF_FIG).	4	30	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	TCF4	TCF4	TCF4	28	29	5	6
p120 depletion increased RhoA activity and decreased the activity of Rac1 , providing a potential mechanistic explanation for the ability of dominant-active Rac mutants and dominant negative RhoA mutants to rescue the defects induced by p120 depletion on Xenopus laevis gastrulation .	p120 depletion increased RhoA activity and decreased the activity of Rac1, providing a potential mechanistic explanation for the ability of dominant-active Rac mutants and dominant negative RhoA mutants to rescue the defects induced by p120 depletion on Xenopus laevis gastrulation.	0	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	0	1	10	11
We next examined whether reexpression of p120 could inhibit the Rac activity observed in knockdown cells .	We next examined whether reexpression of p120 could inhibit the Rac activity observed in knockdown cells.	4	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p120	reexpression of p120	p120	Rac	Rac	rac	6	7	10	11
The observation that p120 depletion blocks both Rac1 activation and growth in soft agar suggested the possibility that p120 promotes the anchorage independent growth of MDA-MB-231 cells through the induction of a Rac1-PAK-MEK-ERK signaling pathway .	The observation that p120 depletion blocks both Rac1 activation and growth in soft agar suggested the possibility that p120 promotes the anchorage independent growth of MDA-MB-231 cells through the induction of a Rac1-PAK-MEK-ERK signaling pathway.	3	8	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p120	p120	p120	Rac1	Rac1	Rac1	3	4	7	8
As shown in XREF_FIG , under basal conditions , p120 depletion resulted in significant reduction of Rac1 activity , which was reversed by expression of murine p120 .	As shown in XREF_FIG, under basal conditions, p120 depletion resulted in significant reduction of Rac1 activity, which was reversed by expression of murine p120.	16	27	reversed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	p120	expression of murine p120	p120	Rac1	Rac1	rac1	26	27	16	17
XREF_FIG shows that the ability of p120 to mediate HGF induced Rac1 activation depends on the levels of cadherin 11 , as a cadherin 11 specific siRNA blocks p120 mediated Rac1 activation , whereas a control siRNA has no effect .	XREF_FIG shows that the ability of p120 to mediate HGF induced Rac1 activation depends on the levels of cadherin 11, as a cadherin 11 specific siRNA blocks p120 mediated Rac1 activation, whereas a control siRNA has no effect.	27	31	mediated	Positive_early_activation	Positive_activation	Negative_activation	p120	p120	p120	Rac1	Rac1	Rac1	28	29	30	31
To directly test this hypothesis , we expressed a constitutively active ( V12 ) mutant of Rac1 in p120 depleted MDA-MB-231 cells ( KD + Rac1 ) and tested its effects on growth in soft agar , cell cycle progression , and tumor growth in mice .	To directly test this hypothesis, we expressed a constitutively active (V12) mutant of Rac1 in p120 depleted MDA-MB-231 cells (KD + Rac1) and tested its effects on growth in soft agar, cell cycle progression, and tumor growth in mice.	7	26	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p120	p120	p120	Rac1	Rac1	Rac1	18	19	25	26
p120 is also responsible for the cortical localization of p190 RhoGAP , a negative regulator of RhoA , which is activated by Src signaling and mediates Rac mediated suppression of RhoA [ XREF_BIBR ] .	p120 is also responsible for the cortical localization of p190 RhoGAP, a negative regulator of RhoA, which is activated by Src signaling and mediates Rac mediated suppression of RhoA [XREF_BIBR].	0	28	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p120	p120	p120	Rac	Rac	Rac	0	1	26	27
Further , recent studies have shown that the reduction of tyrosine phosphorylation of cytoplasmic p120 promotes its interaction with Vav2 and increases the Rac1 activity XREF_BIBR .	Further, recent studies have shown that the reduction of tyrosine phosphorylation of cytoplasmic p120 promotes its interaction with Vav2 and increases the Rac1 activity XREF_BIBR.	10	25	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p120	tyrosine phosphorylation of cytoplasmic p120	p120	Rac1	Rac1	rac1	14	15	23	24
These data suggest that p120 may be involved in cadherin induced Rac1 signaling and proliferation , and support a model in which p120 normally suppresses Rac1 and proliferation until engagement of E-cadherin sequesters p120 , disinhibiting Rac1 activity .	These data suggest that p120 may be involved in cadherin induced Rac1 signaling and proliferation, and support a model in which p120 normally suppresses Rac1 and proliferation until engagement of E-cadherin sequesters p120, disinhibiting Rac1 activity.	22	27	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p120	p120	p120	Rac1	Rac1	Rac1	22	23	25	26
Mib1 mediated ubiquitination of Ctnnd1 K547 attenuated Rac1 activation in cultured cells .	Mib1 mediated ubiquitination of Ctnnd1 K547 attenuated Rac1 activation in cultured cells.	0	8	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ctnnd1	Mib1 mediated ubiquitination of Ctnnd1 K547	ctnnd1	Rac1	Rac1	rac1	4	5	7	8
While loss of beta-arrestin 2 did not alter total cell surface CXCR7 under basal conditions , CXCL12 reduced total cell surface CXCR7 to a greater extent in wild-type cells ( p < 0.01 ) ( XREF_FIG ) .	While loss of beta-arrestin 2 did not alter total cell surface CXCR7 under basal conditions, CXCL12 reduced total cell surface CXCR7 to a greater extent in wild-type cells (p < 0.01) (XREF_FIG).	16	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	16	17	21	22
Full length CXCL12 and the wild-type 17-mer peptide ( peptide 1 ) completely blocked CXCR7 dependent uptake of CXCL12-GL , as did peptides 5 ( RAVM ) and 10 ( ASAW ) .	Full length CXCL12 and the wild-type 17-mer peptide (peptide 1) completely blocked CXCR7 dependent uptake of CXCL12-GL, as did peptides 5 (RAVM) and 10 (ASAW).	0	16	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	2	3	14	15
CXCL12 and CXCR4 complementation , on the other hand , requires the use of two transfected cell lines but has low background and can also allow testing the inhibition of CXCL12 and CXCR7 .	CXCL12 and CXCR4 complementation, on the other hand, requires the use of two transfected cell lines but has low background and can also allow testing the inhibition of CXCL12 and CXCR7.	0	33	allow	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CXCL12	CXCL12	CXCL12	CXCR7	CXCR7	CXCR7	0	1	32	33
The down-regulation of cxcr7 by SDF1 and CXCR4 in wild type embryos is consistent with the idea that the presence of CXCR7 in the leading cells would be detrimental for migration .	The down-regulation of cxcr7 by SDF1 and CXCR4 in wild type embryos is consistent with the idea that the presence of CXCR7 in the leading cells would be detrimental for migration.	1	11	down-regulation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	SDF1	SDF1	SDF1	cxcr7	cxcr7	cxcr7	5	6	3	4
Interestingly , it was reported that high ligand concentrations reduced total cell surface expression of CXCR7 , while SDF-1 does not affect the receptor internalization regardless of ligand level , indicating that high concentrations of SDF-1 inhibit the CXCR7 cycling system .	Interestingly, it was reported that high ligand concentrations reduced total cell surface expression of CXCR7, while SDF-1 does not affect the receptor internalization regardless of ligand level, indicating that high concentrations of SDF-1 inhibit the CXCR7 cycling system.	33	40	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDF-1	SDF-1	SDF-1	CXCR7	CXCR7	CXCR7	35	36	38	39
The disruption through gene mutation of these key beta-catenin degradation components is known to increase the protein levels of beta-catenin which then translocates to the nucleus and activates LEF-1 and TCF transcription factors and gene networks that promote CRC development .	The disruption through gene mutation of these key beta-catenin degradation components is known to increase the protein levels of beta-catenin which then translocates to the nucleus and activates LEF-1 and TCF transcription factors and gene networks that promote CRC development.	17	32	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	levels of beta-catenin	beta-catenin	LEF-1	LEF-1	lef-1	19	20	28	29
A constitutively active beta-catenin enhanced LEF1 dependent repression of Runx2 .	A constitutively active beta-catenin enhanced LEF1 dependent repression of Runx2.	0	7	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	LEF1	LEF1	LEF1	3	4	5	6
In addition , we demonstrate that podocytes release IL-8 in the presence of FCS and that IL-8 down-regulates cell surface CXCR1 .	In addition, we demonstrate that podocytes release IL-8 in the presence of FCS and that IL-8 down-regulates cell surface CXCR1.	16	21	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-8	IL-8	IL-8	CXCR1	CXCR1	CXCR1	16	17	20	21
Accordingly , DAPT decreased beta-catenin activation in ECs treated with or without TSBs , whereas silencing Ctnnb1 reduced Notch1 activation ( Notch intracellular domain ( NICD ) ) in control treated ECs .	Accordingly, DAPT decreased beta-catenin activation in ECs treated with or without TSBs, whereas silencing Ctnnb1 reduced Notch1 activation (Notch intracellular domain (NICD)) in control treated ECs.	15	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Ctnnb1	Ctnnb1	Ctnnb1	Notch1	Notch1	Notch1	16	17	18	19
Moreover , blocking miR-103-mediated repression of lncWDR59 induced a negative feedback loop in which beta-catenin limited Notch1 activation and EC proliferation .	Moreover, blocking miR-103-mediated repression of lncWDR59 induced a negative feedback loop in which beta-catenin limited Notch1 activation and EC proliferation.	14	17	limited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	Notch1	Notch1	Notch1	14	15	16	17
On the contrary , indeed activation of Wnt and beta-catenin signaling by Wnt ligand Wnt3a or 6-bromoindirubin-3aeuro ( 2 )-oxime ( BIO ) , specifically inhibits GSK3 activity and inactivates the destruction complex , resulted in the dose dependent increase in TCF and beta-catenin-dependent transcriptional activity , accumulation of active beta-catenin , NICD and Jagged1 .	On the contrary, indeed activation of Wnt and beta-catenin signaling by Wnt ligand Wnt3a or 6-bromoindirubin-3aeuro (2)-oxime (BIO), specifically inhibits GSK3 activity and inactivates the destruction complex, resulted in the dose dependent increase in TCF and beta-catenin-dependent transcriptional activity, accumulation of active beta-catenin, NICD and Jagged1.	7	53	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	NICD	NICD	NICD	9	10	52	53
Our results suggest that FKN may induce integrin activation ( and perhaps subsequent phenotype changes ) in CX3CR1 negative cells as well , which have not been recognized as target cells for FKN .	Our results suggest that FKN may induce integrin activation (and perhaps subsequent phenotype changes) in CX3CR1 negative cells as well, which have not been recognized as target cells for FKN.	4	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FKN	FKN	FKN	CX3CR1	CX3CR1	CX3CR1	4	5	17	18
Diminished Frequencies of CX3CR1 + CD8 + T Cells and Increased Frequencies of CX3CR1 NEG CD8 + T Cells in Omentum Are Indicative of Fractalkine Mediated CX3CR1 INT to CX3CR1 NEG Conversion .	Diminished Frequencies of CX3CR1 + CD8 + T Cells and Increased Frequencies of CX3CR1 NEG CD8 + T Cells in Omentum Are Indicative of Fractalkine Mediated CX3CR1 INT to CX3CR1 NEG Conversion.	22	27	Mediated	Positive_early_activation	Positive_activation	Positive_activation	Fractalkine	Fractalkine	Fractalkine	CX3CR1	CX3CR1	CX3CR1	24	25	26	27
These changes in human CX3CR1 decrease FKN affinity and several studies support a role for CX3CR1 M280 in susceptibility to age related macular degeneration .	These changes in human CX3CR1 decrease FKN affinity and several studies support a role for CX3CR1 M280 in susceptibility to age related macular degeneration.	4	7	decrease	Negative_activation_token_1_noun	Positive_activation	Negative_activation	FKN	FKN	FKN	CX3CR1	CX3CR1	CX3CR1	6	7	4	5
Activation of beta-catenin , through ectopic expression of stabilized beta-catenin , inhibition of GSK-3beta , or WNT-3A protein , induced Runx2 expression , whereas blockade of WNT and beta-catenin signaling with Porcupine ( PORCN ) inhibitor or Dickkopf-1 ( DKK1 ) protein inhibited Runx2 induction by high-phosphate .	Activation of beta-catenin, through ectopic expression of stabilized beta-catenin, inhibition of GSK-3beta, or WNT-3A protein, induced Runx2 expression, whereas blockade of WNT and beta-catenin signaling with Porcupine (PORCN) inhibitor or Dickkopf-1 (DKK1) protein inhibited Runx2 induction by high-phosphate.	28	44	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	Runx2	Runx2	Runx2	28	29	43	44
beta-catenin , a key regulator of Wnt and beta-catenin signaling , is able to induce osteogenic differentiation of osteoblast precursor cells , and reduce apoptosis of mature osteoblast by directly stimulating Runx2 gene expression XREF_BIBR .	beta-catenin, a key regulator of Wnt and beta-catenin signaling, is able to induce osteogenic differentiation of osteoblast precursor cells, and reduce apoptosis of mature osteoblast by directly stimulating Runx2 gene expression XREF_BIBR.	0	34	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	Runx2	Runx2	Runx2	0	1	31	32
There was also suppression of TCF7 upon Nrf2-transfection , and overexpression of various beta-catenin constructs upregulated TCF7 ( XREF_FIG ) .	There was also suppression of TCF7 upon Nrf2-transfection, and overexpression of various beta-catenin constructs upregulated TCF7 (XREF_FIG).	10	18	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	beta-catenin	overexpression of various beta-catenin	beta-catenin	TCF7	TCF7	tcf7	13	14	16	17
We found that Oct4 , through its action as a transcriptional activator , suppresses Wnt and beta-catenin signaling , a key inducer of mesoderm in the primitive ectoderm .	We found that Oct4, through its action as a transcriptional activator, suppresses Wnt and beta-catenin signaling, a key inducer of mesoderm in the primitive ectoderm.	1	17	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	Oct4	Oct4	Oct4	16	17	3	4
Our results showed that LiCl not only elevated the protein level of active beta-Catenin , but also rescued the reduced Oct4 caused by Rbm46 overexpression , suggesting that Oct4 is regulated by Rbm46 through downregulation of beta-Catenin ( XREF_FIG ) .	Our results showed that LiCl not only elevated the protein level of active beta-Catenin, but also rescued the reduced Oct4 caused by Rbm46 overexpression, suggesting that Oct4 is regulated by Rbm46 through downregulation of beta-Catenin (XREF_FIG).	4	21	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-Catenin	LiCl not only elevated the protein level of active beta-Catenin	beta-catenin	Oct4	Oct4	oct4	13	14	20	21
Overexpression of delta-catenin , but not p120ctn , can rescue the loss of erbin phenotype .	Overexpression of delta-catenin, but not p120ctn, can rescue the loss of erbin phenotype.	0	14	rescue	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	delta-catenin	Overexpression of delta-catenin	delta-catenin	erbin	erbin	erbin	2	3	13	14
We found that overexpression of beta-catenin did not promote the inhibitory effect of TCF7L2 on the expression of G6Pase , PGC1alpha , or Lipin1 , known targets for FoxO1 and CREB and CRTC2 ( XREF_FIG ) .	We found that overexpression of beta-catenin did not promote the inhibitory effect of TCF7L2 on the expression of G6Pase, PGC1alpha, or Lipin1, known targets for FoxO1 and CREB and CRTC2 (XREF_FIG).	3	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	overexpression of beta-catenin	beta-catenin	TCF7L2	TCF7L2	tcf7l2	5	6	13	14
Importantly , we found that activation of Wnt and beta-catenin pathway in HCT116 cells suppressed CREB signaling pathway core factors EP300 and CREB .	Importantly, we found that activation of Wnt and beta-catenin pathway in HCT116 cells suppressed CREB signaling pathway core factors EP300 and CREB.	7	22	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	EP300	EP300	EP300	9	10	20	21
The leukemia inhibitory factor receptor ( LIF-R ) is activated not only by LIF , but also by cardiotrophin-1 , ciliary neurotrophic factor with its receptor , and oncostatin M ( OSM ) .	The leukemia inhibitory factor receptor (LIF-R) is activated not only by LIF, but also by cardiotrophin-1, ciliary neurotrophic factor with its receptor, and oncostatin M (OSM).	1	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	cardiotrophin-1	cardiotrophin-1	cardiotrophin-1	leukemia inhibitory factor receptor	leukemia inhibitory factor receptor	leukemia inhibitory factor receptor	18	19	1	5
This shift in CKIIbeta localization mediated by Pcdh8 decreases Wnt and beta-catenin signaling activity and target gene expression [ XREF_BIBR ] .	This shift in CKIIbeta localization mediated by Pcdh8 decreases Wnt and beta-catenin signaling activity and target gene expression [XREF_BIBR].	3	13	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CKIIbeta	CKIIbeta	CKIIbeta	beta-catenin	beta-catenin	beta-catenin	3	4	11	12
The disruption of MMP results in the release of apoptosis inducing protein cytochrome c ( cyt-c ) that promotes caspase-9 , caspase-3 and PARP activation and apoptosis [ XREF_BIBR ] .	The disruption of MMP results in the release of apoptosis inducing protein cytochrome c (cyt-c) that promotes caspase-9, caspase-3 and PARP activation and apoptosis [XREF_BIBR].	12	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	12	14	19	20
These findings suggest that the protective effect of Danggui extract is mediated by stabilization of the mitochondria membrane potential and inhibition of cytochrome c release against Ang II induced caspase-9 and caspase-3 activation and cell apoptosis .	These findings suggest that the protective effect of Danggui extract is mediated by stabilization of the mitochondria membrane potential and inhibition of cytochrome c release against Ang II induced caspase-9 and caspase-3 activation and cell apoptosis.	22	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	22	24	29	30
Treatment of cancer cells with COX inhibitors induces cytochrome C release from mitochondria , which in turn activates caspase-9 and then caspase-3 [ XREF_BIBR - XREF_BIBR ] .	Treatment of cancer cells with COX inhibitors induces cytochrome C release from mitochondria, which in turn activates caspase-9 and then caspase-3 [XREF_BIBR - XREF_BIBR].	5	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	COX inhibitors induces cytochrome C release from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	8	10	18	19
We showed that DRCKD+ exercise elevated the Bcl-2 and Bax ratio and the intramitochondrial cytochrome c simultaneously downregulated caspase-9 , cleaved caspase-3 , caspase-8 , mu-calpain , and Fas ( XREF_TABLE ) .	We showed that DRCKD+ exercise elevated the Bcl-2 and Bax ratio and the intramitochondrial cytochrome c simultaneously downregulated caspase-9, cleaved caspase-3, caspase-8, mu-calpain, and Fas (XREF_TABLE).	14	20	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	14	16	18	19
In this system it was shown by computer modeling that NGB in the presence of ferric cytochrome c drastically lowers the enzymatic activity of caspase-9 .	In this system it was shown by computer modeling that NGB in the presence of ferric cytochrome c drastically lowers the enzymatic activity of caspase-9.	16	25	lowers	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	16	18	24	25
We found that salinomycin strongly reduces cell viability by means of calpain and cytochrome c mediated caspase 9 and subsequent caspase 3 activation .	We found that salinomycin strongly reduces cell viability by means of calpain and cytochrome c mediated caspase 9 and subsequent caspase 3 activation.	11	20	mediated	Positive_early_activation	Positive_activation	Negative_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	13	15	16	18
When a high ratio of Bax to Bcl-2 causes a loss of mitochondrial membrane potential , cytochrome C is released from the intermembrane space of mitochondria to the cytosol , where it triggers the formation of apoptosome containing apoptotic protease and activates caspase-9 .	When a high ratio of Bax to Bcl-2 causes a loss of mitochondrial membrane potential, cytochrome C is released from the intermembrane space of mitochondria to the cytosol, where it triggers the formation of apoptosome containing apoptotic protease and activates caspase-9.	16	43	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C is released from the intermembrane space of mitochondria to the cytosol	cytochrome c	caspase-9	caspase-9	caspase-9	16	18	42	43
AT-01 induced apoptotic body formation , enhanced annexinV-FITC binding of the cells , increased sub-G ( 0 ) DNA fraction , loss of mitochondrial membrane potential ( Deltapsi ( mt ) ) and release of cytochrome c from mitochondria , activated caspase-9 as well as caspase-3 , and increased cleavage of PARP in HL-60 cells .	AT-01 induced apoptotic body formation, enhanced annexinV-FITC binding of the cells, increased sub-G (0) DNA fraction, loss of mitochondrial membrane potential (Deltapsi (mt)) and release of cytochrome c from mitochondria, activated caspase-9 as well as caspase-3, and increased cleavage of PARP in HL-60 cells.	33	45	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	cytochrome c	release of cytochrome c from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	35	37	41	42
Nelfinavir attenuated apoptosis as well as mitochondrial release of AIF and cytochrome c , and subsequent activation of caspase-9 in vitro , in photoreceptor cultures exposed to starvation or monocyte chemoattractant protein-1-stimulated ( MCP-1-stimulated ) macrophages .	Nelfinavir attenuated apoptosis as well as mitochondrial release of AIF and cytochrome c, and subsequent activation of caspase-9 in vitro, in photoreceptor cultures exposed to starvation or monocyte chemoattractant protein-1-stimulated (MCP-1-stimulated) macrophages.	9	19	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	11	13	18	19
Using an in vitro reconstitution system we exclude any indirect effects of host cell cytosolic components apart from Apaf-1 , caspase 9 and cytochrome c being involved in the inhibition of cytochrome c triggered caspase 9 activation .	Using an in vitro reconstitution system we exclude any indirect effects of host cell cytosolic components apart from Apaf-1, caspase 9 and cytochrome c being involved in the inhibition of cytochrome c triggered caspase 9 activation.	31	36	triggered	Positive_activation_token_1_verb	Positive_activation	Negative_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	31	33	34	36
Moreover , IAPs ( inhibitors of apoptosis ) can inhibit apoptosis by directly binding to activated effector caspases , such as caspase-3 and caspase-7 , and also inhibit mitochondrial cytochrome c induced caspase-9 activation [ XREF_BIBR , XREF_BIBR ] .	Moreover, IAPs (inhibitors of apoptosis) can inhibit apoptosis by directly binding to activated effector caspases, such as caspase-3 and caspase-7, and also inhibit mitochondrial cytochrome c induced caspase-9 activation [XREF_BIBR, XREF_BIBR].	29	33	induced	Positive_early_activation	Positive_activation	Negative_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	29	31	32	33
Furthermore , we demonstrate that Bcl-xL blocks cytochrome c release from mitochondria , causing activation of caspase-9 in anterior horn cells and dorsal root ganglia neurons in mouse embryos at embryonic day 11.5 .	Furthermore, we demonstrate that Bcl-xL blocks cytochrome c release from mitochondria, causing activation of caspase-9 in anterior horn cells and dorsal root ganglia neurons in mouse embryos at embryonic day 11.5.	5	25	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	Bcl-xL blocks cytochrome c release from mitochondria	cytochrome c	caspase-9	caspase-9	caspase-9	7	9	16	17
The phosphorylation of Akt could activate downstream proteins such as Bcl-2-associated death protein ( BAD ) and caspase 9 , thereby inhibiting the Bax dependent apoptosis pathway and blocking cytochrome c mediated caspase 9 activation [ XREF_BIBR , XREF_BIBR ] .	The phosphorylation of Akt could activate downstream proteins such as Bcl-2-associated death protein (BAD) and caspase 9, thereby inhibiting the Bax dependent apoptosis pathway and blocking cytochrome c mediated caspase 9 activation [XREF_BIBR, XREF_BIBR].	29	34	mediated	Positive_early_activation	Positive_activation	Negative_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	29	31	32	34
Disruption of the MMP facilitated the release of mitochondrial cytochrome c , which activates caspase-9 and downstream caspase-3/7 , resulting in DNA fragmentation and up-regulation of p53 in melanoma cells .	Disruption of the MMP facilitated the release of mitochondrial cytochrome c, which activates caspase-9 and downstream caspase-3/7, resulting in DNA fragmentation and up-regulation of p53 in melanoma cells.	9	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	9	11	14	15
HSP27 inhibits specifically the cytochrome C and ATP triggered activity of caspase 9 on the apoptotic pathway .	HSP27 inhibits specifically the cytochrome C and ATP triggered activity of caspase 9 on the apoptotic pathway.	4	13	triggered	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	cytochrome C	cytochrome C	cytochrome C	caspase 9	caspase 9	caspase 9	4	6	11	13
The mitochondrial membrane potential and cytochrome C expression in CD4 + T cells were down-regulated in siTIPE2-burn group ( P < 0.05 ) with a lowered caspase-3 activity compared with TIPE2-burn group ( P < 0.01 ) and decreased caspase-8 and caspase-9 compared with the other groups ( P < 0.05 ) .	The mitochondrial membrane potential and cytochrome C expression in CD4 + T cells were down-regulated in siTIPE2-burn group (P < 0.05) with a lowered caspase-3 activity compared with TIPE2-burn group (P < 0.01) and decreased caspase-8 and caspase-9 compared with the other groups (P < 0.05).	5	42	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cytochrome C	cytochrome C expression	cytochrome c	caspase-9	caspase-9	caspase-9	5	7	41	42
Cytochrome c binds to tRNA both in vivo and in vitro and inhibits caspase-9 activation .	Cytochrome c binds to tRNA both in vivo and in vitro and inhibits caspase-9 activation.	0	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cytochrome c	Cytochrome c	Cytochrome c	caspase-9	caspase-9	caspase-9	0	2	13	14
This suggests that the redox-reaction between cytochrome c and neuroglobin , even if it is not an absolute requirement , modulates the neuroglobin mediated inhibition of cytochrome c induced caspase 9 activation .	This suggests that the redox-reaction between cytochrome c and neuroglobin, even if it is not an absolute requirement, modulates the neuroglobin mediated inhibition of cytochrome c induced caspase 9 activation.	26	31	induced	Positive_early_activation	Positive_activation	Negative_activation	cytochrome c	cytochrome c	cytochrome c	caspase 9	caspase 9	caspase 9	26	28	29	31
tRNA blocked cytochrome c induced caspase-9 activation as potently as total RNA .	tRNA blocked cytochrome c induced caspase-9 activation as potently as total RNA.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	2	4	5	6
As cytochrome-c can inhibit caspase 9 activity in vitro , 21 it is therefore possible that caspase 3 acts upstream of mitochondria , resulting in Deltapsim decrease as it has been already described .	As cytochrome-c can inhibit caspase 9 activity in vitro, 21 it is therefore possible that caspase 3 acts upstream of mitochondria, resulting in Deltapsim decrease as it has been already described.	1	6	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cytochrome-c	cytochrome-c	cytochrome-c	caspase 9	caspase 9	caspase 9	1	2	4	6
The data demonstrate that ATP ( 1 mM ) and cytochrome c ( 3.0 microM ) inhibit caspase-9 activity by approximately 70 % .	The data demonstrate that ATP (1 mM) and cytochrome c (3.0 microM) inhibit caspase-9 activity by approximately 70%.	10	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cytochrome c	cytochrome c	cytochrome c	caspase-9	caspase-9	caspase-9	10	12	17	18
( 2009 ) showed that HBO preconditioning had favorable effects in a model of spinal cord ischemia in rats by enhancing the activities of SOD , catalase , and Bcl-2 expression in the mitochondria ; in parallel , cytosolic cytochrome C was reduced and subsequently attenuated the activity of caspase-9 and caspase-3 ( responsible for apoptosis ) .	(2009) showed that HBO preconditioning had favorable effects in a model of spinal cord ischemia in rats by enhancing the activities of SOD, catalase, and Bcl-2 expression in the mitochondria; in parallel, cytosolic cytochrome C was reduced and subsequently attenuated the activity of caspase-9 and caspase-3 (responsible for apoptosis).	39	51	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cytochrome C	cytochrome C	cytochrome C	caspase-9	caspase-9	caspase-9	39	41	49	50
Of particular interest is that DAB2IP differentially regulates GSK3beta activity in hMSCs and prostate cancer cells ; DAB2IP activates GSK3beta in prostate cancer cells but represses GSK3beta in hMSCs .	Of particular interest is that DAB2IP differentially regulates GSK3beta activity in hMSCs and prostate cancer cells; DAB2IP activates GSK3beta in prostate cancer cells but represses GSK3beta in hMSCs.	17	27	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	GSK3beta	GSK3beta	GSK3beta	17	18	26	27
This suggested that DAB2IP negatively regulates GSK3beta activity in 3A6-hMSCs .	This suggested that DAB2IP negatively regulates GSK3beta activity in 3A6-hMSCs.	3	7	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	GSK3beta	GSK3beta	GSK3beta	3	4	6	7
Other groups previously reported that DAB2IP suppressed EMT by modulating GSK3beta and beta-catenin signaling pathway in prostate cancer [ XREF_BIBR ] .	Other groups previously reported that DAB2IP suppressed EMT by modulating GSK3beta and beta-catenin signaling pathway in prostate cancer [XREF_BIBR].	5	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	GSK3beta	GSK3beta	GSK3beta	5	6	10	11
In 3A6-hMSCs , DAB2IP negatively regulates GSK3beta activity , as evidenced by the reduction in Ser9 phosphorylated GSK3beta in DAB2IP-KD 3A6-hMSCs .	In 3A6-hMSCs, DAB2IP negatively regulates GSK3beta activity, as evidenced by the reduction in Ser9 phosphorylated GSK3beta in DAB2IP-KD 3A6-hMSCs.	3	7	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	GSK3beta	GSK3beta	GSK3beta	3	4	6	7
A C-terminal truncated form of DISC1 ( amino acids 1-598 ) , that could be generated by the chromosomal abnormality identified in the original Scottish pedigree functions as a dominant negative , blocking proper accumulation of DISC1 ( A discussion on possible pathological mechanisms due to this chromosomal abnormality is introduced in BOX 2 ) , NDEL1 , and their dynein associated proteins to the centrosome and disturbing microtubular dynamics 78 .	A C-terminal truncated form of DISC1 (amino acids 1-598), that could be generated by the chromosomal abnormality identified in the original Scottish pedigree functions as a dominant negative, blocking proper accumulation of DISC1 (A discussion on possible pathological mechanisms due to this chromosomal abnormality is introduced in BOX 2), NDEL1, and their dynein associated proteins to the centrosome and disturbing microtubular dynamics 78.	3	57	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DISC1	DISC1	DISC1	NDEL1	NDEL1	NDEL1	5	6	56	57
The knockdown of DISC1 by RNA interference or the dominant negative form of DISC1 inhibited the accumulation of NUDEL , LIS1 , and 14-3-3epsilon at the axons and axon elongation .	The knockdown of DISC1 by RNA interference or the dominant negative form of DISC1 inhibited the accumulation of NUDEL, LIS1, and 14-3-3epsilon at the axons and axon elongation.	1	23	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DISC1	DISC1	DISC1	NUDEL	NUDEL	NUDEL	3	4	18	19
In these experiments a C-terminally truncated form of DISC1 , which functions as a dominant negative protein , was used to block accumulation of DISC1 , NDEL1 and their dynein associated proteins at the centrosome .	In these experiments a C-terminally truncated form of DISC1, which functions as a dominant negative protein, was used to block accumulation of DISC1, NDEL1 and their dynein associated proteins at the centrosome.	6	27	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DISC1	DISC1	DISC1	NDEL1	NDEL1	NDEL1	8	9	26	27
Similar to berberine , DAXX siRNA inhibited MDM2 and induced p53 ( XREF_SUPPLEMENTARY ) , which resulted in cell death ( XREF_SUPPLEMENTARY ) .	Similar to berberine, DAXX siRNA inhibited MDM2 and induced p53 (XREF_SUPPLEMENTARY), which resulted in cell death (XREF_SUPPLEMENTARY).	4	8	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DAXX	DAXX	DAXX	MDM2	MDM2	MDM2	4	5	7	8
Downregulation of Daxx decreases Mdm2 expression levels and Daxx enhances the E3 activity of Mdm2 towards p53 .	Downregulation of Daxx decreases Mdm2 expression levels and Daxx enhances the E3 activity of Mdm2 towards p53.	0	16	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Daxx	Daxx	Daxx	Mdm2	Mdm2	Mdm2	2	3	14	15
XREF_BIBR that DAXX and Mdm2 no longer interact after DAXX is phosphorylated by ATM , thereby enabling Mdm2 degradation , p53 stabilization , and increased expression of p53 regulated genes in the presence of DNA damage .	XREF_BIBR that DAXX and Mdm2 no longer interact after DAXX is phosphorylated by ATM, thereby enabling Mdm2 degradation, p53 stabilization, and increased expression of p53 regulated genes in the presence of DNA damage.	9	18	enabling	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	DAXX	DAXX is phosphorylated	daxx	Mdm2	Mdm2	mdm2	9	10	17	18
XREF_BIBR Most recently , it was proposed that DAXX phosphorylation disrupts the interaction and stabilization of Mdm2 and thereby results in elevated p53 levels and induction of p53 target gene , p21 WAF1 and Cip1 ( p21 ) encoding the CDK inhibitor p21 .	XREF_BIBR Most recently, it was proposed that DAXX phosphorylation disrupts the interaction and stabilization of Mdm2 and thereby results in elevated p53 levels and induction of p53 target gene, p21 WAF1 and Cip1 (p21) encoding the CDK inhibitor p21.	8	17	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DAXX	DAXX phosphorylation	daxx	Mdm2	Mdm2	mdm2	8	9	16	17
Depletion of the formin homologous protein Daam1 prevents Wnt/Fz activation of Rho and planar cell polarity during Xenopus gastrulation .	Depletion of the formin homologous protein Daam1 prevents Wnt/Fz activation of Rho and planar cell polarity during Xenopus gastrulation.	0	15	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Daam1	Daam1	Daam1	Rho	Rho	Rho	6	7	11	12
The N-Daam mutation contains only the amino terminus of Daam 1 , which contains the Rho binding domain and lacks the DVL binding domain , preventing Rho , Daam , and DVL from forming a complex , and so acts as a dominant negative regulator of Rho .	The N-Daam mutation contains only the amino terminus of Daam 1, which contains the Rho binding domain and lacks the DVL binding domain, preventing Rho, Daam, and DVL from forming a complex, and so acts as a dominant negative regulator of Rho.	7	31	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Daam 1	Daam 1	Daam 1	Rho	Rho	Rho	9	11	26	27
Knockdown of Daam1 expression via siRNA transfection inhibited RhoA activation and the cell invasion stimulated by Wnt5a in U251 and T98MG cells .	Knockdown of Daam1 expression via siRNA transfection inhibited RhoA activation and the cell invasion stimulated by Wnt5a in U251 and T98MG cells.	2	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Daam1	Daam1 expression	daam1	RhoA	RhoA	rhoa	2	3	8	9
Interference of Daam1 function via N-Daam1 overexpression or knockdown of Daam1 expression via siRNA transfection inhibited RhoA activation and cell migration by Wnt5a and Dvl2 in MDA-MB-231 cells .	Interference of Daam1 function via N-Daam1 overexpression or knockdown of Daam1 expression via siRNA transfection inhibited RhoA activation and cell migration by Wnt5a and Dvl2 in MDA-MB-231 cells.	10	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Daam1	Daam1 expression	daam1	RhoA	RhoA	rhoa	10	11	16	17
The release of Smac antagonizes several IAPs and assists the initiator caspase-9 and effector caspases ( caspase-3 , caspase-6 , and caspase-7 ) in becoming active , ultimately leading to death of the cell .	The release of Smac antagonizes several IAPs and assists the initiator caspase-9 and effector caspases (caspase-3, caspase-6, and caspase-7) in becoming active, ultimately leading to death of the cell.	1	14	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	3	4	11	12
Since Smac mimetics such as BV6 antagonize XIAP in addition to cIAP1 and cIAP2 proteins , the Smac mimetic induced release of XIAP mediated inhibition of caspase-9 , -7 and -3 results in enforced caspase activation .	Since Smac mimetics such as BV6 antagonize XIAP in addition to cIAP1 and cIAP2 proteins, the Smac mimetic induced release of XIAP mediated inhibition of caspase-9, -7 and -3 results in enforced caspase activation.	16	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	17	18	26	27
Consistent with this finding , binding of the caspase-9 linker peptide and Smac to the BIR3 domain of XIAP is mutually exclusive , suggesting that Smac potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3 .	Consistent with this finding, binding of the caspase-9 linker peptide and Smac to the BIR3 domain of XIAP is mutually exclusive, suggesting that Smac potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3.	25	28	potentiates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smac	Smac	Smac	caspase-9	caspase-9	caspase-9	25	26	27	28
For instance , Raveh et al found that the inactivation or loss of DAPK alone significantly reduces but not completely eliminates p53 in response to c-Myc or E2F-1 [ XREF_BIBR ] .	For instance, Raveh et al found that the inactivation or loss of DAPK alone significantly reduces but not completely eliminates p53 in response to c-Myc or E2F-1 [XREF_BIBR].	9	22	eliminates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DAPK	DAPK	DAPK	p53	p53	p53	13	14	21	22
Since it has been reported that p53 induction and apoptosis is stimulated by the adhesion-inhibitory activity of DAPK [ XREF_BIBR ] , we next evaluated the effect of DANGER on DAPK induced p53 activation and apoptosis .	Since it has been reported that p53 induction and apoptosis is stimulated by the adhesion-inhibitory activity of DAPK [XREF_BIBR], we next evaluated the effect of DANGER on DAPK induced p53 activation and apoptosis.	6	19	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	DAPK	DAPK	DAPK	p53	p53	p53	17	18	6	7
Wild-type DJ-1 protein prevents the translocation of death protein Daxx from nucleus to cytoplasm and inhibits the combination and activation of its effector ASK1 , thus reducing the cell death .	Wild-type DJ-1 protein prevents the translocation of death protein Daxx from nucleus to cytoplasm and inhibits the combination and activation of its effector ASK1, thus reducing the cell death.	1	24	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Daxx	DJ-1 protein prevents the translocation of death protein Daxx from nucleus	daxx	ASK1	ASK1	ask1	9	10	23	24
4-HNE interacts with the Daxx , bound to heat shock factor-1 ( HSF1 ) , translocates Daxx from nucleus to cytoplasm where it binds to Fas , and inhibits activation of ASK1 to limit apoptosis .	4-HNE interacts with the Daxx, bound to heat shock factor-1 (HSF1), translocates Daxx from nucleus to cytoplasm where it binds to Fas, and inhibits activation of ASK1 to limit apoptosis.	0	32	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Daxx	4-HNE interacts with the Daxx, bound to heat shock factor-1 (HSF1), translocates Daxx from nucleus to cytoplasm	daxx	ASK1	ASK1	ask1	16	17	31	32
Loss of p53 did not prevent Dlk and ZIP kinase induced mitochondrial membrane depolarisation and release of cytochrome c. Furthermore , overexpression of Dlk and ZIP kinase did not lead to an increased expression of pro apoptotic p53 target genes in either cell line .	Loss of p53 did not prevent Dlk and ZIP kinase induced mitochondrial membrane depolarisation and release of cytochrome c. Furthermore, overexpression of Dlk and ZIP kinase did not lead to an increased expression of pro apoptotic p53 target genes in either cell line.	6	30	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dlk	overexpression of Dlk	dlk	Dlk	Dlk	dlk	23	24	6	7
DKK1 inhibits WNT signaling by binding as a high-affinity antagonist to the coreceptors LDL receptor related proteins ( LRPs ) 5/6 and Kremen1 and 2 , thereby preventing formation of the active LRP and Frizzled complex .	DKK1 inhibits WNT signaling by binding as a high-affinity antagonist to the coreceptors LDL receptor related proteins (LRPs) 5/6 and Kremen1 and 2, thereby preventing formation of the active LRP and Frizzled complex.	0	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DKK1	DKK1	DKK1	Kremen1	Kremen1	Kremen1	0	1	22	23
While ddx6 ( DEAD-box protein-103 and gemin3 ) is known to regulate the meiosis progression XREF_BIBR , ddx20 directly represses the transcriptional activity of the transcription factor foxL2 and the steroidogenic factor SF-1 XREF_BIBR XREF_BIBR .	While ddx6 (DEAD-box protein-103 and gemin3) is known to regulate the meiosis progression XREF_BIBR, ddx20 directly represses the transcriptional activity of the transcription factor foxL2 and the steroidogenic factor SF-1 XREF_BIBR XREF_BIBR.	17	34	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ddx20	ddx20	ddx20	foxL2	foxL2	foxL2	17	18	27	28
These results suggest that DAAM1 does not simply repress Rac activity but may interfere with processes downstream of Rac .	These results suggest that DAAM1 does not simply repress Rac activity but may interfere with processes downstream of Rac.	4	10	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DAAM1	DAAM1	DAAM1	Rac	Rac	Rac	4	5	9	10
Moreover , unlike with Beclin 1 , starvation induced autophagy does not appear to require disruption of the Bcl-2 and Beclin 2 complex ; we speculate that this may be due to lack of conservation in Beclin 2 of the T119 site in Beclin 1 that is phosphorylated by DAPK to promote disruption of Beclin 1 from binding to Bcl-2 and Bcl-x L.	Moreover, unlike with Beclin 1, starvation induced autophagy does not appear to require disruption of the Bcl-2 and Beclin 2 complex; we speculate that this may be due to lack of conservation in Beclin 2 of the T119 site in Beclin 1 that is phosphorylated by DAPK to promote disruption of Beclin 1 from binding to Bcl-2 and Bcl-x L.	47	56	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	DAPK	DAPK	DAPK	Beclin 1	Beclin 1	Beclin 1	49	50	54	56
Transfection of miR-199a-5p did not induce a change in DDR1 mRNA expression , but significantly down-regulated DDR1 protein in SNU-182 cells .	Transfection of miR-199a-5p did not induce a change in DDR1 mRNA expression, but significantly down-regulated DDR1 protein in SNU-182 cells.	2	17	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DDR1	miR-199a-5p did not induce a change in DDR1 mRNA expression	ddr1	DDR1	DDR1	ddr1	9	10	16	17
Given that Dll1 activates Notch in neighbouring cells ( trans activation ) and inhibits Notch within the same cell ( cis inhibition ) , asymmetric segregation of Dll1 during NSC division would be expected to promote the activation of Notch signalling in the daughter NSC not only by providing a Dll1 signal to its sister cell but also by excluding Dll1 from the daughter NSC .	Given that Dll1 activates Notch in neighbouring cells (trans activation) and inhibits Notch within the same cell (cis inhibition), asymmetric segregation of Dll1 during NSC division would be expected to promote the activation of Notch signalling in the daughter NSC not only by providing a Dll1 signal to its sister cell but also by excluding Dll1 from the daughter NSC.	2	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	2	3	14	15
Unlike embryos that contained at least one wildtype or Dll1 Dll1ki allele , homozygous Dll1 Dll4ki embryos displayed severely reduced and irregular Uncx4.1 expression ( XREF_FIG ) , which indicates disrupted somite patterning and reduced Notch activity in the PSM due to the inability of DLL4 to replace DLL1 .	Unlike embryos that contained at least one wildtype or Dll1 Dll1ki allele, homozygous Dll1 Dll4ki embryos displayed severely reduced and irregular Uncx4.1 expression (XREF_FIG), which indicates disrupted somite patterning and reduced Notch activity in the PSM due to the inability of DLL4 to replace DLL1.	14	36	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	14	15	35	36
8 It is thought that DLL1 laterally inhibits the secretory program in adjacent cells by activating Notch signaling and the absorptive enterocyte differentiation program .	8 It is thought that DLL1 laterally inhibits the secretory program in adjacent cells by activating Notch signaling and the absorptive enterocyte differentiation program.	5	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	5	6	16	17
There are two examples of the latter mode ; shedding of TEX101 from sperm by testis type of angiotensin converting enzyme is involved in sperm maturation and shedding of a metalloprotease inhibitor RECK by glycerophosphodiester phosphodiesterase 2 , resulting in metalloprotease mediated degradation of a Notch ligand DLL1 , which , in turn , reduces Notch signaling in adjacent progenitor cells to induce differentiation into neurons .	There are two examples of the latter mode; shedding of TEX101 from sperm by testis type of angiotensin converting enzyme is involved in sperm maturation and shedding of a metalloprotease inhibitor RECK by glycerophosphodiester phosphodiesterase 2, resulting in metalloprotease mediated degradation of a Notch ligand DLL1, which, in turn, reduces Notch signaling in adjacent progenitor cells to induce differentiation into neurons.	42	56	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	47	48	55	56
We also provide evidence that the Notch ligand Delta like 1 ( Dll1 ) promotes differentiation by reducing Notch signaling through a Cis-inhibition mechanism .	We also provide evidence that the Notch ligand Delta like 1 (Dll1) promotes differentiation by reducing Notch signaling through a Cis-inhibition mechanism.	8	19	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	12	13	18	19
Finally , we show that pharmacological inhibition of Dll1 induced Notch signals delayed T cell development from HPCs , and resulted in a substantial increase in the generation of NK cells with increasing concentrations of inhibitor .	Finally, we show that pharmacological inhibition of Dll1 induced Notch signals delayed T cell development from HPCs, and resulted in a substantial increase in the generation of NK cells with increasing concentrations of inhibitor.	6	11	induced	Positive_early_activation	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	8	9	10	11
It is known that Notch signaling , in which Notch in a cell can be activated by Dll1 in neighboring cells ( trans-activation ) and can also be inhibited by Dll1 within the same cell ( cis-inhibition ) , is important for neural fate decisions .	It is known that Notch signaling, in which Notch in a cell can be activated by Dll1 in neighboring cells (trans-activation) and can also be inhibited by Dll1 within the same cell (cis-inhibition), is important for neural fate decisions.	4	20	activated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	17	18	4	5
Although we could not directly access the modified intermediate species derived from full-length Notch , mutating the crucial lysine residue impaired Dll1 mediated Notch signaling , in accordance with the DeltaE results .	Although we could not directly access the modified intermediate species derived from full-length Notch, mutating the crucial lysine residue impaired Dll1 mediated Notch signaling, in accordance with the DeltaE results.	15	24	mediated	Positive_early_activation	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	21	22	23	24
As represented in XREF_FIG , Dll1 induced Notch stimulation was inhibited in the presence of increasing doses of either P2 ( Lanes C-E ) or shRNA # 1 ( Lanes F-H ) , although Notch1 overall level remained constant ( see bottom of XREF_FIG ) .	As represented in XREF_FIG, Dll1 induced Notch stimulation was inhibited in the presence of increasing doses of either P2 (Lanes C-E) or shRNA # 1 (Lanes F-H), although Notch1 overall level remained constant (see bottom of XREF_FIG).	5	8	induced	Positive_early_activation	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	5	6	7	8
These data indicate that enhanced Dll1 expression inhibits Notch signaling in these subgroups of gliomas .	These data indicate that enhanced Dll1 expression inhibits Notch signaling in these subgroups of gliomas.	5	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1 expression	dll1	Notch	Notch	notch	5	6	8	9
In primary GBM , on the other hand , there is the opposite pattern of Hash-1 and Hes-1 expression , implying that enhanced Dll1 expression inhibits Notch signaling while active Notch characterizes primary GBM .	In primary GBM, on the other hand, there is the opposite pattern of Hash-1 and Hes-1 expression, implying that enhanced Dll1 expression inhibits Notch signaling while active Notch characterizes primary GBM.	23	27	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1 expression	dll1	Notch	Notch	notch	23	24	26	27
In addition to the reduced signaling efficacy from Jag1 in the presence of Mfng , we show that Jag1 can act as a competitive inhibitor of Dll1 induced Notch signaling when Mfng is expressed ( XREF_FIG ) .	In addition to the reduced signaling efficacy from Jag1 in the presence of Mfng, we show that Jag1 can act as a competitive inhibitor of Dll1 induced Notch signaling when Mfng is expressed (XREF_FIG).	24	29	induced	Positive_early_activation	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	26	27	28	29
DLL1 induced NOTCH activation in chick embryos inhibits muscle differentiation .	DLL1 induced NOTCH activation in chick embryos inhibits muscle differentiation.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	DLL1	DLL1	DLL1	NOTCH	NOTCH	NOTCH	0	1	2	3
It is possible that the co-expressed Notch receptors , activated by distinct sets of Notch ligands , mediate unique functions in differentiating SCs with DLL1 and JAG2-NOTCH 1 mediating the HC-repressive function of Notch signaling and JAG1-NOTCH2/3 mediating the instructive function ( s ) of Notch signaling .	It is possible that the co-expressed Notch receptors, activated by distinct sets of Notch ligands, mediate unique functions in differentiating SCs with DLL1 and JAG2-NOTCH 1 mediating the HC-repressive function of Notch signaling and JAG1-NOTCH2/3 mediating the instructive function (s) of Notch signaling.	24	34	mediating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	24	25	33	34
Thus , deletion of Lfng leads to decreased Notch signaling in MaSC and progenitors in puberty ( likely as a result of reduced Dll1 mediated Notch activation at this stage ) , and is associated with expansion of the immature cell compartment .	Thus, deletion of Lfng leads to decreased Notch signaling in MaSC and progenitors in puberty (likely as a result of reduced Dll1 mediated Notch activation at this stage), and is associated with expansion of the immature cell compartment.	20	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	23	24	25	26
Second , inhibition of Dll1 processing by soluble , catalytically inactive extracellular domain of ADAM12 , protein X , elevates the global Notch signaling and increases the pool of Pax7 + / MyoD - cells , with the concomitant decrease of the pool of Pax7 + / MyoD + cells ( XREF_FIG and XREF_FIG ) .	Second, inhibition of Dll1 processing by soluble, catalytically inactive extracellular domain of ADAM12, protein X, elevates the global Notch signaling and increases the pool of Pax7 + / MyoD - cells, with the concomitant decrease of the pool of Pax7 + / MyoD + cells (XREF_FIG and XREF_FIG).	4	23	elevates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	4	5	22	23
PAR-1 rescued neurogenesis downregulated by Dll1 , but not Notch ICD ( XREF_FIG , XREF_SUPPLEMENTARY ) , supporting the idea that PAR-1 functions at the level of Dll1 , upstream of Notch receptor activation .	PAR-1 rescued neurogenesis downregulated by Dll1, but not Notch ICD (XREF_FIG, XREF_SUPPLEMENTARY), supporting the idea that PAR-1 functions at the level of Dll1, upstream of Notch receptor activation.	3	10	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	5	6	9	10
Soluble forms of Dll1 , Dll4 , and Jagged1 have also been used to block Notch signaling .	Soluble forms of Dll1, Dll4, and Jagged1 have also been used to block Notch signaling.	1	16	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	3	4	15	16
Finally , our finding that proliferation is increaed in the context of decreased DLL1 driven Notch signaling highlights the complexity of the Notch pathway in the developing intestinal epithelium .	Finally, our finding that proliferation is increaed in the context of decreased DLL1 driven Notch signaling highlights the complexity of the Notch pathway in the developing intestinal epithelium.	10	16	driven	Positive_activation_token_1_verb	Positive_activation	Negative_activation	DLL1	DLL1	DLL1	Notch	Notch	Notch	13	14	15	16
Furthermore , adult heterozygous Dll1 mice demonstrate impaired collateral growth and reduced endothelial Notch activation in the hindlimb ischemia model leading to impaired blood flow recovery 19 .	Furthermore, adult heterozygous Dll1 mice demonstrate impaired collateral growth and reduced endothelial Notch activation in the hindlimb ischemia model leading to impaired blood flow recovery 19.	4	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	4	5	13	14
Available Notch1 staining decreased to background levels in a dose dependent fashion with increasing expression of either Dll1 or Jag1 , indicating that both Dll1 and Jag1 ligands can fully reduce Notch availability .	Available Notch1 staining decreased to background levels in a dose dependent fashion with increasing expression of either Dll1 or Jag1, indicating that both Dll1 and Jag1 ligands can fully reduce Notch availability.	23	32	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	24	25	31	32
In the adult , Notch plays an important role in satellite cell expansion during muscle regeneration , and inadequate Notch signaling caused by reduced expression of Dll1 in aging muscle contributes to the loss of its regenerative potential .	In the adult, Notch plays an important role in satellite cell expansion during muscle regeneration, and inadequate Notch signaling caused by reduced expression of Dll1 in aging muscle contributes to the loss of its regenerative potential.	19	29	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Dll1	expression of Dll1	dll1	Notch	Notch	notch	26	27	19	20
Similarly soluble forms of human Jagged-1 and DLL-1 composed only of the extracellular domain were reported to inhibit Notch signaling .	Similarly soluble forms of human Jagged-1 and DLL-1 composed only of the extracellular domain were reported to inhibit Notch signaling.	2	19	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL-1	DLL-1	DLL-1	Notch	Notch	Notch	7	8	18	19
The LRRK2 , NEURL4 , and HERC2 complex slows the turnover of Dll1 , which negatively regulates Notch signaling .	The LRRK2, NEURL4, and HERC2 complex slows the turnover of Dll1, which negatively regulates Notch signaling.	10	18	negatively regulates	Negative_activation_syntax_5_verb	Positive_activation	Positive_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	12	13	17	18
The effects of ADAM10 deletion on MZB development , CD21/35 expression , Dtx1 expression , and Dll1 stimulated Notch signaling clearly demonstrate ADAM10 ' s role in Notch2 signaling .	The effects of ADAM10 deletion on MZB development, CD21/35 expression, Dtx1 expression, and Dll1 stimulated Notch signaling clearly demonstrate ADAM10 's role in Notch2 signaling.	4	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	16	17	18	19
Lfng in the Dll1 expressing cell , in the presence of Dll3 , is known to reduce Notch activity in the neighbouring cell .	Lfng in the Dll1 expressing cell, in the presence of Dll3, is known to reduce Notch activity in the neighbouring cell.	3	18	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	3	4	17	18
In order to determine if 20S and Shh induce Notch target gene expression in M2 cells through the canonical Notch signaling pathway , we examined whether 20S and Shh induce the mRNA expression of ligands and the Notch receptors Jagged-1 and -2 ; Delta-1 , -3 , and -4 ; and Notch-1 , -2 , -3 , and -4 that interact to activate the canonical Notch signaling .	In order to determine if 20S and Shh induce Notch target gene expression in M2 cells through the canonical Notch signaling pathway, we examined whether 20S and Shh induce the mRNA expression of ligands and the Notch receptors Jagged-1 and -2; Delta-1, -3, and -4; and Notch-1, -2, -3, and -4 that interact to activate the canonical Notch signaling.	28	66	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Delta-1	Shh induce the mRNA expression of ligands and the Notch receptors Jagged-1 and -2; Delta-1	delta-1	Notch	Notch	notch	43	44	65	66
As expected , elimination of fucose at these sites caused a substantial reduction in Dll1 induced Notch signaling in natural fucose , while the EGF8/12 double mutant had essentially no activity ( XREF_FIG ) .	As expected, elimination of fucose at these sites caused a substantial reduction in Dll1 induced Notch signaling in natural fucose, while the EGF8/12 double mutant had essentially no activity (XREF_FIG).	12	17	induced	Positive_early_activation	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	14	15	16	17
The same was seen when Notch signaling , instead of being artificially activated , was inactivated by mutations in Notch1 , or Dll1 ( Delta1 ) , or Pofut1 ( coding for an enzyme that fucosylates Notch and is required for Notch function ) .	The same was seen when Notch signaling, instead of being artificially activated, was inactivated by mutations in Notch1, or Dll1 (Delta1), or Pofut1 (coding for an enzyme that fucosylates Notch and is required for Notch function).	5	23	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	22	23	5	6
However , when Lfng or Mfng is expressed , only Dll1 , and not Jag1 , is able to reduce Notch availability to background levels .	However, when Lfng or Mfng is expressed, only Dll1, and not Jag1, is able to reduce Notch availability to background levels.	9	21	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	10	11	20	21
Soluble forms of the DSL type ligands Dll1 and Jagged1 have also been successfully used to inhibit Notch signaling .	Soluble forms of the DSL type ligands Dll1 and Jagged1 have also been successfully used to inhibit Notch signaling.	1	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	7	8	17	18
However , we do show that Jag1 can act as an inhibitor of Dll1 induced Notch activation when Notch is glycosylated and that Mfng is highly expressed in endocrine progenitors .	However, we do show that Jag1 can act as an inhibitor of Dll1 induced Notch activation when Notch is glycosylated and that Mfng is highly expressed in endocrine progenitors.	11	16	induced	Positive_early_activation	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	13	14	15	16
However , in contrast to what had been proposed based on in vitro assays [ XREF_BIBR ] , we provide here strong evidence that Dll1 reduces Notch activity cell autonomously through a Cis-inhibition mechanism .	However, in contrast to what had been proposed based on in vitro assays [XREF_BIBR], we provide here strong evidence that Dll1 reduces Notch activity cell autonomously through a Cis-inhibition mechanism.	24	28	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch	Notch	Notch	24	25	26	27
However , Ladi et al reported that DLL3 does not bind or activate any of the known mammalian Notch receptors when presented in trans , although DLL3 inhibited ligand induced Notch signaling when coexpressed with Notch at the cell surface in cis .	However, Ladi et al reported that DLL3 does not bind or activate any of the known mammalian Notch receptors when presented in trans, although DLL3 inhibited ligand induced Notch signaling when coexpressed with Notch at the cell surface in cis.	26	31	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	26	27	30	31
Overexpression of Dll3 in mammalian cells blocks Notch signaling and in Xenopus embyros produces phenotypes indicative of loss of Notch signaling , supporting the notion that Dll3 is a Notch antagonist .	Overexpression of Dll3 in mammalian cells blocks Notch signaling and in Xenopus embyros produces phenotypes indicative of loss of Notch signaling, supporting the notion that Dll3 is a Notch antagonist.	0	8	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll3	Overexpression of Dll3	dll3	Notch	Notch	notch	2	3	7	8
With hypofractionated radiotherapy regimen in mind , it was remarkable that DLL3 , a divergent Notch ligand family member that does not activate Notch signaling in adjacent cells but inhibits Notch receptors when expressed in the same cell [ XREF_BIBR ] , was consistently induced after higher doses of 6 and 8 Gy , suggesting that signaling relevant for breast cancer stem cells at these large fractions differs from signaling seen after conventional fractions of 2 Gy .	With hypofractionated radiotherapy regimen in mind, it was remarkable that DLL3, a divergent Notch ligand family member that does not activate Notch signaling in adjacent cells but inhibits Notch receptors when expressed in the same cell [XREF_BIBR], was consistently induced after higher doses of 6 and 8 Gy, suggesting that signaling relevant for breast cancer stem cells at these large fractions differs from signaling seen after conventional fractions of 2 Gy.	11	44	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	11	12	30	31
If DLL3 inhibits Notch in vivo , loss of Dll3 function should lead to increased Notch activity and , thus , up-regulation of Notch target genes .	If DLL3 inhibits Notch in vivo, loss of Dll3 function should lead to increased Notch activity and, thus, up-regulation of Notch target genes.	1	5	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	1	2	3	4
Although it is unclear how Dll3 inhibits Notch signaling in these cellular contexts , Dll3 coexpressed with Notch is detected at the cell surface and binds Notch , suggesting a role for Dll3 in cis-inhibition .	Although it is unclear how Dll3 inhibits Notch signaling in these cellular contexts, Dll3 coexpressed with Notch is detected at the cell surface and binds Notch, suggesting a role for Dll3 in cis-inhibition.	5	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	5	6	7	8
Overexpression of DLL3 did not reduce baseline Notch activity , but significantly inhibited Notch activation mediated by fibulin-3 or the canonical ligand Jagged-1 .	Overexpression of DLL3 did not reduce baseline Notch activity, but significantly inhibited Notch activation mediated by fibulin-3 or the canonical ligand Jagged-1.	0	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL3	Overexpression of DLL3	dll3	Notch	Notch	notch	2	3	13	14
DLL3 contributes to neuroendocrine tumorigenesis by inhibiting the Notch signaling pathway , whose role is to suppress tumor growth .	DLL3 contributes to neuroendocrine tumorigenesis by inhibiting the Notch signaling pathway, whose role is to suppress tumor growth.	0	10	contributes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	0	1	8	9
Dll3flag did not affect the normal expression of Wg induced along the dorsoventral border by endogenous Dl and Ser in the ptc domain overlapping with the dorsoventral border ( XREF_FIG , arrowheads ) , indicating that expression of Dll3 does not block Notch activation by the endogenous ligands .	Dll3flag did not affect the normal expression of Wg induced along the dorsoventral border by endogenous Dl and Ser in the ptc domain overlapping with the dorsoventral border (XREF_FIG, arrowheads), indicating that expression of Dll3 does not block Notch activation by the endogenous ligands.	36	43	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll3	expression of Dll3	dll3	Notch	Notch	notch	38	39	42	43
Biochemical studies have shown that DLL3 inhibits Notch signaling and DLL4 increases Notch signaling in various contexts .	Biochemical studies have shown that DLL3 inhibits Notch signaling and DLL4 increases Notch signaling in various contexts.	5	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	5	6	7	8
This is because in vitro DLL3 did not activate Notch in trans , but rather inhibited Notch signaling when expressed in the same cell as Notch .	This is because in vitro DLL3 did not activate Notch in trans, but rather inhibited Notch signaling when expressed in the same cell as Notch.	1	15	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	5	6	9	10
In the course of normal development , DLL3 inhibits Notch pathway activation by interacting with Notch and DLL1 and redirecting or retaining them to the late endosomal/lysosomal compartments or in the Golgi , respectively , thereby preventing their localization to the cell surface .	In the course of normal development, DLL3 inhibits Notch pathway activation by interacting with Notch and DLL1 and redirecting or retaining them to the late endosomal/lysosomal compartments or in the Golgi, respectively, thereby preventing their localization to the cell surface.	7	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	7	8	9	10
This suggests for the first time a mechanism for Dll3 mediated cis-inhibition of Notch signalling , with Dll3 targeting newly synthesized Notch1 for lysosomal degradation prior to post-translational processing and cell surface presentation of the receptor .	This suggests for the first time a mechanism for Dll3 mediated cis-inhibition of Notch signalling, with Dll3 targeting newly synthesized Notch1 for lysosomal degradation prior to post-translational processing and cell surface presentation of the receptor.	7	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	9	10	13	14
By inhibiting the Notch receptor pathway , DLL3 might promote neuroendocrine tumorigenesis .	By inhibiting the Notch receptor pathway, DLL3 might promote neuroendocrine tumorigenesis.	3	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	7	8	3	4
Null alleles of Dll3 disrupt transcriptional oscillation of some Notch pathway genes expressed in the PSM , as well as genes involved in determining the rostrocaudal polarity of the somite .	Null alleles of Dll3 disrupt transcriptional oscillation of some Notch pathway genes expressed in the PSM, as well as genes involved in determining the rostrocaudal polarity of the somite.	1	11	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll3	Dll3	Dll3	Notch	Notch	Notch	3	4	9	10
Mutation of the O fucosylation sites in DLL3 does not disrupt the interaction of DLL3 with LFNG or full length Notch1or DLL1 , and O-fucosylation-deficient DLL3 can still inhibit Notch in cis in vitro .	Mutation of the O fucosylation sites in DLL3 does not disrupt the interaction of DLL3 with LFNG or full length Notch1or DLL1, and O-fucosylation-deficient DLL3 can still inhibit Notch in cis in vitro.	24	31	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch	Notch	Notch	25	26	29	30
In summary , our cis-inhibition assays ( XREF_FIG ) reveal a functional difference between DLL1 and DLL4 that was not evident in the trans-activation assays ( XREF_FIG ) : DLL4 , but not DLL1 , is a potent cis-inhibitor of NOTCH1 and cis-inhibition by DLL4 can significantly reduce Notch activation .	In summary, our cis-inhibition assays (XREF_FIG) reveal a functional difference between DLL1 and DLL4 that was not evident in the trans-activation assays (XREF_FIG) : DLL4, but not DLL1, is a potent cis-inhibitor of NOTCH1 and cis-inhibition by DLL4 can significantly reduce Notch activation.	29	41	is a potent cis-inhibitor	Negative_activation_copula_1	Positive_activation	Negative_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	29	30	40	41
We highlight a study in non small cell lung cancer cells ( NSCLC ) revealing a tumor suppressive role for endothelial cell Dll4 activated Notch1 and the underlying molecular mechanism involving suppression of PI3K signaling .	We highlight a study in non small cell lung cancer cells (NSCLC) revealing a tumor suppressive role for endothelial cell Dll4 activated Notch1 and the underlying molecular mechanism involving suppression of PI3K signaling.	18	29	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	22	23	24	25
In tumour vasculature , inhibition of Dll4 mediated Notch1 signaling leads to increased sprouting but unproductive angiogenesis .	In tumour vasculature, inhibition of Dll4 mediated Notch1 signaling leads to increased sprouting but unproductive angiogenesis.	4	9	mediated	Positive_early_activation	Positive_activation	Negative_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	6	7	8	9
Considering recent studies suggesting that the level of Notch signaling activation must be attenuated during the HE to HSC transition , it is interesting to speculate that co-expression of Dll4 with Notch1 on the surface of an HSC precursor could serve to limit Notch1 receptor activation by cis-inhibition , a well established mechanism regulating Notch signaling in other development systems .	Considering recent studies suggesting that the level of Notch signaling activation must be attenuated during the HE to HSC transition, it is interesting to speculate that co-expression of Dll4 with Notch1 on the surface of an HSC precursor could serve to limit Notch1 receptor activation by cis-inhibition, a well established mechanism regulating Notch signaling in other development systems.	27	45	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll4	co-expression of Dll4	dll4	Notch1	Notch1	notch1	29	30	43	44
Galectin-1 knockdown alters Notch-1 activation induced by Delta-4 whereas galectin-3 knockdown alters jagged-1-mediated Notch-1 activation .	Galectin-1 knockdown alters Notch-1 activation induced by Delta-4 whereas galectin-3 knockdown alters jagged-1-mediated Notch-1 activation.	3	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Delta-4	Delta-4	Delta-4	Notch-1	Notch-1	Notch-1	7	8	3	4
DLL4 silencing inhibits GCSPC metastatic potential both in vitro and in vivo by impeding Notch-1 signaling pathway activation , indicating that DLL4 may be a new potential therapeutic target .	DLL4 silencing inhibits GCSPC metastatic potential both in vitro and in vivo by impeding Notch-1 signaling pathway activation, indicating that DLL4 may be a new potential therapeutic target.	0	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	DLL4	DLL4	DLL4	Notch-1	Notch-1	Notch-1	0	1	14	15
The soluble DLL4 SLP ( N-EGF5 ) effectively inhibited Notch1 activation ( XREF_FIG ) .	The soluble DLL4 SLP (N-EGF5) effectively inhibited Notch1 activation (XREF_FIG).	2	10	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL4	DLL4	DLL4	Notch1	Notch1	Notch1	2	3	9	10
XREF_BIBR Blockade of DLL4 mediated NOTCH1 signaling causes excessive angiogenic sprouting and branching resulting in a chaotic vascular network with defective functions .	XREF_BIBR Blockade of DLL4 mediated NOTCH1 signaling causes excessive angiogenic sprouting and branching resulting in a chaotic vascular network with defective functions.	1	6	mediated	Positive_early_activation	Positive_activation	Negative_activation	DLL4	DLL4	DLL4	NOTCH1	NOTCH1	NOTCH1	3	4	5	6
For example , the disruption of Dll4 or endothelium specific loss of Notch1 increases the superficial plexus vascular density and causes an excess of angiogenic sprouts .	For example, the disruption of Dll4 or endothelium specific loss of Notch1 increases the superficial plexus vascular density and causes an excess of angiogenic sprouts.	6	13	loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Dll4	Dll4	Dll4	Notch1	Notch1	Notch1	6	7	12	13
Inhibition of Cdk5 by either knockdown or pharmacologic approaches decreased Dll4 induced NICD generation .	Inhibition of Cdk5 by either knockdown or pharmacologic approaches decreased Dll4 induced NICD generation.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	Dll4	Dll4	Dll4	NICD	NICD	NICD	10	11	12	13
Dtx1 did not regulate the Notch-HES and Her pathway during neuronal differentiation ; on the contrary , Dtx1 reciprocally inhibited Notch during glial differentiation .	Dtx1 did not regulate the Notch-HES and Her pathway during neuronal differentiation; on the contrary, Dtx1 reciprocally inhibited Notch during glial differentiation.	17	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dtx1	Dtx1	Dtx1	Notch	Notch	Notch	17	18	20	21
To investigate whether DTX1 antagonizes NOTCH signaling in osteosarcoma , we overexpressed DTX1 in OS187 cells .	To investigate whether DTX1 antagonizes NOTCH signaling in osteosarcoma, we overexpressed DTX1 in OS187 cells.	3	6	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DTX1	DTX1	DTX1	NOTCH	NOTCH	NOTCH	3	4	5	6
This mechanism appears to regulate invasion of osteosarcoma cells , as Deltex1 blocks osteosarcoma invasiveness by downregulating NOTCH and HES1 signaling .	This mechanism appears to regulate invasion of osteosarcoma cells, as Deltex1 blocks osteosarcoma invasiveness by downregulating NOTCH and HES1 signaling.	11	20	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Deltex1	Deltex1	Deltex1	NOTCH	NOTCH	NOTCH	11	12	17	18
Deltex1 is highly induced by Notch signaling in thymocytes , and overexpression of Deltex1 in T-cell progenitors can block Notch signals , suggesting that Deltex1 may play an important role in regulating Notch signals during T-cell development .	Deltex1 is highly induced by Notch signaling in thymocytes, and overexpression of Deltex1 in T-cell progenitors can block Notch signals, suggesting that Deltex1 may play an important role in regulating Notch signals during T-cell development.	11	20	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Deltex1	overexpression of Deltex1	deltex1	Notch	Notch	notch	13	14	19	20
DTX1 over-expression inhibits Notch signaling , as demonstrated by enhanced B cell lymphocyte development and suppressed T cell development [ XREF_BIBR , XREF_BIBR ] .	DTX1 over-expression inhibits Notch signaling, as demonstrated by enhanced B cell lymphocyte development and suppressed T cell development [XREF_BIBR, XREF_BIBR].	0	4	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DTX1	DTX1 over-expression	dtx1	Notch	Notch	notch	0	1	3	4
One mechanism by which DTX1 may negatively regulate NOTCH is through ubiquitination ; DTX1 may be an E3 ubiquitin ligase , as it contains a RING finger and two WWE domains [ XREF_BIBR ] .	One mechanism by which DTX1 may negatively regulate NOTCH is through ubiquitination; DTX1 may be an E3 ubiquitin ligase, as it contains a RING finger and two WWE domains [XREF_BIBR].	4	9	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DTX1	DTX1	DTX1	NOTCH	NOTCH	NOTCH	4	5	8	9
First , we demonstrate that endogenous DTX1 negatively regulates NOTCH dependent transcriptional activity in osteosarcoma cells and that DTX1 physically binds to ICN1 , inducing ubiquitination and degradation of ICN1 .	First, we demonstrate that endogenous DTX1 negatively regulates NOTCH dependent transcriptional activity in osteosarcoma cells and that DTX1 physically binds to ICN1, inducing ubiquitination and degradation of ICN1.	5	12	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DTX1	DTX1	DTX1	NOTCH	NOTCH	NOTCH	6	7	9	10
DTX1 downregulates NOTCH signaling by ubiquitination of ICN .	DTX1 downregulates NOTCH signaling by ubiquitination of ICN.	0	3	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DTX1	DTX1	DTX1	NOTCH	NOTCH	NOTCH	0	1	2	3
Loss of DLL1 function abolishes formation of NICD in the PSM , indicating that DLL1 is the major activator of Notch1 in the PSM .	Loss of DLL1 function abolishes formation of NICD in the PSM, indicating that DLL1 is the major activator of Notch1 in the PSM.	14	23	is the major activator	Positive_activation_copula_1	Positive_activation	Positive_activation	DLL1	DLL1	DLL1	Notch1	Notch1	Notch1	14	15	20	21
Faster decay rates of Dll1 and Notch1 protein and mRNA reduce NICD amplitudes and the differences between maximum and minimum NICD amplitudes , but the HES7 amplitude and max .-min .	Faster decay rates of Dll1 and Notch1 protein and mRNA reduce NICD amplitudes and the differences between maximum and minimum NICD amplitudes, but the HES7 amplitude and max.-min.	4	12	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	NICD	NICD	NICD	4	5	11	12
In contrast , treatment with fucose analogs 10 and 11 reduced Dll1 induced Notch1 signaling to background levels ( XREF_FIG ) .	In contrast, treatment with fucose analogs 10 and 11 reduced Dll1 induced Notch1 signaling to background levels (XREF_FIG).	3	14	induced	Positive_early_activation	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	Notch1	Notch1	Notch1	11	12	13	14
Conversely , in foetal arteries where both ligands are expressed in the vascular endothelium [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] inactivation of Dll1 causes loss of NOTCH1 activation despite the presence of DLL4 [ XREF_BIBR ] suggesting that DLL4 can not compensate for the loss of DLL1 in fetal endothelial cells .	Conversely, in foetal arteries where both ligands are expressed in the vascular endothelium [XREF_BIBR, XREF_BIBR, XREF_BIBR] inactivation of Dll1 causes loss of NOTCH1 activation despite the presence of DLL4 [XREF_BIBR] suggesting that DLL4 can not compensate for the loss of DLL1 in fetal endothelial cells.	21	28	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Dll1	Dll1	Dll1	NOTCH1	NOTCH1	NOTCH1	23	24	27	28
NOTCH1 is regulated by NUMB , which affects nuclear localization by targeting the transmembrane form of NOTCH1 for ubiquitination by the E3 ligase Itch , resulting in its degradation , and by DELTEX1 , which can both inhibit and activate NOTCH1 signaling .	NOTCH1 is regulated by NUMB, which affects nuclear localization by targeting the transmembrane form of NOTCH1 for ubiquitination by the E3 ligase Itch, resulting in its degradation, and by DELTEX1, which can both inhibit and activate NOTCH1 signaling.	2	41	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DELTEX1	DELTEX1	DELTEX1	NOTCH1	NOTCH1	NOTCH1	32	33	40	41
DTX1 negatively regulates NOTCH1 and HES1 signaling and osteosarcoma invasiveness .	DTX1 negatively regulates NOTCH1 and HES1 signaling and osteosarcoma invasiveness.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DTX1	DTX1	DTX1	NOTCH1	NOTCH1	NOTCH1	0	1	3	4
The DN-MAML led to suppression of Notch1 targets Dtx1 and Ptcra but did not affect Lef1 or Notch1 ( XREF_FIG ) .	The DN-MAML led to suppression of Notch1 targets Dtx1 and Ptcra but did not affect Lef1 or Notch1 (XREF_FIG).	2	10	targets	Positive_activation_token_1_noun	Positive_activation	Negative_activation	Dtx1	Dtx1	Dtx1	Notch1	Notch1	Notch1	8	9	6	7
DTX1 and DTX3L , functioning as a heterodimeric Notch E3 ligase , concertedly downregulate NOTCH1 activity and enhance lymphatic sprouting .	DTX1 and DTX3L, functioning as a heterodimeric Notch E3 ligase, concertedly downregulate NOTCH1 activity and enhance lymphatic sprouting.	0	17	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DTX1	DTX1	DTX1	NOTCH1	NOTCH1	NOTCH1	0	1	14	15
We find that DTX1 silencing leads to enhanced Notch1 recycling from this compartment to the cell surface via a rab4a mediated transport route .	We find that DTX1 silencing leads to enhanced Notch1 recycling from this compartment to the cell surface via a rab4a mediated transport route.	3	12	leads	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	DTX1	DTX1	DTX1	Notch1	Notch1	Notch1	3	4	8	9
CaNDY inhibited DYRK1A , DYRK1B , CLK1 , CLK2 , and Haspin by over 90 % ( XREF_FIG , XREF_SUPPLEMENTARY , and XREF_SUPPLEMENTARY ) .	CaNDY inhibited DYRK1A, DYRK1B, CLK1, CLK2, and Haspin by over 90% (XREF_FIG, XREF_SUPPLEMENTARY, and XREF_SUPPLEMENTARY).	0	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CaNDY	CaNDY	CaNDY	DYRK1A	DYRK1A	DYRK1A	0	1	2	3
To examine whether CaNDY inhibits the catalytic activity of DYRK1A , we performed an in vitro kinase assay using recombinant DYRK1A and a substrate peptide .	To examine whether CaNDY inhibits the catalytic activity of DYRK1A, we performed an in vitro kinase assay using recombinant DYRK1A and a substrate peptide.	3	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CaNDY	CaNDY	CaNDY	DYRK1A	DYRK1A	DYRK1A	3	4	9	10
Overexpression of miR-1246 reduces DYRK1A levels and leads to the nuclear retention of NFATc1 , a protein substrate of DYRK1A , and the induction of apoptosis , whereas a miR-1246-specific inhibitor prevented the nuclear import of NFATc1 .	Overexpression of miR-1246 reduces DYRK1A levels and leads to the nuclear retention of NFATc1, a protein substrate of DYRK1A, and the induction of apoptosis, whereas a miR-1246-specific inhibitor prevented the nuclear import of NFATc1.	0	20	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	DYRK1A	Overexpression of miR-1246 reduces DYRK1A levels	dyrk1a	DYRK1A	DYRK1A	dyrk1a	4	5	19	20
Next we examined whether CaNDY decreased endogenous DYRK1A protein .	Next we examined whether CaNDY decreased endogenous DYRK1A protein.	4	8	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CaNDY	CaNDY	CaNDY	DYRK1A	DYRK1A	DYRK1A	4	5	7	8
Expression of DYRK1A increased during the 4-days culture , and CaNDY prevented accumulation of endogenous DYRK1A ( XREF_FIG and XREF_SUPPLEMENTARY ) , whereas ganetespib also prevented it ( XREF_SUPPLEMENTARY ) .	Expression of DYRK1A increased during the 4-days culture, and CaNDY prevented accumulation of endogenous DYRK1A (XREF_FIG and XREF_SUPPLEMENTARY), whereas ganetespib also prevented it (XREF_SUPPLEMENTARY).	10	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CaNDY	CaNDY	CaNDY	DYRK1A	DYRK1A	DYRK1A	10	11	15	16
Unlike other mammalian Notch family members , DLL3 is predominantly located in the Golgi apparatus and inhibits Notch 1 signalling in cis 120 .	Unlike other mammalian Notch family members, DLL3 is predominantly located in the Golgi apparatus and inhibits Notch 1 signalling in cis 120.	7	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch 1	Notch 1	Notch 1	7	8	17	19
Although our results are consistent with DLL3 activating Notch1 in the neural stem cell compartment at mid gestation , in other systems DLL3 might also behave as inhibitor of Notch1 , possibly through competition with other Notch ligands .	Although our results are consistent with DLL3 activating Notch1 in the neural stem cell compartment at mid gestation, in other systems DLL3 might also behave as inhibitor of Notch1, possibly through competition with other Notch ligands.	22	30	behave as inhibitor	Negative_activation_copula_1	Positive_activation	Negative_activation	DLL3	DLL3	DLL3	Notch1	Notch1	Notch1	22	23	29	30
Inactivation of AKT signalling attenuated DVL1 mediated inhibition of GSK-3beta and accumulation of beta-catenin , in both A2780 and A2780 and Taxol cells .	Inactivation of AKT signalling attenuated DVL1 mediated inhibition of GSK-3beta and accumulation of beta-catenin, in both A2780 and A2780 and Taxol cells.	5	14	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	DVL1	DVL1	DVL1	beta-catenin	beta-catenin	beta-catenin	5	6	13	14
Overexpression of Dvl-1 abrogated H2O2 induced downregulation of beta-catenin .	Overexpression of Dvl-1 abrogated H2O2 induced downregulation of beta-catenin.	0	9	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Dvl-1	Overexpression of Dvl-1	dvl-1	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
In addition , Dyrk1A also promotes the inhibitory effect of RCAN1 on calcineurin through its kinase activity .	In addition, Dyrk1A also promotes the inhibitory effect of RCAN1 on calcineurin through its kinase activity.	3	12	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Dyrk1A	Dyrk1A	Dyrk1A	RCAN1	RCAN1	RCAN1	3	4	10	11
In addition , PKA and Dyrk1A increase the calcineurin inhibitory effect of RCAN1 XREF_BIBR , XREF_BIBR .	In addition, PKA and Dyrk1A increase the calcineurin inhibitory effect of RCAN1 XREF_BIBR, XREF_BIBR.	3	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Dyrk1A	Dyrk1A	Dyrk1A	RCAN1	RCAN1	RCAN1	5	6	12	13
XREF_FIG , SW403 cells treated with GR exhibited increasing expression , in a GR dose dependent manner , of Axin1 and decreasing expression of Dvl2 , p-GSK-3beta , LEF1 and TCF4 as compared with control .	XREF_FIG, SW403 cells treated with GR exhibited increasing expression, in a GR dose dependent manner, of Axin1 and decreasing expression of Dvl2, p-GSK-3beta, LEF1 and TCF4 as compared with control.	19	30	decreasing	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	Dvl2	expression of Dvl2	dvl2	Axin1	Axin1	axin1	24	25	19	20
7 Ectopic expression of ephrin-A1 in hTCEpi cells reduced the expression and junctional distribution of EphA2 ( XREF_FIG A , XREF_FIG B ) .	7 Ectopic expression of ephrin-A1 in hTCEpi cells reduced the expression and junctional distribution of EphA2 (XREF_FIG A, XREF_FIG B).	2	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ephrin-A1	expression of ephrin-A1	ephrin-a1	EphA2	EphA2	epha2	4	5	15	16
SHIP2 silencing enhanced EphrinA1 induced EphA2 internalization and degradation [ XREF_BIBR ] .	SHIP2 silencing enhanced EphrinA1 induced EphA2 internalization and degradation [XREF_BIBR].	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EphrinA1	EphrinA1	EphrinA1	EphA2	EphA2	EphA2	3	4	5	6
In some cell types , such as glioblastoma multiforme cells , EFNA1 expression downregulates EPHA2 and suppresses EPHA2 mediated oncogenesis [ XREF_BIBR , XREF_BIBR ] .	In some cell types, such as glioblastoma multiforme cells, EFNA1 expression downregulates EPHA2 and suppresses EPHA2 mediated oncogenesis [XREF_BIBR, XREF_BIBR].	11	15	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EFNA1	EFNA1 expression	efna1	EPHA2	EPHA2	epha2	11	12	14	15
We reasoned , since ephrin-A1 is the prototypic ligand of EPHA2 receptor and loss of ephrin-A1 can augment EPHA2 activity , that EPHA2 overexpression should have a similar effect on GLS activity and tumor cell growth as ephrin-A1 deficiency .	We reasoned, since ephrin-A1 is the prototypic ligand of EPHA2 receptor and loss of ephrin-A1 can augment EPHA2 activity, that EPHA2 overexpression should have a similar effect on GLS activity and tumor cell growth as ephrin-A1 deficiency.	13	19	augment	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	loss of ephrin-A1	ephrin-a1	EPHA2	EPHA2	epha2	15	16	18	19
The two compounds did not decrease EphA2 levels in unstimulated PC3 cells and did not substantially accelerate EphA2 degradation induced by the ephrin-A1 Fc ligand ( Supplemental Figure S2 , B and C ) .	The two compounds did not decrease EphA2 levels in unstimulated PC3 cells and did not substantially accelerate EphA2 degradation induced by the ephrin-A1 Fc ligand (Supplemental Figure S2, B and C).	17	24	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	22	23	17	18
EphrinA1 stimulation has been observed in many cell types and systems to suppress the malignant character of EphA2 overexpressing tumor cells , both in vitro and in vivo , causing a profound change in cytoskeletal architecture involving the loss of processes and polarity , suppression of migration and invasion , defects in colony formation in soft agar , and decreased tumor growth in vivo .	EphrinA1 stimulation has been observed in many cell types and systems to suppress the malignant character of EphA2 overexpressing tumor cells, both in vitro and in vivo, causing a profound change in cytoskeletal architecture involving the loss of processes and polarity, suppression of migration and invasion, defects in colony formation in soft agar, and decreased tumor growth in vivo.	0	18	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EphrinA1	EphrinA1	EphrinA1	EphA2	EphA2	EphA2	0	1	17	18
However , in view of the potential role of ephrin-A1 in angiogenesis and metastasis , inhibiting EPHA2 receptor , rather than focusing on overexpressing ephrin-A1 , may improve future targeting strategies .	However, in view of the potential role of ephrin-A1 in angiogenesis and metastasis, inhibiting EPHA2 receptor, rather than focusing on overexpressing ephrin-A1, may improve future targeting strategies.	7	17	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ephrin-A1	ephrin-A1	ephrin-A1	EPHA2	EPHA2	EPHA2	9	10	16	17
EphrinA1 overexpression downregulates EphA2 and suppresses malignant properties of GBM cells .	EphrinA1 overexpression downregulates EphA2 and suppresses malignant properties of GBM cells.	0	4	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EphrinA1	EphrinA1 overexpression	ephrina1	EphA2	EphA2	epha2	0	1	3	4
In view of these observations , we propose a model for EphA2 and ephrin-A 1 actions in epidermal homeostasis , in which ephrin-A1 ligand down-regulates EphA2 to allow for normal differentiation .	In view of these observations, we propose a model for EphA2 and ephrin-A 1 actions in epidermal homeostasis, in which ephrin-A1 ligand down-regulates EphA2 to allow for normal differentiation.	22	26	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	22	23	25	26
We found that compound 76D10 inhibits EphA2 tyrosine phosphorylation in response to stimulation with the angiogenic factor TNFalpha ( XREF_FIG ) , which is known to rapidly upregulate expression of endogenous ephrin-A1 thus causing EphA2 activation in endothelial cells .	We found that compound 76D10 inhibits EphA2 tyrosine phosphorylation in response to stimulation with the angiogenic factor TNFalpha (XREF_FIG), which is known to rapidly upregulate expression of endogenous ephrin-A1 thus causing EphA2 activation in endothelial cells.	17	35	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ephrin-A1	TNFalpha (XREF_FIG), which is known to rapidly upregulate expression of endogenous ephrin-A1	ephrin-a1	EphA2	EphA2	epha2	31	32	34	35
Several studies have found that EFNA1 may suppress EPHA2 mediated oncogenesis , or enhance it , depending on cell type and context .	Several studies have found that EFNA1 may suppress EPHA2 mediated oncogenesis, or enhance it, depending on cell type and context.	5	13	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EFNA1	EFNA1	EFNA1	EPHA2	EPHA2	EPHA2	5	6	8	9
Silencing Tiam1 impaired both ephrinA1 dependent activation of Rac1 and EphA2 endocytosis , definitely establishing Tiam1 as an important modulator of EphA2 signalling .	Silencing Tiam1 impaired both ephrinA1 dependent activation of Rac1 and EphA2 endocytosis, definitely establishing Tiam1 as an important modulator of EphA2 signalling.	4	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	4	5	10	11
We therefore investigated whether enhanced Ship2 activity downstream of EphA2 may be responsible for Akt inhibition in cells treated with ephrin-A1 through a reduction of PI ( 3,4,5 ) P3 levels .	We therefore investigated whether enhanced Ship2 activity downstream of EphA2 may be responsible for Akt inhibition in cells treated with ephrin-A1 through a reduction of PI (3,4,5) P3 levels.	6	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	ephrin-A1	ephrin-A1	ephrin-A1	EphA2	EphA2	EphA2	20	21	9	10
These data suggest that in Efna1 expressing tumors , EFNA1 mediated degradation of EPHA2 prevents metastasis .	These data suggest that in Efna1 expressing tumors, EFNA1 mediated degradation of EPHA2 prevents metastasis.	9	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EFNA1	EFNA1	EFNA1	EPHA2	EPHA2	EPHA2	9	10	13	14
EFNA1 can also inhibit EPHA2 mediated breast cancer metastasis .	EFNA1 can also inhibit EPHA2 mediated breast cancer metastasis.	0	8	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EFNA1	EFNA1	EFNA1	EPHA2	EPHA2	EPHA2	0	1	4	5
Third , we found that the natural EphA2 selective ligand , ephrinA1 , reduced EphA2 signaling and enhanced VEM responsiveness .	Third, we found that the natural EphA2 selective ligand, ephrinA1, reduced EphA2 signaling and enhanced VEM responsiveness.	9	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	11	12	14	15
Disrupting Tiam1 function with RNA interference impaired both ephrinA1 dependent Rac1 activation and ephrinA1 induced EphA2 endocytosis .	Disrupting Tiam1 function with RNA interference impaired both ephrinA1 dependent Rac1 activation and ephrinA1 induced EphA2 endocytosis.	11	16	induced	Positive_early_activation	Positive_activation	Positive_activation	ephrinA1	ephrinA1	ephrinA1	EphA2	EphA2	EphA2	13	14	15	16
Here we show that in cancer cells , coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated , while ephrin-B2 can inhibit not only EphB4 but also EphA3 .	Here we show that in cancer cells, coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated, while ephrin-B2 can inhibit not only EphB4 but also EphA3.	9	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ephrin-A3	ephrin-A3	ephrin-A3	EphA3	EphA3	EphA3	9	10	17	18
We indeed found that ephrin-A3 overexpressed in lung cancer cells can inhibit EphA2 and EphA3 activation by ephrins in trans while overexpression of ephrin-B2 can inhibit activation of EphA3 and EphB4 .	We indeed found that ephrin-A3 overexpressed in lung cancer cells can inhibit EphA2 and EphA3 activation by ephrins in trans while overexpression of ephrin-B2 can inhibit activation of EphA3 and EphB4.	4	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ephrin-A3	ephrin-A3 overexpressed	ephrin-a3	EphA3	EphA3	epha3	4	5	14	15
To examine whether in cancer cells ephrin-A3 coexpression impairs the ability of EphA3 to bind ephrin-A ligands in trans , we measured the binding of soluble forms of ephrin-A5 or ephrin-A3 fused to alkaline phosphatase ( AP ) to NCI-H226 and A549 cells expressing EphA3 alone or together with mCherry-ephrin-A3 .	To examine whether in cancer cells ephrin-A3 coexpression impairs the ability of EphA3 to bind ephrin-A ligands in trans, we measured the binding of soluble forms of ephrin-A5 or ephrin-A3 fused to alkaline phosphatase (AP) to NCI-H226 and A549 cells expressing EphA3 alone or together with mCherry-ephrin-A3.	6	13	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ephrin-A3	ephrin-A3 coexpression	ephrin-a3	EphA3	EphA3	epha3	6	7	12	13
Pharmacological blockade of ETB or genetic mutation of ETB increases endogenous ET-1 levels , and therefore , increases ETA activation .	Pharmacological blockade of ETB or genetic mutation of ETB increases endogenous ET-1 levels, and therefore, increases ETA activation.	3	19	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ET-1	ETB or genetic mutation of ETB increases endogenous ET-1 levels	et-1	ETA	ETA	eta	11	12	18	19
These results indicated that the increased tissue level of endothelin-1 may decrease the ET-A receptor mediated vascular response to endothelin-1 .	These results indicated that the increased tissue level of endothelin-1 may decrease the ET-A receptor mediated vascular response to endothelin-1.	7	14	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	endothelin-1	level of endothelin-1	endothelin-1	ET-A	ET-A	et-a	9	10	13	14
Further , suppression of Pax2 ( inhibiting ET-1 ) or impairment of ET-1 signaling ( inhibition of ETAR and/or decrease of NFAT5 ) deactivated mitogen activated protein kinases ( MAPK ) and nuclear factor-kappa B ( NF-kappaB ) signaling pathways , supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling .	Further, suppression of Pax2 (inhibiting ET-1) or impairment of ET-1 signaling (inhibition of ETAR and/or decrease of NFAT5) deactivated mitogen activated protein kinases (MAPK) and nuclear factor-kappa B (NF-kappaB) signaling pathways, supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling.	12	19	inhibition	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	ET-1	ET-1	ET-1	ETAR	ETAR	ETAR	12	13	17	18
Ephrin-A3 coexpression also attenuated ephrin-A3 Fc induced activation of endogenous EphA2 in A549 cells ( XREF_FIG ) .	Ephrin-A3 coexpression also attenuated ephrin-A3 Fc induced activation of endogenous EphA2 in A549 cells (XREF_FIG).	4	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ephrin-A3	ephrin-A3	ephrin-A3	EphA2	EphA2	EphA2	4	5	10	11
Also , transcription of the Mirk gene itself is blocked in cycling cells through Akt and mTOR signaling causing Mirk to be highly expressed predominately in quiescent tumor cells .	Also, transcription of the Mirk gene itself is blocked in cycling cells through Akt and mTOR signaling causing Mirk to be highly expressed predominately in quiescent tumor cells.	2	23	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mirk	transcription of the Mirk	mirk	Mirk	Mirk	mirk	5	6	19	20
The results showed that both ephrin-A5 alpha and ephrin-A5 beta downregulated cyclin D2 , cyclin dependent kinase-4 proteins , and their cognate receptor EphA3 , which were associated with reduced bromodeoxyuridine incorporation in cardiomyocytes .	The results showed that both ephrin-A5 alpha and ephrin-A5 beta downregulated cyclin D2, cyclin dependent kinase-4 proteins, and their cognate receptor EphA3, which were associated with reduced bromodeoxyuridine incorporation in cardiomyocytes.	5	27	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ephrin-A5	ephrin-A5	ephrin-A5	EphA3	EphA3	EphA3	5	6	23	24
Similarly , fibulin-4 was shown to inhibit maturation of elastin like polypeptide but was less potent than fibulin-5 .	Similarly, fibulin-4 was shown to inhibit maturation of elastin like polypeptide but was less potent than fibulin-5.	2	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	fibulin-4	fibulin-4	fibulin-4	elastin	elastin	elastin	2	3	9	10
CCND1 and ELF4 are important in cell-cycle regulation , affecting the G 1 / S phase transition , whilst ELF4 and DYRK2 inhibit p53 mediated induction of apoptosis .	CCND1 and ELF4 are important in cell-cycle regulation, affecting the G 1 / S phase transition, whilst ELF4 and DYRK2 inhibit p53 mediated induction of apoptosis.	19	25	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DYRK2	DYRK2	DYRK2	p53	p53	p53	21	22	23	24
In all cases , 10 % , 0.5 % and 0 % serum , ET-1 reduced the growth rate of CHO ETB .	In all cases, 10%, 0.5% and 0% serum, ET-1 reduced the growth rate of CHO ETB.	14	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ET-1	ET-1	ET-1	ETB	ETB	ETB	14	15	21	22
The EphA4 receptor tyrosine kinase is a promising candidate in this regard , as EphA4 knockout mice display extensive axonal regeneration and functional recovery following spinal cord injury XREF_BIBR , an effect also seen when the EphA4 receptor is blocked by administration of soluble EphA4 decoy receptor or the ephrin-A5 ligand XREF_BIBR .	The EphA4 receptor tyrosine kinase is a promising candidate in this regard, as EphA4 knockout mice display extensive axonal regeneration and functional recovery following spinal cord injury XREF_BIBR, an effect also seen when the EphA4 receptor is blocked by administration of soluble EphA4 decoy receptor or the ephrin-A5 ligand XREF_BIBR.	36	51	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ephrin-A5	ephrin-A5	ephrin-A5	EphA4	EphA4	EphA4	49	50	36	37
EphrinA3 inhibits neurite outgrowth of EphA4 positive neurons in vitro .	EphrinA3 inhibits neurite outgrowth of EphA4 positive neurons in vitro.	0	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EphrinA3	EphrinA3	EphrinA3	EphA4	EphA4	EphA4	0	1	5	6
Together , these results indicate that Rab35 may promote EGF induced EGFR degradation via FLCN independent manner .	Together, these results indicate that Rab35 may promote EGF induced EGFR degradation via FLCN independent manner.	9	12	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
However , in this report we demonstrate that inhibition of epidermal growth factor ( EGF )-stimulated PI3K activity by expression of the kinase deficient PI3K p110 subunit ( p110delta kin ) does not block the lysosomal targeting and degradation of the EGF receptor ( EGFR ) .	However, in this report we demonstrate that inhibition of epidermal growth factor (EGF)-stimulated PI3K activity by expression of the kinase deficient PI3K p110 subunit (p110delta kin) does not block the lysosomal targeting and degradation of the EGF receptor (EGFR).	10	43	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	10	13	41	43
This potentiation can be accounted for in part by a block in the EGF stimulated down-regulation of the EGF-R .	This potentiation can be accounted for in part by a block in the EGF stimulated down-regulation of the EGF-R.	13	19	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	13	14	18	19
In addition to protein interaction , we had previously demonstrated that MUC1 expression inhibits the EGF dependent degradation of EGFR .	In addition to protein interaction, we had previously demonstrated that MUC1 expression inhibits the EGF dependent degradation of EGFR.	15	20	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	19	20
These data , together with the result obtained from analysis of effects of Trak1 deletions on the colocalization with Hrs ( XREF_FIG ) , suggest that the association of Trak1 with Hrs positive early endosomes is required for the inhibitory effect of Trak1 overexpression on EGF induced EGFR degradation .	These data, together with the result obtained from analysis of effects of Trak1 deletions on the colocalization with Hrs (XREF_FIG), suggest that the association of Trak1 with Hrs positive early endosomes is required for the inhibitory effect of Trak1 overexpression on EGF induced EGFR degradation.	36	48	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	45	46	47	48
When GRP cells were treated with EGF and Erlotinib HCl ( an antagonist of EGFR ) simultaneously , the biological effects of EGF on promoting the division and survival was neutralized , and the antigenic phenotypes were similar to those of the control .	When GRP cells were treated with EGF and Erlotinib HCl (an antagonist of EGFR) simultaneously, the biological effects of EGF on promoting the division and survival was neutralized, and the antigenic phenotypes were similar to those of the control.	6	15	antagonist	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	14	15
We thus examined the effect of the T669A mutation on EGF induced EGFR loss in reconstituted CHO cells expressing either EGFR T669A or WT EGFR ( XREF_FIG ) .	We thus examined the effect of the T669A mutation on EGF induced EGFR loss in reconstituted CHO cells expressing either EGFR T669A or WT EGFR (XREF_FIG).	8	13	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
Considering FLCN has GEF activity toward Rab35 , we hypothesized that FLCN might also affect the degradation of EGF induced EGFR and its downstream signaling pathways .	Considering FLCN has GEF activity toward Rab35, we hypothesized that FLCN might also affect the degradation of EGF induced EGFR and its downstream signaling pathways.	16	25	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
Moreover , 10 muM phenobarbital inhibited the activation of EGFR by EGF in mouse primary hepatocytes ( which is within the generally observed range for drug-nuclear receptor interactions ) .	Moreover, 10 muM phenobarbital inhibited the activation of EGFR by EGF in mouse primary hepatocytes (which is within the generally observed range for drug-nuclear receptor interactions).	5	23	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	9	10
K-252a blocks the NGF induced heterodown regulation of the epidermal growth factor receptor , but not the epidermal growth factor induced homodown regulation of the epidermal growth factor receptor .	K-252a blocks the NGF induced heterodown regulation of the epidermal growth factor receptor, but not the epidermal growth factor induced homodown regulation of the epidermal growth factor receptor.	17	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	17	20	25	29
TGF-alpha or EGF inhibits ENaC by activating EGFR since the EGFR inhibitor AG1478 blocks the effects of both .	TGF-alpha or EGF inhibits ENaC by activating EGFR since the EGFR inhibitor AG1478 blocks the effects of both.	0	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	7	8
( iii ) Associated with the inhibitory effect of a lipid mimetic of lyso and GM3 dimer on EGF induced EGFR kinase activity , only Akt kinase activity was significantly inhibited , but kinases associated with other signal transducers were not affected .	(iii) Associated with the inhibitory effect of a lipid mimetic of lyso and GM3 dimer on EGF induced EGFR kinase activity, only Akt kinase activity was significantly inhibited, but kinases associated with other signal transducers were not affected.	3	22	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
These findings indicate that N linked glycan with GlcNAc termini linked to EGFR is the target to interact with GM3 , causing inhibition of EGF induced EGFR tyrosine kinase .	These findings indicate that N linked glycan with GlcNAc termini linked to EGFR is the target to interact with GM3, causing inhibition of EGF induced EGFR tyrosine kinase.	22	28	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
Among 125 patients who were evaluated for an epidermal growth factor receptor gene mutation , 31 were treated with epidermal growth factor receptor-tyrosine kinase inhibitor .	Among 125 patients who were evaluated for an epidermal growth factor receptor gene mutation, 31 were treated with epidermal growth factor receptor-tyrosine kinase inhibitor.	8	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	19	22	8	12
Although these findings are seemingly at odds with the preceding studies , one possible explanation is that EGF causes internalization and degradation of the EGF receptor and therefore a decrease in net EGF receptor activity .	Although these findings are seemingly at odds with the preceding studies, one possible explanation is that EGF causes internalization and degradation of the EGF receptor and therefore a decrease in net EGF receptor activity.	17	34	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	17	18	32	34
Thus , it is conceivable that the relatively decreased EGF induced EGFR downregulation seen in these cells compared to the CHO cell EGFR transfectants could be accounted for in part by the presence in C14 cells of ErbB-2 .	Thus, it is conceivable that the relatively decreased EGF induced EGFR downregulation seen in these cells compared to the CHO cell EGFR transfectants could be accounted for in part by the presence in C14 cells of ErbB-2.	6	12	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
EGFR inhibitors ( gefitinib and AEE788 ) reduced clonogenicity , proliferation and survival of ependymoma-SC lines dose-dependently , and blocked EGF induced activation of EGFR , Akt and extracellular signal regulated kinase 1/2 .	EGFR inhibitors (gefitinib and AEE788) reduced clonogenicity, proliferation and survival of ependymoma-SC lines dose-dependently, and blocked EGF induced activation of EGFR, Akt and extracellular signal regulated kinase 1/2.	20	26	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	24	25
In this regard , it is interesting to note that PA2 mutant HCV viruses , which fail to inhibit EGF stimulated EGFR degradation , did not establish a persistent infection in chimpanzees .	In this regard, it is interesting to note that PA2 mutant HCV viruses, which fail to inhibit EGF stimulated EGFR degradation, did not establish a persistent infection in chimpanzees.	18	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
Overexpression of Trak1 and its mutants inhibit EGF induced EGFR degradation , but not endocytosis .	Overexpression of Trak1 and its mutants inhibit EGF induced EGFR degradation, but not endocytosis.	7	10	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
It should be noted that consistent with previous studies , pretreatment with monensin also blocked EGF induced EGFR degradation , whereas chloroquine had negligible effects on AR induced EGFR recycling ( XREF_SUPPLEMENTARY ) .	It should be noted that consistent with previous studies, pretreatment with monensin also blocked EGF induced EGFR degradation, whereas chloroquine had negligible effects on AR induced EGFR recycling (XREF_SUPPLEMENTARY).	15	27	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
Replacement of 1046/1047 S with alanines in the context of the full-length EGFR and comparison with WT EGFR in a CHO cell reconstitution system revealed that EGFR S1046/1047A exhibited markedly decreased EGF induced EGFR downregulation and enhanced EGF induced signaling ; moreover , a desensitizing effect of EGF on subsequent EGFR kinase activity found in WT EGFR was lost in EGFR S1046/1047A [ XREF_BIBR , XREF_BIBR ] .	Replacement of 1046/1047 S with alanines in the context of the full-length EGFR and comparison with WT EGFR in a CHO cell reconstitution system revealed that EGFR S1046/1047A exhibited markedly decreased EGF induced EGFR downregulation and enhanced EGF induced signaling; moreover, a desensitizing effect of EGF on subsequent EGFR kinase activity found in WT EGFR was lost in EGFR S1046/1047A [XREF_BIBR, XREF_BIBR].	30	36	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	31	32	33	34
It is worthwhile to mention that EGF induces EGFR degradation through receptor mediated endocytosis and endosomal trafficking to the lysosomes .	It is worthwhile to mention that EGF induces EGFR degradation through receptor mediated endocytosis and endosomal trafficking to the lysosomes.	6	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
XREF_FIG A , B ) , but not ligand ( EGF )-induced degradation of EGFR ( lanes 8 and 9 ; Fig .	XREF_FIG A, B), but not ligand (EGF)-induced degradation of EGFR (lanes 8 and 9; Fig.	10	19	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	14	15
In this respect , our findings may indicate two separate roles for 669 T phosphorylation - negative regulation of kinase activity ( perhaps mechanistically similar to that of 654 T phosphorylation referred to above ) and negative regulation of EGF induced EGFR downregulation .	In this respect, our findings may indicate two separate roles for 669 T phosphorylation - negative regulation of kinase activity (perhaps mechanistically similar to that of 654 T phosphorylation referred to above) and negative regulation of EGF induced EGFR downregulation.	37	42	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	39	40	41	42
TIP30 knockdown attenuated EGF induced EGFR downregulation and enhanced EGFR and ERK1/2 phosphorylation without altering p38 MAPK phosphorylation ( XREF_FIG ) .	TIP30 knockdown attenuated EGF induced EGFR downregulation and enhanced EGFR and ERK1/2 phosphorylation without altering p38 MAPK phosphorylation (XREF_FIG).	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Although the EGF induced pEGFR was completely blocked by gefitinib monotherapy in all seven STS cell lines , they were all resistant to gefitinib , suggesting the existence of at least one secondary resistance mechanism .	Although the EGF induced pEGFR was completely blocked by gefitinib monotherapy in all seven STS cell lines, they were all resistant to gefitinib, suggesting the existence of at least one secondary resistance mechanism.	1	7	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	2	3	4	5
However , EGCG required neither an ubiquitin ligase ( c-Cbl ) binding to EGFR nor a phosphorylation of EGFR at tyrosine residues , both of which are reportedly necessary for EGFR degradation induced by epidermal growth factor .	However, EGCG required neither an ubiquitin ligase (c-Cbl) binding to EGFR nor a phosphorylation of EGFR at tyrosine residues, both of which are reportedly necessary for EGFR degradation induced by epidermal growth factor.	30	37	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	34	37	30	31
CHM-09 and EGFR inhibitors could perturb EGF induced EGFR signalling of breast CSC proliferation , migration , mammosphere formation and mesenchymal tri-lineage differentiation .	CHM-09 and EGFR inhibitors could perturb EGF induced EGFR signalling of breast CSC proliferation, migration, mammosphere formation and mesenchymal tri-lineage differentiation.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Furthermore , pretreatment of cells with these inhibitors reduced the rate of EGF induced EGFR degradation and a substantial amount of EGFR was detected even after 120 min of EGF stimulation .	Furthermore, pretreatment of cells with these inhibitors reduced the rate of EGF induced EGFR degradation and a substantial amount of EGFR was detected even after 120 min of EGF stimulation.	10	15	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
The data indicated that DARPP-32 significantly delayed the EGF induced degradation of EGFR protein in MKN-28 cells ( XREF_FIG ) .	The data indicated that DARPP-32 significantly delayed the EGF induced degradation of EGFR protein in MKN-28 cells (XREF_FIG).	7	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	12	13
Ligand independent EGFR signaling results in attenuated but sustained MAPK activation that is different from the high amplitude , transient MAPK signaling that results from EGF induced EGFR activation .	Ligand independent EGFR signaling results in attenuated but sustained MAPK activation that is different from the high amplitude, transient MAPK signaling that results from EGF induced EGFR activation.	23	28	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	27	28
As shown in the present report , MRTs bind to , and internalize into , the target cells very selectively , in that 96 % of binding and 99.5 % of internalization were blocked when cell-surface EGFR was blocked by cold EGF .	As shown in the present report, MRTs bind to, and internalize into, the target cells very selectively, in that 96% of binding and 99.5% of internalization were blocked when cell-surface EGFR was blocked by cold EGF.	35	42	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	41	42	36	37
Acceleration of internalization and degradation of EGFR by EGF results in dramatic decreases in the amount of EGFR at the cell surface ( termed ligand induced receptor down-regulation ) and an eventual decrease of total cellular EGFR protein .	Acceleration of internalization and degradation of EGFR by EGF results in dramatic decreases in the amount of EGFR at the cell surface (termed ligand induced receptor down-regulation) and an eventual decrease of total cellular EGFR protein.	2	9	degradation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	6	7
Rather , the most prominent effect of GH- and PRL induced ERK mediated EGFR PTP101- reactive phosphorylation in those studies was to significantly diminish subsequent EGF induced EGFR downregulation .	Rather, the most prominent effect of GH- and PRL induced ERK mediated EGFR PTP101- reactive phosphorylation in those studies was to significantly diminish subsequent EGF induced EGFR downregulation.	23	28	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	27	28
In PC3-AR cells , we demonstrated a disruption of EGFR signalling properties ( reduced EGF induced EGFR autotransphosphorylation , reduced EGF stimulated PI3K activity as well as EGFR-PI3K interaction ) contributing to the lower invasive phenotype of these cells .	In PC3-AR cells, we demonstrated a disruption of EGFR signalling properties (reduced EGF induced EGFR autotransphosphorylation, reduced EGF stimulated PI3K activity as well as EGFR-PI3K interaction) contributing to the lower invasive phenotype of these cells.	13	17	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
P. aeruginosa ExoS ADPr activity inhibits EGF activated EGFR degradation in HeLa cells .	P. aeruginosa ExoS ADPr activity inhibits EGF activated EGFR degradation in HeLa cells.	5	9	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Our results revealed that CTSS can regulate EGFR signalling by facilitating EGF mediated EGFR degradation .	Our results revealed that CTSS can regulate EGFR signalling by facilitating EGF mediated EGFR degradation.	10	14	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Thus , in cell types in which inactivation of the ESCRT pathway inhibited EGF stimulated EGFR degradation , PCSK9 failed to promote LDLR degradation ( i.e ., Hela cells ) ( XREF_FIG ) , whereas in cell types where PCSK9 was active ( hepatocytes and fibroblasts ) , interrupting the ESCRT pathway did not interfere with EGFR degradation by its ligand .	Thus, in cell types in which inactivation of the ESCRT pathway inhibited EGF stimulated EGFR degradation, PCSK9 failed to promote LDLR degradation (i.e., Hela cells) (XREF_FIG), whereas in cell types where PCSK9 was active (hepatocytes and fibroblasts), interrupting the ESCRT pathway did not interfere with EGFR degradation by its ligand.	12	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Results : Here , we demonstrate that interfering with FLCN , a tumor suppressor , reduces the rate of EGF induced EGFR degradation , resulting in prolonged activation of downstream signaling .	Results : Here, we demonstrate that interfering with FLCN, a tumor suppressor, reduces the rate of EGF induced EGFR degradation, resulting in prolonged activation of downstream signaling.	17	22	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
EGF induced EGFR activation in the cultured neurons was effectively suppressed by gefitinib ( XREF_FIG A ) .	EGF induced EGFR activation in the cultured neurons was effectively suppressed by gefitinib (XREF_FIG A).	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
However , Clone 29.1 unlike Clone 225 binds to a carbohydrate residue on the external portion of EGFR and does not inhibit EGF mediated EGFR signaling XREF_BIBR .	However, Clone 29.1 unlike Clone 225 binds to a carbohydrate residue on the external portion of EGFR and does not inhibit EGF mediated EGFR signaling XREF_BIBR.	21	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	24	25
We next examined and compared the effects of overexpressing wild-type or mutant Trak1 and Hrs on EGF induced EGFR degradation using a quantitative 125 I-EGF degradation assay .	We next examined and compared the effects of overexpressing wild-type or mutant Trak1 and Hrs on EGF induced EGFR degradation using a quantitative 125 I-EGF degradation assay.	14	19	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
Comparing to ligand ( EGF )-induced degradation of EGFR ( lanes 20-24 ) , stress induced degradation of EGFR has two distinguishable traits : ( i ) the degradation rate is much slower than that of ligand induced degradation ; and ( ii ) the degradation products are different from that of ligand induced degradation .	Comparing to ligand (EGF)-induced degradation of EGFR (lanes 20-24), stress induced degradation of EGFR has two distinguishable traits : (i) the degradation rate is much slower than that of ligand induced degradation; and (ii) the degradation products are different from that of ligand induced degradation.	4	9	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	8	9
As shown ( XREF_FIG ) , TM pretreatment blocked EGFR degradation induced by EGF stimulation , possibly through suppression of tyrosine phosphorylation .	As shown (XREF_FIG), TM pretreatment blocked EGFR degradation induced by EGF stimulation, possibly through suppression of tyrosine phosphorylation.	9	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	9	10
In a recent study , a panel of peptides was developed to bind to EGF and block activation of EGFR signaling pathways .	In a recent study, a panel of peptides was developed to bind to EGF and block activation of EGFR signaling pathways.	14	21	block activation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	19	20
Knockdown of alpha-taxilin did not inhibit or promote the degradation of EGFR in HeLaS3 cells stimulated with EGF ( XREF_FIG ) , suggesting that alpha-taxilin is not involved in the EGF induced degradation of EGFR .	Knockdown of alpha-taxilin did not inhibit or promote the degradation of EGFR in HeLaS3 cells stimulated with EGF (XREF_FIG), suggesting that alpha-taxilin is not involved in the EGF induced degradation of EGFR.	30	35	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	30	31	34	35
MIF binds to the extracellular domain of EGFR and inhibits EGF induced EGFR activation .	MIF binds to the extracellular domain of EGFR and inhibits EGF induced EGFR activation.	9	13	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
DARPP-32 activated PI3K-AKT signaling , increased stability of the EGFR , and suppressed EGF- or gefitinib induced degradation of the EGFR .	DARPP-32 activated PI3K-AKT signaling, increased stability of the EGFR, and suppressed EGF- or gefitinib induced degradation of the EGFR.	13	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF-	EGF-	EGF-	EGFR	EGFR	EGFR	13	14	20	21
In line with these findings , purified Flag-MIF S112 and T113A failed to inhibit EGF induced EGFR activation in U87 ( XREF_FIG ) and A431 cells ( XREF_SUPPLEMENTARY ) .	In line with these findings, purified Flag-MIF S112 and T113A failed to inhibit EGF induced EGFR activation in U87 (XREF_FIG) and A431 cells (XREF_SUPPLEMENTARY).	13	17	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
Consistent with these studies , our results show that Rab35 increases the rate of EGF induced EGFR degradation and attenuates its downstream signaling .	Consistent with these studies, our results show that Rab35 increases the rate of EGF induced EGFR degradation and attenuates its downstream signaling.	12	17	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
WDR81 is a BEACH-domain containing protein that is also required for the degradation of EGF stimulated epidermal growth factor receptor ( EGFR ) and functions in a complex with the WDR91 protein .	WDR81 is a BEACH-domain containing protein that is also required for the degradation of EGF stimulated epidermal growth factor receptor (EGFR) and functions in a complex with the WDR91 protein.	12	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	14	15	16	20
Tethered EGF blocks EGFR and ErbB1 endocytic internalization and enhances osteogenic differentiation through providing sustained activation of downstream signaling through EGFR and ErbB1 , whereas 80pM of soluble EGF interferes with osteogenic differentiation through inducing receptor internalization and subsequent degradation [ XREF_BIBR ] , in agreement with Krampera ' s data [ XREF_BIBR ] .	Tethered EGF blocks EGFR and ErbB1 endocytic internalization and enhances osteogenic differentiation through providing sustained activation of downstream signaling through EGFR and ErbB1, whereas 80pM of soluble EGF interferes with osteogenic differentiation through inducing receptor internalization and subsequent degradation [XREF_BIBR], in agreement with Krampera 's data [XREF_BIBR].	0	9	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	1	2	5	6
On the basis of previous observations that glioblastoma cells cultured with serum lose the EGFR amplification rapidly and that EGF can inhibit the growth of EGFR amplified tumor cells , we hypothesized that serum-free and EGF-free culture conditions could promote maintenance of the EGFR amplification .	On the basis of previous observations that glioblastoma cells cultured with serum lose the EGFR amplification rapidly and that EGF can inhibit the growth of EGFR amplified tumor cells, we hypothesized that serum-free and EGF-free culture conditions could promote maintenance of the EGFR amplification.	19	26	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	25	26
Unlike Hrs , overexpression of SIMPLE had no effect on EGF induced EGFR degradation in control cells ( see XREF_FIG ) .	Unlike Hrs, overexpression of SIMPLE had no effect on EGF induced EGFR degradation in control cells (see XREF_FIG).	8	18	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
We first examined the EGF induced endocytic degradation of EGFR in a panel of NSCLC cell lines , which includes all major histologic subtypes : adenocarcinoma ( A549 , H1299 , HCC827 , H1650 , and H1975 ) , large cell carcinoma ( H460 ) , and squamous cell carcinoma ( H226 and SK-MES-1 ) .	We first examined the EGF induced endocytic degradation of EGFR in a panel of NSCLC cell lines, which includes all major histologic subtypes : adenocarcinoma (A549, H1299, HCC827, H1650, and H1975), large cell carcinoma (H460), and squamous cell carcinoma (H226 and SK-MES-1).	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	9	10
EGF induced EGFR activation and mTOR activation in EGFR expressing H460 and A549 NSCLC cell lines was inhibited .	EGF induced EGFR activation and mTOR activation in EGFR expressing H460 and A549 NSCLC cell lines was inhibited.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Furthermore , EGF stimulated EGFR activation was also inhibited by berberine in these two cell lines ( XREF_FIG ) .	Furthermore, EGF stimulated EGFR activation was also inhibited by berberine in these two cell lines (XREF_FIG).	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
Surprisingly enough , when we assessed EGF induced EGFR degradation as a functional readout of MVB , shRNA knockdown of TBK1 did not affect EGFR degradation in A549 cells ( XREF_FIG ) .	Surprisingly enough, when we assessed EGF induced EGFR degradation as a functional readout of MVB, shRNA knockdown of TBK1 did not affect EGFR degradation in A549 cells (XREF_FIG).	5	9	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
MUC1 is a tumor antigen that can modulate EGFR activity , with EGF dependent degradation of EGFR inhibited by co-expression of MUC1 [ XREF_BIBR ] .	MUC1 is a tumor antigen that can modulate EGFR activity, with EGF dependent degradation of EGFR inhibited by co-expression of MUC1 [XREF_BIBR].	12	17	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	16	17
XREF_FIG shows a Western blot from control and gefinitib treated animals and confirms that the presence of gefitinib partially blocked EGF induced EGFR autophosphorylaton .	XREF_FIG shows a Western blot from control and gefinitib treated animals and confirms that the presence of gefitinib partially blocked EGF induced EGFR autophosphorylaton.	19	23	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
The results indicate that , in mussel digestive cells , the binding of heterologous EGF to specific receptors induces a negative feedback response by stimulating the lysosomal degradation of EGFR , thus suggesting the presence of mechanisms responsible for receptor downregulation similar to those observed in mammalian cells .	The results indicate that, in mussel digestive cells, the binding of heterologous EGF to specific receptors induces a negative feedback response by stimulating the lysosomal degradation of EGFR, thus suggesting the presence of mechanisms responsible for receptor downregulation similar to those observed in mammalian cells.	11	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	29	30
To determine if msPMIP was affecting EGF dependent degradation of EGFR in vivo , we generated protein lysates from tumors of MMTV- pyV mT animals injected with EGF and peptide 30 minutes prior to animal sacrifice ( after a standard 21 day drug treatment ) .	To determine if msPMIP was affecting EGF dependent degradation of EGFR in vivo, we generated protein lysates from tumors of MMTV- pyV mT animals injected with EGF and peptide 30 minutes prior to animal sacrifice (after a standard 21 day drug treatment).	6	12	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	10	11
To prove that inhibition of EGF induced EGFR dimerisation was not an antibody specific phenomenon limited to D1/274.5 , we also used different monoclonal and polyclonal AnxA2 antibodies ( XREF_FIG ) .	To prove that inhibition of EGF induced EGFR dimerisation was not an antibody specific phenomenon limited to D1/274.5, we also used different monoclonal and polyclonal AnxA2 antibodies (XREF_FIG).	3	8	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
In support of this notion , in A549 cells carrying the wild-type EGFR , 1.5 and 20ng/ml of EGF induced differential endocytic degradation of EGFR , while the dynamin inhibitor dynasore efficiently suppressed EGFR downregulation .	In support of this notion, in A549 cells carrying the wild-type EGFR, 1.5 and 20ng/ml of EGF induced differential endocytic degradation of EGFR, while the dynamin inhibitor dynasore efficiently suppressed EGFR downregulation.	14	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	24	25
This rightward shift in the AR dose response curve in the presence of EGF indicates that EGF competitively antagonizes AR stimulation of EGFR coupling to proliferation ( XREF_FIG ) .	This rightward shift in the AR dose response curve in the presence of EGF indicates that EGF competitively antagonizes AR stimulation of EGFR coupling to proliferation (XREF_FIG).	16	23	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	22	23
Next , we performed immunoprecipitation to delineate how AMF knockdown influences on EGF activated EGFR as well as HER2 .	Next, we performed immunoprecipitation to delineate how AMF knockdown influences on EGF activated EGFR as well as HER2.	10	18	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
In support of this view , our functional studies indicated that overexpression of Trak1 inhibits EGF induced EGFR degradation by blocking endosome-to-lysosome trafficking of the EGFR .	In support of this view, our functional studies indicated that overexpression of Trak1 inhibits EGF induced EGFR degradation by blocking endosome-to-lysosome trafficking of the EGFR.	14	18	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
Here , our study further established CTTN promotes the proliferation of CRC cells in vitro and in vivo , and increases the MAPK signaling pathway by attenuation of EGF induced EGFR down-regulation .	Here, our study further established CTTN promotes the proliferation of CRC cells in vitro and in vivo, and increases the MAPK signaling pathway by attenuation of EGF induced EGFR down-regulation.	26	31	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	28	29	30	31
Hypoxia significantly increased pEGFR ( Tyr845 ) protein levels and an EGF neutralizing antibody prevented the hypoxic induction of pEGFR .	Hypoxia significantly increased pEGFR (Tyr845) protein levels and an EGF neutralizing antibody prevented the hypoxic induction of pEGFR.	11	20	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	11	12	19	20
One promising target of interest is the epidermal growth factor receptor ( EGFr ) , which is activated by the ligands EGF and TGF-alpha .	One promising target of interest is the epidermal growth factor receptor (EGFr), which is activated by the ligands EGF and TGF-alpha.	7	23	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	21	22	7	11
Our previous work indicated that PTP101-reactive EGFR phosphorylation correlated with diminished EGF induced EGFR downregulation [ XREF_BIBR , XREF_BIBR ] .	Our previous work indicated that PTP101-reactive EGFR phosphorylation correlated with diminished EGF induced EGFR downregulation [XREF_BIBR, XREF_BIBR].	10	14	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Strikingly , loss of PIPKIgammai5 blocked EGF induced EGFR degradation ( XREF_FIG ) .	Strikingly, loss of PIPKIgammai5 blocked EGF induced EGFR degradation (XREF_FIG).	6	9	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
EGF induced EGFR ubiquitinylation was markedly reduced ( XREF_FIG C ) , and EGFR degradation was substantially delayed in Cbl and Cbl-b double-KD MCF10A cells ( XREF_FIG D ) .	EGF induced EGFR ubiquitinylation was markedly reduced (XREF_FIG C), and EGFR degradation was substantially delayed in Cbl and Cbl-b double-KD MCF10A cells (XREF_FIG D).	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Gefitinib effectively blocks activation of EGFR by EGF , inhibits ATC cellular proliferation , and induces apoptosis in vitro .	Gefitinib effectively blocks activation of EGFR by EGF, inhibits ATC cellular proliferation, and induces apoptosis in vitro.	2	8	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	5	6
Low EGF induced EGFR degradation in control cells ( XREF_SUPPLEMENTARY ) .	Low EGF induced EGFR degradation in control cells (XREF_SUPPLEMENTARY).	0	4	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	3	4
To test whether knockdown of ANO1 had an effect on the rate of EGF induced EGFR degradation , we stimulated Te11 cells expressing dox inducible shRNAs against ANO1 ( shRNA-ANO1-# 1/# 2 ) with EGF in the presence of dox and determined the amount of EGFR in the cells by immunoblotting ( XREF_SUPPLEMENTARY ) .	To test whether knockdown of ANO1 had an effect on the rate of EGF induced EGFR degradation, we stimulated Te11 cells expressing dox inducible shRNAs against ANO1 (shRNA-ANO1-# 1/# 2) with EGF in the presence of dox and determined the amount of EGFR in the cells by immunoblotting (XREF_SUPPLEMENTARY).	11	16	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
As can be seen , EGF treatment induced a significant loss of the EGFR protein ; however , with the pretreatment of AT-II , the EGF did not induce the loss of EGFR protein ( XREF_FIG ) .	As can be seen, EGF treatment induced a significant loss of the EGFR protein; however, with the pretreatment of AT-II, the EGF did n't induce the loss of EGFR protein (XREF_FIG).	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	13	14
However , autophagy inhibition can only partially rescue EGF mediated EGFR degradation in cells cotreated with a CTSS inhibitor ( XREF_FIG , b ) .	However, autophagy inhibition can only partially rescue EGF mediated EGFR degradation in cells cotreated with a CTSS inhibitor (XREF_FIG, b).	5	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
XREF_FIG shows that at l0 ng/ml , EGF strongly induced association of EGFR with Shc and Src , which was significantly decreased when treated with 500 ng/ml of EGF ( XREF_FIG ) .	XREF_FIG shows that at l0 ng/ml, EGF strongly induced association of EGFR with Shc and Src, which was significantly decreased when treated with 500 ng/ml of EGF (XREF_FIG).	7	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	12	13
These results suggest that B4GALNT3 knockdown facilitates EGF induced EGFR degradation in colon cancer cells .	These results suggest that B4GALNT3 knockdown facilitates EGF induced EGFR degradation in colon cancer cells.	6	10	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
This knockdown had no affect on the rate of EGF induced EGFR internalization .	This knockdown had no affect on the rate of EGF induced EGFR internalization.	7	12	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
EGFR tyrosine kinase inhibitors , such as PD153035 , AG1478 , as well as non specific tyrosine kinase inhibitor PP2 can not reverse EGF induced down-regulation of EGFR .	EGFR tyrosine kinase inhibitors, such as PD153035, AG1478, as well as non specific tyrosine kinase inhibitor PP2 can not reverse EGF induced down-regulation of EGFR.	22	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	27	28
However , the mutant of EGFR does not affect EGF induced downstream signaling transduction ( XREF_FIG , EGFR and STAT [ signal transducer and activator of transcription ] phosphorylation ) and/or EGF stimulated EGFR endocytotic degradation .	However, the mutant of EGFR does not affect EGF induced downstream signaling transduction (XREF_FIG, EGFR and STAT [signal transducer and activator of transcription] phosphorylation) and/or EGF stimulated EGFR endocytotic degradation.	31	35	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	31	32	33	34
However , EGF induced EGFR nuclear translocation was diminished ~ 70 % in EGFR Y1101F mutant cells as compared to EGFR-WT expressing cells ( XREF_FIG ) .	However, EGF induced EGFR nuclear translocation was diminished ~ 70% in EGFR Y1101F mutant cells as compared to EGFR-WT expressing cells (XREF_FIG).	2	6	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
Our findings suggest that exogenous EGF activated EGFR and ERK signaling in the parasite was inhibited by CI-1033 .	Our findings suggest that exogenous EGF activated EGFR and ERK signaling in the parasite was inhibited by CI-1033.	4	10	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Knockdown of ANO1 reduced EGFR protein levels in all conditions , but did not affect the rate of EGF induced degradation of EGFR ( XREF_SUPPLEMENTARY ) .	Knockdown of ANO1 reduced EGFR protein levels in all conditions, but did not affect the rate of EGF induced degradation of EGFR (XREF_SUPPLEMENTARY).	16	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	22	23
( i ) A lipid mimetic of lyso and GM3 dimer showed similar strong inhibitory effect on EGF induced EGFR tyrosine kinase activity , and similar low cytotoxicity , as the authentic lyso and GM3 dimer .	(i) A lipid mimetic of lyso and GM3 dimer showed similar strong inhibitory effect on EGF induced EGFR tyrosine kinase activity, and similar low cytotoxicity, as the authentic lyso and GM3 dimer.	15	22	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
EGF , but not TGFalpha , efficiently induces degradation of the EGF receptor ( EGFR ) .	EGF, but not TGFalpha, efficiently induces degradation of the EGF receptor (EGFR).	0	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	11	13
The absence of EGF-R on the outer , apical surface of periderm cells that are exposed to amniotic fluid was unexpected and may reflect down-regulation of EGF-R by EGF and TGF-alpha or related fetal growth factors present in amniotic fluid .	The absence of EGF-R on the outer, apical surface of periderm cells that are exposed to amniotic fluid was unexpected and may reflect down-regulation of EGF-R by EGF and TGF-alpha or related fetal growth factors present in amniotic fluid.	23	30	down-regulation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	28	29	26	27
SRC knockdown inhibited EGF induced EGFR dimerization ( XREF_FIG ) and suppressed EGFR phosphorylation at Tyr845 , a known SRC dependent EGFR phosphorylation site 21 , and at Tyr1068 , an autophosphorylation site , under both basal and EGF stimulated conditions ( XREF_FIG ) .	SRC knockdown inhibited EGF induced EGFR dimerization (XREF_FIG) and suppressed EGFR phosphorylation at Tyr845, a known SRC dependent EGFR phosphorylation site 21, and at Tyr1068, an autophosphorylation site, under both basal and EGF stimulated conditions (XREF_FIG).	3	6	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
In conclusion , our results demonstrated that CHAG could suppress the development of OC though blocking the activation of EGF induced activation of EGFR and its downstream signal transduction .	In conclusion, our results demonstrated that CHAG could suppress the development of OC though blocking the activation of EGF induced activation of EGFR and its downstream signal transduction.	17	28	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	23	24
Graduate truncation within 991-1044 progressively lower EGF induced EGFR endocytosis with most significant effects observed for residues 1005-1017 .	Graduate truncation within 991-1044 progressively lower EGF induced EGFR endocytosis with most significant effects observed for residues 1005-1017.	1	9	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
For instance , EGF promotes EGFR degradation after internalization , while TGFalpha induces the recycling of active receptor .	For instance, EGF promotes EGFR degradation after internalization, while TGFalpha induces the recycling of active receptor.	3	6	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
The induction of EGF receptor loss by EGF was a specific effect on the EGF receptor .	The induction of EGF receptor loss by EGF was a specific effect on the EGF receptor.	3	8	loss	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	7	8	3	5
EGF induced various rates of EGFR endocytic degradation in lung cancer cells .	EGF induced various rates of EGFR endocytic degradation in lung cancer cells.	0	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
To test this possibility , we examined the effect of depleting Hsc70 through small interfering RNA ( siRNA ) on EGF induced EGFR degradation .	To test this possibility, we examined the effect of depleting Hsc70 through small interfering RNA (siRNA) on EGF induced EGFR degradation.	15	23	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
Overexpression of full length TSG101 has been shown to inhibit ESCRT-I function and block EGF induced EGFR downregulation [ XREF_BIBR , XREF_BIBR ] .	Overexpression of full length TSG101 has been shown to inhibit ESCRT-I function and block EGF induced EGFR downregulation [XREF_BIBR, XREF_BIBR].	13	17	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
HeLa cells intoxicated with ExoS G + A + or ExoS A + inhibited EGF activated EGFR degradation by ~ 35 % .	HeLa cells intoxicated with ExoS G + A + or ExoS A + inhibited EGF activated EGFR degradation by ~ 35%.	13	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	16	17
Our observations align with these findings and provide compelling evidence for roles of heparanase as a downstream target of EGF activated HER2 and EGFR and player in mechanisms involving HER2 modulation to drive BMBC proliferation events .	Our observations align with these findings and provide compelling evidence for roles of heparanase as a downstream target of EGF activated HER2 and EGFR and player in mechanisms involving HER2 modulation to drive BMBC proliferation events.	17	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	23	24
The ROS generated by the combination of carmustine and selenite exhibited a strong inhibition on EGF stimulated EGFR and its downstream signaling molecules such as Akt , NF-kB , ERK1/2 , and Cyclin D1 .	The ROS generated by the combination of carmustine and selenite exhibited a strong inhibition on EGF stimulated EGFR and its downstream signaling molecules such as Akt, NF-kB, ERK1/2, and Cyclin D1.	13	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
EGF driven endocytosis caused extensive down-regulation ( XREF_FIG ) and eventual degradation ( XREF_FIG ) of EGFR in both control and NR6-EGFR and RALT cells .	EGF driven endocytosis caused extensive down-regulation (XREF_FIG) and eventual degradation (XREF_FIG) of EGFR in both control and NR6-EGFR and RALT cells.	0	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	16	17
Therefore , the EGF ligand was subsequently used to examine whether CTSS activities were indeed involved in EGF mediated EGFR degradation .	Therefore, the EGF ligand was subsequently used to examine whether CTSS activities were indeed involved in EGF mediated EGFR degradation.	17	20	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
As with basal activation , EGF stimulated EGFR activation was suppressed by ST6Gal-I KD ( representative blots in Fig .	As with basal activation, EGF stimulated EGFR activation was suppressed by ST6Gal-I KD (representative blots in Fig.	5	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Finally , depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF activated EGFR .	Finally, depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF activated EGFR.	15	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
An EGFR overexpressing human epithelial carcinoma cell line , A431 , was harvested ( 1 ) prior to any cell treatment ( proliferating cells ) , ( 2 ) after serum starvation overnight and stimulation with EGF , ( 3 ) after cotreatment with 10 mug mL -1 cetuximab ( monoclonal antibody inhibitor of EGFR ) and EGF , and ( 4 ) after cotreatment with 500 nM gefitinib ( small molecule EGFR tyrosine kinase inhibitor ) and EGF .	An EGFR overexpressing human epithelial carcinoma cell line, A431, was harvested (1) prior to any cell treatment (proliferating cells), (2) after serum starvation overnight and stimulation with EGF, (3) after cotreatment with 10 mug mL -1 cetuximab (monoclonal antibody inhibitor of EGFR) and EGF, and (4) after cotreatment with 500 nM gefitinib (small molecule EGFR tyrosine kinase inhibitor) and EGF.	46	58	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	57	58	54	55
In the present study , we carefully examined the EGF induced degradation of endogenous EGFR proteins in a panel of non small cell lung cancer cell lines .	In the present study, we carefully examined the EGF induced degradation of endogenous EGFR proteins in a panel of non small cell lung cancer cell lines.	8	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	14	15
When EGF induced activation of EGFR signaling is completely blocked , EGFR trafficking is also obstructed in the cells pretreated with erlotinib .	When EGF induced activation of EGFR signaling is completely blocked, EGFR trafficking is also obstructed in the cells pretreated with erlotinib.	1	6	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	5	6
After 5 or 20min stimulation , EGFR endocytosis is significantly decreased by ~ 25 % at both 2ng/ml ( XREF_FIG ) and 100ng/ml ( XREF_SUPPLEMENTARY ) of EGF .	After 5 or 20min stimulation, EGFR endocytosis is significantly decreased by ~ 25% at both 2ng/ml (XREF_FIG) and 100ng/ml (XREF_SUPPLEMENTARY) of EGF.	6	28	decreased	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	6	7
Prior studies have suggested that EGF induced EGFR degradation depends on c-CBL .	Prior studies have suggested that EGF induced EGFR degradation depends on c-CBL.	5	8	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Because EGF stimulation dramatically accelerates EGFR degradation , protein synthesis does not significantly contribute in the total concentration of EGFR in EGF stimulated cells , and therefore , cycloheximide treatment is not essential for measurement of the rate of EGF induced EGFR degradation .	Because EGF stimulation dramatically accelerates EGFR degradation, protein synthesis does not significantly contribute in the total concentration of EGFR in EGF stimulated cells, and therefore, cycloheximide treatment is not essential for measurement of the rate of EGF induced EGFR degradation.	37	42	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	39	40	41	42
In addition to blocking autophagy , we speculate that EGFR mediated Beclin 1 tyrosine phosphorylation may also block its own endolysosomal degradation by promoting the binding of Rubicon to tyrosine phosphorylated Beclin 1 , as Rubicon inhibits EGF stimulated EGFR degradation in A549 cells .	In addition to blocking autophagy, we speculate that EGFR mediated Beclin 1 tyrosine phosphorylation may also block its own endolysosomal degradation by promoting the binding of Rubicon to tyrosine phosphorylated Beclin 1, as Rubicon inhibits EGF stimulated EGFR degradation in A549 cells.	36	40	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	37	38	39	40
As expected , EGF decreased EGFR mRNA and protein levels .	As expected, EGF decreased EGFR mRNA and protein levels.	3	6	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Functional studies revealed that rLZ-8 reduced the amount of EGFR in cell membranes by altering EGFR localization to enhance the EGF induced degradation of EGFR .	Functional studies revealed that rLZ-8 reduced the amount of EGFR in cell membranes by altering EGFR localization to enhance the EGF induced degradation of EGFR.	19	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	24	25
To characterize the role of the ALIX supported MVB sorting in lysosome dependent degradation of activated EGFR , we first determined the kinetics of EGF induced EGFR degradation in the presence or absence of the lysosome inhibitor chloroquine ( CQ ) [ XREF_BIBR ] .	To characterize the role of the ALIX supported MVB sorting in lysosome dependent degradation of activated EGFR, we first determined the kinetics of EGF induced EGFR degradation in the presence or absence of the lysosome inhibitor chloroquine (CQ) [XREF_BIBR].	22	27	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
Moreover , when FLCN is overexpressed , the EGF induced EGFR degradation was accelerated and the expressions of p-AKT , p-ERK were significantly weakened .	Moreover, when FLCN is overexpressed, the EGF induced EGFR degradation was accelerated and the expressions of p-AKT, p-ERK were significantly weakened.	7	11	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
In contrast Vps4E228Q-GFP strongly inhibited EGF induced EGFR degradation .	In contrast Vps4E228Q-GFP strongly inhibited EGF induced EGFR degradation.	4	8	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Moreover , overexpression of SNX16 increased the rate of EGF induced EGFR degradation and inhibited the EGF induced up-regulation of ERK and serum response element ( SRE ) .	Moreover, overexpression of SNX16 increased the rate of EGF induced EGFR degradation and inhibited the EGF induced up-regulation of ERK and serum response element (SRE).	7	12	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
Measurements of Texas Red labeled EGF uptake and cell surface EGFR revealed that p130Cas overexpression reduces EGF induced EGFR internalization , while p130Cas depletion enhances it .	Measurements of Texas Red labeled EGF uptake and cell surface EGFR revealed that p130Cas overexpression reduces EGF induced EGFR internalization, while p130Cas depletion enhances it.	15	19	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
Since previous studies documented that EGF induced EGFR activation could decrease IGFBP-3 protein levels in ESCC TE-2 and TE-7 cell lines [ XREF_BIBR ] and IGFBP-3 has been suggested as a key marker of radiosensitivity that enhances the susceptibility of ESCC to RT [ XREF_BIBR ] , in our study , we further examined the levels of IGFBP-3 in EGF treated KYSE30 and TE-1 cell lines before and after Nimotuzumab administration .	Since previous studies documented that EGF induced EGFR activation could decrease IGFBP-3 protein levels in ESCC TE-2 and TE-7 cell lines [XREF_BIBR] and IGFBP-3 has been suggested as a key marker of radiosensitivity that enhances the susceptibility of ESCC to RT [XREF_BIBR], in our study, we further examined the levels of IGFBP-3 in EGF treated KYSE30 and TE-1 cell lines before and after Nimotuzumab administration.	5	8	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Upon potassium depletion of Hep2 cells , EGF induced EGFR endocytosis was inhibited .	Upon potassium depletion of Hep2 cells, EGF induced EGFR endocytosis was inhibited.	7	10	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
In this study , we demonstrate that MDA-MB-231 cells have high level of Spry1 coincident with impaired process of EGF induced EGFR turn over that may contribute , at least partly to their malignancy .	In this study, we demonstrate that MDA-MB-231 cells have high level of Spry1 coincident with impaired process of EGF induced EGFR turn over that may contribute, at least partly to their malignancy.	17	22	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	21	22
Moreover , in MDA453 , SKBR3 , and BT474 cells , which have very high levels of EGFR-ErbB2 heterodimerization , EGF induced EGFR endocytosis was greatly inhibited compared with that in BT20 cells , which have a very low level of EGFR-ErbB2 heterodimerization .	Moreover, in MDA453, SKBR3, and BT474 cells, which have very high levels of EGFR-ErbB2 heterodimerization, EGF induced EGFR endocytosis was greatly inhibited compared with that in BT20 cells, which have a very low level of EGFR-ErbB2 heterodimerization.	20	23	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
As expected XREF_BIBR , EGF induced EGF-R degradation was prevented by Clo in a dose dependent manner in HeLa cells ( XREF_FIG ' ) .	As expected XREF_BIBR, EGF induced EGF-R degradation was prevented by Clo in a dose dependent manner in HeLa cells (XREF_FIG ').	4	7	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	4	5	6	7
Although both 225 and C29.1 antibodies bind to EGFR , C29.1 antibody unlike 225 binds to a carbohydrate residue on the external portion of EGFR and does not inhibit EGF mediated EGFR signaling .	Although both 225 and C29.1 antibodies bind to EGFR, C29.1 antibody unlike 225 binds to a carbohydrate residue on the external portion of EGFR and does not inhibit EGF mediated EGFR signaling.	28	32	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	31	32
In addition , in T98G , ZR30 sensitized EGF mediated EGFR degradation , which was not observed in U251 .	In addition, in T98G, ZR30 sensitized EGF mediated EGFR degradation, which was not observed in U251.	7	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
In particular , whereas EGFR S1046/1047A exhibited enhanced EGF induced signaling and decreased EGF induced EGFR downregulation and EGFR T654A manifested primarily enhanced EGF induced signaling , EGFR T669A in our study displayed both enhanced acute EGF induced EGFR activation and enhanced EGF induced EGFR downregulation .	In particular, whereas EGFR S1046/1047A exhibited enhanced EGF induced signaling and decreased EGF induced EGFR downregulation and EGFR T654A manifested primarily enhanced EGF induced signaling, EGFR T669A in our study displayed both enhanced acute EGF induced EGFR activation and enhanced EGF induced EGFR downregulation.	41	45	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	42	43	44	45
The authors hypothesize that the EGF and TKI combination downregulate the EGF receptor while inhibiting EGF receptor stimulated signaling pathways , thereby fostering chemosensitization .	The authors hypothesize that the EGF and TKI combination downregulate the EGF receptor while inhibiting EGF receptor stimulated signaling pathways, thereby fostering chemosensitization.	5	13	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	5	6	11	13
Addition of phorbol diesters to intact cells causes inhibition of the EGF induced tyrosine protein kinase activity of the EGF receptor and it has been suggested that this effect of phorbol diesters is mediated by the phosphorylation of the receptor by protein kinase C.	Addition of phorbol diesters to intact cells causes inhibition of the EGF induced tyrosine protein kinase activity of the EGF receptor and it has been suggested that this effect of phorbol diesters is mediated by the phosphorylation of the receptor by protein kinase C.	8	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	11	12	19	21
As expected , EGF alone induced the degradation of EGFR in Pkd1 wild type and mutant MEK cells .	As expected, EGF alone induced the degradation of EGFR in Pkd1 wild type and mutant MEK cells.	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	9	10
As shown in Figure XREF_FIG , EGF induced EGFR spatial changes were effectively blocked after treatment with dynasore or dynole 34-2 in gefitinib-insensitive H1703 cells .	As shown in Figure XREF_FIG, EGF induced EGFR spatial changes were effectively blocked after treatment with dynasore or dynole 34-2 in gefitinib-insensitive H1703 cells.	6	10	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
TIP30 , also known as HIV-1 Tat interactive protein 2 ( HTATIP2 ) or CC3 , was of particular interest , because it suppresses metastases in lung , breast and hepatocellular cancers XREF_BIBR , XREF_BIBR , XREF_BIBR and regulates EGF induced EGFR endocytosis .	TIP30, also known as HIV-1 Tat interactive protein 2 (HTATIP2) or CC3, was of particular interest, because it suppresses metastases in lung, breast and hepatocellular cancers XREF_BIBR, XREF_BIBR, XREF_BIBR and regulates EGF induced EGFR endocytosis.	38	42	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	39	40	41	42
The inhibitory effects of monochloro- and dichloro-GM3 on EGF induced EGFR activation were evaluated and compared with that of GM3 using A431 cells , which express a high level of EGFR at the cell surface .	The inhibitory effects of monochloro- and dichloro-GM3 on EGF induced EGFR activation were evaluated and compared with that of GM3 using A431 cells, which express a high level of EGFR at the cell surface.	6	11	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
EGF treatment further enhanced the formation of punctae in both cell lines harbouring the exon 19 deleted EGFR , although the increase in HCC827 cells appeared to be moderate .	EGF treatment further enhanced the formation of punctae in both cell lines harbouring the exon 19 deleted EGFR, although the increase in HCC827 cells appeared to be moderate.	0	18	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	17	18
Over the past decade , the knowledge of EGF overexpression in these tumors has led to the introduction of antibodies targeting EGFR for the treatment of head and neck cancer .	Over the past decade, the knowledge of EGF overexpression in these tumors has led to the introduction of antibodies targeting EGFR for the treatment of head and neck cancer.	8	22	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF overexpression	egf	EGFR	EGFR	egfr	8	9	21	22
To investigate whether FLCN regulates EGFR degradation through Rab35 , Rab35 CA or Rab35 DN were transfected in FLCN silencing or FLCN-overexpression cells to detect EGF induced EGFR degradation separately .	To investigate whether FLCN regulates EGFR degradation through Rab35, Rab35 CA or Rab35 DN were transfected in FLCN silencing or FLCN-overexpression cells to detect EGF induced EGFR degradation separately.	24	28	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	27	28
Despite elevated EGFR levels in NPC1 mutant cells , the rate of EGF induced EGFR degradation was comparable to that of control cells ( XREF_SUPPLEMENTARY ) , suggesting that endocytic trafficking and lysosomal proteolysis are not compromised .	Despite elevated EGFR levels in NPC1 mutant cells, the rate of EGF induced EGFR degradation was comparable to that of control cells (XREF_SUPPLEMENTARY), suggesting that endocytic trafficking and lysosomal proteolysis are not compromised.	10	15	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
In unstimulated Panc1 cells , antibody tagged EGFR was observed on the cell membrane , and the cell surface EGFR was significantly decreased when the cells were treated with EGF , which is consistent with our previous study [ XREF_BIBR ] .	In unstimulated Panc1 cells, antibody tagged EGFR was observed on the cell membrane, and the cell surface EGFR was significantly decreased when the cells were treated with EGF, which is consistent with our previous study [XREF_BIBR].	16	33	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	19	20
Cells were serum starved overnight and then subjected to wound healing assay over a period of 2 hours in the absence and presence of EGF ( 100 ng/ml ) ; this time point was chosen because EGF induced signaling drops significantly within 2 hours due to ligand induced degradation of the EGFR .	Cells were serum starved overnight and then subjected to wound healing assay over a period of 2 hours in the absence and presence of EGF (100 ng/ml); this time point was chosen because EGF induced signaling drops significantly within 2 hours due to ligand induced degradation of the EGFR.	36	52	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	36	37	51	52
The naturally secreted and O GlcNAcylated MIF binds to EGFR , thereby inhibiting the binding of EGF to EGFR and subsequent EGF induced EGFR activation .	The naturally secreted and O GlcNAcylated MIF binds to EGFR, thereby inhibiting the binding of EGF to EGFR and subsequent EGF induced EGFR activation.	12	24	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	23	24
XREF_FIG f , silencing CD24 expression significantly accelerated EGFR degradation stimulated by EGF .	XREF_FIG f, silencing CD24 expression significantly accelerated EGFR degradation stimulated by EGF.	8	13	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	8	9
We further demonstrate that differences in internalization between wild-type and mutant EGFR can not explain differences in EGF mediated EGFR degradation without concomitant changes in EGFR recycling , which we previously quantified .	We further demonstrate that differences in internalization between wild-type and mutant EGFR can not explain differences in EGF mediated EGFR degradation without concomitant changes in EGFR recycling, which we previously quantified.	17	20	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
We also observed that EGF down-regulated epidermal growth factor receptor while it up-regulated estrogen receptor .	We also observed that EGF down-regulated epidermal growth factor receptor while it up-regulated estrogen receptor.	4	10	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	4	5	6	10
Surprisingly , despite the pronounced impact of in situ Sia editing on EGF induced EGFR dimerization and activation , little influence of this treatment on EGF induced EGFR degradation was observed ( XREF_SUPPLEMENTARY ) .	Surprisingly, despite the pronounced impact of in situ Sia editing on EGF induced EGFR dimerization and activation, little influence of this treatment on EGF induced EGFR degradation was observed (XREF_SUPPLEMENTARY).	10	15	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Additionally , they found that 7A7 could inhibit EGF induced EGFR signaling in D122 tumour cells , triggering tumour regression in a T-cell dependent manner [ XREF_BIBR , XREF_BIBR ] .	Additionally, they found that 7A7 could inhibit EGF induced EGFR signaling in D122 tumour cells, triggering tumour regression in a T-cell dependent manner [XREF_BIBR, XREF_BIBR].	7	11	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
Effects of EGF and erlotinib on cisplatin induced EGFR degradation .	Effects of EGF and erlotinib on cisplatin induced EGFR degradation.	0	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	8	9
EGF downregulated EGFR in squamous cell carcinoma cells ( XREF_FIG ) , but had no effect on the expression levels of VEGFR1 and VEGFR2 in endothelial cells ( XREF_FIG ) .	EGF downregulated EGFR in squamous cell carcinoma cells (XREF_FIG), but had no effect on the expression levels of VEGFR1 and VEGFR2 in endothelial cells (XREF_FIG).	0	13	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Iressa and JSI-124 alone did not completely reduce EGF induced STAT3 activation in U87MG-EGFR cells despite that Iressa successfully inhibited EGF induced EGFR activation by means of EGFR autophosphorylation at Y1045 ( XREF_SUPPLEMENTARY ) .	Iressa and JSI-124 alone did not completely reduce EGF induced STAT3 activation in U87MG-EGFR cells despite that Iressa successfully inhibited EGF induced EGFR activation by means of EGFR autophosphorylation at Y1045 (XREF_SUPPLEMENTARY).	19	23	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
Depleting essential components of the ESCRT pathway has been shown to inhibit EGF stimulated degradation of the EGFR in Hela cells .	Depleting essential components of the ESCRT pathway has been shown to inhibit EGF stimulated degradation of the EGFR in Hela cells.	11	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	17	18
The naturally secreted and O GlcNAcylated MIF binds to EGFR , thereby inhibiting the binding of EGF to EGFR and EGF induced EGFR activation , phosphorylation of ERK and c-Jun , cell invasion , proliferation and brain tumour formation .	The naturally secreted and O GlcNAcylated MIF binds to EGFR, thereby inhibiting the binding of EGF to EGFR and EGF induced EGFR activation, phosphorylation of ERK and c-Jun, cell invasion, proliferation and brain tumour formation.	12	23	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	22	23
EGF mediated activation of EGFR and Erk-1/2 was decreased in tumor cells after ZD6474 treatment .	EGF mediated activation of EGFR and Erk-1/2 was decreased in tumor cells after ZD6474 treatment.	0	6	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	4	5
However , other studies failed to restore EGFR amplification after withdrawal of EGF in primary GBM cell lines with high EGF induced EGFR amplification loss [ XREF_BIBR , XREF_BIBR ] .	However, other studies failed to restore EGFR amplification after withdrawal of EGF in primary GBM cell lines with high EGF induced EGFR amplification loss [XREF_BIBR, XREF_BIBR].	10	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	22	23
To our surprise , p38 inhibitor SB203850 had a minor inhibitory effect ( about 30 % ) on ligand ( EGF )-induced degradation of EGFR ( lanes 3 and 4 , Fig .	To our surprise, p38 inhibitor SB203850 had a minor inhibitory effect (about 30%) on ligand (EGF)-induced degradation of EGFR (lanes 3 and 4, Fig.	20	25	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	24	25
Quantification also showed that inhibition of EGF induced EGFR and E-cad internalization by erlotinib in the sensitive cells was stronger than that in the insensitive cells .	Quantification also showed that inhibition of EGF induced EGFR and E-cad internalization by erlotinib in the sensitive cells was stronger than that in the insensitive cells.	4	11	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
After stimulation by EGF ligands for 1h , EGF mediated EGFR degradation was effectively observed in OEC-M1 and MDA-MB-231 cells ; both cell types expressed wild-type EGFR ( XREF_FIG ) .	After stimulation by EGF ligands for 1h, EGF mediated EGFR degradation was effectively observed in OEC-M1 and MDA-MB-231 cells; both cell types expressed wild-type EGFR (XREF_FIG).	8	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
This effect is mediated by EGFR , as increasing concentrations of AREG overcome partial antagonism of EGFR signaling by a fixed concentration of EGF ; the rightward shift of the AREG dose response curve in the presence of a fixed concentration of EGF indicates that EGF competitively antagonizes AREG stimulation of EGFR signaling , thereby reducing the potency ( but not efficacy ) of AREG ( as in XREF_FIG ) .	This effect is mediated by EGFR, as increasing concentrations of AREG overcome partial antagonism of EGFR signaling by a fixed concentration of EGF; the rightward shift of the AREG dose response curve in the presence of a fixed concentration of EGF indicates that EGF competitively antagonizes AREG stimulation of EGFR signaling, thereby reducing the potency (but not efficacy) of AREG (as in XREF_FIG).	45	52	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	45	46	51	52
With TGF-beta 1 exposure , high affinity EGFR was not down-regulated by EGF .	With TGF-beta 1 exposure, high affinity EGFR was not down-regulated by EGF.	5	13	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	7	8
We previously demonstrated that PMIP treatment increases EGF dependent degradation of EGFR [ XREF_BIBR ] .	We previously demonstrated that PMIP treatment increases EGF dependent degradation of EGFR [XREF_BIBR].	7	13	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	11	12
Flow cytometry results indicated that si RNA transfected cells produced ~ 5 times less activated EGFR compared to uninhibited cells treated with EGF ( activation evidenced by increase in fluorescence intensity from untreated control cells ) .	Flow cytometry results indicated that si RNA transfected cells produced ~ 5 times less activated EGFR compared to uninhibited cells treated with EGF (activation evidenced by increase in fluorescence intensity from untreated control cells).	9	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	15	16
Unlike EGF that stimulates EGFR degradation , UV induces stable EGFR accumulation or arrest in endosomal compartments [ XREF_BIBR ] .	Unlike EGF that stimulates EGFR degradation, UV induces stable EGFR accumulation or arrest in endosomal compartments [XREF_BIBR].	0	8	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	4	5
RIN1 ( QM ) , a mutant that blocks ABL activation , caused EGF stimulated membrane ruffling , actin remodeling , dextran uptake and EGFR degradation .	RIN1 (QM), a mutant that blocks ABL activation, caused EGF stimulated membrane ruffling, actin remodeling, dextran uptake and EGFR degradation.	12	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	24	25
Together , these data suggest that active Rab35 is necessary to promote EGF induced EGFR degradation and reduce EGFR signaling activation .	Together, these data suggest that active Rab35 is necessary to promote EGF induced EGFR degradation and reduce EGFR signaling activation.	11	15	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
To further evaluate the effect of HDN-1 on EGFR degradation , we examined EGFR levels in the cells treated with EGF for 1 to 5 h.	To further evaluate the effect of HDN-1 on EGFR degradation, we examined EGFR levels in the cells treated with EGF for 1 to 5 h.	8	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	8	9
In agreement with the dynamics of EGF induced EGFR degradation ( XREF_SUPPLEMENTARY and ) , initial ERK1/2 and Akt activation ( first 10 minutes ) was comparable in both the controls and the HER2 cells , but rapidly declined in the former and sustained in the latter .	In agreement with the dynamics of EGF induced EGFR degradation (XREF_SUPPLEMENTARY and), initial ERK1/2 and Akt activation (first 10 minutes) was comparable in both the controls and the HER2 cells, but rapidly declined in the former and sustained in the latter.	4	9	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
We next assessed the effects of CMTM7 knockdown on EGF stimulated EGFR activation , as determined by the major autophosphorylation site Y1173 , and phosphorylation of the downstream signaling targets AKT and ERK .	We next assessed the effects of CMTM7 knockdown on EGF stimulated EGFR activation, as determined by the major autophosphorylation site Y1173, and phosphorylation of the downstream signaling targets AKT and ERK.	7	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
EGCG inhibits epidermal growth factor dependent activation of EGFR , and EGFR dependent activation of the mitogen activated protein kinases ERK1/2 .	EGCG inhibits epidermal growth factor dependent activation of EGFR, and EGFR dependent activation of the mitogen activated protein kinases ERK1/2.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	2	5	8	9
These data and ours suggest that TGFalpha and AR stimulate EGFR coupling to tumor cell aggressiveness and chemoresistance , whereas EGF does so to a much lesser extent and may antagonize stimulation of pathogenic EGFR signaling by TGFalpha and AR .	These data and ours suggest that TGFalpha and AR stimulate EGFR coupling to tumor cell aggressiveness and chemoresistance, whereas EGF does so to a much lesser extent and may antagonize stimulation of pathogenic EGFR signaling by TGFalpha and AR.	20	35	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	34	35
Microtubule Stability Affected EGF Induced EGFR Degradation .	Microtubule Stability Affected EGF Induced EGFR Degradation.	2	6	Induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Pulse-chase experiments indicated that EGF stimulated the degradation of the wild type EGF receptor but had no effect on the rate of degradation of the EGFR and RET receptor .	Pulse-chase experiments indicated that EGF stimulated the degradation of the wild type EGF receptor but had no effect on the rate of degradation of the EGFR and RET receptor.	4	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	4	5	12	14
Given that c-CBL down-regulation suppresses EGF mediated EGFR degradation , but facilitates its recycling [ XREF_BIBR ] , this indicates that PTPRO may regulate both EGFR stability and recycling by affecting SRC mediated c-CBL phosphorylation at Y731 .	Given that c-CBL down-regulation suppresses EGF mediated EGFR degradation, but facilitates its recycling [XREF_BIBR], this indicates that PTPRO may regulate both EGFR stability and recycling by affecting SRC mediated c-CBL phosphorylation at Y731.	4	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
This effect has been associated with reduced EGF induced EGF receptor ( EGFR ) tyrosine phosphorylation , Grb-2 association , and Ras activation .	This effect has been associated with reduced EGF induced EGF receptor (EGFR) tyrosine phosphorylation, Grb-2 association, and Ras activation.	4	11	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	7	8	9	11
Knockdown of Spry1 results in EGF mediated EGFR degradation , impairs the EGF/EGFR/Snail signaling , increases E-cadherin expression and cell-cell adhesion , and promotes these TNBC reversion from a mesenchymal to an epithelial phenotype .	Knockdown of Spry1 results in EGF mediated EGFR degradation, impairs the EGF/EGFR/Snail signaling, increases E-cadherin expression and cell-cell adhesion, and promotes these TNBC reversion from a mesenchymal to an epithelial phenotype.	5	8	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
To test whether EGF could downregulate EGF-R and biologically affect psoriatic epidermis , split-thickness skin grafts of active psoriatic lesions were sutured onto the dorsal surface of nude mice .	To test whether EGF could downregulate EGF-R and biologically affect psoriatic epidermis, split-thickness skin grafts of active psoriatic lesions were sutured onto the dorsal surface of nude mice.	3	9	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	3	4	6	7
WASH knockdown was later suggested to delay trafficking of the epidermal growth factor receptor ( EGFR ) from endosomes to LAMP1 + lysosomes , although we previously showed that EGF stimulated EGFR degradation proceeded normally in WASH suppressed cells .	WASH knockdown was later suggested to delay trafficking of the epidermal growth factor receptor (EGFR) from endosomes to LAMP1 + lysosomes, although we previously showed that EGF stimulated EGFR degradation proceeded normally in WASH suppressed cells.	29	32	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	29	30	31	32
Suppression of EGF induced EGFR and ERK1/2 activation by LB might contribute in part to retardation of cancer progression .	Suppression of EGF induced EGFR and ERK1/2 activation by LB might contribute in part to retardation of cancer progression.	0	7	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
EGF is able to inhibit TLR4 signaling through EGF mediated epidermal growth factor receptor ( EGFR ) activation [ XREF_BIBR ] .	EGF is able to inhibit TLR4 signaling through EGF mediated epidermal growth factor receptor (EGFR) activation [XREF_BIBR].	4	14	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	8	9	10	14
In fact , in MDA-MB-468 cells 16 hours of EGF stimulation does not produce appreciable degradation of the EGFR ( XREF_FIG and XREF_FIG ) .	In fact, in MDA-MB-468 cells 16 hours of EGF stimulation does not produce appreciable degradation of the EGFR (XREF_FIG and XREF_FIG).	9	22	produce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	18	19
Previous studies have shown that EGF promotes activation dependent endocytosis and degradation of EGFR , potentially regulating the duration of downstream signaling .	Previous studies have shown that EGF promotes activation dependent endocytosis and degradation of EGFR, potentially regulating the duration of downstream signaling.	5	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	13	14
The expression of the EGF antagonist Argos ( aos ) , using either nosGal4 ( XREF_FIG f-ii ) and bamGal4 ( XREF_FIG f-iv ) , is expected to reduce EGFR activations locally during 1-2 cell and 4-16 cell stages , respectively .	The expression of the EGF antagonist Argos (aos), using either nosGal4 (XREF_FIG f-ii) and bamGal4 (XREF_FIG f-iv), is expected to reduce EGFR activations locally during 1-2 cell and 4-16 cell stages, respectively.	1	30	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	expression of the EGF	egf	EGFR	EGFR	egfr	4	5	29	30
Competition with cetuximab for binding to the cell surface generated one clone , termed 11F8 , which displayed a dose dependent inhibitory effect on EGF stimulated EGFR activation in A431 cells .	Competition with cetuximab for binding to the cell surface generated one clone, termed 11F8, which displayed a dose dependent inhibitory effect on EGF stimulated EGFR activation in A431 cells.	22	27	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
EGF treatment induced a faster degradation of EGFR protein in HeLa cells expressing WT USP8 compared to mutants , although EGFR protein levels were comparable in these cells under serum starved conditions ( XREF_FIG ) .	EGF treatment induced a faster degradation of EGFR protein in HeLa cells expressing WT USP8 compared to mutants, although EGFR protein levels were comparable in these cells under serum starved conditions (XREF_FIG).	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	7	8
ES cells were treated with incremental drug doses for 4h ; decreases in EGF induced pEGFR was observed even at the lowest dose ( 1microM ) tested ( XREF_FIG ) .	ES cells were treated with incremental drug doses for 4h; decreases in EGF induced pEGFR was observed even at the lowest dose (1microM) tested (XREF_FIG).	11	17	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	13	14	15	16
EGF treatment greatly reduced the half-life of WT-EGFR , but had relatively little effect on the half-life of 973-EGFR .	EGF treatment greatly reduced the half-life of WT-EGFR, but had relatively little effect on the half-life of 973-EGFR.	0	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	WT-EGFR	WT-EGFR	WT-EGFR	0	1	7	8
This was accompanied by substantial inhibition of EGF induced EGFR downregulation when PRL and EGF cotreatment was compared to EGF treatment alone .	This was accompanied by substantial inhibition of EGF induced EGFR downregulation when PRL and EGF cotreatment was compared to EGF treatment alone.	5	10	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
As shown in XREF_FIG , basal autophagy is slightly involved in EGFR degradation because the pharmacological inhibition of autophagy by 3-MA only slightly attenuates EGF mediated EGFR degradation ( compare lanes 2 and 3 ) .	As shown in XREF_FIG, basal autophagy is slightly involved in EGFR degradation because the pharmacological inhibition of autophagy by 3-MA only slightly attenuates EGF mediated EGFR degradation (compare lanes 2 and 3).	23	27	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
The binding of Epidermal Growth Factor ( EGF ) to its receptor ( EGFR ) triggers EGFR degradation , a process mediated by the interaction between TSG101 and hepatocyte growth factor regulated tyrosine kinase substrate ( HRS ) XREF_BIBR .	The binding of Epidermal Growth Factor (EGF) to its receptor (EGFR) triggers EGFR degradation, a process mediated by the interaction between TSG101 and hepatocyte growth factor regulated tyrosine kinase substrate (HRS) XREF_BIBR.	3	17	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Epidermal Growth Factor	Epidermal Growth Factor	Epidermal Growth Factor	EGFR	EGFR	EGFR	3	6	16	17
Because EGF possesses some ability to stimulate EGFR coupling to cell proliferation , EGF does not fully antagonize EGFR coupling to cell proliferation .	Because EGF possesses some ability to stimulate EGFR coupling to cell proliferation, EGF does not fully antagonize EGFR coupling to cell proliferation.	13	19	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	18	19
EGF induced EGFR degradation was monitored in Western-blot analysis ( XREF_FIG ) .	EGF induced EGFR degradation was monitored in Western-blot analysis (XREF_FIG).	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Because we blocked the protein synthesis in the beginning of the experiments , these results suggest that CTTN may increase EGFR degradation induced by EGF .	Because we blocked the protein synthesis in the beginning of the experiments, these results suggest that CTTN may increase EGFR degradation induced by EGF.	20	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	20	21
Finally , we show that depletion of SGEF significantly inhibits epidermal growth factor induced EGFR signaling cascade and cell migration in the prostate cancer cells .	Finally, we show that depletion of SGEF significantly inhibits epidermal growth factor induced EGFR signaling cascade and cell migration in the prostate cancer cells.	10	16	induced	Positive_early_activation	Positive_activation	Negative_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	10	13	14	15
Aims and Hypothesis : This study aims to investigate the mechanism involved in intracellular regulation of EGFR degradation induced by EGF .	Aims and Hypothesis : This study aims to investigate the mechanism involved in intracellular regulation of EGFR degradation induced by EGF.	16	21	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	16	17
In vitro analyses of intact MINT5 ( IgG1 ) and its F ( ab ' ) 2 fragment indicated that both forms of the MAb inhibited binding of 125I-mEGF to EGFR , induced receptor internalization and blocked EGF induced EGFR tyrosine kinase activation in A431 cells .	In vitro analyses of intact MINT5 (IgG1) and its F (ab ') 2 fragment indicated that both forms of the MAb inhibited binding of 125I-mEGF to EGFR, induced receptor internalization and blocked EGF induced EGFR tyrosine kinase activation in A431 cells.	36	42	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	37	38	39	40
Knockout of RCN2 in HCC cells not only inhibited activation of the EGFR-ERK pathway by blocking EGF mediated EGFR dimerization and internalization but also suppressed cell proliferation and EGFR phosphorylation under long exposure to EGF .	Knockout of RCN2 in HCC cells not only inhibited activation of the EGFR-ERK pathway by blocking EGF mediated EGFR dimerization and internalization but also suppressed cell proliferation and EGFR phosphorylation under long exposure to EGF.	16	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
Celecoxib increased total EGFR levels in colon TAFs by both inducing EGFR neosynthesis and by slowing down EGF triggered EGFR degradation .	Celecoxib increased total EGFR levels in colon TAFs by both inducing EGFR neosynthesis and by slowing down EGF triggered EGFR degradation.	15	20	triggered	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
The antiproliferative activity of tyrphostin nearly correlated quantitatively with its potency as an inhibitor of the EGF stimulated EGF receptor tyrosine kinase activity .	The antiproliferative activity of tyrphostin nearly correlated quantitatively with its potency as an inhibitor of the EGF stimulated EGF receptor tyrosine kinase activity.	13	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	16	17	18	20
First , upon EGF induced EGFR degradation , an RNF11 independent mechanism leads to the up-regulation of SEC23B , SEC24B , and SEC24D , and hence to adapted EGFR transport .	First, upon EGF induced EGFR degradation, an RNF11 independent mechanism leads to the up-regulation of SEC23B, SEC24B, and SEC24D, and hence to adapted EGFR transport.	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
EGF stimulated EGFR degradation was quantitated to determine the extent to which the knockdown of TSG101 stabilizes EGFR .	EGF stimulated EGFR degradation was quantitated to determine the extent to which the knockdown of TSG101 stabilizes EGFR.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
In accordance with the reduced levels of EGFR in EGFR anti-sense-expressing cells , tyrosine phosphorylation of EGFR was decreased compared to untransfected parental cells treated with EGF .	In accordance with the reduced levels of EGFR in EGFR anti-sense-expressing cells, tyrosine phosphorylation of EGFR was decreased compared to untransfected parental cells treated with EGF.	14	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	16	17
Culturing cells in the absence of EGF abolished EGFR depletion induced by AICAR , indicating a requirement for EGF ligand and most likely EGFR activation and turnover ( XREF_FIG ) .	Culturing cells in the absence of EGF abolished EGFR depletion induced by AICAR, indicating a requirement for EGF ligand and most likely EGFR activation and turnover (XREF_FIG).	4	9	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
We then determined the effect of the Y319F FLAG-ALIX Bro1 expression , the WT HA-ALIX V expression or ALIX knockdown on the kinetics of EGF induced EGFR degradation .	We then determined the effect of the Y319F FLAG-ALIX Bro1 expression, the WT HA-ALIX V expression or ALIX knockdown on the kinetics of EGF induced EGFR degradation.	22	27	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	24	25	26	27
It should be mentioned that , another study found that knockdown of GnT-Va ( or Mgat5a ) by siRNA treatment ( which would reduce branching of EGFR glycans ) in MDA-MB231 cells resulted in lower EGF induced rates of EGFR endocytosis .	It should be mentioned that, another study found that knockdown of GnT-Va (or Mgat5a) by siRNA treatment (which would reduce branching of EGFR glycans) in MDA-MB231 cells resulted in lower EGF induced rates of EGFR endocytosis.	34	40	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	35	36	39	40
Treatment of cells with exogenous neutral sphingomyelinase ( SMase ) or a cell permeable ceramide analog , C ( 2 )-ceramide , also caused similar inhibitory effects on EGF induced activation of EGF receptor , tyrosine phosphorylation of PLC-gamma ( 1 ) , and the activation of PLD .	Treatment of cells with exogenous neutral sphingomyelinase (SMase) or a cell permeable ceramide analog, C (2)-ceramide, also caused similar inhibitory effects on EGF induced activation of EGF receptor, tyrosine phosphorylation of PLC-gamma (1), and the activation of PLD.	26	34	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	28	29	32	34
This study demonstrates that , in polarized Madin-Darby canine kidney II cells , EGF induced EGFR activation significantly inhibited claudin-2 expression while simultaneously inducing cellular redistribution and increased expression of claudin-1 , -3 , and -4 .	This study demonstrates that, in polarized Madin-Darby canine kidney II cells, EGF induced EGFR activation significantly inhibited claudin-2 expression while simultaneously inducing cellular redistribution and increased expression of claudin-1, -3, and -4.	13	16	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
The effect of SC4MOL silencing on EGFR signaling was further evaluated in the context of EGFR kinase inhibitor , erlotinib ( XREF_FIG ) , in cells treated with EGF to induce receptor internalization .	The effect of SC4MOL silencing on EGFR signaling was further evaluated in the context of EGFR kinase inhibitor, erlotinib (XREF_FIG), in cells treated with EGF to induce receptor internalization.	15	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	28	29	15	16
Although EGF stimulation normally causes the degradation of EGFR , we observed stabilization of activated EGFR in cells treated with LRRK1 siRNA ( XREF_FIG ) .	Although EGF stimulation normally causes the degradation of EGFR, we observed stabilization of activated EGFR in cells treated with LRRK1 siRNA (XREF_FIG).	1	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	1	2	8	9
EGF mediated EGFR activation reduced significantly the expression levels of HLA-ABC molecules in A431 and H125 cells when compared with cells cultured in the absence of EGF .	EGF mediated EGFR activation reduced significantly the expression levels of HLA-ABC molecules in A431 and H125 cells when compared with cells cultured in the absence of EGF.	0	3	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
Consistent with the concept that sustained EGFR activation in the day 4-7 period enhances osteogenic differentation , both EGFR downregulation by soluble EGF ( sEGF ) and inhibition of EGFR kinase activity by a pharmacological agent each independently served to attenuate tEGF induced increase in alkaline phosphatase expression ( XREF_FIG ) .	Consistent with the concept that sustained EGFR activation in the day 4-7 period enhances osteogenic differentation, both EGFR downregulation by soluble EGF (sEGF) and inhibition of EGFR kinase activity by a pharmacological agent each independently served to attenuate tEGF induced increase in alkaline phosphatase expression (XREF_FIG).	18	24	downregulation	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	22	23	18	19
We reported that berberine significantly inhibited basal level and EGF stimulated EGFR activation and proliferation in the immorto Min mouse colonic epithelial ( IMCE ) cells carrying the APC min mutation and human colonic carcinoma cell line , HT-29 cells .	We reported that berberine significantly inhibited basal level and EGF stimulated EGFR activation and proliferation in the immorto Min mouse colonic epithelial (IMCE) cells carrying the APC min mutation and human colonic carcinoma cell line, HT-29 cells.	5	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
Silencing of CHC by either of two siRNA sequences , conditions that each resulted in an inhibition of EGF stimulated Akt phosphorylation ( XREF_FIG , and Supplemental Figure S1D ) , had no effect on the gain in EGFR pY1068 stimulated by EGF ( XREF_FIG and Supplemental Figure S4A ) .	Silencing of CHC by either of two siRNA sequences, conditions that each resulted in an inhibition of EGF stimulated Akt phosphorylation (XREF_FIG, and Supplemental Figure S1D), had no effect on the gain in EGFR pY1068 stimulated by EGF (XREF_FIG and Supplemental Figure S4A).	38	48	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	42	43	38	39
Upon co-transfection with ubiquitin , Rab5 exhibited abnormalities in endosomal localization and EGF induced EGF receptor degradation .	Upon co-transfection with ubiquitin, Rab5 exhibited abnormalities in endosomal localization and EGF induced EGF receptor degradation.	7	16	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	12	13	14	16
To measure EGF induced EGFR degradation , sub-confluent cultures of cells in 35-mm dishes were first cultured in serum-free medium for 12h and then cultured in the same medium supplemented with 100ngml -1 of recombinant EGF ( Sigma ) for indicated lengths of time .	To measure EGF induced EGFR degradation, sub-confluent cultures of cells in 35-mm dishes were first cultured in serum-free medium for 12h and then cultured in the same medium supplemented with 100ngml -1 of recombinant EGF (Sigma) for indicated lengths of time.	1	5	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
These results suggest that GALNT1 knockdown suppresses EGF induced EGFR activation and enhances EGF induced EGFR degradation in HCC cells .	These results suggest that GALNT1 knockdown suppresses EGF induced EGFR activation and enhances EGF induced EGFR degradation in HCC cells.	13	16	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Herein , for the first time , our investigations demonstrated that NDRG1 inhibits c-Src activation by down-regulating EGFR expression and attenuating EGF induced EGFR activation , leading to a reduction in EGFR-c-Src interactions .	Herein, for the first time, our investigations demonstrated that NDRG1 inhibits c-Src activation by down-regulating EGFR expression and attenuating EGF induced EGFR activation, leading to a reduction in EGFR-c-Src interactions.	20	24	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	23	24
We suggest that the inhibition of EGF stimulated EGFR activity is one of the mechanisms of the antiproliferative effect of lidocaine on CAL27 cells .	We suggest that the inhibition of EGF stimulated EGFR activity is one of the mechanisms of the antiproliferative effect of lidocaine on CAL27 cells.	4	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Future studies that involve incubating cat embryos with EGF and specific inhibitors of EGFR or MAPK will confirm this hypothesis .	Future studies that involve incubating cat embryos with EGF and specific inhibitors of EGFR or MAPK will confirm this hypothesis.	8	15	inhibitors	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	13	14
Inhibition of U87MG growth correlated with suppressed EGF activation of EGFR and of Akt but not mitogen activated protein kinase signaling pathways , whereas DeltaEGFR activity and intracellular signaling in U87MG and Delta were unaffected by Herstatin treatment .	Inhibition of U87MG growth correlated with suppressed EGF activation of EGFR and of Akt but not mitogen activated protein kinase signaling pathways, whereas DeltaEGFR activity and intracellular signaling in U87MG and Delta were unaffected by Herstatin treatment.	7	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	10	11
In addition , the mRNA transcripts for MMP-9 and EGFR were also significantly decreased with MMP-9 siRNA in VSMCs treated with EGF .	In addition, the mRNA transcripts for MMP-9 and EGFR were also significantly decreased with MMP-9 siRNA in VSMCs treated with EGF.	5	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	9	10
Moreover , EGFR internalization and degradation markedly increased in the SH3GL2 overexpressing cells following EGF stimulation thereby restricting EGFR mediated continuous signaling .	Moreover, EGFR internalization and degradation markedly increased in the SH3GL2 overexpressing cells following EGF stimulation thereby restricting EGFR mediated continuous signaling.	14	19	restricting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	14	15	18	19
Recombinant human epidermal growth factor ( rhEGF ) inhibited the growth of EGFR positive MX-1 dose-dependently , whereas no changes were observed in the growth of EGFR negative MCF-7 , Br-10 and T-61 after treatment with rhEGF .	Recombinant human epidermal growth factor (rhEGF) inhibited the growth of EGFR positive MX-1 dose-dependently, whereas no changes were observed in the growth of EGFR negative MCF-7, Br-10 and T-61 after treatment with rhEGF.	2	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	2	5	12	13
EGF induced EGFR internalization was indeed blocked in the presence of high levels of erbB2 or if cbl binding of EGFR was impaired .	EGF induced EGFR internalization was indeed blocked in the presence of high levels of erbB2 or if cbl binding of EGFR was impaired.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
A possible explanation for these observations is that 15 microg unlabelled EGF is insufficient to block most EGFR but causes partial blockade in liver , leading to a reduction in binding of the radiolabelled NP at this site .	A possible explanation for these observations is that 15 microg unlabelled EGF is insufficient to block most EGFR but causes partial blockade in liver, leading to a reduction in binding of the radiolabelled NP at this site.	8	19	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	17	18
Interestingly , unlike in other cell types , we observed no significant EGF mediated EGFR degradation in either NT control ( XREF_FIG ) or parental MDA-MB-231 cells ( data not shown ) .	Interestingly, unlike in other cell types, we observed no significant EGF mediated EGFR degradation in either NT control (XREF_FIG) or parental MDA-MB-231 cells (data not shown).	12	15	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
We next examined EGFR degradation induced by EGF .	We next examined EGFR degradation induced by EGF.	3	8	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	3	4
Consistent with these previous studies , knock down of HRS ( XREF_FIG ) or TSG101 ( XREF_FIG ) inhibited EGF induced EGF-R degradation compared to control cells ( XREF_FIG , lower panels ) .	Consistent with these previous studies, knock down of HRS (XREF_FIG) or TSG101 (XREF_FIG) inhibited EGF induced EGF-R degradation compared to control cells (XREF_FIG, lower panels).	19	22	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	19	20	21	22
In addition , PMIP inhibits MUC1 mediated inhibition of EGF dependent degradation of EGFR .	In addition, PMIP inhibits MUC1 mediated inhibition of EGF dependent degradation of EGFR.	9	14	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	13	14
Whereas inhibition of the EGFR tyrosine kinase effectively inhibited tyrosine phosphorylation and internalisation of EGF activated EGFR , internalisation of UV exposed EGFR was unaffected .	Whereas inhibition of the EGFR tyrosine kinase effectively inhibited tyrosine phosphorylation and internalisation of EGF activated EGFR, internalisation of UV exposed EGFR was unaffected.	9	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	tyrosine phosphorylation and internalisation of EGF	egf	EGFR	EGFR	egfr	14	15	16	17
We show that EGF induced EGFR autotransphosphorylation is reduced in PC3-AR cells compared to PC3 cells transfected only with the vector ( PC3-Neo ) .	We show that EGF induced EGFR autotransphosphorylation is reduced in PC3-AR cells compared to PC3 cells transfected only with the vector (PC3-Neo).	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	5	6
Conversely , EGF significantly ( p < 0.05 ) decreased EGFR in NDRG1 over-expressing and sh-NDRG1 DU145 cells versus these cells without EGF ( XREF_SUPPLEMENTARY ) .	Conversely, EGF significantly (p < 0.05) decreased EGFR in NDRG1 over-expressing and sh-NDRG1 DU145 cells versus these cells without EGF (XREF_SUPPLEMENTARY).	2	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	10	11
In addition , both FN mediated cell adhesion and p130Cas overexpression reduce EGF stimulated dynamin phosphorylation , which is necessary for EGF induced EGFR internalization .	In addition, both FN mediated cell adhesion and p130Cas overexpression reduce EGF stimulated dynamin phosphorylation, which is necessary for EGF induced EGFR internalization.	19	24	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	23	24
We first assessed EGF induced degradation of EGFR in RBE and MMNK-1 cells by Western blotting .	We first assessed EGF induced degradation of EGFR in RBE and MMNK-1 cells by Western blotting.	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	3	4	7	8
EGF or Pep2-Yac treatment induced EGFR degradation in a time dependent manner ( XREF_FIG C ) .	EGF or Pep2-Yac treatment induced EGFR degradation in a time dependent manner (XREF_FIG C).	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
The depletion of ANXA2 with siRNAs caused EGF retention in early endosomes ( XREF_FIG ) and delayed EGFR degradation ( XREF_FIG ; uncropped blots in Supplemental Figure S7 , D-G ; quantification in XREF_FIG ) , much like MSN depletion ( XREF_FIG ) , demonstrating that ANXA2 KD fully recapitulated the effects of MSN KD .	The depletion of ANXA2 with siRNAs caused EGF retention in early endosomes (XREF_FIG) and delayed EGFR degradation (XREF_FIG; uncropped blots in Supplemental Figure S7, D-G; quantification in XREF_FIG), much like MSN depletion (XREF_FIG), demonstrating that ANXA2 KD fully recapitulated the effects of MSN KD.	7	18	retention	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	17	18
After cycloheximide treatment , EGF induced EGFR degradation was accelerated significantly in TACC3 knockdown cells and in cells treated with a small-molecule targeting TACC3 , KHS101 XREF_BIBR , XREF_BIBR .	After cycloheximide treatment, EGF induced EGFR degradation was accelerated significantly in TACC3 knockdown cells and in cells treated with a small-molecule targeting TACC3, KHS101 XREF_BIBR, XREF_BIBR.	4	7	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
In these experiments , therefore , exogenous soluble EGF would have to reduce EGFR number by binding to free EGFR or by successfully competing with tEGF for binding , replacing it , and driving internalization and degradation of the receptor .	In these experiments, therefore, exogenous soluble EGF would have to reduce EGFR number by binding to free EGFR or by successfully competing with tEGF for binding, replacing it, and driving internalization and degradation of the receptor.	6	14	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	13	14
Consistent with previous studies XREF_BIBR , knockdown of Rab7A inhibited EGF induced EGF-R degradation compared to control cells ( XREF_FIG ) .	Consistent with previous studies XREF_BIBR, knockdown of Rab7A inhibited EGF induced EGF-R degradation compared to control cells (XREF_FIG).	10	13	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	10	11	12	13
The role of Hrs mediated early endosomal sorting in the regulation of EGF induced EGFR degradation is well established ; both the overexpression and the depletion of Hrs inhibit ligand induced degradation of the EGFR [ XREF_BIBR , XREF_BIBR ] .	The role of Hrs mediated early endosomal sorting in the regulation of EGF induced EGFR degradation is well established; both the overexpression and the depletion of Hrs inhibit ligand induced degradation of the EGFR [XREF_BIBR, XREF_BIBR].	10	15	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
A lower risk for breast cancer in G/G carriers might be explained through EGF receptor internalization promoted by EGF .	A lower risk for breast cancer in G/G carriers might be explained through EGF receptor internalization promoted by EGF.	13	19	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	18	19	13	15
However , EGF induced ErbB1 decrease in A431 cells is less than that induced by hPEPD-G278D .	However, EGF induced ErbB1 decrease in A431 cells is less than that induced by hPEPD-G278D.	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	ErbB1	ErbB1	ErbB1	2	3	4	5
The results of in vitro experiments showed that CHAG suppressed both basic and EGF induced migration and invasion of OC cells , blocked the activation of EGF initiated EGFR activation , inhibited downstream signal transduction of EGFR , and decreased expression of proliferation and migration and invasion related proteins .	The results of in vitro experiments showed that CHAG suppressed both basic and EGF induced migration and invasion of OC cells, blocked the activation of EGF initiated EGFR activation, inhibited downstream signal transduction of EGFR, and decreased expression of proliferation and migration and invasion related proteins.	24	29	initiated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
These results suggest that Tom1L1 and Y460F , Tom1L1 and Y460F-SH 3 and Tom1L1 and Y392F , which are no longer able to associate with activated EGFR because of defects in Tyr phosphorylation and/or interaction with Grb2 , significantly blocked internalization and degradation of Texas Red-EGF and inhibited EGF stimulated degradation of EGFR ( XREF_FIG ) .	These results suggest that Tom1L1 and Y460F, Tom1L1 and Y460F-SH 3 and Tom1L1 and Y392F, which are no longer able to associate with activated EGFR because of defects in Tyr phosphorylation and/or interaction with Grb2, significantly blocked internalization and degradation of Texas Red-EGF and inhibited EGF stimulated degradation of EGFR (XREF_FIG).	47	54	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	48	49	52	53
Rab5a is required for EGF induced EGFR degradation while Rab5b and Rab5c are not .	Rab5a is required for EGF induced EGFR degradation while Rab5b and Rab5c are not.	4	7	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
EGF increased cell viability in OVCAR-3 cells and aspirin blocked the EGFR activated cell viability in a dose dependent manner .	EGF increased cell viability in OVCAR-3 cells and aspirin blocked the EGFR activated cell viability in a dose dependent manner.	0	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	11	12
Through its interaction with endosomes , RhoB delays EGF induced EGF-R degradation by inhibiting the transfer from late endosomes to lysosomes XREF_BIBR , while oscillation of RhoB GTPase activity is essential for appropriate sorting decisions , and for directing CXCR2 chemokine receptor degradation and recycling - events that are required for optimal chemotaxis XREF_BIBR .	Through its interaction with endosomes, RhoB delays EGF induced EGF-R degradation by inhibiting the transfer from late endosomes to lysosomes XREF_BIBR, while oscillation of RhoB GTPase activity is essential for appropriate sorting decisions, and for directing CXCR2 chemokine receptor degradation and recycling - events that are required for optimal chemotaxis XREF_BIBR.	6	11	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	8	9	10	11
RT-PCR revealed that the infected cornea of VIP (-/-) versus WT mice expressed higher mRNA levels of epidermal growth factor ( EGF ) and hepatocyte growth factor ( HGF ) , reduced FGF , EGFR , and HGFR , with no difference in FGFR ; differences between groups were not seen in normal cornea .	RT-PCR revealed that the infected cornea of VIP (-/-) versus WT mice expressed higher mRNA levels of epidermal growth factor (EGF) and hepatocyte growth factor (HGF), reduced FGF, EGFR, and HGFR, with no difference in FGFR; differences between groups were not seen in normal cornea.	15	41	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	epidermal growth factor	levels of epidermal growth factor	epidermal growth factor	EGFR	EGFR	egfr	17	20	34	35
Interestingly , EGF induced EGFR degradation was observed in the absence of PB treatment .	Interestingly, EGF induced EGFR degradation was observed in the absence of PB treatment.	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	4	5
There was slight phosphorylation of EGFR in the serum starvation treated A431 control cells not treated with epidermal growth factor ( XREF_FIG ) .	There was slight phosphorylation of EGFR in the serum starvation treated A431 control cells not treated with epidermal growth factor (XREF_FIG).	3	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	17	20	5	6
To assay the dimerization of EGFR , cells were prestarved for 24h and then treated with EGF ( 0.1 ng/ml ) for 5min .	To assay the dimerization of EGFR, cells were prestarved for 24h and then treated with EGF (0.1 ng/ml) for 5min.	3	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	5	6
The anti-angiogenic capacity of AF is based on disruption of EGF induced EGFR activation [ XREF_BIBR ] and PI3K/Akt/mTOR activation , in which PI3K/Akt/mTOR signaling induces HIF-1 expression in MDA-MB-231 cells [ XREF_BIBR ] .	The anti-angiogenic capacity of AF is based on disruption of EGF induced EGFR activation [XREF_BIBR] and PI3K/Akt/mTOR activation, in which PI3K/Akt/mTOR signaling induces HIF-1 expression in MDA-MB-231 cells [XREF_BIBR].	8	13	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
We also found that EGFR receptor family members ERBB2 and ERBB3 were upregulated when EGFR signaling is decreased by exogenous EGF ligand removal or EGFR targeted therapy .	We also found that EGFR receptor family members ERBB2 and ERBB3 were upregulated when EGFR signaling is decreased by exogenous EGF ligand removal or EGFR targeted therapy.	14	22	decreased	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	20	21	14	15
Pulse-chase experiments revealed that EGF generally stimulated EGF receptor degradation to a greater extent than TGF-alpha .	Pulse-chase experiments revealed that EGF generally stimulated EGF receptor degradation to a greater extent than TGF-alpha.	4	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	4	5	7	9
To determine the spatial relationship between plasma membrane recruitment and the location of EGF-R , serum starved HEK-GFP-SNX5 cells were treated with EGF for 3 min and non permeabilised cells stained with anti-EGF-R antibodies .	To determine the spatial relationship between plasma membrane recruitment and the location of EGF-R, serum starved HEK-GFP-SNX5 cells were treated with EGF for 3 min and non permeabilised cells stained with anti-EGF-R antibodies.	11	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF-R	EGF-R	EGF-R	22	23	13	14
As we anticipated , EGF induced rapid EGFR degradation by 24 hrs after treatment with cisplatin ( XREF_FIG ) .	As we anticipated, EGF induced rapid EGFR degradation by 24 hrs after treatment with cisplatin (XREF_FIG).	4	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	7	8
Epidermal growth factor ( EGF ) in the medium was replaced with amphiregulin and neuregulin to decrease activation of EGFR and increase activation of EGFR homologs 3 and 4 ( ERBB3 and ERBB4 ) .	Epidermal growth factor (EGF) in the medium was replaced with amphiregulin and neuregulin to decrease activation of EGFR and increase activation of EGFR homologs 3 and 4 (ERBB3 and ERBB4).	0	22	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Epidermal growth factor	Epidermal growth factor	Epidermal growth factor	EGFR	EGFR	EGFR	0	3	19	20
We observed EGF induced degradation of EGFR , and this model was used in the following experiments .	We observed EGF induced degradation of EGFR, and this model was used in the following experiments.	1	7	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	6	7
Interestingly , phosphorylation of EGF induced EGFR was inhibited by gefitinib treatment in both H358 and H1703 cells regardless of the gefitinib response .	Interestingly, phosphorylation of EGF induced EGFR was inhibited by gefitinib treatment in both H358 and H1703 cells regardless of the gefitinib response.	2	8	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
Moreover , androgens and EGF downregulate EGFR , which is probably internalized into the cell and degraded by lisosomes : in fact , a negative linear correlation between EGF , nuclear AR and the high- and low-affinity binding of EGFR is observed .	Moreover, androgens and EGF downregulate EGFR, which is probably internalized into the cell and degraded by lisosomes : in fact, a negative linear correlation between EGF, nuclear AR and the high- and low-affinity binding of EGFR is observed.	2	16	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
EGF decreased the EGF receptor content of NMuMG cells , and this decrease was unaffected by prolactin treatment .	EGF decreased the EGF receptor content of NMuMG cells, and this decrease was unaffected by prolactin treatment.	0	5	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	0	1	3	5
Lysosomal degradation is essential for the termination of EGF stimulated EGF receptor ( EGFR ) signaling .	Lysosomal degradation is essential for the termination of EGF stimulated EGF receptor (EGFR) signaling.	6	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	8	9	10	12
Consistently , we demonstrate here that FLCN-deficiency reduces the rate of EGF induced EGFR degradation , resulting in the continuous activation of ERK1/2 and AKT in an EGFR dependent manner .	Consistently, we demonstrate here that FLCN-deficiency reduces the rate of EGF induced EGFR degradation, resulting in the continuous activation of ERK1/2 and AKT in an EGFR dependent manner.	9	14	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
In Hela cells , the overexpression of a dominant negative-Rab7 ( N125I ) or Rab7 RNAi inhibited EGF induced EGFR degradation , and the EGFR accumulated in ILVs of MVBs XREF_BIBR , XREF_BIBR , where the EGFR would be unable to engage downstream signaling molecules .	In Hela cells, the overexpression of a dominant negative-Rab7 (N125I) or Rab7 RNAi inhibited EGF induced EGFR degradation, and the EGFR accumulated in ILVs of MVBs XREF_BIBR, XREF_BIBR, where the EGFR would be unable to engage downstream signaling molecules.	16	24	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	17	18	19	20
NH 4 Cl , MG132 and lactacystin inhibit EGF mediated degradation of the EGFR .	NH 4 Cl, MG132 and lactacystin inhibit EGF mediated degradation of the EGFR.	7	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	13	14
Overexpression of Rab5 apparently facilitated EGF induced EGFR degradation , as judged by earlier complete degradation after 60 min of EGF treatment ( XREF_FIG upper-right panel ) .	Overexpression of Rab5 apparently facilitated EGF induced EGFR degradation, as judged by earlier complete degradation after 60 min of EGF treatment (XREF_FIG upper-right panel).	4	8	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
EGF stimulation led to turnover of EGFR , causing decreased EGFR protein , however , activated EGFR was still detectable , indicating that EGFR signaling does occur ( XREF_SUPPLEMENTARY ) .	EGF stimulation led to turnover of EGFR, causing decreased EGFR protein, however, activated EGFR was still detectable, indicating that EGFR signaling does occur (XREF_SUPPLEMENTARY).	0	11	causing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	10	11
Specifically , PTPN2 knockdown in T 84 colonic epithelial cells accentuated epidermal growth factor ( EGF ) inhibition of Ca 2+ -stimulated chloride secretion thus promoting EGFR suppression of electrolyte secretion .	Specifically, PTPN2 knockdown in T 84 colonic epithelial cells accentuated epidermal growth factor (EGF) inhibition of Ca 2+ -stimulated chloride secretion thus promoting EGFR suppression of electrolyte secretion.	11	27	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	11	14	26	27
Taken together , WASHout fibroblasts produced enlarged lysosomal structures during EGF stimulation that mediated efficient EGFR degradation .	Taken together, WASHout fibroblasts produced enlarged lysosomal structures during EGF stimulation that mediated efficient EGFR degradation.	10	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	15	16
Similarly , EGF stimulated HEC1A-MUC1-KO cells had decreased pEGFR compared to HEC1A and HEC1A-Cas9 cells .	Similarly, EGF stimulated HEC1A-MUC1-KO cells had decreased pEGFR compared to HEC1A and HEC1A-Cas9 cells.	2	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	2	3	8	9
Inhibition of DHHC20 mediated palmitoylation increases EGF induced EGFR activation .	Inhibition of DHHC20 mediated palmitoylation increases EGF induced EGFR activation.	4	9	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Epidermal growth factor ( EGF )/DNA complexes targeted to cancer cells overexpressing the EGF receptor resulted in efficient transduction of several lung cancer cell lines in vitro .	Epidermal growth factor (EGF)/DNA complexes targeted to cancer cells overexpressing the EGF receptor resulted in efficient transduction of several lung cancer cell lines in vitro.	0	15	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Epidermal growth factor	Epidermal growth factor	Epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	0	3	13	15
As expected , inactivation of the initial steps in the ESCRT pathway inhibited EGF stimulated EGFR degradation in Hela cells ( XREF_FIG ) .	As expected, inactivation of the initial steps in the ESCRT pathway inhibited EGF stimulated EGFR degradation in Hela cells (XREF_FIG).	12	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Loss of PS affected EGFR recycling and degradation , whereas EGF induced EGFR internalization was unaffected .	Loss of PS affected EGFR recycling and degradation, whereas EGF induced EGFR internalization was unaffected.	10	13	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
Our western blot analysis showed similar effects of inhibition of EGF induced EGFR dimerisation upon pretreatment with AnxA2 antibodies in both cell types , as is the case with AnxA2 ( D1/274.5 ) antibody pretreatment .	Our western blot analysis showed similar effects of inhibition of EGF induced EGFR dimerisation upon pretreatment with AnxA2 antibodies in both cell types, as is the case with AnxA2 (D1/274.5) antibody pretreatment.	8	13	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	10	11	12	13
We performed confocal microscopy to monitor EGFR-GFP internalization following agonist stimulation and showed pharmacologic inhibition of PI3K blocked ISO stimulated EGFR internalization but did not affect EGF mediated EGFR internalization ( XREF_FIG ) .	We performed confocal microscopy to monitor EGFR-GFP internalization following agonist stimulation and showed pharmacologic inhibition of PI3K blocked ISO stimulated EGFR internalization but did not affect EGF mediated EGFR internalization (XREF_FIG).	25	29	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
ST6Gal-I knockdown impairs basal and EGF induced EGFR activation in BxPC3 pancreatic cancer cells .	ST6Gal-I knockdown impairs basal and EGF induced EGFR activation in BxPC3 pancreatic cancer cells.	3	8	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
We found that CMTM7 knockdown in NSCLC cells delays EGF induced EGFR internalization and degradation .	We found that CMTM7 knockdown in NSCLC cells delays EGF induced EGFR internalization and degradation.	7	12	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	11	12
Of note , the rate of EGF induced EGFR protein degradation was comparable in the absence and presence of Dox , further supporting the conclusion that increased EGFR protein levels in RanBP6 knockdown cells were not the result of impaired EGFR protein degradation .	Of note, the rate of EGF induced EGFR protein degradation was comparable in the absence and presence of Dox, further supporting the conclusion that increased EGFR protein levels in RanBP6 knockdown cells were not the result of impaired EGFR protein degradation.	4	10	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Silencing LAMC2 partially blocked epidermal growth factor mediated activation of EGFR and its downstream pathway .	Silencing LAMC2 partially blocked epidermal growth factor mediated activation of EGFR and its downstream pathway.	4	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	4	7	10	11
Recently it was suggested that GBM stem like cells with amplified EGFR should be cultured in stem cell medium without EGF , as the presence of EGF induced rapid loss of EGFR amplification .	Recently it was suggested that GBM stem like cells with amplified EGFR should be cultured in stem cell medium without EGF, as the presence of EGF induced rapid loss of EGFR amplification.	24	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	31	32
CIN85-SH3 has a dominant negative effect on EGF stimulated EGFR internalization [ XREF_BIBR ] , whereas CIN85-DeltaCC exhibits no inhibitory effect on EGFR internalization .	CIN85-SH3 has a dominant negative effect on EGF stimulated EGFR internalization [XREF_BIBR], whereas CIN85-DeltaCC exhibits no inhibitory effect on EGFR internalization.	5	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
The inhibition of ROS generation by DPI declined EGF dependent activation of EGF receptor and STAT factors to basal level .	The inhibition of ROS generation by DPI declined EGF dependent activation of EGF receptor and STAT factors to basal level.	8	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	8	9	12	14
Moreover , the delayed effect of EGF mediated EGFR degradation was extended even after 6h of EGF stimulation in CTSS inhibited cells ( XREF_FIG ) .	Moreover, the delayed effect of EGF mediated EGFR degradation was extended even after 6h of EGF stimulation in CTSS inhibited cells (XREF_FIG).	6	9	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
The EFEMP1 initiated reduction of total EGFR , although not as quick as EGF initiated negative-feedback regulation of EGFR , could involve a similar protein degradation mechanism , since EGFR mRNA levels were not reduced upon EFEMP1 treatment .	The EFEMP1 initiated reduction of total EGFR, although not as quick as EGF initiated negative-feedback regulation of EGFR, could involve a similar protein degradation mechanism, since EGFR mRNA levels were not reduced upon EFEMP1 treatment.	13	19	initiated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	18	19
EGF treatment stimulated the degradation of EGFR at 45 min in the control cells , with near complete loss of the receptor by 3 hr , consistent with prior reports ( XREF_FIG ) .	EGF treatment stimulated the degradation of EGFR at 45 min in the control cells, with near complete loss of the receptor by 3 hr, consistent with prior reports (XREF_FIG).	0	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	6	7
The non cytotoxic vacuole inducing analog , MOPIPP , also impaired the EGF induced degradation of EGFR , but the effect was not as severe as with MOMIPP ( XREF_FIG ) .	The non cytotoxic vacuole inducing analog, MOPIPP, also impaired the EGF induced degradation of EGFR, but the effect was not as severe as with MOMIPP (XREF_FIG).	11	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	16	17
Reportedly , Anks1a depletion reduces EGF induced EGFR internalization into recycling endosomes and increases routing to lysosomes XREF_BIBR .	Reportedly, Anks1a depletion reduces EGF induced EGFR internalization into recycling endosomes and increases routing to lysosomes XREF_BIBR.	4	8	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Knockdown of GIT1 expression by small interfering RNA decreased the rate of EGF induced EGFR degradation .	Knockdown of GIT1 expression by small interfering RNA decreased the rate of EGF induced EGFR degradation.	10	15	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Folliculin Interacts with Rab35 to Regulate EGF Induced EGFR Degradation .	Folliculin Interacts with Rab35 to Regulate EGF Induced EGFR Degradation.	5	9	Induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
In accordance with the 3-MA treatment , ATG5 knockdown slightly attenuated EGF mediated EGFR degradation ( XREF_FIG , compare lanes 2 and 6 ) .	In accordance with the 3-MA treatment, ATG5 knockdown slightly attenuated EGF mediated EGFR degradation (XREF_FIG, compare lanes 2 and 6).	10	14	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
Of special interest is the observation that erlotinib , a selective EGFR inhibitor , not only obstructs the EGFR mediated cellular signaling , but also abolishes EGF stimulated EGFR degradation .	Of special interest is the observation that erlotinib, a selective EGFR inhibitor, not only obstructs the EGFR mediated cellular signaling, but also abolishes EGF stimulated EGFR degradation.	25	29	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
The reported role of TBC1D16 in enhancing EGF stimulated EGFR degradation mediated by RAB4A XREF_BIBR and the action of RAB5C in the EGFR downstream pathway XREF_BIBR prompted us to examine whether TBC1D16-47KD exerted an EGFR regulator effect mediated by RAB5C .	The reported role of TBC1D16 in enhancing EGF stimulated EGFR degradation mediated by RAB4A XREF_BIBR and the action of RAB5C in the EGFR downstream pathway XREF_BIBR prompted us to examine whether TBC1D16-47KD exerted an EGFR regulator effect mediated by RAB5C.	6	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Compared with control cells , cells depleted of Rab35 by siRNA suppressed EGF induced EGFR degradation and enhanced EGFR signaling .	Compared with control cells, cells depleted of Rab35 by siRNA suppressed EGF induced EGFR degradation and enhanced EGFR signaling.	12	15	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Deletion of capns1 was associated with enhanced phosphorylation of EGFR ( Y845 ) in tumors from the NIC model ; we therefore tested EGF induced activation of EGFR in vitro in the MTEC system .	Deletion of capns1 was associated with enhanced phosphorylation of EGFR (Y845) in tumors from the NIC model; we therefore tested EGF induced activation of EGFR in vitro in the MTEC system.	23	28	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	23	24	27	28
EGF induced EGFR degradation is both proteasome- and lysosome dependent [ XREF_BIBR - XREF_BIBR ] .	EGF induced EGFR degradation is both proteasome- and lysosome dependent [XREF_BIBR - XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
In contrast , S. nigra lectin ( SNA , which binds to alpha-2 ,6 sialic acid linked to terminal galactose and to lesser degree alpha-2 ,3 linkage ) , peanut agglutinin ( PNA , galactosyl ( beta-1 ,3 ) N-acetylgalactosamine ) and succinylated wheat germ agglutinin ( sWGA , N-acetylglucosamine residues ) had little effect on blocking EGF induced pEGFR activation .	In contrast, S. nigra lectin (SNA, which binds to alpha-2,6 sialic acid linked to terminal galactose and to lesser degree alpha-2,3 linkage), peanut agglutinin (PNA, galactosyl (beta-1,3) N-acetylgalactosamine) and succinylated wheat germ agglutinin (sWGA, N-acetylglucosamine residues) had little effect on blocking EGF induced pEGFR activation.	56	60	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	pEGFR	pEGFR	pEGFR	57	58	59	60
We show that AR activated EGFR in MCF10A AR and SUM149 breast cancer cells exhibits decreased Y1045 phosphorylation as compared with EGF stimulated EGFR in MCF10A cells .	We show that AR activated EGFR in MCF10A AR and SUM149 breast cancer cells exhibits decreased Y1045 phosphorylation as compared with EGF stimulated EGFR in MCF10A cells.	18	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	21	22	23	24
Specific mechanisms of action exerted by PD involved the downregulation of EGFR and the inhibition of EGF induced activation of the EGFR , MAPK , and PI3K and Akt pathways .	Specific mechanisms of action exerted by PD involved the downregulation of EGFR and the inhibition of EGF induced activation of the EGFR, MAPK, and PI3K and Akt pathways.	14	29	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	21	22
As indicated in XREF_FIG , the lifespan of EGF mediated EGFR degradation was reduced in CTSS overexpressing cells .	As indicated in XREF_FIG, the lifespan of EGF mediated EGFR degradation was reduced in CTSS overexpressing cells.	8	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
Consistent with the essential role of SIMPLE in regulation of endosomal sorting and trafficking , our study reveals that SIMPLE is required for efficient attenuation of ERK1/2 signaling downstream of EGF activated EGFR .	Consistent with the essential role of SIMPLE in regulation of endosomal sorting and trafficking, our study reveals that SIMPLE is required for efficient attenuation of ERK1/2 signaling downstream of EGF activated EGFR.	27	33	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	30	31	32	33
The western blotting results showed that exposure of ESCC cells to resveratrol inhibited EGF induced EGFR activation in addition to decreasing the total protein levels of EGFR and membrane and nuclear localization .	The western blotting results showed that exposure of ESCC cells to resveratrol inhibited EGF induced EGFR activation in addition to decreasing the total protein levels of EGFR and membrane and nuclear localization.	12	16	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	15	16
Both EGF and TGF-alpha enhanced EGF receptor degradation , but TGF-alpha was less effective than EGF .	Both EGF and TGF-alpha enhanced EGF receptor degradation, but TGF-alpha was less effective than EGF.	0	7	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	1	2	5	7
We found that exposure of A431 cells to PUVA caused a dramatic inhibition of EGF stimulated EGF receptor tyrosine kinase activity .	We found that exposure of A431 cells to PUVA caused a dramatic inhibition of EGF stimulated EGF receptor tyrosine kinase activity.	12	18	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	14	15	16	18
Moreover , overexpression of ErbB2 had a dominant negative effect on EGF induced EGFR down-regulation [ XREF_BIBR , XREF_BIBR ] .	Moreover, overexpression of ErbB2 had a dominant negative effect on EGF induced EGFR down-regulation [XREF_BIBR, XREF_BIBR].	9	14	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	13	14
These results together with the finding that HDAC6 deficiency induces microtubule hyper-acetylation and promotes microtubule mediated endocytic vesicle transport XREF_BIBR , XREF_BIBR suggest that microtubule mediated endocytic vesicle transport affects EGF induced EGFR degradation .	These results together with the finding that HDAC6 deficiency induces microtubule hyper-acetylation and promotes microtubule mediated endocytic vesicle transport XREF_BIBR, XREF_BIBR suggest that microtubule mediated endocytic vesicle transport affects EGF induced EGFR degradation.	29	33	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	30	31	32	33
We found that SW480 and HCT116 cells transiently transfected with a Fas siRNA displayed a significant reduction of the EGF induced activation of EGFR and consequently , an inhibition of both EGF induced cell proliferation , based on the WST-1 viability assay , and the EGF driven directional migration in the Boyden chamber assay .	We found that SW480 and HCT116 cells transiently transfected with a Fas siRNA displayed a significant reduction of the EGF induced activation of EGFR and consequently, an inhibition of both EGF induced cell proliferation, based on the WST-1 viability assay, and the EGF driven directional migration in the Boyden chamber assay.	16	24	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	19	20	23	24
Further , as expected , only EGFR was substantially lowered by EGF treatment .	Further, as expected, only EGFR was substantially lowered by EGF treatment.	5	12	lowered	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	6	7
Indeed , preliminary data indicate that increasing concentrations of EGF partially antagonize stimulation of EGFR coupling to cell proliferation by a fixed concentration of AREG ( as in XREF_FIG ) .	Indeed, preliminary data indicate that increasing concentrations of EGF partially antagonize stimulation of EGFR coupling to cell proliferation by a fixed concentration of AREG (as in XREF_FIG).	7	15	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	9	10	14	15
Over expression EGF can not rescue the inhibition of EGFR siRNA on HLE cells and the proliferation activity in HLE cells greatly decreased when EGF-EGFR signal pathway blockaded .	Over expression EGF can not rescue the inhibition of EGFR siRNA on HLE cells and the proliferation activity in HLE cells greatly decreased when EGF-EGFR signal pathway blockaded.	2	10	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	9	10
These results indicate that extracellular MIF directly binds to the extracellular domain of EGFR and blocks the binding of EGF to EGFR , thereby inhibiting EGF induced EGFR activation .	These results indicate that extracellular MIF directly binds to the extracellular domain of EGFR and blocks the binding of EGF to EGFR, thereby inhibiting EGF induced EGFR activation.	24	28	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	27	28
Specifically , loss of PRP4K expression reduced EGF stimulated EGFR degradation , promoting anchorage independent cell growth in zebrafish xenografts and increased metastasis in a mouse model of ovarian cancer .	Specifically, loss of PRP4K expression reduced EGF stimulated EGFR degradation, promoting anchorage independent cell growth in zebrafish xenografts and increased metastasis in a mouse model of ovarian cancer.	6	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
However , we show that inhibition of EGFR signaling in non transformed breast epithelial cells by EGF deprivation or gefitinib , an inhibitor of EGFR tyrosine kinase , causes the upregulation of the long isoform of caspase-8 inhibitor FLICE-inhibitory protein ( FLIP ( L ) ) and makes these cells more resistant to the tumor necrosis factor related apoptosis inducing ligand ( TRAIL ) .	However, we show that inhibition of EGFR signaling in non transformed breast epithelial cells by EGF deprivation or gefitinib, an inhibitor of EGFR tyrosine kinase, causes the upregulation of the long isoform of caspase-8 inhibitor FLICE-inhibitory protein (FLIP (L)) and makes these cells more resistant to the tumor necrosis factor related apoptosis inducing ligand (TRAIL).	5	17	inhibition	Negative_activation_syntax_1_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	7	8
Blocking Annexin A2 function suppressed the EGF induced EGFR tyrosine phosphorylation , as well as inhibited the EGFR dependent downstream signaling pathways [ XREF_BIBR ] .	Blocking Annexin A2 function suppressed the EGF induced EGFR tyrosine phosphorylation, as well as inhibited the EGFR dependent downstream signaling pathways [XREF_BIBR].	5	9	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	8	9
Furthermore , EGF treatments enhanced miR-206 levels in MCF-7 cells and ERalpha negative , EGFR positive MDA-MB-231 cells , whereas EGFR small interfering RNA , or PD153035 , an EGFR inhibitor , or U0126 , a MAPK kinase inhibitor , significantly reduced miR-206 levels in MDA-MB-231 cells .	Furthermore, EGF treatments enhanced miR-206 levels in MCF-7 cells and ERalpha negative, EGFR positive MDA-MB-231 cells, whereas EGFR small interfering RNA, or PD153035, an EGFR inhibitor, or U0126, a MAPK kinase inhibitor, significantly reduced miR-206 levels in MDA-MB-231 cells.	2	17	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	2	3	14	15
We have previously shown that LAPTM4B promotes active EGFR signaling by blocking EGF stimulated EGFR intraluminal sorting and lysosomal degradation ( unpublished data ) .	We have previously shown that LAPTM4B promotes active EGFR signaling by blocking EGF stimulated EGFR intraluminal sorting and lysosomal degradation (unpublished data).	11	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	14	15
Controls of the intensity and duration of EGFR signaling are through a negative feedback regulatory mechanism of the EGF induced EGFR downregulation process in which activated EGFR is endocytosed and then differentially destined for lysosomal degradation or recycling via the multi-vesicular bodies ( MVBs ) [ XREF_BIBR ] .	Controls of the intensity and duration of EGFR signaling are through a negative feedback regulatory mechanism of the EGF induced EGFR downregulation process in which activated EGFR is endocytosed and then differentially destined for lysosomal degradation or recycling via the multi-vesicular bodies (MVBs) [XREF_BIBR].	15	22	induced	Positive_early_activation	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	18	19	20	21
EGF induced endocytic degradation of EGFR .	EGF induced endocytic degradation of EGFR.	0	6	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	5	6
RNA interference ( RNAi ) knockdown of Nedd4-1 , not Nedd4-2 , inhibited degradation of both EGFR and ACK , and overexpression of ACK mutants that are deficient in either binding to or ubiquitination by Nedd4-1 blocked EGF induced degradation of EGFR .	RNA interference (RNAi) knockdown of Nedd4-1, not Nedd4-2, inhibited degradation of both EGFR and ACK, and overexpression of ACK mutants that are deficient in either binding to or ubiquitination by Nedd4-1 blocked EGF induced degradation of EGFR.	36	42	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	37	38	41	42
A lower risk for breast cancer in GG carriers might be explained through EGF receptor internalization promoted by EGF .	A lower risk for breast cancer in GG carriers might be explained through EGF receptor internalization promoted by EGF.	13	19	promoted	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGF receptor	EGF receptor	EGF receptor	18	19	13	15
For example calmodulin dependent protein kinase II ( CaM kinase II ) promotes phosphorylation at residues 1046 S and 1047 S ; replacement of these residues by alanine results in decreased EGF induced EGFR downregulation and enhanced EGF signaling [ XREF_BIBR , XREF_BIBR ] .	For example calmodulin dependent protein kinase II (CaM kinase II) promotes phosphorylation at residues 1046 S and 1047 S; replacement of these residues by alanine results in decreased EGF induced EGFR downregulation and enhanced EGF signaling [XREF_BIBR, XREF_BIBR].	30	36	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	31	32	33	34
EGF treatments enhanced miRNA-206 levels in MCF-7 cells and ERalpha negative , EGFR positive MDA-MB-231 cells , while EGFR siRNA , or PD153035 , an EGFR inhibitor , or U0126 , a MAPK kinase [ XREF_BIBR ] inhibitor , significantly reduced miR-206 levels in MDA-MB-231 cells .	EGF treatments enhanced miRNA-206 levels in MCF-7 cells and ERalpha negative, EGFR positive MDA-MB-231 cells, while EGFR siRNA, or PD153035, an EGFR inhibitor, or U0126, a MAPK kinase [XREF_BIBR] inhibitor, significantly reduced miR-206 levels in MDA-MB-231 cells.	0	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	12	13
Down-regulation of GAPex-5 by RNA interference decreases epidermal growth factor stimulated EGFR degradation .	Down-regulation of GAPex-5 by RNA interference decreases epidermal growth factor stimulated EGFR degradation.	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	EGFR	EGFR	EGFR	7	10	11	12
Our data indicate that PEITC is able to inhibit the invasion of EGF stimulated SAS oral cancer cells by targeting EGFR and its downstream signaling molecules and finally lead to the reduced expression and enzymatic activities of both MMP-2 and MMP-9 .	Our data indicate that PEITC is able to inhibit the invasion of EGF stimulated SAS oral cancer cells by targeting EGFR and its downstream signaling molecules and finally lead to the reduced expression and enzymatic activities of both MMP-2 and MMP-9.	10	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	12	13	20	21
We further assessed the effects of EGF ( a ligand for EGFR ) and Erlotinib ( a phosphorylation inhibitor of EGFR ) on cell signaling and anoikis .	We further assessed the effects of EGF (a ligand for EGFR) and Erlotinib (a phosphorylation inhibitor of EGFR) on cell signaling and anoikis.	4	21	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	6	7	20	21
Thus , sulindac metabolite induced downregulation of EGFR seems to be mediated through mechanism ( s ) similar , at least in part , to those involved in EGF induced downregulation of EGFR .	Thus, sulindac metabolite induced downregulation of EGFR seems to be mediated through mechanism (s) similar, at least in part, to those involved in EGF induced downregulation of EGFR.	28	33	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	28	29	32	33
For example , lower concentrations of EGF sufficient for induction of cell proliferation were associated with internalization of EGFR but not its degradation while higher concentrations of EGF promoted EGFR degradation [ XREF_BIBR ] .	For example, lower concentrations of EGF sufficient for induction of cell proliferation were associated with internalization of EGFR but not its degradation while higher concentrations of EGF promoted EGFR degradation [XREF_BIBR].	25	30	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	27	28	29	30
We found that experimental elevation of Brk markedly inhibited downregulation of EGFR after EGF induced activation of EGFR tyrosine kinase in SUM102 breast cancer cells ( XREF_FIG ) as well as in A431 non-breast-cancer cells ( XREF_SUPPLEMENTARY ) .	We found that experimental elevation of Brk markedly inhibited downregulation of EGFR after EGF induced activation of EGFR tyrosine kinase in SUM102 breast cancer cells (XREF_FIG) as well as in A431 non-breast-cancer cells (XREF_SUPPLEMENTARY).	8	19	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	13	14	17	18
Epidermal growth factor treatment down-regulated SNAP25 protein by activating EGF receptor mediated proteasomal degradation of SNAP25 .	Epidermal growth factor treatment down-regulated SNAP25 protein by activating EGF receptor mediated proteasomal degradation of SNAP25.	0	11	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Epidermal growth factor	Epidermal growth factor	Epidermal growth factor	EGF receptor	EGF receptor	EGF receptor	0	3	9	11
In addition , the siRNA silencing approach was used to confirm the involvement of CTSS in EGF mediated EGFR degradation .	In addition, the siRNA silencing approach was used to confirm the involvement of CTSS in EGF mediated EGFR degradation.	16	19	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	16	17	18	19
As shown in XREF_FIG , EGF induced EGFR down-regulation was significantly reduced in the presence of CTEN .	As shown in XREF_FIG, EGF induced EGFR down-regulation was significantly reduced in the presence of CTEN.	5	8	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	5	6	7	8
Deletion of the C-terminal cytoplasmic domain of CD82 ( CD82DeltaC mutant ) inhibits endocytic trafficking of the tetraspanin and compromises its activity toward heparin binding EGF activated EGFR .	Deletion of the C-terminal cytoplasmic domain of CD82 (CD82DeltaC mutant) inhibits endocytic trafficking of the tetraspanin and compromises its activity toward heparin binding EGF activated EGFR.	21	28	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	25	26	27	28
We further found that both basal and EGF induced EGFR signaling including Akt and ERK activation can be completely inhibited by gefitinib and erlotinib in both parental and NNK treated cells .	We further found that both basal and EGF induced EGFR signaling including Akt and ERK activation can be completely inhibited by gefitinib and erlotinib in both parental and NNK treated cells.	5	10	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
While transferrin uptake was not affected by genistein treatment , as evidenced by colocalization of transferrin and the early endosomal antigen 1 ( EEA1 ) , EGF induced EGFR internalization was decreased , resulting in a reduced colocalization of EGFR and EEA1 ( XREF_SUPPLEMENTARY , upper panel ) .	While transferrin uptake was not affected by genistein treatment, as evidenced by colocalization of transferrin and the early endosomal antigen 1 (EEA1), EGF induced EGFR internalization was decreased, resulting in a reduced colocalization of EGFR and EEA1 (XREF_SUPPLEMENTARY, upper panel).	26	29	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	26	27	28	29
Secreted O GlcNAcylated MIF bound to the extracellular domain of human EGFR and competitively inhibited EGF induced EGFR activation .	Secreted O GlcNAcylated MIF bound to the extracellular domain of human EGFR and competitively inhibited EGF induced EGFR activation.	14	18	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	15	16	17	18
To analyze the effects of DARPP-32 on EGF induced EGFR degradation , MKN-28 and DARPP-32 or MKN-28 and pcDNA stable cells were treated with EGF ( 100 ng/ml ) for 30 and 45 min , and EGFR protein levels were determined by Western blot analysis .	To analyze the effects of DARPP-32 on EGF induced EGFR degradation, MKN-28 and DARPP-32 or MKN-28 and pcDNA stable cells were treated with EGF (100 ng/ml) for 30 and 45 min, and EGFR protein levels were determined by Western blot analysis.	1	10	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	7	8	9	10
Inhibition of SRC halted EGF induced EGFR dimerization and inhibited phosphorylation of an EGFR residue known to be SRC dependent phosphorylation site [ XREF_BIBR ] and an autophosphorylation site within EGFR [ XREF_BIBR ] .	Inhibition of SRC halted EGF induced EGFR dimerization and inhibited phosphorylation of an EGFR residue known to be SRC dependent phosphorylation site [XREF_BIBR] and an autophosphorylation site within EGFR [XREF_BIBR].	0	7	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	4	5	6	7
EGF induced EGFR downregulation , an ESCRT-I dependent process , was attenuated in HIV-1 Gag expressing cells [ XREF_BIBR ] .	EGF induced EGFR downregulation, an ESCRT-I dependent process, was attenuated in HIV-1 Gag expressing cells [XREF_BIBR].	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	2	3
After the incubation with 20 muM butein for 60 min , EGF induced activation of EGFR was inhibited by 49.7 % ( n = 3 , p < 0.01 ) , the phosphorylation of ERK1/2 and Akt were also suppressed in a time dependent manner , and the actvitiy of ERK1/2 and Akt decreased by 41.2 % and 48.3 % , respectively , at 60 min ( n = 3 , p < 0.001 ) .	After the incubation with 20 muM butein for 60 min, EGF induced activation of EGFR was inhibited by 49.7% (n = 3, p < 0.01), the phosphorylation of ERK1/2 and Akt were also suppressed in a time dependent manner, and the actvitiy of ERK1/2 and Akt decreased by 41.2% and 48.3%, respectively, at 60 min (n = 3, p < 0.001).	11	16	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	11	12	15	16
Epidermal growth factor receptor-tyrosine kinase inhibitor ( EGFR-TKI ) , which targets EGFR , plays an important role in non small cell lung cancer ( NSCLC ) treatment .	Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), which targets EGFR, plays an important role in non small cell lung cancer (NSCLC) treatment.	0	13	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Epidermal growth factor	Epidermal growth factor	Epidermal growth factor	EGFR	EGFR	EGFR	0	3	12	13
EGF stimulation causes EGFR degradation by delivery to the lysosomes .	EGF stimulation causes EGFR degradation by delivery to the lysosomes.	0	4	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	0	1	3	4
Interestingly , following exogenous expression of CMS-PP , EGF mediated EGFR degradation was restored in WT NS5A expressing cells , where a clear loss of EGFR levels was observed ( XREF_FIG ) .	Interestingly, following exogenous expression of CMS-PP, EGF mediated EGFR degradation was restored in WT NS5A expressing cells, where a clear loss of EGFR levels was observed (XREF_FIG).	8	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	EGFR	EGFR	EGFR	8	9	10	11
First generation EGFR-TKIs , gefitinib and erlotinib , were designed to reversibly combine with the ATP binding sites , thus blocking EGFR induced activation of downstream signalling , whereas the second generation EGFR-TKIs , such as afatinib and dacomitinib , are irreversible inhibitors with greater affinity for the EGFR kinase domain also inhibiting other members of the EGFR family ( ErbB2 , ErbB3 and ErbB4 ) .	First generation EGFR-TKIs, gefitinib and erlotinib, were designed to reversibly combine with the ATP binding sites, thus blocking EGFR induced activation of downstream signalling, whereas the second generation EGFR-TKIs, such as afatinib and dacomitinib, are irreversible inhibitors with greater affinity for the EGFR kinase domain also inhibiting other members of the EGFR family (ErbB2, ErbB3 and ErbB4).	48	58	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	EGFR	EGFR	EGFR	48	49	57	58
We found little to no tyrosine phosphorylated EGFR in the tumor samples we examined consistent with either lack of activation of these tumors at baseline or gefitinib induced inhibition of EGFR phosphorylation ( XREF_FIG ) .	We found little to no tyrosine phosphorylated EGFR in the tumor samples we examined consistent with either lack of activation of these tumors at baseline or gefitinib induced inhibition of EGFR phosphorylation (XREF_FIG).	27	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR phosphorylation	egfr	EGFR	EGFR	egfr	30	31	30	31
We also found that pharmacologic inhibition of p38 almost completely blocks cisplatin induced EGFR downregulation , further supporting that cisplatin promotes EGFR degradation via p38 signaling .	We also found that pharmacologic inhibition of p38 almost completely blocks cisplatin induced EGFR downregulation, further supporting that cisplatin promotes EGFR degradation via p38 signaling.	7	22	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	p38 almost completely blocks cisplatin induced EGFR	egfr	EGFR	EGFR	egfr	13	14	21	22
Several studies have suggested that EGFR is negatively regulated by c-Cbl , which monoubiquitinates EGFR , and thus facilitates its endocytosis followed by lysosomal degradation .	Several studies have suggested that EGFR is negatively regulated by c-Cbl, which monoubiquitinates EGFR, and thus facilitates its endocytosis followed by lysosomal degradation.	5	15	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGFR	c-Cbl, which monoubiquitinates EGFR	egfr	EGFR	EGFR	egfr	14	15	5	6
Feedback phosphorylation of EGFR at Thr669 by ERK has been found to negatively regulate constitutive EGFR tyrosine kinase activity and HER3 driven Akt activation by suppressing heterodimerization of EGFR and HER3 in lung cancer and triple negative MDA-MB-468 breast cancer cells ( Sato etal ., 2013 ; Turke etal ., 2012 ) .	Feedback phosphorylation of EGFR at Thr669 by ERK has been found to negatively regulate constitutive EGFR tyrosine kinase activity and HER3 driven Akt activation by suppressing heterodimerization of EGFR and HER3 in lung cancer and triple negative MDA-MB-468 breast cancer cells (Sato etal., 2013; Turke etal., 2012).	1	31	negatively regulate	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	EGFR	phosphorylation of EGFR at Thr669	egfr	EGFR	HER3 driven Akt activation by suppressing heterodimerization of EGFR and HER3	egfr	3	4	28	29
Multiple lines of evidence , in both mammalian and C. elegans models , indicate the Cbl mediated ubiquitination of the EGFR negatively regulates EGFR signaling .	Multiple lines of evidence, in both mammalian and C. elegans models, indicate the Cbl mediated ubiquitination of the EGFR negatively regulates EGFR signaling.	15	24	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	Cbl mediated ubiquitination of the EGFR	egfr	EGFR	EGFR	egfr	20	21	23	24
As a result , RAK decreased the levels of EGFR at the plasma membrane , although it is unclear whether this was due to increased EGFR endocytosis , decreased EGFR transport to the plasma membrane , or some other factor .	As a result, RAK decreased the levels of EGFR at the plasma membrane, although it is unclear whether this was due to increased EGFR endocytosis, decreased EGFR transport to the plasma membrane, or some other factor.	7	30	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	levels of EGFR	egfr	EGFR	EGFR	egfr	9	10	29	30
CQ did not enhance erlotinib induced inhibition of EGFR , AKT and ERK phosphorylation , suggesting that the cytotoxicity sensitization effect is not due to further inhibition of the EGFR pathway .	CQ did not enhance erlotinib induced inhibition of EGFR, AKT and ERK phosphorylation, suggesting that the cytotoxicity sensitization effect is not due to further inhibition of the EGFR pathway.	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR, AKT and ERK phosphorylation	egfr	EGFR	EGFR	egfr	8	9	8	9
Decreased p-EGFR was detected in tumors from 6 of 9 patients ( XREF_FIG ) , with increased intra-tumor lapatinib concentration in tumors that demonstrated decreased EGFR phosphorylation ( XREF_SUPPLEMENTARY ) .	Decreased p-EGFR was detected in tumors from 6 of 9 patients (XREF_FIG), with increased intra-tumor lapatinib concentration in tumors that demonstrated decreased EGFR phosphorylation (XREF_SUPPLEMENTARY).	0	27	Decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR phosphorylation	egfr	p-EGFR	p-EGFR	p-egfr	25	26	1	2
Transgenic mice in which erbB signaling in adult supporting cells is disrupted by expression of a dominant negative erbB receptor show severe hearing loss and 80 % postnatal loss of type-I SGNs without concomitant loss of the sensory cells that they contact .	Transgenic mice in which erbB signaling in adult supporting cells is disrupted by expression of a dominant negative erbB receptor show severe hearing loss and 80% postnatal loss of type-I SGNs without concomitant loss of the sensory cells that they contact.	4	20	disrupted	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	erbB	expression of a dominant negative erbB	erbb	erbB	erbB	erbb	18	19	4	5
EGFR activity is enhanced by upregulation of EGFR protein expression , inhibition and deletion of downstream pathway inhibitors , constitutively active EGFR ( EGFRvIII ) , and EGFR amplification .	EGFR activity is enhanced by upregulation of EGFR protein expression, inhibition and deletion of downstream pathway inhibitors, constitutively active EGFR (EGFRvIII), and EGFR amplification.	0	10	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	EGFR	EGFR protein expression	egfr	EGFR	EGFR	egfr	7	8	0	1
Given that only a small percentage of patients may benefit from treatment with inhibitors that target the EGF receptor ( EGFR ) , substantial effort has been devoted to identifying biomarkers that are predictive of the highest likelihood of benefit from these drugs .	Given that only a small percentage of patients may benefit from treatment with inhibitors that target the EGF receptor (EGFR), substantial effort has been devoted to identifying biomarkers that are predictive of the highest likelihood of benefit from these drugs.	13	21	target	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	EGF receptor	EGF receptor	EGF receptor	20	21	17	19
Our model is also supported by a previous study showing that an EGFR antibody ( 528 ) that inhibits binding of ligand to EGFRwt inhibits EGFRvIII mediated tumor growth in xenograft studies .	Our model is also supported by a previous study showing that an EGFR antibody (528) that inhibits binding of ligand to EGFRwt inhibits EGFRvIII mediated tumor growth in xenograft studies.	12	26	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	12	13	25	26
These results , especially when combined with those obtained in the CHO system described above , strengthen the importance of Y1045 phosphorylation of EGFR in cisplatin induced EGFR degradation and resulting cytotoxicity .	These results, especially when combined with those obtained in the CHO system described above, strengthen the importance of Y1045 phosphorylation of EGFR in cisplatin induced EGFR degradation and resulting cytotoxicity.	20	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	Y1045 phosphorylation of EGFR	egfr	EGFR	EGFR	egfr	23	24	27	28
Additionally , VHR-knockout fibroblast and lung epithelial cells had elevated ligand induced epidermal growth factor receptor ( EGFR ) phosphorylation .	Additionally, VHR-knockout fibroblast and lung epithelial cells had elevated ligand induced epidermal growth factor receptor (EGFR) phosphorylation.	11	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor (EGFR) phosphorylation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	12	16	12	16
To test whether EGFR activation is required for CoV induced macropinocytosis , we utilized gefitinib , which specifically inhibits EGFR autophosphorylation and prevents EGFR activation .	To test whether EGFR activation is required for CoV induced macropinocytosis, we utilized gefitinib, which specifically inhibits EGFR autophosphorylation and prevents EGFR activation.	14	24	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	gefitinib, which specifically inhibits EGFR autophosphorylation	egfr	EGFR	EGFR	egfr	19	20	23	24
The pre-activation of EGFR phosphorylation upon PTPRG knockdown ( XREF_FIG E and XREF_FIG A [ top ] ) impedes EGFR responsiveness to EGF , and we therefore did not perform this experiment .	The pre-activation of EGFR phosphorylation upon PTPRG knockdown (XREF_FIG E and XREF_FIG A [top]) impedes EGFR responsiveness to EGF, and we therefore did not perform this experiment.	3	20	impedes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR phosphorylation	egfr	EGFR	EGFR	egfr	3	4	19	20
For example , AGE precursors inhibit epidermal growth factor receptor ( EGFR ) dephosphorylation , and promote EGFR crosslinking thereby modifying EGF signaling XREF_BIBR .	For example, AGE precursors inhibit epidermal growth factor receptor (EGFR) dephosphorylation, and promote EGFR crosslinking thereby modifying EGF signaling XREF_BIBR.	3	18	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	AGE precursors inhibit epidermal growth factor receptor (EGFR) dephosphorylation	epidermal growth factor receptor	EGFR	EGFR	egfr	6	10	17	18
The focus of the prospective biomarker analyses in the ZODIAC study was on as potential markers of differential benefit from EGFR tyrosine kinase inhibitors ( TKIs ) , including EGFR protein expression , EGFR gene amplification , EGFR gene mutation [ XREF_BIBR , XREF_BIBR ] , and KRAS gene mutation [ XREF_BIBR ] , since , at the study outset , no tumor biomarkers predicting sensitivity to VEGFR2 inhibitors in NSCLC had been identified .	The focus of the prospective biomarker analyses in the ZODIAC study was on as potential markers of differential benefit from EGFR tyrosine kinase inhibitors (TKIs), including EGFR protein expression, EGFR gene amplification, EGFR gene mutation [XREF_BIBR, XREF_BIBR], and KRAS gene mutation [XREF_BIBR], since, at the study outset, no tumor biomarkers predicting sensitivity to VEGFR2 inhibitors in NSCLC had been identified.	20	32	inhibitors	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	EGFR	EGFR protein expression	egfr	EGFR	EGFR	egfr	29	30	20	21
Discovery of EGFR overexpression in cancer has led to substantial efforts over the last four decades to target the EGFR as a cancer treatment strategy .	Discovery of EGFR overexpression in cancer has led to substantial efforts over the last four decades to target the EGFR as a cancer treatment strategy.	2	20	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR overexpression	egfr	EGFR	EGFR	egfr	2	3	19	20
Our study found that CTTN expression in CRC cells increased EGFR protein levels , and inhibited the association of EGFR with c-Cbl .	Our study found that CTTN expression in CRC cells increased EGFR protein levels, and inhibited the association of EGFR with c-Cbl.	4	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	CTTN expression in CRC cells increased EGFR protein levels	egfr	EGFR	EGFR	egfr	10	11	19	20
In the MGH-CH1 cells , there was a dramatic loss of EGFR though basal levels of pEGFR were undetectable .	In the MGH-CH1 cells, there was a dramatic loss of EGFR though basal levels of pEGFR were undetectable.	6	12	was a dramatic loss	Negative_activation_copula_1	Positive_activation	Negative_activation	EGFR	loss of EGFR	egfr	EGFR	EGFR	egfr	11	12	11	12
Our results found that curcumin can decrease EGFR protein expression might through down-regulated EGFR protein in gefitinib resistant NSCLC cells .	Our results found that curcumin can decrease EGFR protein expression might through down-regulated EGFR protein in gefitinib resistant NSCLC cells.	4	14	down-regulated	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	EGFR	curcumin can decrease EGFR protein expression	egfr	EGFR	EGFR	egfr	7	8	13	14
Receptor protein tyrosine phosphatase-kappa ( PTPRK ) directly dephosphorylates epidermal growth factor receptor ( EGFR ) , thereby suppressing the EGFR pathway .	Receptor protein tyrosine phosphatase-kappa (PTPRK) directly dephosphorylates epidermal growth factor receptor (EGFR), thereby suppressing the EGFR pathway.	8	21	suppressing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	epidermal growth factor receptor	dephosphorylates epidermal growth factor receptor	epidermal growth factor receptor	EGFR	EGFR	egfr	9	13	20	21
We recently isolated a novel negative regulator of EGFR , termed EGF receptor related protein ( ERRP ) , whose expression appears to attenuate EGFR activation .	We recently isolated a novel negative regulator of EGFR, termed EGF receptor related protein (ERRP), whose expression appears to attenuate EGFR activation.	11	25	attenuate	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	EGF receptor	EGF receptor	EGF receptor	EGFR	EGFR	EGFR	11	13	24	25
Western blot results showed that both the phosphorylation levels of AKT and ERK were significantly increased by the reduction of E-cad , but the total levels of both AKT and ERK were not changed , suggesting that reduction of E-cad not only increased the protein and phosphorylation level of EGFR but also activated the downstream targets of EGFR .	Western blot results showed that both the phosphorylation levels of AKT and ERK were significantly increased by the reduction of E-cad, but the total levels of both AKT and ERK were not changed, suggesting that reduction of E-cad not only increased the protein and phosphorylation level of EGFR but also activated the downstream targets of EGFR.	39	58	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	E-cad not only increased the protein and phosphorylation level of EGFR	egfr	EGFR	EGFR	egfr	49	50	57	58
XREF_BIBR Since EGFR is also expressed by non malignant , epithelial tissues ( www.proteinatlas.org/ENSG00000146648/normal ) , enhancing the efficacy of EGFR targeting antibodies may be accompanied by increased toxicity .	XREF_BIBR Since EGFR is also expressed by non malignant, epithelial tissues (www.proteinatlas.org/ENSG00000146648/normal), enhancing the efficacy of EGFR targeting antibodies may be accompanied by increased toxicity.	2	22	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR is also expressed	egfr	EGFR	EGFR	egfr	2	3	20	21
While the nutlin-3-induced EGFR phosphorylation was prevented by the inactivation of ERK1/2 , the nutlin-3-induced MEK1/2-ERK 1/2 phosphorylation was still observed in the cells in which EGFR phosphorylation was inhibited using EGFR siRNA and AG1478 , an inhibitor of EGFR tyrosine kinase .	While the nutlin-3-induced EGFR phosphorylation was prevented by the inactivation of ERK1/2, the nutlin-3-induced MEK1/2-ERK 1/2 phosphorylation was still observed in the cells in which EGFR phosphorylation was inhibited using EGFR siRNA and AG1478, an inhibitor of EGFR tyrosine kinase.	26	32	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR phosphorylation	egfr	EGFR	EGFR	egfr	26	27	31	32
In agreement with these observations , we show that the treatment of EGFRvIII expressing U87MG cells with CL4 strongly inhibits the formation of high-order EGFRvIII active complexes that is accompanied by a consistent reduction of the phosphorylation of ERK1/2 and STAT3 downstream signaling effectors .	In agreement with these observations, we show that the treatment of EGFRvIII expressing U87MG cells with CL4 strongly inhibits the formation of high-order EGFRvIII active complexes that is accompanied by a consistent reduction of the phosphorylation of ERK1/2 and STAT3 downstream signaling effectors.	10	26	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFRvIII	EGFRvIII expressing	egfrviii	EGFRvIII	EGFRvIII	egfrviii	12	13	24	25
EGFRvIII expressing cells and vector transfected controls were compared for growth rates in vitro and in vivo as well as chemotherapy induced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux .	EGFRvIII expressing cells and vector transfected controls were compared for growth rates in vitro and in vivo as well as chemotherapy induced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux.	0	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFRvIII	EGFRvIII	EGFRvIII	EGFR	EGFR	EGFR	0	1	27	28
Importantly , the fibrogenic cytokine transforming growth factor ( TGF )-beta prolonged HDM induced EGFR phosphorylation and inhibited ligand induced EGFR internalisation and degradation , which resulted in sustained E-cadherin and ZO-1 redistribution .	Importantly, the fibrogenic cytokine transforming growth factor (TGF)-beta prolonged HDM induced EGFR phosphorylation and inhibited ligand induced EGFR internalisation and degradation, which resulted in sustained E-cadherin and ZO-1 redistribution.	3	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	fibrogenic cytokine transforming growth factor (TGF)-beta prolonged HDM induced EGFR phosphorylation	egfr	EGFR	EGFR	egfr	14	15	20	21
Role of EGFR ubiquitination in cisplatin induced EGFR degradation .	Role of EGFR ubiquitination in cisplatin induced EGFR degradation.	2	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR ubiquitination	egfr	EGFR	EGFR	egfr	2	3	7	8
We have recently developed an EGF receptor variant III ( EGFRvIII ) -targeted bispecific antibody that redirects T cells to eliminate EGFRvIII expressing GBM .	We have recently developed an EGF receptor variant III (EGFRvIII) -targeted bispecific antibody that redirects T cells to eliminate EGFRvIII expressing GBM.	5	22	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF receptor	EGF receptor	EGF receptor	EGFRvIII	EGFRvIII	EGFRvIII	5	7	21	22
Two mAbs that block EGFR ( erbB1 ) , cetuximab and panitumumab , have been approved by FDA .	Two mAbs that block EGFR (erbB1), cetuximab and panitumumab, have been approved by FDA.	1	7	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	erbB1	erbB1	erbB1	EGFR	EGFR	EGFR	6	7	4	5
Conversely , our trastuzumab , lapatinib and trastuzumab plus lapatinib resistant models show a decrease in HER3 expression and activation , whereas an overexpression of EGFR and increased expression levels of EGFR ( EGF and TGF-alpha ) and EGFR-HER4 ( EREG and HB-EGF ) ligands .	Conversely, our trastuzumab, lapatinib and trastuzumab plus lapatinib resistant models show a decrease in HER3 expression and activation, whereas an overexpression of EGFR and increased expression levels of EGFR (EGF and TGF-alpha) and EGFR-HER4 (EREG and HB-EGF) ligands.	23	38	overexpression	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	EGFR	levels of EGFR	egfr	EGFR	EGFR	egfr	31	32	25	26
In addition , 42degreesC ( hyperthermia ) and cisplatin ( chemotherapy ) synergistically downregulate the EGFR protein levels and inhibit EGFR signaling , leading to the activation of apoptotic pathways .	In addition, 42degreesC (hyperthermia) and cisplatin (chemotherapy) synergistically downregulate the EGFR protein levels and inhibit EGFR signaling, leading to the activation of apoptotic pathways.	8	21	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	cisplatin (chemotherapy) synergistically downregulate the EGFR protein levels	egfr	EGFR	EGFR	egfr	15	16	20	21
Cbl proteins recognize and bind Tyr phosphorylated EGFR through their TKB domain , enabling the E3 ligase activity of the RING domain to mono-ubiquitinate EGFR which promotes EGFR degradation through the endocytic pathway .	Cbl proteins recognize and bind Tyr phosphorylated EGFR through their TKB domain, enabling the E3 ligase activity of the RING domain to mono-ubiquitinate EGFR which promotes EGFR degradation through the endocytic pathway.	23	28	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	mono-ubiquitinate EGFR	egfr	EGFR	EGFR	egfr	24	25	27	28
Differences in intrinsic EGFR tumoral expression may modulate the final impact of the dual EGFR targeting and explain the differences between the present conclusions and those reported by the two other groups ( Huang et al , 2004 ; Matar et al , 2004 ) .	Differences in intrinsic EGFR tumoral expression may modulate the final impact of the dual EGFR targeting and explain the differences between the present conclusions and those reported by the two other groups (Huang et al, 2004; Matar et al, 2004).	3	15	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR tumoral expression	egfr	EGFR	EGFR	egfr	3	4	14	15
Previous studies showed that shikonin inhibits EGFR phosphorylation and modulates the EGFR signaling cascade [ XREF_BIBR ] , and we concentrated on the IGF1R for our further analysis of shikonin action , due to its known evolvement in drug evasion .	Previous studies showed that shikonin inhibits EGFR phosphorylation and modulates the EGFR signaling cascade [XREF_BIBR], and we concentrated on the IGF1R for our further analysis of shikonin action, due to its known evolvement in drug evasion.	4	13	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	shikonin inhibits EGFR phosphorylation	egfr	EGFR	EGFR	egfr	6	7	11	12
In the present study , NAG-1 affected the expression of EGFR and subsequently suppression of NAG-1 expression downregulated EGFR linked signals such as ERK1/2 MAPK .	In the present study, NAG-1 affected the expression of EGFR and subsequently suppression of NAG-1 expression downregulated EGFR linked signals such as ERK1/2 MAPK.	8	20	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	expression of EGFR	egfr	EGFR	EGFR	egfr	10	11	18	19
The peptide mimics and antipeptide Abs to all three epitopes inhibited cancer cell growth , prevented EGFR specific phosphorylation , downregulated EGFR signaling pathways , and caused increased apoptosis and ADCC in EGFR expressing cells .	The peptide mimics and antipeptide Abs to all three epitopes inhibited cancer cell growth, prevented EGFR specific phosphorylation, downregulated EGFR signaling pathways, and caused increased apoptosis and ADCC in EGFR expressing cells.	5	23	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	Abs to all three epitopes inhibited cancer cell growth, prevented EGFR specific phosphorylation	egfr	EGFR	EGFR	egfr	16	17	21	22
EGFR is negatively regulated by another EGFR family member , ERBB4 , in breast cancer XREF_BIBR .	EGFR is negatively regulated by another EGFR family member, ERBB4, in breast cancer XREF_BIBR.	0	8	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	EGFR	EGFR	EGFR	6	7	0	1
As shown in this study , phenobarbital antagonizes EGF stimulated EGFR phosphorylation and activation ; abrogation of EGFR signaling further induces the dephosphorylation of the downstream receptor for activated C kinase 1 ( RACK1 ) at the residue of Tyr 52 .	As shown in this study, phenobarbital antagonizes EGF stimulated EGFR phosphorylation and activation; abrogation of EGFR signaling further induces the dephosphorylation of the downstream receptor for activated C kinase 1 (RACK1) at the residue of Tyr 52.	6	18	abrogation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	EGFR	phenobarbital antagonizes EGF stimulated EGFR phosphorylation	egfr	EGFR	EGFR	egfr	10	11	17	18
Markers that enrich for cells with high colony forming ability include beta1 integrin extracellular matrix ( ECM ) receptors , the Notch ligand delta like 1 ( DLL1 ) , the transmembrane proteoglycan MCSP ( NG2 , CSPG4 ) and LRIG1 , a transmembrane protein that negatively regulates the EGF receptor ( EGFR ) .	Markers that enrich for cells with high colony forming ability include beta1 integrin extracellular matrix (ECM) receptors, the Notch ligand delta like 1 (DLL1), the transmembrane proteoglycan MCSP (NG2, CSPG4) and LRIG1, a transmembrane protein that negatively regulates the EGF receptor (EGFR).	44	53	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	EGF receptor	EGF receptor	EGF receptor	52	53	49	51
EGFR signaling is also deregulated by HPV oncoproteins independent of EGFR expression level .	EGFR signaling is also deregulated by HPV oncoproteins independent of EGFR expression level.	0	13	deregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGFR	EGFR expression level	egfr	EGFR	EGFR	egfr	10	11	0	1
Similarly , EGFRvIII expressing GBM cells that were treated with the EGFR tyrosine kinase inhibitor ( TKI ) , Gefitinib , demonstrated increased uPA expression and accelerated cell migration .	Similarly, EGFRvIII expressing GBM cells that were treated with the EGFR tyrosine kinase inhibitor (TKI), Gefitinib, demonstrated increased uPA expression and accelerated cell migration.	2	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	11	12	2	3
EGFR wild type antagonizes EGFRvIII mediated activation of Met in glioblastoma .	EGFR wild type antagonizes EGFRvIII mediated activation of Met in glioblastoma.	0	6	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	EGFRvIII	EGFRvIII	EGFRvIII	0	1	4	5
The present findings imply firstly that the lung adenocarcinoma tumoral cells , in addition to EGFR and HER-2 and neu gene deregulation , successfully treated with EGFR family inhibitors ( Bunn et al , 2006 ) , may harbour gene amplification and phosphorylation of Imatinib sensitive RTKs , and so the spectrum of deregulated RTK genes in NSCLC is wider than believed .	The present findings imply firstly that the lung adenocarcinoma tumoral cells, in addition to EGFR and HER-2 and neu gene deregulation, successfully treated with EGFR family inhibitors (Bunn et al, 2006), may harbour gene amplification and phosphorylation of Imatinib sensitive RTKs, and so the spectrum of deregulated RTK genes in NSCLC is wider than believed.	8	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	EGFR	EGFR	EGFR	26	27	15	16
Down-regulated EGFR expression in cells with the anti-sense construct can be confirmed by Scatchard analysis and suppressed EGFR kinase activity .	Down-regulated EGFR expression in cells with the anti-sense construct can be confirmed by Scatchard analysis and suppressed EGFR kinase activity.	1	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR expression	egfr	EGFR	EGFR	egfr	1	2	17	18
After VHL loss , activated HIF up-regulates the expression of the EGFR agonist TGF-alpha XREF_BIBR and enhances the translational efficiency of EGFR XREF_BIBR to promote autonomous growth of VHL defective ccRCC cells .	After VHL loss, activated HIF up-regulates the expression of the EGFR agonist TGF-alpha XREF_BIBR and enhances the translational efficiency of EGFR XREF_BIBR to promote autonomous growth of VHL defective ccRCC cells.	5	22	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	HIF up-regulates the expression of the EGFR	egfr	EGFR	EGFR	egfr	11	12	21	22
In this study , we found that EGF remarkably induced expression of major IGF signaling components , insulin receptor substrate ( IRS ) -1 and IRS-2 , an effect that could be blocked by EGF receptor ( EGFR ) tyrosine kinase inhibitors .	In this study, we found that EGF remarkably induced expression of major IGF signaling components, insulin receptor substrate (IRS) -1 and IRS-2, an effect that could be blocked by EGF receptor (EGFR) tyrosine kinase inhibitors.	28	38	blocked	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	EGF receptor	EGF receptor	EGF receptor	EGFR	EGFR	EGFR	34	36	37	38
Although EGFR overexpression correlates with HPV negative status , EGFR activation and trafficking are deregulated by HPV oncoproteins independent of EGFR expression level [ XREF_BIBR - XREF_BIBR ] .	Although EGFR overexpression correlates with HPV negative status, EGFR activation and trafficking are deregulated by HPV oncoproteins independent of EGFR expression level [XREF_BIBR - XREF_BIBR].	9	23	deregulated	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	EGFR	EGFR	egfr	EGFR	EGFR expression level	egfr	9	10	20	21
HDAC6 inhibitors decrease EGFR protein levels and impair the activation of the EGFR pathway .	HDAC6 inhibitors decrease EGFR protein levels and impair the activation of the EGFR pathway.	0	13	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	HDAC6 inhibitors decrease EGFR protein levels	egfr	EGFR	EGFR	egfr	3	4	12	13
In addition , siRNA directed towards Yes and Lyn decreased the phosphorylation of EGFR Y845 and Y1101 ( XREF_FIG ) .	In addition, siRNA directed towards Yes and Lyn decreased the phosphorylation of EGFR Y845 and Y1101 (XREF_FIG).	9	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	phosphorylation of EGFR Y845	egfr	EGFR	EGFR	egfr	13	14	13	14
The increase in EGFR expression due to the presence of the normal MECs in turn depletes the availability of EGFR specific ligands whose receptor interactions results in EGFR-erbB2 heterodimers , thus reducing the number of activated erbB2 receptors and subsequent erbB2 induced intracellular signaling .	The increase in EGFR expression due to the presence of the normal MECs in turn depletes the availability of EGFR specific ligands whose receptor interactions results in EGFR-erbB2 heterodimers, thus reducing the number of activated erbB2 receptors and subsequent erbB2 induced intracellular signaling.	3	21	depletes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR expression	egfr	EGFR	EGFR	egfr	3	4	19	20
Evaluation of renal function in HCT patients over longer periods of time may prove that there is continued annual loss of eGFR at a rate that exceeds the decline seen in the general population .	Evaluation of renal function in HCT patients over longer periods of time may prove that there is continued annual loss of eGFR at a rate that exceeds the decline seen in the general population.	16	22	is continued annual loss	Negative_activation_copula_1	Positive_activation	Negative_activation	eGFR	loss of eGFR	egfr	eGFR	eGFR	egfr	21	22	21	22
It was also noticed that signaling through S1PR3 increased the expression of EGFR and silencing of S1PR3 abolished the S1P dependent EGFR activation .	It was also noticed that signaling through S1PR3 increased the expression of EGFR and silencing of S1PR3 abolished the S1P dependent EGFR activation.	10	22	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	expression of EGFR	egfr	EGFR	EGFR	egfr	12	13	21	22
Following HTATIP2 and TIP30-knockout , EGF induced EGFR degradation was inhibited , possibly due to the fact that HTATIP2 and TIP30 , ACSL4 and endophilin B1 formed a complex protein , which promoted EGFR from early endosomes into liposomal sorting , and then accelerated the degradation of EGFR in liver cells in mice and mammary cells .	Following HTATIP2 and TIP30-knockout, EGF induced EGFR degradation was inhibited, possibly due to the fact that HTATIP2 and TIP30, ACSL4 and endophilin B1 formed a complex protein, which promoted EGFR from early endosomes into liposomal sorting, and then accelerated the degradation of EGFR in liver cells in mice and mammary cells.	5	48	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGF induced EGFR	egfr	EGFR	EGFR	egfr	7	8	47	48
In a related report , Cbl mutation and reduced EGFR ubiquitination inhibited early endosome fusion and EGFR degradation in HEK 293 cells [ XREF_BIBR ] .	In a related report, Cbl mutation and reduced EGFR ubiquitination inhibited early endosome fusion and EGFR degradation in HEK 293 cells [XREF_BIBR].	9	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR ubiquitination	egfr	EGFR	EGFR	egfr	9	10	16	17
Neratinib is an orally available tyrosine kinase inhibitor targeting HER2 ( ERBB2 ) and EGFR ( ERBB ) .	Neratinib is an orally available tyrosine kinase inhibitor targeting HER2 (ERBB2) and EGFR (ERBB).	7	17	targeting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERBB	ERBB	ERBB	EGFR	EGFR	EGFR	16	17	14	15
Although MSKQLL1 and SCCQLL1 cells showed overexpression of various surface molecules related to low sensitivity to EGFR inhibition such as HER-2 , -3 , c-Met , and p53 and these overexpressions of EGFR resistance related signals may explain the reason of nearly complete resistance to cetuximab of both cell lines , all of the oral cancer cells analyzed in this study , interestingly , showed intense expression of NF-kappaB .	Although MSKQLL1 and SCCQLL1 cells showed overexpression of various surface molecules related to low sensitivity to EGFR inhibition such as HER-2, -3, c-Met, and p53 and these overexpressions of EGFR resistance related signals may explain the reason of nearly complete resistance to cetuximab of both cell lines, all of the oral cancer cells analyzed in this study, interestingly, showed intense expression of NF-kappaB.	16	35	inhibition	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	EGFR	overexpressions of EGFR	egfr	EGFR	EGFR	egfr	32	33	16	17
To clarify the mechanisms behind the synergism between gemcitabine and erlotinib , other investigators have shown that gemcitabine increases EGFR -phosphorylation and subsequently induces the EGFR degradation that may be a mechanism for gemcitabine mediated cell death XREF_BIBR .	To clarify the mechanisms behind the synergism between gemcitabine and erlotinib, other investigators have shown that gemcitabine increases EGFR -phosphorylation and subsequently induces the EGFR degradation that may be a mechanism for gemcitabine mediated cell death XREF_BIBR.	17	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	gemcitabine increases EGFR -phosphorylation	egfr	EGFR	EGFR	egfr	19	20	25	26
Our findings provide further evidence in favor of the model that UBPY mediated EGFR de-ubiquitination promotes EGFR degradation .	Our findings provide further evidence in favor of the model that UBPY mediated EGFR de-ubiquitination promotes EGFR degradation.	11	17	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	UBPY mediated EGFR de-ubiquitination	egfr	EGFR	EGFR	egfr	13	14	16	17
The activation of EGFR and ErbB2 was blocked when EGFR kinase was inhibited either by the inhibitor AG1478 or by the expression of dominant negative EGFR [ XREF_BIBR ] .	The activation of EGFR and ErbB2 was blocked when EGFR kinase was inhibited either by the inhibitor AG1478 or by the expression of dominant negative EGFR [XREF_BIBR].	9	27	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGFR	expression of dominant negative EGFR	egfr	EGFR	EGFR	egfr	25	26	9	10
EGF receptor ( EGFR ) inhibitors block osteolytic bone metastasis by targeting EGFR signaling in bone stromal cells .	EGF receptor (EGFR) inhibitors block osteolytic bone metastasis by targeting EGFR signaling in bone stromal cells.	0	13	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	EGFR	EGFR	EGFR	0	2	12	13
Full-length CAGE , but not KH1 deletion construct , increased the expression of pEGFR Y845 and HER2 , and induced interaction of EGFR with CAGE and HER2 .	Full-length CAGE, but not KH1 deletion construct, increased the expression of pEGFR Y845 and HER2, and induced interaction of EGFR with CAGE and HER2.	1	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pEGFR	CAGE, but not KH1 deletion construct, increased the expression of pEGFR	pegfr	EGFR	EGFR	egfr	13	14	22	23
We then examined whether knockdown of EGFR , HER2 or HER3 by their cognate siRNAs could modulate activation of Akt and EGFR family proteins .	We then examined whether knockdown of EGFR, HER2 or HER3 by their cognate siRNAs could modulate activation of Akt and EGFR family proteins.	4	23	modulate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	EGFR	EGFR	EGFR	6	7	21	22
Phosphorylation of the EGFR at specific serine ( Ser ) and threonine residues inhibits EGFR kinase activity .	Phosphorylation of the EGFR at specific serine (Ser) and threonine residues inhibits EGFR kinase activity.	0	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	Phosphorylation of the EGFR at specific serine (Ser	egfr	EGFR	EGFR	egfr	3	4	14	15
We found that BB potently down-regulated ER-alpha36 expression and phosphorylation levels of EGFR and HER2 but weakly down-regulated expression levels of EGFR and HER2 proteins in MCF7 and TAM cells ( XREF_FIG ) .	We found that BB potently down-regulated ER-alpha36 expression and phosphorylation levels of EGFR and HER2 but weakly down-regulated expression levels of EGFR and HER2 proteins in MCF7 and TAM cells (XREF_FIG).	3	24	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	BB potently down-regulated ER-alpha36 expression and phosphorylation levels of EGFR	egfr	EGFR	EGFR	egfr	12	13	21	22
We demonstrated that EGFR phosphorylation was induced upon EGF treatment in over-expressing COX-2 MM cell lines and that , in these cell lines , EGFR inhibition with gefitinib and COX-2 inhibition with rofecoxib lead to decreases in proliferation .	We demonstrated that EGFR phosphorylation was induced upon EGF treatment in over-expressing COX-2 MM cell lines and that, in these cell lines, EGFR inhibition with gefitinib and COX-2 inhibition with rofecoxib lead to decreases in proliferation.	3	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR phosphorylation	egfr	EGFR	EGFR	egfr	3	4	24	25
Several previous studies have performed single-molecule imaging of EGFRs and reported that EGF can induce EGFR phosphorylation , which slows EGFR mobility within a confined area on the membrane , a phenomenon accompanied by EGFR clustering XREF_BIBR - XREF_BIBR .	Several previous studies have performed single-molecule imaging of EGFRs and reported that EGF can induce EGFR phosphorylation, which slows EGFR mobility within a confined area on the membrane, a phenomenon accompanied by EGFR clustering XREF_BIBR - XREF_BIBR.	12	21	slows	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGF can induce EGFR phosphorylation	egfr	EGFR	EGFR	egfr	15	16	20	21
Moreover , PKP2 knockdown reduces EGFR phosphorylation and attenuates EGFR mediated signal activation , resulting in a significant decrease in proliferation and migration of cancer cells and tumor development .	Moreover, PKP2 knockdown reduces EGFR phosphorylation and attenuates EGFR mediated signal activation, resulting in a significant decrease in proliferation and migration of cancer cells and tumor development.	2	14	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	PKP2 knockdown reduces EGFR phosphorylation	egfr	EGFR	EGFR	egfr	5	6	9	10
In contrast , here we report that knockdown of GALNT1 suppresses EGF induced EGFR phosphorylation , accelerates EGFR internalization , and enhances EGFR degradation .	In contrast, here we report that knockdown of GALNT1 suppresses EGF induced EGFR phosphorylation, accelerates EGFR internalization, and enhances EGFR degradation.	9	18	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	GALNT1 suppresses EGF induced EGFR phosphorylation	egfr	EGFR	EGFR	egfr	13	14	17	18
Recent work from our laboratory showed that a small molecule ESX inhibitor reduces EGFR and Her2 levels and enhances the anti-tumor effect of afatinib , an EGFR and Her2 TKI , in vitro and in vivo .	Recent work from our laboratory showed that a small molecule ESX inhibitor reduces EGFR and Her2 levels and enhances the anti-tumor effect of afatinib, an EGFR and Her2 TKI, in vitro and in vivo.	10	27	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	ESX inhibitor reduces EGFR and Her2 levels	egfr	EGFR	EGFR	egfr	13	14	26	27
Importantly , the epithelial hyperplasia induced by E5 is attenuated when the EGFR pathway is inhibited by expression of a dominant negative EGFR [ XREF_BIBR ] .	Importantly, the epithelial hyperplasia induced by E5 is attenuated when the EGFR pathway is inhibited by expression of a dominant negative EGFR [XREF_BIBR].	12	24	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGFR	expression of a dominant negative EGFR	egfr	EGFR	EGFR	egfr	22	23	12	13
In contrast , inhibition of the EGFRvIII constitutive tyrosine phosphorylation by AG1478 increased association of EGFRvIII with caveolin-1 .	In contrast, inhibition of the EGFRvIII constitutive tyrosine phosphorylation by AG1478 increased association of EGFRvIII with caveolin-1.	3	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFRvIII	inhibition of the EGFRvIII constitutive tyrosine phosphorylation by AG1478	egfrviii	EGFRvIII	EGFRvIII	egfrviii	6	7	15	16
Isolated epithelia were treated for 4 h with FGF10 ( which allows the isolated epithelia to survive in culture ) and either an FGFR2b inhibitor ( Fgfr2b-Fc , 25 nM ) , a mitogen activated protein kinase ( MAPK ) inhibitor ( U0126 , 20 muM ) , a phosphatidylinositol 3-kinase ( PI3K ) inhibitor ( LY294002 , 25 muM ) , or an epidermal growth factor receptor ( EGFR ) inhibitor ( PD168393 , 10 muM ) , which also inhibits other erbB receptors ( XREF_FIG ) .	Isolated epithelia were treated for 4 h with FGF10 (which allows the isolated epithelia to survive in culture) and either an FGFR2b inhibitor (Fgfr2b-Fc, 25 nM), a mitogen activated protein kinase (MAPK) inhibitor (U0126, 20 muM), a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002, 25 muM), or an epidermal growth factor receptor (EGFR) inhibitor (PD168393, 10 muM), which also inhibits other erbB receptors (XREF_FIG).	69	84	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	erbB	erbB	erbB	69	70	83	84
In contrast to the retardation effect of ALG-2 knockdown , ectopic expression of WT FLAG-ALG-2 , but not of Mut FLAG-ALG-2 , decreased both the basal level of EGFR ( 35 % , P-value < 0.05 ) and the percentage of remaining EGFR at 1 , 2 , and 3h , accelerating the 50 % EGFR degradation from 1 to 0.5 h ( XREF_FIG ) .	In contrast to the retardation effect of ALG-2 knockdown, ectopic expression of WT FLAG-ALG-2, but not of Mut FLAG-ALG-2, decreased both the basal level of EGFR (35%, P-value < 0.05) and the percentage of remaining EGFR at 1, 2, and 3h, accelerating the 50% EGFR degradation from 1 to 0.5 h (XREF_FIG).	11	56	accelerating	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	expression of WT FLAG-ALG-2, but not of Mut FLAG-ALG-2, decreased both the basal level of EGFR	egfr	EGFR	EGFR	egfr	28	29	55	56
Prl induces threonine phosphorylation of EGFR through ERK pathway and synergistically augments EGF signaling by inhibiting the downregulation of activated EGFR XREF_BIBR , XREF_BIBR .	Prl induces threonine phosphorylation of EGFR through ERK pathway and synergistically augments EGF signaling by inhibiting the downregulation of activated EGFR XREF_BIBR, XREF_BIBR.	0	21	augments	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	Prl induces threonine phosphorylation of EGFR	egfr	EGFR	EGFR	egfr	5	6	20	21
Additionally , at concentration of 2.0 micromol/L , although ZD6474 inhibits phosphorylation of EGFR , Akt , Stat3 , ERK1/2 , and Bcl-X L expression in EGF stimulated U87MG and EGFR or nonstimulated GBM12 cells that only overexpress WT EGFR , lesser inhibition of cell growth and survival was seen compared with U87MG and EGFRvIII and GBM6 cells that only express EGFRvIII .	Additionally, at concentration of 2.0 micromol/L, although ZD6474 inhibits phosphorylation of EGFR, Akt, Stat3, ERK1/2, and Bcl-X L expression in EGF stimulated U87MG and EGFR or nonstimulated GBM12 cells that only overexpress WT EGFR, lesser inhibition of cell growth and survival was seen compared with U87MG and EGFRvIII and GBM6 cells that only express EGFRvIII.	9	31	stimulated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	EGFR	ZD6474 inhibits phosphorylation of EGFR	egfr	EGFR	EGFR	egfr	13	14	30	31
We show that sunitinib treatment does not inhibit EGF induced EGFR phosphorylation , confirming the specificity of sunitinib to block PDGFR activation , and as a result , prevents PDGF-BB mediated transactivation of EGFR ( XREF_FIG ) .	We show that sunitinib treatment does not inhibit EGF induced EGFR phosphorylation, confirming the specificity of sunitinib to block PDGFR activation, and as a result, prevents PDGF-BB mediated transactivation of EGFR (XREF_FIG).	3	35	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	sunitinib treatment does not inhibit EGF induced EGFR phosphorylation	egfr	EGFR	EGFR	egfr	10	11	33	34
Genetic ablation of ESX decreased EGFR and Her2 levels and enhanced the anti-proliferative effects of EGFR and Her2 tyrosine kinase inhibitors , lapatinib and afatinib .	Genetic ablation of ESX decreased EGFR and Her2 levels and enhanced the anti-proliferative effects of EGFR and Her2 tyrosine kinase inhibitors, lapatinib and afatinib.	3	19	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	ESX decreased EGFR and Her2 levels	egfr	EGFR	EGFR	egfr	5	6	15	16
In addition , lapatinib , a dual tyrosine kinase inhibitor of EGFR and ERBB2 , induced autophagic cell death in breast cancer cells overexpressing ERBB2 40 , human hepatoma cells 41 , and acute myeloblastic leukemia 42 .	In addition, lapatinib, a dual tyrosine kinase inhibitor of EGFR and ERBB2, induced autophagic cell death in breast cancer cells overexpressing ERBB2 40, human hepatoma cells 41, and acute myeloblastic leukemia 42.	9	35	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ERBB2	ERBB2	ERBB2	11	12	24	25
Here , we take a systems biology approach to understand the molecular mechanisms that prevent breast cancer ( BC ) cells from responding to lapatinib , a dual kinase inhibitor that targets human epidermal growth factor receptor 2 ( HER2 ) and epidermal growth factor receptor ( EGFR ) .	Here, we take a systems biology approach to understand the molecular mechanisms that prevent breast cancer (BC) cells from responding to lapatinib, a dual kinase inhibitor that targets human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR).	29	48	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	47	48	39	40
Also , EGFR down-regulation and coordinate up-regulation of ErbB2 and ErbB3 in HNSCC are described in response to the EGFR targeted small molecule gefitinib .	Also, EGFR down-regulation and coordinate up-regulation of ErbB2 and ErbB3 in HNSCC are described in response to the EGFR targeted small molecule gefitinib.	2	12	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ErbB2	ErbB2	ErbB2	2	3	8	9
High levels of ERBB3 is strongly associated with tumor progression and poor prognosis of patients with GC XREF_BIBR - XREF_BIBR and the EGFR kinase inhibitors gefitinib could prevent EGFR and ERBB2 activation of ERBB3 .	High levels of ERBB3 is strongly associated with tumor progression and poor prognosis of patients with GC XREF_BIBR - XREF_BIBR and the EGFR kinase inhibitors gefitinib could prevent EGFR and ERBB2 activation of ERBB3.	22	31	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ERBB2	ERBB2	ERBB2	22	23	30	31
Background : Emergence of Human epidermal growth factor receptor 2 ( HER2 ) therapy resistance in HER2 positive ( HER2+ ) breast cancer ( BC ) poses a major clinical challenge .	Background : Emergence of Human epidermal growth factor receptor 2 (HER2) therapy resistance in HER2 positive (HER2+) breast cancer (BC) poses a major clinical challenge.	5	22	resistance	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	HER2	HER2	HER2	5	9	16	17
Pertuzumab is a recombinant , humanized monoclonal antibody that binds to the dimerization domain of human epidermal growth factor receptor 2 ( HER2 ) , inhibiting the heterodimerization of HER2 with other HER receptors .	Pertuzumab is a recombinant, humanized monoclonal antibody that binds to the dimerization domain of human epidermal growth factor receptor 2 (HER2), inhibiting the heterodimerization of HER2 with other HER receptors.	16	30	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	HER2	HER2	HER2	16	20	29	30
The Her2 specific antibody trastuzumab and the dual EGFR and Her2 inhibitor lapatinib have been shown to decrease growth of Her2 overexpressing tumors , however a majority of patients treated with trastuzamab develop resistance , indicating the importance of elucidating alternative therapeutic targets in this disease .	The Her2 specific antibody trastuzumab and the dual EGFR and Her2 inhibitor lapatinib have been shown to decrease growth of Her2 overexpressing tumors, however a majority of patients treated with trastuzamab develop resistance, indicating the importance of elucidating alternative therapeutic targets in this disease.	4	22	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	Her2	Her2	Her2	8	9	20	21
In contrast , HER2 heterodimerization activated PI3K signaling , which was not inhibited by trastuzumab , but was reduced by pertuzumab and the dual EGFR and HER2 kinase inhibitor lapatinib ( XREF_FIG ) [ XREF_BIBR ] .	In contrast, HER2 heterodimerization activated PI3K signaling, which was not inhibited by trastuzumab, but was reduced by pertuzumab and the dual EGFR and HER2 kinase inhibitor lapatinib (XREF_FIG) [XREF_BIBR].	3	25	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	24	25	3	4
We showed , that ( 1 ) PTPIP51 and c-Src interaction is differently regulated in SK-BR3 and BT474 cells correlating with their particular sensitivity to EGFR targeted TKIs , ( 2 ) selective inhibition of HER2 specifically recruited PTPIP51 to the HER2 receptor and to c-Src reflecting a probable mechanism for resistance , and ( 3 ) PTPIP51 is essential for the activation of Akt signaling under selective HER2 inhibition .	We showed, that (1) PTPIP51 and c-Src interaction is differently regulated in SK-BR3 and BT474 cells correlating with their particular sensitivity to EGFR targeted TKIs, (2) selective inhibition of HER2 specifically recruited PTPIP51 to the HER2 receptor and to c-Src reflecting a probable mechanism for resistance, and (3) PTPIP51 is essential for the activation of Akt signaling under selective HER2 inhibition.	19	37	targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	25	26	35	36
Lapatinib is a dual EGFR and ErbB2 reversible tyrosine kinase inhibitor blocking both HER1 and HER2 and consequently the downstream pathways of MAPK/Erk1/2 and PI3K and Akt pathways XREF_BIBR .	Lapatinib is a dual EGFR and ErbB2 reversible tyrosine kinase inhibitor blocking both HER1 and HER2 and consequently the downstream pathways of MAPK/Erk1/2 and PI3K and Akt pathways XREF_BIBR.	2	16	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	4	5	15	16
None of the EGFR agonists tested ( EGF , beta-cellulin , or heparin binding EGF ) inhibited growth of ErbB2 overexpressing cells .	None of the EGFR agonists tested (EGF, beta-cellulin, or heparin binding EGF) inhibited growth of ErbB2 overexpressing cells.	3	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ErbB2	ErbB2	ErbB2	3	4	19	20
These included afatinib , a covalent EGFR and HER2 inhibitor , the EGFR inhibitor osimertinib ( AZD9291 ) , which exhibits selectivity against mutant EGFR ( including T790M ) but does not block WT HER2 , and AZ5104 , an osimertinib metabolite that inhibits WT HER2 and EGFR .	These included afatinib, a covalent EGFR and HER2 inhibitor, the EGFR inhibitor osimertinib (AZD9291), which exhibits selectivity against mutant EGFR (including T790M) but does not block WT HER2, and AZ5104, an osimertinib metabolite that inhibits WT HER2 and EGFR.	1	37	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	6	7	34	35
This phase I first-in-human study was conducted in Japanese patients to investigate the safety , pharmacokinetics ( PKs ) , and determine the maximum tolerated dose ( MTD ) of oral TAK-285 , a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor ( EGFR ) and HER2 .	This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2.	36	53	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	erbB	erbB	erbB	HER2	HER2	HER2	36	37	52	53
Recapitulation of EGFR in miR-124 over-expressing HNSCC cells completely blocked the anti-proliferative activities of the EGFR and Her2 TKIs .	Recapitulation of EGFR in miR-124 over-expressing HNSCC cells completely blocked the anti-proliferative activities of the EGFR and Her2 TKIs.	0	18	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	Her2	Her2	Her2	2	3	17	18
HER2 inhibition by trastuzumab or a dual EGFR and HER2 TKI has previously been shown to activate Notch signaling in HER2 positive breast cancer cell lines [ XREF_BIBR ] .	HER2 inhibition by trastuzumab or a dual EGFR and HER2 TKI has previously been shown to activate Notch signaling in HER2 positive breast cancer cell lines [XREF_BIBR].	0	10	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	7	8	0	1
In particular , basal like or triple negative breast cancers are largely ErbB2 negative yet frequently overexpress EGFR and may be effectively treated with drugs targeting EGFR signaling .	In particular, basal like or triple negative breast cancers are largely ErbB2 negative yet frequently overexpress EGFR and may be effectively treated with drugs targeting EGFR signaling.	1	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB2	ErbB2	ErbB2	26	27	12	13
As such , EGFR and ErbB2 are important targets of anticancer therapeutics , with a number of antagonistic monoclonal antibodies and small molecule tyrosine kinase inhibitors currently available to inhibit EGFR and ErbB2 signaling .	As such, EGFR and ErbB2 are important targets of anticancer therapeutics, with a number of antagonistic monoclonal antibodies and small molecule tyrosine kinase inhibitors currently available to inhibit EGFR and ErbB2 signaling.	3	33	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ErbB2	ErbB2	ErbB2	3	4	32	33
Lapatinib ( Tykerb ; GlaxoSmithKline ) is a dual EGFR and HER2 kinase inhibitor that reduces EGFR and HER2 signaling and induces apoptosis in multiple models of HER2 overexpressing breast cancer [ XREF_BIBR , XREF_BIBR ] .	Lapatinib (Tykerb; GlaxoSmithKline) is a dual EGFR and HER2 kinase inhibitor that reduces EGFR and HER2 signaling and induces apoptosis in multiple models of HER2 overexpressing breast cancer [XREF_BIBR, XREF_BIBR].	0	21	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	9	10	18	19
Trastuzumab could not block p95HER2 signaling ; in contrast , the EGFR and HER2 kinase inhibitor lapatinib suppressed HER2 signaling through PI3K and MAPK [ XREF_BIBR , XREF_BIBR ] .	Trastuzumab could not block p95HER2 signaling; in contrast, the EGFR and HER2 kinase inhibitor lapatinib suppressed HER2 signaling through PI3K and MAPK [XREF_BIBR, XREF_BIBR].	10	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	11	12	18	19
Neratinib ( XREF_FIG ) is an irreversible EGFR and HER-TKI targeting EGFR , HER2 , and HER4 , which was found to be more effective at suppressing cell proliferation than gefitinib in lung cancer cells with both actEGFRm and EGFR T790M in pre-clinical studies .	Neratinib (XREF_FIG) is an irreversible EGFR and HER-TKI targeting EGFR, HER2, and HER4, which was found to be more effective at suppressing cell proliferation than gefitinib in lung cancer cells with both actEGFRm and EGFR T790M in pre-clinical studies.	0	24	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	7	8	13	14
Furthermore , honokiol also promoted the growth inhibitory activity of the EGFR inhibiting agents erlotinib and lapatinib in HNSCC and Her-2 over-expressing breast cancer cells , respectively .	Furthermore, honokiol also promoted the growth inhibitory activity of the EGFR inhibiting agents erlotinib and lapatinib in HNSCC and Her-2 over-expressing breast cancer cells, respectively.	8	24	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	Her-2	Her-2	Her-2	11	12	20	21
In addition to combination therapies , the development of the dual EGFR and HER2 small molecule inhibitor lapatinib allows the simultaneous inhibition of EGFR and HER2 with a single drug .	In addition to combination therapies, the development of the dual EGFR and HER2 small molecule inhibitor lapatinib allows the simultaneous inhibition of EGFR and HER2 with a single drug.	7	26	allows	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	11	12	25	26
Afatinib is a second generation EGFR TKI , which is able to block EGFR , HER2 , and HER4 kinases covalently and irreversibly .	Afatinib is a second generation EGFR TKI, which is able to block EGFR, HER2, and HER4 kinases covalently and irreversibly.	5	16	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	5	6	15	16
The small EGFR tyrosine kinase inhibitor lapatinib can block the functions of EGFR and HER2 .	The small EGFR tyrosine kinase inhibitor lapatinib can block the functions of EGFR and HER2.	2	15	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	2	3	14	15
Since HER2 plays an important role in dimerization of receptors and phosphorylation and is important in driving the MAPK and PI3K and Akt pathways , targeting HER2 and inhibiting EGFR : HER2 and HER2 : HER3 dimerization should have a significant impact on HER2 overexpressed lung cancer , in particular , NSCLC .	Since HER2 plays an important role in dimerization of receptors and phosphorylation and is important in driving the MAPK and PI3K and Akt pathways, targeting HER2 and inhibiting EGFR : HER2 and HER2 : HER3 dimerization should have a significant impact on HER2 overexpressed lung cancer, in particular, NSCLC.	25	33	inhibiting	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	29	30	26	27
In addition , second generation EGFR TKIs inhibit human epidermal growth factor receptor 2 ( HER2 ) , a common dimerization partner of EGFR , and some inhibit HER4 as well , to affect signaling transduction , thus allowing a more complete blockade of the EGFR signaling pathway [ XREF_BIBR ] .	In addition, second generation EGFR TKIs inhibit human epidermal growth factor receptor 2 (HER2), a common dimerization partner of EGFR, and some inhibit HER4 as well, to affect signaling transduction, thus allowing a more complete blockade of the EGFR signaling pathway [XREF_BIBR].	5	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	5	6	15	16
Although activation of EGFR and HER3 signaling significantly abrogates IFNgamma and TNFalpha and trastuzumab induced class I restoration , EGFR and HER3 receptor blockade rescues class I expression and ensuing HER2 369-377 -CD8 + cytotoxicity of HER2 and neu expressing cells .	Although activation of EGFR and HER3 signaling significantly abrogates IFNgamma and TNFalpha and trastuzumab induced class I restoration, EGFR and HER3 receptor blockade rescues class I expression and ensuing HER2 369-377 -CD8 + cytotoxicity of HER2 and neu expressing cells.	17	31	rescues	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	19	20	30	31
These include : HKI-272 , BIBW-2992 , and BMS-599626 targeting EGFR and ErbB2 ; CI-1033 targeting EGFR , ErbB2 , and erbB4 ; and ZD6474 and AEE788 targeting EGFR , ErbB2 , and VEGFR .	These include : HKI-272, BIBW-2992, and BMS-599626 targeting EGFR and ErbB2; CI-1033 targeting EGFR, ErbB2, and erbB4; and ZD6474 and AEE788 targeting EGFR, ErbB2, and VEGFR.	1	33	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB2	ErbB2	ErbB2	28	29	12	13
These results suggest that inhibition of HER2 Thr701 but not EGFR Thr669 phosphorylation by MEK inhibitors can enhance the tyrosine kinase activity of HER2 to transactivate EGFR and its downstream Akt pathway although ERK can phosphorylate both EGFR and HER2 at these residues .	These results suggest that inhibition of HER2 Thr701 but not EGFR Thr669 phosphorylation by MEK inhibitors can enhance the tyrosine kinase activity of HER2 to transactivate EGFR and its downstream Akt pathway although ERK can phosphorylate both EGFR and HER2 at these residues.	10	24	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR Thr669 phosphorylation	egfr	HER2	HER2	her2	10	11	23	24
Moreover , amplified EGFR status has been shown to lead to decrease response in HER2 positive tumors treated with Herceptin ( an anti-HER2 antibody ) 35 .	Moreover, amplified EGFR status has been shown to lead to decrease response in HER2 positive tumors treated with Herceptin (an anti-HER2 antibody) 35.	3	16	lead	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	3	4	14	15
Another report showed that lapatinib , a dual TKI of EGFR and HER2 , inhibits the nuclear transport of EGFR and HER2 and sensitizes cancer cells to fluoropyrimidine by downregulating thymidylate synthase , which is frequently overexpressed in fluoropyrimidine resistant cancer cells [ XREF_BIBR ] .	Another report showed that lapatinib, a dual TKI of EGFR and HER2, inhibits the nuclear transport of EGFR and HER2 and sensitizes cancer cells to fluoropyrimidine by downregulating thymidylate synthase, which is frequently overexpressed in fluoropyrimidine resistant cancer cells [XREF_BIBR].	8	22	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	10	11	21	22
For example , the dual ERBB1 and ERBB2 kinase tyrosine inhibitor lapatinib , either alone or combined with doxorubicin , was shown to inhibit the growth of HER2 positive breast cancer with intensified tumor infiltration of IFNgamma producing CTLs .	For example, the dual ERBB1 and ERBB2 kinase tyrosine inhibitor lapatinib, either alone or combined with doxorubicin, was shown to inhibit the growth of HER2 positive breast cancer with intensified tumor infiltration of IFNgamma producing CTLs.	3	30	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERBB1	ERBB1	ERBB1	HER2	HER2	HER2	5	6	27	28
EGFR specific tyrosine kinase inhibitor gefitinib ( Iressa ) , which was shown to decrease basal EGFR and HER2 dimerization , produced an increase in donor fluorescence lifetime when compared to that of untreated cells ( P < 0.005 ) .	EGFR specific tyrosine kinase inhibitor gefitinib (Iressa), which was shown to decrease basal EGFR and HER2 dimerization, produced an increase in donor fluorescence lifetime when compared to that of untreated cells (P < 0.005).	0	19	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER2	HER2	HER2	0	1	18	19
Interestingly , suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6 .	Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6.	2	12	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	4	5	11	12
STAT proteins , including Stat3 , are activated by TGF-alpha and EGFR and strategies that downmodulate TGF-alpha or EGFR inhibit SCCHN cell proliferation and abrogate Stat3 activation .	STAT proteins, including Stat3, are activated by TGF-alpha and EGFR and strategies that downmodulate TGF-alpha or EGFR inhibit SCCHN cell proliferation and abrogate Stat3 activation.	16	26	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	18	19	25	26
IL6 functioned downstream of NF-kappaB , as we observed that PBS-1086 treatment suppressed the induction of p-STAT3 by EGFR TKI treatment in the absence but not presence of exogenous IL6 ( XREF_FIG ) .	IL6 functioned downstream of NF-kappaB, as we observed that PBS-1086 treatment suppressed the induction of p-STAT3 by EGFR TKI treatment in the absence but not presence of exogenous IL6 (XREF_FIG).	14	20	induction	Positive_activation_token_2_noun	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	p-STAT3	p-STAT3	p-STAT3	18	19	16	17
In our study , similar to gefitinib , the FDA approved third generation EGFR TKI AZD9291 ( osimertinib ) also failed to suppress STAT3 activation in EGFR-mutant cells .	In our study, similar to gefitinib, the FDA approved third generation EGFR TKI AZD9291 (osimertinib) also failed to suppress STAT3 activation in EGFR-mutant cells.	13	24	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	13	14	23	24
Our data reveal that in basal conditions expression of 247R genetic variant of alpha 1a AR leads to STAT3 activation that is inhibited by EGFR- and MMP- specific inhibitors , demonstrating EGFR transactivation dependent STAT3 activation .	Our data reveal that in basal conditions expression of 247R genetic variant of alpha 1a AR leads to STAT3 activation that is inhibited by EGFR- and MMP- specific inhibitors, demonstrating EGFR transactivation dependent STAT3 activation.	22	35	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR-	EGFR-	EGFR-	STAT3	STAT3	STAT3	24	25	34	35
Inhibitor of EGFR Downregulates the Constitutive Activation of Stat3 in HSC-1 Cells , and a Combination of Inhibitors of EGFR and PI3K and Akt Abrogates Stat3 Activation .	Inhibitor of EGFR Downregulates the Constitutive Activation of Stat3 in HSC-1 Cells, and a Combination of Inhibitors of EGFR and PI3K and Akt Abrogates Stat3 Activation.	0	11	Downregulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	2	3	8	9
We have shown that EGFR inhibition results in the adaptive activation of not only STAT3 but also Src-YAP1 signaling , potentially operating downstream of IL-6 , to promote cell survival and limit the initial response to EGFR TKI treatment in EGFR-mutant lung cancer ( XREF_FIG ) .	We have shown that EGFR inhibition results in the adaptive activation of not only STAT3 but also Src-YAP1 signaling, potentially operating downstream of IL-6, to promote cell survival and limit the initial response to EGFR TKI treatment in EGFR-mutant lung cancer (XREF_FIG).	4	18	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	4	5	14	15
More recently , inhibition of oncogenic EGFR was shown to increase STAT3 signaling and thereby rescue tumor cells from death upon EGFR targeted therapy in NSCLC cells 32 .	More recently, inhibition of oncogenic EGFR was shown to increase STAT3 signaling and thereby rescue tumor cells from death upon EGFR targeted therapy in NSCLC cells 32.	3	12	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	6	7	11	12
Maximum suppression was achieved by a combination of AG1478 and wortmannin ( XREF_FIG ) , indicating that EGFR and PI3K and Akt signaling directly or indirectly activate Stat3 through independent pathways in HSC-1 cells .	Maximum suppression was achieved by a combination of AG1478 and wortmannin (XREF_FIG), indicating that EGFR and PI3K and Akt signaling directly or indirectly activate Stat3 through independent pathways in HSC-1 cells.	17	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	17	18	27	28
Furthermore , it promotes intracellular secretary homotypic vesicle fusion in hematopoietic cells , and dephosphorylation of epidermal growth factor receptor ( EGFR ) and ErbB2 resulted in the impaired activation of Signal transducer and activator of transcription 3 ( STAT3 ) and Signal transducer and activator of transcription 5 ( STAT5 ) in breast cancer cells [ XREF_BIBR , XREF_BIBR ] .	Furthermore, it promotes intracellular secretary homotypic vesicle fusion in hematopoietic cells, and dephosphorylation of epidermal growth factor receptor (EGFR) and ErbB2 resulted in the impaired activation of Signal transducer and activator of transcription 3 (STAT3) and Signal transducer and activator of transcription 5 (STAT5) in breast cancer cells [XREF_BIBR, XREF_BIBR].	14	40	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	epidermal growth factor receptor	dephosphorylation of epidermal growth factor receptor	epidermal growth factor receptor	STAT3	STAT3	stat3	16	20	39	40
XREF_BIBR Whereas the reduced levels of Cav-1 function by hypoxia increases epidermal growth factor receptor ( EGFR ) activation , leading to the activation of signal transducer and activator of transcription 3 ( STAT3 ) , resulting in the downregulation of E-cadherin and upregulation of mesenchymal markers ( Slug , a-SMA , N-cadherin and vimentin ) , suggesting that Cav-1 can mediate the EMT and promote the invasive potency in gastric cancer ( GC ) .	XREF_BIBR Whereas the reduced levels of Cav-1 function by hypoxia increases epidermal growth factor receptor (EGFR) activation, leading to the activation of signal transducer and activator of transcription 3 (STAT3), resulting in the downregulation of E-cadherin and upregulation of mesenchymal markers (Slug, a-SMA, N-cadherin and vimentin), suggesting that Cav-1 can mediate the EMT and promote the invasive potency in gastric cancer (GC).	11	34	leading to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	STAT3	STAT3	STAT3	11	15	33	34
17 It has been demonstrated that EGFR inhibition decreases STAT3 activity and that in vitro suppression of STAT3 , in breast and cervical cancers , decreases VEGF production .	17 It has been demonstrated that EGFR inhibition decreases STAT3 activity and that in vitro suppression of STAT3, in breast and cervical cancers, decreases VEGF production.	6	10	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	6	7	9	10
Indeed , a previous report showed that suppression of EGFR signaling induced Stat3 activation in EGFR-mutant but not in EGFR wildtype lung cancer cells .	Indeed, a previous report showed that suppression of EGFR signaling induced Stat3 activation in EGFR-mutant but not in EGFR wildtype lung cancer cells.	9	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	Stat3	Stat3	Stat3	9	10	12	13
The cell associated fluorescence of the accumulated compounds tightly correlates with the light induced photoreaction leading to STAT3 crosslinking , p38 activation and EGFR loss ( XREF_FIG ) .	The cell associated fluorescence of the accumulated compounds tightly correlates with the light induced photoreaction leading to STAT3 crosslinking, p38 activation and EGFR loss (XREF_FIG).	13	24	induced	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	23	24	17	18
Suppressor of cytokine signaling-1 ( SOCS-1 ) has been implicated recently in the negative regulation of IL-6R and Janus activated kinase ( JAK )-mediated activation of STAT3 , suggesting that SOCS-1 could affect alternative activation of STAT3 by EGFR , IL-6R , and associated kinases .	Suppressor of cytokine signaling-1 (SOCS-1) has been implicated recently in the negative regulation of IL-6R and Janus-activated kinase (JAK)-mediated activation of STAT3, suggesting that SOCS-1 could affect alternative activation of STAT3 by EGFR, IL-6R, and associated kinases.	32	44	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	38	39	36	37
In addition , combined inhibition of SRC and EGFR with dasatinib , erlotinib and gemcitabine synergistically blocked constitutively activated STAT3 and consequently growth in a mouse model of pancreatic cancer 59 .	In addition, combined inhibition of SRC and EGFR with dasatinib, erlotinib and gemcitabine synergistically blocked constitutively activated STAT3 and consequently growth in a mouse model of pancreatic cancer 59.	4	22	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	8	9	19	20
Several studies have revealed that inhibition of EGFR by erlotinib induces activation of STAT3 , which contributes to erlotinib resistance .	Several studies have revealed that inhibition of EGFR by erlotinib induces activation of STAT3, which contributes to erlotinib resistance.	5	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	7	8	13	14
The main problem is that STAT3 activation is not abrogated by single EGFR TKI treatment with gefitinib , erlotinib , afatinib or dacomitinib XREF_BIBR , XREF_BIBR - XREF_BIBR .	The main problem is that STAT3 activation is not abrogated by single EGFR TKI treatment with gefitinib, erlotinib, afatinib or dacomitinib XREF_BIBR, XREF_BIBR - XREF_BIBR.	5	14	abrogated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	12	13	5	6
In the present report , we discovered that inhibition of EGFR by erlotinib induces activation of STAT3 by suppressing its physiological phosphatase PP ( TM ) eg2 leading to increased Bcl2 and Bcl-XL , which contributes to the acquired erlotinib resistance ( XREF_FIG - XREF_FIG ) .	In the present report, we discovered that inhibition of EGFR by erlotinib induces activation of STAT3 by suppressing its physiological phosphatase PP (TM) eg2 leading to increased Bcl2 and Bcl-XL, which contributes to the acquired erlotinib resistance (XREF_FIG - XREF_FIG).	8	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT3	STAT3	STAT3	10	11	16	17
Strikingly , proteosome inhibition by MG132 restored LPS induced PKR activation in endotoxin tolerized macrophages and prevented the inducible loss of PKR protein ( XREF_FIG , top and middle , respectively ) .	Strikingly, proteosome inhibition by MG132 restored LPS induced PKR activation in endotoxin tolerized macrophages and prevented the inducible loss of PKR protein (XREF_FIG, top and middle, respectively).	5	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	MG132 restored LPS induced PKR	pkr	PKR	PKR	pkr	9	10	21	22
These results suggested that phosphorylation of PKR at Y162 abolished the activation of PKR by SUMO .	These results suggested that phosphorylation of PKR at Y162 abolished the activation of PKR by SUMO.	4	14	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKR	phosphorylation of PKR at Y162	pkr	PKR	PKR	pkr	6	7	13	14
These data indicate that IAV has evolved a critical mechanism by which NS1 mediated PKR inhibition is mediated by upregulation of the host factor vault RNAs that inactivates PKR and blocks the production of downstream effector molecules of IFNs .	These data indicate that IAV has evolved a critical mechanism by which NS1 mediated PKR inhibition is mediated by upregulation of the host factor vault RNAs that inactivates PKR and blocks the production of downstream effector molecules of IFNs.	12	29	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKR	NS1 mediated PKR inhibition is mediated by upregulation of the host factor vault	pkr	PKR	PKR	pkr	14	15	28	29
In contrast , cell proliferation was suppressed by silencing PKR expression in the hypoxic RF/6A cells using PKR siRNA transfection ( XREF_FIG ) .	In contrast, cell proliferation was suppressed by silencing PKR expression in the hypoxic RF/6A cells using PKR siRNA transfection (XREF_FIG).	6	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PKR expression	pkr	PKR	PKR	pkr	9	10	17	18
It is homologous to the N-terminal S1 domain of eIF2alpha and binds to the catalytic domain of activated PKR , which is phosphorylated on serine 446 ( human PKR ) and thereby inhibits access of PKR to its target and also prevents secondary PKR authophosphorylation events ( XREF_FIG ) .	It is homologous to the N-terminal S1 domain of eIF2alpha and binds to the catalytic domain of activated PKR, which is phosphorylated on serine 446 (human PKR) and thereby inhibits access of PKR to its target and also prevents secondary PKR authophosphorylation events (XREF_FIG).	15	36	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKR	PKR, which is phosphorylated on serine 446	pkr	PKR	PKR	pkr	18	19	35	36
Overexpression of PKR significantly enhanced caspase-1 activation and IL-1beta cleavage , and knockdown of endogenous PKR by shRNA abolished caspase-1 cleavage in the NLRP3 inflammasome reconstituted cells ( XREF_FIG ) .	Overexpression of PKR significantly enhanced caspase-1 activation and IL-1beta cleavage, and knockdown of endogenous PKR by shRNA abolished caspase-1 cleavage in the NLRP3 inflammasome reconstituted cells (XREF_FIG).	0	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKR	Overexpression of PKR	pkr	PKR	PKR	pkr	2	3	15	16
In conclusion , the level of PKR was reduced in HCC tumor tissues , suggesting a possible role of PKR in promoting the growth of tumor .	In conclusion, the level of PKR was reduced in HCC tumor tissues, suggesting a possible role of PKR in promoting the growth of tumor.	4	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKR	level of PKR	pkr	PKR	PKR	pkr	6	7	19	20
Importantly , ISG protein expression is restored and the antiviral effect of IFN enhanced in PKR-down-regulated cells , suggesting that by inducing PKR phosphorylation HCV inhibits the production of antiviral ISG proteins in infected cells .	Importantly, ISG protein expression is restored and the antiviral effect of IFN enhanced in PKR-down-regulated cells, suggesting that by inducing PKR phosphorylation HCV inhibits the production of antiviral ISG proteins in infected cells.	21	26	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKR	PKR phosphorylation	pkr	PKR	PKR	pkr	22	23	22	23
Since type I IFN treatment itself can stimulate PKR expression , even with shRNA mediated PKR knockdown ( data not shown ) , we have constructed PKR-knockout human HeLa cell lines using CRISPR technology , which respond to exogenous type I IFN , like the human fibroblasts cell line GM02504 .	Since type I IFN treatment itself can stimulate PKR expression, even with shRNA mediated PKR knockdown (data not shown), we have constructed PKR-knockout human HeLa cell lines using CRISPR technology, which respond to exogenous type I IFN, like the human fibroblasts cell line GM02504.	8	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKR	PKR expression	pkr	PKR	PKR	pkr	8	9	15	16
In HEK 293T cells transfected with an HIV-1 molecular clone , PACT unexpectedly inhibited PKR and eIF2alpha phosphorylation and increased HIV-1 protein expression and virion production in the presence of either endogenous PKR alone or overexpressed PKR .	In HEK 293T cells transfected with an HIV-1 molecular clone, PACT unexpectedly inhibited PKR and eIF2alpha phosphorylation and increased HIV-1 protein expression and virion production in the presence of either endogenous PKR alone or overexpressed PKR.	11	35	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PACT unexpectedly inhibited PKR and eIF2alpha phosphorylation	pkr	PKR	PKR	pkr	14	15	32	33
First , we assessed if inhibiting EGFR would also result in HER3 mRNA upregulation as a result of negative feedback signaling disruption .	First, we assessed if inhibiting EGFR would also result in HER3 mRNA upregulation as a result of negative feedback signaling disruption.	5	14	upregulation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	6	7	11	12
Patritumab is a fully human anti-human epidermal growth factor receptor 3 ( HER3 ) antibody that inhibits HER3 from binding to HRG .	Patritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that inhibits HER3 from binding to HRG.	6	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	HER3	HER3	HER3	6	10	17	18
A study by Tao et al showed a similar upregulation of HER3 as described above , which was reduced by the addition of a dual EGFR and HER3 inhibitor [ XREF_BIBR ] .	A study by Tao et al showed a similar upregulation of HER3 as described above, which was reduced by the addition of a dual EGFR and HER3 inhibitor [XREF_BIBR].	9	30	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	25	26	11	12
11 EGFR tyrosine kinase inhibitors blocked ERBB3 activation in these lung tumor cells .	11 EGFR tyrosine kinase inhibitors blocked ERBB3 activation in these lung tumor cells.	1	7	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ERBB3	ERBB3	ERBB3	1	2	6	7
Inhibition of either EGFR or c-Met alone resulted in persistent ErbB3 mediated PI3K pathway activation ; only the concurrent inhibition of both EGFR and c-Met completely eliminated ErbB3 activation .	Inhibition of either EGFR or c-Met alone resulted in persistent ErbB3 mediated PI3K pathway activation; only the concurrent inhibition of both EGFR and c-Met completely eliminated ErbB3 activation.	19	28	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	ErbB3	ErbB3	ErbB3	22	23	27	28
Consequently , EGFR inhibition would block AKT and thus allow upregulation of HER3 mRNA .	Consequently, EGFR inhibition would block AKT and thus allow upregulation of HER3 mRNA.	2	13	allow	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	HER3	HER3	HER3	2	3	12	13
Our findings suggest that direct ERK mediated phosphorylation of EGFR T669 and HER2 T677 suppresses activation of ERBB3 .	Our findings suggest that direct ERK mediated phosphorylation of EGFR T669 and HER2 T677 suppresses activation of ERBB3.	5	18	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	ERK mediated phosphorylation of EGFR T669 and HER2 T677	egfr	ERBB3	ERBB3	erbb3	9	10	17	18
Lower doses of leptin or EGF ( 10 , 25 and 50 ng/mL ) did not induce any HER2 response in MCF-7 cell model ( data not shown ) .	Lower doses of leptin or EGF (10, 25 and 50 ng/mL) did not induce any HER2 response in MCF-7 cell model (data not shown).	1	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	HER2	HER2	HER2	5	6	18	19
Unexpectedly , EGF induced HER2 degradation was significantly decreased , rather than increased , by knockdown of endogenous PTPN18 ( XREF_FIG ) .	Unexpectedly, EGF induced HER2 degradation was significantly decreased, rather than increased, by knockdown of endogenous PTPN18 (XREF_FIG).	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	HER2	HER2	HER2	2	3	4	5
Conversely , overexpression of PTPN18 , but not PTP-MEG2 , augmented EGF induced HER2 degradation ( XREF_FIG ) .	Conversely, overexpression of PTPN18, but not PTP-MEG2, augmented EGF induced HER2 degradation (XREF_FIG).	11	14	induced	Positive_early_activation	Positive_activation	Negative_activation	EGF	EGF	EGF	HER2	HER2	HER2	11	12	13	14
To understand the mechanism underlying immunotherapy , we concentrated on antibody- and epidermal growth factor induced degradation of ErbB-2 .	To understand the mechanism underlying immunotherapy, we concentrated on antibody- and epidermal growth factor induced degradation of ErbB-2.	10	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	ErbB-2	ErbB-2	ErbB-2	12	15	18	19
EGF and heregulin treatment decreased the homoclusters of ErbB2 whereas ErbB1 clusters showed increase in homoclustering upon EGF treatment [ XREF_BIBR ] .	EGF and heregulin treatment decreased the homoclusters of ErbB2 whereas ErbB1 clusters showed increase in homoclustering upon EGF treatment [XREF_BIBR].	0	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	ErbB2	ErbB2	ErbB2	0	1	8	9
In particular , revisiting the experimental data , one can see that the interplay between adaptation and signal integration ( Materials and Methods ) is also present in the EGFR pathway , in which down-regulation of erbB-2 by EGF concurs with adaptation of the signal transmitted by EGFR .	In particular, revisiting the experimental data, one can see that the interplay between adaptation and signal integration (Materials and Methods) is also present in the EGFR pathway, in which down-regulation of erbB-2 by EGF concurs with adaptation of the signal transmitted by EGFR.	34	39	down-regulation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	EGF	EGF	EGF	erbB-2	erbB-2	erbB-2	38	39	36	37
Stable silencing of Endo II in HER2+ cell lines led to elevated levels of HER2 on the cell surface , impaired epidermal growth factor induced HER2 internalization , and reduced signaling to downstream effector kinases Akt and Erk .	Stable silencing of Endo II in HER2+ cell lines led to elevated levels of HER2 on the cell surface, impaired epidermal growth factor induced HER2 internalization, and reduced signaling to downstream effector kinases Akt and Erk.	20	26	induced	Positive_early_activation	Positive_activation	Positive_activation	epidermal growth factor	epidermal growth factor	epidermal growth factor	HER2	HER2	HER2	21	24	25	26
As expected , EGF treatment for 15 minutes led to HER2 internalization , marked by a left shift in the histogram and reduced mean fluorescence intensity ( MFI ) of HER2 staining in control HCC1954 pLKO cells .	As expected, EGF treatment for 15 minutes led to HER2 internalization, marked by a left shift in the histogram and reduced mean fluorescence intensity (MFI) of HER2 staining in control HCC1954 pLKO cells.	3	31	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGF	EGF	EGF	HER2	HER2	HER2	3	4	30	31
The lack of efficacy of erlotinib on established tumors was seen in ER negative and ER positive tumors , further confirming that EGFR inhibition prevented the emergence of ER negative tumors but likely did not kill nascent ER negative tumors .	The lack of efficacy of erlotinib on established tumors was seen in ER negative and ER positive tumors, further confirming that EGFR inhibition prevented the emergence of ER negative tumors but likely did not kill nascent ER negative tumors.	22	39	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ER	ER	ER	22	23	37	38
Dual epidermal growth factor receptor ( EGFR ) and HER2 targeting with the tyrosine kinase inhibitor lapatinib is approved for treating advanced HER2 positive breast cancer and can prevent estrogen receptor ( ER )-negative mammary tumors in HER2 transgenic mouse models .	Dual epidermal growth factor receptor (EGFR) and HER2 targeting with the tyrosine kinase inhibitor lapatinib is approved for treating advanced HER2 positive breast cancer and can prevent estrogen receptor (ER)-negative mammary tumors in HER2 transgenic mouse models.	1	31	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	estrogen receptor	estrogen receptor	estrogen receptor	1	5	29	31
Jab1 is a target of EGFR signaling in ERalpha negative breast cancer .	Jab1 is a target of EGFR signaling in ERalpha negative breast cancer.	5	11	signaling	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ERalpha	ERalpha	ERalpha	5	6	8	9
We have previously demonstrated that hyperactivation of MAPK ( hMAPK ) downstream of overexpressed EGFR or overexpression and amplification of Her2 represses ER protein and mRNA expression .	We have previously demonstrated that hyperactivation of MAPK (hMAPK) downstream of overexpressed EGFR or overexpression and amplification of Her2 represses ER protein and mRNA expression.	5	23	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ER	ER	ER	14	15	22	23
Furthermore , AGO2 function is directly modulated by EGFR signaling in ERalpha negative breast cancer under states of hypoxic stress .	Furthermore, AGO2 function is directly modulated by EGFR signaling in ERalpha negative breast cancer under states of hypoxic stress.	8	14	signaling	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ERalpha	ERalpha	ERalpha	8	9	11	12
Tip30 Deletion in MMTV-Neu Mice Leads to Enhanced EGFR Signaling and Development of Estrogen Receptor Positive and Progesterone Receptor Negative Mammary Tumors .	Tip30 Deletion in MMTV-Neu Mice Leads to Enhanced EGFR Signaling and Development of Estrogen Receptor Positive and Progesterone Receptor Negative Mammary Tumors.	8	15	Signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Estrogen Receptor	Estrogen Receptor	Estrogen Receptor	8	9	13	15
Loss of BRCA1 leads to an increase in epidermal growth factor receptor expression in mammary epithelial cells , and epidermal growth factor receptor inhibition prevents estrogen receptor negative cancers in BRCA1-mutant mice .	Loss of BRCA1 leads to an increase in epidermal growth factor receptor expression in mammary epithelial cells, and epidermal growth factor receptor inhibition prevents estrogen receptor negative cancers in BRCA1-mutant mice.	19	28	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	estrogen receptor	estrogen receptor	estrogen receptor	19	23	25	27
EGFR inhibition prevents the emergence of ER negative but not of ER positive breast cancers in BRCA1-mutant mice .	EGFR inhibition prevents the emergence of ER negative but not of ER positive breast cancers in BRCA1-mutant mice.	0	14	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ER	ER	ER	0	1	6	7
We then tested whether 0.02 mg/kg tunicamycin treatment could decrease the expression of EGFR family and induce ER stress in tumor and in liver tissues .	We then tested whether 0.02 mg/kg tunicamycin treatment could decrease the expression of EGFR family and induce ER stress in tumor and in liver tissues.	6	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	tunicamycin treatment could decrease the expression of EGFR	egfr	ER	ER	er	13	14	17	18
V2O5 suppressed H2O2 for as long as 24 h. Differences in the temporal activation of STAT-1 and p38 MAPK were observed following V2O5 or H2O2 treatment , and STAT-1 activation by V2O5 or H2O2 was attenuated by an inhibitor of the EGF receptor tyrosine kinase ( AG1478 ) or p38 MAPK ( SB203580 ) .	V2O5 suppressed H2O2 for as long as 24 h. Differences in the temporal activation of STAT-1 and p38 MAPK were observed following V2O5 or H2O2 treatment, and STAT-1 activation by V2O5 or H2O2 was attenuated by an inhibitor of the EGF receptor tyrosine kinase (AG1478) or p38 MAPK (SB203580).	28	44	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	EGF receptor	EGF receptor	EGF receptor	STAT-1	STAT-1	STAT-1	41	43	28	29
Inhibiting EGFR can enhance STAT1 signaling , hence stimulating TAA presentation , and inhibit STAT3 , hence favoring the conversion of an immunosuppressive tumor microenvironment into an immunostimulatory one .	Inhibiting EGFR can enhance STAT1 signaling, hence stimulating TAA presentation, and inhibit STAT3, hence favoring the conversion of an immunosuppressive tumor microenvironment into an immunostimulatory one.	0	13	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	1	2	4	5
SHP2 phosphatase depletion using siRNA enhanced cetuximab induced p-STAT1 ( Tyr701 ) , as well as total STAT1 , expression suggesting that high SHP2 expression downstream of EGFR in HNC cells prevents STAT1 mediated signaling .	SHP2 phosphatase depletion using siRNA enhanced cetuximab induced p-STAT1 (Tyr701), as well as total STAT1, expression suggesting that high SHP2 expression downstream of EGFR in HNC cells prevents STAT1 mediated signaling.	24	34	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	expression downstream of EGFR	egfr	STAT1	STAT1	stat1	27	28	32	33
The epidermal growth factor receptor ( EGFR ) supports the escape of malignant cells from immunosurveillance by inhibiting the activation of signal transducer and activator of transcription 1 ( STAT1 ) while promoting that of STAT3 .	The epidermal growth factor receptor (EGFR) supports the escape of malignant cells from immunosurveillance by inhibiting the activation of signal transducer and activator of transcription 1 (STAT1) while promoting that of STAT3.	1	30	supports	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	STAT1	STAT1	STAT1	1	5	29	30
EGFR dependent SHP2 overactivation downregulates STAT1 mediated synthesis of HLA class I molecules and APM components by two mechanisms .	EGFR dependent SHP2 overactivation downregulates STAT1 mediated synthesis of HLA class I molecules and APM components by two mechanisms.	0	7	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	0	1	5	6
EGFR blockade triggered STAT1 activation and HLA upregulation , in a src homology containing protein ( SHP )-2-dependent fashion , more prominently in HLA-B/C than in HLA-A alleles .	EGFR blockade triggered STAT1 activation and HLA upregulation, in a src homology containing protein (SHP)-2-dependent fashion, more prominently in HLA-B/C than in HLA-A alleles.	0	4	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	0	1	3	4
Thus , the goal of this study was to investigate the mechanism by which EGFR activation inhibits STAT1 activation as well as the HLA class I APM pathway and resulting adaptive antitumor immunity .	Thus, the goal of this study was to investigate the mechanism by which EGFR activation inhibits STAT1 activation as well as the HLA class I APM pathway and resulting adaptive antitumor immunity.	14	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	STAT1	STAT1	STAT1	14	15	17	18
First , betaPIX sequesters Cbl from EGFR , thereby preventing EGFR ubiquitination and downregulation [ XREF_BIBR , XREF_BIBR ] ; and second , betaPIX , Cbl and EGFR form a stable complex at the plasma membrane , which blocks EGFR endocytosis , probably by preventing Cbl from engaging essential endocytic proteins [ XREF_BIBR , XREF_BIBR ] .	First, betaPIX sequesters Cbl from EGFR, thereby preventing EGFR ubiquitination and downregulation [XREF_BIBR, XREF_BIBR]; and second, betaPIX, Cbl and EGFR form a stable complex at the plasma membrane, which blocks EGFR endocytosis, probably by preventing Cbl from engaging essential endocytic proteins [XREF_BIBR, XREF_BIBR].	2	28	sequesters	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	Cbl	Cbl	Cbl	27	28	4	5
Hence , the low level of EGFR autophosphorylation on Y1068 in the presence of HER2 reduces the interaction of Grb2 directly and that of c-Cbl and Shc proteins indirectly .	Hence, the low level of EGFR autophosphorylation on Y1068 in the presence of HER2 reduces the interaction of Grb2 directly and that of c-Cbl and Shc proteins indirectly.	6	27	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR autophosphorylation on Y1068	egfr	c-Cbl	c-Cbl	c-cbl	6	7	24	25
We conclude that HT downregulates EGFR expression via lysosomal and proteasomal degradation , activated by HT induced EGFR phosphorylation at pY1045 and increased Cbl activity .	We conclude that HT downregulates EGFR expression via lysosomal and proteasomal degradation, activated by HT induced EGFR phosphorylation at pY1045 and increased Cbl activity.	5	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EGFR	EGFR expression	egfr	Cbl	Cbl	cbl	5	6	23	24
The first group of damaging mutants included C396R , H398Q , Y371H , K382E and C381A which completely abolished CBL activity ( relative densitometry was less than 10 % ) ( XREF_FIG ) and the levels of total EGFR were not decreased by these mutants ( XREF_FIG ) .	The first group of damaging mutants included C396R, H398Q, Y371H, K382E and C381A which completely abolished CBL activity (relative densitometry was less than 10%) (XREF_FIG) and the levels of total EGFR were not decreased by these mutants (XREF_FIG).	18	39	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	levels of total EGFR	egfr	CBL	CBL	cbl	38	39	19	20
To test whether increased EGFR ubiquitylation results in attenuation of the EGFR signaling and tumorigenesis , HSC3 and EGFR-GFP cells overexpressing c-Cbl under tet inducible promoter were generated .	To test whether increased EGFR ubiquitylation results in attenuation of the EGFR signaling and tumorigenesis, HSC3 and EGFR-GFP cells overexpressing c-Cbl under tet inducible promoter were generated.	11	22	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	c-Cbl	c-Cbl	c-Cbl	11	12	21	22
The results presented in XREF_FIG demonstrated that autophosphorylation of the EGFR and possibly HER2 on the c-Cbl and the major Grb2 binding sites is very low in the presence of HER2 , eliminating the direct and indirect interaction of c-Cbl .	The results presented in XREF_FIG demonstrated that autophosphorylation of the EGFR and possibly HER2 on the c-Cbl and the major Grb2 binding sites is very low in the presence of HER2, eliminating the direct and indirect interaction of c-Cbl.	7	40	eliminating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	autophosphorylation of the EGFR	egfr	c-Cbl	c-Cbl	c-cbl	10	11	39	40
Tissue specific knockout of Mig6 increases EGFR signaling and the proliferation of epithelial cells in mouse lungs , suggesting that Mig6 is essential for lung homeostasis .	Tissue specific knockout of Mig6 increases EGFR signaling and the proliferation of epithelial cells in mouse lungs, suggesting that Mig6 is essential for lung homeostasis.	4	7	increases	Positive_activation_token_1_noun	Positive_activation	Positive_activation	EGFR	EGFR	EGFR	Mig6	Mig6	Mig6	6	7	4	5
Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib , an EGFR kinase inhibitor .	Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor.	6	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	ERRFI1	ERRFI1	ERRFI1	18	19	9	10
Thus , a model of Ras or EGFR activation induced tumor cell migration could be as follows : activated Ras or EGFR has reduced overall FAK activity mediated by PTP-PEST-dependent dephosphorylation ; as a result , the number of cell-ECM contacts is reduced , and cells become less adherent and more motile .	Thus, a model of Ras or EGFR activation induced tumor cell migration could be as follows : activated Ras or EGFR has reduced overall FAK activity mediated by PTP-PEST-dependent dephosphorylation; as a result, the number of cell-ECM contacts is reduced, and cells become less adherent and more motile.	19	26	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	FAK	FAK	FAK	21	22	25	26
In N18TG2 cells , CB 1 -stimulated FAK 576/577 Tyr P was significantly reduced by Flk-1 VEGFR and EGFR specific inhibitors which confirmed involvement of these RTKs in this process .	In N18TG2 cells, CB 1 -stimulated FAK 576/577 Tyr P was significantly reduced by Flk-1 VEGFR and EGFR specific inhibitors which confirmed involvement of these RTKs in this process.	7	19	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	FAK	FAK	FAK	18	19	7	8
EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury .	EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury.	0	5	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EphrinB3	EphrinB3	EphrinB3	EphB3	EphB3	EphB3	0	1	2	3
Infusion of soluble ephrin-B3 into the lateral ventricles reversed the proliferation defect in ephrin-B3 knockout mice but not the EphB3 receptor knockout mice .	Infusion of soluble ephrin-B3 into the lateral ventricles reversed the proliferation defect in ephrin-B3 knockout mice but not the EphB3 receptor knockout mice.	0	22	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ephrin-B3	ephrin-B3	ephrin-B3	EphB3	EphB3	EphB3	3	4	19	20
The authors hypothesized that lactate production is regulated by MYC via transcriptional regulation , since MYC is decreased at both protein and mRNA levels following treatment by EGFR TKIs .	The authors hypothesized that lactate production is regulated by MYC via transcriptional regulation, since MYC is decreased at both protein and mRNA levels following treatment by EGFR TKIs.	15	28	decreased	Negative_activation_syntax_4_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	MYC	MYC	MYC	27	28	15	16
The drawback is that inhibition of the EGFR pathway may cause downregulation of MYC .	The drawback is that inhibition of the EGFR pathway may cause downregulation of MYC.	7	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	MYC	MYC	MYC	7	8	13	14
Activation of EGFR inhibits the interaction of PCNA with CUL4A , whereas inhibition of EGFR leads to increased CUL4A-PCNA interaction and CUL4A dependent ubiquitin mediated degradation of PCNA .	Activation of EGFR inhibits the interaction of PCNA with CUL4A, whereas inhibition of EGFR leads to increased CUL4A-PCNA interaction and CUL4A dependent ubiquitin mediated degradation of PCNA.	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	PCNA	PCNA	PCNA	2	3	7	8
We then analyzed whether EphA4 cleavage could also be blocked by application of ephrinB3 .	We then analyzed whether EphA4 cleavage could also be blocked by application of ephrinB3.	4	14	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ephrinB3	ephrinB3	ephrinB3	EphA4	EphA4	EphA4	13	14	4	5
Eph and ephrin signaling plays an essential role in CIN guidance , where expression of ephrinB3 in midline spinal populations prevents the crossing of excitatory EphA4 positive ipsilaterally projecting interneurons ( IINs ) .	Eph and ephrin signaling plays an essential role in CIN guidance, where expression of ephrinB3 in midline spinal populations prevents the crossing of excitatory EphA4 positive ipsilaterally projecting interneurons (IINs).	13	26	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ephrinB3	expression of ephrinB3	ephrinb3	EphA4	EphA4	epha4	15	16	25	26
This , together with the lack of effect of full-length galectin-3 on EGFR activation in MUC1 negative cells and the lack of effect of truncated galectin-3C on EGFR activation in the MUC1 positive cells , indicates that galectin-3-mediated EGFR activation is associated with its effect on alteration of MUC1 cell surface localization .	This, together with the lack of effect of full-length galectin-3 on EGFR activation in MUC1 negative cells and the lack of effect of truncated galectin-3C on EGFR activation in the MUC1 positive cells, indicates that galectin-3-mediated EGFR activation is associated with its effect on alteration of MUC1 cell surface localization.	12	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	EGFR	EGFR	EGFR	MUC1	MUC1	MUC1	12	13	15	16
362 Epidermal growth factor receptor ( EGFR ) negatively regulates PLD2 lipase activity via phosphorylation at Tyr296 .	362 Epidermal growth factor receptor (EGFR) negatively regulates PLD2 lipase activity via phosphorylation at Tyr296.	1	12	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Epidermal growth factor receptor	Epidermal growth factor receptor	Epidermal growth factor receptor	PLD2	PLD2	PLD2	1	5	10	11
However , overexpression of p300 relieved this p53 induced repression , in a dose dependent manner ( XREF_FIG ) .	However, overexpression of p300 relieved this p53 induced repression, in a dose dependent manner (XREF_FIG).	2	8	relieved	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	overexpression of p300	p300	p53	p53	p53	4	5	7	8
When in the inactive state ( in the absence of cellular stress ) , TP53 can be inactivated via ubiquitination by either MDM2 or EP300 .	When in the inactive state (in the absence of cellular stress), TP53 can be inactivated via ubiquitination by either MDM2 or EP300.	14	25	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	EP300	EP300	EP300	TP53	TP53	TP53	24	25	14	15
Based on their results , p300 stabilized p53 in the presence of lower level of MDM2 , whereas p300 promoted MDM2 dependent proteasomal degradation of p53 in the presence of a higher level of MDM2 .	Based on their results, p300 stabilized p53 in the presence of lower level of MDM2, whereas p300 promoted MDM2 dependent proteasomal degradation of p53 in the presence of a higher level of MDM2.	18	26	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300	p300	p53	p53	p53	18	19	25	26
CBP and p300 can both positively and negatively regulate p53 transactivation , as well as p53 protein turnover , depending on cellular context and environmental stimuli .	CBP and p300 can both positively and negatively regulate p53 transactivation, as well as p53 protein turnover, depending on cellular context and environmental stimuli.	0	10	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300	p300	p53	p53	p53	2	3	9	10
In addition , p300 modifies H3 acetylation to promote gene translation , XREF_BIBR , XREF_BIBR acetylates PCNA to link its degradation with nucleotide excision repair synthesis , 35 and also modifies anti-apoptotic protein p53 acetylation and inhibits the anti-apoptotic effects of p53 .	In addition, p300 modifies H3 acetylation to promote gene translation, XREF_BIBR, XREF_BIBR acetylates PCNA to link its degradation with nucleotide excision repair synthesis, 35 and also modifies anti-apoptotic protein p53 acetylation and inhibits the anti-apoptotic effects of p53.	3	42	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300	p300	p53	p53	p53	3	4	41	42
E2f1-3 loss did not induce p53 phosphorylation ( data not shown ) but markedly increased acetylation ( XREF_FIG ) , which is essential for p53 activity XREF_BIBR is mediated by Tip60 , Pcaf and Cbp and p300 and reversed by Hdacs and Sirt1 XREF_BIBR .	E2f1-3 loss did not induce p53 phosphorylation (data not shown) but markedly increased acetylation (XREF_FIG), which is essential for p53 activity XREF_BIBR is mediated by Tip60, Pcaf and Cbp and p300 and reversed by Hdacs and Sirt1 XREF_BIBR.	24	37	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	36	37	24	25
The interaction of protein p300 with MDM2 promotes p53 degradation .	The interaction of protein p300 with MDM2 promotes p53 degradation.	1	9	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300	p300	p53	p53	p53	4	5	8	9
The phosphorylation of MDM2 at Ser 166/186 promotes its nuclear localization and its interaction with p300 , a transcriptional co-activator that forms a complex with MDM2 and promotes p53 degradation XREF_BIBR XREF_BIBR XREF_BIBR .	The phosphorylation of MDM2 at Ser 166/186 promotes its nuclear localization and its interaction with p300, a transcriptional co-activator that forms a complex with MDM2 and promotes p53 degradation XREF_BIBR XREF_BIBR XREF_BIBR.	7	29	promotes	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	p300	p300	p300	p53	p53	p53	15	16	28	29
These results suggested that by inducing aggregation , p300 might sequester p53 from proteasomal degradation .	These results suggested that by inducing aggregation, p300 might sequester p53 from proteasomal degradation.	8	12	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300	p300	p53	p53	p53	8	9	11	12
These results suggest that CBP and p300 expression normally suppresses p53 dependent apoptosis in neurons and HCT116 cancer cells .	These results suggest that CBP and p300 expression normally suppresses p53 dependent apoptosis in neurons and HCT116 cancer cells.	4	12	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300 expression	p300	p53	p53	p53	6	7	10	11
Specifically , on one side , p300 might promote p53 degradation via its N-terminal activities , on the other side , the C-terminal region of p300 might lead to p53 stabilization .	Specifically, on one side, p300 might promote p53 degradation via its N-terminal activities, on the other side, the C-terminal region of p300 might lead to p53 stabilization.	6	10	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300	p300	p53	p53	p53	6	7	9	10
Knockdown of p300 prevented UV induction of gamma-H2AX , p53 , and acetyl-H3 ( XREF_FIG ) .	Knockdown of p300 prevented UV induction of gamma-H2AX, p53, and acetyl-H3 (XREF_FIG).	0	10	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p300	p300	p300	p53	p53	p53	2	3	9	10
Together , our work establishes that some beta-HPVs target p300 for destabilization to efficiently reprogram their host cell much like HR-alpha HPVs promote p53 degradation to alter the host cell .	Together, our work establishes that some beta-HPVs target p300 for destabilization to efficiently reprogram their host cell much like HR-alpha HPVs promote p53 degradation to alter the host cell.	6	24	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300	p300	p53	p53	p53	9	10	23	24
The relevance of p53 transcriptional specificity is manifested by the observation that overexpression of p300 or CBP can block the effect of p53 , but the PCAF coactivator does not .	The relevance of p53 transcriptional specificity is manifested by the observation that overexpression of p300 or CBP can block the effect of p53, but the PCAF coactivator does not.	12	23	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	overexpression of p300	p300	p53	p53	p53	14	15	22	23
Through physical interaction with p53 , p300 and CBP can both positively and negatively regulate p53 transactivation , as well as p53 protein turnover depending on cellular context and environmental stimuli , such as DNA damage .	Through physical interaction with p53, p300 and CBP can both positively and negatively regulate p53 transactivation, as well as p53 protein turnover depending on cellular context and environmental stimuli, such as DNA damage.	6	16	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300	p300	p53	p53	p53	6	7	15	16
In contrast to AKT , we did not detect rapid loss of PKA activation after stimulation of EphA2 canonical signaling , based on the lack of effect of ephrin-A1 Fc on CREB S133 phosphorylation as well as EphA2 S897 phosphorylation in PC3 cells treated with forskolin ( XREF_FIG ) .	In contrast to AKT, we did not detect rapid loss of PKA activation after stimulation of EphA2 canonical signaling, based on the lack of effect of ephrin-A1 Fc on CREB S133 phosphorylation as well as EphA2 S897 phosphorylation in PC3 cells treated with forskolin (XREF_FIG).	15	40	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EphA2	EphA2 canonical signaling, based on the lack of effect of ephrin-A1 Fc on CREB S133 phosphorylation as well as EphA2 S897 phosphorylation	epha2	EphA2	EphA2	epha2	17	18	17	18
XREF_BIBR , XREF_BIBR Dephosphorylation of EphA2 may be accelerated in old hCPCs , attenuating EphA2 signaling .	XREF_BIBR, XREF_BIBR Dephosphorylation of EphA2 may be accelerated in old hCPCs, attenuating EphA2 signaling.	3	15	attenuating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EphA2	Dephosphorylation of EphA2	epha2	EphA2	EphA2	epha2	5	6	14	15
XREF_BIBR - XREF_BIBR Ephrin-A1 inhibits proliferation and migration of MPM cells by downregulation of EphA2 expression via binding to the EphA2 receptor on the cell membrane .	XREF_BIBR - XREF_BIBR Ephrin-A1 inhibits proliferation and migration of MPM cells by downregulation of EphA2 expression via binding to the EphA2 receptor on the cell membrane.	4	21	inhibits	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	EphA2	EphA2 expression	epha2	EphA2	EphA2	epha2	14	15	20	21
In this cross-talk , EphA2 phosphorylation by PKA blocks ephrin-A1-induced cell retraction by potentiating EphA2 noncanonical signaling .	In this cross-talk, EphA2 phosphorylation by PKA blocks ephrin-A1-induced cell retraction by potentiating EphA2 noncanonical signaling.	4	16	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EphA2	EphA2 phosphorylation	epha2	EphA2	EphA2	epha2	4	5	14	15
This role is not specific for PERK , because the eIF2alpha kinase PKR also promotes p53 degradation in response to double stranded RNA .	This role is not specific for PERK, because the eIF2alpha kinase PKR also promotes p53 degradation in response to double stranded RNA.	9	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKR	PKR	PKR	p53	p53	p53	12	13	15	16
Recently , we showed that the transfection of PKR siRNA to Abeta42 treated SH-SY5Y cells significantly decreased the p66 isoform of p53 , the transcriptional expression of Redd1 and increased the levels of phosphorylated TSC2 [ XREF_BIBR ] .	Recently, we showed that the transfection of PKR siRNA to Abeta42 treated SH-SY5Y cells significantly decreased the p66 isoform of p53, the transcriptional expression of Redd1 and increased the levels of phosphorylated TSC2 [XREF_BIBR].	8	25	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKR	PKR	PKR	p53	p53	p53	8	9	21	22
Although PKR promotes the proteosomal degradation of p53 through the glycogen synthase kinase 3 XREF_BIBR , if PKR stability protein is also regulated by p53 is still unknown .	Although PKR promotes the proteosomal degradation of p53 through the glycogen synthase kinase 3 XREF_BIBR, if PKR stability protein is also regulated by p53 is still unknown.	1	8	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKR	PKR	PKR	p53	p53	p53	1	2	7	8
Results shown in XREF_FIG indicate that silencing PERK expression clearly inhibited PERK signaling as demonstrated by the reduced phosphorylation of the PERK substrate eIF2alpha and the inhibition of ER stress mediated up-regulation of the transcriptional regulator CHOP .	Results shown in XREF_FIG indicate that silencing PERK expression clearly inhibited PERK signaling as demonstrated by the reduced phosphorylation of the PERK substrate eIF2alpha and the inhibition of ER stress mediated up-regulation of the transcriptional regulator CHOP.	7	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PERK	PERK expression	perk	PERK	PERK	perk	7	8	11	12
In particular , PERK tyrosine phosphorylation in the kinase domain at Y 615 was associated with optimal activation of PERK under ER stress , but our findings reveal that PERK phosphorylation at Y 561 negatively regulates PERK activation .	In particular, PERK tyrosine phosphorylation in the kinase domain at Y 615 was associated with optimal activation of PERK under ER stress, but our findings reveal that PERK phosphorylation at Y 561 negatively regulates PERK activation.	29	37	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PERK	PERK phosphorylation	perk	PERK	PERK	perk	29	30	36	37
Prion infected mice show sustained UPR induction , protracted eIF2alpha phosphorylation and PERK activation leading to repression of translation , synaptic dysfunction and neuronal death [ XREF_BIBR ] , and inhibiting the PERK pathway prevented neurodegeneration [ XREF_BIBR ] .	Prion infected mice show sustained UPR induction, protracted eIF2alpha phosphorylation and PERK activation leading to repression of translation, synaptic dysfunction and neuronal death [XREF_BIBR], and inhibiting the PERK pathway prevented neurodegeneration [XREF_BIBR].	10	33	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PERK	phosphorylation and PERK	perk	PERK	PERK	perk	12	13	32	33
Furthermore , overexpression of the PERK chaperone BiP and GRP78 blocked mda-7 and IL-24-induced PERK activation and cell killing .	Furthermore, overexpression of the PERK chaperone BiP and GRP78 blocked mda-7 and IL-24-induced PERK activation and cell killing.	2	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PERK	overexpression of the PERK	perk	PERK	PERK	perk	5	6	14	15
Kal7 or EphB2 expression was reduced with shRNA sequences targeting mouse Kal7 or EphB2 under the U6 promoter .	Kal7 or EphB2 expression was reduced with shRNA sequences targeting mouse Kal7 or EphB2 under the U6 promoter.	0	14	targeting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EphB2	EphB2 expression	ephb2	EphB2	EphB2	ephb2	2	3	13	14
Overexpression of EphB2 in hippocampus rescues the decreased total and surface expression of EphB2 , as well as the GluN2B containing NMDA receptors trafficking in APP and PS1 transgenic mice .	Overexpression of EphB2 in hippocampus rescues the decreased total and surface expression of EphB2, as well as the GluN2B containing NMDA receptors trafficking in APP and PS1 transgenic mice.	0	14	rescues	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EphB2	Overexpression of EphB2	ephb2	EphB2	EphB2	ephb2	2	3	13	14
am potently inhibits ephrin induced EphA4 activation in cells and EphA4 dependent neuronal growth cone collapse , while retaining high selectivity for EphA4 .	am potently inhibits ephrin induced EphA4 activation in cells and EphA4 dependent neuronal growth cone collapse, while retaining high selectivity for EphA4.	3	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	EphA4	ephrin induced EphA4	epha4	EphA4	EphA4	epha4	5	6	10	11
Importantly , coexpression of EphA4 and DN blocked ephrin B1 stimulated EphA4 activation ( XREF_FIG , right panel ) .	Importantly, coexpression of EphA4 and DN blocked ephrin B1 stimulated EphA4 activation (XREF_FIG, right panel).	2	12	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EphA4	coexpression of EphA4	epha4	EphA4	EphA4	epha4	4	5	11	12
The Src inhibition is likely to result from both direct inhibition by CTA095 , as well as the diminished activity Etk , which activates Src .	The Src inhibition is likely to result from both direct inhibition by CTA095, as well as the diminished activity Etk, which activates Src.	6	25	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Etk	Etk	Etk	Src	Src	Src	20	21	24	25
Overexpression of p300 decreased the half-life of MAML1 to 2 hours compared to 2.5 hours for MAML1 alone ( XREF_FIG ) and this change was significant ( p = 0.025 ) as determined by a student ' s t-test .	Overexpression of p300 decreased the half-life of MAML1 to 2 hours compared to 2.5 hours for MAML1 alone (XREF_FIG) and this change was significant (p = 0.025) as determined by a student 's t-test.	0	8	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	Overexpression of p300	p300	MAML1	MAML1	maml1	2	3	7	8
As expected , pretreatment of EphB2 + cells with two different Src inhibitors , PP2 and SU6656 , before activation of Eph forward signaling prevented Src activation ( XREF_FIG , extract ) .	As expected, pretreatment of EphB2 + cells with two different Src inhibitors, PP2 and SU6656, before activation of Eph forward signaling prevented Src activation (XREF_FIG, extract).	3	26	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EphB2	EphB2	EphB2	Src	Src	Src	5	6	25	26
The EphB2 receptor was reported to inhibit cell-matrix adhesion by phosphorylating tyrosine 66 in the effector domain of R-Ras , a Ras family protein known to regulate cell adhesion and motility .	The EphB2 receptor was reported to inhibit cell-matrix adhesion by phosphorylating tyrosine 66 in the effector domain of R-Ras, a Ras family protein known to regulate cell adhesion and motility.	1	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EphB2	EphB2	EphB2	R-Ras	R-Ras	R-Ras	1	2	18	19
As expected , EphA8 level significantly increased by depletion of RINL ( XREF_FIG ) , consistent with the ability of RINL to stimulate the degradation of EphA8 .	As expected, EphA8 level significantly increased by depletion of RINL (XREF_FIG), consistent with the ability of RINL to stimulate the degradation of EphA8.	3	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EphA8	EphA8 level	epha8	EphA8	EphA8	epha8	3	4	26	27
Therefore , we predicted that addition of excess p300 might be sufficient to rescue the NFATc1 mediated inhibition of MyoD .	Therefore, we predicted that addition of excess p300 might be sufficient to rescue the NFATc1 mediated inhibition of MyoD.	5	20	rescue	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p300	p300	p300	MyoD	MyoD	MyoD	8	9	19	20
On the basis that gene expression is known to be altered in multiple models of heart failure , we examined differential gene expression of iPSC derived cardiomyocytes treated at day 11 with the ERBB2 targeted monoclonal antibody , trastuzumab for 48h and the small molecule tyrosine kinase inhibitor of EGFR and ERBB2 .	On the basis that gene expression is known to be altered in multiple models of heart failure, we examined differential gene expression of iPSC derived cardiomyocytes treated at day 11 with the ERBB2 targeted monoclonal antibody, trastuzumab for 48h and the small molecule tyrosine kinase inhibitor of EGFR and ERBB2.	27	51	targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERBB2	ERBB2	ERBB2	EGFR	EGFR	EGFR	33	34	49	50
CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor ( EGFR ) , human growth factor receptor 2 ( HER2 ) , and histone deacetylase ( HDAC ) with preclinical activity in head and neck squamous cell cancer ( HNSCC ) .	CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC).	4	24	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	23	24	9	13
Tyrosine kinase inhibitors ( TKIs ) , such as erlotinib , gefitinib , and lapatinib , that target EGFR and or HER2 have been investigated in clinical studies of SCCHN but have not demonstrated a survival advantage in randomized trials XREF_BIBR , XREF_BIBR , XREF_BIBR .	Tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and lapatinib, that target EGFR and or HER2 have been investigated in clinical studies of SCCHN but have not demonstrated a survival advantage in randomized trials XREF_BIBR, XREF_BIBR, XREF_BIBR.	2	22	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	21	22	18	19
Lapatinib , or N-[ 3-chloro-4-[ ( 3-fluorophenyl ) methoxy ] phenyl ]-6-[ 5-[ ( 2methylsulfonylethylamino ) methyl ]-2-furyl ] quinazolin-4-amine , is a dual tyrosine kinase inhibitor ( TKI ) targeting both the epidermal growth factor receptor ( EGFR ) and the human epidermal growth factor receptor-2 ( HER-2 , c-erbB2 , c-neu ) .	Lapatinib, or N-[3-chloro-4-[(3-fluorophenyl) methoxy] phenyl]-6-[5-[(2methylsulfonylethylamino) methyl]-2-furyl] quinazolin-4-amine, is a dual tyrosine kinase inhibitor (TKI) targeting both the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2, c-erbB2, c-neu).	30	52	targeting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HER-2	HER-2	HER-2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	48	49	33	37
Similar findings were observed in HepG2 cells treated with PD168393 , an ErbB1 Tyr kinase inhibitor , or in Fao cells treated with the ErbB2 kinase inhibitor AG825 .	Similar findings were observed in HepG2 cells treated with PD168393, an ErbB1 Tyr kinase inhibitor, or in Fao cells treated with the ErbB2 kinase inhibitor AG825.	12	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	ErbB1	ErbB1	ErbB1	24	25	12	13
Three examples of inhibitors of protein kinases are reviewed , including low-molecular weight compounds targeting the cell cycle kinases ; a potent and selective inhibitor of the HER1 and HER2 receptor tyrosine kinase , the pyrollopyrimidine PKI166 ; and the 2-phenyl-aminopyrimidine STI571 ( Glivec ( R ) , Gleevec ) a targeted drug therapy directed toward Bcr-Abl , the key player in chronic leukemia ( CML ) .	Three examples of inhibitors of protein kinases are reviewed, including low-molecular weight compounds targeting the cell cycle kinases; a potent and selective inhibitor of the HER1 and HER2 receptor tyrosine kinase, the pyrollopyrimidine PKI166; and the 2-phenyl-aminopyrimidine STI571 (Glivec (R), Gleevec) a targeted drug therapy directed toward Bcr-Abl, the key player in chronic leukemia (CML).	24	32	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	HER2	HER2	HER2	HER1	HER1	HER1	29	30	27	28
In some cases , it has been demonstrated that ErbB2 prevented CME of EGFR [ XREF_BIBR , XREF_BIBR ] .	In some cases, it has been demonstrated that ErbB2 prevented CME of EGFR [XREF_BIBR, XREF_BIBR].	9	17	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	9	10	13	14
To further study whether HER2 T701 phosphorylation plays a role in feedback negatively regulating EGFR and HER2 kinase activity , we pretreated SkBr3 cells with MEK inhibitors followed by EGF stimulation .	To further study whether HER2 T701 phosphorylation plays a role in feedback negatively regulating EGFR and HER2 kinase activity, we pretreated SkBr3 cells with MEK inhibitors followed by EGF stimulation.	4	18	negatively regulating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2 T701 phosphorylation	her2	EGFR	EGFR	egfr	4	5	14	15
Literature shows that HER2 and neu positive breast cancer cells are more sensitive to radiation induced apoptosis by targeting the epidermal growth factor receptor family tyrosine kinase .	Literature shows that HER2 and neu positive breast cancer cells are more sensitive to radiation induced apoptosis by targeting the epidermal growth factor receptor family tyrosine kinase.	3	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	neu	neu	neu	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	5	6	20	24
We have selectively targeted the EGFr in human glioblastoma cells with kinase deficient mutants of the erbB family derived from the ectodomain of the Neu oncogene that are able to form heterodimers with EGFr and inhibit EGFr dependent phenotypes .	We have selectively targeted the EGFr in human glioblastoma cells with kinase deficient mutants of the erbB family derived from the ectodomain of the Neu oncogene that are able to form heterodimers with EGFr and inhibit EGFr dependent phenotypes.	24	38	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Neu	Neu	Neu	EGFr	EGFr	EGFr	24	25	36	37
These results provide the first evidence that kinase deficient Neu proteins suppress normal EGFR function and display a dominant negative mutant phenotype .	These results provide the first evidence that kinase deficient Neu proteins suppress normal EGFR function and display a dominant negative mutant phenotype.	9	14	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Neu	Neu	Neu	EGFR	EGFR	EGFR	9	10	13	14
We examined SIRPalpha1 regulation in U87MG and U373MG cells in comparison with clonal derivatives that express a truncated form of erbB2 , which negatively regulates EGFR signaling by inducing the formation of nonfunctional heterodimeric complexes .	We examined SIRPalpha1 regulation in U87MG and U373MG cells in comparison with clonal derivatives that express a truncated form of erbB2, which negatively regulates EGFR signaling by inducing the formation of nonfunctional heterodimeric complexes.	18	26	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	erbB2	erbB2	erbB2	EGFR	EGFR	EGFR	20	21	25	26
Ultimately , the question remains as to whether dual EGFR and ERBB2 inhibition will itself be limited by de novo or induced upregulation of the remaining ERBB receptors .	Ultimately, the question remains as to whether dual EGFR and ERBB2 inhibition will itself be limited by de novo or induced upregulation of the remaining ERBB receptors.	11	27	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERBB2	ERBB2	ERBB2	ERBB	ERBB	ERBB	11	12	26	27
However , recent literature suggested that HER2 overexpression and heterodimerization slows down EGFR internalization and degradation [ XREF_BIBR - XREF_BIBR ] .	However, recent literature suggested that HER2 overexpression and heterodimerization slows down EGFR internalization and degradation [XREF_BIBR - XREF_BIBR].	6	13	slows	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2 overexpression	her2	EGFR	EGFR	egfr	6	7	12	13
The HER2 specific TKI tucatinib ( ONT-380 ) does not block EGFR and thus may have more favorable side effects [ XREF_BIBR ] ; whether this drug blocks mutant HER2 has not yet been tested .	The HER2 specific TKI tucatinib (ONT-380) does not block EGFR and thus may have more favorable side effects [XREF_BIBR]; whether this drug blocks mutant HER2 has not yet been tested.	1	12	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	1	2	11	12
In this respect we also find anti-correlated changes of the paralogous receptors EGFR and ErbB2 , which slow down EGFR recycling through heterodimer formation [ XREF_BIBR ] .	In this respect we also find anti-correlated changes of the paralogous receptors EGFR and ErbB2, which slow down EGFR recycling through heterodimer formation [XREF_BIBR].	7	20	slow	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	14	15	19	20
Reduced HER3 degradation following TAb6 or PAb6 treatment is consistent with the inhibitory effects of HER2 expression on the internalization of ligand activated EGFR or HER3 .	Reduced HER3 degradation following TAb6 or PAb6 treatment is consistent with the inhibitory effects of HER2 expression on the internalization of ligand activated EGFR or HER3.	15	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2 expression	her2	EGFR	EGFR	egfr	15	16	23	24
Concomitant treatment of L and PLD showed additive effects in HER2 positive BC cell lines , and a potential synergy in other EGFR positive , HER2 negative cell lines .	Concomitant treatment of L and PLD showed additive effects in HER2 positive BC cell lines, and a potential synergy in other EGFR positive, HER2 negative cell lines.	19	28	synergy	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	25	26	22	23
Examples of this include the use of v-erb-b2 erythroblastic leukaemia viral oncogene homolog 2 ( HER2 ) blocking antibodies in breast cancer , epidermal growth factor receptor ( EGFR ) and anaplastic lymphoma kinase ( ALK ) inhibitor in lung cancer [ XREF_BIBR , XREF_BIBR ] , specific v-raf murine sarcoma viral oncogene homolog B1 ( BRAF ) inhibitors in melanoma [ XREF_BIBR ] , and selection of EGFR blocking antibodies for the treatments of v-Ki-ras Kirsten rat sarcoma viral oncogene homolog ( KRAS ) wild-type colon cancers [ XREF_BIBR ] .	Examples of this include the use of v-erb-b2 erythroblastic leukaemia viral oncogene homolog 2 (HER2) blocking antibodies in breast cancer, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitor in lung cancer [XREF_BIBR, XREF_BIBR], specific v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors in melanoma [XREF_BIBR], and selection of EGFR blocking antibodies for the treatments of v-Ki-ras Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type colon cancers [XREF_BIBR].	9	27	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	15	16	23	27
This notion is consistent with the observations from previous studies that ErbB2 expression prevents EGFR from being recruited to CCPs .	This notion is consistent with the observations from previous studies that ErbB2 expression prevents EGFR from being recruited to CCPs.	11	15	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2 expression	erbb2	EGFR	EGFR	egfr	11	12	14	15
In other cells , ErbB2 did not slow down EGFR internalization but re-routed internalized EGFR from the degradation to the recycling pathway [ XREF_BIBR ] .	In other cells, ErbB2 did not slow down EGFR internalization but re-routed internalized EGFR from the degradation to the recycling pathway [XREF_BIBR].	4	10	slow	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	4	5	9	10
Afatinib is a TKI that irreversibly inhibits EGFR ( including EGFR vIII ) , HER2 and HER4 kinases .	Afatinib is a TKI that irreversibly inhibits EGFR (including EGFR vIII), HER2 and HER4 kinases.	6	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	14	15	7	8
A subset of ERalpha negative cancers are characterized by amplification or overexpression of human epidermal growth factor receptor 2 ( HER2 ) and can be treated with HER2 targeting agents .	A subset of ERalpha negative cancers are characterized by amplification or overexpression of human epidermal growth factor receptor 2 (HER2) and can be treated with HER2 targeting agents.	14	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	HER2	HER2	HER2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	27	28	14	18
Peptides modeled on disulfide bonded modules of domain IV of EGFR and HER2 can disrupt EGFR dimerization .	Peptides modeled on disulfide bonded modules of domain IV of EGFR and HER2 can disrupt EGFR dimerization.	12	16	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	12	13	15	16
Remarkably , in addition to being itself endocytosis deficient , ErbB2 also prevents internalization of EGFR upon heterodimerization [ XREF_BIBR ] .	Remarkably, in addition to being itself endocytosis deficient, ErbB2 also prevents internalization of EGFR upon heterodimerization [XREF_BIBR].	10	16	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	10	11	15	16
Significantly , down-regulation of activated EGFR was also inhibited by erbB-2 amplification , resulting in enhanced ligand dependent activation of the EGFR .	Significantly, down-regulation of activated EGFR was also inhibited by erbB-2 amplification, resulting in enhanced ligand dependent activation of the EGFR.	8	22	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	erbB-2	erbB-2	erbB-2	EGFR	EGFR	EGFR	10	11	21	22
23 Since HER2 can sequester EGFR at the plasma membrane , XREF_BIBR , XREF_BIBR the possibility exists for SHP2 to be sequestered with EGFR in these cells as well .	23 Since HER2 can sequester EGFR at the plasma membrane, XREF_BIBR, XREF_BIBR the possibility exists for SHP2 to be sequestered with EGFR in these cells as well.	2	6	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	2	3	5	6
HER2 over-expression down-regulates HER1 and EGFR associated downstream pathways [ XREF_BIBR ] .	HER2 over-expression down-regulates HER1 and EGFR associated downstream pathways [XREF_BIBR].	0	6	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2 over-expression	her2	EGFR	EGFR	egfr	0	1	5	6
One line of evidence suggests that HER2 blocks ligand induced internalization [ XREF_BIBR ] , while another proposes that HER2 does not block ligand induced EGFR internalization [ XREF_BIBR ] .	One line of evidence suggests that HER2 blocks ligand induced internalization [XREF_BIBR], while another proposes that HER2 does not block ligand induced EGFR internalization [XREF_BIBR].	19	26	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	19	20	25	26
Interestingly , ErbB2 coexpression was shown to inhibit downregulation of activated ErbB1 by increasing its rate of recycling [ XREF_BIBR , XREF_BIBR ] .	Interestingly, ErbB2 coexpression was shown to inhibit downregulation of activated ErbB1 by increasing its rate of recycling [XREF_BIBR, XREF_BIBR].	2	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2 coexpression	erbb2	ErbB1	ErbB1	erbb1	2	3	11	12
By constructing stably transfected cells harboring the same amount of epidermal growth factor ( EGF ) receptor ( EGFR ) , but with increasing overexpression of ErbB2 , we have demonstrated that ErbB2 efficiently inhibits internalization of ligand bound EGFR .	By constructing stably transfected cells harboring the same amount of epidermal growth factor (EGF) receptor (EGFR), but with increasing overexpression of ErbB2, we have demonstrated that ErbB2 efficiently inhibits internalization of ligand bound EGFR.	32	40	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	32	33	39	40
We conclude that ErbB2 expression impairs EGFR downregulation via a posttranscriptional mechanism and propose that ErbB2 overexpression may sensitize tumor cells to the mitogenic effects of heterologous growth factors by retarding degradation of liganded heterodimers .	We conclude that ErbB2 expression impairs EGFR downregulation via a posttranscriptional mechanism and propose that ErbB2 overexpression may sensitize tumor cells to the mitogenic effects of heterologous growth factors by retarding degradation of liganded heterodimers.	3	7	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2 expression	erbb2	EGFR	EGFR	egfr	3	4	6	7
Tumours from bitransgenic mice overexpress the myr-Akt1 and ErbB2 transgenes , but there was dramatically less overexpression and phosphorylation of ErbB3 , diminished phosphorylation of ErbB2 , decreased level of EGFR protein and undetectable ErbB4 protein .	Tumours from bitransgenic mice overexpress the myr-Akt1 and ErbB2 transgenes, but there was dramatically less overexpression and phosphorylation of ErbB3, diminished phosphorylation of ErbB2, decreased level of EGFR protein and undetectable ErbB4 protein.	16	31	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	overexpression and phosphorylation of ErbB3, diminished phosphorylation of ErbB2	erbb2	EGFR	EGFR	egfr	25	26	30	31
One view proposes that HER2 impairs endocytosis by sequestering EGFR at endocytosis-incompetent sites of the plasma membrane ( non-clathrin-coated pits ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , while the other view suggests that HER2 does not interfere with ligand induced internalization [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	One view proposes that HER2 impairs endocytosis by sequestering EGFR at endocytosis-incompetent sites of the plasma membrane (non-clathrin-coated pits) [XREF_BIBR, XREF_BIBR, XREF_BIBR], while the other view suggests that HER2 does not interfere with ligand induced internalization [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	10	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	4	5	9	10
Overexpression of herstatin , a soluble ErbB2 receptor that acts in a dominant negative fashion to inhibit EGFR signaling , under the limb specific Prx1 promoter in mice resulted in shortened limbs and an expanded hypertrophic zone .	Overexpression of herstatin, a soluble ErbB2 receptor that acts in a dominant negative fashion to inhibit EGFR signaling, under the limb specific Prx1 promoter in mice resulted in shortened limbs and an expanded hypertrophic zone.	6	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	6	7	17	18
There are several clinical studies that are underway targeting other pathways of EGFR resistance including HER2 and ERBB2 amplifications or mutations , MET amplifications , and , notch dysregulation in NSCLC patients .	There are several clinical studies that are underway targeting other pathways of EGFR resistance including HER2 and ERBB2 amplifications or mutations, MET amplifications, and, notch dysregulation in NSCLC patients.	12	18	resistance	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	ERBB2	ERBB2	ERBB2	EGFR	EGFR	EGFR	17	18	12	13
ErbB2 negative breast cancer cells , such as MCF7 and T47D , do not invade following treatment with IR nor do MCF10A cells overexpressing epidermal growth factor receptor .	ErbB2 negative breast cancer cells, such as MCF7 and T47D, do not invade following treatment with IR nor do MCF10A cells overexpressing epidermal growth factor receptor.	0	28	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	24	28
In contrast , ErbB2 dependent impairment of EGFR downregulation both prolongs and intensifies growth factor signalling ( Huang et al , 1999 ) , an outcome associated with the increased apoptosis reported here .	In contrast, ErbB2 dependent impairment of EGFR downregulation both prolongs and intensifies growth factor signalling (Huang et al, 1999), an outcome associated with the increased apoptosis reported here.	3	8	impairment	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	3	4	7	8
Three other HER2 targeted agents have also been approved for the treatment of HER2 positive metastatic breast cancer ( MBC ) : lapatinib , a dual tyrosine kinase inhibitor of HER1 ( EGFR ) and HER2 ; pertuzumab , a humanized mAb targeting the heterodimerization domain ( subdomain II ) of HER2 ; and trastuzumab emtansine ( T-DM1 ) , an antibody-drug conjugate composed of trastuzumab conjugated to the cytotoxic agent DM1 via a stable thioether linker .	Three other HER2 targeted agents have also been approved for the treatment of HER2 positive metastatic breast cancer (MBC) : lapatinib, a dual tyrosine kinase inhibitor of HER1 (EGFR) and HER2; pertuzumab, a humanized mAb targeting the heterodimerization domain (subdomain II) of HER2; and trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of trastuzumab conjugated to the cytotoxic agent DM1 via a stable thioether linker.	0	66	targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER1	HER1	HER1	2	3	30	31
Importantly , intravenous injection of scFv-9R , HER2 , and siRNA complex markedly suppressed growth of EGFR positive NSCLC xenograft in nude mice , resulting from downregulated HER2 expression , reduced cell proliferation and enhanced cell apoptosis .	Importantly, intravenous injection of scFv-9R, HER2, and siRNA complex markedly suppressed growth of EGFR positive NSCLC xenograft in nude mice, resulting from downregulated HER2 expression, reduced cell proliferation and enhanced cell apoptosis.	3	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	7	8	16	17
The antagonists also decreased the protein levels for EGFR by 21-34 % , HER-2 by 36-68 % and HER-3 by 43-49 % .	The antagonists also decreased the protein levels for EGFR by 21-34%, HER-2 by 36-68% and HER-3 by 43-49%.	3	16	decreased	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	HER-2	HER-2	HER-2	EGFR	EGFR	EGFR	13	14	8	9
HER2 overexpression may also prevent EGFR internalization by clathrin dependent endocytosis , and it ' s re-directed from the degradation to the recycling pathway [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	HER2 overexpression may also prevent EGFR internalization by clathrin dependent endocytosis, and it 's re-directed from the degradation to the recycling pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	6	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2 overexpression	her2	EGFR	EGFR	egfr	0	1	5	6
Mechanisms to TKI resistance include the development of a recurrent T790M EGFR mutation , amplification of signalling molecules that bypass EGFR inhibition ( such as MET and HER2 ) , mutations in other oncogenic drivers ( eg , PIK3CA and B-RAF ) and conversion to small-cell lung cancer ( SCLC ) .	Mechanisms to TKI resistance include the development of a recurrent T790M EGFR mutation, amplification of signalling molecules that bypass EGFR inhibition (such as MET and HER2), mutations in other oncogenic drivers (eg, PIK3CA and B-RAF) and conversion to small-cell lung cancer (SCLC).	20	28	inhibition	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	27	28	20	21
Inhibiting ErbB2 caused an enhanced MAPK response simulating an amplified ErbB1 ( or 4 ) response .	Inhibiting ErbB2 caused an enhanced MAPK response simulating an amplified ErbB1 (or 4) response.	0	15	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	ErbB1	ErbB1	ErbB1	1	2	10	11
XREF_BIBR This study showed that compound 8 induces apoptosis in HER2 overexpressing breast cancer cells that are either naive or refractory to trastuzumab ; in addition to blocking HER2 and EGFR signaling , 8 reduced IGF1R signaling in HER2 overexpressing breast cancer cells , and co-treatment with an IGF1R targeted antibody increased 8 mediated growth inhibition yet further .	XREF_BIBR This study showed that compound 8 induces apoptosis in HER2 overexpressing breast cancer cells that are either naive or refractory to trastuzumab; in addition to blocking HER2 and EGFR signaling, 8 reduced IGF1R signaling in HER2 overexpressing breast cancer cells, and co-treatment with an IGF1R targeted antibody increased 8 mediated growth inhibition yet further.	8	31	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	EGFR	EGFR	EGFR	10	11	30	31
Since ErbB2 inhibits endocytic down-regulation of EGFR , EGFR-ErbB2 heterodimers accumulate at the plasma membrane .	Since ErbB2 inhibits endocytic down-regulation of EGFR, EGFR-ErbB2 heterodimers accumulate at the plasma membrane.	1	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	EGFR	EGFR	EGFR	1	2	6	7
Inhibition of HER RTKs by HER pan-inhibitor CI-1033 notably enhances the radiosensitivity of human colon carcinoma cells both in vitro and in vivo , while HER1 inhibition by gefitinib and HER2 inhibition by herceptin , respectively , radiosensitizes EGFR amplified glioma cells and breast cancer cells .	Inhibition of HER RTKs by HER pan-inhibitor CI-1033 notably enhances the radiosensitivity of human colon carcinoma cells both in vitro and in vivo, while HER1 inhibition by gefitinib and HER2 inhibition by herceptin, respectively, radiosensitizes EGFR amplified glioma cells and breast cancer cells.	25	31	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Positive_activation	HER2	HER2	HER2	HER1	HER1	HER1	30	31	25	26
Activation of DeltaCRAF : ER did not prevent the Tm induced expression of CHOP ( XREF_FIG ) indicating that ERK1/2 signalling did not reduce ER stress or inhibit UPR signalling .	Activation of DeltaCRAF : ER did not prevent the Tm induced expression of CHOP (XREF_FIG) indicating that ERK1/2 signalling did not reduce ER stress or inhibit UPR signalling.	19	25	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	19	20	24	25
An exception to this relationship is that hyperactivation of MAPK does not lead to re-expression of ERalpha in SUM-102 and SUM-159 , two ER negative basal typebreast cancer cell lines that are found to exhibit hypermethylation of the ESR1 promoter suggesting that additional mechanisms may operate to repress ERalpha expression in these cell lines [ XREF_BIBR ] .	An exception to this relationship is that hyperactivation of MAPK does not lead to re-expression of ERalpha in SUM-102 and SUM-159, two ER negative basal typebreast cancer cell lines that are found to exhibit hypermethylation of the ESR1 promoter suggesting that additional mechanisms may operate to repress ERalpha expression in these cell lines [XREF_BIBR].	7	39	lead	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	MAPK	MAPK	mapk	ER	ER negative basal typebreast cancer cell lines that are found to exhibit hypermethylation of the ESR1	er	9	10	23	24
Sorafenib induced UPR is unrelated to MAPK inhibition because ERK repression can not stimulate ER stress .	Sorafenib induced UPR is unrelated to MAPK inhibition because ERK repression can not stimulate ER stress.	9	15	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	ER	ER	ER	9	10	14	15
Activation of ERK1/2 is associated with protection against apoptosis , and is required specifically to suppress the ER stress response .	Activation of ERK1/2 is associated with protection against apoptosis, and is required specifically to suppress the ER stress response.	0	19	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	2	3	17	18
Using dominant negative constructs , they show that hyperactivated ERK1/2 MAPK downregulate ERalpha via a common substrate .	Using dominant negative constructs, they show that hyperactivated ERK1/2 MAPK downregulate ERalpha via a common substrate.	9	16	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2 MAPK	ERK1/2 MAPK	ERK1/2 MAPK	ERalpha	ERalpha	ERalpha	9	11	12	13
Although both of the receptors stimulate downstream EGF signaling , the receptor specific signatures revealed that the MAPK pathway is activated by either EGFR or HER2 , rather than both , and that EGFR is the main driver of MAPK signaling in ER negative breast cancers .	Although both of the receptors stimulate downstream EGF signaling, the receptor specific signatures revealed that the MAPK pathway is activated by either EGFR or HER2, rather than both, and that EGFR is the main driver of MAPK signaling in ER negative breast cancers.	39	45	signaling	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ER	ER	ER	39	40	42	43
Hyperactivation of MAPK results in the down-regulation of ER expression and inhibition of this hyperactive MAPK results in restoration of functional ER protein .	Hyperactivation of MAPK results in the down-regulation of ER expression and inhibition of this hyperactive MAPK results in restoration of functional ER protein.	11	22	results in restoration	Positive_activation_syntax_8_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ER	ER	ER	15	16	21	22
CAFs secreted miRNAs may contribute to MAPK induced ER repression to drive the ER negative phenotype in breast cancer cells .	CAFs secreted miRNAs may contribute to MAPK induced ER repression to drive the ER negative phenotype in breast cancer cells.	4	9	induced	Positive_early_activation	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ER	ER	ER	6	7	8	9
Extending these studies , Holloway and colleagues have now begun to decipher the mechanism of MAPK mediated ERalpha loss in these various transfected models .	Extending these studies, Holloway and colleagues have now begun to decipher the mechanism of MAPK mediated ERalpha loss in these various transfected models.	13	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	15	16	17	18
These results suggest that activated MAPK signaling cascade attenuates antagonist induced recruitment of SMRT to ERalpha , suggesting corepressor mediates inhibition of ERalpha transactivation and breast cancer cell growth by antagonist .	These results suggest that activated MAPK signaling cascade attenuates antagonist induced recruitment of SMRT to ERalpha, suggesting corepressor mediates inhibition of ERalpha transactivation and breast cancer cell growth by antagonist.	5	23	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	5	6	22	23
HepG2 cells were pretreated with the potent MEK inhibitor , PD184352 , which prevents ERK1/2 phosphorylation ( activation ) , followed by treatment with tunicamycin to induce ER stress .	HepG2 cells were pretreated with the potent MEK inhibitor, PD184352, which prevents ERK1/2 phosphorylation (activation), followed by treatment with tunicamycin to induce ER stress.	7	28	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	MEK inhibitor, PD184352, which prevents ERK1/2 phosphorylation	erk1/2	ER	ER	er	14	15	27	28
Hence , we reasonably assumed that the observed GI transcriptional downregulation could be consequent to the ROS induced Erk1/2 mediated downregulation of ERalpha .	Hence, we reasonably assumed that the observed GI transcriptional downregulation could be consequent to the ROS induced Erk1/2 mediated downregulation of ERalpha.	16	23	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Erk1/2	ROS induced Erk1/2	erk1/2	ERalpha	ERalpha	eralpha	18	19	22	23
Since MAPK is the downstream molecule of these growth factor signalling pathways , inhibition of this hyperactive MAPK restores ERalpha and acquired anti-oestrogen response [ XREF_BIBR , XREF_BIBR ] .	Since MAPK is the downstream molecule of these growth factor signalling pathways, inhibition of this hyperactive MAPK restores ERalpha and acquired anti-oestrogen response [XREF_BIBR, XREF_BIBR].	13	20	restores	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ERalpha	ERalpha	ERalpha	17	18	19	20
To test whether ERK and P65 activator also inhibits growth of ER + / CCKBR - / ERK - / P65 - BC cells , MFC-7 and T-47D cells were treated with the activators and the inhibitors of ERK and P65 , respectively .	To test whether ERK and P65 activator also inhibits growth of ER + / CCKBR - / ERK - / P65 - BC cells, MFC-7 and T-47D cells were treated with the activators and the inhibitors of ERK and P65, respectively.	3	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	ER	ER	ER	3	4	11	12
In ER positive BC cells that have developed endocrine resistance , ER expression may be suppressed directly by enhanced peptide growth factor receptor signaling that is due to overexpression of the type I growth factor receptors , such as EGFR and HER2 , with subsequent downstream MAPK activation that inhibits ER transcriptional expression XREF_BIBR .	In ER positive BC cells that have developed endocrine resistance, ER expression may be suppressed directly by enhanced peptide growth factor receptor signaling that is due to overexpression of the type I growth factor receptors, such as EGFR and HER2, with subsequent downstream MAPK activation that inhibits ER transcriptional expression XREF_BIBR.	46	53	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ER	ER	ER	46	47	50	51
Taken together , our results suggest that H 2 S plays a protective role in IVDD and the underlying mechanism involves PI3K and Akt and ERK1/2 signaling pathways mediated suppression of ER stress and mitochondrial dysfunction in IL-1beta-induced NP cells .	Taken together, our results suggest that H 2 S plays a protective role in IVDD and the underlying mechanism involves PI3K and Akt and ERK1/2 signaling pathways mediated suppression of ER stress and mitochondrial dysfunction in IL-1beta-induced NP cells.	25	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	25	26	31	32
These findings indicate that activation of TrkB receptor mediated ERK1/2 by PYP attenuates glutamate induced ER stress , which may improve the survival of hippocampal neurons with age .	These findings indicate that activation of TrkB receptor mediated ERK1/2 by PYP attenuates glutamate induced ER stress, which may improve the survival of hippocampal neurons with age.	6	16	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	TrkB receptor mediated ERK1/2	erk1/2	ER	ER	er	9	10	15	16
In addition , this ERK1/2 phosphorylation was inhibited by ICI 182,780 , again suggesting involvement of the ER ( XREF_FIG ) .	In addition, this ERK1/2 phosphorylation was inhibited by ICI 182,780, again suggesting involvement of the ER (XREF_FIG).	4	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2 phosphorylation	erk1/2	ER	ER	er	4	5	17	18
Pharmacological or genetic inhibition of ERK1/2 promoted ER stress induced apoptosis XREF_BIBR .	Pharmacological or genetic inhibition of ERK1/2 promoted ER stress induced apoptosis XREF_BIBR.	3	8	promoted	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	ER	ER	ER	5	6	7	8
Collectively , our results demonstrate that CAF secreted microRNAs are directly involved in ER-repression , and may contribute to the MAPK induced ER repression in breast cancer cells .	Collectively, our results demonstrate that CAF secreted microRNAs are directly involved in ER-repression, and may contribute to the MAPK induced ER repression in breast cancer cells.	17	23	induced	Positive_early_activation	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ER	ER	ER	20	21	22	23
In turn , activation of MAPK and PI3K pathways by growth factor receptors downregulates estrogen receptor signaling .	In turn, activation of MAPK and PI3K pathways by growth factor receptors downregulates estrogen receptor signaling.	5	16	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	estrogen receptor	estrogen receptor	estrogen receptor	5	6	14	16
Likewise , hyperactive p44/42 MAPK signaling has been shown to downregulate ER at both mRNA and protein levels , via mechanisms involving epigenomic proteins and NF-kappaB .	Likewise, hyperactive p44/42 MAPK signaling has been shown to downregulate ER at both mRNA and protein levels, via mechanisms involving epigenomic proteins and NF-kappaB.	4	12	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ER	ER	ER	4	5	11	12
In contrast , transfection of activated MAPK kinase , an immediate upstream activator of MAPK ( ERK 1 and 2 ) into MCF-7 cells leads to phosphorylation of Ser118 in the AF-1 domain of ERalpha , inhibition of ER amplified in breast cancer 1 ( ER : AIB1 ) interaction in the presence of Tam , and maintenance of sensitivity to tamoxifen .	In contrast, transfection of activated MAPK kinase, an immediate upstream activator of MAPK (ERK 1 and 2) into MCF-7 cells leads to phosphorylation of Ser118 in the AF-1 domain of ERalpha, inhibition of ER amplified in breast cancer 1 (ER : AIB1) interaction in the presence of Tam, and maintenance of sensitivity to tamoxifen.	12	39	leads	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ER	ER	ER	14	15	38	39
Both compounds did not activate the classical ER in MCF7 cells , whereas one of the two compounds synthesized triggered through GPER the rapid ERK activation in ER negative SkBr3 cells , demonstrating a good affinity for GPER in docking studies .	Both compounds did not activate the classical ER in MCF7 cells, whereas one of the two compounds synthesized triggered through GPER the rapid ERK activation in ER negative SkBr3 cells, demonstrating a good affinity for GPER in docking studies.	24	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	ERK	ERK	ERK	ER	ER	ER	24	25	27	28
Abrogation of ERK ( extracellular signal regulated kinase ) activity with the use of either pharmacologic inhibitors or dominant negative ERK constructs reverses the downregulation of ERalpha and restores its activity [ XREF_BIBR ] .	Abrogation of ERK (extracellular signal regulated kinase) activity with the use of either pharmacologic inhibitors or dominant negative ERK constructs reverses the downregulation of ERalpha and restores its activity [XREF_BIBR].	0	27	reverses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	ERalpha	ERalpha	ERalpha	2	3	26	27
Treatment of ERalpha (-) tumor specimens with MAPK inhibitors results in restoration of ERalpha mRNA , and similarly in epithelial cultures from ERalpha (-) tumors , MAPK inhibition restores both ERalpha protein and antiestrogen response .	Treatment of ERalpha (-) tumor specimens with MAPK inhibitors results in restoration of ERalpha mRNA, and similarly in epithelial cultures from ERalpha (-) tumors, MAPK inhibition restores both ERalpha protein and antiestrogen response.	26	32	restores	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ERalpha protein	ERalpha protein	ERalpha protein	26	27	30	32
Gastrin or ERK and P65 activators inhibited ER + BC through CCKBR mediated activation of ERK and P65 .	Gastrin or ERK and P65 activators inhibited ER + BC through CCKBR mediated activation of ERK and P65.	2	8	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	ER	ER	ER	2	3	7	8
XREF_BIBR Unlike breast cancer cells in which increased ERK activity represses ERalpha , both ERalpha and ERK are upregulated and activated in the uterine artery of pregnant animals .	XREF_BIBR Unlike breast cancer cells in which increased ERK activity represses ERalpha, both ERalpha and ERK are upregulated and activated in the uterine artery of pregnant animals.	8	16	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	ERalpha	ERalpha	ERalpha	8	9	11	12
Of course , the UPR is unlikely to function as the sole stress response pathway that operates under conditions of ER stress , and there is evidence that both the calcineurin and MAPK signaling pathways may work in parallel with the canonical UPR to relieve ER stress in this fungus .	Of course, the UPR is unlikely to function as the sole stress response pathway that operates under conditions of ER stress, and there is evidence that both the calcineurin and MAPK signaling pathways may work in parallel with the canonical UPR to relieve ER stress in this fungus.	32	46	relieve	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ER	ER	ER	32	33	45	46
Curcumin significantly activates the JNK and p38 MAPK , but not the ERK , signaling pathways via phosphorylation , thus down-regulating anti-apoptotic proteins Bcl-2 , Bcl-XL , Mcl-1 , and survivin in human HCT-116 colon cancer cells during apoptosis process .	Curcumin significantly activates the JNK and p38 MAPK, but not the ERK, signaling pathways via phosphorylation, thus down-regulating anti-apoptotic proteins Bcl-2, Bcl-XL, Mcl-1, and survivin in human HCT-116 colon cancer cells during apoptosis process.	7	36	down-regulating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	12	13	23	24
The third member of the MAPK family , the c-Jun N-terminal kinases ( JNKs ) , can also upregulate DR5 ( via an Sp1 mediated mechanism ) and downregulate Bcl-2 and Mcl-1 .	The third member of the MAPK family, the c-Jun N-terminal kinases (JNKs), can also upregulate DR5 (via an Sp1 mediated mechanism) and downregulate Bcl-2 and Mcl-1.	5	31	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	Bcl-2	Bcl-2	Bcl-2	5	6	29	30
While ERK1/2 knockdown caused downregulation of Bcl-2 and Mcl-1 , increased levels of Bax were evident ( XREF_FIG ) .	While ERK1/2 knockdown caused downregulation of Bcl-2 and Mcl-1, increased levels of Bax were evident (XREF_FIG).	1	8	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	1	2	6	7
Downmodulation of the ERK1/2 and NF-kappa B pathways inhibits the transcriptional activity of AP-1 and NF-kappa B transcription factors , respectively , both of which lead to the downregulation of Bcl-( xL ) ( Bcl-2 related gene ( long alternatively spliced variant of Bcl-x gene ) ) transcription and expression and sensitization to drug induced apoptosis .	Downmodulation of the ERK1/2 and NF-kappa B pathways inhibits the transcriptional activity of AP-1 and NF-kappa B transcription factors, respectively, both of which lead to the downregulation of Bcl-(xL) (Bcl-2 related gene (long alternatively spliced variant of Bcl-x gene)) transcription and expression and sensitization to drug induced apoptosis.	0	35	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	3	4	34	35
Both the PI3K and MAPK pathways contribute to tumor progression by disrupting the balance of pro- and anti-apoptotic proteins of the BCL-2 protein family in the mitochondrial ( also known as intrinsic ) pathway of apoptosis [ XREF_BIBR , XREF_BIBR ] .	Both the PI3K and MAPK pathways contribute to tumor progression by disrupting the balance of pro- and anti-apoptotic proteins of the BCL-2 protein family in the mitochondrial (also known as intrinsic) pathway of apoptosis [XREF_BIBR, XREF_BIBR].	4	23	contribute	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	BCL-2	BCL-2	BCL-2	4	5	21	22
Furthermore , ERK dependent down-regulation of the Bcl-2 family member Bim has been shown to promote BAFF mediated B-cell survival .	Furthermore, ERK dependent down-regulation of the Bcl-2 family member Bim has been shown to promote BAFF mediated B-cell survival.	2	10	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	2	3	7	8
In KOSR protected CML cells , imatinib still inhibited the BCR-ABL tyrosine kinase , reduced the phosphorylation of STAT , ERK and AKT , down-regulated BCL2 , BCLxL , MCL1 and up-regulated BIM .	In KOSR protected CML cells, imatinib still inhibited the BCR-ABL tyrosine kinase, reduced the phosphorylation of STAT, ERK and AKT, down-regulated BCL2, BCLxL, MCL1 and up-regulated BIM.	6	27	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	imatinib still inhibited the BCR-ABL tyrosine kinase, reduced the phosphorylation of STAT, ERK	erk	BCL2	BCL2	bcl2	20	21	25	26
Taken together , these results suggest that activation of p38alpha MAPK promotes pathological remodeling by reducing the activity or expression of the anti-apoptotic family members Bcl-X L and Bcl-2 .	Taken together, these results suggest that activation of p38alpha MAPK promotes pathological remodeling by reducing the activity or expression of the anti-apoptotic family members Bcl-X L and Bcl-2.	7	29	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	Bcl-2	Bcl-2	Bcl-2	10	11	28	29
These data indicate that glucose deficiency decreases the phosphorylation of ERK and GSK3beta and increases apoptotic Bax and Bcl2 ratio through the increased ROS production .	These data indicate that glucose deficiency decreases the phosphorylation of ERK and GSK3beta and increases apoptotic Bax and Bcl2 ratio through the increased ROS production.	4	19	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	glucose deficiency decreases the phosphorylation of ERK	erk	Bcl2	Bcl2	bcl2	10	11	18	19
Inhibition of AK + BTK reduced phosphorylation of AKT and mTOR and ERK-1/2 , upregulated phospho-H2A-X and Chk-2 ( DNA damage ) , reduced Bcl-6 , and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage .	Inhibition of AK + BTK reduced phosphorylation of AKT and mTOR and ERK-1/2, upregulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6, and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage.	6	30	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK-1/2	phosphorylation of AKT and mTOR and ERK-1/2	erk-1/2	Bcl-2	Bcl-2	bcl-2	12	13	28	29
In another scenario , AT2R signaling stimulates a MAPK tyrosine phosphatase , ( MKP )-1, which inhibits MAPK activation and consequentially inactivates Bcl-2 and induces apoptosis in proximal tubular cells XREF_BIBR .	In another scenario, AT2R signaling stimulates a MAPK tyrosine phosphatase, (MKP)-1, which inhibits MAPK activation and consequentially inactivates Bcl-2 and induces apoptosis in proximal tubular cells XREF_BIBR.	8	23	inactivates	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	Bcl-2	Bcl-2	Bcl-2	8	9	22	23
Moreover , CXB up-regulated the cell cycle negative regulator p21 CIP and WAF1 and the cell cycle positive regulator Cyclin A , blocked ERK1/2 phosphorylation , induced apoptotic factors ( Bax and caspase-3 ) and reduced Bcl-2 .	Moreover, CXB up-regulated the cell cycle negative regulator p21 CIP and WAF1 and the cell cycle positive regulator Cyclin A, blocked ERK1/2 phosphorylation, induced apoptotic factors (Bax and caspase-3) and reduced Bcl-2.	2	37	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	CXB up-regulated the cell cycle negative regulator p21 CIP and WAF1 and the cell cycle positive regulator Cyclin A, blocked ERK1/2 phosphorylation	erk1/2	Bcl-2	Bcl-2	bcl-2	23	24	36	37
Furthermore , inhibition of Erk1/2 phosphorylation by MEK1/2 inhibitors increased sensitivity of GNAQ wild type cells to enzastaurin and was associated with similar alterations in the expression of p27 Kip1 , cyclin D1 , Bcl-2 and/or survivin to GNAQ mutant cells treated with enzastaurin .	Furthermore, inhibition of Erk1/2 phosphorylation by MEK1/2 inhibitors increased sensitivity of GNAQ wild type cells to enzastaurin and was associated with similar alterations in the expression of p27 Kip1, cyclin D1, Bcl-2 and/or survivin to GNAQ mutant cells treated with enzastaurin.	4	35	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Erk1/2	Erk1/2 phosphorylation	erk1/2	Bcl-2	Bcl-2	bcl-2	4	5	34	35
In human pancreatic cancer cells , inhibition of ERK1/2 activities caused downregulation of antiapoptotic proteins BCL-2 , MCL-1 , and BCL-Xl without affecting the proapoptotic proteins BAX and BAK [ XREF_BIBR ] .	In human pancreatic cancer cells, inhibition of ERK1/2 activities caused downregulation of antiapoptotic proteins BCL-2, MCL-1, and BCL-Xl without affecting the proapoptotic proteins BAX and BAK [XREF_BIBR].	8	20	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	BCL-2	BCL-2	BCL-2	8	9	15	16
This indicated that the inhibition of ERK activity by U0126 enhanced the upregulation of Bax , caspase-3 and -9 , and the downregulation of Bcl-2 induced by NC .	This indicated that the inhibition of ERK activity by U0126 enhanced the upregulation of Bax, caspase-3 and -9, and the downregulation of Bcl-2 induced by NC.	6	25	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	Bcl-2	Bcl-2	Bcl-2	6	7	24	25
As the results showed , the inhibition of ERK1/2 can restore the antiapoptotic protein Bcl-2 and downregulated the proapoptotic protein Bax .	As the results showed, the inhibition of ERK1/2 can restore the antiapoptotic protein Bcl-2 and downregulated the proapoptotic protein Bax.	6	15	restore	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	8	9	14	15
SCARA5 decreased the phosphorylation of ERK1/2 , AKT , and STAT3 , and downregulated downstream signaling effectors , including MMP-2 , 3 , and 9 , VEGF-A , VEGF-C , Bax , Cyclin B1 , Cyclin D1 , and Cyclin E1 , and upregulated E-cadherin , Bcl-2 , and caspase 3 .	SCARA5 decreased the phosphorylation of ERK1/2, AKT, and STAT3, and downregulated downstream signaling effectors, including MMP-2, 3, and 9, VEGF-A, VEGF-C, Bax, Cyclin B1, Cyclin D1, and Cyclin E1, and upregulated E-cadherin, Bcl-2, and caspase 3.	0	47	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	SCARA5 decreased the phosphorylation of ERK1/2	erk1/2	Bcl-2	Bcl-2	bcl-2	5	6	46	47
In addition , kinases downstream of ERK ( e.g ., RSK , S6K ) directly phosphorylate and inactivate the pro apoptotic BCL-2 family member BAD , as well as caspase-9 and APAF-1 [ XREF_BIBR - XREF_BIBR ] .	In addition, kinases downstream of ERK (e.g., RSK, S6K) directly phosphorylate and inactivate the pro apoptotic BCL-2 family member BAD, as well as caspase-9 and APAF-1 [XREF_BIBR - XREF_BIBR].	3	24	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	BCL-2	BCL-2	BCL-2	6	7	21	22
Inhibition of Erk1/2 phosphorylation with a MEK specific inhibitor enhanced the sensitivity of GNAQ wild type cells to enzastaurin , accompanied by p27 Kip1 accumulation and/or inhibition of enzastaurin induced survivin and Bcl-2 upregulation .	Inhibition of Erk1/2 phosphorylation with a MEK specific inhibitor enhanced the sensitivity of GNAQ wild type cells to enzastaurin, accompanied by p27 Kip1 accumulation and/or inhibition of enzastaurin induced survivin and Bcl-2 upregulation.	2	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Erk1/2	Erk1/2 phosphorylation	erk1/2	Bcl-2	Bcl-2	bcl-2	2	3	32	33
Persistent ERK1/2 activation by BAFFR suppresses the accumulation of pro apoptotic Bcl-2 family member BIM , saving the cell from apoptosis [ XREF_BIBR , XREF_BIBR ] .	Persistent ERK1/2 activation by BAFFR suppresses the accumulation of pro apoptotic Bcl-2 family member BIM, saving the cell from apoptosis [XREF_BIBR, XREF_BIBR].	1	14	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	1	2	11	12
In contrast , antiapoptotic proteins BCL-2 and BCL-Xl were downregulated by ERK1/2 activation .	In contrast, antiapoptotic proteins BCL-2 and BCL-Xl were downregulated by ERK1/2 activation.	3	12	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	BCL-2	BCL-2	BCL-2	11	12	5	6
This pro apoptotic BCL2 family member is upregulated by inhibition of ERK signaling and in BRAF V600E melanoma cells treated with vemurafenib .	This pro apoptotic BCL2 family member is upregulated by inhibition of ERK signaling and in BRAF V600E melanoma cells treated with vemurafenib.	3	12	upregulated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	BCL2	BCL2	BCL2	11	12	3	4
[ XREF_BIBR ] It is suggested that elevated ERK phosphorylation blocks apoptosis by enhancing the antiapoptotic protein Bcl-2 via CREB activation in cerebral ischemia .	[XREF_BIBR] It is suggested that elevated ERK phosphorylation blocks apoptosis by enhancing the antiapoptotic protein Bcl-2 via CREB activation in cerebral ischemia.	8	20	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK phosphorylation	erk	Bcl-2	Bcl-2	bcl-2	8	9	17	18
ERK1/2 activation may also inhibit apoptosis by down regulating Bad and up-regulating Bcl-2 [ XREF_BIBR ] .	ERK1/2 activation may also inhibit apoptosis by down regulating Bad and up-regulating Bcl-2 [XREF_BIBR].	0	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	0	1	12	13
Therefore , ERK1/2 knockdown caused the increased cell death by activating pro apoptotic Bcl-2 members , while inhibiting the anti-apoptotic ones .	Therefore, ERK1/2 knockdown caused the increased cell death by activating pro apoptotic Bcl-2 members, while inhibiting the anti-apoptotic ones.	2	14	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	Bcl-2	Bcl-2	Bcl-2	2	3	13	14
MAPK and p53 inhibition abolished the BCL-2 suppression and p21 Cip1 elevation that was induced by DDIT4 downregulation .	MAPK and p53 inhibition abolished the BCL-2 suppression and p21 Cip1 elevation that was induced by DDIT4 downregulation.	0	7	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	BCL-2	BCL-2	BCL-2	0	1	6	7
In this study , we demonstrate that expression of ErbB2 as such did not block constitutive internalization of ErbB3 , but that heregulin induced degradation of ErbB3 was significantly slowed in cells expressing high levels of ErbB2 .	In this study, we demonstrate that expression of ErbB2 as such did not block constitutive internalization of ErbB3, but that heregulin induced degradation of ErbB3 was significantly slowed in cells expressing high levels of ErbB2.	7	19	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	expression of ErbB2	erbb2	ErbB3	ErbB3	erbb3	9	10	18	19
While the reason for this finding is presently not understood , it is plausible that inhibition of ErbB2 by Lapatinib may result in up-regulation of ErbB3 as reported by Garrett et al ..	While the reason for this finding is presently not understood, it is plausible that inhibition of ErbB2 by Lapatinib may result in up-regulation of ErbB3 as reported by Garrett et al..	15	26	result in up-regulation	Positive_activation_syntax_8_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	17	18	25	26
These two miRNAs are potential tumor suppressors and their overexpression in SKBR3 cells ( a HER2 dependent human breast cancer cell line ) suppresses HER2 and HER3 mRNA and protein levels , leading to a reduction in anchorage dependent growth , cell motility , and invasiveness [ XREF_BIBR ] .	These two miRNAs are potential tumor suppressors and their overexpression in SKBR3 cells (a HER2 dependent human breast cancer cell line) suppresses HER2 and HER3 mRNA and protein levels, leading to a reduction in anchorage dependent growth, cell motility, and invasiveness [XREF_BIBR].	12	27	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	15	16	26	27
We tested this hypothesis in a bleomycin lung injury model using 2C4 , a monoclonal antibody directed against HER2 that blocks HER2 and HER3 signaling .	We tested this hypothesis in a bleomycin lung injury model using 2C4, a monoclonal antibody directed against HER2 that blocks HER2 and HER3 signaling.	16	24	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	18	19	23	24
This is consistent with our observation that bispecific HER2 and HER3 specific antibodies can sequester HER3 into HER2-HER3 heterodimers that , if inhibited by HER2 specific TKIs , effectively silence HER3 .	This is consistent with our observation that bispecific HER2 and HER3 specific antibodies can sequester HER3 into HER2-HER3 heterodimers that, if inhibited by HER2 specific TKIs, effectively silence HER3.	7	16	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	8	9	15	16
Expression of the H1047R PIK3CA mutation in cells that overexpress HER2 upregulates the HER3 and HER4 ligand heregulin ( HRG ) and knockdown of HER3 inhibits growth of HER2 +/PI3K mutant cells .	Expression of the H1047R PIK3CA mutation in cells that overexpress HER2 upregulates the HER3 and HER4 ligand heregulin (HRG) and knockdown of HER3 inhibits growth of HER2 +/PI3K mutant cells.	10	22	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	10	11	13	14
In order to measure the inhibition of HER2 mediated HER3 activation , we tested three drugs that target HER2 ( 2C4 , trastuzumab and lapatinib ) using FFPE cell-lines as our model system .	In order to measure the inhibition of HER2 mediated HER3 activation, we tested three drugs that target HER2 (2C4, trastuzumab and lapatinib) using FFPE cell-lines as our model system.	5	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	7	8	9	10
Indeed , lapatinib , a clinical ERBB2 and EGFR inhibitor , effectively inhibited the ERBB3 and ERBB2 pathway and importantly , delayed melanoma tumor growth in both mutated and wild type BRAF cells [ XREF_BIBR ] .	Indeed, lapatinib, a clinical ERBB2 and EGFR inhibitor, effectively inhibited the ERBB3 and ERBB2 pathway and importantly, delayed melanoma tumor growth in both mutated and wild type BRAF cells [XREF_BIBR].	2	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERBB2	ERBB2	ERBB2	ERBB3	ERBB3	ERBB3	6	7	14	15
Our findings are consistent with previous studies demonstrating that persistence of HER3 activation in cells treated with EGFR or HER2 kinase inhibitors is a crucial factor in mediating resistance to these inhibitors .	Our findings are consistent with previous studies demonstrating that persistence of HER3 activation in cells treated with EGFR or HER2 kinase inhibitors is a crucial factor in mediating resistance to these inhibitors.	11	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	19	20	11	12
Furthermore , SSO111 served as a platform for the identification of a novel HER2 ECD variant ; the protein encoded by the exon 15 skipped HER2 mRNA , Delta15HER2 , was able to downregulate HER2 and HER3 , interfere with HER2 mediated transactivation of HER3 , and specifically kill HER2 dependent cells .	Furthermore, SSO111 served as a platform for the identification of a novel HER2 ECD variant; the protein encoded by the exon 15 skipped HER2 mRNA, Delta15HER2, was able to downregulate HER2 and HER3, interfere with HER2 mediated transactivation of HER3, and specifically kill HER2 dependent cells.	25	37	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	25	26	36	37
XREF_BIBR , XREF_BIBR Data have indicated that HER3 is as critical as HER2 to maintaining cell proliferation in breast cancer cells , and a HER2 antibody that inhibits HER3 signaling by blocking ligand induced heterodimerization can induce tumor regression with effects that are distinct from those of trastuzumab .	XREF_BIBR, XREF_BIBR Data have indicated that HER3 is as critical as HER2 to maintaining cell proliferation in breast cancer cells, and a HER2 antibody that inhibits HER3 signaling by blocking ligand induced heterodimerization can induce tumor regression with effects that are distinct from those of trastuzumab.	24	29	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	24	25	28	29
Inhibition of IGF-IR and/or ErbB2 mediated activation of ErbB3 with tyrosine kinase inhibitors restored hormone-dependence and the growth inhibitory effect of tamoxifen and fulvestrant on shPTEN cells , suggesting that co-targeting both ER and receptor tyrosine kinase pathways holds promise for the treatment of patients with ER+ , PTEN deficient breast cancers .	Inhibition of IGF-IR and/or ErbB2 mediated activation of ErbB3 with tyrosine kinase inhibitors restored hormone-dependence and the growth inhibitory effect of tamoxifen and fulvestrant on shPTEN cells, suggesting that co-targeting both ER and receptor tyrosine kinase pathways holds promise for the treatment of patients with ER+, PTEN deficient breast cancers.	4	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	4	5	8	9
[ XREF_BIBR , XREF_BIBR ] Furthermore , targeting HER2 with either mAbs or TKIs has been shown to reactivate HER3 via an AKT mediated feedback loop .	[XREF_BIBR, XREF_BIBR] Furthermore, targeting HER2 with either mAbs or TKIs has been shown to reactivate HER3 via an AKT mediated feedback loop.	7	22	reactivate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	HER2	HER2	HER3	HER3	HER3	8	9	19	20
In a mouse model of mammary carcinoma driven by the polyomavirus middle T ( PyVmT ) oncogene , the ErbB2 tyrosine kinase inhibitor lapatinib reduced the activation of ErbB3 and Akt along with tumor cell growth .	In a mouse model of mammary carcinoma driven by the polyomavirus middle T (PyVmT) oncogene, the ErbB2 tyrosine kinase inhibitor lapatinib reduced the activation of ErbB3 and Akt along with tumor cell growth.	19	30	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	ErbB3	ErbB3	ErbB3	19	20	28	29
Treatment of HER2+ breast cancers has been greatly improved in recent years , but the accompanying upregulation of HER3 induced by HER2 blockade has subdued the therapeutic effect .	Treatment of HER2+ breast cancers has been greatly improved in recent years, but the accompanying upregulation of HER3 induced by HER2 blockade has subdued the therapeutic effect.	16	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	21	22	18	19
Furthermore , the consistent role for HER3 and the required release of its ligand by ADAM10 implies that in any HER2 positive EAC that develops resistance to HER2 inhibiting drugs , HER3 , ADAM10 and NRG-1beta can all be effective secondary targets .	Furthermore, the consistent role for HER3 and the required release of its ligand by ADAM10 implies that in any HER2 positive EAC that develops resistance to HER2 inhibiting drugs, HER3, ADAM10 and NRG-1beta can all be effective secondary targets.	24	32	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	27	28	31	32
Concomitant to this , we observed an induction of HER2 : HER3 heterodimers , suggesting that HER2 allows the kinase impaired HER3 receptor to gain signaling capacity .	Concomitant to this, we observed an induction of HER2 : HER3 heterodimers, suggesting that HER2 allows the kinase impaired HER3 receptor to gain signaling capacity.	16	22	allows	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	16	17	21	22
A solely HER2 targeted therapy , like trastuzumab and pertuzumab combination is unable to suppress HER3 driven PI3K pathway signaling resulting from a switch from HER2/3 heterodimers to alternate signaling , such as EGFR and HER3 heterodimers .	A solely HER2 targeted therapy, like trastuzumab and pertuzumab combination is unable to suppress HER3 driven PI3K pathway signaling resulting from a switch from HER2/3 heterodimers to alternate signaling, such as EGFR and HER3 heterodimers.	0	36	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	2	3	15	16
XREF_BIBR Trastuzumab ( Herceptin ( R ) ; Genentech , Inc , South San Francisco , CA , USA ) is a recombinant monoclonal antibody that binds to the extracellular domain IV of HER2 , thereby inhibiting ligand independent HER2 and HER3 signaling .	XREF_BIBR Trastuzumab (Herceptin (R); Genentech, Inc, South San Francisco, CA, USA) is a recombinant monoclonal antibody that binds to the extracellular domain IV of HER2, thereby inhibiting ligand independent HER2 and HER3 signaling.	31	42	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	33	34	41	42
Loss of HER2 upregulates HER3 and MUC4 in pancreatic cancer cells .	Loss of HER2 upregulates HER3 and MUC4 in pancreatic cancer cells.	0	10	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HER2	Loss of HER2	her2	HER3	HER3	her3	2	3	4	5
The HER2 targeted antibody pertuzumab ( Perjeta ( TM ) ) reportedly inhibits ligand induced HER3 activity by preventing HER2 and HER3 dimerization .	The HER2 targeted antibody pertuzumab (Perjeta (TM)) reportedly inhibits ligand induced HER3 activity by preventing HER2 and HER3 dimerization.	0	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	HER3	HER3	HER3	1	2	15	16
Somatostatin and SSTR1 , -2 , and -5 agonists strongly inhibited in vivo C6 tumor growth , intratumoral neovessel formation , Ki-67 expression , and ERK1/2 phosphorylation and induced upregulation of p27 ( Kip1 ) , whereas only a modest activation of caspase-3 was observed .	Somatostatin and SSTR1, -2, and -5 agonists strongly inhibited in vivo C6 tumor growth, intratumoral neovessel formation, Ki-67 expression, and ERK1/2 phosphorylation and induced upregulation of p27 (Kip1), whereas only a modest activation of caspase-3 was observed.	0	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	Somatostatin and SSTR1, -2, and -5 agonists strongly inhibited in vivo C6 tumor growth, intratumoral neovessel formation, Ki-67 expression, and ERK1/2 phosphorylation	erk1/2	p27	p27	p27	25	26	31	32
As shown in XREF_FIG , ectopic overexpression of Raf1 and ERK prevented the induction of p27 , but did not affect the repression of cyclin D1 in Mcm7 depleted cells .	As shown in XREF_FIG, ectopic overexpression of Raf1 and ERK prevented the induction of p27, but did not affect the repression of cyclin D1 in Mcm7 depleted cells.	6	16	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	overexpression of Raf1 and ERK	erk	p27	p27	p27	10	11	15	16
Active PTEN results in decreased phosphorylation of Akt and MAPK , the up-regulation of p27 and down-regulation of cyclin D1 protein levels resulting in decreased proliferation and an increase in apoptosis .	Active PTEN results in decreased phosphorylation of Akt and MAPK, the up-regulation of p27 and down-regulation of cyclin D1 protein levels resulting in decreased proliferation and an increase in apoptosis.	1	15	up-regulation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	MAPK	PTEN results in decreased phosphorylation of Akt and MAPK	mapk	p27	p27	p27	9	10	14	15
TEM8 knock-down attenuated ERK1/2 phosphorylation , down-regulated cyclinD1 expression and upregulated p21 and p27 in osteosarcoma .	TEM8 knock-down attenuated ERK1/2 phosphorylation, down-regulated cyclinD1 expression and upregulated p21 and p27 in osteosarcoma.	0	14	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	TEM8 knock-down attenuated ERK1/2 phosphorylation	erk1/2	p27	p27	p27	3	4	13	14
Inhibition of PI3-kinase action or MAPK activity abolished the reduction in p27 ( Kip1 ) expression induced by EGF .	Inhibition of PI3-kinase action or MAPK activity abolished the reduction in p27 (Kip1) expression induced by EGF.	5	12	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	p27	p27	p27	5	6	11	12
Consistent with their ability to activate Rac1 , expression of either full-length murine p120 or of the N-terminally truncated p120 mutant ( DeltaN ) rescued both Raf and MEK phosphorylation at these sites , induced activation of ERK1/2 , increased expression of cyclin D1 , and inhibited p27 .	Consistent with their ability to activate Rac1, expression of either full-length murine p120 or of the N-terminally truncated p120 mutant (DeltaN) rescued both Raf and MEK phosphorylation at these sites, induced activation of ERK1/2, increased expression of cyclin D1, and inhibited p27.	29	48	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	phosphorylation at these sites, induced activation of ERK1/2	erk1/2	p27	p27	p27	37	38	47	48
We conclude that loss of canonical insulin signaling results in increased ERK-1/2 activation in response to physiological insulin that decreases p27 ( Kip1 ) mRNA .	We conclude that loss of canonical insulin signaling results in increased ERK-1/2 activation in response to physiological insulin that decreases p27 (Kip1) mRNA.	11	24	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK-1/2	ERK-1/2	ERK-1/2	p27	p27	p27	11	12	20	21
By contrast , overexpression of ClC-3 potentiated cell proliferation induced by IGF-1 , raised the percentage of S phase cells , enhanced phosphorylation of ERK1/2 , downregulated p27 and p21 and upregulated cyclin E and cyclin D1 .	By contrast, overexpression of ClC-3 potentiated cell proliferation induced by IGF-1, raised the percentage of S phase cells, enhanced phosphorylation of ERK1/2, downregulated p27 and p21 and upregulated cyclin E and cyclin D1.	3	29	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	overexpression of ClC-3 potentiated cell proliferation induced by IGF-1, raised the percentage of S phase cells, enhanced phosphorylation of ERK1/2	erk1/2	p27	p27	p27	24	25	27	28
Knockdown of HMP19 increased localization of activated ERK1/2 in the nucleus , corresponding to facilitated cell proliferation , decreased p27 Kip1 and increased cyclin E1 .	Knockdown of HMP19 increased localization of activated ERK1/2 in the nucleus, corresponding to facilitated cell proliferation, decreased p27 Kip1 and increased cyclin E1.	4	21	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	p27 Kip1	p27 Kip1	p27 Kip1	7	8	19	21
Upon activation of the cascade , phosphorylation of the downstream effector kinases ( ERK1/2 ) leads to transcriptional activation of cyclin D1 , degradation of CDK inhibitor p27 , and activation of p90 ribosomal S6 kinase ( p90RSK ) , which in turn inactivates the cell cycle-inhibitory protein myelin transcription factor 1 ( MYT1 ) [ XREF_BIBR , XREF_BIBR ] .	Upon activation of the cascade, phosphorylation of the downstream effector kinases (ERK1/2) leads to transcriptional activation of cyclin D1, degradation of CDK inhibitor p27, and activation of p90 ribosomal S6 kinase (p90RSK), which in turn inactivates the cell cycle-inhibitory protein myelin transcription factor 1 (MYT1) [XREF_BIBR, XREF_BIBR].	6	28	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	ERK1/2	phosphorylation of the downstream effector kinases (ERK1/2	erk1/2	p27	p27	p27	13	14	27	28
106 Once activated , ERK/p38/JNK MAPK can upregulate CDK6 ( a member of cyclin dependent kinases ) , CCND1 and CCNE1 ( members of cyclins ) , and downregulate p16 , p21 and p27 ( members of CDKIs ) , thus inducing the G1/S and G 2 / M transitions and cell proliferation .	106 Once activated, ERK/p38/JNK MAPK can upregulate CDK6 (a member of cyclin dependent kinases), CCND1 and CCNE1 (members of cyclins), and downregulate p16, p21 and p27 (members of CDKIs), thus inducing the G1/S and G 2 / M transitions and cell proliferation.	4	34	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	p27	p27	p27	5	6	33	34
In melanoma cells , ERK can inhibit the cell cycle regulator p27 kip1 [ XREF_BIBR ] .	In melanoma cells, ERK can inhibit the cell cycle regulator p27 kip1 [XREF_BIBR].	4	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	p27 kip1	p27 kip1	p27 kip1	4	5	11	13
Lastly , Cyclin E1 is known to be regulated by EGFR signaling [ XREF_BIBR ] , where both AKT and ERK can inhibit p27 kip1 , which is a negative regulator of CDK2 and Cyclin E1 complex [ XREF_BIBR , XREF_BIBR ] .	Lastly, Cyclin E1 is known to be regulated by EGFR signaling [XREF_BIBR], where both AKT and ERK can inhibit p27 kip1, which is a negative regulator of CDK2 and Cyclin E1 complex [XREF_BIBR, XREF_BIBR].	18	25	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	p27 kip1	p27 kip1	p27 kip1	20	21	23	25
Inhibition of ERK , but not other subtypes of the mitogen activated protein kinase family , prevented the reduction of p27 protein and mRNA .	Inhibition of ERK, but not other subtypes of the mitogen activated protein kinase family, prevented the reduction of p27 protein and mRNA.	0	21	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	p27	p27	p27	2	3	20	21
We show that these changes are due to ERK dependent dysregulation of cyclin D1 and p27 ( Kip1 ) , resulting in cell cycle elongation , favoring neurogenic over self renewing divisions .	We show that these changes are due to ERK dependent dysregulation of cyclin D1 and p27 (Kip1), resulting in cell cycle elongation, favoring neurogenic over self renewing divisions.	8	16	dysregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ERK	ERK	ERK	p27	p27	p27	8	9	15	16
In fibroblasts , dominant negative ras transfection increased p27 concentrations and caused G1 arrest ; moreover , Ras mediated activation of the MAPK stimulated p27 proteolysis [ XREF_BIBR , XREF_BIBR ] .	In fibroblasts, dominant negative ras transfection increased p27 concentrations and caused G1 arrest; moreover, Ras mediated activation of the MAPK stimulated p27 proteolysis [XREF_BIBR, XREF_BIBR].	17	25	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK	Ras mediated activation of the MAPK	mapk	p27	p27	p27	22	23	24	25
Therefore , we proposed a mechanistic model to illustrate how Twist activates both Akt and ERK pathways through their phosphorylation , further up-regulates phsopho-GSK-3beta and down-regulates p27 , and in turn induces EMT ( XREF_FIG ) .	Therefore, we proposed a mechanistic model to illustrate how Twist activates both Akt and ERK pathways through their phosphorylation, further up-regulates phsopho-GSK-3beta and down-regulates p27, and in turn induces EMT (XREF_FIG).	13	27	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	p27	p27	p27	15	16	26	27
Additionally , persistent ERK signaling decreases the intracellular levels of negative inhibitors of the cell cycle , namely p27 kip1 , allowing for increased proliferation in the face of limiting IL-2 levels [ XREF_BIBR ] .	Additionally, persistent ERK signaling decreases the intracellular levels of negative inhibitors of the cell cycle, namely p27 kip1, allowing for increased proliferation in the face of limiting IL-2 levels [XREF_BIBR].	3	20	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	p27 kip1	p27 kip1	p27 kip1	3	4	18	20
Our recent population based study evaluating HER2 overexpression and hormone receptor status has unexpectedly found that the majority of HER2 overexpressing tumors are hormone receptor positive and are more common than HER2 overexpressing ER negative breast cancers .	Our recent population based study evaluating HER2 overexpression and hormone receptor status has unexpectedly found that the majority of HER2 overexpressing tumors are hormone receptor positive and are more common than HER2 overexpressing ER negative breast cancers.	29	36	overexpressing	Positive_activation_token_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	ER	ER	ER	31	32	33	34
Additional inhibition of the HER2 pathway may reactivate ERalpha and sensitise the tumour to antihormonal therapies .	Additional inhibition of the HER2 pathway may reactivate ERalpha and sensitise the tumour to antihormonal therapies.	4	9	reactivate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	4	5	8	9
Expression of HER2 and/or ERbeta2 reduces estrogen responsiveness in ERalpha positive tumor cells .	Expression of HER2 and/or ERbeta2 reduces estrogen responsiveness in ERalpha positive tumor cells.	0	12	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	Expression of HER2	her2	ERalpha	ERalpha	eralpha	2	3	9	10
To investigate whether suppressing Her-2 resulted in upregulation of ERalpha and aromatase was limited to LTLT-Ca cells , we carried out the same experiment with ER negative and Her-2 positive SKBr-3 cells .	To investigate whether suppressing Her-2 resulted in upregulation of ERalpha and aromatase was limited to LTLT-Ca cells, we carried out the same experiment with ER negative and Her-2 positive SKBr-3 cells.	3	11	resulted in upregulation	Positive_activation_syntax_8_verb	Positive_activation	Negative_activation	Her-2	Her-2	Her-2	ERalpha	ERalpha	ERalpha	4	5	9	10
Although our studies indicate that ERalpha is negatively regulated by HER-2 , other mechanism may lead to suppression of the estrogen receptor in breast cancer .	Although our studies indicate that ERalpha is negatively regulated by HER-2, other mechanism may lead to suppression of the estrogen receptor in breast cancer.	5	11	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	HER-2	HER-2	HER-2	ERalpha	ERalpha	ERalpha	10	11	5	6
Inhibition of HER2 can increase ER activity .	Inhibition of HER2 can increase ER activity.	0	6	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	ER	ER	ER	2	3	5	6
HER2 and ERbeta2 downregulate estrogen responsive element mediated transcription activity of ERalpha positive cells in response to estrogen stimulation .	HER2 and ERbeta2 downregulate estrogen responsive element mediated transcription activity of ERalpha positive cells in response to estrogen stimulation.	0	13	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	ERalpha	ERalpha	ERalpha	0	1	11	12
There are many issues to be further investigated such as whether AR is an independent prognostic factor , whether it is a therapeutic target for the triple negative breast cancers and whether it is associated with HER-2 signaling in ER negative tumors .	There are many issues to be further investigated such as whether AR is an independent prognostic factor, whether it is a therapeutic target for the triple negative breast cancers and whether it is associated with HER-2 signaling in ER negative tumors.	36	41	signaling	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	HER-2	HER-2	HER-2	ER	ER	ER	36	37	39	40
HER2 negatively regulates ER , and that is why the authors noted the re-expression of ER when HER2 was blocked .	HER2 negatively regulates ER, and that is why the authors noted the re-expression of ER when HER2 was blocked.	0	4	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	ER	ER	ER	0	1	3	4
To explore the differences among intrinsic subtypes of breast cancer cell lines , we studied the inhibition of cell growth in four different human breast cancer cell lines : ER positive and HER2 negative MCF7 cells , ER negative and HER2 overexpressing SKBR3 cells , ER negative and HER2 negative MDA-MB-231 cells , and ER positive and HER2 negative BT474 cells .	To explore the differences among intrinsic subtypes of breast cancer cell lines, we studied the inhibition of cell growth in four different human breast cancer cell lines : ER positive and HER2 negative MCF7 cells, ER negative and HER2 overexpressing SKBR3 cells, ER negative and HER2 negative MDA-MB-231 cells, and ER positive and HER2 negative BT474 cells.	40	46	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	ER	ER	ER	40	41	45	46
HER2 overexpressing ER negative tumors are generally classified within a single subtype denoted ERBB2 overexpressing .	HER2 overexpressing ER negative tumors are generally classified within a single subtype denoted ERBB2 overexpressing.	0	7	overexpressing	Positive_activation_token_1_verb	Positive_activation	Negative_activation	HER2	HER2	HER2	ER	ER	ER	0	1	2	3
4 ) In addition , the overexpression of HER2 sequesters ERalpha in the cytosol , which augments the non genomic activity of ERalpha ( XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	4) In addition, the overexpression of HER2 sequesters ERalpha in the cytosol, which augments the non genomic activity of ERalpha (XREF_FIG) [XREF_BIBR, XREF_BIBR].	6	11	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HER2	overexpression of HER2	her2	ERalpha	ERalpha	eralpha	8	9	10	11
These data are consistent with our results and suggest that Her-2 suppresses ERalpha , as resistance to trastuzumab is associated with up-regulation of ERalpha responsive genes .	These data are consistent with our results and suggest that Her-2 suppresses ERalpha, as resistance to trastuzumab is associated with up-regulation of ERalpha responsive genes.	10	13	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Her-2	Her-2	Her-2	ERalpha	ERalpha	ERalpha	10	11	12	13
Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ER , a large proportion of the perturbed genes in the ' low-confidence '/ERBB2+ samples are not known to be estrogen responsive , and a recently described bioinformatic algorithm ( DEREF ) was used to demonstrate the absence of potential estrogen response elements ( EREs ) in their promoters .	Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ER, a large proportion of the perturbed genes in the ' low-confidence '/ERBB2+ samples are not known to be estrogen responsive, and a recently described bioinformatic algorithm (DEREF) was used to demonstrate the absence of potential estrogen response elements (EREs) in their promoters.	1	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERBB2	ERBB2	ERBB2	ER	ER	ER	1	2	12	13
The results suggest that inhibition of Her-2 restores ERalpha and E 2 sensitivity and that Her-2 is a negative regulator of ER .	The results suggest that inhibition of Her-2 restores ERalpha and E 2 sensitivity and that Her-2 is a negative regulator of ER.	4	12	restores	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Her-2	Her-2	Her-2	ERalpha	ERalpha	ERalpha	6	7	8	9
We hypothesized that blockade of AP-1 in mouse mammary epithelial cells will suppress ER negative tumorigenesis induced by erbB2 .	We hypothesized that blockade of AP-1 in mouse mammary epithelial cells will suppress ER negative tumorigenesis induced by erbB2.	13	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	erbB2	erbB2	erbB2	ER	ER	ER	18	19	13	14
Factors which disrupt this pathway , such as activation of ErbB2 or other RTKs which repress ERalpha function ( 50 ) , would lead to lower Lrig1 levels , accelerated tumor growth and worsened prognosis .	Factors which disrupt this pathway, such as activation of ErbB2 or other RTKs which repress ERalpha function (50), would lead to lower Lrig1 levels, accelerated tumor growth and worsened prognosis.	10	17	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ErbB2	ErbB2	ErbB2	ERalpha	ERalpha	ERalpha	10	11	16	17
Our previous studies have shown that inhibition of Her-2 ( with trastuzumab ) can activate ERalpha and increase aromatase activity in ERalpha dependent manner .	Our previous studies have shown that inhibition of Her-2 (with trastuzumab) can activate ERalpha and increase aromatase activity in ERalpha dependent manner.	6	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Her-2	Her-2	Her-2	ERalpha	ERalpha	ERalpha	8	9	15	16
Here , we show that Epo accelerates the growth of EpoR negative tumors by promoting tumor angiogenesis .	Here, we show that Epo accelerates the growth of EpoR negative tumors by promoting tumor angiogenesis.	5	12	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	5	6	10	11
In visceral epididymal white adipocytes , cells from EPO treated WT mice only showed increased expression of Ucp3 , Pparalpha , and Pgc-1alpha , and the expression of these genes was reduced in adipocytes from EpoR aP2KO mice and remained unchanged in EpoR aP2KO mice treated with EPO ( XREF_FIG ) .	In visceral epididymal white adipocytes, cells from EPO treated WT mice only showed increased expression of Ucp3, Pparalpha, and Pgc-1alpha, and the expression of these genes was reduced in adipocytes from EpoR aP2KO mice and remained unchanged in EpoR aP2KO mice treated with EPO (XREF_FIG).	42	49	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	EPO	EPO	EPO	EpoR	EpoR	EpoR	47	48	42	43
To evaluate the protective effect of endogenous EPO from astrocyte to OPCs , EPO and EPOR signaling was blocked by EPO siRNA or EPOR siRNA gene silencing in in vitro study .	To evaluate the protective effect of endogenous EPO from astrocyte to OPCs, EPO and EPOR signaling was blocked by EPO siRNA or EPOR siRNA gene silencing in in vitro study.	15	21	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	20	21	15	16
EPO mediated EPOR signaling reduced the viability of myeloma cell lines and of malignant primary plasma cells in vitro .	EPO mediated EPOR signaling reduced the viability of myeloma cell lines and of malignant primary plasma cells in vitro.	0	3	mediated	Positive_early_activation	Positive_activation	Negative_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	0	1	2	3
Epo induced EpoR degradation was tested to ascertain the effects of LLnL and methylamine since we have previously demonstrated that proteasome inhibitors protect the cell surface form of the activated EpoR XREF_BIBR .	Epo induced EpoR degradation was tested to ascertain the effects of LLnL and methylamine since we have previously demonstrated that proteasome inhibitors protect the cell surface form of the activated EpoR XREF_BIBR.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	0	1	2	3
EPO downregulated EPOR and vitamin C and upregulated EPOR .	EPO downregulated EPOR and vitamin C and upregulated EPOR.	0	7	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	0	1	2	3
Exogenous EPO antagonized trastuzumab induced inhibition of cell proliferation in HER2 and EPOR dual positive breast cancer cells .	Exogenous EPO antagonized trastuzumab induced inhibition of cell proliferation in HER2 and EPOR dual positive breast cancer cells.	0	13	antagonized	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EPO	EPO	EPO	EPOR	EPOR	EPOR	1	2	12	13
Then we explored to inhibit the Epo-EpoR signaling with an EpoR antagonist Epo mimetic peptide 9 ( EMP9 ) that is a derivative of an Epo mimicking peptide EMP1 .	Then we explored to inhibit the Epo-EpoR signaling with an EpoR antagonist Epo mimetic peptide 9 (EMP9) that is a derivative of an Epo mimicking peptide EMP1.	4	14	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	12	13	10	11
While Epo prevents apoptosis of erythroid progenitors by activating homodimeric EpoR , its protective functions in the nervous system and other non hematopoietic tissues are also mediated by alternative receptors .	While Epo prevents apoptosis of erythroid progenitors by activating homodimeric EpoR, its protective functions in the nervous system and other non hematopoietic tissues are also mediated by alternative receptors.	1	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Epo	Epo	Epo	EpoR	EpoR	EpoR	1	2	10	11
The other transcription factors recruited to the TNFalpha promoter involve Sp1 , the ERK targets Egr-1 , Ets and Elk-1 [ XREF_BIBR ] , as well as the JNK targets c-Jun and ATF-2 [ XREF_BIBR ] .	The other transcription factors recruited to the TNFalpha promoter involve Sp1, the ERK targets Egr-1, Ets and Elk-1 [XREF_BIBR], as well as the JNK targets c-Jun and ATF-2 [XREF_BIBR].	12	34	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	c-Jun	c-Jun	c-Jun	13	14	30	31
PKC and ERK1/2 independently down-regulated JNK and c-Jun , since inhibition of either kinase failed to affect activation of the other kinase , and simultaneous inhibition of both pathways caused additive JNK and c-Jun activation and cell death .	PKC and ERK1/2 independently down-regulated JNK and c-Jun, since inhibition of either kinase failed to affect activation of the other kinase, and simultaneous inhibition of both pathways caused additive JNK and c-Jun activation and cell death.	0	8	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	c-Jun	c-Jun	c-Jun	2	3	7	8
Knockdown of ERK1/2 inhibits the synergistic activation of activator protein-1 in IBDC cells by EGF and IL-1beta .	Knockdown of ERK1/2 inhibits the synergistic activation of activator protein-1 in IBDC cells by EGF and IL-1beta.	0	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	activator protein-1	activator protein-1	activator protein-1	2	3	8	10
In addition , signaling network analysis of proteomic data revealed that inhibition of both the MEK and MAPK and PI3K and AKT pathways increases the activation of the transcription factor c-jun .	In addition, signaling network analysis of proteomic data revealed that inhibition of both the MEK and MAPK and PI3K and AKT pathways increases the activation of the transcription factor c-jun.	11	31	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	c-jun	c-jun	c-jun	17	18	30	31
Furthermore , pretreatment with SB203580 , a p38-mitogen-activated protein kinase ( MAPK ) inhibitor , decreased Dex induced Runx2 , c-Jun and BIM , suggesting that p38-MAPK activation is upstream of the induction of these molecules .	Furthermore, pretreatment with SB203580, a p38-mitogen-activated protein kinase (MAPK) inhibitor, decreased Dex induced Runx2, c-Jun and BIM, suggesting that p38-MAPK activation is upstream of the induction of these molecules.	9	21	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	11	12	20	21
Alternatively , the activation of p42 and p44 MAPK by NRG1 is a critical upstream signal for promoting demyelination and inhibiting the activation of p42 and p44 MAPK blocked c-Jun induction by NRG1 .	Alternatively, the activation of p42 and p44 MAPK by NRG1 is a critical upstream signal for promoting demyelination and inhibiting the activation of p42 and p44 MAPK blocked c-Jun induction by NRG1.	22	30	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	c-Jun	c-Jun	c-Jun	27	28	29	30
In addition , when AP-1 was blocked using pharmacological inhibitors during BGP treatment , PD-98059 ( PD ) , which inhibits phosphorylation of ERK 1/2 by MEK and subsequently c-Fos , and SP-600125 ( SP ) , which inhibits JNK and prevents c-Jun activation ; we found that they were able to block endothelial senescence induced by BGP , measured as SA-beta-GAL activity and p16 protein expression .	In addition, when AP-1 was blocked using pharmacological inhibitors during BGP treatment, PD-98059 (PD), which inhibits phosphorylation of ERK 1/2 by MEK and subsequently c-Fos, and SP-600125 (SP), which inhibits JNK and prevents c-Jun activation; we found that they were able to block endothelial senescence induced by BGP, measured as SA-beta-GAL activity and p16 protein expression.	14	43	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK 1/2	PD-98059 (PD), which inhibits phosphorylation of ERK 1/2 by MEK and subsequently c-Fos, and SP-600125	erk 1/2	c-Jun	c-Jun	c-jun	23	25	42	43
In contrast , coexpression of either wild-type or kinase defective ERKs inhibited Ras and Raf activation of c-Jun transcriptional activity .	In contrast, coexpression of either wild-type or kinase defective ERKs inhibited Ras and Raf activation of c-Jun transcriptional activity.	3	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERKs	coexpression of either wild-type or kinase defective ERKs	erks	c-Jun	c-Jun	c-jun	10	11	17	18
Application of the ERK pathway inhibitor U0126 attenuates photic induction of both P-ERK and P-Elk-1 and phase advances of wheel running behavior .	Application of the ERK pathway inhibitor U0126 attenuates photic induction of both P-ERK and P-Elk-1 and phase advances of wheel running behavior.	3	17	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	P-Elk-1	P-Elk-1	P-Elk-1	3	4	14	15
Our results suggest that the persistent activation of ERK by bFGF may deregulate the activity of Elk-1 by perturbing the equilibrium between conjugation and de-conjugation of SUMO to Elk-1 .	Our results suggest that the persistent activation of ERK by bFGF may deregulate the activity of Elk-1 by perturbing the equilibrium between conjugation and de-conjugation of SUMO to Elk-1.	6	17	deregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	Elk-1	Elk-1	Elk-1	8	9	16	17
In isolated perfused mouse lungs , the MAPK and ERK kinase inhibitor U0126 prevented ventilation induced activation of ERK-1/2 and Elk-1 , but had no effect on ventilation induced cytokine release .	In isolated perfused mouse lungs, the MAPK and ERK kinase inhibitor U0126 prevented ventilation induced activation of ERK-1/2 and Elk-1, but had no effect on ventilation induced cytokine release.	6	23	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	Elk-1	Elk-1	Elk-1	7	8	20	21
This primary screen was designed to identify siRNA pools that encoded negative regulators of ERK mediated ELK1 activation and yielded 581 hits where ELK1 activity was elevated > 5 absolute deviations above the median in one experiment ( or in both experiments when performed in duplicate ) .	This primary screen was designed to identify siRNA pools that encoded negative regulators of ERK mediated ELK1 activation and yielded 581 hits where ELK1 activity was elevated> 5 absolute deviations above the median in one experiment (or in both experiments when performed in duplicate).	12	17	mediated	Positive_early_activation	Positive_activation	Negative_activation	ERK	ERK	ERK	ELK1	ELK1	ELK1	14	15	16	17
We demonstrated that gal-1 significantly inhibited ERK1/2 , Akt-3 and pan and GSK-3alpha and beta phosphorylation in BeWo cells and in addition induced Elk1 transcription factor activation .	We demonstrated that gal-1 significantly inhibited ERK1/2, Akt-3 and pan and GSK-3alpha and beta phosphorylation in BeWo cells and in addition induced Elk1 transcription factor activation.	3	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	gal-1 significantly inhibited ERK1/2, Akt-3 and pan and GSK-3alpha and beta phosphorylation	erk1/2	Elk1	Elk1	elk1	6	7	23	24
Inhibition of the Na ( + )/Ca ( 2+ ) exchanger by KB-R7943 and of protein kinase C ( PKC ) by Ro-31-8220 suppressed ERK activation and gene expressions of c-fos and IL-1 beta .	Inhibition of the Na (+)/Ca (2+) exchanger by KB-R7943 and of protein kinase C (PKC) by Ro-31-8220 suppressed ERK activation and gene expressions of c-fos and IL-1 beta.	24	33	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK	ERK	ERK	c-fos	c-fos	c-fos	24	25	30	31
Downstream targets of ERK1/2 induce and activate c-Fos , a transcription factor for AP-1 , which is essential for osteoclastogenesis [ XREF_BIBR ] .	Downstream targets of ERK1/2 induce and activate c-Fos, a transcription factor for AP-1, which is essential for osteoclastogenesis [XREF_BIBR].	1	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	3	4	7	8
Constitutive ERK1/2 activation reduces the presence of c-Fos in the ERNF .	Constitutive ERK1/2 activation reduces the presence of c-Fos in the ERNF.	1	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	1	2	7	8
Inhibition of Erk1/2 activation or knockdown of c-Fos or Egr1 largely rescued neutrophil development in cells expressing G-CSFR Y729F .	Inhibition of Erk1/2 activation or knockdown of c-Fos or Egr1 largely rescued neutrophil development in cells expressing G-CSFR Y729F.	2	9	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	c-Fos	c-Fos	c-Fos	2	3	7	8
ERK1/2 inhibition increases the interaction of c-Fos with lamin A in vivo .	ERK1/2 inhibition increases the interaction of c-Fos with lamin A in vivo.	0	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	c-Fos	c-Fos	c-Fos	0	1	6	7
Inhibition of the MAPK pathway with PD98059 or U0126 blocked the DFMO induced induction of p21 and the reduction of cdk-2 protein .	Inhibition of the MAPK pathway with PD98059 or U0126 blocked the DFMO induced induction of p21 and the reduction of cdk-2 protein.	3	22	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	cdk-2 protein	cdk-2 protein	cdk-2 protein	3	4	20	22
Indeed , sustained ERK1/2 can induce the expression p15 , p16 and p21 and inhibit CDK2 , as we observed following P. gingivalis infection .	Indeed, sustained ERK1/2 can induce the expression p15, p16 and p21 and inhibit CDK2, as we observed following P. gingivalis infection.	2	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	CDK2	CDK2	CDK2	3	4	15	16
We found previously that inhibition of HGF induced proliferation in HepG2 hepatoma cells is caused by cell cycle arrest at G1 through a high intensity ERK signal , which represses Cdk2 activity .	We found previously that inhibition of HGF induced proliferation in HepG2 hepatoma cells is caused by cell cycle arrest at G1 through a high intensity ERK signal, which represses Cdk2 activity.	25	31	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	Cdk2	Cdk2	Cdk2	25	26	30	31
Abolishing ERK activity by MEK inhibition or expression of dominant negative ERK significantly reduces cdk2 activity in mammalian cells .	Abolishing ERK activity by MEK inhibition or expression of dominant negative ERK significantly reduces cdk2 activity in mammalian cells.	2	15	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	cdk2	cdk2	cdk2	11	12	14	15
These data suggest that the ERK1/2 pathway may activate inhibitors of C/EBPbeta and thereby inhibit COX-2 expression .	These data suggest that the ERK1/2 pathway may activate inhibitors of C/EBPbeta and thereby inhibit COX-2 expression.	5	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	C/EBPbeta	C/EBPbeta	C/EBPbeta	5	6	11	12
Data suggest that ERK1/2 signaling can repress C/EBPbeta activity through direct phosphorylation XREF_BIBR .	Data suggest that ERK1/2 signaling can repress C/EBPbeta activity through direct phosphorylation XREF_BIBR.	3	8	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	C/EBPbeta	C/EBPbeta	C/EBPbeta	3	4	7	8
Lastly , blocking ERK1/2 activation was shown to block IL-1beta- or C/EBPbeta mediated increases in TIMP-1 promoter activity , suggesting ERK1/2 signals to key transcription factors necessary for C/EBPbeta mediated TIMP-1 promoter regulation .	Lastly, blocking ERK1/2 activation was shown to block IL-1beta- or C/EBPbeta mediated increases in TIMP-1 promoter activity, suggesting ERK1/2 signals to key transcription factors necessary for C/EBPbeta mediated TIMP-1 promoter regulation.	3	12	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	C/EBPbeta	C/EBPbeta	C/EBPbeta	3	4	11	12
This suggests that ERK might inhibit adipogenic differentiation though PPARgamma suppression , but not through C/EBPalpha or C/EBPbeta .	This suggests that ERK might inhibit adipogenic differentiation though PPARgamma suppression, but not through C/EBPalpha or C/EBPbeta.	3	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	C/EBPbeta	C/EBPbeta	C/EBPbeta	3	4	17	18
Thus , reduced PKC signalling might cause decreased ERK activation in Adam17 -/- keratinocytes .	Thus, reduced PKC signalling might cause decreased ERK activation in Adam17 -/- keratinocytes.	8	13	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	ERK	ERK	ERK	Adam17	Adam17	Adam17	8	9	11	12
Restoration of ERK activation increased the processing of proADAM17 into ADAM17 in PLA2 treated cells , while inactivation of ERK reduced ADAM17 maturation in untreated and SB202190 and BPB-PLA 2 treated cells .	Restoration of ERK activation increased the processing of proADAM17 into ADAM17 in PLA2 treated cells, while inactivation of ERK reduced ADAM17 maturation in untreated and SB202190 and BPB-PLA 2 treated cells.	17	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	ADAM17	ADAM17	ADAM17	19	20	21	22
The intensity of the faster migrating band ( form II ) was lower when TACE activation was decreased by transfection of p38alpha MAPK siRNA , suggesting that this may represent an active conformation of TACE .	The intensity of the faster migrating band (form II) was lower when TACE activation was decreased by transfection of p38alpha MAPK siRNA, suggesting that this may represent an active conformation of TACE.	14	23	decreased	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MAPK	MAPK	MAPK	TACE	TACE	TACE	22	23	14	15
Although we used a different suspension culture system than the authors and cultured the cells for a maximum of 24h under EGF supplementation , we saw reduced ERK activation in Adam17 -/- keratinocytes .	Although we used a different suspension culture system than the authors and cultured the cells for a maximum of 24h under EGF supplementation, we saw reduced ERK activation in Adam17 -/- keratinocytes.	27	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	ERK	ERK	ERK	Adam17	Adam17	Adam17	27	28	30	31
Because saturating concentrations of AR and EPR do not induce degradation of EGFR , we reasoned that these ligands might induce recycling of EGFR .	Because saturating concentrations of AR and EPR do not induce degradation of EGFR, we reasoned that these ligands might induce recycling of EGFR.	2	13	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EPR	EPR	EPR	EGFR	EGFR	EGFR	6	7	12	13
Blocking this AREG and EREG induced activation of EGFR might promote cancer cell death .	Blocking this AREG and EREG induced activation of EGFR might promote cancer cell death.	0	9	induced	Positive_early_activation	Positive_activation	Negative_activation	EREG	EREG	EREG	EGFR	EGFR	EGFR	4	5	8	9
Epiregulin neutralisation by an inhibitory antibody reduced pEGFR to basal levels .	Epiregulin neutralisation by an inhibitory antibody reduced pEGFR to basal levels.	0	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Epiregulin	Epiregulin	Epiregulin	pEGFR	pEGFR	pEGFR	0	1	7	8
The PTB domain of ShcA has been shown to interact with multiple receptor TKs critical in cardiac function , such as VEGFR3 , ErbB2 , and ErbB4 7 ; in particular , loss of ErbB2 in cardiomyocytes produces a similar phenotype to ShcA in cardiac ablation studies .	The PTB domain of ShcA has been shown to interact with multiple receptor TKs critical in cardiac function, such as VEGFR3, ErbB2, and ErbB4 7; in particular, loss of ErbB2 in cardiomyocytes produces a similar phenotype to ShcA in cardiac ablation studies.	32	46	produces	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	ErbB2	loss of ErbB2	erbb2	ShcA	ShcA	shca	34	35	42	43
Both ERK1/2 signaling inhibitor U0126 and ERK-phosphoacceptor-site mutant ( GFP-hnRNPK S284/353A ) diminish cytoplasmic accumulation of hnRNPK induced by TRAIL .	Both ERK1/2 signaling inhibitor U0126 and ERK-phosphoacceptor-site mutant (GFP-hnRNPK S284/353A) diminish cytoplasmic accumulation of hnRNPK induced by TRAIL.	1	17	diminish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	hnRNPK	hnRNPK	hnRNPK	1	2	16	17
ErbB4 activation promoted YAP expression with its downstream protein PIK3CB , which were both remarkably decreased by ErbB4 siRNA administration ( p < 0.05 , Figures XREF_FIG ) .	ErbB4 activation promoted YAP expression with its downstream protein PIK3CB, which were both remarkably decreased by ErbB4 siRNA administration (p < 0.05, Figures XREF_FIG).	2	19	decreased	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ErbB4	ErbB4	ErbB4	PIK3CB	PIK3CB	PIK3CB	17	18	9	10
For ERbeta , the coexpression of ERalpha enhanced slightly the degradation of ERbeta .	For ERbeta, the coexpression of ERalpha enhanced slightly the degradation of ERbeta.	4	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERalpha	coexpression of ERalpha	eralpha	ERbeta	ERbeta	erbeta	6	7	12	13
Ginsenoside protopanaxadiol and g-PPT increased [ Ca ( 2+ ) ] ( i ) , eNOS phosphorylation and NO production in HUVECs , which were inhibited by the GR antagonist , RU486 , the ER antagonist , ICI 182,780 and siRNA targeting GR or ERbeta .	Ginsenoside protopanaxadiol and g-PPT increased [Ca (2+)] (i), eNOS phosphorylation and NO production in HUVECs, which were inhibited by the GR antagonist, RU486, the ER antagonist, ICI 182,780 and siRNA targeting GR or ERbeta.	1	45	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ER	protopanaxadiol and g-PPT increased [Ca (2+)] (i), eNOS phosphorylation and NO production in HUVECs, which were inhibited by the GR antagonist, RU486, the ER	er	ERbeta	ERbeta	erbeta	34	35	44	45
This hypothesis is derived primarily from findings that many of the rapid effects of E2 can be induced by selective ERalpha or ERbeta ligands , antagonized by the ER antagonist ICI 182,780 , and/or absent in animals bearing mutations in the ERalpha and/or ERbeta genes .	This hypothesis is derived primarily from findings that many of the rapid effects of E2 can be induced by selective ERalpha or ERbeta ligands, antagonized by the ER antagonist ICI 182,780, and/or absent in animals bearing mutations in the ERalpha and/or ERbeta genes.	22	30	antagonized	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	28	29	22	23
PE downregulated the expression of intratumor ER-alpha and ER-beta and lowered ER-alpha : ER-beta ratio .	PE downregulated the expression of intratumor ER-alpha and ER-beta and lowered ER-alpha : ER-beta ratio.	0	14	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ER-alpha	PE downregulated the expression of intratumor ER-alpha	er-alpha	ER-beta	ER-beta	er-beta	6	7	13	14
The ER antagonist CI-628 can inhibit ERalpha and ERbeta , but has partial agonist activity .	The ER antagonist CI-628 can inhibit ERalpha and ERbeta, but has partial agonist activity.	1	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	1	2	8	9
Also the stimulation of ERalpha in 17beta-estradiol treated in spontaneous hypertensive rats reduced the up-regulation of ERbeta with 8beta-VE2 .	Also the stimulation of ERalpha in 17beta-estradiol treated in spontaneous hypertensive rats reduced the up-regulation of ERbeta with 8beta-VE2.	2	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	4	5	16	17
In addition to SERMs , selective estrogen receptor downregulators ( SERDs ) such as ICI 182,780 , which abolish ERalpha and ERbeta signaling regardless of the type of tissue , have been used experimentally and therapeutically [ XREF_BIBR ] .	In addition to SERMs, selective estrogen receptor downregulators (SERDs) such as ICI 182,780, which abolish ERalpha and ERbeta signaling regardless of the type of tissue, have been used experimentally and therapeutically [XREF_BIBR].	6	22	abolish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	estrogen receptor	estrogen receptor	estrogen receptor	ERbeta	ERbeta	ERbeta	6	8	21	22
Previous studies demonstrated that testosterone induced ER-alpha expression but decreased that of ER-beta and its downstream effector ; P21 in experimental model of BPH XREF_BIBR .	Previous studies demonstrated that testosterone induced ER-alpha expression but decreased that of ER-beta and its downstream effector; P21 in experimental model of BPH XREF_BIBR.	4	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ER-alpha	testosterone induced ER-alpha expression	er-alpha	ER-beta	ER-beta	er-beta	6	7	12	13
With the discovery of these other ER ' s , the ER antagonist ICI 182,780 was also found to inhibit more than just ERalpha and ERbeta .	With the discovery of these other ER 's, the ER antagonist ICI 182,780 was also found to inhibit more than just ERalpha and ERbeta.	11	26	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	11	12	25	26
Conversely , in JKT-1 cells , estradiol inhibits cell proliferation through an ESR2 dependent mechanism that is completely suppressed by the ER antagonist ICI182780 .	Conversely, in JKT-1 cells, estradiol inhibits cell proliferation through an ESR2 dependent mechanism that is completely suppressed by the ER antagonist ICI182780.	12	23	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ER	ER	ER	ESR2	ESR2	ESR2	21	22	12	13
The contribution of specific ERs appears to be stimulus specific , with ER-alpha primarily modulating phenylephrine induced vasoconstriction , and ER-beta inhibiting HPV .	The contribution of specific ERs appears to be stimulus specific, with ER-alpha primarily modulating phenylephrine induced vasoconstriction, and ER-beta inhibiting HPV.	8	22	modulating	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ER-alpha	ER-alpha	ER-alpha	ER-beta	ER-beta	ER-beta	12	13	20	21
Both ERalpha and ERbeta activities on the LPL ERE reporter were abrogated by the ER antagonist ICI 182,780 .	Both ERalpha and ERbeta activities on the LPL ERE reporter were abrogated by the ER antagonist ICI 182,780.	1	16	abrogated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	14	15	3	4
Selective ER modulators , such as tamoxifen and raloxifen , were also shown to inhibit the growth of bladder cancer cell lines expressing ERbeta [ XREF_BIBR , XREF_BIBR ] .	Selective ER modulators, such as tamoxifen and raloxifen, were also shown to inhibit the growth of bladder cancer cell lines expressing ERbeta [XREF_BIBR, XREF_BIBR].	1	27	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	1	2	23	24
In our data , ERK1 and ERK2 phosphorylation induced by E 2 was inhibited in the presence of ICI 182 780 , an ER antagonist that inhibits both ERalpha and ERbeta activities .	In our data, ERK1 and ERK2 phosphorylation induced by E 2 was inhibited in the presence of ICI 182 780, an ER antagonist that inhibits both ERalpha and ERbeta activities.	23	31	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	23	24	30	31
The suppressive effects of E2 and/or ERbeta in hypoxia treated NRVMs were totally reversed by ER antagonist , ICI .	The suppressive effects of E2 and/or ERbeta in hypoxia treated NRVMs were totally reversed by ER antagonist, ICI.	2	16	reversed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	15	16	6	7
In in vitro studies , estradiol significantly increased cell proliferation of A549 + ERalpha or A549 + ERbeta , which was significantly suppressed by selective ER modulators , tamoxifen or raloxifene .	In in vitro studies, estradiol significantly increased cell proliferation of A549 + ERalpha or A549 + ERbeta, which was significantly suppressed by selective ER modulators, tamoxifen or raloxifene.	7	26	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	25	26	17	18
The results show that IL-2 up-regulates the level of ERalpha protein and the expression of ERalpha mRNA , but down-regulates those of ERbeta .	The results show that IL-2 up-regulates the level of ERalpha protein and the expression of ERalpha mRNA, but down-regulates those of ERbeta.	4	23	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERalpha protein	IL-2 up-regulates the level of ERalpha protein	eralpha protein	ERbeta	ERbeta	erbeta	9	11	22	23
Immunocytochemical staining showed that leptin significantly increased the expression of ER-alpha and decreased that of ER-beta in PC-3 cells .	Immunocytochemical staining showed that leptin significantly increased the expression of ER-alpha and decreased that of ER-beta in PC-3 cells.	4	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ER-alpha	leptin significantly increased the expression of ER-alpha	er-alpha	ER-beta	ER-beta	er-beta	10	11	15	16
Based on our preliminary study [ XREF_BIBR ] , we hypothesize that the primary pathway by which isoflavones will suppress prostate tumorigenesis is mediated by the ERbeta , which can be suppressed by ERalpha in prostate cancer cells such that ERbeta is decreased .	Based on our preliminary study [XREF_BIBR], we hypothesize that the primary pathway by which isoflavones will suppress prostate tumorigenesis is mediated by the ERbeta, which can be suppressed by ERalpha in prostate cancer cells such that ERbeta is decreased.	23	37	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	33	34	26	27
Our previous data demonstrated that ER-alpha and ER-beta proteins are expressed in the oligodendrocyte lineage and decrease with maturation , suggesting an important role of ER-alpha and ER-beta during oligodendroglial development .	Our previous data demonstrated that ER-alpha and ER-beta proteins are expressed in the oligodendrocyte lineage and decrease with maturation, suggesting an important role of ER-alpha and ER-beta during oligodendroglial development.	5	28	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ER-alpha	ER-alpha	ER-alpha	ER-beta	ER-beta	ER-beta	5	6	27	28
In essence , the suppression of more than half of the ERalpha repressed genes was reversed in the presence of ERbeta .	In essence, the suppression of more than half of the ERalpha repressed genes was reversed in the presence of ERbeta.	8	21	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	11	12	20	21
The ERalpha agonist and ERbeta antagonist R , R-THC [ XREF_BIBR ] significantly inhibited the ERbeta mediated induction of ERELUC activity by E 2 , DHEA , 7-oxo-DHEA , ADIOL , and ADIONE , but did not inhibit ERELUC activation mediated by ERalpha .	The ERalpha agonist and ERbeta antagonist R,R-THC [XREF_BIBR] significantly inhibited the ERbeta mediated induction of ERELUC activity by E 2, DHEA, 7-oxo-DHEA, ADIOL, and ADIONE, but did not inhibit ERELUC activation mediated by ERalpha.	1	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	1	2	15	16
Given that combined inhibition of ERalpha and ERbeta using ICI caused partial reversal of NO mediated inhibition of VSMC , but not ERalpha or ERbeta alone , we wanted to examine this further .	Given that combined inhibition of ERalpha and ERbeta using ICI caused partial reversal of NO mediated inhibition of VSMC, but not ERalpha or ERbeta alone, we wanted to examine this further.	3	25	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	5	6	24	25
2 ) JKF and PTH up-regulated ERalpha and JKF downregulated ERbeta in both Ob , while PTH stimulated it in post- ( poOb ) and inhibited it in prOb .	2) JKF and PTH up-regulated ERalpha and JKF downregulated ERbeta in both Ob, while PTH stimulated it in post- (poOb) and inhibited it in prOb.	6	11	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	6	7	10	11
In addition , the pure ER antagonist , ICI , blocked ERalpha and ERbeta transcriptional activity in response to all three EDCs [ see Supplemental Material , XREF_SUPPLEMENTARY ( http://dx.doi.org/10.1289/ehp.1104689 ) ] .	In addition, the pure ER antagonist, ICI, blocked ERalpha and ERbeta transcriptional activity in response to all three EDCs [see Supplemental Material, XREF_SUPPLEMENTARY (http://dx.doi.org/10.1289/ehp.1104689)].	5	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ER	ER	ER	ERbeta	ERbeta	ERbeta	5	6	13	14
ERalpha , ERbeta , and PR expression was upregulated in MetS bladder , where tamoxifen decreased ERalpha and PR expression , further stimulating ERbeta .	ERalpha, ERbeta, and PR expression was upregulated in MetS bladder, where tamoxifen decreased ERalpha and PR expression, further stimulating ERbeta.	10	24	stimulating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERalpha	MetS bladder, where tamoxifen decreased ERalpha and PR expression	eralpha	ERbeta	ERbeta	erbeta	16	17	23	24
On the other hand , a low dose of BPA ( 2 mug/kg/day ) increased Esr1 expression in whole hypothalamus of male and female rats , and decreased Esr2 , an effect that was seen only in males .	On the other hand, a low dose of BPA (2 mug/kg/day) increased Esr1 expression in whole hypothalamus of male and female rats, and decreased Esr2, an effect that was seen only in males.	9	31	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Esr1	BPA (2 mug/kg/day) increased Esr1 expression	esr1	Esr2	Esr2	esr2	15	16	28	29
In this clinical trial , we are testing the hypothesis that the pathway by which Isoflavones will suppress prostate tumorigenesis is mediated by the ERbeta , which can be suppressed by ERalpha in PCa cells such that ERbeta is decreased .	In this clinical trial, we are testing the hypothesis that the pathway by which Isoflavones will suppress prostate tumorigenesis is mediated by the ERbeta, which can be suppressed by ERalpha in PCa cells such that ERbeta is decreased.	21	34	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	31	32	24	25
Specific activation of ERbeta by DPN can regulate GluR2 and GluR3 expression while activation of ERalpha by estradiol or PPT does not regulate these subunits and may block ERbeta regulation as shown by co-administration of DPN and PPT .	Specific activation of ERbeta by DPN can regulate GluR2 and GluR3 expression while activation of ERalpha by estradiol or PPT does not regulate these subunits and may block ERbeta regulation as shown by co-administration of DPN and PPT.	13	29	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERalpha	ERalpha	ERalpha	ERbeta	ERbeta	ERbeta	15	16	28	29
In the TNF-alpha signaling pathways , activation of IKK , ERK and JNK ( c-JUN NH2 terminal kinase ) were reported to inhibit the transcriptional activity of PPARgamma , but p38 was reported to enhance the function of PPARgamma .	In the TNF-alpha signaling pathways, activation of IKK, ERK and JNK (c-JUN NH2 terminal kinase) were reported to inhibit the transcriptional activity of PPARgamma, but p38 was reported to enhance the function of PPARgamma.	6	28	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	10	11	27	28
By preferentially dephosphorylating both transcription factors at their respective ERK phosphorylation sites , PP5 suppresses RUNX2 and stimulates PPARgamma transcriptional activity .	By preferentially dephosphorylating both transcription factors at their respective ERK phosphorylation sites, PP5 suppresses RUNX2 and stimulates PPARgamma transcriptional activity.	2	20	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	dephosphorylating both transcription factors at their respective ERK phosphorylation sites, PP5 suppresses	erk	PPARgamma	PPARgamma	ppargamma	9	10	18	19
Since ERK inhibits PPARgamma and targets it for proteasomal degradation , this effect may also account for the reduction of PPARgamma in the mammary gland of pregnant transgenic mice ( XREF_SUPPLEMENTARY ) .	Since ERK inhibits PPARgamma and targets it for proteasomal degradation, this effect may also account for the reduction of PPARgamma in the mammary gland of pregnant transgenic mice (XREF_SUPPLEMENTARY).	1	5	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	1	2	3	4
Because the PGF2alpha receptor can activiate the MAPK pathway while the activiation of the MAPK pathway can inhibit the PPARgamma pathway .	Because the PGF2alpha receptor can activiate the MAPK pathway while the activiation of the MAPK pathway can inhibit the PPARgamma pathway.	14	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	14	15	19	20
Several studies demonstrate that MAPK phosphorylation deactivates PPARgamma and reduces basal and ligand dependent transcriptional activity .	Several studies demonstrate that MAPK phosphorylation deactivates PPARgamma and reduces basal and ligand dependent transcriptional activity.	4	8	deactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK phosphorylation	mapk	PPARgamma	PPARgamma	ppargamma	4	5	7	8
PD98 ,059 , a MAPK and ERK kinase inhibitor , reversed the stretch induced reduction of PPARgamma ( 2 ) at both mRNA and protein levels achieved during the induction period .	PD98,059, a MAPK and ERK kinase inhibitor, reversed the stretch induced reduction of PPARgamma (2) at both mRNA and protein levels achieved during the induction period.	6	26	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	6	7	16	17
Persistent activation of ERK was shown to inhibit PPARgamma activity through a direct phosphorylation [ XREF_BIBR ] ( XREF_FIG ) .	Persistent activation of ERK was shown to inhibit PPARgamma activity through a direct phosphorylation [XREF_BIBR] (XREF_FIG).	1	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	3	4	8	9
ERK suppresses the PPAR-gamma transcriptional activity .	ERK suppresses the PPAR-gamma transcriptional activity.	0	5	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPAR-gamma	PPAR-gamma	PPAR-gamma	0	1	3	4
It is conceivable that the ability of MKP-1 to regulate ERK1/2 activity in adipocytes may influence the activity of the master regulator of adipogenesis , the peroxisome proliferator activated receptor gamma ( PPARgamma ) , which is negatively regulated by ERK1/2 phosphorylation [ XREF_BIBR ] .	It is conceivable that the ability of MKP-1 to regulate ERK1/2 activity in adipocytes may influence the activity of the master regulator of adipogenesis, the peroxisome proliferator activated receptor gamma (PPARgamma), which is negatively regulated by ERK1/2 phosphorylation [XREF_BIBR].	30	43	negatively regulated	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2 phosphorylation	erk1/2	PPARgamma	PPARgamma	ppargamma	40	41	32	33
Specific inhibitors of JNK and p38MAPK , but not ERK , effectively inhibited AGEs induced down-regulation of PPARgamma and the reduction of collagen II.	Specific inhibitors of JNK and p38MAPK, but not ERK, effectively inhibited AGEs induced down-regulation of PPARgamma and the reduction of collagen II.	1	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	9	10	17	18
Conversely , the dual specific GRK2 and ERK cascade inhibitor , RKIP ( Raf kinase inhibitor protein ) , triggered dysfunctional cardiomyocyte energetics and the expression of heart failure promoting Pparg regulated genes .	Conversely, the dual specific GRK2 and ERK cascade inhibitor, RKIP (Raf kinase inhibitor protein), triggered dysfunctional cardiomyocyte energetics and the expression of heart failure promoting Pparg regulated genes.	7	31	promoting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	Pparg	Pparg	Pparg	7	8	30	31
Thus , it can be suggested that UDCA may lower sensitivity of cells to adipogenic stimuli by Erk1/2 - dependent inhibition of PPARgamma .	Thus, it can be suggested that UDCA may lower sensitivity of cells to adipogenic stimuli by Erk1/2 - dependent inhibition of PPARgamma.	9	23	inhibition	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	Erk1/2	Erk1/2	Erk1/2	PPARgamma	PPARgamma	PPARgamma	17	18	22	23
Supporting the authors arguments , the AKR1C3 mediated product PGF 2 , binds to its prostanoid receptor and induces MAPK signaling , thereby inactivating PPARgamma .	Supporting the authors arguments, the AKR1C3 mediated product PGF 2, binds to its prostanoid receptor and induces MAPK signaling, thereby inactivating PPARgamma.	19	25	inactivating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	19	20	24	25
Reciprocally MAPK cascade activation antagonizes PPARgamma by promoting its nuclear exclusion [ XREF_BIBR ] .	Reciprocally MAPK cascade activation antagonizes PPARgamma by promoting its nuclear exclusion [XREF_BIBR].	1	6	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	1	2	5	6
However , GPR40 activation by these drugs also turns on ERK1/2 , a stress kinase pathway that suppresses PPARgamma signaling and promotes inflammation .	However, GPR40 activation by these drugs also turns on ERK1/2, a stress kinase pathway that suppresses PPARgamma signaling and promotes inflammation.	8	19	suppresses	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	PPARgamma	PPARgamma	PPARgamma	10	11	18	19
If this serine is substituted by alanine ( S82A in mice , or S84A in human ) , MAPK mediated PPARgamma inhibition is lost [ XREF_BIBR , XREF_BIBR ] .	If this serine is substituted by alanine (S82A in mice, or S84A in human), MAPK mediated PPARgamma inhibition is lost [XREF_BIBR, XREF_BIBR].	18	21	mediated	Positive_early_activation	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	18	19	20	21
While GPR40 and p38 MAPK activation augments the genomic effects of PPARgamma , ERK1/2 phosphorylates and thereby inactivates PPARgamma , and separately has inflammatory and proliferative effects in the vasculature .	While GPR40 and p38 MAPK activation augments the genomic effects of PPARgamma, ERK1/2 phosphorylates and thereby inactivates PPARgamma, and separately has inflammatory and proliferative effects in the vasculature.	13	22	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	PPARgamma	PPARgamma	PPARgamma	13	14	18	19
( iv ) AngII-TGF-beta1-p38 MAPK mediated reduction of PPARgamma in VSMCs is independent of AngII induced Bcr kinase activation .	(iv) AngII-TGF-beta1-p38 MAPK mediated reduction of PPARgamma in VSMCs is independent of AngII induced Bcr kinase activation.	3	10	reduction	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	PPARgamma	PPARgamma	PPARgamma	4	5	8	9
Various studies have shown that PPARgamma is one of the downstream effectors and that activation of the ERK1/2 cascade can phosphorylate and thereby inhibit PPARgamma activity XREF_BIBR - XREF_BIBR .	Various studies have shown that PPARgamma is one of the downstream effectors and that activation of the ERK1/2 cascade can phosphorylate and thereby inhibit PPARgamma activity XREF_BIBR - XREF_BIBR.	17	26	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	PPARgamma	PPARgamma	PPARgamma	17	18	24	25
Whereas activation of ERK during precursor cell proliferation is required for clonal expansion , activation of ERK at the final stages of differentiation inhibits PPARgamma and abrogates adipocyte differentiation XREF_BIBR .	Whereas activation of ERK during precursor cell proliferation is required for clonal expansion, activation of ERK at the final stages of differentiation inhibits PPARgamma and abrogates adipocyte differentiation XREF_BIBR.	14	25	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	16	17	24	25
On the other hand , in non Smad pathway curcumin reduced TGF-beta1-induced ERK phosphorylation and PPARgamma phosphorylation , and promoted nuclear translocation of PPARgamma .	On the other hand, in non Smad pathway curcumin reduced TGF-beta1-induced ERK phosphorylation and PPARgamma phosphorylation, and promoted nuclear translocation of PPARgamma.	9	24	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	curcumin reduced TGF-beta1-induced ERK phosphorylation	erk	PPARgamma	PPARgamma	ppargamma	12	13	23	24
ERK and JNK was reported to inhibit PPARgamma function by a direct phosphorylation of serine residues in PPARgamma , such as Ser112 in PPARgamma2 .	ERK and JNK was reported to inhibit PPARgamma function by a direct phosphorylation of serine residues in PPARgamma, such as Ser112 in PPARgamma2.	0	8	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	0	1	7	8
It is probable that the dasatinib associated inhibition of Erk1/2 activity might induce a partial increase of PPARgamma strongly potentiated by dexamethsone .	It is probable that the dasatinib associated inhibition of Erk1/2 activity might induce a partial increase of PPARgamma strongly potentiated by dexamethsone.	9	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Erk1/2	Erk1/2	Erk1/2	PPARgamma	PPARgamma	PPARgamma	9	10	17	18
ERK and p-38 activation have been previously established as part of GPR54 signaling , On the other hand , inhibition of MAPK and ERK signaling pathway was reported to suppress adipogenesis and down regulation of PPARgamma .	ERK and p-38 activation have been previously established as part of GPR54 signaling, On the other hand, inhibition of MAPK and ERK signaling pathway was reported to suppress adipogenesis and down regulation of PPARgamma.	0	36	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PPARgamma	PPARgamma	PPARgamma	0	1	35	36
It was previously demonstrated that PPARgamma activity is attenuated upon mitogenic stimulation due to phosphorylation of its Ser84 by ERKs .	It was previously demonstrated that PPARgamma activity is attenuated upon mitogenic stimulation due to phosphorylation of its Ser84 by ERKs.	5	20	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ERKs	ERKs	ERKs	PPARgamma	PPARgamma	PPARgamma	19	20	5	6
Notably , 6 h thrombin treatment significantly upregulated thrombin receptor Par4 and down-regulated thrombin receptor Par 3 while there was no change in the expression of thrombin receptor Par 1 .	Notably, 6 h thrombin treatment significantly upregulated thrombin receptor Par4 and down-regulated thrombin receptor Par 3 while there was no change in the expression of thrombin receptor Par 1.	4	15	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	4	5	13	15
9 PZ-128 was found to be effective at inhibiting both thrombin induced PAR1 activation and collagen initiated arterial thrombosis XREF_BIBR , XREF_BIBR in guinea pigs triggered by FeCl 3 injury .	9 PZ-128 was found to be effective at inhibiting both thrombin induced PAR1 activation and collagen initiated arterial thrombosis XREF_BIBR, XREF_BIBR in guinea pigs triggered by FeCl 3 injury.	8	13	induced	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	10	11	12	13
Given the pro- and anti-inflammatory effects mediated by PAR1 activation by thrombin and APC respectively , one attractive possibility is the selective inhibition of thrombin mediated PAR1 dependent vascular endothelial inflammatory effects in conditions such as sepsis .	Given the pro- and anti-inflammatory effects mediated by PAR1 activation by thrombin and APC respectively, one attractive possibility is the selective inhibition of thrombin mediated PAR1 dependent vascular endothelial inflammatory effects in conditions such as sepsis.	22	27	mediated	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	24	25	26	27
These effects were most likely targeted at PAR1 receptor cleavage , because ( 1 ) the level of thrombin generated during CPB did not vary significantly between groups , ( 2 ) expression of SPAN12 , which detects only uncleaved PAR1 receptors , was preserved in the aprotinin but not the placebo group ( P < 0.05 ) , and ( 3 ) supporting evidence in vitro showed reduced thrombin induced PAR1 cleavage ( P < 0.001 ) and platelet aggregation ( P < 0.001 ) in the presence of aprotinin .	These effects were most likely targeted at PAR1 receptor cleavage, because (1) the level of thrombin generated during CPB did not vary significantly between groups, (2) expression of SPAN12, which detects only uncleaved PAR1 receptors, was preserved in the aprotinin but not the placebo group (P < 0.05), and (3) supporting evidence in vitro showed reduced thrombin induced PAR1 cleavage (P < 0.001) and platelet aggregation (P < 0.001) in the presence of aprotinin.	68	72	induced	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	69	70	71	72
XREF_BIBR found that thrombin induced PAR-1 activation reduces alkaline phosphatase activity .	XREF_BIBR found that thrombin induced PAR-1 activation reduces alkaline phosphatase activity.	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	3	4	5	6
With the use of a synthetic peptide , corresponding to the tethered thrombin receptor ligand , and of a recombinant inactive form of thrombin , we provide direct evidence that both the inhibitory effect of thrombin on megakaryocyte proliferation and its agonist effect on mature megakaryocytes are mediated by a receptor analogous to the recently cloned platelet thrombin receptor .	With the use of a synthetic peptide, corresponding to the tethered thrombin receptor ligand, and of a recombinant inactive form of thrombin, we provide direct evidence that both the inhibitory effect of thrombin on megakaryocyte proliferation and its agonist effect on mature megakaryocytes are mediated by a receptor analogous to the recently cloned platelet thrombin receptor.	33	59	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	35	36	57	59
All anticoagulants were concentration dependent inhibitors of thrombin induced platelet activation and PAR-1 cleavage , but none inhibited PAR-1-AP or PAR-4-AP induced activation .	All anticoagulants were concentration dependent inhibitors of thrombin induced platelet activation and PAR-1 cleavage, but none inhibited PAR-1-AP or PAR-4-AP induced activation.	5	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	7	8	12	13
XREF_BIBR Blockage of ET A with BQ123 inhibits the effect of PAR-1 activated by thrombin on NMDA mediated nociceptive activity .	XREF_BIBR Blockage of ET A with BQ123 inhibits the effect of PAR-1 activated by thrombin on NMDA mediated nociceptive activity.	9	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	14	15	11	12
Thus , similar to the effect of RUNX1 depletion , 9 thrombin induced PAR-1 activation leads to CDKN1A and p21 upregulation and inhibits cell-cycle progression in human MLL-AF9 cells .	Thus, similar to the effect of RUNX1 depletion, 9 thrombin induced PAR-1 activation leads to CDKN1A and p21 upregulation and inhibits cell-cycle progression in human MLL-AF9 cells.	10	14	induced	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	11	12	13	14
Pre-treatment of GEC with either PR3 or elastase ( 1-5 microg/ml for 10 min ) induced a concentration dependent inhibition of thrombin mediated PAR1 receptor activation ( XREF_FIG ) .	Pre-treatment of GEC with either PR3 or elastase (1-5 microg/ml for 10 min) induced a concentration dependent inhibition of thrombin mediated PAR1 receptor activation (XREF_FIG).	19	25	mediated	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	21	22	23	24
Thus , the TM fragment containing epidermal growth factor like domains 4-6 potently inhibited the activation of PAR-1 by thrombin on HUVECs .	Thus, the TM fragment containing epidermal growth factor like domains 4-6 potently inhibited the activation of PAR-1 by thrombin on HUVECs.	13	20	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	19	20	17	18
Selective inhibition of thrombin mediated PAR1 activation may prevent the clear pro inflammatory effects of thrombin while allowing the cytoprotective effects of APC treatment in this condition .	Selective inhibition of thrombin mediated PAR1 activation may prevent the clear pro inflammatory effects of thrombin while allowing the cytoprotective effects of APC treatment in this condition.	1	6	mediated	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	3	4	5	6
Although CatS , NE , PR3 , and thrombin downregulated PAR1 these proteases did not significantly alter expression of MHC I in SC35 , SC38 , and SC40 , which might account for their different proteolytic cleavage sites .	Although CatS, NE, PR3, and thrombin downregulated PAR1 these proteases did not significantly alter expression of MHC I in SC35, SC38, and SC40, which might account for their different proteolytic cleavage sites.	1	11	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	8	9	10	11
However , in contrast to our findings , higher concentrations of thrombin are necessary to activate PAR4 because of the lack of a hirudin like thrombin binding sequence on PAR4 , while lower concentrations of thrombin are sufficient to activate PAR1 , which possesses this binding sequence ( Xu et al ., 1998 ) .	However, in contrast to our findings, higher concentrations of thrombin are necessary to activate PAR4 because of the lack of a hirudin like thrombin binding sequence on PAR4, while lower concentrations of thrombin are sufficient to activate PAR1, which possesses this binding sequence (Xu et al., 1998).	33	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	35	36	40	41
3.2.3 LMWH mediated attenuation of thrombin induced endothelial permeability is not achieved through inhibition of thrombin mediated PAR-1 cleavage .	3.2.3 LMWH mediated attenuation of thrombin induced endothelial permeability is not achieved through inhibition of thrombin mediated PAR-1 cleavage.	13	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	15	16	17	18
In conjunction with this , PAR-1 may have been down-regulated in response to activation by thrombin or/and MMP-1 .	In conjunction with this, PAR-1 may have been down-regulated in response to activation by thrombin or/and MMP-1.	5	17	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	15	16	5	6
In the present study , we demonstrate for the first time that SE increases thrombin levels and decreases PAR1 immunoreactivity .	In the present study, we demonstrate for the first time that SE increases thrombin levels and decreases PAR1 immunoreactivity.	12	19	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	thrombin	SE increases thrombin levels	thrombin	PAR1	PAR1	par1	14	15	18	19
Silencing of hPar2 by shRNA attenuated thrombin induced PAR1 signaling as recapitulated by inhibiting the assembly of Etk and Bmx or Akt onto PAR1-C-tail , by thrombin instigated colony formation and invasion .	Silencing of hPar2 by shRNA attenuated thrombin induced PAR1 signaling as recapitulated by inhibiting the assembly of Etk and Bmx or Akt onto PAR1-C-tail, by thrombin instigated colony formation and invasion.	6	9	induced	Positive_early_activation	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	6	7	8	9
EPCR on tumor cells may simply inhibit the tumor growth by inhibiting thrombin generation , and thereby reducing thrombin mediated PAR1 dependent tumor growth .	EPCR on tumor cells may simply inhibit the tumor growth by inhibiting thrombin generation, and thereby reducing thrombin mediated PAR1 dependent tumor growth.	17	21	mediated	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	18	19	20	21
Initially , we considered the rTM ' s thrombin inhibitory effects with thrombin activated PAR-1 signal downregulation and reduced endothelial inflammation were the major mechanisms 19 .	Initially, we considered the rTM 's thrombin inhibitory effects with thrombin activated PAR-1 signal downregulation and reduced endothelial inflammation were the major mechanisms 19.	3	18	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	8	9	14	15
Inhibition of thrombin mediated PAR-1 activation could add a new dimension in the domain of antiplatelet therapy .	Inhibition of thrombin mediated PAR-1 activation could add a new dimension in the domain of antiplatelet therapy.	0	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	4	5
Protein kinase C inhibitors , staurosporine and GF 109 203 X , do not affect thrombin receptor internalization induced by thrombin and TRAP but block receptor internalization stimulated by PMA .	Protein kinase C inhibitors, staurosporine and GF 109 203 X, do not affect thrombin receptor internalization induced by thrombin and TRAP but block receptor internalization stimulated by PMA.	15	22	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	thrombin receptor	thrombin receptor	thrombin receptor	20	21	15	17
Silencing PAR-2 by shRNA attenuates thrombin mediated PAR-1 activation , leading to reduced colony formation and decreased cell invasion [ XREF_BIBR ] .	Silencing PAR-2 by shRNA attenuates thrombin mediated PAR-1 activation, leading to reduced colony formation and decreased cell invasion [XREF_BIBR].	4	8	mediated	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	5	6	7	8
Irreversibly inhibiting thrombin using aspirin would also indirectly decrease PAR1 signaling by decreasing thrombin activity .	Irreversibly inhibiting thrombin using aspirin would also indirectly decrease PAR1 signaling by decreasing thrombin activity.	1	10	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	2	3	9	10
Here , we report that dabigatran at clinically relevant concentrations is an effective and acute inhibitor of thrombin induced PAR1 cleavage , activation , internalization , and beta-arrestin recruitment in vitro .	Here, we report that dabigatran at clinically relevant concentrations is an effective and acute inhibitor of thrombin induced PAR1 cleavage, activation, internalization, and beta-arrestin recruitment in vitro.	15	20	induced	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR1	PAR1	PAR1	17	18	19	20
They inhibits thrombin induced platelet aggregation by competitively inhibiting PAR-1 .	They inhibits thrombin induced platelet aggregation by competitively inhibiting PAR-1.	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	2	3	9	10
We have demonstrated that ODSH significantly attenuates activation of PAR-1 by thrombin thereby preventing adverse effects of thrombin on human lung EC permeability .	We have demonstrated that ODSH significantly attenuates activation of PAR-1 by thrombin thereby preventing adverse effects of thrombin on human lung EC permeability.	6	13	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	11	12	9	10
The inhibition of atrial dilation was maximal at DTI concentrations ranging from 30 to 100 nmol/l as previously reported for the inhibition of thrombin mediated PAR-1 cleavage by dabigatran XREF_BIBR , but it decreased with high plasma concentrations ( XREF_FIG ) .	The inhibition of atrial dilation was maximal at DTI concentrations ranging from 30 to 100 nmol/l as previously reported for the inhibition of thrombin mediated PAR-1 cleavage by dabigatran XREF_BIBR, but it decreased with high plasma concentrations (XREF_FIG).	21	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	thrombin	thrombin	thrombin	PAR-1	PAR-1	PAR-1	23	24	25	26
sFasL can also compete with mFasL for Fas binding , thereby inhibiting FasL and Fas signaling [ XREF_BIBR ] .	sFasL can also compete with mFasL for Fas binding, thereby inhibiting FasL and Fas signaling [XREF_BIBR].	0	17	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	0	1	14	15
This autocrine secretion and binding of soluble FasL to Fas on melanoma cells blocks engagement of Fas with cell membrane FasL that is expressed on CTL and NK cells .	This autocrine secretion and binding of soluble FasL to Fas on melanoma cells blocks engagement of Fas with cell membrane FasL that is expressed on CTL and NK cells.	2	17	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	7	8	16	17
Fas-Fc , which contains the extracellular domain of Fas fused to an Ig Fc domain , is an antagonist known to block activation of Fas by FasL .	Fas-Fc, which contains the extracellular domain of Fas fused to an Ig Fc domain, is an antagonist known to block activation of Fas by FasL.	21	27	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	26	27	24	25
Moreover , pre-treatment of FasL transfected L5178Y cells with either oestradiol or anti-FasL antibody inhibited significantly the apoptosis of Fas sensitive Hela cells when two types of cells were co-cultured .	Moreover, pre-treatment of FasL transfected L5178Y cells with either oestradiol or anti-FasL antibody inhibited significantly the apoptosis of Fas sensitive Hela cells when two types of cells were co-cultured.	2	22	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	4	5	19	20
FasL suppresses immune responses by inducing apoptosis of Fas bearing activated lymphocytes .	FasL suppresses immune responses by inducing apoptosis of Fas bearing activated lymphocytes.	0	9	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	0	1	8	9
APG101 effectively binds to CD95L expressed on target cells as well as to functionally active ligand in solution , and thus inhibiting CD95 activation .	APG101 effectively binds to CD95L expressed on target cells as well as to functionally active ligand in solution, and thus inhibiting CD95 activation.	2	23	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD95L	CD95L expressed	cd95l	CD95	CD95	cd95	4	5	22	23
Transcriptional regulation of FasL results in constitutive expression in tissues such as the eye and testis that may contribute to immune tolerance through inducing apoptosis in infiltrating lymphocytes , whereas FasL dynamically expressed on T cells can eliminate Fas sensitive cells in tissues where FasL may not be expressed .	Transcriptional regulation of FasL results in constitutive expression in tissues such as the eye and testis that may contribute to immune tolerance through inducing apoptosis in infiltrating lymphocytes, whereas FasL dynamically expressed on T cells can eliminate Fas sensitive cells in tissues where FasL may not be expressed.	30	40	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	FasL dynamically expressed	fasl	Fas	Fas	fas	30	31	38	39
Although CD95 deficient neutrophils rolled at a similar velocity as Fas <_f/f> neutrophils ( XREF_FIG ) , CD95L i.v .-injection or CD95L coating failed to reduce neutrophils ' rolling velocity in Fas <_f/f> : : Lyz2 <Cre> mice ( XREF_FIG ) .	Although CD95 deficient neutrophils rolled at a similar velocity as Fas < f/f> neutrophils (XREF_FIG), CD95L i.v.-injection or CD95L coating failed to reduce neutrophils ' rolling velocity in Fas < f/f> : : Lyz2 <Cre> mice (XREF_FIG).	17	32	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD95L	CD95L	CD95L	Fas	Fas	Fas	17	18	31	32
We deem that FasL positive hepatocytes might express cytotoxic activity and eliminate Fas positive hepatocytes by both ' fratricide ' and ' suicide ' .	We deem that FasL positive hepatocytes might express cytotoxic activity and eliminate Fas positive hepatocytes by both ' fratricide ' and ' suicide '.	3	14	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	12	13
In contrast to the conventional paradigm , which holds that Fas dependent apoptosis is initiated by the binding of lymphocyte Fas ligand to target cell Fas , our data suggest that up-regulated RTC Fas binds to Fas ligand on adjacent RTC , which then leads to RTC death by fratricide .	In contrast to the conventional paradigm, which holds that Fas dependent apoptosis is initiated by the binding of lymphocyte Fas ligand to target cell Fas, our data suggest that up-regulated RTC Fas binds to Fas ligand on adjacent RTC, which then leads to RTC death by fratricide.	10	22	initiated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	20	22	10	11
Therefore , high expression of FasL and TRAIL in SCC prevents the effectors cells to attack , and , moreover , this expression is misleading TRAIL-R1 , -R2 , Fas and FLIP , and accounts for tumor resistance to apoptosis .	Therefore, high expression of FasL and TRAIL in SCC prevents the effectors cells to attack, and, moreover, this expression is misleading TRAIL-R1, -R2, Fas and FLIP, and accounts for tumor resistance to apoptosis.	3	30	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	expression of FasL	fasl	Fas	Fas	fas	5	6	29	30
Interestingly , low expression of cell surface FasL , vs. high levels of the apoptosis inhibiting soluble Fas ( sFas ) has also been related to fibro proliferation .	Interestingly, low expression of cell surface FasL, vs. high levels of the apoptosis inhibiting soluble Fas (sFas) has also been related to fibro proliferation.	3	19	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	expression of cell surface FasL	fasl	Fas	Fas	fas	7	8	17	18
There is also an inhibition of the death receptor Fas and its ligand FasL in splenic erythroid cells , which promotes survival .	There is also an inhibition of the death receptor Fas and its ligand FasL in splenic erythroid cells, which promotes survival.	1	17	is also an inhibition	Negative_activation_copula_1	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	13	14	9	10
Constitutive expression of Fas ligand within the privileged site might also prevent immune mediated damage by eliminating Fas expressing T cells .	Constitutive expression of Fas ligand within the privileged site might also prevent immune mediated damage by eliminating Fas expressing T cells.	1	18	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fas ligand	expression of Fas ligand	fas ligand	Fas	Fas	fas	3	5	17	18
Tumor infiltrating , Fas ligand ( FasL )-expressing lymphocytes are able to eliminate Fas bearing tumor cells by apoptosis induction .	Tumor infiltrating, Fas ligand (FasL)-expressing lymphocytes are able to eliminate Fas bearing tumor cells by apoptosis induction.	3	16	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	3	5	13	14
Blocking of SW480 FasL activity with a recombinant anti-FasL significantly reduced mesothelial apoptosis in our co-culture model and supports the role of the Fas death ligand and receptor system in mesothelial invasion .	Blocking of SW480 FasL activity with a recombinant anti-FasL significantly reduced mesothelial apoptosis in our co-culture model and supports the role of the Fas death ligand and receptor system in mesothelial invasion.	3	25	supports	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	3	4	23	24
Through structure-function studies , we found that a YLGA amino-acid motif located near the extracellular N terminus of the Met alpha-subunit is necessary and sufficient to specifically bind the extracellular portion of Fas and to act as a potent FasL antagonist and inhibitor of Fas trimerization .	Through structure-function studies, we found that a YLGA amino-acid motif located near the extracellular N terminus of the Met alpha-subunit is necessary and sufficient to specifically bind the extracellular portion of Fas and to act as a potent FasL antagonist and inhibitor of Fas trimerization.	39	45	antagonist	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	39	40	44	45
Mutations of this critical cysteine residue highlight the physiological relevance of palmitoylation in Fas signalling , as formation of high-molecular Fas aggregates , Fas association with lipid rafts , FasL induced Fas internalisation , DISC formation and apoptosis were all strongly diminished .	Mutations of this critical cysteine residue highlight the physiological relevance of palmitoylation in Fas signalling, as formation of high-molecular Fas aggregates, Fas association with lipid rafts, FasL induced Fas internalisation, DISC formation and apoptosis were all strongly diminished.	27	32	induced	Positive_early_activation	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	29	30	31	32
FasL expressing mDC eliminated Fas ( + ) Jurkat T cells as well as activated primary T cells by apoptosis , whereas nonactivated primary T cells were not deleted .	FasL expressing mDC eliminated Fas (+) Jurkat T cells as well as activated primary T cells by apoptosis, whereas nonactivated primary T cells were not deleted.	0	5	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	FasL expressing	fasl	Fas	Fas	fas	0	1	4	5
Reporter gene and mRNA expression assays show that FasL activates fas transcriptional activity and this effect is inhibited by PI3K and Akt suppression .	Reporter gene and mRNA expression assays show that FasL activates fas transcriptional activity and this effect is inhibited by PI3K and Akt suppression.	8	12	activates	Positive_activation_token_1_verb	Positive_activation	Negative_activation	FasL	FasL	FasL	fas	fas	fas	8	9	10	11
FasL is constitutively expressed in the lung microenvironment and eliminates Fas + osteosarcoma cells leaving Fas - cells to form metastases .	FasL is constitutively expressed in the lung microenvironment and eliminates Fas + osteosarcoma cells leaving Fas - cells to form metastases.	0	13	eliminates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	FasL is constitutively expressed	fasl	Fas	Fas	fas	0	1	10	11
We have previously reported that the pro apoptotic protein FasL could potently suppress spontaneous lung metastasis of the Fas sensitive melanoma , K1735-P .	We have previously reported that the pro apoptotic protein FasL could potently suppress spontaneous lung metastasis of the Fas sensitive melanoma, K1735-P.	5	20	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	9	10	18	19
This relies on the YLGA aminoacid motif located near the N-terminal region of MET that specifically binds to the extracellular portion of FAS and acts as a FASL antagonist and inhibitor of FAS trimerization [ XREF_BIBR ] .	This relies on the YLGA aminoacid motif located near the N-terminal region of MET that specifically binds to the extracellular portion of FAS and acts as a FASL antagonist and inhibitor of FAS trimerization [XREF_BIBR].	27	35	antagonist	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	FASL	FASL	FASL	FAS	FAS	FAS	27	28	32	33
However , the upregulation of FasL by epithelial cells appears to block the effects of extrinsic Fas stimulation , probably functioning as a self-regulatory mechanism .	However, the upregulation of FasL by epithelial cells appears to block the effects of extrinsic Fas stimulation, probably functioning as a self-regulatory mechanism.	3	17	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FasL	FasL	FasL	Fas	Fas	Fas	5	6	16	17
Fas defective MRL and lpr mice exhibit lymphoaccumulation and accelerated lupus like disease due to impaired Fas mediated deletion of pathogenic T and B cells by Fas ligand ( FasL ) bearing CD4 and CD8 T cells [ XREF_BIBR ] .	Fas defective MRL and lpr mice exhibit lymphoaccumulation and accelerated lupus like disease due to impaired Fas mediated deletion of pathogenic T and B cells by Fas ligand (FasL) bearing CD4 and CD8 T cells [XREF_BIBR].	6	28	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Fas ligand	Fas ligand	Fas ligand	Fas	Fas	Fas	26	28	16	17
22 Conversely , in WT mice , metalloproteinases cleave mFasL to produce sFasL , which reduces the Fas death signaling .	22 Conversely, in WT mice, metalloproteinases cleave mFasL to produce sFasL, which reduces the Fas death signaling.	11	19	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	sFasL	sFasL	sFasL	Fas	Fas	Fas	12	13	17	18
In our investigations , although other death domain signaling pathways were not examined , we did confirmed that SpA induced deletion was unimpaired in Fas deficient mice ( XREF_FIG E ) .	In our investigations, although other death domain signaling pathways were not examined, we did confirmed that SpA induced deletion was unimpaired in Fas deficient mice (XREF_FIG E).	18	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SpA	SpA	SpA	Fas	Fas	Fas	18	19	24	25
FADD-DN inhibited caspase-8 activation induced by TRAIL in the transfectants of CM and NES2Y cells .	FADD-DN inhibited caspase-8 activation induced by TRAIL in the transfectants of CM and NES2Y cells.	0	3	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD-DN	FADD-DN	FADD-DN	caspase-8	caspase-8	caspase-8	0	1	2	3
Moreover , caspase-10 and caspase-8 , downstream targets of Fas and FADD , were activated and promoted release of the caspase-8 active fragments p18 and p10 ( XREF_FIG ) .	Moreover, caspase-10 and caspase-8, downstream targets of Fas and FADD, were activated and promoted release of the caspase-8 active fragments p18 and p10 (XREF_FIG).	7	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	11	12	20	21
Caspase-8 cleavage , for instance , can be inhibited by adaptor proteins such as phosphorprotein enriched in astrocytes-15 kDa and diabetes ( PEA-15 and PED ) , cellular FADD like interleukin-1beta-converting enzyme-inhibitory protein ( c-FLIP ) , and receptor interacting protein that are recruited by FADD to the DISC where they interact with caspase-8 , resulting in the inhibition of caspase-8 in the DISC and the cell resistance to TRAIL treatment .	Caspase-8 cleavage, for instance, can be inhibited by adaptor proteins such as phosphorprotein enriched in astrocytes-15 kDa and diabetes (PEA-15 and PED), cellular FADD like interleukin-1beta-converting enzyme-inhibitory protein (c-FLIP), and receptor interacting protein that are recruited by FADD to the DISC where they interact with caspase-8, resulting in the inhibition of caspase-8 in the DISC and the cell resistance to TRAIL treatment.	0	34	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FADD	FADD	FADD	Caspase-8	Caspase-8	Caspase-8	28	29	0	1
FADD down-regulation neither restored viability of PILP-1-treated cells nor attenuated production of active caspase-8 and t-Bid in PILP-1-treated cells , suggesting that the death receptor mediated pathway was not involved in the cytotoxicity of PILP-1 .	FADD down-regulation neither restored viability of PILP-1-treated cells nor attenuated production of active caspase-8 and t-Bid in PILP-1-treated cells, suggesting that the death receptor mediated pathway was not involved in the cytotoxicity of PILP-1.	0	15	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	0	1	13	14
As predicted , overexpression of FADD-DN prevented activation of caspase-8 and Bid cleavage and attenuated the release of cytochrome c and activation of caspases -2 , -7 , and -9 .	As predicted, overexpression of FADD-DN prevented activation of caspase-8 and Bid cleavage and attenuated the release of cytochrome c and activation of caspases -2, -7, and -9.	3	12	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD-DN	overexpression of FADD-DN	fadd-dn	caspase-8	caspase-8	caspase-8	5	6	9	10
This observation , coupled with the finding that non cleavable caspase-8 can rescue the developmental but not the apoptotic defects of the caspase-8 deficient animal [ XREF_BIBR ] , has led to the hypothesis that FADD dependent formation of a heterodimer composed of non cleaved caspase-8 and FLIP L could allow limited activation of caspase-8 .	This observation, coupled with the finding that non cleavable caspase-8 can rescue the developmental but not the apoptotic defects of the caspase-8 deficient animal [XREF_BIBR], has led to the hypothesis that FADD dependent formation of a heterodimer composed of non cleaved caspase-8 and FLIP L could allow limited activation of caspase-8.	35	55	allow	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	35	36	54	55
The combination of SD and hypoxia induced rapid activation of caspase-3 and -8 as well as DNA fragmentation , reaching a plateau within 4-8 h. Adenoviral expression of FADD-dn inhibited caspase-8 activation as well as hypoxia/SD induced apoptosis at 24 h in an moi ( multiplicity of infection )-dependent manner .	The combination of SD and hypoxia induced rapid activation of caspase-3 and -8 as well as DNA fragmentation, reaching a plateau within 4-8 h. Adenoviral expression of FADD-dn inhibited caspase-8 activation as well as hypoxia/SD induced apoptosis at 24 h in an moi (multiplicity of infection)-dependent manner.	26	31	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD-dn	expression of FADD-dn	fadd-dn	caspase-8	caspase-8	caspase-8	28	29	30	31
GlcNacylation of TRADD and FADD arginines prevented the maturation of Caspase-8 , a necessary component of the host apoptotic pathway , thus affording A/E pathogens the ability to thwart innate immune defense mechanisms of host cells .	GlcNacylation of TRADD and FADD arginines prevented the maturation of Caspase-8, a necessary component of the host apoptotic pathway, thus affording A/E pathogens the ability to thwart innate immune defense mechanisms of host cells.	2	14	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD	FADD	FADD	Caspase-8	Caspase-8	Caspase-8	4	5	10	11
BCG infection of BEAS-2B cells inhibits proliferation , induces cell cycle arrest at the G ( 0 )/G ( 1 ) phase , causes apoptosis , modulates transcription of multiple apoptosis-relevant genes , promotes translation of Fas , Fas-L , and FADD , upregulates expression of Fas and FADD proteins , and increases activity of caspase-3 and caspase-8 .	BCG infection of BEAS-2B cells inhibits proliferation, induces cell cycle arrest at the G (0)/G (1) phase, causes apoptosis, modulates transcription of multiple apoptosis-relevant genes, promotes translation of Fas, Fas-L, and FADD, upregulates expression of Fas and FADD proteins, and increases activity of caspase-3 and caspase-8.	0	58	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FADD	BCG infection of BEAS-2B cells inhibits proliferation, induces cell cycle arrest at the G (0)/G (1) phase, causes apoptosis, modulates transcription of multiple apoptosis-relevant genes, promotes translation of Fas, Fas-L, and FADD, upregulates expression of Fas and FADD	fadd	caspase-8	caspase-8	caspase-8	48	49	57	58
Similar to the keratinocytes , we generated FADD deficient Sharpin cpdm and cpdm MEFs and analyzed the effect of FADD deficiency on apoptosis induced by TNF alone and by TNF + CHX in Sharpin cpdm and cpdm MEFs ( XREF_FIG ) and observed that FADD deficiency significantly suppressed the annexin V positive cells and caspase-8 activity in Sharpin cpdm and cpdm MEFs ( XREF_FIG ) .	Similar to the keratinocytes, we generated FADD deficient Sharpin cpdm and cpdm MEFs and analyzed the effect of FADD deficiency on apoptosis induced by TNF alone and by TNF + CHX in Sharpin cpdm and cpdm MEFs (XREF_FIG) and observed that FADD deficiency significantly suppressed the annexin V positive cells and caspase-8 activity in Sharpin cpdm and cpdm MEFs (XREF_FIG).	44	55	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	44	45	54	55
Caspase-8 activation can be blocked by cellular FADD Like interleukin-1beta-converting enzyme Inhibitory Protein ( c-FLIP ) .	Caspase-8 activation can be blocked by cellular FADD Like interleukin-1beta-converting enzyme Inhibitory Protein (c-FLIP).	0	8	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FADD	FADD	FADD	Caspase-8	Caspase-8	Caspase-8	7	8	0	1
Interestingly , a Fas associated death-domain-containing protein ( FADD ) dominant negative mutant , which interfered with transmission of the extracellular death signals into cells through the Fas and tumour necrosis factor ( TNF ) receptor , failed to block JEV induced apoptosis and caspase-8 activation , implying that receptor oligomerization of the Fas and TNF pathway might not participate in JEV induced apoptosis .	Interestingly, a Fas associated death-domain-containing protein (FADD) dominant negative mutant, which interfered with transmission of the extracellular death signals into cells through the Fas and tumour necrosis factor (TNF) receptor, failed to block JEV induced apoptosis and caspase-8 activation, implying that receptor oligomerization of the Fas and TNF pathway might not participate in JEV induced apoptosis.	6	45	block	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	FADD	FADD	FADD	caspase-8	caspase-8	caspase-8	8	9	44	45
Coexpression of E1B 19K , FADD , and FLICE inhibited FLICE activation as indicated by the abundance of unprocessed proFLICE .	Coexpression of E1B 19K, FADD, and FLICE inhibited FLICE activation as indicated by the abundance of unprocessed proFLICE.	0	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD	Coexpression of E1B 19K, FADD	fadd	FLICE	FLICE	flice	5	6	10	11
Interestingly , loss of Fas did not cause a rescue of thymic cellularity in cwLckCre-CAML fl/fl ; Fas lpr and lpr mice ( XREF_FIG , compare 3 rd and 4 th columns ) .	Interestingly, loss of Fas did not cause a rescue of thymic cellularity in cwLckCre-CAML fl/fl; Fas lpr and lpr mice (XREF_FIG, compare 3 rd and 4 th columns).	2	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	loss of Fas	fas	Fas	Fas	fas	4	5	17	18
Taken together , the data illustrate that Fas resistance can be caused by reduced Fas expression , which is a result of an unidentified mode of regulation .	Taken together, the data illustrate that Fas resistance can be caused by reduced Fas expression, which is a result of an unidentified mode of regulation.	7	16	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Fas	Fas expression	fas	Fas	Fas	fas	14	15	7	8
Cu excess induced Cu accumulation , reduced the lipid content , FAS activity as well as the mRNA levels of 6PGD , G6PD , FAS , ACCalpha , PPARgamma , HSL and ATGL .	Cu excess induced Cu accumulation, reduced the lipid content, FAS activity as well as the mRNA levels of 6PGD, G6PD, FAS, ACCalpha, PPARgamma, HSL and ATGL.	6	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAS	levels of 6PGD, G6PD, FAS	fas	FAS	FAS	fas	24	25	11	12
These findings conflict with the generally accepted view that Fas mediates immune cell triggered apoptosis ; however , Fas stimulation can be antagonised by the expression of non functional Fas splicing variants , Decoy receptor 3 , the presence of soluble Fas , by Fas gene mutations , or by the expression of downstream inhibitors , such as XIAP or Bcl-2 .	These findings conflict with the generally accepted view that Fas mediates immune cell triggered apoptosis; however, Fas stimulation can be antagonised by the expression of non functional Fas splicing variants, Decoy receptor 3, the presence of soluble Fas, by Fas gene mutations, or by the expression of downstream inhibitors, such as XIAP or Bcl-2.	18	31	antagonised	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Fas	expression of non functional Fas	fas	Fas	Fas	fas	29	30	18	19
Fas expression at the cell surface can be modulated by MMP7 in a direct way ( by cleavage of the receptor ) XREF_BIBR or indirectly by upregulation of soluble forms of FasL which can block Fas XREF_BIBR .	Fas expression at the cell surface can be modulated by MMP7 in a direct way (by cleavage of the receptor) XREF_BIBR or indirectly by upregulation of soluble forms of FasL which can block Fas XREF_BIBR.	0	36	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fas	Fas expression at the cell surface can be modulated by MMP7	fas	Fas	Fas	fas	0	1	35	36
The elongation and desaturation of omega-6 and omega-3 FAs involve the same enzyme [ XREF_BIBR ] , indicating that high levels of omega-6 FAs can inhibit the conversion of omega-3 FAs .	The elongation and desaturation of omega-6 and omega-3 FAs involve the same enzyme [XREF_BIBR], indicating that high levels of omega-6 FAs can inhibit the conversion of omega-3 FAs.	20	31	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAs	levels of omega-6 FAs	fas	FAs	FAs	fas	23	24	30	31
Direct effects on bone-cell differentiation and apoptosis in vivo were confirmed in vitro , where addition of estradiol decreased Fas expression and partially abrogated the apoptotic and differentiation-inhibitory effect of Fas in osteoblast lineage cells , while having no effect on Fas induced apoptosis in osteoclast lineage cells .	Direct effects on bone-cell differentiation and apoptosis in vivo were confirmed in vitro, where addition of estradiol decreased Fas expression and partially abrogated the apoptotic and differentiation-inhibitory effect of Fas in osteoblast lineage cells, while having no effect on Fas induced apoptosis in osteoclast lineage cells.	17	31	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fas	estradiol decreased Fas expression	fas	Fas	Fas	fas	19	20	30	31
Interestingly , we found that combined resveratrol at non cytotoxic doses ( 5 , 10 , 20 , 40 and 50 muM , respectively ) with tamoxifen ( 50 muM ) could significantly reduce Akt and ERK1/2 phosphorylation and promote caspase-3 activation and PARP cleavage .	Interestingly, we found that combined resveratrol at non cytotoxic doses (5, 10, 20, 40 and 50 muM, respectively) with tamoxifen (50 muM) could significantly reduce Akt and ERK1/2 phosphorylation and promote caspase-3 activation and PARP cleavage.	6	44	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1/2	resveratrol at non cytotoxic doses (5, 10, 20, 40 and 50 muM, respectively) with tamoxifen (50 muM) could significantly reduce Akt and ERK1/2 phosphorylation	erk1/2	PARP	PARP	parp	36	37	43	44
Bosutinib blocks PF induced ERK1/2 activation and cleavage of caspase-3 and PARP but not BCR and ABL signaling .	Bosutinib blocks PF induced ERK1/2 activation and cleavage of caspase-3 and PARP but not BCR and ABL signaling.	0	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	ERK1/2	Bosutinib blocks PF induced ERK1/2	erk1/2	PARP	PARP	parp	4	5	11	12
Putative ERK targets such as histones , chromatin resident kinases and/or chromatin modifiers may act to activate PARP1 in a gene promoter specific manner in microglia by the modification of promoter chromatin structure .	Putative ERK targets such as histones, chromatin resident kinases and/or chromatin modifiers may act to activate PARP1 in a gene promoter specific manner in microglia by the modification of promoter chromatin structure.	1	18	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	PARP1	PARP1	PARP1	1	2	17	18
Similar to western blot analysis , PARP cleavage was primarily observed in cells treated with combined Src and MAPK pathway inhibitors .	Similar to western blot analysis, PARP cleavage was primarily observed in cells treated with combined Src and MAPK pathway inhibitors.	6	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	PARP	PARP	PARP	18	19	6	7
Compared with AAP treatment alone , IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage .	Compared with AAP treatment alone, IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage.	6	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	IGF-I and AAP co-treatment increased ERK1/2 phosphorylation	erk1/2	PARP	PARP	parp	11	12	15	16
Inhibition of ERK1/2 activities enhances a stimulation of PARP cleavage , a programmed cell death by apoptosis and chemosensitivity .	Inhibition of ERK1/2 activities enhances a stimulation of PARP cleavage, a programmed cell death by apoptosis and chemosensitivity.	2	9	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	PARP	PARP	PARP	2	3	8	9
In both cell lines , inhibition of ERK activity potentiated paclitaxel induced PARP cleavage and phosphatidylserine externalization , suggesting that ERK activity coincided with , but did not mediate , the cytotoxic effects of paclitaxel .	In both cell lines, inhibition of ERK activity potentiated paclitaxel induced PARP cleavage and phosphatidylserine externalization, suggesting that ERK activity coincided with, but did not mediate, the cytotoxic effects of paclitaxel.	7	13	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	PARP	PARP	PARP	7	8	12	13
Consequently , the activation of ERK1/2 ( pERK and ERK ) was also reduced ( pERK1 and ERK1 by 43.8 % and pERK2 and ERK2 by 53.3 % ; p < 0.05 ) in the HFD group .	Consequently, the activation of ERK1/2 (pERK and ERK) was also reduced (pERK1 and ERK1 by 43.8% and pERK2 and ERK2 by 53.3%; p < 0.05) in the HFD group.	3	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	ERK1	ERK1	ERK1	5	6	17	18
In T cell acute lymphoblastic leukaemia ( T-ALL ) , ERK1 , ERK2 and p38 are inactivated by the ERK and p38 phosphatase MKP1 ( also known as DUSP1 ) 48 .	In T cell acute lymphoblastic leukaemia (T-ALL), ERK1, ERK2 and p38 are inactivated by the ERK and p38 phosphatase MKP1 (also known as DUSP1) 48.	10	30	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	ERK1	ERK1	ERK1	19	20	10	11
Second , the p38 inhibitors SB202190 and SB203580 reduced nucleotide induced blebbing and actin reorganization , whereas the MAPK kinase-1/2 inhibitor U0126 , which blocks ERK1 and ERK2 activation , had no discernable effect .	Second, the p38 inhibitors SB202190 and SB203580 reduced nucleotide induced blebbing and actin reorganization, whereas the MAPK kinase-1/2 inhibitor U0126, which blocks ERK1 and ERK2 activation, had no discernable effect.	18	28	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ERK1	ERK1	ERK1	18	19	25	26
We conclude that ERK1 slowly autophosphorylates the T207 site and this phosphorylation is markedly stimulated with ERK1 activation , phosphorylation at this site inhibits the phosphotransferase activity of ERK1 toward other substrates , and it is involved in the dephosphorylation and deactivation of ERK1 by MAPK phosphatases .	We conclude that ERK1 slowly autophosphorylates the T207 site and this phosphorylation is markedly stimulated with ERK1 activation, phosphorylation at this site inhibits the phosphotransferase activity of ERK1 toward other substrates, and it is involved in the dephosphorylation and deactivation of ERK1 by MAPK phosphatases.	39	46	deactivation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	MAPK	MAPK	MAPK	ERK1	ERK1	ERK1	45	46	43	44
The expression of either an ERK inactivating phosphatase ( CL100 ) , or a kinase defective ERK1 , decreased the activity of a u-PAR promoter driven CAT reporter in RKO cells .	The expression of either an ERK inactivating phosphatase (CL100), or a kinase defective ERK1, decreased the activity of a u-PAR promoter driven CAT reporter in RKO cells.	1	17	inactivating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	expression of either an ERK	erk	ERK1	ERK1	erk1	5	6	16	17
Furthermore , EZH2 depletion does not change the AR levels , but decreases AR associated lysine methylation , leading to a change in the induction of its target genes .	Furthermore, EZH2 depletion does not change the AR levels, but decreases AR associated lysine methylation, leading to a change in the induction of its target genes.	2	14	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	EZH2	EZH2	EZH2	AR	AR	AR	2	3	13	14
Furthermore , it was demonstrated that depletion of EZH2 causes a decrease in AR associated lysine methylation at lysine 630 and 632 but the AR levels remain unchanged .	Furthermore, it was demonstrated that depletion of EZH2 causes a decrease in AR associated lysine methylation at lysine 630 and 632 but the AR levels remain unchanged.	6	14	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	EZH2	EZH2	EZH2	AR	AR	AR	8	9	13	14
Further , EZH2 may activate AR repressed genes in an androgen deprived environment because EZH2 is frequently overexpressed in metastatic prostate cancers 35 .	Further, EZH2 may activate AR repressed genes in an androgen deprived environment because EZH2 is frequently overexpressed in metastatic prostate cancers 35.	2	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	EZH2	EZH2	EZH2	AR	AR	AR	2	3	5	6
This study reported that the overexpression of N-Myc , a neuronal specific transcription factor highly enriched in ~ 40 % of CRPC-NE tumors and is associated with a range of neural cancers , increases EZH2 activity , which in turn , represses AR signaling and promotes an enhanced activation of the PI3K and AKT pathway to drive CRPC-NE development .	This study reported that the overexpression of N-Myc, a neuronal specific transcription factor highly enriched in ~ 40% of CRPC-NE tumors and is associated with a range of neural cancers, increases EZH2 activity, which in turn, represses AR signaling and promotes an enhanced activation of the PI3K and AKT pathway to drive CRPC-NE development.	34	43	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	EZH2	EZH2	EZH2	AR	AR	AR	34	35	42	43
These results suggest that the FADD- and caspase-8- dependent pathways block RIPK1- and RIPK3 dependent necroptosis during normal development .	These results suggest that the FADD- and caspase-8- dependent pathways block RIPK1- and RIPK3 dependent necroptosis during normal development.	4	15	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD-	FADD-	FADD-	RIPK1-	RIPK1-	RIPK1-	5	6	11	12
It was reported that RIPK1 is negatively regulated by caspase-8 and FADD once incorporated in the ripoptosome complex .	It was reported that RIPK1 is negatively regulated by caspase-8 and FADD once incorporated in the ripoptosome complex.	4	12	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FADD	FADD	FADD	RIPK1	RIPK1	RIPK1	11	12	4	5
However , the mechanism by which caspase-8 , FADD , and FLIP prevent runaway RIPK activation is unknown , and the signals that trigger these events during development and immune cell activation remain at large .	However, the mechanism by which caspase-8, FADD, and FLIP prevent runaway RIPK activation is unknown, and the signals that trigger these events during development and immune cell activation remain at large.	6	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FADD	FADD	FADD	RIPK	RIPK	RIPK	8	9	14	15
Finally , it is possible that a threshold effect might operate whereby lower levels of ERK1/2 activation are sufficient to activate RSK2 , but an increased level of activity is required for RSK1 .	Finally, it is possible that a threshold effect might operate whereby lower levels of ERK1/2 activation are sufficient to activate RSK2, but an increased level of activity is required for RSK1.	15	22	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	15	16	21	22
We also showed in vitro that inactivating mutations of RPS6KA3 ( 7 % ) induced an activation of the RAS and MAPK pathway with an over-expression of phosphorylated ERK1/2 ( XREF_SUPPLEMENTARY ) suggesting that RPS6KA3 mutated HCC could be targeted by ERK or MEK inhibitors .	We also showed in vitro that inactivating mutations of RPS6KA3 (7%) induced an activation of the RAS and MAPK pathway with an over-expression of phosphorylated ERK1/2 (XREF_SUPPLEMENTARY) suggesting that RPS6KA3 mutated HCC could be targeted by ERK or MEK inhibitors.	34	44	targeted	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	RPS6KA3	RPS6KA3	RPS6KA3	41	42	34	35
Furthermore , we found that AP-1 and NF-kappaB transactivation activities were downregulated by the inhibition of ERK1/2 mediated RSK2 activity [ XREF_BIBR , XREF_BIBR ] , suggesting that magnolin may suppress the gene expression of Cox-2 , an enzyme that plays an important role in cancer cell proliferation , motility and metastasis [ XREF_BIBR ] .	Furthermore, we found that AP-1 and NF-kappaB transactivation activities were downregulated by the inhibition of ERK1/2 mediated RSK2 activity [XREF_BIBR, XREF_BIBR], suggesting that magnolin may suppress the gene expression of Cox-2, an enzyme that plays an important role in cancer cell proliferation, motility and metastasis [XREF_BIBR].	14	19	mediated	Positive_early_activation	Positive_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	RSK2	RSK2	RSK2	16	17	18	19
This study investigates the role of caspase-8 and DN-FADD , an inhibitor of CD95 dependent caspase-8 activation , in gemcitabine induced apoptosis of Colo357 pancreatic cancer cells .	This study investigates the role of caspase-8 and DN-FADD, an inhibitor of CD95 dependent caspase-8 activation, in gemcitabine induced apoptosis of Colo357 pancreatic cancer cells.	4	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	CD95	CD95	CD95	DN-FADD	DN-FADD	DN-FADD	13	14	8	9
To assess the relative contribution of death receptor pathways to this sensitivity and to determine whether these effects are intrinsic to the tumor cells , we compared the chemosensitivity of isogenic BJAB human lymphoma cells where Fas and TRAIL receptors or just TRAIL receptors were inhibited using mutants of the adaptor protein FADD or by altering the expression of the homeobox transcription factor Six1 .	To assess the relative contribution of death receptor pathways to this sensitivity and to determine whether these effects are intrinsic to the tumor cells, we compared the chemosensitivity of isogenic BJAB human lymphoma cells where Fas and TRAIL receptors or just TRAIL receptors were inhibited using mutants of the adaptor protein FADD or by altering the expression of the homeobox transcription factor Six1.	36	53	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fas	Fas	Fas	protein FADD	protein FADD	protein FADD	36	37	51	53
If Fas and TLRs are activated simultaneously , activated Fas sequesters FADD and liberates MyD88 , allowing constitutive inflammation XREF_BIBR .	If Fas and TLRs are activated simultaneously, activated Fas sequesters FADD and liberates MyD88, allowing constitutive inflammation XREF_BIBR.	8	13	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fas	Fas	Fas	FADD	FADD	FADD	9	10	11	12
PKC , ERK , and ERBB2 kinase inhibitors suppress PMA induction of Sp1 and the specific isozyme PKCalpha enhances Sp1 cleavage .	PKC, ERK, and ERBB2 kinase inhibitors suppress PMA induction of Sp1 and the specific isozyme PKCalpha enhances Sp1 cleavage.	0	20	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	Sp1	Sp1	Sp1	2	3	19	20
ERK inhibition significantly decreased the abundance of SP-1 in the absence of protein synthesis in Rac1 null cells suggesting that ERK activation increases SP-1 stability ( XREF_FIG ) .	ERK inhibition significantly decreased the abundance of SP-1 in the absence of protein synthesis in Rac1 null cells suggesting that ERK activation increases SP-1 stability (XREF_FIG).	20	24	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK	ERK	ERK	SP-1	SP-1	SP-1	20	21	23	24
In addition , Hsp27 can inhibit the Fas induced apoptotic pathway by blocking the interaction of Daxx with Fas .	In addition, Hsp27 can inhibit the Fas induced apoptotic pathway by blocking the interaction of Daxx with Fas.	6	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	Daxx	Daxx	Daxx	7	8	16	17
Disruption of lipid rafts and Fas aggregation by MbetaCD restored the presence of Daxx in lipid rafts ( XREF_FIG ) .	Disruption of lipid rafts and Fas aggregation by MbetaCD restored the presence of Daxx in lipid rafts (XREF_FIG).	5	14	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Fas	Fas	Fas	Daxx	Daxx	Daxx	5	6	13	14
Furthermore , in S. mansoni the linker region of common mediator ( Co-) Smad4 contains three ERK phosphorylation motifs opening the possibility that ERK could restrict interaction of Smad4 with receptor activated ( R-) Smad2 to modify TGFbeta mediated outcomes XREF_BIBR XREF_BIBR .	Furthermore, in S. mansoni the linker region of common mediator (Co-) Smad4 contains three ERK phosphorylation motifs opening the possibility that ERK could restrict interaction of Smad4 with receptor activated (R-) Smad2 to modify TGFbeta mediated outcomes XREF_BIBR XREF_BIBR.	23	29	restrict	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK	ERK	ERK	Smad4	Smad4	Smad4	23	24	28	29
Our current study demonstrates that administration of FGF-2 suppressed the FGFR3 gene via the activation of ERK and MAPK in human articular chondrocytes .	Our current study demonstrates that administration of FGF-2 suppressed the FGFR3 gene via the activation of ERK and MAPK in human articular chondrocytes.	5	11	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF-2	FGF-2	FGF-2	FGFR3	FGFR3	FGFR3	7	8	10	11
FGF-2 highly upregulates FGFR3 in murine chondrocytes ( current study ) , whereas FGF-2 significantly downregulates FGFR3 in human articular chondrocytes ( 26 ) .	FGF-2 highly upregulates FGFR3 in murine chondrocytes (current study), whereas FGF-2 significantly downregulates FGFR3 in human articular chondrocytes (26).	13	20	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF-2	FGF-2	FGF-2	FGFR3	FGFR3	FGFR3	13	14	16	17
Our results also demonstrate that FGFR3 was negatively regulated by FGF-2 at the transcriptional level through the FGFR1-ERK ( extracellular signal regulated kinase ) signaling pathway in human articular chondrocytes .	Our results also demonstrate that FGFR3 was negatively regulated by FGF-2 at the transcriptional level through the FGFR1-ERK (extracellular signal regulated kinase) signaling pathway in human articular chondrocytes.	5	11	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FGF-2	FGF-2	FGF-2	FGFR3	FGFR3	FGFR3	10	11	5	6
Interestingly , both FGF-2 and FGF-18 down-regulated FGFR-3 mRNA and up-regulated FGF-18 mRNA .	Interestingly, both FGF-2 and FGF-18 down-regulated FGFR-3 mRNA and up-regulated FGF-18 mRNA.	2	10	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF-2	FGF-2	FGF-2	FGFR-3	FGFR-3	FGFR-3	3	4	7	8
To test whether desensitization to imatinib is , indeed , mediated by FGFR3 , we performed siRNA knockdown of FGFR1 , FGFR2 , and FGFR3 in GIST T1 , and subsequently treated with imatinib and FGF2 ( XREF_FIG ) .	To test whether desensitization to imatinib is, indeed, mediated by FGFR3, we performed siRNA knockdown of FGFR1, FGFR2, and FGFR3 in GIST T1, and subsequently treated with imatinib and FGF2 (XREF_FIG).	17	36	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	35	36	24	25
In addition , it has been reported that FGFR-3 is down-regulated by FGF-2 via the FGFR-1/ERK/MAPK pathway in human articular chondrocytes .	In addition, it has been reported that FGFR-3 is down-regulated by FGF-2 via the FGFR-1/ERK/MAPK pathway in human articular chondrocytes.	8	16	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FGF-2	FGF-2	FGF-2	FGFR-3	FGFR-3	FGFR-3	12	13	8	9
HuFGF23R176Q+ Klotho treatment upregulated FGFR1 ( IIIc ) and FGFR3 ( IIIc ) and downregulated FGFR2 ( IIIc ) , whereas FGF2 upregulated FGFR1 ( IIIc ) and downregulated both FGFR2 ( IIIc ) and FGFR3 ( IIIc ) .	HuFGF23R176Q+ Klotho treatment upregulated FGFR1 (IIIc) and FGFR3 (IIIc) and downregulated FGFR2 (IIIc), whereas FGF2 upregulated FGFR1 (IIIc) and downregulated both FGFR2 (IIIc) and FGFR3 (IIIc).	21	37	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF2	FGF2	FGF2	FGFR3	FGFR3	FGFR3	21	22	35	36
In addition , FGFR3 is down-regulated by FGF-2 signaling through FGFR1-ERK axis .	In addition, FGFR3 is down-regulated by FGF-2 signaling through FGFR1-ERK axis.	3	8	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FGF-2	FGF-2	FGF-2	FGFR3	FGFR3	FGFR3	7	8	3	4
Runx2 and FGF2 synergistically enhance Osteopontin expression ( > 100 fold ) , while FGF2 blocks Runx2 induction of Alkaline Phosphatase .	Runx2 and FGF2 synergistically enhance Osteopontin expression (> 100 fold), while FGF2 blocks Runx2 induction of Alkaline Phosphatase.	14	17	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	14	15	16	17
Moreover , in accordance with these changes , bFGF treatment delayed the downregulation of TERT , Sox2 and Oct4 , and suppressed the upregulation of Runx2 and ALP in culture MSCs .	Moreover, in accordance with these changes, bFGF treatment delayed the downregulation of TERT, Sox2 and Oct4, and suppressed the upregulation of Runx2 and ALP in culture MSCs.	8	27	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	bFGF	bFGF	bFGF	Runx2	Runx2	Runx2	8	9	25	26
Treatment of MC3T3 osteoblasts with the PLC inhibitor U73122 ( 2muM ) reduced the Cx43 dependent potentiation of the FGF2 induced Runx2 mediated transcription relative to vehicle treated controls ( XREF_FIG ) .	Treatment of MC3T3 osteoblasts with the PLC inhibitor U73122 (2muM) reduced the Cx43 dependent potentiation of the FGF2 induced Runx2 mediated transcription relative to vehicle treated controls (XREF_FIG).	16	23	induced	Positive_early_activation	Positive_activation	Negative_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	19	20	21	22
Interestingly , the depletion of FGF-2 by the specific siRNA , blocked the increased synthesis of both Runx-2 and CREBs induced by PTH ( 10 -9 M ) ( XREF_FIG ) .	Interestingly, the depletion of FGF-2 by the specific siRNA, blocked the increased synthesis of both Runx-2 and CREBs induced by PTH (10 -9 M) (XREF_FIG).	3	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FGF-2	FGF-2	FGF-2	Runx-2	Runx-2	Runx-2	5	6	17	18
Specifically , FGF-2 significantly downregulated Oct3/4 and Nanog , stem cell pluripotency markers ( XREF_FIG ) , upregulated Sox9 and PPARgamma2 , transcription factors that regulate chondrogenic- and adipogenic specific gene expression ( XREF_FIG ) , and downregulated Runx2 , a transcription factor that regulates osteogenic specific gene expression ( XREF_FIG ) .	Specifically, FGF-2 significantly downregulated Oct3/4 and Nanog, stem cell pluripotency markers (XREF_FIG), upregulated Sox9 and PPARgamma2, transcription factors that regulate chondrogenic- and adipogenic specific gene expression (XREF_FIG), and downregulated Runx2, a transcription factor that regulates osteogenic specific gene expression (XREF_FIG).	2	42	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF-2	FGF-2	FGF-2	Runx2	Runx2	Runx2	2	3	38	39
This result implies that the FGF2 induced anti-osteogenic effect may be a result of the COUP-TFII-mediated Runx2 suppression .	This result implies that the FGF2 induced anti-osteogenic effect may be a result of the COUP-TFII-mediated Runx2 suppression.	4	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF2	FGF2	FGF2	Runx2	Runx2	Runx2	5	6	16	17
Moreover , surface modification of FLG by alginate significantly increased the whole-body and intestinal levels of FLG , but reduced the internalization of FLG to the intestinal epithelial cells .	Moreover, surface modification of FLG by alginate significantly increased the whole-body and intestinal levels of FLG, but reduced the internalization of FLG to the intestinal epithelial cells.	3	17	increased	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	FLG	FLG	flg	FLG	levels of FLG	flg	5	6	16	17
The use of this system is required to achieve high level expression of the truncated FGFR-1 necessary to block endogenous FGFR-1 signaling with relatively low amounts of expression vector used for the transient transfection assays .	The use of this system is required to achieve high level expression of the truncated FGFR-1 necessary to block endogenous FGFR-1 signaling with relatively low amounts of expression vector used for the transient transfection assays.	11	21	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGFR-1	expression of the truncated FGFR-1	fgfr-1	FGFR-1	FGFR-1	fgfr-1	15	16	20	21
Furthermore , patients with coronary atherosclerosis showed that the loss of endothelial fibroblast growth factor receptor1 ( FGFR1 ) expression leads to activation of endothelial TGF-beta signaling and the development of EndMT in atherosclerotic plaques [ XREF_BIBR ] .	Furthermore, patients with coronary atherosclerosis showed that the loss of endothelial fibroblast growth factor receptor1 (FGFR1) expression leads to activation of endothelial TGF-beta signaling and the development of EndMT in atherosclerotic plaques [XREF_BIBR].	9	20	loss	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	fibroblast growth factor receptor1	fibroblast growth factor receptor1 (FGFR1) expression	fibroblast growth factor receptor1	fibroblast growth factor receptor1	fibroblast growth factor receptor1	fibroblast growth factor receptor1	12	16	12	16
Analysis of downstream pathways showed that constitutive expression of FGFR1 in M07e cells activated typical FGFR1 targets such as STAT3 , AKT and STAT5 .	Analysis of downstream pathways showed that constitutive expression of FGFR1 in M07e cells activated typical FGFR1 targets such as STAT3, AKT and STAT5.	7	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FGFR1	expression of FGFR1	fgfr1	FGFR1	FGFR1	fgfr1	9	10	15	16
Hippocampal FGFR1 mRNA expression has been reported to be upregulated in schizophrenia and major depression patients 12 and transgenic mice expressing a dominant negative mutant [ FGFR1 ( TK-) ] from the catecholaminergic , neuron specific tyrosine hydroxylase ( TH ) gene promoter have been found to exhibit a schizophrenia like syndrome 13 .	Hippocampal FGFR1 mRNA expression has been reported to be upregulated in schizophrenia and major depression patients 12 and transgenic mice expressing a dominant negative mutant [FGFR1 (TK-)] from the catecholaminergic, neuron specific tyrosine hydroxylase (TH) gene promoter have been found to exhibit a schizophrenia like syndrome 13.	1	27	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FGFR1	FGFR1 mRNA expression	fgfr1	FGFR1	FGFR1	fgfr1	1	2	26	27
As a positive control we also treated cells with FGF2 , which reduced membrane and total FGFR2 even more strongly than the mAbs .	As a positive control we also treated cells with FGF2, which reduced membrane and total FGFR2 even more strongly than the mAbs.	6	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF2	FGF2	FGF2	FGFR2	FGFR2	FGFR2	9	10	16	17
Similarly , LS174T cells treated with 3E8-mEndo or mEndo showed significant inhibition of bFGF induced FGFR-2 activation and the downstream signaling pathways including Akt and Src phosphorylation ( XREF_SUPPLEMENTARY ) .	Similarly, LS174T cells treated with 3E8-mEndo or mEndo showed significant inhibition of bFGF induced FGFR-2 activation and the downstream signaling pathways including Akt and Src phosphorylation (XREF_SUPPLEMENTARY).	11	16	induced	Positive_early_activation	Positive_activation	Negative_activation	bFGF	bFGF	bFGF	FGFR-2	FGFR-2	FGFR-2	13	14	15	16
The effects of FGF-9 and FGF-2 on FGFR and myelin protein levels were comparable ; both up-regulated FGFR-1 , and down-regulated FGFR-2 , CNP , PLP and MBP .	The effects of FGF-9 and FGF-2 on FGFR and myelin protein levels were comparable; both up-regulated FGFR-1, and down-regulated FGFR-2, CNP, PLP and MBP.	1	27	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF-2	FGF-2	FGF-2	FGFR-2	FGFR-2	FGFR-2	5	6	21	22
B-FGF induced FGFR2 activation attenuates PF induced growth inhibition and motility suppression .	B-FGF induced FGFR2 activation attenuates PF induced growth inhibition and motility suppression.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	B-FGF	B-FGF	B-FGF	FGFR2	FGFR2	FGFR2	0	1	2	3
Both fibulin-5 and fibrillin-1 , at molar ratios similar to those used here , have been reported to significantly lower the coacervation temperature of tropoelastin .	Both fibulin-5 and fibrillin-1, at molar ratios similar to those used here, have been reported to significantly lower the coacervation temperature of tropoelastin.	0	25	lower	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	fibulin-5	fibulin-5	fibulin-5	tropoelastin	tropoelastin	tropoelastin	1	2	24	25
If so , then reducing FGF10 mediated FGFR2 signaling by reducing Fgf10 or Fgfr2 gene dosage in Spry1/2 DKO embryos might rescue the mutant phenotype .	If so, then reducing FGF10 mediated FGFR2 signaling by reducing Fgf10 or Fgfr2 gene dosage in Spry1/2 DKO embryos might rescue the mutant phenotype.	4	8	mediated	Positive_early_activation	Positive_activation	Negative_activation	FGF10	FGF10	FGF10	FGFR2	FGFR2	FGFR2	5	6	7	8
The genetic knockdown of Fgf10 can rescue the skeletal as well as some of the visceral defects observed in this AS model , and restore a near normal level of FgfR2 signaling involving an apparent switch between ERK ( p44 and p42 ) and p38 phosphorylation .	The genetic knockdown of Fgf10 can rescue the skeletal as well as some of the visceral defects observed in this AS model, and restore a near normal level of FgfR2 signaling involving an apparent switch between ERK (p44 and p42) and p38 phosphorylation.	2	31	restore	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Fgf10	Fgf10	Fgf10	FgfR2	FgfR2	FgfR2	4	5	30	31
We herein demonstrated that stable FGF1 mutants with strong mitogenic activity not only exerted strong radioprotective effects , but also reduced the proliferative , invasive and migration capabilities of the murine angiosarcoma cell line ISOS-1 by strong FGF1 signaling through FGFR1 .	We herein demonstrated that stable FGF1 mutants with strong mitogenic activity not only exerted strong radioprotective effects, but also reduced the proliferative, invasive and migration capabilities of the murine angiosarcoma cell line ISOS-1 by strong FGF1 signaling through FGFR1.	20	41	reduced	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	FGF1	FGF1	FGF1	FGFR1	FGFR1	FGFR1	37	38	40	41
In line with the published data , we observed that in the presence of cycloheximide FGF1 induced time-course degradation of FGFR1 19 .	In line with the published data, we observed that in the presence of cycloheximide FGF1 induced time-course degradation of FGFR1 19.	15	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FGF1	FGF1	FGF1	FGFR1	FGFR1	FGFR1	15	16	20	21
In cell growth experiments , FGF1 , 2 , and 17 but not FGF19 inhibited the proliferation of FGFR3 expressing rat chondrosarcoma chondrocytes ( RCS ) with relative potency FGF2 > > FGF1 = FGF17 .	In cell growth experiments, FGF1, 2, and 17 but not FGF19 inhibited the proliferation of FGFR3 expressing rat chondrosarcoma chondrocytes (RCS) with relative potency FGF2>> FGF1 = FGF17.	5	20	inhibited	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	FGF1	FGF1	fgf1	FGFR3	FGFR3 expressing	fgfr3	5	6	18	19
To further document that inhibition of cleavage coincides with trapping FGFR3 at the PM , serum starved cells were treated with FGF1 in the presence or absence of inhibitors , cell surface biotinylated at the times indicated , and precipitated with NeutrAvidin Gel .	To further document that inhibition of cleavage coincides with trapping FGFR3 at the PM, serum starved cells were treated with FGF1 in the presence or absence of inhibitors, cell surface biotinylated at the times indicated, and precipitated with NeutrAvidin Gel.	7	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	FGF1	FGF1	FGF1	FGFR3	FGFR3	FGFR3	21	22	10	11
Wild-type FGFR4 phosphorylation was inhibited by ponatinib in a dose dependent manner for two fusion positive cell lines , RH4 and RH5 ( XREF_FIG ) , as well as the mutationally activated FGFR4 cell lines , RMS772 and FGFR4 N535K and FGFR4 V550E ( XREF_FIG ) .	Wild-type FGFR4 phosphorylation was inhibited by ponatinib in a dose dependent manner for two fusion positive cell lines, RH4 and RH5 (XREF_FIG), as well as the mutationally activated FGFR4 cell lines, RMS772 and FGFR4 N535K and FGFR4 V550E (XREF_FIG).	1	33	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FGFR4	FGFR4 phosphorylation	fgfr4	FGFR4	FGFR4	fgfr4	1	2	32	33
Dexamethasone significantly suppresses bFGF stimulated RGM-1 cells proliferation in part via down-regulation of FGFR1 and FGFR2 , then decreasing bFGF stimulated activation of ERK1 and ERK2 , followed by inhibition of COX-2 activation , and finally DNA synthesis .	Dexamethasone significantly suppresses bFGF stimulated RGM-1 cells proliferation in part via down-regulation of FGFR1 and FGFR2, then decreasing bFGF stimulated activation of ERK1 and ERK2, followed by inhibition of COX-2 activation, and finally DNA synthesis.	18	26	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	bFGF	bFGF	bFGF	ERK2	ERK2	ERK2	19	20	25	26
In vitro methylation of a robustly active FES promoter that mimics methylation patterns observed by bisulfite sequencing of HT-29 cell genomic DNA completely blocked the activity of the FES promoter in a reporter gene assay ( XREF_FIG ) .	In vitro methylation of a robustly active FES promoter that mimics methylation patterns observed by bisulfite sequencing of HT-29 cell genomic DNA completely blocked the activity of the FES promoter in a reporter gene assay (XREF_FIG).	2	29	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FES	methylation of a robustly active FES	fes	FES	FES	fes	7	8	28	29
In addition , myogenin expression was a positive target of this cooperation and this regulation occurred through a stimulation of myogenin promoter activity : ( 1 ) whereas c-Fos or Fra2 co-expression abrogated c-Jun stimulatory activity on this promoter , ATF2 co-expression potentiated this influence ; ( 2 ) using a dominant negative ATF2 mutant , we established that c-Jun transcriptional activity required functionality of endogenous ATF2 .	In addition, myogenin expression was a positive target of this cooperation and this regulation occurred through a stimulation of myogenin promoter activity : (1) whereas c-Fos or Fra2 co-expression abrogated c-Jun stimulatory activity on this promoter, ATF2 co-expression potentiated this influence; (2) using a dominant negative ATF2 mutant, we established that c-Jun transcriptional activity required functionality of endogenous ATF2.	28	35	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Fos	c-Fos or Fra2 co-expression	c-fos	c-Jun	c-Jun	c-jun	28	29	33	34
Knockdown of c-Fos , c-Jun and ATF-2 by siRNA reflected that c-Fos attenuated the effect of c-Jun and ATF-2 on Fas and FasL up-regulation .	Knockdown of c-Fos, c-Jun and ATF-2 by siRNA reflected that c-Fos attenuated the effect of c-Jun and ATF-2 on Fas and FasL up-regulation.	11	18	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Fos	c-Fos	c-Fos	c-Jun	c-Jun	c-Jun	11	12	16	17
Finally , we established that overexpressed c-fos and c-jun partially abolished the ability of retinoids to inhibit AP1 activity , suggesting that c-jun and/or c-fos containing dimers may constitute one target of retinoids for transrepression of AP1 .	Finally, we established that overexpressed c-fos and c-jun partially abolished the ability of retinoids to inhibit AP1 activity, suggesting that c-jun and/or c-fos containing dimers may constitute one target of retinoids for transrepression of AP1.	5	23	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-fos	c-fos	c-fos	c-jun	c-jun	c-jun	6	7	22	23
This c-Jun activity is inhibited by c-Fos , another protooncoprotein that can dimerize with c-Jun to form the transcription factor AP-1 .	This c-Jun activity is inhibited by c-Fos, another protooncoprotein that can dimerize with c-Jun to form the transcription factor AP-1.	1	9	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	c-Fos	c-Fos	c-Fos	c-Jun	c-Jun	c-Jun	6	7	1	2
The authors concluded that the phenotype of male 52KO mice is due to loss of Fkbp52 enhanced AR function [ XREF_BIBR , XREF_BIBR ] , affecting its association with Hsp90 , an important step in establishing and maintaining hormone binding ability [ XREF_BIBR - XREF_BIBR ] .	The authors concluded that the phenotype of male 52KO mice is due to loss of Fkbp52 enhanced AR function [XREF_BIBR, XREF_BIBR], affecting its association with Hsp90, an important step in establishing and maintaining hormone binding ability [XREF_BIBR - XREF_BIBR].	13	18	enhanced	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Fkbp52	loss of Fkbp52	fkbp52	AR	AR	ar	15	16	17	18
We used a modified receptor mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52 enhanced AR function .	We used a modified receptor mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52 enhanced AR function.	18	23	enhanced	Positive_activation_token_1_verb	Positive_activation	Negative_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	20	21	22	23
MJC13 effectively blocks beta-catenin interaction with the AR LBD and the synergistic up-regulation of AR by FKBP52 and beta-catenin .	MJC13 effectively blocks beta-catenin interaction with the AR LBD and the synergistic up-regulation of AR by FKBP52 and beta-catenin.	2	18	up-regulation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	FKBP52	FKBP52	FKBP52	AR	AR	AR	16	17	14	15
Knockdown of FKBP4 expression in HeLa cells decreases androgen receptor protein and reduces hormonal efficacy .	Knockdown of FKBP4 expression in HeLa cells decreases androgen receptor protein and reduces hormonal efficacy.	2	10	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP4	FKBP4 expression	fkbp4	androgen receptor	androgen receptor	androgen receptor	2	3	8	10
Together , these results indicated that with subsequent loss of ID4 , Hsp27 and FKBP52 promote nuclear translocation and transcriptional activity of AR , followed by increased cell proliferation in prostate cancer L (-) ID4 cell lines .	Together, these results indicated that with subsequent loss of ID4, Hsp27 and FKBP52 promote nuclear translocation and transcriptional activity of AR, followed by increased cell proliferation in prostate cancer L (-) ID4 cell lines.	8	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FKBP52	loss of ID4, Hsp27 and FKBP52	fkbp52	AR	AR	ar	14	15	22	23
Hoxa9-/- and Flt3l-/- mice each have significantly reduced numbers of Flt3 + CLPs .	Hoxa9-/- and Flt3l-/- mice each have significantly reduced numbers of Flt3 + CLPs.	0	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Flt3l-/-	Flt3l-/-	Flt3l-/-	Flt3	Flt3	Flt3	2	3	10	11
XREF_BIBR In fact , increased levels of FLT3-L significantly impaired the ability of FLT3 TKI to inhibit FLT3-ITD activity and induce cytotoxicity in FLT3-ITD AML .	XREF_BIBR In fact, increased levels of FLT3-L significantly impaired the ability of FLT3 TKI to inhibit FLT3-ITD activity and induce cytotoxicity in FLT3-ITD AML.	5	14	impaired	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FLT3-L	levels of FLT3-L	flt3-l	FLT3	FLT3	flt3	7	8	13	14
However , it is equally possible that CD135 could be downregulated upon continuous receptor engagement by FLT3L or may no longer be available for antibody binding .	However, it is equally possible that CD135 could be downregulated upon continuous receptor engagement by FLT3L or may no longer be available for antibody binding.	7	22	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FLT3L	FLT3L	FLT3L	CD135	CD135	CD135	16	17	7	8
Further studies revealed that NDRG1 inhibits beta-catenin phosphorylation and nuclear translocation , specifically by up-regulating FRAT1 , which prevents GSK3beta from binding the beta-catenin destruction complex [ XREF_BIBR ] .	Further studies revealed that NDRG1 inhibits beta-catenin phosphorylation and nuclear translocation, specifically by up-regulating FRAT1, which prevents GSK3beta from binding the beta-catenin destruction complex [XREF_BIBR].	14	20	prevents	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	FRAT1	FRAT1	FRAT1	GSK3beta	GSK3beta	GSK3beta	15	16	19	20
Another protein that has been linked to promoting GBM invasion is FRAT1 ( frequently rearranged in advanced T-cell lymphomas-1 ) , a positive regulator of the beta-catenin-dependent Wnt pathway that inhibits GSK3beta from marking beta-catenin for degradation .	Another protein that has been linked to promoting GBM invasion is FRAT1 (frequently rearranged in advanced T-cell lymphomas-1), a positive regulator of the beta-catenin-dependent Wnt pathway that inhibits GSK3beta from marking beta-catenin for degradation.	1	32	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	FRAT1	FRAT1	FRAT1	GSK3beta	GSK3beta	GSK3beta	11	12	31	32
FRAT1 is reported to prevent GSK3beta from binding to the Axin1 , APC , and CK1 complex by competing with Axin1 for a common or closely overlapping binding site on GSK3beta [ XREF_BIBR ] .	FRAT1 is reported to prevent GSK3beta from binding to the Axin1, APC, and CK1 complex by competing with Axin1 for a common or closely overlapping binding site on GSK3beta [XREF_BIBR].	0	7	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRAT1	FRAT1	FRAT1	GSK3beta	GSK3beta	GSK3beta	0	1	5	6
XREF_BIBR Treatment with both agents resulted in significantly greater apoptosis than either agent alone ( twofold greater versus decitabine , 0.5-fold versus midostaurin ) ; further , inhibition of phosphorylation of FLT3 and its downstream targets Akt and STAT5 were increased implicating an FLT3 dependent mechanism of inhibition .	XREF_BIBR Treatment with both agents resulted in significantly greater apoptosis than either agent alone (twofold greater versus decitabine, 0.5-fold versus midostaurin); further, inhibition of phosphorylation of FLT3 and its downstream targets Akt and STAT5 were increased implicating an FLT3 dependent mechanism of inhibition.	29	45	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FLT3	phosphorylation of FLT3	flt3	FLT3	FLT3	flt3	31	32	43	44
Taken together these data demonstrate that BPR-1J340 inhibits cellular FLT3 phosphorylation and modulates the FLT3 signaling pathway , particularly the FLT3-ITD pathway .	Taken together these data demonstrate that BPR-1J340 inhibits cellular FLT3 phosphorylation and modulates the FLT3 signaling pathway, particularly the FLT3-ITD pathway.	6	16	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	BPR-1J340 inhibits cellular FLT3 phosphorylation	flt3	FLT3	FLT3	flt3	9	10	14	15
These data support an association between decreased p-Akt protein levels and the increased UPS activation in beta 2 KO MI mice that could be mediated by FoxO transcription factors , as FoxO phosphorylation by Akt inhibits FoxO induction of atrogin-1 and MuRF1 transcription [ XREF_BIBR , XREF_BIBR ] .	These data support an association between decreased p-Akt protein levels and the increased UPS activation in beta 2 KO MI mice that could be mediated by FoxO transcription factors, as FoxO phosphorylation by Akt inhibits FoxO induction of atrogin-1 and MuRF1 transcription [XREF_BIBR, XREF_BIBR].	36	43	induction	Positive_regulation_syntax_3_noun	Positive_activation	Positive_regulation	FoxO	FoxO	foxo	MuRF1	MuRF1 transcription	murf1	36	37	41	42
Under catabolic conditions , the PI3K-Akt pathway is suppressed and hypophosphorylated FoxO translocates into the nucleus causing murf1 induction and muscle atrophy .	Under catabolic conditions, the PI3K-Akt pathway is suppressed and hypophosphorylated FoxO translocates into the nucleus causing murf1 induction and muscle atrophy.	5	18	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxO	PI3K-Akt pathway is suppressed and hypophosphorylated FoxO	foxo	murf1	murf1	murf1	11	12	17	18
Phosphorylation of FOXO proteins by IGF1 downregulates Murf1 and MAFbx XREF_BIBR and transcripts for MAFbx had decreased 20-30-fold to almost undetectable levels by 16 h ( XREF_FIG ) .	Phosphorylation of FOXO proteins by IGF1 downregulates Murf1 and MAFbx XREF_BIBR and transcripts for MAFbx had decreased 20-30-fold to almost undetectable levels by 16 h (XREF_FIG).	0	10	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FOXO	Phosphorylation of FOXO	foxo	Murf1	Murf1	murf1	2	3	7	8
-PEDF can promote gamma-secretase-dependent proteolysis of the transmembrane portion of VEGFR1 and VEGFR2 and also inhibit VEGF induced VEGFR1 phosphorylation , or promote the dephosphorylation of this receptor , by inducing the upregulation of presenilin-1 and the subsequent aggregation of vascular endothelial protein-tyrosine phosphatase and VEGFR1 .	-PEDF can promote gamma-secretase-dependent proteolysis of the transmembrane portion of VEGFR1 and VEGFR2 and also inhibit VEGF induced VEGFR1 phosphorylation, or promote the dephosphorylation of this receptor, by inducing the upregulation of presenilin-1 and the subsequent aggregation of vascular endothelial protein-tyrosine phosphatase and VEGFR1.	0	46	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR1	-PEDF can promote gamma-secretase-dependent proteolysis of the transmembrane portion of VEGFR1 and VEGFR2 and also inhibit VEGF induced VEGFR1 phosphorylation	vegfr1	VEGFR1	VEGFR1	vegfr1	18	19	45	46
Moreover , soluble VEGFR-3 expressed in adenovirus , which blocks VEGFR-3 signaling through binding VEGF-C and VEGF-D , is effective for inhibiting tumor lymphangiogenesis and lymphatic metastasis XREF_BIBR - XREF_BIBR .	Moreover, soluble VEGFR-3 expressed in adenovirus, which blocks VEGFR-3 signaling through binding VEGF-C and VEGF-D, is effective for inhibiting tumor lymphangiogenesis and lymphatic metastasis XREF_BIBR - XREF_BIBR.	2	19	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFR-3	VEGFR-3 expressed	vegfr-3	VEGFR-3	VEGFR-3	vegfr-3	3	4	10	11
The reduced phosphorylation of VEGFR-3 was due to reduced total levels of VEGFR-3 , as overexpression of VEGFR-3 lacking the 3 ' UTR rescued VEGFR-3 signaling ( XREF_SUPPLEMENTARY ) .	The reduced phosphorylation of VEGFR-3 was due to reduced total levels of VEGFR-3, as overexpression of VEGFR-3 lacking the 3 ' UTR rescued VEGFR-3 signaling (XREF_SUPPLEMENTARY).	15	25	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR-3	overexpression of VEGFR-3	vegfr-3	VEGFR-3	VEGFR-3	vegfr-3	17	18	24	25
Based on the cellular signaling model developed from the subcutaneous tumor studies , it was found that the free concentration of the bifunctional FLT3 ITD -CDK4/6 inhibitor AMG925 eliciting half-maximal inhibition of pSTAT5 is comparable to that for its pRb inhibition ( IC50 AMG = 28 nM , IC50 AMGpRb = 43 nM , see XREF_TABLE ) ) , which indicates that AMG925 has a similar inhibitory potency on FLT3 ITD and CDK4/6 .	Based on the cellular signaling model developed from the subcutaneous tumor studies, it was found that the free concentration of the bifunctional FLT3 ITD -CDK4/6 inhibitor AMG925 eliciting half-maximal inhibition of pSTAT5 is comparable to that for its pRb inhibition (IC50 AMG = 28 nM, IC50 AMGpRb = 43 nM, see XREF_TABLE)), which indicates that AMG925 has a similar inhibitory potency on FLT3 ITD and CDK4/6.	23	33	eliciting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FLT3	FLT3	FLT3	pSTAT5	pSTAT5	pSTAT5	23	24	32	33
FoxO3a siRNA effectively abrogated the increase in Gilz and Mkp-1 mRNA ( XREF_FIG ) expression in MIF -/- cells .	FoxO3a siRNA effectively abrogated the increase in Gilz and Mkp-1 mRNA (XREF_FIG) expression in MIF -/- cells.	0	8	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FoxO3a	FoxO3a	FoxO3a	Gilz	Gilz	Gilz	0	1	7	8
Fiz1 suppressed NRL- but not CRX mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells .	Fiz1 suppressed NRL- but not CRX mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells.	0	7	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fiz1	Fiz1	Fiz1	NRL-	NRL-	NRL-	0	1	2	3
Loss of STS1 and STS2 induces hyperphosphorylation of FLT3 , enhances AKT signaling , and confers a strong proliferative advantage .	Loss of STS1 and STS2 induces hyperphosphorylation of FLT3, enhances AKT signaling, and confers a strong proliferative advantage.	0	12	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FLT3	Loss of STS1 and STS2 induces hyperphosphorylation of FLT3	flt3	AKT	AKT	akt	8	9	11	12
Suppression of FLI-1 inhibits cell proliferation and induces cell apoptosis of human cancer cell by targeting Rb , GATA-1 , and BCL-2 [ XREF_BIBR - XREF_BIBR ] .	Suppression of FLI-1 inhibits cell proliferation and induces cell apoptosis of human cancer cell by targeting Rb, GATA-1, and BCL-2 [XREF_BIBR - XREF_BIBR].	0	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	FLI-1	FLI-1	FLI-1	GATA-1	GATA-1	GATA-1	2	3	18	19
STEP dephosphorylates Fyn at a regulatory tyrosine residue ( tyr 420 ) , thereby inactivating Fyn .	STEP dephosphorylates Fyn at a regulatory tyrosine residue (tyr 420), thereby inactivating Fyn.	0	16	inactivating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fyn	STEP dephosphorylates Fyn at a regulatory tyrosine residue	fyn	Fyn	Fyn	fyn	2	3	15	16
Laminin deficient brains showed dysregulated Fyn and elevated levels of C-terminal Src kinase ( Csk ) and Csk-binding-protein ( Cbp ) , proteins that suppress Fyn activity .	Laminin deficient brains showed dysregulated Fyn and elevated levels of C-terminal Src kinase (Csk) and Csk-binding-protein (Cbp), proteins that suppress Fyn activity.	5	26	suppress	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Fyn	Fyn and elevated levels	fyn	Fyn	Fyn	fyn	5	6	25	26
High levels of kinase-inactive SLK in muscle tissue produced an overall decrease in SLK activity in muscle tissue , resulting in altered muscle organization , reduced litter sizes , and reduced breeding capacity .	High levels of kinase-inactive SLK in muscle tissue produced an overall decrease in SLK activity in muscle tissue, resulting in altered muscle organization, reduced litter sizes, and reduced breeding capacity.	1	14	produced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SLK	levels of kinase-inactive SLK	slk	SLK	SLK	slk	4	5	13	14
CD5 Stimulation Induces Fyn Phosphorylation in the C-terminal Inhibitory Tyrosine Residue and Down-regulates the Kinase Activity of Fyn .	CD5 Stimulation Induces Fyn Phosphorylation in the C-terminal Inhibitory Tyrosine Residue and Down-regulates the Kinase Activity of Fyn.	0	18	Down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fyn	CD5 Stimulation Induces Fyn Phosphorylation	fyn	Fyn	Fyn	fyn	3	4	17	18
Effects of Src inhibitors on Furin induced Notch-1 cleavage .	Effects of Src inhibitors on Furin induced Notch-1 cleavage.	3	8	induced	Positive_early_activation	Positive_activation	Negative_activation	Furin	Furin	Furin	Notch-1	Notch-1	Notch-1	5	6	7	8
This leads to Notch1 signal amplification , which can promote melanoma tumor growth and progression , as demonstrated by the inhibition of cell migration and invasion upon furin inhibition downstream of Notch1 .	This leads to Notch1 signal amplification, which can promote melanoma tumor growth and progression, as demonstrated by the inhibition of cell migration and invasion upon furin inhibition downstream of Notch1.	27	32	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	furin	furin	furin	Notch1	Notch1	Notch1	27	28	31	32
These observations suggest that PC inhibition promotes airway ciliated cell differentiation , possibly through suppression of furin mediated Notch1 processing .	These observations suggest that PC inhibition promotes airway ciliated cell differentiation, possibly through suppression of furin mediated Notch1 processing.	14	19	mediated	Positive_early_activation	Positive_activation	Negative_activation	furin	furin	furin	Notch1	Notch1	Notch1	16	17	18	19
Furin can degrade Notch1 and produce NICD fragments , which function as transcription factor .	Furin can degrade Notch1 and produce NICD fragments, which function as transcription factor.	0	5	degrade	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Furin	Furin	Furin	Notch1	Notch1	Notch1	0	1	3	4
Our result shows that knockdown of FZD7 suppresses RhoA but upregulates Rac1 .	Our result shows that knockdown of FZD7 suppresses RhoA but upregulates Rac1.	4	12	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FZD7	FZD7	FZD7	Rac1	Rac1	Rac1	6	7	11	12
FZD7 knockdown reciprocally inhibits RhoA and activates Rac1 activities , redistributes cellular tensile forces and decreases directional cell migration .	FZD7 knockdown reciprocally inhibits RhoA and activates Rac1 activities, redistributes cellular tensile forces and decreases directional cell migration.	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FZD7	FZD7	FZD7	Rac1	Rac1	Rac1	0	1	7	8
Fyn deletion results in decreased tyrosine phosphorylation ( pY ) of NR2B and Fyn overexpression ( Fyn OE ) leads to elevated pY NR2B .	Fyn deletion results in decreased tyrosine phosphorylation (pY) of NR2B and Fyn overexpression (Fyn OE) leads to elevated pY NR2B.	0	24	leads	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	Fyn	Fyn	Fyn	NR2B	NR2B	NR2B	0	1	23	24
Fyn protein levels can also be down-regulated by the Src activating and signaling molecule Srcasm , but since Srcasm does not influence Fyn mRNA levels , it can not account for regulation of Fyn by active Ras we observed .	Fyn protein levels can also be down-regulated by the Src activating and signaling molecule Srcasm, but since Srcasm does not influence Fyn mRNA levels, it can not account for regulation of Fyn by active Ras we observed.	0	15	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fyn	Fyn protein levels	fyn	Srcasm	Srcasm	srcasm	0	1	14	15
The results showed that Fyn inhibited NR1 and NR2A endocytosis , but Fyn had less effect on NR1 and NR2A 3CS ( XREF_FIG ) .	The results showed that Fyn inhibited NR1 and NR2A endocytosis, but Fyn had less effect on NR1 and NR2A 3CS (XREF_FIG).	4	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fyn	Fyn	Fyn	NR2A	NR2A	NR2A	4	5	8	9
This may be due to growth hormone resistance caused by cytokine induced suppression of growth hormone receptor ( GHR ) gene expression .	This may be due to growth hormone resistance caused by cytokine induced suppression of growth hormone receptor (GHR) gene expression.	5	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	growth hormone	growth hormone	growth hormone	growth hormone receptor	growth hormone receptor	growth hormone receptor	5	7	14	17
In control cells GH induced complete degradation of the GHR within 60 min , while staurosporin treatment stabilised the mature GHR ( XREF_FIG ) .	In control cells GH induced complete degradation of the GHR within 60 min, while staurosporin treatment stabilised the mature GHR (XREF_FIG).	3	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	3	4	9	10
The GH antagonist , B2036 , blocked Jak2-Stat5-mediated GHR signaling but was internalized with a similar time course to native GH .	The GH antagonist, B2036, blocked Jak2-Stat5-mediated GHR signaling but was internalized with a similar time course to native GH.	1	9	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	1	2	8	9
In contrast to acute effects , GH incubation for 2 h or longer yielded diminished STAT5 phosphorylation in T47D-ShPRLR cells compared with T47D-SCR , a finding perhaps explained by markedly greater GH induced GHR down-regulation in cells with diminished PRLR .	In contrast to acute effects, GH incubation for 2 h or longer yielded diminished STAT5 phosphorylation in T47D-ShPRLR cells compared with T47D-SCR, a finding perhaps explained by markedly greater GH induced GHR down-regulation in cells with diminished PRLR.	27	34	induced	Positive_early_activation	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	31	32	33	34
Quantification showed that GH stimulated GHR endocytosis is reduced from 50 % to about 20 % under conditions of either clathrin or betaTrCP depletion , indicating that both proteins are required for GH induced GHR endocytosis .	Quantification showed that GH stimulated GHR endocytosis is reduced from 50% to about 20% under conditions of either clathrin or betaTrCP depletion, indicating that both proteins are required for GH induced GHR endocytosis.	32	35	induced	Positive_early_activation	Positive_activation	Positive_activation	GH	GH	GH	GHR	GHR	GHR	32	33	34	35
Both lactacystin ( a proteasome inhibitor ) and chloroquine ( a lysosome inhibitor ) blocked GH induced GHR loss .	Both lactacystin (a proteasome inhibitor) and chloroquine (a lysosome inhibitor) blocked GH induced GHR loss.	15	18	induced	Positive_early_activation	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	15	16	17	18
Recombinant mouse growth hormone ( rmGH ) treatment ( 0.02 mg/kg , once a day for 6 weeks ) significantly restored the plasma GH , inhibited GHR up-regulation and attenuated proteinuria .	Recombinant mouse growth hormone (rmGH) treatment (0.02 mg/kg, once a day for 6 weeks) significantly restored the plasma GH, inhibited GHR up-regulation and attenuated proteinuria.	2	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	growth hormone	growth hormone	growth hormone	GHR	GHR	GHR	2	4	26	27
Pegvisomant is a GH analogue that binds to GH receptors on the cell surface , and blocks GH receptor dimerisation XREF_BIBR .	Pegvisomant is a GH analogue that binds to GH receptors on the cell surface, and blocks GH receptor dimerisation XREF_BIBR.	3	20	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH analogue that binds to GH receptors	gh	GH receptor	GH receptor	gh receptor	3	4	17	19
These data indicate that GH is able to increase GHR endocytosis and lower the GHR steady state level only in the presence of Jak2 .	These data indicate that GH is able to increase GHR endocytosis and lower the GHR steady state level only in the presence of Jak2.	4	17	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	4	5	14	15
In cells that expressed JAK2 , but not cells lacking JAK2 , GH markedly enhanced GHR degradation .	In cells that expressed JAK2, but not cells lacking JAK2, GH markedly enhanced GHR degradation.	12	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	12	13	15	16
Our data suggest that GH inhibits PMA induced GHR proteolysis and GHBP shedding by inducing GHR dimerization and that this effect does not appear to be related to GH site 1 binding , GHR internalization , or GHR signaling .	Our data suggest that GH inhibits PMA induced GHR proteolysis and GHBP shedding by inducing GHR dimerization and that this effect does not appear to be related to GH site 1 binding, GHR internalization, or GHR signaling.	4	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GHBP	GHBP	GHBP	4	5	11	12
Pre-treatment of IM9 cells with MG132 indeed completely inhibited GH induced GHR degradation ( XREF_FIG , lanes 7-9 ) .	Pre-treatment of IM9 cells with MG132 indeed completely inhibited GH induced GHR degradation (XREF_FIG, lanes 7-9).	9	12	induced	Positive_early_activation	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	9	10	11	12
Next , we examined its antagonistic activity using in vitro cell models , and the results showed that CG-86 could effectively inhibit growth hormone receptor mediated signalling and effectively inhibit growth hormone induced Ba/F3-GHR 638 proliferation .	Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor mediated signalling and effectively inhibit growth hormone induced Ba/F3-GHR 638 proliferation.	18	25	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CG-86	CG-86	CG-86	growth hormone receptor	growth hormone receptor	growth hormone receptor	18	19	22	25
Medical therapy is based on GH lowering drugs ( somatostatin receptor agonists and , in some cases , dopaminergic agents ) and GH receptor antagonists ( pegvisomant ) .	Medical therapy is based on GH lowering drugs (somatostatin receptor agonists and, in some cases, dopaminergic agents) and GH receptor antagonists (pegvisomant).	3	24	lowering	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GH receptor	GH receptor	GH receptor	5	6	22	24
Upon GH treatment we observed that mutation of the UbE motif resulted in inhibition of GH induced GHR endocytosis ( XREF_FIG ) , indicating that the UbE motif is essential for GH induced GHR endocytosis .	Upon GH treatment we observed that mutation of the UbE motif resulted in inhibition of GH induced GHR endocytosis (XREF_FIG), indicating that the UbE motif is essential for GH induced GHR endocytosis.	13	18	induced	Positive_early_activation	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	15	16	17	18
We previously demonstrated that naturally occurring truncated membrane bound GH receptors ( GHRs ) can block GH receptor signaling .	We previously demonstrated that naturally occurring truncated membrane bound GH receptors (GHRs) can block GH receptor signaling.	9	18	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GH receptor	GH receptor	GH receptor	9	10	16	18
These findings indicate that the heterologous reduction of GHR by insulin occurs via transcriptional downregulation , and the homologous reduction of GHR by GH occurs via a different mechanism .	These findings indicate that the heterologous reduction of GHR by insulin occurs via transcriptional downregulation, and the homologous reduction of GHR by GH occurs via a different mechanism.	19	24	reduction	Negative_activation_token_2_noun	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	23	24	21	22
The GH receptor mRNA was decreased in cows treated with GH whereas the mRNA for IGF-I , IGFBP-2 , or IGFBP-3 was not changed .	The GH receptor mRNA was decreased in cows treated with GH whereas the mRNA for IGF-I, IGFBP-2, or IGFBP-3 was not changed.	1	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	GH	GH	GH	GH receptor	GH receptor	GH receptor	10	11	1	3
TACE dependent GHR proteolysis can be inhibited by GH as the dimerized GHR is resistant to cleavage .	TACE dependent GHR proteolysis can be inhibited by GH as the dimerized GHR is resistant to cleavage.	2	9	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	8	9	2	3
GH and IGF significantly decreased GHR mRNA in proliferative cells .	GH and IGF significantly decreased GHR mRNA in proliferative cells.	0	6	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	0	1	5	6
XREF_BIBR , in any case the final result is an almost complete GH induced degradation of GHR after 60 min .	XREF_BIBR, in any case the final result is an almost complete GH induced degradation of GHR after 60 min.	12	19	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	12	13	16	17
Growth hormone ( GH )-inducible suppressors of cytokine signaling ( SOCS and CIS proteins ) inhibit GH receptor ( GHR ) signaling to STAT5b via phosphotyrosine dependent binding interactions with the tyrosine kinase JAK2 ( SOCS-1 ) and/or the cytoplasmic tail of GHR ( CIS and SOCS-3 ) .	Growth hormone (GH)-inducible suppressors of cytokine signaling (SOCS and CIS proteins) inhibit GH receptor (GHR) signaling to STAT5b via phosphotyrosine dependent binding interactions with the tyrosine kinase JAK2 (SOCS-1) and/or the cytoplasmic tail of GHR (CIS and SOCS-3).	0	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Growth hormone	Growth hormone	Growth hormone	GH receptor	GH receptor	GH receptor	0	2	16	18
Mutating the DSGxxS motif did not inhibit GH induced GHR endocytosis ( XREF_FIG ) .	Mutating the DSGxxS motif did not inhibit GH induced GHR endocytosis (XREF_FIG).	6	10	induced	Positive_early_activation	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	7	8	9	10
Furthermore , constant GH exposure might theoretically downregulate the GH receptor .	Furthermore, constant GH exposure might theoretically downregulate the GH receptor.	3	11	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GH receptor	GH receptor	GH receptor	3	4	9	11
GH treatment dramatically reduced GHR protein , but caused only a modest reduction in GHR mRNA .	GH treatment dramatically reduced GHR protein, but caused only a modest reduction in GHR mRNA.	0	5	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	0	1	4	5
Modeling and direct measurements of the off-rate of GH from its high affinity GHBP indicated normal dissociation rate constants but decreased molar concentrations of the GHBP in uremic plasma .	Modeling and direct measurements of the off-rate of GH from its high affinity GHBP indicated normal dissociation rate constants but decreased molar concentrations of the GHBP in uremic plasma.	6	28	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GH	GH	GH	GHBP	GHBP	GHBP	8	9	25	26
The distinct actions of exogenous and autocrine GH were accompanied by differences in the involvement of GHR associated signal transduction pathways , and were paralleled by an alteration in the subcellular localization of GHR , in which autocrine GH appeared to sequester GHR in the Golgi and endoplasmic reticulum .	The distinct actions of exogenous and autocrine GH were accompanied by differences in the involvement of GHR associated signal transduction pathways, and were paralleled by an alteration in the subcellular localization of GHR, in which autocrine GH appeared to sequester GHR in the Golgi and endoplasmic reticulum.	37	48	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GH	GH	GH	GHR	GHR	GHR	38	39	42	43
Chronic infusion of OXM decreases body weight in Glp1r -/- mice .	Chronic infusion of OXM decreases body weight in Glp1r -/- mice.	1	10	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	OXM	OXM	OXM	Glp1r	Glp1r	Glp1r	3	4	8	9
We demonstrated that chronic infusion of OXM decreases body weight gain in Glp1r -/- mice , although the effect was reduced compared to wild-type mice , suggesting that the body weight lowering action of OXM is not entirely mediated by activation of the GLP1R .	We demonstrated that chronic infusion of OXM decreases body weight gain in Glp1r -/- mice, although the effect was reduced compared to wild-type mice, suggesting that the body weight lowering action of OXM is not entirely mediated by activation of the GLP1R.	4	14	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	OXM	OXM	OXM	Glp1r	Glp1r	Glp1r	6	7	12	13
Unlike the glucose lowering effect of GLP-1 ( 7-37 ) , the glucose lowering effect of GLP-1 ( 1-37 ) could not be blocked by the GLP-1R antagonist exendin ( 9-39 ) , suggesting that GLP-1 ( 1-37 ) might activate the GLP-1R via a different mechanism .	Unlike the glucose lowering effect of GLP-1 (7-37), the glucose lowering effect of GLP-1 (1-37) could not be blocked by the GLP-1R antagonist exendin (9-39), suggesting that GLP-1 (1-37) might activate the GLP-1R via a different mechanism.	35	46	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	35	36	42	43
We postulate that sustained GLP-1 expression from beta-cells might downregulate the GLP-1 receptor signaling pathway for beta-cell proliferation .	We postulate that sustained GLP-1 expression from beta-cells might downregulate the GLP-1 receptor signaling pathway for beta-cell proliferation.	4	14	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GLP-1	GLP-1 expression	glp-1	GLP-1 receptor	GLP-1 receptor	glp-1 receptor	4	5	11	13
However , while GLP-1 ( 7-36 ) is the physiologic agonist of the GLP-1 receptor and increases plasma concentrations of insulin after food intake , the metabolite GLP-1 ( 9-36 ) is an antagonist of the GLP-1 receptor and metabolically inactive XREF_BIBR , XREF_BIBR .	However, while GLP-1 (7-36) is the physiologic agonist of the GLP-1 receptor and increases plasma concentrations of insulin after food intake, the metabolite GLP-1 (9-36) is an antagonist of the GLP-1 receptor and metabolically inactive XREF_BIBR, XREF_BIBR.	25	38	is an antagonist	Negative_activation_copula_1	Positive_activation	Negative_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	27	28	36	38
Here we show that GLP-1 ( 9-36 ) amide directly suppresses glucose production in isolated mouse hepatocytes ex vivo independent of the GLP-1 receptor .	Here we show that GLP-1 (9-36) amide directly suppresses glucose production in isolated mouse hepatocytes ex vivo independent of the GLP-1 receptor.	4	24	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	4	5	22	24
Increased GLP-1 levels may impair hypothalamic and/or peripheral GLP-1R signaling , exert long-term negative effects on the hypothalamic nuclei regulating energy homeostasis and increase the risks for obesity and diabetes.International Journal of Obesity accepted article preview online , 01 November 2017 .	Increased GLP-1 levels may impair hypothalamic and/or peripheral GLP-1R signaling, exert long-term negative effects on the hypothalamic nuclei regulating energy homeostasis and increase the risks for obesity and diabetes.International Journal of Obesity accepted article preview online, 01 November 2017.	1	9	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GLP-1	GLP-1 levels	glp-1	GLP-1R	GLP-1R	glp-1r	1	2	8	9
DPP-4 inhibition by sitagliptin administration increases GLP-1 availability which stimulates GLP-1R in blood vessels , through the sequential activation of the PKA/LKB1/AMPKalpha/eNOS axis , thus inducing relaxation of smooth muscle and improvement of renal blood flow [ XREF_BIBR , XREF_BIBR ] .	DPP-4 inhibition by sitagliptin administration increases GLP-1 availability which stimulates GLP-1R in blood vessels, through the sequential activation of the PKA/LKB1/AMPKalpha/eNOS axis, thus inducing relaxation of smooth muscle and improvement of renal blood flow [XREF_BIBR, XREF_BIBR].	6	11	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GLP-1	GLP-1	GLP-1	GLP-1R	GLP-1R	GLP-1R	6	7	10	11
GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 ( Ex-9 ) , whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 ( DPP-4 ) inhibitor preventing the formation of PYY 3-36 .	GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYY 3-36.	0	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GLP-1	GLP-1	GLP-1	GLP-1 receptor	GLP-1 receptor	GLP-1 receptor	0	1	7	9
Moreover , Axl phosphorylation in response to binding of its ligand , Gas6 , was abrogated by curcumin , suggesting the inhibitory effect of curcumin on Gas6 induced Axl activation .	Moreover, Axl phosphorylation in response to binding of its ligand, Gas6, was abrogated by curcumin, suggesting the inhibitory effect of curcumin on Gas6 induced Axl activation.	24	29	induced	Positive_early_activation	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	26	27	28	29
Warfarin blocks Gas6 mediated Axl activation required for pancreatic cancer epithelial plasticity and metastasis .	Warfarin blocks Gas6 mediated Axl activation required for pancreatic cancer epithelial plasticity and metastasis.	1	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	2	3	4	5
Moreover , hypoxia inhibits GAS6 mediated downregulation of the AXL receptor in prostate cells [ XREF_BIBR ] .	Moreover, hypoxia inhibits GAS6 mediated downregulation of the AXL receptor in prostate cells [XREF_BIBR].	4	10	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	4	5	9	10
In macrophages , Gas6 stimulated Axl signaling normally represses inflammatory cytokine expression by induction of transcription factor and inhibitor Twist [ XREF_BIBR ] .	In macrophages, Gas6 stimulated Axl signaling normally represses inflammatory cytokine expression by induction of transcription factor and inhibitor Twist [XREF_BIBR].	3	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	3	4	5	6
Hypoxia prevents GAS6 mediated down-regulation of Axl in PCa cells .	Hypoxia prevents GAS6 mediated down-regulation of Axl in PCa cells.	2	7	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	2	3	6	7
As shown in Figure XREF_FIG and XREF_FIG , a similar inhibitory effect of DN10764 on GAS6 induced AXL signaling was observed in the Hs578T cell line , another AXL expressing breast cancer cell line , and in the A549/C is cell line , which is a cisplatin resistant derivative of the human A549 lung cancer cell line that expresses significantly more AXL compared to the parental A549 cell line [ XREF_BIBR ] .	As shown in Figure XREF_FIG and XREF_FIG, a similar inhibitory effect of DN10764 on GAS6 induced AXL signaling was observed in the Hs578T cell line, another AXL expressing breast cancer cell line, and in the A549/C is cell line, which is a cisplatin resistant derivative of the human A549 lung cancer cell line that expresses significantly more AXL compared to the parental A549 cell line [XREF_BIBR].	13	18	induced	Positive_early_activation	Positive_activation	Negative_activation	GAS6	GAS6	GAS6	AXL	AXL	AXL	15	16	17	18
Although EGFR activation promotes ACK1 turnover , Axl activation by GAS6 does not ; interestingly , the reciprocal down-regulation of GAS6 stimulated Axl is blocked by removing ACK1 .	Although EGFR activation promotes ACK1 turnover, Axl activation by GAS6 does not; interestingly, the reciprocal down-regulation of GAS6 stimulated Axl is blocked by removing ACK1.	18	24	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	20	21	22	23
XREF_BIBR The blocking of vitamin K dependent gamma carboxylation of Gas6 inhibits Axl activation on tumor cells and reduces tumor progression and metastasis in preclinical tumor models .	XREF_BIBR The blocking of vitamin K dependent gamma carboxylation of Gas6 inhibits Axl activation on tumor cells and reduces tumor progression and metastasis in preclinical tumor models.	0	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	10	11	12	13
In this paper , we used a hypoxia mimicking agent , CoCl2 , to demonstrate that GAS6 secretion is not able to negatively regulate expression Axl in PC3 and DU145 cells under hypoxic conditions .	In this paper, we used a hypoxia mimicking agent, CoCl2, to demonstrate that GAS6 secretion is not able to negatively regulate expression Axl in PC3 and DU145 cells under hypoxic conditions.	16	26	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	16	17	25	26
In addition , depleting Gas6 using siRNA significantly reduced GO-LDL-induced Axl upregulation in MMCs .	In addition, depleting Gas6 using siRNA significantly reduced GO-LDL-induced Axl upregulation in MMCs.	3	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	4	5	10	11
Moreover , CoCl2 , a hypoxia mimicking agent , prevented GAS6 mediated down-regulation of Axl in these cell lines .	Moreover, CoCl2, a hypoxia mimicking agent, prevented GAS6 mediated down-regulation of Axl in these cell lines.	10	15	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	10	11	14	15
Axl is significantly activated by Gas6 but not by protein S ; however , the coaddition of Gas6 and protein S suppresses Axl activation ( XREF_FIG F- XREF_FIG H ) .	Axl is significantly activated by Gas6 but not by protein S; however, the coaddition of Gas6 and protein S suppresses Axl activation (XREF_FIG F- XREF_FIG H).	17	23	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	17	18	22	23
These results strongly suggest that the anecdotal anti-tumor effects observed clinically with coumarin based anticoagulants are due in part to specific inhibition of Gas6 mediated Axl activation on tumor cells .	These results strongly suggest that the anecdotal anti-tumor effects observed clinically with coumarin based anticoagulants are due in part to specific inhibition of Gas6 mediated Axl activation on tumor cells.	21	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	23	24	25	26
Together these data suggest that Gas6 activates Axl , and that protein S exerts its cellular effects on SVZ cells by activating Tyro3 pathway and inhibiting Gas6 induced Axl activation .	Together these data suggest that Gas6 activates Axl, and that protein S exerts its cellular effects on SVZ cells by activating Tyro3 pathway and inhibiting Gas6 induced Axl activation.	13	29	induced	Positive_early_activation	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Axl	Axl	Axl	26	27	28	29
Together these results demonstrate that GAS6 negatively regulates Axl under normoxic conditions ( XREF_FIG , XREF_FIG ) , but not under hypoxic conditions in vitro , and within a hypoxic tumor Axl expression remains high ( XREF_FIG ) despite the presence of abundant GAS6 expression ( XREF_FIG ) .	Together these results demonstrate that GAS6 negatively regulates Axl under normoxic conditions (XREF_FIG, XREF_FIG), but not under hypoxic conditions in vitro, and within a hypoxic tumor Axl expression remains high (XREF_FIG) despite the presence of abundant GAS6 expression (XREF_FIG).	5	22	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GAS6	GAS6	GAS6	Axl	Axl	Axl	5	6	8	9
Impact of different small kinase inhibitors on GDNF induced RET signaling in ER +/RET+ MCF7 cells .	Impact of different small kinase inhibitors on GDNF induced RET signaling in ER +/RET+ MCF7 cells.	5	10	induced	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	RET	RET	RET	7	8	9	10
We used two Ret selective kinase inhibitors , NVP-BBT594 and NVP-AST487 that block GDNF induced Ret activation ( XREF_FIG B and Supporting Information XREF_SUPPLEMENTARY A ) to examine motility in response to IL6 and GDNF .	We used two Ret selective kinase inhibitors, NVP-BBT594 and NVP-AST487 that block GDNF induced Ret activation (XREF_FIG B and Supporting Information XREF_SUPPLEMENTARY A) to examine motility in response to IL6 and GDNF.	12	16	induced	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	13	14	15	16
Of the compounds used , NVP-BBT594 showed the highest suppression of GDNF induced RET signaling , as assessed by RET , ERK1/2 , AKT and ER phosphorylation .	Of the compounds used, NVP-BBT594 showed the highest suppression of GDNF induced RET signaling, as assessed by RET, ERK1/2, AKT and ER phosphorylation.	9	14	induced	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	RET	RET	RET	11	12	13	14
In this study , we demonstrate that NVP-AST487 and NVP-BBT594 have comparable potencies as inhibitors of GDNF induced RET signaling in ER+ breast cancer cells in vitro .	In this study, we demonstrate that NVP-AST487 and NVP-BBT594 have comparable potencies as inhibitors of GDNF induced RET signaling in ER+ breast cancer cells in vitro.	14	19	induced	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	RET	RET	RET	16	17	18	19
Blocking PLC with U73122 significantly inhibited the GDNF and RET stimulated migratory movement ( 1.0 +/-0.1-fold increase , n = 6 ) of RET WT expressing cells ( XREF_FIG ) .	Blocking PLC with U73122 significantly inhibited the GDNF and RET stimulated migratory movement (1.0 +/-0.1-fold increase, n = 6) of RET WT expressing cells (XREF_FIG).	6	24	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	7	8	23	24
After Lat B pretreatment , GDNF induced Ret translocation was reduced , and Ret mainly remained in the non raft fractions with CD71 .	After Lat B pretreatment, GDNF induced Ret translocation was reduced, and Ret mainly remained in the non raft fractions with CD71.	5	8	induced	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	5	6	7	8
Furthermore , knockdown of p75 levels within DRG neurons resulted in a drastic impairment in GDNF mediated Ret activation , and a subsequent loss of cell surface localization of Ret , suggesting that p75 potentiates GDNF-Ret signal transduction through enhancing receptor availability to ligand , or by enhancing recycling .	Furthermore, knockdown of p75 levels within DRG neurons resulted in a drastic impairment in GDNF mediated Ret activation, and a subsequent loss of cell surface localization of Ret, suggesting that p75 potentiates GDNF-Ret signal transduction through enhancing receptor availability to ligand, or by enhancing recycling.	13	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	15	16	17	18
Correspondingly , p75 deletion results in a substantial reduction in GDNF and NRTN mediated survival of Ret + nonpeptidergic neurons , but not TrkA + peptidergic neurons .	Correspondingly, p75 deletion results in a substantial reduction in GDNF and NRTN mediated survival of Ret + nonpeptidergic neurons, but not TrkA + peptidergic neurons.	8	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	10	11	16	17
This strategy revealed that any disruption of GDNF mediated Ret signalling results in a lack of SSC self-renewal and induces the progressive loss of spermatogenesis by germ cell depletion .	This strategy revealed that any disruption of GDNF mediated Ret signalling results in a lack of SSC self-renewal and induces the progressive loss of spermatogenesis by germ cell depletion.	5	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	7	8	9	10
In T47D , RET was down-regulated by IL8 , after both 6 and 24 hours of treatment , and by GDNF , after 24 hours .	In T47D, RET was down-regulated by IL8, after both 6 and 24 hours of treatment, and by GDNF, after 24 hours.	3	21	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	RET	RET	RET	20	21	3	4
Our hypothesis that GDNF expression limits RET dependent endocrine resistance implies that these GDNF-high samples should be prone to endocrine resistance .	Our hypothesis that GDNF expression limits RET dependent endocrine resistance implies that these GDNF-high samples should be prone to endocrine resistance.	3	9	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GDNF	GDNF expression	gdnf	RET	RET	ret	3	4	6	7
The partial reduction of GDNF induced Ret51 signaling in hippocampal neurons subjected to excitotoxic stimulation contrasts with a full inhibition of the two downstream pathways , PLCgamma and ERK1/2 .	The partial reduction of GDNF induced Ret51 signaling in hippocampal neurons subjected to excitotoxic stimulation contrasts with a full inhibition of the two downstream pathways, PLCgamma and ERK1/2.	2	7	induced	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	Ret51	Ret51	Ret51	4	5	6	7
Given the striking loss of GDNF mediated Ret activation , we hypothesized that loss of p75 may result in changes of cell surface localization of Ret .	Given the striking loss of GDNF mediated Ret activation, we hypothesized that loss of p75 may result in changes of cell surface localization of Ret.	3	8	mediated	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	Ret	Ret	Ret	5	6	7	8
Targeting ER function with endocrine therapy is the most common and effective treatment for this subset of breast cancers , but recent data have shown that RET signalling , driven by its ligand GDNF , has a negative impact on the response of ER positive breast cancer cells to aromatase inhibitors [ XREF_BIBR ] and tamoxifen [ XREF_BIBR , XREF_BIBR ] .	Targeting ER function with endocrine therapy is the most common and effective treatment for this subset of breast cancers, but recent data have shown that RET signalling, driven by its ligand GDNF, has a negative impact on the response of ER positive breast cancer cells to aromatase inhibitors [XREF_BIBR] and tamoxifen [XREF_BIBR, XREF_BIBR].	26	34	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	GDNF	GDNF	GDNF	RET	RET	RET	33	34	26	27
The results show no decrease of the GDNF induced pRet51 and Ret51 ratio following excitotoxic injury , in the absence or in the presence of the calpain inhibitor , indicating that the receptor population remaining after injury can still be phosphorylated .	The results show no decrease of the GDNF induced pRet51 and Ret51 ratio following excitotoxic injury, in the absence or in the presence of the calpain inhibitor, indicating that the receptor population remaining after injury can still be phosphorylated.	4	12	induced	Positive_early_activation	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	pRet51	pRet51	pRet51	7	8	9	10
The impaired GH response to ghrelin could reflect desensitization of the ghrelin receptor induced by chronic elevation of ghrelin levels in this pathological state .	The impaired GH response to ghrelin could reflect desensitization of the ghrelin receptor induced by chronic elevation of ghrelin levels in this pathological state.	11	20	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	ghrelin	ghrelin levels	ghrelin	ghrelin receptor	ghrelin receptor	ghrelin receptor	18	19	11	13
HFD : leptin decreased GHS-R and GPR7 , ghrelin increased GHS-R and GPR7 .	HFD : leptin decreased GHS-R and GPR7, ghrelin increased GHS-R and GPR7.	8	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	8	9	10	11
GHRH and ghrelin decreased the expression of their respective receptors ( GHRH-R and GHS-R ) .	GHRH and ghrelin decreased the expression of their respective receptors (GHRH-R and GHS-R).	0	14	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	2	3	13	14
SLD : leptin reduced LepR , GPR7 , increased GHS-R and CCK1R mRNA ; ghrelin increased LepR , GPR7 , CCK1R , and decreased GHS-R .	SLD : leptin reduced LepR, GPR7, increased GHS-R and CCK1R mRNA; ghrelin increased LepR, GPR7, CCK1R, and decreased GHS-R.	14	25	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ghrelin	ghrelin	ghrelin	GHS-R	GHS-R	GHS-R	14	15	24	25
For example , T-bet and GATA3 are transiently co-expressed in recently activated CD4 + T cells and can functionally interact , limiting the action of Gata3 .	For example, T-bet and GATA3 are transiently co-expressed in recently activated CD4 + T cells and can functionally interact, limiting the action of Gata3.	3	26	limiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GATA3	GATA3 are transiently co-expressed	gata3	Gata3	Gata3	gata3	5	6	25	26
For example , T-bet and GATA3 are transiently co-expressed in recently activated CD4 T cells and can functionally interact , limiting the action of GATA3 122 .	For example, T-bet and GATA3 are transiently co-expressed in recently activated CD4 T cells and can functionally interact, limiting the action of GATA3 122.	3	25	limiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GATA3	GATA3 are transiently co-expressed	gata3	GATA3	GATA3	gata3	5	6	24	25
The I3C mediated degradation of ERalpha protein directly down-regulates expression of GATA3 , which then disrupts the GATA3 and ERalpha cross-regulatory loop because of the loss of GATA3 stimulated ESR1 promoter activity .	The I3C mediated degradation of ERalpha protein directly down-regulates expression of GATA3, which then disrupts the GATA3 and ERalpha cross-regulatory loop because of the loss of GATA3 stimulated ESR1 promoter activity.	9	21	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GATA3	expression of GATA3	gata3	GATA3	GATA3	gata3	11	12	17	18
MERTK activity may also be limited by availability of its ligand Gas6 , which is required for binding to apoptotic cells 60 .	MERTK activity may also be limited by availability of its ligand Gas6, which is required for binding to apoptotic cells 60.	0	12	limited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	MERTK	MERTK	MERTK	11	12	0	1
sMer can bind to Gas6 and inhibit Gas6 mediated MERTK activation XREF_BIBR , which in turn could result in the impaired phagocytosis and retinopathy .	sMer can bind to Gas6 and inhibit Gas6 mediated MERTK activation XREF_BIBR, which in turn could result in the impaired phagocytosis and retinopathy.	6	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	MERTK	MERTK	MERTK	7	8	9	10
MERTK activity may also be limited by availability of its ligand Gas6 , which is required for binding to apoptotic cells .	MERTK activity may also be limited by availability of its ligand Gas6, which is required for binding to apoptotic cells.	0	12	limited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	MERTK	MERTK	MERTK	11	12	0	1
This GAS6 sequestration prevented MERTK signaling on endothelial cells .	This GAS6 sequestration prevented MERTK signaling on endothelial cells.	1	5	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GAS6	GAS6	GAS6	MERTK	MERTK	MERTK	1	2	4	5
Neither M35 nor M40 , two galanin analogues with putative antagonistic action , prevented GALR2 agonist induced internalization of GALR2-EGFP , suggesting that they are not antagonists at this receptor under the present circumstances .	Neither M35 nor M40, two galanin analogues with putative antagonistic action, prevented GALR2 agonist induced internalization of GALR2-EGFP, suggesting that they are not antagonists at this receptor under the present circumstances.	6	20	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	galanin	galanin	galanin	GALR2-EGFP	GALR2-EGFP	GALR2-EGFP	6	7	19	20
To better understand the role of GALR2 in arrest of tumor cell proliferation , starved cells were treated with 1 microM of galanin for 24 hours and the expression of these regulatory proteins was measured by immunoblotting using specific antibodies .	To better understand the role of GALR2 in arrest of tumor cell proliferation, starved cells were treated with 1 microM of galanin for 24 hours and the expression of these regulatory proteins was measured by immunoblotting using specific antibodies.	4	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	galanin	galanin	galanin	GALR2	GALR2	GALR2	22	23	6	7
However , the same group showed that a caspase-3 inhibitor was unable to block apoptotic morphology and the inhibition of cell proliferation in galanin stimulated SY5Y and GALR2 cells .	However, the same group showed that a caspase-3 inhibitor was unable to block apoptotic morphology and the inhibition of cell proliferation in galanin stimulated SY5Y and GALR2 cells.	21	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	galanin	galanin	galanin	GALR2	GALR2	GALR2	23	24	27	28
To test the extent to which compensation by ALK2 and other type I receptors for the loss of ALK1 accounts for SMAD1/5/8 phosphorylation in 2f/1f and 1f/1f pECs treated with high concentrations of BMP-9 , we treated cells with LDN-193189 , a selective BMP inhibitor XREF_BIBR .	To test the extent to which compensation by ALK2 and other type I receptors for the loss of ALK1 accounts for SMAD1/5/8 phosphorylation in 2f/1f and 1f/1f pECs treated with high concentrations of BMP-9, we treated cells with LDN-193189, a selective BMP inhibitor XREF_BIBR.	18	34	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	BMP-9	BMP-9	BMP-9	ALK1	ALK1	ALK1	33	34	18	19
The use of small interfering RNA revealed that TGFbeta1 stimulated VEGF expression by activating ALK5 , TGFbeta type II receptor , and SMAD2 , whereas BMP-9 suppressed it by activating ALK1 , BMP type II receptor , and SMAD1 .	The use of small interfering RNA revealed that TGFbeta1 stimulated VEGF expression by activating ALK5, TGFbeta type II receptor, and SMAD2, whereas BMP-9 suppressed it by activating ALK1, BMP type II receptor, and SMAD1.	25	38	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BMP-9	BMP-9	BMP-9	ALK1	ALK1	ALK1	25	26	30	31
At 100 nM where it inhibits greater than 75 % of the ALK2 activity XREF_BIBR , LDN-193189 treatment more effectively inhibited SMAD1/5/8 phosphorylation in 1f/1f-ECs than it did in 2f/2f-ECs ( XREF_FIG ) , indicating that ALK2 and other ALKs can partly compensate for the loss of ALK1 in SMAD1/5/8 phosphorylation when treated with high BMP-9 concentrations .	At 100 nM where it inhibits greater than 75% of the ALK2 activity XREF_BIBR, LDN-193189 treatment more effectively inhibited SMAD1/5/8 phosphorylation in 1f/1f-ECs than it did in 2f/2f-ECs (XREF_FIG), indicating that ALK2 and other ALKs can partly compensate for the loss of ALK1 in SMAD1/5/8 phosphorylation when treated with high BMP-9 concentrations.	45	56	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	BMP-9	BMP-9	BMP-9	ALK1	ALK1	ALK1	55	56	47	48
One counterintuitive part of our results is that Gas6 impedes the ability of Tyro3 to inhibit Abeta production , which contradicts previous reports of the neuroprotective and neurotrophic effects of Gas6 on Alzheimer ' s disease like disorders XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR , XREF_BIBR .	One counterintuitive part of our results is that Gas6 impedes the ability of Tyro3 to inhibit Abeta production, which contradicts previous reports of the neuroprotective and neurotrophic effects of Gas6 on Alzheimer 's disease like disorders XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR, XREF_BIBR.	8	14	impedes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	8	9	13	14
However , the former study lacked animal- or molecular based evidence , and the latter reported the contradictory finding that Gas6 inhibits the effect of Tyro3 .	However, the former study lacked animal- or molecular based evidence, and the latter reported the contradictory finding that Gas6 inhibits the effect of Tyro3.	20	26	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	20	21	25	26
Gas6 treatment also inhibited the effects of Tyro3 receptor on BACE1 expression .	Gas6 treatment also inhibited the effects of Tyro3 receptor on BACE1 expression.	0	8	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Gas6	Gas6	Gas6	Tyro3	Tyro3	Tyro3	0	1	7	8
Substituting the native glutamine ( Gln ) at amino acid position 3 of OXM for glutamate ( Glu ) has previously been shown to diminish GCGr activity without affecting GLP-1r activity .	Substituting the native glutamine (Gln) at amino acid position 3 of OXM for glutamate (Glu) has previously been shown to diminish GCGr activity without affecting GLP-1r activity.	11	26	diminish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	OXM	OXM	OXM	GCGr	GCGr	GCGr	13	14	25	26
One interactor of interest , YWHAB , may be involved in GCGR desensitization , attenuating glucagon stimulated glucose production .	One interactor of interest, YWHAB, may be involved in GCGR desensitization, attenuating glucagon stimulated glucose production.	11	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	glucagon	glucagon	glucagon	GCGR	GCGR	GCGR	15	16	11	12
The glucagon ( 1-17 ) has markedly reduced affinity for binding to the glucagon receptor as well as markedly reduced ability to stimulate adenylate cyclase activity which is not affected by the presence of glucagon ( 19-29 ) .	The glucagon (1-17) has markedly reduced affinity for binding to the glucagon receptor as well as markedly reduced ability to stimulate adenylate cyclase activity which is not affected by the presence of glucagon (19-29).	7	36	reduced	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	glucagon	glucagon	glucagon	glucagon receptor	glucagon receptor	glucagon receptor	34	35	13	15
Knock-down of GMPS prevents p53 stabilization in response to genotoxic stress 59 , while concomitant overexpression of both USP7 and GMPS leads to p53 stabilization and apoptosis , even in the absence of genotoxic stress 59 .	Knock-down of GMPS prevents p53 stabilization in response to genotoxic stress 59, while concomitant overexpression of both USP7 and GMPS leads to p53 stabilization and apoptosis, even in the absence of genotoxic stress 59.	0	5	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GMPS	GMPS	GMPS	p53	p53	p53	2	3	4	5
GMPS retention in the cytoplasm is mediated by a ubiquitylation dependent mechanism , thus preventing p53 induction .	GMPS retention in the cytoplasm is mediated by a ubiquitylation dependent mechanism, thus preventing p53 induction.	0	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GMPS	GMPS	GMPS	p53	p53	p53	0	1	15	16
Therefore , specific downregulation of Fzd receptors by CD82 may reduce Wnt and beta-catenin signalling .	Therefore, specific downregulation of Fzd receptors by CD82 may reduce Wnt and beta-catenin signalling.	5	14	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fzd	Fzd	Fzd	beta-catenin	beta-catenin	beta-catenin	5	6	13	14
Loss of gastrin induced proliferation was observed in the CCK-BR KO mouse derived organoids ( XREF_FIG ) .	Loss of gastrin induced proliferation was observed in the CCK-BR KO mouse derived organoids (XREF_FIG).	0	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gastrin	Loss of gastrin	gastrin	CCK-BR	CCK-BR	cck-br	2	3	9	10
In this sense , a model of metastatic medullary thyroid cancer has been successfully used to evaluate the diagnostic and therapeutic potential of radiolabeled gastrin directed to target CCKB receptor expressing tumors in vivo .	In this sense, a model of metastatic medullary thyroid cancer has been successfully used to evaluate the diagnostic and therapeutic potential of radiolabeled gastrin directed to target CCKB receptor expressing tumors in vivo.	23	30	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	gastrin	gastrin	gastrin	CCKB receptor	CCKB receptor	CCKB receptor	24	25	28	30
However , the tripartite complex GATA1 , FOG-1 , and NuRD has been shown to activate and repress GATA1 and FOG- 1 target genes .	However, the tripartite complex GATA1, FOG-1, and NuRD has been shown to activate and repress GATA1 and FOG- 1 target genes.	2	22	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GATA1	GATA1	GATA1	FOG- 1	FOG- 1	FOG- 1	5	6	20	22
However , GDNF in the presence of soluble or immobilized GFRalpha1 reverse the GDNF independent GFRalpha1 modulation of neurite growth .	However, GDNF in the presence of soluble or immobilized GFRalpha1 reverse the GDNF independent GFRalpha1 modulation of neurite growth.	2	16	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GDNF	GDNF	GDNF	GFRalpha1	GFRalpha1	GFRalpha1	2	3	15	16
In contrast slow GNRH pulses ( every 240min ) increased Egr1 PT at 24h ( 6-fold ; p < 0.05 ) , but increased Egr1 mRNA 4-5 fold between 4 and 24h .	In contrast slow GNRH pulses (every 240min) increased Egr1 PT at 24h (6-fold; p < 0.05), but increased Egr1 mRNA 4-5 fold between 4 and 24h.	3	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GNRH	GNRH	GNRH	Egr1	Egr1	Egr1	3	4	10	11
Surprisingly , a GNRH induced increase in Egr1 mRNA was seen earlier ( beginning at 4h ) , suggesting that slow frequency GNRH pulses increase Egr1 mRNA via a non transcriptional mechanism , such as increased mRNA stability .	Surprisingly, a GNRH induced increase in Egr1 mRNA was seen earlier (beginning at 4h), suggesting that slow frequency GNRH pulses increase Egr1 mRNA via a non transcriptional mechanism, such as increased mRNA stability.	22	26	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GNRH	GNRH	GNRH	Egr1	Egr1	Egr1	22	23	25	26
Inhibitors of Mitogen Activated Protein Kinases 8/9 ( MAPK8/9 [ aka JNK ] ; SP600125 ) and MAP Kinase Kinase 1 ( MAP2K1 [ aka MEK1 ] ; PD98059 ) either blunted or totally suppressed the GNRH induction of Lhb PT and Egr1 PT/mRNA , whereas the MAPK14 ( aka p38 ) inhibitor SB203580 did not .	Inhibitors of Mitogen Activated Protein Kinases 8/9 (MAPK8/9 [aka JNK]; SP600125) and MAP Kinase Kinase 1 (MAP2K1 [aka MEK1]; PD98059) either blunted or totally suppressed the GNRH induction of Lhb PT and Egr1 PT/mRNA, whereas the MAPK14 (aka p38) inhibitor SB203580 did not.	36	43	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	GNRH	GNRH	GNRH	Egr1	Egr1	Egr1	36	37	42	43
GOLPH3 can activate mammalian target of rapamycin ( mTOR ) , which in turn can promote cell growth .	GOLPH3 can activate mammalian target of rapamycin (mTOR), which in turn can promote cell growth.	0	7	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GOLPH3	GOLPH3	GOLPH3	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	3	7
Here , we show that RGS16 inhibits G alpha 13 mediated , RhoA dependent reversal of stellation and SRE activation .	Here, we show that RGS16 inhibits G alpha 13 mediated, RhoA dependent reversal of stellation and SRE activation.	7	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	G alpha 13	G alpha 13	G alpha 13	RhoA	RhoA	RhoA	7	10	12	13
GNA13 and RHOA mutations impair RhoA activity .	GNA13 and RHOA mutations impair RhoA activity.	0	6	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GNA13	GNA13	GNA13	RhoA	RhoA	RhoA	0	1	5	6
Considering that the glypican-4 ectodomain released from the cell surface inhibits Wnt5a signaling4 , glypican-4 might also regulate insulin sensitivity by decreasing a pro inflammatory state through Wnt signaling in adipose tissue .	Considering that the glypican-4 ectodomain released from the cell surface inhibits Wnt5a signaling4, glypican-4 might also regulate insulin sensitivity by decreasing a pro inflammatory state through Wnt signaling in adipose tissue.	3	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	glypican-4	glypican-4	glypican-4	Wnt5a	Wnt5a	Wnt5a	3	4	11	12
GSK3beta activity is suppressed by phosphorylation of GSK3beta at Ser9 via the RAS/MEK/ERK and the PI3K and AKT signaling XREF_BIBR XREF_BIBR .	GSK3beta activity is suppressed by phosphorylation of GSK3beta at Ser9 via the RAS/MEK/ERK and the PI3K and AKT signaling XREF_BIBR XREF_BIBR.	0	10	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta at Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	7	8	0	1
BDNF also increased serine ( 9 ) -phosphorylation of GSK3beta , which inhibits GSK3beta activity .	BDNF also increased serine (9) -phosphorylation of GSK3beta, which inhibits GSK3beta activity.	0	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	BDNF also increased serine (9) -phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	9	10	13	14
Ser9 phosphorylation of GSK-3beta decreases GSK-3beta activity , whereas Tyr216 phosphorylation increases GSK-3beta activity [ XREF_BIBR ] .	Ser9 phosphorylation of GSK-3beta decreases GSK-3beta activity, whereas Tyr216 phosphorylation increases GSK-3beta activity [XREF_BIBR].	1	6	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	3	4	5	6
Reelin stimulates serine 9 phosphorylation of glycogen-synthase kinase 3beta ( GSK3beta ) , which decreases GSK3beta activity .	Reelin stimulates serine 9 phosphorylation of glycogen-synthase kinase 3beta (GSK3beta), which decreases GSK3beta activity.	0	16	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	glycogen-synthase kinase 3beta	Reelin stimulates serine 9 phosphorylation of glycogen-synthase kinase 3beta	glycogen-synthase kinase 3beta	GSK3beta	GSK3beta	gsk3beta	6	9	15	16
We showed that UVB irradiation increased the level of pGSK3beta ( Ser 9 ) and decreased pGSK3beta ( Tyr 216 ) , indicating it inhibited GSK3beta activity ( XREF_FIG ) .	We showed that UVB irradiation increased the level of pGSK3beta (Ser 9) and decreased pGSK3beta (Tyr 216), indicating it inhibited GSK3beta activity (XREF_FIG).	3	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	pGSK3beta	UVB irradiation increased the level of pGSK3beta	pgsk3beta	pGSK3beta	pGSK3beta	pgsk3beta	9	10	16	17
AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase ( GSK-3beta ) but reduced GSK-3beta and caspase-3 activities in the heart .	AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3beta) but reduced GSK-3beta and caspase-3 activities in the heart.	0	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	12	13	16	17
DYRK1A directly phosphorylates GSK-3beta on Thr 356 , thereby inhibiting GSK-3beta activity .	DYRK1A directly phosphorylates GSK-3beta on Thr 356, thereby inhibiting GSK-3beta activity.	0	11	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	DYRK1A directly phosphorylates GSK-3beta on Thr 356	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	3	4	10	11
GSK3beta ( S9 ) phosphorylated by active AKT ( i.e ., AKT S473 phosphorylated form ) inhibits GSK3beta kinase activity [ XREF_BIBR ] .	GSK3beta (S9) phosphorylated by active AKT (i.e., AKT S473 phosphorylated form) inhibits GSK3beta kinase activity [XREF_BIBR].	0	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta (S9) phosphorylated by active AKT (i.e., AKT S473	gsk3beta	GSK3beta	GSK3beta	gsk3beta	0	1	17	18
Phosphorylation of GSK-3beta at Ser9 inhibits GSK-3beta , which reduces the formation of mitochondrial permeability transition pore and the mitochondrial membrane permeation .	Phosphorylation of GSK-3beta at Ser9 inhibits GSK-3beta, which reduces the formation of mitochondrial permeability transition pore and the mitochondrial membrane permeation.	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Phosphorylation of GSK-3beta at Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	6	7
In addition , lithium also can increase Ser9 phosphorylation of GSK-3beta , thereby inhibiting GSK-3beta activity .	In addition, lithium also can increase Ser9 phosphorylation of GSK-3beta, thereby inhibiting GSK-3beta activity.	3	15	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	lithium also can increase Ser9 phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	10	11	14	15
It suggests that nicotine mediated heightened serine 9 phosphorylation of GSK3beta may inactivate cardiac GSK3beta , leading to an increase in I/R induced cardiac injury .	It suggests that nicotine mediated heightened serine 9 phosphorylation of GSK3beta may inactivate cardiac GSK3beta, leading to an increase in I/R induced cardiac injury.	8	15	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	10	11	14	15
The reduction of RelB protein levels as a result of GSK-3beta overexpression supports GSK-3beta as a new target for inducing tolerogenic DCs .	The reduction of RelB protein levels as a result of GSK-3beta overexpression supports GSK-3beta as a new target for inducing tolerogenic DCs.	10	14	supports	Positive_activation_token_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta overexpression	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	10	11	13	14
Activated AKT can inhibit activation of GSK3beta by phosphorylating GSK3beta at the Ser residue , and decrease the expression of Caspase3 as they induce anti-apoptosis effects .	Activated AKT can inhibit activation of GSK3beta by phosphorylating GSK3beta at the Ser residue, and decrease the expression of Caspase3 as they induce anti-apoptosis effects.	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	GSK3beta	phosphorylating GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	9	10	6	7
We also show that the reduced levels of npS9 GSK3beta in HEK293 cells treated with protein phosphatase inhibitor causes a reduction in GSK3beta kinase activity by using the 12B2 npS9 GSK3beta antibody .	We also show that the reduced levels of npS9 GSK3beta in HEK293 cells treated with protein phosphatase inhibitor causes a reduction in GSK3beta kinase activity by using the 12B2 npS9 GSK3beta antibody.	6	24	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	levels of npS9 GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	9	10	22	23
More in depth analysis showed that TZD alone can significantly attenuate GSK3beta expression , which inhibited total GSK3beta via antagonizing its transcription .	More in depth analysis showed that TZD alone can significantly attenuate GSK3beta expression, which inhibited total GSK3beta via antagonizing its transcription.	6	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	TZD alone can significantly attenuate GSK3beta expression	gsk3beta	GSK3beta	GSK3beta	gsk3beta	11	12	17	18
In a mouse model of mammary tumorigenesis , inhibition of GSK3beta by overexpression of kinase-inactive GSK3beta in mouse mammary glands promotes mammary tumorigenesis ; this is accompanied by the over-expression of beta-catenin and cyclin D1 [ XREF_BIBR ] , supporting that GSK3beta inhibition causes dysregulation of the Wnt and beta-catenin pathway which results in tumor promotion .	In a mouse model of mammary tumorigenesis, inhibition of GSK3beta by overexpression of kinase-inactive GSK3beta in mouse mammary glands promotes mammary tumorigenesis; this is accompanied by the over-expression of beta-catenin and cyclin D1 [XREF_BIBR], supporting that GSK3beta inhibition causes dysregulation of the Wnt and beta-catenin pathway which results in tumor promotion.	8	19	inhibition	Negative_activation_token_2_noun	Positive_activation	Negative_activation	GSK3beta	overexpression of kinase-inactive GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	15	16	10	11
Phosphorylation of GSK3beta at Ser9 ( an AKT site that suppresses GSK3beta activity ) was strikingly elevated in KPiP compared to KP cells and substantially reduced by GDC-0941 , BYL719 , or their combinations with PD901 , while these agents had little to no effect on pGSK3beta in KP cells ( XREF_FIG ) .	Phosphorylation of GSK3beta at Ser9 (an AKT site that suppresses GSK3beta activity) was strikingly elevated in KPiP compared to KP cells and substantially reduced by GDC-0941, BYL719, or their combinations with PD901, while these agents had little to no effect on pGSK3beta in KP cells (XREF_FIG).	0	12	suppresses	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	GSK3beta	Phosphorylation of GSK3beta at Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	2	3	11	12
82 Phosphorylation of GSK3beta on serine 9 by Akt inhibits GSK3beta activity .	82 Phosphorylation of GSK3beta on serine 9 by Akt inhibits GSK3beta activity.	1	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Phosphorylation of GSK3beta on serine 9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	3	4	10	11
In the PI3K and AKT signaling pathway , AKT phosphorylates Ser 9 of GSK3beta and inhibits GSK3beta activity for cell proliferation [ XREF_BIBR ] .	In the PI3K and AKT signaling pathway, AKT phosphorylates Ser 9 of GSK3beta and inhibits GSK3beta activity for cell proliferation [XREF_BIBR].	8	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	AKT phosphorylates Ser 9 of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	13	14	16	17
AKT1 mediates Ser9 phosphorylation of GSK3beta , which inhibits GSK3beta and promotes MT anchoring to the periphery in interphase via regulation of APC and CLASP2 phosphorylation XREF_BIBR , XREF_BIBR .	AKT1 mediates Ser9 phosphorylation of GSK3beta, which inhibits GSK3beta and promotes MT anchoring to the periphery in interphase via regulation of APC and CLASP2 phosphorylation XREF_BIBR, XREF_BIBR.	0	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	AKT1 mediates Ser9 phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	5	6	9	10
In order to verify that Akt was actually involved in the regulation of HB9 , we inhibited Akt directly using several inhibitors , and found that Akt inhibition increased HB9 levels , which correlated with a decrease in GSK3beta phosphorylation at Ser9 , a modification that decreases GSK3beta activity .	In order to verify that Akt was actually involved in the regulation of HB9, we inhibited Akt directly using several inhibitors, and found that Akt inhibition increased HB9 levels, which correlated with a decrease in GSK3beta phosphorylation at Ser9, a modification that decreases GSK3beta activity.	38	48	decreases	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta phosphorylation at Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	38	39	47	48
There are reports that Akt phosphorylates GSK-3beta on Ser9 , and thereby inhibits GSK-3beta activity .	There are reports that Akt phosphorylates GSK-3beta on Ser9, and thereby inhibits GSK-3beta activity.	4	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Akt phosphorylates GSK-3beta on Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	6	7	13	14
Phosphorylation of GSK3beta at Ser9 inhibits GSK3beta , which then reduces opening of the mitochondrial permeability transition pore ( mPTP ) .	Phosphorylation of GSK3beta at Ser9 inhibits GSK3beta, which then reduces opening of the mitochondrial permeability transition pore (mPTP).	0	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Phosphorylation of GSK3beta at Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	2	3	6	7
Since phosphorylation of GSK3B at serine 9 inhibits GSK3B activity , melatonin can enhance GSK3B activity through decreasing P-GSK3B at serine 9 .	Since phosphorylation of GSK3B at serine 9 inhibits GSK3B activity, melatonin can enhance GSK3B activity through decreasing P-GSK3B at serine 9.	1	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3B	phosphorylation of GSK3B at serine 9	gsk3b	GSK3B	GSK3B	gsk3b	3	4	8	9
Activation of GSK3beta was obligatory for thapsigargin induced activation of caspase-3 , because inhibition of GSK3beta by expression of dominant negative GSK3beta or by the GSK3beta inhibitor lithium blocked caspase-3 activation .	Activation of GSK3beta was obligatory for thapsigargin induced activation of caspase-3, because inhibition of GSK3beta by expression of dominant negative GSK3beta or by the GSK3beta inhibitor lithium blocked caspase-3 activation.	13	27	inhibition	Negative_activation_token_2_noun	Positive_activation	Negative_activation	GSK3beta	expression of dominant negative GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	21	22	15	16
However , APAP attenuated the reduction by phosphorylating GSK3beta in the hippocampus and blocked GSK-3beta activity in response to LPS , thus providing protection from LPS induced apoptosis and cognitive impairment .	However, APAP attenuated the reduction by phosphorylating GSK3beta in the hippocampus and blocked GSK-3beta activity in response to LPS, thus providing protection from LPS induced apoptosis and cognitive impairment.	2	15	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	APAP attenuated the reduction by phosphorylating GSK3beta	gsk3beta	GSK-3beta	GSK-3beta	gsk-3beta	8	9	14	15
Increased phosphorylation of AKT ( increased AKT activities ) causes phosphorylation of GSK3beta ( suppression of GSK3beta activities ) at the serine 9 residue while reduced phosphorylation of AKT ( reduced AKT activities ) decreases levels of phosphorylation of GSK3beta ( increased GSK3beta activities ) .	Increased phosphorylation of AKT (increased AKT activities) causes phosphorylation of GSK3beta (suppression of GSK3beta activities) at the serine 9 residue while reduced phosphorylation of AKT (reduced AKT activities) decreases levels of phosphorylation of GSK3beta (increased GSK3beta activities).	1	17	suppression	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	GSK3beta	phosphorylation of AKT (increased AKT activities) causes phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	12	13	16	17
Lithium chloride ( LiCl ) induces GSK3beta ( ser9 ) phosphorylation and inhibits GSK3beta activity [ XREF_BIBR , XREF_BIBR ] .	Lithium chloride (LiCl) induces GSK3beta (ser9) phosphorylation and inhibits GSK3beta activity [XREF_BIBR, XREF_BIBR].	0	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Lithium chloride (LiCl) induces GSK3beta (ser9) phosphorylation	gsk3beta	GSK3beta	GSK3beta	gsk3beta	6	7	13	14
Upon insulin stimulation , Akt mediated phosphorylation of GSK3beta inhibits GSK3beta activity and causes its substrate , eukaryotic initiation factor 2B ( eIF2B ) , to become dephosphorylated and thus activated XREF_BIBR - XREF_BIBR .	Upon insulin stimulation, Akt mediated phosphorylation of GSK3beta inhibits GSK3beta activity and causes its substrate, eukaryotic initiation factor 2B (eIF2B), to become dephosphorylated and thus activated XREF_BIBR - XREF_BIBR.	4	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Akt mediated phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	8	9	10	11
Phosphorylation of GSK-3beta by Akt inactivates GSK-3beta and concurrent Mcl-1 degradation XREF_BIBR .	Phosphorylation of GSK-3beta by Akt inactivates GSK-3beta and concurrent Mcl-1 degradation XREF_BIBR.	0	11	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	6	7
In line with this , knockin mice carrying a transgene that impairs serine phosphorylation of GSK-3beta ( P-GSK-3beta-KI ) , which effectively prevents GSK-3beta inactivation , are more susceptible to stress induced depression related behaviors .	In line with this, knockin mice carrying a transgene that impairs serine phosphorylation of GSK-3beta (P-GSK-3beta-KI), which effectively prevents GSK-3beta inactivation, are more susceptible to stress induced depression related behaviors.	12	24	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	serine phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	15	16	23	24
To test whether the increases in the levels of pGSK-3beta that inactivate GSK-3beta are functionally relevant to elevated pNFH , we blocked GSK-3beta activity using two structurally unrelated non ATP competitive GSK-3beta inhibitors , inhibitor I and VII .	To test whether the increases in the levels of pGSK-3beta that inactivate GSK-3beta are functionally relevant to elevated pNFH, we blocked GSK-3beta activity using two structurally unrelated non ATP competitive GSK-3beta inhibitors, inhibitor I and VII.	7	13	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	pGSK-3beta	levels of pGSK-3beta	pgsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	9	10	12	13
Akt is known to phosphorylate GSK-3beta , which negatively regulates GSK-3beta function .	Akt is known to phosphorylate GSK-3beta, which negatively regulates GSK-3beta function.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Akt is known to phosphorylate GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	5	6	10	11
Because the phosphorylation of GSK3beta at Ser9 inhibits the kinase activity of GSK3beta [ XREF_BIBR ] , the PMA induced phosphorylation of GSK3beta may decrease the possibility for NFAT phosphorylation by GSK3beta .	Because the phosphorylation of GSK3beta at Ser9 inhibits the kinase activity of GSK3beta [XREF_BIBR], the PMA induced phosphorylation of GSK3beta may decrease the possibility for NFAT phosphorylation by GSK3beta.	2	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta at Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	4	5	12	13
The phosphorylation of GSK-3beta at the Ser9 residue inhibits the activity of GSK-3beta in response to upstream signals .	The phosphorylation of GSK-3beta at the Ser9 residue inhibits the activity of GSK-3beta in response to upstream signals.	1	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta at the Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	3	4	12	13
However , mice in siILK-NonE group exhibited reduced GSK3beta Ser 9 phosphorylation levels in the DG compared with mice in Scramble-NonE group ( XREF_FIG , vector , F ( 1,18 ) = 37.97 , p < 0.001 , two-way ANOVA ) , suggesting that decreased ILK levels led to elevated GSK3beta activity , as the GSK3beta Ser 9 phosphorylation could inhibit the GSK3beta activity XREF_BIBR .	However, mice in siILK-NonE group exhibited reduced GSK3beta Ser 9 phosphorylation levels in the DG compared with mice in Scramble-NonE group (XREF_FIG, vector, F (1,18) = 37.97, p < 0.001, two-way ANOVA), suggesting that decreased ILK levels led to elevated GSK3beta activity, as the GSK3beta Ser 9 phosphorylation could inhibit the GSK3beta activity XREF_BIBR.	55	64	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta Ser 9 phosphorylation	gsk3beta	GSK3beta	GSK3beta	gsk3beta	55	56	62	63
PI3-K-dependent phosphorylation of GSK-3beta at Ser9 inhibits activation of GSK-3beta and thus stabilizes cyclin D1 .	PI3-K-dependent phosphorylation of GSK-3beta at Ser9 inhibits activation of GSK-3beta and thus stabilizes cyclin D1.	1	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta at Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	3	4	9	10
Activation of the PI3K and Akt signal pathway causes GSK3beta phosphorylation at Ser9 and inactivates GSK3beta .	Activation of the PI3K and Akt signal pathway causes GSK3beta phosphorylation at Ser9 and inactivates GSK3beta.	3	16	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	PI3K and Akt signal pathway causes GSK3beta phosphorylation at Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	9	10	15	16
One possibility for the discrepant labeling could be that phosphorylation at serine 9 of GSK3beta may partially block the immunoreactivity of the phospho independent GSK3beta antibody , thus regions with a high concentration of pSer9GSK3beta may appear as devoid of GSK3beta .	One possibility for the discrepant labeling could be that phosphorylation at serine 9 of GSK3beta may partially block the immunoreactivity of the phospho independent GSK3beta antibody, thus regions with a high concentration of pSer9GSK3beta may appear as devoid of GSK3beta.	9	25	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation at serine 9 of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	14	15	24	25
Several preclinical and clinical data strongly link GSK-3beta to dementia : different inhibitors of GSK3B activity block neurodegeneration in vitro , and GSK-3beta -mediated Wnt signaling can mediate amyloid peptide toxicity in vitro [ XREF_BIBR , XREF_BIBR ] .	Several preclinical and clinical data strongly link GSK-3beta to dementia : different inhibitors of GSK3B activity block neurodegeneration in vitro, and GSK-3beta -mediated Wnt signaling can mediate amyloid peptide toxicity in vitro [XREF_BIBR, XREF_BIBR].	6	17	inhibitors	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	GSK3B	GSK3B	GSK3B	7	8	14	15
Phosphorylation of GSK-3beta by AKT is known to inhibit the activity of GSK-3beta and is essential for both physiological and pathological hypertrophy .	Phosphorylation of GSK-3beta by AKT is known to inhibit the activity of GSK-3beta and is essential for both physiological and pathological hypertrophy.	0	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	12	13
Pharmacologically inhibiting the canonical Wnt and GSK3beta pathway significantly reduced the electrotactic response of NPCs ( vm ) , which is associated with the down-regulation of GSK3beta phosphorylation , beta-catenin activation and CLASP2 expression .	Pharmacologically inhibiting the canonical Wnt and GSK3beta pathway significantly reduced the electrotactic response of NPCs (vm), which is associated with the down-regulation of GSK3beta phosphorylation, beta-catenin activation and CLASP2 expression.	1	28	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta phosphorylation	gsk3beta	GSK3beta	GSK3beta	gsk3beta	26	27	6	7
Transgenic PKCbetaII mice exhibit decreased GSK3beta activity in the colonic epithelium in vivo , consistent with the finding that PKCbetaII can directly phosphorylate GSK3beta at Serine 9 , a phosphorylation event that inhibits GSK3beta activity .	Transgenic PKCbetaII mice exhibit decreased GSK3beta activity in the colonic epithelium in vivo, consistent with the finding that PKCbetaII can directly phosphorylate GSK3beta at Serine 9, a phosphorylation event that inhibits GSK3beta activity.	19	34	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	GSK3beta	PKCbetaII can directly phosphorylate GSK3beta at Serine 9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	23	24	33	34
AZD8055 treatment reduced pGSK3beta , pS6 and pAkt levels and in contrast rapamycin inhibited S6 phosphorylation but failed to prevent Akt activation or GSK3beta inhibition .	AZD8055 treatment reduced pGSK3beta, pS6 and pAkt levels and in contrast rapamycin inhibited S6 phosphorylation but failed to prevent Akt activation or GSK3beta inhibition.	0	24	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	pGSK3beta	AZD8055 treatment reduced pGSK3beta, pS6 and pAkt levels	pgsk3beta	GSK3beta	GSK3beta	gsk3beta	3	4	23	24
The Wnt signaling protein beta-catenin was upregulated ( 3.3-fold decrease in p-beta-catenin and beta-catenin ) while the glycogen synthase kinase-3beta ( GSK-3beta ) was downregulated ( 2.6-fold increase in p-GSK-3beta and GSK-3beta ) in preglomerular vessels of diabetic mice .	The Wnt signaling protein beta-catenin was upregulated (3.3-fold decrease in p-beta-catenin and beta-catenin) while the glycogen synthase kinase-3beta (GSK-3beta) was downregulated (2.6-fold increase in p-GSK-3beta and GSK-3beta) in preglomerular vessels of diabetic mice.	19	31	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	p-GSK-3beta	p-GSK-3beta	p-GSK-3beta	21	22	29	30
Here we show that phosphorylation of GSK3beta on Ser 389 mediated by p38 MAPK specifically inactivates nuclear GSK3beta in the cortex and hippocampus .	Here we show that phosphorylation of GSK3beta on Ser 389 mediated by p38 MAPK specifically inactivates nuclear GSK3beta in the cortex and hippocampus.	4	22	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta on Ser 389	gsk3beta	GSK3beta	GSK3beta	gsk3beta	6	7	17	18
In recent years , an increasing number of reports have described the influential role of the interaction between the PI3K and AKT and Wnt and beta-catenin pathways , through the AKT/GSK-3beta/beta-catenin axis , in tumor progression.33 , 34 Protein kinase B is a decisive molecule of PI3K and AKT signaling , and p-AKT can phosphorylate the serine 9 of GSK-3beta phosphorylated by p-AKT can limit1the activity of GSK-3beta .	In recent years, an increasing number of reports have described the influential role of the interaction between the PI3K and AKT and Wnt and beta-catenin pathways, through the AKT/GSK-3beta/beta-catenin axis, in tumor progression.33, 34 Protein kinase B is a decisive molecule of PI3K and AKT signaling, and p-AKT can phosphorylate the serine 9 of GSK-3beta phosphorylated by p-AKT can limit1the activity of GSK-3beta.	56	68	limit1the	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	serine 9 of GSK-3beta phosphorylated	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	59	60	67	68
By stimulating PI3K and AKT and Ras and ERK , RET and PTC promotes GSK3beta phosphorylation , thereby reducing GSK3beta mediated N-terminal beta-catenin ( Ser33/Ser37/Thr41 ) phosphorylation .	By stimulating PI3K and AKT and Ras and ERK, RET and PTC promotes GSK3beta phosphorylation, thereby reducing GSK3beta mediated N-terminal beta-catenin (Ser33/Ser37/Thr41) phosphorylation.	10	20	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	RET and PTC promotes GSK3beta phosphorylation	gsk3beta	GSK3beta	GSK3beta	gsk3beta	14	15	19	20
AKT phosphorylates residue 9 of GSK3beta ( glycogen synthase kinase 3 beta ) , which prevents GSK3beta from phosphorylating Thr286 of cyclin D1 and subsequently promoting nuclear export and proteasomal degradation of cyclin D1 .	AKT phosphorylates residue 9 of GSK3beta (glycogen synthase kinase 3 beta), which prevents GSK3beta from phosphorylating Thr286 of cyclin D1 and subsequently promoting nuclear export and proteasomal degradation of cyclin D1.	0	17	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	AKT phosphorylates residue 9 of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	5	6	16	17
Phosphorylation of GSK-3beta at Ser9 causes the reduction of GSK-3beta activity [ XREF_BIBR ] .	Phosphorylation of GSK-3beta at Ser9 causes the reduction of GSK-3beta activity [XREF_BIBR].	0	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Phosphorylation of GSK-3beta at Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	9	10
In addition , a previous report by our group showed that inhibition of the upstream phosphatidylinositol 3-kinase/Akt signaling pathway , which is known to activate GSK3beta , and untargeted overexpression of GSK3beta facilitated MPP + and rotenone induced apoptosis .	In addition, a previous report by our group showed that inhibition of the upstream phosphatidylinositol 3-kinase/Akt signaling pathway, which is known to activate GSK3beta, and untargeted overexpression of GSK3beta facilitated MPP + and rotenone induced apoptosis.	24	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	overexpression of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	31	32	25	26
34 PI3K and Akt activation phosphorylates and inactivates GSK3beta and thus inhibits active GSK3beta ( i.e ., dephosphorylated form )-induced degradation of Snail protein .	34 PI3K and Akt activation phosphorylates and inactivates GSK3beta and thus inhibits active GSK3beta (i.e., dephosphorylated form)-induced degradation of Snail protein.	1	20	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	PI3K and Akt activation phosphorylates and inactivates GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	8	9	13	14
Activated AKT can phosphorylate GSK-3beta at Ser9 which then inactivates GSK-3beta .	Activated AKT can phosphorylate GSK-3beta at Ser9 which then inactivates GSK-3beta.	3	11	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	phosphorylate GSK-3beta at Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	4	5	10	11
Serine 9 phosphorylation of GSK3beta ( pGSK3betaSer9 ) , usually promoted by activation of the PI3K and Akt survival pathway , triggers GSK3beta inhibition .	Serine 9 phosphorylation of GSK3beta (pGSK3betaSer9), usually promoted by activation of the PI3K and Akt survival pathway, triggers GSK3beta inhibition.	0	23	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Serine 9 phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	4	5	22	23
We identified a novel positive-feedback loop mechanism via the INSM1 transcription factor that activated the PI3K and AKT signaling pathway , which subsequently induced phosphorylation of GSK3beta kinase and blocked GSK3beta kinase activity to stabilize N-myc .	We identified a novel positive-feedback loop mechanism via the INSM1 transcription factor that activated the PI3K and AKT signaling pathway, which subsequently induced phosphorylation of GSK3beta kinase and blocked GSK3beta kinase activity to stabilize N-myc.	15	32	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	PI3K and AKT signaling pathway, which subsequently induced phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	26	27	30	31
Recent studies link neurotrophin signaling to the activity dependent phosphorylation of glycogen synthase kinase-3beta ( GSK3beta ) at serine 9 in hippocampal neurons , which inhibits GSK3beta activity and promotes dendrite growth , [ XREF_BIBR ] .	Recent studies link neurotrophin signaling to the activity dependent phosphorylation of glycogen synthase kinase-3beta (GSK3beta) at serine 9 in hippocampal neurons, which inhibits GSK3beta activity and promotes dendrite growth, [XREF_BIBR].	9	27	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation of glycogen synthase kinase-3beta (GSK3beta) at serine 9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	15	16	26	27
It is well known that Akt phosphorylates GSK3beta on Ser9 and thereby inhibits GSK3beta activity XREF_BIBR , XREF_BIBR .	It is well known that Akt phosphorylates GSK3beta on Ser9 and thereby inhibits GSK3beta activity XREF_BIBR, XREF_BIBR.	5	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Akt phosphorylates GSK3beta on Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	7	8	13	14
In contrast to other protein kinases , GSK-3beta phosphorylation inhibits GSK-3beta activity , thus inhibiting cardiomyocyte apoptosis , exerting cardioprotective effects .	In contrast to other protein kinases, GSK-3beta phosphorylation inhibits GSK-3beta activity, thus inhibiting cardiomyocyte apoptosis, exerting cardioprotective effects.	7	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	7	8	10	11
FAK promotes the phosphorylation and activation of AKT , which in turn phosphorylates GSK-3beta on the serine 9 residue and inactivates GSK-3beta ; the latter phosphorylates beta-Catenin , driving its degradation [ XREF_BIBR ] .	FAK promotes the phosphorylation and activation of AKT, which in turn phosphorylates GSK-3beta on the serine 9 residue and inactivates GSK-3beta; the latter phosphorylates beta-Catenin, driving its degradation [XREF_BIBR].	0	22	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	FAK promotes the phosphorylation and activation of AKT, which in turn phosphorylates GSK-3beta on the serine 9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	13	14	21	22
Reductions in the phosphorylation at serine 9 of GSK3beta enhance the activation of GSK3beta XREF_BIBR - XREF_BIBR .	Reductions in the phosphorylation at serine 9 of GSK3beta enhance the activation of GSK3beta XREF_BIBR - XREF_BIBR.	3	14	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation at serine 9 of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	8	9	13	14
Inactivation of GSK-3beta by phosphorylation of Ser 9 in the N-terminal domain of GSK-3beta is involved in the interruption of cell signaling pathways , including the Akt and beta-catenin pathways in acute monophasic rat EAE .	Inactivation of GSK-3beta by phosphorylation of Ser 9 in the N-terminal domain of GSK-3beta is involved in the interruption of cell signaling pathways, including the Akt and beta-catenin pathways in acute monophasic rat EAE.	0	14	Inactivation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	GSK-3beta	phosphorylation of Ser 9 in the N-terminal domain of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	13	14	2	3
SB216763 increased phospho-GSK-3beta levels and suppressed GSK-3beta activity ( 1880 +/-229 vs 3280 +/-272 cpm , P < 0.01 ) .	SB216763 increased phospho-GSK-3beta levels and suppressed GSK-3beta activity (1880 +/-229 vs 3280 +/-272 cpm, P < 0.01).	0	7	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	phospho-GSK-3beta	SB216763 increased phospho-GSK-3beta levels	phospho-gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	6	7
Insulin-PI3K-AKT-mediated phosphorylation of Glycogen Synthase Kinase-3beta ( pGSK3beta ) inhibits GSK3beta activity and subsequently dis-inhibits glycogen synthase , allowing glucose to be stored as glycogen 35 .	Insulin-PI3K-AKT-mediated phosphorylation of Glycogen Synthase Kinase-3beta (pGSK3beta) inhibits GSK3beta activity and subsequently dis-inhibits glycogen synthase, allowing glucose to be stored as glycogen 35.	1	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	pGSK3beta	phosphorylation of Glycogen Synthase Kinase-3beta (pGSK3beta	pgsk3beta	GSK3beta	GSK3beta	gsk3beta	7	8	10	11
It is also known that Akt activation phosphorylated GSK3beta at Ser9 and inhibited GSK-3beta activity , leading to nuclear beta-catenin accumulation and ultimately triggering tumor progression [ XREF_BIBR , XREF_BIBR ] .	It is also known that Akt activation phosphorylated GSK3beta at Ser9 and inhibited GSK-3beta activity, leading to nuclear beta-catenin accumulation and ultimately triggering tumor progression [XREF_BIBR, XREF_BIBR].	5	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Akt activation phosphorylated GSK3beta at Ser9	gsk3beta	GSK-3beta	GSK-3beta	gsk-3beta	8	9	13	14
Moreover , PI3K induces phosphorylation of AKT at Ser 473 , thereby facilitating the phosphorylation of GSK3beta at Ser 9 , which in turn inactivates GSK3beta kinase activity .	Moreover, PI3K induces phosphorylation of AKT at Ser 473, thereby facilitating the phosphorylation of GSK3beta at Ser 9, which in turn inactivates GSK3beta kinase activity.	14	27	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta at Ser 9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	16	17	25	26
Akt dependent phosphorylation of GSK-3beta inhibits GSK-3beta activity and thereby decreases apoptosis XREF_BIBR , XREF_BIBR .	Akt dependent phosphorylation of GSK-3beta inhibits GSK-3beta activity and thereby decreases apoptosis XREF_BIBR, XREF_BIBR.	0	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Akt dependent phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	4	5	6	7
It is likely that phosphorylation of GSK-3beta at Ser 9 by AKT inhibits GSK-3beta activity and leads to beta-catenin stabilization during cadmium induced carcinogenesis .	It is likely that phosphorylation of GSK-3beta at Ser 9 by AKT inhibits GSK-3beta activity and leads to beta-catenin stabilization during cadmium induced carcinogenesis.	4	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta at Ser 9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	6	7	13	14
Our results also indicate that SB treatment increased the phosphorylation of GSK3beta at Ser9 ( Additional file 10 : Figure S9A ) , which is known to inactivate GSK3beta [ XREF_BIBR ] , and increased the nuclear localization of beta-catenin ( Additional file 10 : Figure S9B ) .	Our results also indicate that SB treatment increased the phosphorylation of GSK3beta at Ser9 (Additional file 10 : Figure S9A), which is known to inactivate GSK3beta [XREF_BIBR], and increased the nuclear localization of beta-catenin (Additional file 10 : Figure S9B).	5	30	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	SB treatment increased the phosphorylation of GSK3beta at Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	11	12	28	29
Although GSK3beta can be phosphorylated at Ser9 by multiple kinases such as Akt , ERK and PKA , such a phosphorylation of GSK3beta will only inactivate GSK3beta , and thus can not explain an ethanol induced activation of GSK3beta .	Although GSK3beta can be phosphorylated at Ser9 by multiple kinases such as Akt, ERK and PKA, such a phosphorylation of GSK3beta will only inactivate GSK3beta, and thus can not explain an ethanol induced activation of GSK3beta.	20	27	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	22	23	26	27
Striatal GSK-3B may be upregulated in HD since serine 9 phosphorylation of GSK-3beta negatively regulates GSK-3beta , and it was shown that this phospho-GSK-3beta was reduced in both the striatum and cerebral cortex at the onset of behavioral manifestations in both N171-82Q and YAC128 HD transgenic mice [ XREF_BIBR ] .	Striatal GSK-3B may be upregulated in HD since serine 9 phosphorylation of GSK-3beta negatively regulates GSK-3beta, and it was shown that this phospho-GSK-3beta was reduced in both the striatum and cerebral cortex at the onset of behavioral manifestations in both N171-82Q and YAC128 HD transgenic mice [XREF_BIBR].	8	16	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	serine 9 phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	12	13	15	16
GSK3beta ( Ser9 ) phosphorylation inhibits GSK3beta activity , allowing beta-catenin stabilization and activation .	GSK3beta (Ser9) phosphorylation inhibits GSK3beta activity, allowing beta-catenin stabilization and activation.	0	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta (Ser9) phosphorylation	gsk3beta	GSK3beta	GSK3beta	gsk3beta	0	1	6	7
It is well established that SGK3 promotes the inactivation of GSK-3beta by phosphorylation of GSK-3beta on Ser9 [ XREF_BIBR ] .	It is well established that SGK3 promotes the inactivation of GSK-3beta by phosphorylation of GSK-3beta on Ser9 [XREF_BIBR].	8	17	inactivation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta on Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	14	15	10	11
Phosphorylated Ser9 GSK-3beta ( p-GSK-3beta ) , which decreases GSK-3beta activity , also increased after fibrin treatment , and was attenuated by QLT-0267 .	Phosphorylated Ser9 GSK-3beta (p-GSK-3beta), which decreases GSK-3beta activity, also increased after fibrin treatment, and was attenuated by QLT-0267.	2	10	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p-GSK-3beta	p-GSK-3beta	p-GSK-3beta	GSK-3beta	GSK-3beta	GSK-3beta	4	5	9	10
Reports showed that activated ERK1/2 leads to phosphorylation of GSK-3beta , which inactivates GSK-3beta .	Reports showed that activated ERK1/2 leads to phosphorylation of GSK-3beta, which inactivates GSK-3beta.	4	14	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	ERK1/2 leads to phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	9	10	13	14
Endogenous IGF-I stimulated GSK-3 beta phosphorylation and inhibited GSK-3 beta activity ( measured by in vitro kinase assay ) in these cells .	Endogenous IGF-I stimulated GSK-3 beta phosphorylation and inhibited GSK-3 beta activity (measured by in vitro kinase assay) in these cells.	1	10	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3 beta	IGF-I stimulated GSK-3 beta phosphorylation	gsk-3 beta	GSK-3 beta	GSK-3 beta	gsk-3 beta	3	5	8	10
It is likely that phosphorylation of GSK-3beta at Ser 9 by AKT inhibits GSK-3beta activity and leads to beta-catenin stabilization during Cr ( VI )-induced carcinogenesis .	It is likely that phosphorylation of GSK-3beta at Ser 9 by AKT inhibits GSK-3beta activity and leads to beta-catenin stabilization during Cr (VI)-induced carcinogenesis.	4	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta at Ser 9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	6	7	13	14
Inhibitors of c-Abl and PKC-delta , such as imatinib and rottlerin , counteract the phosphorylation of GSK-3beta , which allows GSK-3beta to phosphorylate Snail-1 , targeting it for proteasomal degradation and ultimately abolishing the transdifferentiation of ECs into myofibroblasts .	Inhibitors of c-Abl and PKC-delta, such as imatinib and rottlerin, counteract the phosphorylation of GSK-3beta, which allows GSK-3beta to phosphorylate Snail-1, targeting it for proteasomal degradation and ultimately abolishing the transdifferentiation of ECs into myofibroblasts.	14	24	allows	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	GSK-3beta	phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta to phosphorylate Snail-1	gsk-3beta	16	17	20	21
Cordycepin mediated inhibition of ERK led to a reduction in phospho-GSK3beta ( p-GSK3beta ) and Slug levels , whereas LiCl , an inhibitor of GSK3beta , upregulated p-GSK3beta and Slug .	Cordycepin mediated inhibition of ERK led to a reduction in phospho-GSK3beta (p-GSK3beta) and Slug levels, whereas LiCl, an inhibitor of GSK3beta, upregulated p-GSK3beta and Slug.	22	29	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	p-GSK3beta	p-GSK3beta	p-GSK3beta	24	25	27	28
p38 mitogen activated protein kinase ( MAPK ) inactivates GSK3beta by direct phosphorylation at Ser 389 site and p38 MAPK mediated phosphorylation of GSK3beta at Ser 389 is sufficient to inhibit GSK3beta activity XREF_BIBR .	p38 mitogen activated protein kinase (MAPK) inactivates GSK3beta by direct phosphorylation at Ser 389 site and p38 MAPK mediated phosphorylation of GSK3beta at Ser 389 is sufficient to inhibit GSK3beta activity XREF_BIBR.	18	33	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	p38 MAPK mediated phosphorylation of GSK3beta at Ser 389	gsk3beta	GSK3beta	GSK3beta	gsk3beta	23	24	31	32
Coexpression of GSK3beta and pharmacological inhibition of GSK3beta , respectively , increased and decreased this phenotype , suggesting that Tau phosphorylation could enhance axonal transport disruption [ XREF_BIBR ] .	Coexpression of GSK3beta and pharmacological inhibition of GSK3beta, respectively, increased and decreased this phenotype, suggesting that Tau phosphorylation could enhance axonal transport disruption [XREF_BIBR].	0	8	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	GSK3beta	Coexpression of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	2	3	7	8
Hyperphosphorylation of GSK3beta at both the activating Y216 and inactivating S9 epitopes may indicate an attempt by neurons to halt over activation of signaling , as GSK3beta ( S9 ) phosphorylation acts to negatively regulate GSK3beta activity .	Hyperphosphorylation of GSK3beta at both the activating Y216 and inactivating S9 epitopes may indicate an attempt by neurons to halt over activation of signaling, as GSK3beta (S9) phosphorylation acts to negatively regulate GSK3beta activity.	13	36	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta (S9) phosphorylation	gsk3beta	GSK3beta	GSK3beta	gsk3beta	26	27	35	36
Similarly , phosphorylation of GSK 3beta at serine 9 , which inhibits GSK 3beta activity , was also increased starting at 1day and persisted until at least 6weeks after primary blast on the ipsilateral side .	Similarly, phosphorylation of GSK 3beta at serine 9, which inhibits GSK 3beta activity, was also increased starting at 1day and persisted until at least 6weeks after primary blast on the ipsilateral side.	2	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK 3beta	phosphorylation of GSK 3beta at serine 9	gsk 3beta	GSK 3beta	GSK 3beta	gsk 3beta	4	6	12	14
Phosphorylation of GSK-3beta at Ser9 by Akt and PKB effectively inhibits the high basal and constitutive activity of GSK-3beta .	Phosphorylation of GSK-3beta at Ser9 by Akt and PKB effectively inhibits the high basal and constitutive activity of GSK-3beta.	0	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Phosphorylation of GSK-3beta at Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	18	19
Phosphorylation of GSK-3beta at serine 9 inactivates GSK-3beta activity and causes the stabilization and activation of beta-catenin signaling , which subsequently enhances P-gp expression [ XREF_BIBR , XREF_BIBR ] .	Phosphorylation of GSK-3beta at serine 9 inactivates GSK-3beta activity and causes the stabilization and activation of beta-catenin signaling, which subsequently enhances P-gp expression [XREF_BIBR, XREF_BIBR].	0	8	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Phosphorylation of GSK-3beta at serine 9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	7	8
Moreover , IL-12 also enhanced the levels of phospho-GSK3beta ( S9 ) , which is a phospho specific site that represses GSK3beta activity ( XREF_FIG ) .	Moreover, IL-12 also enhanced the levels of phospho-GSK3beta (S9), which is a phospho specific site that represses GSK3beta activity (XREF_FIG).	2	22	represses	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	phospho-GSK3beta	IL-12 also enhanced the levels of phospho-GSK3beta	phospho-gsk3beta	GSK3beta	GSK3beta	gsk3beta	8	9	21	22
As expected , LiCl and BIO increased the phosphorylation of GSK3beta , thus inhibiting GSK3beta activity ( XREF_FIG ) .	As expected, LiCl and BIO increased the phosphorylation of GSK3beta, thus inhibiting GSK3beta activity (XREF_FIG).	3	15	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	LiCl and BIO increased the phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	10	11	14	15
Phosphorylation of GSK3beta at Ser9 suppresses GSK3beta kinase activity [ XREF_BIBR , XREF_BIBR ] , and PP2A treatment can reverse this kinase activity in vitro [ XREF_BIBR ] .	Phosphorylation of GSK3beta at Ser9 suppresses GSK3beta kinase activity [XREF_BIBR, XREF_BIBR], and PP2A treatment can reverse this kinase activity in vitro [XREF_BIBR].	0	8	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Phosphorylation of GSK3beta at Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	2	3	6	7
Phosphorylation of GSK-3beta inactivates GSK-3beta .	Phosphorylation of GSK-3beta inactivates GSK-3beta.	0	5	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	4	5
Data provided by XREF_BIBR demonstrated that tDCS enhanced GSK-3beta phosphorylation at Ser 9 ( pGSK-3betaSer 9 ) , which is known to promote GSK-3beta inhibition resulting in LTP enhancement .	Data provided by XREF_BIBR demonstrated that tDCS enhanced GSK-3beta phosphorylation at Ser 9 (pGSK-3betaSer 9), which is known to promote GSK-3beta inhibition resulting in LTP enhancement.	6	24	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	tDCS enhanced GSK-3beta phosphorylation at Ser 9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	8	9	23	24
In general , the data suggest that phosphorylation levels of GSK3beta are reduced in schizophrenia , resulting in increased GSK3beta activity .	In general, the data suggest that phosphorylation levels of GSK3beta are reduced in schizophrenia, resulting in increased GSK3beta activity.	8	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	levels of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	10	11	19	20
Insulin stimulated Akt phosphorylates GSK3B at serine 9 , thus inactivating GSK3B [ XREF_BIBR , XREF_BIBR ] .	Insulin stimulated Akt phosphorylates GSK3B at serine 9, thus inactivating GSK3B [XREF_BIBR, XREF_BIBR].	0	15	inactivating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3B	Insulin stimulated Akt phosphorylates GSK3B at serine 9	gsk3b	GSK3B	GSK3B	gsk3b	4	5	11	12
In addition , GSK-3beta activity was involved in regulating the phosphorylation of beta-catenin , and GSK-3beta activity could be inhibited by the increase of GSK-3beta phosphorylation and resulted in more beta-catenin accumulation in the cytoplasm .	In addition, GSK-3beta activity was involved in regulating the phosphorylation of beta-catenin, and GSK-3beta activity could be inhibited by the increase of GSK-3beta phosphorylation and resulted in more beta-catenin accumulation in the cytoplasm.	15	26	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	24	25	15	16
To examine whether the stabilization of Snail by TNFalpha is mediated by regulation of GSK-3beta activity , we treated Snail and HEK293 cells with the PI3K inhibitor LY294002 to activate GSK-3beta prior to TNFalpha treatment ( loss of GSK-3beta phosphorylation at Serine 9 enhances GSK-3beta activity ) .	To examine whether the stabilization of Snail by TNFalpha is mediated by regulation of GSK-3beta activity, we treated Snail and HEK293 cells with the PI3K inhibitor LY294002 to activate GSK-3beta prior to TNFalpha treatment (loss of GSK-3beta phosphorylation at Serine 9 enhances GSK-3beta activity).	38	45	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta phosphorylation at Serine	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	38	39	44	45
Phosphorylation of serine 9 in GSK3beta has been shown to inactivate GSK3beta and the lysine residue K85 is essential for GSK3beta kinase activity .	Phosphorylation of serine 9 in GSK3beta has been shown to inactivate GSK3beta and the lysine residue K85 is essential for GSK3beta kinase activity.	0	12	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Phosphorylation of serine 9 in GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	5	6	11	12
Phosphorylation of GSK3-beta and cdk5 was significantly increased in torpid animals , indicating inhibition of GSK3-beta and activation of cdk5 activity during torpor ( XREF_FIG ) .	Phosphorylation of GSK3-beta and cdk5 was significantly increased in torpid animals, indicating inhibition of GSK3-beta and activation of cdk5 activity during torpor (XREF_FIG).	0	17	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3-beta	Phosphorylation of GSK3-beta	gsk3-beta	GSK3-beta	GSK3-beta	gsk3-beta	2	3	15	16
PKA has been shown to phosphorylate GSK3beta at S9 , which inactivates GSK3beta [ XREF_BIBR , XREF_BIBR ] .	PKA has been shown to phosphorylate GSK3beta at S9, which inactivates GSK3beta [XREF_BIBR, XREF_BIBR].	0	16	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	PKA has been shown to phosphorylate GSK3beta at S9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	6	7	12	13
Previous studies have shown that overexpression of ILK results in the phosphorylation of Akt and PKB and GSK3beta [ XREF_BIBR ] and that the phosphorylation of GSK3beta at Ser9 inhibits the activity of GSK3beta followed by activation of the activator protein 1 ( AP-1 ) transcription factor complex [ XREF_BIBR ] .	Previous studies have shown that overexpression of ILK results in the phosphorylation of Akt and PKB and GSK3beta [XREF_BIBR] and that the phosphorylation of GSK3beta at Ser9 inhibits the activity of GSK3beta followed by activation of the activator protein 1 (AP-1) transcription factor complex [XREF_BIBR].	24	34	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta at Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	26	27	33	34
Akt phosphorylates the N-terminus of GSK-3beta thereby inhibiting the ability of GSK-3beta to phosphorylate beta-catenin XREF_BIBR .	Akt phosphorylates the N-terminus of GSK-3beta thereby inhibiting the ability of GSK-3beta to phosphorylate beta-catenin XREF_BIBR.	0	12	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Akt phosphorylates the N-terminus of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	5	6	11	12
It has been well documented that Akt phosphorylates GSK3beta at Ser9 residue and inactivates GSK3beta 51 .	It has been well documented that Akt phosphorylates GSK3beta at Ser9 residue and inactivates GSK3beta 51.	6	15	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Akt phosphorylates GSK3beta at Ser9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	8	9	14	15
Treatment of these cells with either insulin or phenylephrine ( PE ) , an alpha1-adrenergic receptor agonist , induced Ser 9 phosphorylation of GSK-3beta and inhibited GSK-3beta activity .	Treatment of these cells with either insulin or phenylephrine (PE), an alpha1-adrenergic receptor agonist, induced Ser 9 phosphorylation of GSK-3beta and inhibited GSK-3beta activity.	10	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	PE), an alpha1-adrenergic receptor agonist, induced Ser 9 phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	23	24	26	27
Lithium has been used for treating psychiatric conditions for decades and also inhibits glycogen-synthase kinase 3 beta ( GSK3beta ) , which affects both APP processing and tau aggregation .	Lithium has been used for treating psychiatric conditions for decades and also inhibits glycogen-synthase kinase 3 beta (GSK3beta), which affects both APP processing and tau aggregation.	12	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	glycogen-synthase kinase 3 beta	glycogen-synthase kinase 3 beta	glycogen-synthase kinase 3 beta	18	19	13	17
However , when GSK3beta activity was inhibited after cells were transfected with GSK3beta-KD or treated with lithium , both p-GSK3beta ( Ser9 ) and EZH2 were significantly upregulated in CNE-1 and CNE-2 cells .	However, when GSK3beta activity was inhibited after cells were transfected with GSK3beta-KD or treated with lithium, both p-GSK3beta (Ser9) and EZH2 were significantly upregulated in CNE-1 and CNE-2 cells.	3	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	p-GSK3beta	p-GSK3beta	p-GSK3beta	GSK3beta	GSK3beta	GSK3beta	19	20	3	4
Moreover , exogenous expression of mutant GSK-3beta ( via vector S9A ) prevented the increase in SREBP-1 expression and cellular lipogenesis by decreasing the phospho-GSK-3beta content and increasing the GSK-3beta activity in high-glucose-treated cells .	Moreover, exogenous expression of mutant GSK-3beta (via vector S9A) prevented the increase in SREBP-1 expression and cellular lipogenesis by decreasing the phospho-GSK-3beta content and increasing the GSK-3beta activity in high-glucose-treated cells.	3	30	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mutant GSK-3beta	expression of mutant GSK-3beta	mutant gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	5	7	29	30
Since phospho-GSK3beta at Ser9 decreases GSK3beta activity , our results suggest that volatile anesthetic postconditioning in human neuron like cells may be mediated by GSK3beta inhibition .	Since phospho-GSK3beta at Ser9 decreases GSK3beta activity, our results suggest that volatile anesthetic postconditioning in human neuron like cells may be mediated by GSK3beta inhibition.	1	6	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	phospho-GSK3beta	phospho-GSK3beta	phospho-GSK3beta	GSK3beta	GSK3beta	GSK3beta	1	2	5	6
Phosphorylation at serine 9 of GSK3beta inhibits the activity of GSK3beta [ XREF_BIBR - XREF_BIBR ] .	Phosphorylation at serine 9 of GSK3beta inhibits the activity of GSK3beta [XREF_BIBR - XREF_BIBR].	0	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Phosphorylation at serine 9 of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	5	6	10	11
Phosphorylation of GSK-3beta by Akt inhibits the enzymatic activity of GSK-3beta and results in the prevention of the proteasomal degradation of beta-catenin , as is the case with canonical Wnt signaling pathways ( Katoh et al ., 2006 ) .	Phosphorylation of GSK-3beta by Akt inhibits the enzymatic activity of GSK-3beta and results in the prevention of the proteasomal degradation of beta-catenin, as is the case with canonical Wnt signaling pathways (Katoh et al., 2006).	0	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	Phosphorylation of GSK-3beta	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	2	3	10	11
Phosphorylation at serine 9 of GSK3beta inhibits the activation of GSK3beta XREF_BIBR - XREF_BIBR .	Phosphorylation at serine 9 of GSK3beta inhibits the activation of GSK3beta XREF_BIBR - XREF_BIBR.	0	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Phosphorylation at serine 9 of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	5	6	10	11
Phosphorylation of GSK3beta by PKB inhibits GSK3beta kinase activity [ XREF_BIBR ] .	Phosphorylation of GSK3beta by PKB inhibits GSK3beta kinase activity [XREF_BIBR].	0	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	2	3	6	7
We speculate that there must be some interactions between GSK-3beta and Twist1 , which enables GSK-3beta to facilitate Twist1 ubiquitination and weaken its stability , while bFGF likely decreases the association between GSK-3beta and Twist1 through phosphorylating GSK-3beta to deactivate GSK-3beta by activating the AKT and GSK-3beta pathway and eventually induces EMT in HepG2 and Huh7 cells .	We speculate that there must be some interactions between GSK-3beta and Twist1, which enables GSK-3beta to facilitate Twist1 ubiquitination and weaken its stability, while bFGF likely decreases the association between GSK-3beta and Twist1 through phosphorylating GSK-3beta to deactivate GSK-3beta by activating the AKT and GSK-3beta pathway and eventually induces EMT in HepG2 and Huh7 cells.	7	50	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	interactions between GSK-3beta and Twist1	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	9	10	15	16
Again , the interpretation of these results is that phosphorylation of GSK-3beta by Akt and PKB at Ser9 , which inhibits GSK-3beta activity , is required for the down regulation of NFAT activity .	Again, the interpretation of these results is that phosphorylation of GSK-3beta by Akt and PKB at Ser9, which inhibits GSK-3beta activity, is required for the down regulation of NFAT activity.	9	22	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	phosphorylation of GSK-3beta by Akt and PKB at Ser9	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	11	12	21	22
Gallic acid also increased GSK3beta and p-beta-catenin expression but down-regulated p-GSK3beta .	Gallic acid also increased GSK3beta and p-beta-catenin expression but down-regulated p-GSK3beta.	0	11	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Gallic acid also increased GSK3beta and p-beta-catenin expression	gsk3beta	p-GSK3beta	p-GSK3beta	p-gsk3beta	4	5	10	11
Results suggested that TMT inhibited GSK-3beta phosphorylation which activated GSK-3beta signaling .	Results suggested that TMT inhibited GSK-3beta phosphorylation which activated GSK-3beta signaling.	3	10	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	TMT inhibited GSK-3beta phosphorylation	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	5	6	9	10
Phosphorylation of GSK3beta at Ser 389 by p38 MAPK inhibits GSK3beta probably through a mechanism similar to the mechanism reported for the phosphorylation at the Ser 9 .	Phosphorylation of GSK3beta at Ser 389 by p38 MAPK inhibits GSK3beta probably through a mechanism similar to the mechanism reported for the phosphorylation at the Ser 9.	0	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Phosphorylation of GSK3beta at Ser 389	gsk3beta	GSK3beta	GSK3beta	gsk3beta	2	3	10	11
Our research here demonstrated that bufalin inhibited the phosphorylation of AKT , which in turn inhibited cell proliferation , migration , and invasion in the two hepatoma cell lines , and revealed that bufalin was able to suppress the phosphorylation of GSK3beta ( Ser 9 ) and increase the activated form of GSK3beta .	Our research here demonstrated that bufalin inhibited the phosphorylation of AKT, which in turn inhibited cell proliferation, migration, and invasion in the two hepatoma cell lines, and revealed that bufalin was able to suppress the phosphorylation of GSK3beta (Ser 9) and increase the activated form of GSK3beta.	33	53	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	bufalin was able to suppress the phosphorylation of GSK3beta (Ser 9	gsk3beta	GSK3beta	GSK3beta	gsk3beta	41	42	52	53
Our data revealed increased GSK-3beta phosphorylation in high fat diet fed mice following TUDCA treatment , favoring a likely role of GSK-3beta phosphorylation ( or inactivation of GSK-3beta ) in the preserved mitochondrial function in high fat diet induced obesity .	Our data revealed increased GSK-3beta phosphorylation in high fat diet fed mice following TUDCA treatment, favoring a likely role of GSK-3beta phosphorylation (or inactivation of GSK-3beta) in the preserved mitochondrial function in high fat diet induced obesity.	21	28	inactivation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	21	22	27	28
Increased phosphorylation of Akt ( increased Akt activities ) causes phosphorylation of GSK3beta ( suppression of GSK3beta activities ) at the serine 9 residue while reduced phosphorylation of Akt ( reduced Akt activities ) decreases levels of phosphorylation of GSK3beta ( increased GSK3beta activities ) .	Increased phosphorylation of Akt (increased Akt activities) causes phosphorylation of GSK3beta (suppression of GSK3beta activities) at the serine 9 residue while reduced phosphorylation of Akt (reduced Akt activities) decreases levels of phosphorylation of GSK3beta (increased GSK3beta activities).	1	17	suppression	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	GSK3beta	phosphorylation of Akt (increased Akt activities) causes phosphorylation of GSK3beta	gsk3beta	GSK3beta	GSK3beta	gsk3beta	12	13	16	17
Our data suggest that reduction in galectin-3 decreases GSK-3beta phosphorylation and increases GSK-3beta activity , which may mediate beta-catenin accumulation and Wnt signaling in colon cancer cells .	Our data suggest that reduction in galectin-3 decreases GSK-3beta phosphorylation and increases GSK-3beta activity, which may mediate beta-catenin accumulation and Wnt signaling in colon cancer cells.	6	13	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK-3beta	galectin-3 decreases GSK-3beta phosphorylation	gsk-3beta	GSK-3beta	GSK-3beta	gsk-3beta	8	9	12	13
When a specific sh-GSK-3alpha construct ( # 595 ) was transduced into CGCs via lentivirus to knockdown GSK-3alpha by about 50 % , a relatively small increase in FGF-21 mRNA level was observed either in the absence or presence of lithium or VPA , while a nearly 20-fold increase was observed with GSK-3alpha shRNA used in the presence of both lithium and VPA , compared with about a 12-fold increase induced by lithium-VPA co-treatment ( XREF_SUPPLEMENTARY ) .	When a specific sh-GSK-3alpha construct (# 595) was transduced into CGCs via lentivirus to knockdown GSK-3alpha by about 50%, a relatively small increase in FGF-21 mRNA level was observed either in the absence or presence of lithium or VPA, while a nearly 20-fold increase was observed with GSK-3alpha shRNA used in the presence of both lithium and VPA, compared with about a 12-fold increase induced by lithium-VPA co-treatment (XREF_SUPPLEMENTARY).	3	18	knockdown	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	sh-GSK-3alpha	sh-GSK-3alpha	sh-GSK-3alpha	GSK-3alpha	GSK-3alpha	GSK-3alpha	3	4	17	18
IKKi ( also known as IKKepsilon or I kappaB kinase epsilon ) is then activated to mediate IL-1-induced GSK3alpha phosphorylation at S21 and consequent inactivation of GSK3alpha , resulting in AKT-mTOR activation .	IKKi (also known as IKKepsilon or I kappaB kinase epsilon) is then activated to mediate IL-1-induced GSK3alpha phosphorylation at S21 and consequent inactivation of GSK3alpha, resulting in AKT-mTOR activation.	18	27	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	GSK3alpha	GSK3alpha phosphorylation at S21	gsk3alpha	GSK3alpha	GSK3alpha	gsk3alpha	18	19	26	27
The Akt mediated phosphorylation of GSK3alpha and beta-Ser 21/9 in vitro suppresses the activity of GSK3alpha and beta .	The Akt mediated phosphorylation of GSK3alpha and beta-Ser 21/9 in vitro suppresses the activity of GSK3alpha and beta.	1	17	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3alpha	Akt mediated phosphorylation of GSK3alpha	gsk3alpha	GSK3alpha	GSK3alpha	gsk3alpha	5	6	15	16
Upon IL-1 stimulation , IKKi was activated to mediate GSK3alpha phosphorylation at S21 , thereby inactivating GSK3alpha to promote IL-1-induced AKT-mTOR activation .	Upon IL-1 stimulation, IKKi was activated to mediate GSK3alpha phosphorylation at S21, thereby inactivating GSK3alpha to promote IL-1-induced AKT-mTOR activation.	4	17	inactivating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3alpha	IKKi was activated to mediate GSK3alpha phosphorylation at S21	gsk3alpha	GSK3alpha	GSK3alpha	gsk3alpha	9	10	16	17
This is similar to what is usually reported in the literature wherein a decrease in the phosphorylation of GSK3alpha and beta-Ser 21/9 inhibition sites would enhance the enzyme activity of GSK3alpha and beta [ XREF_BIBR , XREF_BIBR ] .	This is similar to what is usually reported in the literature wherein a decrease in the phosphorylation of GSK3alpha and beta-Ser 21/9 inhibition sites would enhance the enzyme activity of GSK3alpha and beta [XREF_BIBR, XREF_BIBR].	16	34	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3alpha	phosphorylation of GSK3alpha	gsk3alpha	GSK3alpha	GSK3alpha	gsk3alpha	18	19	30	31
GSK3alpha and beta is inactivated by the phosphorylation of serine 21 of GSK3alpha or serine 9 of GSK3beta by Akt [ XREF_BIBR , XREF_BIBR ] and/or PKC ( e.g ., alpha , epsilon , zeta ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	GSK3alpha and beta is inactivated by the phosphorylation of serine 21 of GSK3alpha or serine 9 of GSK3beta by Akt [XREF_BIBR, XREF_BIBR] and/or PKC (e.g., alpha, epsilon, zeta) [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	13	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	GSK3alpha	phosphorylation of serine 21 of GSK3alpha	gsk3alpha	GSK3alpha	GSK3alpha	gsk3alpha	12	13	0	1
Therefore , it is possible that IKKi mediated GSK3alpha phosphorylation at Ser21 also attenuates GSK3alpha kinase activity , thereby removing the inhibitory effect of GSK3alpha on IL-1-induced AKT-mTOR activity .	Therefore, it is possible that IKKi mediated GSK3alpha phosphorylation at Ser21 also attenuates GSK3alpha kinase activity, thereby removing the inhibitory effect of GSK3alpha on IL-1-induced AKT-mTOR activity.	6	16	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3alpha	IKKi mediated GSK3alpha phosphorylation at Ser21	gsk3alpha	GSK3alpha	GSK3alpha	gsk3alpha	8	9	14	15
In the latter case , normal two-step rhodopsin inactivation by RK phosphorylation and arrestin binding is fully operative , whereas in the former rhodopsin is inactivated by stochastic thermal decay taking place on a much longer time course .	In the latter case, normal two-step rhodopsin inactivation by RK phosphorylation and arrestin binding is fully operative, whereas in the former rhodopsin is inactivated by stochastic thermal decay taking place on a much longer time course.	7	12	inactivation	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	RK	RK phosphorylation	rk	rhodopsin	rhodopsin	rhodopsin	10	11	7	8
In retinal rods , photoexcited rhodopsin ( R * ) is inactivated upon phosphorylation by rhodopsin kinase and the subsequent binding of arrestin .	In retinal rods, photoexcited rhodopsin (R *) is inactivated upon phosphorylation by rhodopsin kinase and the subsequent binding of arrestin.	4	17	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	rhodopsin kinase	rhodopsin kinase	rhodopsin kinase	rhodopsin	rhodopsin	rhodopsin	15	17	5	6
After light activation , rhodopsin kinase and arrestin inactivate the rhodopsin activity [ XREF_BIBR - XREF_BIBR ] .	After light activation, rhodopsin kinase and arrestin inactivate the rhodopsin activity [XREF_BIBR - XREF_BIBR].	4	11	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	rhodopsin kinase	rhodopsin kinase	rhodopsin kinase	rhodopsin	rhodopsin	rhodopsin	4	6	10	11
Our data showed that inhibition of GSK-3beta enhanced morphine induced changes of Bax and Bcl-2 .	Our data showed that inhibition of GSK-3beta enhanced morphine induced changes of Bax and Bcl-2.	4	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Bax	Bax	Bax	6	7	12	13
Furthermore , AH is found to improve the protein expression of Bcl-2 , phosphorylation of Akt and GSK-3beta , downregulate the protein of Bax .	Furthermore, AH is found to improve the protein expression of Bcl-2, phosphorylation of Akt and GSK-3beta, downregulate the protein of Bax.	13	24	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	phosphorylation of Akt and GSK-3beta	gsk-3beta	Bax	Bax	bax	17	18	23	24
We found that inhibition of GSK-3beta by GSK-3beta inhibitor SB216763 increased morphine induced changes of Bax and Bcl-2 ( XREF_FIG ) .	We found that inhibition of GSK-3beta by GSK-3beta inhibitor SB216763 increased morphine induced changes of Bax and Bcl-2 (XREF_FIG).	3	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Bax	Bax	Bax	5	6	15	16
One of the mechanisms for these responses is mediated by the transcription factor Snail and its upstream kinase GSK3beta which can negatively regulate Occludin and E-cadherin [ XREF_BIBR ] .	One of the mechanisms for these responses is mediated by the transcription factor Snail and its upstream kinase GSK3beta which can negatively regulate Occludin and E-cadherin [XREF_BIBR].	8	26	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	E-cadherin	E-cadherin	E-cadherin	18	19	25	26
To further examine whether GSK-3beta inhibition enhanced the stability of CDH1 mRNA that can in turn increase E-Cadherin synthesis , full-length 3 ' UTR of CDH1 mRNA was cloned downstream of Rluc in psiCHECK2 vector and luciferase activity was measured during GSK-3beta inhibition in Huh7.5 M cells .	To further examine whether GSK-3beta inhibition enhanced the stability of CDH1 mRNA that can in turn increase E-Cadherin synthesis, full-length 3 ' UTR of CDH1 mRNA was cloned downstream of Rluc in psiCHECK2 vector and luciferase activity was measured during GSK-3beta inhibition in Huh7.5 M cells.	4	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	CDH1	CDH1	CDH1	4	5	10	11
GSK3beta has been shown to inhibit EMT by targeting Snail for proteasomal degradation , thus releasing E-cadherin from transcriptional repression by Snail and promoting metastasis .	GSK3beta has been shown to inhibit EMT by targeting Snail for proteasomal degradation, thus releasing E-cadherin from transcriptional repression by Snail and promoting metastasis.	0	19	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	E-cadherin	E-cadherin	E-cadherin	0	1	16	17
CG0009 enhanced the inactivating phosphorylation of GSK3alpha at Ser21 and GSK3beta at Ser9 and simultaneously decreased activating phosphorylation of GSK3beta at Tyr216 , and induced caspase dependent apoptosis independently of estrogen receptor alpha ( ERalpha ) expression status , which was not observed with the other GSK3 inhibitors examined , including SB216763 , kenpaullone and LiCl .	CG0009 enhanced the inactivating phosphorylation of GSK3alpha at Ser21 and GSK3beta at Ser9 and simultaneously decreased activating phosphorylation of GSK3beta at Tyr216, and induced caspase dependent apoptosis independently of estrogen receptor alpha (ERalpha) expression status, which was not observed with the other GSK3 inhibitors examined, including SB216763, kenpaullone and LiCl.	0	32	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	CG0009 enhanced the inactivating phosphorylation of GSK3alpha at Ser21 and GSK3beta at Ser9 and simultaneously decreased activating phosphorylation of GSK3beta at Tyr216	gsk3beta	estrogen receptor	estrogen receptor	estrogen receptor	19	20	30	32
Furthermore , depletion of DDB1 inhibited Hsp90 inhibitor induced GRK5 destabilization and UV irradiation induced GRK5 degradation .	Furthermore, depletion of DDB1 inhibited Hsp90 inhibitor induced GRK5 destabilization and UV irradiation induced GRK5 degradation.	6	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GRK5	Hsp90 inhibitor induced GRK5	grk5	GRK5	GRK5	grk5	9	10	15	16
PKC mediated phosphorylation of GRK5 at Ser572 and either Ser566 or Ser568 , or at the auto-regulatory sites Ser484 or Thr485 , dramatically inhibits GRK5 affinity and activity at agonist bound GPCRs .	PKC mediated phosphorylation of GRK5 at Ser572 and either Ser566 or Ser568, or at the auto-regulatory sites Ser484 or Thr485, dramatically inhibits GRK5 affinity and activity at agonist bound GPCRs.	0	25	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GRK5	PKC mediated phosphorylation of GRK5 at Ser572 and either Ser566	grk5	GRK5	GRK5	grk5	4	5	24	25
Furthermore , the depletion of DDB1 decreased Hsp90 inhibitor induced GRK5 destabilization and UV irradiation induced GRK5 degradation .	Furthermore, the depletion of DDB1 decreased Hsp90 inhibitor induced GRK5 destabilization and UV irradiation induced GRK5 degradation.	5	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	GRK5	DDB1 decreased Hsp90 inhibitor induced GRK5	grk5	GRK5	GRK5	grk5	10	11	16	17
Consistently , overexpression of GSK-3beta in HUVEC ( confirmed by western blotting ; XREF_SUPPLEMENTARY ) led to diminished occupancy of C/EBPbeta at the EDIL3 promoter region relative to cells transfected with control vector ( XREF_FIG , last two lanes ) .	Consistently, overexpression of GSK-3beta in HUVEC (confirmed by western blotting; XREF_SUPPLEMENTARY) led to diminished occupancy of C/EBPbeta at the EDIL3 promoter region relative to cells transfected with control vector (XREF_FIG, last two lanes).	2	21	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	overexpression of GSK-3beta	gsk-3beta	C/EBPbeta	C/EBPbeta	c/ebpbeta	4	5	20	21
In addition , LPS induced GSK-3beta activation induces NF-kappaB activation and inhibits C/EBPbeta , CREB , and AP-1 transcriptional activities , diminishing the production of the anti-inflammatory cytokine , IL-10 .	In addition, LPS induced GSK-3beta activation induces NF-kappaB activation and inhibits C/EBPbeta, CREB, and AP-1 transcriptional activities, diminishing the production of the anti-inflammatory cytokine, IL-10.	3	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	LPS induced GSK-3beta	gsk-3beta	C/EBPbeta	C/EBPbeta	c/ebpbeta	5	6	12	13
AMF also prevents Gp78 induced degradation of the mitochondrial fusion proteins , mitofusin 1 and 2 in a dynamin-, Rac1- and phosphoinositide 3-kinase ( PI3K )-dependent manner .	AMF also prevents Gp78 induced degradation of the mitochondrial fusion proteins, mitofusin 1 and 2 in a dynamin-, Rac1- and phosphoinositide 3-kinase (PI3K)-dependent manner.	0	4	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AMF	AMF	AMF	Gp78	Gp78	Gp78	0	1	3	4
A previous study has indicated that CREB1 activity was increased by inhibition of GSK3beta in cultured rat cerebral cortical neurons XREF_BIBR .	A previous study has indicated that CREB1 activity was increased by inhibition of GSK3beta in cultured rat cerebral cortical neurons XREF_BIBR.	6	14	increased	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	CREB1	CREB1	CREB1	13	14	6	7
High titers of GRP specific Abs could neutralize elevated levels of the GRP self-peptide made by tumor cells and block the GRP and GRPR autocrine loop of GRP dependent tumors .	High titers of GRP specific Abs could neutralize elevated levels of the GRP self-peptide made by tumor cells and block the GRP and GRPR autocrine loop of GRP dependent tumors.	3	25	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GRP	GRP	GRP	GRPR	GRPR	GRPR	3	4	23	24
Hence , dn SH2 Grb2 sequesters SOS1 in the cytoplasm .	Hence, dn SH2 Grb2 sequesters SOS1 in the cytoplasm.	2	9	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Grb2	Grb2	Grb2	SOS1	SOS1	SOS1	4	5	6	7
Function blocking antibodies directed against integrin alpha5beta1 or soluble Arg-Gly-Asp peptide fragments derived from FN specifically inhibited GPR30 mediated epidermal growth factor receptor transactivation .	Function blocking antibodies directed against integrin alpha5beta1 or soluble Arg-Gly-Asp peptide fragments derived from FN specifically inhibited GPR30 mediated epidermal growth factor receptor transactivation.	17	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	GPR30	GPR30	GPR30	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	17	18	19	23
Genetic knock-down of HDAC3 was found to suppress HDAC1 induced neurotoxicity , and correspondingly , genetic knock-down of HDAC1 was found to reduce HDAC3 neurotoxicity .	Genetic knock-down of HDAC3 was found to suppress HDAC1 induced neurotoxicity, and correspondingly, genetic knock-down of HDAC1 was found to reduce HDAC3 neurotoxicity.	1	9	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HDAC3	HDAC3	HDAC3	HDAC1	HDAC1	HDAC1	3	4	8	9
The biochemical IC 50 values obtained using in vitro HDAC assays showed that a 7.4-fold and 3.3-fold higher concentration of ACY-1044 ( the HDAC3 selective inhibitor ) was required to inhibit HDAC1 and HDAC2 , respectively , when compared to HDAC3 .	The biochemical IC 50 values obtained using in vitro HDAC assays showed that a 7.4-fold and 3.3-fold higher concentration of ACY-1044 (the HDAC3 selective inhibitor) was required to inhibit HDAC1 and HDAC2, respectively, when compared to HDAC3.	20	33	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HDAC3	HDAC3	HDAC3	HDAC1	HDAC1	HDAC1	23	24	31	32
Our results indicate that proteasome inhibitor treatment induced the expression of EGF , epiregulin and HB-EGF but that only HB-EGF knock-down could abrogate EGFR activation .	Our results indicate that proteasome inhibitor treatment induced the expression of EGF, epiregulin and HB-EGF but that only HB-EGF knock-down could abrogate EGFR activation.	19	24	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	19	20	23	24
Since HB-EGF is a ligand generated by ADAM-17 to activate EGFR XREF_BIBR and H. pylori stimulates production of HB-EGF , we next determined whether inhibition of HB-EGF altered H. pylori stimulated EGFR activation and apoptosis .	Since HB-EGF is a ligand generated by ADAM-17 to activate EGFR XREF_BIBR and H. pylori stimulates production of HB-EGF, we next determined whether inhibition of HB-EGF altered H. pylori stimulated EGFR activation and apoptosis.	26	32	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	26	27	31	32
Furthermore , HB-EGF neutralizing antibody inhibited Akt and EGFR activation by H. pylori ( XREF_FIG ) .	Furthermore, HB-EGF neutralizing antibody inhibited Akt and EGFR activation by H. pylori (XREF_FIG).	2	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	2	3	8	9
IL-4-stimulated STAT6 activation , Arg1 and YM1 gene expression , and HB-EGF production were further enhanced by inhibition of EGFR activity in Raw 264.7 cells using an EGFR kinase inhibitor and in peritoneal macrophages from Egfr ( wa5 ) mice with kinase inactive EGFR and by knockdown of EGFR in peritoneal macrophages from Egfr ( fl/fl ) LysM-Cre mice with myeloid cell specific EGFR deletion .	IL-4-stimulated STAT6 activation, Arg1 and YM1 gene expression, and HB-EGF production were further enhanced by inhibition of EGFR activity in Raw 264.7 cells using an EGFR kinase inhibitor and in peritoneal macrophages from Egfr (wa5) mice with kinase inactive EGFR and by knockdown of EGFR in peritoneal macrophages from Egfr (fl/fl) LysM-Cre mice with myeloid cell specific EGFR deletion.	11	29	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	11	12	27	28
Knockdown of HB-EGF in macrophages inhibited EGFR transactivation by IL-4 .	Knockdown of HB-EGF in macrophages inhibited EGFR transactivation by IL-4.	0	7	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGFR	EGFR	EGFR	2	3	6	7
Acquired production of the positive feedback components , such as HBEGF and simultaneous inhibition of EGFR by negative feedback might reflect a shift toward HER2 heterodimer activation , as previously reported [ XREF_BIBR , XREF_BIBR ] .	Acquired production of the positive feedback components, such as HBEGF and simultaneous inhibition of EGFR by negative feedback might reflect a shift toward HER2 heterodimer activation, as previously reported [XREF_BIBR, XREF_BIBR].	10	16	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	HBEGF	HBEGF	HBEGF	EGFR	EGFR	EGFR	10	11	15	16
Inhibition of the EGF receptor blocked this effect , consistent with a mechanism involving HB-EGF stimulation of EGF receptor signaling .	Inhibition of the EGF receptor blocked this effect, consistent with a mechanism involving HB-EGF stimulation of EGF receptor signaling.	14	19	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	HB-EGF	HB-EGF	HB-EGF	EGF receptor	EGF receptor	EGF receptor	14	15	17	19
Exogenous HB-EGF induced the loss of more than 70 % of the EGF receptor from the cell surface within 30 min , with similar kinetics to that of EGF .	Exogenous HB-EGF induced the loss of more than 70% of the EGF receptor from the cell surface within 30 min, with similar kinetics to that of EGF.	0	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HB-EGF	HB-EGF	HB-EGF	EGF receptor	EGF receptor	EGF receptor	1	2	12	14
Importantly , our discovery that GSK3beta association with Notch1 positive endosomes appears to be dynamic and that GSK3beta inhibition enhances Notch1 recycling from endosomal stores supports a model where cells can directly modulate Notch1 signaling capacity and bypass the need for additional transcription of the receptor .	Importantly, our discovery that GSK3beta association with Notch1 positive endosomes appears to be dynamic and that GSK3beta inhibition enhances Notch1 recycling from endosomal stores supports a model where cells can directly modulate Notch1 signaling capacity and bypass the need for additional transcription of the receptor.	17	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	17	18	20	21
Consequently , GSK3beta remains active and inhibits Notch-1 signaling as observed by decreased Hes-1 and Deltex expression in thymic progenitors .	Consequently, GSK3beta remains active and inhibits Notch-1 signaling as observed by decreased Hes-1 and Deltex expression in thymic progenitors.	2	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Notch-1	Notch-1	Notch-1	2	3	7	8
Our finding that GSK3beta inhibition enhances signaling by promoting Notch1 recycling through a rab4a mediated transport route is consistent with results where 1 ) GSK3beta inactivation leads to misrouting of the mannose 6-phosphate receptor to the cell surface and 2 ) constitutively active forms of GSK3beta suppress alphavbeta3 and alpha5beta1 integrin recycling .	Our finding that GSK3beta inhibition enhances signaling by promoting Notch1 recycling through a rab4a mediated transport route is consistent with results where 1) GSK3beta inactivation leads to misrouting of the mannose 6-phosphate receptor to the cell surface and 2) constitutively active forms of GSK3beta suppress alphavbeta3 and alpha5beta1 integrin recycling.	3	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	3	4	9	10
DAPT and LiCl decrease NICD , Hes-1 and GSK-3beta but enhance p-GSK-3beta and p-AKT immunofluorescence in BV-2 cells .	DAPT and LiCl decrease NICD, Hes-1 and GSK-3beta but enhance p-GSK-3beta and p-AKT immunofluorescence in BV-2 cells.	3	11	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	NICD	NICD	NICD	8	9	4	5
On the basis of this , we conclude that GSK3beta activity inhibits Notch1 recycling from endosomal stores .	On the basis of this, we conclude that GSK3beta activity inhibits Notch1 recycling from endosomal stores.	9	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	9	10	12	13
We find that GSK3beta silencing or pharmacologic inhibition increases Notch1 signaling ( XREF_FIG ) , demonstrating that in this system , GSK3beta regulates the signaling pathway negatively .	We find that GSK3beta silencing or pharmacologic inhibition increases Notch1 signaling (XREF_FIG), demonstrating that in this system, GSK3beta regulates the signaling pathway negatively.	3	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	3	4	9	10
Thus , we conclude that in our cell culture assay , GSK3beta inhibits Notch1 ICD activity to the same extent in both the presence and absence of overexpressed MAML1 .	Thus, we conclude that in our cell culture assay, GSK3beta inhibits Notch1 ICD activity to the same extent in both the presence and absence of overexpressed MAML1.	11	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	Notch1	Notch1	Notch1	11	12	13	14
Pharmacologic modulation of GSK-3beta markedly impaired p53 dependent transactivation of targets including p21 and Puma but promoted p53 dependent conformational activation of Bax , resulting in cytochrome c release , loss of mitochondrial membrane potential , and caspase-9 processing .	Pharmacologic modulation of GSK-3beta markedly impaired p53 dependent transactivation of targets including p21 and Puma but promoted p53 dependent conformational activation of Bax, resulting in cytochrome c release, loss of mitochondrial membrane potential, and caspase-9 processing.	1	8	impaired	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	3	4	6	7
First , the increased stability of p53 in PGRMC1 knockdown hPSCs may be due to the inhibitory phosphorylation of GSK-3beta , because studies have shown that inhibition of GSK-3beta rescues p53 from degradation XREF_BIBR , XREF_BIBR .	First, the increased stability of p53 in PGRMC1 knockdown hPSCs may be due to the inhibitory phosphorylation of GSK-3beta, because studies have shown that inhibition of GSK-3beta rescues p53 from degradation XREF_BIBR, XREF_BIBR.	26	31	rescues	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	28	29	30	31
Inhibition of GSK-3beta rescues p53 from degradation XREF_BIBR , XREF_BIBR .	Inhibition of GSK-3beta rescues p53 from degradation XREF_BIBR, XREF_BIBR.	0	5	rescues	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	p53	p53	p53	2	3	4	5
In addition , CDH17 knockdown increased P53 expression ; a possible mechanism would be that CDH17 knockdown leads to reduced GSK-3beta phosphorylation , which in turn activates p53 dependent apoptosis and antagonizes tumor growth XREF_BIBR .	In addition, CDH17 knockdown increased P53 expression; a possible mechanism would be that CDH17 knockdown leads to reduced GSK-3beta phosphorylation, which in turn activates p53 dependent apoptosis and antagonizes tumor growth XREF_BIBR.	20	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	p53	p53	p53	20	21	27	28
reported that GSK3beta binds and promotes the transcriptional and apoptotic activities of p53 following camptothecin treatment , inconsistent with the finding that GSK3beta suppresses p53 mediated apoptotic function after adriamycin , etoposide and 5-FU treatment in HCT 116 cells , and the GSK3 inhibitor , LY2119301 , alone does not active stress responses XREF_BIBR .	reported that GSK3beta binds and promotes the transcriptional and apoptotic activities of p53 following camptothecin treatment, inconsistent with the finding that GSK3beta suppresses p53 mediated apoptotic function after adriamycin, etoposide and 5-FU treatment in HCT 116 cells, and the GSK3 inhibitor, LY2119301, alone does not active stress responses XREF_BIBR.	22	27	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	p53	p53	p53	22	23	24	25
Hypocretin antagonists , especially those that block Hcrtr1 or both Hcrtr1 and Hcrtr2 receptors , have been studied mainly as new drugs for sleep disorders .	Hypocretin antagonists, especially those that block Hcrtr1 or both Hcrtr1 and Hcrtr2 receptors, have been studied mainly as new drugs for sleep disorders.	0	13	block	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Hypocretin	Hypocretin	Hypocretin	Hcrtr1	Hcrtr1	Hcrtr1	0	1	7	8
The antinociceptive effect of orexin was blocked by intra-PAG injection of SB-334867 , a putative type 1 orexin receptor antagonist , suggesting the involvement of orexin receptor type 1 in antinociception produced with intra-PAG injection of orexin-A .	The antinociceptive effect of orexin was blocked by intra-PAG injection of SB-334867, a putative type 1 orexin receptor antagonist, suggesting the involvement of orexin receptor type 1 in antinociception produced with intra-PAG injection of orexin-A.	2	29	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	orexin	orexin	orexin	orexin receptor type 1	orexin receptor type 1	orexin receptor type 1	4	5	25	29
The inhibitory effect of orexin on forskolin stimulated cAMP accumulation was not observed in OX1R expressing cells .	The inhibitory effect of orexin on forskolin stimulated cAMP accumulation was not observed in OX1R expressing cells.	2	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	orexin	orexin	orexin	OX1R	OX1R	OX1R	4	5	14	15
Specific OXR antagonists SB-334867 ( a selective antagonist of OX1R ) and TCS OX 229 ( a potent and selective antagonist of OX2R ) abolished the effects of OXA and OXB ( XREF_FIG ) .	Specific OXR antagonists SB-334867 (a selective antagonist of OX1R) and TCS OX 229 (a potent and selective antagonist of OX2R) abolished the effects of OXA and OXB (XREF_FIG).	3	24	antagonist	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	OX	OX	OX	OX1R	OX1R	OX1R	13	14	9	10
Orexin A ( > = 30nM ) attenuated LTP induced by theta burst stimulation ( TBS ) in a manner antagonized by an OX1R ( SB-334867 ) , but not OX2R ( EMPA ) , antagonist .	Orexin A (> = 30nM) attenuated LTP induced by theta burst stimulation (TBS) in a manner antagonized by an OX1R (SB-334867), but not OX2R (EMPA), antagonist.	0	35	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Orexin	Orexin	Orexin	OX2R	OX2R	OX2R	0	1	30	31
Indeed , endogenous phosphorylation of H2AX on its last residue ( tyrosine 142 ) ( P Y142 -H2AX ) has been shown to prevent the binding of MDC1 to the neighboring phosphorylated serine 139 ( gamma-H2AX ) , and retention of Y142 phosphorylation ( P Y142 -H2AX ) proposed to drive the apoptotic response .	Indeed, endogenous phosphorylation of H2AX on its last residue (tyrosine 142) (P Y142 -H2AX) has been shown to prevent the binding of MDC1 to the neighboring phosphorylated serine 139 (gamma-H2AX), and retention of Y142 phosphorylation (P Y142 -H2AX) proposed to drive the apoptotic response.	3	28	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	H2AX	phosphorylation of H2AX	h2ax	MDC1	MDC1	mdc1	5	6	27	28
Importantly , depletion of the DNA-SCARS-stabilizing component histone H2AX did not deplete 53BP1 from DNA-SCARS but diminished the presence of MDC1 and activated CHK2 .	Importantly, depletion of the DNA-SCARS-stabilizing component histone H2AX did not deplete 53BP1 from DNA-SCARS but diminished the presence of MDC1 and activated CHK2.	7	23	diminished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	histone H2AX	histone H2AX	histone H2AX	MDC1	MDC1	MDC1	7	9	20	21
As a functional consequence , we show that the H2AX K120R mutant abolishes H2AX monoubiquitination , impairs the recruitment of p-ATM ( Ser ( 1981 ) ) to DSBs , and thereby reduces the formation of gamma-H2AX and the recruitment of MDC1 to DNA damage sites .	As a functional consequence, we show that the H2AX K120R mutant abolishes H2AX monoubiquitination, impairs the recruitment of p-ATM (Ser (1981)) to DSBs, and thereby reduces the formation of gamma-H2AX and the recruitment of MDC1 to DNA damage sites.	9	42	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	H2AX	H2AX K120R mutant abolishes H2AX monoubiquitination	h2ax	MDC1	MDC1	mdc1	9	10	41	42
Coexpression of HA-Akt augmented dHAND phosphorylation at multiple serine and threonine residues mainly located in the bHLH domain and , as a result , decreased the transcriptional activity of dHAND .	Coexpression of HA-Akt augmented dHAND phosphorylation at multiple serine and threonine residues mainly located in the bHLH domain and, as a result, decreased the transcriptional activity of dHAND.	0	30	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	dHAND	Coexpression of HA-Akt augmented dHAND phosphorylation at multiple serine	dhand	dHAND	dHAND	dhand	4	5	29	30
Hand2 for example , is expressed in the mediodistal region of the mandibular prominence 51 and targeted deletion of a specific enhancer of Hand2 in NCC of the 1 st and 2 nd PA leads to mandibular hypoplasia , 52 mimicking the Dlx5/6 mutant homeotic transformation phenotype .	Hand2 for example, is expressed in the mediodistal region of the mandibular prominence 51 and targeted deletion of a specific enhancer of Hand2 in NCC of the 1 st and 2 nd PA leads to mandibular hypoplasia, 52 mimicking the Dlx5/6 mutant homeotic transformation phenotype.	0	24	targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Hand2	Hand2 for example, is expressed	hand2	Hand2	Hand2	hand2	0	1	23	24
Overexpression of AKT3 increased the protein expression of total AKT , phospho-AKT S473 , phospho-AKT T308 , B-Raf , c-Myc , Skp2 , cyclin E , GSK3beta , phospho-GSK3beta S9 , phospho-mTOR S2448 , and phospho-p70S6K T421 and S424 , but decreased TSC1 ( tuberous sclerosis 1 ) and TSC2 ( tuberous Sclerosis Complex 2 ) proteins in PC-3 PCa cells .	Overexpression of AKT3 increased the protein expression of total AKT, phospho-AKT S473, phospho-AKT T308, B-Raf, c-Myc, Skp2, cyclin E, GSK3beta, phospho-GSK3beta S9, phospho-mTOR S2448, and phospho-p70S6K T421 and S424, but decreased TSC1 (tuberous sclerosis 1) and TSC2 (tuberous Sclerosis Complex 2) proteins in PC-3 PCa cells.	0	53	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	Overexpression of AKT3 increased the protein expression of total AKT, phospho-AKT S473, phospho-AKT T308, B-Raf, c-Myc, Skp2, cyclin E, GSK3beta	gsk3beta	TSC2	TSC2	tsc2	26	27	49	50
Akt directly inactivates GSK3beta , increasing Cyclin D1 which then inhibits Forkhead family transcription factors and the tumor suppressor tuberin ( TSC2 ) , reducing p27Kip levels [ XREF_BIBR ] .	Akt directly inactivates GSK3beta, increasing Cyclin D1 which then inhibits Forkhead family transcription factors and the tumor suppressor tuberin (TSC2), reducing p27Kip levels [XREF_BIBR].	3	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	tuberin	tuberin	tuberin	3	4	19	20
Moreover , siRNA mediated knockdown studies showed that PRMT5 , HDAC3 and SKI mediate transcriptional repression of SMAD7 in the absence of transforming growth factor ( TGF )-beta .	Moreover, siRNA mediated knockdown studies showed that PRMT5, HDAC3 and SKI mediate transcriptional repression of SMAD7 in the absence of transforming growth factor (TGF)-beta.	8	18	mediate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HDAC3	HDAC3	HDAC3	SMAD7	SMAD7	SMAD7	10	11	17	18
Another well-known tau kinase , GSK3beta , downregulates the neuroprotective isoform PKCepsilon during AD [ XREF_BIBR ] .	Another well-known tau kinase, GSK3beta, downregulates the neuroprotective isoform PKCepsilon during AD [XREF_BIBR].	3	12	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	PKCepsilon	PKCepsilon	PKCepsilon	5	6	11	12
Inactivation of Hck SH3 function by Ala replacement of a conserved Trp residue ( W93A mutant ) completely abolished STAT3 activation by Hck-YF and reduced transforming activity by 50 % without affecting Hck kinase activity .	Inactivation of Hck SH3 function by Ala replacement of a conserved Trp residue (W93A mutant) completely abolished STAT3 activation by Hck-YF and reduced transforming activity by 50% without affecting Hck kinase activity.	2	20	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Hck	Hck	Hck	STAT3	STAT3	STAT3	2	3	19	20
TAK-701 is a humanized antibody that binds hepatocyte growth factor ( HGF ) , thus suppressing c-Met transduced signaling and c-Met dependent proliferation and migration of tumor cells .	TAK-701 is a humanized antibody that binds hepatocyte growth factor (HGF), thus suppressing c-Met transduced signaling and c-Met dependent proliferation and migration of tumor cells.	7	17	suppressing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	c-Met	c-Met	c-Met	7	10	16	17
Regardless of the decrease in HGF induced activation of c-Met in SB- and CsA pretreated cells , however , treatment with DIM did not further inhibit c-Met activation .	Regardless of the decrease in HGF induced activation of c-Met in SB- and CsA pretreated cells, however, treatment with DIM did not further inhibit c-Met activation.	3	10	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	9	10
Furthermore , the silencing of MUC1 increases HGF induced c-Met activation as well as the invasion of Mahlavu and 449 cells , showing that MUC1 down-regulation is an important regulator of c-Met activation in HCC .	Furthermore, the silencing of MUC1 increases HGF induced c-Met activation as well as the invasion of Mahlavu and 449 cells, showing that MUC1 down-regulation is an important regulator of c-Met activation in HCC.	3	10	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	7	8	9	10
Collectively , these findings indicated that curcumin could inhibit HGF promoted EMT and angiogenesis by targeting c-Met and blocking PI3K/Akt/mTOR pathways .	Collectively, these findings indicated that curcumin could inhibit HGF promoted EMT and angiogenesis by targeting c-Met and blocking PI3K/Akt/mTOR pathways.	9	17	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	9	10	16	17
Knocking down of MTP in NS/P cells with specific siRNA impaired HGF stimulation of c-Met , Akt and FAK activation , blocked HGF induced production of MMP2 and inhibited HGF stimulated NS/P cell motility .	Knocking down of MTP in NS/P cells with specific siRNA impaired HGF stimulation of c-Met, Akt and FAK activation, blocked HGF induced production of MMP2 and inhibited HGF stimulated NS/P cell motility.	11	15	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	14	15
Ficlatuzumab ( AV-299 ; SCH 900105 ) , a humanized IgG 1 kappa HGF inhibitory monoclonal antibody , prevents HGF and c-Met pathway ligand mediated activation .	Ficlatuzumab (AV-299; SCH 900105), a humanized IgG 1 kappa HGF inhibitory monoclonal antibody, prevents HGF and c-Met pathway ligand mediated activation.	0	25	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	13	14	21	22
Notably , several different epithelial tumor cell lines expressing the uncleavable HGF ( inactive precursor ) that inhibits HGF induced c-met activation using a lentaviral vector , showed suppressed tumor growth and decreased metastases [ XREF_BIBR ] .	Notably, several different epithelial tumor cell lines expressing the uncleavable HGF (inactive precursor) that inhibits HGF induced c-met activation using a lentaviral vector, showed suppressed tumor growth and decreased metastases [XREF_BIBR].	17	21	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-met	c-met	c-met	18	19	20	21
Consistent with this hypothesis , we found that mouse tumor cells with impaired HGF induced c-Met activation due to Spsb1 knockdown were less efficient at forming colonies than control cells when grown in the presence of HGF following HER2 and neu down-regulation ( XREF_FIG , p < 0.01 ) .	Consistent with this hypothesis, we found that mouse tumor cells with impaired HGF induced c-Met activation due to Spsb1 knockdown were less efficient at forming colonies than control cells when grown in the presence of HGF following HER2 and neu down-regulation (XREF_FIG, p < 0.01).	10	16	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	13	14	15	16
It is a humanized monoclonal antibody that sequesters HGF , thereby preventing the stimulation of c-Met by HGF .	It is a humanized monoclonal antibody that sequesters HGF, thereby preventing the stimulation of c-Met by HGF.	11	18	stimulation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	17	18	15	16
Inhibition of HGF induced c-Met , PI3K and Akt and MEK and ERK activation were observed in shikonin treated cells .	Inhibition of HGF induced c-Met, PI3K and Akt and MEK and ERK activation were observed in shikonin treated cells.	0	15	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	4	5
To investigate whether DIM inhibits activation of c-Met by HGF , we determined the degree of tyrosine phosphorylation of c-Met at Tyr1234/1235 after treatment with DMSO or 25 muM DIM for 4 hours and 40 ng/mL HGF for 0-30 minutes via Western blotting ( XREF_FIG ) .	To investigate whether DIM inhibits activation of c-Met by HGF, we determined the degree of tyrosine phosphorylation of c-Met at Tyr1234/1235 after treatment with DMSO or 25 muM DIM for 4 hours and 40 ng/mL HGF for 0-30 minutes via Western blotting (XREF_FIG).	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	9	10	7	8
HGF decreased sensitivity to PAC by activating c-Met in vivo .	HGF decreased sensitivity to PAC by activating c-Met in vivo.	0	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	0	1	7	8
Accordingly , (-)-oleocanthal treatment effectively blocked growth and mitogenesis through suppression of HGF induced c-Met activation and subsequent activation of downstream effectors .	Accordingly, (-)-oleocanthal treatment effectively blocked growth and mitogenesis through suppression of HGF induced c-Met activation and subsequent activation of downstream effectors.	10	15	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	12	13	14	15
c-MET inhibitors block HGF induced activation of c-MET and its downstream signaling .	c-MET inhibitors block HGF induced activation of c-MET and its downstream signaling.	3	11	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	3	4	7	8
In support of this model , the inhibition of HGF induced c-Met activation restores MUC1 expression , which results in decreased cellular motility and invasiveness .	In support of this model, the inhibition of HGF induced c-Met activation restores MUC1 expression, which results in decreased cellular motility and invasiveness.	7	12	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	9	10	11	12
In this report , we tested the relevance of our published mechanistic data on lateral signaling to determine if enhanced anti-tumor effects could be achieved by blocking the activation of c-Met by HGF using a c-Met small molecule tyrosine kinase inhibitor , along with blockade of c-Met downstream reinforcing signaling that is initiated by PGE2 using a COX-2 inhibitor .	In this report, we tested the relevance of our published mechanistic data on lateral signaling to determine if enhanced anti-tumor effects could be achieved by blocking the activation of c-Met by HGF using a c-Met small molecule tyrosine kinase inhibitor, along with blockade of c-Met downstream reinforcing signaling that is initiated by PGE2 using a COX-2 inhibitor.	26	33	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	32	33	30	31
These effects are found to be mediated , at least in part , via the inhibition of HGF induced c-Met activation and its downstream mitogenic signaling pathways ( RAS , PI3K , beta-catenin , or STAT pathways ) that are related to proliferation and surveillance of cells .	These effects are found to be mediated, at least in part, via the inhibition of HGF induced c-Met activation and its downstream mitogenic signaling pathways (RAS, PI3K, beta-catenin, or STAT pathways) that are related to proliferation and surveillance of cells.	15	20	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	17	18	19	20
In addition , heparin reduced HGF induced activation of c-Met and MAPK in a dose dependent manner , as well as decreased transcriptional activation and expression of Early growth response factor 1 ( Egr1 ) .	In addition, heparin reduced HGF induced activation of c-Met and MAPK in a dose dependent manner, as well as decreased transcriptional activation and expression of Early growth response factor 1 (Egr1).	4	11	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	5	6	9	10
V6-peptides can efficiently block HGF induced hepatocyte growth factor receptor ( or Met ) activation and downstream signaling.20 Furthermore , v6-peptide treatment of HT29 colon carcinoma cells has been shown to strongly inhibit their HGF and Met stimulated cell detachment and scattering .	V6-peptides can efficiently block HGF induced hepatocyte growth factor receptor (or Met) activation and downstream signaling.20 Furthermore, v6-peptide treatment of HT29 colon carcinoma cells has been shown to strongly inhibit their HGF and Met stimulated cell detachment and scattering.	4	10	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	hepatocyte growth factor receptor	hepatocyte growth factor receptor	hepatocyte growth factor receptor	4	5	6	10
BsAb inhibits HGF triggered c-MET downstream molecules and promotes c-MET degradation .	BsAb inhibits HGF triggered c-MET downstream molecules and promotes c-MET degradation.	2	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	2	3	9	10
Wortmannin , an inhibitor of phosphoinositide ( PI ) 3-kinase , inhibited the HGF induced disruption of cell-cell junction and endocytosis of E-cadherin and c-Met , but not the TPA induced ones .	Wortmannin, an inhibitor of phosphoinositide (PI) 3-kinase, inhibited the HGF induced disruption of cell-cell junction and endocytosis of E-cadherin and c-Met, but not the TPA induced ones.	12	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	13	14	24	25
We observed that the downstream response to both EGF induced PI3K/Akt/mTOR pathway activation and HGF induced c-Met augmentation were suppressed by combined treatment with MTE and erlotinib or gefitinib .	We observed that the downstream response to both EGF induced PI3K/Akt/mTOR pathway activation and HGF induced c-Met augmentation were suppressed by combined treatment with MTE and erlotinib or gefitinib.	12	17	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	14	15	16	17
Matriptase silencing abrogates pro HGF mediated c-Met signaling in human IBC cell lines .	Matriptase silencing abrogates pro HGF mediated c-Met signaling in human IBC cell lines.	2	7	mediated	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	6	7
In contrast , HGF mediated c-MET activation increased angiogenesis and reduced fibrosis .	In contrast, HGF mediated c-MET activation increased angiogenesis and reduced fibrosis.	3	6	mediated	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	3	4	5	6
Exogenous HGF within physiologic range increased the proliferation of Pan02 pancreatic cancer cells , and knockdown of adipocyte derived HGF and specific blockade of the only known HGF receptor , c-met , both significantly attenuated adipocyte induced excess Pan02 proliferation .	Exogenous HGF within physiologic range increased the proliferation of Pan02 pancreatic cancer cells, and knockdown of adipocyte derived HGF and specific blockade of the only known HGF receptor, c-met, both significantly attenuated adipocyte induced excess Pan02 proliferation.	19	29	blockade	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	HGF	HGF	HGF	HGF receptor	HGF receptor	HGF receptor	19	20	27	29
When HGF induced c-Met activation was blocked by a c-Met specific inhibitor , beta-catenin activation and concurrently c-Myc expression were suppressed .	When HGF induced c-Met activation was blocked by a c-Met specific inhibitor, beta-catenin activation and concurrently c-Myc expression were suppressed.	1	4	induced	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	1	2	3	4
In vivo inhibition of HGF mediated c-Met activation blocked early , enhanced colon dysplasia in Tpl2 deficient mice , indicating that Tpl2 normally suppresses the HGF and c-Met pathway .	In vivo inhibition of HGF mediated c-Met activation blocked early, enhanced colon dysplasia in Tpl2 deficient mice, indicating that Tpl2 normally suppresses the HGF and c-Met pathway.	2	7	mediated	Positive_early_activation	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	6	7
HGF neutralizing antibody effectively reduces the activation of HGF and c-MET signaling , which blocks its ability to promote CPT-11 resistance in colorectal cancer cells .	HGF neutralizing antibody effectively reduces the activation of HGF and c-MET signaling, which blocks its ability to promote CPT-11 resistance in colorectal cancer cells.	0	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HGF	HGF	HGF	c-MET	c-MET	c-MET	0	1	10	11
Some HGF antagonists may also partially inhibit HGF independent c-Met signaling by inducing c-Met internalization , thereby lowering cell surface expression.38 c-Met TKIs can reliably inhibit both HGF dependent and HGF independent c-Met signaling because both mechanisms depend on c-Met kinase activity .	Some HGF antagonists may also partially inhibit HGF independent c-Met signaling by inducing c-Met internalization, thereby lowering cell surface expression.38 c-Met TKIs can reliably inhibit both HGF dependent and HGF independent c-Met signaling because both mechanisms depend on c-Met kinase activity.	6	33	inhibit	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	7	8	32	33
Since the HGF and c-Met inhibitor targets the activation of c-Met on the tumor cell surface , it showed no effect on the expression of SMA .	Since the HGF and c-Met inhibitor targets the activation of c-Met on the tumor cell surface, it showed no effect on the expression of SMA.	2	11	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	2	3	10	11
Silencing of MUC1 improves HGF induced c-Met signaling .	Silencing of MUC1 improves HGF induced c-Met signaling.	4	7	induced	Positive_early_activation	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	4	5	6	7
This effect was inhibited by heat treatment , hepatocyte growth factor ( HGF ) blocking antibodies and a HGF receptor ( cMet ) inhibitor .	This effect was inhibited by heat treatment, hepatocyte growth factor (HGF) blocking antibodies and a HGF receptor (cMet) inhibitor.	3	23	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	hepatocyte growth factor	hepatocyte growth factor	hepatocyte growth factor	HGF receptor	HGF receptor	HGF receptor	8	11	18	20
Inhibition of PTPs increases c-Met activation and cell signaling stimulated by HGF , as well as the rate of epithelial wound healing .	Inhibition of PTPs increases c-Met activation and cell signaling stimulated by HGF, as well as the rate of epithelial wound healing.	4	12	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	4	5
Intriguingly , the temporal expression profile of differentiating myoblasts showed a decline in c-Met levels after 48 h , and a drastic increase of Hgf levels between 48-96 h [ XREF_BIBR ] , highly suggestive of a role for HGF produced by nascent myotubes to recruit lower c-Met expressing myoblasts for the second round of fusion .	Intriguingly, the temporal expression profile of differentiating myoblasts showed a decline in c-Met levels after 48 h, and a drastic increase of Hgf levels between 48-96 h [XREF_BIBR], highly suggestive of a role for HGF produced by nascent myotubes to recruit lower c-Met expressing myoblasts for the second round of fusion.	24	48	produced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Hgf	Hgf levels	hgf	c-Met	c-Met	c-met	24	25	47	48
Furthermore , both enantiomers ( 27 and 28 ) significantly inhibited HGF promoted MDCK cell migration by targeting the HGF and c-Met pathway [ XREF_BIBR ] .	Furthermore, both enantiomers (27 and 28) significantly inhibited HGF promoted MDCK cell migration by targeting the HGF and c-Met pathway [XREF_BIBR].	11	24	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HGF	HGF	HGF	c-Met	c-Met	c-Met	11	12	21	22
The protective effect of rHMGB1 preconditioning involved Siglec-G upregulation , a negative regulator of HMGB1 mediated TLR4 pathway activation .	The protective effect of rHMGB1 preconditioning involved Siglec-G upregulation, a negative regulator of HMGB1 mediated TLR4 pathway activation.	12	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	14	15	16	17
These results suggested HMGB1 neutralization specifically inhibits CD4 + T cell infiltration in the CNS of EAE mice and TLR2 and TLR4 upregulation in EAE lesions but gives no indication if anti-HMGB1 treatment alters immune responses systemically .	These results suggested HMGB1 neutralization specifically inhibits CD4 + T cell infiltration in the CNS of EAE mice and TLR2 and TLR4 upregulation in EAE lesions but gives no indication if anti-HMGB1 treatment alters immune responses systemically.	3	22	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	3	4	21	22
In addition to the common up-regulated genes , the common TLR4 dependent down-regulated genes by LPS and HMGB1 were enriched within pathways including ubiquitin mediated proteolysis , protein processing in endoplasmic reticulum , and MAPK signaling pathways .	In addition to the common up-regulated genes, the common TLR4 dependent down-regulated genes by LPS and HMGB1 were enriched within pathways including ubiquitin mediated proteolysis, protein processing in endoplasmic reticulum, and MAPK signaling pathways.	8	19	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	17	18	10	11
EP downregulated the mRNA and protein levels of HMGB1 , inhibited the TLR4 signaling pathways ( TLR4 , MYD88 and pNF-kappaB p65 ) and reduced the secretion of proinflammatory mediators ( HMGB1 , IL-1beta , IL-6 and TNF-alpha ) in the SW480 and THP-1 cells activated by LPS but not in the unstimulated cells .	EP downregulated the mRNA and protein levels of HMGB1, inhibited the TLR4 signaling pathways (TLR4, MYD88 and pNF-kappaB p65) and reduced the secretion of proinflammatory mediators (HMGB1, IL-1beta, IL-6 and TNF-alpha) in the SW480 and THP-1 cells activated by LPS but not in the unstimulated cells.	0	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	EP downregulated the mRNA and protein levels of HMGB1	hmgb1	TLR4	TLR4	tlr4	8	9	12	13
Finally , knock-out of TLR4 or antagonizing HMGB1 by A-box inhibited MMP-2 and MMP-9 activity , and rHMGB1-treatmet increased MMP-2 and MMP-9 activity significantly ( XREF_FIG ) .	Finally, knock-out of TLR4 or antagonizing HMGB1 by A-box inhibited MMP-2 and MMP-9 activity, and rHMGB1-treatmet increased MMP-2 and MMP-9 activity significantly (XREF_FIG).	2	9	antagonizing	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	7	8	4	5
Interestingly , a recent study hypothesized the anti-inflammatory effect of MTX is due to direct binding to HMGB1 and inhibition of HMGB1 induced TLR4 signaling .	Interestingly, a recent study hypothesized the anti-inflammatory effect of MTX is due to direct binding to HMGB1 and inhibition of HMGB1 induced TLR4 signaling.	19	24	induced	Positive_early_activation	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	21	22	23	24
HMGB1 also binds to CD24 , a membrane protein expressed by immunocytes , which in turn associates with Siglec-10 to selectively suppress the nuclear translocation of NF-kappaB induced by HMGB1 mediated TLR4 activation , but not pathogen mediated TLR activation .	HMGB1 also binds to CD24, a membrane protein expressed by immunocytes, which in turn associates with Siglec-10 to selectively suppress the nuclear translocation of NF-kappaB induced by HMGB1 mediated TLR4 activation, but not pathogen mediated TLR activation.	27	32	mediated	Positive_early_activation	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	29	30	31	32
Activated by LPS , the overexpression of HMGB1 A-box in the SW480 cells also inhibited the HMGB1 and TLR4 signaling pathways and reduced the secretion of these proinflammatory mediators in the THP-1 cells but not in the transfected and unstimulated cells .	Activated by LPS, the overexpression of HMGB1 A-box in the SW480 cells also inhibited the HMGB1 and TLR4 signaling pathways and reduced the secretion of these proinflammatory mediators in the THP-1 cells but not in the transfected and unstimulated cells.	5	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	overexpression of HMGB1	hmgb1	TLR4	TLR4	tlr4	7	8	18	19
Here we report , that the first generation HIV-PI saquinavir ( SQV ) , as well as a newly identified mammalian protease inhibitor STO33438 ( 334 ) , potently block disulfide HMGB1 induced TLR4 activation , as assayed by the production of TNF-alpha by human monocyte derived macrophages ( THP-1 ) .	Here we report, that the first generation HIV-PI saquinavir (SQV), as well as a newly identified mammalian protease inhibitor STO33438 (334), potently block disulfide HMGB1 induced TLR4 activation, as assayed by the production of TNF-alpha by human monocyte derived macrophages (THP-1).	29	34	induced	Positive_early_activation	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	31	32	33	34
XREF_FIG , HMGB1 significantly enhanced proliferation of TLR4 silenced HaCaT cells ( p = 0.001 ) and increased their migration ( p = 0.001 ) .	XREF_FIG, HMGB1 significantly enhanced proliferation of TLR4 silenced HaCaT cells (p = 0.001) and increased their migration (p = 0.001).	0	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	7	8
P5779 is a small molecule inhibitor of HMGB1 that was shown recently to prevent MD-2 and HMGB1 interaction and block HMGB1 induced TLR4 signaling , while not interfering with LPS induced cytokine and chemokine induction 27 .	P5779 is a small molecule inhibitor of HMGB1 that was shown recently to prevent MD-2 and HMGB1 interaction and block HMGB1 induced TLR4 signaling, while not interfering with LPS induced cytokine and chemokine induction 27.	13	23	induced	Positive_early_activation	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	20	21	22	23
Notably , HMGB1 A-box blocked IL-1beta-induced HMGB1 release , and preferentially attenuated TLR4 , Myd88 and P65 in astrocyte cultures .	Notably, HMGB1 A-box blocked IL-1beta-induced HMGB1 release, and preferentially attenuated TLR4, Myd88 and P65 in astrocyte cultures.	2	16	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	2	3	12	13
Knock-out of TLR4 or antagonizing HMGB1 by specific antagonist A-box inhibited ILA notably .	Knock-out of TLR4 or antagonizing HMGB1 by specific antagonist A-box inhibited ILA notably.	0	9	antagonizing	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	5	6	2	3
In addition , after TLR4 inhibition , rats treated with HMGB1 exhibited reduced lung injury as well as levels of proinflammatory cytokines in the lung tissue .	In addition, after TLR4 inhibition, rats treated with HMGB1 exhibited reduced lung injury as well as levels of proinflammatory cytokines in the lung tissue.	4	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	10	11	4	5
SiRNA HMGB-1 down-regulate TLR-4 and NF-kappaB mRNA and protein expression .	SiRNA HMGB-1 down-regulate TLR-4 and NF-kappaB mRNA and protein expression.	0	6	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB-1	HMGB-1	HMGB-1	TLR-4	TLR-4	TLR-4	1	2	3	4
Blocking TLR4 and RAGE rather than TLR2 also decreased oxygen radical production and lactoferrin release in HMGB1 primed neutrophils induced by ANCA positive IgG from AAV patients .	Blocking TLR4 and RAGE rather than TLR2 also decreased oxygen radical production and lactoferrin release in HMGB1 primed neutrophils induced by ANCA positive IgG from AAV patients.	0	17	Blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	16	17	1	2
HMGB1 , another TLR4 activator , affects cell-matrix adhesiveness in enterocytes , and HMGB1 induced TLR4 activation inhibits enterocyte migration through activation of the RhoA ( Ras homolog gene family , member A ) as indicated by increased phosphorylation of cofilin [ XREF_BIBR ] .	HMGB1, another TLR4 activator, affects cell-matrix adhesiveness in enterocytes, and HMGB1 induced TLR4 activation inhibits enterocyte migration through activation of the RhoA (Ras homolog gene family, member A) as indicated by increased phosphorylation of cofilin [XREF_BIBR].	13	16	induced	Positive_early_activation	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	13	14	15	16
Our in vivo experiments show that the above pro lymphangiogenesis molecules were up-regulated in HMGB1-treatmet ILA corneas and were down-regulated in ILA corneas with Knock-out of TLR4 or antagonizing HMGB1 by A-box .	Our in vivo experiments show that the above pro lymphangiogenesis molecules were up-regulated in HMGB1-treatmet ILA corneas and were down-regulated in ILA corneas with Knock-out of TLR4 or antagonizing HMGB1 by A-box.	24	31	antagonizing	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	29	30	26	27
HMGB1 levels are increased shortly after ischemia-reperfusion and blockade of HMGB1 by a neutralizing antibody reduces injury in wild-type but not TLR4 deficient mice .	HMGB1 levels are increased shortly after ischemia-reperfusion and blockade of HMGB1 by a neutralizing antibody reduces injury in wild-type but not TLR4 deficient mice.	6	23	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	TLR4	TLR4	TLR4	10	11	21	22
HIPK2 suppresses tumor growth by activating p53 and inducing tumor cell apoptosis .	HIPK2 suppresses tumor growth by activating p53 and inducing tumor cell apoptosis.	0	7	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	0	1	6	7
As phosphorylation of p53Ser46 is essential for the induction of cell death [ XREF_BIBR ] , impaired HIPK2 mediated p53 modification will deteriorate chemotherapy induced apoptosis in HG condition .	As phosphorylation of p53Ser46 is essential for the induction of cell death [XREF_BIBR], impaired HIPK2 mediated p53 modification will deteriorate chemotherapy induced apoptosis in HG condition.	16	22	mediated	Positive_early_activation	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	17	18	19	20
In our study , we added a level of knowledge to this issue by demonstrating that HG induced HIPK2 degradation strongly inhibited p53 apoptotic activity .	In our study, we added a level of knowledge to this issue by demonstrating that HG induced HIPK2 degradation strongly inhibited p53 apoptotic activity.	16	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HG induced HIPK2	hipk2	p53	p53	p53	18	19	22	23
We found that nonapoptotic DNA damage induces p53 acetylation mediated by the HAT protein PCAF and this p53 post-translational modification is abolished by HIPK2 depletion .	We found that nonapoptotic DNA damage induces p53 acetylation mediated by the HAT protein PCAF and this p53 post-translational modification is abolished by HIPK2 depletion.	17	24	abolished	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	23	24	17	18
Importantly , loss of one allele of Hipk2 also accelerated tumorigenesis in irradiated p53 +/- mice ( P = 0.015 for tumorigenesis in 29 p53 +/- mice versus 36 Hipk2 +/-p53 +/- mice ; XREF_FIG ) , in agreement with the observation of p53 independent deletions of this chromosomal region in mouse lymphomas .	Importantly, loss of one allele of Hipk2 also accelerated tumorigenesis in irradiated p53 +/- mice (P = 0.015 for tumorigenesis in 29 p53 +/- mice versus 36 Hipk2 +/-p53 +/- mice; XREF_FIG), in agreement with the observation of p53 independent deletions of this chromosomal region in mouse lymphomas.	5	14	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Hipk2	Hipk2	Hipk2	p53	p53	p53	7	8	13	14
We recently reported that MYCN induces the expression of both p53 and HIPK2 XREF_BIBR and HIPK2 activated p53 can repress Gal-3 transcription XREF_BIBR .	We recently reported that MYCN induces the expression of both p53 and HIPK2 XREF_BIBR and HIPK2 activated p53 can repress Gal-3 transcription XREF_BIBR.	7	19	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	HIPK2	expression of both p53 and HIPK2 XREF_BIBR and HIPK2	hipk2	p53	p53	p53	15	16	17	18
These results recapitulate the negative effect of constitutive hypoxic phenotype on HIPK2 induced p53 apoptotic transcriptional activity and cell response to drug .	These results recapitulate the negative effect of constitutive hypoxic phenotype on HIPK2 induced p53 apoptotic transcriptional activity and cell response to drug.	9	16	induced	Positive_early_activation	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	11	12	13	14
Thus , HIPK2 depletion inhibits p53 apoptotic activation and leads to chemoresistance XREF_BIBR , XREF_BIBR .	Thus, HIPK2 depletion inhibits p53 apoptotic activation and leads to chemoresistance XREF_BIBR, XREF_BIBR.	2	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	2	3	5	6
These results suggest that HIPK2 induced p53 activation was reduced by PARP1 overexpression .	These results suggest that HIPK2 induced p53 activation was reduced by PARP1 overexpression.	4	7	induced	Positive_early_activation	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	4	5	6	7
We have recently shown that HIPK2 knockdown induces p53 misfolding that can be reverted by zinc supplementation XREF_BIBR , XREF_BIBR .	We have recently shown that HIPK2 knockdown induces p53 misfolding that can be reverted by zinc supplementation XREF_BIBR, XREF_BIBR.	5	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	5	6	8	9
In addition to PML itself , numerous further tumour suppressors including transcriptional regulator p53 , acetyl transferase CBP ( CREB binding protein ) and protein kinase HIPK2 ( homeodomain interacting protein kinase 2 ) are recruited to PML NBs in response to genotoxic stress or oncogenic transformation and drive the senescence and apoptosis response by regulating p53 activity .	In addition to PML itself, numerous further tumour suppressors including transcriptional regulator p53, acetyl transferase CBP (CREB binding protein) and protein kinase HIPK2 (homeodomain interacting protein kinase 2) are recruited to PML NBs in response to genotoxic stress or oncogenic transformation and drive the senescence and apoptosis response by regulating p53 activity.	9	57	drive	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	26	27	56	57
Indeed , HIPK2 depletion by siRNA strongly impairs p53 function , affecting not only Ser46 phosphorylation [ XREF_BIBR ] but also p53 wild-type conformation due to deregulation of metallothionein and zinc [ XREF_BIBR , XREF_BIBR ] .	Indeed, HIPK2 depletion by siRNA strongly impairs p53 function, affecting not only Ser46 phosphorylation [XREF_BIBR] but also p53 wild-type conformation due to deregulation of metallothionein and zinc [XREF_BIBR, XREF_BIBR].	2	9	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	2	3	8	9
19 Chronic HIPK2 depletion impairs p53 function by inducing p53 protein misfolding that can be reversed by zinc supplementation .	19 Chronic HIPK2 depletion impairs p53 function by inducing p53 protein misfolding that can be reversed by zinc supplementation.	2	6	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	2	3	5	6
These results show a critical role of HIPK2 in maintaining the transactivation activity of wtp53 and further suggest that low expression of HIPK2 may impair the p53 function in tumors harboring wtp53 .	These results show a critical role of HIPK2 in maintaining the transactivation activity of wtp53 and further suggest that low expression of HIPK2 may impair the p53 function in tumors harboring wtp53.	20	27	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HIPK2	expression of HIPK2	hipk2	p53	p53	p53	22	23	26	27
Consistently , p53 and HIPK2 depletion via RNA interference ( RNAi ) impairs apoptosis induced by DNA damaging drugs and p53 reactivating compounds in MNA and MYCN overexpressing cells XREF_BIBR , XREF_BIBR , XREF_BIBR ( see also XREF_FIG ) .	Consistently, p53 and HIPK2 depletion via RNA interference (RNAi) impairs apoptosis induced by DNA damaging drugs and p53 reactivating compounds in MNA and MYCN overexpressing cells XREF_BIBR, XREF_BIBR, XREF_BIBR (see also XREF_FIG).	2	35	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	4	5	20	21
We have previously demonstrated that RKO undergoes apoptosis and that HIPK2 depletion inhibits p53 dependent apoptosis [ XREF_BIBR , XREF_BIBR ] ( Additional file XREF_SUPPLEMENTARY , Table S1 ) .	We have previously demonstrated that RKO undergoes apoptosis and that HIPK2 depletion inhibits p53 dependent apoptosis [XREF_BIBR, XREF_BIBR] (Additional file XREF_SUPPLEMENTARY, Table S1).	10	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	10	11	13	14
Hypoxia induced ubiquitin ligases such as Siah2 [ XREF_BIBR ] or p53 targets MDM2 [ XREF_BIBR ] and Siah1 [ XREF_BIBR ] trigger HIPK2 degradation strongly affecting drug induced p53 apoptotic activity .	Hypoxia induced ubiquitin ligases such as Siah2 [XREF_BIBR] or p53 targets MDM2 [XREF_BIBR] and Siah1 [XREF_BIBR] trigger HIPK2 degradation strongly affecting drug induced p53 apoptotic activity.	23	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	23	24	29	30
We have shown that stable knockdown of HIPK2 induces p53 misfolding with inhibition of p53 target gene transcription .	We have shown that stable knockdown of HIPK2 induces p53 misfolding with inhibition of p53 target gene transcription.	5	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	7	8	9	10
Upon DNA damage , HIPK2 activated p53 can repress Gal-3 and its antiapoptotic activity XREF_BIBR .	Upon DNA damage, HIPK2 activated p53 can repress Gal-3 and its antiapoptotic activity XREF_BIBR.	4	8	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	HIPK2	HIPK2	HIPK2	p53	p53	p53	4	5	6	7
By activating RAGE , HMGB1 impaired fibroblast mediated collagen synthesis with reduced tensile strength .	By activating RAGE, HMGB1 impaired fibroblast mediated collagen synthesis with reduced tensile strength.	1	8	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	2	3
Neutralising HMGB1 reduces PVM infection and ASM mass in RAGE deficient mice during an early life PVM infection .	Neutralising HMGB1 reduces PVM infection and ASM mass in RAGE deficient mice during an early life PVM infection.	0	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	1	2	9	10
In vitro , suppression of RAGE and HMGB1 by antisense S-oligodeoxynucleotide or HMGB1 150-183 peptide ( RAGE binding motif ) inhibits growth , migration , and invasion in cancer cells .	In vitro, suppression of RAGE and HMGB1 by antisense S-oligodeoxynucleotide or HMGB1 150-183 peptide (RAGE binding motif) inhibits growth, migration, and invasion in cancer cells.	3	14	suppression	Negative_activation_syntax_1_noun	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	12	13	5	6
The inhibition of the HMGB1 activated macrophage indicated that HMGB1 A box protein could be act as a competitive inhibitor against TLR and/or RAGE on macrophage .	The inhibition of the HMGB1 activated macrophage indicated that HMGB1 A box protein could be act as a competitive inhibitor against TLR and/or RAGE on macrophage.	1	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	23	24
We first investigated whether sRAGE could inhibit expression of RAGE protein levels in VSMCs treated with AngII or HMGB1 .	We first investigated whether sRAGE could inhibit expression of RAGE protein levels in VSMCs treated with AngII or HMGB1.	9	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	18	19	9	10
Our data suggest that HMGB1 regionally secreted by macrophages mediates pancreatic pain by targeting RAGE and CXCL12 and CXCR4 axis in the early stage of acute pancreatitis .	Our data suggest that HMGB1 regionally secreted by macrophages mediates pancreatic pain by targeting RAGE and CXCL12 and CXCR4 axis in the early stage of acute pancreatitis.	4	19	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	14	15
Indeed , reducible HMGB1 induces Rage and Beclin1 dependent autophagy in cancer cells , promoting tumor resistance to chemotherapeutic agents or radiotherapy , whereas oxidized HMGB1 enhances the cytotoxicity of these chemotherapeutics and triggers apoptosis mediated by the caspase-9/-3 intrinsic pathway 124 .	Indeed, reducible HMGB1 induces Rage and Beclin1 dependent autophagy in cancer cells, promoting tumor resistance to chemotherapeutic agents or radiotherapy, whereas oxidized HMGB1 enhances the cytotoxicity of these chemotherapeutics and triggers apoptosis mediated by the caspase-9/-3 intrinsic pathway 124.	2	9	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	Rage	Rage	Rage	3	4	5	6
Our studies imply that sRAGEs produced by bacterial or insect expression systems and commonly used in in vitro studies and in mouse models may be differentially glycosylated or partially glycosylated and may not provide strong inhibitors of S100A8/A9 , S100A12 or HMGB1 mediated RAGE signaling .	Our studies imply that sRAGEs produced by bacterial or insect expression systems and commonly used in in vitro studies and in mouse models may be differentially glycosylated or partially glycosylated and may not provide strong inhibitors of S100A8/A9, S100A12 or HMGB1 mediated RAGE signaling.	35	44	mediated	Positive_early_activation	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	41	42	43	44
Assessment of the influence of HMGB1 neutralizing antibody on MPTP induced effects in the mouse midbrain by use of immunoblotting ( XREF_FIG A ) revealed significantly lower RAGE protein levels in mice treated with HMGB1 antibody , compared to mice only receiving MPTP ( XREF_FIG B ) .	Assessment of the influence of HMGB1 neutralizing antibody on MPTP induced effects in the mouse midbrain by use of immunoblotting (XREF_FIG A) revealed significantly lower RAGE protein levels in mice treated with HMGB1 antibody, compared to mice only receiving MPTP (XREF_FIG B).	27	35	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	34	35	27	28
Administration of an HMGB1 neutralizing antibody blocking HMGB1 and RAGE signaling depressed the RAGE level and significantly alleviated mechanical allodynia in a SNL model [ XREF_BIBR ] .	Administration of an HMGB1 neutralizing antibody blocking HMGB1 and RAGE signaling depressed the RAGE level and significantly alleviated mechanical allodynia in a SNL model [XREF_BIBR].	3	10	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	3	4	9	10
For example , reducible HMGB1 induces RAGE dependent autophagy , leading to resistance to chemotherapeutic agents or radiotherapy , while oxidized HMGB1 increases the cytotoxicity of these chemotherapeutics via induction of apoptosis [ XREF_BIBR ] .	For example, reducible HMGB1 induces RAGE dependent autophagy, leading to resistance to chemotherapeutic agents or radiotherapy, while oxidized HMGB1 increases the cytotoxicity of these chemotherapeutics via induction of apoptosis [XREF_BIBR].	3	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HMGB1	HMGB1	HMGB1	RAGE	RAGE	RAGE	4	5	6	7
Faber et al showed that loss of Hoxa9 causes downregulation of the Meis1 mRNA , while overexpression of HOXA9 upregulates Meis1 [ XREF_BIBR ] .	Faber et al showed that loss of Hoxa9 causes downregulation of the Meis1 mRNA, while overexpression of HOXA9 upregulates Meis1 [XREF_BIBR].	5	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hoxa9	loss of Hoxa9	hoxa9	Meis1	Meis1	meis1	7	8	12	13
Suppression of HOXA9 by shRNA induced immediate downregulation of MEIS1 in multiple human leukemia cell lines examined [ XREF_BIBR ] .	Suppression of HOXA9 by shRNA induced immediate downregulation of MEIS1 in multiple human leukemia cell lines examined [XREF_BIBR].	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HOXA9	HOXA9	HOXA9	MEIS1	MEIS1	MEIS1	2	3	9	10
Loss of Hoxa9 resulted in a decrease in Creb1 and Pknox1 mRNA , and forced expression of CREB1 in Hoxa9 (-/-) bone marrow cells increased Meis1 mRNA almost as well as HOXA9 , suggesting that CREB1 may mediate HOXA9 modulation of Meis1 expression .	Loss of Hoxa9 resulted in a decrease in Creb1 and Pknox1 mRNA, and forced expression of CREB1 in Hoxa9 (-/-) bone marrow cells increased Meis1 mRNA almost as well as HOXA9, suggesting that CREB1 may mediate HOXA9 modulation of Meis1 expression.	38	43	modulation	Positive_regulation_syntax_3_noun	Positive_activation	Positive_regulation	Hoxa9	HOXA9	hoxa9	Meis1	Meis1 expression	meis1	38	39	41	42
Loss of Hoxa9 caused downregulation of the Meis1 mRNA and protein , while forced HOXA9 expression upregulated Meis1 .	Loss of Hoxa9 caused downregulation of the Meis1 mRNA and protein, while forced HOXA9 expression upregulated Meis1.	14	18	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Hoxa9	HOXA9 expression	hoxa9	Meis1	Meis1	meis1	14	15	17	18
Indeed , inhibition of LILRB1 + NK-cell function is sensitive to the conformation of HLA-G , as the heavy chain of HLA-G alone does not inhibit LILRB1 + NK cells .	Indeed, inhibition of LILRB1 + NK-cell function is sensitive to the conformation of HLA-G, as the heavy chain of HLA-G alone does not inhibit LILRB1 + NK cells.	19	29	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HLA-G	HLA-G	HLA-G	LILRB1	LILRB1	LILRB1	21	22	26	27
By directly binding to the inhibitory receptors KIR2DL4 , ILT-2 and ILT-4 that are present on NK and CD8+ T cells , HLA-G can also inhibit differentiation , proliferation , cytolysis , cytokine secretion , and immunoglobulin production .	By directly binding to the inhibitory receptors KIR2DL4, ILT-2 and ILT-4 that are present on NK and CD8+ T cells, HLA-G can also inhibit differentiation, proliferation, cytolysis, cytokine secretion, and immunoglobulin production.	2	26	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HLA-G	HLA-G	HLA-G	ILT-2	ILT-2	ILT-2	22	23	9	10
In contrast , Raines et al 58 demonstrated that S nitrosylation of H-Ras at cysteine 118 is sufficient to block oncogenically mutated H-Ras activity and disrupt the activation of Raf-1 and propagation of mitogen activated protein ( MAP ) kinase kinase and extracellular signal regulated kinase signaling in N293 cells whose intracellular NO production is regulated by nNOS .	In contrast, Raines et al 58 demonstrated that S nitrosylation of H-Ras at cysteine 118 is sufficient to block oncogenically mutated H-Ras activity and disrupt the activation of Raf-1 and propagation of mitogen activated protein (MAP) kinase kinase and extracellular signal regulated kinase signaling in N293 cells whose intracellular NO production is regulated by nNOS.	10	31	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	H-Ras	H-Ras	H-Ras	Raf-1	Raf-1	Raf-1	12	13	29	30
Taken together , these data are consistent with selective inhibition of Shh palmitoylation by Hhat in cells by RUSKI-201 , and with Hhat dependent inhibition of Shh dependent signaling in the Shh-Light2 assay .	Taken together, these data are consistent with selective inhibition of Shh palmitoylation by Hhat in cells by RUSKI-201, and with Hhat dependent inhibition of Shh dependent signaling in the Shh-Light2 assay.	22	28	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Hhat	Hhat	Hhat	Shh	Shh	Shh	22	23	26	27
In contrast , a constitutively active H-Ras , which activates Erk but not the R-Ras pathway , failed to prevent ephrin-A5-induced collapse , consistent with our observations in this study that both constitutively active MEK1 and B-Raf which activate Erk activity failed to block ephrin-A5-induced collapse .	In contrast, a constitutively active H-Ras, which activates Erk but not the R-Ras pathway, failed to prevent ephrin-A5-induced collapse, consistent with our observations in this study that both constitutively active MEK1 and B-Raf which activate Erk activity failed to block ephrin-A5-induced collapse.	3	38	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	H-Ras	H-Ras	H-Ras	B-Raf	B-Raf	B-Raf	6	7	36	37
Phosphatase and tensin homolog deleted on chromosome ten ( PTEN ) down regulates PI3K and AKT pathway inhibiting activation of AKT by IGF-1R signaling .	Phosphatase and tensin homolog deleted on chromosome ten (PTEN) down regulates PI3K and AKT pathway inhibiting activation of AKT by IGF-1R signaling.	18	23	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	22	23	20	21
We therefore hypothesize that independent activation of PI3K by Src ( which directly binds PI3K ) and IGF-1R leads to the inability of dasatinib or BMS-754807 to completely inhibit Akt functions if used as single agents .	We therefore hypothesize that independent activation of PI3K by Src (which directly binds PI3K) and IGF-1R leads to the inability of dasatinib or BMS-754807 to completely inhibit Akt functions if used as single agents.	5	30	leads	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	17	18	29	30
Post-hoc tests demonstrated that ethanol significantly increased expression of IGF-1R relative to all other groups ( XREF_FIG ) , and increased IRS-1 ( XREF_FIG ) , but decreased Akt ( XREF_FIG ) relative to control .	Post-hoc tests demonstrated that ethanol significantly increased expression of IGF-1R relative to all other groups (XREF_FIG), and increased IRS-1 (XREF_FIG), but decreased Akt (XREF_FIG) relative to control.	4	30	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	ethanol significantly increased expression of IGF-1R	igf-1r	Akt	Akt	akt	9	10	28	29
Luciferase assay confirmed that IGF1R was directly regulated by miR-100 in RGC-5 cells , and siRNA mediated IGF1R knockdown activated AKT protein through phosphorylation , down-regulated miR-100 , therefore exerted a protective effect on RGC-5 apoptosis .	Luciferase assay confirmed that IGF1R was directly regulated by miR-100 in RGC-5 cells, and siRNA mediated IGF1R knockdown activated AKT protein through phosphorylation, down-regulated miR-100, therefore exerted a protective effect on RGC-5 apoptosis.	17	21	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	17	18	20	21
Accordingly , the combination of IGF-IR suppression by h7C10 and downstream targeting of mammalian target of rapamycin ( mTOR ) results in a dual benefit of preventing tumor escape seen after h7C10 treatment alone , presumably by mTOR inhibition downstream of AKT and limiting the potential problem of mTOR induced up-regulation of AKT .	Accordingly, the combination of IGF-IR suppression by h7C10 and downstream targeting of mammalian target of rapamycin (mTOR) results in a dual benefit of preventing tumor escape seen after h7C10 treatment alone, presumably by mTOR inhibition downstream of AKT and limiting the potential problem of mTOR induced up-regulation of AKT.	5	53	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-IR	IGF-IR	IGF-IR	AKT	AKT	AKT	5	6	52	53
Armed with our recent pre-clinical data that targeting the IGF-1R in human ACC cells effectively antagonizes downstream activation of AKT and has a marked inhibitory effect on tumor growth in human ACC xenograft models , we aimed to initiate a Phase I trial of IGF-1R inhibition in patients with ACC [ XREF_BIBR ] .	Armed with our recent pre-clinical data that targeting the IGF-1R in human ACC cells effectively antagonizes downstream activation of AKT and has a marked inhibitory effect on tumor growth in human ACC xenograft models, we aimed to initiate a Phase I trial of IGF-1R inhibition in patients with ACC [XREF_BIBR].	8	21	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	9	10	19	20
Moreover , re-expression of IGF1R could totally reverse the inhibition of PI3K and Akt signal pathway profile ( XREF_FIG ) .	Moreover, re-expression of IGF1R could totally reverse the inhibition of PI3K and Akt signal pathway profile (XREF_FIG).	2	16	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	re-expression of IGF1R	igf1r	Akt	Akt	akt	4	5	13	14
Therefore , we assumed that down-regulation of IGF-1R and IR due to PTB-U-box expression also attenuate Akt and ERK activation .	Therefore, we assumed that down-regulation of IGF-1R and IR due to PTB-U-box expression also attenuate Akt and ERK activation.	5	19	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	7	8	16	17
XREF_BIBR When R273H of P53 mutates , miR-30a would not inhibit the expression of IGF-1R ( insulin like growth factor 1 receptor ) anymore , but activate the AKT ( serine/threonine kinase ) signaling pathway .	XREF_BIBR When R273H of P53 mutates, miR-30a would not inhibit the expression of IGF-1R (insulin like growth factor 1 receptor) anymore, but activate the AKT (serine/threonine kinase) signaling pathway.	4	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	P53 mutates, miR-30a would not inhibit the expression of IGF-1R	igf-1r	AKT	AKT	akt	14	15	28	29
Therefore , the targeted degradation of IGF-1R and IR effectively attenuates the downstream MAPK and PI3K and Akt signaling pathway .	Therefore, the targeted degradation of IGF-1R and IR effectively attenuates the downstream MAPK and PI3K and Akt signaling pathway.	4	19	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	6	7	17	18
The feedback survival signal upon mTOR inhibition was fully terminated by the co-administration with PD through reduced epidermal growth factor receptor ( EGFR ) and insulin growth factor 1 receptor ( IGF1R ) expression , suppressed AKT activity , and reinforced 4E-BP1 inhibition .	The feedback survival signal upon mTOR inhibition was fully terminated by the co-administration with PD through reduced epidermal growth factor receptor (EGFR) and insulin growth factor 1 receptor (IGF1R) expression, suppressed AKT activity, and reinforced 4E-BP1 inhibition.	29	37	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	31	32	36	37
Over expression of DN-myb in HNSCC cells inhibited in vitro cell proliferation , expression of growth factors such as IGF-I , -II , IGF-1R , and VEGF , inhibited Akt and PKB pathway activation , and enhanced induction of apoptosis .	Over expression of DN-myb in HNSCC cells inhibited in vitro cell proliferation, expression of growth factors such as IGF-I, -II, IGF-1R, and VEGF, inhibited Akt and PKB pathway activation, and enhanced induction of apoptosis.	7	36	inhibited	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	PKB	PKB	PKB	23	24	31	32
We also found that Igf1r knock-down caused a reduction in the phosphorylated forms of Igf1r , MAPK , Akt , IRS , and P70 S6 kinase , thereby indicating that Igf1r siRNA treatment prevented the activation of Igf1r signaling pathway ( XREF_SUPPLEMENTARY ) .	We also found that Igf1r knock-down caused a reduction in the phosphorylated forms of Igf1r, MAPK, Akt, IRS, and P70 S6 kinase, thereby indicating that Igf1r siRNA treatment prevented the activation of Igf1r signaling pathway (XREF_SUPPLEMENTARY).	4	19	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Igf1r	Igf1r	Igf1r	Akt	Akt	Akt	4	5	18	19
The latter issue is raised by preclinical data demonstrating that IGF-1R antibodies may inadequately maintain in vivo IGF-1R down-regulation or suppression of PI3K-AKT signalling [ XREF_BIBR , XREF_BIBR ] .	The latter issue is raised by preclinical data demonstrating that IGF-1R antibodies may inadequately maintain in vivo IGF-1R down-regulation or suppression of PI3K-AKT signalling [XREF_BIBR, XREF_BIBR].	17	23	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	PI3K-AKT	PI3K-AKT	PI3K-AKT	17	18	22	23
To investigate whether the inhibition of IGF1R can induce the inactivation of PI3K and Akt signaling pathway in vivo , we examined the activity of key molecules of IGF1R/PI3K/Akt signaling pathway in tumor tissues via western blot analysis .	To investigate whether the inhibition of IGF1R can induce the inactivation of PI3K and Akt signaling pathway in vivo, we examined the activity of key molecules of IGF1R/PI3K/Akt signaling pathway in tumor tissues via western blot analysis.	4	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF1R	IGF1R	Akt	Akt	Akt	6	7	14	15
Phosphorylation of IRS-1 ( Ser312 ) by P-mTOR promotes conformational changes and subsequent detachment from the receptor and degradation [ XREF_BIBR ] , and inhibits potentiation of Akt by IGF-1R and IRS-1 signaling [ XREF_BIBR ] .	Phosphorylation of IRS-1 (Ser312) by P-mTOR promotes conformational changes and subsequent detachment from the receptor and degradation [XREF_BIBR], and inhibits potentiation of Akt by IGF-1R and IRS-1 signaling [XREF_BIBR].	25	34	potentiation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	29	30	27	28
XREF_BIBR Along these lines , blockade of IGF-1 and its receptor , IGF-1R , enhanced the antiproliferative effect of rapamycin , and , therefore , blocking IGF-1R appears to prevent mTOR inhibitor induced feedback activation of PI3K and Akt and sensitizes tumor cell lines ( including breast cancer ) to the antiproliferative effects of mTOR inhibitors .	XREF_BIBR Along these lines, blockade of IGF-1 and its receptor, IGF-1R, enhanced the antiproliferative effect of rapamycin, and, therefore, blocking IGF-1R appears to prevent mTOR inhibitor induced feedback activation of PI3K and Akt and sensitizes tumor cell lines (including breast cancer) to the antiproliferative effects of mTOR inhibitors.	5	39	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	12	13	38	39
Thus , the combination of MEK and IGF1R therapy robustly inhibits MEK and ERK , PI3K and AKT , and mTORC1 ( XREF_FIG ) .	Thus, the combination of MEK and IGF1R therapy robustly inhibits MEK and ERK, PI3K and AKT, and mTORC1 (XREF_FIG).	5	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	7	8	17	18
Downregulation of IGF-1R inhibited the activity of Akt and suppressed cellular growth and metabolism .	Downregulation of IGF-1R inhibited the activity of Akt and suppressed cellular growth and metabolism.	0	8	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	2	3	7	8
Reduction in IGF-1R levels causes activation of the AKT and CREB pathway and inhibition of the ERK and ELK -1 pathway , which results in higher levels of SMN .	Reduction in IGF-1R levels causes activation of the AKT and CREB pathway and inhibition of the ERK and ELK -1 pathway, which results in higher levels of SMN.	2	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R levels	igf-1r	AKT	AKT	akt	2	3	8	9
KNOCKDOWN OF IGF1R ENHANCES THE INHIBITION EFFICACY OF SORAFENIB ON HCC CELL GROWTH BY INHIBITING AKT .	KNOCKDOWN OF IGF1R ENHANCES THE INHIBITION EFFICACY OF SORAFENIB ON HCC CELL GROWTH BY INHIBITING AKT.	0	16	ENHANCES	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF1R	IGF1R	AKT	AKT	AKT	2	3	15	16
In addition , they demonstrated that miR-7-mediated downregulation of IGF-1R attenuated the IGF-1-induced activation of AKT and led to reduced cell proliferation and cell cycle arrest , and to an increase in apoptosis rate .	In addition, they demonstrated that miR-7-mediated downregulation of IGF-1R attenuated the IGF-1-induced activation of AKT and led to reduced cell proliferation and cell cycle arrest, and to an increase in apoptosis rate.	7	16	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	9	10	15	16
In early experiments conducted on the effects of ethanol on IGF-IR signaling , the presence of ethanol was shown to inhibit IGF-I-induced auto-phosphorylation of the IGF-IR , attenuate tyrosine phosphorylation of insulin-receptor substrate I ( IRS-I ) , and reduce the phosphorylation dependent activation of downstream kinases , Akt and ERKs1/2 .	In early experiments conducted on the effects of ethanol on IGF-IR signaling, the presence of ethanol was shown to inhibit IGF-I-induced auto-phosphorylation of the IGF-IR, attenuate tyrosine phosphorylation of insulin-receptor substrate I (IRS-I), and reduce the phosphorylation dependent activation of downstream kinases, Akt and ERKs1/2.	16	49	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-IR	ethanol was shown to inhibit IGF-I-induced auto-phosphorylation of the IGF-IR	igf-ir	Akt	Akt	akt	25	26	48	49
In this article , we report that inhibition of the IGF-1R pathway by cixutumumab ( IMC-A12 ) , a fully humanized IgG1 mAb , results in stimulation of the Akt and mammalian target of rapamycin ( mTOR ) pathway through increasing synthesis of EGFR , Akt1 , and antiapoptotic survivin proteins .	In this article, we report that inhibition of the IGF-1R pathway by cixutumumab (IMC-A12), a fully humanized IgG1 mAb, results in stimulation of the Akt and mammalian target of rapamycin (mTOR) pathway through increasing synthesis of EGFR, Akt1, and antiapoptotic survivin proteins.	10	30	results in stimulation	Positive_activation_syntax_8_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	10	11	29	30
Knockdown of InsR and IGF-1R inhibits hormone independent growth and PI3K and AKT .	Knockdown of InsR and IGF-1R inhibits hormone independent growth and PI3K and AKT.	0	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	4	5	12	13
The most likely scenario is that IGF-1R inhibition blocks AKT dependent degradation of p27 , and stabilized p27 then mediates cytoprotective arrest or delay in G1-phase .	The most likely scenario is that IGF-1R inhibition blocks AKT dependent degradation of p27, and stabilized p27 then mediates cytoprotective arrest or delay in G1-phase.	6	11	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	6	7	9	10
Either loss of PTEN alone ( KPTEN alveolar cells ) or high expression levels of ENTPD5 and IGF1R ( Kp53 and wild-type bronchiolar tumors ) are not sufficient to drive high Akt activation .	Either loss of PTEN alone (KPTEN alveolar cells) or high expression levels of ENTPD5 and IGF1R (Kp53 and wild-type bronchiolar tumors) are not sufficient to drive high Akt activation.	13	32	drive	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	levels of ENTPD5 and IGF1R	igf1r	Akt	Akt	akt	17	18	31	32
Recent studies showed that miR-497 targeted IGF-1R to inhibit proliferation , invasion and metastasis by regulating PI3K and AKT signaling pathway activation in colorectal cancer [ XREF_BIBR ] and to function as an oncogene in cervical cancer [ XREF_BIBR ] .	Recent studies showed that miR-497 targeted IGF-1R to inhibit proliferation, invasion and metastasis by regulating PI3K and AKT signaling pathway activation in colorectal cancer [XREF_BIBR] and to function as an oncogene in cervical cancer [XREF_BIBR].	6	30	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	6	7	18	19
Although EGFR inhibitors do not decrease activation of AKT following MEK suppression , both IGF-1R and ILK inhibitors significantly suppress feedback activation of AKT .	Although EGFR inhibitors do not decrease activation of AKT following MEK suppression, both IGF-1R and ILK inhibitors significantly suppress feedback activation of AKT.	13	24	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	14	15	23	24
These data suggest that inhibition of InsR and IGF-1R with OSI-906 prevents the emergence of hormone independent tumors and inhibits growth of established xenografts at least in part by inhibiting PI3K and AKT .	These data suggest that inhibition of InsR and IGF-1R with OSI-906 prevents the emergence of hormone independent tumors and inhibits growth of established xenografts at least in part by inhibiting PI3K and AKT.	4	33	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	8	9	32	33
Upon being combined with corresponding ligands , IGF-1R inactivates the BAD protein , a member of the bcl family , by activating the PI3K and Akt or Ras/Raf-1/MAPK family to avoid apoptosis .	Upon being combined with corresponding ligands, IGF-1R inactivates the BAD protein, a member of the bcl family, by activating the PI3K and Akt or Ras/Raf-1/MAPK family to avoid apoptosis.	7	26	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	Akt	Akt	Akt	7	8	25	26
The most likely scenario is that IGF-1R inhibition blocks AKT dependent degradation of p27 , and stabilized p27 then mediates cytoprotective arrest or delay in G1-phase that allows DNA repair and survival ( XREF_FIG ) .	The most likely scenario is that IGF-1R inhibition blocks AKT dependent degradation of p27, and stabilized p27 then mediates cytoprotective arrest or delay in G1-phase that allows DNA repair and survival (XREF_FIG).	6	11	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	AKT	AKT	AKT	6	7	9	10
Furthermore , as the expression of ERbeta gradually increased with calycosin , the levels of IGF-1R in calycosin treated MCF-7 and T-47D cells were observed to decrease in a dose dependent manner , indicating the regulation of IGF-1R by calycosin through activation of ERbeta .	Furthermore, as the expression of ERbeta gradually increased with calycosin, the levels of IGF-1R in calycosin treated MCF-7 and T-47D cells were observed to decrease in a dose dependent manner, indicating the regulation of IGF-1R by calycosin through activation of ERbeta.	13	38	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	levels of IGF-1R	igf-1r	IGF-1R	IGF-1R	igf-1r	15	16	37	38
EM164 , a full antagonistic anti-IGF1R antibody , did not stimulate IGF1R autophosphorylation , but downregulated IGF1R in vitro and in vivo .	EM164, a full antagonistic anti-IGF1R antibody, did not stimulate IGF1R autophosphorylation, but downregulated IGF1R in vitro and in vivo.	0	19	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	EM164, a full antagonistic anti-IGF1R antibody, did not stimulate IGF1R autophosphorylation	igf1r	IGF1R	IGF1R	igf1r	11	12	16	17
In vitro , IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1 % +/- 6.0 % and by liposomal magnetofection by 85.1 % +/- 3.0 % .	In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1% +/- 6.0% and by liposomal magnetofection by 85.1% +/- 3.0%.	3	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	IGF-1R protein	IGF-1R protein	IGF-1R protein	3	4	9	11
Aberrant IGF-1R glycosylation is reported to impair insertion of IGF-1R into the plasma membrane , conferring resistance to IGF-1R antibody [ XREF_BIBR ] , consistent with a model in which only receptors on the plasma membrane are accessible to antibody binding .	Aberrant IGF-1R glycosylation is reported to impair insertion of IGF-1R into the plasma membrane, conferring resistance to IGF-1R antibody [XREF_BIBR], consistent with a model in which only receptors on the plasma membrane are accessible to antibody binding.	1	10	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R glycosylation	igf-1r	IGF-1R	IGF-1R	igf-1r	1	2	9	10
Overexpression of beta-arrestin1 by plasmid transfection enhanced the CP induced IGF-1R degradation and down-regulation of beta-arrestin1 by siRNA transfection partially reversed the IGF-1R degradation ( XREF_FIG ) .	Overexpression of beta-arrestin1 by plasmid transfection enhanced the CP induced IGF-1R degradation and down-regulation of beta-arrestin1 by siRNA transfection partially reversed the IGF-1R degradation (XREF_FIG).	0	23	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	Overexpression of beta-arrestin1 by plasmid transfection enhanced the CP induced IGF-1R	igf-1r	IGF-1R	IGF-1R	igf-1r	10	11	22	23
Notably , the normalization of IGF1R and IRAIN transcription inhibited the IGF1R signaling pathway in breast cancer cells , decreasing cell proliferation , tumor sphere formation , migration , and invasion .	Notably, the normalization of IGF1R and IRAIN transcription inhibited the IGF1R signaling pathway in breast cancer cells, decreasing cell proliferation, tumor sphere formation, migration, and invasion.	5	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF1R and IRAIN transcription	igf1r	IGF1R	IGF1R	igf1r	5	6	11	12
We demonstrate here that IGF mediated IGF1R stimulation enhances EN tyrosine phosphorylation and that blocking IGF1R activity or decreasing protein levels of the adaptor protein insulin receptor substrate 1/2 ( IRS1/2 ) results in rapid EN degradation .	We demonstrate here that IGF mediated IGF1R stimulation enhances EN tyrosine phosphorylation and that blocking IGF1R activity or decreasing protein levels of the adaptor protein insulin receptor substrate 1/2 (IRS1/2) results in rapid EN degradation.	4	16	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF mediated IGF1R	igf1r	IGF1R	IGF1R	igf1r	6	7	15	16
In one report , it was demonstrated that GRKs phosphorylate IGF-IR , which recruits beta-arrestin and subsequently modulates downstream ERK and AKT mediated signaling as well as IGF-IR degradation .	In one report, it was demonstrated that GRKs phosphorylate IGF-IR, which recruits beta-arrestin and subsequently modulates downstream ERK and AKT mediated signaling as well as IGF-IR degradation.	8	28	modulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-IR	GRKs phosphorylate IGF-IR	igf-ir	IGF-IR	IGF-IR	igf-ir	10	11	27	28
Relative expression of IGF1R mRNA decreased approximately 50 % and Western blot analysis revealed a 30 % of reduction in IGF-1R protein .	Relative expression of IGF1R mRNA decreased approximately 50% and Western blot analysis revealed a 30% of reduction in IGF-1R protein.	3	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1R	IGF1R	IGF1R	IGF-1R protein	IGF-1R protein	IGF-1R protein	3	4	20	22
In vitro , IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1 +/-6% and by liposomal magnetofection by 85.1 +/-3% .	In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1 +/-6% and by liposomal magnetofection by 85.1 +/-3%.	3	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1R	IGF-1R	IGF-1R	IGF-1R protein	IGF-1R protein	IGF-1R protein	3	4	9	11
The protective effect of IFNbeta in ischemic stroke is mediated through type I IFN receptor because IFNbeta failed to reduce infarct volume in Ifnar1 -/- MCAO/R mice compared with vehicle treated controls .	The protective effect of IFNbeta in ischemic stroke is mediated through type I IFN receptor because IFNbeta failed to reduce infarct volume in Ifnar1 -/- MCAO/R mice compared with vehicle treated controls.	16	26	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IFNbeta	IFNbeta	IFNbeta	Ifnar1	Ifnar1	Ifnar1	16	17	23	24
Thus , to determine how IFNs affect T reg proliferation in this setting , we cultured WT or Ifnar1 -/- T reg cells with WT APCs in the presence or absence of IFN-beta for 72 h. Interestingly , IFN-beta inhibited the proliferation of WT T reg cells but not Ifnar1 -/- T reg cells to the same extent whether in the presence of WT or Ifnar1 -/- APCs , suggesting that inhibition was due to a direct effect of IFN-beta on T reg cells and not due to an indirect effect on APCs ( XREF_FIG ) .	Thus, to determine how IFNs affect T reg proliferation in this setting, we cultured WT or Ifnar1 -/- T reg cells with WT APCs in the presence or absence of IFN-beta for 72 h. Interestingly, IFN-beta inhibited the proliferation of WT T reg cells but not Ifnar1 -/- T reg cells to the same extent whether in the presence of WT or Ifnar1 -/- APCs, suggesting that inhibition was due to a direct effect of IFN-beta on T reg cells and not due to an indirect effect on APCs (XREF_FIG).	38	53	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IFN-beta	IFN-beta	IFN-beta	Ifnar1	Ifnar1	Ifnar1	38	39	49	50
Significantly , IFNbeta levels were decreased in IFNAR1 KD cells at 2 h ( 4.5-fold vs. 1.3-fold ) and 4 h ( 3.7-fold vs. 1.4-fold ) in comparison to NC shRNA cells .	Significantly, IFNbeta levels were decreased in IFNAR1 KD cells at 2 h (4.5-fold vs. 1.3-fold) and 4 h (3.7-fold vs. 1.4-fold) in comparison to NC shRNA cells.	2	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IFNbeta	IFNbeta levels	ifnbeta	IFNAR1	IFNAR1	ifnar1	2	3	7	8
However , increasing concentrations of IFN-beta substantially reduced the proliferation of WT but not Ifnar1 -/- T reg cells ( XREF_FIG and not depicted ) .	However, increasing concentrations of IFN-beta substantially reduced the proliferation of WT but not Ifnar1 -/- T reg cells (XREF_FIG and not depicted).	3	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IFN-beta	IFN-beta	IFN-beta	Ifnar1	Ifnar1	Ifnar1	5	6	14	15
For example , IFNbeta induced IFNAR signaling inhibits reactive oxygen species production and inflammasome activation [ XREF_BIBR ] .	For example, IFNbeta induced IFNAR signaling inhibits reactive oxygen species production and inflammasome activation [XREF_BIBR].	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	IFNbeta	IFNbeta	IFNbeta	IFNAR	IFNAR	IFNAR	3	4	5	6
More recently , we reported that a tumor with decreased expression of IFN alpha receptors ( IFNAR ) could be effectively treated with antibody linked to IFNbeta , which has a higher affinity for the IFNAR [ XREF_BIBR ] .	More recently, we reported that a tumor with decreased expression of IFN alpha receptors (IFNAR) could be effectively treated with antibody linked to IFNbeta, which has a higher affinity for the IFNAR [XREF_BIBR].	14	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IFNbeta	IFNbeta	IFNbeta	IFNAR	IFNAR	IFNAR	26	27	16	17
Low-oxygen tension maintained higher levels of IGF-I receptor and insulin receptor substrate 1 that were otherwise decreased by exposure to IGF-I and induced a differential phosphorylation pattern on IGF-I receptorbeta and insulin receptor substrate 1 .	Low-oxygen tension maintained higher levels of IGF-I receptor and insulin receptor substrate 1 that were otherwise decreased by exposure to IGF-I and induced a differential phosphorylation pattern on IGF-I receptorbeta and insulin receptor substrate 1.	4	35	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-I receptor	levels of IGF-I receptor	igf-i receptor	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	6	8	31	35
Here , we report that AFB1 stimulates IGF-IR phosphorylation , down-regulates IRS1 , but up-regulates IRS2 expression , which contributes to AFB1 induced hepatoma cell migration .	Here, we report that AFB1 stimulates IGF-IR phosphorylation, down-regulates IRS1, but up-regulates IRS2 expression, which contributes to AFB1 induced hepatoma cell migration.	5	12	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-IR	AFB1 stimulates IGF-IR phosphorylation	igf-ir	IRS1	IRS1	irs1	7	8	11	12
Since AFB1 induces IGF-IR phosphorylation , up-regulates IRS2 , but down-regulates IRS1 , it is unclear how AFB1 may affect hepatoma cell proliferation .	Since AFB1 induces IGF-IR phosphorylation, up-regulates IRS2, but down-regulates IRS1, it is unclear how AFB1 may affect hepatoma cell proliferation.	1	12	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-IR	AFB1 induces IGF-IR phosphorylation	igf-ir	IRS1	IRS1	irs1	3	4	11	12
Blockade of IGF-1R signalling by specific inhibitors can decrease tumour growth in a xenograft mouse model by disrupting the association of IRS-1 with PI3K and downregulating PI3K and AKT signalling .	Blockade of IGF-1R signalling by specific inhibitors can decrease tumour growth in a xenograft mouse model by disrupting the association of IRS-1 with PI3K and downregulating PI3K and AKT signalling.	2	22	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-1R	IGF-1R	IGF-1R	IRS-1	IRS-1	IRS-1	2	3	21	22
This early production of IFNgamma by induced Treg cells during an immune response can directly inhibit the activation and proliferation of IFNgammaR1- and IFNgammaR2 bearing T cells .	This early production of IFNgamma by induced Treg cells during an immune response can directly inhibit the activation and proliferation of IFNgammaR1- and IFNgammaR2 bearing T cells.	2	26	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IFNgamma	IFNgamma	IFNgamma	IFNgammaR1-	IFNgammaR1-	IFNgammaR1-	4	5	21	22
Notably , inhibiting GSK-3 decreased Con A induced IFN-gamma production in both wild-type and IFN-gamma receptor 1 deficient C57BL/6 mice .	Notably, inhibiting GSK-3 decreased Con A induced IFN-gamma production in both wild-type and IFN-gamma receptor 1 deficient C57BL/6 mice.	3	17	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	IFN-gamma	GSK-3 decreased Con A induced IFN-gamma	ifn-gamma	IFN-gamma receptor 1	IFN-gamma receptor 1	ifn-gamma receptor 1	8	9	14	17
IFN-gamma decreased the FRET efficiency between IFN-gammaR1 and CiFP and either IFN-gammaR2 and StFP or IFN-gammaR2/alphaR2b/TFP to no more than 35 % and 20 % respectively ( XREF_FIG , open circles ) , but only when all three chains were present ( data not shown ) .	IFN-gamma decreased the FRET efficiency between IFN-gammaR1 and CiFP and either IFN-gammaR2 and StFP or IFN-gammaR2/alphaR2b/TFP to no more than 35% and 20% respectively (XREF_FIG, open circles), but only when all three chains were present (data not shown).	0	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IFN-gamma	IFN-gamma	IFN-gamma	IFN-gammaR2	IFN-gammaR2	IFN-gammaR2	0	1	11	12
In agreement with the floatation studies , IFNgamma activation could elicit a partial increase in the colocalization efficiency at the early hours of LD infection ( 62.5 % ) , though absence of the same at late hours of infection denotes a conspicuous block in the IFNgamma triggered translocational behavior of IFNgammaR2 .	In agreement with the floatation studies, IFNgamma activation could elicit a partial increase in the colocalization efficiency at the early hours of LD infection (62.5%), though absence of the same at late hours of infection denotes a conspicuous block in the IFNgamma triggered translocational behavior of IFNgammaR2.	43	52	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IFNgamma	IFNgamma	IFNgamma	IFNgammaR2	IFNgammaR2	IFNgammaR2	46	47	51	52
XREF_BIBR Findings from a recent independent study supported this mechanism and further showed that the putative oncogene inhibitor of differentiation-1 induced Akt activation by promoting the binding activity of cav-1 and PP-2A .	XREF_BIBR Findings from a recent independent study supported this mechanism and further showed that the putative oncogene inhibitor of differentiation-1 induced Akt activation by promoting the binding activity of cav-1 and PP-2A.	14	22	induced	Positive_early_activation	Positive_activation	Positive_activation	inhibitor of differentiation-1	inhibitor of differentiation-1	inhibitor of differentiation-1	Akt	Akt	Akt	17	20	21	22
In addition , we demonstrated the induction of ICAM-1 and VCAM-1 expression in afferent lymphatic vessels draining the skin of oxazolone treated mice in vivo and presented evidence that administration of ICAM-1- and VCAM-1-neutralizing antibodies blocked exit of CD11c positive skin DCs via afferent lymphatics .	In addition, we demonstrated the induction of ICAM-1 and VCAM-1 expression in afferent lymphatic vessels draining the skin of oxazolone treated mice in vivo and presented evidence that administration of ICAM-1- and VCAM-1-neutralizing antibodies blocked exit of CD11c positive skin DCs via afferent lymphatics.	31	41	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ICAM-1-	ICAM-1-	ICAM-1-	CD11c	CD11c	CD11c	31	32	38	39
Knockdown of IGF1R sensitizes HCC cells to sorafenib treatment and decreases protein kinase B ( AKT ) activation .	Knockdown of IGF1R sensitizes HCC cells to sorafenib treatment and decreases protein kinase B (AKT) activation.	0	14	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1R	IGF1R	IGF1R	protein kinase B	protein kinase B	protein kinase B	2	3	11	14
Increased IFNAR2 downregulation by the higher affinity IFNbeta , compared to IFNalpha2 , has been previously suggested to be responsible for differential cellular responses .	Increased IFNAR2 downregulation by the higher affinity IFNbeta, compared to IFNalpha2, has been previously suggested to be responsible for differential cellular responses.	1	11	downregulation	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	IFNbeta	IFNbeta	IFNbeta	IFNAR2	IFNAR2	IFNAR2	7	8	1	2
Infusion of equimolar concentrations of IGF-I did not affect IGF-I mRNA , but decreased the level of IGF-I receptor mRNA in skeletal muscle .	Infusion of equimolar concentrations of IGF-I did not affect IGF-I mRNA, but decreased the level of IGF-I receptor mRNA in skeletal muscle.	3	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	5	6	17	19
As shown in XREF_FIG , IGF-1 could induce obvious IGF-1R ubiquitination at 10min compared with control ( only serum free , no stimulation ) , indicating IGF-1 down-regulates the IGF-1R by increasing the receptor degradation dependent on ubiquitination .	As shown in XREF_FIG, IGF-1 could induce obvious IGF-1R ubiquitination at 10min compared with control (only serum free, no stimulation), indicating IGF-1 down-regulates the IGF-1R by increasing the receptor degradation dependent on ubiquitination.	26	30	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	26	27	29	30
We considered whether elevated insulin could be linked to the reduced IGF1R mRNA in cases , since elevated insulin is known to down-regulate IGFBP1 resulting in higher levels of free circulating IGF1 that can down-regulate IGF1R .	We considered whether elevated insulin could be linked to the reduced IGF1R mRNA in cases, since elevated insulin is known to down-regulate IGFBP1 resulting in higher levels of free circulating IGF1 that can down-regulate IGF1R.	30	36	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	31	32	35	36
IGF-I Inhibition of IGFI receptor signaling can enhance rodent lifespan , although these effects are sex and background dependent .	IGF-I Inhibition of IGFI receptor signaling can enhance rodent lifespan, although these effects are sex and background dependent.	0	5	Inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGFI receptor	IGFI receptor	IGFI receptor	0	1	3	5
IGF1 decoy is expected to inhibit IGF1R signaling in CSCs , and suppress stemness or the number of CSCs .	IGF1 decoy is expected to inhibit IGF1R signaling in CSCs, and suppress stemness or the number of CSCs.	0	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	0	1	6	7
The response to GH could not be abolished by the IGF-I receptor blocker IGF-I analogue indicating an IGF-I-independent action of GH .	The response to GH could not be abolished by the IGF-I receptor blocker IGF-I analogue indicating an IGF-I-independent action of GH.	10	14	blocker	Negative_activation_token_1_noun	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	13	14	10	12
Keratinocyte specific overexpression of IGF-1 in mouse epidermis promotes keratinocyte proliferation , migration , and wound re-epithelialization , and epidermis specific IGF1R knockout limits epidermal stratification in morphogenesis .	Keratinocyte specific overexpression of IGF-1 in mouse epidermis promotes keratinocyte proliferation, migration, and wound re-epithelialization, and epidermis specific IGF1R knockout limits epidermal stratification in morphogenesis.	2	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1	overexpression of IGF-1	igf-1	IGF1R	IGF1R	igf1r	4	5	21	22
Increased serum IGF-1 levels in patients with acromegaly may downregulate IGF-1Rbeta ; however , the autocrine and paracrine effects of IGF-1 can be induced by local expression of IGF-1Rbeta in tumor tissue .	Increased serum IGF-1 levels in patients with acromegaly may downregulate IGF-1Rbeta; however, the autocrine and paracrine effects of IGF-1 can be induced by local expression of IGF-1Rbeta in tumor tissue.	2	11	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1	IGF-1 levels	igf-1	IGF-1Rbeta	IGF-1Rbeta	igf-1rbeta	2	3	10	11
Accordingly , attenuation of IGF1 induced activation of the IGF1R and AKT pathway could be a mechanism of CRM1 inhibition for targeting ES [ XREF_BIBR ] .	Accordingly, attenuation of IGF1 induced activation of the IGF1R and AKT pathway could be a mechanism of CRM1 inhibition for targeting ES [XREF_BIBR].	2	12	induced	Positive_early_activation	Positive_activation	Negative_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	4	5	9	10
If endogenous IRS-1 inhibits IGF-IR internalization , knockdown of IRS-1 would accelerate the process of active IGF-IR reduction triggered by long-term IGF-I stimulation .	If endogenous IRS-1 inhibits IGF-IR internalization, knockdown of IRS-1 would accelerate the process of active IGF-IR reduction triggered by long-term IGF-I stimulation.	16	22	triggered	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	21	22	16	17
TNF induced cytotoxicity of 3T3 cells that overexpress the human IGF-I receptor ( p6 cells ) was prevented by IGF-I alone in the absence of serum .	TNF induced cytotoxicity of 3T3 cells that overexpress the human IGF-I receptor (p6 cells) was prevented by IGF-I alone in the absence of serum.	10	20	prevented	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	19	20	10	12
In low oxygen tension , the IGF-1R was increased in differentiation conditions but reduced by both IGF-1 and IGF-2 ( XREF_FIG , right ) , whereas no change in IR was observed in differentiation conditions ( XREF_FIG ) .	In low oxygen tension, the IGF-1R was increased in differentiation conditions but reduced by both IGF-1 and IGF-2 (XREF_FIG, right), whereas no change in IR was observed in differentiation conditions (XREF_FIG).	5	18	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	16	17	6	7
We used small interfering RNA ( siRNA ) technology to specifically down-regulate IGF1R by 60 % to 80 % in the MDA-435 and LCC6 cell line , which was sufficient to diminish activation of IGF1R by IGF-I .	We used small interfering RNA (siRNA) technology to specifically down-regulate IGF1R by 60% to 80% in the MDA-435 and LCC6 cell line, which was sufficient to diminish activation of IGF1R by IGF-I.	31	37	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF1R	IGF1R	IGF1R	36	37	34	35
In a previous report , when HtrA1 far exceeds IGF-1 levels in cell-free solution , we co-immunoprecipitated IGF-1 with purified , full-length or affinity tagged Mac25/KI fragments of HtrA1 , and pre-incubation of IGF-1 with HtrA1 prevented ligand mediated IGF1R activation in cultured endothelial cells .	In a previous report, when HtrA1 far exceeds IGF-1 levels in cell-free solution, we co-immunoprecipitated IGF-1 with purified, full-length or affinity tagged Mac25/KI fragments of HtrA1, and pre-incubation of IGF-1 with HtrA1 prevented ligand mediated IGF1R activation in cultured endothelial cells.	31	40	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1	IGF-1	IGF-1	IGF1R	IGF1R	IGF1R	33	34	39	40
Compared to untreated cells , c9 , t11 or t10 , c12 CLA significantly reduced the metabolic activity of IGF-I stimulated MCF-7 cells , increased lactate dehydrogenase ( LDH ) release , and decreased cellular concentrations of the IGF-I receptor ( IGF-IR ) and insulin receptor substrate-1 ( p < 0.05 ) .	Compared to untreated cells, c9, t11 or t10, c12 CLA significantly reduced the metabolic activity of IGF-I stimulated MCF-7 cells, increased lactate dehydrogenase (LDH) release, and decreased cellular concentrations of the IGF-I receptor (IGF-IR) and insulin receptor substrate-1 (p < 0.05).	17	40	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	19	20	38	40
Recombinant IGF1 rescued inhibition of the IGF1R and AKT pathway by JQ1 .	Recombinant IGF1 rescued inhibition of the IGF1R and AKT pathway by JQ1.	0	9	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF1	IGF1	IGF1	IGF1R	IGF1R	IGF1R	1	2	6	7
There was a significant decrease in the IGF-IR expression after the cells were treated with lycopene and IGF-I .	There was a significant decrease in the IGF-IR expression after the cells were treated with lycopene and IGF-I.	7	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	17	18	7	8
In the presence of IGF-1R shRNA knockdown , IGF-1 no longer activated pAKT ( XREF_FIG ) , and the extent of IGF-1R knockdown correlated with pAKT expression .	In the presence of IGF-1R shRNA knockdown, IGF-1 no longer activated pAKT (XREF_FIG), and the extent of IGF-1R knockdown correlated with pAKT expression.	8	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	8	9	21	22
IGF-I increased levels of IGF-I mRNA in heart muscle , and markedly decreased levels of IGF-I receptor mRNA in skeletal muscle and heart muscle from non diabetic and diabetic rats .	IGF-I increased levels of IGF-I mRNA in heart muscle, and markedly decreased levels of IGF-I receptor mRNA in skeletal muscle and heart muscle from non diabetic and diabetic rats.	0	17	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	0	1	15	17
Both IGF-1 and sunitinib could obviously induce the IGF-1R ubiquitination at 10min compared with control ( only serum free , no stimulation ) , indicating IGF-1 and sunitinib down-regulate the IGF-1R by increasing the receptor degradation through ubiquitination dependent proteasome pathway .	Both IGF-1 and sunitinib could obviously induce the IGF-1R ubiquitination at 10min compared with control (only serum free, no stimulation), indicating IGF-1 and sunitinib down-regulate the IGF-1R by increasing the receptor degradation through ubiquitination dependent proteasome pathway.	25	31	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	25	26	30	31
Thus , IGF-I signaling and miR-133b co-regulate potential neural differentiation of ADSC through a feedback mechanism , in which IGF-I upregulates miR-133b while miR-133b in turn downregulates IGF-IR .	Thus, IGF-I signaling and miR-133b co-regulate potential neural differentiation of ADSC through a feedback mechanism, in which IGF-I upregulates miR-133b while miR-133b in turn downregulates IGF-IR.	2	28	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	2	3	27	28
Thus , IGF-I down-regulated functional IGF-I receptor via GSK-3beta inhibition and mTOR activation ; constitutive activity of GSK-3beta maintained IGF-I receptor level in nonstimulated cells .	Thus, IGF-I down-regulated functional IGF-I receptor via GSK-3beta inhibition and mTOR activation; constitutive activity of GSK-3beta maintained IGF-I receptor level in nonstimulated cells.	2	7	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	2	3	5	7
To further investigate the relationship between miR-99a and IGF-1R , we assessed miR-99a expression in serum starved PHK cells treated with increasing concentrations of IGF1 .	To further investigate the relationship between miR-99a and IGF-1R, we assessed miR-99a expression in serum starved PHK cells treated with increasing concentrations of IGF1.	4	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IGF1	IGF1	IGF1	IGF-1R	IGF-1R	IGF-1R	24	25	8	9
High levels of IGFBPs sequester large amounts of IGF1 , effectively reducing the level of IGF1 and actually enhance the impact of IGF1R blocking antibody relative to low IGFBP conditions .	High levels of IGFBPs sequester large amounts of IGF1, effectively reducing the level of IGF1 and actually enhance the impact of IGF1R blocking antibody relative to low IGFBP conditions.	1	23	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF1	levels of IGFBPs sequester large amounts of IGF1	igf1	IGF1R	IGF1R	igf1r	8	9	22	23
We tested a fully human anti-IGF-IR antibody ( A12 ) against MM , and showed specific inhibition of IGF-I or serum induced IGF-IR signaling in MM cells in vitro .	We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum induced IGF-IR signaling in MM cells in vitro.	16	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	18	19	22	23
Both studies reported a reduction in the phosphorylation of the canonical ATR substrate CHK1 after UVB exposure when the IGF-1R was inactivated by either IGF-1 withdrawal or pharmacological inhibition .	Both studies reported a reduction in the phosphorylation of the canonical ATR substrate CHK1 after UVB exposure when the IGF-1R was inactivated by either IGF-1 withdrawal or pharmacological inhibition.	18	25	inactivated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	24	25	19	20
SB216763 ( an inhibitor of glycogen synthase kinase-3 [ GSK-3 ] ) down-regulated IGF-I receptor , which was further decreased by IGF-I .	SB216763 (an inhibitor of glycogen synthase kinase-3 [GSK-3]) down-regulated IGF-I receptor, which was further decreased by IGF-I.	13	22	decreased	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	21	22	13	15
In contrast , glycosylation of pro-IGF-I appears to impair IGF-IR activation .	In contrast, glycosylation of pro-IGF-I appears to impair IGF-IR activation.	3	10	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	pro-IGF-I	glycosylation of pro-IGF-I	pro-igf-i	IGF-IR	IGF-IR	igf-ir	5	6	9	10
A possible explanation could be that the chronic increase of IGF-1 by peripheral treatment might down-regulate IGF-1R signalling .	A possible explanation could be that the chronic increase of IGF-1 by peripheral treatment might down-regulate IGF-1R signalling.	8	17	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	10	11	16	17
Pretreatment of the cells with EGF , concomitantly with IGF-I , had no effect on [ 125I ]-IGF-I binding but it augmented the IGF-I down-regulation of IGF-I receptor .	Pretreatment of the cells with EGF, concomitantly with IGF-I, had no effect on [125I]-IGF-I binding but it augmented the IGF-I down-regulation of IGF-I receptor.	23	28	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	23	24	26	28
The upregulation of PLCbeta3 by IGF-I was abolished by preincubation of cardiomyocytes with the IGF-I receptor antagonist IGF-I analogue , the tyrosine kinase inhibitor genistein , the extracellular signal related kinase ( ERK ) inhibitor PD 98059 , the phosphatidylinositol-3- ( PI-3 ) kinase inhibitor wortmannin and the p70 S6 kinase inhibitor rapamycin .	The upregulation of PLCbeta3 by IGF-I was abolished by preincubation of cardiomyocytes with the IGF-I receptor antagonist IGF-I analogue, the tyrosine kinase inhibitor genistein, the extracellular signal related kinase (ERK) inhibitor PD 98059, the phosphatidylinositol-3- (PI-3) kinase inhibitor wortmannin and the p70 S6 kinase inhibitor rapamycin.	14	18	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	17	18	14	16
IGF-I inhibition of GH secretion is enhanced 3-5-fold in GC rat pituitary cells overexpressing the wild type 950Tyr human IGF-I receptor which autophosphorylates appropriately .	IGF-I inhibition of GH secretion is enhanced 3-5-fold in GC rat pituitary cells overexpressing the wild type 950Tyr human IGF-I receptor which autophosphorylates appropriately.	0	23	enhanced	Positive_regulation_syntax_1_verb	Positive_activation	Negative_regulation	IGF-I	IGF-I	igf-i	IGF-I receptor	IGF-I receptor which autophosphorylates	igf-i receptor	0	1	19	21
Importantly , ectopically applied IGF-1 rescues shIGF1 induced reduction in IGF-1R activity and Pr .	Importantly, ectopically applied IGF-1 rescues shIGF1 induced reduction in IGF-1R activity and Pr.	4	11	rescues	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-1	IGF-1	IGF-1	IGF-1R	IGF-1R	IGF-1R	4	5	10	11
IGF-I down-regulates IGF-IR transcriptional activity as deduced from experiments in which the levels of pre-mRNA and mRNA were measured .	IGF-I down-regulates IGF-IR transcriptional activity as deduced from experiments in which the levels of pre-mRNA and mRNA were measured.	0	4	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-IR	IGF-IR	IGF-IR	0	1	2	3
This interaction lowers the threshold levels of IGF-I necessary to stimulate IGF-IR activation .	This interaction lowers the threshold levels of IGF-I necessary to stimulate IGF-IR activation.	5	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-I	levels of IGF-I	igf-i	IGF-IR	IGF-IR	igf-ir	7	8	11	12
In conclusion , exogenous IGF-I and insulin can increase IGF-I mRNA and decrease IGF-I receptor mRNA , indicating that both insulin and IGF-I can act as regulators of the IGF-I system in muscle in vivo .	In conclusion, exogenous IGF-I and insulin can increase IGF-I mRNA and decrease IGF-I receptor mRNA, indicating that both insulin and IGF-I can act as regulators of the IGF-I system in muscle in vivo.	3	15	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-I	IGF-I	IGF-I	IGF-I receptor	IGF-I receptor	IGF-I receptor	4	5	13	15
In both assays , incubation of IL-17A with HAP effectively blocks the binding of IL-17A to immobilized IL-17RA with similar sub-nM IC 50 ( XREF_TABLE ) .	In both assays, incubation of IL-17A with HAP effectively blocks the binding of IL-17A to immobilized IL-17RA with similar sub-nM IC 50 (XREF_TABLE).	4	18	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	6	7	17	18
Deficiency of IL-17A or IL-17RA significantly reduced the T cell content of Il17a -/- Apoe -/- and Il17ra -/- Apoe -/- aortic arches ( XREF_FIG ) .	Deficiency of IL-17A or IL-17RA significantly reduced the T cell content of Il17a -/- Apoe -/- and Il17ra -/- Apoe -/- aortic arches (XREF_FIG).	0	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-17A	IL-17A	IL-17A	Il17ra	Il17ra	Il17ra	2	3	17	18
Detailed knowledge of IL-17A biology in humans has led to the targeted development of immunotherapeutic monoclonal antibodies ( mabs ) to block IL-17A and the IL-17RA receptor for the treatment and control of psoriasis , multiple sclerosis and rheumatoid arthritis [ XREF_BIBR ] .	Detailed knowledge of IL-17A biology in humans has led to the targeted development of immunotherapeutic monoclonal antibodies (mabs) to block IL-17A and the IL-17RA receptor for the treatment and control of psoriasis, multiple sclerosis and rheumatoid arthritis [XREF_BIBR].	3	26	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	3	4	25	26
Of note , IL-17a antibody blockade of the IL-17a and IL-17Ra signaling pathway did not result in a concomitant increase of the serum IL-10 levels , and IL-17a mRNA expression was not detected in fetal brain at E14.5 , regardless of poly ( I : C ) injection .	Of note, IL-17a antibody blockade of the IL-17a and IL-17Ra signaling pathway did not result in a concomitant increase of the serum IL-10 levels, and IL-17a mRNA expression was not detected in fetal brain at E14.5, regardless of poly (I : C) injection.	3	12	blockade	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IL-17a	IL-17a	IL-17a	IL-17Ra	IL-17Ra	IL-17Ra	3	4	10	11
The monoclonal antibodies ixekizumab and secukinumab both target IL-17A , while brodalumab blocks the IL-17 receptor IL-17RA .	The monoclonal antibodies ixekizumab and secukinumab both target IL-17A, while brodalumab blocks the IL-17 receptor IL-17RA.	3	17	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-17A	IL-17A	IL-17A	IL-17RA	IL-17RA	IL-17RA	8	9	16	17
The data showed that ( 1 ) IL-17 is selectively up-regulated in astrocytes , 2 ) IL-17RA is localized and up-regulated in NR1-immunoreactive neurons , and 3 ) an IL-17 antibody at 2 microg and rat significantly increased PWL ( p < 0.05 ) and decreased p-NR1 and IL-17RA in CFA- and IL-17-injected rats compared to control .	The data showed that (1) IL-17 is selectively up-regulated in astrocytes, 2) IL-17RA is localized and up-regulated in NR1-immunoreactive neurons, and 3) an IL-17 antibody at 2 microg and rat significantly increased PWL (p < 0.05) and decreased p-NR1 and IL-17RA in CFA- and IL-17-injected rats compared to control.	29	49	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-17	IL-17	IL-17	IL-17RA	IL-17RA	IL-17RA	29	30	48	49
An IL-17 antibody attenuates inflammatory hyperalgesia and suppresses IL-17RA and P-NR1 .	An IL-17 antibody attenuates inflammatory hyperalgesia and suppresses IL-17RA and P-NR1.	1	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-17	IL-17	IL-17	IL-17RA	IL-17RA	IL-17RA	1	2	8	9
In parallel , coated but not soluble IL-17A inhibited both wildtype and Il17ra -/- T REG polarization ( XREF_SUPPLEMENTARY ) .	In parallel, coated but not soluble IL-17A inhibited both wildtype and Il17ra -/- T REG polarization (XREF_SUPPLEMENTARY).	3	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-17A	IL-17A	IL-17A	Il17ra	Il17ra	Il17ra	7	8	12	13
IGF-2 could decrease the inhibitory effect of IGF-1R targeting antibodies , suggesting that IGF-1R antibodies as single agents are probably not sufficient for complete tumor inhibition , calling for combination therapies .	IGF-2 could decrease the inhibitory effect of IGF-1R targeting antibodies, suggesting that IGF-1R antibodies as single agents are probably not sufficient for complete tumor inhibition, calling for combination therapies.	0	9	decrease	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IGF-1R	IGF-1R	IGF-1R	0	1	7	8
The addition of IGF-II to undifferentiated myoblasts resulted in downregulation of the IGF-I receptor which was associated with decreased IGF-I receptor biosynthesis and decreased IGF-I receptor mRNA abundance .	The addition of IGF-II to undifferentiated myoblasts resulted in downregulation of the IGF-I receptor which was associated with decreased IGF-I receptor biosynthesis and decreased IGF-I receptor mRNA abundance.	1	27	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-II	IGF-II	IGF-II	IGF-I receptor	IGF-I receptor	IGF-I receptor	3	4	24	26
Strategies to inhibit IGF-IR signaling in human cancers include : ( 1 ) monoclonal antibodies that directly block IGF-IR ; ( 2 ) monoclonal antibodies that function by neutralizing the circulating ligands IGF-I or IGF-II , which prevents IGF-IR from being activated ; and ( 3 ) small molecule inhibitors that antagonize the kinase activity of IGF-IR [ XREF_BIBR ] .	Strategies to inhibit IGF-IR signaling in human cancers include : (1) monoclonal antibodies that directly block IGF-IR; (2) monoclonal antibodies that function by neutralizing the circulating ligands IGF-I or IGF-II, which prevents IGF-IR from being activated; and (3) small molecule inhibitors that antagonize the kinase activity of IGF-IR [XREF_BIBR].	28	48	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-II	IGF-II	IGF-II	IGF-IR	IGF-IR	IGF-IR	34	35	38	39
Furthermore , inactivation of IGF-II in conditioned GEO culture medium by a neutralizing antibody diminished IGF-IR activation , indicating the presence of a functional IGF-II and IGF-IR autocrine loop in GEO cells .	Furthermore, inactivation of IGF-II in conditioned GEO culture medium by a neutralizing antibody diminished IGF-IR activation, indicating the presence of a functional IGF-II and IGF-IR autocrine loop in GEO cells.	2	16	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-II	IGF-II	IGF-II	IGF-IR	IGF-IR	IGF-IR	4	5	15	16
This antibody , m708.5 , potently inhibited both IGF1- and IGF2 induced phosphorylation of IGF1R as well as IGF2 induced phosphorylation of the IR , and less potently growth of MCF-7 cancer cell expressing IGF1R .	This antibody, m708.5, potently inhibited both IGF1- and IGF2 induced phosphorylation of IGF1R as well as IGF2 induced phosphorylation of the IR, and less potently growth of MCF-7 cancer cell expressing IGF1R.	8	18	induced	Positive_early_regulation	Positive_activation	Positive_regulation	IGF2	IGF2	igf2	IGF1R	phosphorylation of IGF1R	igf1r	10	11	14	15
In IGF-I receptor down-regulation studies , IGF-II pretreatment significantly decreased binding of IGF-I to the IGF-I receptor and decreased IGF-I receptor mRNA , whereas the IGF-II analog had only minimal effects .	In IGF-I receptor down-regulation studies, IGF-II pretreatment significantly decreased binding of IGF-I to the IGF-I receptor and decreased IGF-I receptor mRNA, whereas the IGF-II analog had only minimal effects.	6	21	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-II	IGF-II	IGF-II	IGF-I receptor	IGF-I receptor	IGF-I receptor	6	7	19	21
Furthermore , DEXA increased ( P < 0.05 ) mRNA levels of IGF-II ( pylorus ) , IGFBP-3 ( duodenum ) , IGF2R ( pylorus ) , and GHR ( ileum ) , but decreased mRNA levels of IGFBP-2 ( ileum ) , and IGF1R ( fundus ) .	Furthermore, DEXA increased (P < 0.05) mRNA levels of IGF-II (pylorus), IGFBP-3 (duodenum), IGF2R (pylorus), and GHR (ileum), but decreased mRNA levels of IGFBP-2 (ileum), and IGF1R (fundus).	10	46	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IGF-II	levels of IGF-II	igf-ii	IGF1R	IGF1R	igf1r	12	13	44	45
Taken together , these results indicate that MAVS and IKKbeta are necessary for gammaHV68 to induce rapid RelA degradation .	Taken together, these results indicate that MAVS and IKKbeta are necessary for gammaHV68 to induce rapid RelA degradation.	7	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	RelA	RelA	RelA	9	10	17	18
We also observed that zinc inhibited NF-kappaB activity driven by overexpression of MyD88 , TRAF6 and IKKbeta , but not p65 , mapping the location of the effect at IKK , identical to our previous findings involving ZIP8 co-transfection ( XREF_SUPPLEMENTARY ) .	We also observed that zinc inhibited NF-kappaB activity driven by overexpression of MyD88, TRAF6 and IKKbeta, but not p65, mapping the location of the effect at IKK, identical to our previous findings involving ZIP8 co-transfection (XREF_SUPPLEMENTARY).	5	21	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IKKbeta	overexpression of MyD88, TRAF6 and IKKbeta	ikkbeta	p65	p65	p65	16	17	20	21
Evidence of mechanism was provided by the use of BMS345541 , an inhibitor of the IKKbeta and NFkappaBp65 signaling pathway , which inhibited the IKKbeta and NFkappaBp65 response to IL-13 stimulation , suggesting that IL-13 plays the role of an upstream activator in the IKKbeta and NFkappaBp65 signaling pathway .	Evidence of mechanism was provided by the use of BMS345541, an inhibitor of the IKKbeta and NFkappaBp65 signaling pathway, which inhibited the IKKbeta and NFkappaBp65 response to IL-13 stimulation, suggesting that IL-13 plays the role of an upstream activator in the IKKbeta and NFkappaBp65 signaling pathway.	12	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	NFkappaBp65	NFkappaBp65	NFkappaBp65	15	16	26	27
WA pretreatment inhibited the activated IKKbeta phosphorylation and completely inhibited NF-kappaB phosphorylation by inhibiting p65 activation .	WA pretreatment inhibited the activated IKKbeta phosphorylation and completely inhibited NF-kappaB phosphorylation by inhibiting p65 activation.	0	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKbeta	WA pretreatment inhibited the activated IKKbeta phosphorylation	ikkbeta	p65	p65	p65	5	6	14	15
Here , we found overexpression of Best-3 inhibited TNFalpha induced IKKbeta and IkappaBalpha phosphorylation , blocked TNFalpha induced ubiquitination and subsequent degradation of IkappaBalpha , and suppressed the nuclear translocation of p65 and p50 .	Here, we found overexpression of Best-3 inhibited TNFalpha induced IKKbeta and IkappaBalpha phosphorylation, blocked TNFalpha induced ubiquitination and subsequent degradation of IkappaBalpha, and suppressed the nuclear translocation of p65 and p50.	4	33	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKbeta	overexpression of Best-3 inhibited TNFalpha induced IKKbeta and IkappaBalpha phosphorylation	ikkbeta	p65	p65	p65	10	11	31	32
In contrast to the general notion that NEMO exerts its effects via NF-kappaB , these findings indicate that TAK1 and NEMO can prevent cell death independent of NF-kappaB , at least of the p65 subunit and its main activator in the canonical pathway , IKK2 .	In contrast to the general notion that NEMO exerts its effects via NF-kappaB, these findings indicate that TAK1 and NEMO can prevent cell death independent of NF-kappaB, at least of the p65 subunit and its main activator in the canonical pathway, IKK2.	18	34	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NEMO	NEMO	NEMO	p65	p65	p65	20	21	33	34
Functional macrophage IL-4Ralpha data from Lck cre IL-4Ralpha -/lox mice were demonstrated in XREF_FIG C. NO production was suppressed by IL-4 and IL-13 in macrophages from Lck cre IL-4Ralpha -/lox and WT mice ( XREF_FIG C ) , but not IL-4Ralpha -/- macrophages , showing IL-4Ralpha specificity .	Functional macrophage IL-4Ralpha data from Lck cre IL-4Ralpha -/lox mice were demonstrated in XREF_FIG C. NO production was suppressed by IL-4 and IL-13 in macrophages from Lck cre IL-4Ralpha -/lox and WT mice (XREF_FIG C), but not IL-4Ralpha -/- macrophages, showing IL-4Ralpha specificity.	18	46	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-13	IL-13	IL-13	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	22	23	45	46
IL-15Ralpha is rapidly depleted by IL-15 .	IL-15Ralpha is rapidly depleted by IL-15.	0	6	depleted	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-15	IL-15	IL-15	IL-15Ralpha	IL-15Ralpha	IL-15Ralpha	5	6	0	1
Notably , IL-15 -- IL-15Ralpha complexes did not demonstrate a biphasic dose response curve as the presence of soluble IL-15Ralpha likely impeded engagement of membrane bound IL-15Ralpha .	Notably, IL-15 -- IL-15Ralpha complexes did not demonstrate a biphasic dose response curve as the presence of soluble IL-15Ralpha likely impeded engagement of membrane bound IL-15Ralpha.	2	27	impeded	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-15	IL-15	IL-15	IL-15Ralpha	IL-15Ralpha	IL-15Ralpha	2	3	26	27
IL-13Ralpha1 ( CD213a1 ) on blood eosinophils is upregulated by various cytokines ( up to about 2.5-fold ) ( XREF_TABLE ) but downregulated by its own ligand IL-13 and the related cytokine IL-4 ( to about a 0.5-fold level ) [ XREF_BIBR ] .	IL-13Ralpha1 (CD213a1) on blood eosinophils is upregulated by various cytokines (up to about 2.5-fold) (XREF_TABLE) but downregulated by its own ligand IL-13 and the related cytokine IL-4 (to about a 0.5-fold level) [XREF_BIBR].	0	32	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-13	IL-13	IL-13	IL-13Ralpha1	IL-13Ralpha1	IL-13Ralpha1	27	28	0	1
IL-13Ralpha1 is upregulated by various cytokines including IL-5 or GM-CSF ( XREF_TABLE ) but downregulated by IL-4 or IL-13 [ XREF_BIBR ] .	IL-13Ralpha1 is upregulated by various cytokines including IL-5 or GM-CSF (XREF_TABLE) but downregulated by IL-4 or IL-13 [XREF_BIBR].	0	20	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-13	IL-13	IL-13	IL-13Ralpha1	IL-13Ralpha1	IL-13Ralpha1	18	19	0	1
Co-inhibition of IR and IGF-1R may confer a better anti-tumor effect because IR signaling induced by insulin or IGF-2 has been implicated in a number of preclinical tumor models XREF_BIBR , including breast cancer XREF_BIBR .	Co-inhibition of IR and IGF-1R may confer a better anti-tumor effect because IR signaling induced by insulin or IGF-2 has been implicated in a number of preclinical tumor models XREF_BIBR, including breast cancer XREF_BIBR.	12	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	IR	IR	IR	18	19	12	13
Selective targeting of the IGF signaling network has proven to be extremely challenging due , in part , to the fact that insulin , IGF-1 and IGF-2 can all activate IGF-1-R and/or IGF-2R , as well as the insulin receptor ( XREF_FIG ) .	Selective targeting of the IGF signaling network has proven to be extremely challenging due, in part, to the fact that insulin, IGF-1 and IGF-2 can all activate IGF-1-R and/or IGF-2R, as well as the insulin receptor (XREF_FIG).	22	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IGF-2	IGF-2	IGF-2	insulin receptor	insulin receptor	insulin receptor	26	27	38	40
Monomeric IL-10 induces lower IL-10R signaling compared to dimeric human IL-10 .	Monomeric IL-10 induces lower IL-10R signaling compared to dimeric human IL-10.	0	5	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-10	IL-10	IL-10	IL-10R	IL-10R	IL-10R	1	2	4	5
Down-regulation of cell surface IL-10R expression would be predicted to diminish the activation of IL-10R-associated Jak1 .	Down-regulation of cell surface IL-10R expression would be predicted to diminish the activation of IL-10R-associated Jak1.	4	16	diminish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-10R	IL-10R expression	il-10r	Jak1	Jak1	jak1	4	5	15	16
In conclusion , both focal upregulation of IGF-2 and general downregulation of M6P and IGF-2R seem to represent mechanisms operative early before the appearance of dysplastic changes in cirrhotic liver , particularly when related to chronic HBV and HCV infection .	In conclusion, both focal upregulation of IGF-2 and general downregulation of M6P and IGF-2R seem to represent mechanisms operative early before the appearance of dysplastic changes in cirrhotic liver, particularly when related to chronic HBV and HCV infection.	7	15	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IGF-2	IGF-2	IGF-2	IGF-2R	IGF-2R	IGF-2R	7	8	14	15
HSCARG also interacted with Ikappa-B kinase epsilon ( IKKepsilon ) after viral infection and impaired the association between TRAF3 and IKKepsilon , which further decreased the phosphorylation of IKKepsilon and interferon response factor 3 ( IRF3 ) , thus suppressed the dimerization and nuclear translocation of IRF3 .	HSCARG also interacted with Ikappa-B kinase epsilon (IKKepsilon) after viral infection and impaired the association between TRAF3 and IKKepsilon, which further decreased the phosphorylation of IKKepsilon and interferon response factor 3 (IRF3), thus suppressed the dimerization and nuclear translocation of IRF3.	16	47	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IKKepsilon	association between TRAF3 and IKKepsilon, which further decreased the phosphorylation of IKKepsilon	ikkepsilon	IRF3	IRF3	irf3	28	29	46	47
Immnunoblot analyses showed that IL-11 and CT-1 activated signal transducer and activator of transcription 3 ( STAT3 ) , a downstream target of gp130 , but not other cytokines .	Immnunoblot analyses showed that IL-11 and CT-1 activated signal transducer and activator of transcription 3 (STAT3), a downstream target of gp130, but not other cytokines.	4	24	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-11	IL-11	IL-11	gp130	gp130	gp130	4	5	23	24
Similarly , MCV MC159 and MC160 , were shown to interact with NEMO preventing IKKbeta activation and induce degradation of IKKalpha , respectively [ XREF_BIBR , XREF_BIBR ] .	Similarly, MCV MC159 and MC160, were shown to interact with NEMO preventing IKKbeta activation and induce degradation of IKKalpha, respectively [XREF_BIBR, XREF_BIBR].	10	15	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NEMO	NEMO	NEMO	IKKbeta	IKKbeta	IKKbeta	12	13	14	15
Exogenous IL-10 fails to prevent colitis in Rag2 -/- Il10rb -/- following T cell transfer .	Exogenous IL-10 fails to prevent colitis in Rag2 -/- Il10rb -/- following T cell transfer.	0	10	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-10	IL-10	IL-10	Il10rb	Il10rb	Il10rb	1	2	9	10
12 IL-22BP suppresses the function of IL-22 which is produced from innate lymphoid cells in response to cellular and tissue damage and which potently stimulates the proliferation of intestinal epithelial cells .	12 IL-22BP suppresses the function of IL-22 which is produced from innate lymphoid cells in response to cellular and tissue damage and which potently stimulates the proliferation of intestinal epithelial cells.	0	7	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	1	2	6	7
Therefore , high IL-22BP production in SLO could be necessary to prevent IL-22 actions on tumor cells thus limiting the installation of these malignancies .	Therefore, high IL-22BP production in SLO could be necessary to prevent IL-22 actions on tumor cells thus limiting the installation of these malignancies.	3	13	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	3	4	12	13
In this study , we identified that IL-22BP is highly expressed by PP CD11b + CD8alpha - DCs and that IL-22BP blocks IL-22 signaling in FAE .	In this study, we identified that IL-22BP is highly expressed by PP CD11b + CD8alpha - DCs and that IL-22BP blocks IL-22 signaling in FAE.	20	23	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	20	21	22	23
These results , together with the preferential location of LysoDC and TIM-4 - LysoMac in the SED , support their role in the secretion of IL-22BP , which in turn inhibits IL-22 signaling , alters the FAE transcriptional program , and favors the internalization of both commensal and pathogenic bacteria .	These results, together with the preferential location of LysoDC and TIM-4 - LysoMac in the SED, support their role in the secretion of IL-22BP, which in turn inhibits IL-22 signaling, alters the FAE transcriptional program, and favors the internalization of both commensal and pathogenic bacteria.	23	41	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	25	26	31	32
Therefore , deletion of IL-22BP allows IL-22 to act stronger under inflammatory settings in IL-22BP deficient animals than in WT animals .	Therefore, deletion of IL-22BP allows IL-22 to act stronger under inflammatory settings in IL-22BP deficient animals than in WT animals.	2	8	allows	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	4	5	6	7
IL-22BP is an inhibitor of IL-22 which has 20-1000x more affinity to bind with IL-22 compared to IL-22R1 that inhibits IL-22 activity .	IL-22BP is an inhibitor of IL-22 which has 20-1000x more affinity to bind with IL-22 compared to IL-22R1 that inhibits IL-22 activity.	0	6	is an inhibitor	Negative_activation_copula_1	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	0	1	5	6
Other transcripts consistent with immune cell recruitment and activation were differentially regulated in BB rat islets , including the neutrophil chemoattractant Cxcl1 ( 2.6-fold , P = 0.016 ) and the IL22 antagonist Il22ra2 ( -2.74-fold , P = 0.002 ) .	Other transcripts consistent with immune cell recruitment and activation were differentially regulated in BB rat islets, including the neutrophil chemoattractant Cxcl1 (2.6-fold, P = 0.016) and the IL22 antagonist Il22ra2 (-2.74-fold, P = 0.002).	11	34	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	Il22ra2	Il22ra2	Il22ra2	IL22	IL22	IL22	33	34	31	32
During cellular damage , IL-22BP is downregulated , allowing IL-22 to induce tissue repair .	During cellular damage, IL-22BP is downregulated, allowing IL-22 to induce tissue repair.	4	11	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	4	5	9	10
Since IL-22R1 is a functional receptor for IL-22 , but IL-22BP is an antagonist of IL-22 , the ratio of IL-22R1 and IL-22BP expression was also calculated as a measure of IL-22 activity .	Since IL-22R1 is a functional receptor for IL-22, but IL-22BP is an antagonist of IL-22, the ratio of IL-22R1 and IL-22BP expression was also calculated as a measure of IL-22 activity.	10	16	is an antagonist	Negative_activation_copula_1	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	10	11	15	16
63 IL-22BP lacks a transmembrane and intracellular domain and therefore antagonizes IL-22 signaling , which also has a key role in intestinal inflammation and repair .	63 IL-22BP lacks a transmembrane and intracellular domain and therefore antagonizes IL-22 signaling, which also has a key role in intestinal inflammation and repair.	0	12	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	1	2	11	12
Therefore another hypothesis for the increased experimental colon tumorigenesis in Il22bp -/- mice is that the effect of IL-22BP is to inhibit IL-22 induced epithelial cell proliferation .	Therefore another hypothesis for the increased experimental colon tumorigenesis in Il22bp -/- mice is that the effect of IL-22BP is to inhibit IL-22 induced epithelial cell proliferation.	16	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	18	19	22	23
The overproduction of IL-22BP in the inflamed mucosa may block IL-22 protective actions .	The overproduction of IL-22BP in the inflamed mucosa may block IL-22 protective actions.	1	12	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	3	4	10	11
IL-22bp can hence inhibit the activity of IL-22 .	IL-22bp can hence inhibit the activity of IL-22.	0	8	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22bp	IL-22bp	IL-22bp	IL-22	IL-22	IL-22	0	1	7	8
64 In agreement with impaired IL-18 production in Aim2 -/- IECs , we observed enhanced production and release of IL-22BP , which prevented appropriate IL-22 signaling in naive mice .	64 In agreement with impaired IL-18 production in Aim2 -/- IECs, we observed enhanced production and release of IL-22BP, which prevented appropriate IL-22 signaling in naive mice.	15	25	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	19	20	24	25
The decrease of IL-22BP expression probably increases bioactive IL-22 at local level .	The decrease of IL-22BP expression probably increases bioactive IL-22 at local level.	3	9	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP expression	il-22bp	IL-22	IL-22	il-22	3	4	8	9
IL-22BP blocks IL-22 signaling on the FAE .	IL-22BP blocks IL-22 signaling on the FAE.	0	3	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	0	1	2	3
Therefore , IL-22BP can strongly inhibit the biological activity of IL-22 in vitro and in vivo by competing with IL-22R1 and IL-22 interaction [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Therefore, IL-22BP can strongly inhibit the biological activity of IL-22 in vitro and in vivo by competing with IL-22R1 and IL-22 interaction [XREF_BIBR, XREF_BIBR - XREF_BIBR].	2	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	2	3	10	11
The secreted receptor that inhibits IL22 , IL22BP , is constitutively produced by mouse intestinal CD11b + CD103 + DCs .	The secreted receptor that inhibits IL22, IL22BP, is constitutively produced by mouse intestinal CD11b + CD103 + DCs.	2	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL22BP	IL22BP	IL22BP	IL22	IL22	IL22	7	8	5	6
Eosinophil derived IL-4 is important for chronic disease progression in myocarditis , and IL-22BP blocks protective functions of IL-22 in UC .	Eosinophil derived IL-4 is important for chronic disease progression in myocarditis, and IL-22BP blocks protective functions of IL-22 in UC.	13	20	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	13	14	18	19
IL-22Ralpha2 is a secreted inhibitor of IL-22 , a cytokine involved in the initiation of innate immune responses .	IL-22Ralpha2 is a secreted inhibitor of IL-22, a cytokine involved in the initiation of innate immune responses.	0	9	is a secreted inhibitor	Negative_activation_copula_1	Positive_activation	Negative_activation	IL-22Ralpha2	IL-22Ralpha2	IL-22Ralpha2	IL-22	IL-22	IL-22	0	1	6	7
It is also noteworthy that IL22RA2 , a soluble receptor for IL22 that antagonizes IL22 which is primarily produced by activated T cells [ XREF_BIBR ] , CD7 which promotes T cell apoptosis [ XREF_BIBR ] , Lgals2 ( galectin-2 ) , a proapoptotic effector of activated T-cells [ XREF_BIBR ] , and IL2 receptor gamma [ XREF_BIBR ] are all increased in the CFA group compared to the naive group .	It is also noteworthy that IL22RA2, a soluble receptor for IL22 that antagonizes IL22 which is primarily produced by activated T cells [XREF_BIBR], CD7 which promotes T cell apoptosis [XREF_BIBR], Lgals2 (galectin-2), a proapoptotic effector of activated T-cells [XREF_BIBR], and IL2 receptor gamma [XREF_BIBR] are all increased in the CFA group compared to the naive group.	5	61	antagonizes	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	IL22RA2	IL22RA2	IL22RA2	IL22	IL22	IL22	5	6	14	15
IL-22BP shows 20-1000x more affinity for IL-22 compared to IL-22R1 and thus inhibits IL-22 action and regulates the extent of liver ailments [ XREF_BIBR ] .	IL-22BP shows 20-1000x more affinity for IL-22 compared to IL-22R1 and thus inhibits IL-22 action and regulates the extent of liver ailments [XREF_BIBR].	0	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	0	1	13	14
Interestingly , levels of IL-22BP decrease in parallel , further increasing the activity of IL-22 .	Interestingly, levels of IL-22BP decrease in parallel, further increasing the activity of IL-22.	4	15	increasing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	4	5	14	15
So , IL-22BP attenuates effects of IL-22 and inhibits its exaggeration .	So, IL-22BP attenuates effects of IL-22 and inhibits its exaggeration.	2	8	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	2	3	6	7
IL-22BP , an inhibitor of IL-22 , blocks IL-22 from binding to IL-22R complex and was found to be positively correlated with the severity of liver damage and fibrosis .	IL-22BP, an inhibitor of IL-22, blocks IL-22 from binding to IL-22R complex and was found to be positively correlated with the severity of liver damage and fibrosis.	0	20	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	0	1	8	9
Surprisingly however , IL-22BP levels were recently shown to be elevated in patients with IBD and thus limit the tissue healing effects of IL-22 , suggesting that a disturbed IL-22-IL-22BP axis might be one of the mechanisms contributing to the chronification of inflammation .	Surprisingly however, IL-22BP levels were recently shown to be elevated in patients with IBD and thus limit the tissue healing effects of IL-22, suggesting that a disturbed IL-22-IL-22BP axis might be one of the mechanisms contributing to the chronification of inflammation.	3	24	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP levels	il-22bp	IL-22	IL-22	il-22	3	4	23	24
IL-22BP negatively regulates IL-22 activity and was shown to limit chemically induced colon carcinomas .	IL-22BP negatively regulates IL-22 activity and was shown to limit chemically induced colon carcinomas.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	0	1	3	4
Because IL-22BP is known to antagonize IL-22 signaling , a primarily pro inflammatory cytokine , we hypothesized that the Il22ra2 deficient mice would have more severe EAE .	Because IL-22BP is known to antagonize IL-22 signaling, a primarily pro inflammatory cytokine, we hypothesized that the Il22ra2 deficient mice would have more severe EAE.	1	7	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	1	2	6	7
In contrast , nuclear pSTAT3 was almost absent in the FAE of the same mice , suggesting that IL-22BP expressed in SED preferentially blocks IL-22 signaling in the FAE ( XREF_FIG ) .	In contrast, nuclear pSTAT3 was almost absent in the FAE of the same mice, suggesting that IL-22BP expressed in SED preferentially blocks IL-22 signaling in the FAE (XREF_FIG).	18	25	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP expressed	il-22bp	IL-22	IL-22	il-22	18	19	24	25
XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR IL-22BP is necessary to suppress IL-22 function , which can promote the proliferation of intestinal epithelial cells following damage by carcinogens or inflammatory agents .	XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR IL-22BP is necessary to suppress IL-22 function, which can promote the proliferation of intestinal epithelial cells following damage by carcinogens or inflammatory agents.	6	13	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	7	8	12	13
IL-22BP ( IL-22RA2 ) is an inhibitor of IL-22 which lacks intracellular and transmembrane domains which check IL-22 binding to IL-22R1 .	IL-22BP (IL-22RA2) is an inhibitor of IL-22 which lacks intracellular and transmembrane domains which check IL-22 binding to IL-22R1.	0	9	is an inhibitor	Negative_activation_copula_1	Positive_activation	Negative_activation	IL-22BP	IL-22BP	IL-22BP	IL-22	IL-22	IL-22	0	1	8	9
Moreover , IL-2 reduced significantly the percentages of CD25 and FoxP3+ cells , although the effect was less striking than that observed for the GMF ( XREF_FIG ) .	Moreover, IL-2 reduced significantly the percentages of CD25 and FoxP3+ cells, although the effect was less striking than that observed for the GMF (XREF_FIG).	2	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	8	9
The addition of IL-2 at the initiation of the day 4 cultures produced IL-2 effectors from aged and young mice that expressed a similar and fully differentiated activated phenotype ( CD44 hi CD62L lower CD25 hi ) .	The addition of IL-2 at the initiation of the day 4 cultures produced IL-2 effectors from aged and young mice that expressed a similar and fully differentiated activated phenotype (CD44 hi CD62L lower CD25 hi).	1	35	produced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	34	35
DAB and IL2 transiently depletes CD4 + , CD8 + and CD4 + / CD25 + / Foxp3 + T cells .	DAB and IL2 transiently depletes CD4 +, CD8 + and CD4 + / CD25 + / Foxp3 + T cells.	0	15	depletes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL2	IL2	IL2	CD25	CD25	CD25	2	3	14	15
IL-2 -/-, IL-2Ralpha -/-, or IL-2Rbeta -/- KO mice have decreased numbers of natural CD4 + CD25 + Tregs XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR and suffer from autoimmunity XREF_BIBR , XREF_BIBR , XREF_BIBR or fatal lymphoproliferative disease XREF_BIBR .	IL-2 -/-, IL-2Ralpha -/-, or IL-2Rbeta -/- KO mice have decreased numbers of natural CD4 + CD25 + Tregs XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR and suffer from autoimmunity XREF_BIBR, XREF_BIBR, XREF_BIBR or fatal lymphoproliferative disease XREF_BIBR.	0	27	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	16	17
Activated CD4 ( + ) CD25 (-) cells from both FIV (-) and FIV ( + ) cats cocultured with autologous CD4 ( + ) CD25 ( + ) cells or treated with TGF-beta demonstrated decreased IL-2 production ; however , NFAT2 mRNA levels were unaffected .	Activated CD4 (+) CD25 (-) cells from both FIV (-) and FIV (+) cats cocultured with autologous CD4 (+) CD25 (+) cells or treated with TGF-beta demonstrated decreased IL-2 production; however, NFAT2 mRNA levels were unaffected.	25	43	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	36	37	25	26
IL2 neutralization treatment downregulated CD25 in the donor and host Tregs ( XREF_SUPPLEMENTARY ) but did not cause a significant change in the CNS2 demethylation status .	IL2 neutralization treatment downregulated CD25 in the donor and host Tregs (XREF_SUPPLEMENTARY) but did not cause a significant change in the CNS2 demethylation status.	0	5	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL2	IL2	IL2	CD25	CD25	CD25	0	1	4	5
Reduced IL-2 responsiveness resulting from reduced TCR induced upregulation of CD25 may underlie the observed reduction in splenic and peripheral expansion of CD8 + T cells in LCMV infected IRAK-4 -/- mice XREF_BIBR .	Reduced IL-2 responsiveness resulting from reduced TCR induced upregulation of CD25 may underlie the observed reduction in splenic and peripheral expansion of CD8 + T cells in LCMV infected IRAK-4 -/- mice XREF_BIBR.	1	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	10	11
Production of IL-2 and IL-2 mRNA was not effectively suppressed by littermate CD4 + CD25 + T reg cells .	Production of IL-2 and IL-2 mRNA was not effectively suppressed by littermate CD4 + CD25 + T reg cells.	2	18	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	14	15
IL-2 -/- T cells express higher levels of IL-7R and blocking IL-2R CD25 chain induces increased IL-7 mediated homeostatic proliferation of T cells by increasing the formation of IL-7R and affecting its turnover rate .	IL-2 -/- T cells express higher levels of IL-7R and blocking IL-2R CD25 chain induces increased IL-7 mediated homeostatic proliferation of T cells by increasing the formation of IL-7R and affecting its turnover rate.	0	14	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2 -/- T cells express	il-2	CD25	CD25	cd25	0	1	12	13
CD25 - Tfr cells , mostly localized in the GCs and acting as the primary suppressive cells in established GCs , could be inhibited by high levels of IL-2 during the immune response .	CD25 - Tfr cells, mostly localized in the GCs and acting as the primary suppressive cells in established GCs, could be inhibited by high levels of IL-2 during the immune response.	0	29	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-2	levels of IL-2	il-2	CD25	CD25	cd25	28	29	0	1
Previously , it has been reported that exogenous IL-2 abrogated the suppressive activity of CD4 + CD25 + Tregs in vitro [ XREF_BIBR , XREF_BIBR ] .	Previously, it has been reported that exogenous IL-2 abrogated the suppressive activity of CD4 + CD25 + Tregs in vitro [XREF_BIBR, XREF_BIBR].	7	24	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	8	9	16	17
We were surprised that the peripheral blood CD4 + CD25 - T cell concentration was depleted by DAB and IL2 albeit to a lesser extent than CD4 + CD25 + and CD4 + CD25 HI T cells .	We were surprised that the peripheral blood CD4 + CD25 - T cell concentration was depleted by DAB and IL2 albeit to a lesser extent than CD4 + CD25 + and CD4 + CD25 HI T cells.	7	20	depleted	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL2	IL2	IL2	CD25	CD25	CD25	19	20	9	10
For example , IL-2 deficiency substantially reduced natural CD25 + CD4 + T reg cells , and transfer of CD25 + CD4 + T cells suppressed IL-2 -/- T cell proliferation .	For example, IL-2 deficiency substantially reduced natural CD25 + CD4 + T reg cells, and transfer of CD25 + CD4 + T cells suppressed IL-2 -/- T cell proliferation.	3	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	3	4	8	9
Second , neutralization of IL-2 in normal mice inhibited the physiological proliferation of peripheral CD25 + CD4 + T cells .	Second, neutralization of IL-2 in normal mice inhibited the physiological proliferation of peripheral CD25 + CD4 + T cells.	2	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	4	5	14	15
By contrast , IL-15-driven CD25 upregulation was partially inhibited by IL-2 : there was a trend for the proportion of NK cells expressing CD25 to decrease with increasing concentrations of IL-2 in all cytokine combinations that included IL-15 , with a statistically significant impact observed in NK cells stimulated with IL-15 plus IL-18 ( median without IL-2 = 38.1 % vs. median with high concentration IL-2 = 29.0 % ; linear test for trend , p = 0.04 ; Figure XREF_FIG D ) .	By contrast, IL-15-driven CD25 upregulation was partially inhibited by IL-2 : there was a trend for the proportion of NK cells expressing CD25 to decrease with increasing concentrations of IL-2 in all cytokine combinations that included IL-15, with a statistically significant impact observed in NK cells stimulated with IL-15 plus IL-18 (median without IL-2 = 38.1% vs. median with high concentration IL-2 = 29.0%; linear test for trend, p = 0.04; Figure XREF_FIG D).	4	11	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	10	11	4	5
Based on these findings , we first determined whether IL-2 neutralization in normal nonlymphopenic mice blocked natural proliferation of CD25 + CD4 + T cells .	Based on these findings, we first determined whether IL-2 neutralization in normal nonlymphopenic mice blocked natural proliferation of CD25 + CD4 + T cells.	9	24	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	9	10	19	20
Isolated CD4 ( + ) CD25 ( + ) T cells are susceptible to apoptosis that is associated with low Bcl-2 expression , but this death can be prevented by IL-2 or fibroblast secreted IFN-beta .	Isolated CD4 (+) CD25 (+) T cells are susceptible to apoptosis that is associated with low Bcl-2 expression, but this death can be prevented by IL-2 or fibroblast secreted IFN-beta.	0	32	prevented	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	30	31	5	6
Neutralization of IL-2 by a specific mAb selectively reduces CD25 + CD4 + T cells in normal mice .	Neutralization of IL-2 by a specific mAb selectively reduces CD25 + CD4 + T cells in normal mice.	0	14	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	9	10
Moreover , only Cd25 +/+ Tfh are suppressed by the addition of IL-2 in B6 : Cd25 -/- chimeric mice , despite the equal opportunity of Tregs to interact with both B6 and Cd25 -/- T cells .	Moreover, only Cd25 +/+ Tfh are suppressed by the addition of IL-2 in B6 : Cd25 -/- chimeric mice, despite the equal opportunity of Tregs to interact with both B6 and Cd25 -/- T cells.	2	28	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	Cd25	Cd25	Cd25	12	13	3	4
Our observations that in vitro neutralization of IL-2 reduced CD25 up-regulation , abrogated antigen specific CD4 T cell proliferation , and almost completely abrogated productive HIV infection of CD4 T cells supports a central role for the IL-2-CD25 signaling pathway in the productive infection of antigen specific CD4 T cells .	Our observations that in vitro neutralization of IL-2 reduced CD25 up-regulation, abrogated antigen specific CD4 T cell proliferation, and almost completely abrogated productive HIV infection of CD4 T cells supports a central role for the IL-2-CD25 signaling pathway in the productive infection of antigen specific CD4 T cells.	5	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	7	8	9	10
We and several other groups have demonstrated that addition of IL-2 alongside vaccination or infection in mice inhibits the formation of CD25 - Tfr cells while at the same time causing expansion of Tregs .	We and several other groups have demonstrated that addition of IL-2 alongside vaccination or infection in mice inhibits the formation of CD25 - Tfr cells while at the same time causing expansion of Tregs.	8	22	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	10	11	21	22
Porcine IL-2 Fusion Toxins Deplete Porcine CD25 + Tumor Cells in Vitro .	Porcine IL-2 Fusion Toxins Deplete Porcine CD25 + Tumor Cells in Vitro.	1	9	Deplete	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	1	2	6	7
IL-2 neutralization inhibits physiological proliferation of peripheral CD25 + CD4 + T cells that are presumably responding to normal self-antigens , whereas it is unable to inhibit their lymphopenia induced homeostatic expansion in a T cell deficient environment .	IL-2 neutralization inhibits physiological proliferation of peripheral CD25 + CD4 + T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia induced homeostatic expansion in a T cell deficient environment.	0	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	0	1	7	8
Patients ' lymphocytes whose IL-2 responsiveness was decreased still expressed Tac antigen ( low-affinity IL-2 receptors ) but , in contrast to the patients ' original lymphocytes , did not absorb or respond to IL-2 , suggesting the loss of high-affinity IL-2 receptors ( p55 and p75 ) from these cells .	Patients ' lymphocytes whose IL-2 responsiveness was decreased still expressed Tac antigen (low-affinity IL-2 receptors) but, in contrast to the patients ' original lymphocytes, did not absorb or respond to IL-2, suggesting the loss of high-affinity IL-2 receptors (p55 and p75) from these cells.	4	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	Tac antigen	Tac antigen	Tac antigen	4	5	10	12
Thus , IL-2 prevented the cytotoxic effect of Sirolimus on CD3 and CD28 stimulated CD4 + CD25 high T cells .	Thus, IL-2 prevented the cytotoxic effect of Sirolimus on CD3 and CD28 stimulated CD4 + CD25 high T cells.	2	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	2	3	16	17
Normal BALB/c mice were injected with anti-IL-2 mAb or saline and subsequently with 1 mg 5-bromo-2 '-deoxyuridine ( BrdU ) every 12 h for 3 d. IL-2 neutralization reduced incorporation of BrdU in CD25 + CD4 + T cells to one third of control mice , with no reduction in CD25 - CD4 + T cells , indicating that CD25 + CD4 + T cells require IL-2 for their physiological proliferation in the periphery ( XREF_FIG ) .	Normal BALB/c mice were injected with anti-IL-2 mAb or saline and subsequently with 1 mg 5-bromo-2 '-deoxyuridine (BrdU) every 12 h for 3 d. IL-2 neutralization reduced incorporation of BrdU in CD25 + CD4 + T cells to one third of control mice, with no reduction in CD25 - CD4 + T cells, indicating that CD25 + CD4 + T cells require IL-2 for their physiological proliferation in the periphery (XREF_FIG).	26	34	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-2	IL-2	IL-2	CD25	CD25	CD25	26	27	33	34
DAB and IL2 administration transiently decreased CD4 + CD25 -, CD4 + CD25 + , CD4 + CD25 HI Foxp3 -, CD4 + CD25 HI Foxp3 + , CD8 + T cells and , in certain patients , melanoma antigen specific CD8 + T cells .	DAB and IL2 administration transiently decreased CD4 + CD25 -, CD4 + CD25 +, CD4 + CD25 HI Foxp3 -, CD4 + CD25 HI Foxp3 +, CD8 + T cells and, in certain patients, melanoma antigen specific CD8 + T cells.	0	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL2	IL2	IL2	CD25	CD25	CD25	2	3	8	9
IL-1beta at concentrations of 1.5 nM and 7.5 nM significantly inhibited the neuritogenic effect of both IL-1Ra and Ilantide-t .	IL-1beta at concentrations of 1.5 nM and 7.5 nM significantly inhibited the neuritogenic effect of both IL-1Ra and Ilantide-t.	0	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	0	1	16	17
As an alternative approach to the inhibition of IL-1beta synthesis , blocking IL-1R1 -the effector for the inflammatory actions of IL-1 - might represent another anti-inflammatory strategy .	As an alternative approach to the inhibition of IL-1beta synthesis, blocking IL-1R1 -the effector for the inflammatory actions of IL-1 - might represent another anti-inflammatory strategy.	8	14	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	8	9	12	13
We hypothesize that greater IL-1beta and TNF-alpha production , decreased IL-1Ra , sTNFR1 , and sTNFR2 production , and decreased cortisol responsiveness at each time point as well as a more expedient alignment with this unfavorable profile over time will be associated with PTB .	We hypothesize that greater IL-1beta and TNF-alpha production, decreased IL-1Ra, sTNFR1, and sTNFR2 production, and decreased cortisol responsiveness at each time point as well as a more expedient alignment with this unfavorable profile over time will be associated with PTB.	3	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	4	5	10	11
It is thus possible that IL-1beta and AHR work together to tightly repress IL-1R1 hi ILC3 differentiation to stage 4 mature NK cells - that is to say , IL-1beta induces AHR and thus helps expand IL-22-producing IL-1R1 hi ILC3s in response to appropriate environmental stimuli when these cells are necessary for mucosal immunity .	It is thus possible that IL-1beta and AHR work together to tightly repress IL-1R1 hi ILC3 differentiation to stage 4 mature NK cells - that is to say, IL-1beta induces AHR and thus helps expand IL-22-producing IL-1R1 hi ILC3s in response to appropriate environmental stimuli when these cells are necessary for mucosal immunity.	5	16	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	5	6	13	14
Specifically , we posit that greater IL-1beta and TNF-alpha production , decreased IL-1Ra , sTNFR1 , and sTNFR2 production , and decreased cortisol responsiveness at each time point as well as a more expedient alignment with this unfavorable profile over time will be associated with PTB .	Specifically, we posit that greater IL-1beta and TNF-alpha production, decreased IL-1Ra, sTNFR1, and sTNFR2 production, and decreased cortisol responsiveness at each time point as well as a more expedient alignment with this unfavorable profile over time will be associated with PTB.	5	21	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1Ra	IL-1Ra	IL-1Ra	6	7	12	13
We have also previously shown that IL-1beta upregulates itself and IL-1alpha whilst downregulating IL-1R1 and having no effect on the expression of IL-1Ra in IVD [ XREF_BIBR ] .	We have also previously shown that IL-1beta upregulates itself and IL-1alpha whilst downregulating IL-1R1 and having no effect on the expression of IL-1Ra in IVD [XREF_BIBR].	6	14	downregulating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R1	IL-1R1	IL-1R1	6	7	13	14
As such , IL-4 compared to IL-10 , is more potent inhibitor of IL-1beta and only IL-4 ( not IL-10 ) can induce the production of IL-1ra XREF_BIBR .	As such, IL-4 compared to IL-10, is more potent inhibitor of IL-1beta and only IL-4 (not IL-10) can induce the production of IL-1ra XREF_BIBR.	11	27	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1ra	IL-1ra	IL-1ra	13	14	26	27
Genetic deletion of IL-1beta and IL-1R significantly decreased thoracic aortic dilation ( IL-1beta knockout = 54.2 +/-16.8 % and IL-1R knockout = 62.6 +/-17.2 % versus WT TAA = 104.7 +/-23.8 % ; P < 0.001 for both ) .	Genetic deletion of IL-1beta and IL-1R significantly decreased thoracic aortic dilation (IL-1beta knockout = 54.2 +/-16.8% and IL-1R knockout = 62.6 +/-17.2% versus WT TAA = 104.7 +/-23.8%; P < 0.001 for both).	1	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	3	4	19	20
Furthermore , for IL-1 beta induced IL-1ra , immunoprecipitation of IL-1 beta with an anti-IL-1 beta antibody , but not a preimmune antibody , blocked the induction of IL-1ra .	Furthermore, for IL-1 beta induced IL-1ra, immunoprecipitation of IL-1 beta with an anti-IL-1 beta antibody, but not a preimmune antibody, blocked the induction of IL-1ra.	3	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-1 beta	IL-1 beta	IL-1 beta	IL-1ra	IL-1ra	IL-1ra	3	5	6	7
Thus , CCL-18 could act as an endogenous inhibitor of GPER , similar to the actions of IL-1ra , which attenuates the activation of IL-1R by IL-1beta .	Thus, CCL-18 could act as an endogenous inhibitor of GPER, similar to the actions of IL-1ra, which attenuates the activation of IL-1R by IL-1beta.	20	27	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	26	27	24	25
We found that the inhibition of gamma-secretase significantly reduced COX-2 upregulation in MSCs in response to IL-1R activation by IL-1beta .	We found that the inhibition of gamma-secretase significantly reduced COX-2 upregulation in MSCs in response to IL-1R activation by IL-1beta.	8	20	reduced	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R	IL-1R	IL-1R	19	20	16	17
In the same way , IL-1alpha treatment also inhibited IL-1ra secretion and overproduction , reciprocally ( XREF_FIG ) .	In the same way, IL-1alpha treatment also inhibited IL-1ra secretion and overproduction, reciprocally (XREF_FIG).	5	10	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1alpha	IL-1alpha	IL-1alpha	IL-1ra	IL-1ra	IL-1ra	5	6	9	10
However , as intracellular IL-1Ra could regulate the action of intracellular IL-1alpha [ XREF_BIBR ] , it is possible that also IL-1alpha levels are decreased in our Syn1creIKK2 fl/fl mice shifting the IL-1Ra and IL-1 towards neuroprotection .	However, as intracellular IL-1Ra could regulate the action of intracellular IL-1alpha [XREF_BIBR], it is possible that also IL-1alpha levels are decreased in our Syn1creIKK2 fl/fl mice shifting the IL-1Ra and IL-1 towards neuroprotection.	21	36	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1alpha	IL-1alpha levels	il-1alpha	IL-1Ra	IL-1Ra	il-1ra	21	22	32	33
However , IL-1Ra administration significantly reduced IRAK activity for both groups compared to saline , demonstrating that the IL-1 receptor inhibitor crossed the BBB into grafted hippocampus and affected IL-1 signaling .	However, IL-1Ra administration significantly reduced IRAK activity for both groups compared to saline, demonstrating that the IL-1 receptor inhibitor crossed the BBB into grafted hippocampus and affected IL-1 signaling.	2	7	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1Ra	IL-1Ra	IL-1Ra	IRAK	IRAK	IRAK	2	3	6	7
For both the HFHC fed and control fed hosts , IL-1Ra topical administration reduced IRAK activity compared to saline administration , strongly suggesting that the IL-1 receptor blocker crossed the BBB and exerted effects on IL-1 signaling in the grafted tissue .	For both the HFHC fed and control fed hosts, IL-1Ra topical administration reduced IRAK activity compared to saline administration, strongly suggesting that the IL-1 receptor blocker crossed the BBB and exerted effects on IL-1 signaling in the grafted tissue.	10	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1Ra	IL-1Ra	IL-1Ra	IRAK	IRAK	IRAK	10	11	14	15
These data demonstrated that IL-1Ra treatment reduced IRAK staining in both control and HFHC diet treated recipient rats .	These data demonstrated that IL-1Ra treatment reduced IRAK staining in both control and HFHC diet treated recipient rats.	4	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1Ra	IL-1Ra	IL-1Ra	IRAK	IRAK	IRAK	4	5	7	8
In this study , we demonstrate that normal CD34 + cells , but not nonhematopoietic cells , express a novel functional hybrid receptor composed of the gammac and GM-CSFRbeta chains , in which the GM-CSFRbeta chain may inhibit gammac and JAK3 signaling .	In this study, we demonstrate that normal CD34 + cells, but not nonhematopoietic cells, express a novel functional hybrid receptor composed of the gammac and GM-CSFRbeta chains, in which the GM-CSFRbeta chain may inhibit gammac and JAK3 signaling.	26	41	inhibit	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	gammac	gammac	gammac	JAK3	JAK3	JAK3	26	27	40	41
Thus the IL-1Ra competitively inhibits the formation of active IL-1R1 and IL-1RAcP signaling complexes , thus preventing the proinflammatory signaling of IL-1alpha and IL-1beta ( XREF_FIG ) .	Thus the IL-1Ra competitively inhibits the formation of active IL-1R1 and IL-1RAcP signaling complexes, thus preventing the proinflammatory signaling of IL-1alpha and IL-1beta (XREF_FIG).	1	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-1Ra	IL-1Ra	IL-1Ra	IL-1RAcP	IL-1RAcP	IL-1RAcP	2	3	11	12
IL30 inhibits the toxicity of the liver independently of IL27 or WSX1 .	IL30 inhibits the toxicity of the liver independently of IL27 or WSX1.	0	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL30	IL30	IL30	WSX1	WSX1	WSX1	0	1	11	12
We also show that IL-34 inhibited SK-BR-3 migration independent of the CSF-1R as shown in cells treated with the CSF-1R blocking antibody .	We also show that IL-34 inhibited SK-BR-3 migration independent of the CSF-1R as shown in cells treated with the CSF-1R blocking antibody.	4	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-34	IL-34	IL-34	CSF-1R	CSF-1R	CSF-1R	4	5	11	12
IL-21 stimulated RA-FLS proliferation and promoted the production of TNF-alpha and IL-6 and blockade of IL-21 and IL-21R pathway with IL-21R .	IL-21 stimulated RA-FLS proliferation and promoted the production of TNF-alpha and IL-6 and blockade of IL-21 and IL-21R pathway with IL-21R.	0	18	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-21	IL-21	IL-21	IL-21R	IL-21R	IL-21R	0	1	17	18
This is not surprising given the above observations that IL-6Ralpha levels and IL-6 induced pSTAT3 are markedly decreased by day two .	This is not surprising given the above observations that IL-6Ralpha levels and IL-6 induced pSTAT3 are markedly decreased by day two.	10	17	induced	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	12	13	14	15
LNCap cells , which express STAT3 but lack constitutively active STAT3 and are attenuated the proliferation by IL-6 treatment , XREF_BIBR were treated with IL-6 and then examined for phosphorylated STAT3 .	LNCap cells, which express STAT3 but lack constitutively active STAT3 and are attenuated the proliferation by IL-6 treatment, XREF_BIBR were treated with IL-6 and then examined for phosphorylated STAT3.	5	18	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	17	18	5	6
A recent study shows that nitric oxide suppresses the activation of Stat3 by interleukin-6 in hepatocytes ; Stat3 is crucial for the IL-6-mediated induction of CRP and various other acute phase reactants .	A recent study shows that nitric oxide suppresses the activation of Stat3 by interleukin-6 in hepatocytes; Stat3 is crucial for the IL-6-mediated induction of CRP and various other acute phase reactants.	7	15	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	interleukin-6	interleukin-6	interleukin-6	Stat3	Stat3	Stat3	13	14	11	12
Matrine can also decrease the expression of IL-6 and activation of the IL-6 receptor mediated JAK and STAT3 signaling pathway .	Matrine can also decrease the expression of IL-6 and activation of the IL-6 receptor mediated JAK and STAT3 signaling pathway.	0	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	Matrine can also decrease the expression of IL-6 and activation of the IL-6	il-6	STAT3	STAT3	stat3	12	13	17	18
IL6 inhibits cell death by activating the transcription factor signal transducer and activator of transcription 3 ( STAT3 ) , which in turn can upregulate survival factors such as myeloid cell leukemia sequence 1 ( MCL1 ) and BCL-XL , anti-apoptotic BCL2 family members [ XREF_BIBR , XREF_BIBR ] .	IL6 inhibits cell death by activating the transcription factor signal transducer and activator of transcription 3 (STAT3), which in turn can upregulate survival factors such as myeloid cell leukemia sequence 1 (MCL1) and BCL-XL, anti-apoptotic BCL2 family members [XREF_BIBR, XREF_BIBR].	0	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	0	1	17	18
Our IL-6 knockdown system attenuated STAT3 activation ( XREF_FIG ) .	Our IL-6 knockdown system attenuated STAT3 activation (XREF_FIG).	1	6	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	5	6
In line with the drug screening results , JAK1 knockdown caused over 90 % inhibition in IL6 stimulated WT STAT3 , whereas mutated STAT3 activity remained unaltered .	In line with the drug screening results, JAK1 knockdown caused over 90% inhibition in IL6 stimulated WT STAT3, whereas mutated STAT3 activity remained unaltered.	14	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	16	17	19	20
An IL-6 neutralizing mAb reduced STAT3 activation and also completely reversed IL-17-stimulated tumor invasion in vitro , while exogenous IL-6 completely recovered IL-17-induced invasion of siRNA-AKT-SMMC7721 and siRNA-AKT-Huh7 cells .	An IL-6 neutralizing mAb reduced STAT3 activation and also completely reversed IL-17-stimulated tumor invasion in vitro, while exogenous IL-6 completely recovered IL-17-induced invasion of siRNA-AKT-SMMC7721 and siRNA-AKT-Huh7 cells.	1	6	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	5	6
Although the untreated group consisted of only three individuals , the reduced induction of pSTAT3 by IL-6 stimulation , and both pSTAT1 and pSTAT3 by IFN-alpha stimulation , remained statistically significant in pDCs ( P = 0.017 , P = 0.027 , and P = 0.020 , respectively ) .	Although the untreated group consisted of only three individuals, the reduced induction of pSTAT3 by IL-6 stimulation, and both pSTAT1 and pSTAT3 by IFN-alpha stimulation, remained statistically significant in pDCs (P = 0.017, P = 0.027, and P = 0.020, respectively).	12	17	induction	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	16	17	14	15
Quercetin inhibits epithelial-mesenchymal transition , decreases invasiveness and metastasis , and reverses IL-6 induced epithelial-mesenchymal transition , expression of MMP by inhibiting STAT3 signaling in pancreatic cancer cells .	Quercetin inhibits epithelial-mesenchymal transition, decreases invasiveness and metastasis, and reverses IL-6 induced epithelial-mesenchymal transition, expression of MMP by inhibiting STAT3 signaling in pancreatic cancer cells.	12	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	22	23
In an IL6 ko neuroblastoma model , the absence of IL-6 protein had no effect on tumor development and prevented neither STAT3 activation nor MYC up-regulation .	In an IL6 ko neuroblastoma model, the absence of IL-6 protein had no effect on tumor development and prevented neither STAT3 activation nor MYC up-regulation.	10	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	21	22
Thus , this may explain the observed inhibition of IL6 induced STAT3 activity by these compounds .	Thus, this may explain the observed inhibition of IL6 induced STAT3 activity by these compounds.	7	12	induced	Positive_early_activation	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	9	10	11	12
In addition , IL-6 ( 10 ng/ml ) reversed RY10-4-induced STAT3 inactivation , followed by the increase of cyclin E expression in RY10-4-treated HepG2 cells ( XREF_FIG ) .	In addition, IL-6 (10 ng/ml) reversed RY10-4-induced STAT3 inactivation, followed by the increase of cyclin E expression in RY10-4-treated HepG2 cells (XREF_FIG).	3	11	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	10	11
Moreover , DMC suppressed LPS induced IL-6 production , thereby blocking subsequent Stat3 activation .	Moreover, DMC suppressed LPS induced IL-6 production, thereby blocking subsequent Stat3 activation.	2	13	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	DMC suppressed LPS induced IL-6	il-6	Stat3	Stat3	stat3	6	7	12	13
Interleukin 6 induced p-STAT3 activation was completely suppressed in TF-1 cells by pretreatment with JAK inhibitor ruxolitinib for 1 hour ( XREF_FIG ) .	Interleukin 6 induced p-STAT3 activation was completely suppressed in TF-1 cells by pretreatment with JAK inhibitor ruxolitinib for 1 hour (XREF_FIG).	0	4	induced	Positive_early_activation	Positive_activation	Negative_activation	Interleukin 6	Interleukin 6	Interleukin 6	p-STAT3	p-STAT3	p-STAT3	0	2	3	4
We show that IL-6 reduced PCAT29 mRNA by activating STAT3 and miR-21 .	We show that IL-6 reduced PCAT29 mRNA by activating STAT3 and miR-21.	3	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	9	10
Perturbation of IL6 signaling in GSCs attenuates signal transducers and activators of transcription 3 ( STAT3 ) activation , and small molecule inhibitors of STAT3 potently induce GSC apoptosis .	Perturbation of IL6 signaling in GSCs attenuates signal transducers and activators of transcription 3 (STAT3) activation, and small molecule inhibitors of STAT3 potently induce GSC apoptosis.	2	16	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	2	3	15	16
Interleukin-6 receptor antagonist tocilizumab did not block the p-JAK2 or p-STAT3 downregulation induced by B7-H4 silence .	Interleukin-6 receptor antagonist tocilizumab did not block the p-JAK2 or p-STAT3 downregulation induced by B7-H4 silence.	0	11	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Interleukin-6	Interleukin-6	Interleukin-6	p-STAT3	p-STAT3	p-STAT3	0	1	10	11
Unexpectedly , IL6 induced Stat3 activation was also blocked by both Fak inhibitors ( XREF_FIG B-C ) .	Unexpectedly, IL6 induced Stat3 activation was also blocked by both Fak inhibitors (XREF_FIG B-C).	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	2	3	4	5
Reduced NF-KB additionally may reduce IL-6 mRNA expression , which in turn could inhibit IL-6 protein expression and reduce STAT-3 activation and affect its target genes ( such as IL-6 and c-myc ) involved in cell proliferation .	Reduced NF-KB additionally may reduce IL-6 mRNA expression, which in turn could inhibit IL-6 protein expression and reduce STAT-3 activation and affect its target genes (such as IL-6 and c-myc) involved in cell proliferation.	1	20	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	NF-KB additionally may reduce IL-6 mRNA expression	il-6	STAT-3	STAT-3	stat-3	5	6	19	20
In conclusion , prednisone , ibuprofen and betamethasone may prevent OA by suppressing the expression of IL-6 and IL-8 , subsequently inactivating NF-kappaB and STAT3 pathways , and ultimately , leading to decreased levels of collagen I , MMP-1 , and MMP-13 .	In conclusion, prednisone, ibuprofen and betamethasone may prevent OA by suppressing the expression of IL-6 and IL-8, subsequently inactivating NF-kappaB and STAT3 pathways, and ultimately, leading to decreased levels of collagen I, MMP-1, and MMP-13.	3	25	inactivating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	prednisone, ibuprofen and betamethasone may prevent OA by suppressing the expression of IL-6	il-6	STAT3	STAT3	stat3	16	17	24	25
As expected , re-expression of IL-6 in A549 HIC1 and H292 HIC1 cells somehow rescued HIC1 induced reduction of p-STAT3 Y705 , Bcl-2 , Survivin and MMP2 .	As expected, re-expression of IL-6 in A549 HIC1 and H292 HIC1 cells somehow rescued HIC1 induced reduction of p-STAT3 Y705, Bcl-2, Survivin and MMP2.	3	20	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	re-expression of IL-6	il-6	p-STAT3	p-STAT3	p-stat3	5	6	19	20
Both are being trialled in solid tumor indications and a role of siltuximab in suppressing IL-6 mediated STAT3 activation has been described [ XREF_BIBR ] .	Both are being trialled in solid tumor indications and a role of siltuximab in suppressing IL-6 mediated STAT3 activation has been described [XREF_BIBR].	12	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	15	16	17	18
Although the neutralizing antibody against IL-6 had minimal effects , the production of Arg1 and the phosphorylation of STAT3 were completely inhibited in BCG infected macrophages treated with neutralizing antibodies against IL-6 , IL-10 , and G-CSF ( XREF_FIG ) .	Although the neutralizing antibody against IL-6 had minimal effects, the production of Arg1 and the phosphorylation of STAT3 were completely inhibited in BCG infected macrophages treated with neutralizing antibodies against IL-6, IL-10, and G-CSF (XREF_FIG).	16	38	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	31	32	18	19
To evaluate the relevance of STAT3-decoy ODN and STAT3 interaction in the reduction of nuclear STAT3 , cells were transfected with STAT3-decoy ODN and treated with IL-6 , and nuclear STAT3 was analyzed .	To evaluate the relevance of STAT3-decoy ODN and STAT3 interaction in the reduction of nuclear STAT3, cells were transfected with STAT3-decoy ODN and treated with IL-6, and nuclear STAT3 was analyzed.	12	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	15	16
In vivo neutralization of IL-6 trans signaling decreased STAT3 activation in myofibroblasts .	In vivo neutralization of IL-6 trans signaling decreased STAT3 activation in myofibroblasts.	4	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	8	9
Blocking IL-6 would inhibit STAT3 mediated IL-6 signaling , which maintains the CSC phenotype , and downregulate STAT3 target gene induction such as Bcl-xL , Survivin , and c-Myc .	Blocking IL-6 would inhibit STAT3 mediated IL-6 signaling, which maintains the CSC phenotype, and downregulate STAT3 target gene induction such as Bcl-xL, Survivin, and c-Myc.	0	7	inhibit	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	IL-6	IL-6	il-6	STAT3	STAT3 mediated IL-6	stat3	1	2	4	5
Ectopic expression of IRE1alpha and XBP1s in melanocytes and melanoma cells increased IL-6 levels and then activated intracellular STAT3 signaling , which was diminished by the addition of IL-6 antibodies .	Ectopic expression of IRE1alpha and XBP1s in melanocytes and melanoma cells increased IL-6 levels and then activated intracellular STAT3 signaling, which was diminished by the addition of IL-6 antibodies.	18	29	diminished	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	28	29	18	19
PROS reduced phosphorylation of signal transducer and activator of transcription 3 ( STAT3 ) ( Tyr705 ) as a transcription factor in A549 and H460 cells and also attenuated the phosphorylation of interleukin 6 ( IL-6 ) activated ERK and STAT3 in STAT3 low level H1299 cells .	PROS reduced phosphorylation of signal transducer and activator of transcription 3 (STAT3) (Tyr705) as a transcription factor in A549 and H460 cells and also attenuated the phosphorylation of interleukin 6 (IL-6) activated ERK and STAT3 in STAT3 low level H1299 cells.	30	41	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	interleukin 6	phosphorylation of interleukin 6	interleukin 6	STAT3	STAT3	stat3	32	34	40	41
IL-6 is known to increase NFkappaB and STAT3 causing inhibition of apoptosis and increased myeloproliferation , hence creating an environment favorable to malignant transformation and expansion [ XREF_BIBR , XREF_BIBR ] .	IL-6 is known to increase NFkappaB and STAT3 causing inhibition of apoptosis and increased myeloproliferation, hence creating an environment favorable to malignant transformation and expansion [XREF_BIBR, XREF_BIBR].	0	13	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	0	1	7	8
RA serum was able to induce tyrosine phosphorylation of STAT3 but not STAT1 , and this STAT3 activation was mostly abolished by neutralization of IL-6 activity .	RA serum was able to induce tyrosine phosphorylation of STAT3 but not STAT1, and this STAT3 activation was mostly abolished by neutralization of IL-6 activity.	16	25	abolished	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	24	25	16	17
Results demonstrated a substantial reduction of STAT-3 activation in the lungs of Ada -/- mice treated with IL-6 neutralizing antibodies ( XREF_FIG ) or following the genetic removal of IL-6 ( XREF_FIG ) .	Results demonstrated a substantial reduction of STAT-3 activation in the lungs of Ada -/- mice treated with IL-6 neutralizing antibodies (XREF_FIG) or following the genetic removal of IL-6 (XREF_FIG).	6	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	17	18	6	7
In contrast , the pSTAT3 : pSTAT1 ratio was significantly lowered in T cells treated with IL-27+ IL-6 compared to T cells treated with IL-6 alone , resulting in inhibition of Th17 differentiation .	In contrast, the pSTAT3 : pSTAT1 ratio was significantly lowered in T cells treated with IL-27+ IL-6 compared to T cells treated with IL-6 alone, resulting in inhibition of Th17 differentiation.	3	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	17	18	4	5
Dominguez et al suggested that intrathecal injection of anti-rat IL-6 antibodies obviously prevented SNL induced accumulation of phospho-STAT3 in dorsal spinal cord microglia .	Dominguez et al suggested that intrathecal injection of anti-rat IL-6 antibodies obviously prevented SNL induced accumulation of phospho-STAT3 in dorsal spinal cord microglia.	9	18	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	phospho-STAT3	phospho-STAT3	phospho-STAT3	9	10	17	18
However , there remain some questions as to whether matrine can inhibit the expression of IL-6 or promote inactivation of the JAK1 and STAT3 signaling pathway in H1975 cells stimulated by afatinib , and whether a combination of matrine and afatinib can further inhibit H1975 cells .	However, there remain some questions as to whether matrine can inhibit the expression of IL-6 or promote inactivation of the JAK1 and STAT3 signaling pathway in H1975 cells stimulated by afatinib, and whether a combination of matrine and afatinib can further inhibit H1975 cells.	9	25	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	matrine can inhibit the expression of IL-6	il-6	STAT3	STAT3	stat3	15	16	23	24
In contrast , IL-6 did not prevent apoptosis of Stat3 deficient T cells .	In contrast, IL-6 did not prevent apoptosis of Stat3 deficient T cells.	3	12	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	3	4	9	10
The presence of an IL-6 monoclonal antibody that neutralized secreted IL-6 reduced the levels of both pYB-1 S102 and pSTAT3 Y705 .	The presence of an IL-6 monoclonal antibody that neutralized secreted IL-6 reduced the levels of both pYB-1 S102 and pSTAT3 Y705.	4	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	4	5	19	20
RBM47 was directly suppressed during EMT induced by IL6 activated STAT3 or ectopic SNAIL and SLUG expression via conserved binding motifs of these factors within the RBM47 promoter .	RBM47 was directly suppressed during EMT induced by IL6 activated STAT3 or ectopic SNAIL and SLUG expression via conserved binding motifs of these factors within the RBM47 promoter.	6	16	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	8	9	10	11
Reduced expression of IL-6 receptor components or other IL-6 family members that , similar to IL-6 , promote STAT3 activation could be responsible for reduced STAT3 phosphorylation in egr-1-/- mice , despite normal IL-6 expression .	Reduced expression of IL-6 receptor components or other IL-6 family members that, similar to IL-6, promote STAT3 activation could be responsible for reduced STAT3 phosphorylation in egr-1-/- mice, despite normal IL-6 expression.	8	19	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	18	19
Our data indicate that IL-6 inhibits starvation induced autophagy and activates p-STAT3 to regulate the effect of Bcl-2 on Beclin 1 and VPS34 .	Our data indicate that IL-6 inhibits starvation induced autophagy and activates p-STAT3 to regulate the effect of Bcl-2 on Beclin 1 and VPS34.	4	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	4	5	11	12
The inhibitory effect of INPP5F on STAT3 phosphorylation was further demonstrated in INPP5F overexpressing GSC923 cells after treated with interleukin-6 ( IL-6 ) stimulation ( XREF_FIG ) .	The inhibitory effect of INPP5F on STAT3 phosphorylation was further demonstrated in INPP5F overexpressing GSC923 cells after treated with interleukin-6 (IL-6) stimulation (XREF_FIG).	6	22	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	21	22	6	7
In line with these findings , we demonstrated that loss of SOCS3 protein expression in MCF10A-p53 - PTEN - cells plays crucial role in tumor development and progression via activating IL6 mediated Stat3 and NF-kappaB pathway .	In line with these findings, we demonstrated that loss of SOCS3 protein expression in MCF10A-p53 - PTEN - cells plays crucial role in tumor development and progression via activating IL6 mediated Stat3 and NF-kappaB pathway.	22	35	mediated	Positive_early_activation	Positive_activation	Negative_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	30	31	32	33
When KPL-4-Stat3-Luc cells were directly exposed to malignant pleural effusions , we again observed significant activation of Stat3 ( XREF_FIG ) , which was inhibited by addition of neutralizing IL-6 antibody ( XREF_FIG ) .	When KPL-4-Stat3-Luc cells were directly exposed to malignant pleural effusions, we again observed significant activation of Stat3 (XREF_FIG), which was inhibited by addition of neutralizing IL-6 antibody (XREF_FIG).	15	30	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	29	30	17	18
It is conceivable that down regulation of IL-6 receptors or the induction of protein inhibitor of activated STAT3 ( PIAS3 ) may have diminished the smoke mediated induction of STAT3 at the 1-year time point .	It is conceivable that down regulation of IL-6 receptors or the induction of protein inhibitor of activated STAT3 (PIAS3) may have diminished the smoke mediated induction of STAT3 at the 1-year time point.	7	30	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	29	30
These findings suggest that alveolar airway epithelial cells are a major target of adenosine and IL-6 mediated STAT-3 activation in the lungs of Ada -/- mice .	These findings suggest that alveolar airway epithelial cells are a major target of adenosine and IL-6 mediated STAT-3 activation in the lungs of Ada -/- mice.	11	18	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT-3	STAT-3	STAT-3	15	16	17	18
Finally , although RIP4 is known to activate NF-kappaB signaling , reducing NEMO did not alter the impact of RIP4 on IL6 mediated STAT3 nuclear localization ( XREF_SUPPLEMENTARY ) .	Finally, although RIP4 is known to activate NF-kappaB signaling, reducing NEMO did not alter the impact of RIP4 on IL6 mediated STAT3 nuclear localization (XREF_SUPPLEMENTARY).	15	25	mediated	Positive_early_activation	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	21	22	23	24
However , during obesity IL6 inhibits peripheral insulin signalling by stimulating STAT3 to SOCS3 signalling [ XREF_BIBR ] .	However, during obesity IL6 inhibits peripheral insulin signalling by stimulating STAT3 to SOCS3 signalling [XREF_BIBR].	3	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	4	5	11	12
Therefore , excessive CUDR promotes and CUDR knockdown inhibited the transcription ( XREF_FIG ) , translation and phosphorylation ( XREF_FIG ) of Stat3 in hepatocyte like cells treated with IL6 .	Therefore, excessive CUDR promotes and CUDR knockdown inhibited the transcription (XREF_FIG), translation and phosphorylation (XREF_FIG) of Stat3 in hepatocyte like cells treated with IL6.	15	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	29	30	22	23
In our model of T/HS , proinflammatory genes upregulated by T/HS are likely to be mediators of liver inflammation , which is likely prevented by IL-6 normalizing effect on their expression through Stat3 activation .	In our model of T/HS, proinflammatory genes upregulated by T/HS are likely to be mediators of liver inflammation, which is likely prevented by IL-6 normalizing effect on their expression through Stat3 activation.	23	33	prevented	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	25	26	32	33
The ETS factor ESE3 and EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem like compartment .	The ETS factor ESE3 and EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem like compartment.	6	10	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
However , the level of IL-6 induced STAT3 transcriptional activity within NH 4 Cl treated cells as compared to cells without inhibitor was significantly reduced ( XREF_FIG ) .	However, the level of IL-6 induced STAT3 transcriptional activity within NH 4 Cl treated cells as compared to cells without inhibitor was significantly reduced (XREF_FIG).	3	9	induced	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
In contrast , simultaneous neutralization of both IL-17A and TNF-alpha , which abrogates NF-kB signaling , and IL-22 and IL-6 , which abrogates STAT3 signaling , reduces the mitogenic effect of supernatants in CRC cells .	In contrast, simultaneous neutralization of both IL-17A and TNF-alpha, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells.	14	24	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	23	24
Simultaneous neutralization of IL-17A , TNF-alpha , IL-22 and IL-6 reduced both STAT3 and NF-kB activation and significantly inhibited growth of cells induced by TIL derived supernatants compared with cells preincubated with anti-IL-22 and anti-IL-6 ( XREF_FIG ) .	Simultaneous neutralization of IL-17A, TNF-alpha, IL-22 and IL-6 reduced both STAT3 and NF-kB activation and significantly inhibited growth of cells induced by TIL derived supernatants compared with cells preincubated with anti-IL-22 and anti-IL-6 (XREF_FIG).	1	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	12	13
Unexpectedly , we found that tocilizumab , a humanized anti-human IL-6 receptor antibody , could not block rhIL-6-mediated STAT3 activation in PAECs .	Unexpectedly, we found that tocilizumab, a humanized anti-human IL-6 receptor antibody, could not block rhIL-6-mediated STAT3 activation in PAECs.	10	19	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	18	19
Therefore , it is possible that SK1 regulation of IL6 in colon tissues ( XREF_FIG ) indirectly prevents STAT3 activation by modulation of IL6 .	Therefore, it is possible that SK1 regulation of IL6 in colon tissues (XREF_FIG) indirectly prevents STAT3 activation by modulation of IL6.	7	19	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	9	10	18	19
Targets of let-7 include HMGA2 , which promotes EMT , Ras , which promotes self-renewal , and IL6 , which activates Stat3 to promote cell motility , growth , and self-renewal [ XREF_BIBR , XREF_BIBR ] .	Targets of let-7 include HMGA2, which promotes EMT, Ras, which promotes self-renewal, and IL6, which activates Stat3 to promote cell motility, growth, and self-renewal [XREF_BIBR, XREF_BIBR].	4	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	17	18	21	22
IL-6 can induce P-STAT3 and other downstream target ( such as AKT or ERK ) through autocrine pathway .	IL-6 can induce P-STAT3 and other downstream target (such as AKT or ERK) through autocrine pathway.	0	7	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	P-STAT3	P-STAT3	P-STAT3	0	1	3	4
To elucidate the role of IL-6 in the interactions between cardiac fibroblasts and myocytes , we performed in vitro studies and demonstrated that IL-6 deficiency attenuated the activation of the STAT3 pathway and VEGF production .	To elucidate the role of IL-6 in the interactions between cardiac fibroblasts and myocytes, we performed in vitro studies and demonstrated that IL-6 deficiency attenuated the activation of the STAT3 pathway and VEGF production.	23	31	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	23	24	30	31
We found cross-inhibition of IL-6 induced STAT3 activation by the anti-inflammatory annexin peptide , whereas STAT3 activation induced by the annexin peptide is not affected by prior IL-6 challenge .	We found cross-inhibition of IL-6 induced STAT3 activation by the anti-inflammatory annexin peptide, whereas STAT3 activation induced by the annexin peptide is not affected by prior IL-6 challenge.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
Second , prostate cancer cells transfected for constitutive production of SOCS1 protein had reduced activation of STAT3 by IL6 treatment .	Second, prostate cancer cells transfected for constitutive production of SOCS1 protein had reduced activation of STAT3 by IL6 treatment.	14	19	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	18	19	16	17
Furthermore , Chromatin immunoprecipitation ( ChIP ) assays revealed decreased binding of pSTAT3 to the SOCS3 promoter in DOCK8 deficient T cells treated with IL-6 , consistent with the decreased SOCS3 transcription in these cells ( XREF_FIG ) .	Furthermore, Chromatin immunoprecipitation (ChIP) assays revealed decreased binding of pSTAT3 to the SOCS3 promoter in DOCK8 deficient T cells treated with IL-6, consistent with the decreased SOCS3 transcription in these cells (XREF_FIG).	10	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	24	25	12	13
Western blot analysis revealed a dose dependent decrease of STAT3 pY705 phosphorylation when cells were treated with 40ng/ml IL-6 in the presence of 250-750 nM CPT for 12h .	Western blot analysis revealed a dose dependent decrease of STAT3 pY705 phosphorylation when cells were treated with 40ng/ml IL-6 in the presence of 250-750 nM CPT for 12h.	9	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	9	10
Moreover , excessive CUDR increased and CUDR knockdown reduced the Stat3 promoter luciferase activity in hepatocyte like stem cells treated with IL6 ( XREF_FIG ) .	Moreover, excessive CUDR increased and CUDR knockdown reduced the Stat3 promoter luciferase activity in hepatocyte like stem cells treated with IL6 (XREF_FIG).	10	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	21	22	10	11
BTK knockdown in INA6 cells did not change IL-6 mediated STAT3 or STAT5 phosphorylation state , negating the role of BTK upstream of STAT activation in IL-6 signaling pathway [ XREF_BIBR ] .	BTK knockdown in INA6 cells did not change IL-6 mediated STAT3 or STAT5 phosphorylation state, negating the role of BTK upstream of STAT activation in IL-6 signaling pathway [XREF_BIBR].	7	14	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
Experimental studies are currently being conducted to identify selective inhibitors of IL-6 induced STAT3 in the treatment of HNC [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Experimental studies are currently being conducted to identify selective inhibitors of IL-6 induced STAT3 in the treatment of HNC [XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	14	induced	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	11	12	13	14
As shown previously , IL-6 induced STAT3 activation was inhibited by the anti-gp130 mAb .	As shown previously, IL-6 induced STAT3 activation was inhibited by the anti-gp130 mAb.	4	7	induced	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
To provide evidence that supported the hypothesis that phosphorylated-Stat3 expression may promote cisplatin resistance , ectopic Stat3 was expressed by IL-6 stimulation that partially abrogates Stat3 , as opposed to the knock-down of Stat3 by specific siRNA that restores cisplatin sensitivity against ovarian cancer cells .	To provide evidence that supported the hypothesis that phosphorylated-Stat3 expression may promote cisplatin resistance, ectopic Stat3 was expressed by IL-6 stimulation that partially abrogates Stat3, as opposed to the knock-down of Stat3 by specific siRNA that restores cisplatin sensitivity against ovarian cancer cells.	20	26	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	20	21	25	26
In contrast , the absence of IL-6 , but not IL-11 signaling , prevented the splenomegaly , abnormal lymphopoiesis , and STAT3 hyperactivation in lymphoid organs of gp130 ( Y757F and Y757F ) mice .	In contrast, the absence of IL-6, but not IL-11 signaling, prevented the splenomegaly, abnormal lymphopoiesis, and STAT3 hyperactivation in lymphoid organs of gp130 (Y757F and Y757F) mice.	4	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	6	7	21	22
Both IL6 and TGFbeta exposure attenuated luciferase activity of the Ces3-1.4 k reporter with putative signal transducer and activator of transcription 3 ( STAT3 ) - and MAD homolog 3 ( SMAD3 )-binding sites in Hepa1c1 cells , but they did not affect the Ces3-0.7 k reporter without the sites ( XREF_FIG ) .	Both IL6 and TGFbeta exposure attenuated luciferase activity of the Ces3-1.4 k reporter with putative signal transducer and activator of transcription 3 (STAT3) - and MAD homolog 3 (SMAD3)-binding sites in Hepa1c1 cells, but they did not affect the Ces3-0.7 k reporter without the sites (XREF_FIG).	1	24	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	1	2	23	24
In addition , antibodies to IL-6 , and in particular mAb # 8 , a monoclonal IL-6 antibody that binds the interaction site between IL-6 and IL-6Ralpha XREF_BIBR , failed to block Stat3 activation in T cells in response to LPS activated co-cultured BMDCs ( XREF_FIG ) .	In addition, antibodies to IL-6, and in particular mAb # 8, a monoclonal IL-6 antibody that binds the interaction site between IL-6 and IL-6Ralpha XREF_BIBR, failed to block Stat3 activation in T cells in response to LPS activated co-cultured BMDCs (XREF_FIG).	16	33	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	16	17	32	33
In addition , it inhibited the activation of STAT3 by IL-6 and subsequent synthesis of downstream molecules in HCC and W4P-NIH3T3 cells .	In addition, it inhibited the activation of STAT3 by IL-6 and subsequent synthesis of downstream molecules in HCC and W4P-NIH3T3 cells.	6	13	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	8	9
Stat3 activation in SKOV3 cells was abrogated by simultaneous neutralization of IL-6 and IL-10 .	Stat3 activation in SKOV3 cells was abrogated by simultaneous neutralization of IL-6 and IL-10.	0	13	abrogated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	11	12	0	1
Interleukin-6 ( IL-6 ) deficiency inhibited the activation of STAT3 and the induction of select APPs in the livers of pneumonic mice .	Interleukin-6 (IL-6) deficiency inhibited the activation of STAT3 and the induction of select APPs in the livers of pneumonic mice.	0	10	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Interleukin-6	Interleukin-6	Interleukin-6	STAT3	STAT3	STAT3	0	1	9	10
Resveratrol inhibited both the constitutive and the interleukin 6 induced activation of STAT3 .	Resveratrol inhibited both the constitutive and the interleukin 6 induced activation of STAT3.	4	13	induced	Positive_early_activation	Positive_activation	Positive_activation	interleukin 6	interleukin 6	interleukin 6	STAT3	STAT3	STAT3	7	9	12	13
We therefore tested whether the CO donors TCDC and MC suppress IL6 induced STAT3 activation .	We therefore tested whether the CO donors TCDC and MC suppress IL6 induced STAT3 activation.	10	14	induced	Positive_early_activation	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	11	12	13	14
Transient transfection of HA-RKIP inhibited IL-6 mediated STAT3 pY 705 phosphorylation 50 % ( relative intensity 2.82 vs. 1.4 ) .	Transient transfection of HA-RKIP inhibited IL-6 mediated STAT3 pY 705 phosphorylation 50% (relative intensity 2.82 vs. 1.4).	4	8	mediated	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	7	8
Second , LNCaP prostate cancer cells transfected for constitutive production of SOCS-1 protein had reduced activation of STAT3 by IL-6 treatment .	Second, LNCaP prostate cancer cells transfected for constitutive production of SOCS-1 protein had reduced activation of STAT3 by IL-6 treatment.	15	20	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	19	20	17	18
Moreover , OSU-53 suppressed interleukin-6 ( IL-6 ) production , thereby blocking subsequent Stat3 activation and inhibited hypoxia induced epithelial-mesenchymal transition .	Moreover, OSU-53 suppressed interleukin-6 (IL-6) production, thereby blocking subsequent Stat3 activation and inhibited hypoxia induced epithelial-mesenchymal transition.	4	14	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	6	7	13	14
The genetic ablation of IL-6 suppressed STAT3 induction and delayed disease onset in Rrm2b -/- mice , extending their life span .	The genetic ablation of IL-6 suppressed STAT3 induction and delayed disease onset in Rrm2b -/- mice, extending their life span.	2	7	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
Insulin signaling in the hypothalamus stimulates IL-6 production in the liver , and IL6 in turn suppresses gluconeogenesis by activating STAT3 .	Insulin signaling in the hypothalamus stimulates IL-6 production in the liver, and IL6 in turn suppresses gluconeogenesis by activating STAT3.	13	21	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	13	14	20	21
Neutralizing IL-6 with a specific antibody partially inhibited the IL-6 and STAT3 signaling pathway and reversed the promoter role of BC-MSCs in MCF-7 cells .	Neutralizing IL-6 with a specific antibody partially inhibited the IL-6 and STAT3 signaling pathway and reversed the promoter role of BC-MSCs in MCF-7 cells.	0	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	11	12
This observation indicated that , consistent with the results reported by earlier workers , the reduction of the Bcl2 protein level caused by quercetin might have occurred as a result of the inhibition of the IL-6 induced STAT3 signaling and by the down-regulation of NF-kappaB activity [ XREF_BIBR , XREF_BIBR ] .	This observation indicated that, consistent with the results reported by earlier workers, the reduction of the Bcl2 protein level caused by quercetin might have occurred as a result of the inhibition of the IL-6 induced STAT3 signaling and by the down-regulation of NF-kappaB activity [XREF_BIBR, XREF_BIBR].	32	38	induced	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	35	36	37	38
Silencing IL-6 in immDCs with IL-6 specific siRNA failed to cause STAT3 activation , thus indicating the involvement of IL-6 in Nef dependent STAT3 activation .	Silencing IL-6 in immDCs with IL-6 specific siRNA failed to cause STAT3 activation, thus indicating the involvement of IL-6 in Nef dependent STAT3 activation.	0	12	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	11	12
Following iron chelation or disruption of DMT1 in the tumors , IL6 induced STAT3 signaling was significantly attenuated .	Following iron chelation or disruption of DMT1 in the tumors, IL6 induced STAT3 signaling was significantly attenuated.	11	14	induced	Positive_early_activation	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	11	12	13	14
Consistent with the findings of other studies , these results indicated that IL-6 inhibits the apoptosis of astrocytes by activating the IL-6 and STAT3 signaling pathway XREF_BIBR XREF_BIBR .	Consistent with the findings of other studies, these results indicated that IL-6 inhibits the apoptosis of astrocytes by activating the IL-6 and STAT3 signaling pathway XREF_BIBR XREF_BIBR.	12	27	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	23	24
Neutralizing IL-6 was sufficient to block activation of STAT3 .	Neutralizing IL-6 was sufficient to block activation of STAT3.	0	9	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	1	2	8	9
In cells pre-incubated with Sant7 , IL-6 mediated pSTAT3 was significantly reduced ( XREF_FIG ) .	In cells pre-incubated with Sant7, IL-6 mediated pSTAT3 was significantly reduced (XREF_FIG).	6	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	6	7	8	9
In these cells , IL-6 induced a marked reduction in the immunologic accessibility of cytoplasmic and nuclear STAT3 and STAT5 within 20 to 30 min that lasted 2 to 4 h ( STAT masking ) provided that the cells had been previously cultured at 32.5 degrees C for at least 18 to 20 h.	In these cells, IL-6 induced a marked reduction in the immunologic accessibility of cytoplasmic and nuclear STAT3 and STAT5 within 20 to 30 min that lasted 2 to 4 h (STAT masking) provided that the cells had been previously cultured at 32.5 degrees C for at least 18 to 20 h.	4	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	17	18
Combined neutralization of IL-22 and IL-6 reduced but did not abrogate TIL supernatant induced STAT3 activation and CRC cell proliferation , probably because of the presence of additional STAT3 activating cytokines and factors in TIL derived supernatants ( for example , IL-11 or EGF ) .	Combined neutralization of IL-22 and IL-6 reduced but did not abrogate TIL supernatant induced STAT3 activation and CRC cell proliferation, probably because of the presence of additional STAT3 activating cytokines and factors in TIL derived supernatants (for example, IL-11 or EGF).	1	15	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	14	15
The diminished amount of IL-6 in the supernatant resulted in a weaker activation of STAT3 and , consequently , in the diminished induction of IDO and of PD-L1 .	The diminished amount of IL-6 in the supernatant resulted in a weaker activation of STAT3 and, consequently, in the diminished induction of IDO and of PD-L1.	2	15	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	IL-6	amount of IL-6	il-6	STAT3	STAT3	stat3	4	5	14	15
SOCS3 inhibits IL6 mediated Stat3 signaling by binding to the Jak2 kinase domain and IL6 receptor beta-chain .	SOCS3 inhibits IL6 mediated Stat3 signaling by binding to the Jak2 kinase domain and IL6 receptor beta-chain.	1	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	2	3	4	5
Interleukin-6 Promotes Proliferation but Inhibits Tenogenic Differentiation via the Janus Kinase and Signal Transducers and Activators of Transcription 3 ( JAK and STAT3 ) Pathway in Tendon Derived Stem Cells .	Interleukin-6 Promotes Proliferation but Inhibits Tenogenic Differentiation via the Janus Kinase and Signal Transducers and Activators of Transcription 3 (JAK and STAT3) Pathway in Tendon Derived Stem Cells.	0	23	Inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Interleukin-6	Interleukin-6	Interleukin-6	STAT3	STAT3	STAT3	0	1	22	23
Repression of prdm1 by Bcl6 occurs under T FH -priming conditions , likely because IL-6 and IL-21 under these conditions strongly induce Stat3 .	Repression of prdm1 by Bcl6 occurs under T FH -priming conditions, likely because IL-6 and IL-21 under these conditions strongly induce Stat3.	14	23	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	14	15	22	23
Neutralizing IL-6 in the conditioned media did not seem to significantly reduce p-STAT3 .	Neutralizing IL-6 in the conditioned media did not seem to significantly reduce p-STAT3.	0	13	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	1	2	12	13
Using cultured GBM cell lines as well as primary human GBM xenografts , we elucidated the signaling crosstalk between the NF-kappaB and STAT3 pathways utilizing approaches that either a ) reduce NF-kappaB p65 expression , b ) inhibit NF-kappaB activation , c ) interfere with IL-6 signaling , or d ) inhibit STAT3 activation .	Using cultured GBM cell lines as well as primary human GBM xenografts, we elucidated the signaling crosstalk between the NF-kappaB and STAT3 pathways utilizing approaches that either a) reduce NF-kappaB p65 expression, b) inhibit NF-kappaB activation, c) interfere with IL-6 signaling, or d) inhibit STAT3 activation.	45	53	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	45	46	52	53
Induction of these two signalling pathways with exogenous ligands had opposite effects on 15d-PGJ 2 activity in that only TGF-alpha , but not IL-6 , stimulation could reverse 15d-PGJ 2 -induced Stat3 downregulation .	Induction of these two signalling pathways with exogenous ligands had opposite effects on 15d-PGJ 2 activity in that only TGF-alpha, but not IL-6, stimulation could reverse 15d-PGJ 2 -induced Stat3 downregulation.	19	32	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	Stat3	Stat3	Stat3	23	24	31	32
The majority of STAT3 targets that were induced by IL-6 were also induced during kidney aging ( 84 % concordance , p < 0.001 , Binomial test ) .	The majority of STAT3 targets that were induced by IL-6 were also induced during kidney aging (84% concordance, p < 0.001, Binomial test).	3	10	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	9	10	3	4
Furthermore , berberine also inhibited the activation of STAT3 by IL-6 in NPC cells .	Furthermore, berberine also inhibited the activation of STAT3 by IL-6 in NPC cells.	4	13	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	8	9
The data suggested that IL-6 induced STAT3 activation and the IL-6-induced STAT3 activation was inhibited by Stattic in a dose dependent manner .	The data suggested that IL-6 induced STAT3 activation and the IL-6-induced STAT3 activation was inhibited by Stattic in a dose dependent manner.	4	7	induced	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	6	7
XREF_BIBR , XREF_BIBR By using a high content phenotypic screen ( HCS ) to identify selective inhibitors of IL-6 induced activation of the STAT3 pathway , 11 we identified the quinazoline 11a ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR By using a high content phenotypic screen (HCS) to identify selective inhibitors of IL-6 induced activation of the STAT3 pathway, 11 we identified the quinazoline 11a (XREF_FIG).	16	24	induced	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	18	19	23	24
The concurrent neutralization of either IL-6 and IL-22 or TNF-alpha and IL-17A inhibited NF-kappaB or STAT3 signaling , respectively , and reduced the mitogenic effects of these cytokines on human colorectal cancer cells .	The concurrent neutralization of either IL-6 and IL-22 or TNF-alpha and IL-17A inhibited NF-kappaB or STAT3 signaling, respectively, and reduced the mitogenic effects of these cytokines on human colorectal cancer cells.	2	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	15	16
Therefore , it appears that beta1 integrin and IL-6 mediated STAT3 signaling in RPMI 8226 cells may target alternate anti-apoptotic and/or proliferative factor ( s ) .	Therefore, it appears that beta1 integrin and IL-6 mediated STAT3 signaling in RPMI 8226 cells may target alternate anti-apoptotic and/or proliferative factor (s).	6	11	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	8	9	10	11
As shown in XREF_FIG , the antibody mediated neutralization of IL-6 in irradiated tumor supernatants reduced STAT3 activation in splenocytes .	As shown in XREF_FIG, the antibody mediated neutralization of IL-6 in irradiated tumor supernatants reduced STAT3 activation in splenocytes.	8	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	10	11	16	17
As large excess of exogenous IL-6 reversed the let-7-mediated downregulation of STAT3 signaling , there is likely no defect in JAK activity in the PDAC cells in our experiments .	As large excess of exogenous IL-6 reversed the let-7-mediated downregulation of STAT3 signaling, there is likely no defect in JAK activity in the PDAC cells in our experiments.	2	12	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	5	6	11	12
We confirmed that addition of AF from OC patients into PBMC from healthy donors induced a rapid and durative activation of STAT3 signaling pathway where inclusion of Stattic as well as IL-6 and IL-10 neutralizing antibodies blocked STAT3 activation ( XREF_SUPPLEMENTARY ) .	We confirmed that addition of AF from OC patients into PBMC from healthy donors induced a rapid and durative activation of STAT3 signaling pathway where inclusion of Stattic as well as IL-6 and IL-10 neutralizing antibodies blocked STAT3 activation (XREF_SUPPLEMENTARY).	31	38	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	31	32	37	38
The data showed that once gp130 and STAT3 activation in BMSCs was blocked by sgp130 , the increase in migration and cell numbers of BMSCs by IL-6 protein or conditioned media treatment was abolished .	The data showed that once gp130 and STAT3 activation in BMSCs was blocked by sgp130, the increase in migration and cell numbers of BMSCs by IL-6 protein or conditioned media treatment was abolished.	5	27	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	26	27	7	8
IL-6 neutralising antibodies significantly reduced p-STAT3 .	IL-6 neutralising antibodies significantly reduced p-STAT3.	0	6	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	0	1	5	6
Similarly , AG490 blocked only in part the activation of STAT3 by IL-6 ( XREF_SUPPLEMENTARY ) .	Similarly, AG490 blocked only in part the activation of STAT3 by IL-6 (XREF_SUPPLEMENTARY).	8	14	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	12	13	10	11
In a concentration dependent manner , Il6 neutralizing antibodies also decreased proliferation of the double mutant MEFs ( XREF_SUPPLEMENTARY ) and suppressed Stat3 and Myc activation ( XREF_SUPPLEMENTARY ) .	In a concentration dependent manner, Il6 neutralizing antibodies also decreased proliferation of the double mutant MEFs (XREF_SUPPLEMENTARY) and suppressed Stat3 and Myc activation (XREF_SUPPLEMENTARY).	6	25	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Il6	Il6	Il6	Stat3	Stat3	Stat3	6	7	22	23
Furthermore , the Ref-1 inhibitor E3330 blocks IL-6 induced STAT3 DNA binding without affecting total STAT3 protein levels or the phosphorylation of Y 705 [ XREF_BIBR ] .	Furthermore, the Ref-1 inhibitor E3330 blocks IL-6 induced STAT3 DNA binding without affecting total STAT3 protein levels or the phosphorylation of Y 705 [XREF_BIBR].	7	11	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	9	10
In WT mice , IL-6 neutralization only slightly reduced pSTAT3 without affecting fibrin ( XREF_FIG ) indicating that IL-6 induced pSTAT3 is strongly regulated by CYLD , which limits STAT3 activity and STAT3 dependent fibrin production .	In WT mice, IL-6 neutralization only slightly reduced pSTAT3 without affecting fibrin (XREF_FIG) indicating that IL-6 induced pSTAT3 is strongly regulated by CYLD, which limits STAT3 activity and STAT3 dependent fibrin production.	18	23	induced	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	pSTAT3	pSTAT3	pSTAT3	18	19	20	21
In addition , the intrathecal injection of anti-rat IL-6 antibodies prevented the SNL induced accumulation of p-STAT3 in the spinal cord .	In addition, the intrathecal injection of anti-rat IL-6 antibodies prevented the SNL induced accumulation of p-STAT3 in the spinal cord.	8	17	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	8	9	16	17
Remarkably , ablation of either type I TNF receptor ( TNFR1 ) or IL-6 reduced JNK and STAT3 activation , decreased hepatosteatosis , steatohepatitis and HCC development 27 .	Remarkably, ablation of either type I TNF receptor (TNFR1) or IL-6 reduced JNK and STAT3 activation, decreased hepatosteatosis, steatohepatitis and HCC development 27.	2	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	13	14	17	18
Wierenga and colleagues showed a reduction in IL6 mediated Stat3 activation in the presence of TGFbeta in leukemia cells , a process which involved interruption of JAK activation and induction of cellular apoptosis .	Wierenga and colleagues showed a reduction in IL6 mediated Stat3 activation in the presence of TGFbeta in leukemia cells, a process which involved interruption of JAK activation and induction of cellular apoptosis.	5	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	IL6	IL6	IL6	Stat3	Stat3	Stat3	7	8	9	10
IL-6 could down-regulate p-STAT3 , however up-regulate the p-MEK and p-ERK and NF-kB and iNOS expression , and it also facilitated the promotion on p-JAK2 and p-MEK and p-ERK by either sorafenib or IFN-alpha .	IL-6 could down-regulate p-STAT3, however up-regulate the p-MEK and p-ERK and NF-kB and iNOS expression, and it also facilitated the promotion on p-JAK2 and p-MEK and p-ERK by either sorafenib or IFN-alpha.	0	4	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	p-STAT3	p-STAT3	p-STAT3	0	1	3	4
Furthermore , neutralizing IL-6 with a blocking mAb reduced JAK2 and STAT3 activation and inhibited upregulation of IL-8 , MMP2 , and VEGF by IL-17 , whereas AKT activation by IL-17 was not affected .	Furthermore, neutralizing IL-6 with a blocking mAb reduced JAK2 and STAT3 activation and inhibited upregulation of IL-8, MMP2, and VEGF by IL-17, whereas AKT activation by IL-17 was not affected.	2	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	11	12
Our in vitro data suggest that by inhibiting NF-kappaB signaling , and thus the expression of IL-6 , subsequent STAT3 activation will be inhibited .	Our in vitro data suggest that by inhibiting NF-kappaB signaling, and thus the expression of IL-6, subsequent STAT3 activation will be inhibited.	14	24	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-6	expression of IL-6	il-6	STAT3	STAT3	stat3	16	17	19	20
A previous study had demonstrated that genetic deletion of STAT3 in IL6 stimulated mouse fibroblasts also resulted in increased and prolonged phospho-STAT1 signaling and up-regulation of STAT1 target genes STAT3 target genes ( i.e. Arginase1 ) .	A previous study had demonstrated that genetic deletion of STAT3 in IL6 stimulated mouse fibroblasts also resulted in increased and prolonged phospho-STAT1 signaling and up-regulation of STAT1 target genes STAT3 target genes (i.e. Arginase1).	9	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL6	IL6	IL6	STAT3	STAT3	STAT3	11	12	29	30
Physapubescin B inhibits IL-6 mediated STAT3 activation in taxol-resistance A2780 cells .	Physapubescin B inhibits IL-6 mediated STAT3 activation in taxol-resistance A2780 cells.	2	6	mediated	Positive_early_activation	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	3	4	5	6
To explore whether exogenous IL-6 can rescue Ad-bFGF-siRNA-inhibited STAT3 activation , U251 cells infected for 48 h were treated with serum-free DMEM in the presence or absence of recombinant IL-6 ( 100 ng/ml ) for 24 h. Cells treated with DMSO for 72 h were used as a negative control .	To explore whether exogenous IL-6 can rescue Ad-bFGF-siRNA-inhibited STAT3 activation, U251 cells infected for 48 h were treated with serum-free DMEM in the presence or absence of recombinant IL-6 (100 ng/ml) for 24 h. Cells treated with DMSO for 72 h were used as a negative control.	3	9	rescue	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	4	5	8	9
Although previous observations suggest that fenofibrate can reduce the activation of STAT3 in liver due to gp80 and gp130 suppression [ XREF_BIBR ] depending on PPARalpha , and that elevated activation of PPARalpha in cardiomyocytes can suppress the activation of STAT3 by IL-6 [ XREF_BIBR ] , fenofibrate might suppress STAT3 activation through some other mechanisms because of the PPARalpha independent fashion .	Although previous observations suggest that fenofibrate can reduce the activation of STAT3 in liver due to gp80 and gp130 suppression [XREF_BIBR] depending on PPARalpha, and that elevated activation of PPARalpha in cardiomyocytes can suppress the activation of STAT3 by IL-6 [XREF_BIBR], fenofibrate might suppress STAT3 activation through some other mechanisms because of the PPARalpha independent fashion.	38	44	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	42	43	40	41
We demonstrated that LY5 inhibited constitutive Interleukin-6 ( IL-6 )-induced STAT3 phosphorylation , STAT3 nuclear translocation , decreased STAT3 downstream targeted gene expression and induced apoptosis in liver and colon cancer cells .	We demonstrated that LY5 inhibited constitutive Interleukin-6 (IL-6)-induced STAT3 phosphorylation, STAT3 nuclear translocation, decreased STAT3 downstream targeted gene expression and induced apoptosis in liver and colon cancer cells.	8	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6)-induced STAT3 phosphorylation	il-6	STAT3	STAT3	stat3	8	9	18	19
Taken together , these results indicate that IL-6 directly inhibits effector CD8 + T cell activity by inducing the STAT3 signaling pathway and suppressing the STAT4 signaling pathway .	Taken together, these results indicate that IL-6 directly inhibits effector CD8 + T cell activity by inducing the STAT3 signaling pathway and suppressing the STAT4 signaling pathway.	7	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	7	8	19	20
Intrathecal injection of anti-rat IL-6 antibodies prevented the SNL induced accumulation of phospho-STAT3 in the spinal cord .	Intrathecal injection of anti-rat IL-6 antibodies prevented the SNL induced accumulation of phospho-STAT3 in the spinal cord.	4	13	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	phospho-STAT3	phospho-STAT3	phospho-STAT3	4	5	12	13
Perturbation of IL-6 signaling in GSCs attenuates signal transducers and STAT3 activation , and small molecule inhibitors of STAT3 potently induce GSC apoptosis .	Perturbation of IL-6 signaling in GSCs attenuates signal transducers and STAT3 activation, and small molecule inhibitors of STAT3 potently induce GSC apoptosis.	2	11	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	STAT3	STAT3	STAT3	2	3	10	11
Low IL-6 levels inhibit activation of Stat3 , resulting in the increased formation of MDSCs in BC .	Low IL-6 levels inhibit activation of Stat3, resulting in the increased formation of MDSCs in BC.	1	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6 levels	il-6	Stat3	Stat3	stat3	1	2	6	7
IL-6 Pretreatment Downregulates Membrane IL-6Ralpha and gp130 for Decreased IL-30- and IL-27-Induced IP-10 Production .	IL-6 Pretreatment Downregulates Membrane IL-6Ralpha and gp130 for Decreased IL-30- and IL-27-Induced IP-10 Production.	0	7	Downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	0	1	6	7
Results from this study demonstrated that IL-6 suppressed voltage gated Na + channel currents and diminished the peak of action potential in neurons ( using receptor IL-6ra and gp130 ) in time- and dose dependent manners , but did not alter voltage gated Na + channel activation and inactivation .	Results from this study demonstrated that IL-6 suppressed voltage gated Na + channel currents and diminished the peak of action potential in neurons (using receptor IL-6ra and gp130) in time- and dose dependent manners, but did not alter voltage gated Na + channel activation and inactivation.	6	40	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	6	7	28	29
Therefore , we explored the role of the pro survival kinase Pim1 , an additional downstream target of IL6 mediated GP130 signaling identified as significantly up-regulated in heterokaryons ( XREF_FIG ) .	Therefore, we explored the role of the pro survival kinase Pim1, an additional downstream target of IL6 mediated GP130 signaling identified as significantly up-regulated in heterokaryons (XREF_FIG).	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL6	IL6	IL6	GP130	GP130	GP130	18	19	20	21
Furthermore , levels of interferon- gamma , interleukin-6 , and the chemokine cytokine induced neutrophil chemoattractant were significantly lower in gp130 deficient mice than in wild-type mice .	Furthermore, levels of interferon- gamma, interleukin-6, and the chemokine cytokine induced neutrophil chemoattractant were significantly lower in gp130 deficient mice than in wild-type mice.	2	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	interleukin-6	levels of interferon- gamma, interleukin-6	interleukin-6	gp130	gp130	gp130	7	8	20	21
Here we found that IL-6 stimulation induced lysosome dependent degradation of gp130 , which correlated with an increase in the K63 linked polyubiquitination of gp130 .	Here we found that IL-6 stimulation induced lysosome dependent degradation of gp130, which correlated with an increase in the K63 linked polyubiquitination of gp130.	4	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	4	5	11	12
Limited cells , mainly hepatocytes and leukocytes express membrane bound IL-6 receptor ( IL-6R ) and IL-6 mediated activation of IL-6R leads to a classic activation 16 .	Limited cells, mainly hepatocytes and leukocytes express membrane bound IL-6 receptor (IL-6R) and IL-6 mediated activation of IL-6R leads to a classic activation 16.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	IL-6	IL-6	IL-6	IL-6R	IL-6R	IL-6R	16	17	20	21
Conversely , interleukin-6 ( IL-6 ) -- a potent cytokine -- inhibits myeloma cell apoptosis by activating GP130 through the IL-6 receptor ( IL-6R ) .	Conversely, interleukin-6 (IL-6) -- a potent cytokine -- inhibits myeloma cell apoptosis by activating GP130 through the IL-6 receptor (IL-6R).	2	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	interleukin-6	interleukin-6	interleukin-6	GP130	GP130	GP130	2	3	17	18
IL- 6 itself was found to suppress the IL-6-R at high concentrations .	IL- 6 itself was found to suppress the IL-6-R at high concentrations.	0	9	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL- 6	IL- 6	IL- 6	IL-6-R	IL-6-R	IL-6-R	0	2	8	9
Second , IFN-alpha-induced IL-6 predominantly down-regulated membrane bound gp130 .	Second, IFN-alpha-induced IL-6 predominantly down-regulated membrane bound gp130.	2	9	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	3	4	8	9
In this review we focus on the use of tocilizumab , a monoclonal antibody directed against the IL6 receptor ( IL6R ) , which potently inhibits IL-6 and IL6R signaling .	In this review we focus on the use of tocilizumab, a monoclonal antibody directed against the IL6 receptor (IL6R), which potently inhibits IL-6 and IL6R signaling.	17	29	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL6	IL6	IL6	IL6R	IL6R	IL6R	17	18	28	29
Using q-RTPCR , we found that IL-6 deficiency decreased protein , but not mRNA levels , of its signal transducer gp130 .	Using q-RTPCR, we found that IL-6 deficiency decreased protein, but not mRNA levels, of its signal transducer gp130.	6	21	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	6	7	20	21
In glioblastoma , a constitutively active mutant of epidermal growth factor receptor was found , and this mutant contributes to and sustains STAT3 activation by inducing a cytokine circuit involving IL-6 and leukemia inhibitory factor , which in turn activates gp130 in the neighboring cells that harbor wild-type epidermal growth factor receptor , leading to an enhanced growth of the entire tumor [ XREF_BIBR ] .	In glioblastoma, a constitutively active mutant of epidermal growth factor receptor was found, and this mutant contributes to and sustains STAT3 activation by inducing a cytokine circuit involving IL-6 and leukemia inhibitory factor, which in turn activates gp130 in the neighboring cells that harbor wild-type epidermal growth factor receptor, leading to an enhanced growth of the entire tumor [XREF_BIBR].	30	41	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	30	31	40	41
The inhibitory effect of IL-6 on Fas ligand expression during activation induced cell death ( AICD ) was augmented in gp130 F759 and F759 T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation .	The inhibitory effect of IL-6 on Fas ligand expression during activation induced cell death (AICD) was augmented in gp130 F759 and F759 T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation.	2	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	4	5	20	21
Interestingly , injections of IL-6 blocked oxidation of IL-6Ralpha and gp130 in the cerebral ischemic cortex .	Interestingly, injections of IL-6 blocked oxidation of IL-6Ralpha and gp130 in the cerebral ischemic cortex.	2	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6	IL-6	IL-6	gp130	gp130	gp130	4	5	10	11
Pitrakinra is a recombinant human IL-4 variant that competitively inhibits the IL-4Ralpha complex thus interfering with downstream signaling of both IL-4 and IL-13 .	Pitrakinra is a recombinant human IL-4 variant that competitively inhibits the IL-4Ralpha complex thus interfering with downstream signaling of both IL-4 and IL-13.	5	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	5	6	11	12
IL-4 inhibition of Il4ra F709 iTreg cell differentiation was not a dilutional artifact of excessive CD4 + Foxp3 - T cell proliferation as evidenced by enumeration of the respective cell population ( XREF_FIG ) .	IL-4 inhibition of Il4ra F709 iTreg cell differentiation was not a dilutional artifact of excessive CD4 + Foxp3 - T cell proliferation as evidenced by enumeration of the respective cell population (XREF_FIG).	0	4	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IL-4	IL-4	IL-4	Il4ra	Il4ra	Il4ra	0	1	3	4
A 14 kD IL-4 mutein that blocks IL-4Ralpha has been shown to be effective for both atopic dermatitis when given subcutaneously and asthma when given by inhalation .	A 14 kD IL-4 mutein that blocks IL-4Ralpha has been shown to be effective for both atopic dermatitis when given subcutaneously and asthma when given by inhalation.	3	8	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	3	4	7	8
Normal human fibroblast and endothelial cell lines also expressed high affinity IL-4R , however , IL-4 did not inhibit their growth in vitro .	Normal human fibroblast and endothelial cell lines also expressed high affinity IL-4R, however, IL-4 did not inhibit their growth in vitro.	8	19	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-4	IL-4	IL-4	IL-4R	IL-4R	IL-4R	15	16	11	12
Moreover , this Anticalin protein showed significantly higher in vitro potency than pitrakinra , an IL-4 mutein that also antagonizes IL-4Ralpha and was in clinical testing via the inhalation route .	Moreover, this Anticalin protein showed significantly higher in vitro potency than pitrakinra, an IL-4 mutein that also antagonizes IL-4Ralpha and was in clinical testing via the inhalation route.	15	21	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	15	16	20	21
The recombinant human IL-4 variant , pitrakinra ( Aerovant ) competitively inhibits the IL-4Ra receptor complex to interfere with the actions of both IL-4 and IL-13 and initial clinical trials indicated that such an approach may prove beneficial in patients with atopic asthma .	The recombinant human IL-4 variant, pitrakinra (Aerovant) competitively inhibits the IL-4Ra receptor complex to interfere with the actions of both IL-4 and IL-13 and initial clinical trials indicated that such an approach may prove beneficial in patients with atopic asthma.	4	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	pitrakinra	pitrakinra	pitrakinra	IL-4Ra	IL-4Ra	IL-4Ra	6	7	13	14
Pitrakinra is a recombinant IL-4 variant that competitively antagonises the IL-4Ralpha , and therefore interferes with the function of both IL-4 and IL-13 at the IL-4Ralpha and IL-13Ralpha1 receptor complex .	Pitrakinra is a recombinant IL-4 variant that competitively antagonises the IL-4Ralpha, and therefore interferes with the function of both IL-4 and IL-13 at the IL-4Ralpha and IL-13Ralpha1 receptor complex.	4	11	antagonises	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-4	IL-4	IL-4	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	4	5	10	11
Although murine studies suggest that IL-4Ralpha antagonists have therapeutic potential , pitrakinra , a recombinant IL-4 variant that competitively inhibits IL-4Ralpha to interfere with IL-4 and IL-13 signaling , was only successful in reducing exacerbations and improving asthma symptoms in those patients with eosinophilia , and not in a broad population of asthmatics .	Although murine studies suggest that IL-4Ralpha antagonists have therapeutic potential, pitrakinra, a recombinant IL-4 variant that competitively inhibits IL-4Ralpha to interfere with IL-4 and IL-13 signaling, was only successful in reducing exacerbations and improving asthma symptoms in those patients with eosinophilia, and not in a broad population of asthmatics.	11	31	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	pitrakinra	pitrakinra	pitrakinra	IL-4Ralpha	IL-4Ralpha	IL-4Ralpha	11	12	20	21
Pitrakinra , an IL-4 variant that inhibits binding of both IL-4 and IL-13 to a high-affinity IL-4-binding receptor subunit ( IL-4Ralpha ) , attenuates signaling downstream of IL-4R .	Pitrakinra, an IL-4 variant that inhibits binding of both IL-4 and IL-13 to a high-affinity IL-4-binding receptor subunit (IL-4Ralpha), attenuates signaling downstream of IL-4R.	3	28	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-4	IL-4	IL-4	IL-4R	IL-4R	IL-4R	3	4	27	28
The binding of IL-7 has also been shown to down-regulate IL-7Ralpha by modulating its gene expression .	The binding of IL-7 has also been shown to down-regulate IL-7Ralpha by modulating its gene expression.	1	11	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	3	4	10	11
We first focused on IL-7 and found that down-regulation of CD127 by IL-7 was due to internalization of the receptor .	We first focused on IL-7 and found that down-regulation of CD127 by IL-7 was due to internalization of the receptor.	8	13	down-regulation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	CD127	CD127	CD127	12	13	10	11
This finding is consistent with previous findings of down-regulation of IL-7R by IL-7 , which suggests a specific regulator role of IL-7 on IL-7Ralpha .	This finding is consistent with previous findings of down-regulation of IL-7R by IL-7, which suggests a specific regulator role of IL-7 on IL-7Ralpha.	3	15	down-regulation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	IL-7R	IL-7R	IL-7R	12	13	10	11
To provide an exhaustive analysis of the influence of IL-7 on Treg homeostasis in vivo , we first examined mice in which IL-7 signaling was genetically disrupted ( IL-7Ralpha-/- or IL-7-/-) or increased ( IL-7 Tg ) .	To provide an exhaustive analysis of the influence of IL-7 on Treg homeostasis in vivo, we first examined mice in which IL-7 signaling was genetically disrupted (IL-7Ralpha-/- or IL-7-/-) or increased (IL-7 Tg).	22	29	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	IL-7Ralpha-/-	IL-7Ralpha-/-	IL-7Ralpha-/-	22	23	28	29
Although short-term IL-7 stimulation downregulated surface IL-7Ralpha , T cells restored their IL-7Ralpha expression on the cell membrane at the end of 3-day culture ( XREF_SUPPLEMENTARY ) .	Although short-term IL-7 stimulation downregulated surface IL-7Ralpha, T cells restored their IL-7Ralpha expression on the cell membrane at the end of 3-day culture (XREF_SUPPLEMENTARY).	2	7	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	2	3	6	7
To test this hypothesis , we wanted to compare the combinatorial effect of TGF-beta and various different cgammac cytokines on the survival of effector CD8 + T cells ; however , treatment of in vivo generated effector cells with these cytokines results in modulation of the perspective receptors ( i.e. IL-7 down-regulates IL-7Ralpha ) compromising the analysis on the different sub-populations based on CD127 and KLRG1 expression .	To test this hypothesis, we wanted to compare the combinatorial effect of TGF-beta and various different cgammac cytokines on the survival of effector CD8 + T cells; however, treatment of in vivo generated effector cells with these cytokines results in modulation of the perspective receptors (i.e. IL-7 down-regulates IL-7Ralpha) compromising the analysis on the different sub-populations based on CD127 and KLRG1 expression.	50	53	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	50	51	52	53
Additionally , we are still uncertain as to how only IL-7Ralpha is separately downregulated by the binding of IL-7 from the IL-7Ralpha and gammac complex .	Additionally, we are still uncertain as to how only IL-7Ralpha is separately downregulated by the binding of IL-7 from the IL-7Ralpha and gammac complex.	9	19	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	18	19	10	11
Theoretically , due to its role as a major regulator of T-lymphocyte homeostasis , IL-7 might be particularly helpful in patients on HAART with persistent CD4+ lymphopenia , but the actual clinical value of IL-7 treatment in these patients is questioned by the evidence of already elevated endogenous IL-7 levels and reduced IL-7Ralpha expression XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Theoretically, due to its role as a major regulator of T-lymphocyte homeostasis, IL-7 might be particularly helpful in patients on HAART with persistent CD4+ lymphopenia, but the actual clinical value of IL-7 treatment in these patients is questioned by the evidence of already elevated endogenous IL-7 levels and reduced IL-7Ralpha expression XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	34	54	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	34	35	52	53
In agreement with previous findings , we found that IL-2 enhanced its receptor ( IL-2Ralpha ) ( XREF_FIG , left panel ) that enabled its own signal amplification , whereas IL-7 signaling downregulated IL-7Ralpha ( XREF_FIG , right panel ) , thereby decreasing its signal strength [ XREF_BIBR ] .	In agreement with previous findings, we found that IL-2 enhanced its receptor (IL-2Ralpha) (XREF_FIG, left panel) that enabled its own signal amplification, whereas IL-7 signaling downregulated IL-7Ralpha (XREF_FIG, right panel), thereby decreasing its signal strength [XREF_BIBR].	30	35	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	IL-7Ralpha	IL-7Ralpha	IL-7Ralpha	30	31	33	34
Other downstream targets of ILK induced AKT include mTOR and NF-KB .	Other downstream targets of ILK induced AKT include mTOR and NF-KB.	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	ILK	ILK	ILK	AKT	AKT	AKT	4	5	6	7
Therefore , ILK promotes cell survival by inhibiting GSK-3beta and inhibits apoptosis by activating AKT .	Therefore, ILK promotes cell survival by inhibiting GSK-3beta and inhibits apoptosis by activating AKT.	2	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ILK	ILK	ILK	AKT	AKT	AKT	2	3	14	15
XREF_BIBR , XREF_BIBR Interestingly , ILK-1 contributes to anoikis resistance by inhibiting apoptosis signals , such as initiator caspase-8 and executioner caspase-3 , even in the absence of integrin and ECM signal activation , but possibly via a parvin mediated targeting of AKT signaling to lipid rafts .	XREF_BIBR, XREF_BIBR Interestingly, ILK-1 contributes to anoikis resistance by inhibiting apoptosis signals, such as initiator caspase-8 and executioner caspase-3, even in the absence of integrin and ECM signal activation, but possibly via a parvin mediated targeting of AKT signaling to lipid rafts.	5	43	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK-1	ILK-1	ILK-1	AKT	AKT	AKT	5	6	42	43
Knockdown of ILK decreases Akt kinase activity .	Knockdown of ILK decreases Akt kinase activity.	0	6	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK	ILK	Akt	Akt	Akt	2	3	4	5
Thus , IL-6-mediated STAT3 activation may downregulate miR-204 , which may reversibly inhibit IL-6R expression to further repress the IL-6R and STAT3 pathway and form a regulatory loop between miRNAs and the IL-6 and STAT3 signaling pathway .	Thus, IL-6-mediated STAT3 activation may downregulate miR-204, which may reversibly inhibit IL-6R expression to further repress the IL-6R and STAT3 pathway and form a regulatory loop between miRNAs and the IL-6 and STAT3 signaling pathway.	13	22	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-6R	IL-6R expression	il-6r	IL-6R	IL-6R	il-6r	13	14	19	20
In this study , we investigated the effects of IL-6 , IL-6 receptor antagonist ( IL-6RA ) , and gp130 antagonist ( gp130A ) on the membrane expressions of IL-6R and gp130 , on the viability , on the proliferation , on the DNA synthesis , and on the cell cycle phases in several multiple myeloma ( MM ) cell lines and B cell lymphoma cell lines .	In this study, we investigated the effects of IL-6, IL-6 receptor antagonist (IL-6RA), and gp130 antagonist (gp130A) on the membrane expressions of IL-6R and gp130, on the viability, on the proliferation, on the DNA synthesis, and on the cell cycle phases in several multiple myeloma (MM) cell lines and B cell lymphoma cell lines.	19	31	antagonist	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	gp130	gp130	gp130	IL-6R	IL-6R	IL-6R	19	20	29	30
Moreover , overexpression of wild-type gp130 impaired the activity of the mutant gp130 S187_Y190del in a dose dependent manner ( XREF_FIG ) ; therefore , mutant gp130 activity appears to be driven by its homodimerization that can be competed by the wild-type protein .	Moreover, overexpression of wild-type gp130 impaired the activity of the mutant gp130 S187_Y190del in a dose dependent manner (XREF_FIG); therefore, mutant gp130 activity appears to be driven by its homodimerization that can be competed by the wild-type protein.	2	13	impaired	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	gp130	overexpression of wild-type gp130	gp130	gp130	gp130	gp130	5	6	12	13
Of note , the soluble gp130 form , which circulates in human plasma , blocks IL-6R trans-signaling responses and does not show species specificity , meaning that it interacts with human and mouse sIL-6R complexes [ XREF_BIBR ] .	Of note, the soluble gp130 form, which circulates in human plasma, blocks IL-6R trans-signaling responses and does not show species specificity, meaning that it interacts with human and mouse sIL-6R complexes [XREF_BIBR].	5	17	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	gp130	gp130	gp130	IL-6R	IL-6R	IL-6R	5	6	15	16
In breast cancer cell lines previously identified to contain LOH at 11p15.5 , there was a complete loss or significant down-regulation of ILK , whereas the expression was inverse in normal and non malignant breast epithelial cells .	In breast cancer cell lines previously identified to contain LOH at 11p15.5, there was a complete loss or significant down-regulation of ILK, whereas the expression was inverse in normal and non malignant breast epithelial cells.	14	23	was a complete loss	Negative_activation_copula_1	Positive_activation	Negative_activation	ILK	loss or significant down-regulation of ILK	ilk	ILK	ILK	ilk	22	23	22	23
The pro atherogenic mediator angiotensin II increases ILK protein expression and kinase activity while statin treatment down-regulates ILK in VSMC .	The pro atherogenic mediator angiotensin II increases ILK protein expression and kinase activity while statin treatment down-regulates ILK in VSMC.	4	19	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ILK	angiotensin II increases ILK protein expression	ilk	ILK	ILK	ilk	7	8	17	18
Afterwards , the ILK expression is down-regulated using ILK specific siRNA ( ILKsi ) and then the MAPK activity is determined .	Afterwards, the ILK expression is down-regulated using ILK specific siRNA (ILKsi) and then the MAPK activity is determined.	3	10	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ILK	ILK expression	ilk	ILK	ILK	ilk	3	4	8	9
However , since IL-4 downregulates gammac ( but not IL-2/15Rbeta ) chain selectively on naive T cells , their proliferation still requires the contribution of DC derived cytokines for the upregulation of gammac chain expression .	However, since IL-4 downregulates gammac (but not IL-2/15Rbeta) chain selectively on naive T cells, their proliferation still requires the contribution of DC derived cytokines for the upregulation of gammac chain expression.	3	6	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-4	IL-4	IL-4	gammac	gammac	gammac	3	4	5	6
First , IL-4 signaling through the type I IL-4R inhibited the induction of a set of IL-13-specific genes ( Ccl11 , Itln2 , Retnlb , Sprr2a , Slc5a1 , Aass , Scin , Agr2 ) , that are not upregulated by rIL-4 , but are however STAT6 dependent , and gammaC independent [ XREF_BIBR ] .	First, IL-4 signaling through the type I IL-4R inhibited the induction of a set of IL-13-specific genes (Ccl11, Itln2, Retnlb, Sprr2a, Slc5a1, Aass, Scin, Agr2), that are not upregulated by rIL-4, but are however STAT6 dependent, and gammaC independent [XREF_BIBR].	2	53	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-4	IL-4	IL-4	gammaC	gammaC	gammaC	2	3	50	51
Coexpression of catalytically inactive , but not wild-type , SHP-2 reduced LIFR- and gp130 mediated activation of MAPK up to 75 % .	Coexpression of catalytically inactive, but not wild-type, SHP-2 reduced LIFR- and gp130 mediated activation of MAPK up to 75%.	10	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	gp130	gp130	gp130	MAPK	MAPK	MAPK	13	14	17	18
LPS stimulated peritoneal macrophages of gp130 757F/F mice showed increased STAT3 and decreased ERK1/2 activation compared to WT mice ( XREF_FIG Bi , ii ) .	LPS stimulated peritoneal macrophages of gp130 757F/F mice showed increased STAT3 and decreased ERK1/2 activation compared to WT mice (XREF_FIG Bi, ii).	5	14	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	gp130	gp130	gp130	ERK1/2	ERK1/2	ERK1/2	5	6	13	14
XREF_BIBR XREF_BIBR This mouse has a single base pair substitution at position 757 of gp130 , which simultaneously blocks downstream ERK and MAPK signalling , while STAT1/3 is constitutively activated , resulting in antral stomach tumour development with complete penetrance .	XREF_BIBR XREF_BIBR This mouse has a single base pair substitution at position 757 of gp130, which simultaneously blocks downstream ERK and MAPK signalling, while STAT1/3 is constitutively activated, resulting in antral stomach tumour development with complete penetrance.	11	29	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	gp130	gp130	gp130	ERK	ERK	ERK	14	15	20	21
This resulted in an IL-7 dependent reduction of surface gammac protein on LNT cells ( XREF_FIG ) .	This resulted in an IL-7 dependent reduction of surface gammac protein on LNT cells (XREF_FIG).	4	10	reduction	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	gammac	gammac	gammac	4	5	9	10
Our data demonstrated that only IL-7 could rapidly reduce detection of surface gammac protein and the reduction is dependent on IL-7Ralpha expression .	Our data demonstrated that only IL-7 could rapidly reduce detection of surface gammac protein and the reduction is dependent on IL-7Ralpha expression.	4	13	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IL-7	IL-7	IL-7	gammac	gammac	gammac	5	6	12	13
NF-IL3 ( E4bp4 ) is up-regulated by the action of 4 out of 6 PTKs ( XREF_TABLE ) a target of IL-3 it plays an important role in survival ; indeed over-expression of NF-IL3 leads to IL-3 independence in Ba/F3 cells XREF_BIBR .	NF-IL3 (E4bp4) is up-regulated by the action of 4 out of 6 PTKs (XREF_TABLE) a target of IL-3 it plays an important role in survival; indeed over-expression of NF-IL3 leads to IL-3 independence in Ba/F3 cells XREF_BIBR.	0	23	up-regulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	IL-3	IL-3	IL-3	NF-IL3	NF-IL3	NF-IL3	21	22	0	1
IL-5Ralpha ( CD125 ) on blood eosinophils is downregulated in vitro by its own ligand IL-5 as well as by the related cytokines GM-CSF and IL-3 ( to about 0.1-0.3-fold level , by intensity or CF , or from about 80-90 % to 10 % positive cells ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] , through the involvement of metalloproteinase mediated shedding [ XREF_BIBR ] .	IL-5Ralpha (CD125) on blood eosinophils is downregulated in vitro by its own ligand IL-5 as well as by the related cytokines GM-CSF and IL-3 (to about 0.1-0.3-fold level, by intensity or CF, or from about 80-90% to 10% positive cells) [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR], through the involvement of metalloproteinase mediated shedding [XREF_BIBR].	0	16	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IL-5	IL-5	IL-5	CD125	CD125	CD125	15	16	2	3
T315I is an integrin linked kinase ( ILK ) inhibitor , which downregulates protein kinase B ( Akt ) and p-Akt and decreases cell activity of AML [ XREF_BIBR ] .	T315I is an integrin linked kinase (ILK) inhibitor, which downregulates protein kinase B (Akt) and p-Akt and decreases cell activity of AML [XREF_BIBR].	5	16	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ILK	ILK	ILK	protein kinase B	protein kinase B	protein kinase B	7	8	13	16
In the liver , insulin suppresses hepatic gluconeogenesis by activating Akt , which inactivates the key gluconeogenic transcription factor FoxO1 ( Forkhead Box O1 ) .	In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1).	4	13	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	10	11
In accordance , we also observed a decrease in insulin induced Akt activation in these tissues .	In accordance, we also observed a decrease in insulin induced Akt activation in these tissues.	7	12	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
It does not seem to be required for the development of glucose and insulin induced insulin resistance of glucose transport and Akt activation in 3T3-L1 adipocytes .	It does not seem to be required for the development of glucose and insulin induced insulin resistance of glucose transport and Akt activation in 3T3-L1 adipocytes.	15	22	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	15	16	21	22
Under normoxic conditions , cardiac systolic and diastolic functions and insulin mediated Akt and GLUT4 ( glucose transporter 4 ) activation were impaired in STZ-diabetic rats .	Under normoxic conditions, cardiac systolic and diastolic functions and insulin mediated Akt and GLUT4 (glucose transporter 4) activation were impaired in STZ-diabetic rats.	8	22	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
Similarly , conditional over-expression of miR-143 in mice has been shown to impair glucose metabolism and insulin stimulated AKT activation in the liver of these animals [ Jordan et al ., 2011 ] .	Similarly, conditional over-expression of miR-143 in mice has been shown to impair glucose metabolism and insulin stimulated AKT activation in the liver of these animals [Jordan et al., 2011].	12	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	18	19
With respect to glucose metabolism , insulin diminishes hepatic gluconeogenesis primarily by activating hepatic Akt , and this mechanism is essential for preventing the development of hyperglycemia .	With respect to glucose metabolism, insulin diminishes hepatic gluconeogenesis primarily by activating hepatic Akt, and this mechanism is essential for preventing the development of hyperglycemia.	6	15	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	14	15
This inhibitory phosphorylation leads to reduced insulin activation of Akt and eNOS in endothelial cells .	This inhibitory phosphorylation leads to reduced insulin activation of Akt and eNOS in endothelial cells.	6	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	9	10
However , the effects of mTOR inhibitor , rapamycin and Go-6976 were not additive and only rapamycin restored impaired insulin stimulated AKT activation .	However, the effects of mTOR inhibitor, rapamycin and Go-6976 were not additive and only rapamycin restored impaired insulin stimulated AKT activation.	17	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	19	20	21	22
In addition to DAG , increased FFAs supply can raise intracellular ceramides , which induce inflammation associated insulin resistance by impairing insulin mediated Akt activation in muscle .	In addition to DAG, increased FFAs supply can raise intracellular ceramides, which induce inflammation associated insulin resistance by impairing insulin mediated Akt activation in muscle.	20	24	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	23	24
At the whole muscle level , the same two week HFD protocol did not result in significantly diminished insulin stimulated Akt activation 9 .	At the whole muscle level, the same two week HFD protocol did not result in significantly diminished insulin stimulated Akt activation 9.	14	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	20	21
PDK1 , in the presence of PIP 3 , stimulates the insulin responsive PI3-K and Akt pathway and overexpression of miR-375 would diminish this effect , decreasing PI3-K and Akt signaling XREF_BIBR .	PDK1, in the presence of PIP 3, stimulates the insulin responsive PI3-K and Akt pathway and overexpression of miR-375 would diminish this effect, decreasing PI3-K and Akt signaling XREF_BIBR.	10	31	diminish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	29	30
In human arterial endothelial cells , activation of eNOS by phosphorylation at Serine 1177 is inhibited directly by hyperglycemia induced O GlcNAcylation at this site 45 , and indirectly by reduced insulin stimulated phosphatidylinositol 3-kinase ( PI3-K ) and Akt activity by O-GlcNAc modification .	In human arterial endothelial cells, activation of eNOS by phosphorylation at Serine 1177 is inhibited directly by hyperglycemia induced O GlcNAcylation at this site 45, and indirectly by reduced insulin stimulated phosphatidylinositol 3-kinase (PI3-K) and Akt activity by O-GlcNAc modification.	28	40	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	39	40
Strikingly , insulin stimulated Akt activity , but not phosphatidylinositol 3 kinase activity , was blocked at 19 C. Consistent with a multistep process in GLUT4 trafficking , insulin stimulated GLUT4 translocation could be primed by treating cells with insulin at 19 C , whereas this was not the case for Akt activation .	Strikingly, insulin stimulated Akt activity, but not phosphatidylinositol 3 kinase activity, was blocked at 19 C. Consistent with a multistep process in GLUT4 trafficking, insulin stimulated GLUT4 translocation could be primed by treating cells with insulin at 19 C, whereas this was not the case for Akt activation.	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
In cell culture , IL-1beta dampens insulin sensitivity by inducing JNK dependent serine phosphorylation of insulin receptor substrate-1 ( IRS-1 ) , resulting in the disruption of insulin induced PI3K-Akt signaling in insulin targeted cells .	In cell culture, IL-1beta dampens insulin sensitivity by inducing JNK dependent serine phosphorylation of insulin receptor substrate-1 (IRS-1), resulting in the disruption of insulin induced PI3K-Akt signaling in insulin targeted cells.	25	30	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	27	28	29	30
However , recent studies indicate that deletion of mTOR impairs myocardial palmitate oxidation and reduces expression of several genes associated with FA metabolism while also reducing insulin stimulated AKT Ser 473 phosphorylation .	However, recent studies indicate that deletion of mTOR impairs myocardial palmitate oxidation and reduces expression of several genes associated with FA metabolism while also reducing insulin stimulated AKT Ser 473 phosphorylation.	25	29	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	26	27	28	29
Mechanisms leading to loss of muscle proteins include insulin resistance , which suppresses Akt activity and thus stimulates protein degradation via the ubiquitin-proteasome system .	Mechanisms leading to loss of muscle proteins include insulin resistance, which suppresses Akt activity and thus stimulates protein degradation via the ubiquitin-proteasome system.	8	14	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	13	14
Activation of insulin signaling enhances TOR activity by releasing the negative feedback of Akt on TSC1/2 [ XREF_BIBR - XREF_BIBR ] .	Activation of insulin signaling enhances TOR activity by releasing the negative feedback of Akt on TSC1/2 [XREF_BIBR - XREF_BIBR].	2	17	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	13	14
This suggests that high blood glucose and insulin levels inhibited Akt activity , consistent with the findings of Tomas et al .	This suggests that high blood glucose and insulin levels inhibited Akt activity, consistent with the findings of Tomas et al.	7	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin levels	insulin	Akt	Akt	akt	7	8	10	11
Insulin mediated activation of Akt , a marker of PI3Kalpha activity , was impaired with increased ERK1/2 activation in PI3Kalpha mutant hearts .	Insulin mediated activation of Akt, a marker of PI3Kalpha activity, was impaired with increased ERK1/2 activation in PI3Kalpha mutant hearts.	0	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
Further , it was found that miR-143/145 null mice are protected from the development T2DM , whereas transgenic overexpression of miR-143 , but not miR-145 , impaired insulin induced AKT activation and glucose homeostasis 301 .	Further, it was found that miR-143/145 null mice are protected from the development T2DM, whereas transgenic overexpression of miR-143, but not miR-145, impaired insulin induced AKT activation and glucose homeostasis 301.	18	30	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	27	28	29	30
Since adipose glucose metabolism and flux through the DNL pathway are known to be regulated by signaling through the protein kinase AKT , we asked whether the decreased DNL in ob/ob mice might be mediated by disrupted insulin induced AKT activation .	Since adipose glucose metabolism and flux through the DNL pathway are known to be regulated by signaling through the protein kinase AKT, we asked whether the decreased DNL in ob/ob mice might be mediated by disrupted insulin induced AKT activation.	34	40	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	37	38	39	40
60 They found that miR-143 downregulated oxysterol binding protein related protein 8 ( ORP8 ) and inhibited insulin stimulated Akt activation and glucose metabolism .	60 They found that miR-143 downregulated oxysterol binding protein related protein 8 (ORP8) and inhibited insulin stimulated Akt activation and glucose metabolism.	16	20	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	19	20
This post-Akt2 signaling defect in mice consuming 40 % of calories from fat contrasts with impaired insulin stimulated hepatic Akt activation in mice consuming 60 % of calories from fat and presumably reflects an earlier stage of development of hepatic insulin resistance in HFF and DIO .	This post-Akt2 signaling defect in mice consuming 40% of calories from fat contrasts with impaired insulin stimulated hepatic Akt activation in mice consuming 60% of calories from fat and presumably reflects an earlier stage of development of hepatic insulin resistance in HFF and DIO.	13	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	19	20
Insulin increased P ~ p42/44 mapk / p42/44 mapk , but reduced P ~ Akt and Akt ratios in normal pregnancies ; however , blocked GDM effect on these molecules .	Insulin increased P ~ p42/44 mapk / p42/44 mapk, but reduced P ~ Akt and Akt ratios in normal pregnancies; however, blocked GDM effect on these molecules.	0	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	14	15
The insulin induced Akt activation was inhibited by LY294002 in a dose dependent manner .	The insulin induced Akt activation was inhibited by LY294002 in a dose dependent manner.	0	4	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
Consistent with impaired insulin stimulated Akt activation , FoxO1 inactivation and gluconeogenic gene expression , it was found that insulin-suppression of gluconeogenesis ( from 2 mM pyruvate ) was similarly impaired in hepatocytes treated with palmitate ( XREF_FIG ) .	Consistent with impaired insulin stimulated Akt activation, FoxO1 inactivation and gluconeogenic gene expression, it was found that insulin-suppression of gluconeogenesis (from 2 mM pyruvate) was similarly impaired in hepatocytes treated with palmitate (XREF_FIG).	0	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
Insulin can inhibit apoptosis by downregulating macrophage scavenger receptors , by activating Akt , inhibiting FoxO1 , or inhibiting XBP-1 .	Insulin can inhibit apoptosis by downregulating macrophage scavenger receptors, by activating Akt, inhibiting FoxO1, or inhibiting XBP-1.	0	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	12	13
The phosphorylation of insulin stimulated Akt was reduced after treatment with BP extracts , although the expression levels of wild type Akt did not change compared with the controls ( XREF_FIG ) .	The phosphorylation of insulin stimulated Akt was reduced after treatment with BP extracts, although the expression levels of wild type Akt did not change compared with the controls (XREF_FIG).	1	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	phosphorylation of insulin	insulin	Akt	Akt	akt	3	4	5	6
In light of the GWAS association , the metabolic profile of NPC1 null mice and these molecular data , we speculated that disruption of NPC1 function may impact metabolic homeostasis through reduced insulin stimulated Akt activation and that the association between NPC1 and insulin resistance may be due to effects on insulin action in its target tissues .	In light of the GWAS association, the metabolic profile of NPC1 null mice and these molecular data, we speculated that disruption of NPC1 function may impact metabolic homeostasis through reduced insulin stimulated Akt activation and that the association between NPC1 and insulin resistance may be due to effects on insulin action in its target tissues.	27	35	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	32	33	34	35
Glucosamine , however , severely impaired insulin stimulation of Akt .	Glucosamine, however, severely impaired insulin stimulation of Akt.	6	10	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	9	10
In addition , we found that the treatment of human hepatocyte HepG2 cells with oleic acid decreased the expression of GRP78 , and attenuated the activation of AKT by insulin stimulation .	In addition, we found that the treatment of human hepatocyte HepG2 cells with oleic acid decreased the expression of GRP78, and attenuated the activation of AKT by insulin stimulation.	25	30	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	29	30	27	28
In summary , our data suggest that insulin prevent apoptosis in ES-NPCs by activating Akt and inhibiting ERK through the PI3K pathway .	In summary, our data suggest that insulin prevent apoptosis in ES-NPCs by activating Akt and inhibiting ERK through the PI3K pathway.	7	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	14	15
Here , we show that a downstream target of insulin induced Akt activation , Clk2 , triggers Akt dephosphorylation through the PP2A phosphatase complex .	Here, we show that a downstream target of insulin induced Akt activation, Clk2, triggers Akt dephosphorylation through the PP2A phosphatase complex.	7	12	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
Deletion of insulin induced PI3K-Akt signaling in GALP neurons .	Deletion of insulin induced PI3K-Akt signaling in GALP neurons.	0	5	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	2	3	4	5
Administration of insulin or IGF-I reduces postischemic myocardial apoptotic death and infarct size by activating the PI3K and AKT signaling pathway .	Administration of insulin or IGF-I reduces postischemic myocardial apoptotic death and infarct size by activating the PI3K and AKT signaling pathway.	0	20	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	18	19
Long-term regulation occurs via the transcription factors FoxO and TFEB , which control the transcription of autophagic genes and are inhibited by insulin induced activation of Akt and PKB and mTOR , respectively [ XREF_BIBR ] .	Long-term regulation occurs via the transcription factors FoxO and TFEB, which control the transcription of autophagic genes and are inhibited by insulin induced activation of Akt and PKB and mTOR, respectively [XREF_BIBR].	20	30	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	26	27
Further analysis demonstrated that both normalization of hyperglycemia and increased ocular insulin signaling reversed diabetes induced insulin receptor and Akt signaling defects .	Further analysis demonstrated that both normalization of hyperglycemia and increased ocular insulin signaling reversed diabetes induced insulin receptor and Akt signaling defects.	11	21	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	19	20
Thus , insulin stimulated AKT activation is suppressed in muscle , liver , and adipose tissue of HFD fed M ( WT ) mice but is suppressed only in the liver and adipose tissue of M ( KO ) mice .	Thus, insulin stimulated AKT activation is suppressed in muscle, liver, and adipose tissue of HFD fed M (WT) mice but is suppressed only in the liver and adipose tissue of M (KO) mice.	2	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	4	5
Akt2 activation is closely correlated to Glut4 translocation via insulin activated PI3K signals in adipocytes , 19 and T2D patients have reduced Akt activation in adipocytes and skeletal muscle .	Akt2 activation is closely correlated to Glut4 translocation via insulin activated PI3K signals in adipocytes, 19 and T2D patients have reduced Akt activation in adipocytes and skeletal muscle.	7	23	reduced	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	22	23
Consistent with unimpaired insulin activation of PKB , the stimulation of Ser 21 and Ser 9 phosphorylation of glycogen synthase kinase 3-alpha and -beta , and the apparent phosphorylation level of 4E-BP1 ( eukaryotic initiation factor 4 binding protein 1 ) , were similar in transduced and control hepatocytes .	Consistent with unimpaired insulin activation of PKB, the stimulation of Ser 21 and Ser 9 phosphorylation of glycogen synthase kinase 3-alpha and -beta, and the apparent phosphorylation level of 4E-BP1 (eukaryotic initiation factor 4 binding protein 1), were similar in transduced and control hepatocytes.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	3	4	6	7
However , this EGF and insulin induced AKT activation was severely inhibited in AK023948 KO cells ( XREF_FIG ) .	However, this EGF and insulin induced AKT activation was severely inhibited in AK023948 KO cells (XREF_FIG).	3	8	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	5	6	7	8
Independently of fiber type , insulin signaling was similar ( TBC1D1 , GS , and PDH-E1alpha ) or decreased ( Akt and TBC1D4 ) in muscle from patients with type 2 diabetes compared with lean and obese subjects .	Independently of fiber type, insulin signaling was similar (TBC1D1, GS, and PDH-E1alpha) or decreased (Akt and TBC1D4) in muscle from patients with type 2 diabetes compared with lean and obese subjects.	5	25	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	20	21
The reduced activation of AKT by insulin following PTH treatment is consistent with the effects of PTH to reduce insulin stimulated glucose uptake .	The reduced activation of AKT by insulin following PTH treatment is consistent with the effects of PTH to reduce insulin stimulated glucose uptake.	2	9	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	6	7	4	5
Research in the field highlights Akt and PKB as a major signaling intermediate in insulin stimulated glucose transport in type 2 diabetes characterized by reduced insulin signaling of Akt and PKB .	Research in the field highlights Akt and PKB as a major signaling intermediate in insulin stimulated glucose transport in type 2 diabetes characterized by reduced insulin signaling of Akt and PKB.	25	30	signaling	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	28	29
Suppression of TRAF6 expression attenuates insulin mediated ubiquitination and membrane targeting of APPL1 , leading to an impairment of insulin stimulated Akt activation and inhibition of gluconeogenesis in hepatocytes .	Suppression of TRAF6 expression attenuates insulin mediated ubiquitination and membrane targeting of APPL1, leading to an impairment of insulin stimulated Akt activation and inhibition of gluconeogenesis in hepatocytes.	17	22	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
Overexpressing a dominant negative form of Akt abrogated the heme oxygenase-1-inducing effects of insulin , whereas cells transfected with a constitutively active Akt construct demonstrated an increase in heme oxygenase-1 promoter activity and protein expression .	Overexpressing a dominant negative form of Akt abrogated the heme oxygenase-1-inducing effects of insulin, whereas cells transfected with a constitutively active Akt construct demonstrated an increase in heme oxygenase-1 promoter activity and protein expression.	0	14	Overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	6	7
Intravenous injection of caffeine at a physiological dose ( 5 mg/kg ) in rats inhibited the phosphorylation of insulin stimulated IRS-1 Tyr ( 612 ) and Akt Ser ( 473 ) in epitrochlearis muscle .	Intravenous injection of caffeine at a physiological dose (5 mg/kg) in rats inhibited the phosphorylation of insulin stimulated IRS-1 Tyr (612) and Akt Ser (473) in epitrochlearis muscle.	3	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	caffeine at a physiological dose (5 mg/kg) in rats inhibited the phosphorylation of insulin	insulin	Akt	Akt	akt	18	19	26	27
Moreover , PERK activation leads to the induction of a transcription factor called ATF4 , which induces an inhibitor of insulin induced AKT activation called Tribbles 3 .	Moreover, PERK activation leads to the induction of a transcription factor called ATF4, which induces an inhibitor of insulin induced AKT activation called Tribbles 3.	18	23	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	22	23
In ob/ob mice , both the DRG and sciatic nerve displayed reduced insulin induced Akt activation , a classic indication of insulin resistance .	In ob/ob mice, both the DRG and sciatic nerve displayed reduced insulin induced Akt activation, a classic indication of insulin resistance.	11	15	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	14	15
Increased basal phosphorylation of Ser307 IRS-1 in the obese and type 2 diabetic subjects corresponds with decrease in insulin stimulated IRS-1 tyrosine phosphorylation , PI 3-kinase activity , and insulin induced activation of Akt and , more prominently , PKC-zeta and lambda .	Increased basal phosphorylation of Ser307 IRS-1 in the obese and type 2 diabetic subjects corresponds with decrease in insulin stimulated IRS-1 tyrosine phosphorylation, PI 3-kinase activity, and insulin induced activation of Akt and, more prominently, PKC-zeta and lambda.	19	34	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	33	34
Through its substrate S6K , mTORC1 causes inhibitory serine phosphorylation of insulin receptor substrates ( IRS ) , thereby contributing to insulin resistance and subsequent attenuation of insulin induced AKT activity .	Through its substrate S6K, mTORC1 causes inhibitory serine phosphorylation of insulin receptor substrates (IRS), thereby contributing to insulin resistance and subsequent attenuation of insulin induced AKT activity.	25	30	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	27	28	29	30
FFAR2 also reportedly inhibits the induction of Akt by insulin in adipocytes in a PT sensitive manner XREF_BIBR .	FFAR2 also reportedly inhibits the induction of Akt by insulin in adipocytes in a PT sensitive manner XREF_BIBR.	3	11	induction	Positive_activation_token_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	7	8
Recent studies indicated that insulin could inhibit inflammation by activating phosphatidylinositol 3-kinase-Akt-dependent ( PI3K-Akt ) signaling pathway .	Recent studies indicated that insulin could inhibit inflammation by activating phosphatidylinositol 3-kinase-Akt-dependent (PI3K-Akt) signaling pathway.	4	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	PI3K-Akt	PI3K-Akt	PI3K-Akt	4	5	13	14
RANKL induced Akt phosphorylation was strongly inhibited by berberine ; however , neither monocyte and macrophage-colony stimulating factor ( M-CSF )-induced nor insulin induced Akt activation was inhibited by the drug .	RANKL induced Akt phosphorylation was strongly inhibited by berberine; however, neither monocyte and macrophage-colony stimulating factor (M-CSF)-induced nor insulin induced Akt activation was inhibited by the drug.	13	25	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	24	25
Moreover , insulin induced Akt signaling was decreased in HGF-Ab groups as compared to saline group under HFD condition .	Moreover, insulin induced Akt signaling was decreased in HGF-Ab groups as compared to saline group under HFD condition.	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
In line with the strongly reduced AKT hydrophobic motif phosphorylation , the insulin induced AKT kinase activity was reduced to ~ 20 % in both cell lines upon Rictor depletion .	In line with the strongly reduced AKT hydrophobic motif phosphorylation, the insulin induced AKT kinase activity was reduced to ~ 20% in both cell lines upon Rictor depletion.	11	16	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	14	15
However , in insulin resistance , IR-B preferential activation by insulin results in IRS1/2 mediated increase in the activity of the p85alpha regulatory subunit of PI3K ( PI3K p85alpha ) , which inhibits Akt thus reducing NO generation .	However, in insulin resistance, IR-B preferential activation by insulin results in IRS1/2 mediated increase in the activity of the p85alpha regulatory subunit of PI3K (PI3K p85alpha), which inhibits Akt thus reducing NO generation.	3	35	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	33	34
Cells with reduced IR demonstrated reduced insulin stimulated Akt activation , without affecting IGF1R activation .	Cells with reduced IR demonstrated reduced insulin stimulated Akt activation, without affecting IGF1R activation.	4	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
Glycogen synthase kinase 3 ( GSK3 ) alpha and beta were also detected , since there is evidence suggesting that GSK3 contributes to the induction by insulin resistance independently of insulin receptor signaling or PI3K-AKT activity [ XREF_BIBR ] .	Glycogen synthase kinase 3 (GSK3) alpha and beta were also detected, since there is evidence suggesting that GSK3 contributes to the induction by insulin resistance independently of insulin receptor signaling or PI3K-AKT activity [XREF_BIBR].	26	35	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	26	27	34	35
In hepatocytes insulin suppresses HGP by stimulating AKT to inhibit FOXO1 .	In hepatocytes insulin suppresses HGP by stimulating AKT to inhibit FOXO1.	2	9	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	7	8
Importantly , silencing of TBC1D3 suppressed the activation of Akt by insulin .	Importantly, silencing of TBC1D3 suppressed the activation of Akt by insulin.	5	12	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	9	10
Replacing either one of them with alanine residue will significantly impair the insulin induced AKT activity [ XREF_BIBR ] .	Replacing either one of them with alanine residue will significantly impair the insulin induced AKT activity [XREF_BIBR].	11	15	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	12	13	14	15
However , some investigators reported that feeding rats a high-fat diet results in decreased activation of IRS-1 , PI 3-kinase and PKB ( Akt ) by insulin in muscles within 4 wk [ XREF_BIBR - XREF_BIBR ] , which could account for the development of insulin resistance .	However, some investigators reported that feeding rats a high-fat diet results in decreased activation of IRS-1, PI 3-kinase and PKB (Akt) by insulin in muscles within 4 wk [XREF_BIBR - XREF_BIBR], which could account for the development of insulin resistance.	14	27	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	PKB	PKB	PKB	26	27	21	22
High concentrations of glucose appear capable of provoking glycosylation of eNOS on the same residue ( serine 1177 ) that is a target for insulin activated Akt .	High concentrations of glucose appear capable of provoking glycosylation of eNOS on the same residue (serine 1177) that is a target for insulin activated Akt.	4	27	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	24	25	26	27
Insulin independent activation of IR substrate-1 ( IRS-1 ) and diminished Akt activation by palmitate .	Insulin independent activation of IR substrate-1 (IRS-1) and diminished Akt activation by palmitate.	0	12	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	11	12
Leucine restriction ( LR ) also improved glucose tolerance , increased hepatic release of FGF21 into the blood stream , and enhanced insulin dependent activation of Akt in liver .	Leucine restriction (LR) also improved glucose tolerance, increased hepatic release of FGF21 into the blood stream, and enhanced insulin dependent activation of Akt in liver.	22	27	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	22	23	26	27
HFD fed F WT mice exhibited reduced insulin stimulated AKT activation in adipose tissue ( XREF_FIG ) , liver ( XREF_FIG ) , and muscle ( XREF_SUPPLEMENTARY ) .	HFD fed F WT mice exhibited reduced insulin stimulated AKT activation in adipose tissue (XREF_FIG), liver (XREF_FIG), and muscle (XREF_SUPPLEMENTARY).	5	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	9	10
Decreased insulin stimulated Akt kinase activity has been previously reported in type 2 diabetic subject XREF_BIBR , XREF_BIBR and non obese spontaneously diabetic Goto-Kakizaki ( GK ) rats XREF_BIBR .	Decreased insulin stimulated Akt kinase activity has been previously reported in type 2 diabetic subject XREF_BIBR, XREF_BIBR and non obese spontaneously diabetic Goto-Kakizaki (GK) rats XREF_BIBR.	0	5	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
JNK mediated phosphorylation of insulin receptor substrates 1 and 2 disrupts Akt signaling XREF_BIBR , XREF_BIBR possibly by releasing Bad for translocation to the mitochondria 23 or association with Bcl-2 and Bcl-xL and initiation of apoptosis .	JNK mediated phosphorylation of insulin receptor substrates 1 and 2 disrupts Akt signaling XREF_BIBR, XREF_BIBR possibly by releasing Bad for translocation to the mitochondria 23 or association with Bcl-2 and Bcl-xL and initiation of apoptosis.	0	13	disrupts	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	insulin	JNK mediated phosphorylation of insulin	insulin	Akt	Akt	akt	4	5	11	12
Since insulin resistance impairs the PI3K and AKT signaling pathway , we determined the pAKT ( S473 ) status in these livers .	Since insulin resistance impairs the PI3K and AKT signaling pathway, we determined the pAKT (S473) status in these livers.	1	9	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	1	2	7	8
Similarly , caveolin-1 overexpression attenuated basal and insulin stimulated NO synthesis along with impaired insulin dependent activation of AKT and eNOS , with no effect on insulin stimulated ERK1/2 phosphorylation and endothelin-1 transcription .	Similarly, caveolin-1 overexpression attenuated basal and insulin stimulated NO synthesis along with impaired insulin dependent activation of AKT and eNOS, with no effect on insulin stimulated ERK1/2 phosphorylation and endothelin-1 transcription.	14	20	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	14	15	18	19
Meanwhile , long-term treadmill exercise seems to decrease Abeta generation by decreasing activation of beta or gamma-secretase through improvement of insulin mediated insulin signaling impairment ( PI3-K and Akt signaling activation increase and GSK-3beta activation decrease ) .	Meanwhile, long-term treadmill exercise seems to decrease Abeta generation by decreasing activation of beta or gamma-secretase through improvement of insulin mediated insulin signaling impairment (PI3-K and Akt signaling activation increase and GSK-3beta activation decrease).	18	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	28	29
In addition , cells cultured for 4h in the presence of WT showed reduced activation of Akt and PKB by IGF1 and by insulin but marked phosphorylation of Akt and PKB was still observed when WT was added only for the last 3h ( not shown ) .	In addition, cells cultured for 4h in the presence of WT showed reduced activation of Akt and PKB by IGF1 and by insulin but marked phosphorylation of Akt and PKB was still observed when WT was added only for the last 3h (not shown).	14	24	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	PKB	PKB	PKB	23	24	18	19
In contrast to hepatic aPKC , whereas activation and Ser-473-phosphorylation of hepatic PKB was , as expected , markedly impaired in GK-diabetic rats treated with adenovirus alone , insulin stimulated PKB activity ( XREF_FIG ) and Ser-473-phosphorylation ( XREF_FIG ) improved substantially following treatment with adenovirus encoding kinase-inactive PKC-zeta .	In contrast to hepatic aPKC, whereas activation and Ser-473-phosphorylation of hepatic PKB was, as expected, markedly impaired in GK-diabetic rats treated with adenovirus alone, insulin stimulated PKB activity (XREF_FIG) and Ser-473-phosphorylation (XREF_FIG) improved substantially following treatment with adenovirus encoding kinase-inactive PKC-zeta.	7	29	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	insulin	insulin	insulin	PKB	PKB	PKB	28	29	12	13
The impairment of insulin induced Akt activation by CRP was also demonstrated both in cultured endothelial cells and in vivo in the lung .	The impairment of insulin induced Akt activation by CRP was also demonstrated both in cultured endothelial cells and in vivo in the lung.	1	6	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
In this system , suppression of Atg7 expression ( ~ 70 % ) resulted in decreased insulin stimulated Akt Ser 473 ( ~ 50 % ) and IR beta subunit ( ~ 60 % ) phosphorylation ( XREF_FIG ) .	In this system, suppression of Atg7 expression (~ 70%) resulted in decreased insulin stimulated Akt Ser 473 (~ 50%) and IR beta subunit (~ 60%) phosphorylation (XREF_FIG).	13	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	18	19
For example , APPL1 KO mice show the opposite metabolic phenotype to C2beta D1212A and D1212A mice , being insulin resistant and glucose-intolerant with decreased insulin stimulated Akt signaling in the liver , muscle , and adipose tissue .	For example, APPL1 KO mice show the opposite metabolic phenotype to C2beta D1212A and D1212A mice, being insulin resistant and glucose-intolerant with decreased insulin stimulated Akt signaling in the liver, muscle, and adipose tissue.	19	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
Moreover insulin inhibition of PI3K and Akt -1 pathway leads to impaired NO availability XREF_BIBR , XREF_BIBR .	Moreover insulin inhibition of PI3K and Akt -1 pathway leads to impaired NO availability XREF_BIBR, XREF_BIBR.	1	8	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	6	7
Higher levels of glucose , insulin , and free fatty acid , inhibited Akt activity , and decreased glucose transporter 4 ( GLUT4 ) expression were observed in SAMP8 mice compared to the normal aging group , SAM resistant 1 mice .	Higher levels of glucose, insulin, and free fatty acid, inhibited Akt activity, and decreased glucose transporter 4 (GLUT4) expression were observed in SAMP8 mice compared to the normal aging group, SAM resistant 1 mice.	1	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	levels of glucose, insulin	insulin	Akt	Akt	akt	5	6	13	14
Insulin resistance disrupts PI3K and Akt signaling , known to regulate DAT [ XREF_BIBR ] , causing reduced DAT expression on the plasma membrane [ XREF_BIBR ] .	Insulin resistance disrupts PI3K and Akt signaling, known to regulate DAT [XREF_BIBR], causing reduced DAT expression on the plasma membrane [XREF_BIBR].	0	6	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	5	6
Of note , denervation induced decrease in Akt activity is reminiscent of decreased insulin stimulated Akt activation in skeletal muscle of burned mice XREF_BIBR , XREF_BIBR , which can be reversed by FTI-277 17 .	Of note, denervation induced decrease in Akt activity is reminiscent of decreased insulin stimulated Akt activation in skeletal muscle of burned mice XREF_BIBR, XREF_BIBR, which can be reversed by FTI-277 17.	10	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
In addition , serine 307 in Irs1 is phosphorylated by the JNK and PI 3-kinase/mTor signalling pathways [ XREF_BIBR ] , and in vivo , enhanced levels of serine 307 phosphorylation were found in skeletal muscle biopsies of obese , insulin resistant non diabetic subjects , and accompanied by a decrease in Irs1 tyrosine phosphorylation as well as reduced insulin dependent activation of Akt [ XREF_BIBR ] .	In addition, serine 307 in Irs1 is phosphorylated by the JNK and PI 3-kinase/mTor signalling pathways [XREF_BIBR], and in vivo, enhanced levels of serine 307 phosphorylation were found in skeletal muscle biopsies of obese, insulin resistant non diabetic subjects, and accompanied by a decrease in Irs1 tyrosine phosphorylation as well as reduced insulin dependent activation of Akt [XREF_BIBR].	59	65	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	59	60	63	64
Inhibition of RhoA action , which is necessary for the formation of FA formation [ XREF_BIBR ] , also blocks mechanical activation of Akt but not Akt activation by insulin ( XREF_FIG ) .	Inhibition of RhoA action, which is necessary for the formation of FA formation [XREF_BIBR], also blocks mechanical activation of Akt but not Akt activation by insulin (XREF_FIG).	26	31	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	26	27
Furthermore , insulin stimulated AKT activation was suppressed by a p110alpha selective inhibitor BYL719 but not by a p110beta inhibitor TGX221 .	Furthermore, insulin stimulated AKT activation was suppressed by a p110alpha selective inhibitor BYL719 but not by a p110beta inhibitor TGX221.	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	4	5
A common denominator for insulin resistance at the cellular level is decreased activation of Akt by insulin .	A common denominator for insulin resistance at the cellular level is decreased activation of Akt by insulin.	11	17	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	16	17	14	15
Adipocytes lacking Rictor demonstrate selective insulin resistance in that only insulin stimulated glucose uptake and not insulin stimulated AKT signalling is impaired .	Adipocytes lacking Rictor demonstrate selective insulin resistance in that only insulin stimulated glucose uptake and not insulin stimulated AKT signalling is impaired.	13	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	16	17	18	19
Cerebellar neurons isolated from ethanol exposed pups had reduced levels of insulin stimulated phosphoinositol 3-kinase and Akt kinase activities and reduced insulin inhibition of PTEN and glycogen synthase kinase-3 activity .	Cerebellar neurons isolated from ethanol exposed pups had reduced levels of insulin stimulated phosphoinositol 3-kinase and Akt kinase activities and reduced insulin inhibition of PTEN and glycogen synthase kinase-3 activity.	9	18	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	levels of insulin	insulin	Akt	Akt	akt	11	12	16	17
Insulin stimulated Akt activity and phosphorylation and 2-deoxyglucose uptake were reduced with SCD1 siRNA .	Insulin stimulated Akt activity and phosphorylation and 2-deoxyglucose uptake were reduced with SCD1 siRNA.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	2	3
This lower dose was found to normalize phosphorylation of insulin stimulated insulin receptor and insulin receptor substrate 2 ( IRS-2 ) as well as activation of IRS-2-associated PI3K and Akt in the liver 154 .	This lower dose was found to normalize phosphorylation of insulin stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) as well as activation of IRS-2-associated PI3K and Akt in the liver 154.	7	30	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	phosphorylation of insulin	insulin	Akt	Akt	akt	9	10	29	30
The overexpression of hepatic miR-143 impaired insulin stimulated AKT activation and glucose homeostasis by targeting insulin signalling and its regulation .	The overexpression of hepatic miR-143 impaired insulin stimulated AKT activation and glucose homeostasis by targeting insulin signalling and its regulation.	1	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	overexpression of hepatic miR-143 impaired insulin	insulin	AKT	AKT	akt	6	7	8	9
This was associated with decreased whole-body insulin sensitivity as a consequence of JNK inhibiting insulin stimulated Akt activation .	This was associated with decreased whole-body insulin sensitivity as a consequence of JNK inhibiting insulin stimulated Akt activation.	10	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
Therefore , chronic downregulation of AMPK activity upon Sestrin2 deficiency results in enhanced mTORC1 activation , thereby attenuating insulin induced AKT activity .	Therefore, chronic downregulation of AMPK activity upon Sestrin2 deficiency results in enhanced mTORC1 activation, thereby attenuating insulin induced AKT activity.	17	21	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	18	19	20	21
In RINm5F cells , the diminished IRS phosphorylation was accompanied by a reduced insulin stimulated activation of phosphatidylinositol 3-kinase ( PI3K ) , AKT and Extracellular Signal Regulated Kinase , partly due to an increased basal activity .	In RINm5F cells, the diminished IRS phosphorylation was accompanied by a reduced insulin stimulated activation of phosphatidylinositol 3-kinase (PI3K), AKT and Extracellular Signal Regulated Kinase, partly due to an increased basal activity.	13	24	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	13	14	23	24
Mechanistically , the current model for insulin resistance in obesity suggests that adipose tissue macrophage ( ATM ) infiltration and proinflammatory cytokine release activates inflammatory pathways such as inhibitor of kappa B kinase beta ( IKKbeta ) and Jun NH 2 -terminal kinase ( JNK ) , which impinge upon the insulin signaling cascade by inhibiting tyrosine phosphorylation of insulin receptor substrate 1 ( IRS1 ) , leading to impaired insulin activation of phosphoinositide 3-kinase ( PI3K ) and Akt .	Mechanistically, the current model for insulin resistance in obesity suggests that adipose tissue macrophage (ATM) infiltration and proinflammatory cytokine release activates inflammatory pathways such as inhibitor of kappa B kinase beta (IKKbeta) and Jun NH 2 -terminal kinase (JNK), which impinge upon the insulin signaling cascade by inhibiting tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), leading to impaired insulin activation of phosphoinositide 3-kinase (PI3K) and Akt.	70	80	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	70	71	79	80
Kurowski et al and Oku et al reported that a high glucose concentration reduced p-Akt levels and reduced the insulin induced Akt activation in skeletal muscles XREF_BIBR , XREF_BIBR .	Kurowski et al and Oku et al reported that a high glucose concentration reduced p-Akt levels and reduced the insulin induced Akt activation in skeletal muscles XREF_BIBR, XREF_BIBR.	17	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
The findings confirm that altered insulin receptors activity directly impairs insulin and Akt signaling in this disease [ XREF_BIBR ] .	The findings confirm that altered insulin receptors activity directly impairs insulin and Akt signaling in this disease [XREF_BIBR].	5	13	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	12	13
However , IR-B knockdown blocked insulin restoration of GDM reduced P ~ Akt and Akt ( XREF_FIG ) .	However, IR-B knockdown blocked insulin restoration of GDM reduced P ~ Akt and Akt (XREF_FIG).	5	16	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	12	13
Interestingly , we observed that in vitro insulin treatment decreased total Akt relative to basal levels following 2 hr ( basal : 100 +/- 4 % vs. insulin : 35 +/- 3 % , P < 0.05 ) .	Interestingly, we observed that in vitro insulin treatment decreased total Akt relative to basal levels following 2 hr (basal : 100 +/- 4% vs. insulin : 35 +/- 3%, P < 0.05).	7	12	decreased	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	11	12
In contrast , the fatty acid mixtures only modestly impaired insulin stimulated pAkt Thr308M / Akt , and we found no differences between NORM and HSFA .	In contrast, the fatty acid mixtures only modestly impaired insulin stimulated pAkt Thr308M / Akt, and we found no differences between NORM and HSFA.	3	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	15	16
Therefore , it is conceivable that inhibition of insulin induced Akt activation is reflected in insulin resistant states .	Therefore, it is conceivable that inhibition of insulin induced Akt activation is reflected in insulin resistant states.	6	11	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	10	11
Insulin or IGF-1 can block this process by stimulating activity of the PI3K and Akt pathway to suppress the expression of Atrogin-1 .	Insulin or IGF-1 can block this process by stimulating activity of the PI3K and Akt pathway to suppress the expression of Atrogin-1.	0	15	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	14	15
These results agree with previous studies in myotubes and isolated rodent and human skeletal muscle demonstrating impaired insulin stimulated Akt activation and glucose uptake when ceramides are elevated .	These results agree with previous studies in myotubes and isolated rodent and human skeletal muscle demonstrating impaired insulin stimulated Akt activation and glucose uptake when ceramides are elevated.	15	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	19	20
In contrast insulin is shown to reduce oxidative stress by activating serine threonine kinase Akt signaling pathway which in turn influences several proteins involved in apoptosis ; survival is also enhanced by insulin by shuttling Akt into various sub cellular compartments .	In contrast insulin is shown to reduce oxidative stress by activating serine threonine kinase Akt signaling pathway which in turn influences several proteins involved in apoptosis; survival is also enhanced by insulin by shuttling Akt into various sub cellular compartments.	2	16	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	14	15
Moreover , muscle insulin resistant individuals and type 2 diabetes patients have impaired insulin stimulated Akt Thr 308 and Ser 473 phosphorylation , lower insulin stimulated Akt substrate of 160 kDa ( AS160 and TBC1D4 ) phosphorylation on multiple sites , and impaired insulin stimulated glycogen synthase ( GS ) activity .	Moreover, muscle insulin resistant individuals and type 2 diabetes patients have impaired insulin stimulated Akt Thr 308 and Ser 473 phosphorylation, lower insulin stimulated Akt substrate of 160 kDa (AS160 and TBC1D4) phosphorylation on multiple sites, and impaired insulin stimulated glycogen synthase (GS) activity.	14	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin stimulated Akt substrate of 160 kDa (AS160 and TBC1D4) phosphorylation	insulin	Akt	Akt	akt	24	25	15	16
Notably , the insulin effect was capably blocked by simultaneous presence of LY294002 , positioning PI3-K and AKT at the upstream level to control protein synthesis of Mfn-2 and COX IV ( XREF_FIG ) .	Notably, the insulin effect was capably blocked by simultaneous presence of LY294002, positioning PI3-K and AKT at the upstream level to control protein synthesis of Mfn-2 and COX IV (XREF_FIG).	3	18	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	17	18
In addition , previous studies have demonstrated that exposure of vascular endothelial cells to high glucose causes a significant increase in apoptosis , possibly associated with an increase in intracellular ROS , alteration in fatty-acid metabolism , impaired Akt activation by insulin and increased caspase-3 activity [ XREF_BIBR , XREF_BIBR ] .	In addition, previous studies have demonstrated that exposure of vascular endothelial cells to high glucose causes a significant increase in apoptosis, possibly associated with an increase in intracellular ROS, alteration in fatty-acid metabolism, impaired Akt activation by insulin and increased caspase-3 activity [XREF_BIBR, XREF_BIBR].	38	42	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	41	42	38	39
In 3T3-L1 adipocytes , we previously reported that glucosamine impairs insulin stimulation of glucose transport , which is accompanied by impaired insulin stimulation of serine/threonine kinase Akt .	In 3T3-L1 adipocytes, we previously reported that glucosamine impairs insulin stimulation of glucose transport, which is accompanied by impaired insulin stimulation of serine/threonine kinase Akt.	21	27	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	26	27
In the adipose tissue of wild-type mice , a dramatic increase in S6K1 activation is observed in response to a high fat diet or in genetic models of obesity , and this is accompanied by an increase in IRS-1 phosphorylation on S307 , S632 , and S635 and by attenuation of insulin induced Akt activation .	In the adipose tissue of wild-type mice, a dramatic increase in S6K1 activation is observed in response to a high fat diet or in genetic models of obesity, and this is accompanied by an increase in IRS-1 phosphorylation on S307, S632, and S635 and by attenuation of insulin induced Akt activation.	49	54	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	51	52	53	54
Inhibition of PKC theta restored insulin mediated vasoreactivity and insulin mediated activation of Akt and ERK1/2 in the presence of PA ..	Inhibition of PKC theta restored insulin mediated vasoreactivity and insulin mediated activation of Akt and ERK1/2 in the presence of PA..	7	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	13	14
Insulin ( 10mug/mL ) as the positive control upregulated GLUT4 gene and downregulated AKT , HSL , PI3KA , and Srebp1 genes compared to the untreated cells in the present study .	Insulin (10mug/mL) as the positive control upregulated GLUT4 gene and downregulated AKT, HSL, PI3KA, and Srebp1 genes compared to the untreated cells in the present study.	0	21	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	10mug/mL	10mug/mL	10mug/mL	AKT	AKT	AKT	2	3	13	14
Skeletal muscle insulin resistance was measurable as reduced insulin activation of the insulin receptor and AKT and PKB ( Protein Kinase B ) , which may involve changes in Tribbles homolog 3 ( TRIB3 ) gene expression and/or increased proinflammatory cytokine mRNA levels in skeletal muscle following polytrauma .	Skeletal muscle insulin resistance was measurable as reduced insulin activation of the insulin receptor and AKT and PKB (Protein Kinase B), which may involve changes in Tribbles homolog 3 (TRIB3) gene expression and/or increased proinflammatory cytokine mRNA levels in skeletal muscle following polytrauma.	8	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	PKB	PKB	PKB	8	9	17	18
To determine whether the impaired insulin stimulated Akt activation in thapsigargin treated HL-1 cells was correlated with TRB3 induction , TRB3 protein levels were determined by immunoblotting ( XREF_FIG ) .	To determine whether the impaired insulin stimulated Akt activation in thapsigargin treated HL-1 cells was correlated with TRB3 induction, TRB3 protein levels were determined by immunoblotting (XREF_FIG).	3	15	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Evidence from both human and animal work links insulin resistance with defects to both upstream and downstream targets of Akt and PKB in the form of dephosphorylation of protein side chains on insulin receptor substrates as well as complete loss of insulin receptor substrates from the cell surface membrane , XREF_BIBR reduced PI3 kinase activity XREF_BIBR and impaired phosphorylation of the Akt and PKB substrate , AS160 , in type 2 diabetic skeletal muscle .	Evidence from both human and animal work links insulin resistance with defects to both upstream and downstream targets of Akt and PKB in the form of dephosphorylation of protein side chains on insulin receptor substrates as well as complete loss of insulin receptor substrates from the cell surface membrane, XREF_BIBR reduced PI3 kinase activity XREF_BIBR and impaired phosphorylation of the Akt and PKB substrate, AS160, in type 2 diabetic skeletal muscle.	8	20	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	19	20
Furthermore , recent in vitro and in vivo experimental data showed that apoCIII may directly induce endothelial dysfunction via inhibition of insulin induced activation of Akt resulting in reduced nitric oxide ( NO ) release and subsequent impaired vasodilation [ XREF_BIBR ] .	Furthermore, recent in vitro and in vivo experimental data showed that apoCIII may directly induce endothelial dysfunction via inhibition of insulin induced activation of Akt resulting in reduced nitric oxide (NO) release and subsequent impaired vasodilation [XREF_BIBR].	19	26	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	25	26
Concomitantly , insulin induced activation of Akt and PKB and of ERK1/2 was strongly inhibited .	Concomitantly, insulin induced activation of Akt and PKB and of ERK1/2 was strongly inhibited.	2	8	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	6	7
Attenuated insulin activation of cardiac PI3K and Akt was also reported in ob/ob type 2 diabetic mice and a porcine model of diet induced obesity and insulin resistance .	Attenuated insulin activation of cardiac PI3K and Akt was also reported in ob/ob type 2 diabetic mice and a porcine model of diet induced obesity and insulin resistance.	1	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	7	8
Apart from a tendency toward an approximately 20 % reduction in both basal and insulin stimulated Akt Ser ( 473 ) phosphorylation ( P = 0.051 ) in the CAF group , there were no differences in insulin signaling ( IR Tyr ( 1150/1151 ) , PI 3-kinase activity , Akt Thr ( 308 ) , TBC1D4 Thr ( 642 ) , GSK3-alpha and beta Ser ( 21/9 ) ) or changes in AMPKalpha1 or -alpha2 , GLUT4 , Munc18c , or syntaxin 4 protein expression or in phosphorylation of AMPK Thr ( 172 ) among the groups .	Apart from a tendency toward an approximately 20% reduction in both basal and insulin stimulated Akt Ser (473) phosphorylation (P = 0.051) in the CAF group, there were no differences in insulin signaling (IR Tyr (1150/1151), PI 3-kinase activity, Akt Thr (308), TBC1D4 Thr (642), GSK3-alpha and beta Ser (21/9)) or changes in AMPKalpha1 or -alpha2, GLUT4, Munc18c, or syntaxin 4 protein expression or in phosphorylation of AMPK Thr (172) among the groups.	9	17	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
ATP2B1 gene silencing resulted in enhanced intracellular calcium concentrations and increased insulin induced Akt activation compared to that in the negative siRNA transfected HUVECs ( Human Umbilical Vein Endothelial Cells ) .	ATP2B1 gene silencing resulted in enhanced intracellular calcium concentrations and increased insulin induced Akt activation compared to that in the negative siRNA transfected HUVECs (Human Umbilical Vein Endothelial Cells).	3	14	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Our results suggest that when GnRH and insulin are co-treated , there is a dramatic attenuation in insulin induced Akt activation in the LbetaT2 cell line .	Our results suggest that when GnRH and insulin are co-treated, there is a dramatic attenuation in insulin induced Akt activation in the LbetaT2 cell line.	15	20	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	17	18	19	20
Treatment with 20-HETE decreased the insulin stimulated binding of IRS-1 to the p85 subunit by 30 % and decreased Ser473 Akt activation by 40 % .	Treatment with 20-HETE decreased the insulin stimulated binding of IRS-1 to the p85 subunit by 30% and decreased Ser473 Akt activation by 40%.	4	21	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	20	21
Briefly , short-term inhibition of autophagy in NAFLD could be induced through the mTOR complex , while long-term inhibition could be regulated via the transcription factors FoxO and TFEB , which control the transcription of autophagic genes and are inhibited by insulin induced activation of Akt and PKB and mTOR , respectively .	Briefly, short-term inhibition of autophagy in NAFLD could be induced through the mTOR complex, while long-term inhibition could be regulated via the transcription factors FoxO and TFEB, which control the transcription of autophagic genes and are inhibited by insulin induced activation of Akt and PKB and mTOR, respectively.	39	49	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	41	42	45	46
XREF_BIBR also showed a reduction of Akt kinase activity in the skeletal muscle of T2DM patients compared to healthy individuals upon high doses of insulin stimulation , suggesting that T2DM patients exhibit impaired insulin stimulated Akt signaling .	XREF_BIBR also showed a reduction of Akt kinase activity in the skeletal muscle of T2DM patients compared to healthy individuals upon high doses of insulin stimulation, suggesting that T2DM patients exhibit impaired insulin stimulated Akt signaling.	31	36	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	33	34	35	36
Experimental data show that extended ( 24 h ) pretreatment of IL-6 impaired the activation of Akt by insulin [ XREF_BIBR ] , whereas TNFalpha impaired the insulin signaling at IRS1 , through activating S6K related negative feedback signaling [ XREF_BIBR ] , both contributing to insulin resistance .	Experimental data show that extended (24 h) pretreatment of IL-6 impaired the activation of Akt by insulin [XREF_BIBR], whereas TNFalpha impaired the insulin signaling at IRS1, through activating S6K related negative feedback signaling [XREF_BIBR], both contributing to insulin resistance.	14	20	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	16	17
Moreover , shear stress and insulin could inhibit endothelial cell apoptosis by activating Akt [ XREF_BIBR , XREF_BIBR ] .	Moreover, shear stress and insulin could inhibit endothelial cell apoptosis by activating Akt [XREF_BIBR, XREF_BIBR].	3	17	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	13	14
Consistently , insulin stimulated Akt Ser 473 was also significantly decreased with overexpression of TRB3 ( XREF_FIG ) .	Consistently, insulin stimulated Akt Ser 473 was also significantly decreased with overexpression of TRB3 (XREF_FIG).	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
In myotubes palmitate induced ceramide generation and exogenous C2-ceramide treatment impaired insulin stimulated Akt activation [ XREF_BIBR ] .	In myotubes palmitate induced ceramide generation and exogenous C2-ceramide treatment impaired insulin stimulated Akt activation [XREF_BIBR].	3	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	11	12	13	14
Impairment of insulin stimulated Akt and GLUT4 signaling is associated with cardiac contractile dysfunction and aggravates I/R injury in STZ-diabetic Rats .	Impairment of insulin stimulated Akt and GLUT4 signaling is associated with cardiac contractile dysfunction and aggravates I/R injury in STZ-diabetic Rats.	0	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
However , there was a complete loss of insulin stimulated P-Akt ( S473 ; XREF_FIG ) as early as 15 min ( TH15 ' ) , as well as at 30 and 60 min following the combination of trauma and hemorrhage ( XREF_FIG ) .	However, there was a complete loss of insulin stimulated P-Akt (S473; XREF_FIG) as early as 15 min (TH15 '), as well as at 30 and 60 min following the combination of trauma and hemorrhage (XREF_FIG).	6	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	loss of insulin	insulin	P-Akt	P-Akt	p-akt	8	9	10	11
Insulin resistance downregulates Akt activity via a PI3K dependent pathway in DRG neurons .	Insulin resistance downregulates Akt activity via a PI3K dependent pathway in DRG neurons.	0	4	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	3	4
Reduced insulin stimulated Akt is evident in insulin resistant obese individuals .	Reduced insulin stimulated Akt is evident in insulin resistant obese individuals.	0	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
Impairment of insulin stimulated AKT and GLUT4 signaling parallels ventricular contractile dysfunction and increased mortality rate of streptozotocin induced diabetic rats subjected to ischemia-reperfusion treatment .	Impairment of insulin stimulated AKT and GLUT4 signaling parallels ventricular contractile dysfunction and increased mortality rate of streptozotocin induced diabetic rats subjected to ischemia-reperfusion treatment.	0	7	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	2	3	4	5
Further , insulin induced increase of pY-IRS1 was attenuated in SERT-/- mice ( XREF_FIG ) , parallel to the reduced insulin induced AKT activation .	Further, insulin induced increase of pY-IRS1 was attenuated in SERT-/- mice (XREF_FIG), parallel to the reduced insulin induced AKT activation.	16	23	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	20	21	22	23
XREF_BIBR , XREF_BIBR Decreased insulin response reduces the PI3K-AKT pathway activity , which would negatively affect mTORC2 .	XREF_BIBR, XREF_BIBR Decreased insulin response reduces the PI3K-AKT pathway activity, which would negatively affect mTORC2.	4	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	4	5	8	9
Insulin induced activation of Akt disrupted interactions between the C/EBPbeta transactivation domain and certain coactivator proteins ( such as p300 and CBP ) , abrogating C/EBP mediated activation of genes .	Insulin induced activation of Akt disrupted interactions between the C/EBPbeta transactivation domain and certain coactivator proteins (such as p300 and CBP), abrogating C/EBP mediated activation of genes.	0	5	induced	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt	Akt	Akt	0	1	4	5
The insulin resistance in the PDK1 K465E and K465E animals is thought to result from partial inhibition of insulin induced activation of Akt isoforms .	The insulin resistance in the PDK1 K465E and K465E animals is thought to result from partial inhibition of insulin induced activation of Akt isoforms.	1	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	22	23
Nox4 gene silencing had a much greater inhibitory effect on insulin induced AKT activation than ERK1/2 activation , whereas it had little effect on the expression of the phosphatases such as MKP-1 and SHIP .	Nox4 gene silencing had a much greater inhibitory effect on insulin induced AKT activation than ERK1/2 activation, whereas it had little effect on the expression of the phosphatases such as MKP-1 and SHIP.	3	13	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	10	11	12	13
In some tissues , such as cardiac muscle , insulin antagonizes activation of AMPK by activating Akt .	In some tissues, such as cardiac muscle, insulin antagonizes activation of AMPK by activating Akt.	9	17	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	16	17
Rab8 , Rab10 and Rab14 , the putative targets of AS160 XREF_BIBR , a RabGAP inactivated by the insulin induced PKB pathway XREF_BIBR , were also suspected to play a role in GLUT4 recycling .	Rab8, Rab10 and Rab14, the putative targets of AS160 XREF_BIBR, a RabGAP inactivated by the insulin induced PKB pathway XREF_BIBR, were also suspected to play a role in GLUT4 recycling.	15	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	PKB	PKB	PKB	18	19	20	21
There is , therefore , an emerging consensus that loss of insulin signaling and , more specifically , insulin stimulated Akt and FoxO signaling , accelerates atherosclerosis .	There is, therefore, an emerging consensus that loss of insulin signaling and, more specifically, insulin stimulated Akt and FoxO signaling, accelerates atherosclerosis.	9	23	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	loss of insulin signaling and, more specifically, insulin	insulin	Akt	Akt	akt	18	19	20	21
Ang II inhibition of insulin stimulated IRS-1 tyrosyl phophorylation and Akt activation were reversed by PD98059 but not by SP600125 .	Ang II inhibition of insulin stimulated IRS-1 tyrosyl phophorylation and Akt activation were reversed by PD98059 but not by SP600125.	2	11	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	10	11
Relative Srebp1c mRNA abundance was lower in Bad -/- liver ( XREF_SUPPLEMENTARY ) , which is consistent with reduced insulin stimulation of PI3K-AKT signaling in these mice .	Relative Srebp1c mRNA abundance was lower in Bad -/- liver (XREF_SUPPLEMENTARY), which is consistent with reduced insulin stimulation of PI3K-AKT signaling in these mice.	19	23	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	19	20	22	23
In agreement with this idea is that insulin resistant macrophages have reduced Akt activity , and are more susceptible to endoplasmic reticulum stress associated apoptosis contributing to macrophage death and necrotic core formation in atherosclerotic plaques XREF_BIBR , XREF_BIBR .	In agreement with this idea is that insulin resistant macrophages have reduced Akt activity, and are more susceptible to endoplasmic reticulum stress associated apoptosis contributing to macrophage death and necrotic core formation in atherosclerotic plaques XREF_BIBR, XREF_BIBR.	7	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	7	8	12	13
Furthermore , overexpression of an Akt mutant in which the phosphorylation sites targeted by growth factors are replaced by alanine resulted in inhibition of insulin induced activation of Akt but not of PKClambda .	Furthermore, overexpression of an Akt mutant in which the phosphorylation sites targeted by growth factors are replaced by alanine resulted in inhibition of insulin induced activation of Akt but not of PKClambda.	22	29	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	24	25	28	29
Such changes are accompanied by diminished insulin stimulated Akt activation .	Such changes are accompanied by diminished insulin stimulated Akt activation.	3	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	6	7	8	9
To determine whether the observed improvements in insulin resistance and phosphorylation status of IRS-1 and AKT are directly linked to TNF blockade or are secondary to reduction in disease activity and inflammation , we studied seven patients with RA , who received abatacept ( CTLA4.Ig ) due to high disease activity .	To determine whether the observed improvements in insulin resistance and phosphorylation status of IRS-1 and AKT are directly linked to TNF blockade or are secondary to reduction in disease activity and inflammation, we studied seven patients with RA, who received abatacept (CTLA4.Ig) due to high disease activity.	7	16	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	15	16
Silencing of miR-155 targets ( i.e. C/EBPbeta and HDAC4 ) and C/EBPbeta target PDK4 in cultured liver cells enhanced insulin stimulated AKT activation and glucose uptake .	Silencing of miR-155 targets (i.e. C/EBPbeta and HDAC4) and C/EBPbeta target PDK4 in cultured liver cells enhanced insulin stimulated AKT activation and glucose uptake.	18	22	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	19	20	21	22
The results indicate that alterations in fatty-acid metabolism , impaired Akt activation by insulin , and increased caspase-3 activity precede visible evidence of apoptosis in HUVEC incubated in a hyperglycemic medium .	The results indicate that alterations in fatty-acid metabolism, impaired Akt activation by insulin, and increased caspase-3 activity precede visible evidence of apoptosis in HUVEC incubated in a hyperglycemic medium.	10	14	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	10	11
However , at this concentration , methyl-beta-cyclodextrin perturbed CMD of hepatocyte PM and inhibited insulin induced Akt activation and glycogen synthesis but did not affect insulin induced insulin receptor kinase tyrosine phosphorylation .	However, at this concentration, methyl-beta-cyclodextrin perturbed CMD of hepatocyte PM and inhibited insulin induced Akt activation and glycogen synthesis but did not affect insulin induced insulin receptor kinase tyrosine phosphorylation.	8	17	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	14	15	16	17
HFD causes insulin resistance in cortical and limbic structures , including decreased insulin stimulation of Akt , S6K , GSK3beta , and mTORC1 signaling , while AMP activated protein kinase ( AMPK ) stimulation is increased 104 .	HFD causes insulin resistance in cortical and limbic structures, including decreased insulin stimulation of Akt, S6K, GSK3beta, and mTORC1 signaling, while AMP activated protein kinase (AMPK) stimulation is increased 104.	12	19	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	12	13	15	16
Similarly , insulin induced Akt stimulation is also reduced in DRG neurons from animal models of T2D that develop DN : db/db and ob/ob mice [ XREF_BIBR , XREF_BIBR ] .	Similarly, insulin induced Akt stimulation is also reduced in DRG neurons from animal models of T2D that develop DN : db/db and ob/ob mice [XREF_BIBR, XREF_BIBR].	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	2	3	4	5
Individuals with insulin resistance display reduced insulin stimulation of the PI-3K pathway [ XREF_BIBR ] , and insulin stimulated AKT kinase activity is reduced in patients with T2DM [ XREF_BIBR , XREF_BIBR ] .	Individuals with insulin resistance display reduced insulin stimulation of the PI-3K pathway [XREF_BIBR], and insulin stimulated AKT kinase activity is reduced in patients with T2DM [XREF_BIBR, XREF_BIBR].	17	21	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	17	18	19	20
IGF1R JM analogue 16 inhibited IGF-1 induced activity of AKT in a dose dependent manner ( XREF_FIG ) and was significantly less effective in inhibiting insulin induced activation of AKT .	IGF1R JM analogue 16 inhibited IGF-1 induced activity of AKT in a dose dependent manner (XREF_FIG) and was significantly less effective in inhibiting insulin induced activation of AKT.	24	30	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	25	26	29	30
Because insulin resistance also partially impedes Akt signaling , we reasoned that the two pathways might be additive .	Because insulin resistance also partially impedes Akt signaling, we reasoned that the two pathways might be additive.	1	7	impedes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	6	7
Moreover , prolonged palmitate treatment of L6 myotubes invitro ( which mimics the high fatty acid levels observed in obesity ) led to constitutive STAT3 activation , increased SOCS3 protein abundance and impaired insulin stimulated Akt signaling XREF_BIBR .	Moreover, prolonged palmitate treatment of L6 myotubes invitro (which mimics the high fatty acid levels observed in obesity) led to constitutive STAT3 activation, increased SOCS3 protein abundance and impaired insulin stimulated Akt signaling XREF_BIBR.	27	37	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	33	34	35	36
Similar to activation of the hexosamine pathway , also PKC activation is likely to result in retinal cell damage due to inhibition of insulin induced Akt activation [ XREF_BIBR ] .	Similar to activation of the hexosamine pathway, also PKC activation is likely to result in retinal cell damage due to inhibition of insulin induced Akt activation [XREF_BIBR].	21	26	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	23	24	25	26
Genetic deletion of GNMT impaired glucose tolerance and insulin sensitivity via the accumulation of triglycerides and deregulation of insulin stimulated Akt activation and gluconeogenesis in the liver .	Genetic deletion of GNMT impaired glucose tolerance and insulin sensitivity via the accumulation of triglycerides and deregulation of insulin stimulated Akt activation and gluconeogenesis in the liver.	8	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	20	21
Moreover , OLGly induced enhancement of adipogenesis , activation of insulin mediated Akt signaling pathway and inactivation of FoxO1 were effectively blocked by Wortmannin , a specific PI3K and Akt inhibitor , indicating the essential role of Akt signaling pathway in the process of OLGly stimulated 3T3-L1 adipogenesis .	Moreover, OLGly induced enhancement of adipogenesis, activation of insulin mediated Akt signaling pathway and inactivation of FoxO1 were effectively blocked by Wortmannin, a specific PI3K and Akt inhibitor, indicating the essential role of Akt signaling pathway in the process of OLGly stimulated 3T3-L1 adipogenesis.	8	14	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
For example , mice with endothelial deletion of the insulin receptor and knockout of apolipoprotein E ( EIRAKO mice ) fed a high fat diet demonstrated decreased Akt activation by insulin in association with impaired endothelium depending vasodilatation and accelerated atherosclerosis .	For example, mice with endothelial deletion of the insulin receptor and knockout of apolipoprotein E (EIRAKO mice) fed a high fat diet demonstrated decreased Akt activation by insulin in association with impaired endothelium depending vasodilatation and accelerated atherosclerosis.	27	32	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	30	31	27	28
Furthermore , the insulin induced activation of Akt was completely blocked by a PI3K inhibitor , suggesting that the activation of Akt is dependent on the activation of PI3K , the downstream effector of the IR .	Furthermore, the insulin induced activation of Akt was completely blocked by a PI3K inhibitor, suggesting that the activation of Akt is dependent on the activation of PI3K, the downstream effector of the IR.	2	8	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	7	8
In the insulin stimulated state , phosphorylation at IRS-1 Ser 1101 was elevated in PARL (-) muscle relative to control , in parallel with lower insulin stimulated Akt -Ser473 phosporylation ( XREF_FIG ) .	In the insulin stimulated state, phosphorylation at IRS-1 Ser 1101 was elevated in PARL (-) muscle relative to control, in parallel with lower insulin stimulated Akt -Ser473 phosporylation (XREF_FIG).	19	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
Ou et al reported that glucose but not insulin induced AKT activation in TBK1 null MEFs and EGF mediated activation was slightly impaired .	Ou et al reported that glucose but not insulin induced AKT activation in TBK1 null MEFs and EGF mediated activation was slightly impaired.	5	11	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	8	9	10	11
IGF1 induced Akt activation is inhibited by myostatin in skeletal muscle cells [ XREF_BIBR , XREF_BIBR ] , but a role for myostatin in the inhibition of insulin induced activation of Akt has not yet been demonstrated .	IGF1 induced Akt activation is inhibited by myostatin in skeletal muscle cells [XREF_BIBR, XREF_BIBR], but a role for myostatin in the inhibition of insulin induced activation of Akt has not yet been demonstrated.	25	32	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	27	28	31	32
There was decreased phosphorylation of insulin stimulated Akt , indicating impaired insulin signalling , in gonadal white adipose tissue ( WAT ; Figure XREF_FIG A ) , but not in the quadriceps ( Supplementary material online , Figure S10 ) or liver ( Supplementary material online , Figure S11 ) of WT vs. CD36 -/- mice .	There was decreased phosphorylation of insulin stimulated Akt, indicating impaired insulin signalling, in gonadal white adipose tissue (WAT; Figure XREF_FIG A), but not in the quadriceps (Supplementary material online, Figure S10) or liver (Supplementary material online, Figure S11) of WT vs. CD36 -/- mice.	3	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	phosphorylation of insulin	insulin	Akt	Akt	akt	5	6	7	8
These FOXOs are also negatively regulated by insulin and IGF -1 signaling [ XREF_BIBR ] : Activation of insulin and IGF -1 signaling increases activity of a serine threonine kinase Akt , which in turn phosphorylates FOXOs .	These FOXOs are also negatively regulated by insulin and IGF -1 signaling [XREF_BIBR] : Activation of insulin and IGF -1 signaling increases activity of a serine threonine kinase Akt, which in turn phosphorylates FOXOs.	18	31	increases activity	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	30	31
All of these data indicate that IL-6-impaired insulin activation of IRS and AKT signaling cascades in a JNK dependent manner , in a similar fashion as detected for glucose uptake .	All of these data indicate that IL-6-impaired insulin activation of IRS and AKT signaling cascades in a JNK dependent manner, in a similar fashion as detected for glucose uptake.	7	14	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	AKT	AKT	AKT	7	8	12	13
To test whether the higher insulin induced Akt activity in the ATP2B1 silenced endothelial cells is dependent on calmodulin , a calmodulin specific antagonist , W7 , was used .	To test whether the higher insulin induced Akt activity in the ATP2B1 silenced endothelial cells is dependent on calmodulin, a calmodulin specific antagonist, W7, was used.	3	8	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Palmitate treatment enhanced the expression of phospho-PKCtheta , suggesting that this PKC isoform was involved in the changes reported , and coincubation of palmitate treated cells with the PKC inhibitor chelerythrine prevented the palmitate induced reduction in the expression of IkappaBalpha and insulin stimulated Akt activation .	Palmitate treatment enhanced the expression of phospho-PKCtheta, suggesting that this PKC isoform was involved in the changes reported, and coincubation of palmitate treated cells with the PKC inhibitor chelerythrine prevented the palmitate induced reduction in the expression of IkappaBalpha and insulin stimulated Akt activation.	38	45	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	expression of IkappaBalpha and insulin	insulin	Akt	Akt	akt	42	43	44	45
In muscle , loss of p50alpha and p55alpha results in reduced levels of insulin stimulated insulin receptor substrate 1 ( IRS-1 ) and phosphotyrosine associated PI 3-kinase but enhanced levels of IRS-2-associated PI 3-kinase and Akt activation , whereas in adipocytes levels of both insulin stimulated PI 3-kinase and Akt are unchanged .	In muscle, loss of p50alpha and p55alpha results in reduced levels of insulin stimulated insulin receptor substrate 1 (IRS-1) and phosphotyrosine associated PI 3-kinase but enhanced levels of IRS-2-associated PI 3-kinase and Akt activation, whereas in adipocytes levels of both insulin stimulated PI 3-kinase and Akt are unchanged.	41	50	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of both insulin	insulin	Akt	Akt	akt	44	45	49	50
Chronic insulin or IGF-1 treatment of IRS-1-deficient mouse embryo fibroblasts inhibited IRS-2-mediated activation of Akt and ERK1/2 , which was reversed by lactacystin pretreatment .	Chronic insulin or IGF-1 treatment of IRS-1-deficient mouse embryo fibroblasts inhibited IRS-2-mediated activation of Akt and ERK1/2, which was reversed by lactacystin pretreatment.	0	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	14	15
Silencing of either or both proteins had no effect on Akt phosphorylation when compared to scrambled siRNA transfected cells treated with insulin ( XREF_FIG ) ; this indicates that this metabolic effect of insulin does not depend on IR translocation to the nucleus whereas nuclear Ca 2+ signals and cell proliferation do .	Silencing of either or both proteins had no effect on Akt phosphorylation when compared to scrambled siRNA transfected cells treated with insulin (XREF_FIG); this indicates that this metabolic effect of insulin does not depend on IR translocation to the nucleus whereas nuclear Ca 2+ signals and cell proliferation do.	10	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	21	22	10	11
Evidence from our , and several other , experimental models of insulin resistance and T2DM has revealed impaired insulin mediated Akt and eNOS dependent signaling in the vasculature XREF_BIBR - XREF_BIBR .	Evidence from our, and several other, experimental models of insulin resistance and T2DM has revealed impaired insulin mediated Akt and eNOS dependent signaling in the vasculature XREF_BIBR - XREF_BIBR.	16	30	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	20	21
Reduced insulin stimulated Akt activation is explained by reduced stimulation of phosphorylation at both Thr 308 and Ser 473 residues , which appear to be due to increased physical interaction of TRIB3 with the pleckstrin homology domain of Akt .	Reduced insulin stimulated Akt activation is explained by reduced stimulation of phosphorylation at both Thr 308 and Ser 473 residues, which appear to be due to increased physical interaction of TRIB3 with the pleckstrin homology domain of Akt.	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
In skeletal muscle from obese humans and animal models of insulin resistance , insulin mediated Akt activation is reduced .	In skeletal muscle from obese humans and animal models of insulin resistance, insulin mediated Akt activation is reduced.	13	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
These data implicate decreased insulin stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice .	These data implicate decreased insulin stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice.	2	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Incubation of L6E9 myotubes with palmitate caused accumulation of triglycerides , diacylgycerol , and ceramide , produced an activation of PKCtheta and PKCzeta , and blocked insulin stimulated glucose metabolism , reducing insulin stimulated PKB activity by 60 % .	Incubation of L6E9 myotubes with palmitate caused accumulation of triglycerides, diacylgycerol, and ceramide, produced an activation of PKCtheta and PKCzeta, and blocked insulin stimulated glucose metabolism, reducing insulin stimulated PKB activity by 60%.	31	35	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	PKB	PKB	PKB	32	33	34	35
As shown in XREF_FIG , expression of G6pc and Pck1 was suppressed by insulin to the same extent in the TLKO livers as in the control livers , indicating that insulin was able to suppress the transcription of these two genes independent of Akt and Foxo1 in liver .	As shown in XREF_FIG, expression of G6pc and Pck1 was suppressed by insulin to the same extent in the TLKO livers as in the control livers, indicating that insulin was able to suppress the transcription of these two genes independent of Akt and Foxo1 in liver.	30	45	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	30	31	43	44
XREF_FIG ) , insulin stimulated Akt and FoxO1 activation decreased , and fasting blood glucose ( XREF_FIG ) , insulin levels ( XREF_FIG ) and glucose tolerance ( XREF_FIG , quantified in XREF_SUPPLEMENTARY ) returned to levels seen in wild-type mice .	XREF_FIG), insulin stimulated Akt and FoxO1 activation decreased, and fasting blood glucose (XREF_FIG), insulin levels (XREF_FIG) and glucose tolerance (XREF_FIG, quantified in XREF_SUPPLEMENTARY) returned to levels seen in wild-type mice.	3	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	3	4	5	6
The present study was undertaken to determine whether ceramides or other sphingolipids are increased in muscle from obese insulin resistant subjects and to assess whether ceramide plays a role in the insulin resistance of Akt in human muscle .	The present study was undertaken to determine whether ceramides or other sphingolipids are increased in muscle from obese insulin resistant subjects and to assess whether ceramide plays a role in the insulin resistance of Akt in human muscle.	31	37	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	34	35
In summary , impaired vasorelaxation to insulin in aging was independent of metabolic insulin sensitivity and associated with impaired insulin mediated activation of the Akt and eNOS pathway , but intact activation of the acetylcholine mediated Ca ( 2+ )-calmodulin/eNOS pathway .	In summary, impaired vasorelaxation to insulin in aging was independent of metabolic insulin sensitivity and associated with impaired insulin mediated activation of the Akt and eNOS pathway, but intact activation of the acetylcholine mediated Ca (2+)-calmodulin/eNOS pathway.	19	27	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	24	25
Increased insulin resistance perturbs the PI3K-AKT pathway and increases activation of GSK3 , which further disrupts glucose homeostasis by negatively regulating key insulin signaling pathway molecules .	Increased insulin resistance perturbs the PI3K-AKT pathway and increases activation of GSK3, which further disrupts glucose homeostasis by negatively regulating key insulin signaling pathway molecules.	1	6	perturbs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	PI3K-AKT	PI3K-AKT	PI3K-AKT	1	2	5	6
While the expression of a NEP wt variant decreased activation of Akt by insulin and IGF-1 , a pseudophosphorylated ( Ser6Asp ) mutant had no significant effect .	While the expression of a NEP wt variant decreased activation of Akt by insulin and IGF-1, a pseudophosphorylated (Ser6Asp) mutant had no significant effect.	8	15	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	11	12
Thus these results are consistent with ATP relieving an insulin induced Akt dependent inhibitory effect on the ERK signaling pathway , leading to synergistic stimulation of CASMC proliferation .	Thus these results are consistent with ATP relieving an insulin induced Akt dependent inhibitory effect on the ERK signaling pathway, leading to synergistic stimulation of CASMC proliferation.	8	14	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
In contrast , studies in more severe models of insulin resistance such as ob/ob mice or following a more aggressive high-fat protocol with 60 % fat leads to impaired insulin mediated activation of Akt and with FOXO1 dephosphorylation and nuclear localization 128 .	In contrast, studies in more severe models of insulin resistance such as ob/ob mice or following a more aggressive high-fat protocol with 60% fat leads to impaired insulin mediated activation of Akt and with FOXO1 dephosphorylation and nuclear localization 128.	29	34	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	33	34
In addition , impaired insulin induced Akt and PKB activation was also normalized .	In addition, impaired insulin induced Akt and PKB activation was also normalized.	3	9	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	4	5	6	7
Consequently , both baseline and insulin stimulated Akt activities were suppressed in the Tsc1-/- liver ( XREF_FIG ) .	Consequently, both baseline and insulin stimulated Akt activities were suppressed in the Tsc1-/- liver (XREF_FIG).	3	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Together , these data suggest that global reductions of Pik3ca , and to a lesser extent Pik3cb lead to peripheral insulin resistance , likely due to an inability of insulin to activate Akt dependent processes .	Together, these data suggest that global reductions of Pik3ca, and to a lesser extent Pik3cb lead to peripheral insulin resistance, likely due to an inability of insulin to activate Akt dependent processes.	24	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	29	30	32	33
We showed that in vitro CAPE inhibits FGF stimulated Akt activation but not insulin stimulated Akt activation .	We showed that in vitro CAPE inhibits FGF stimulated Akt activation but not insulin stimulated Akt activation.	8	16	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	13	14	15	16
Again , the insulin induced AKT activity was substantially decreased in AK023948 KO cells as compared with gRNA control ( XREF_SUPPLEMENTARY ) .	Again, the insulin induced AKT activity was substantially decreased in AK023948 KO cells as compared with gRNA control (XREF_SUPPLEMENTARY).	2	6	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	AKT	AKT	AKT	3	4	5	6
Blunted insulin stimulated vasodilation , which was reversed with acute PKCbeta inhibition ( LY333-351 ) , occurred alongside decreased tissue perfusion as well as reduced insulin stimulated Akt signaling in the prefrontal cortex , but not the triceps .	Blunted insulin stimulated vasodilation, which was reversed with acute PKCbeta inhibition (LY333-351), occurred alongside decreased tissue perfusion as well as reduced insulin stimulated Akt signaling in the prefrontal cortex, but not the triceps.	0	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	25	26	27	28
Defective insulin stimulated glucose transport activity in skeletal muscle of the obese Zucker rat can be attributed to reduced GLUT-4 translocation arising from impairments in the insulin signalling cascade , including decreased tyrosine phosphorylation of IR and IRS-1 , reduced Akt activation , and GSK-3 over-activity .	Defective insulin stimulated glucose transport activity in skeletal muscle of the obese Zucker rat can be attributed to reduced GLUT-4 translocation arising from impairments in the insulin signalling cascade, including decreased tyrosine phosphorylation of IR and IRS-1, reduced Akt activation, and GSK-3 over-activity.	0	41	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	40	41
Treatment of C57BL/6J mice with IL-6 resulted in impaired insulin dependent activation of the Akt and eNOS pathway in the aorta as a result of JNK and ERK1/2 activation .	Treatment of C57BL/6J mice with IL-6 resulted in impaired insulin dependent activation of the Akt and eNOS pathway in the aorta as a result of JNK and ERK1/2 activation.	9	17	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	14	15
Given the potential bi-phasic changes in insulin signaling that occur in the evolution of heart failure or systemic insulin resistance namely an activation of Akt , followed later by loss of insulin mediated Akt signaling , pathways by which Akt activation may promote heart failure versus mechanisms linking impaired insulin signaling with heart failure will be discussed separately .	Given the potential bi-phasic changes in insulin signaling that occur in the evolution of heart failure or systemic insulin resistance namely an activation of Akt, followed later by loss of insulin mediated Akt signaling, pathways by which Akt activation may promote heart failure versus mechanisms linking impaired insulin signaling with heart failure will be discussed separately.	29	34	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	31	32	33	34
Insulin deficiency has been shown to cause the reduced function of AKT serine/threonine kinase 2 that suppresses the function of the intracellular motor , Myo5a .	Insulin deficiency has been shown to cause the reduced function of AKT serine/threonine kinase 2 that suppresses the function of the intracellular motor, Myo5a.	0	13	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	AKT	AKT	AKT	0	1	11	12
Insulin stimulated Akt Thr 308 ( XREF_FIG ) andGSK-3alpha and beta ( datanot shown ) phosphorylation was not affected , indicating that Ang II/AT 1 R mediated EGF receptor transactivation is necessary for the inhibitory effect of Ang II on insulin induced Akt Thr 308 and GSK-3alpha and beta phosphorylation .	Insulin stimulated Akt Thr 308 (XREF_FIG) andGSK-3alpha and beta (datanot shown) phosphorylation was not affected, indicating that Ang II/AT 1 R mediated EGF receptor transactivation is necessary for the inhibitory effect of Ang II on insulin induced Akt Thr 308 and GSK-3alpha and beta phosphorylation.	38	43	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	40	41	42	43
Peripheral insulin resistance and ectopic lipid accumulation in mutant skeletal muscle , heart , and kidneys were accompanied by impaired insulin mediated Akt signaling in these organs .	Peripheral insulin resistance and ectopic lipid accumulation in mutant skeletal muscle, heart, and kidneys were accompanied by impaired insulin mediated Akt signaling in these organs.	17	23	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	20	21	22	23
The deletion of PIK3R2 increases insulin induced Akt activation , leading to increased anti-apoptosis [ XREF_BIBR ] .	The deletion of PIK3R2 increases insulin induced Akt activation, leading to increased anti-apoptosis [XREF_BIBR].	1	8	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Disruption of mTORC2 impairs the insulin induced activation of Akt , an mTORC2 substrate .	Disruption of mTORC2 impairs the insulin induced activation of Akt, an mTORC2 substrate.	4	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	9	10
In HF diet fed mice , resting and basal and insulin stimulated Akt and aPKC activities were diminished in muscle , but in liver , these activities were elevated basally and were increased by insulin to normal levels .	In HF diet fed mice, resting and basal and insulin stimulated Akt and aPKC activities were diminished in muscle, but in liver, these activities were elevated basally and were increased by insulin to normal levels.	6	15	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
The decreased activation of SREBP1c in LTsc1KO hepatocytes is the result of mTORC1 driven inhibitory feedback mechanisms causing insulin resistance and attenuation of Akt signaling to its other downstream pathways .	The decreased activation of SREBP1c in LTsc1KO hepatocytes is the result of mTORC1 driven inhibitory feedback mechanisms causing insulin resistance and attenuation of Akt signaling to its other downstream pathways.	18	24	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	18	19	23	24
We have previously shown that in endothelial cells , palmitate mediated activation of NF-kappaB signaling is associated with reduced insulin mediated Akt and eNOS signaling in endothelial cells XREF_BIBR .	We have previously shown that in endothelial cells, palmitate mediated activation of NF-kappaB signaling is associated with reduced insulin mediated Akt and eNOS signaling in endothelial cells XREF_BIBR.	16	24	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	19	20	21	22
According to this concept , insulin stimulated Akt activation is impaired in endothelial cells in obesity or diabetes .	According to this concept, insulin stimulated Akt activation is impaired in endothelial cells in obesity or diabetes.	5	8	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	5	6	7	8
Decreased insulin stimulated Akt activation results in an impaired ability of insulin to suppress hepatic glucose output .	Decreased insulin stimulated Akt activation results in an impaired ability of insulin to suppress hepatic glucose output.	0	4	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	Akt	Akt	Akt	1	2	3	4
In these cells , Ang II specifically inhibited activation of insulin induced Akt Thr 308 and its immediate downstream substrate GSK-3alpha and beta in a time dependent fashion , with ~ 70 % reduction at 15min .	In these cells, Ang II specifically inhibited activation of insulin induced Akt Thr 308 and its immediate downstream substrate GSK-3alpha and beta in a time dependent fashion, with ~ 70% reduction at 15min.	8	13	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	10	11	12	13
Knocking down the PTEN gene prevented oleate to inhibit insulin activation of Akt and insulin suppression of gluconeogenesis .	Knocking down the PTEN gene prevented oleate to inhibit insulin activation of Akt and insulin suppression of gluconeogenesis.	9	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	12	13
Primary LH hepatocytes and high-fat-fed LH livers exhibited decreased insulin stimulated Akt activation ( XREF_FIG and XREF_FIG ) .	Primary LH hepatocytes and high-fat-fed LH livers exhibited decreased insulin stimulated Akt activation (XREF_FIG and XREF_FIG).	7	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	9	10	11	12
ADP also inhibits the activation of Akt by insulin .	ADP also inhibits the activation of Akt by insulin.	2	9	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt	Akt	Akt	8	9	6	7
These results indicate that insulin reduces the overall mobility of GLUT4 vesicles , and Myo1c is required for the immobilizing effect of the hormone .	These results indicate that insulin reduces the overall mobility of GLUT4 vesicles, and Myo1c is required for the immobilizing effect of the hormone.	4	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	10	11
A transgenic mouse model of Munc18c protein overexpression in adipose , skeletal muscle , and pancreas , exhibits peripheral insulin resistance resulting from impaired insulin stimulated glucose uptake and GLUT4 vesicle exocytosis , and decreased GSIS XREF_BIBR .	A transgenic mouse model of Munc18c protein overexpression in adipose, skeletal muscle, and pancreas, exhibits peripheral insulin resistance resulting from impaired insulin stimulated glucose uptake and GLUT4 vesicle exocytosis, and decreased GSIS XREF_BIBR.	21	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	24	25	29	30
In summary , LBP-4a improved insulin resistance via translocation and activation of GLUT4 in OLETF rats , and the activation of PI3-K and p38 MAPK contributed to these effects .	In summary, LBP-4a improved insulin resistance via translocation and activation of GLUT4 in OLETF rats, and the activation of PI3-K and p38 MAPK contributed to these effects.	5	13	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	12	13
Inhibitors of protein kinase C-zeta ( PKC-zeta ) abolish the insulin induced GLUT4 recruitment in rat adipocytes .	Inhibitors of protein kinase C-zeta (PKC-zeta) abolish the insulin induced GLUT4 recruitment in rat adipocytes.	9	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
Moreover , insulin stimulated Glut4 exocytosis over a time-course spanning 60min is also slower in ChREBP KO adipocytes with a half-time ( t 1/2 ) of ~ 7.35 min in ChREBP fl/fl and ~ 32.71 min in ChREBP KO adipocytes ( XREF_SUPPLEMENTARY ) .	Moreover, insulin stimulated Glut4 exocytosis over a time-course spanning 60min is also slower in ChREBP KO adipocytes with a half-time (t 1/2) of ~ 7.35 min in ChREBP fl/fl and ~ 32.71 min in ChREBP KO adipocytes (XREF_SUPPLEMENTARY).	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	2	3	4	5
Concomitantly , insulin decreases GLUT4 equally from all intracellular locations , in agreement with the concept that the entire cellular GLUT4 pool contributes to insulin stimulated exocytosis .	Concomitantly, insulin decreases GLUT4 equally from all intracellular locations, in agreement with the concept that the entire cellular GLUT4 pool contributes to insulin stimulated exocytosis.	2	5	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
XREF_BIBR Insulin stimulated GLUT4 translocation is generally impaired in type 2 diabetes .	XREF_BIBR Insulin stimulated GLUT4 translocation is generally impaired in type 2 diabetes.	0	4	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	1	2	3	4
Disruption of either protein yielded abnormal actin remodeling and subsequent inhibition in insulin mediated GLUT4 translocation ( XREF_FIG C , XREF_FIG B , and XREF_FIG C ) .	Disruption of either protein yielded abnormal actin remodeling and subsequent inhibition in insulin mediated GLUT4 translocation (XREF_FIG C, XREF_FIG B, and XREF_FIG C).	4	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
When the AS160-14-3-3 interaction was disrupted through a point mutation in a knockin mouse ( in which a non phosphorylatable alanine residue replaces Thr 642 on AS160 ) , insulin stimulated GLUT4 trafficking and glucose uptake was impaired in muscle , which consequently rendered the AS160 knockin mouse less sensitive to insulin [ XREF_BIBR ] .	When the AS160-14-3-3 interaction was disrupted through a point mutation in a knockin mouse (in which a non phosphorylatable alanine residue replaces Thr 642 on AS160), insulin stimulated GLUT4 trafficking and glucose uptake was impaired in muscle, which consequently rendered the AS160 knockin mouse less sensitive to insulin [XREF_BIBR].	29	32	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	29	30	31	32
Interestingly , in 3T3-L1 adipocytes , selective p38 MAPK inhibition with A304000 ameliorated the insulin dependent loss of GLUT-4 protein , but not the loss of IRS-1 protein , and resulted in increased insulin stimulated glucose transport activity [ XREF_BIBR ] .	Interestingly, in 3T3-L1 adipocytes, selective p38 MAPK inhibition with A304000 ameliorated the insulin dependent loss of GLUT-4 protein, but not the loss of IRS-1 protein, and resulted in increased insulin stimulated glucose transport activity [XREF_BIBR].	14	19	loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	14	15	18	19
Insulin signaling also inhibits GLUT4 endocytosis , ensuring a longer duration of GLUT4 residence in the PM .	Insulin signaling also inhibits GLUT4 endocytosis, ensuring a longer duration of GLUT4 residence in the PM.	0	5	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	4	5
These results indicate that insulin reduces the average mobility of GLUT4 vesicles , and Myo1c binding to actin mediates this immobilizing effect .	These results indicate that insulin reduces the average mobility of GLUT4 vesicles, and Myo1c binding to actin mediates this immobilizing effect.	4	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	10	11
By contrast , insulin stimulated GLUT4 translocation was impaired upon IRAP knockdown , indicating that IRAP plays a role in GSV trafficking .	By contrast, insulin stimulated GLUT4 translocation was impaired upon IRAP knockdown, indicating that IRAP plays a role in GSV trafficking.	3	6	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
Mutation of this motif causes a decrease in the insulin induced exposure of GLUT4 at the cell surface of 3T3-L1 adipocytes via an effect on vesicle fusion .	Mutation of this motif causes a decrease in the insulin induced exposure of GLUT4 at the cell surface of 3T3-L1 adipocytes via an effect on vesicle fusion.	6	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	13	14
In the present study , we have confirmed the insulin induced repression of the rat GLUT4 promoter , used as a control for the activity of the Fugu GLUT4 promoter .	In the present study, we have confirmed the insulin induced repression of the rat GLUT4 promoter, used as a control for the activity of the Fugu GLUT4 promoter.	8	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	15	16
In addition , insulin induced suppression of hepatic glucose production is impaired in adipose specific GLUT4 knockout mice .	In addition, insulin induced suppression of hepatic glucose production is impaired in adipose specific GLUT4 knockout mice.	3	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	15	16
Thus , it is likely that a 50 % reduction in Munc18c protein in skeletal muscle , unlike in the heart [ XREF_BIBR ] , accounted for the impaired insulin stimulated GLUT4 appearance at the PM , and glucose transport into muscle , as insulin stimulated Akt phosphorylation and syntaxin4 protein levels were normal in the Munc18c -/+ mice , as shown previously [ XREF_BIBR ] .	Thus, it is likely that a 50% reduction in Munc18c protein in skeletal muscle, unlike in the heart [XREF_BIBR], accounted for the impaired insulin stimulated GLUT4 appearance at the PM, and glucose transport into muscle, as insulin stimulated Akt phosphorylation and syntaxin4 protein levels were normal in the Munc18c -/+ mice, as shown previously [XREF_BIBR].	25	32	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	29	30	31	32
When pool 1 was still largely depleted of GLUT4 , a second insulin challenge did reduce GLUT4 in pool 2 and stimulated glucose transport to the same extent as the first insulin treatment .	When pool 1 was still largely depleted of GLUT4, a second insulin challenge did reduce GLUT4 in pool 2 and stimulated glucose transport to the same extent as the first insulin treatment.	12	17	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	16	17
However , in the presence of the inhibitor ( at 20 , 50 and 100microm ) , the amount of GLUT4 at the cell periphery during insulin stimulation was dramatically reduced ( ~ 75 % decrease in insulin stimulated GLUT4 at the cortex with 50 and 100microm TR100 ) .	However, in the presence of the inhibitor (at 20, 50 and 100microm), the amount of GLUT4 at the cell periphery during insulin stimulation was dramatically reduced (~ 75% decrease in insulin stimulated GLUT4 at the cortex with 50 and 100microm TR100).	35	40	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	37	38	39	40
Consistently , myofibers isolated from heterozygous knock-in ( KI ) mice harboring the mutation p.R465W , an animal model of CNM 11 , exhibit reduced actin polymerization , altered actin organization and impaired insulin induced insertion of GLUT4 into the sarcolemma .	Consistently, myofibers isolated from heterozygous knock-in (KI) mice harboring the mutation p.R465W, an animal model of CNM 11, exhibit reduced actin polymerization, altered actin organization and impaired insulin induced insertion of GLUT4 into the sarcolemma.	26	38	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	33	34	37	38
Although insulin and cAMP both repress the GLUT4 promoter through this cis-element , they appear to do this through different mechanisms , as treatment with 8-Br-cAMP does not induce the phosphorylation of NF1 that is induced by insulin treatment .	Although insulin and cAMP both repress the GLUT4 promoter through this cis-element, they appear to do this through different mechanisms, as treatment with 8-Br-cAMP does not induce the phosphorylation of NF1 that is induced by insulin treatment.	1	8	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	7	8
CDP138 mutants lacking the Ca 2+ -binding sites in the C2 domain or Akt2 phosphorylation site Ser197 inhibit insulin stimulated GLUT4 insertion into the PM , a rate limiting step of GLUT4 translocation .	CDP138 mutants lacking the Ca 2+ -binding sites in the C2 domain or Akt2 phosphorylation site Ser197 inhibit insulin stimulated GLUT4 insertion into the PM, a rate limiting step of GLUT4 translocation.	17	21	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	18	19	20	21
A short-term insulin stimulation reduced the content of GLUT4 in the GSV fraction ( 51 +/- 3.5 % ) with only a modest decrease from the endosomal fraction ( 23 +/- 2.6 % ) .	A short-term insulin stimulation reduced the content of GLUT4 in the GSV fraction (51 +/- 3.5%) with only a modest decrease from the endosomal fraction (23 +/- 2.6%).	2	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	8	9
In conclusion , we present evidence that insulin reduces the mobility of GLUT4 vesicles within the TIRF zone , and Myo1c is required for such immobilization through its association with submembrane actin .	In conclusion, we present evidence that insulin reduces the mobility of GLUT4 vesicles within the TIRF zone, and Myo1c is required for such immobilization through its association with submembrane actin.	7	13	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	12	13
The insulin dependent loss of GLUT4 vesicles from the TIRF zone was greatly attenuated in cells depleted of Myo1c , which instead exhibited only a 29 +/- 9 % drop in GLUT4 vesicle number in response to insulin relative to the basal condition ( n = 4 , 6-8 ROI and cell ; Figure S2B ) .	The insulin dependent loss of GLUT4 vesicles from the TIRF zone was greatly attenuated in cells depleted of Myo1c, which instead exhibited only a 29 +/- 9% drop in GLUT4 vesicle number in response to insulin relative to the basal condition (n = 4, 6-8 ROI and cell; Figure S2B).	1	6	loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	5	6
In cells depleted of mVps45 , insulin stimulated GLUT4 translocation was significantly impaired ( fluorescent rings of GFP-GLUT4 were evident in < 15 % of cells from three separate experiments of this type ) .	In cells depleted of mVps45, insulin stimulated GLUT4 translocation was significantly impaired (fluorescent rings of GFP-GLUT4 were evident in < 15% of cells from three separate experiments of this type).	6	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
Interestingly , reduced PM PIP 2 and cortical F-actin structure are observed in hyperinsulinemia induced insulin resistant 3T3-L1 adipocytes and L6 myotubes where insulin stimulated GLUT4 translocation is impaired , but corrected with exogenous PIP 2 addition to the PM by provoking a restoration of cortical F-actin structure [ XREF_BIBR , XREF_BIBR ] .	Interestingly, reduced PM PIP 2 and cortical F-actin structure are observed in hyperinsulinemia induced insulin resistant 3T3-L1 adipocytes and L6 myotubes where insulin stimulated GLUT4 translocation is impaired, but corrected with exogenous PIP 2 addition to the PM by provoking a restoration of cortical F-actin structure [XREF_BIBR, XREF_BIBR].	23	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
Indeed , loss of ChREBP in adipocytes delays insulin stimulated Glut4 exocytosis .	Indeed, loss of ChREBP in adipocytes delays insulin stimulated Glut4 exocytosis.	7	11	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	8	9	10	11
Insulin decreases the rate of GLUT4 endocytosis in addition to increasing its exocytosis .	Insulin decreases the rate of GLUT4 endocytosis in addition to increasing its exocytosis.	0	6	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	5	6
Calorie restriction improved insulin sensitivity in Pinx rats , and this was related to increased GLUT4 gene expression and insulin induced GLUT4 translocation to the plasma membrane in WAT .	Calorie restriction improved insulin sensitivity in Pinx rats, and this was related to increased GLUT4 gene expression and insulin induced GLUT4 translocation to the plasma membrane in WAT.	19	22	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	21	22
Insulin slows GLUT4 internalization by an unknown mechanism .	Insulin slows GLUT4 internalization by an unknown mechanism.	0	3	slows	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Insulin induced GLUT4 translocation is disrupted in muscle fibers isolated from HTZ KI-R465W mice .	Insulin induced GLUT4 translocation is disrupted in muscle fibers isolated from HTZ KI-R465W mice.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Instead , insulin stimulated muscle glucose uptake was diminished with concomitant reductions in glucose transporter 4 ( GLUT4 ) protein content .	Instead, insulin stimulated muscle glucose uptake was diminished with concomitant reductions in glucose transporter 4 (GLUT4) protein content.	2	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	17	18
OPA also significantly decreased the level of serum insulin , augmented the activation of AMP activated protein kinase ( AMPK ) , and increased the expression of glucose transporter 4 ( GLUT4 ) protein in skeletal muscle .	OPA also significantly decreased the level of serum insulin, augmented the activation of AMP activated protein kinase (AMPK), and increased the expression of glucose transporter 4 (GLUT4) protein in skeletal muscle.	0	33	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	OPA also significantly decreased the level of serum insulin	insulin	GLUT4	GLUT4	glut4	8	9	31	32
The ability of insulin to inhibit Rip11 internalisation requires dynamin and class I PI3-kinases , but is independent of the activation of the protein kinase Akt ; characteristics which are very similar to the mechanism by which insulin inhibits GLUT4 endocytosis .	The ability of insulin to inhibit Rip11 internalisation requires dynamin and class I PI3-kinases, but is independent of the activation of the protein kinase Akt; characteristics which are very similar to the mechanism by which insulin inhibits GLUT4 endocytosis.	37	40	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	37	38	39	40
In fact in insulin resistant humans and rodents , insulin stimulated Glut4 translocation is also impaired in adipocytes .	In fact in insulin resistant humans and rodents, insulin stimulated Glut4 translocation is also impaired in adipocytes.	9	12	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	9	10	11	12
Insulin stimulated glucose uptake in skeletal muscle is decreased in type 2 diabetes due to impaired translocation of insulin sensitive glucose transporter 4 ( GLUT4 ) from intracellular pool to plasma membrane .	Insulin stimulated glucose uptake in skeletal muscle is decreased in type 2 diabetes due to impaired translocation of insulin sensitive glucose transporter 4 (GLUT4) from intracellular pool to plasma membrane.	0	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	24	25
Myo1c knockdown reduces insulin stimulated gain in surface GLUT4 .	Myo1c knockdown reduces insulin stimulated gain in surface GLUT4.	2	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	8	9
GAPDH knockdown had no effect on surface exposed GLUT4-Myc in basal or insulin stimulated cells , but markedly and selectively diminished insulin stimulated 3-O-methyl glucose uptake and GLUT4-Myc photolabelling with ATB-BMPA { 2-N-[ 4-( 1-azitrifluoroethyl ) benzoyl ] -1,3-bis-( D-mannos-4-yloxy )-2-propylamine } , suggesting that the exofacial glucose binding site was inaccessible .	GAPDH knockdown had no effect on surface exposed GLUT4-Myc in basal or insulin stimulated cells, but markedly and selectively diminished insulin stimulated 3-O-methyl glucose uptake and GLUT4-Myc photolabelling with ATB-BMPA {2-N-[4-(1-azitrifluoroethyl) benzoyl] -1,3-bis-(D-mannos-4-yloxy)-2-propylamine}, suggesting that the exofacial glucose binding site was inaccessible.	20	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4-Myc	GLUT4-Myc	GLUT4-Myc	21	22	27	28
XREF_BIBR In that study , Col5a3-null adipocytes and skeletal muscles displayed insulin resistance due to the suppression of insulin induced Glut4 translocation .	XREF_BIBR In that study, Col5a3-null adipocytes and skeletal muscles displayed insulin resistance due to the suppression of insulin induced Glut4 translocation.	16	21	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	18	19	20	21
We hypothesize that insulin may reduce GLUT4 endocytosis by regulating the function of dynamin II at the cell surface , as part of the mechanism to increase glucose uptake .	We hypothesize that insulin may reduce GLUT4 endocytosis by regulating the function of dynamin II at the cell surface, as part of the mechanism to increase glucose uptake.	3	7	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	6	7
A recent study by Zhao et al XREF_BIBR further reported that LBPs improved insulin resistance via translocation and activation of GLUT4 in OLETF rats .	A recent study by Zhao et al XREF_BIBR further reported that LBPs improved insulin resistance via translocation and activation of GLUT4 in OLETF rats.	13	23	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	20	21
Finally , immunofluorescence analysis and quantification confirmed the inhibitory effect of CX-4945 on the insulin induced GLUT4 translocation to the plasma membrane in human adipocytes .	Finally, immunofluorescence analysis and quantification confirmed the inhibitory effect of CX-4945 on the insulin induced GLUT4 translocation to the plasma membrane in human adipocytes.	11	17	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Conversely , insulin arrested the majority of GLUT4 transcripts in monosomes .	Conversely, insulin arrested the majority of GLUT4 transcripts in monosomes.	2	8	arrested	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	7	8
Insulin stimulation also reduced the number of GLUT4 vesicles in the TIRF zone , presumably because they are consumed by fusion with the plasma membrane faster than they arrive at this zone .	Insulin stimulation also reduced the number of GLUT4 vesicles in the TIRF zone, presumably because they are consumed by fusion with the plasma membrane faster than they arrive at this zone.	0	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	7	8
Insulin stimulation resulted in increased number of freely diffusing GLUT4 molecules , and effectively reduced the fraction of GLUT4 confined in clusters to 25-30 % ( XREF_FIG ) .	Insulin stimulation resulted in increased number of freely diffusing GLUT4 molecules, and effectively reduced the fraction of GLUT4 confined in clusters to 25-30% (XREF_FIG).	0	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	18	19
Silencing AS160 or TBC1D1 increased surface GLUT4 in unstimulated cells but did not prevent insulin induced GLUT4 translocation .	Silencing AS160 or TBC1D1 increased surface GLUT4 in unstimulated cells but did not prevent insulin induced GLUT4 translocation.	13	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Indeed , a recent report shows that prolonged insulin stimulation suppresses Glut4 retrieval from endosomes and increases its lysosomal degradation .	Indeed, a recent report shows that prolonged insulin stimulation suppresses Glut4 retrieval from endosomes and increases its lysosomal degradation.	8	12	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	8	9	11	12
It has been shown that exogenous SLs , such as ceramide and GM 3 , inhibit the insulin receptor mediated response and insulin stimulated GLUT4 translocation [ XREF_BIBR , XREF_BIBR ] .	It has been shown that exogenous SLs, such as ceramide and GM 3, inhibit the insulin receptor mediated response and insulin stimulated GLUT4 translocation [XREF_BIBR, XREF_BIBR].	15	25	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	22	23	24	25
Insulin stimulated GLUT4 translocation is decreased in Adcy3 deficient 3T3-L1 adipocytes .	Insulin stimulated GLUT4 translocation is decreased in Adcy3 deficient 3T3-L1 adipocytes.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Furthermore , in vitro studies have demonstrated that AKT2 silencing causes inhibition of insulin induced GLUT4 translocation to the plasma membrane .	Furthermore, in vitro studies have demonstrated that AKT2 silencing causes inhibition of insulin induced GLUT4 translocation to the plasma membrane.	11	16	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	15	16
When Axin , TNKS and KIF3A were knocked down individually by siRNA in 3T3-L1 adipocytes , insulin induced GLUT4 translocation and glucose uptake were obviously impaired .	When Axin, TNKS and KIF3A were knocked down individually by siRNA in 3T3-L1 adipocytes, insulin induced GLUT4 translocation and glucose uptake were obviously impaired.	16	19	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
Moreover , insulin induced GLUT4 localization to the cell surface is completely blocked in 3T3-L1 adipocytes expressing ING2 PHD , a PI5P binding peptide predicted to interfere with PI5P binding to appropriate effectors .	Moreover, insulin induced GLUT4 localization to the cell surface is completely blocked in 3T3-L1 adipocytes expressing ING2 PHD, a PI5P binding peptide predicted to interfere with PI5P binding to appropriate effectors.	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Finally , we show that the R125W variant of TBC1D1 , which has been genetically associated with obesity , is equally inhibitory to insulin stimulated GLUT4 translocation , as is wild-type TBC1D1 , and that healthy and type 2 diabetic individuals express approximately the same level of TBC1D1 in biopsies of vastus lateralis muscle .	Finally, we show that the R125W variant of TBC1D1, which has been genetically associated with obesity, is equally inhibitory to insulin stimulated GLUT4 translocation, as is wild-type TBC1D1, and that healthy and type 2 diabetic individuals express approximately the same level of TBC1D1 in biopsies of vastus lateralis muscle.	21	26	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	23	24	25	26
Glucosamine ( Glmn ) , a product of glucose metabolism via the hexosamine pathway , causes insulin resistance in isolated adipocytes by impairing insulin induced GLUT 4 glucose transporter translocation to the plasma membrane .	Glucosamine (Glmn), a product of glucose metabolism via the hexosamine pathway, causes insulin resistance in isolated adipocytes by impairing insulin induced GLUT 4 glucose transporter translocation to the plasma membrane.	22	27	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	23	24	25	27
The insulin induced GLUT4 translocation was completely blocked by treatment with inhibitors by comparing the fluorescent density on the plasma membrane of treated cells ( XREF_FIG ) .	The insulin induced GLUT4 translocation was completely blocked by treatment with inhibitors by comparing the fluorescent density on the plasma membrane of treated cells (XREF_FIG).	0	4	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	3	4
Patients with diabetes mellitus present reduced insulin induced GLUT4 translocation and glucose uptake resulting in elevated plasma glucose concentrations .	Patients with diabetes mellitus present reduced insulin induced GLUT4 translocation and glucose uptake resulting in elevated plasma glucose concentrations.	5	9	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	8	9
As a result , insulin stimulated GLUT4 translocation is impaired , resulting in IR .	As a result, insulin stimulated GLUT4 translocation is impaired, resulting in IR.	4	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	6	7
Summarizing the existing data , androgens promote IR at the tissue level of SM by reducing capillary network formation for adequate delivery of insulin to SM , switching muscle fiber isoforms , reducing glycogen synthase activity and impairing insulin mediated GLUT4 plasma membrane translocation [ XREF_BIBR ] .	Summarizing the existing data, androgens promote IR at the tissue level of SM by reducing capillary network formation for adequate delivery of insulin to SM, switching muscle fiber isoforms, reducing glycogen synthase activity and impairing insulin mediated GLUT4 plasma membrane translocation [XREF_BIBR].	37	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	38	39	40	41
For example , adipocyte specific GLUT4 over-expression normalizes glucose tolerance , expands fat mass , and improves whole body insulin resistance caused my muscle deletion of GLUT4 .	For example, adipocyte specific GLUT4 over-expression normalizes glucose tolerance, expands fat mass, and improves whole body insulin resistance caused my muscle deletion of GLUT4.	19	27	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	19	20	26	27
So far , it is unclear how insulin could inhibit the F 5 QQI and clathrin dependent basal GLUT4 endocytosis pathway .	So far, it is unclear how insulin could inhibit the F 5 QQI and clathrin dependent basal GLUT4 endocytosis pathway.	7	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	18	19
These data complement a previous study with another muscle specific Rac1-knockout mouse model , in which insulin triggered GLUT4 translocation was reduced .	These data complement a previous study with another muscle specific Rac1-knockout mouse model, in which insulin triggered GLUT4 translocation was reduced.	16	19	triggered	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	16	17	18	19
Furthermore , insulin stimulated GLUT4 translocation was reduced by adipocyte conditioned medium .	Furthermore, insulin stimulated GLUT4 translocation was reduced by adipocyte conditioned medium.	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Insulin stimulated GLUT4 translocation is generally impaired in people with type 2 diabetes , but muscle contractions during both aerobic and resistance exercise increase GLUT4 abundance and enhance muscular glucose uptake even in these individuals .	Insulin stimulated GLUT4 translocation is generally impaired in people with type 2 diabetes, but muscle contractions during both aerobic and resistance exercise increase GLUT4 abundance and enhance muscular glucose uptake even in these individuals.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
However , others have reported that ROZ stimulates trafficking of a glucose transporter , GLUT4 , in adipocytes 50 , and it has been speculated that acute 20-min insulin exposure prevents GLUT4 internalization by dynein 51 .	However, others have reported that ROZ stimulates trafficking of a glucose transporter, GLUT4, in adipocytes 50, and it has been speculated that acute 20-min insulin exposure prevents GLUT4 internalization by dynein 51.	28	32	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	28	29	31	32
The improved insulin sensitivity suggested that Doc2b may be limiting for insulin signalling or insulin stimulated GLUT4 vesicle translocation to the cell surface membranes in skeletal muscle , given that skeletal muscle accounts for ~ 80 % of glucose uptake in humans [ XREF_BIBR ] .	The improved insulin sensitivity suggested that Doc2b may be limiting for insulin signalling or insulin stimulated GLUT4 vesicle translocation to the cell surface membranes in skeletal muscle, given that skeletal muscle accounts for ~ 80% of glucose uptake in humans [XREF_BIBR].	9	18	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	16	17
Cofilin Knockdown Promotes F-Actin Accumulation and Decreases Insulin mediated GLUT4 Translocation .	Cofilin Knockdown Promotes F-Actin Accumulation and Decreases Insulin mediated GLUT4 Translocation.	6	10	mediated	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
The inhibition of the transcriptional activity of the fish and mammalian GLUT4 promoters by insulin is difficult to reconcile with the known stimulatory effects of insulin on GLUT4 mRNA levels in skeletal muscle in fish and mammalian species .	The inhibition of the transcriptional activity of the fish and mammalian GLUT4 promoters by insulin is difficult to reconcile with the known stimulatory effects of insulin on GLUT4 mRNA levels in skeletal muscle in fish and mammalian species.	11	15	promoters	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	14	15	11	12
Insulin is known to stimulate insulin receptor ( IR )-mediated signaling cascades that ultimately result in the recruitment of GLUT4 to the cell surface by dramatically accelerating GLUT4 insertion into the PM by exocytosis and inhibiting GLUT4 endocytosis , thereby increasing glucose flux into the cells .	Insulin is known to stimulate insulin receptor (IR)-mediated signaling cascades that ultimately result in the recruitment of GLUT4 to the cell surface by dramatically accelerating GLUT4 insertion into the PM by exocytosis and inhibiting GLUT4 endocytosis, thereby increasing glucose flux into the cells.	0	28	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	27	28
Insulin induced GLUT4 translocation was inhibited at every insulin dose by 1muM MK-2206 treatment in cells expressing Akt1 WT and Akt2 WT ( XREF_FIG E ) .	Insulin induced GLUT4 translocation was inhibited at every insulin dose by 1muM MK-2206 treatment in cells expressing Akt1 WT and Akt2 WT (XREF_FIG E).	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Insulin signaling promotes the transport of GLUT4 vesicles to the cell surface and simultaneously limits endocytosis of GLUT4 [ XREF_BIBR ] .	Insulin signaling promotes the transport of GLUT4 vesicles to the cell surface and simultaneously limits endocytosis of GLUT4 [XREF_BIBR].	0	19	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	17	18
These data indicate that the insulin sensitive membrane compartment that sequesters GLUT4 in fat cells contains long chain acyl-CoA synthetase-1 and its product fatty acyl-CoA , shown previously to be required for budding and fusion in membrane trafficking processes .	These data indicate that the insulin sensitive membrane compartment that sequesters GLUT4 in fat cells contains long chain acyl-CoA synthetase-1 and its product fatty acyl-CoA, shown previously to be required for budding and fusion in membrane trafficking processes.	5	14	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	11	12
Moreover , the insulin enhanced GLUT4 translocation in myotubes was inhibited by the treatment of P. panacis EVs , but not of P. cedrina EVs or LPS ( XREF_FIG ) .	Moreover, the insulin enhanced GLUT4 translocation in myotubes was inhibited by the treatment of P. panacis EVs, but not of P. cedrina EVs or LPS (XREF_FIG).	2	6	enhanced	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
In addition , the insulin deficient streptozotocin diabetic rodent has reduced GLUT4 , whereas the diabetic hyperinsulinemic db/db mouse has increased GLUT4 in the cerebellum .	In addition, the insulin deficient streptozotocin diabetic rodent has reduced GLUT4, whereas the diabetic hyperinsulinemic db/db mouse has increased GLUT4 in the cerebellum.	4	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	11	12
The loss of insulin stimulated glucose uptake in the adipose specific GLUT4 KO is linked to transcriptional alterations that contribute to the systemic insulin resistance .	The loss of insulin stimulated glucose uptake in the adipose specific GLUT4 KO is linked to transcriptional alterations that contribute to the systemic insulin resistance.	1	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	loss of insulin	insulin	GLUT4	GLUT4	glut4	3	4	11	12
When DGKzeta was knocked-down in 3T3-L1 adipocytes , insulin induced GLUT4 translocation was inhibited without affecting other mediators of insulin dependent signaling .	When DGKzeta was knocked-down in 3T3-L1 adipocytes, insulin induced GLUT4 translocation was inhibited without affecting other mediators of insulin dependent signaling.	8	11	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	10	11
Despite these differences , denervated soleus and plantaris muscles exhibited comparable decreases in insulin stimulated activities of the insulin receptor ( approximately 40 % ) and phosphatidylinositol 3-kinase ( approximately 50 % ) and a pronounced decrease in GLUT-4 .	Despite these differences, denervated soleus and plantaris muscles exhibited comparable decreases in insulin stimulated activities of the insulin receptor (approximately 40%) and phosphatidylinositol 3-kinase (approximately 50%) and a pronounced decrease in GLUT-4.	9	39	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	13	14	38	39
In addition , insulin attenuates endocytic processes of cell surface GLUT4 molecules in adipocytes .	In addition, insulin attenuates endocytic processes of cell surface GLUT4 molecules in adipocytes.	3	11	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	10	11
Moreover , Doc2b knockout mice exhibit peripheral insulin resistance and impaired insulin stimulated GLUT4 accumulation at skeletal muscle cell surfaces [ XREF_BIBR ] .	Moreover, Doc2b knockout mice exhibit peripheral insulin resistance and impaired insulin stimulated GLUT4 accumulation at skeletal muscle cell surfaces [XREF_BIBR].	7	14	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	13	14
Insulin induced GLUT4 translocation was inhibited by pretreatment with ET-1 for 24 h.	Insulin induced GLUT4 translocation was inhibited by pretreatment with ET-1 for 24 h.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
RAB10 knockdown blunts the insulin stimulated increase in GLUT4 exocytosis .	RAB10 knockdown blunts the insulin stimulated increase in GLUT4 exocytosis.	2	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	8	9
Insulin induced GLUT4 translocation was inhibited by pretreatment with ET-1 for 24 h , and we found that this inhibitory effect was rescued by microinjection of anti-GRK2 antibody or GRK2 short interfering RNA .	Insulin induced GLUT4 translocation was inhibited by pretreatment with ET-1 for 24 h, and we found that this inhibitory effect was rescued by microinjection of anti-GRK2 antibody or GRK2 short interfering RNA.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Importantly , 9-PAHSA can rescue both reduced insulin stimulated Glut4 exocytosis and glucose transport in ChREBP KO adipocytes .	Importantly, 9-PAHSA can rescue both reduced insulin stimulated Glut4 exocytosis and glucose transport in ChREBP KO adipocytes.	4	10	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	7	8	9	10
This mutant , however , does not block insulin induced inhibition of GLUT4 endocytosis .	This mutant, however, does not block insulin induced inhibition of GLUT4 endocytosis.	7	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	12	13
LBPs improved insulin resistance via translocation and activation of GLUT4 in OLETF rats , and the activation of PI3K and p38 MAPK contributed to these effects .	LBPs improved insulin resistance via translocation and activation of GLUT4 in OLETF rats, and the activation of PI3K and p38 MAPK contributed to these effects.	2	10	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	9	10
Insulin induced GLUT4 translocation was partially inhibited at substantially higher doses , comparable to those required for inhibition of insulin induced phosphorylation of Akt and PKB .	Insulin induced GLUT4 translocation was partially inhibited at substantially higher doses, comparable to those required for inhibition of insulin induced phosphorylation of Akt and PKB.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
DVC GLUT4 and GK mRNA were decreased by insulin alone in OVX + O but not OVX + E , but were suppressed by lactate plus insulin treatment in the latter group .	DVC GLUT4 and GK mRNA were decreased by insulin alone in OVX + O but not OVX + E, but were suppressed by lactate plus insulin treatment in the latter group.	0	22	decreased	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	8	9	1	2
The high fat diet caused : ( 1 ) a 58 % decrease in insulin receptor substrate-1 ( IRS-1 ) content with a 58 % decrease in IRS-1 tyrosine phosphorylation ; ( 2 ) reductions of 56 % and 73 % respectively in insulin induced maximal PI 3-kinase activation in anti-phosphotyrosine and anti-IRS-1 antibody immunoprecipitates ; ( 3 ) a 46 % reduction in the glucose transporter protein , GLUT4 content and , consequently , ( 4 ) severely impaired insulin induced GLUT4 translocation to the plasma membrane and glucose uptake in adipocytes .	The high fat diet caused : (1) a 58% decrease in insulin receptor substrate-1 (IRS-1) content with a 58% decrease in IRS-1 tyrosine phosphorylation; (2) reductions of 56% and 73% respectively in insulin induced maximal PI 3-kinase activation in anti-phosphotyrosine and anti-IRS-1 antibody immunoprecipitates; (3) a 46% reduction in the glucose transporter protein, GLUT4 content and, consequently, (4) severely impaired insulin induced GLUT4 translocation to the plasma membrane and glucose uptake in adipocytes.	44	83	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	80	81	82	83
Insulin stimulated GLUT4 translocation is generally impaired in type 2 diabetes .	Insulin stimulated GLUT4 translocation is generally impaired in type 2 diabetes.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Even though insulin resistance and diabetes do not reduce the pool of GLUT4 molecules in skeletal muscle , muscle specific transgenic expression of GLUT4 significantly improved insulin action in diabetic mice [ XREF_BIBR ] .	Even though insulin resistance and diabetes do not reduce the pool of GLUT4 molecules in skeletal muscle, muscle specific transgenic expression of GLUT4 significantly improved insulin action in diabetic mice [XREF_BIBR].	2	13	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	12	13
GLUT4 trafficking has been extensively studied in adipocytes where it has been found that the major effect of insulin is to stimulate exocytosis , although it has been reported that insulin also inhibits GLUT4 endocytosis .	GLUT4 trafficking has been extensively studied in adipocytes where it has been found that the major effect of insulin is to stimulate exocytosis, although it has been reported that insulin also inhibits GLUT4 endocytosis.	30	34	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	30	31	33	34
Insulin mediated GLUT4 translocation was inhibited by more than 80 % in nocodazole treated cells .	Insulin mediated GLUT4 translocation was inhibited by more than 80% in nocodazole treated cells.	0	3	mediated	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Fourth , in insulin resistance , expression levels of molecules implicated in insulin induced GLUT4 translocation are decreased XREF_BIBR , XREF_BIBR .	Fourth, in insulin resistance, expression levels of molecules implicated in insulin induced GLUT4 translocation are decreased XREF_BIBR, XREF_BIBR.	10	15	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	14	15
Insulin stimulated GLUT4 translocation is impaired in people with type 2 diabetes .	Insulin stimulated GLUT4 translocation is impaired in people with type 2 diabetes.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
The insulin induced GLUT4 translocation was markedly inhibited after addition of wortmannin ( P < 0.01 ) .	The insulin induced GLUT4 translocation was markedly inhibited after addition of wortmannin (P < 0.01).	0	4	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	3	4
Exogenous insulin uniformly further enhanced sarcolemmal association of these macronutrient transporter proteins above that of basal , with the exception of insulin resistance of FATP1 and GLUT4 in IUGR and FAT and CD36 in PNGR .	Exogenous insulin uniformly further enhanced sarcolemmal association of these macronutrient transporter proteins above that of basal, with the exception of insulin resistance of FATP1 and GLUT4 in IUGR and FAT and CD36 in PNGR.	21	27	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	26	27
Early cellular markers of insulin resistance in adipose tissue are reduced adipose cell GLUT 4 and IRS 1 protein expression [ XREF_BIBR - XREF_BIBR ] .	Early cellular markers of insulin resistance in adipose tissue are reduced adipose cell GLUT 4 and IRS 1 protein expression [XREF_BIBR - XREF_BIBR].	4	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT 4	GLUT 4	GLUT 4	4	5	13	15
In addition , TIRFM studies on rat primary white adipocytes showed that insulin stimulation decreased GLUT4 trafficking as a result of vesicle tethering to the membrane XREF_BIBR , XREF_BIBR .	In addition, TIRFM studies on rat primary white adipocytes showed that insulin stimulation decreased GLUT4 trafficking as a result of vesicle tethering to the membrane XREF_BIBR, XREF_BIBR.	12	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	12	13	15	16
Insulin resistance causes the impairment of IRS1 and GLUT4 , which lead to obstacle of glucose utilization [ XREF_BIBR ] .	Insulin resistance causes the impairment of IRS1 and GLUT4, which lead to obstacle of glucose utilization [XREF_BIBR].	0	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	8	9
Estradiol , T , and insulin increased RBP4 secretion and decreased GLUT4 secretion in these tissues , although only the effect of E 2 reached statistical significance .	Estradiol, T, and insulin increased RBP4 secretion and decreased GLUT4 secretion in these tissues, although only the effect of E 2 reached statistical significance.	0	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	5	6	11	12
Moreover , insulin stimulated GLUT4 translocation was markedly inhibited in rac1 knockout mouse gastrocnemius muscle [ XREF_BIBR ] .	Moreover, insulin stimulated GLUT4 translocation was markedly inhibited in rac1 knockout mouse gastrocnemius muscle [XREF_BIBR].	2	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Thus , while insulin stimulation reduced total GLUT4 in the control subjects , consistent with two previous reports XREF_BIBR , XREF_BIBR , no such effect was observed in LBW men .	Thus, while insulin stimulation reduced total GLUT4 in the control subjects, consistent with two previous reports XREF_BIBR, XREF_BIBR, no such effect was observed in LBW men.	3	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	7	8
Insulin accelerates GLUT4 and IRAP transport to the cell surface and simultaneously reduces GLUT4 internalization having as a global effect a rapid increase of GLUT4 in the plasma membrane of insulin stimulated adipocytes .	Insulin accelerates GLUT4 and IRAP transport to the cell surface and simultaneously reduces GLUT4 internalization having as a global effect a rapid increase of GLUT4 in the plasma membrane of insulin stimulated adipocytes.	0	12	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Insulin reduces the velocity of mobile Myo1c positive GLUT4 vesicles beneath the muscle cell plasma membrane as visualized by total internal reflection fluorescence microscopy .	Insulin reduces the velocity of mobile Myo1c positive GLUT4 vesicles beneath the muscle cell plasma membrane as visualized by total internal reflection fluorescence microscopy.	0	9	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	8	9
In 3T3-L1 adipocytes , naringenin repressed glucose uptake [ XREF_BIBR ] and suppressed PI3K and Akt phosphorylation normally induced by insulin , thus regulating insulin induced GLUT4 translocation [ XREF_BIBR ] .	In 3T3-L1 adipocytes, naringenin repressed glucose uptake [XREF_BIBR] and suppressed PI3K and Akt phosphorylation normally induced by insulin, thus regulating insulin induced GLUT4 translocation [XREF_BIBR].	24	27	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	24	25	26	27
Our results indicate that insulin significantly reduced the activity of the Fugu GLUT4 promoter in a dose- and time dependent fashion .	Our results indicate that insulin significantly reduced the activity of the Fugu GLUT4 promoter in a dose- and time dependent fashion.	4	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	12	13
ChREBP KO adipocytes have slower insulin stimulated Glut4 exocytosis at 15min after insulin stimulation ( XREF_FIG ) .	ChREBP KO adipocytes have slower insulin stimulated Glut4 exocytosis at 15min after insulin stimulation (XREF_FIG).	3	8	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	5	6	7	8
Insulin deficiency decreased GLUT4 protein concentration in innervated soleus muscle .	Insulin deficiency decreased GLUT4 protein concentration in innervated soleus muscle.	0	5	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	3	4
Levels of insulin induced GLUT4 translocation in skeletal muscle of type 2 diabetic patients are markedly decreased [ XREF_BIBR ] .	Levels of insulin induced GLUT4 translocation in skeletal muscle of type 2 diabetic patients are markedly decreased [XREF_BIBR].	0	5	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
In parallel , insulin stimulated GLUT4 translocation in skeletal muscle was also significantly reduced in these mice .	In parallel, insulin stimulated GLUT4 translocation in skeletal muscle was also significantly reduced in these mice.	3	6	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	3	4	5	6
The dysfunctional SAT in insulin resistance has reduced adipose cell GLUT4 protein - the insulin regulated glucose transporter .	The dysfunctional SAT in insulin resistance has reduced adipose cell GLUT4 protein - the insulin regulated glucose transporter.	4	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	10	11
Moreover , defects in insulin action on AS160 may impair GLUT4 trafficking in type 2 diabetes .	Moreover, defects in insulin action on AS160 may impair GLUT4 trafficking in type 2 diabetes.	4	11	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	4	5	10	11
Interestingly , wortmannin also inhibits the insulin induced activation of the GLUT4 glucose transporter [ XREF_BIBR ] .	Interestingly, wortmannin also inhibits the insulin induced activation of the GLUT4 glucose transporter [XREF_BIBR].	5	13	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	6	7	11	12
Maximum insulin induced GLUT4 translocation into musculus semitendinosus plasma membrane was significantly lower in bovines than in porcines .	Maximum insulin induced GLUT4 translocation into musculus semitendinosus plasma membrane was significantly lower in bovines than in porcines.	0	4	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	3	4
Suppression of PIKfyve activity reduces insulin induced Glut4 translocation in cultured adipocytes .	Suppression of PIKfyve activity reduces insulin induced Glut4 translocation in cultured adipocytes.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	5	6	7	8
We found a similar response in CHO cells transfected with AS160-4A : addition of AS160-4A to CHO cells conferred basal retention of GLUT4 to these cells ; however , insulin stimulated GLUT4 translocation was blocked ( XREF_FIG ) .	We found a similar response in CHO cells transfected with AS160-4A : addition of AS160-4A to CHO cells conferred basal retention of GLUT4 to these cells; however, insulin stimulated GLUT4 translocation was blocked (XREF_FIG).	29	32	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	29	30	31	32
Previous studies suggested that Sortilin mediates the biogenesis of insulin responsive compartments during differentiation , since the absence of Sortilin reduced the in vitro formation of these compartments , and adipocytes stably knocked down for Sortilin displayed impaired insulin mediated GLUT4 translocation .	Previous studies suggested that Sortilin mediates the biogenesis of insulin responsive compartments during differentiation, since the absence of Sortilin reduced the in vitro formation of these compartments, and adipocytes stably knocked down for Sortilin displayed impaired insulin mediated GLUT4 translocation.	36	41	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	38	39	40	41
The Rab4-( 191-210 ) peptide also reduced insulin induced GLUT4 translocation from the intracellular pool to the plasma membrane .	The Rab4-(191-210) peptide also reduced insulin induced GLUT4 translocation from the intracellular pool to the plasma membrane.	7	10	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	7	8	9	10
However , the insulin dependent reduction in k in was partially retained in the presence of Akti , suggesting that the insulin stimulated decrease in GLUT4 internalization is independent of Akt .	However, the insulin dependent reduction in k in was partially retained in the presence of Akti, suggesting that the insulin stimulated decrease in GLUT4 internalization is independent of Akt.	20	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	25	26
Long-term insulin treatment decreased cellular GLUT4 content by about 40 % and diminished the ability of a short-term insulin challenge to promote GLUT4 translocation .	Long-term insulin treatment decreased cellular GLUT4 content by about 40% and diminished the ability of a short-term insulin challenge to promote GLUT4 translocation.	1	6	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	1	2	5	6
In adipose tissues , decreased GUR was also shown to be significantly improved with a normalization of insulin induced GLUT-4 translocation .	In adipose tissues, decreased GUR was also shown to be significantly improved with a normalization of insulin induced GLUT-4 translocation.	15	20	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	17	18	19	20
Ectopic expression of TBC1D1-3P mutant ( in which alanine replaces Ser489 , Thr499 and Ser501 , and Thr590 on mouse TBC1D1 protein ) exerted robust inhibition on insulin induced GLUT4 translocation , indicating that phosphorylation of TBC1D1 also regulates GLUT4 trafficking .	Ectopic expression of TBC1D1-3P mutant (in which alanine replaces Ser489, Thr499 and Ser501, and Thr590 on mouse TBC1D1 protein) exerted robust inhibition on insulin induced GLUT4 translocation, indicating that phosphorylation of TBC1D1 also regulates GLUT4 trafficking.	25	30	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	27	28	29	30
Insulin stimulated GLUT4 translocation is completely inhibited under these conditions .	Insulin stimulated GLUT4 translocation is completely inhibited under these conditions.	0	3	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
Pharmacological agents also point to CME and non CME mechanisms of GLUT4 endocytosis in adipocytes , and insulin reduces GLUT4 internalization in adipocytes .	Pharmacological agents also point to CME and non CME mechanisms of GLUT4 endocytosis in adipocytes, and insulin reduces GLUT4 internalization in adipocytes.	17	20	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Insulin signaling reduces GLUT4 retention allowing GLUT4 to move towards the cell periphery XREF_BIBR , increases its endosomal recycling XREF_BIBR , and enhances its docking and fusion with the plasma membrane XREF_BIBR .	Insulin signaling reduces GLUT4 retention allowing GLUT4 to move towards the cell periphery XREF_BIBR, increases its endosomal recycling XREF_BIBR, and enhances its docking and fusion with the plasma membrane XREF_BIBR.	0	4	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	3	4
Furthermore , insulin induced GLUT4 presence in plasma membranes of cardiac cells was decreased by fructose diet , as well as insulin stimulation of eNOS phosphorylation at Ser ( 1177 ) .	Furthermore, insulin induced GLUT4 presence in plasma membranes of cardiac cells was decreased by fructose diet, as well as insulin stimulation of eNOS phosphorylation at Ser (1177).	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	4	5
Insulin decreased the GLUT4 content of the IM in both animal groups and of a second , heavier intracellular membrane fraction only in TG mice .	Insulin decreased the GLUT4 content of the IM in both animal groups and of a second, heavier intracellular membrane fraction only in TG mice.	0	4	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	3	4
Furthermore , these data support a model in which insulin stimulates GLUT4 exocytosis by releasing an inhibitor of GLUT4 movement to the cell surface , and it is this clamp on basal exocytosis that is missing in adipocytes lacking C/EBPalpha .	Furthermore, these data support a model in which insulin stimulates GLUT4 exocytosis by releasing an inhibitor of GLUT4 movement to the cell surface, and it is this clamp on basal exocytosis that is missing in adipocytes lacking C/EBPalpha.	9	12	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	9	10	11	12
Insulin treatment in vivo had no effect on the microsomal membrane content of small GTP binding proteins , but significantly decreased the 24 kDa species in GLUT4 enriched vesicles by 36 +/- 5 % ( n = 3 ) .	Insulin treatment in vivo had no effect on the microsomal membrane content of small GTP binding proteins, but significantly decreased the 24 kDa species in GLUT4 enriched vesicles by 36 +/- 5% (n = 3).	0	28	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	26	27
Fusicoccane diterpenoids exhibit diverse biological activities , such as plant growth regulating activity ( fusicoccins ) XREF_BIBR , lysophospholipase inhibitory activity ( cyclooctatin ) XREF_BIBR , antimicrobial activity ( periconicins ) XREF_BIBR XREF_BIBR , nitrification inhibitory activity ( brachialactone ) XREF_BIBR , cytotoxicity against tumor cells ( cotylenins ) XREF_BIBR , inhibiting insulin stimulated GLUT4 fusion activity ( fusicoccins ) XREF_BIBR , and so on .	Fusicoccane diterpenoids exhibit diverse biological activities, such as plant growth regulating activity (fusicoccins) XREF_BIBR, lysophospholipase inhibitory activity (cyclooctatin) XREF_BIBR, antimicrobial activity (periconicins) XREF_BIBR XREF_BIBR, nitrification inhibitory activity (brachialactone) XREF_BIBR, cytotoxicity against tumor cells (cotylenins) XREF_BIBR, inhibiting insulin stimulated GLUT4 fusion activity (fusicoccins) XREF_BIBR, and so on.	51	56	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	52	53	54	55
Moreover , expression of the MICAL-L2-CT fragment that binds Rab13 but lacks ability to interact with actin also markedly reduced insulin triggered GLUT4 translocation ( XREF_FIG ) .	Moreover, expression of the MICAL-L2-CT fragment that binds Rab13 but lacks ability to interact with actin also markedly reduced insulin triggered GLUT4 translocation (XREF_FIG).	19	23	triggered	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	20	21	22	23
Silencing of the transient receptor potential ( TRP ) 3 Ca 2+ channel in mouse flexor digitorum brevis single muscle fibres reduced insulin stimulated glucose transport XREF_BIBR , suggesting a role of extracellular Ca 2+ in insulin stimulated GLUT4 vesicle membrane fusion .	Silencing of the transient receptor potential (TRP) 3 Ca 2+ channel in mouse flexor digitorum brevis single muscle fibres reduced insulin stimulated glucose transport XREF_BIBR, suggesting a role of extracellular Ca 2+ in insulin stimulated GLUT4 vesicle membrane fusion.	33	41	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	36	37	38	39
A binding site for nuclear factor 1 ( NF1 ) , that mediates insulin and cAMP induced repression of GLUT4 in 3T3-L1 adipocytes is located between bases -700 and -688 .	A binding site for nuclear factor 1 (NF1), that mediates insulin and cAMP induced repression of GLUT4 in 3T3-L1 adipocytes is located between bases -700 and -688.	13	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	13	14	19	20
These data indicate that short-term ( 24-h ) denervation , which lowers insulin stimulated glucose transport , is associated with decreased Akt-alpha activation and impaired insulin stimulated GLUT-4 appearance at the muscle surface .	These data indicate that short-term (24-h) denervation, which lowers insulin stimulated glucose transport, is associated with decreased Akt-alpha activation and impaired insulin stimulated GLUT-4 appearance at the muscle surface.	18	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT-4	GLUT-4	GLUT-4	25	26	27	28
Premixing and coinjection of the Rab4 antibody with WT Rab4 almost completely abolished its inhibitory effect on insulin induced GLUT4 translocation .	Premixing and coinjection of the Rab4 antibody with WT Rab4 almost completely abolished its inhibitory effect on insulin induced GLUT4 translocation.	15	20	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	17	18	19	20
Although preventing actin remodeling by Arp2/3 knockdown did not reduce the overall level of P-Akt , failure to accumulate phosphorylated Akt near the membrane may be a factor in the loss of insulin induced GLUT4 translocation .	Although preventing actin remodeling by Arp2/3 knockdown did not reduce the overall level of P-Akt, failure to accumulate phosphorylated Akt near the membrane may be a factor in the loss of insulin induced GLUT4 translocation.	30	35	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	32	33	34	35
Furthermore , Glut-4 can be inhibited and/or down-regulated by sustained insulin deficiency , partially via c-AMP-dependent pathways .	Furthermore, Glut-4 can be inhibited and/or down-regulated by sustained insulin deficiency, partially via c-AMP-dependent pathways.	2	11	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut-4	Glut-4	Glut-4	10	11	2	3
Inhibition of phosphoinositide ( PI ) 3-kinase activity with chemical agents such as wortmannin or LY294002 partially blocked insulin induced GLUT4 mRNA accumulation , insulin induced GLUT4 protein content , GLUT4-CAT transactivation and glucose uptake .	Inhibition of phosphoinositide (PI) 3-kinase activity with chemical agents such as wortmannin or LY294002 partially blocked insulin induced GLUT4 mRNA accumulation, insulin induced GLUT4 protein content, GLUT4-CAT transactivation and glucose uptake.	24	28	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	24	25	26	27
In streptozotocin treated mice ( three groups of seven mice , diet induced insulin resistance decreased Cox4i1 and Glut4 ( P < 0.001 for both ) .	In streptozotocin treated mice (three groups of seven mice, diet induced insulin resistance decreased Cox4i1 and Glut4 (P < 0.001 for both).	13	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	13	14	18	19
Given that insulin has been reported to inhibit GLUT4 endocytosis in adipocytes XREF_BIBR , XREF_BIBR we next asked whether an inhibition of Rip11 endocytosis by insulin might be the underlying cause of the apparent translocation we observe .	Given that insulin has been reported to inhibit GLUT4 endocytosis in adipocytes XREF_BIBR, XREF_BIBR we next asked whether an inhibition of Rip11 endocytosis by insulin might be the underlying cause of the apparent translocation we observe.	2	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	2	3	8	9
In the actin disrupted adipocytes treated with latrunculin A , insulin induced GLUT4 translocation was inhibited completely .	In the actin disrupted adipocytes treated with latrunculin A, insulin induced GLUT4 translocation was inhibited completely.	10	13	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	10	11	12	13
This , however , may not represent the only factor affecting Glut4 protein levels because prolonged insulin stimulation decreases the half-life of the Glut4 protein more than threefold and causes insulin resistance .	This, however, may not represent the only factor affecting Glut4 protein levels because prolonged insulin stimulation decreases the half-life of the Glut4 protein more than threefold and causes insulin resistance.	16	24	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Glut4	Glut4	Glut4	16	17	23	24
After nocodazole treatment to disrupt microtubules , GLUT4 vesicles were dispersed from the perinuclear region in the basal state , and insulin induced GLUT4 translocation was partially inhibited by 20-30 % , consistent with other reports .	After nocodazole treatment to disrupt microtubules, GLUT4 vesicles were dispersed from the perinuclear region in the basal state, and insulin induced GLUT4 translocation was partially inhibited by 20-30%, consistent with other reports.	21	24	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	GLUT4	GLUT4	GLUT4	21	22	23	24
Insulin and hyperosmolarity both decreased the recycling time of GLUT4 from 2 h to 40 and 70 min , respectively .	Insulin and hyperosmolarity both decreased the recycling time of GLUT4 from 2 h to 40 and 70 min, respectively.	0	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	9	10
Insulin inhibits GLUT4 uptake by the nystatin sensitive pathway and , consequently , GLUT4 is internalized by the AP-2-dependent pathway in stimulated adipocytes .	Insulin inhibits GLUT4 uptake by the nystatin sensitive pathway and, consequently, GLUT4 is internalized by the AP-2-dependent pathway in stimulated adipocytes.	0	3	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	GLUT4	GLUT4	GLUT4	0	1	2	3
We next explored inhibitory serine phosphorylation of IRS1 as the source of insulin resistance downstream of IR in the white adipose tissue .	We next explored inhibitory serine phosphorylation of IRS1 as the source of insulin resistance downstream of IR in the white adipose tissue.	12	21	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	12	13	16	17
Constant insulin delivery that did not normalize glycemia but significantly reduced blood glucose from onset of diabetes did partially prevent the insulin receptor activation by ex vivo insulin ( 0.1 nM ) stimulation ( XREF_FIG ) in sciatic nerve from diabetic rats .	Constant insulin delivery that did not normalize glycemia but significantly reduced blood glucose from onset of diabetes did partially prevent the insulin receptor activation by ex vivo insulin (0.1 nM) stimulation (XREF_FIG) in sciatic nerve from diabetic rats.	1	23	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	21	23
On the other hand , IGFBP1 , CTGF , INSR and DCN were significantly down-regulated by insulin in a dose dependent fashion , while LEFTY2 was not significantly changed ( XREF_FIG ) .	On the other hand, IGFBP1, CTGF, INSR and DCN were significantly down-regulated by insulin in a dose dependent fashion, while LEFTY2 was not significantly changed (XREF_FIG).	5	28	down-regulated	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	INSR	INSR	INSR	16	17	9	10
Therefore , the reduced formation of the tris phosphorylated regulatory region in the diabetic receptors suggests that a defective autophosphorylation cascade leading to tris phosphorylation of the regulatory region may cause , in part , the reduced insulin stimulated kinase activity of the insulin receptor in muscle of NIDDM patients .	Therefore, the reduced formation of the tris phosphorylated regulatory region in the diabetic receptors suggests that a defective autophosphorylation cascade leading to tris phosphorylation of the regulatory region may cause, in part, the reduced insulin stimulated kinase activity of the insulin receptor in muscle of NIDDM patients.	33	45	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	37	38	43	45
In contrast , even after prolonged incubation with imatinib for 3 h and 24 h , there were no decreases in insulin induced insulin receptor tyrosine phosphorylation ( XREF_FIG ) .	In contrast, even after prolonged incubation with imatinib for 3 h and 24 h, there were no decreases in insulin induced insulin receptor tyrosine phosphorylation (XREF_FIG).	19	25	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	21	22	23	25
By contrast , insulin stimulated P-INSR and IGF1R was decreased by 50 % in IR-M1 and IR-M2 but unchanged in IR-M3 iPSCs ( XREF_FIG ) .	By contrast, insulin stimulated P-INSR and IGF1R was decreased by 50% in IR-M1 and IR-M2 but unchanged in IR-M3 iPSCs (XREF_FIG).	3	9	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	P-INSR	P-INSR	P-INSR	3	4	5	6
The stimulatory action of native insulin is closely related to its ability to inhibit the labeling of the insulin receptor by 125I-insulin such that the uptake of xylose and AIB is maximally stimulated when 80 % of insulin receptor 125I-affinity labeling is inhibited .	The stimulatory action of native insulin is closely related to its ability to inhibit the labeling of the insulin receptor by 125I-insulin such that the uptake of xylose and AIB is maximally stimulated when 80% of insulin receptor 125I-affinity labeling is inhibited.	2	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	18	20
In addition , induction of peripheral insulin resistance in an AD transgenic mouse model reduced brain insulin receptor signalling and increased Abeta content and amyloid plaque burden [ XREF_BIBR ] .	In addition, induction of peripheral insulin resistance in an AD transgenic mouse model reduced brain insulin receptor signalling and increased Abeta content and amyloid plaque burden [XREF_BIBR].	6	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	16	18
Interestingly , using a genetic model insulin resistance ( inactivation of hepatic insulin receptor ) , Kulkarni and colleagues have recently identified the protease inhibitor SerpinB1 as a hepatically derived factor responsible for the marked beta-cell proliferation in this model [ XREF_BIBR ] .	Interestingly, using a genetic model insulin resistance (inactivation of hepatic insulin receptor), Kulkarni and colleagues have recently identified the protease inhibitor SerpinB1 as a hepatically derived factor responsible for the marked beta-cell proliferation in this model [XREF_BIBR].	6	14	inactivation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	12	14
The major mechanism through which T2DM may influence AD includes central insulin resistance , which leads to reduced sensitivity to insulin in the brain , resulting in hyperinsulinemia , impaired insulin receptor ( IR ) signaling , and glucose toxicity .	The major mechanism through which T2DM may influence AD includes central insulin resistance, which leads to reduced sensitivity to insulin in the brain, resulting in hyperinsulinemia, impaired insulin receptor (IR) signaling, and glucose toxicity.	11	36	signaling	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	11	12	33	34
HFD induced insulin resistance also caused a decrease in IR and IRS-1 protein in muscle by 60 % and 64 % , respectively ( XREF_FIG ) and a reduction of IR protein in fat by 48 % ( XREF_FIG and XREF_SUPPLEMENTARY ) , whereas AKT protein levels were increased upon HFD feeding ( XREF_FIG ) .	HFD induced insulin resistance also caused a decrease in IR and IRS-1 protein in muscle by 60% and 64%, respectively (XREF_FIG) and a reduction of IR protein in fat by 48% (XREF_FIG and XREF_SUPPLEMENTARY), whereas AKT protein levels were increased upon HFD feeding (XREF_FIG).	0	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	HFD induced insulin	insulin	IR	IR	ir	2	3	9	10
Ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) , originally described as a plasma cell allo-antigen and named plasma cell membrane glycoprotein ( PC-1 ) , is an inhibitor of insulin induced activation of the insulin receptor .	Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), originally described as a plasma cell allo-antigen and named plasma cell membrane glycoprotein (PC-1), is an inhibitor of insulin induced activation of the insulin receptor.	26	35	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	28	29	33	35
Stressed rats also exhibited elevated levels of glycogen and triglyceride in the liver and impaired hepatic insulin production via insulin induced insulin receptor and insulin receptor substrate 1/glycogen synthase kinase 3beta signalling , which persisted for 3-14 days after cessation of noise exposure .	Stressed rats also exhibited elevated levels of glycogen and triglyceride in the liver and impaired hepatic insulin production via insulin induced insulin receptor and insulin receptor substrate 1/glycogen synthase kinase 3beta signalling, which persisted for 3-14 days after cessation of noise exposure.	17	23	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	19	20	21	23
Such impaired interactions abolished the ability of IRS-1 to undergo insulin induced Tyr phosphorylation and further propagate the insulin receptor signal .	Such impaired interactions abolished the ability of IRS-1 to undergo insulin induced Tyr phosphorylation and further propagate the insulin receptor signal.	9	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	18	20
Third , we could not completely rule out the confounding effects of various medications , such as insulin , metformin , and lipid lowering agents which may influence fasting glucose and C-peptide levels , or the degree of IR and visceral obesity .	Third, we could not completely rule out the confounding effects of various medications, such as insulin, metformin, and lipid lowering agents which may influence fasting glucose and C-peptide levels, or the degree of IR and visceral obesity.	10	41	lowering	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	17	18	38	39
Inhibition of iNOS improves insulin stimulated insulin receptor substrate-1-mediated signal transduction in skeletal muscle of obese diabetic mice and burned mice [ XREF_BIBR , XREF_BIBR ] .	Inhibition of iNOS improves insulin stimulated insulin receptor substrate-1-mediated signal transduction in skeletal muscle of obese diabetic mice and burned mice [XREF_BIBR, XREF_BIBR].	4	19	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	6	8
Abnormalities in CNS insulin action reflect defects in insulin transport across the BBB or impaired insulin signaling in insulin receptor expressing cells of the CNS , or a combination of the two .	Abnormalities in CNS insulin action reflect defects in insulin transport across the BBB or impaired insulin signaling in insulin receptor expressing cells of the CNS, or a combination of the two.	15	21	signaling	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	15	16	18	20
We conclude that insulin resistance secondary to obesity in rhesus monkeys is associated with increased levels of PC-1 and decreased IR signaling capacity in skeletal muscle .	We conclude that insulin resistance secondary to obesity in rhesus monkeys is associated with increased levels of PC-1 and decreased IR signaling capacity in skeletal muscle.	3	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	3	4	20	21
In the presence of relatively low concentrations of DTT , insulin was found to potentiate the apparent insulin receptor subunit reduction of the native alpha 2 beta 2 heterotetrameric complex into alpha beta heterodimers , when observed by silver staining of sodium dodecyl sulfate-polyacrylamide gels .	In the presence of relatively low concentrations of DTT, insulin was found to potentiate the apparent insulin receptor subunit reduction of the native alpha 2 beta 2 heterotetrameric complex into alpha beta heterodimers, when observed by silver staining of sodium dodecyl sulfate-polyacrylamide gels.	10	20	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	17	19
Termination of the insulin signal cascade is also accomplished by PTPs , which dephosphorylate and inactivate the IR , inactivating its downstream substrates .	Termination of the insulin signal cascade is also accomplished by PTPs, which dephosphorylate and inactivate the IR, inactivating its downstream substrates.	3	18	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	3	4	17	18
Sustained insulin delivery that normalized blood glucose for 8 weeks of diabetes significantly prevented activation of insulin receptor by ex vivo insulin at 0.1 nM ( #p < 0.05 ) ( XREF_FIG ) .	Sustained insulin delivery that normalized blood glucose for 8 weeks of diabetes significantly prevented activation of insulin receptor by ex vivo insulin at 0.1 nM (#p < 0.05) (XREF_FIG).	1	18	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	16	18
Suppression of insulin production or inactivation of the insulin receptor or receptor substrate resulted in miniature flies [ XREF_BIBR ] , whereas overexpression of insulin resulted in giant flies [ XREF_BIBR ] .	Suppression of insulin production or inactivation of the insulin receptor or receptor substrate resulted in miniature flies [XREF_BIBR], whereas overexpression of insulin resulted in giant flies [XREF_BIBR].	2	10	production	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	8	10
In liver of PC-1 animals , insulin stimulated IR tyrosine kinase and Akt and protein kinase B activation were both decreased .	In liver of PC-1 animals, insulin stimulated IR tyrosine kinase and Akt and protein kinase B activation were both decreased.	6	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	6	7	8	9
The increased insulin sensitivity in CBLB ( Cbl-b ) knockout mice suggests that this ligase could also be a potential target in spite of the lack of evidence that CBLB ubiquitylates and downregulates the insulin receptor .	The increased insulin sensitivity in CBLB (Cbl-b) knockout mice suggests that this ligase could also be a potential target in spite of the lack of evidence that CBLB ubiquitylates and downregulates the insulin receptor.	2	36	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	34	36
The loss of insulin mediated inhibition of MTP gene expression could play a role in VLDL overproduction in states of IR .	The loss of insulin mediated inhibition of MTP gene expression could play a role in VLDL overproduction in states of IR.	1	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	loss of insulin	insulin	IR	IR	ir	3	4	20	21
Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 ( ENPP1 ) is an inhibitor of insulin induced activation of the insulin receptor .	Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) is an inhibitor of insulin induced activation of the insulin receptor.	10	19	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	17	19
It is conceivable that insulin sensitizers might reverse not only IR , but also liver damage observed in NAFLD .	It is conceivable that insulin sensitizers might reverse not only IR, but also liver damage observed in NAFLD.	4	15	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	4	5	10	11
CAV3 knock out mice show a loss of caveolae at the sarcolemma ( but not endothelial cells ) , exclusion of dystrophin-glycoprotein complexes from the lipid rafts , abnormalities of the T-tubule system , insulin resistance and instability of the insulin receptor in skeletal muscle [ XREF_BIBR , XREF_BIBR ] .	CAV3 knock out mice show a loss of caveolae at the sarcolemma (but not endothelial cells), exclusion of dystrophin-glycoprotein complexes from the lipid rafts, abnormalities of the T-tubule system, insulin resistance and instability of the insulin receptor in skeletal muscle [XREF_BIBR, XREF_BIBR].	34	42	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	34	35	40	42
The insulin receptor was downregulated to a similar degree by glargine and regular human insulin at high insulin concentrations ( P < 0.0001 for glargine , P = 0.002 for regular human insulin ) .	The insulin receptor was downregulated to a similar degree by glargine and regular human insulin at high insulin concentrations (P < 0.0001 for glargine, P = 0.002 for regular human insulin).	1	20	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	14	15	1	3
Consequently , the biological activity of insulin was reduced , resulting in the occurrence of IR .	Consequently, the biological activity of insulin was reduced, resulting in the occurrence of IR.	4	16	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	6	7	15	16
Insulin downregulates the IR in various target tissues .	Insulin downregulates the IR in various target tissues.	0	7	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	3	4
Our results demonstrate that smoking decreases peripheral insulin sensitivity reducing insulin receptor affinity .	Our results demonstrate that smoking decreases peripheral insulin sensitivity reducing insulin receptor affinity.	7	12	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	7	8	10	12
There was a negative correlation between insulin resistance levels and pTyr1R suggesting that the increased insulin resistance in the body may disrupt insulin receptor signaling in the brain .	There was a negative correlation between insulin resistance levels and pTyr1R suggesting that the increased insulin resistance in the body may disrupt insulin receptor signaling in the brain.	15	24	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	15	16	22	24
To assess whether PQIP inhibits both IGF1R and InsR , MCF-7 cells were treated with either IGF-I or insulin , and with increasing concentrations of PQIP .	To assess whether PQIP inhibits both IGF1R and InsR, MCF-7 cells were treated with either IGF-I or insulin, and with increasing concentrations of PQIP.	4	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	insulin	insulin	insulin	InsR	InsR	InsR	18	19	8	9
Nevertheless , insulin resistance ( of the IR ) developed by the undefined ( acquired and inherited ) causes would block the signal pathway , resulting in an accumulation of Glc in the circulation ( ie , hyperglycemia ) .	Nevertheless, insulin resistance (of the IR) developed by the undefined (acquired and inherited) causes would block the signal pathway, resulting in an accumulation of Glc in the circulation (ie, hyperglycemia).	2	8	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	2	3	7	8
A low dose of insulin , insufficient to affect systemic glycemia , partially restored the impaired peripheral nerve insulin receptor signaling involving the deactivation of p44/42 MAPK and ameliorated peripheral sensory nerve dysfunction in STZ induced diabetic rats .	A low dose of insulin, insufficient to affect systemic glycemia, partially restored the impaired peripheral nerve insulin receptor signaling involving the deactivation of p44/42 MAPK and ameliorated peripheral sensory nerve dysfunction in STZ induced diabetic rats.	2	20	restored	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	18	20
Nine weeks of insulin deficiency resulted in reduced IDE , reduced learning capacity , and reduced insulin receptor signaling .	Nine weeks of insulin deficiency resulted in reduced IDE, reduced learning capacity, and reduced insulin receptor signaling.	3	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	16	18
Here we further show that insulin dose-dependently down-regulates the FOXO1 target genes IGFBP1 , CTGF , INSR and DCN , which are up-regulated upon decidualization .	Here we further show that insulin dose-dependently down-regulates the FOXO1 target genes IGFBP1, CTGF, INSR and DCN, which are up-regulated upon decidualization.	5	22	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	INSR	INSR	INSR	5	6	16	17
Together , these early studies suggested that impaired insulin secretion , tissue response to insulin , non oxidative glucose disposal , and glucagon response to glucose all contribute to IR in alcoholic cirrhotic patients .	Together, these early studies suggested that impaired insulin secretion, tissue response to insulin, non oxidative glucose disposal, and glucagon response to glucose all contribute to IR in alcoholic cirrhotic patients.	8	30	contribute	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	8	9	29	30
0.1 ( n = 5 ) and 2.0 U ( n = 7 ) of intracranial insulin increased the brain insulin content to supraphysiologic concentrations ( p less than 0.01 ) and decreased the fetal brain insulin receptor number ( p less than 0.01 ) , the affinity remaining constant .	0.1 (n = 5) and 2.0 U (n = 7) of intracranial insulin increased the brain insulin content to supraphysiologic concentrations (p less than 0.01) and decreased the fetal brain insulin receptor number (p less than 0.01), the affinity remaining constant.	8	38	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	16	17	36	38
Improvement of insulin sensitivity may increase the response rate to antiviral treatment and prevent IR complications , including vascular diseases .	Improvement of insulin sensitivity may increase the response rate to antiviral treatment and prevent IR complications, including vascular diseases.	2	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	2	3	14	15
From the biological point of view , it is interesting that the PN approach models , for the first time , the experimentally well-known insulin stimulated degradation of IR [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] which plays a fundamental role in the insulin resistance and metabolic disorders [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	From the biological point of view, it is interesting that the PN approach models, for the first time, the experimentally well-known insulin stimulated degradation of IR [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] which plays a fundamental role in the insulin resistance and metabolic disorders [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	21	89	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	24	25	28	29
Finally , we found that dominant negative Rab8A and Rab10 mutants impaired insulin induced intracellular signaling of the IR/PI3K/Akt axis , suggesting that these GTPase proteins as well as the LRP1 level at the cell surface are involved in insulin induced IR activation .	Finally, we found that dominant negative Rab8A and Rab10 mutants impaired insulin induced intracellular signaling of the IR/PI3K/Akt axis, suggesting that these GTPase proteins as well as the LRP1 level at the cell surface are involved in insulin induced IR activation.	37	42	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	39	40	41	42
In a similar protocol ( 1 mg/kg , b.w ., for 5 days ) , DEX treatment provoked a decrease in insulin induced insulin receptor and insulin receptor substrate ( IRS ) -1 tyrosine phosphorylation in the liver of rats .	In a similar protocol (1 mg/kg, b.w., for 5 days), DEX treatment provoked a decrease in insulin induced insulin receptor and insulin receptor substrate (IRS) -1 tyrosine phosphorylation in the liver of rats.	19	25	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	21	22	23	25
Moreover , in these cells , insulin decreases IR biosynthesis by approximately 50 % .	Moreover, in these cells, insulin decreases IR biosynthesis by approximately 50%.	6	9	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	6	7	8	9
XREF_BIBR - XREF_BIBR There is also evidence that MBF and insulin stimulated glucose uptake in adipose tissue is reduced in IR states .	XREF_BIBR - XREF_BIBR There is also evidence that MBF and insulin stimulated glucose uptake in adipose tissue is reduced in IR states.	8	21	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	10	11	20	21
Insulin induced activation of IR , IRS-1 , IRS-1-PI3K coupling , phosphorylation of Akt , and GLUT4 translocation were attenuated in skeletal muscles of HFD animals .	Insulin induced activation of IR, IRS-1, IRS-1-PI3K coupling, phosphorylation of Akt, and GLUT4 translocation were attenuated in skeletal muscles of HFD animals.	0	17	induced	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	IR	IR	IR	0	1	4	5
Insulin decreased the Km of the insulin receptor for progesterone receptor subunits as substrates , but had no significant effect on Vmax values .	Insulin decreased the Km of the insulin receptor for progesterone receptor subunits as substrates, but had no significant effect on Vmax values.	0	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	6	8
In contrast , Type 2 diabetes models are associated with insulin resistance and down-regulation of insulin receptor signaling [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In contrast, Type 2 diabetes models are associated with insulin resistance and down-regulation of insulin receptor signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR].	10	17	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	10	11	15	17
Insulin-resistance induced by TNF-alpha was shown to be associated with increased GM3 and reduced insulin receptor accumulation in detergent resistant membrane microdomains , together with uncoupling of insulin receptor-IRS-1 signaling , Correspondingly , chemical inhibition of GM3 restores insulin responsiveness in leptin deficient , insulin resistant states .	Insulin-resistance induced by TNF-alpha was shown to be associated with increased GM3 and reduced insulin receptor accumulation in detergent resistant membrane microdomains, together with uncoupling of insulin receptor-IRS-1 signaling, Correspondingly, chemical inhibition of GM3 restores insulin responsiveness in leptin deficient, insulin resistant states.	14	46	restores	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	44	45	14	16
Sustained insulin delivery that did not normalize glycemia but significantly reduced blood glucose from onset of diabetes did prevent the insulin receptor activation by ex vivo insulin stimulation ( XREF_FIG ) in hippocampus from diabetic rats .	Sustained insulin delivery that did not normalize glycemia but significantly reduced blood glucose from onset of diabetes did prevent the insulin receptor activation by ex vivo insulin stimulation (XREF_FIG) in hippocampus from diabetic rats.	1	22	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	20	22
In obese humans , insulin resistance is accompanied by elevated levels of plasma cell membrane glycoprotein ( PC-1 ) and decreased insulin receptor ( IR ) tyrosine kinase activity in skeletal muscle .	In obese humans, insulin resistance is accompanied by elevated levels of plasma cell membrane glycoprotein (PC-1) and decreased insulin receptor (IR) tyrosine kinase activity in skeletal muscle.	4	23	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	4	5	21	23
It is also possible that high adiponectin levels may have attenuated the systemic insulin resistance of IR exposed offspring .	It is also possible that high adiponectin levels may have attenuated the systemic insulin resistance of IR exposed offspring.	13	18	resistance	Negative_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	13	14	16	17
Importantly , the insulin stimulated IR degradation to large extend could be rescued by inhibition of lysosomal activity confirming that the lysosomal pathway is a major route of receptor degradation ( XREF_SUPPLEMENTARY ) .	Importantly, the insulin stimulated IR degradation to large extend could be rescued by inhibition of lysosomal activity confirming that the lysosomal pathway is a major route of receptor degradation (XREF_SUPPLEMENTARY).	2	9	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	3	4	5	6
Together , these results suggest that IR degradation , caused by high levels of insulin , drives early podocyte insulin resistance , and that both the IR and nephrin are required for full insulin sensitivity of this cell .	Together, these results suggest that IR degradation, caused by high levels of insulin, drives early podocyte insulin resistance, and that both the IR and nephrin are required for full insulin sensitivity of this cell.	6	16	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	levels of insulin	insulin	IR	IR	ir	14	15	6	7
Grb14 is an effector of insulin signaling , which directly inhibits insulin receptor catalytic activity in vitro .	Grb14 is an effector of insulin signaling, which directly inhibits insulin receptor catalytic activity in vitro.	5	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	11	13
The decreased activation of insulin receptor caused by insulin resistance results in a decreased phosphorylation of GSK3 , turning it more active .	The decreased activation of insulin receptor caused by insulin resistance results in a decreased phosphorylation of GSK3, turning it more active.	4	9	caused	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	4	6
Transcript levels of the gluconeogenic enzyme PEPCK were significantly increased in cAMP and DEXA stimulated hPTC cells ( n = 3 , P < 0.05 ) , and insulin attenuated this upregulation Furthermore , the effect of insulin on cAMP and DEXA induced gluconeogenesis and PEPCK induction was significantly attenuated in IR ( siRNA ) silenced hPTC ( n = 3 , P < 0.05 ) .	Transcript levels of the gluconeogenic enzyme PEPCK were significantly increased in cAMP and DEXA stimulated hPTC cells (n = 3, P < 0.05), and insulin attenuated this upregulation Furthermore, the effect of insulin on cAMP and DEXA induced gluconeogenesis and PEPCK induction was significantly attenuated in IR (siRNA) silenced hPTC (n = 3, P < 0.05).	35	53	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	37	38	51	52
These data demonstrate that after unilateral nephrectomy there is a decrease in insulin induced insulin receptor and IRS-1 tyrosine phosphorylation levels in kidney but not in liver and muscle .	These data demonstrate that after unilateral nephrectomy there is a decrease in insulin induced insulin receptor and IRS-1 tyrosine phosphorylation levels in kidney but not in liver and muscle.	10	16	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	14	16
It has been characterized that insulin degrading enzyme ( IDE ) , which degrades both insulin and Abeta , is up-regulated by insulin receptor signaling , XREF_BIBR , XREF_BIBR but degradation of insulin subsequently down-regulates insulin receptor signaling , serving as a negative feedback mechanism on IDE .	It has been characterized that insulin degrading enzyme (IDE), which degrades both insulin and Abeta, is up-regulated by insulin receptor signaling, XREF_BIBR, XREF_BIBR but degradation of insulin subsequently down-regulates insulin receptor signaling, serving as a negative feedback mechanism on IDE.	26	37	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	32	33	35	37
Increases in episodic basal and post-prandial insulin secretion initiated by these environmental shifts gradually lead to insulin receptor insensitivity , insulin resistance and diminished downstream insulin receptor signaling in target cells .	Increases in episodic basal and post-prandial insulin secretion initiated by these environmental shifts gradually lead to insulin receptor insensitivity, insulin resistance and diminished downstream insulin receptor signaling in target cells.	3	27	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	25	27
Studying AR42J pancreatic acinar cells , we also found that insulin accelerates IR degradation .	Studying AR42J pancreatic acinar cells, we also found that insulin accelerates IR degradation.	10	13	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	10	11	12	13
Rosiglitazone in insulin resistant PCOS promoted ovulation and dose-dependently decreased IR and insulinaemia ; ovulators had lower circulating insulin and testosterone .	Rosiglitazone in insulin resistant PCOS promoted ovulation and dose-dependently decreased IR and insulinaemia; ovulators had lower circulating insulin and testosterone.	2	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	2	3	10	11
Insulin resistance expressed in Psammomys at stages B and C was demonstrated by nonsuppression of the hepatic gluconeogenesis enzyme phosphoenolpyruvate carboxykinase by the endogenous hyperinsulinemia and by the reduced capacity of insulin to activate muscle and liver tyrosine kinase of the insulin receptor .	Insulin resistance expressed in Psammomys at stages B and C was demonstrated by nonsuppression of the hepatic gluconeogenesis enzyme phosphoenolpyruvate carboxykinase by the endogenous hyperinsulinemia and by the reduced capacity of insulin to activate muscle and liver tyrosine kinase of the insulin receptor.	0	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	41	43
Constant insulin delivery that normalized blood glucose for 8 weeks of diabetes significantly prevented activation of insulin receptor by ex vivo insulin at 0.1 nM ( # # p < 0.01 ) ( XREF_FIG ) .	Constant insulin delivery that normalized blood glucose for 8 weeks of diabetes significantly prevented activation of insulin receptor by ex vivo insulin at 0.1 nM (## p < 0.01) (XREF_FIG).	1	18	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	1	2	16	18
IR down-regulation and synaptic loss are markedly decreased by insulin treatment .	IR down-regulation and synaptic loss are markedly decreased by insulin treatment.	0	10	decreased	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	9	10	0	1
Agpat2 -/- mice developed a severe whole body insulin resistance and reduced expression of IR , IRS-1 and IRS-2 might be responsible for hepatic insulin resistance in the Agpat2 -/- mice ; a finding that is consistent with previous observations , The observed islet hypertrophy is likely a compensatory phenomenon in response to severe insulin resistance .	Agpat2 -/- mice developed a severe whole body insulin resistance and reduced expression of IR, IRS-1 and IRS-2 might be responsible for hepatic insulin resistance in the Agpat2 -/- mice; a finding that is consistent with previous observations, The observed islet hypertrophy is likely a compensatory phenomenon in response to severe insulin resistance.	8	18	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	8	9	14	15
SRSF1 knockdown reduced INSR exon 11 inclusion in MIN6 cells under normal serum condition and completely abolished INSR exon 11 inclusion following insulin stimulation , suggesting that indeed SRSF1 mediates insulin induced INSR exon 11 inclusion ( XREF_FIG ) .	SRSF1 knockdown reduced INSR exon 11 inclusion in MIN6 cells under normal serum condition and completely abolished INSR exon 11 inclusion following insulin stimulation, suggesting that indeed SRSF1 mediates insulin induced INSR exon 11 inclusion (XREF_FIG).	29	33	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	30	31	32	33
Decrease in the protein levels of insulin signaling molecules insulin receptor ( IR ) , IR substrate ( IRS )-1, IRS-2 and phosphatidylinositol-3-kinase were observed with parallel increase in H ( 2 ) O ( 2 ) levels in the liver of NP treated rats .	Decrease in the protein levels of insulin signaling molecules insulin receptor (IR), IR substrate (IRS)-1, IRS-2 and phosphatidylinositol-3-kinase were observed with parallel increase in H (2) O (2) levels in the liver of NP treated rats.	4	11	signaling	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	levels of insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	9	11
Furthermore , insulin sensitivity in peripheral tissues may be reduced , resulting in IR .	Furthermore, insulin sensitivity in peripheral tissues may be reduced, resulting in IR.	2	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	2	3	13	14
Furthermore , it is widely known that normal levels of insulin inhibit G6Pase and PEPCK gene transcription and overexpression of these enzymes is a consequence of IR XREF_BIBR .	Furthermore, it is widely known that normal levels of insulin inhibit G6Pase and PEPCK gene transcription and overexpression of these enzymes is a consequence of IR XREF_BIBR.	8	27	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	levels of insulin	insulin	IR	IR	ir	10	11	26	27
Impaired insulin signaling was also evident with respect to insulin stimulated tyrosyl phosphorylation of insulin receptor substrate-1 ( IRS-1 ) ( XREF_FIG ) , a molecule that normally transmits the downstream signals of the insulin activated IR .	Impaired insulin signaling was also evident with respect to insulin stimulated tyrosyl phosphorylation of insulin receptor substrate-1 (IRS-1) (XREF_FIG), a molecule that normally transmits the downstream signals of the insulin activated IR.	31	37	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	34	35	36	37
Fetuin inhibits insulin induced insulin receptor ( IR ) autophosphorylation and tyrosine kinase activity in vitro , in intact cells , and in vivo .	Fetuin inhibits insulin induced insulin receptor (IR) autophosphorylation and tyrosine kinase activity in vitro, in intact cells, and in vivo.	1	6	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	4	6
Inhibition of HIF activity restores insulin stimulation of the insulin receptor .	Inhibition of HIF activity restores insulin stimulation of the insulin receptor.	5	11	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	5	6	9	11
GDM women had decreased skeletal muscle insulin stimulated insulin receptor and insulin receptor substrate 1 ( IRS1 ) tyrosine activation and reduced IRS1 , concomitant with increased basal IRS1 serine phosphorylation and basal p70 S6-kinase ( S6K1 ) activation , which resolved postpartum .	GDM women had decreased skeletal muscle insulin stimulated insulin receptor and insulin receptor substrate 1 (IRS1) tyrosine activation and reduced IRS1, concomitant with increased basal IRS1 serine phosphorylation and basal p70 S6-kinase (S6K1) activation, which resolved postpartum.	3	10	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	8	10
HF diet consumption also caused impaired insulin induced long-term depression in hippocampus and impaired neuronal insulin receptor function and signaling , indicating neuronal insulin resistance , in both male and female rats .	HF diet consumption also caused impaired insulin induced long-term depression in hippocampus and impaired neuronal insulin receptor function and signaling, indicating neuronal insulin resistance, in both male and female rats.	5	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	6	7	15	17
In both HTC-IR and HTC-IR/M -1030 cells , insulin enhanced insulin receptor degradation .	In both HTC-IR and HTC-IR/M -1030 cells, insulin enhanced insulin receptor degradation.	8	12	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	10	12
By contrast , pretreatment with the beta ( 3 )-adrenoceptor agonist inhibited the insulin induced insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity by 50 % and protein kinase B phosphorylation by 40 % without affecting insulin receptor kinase activity upstream .	By contrast, pretreatment with the beta (3)-adrenoceptor agonist inhibited the insulin induced insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity by 50% and protein kinase B phosphorylation by 40% without affecting insulin receptor kinase activity upstream.	12	17	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	13	14	15	17
Additional genetic epistasis analysis indicated that INS-1 and insulin genetically inhibits the DAF-2 and insulin receptor through a negative regulation of INS-6 and insulin ( XREF_FIG , XREF_SUPPLEMENTARY ) XREF_BIBR XREF_BIBR .	Additional genetic epistasis analysis indicated that INS-1 and insulin genetically inhibits the DAF-2 and insulin receptor through a negative regulation of INS-6 and insulin (XREF_FIG, XREF_SUPPLEMENTARY) XREF_BIBR XREF_BIBR.	6	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	14	16
As compared to untransfected cells , a progressive increase of ENPP1 inhibitory activity on insulin induced IR beta-subunit autophosphorylation and on Akt-S ( 473 ) phosphorylation was observed in ENPP1-3 ' myc , ENPP1-DeltaI-3 ' myc and ENPP1-DeltaII-3 ' myc cells .	As compared to untransfected cells, a progressive increase of ENPP1 inhibitory activity on insulin induced IR beta-subunit autophosphorylation and on Akt-S (473) phosphorylation was observed in ENPP1-3 ' myc, ENPP1-DeltaI-3 ' myc and ENPP1-DeltaII-3 ' myc cells.	12	17	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	14	15	16	17
The ectoenzyme ENPP1 ( also termed membrane glycoprotein PC-1 or ENPP1 and PC-1 ) is an inhibitor of insulin induced activation of the insulin receptor .	The ectoenzyme ENPP1 (also termed membrane glycoprotein PC-1 or ENPP1/PC-1) is an inhibitor of insulin induced activation of the insulin receptor.	16	25	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	18	19	23	25
The Petri net approach confirms the experimental results of insulin stimulated degradation of the insulin receptor , which represents a common feature of insulin resistant , hyperinsulinaemic states .	The Petri net approach confirms the experimental results of insulin stimulated degradation of the insulin receptor, which represents a common feature of insulin resistant, hyperinsulinaemic states.	7	27	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	14	16
In addition , HFD ( high-fat diet ) induction of peripheral insulin resistance in an AD transgenic mouse model reduced brain insulin and insulin receptor signalling , and increased AD pathology [ XREF_BIBR ] .	In addition, HFD (high-fat diet) induction of peripheral insulin resistance in an AD transgenic mouse model reduced brain insulin and insulin receptor signalling, and increased AD pathology [XREF_BIBR].	11	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	11	12	23	25
Moreover , heightened local IR caused by impaired insulin signaling has been observed in the placentae of GDM compared with the control group .	Moreover, heightened local IR caused by impaired insulin signaling has been observed in the placentae of GDM compared with the control group.	2	12	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	8	9	4	5
However , after 1 year of follow-up , liraglutide did not affect the serum concentration of anti-insulin antibodies ; spontaneous remission of type B insulin resistance syndrome reversed the insulin receptor signaling and partially improved the glucose profile .	However, after 1 year of follow-up, liraglutide did not affect the serum concentration of anti-insulin antibodies; spontaneous remission of type B insulin resistance syndrome reversed the insulin receptor signaling and partially improved the glucose profile.	20	34	reversed	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	24	25	29	31
Slow dissociating , high affinity insulin analogs induce sustained activation of IR , and this is associated with increased receptor internalization , Shc phosphorylation and ERK activation that may reflect signaling from intracellular sites .	Slow dissociating, high affinity insulin analogs induce sustained activation of IR, and this is associated with increased receptor internalization, Shc phosphorylation and ERK activation that may reflect signaling from intracellular sites.	5	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	5	6	11	12
The reduction in AMPKalpha did not impair basal and insulin stimulated insulin receptor signaling ( data not shown ) or signaling to Akt2 Ser474 in any of the treatment groups ( XREF_FIG ) .	The reduction in AMPKalpha did not impair basal and insulin stimulated insulin receptor signaling (data not shown) or signaling to Akt2 Ser474 in any of the treatment groups (XREF_FIG).	9	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	11	13
However , hypertension ( high blood pressure ) occurs in IR , increases fluid volume , arterial stiffness , and even impaired insulin handling , leading to narrowed lumen diameter , which contributes to the development of atherosclerosis .	However, hypertension (high blood pressure) occurs in IR, increases fluid volume, arterial stiffness, and even impaired insulin handling, leading to narrowed lumen diameter, which contributes to the development of atherosclerosis.	8	23	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	22	23	10	11
However , rhGH decreased VAT , increased lean mass , and increased insulin resistance , while Rosi increased limb fat content , decreased IR and abrogated the adverse effects of rhGH on IR as seen in the parent study .	However, rhGH decreased VAT, increased lean mass, and increased insulin resistance, while Rosi increased limb fat content, decreased IR and abrogated the adverse effects of rhGH on IR as seen in the parent study.	12	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	12	13	23	24
These studies indicate , therefore , that in cells expressing kinase defective insulin receptors , insulin down-regulates insulin receptor number via enhanced receptor degradation , and up-regulates receptor affinity .	These studies indicate, therefore, that in cells expressing kinase defective insulin receptors, insulin down-regulates insulin receptor number via enhanced receptor degradation, and up-regulates receptor affinity.	15	26	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	15	16	17	19
miR-21 reverses high glucose and high insulin induced IR in 3T3-L1 adipocytes through targeting phosphatase and tensin homologue [ XREF_BIBR ] .	miR-21 reverses high glucose and high insulin induced IR in 3T3-L1 adipocytes through targeting phosphatase and tensin homologue [XREF_BIBR].	3	11	induced	Positive_early_activation	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	6	7	8	9
When we analyzed hepatic insulin signaling after administration of insulin in the portal vein , we detected an attenuation of insulin induced InsR , Akt ( S473 ) , and FoxO1 ( S256 ) phosphorylation ( XREF_FIG , XREF_SUPPLEMENTARY ) .	When we analyzed hepatic insulin signaling after administration of insulin in the portal vein, we detected an attenuation of insulin induced InsR, Akt (S473), and FoxO1 (S256) phosphorylation (XREF_FIG, XREF_SUPPLEMENTARY).	18	30	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	InsR	InsR	InsR	20	21	22	23
From these results , it can be concluded that the onset of glucose stimulated insulin secretion appears in fetal rats on D20 of gestation and the elevation of endogeneous insulin rapidly down-regulates the number of hepatic insulin receptor in fetal rats .	From these results, it can be concluded that the onset of glucose stimulated insulin secretion appears in fetal rats on D20 of gestation and the elevation of endogeneous insulin rapidly down-regulates the number of hepatic insulin receptor in fetal rats.	26	38	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	29	30	36	38
Such impaired interactions abolish the ability of IRS-1 and IRS-2 to undergo insulin induced Tyr phosphorylation and further propagate the insulin receptor signal .	Such impaired interactions abolish the ability of IRS-1 and IRS-2 to undergo insulin induced Tyr phosphorylation and further propagate the insulin receptor signal.	11	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	20	22
In HepG2 cells , pre-treatment with PANDER ranging from 4 pM to 4 nM for 8h resulted in a maximal inhibition of insulin stimulated activation of insulin receptor and insulin receptor substrate 1 by 52 % and 63 % , respectively .	In HepG2 cells, pre-treatment with PANDER ranging from 4 pM to 4 nM for 8h resulted in a maximal inhibition of insulin stimulated activation of insulin receptor and insulin receptor substrate 1 by 52% and 63%, respectively.	20	28	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	22	23	26	28
Inhibiting or blocking this pathway may reduce the physiological effects of insulin , which lead to IR .	Inhibiting or blocking this pathway may reduce the physiological effects of insulin, which lead to IR.	9	17	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	11	12	16	17
Type C insulin resistance in insulin receptor mutations is characterized by normal insulin binding to cultured fibroblasts or EB virus transformed lymphocytes from the patients and decreased insulin receptor kinase activities .	Type C insulin resistance in insulin receptor mutations is characterized by normal insulin binding to cultured fibroblasts or EB virus transformed lymphocytes from the patients and decreased insulin receptor kinase activities.	2	30	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	2	3	27	29
Deficiencies in glucose clearance might result from peripheral insulin resistance that diminishes insulin receptor activation in multiple tissues , resulting in reduction in insulin signaling cascades and insulin dependent actions , such as transporting glucose into the cells via glucose transporters .	Deficiencies in glucose clearance might result from peripheral insulin resistance that diminishes insulin receptor activation in multiple tissues, resulting in reduction in insulin signaling cascades and insulin dependent actions, such as transporting glucose into the cells via glucose transporters.	8	14	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	8	9	12	14
1 However , EP pills do not treat IR or components of the metabolic syndrome 5 and are instead associated with glucose intolerance , decreased insulin sensitivity , abnormal lipid profiles and CV disease .	1 However, EP pills do not treat IR or components of the metabolic syndrome 5 and are instead associated with glucose intolerance, decreased insulin sensitivity, abnormal lipid profiles and CV disease.	7	26	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	25	26	8	9
11 They demonstrated , both in vivo and in vitro , that AII could phosphorylate serine , instead of tyrosine , to inhibit the association between insulin stimulated insulin receptor substrates and phosphatidylinositol ( PI ) 3-kinase .	11 They demonstrated, both in vivo and in vitro, that AII could phosphorylate serine, instead of tyrosine, to inhibit the association between insulin stimulated insulin receptor substrates and phosphatidylinositol (PI) 3-kinase.	24	30	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	26	27	28	30
Decreasing or blocking this pathway can reduce the physiological effects of insulin , which may lead to IR .	Decreasing or blocking this pathway can reduce the physiological effects of insulin, which may lead to IR.	9	18	lead	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IR	IR	IR	11	12	17	18
Insulin internalization rate was reduced , insulin receptor beta-subunit ( IRbeta ) expression was decreased at the plasma membrane and increased in the Golgi apparatus , and a significant reduction in insulin gene expression was detected .	Insulin internalization rate was reduced, insulin receptor beta-subunit (IRbeta) expression was decreased at the plasma membrane and increased in the Golgi apparatus, and a significant reduction in insulin gene expression was detected.	0	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	insulin receptor	insulin receptor	insulin receptor	0	1	6	8
Additionally 3T3-L1 adipocytes exposed to exogenous MIF demonstrated impaired insulin stimulated glucose uptake and insulin receptor signal transduction .	Additionally 3T3-L1 adipocytes exposed to exogenous MIF demonstrated impaired insulin stimulated glucose uptake and insulin receptor signal transduction.	7	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	9	10	14	16
We also show that over-expression of ENPP1 in transfected 3T3-L1 cells will affect maturation process in association with decreased insulin mediated activation of insulin receptor and with insulin mediated glucose uptake .	We also show that over-expression of ENPP1 in transfected 3T3-L1 cells will affect maturation process in association with decreased insulin mediated activation of insulin receptor and with insulin mediated glucose uptake.	19	25	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	19	20	23	25
Blocking MEK1-ERK signaling pharmacologically inhibits insulin induction of SRSF1 and inclusion of INSR exon 11 ( XREF_FIG ) .	Blocking MEK1-ERK signaling pharmacologically inhibits insulin induction of SRSF1 and inclusion of INSR exon 11 (XREF_FIG).	5	13	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	insulin	insulin	insulin	INSR	INSR	INSR	5	6	12	13
Overall , our data suggest a central role for omental GLUT4 in the pathogenesis of IR and ultimately diabetes , such that a reduction of insulin stimulated glucose transport in omental adipocytes could secondarily induce IR in other insulin target tissues .	Overall, our data suggest a central role for omental GLUT4 in the pathogenesis of IR and ultimately diabetes, such that a reduction of insulin stimulated glucose transport in omental adipocytes could secondarily induce IR in other insulin target tissues.	23	36	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	25	26	35	36
We suggest that insulin aggregates which may have blocked insulin receptor sites , causing insulin resistance , were removed by haemodialysis .	We suggest that insulin aggregates which may have blocked insulin receptor sites, causing insulin resistance, were removed by haemodialysis.	3	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	3	4	9	11
The results of these experiments thus indicate that ( 1 ) endogenous Gsk-3beta activity contributes to ambient insulin sensitivity , and ( 2 ) that Gsk-3beta activity is a downstream mediator of the insulin resistance of the Ir +/- mice .	The results of these experiments thus indicate that (1) endogenous Gsk-3beta activity contributes to ambient insulin sensitivity, and (2) that Gsk-3beta activity is a downstream mediator of the insulin resistance of the Ir +/- mice.	33	39	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	Ir	Ir	Ir	33	34	37	38
In line with this , insulin failed to suppress INSR mRNA in the absence of HMGA1 , as observed in primary cultured hepatocytes from HMGA1-null mice ( XREF_FIG ) , and no changes on INSR mRNA levels were observed in insulin treated HEK-293 cells overexpressing single ( HMGA1am-Ser ) or triple ( HMGA1am ) HMGA1 protein mutants ( XREF_FIG ) .	In line with this, insulin failed to suppress INSR mRNA in the absence of HMGA1, as observed in primary cultured hepatocytes from HMGA1-null mice (XREF_FIG), and no changes on INSR mRNA levels were observed in insulin treated HEK-293 cells overexpressing single (HMGA1am-Ser) or triple (HMGA1am) HMGA1 protein mutants (XREF_FIG).	5	10	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	INSR	INSR	INSR	5	6	9	10
Metformin , an insulin sensitizer , reduces IR , hyperinsulinaemia and androgen levels in PCOS , but is not as effective as EP at restoring menstrual cyclicity .	Metformin, an insulin sensitizer, reduces IR, hyperinsulinaemia and androgen levels in PCOS, but is not as effective as EP at restoring menstrual cyclicity.	3	12	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	3	4	7	8
In septic animals , insulin resistance was accompanied by a reduction in insulin induced IR , IRS-1 tyrosine phosphorylation and in insulin induced Akt phosphorylation , in liver , muscle and adipose tissue .	In septic animals, insulin resistance was accompanied by a reduction in insulin induced IR, IRS-1 tyrosine phosphorylation and in insulin induced Akt phosphorylation, in liver, muscle and adipose tissue.	10	32	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	12	13	14	15
The insulin resistant response of glucose transport in T2D is also evident within the volume of distribution parameters for [ 11 C ] 3-OMG ( XREF_TABLE ) , which reveals that although there was evidence of soleus response to insulin in T2D compared with basal conditions , the amplitude of this response was attenuated in T2D , indicating that impaired insulin stimulation of glucose transport contributes strongly to muscle IR .	The insulin resistant response of glucose transport in T2D is also evident within the volume of distribution parameters for [11 C] 3-OMG (XREF_TABLE), which reveals that although there was evidence of soleus response to insulin in T2D compared with basal conditions, the amplitude of this response was attenuated in T2D, indicating that impaired insulin stimulation of glucose transport contributes strongly to muscle IR.	60	70	contributes	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IR	IR	IR	60	61	69	70
At the molecular level , insulin resistance is characterized by an impaired insulin activated insulin receptor and insulin receptor substrate and phosphoinositide 3-kinase/protein kinase B ( IR/IRS-PI 3K-Akt ) pathway , the major player in the metabolic action of insulin , which leads to suppressed insulin induced glucose uptake in insulin sensitive organs , including the heart [ XREF_BIBR , XREF_BIBR ] .	At the molecular level, insulin resistance is characterized by an impaired insulin activated insulin receptor and insulin receptor substrate and phosphoinositide 3-kinase/protein kinase B (IR/IRS-PI 3K-Akt) pathway, the major player in the metabolic action of insulin, which leads to suppressed insulin induced glucose uptake in insulin sensitive organs, including the heart [XREF_BIBR, XREF_BIBR].	8	16	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	insulin receptor	insulin receptor	insulin receptor	12	13	14	16
Finally , acting on lipid metabolism favoring the passage of fatty acids into cells , insulin stimulates the synthesis of fatty acids from glucose and amino acid in excess and inhibits lipolysis by stimulating lipoprotein lipase ( LPL ) and hormone inhibiting lipase sensitive ( HSL ) and therefore , in conclusion , would support the use of fatty acids for energy .	Finally, acting on lipid metabolism favoring the passage of fatty acids into cells, insulin stimulates the synthesis of fatty acids from glucose and amino acid in excess and inhibits lipolysis by stimulating lipoprotein lipase (LPL) and hormone inhibiting lipase sensitive (HSL) and therefore, in conclusion, would support the use of fatty acids for energy.	15	54	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	15	16	34	36
Conversely , decreased insulin responses to fructose consumption lead to decreased insulin mediated LPL activity in SAT , allowing for greater TG uptake by VAT ( XREF_FIG ) .	Conversely, decreased insulin responses to fructose consumption lead to decreased insulin mediated LPL activity in SAT, allowing for greater TG uptake by VAT (XREF_FIG).	2	14	mediated	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	11	12	13	14
Both insulin deprivation and insulin resistance attenuate the activity of lipoprotein lipase , a key enzyme in the removal and degradation of triglycerides from circulation [ XREF_BIBR ] .	Both insulin deprivation and insulin resistance attenuate the activity of lipoprotein lipase, a key enzyme in the removal and degradation of triglycerides from circulation [XREF_BIBR].	1	12	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	1	2	10	12
For example , insulin deficiency decreases the lipoprotein lipase activity increasing blood triacylglycerol [ XREF_BIBR ] .	For example, insulin deficiency decreases the lipoprotein lipase activity increasing blood triacylglycerol [XREF_BIBR].	3	9	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	7	9
These results suggest the possibility that early insulin resistance in the obese young men may have caused the decrease of lipoprotein lipase activity and induced delayed TRL metabolism .	These results suggest the possibility that early insulin resistance in the obese young men may have caused the decrease of lipoprotein lipase activity and induced delayed TRL metabolism.	7	22	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	7	8	20	22
Insulin resistance cause impaired glycogen synthesis and protein catabolism in skeletal muscles and inhibit lipoprotein lipase activity in adipocytes leading to an increased release of free fatty acids and inflammatory cytokines such as IL-6 , TNFalpha , and leptin .	Insulin resistance cause impaired glycogen synthesis and protein catabolism in skeletal muscles and inhibit lipoprotein lipase activity in adipocytes leading to an increased release of free fatty acids and inflammatory cytokines such as IL-6, TNFalpha, and leptin.	0	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	14	16
Lipoprotein lipase ( LpL ) is suppressed by insulin , and therefore in insulin deficiency states , lipolysis increases even in a high-glucose environment .	Lipoprotein lipase (LpL) is suppressed by insulin, and therefore in insulin deficiency states, lipolysis increases even in a high-glucose environment.	0	9	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Lipoprotein lipase	Lipoprotein lipase	Lipoprotein lipase	8	9	0	2
From these results , the authors tentatively concluded that the main cause of pancreatectomy induced hyperlipemia was a delay in the removal of lipids from the blood , due to decreased LPL activity caused by a lack of insulin .	From these results, the authors tentatively concluded that the main cause of pancreatectomy induced hyperlipemia was a delay in the removal of lipids from the blood, due to decreased LPL activity caused by a lack of insulin.	31	39	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	38	39	31	32
Relative insulin deficiency also decreases the activity of lipoprotein lipase ( LPL ) , the rate limiting enzyme of the catabolism of TG rich lipoproteins such as CM , VLDL and IDL [ XREF_BIBR ] .	Relative insulin deficiency also decreases the activity of lipoprotein lipase (LPL), the rate limiting enzyme of the catabolism of TG rich lipoproteins such as CM, VLDL and IDL [XREF_BIBR].	1	10	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	1	2	8	10
Smooth muscle LPL is modestly down-regulated by insulin in normal weight insulin responsive individuals , but is unaffected in insulin resistant obese or type 2 diabetic individuals [ XREF_BIBR , XREF_BIBR ] .	Smooth muscle LPL is modestly down-regulated by insulin in normal weight insulin responsive individuals, but is unaffected in insulin resistant obese or type 2 diabetic individuals [XREF_BIBR, XREF_BIBR].	0	17	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	7	8	2	3
The results suggest that insulin does not exert a direct effect on the LPL secretion by macrophages but that deficiency of insulin indirectly causes a profound decrease in macrophage LPL secretion .	The results suggest that insulin does not exert a direct effect on the LPL secretion by macrophages but that deficiency of insulin indirectly causes a profound decrease in macrophage LPL secretion.	19	30	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	21	22	29	30
XREF_BIBR Decreased insulin sensitivity ( regulated by human placental lactogen , cortisol and sex steroids ) , reduced adipose tissue LPL sensitivity , increased activity of hormone sensitive lipase and enhanced amounts of free fatty acids in circulation are associated with hyperlipidaemia in late pregnancy .	XREF_BIBR Decreased insulin sensitivity (regulated by human placental lactogen, cortisol and sex steroids), reduced adipose tissue LPL sensitivity, increased activity of hormone sensitive lipase and enhanced amounts of free fatty acids in circulation are associated with hyperlipidaemia in late pregnancy.	2	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	2	3	20	21
The relative insulin deficiency that occurs in type 2 diabetes impairs the action of lipoprotein lipase and results in lower HDL-C levels and higher TG levels , which may improve with improved glycemic control [ XREF_BIBR ] .	The relative insulin deficiency that occurs in type 2 diabetes impairs the action of lipoprotein lipase and results in lower HDL-C levels and higher TG levels, which may improve with improved glycemic control [XREF_BIBR].	2	16	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	14	16
Insulin resistance could also decrease HDL-cholesterol by blunting the stimulation of lipoprotein lipase activity , increasing triglyceride-enrichment of HDL and increasing hepatic lipase activity [ XREF_BIBR - XREF_BIBR ] .	Insulin resistance could also decrease HDL-cholesterol by blunting the stimulation of lipoprotein lipase activity, increasing triglyceride-enrichment of HDL and increasing hepatic lipase activity [XREF_BIBR - XREF_BIBR].	0	13	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	11	13
Increased insulin resistance causes inhibition of lipoprotein lipase of peripheral tissues XREF_BIBR , XREF_BIBR .	Increased insulin resistance causes inhibition of lipoprotein lipase of peripheral tissues XREF_BIBR, XREF_BIBR.	1	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	1	2	6	8
Chronic ( 12-day ) insulin treatment of SHR-diabetic rats reduced the augmented heparin-releasable LPL activity and increased cell associated LPL activity .	Chronic (12-day) insulin treatment of SHR-diabetic rats reduced the augmented heparin-releasable LPL activity and increased cell associated LPL activity.	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	LPL	LPL	LPL	4	5	19	20
Insulin injection to the hypertriglyceridemic rabbits induced a significant recovery of the decreased plasma LPL activity with a concomitant decrease of plasma triglyceride levels , while abeyance of insulin injection resulted in a decrease of LPL activity again .	Insulin injection to the hypertriglyceridemic rabbits induced a significant recovery of the decreased plasma LPL activity with a concomitant decrease of plasma triglyceride levels, while abeyance of insulin injection resulted in a decrease of LPL activity again.	0	15	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	LPL	LPL	LPL	0	1	14	15
For instance , the decreased insulin release with oral fructose leads to decreased insulin stimulated upregulation of lipoprotein lipase in visceral adipose tissue .	For instance, the decreased insulin release with oral fructose leads to decreased insulin stimulated upregulation of lipoprotein lipase in visceral adipose tissue.	10	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	13	14	17	19
An increased plasma non esterified fatty acid concentration , probably due to a salt restriction related insulin resistance , may have impaired the activity of the enzyme lipoprotein lipase .	An increased plasma non esterified fatty acid concentration, probably due to a salt restriction related insulin resistance, may have impaired the activity of the enzyme lipoprotein lipase.	16	29	impaired	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	16	17	27	29
In the present study , we observed that postprandial triglyceride concentrations in KPDM remained elevated , suggesting delayed clearance of exogenous triglyceride rich lipoproteins , which may result from reduced lipoprotein lipase activity driven by insulin resistance XREF_BIBR .	In the present study, we observed that postprandial triglyceride concentrations in KPDM remained elevated, suggesting delayed clearance of exogenous triglyceride rich lipoproteins, which may result from reduced lipoprotein lipase activity driven by insulin resistance XREF_BIBR.	30	37	driven	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	35	36	30	32
During diabetic state , insulin deficiency inactivates the lipoprotein lipase , which promotes liver conversion of free fatty acids into cholesterol and triglyceride and finally discharged into blood causing elevation of serum cholesterol and triglyceride levels .	During diabetic state, insulin deficiency inactivates the lipoprotein lipase, which promotes liver conversion of free fatty acids into cholesterol and triglyceride and finally discharged into blood causing elevation of serum cholesterol and triglyceride levels.	4	10	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	8	10
The action of PKD1 to regulate LPL mediated triglyceride accumulation was discovered in mice treated with diazoxide to decrease insulin secretion and cause hyperglycemia .	The action of PKD1 to regulate LPL mediated triglyceride accumulation was discovered in mice treated with diazoxide to decrease insulin secretion and cause hyperglycemia.	6	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	19	20	6	7
Insulin inhibits adipocyte hormone sensitive lipase and activates lipoprotein lipase [ XREF_BIBR , XREF_BIBR ] .	Insulin inhibits adipocyte hormone sensitive lipase and activates lipoprotein lipase [XREF_BIBR, XREF_BIBR].	0	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	8	10
Thus , insulin resistance did not diminish LPL activity among AA , one explanation for apparent protection from the elevated TG that is associated with insulin resistance [ XREF_BIBR ] .	Thus, insulin resistance did not diminish LPL activity among AA, one explanation for apparent protection from the elevated TG that is associated with insulin resistance [XREF_BIBR].	2	8	diminish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	2	3	7	8
The lower insulin excursion after fructose may result in less activation of adipose tissue lipoprotein lipase , which led to impaired triacylglycerol clearance .	The lower insulin excursion after fructose may result in less activation of adipose tissue lipoprotein lipase, which led to impaired triacylglycerol clearance.	2	16	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	14	16
Lipoprotein catabolic rate is reduced , but the cause of hyperlipidemia is multifactorial ; reduced lipoprotein lipase ( LPL ) activity , increased concentration of apo C-III ( a specific inhibitor of LPL ) in plasma , secondary hyperparathyroidism , insulin resistance .	Lipoprotein catabolic rate is reduced, but the cause of hyperlipidemia is multifactorial; reduced lipoprotein lipase (LPL) activity, increased concentration of apo C-III (a specific inhibitor of LPL) in plasma, secondary hyperparathyroidism, insulin resistance.	22	41	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	40	41	32	33
The underlying insulin resistance may impair the activity of lipoprotein lipase leading to decreased catabolism of triglyceride rich Apo B lipoproteins [ XREF_BIBR ] .	The underlying insulin resistance may impair the activity of lipoprotein lipase leading to decreased catabolism of triglyceride rich Apo B lipoproteins [XREF_BIBR].	2	11	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	9	11
Because insulin resistance also suppresses LPL activity and is an impediment to the catabolism of very low-density lipoprotein ( VLDL ) , production of VLDL in the liver is increased and hyperlipidemia occurs .	Because insulin resistance also suppresses LPL activity and is an impediment to the catabolism of very low-density lipoprotein (VLDL), production of VLDL in the liver is increased and hyperlipidemia occurs.	1	6	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	1	2	5	6
Insulin deficiency diminishes lipoprotein lipase ( LPL ) activity .	Insulin deficiency diminishes lipoprotein lipase (LPL) activity.	0	5	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	3	5
Lipoprotein lipase activity , which hydrolyzes lipoproteins to FFAs and glycerol mainly in the epithelium of capillary beds , is reduced by insulin in skeletal muscle .	Lipoprotein lipase activity, which hydrolyzes lipoproteins to FFAs and glycerol mainly in the epithelium of capillary beds, is reduced by insulin in skeletal muscle.	0	25	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Lipoprotein lipase	Lipoprotein lipase	Lipoprotein lipase	22	23	0	2
Insulin decreases triglycerides by stimulating lipoprotein lipase activity , which degrades triglycerides into fatty acids and glycerol [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Insulin decreases triglycerides by stimulating lipoprotein lipase activity, which degrades triglycerides into fatty acids and glycerol [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	7	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	5	7
Two possible mechanisms explaining the increased level of RLP-TG could be presented , one is the decreased metabolism of TG caused by decreased LPL activity induced by insulin resistance [ XREF_BIBR ] and another is the overproduction of TG .	Two possible mechanisms explaining the increased level of RLP-TG could be presented, one is the decreased metabolism of TG caused by decreased LPL activity induced by insulin resistance [XREF_BIBR] and another is the overproduction of TG.	23	30	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	27	28	23	24
Insulin resistance also decreases lipoprotein lipase activity , a major mediator of VLDL clearance .	Insulin resistance also decreases lipoprotein lipase activity, a major mediator of VLDL clearance.	0	6	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	4	6
XREF_BIBR , XREF_BIBR Furthermore , in blacks insulin resistance does not appear to impair LPL activity , so that even in the presence of insulin resistance blacks can clear triglyceride from the circulation .	XREF_BIBR, XREF_BIBR Furthermore, in blacks insulin resistance does not appear to impair LPL activity, so that even in the presence of insulin resistance blacks can clear triglyceride from the circulation.	7	15	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	7	8	14	15
During pregnancy , synthesis of lipoprotein increases in connection with the rise of strogen concentration , and increased insulin resistance reduces the activity of lipoprotein lipase and , as a result , the concentration of blood triglyceride increases to approximately 2 to 3 times higher than the normal level .	During pregnancy, synthesis of lipoprotein increases in connection with the rise of strogen concentration, and increased insulin resistance reduces the activity of lipoprotein lipase and, as a result, the concentration of blood triglyceride increases to approximately 2 to 3 times higher than the normal level.	18	26	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	18	19	24	26
In addition , increasing insulin resistance with age may contribute to lower lipoprotein lipase ( LPL ) activity , which is a determinant of lower HDL-C , and in concert with hepatic lipase as a determinant of lower levels of cholesterol carried by the larger HDL 2 particles XREF_BIBR .	In addition, increasing insulin resistance with age may contribute to lower lipoprotein lipase (LPL) activity, which is a determinant of lower HDL-C, and in concert with hepatic lipase as a determinant of lower levels of cholesterol carried by the larger HDL 2 particles XREF_BIBR.	4	14	contribute	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	4	5	12	14
Insulin deficiency also causes decreased synthesis of lipoprotein lipase and hence abnormal lipid metabolism .	Insulin deficiency also causes decreased synthesis of lipoprotein lipase and hence abnormal lipid metabolism.	0	9	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	7	9
These results suggest that the decreased LPL activities seen in the tumor bearing state may be mediated by insulin resistance .	These results suggest that the decreased LPL activities seen in the tumor bearing state may be mediated by insulin resistance.	6	19	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	18	19	6	7
Chronically low plasma insulin levels may reduce adipose and muscle lipoprotein lipase activity as well as VLDL receptor number .	Chronically low plasma insulin levels may reduce adipose and muscle lipoprotein lipase activity as well as VLDL receptor number.	3	12	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin levels	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	3	4	10	12
In addition , previous studies have suggested that muscle activity of lipoprotein lipase ( LPL ) is related to insulin resistance XREF_BIBR and that insulin may downregulate the activity of lipoprotein lipase in skeletal muscle XREF_BIBR .	In addition, previous studies have suggested that muscle activity of lipoprotein lipase (LPL) is related to insulin resistance XREF_BIBR and that insulin may downregulate the activity of lipoprotein lipase in skeletal muscle XREF_BIBR.	24	32	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	24	25	30	32
Nevertheless , insulin deficiency inactivates the lipoprotein lipase promoting liver conversion of free fatty acids into phospholipids and cholesterol which get discharged into blood resulting in elevated serum phospholipid level [ XREF_BIBR ] .	Nevertheless, insulin deficiency inactivates the lipoprotein lipase promoting liver conversion of free fatty acids into phospholipids and cholesterol which get discharged into blood resulting in elevated serum phospholipid level [XREF_BIBR].	2	8	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	6	8
In [ 35S ] methionine pulse labeled adipocytes , insulin decreased LPL protein synthetic rate measured by immunoprecipitation 42-48 % , although increases ( 75-340 % ) in heparin-releasable LPL activity were detected in the same cells .	In [35S] methionine pulse labeled adipocytes, insulin decreased LPL protein synthetic rate measured by immunoprecipitation 42-48%, although increases (75-340%) in heparin-releasable LPL activity were detected in the same cells.	9	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	9	10	11	12
This rebound is due to a restoration of lipolysis , a decrease in NEFA reesterification by adipose tissue and an increased LPL-as insulin activates LPL with a delay of several hours .	This rebound is due to a restoration of lipolysis, a decrease in NEFA reesterification by adipose tissue and an increased LPL-as insulin activates LPL with a delay of several hours.	14	25	activates	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	LPL	LPL	LPL	22	23	24	25
Insulin deficiency inactivates lipoprotein lipase which hydrolyses triglycerides and prevents mobilization of free fatty acid in normal state , thereby resulting in phospholipid level [ XREF_BIBR , XREF_BIBR ] .	Insulin deficiency inactivates lipoprotein lipase which hydrolyses triglycerides and prevents mobilization of free fatty acid in normal state, thereby resulting in phospholipid level [XREF_BIBR, XREF_BIBR].	0	5	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	3	5
Insulin resistance resulting from obesity decreases lipoprotein lipase ( LPL ) activity , and then , a reduced LPL activity leads to the decreased clearance of fasting and postprandial TG rich lipoproteins and to the decreased production of HDL [ XREF_BIBR ] .	Insulin resistance resulting from obesity decreases lipoprotein lipase (LPL) activity, and then, a reduced LPL activity leads to the decreased clearance of fasting and postprandial TG rich lipoproteins and to the decreased production of HDL [XREF_BIBR].	0	8	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	6	8
Insulin resistance tends to gain TG levels and reduce lipoprotein lipase activity , which boost HDL-C levels .	Insulin resistance tends to gain TG levels and reduce lipoprotein lipase activity, which boost HDL-C levels.	0	11	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	9	11
Fourth , insulin resistance and type 2 diabetes resulting from this secondary mitochondrial dysfunction results in inhibition of hormone sensitive lipase of adipocytes and decreased endothelial lipoprotein lipase function and the subsequent increase in production of FFA .	Fourth, insulin resistance and type 2 diabetes resulting from this secondary mitochondrial dysfunction results in inhibition of hormone sensitive lipase of adipocytes and decreased endothelial lipoprotein lipase function and the subsequent increase in production of FFA.	2	28	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	26	28
Insulin induced activation of protein kinase B , a known mediator of insulin action , was not inhibited by 100 micromol/L , but to a low extent by 1 mmol/L DMAP in intact cells .	Insulin induced activation of protein kinase B, a known mediator of insulin action, was not inhibited by 100 micromol/L, but to a low extent by 1 mmol/L DMAP in intact cells.	0	7	induced	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	4	7
Herein we demonstrate that exposing muscle cells to particular saturated free fatty acids ( FFAs ) , but not mono-unsaturated FFAs , inhibits insulin stimulation of Akt and protein kinase B , a serine/threonine kinase that is a central mediator of insulin stimulated anabolic metabolism .	Herein we demonstrate that exposing muscle cells to particular saturated free fatty acids (FFAs), but not mono-unsaturated FFAs, inhibits insulin stimulation of Akt and protein kinase B, a serine/threonine kinase that is a central mediator of insulin stimulated anabolic metabolism.	23	31	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	23	24	28	31
For instance , rapamycin is a direct mTORC1-inhibitor and thus a potent inducer of autophagy , whereas CR reduces insulin signaling ( and IGF-1 levels ) , which can inactivate protein kinase B ( AKT and PKB ) and its downstream target mTORC1 .	For instance, rapamycin is a direct mTORC1-inhibitor and thus a potent inducer of autophagy, whereas CR reduces insulin signaling (and IGF-1 levels), which can inactivate protein kinase B (AKT and PKB) and its downstream target mTORC1.	19	33	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	19	20	30	33
Insulin induced PKBalpha activity was markedly reduced in the skeletal muscle of fatty Zucker rats as compared to lean littermates ( fatty : 7-fold vs. lean : 14-fold ) .	Insulin induced PKBalpha activity was markedly reduced in the skeletal muscle of fatty Zucker rats as compared to lean littermates (fatty : 7-fold vs. lean : 14-fold).	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	PKBalpha	PKBalpha	PKBalpha	0	1	2	3
Insulin mediated activation of protein kinase B was significantly diminished in cells differentiated in the presence of TNF-alpha .	Insulin mediated activation of protein kinase B was significantly diminished in cells differentiated in the presence of TNF-alpha.	0	7	mediated	Positive_early_activation	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	4	7
Proposed mechanisms for these observations include attenuating palmitate induced ER stress ( Colvin etal ., 2017 ) , preventing activation of the unfolded protein response ( Sommerweiss etal ., 2013 ) , activating prosurvival pathways of ER stress ( Sargsyan etal ., 2016 ) , restoring insulin stimulated protein kinase B ( Akt ) signaling ( Capel etal ., 2016 ) , and activating AMP activated protein kinase and mechanistic target of rapamycin signaling ( Kwon and Querfurth , 2015 ) .	Proposed mechanisms for these observations include attenuating palmitate induced ER stress (Colvin etal., 2017), preventing activation of the unfolded protein response (Sommerweiss etal., 2013), activating prosurvival pathways of ER stress (Sargsyan etal., 2016), restoring insulin stimulated protein kinase B (Akt) signaling (Capel etal., 2016), and activating AMP activated protein kinase and mechanistic target of rapamycin signaling (Kwon and Querfurth, 2015).	45	51	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	46	47	48	51
Researches have demonstrated that acute inhibition of SPT using myriocin ameliorates the loss in insulin stimulated protein kinase B ( PKB and AKT ) activation in cultured L6 or C2C12 myotubes [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Researches have demonstrated that acute inhibition of SPT using myriocin ameliorates the loss in insulin stimulated protein kinase B (PKB and AKT) activation in cultured L6 or C2C12 myotubes [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	12	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	loss in insulin	insulin	protein kinase B	protein kinase B	protein kinase b	14	15	16	19
419 , 101-109 ) , long-chain saturated FFAs inhibited insulin stimulation of Akt and protein kinase B , a central regulator of glucose uptake and anabolic metabolism .	419, 101-109), long-chain saturated FFAs inhibited insulin stimulation of Akt and protein kinase B, a central regulator of glucose uptake and anabolic metabolism.	9	17	stimulation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	9	10	14	17
Several studies have reported that acute inhibition of SPT using myriocin ameliorates the loss of insulin stimulated protein kinase B activation in cultures L6 or C2C12 myotubes caused by palmitate driven ceramide synthesis .	Several studies have reported that acute inhibition of SPT using myriocin ameliorates the loss of insulin stimulated protein kinase B activation in cultures L6 or C2C12 myotubes caused by palmitate driven ceramide synthesis.	13	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	loss of insulin	insulin	protein kinase B	protein kinase B	protein kinase b	15	16	17	20
Despite the development of insulin resistance , insulin induced activation of PKBalpha was not impaired in the STZ-diabetic rats up to 9 weeks of diabetes , excluding a role for PKBalpha in the development of insulin resistance in type 1 diabetes .	Despite the development of insulin resistance, insulin induced activation of PKBalpha was not impaired in the STZ-diabetic rats up to 9 weeks of diabetes, excluding a role for PKBalpha in the development of insulin resistance in type 1 diabetes.	7	12	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	PKBalpha	PKBalpha	PKBalpha	7	8	11	12
Insulin inhibits AMPK activity by stimulating protein kinase B ( PKB ) to phosphorylate the Ser 485 residue of the alpha subunit , thereby inhibiting phosphorylation at Thr 172 [ XREF_BIBR ] .	Insulin inhibits AMPK activity by stimulating protein kinase B (PKB) to phosphorylate the Ser 485 residue of the alpha subunit, thereby inhibiting phosphorylation at Thr 172 [XREF_BIBR].	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	protein kinase B	protein kinase B	protein kinase B	0	1	6	9
Insulin resistance in the liver of AKT1 Myr transgenic mice .	Insulin resistance in the liver of AKT1 Myr transgenic mice.	0	9	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	AKT1	AKT1	AKT1	0	1	6	7
For example , PKCzeta mediated phosphorylation of the PH domain of the protein kinase B at Thr34 inhibits binding to PtdIns ( 3,4,5 ) P 3 , impairing protein kinase B activation by insulin XREF_BIBR .	For example, PKCzeta mediated phosphorylation of the PH domain of the protein kinase B at Thr34 inhibits binding to PtdIns (3,4,5) P 3, impairing protein kinase B activation by insulin XREF_BIBR.	28	34	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	33	34	28	31
Insulin stimulated Complex V activity was not impaired in the Akt1 -/- myocardium , due to compensatory translocation of Akt2 to mitochondria .	Insulin stimulated Complex V activity was not impaired in the Akt1 -/- myocardium, due to compensatory translocation of Akt2 to mitochondria.	0	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	Akt1	Akt1	Akt1	0	1	10	11
In obese rats , insulin stimulated Akt1 activity decreases in muscle and adipose tissue but increases in liver , while insulin stimulated Akt2 activity decreases in muscle and liver but increases in adipose tissue [ XREF_BIBR ] .	In obese rats, insulin stimulated Akt1 activity decreases in muscle and adipose tissue but increases in liver, while insulin stimulated Akt2 activity decreases in muscle and liver but increases in adipose tissue [XREF_BIBR].	4	7	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	4	5	6	7
At the level of transcriptional changes , insulin and IGF repressed subunits of PI3K as well as Akt1 and Akt2 .	At the level of transcriptional changes, insulin and IGF repressed subunits of PI3K as well as Akt1 and Akt2.	7	19	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	Akt1	Akt1	Akt1	7	8	17	18
Using specific inhibitors to key kinases of both pathways and PKCzeta small interference RNA , protein kinase C zeta ( PKCzeta ) was found to regulate insulin stimulated protein kinase B ( PKB ) activation and inhibit AMPK activity on dorsal cell surface .	Using specific inhibitors to key kinases of both pathways and PKCzeta small interference RNA, protein kinase C zeta (PKCzeta) was found to regulate insulin stimulated protein kinase B (PKB) activation and inhibit AMPK activity on dorsal cell surface.	25	31	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	protein kinase B	protein kinase B	protein kinase B	26	27	28	31
Obese patients have been shown to have higher circulating levels of IGF-1 than non obese patients in the presence of hyperinsulinemia [ XREF_BIBR ] , and animal studies have revealed that insulin resistance and activation of the IGF and IGF-1R axis are implicated in obesity- and diabetes related liver carcinogenesis [ XREF_BIBR , XREF_BIBR ] .	Obese patients have been shown to have higher circulating levels of IGF-1 than non obese patients in the presence of hyperinsulinemia [XREF_BIBR], and animal studies have revealed that insulin resistance and activation of the IGF and IGF-1R axis are implicated in obesity- and diabetes related liver carcinogenesis [XREF_BIBR, XREF_BIBR].	31	40	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	31	32	39	40
Since cases had slightly higher plasma insulin levels than controls , and elevated insulin can down-regulate IGF1R as a consequence of increased free IGF1 in the circulation , we asked if the lower IGF1R mRNA observed in cases could be associated with higher plasma insulin .	Since cases had slightly higher plasma insulin levels than controls, and elevated insulin can down-regulate IGF1R as a consequence of increased free IGF1 in the circulation, we asked if the lower IGF1R mRNA observed in cases could be associated with higher plasma insulin.	12	17	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	13	14	16	17
Thus IR inhibition in cancer cell lines ( LCC6 and T47D ) causes reduced Akt activation by insulin , with no involvement of the IGF-1R .	Thus IR inhibition in cancer cell lines (LCC6 and T47D) causes reduced Akt activation by insulin, with no involvement of the IGF-1R.	13	25	reduced	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	17	18	24	25
Insulin did not significantly affect levels of IGF-I mRNA , but decreased levels of IGF-I receptor mRNA in skeletal muscle and aorta .	Insulin did not significantly affect levels of IGF-I mRNA, but decreased levels of IGF-I receptor mRNA in skeletal muscle and aorta.	0	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	IGF-I receptor	IGF-I receptor	IGF-I receptor	0	1	14	16
Additionally , elevated insulin and maternal insulin resistance can downregulate the embryo IGF1R and attendant glucose uptake , and this downregulation can be harmful to the embryo .	Additionally, elevated insulin and maternal insulin resistance can downregulate the embryo IGF1R and attendant glucose uptake, and this downregulation can be harmful to the embryo.	2	16	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	3	4	12	13
R36E and R37E suppressed activation of IGF1R by insulin .	R36E and R37E suppressed activation of IGF1R by insulin.	3	9	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	IGF1R	IGF1R	IGF1R	8	9	6	7
Addition of 100 nm of insulin for 3 days in media containing 27.8 mm glucose decreased IGF-1R to that of 5.6 mm .	Addition of 100 nm of insulin for 3 days in media containing 27.8 mm glucose decreased IGF-1R to that of 5.6 mm.	3	17	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	5	6	16	17
Restoring insulin mediated endothelial responses in mice with whole-body haploinsufficiency of IR by reducing IGF-1R .	Restoring insulin mediated endothelial responses in mice with whole-body haploinsufficiency of IR by reducing IGF-1R.	0	15	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin	insulin	insulin	IGF-1R	IGF-1R	IGF-1R	1	2	14	15
Insulin deficiency downregulates HSP60 and IGF-I receptor signaling and disrupts intracellular signaling homeostasis in diabetic cardiac muscle .	Insulin deficiency downregulates HSP60 and IGF-I receptor signaling and disrupts intracellular signaling homeostasis in diabetic cardiac muscle.	0	7	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	IGF-I receptor	IGF-I receptor	IGF-I receptor	0	1	5	7
Insulin can also down-regulate IGF1R , potentially by increasing levels of free IGF1 in plasma .	Insulin can also down-regulate IGF1R, potentially by increasing levels of free IGF1 in plasma.	0	5	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Insulin	Insulin	Insulin	IGF1R	IGF1R	IGF1R	0	1	4	5
PTPs can dephosphorylate IR at autophosphorylated tyrosines and thus inactivate IR .	PTPs can dephosphorylate IR at autophosphorylated tyrosines and thus inactivate IR.	0	11	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IR	PTPs can dephosphorylate IR	ir	IR	IR	ir	3	4	10	11
This increase in insulin sensitivity was associated with an increase in insulin induced insulin receptor ( IR ) tyrosine phosphorylation and , in parallel , a decrease in IR serine phosphorylation and association with PTP1B .	This increase in insulin sensitivity was associated with an increase in insulin induced insulin receptor (IR) tyrosine phosphorylation and, in parallel, a decrease in IR serine phosphorylation and association with PTP1B.	12	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IR	IR serine phosphorylation	ir	insulin receptor	insulin receptor	insulin receptor	28	29	13	15
Activation of the D 3 receptor ( PD128907 , 10 -7 mol/l ) increased insulin receptor phosphorylation ( XREF_FIG ) , and increased insulin receptor protein degradation in A10 cells ( XREF_FIG ) , while in the presence of PKA inhibitor ( PKA inhibitor 14-22 ) , the stimulatory effects of D 3 receptor on insulin receptor phosphorylation and degradation were blocked ( XREF_FIG ) , suggesting that PKA was involved in those signal pathways .	Activation of the D 3 receptor (PD128907, 10 -7 mol/l) increased insulin receptor phosphorylation (XREF_FIG), and increased insulin receptor protein degradation in A10 cells (XREF_FIG), while in the presence of PKA inhibitor (PKA inhibitor 14-22), the stimulatory effects of D 3 receptor on insulin receptor phosphorylation and degradation were blocked (XREF_FIG), suggesting that PKA was involved in those signal pathways.	3	26	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin receptor	D 3 receptor (PD128907, 10 -7 mol/l) increased insulin receptor phosphorylation	insulin receptor	insulin receptor	insulin receptor	insulin receptor	14	16	23	25
The insulin receptor kinase is also inhibited in intact cells by phorbol esters that mediate serine/threonine phosphorylation of the insulin receptor , presumably via the Ca+ +-phospholipid-dependent protein kinase .	The insulin receptor kinase is also inhibited in intact cells by phorbol esters that mediate serine/threonine phosphorylation of the insulin receptor, presumably via the Ca+ +-phospholipid-dependent protein kinase.	1	21	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	insulin receptor	phorbol esters that mediate serine/threonine phosphorylation of the insulin receptor	insulin receptor	insulin receptor	insulin receptor	insulin receptor	19	21	1	3
Furthermore , the increased PIP2-PLC in diabetic liver may result in : ( a ) increased intracellular concentrations of IP3 and thus increased Ca2+ , which has been postulated to induce insulin resistance ; and ( b ) increased diacylglycerol and thus increased protein kinase C which phosphorylates the insulin receptor at serine residues inactivating the insulin receptor kinase .	Furthermore, the increased PIP2-PLC in diabetic liver may result in : (a) increased intracellular concentrations of IP3 and thus increased Ca2+, which has been postulated to induce insulin resistance; and (b) increased diacylglycerol and thus increased protein kinase C which phosphorylates the insulin receptor at serine residues inactivating the insulin receptor kinase.	43	58	inactivating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin receptor	protein kinase C which phosphorylates the insulin receptor at serine residues	insulin receptor	insulin receptor	insulin receptor	insulin receptor	49	51	56	58
This defect is thought to arise from fatty acid induced inhibition of insulin receptor ( IRS-1 ) phosphorylation , potentially due to intramyocellular fatty acid accumulation that may result from abnormal mitochondrial fatty acid oxidation 11 .	This defect is thought to arise from fatty acid induced inhibition of insulin receptor (IRS-1) phosphorylation, potentially due to intramyocellular fatty acid accumulation that may result from abnormal mitochondrial fatty acid oxidation 11.	9	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin receptor	insulin receptor (IRS-1) phosphorylation	insulin receptor	insulin receptor	insulin receptor	insulin receptor	12	14	12	14
Reduced insulin receptor phosphorylation by ectopic expression of dominant negative insulin receptor ( dnIR ) , which contains a point mutation to abolish insulin receptor binding to ATP , or decrease insulin receptor protein by morpholino mediated knockdown in tectal neurons , severely decreases their glutamatergic synaptic input and reduces their responses to natural light stimuli .	Reduced insulin receptor phosphorylation by ectopic expression of dominant negative insulin receptor (dnIR), which contains a point mutation to abolish insulin receptor binding to ATP, or decrease insulin receptor protein by morpholino mediated knockdown in tectal neurons, severely decreases their glutamatergic synaptic input and reduces their responses to natural light stimuli.	1	28	abolish	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	insulin receptor	insulin receptor phosphorylation by ectopic expression of dominant negative insulin receptor	insulin receptor	insulin receptor	insulin receptor binding to ATP	insulin receptor	1	3	23	25
Bacterial infection of IRAK4 KI macrophages led to attenuated activation of IRAK1 , MAPKs and NF-kappaB , impaired induction of inducible NO synthase mRNA and secretion of NO , but resulted in elevated microbial burdens .	Bacterial infection of IRAK4 KI macrophages led to attenuated activation of IRAK1, MAPKs and NF-kappaB, impaired induction of inducible NO synthase mRNA and secretion of NO, but resulted in elevated microbial burdens.	3	15	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	3	4	11	12
TOLLIP inhibits the activation of IRAK1 by IRAK 4 .	TOLLIP inhibits the activation of IRAK1 by IRAK 4.	1	9	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	IRAK 4	IRAK 4	IRAK 4	IRAK1	IRAK1	IRAK1	7	9	5	6
These results suggested that the expression of IRAK-4 alone is sufficient to cause the degradation of IRAK-1 ; the autophosphorylation of IRAK-1 is not necessary to terminate the TLR induced activation of NF-kappaB .	These results suggested that the expression of IRAK-4 alone is sufficient to cause the degradation of IRAK-1; the autophosphorylation of IRAK-1 is not necessary to terminate the TLR induced activation of NF-kappaB.	5	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IRAK-4	expression of IRAK-4	irak-4	IRAK-1	IRAK-1	irak-1	7	8	16	17
In addition , IRAK-4 is able to phosphorylate IRAK-1 , and overexpression of dominant negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1 , suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL -1 receptors , upstream of IRAK-1 .	In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL -1 receptors, upstream of IRAK-1.	11	25	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRAK-4	overexpression of dominant negative IRAK-4	irak-4	IRAK-1	IRAK-1	irak-1	15	16	24	25
XREF_FIG C demonstrates that , unlike WT IRAK-4 , this more truncated form of IRAK-4 also failed to augment endogenous IRAK-1 kinase activity and inhibited endogenous basal and IL-1-induced IRAK-1 activity , although less than observed upon overexpression of pRK7-IRAK4 ( M # 1 ) .	XREF_FIG C demonstrates that, unlike WT IRAK-4, this more truncated form of IRAK-4 also failed to augment endogenous IRAK-1 kinase activity and inhibited endogenous basal and IL-1-induced IRAK-1 activity, although less than observed upon overexpression of pRK7-IRAK4 (M # 1).	12	30	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRAK-4	IRAK-4	IRAK-4	IRAK-1	IRAK-1	IRAK-1	14	15	29	30
On the other hand , PMOC affected neither the IRAK-4 auto-phosphorylation in LPS- or CpG ODN activated whole liver cells and RAW 264.7 cells , in which N-( 2-morpholinylethyl )-2-( 3-nitrobenzoylamindo )-benzimidazole ( IS409 , IRAK-1/4 inhibitor ) was used as a positive control agent ( XREF_SUPPLEMENTARY ) , nor the IRAK-1 degradation in LPS activated cells ( XREF_SUPPLEMENTARY ) .	On the other hand, PMOC affected neither the IRAK-4 auto-phosphorylation in LPS- or CpG ODN activated whole liver cells and RAW 264.7 cells, in which N-(2-morpholinylethyl)-2-(3-nitrobenzoylamindo)-benzimidazole (IS409, IRAK-1/4 inhibitor) was used as a positive control agent (XREF_SUPPLEMENTARY), nor the IRAK-1 degradation in LPS activated cells (XREF_SUPPLEMENTARY).	9	52	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IRAK-4	IRAK-4 auto-phosphorylation	irak-4	IRAK-1	IRAK-1	irak-1	9	10	51	52
MyD88 recruits IL-1R-associated kinase-4 ( IRAK4 ) , which subsequently recruits , activates and degrades IRAK1 .	MyD88 recruits IL-1R-associated kinase-4 (IRAK4), which subsequently recruits, activates and degrades IRAK1.	3	16	degrades	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRAK4	IRAK4	IRAK4	IRAK1	IRAK1	IRAK1	5	6	15	16
IGFBP-3 NB increased insulin receptor phosphorylation and reduced IRS-1 Ser307 in diabetic rat retina .	IGFBP-3 NB increased insulin receptor phosphorylation and reduced IRS-1 Ser307 in diabetic rat retina.	0	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin receptor	IGFBP-3 NB increased insulin receptor phosphorylation	insulin receptor	IRS-1	IRS-1	irs-1	3	5	8	9
Microglial interleukin-1 ( IL-1 ) , interleukin-6 ( IL-6 ) , and tumor necrosis factor-alpha ( TNF-alpha ) are known activators of insulin receptor sustrate-1 ( IRS-1 ) serine kinases ( IkappaB kinase , c-Jun N-terminal kinase , and extracellular signal regulated kinase-2 ) , which decrease IRS-1 activity by phosphorylation [ XREF_BIBR ] as seen in AD [ XREF_BIBR ] .	Microglial interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) are known activators of insulin receptor sustrate-1 (IRS-1) serine kinases (IkappaB kinase, c-Jun N-terminal kinase, and extracellular signal regulated kinase-2), which decrease IRS-1 activity by phosphorylation [XREF_BIBR] as seen in AD [XREF_BIBR].	22	48	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin receptor	insulin receptor	insulin receptor	IRS-1	IRS-1	IRS-1	22	24	47	48
C6 ceramide exposure significantly increased the mean levels of insulin , insulin receptor , IGF-1 receptor , and IRS-4 , and decreased the mean levels of IGF-2 receptor and IRS-1 mRNA as demonstrated by qRT-PCR analysis and one-way ANOVA tests ( XREF_FIG ) .	C6 ceramide exposure significantly increased the mean levels of insulin, insulin receptor, IGF-1 receptor, and IRS-4, and decreased the mean levels of IGF-2 receptor and IRS-1 mRNA as demonstrated by qRT-PCR analysis and one-way ANOVA tests (XREF_FIG).	0	30	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin receptor	C6 ceramide exposure significantly increased the mean levels of insulin, insulin receptor	insulin receptor	IRS-1	IRS-1	irs-1	11	13	29	30
Serine phosphorylation of IRS-1 inhibits association with the insulin receptor stimulating degradation of IRS-1 ( Fasshauer etal ., 2003 ) .	Serine phosphorylation of IRS-1 inhibits association with the insulin receptor stimulating degradation of IRS-1 (Fasshauer etal., 2003).	8	15	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin receptor	insulin receptor	insulin receptor	IRS-1	IRS-1	IRS-1	8	10	13	14
Injection of IGFBP-3 NB restored insulin receptor phosphorylation to control levels ( XREF_FIG ) , and significantly reduced IRS-1 Ser307 ( XREF_FIG ) .	Injection of IGFBP-3 NB restored insulin receptor phosphorylation to control levels (XREF_FIG), and significantly reduced IRS-1 Ser307 (XREF_FIG).	2	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin receptor	IGFBP-3 NB restored insulin receptor phosphorylation	insulin receptor	IRS-1	IRS-1	irs-1	5	7	18	19
IL-6 has been shown to suppress insulin action through the activation of STAT3 , which then acts on the insulin receptor suppressing the activation of IRS-1 and downstream targets [ XREF_BIBR , XREF_BIBR ] .	IL-6 has been shown to suppress insulin action through the activation of STAT3, which then acts on the insulin receptor suppressing the activation of IRS-1 and downstream targets [XREF_BIBR, XREF_BIBR].	19	32	suppressing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin receptor	insulin receptor	insulin receptor	IRS-1	IRS-1	IRS-1	19	21	25	26
Gel shift analysis revealed that 6 h of insulin treatment decreased the binding of nuclear C/EBP alpha while increasing binding of nuclear C/EBP beta and C/EBP delta .	Gel shift analysis revealed that 6 h of insulin treatment decreased the binding of nuclear C/EBP alpha while increasing binding of nuclear C/EBP beta and C/EBP delta.	8	17	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	C/EBP alpha	C/EBP alpha	C/EBP alpha	8	9	15	17
In the hepatocyte C/EBPalpha activity is linked to cAMP induction of genes , so insulin inhibition of C/EBPalpha could explain repression of these genes by insulin .	In the hepatocyte C/EBPalpha activity is linked to cAMP induction of genes, so insulin inhibition of C/EBPalpha could explain repression of these genes by insulin.	14	18	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	insulin	insulin	insulin	C/EBPalpha	C/EBPalpha	C/EBPalpha	14	15	17	18
At a concentration of 10 -7 M , insulin decreased the C/EBP alpha mRNA by 51 % ( p < 0.01 ) , whereas C/EBP delta mRNA expression was unchanged .	At a concentration of 10 -7 M, insulin decreased the C/EBP alpha mRNA by 51% (p < 0.01), whereas C/EBP delta mRNA expression was unchanged.	8	13	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	C/EBP alpha	C/EBP alpha	C/EBP alpha	8	9	11	13
In vitro studies revealed that repression of TRAF6 and/or IRAK1 in THP-1 human monocytes resulted in up to an 86 % reduction in tumor necrosis factor alpha ( TNFalpha ) production , indicating that normal miR-146 function could be critical for the regulation of TNFalpha production .	In vitro studies revealed that repression of TRAF6 and/or IRAK1 in THP-1 human monocytes resulted in up to an 86% reduction in tumor necrosis factor alpha (TNFalpha) production, indicating that normal miR-146 function could be critical for the regulation of TNFalpha production.	3	14	repression	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	IRAK1	IRAK1	IRAK1	TRAF6	TRAF6	TRAF6	9	10	7	8
However , overexpression of PTP1B in HepG2 cells led to diminished insulin induced IR phosphorylation , supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes .	However, overexpression of PTP1B in HepG2 cells led to diminished insulin induced IR phosphorylation, supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes.	2	21	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	overexpression of PTP1B in HepG2 cells led to diminished insulin induced IR phosphorylation	ir	PTP1B	PTP1B	ptp1b	13	14	20	21
Photoreceptor specific deletion of PTP1B results in enhanced retinal IR mediated neuroprotection indicating the importance of PTP1B as a negative regulator in the retina .	Photoreceptor specific deletion of PTP1B results in enhanced retinal IR mediated neuroprotection indicating the importance of PTP1B as a negative regulator in the retina.	5	17	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IR	IR	IR	PTP1B	PTP1B	PTP1B	9	10	16	17
Furthermore , LTB4 decreased insulin receptor tyrosine phosphorylation in hepatocytes , activated the NFkappaB pathway , and up-regulated PTP1B and PTEN , these effects being mediated by LTB4 receptor BTL1 .	Furthermore, LTB4 decreased insulin receptor tyrosine phosphorylation in hepatocytes, activated the NFkappaB pathway, and up-regulated PTP1B and PTEN, these effects being mediated by LTB4 receptor BTL1.	2	23	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	insulin receptor	LTB4 decreased insulin receptor tyrosine phosphorylation	insulin receptor	PTP1B	PTP1B	ptp1b	4	6	18	19
SIRT1 can also enhance post-receptor insulin signalling by increasing serine phosphorylation of Akt and tyrosine phosphorylation of the insulin receptor and IRS-1 , primarily through transcriptional repression of the phosphorylase Ptpn1 ( protein tyrosine phosphatase , non receptor type1 ) .	SIRT1 can also enhance post-receptor insulin signalling by increasing serine phosphorylation of Akt and tyrosine phosphorylation of the insulin receptor and IRS-1, primarily through transcriptional repression of the phosphorylase Ptpn1 (protein tyrosine phosphatase, non receptor type1).	10	34	repression	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	insulin receptor	phosphorylation of Akt and tyrosine phosphorylation of the insulin receptor	insulin receptor	Ptpn1	Ptpn1	ptpn1	18	20	30	31
The increase in pDCs in IRF1 -/- mice suggests that IRF-1 might repress or inhibit IRF-8 .	The increase in pDCs in IRF1 -/- mice suggests that IRF-1 might repress or inhibit IRF-8.	10	16	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRF-1	IRF-1	IRF-1	IRF-8	IRF-8	IRF-8	10	11	15	16
Moreover , overexpression of IRF-1 and IRF-8 induces TNF-alpha production in unstimulated RAW 264.7 macrophages , comparable to the production of TNF-alpha elicited by IFN-gamma stimulation , and silencing of IRF-1 and/or IRF-8 with specific small interfering RNAs , decreases IFN-gamma-elicited TNF-alpha production .	Moreover, overexpression of IRF-1 and IRF-8 induces TNF-alpha production in unstimulated RAW 264.7 macrophages, comparable to the production of TNF-alpha elicited by IFN-gamma stimulation, and silencing of IRF-1 and/or IRF-8 with specific small interfering RNAs, decreases IFN-gamma-elicited TNF-alpha production.	2	40	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRF-1	overexpression of IRF-1	irf-1	IRF-8	IRF-8	irf-8	4	5	32	33
In addition to activating IRAK1 , phosphorylation of IRAK1 by IRAK4 has been shown to induce degradation of IRAK1 , providing a negative feedback mechanism for TLR signaling 88 .	In addition to activating IRAK1, phosphorylation of IRAK1 by IRAK4 has been shown to induce degradation of IRAK1, providing a negative feedback mechanism for TLR signaling 88.	6	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IRAK1	phosphorylation of IRAK1	irak1	IRAK1	IRAK1	irak1	8	9	18	19
We found that knockdown of Src and PKCzeta could inhibit CHIP mediated increase in the phosphorylated levels of IRAK1 and TBK1 ( XREF_FIG ) , indicating that CHIP may promote the activation of Src and PKCzeta , which , in turn , phosphorylated and activated IRAK1 and TBK1 .	We found that knockdown of Src and PKCzeta could inhibit CHIP mediated increase in the phosphorylated levels of IRAK1 and TBK1 (XREF_FIG), indicating that CHIP may promote the activation of Src and PKCzeta, which, in turn, phosphorylated and activated IRAK1 and TBK1.	5	47	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IRAK1	Src and PKCzeta could inhibit CHIP mediated increase in the phosphorylated levels of IRAK1	irak1	IRAK1	IRAK1	irak1	18	19	45	46
Thus , IRF2BP2 is the major repressor of IRF2 to mediate the suppressive effect of IFNbeta .	Thus, IRF2BP2 is the major repressor of IRF2 to mediate the suppressive effect of IFNbeta.	2	9	is the major repressor	Negative_activation_copula_1	Positive_activation	Negative_activation	IRF2BP2	IRF2BP2	IRF2BP2	IRF2	IRF2	IRF2	2	3	8	9
22 IRF2BP2 is a transcriptional co-repressor of IRF2 .	22 IRF2BP2 is a transcriptional co-repressor of IRF2.	0	8	is a transcriptional co-repressor	Negative_activation_copula_1	Positive_activation	Negative_activation	IRF2BP2	IRF2BP2	IRF2BP2	IRF2	IRF2	IRF2	1	2	7	8
mAb to CD11a ( LFA-1 ) , the alleged ligand of ICAM-1 , inhibited the ICAM-1 but not the HD lectin mediated lymphocyte stimulation .	mAb to CD11a (LFA-1), the alleged ligand of ICAM-1, inhibited the ICAM-1 but not the HD lectin mediated lymphocyte stimulation.	0	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CD11a	CD11a	CD11a	ICAM-1	ICAM-1	ICAM-1	2	3	15	16
In our screen , we found that ruboxistaurin , a bis-indole that is chemically related to Ro-31-8425 , as well as other PKC inhibitors , did not elicit CD11a expression on MSCs ( XREF_SUPPLEMENTARY ) and also did not increase MSC firm adhesion to ICAM-1 ( XREF_FIG ) .	In our screen, we found that ruboxistaurin, a bis-indole that is chemically related to Ro-31-8425, as well as other PKC inhibitors, did not elicit CD11a expression on MSCs (XREF_SUPPLEMENTARY) and also did not increase MSC firm adhesion to ICAM-1 (XREF_FIG).	7	46	increase	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	CD11a	ruboxistaurin, a bis-indole that is chemically related to Ro-31-8425, as well as other PKC inhibitors, did not elicit CD11a expression	cd11a	ICAM-1	ICAM-1	icam-1	28	29	44	45
Insulin stimulation reduced c/EBPbeta expression in cardiomyocytes plated on gelatin ( XREF_FIG ) , but cells plated on Fn were insensitive for insulin induced c/EBPbeta reduction .	Insulin stimulation reduced c/EBPbeta expression in cardiomyocytes plated on gelatin (XREF_FIG), but cells plated on Fn were insensitive for insulin induced c/EBPbeta reduction.	22	25	induced	Positive_early_activation	Positive_activation	Negative_activation	insulin	insulin	insulin	c/EBPbeta	c/EBPbeta	c/EBPbeta	22	23	24	25
However , the effect of insulin on C/EBP beta was unexpected and paradoxical : while insulin completely inhibited the transcriptional activation of the C/EBP beta gene in cytokine- and dexamethasone treated cells , the level of cytoplasmic C/EBP beta RNA was elevated .	However, the effect of insulin on C/EBP beta was unexpected and paradoxical : while insulin completely inhibited the transcriptional activation of the C/EBP beta gene in cytokine- and dexamethasone treated cells, the level of cytoplasmic C/EBP beta RNA was elevated.	15	25	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	insulin	insulin	insulin	C/EBP beta	C/EBP beta	C/EBP beta	15	16	23	25
The combination treatment of pUC + IR again reduced interaction of p-FAK with Grb2 when compared with pSV+ IR in IOMM-Lee ( 55 % ) , CH-157MN ( 40 % ) and in nude mice ( 90 % ) ( XREF_FIG ) .	The combination treatment of pUC + IR again reduced interaction of p-FAK with Grb2 when compared with pSV+ IR in IOMM-Lee (55%), CH-157MN (40%) and in nude mice (90%) (XREF_FIG).	2	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IR	IR	IR	p-FAK	p-FAK	p-FAK	6	7	11	12
Surprisingly , IRS1 associated phosphatidylinositol kinase activity in response to insulin was intact in the L-DKO , despite lack of p110alpha kinase activity and decreased p110beta activity ( XREF_FIG ) .	Surprisingly, IRS1 associated phosphatidylinositol kinase activity in response to insulin was intact in the L-DKO, despite lack of p110alpha kinase activity and decreased p110beta activity (XREF_FIG).	2	26	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRS1	IRS1	IRS1	p110beta	p110beta	p110beta	2	3	25	26
Insulin resistance in the setting of obesity is accompanied by additional changes , including altered expression of insulin signaling genes ( increased IRS-1 , PI3Kgamma , Akt2 , GLUT4 , GLUT1 ; decreased PI3Kalpha , PDK2 , mTor , Rheb , 4EBP , eIF members , Ras and MEK1/2 kinase ) when compared to either lean or obese , insulin sensitive subjects .	Insulin resistance in the setting of obesity is accompanied by additional changes, including altered expression of insulin signaling genes (increased IRS-1, PI3Kgamma, Akt2, GLUT4, GLUT1; decreased PI3Kalpha, PDK2, mTor, Rheb, 4EBP, eIF members, Ras and MEK1/2 kinase) when compared to either lean or obese, insulin sensitive subjects.	22	49	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRS-1	IRS-1	IRS-1	PI3Kalpha	PI3Kalpha	PI3Kalpha	22	23	33	34
Also , there are decreased insulin stimulated tyrosine phosphorylation of IRS-1 and IRS-2 ; decreased binding of grb2 and the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 and IRS-2 , and a marked inhibition of insulin stimulated phosphatidylinositol 3-kinase [ XREF_BIBR ] .	Also, there are decreased insulin stimulated tyrosine phosphorylation of IRS-1 and IRS-2; decreased binding of grb2 and the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 and IRS-2, and a marked inhibition of insulin stimulated phosphatidylinositol 3-kinase [XREF_BIBR].	5	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IRS-1	insulin stimulated tyrosine phosphorylation of IRS-1	irs-1	grb2	grb2	grb2	10	11	17	18
Similarly , the absence of Jak1 profoundly affects the IL-6 pathway as elimination of Jak1 was sufficient to fully abrogate any detectable phospho-STAT1 and greatly reduce phospho-STAT3 following IL-6 addition XREF_BIBR , XREF_BIBR .	Similarly, the absence of Jak1 profoundly affects the IL-6 pathway as elimination of Jak1 was sufficient to fully abrogate any detectable phospho-STAT1 and greatly reduce phospho-STAT3 following IL-6 addition XREF_BIBR, XREF_BIBR.	12	30	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak1	Jak1	Jak1	phospho-STAT3	phospho-STAT3	phospho-STAT3	14	15	26	27
Selective Jak1 and Jak2 inhibitors can also inhibit Il-6 and Stat3 signaling and concomitantly reduce tumor growth in xenograft models XREF_BIBR .	Selective Jak1 and Jak2 inhibitors can also inhibit Il-6 and Stat3 signaling and concomitantly reduce tumor growth in xenograft models XREF_BIBR.	0	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak1	Jak1	Jak1	Stat3	Stat3	Stat3	1	2	10	11
JAK1 knockdown in MCF-7 cells abrogated IL-6-induced STAT3 phosphorylation , consistent with its dependence on this kinase ( XREF_FIG , left ) , whereas silencing JAK2 had no apparent effect on IL-6-induced STAT3 phosphorylation , indicating that MUC1-C regulates JAK1 mediated activation of STAT3 ( XREF_FIG , right ) .	JAK1 knockdown in MCF-7 cells abrogated IL-6-induced STAT3 phosphorylation, consistent with its dependence on this kinase (XREF_FIG, left), whereas silencing JAK2 had no apparent effect on IL-6-induced STAT3 phosphorylation, indicating that MUC1-C regulates JAK1 mediated activation of STAT3 (XREF_FIG, right).	39	45	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	39	40	43	44
JAK1 siRNA completely blocked STAT3 activation by IL-6 .	JAK1 siRNA completely blocked STAT3 activation by IL-6.	0	5	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	0	1	4	5
Computer models with docking simulation showed that LLL12 binds directly to the phosphorylated tyrosine 705 binding site of the STAT3 monomers , and this is confirmed in this study in that LLL12 did not inhibit the activation of STAT3 upstream kinases , JAK1 , JAK2 and TYK2 ( XREF_FIG ) .	Computer models with docking simulation showed that LLL12 binds directly to the phosphorylated tyrosine 705 binding site of the STAT3 monomers, and this is confirmed in this study in that LLL12 did not inhibit the activation of STAT3 upstream kinases, JAK1, JAK2 and TYK2 (XREF_FIG).	34	48	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	42	43	38	39
Knockdown of JAK1 inhibited P-STAT3 but not P-STAT6 , whereas knockdown of JAK2 inhibited P-STAT6 but not P-STAT3 ( XREF_FIG ) .	Knockdown of JAK1 inhibited P-STAT3 but not P-STAT6, whereas knockdown of JAK2 inhibited P-STAT6 but not P-STAT3 (XREF_FIG).	0	7	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK1	JAK1	JAK1	P-STAT3	P-STAT3	P-STAT3	2	3	4	5
miR-449a and miR-107 target IL-6R and JAK1 respectively and inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes .	miR-449a and miR-107 target IL-6R and JAK1 respectively and inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes.	0	15	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK1	JAK1	JAK1	STAT3	STAT3	STAT3	6	7	14	15
Here , we report that TRAF3 associates with PTPN22 in B cells to inhibit the IL-6-dependent activation of STAT3 by Jak1 .	Here, we report that TRAF3 associates with PTPN22 in B cells to inhibit the IL-6-dependent activation of STAT3 by Jak1.	13	21	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Jak1	Jak1	Jak1	STAT3	STAT3	STAT3	20	21	18	19
In summary , these data suggest that activated EGFR is negatively regulated by activated JAK2 in part by bringing SOCS5 to EGFR , leading to its degradation .	In summary, these data suggest that activated EGFR is negatively regulated by activated JAK2 in part by bringing SOCS5 to EGFR, leading to its degradation.	7	16	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	EGFR	EGFR	EGFR	14	15	8	9
JAK2 inhibition increases EGFR signaling .	JAK2 inhibition increases EGFR signaling.	0	4	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	EGFR	EGFR	EGFR	0	1	3	4
Conversely , we asked whether overexpression of a constitutively active form of JAK2 ( JAK2 V617F ) could decrease pEGFR abundance in NSCLC cell lines .	Conversely, we asked whether overexpression of a constitutively active form of JAK2 (JAK2 V617F) could decrease pEGFR abundance in NSCLC cell lines.	10	20	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	pEGFR	pEGFR	pEGFR	12	13	19	20
Conversely , enforced expression of activated JAK2 could attenuate EGFR signaling possibly through a mechanism involving JAK2 mediated increased SOCS4/5 recruitment to the EGFR .	Conversely, enforced expression of activated JAK2 could attenuate EGFR signaling possibly through a mechanism involving JAK2 mediated increased SOCS4/5 recruitment to the EGFR.	3	10	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	expression of activated JAK2	jak2	EGFR	EGFR	egfr	6	7	9	10
In summary , these data suggest that activated JAK2 reduces EGFR abundance by coupling the negative regulatory SOCS4/5 proteins to EGFR ( XREF_FIG ) .	In summary, these data suggest that activated JAK2 reduces EGFR abundance by coupling the negative regulatory SOCS4/5 proteins to EGFR (XREF_FIG).	7	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	EGFR	EGFR	EGFR	8	9	10	11
Together , our data demonstrate that JAK2 inhibition enhances EGFR signaling in NSCLC cell lines , xenografts , and transgenic mice .	Together, our data demonstrate that JAK2 inhibition enhances EGFR signaling in NSCLC cell lines, xenografts, and transgenic mice.	6	10	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	EGFR	EGFR	EGFR	6	7	9	10
JAK2 inhibition increases the surface abundance of EGFR by decreasing the association of EGFR with SOCS5 .	JAK2 inhibition increases the surface abundance of EGFR by decreasing the association of EGFR with SOCS5.	0	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	EGFR	EGFR	EGFR	0	1	7	8
Silencing of miR-199b-5p due to epigenetic changes , including promoter CpG island methylation , activates the JAG1 mediated Notch1 signaling cascade , leading to the development of acquired resistance in ovarian cancer .	Silencing of miR-199b-5p due to epigenetic changes, including promoter CpG island methylation, activates the JAG1 mediated Notch1 signaling cascade, leading to the development of acquired resistance in ovarian cancer.	15	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	Notch1	Notch1	Notch1	16	17	18	19
N1 1-13 decoy inhibited DLL4 induced Notch1 signaling but not JAG1 mediated Notch1 signaling ( XREF_FIG ) .	N1 1-13 decoy inhibited DLL4 induced Notch1 signaling but not JAG1 mediated Notch1 signaling (XREF_FIG).	5	13	mediated	Positive_early_activation	Positive_activation	Negative_activation	JAG1	JAG1	JAG1	Notch1	Notch1	Notch1	10	11	12	13
Interestingly , suppression of Jagged1 induced Notch1 signaling did not correlate with changes in Jagged1 binding as found for Delta1 .	Interestingly, suppression of Jagged1 induced Notch1 signaling did not correlate with changes in Jagged1 binding as found for Delta1.	2	7	induced	Positive_early_activation	Positive_activation	Negative_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	4	5	6	7
EGFL7 -/- neurospheres displayed an increased self-renewal potential and became larger , which was likely mediated by the previously reported inhibition of Jagged1 induced Notch1 signalling XREF_BIBR .	EGFL7 -/- neurospheres displayed an increased self-renewal potential and became larger, which was likely mediated by the previously reported inhibition of Jagged1 induced Notch1 signalling XREF_BIBR.	20	26	induced	Positive_early_activation	Positive_activation	Negative_activation	Jagged1	Jagged1	Jagged1	Notch1	Notch1	Notch1	22	23	24	25
In cell lines expressing Lfng or Mfng , even saturating expression of Jag1 was not sufficient to reduce Notch1 availability to background levels , in contrast to Dll1 , indicating that Lfng and Mfng reduce cis interactions for Jag1 , but not Dll1 ( XREF_FIG ) .	In cell lines expressing Lfng or Mfng, even saturating expression of Jag1 was not sufficient to reduce Notch1 availability to background levels, in contrast to Dll1, indicating that Lfng and Mfng reduce cis interactions for Jag1, but not Dll1 (XREF_FIG).	10	19	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jag1	expression of Jag1	jag1	Notch1	Notch1	notch1	12	13	18	19
However , the decrease in Jagged1 triggered Notch2 signaling by mFng was again greater than that by lFng .	However, the decrease in Jagged1 triggered Notch2 signaling by mFng was again greater than that by lFng.	3	8	triggered	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Jagged1	Jagged1	Jagged1	Notch2	Notch2	Notch2	5	6	7	8
Icariin improves osteoporosis , inhibits the expression of PPARgamma , C/EBPalpha , FABP4 mRNA , N1ICD and jagged1 proteins , and increases Notch2 mRNA in ovariectomized rats .	Icariin improves osteoporosis, inhibits the expression of PPARgamma, C/EBPalpha, FABP4 mRNA, N1ICD and jagged1 proteins, and increases Notch2 mRNA in ovariectomized rats.	0	23	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	jagged1	Icariin improves osteoporosis, inhibits the expression of PPARgamma, C/EBPalpha, FABP4 mRNA, N1ICD and jagged1	jagged1	Notch2	Notch2	notch2	17	18	22	23
JAG1 is highly expressed in the vast majority of MBs and homogeneously distributed across subgroups ; moreover , JAG1 depletion inhibited pro proliferative NOTCH2 signals and caused a decrease in expression of HES1 , which plays a central role in MB pathogenesis [ XREF_BIBR - XREF_BIBR ] .	JAG1 is highly expressed in the vast majority of MBs and homogeneously distributed across subgroups; moreover, JAG1 depletion inhibited pro proliferative NOTCH2 signals and caused a decrease in expression of HES1, which plays a central role in MB pathogenesis [XREF_BIBR - XREF_BIBR].	18	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAG1	JAG1	JAG1	NOTCH2	NOTCH2	NOTCH2	18	19	23	24
A significant reduction in CD133 , VASP , LAMB1 , IQGAP1 , ROCK2 ( p < 0.05 ) and NOTCH2 , JAG1 , RAB25 ( p < 0.01 ) expression was observed ( XREF_FIG B ) .	A significant reduction in CD133, VASP, LAMB1, IQGAP1, ROCK2 (p < 0.05) and NOTCH2, JAG1, RAB25 (p < 0.01) expression was observed (XREF_FIG B).	2	30	reduction	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	JAG1	JAG1, RAB25 (p < 0.01) expression	jag1	NOTCH2	NOTCH2	notch2	21	22	19	20
These JAK2 variants also reduced the responsiveness of erythropoietin receptor ( EpoR )-expressing Ba/F3 cells to this JAK inhibitor .	These JAK2 variants also reduced the responsiveness of erythropoietin receptor (EpoR)-expressing Ba/F3 cells to this JAK inhibitor.	1	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	erythropoietin receptor	erythropoietin receptor	erythropoietin receptor	1	2	8	10
This is consistent with previous findings showing that JAK2 mediated degradation of EPOR is dependent on another E3 ligase containing the F-box protein beta-TrCP XREF_BIBR , XREF_BIBR and that progenitor cells from SOCS-1 -/- mice are hypersensitive towards GM-CSF but not to other cytokines such as M-CSF or G-CSF XREF_BIBR , XREF_BIBR .	This is consistent with previous findings showing that JAK2 mediated degradation of EPOR is dependent on another E3 ligase containing the F-box protein beta-TrCP XREF_BIBR, XREF_BIBR and that progenitor cells from SOCS-1 -/- mice are hypersensitive towards GM-CSF but not to other cytokines such as M-CSF or G-CSF XREF_BIBR, XREF_BIBR.	8	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	EPOR	EPOR	EPOR	8	9	12	13
Taken together , these data suggest that inhibition of JAK2 by toxin A in colonocytes causes inactivation of EpoR , thereby enhancing the inhibition of focal contact formation and loss of tight junctions known to be associated with the enzymatic activity of toxin A.	Taken together, these data suggest that inhibition of JAK2 by toxin A in colonocytes causes inactivation of EpoR, thereby enhancing the inhibition of focal contact formation and loss of tight junctions known to be associated with the enzymatic activity of toxin A.	7	19	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	EpoR	EpoR	EpoR	9	10	18	19
However , in that system , dephosphorylation of JAK2 by SHP-1 does not prevent EPO-R signaling but acts as negative feedback to return the EPO-R to its basal , unphosphorylated , state .	However, in that system, dephosphorylation of JAK2 by SHP-1 does not prevent EPO-R signaling but acts as negative feedback to return the EPO-R to its basal, unphosphorylated, state.	6	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	dephosphorylation of JAK2	jak2	EPO-R	EPO-R	epo-r	8	9	14	15
Our results demonstrated substantial inhibition of Stat6 activation in monocytes treated with Jak1 antisense ODN , whereas treatment with the scrambled ODN control showed no inhibitory effect on Stat6 activation and tyrosine phosphorylation ( XREF_FIG , upper panel ) .	Our results demonstrated substantial inhibition of Stat6 activation in monocytes treated with Jak1 antisense ODN, whereas treatment with the scrambled ODN control showed no inhibitory effect on Stat6 activation and tyrosine phosphorylation (XREF_FIG, upper panel).	6	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Jak1	Jak1	Jak1	Stat6	Stat6	Stat6	12	13	6	7
We showed here that Jag-1 expression by cancer cells was important to limit the dependence receptor function of Notch3 .	We showed here that Jag-1 expression by cancer cells was important to limit the dependence receptor function of Notch3.	4	19	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jag-1	Jag-1 expression	jag-1	Notch3	Notch3	notch3	4	5	18	19
We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro apoptotic activity is blocked by Jagged-1 .	We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro apoptotic activity is blocked by Jagged-1.	2	21	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Jagged-1	Jagged-1	Jagged-1	Notch3	Notch3	Notch3	20	21	3	4
STAT1 was phosphorylated in MCF-7 cells treated with ASC-CM , and JAK1 and JAK2 inhibitor treatment decreased STAT1 phosphorylation .	STAT1 was phosphorylated in MCF-7 cells treated with ASC-CM, and JAK1 and JAK2 inhibitor treatment decreased STAT1 phosphorylation.	0	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	JAK1	JAK1	JAK1	STAT1	STAT1	STAT1	11	12	0	1
Knockdown of Jagged2 by expressing shRNAs inhibited the activation of NOTCH1 , suppressed epithelial-mesenchymal transition ( EMT ) and invasion , and abrogated metastasis in a syngeneic tumor metastasis model using lung adenocarcinoma cell lines derived from the KRAS G12D ; p53 R172HDeltaG mice [ XREF_BIBR ] .	Knockdown of Jagged2 by expressing shRNAs inhibited the activation of NOTCH1, suppressed epithelial-mesenchymal transition (EMT) and invasion, and abrogated metastasis in a syngeneic tumor metastasis model using lung adenocarcinoma cell lines derived from the KRAS G12D; p53 R172HDeltaG mice [XREF_BIBR].	0	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Jagged2	Jagged2 by expressing	jagged2	NOTCH1	NOTCH1	notch1	2	3	10	11
Also , the HGF induced Jak2 dependent activation of a STAT3 reporter construct was attenuated after downregulation of Nox2 .	Also, the HGF induced Jak2 dependent activation of a STAT3 reporter construct was attenuated after downregulation of Nox2.	3	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	Jak2	HGF induced Jak2	jak2	STAT3	STAT3	stat3	5	6	10	11
From the above data , we concluded that Sch A may achieve an anti-inflammatory effect by inhibiting Jak2 and Stat3 phosphorylation and further blocking the nuclear translocation of Stat3 .	From the above data, we concluded that Sch A may achieve an anti-inflammatory effect by inhibiting Jak2 and Stat3 phosphorylation and further blocking the nuclear translocation of Stat3.	17	29	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	Jak2 and Stat3 phosphorylation	jak2	Stat3	Stat3	stat3	17	18	28	29
JAK2 dependent pharmacological inhibition of pSTAT3 reduces occlusion and reperfusion induced damage in adult models of middle cerebral artery occlusion ( Lei etal .	JAK2 dependent pharmacological inhibition of pSTAT3 reduces occlusion and reperfusion induced damage in adult models of middle cerebral artery occlusion (Lei etal.	0	6	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	pSTAT3	pSTAT3	pSTAT3	0	1	5	6
Furthermore , ablation of the Jak2 alleles in CD5 + B cells from tumor bearing mice abrogated tumor induced Stat3 activation in the CD5 + B cells ( XREF_FIG ) .	Furthermore, ablation of the Jak2 alleles in CD5 + B cells from tumor bearing mice abrogated tumor induced Stat3 activation in the CD5 + B cells (XREF_FIG).	5	20	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	5	6	19	20
Meanwhile , AG490 ( a specific inhibitor of the JAK2 and STAT3 signaling pathway ) and JAK2 siRNA were used to manipulate JAK2 and STAT3 activity .	Meanwhile, AG490 (a specific inhibitor of the JAK2 and STAT3 signaling pathway) and JAK2 siRNA were used to manipulate JAK2 and STAT3 activity.	6	17	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	16	17	11	12
When STAT3 activation was blocked by JAK2 and STAT3 inhibitor AG490 , RANKL failed to shut down CXCR6 expression during osteoclastogenesis .	When STAT3 activation was blocked by JAK2 and STAT3 inhibitor AG490, RANKL failed to shut down CXCR6 expression during osteoclastogenesis.	1	10	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	6	7	1	2
As shown above , the inhibition of JAK2 or signal blocking of STAT3 did not abolish completely the effect of icaritin on growth inhibiting and apoptosis-inducement of U266 cells .	As shown above, the inhibition of JAK2 or signal blocking of STAT3 did not abolish completely the effect of icaritin on growth inhibiting and apoptosis-inducement of U266 cells.	7	13	blocking	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	7	8	12	13
Inclusion of the Jak2 and Stat3 phoshorylation inhibitor AG490 ( Calbiochem , La Jolla , CA ) into the culture prevented Epo activation of Jak2 and Stat3 ( XREF_FIG , quantified in XREF_SUPPLEMENTARY -C ) .	Inclusion of the Jak2 and Stat3 phoshorylation inhibitor AG490 (Calbiochem, La Jolla, CA) into the culture prevented Epo activation of Jak2 and Stat3 (XREF_FIG, quantified in XREF_SUPPLEMENTARY -C).	0	28	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	Jak2	Jak2	Stat3	Stat3	Stat3	3	4	26	27
It appears that PTP1B mediated hypophosphorylation of Jak2 can abrogate leptin dependent induction of the STAT3 and MAPK inducible SOCS3 and c-fos genes , respectively .	It appears that PTP1B mediated hypophosphorylation of Jak2 can abrogate leptin dependent induction of the STAT3 and MAPK inducible SOCS3 and c-fos genes, respectively.	3	16	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	PTP1B mediated hypophosphorylation of Jak2	jak2	STAT3	STAT3	stat3	7	8	15	16
In the present study , the effect of an AA derivative - AA-PMe - on signaling pathway of both constitutively active and JAK2 inhibited STAT3 in two gastric cancer cell lines .	In the present study, the effect of an AA derivative - AA-PMe - on signaling pathway of both constitutively active and JAK2 inhibited STAT3 in two gastric cancer cell lines.	6	25	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	22	23	24	25
As expected , AG490 and JAK2 siRNA effectively inhibited p-JAK2 and p-STAT3 .	As expected, AG490 and JAK2 siRNA effectively inhibited p-JAK2 and p-STAT3.	3	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	p-STAT3	p-STAT3	p-STAT3	5	6	11	12
Both the STAT3 selective inhibitor stattic and the JAK2 ( Janus kinase 2 )/STAT3-selective inhibitors AG490 and Go6976 inhibited STAT3 activation , leading to the suppression of adipocyte differentiation .	Both the STAT3 selective inhibitor stattic and the JAK2 (Janus kinase 2)/STAT3-selective inhibitors AG490 and Go6976 inhibited STAT3 activation, leading to the suppression of adipocyte differentiation.	5	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	19	20
AG490 ( a specific inhibitor of the JAK2 and STAT3 signaling pathway ) and JAK2 siRNA were used to manipulate JAK2 and STAT3 activity , and the results showed that AG490 and JAK2 siRNA inhibited OSI and the levels of p-JAK2 and p-STAT3 .	AG490 (a specific inhibitor of the JAK2 and STAT3 signaling pathway) and JAK2 siRNA were used to manipulate JAK2 and STAT3 activity, and the results showed that AG490 and JAK2 siRNA inhibited OSI and the levels of p-JAK2 and p-STAT3.	4	15	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	14	15	9	10
Furthermore , inhibition of JAK2 with AG490 prevented AngII induced hypertension and decreased the activity of STAT3 .	Furthermore, inhibition of JAK2 with AG490 prevented AngII induced hypertension and decreased the activity of STAT3.	2	17	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	4	5	16	17
Next , the AG490 JAK2 and STAT3 inhibitor was used to inhibit STAT3 activation .	Next, the AG490 JAK2 and STAT3 inhibitor was used to inhibit STAT3 activation.	2	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	4	5	12	13
We next asked whether pacritinib demonstrated specificity for reducing JAK2 mediated STAT3 activity .	We next asked whether pacritinib demonstrated specificity for reducing JAK2 mediated STAT3 activity.	8	12	mediated	Positive_early_activation	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	9	10	11	12
In this model , STAT-3 activation is blocked by a dominant negative mutant of Src , but not that of JAK-2 .	In this model, STAT-3 activation is blocked by a dominant negative mutant of Src, but not that of JAK-2.	4	21	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	JAK-2	JAK-2	JAK-2	STAT-3	STAT-3	STAT-3	20	21	4	5
Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570 , reduces JAK2 and STAT3 signaling , inhibits TGFbeta induced fibroblast activation and ameliorates dermal and pulmonary fibrosis .	Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570, reduces JAK2 and STAT3 signaling, inhibits TGFbeta induced fibroblast activation and ameliorates dermal and pulmonary fibrosis.	5	18	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	SHP2 promotes accumulation of JAK2 phosphorylated at Y570	jak2	STAT3	STAT3	stat3	9	10	17	18
AG490 and TG101348 , two JAK2 specific inhibitors , have been shown to impair the JAK2 and STAT3 signaling pathway in platelets , inhibiting platelet aggregation and activation in collagen stimulated human platelets and platelet plug formation in a mouse model of irradiated mesenteric venules [ XREF_BIBR ] .	AG490 and TG101348, two JAK2 specific inhibitors, have been shown to impair the JAK2 and STAT3 signaling pathway in platelets, inhibiting platelet aggregation and activation in collagen stimulated human platelets and platelet plug formation in a mouse model of irradiated mesenteric venules [XREF_BIBR].	0	19	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	5	6	17	18
Application of the JAK2 and STAT3 signaling pathway blocker AG490 partially blocked the activation of the JAK2 and STAT3 signaling pathway and reduced the Bax and Bcl -2 ratio and finally caused a significant decrease in the cell apoptosis rate .	Application of the JAK2 and STAT3 signaling pathway blocker AG490 partially blocked the activation of the JAK2 and STAT3 signaling pathway and reduced the Bax and Bcl -2 ratio and finally caused a significant decrease in the cell apoptosis rate.	0	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	3	4	18	19
Previous studies in non lymphoid cells demonstrated that treatment with WP1066 , a derivative of the classic JAK2 inhibiting compound AG490 , inhibited both JAK2 and STAT3 activation , leading to inhibition of proliferation and induction of apoptosis in malignant glioma and melanoma cells .	Previous studies in non lymphoid cells demonstrated that treatment with WP1066, a derivative of the classic JAK2 inhibiting compound AG490, inhibited both JAK2 and STAT3 activation, leading to inhibition of proliferation and induction of apoptosis in malignant glioma and melanoma cells.	13	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	17	18	26	27
BBMD3 , another JAK2 inhibitor , which inhibited autophosphorylation of JAK2 and blocked activation of downstream STAT3 signaling in melanoma cells [ XREF_BIBR ] .	BBMD3, another JAK2 inhibitor, which inhibited autophosphorylation of JAK2 and blocked activation of downstream STAT3 signaling in melanoma cells [XREF_BIBR].	0	17	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	BBMD3, another JAK2 inhibitor, which inhibited autophosphorylation of JAK2	jak2	STAT3	STAT3	stat3	10	11	16	17
The combination of TYK2 and JAK2 depletion completely abrogated the reactivation of STAT3 after dasatinib exposure ( XREF_FIG ) .	The combination of TYK2 and JAK2 depletion completely abrogated the reactivation of STAT3 after dasatinib exposure (XREF_FIG).	3	13	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	5	6	12	13
These data show essential roles for Src and JAK2 inactivation of STAT3 .	These data show essential roles for Src and JAK2 inactivation of STAT3.	6	12	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	8	9	11	12
However , the JAK2 and STAT3 inhibitor WP1066 prevented IL-6-induced activation of the JAK2 and STAT3 pathway and EMT .	However, the JAK2 and STAT3 inhibitor WP1066 prevented IL-6-induced activation of the JAK2 and STAT3 pathway and EMT.	2	16	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	STAT3	STAT3	STAT3	3	4	15	16
Investigated was the role of MKPs in the PTH induced attenuation of MAPK and Jun N-terminal kinase ( JNK ) signaling in osteoblast like UMR106-01 cells .	Investigated was the role of MKPs in the PTH induced attenuation of MAPK and Jun N-terminal kinase (JNK) signaling in osteoblast like UMR106-01 cells.	9	19	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	Jun	Jun	Jun	18	19	14	15
In addition , Ang-( 1-7 ) via Mas prevented the apoptosis of alveolar epithelial cells and the Jun N-terminal kinase ( JNK ) activation induced by bleomycin [ XREF_BIBR ] .	In addition, Ang-(1-7) via Mas prevented the apoptosis of alveolar epithelial cells and the Jun N-terminal kinase (JNK) activation induced by bleomycin [XREF_BIBR].	8	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	Jun	Jun	Jun	21	22	17	18
GR mediated inhibition of AP-1 is achieved by three mechanisms ( XREF_FIG ) : 1 ) binding to a GRE on the promoter and tethering to c-Jun to repress the transcriptional activity of AP-1 ; 2 ) direct interaction of GR ( tethering ) with the c-Jun subunit of AP-1 ; 3 ) induction of MKP-1 to inactivate JNK , which in turn decreases c-Jun transcriptional activity .	GR mediated inhibition of AP-1 is achieved by three mechanisms (XREF_FIG) : 1) binding to a GRE on the promoter and tethering to c-Jun to repress the transcriptional activity of AP-1; 2) direct interaction of GR (tethering) with the c-Jun subunit of AP-1; 3) induction of MKP-1 to inactivate JNK, which in turn decreases c-Jun transcriptional activity.	57	66	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	58	59	64	65
Thus the transactivation domain of c-Jun recruits Mbd3 and NuRD to AP-1 target genes to mediate gene repression , and this repression is relieved by JNK mediated c-Jun N-terminal phosphorylation .	Thus the transactivation domain of c-Jun recruits Mbd3 and NuRD to AP-1 target genes to mediate gene repression, and this repression is relieved by JNK mediated c-Jun N-terminal phosphorylation.	23	28	mediated	Positive_early_activation	Positive_activation	Negative_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	25	26	27	28
All three major isozymes ( alpha , mu , and pi ) bind to JNK-jun complexes and inhibit activation of jun by JNK .	All three major isozymes (alpha, mu, and pi) bind to JNK-jun complexes and inhibit activation of jun by JNK.	17	23	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	JNK	JNK	JNK	jun	jun	jun	22	23	20	21
MKN-1 proliferation was suppressed by DUSP9 by inhibiting c-Jun , which was induced by JNK signaling .	MKN-1 proliferation was suppressed by DUSP9 by inhibiting c-Jun, which was induced by JNK signaling.	3	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	14	15	8	9
Biochemically , JNK2 has a 25-fold higher binding affinity for c-Jun than JNK1 , which is the major JNK isoform that binds to and constitutively degrades c-Jun under steady-state conditions [ XREF_BIBR , XREF_BIBR ] .	Biochemically, JNK2 has a 25-fold higher binding affinity for c-Jun than JNK1, which is the major JNK isoform that binds to and constitutively degrades c-Jun under steady-state conditions [XREF_BIBR, XREF_BIBR].	18	27	degrades	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	18	19	26	27
We hypothesized that reduced MAP3K11 expression would result in decreased JNK mediated activation of c-Jun , a component of the AP-1 transcription factor , which enhances cyclin D1 transcription [ XREF_BIBR ] .	We hypothesized that reduced MAP3K11 expression would result in decreased JNK mediated activation of c-Jun, a component of the AP-1 transcription factor, which enhances cyclin D1 transcription [XREF_BIBR].	10	17	mediated	Positive_early_activation	Positive_activation	Negative_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	10	11	14	15
puckered ( puc ) encodes a VH1 like phosphatase that down-regulates Jun kinase ( JNK ) activity during dorsal closure of the Drosophila embryo .	puckered (puc) encodes a VH1 like phosphatase that down-regulates Jun kinase (JNK) activity during dorsal closure of the Drosophila embryo.	8	15	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	Jun	Jun	Jun	14	15	11	12
In addition , JNK1/2 mediated c-Jun activation inhibited MDR1 expression in multidrug resistant K562 and A02 cells [ XREF_BIBR ] .	In addition, JNK1/2 mediated c-Jun activation inhibited MDR1 expression in multidrug resistant K562 and A02 cells [XREF_BIBR].	3	6	mediated	Positive_early_activation	Positive_activation	Negative_activation	JNK1/2	JNK1/2	JNK1/2	c-Jun	c-Jun	c-Jun	3	4	5	6
Therefore , it is very reasonable to suggest that the observed inhibition of c-Jun mRNA by PPS could be an indication of PPS ability to directly interact with JNK thereby impairing the activation of c-Jun .	Therefore, it is very reasonable to suggest that the observed inhibition of c-Jun mRNA by PPS could be an indication of PPS ability to directly interact with JNK thereby impairing the activation of c-Jun.	26	35	impairing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	28	29	34	35
Targeted inhibition of JNK with BI-78D3 ( Tocris Bioscience , Bristol , UK ) resulted in increased levels of the JNK target c-Jun in the cytoplasm , but no change in the subcellular localization of the nuclear factor-kappaB RelA subunit ( XREF_SUPPLEMENTARY ) .	Targeted inhibition of JNK with BI-78D3 (Tocris Bioscience, Bristol, UK) resulted in increased levels of the JNK target c-Jun in the cytoplasm, but no change in the subcellular localization of the nuclear factor-kappaB RelA subunit (XREF_SUPPLEMENTARY).	17	23	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	20	21	22	23
[ XREF_BIBR ] Some investigations have shown that JNK might decrease cell proliferation by activating its downstream effector c-Jun .	[XREF_BIBR] Some investigations have shown that JNK might decrease cell proliferation by activating its downstream effector c-Jun.	8	19	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	8	9	18	19
In support of this hypothesis , we demonstrate that the decrease of BDNF promoter activity by acrolein and 4HNE could be restored ( i ) by cotransfection with CBP , ( ii ) by cotransfection with VP 16-CREB , a constitutively active form of CREB that does not depend on CBP for its activation , or ( iii ) by inhibiting JNK mediated c-jun activation .	In support of this hypothesis, we demonstrate that the decrease of BDNF promoter activity by acrolein and 4HNE could be restored (i) by cotransfection with CBP, (ii) by cotransfection with VP 16-CREB, a constitutively active form of CREB that does not depend on CBP for its activation, or (iii) by inhibiting JNK mediated c-jun activation.	60	64	mediated	Positive_early_activation	Positive_activation	Negative_activation	JNK	JNK	JNK	c-jun	c-jun	c-jun	61	62	63	64
NleD cleaves the c-Jun N-terminal kinase ( JNK ) thus blocking activator protein-1 ( AP-1 ) activation .	NleD cleaves the c-Jun N-terminal kinase (JNK) thus blocking activator protein-1 (AP-1) activation.	3	13	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	activator protein-1	activator protein-1	activator protein-1	3	6	11	13
Notably , Down-regulation of the phosphorylation level of JNK inhibited the activity of c-Jun and its transcription , which further affect its protein level .	Notably, Down-regulation of the phosphorylation level of JNK inhibited the activity of c-Jun and its transcription, which further affect its protein level.	6	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	level of JNK	jnk	c-Jun	c-Jun	c-jun	8	9	13	14
The results showed that the virally mediated expression of Hsp70 mirrored the effects of the c-Jun-N-terminal kinase ( JNK ) binding domain ( JBD ) of JNK interacting protein ( an inhibitor of JNK and c-Jun activation ) and suppressed the phosphorylation of c-Jun .	The results showed that the virally mediated expression of Hsp70 mirrored the effects of the c-Jun-N-terminal kinase (JNK) binding domain (JBD) of JNK interacting protein (an inhibitor of JNK and c-Jun activation) and suppressed the phosphorylation of c-Jun.	26	36	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	26	27	35	36
In the present study , we demonstrate that an anthrapyrazole SP600125 , a reversible ATP-competitive inhibitor of JNK inhibits proliferation of human HMC-1 showed constitutive activation of JNK and c-Jun , and the inhibitory effect of SP600125 on cell proliferation was associated with cell cycle arrest at the G1 phase and apoptosis accompanied by the cleavage of caspase-3 and PARP .	In the present study, we demonstrate that an anthrapyrazole SP600125, a reversible ATP-competitive inhibitor of JNK inhibits proliferation of human HMC-1 showed constitutive activation of JNK and c-Jun, and the inhibitory effect of SP600125 on cell proliferation was associated with cell cycle arrest at the G1 phase and apoptosis accompanied by the cleavage of caspase-3 and PARP.	15	30	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	17	18	29	30
It has been suggested that inactive JNK downregulates c-Jun transcriptional activity by binding to the c-Jun delta-domain .	It has been suggested that inactive JNK downregulates c-Jun transcriptional activity by binding to the c-Jun delta-domain.	5	10	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	c-Jun	c-Jun	c-Jun	6	7	8	9
Indeed , JNK was found to phosphorylate the E3 ubiquitin ligase Itch , leading to its functional activation and consequently , accelerated degradation of c-Jun and JunB .	Indeed, JNK was found to phosphorylate the E3 ubiquitin ligase Itch, leading to its functional activation and consequently, accelerated degradation of c-Jun and JunB.	2	26	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK was found to phosphorylate the E3 ubiquitin ligase Itch	jnk	c-Jun	c-Jun	c-jun	2	3	24	25
For example , reduced activation of Jun NH2-terminal kinase ( JNK ) , inhibitor of k-B kinase-beta ( IKK-beta ) , or TLR4 in immune cells and parenchymal cells has been demonstrated to reduce the systemic inflammation associated with obesity and to improve the metabolic profile .	For example, reduced activation of Jun NH2-terminal kinase (JNK), inhibitor of k-B kinase-beta (IKK-beta), or TLR4 in immune cells and parenchymal cells has been demonstrated to reduce the systemic inflammation associated with obesity and to improve the metabolic profile.	3	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	Jun	Jun	Jun	10	11	6	7
It is conceivable that increased JNK expression and function perturbs the capacity of high pAKT levels to inhibit FOXO function [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It is conceivable that increased JNK expression and function perturbs the capacity of high pAKT levels to inhibit FOXO function [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	19	perturbs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK	JNK expression	jnk	FOXO	FOXO	foxo	5	6	18	19
Experiments in Drosophila have further shown that the JNK pathway normally antagonizes insulin signaling in neuroendocrine cells by promoting nuclear localization of FOXO .	Experiments in Drosophila have further shown that the JNK pathway normally antagonizes insulin signaling in neuroendocrine cells by promoting nuclear localization of FOXO.	8	23	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	FOXO	FOXO	FOXO	8	9	22	23
JNK Silencing Modulates the Activity of the Downstream Substrates of Insulin Signaling GSK3beta and FoxO in Cytokine treated Cells .	JNK Silencing Modulates the Activity of the Downstream Substrates of Insulin Signaling GSK3beta and FoxO in Cytokine treated Cells.	0	15	Modulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	FoxO	FoxO	FoxO	0	1	14	15
While JNK has clearly been shown to antagonize IIS ( activate Foxo ) in C. elegans and Drosophila , that exact mechanism by which Foxo activation is achieved may be divergent in mammals .	While JNK has clearly been shown to antagonize IIS (activate Foxo) in C. elegans and Drosophila, that exact mechanism by which Foxo activation is achieved may be divergent in mammals.	1	12	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	Foxo	Foxo	Foxo	1	2	11	12
To assess the involvement of JNK in P. gingivalis induced FOXO activity , JNK was inhibited pharmacologically and by siRNA .	To assess the involvement of JNK in P. gingivalis induced FOXO activity, JNK was inhibited pharmacologically and by siRNA.	10	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	FOXO	FOXO	FOXO	13	14	10	11
Bcl-2 and Bim , the apoptosis inducing substrates of JNK , are inhibited and activated by JNK phosphorylation , respectively [ XREF_BIBR , XREF_BIBR ] .	Bcl-2 and Bim, the apoptosis inducing substrates of JNK, are inhibited and activated by JNK phosphorylation, respectively [XREF_BIBR, XREF_BIBR].	0	18	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	JNK	JNK phosphorylation	jnk	Bim	Bim	bim	16	17	2	3
In the presence of toxic levels of Abeta , we observe that E2 attenuates indices of neuronal apoptosis : c-Jun N-terminal kinase ( JNK )-dependent downregulation of Bcl-w and upregulation of Bim , mitochondrial release of cytochrome c and Smac , and cell death .	In the presence of toxic levels of Abeta, we observe that E2 attenuates indices of neuronal apoptosis : c-Jun N-terminal kinase (JNK)-dependent downregulation of Bcl-w and upregulation of Bim, mitochondrial release of cytochrome c and Smac, and cell death.	19	32	downregulation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	c-Jun N-terminal kinase	c-Jun N-terminal kinase	c-Jun N-terminal kinase	Bim	Bim	Bim	19	22	31	32
Furthermore , the DP1 agonist suppressed JAK2 and STAT1 phosphorylation , also increasing that of STAT6 in macrophages .	Furthermore, the DP1 agonist suppressed JAK2 and STAT1 phosphorylation, also increasing that of STAT6 in macrophages.	3	16	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JAK2	DP1 agonist suppressed JAK2 and STAT1 phosphorylation	jak2	STAT6	STAT6	stat6	6	7	15	16
Our results , presented in XREF_FIG ( upper panel ) , further reveal that antisense ODN against Tyk2 significantly blocked the IL-13-stimulated activation of Stat6 ( phosphorylation at a specific tyrosine residue , Tyr 641 ) whereas Jak2 antisense , Jak2 sense and Tyk2 sense ODN did not inhibit Stat6 activation .	Our results, presented in XREF_FIG (upper panel), further reveal that antisense ODN against Tyk2 significantly blocked the IL-13-stimulated activation of Stat6 (phosphorylation at a specific tyrosine residue, Tyr 641) whereas Jak2 antisense, Jak2 sense and Tyk2 sense ODN did not inhibit Stat6 activation.	37	50	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	Jak2	Jak2	Stat6	Stat6	Stat6	37	38	49	50
The drug ASP015K inhibits JAK 3 and INCB28050 inhibits JAK 1 and JAK 2 .	The drug ASP015K inhibits JAK 3 and INCB28050 inhibits JAK 1 and JAK 2.	4	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK 3	JAK 3	JAK 3	JAK 1	JAK 1	JAK 1	4	6	9	11
A secondary level of specificity is present in that SOCS3 can only inhibit JAK1 , JAK2 and TYK2 but not JAK3 ( See XREF_FIG ) .	A secondary level of specificity is present in that SOCS3 can only inhibit JAK1, JAK2 and TYK2 but not JAK3 (See XREF_FIG).	6	22	inhibit	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	JAK3	JAK3	JAK3	JAK1	JAK1	JAK1	20	21	13	14
In turn , BBT594 fully inhibited both , constitutive and TSLP induced p-JAK2 and inhibited p-STAT5 to the baseline level .	In turn, BBT594 fully inhibited both, constitutive and TSLP induced p-JAK2 and inhibited p-STAT5 to the baseline level.	10	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p-JAK2	TSLP induced p-JAK2	p-jak2	p-STAT5	p-STAT5	p-stat5	12	13	15	16
Following differentiation , SOCS6 was found to form a ternary complex with IGFR ( Insulin Like Growth Factor-1 Receptor ) and JAK2 which acted in a negative feedback loop to inhibit pStat5 activation .	Following differentiation, SOCS6 was found to form a ternary complex with IGFR (Insulin Like Growth Factor-1 Receptor) and JAK2 which acted in a negative feedback loop to inhibit pStat5 activation.	7	32	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JAK2	JAK2	JAK2	pStat5	pStat5	pStat5	21	22	31	32
Both compounds efficiently inhibit ATF2 transcriptional activities , activate JNK , and increase c-Jun transcriptional activities .	Both compounds efficiently inhibit ATF2 transcriptional activities, activate JNK, and increase c-Jun transcriptional activities.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	ATF2	ATF2	ATF2	9	10	4	5
Furthermore , expression of dominant negative JNK inhibited ATF2 transcriptional activity .	Furthermore, expression of dominant negative JNK inhibited ATF2 transcriptional activity.	2	10	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	expression of dominant negative JNK	jnk	ATF2	ATF2	atf2	6	7	8	9
Immunodepletion of Jak2 virtually eliminated the ligand dependent binding of STAT1 to the AT ( 1 ) receptor .	Immunodepletion of Jak2 virtually eliminated the ligand dependent binding of STAT1 to the AT (1) receptor.	0	11	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	Jak2	Jak2	STAT1	STAT1	STAT1	2	3	10	11
In mechanistic studies , Jak2 deficiency attenuated Raf-1 and MEK1 signaling , which then reduced activity of Sp-1 , an essential transcription factor responsible for eNOS expression .	In mechanistic studies, Jak2 deficiency attenuated Raf-1 and MEK1 signaling, which then reduced activity of Sp-1, an essential transcription factor responsible for eNOS expression.	4	10	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Jak2	Jak2	Jak2	Raf-1	Raf-1	Raf-1	4	5	7	8
As beta-catenin promotes activation through forming a complex with TCF4 on the WRE , we wanted to determine if c-Jun inhibited the ability of TCF4 , in addition to beta-catenin , to activate the DKK1 promoter .	As beta-catenin promotes activation through forming a complex with TCF4 on the WRE, we wanted to determine if c-Jun inhibited the ability of TCF4, in addition to beta-catenin, to activate the DKK1 promoter.	19	25	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Jun	c-Jun	c-Jun	TCF4	TCF4	TCF4	19	20	24	25
Here , we report that the SAPK and JNK pathway inhibits the Smad3 pathway .	Here, we report that the SAPK and JNK pathway inhibits the Smad3 pathway.	6	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK	JNK	JNK	Smad3	Smad3	Smad3	8	9	12	13
However , SCF induced KIT trafficking from early to late endosome was severely impaired in CALM -/- MEFs .	However, SCF induced KIT trafficking from early to late endosome was severely impaired in CALM -/- MEFs.	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	SCF	SCF	SCF	KIT	KIT	KIT	2	3	4	5
Inhibition of SCF stimulated Kit activation and cell growth in the H526 cell line was dose dependent .	Inhibition of SCF stimulated Kit activation and cell growth in the H526 cell line was dose dependent.	0	5	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	SCF	SCF	SCF	Kit	Kit	Kit	2	3	4	5
Silencing of RIN3 increased the rate of SCF induced KIT internalization , while persistent RIN3 over-expression led to KIT down regulation .	Silencing of RIN3 increased the rate of SCF induced KIT internalization, while persistent RIN3 over-expression led to KIT down regulation.	5	10	induced	Positive_early_activation	Positive_activation	Positive_activation	SCF	SCF	SCF	KIT	KIT	KIT	7	8	9	10
Glyceollins have a depigmentation and whitening activity in vitro and in vivo , and that this effect may be due to the inhibition of SCF induced c-kit and tyrosinase activity through the blockade of downstream signaling pathway .	Glyceollins have a depigmentation and whitening activity in vitro and in vivo, and that this effect may be due to the inhibition of SCF induced c-kit and tyrosinase activity through the blockade of downstream signaling pathway.	22	29	induced	Positive_early_activation	Positive_activation	Negative_activation	SCF	SCF	SCF	c-kit	c-kit	c-kit	24	25	26	27
KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT , signifying oncogenic autocrine and paracrine KITLG-KIT signaling .	KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine and paracrine KITLG-KIT signaling.	0	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	KITLG	KITLG	KITLG	KIT	KIT	KIT	0	1	12	13
However , stem cell factor reduced significantly the number of Kit positive cells already on day 2 indicating that the cells had responded .	However, stem cell factor reduced significantly the number of Kit positive cells already on day 2 indicating that the cells had responded.	2	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	stem cell factor	stem cell factor	stem cell factor	Kit	Kit	Kit	2	5	10	11
SCF is the ligand for c-KIT and inhibits the growth of KIT expressing melanoma cells [ XREF_BIBR ] .	SCF is the ligand for c-KIT and inhibits the growth of KIT expressing melanoma cells [XREF_BIBR].	0	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SCF	SCF	SCF	KIT	KIT	KIT	0	1	11	12
Pretreatment of the H526 small cell lung cancer ( SCLC ) cell line with STI571 inhibited SCF mediated Kit activation with an IC50 of 0.1 microM as measured by inhibition of receptor tyrosine phosphorylation and 0.2 microM as measured by immune complex kinase assay .	Pretreatment of the H526 small cell lung cancer (SCLC) cell line with STI571 inhibited SCF mediated Kit activation with an IC50 of 0.1 microM as measured by inhibition of receptor tyrosine phosphorylation and 0.2 microM as measured by immune complex kinase assay.	15	19	mediated	Positive_early_activation	Positive_activation	Negative_activation	SCF	SCF	SCF	Kit	Kit	Kit	16	17	18	19
Of possible interest is the ability of PKC to directly phosphorylate serine residues on Kit , thereby inhibiting SCF mediated activation of Kit .	Of possible interest is the ability of PKC to directly phosphorylate serine residues on Kit, thereby inhibiting SCF mediated activation of Kit.	17	23	mediated	Positive_early_activation	Positive_activation	Negative_activation	SCF	SCF	SCF	Kit	Kit	Kit	18	19	22	23
These results again indicate that SCF induced KIT trafficking from early to late endosome was impaired in CALM -/- MEFs .	These results again indicate that SCF induced KIT trafficking from early to late endosome was impaired in CALM -/- MEFs.	5	8	induced	Positive_early_activation	Positive_activation	Negative_activation	SCF	SCF	SCF	KIT	KIT	KIT	5	6	7	8
Kinetics of KIT surface level decrease were similar when cells were treated with SCF from 1 to 24 h , but after 72 h KIT surface levels stayed low with antibodies while going back to initial levels with SCF ( XREF_FIG ) , both treatments decreasing similarly slightly total KIT levels ( XREF_FIG ) .	Kinetics of KIT surface level decrease were similar when cells were treated with SCF from 1 to 24 h, but after 72 h KIT surface levels stayed low with antibodies while going back to initial levels with SCF (XREF_FIG), both treatments decreasing similarly slightly total KIT levels (XREF_FIG).	2	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	SCF	SCF	SCF	KIT	KIT	KIT	13	14	2	3
SCF induced KIT trafficking was severely impaired in CALM deficient MEFs leading to the excessive activation of Akt 27 .	SCF induced KIT trafficking was severely impaired in CALM deficient MEFs leading to the excessive activation of Akt 27.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	SCF	SCF	SCF	KIT	KIT	KIT	0	1	2	3
In summary , KTN0158 was found to be a potent inhibitor of SCF induced KIT activation in vitro with evidence of pathophysiologically relevant target modulation , an acceptable safety profile and clinical benefit in canine MCT patients independent of KIT mutational status .	In summary, KTN0158 was found to be a potent inhibitor of SCF induced KIT activation in vitro with evidence of pathophysiologically relevant target modulation, an acceptable safety profile and clinical benefit in canine MCT patients independent of KIT mutational status.	10	15	induced	Positive_early_activation	Positive_activation	Negative_activation	SCF	SCF	SCF	KIT	KIT	KIT	12	13	14	15
To sum up , these data show that bivalent 2D1 and 3G1 scFv-Fc antibodies , that target KIT D5 membrane proximal region do not induce KIT phosphorylation and downsteam signaling but inhibit SCF induced KIT signaling resulting in reduced growth of KIT dependent cell lines .	To sum up, these data show that bivalent 2D1 and 3G1 scFv-Fc antibodies, that target KIT D5 membrane proximal region do not induce KIT phosphorylation and downsteam signaling but inhibit SCF induced KIT signaling resulting in reduced growth of KIT dependent cell lines.	31	35	induced	Positive_early_activation	Positive_activation	Negative_activation	SCF	SCF	SCF	KIT	KIT	KIT	32	33	34	35
Real-time PCR analysis indicated that knockdown of plexin-A1 decreased the basal levels of plexin-A1 and VEGFR2 expression and inhibited isoprenaline induced up-regulation of both plexin-A1 and VEGFR2 at mRNA levels .	Real-time PCR analysis indicated that knockdown of plexin-A1 decreased the basal levels of plexin-A1 and VEGFR2 expression and inhibited isoprenaline induced up-regulation of both plexin-A1 and VEGFR2 at mRNA levels.	7	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGFR2	plexin-A1 decreased the basal levels of plexin-A1 and VEGFR2 expression	vegfr2	VEGFR2	VEGFR2	vegfr2	15	16	26	27
In the present study , we demonstrated that high concentration of VEGF initially increased the expression of VEGFR-2 protein , but decreased the VEGFR-2 protein time-dependently with a gradual increase in MMP-3 or MMP-9 .	In the present study, we demonstrated that high concentration of VEGF initially increased the expression of VEGFR-2 protein, but decreased the VEGFR-2 protein time-dependently with a gradual increase in MMP-3 or MMP-9.	11	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFR-2	VEGF initially increased the expression of VEGFR-2	vegfr-2	VEGFR-2	VEGFR-2	vegfr-2	17	18	23	24
Taken together , these data support that SUMOylation of VEGFR2 attenuates VEGFR2 activity and itsdependent angiogenic signalling .	Taken together, these data support that SUMOylation of VEGFR2 attenuates VEGFR2 activity and itsdependent angiogenic signalling.	7	12	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFR2	SUMOylation of VEGFR2	vegfr2	VEGFR2	VEGFR2	vegfr2	9	10	11	12
Augmentation of svegfr-2 expression in wild-type mouse corneas using in vivo transfection with psvegfr-2 , reduced suture injury induced lymphangiogenesis and did not influence hemangiogenesis , confirming a selective anti-lymphangiogenic effect of svegfr-2 in vivo .	Augmentation of svegfr-2 expression in wild-type mouse corneas using in vivo transfection with psvegfr-2, reduced suture injury induced lymphangiogenesis and did not influence hemangiogenesis, confirming a selective anti-lymphangiogenic effect of svegfr-2 in vivo.	2	34	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	svegfr-2	svegfr-2 expression	svegfr-2	svegfr-2	svegfr-2	svegfr-2	2	3	32	33
53 Further experiments on human umbilical vein endothelial cells indicate that VEGF can induce down-regulation of VEGFR-2 expression on endothelial cells and concomitantly decrease the soluble form of VEGFR-2 in condition media .	53 Further experiments on human umbilical vein endothelial cells indicate that VEGF can induce down-regulation of VEGFR-2 expression on endothelial cells and concomitantly decrease the soluble form of VEGFR-2 in condition media.	11	29	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFR-2	VEGF can induce down-regulation of VEGFR-2 expression	vegfr-2	VEGFR-2	VEGFR-2	vegfr-2	16	17	28	29
In this complex , PTPRB can dephosphorylate and inactivate VEGFR2 , and thus limit the duration and magnitude of the VEGFR2 signal .	In this complex, PTPRB can dephosphorylate and inactivate VEGFR2, and thus limit the duration and magnitude of the VEGFR2 signal.	4	21	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFR2	PTPRB can dephosphorylate and inactivate VEGFR2	vegfr2	VEGFR2	VEGFR2	vegfr2	9	10	20	21
Metastin was shown to inhibit the chemotaxis and invasion of GPR54 transfected Chinese hamster ovary cells in vitro , while it inhibited the pulmonary metastasis of GPR54 transfected melanoma cells in vivo [ XREF_BIBR ] .	Metastin was shown to inhibit the chemotaxis and invasion of GPR54 transfected Chinese hamster ovary cells in vitro, while it inhibited the pulmonary metastasis of GPR54 transfected melanoma cells in vivo [XREF_BIBR].	0	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Metastin	Metastin	Metastin	GPR54	GPR54	GPR54	0	1	10	11
Metastin inhibits chemotaxis and invasion of hOT7T175 transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175 transfected B16-BL6 melanomas in vivo .	Metastin inhibits chemotaxis and invasion of hOT7T175 transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175 transfected B16-BL6 melanomas in vivo.	0	18	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Metastin	Metastin	Metastin	hOT7T175	hOT7T175	hOT7T175	0	1	17	18
Metastin has been shown to suppress the motility of hOT7T175 transfected melanoma cells ; however , studies of the physiological function of metastin have begun only recently .	Metastin has been shown to suppress the motility of hOT7T175 transfected melanoma cells; however, studies of the physiological function of metastin have begun only recently.	0	10	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Metastin	Metastin	Metastin	hOT7T175	hOT7T175	hOT7T175	0	1	9	10
Pep 234 ( a mammalian KISS1 antagonist ) antagonizes Kiss1r signaling activated by Kiss1 and Kiss2 , and pep 359 ( a novel analog ) antagonizes Kiss2 activation of both receptors .	Pep 234 (a mammalian KISS1 antagonist) antagonizes Kiss1r signaling activated by Kiss1 and Kiss2, and pep 359 (a novel analog) antagonizes Kiss2 activation of both receptors.	9	15	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	KISS1	Kiss1	Kiss1	Kiss1r	Kiss1r	Kiss1r	13	14	9	10
In MCF7 cells , AKT binds and phosphorylates KMT2D , which attenuates methyltransferase activity and ERalpha function .	In MCF7 cells, AKT binds and phosphorylates KMT2D, which attenuates methyltransferase activity and ERalpha function.	5	16	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	KMT2D	phosphorylates KMT2D	kmt2d	ERalpha	ERalpha	eralpha	8	9	15	16
Direct phosphorylation of KMT2D by AKT suppresses the methyltransferase activity of KMT2D , which in turn suppresses ER transcriptional activity ( XREF_SUPPLEMENTARY ) .	Direct phosphorylation of KMT2D by AKT suppresses the methyltransferase activity of KMT2D, which in turn suppresses ER transcriptional activity (XREF_SUPPLEMENTARY).	9	19	suppresses	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	KMT2D	KMT2D	KMT2D	ER	ER	ER	11	12	17	18
Interestingly , MLL4 depletion was also shown to impede proliferation and invasion of ERalpha negative cells [ XREF_BIBR ] .	Interestingly, MLL4 depletion was also shown to impede proliferation and invasion of ERalpha negative cells [XREF_BIBR].	2	15	impede	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MLL4	MLL4	MLL4	ERalpha	ERalpha	ERalpha	2	3	13	14
Moreover , ICCs might transdifferentiate to a type of alpha-SMA ( + ) cells , perhaps a phenotype of smooth muscle cells , when there is a loss-of-function of Kit .	Moreover, ICCs might transdifferentiate to a type of alpha-SMA (+) cells, perhaps a phenotype of smooth muscle cells, when there is a loss-of-function of Kit.	25	30	is a loss-of-function	Negative_activation_copula_1	Positive_activation	Negative_activation	Kit	loss-of-function of Kit	kit	Kit	Kit	kit	29	30	29	30
We hypothesized that there is a loss of Kit in diabetic gastroparesis due to elevated oxidative stress and that the elevated oxidative stress is due to low levels of heme oxygenase-1 ( HO1 ) , an important cytoprotective molecule against oxidative injury .	We hypothesized that there is a loss of Kit in diabetic gastroparesis due to elevated oxidative stress and that the elevated oxidative stress is due to low levels of heme oxygenase-1 (HO1), an important cytoprotective molecule against oxidative injury.	4	11	is a loss	Negative_activation_copula_1	Positive_activation	Negative_activation	Kit	loss of Kit	kit	Kit	Kit	kit	8	9	8	9
KIT knockdown also increased RAS and MAPK pathway activation in a BRAF V600E -mutant human melanoma cell line .	KIT knockdown also increased RAS and MAPK pathway activation in a BRAF V600E -mutant human melanoma cell line.	0	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	KIT	KIT	KIT	MAPK	MAPK	MAPK	0	1	6	7
Expression of an RNAi resistant N-terminal truncation of KNL-1 ( Delta85-505 ) , that removes all eight MELTs , prevents kinetochore localization of BUB-1 when endogenous KNL-1 is absent ( XREF_FIG ) 29 .	Expression of an RNAi resistant N-terminal truncation of KNL-1 (Delta85-505), that removes all eight MELTs, prevents kinetochore localization of BUB-1 when endogenous KNL-1 is absent (XREF_FIG) 29.	6	30	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	KNL-1	KNL-1	KNL-1	BUB-1	BUB-1	BUB-1	8	9	23	24
Specifically , it is possible that changes at the kinetochore during late mitosis result in decreased KNL1 mediated Bub1 kinase activity and Aurora B mediated phosphorylation of kinetochore substrates .	Specifically, it is possible that changes at the kinetochore during late mitosis result in decreased KNL1 mediated Bub1 kinase activity and Aurora B mediated phosphorylation of kinetochore substrates.	13	20	mediated	Positive_early_activation	Positive_activation	Negative_activation	KNL1	KNL1	KNL1	Bub1	Bub1	Bub1	16	17	18	19
Furthermore , the Kit tyrosine-567-phenylalanine substitution mutation blocks docking of the tyrosine phosphatase SHP-2 , the adaptor protein APS , and the Csk-homologous kinase .	Furthermore, the Kit tyrosine-567-phenylalanine substitution mutation blocks docking of the tyrosine phosphatase SHP-2, the adaptor protein APS, and the Csk-homologous kinase.	3	23	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Kit	Kit	Kit	SHP-2	SHP-2	SHP-2	3	4	13	14
DNMT inhibition by 5Aza or RG108 rescued Klf4 expression and reversed the d-flow-induced suppression of the downstream targets eNOS and thrombomodulin .	DNMT inhibition by 5Aza or RG108 rescued Klf4 expression and reversed the d-flow-induced suppression of the downstream targets eNOS and thrombomodulin.	0	21	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Klf4	DNMT inhibition by 5Aza or RG108 rescued Klf4 expression	klf4	thrombomodulin	thrombomodulin	thrombomodulin	7	8	20	21
Comparison of the effect on Kras driven autochthonous tumors of total deletion of p110alpha with the removal of the ability of p110alpha to interact with RAS reveals similar levels of tumor regression and stasis .	Comparison of the effect on Kras driven autochthonous tumors of total deletion of p110alpha with the removal of the ability of p110alpha to interact with RAS reveals similar levels of tumor regression and stasis.	3	14	driven	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Kras	Kras	Kras	p110alpha	p110alpha	p110alpha	5	6	13	14
In contrast , the phosphorylation of Lck Tyr505 in the absence of phosphorylated Tyr394 , promotes the inactive , auto-inhibited conformation of Lck .	In contrast, the phosphorylation of Lck Tyr505 in the absence of phosphorylated Tyr394, promotes the inactive, auto-inhibited conformation of Lck.	4	23	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lck	phosphorylation of Lck Tyr505	lck	Lck	Lck	lck	6	7	22	23
The phosphorylation of Tyr505 in LCK by CSK inhibits LCK activity via auto-phosphorylation of Tyr394 in the catalytic domain .	The phosphorylation of Tyr505 in LCK by CSK inhibits LCK activity via auto-phosphorylation of Tyr394 in the catalytic domain.	1	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LCK	phosphorylation of Tyr505 in LCK	lck	LCK	LCK	lck	5	6	9	10
Besides BIBF1120 , LCK has been found as a target of several tyrosine kynase inhibitors , such as Imatinib and Dasatinib , and it has been demonstrated in multiple studies that TKI treatment specifically down-regulates LCK expression and diminishes LCK activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Besides BIBF1120, LCK has been found as a target of several tyrosine kynase inhibitors, such as Imatinib and Dasatinib, and it has been demonstrated in multiple studies that TKI treatment specifically down-regulates LCK expression and diminishes LCK activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	31	40	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LCK	TKI treatment specifically down-regulates LCK expression	lck	LCK	LCK	lck	35	36	39	40
We conclude that CD45 induces the dephosphorylation of Lck at Y394 , thereby preventing sustained Lck activation and propose that the amplitude of the Src family kinase dependent signal regulates the outcome of CD44 mediated signaling to the actin cytoskeleton and T cell spreading .	We conclude that CD45 induces the dephosphorylation of Lck at Y394, thereby preventing sustained Lck activation and propose that the amplitude of the Src family kinase dependent signal regulates the outcome of CD44 mediated signaling to the actin cytoskeleton and T cell spreading.	3	16	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lck	CD45 induces the dephosphorylation of Lck at Y394	lck	Lck	Lck	lck	8	9	15	16
Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase ( Csk ) , which negatively regulates Lck , is essential for the inhibitory effect of cAMP on zeta chain phosphorylation .	Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase (Csk), which negatively regulates Lck, is essential for the inhibitory effect of cAMP on zeta chain phosphorylation.	0	18	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lck	Phosphorylation of residue Y505 in Lck	lck	Lck	Lck	lck	5	6	17	18
HIV-1 replication was approximately 30 % lower in primary CD4 + T cells in which Lck expression was reduced using Lck shRNA as compared to controls ( XREF_FIG ) .	HIV-1 replication was approximately 30% lower in primary CD4 + T cells in which Lck expression was reduced using Lck shRNA as compared to controls (XREF_FIG).	15	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Lck	Lck expression	lck	Lck	Lck	lck	15	16	20	21
In this model , serine phosphorylation of Lck by pERK prevents Lck inactivation and amplifies TCR signaling .	In this model, serine phosphorylation of Lck by pERK prevents Lck inactivation and amplifies TCR signaling.	4	12	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lck	serine phosphorylation of Lck	lck	Lck	Lck	lck	7	8	11	12
Phosphorylation of Lck Tyr 505 by Csk inhibits the kinase activity of Lck through an intramolecular interaction between the Lck SH2 domain and pTyr 505 , which induces a closed-clasp conformation .	Phosphorylation of Lck Tyr 505 by Csk inhibits the kinase activity of Lck through an intramolecular interaction between the Lck SH2 domain and pTyr 505, which induces a closed-clasp conformation.	0	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lck	Phosphorylation of Lck Tyr 505	lck	Lck	Lck	lck	2	3	12	13
Together with an activation effect by K-Ras ( down-regulated in SqCC normal ) , c-Raf is down-regulated and eventually inhibits cell proliferation .	Together with an activation effect by K-Ras (down-regulated in SqCC normal), c-Raf is down-regulated and eventually inhibits cell proliferation.	4	19	down-regulated	Negative_activation_syntax_4_verb	Positive_activation	Negative_activation	K-Ras	K-Ras	K-Ras	c-Raf	c-Raf	c-Raf	6	7	14	15
In summary , based on our current report and other studies XREF_BIBR - XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR , XREF_BIBR , we propose that there are two LRP6 turnover pathways : Kremen mediated LRP6 degradation , and Wnt/Fz mediated LRP6 down-regulation ( XREF_FIG ) .	In summary, based on our current report and other studies XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR, XREF_BIBR, we propose that there are two LRP6 turnover pathways : Kremen mediated LRP6 degradation, and Wnt/Fz mediated LRP6 down-regulation (XREF_FIG).	33	36	mediated	Positive_early_activation	Positive_activation	Negative_activation	Kremen	Kremen	Kremen	LRP6	LRP6	LRP6	33	34	35	36
Importantly , MHC independent in vivo signaling of Quad KO thymocytes required alphabetaTCR and Lck proteins , as deficiency in TCRalpha , RAG2 , or Lck reduced or abolished CD5 up-regulation ( XREF_FIG ) .	Importantly, MHC independent in vivo signaling of Quad KO thymocytes required alphabetaTCR and Lck proteins, as deficiency in TCRalpha, RAG2, or Lck reduced or abolished CD5 up-regulation (XREF_FIG).	18	30	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lck	Lck	Lck	CD5	CD5	CD5	25	26	29	30
Even though Lck did not affect the amount of LAT present in the cell lysates , Lck abrogated the ability of LAT to be immunoprecipitated by anti-CD8alpha ( XREF_FIG ) .	Even though Lck did not affect the amount of LAT present in the cell lysates, Lck abrogated the ability of LAT to be immunoprecipitated by anti-CD8alpha (XREF_FIG).	16	22	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lck	Lck	Lck	LAT	LAT	LAT	16	17	21	22
The results demonstrate that constitutive levels of non-CD4-associated Lck functionally limit CD28 mediated signaling .	The results demonstrate that constitutive levels of non-CD4-associated Lck functionally limit CD28 mediated signaling.	5	13	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lck	levels of non-CD4-associated Lck	lck	CD28	CD28	cd28	8	9	11	12
The KSR1 sub-cluster could be therapeutically targeted in RF-ve polyarticular JIA patients , using small-molecule inhibitors of RAF1 .	The KSR1 sub-cluster could be therapeutically targeted in RF-ve polyarticular JIA patients, using small-molecule inhibitors of RAF1.	1	18	targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	KSR1	KSR1	KSR1	RAF1	RAF1	RAF1	1	2	17	18
In contrast , the inhibition or absence of leptin has been reported to trigger a compensatory upregulation of the leptin receptor , which makes the cells more responsive to leptin .	In contrast, the inhibition or absence of leptin has been reported to trigger a compensatory upregulation of the leptin receptor, which makes the cells more responsive to leptin.	4	21	trigger	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	8	9	19	21
Celastrol suppresses food intake , blocks reduction of energy expenditure and leads up to 45 % weight loss in hyperleptinemic diet induced obese ( DIO ) mice by increasing leptin sensitivity , but is ineffective in leptin deficient ( ob/ob ) or leptin receptor deficient ( db/db ) mouse models .	Celastrol suppresses food intake, blocks reduction of energy expenditure and leads up to 45% weight loss in hyperleptinemic diet induced obese (DIO) mice by increasing leptin sensitivity, but is ineffective in leptin deficient (ob/ob) or leptin receptor deficient (db/db) mouse models.	21	44	induced	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	29	30	42	44
Flow cytometry and quantitative PCR showed that airway epithelial cells expressed leptin receptor ( Ob-R ) , whose expression level was downregulated by leptin itself .	Flow cytometry and quantitative PCR showed that airway epithelial cells expressed leptin receptor (Ob-R), whose expression level was downregulated by leptin itself.	11	24	downregulated	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	23	24	11	13
This is consistent with the observations that NTS leptin expression did not stimulate P-STAT3 in the MBH , and leptin receptor blockade in MBH , did not reduce leptin mediated P-STAT3 in the NTS .	This is consistent with the observations that NTS leptin expression did not stimulate P-STAT3 in the MBH, and leptin receptor blockade in MBH, did not reduce leptin mediated P-STAT3 in the NTS.	8	21	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin expression	leptin	leptin receptor	leptin receptor	leptin receptor	8	9	19	21
Previous studies with chronic decerebrate rats and rats infused with leptin into the 4 th ventricle suggest that hindbrain leptin receptors attenuate the catabolic effect of forebrain leptin receptor activation .	Previous studies with chronic decerebrate rats and rats infused with leptin into the 4 th ventricle suggest that hindbrain leptin receptors attenuate the catabolic effect of forebrain leptin receptor activation.	19	29	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	19	20	27	29
Early work by the Flier laboratory showed that leptin administration causes a rapid induction of hypothalamic Socs3 mRNA in mice and mediates feedback inhibition of the leptin receptor .	Early work by the Flier laboratory showed that leptin administration causes a rapid induction of hypothalamic Socs3 mRNA in mice and mediates feedback inhibition of the leptin receptor.	8	28	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	8	9	26	28
It appears that the presence of normal leptin signaling in astrocytes helped to reduce glutamate induced gliotoxicity , though we have not been able to determine the differential effects of ObRa and ObRb , or a role of the soluble leptin receptor .	It appears that the presence of normal leptin signaling in astrocytes helped to reduce glutamate induced gliotoxicity, though we have not been able to determine the differential effects of ObRa and ObRb, or a role of the soluble leptin receptor.	7	42	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	7	8	40	42
Normal Leptin Expression , Lower Adipogenic Ability , Decreased Leptin Receptor and Hyposensitivity to Leptin in Adolescent Idiopathic Scoliosis .	Normal Leptin Expression, Lower Adipogenic Ability, Decreased Leptin Receptor and Hyposensitivity to Leptin in Adolescent Idiopathic Scoliosis.	1	11	Decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Leptin	Leptin Expression	leptin	Leptin Receptor	Leptin Receptor	leptin receptor	1	2	9	11
We have previously identified suppressor of cytokine signaling-3 ( Socs3 ) as a leptin induced negative regulator of leptin receptor signaling and potential mediator of leptin resistance .	We have previously identified suppressor of cytokine signaling-3 (Socs3) as a leptin induced negative regulator of leptin receptor signaling and potential mediator of leptin resistance.	12	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	13	14	18	20
The use of a leptin antagonist negated the induction of visfatin and soluble leptin receptor by leptin .	The use of a leptin antagonist negated the induction of visfatin and soluble leptin receptor by leptin.	4	15	negated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	4	5	13	15
Mutations in leptin and leptin receptor can decrease the leptin receptor signals [ XREF_BIBR ] .	Mutations in leptin and leptin receptor can decrease the leptin receptor signals [XREF_BIBR].	2	13	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	2	3	9	11
Re-constitution of neuronal leptin receptors completely reverses the lipotoxic , dysmetabolic phenotype of leptin receptor deficient db/db mice [ XREF_BIBR ] .	Re-constitution of neuronal leptin receptors completely reverses the lipotoxic, dysmetabolic phenotype of leptin receptor deficient db/db mice [XREF_BIBR].	3	19	reverses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	3	4	13	15
1 Either peripheral or central administration of leptin has been demonstrated to reduce food intake and body weight and increase energy expenditure in rodents , 18 and activation of hypothalamic neurons expressing the leptin receptor has suggested the mediation of its effects via this central region .	1 Either peripheral or central administration of leptin has been demonstrated to reduce food intake and body weight and increase energy expenditure in rodents, 18 and activation of hypothalamic neurons expressing the leptin receptor has suggested the mediation of its effects via this central region.	5	35	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	7	8	33	35
Leptin ( 10 (-7)-10(-6) M ) significantly inhibited expression of OB-Rb mRNA , with maximum inhibition ( 43 % of control ) at 10 (-6) M. Expression of OB-R219.1 and OB-R219.3 , two short isoforms of leptin receptor , were also reduced in cells treated with leptin most remarkably at 10 (-7) M for OB-R219.1 ( 44 % of the control ) and at 10 (-6) M for Ob-R219.3 ( 49 % of the control ) .	Leptin (10 (-7)-10(-6) M) significantly inhibited expression of OB-Rb mRNA, with maximum inhibition (43% of control) at 10 (-6) M. Expression of OB-R219.1 and OB-R219.3, two short isoforms of leptin receptor, were also reduced in cells treated with leptin most remarkably at 10 (-7) M for OB-R219.1 (44% of the control) and at 10 (-6) M for Ob-R219.3 (49% of the control).	36	66	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	46	47	36	38
Twice daily leptin administration for 7 days profoundly affected food intake , reduced leptin receptor mRNA in the arcuate nucleus , and had a similar effect on neuropeptide Y gene expression .	Twice daily leptin administration for 7 days profoundly affected food intake, reduced leptin receptor mRNA in the arcuate nucleus, and had a similar effect on neuropeptide Y gene expression.	2	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	leptin	leptin	leptin receptor	leptin receptor	leptin receptor	2	3	13	15
In this study we demonstrate that histamine deficiency elevates serum leptin level and decreases full-length leptin receptor isoform with a slight increase of the short one and results in mild late onset obesity .	In this study we demonstrate that histamine deficiency elevates serum leptin level and decreases full-length leptin receptor isoform with a slight increase of the short one and results in mild late onset obesity.	6	17	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	leptin	histamine deficiency elevates serum leptin level	leptin	leptin receptor	leptin receptor	leptin receptor	10	11	15	17
The LRP6 PPPSPxS motif can inhibit GSK3beta both toward beta-catenin and glycogen synthase .	The LRP6 PPPSPxS motif can inhibit GSK3beta both toward beta-catenin and glycogen synthase.	1	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LRP6	LRP6	LRP6	GSK3beta	GSK3beta	GSK3beta	1	2	6	7
In vitro assays using immunoprecipitated proteins demonstrated that the C terminus of LRP6 significantly attenuated the activity of GSK3beta .	In vitro assays using immunoprecipitated proteins demonstrated that the C terminus of LRP6 significantly attenuated the activity of GSK3beta.	10	19	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LRP6	LRP6	LRP6	GSK3beta	GSK3beta	GSK3beta	12	13	18	19
Because GSK-3beta activation is deleterious to the brain XREF_BIBR , XREF_BIBR and LRP6 inhibits GSK-3beta activity , XREF_BIBR , XREF_BIBR we examined the phosphorylation state of GSK-3beta in LRP6 +/- mice .	Because GSK-3beta activation is deleterious to the brain XREF_BIBR, XREF_BIBR and LRP6 inhibits GSK-3beta activity, XREF_BIBR, XREF_BIBR we examined the phosphorylation state of GSK-3beta in LRP6 +/- mice.	10	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LRP6	LRP6	LRP6	GSK-3beta	GSK-3beta	GSK-3beta	12	13	14	15
Phospho-Lrp6 is thought to directly inhibit GSK3beta activity in the destruction complex , leading to reduced phosphorylation of beta-catenin as well as Axin1 itself .	Phospho-Lrp6 is thought to directly inhibit GSK3beta activity in the destruction complex, leading to reduced phosphorylation of beta-catenin as well as Axin1 itself.	0	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Phospho-Lrp6	Phospho-Lrp6	Phospho-Lrp6	GSK3beta	GSK3beta	GSK3beta	0	1	6	7
Previously , we showed that the free LRP6 intracellular domain ( LRP6-ICD ) can activate the Wnt and beta-catenin pathway in a beta-catenin and TCF/LEF -1 dependent manner , as well as interact with and attenuate GSK3beta activity .	Previously, we showed that the free LRP6 intracellular domain (LRP6-ICD) can activate the Wnt and beta-catenin pathway in a beta-catenin and TCF/LEF -1 dependent manner, as well as interact with and attenuate GSK3beta activity.	7	37	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LRP6	LRP6	LRP6	GSK3beta	GSK3beta	GSK3beta	7	8	36	37
It is believed that inhibition of GSK3b by LRP6 occurs independently of P-Ser9 , so that PDGF likely stimulates GSK3b Ser9 phosphorylation in OPCs through a different pathway .	It is believed that inhibition of GSK3b by LRP6 occurs independently of P-Ser9, so that PDGF likely stimulates GSK3b Ser9 phosphorylation in OPCs through a different pathway.	4	9	inhibition	Negative_activation_token_2_noun	Positive_activation	Negative_activation	LRP6	LRP6	LRP6	GSK3b	GSK3b	GSK3b	8	9	6	7
Lfng overexpression only marginally reduced the already very small DP thymocyte pools in Notch1 12f/f mice ( p < 0.07 ) ( XREF_FIG ) .	Lfng overexpression only marginally reduced the already very small DP thymocyte pools in Notch1 12f/f mice (p < 0.07) (XREF_FIG).	0	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lfng	Lfng overexpression	lfng	Notch1	Notch1	notch1	0	1	13	14
Thus , LFNG not only represses D/N signaling inside the LFNG expressing cell by modifying NOTCH1 cell-autonomously , but also represses D/N signaling between neighboring cells by also modifying the DLL1 ligand .	Thus, LFNG not only represses D/N signaling inside the LFNG expressing cell by modifying NOTCH1 cell-autonomously, but also represses D/N signaling between neighboring cells by also modifying the DLL1 ligand.	2	20	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LFNG	LFNG	LFNG	NOTCH1	NOTCH1	NOTCH1	2	3	15	16
Notch pathway activation is further supported by an 8.2-fold downregulation of lunatic fringe ( Lfng ) , which has been previously shown to suppress Jagged-1 and Notch-1 signaling [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	Notch pathway activation is further supported by an 8.2-fold downregulation of lunatic fringe (Lfng), which has been previously shown to suppress Jagged-1 and Notch-1 signaling [XREF_BIBR; XREF_BIBR; XREF_BIBR].	12	31	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lfng	Lfng	Lfng	Notch-1	Notch-1	Notch-1	14	15	26	27
Lfng inhibits the cleavage of NICD from the Notch receptor , so knocking out of the Lfng gene led to an increase of NICD .	Lfng inhibits the cleavage of NICD from the Notch receptor, so knocking out of the Lfng gene led to an increase of NICD.	0	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lfng	Lfng	Lfng	NICD	NICD	NICD	0	1	5	6
NICD activates Lfng transcription , and Lfng inhibits NICD production to form a negative feedback loop .	NICD activates Lfng transcription, and Lfng inhibits NICD production to form a negative feedback loop.	6	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lfng	Lfng	Lfng	NICD	NICD	NICD	6	7	8	9
Deletion of Lfng in the Kras ( LSL-G12D/+ ) ; Pdx1-Cre mouse model caused increased activation of Notch3 throughout PDAC initiation and progression , and Notch1 after the onset of disease , associated with marked upregulation of Notch target gene Hes1 .	Deletion of Lfng in the Kras (LSL-G12D/+); Pdx1-Cre mouse model caused increased activation of Notch3 throughout PDAC initiation and progression, and Notch1 after the onset of disease, associated with marked upregulation of Notch target gene Hes1.	0	32	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Lfng	Lfng	Lfng	Notch1	Notch1	Notch1	2	3	25	26
Adenovirus mediated delivery of SOCS3 into cardiomyocytes was identified to suppress hypertrophic and anti-apoptotic phenotype induced by LIF mediated gp130 receptor signaling through Jak and Stat pathway , where LIF was also identified to induce Akt , MEK and ERK activation indicating that SOCS3 is induced by mechanical stress [ XREF_BIBR ] .	Adenovirus mediated delivery of SOCS3 into cardiomyocytes was identified to suppress hypertrophic and anti-apoptotic phenotype induced by LIF mediated gp130 receptor signaling through Jak and Stat pathway, where LIF was also identified to induce Akt, MEK and ERK activation indicating that SOCS3 is induced by mechanical stress [XREF_BIBR].	15	21	mediated	Positive_early_activation	Positive_activation	Negative_activation	LIF	LIF	LIF	gp130	gp130	gp130	17	18	19	20
Activation of gp130 by leukemia inhibitory factor is sufficient to induce myocardial cell hypertrophy accompanied by specific changes in the pattern of gene expression .	Activation of gp130 by leukemia inhibitory factor is sufficient to induce myocardial cell hypertrophy accompanied by specific changes in the pattern of gene expression.	0	7	Activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	leukemia inhibitory factor	leukemia inhibitory factor	leukemia inhibitory factor	gp130	gp130	gp130	4	7	2	3
The cytokine leukemia inhibitory factor ( LIF ) activates Janus kinas and signal transducer and activator of transcription 3 ( JAK and STAT3 ) pathway by inducing heterodimerization of LIF receptor and the signal transducer protein gp130 [ XREF_BIBR , XREF_BIBR ] .	The cytokine leukemia inhibitory factor (LIF) activates Janus kinas and signal transducer and activator of transcription 3 (JAK and STAT3) pathway by inducing heterodimerization of LIF receptor and the signal transducer protein gp130 [XREF_BIBR, XREF_BIBR].	4	38	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	LIF	LIF	LIF	gp130	gp130	gp130	6	7	36	37
Another prominent example is that SHP-2 negatively regulates gp130 signaling triggered by leukemia inhibitory factor , ciliary neurotrophic factor , and interleukin-6 ( IL-6 ) [ XREF_BIBR , XREF_BIBR ] .	Another prominent example is that SHP-2 negatively regulates gp130 signaling triggered by leukemia inhibitory factor, ciliary neurotrophic factor, and interleukin-6 (IL-6) [XREF_BIBR, XREF_BIBR].	8	15	triggered	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	leukemia inhibitory factor	leukemia inhibitory factor	leukemia inhibitory factor	gp130	gp130	gp130	12	15	8	9
Thermal control of adhesion is maintained in IL-6-deficient mice through a gp130 dependent compensatory mechanism mediated by IL-6-related cytokines ( i.e ., oncostatin M [ OSM ] , leukemia inhibitory factor [ LIF ] , and IL-11 ) .	Thermal control of adhesion is maintained in IL-6-deficient mice through a gp130 dependent compensatory mechanism mediated by IL-6-related cytokines (i.e., oncostatin M [OSM], leukemia inhibitory factor [LIF], and IL-11).	11	31	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	leukemia inhibitory factor	leukemia inhibitory factor	leukemia inhibitory factor	gp130	gp130	gp130	28	31	11	12
OSM , LIF , and CT can downregulate the LIFR thus incorporating cross-talk and inhibition between these cytokines [ XREF_BIBR ] .	OSM, LIF, and CT can downregulate the LIFR thus incorporating cross-talk and inhibition between these cytokines [XREF_BIBR].	0	11	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LIF	LIF	LIF	LIFR	LIFR	LIFR	2	3	9	10
To determine if the mutant altered LIFR function , cells were treated with leukemia inhibitory factor ( LIF ) to stimulate downstream STAT3 phosphorylation .	To determine if the mutant altered LIFR function, cells were treated with leukemia inhibitory factor (LIF) to stimulate downstream STAT3 phosphorylation.	6	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	leukemia inhibitory factor	leukemia inhibitory factor	leukemia inhibitory factor	LIFR	LIFR	LIFR	13	16	6	7
Recently , LFNG has been shown to repress DLL1 function in NIH3T3 cells that simultaneously express DLL3 and Notch1 , whereas coexpression of DLL3 with DLL1 in L cells had no effect on DLL1 mediated Notch activation [ XREF_BIBR ] .	Recently, LFNG has been shown to repress DLL1 function in NIH3T3 cells that simultaneously express DLL3 and Notch1, whereas coexpression of DLL3 with DLL1 in L cells had no effect on DLL1 mediated Notch activation [XREF_BIBR].	2	9	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LFNG	LFNG	LFNG	DLL1	DLL1	DLL1	2	3	8	9
By analysing Lunatic fringe ( Lfng ) chimeric embryos and Notch signal reporter assays using a co-culture system , we further find that Lfng represses Notch activity in neighbouring cells by modulating Dll1 function .	By analysing Lunatic fringe (Lfng) chimeric embryos and Notch signal reporter assays using a co-culture system, we further find that Lfng represses Notch activity in neighbouring cells by modulating Dll1 function.	23	33	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lfng	Lfng	Lfng	Dll1	Dll1	Dll1	23	24	32	33
We also observed that Isl1 co-immunoprecipitation with Onecut1 is disrupted by increasing concentration of Lhx3 , supporting the competitive binding of the two TFs to Isl1 .	We also observed that Isl1 co-immunoprecipitation with Onecut1 is disrupted by increasing concentration of Lhx3, supporting the competitive binding of the two TFs to Isl1.	4	15	disrupted	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Lhx3	Lhx3	Lhx3	Isl1	Isl1	Isl1	14	15	4	5
However , more recent studies demonstrated that LRIG1 promotes degradation of the receptors independent of c-Cbl , leaving the mechanism of LRIG1 action unclear .	However, more recent studies demonstrated that LRIG1 promotes degradation of the receptors independent of c-Cbl, leaving the mechanism of LRIG1 action unclear.	7	16	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	LRIG1	LRIG1	LRIG1	c-Cbl	c-Cbl	c-Cbl	7	8	15	16
LFng coexpression with Dll3 further inhibited N1 signaling that was induced by J1 , yet reversed the Dll3 inhibition of signaling in response to Dll1 .	LFng coexpression with Dll3 further inhibited N1 signaling that was induced by J1, yet reversed the Dll3 inhibition of signaling in response to Dll1.	0	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LFng	LFng coexpression	lfng	Dll3	Dll3	dll3	0	1	17	18
LRRK2 WT and mutant proteins may also cause deficits in the degradation of alpha-synuclein by interfering with the chaperone mediated autophagy [ XREF_BIBR ] .	LRRK2 WT and mutant proteins may also cause deficits in the degradation of alpha-synuclein by interfering with the chaperone mediated autophagy [XREF_BIBR].	0	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	0	1	13	14
Conversely , genetic ablation of LRRK2 preserved the Golgi structure and suppressed the aggregation and somatic accumulation of alpha-synuclein , thereby delaying the progression of neuropathology in A53T mice .	Conversely, genetic ablation of LRRK2 preserved the Golgi structure and suppressed the aggregation and somatic accumulation of alpha-synuclein, thereby delaying the progression of neuropathology in A53T mice.	3	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	5	6	18	19
On the other hand , LRRK2 over-expression enhances alpha-synuclein-mediated neuropathology by promoting the abnormal aggregation and toxicity of alpha-synuclein , while alpha-synuclein cytotoxicity was abrogated by genetic ablation of LRRK2 [ XREF_BIBR , XREF_BIBR ] .	On the other hand, LRRK2 over-expression enhances alpha-synuclein-mediated neuropathology by promoting the abnormal aggregation and toxicity of alpha-synuclein, while alpha-synuclein cytotoxicity was abrogated by genetic ablation of LRRK2 [XREF_BIBR, XREF_BIBR].	21	33	abrogated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	29	30	21	22
Conversely , genetic ablation of LRRK2 preserved the Golgi structure , suppressed the aggregation and somatic accumulation of alpha-synuclein , and thereby delayed the progression of neuropathology in A53T mice .	Conversely, genetic ablation of LRRK2 preserved the Golgi structure, suppressed the aggregation and somatic accumulation of alpha-synuclein, and thereby delayed the progression of neuropathology in A53T mice.	3	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	5	6	18	19
Although these proteins are beneficial at young ages , competitive actions of LRRK2 and alpha-synuclein on similar uptake systems might impede removal of alpha-synuclein aggregates , producing a synergistic inhibition of autophagy , a corresponding accumulation of insoluble , oligomeric alpha-synuclein and synergistic increases degeneration of DA neurons .	Although these proteins are beneficial at young ages, competitive actions of LRRK2 and alpha-synuclein on similar uptake systems might impede removal of alpha-synuclein aggregates, producing a synergistic inhibition of autophagy, a corresponding accumulation of insoluble, oligomeric alpha-synuclein and synergistic increases degeneration of DA neurons.	10	24	impede	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	12	13	23	24
LRRK2 negatively regulates the clearance of alphaSYN accompanied by down-regulation of the endocytosis pathway .	LRRK2 negatively regulates the clearance of alphaSYN accompanied by down-regulation of the endocytosis pathway.	0	7	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LRRK2	LRRK2	LRRK2	alphaSYN	alphaSYN	alphaSYN	0	1	6	7
This novel LRRK2 self perpetuating inhibitory effect on CMA could underlie toxicity in PD by compromising the degradation of alpha-synuclein , another PD related protein degraded by this pathway .	This novel LRRK2 self perpetuating inhibitory effect on CMA could underlie toxicity in PD by compromising the degradation of alpha-synuclein, another PD related protein degraded by this pathway.	2	24	underlie	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	LRRK2	LRRK2	LRRK2	alpha-synuclein	alpha-synuclein	alpha-synuclein	2	3	19	20
First , Lyn deficiency partially reversed the survival effect of Btk deficiency .	First, Lyn deficiency partially reversed the survival effect of Btk deficiency.	2	11	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	2	3	10	11
Lyn Negatively Regulates Btk dependent Signaling Pathways .	Lyn Negatively Regulates Btk dependent Signaling Pathways.	0	6	Negatively Regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	0	1	3	4
These observations indicate that the net outcome of Lyn function in vivo is to inhibit Btk dependent pathways in B and myeloid cells , and that Btk lo mice are a useful sensitized system to identify regulatory components of Btk signaling pathways .	These observations indicate that the net outcome of Lyn function in vivo is to inhibit Btk dependent pathways in B and myeloid cells, and that Btk lo mice are a useful sensitized system to identify regulatory components of Btk signaling pathways.	8	17	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	8	9	15	16
Both the failure of Btk -/- lyn -/- B cells to proliferate in response to anti-IgM and the observation that Btk is no longer limiting for response to BCR engagement in the absence of Lyn suggest that Lyn downregulates Btk dependent signaling pathways .	Both the failure of Btk -/- lyn -/- B cells to proliferate in response to anti-IgM and the observation that Btk is no longer limiting for response to BCR engagement in the absence of Lyn suggest that Lyn downregulates Btk dependent signaling pathways.	37	42	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lyn	Lyn	Lyn	Btk	Btk	Btk	37	38	39	40
As previously described in this review , LTBP1 is a critical part of the TGF-beta1 latent complex , therefore fibronectin mediated regulation of LTBP1 in the ECM directly diminishes TGF-beta1 bioavailability .	As previously described in this review, LTBP1 is a critical part of the TGF-beta1 latent complex, therefore fibronectin mediated regulation of LTBP1 in the ECM directly diminishes TGF-beta1 bioavailability.	21	30	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LTBP1	LTBP1	LTBP1	TGF-beta1	TGF-beta1	TGF-beta1	23	24	29	30
The decrease in LTBP-1 , increase in uPA induced plasmin , and increase in MMP-9 all feedback to activate additional TGF-beta 1 .	The decrease in LTBP-1, increase in uPA induced plasmin, and increase in MMP-9 all feedback to activate additional TGF-beta 1.	1	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	LTBP-1	LTBP-1	LTBP-1	TGF-beta 1	TGF-beta 1	TGF-beta 1	3	4	20	22
Modification of LTBP gene may prevent secretion and activation of latent TGF and beta complex and abrogate fibrotic action of TGF-beta1 .	Modification of LTBP gene may prevent secretion and activation of latent TGF and beta complex and abrogate fibrotic action of TGF-beta1.	2	21	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LTBP	LTBP	LTBP	TGF-beta1	TGF-beta1	TGF-beta1	2	3	20	21
Incorporation of LTBP-1 into disorganized ECM impairs mechanical activation of TGF-beta1 .	Incorporation of LTBP-1 into disorganized ECM impairs mechanical activation of TGF-beta1.	0	11	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LTBP-1	LTBP-1	LTBP-1	TGF-beta1	TGF-beta1	TGF-beta1	2	3	10	11
Thus , partial loss of both Lyn and Ets1 promotes a breach of checkpoint one and production of IgM autoAbs , but is insufficient to cause increased IgG autoAbs ( checkpoint two ) relative to heterozygosity of Lyn alone .	Thus, partial loss of both Lyn and Ets1 promotes a breach of checkpoint one and production of IgM autoAbs, but is insufficient to cause increased IgG autoAbs (checkpoint two) relative to heterozygosity of Lyn alone.	3	38	cause	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lyn	loss of both Lyn	lyn	Lyn	Lyn	lyn	6	7	37	38
As indicated by Western blot analysis and fluorescence microscopy , there is a smaller loss of Lyn due to cholesterol depletion , and there is no detectable loss of other cellular proteins by silver stain analysis of whole cell lysates ( data not shown ) .	As indicated by Western blot analysis and fluorescence microscopy, there is a smaller loss of Lyn due to cholesterol depletion, and there is no detectable loss of other cellular proteins by silver stain analysis of whole cell lysates (data not shown).	11	17	is a smaller loss	Negative_activation_copula_1	Positive_activation	Negative_activation	Lyn	loss of Lyn	lyn	Lyn	Lyn	lyn	16	17	16	17
Although further investigation of premalignant GC is necessary , this finding suggests that individuals with the loss of SRC and LYN methylation in the gastric mucosa may have a higher risk for GC .	Although further investigation of premalignant GC is necessary, this finding suggests that individuals with the loss of SRC and LYN methylation in the gastric mucosa may have a higher risk for GC.	16	22	loss	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	LYN	LYN methylation	lyn	LYN	LYN	lyn	20	21	20	21
Loss of Lyn promoted DC expansion in vitro from bone marrow precursors due to enhanced generation and accelerated differentiation of Lyn deficient DC progenitors .	Loss of Lyn promoted DC expansion in vitro from bone marrow precursors due to enhanced generation and accelerated differentiation of Lyn deficient DC progenitors.	0	23	accelerated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lyn	Loss of Lyn	lyn	Lyn	Lyn	lyn	2	3	20	21
Notably , these mice also developed squamous hyperplasia in the alveoli [ XREF_BIBR ] , suggesting that inactivation of NOTCH1 signaling by dominant negative Maml1 may have distinct effects on the malignant transformation of different types of lung epithelial cells and the development of subtypes of lung tumors .	Notably, these mice also developed squamous hyperplasia in the alveoli [XREF_BIBR], suggesting that inactivation of NOTCH1 signaling by dominant negative Maml1 may have distinct effects on the malignant transformation of different types of lung epithelial cells and the development of subtypes of lung tumors.	19	25	signaling	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	Maml1	Maml1	Maml1	NOTCH1	NOTCH1	NOTCH1	24	25	19	20
In reporter experiments , co-transfection of a fixed amount of MAML1 with p53 partially rescued p53 mediated inhibition of CBF-1 luciferase activity .	In reporter experiments, co-transfection of a fixed amount of MAML1 with p53 partially rescued p53 mediated inhibition of CBF-1 luciferase activity.	8	21	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MAML1	amount of MAML1	maml1	CBF-1	CBF-1	cbf-1	10	11	19	20
Whereas transcription would be affected broadly by targeted elimination of MAML1 or chemical inhibiton of p300 or CDK8 , the more selective SAHM1 peptide may simply uncouple MAML1 from the Notch pathway while leaving its other activities intact .	Whereas transcription would be affected broadly by targeted elimination of MAML1 or chemical inhibiton of p300 or CDK8, the more selective SAHM1 peptide may simply uncouple MAML1 from the Notch pathway while leaving its other activities intact.	10	18	inhibiton	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MAML1	MAML1	MAML1	CDK8	CDK8	CDK8	10	11	17	18
Expression of Lyn B alone showed reduced phosphorylation of both phospholipase Cgamma-1 and 2 and decreased interaction of phospholipase Cgamma-1 with the phosphorylated linker for activation of T cells .	Expression of Lyn B alone showed reduced phosphorylation of both phospholipase Cgamma-1 and 2 and decreased interaction of phospholipase Cgamma-1 with the phosphorylated linker for activation of T cells.	0	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lyn	Expression of Lyn	lyn	phospholipase Cgamma-1	phospholipase Cgamma-1	phospholipase cgamma-1	2	3	18	20
Lyn negatively regulated the proapoptotic function of GADD34 in a kinase dependent manner .	Lyn negatively regulated the proapoptotic function of GADD34 in a kinase dependent manner.	0	8	negatively regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Lyn	Lyn	Lyn	GADD34	GADD34	GADD34	0	1	7	8
Taken together , our results strongly suggest that SP suppresses IgE mediated mast cell activation and allergic responses by inhibiting Lyn induced PLC-gamma2 and MAPK signaling in mast cells .	Taken together, our results strongly suggest that SP suppresses IgE mediated mast cell activation and allergic responses by inhibiting Lyn induced PLC-gamma2 and MAPK signaling in mast cells.	14	25	induced	Positive_early_activation	Positive_activation	Negative_activation	Lyn	Lyn	Lyn	PLC-gamma2	PLC-gamma2	PLC-gamma2	20	21	22	23
ERK activation in the presence of cAMP did not appear to involve any of the Raf isoforms and was blocked by expression of dominant negative MEK1 or treatment with a MEK inhibitor , PD98059 .	ERK activation in the presence of cAMP did not appear to involve any of the Raf isoforms and was blocked by expression of dominant negative MEK1 or treatment with a MEK inhibitor, PD98059.	0	27	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MEK1	expression of dominant negative MEK1	mek1	ERK	ERK	erk	25	26	0	1
As shown in XREF_FIG D , MAPK inhibition by UO126 or Mek1 dominant mutants prevented ErbB induced anchorage independent growth in soft agar in FAK +/+ -2/3 cells and FAK reconstituted FAK -/- -2/3 cells .	As shown in XREF_FIG D, MAPK inhibition by UO126 or Mek1 dominant mutants prevented ErbB induced anchorage independent growth in soft agar in FAK +/+ -2/3 cells and FAK reconstituted FAK -/- -2/3 cells.	6	12	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	Mek1	Mek1	Mek1	MAPK	MAPK	MAPK	11	12	6	7
Incubation of Jurkat cells with SB202190 completely abolished NaCl induced expression of nfat5 mRNA , whereas the MEK1 inhibitor PD98059 , which inhibits the activation of ERK1/2 by MEK1 , showed no effect .	Incubation of Jurkat cells with SB202190 completely abolished NaCl induced expression of nfat5 mRNA, whereas the MEK1 inhibitor PD98059, which inhibits the activation of ERK1/2 by MEK1, showed no effect.	22	29	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	28	29	26	27
The MKK1 inhibitor , PD98059 and transfection of a dominant negative MKK1 blocked ras induced instability of MTs but did not modify the association of erk with MTs or affect MT stability of the parental cells .	The MKK1 inhibitor, PD98059 and transfection of a dominant negative MKK1 blocked ras induced instability of MTs but did not modify the association of erk with MTs or affect MT stability of the parental cells.	2	26	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK1	MKK1	MKK1	erk	erk	erk	11	12	25	26
Moreover , MAPK and Slug pathway inhibition by si-MAPK1 and si-MAP2K1 enhanced the cisplatin sensitivity and apoptosis of A549 and DPP cells .	Moreover, MAPK and Slug pathway inhibition by si-MAPK1 and si-MAP2K1 enhanced the cisplatin sensitivity and apoptosis of A549 and DPP cells.	2	11	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	si-MAP2K1	si-MAP2K1	si-MAP2K1	MAPK	MAPK	MAPK	10	11	2	3
MEK1 Inhibits PPARalpha Activity in an ERK1/2 independent Fashion .	MEK1 Inhibits PPARalpha Activity in an ERK1/2 independent Fashion.	0	8	Inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	0	1	6	7
Phosphorylation of MEK1 by Cdk5 down-regulates the MAPK pathway , and this modulation may also be implicated in the regulation of neuronal survival .	Phosphorylation of MEK1 by Cdk5 down-regulates the MAPK pathway, and this modulation may also be implicated in the regulation of neuronal survival.	0	8	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	Phosphorylation of MEK1	mek1	MAPK	MAPK	mapk	2	3	7	8
XREF_FIG A. Cotransfection of N17Ras , DNRaf , and MEK1 DN caused ~ 70 % inhibition of ERK activity mediated by cross linking of full-length CD40 .	XREF_FIG A. Cotransfection of N17Ras, DNRaf, and MEK1 DN caused ~ 70% inhibition of ERK activity mediated by cross linking of full-length CD40.	2	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	9	10	17	18
Similar to WIPK and SIPK , virus induced gene silencing ( VIGS ) of several other MAPK components NPK1 ( MAPKKK ) , MEK1 ( MAPKK ) , or NTF6 ( MAPK ) attenuate N gene- and Pto mediated resistance against TMV XREF_BIBR XREF_BIBR , indicating that the NPK1-MEK1-NTF6 pathway is another MAPK cascade involved in TMV resistance .	Similar to WIPK and SIPK, virus induced gene silencing (VIGS) of several other MAPK components NPK1 (MAPKKK), MEK1 (MAPKK), or NTF6 (MAPK) attenuate N gene- and Pto mediated resistance against TMV XREF_BIBR XREF_BIBR, indicating that the NPK1-MEK1-NTF6 pathway is another MAPK cascade involved in TMV resistance.	7	29	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	23	24	16	17
This ERK1/2 mediated cyto-protection was inhibited by DN-MEK1 and , conversely , enhanced by expression of constitutively active-MEK1 through reduction in accumulation of cleaved caspase-8 with retention of the uncleaved procaspase-8 .	This ERK1/2 mediated cyto-protection was inhibited by DN-MEK1 and, conversely, enhanced by expression of constitutively active-MEK1 through reduction in accumulation of cleaved caspase-8 with retention of the uncleaved procaspase-8.	0	12	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	DN-MEK1	DN-MEK1	DN-MEK1	ERK1/2	ERK1/2	ERK1/2	7	8	1	2
Further investigation demonstrated that the MAPK and ERK pathway is downregulated by MEK1 SUMOylation , which is inhibited by influenza virus infection .	Further investigation demonstrated that the MAPK and ERK pathway is downregulated by MEK1 SUMOylation, which is inhibited by influenza virus infection.	5	14	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MEK1	MEK1 SUMOylation	mek1	ERK	ERK	erk	12	13	7	8
UO126 , an inhibitor of MAP kinase kinase 1 ( MEK1 ) , suppressed focal adhesion targeting of active ERK and cell spreading .	UO126, an inhibitor of MAP kinase kinase 1 (MEK1), suppressed focal adhesion targeting of active ERK and cell spreading.	5	22	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP kinase kinase 1	MAP kinase kinase 1	MAP kinase kinase 1	ERK	ERK	ERK	5	9	19	20
In addition , we provided evidence to support that MEK1 functions in concert with Ubc9 to suppress ERK signaling , thereby negatively controlling influenza virus .	In addition, we provided evidence to support that MEK1 functions in concert with Ubc9 to suppress ERK signaling, thereby negatively controlling influenza virus.	9	18	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	9	10	17	18
Thus , Mek1 phosphorylation by Erk limits the activation of both the Erk and the Akt pathway .	Thus, Mek1 phosphorylation by Erk limits the activation of both the Erk and the Akt pathway.	2	16	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mek1	Mek1 phosphorylation	mek1	Erk	Erk	erk	2	3	12	13
PD98059 is an MEK1 ( also called MAPKK or Erk kinase ) inhibitor used to block Erk activation .	PD98059 is an MEK1 (also called MAPKK or Erk kinase) inhibitor used to block Erk activation.	0	17	block	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	Erk	Erk	Erk	3	4	16	17
Moreover , acute disruption of the MAPK module by AMF , a selective inhibitor of MEK1 , suppressed both basal and drug stimulated MAPK activity and sharply increased the cytotoxicity of ara-C , suggesting the direct involvement of MAPK as a downstream antiapoptotic effector for PKC .	Moreover, acute disruption of the MAPK module by AMF, a selective inhibitor of MEK1, suppressed both basal and drug stimulated MAPK activity and sharply increased the cytotoxicity of ara-C, suggesting the direct involvement of MAPK as a downstream antiapoptotic effector for PKC.	13	24	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	15	16	23	24
Thus , our work suggests that modulation of MEK1 acetylation by SIRT1 and SIRT2 negatively regulates MAPK pathways during pre-oncogenic events .	Thus, our work suggests that modulation of MEK1 acetylation by SIRT1 and SIRT2 negatively regulates MAPK pathways during pre-oncogenic events.	6	17	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	modulation of MEK1 acetylation by SIRT1	mek1	MAPK	MAPK	mapk	8	9	16	17
We have found that inhibition of ERK activation by the MEK inhibitor or dominant negative MEK1 even immediately before the onset of S phase leads to the cessation of S phase entry .	We have found that inhibition of ERK activation by the MEK inhibitor or dominant negative MEK1 even immediately before the onset of S phase leads to the cessation of S phase entry.	6	16	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK	ERK	ERK	15	16	6	7
Collectively , these results indicate that B [ a ] PDE inhibits serum induced SAE cell differentiation , possibly involving activating signals through a PI-3K and MEK1 mediated MAPK pathway , whereas myo-inositol protects SAE cells against this inhibitory effect of B [ a ] PDE perhaps through both PI-3K and MEK1 and p38 MAPK pathways .	Collectively, these results indicate that B [a] PDE inhibits serum induced SAE cell differentiation, possibly involving activating signals through a PI-3K and MEK1 mediated MAPK pathway, whereas myo-inositol protects SAE cells against this inhibitory effect of B [a] PDE perhaps through both PI-3K and MEK1 and p38 MAPK pathways.	26	29	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	MAPK	MAPK	MAPK	26	27	28	29
U0126 is a selective inhibitor of MEK1 and MEK2 , which inhibit ERK1/2 activation .	U0126 is a selective inhibitor of MEK1 and MEK2, which inhibit ERK1/2 activation.	4	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	6	7	12	13
Inhibition of MEK1 ( an upstream activator of ERK1/2 ) by the addition of PD98059 , inhibited both the basal level of ERK1/2 activation , and the increased phosphorylation seen upon Nox4 overexpression ( XREF_FIG E ) .	Inhibition of MEK1 (an upstream activator of ERK1/2) by the addition of PD98059, inhibited both the basal level of ERK1/2 activation, and the increased phosphorylation seen upon Nox4 overexpression (XREF_FIG E).	0	12	activator	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK1/2	ERK1/2	ERK1/2	2	3	8	9
Oxidative stress induced apoptosis was abrogated by dominant negative stress activated protein kinase and extracellular signal regulated kinase kinase-1 ( SEK1 )-mediated inhibition of the JNK pathway , whereas activation of the JNK pathway by constitutively active SEK1 was sufficient to cause apoptosis .	Oxidative stress induced apoptosis was abrogated by dominant negative stress activated protein kinase and extracellular signal regulated kinase kinase-1 (SEK1)-mediated inhibition of the JNK pathway, whereas activation of the JNK pathway by constitutively active SEK1 was sufficient to cause apoptosis.	20	26	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	20	21	25	26
Functional synergy between MKK4 and MKK7 could explain why overexpression of dominant inhibitory MKK4 or dominant negative MKK7 inhibits activation of SAPK and JNK in response to multiple stimuli .	Functional synergy between MKK4 and MKK7 could explain why overexpression of dominant inhibitory MKK4 or dominant negative MKK7 inhibits activation of SAPK and JNK in response to multiple stimuli.	9	24	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	overexpression of dominant inhibitory MKK4	mkk4	JNK	JNK	jnk	13	14	23	24
In that paper , overexpression of a dominant interfering form of SEK1 ( MKK4 ) , the upstream kinase of JNK , prevented the cell death induced by Abeta and inhibited JNK activation .	In that paper, overexpression of a dominant interfering form of SEK1 (MKK4), the upstream kinase of JNK, prevented the cell death induced by Abeta and inhibited JNK activation.	9	32	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SEK1	SEK1	SEK1	JNK	JNK	JNK	11	12	31	32
The inactivation of MKK4 and MKK7 can block the JNK signal transduction pathway , which is an ideal method to control neuronal hypoxia injury .	The inactivation of MKK4 and MKK7 can block the JNK signal transduction pathway, which is an ideal method to control neuronal hypoxia injury.	1	12	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	3	4	9	10
Depletion of MKK4 or its upstream molecule HGK remarkably attenuated TNF-alpha-induced JNK and c-Jun and p38 and ATF2 activation , and subsequently the production of matrix degrading enzymes .	Depletion of MKK4 or its upstream molecule HGK remarkably attenuated TNF-alpha-induced JNK and c-Jun and p38 and ATF2 activation, and subsequently the production of matrix degrading enzymes.	0	23	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	2	3	11	12
In contrast , compound ablation of Map2k4 plus Map2k7 ( like compound ablation of Mapk8 plus Mapk9 ) prevented JNK signaling in hepatocytes ( XREF_FIG ) .	In contrast, compound ablation of Map2k4 plus Map2k7 (like compound ablation of Mapk8 plus Mapk9) prevented JNK signaling in hepatocytes (XREF_FIG).	4	20	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Map2k4	Map2k4	Map2k4	JNK	JNK	JNK	6	7	19	20
Moreover , JNK signaling is also inhibited by phosphorylation of MAP2K4 by AKT in breast tumors with AKT activation caused by ' driver ' mutations in PTEN or PIK3CA .	Moreover, JNK signaling is also inhibited by phosphorylation of MAP2K4 by AKT in breast tumors with AKT activation caused by ' driver ' mutations in PTEN or PIK3CA.	2	11	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MAP2K4	phosphorylation of MAP2K4	map2k4	JNK	JNK	jnk	10	11	2	3
Ablation of the upstream MAP kinase kinase ( MAP2K7 ) in ES cells prevented JNK activation , whereas ablation of MAP2K4 prevented both JNK and p38 activation .	Ablation of the upstream MAP kinase kinase (MAP2K7) in ES cells prevented JNK activation, whereas ablation of MAP2K4 prevented both JNK and p38 activation.	18	26	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAP2K4	MAP2K4	MAP2K4	JNK	JNK	JNK	20	21	23	24
In that study , expression of dominant negative JNKK reduced JNK activation by detachment to a similar degree to what we find here , yet it completely protected MDCK cells from detachment- induced apoptosis .	In that study, expression of dominant negative JNKK reduced JNK activation by detachment to a similar degree to what we find here, yet it completely protected MDCK cells from detachment- induced apoptosis.	4	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNKK	expression of dominant negative JNKK	jnkk	JNK	JNK	jnk	8	9	10	11
MKK7 is commonly essential for stress stimulated JNK activation , whereas MKK4 deficiency causes a reduction in basal JNK activity [ XREF_BIBR ] .	MKK7 is commonly essential for stress stimulated JNK activation, whereas MKK4 deficiency causes a reduction in basal JNK activity [XREF_BIBR].	11	21	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	11	12	18	19
At the molecular level , MKK4 knockdown causes activation of JNK signaling .	At the molecular level, MKK4 knockdown causes activation of JNK signaling.	5	11	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	5	6	10	11
JNK activation and cell death were inhibited by overexpression of a dominant negative SEK1 ( SEK1-AL ) construct .	JNK activation and cell death were inhibited by overexpression of a dominant negative SEK1 (SEK1-AL) construct.	0	17	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	SEK1	overexpression of a dominant negative SEK1	sek1	JNK	JNK	jnk	13	14	0	1
The ephrin-B1-mediated JNK activation was reduced significantly by dominant negative TAK1 , MKK4 , or MKK7 .	The ephrin-B1-mediated JNK activation was reduced significantly by dominant negative TAK1, MKK4, or MKK7.	2	13	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	12	13	2	3
Disruption of the MKK4 gene in mice has shown that MKK4 is a physiological activator of JNK 7 8 .	Disruption of the MKK4 gene in mice has shown that MKK4 is a physiological activator of JNK 7 8.	10	18	is a physiological activator	Positive_activation_copula_1	Positive_activation	Positive_activation	MKK4	MKK4	MKK4	JNK	JNK	JNK	10	11	16	17
In contrast , MAP2K4 and MAP2K7 serve as non redundant activators of JNK and mutation of either MAP2K4 or MAP2K7 causes JNK inhibition .	In contrast, MAP2K4 and MAP2K7 serve as non redundant activators of JNK and mutation of either MAP2K4 or MAP2K7 causes JNK inhibition.	12	22	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MAP2K4	MAP2K4	MAP2K4	JNK	JNK	JNK	17	18	21	22
MEKK1 phosphorylates several MEKs , and its major targets are MKK3 and MKK4 , which in turn activates JNK [ XREF_BIBR , XREF_BIBR ] .	MEKK1 phosphorylates several MEKs, and its major targets are MKK3 and MKK4, which in turn activates JNK [XREF_BIBR, XREF_BIBR].	0	22	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK4	MEKK1 phosphorylates several MEKs, and its major targets are MKK3 and MKK4	mkk4	JNK	JNK	jnk	12	13	18	19
Three genes linked to inhibition of cardiac hypertrophy were upregulate , viz ., DKK3 ( Dickkopf-3 ) , FBXO32 ( encoding E3 ligase , Fbxo32 ) , and GADD45B , which blocks MKK7 induced JNK activation .	Three genes linked to inhibition of cardiac hypertrophy were upregulate, viz., DKK3 (Dickkopf-3), FBXO32 (encoding E3 ligase, Fbxo32), and GADD45B, which blocks MKK7 induced JNK activation.	32	35	induced	Positive_early_activation	Positive_activation	Positive_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	32	33	34	35
The fact that 30 % of wide type mouse embryonic stem cells and 60 % of MAP2K7 deficient mouse embryonic stem cells developed rhythmic contractile cardiomyocytes suggests the inhibitory effect of JNK on the differentiation , since ablation of the upstream MAP kinase kinase ( MAP2K7 ) in embryonic stem cells prevented JNK activation XREF_BIBR .	The fact that 30% of wide type mouse embryonic stem cells and 60% of MAP2K7 deficient mouse embryonic stem cells developed rhythmic contractile cardiomyocytes suggests the inhibitory effect of JNK on the differentiation, since ablation of the upstream MAP kinase kinase (MAP2K7) in embryonic stem cells prevented JNK activation XREF_BIBR.	43	54	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAP2K7	MAP2K7	MAP2K7	JNK	JNK	JNK	45	46	52	53
Sequestration of MKK7 by GADD45beta prevented the activation of JNK and subsequent cell death .	Sequestration of MKK7 by GADD45beta prevented the activation of JNK and subsequent cell death.	0	13	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	2	3	9	10
On the other hand , AvrA targeting MKK4 and MKK7 inhibits JNK signaling and thus slows down apoptosis [ XREF_BIBR , XREF_BIBR ] .	On the other hand, AvrA targeting MKK4 and MKK7 inhibits JNK signaling and thus slows down apoptosis [XREF_BIBR, XREF_BIBR].	7	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	9	10	11	12
However , adenovirus mediated overexpression of MKP-1 only slightly decreased JNK and c-Jun phosphorylation compared with the severe inactivation of JNK activities induced by MKK7 knockdown .	However, adenovirus mediated overexpression of MKP-1 only slightly decreased JNK and c-Jun phosphorylation compared with the severe inactivation of JNK activities induced by MKK7 knockdown.	20	25	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	24	25	20	21
Therefore , the inactivation of MKK7 can inhibit the JNK signal transduction pathway , which may be an effective approach for controlling cellular hypoxia injury .	Therefore, the inactivation of MKK7 can inhibit the JNK signal transduction pathway, which may be an effective approach for controlling cellular hypoxia injury.	3	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	5	6	9	10
Furthermore , MKK7 knockdown by siRNAs consistently reduced JNK and c-Jun activation and cell proliferation , whereas silencing MKK4 had no such effects .	Furthermore, MKK7 knockdown by siRNAs consistently reduced JNK and c-Jun activation and cell proliferation, whereas silencing MKK4 had no such effects.	2	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	2	3	8	9
Mutations in MAP2K4 and MKK4 and MAP2K7 and MKK7 [ XREF_BIBR , XREF_BIBR ] , two key upstream kinases of JNK , impair JNK activation , in line with their tumor-suppressive functions [ XREF_BIBR , XREF_BIBR ] .	Mutations in MAP2K4 and MKK4 and MAP2K7 and MKK7 [XREF_BIBR, XREF_BIBR], two key upstream kinases of JNK, impair JNK activation, in line with their tumor-suppressive functions [XREF_BIBR, XREF_BIBR].	6	24	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	8	9	23	24
The Gadd45-beta protein forms a complex with MKK7 , the upstream regulator of JNK , inhibiting JNK activation .	The Gadd45-beta protein forms a complex with MKK7, the upstream regulator of JNK, inhibiting JNK activation.	7	17	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK7	MKK7	MKK7	JNK	JNK	JNK	7	8	16	17
However , the inhibition efficiency of these two MEK5 blockers in growth factor induced activation of BMK1 still needs to be examined .	However, the inhibition efficiency of these two MEK5 blockers in growth factor induced activation of BMK1 still needs to be examined.	8	17	blockers	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MEK5	MEK5	MEK5	BMK1	BMK1	BMK1	8	9	16	17
As shown in XREF_FIG , MEK5 depletion abolished CA-MEKK3-mediated ERK5 transcriptional activity .	As shown in XREF_FIG, MEK5 depletion abolished CA-MEKK3-mediated ERK5 transcriptional activity.	5	11	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	5	6	9	10
Remarkably , we found that ERK5 inhibition by DN-MEK5 significantly increased both basal ( p < 0.01 ) and 5-FU-induced ( p < 0.01 ) p53 transcriptional activation , compared with empty controls .	Remarkably, we found that ERK5 inhibition by DN-MEK5 significantly increased both basal (p < 0.01) and 5-FU-induced (p < 0.01) p53 transcriptional activation, compared with empty controls.	5	9	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	DN-MEK5	DN-MEK5	DN-MEK5	ERK5	ERK5	ERK5	8	9	5	6
This reduces the ability of MEKK3 to phosphorylate MEK5 which is required to activate ERK5 .	This reduces the ability of MEKK3 to phosphorylate MEK5 which is required to activate ERK5.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	phosphorylate MEK5	mek5	ERK5	ERK5	erk5	8	9	14	15
We confirmed that ERK5 activation was induced through MEK5 because two separate MEK5 selective kinase inhibitors , designated BIX2189 and BIX2188 [ XREF_BIBR ] , led to a dose dependent ERK5 band-shift diminution , indicating ERK5 inactivation .	We confirmed that ERK5 activation was induced through MEK5 because two separate MEK5 selective kinase inhibitors, designated BIX2189 and BIX2188 [XREF_BIBR], led to a dose dependent ERK5 band-shift diminution, indicating ERK5 inactivation.	12	36	led	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	12	13	35	36
To determine whether MEKK3 regulates Klf and Adamts gene expression through the ERK5 MAPK pathway we cultured wild-type E10.5 explanted hearts in the presence of BIX02189 , a highly specific inhibitor of MEK5 , the MAPK2K that is activated by MEKK3 and in turn activates ERK5 .	To determine whether MEKK3 regulates Klf and Adamts gene expression through the ERK5 MAPK pathway we cultured wild-type E10.5 explanted hearts in the presence of BIX02189, a highly specific inhibitor of MEK5, the MAPK2K that is activated by MEKK3 and in turn activates ERK5.	30	46	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	32	33	45	46
Recent studies have identified pharmacological inhibitors that are reasonably selective for MEK5 causing inhibition of the ERK5 pathway without affecting ERK1/2 signaling .	Recent studies have identified pharmacological inhibitors that are reasonably selective for MEK5 causing inhibition of the ERK5 pathway without affecting ERK1/2 signaling.	11	17	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	11	12	16	17
Constitutively active ( CA ) and dominant negative ( DN ) forms of MEK5 were used to induce or block ERK5 activation , respectively .	Constitutively active (CA) and dominant negative (DN) forms of MEK5 were used to induce or block ERK5 activation, respectively.	11	21	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	13	14	20	21
The short inhibitory RNAs ( siRNAs ) specific for MAPK7 ( which encodes ERK5 ) and MAP2K5 ( which encodes MEK5 ) substantially reduced the abundances of ERK5 and MEK5 , respectively , but did not affect the abundances of ERK1 and ERK2 or of MEK1 and MEK2 , which have kinase domain sequences most similar to those of ERK5 and MEK5 , respectively ( XREF_FIG ) .	The short inhibitory RNAs (siRNAs) specific for MAPK7 (which encodes ERK5) and MAP2K5 (which encodes MEK5) substantially reduced the abundances of ERK5 and MEK5, respectively, but did not affect the abundances of ERK1 and ERK2 or of MEK1 and MEK2, which have kinase domain sequences most similar to those of ERK5 and MEK5, respectively (XREF_FIG).	3	29	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAP2K5	MAP2K5	MAP2K5	ERK5	ERK5	ERK5	16	17	27	28
With this consideration it would appear from our work that TGFbeta1 has the potential to modify the specialized phenotype of the podocyte in a manner likely to alter its function , and consequently still represents a loss of barrier function which can be mitigated to a large extent by inhibiting the activation of Erk5 by Mek5 .	With this consideration it would appear from our work that TGFbeta1 has the potential to modify the specialized phenotype of the podocyte in a manner likely to alter its function, and consequently still represents a loss of barrier function which can be mitigated to a large extent by inhibiting the activation of Erk5 by Mek5.	49	56	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Mek5	Mek5	Mek5	Erk5	Erk5	Erk5	55	56	53	54
On the other hand , inhibition of ERK5 by DN-MEK5 enhanced 5-FU cytotoxicity , increasing general cell death after 5-FU exposure ( p < 0.05 ) .	On the other hand, inhibition of ERK5 by DN-MEK5 enhanced 5-FU cytotoxicity, increasing general cell death after 5-FU exposure (p < 0.05).	5	10	inhibition	Negative_activation_token_2_noun	Positive_activation	Negative_activation	DN-MEK5	DN-MEK5	DN-MEK5	ERK5	ERK5	ERK5	9	10	7	8
In contrast , MEK5 depletion did not inhibit ERK5 transcriptional activity ( XREF_FIG and XREF_SUPPLEMENTARY ) .	In contrast, MEK5 depletion did not inhibit ERK5 transcriptional activity (XREF_FIG and XREF_SUPPLEMENTARY).	3	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK5	MEK5	MEK5	ERK5	ERK5	ERK5	3	4	8	9
Of note , although XREF_BIBR , XREF_BIBR ) argue that AKT phosphorylates and inhibits GSK3beta , which subsequently stabilizes CRMP2 and microtubules to prevent axonal degeneration , XREF_BIBR claim that AKT promotes axonal survival by phosphorylation of MKK4 at serine 78 , which suppresses MKK4 mediated activation of prodegenerative JNK signaling .	Of note, although XREF_BIBR, XREF_BIBR) argue that AKT phosphorylates and inhibits GSK3beta, which subsequently stabilizes CRMP2 and microtubules to prevent axonal degeneration, XREF_BIBR claim that AKT promotes axonal survival by phosphorylation of MKK4 at serine 78, which suppresses MKK4 mediated activation of prodegenerative JNK signaling.	35	46	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	phosphorylation of MKK4 at serine 78	mkk4	MKK4	MKK4	mkk4	37	38	44	45
We found that sek-1 expression in adults rescues the sek-1 slow locomotion phenotype ( XREF_FIG ) .	We found that sek-1 expression in adults rescues the sek-1 slow locomotion phenotype (XREF_FIG).	3	12	rescues	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	sek-1	sek-1 expression	sek-1	sek-1	sek-1	sek-1	3	4	9	10
BIN2 phosphorylates a GSK3 and Shaggy like kinase recognition motif in MKK4 , which reduces MKK4 activity against its substrate MPK6 in vitro .	BIN2 phosphorylates a GSK3 and Shaggy like kinase recognition motif in MKK4, which reduces MKK4 activity against its substrate MPK6 in vitro.	1	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	phosphorylates a GSK3 and Shaggy like kinase recognition motif in MKK4	mkk4	MKK4	MKK4	mkk4	11	12	15	16
Overexpression of MKK4 decreased proliferation and promoted a senescent phenotype in young WI-38 human diploid fibroblasts and conversely , when MKK4 levels were lowered by several microRNAs targeting the MKK4 mRNA , the senescent phenotype was ameliorated and cells proliferated more rapidly [ XREF_BIBR ] .	Overexpression of MKK4 decreased proliferation and promoted a senescent phenotype in young WI-38 human diploid fibroblasts and conversely, when MKK4 levels were lowered by several microRNAs targeting the MKK4 mRNA, the senescent phenotype was ameliorated and cells proliferated more rapidly [XREF_BIBR].	20	30	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	MKK4 levels	mkk4	MKK4	MKK4	mkk4	20	21	29	30
Expression of sek-1 in acetylcholine motorneurons rescued the sek-1 slow locomotion phenotype , suggesting that the slow locomotion of sek-1 mutants is due to a loss of sek-1 in acetylcholine motorneurons .	Expression of sek-1 in acetylcholine motorneurons rescued the sek-1 slow locomotion phenotype, suggesting that the slow locomotion of sek-1 mutants is due to a loss of sek-1 in acetylcholine motorneurons.	0	11	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	sek-1	Expression of sek-1	sek-1	sek-1	sek-1	sek-1	2	3	8	9
There is also feedback inhibition of MEK1 by ERK1/2 catalyzed phosphorylation of threonine 292 of MEK1 .	There is also feedback inhibition of MEK1 by ERK1/2 catalyzed phosphorylation of threonine 292 of MEK1.	4	16	inhibition	Negative_activation_token_2_noun	Positive_activation	Negative_activation	MEK1	ERK1/2 catalyzed phosphorylation of threonine 292 of MEK1	mek1	MEK1	MEK1	mek1	15	16	6	7
Moreover , the overexpression of MEK1 ( 3A ) failed to block endogenous MEK1 activation , although MEK1 ( 3A ) formed complexes with both c-Raf and B-Raf as well as p42 and p44 MAPK .	Moreover, the overexpression of MEK1 (3A) failed to block endogenous MEK1 activation, although MEK1 (3A) formed complexes with both c-Raf and B-Raf as well as p42 and p44 MAPK.	3	14	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	overexpression of MEK1	mek1	MEK1	MEK1	mek1	5	6	13	14
Taken together , in normal cells , MEK1 SUMOylation attenuates the activity of MEK1 toward ERK , thereby inhibiting the ERK pathway .	Taken together, in normal cells, MEK1 SUMOylation attenuates the activity of MEK1 toward ERK, thereby inhibiting the ERK pathway.	7	14	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	MEK1 SUMOylation	mek1	MEK1	MEK1	mek1	7	8	13	14
Phosphorylation of these sites triggers autophosphorylation of Mek1 ; indeed , alanine replacement mutations of Mek1-T318 and -T322 residues in the activation loop of Mek1 reduced Mek1 kinase activity and meiotic recombination rates .	Phosphorylation of these sites triggers autophosphorylation of Mek1; indeed, alanine replacement mutations of Mek1-T318 and -T322 residues in the activation loop of Mek1 reduced Mek1 kinase activity and meiotic recombination rates.	5	28	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mek1	autophosphorylation of Mek1; indeed, alanine	mek1	Mek1	Mek1	mek1	7	8	26	27
Co-silencing up-stream kinases MKK4 or MKK 7 with JNK2 only partially rescued JNK1 dependent apoptosis ( XREF_SUPPLEMENTARY ) , further substantiating the ability of JNK1 to promote apoptosis in the absence of enhanced T183 and Y185 phosphorylations .	Co-silencing up-stream kinases MKK4 or MKK 7 with JNK2 only partially rescued JNK1 dependent apoptosis (XREF_SUPPLEMENTARY), further substantiating the ability of JNK1 to promote apoptosis in the absence of enhanced T183 and Y185 phosphorylations.	3	14	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MKK 7	MKK 7	MKK 7	JNK1	JNK1	JNK1	5	7	12	13
It has been shown that MAP2K7 mediates JNK activation during the deletion of CD4 and CD8 double positive thymocytes , MAP2K7 is an essential regulator of stress induced SAPK and JNK activation in mast cells and negatively regulates proliferation in hematopoietic cells , and MAP2K7 sequesters JNK1 in the cytosol , preventing pro survival functions in Jurkat cells .	It has been shown that MAP2K7 mediates JNK activation during the deletion of CD4 and CD8 double positive thymocytes, MAP2K7 is an essential regulator of stress induced SAPK and JNK activation in mast cells and negatively regulates proliferation in hematopoietic cells, and MAP2K7 sequesters JNK1 in the cytosol, preventing pro survival functions in Jurkat cells.	44	49	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAP2K7	MAP2K7	MAP2K7	JNK1	JNK1	JNK1	44	45	46	47
Akt directly phosphorylates PLB at Thr 17 to modulate SR Ca 2+ handling in rat ventricular myocytes [ XREF_BIBR ] ; therefore , we extended our hypothesis to integrate Akt activation and targeting to the SR as an effector of MEK7 mediated JNK1 regulation .	Akt directly phosphorylates PLB at Thr 17 to modulate SR Ca 2+ handling in rat ventricular myocytes [XREF_BIBR]; therefore, we extended our hypothesis to integrate Akt activation and targeting to the SR as an effector of MEK7 mediated JNK1 regulation.	38	43	mediated	Positive_early_activation	Positive_activation	Positive_activation	MEK7	MEK7	MEK7	JNK1	JNK1	JNK1	40	41	42	43
We reported that estrogen induced AKT directly phosphorylate MLK3 on Ser674 site that significantly inhibit MLK3 kinase activity , leading to ER + breast cancer cell survival .	We reported that estrogen induced AKT directly phosphorylate MLK3 on Ser674 site that significantly inhibit MLK3 kinase activity, leading to ER + breast cancer cell survival.	3	17	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MLK3	estrogen induced AKT directly phosphorylate MLK3 on Ser674	mlk3	MLK3	MLK3	mlk3	8	9	15	16
Since inhibition of proteosome activity elevates total MLK3 protein levels we suggest that K48 linked ubiquitination of MLK3 may function to target MLK3 for proteosomal degradation by the ubiquitin-proteosome pathway .	Since inhibition of proteosome activity elevates total MLK3 protein levels we suggest that K48 linked ubiquitination of MLK3 may function to target MLK3 for proteosomal degradation by the ubiquitin-proteosome pathway.	13	25	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MLK3	K48 linked ubiquitination of MLK3	mlk3	MLK3	MLK3	mlk3	17	18	22	23
We observed a significant increase in the interaction between S705A-S758A-FLAG-MLK3 and GST-B-Raf compared to the interaction between WT-FLAG-MLK3 and GST-B-Raf ( XREF_FIG ) , which suggests the ERK1/2 mediated phosphorylation of MLK3 limits the interaction of MLK3 with B-Raf ; however , we still detect a significant interaction between WT-MLK3 and B-Raf in H 2 O 2 -treated cells ( XREF_FIG ) .	We observed a significant increase in the interaction between S705A-S758A-FLAG-MLK3 and GST-B-Raf compared to the interaction between WT-FLAG-MLK3 and GST-B-Raf (XREF_FIG), which suggests the ERK1/2 mediated phosphorylation of MLK3 limits the interaction of MLK3 with B-Raf; however, we still detect a significant interaction between WT-MLK3 and B-Raf in H 2 O 2 -treated cells (XREF_FIG).	27	37	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MLK3	ERK1/2 mediated phosphorylation of MLK3	mlk3	MLK3	MLK3	mlk3	31	32	36	37
SEK-1 ( KR ) completely inhibited ET-1-induced SAPK activation without affecting activation of the other MAP kinases implicated in the hypertrophic response , p38 and extracellular signal regulated protein kinases ( ERK )-1/ERK-2 .	SEK-1 (KR) completely inhibited ET-1-induced SAPK activation without affecting activation of the other MAP kinases implicated in the hypertrophic response, p38 and extracellular signal regulated protein kinases (ERK)-1/ERK-2.	0	8	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SEK-1	SEK-1	SEK-1	SAPK	SAPK	SAPK	0	1	7	8
We now report that gene transfer of SEK-1 ( KR ) to the adult rat heart blocks SAPK activation by pressure overload , demonstrating that the activity of cytosolic signaling pathways can be inhibited by gene transfer of loss-of-function mutants in vivo .	We now report that gene transfer of SEK-1 (KR) to the adult rat heart blocks SAPK activation by pressure overload, demonstrating that the activity of cytosolic signaling pathways can be inhibited by gene transfer of loss-of-function mutants in vivo.	5	18	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SEK-1	SEK-1	SEK-1	SAPK	SAPK	SAPK	7	8	17	18
Moreover , dominant negative MKK7 , but not dominant negative MKK4 and SEK1 , blocked JNK1 activation and apoptosis induced by parthenolide and HDACI regimens .	Moreover, dominant negative MKK7, but not dominant negative MKK4 and SEK1, blocked JNK1 activation and apoptosis induced by parthenolide and HDACI regimens.	4	16	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK4	MKK4	MKK4	JNK1	JNK1	JNK1	10	11	15	16
HPK1 binds and phosphorylates MEKK1 directly , whereas JNK1 activation by HPK1 is inhibited by a dominant negative MEKK1 or MKK4 and SEK mutant .	HPK1 binds and phosphorylates MEKK1 directly, whereas JNK1 activation by HPK1 is inhibited by a dominant negative MEKK1 or MKK4 and SEK mutant.	8	23	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MKK4	MKK4	MKK4	JNK1	JNK1	JNK1	20	21	8	9
Expression of the dominant negative MEK1 inhibited platelet derived growth factor ( PDGF )-induced ERK2 activation , whereas expression of the constitutively active MEK1 induced ERK2 activation , suggesting that MEK1 is required and sufficient for ERK activation in these cells .	Expression of the dominant negative MEK1 inhibited platelet derived growth factor (PDGF)-induced ERK2 activation, whereas expression of the constitutively active MEK1 induced ERK2 activation, suggesting that MEK1 is required and sufficient for ERK activation in these cells.	18	26	induced	Positive_early_activation	Positive_activation	Positive_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	23	24	25	26
Inhibition of MEK1 and MEK2 ( activators of ERK1 and ERK2 ) , PI3-kinase ( activator of Akt ) or Akt inhibited the axon growth promoting action of APRIL , as did pharmacological activation of GSK-3beta and the expression of a constitutively active form of GSK-3beta .	Inhibition of MEK1 and MEK2 (activators of ERK1 and ERK2), PI3-kinase (activator of Akt) or Akt inhibited the axon growth promoting action of APRIL, as did pharmacological activation of GSK-3beta and the expression of a constitutively active form of GSK-3beta.	0	20	activators	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	2	3	10	11
Consistent with its recognition of the MAP kinase insert , PEA-15 blocked activation of ERK2 by MEK1 , which also requires the MAP kinase insert to interact productively with ERK2 .	Consistent with its recognition of the MAP kinase insert, PEA-15 blocked activation of ERK2 by MEK1, which also requires the MAP kinase insert to interact productively with ERK2.	11	20	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK2	ERK2	ERK2	16	17	14	15
Further , treatment of RKO cells with a specific inhibitor ( PD 098059 ) of MEK1 activation , which diminished ERK1 activity , reduced the amount of urokinase specifically bound to the cell surface and this was associated with reduced laminin degradation .	Further, treatment of RKO cells with a specific inhibitor (PD 098059) of MEK1 activation, which diminished ERK1 activity, reduced the amount of urokinase specifically bound to the cell surface and this was associated with reduced laminin degradation.	15	21	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1	MEK1	MEK1	ERK1	ERK1	ERK1	15	16	20	21
Each peptide inhibited multiple reactions ; for example , the MEK2 peptide inhibited not only MEK2 , but also ERK2 and MKP-1 .	Each peptide inhibited multiple reactions; for example, the MEK2 peptide inhibited not only MEK2, but also ERK2 and MKP-1.	10	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK2	MEK2	MEK2	ERK2	ERK2	ERK2	10	11	19	20
U0126 is a highly selective inhibitor on both MEK1 and MEK2 , a type of MAPK and ERK kinase , blocks ERK pathway .	U0126 is a highly selective inhibitor on both MEK1 and MEK2, a type of MAPK and ERK kinase, blocks ERK pathway.	10	22	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK2	MEK2	MEK2	ERK	ERK	ERK	10	11	21	22
We show using purified kinases that inhibitory activity is specific for the combination of SEK and SAPK : SEK can activate but not inhibit p38 , and MKK6 can activate but not inhibit SAPK beta and p38 .	We show using purified kinases that inhibitory activity is specific for the combination of SEK and SAPK : SEK can activate but not inhibit p38, and MKK6 can activate but not inhibit SAPK beta and p38.	27	34	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MKK6	MKK6	MKK6	SAPK	SAPK	SAPK	27	28	33	34
PP5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ASK1 and thereby inactivated ASK1 activity in vitro and in vivo .	PP5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ASK1 and thereby inactivated ASK1 activity in vitro and in vivo.	0	17	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	PP5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ASK1	ask1	ASK1	ASK1	ask1	12	13	16	17
Phosphorylation of ASK1 Ser83 by AKT attenuates ASK1 kinase activity .	Phosphorylation of ASK1 Ser83 by AKT attenuates ASK1 kinase activity.	0	9	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	Phosphorylation of ASK1 Ser83	ask1	ASK1	ASK1	ask1	2	3	7	8
Phosphorylation of ASK1 at S83 by Akt and PKB ( protein kinase B ) and dephosphorylation at S845 by protein phosphatase 5 ( PP5 ) both decrease ASK1 activity .	Phosphorylation of ASK1 at S83 by Akt and PKB (protein kinase B) and dephosphorylation at S845 by protein phosphatase 5 (PP5) both decrease ASK1 activity.	0	28	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	Phosphorylation of ASK1 at S83	ask1	ASK1	ASK1	ask1	2	3	27	28
In this study , we observed that RASSF1A increased ASK1 mRNA and protein level but inhibited phosphorylation of ASK1 ( inactivation of ASK1 ) .	In this study, we observed that RASSF1A increased ASK1 mRNA and protein level but inhibited phosphorylation of ASK1 (inactivation of ASK1).	7	23	inactivation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	ASK1	RASSF1A increased ASK1 mRNA and protein level but inhibited phosphorylation of ASK1	ask1	ASK1	ASK1	ask1	18	19	22	23
On the MAP3K level , phosphorylation of ASK1 at Ser 83 by AKT reduced JNK activity in response to oxidative stress and serum starvation , and decreased ASK1 dependent apoptosis in HEK 293 and L929 cells .	On the MAP3K level, phosphorylation of ASK1 at Ser 83 by AKT reduced JNK activity in response to oxidative stress and serum starvation, and decreased ASK1 dependent apoptosis in HEK 293 and L929 cells.	5	29	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	phosphorylation of ASK1 at Ser 83	ask1	ASK1	ASK1	ask1	7	8	27	28
A Novel ASK Inhibitor AGI-1067 Inhibits TLR-4-Mediated Activation of ASK1 by Preventing Dissociation of Thioredoxin from ASK1 .	A Novel ASK Inhibitor AGI-1067 Inhibits TLR-4-Mediated Activation of ASK1 by Preventing Dissociation of Thioredoxin from ASK1.	2	10	Inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK	ASK	ASK	ASK1	ASK1	ASK1	2	3	9	10
This was triggered by attenuating apoptosis signal regulated kinase 1 ( ASK1 ) methylation and increasing ubiquitination mediated ASK1 protein degradation .	This was triggered by attenuating apoptosis signal regulated kinase 1 (ASK1) methylation and increasing ubiquitination mediated ASK1 protein degradation.	11	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	ASK1) methylation and increasing ubiquitination	ask1	ASK1	ASK1	ask1	11	12	18	19
Phosphorylation of ASK1 on Ser83 by AKT kinase and de-phosphorylation of Ser845 by protein phosphatase 5 decreases ASK1 activity .	Phosphorylation of ASK1 on Ser83 by AKT kinase and de-phosphorylation of Ser845 by protein phosphatase 5 decreases ASK1 activity.	0	18	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	Phosphorylation of ASK1 on Ser83	ask1	ASK1	ASK1	ask1	2	3	17	18
On the basis of our finding that methylation of ASK1 negatively regulates H 2 O 2 -induced activation of ASK1 , we next asked whether methylation of ASK1 at Arg 89 affects Ser 83 in vitro and in vivo .	On the basis of our finding that methylation of ASK1 negatively regulates H 2 O 2 -induced activation of ASK1, we next asked whether methylation of ASK1 at Arg 89 affects Ser 83 in vitro and in vivo.	7	20	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	methylation of ASK1	ask1	ASK1	ASK1	ask1	9	10	19	20
Although we show phosphorylation on Ser83 of ASK1 by PIM1 inhibits ASK1 activity , the mechanism underlying how phosphorylation on Ser83 inhibits its kinase activity remains unclear .	Although we show phosphorylation on Ser83 of ASK1 by PIM1 inhibits ASK1 activity, the mechanism underlying how phosphorylation on Ser83 inhibits its kinase activity remains unclear.	3	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	phosphorylation on Ser83 of ASK1	ask1	ASK1	ASK1	ask1	7	8	11	12
In our observation , 5 '-AMP attenuated the methylation of ASK1 and enhanced the ubiquitination of ASK1 , which accelerate ASK1 degradation , leading to an inhibition of MAPKs cascade .	In our observation, 5 '-AMP attenuated the methylation of ASK1 and enhanced the ubiquitination of ASK1, which accelerate ASK1 degradation, leading to an inhibition of MAPKs cascade.	4	19	enhanced	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ASK1	5 '-AMP attenuated the methylation of ASK1	ask1	ASK1	ubiquitination of ASK1	ask1	10	11	16	17
It has been shown by others that ASK1 can be phosphorylated at several sites which either up- or down-regulate ASK1 kinase activity .	It has been shown by others that ASK1 can be phosphorylated at several sites which either up- or down-regulate ASK1 kinase activity.	7	21	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	ASK1 can be phosphorylated	ask1	ASK1	ASK1	ask1	7	8	19	20
Our results show that nickel treatment induced ASK1 phosphorylation at Thr838 , not Ser83 , which decreases ASK1 activity .	Our results show that nickel treatment induced ASK1 phosphorylation at Thr838, not Ser83, which decreases ASK1 activity.	4	18	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	nickel treatment induced ASK1 phosphorylation at Thr838	ask1	ASK1	ASK1	ask1	7	8	17	18
PIM1 phosphorylation of ASK1 decreases ASK1 kinase activity .	PIM1 phosphorylation of ASK1 decreases ASK1 kinase activity.	0	7	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	PIM1 phosphorylation of ASK1	ask1	ASK1	ASK1	ask1	3	4	5	6
In summary , H 2 O 2 -induced ASK1 activity can be inhibited by PRMT5 methylation of ASK1 at Arg 89 , which in turn promotes interaction between ASK1 and Akt and enhances phosphorylation of ASK1 at Ser 83 , which inhibits endothelial cells apoptosis .	In summary, H 2 O 2 -induced ASK1 activity can be inhibited by PRMT5 methylation of ASK1 at Arg 89, which in turn promotes interaction between ASK1 and Akt and enhances phosphorylation of ASK1 at Ser 83, which inhibits endothelial cells apoptosis.	14	31	promotes	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	ASK1	PRMT5 methylation of ASK1 at Arg 89	ask1	ASK1	interaction between ASK1 and Akt	ask1	17	18	28	29
In contrast , knockdown of TAK1 by si-TAK1 increased HBV transcripts ( XREF_FIG ) and CP activity approximately 2.5-fold , but had no significant effect on other ( XP , SP1 , and SP2 ) promoters ( XREF_FIG ) .	In contrast, knockdown of TAK1 by si-TAK1 increased HBV transcripts (XREF_FIG) and CP activity approximately 2.5-fold, but had no significant effect on other (XP, SP1, and SP2) promoters (XREF_FIG).	3	8	knockdown	Negative_activation_token_2_noun	Positive_activation	Negative_activation	si-TAK1	si-TAK1	si-TAK1	TAK1	TAK1	TAK1	7	8	5	6
Lys48 linked TAK1 polyubiquitination mediated TAK1 degradation plays a critical role in the termination of TNFalpha induced NF-kappaB activation [ XREF_BIBR , XREF_BIBR ] .	Lys48 linked TAK1 polyubiquitination mediated TAK1 degradation plays a critical role in the termination of TNFalpha induced NF-kappaB activation [XREF_BIBR, XREF_BIBR].	2	6	mediated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	TAK1	TAK1 polyubiquitination	tak1	TAK1	TAK1	tak1	2	3	5	6
To test the hypothesis that lysine 72 polyubiquitination of TAK1 negatively regulates TAK1 activation in the later time point of TNFalpha stimulation , we stably re-introduced Flag-TAK1 wild-type and K72R mutant into TAK1 deficient MEF cells and treated these two cells with TNFalpha at four consecutive time points ( at 30 , 60 , 90 and 120 mins ) in the presence of MG132 .	To test the hypothesis that lysine 72 polyubiquitination of TAK1 negatively regulates TAK1 activation in the later time point of TNFalpha stimulation, we stably re-introduced Flag-TAK1 wild-type and K72R mutant into TAK1 deficient MEF cells and treated these two cells with TNFalpha at four consecutive time points (at 30, 60, 90 and 120 mins) in the presence of MG132.	5	13	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TAK1	lysine 72 polyubiquitination of TAK1	tak1	TAK1	TAK1	tak1	9	10	12	13
After TAK1 is activated with Lys63 linked polyubiquitination by Dox , USP4 deubiquitinates TAK1 and inhibits TAK1 mediated signaling .	After TAK1 is activated with Lys63 linked polyubiquitination by Dox, USP4 deubiquitinates TAK1 and inhibits TAK1 mediated signaling.	11	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TAK1	USP4 deubiquitinates TAK1	tak1	TAK1	TAK1	tak1	13	14	16	17
Suppression of TAK1 signaling by dn-TAK1 in breast carcinoma cells impairs the bone invasive capacity of carcinoma cells and the bone osteolysis .	Suppression of TAK1 signaling by dn-TAK1 in breast carcinoma cells impairs the bone invasive capacity of carcinoma cells and the bone osteolysis.	2	9	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	dn-TAK1	dn-TAK1	dn-TAK1	TAK1	TAK1	TAK1	5	6	2	3
Therefore , we examined TAK1 protein level and Dox induced TAK1 degradation in wildtype and ITCH deficient MEFs .	Therefore, we examined TAK1 protein level and Dox induced TAK1 degradation in wildtype and ITCH deficient MEFs.	4	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TAK1	TAK1 protein level	tak1	TAK1	TAK1	tak1	4	5	10	11
These data suggest that TAK1 deletion in myeloid cell lineage does not alter the numbers of T cells , but markedly increases the activated T cell population in Map3k7 DeltaM and DeltaM mice , probably because of the proinflammatory cytokine environment .	These data suggest that TAK1 deletion in myeloid cell lineage does not alter the numbers of T cells, but markedly increases the activated T cell population in Map3k7 DeltaM and DeltaM mice, probably because of the proinflammatory cytokine environment.	4	29	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TAK1	TAK1	TAK1	Map3k7	Map3k7	Map3k7	4	5	28	29
TGF-beta-activated kinase-1 protein was reduced by 77 % and 85 % in the two TAK1 shRNA clones compared with control cells ( XREF_FIG ) and cell proliferation did not change ( XREF_SUPPLEMENTARY ) .	TGF-beta-activated kinase-1 protein was reduced by 77% and 85% in the two TAK1 shRNA clones compared with control cells (XREF_FIG) and cell proliferation did not change (XREF_SUPPLEMENTARY).	0	16	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TAK1	TAK1	TAK1	TGF-beta-activated kinase-1	TGF-beta-activated kinase-1	TGF-beta-activated kinase-1	14	15	0	2
Lys48 linked TAK1 polyubiquitination mediated TAK1 degradation is critical for the termination of TNFalpha induced NF-kappaB activation [ XREF_BIBR , XREF_BIBR ] .	Lys48 linked TAK1 polyubiquitination mediated TAK1 degradation is critical for the termination of TNFalpha induced NF-kappaB activation [XREF_BIBR, XREF_BIBR].	2	6	mediated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	TAK1	TAK1 polyubiquitination	tak1	TAK1	TAK1	tak1	2	3	5	6
Disruption of TAK1 signaling by dn-TAK1 or by siRNA did not affect p38MAPK signaling in MDA-MB-231 cells .	Disruption of TAK1 signaling by dn-TAK1 or by siRNA did not affect p38MAPK signaling in MDA-MB-231 cells.	2	6	signaling	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	dn-TAK1	dn-TAK1	dn-TAK1	TAK1	TAK1	TAK1	5	6	2	3
Finally , we also observed that calcineurin dependent dephosphorylation of the TAK1 and TAB1 complex reduced TAK1 kinase activity ( XREF_FIG ) .	Finally, we also observed that calcineurin dependent dephosphorylation of the TAK1 and TAB1 complex reduced TAK1 kinase activity (XREF_FIG).	6	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TAK1	calcineurin dependent dephosphorylation of the TAK1	tak1	TAK1	TAK1	tak1	11	12	16	17
Depletion of Tpl2 by RNAi or activity by a Tpl2 kinase inhibitor in human ccRCC cells remarkably suppressed MAPK pathways and impaired in vitro cell proliferation , clonogenicity , anoikis resistance , migration , and invasion capabilities .	Depletion of Tpl2 by RNAi or activity by a Tpl2 kinase inhibitor in human ccRCC cells remarkably suppressed MAPK pathways and impaired in vitro cell proliferation, clonogenicity, anoikis resistance, migration, and invasion capabilities.	0	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tpl2	Tpl2	Tpl2	MAPK	MAPK	MAPK	2	3	18	19
Furthermore , lack of TPL2 signaling in adipose tissue attenuated obesity induced activation of ERK and JNK , which is consistent with our observation of reduced inflammatory gene expression ( XREF_FIG ) .	Furthermore, lack of TPL2 signaling in adipose tissue attenuated obesity induced activation of ERK and JNK, which is consistent with our observation of reduced inflammatory gene expression (XREF_FIG).	4	20	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TPL2	TPL2	TPL2	ERK	ERK	ERK	4	5	14	15
Overall , ablation of TPL2 blocks the actions of cytokines ( TNF-alpha and IL-1beta ) and proinflammatory stimuli ( lipopolysaccharide ) to activate ERK , and in certain cell types , JNK .	Overall, ablation of TPL2 blocks the actions of cytokines (TNF-alpha and IL-1beta) and proinflammatory stimuli (lipopolysaccharide) to activate ERK, and in certain cell types, JNK.	2	31	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TPL2	TPL2	TPL2	ERK	ERK	ERK	4	5	23	24
TPL2 ablation largely blocks the TLR stimulated activation of ERK without affecting the activation of JNK , p38 , or IKK and NF-kappaB .	TPL2 ablation largely blocks the TLR stimulated activation of ERK without affecting the activation of JNK, p38, or IKK and NF-kappaB.	0	10	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TPL2	TPL2	TPL2	ERK	ERK	ERK	0	1	9	10
To determine if RAF and MEK inhibitors together can overcome single-agent resistance , MAP3K8 expressing A375 cells treated with PLX4720 along with MEK inhibitors significantly inhibited both cell viability and ERK activation compared to treatment with PLX4720 alone , as reported in Figures 4E-F .	To determine if RAF and MEK inhibitors together can overcome single-agent resistance, MAP3K8 expressing A375 cells treated with PLX4720 along with MEK inhibitors significantly inhibited both cell viability and ERK activation compared to treatment with PLX4720 alone, as reported in Figures 4E-F.	13	31	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAP3K8	MAP3K8 expressing	map3k8	ERK	ERK	erk	13	14	30	31
p105 degradation also liberates the p105 associated MAP kinase ( mitogen activated protein kinase ) kinase kinase TPL-2 ( tumour progression locus-2 ) , which can then activate the ERK ( extracellular-signal-regulated kinase )/MAP kinase cascade .	p105 degradation also liberates the p105 associated MAP kinase (mitogen activated protein kinase) kinase kinase TPL-2 (tumour progression locus-2), which can then activate the ERK (extracellular-signal-regulated kinase)/MAP kinase cascade.	8	30	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TPL-2	TPL-2	TPL-2	ERK	ERK	ERK	17	18	29	30
Some limited clinical evidence was provided implicating MAP3K8 or Cot in acquired vemurafenib resistance and it was noted that overexpression of MAP3K8 in preclinical studies strongly upregulated MAPK signaling and limited the responses to BRAF inhibition [ XREF_BIBR ] .	Some limited clinical evidence was provided implicating MAP3K8 or Cot in acquired vemurafenib resistance and it was noted that overexpression of MAP3K8 in preclinical studies strongly upregulated MAPK signaling and limited the responses to BRAF inhibition [XREF_BIBR].	19	28	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K8	overexpression of MAP3K8	map3k8	MAPK	MAPK	mapk	21	22	27	28
However , TAK1 deficiency significantly decreased P-JNK , P-MKK4 and P-MKK7 induction compared with scrambled control .	However, TAK1 deficiency significantly decreased P-JNK, P-MKK4 and P-MKK7 induction compared with scrambled control.	2	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TAK1	TAK1	TAK1	P-MKK4	P-MKK4	P-MKK4	2	3	8	9
In addition , TAK1 knockdown modestly inhibited MKK4 and MKK7 kinase activity ( average inhibition : MKK4 , 28 +/- 4 % ( p = 0.01 ) ; MKK7 , 28 +/- 8 % ( p = 0.03 ) ; n = 3 each ; Figure XREF_FIG ) .	In addition, TAK1 knockdown modestly inhibited MKK4 and MKK7 kinase activity (average inhibition : MKK4, 28 +/- 4% (p = 0.01); MKK7, 28 +/- 8% (p = 0.03); n = 3 each; Figure XREF_FIG).	3	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	MKK4	MKK4	MKK4	3	4	7	8
Using either small interfering RNA knockdown or knockout FLS , TAK1 deficiency significantly decreased P-JNK , P-MKK4 and P-MKK7 induction but did not affect p38 activation .	Using either small interfering RNA knockdown or knockout FLS, TAK1 deficiency significantly decreased P-JNK, P-MKK4 and P-MKK7 induction but did not affect p38 activation.	10	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TAK1	TAK1	TAK1	P-MKK4	P-MKK4	P-MKK4	10	11	16	17
As an example , PPM1B ( or PP2Cbeta ) inhibits TAK1 mediated MKK4 -JNK and MKK6-p38 signaling pathways by dephosphorylating TAK1 [ XREF_BIBR ] .	As an example, PPM1B (or PP2Cbeta) inhibits TAK1 mediated MKK4 -JNK and MKK6-p38 signaling pathways by dephosphorylating TAK1 [XREF_BIBR].	9	13	mediated	Positive_early_activation	Positive_activation	Negative_activation	TAK1	TAK1	TAK1	MKK4	MKK4	MKK4	10	11	12	13
Coadministration of alpha-lipoic acid ( ALA ) , a thiol antioxidant , abolished the activation of ASK1 and phosphorylation of downstream kinases , MKK4 , and JNK and prevented the down-regulation of DJ-1 and translocation of Daxx to the cytosol seen after MPTP .	Coadministration of alpha-lipoic acid (ALA), a thiol antioxidant, abolished the activation of ASK1 and phosphorylation of downstream kinases, MKK4, and JNK and prevented the down-regulation of DJ-1 and translocation of Daxx to the cytosol seen after MPTP.	2	37	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	alpha-lipoic acid (ALA), a thiol antioxidant, abolished the activation of ASK1 and phosphorylation	ask1	Daxx	Daxx	daxx	16	17	36	37
The JNK kinase kinase Apoptosis Signal Regulating Kinase 1 ( ASK1 ) sequesters Daxx in the cytoplasm and thus inhibits the repressive activity of Daxx in transcription [ XREF_BIBR ] .	The JNK kinase kinase Apoptosis Signal Regulating Kinase 1 (ASK1) sequesters Daxx in the cytoplasm and thus inhibits the repressive activity of Daxx in transcription [XREF_BIBR].	4	16	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Apoptosis Signal Regulating Kinase 1	Apoptosis Signal Regulating Kinase 1	Apoptosis Signal Regulating Kinase 1	Daxx	Daxx	Daxx	4	9	13	14
ASK1 sequestered Daxx in the cytoplasm and inhibited the repressive activity of Daxx in transcription .	ASK1 sequestered Daxx in the cytoplasm and inhibited the repressive activity of Daxx in transcription.	0	7	sequestered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASK1	ASK1	ASK1	Daxx	Daxx	Daxx	0	1	2	3
Moreover , the demonstration that silencing TAK1 in TNFalpha stimulated non malignant epithelial cells suppresses MUC1-C-mediated activation of IKKbeta and NF-kappaB , indicated that MUC1-C and TAK1 are functionally linked in the inflammatory response .	Moreover, the demonstration that silencing TAK1 in TNFalpha stimulated non malignant epithelial cells suppresses MUC1-C-mediated activation of IKKbeta and NF-kappaB, indicated that MUC1-C and TAK1 are functionally linked in the inflammatory response.	5	20	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	6	7	18	19
E1A derepressed this inhibitory pathway by stimulating expression of the PP2A/C protein phosphatases , which by binding to the TGFbeta activated kinase TAK1 inhibited its ability to activate IKKbeta and thereby to suppress betaTrCP mediated degradation of FOXO3a .	E1A derepressed this inhibitory pathway by stimulating expression of the PP2A/C protein phosphatases, which by binding to the TGFbeta activated kinase TAK1 inhibited its ability to activate IKKbeta and thereby to suppress betaTrCP mediated degradation of FOXO3a.	21	29	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TAK1	TAK1	TAK1	IKKbeta	IKKbeta	IKKbeta	22	23	28	29
Knockdown of MAP3K3 expression significantly inhibited cell proliferation and colony formation in MAP3K3 amplified breast cancer cell lines MCF-7 and MDA-MB-361 but not in MAP3K3 non amplified breast cancer cells .	Knockdown of MAP3K3 expression significantly inhibited cell proliferation and colony formation in MAP3K3 amplified breast cancer cell lines MCF-7 and MDA-MB-361 but not in MAP3K3 non amplified breast cancer cells.	2	26	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAP3K3	MAP3K3 expression	map3k3	MAP3K3	MAP3K3	map3k3	2	3	24	25
ATP also inhibited the activation of cRaf-1 by other growth factors , epidermal growth factor and platelet derived growth factor , as well as other MEK1 activators stimulated by FGF-2 , MEK kinase 1 ( MEKK1 ) and MEKK2 .	ATP also inhibited the activation of cRaf-1 by other growth factors, epidermal growth factor and platelet derived growth factor, as well as other MEK1 activators stimulated by FGF-2, MEK kinase 1 (MEKK1) and MEKK2.	25	34	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK kinase 1	MEK kinase 1	MEK kinase 1	MEK1	MEK1	MEK1	31	34	25	26
More specifically , we observed expression and cytokine induced phosphorylation of MEKK-1 in beta-cells , and that loss of MEKK-1 resulted in a weaker activation of MKK4 , JNK , IkappaB degradation , NF-kappaB translocation , and iNOS induction in response to cytokines .	More specifically, we observed expression and cytokine induced phosphorylation of MEKK-1 in beta-cells, and that loss of MEKK-1 resulted in a weaker activation of MKK4, JNK, IkappaB degradation, NF-kappaB translocation, and iNOS induction in response to cytokines.	17	38	activation	Positive_activation_syntax_results_in	Positive_activation	Positive_activation	MEKK-1	loss of MEKK-1	mekk-1	MKK4	MKK4	mkk4	19	20	26	27
Both shRNA mediated and pharmacological silencing of Mapk14 ( p38alpha ) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14 dependent activation of Mek-Erk and Atf2 signaling .	Both shRNA mediated and pharmacological silencing of Mapk14 (p38alpha) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14 dependent activation of Mek-Erk and Atf2 signaling.	25	32	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Mapk14	Mapk14	Mapk14	Atf2	Atf2	Atf2	25	26	31	32
To achieve the antiviral and anti-apoptosis activities , JNK3 promoted the activation of genes ISRE and type I IFN in the antiviral IFN signaling pathway , and inhibited the activation of transcription factors NF-kappaB and p53 relating to apoptosis , respectively .	To achieve the antiviral and anti-apoptosis activities, JNK3 promoted the activation of genes ISRE and type I IFN in the antiviral IFN signaling pathway, and inhibited the activation of transcription factors NF-kappaB and p53 relating to apoptosis, respectively.	8	36	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK3	JNK3	JNK3	p53	p53	p53	8	9	35	36
In addition , JNK3 was shown to be expressed in human pancreatic islets , but given that knockdown of JNK3 increased c-Jun levels XREF_BIBR , it is unclear whether JNK3 contributes to the glucose responsive regulation of ADAR2 in pancreatic beta-cells .	In addition, JNK3 was shown to be expressed in human pancreatic islets, but given that knockdown of JNK3 increased c-Jun levels XREF_BIBR, it is unclear whether JNK3 contributes to the glucose responsive regulation of ADAR2 in pancreatic beta-cells.	17	23	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK3	JNK3	JNK3	c-Jun	c-Jun	c-Jun	19	20	21	22
The expression of MAPK1 significantly decreased following the transfection of Mm/Hs _ MAPK1 control siRNA ( results not shown ) , and AllStars negative control siRNA did not alter the gene expression .	The expression of MAPK1 significantly decreased following the transfection of Mm/Hs _ MAPK1 control siRNA (results not shown), and AllStars negative control siRNA did not alter the gene expression.	1	14	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MAPK1	expression of MAPK1	mapk1	MAPK1	MAPK1	mapk1	3	4	12	13
As shown in Figure XREF_FIG ( C and D ) , the results confirmed that the phosphorylation of ERK2 was inhibited by LV expressing ERK2 siRNA2 following TGF-beta1 stimulation .	As shown in Figure XREF_FIG (C and D), the results confirmed that the phosphorylation of ERK2 was inhibited by LV expressing ERK2 siRNA2 following TGF-beta1 stimulation.	16	25	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	phosphorylation of ERK2	erk2	ERK2	ERK2	erk2	18	19	24	25
N-Acetylsphingosine ( C2-ceramide ) inhibited phagocytosis , reduced ERK1 and ERK2 phosphorylation to basal levels , and reduced ERK1 and ERK2 activity by 85 to 90 % and 70 to 80 % , respectively .	N-Acetylsphingosine (C2-ceramide) inhibited phagocytosis, reduced ERK1 and ERK2 phosphorylation to basal levels, and reduced ERK1 and ERK2 activity by 85 to 90% and 70 to 80%, respectively.	2	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK2	C2-ceramide) inhibited phagocytosis, reduced ERK1 and ERK2 phosphorylation	erk2	ERK2	ERK2	erk2	10	11	20	21
Indeed , siRNA mediated ERK2 depletion efficiently reduced Bmf mobility shift in both cell lines , whereas ERK1 and p38alpha knockdown showed no effect ( XREF_FIG ) , consistent with previous results .	Indeed, siRNA mediated ERK2 depletion efficiently reduced Bmf mobility shift in both cell lines, whereas ERK1 and p38alpha knockdown showed no effect (XREF_FIG), consistent with previous results.	2	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK2	ERK2	ERK2	Bmf	Bmf	Bmf	4	5	8	9
ERK2 but not ERK1 knockdown significantly reduced Bmf mobility shift comparable to U0126 treatment ( XREF_FIG ) .	ERK2 but not ERK1 knockdown significantly reduced Bmf mobility shift comparable to U0126 treatment (XREF_FIG).	0	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK2	ERK2	ERK2	Bmf	Bmf	Bmf	0	1	7	8
Abolishing ERK2 activity by a MEK inhibitor significantly reduces CDK2 activity in mammalian cells XREF_BIBR .	Abolishing ERK2 activity by a MEK inhibitor significantly reduces CDK2 activity in mammalian cells XREF_BIBR.	1	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK2	ERK2	ERK2	CDK2	CDK2	CDK2	1	2	9	10
They also suggested that the roles of ERK in insulin signaling were tissue specific and hepatic ERK2 , which could suppress ER stress , was protective against metabolic remodeling induced by HST in ORD .	They also suggested that the roles of ERK in insulin signaling were tissue specific and hepatic ERK2, which could suppress ER stress, was protective against metabolic remodeling induced by HST in ORD.	13	25	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK2	ERK2	ERK2	ER	ER	ER	16	17	21	22
Interestingly , however , only downregulation of ERK1 but not ERK2 significantly reduced upregulation of SphK1 by LPA ( XREF_FIG ) 3.4 .	Interestingly, however, only downregulation of ERK1 but not ERK2 significantly reduced upregulation of SphK1 by LPA (XREF_FIG) 3.4.	5	16	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK2	ERK2	ERK2	SphK1	SphK1	SphK1	10	11	15	16
siRNA down-regulation of ERK2 expression in astrocytes also blocked PARP-1 activation and cell death .	siRNA down-regulation of ERK2 expression in astrocytes also blocked PARP-1 activation and cell death.	3	10	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK2	ERK2 expression	erk2	PARP-1	PARP-1	parp-1	3	4	9	10
As shown in Figure XREF_FIG ( D ) , the results confirm that ERK1 phosphorylation was inhibited by LV expressing ERK1 siRNA2 following TGF-beta1 stimulation .	As shown in Figure XREF_FIG (D), the results confirm that ERK1 phosphorylation was inhibited by LV expressing ERK1 siRNA2 following TGF-beta1 stimulation.	13	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK1	ERK1 phosphorylation	erk1	ERK1	ERK1	erk1	13	14	20	21
MWCNTs caused ERK1 ,2 activation and inhibition of ERK1 ,2 ( U0126 ) blocked MWCNT induction of COX-2 and PGE 2 production , but did not reduce the induction of iNOS .	MWCNTs caused ERK1,2 activation and inhibition of ERK1,2 (U0126) blocked MWCNT induction of COX-2 and PGE 2 production, but did not reduce the induction of iNOS.	2	31	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1	ERK1	ERK1	iNOS	iNOS	iNOS	2	3	30	31
MWCNTs increase ERK1 ,2 activation and inhibition of ERK1 ,2 activation decreases COX-2 induction , but not iNOS induction .	MWCNTs increase ERK1,2 activation and inhibition of ERK1,2 activation decreases COX-2 induction, but not iNOS induction.	2	18	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1	ERK1	ERK1	iNOS	iNOS	iNOS	2	3	17	18
We used mice with floxed HIF-1alpha alleles and tamoxifen inducible Cre and ERT2 recombinase under ubiquitin C promoter to induce global HIF-1alpha deletion .	We used mice with floxed HIF-1alpha alleles and tamoxifen inducible Cre and ERT2 recombinase under ubiquitin C promoter to induce global HIF-1alpha deletion.	12	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERT2	ERT2	ERT2	HIF-1alpha	HIF-1alpha	HIF-1alpha	12	13	21	22
In human HCCs , JNK1 upregulates c-Myc and downregulates p21 ; JNK1 also regulates expression of factors that control the cell cycle , proliferation and metabolism , through methylation of histone H3 lysine 4 and 9 by MLL3 and EZH2 XREF_BIBR , XREF_BIBR .	In human HCCs, JNK1 upregulates c-Myc and downregulates p21; JNK1 also regulates expression of factors that control the cell cycle, proliferation and metabolism, through methylation of histone H3 lysine 4 and 9 by MLL3 and EZH2 XREF_BIBR, XREF_BIBR.	4	10	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	p21	p21	p21	4	5	9	10
RNAi induced silencing of lamin A/C or of JNK1 did not induce any change in p53 or p21 WAF1 , a p53 dependent target gene ( XREF_FIG for JNK1 siRNA and XREF_SUPPLEMENTARY for lamin A/C siRNA ) , thus confirming that the conditions of RNAi per se do not initiate a p53 stress response .	RNAi induced silencing of lamin A/C or of JNK1 did not induce any change in p53 or p21 WAF1, a p53 dependent target gene (XREF_FIG for JNK1 siRNA and XREF_SUPPLEMENTARY for lamin A/C siRNA), thus confirming that the conditions of RNAi per se do not initiate a p53 stress response.	2	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	p21 WAF1	p21 WAF1	p21 WAF1	8	9	17	19
JNK1 dependent downregulation of p21 is mediated by c-Myc upregulation , independently of c-Jun and its phosphorylation .	JNK1 dependent downregulation of p21 is mediated by c-Myc upregulation, independently of c-Jun and its phosphorylation.	0	5	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	p21	p21	p21	0	1	4	5
Interestingly , p21 deficiency reversed defective regeneration in Jnk1 -/- livers , indicating that JNK1 promotes hepatocyte proliferation by inhibiting p21 XREF_BIBR , XREF_BIBR .	Interestingly, p21 deficiency reversed defective regeneration in Jnk1 -/- livers, indicating that JNK1 promotes hepatocyte proliferation by inhibiting p21 XREF_BIBR, XREF_BIBR.	14	21	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	JNK1	JNK1	p21	p21	p21	14	15	20	21
ERK5 inhibition resulted in an expected decrease in MEF2C activation .	ERK5 inhibition resulted in an expected decrease in MEF2C activation.	0	10	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	ERK5	ERK5	ERK5	MEF2C	MEF2C	MEF2C	0	1	8	9
Results showed that ERK5 siRNA transfection abolished high-glucose-induced increase of ERK5 , MEF2C , KLF2 mRNA , whereas promoted upregulation of VEGF mRNA ( XREF_FIG ) .	Results showed that ERK5 siRNA transfection abolished high-glucose-induced increase of ERK5, MEF2C, KLF2 mRNA, whereas promoted upregulation of VEGF mRNA (XREF_FIG).	3	15	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK5	ERK5	ERK5	MEF2C	MEF2C	MEF2C	3	4	12	13
ERK5 siRNA inhibited MEF2C activation , whereas it reduced CREB phosphorylation only 50 % .	ERK5 siRNA inhibited MEF2C activation, whereas it reduced CREB phosphorylation only 50%.	0	4	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	MEF2C	MEF2C	MEF2C	0	1	3	4
JNK-1 depletion also partially inhibited the Ngo induced release of Bim and Bmf from the cytoskeleton ( XREF_FIG ) .	JNK-1 depletion also partially inhibited the Ngo induced release of Bim and Bmf from the cytoskeleton (XREF_FIG).	0	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK-1	JNK-1	JNK-1	Bmf	Bmf	Bmf	0	1	12	13
In conclusion , JNK-1 depletion can prevent the post-transcriptional modification of Bim and Bmf , reduce their loss from the cytoskeleton fraction and inhibit apoptosis of Ngo infected cells .	In conclusion, JNK-1 depletion can prevent the post-transcriptional modification of Bim and Bmf, reduce their loss from the cytoskeleton fraction and inhibit apoptosis of Ngo infected cells.	3	14	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK-1	JNK-1	JNK-1	Bmf	Bmf	Bmf	3	4	13	14
In agreement with these reports , we found that MEKK3-MEK5 axis promotes ERK5 activation upon loss of CCM1 and inhibition of ERK5 prevents KLF4 upregulation and EndMT induction in cultured CCM1 KO ECs .	In agreement with these reports, we found that MEKK3-MEK5 axis promotes ERK5 activation upon loss of CCM1 and inhibition of ERK5 prevents KLF4 upregulation and EndMT induction in cultured CCM1 KO ECs.	12	24	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK5	ERK5	ERK5	KLF4	KLF4	KLF4	12	13	23	24
The downregulation of ERK5 strongly prevented KLF4 upregulation in Ccm1 silenced ECs ( Fig XREF_FIG B ) .	The downregulation of ERK5 strongly prevented KLF4 upregulation in Ccm1 silenced ECs (Fig XREF_FIG B).	1	7	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK5	ERK5	ERK5	KLF4	KLF4	KLF4	3	4	6	7
ERK5 SUMOylation inhibits KLF2 and eNOS and up-regulates adhesion molecule expression in Senp2 +/- ECs .	ERK5 SUMOylation inhibits KLF2 and eNOS and up-regulates adhesion molecule expression in Senp2 +/- ECs.	0	5	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK5	ERK5 SUMOylation	erk5	KLF2	KLF2	klf2	0	1	3	4
Therefore , in the presence of higher concentration of M3/6 , more JIP1 scaffolds are needed to sequester JNK and MKK7 to increase the incidence of the forward reaction leading to a higher value of optimum required for signal amplification .	Therefore, in the presence of higher concentration of M3/6, more JIP1 scaffolds are needed to sequester JNK and MKK7 to increase the incidence of the forward reaction leading to a higher value of optimum required for signal amplification.	12	21	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JIP1	JIP1	JIP1	MKK7	MKK7	MKK7	12	13	20	21
Strikingly , CYR61 overexpression impaired the accumulation of wild-type p53 following Taxol exposure , while inhibition of alphavbeta3 or ERK1 and ERK2 MAPK signalings completely restored Taxol induced upregulation of p53 .	Strikingly, CYR61 overexpression impaired the accumulation of wild-type p53 following Taxol exposure, while inhibition of alphavbeta3 or ERK1 and ERK2 MAPK signalings completely restored Taxol induced upregulation of p53.	15	31	restored	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ERK1	ERK1	ERK1	p53	p53	p53	19	20	30	31
For instance , the downstream target of NGF , ERK5 can activate transcription factor MEF2D , which in turn induces expression of anti-apoptotic protein bcl-w , promoting survival of the developing sensory neurons .	For instance, the downstream target of NGF, ERK5 can activate transcription factor MEF2D, which in turn induces expression of anti-apoptotic protein bcl-w, promoting survival of the developing sensory neurons.	7	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	ERK5	ERK5	ERK5	MEF2D	MEF2D	MEF2D	9	10	14	15
Immunoblot analysis using a phospho specific antibody against ERK5 confirmed that ectopic expression of DN-ERK5 blocked the ability of MEK5 to activate ERK5 ( XREF_FIG ) .	Immunoblot analysis using a phospho specific antibody against ERK5 confirmed that ectopic expression of DN-ERK5 blocked the ability of MEK5 to activate ERK5 (XREF_FIG).	12	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DN-ERK5	expression of DN-ERK5	dn-erk5	MEK5	MEK5	mek5	14	15	19	20
Interestingly , our study showed that JNK2 knockdown but not JNK1 knockdown largely suppressed activation of ATF-2 , suggesting that JNK2 might promote CSC phenotype in TNBC through both ATF-2 and c-Jun , which form heterodimers and stimulate CRE dependent transcription 33 .	Interestingly, our study showed that JNK2 knockdown but not JNK1 knockdown largely suppressed activation of ATF-2, suggesting that JNK2 might promote CSC phenotype in TNBC through both ATF-2 and c-Jun, which form heterodimers and stimulate CRE dependent transcription 33.	7	17	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	ATF-2	ATF-2	ATF-2	10	11	16	17
Subsequent to Erk5 activation , Mef2a activity indicated by its nuclear composition was observed following palmitate , whereas knockdown of Erk5 deprived palmitate induced Mef2a nuclear accumulation .	Subsequent to Erk5 activation, Mef2a activity indicated by its nuclear composition was observed following palmitate, whereas knockdown of Erk5 deprived palmitate induced Mef2a nuclear accumulation.	18	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Erk5	Erk5	Erk5	Mef2a	Mef2a	Mef2a	20	21	24	25
NEAT1 was able to increase MAPK6 expression and hsa-mir-98-5p mimics can inhibit MAPK6 via downregulating NEAT1 levels .	NEAT1 was able to increase MAPK6 expression and hsa-mir-98-5p mimics can inhibit MAPK6 via downregulating NEAT1 levels.	5	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAPK6	MAPK6 expression	mapk6	MAPK6	MAPK6	mapk6	5	6	12	13
Thus , miR-126-5p-provoked reduction in JIP-2 levels activates JNK1 > AP-1 signalling and provides an epigenetic explanation for both T. annulata induced leukocyte transformation , and for the attenuated phenotype of live vaccines against tropical theileriosis .	Thus, miR-126-5p-provoked reduction in JIP-2 levels activates JNK1> AP-1 signalling and provides an epigenetic explanation for both T. annulata induced leukocyte transformation, and for the attenuated phenotype of live vaccines against tropical theileriosis.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JIP-2	JIP-2 levels	jip-2	JNK1	JNK1	jnk1	5	6	8	9
In conclusion , our present data demonstrate that activated JNK2 promoted beta-catenin degradation and inhibited the canonical Wnt and beta-catenin signaling in vitro , and that JNK2 deficiency upregulated beta-catenin signaling in vivo , in which GSK3beta is likely to play a critical role .	In conclusion, our present data demonstrate that activated JNK2 promoted beta-catenin degradation and inhibited the canonical Wnt and beta-catenin signaling in vitro, and that JNK2 deficiency upregulated beta-catenin signaling in vivo, in which GSK3beta is likely to play a critical role.	8	14	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	9	10	11	12
Although our data strongly demonstrate that JNK2 suppresses beta-catenin signaling through GSK3beta-proteasome pathway , the mechanism underlying the regulation of GSK3beta activity by active JNK2 remains elusive .	Although our data strongly demonstrate that JNK2 suppresses beta-catenin signaling through GSK3beta-proteasome pathway, the mechanism underlying the regulation of GSK3beta activity by active JNK2 remains elusive.	6	9	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	6	7	8	9
Moreover , targeted mutations at GSK3beta phosphorylation sites ( Ser33 and Ser37 ) of beta-catenin abrogated JNK2 mediated suppression of beta-catenin .	Moreover, targeted mutations at GSK3beta phosphorylation sites (Ser33 and Ser37) of beta-catenin abrogated JNK2 mediated suppression of beta-catenin.	16	21	suppression	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	16	17	20	21
As shown in XREF_FIG , MG132 blocked JNK2 induced beta-catenin inhibition ( lane 4 versus 3 ) , demonstrating that JNK2 caused beta-catenin degradation was through proteasomal degradation system .	As shown in XREF_FIG, MG132 blocked JNK2 induced beta-catenin inhibition (lane 4 versus 3), demonstrating that JNK2 caused beta-catenin degradation was through proteasomal degradation system.	7	10	induced	Positive_early_activation	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
In this study , we found that , like JNK1 , JNK2 interacts with and inhibits beta-catenin signaling , in which GSK3beta functions upstream of proteasome pathway and plays a critical role in JNK2-mediate beta-catenin degradation .	In this study, we found that, like JNK1, JNK2 interacts with and inhibits beta-catenin signaling, in which GSK3beta functions upstream of proteasome pathway and plays a critical role in JNK2-mediate beta-catenin degradation.	9	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK1, JNK2 interacts	jnk2	beta-catenin	beta-catenin	beta-catenin	11	12	16	17
To determine the role of the most common GSK3beta regualated pathway in the downregulation of beta-catenin by JNK2 activation , we detected the phosphorylation status of GSK3beta .	To determine the role of the most common GSK3beta regualated pathway in the downregulation of beta-catenin by JNK2 activation, we detected the phosphorylation status of GSK3beta.	13	18	downregulation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	17	18	15	16
The ability of activated JNK2 to downregulate beta-catenin was almost completely abrogated upon LiCl treatment ( lane 4 versus 3 ) , suggesting that GSK3beta is required for JNK2 mediated beta-catenin degradation .	The ability of activated JNK2 to downregulate beta-catenin was almost completely abrogated upon LiCl treatment (lane 4 versus 3), suggesting that GSK3beta is required for JNK2 mediated beta-catenin degradation.	26	31	mediated	Positive_early_activation	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	28	29	30	31
Since overexpressed beta-catenin is mainly restricted in the nucleus as shown in XREF_FIG and reported previously XREF_BIBR , XREF_BIBR , it is postulated that activated JNK2 promotes beta-catenin degradation by increasing GSK3beta and proteasome activity and potentially degrading beta-catenin in the cytoplasm by driving beta-catenin translocation .	Since overexpressed beta-catenin is mainly restricted in the nucleus as shown in XREF_FIG and reported previously XREF_BIBR, XREF_BIBR, it is postulated that activated JNK2 promotes beta-catenin degradation by increasing GSK3beta and proteasome activity and potentially degrading beta-catenin in the cytoplasm by driving beta-catenin translocation.	24	28	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	25	26	27	28
GSK3beta Is Involved in JNK2 Mediated beta-Catenin Inhibition .	GSK3beta Is Involved in JNK2 Mediated beta-Catenin Inhibition.	2	7	Mediated	Positive_early_activation	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-Catenin	beta-Catenin	beta-Catenin	4	5	6	7
GSK3beta Functions Upstream of the Proteasome to Mediate the Reduction of beta-catenin by JNK2 Activation .	GSK3beta Functions Upstream of the Proteasome to Mediate the Reduction of beta-catenin by JNK2 Activation.	9	14	Reduction	Negative_activation_token_2_noun	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	13	14	11	12
To further confirm the role of GSK3beta in beta-catenin degradation induced by JNK2 activation , we generated series of constructs expressing beta catenin mutants XREF_BIBR and co-transfected them with pMKK7-JNK2 into HKE293T cells .	To further confirm the role of GSK3beta in beta-catenin degradation induced by JNK2 activation, we generated series of constructs expressing beta catenin mutants XREF_BIBR and co-transfected them with pMKK7-JNK2 into HKE293T cells.	8	13	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	12	13	8	9
In general , our data suggested that JNK2 , like JNK1 , interacts with and suppresses beta-catenin signaling in vitro and in vivo , in which GSK3beta plays a key role , although previous studies have shown distinct functions of JNK1 and JNK2 .	In general, our data suggested that JNK2, like JNK1, interacts with and suppresses beta-catenin signaling in vitro and in vivo, in which GSK3beta plays a key role, although previous studies have shown distinct functions of JNK1 and JNK2.	7	17	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	7	8	16	17
To determine whether activated JNK2 can inhibit the aberrantly accumulated nuclear beta-catenin in cancer cells , a human lung cancer cell line A549 was transfected with MKK7-JNK2 .	To determine whether activated JNK2 can inhibit the aberrantly accumulated nuclear beta-catenin in cancer cells, a human lung cancer cell line A549 was transfected with MKK7-JNK2.	3	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	beta-catenin	beta-catenin	beta-catenin	4	5	11	12
As shown in Figure XREF_FIG , the expression of JNK1 or JNK2 was successfully depleted using the specific JNK1 or JNK2 siRNA .	As shown in Figure XREF_FIG, the expression of JNK1 or JNK2 was successfully depleted using the specific JNK1 or JNK2 siRNA.	7	21	depleted	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	expression of JNK1	jnk1	JNK2	JNK2	jnk2	9	10	20	21
IFNbeta increased JNK activation in hepatocytes ( XREF_FIG ) ; interestingly , anti-IFNbeta Ab inhibited LPS and HSC induced activation of JNK1 , but strongly increased JNK2 activation beyond that by LPS and HSC ( XREF_FIG ) .	IFNbeta increased JNK activation in hepatocytes (XREF_FIG); interestingly, anti-IFNbeta Ab inhibited LPS and HSC induced activation of JNK1, but strongly increased JNK2 activation beyond that by LPS and HSC (XREF_FIG).	12	27	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	JNK1	anti-IFNbeta Ab inhibited LPS and HSC induced activation of JNK1	jnk1	JNK2	JNK2	jnk2	21	22	26	27
Inhibition of JNK1 and JNK2 ( but not of p38 ) antagonized blasticidin induced apoptosis , whereas targeting alternative ribosomal sites with KSM or CHX limited translation , but failed to activate the SAPK cascade or initiate apoptosis .	Inhibition of JNK1 and JNK2 (but not of p38) antagonized blasticidin induced apoptosis, whereas targeting alternative ribosomal sites with KSM or CHX limited translation, but failed to activate the SAPK cascade or initiate apoptosis.	0	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	SAPK	SAPK	SAPK	2	3	33	34
There is early evidence in rodent models that ROS activation of cellular stress kinases , particularly c-Jun N-terminal Kinase-1 ( JNK1 ) promotes SIRT1 degradation leading to hepatic steatosis [ XREF_BIBR ] .	There is early evidence in rodent models that ROS activation of cellular stress kinases, particularly c-Jun N-terminal Kinase-1 (JNK1) promotes SIRT1 degradation leading to hepatic steatosis [XREF_BIBR].	13	24	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	SIRT1	SIRT1	SIRT1	20	21	23	24
It has been suggested that persistent JNK1 activation leads SIRT1 inhibition through increased protein degradation and 3,5-T2 treatment attenuated JNK phosphorylation , what could be the mechanism of protection induced by 3,5-T2 that is apparently different from the pathways activated by T3 that are dependent on PI3K .	It has been suggested that persistent JNK1 activation leads SIRT1 inhibition through increased protein degradation and 3,5-T2 treatment attenuated JNK phosphorylation, what could be the mechanism of protection induced by 3,5-T2 that is apparently different from the pathways activated by T3 that are dependent on PI3K.	6	10	leads	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	SIRT1	SIRT1	SIRT1	6	7	9	10
In mouse models of obesity , a high-fat diet induces persistent activation of c-Jun N-terminal kinase 1 ( JNK1 ) , which enhances SIRT1 degradation in the liver , leading to hepatic steatosis XREF_BIBR .	In mouse models of obesity, a high-fat diet induces persistent activation of c-Jun N-terminal kinase 1 (JNK1), which enhances SIRT1 degradation in the liver, leading to hepatic steatosis XREF_BIBR.	15	24	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	SIRT1	SIRT1	SIRT1	18	19	23	24
JNK1 , ERK1 , ERK2 and p38 overexpression all decreased SIRT1 , whereas only ERK1 and ERK2 decreased SIRT7 ( XREF_FIG ) .	JNK1, ERK1, ERK2 and p38 overexpression all decreased SIRT1, whereas only ERK1 and ERK2 decreased SIRT7 (XREF_FIG).	0	11	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1, ERK1, ERK2 and p38 overexpression	jnk1	SIRT1	SIRT1	sirt1	0	1	10	11
XREF_BIBR - XREF_BIBR Conversely , mTOR and JNK1 can inhibit Sirt1 under conditions of persistent stimulation .	XREF_BIBR - XREF_BIBR Conversely, mTOR and JNK1 can inhibit Sirt1 under conditions of persistent stimulation.	5	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	Sirt1	Sirt1	Sirt1	7	8	10	11
Because MT tumors and cell lines express wildtype p53 [ XREF_BIBR ] , we hypothesized that JNK2 inhibits Notch1 in a p53 dependent fashion .	Because MT tumors and cell lines express wildtype p53 [XREF_BIBR], we hypothesized that JNK2 inhibits Notch1 in a p53 dependent fashion.	16	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	p53	p53	p53	16	17	21	22
These results indicate that JNK2 prevents p53 from MDM2 dependent ubiquitination by blocking the MDM2 and p53 complex formation .	These results indicate that JNK2 prevents p53 from MDM2 dependent ubiquitination by blocking the MDM2 and p53 complex formation.	4	7	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	p53	p53	p53	4	5	6	7
These data show that JNK2 inhibits luminal lineage commitment independently of p53 .	These data show that JNK2 inhibits luminal lineage commitment independently of p53.	4	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	p53	p53	p53	4	5	11	12
In contrast , Cantrell et al showed that JNK2 inhibited p53 and Notch1 dependent cell differentiation in normal and cancer derived mammary cells through down-regulation of Notch1 transcription 43 .	In contrast, Cantrell et al showed that JNK2 inhibited p53 and Notch1 dependent cell differentiation in normal and cancer derived mammary cells through down-regulation of Notch1 transcription 43.	8	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	p53	p53	p53	8	9	10	11
JNK2 prevents p53 from MDM2 mediated degradation .	JNK2 prevents p53 from MDM2 mediated degradation.	0	3	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK2	JNK2	JNK2	p53	p53	p53	0	1	2	3
These results suggest that JNK1 knockdown prevents the degradation of existing Mcl-1 .	These results suggest that JNK1 knockdown prevents the degradation of existing Mcl-1.	4	12	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	Mcl-1	Mcl-1	Mcl-1	4	5	11	12
While knockdown of JNK1 increased Mcl-1 by approximately 1.9-fold ( 1 vs 1.88 ) when compared with control non targeting siRNA transfected cells , it increased Mcl-1 by 5.3-fold ( 0.35 vs 1.88 ) when compared with S6K2 siRNA transfected cells .	While knockdown of JNK1 increased Mcl-1 by approximately 1.9-fold (1 vs 1.88) when compared with control non targeting siRNA transfected cells, it increased Mcl-1 by 5.3-fold (0.35 vs 1.88) when compared with S6K2 siRNA transfected cells.	1	6	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	Mcl-1	Mcl-1	Mcl-1	3	4	5	6
Our data indicate that MMP-2 and MMP-9 downregulation in gallic acid treated K562 cells are mediated through suppression of JNK1 mediated c-Jun and ATF -2 and Akt and ERK mediated c-Jun and c-Fos pathways , respectively .	Our data indicate that MMP-2 and MMP-9 downregulation in gallic acid treated K562 cells are mediated through suppression of JNK1 mediated c-Jun and ATF -2 and Akt and ERK mediated c-Jun and c-Fos pathways, respectively.	17	29	mediated	Positive_early_activation	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	c-Jun	c-Jun	c-Jun	19	20	21	22
Compared to the controls , MK2 siRNA reduced cytoplasmic HuR but had minimal effect on the nuclear HuR levels .	Compared to the controls, MK2 siRNA reduced cytoplasmic HuR but had minimal effect on the nuclear HuR levels.	5	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	5	6	9	10
However , after the stimulation of TNF-alpha , silencing MK2 inhibited HuR accumulation to cytoplasm from nucleus in HPMECs .	However, after the stimulation of TNF-alpha, silencing MK2 inhibited HuR accumulation to cytoplasm from nucleus in HPMECs.	8	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MK2	MK2	MK2	HuR	HuR	HuR	9	10	11	12
A jnk2 knockdown increased hepatic expression of the pro apoptotic Bcl-2 family members Bim and Bax and the increase in liver injury resulted in part from a Bim dependent activation of the mitochondrial death pathway .	A jnk2 knockdown increased hepatic expression of the pro apoptotic Bcl-2 family members Bim and Bax and the increase in liver injury resulted in part from a Bim dependent activation of the mitochondrial death pathway.	1	16	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	jnk2	jnk2	jnk2	Bax	Bax	Bax	1	2	15	16
Expression of constitutively active MEK1 , the kinase that activates ERKs , or overexpression of ERK2 , but not JNK1 , inhibited Stat3 activation .	Expression of constitutively active MEK1, the kinase that activates ERKs, or overexpression of ERK2, but not JNK1, inhibited Stat3 activation.	13	23	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	overexpression of ERK2, but not JNK1	jnk1	Stat3	Stat3	stat3	19	20	22	23
Moreover , sustained activation of JNK1 downregulated p53 during apoptosis .	Moreover, sustained activation of JNK1 downregulated p53 during apoptosis.	3	8	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	JNK1	JNK1	JNK1	p53	p53	p53	5	6	7	8
The authors also found that bacterial internalization and IFN-gamma-stimulated ERK1/2 activation was reduced by MEK1/2 , PI3K and Src inhibition .	The authors also found that bacterial internalization and IFN-gamma-stimulated ERK1/2 activation was reduced by MEK1/2, PI3K and Src inhibition.	9	19	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	14	15	9	10
When the cells were treated with HB-EGF , EGFR phosphorylation and degradation 46 were insensitive to inhibitor treatment , suggesting that HB-EGF bypasses MEK inhibition and functions downstream of ERK activation after wounding ( XREF_FIG ) .	When the cells were treated with HB-EGF, EGFR phosphorylation and degradation 46 were insensitive to inhibitor treatment, suggesting that HB-EGF bypasses MEK inhibition and functions downstream of ERK activation after wounding (XREF_FIG).	23	30	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	23	24	29	30
MEK1/2 siRNA simultaneously blocked NGR2 mediated the activation of ERK1/2 , P90RSK , and Nrf2 as well as the subsequent activation of their respective downstream targets .	MEK1/2 siRNA simultaneously blocked NGR2 mediated the activation of ERK1/2, P90RSK, and Nrf2 as well as the subsequent activation of their respective downstream targets.	0	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	0	1	9	10
At 2 muM , both agents effectively inhibited EphA2 Ser897 and AKT Ser473 phosphorylation ; at 10 muM , efficient inhibition of MEK and partial inhibition of ERK were also achieved .	At 2 muM, both agents effectively inhibited EphA2 Ser897 and AKT Ser473 phosphorylation; at 10 muM, efficient inhibition of MEK and partial inhibition of ERK were also achieved.	22	28	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	22	23	27	28
The results shown in Figures XREF_FIG B , D indicate that activated Dok-1 binds to RasGAP during infection of opsonized Schu S4 , particularly apparent at 1 and 2min , suggesting that Dok-1 ' s ability to inhibit Raf and MEK mediated ERK activation is at least in part via its binding to RasGAP .	The results shown in Figures XREF_FIG B, D indicate that activated Dok-1 binds to RasGAP during infection of opsonized Schu S4, particularly apparent at 1 and 2min, suggesting that Dok-1 's ability to inhibit Raf and MEK mediated ERK activation is at least in part via its binding to RasGAP.	37	43	mediated	Positive_early_activation	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	40	41	42	43
Moreover , XREF_FIG is another example of how to quantify protein levels from fluorescent Western blots , which shows the protein quantification of phospho-ERK1/2 normalized to total ERK1/2 protein levels of WM793 melanoma cells treated with and without MEK inhibition from XREF_FIG .	Moreover, XREF_FIG is another example of how to quantify protein levels from fluorescent Western blots, which shows the protein quantification of phospho-ERK1/2 normalized to total ERK1/2 protein levels of WM793 melanoma cells treated with and without MEK inhibition from XREF_FIG.	27	39	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	38	39	27	28
MEK inhibition during treatment enhanced the late ERK activation possibly through prolonged downregulation of MAPK phosphatase-1 ( MKP-1 ) .	MEK inhibition during treatment enhanced the late ERK activation possibly through prolonged downregulation of MAPK phosphatase-1 (MKP-1).	0	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	7	8
The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents , and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse ( GEM ) models .	The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents, and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse (GEM) models.	1	9	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	1	2	7	8
It is , however , reduced by MEK ( mitogen activated protein kinase and ERK kinase ) inhibition and by mutations preventing TEY phosphorylation or in the ERK common docking region .	It is, however, reduced by MEK (mitogen activated protein kinase and ERK kinase) inhibition and by mutations preventing TEY phosphorylation or in the ERK common docking region.	5	30	reduced	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	7	8	27	28
Second , MEK inhibition leads to loss of expression of DUSPs , allowing ERK activity to increase dramatically , again off setting the effects of MEK inhibition .	Second, MEK inhibition leads to loss of expression of DUSPs, allowing ERK activity to increase dramatically, again off setting the effects of MEK inhibition.	2	14	allowing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	2	3	13	14
In fact , in both ALK- and EGFR driven NSCLC , upfront combination ALK and MEK or EGFR and MEK inhibition has been shown to prevent the emergence of MAPK pathway addicted resistance mechanisms .	In fact, in both ALK- and EGFR driven NSCLC, upfront combination ALK and MEK or EGFR and MEK inhibition has been shown to prevent the emergence of MAPK pathway addicted resistance mechanisms.	17	30	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	19	20	29	30
In this article , we investigate whether MEK and ERK inhibition , by the MEK and ERK inhibitor U0126 , affects c-Myc protein level and growth of RMS tumor in an in vivo xenograft model .	In this article, we investigate whether MEK and ERK inhibition, by the MEK and ERK inhibitor U0126, affects c-Myc protein level and growth of RMS tumor in an in vivo xenograft model.	7	18	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	14	15	9	10
In the control shLuc-cells , disruption of MEK and ERK or PI3K and Akt pathway by a MEK inhibitor , PD98059 , or a PI3K inhibitor , LY294002 , respectively , suppressed cell growth , and knockdown of ERK or Akt also effectively reduced cell growth ( white bars , Figure XREF_FIG ) .	In the control shLuc-cells, disruption of MEK and ERK or PI3K and Akt pathway by a MEK inhibitor, PD98059, or a PI3K inhibitor, LY294002, respectively, suppressed cell growth, and knockdown of ERK or Akt also effectively reduced cell growth (white bars, Figure XREF_FIG).	5	40	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	7	8	38	39
In transgenic mouse models in which mTOR was hyperactivated either through the KRAS/MEK/ERK cascade , by loss of PTEN , or through TSC1 haploinsufficiency , single inhibition of mTOR or MEK elicited strong feedback activation of ERK or AKT .	In transgenic mouse models in which mTOR was hyperactivated either through the KRAS/MEK/ERK cascade, by loss of PTEN, or through TSC1 haploinsufficiency, single inhibition of mTOR or MEK elicited strong feedback activation of ERK or AKT.	26	38	elicited	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	30	31	36	37
This result suggests that the deficit in GSEP in Ca v 1.2/II- III cells is upstream of Raf-MEK-ERK signaling , and not a reduced capacity of Raf or MEK to activate ERK .	This result suggests that the deficit in GSEP in Ca v 1.2/II- III cells is upstream of Raf-MEK-ERK signaling, and not a reduced capacity of Raf or MEK to activate ERK.	24	32	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	28	29	31	32
Inhibition of MEK dependent activation of ERK1/2 via the MEK inhibitor PD98059 significantly attenuated VEGF-A-induced mechanical hypersensitivity , but did not affect VEGF-A-induced thermal hyperalgesia ( XREF_FIG C ; p = 0.322 ) .	Inhibition of MEK dependent activation of ERK1/2 via the MEK inhibitor PD98059 significantly attenuated VEGF-A-induced mechanical hypersensitivity, but did not affect VEGF-A-induced thermal hyperalgesia (XREF_FIG C; p = 0.322).	2	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	2	3	6	7
To determine whether enhanced ERK activation is required for the phenotypes induced by Akt1 down-regulation , we examined the effects of inhibiting MEK induced ERK activation using UO126 , a specific MEK inhibitor .	To determine whether enhanced ERK activation is required for the phenotypes induced by Akt1 down-regulation, we examined the effects of inhibiting MEK induced ERK activation using UO126, a specific MEK inhibitor.	19	25	induced	Positive_early_activation	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	22	23	24	25
SB203580 is a class of pyridinyl imidazoles that specifically inhibits activation of MAPKAPK-2 by p38 MAPK and subsequent phosphorylation of HSP27 [ XREF_BIBR ] , while U0126 very selectively inhibits the kinase activity of MEK1/2 thus preventing the activation of MAPK p42 and MAPK p44 , which are encoded by the ERK1 and ERK2 genes respectively [ XREF_BIBR ] .	SB203580 is a class of pyridinyl imidazoles that specifically inhibits activation of MAPKAPK-2 by p38 MAPK and subsequent phosphorylation of HSP27 [XREF_BIBR], while U0126 very selectively inhibits the kinase activity of MEK1/2 thus preventing the activation of MAPK p42 and MAPK p44, which are encoded by the ERK1 and ERK2 genes respectively [XREF_BIBR].	32	41	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	34	35	40	41
MEK ( ERK1/2 kinase ) inhibitor PD98059 is specific for ERK1/2 pathway , by noncompetitively binding to MEK , it is commonly used to block ERK1/2 pathway .	MEK (ERK1/2 kinase) inhibitor PD98059 is specific for ERK1/2 pathway, by noncompetitively binding to MEK, it is commonly used to block ERK1/2 pathway.	0	26	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	0	1	25	26
A specific inhibitor of mitogen activated ERK kinase ( MEK ) , PD98059 , was used to inhibit the ERK pathway .	A specific inhibitor of mitogen activated ERK kinase (MEK), PD98059, was used to inhibit the ERK pathway.	7	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	9	10	19	20
The inhibitors of BRAF and MEK targeting MAPK signaling pathway provide a comparatively effective therapeutic strategy for melanoma caused by BRAF mutation .	The inhibitors of BRAF and MEK targeting MAPK signaling pathway provide a comparatively effective therapeutic strategy for melanoma caused by BRAF mutation.	1	9	targeting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	5	6	7	8
We and others reported that the rapamycin or RAD001 combined with a MEK ( the direct upstream activator of ERK ) inhibitor ( e.g ., UO126 or PD0325901 ) was more potent than each single agent in inhibiting the growth of cancer cells ; this effect was associated with the abrogation of the feedback ERK activation .	We and others reported that the rapamycin or RAD001 combined with a MEK (the direct upstream activator of ERK) inhibitor (e.g., UO126 or PD0325901) was more potent than each single agent in inhibiting the growth of cancer cells; this effect was associated with the abrogation of the feedback ERK activation.	12	21	activator	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	12	13	19	20
Selumetinib is a potent small molecule inhibitor of MEK1/2 , which blocks ERK1/2 activation .	Selumetinib is a potent small molecule inhibitor of MEK1/2, which blocks ERK1/2 activation.	6	13	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	8	9	12	13
Therefore , inhibition of MEK mediated ERK activation is very appealing in cancer therapy .	Therefore, inhibition of MEK mediated ERK activation is very appealing in cancer therapy.	2	7	mediated	Positive_early_activation	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	4	5	6	7
LY is a specific inhibitor of phosphatidylinositol 3-kinase ( PI3K ) that inhibits AKT activation , and PD is a specific inhibitor of mitogen activated protein and extracellular signal regulated protein kinases ( ERK ) kinase 1 ( MEK ) that inhibits ERK activation .	LY is a specific inhibitor of phosphatidylinositol 3-kinase (PI3K) that inhibits AKT activation, and PD is a specific inhibitor of mitogen activated protein and extracellular signal regulated protein kinases (ERK) kinase 1 (MEK) that inhibits ERK activation.	31	43	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	38	39	42	43
The MEK specific inhibitors PD98059 and U0126 blocked Erk activation and release of IL-8 following infection with Ad7 .	The MEK specific inhibitors PD98059 and U0126 blocked Erk activation and release of IL-8 following infection with Ad7.	1	9	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	Erk	Erk	Erk	1	2	8	9
The MEK ( MAPK kinase ) inhibitor PD98059 ( 10 (-6) M ) completely inhibited the HGF dependent increase in MAPK activity .	The MEK (MAPK kinase) inhibitor PD98059 (10 (-6) M) completely inhibited the HGF dependent increase in MAPK activity.	0	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	1	2	20	21
MEK specific inhibitor PD98059 suppressed Erk1/2 activation as well as EGR-1 and TF elevation , indicating a PKC/Erk/EGR -1 pathway as one pathway contributing to the TF induction by OxPAPC [ XREF_BIBR ] .	MEK specific inhibitor PD98059 suppressed Erk1/2 activation as well as EGR-1 and TF elevation, indicating a PKC/Erk/EGR -1 pathway as one pathway contributing to the TF induction by OxPAPC [XREF_BIBR].	0	6	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	Erk1/2	Erk1/2	Erk1/2	0	1	5	6
As previously demonstrated , MEK1/2 ( PD0325901 and MEKi 1 ) or BRAF V600E ( PLX-4032 and BRAFi 2 ) inhibition led to decreased P-ERK , P-p70 S6K and P-rpS6 with only modest inhibition of P-4E-BP1 .	As previously demonstrated, MEK1/2 (PD0325901 and MEKi 1) or BRAF V600E (PLX-4032 and BRAFi 2) inhibition led to decreased P-ERK, P-p70 S6K and P-rpS6 with only modest inhibition of P-4E-BP1.	4	29	led	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	P-ERK	P-ERK	P-ERK	4	5	24	25
Furthermore , the authors of this study observed that a Mitogen activated protein kinase kinase ( MEK ) inhibitor was able to reduce MAPK activation and reduce cell growth .	Furthermore, the authors of this study observed that a Mitogen activated protein kinase kinase (MEK) inhibitor was able to reduce MAPK activation and reduce cell growth.	14	24	reduce	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	16	17	23	24
Treatment with trametinib in a panel of KRAS mutant lung cancer cell lines further demonstrated that long term MEK inhibition induces rebound activation of ERK signaling ( XREF_SUPPLEMENTARY ) .	Treatment with trametinib in a panel of KRAS mutant lung cancer cell lines further demonstrated that long term MEK inhibition induces rebound activation of ERK signaling (XREF_SUPPLEMENTARY).	18	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	18	19	24	25
Our data shows that ERK1/2 is activated upon stimulation by 2ME2 and G1 , and is effectively inhibited by antagonism of GPR30 , EGFR , and MEK .	Our data shows that ERK1/2 is activated upon stimulation by 2ME2 and G1, and is effectively inhibited by antagonism of GPR30, EGFR, and MEK.	4	27	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	26	27	4	5
Small molecule inhibitors of MAPK kinase ( MEK ) have been assessed previously for their radiosensitizing potential in in vitro and in vivo investigations , and enable the involvement of the ERK pathway in the radiation response to be assessed .	Small molecule inhibitors of MAPK kinase (MEK) have been assessed previously for their radiosensitizing potential in in vitro and in vivo investigations, and enable the involvement of the ERK pathway in the radiation response to be assessed.	2	32	enable	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	7	8	31	32
This effect was inhibited by PD 98059 and U 0126 , specific inhibitors of MEK , indicating that MEK , an upstream activator of ERK1/2 , was directly involved in ACN induced ERK1/2 activation .	This effect was inhibited by PD 98059 and U 0126, specific inhibitors of MEK, indicating that MEK, an upstream activator of ERK1/2, was directly involved in ACN induced ERK1/2 activation.	12	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	14	15	32	33
Inhibition of MEK mediated ERK activation , therefore , compromises checkpoint activation .	Inhibition of MEK mediated ERK activation, therefore, compromises checkpoint activation.	0	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	2	3	4	5
PD98059 , an antagonist of MEK1/2 , which blocks ERK activation during the application of 2500 microepsilon of mechanical strain , leads to a significant decrease in cell proliferation .	PD98059, an antagonist of MEK1/2, which blocks ERK activation during the application of 2500 microepsilon of mechanical strain, leads to a significant decrease in cell proliferation.	3	10	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	5	6	9	10
To test whether the lower mobility Fra-2 band was ERK 1/2 dependent , we used an inhibitor of activated MEK 1/2 ( PD 98059 ) to block ERK 1/2 activation .	To test whether the lower mobility Fra-2 band was ERK 1/2 dependent, we used an inhibitor of activated MEK 1/2 (PD 98059) to block ERK 1/2 activation.	16	29	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK 1/2	MEK 1/2	MEK 1/2	ERK 1/2	ERK 1/2	ERK 1/2	19	21	27	29
Accordingly , we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival .	Accordingly, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival.	7	11	signaling	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	10	11	7	8
The MEK specific inhibitor U0126 effectively inhibited the ERK1/2 activation stimulated by E2 and tamoxifen ( XREF_FIG ) .	The MEK specific inhibitor U0126 effectively inhibited the ERK1/2 activation stimulated by E2 and tamoxifen (XREF_FIG).	0	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	1	2	8	9
Although a seminary study demonstrated that a constitutively active MEK-ERK chimera can sufficiently induce neurite like processing of PC12 cells and NIH3T3 transformation [ XREF_BIBR ] , MEK dependent nature of the reagent limits determination of ERK sufficiency in the signaling .	Although a seminary study demonstrated that a constitutively active MEK-ERK chimera can sufficiently induce neurite like processing of PC12 cells and NIH3T3 transformation [XREF_BIBR], MEK dependent nature of the reagent limits determination of ERK sufficiency in the signaling.	27	37	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	27	28	36	37
A MAPK kinase ( MEK ) 1/2 inhibitor , U0126 also abolished MAPK activation and partially inhibited transcriptional activation by TGF-beta , suggesting that MAPK may be partially involved in this pathway .	A MAPK kinase (MEK) 1/2 inhibitor, U0126 also abolished MAPK activation and partially inhibited transcriptional activation by TGF-beta, suggesting that MAPK may be partially involved in this pathway.	2	13	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	4	5	12	13
Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt , respectively .	Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively.	1	13	elicited	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Mek	Mek	Mek	Erk	Erk	Erk	5	6	11	12
MEK inhibition during DOX treatment did not affect the early ERK activation , but enhanced the late ERK activation .	MEK inhibition during DOX treatment did not affect the early ERK activation, but enhanced the late ERK activation.	0	18	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	17	18
Pretreatment of hBMEC with these individual inhibitors resulted in a dose dependent decrease in IL-8 secretion by WT SPN ; however inhibition of MEK1/2 and subsequent inhibition of ERK signaling pathways with inhibitor U0126 had the most potent effect .	Pretreatment of hBMEC with these individual inhibitors resulted in a dose dependent decrease in IL-8 secretion by WT SPN; however inhibition of MEK1/2 and subsequent inhibition of ERK signaling pathways with inhibitor U0126 had the most potent effect.	23	30	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	23	24	28	29
Whereas BRAF and MEK targeted agents specifically inhibit a node in the MAPK signaling pathway that can eventually be overcome by tumor mutation , cancer immunotherapy has the potential to induce the inherent capacity of the immune system to adapt to mutational tumor changes .	Whereas BRAF and MEK targeted agents specifically inhibit a node in the MAPK signaling pathway that can eventually be overcome by tumor mutation, cancer immunotherapy has the potential to induce the inherent capacity of the immune system to adapt to mutational tumor changes.	1	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	3	4	12	13
Conversely , inhibition of Ras [ XREF_BIBR ] , BRAF [ XREF_BIBR - XREF_BIBR ] , or MEK blocks ERK activity and inhibits the growth of melanoma cells both in vitro and in vivo .	Conversely, inhibition of Ras [XREF_BIBR], BRAF [XREF_BIBR - XREF_BIBR], or MEK blocks ERK activity and inhibits the growth of melanoma cells both in vitro and in vivo.	2	20	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	17	18	19	20
However , MEK inhibition caused an increase in PI3K and AKT activation , and , vice versa , PI3K and AKT inhibition caused an increase in MAPK activation ( XREF_FIG ) .	However, MEK inhibition caused an increase in PI3K and AKT activation, and, vice versa, PI3K and AKT inhibition caused an increase in MAPK activation (XREF_FIG).	2	27	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	2	3	26	27
Suppression of ERK activation by the MEK1/2 phosphorylation inhibitor U0126 led to decreased mRNA and protein expression of SPARC in Snail overexpressing HBEC lines ( XREF_FIG ) .	Suppression of ERK activation by the MEK1/2 phosphorylation inhibitor U0126 led to decreased mRNA and protein expression of SPARC in Snail overexpressing HBEC lines (XREF_FIG).	2	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2 phosphorylation	mek1/2	ERK	ERK	erk	6	7	2	3
The late ERK activation was potentiated by MEK inhibition during DOX treatment .	The late ERK activation was potentiated by MEK inhibition during DOX treatment.	2	8	potentiated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	7	8	2	3
Our results indicate that extracellular regulated kinase ( ERK ) represents a central nexus in the mechanism of resistance conferred by stroma and FL towards FLT3 inhibition , and that targeting MEK ( MAPK and ERK Kinase ) , which activates ERK , abrogates much of this microenvironmental resistance .	Our results indicate that extracellular regulated kinase (ERK) represents a central nexus in the mechanism of resistance conferred by stroma and FL towards FLT3 inhibition, and that targeting MEK (MAPK and ERK Kinase), which activates ERK, abrogates much of this microenvironmental resistance.	30	43	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	31	32	41	42
Furthermore , the combination of the FLT3 inhibitor , sunitinib , with MAPK inhibition by the MEK1/2 kinase inhibitor AZD6244 in FLT3 positive cell lines synergistically inhibited the phosphorylation of ERK1/2 and p70S6K , effectors critical to cell proliferation and survival .	Furthermore, the combination of the FLT3 inhibitor, sunitinib, with MAPK inhibition by the MEK1/2 kinase inhibitor AZD6244 in FLT3 positive cell lines synergistically inhibited the phosphorylation of ERK1/2 and p70S6K, effectors critical to cell proliferation and survival.	12	19	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	16	17	12	13
Furthermore , pharmacological inhibition by PD98059 or UO126 of MEK and therefore of ERK1/2 activation restored sensitivity of STC1-/- cells to oxidative stress .	Furthermore, pharmacological inhibition by PD98059 or UO126 of MEK and therefore of ERK1/2 activation restored sensitivity of STC1-/- cells to oxidative stress.	3	14	inhibition	Negative_activation_syntax_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	9	10	13	14
The downstream target of BRAF , MEK stimulates ERK when activated .	The downstream target of BRAF, MEK stimulates ERK when activated.	4	9	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	8	9
Patch-clamp recordings from wild-type Ca ( v ) 2.2 , beta1b , alpha2delta1 versus mutant Ca ( v ) 2.2 ( S447A ) or Ca ( v ) 2.2 ( S409A ) channels revealed that mutation of either site significantly reduced current inhibition by UO126 , a MEK ( ERK kinase )-specific inhibitor that down-regulates ERK activity .	Patch-clamp recordings from wild-type Ca (v) 2.2, beta1b, alpha2delta1 versus mutant Ca (v) 2.2 (S447A) or Ca (v) 2.2 (S409A) channels revealed that mutation of either site significantly reduced current inhibition by UO126, a MEK (ERK kinase)-specific inhibitor that down-regulates ERK activity.	47	56	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	47	48	55	56
Here we report that the ERK pathway is downregulated by MEK ( MAPK-ERK kinase ) SUMOylation , which is inhibited by oncogenic Ras .	Here we report that the ERK pathway is downregulated by MEK (MAPK-ERK kinase) SUMOylation, which is inhibited by oncogenic Ras.	5	16	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MEK	MEK (MAPK-ERK kinase) SUMOylation	mek	ERK	ERK	erk	10	11	5	6
It must be noted that both MEK and ERK inhibitors will cause loss of ERK activity and initiate adaptive responses involving upregulation of receptor tyrosine kinases that will not only activate the Ras-Raf network but alternative pathways such as PI3K and AKT .	It must be noted that both MEK and ERK inhibitors will cause loss of ERK activity and initiate adaptive responses involving upregulation of receptor tyrosine kinases that will not only activate the Ras-Raf network but alternative pathways such as PI3K and AKT.	5	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	14	15
BRAF and MEK inhibition vertically target two distinct proteins in the MAPK pathway ; however , activation of alternative proliferative pathways can continue to drive oncogenesis ( XREF_FIG ) .	BRAF and MEK inhibition vertically target two distinct proteins in the MAPK pathway; however, activation of alternative proliferative pathways can continue to drive oncogenesis (XREF_FIG).	0	12	target	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	2	3	11	12
Biliverdin reductase-A functions as a scaffold protein for the activation of ERK by MEK1/2 and of Elk1 by ERK .	Biliverdin reductase-A functions as a scaffold protein for the activation of ERK by MEK1/2 and of Elk1 by ERK.	9	16	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	13	14	11	12
Inhibition of MAPK activation by anti-sense MEK expression in MDA-MB-468 cells significantly inhibits cell migration and in vitro invasion .	Inhibition of MAPK activation by anti-sense MEK expression in MDA-MB-468 cells significantly inhibits cell migration and in vitro invasion.	2	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	MEK	MEK expression	mek	MAPK	MAPK	mapk	6	7	2	3
4-OH Tamoxifen and ICI 182,780 treatment increased ERK1/2 phosphorylation in CM and CF , and ERK1/2 kinase ( MEK )-dependent inhibition of ERK1/2 activation attenuated ICI 182,780-mediated suppression of DNA synthesis .	4-OH Tamoxifen and ICI 182,780 treatment increased ERK1/2 phosphorylation in CM and CF, and ERK1/2 kinase (MEK)-dependent inhibition of ERK1/2 activation attenuated ICI 182,780-mediated suppression of DNA synthesis.	18	23	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	18	19	22	23
Inhibition of MEK , the upstream kinase that activates ERK , however , leads to neuroprotection in models of cerebral ischemia and trauma , suggesting that in this context ERK activation contributes to cellular damage .	Inhibition of MEK, the upstream kinase that activates ERK, however, leads to neuroprotection in models of cerebral ischemia and trauma, suggesting that in this context ERK activation contributes to cellular damage.	0	10	activates	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	2	3	9	10
Inhibition of MEK1/2 blocks Chk1 inhibitor -stimulated ERK1/2 activation and causes a profound increase in tumor cell killing both in vitro and in vivo .	Inhibition of MEK1/2 blocks Chk1 inhibitor -stimulated ERK1/2 activation and causes a profound increase in tumor cell killing both in vitro and in vivo.	0	8	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	2	3	7	8
It is known that repression of MAPK signalling by MEK inhibition is required to maintain ES cells in pluripotency and repress somatic differentiation .	It is known that repression of MAPK signalling by MEK inhibition is required to maintain ES cells in pluripotency and repress somatic differentiation.	6	10	signalling	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	9	10	6	7
Abrogation of MEK activity by small molecule inhibitors has been shown to suppress ERK 1/2 activation and lead to an inhibition of proliferation .	Abrogation of MEK activity by small molecule inhibitors has been shown to suppress ERK 1/2 activation and lead to an inhibition of proliferation.	2	15	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK 1/2	ERK 1/2	ERK 1/2	2	3	13	15
Furthermore , compound C also suppressed TGF-beta-stimulated phosphorylation of MEK1/2 , an upstream kinase that activates p44 and p42 MAPK ( XREF_FIG ) .	Furthermore, compound C also suppressed TGF-beta-stimulated phosphorylation of MEK1/2, an upstream kinase that activates p44 and p42 MAPK (XREF_FIG).	2	21	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	MEK1/2	compound C also suppressed TGF-beta-stimulated phosphorylation of MEK1/2	mek1/2	MAPK	MAPK	mapk	9	10	19	20
Sustained inhibition of MEK and ERK signaling by the BET and MEK combination .	Sustained inhibition of MEK and ERK signaling by the BET and MEK combination.	1	12	inhibition	Negative_activation_syntax_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	11	12	5	6
Local infusion of MEK ( MAP kinase kinase ) inhibitors ( PD98059 and U0126 ) during BDNF delivery abolished BDNF-LTP and the associated ERK activation .	Local infusion of MEK (MAP kinase kinase) inhibitors (PD98059 and U0126) during BDNF delivery abolished BDNF-LTP and the associated ERK activation.	1	24	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	3	4	23	24
Artificial down-regulation of MEK expression can significantly down-regulate the MAPK and ERK signaling and consequently suppress the cell proliferation on MHA samples .	Artificial down-regulation of MEK expression can significantly down-regulate the MAPK and ERK signaling and consequently suppress the cell proliferation on MHA samples.	3	12	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK expression	mek	MAPK	MAPK	mapk	3	4	9	10
Degradation of this protein releases Tpl2 kinase which phosphorylates MEK and leads to ERK activation , and both phosphorylated MEK and ERK kinases were found to be confined to the DRM fraction of RAW264 cells [ XREF_BIBR , XREF_BIBR ] .	Degradation of this protein releases Tpl2 kinase which phosphorylates MEK and leads to ERK activation, and both phosphorylated MEK and ERK kinases were found to be confined to the DRM fraction of RAW264 cells [XREF_BIBR, XREF_BIBR].	5	14	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	MEK	Tpl2 kinase which phosphorylates MEK	mek	ERK	ERK	erk	9	10	13	14
PKCbeta inhibition reduced ERK activity to levels observed in the absence of TSP-1 , whereas MEK inhibition essentially abolished ERK activity ( XREF_FIG ) .	PKCbeta inhibition reduced ERK activity to levels observed in the absence of TSP-1, whereas MEK inhibition essentially abolished ERK activity (XREF_FIG).	15	20	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK	MEK	MEK	ERK	ERK	ERK	15	16	19	20
It was recently demonstrated that in response to growth factor stimulation , SIRT1 can directly deacetylate MEK ( K175 ) to inhibit downstream ERK activation .	It was recently demonstrated that in response to growth factor stimulation, SIRT1 can directly deacetylate MEK (K175) to inhibit downstream ERK activation.	12	24	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	SIRT1 can directly deacetylate MEK (K175	mek	ERK	ERK	erk	16	17	23	24
Inhibition of the ERK activator MEK , as well as of p38 , significantly reduced caspase activation and necrosis , whereas c-Jun N-terminal kinase ( JNK ) inhibition diminished only caspase activity .	Inhibition of the ERK activator MEK, as well as of p38, significantly reduced caspase activation and necrosis, whereas c-Jun N-terminal kinase (JNK) inhibition diminished only caspase activity.	0	6	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	5	6	3	4
U0126 , a specific MAP kinase ( MEK1/2 ) inhibitor , blocked the ERK1/2 activation by MBS .	U0126, a specific MAP kinase (MEK1/2) inhibitor, blocked the ERK1/2 activation by MBS.	5	14	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	7	8	13	14
In RCS cells , only ERK was strongly activated by FGF2 ( XREF_FIG ) , and chemical inhibition of MEK ( a kinase upstream of ERK ) by U0126 or FGFR3 by SU5402 suppressed FGF2 mediated LRP6 phosphorylation ( XREF_FIG ) .	In RCS cells, only ERK was strongly activated by FGF2 (XREF_FIG), and chemical inhibition of MEK (a kinase upstream of ERK) by U0126 or FGFR3 by SU5402 suppressed FGF2 mediated LRP6 phosphorylation (XREF_FIG).	4	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	19	20	5	6
While combined inhibition of EGFR and MEK blocked both ERK and RPS6 activation in cells with higher RAS activation probability , EGFR monotherapy on the other hand only inhibited the activation of AKT and RPS6 with little effect on ERK , while MEK monotherapy only inhibited activation of ERK with a small effect on RPS6 .	While combined inhibition of EGFR and MEK blocked both ERK and RPS6 activation in cells with higher RAS activation probability, EGFR monotherapy on the other hand only inhibited the activation of AKT and RPS6 with little effect on ERK, while MEK monotherapy only inhibited activation of ERK with a small effect on RPS6.	42	49	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	42	43	48	49
These alternate growth signalling pathways may compensate for MEK inhibition of the MAPK pathway .	These alternate growth signalling pathways may compensate for MEK inhibition of the MAPK pathway.	8	13	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	8	9	12	13
Conversely , treatment with U0126 , a potent inhibitor of MEK mediated ERK activation , prevented FAK phosphorylation at Ser 910 induced by PDGF but did not interfere with PDGF induced FAK phosphorylation at Tyr 397 .	Conversely, treatment with U0126, a potent inhibitor of MEK mediated ERK activation, prevented FAK phosphorylation at Ser 910 induced by PDGF but did not interfere with PDGF induced FAK phosphorylation at Tyr 397.	8	13	mediated	Positive_early_activation	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	10	11	12	13
Notably , patients treated with BRAF inhibitor monotherapy experienced higher rates of cutaneous squamous cell carcinoma , due to activation of the MAPK pathway , compared to patients treated with combined BRAF and MEK inhibition [ XREF_BIBR , XREF_BIBR ] .	Notably, patients treated with BRAF inhibitor monotherapy experienced higher rates of cutaneous squamous cell carcinoma, due to activation of the MAPK pathway, compared to patients treated with combined BRAF and MEK inhibition [XREF_BIBR, XREF_BIBR].	22	34	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	33	34	22	23
Under these steady-state conditions , ERK1 and ERK2 protein levels were also unaffected , however phosphorylation of ERK1/2 was significantly decreased , consistent with the known capacity of U0126 to inhibit activation of ERK1/2 by MEK1/2 ( Favata etal ., 1998 ) .	Under these steady-state conditions, ERK1 and ERK2 protein levels were also unaffected, however phosphorylation of ERK1/2 was significantly decreased, consistent with the known capacity of U0126 to inhibit activation of ERK1/2 by MEK1/2 (Favata etal., 1998).	30	39	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	35	36	33	34
The MAP kinase kinase ( MEK ) inhibitor , PD98059 , significantly decreased the effect of lead on NGF induced neurite outgrowth and ERK activation .	The MAP kinase kinase (MEK) inhibitor, PD98059, significantly decreased the effect of lead on NGF induced neurite outgrowth and ERK activation.	3	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	5	6	23	24
In order to further investigate whether the ERK signaling pathway regulates hepatocyte differentiation , cells were treated with an inhibitor of MEK1/2 , U0126 , at 5 or 10 uM from day 2 to day 10 during hepatocyte differentiation of hESC derived progenitor cells .	In order to further investigate whether the ERK signaling pathway regulates hepatocyte differentiation, cells were treated with an inhibitor of MEK1/2, U0126, at 5 or 10 uM from day 2 to day 10 during hepatocyte differentiation of hESC derived progenitor cells.	7	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK	ERK	ERK	21	22	7	8
Although it remains unclear how MEK and ERK signaling represses differentiation , MEK and ERK signaling plays an essential role in the maintenance of undifferentiated spermatogonial stem cells .	Although it remains unclear how MEK and ERK signaling represses differentiation, MEK and ERK signaling plays an essential role in the maintenance of undifferentiated spermatogonial stem cells.	5	15	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	5	6	14	15
We found that neither wortmannin mediated PI3K inhibition nor MEK1/2 mediated MAPK inhibition prevented EGF induced PD-L1 upregulation ( XREF_SUPPLEMENTARY ) .	We found that neither wortmannin mediated PI3K inhibition nor MEK1/2 mediated MAPK inhibition prevented EGF induced PD-L1 upregulation (XREF_SUPPLEMENTARY).	5	12	mediated	Positive_early_activation	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	MAPK	MAPK	MAPK	9	10	11	12
Human biliverdin reductase ( hBVR ) , a Ser/Thr/Tyr kinase and intracellular scaffold/bridge/anchor , is a nuclear transporter of MEK1/2 stimulated ERK1/2 ( Lerner-Marmarosh , N ., Miralem , T ., Gibbs , P. E ., and Maines , M. D. ( 2008 ) Proc .	Human biliverdin reductase (hBVR), a Ser/Thr/Tyr kinase and intracellular scaffold/bridge/anchor, is a nuclear transporter of MEK1/2 stimulated ERK1/2 (Lerner-Marmarosh, N., Miralem, T., Gibbs, P. E., and Maines, M. D. (2008) Proc.	17	37	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	19	20	21	22
The knockdown of MR-1 inhibited proliferation and induced blast cell differentiation forward MK lineage through activation of the MEK and ERK signaling pathway induced by the upregulation of MEK phosphorylation .	The knockdown of MR-1 inhibited proliferation and induced blast cell differentiation forward MK lineage through activation of the MEK and ERK signaling pathway induced by the upregulation of MEK phosphorylation.	20	30	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK phosphorylation	mek	ERK	ERK	erk	28	29	20	21
MEK inhibition increased HSD11B1 mRNA levels , though whether this was via MEK or ERK ( ERK is activated by MEK phosphorylation ) was not investigated .	MEK inhibition increased HSD11B1 mRNA levels, though whether this was via MEK or ERK (ERK is activated by MEK phosphorylation) was not investigated.	16	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	MEK phosphorylation	mek	ERK	ERK	erk	20	21	16	17
The application of 25 muM PD098059 ( right ) efficiently inhibits the activation of Erk by MEK in mast cells .	The application of 25 muM PD098059 (right) efficiently inhibits the activation of Erk by MEK in mast cells.	10	19	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	Erk	Erk	Erk	16	17	14	15
MEK specific inhibitor U0126 effectively inhibited the ERK1/2 activation stimulated by E2 and tamoxifen ( XREF_FIG ) .	MEK specific inhibitor U0126 effectively inhibited the ERK1/2 activation stimulated by E2 and tamoxifen (XREF_FIG).	0	8	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	0	1	7	8
P38 and ERK1/2 signaling silencing , using BIRB0796 ( small molecular inhibitor of p38 MAPK ) and PD184352 ( inhibitor of MEK1/2 kinases that activate ERK1/2 ) , significantly abated LPS induced migration and invasion of B16 cells .	P38 and ERK1/2 signaling silencing, using BIRB0796 (small molecular inhibitor of p38 MAPK) and PD184352 (inhibitor of MEK1/2 kinases that activate ERK1/2), significantly abated LPS induced migration and invasion of B16 cells.	21	26	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	21	22	25	26
ERK phosphorylation was greater in three of four cell lines treated with combined RAF and MEK inhibition compared with MEK inhibition alone ( XREF_FIG ) , suggesting that combined use of vemurafenib attenuated the antileukemic effect of cobimetinib .	ERK phosphorylation was greater in three of four cell lines treated with combined RAF and MEK inhibition compared with MEK inhibition alone (XREF_FIG), suggesting that combined use of vemurafenib attenuated the antileukemic effect of cobimetinib.	0	16	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	15	16	0	1
Therefore , inhibition of MEK mediated ERK activation may be an effective option in cancer therapy .	Therefore, inhibition of MEK mediated ERK activation may be an effective option in cancer therapy.	2	7	mediated	Positive_early_activation	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	4	5	6	7
MEK inhibition during DOX treatment simultaneously enhanced the late activation of ERK and blocked the increase in basal excitability .	MEK inhibition during DOX treatment simultaneously enhanced the late activation of ERK and blocked the increase in basal excitability.	0	12	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	11	12
Late ERK activation was enhanced by MEK inhibition during DOX treatment .	Late ERK activation was enhanced by MEK inhibition during DOX treatment.	1	7	enhanced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	1	2
U0126 , a selective inhibitor of MAPK kinase ( MEK1/2 ) , the immediate upstream activator of ERK1/2 , inhibits ERK1/2 activation in acute slices .	U0126, a selective inhibitor of MAPK kinase (MEK1/2), the immediate upstream activator of ERK1/2, inhibits ERK1/2 activation in acute slices.	0	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	9	10	20	21
We next investigated whether the DN MEK mice had reduced activation of ERK following formalin injection .	We next investigated whether the DN MEK mice had reduced activation of ERK following formalin injection.	6	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	6	7	12	13
Trametinib has been shown to prevent RAS dependent MEK phosphorylation and cause prolonged inhibition of ERK signaling [ XREF_BIBR ] .	Trametinib has been shown to prevent RAS dependent MEK phosphorylation and cause prolonged inhibition of ERK signaling [XREF_BIBR].	0	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	Trametinib has been shown to prevent RAS dependent MEK phosphorylation	mek	ERK	ERK	erk	8	9	15	16
Deletion of EGFR prevented endogenous and mechanical stretch induced type II cell differentiation via the ERK pathway , which was rescued by overexpression of a constitutively active MEK .	Deletion of EGFR prevented endogenous and mechanical stretch induced type II cell differentiation via the ERK pathway, which was rescued by overexpression of a constitutively active MEK.	15	28	rescued	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	MEK	overexpression of a constitutively active MEK	mek	ERK	ERK	erk	27	28	15	16
DN MEK overexpression markedly inhibited ERK1/2 activation observed in GFP infected ( control ) cultures ( XREF_FIG C ) .	DN MEK overexpression markedly inhibited ERK1/2 activation observed in GFP infected (control) cultures (XREF_FIG C).	1	6	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK overexpression	mek	ERK1/2	ERK1/2	erk1/2	1	2	5	6
The MAPK kinase ( MEK ) inhibitor U0126 completely inhibited Erk activation by NSC 95397 and NSC 672121 .	The MAPK kinase (MEK) inhibitor U0126 completely inhibited Erk activation by NSC 95397 and NSC 672121.	2	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	Erk	Erk	Erk	4	5	10	11
However , pre-clinical in vivo studies showed that both MEK and PKC inhibition is needed to completely abolish MAPK signaling and thereby tumor growth 9 .	However, pre-clinical in vivo studies showed that both MEK and PKC inhibition is needed to completely abolish MAPK signaling and thereby tumor growth 9.	8	19	abolish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	9	10	18	19
Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAF V600E targeted inhibition in a novel syngeneic murine glioma model .	Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAF V600E targeted inhibition in a novel syngeneic murine glioma model.	0	7	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	1	2	5	6
MEK specific inhibitor PD98059 was shown to prevent the observed effects of MEK and ERK on MMP and the development of radioresistance [ XREF_BIBR ] .	MEK specific inhibitor PD98059 was shown to prevent the observed effects of MEK and ERK on MMP and the development of radioresistance [XREF_BIBR].	0	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK	ERK	ERK	0	1	14	15
The combination of PLX4720 and the mapk and Erk kinase ( MEK ) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC bearing animals .	The combination of PLX4720 and the mapk and Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC bearing animals.	9	20	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK	MAPK	MAPK	11	12	18	19
Selumetinib ( AZD6244 and ARRY-142866 , AstraZeneca ) , an oral highly selective and potent uncompetitive inhibitor of mitogen activated protein kinase 1/2 ( MEK1/2 ) was able to prevent ERK1/2 mediated growth factor independent survival [ XREF_BIBR ] .	Selumetinib (AZD6244/ARRY-142866, AstraZeneca), an oral highly selective and potent uncompetitive inhibitor of mitogen activated protein kinase 1/2 (MEK1/2) was able to prevent ERK1/2 mediated growth factor independent survival [XREF_BIBR].	0	31	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK1/2	MEK1/2	MEK1/2	ERK1/2	ERK1/2	ERK1/2	24	25	30	31
The MEK specific inhibitor U0126 effectively inhibited the ERK1/2 activation stimulated by testosterone .	The MEK specific inhibitor U0126 effectively inhibited the ERK1/2 activation stimulated by testosterone.	0	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK1/2	ERK1/2	ERK1/2	1	2	8	9
In contrast , Max knock-down abolished the binding of c-Myc at all position tested .	In contrast, Max knock-down abolished the binding of c-Myc at all position tested.	3	10	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	Max	Max	c-Myc	c-Myc	c-Myc	3	4	9	10
In other studies , miR-210 has been shown to modulate mitochondrial oxygen uptake and create a pseudo-hypoxic environment [ XREF_BIBR ] , or to act as an oncomiR by repressing the Myc antagonist Max binding protein [ XREF_BIBR ] ( MNT ) and as pro angiomir by targeting ephrin-A3 [ XREF_BIBR ] in other cancers .	In other studies, miR-210 has been shown to modulate mitochondrial oxygen uptake and create a pseudo-hypoxic environment [XREF_BIBR], or to act as an oncomiR by repressing the Myc antagonist Max binding protein [XREF_BIBR] (MNT) and as pro angiomir by targeting ephrin-A3 [XREF_BIBR] in other cancers.	31	35	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	Max	Max	Max	Myc	Myc	Myc	33	34	31	32
Max interactor protein , MXI1 ( gene L07648 ) competes for MAX thus negatively regulates MYC function and may play a role in insulin resistance .	Max interactor protein, MXI1 (gene L07648) competes for MAX thus negatively regulates MYC function and may play a role in insulin resistance.	11	19	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAX	MAX	MAX	MYC	MYC	MYC	11	12	15	16
These results suggest that elevation of Max expression in vivo inhibits the function of Myc .	These results suggest that elevation of Max expression in vivo inhibits the function of Myc.	6	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	Max expression	max	Myc	Myc	myc	6	7	14	15
Thus , MYC and MAX heteromeric complexes can activate transcription , whereas MXD and MAX or MAX and MAX complexes can suppress activation of MYC target genes .	Thus, MYC and MAX heteromeric complexes can activate transcription, whereas MXD and MAX or MAX and MAX complexes can suppress activation of MYC target genes.	12	26	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAX	MAX	MAX	MYC	MYC	MYC	14	15	24	25
Conversely , the homodimerization of Max and the ability of the homodimer to bind DNA ( specific and non specific ) with high affinity limits the access of c-Myc and Max to DNA [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Conversely, the homodimerization of Max and the ability of the homodimer to bind DNA (specific and non specific) with high affinity limits the access of c-Myc and Max to DNA [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	30	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	Max	Max	c-Myc	c-Myc	c-Myc	5	6	28	29
MAX may also bind to other transcription factors of the families MXD1 , MNT , and MGA that compete with MYC for the promoter E-box sequences and reduce the activity of the MYC target genes , thus potentially inhibiting cell growth and facilitating their terminal differentiation [ XREF_BIBR ] .	MAX may also bind to other transcription factors of the families MXD1, MNT, and MGA that compete with MYC for the promoter E-box sequences and reduce the activity of the MYC target genes, thus potentially inhibiting cell growth and facilitating their terminal differentiation [XREF_BIBR].	0	34	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAX	MAX	MAX	MYC	MYC	MYC	0	1	32	33
Down-regulation of SOX5 and MAX in LN+ tumors is consistent with the enrichment of their binding motifs when their mode of action is considered : SOX5 is reported as predominantly a repressor 25 and MAX is able to repress MYC activity although it has a dual function 26 .	Down-regulation of SOX5 and MAX in LN+ tumors is consistent with the enrichment of their binding motifs when their mode of action is considered : SOX5 is reported as predominantly a repressor 25 and MAX is able to repress MYC activity although it has a dual function 26.	31	40	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAX	MAX	MAX	MYC	MYC	MYC	34	35	39	40
Hence , the overexpression of WT Max in GBM cells can be expected to reduce c-Myc transcriptional activities and proliferation , consistent with results reported by others [ XREF_BIBR - XREF_BIBR , XREF_BIBR ] .	Hence, the overexpression of WT Max in GBM cells can be expected to reduce c-Myc transcriptional activities and proliferation, consistent with results reported by others [XREF_BIBR - XREF_BIBR, XREF_BIBR].	3	16	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	overexpression of WT Max	max	c-Myc	c-Myc	c-myc	6	7	15	16
However , whether TGF-beta1 might also increase the expression of a Max interacting factor that blocks myc function by competing with myc for Max binding is not known .	However, whether TGF-beta1 might also increase the expression of a Max interacting factor that blocks myc function by competing with myc for Max binding is not known.	3	17	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	TGF-beta1 might also increase the expression of a Max	max	myc	myc	myc	11	12	16	17
Max siRNA expression , or expression of a Myc construct lacking the HLH/LZ ( Max interacting ) region , also reduces Myc repression of C/EBPdelta promoter activity .	Max siRNA expression, or expression of a Myc construct lacking the HLH/LZ (Max interacting) region, also reduces Myc repression of C/EBPdelta promoter activity.	0	22	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Max	Max siRNA expression	max	Myc	Myc	myc	0	1	21	22
Mnt : Max complexes also efficiently suppress Myc dependent activation from the same promoter .	Mnt : Max complexes also efficiently suppress Myc dependent activation from the same promoter.	2	9	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	Max	Max	Myc	Myc	Myc	2	3	7	8
HIF-2alpha is known to augment c-Myc activity through the stabilization of c-Myc : Max complex , which promotes cell cycle progression ; in contrast HIF-1alpha inhibits the function of c-Myc resulting in cell cycle arrest .	HIF-2alpha is known to augment c-Myc activity through the stabilization of c-Myc : Max complex, which promotes cell cycle progression; in contrast HIF-1alpha inhibits the function of c-Myc resulting in cell cycle arrest.	13	30	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	Max	Max	c-Myc	c-Myc	c-Myc	13	14	29	30
Max proteins homodimerize weakly , whereas forced Max expression blocks the c-Myc biological activity through competition for E-box sites [ XREF_BIBR ] .	Max proteins homodimerize weakly, whereas forced Max expression blocks the c-Myc biological activity through competition for E-box sites [XREF_BIBR].	7	13	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	Max expression	max	c-Myc	c-Myc	c-myc	7	8	11	12
Interestingly , the three Max residues acetylated in vivo and in vitro by p300 are important for Max nuclear localization and Max mediated suppression of Myc transactivation .	Interestingly, the three Max residues acetylated in vivo and in vitro by p300 are important for Max nuclear localization and Max mediated suppression of Myc transactivation.	17	26	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	Max	Max	Myc	Myc	Myc	17	18	25	26
One option is to use small molecule inhibitors that target MYC-MAX heterodimerization thereby preventing transactivation of MYC target genes .	One option is to use small molecule inhibitors that target MYC-MAX heterodimerization thereby preventing transactivation of MYC target genes.	10	18	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MYC-MAX	MYC-MAX	MYC-MAX	MYC	MYC	MYC	10	11	16	17
Previous studies have demonstrated that MAX may impair MYC function by impairing the ability of MYC to bind to DNA .	Previous studies have demonstrated that MAX may impair MYC function by impairing the ability of MYC to bind to DNA.	5	9	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAX	MAX	MAX	MYC	MYC	MYC	5	6	8	9
XREF_BIBR , XREF_BIBR MYC and MAX activity may itself be inhibited by the competitive binding of MAX by MAD1 .	XREF_BIBR, XREF_BIBR MYC and MAX activity may itself be inhibited by the competitive binding of MAX by MAD1.	0	17	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MAX	MAX	MAX	MYC	MYC	MYC	16	17	3	4
The introduction of wild-type MAX cDNA into PC12 cells significantly decreased MYC ' s ability to bind to canonical E-boxes , while pathogenic MAX proteins were not able to fully repress MYC activity .	The introduction of wild-type MAX cDNA into PC12 cells significantly decreased MYC 's ability to bind to canonical E-boxes, while pathogenic MAX proteins were not able to fully repress MYC activity.	4	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAX	MAX	MAX	MYC	MYC	MYC	4	5	11	12
Max also heterodimerizes with the Mad family of proteins to repress transcription , antagonize c-Myc , and promote cellular differentiation .	Max also heterodimerizes with the Mad family of proteins to repress transcription, antagonize c-Myc, and promote cellular differentiation.	0	17	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	Max	Max	c-Myc	c-Myc	c-Myc	0	1	14	15
The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities .	The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities.	1	11	Inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Max	Max	Max	c-Myc	c-Myc	c-Myc	1	2	9	10
The antagonistic activity of ABT-700 required the bivalent nature of the antibody because the Fab fragment did not inhibit c-Met phosphorylation or induce c-Met down-regulation .	The antagonistic activity of ABT-700 required the bivalent nature of the antibody because the Fab fragment did not inhibit c-Met phosphorylation or induce c-Met down-regulation.	14	24	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Met	Fab fragment did not inhibit c-Met phosphorylation	c-met	c-Met	c-Met	c-met	19	20	23	24
In this context , VEGF blockade abrogated the suppression of c-met phosphorylation , activating the c-met and HGF pathway directly in cancer cells .	In this context, VEGF blockade abrogated the suppression of c-met phosphorylation, activating the c-met and HGF pathway directly in cancer cells.	4	18	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-met	VEGF blockade abrogated the suppression of c-met phosphorylation	c-met	c-met	c-met	c-met	10	11	15	16
Cotreatment with an HGF receptor blocking antibody or c-Met antagonist downregulated this enhancement .	Cotreatment with an HGF receptor blocking antibody or c-Met antagonist downregulated this enhancement.	3	9	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HGF receptor	HGF receptor	HGF receptor	c-Met	c-Met	c-Met	3	5	8	9
In the present study , miRNA-454-3p was proven to directly target c-Met , and the overexpression of miRNA-454-3p greatly suppressed c-Met expression in human cervical cancer cells .	In the present study, miRNA-454-3p was proven to directly target c-Met, and the overexpression of miRNA-454-3p greatly suppressed c-Met expression in human cervical cancer cells.	10	22	target	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	c-Met	overexpression of miRNA-454-3p greatly suppressed c-Met expression	c-met	c-Met	c-Met	c-met	20	21	11	12
Therefore , Mff and MIEF1 positively and negatively regulate Drp1 mediated mitochondrial fission in vertebrates , respectively .	Therefore, Mff and MIEF1 positively and negatively regulate Drp1 mediated mitochondrial fission in vertebrates, respectively.	2	10	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	2	3	9	10
Mff-proteoliposomes yielded similar results indicating that the VD inhibition of Mff induced Drp1 GTPase stimulation occurs independently of membrane curvature .	Mff-proteoliposomes yielded similar results indicating that the VD inhibition of Mff induced Drp1 GTPase stimulation occurs independently of membrane curvature.	8	14	induced	Positive_early_activation	Positive_activation	Negative_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	10	11	12	13
Knockdown of MFF abrogates the fission stage of peroxisomal division and is associated with failure to recruit DLP1 to peroxisomes , while ectopic expression of MFF increases the peroxisomal targeting of DLP1 .	Knockdown of MFF abrogates the fission stage of peroxisomal division and is associated with failure to recruit DLP1 to peroxisomes, while ectopic expression of MFF increases the peroxisomal targeting of DLP1.	23	32	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MFF	expression of MFF	mff	DLP1	DLP1	dlp1	25	26	31	32
As expected , Mff ablation significantly reduced mitochondrial localization of Drp1 .	As expected, Mff ablation significantly reduced mitochondrial localization of Drp1.	3	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	3	4	10	11
Conversely , Mff deficiency leads to reduced Drp1 at the mitochondrial and to mitochondrial elongation .	Conversely, Mff deficiency leads to reduced Drp1 at the mitochondrial and to mitochondrial elongation.	2	10	leads	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	2	3	7	8
Mff suppression by siRNA causes similar effects , including dramatic inhibition of mitochondrial division in either unstimulated or ionomycin stimulated cells , and near-complete elimination of all Drp1 punctae in GFP-Drp1-KI cells ( Figs .	Mff suppression by siRNA causes similar effects, including dramatic inhibition of mitochondrial division in either unstimulated or ionomycin stimulated cells, and near-complete elimination of all Drp1 punctae in GFP-Drp1-KI cells (Figs.	0	28	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Mff	Mff	Mff	Drp1	Drp1	Drp1	0	1	27	28
Moreover , the present study showed that the interplay between DLP1 and Pex11pbeta was altered in cells treated with siRNA targeting MFF , but not FIS1 ( XREF_FIG ) , suggesting that in mammalian cells Fis1 contributes less to peroxisomal morphogenesis than Mff .	Moreover, the present study showed that the interplay between DLP1 and Pex11pbeta was altered in cells treated with siRNA targeting MFF, but not FIS1 (XREF_FIG), suggesting that in mammalian cells Fis1 contributes less to peroxisomal morphogenesis than Mff.	8	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	MFF	MFF	MFF	DLP1	DLP1	DLP1	21	22	10	11
GSK-3beta is also inhibited by the PI-3 '-kinase pathway through PKB and Akt , and also by the MEK and ERK and p38 MAPK pathways , PKA , p90 RSK / MAPKAP kinase-1 , and S6 kinase .	GSK-3beta is also inhibited by the PI-3 '-kinase pathway through PKB and Akt, and also by the MEK and ERK and p38 MAPK pathways, PKA, p90 RSK / MAPKAP kinase-1, and S6 kinase.	0	24	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	GSK-3beta	GSK-3beta	GSK-3beta	18	19	0	1
Not only did Mek inhibition block differentiation in low PI3K and Akt activity , it also suppressed the inactivation of Gsk3beta ( XREF_FIG ) , supporting the idea that Mek and Erk signaling inhibits Gsk3beta activity .	Not only did Mek inhibition block differentiation in low PI3K and Akt activity, it also suppressed the inactivation of Gsk3beta (XREF_FIG), supporting the idea that Mek and Erk signaling inhibits Gsk3beta activity.	29	35	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mek	Mek	Mek	Gsk3beta	Gsk3beta	Gsk3beta	29	30	34	35
Specifically , inhibition of GSK-3beta led to increased ERK phosphorylation , and inhibition of MEK completely blocked the effects of GSK-3beta inhibition on dendrite initiation and growth .	Specifically, inhibition of GSK-3beta led to increased ERK phosphorylation, and inhibition of MEK completely blocked the effects of GSK-3beta inhibition on dendrite initiation and growth.	12	21	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	GSK-3beta	GSK-3beta	GSK-3beta	14	15	20	21
Blockage of ROS generation and MEK and ERK signaling reduced the radiation induced deactivation of GSK3beta , activation of Snail and induction of EMT .	Blockage of ROS generation and MEK and ERK signaling reduced the radiation induced deactivation of GSK3beta, activation of Snail and induction of EMT.	5	16	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	GSK3beta	GSK3beta	GSK3beta	5	6	15	16
mGluR5 is known to activate the PI3K and Akt and MEK and ERK pathways , both of which can inhibit GSK3beta .	mGluR5 is known to activate the PI3K and Akt and MEK and ERK pathways, both of which can inhibit GSK3beta.	10	21	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	GSK3beta	GSK3beta	GSK3beta	10	11	20	21
It suggests that inhibition of MEK ( possible activator of GSK-3beta ) might lead to drop of GSK-3beta activity and GSK-3beta is engaged in the assembly of these protein partners .	It suggests that inhibition of MEK (possible activator of GSK-3beta) might lead to drop of GSK-3beta activity and GSK-3beta is engaged in the assembly of these protein partners.	3	11	activator	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	MEK	MEK	MEK	GSK-3beta	GSK-3beta	GSK-3beta	5	6	10	11
Indeed , we observed that ERK translocation into or out of the organelle was regulated by oxidative stimuli or serum , and that the formation of MEK-ERK complexes in these organelles was regulated by the oxidation of a redox sensitive cysteine in ERK2 and the impeded binding to MEK caused ERK2 retention in the organelle in detriment of its shuttle into the nuclei XREF_BIBR .	Indeed, we observed that ERK translocation into or out of the organelle was regulated by oxidative stimuli or serum, and that the formation of MEK-ERK complexes in these organelles was regulated by the oxidation of a redox sensitive cysteine in ERK2 and the impeded binding to MEK caused ERK2 retention in the organelle in detriment of its shuttle into the nuclei XREF_BIBR.	46	51	caused	Positive_activation_token_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	48	49	50	51
Indeed , it has been demonstrated that VEGF increases human endothelial permeability via the MEK pathway , that incubation of endothelial cells with PD98059 reduces MAPK 1 activity , and that VEGF induces the phosphorylation of MAPK 1/2 .	Indeed, it has been demonstrated that VEGF increases human endothelial permeability via the MEK pathway, that incubation of endothelial cells with PD98059 reduces MAPK 1 activity, and that VEGF induces the phosphorylation of MAPK 1/2.	14	27	reduces	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	MAPK 1	MAPK 1	MAPK 1	14	15	25	27
To further examine the pathway leading to ERK2 phosphorylation , cultures were treated with MEK and tyrosine kinase inhibitors .	To further examine the pathway leading to ERK2 phosphorylation, cultures were treated with MEK and tyrosine kinase inhibitors.	7	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	14	15	7	8
Furthermore , the selective MEK 1 inhibitor , PD 98059 , inhibits oestradiol and progestin stimulation of Erk-2 and the steroid dependent S-phase entry .	Furthermore, the selective MEK 1 inhibitor, PD 98059, inhibits oestradiol and progestin stimulation of Erk-2 and the steroid dependent S-phase entry.	2	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	Erk-2	Erk-2	Erk-2	4	5	17	18
In fusion negative rhabdomyosarcoma ( FN-RMS ) , MEK inhibition relieves ERK2 mediated repression of MYOG .	In fusion negative rhabdomyosarcoma (FN-RMS), MEK inhibition relieves ERK2 mediated repression of MYOG.	8	13	relieves	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	8	9	11	12
Second , when MEK and OspF were mixed at equimolar concentrations in vitro , the presence of MEK prevented ERK2 from being dephosphorylated by OspF ( XREF_SUPPLEMENTARY ) .	Second, when MEK and OspF were mixed at equimolar concentrations in vitro, the presence of MEK prevented ERK2 from being dephosphorylated by OspF (XREF_SUPPLEMENTARY).	15	20	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEK	MEK	MEK	ERK2	ERK2	ERK2	17	18	19	20
Pretreatment with the ADAM17 ( a disintegrin and metalloproteinase-17 ) inhibitor TAPI-0 ( tumor necrosis factor alpha protease inhibitor-0 ) reduced LPS induced production of soluble Mer protein in bronchoalveolar lavage ( BAL ) fluid , restored membrane bound Mer expression , and increased Mer activation in alveolar macrophages and lungs after LPS treatment .	Pretreatment with the ADAM17 (a disintegrin and metalloproteinase-17) inhibitor TAPI-0 (tumor necrosis factor alpha protease inhibitor-0) reduced LPS induced production of soluble Mer protein in bronchoalveolar lavage (BAL) fluid, restored membrane bound Mer expression, and increased Mer activation in alveolar macrophages and lungs after LPS treatment.	26	41	restored	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	Mer	Mer	mer	Mer	Mer expression	mer	26	27	39	40
In the present study , we found that isoflurane increased the total and surface expression of Mer in BMDMs without a change in cytosolic level of Mer , raising the possibility that isoflurane suppresses Mer cleavage .	In the present study, we found that isoflurane increased the total and surface expression of Mer in BMDMs without a change in cytosolic level of Mer, raising the possibility that isoflurane suppresses Mer cleavage.	8	35	raising	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Mer	isoflurane increased the total and surface expression of Mer	mer	Mer	Mer	mer	16	17	34	35
This occurred despite normal phosphorylation of H2AX , indicating that lack of Mdc1 does not impair this DSB induced chromatin change , but rather precludes the sustained engagement of Nbs1 with these regions .	This occurred despite normal phosphorylation of H2AX, indicating that lack of Mdc1 does not impair this DSB induced chromatin change, but rather precludes the sustained engagement of Nbs1 with these regions.	10	32	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mdc1	Mdc1	Mdc1	Nbs1	Nbs1	Nbs1	12	13	29	30
Mammalian MDC1 contains a total of six SDT motifs : five are located within the region of MDC1 , whose deletion abrogates MRN foci ( XREF_FIG ) , and one is located ~ 80 amino acids N terminal to this region ( not depicted ) .	Mammalian MDC1 contains a total of six SDT motifs : five are located within the region of MDC1, whose deletion abrogates MRN foci (XREF_FIG), and one is located ~ 80 amino acids N terminal to this region (not depicted).	15	23	abrogates	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	MDC1	MDC1	MDC1	MRN	MRN	MRN	17	18	22	23
Knockdown of NFBD1 , or to a lesser degree , 53BP1 reduced NBS1 IRIF ( ~ 70 % versus ~ 40 % ) ( XREF_FIG ) .	Knockdown of NFBD1, or to a lesser degree, 53BP1 reduced NBS1 IRIF (~ 70% versus ~ 40%) (XREF_FIG).	0	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	NFBD1	NFBD1	NFBD1	NBS1	NBS1	NBS1	2	3	12	13
Mib1 blocks the ability of Dll1 to Cis-inhibit Notch signaling .	Mib1 blocks the ability of Dll1 to Cis-inhibit Notch signaling.	0	6	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mib1	Mib1	Mib1	Dll1	Dll1	Dll1	0	1	5	6
Mib1 promotes Trans-activation and blocks the ability of Dll1 to induce differentiation .	Mib1 promotes Trans-activation and blocks the ability of Dll1 to induce differentiation.	0	9	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mib1	Mib1	Mib1	Dll1	Dll1	Dll1	0	1	8	9
Taken together , these results indicate that Dll1 overexpression promotes differentiation of neural progenitors cell autonomously through Cis-inhibition of Notch signaling and that Mib1 is able to block this effect by converting Dll1 from a Cis inhibiting to a Trans-activating ligand .	Taken together, these results indicate that Dll1 overexpression promotes differentiation of neural progenitors cell autonomously through Cis-inhibition of Notch signaling and that Mib1 is able to block this effect by converting Dll1 from a Cis inhibiting to a Trans-activating ligand.	23	33	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mib1	Mib1	Mib1	Dll1	Dll1	Dll1	23	24	32	33
Of note , exogenous restoration of MELK by overexpression of the MELK coding region in MELK 3 ' UT shRNA treated U87 cells reversed the phenotype ( XREF_FIG right panel , XREF_SUPPLEMENTARY ) .	Of note, exogenous restoration of MELK by overexpression of the MELK coding region in MELK 3 ' UT shRNA treated U87 cells reversed the phenotype (XREF_FIG right panel, XREF_SUPPLEMENTARY).	4	13	restoration	Positive_activation_token_2_noun	Positive_activation	Positive_activation	MELK	overexpression of the MELK	melk	MELK	MELK	melk	11	12	6	7
Intriguingly , we found that Notch1 signaling activation was obviously attenuated by MDM2 depletion in GMCs with high glucose exposure .	Intriguingly, we found that Notch1 signaling activation was obviously attenuated by MDM2 depletion in GMCs with high glucose exposure.	5	13	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	MDM2	MDM2	MDM2	Notch1	Notch1	Notch1	12	13	5	6
Notably , TP53 regulates intercellular adhesion molecule 1 ( ICAM-1 ) , which controls immune cell migration and adhesion , and interferon related developmental regulator 1 ( IFRD1 and PC4 ) , which regulates p53 transcriptional activity and is required for myoblast differentiation , and also inhibits MyoD and MADS box transcription enhancer factor 2 , polypeptide C ( MEF2C ) .	Notably, TP53 regulates intercellular adhesion molecule 1 (ICAM-1), which controls immune cell migration and adhesion, and interferon related developmental regulator 1 (IFRD1 and PC4), which regulates p53 transcriptional activity and is required for myoblast differentiation, and also inhibits MyoD and MADS box transcription enhancer factor 2, polypeptide C (MEF2C).	46	60	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MEF2C	MEF2C	MEF2C	MyoD	MyoD	MyoD	59	60	47	48
Mfng expression reduced Notch1 activation in cells plated on Jag1 ligand slightly , confirming previous results ( lanes 3 & 4 ;) .	Mfng expression reduced Notch1 activation in cells plated on Jag1 ligand slightly, confirming previous results (lanes 3 & 4;).	0	4	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mfng	Mfng expression	mfng	Notch1	Notch1	notch1	0	1	3	4
We report now that , downstream Cdk1 inactivation , Fcp1 dephosphorylates Gwl at sites probably phosphorylated by Cdk1 and downregulates Gwl kinase activity towards Ensa and ARPP19 ( XREF_FIG ) .	We report now that, downstream Cdk1 inactivation, Fcp1 dephosphorylates Gwl at sites probably phosphorylated by Cdk1 and downregulates Gwl kinase activity towards Ensa and ARPP19 (XREF_FIG).	6	28	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Gwl	Cdk1 inactivation, Fcp1 dephosphorylates Gwl	gwl	ARPP19	ARPP19	arpp19	11	12	26	27
It has been suggested that the mTOR complex 1 ( mTORC1 )/p70S6K axis represses upstream PI3K and Akt signaling through phosphorylation of IRS-1 and its subsequent degradation .	It has been suggested that the mTOR complex 1 (mTORC1)/p70S6K axis represses upstream PI3K and Akt signaling through phosphorylation of IRS-1 and its subsequent degradation.	6	18	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	6	7	17	18
As reported by Khuri colleagues , mTOR inhibition triggers rapid and sustained activation of the PI3K and Akt survival pathway in the human lung and other types of cancer cells ; therefore , the combination of mTOR targeted therapy with drugs that block PI3K and Akt activation might also be reasonable .	As reported by Khuri colleagues, mTOR inhibition triggers rapid and sustained activation of the PI3K and Akt survival pathway in the human lung and other types of cancer cells; therefore, the combination of mTOR targeted therapy with drugs that block PI3K and Akt activation might also be reasonable.	6	19	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	6	7	17	18
The effects of unwanted Akt activation by mTOR inhibition might be decreased upon treatment with a dual kinase inhibitor .	The effects of unwanted Akt activation by mTOR inhibition might be decreased upon treatment with a dual kinase inhibitor.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	7	8	4	5
It is well known that mTOR inhibition activates PI3-K and Akt by up-regulating IGF-1R signaling , and therapeutic inhibition of the IGF-1R pathway as a strategy to overcome resistance to mTOR inhibitor has been suggested in a variety of cancers , including HNSCC , in which mTOR overexpression has been observed .	It is well known that mTOR inhibition activates PI3-K and Akt by up-regulating IGF-1R signaling, and therapeutic inhibition of the IGF-1R pathway as a strategy to overcome resistance to mTOR inhibitor has been suggested in a variety of cancers, including HNSCC, in which mTOR overexpression has been observed.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	10	11
mTOR inhibition causes induction of PI3K and AKT signaling through increased IGF-1R signaling , and combined mTOR and PI3K and AKT inhibition leads to additive antiproliferative effects in AML 47 .	mTOR inhibition causes induction of PI3K and AKT signaling through increased IGF-1R signaling, and combined mTOR and PI3K and AKT inhibition leads to additive antiproliferative effects in AML 47.	0	8	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	7	8
The underlying mechanism has not been fully clarified ; however , it seems that high mTOR signal in TSC1/2 deficient cells may suppress Akt activity through a negative feedback regulation , which is important for the NF-kappaB activation upon certain stimuli .	The underlying mechanism has not been fully clarified; however, it seems that high mTOR signal in TSC1/2 deficient cells may suppress Akt activity through a negative feedback regulation, which is important for the NF-kappaB activation upon certain stimuli.	15	24	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	15	16	23	24
More importantly , the dual knock-down of mTOR and Src significantly promoted the inhibition of PI3K and AKT , p70S6K/4E-BP 1 , and resulted in the up-regulation of CDK inhibitor proteins , when compared to either si-mTOR or si-Src alone .	More importantly, the dual knock-down of mTOR and Src significantly promoted the inhibition of PI3K and AKT, p70S6K/4E-BP 1, and resulted in the up-regulation of CDK inhibitor proteins, when compared to either si-mTOR or si-Src alone.	5	18	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	7	8	17	18
mTOR inhibition induces activation of Akt signaling pathways , through elimination of negative feedback loops .	mTOR inhibition induces activation of Akt signaling pathways, through elimination of negative feedback loops.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	5	6
Furthermore , we show that inhibition of mTOR by rapamycin induces the activation of Akt as shown by increased Akt phosphorylation at Ser ( 473 ) and the inhibition of 6-TG-induced apoptosis and cell death .	Furthermore, we show that inhibition of mTOR by rapamycin induces the activation of Akt as shown by increased Akt phosphorylation at Ser (473) and the inhibition of 6-TG-induced apoptosis and cell death.	5	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	7	8	14	15
The growth inhibitory effect of salirasib in HCC cell lines is associated with mTOR inhibition independent of ERK or Akt activation .	The growth inhibitory effect of salirasib in HCC cell lines is associated with mTOR inhibition independent of ERK or Akt activation.	13	20	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	13	14	19	20
Considering that accumulated adverse side effects produced by a combination of therapies that inhibits multiple canonical signaling pathways , and that the mTOR inhibition induced feedback activation of upstream receptor tyrosine kinases and AKT and ERK signaling that may reduce anti-tumor effects of mTOR inhibitors , targeting 4E-BP1-regulated translation that can block upstream oncogenic signals on the expression of multiple , important oncoproteins may provide a potentially viable therapeutic strategy against the metastatic progression of cancer with less toxicity .	Considering that accumulated adverse side effects produced by a combination of therapies that inhibits multiple canonical signaling pathways, and that the mTOR inhibition induced feedback activation of upstream receptor tyrosine kinases and AKT and ERK signaling that may reduce anti-tumor effects of mTOR inhibitors, targeting 4E-BP1-regulated translation that can block upstream oncogenic signals on the expression of multiple, important oncoproteins may provide a potentially viable therapeutic strategy against the metastatic progression of cancer with less toxicity.	22	36	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	22	23	33	34
PIP3 anchors AKT to the membrane , where AKT is activated through its phosphorylation by phosphoinositide dependent kinase-1 ( PDK1 ) and mammalian target of rapamycin complex 2 ( mTORC2 ) .	PIP3 anchors AKT to the membrane, where AKT is activated through its phosphorylation by phosphoinositide dependent kinase-1 (PDK1) and mammalian target of rapamycin complex 2 (mTORC2).	8	26	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	22	26	8	9
Inhibition of mTOR has been shown to activate receptor signaling and reactivate PI3K and AKT , whereas AKT inhibition inhibits AKT but still reactivates PI3K .	Inhibition of mTOR has been shown to activate receptor signaling and reactivate PI3K and AKT, whereas AKT inhibition inhibits AKT but still reactivates PI3K.	0	15	reactivate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	14	15
Receptor mediated activation of PI3K family kinases generates inositol phospholipids that activate the protein kinase Akt , which phosphorylates multiple substrates including Foxo transcription factors , glycogen synthase kinase ( GSK3beta ) , and the mammalian target of rapamycin ( mTOR ) .	Receptor mediated activation of PI3K family kinases generates inositol phospholipids that activate the protein kinase Akt, which phosphorylates multiple substrates including Foxo transcription factors, glycogen synthase kinase (GSK3beta), and the mammalian target of rapamycin (mTOR).	11	39	activate	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	35	39	15	16
One explanation is that activation of Ras and Raf signaling pathways and the mTOR signaling cascade , may limit the efficacy of Akt and PKB targeted therapy , and suggests that the feedback phosphorylation of Akt and activation of the PI3K and Akt pathway may be a mechanism for resistance .	One explanation is that activation of Ras and Raf signaling pathways and the mTOR signaling cascade, may limit the efficacy of Akt and PKB targeted therapy, and suggests that the feedback phosphorylation of Akt and activation of the PI3K and Akt pathway may be a mechanism for resistance.	13	25	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	13	14	22	23
6 However , inhibition of mTOR Complex 1 ( mTORC1 ) by RAD001 may induce upstream AKT upregulation .	6 However, inhibition of mTOR Complex 1 (mTORC1) by RAD001 may induce upstream AKT upregulation.	5	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	5	6	16	17
It was also found that mTOR inhibition by BA145 triggered Akt activation via feedback loop involving IGFR and PI3k signaling .	It was also found that mTOR inhibition by BA145 triggered Akt activation via feedback loop involving IGFR and PI3k signaling.	5	11	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	10	11
At the plasma membrane , AKT is fully activated upon phosphorylation by 3-phosphoinositide-dependent kinase ( PDK1 ) and the rapamycin-insensitive mammalian target of rapamycin complex ( mTORC2 ) .	At the plasma membrane, AKT is fully activated upon phosphorylation by 3-phosphoinositide-dependent kinase (PDK1) and the rapamycin-insensitive mammalian target of rapamycin complex (mTORC2).	5	24	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	20	24	5	6
Activated AKT positively modulates mammalian target of rapamycin ( mTOR ) function .	Activated AKT positively modulates mammalian target of rapamycin (mTOR) function.	0	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	4	8	1	2
Akt has been shown to directly phosphorylate and activate mTOR as well as mTOR can negatively regulate PI3K and Akt activity .	Akt has been shown to directly phosphorylate and activate mTOR as well as mTOR can negatively regulate PI3K and Akt activity.	0	20	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	Akt has been shown to directly phosphorylate and activate mTOR	mtor	Akt	Akt	akt	9	10	19	20
In early studies mTOR inhibition led to p70 ribosomal protein S6 kinase ( S6K ) suppression , IRS1 upregulation , and PI3K-AKT activation 181 .	In early studies mTOR inhibition led to p70 ribosomal protein S6 kinase (S6K) suppression, IRS1 upregulation, and PI3K-AKT activation 181.	3	22	led	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	21	22
Additionally , experiments with Tsc2 +/- and Pten +/- mice have shown that benign tumors arise in Tsc2 +/- mice and more aggressive tumors arise in Tsc2 +/- Pten +/- mice , thus suggesting that loss of Tsc2 creates an inhibitor feedback loop , in which mTOR or one of its downstream effectors suppresses Akt , which is overcome with loss of Pten .	Additionally, experiments with Tsc2 +/- and Pten +/- mice have shown that benign tumors arise in Tsc2 +/- mice and more aggressive tumors arise in Tsc2 +/- Pten +/- mice, thus suggesting that loss of Tsc2 creates an inhibitor feedback loop, in which mTOR or one of its downstream effectors suppresses Akt, which is overcome with loss of Pten.	46	58	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	46	47	54	55
Recent data demonstrate that mTOR inhibition can lead to activation of the mitogen activated protein kinase ( MAPK ) and Akt pathways and that targeting these pathways enhanced mTOR efficacy .	Recent data demonstrate that mTOR inhibition can lead to activation of the mitogen activated protein kinase (MAPK) and Akt pathways and that targeting these pathways enhanced mTOR efficacy.	4	21	lead	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	20	21
Phospho signaling studies in samples with CRLF2-re with or without JAK2 mutation showed findings consistent with cell lines studies , i.e. greater inhibition of AKT and mTOR outputs upon JAK2 and mTOR inhibitors combinations , whereby only AZD2014 based combinations were capable of inhibiting p-4E-BP1 .	Phospho signaling studies in samples with CRLF2-re with or without JAK2 mutation showed findings consistent with cell lines studies, i.e. greater inhibition of AKT and mTOR outputs upon JAK2 and mTOR inhibitors combinations, whereby only AZD2014 based combinations were capable of inhibiting p-4E-BP1.	22	27	inhibition	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	26	27	24	25
Inhibition of mTOR Complex 1 ( mTORC1 ) can activate AKT , an effect attributed to Ribosomal S6 Kinase 1 ( S6K1 ) -mediated feedback mechanisms XREF_BIBR , XREF_BIBR - XREF_BIBR .	Inhibition of mTOR Complex 1 (mTORC1) can activate AKT, an effect attributed to Ribosomal S6 Kinase 1 (S6K1) -mediated feedback mechanisms XREF_BIBR, XREF_BIBR - XREF_BIBR.	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	10	11
Moreover , LY294002 , a PI3K inhibitor , reversed the rapamycin ( a mTOR inhibitor )-induced activation of Akt in PC3 PDGF-D cells , suggesting that prolonged exposure of cells to PDGF-D activates the mTOR pathway , which , in turn , represses Akt activity in PC3 PDGF-D cells through a PI3K dependent manner [ XREF_BIBR ] .	Moreover, LY294002, a PI3K inhibitor, reversed the rapamycin (a mTOR inhibitor)-induced activation of Akt in PC3 PDGF-D cells, suggesting that prolonged exposure of cells to PDGF-D activates the mTOR pathway, which, in turn, represses Akt activity in PC3 PDGF-D cells through a PI3K dependent manner [XREF_BIBR].	34	44	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	34	35	43	44
The phosphorylation of Akt , mTOR and S6 ribosomal protein in response to Nrf2 overexpression was inhibited by overexpression of Keap1 ( XREF_FIG ) , supporting the notion that Nrf2 modulates the PI3K and Akt pathway .	The phosphorylation of Akt, mTOR and S6 ribosomal protein in response to Nrf2 overexpression was inhibited by overexpression of Keap1 (XREF_FIG), supporting the notion that Nrf2 modulates the PI3K and Akt pathway.	1	35	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of Akt, mTOR and S6 ribosomal protein in response to Nrf2 overexpression was inhibited by overexpression of Keap1	mtor	Akt	Akt	akt	5	6	34	35
We and others previously reported that inhibition of mTOR ( i.e ., mTOR and raptor complex ) with rapamycin or its related derivatives induces feedback activation of the Akt survival pathway in various types of cancer cells and cancer specimens exposed to an mTOR inhibitor XREF_BIBR , XREF_BIBR .	We and others previously reported that inhibition of mTOR (i.e., mTOR and raptor complex) with rapamycin or its related derivatives induces feedback activation of the Akt survival pathway in various types of cancer cells and cancer specimens exposed to an mTOR inhibitor XREF_BIBR, XREF_BIBR.	6	30	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	8	9	28	29
We further showed that Akt activation upon p53 expression is mediated by mammalian target of rapamycin complex 2 .	We further showed that Akt activation upon p53 expression is mediated by mammalian target of rapamycin complex 2.	4	16	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	12	16	4	5
Since mTOR inhibition promotes hyperactivation of the PI3K and Akt pathway , which could limit the drug treatment efficacy , most of current trials take advantage of combined therapies by administering dual PI3K-mTOR inhibitor or new generation compounds such as ATP-competitive mTOR inhibitors , which inhibit both mTORC1 and mTORC2 [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Since mTOR inhibition promotes hyperactivation of the PI3K and Akt pathway, which could limit the drug treatment efficacy, most of current trials take advantage of combined therapies by administering dual PI3K-mTOR inhibitor or new generation compounds such as ATP-competitive mTOR inhibitors, which inhibit both mTORC1 and mTORC2 [XREF_BIBR, XREF_BIBR - XREF_BIBR].	1	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	1	2	9	10
Further , preclinical studies and sequential biopsies in patients treated in a Phase I trial of mTOR inhibitors have determined that mTOR inhibition induces feedback loop activation of Akt , a mechanism that may potentially limit its antitumor activity .	Further, preclinical studies and sequential biopsies in patients treated in a Phase I trial of mTOR inhibitors have determined that mTOR inhibition induces feedback loop activation of Akt, a mechanism that may potentially limit its antitumor activity.	21	31	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	21	22	28	29
Inhibition of mTOR in cancer cell lines and in patient tumor biopsies causes activation of AKT kinase , which is associated with induction of IRS1 but could be prevented by IGF1R inhibition .	Inhibition of mTOR in cancer cell lines and in patient tumor biopsies causes activation of AKT kinase, which is associated with induction of IRS1 but could be prevented by IGF1R inhibition.	0	16	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	15	16
Interestingly , inhibition of mTOR activates PI3K and Akt by up-regulating IGF-1R signaling .	Interestingly, inhibition of mTOR activates PI3K and Akt by up-regulating IGF-1R signaling.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	8	9
A recent report showed that mTOR inhibition activates PI3-kinase and Akt by up-regulating IGF-1R signaling in acute myeloid leukemia mostly due to up-regulation IRS-2 .	A recent report showed that mTOR inhibition activates PI3-kinase and Akt by up-regulating IGF-1R signaling in acute myeloid leukemia mostly due to up-regulation IRS-2.	5	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	10	11
mTOR inhibition led to activation of upstream receptor tyrosine kinases ( RTKs ) and AKT , which may attenuate the efficacy of mTOR kinase inhibitors .	mTOR inhibition led to activation of upstream receptor tyrosine kinases (RTKs) and AKT, which may attenuate the efficacy of mTOR kinase inhibitors.	0	18	led	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	14	15
Moreover , S9 overcomes drug resistance caused by low expression of 4E-BP1 or overexpression of Bcr-Abl ( XREF_FIG ) and circumvents Akt activation triggered by mTOR inhibition .	Moreover, S9 overcomes drug resistance caused by low expression of 4E-BP1 or overexpression of Bcr-Abl (XREF_FIG) and circumvents Akt activation triggered by mTOR inhibition.	21	26	triggered	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	25	26	21	22
In the case of Akt and mTOR combinatorial therapy , the fact that mTOR inhibition can induce Akt activation through IRS-1 may explain why targeting the same pathway at multiple sites is associated with better efficacy .	In the case of Akt and mTOR combinatorial therapy, the fact that mTOR inhibition can induce Akt activation through IRS-1 may explain why targeting the same pathway at multiple sites is associated with better efficacy.	13	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	13	14	17	18
Previous findings reveal that inhibition of mTOR by rapamycin can activate Akt and ERK1/2 .	Previous findings reveal that inhibition of mTOR by rapamycin can activate Akt and ERK1/2.	4	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	6	7	11	12
Similarly , mammalian target of rapamycin ( m-TOR ) inhibitors can activate PI3K-Akt pathway via loss of negative feedback on IRS-1 ( insulin receptor substrate -- 1 ) , an effect that can be suppressed by IGF-1R blockade [ XREF_BIBR - XREF_BIBR ] .	Similarly, mammalian target of rapamycin (m-TOR) inhibitors can activate PI3K-Akt pathway via loss of negative feedback on IRS-1 (insulin receptor substrate -- 1), an effect that can be suppressed by IGF-1R blockade [XREF_BIBR - XREF_BIBR].	2	13	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	PI3K-Akt	PI3K-Akt	PI3K-Akt	2	6	12	13
mTOR inhibition results in AKT activation , and counteracting this activation with Tz or the AKT inhibitor improves response to treatment .	mTOR inhibition results in AKT activation, and counteracting this activation with Tz or the AKT inhibitor improves response to treatment.	0	6	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	4	5
Our data support a model in which rapamycin blocks translation of RTP801 , thereby relieving RTP801 inhibition of mTOR and , consequently , of the survival promoting kinase Akt ( XREF_FIG ) .	Our data support a model in which rapamycin blocks translation of RTP801, thereby relieving RTP801 inhibition of mTOR and, consequently, of the survival promoting kinase Akt (XREF_FIG).	14	30	promoting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	18	19	28	29
However , ligation of either HLA class I or class II with antibodies activates mammalian target of rapamycin ( mTOR ) signaling through the SRC and FAK-PI 3K-AKT pathway and increases Akt dependent cell survival signaling , through upregulation of Bcl-2 and HO-1 .	However, ligation of either HLA class I or class II with antibodies activates mammalian target of rapamycin (mTOR) signaling through the SRC and FAK-PI 3K-AKT pathway and increases Akt dependent cell survival signaling, through upregulation of Bcl-2 and HO-1.	17	32	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	19	20	31	32
Akt is activated by mTOR inhibition but does not account for cell protection While in most cancer related models the mTOR cascade exerts antiapoptotic functions downstream of the PI3 kinase and AkT PKB signaling axis [ XREF_BIBR ] , few examples of cell protection by inhibition of mTOR and S6K have been reported [ XREF_BIBR - XREF_BIBR ] .	Akt is activated by mTOR inhibition but does not account for cell protection While in most cancer related models the mTOR cascade exerts antiapoptotic functions downstream of the PI3 kinase and AkT PKB signaling axis [XREF_BIBR], few examples of cell protection by inhibition of mTOR and S6K have been reported [XREF_BIBR - XREF_BIBR].	0	9	activated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	0	1
PTEN is a dual specificity phosphatase that inhibits both the PI3K and AKT and MAPK pathways , and thus curbs mTOR signaling ( reviewed in ) .	PTEN is a dual specificity phosphatase that inhibits both the PI3K and AKT and MAPK pathways, and thus curbs mTOR signaling (reviewed in).	7	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	20	21	12	13
Akt suppression of autophagy can be mediated by activation of mTOR , which inhibits the autophagy initiating ULK1 kinase complex .	Akt suppression of autophagy can be mediated by activation of mTOR, which inhibits the autophagy initiating ULK1 kinase complex.	0	13	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	10	11	0	1
Akt and mTOR afford attractive therapeutic targets in cancer yet , due to pathways ' interactions , inhibitors of mTOR frequently activate Akt and vise versa .	Akt and mTOR afford attractive therapeutic targets in cancer yet, due to pathways ' interactions, inhibitors of mTOR frequently activate Akt and vise versa.	17	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	19	20	22	23
In response to PI3K activation , PDK1 and the mammalian target of rapamycin mTOR , acting in the rapamycin-insensitive TORC2 complex , activate Akt via phosphorylation of two key residues , T308 and S473 .	In response to PI3K activation, PDK1 and the mammalian target of rapamycin mTOR, acting in the rapamycin-insensitive TORC2 complex, activate Akt via phosphorylation of two key residues, T308 and S473.	10	25	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	13	14	23	24
Rapamycin treatment inhibits phosphorylation of the mTOR targets p70 S6 kinase and Akt in skin gammadelta T cells .	Rapamycin treatment inhibits phosphorylation of the mTOR targets p70 S6 kinase and Akt in skin gammadelta T cells.	3	17	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	phosphorylation of the mTOR	mtor	Akt	Akt	akt	6	7	12	13
Recent study indicates that mTOR inhibition by rapamycin triggers rapid and sustained activation of PI3K and Akt survival pathway in human lung and other types of cancer cells [ XREF_BIBR ] .	Recent study indicates that mTOR inhibition by rapamycin triggers rapid and sustained activation of PI3K and Akt survival pathway in human lung and other types of cancer cells [XREF_BIBR].	4	18	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	16	17
Numerous studies have shown that mammalian target of rapamycin ( mTOR ) inhibitor activates Akt signaling pathway via a negative feedback loop while inhibiting mTORC1 signaling .	Numerous studies have shown that mammalian target of rapamycin (mTOR) inhibitor activates Akt signaling pathway via a negative feedback loop while inhibiting mTORC1 signaling.	5	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	5	9	14	15
We further found that mTOR inhibition by rapamycin activates Akt , probably through relieving the negative feedback inhibition by mTOR-S6K1 [ XREF_BIBR ] .	We further found that mTOR inhibition by rapamycin activates Akt, probably through relieving the negative feedback inhibition by mTOR-S6K1 [XREF_BIBR].	4	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	9	10
The latter finding is consistent with the results of other studies showing that in some tumor model systems , the inhibition of mTOR with rapamycin activates PI3K and Akt pathway through a feedback loop resulting in increased p-Akt expression [ XREF_BIBR ] .	The latter finding is consistent with the results of other studies showing that in some tumor model systems, the inhibition of mTOR with rapamycin activates PI3K and Akt pathway through a feedback loop resulting in increased p-Akt expression [XREF_BIBR].	20	29	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	22	23	28	29
mTOR kinase inhibition causes feedback dependent biphasic regulation of AKT signaling .	mTOR kinase inhibition causes feedback dependent biphasic regulation of AKT signaling.	0	10	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	9	10
A key IGF-1 pathway is regulated by phosphatidylinositol-3 kinase ( PI3K ) and its downstream partner , the mammalian target of rapamycin ( mTOR ) , which upregulates Akt driving growth .	A key IGF-1 pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of rapamycin (mTOR), which upregulates Akt driving growth.	18	29	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	18	22	28	29
mTOR inhibition by rapamycin can cancel this negative feedback and activate Akt in some cancer cell lines and tumor samples , but the potential clinical impact is unknown [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	mTOR inhibition by rapamycin can cancel this negative feedback and activate Akt in some cancer cell lines and tumor samples, but the potential clinical impact is unknown [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	11	12
Inhibition of mTOR signaling by rapamycin has been demonstrated to activate ERK1/2 and Akt in various types of cancer cells , which contributes to rapamycin resistance .	Inhibition of mTOR signaling by rapamycin has been demonstrated to activate ERK1/2 and Akt in various types of cancer cells, which contributes to rapamycin resistance.	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	13	14
The opposing effects of PI3K-Akt versus mTOR inhibition on Treg may be explained by a feedback loop in which mTOR Inhibition results in PI3K dependent Akt activation , and which , in turn , sustains signaling through mTOR .	The opposing effects of PI3K-Akt versus mTOR inhibition on Treg may be explained by a feedback loop in which mTOR Inhibition results in PI3K dependent Akt activation, and which, in turn, sustains signaling through mTOR.	19	27	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	19	20	25	26
In the absence of the TSC1 and TSC2 brake , mTOR activity is unleashed to inhibit Akt via an inhibitory feedback mechanism .	In the absence of the TSC1 and TSC2 brake, mTOR activity is unleashed to inhibit Akt via an inhibitory feedback mechanism.	10	21	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	10	11	16	17
Cytarabine induced autophagy in leukemic cells is associated with mTOR inhibition and modulation of Akt , AMPK and ERK .	Cytarabine induced autophagy in leukemic cells is associated with mTOR inhibition and modulation of Akt, AMPK and ERK.	9	18	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	9	10	14	15
Our rationale for adding an EGFR and HER2 inhibitor to the mTOR inhibitor was based on reports that inhibition of mTOR can cause feedback activation of Akt via receptor tyrosine kinases [ XREF_BIBR ] .	Our rationale for adding an EGFR and HER2 inhibitor to the mTOR inhibitor was based on reports that inhibition of mTOR can cause feedback activation of Akt via receptor tyrosine kinases [XREF_BIBR].	18	30	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	20	21	26	27
Thus , mTOR inhibition by Rapamycin or TSC1/2 results in increased PI3K-Akt activation .	Thus, mTOR inhibition by Rapamycin or TSC1/2 results in increased PI3K-Akt activation.	2	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	PI3K-Akt	PI3K-Akt	PI3K-Akt	2	3	11	12
Akt targets including glycogen synthase kinase-3beta ( GSK-3beta ) [ XREF_BIBR ] , mammalian target of rapamycin ( mTOR ) [ XREF_BIBR ] , endothelial nitric oxide synthase ( eNOS or NOS3 ) [ XREF_BIBR , XREF_BIBR ] , 6-phospho-fructo-2-kinase ( PFK2 ) [ XREF_BIBR ] , c-Raf ( a serine/threonine kinase ) [ XREF_BIBR ] and several anti-apoptotic effectors [ XREF_BIBR - XREF_BIBR ] are localized throughout the cell in cytoplasmic , mitochondrial and nuclear compartments .	Akt targets including glycogen synthase kinase-3beta (GSK-3beta) [XREF_BIBR], mammalian target of rapamycin (mTOR) [XREF_BIBR], endothelial nitric oxide synthase (eNOS or NOS3) [XREF_BIBR, XREF_BIBR], 6-phospho-fructo-2-kinase (PFK2) [XREF_BIBR], c-Raf (a serine/threonine kinase) [XREF_BIBR] and several anti-apoptotic effectors [XREF_BIBR - XREF_BIBR] are localized throughout the cell in cytoplasmic, mitochondrial and nuclear compartments.	0	17	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	13	17	0	1
As in other cell types , mTOR inhibition induces Akt activation in pituitary cells in vitro , and this may contribute to resistance to mTOR inhibitors , which may limit their clinical efficacy .	As in other cell types, mTOR inhibition induces Akt activation in pituitary cells in vitro, and this may contribute to resistance to mTOR inhibitors, which may limit their clinical efficacy.	6	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	6	7	9	10
SMC differentiation is promoted by activating phosphatidylinositol 3-kinase ( PI3K ) and Akt which are negatively regulated by mTOR and S6 kinase 1 ( S6K1 ) .	SMC differentiation is promoted by activating phosphatidylinositol 3-kinase (PI3K) and Akt which are negatively regulated by mTOR and S6 kinase 1 (S6K1).	3	24	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	18	19	12	13
Pharmacological inhibition of the Akt effector , mammalian target of rapamycin ( mTOR ) , with rapamycin prevents the morphological disruption elicited by Akt activation , including its effect on cell size and number , and the cooperative effect of Akt on oncogene driven proliferation , indicating that mTOR function is required for the multiple biological effects of Akt activation during morphogenesis .	Pharmacological inhibition of the Akt effector, mammalian target of rapamycin (mTOR), with rapamycin prevents the morphological disruption elicited by Akt activation, including its effect on cell size and number, and the cooperative effect of Akt on oncogene driven proliferation, indicating that mTOR function is required for the multiple biological effects of Akt activation during morphogenesis.	7	42	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	7	11	40	41
mTOR pathway inhibition in MTC tumor cells does not induce MAPK or AKT pathway activation .	mTOR pathway inhibition in MTC tumor cells does not induce MAPK or AKT pathway activation.	0	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	12	13
These results demonstrate the existence of a negative regulatory loop where mTOR inhibition induces the activation of Akt in mouse gliomas , as shown to be the case in various tumor types XREF_BIBR , XREF_BIBR .	These results demonstrate the existence of a negative regulatory loop where mTOR inhibition induces the activation of Akt in mouse gliomas, as shown to be the case in various tumor types XREF_BIBR, XREF_BIBR.	11	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	11	12	17	18
Conversely , mTOR inhibition also promotes Akt activation through a feedback loop , but this compensatory mechanism can be blocked via IGF-IR inhibition .	Conversely, mTOR inhibition also promotes Akt activation through a feedback loop, but this compensatory mechanism can be blocked via IGF-IR inhibition.	2	7	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	6	7
16 Preclinical evidence indicates that isolated mTOR inhibition alleviates feedback inhibition on PI3K and thereby allows restoration of PI3K and downstream AKT signaling .	16 Preclinical evidence indicates that isolated mTOR inhibition alleviates feedback inhibition on PI3K and thereby allows restoration of PI3K and downstream AKT signaling.	6	22	allows	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	6	7	21	22
AKT signals through the phosphorylation and subsequent activation or inhibition of downstream substrates , such as mammalian target of rapamycin complex 1 ( mTORC1 ) or glycogen synthase kinase 3 beta ( GSK-3beta ) , respectively .	AKT signals through the phosphorylation and subsequent activation or inhibition of downstream substrates, such as mammalian target of rapamycin complex 1 (mTORC1) or glycogen synthase kinase 3 beta (GSK-3beta), respectively.	0	20	signals	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	16	20	0	1
NVP-BEZ235 activates ERK in some cancer cells 28 whereas we did not observe an ERK activation in our polycystic kidney models , nor in primary renal tubular epithelial cells XREF_BIBR , XREF_BIBR , XREF_BIBR Thus , dual mTOR and PI3K inhibition abrogates the up-regulation of Akt and ERK signaling pathways .	NVP-BEZ235 activates ERK in some cancer cells 28 whereas we did not observe an ERK activation in our polycystic kidney models, nor in primary renal tubular epithelial cells XREF_BIBR, XREF_BIBR, XREF_BIBR Thus, dual mTOR and PI3K inhibition abrogates the up-regulation of Akt and ERK signaling pathways.	36	49	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	37	38	45	46
We next sought to determine whether 4EBP1 is the relevant PP242 pharmacological target , downstream of mTOR , responsible for PP242 induced cell death of AKT T tumor cells .	We next sought to determine whether 4EBP1 is the relevant PP242 pharmacological target, downstream of mTOR, responsible for PP242 induced cell death of AKT T tumor cells.	14	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	16	17	25	26
Indeed , inhibition of mTOR is known to activate PI3K and AKT signaling via the operation of well established negative feedback loops sparked by mTOR feeding back at the level of PI3K and AKT activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Indeed, inhibition of mTOR is known to activate PI3K and AKT signaling via the operation of well established negative feedback loops sparked by mTOR feeding back at the level of PI3K and AKT activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	4	5	11	12
Indeed , mTOR inhibition increases Akt activity via the IGF-IR pathway , leading to the reduction of mTOR inhibitor effects .	Indeed, mTOR inhibition increases Akt activity via the IGF-IR pathway, leading to the reduction of mTOR inhibitor effects.	2	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	5	6
Inhibition of mTOR signaling pathways in cancer can promote activation of PI 3-K , Akt , and Ras-mitogen activated protein kinase ( MAPK ) signaling that foster further tumourigenesis .	Inhibition of mTOR signaling pathways in cancer can promote activation of PI 3-K, Akt, and Ras-mitogen activated protein kinase (MAPK) signaling that foster further tumourigenesis.	2	15	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	14	15
Inhibition of mTOR induces feedback activation of AKT , which may potentially counteract antitumor effects of mTOR inhibitors .	Inhibition of mTOR induces feedback activation of AKT, which may potentially counteract antitumor effects of mTOR inhibitors.	0	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	7	8
mTOR kinase inhibitors ( mTorKIs ) do not cause Akt feedback activation observed with Rapalogs .	mTOR kinase inhibitors (mTorKIs) do not cause Akt feedback activation observed with Rapalogs.	0	11	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	9	10
Dual PI3K and mTOR inhibitors target the active sites of both the PI3K and mTOR , inhibiting the PI3K/Akt/mTOR pathway both upstream and downstream of Akt , thus avoiding the Akt activation following abolition of the mTORC1/S6K1/insulin receptor substrate 1 negative feedback loop , which is known to occur with rapalogs 61 .	Dual PI3K and mTOR inhibitors target the active sites of both the PI3K and mTOR, inhibiting the PI3K/Akt/mTOR pathway both upstream and downstream of Akt, thus avoiding the Akt activation following abolition of the mTORC1/S6K1/insulin receptor substrate 1 negative feedback loop, which is known to occur with rapalogs 61.	8	26	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	14	15	25	26
Inhibition of the mTOR complex 1 ( mTORC1 ) by rapamycin and rapalogues everolimus and temsirolimus has been found to activate PI3K-Akt via a pro oncogenic feedback loop that can be suppressed by IGF-1R blockade [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Inhibition of the mTOR complex 1 (mTORC1) by rapamycin and rapalogues everolimus and temsirolimus has been found to activate PI3K-Akt via a pro oncogenic feedback loop that can be suppressed by IGF-1R blockade [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	PI3K-Akt	PI3K-Akt	PI3K-Akt	3	4	21	22
Given recent investigations implicating mTOR signaling in ceramide induced inhibition of Akt activity , we investigated levels of mTOR and found a significant increase in mTOR protein content ( XREF_FIG ) after overfeeding .	Given recent investigations implicating mTOR signaling in ceramide induced inhibition of Akt activity, we investigated levels of mTOR and found a significant increase in mTOR protein content (XREF_FIG) after overfeeding.	4	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	11	12
A recent study in SCC cell lines demonstrates that inhibition of mTOR induces activation of Akt and results in antitumor effects in this tumour type ( Amornphimoltham et al , 2005 ) .	A recent study in SCC cell lines demonstrates that inhibition of mTOR induces activation of Akt and results in antitumor effects in this tumour type (Amornphimoltham et al, 2005).	9	16	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	11	12	15	16
The serine/threonine kinase mammalian target of rapamycin ( mTOR ) is a downstream target of PI3K and AKT that regulates mRNA translation in mammalian cells , controlling cell growth and proliferation .	The serine/threonine kinase mammalian target of rapamycin (mTOR) is a downstream target of PI3K and AKT that regulates mRNA translation in mammalian cells, controlling cell growth and proliferation.	3	18	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	3	7	17	18
In addition , AKT downstream targets such as mammalian target of rapamycin complex 2 ( mTORC2 ) and GSK3beta have been described as cytoskeleton regulators [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, AKT downstream targets such as mammalian target of rapamycin complex 2 (mTORC2) and GSK3beta have been described as cytoskeleton regulators [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	12	targets	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	8	12	3	4
Recently , it was demonstrated that the combination of PIK3CA and mTOR inhibitors could prevent the increase in AKT signaling caused by mTOR inhibition alone [ XREF_BIBR ] .	Recently, it was demonstrated that the combination of PIK3CA and mTOR inhibitors could prevent the increase in AKT signaling caused by mTOR inhibition alone [XREF_BIBR].	18	23	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	22	23	18	19
We found that PTEN deficient bladder tumour cells were indeed more resistant to rapamycin than PTEN positive cells because of their inability to abrogate the activation of the pro survival Akt signaling cascade induced by mTOR inhibition itself .	We found that PTEN deficient bladder tumour cells were indeed more resistant to rapamycin than PTEN positive cells because of their inability to abrogate the activation of the pro survival Akt signaling cascade induced by mTOR inhibition itself.	30	36	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	35	36	30	31
In light of the fact that emergence of resistant RCC remain a significant clinical challenge , emerging evidence has indicated involvement of feed-back activation of PI3K-Akt node in patients treated with therapies targeting mToR complex [ XREF_BIBR ] .	In light of the fact that emergence of resistant RCC remain a significant clinical challenge, emerging evidence has indicated involvement of feed-back activation of PI3K-Akt node in patients treated with therapies targeting mToR complex [XREF_BIBR].	25	34	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	mToR	mToR	mToR	PI3K-Akt	PI3K-Akt	PI3K-Akt	33	34	25	26
Mammalian target of rapamycin ( mTOR ) , a serine/threonine kinase involved in diverse cellular processes , including protein translation , mRNA turnover , and protein stability , mediates , at least in part , some of the biological actions of Akt .	Mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in diverse cellular processes, including protein translation, mRNA turnover, and protein stability, mediates, at least in part, some of the biological actions of Akt.	3	42	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	41	42
Dual inhibition of PI3K and mTOR also increases activation of JAK2 and STAT5 to promote the reactivation of Akt [ XREF_BIBR ] .	Dual inhibition of PI3K and mTOR also increases activation of JAK2 and STAT5 to promote the reactivation of Akt [XREF_BIBR].	1	20	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	18	19
Direct inhibition of mTOR kinase can induce PI3K-AKT signaling by relieving mTOR dependent feedback inhibition .	Direct inhibition of mTOR kinase can induce PI3K-AKT signaling by relieving mTOR dependent feedback inhibition.	3	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	7	8
At variance , mTOR knockdown , triggering a feedback loop , induces AKT over-activation and does not affect proliferation .	At variance, mTOR knockdown, triggering a feedback loop, induces AKT over-activation and does not affect proliferation.	3	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	3	4	12	13
IGF-1 also rescued ATP levels , reduced AMPK phosphorylation and increased p70 ( S6K ) phosphorylation , which indicates that in addition to Akt and mTOR , IGF-1 inhibits autophagy by the AMPK and mTOR axis .	IGF-1 also rescued ATP levels, reduced AMPK phosphorylation and increased p70 (S6K) phosphorylation, which indicates that in addition to Akt and mTOR, IGF-1 inhibits autophagy by the AMPK and mTOR axis.	20	35	inhibits	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	34	35	23	24
Via this mechanism , metformin counteracts the oncogenic AKT activation that is induced by mTOR inhibition [ XREF_BIBR , XREF_BIBR ] .	Via this mechanism, metformin counteracts the oncogenic AKT activation that is induced by mTOR inhibition [XREF_BIBR, XREF_BIBR].	8	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	14	15	8	9
57 Mechanistic target of rapamycin ( mTOR ) is a direct target of Akt for the regulation of cell growth , autophagy , and metabolism .	57 Mechanistic target of rapamycin (mTOR) is a direct target of Akt for the regulation of cell growth, autophagy, and metabolism.	1	16	is a direct target	Positive_activation_copula_1	Positive_activation	Positive_activation	Mechanistic target of rapamycin	Mechanistic target of rapamycin	Mechanistic target of rapamycin	Akt	Akt	Akt	1	5	13	14
XREF_BIBR PI-103 , a novel inhibitor of both PI3K and mTOR , has shown promising activity in both in vitro and in vivo models of malignant gliomas , possibly by blocking the activated PI3K and AKT induced by the mTOR inhibition .	XREF_BIBR PI-103, a novel inhibitor of both PI3K and mTOR, has shown promising activity in both in vitro and in vivo models of malignant gliomas, possibly by blocking the activated PI3K and AKT induced by the mTOR inhibition.	30	40	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	39	40	35	36
However , mTOR feedback inhibits the activity of the PI3K and Akt pathway and inhibition of mTOR could result in increased activity of the PI3K/Akt/NF-kB pathway .	However, mTOR feedback inhibits the activity of the PI3K and Akt pathway and inhibition of mTOR could result in increased activity of the PI3K/Akt/NF-kB pathway.	2	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	11	12
Upregulation of PI3K and AKT is frequently seen in tumors both when treated with chemotherapy and when mTOR has been inhibited .	Upregulation of PI3K and AKT is frequently seen in tumors both when treated with chemotherapy and when mTOR has been inhibited.	0	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	17	18	4	5
As shown earlier , the mammalian target of rapamycin , a potent inhibitor of autophagy , is a down-stream target of Akt , and chemical inhibition of the PI3K and Akt pathway in PTEN-deficit glioma cell lines increases autophagy XREF_BIBR .	As shown earlier, the mammalian target of rapamycin, a potent inhibitor of autophagy, is a down-stream target of Akt, and chemical inhibition of the PI3K and Akt pathway in PTEN-deficit glioma cell lines increases autophagy XREF_BIBR.	5	22	is a down-stream target	Positive_activation_copula_1	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	5	9	21	22
It is not clear how long-term inhibition of mTOR triggers Akt activation .	It is not clear how long-term inhibition of mTOR triggers Akt activation.	6	11	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	8	9	10	11
Mechanistic target of rapamycin complex ( mTORC2 ) enables the complete activation of AKT through phosphorylation of Ser473 .	Mechanistic target of rapamycin complex (mTORC2) enables the complete activation of AKT through phosphorylation of Ser473.	0	14	enables	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mechanistic target of rapamycin	Mechanistic target of rapamycin	Mechanistic target of rapamycin	AKT	AKT	AKT	0	4	13	14
However , inhibition of mTOR activates Akt survival signaling , which in turn attenuates mTOR inhibitors ' anticancer efficacy .	However, inhibition of mTOR activates Akt survival signaling, which in turn attenuates mTOR inhibitors ' anticancer efficacy.	2	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	6	7
We observed that both rapamycin and mTOR knockdown caused PI3K-Akt activation which may through a negative feedback loop originating from S6K1 as reported by other groups .	We observed that both rapamycin and mTOR knockdown caused PI3K-Akt activation which may through a negative feedback loop originating from S6K1 as reported by other groups.	6	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	PI3K-Akt	PI3K-Akt	PI3K-Akt	6	7	9	10
Reinduction of AKT activity in tumors treated with mTOR kinase inhibitors may attenuate the biologic and therapeutic effects of these drugs .	Reinduction of AKT activity in tumors treated with mTOR kinase inhibitors may attenuate the biologic and therapeutic effects of these drugs.	2	10	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	8	9	2	3
In addition , mTOR inhibition induces AKT activation via an IGF dependent mechanism , supporting the rationale for this combination [ XREF_BIBR ] .	In addition, mTOR inhibition induces AKT activation via an IGF dependent mechanism, supporting the rationale for this combination [XREF_BIBR].	3	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	3	4	6	7
We also noted that mTOR shRNA decreased P-S6 and P-Akt IF levels less efficiently than shRaptor and shRictor , respectively .	We also noted that mTOR shRNA decreased P-S6 and P-Akt IF levels less efficiently than shRaptor and shRictor, respectively.	4	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	P-Akt	P-Akt	P-Akt	4	5	9	10
Rapamycin , a highly selective allosteric and potent inhibitor of mTOR , reduced negative feedback and restored Akt signaling XREF_BIBR , but is not a viable candidate for the physiological modulation of mTOR and preservation of insulin content XREF_BIBR .	Rapamycin, a highly selective allosteric and potent inhibitor of mTOR, reduced negative feedback and restored Akt signaling XREF_BIBR, but is not a viable candidate for the physiological modulation of mTOR and preservation of insulin content XREF_BIBR.	8	19	restored	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	10	11	17	18
The catalytic PI3K isoforms can be regulated by receptor tyrosine kinases and/or G protein coupled receptors and activate AKT , serum and glucocorticoid regulated kinase ( SGK ) , phosphoinositide dependent kinase 1 ( PDK1 ) , mammalian target of rapamycin ( mTOR ) , and several other pathways that control a variety of cellular processes including proliferation , growth , apoptosis , migration , and metabolism 5 .	The catalytic PI3K isoforms can be regulated by receptor tyrosine kinases and/or G protein coupled receptors and activate AKT, serum and glucocorticoid regulated kinase (SGK), phosphoinositide dependent kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and several other pathways that control a variety of cellular processes including proliferation, growth, apoptosis, migration, and metabolism 5.	17	43	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	42	43	18	19
TSC2 is an AKT target , and when phosphorylated , inhibits Rheb , also a negative regulator of mTOR .	TSC2 is an AKT target, and when phosphorylated, inhibits Rheb, also a negative regulator of mTOR.	3	19	inhibits	Negative_regulation_syntax_1_verb	Positive_activation	Positive_regulation	mTOR	mTOR	mtor	AKT	AKT target, and when phosphorylated	akt	18	19	3	4
Host centrosome positioning at the Toxoplasma PV requires the function of the host mammalian target of rapamycin complex 2 ( mTORC2 ) , which activates the Akt signaling pathway .	Host centrosome positioning at the Toxoplasma PV requires the function of the host mammalian target of rapamycin complex 2 (mTORC2), which activates the Akt signaling pathway.	13	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	13	17	26	27
Reversal of this feedback loop by mTOR induces Akt activation .	Reversal of this feedback loop by mTOR induces Akt activation.	4	9	induces	Positive_activation_token_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	6	7	8	9
The Akt downstream target mTORC1 was likewise activated as indicated by both mTOR phosphorylation and phosphorylation of the mTORC1 target p70 S6K ( XREF_FIG ) .	The Akt downstream target mTORC1 was likewise activated as indicated by both mTOR phosphorylation and phosphorylation of the mTORC1 target p70 S6K (XREF_FIG).	0	14	activated	Positive_activation_syntax_4_verb	Positive_activation	Positive_activation	mTOR	mTOR phosphorylation	mtor	Akt	Akt	akt	12	13	1	2
Anecdotally , in many cell lines and patient tumour biopsies ( O'Reilly et al , 2006 ) , inhibition of mTOR activates Akt and inhibits downstream substrates ( FoxO transcription factors , Bad , and GSK3alpha and beta ) .	Anecdotally, in many cell lines and patient tumour biopsies (O'Reilly et al, 2006), inhibition of mTOR activates Akt and inhibits downstream substrates (FoxO transcription factors, Bad, and GSK3alpha and beta).	18	23	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	20	21	22	23
Mammalian target of rapamycin ( mTOR ) is a downstream target of Akt .	Mammalian target of rapamycin (mTOR) is a downstream target of Akt.	0	13	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	Akt	Akt	Akt	0	4	12	13
Moreover , co-current treatment with S9 and rapamycin completely attenuated the hyper-phosphorylation of Akt at Ser 473 induced by rapamycin ( XREF_FIG ) , indicating S9 could circumvent activation of Akt triggered by mTOR inhibition .	Moreover, co-current treatment with S9 and rapamycin completely attenuated the hyper-phosphorylation of Akt at Ser 473 induced by rapamycin (XREF_FIG), indicating S9 could circumvent activation of Akt triggered by mTOR inhibition.	28	34	triggered	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	33	34	30	31
Akt is then activated by PDK1 and mammalian target of rapamycin ( mTOR ) complex 2 ( mTORC2 ) through two distinct phosphorylation on T308 and S473 , respectively XREF_BIBR XREF_BIBR .	Akt is then activated by PDK1 and mammalian target of rapamycin (mTOR) complex 2 (mTORC2) through two distinct phosphorylation on T308 and S473, respectively XREF_BIBR XREF_BIBR.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	7	11	0	1
Moreover , prevention of Akt activation induced by mTOR inhibition exhibits enhanced cancer therapeutic efficacy in different preclinical studies [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Moreover, prevention of Akt activation induced by mTOR inhibition exhibits enhanced cancer therapeutic efficacy in different preclinical studies [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	9	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	8	9	4	5
Recently developed mTOR kinase inhibitors effectively block the activities of both complexes , thereby more dramatically inhibiting protein synthesis , suppressing AKT activation and inducing G 1 arrest or apoptosis in tumor cells as compared to rapamycin [ XREF_BIBR ] .	Recently developed mTOR kinase inhibitors effectively block the activities of both complexes, thereby more dramatically inhibiting protein synthesis, suppressing AKT activation and inducing G 1 arrest or apoptosis in tumor cells as compared to rapamycin [XREF_BIBR].	2	22	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	21	22
mTOR signaling inhibition by nonspecific allosteric inhibitors such as rapamycin suppressed p70S6 kinase activity but paradoxically also increased the activation of AKT and eIF4E , which attenuated the therapeutic efficacy of these agents .	mTOR signaling inhibition by nonspecific allosteric inhibitors such as rapamycin suppressed p70S6 kinase activity but paradoxically also increased the activation of AKT and eIF4E, which attenuated the therapeutic efficacy of these agents.	0	26	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	21	22
Importantly , Cixutumumab has been shown to abrogate AKT activation that was induced by mTOR inhibition in breast cancer cell lines .	Importantly, Cixutumumab has been shown to abrogate AKT activation that was induced by mTOR inhibition in breast cancer cell lines.	8	15	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	14	15	8	9
Early clinical trials of everolimus , an inhibitor of mammalian target of rapamycin ( mTOR ) which activates the AKT pathway , [ XREF_BIBR ] failed to show activity against GBM which was attributed to p-glycoprotein-mediated mutli-drug resistance pathway expression , [ XREF_BIBR ] drug detoxification , and/or the redundancy of growth pathways that circumvented inhibition of AKT .	Early clinical trials of everolimus, an inhibitor of mammalian target of rapamycin (mTOR) which activates the AKT pathway, [XREF_BIBR] failed to show activity against GBM which was attributed to p-glycoprotein-mediated mutli-drug resistance pathway expression, [XREF_BIBR] drug detoxification, and/or the redundancy of growth pathways that circumvented inhibition of AKT.	9	20	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	9	13	19	20
Western blot and QD-IHF studies indicate that inhibition of mTOR by RAD001 resulted in activation of AKT and upregulation of S184 Bax phosphorylation ( XREF_FIG ) .	Western blot and QD-IHF studies indicate that inhibition of mTOR by RAD001 resulted in activation of AKT and upregulation of S184 Bax phosphorylation (XREF_FIG).	7	22	resulted in activation	Positive_activation_syntax_8_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	9	10	16	17
In addition to directly activating Akt as part of mTORC2 , mTOR , as part of mTORC1 , also negatively regulates Akt by suppressing the growth factor driven pathways upstream of it .	In addition to directly activating Akt as part of mTORC2, mTOR, as part of mTORC1, also negatively regulates Akt by suppressing the growth factor driven pathways upstream of it.	11	22	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	11	12	21	22
AKT reactivation induced by mTOR inhibition in tumor cells is likely to reduce its antitumor effects by activating pathways that attenuate its effects on proliferation and apoptosis ; thus , it is an unexpected and potentially undesirable consequence of mTOR inhibition [ XREF_BIBR ] .	AKT reactivation induced by mTOR inhibition in tumor cells is likely to reduce its antitumor effects by activating pathways that attenuate its effects on proliferation and apoptosis; thus, it is an unexpected and potentially undesirable consequence of mTOR inhibition [XREF_BIBR].	0	5	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	4	5	0	1
It is known that mTOR inhibitor- can induce a feedback activation of Akt thus contributing to a lesser therapeutic efficiency XREF_BIBR .	It is known that mTOR inhibitor- can induce a feedback activation of Akt thus contributing to a lesser therapeutic efficiency XREF_BIBR.	4	14	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	12	13
XREF_BIBR , XREF_BIBR Blockade of mTOR alone paradoxically activates Akt .	XREF_BIBR, XREF_BIBR Blockade of mTOR alone paradoxically activates Akt.	3	10	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	9	10
mTOR inhibition with rapamycin prevents Akt mediated disruption of glandular morphology .	mTOR inhibition with rapamycin prevents Akt mediated disruption of glandular morphology.	0	7	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	5	6
PI3K and Akt signaling and downstream mediators , such as mammalian target of rapamycin ( mTOR ) and VEGF , contribute to oncogenesis through effects on multiple cellular processes , including proliferation , motility , angiogenesis , transformation , apoptosis and survival , and DNA repair .	PI3K and Akt signaling and downstream mediators, such as mammalian target of rapamycin (mTOR) and VEGF, contribute to oncogenesis through effects on multiple cellular processes, including proliferation, motility, angiogenesis, transformation, apoptosis and survival, and DNA repair.	0	14	signaling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	10	14	2	3
It has been shown that increased activation of the mTOR pathway can diminish the ability of Akt to function properly in fat fed obese rats [ XREF_BIBR ] .	It has been shown that increased activation of the mTOR pathway can diminish the ability of Akt to function properly in fat fed obese rats [XREF_BIBR].	9	17	diminish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	9	10	16	17
Inhibition of mTOR signaling often activates PI3Kinase and Akt pathway as a feedback mechanism in many cancers by up regulating insulin like growth factor-1 receptor ( IGF-IR ) signaling XREF_BIBR .	Inhibition of mTOR signaling often activates PI3Kinase and Akt pathway as a feedback mechanism in many cancers by up regulating insulin like growth factor-1 receptor (IGF-IR) signaling XREF_BIBR.	2	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	8	9
Therefore , combining KU-55933 with rapamycin may provide a highly effective approach for improving mammalian target of rapamycin targeted anticancer therapy that is currently hindered by rapamycin induced feedback activation of Akt .	Therefore, combining KU-55933 with rapamycin may provide a highly effective approach for improving mammalian target of rapamycin targeted anticancer therapy that is currently hindered by rapamycin induced feedback activation of Akt.	14	32	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	14	18	31	32
mTOR inhibition with the ATP-competitive kinase inhibitor AZD8055 induces receptor tyrosine kinase dependent feedback activation of AKT .	mTOR inhibition with the ATP-competitive kinase inhibitor AZD8055 induces receptor tyrosine kinase dependent feedback activation of AKT.	0	17	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	16	17
Accordingly , co-targeting mTOR and PI3K and Akt signaling prevents mTOR inhibition initiated Akt activation and enhances antitumor effects both in cell cultures and in animal xenograft models , suggesting an effective cancer therapeutic strategy .	Accordingly, co-targeting mTOR and PI3K and Akt signaling prevents mTOR inhibition initiated Akt activation and enhances antitumor effects both in cell cultures and in animal xenograft models, suggesting an effective cancer therapeutic strategy.	2	14	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	3	4	13	14
However , inhibition of mTOR is also known to cause feedback activation of Akt , whose over activation can lead to the development of cancer .	However, inhibition of mTOR is also known to cause feedback activation of Akt, whose over activation can lead to the development of cancer.	2	19	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	13	14
This finding contrasted previous studies in breast cancer that mTOR suppresses PI3K and AKT signalling XREF_BIBR XREF_BIBR .	This finding contrasted previous studies in breast cancer that mTOR suppresses PI3K and AKT signalling XREF_BIBR XREF_BIBR.	9	16	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	9	10	13	14
Consistently , acetate treatment also attenuated the phosphorylation of MSK2 , which is activated by ERK and p38 signalling , while the mTOR phosphorylation ( a target of Akt inhibition ) was enhanced [ XREF_FIG ] .	Consistently, acetate treatment also attenuated the phosphorylation of MSK2, which is activated by ERK and p38 signalling, while the mTOR phosphorylation (a target of Akt inhibition) was enhanced [XREF_FIG].	22	29	target	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	mTOR	mTOR phosphorylation	mtor	Akt	Akt	akt	22	23	28	29
Accordingly , simultaneous inhibition of mTOR and DNA-PK did not stimulate Akt activity and synergistically inhibited the growth of cancer cells both in vitro and in vivo .	Accordingly, simultaneous inhibition of mTOR and DNA-PK did not stimulate Akt activity and synergistically inhibited the growth of cancer cells both in vitro and in vivo.	3	12	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	11	12
Importantly , in HNSCC cells expressing mutant PIK3CA and RAS cetuximab prevented the upregulation of AKT activity caused by mTOR inhibition ( XREF_FIG ; Supplementary Figure 2 , B and D , available online ) .	Importantly, in HNSCC cells expressing mutant PIK3CA and RAS cetuximab prevented the upregulation of AKT activity caused by mTOR inhibition (XREF_FIG; Supplementary Figure 2, B and D, available online).	15	20	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	19	20	15	16
mTOR inhibition releases the inhibitory feedback loop on the insulin receptor substrate 1 ( IRS-1 ) and , therefore , upregulates PI3K and Akt in an IGF-1 and IGF-1R dependent manner XREF_BIBR , XREF_BIBR .	mTOR inhibition releases the inhibitory feedback loop on the insulin receptor substrate 1 (IRS-1) and, therefore, upregulates PI3K and Akt in an IGF-1 and IGF-1R dependent manner XREF_BIBR, XREF_BIBR.	0	24	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	0	1	23	24
Itraconazole also has been reported to inhibit mTOR activity and ATO has been reported to upregulate PTEN and degrade AKT .	Itraconazole also has been reported to inhibit mTOR activity and ATO has been reported to upregulate PTEN and degrade AKT.	7	20	degrade	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	7	8	19	20
Inhibitors of mTOR , such as miRNAs , can inhibit tumor cell growth in many cancers by blocking the AKT and mTOR signaling pathway [ XREF_BIBR - XREF_BIBR , XREF_BIBR ] .	Inhibitors of mTOR, such as miRNAs, can inhibit tumor cell growth in many cancers by blocking the AKT and mTOR signaling pathway [XREF_BIBR - XREF_BIBR, XREF_BIBR].	0	25	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	2	3	19	20
PKB is activated by both 3-phosphoinositide-dependent protein kinase 1 ( PDK1 ) and mammalian target of rapamycin protein kinase c2 ( mTORc2 ) through phosphorylation on different amino acid of PKB .	PKB is activated by both 3-phosphoinositide-dependent protein kinase 1 (PDK1) and mammalian target of rapamycin protein kinase c2 (mTORc2) through phosphorylation on different amino acid of PKB.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	PKB	PKB	PKB	13	17	0	1
Combined Inhibition of the Mammalian Target of Rapamycin ( mTOR ) and EGFR Persistently Inhibits AKT Activation and Synergistically Inhibits Cell Growth in Vitro .	Combined Inhibition of the Mammalian Target of Rapamycin (mTOR) and EGFR Persistently Inhibits AKT Activation and Synergistically Inhibits Cell Growth in Vitro.	4	16	Inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mammalian Target of Rapamycin	Mammalian Target of Rapamycin	Mammalian Target of Rapamycin	AKT	AKT	AKT	4	8	15	16
Thus , studies on insulin signaling in mammalian skeletal muscle cells , adipocytes , and fibroblasts have demonstrated that mTOR activation by insulin initiates a feedback inhibition of PI3K and Akt , likely through p70S6K activation and its subsequent phosphorylation of IRS-1 .	Thus, studies on insulin signaling in mammalian skeletal muscle cells, adipocytes, and fibroblasts have demonstrated that mTOR activation by insulin initiates a feedback inhibition of PI3K and Akt, likely through p70S6K activation and its subsequent phosphorylation of IRS-1.	19	31	initiates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	19	20	30	31
These results provided evidence for the hypothesis of individuation at MAM of both negative regulators of Akt ( the tumor suppressors PTEN and PML , see section below ) and the Akt activator mechanistic target of rapamycin complex 2 ( mTORc2 ) .	These results provided evidence for the hypothesis of individuation at MAM of both negative regulators of Akt (the tumor suppressors PTEN and PML, see section below) and the Akt activator mechanistic target of rapamycin complex 2 (mTORc2).	31	37	activator	Positive_activation_token_1_noun	Positive_activation	Positive_activation	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	Akt	Akt	Akt	33	37	31	32
mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates AKT in acute myelogenous leukemia ( AML ) cells [ XREF_BIBR ] .	mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates AKT in acute myelogenous leukemia (AML) cells [XREF_BIBR].	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	10	11
We tested the hypothesis that protein ingestion impairs insulin mediated glucose disposal by leucine mediated mTOR signaling , which can inhibit AKT .	We tested the hypothesis that protein ingestion impairs insulin mediated glucose disposal by leucine mediated mTOR signaling, which can inhibit AKT.	15	22	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	15	16	21	22
Mammalian target of rapamycin ( mTOR ) is a downstream target of PI3K and AKT and acts as an integrator for a variety of stimuli , including mitogens as well as energy- and nutrient-levels , and takes influence on translation , proliferation and autophagy XREF_BIBR .	Mammalian target of rapamycin (mTOR) is a downstream target of PI3K and AKT and acts as an integrator for a variety of stimuli, including mitogens as well as energy- and nutrient-levels, and takes influence on translation, proliferation and autophagy XREF_BIBR.	0	15	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	AKT	AKT	AKT	0	4	14	15
Therefore , loss of TSC1 and TSC2 complex led to mTOR independent inhibition of AKT at least partially through downregulation of the SOX9-OPN signalling cascade .	Therefore, loss of TSC1 and TSC2 complex led to mTOR independent inhibition of AKT at least partially through downregulation of the SOX9-OPN signalling cascade.	10	15	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	10	11	14	15
However , pure mTOR inhibition ( alone or in combination with other cytostatics ) should be carefully reconsidered , because inhibition of mTOR results in activation of Akt in some tumor entities including RMS XREF_BIBR , XREF_BIBR , XREF_BIBR ( this study , see XREF_FIG ) .	However, pure mTOR inhibition (alone or in combination with other cytostatics) should be carefully reconsidered, because inhibition of mTOR results in activation of Akt in some tumor entities including RMS XREF_BIBR, XREF_BIBR, XREF_BIBR (this study, see XREF_FIG).	20	28	results in activation	Positive_activation_syntax_8_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	22	23	27	28
The phosphorylation of IRS1 results in the downstream activation of AKT , mammalian target of rapamycin ( mTOR ) , growth receptor binding protein 2 ( GRB2 ) , mitogen activated protein kinase ( MAPK ) and GSK3B , thereby promoting the APP transport and clearance of amyloid-beta from the BBB XREF_BIBR , XREF_BIBR .	The phosphorylation of IRS1 results in the downstream activation of AKT, mammalian target of rapamycin (mTOR), growth receptor binding protein 2 (GRB2), mitogen activated protein kinase (MAPK) and GSK3B, thereby promoting the APP transport and clearance of amyloid-beta from the BBB XREF_BIBR, XREF_BIBR.	8	31	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	12	16	10	11
Our results indicate that inhibition of mTOR using rapamycin caused dysregulation of Akt signaling in keratinocyte cell culture and in mouse skin .	Our results indicate that inhibition of mTOR using rapamycin caused dysregulation of Akt signaling in keratinocyte cell culture and in mouse skin.	4	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	6	7	12	13
Preclinical and clinical studies also suggest that mTOR inhibition could result in feedback activation of Akt , which may limit the efficacy of these drugs as anticancer agents .	Preclinical and clinical studies also suggest that mTOR inhibition could result in feedback activation of Akt, which may limit the efficacy of these drugs as anticancer agents.	7	19	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	7	8	15	16
This data suggests a feedback loop for Akt whereby inhibition of mTOR by rapamycin activates the Akt survival pathway .	This data suggests a feedback loop for Akt whereby inhibition of mTOR by rapamycin activates the Akt survival pathway.	9	18	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	11	12	16	17
Furthermore , everolimus was shown to potently inhibit growth in many tumor types with activated mTOR in combination with lower doses of the catalytic mTOR inhibitor BEZ235 , used to reduce survival via feedback loops activating Akt .	Furthermore, everolimus was shown to potently inhibit growth in many tumor types with activated mTOR in combination with lower doses of the catalytic mTOR inhibitor BEZ235, used to reduce survival via feedback loops activating Akt.	7	37	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	15	16	36	37
In addition , we found that TSC2 was up-regulated and mTOR was down-regulated , which were the downstream molecules of Akt ( XREF_FIG ) .	In addition, we found that TSC2 was up-regulated and mTOR was down-regulated, which were the downstream molecules of Akt (XREF_FIG).	10	22	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	10	11	20	21
Also , the limited efficacy of Rapamycin on HCC cell growth restraint agrees with the previous observations showing that suppression of mTOR by Rapamycin triggers upregulation of Akt XREF_BIBR .	Also, the limited efficacy of Rapamycin on HCC cell growth restraint agrees with the previous observations showing that suppression of mTOR by Rapamycin triggers upregulation of Akt XREF_BIBR.	19	28	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	21	22	27	28
Downstream effectors of the PI3K pathway include AKT ( protein kinase B ) , a serine threonine kinase , directly activated by PI3K and the mTOR ( mammalian target of rapamycin ) , another serine threonine kinase leading to an increased translation of various mRNAs encoding cell cycle regulators , including MYC and cyclin D1 and a potential target of therapeutic inhibition .	Downstream effectors of the PI3K pathway include AKT (protein kinase B), a serine threonine kinase, directly activated by PI3K and the mTOR (mammalian target of rapamycin), another serine threonine kinase leading to an increased translation of various mRNAs encoding cell cycle regulators, including MYC and cyclin D1 and a potential target of therapeutic inhibition.	6	58	directly activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	27	31	7	8
Hyperactive mTOR mediated negative feedback regulation of AKT partially contributes to the benign nature of TSC associated tumours .	Hyperactive mTOR mediated negative feedback regulation of AKT partially contributes to the benign nature of TSC associated tumours.	0	9	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	1	2	7	8
Akt is fully activated after phosphorylation at Thr 308 and Ser 473 by PDK1 ( phosphoinositide dependent protein kinase 1 ) or mTORC2 ( mammalian target of rapamycin complex 2 ) XREF_BIBR .	Akt is fully activated after phosphorylation at Thr 308 and Ser 473 by PDK1 (phosphoinositide dependent protein kinase 1) or mTORC2 (mammalian target of rapamycin complex 2) XREF_BIBR.	0	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	24	28	0	1
mTOR inhibition can result in undesirable AKT activation through a positive feedback loop that results in upregulation of receptor tyrosine kinases such as IGF-1R .	mTOR inhibition can result in undesirable AKT activation through a positive feedback loop that results in upregulation of receptor tyrosine kinases such as IGF-1R.	0	8	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	6	7
For example , inhibition of mTOR induces a paradoxal activation of Akt [ XREF_BIBR ] .	For example, inhibition of mTOR induces a paradoxal activation of Akt [XREF_BIBR].	3	13	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	5	6	11	12
The effects of detrimental Akt activation by mTOR inhibition might be avoided upon treatment with a dual kinase inhibitor .	The effects of detrimental Akt activation by mTOR inhibition might be avoided upon treatment with a dual kinase inhibitor.	4	8	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	7	8	4	5
For example , the dual PI3K and mTOR ( mTORC1 and mTORC2 ) inhibitor BEZ235 ( Selleck Chemicals , Houston , TX ) has been found to prevent feedback activation of Akt in NET cell lines , a well-known AE of single mTOR inhibition that has been suggested to attenuate the antitumor efficacy of mTOR inhibition 80 , 81 .	For example, the dual PI3K and mTOR (mTORC1 and mTORC2) inhibitor BEZ235 (Selleck Chemicals, Houston, TX) has been found to prevent feedback activation of Akt in NET cell lines, a well-known AE of single mTOR inhibition that has been suggested to attenuate the antitumor efficacy of mTOR inhibition 80, 81.	5	32	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	7	8	31	32
Mammalian target of rapamycin complex 2 ( mTORC2 ) and DNA dependent protein kinase ( DNA-PK ) can both phosphorylate Ser473 and activate PKB .	Mammalian target of rapamycin complex 2 (mTORC2) and DNA dependent protein kinase (DNA-PK) can both phosphorylate Ser473 and activate PKB.	0	24	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	PKB	PKB	PKB	0	4	23	24
Activated Akt , in turn , activates the mammalian target of rapamycin ( mTOR ) , which helps induce cellular proliferation and block apoptosis .	Activated Akt, in turn, activates the mammalian target of rapamycin (mTOR), which helps induce cellular proliferation and block apoptosis.	0	14	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	13	14	1	2
mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin .	mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin.	0	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	0	1	16	17
Activated Akt subsequently phosphorylates mammalian target of rapamycin ( mTOR ) , which has wide ranging substrates and influences several processes involved in cellular metabolism and survival .	Activated Akt subsequently phosphorylates mammalian target of rapamycin (mTOR), which has wide ranging substrates and influences several processes involved in cellular metabolism and survival.	0	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	phosphorylates mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	akt	4	8	1	2
The analysis of pathway activation showed an upstream activation in Akt induced by mTOR inhibition in the EGFR resistant cell line ; other groups have previously described this phenomenon ( O'Reilly et al , 2006 ) .	The analysis of pathway activation showed an upstream activation in Akt induced by mTOR inhibition in the EGFR resistant cell line; other groups have previously described this phenomenon (O'Reilly et al, 2006).	5	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	13	14	10	11
In addition , recent preclinical studies have shown that dual inhibition of mTOR with rapamycin and Akt with perifosine prevents mTOR inhibition initiated Akt activation and significantly enhances antitumor effects in lung cancer [ XREF_BIBR ] and multiple myeloma [ XREF_BIBR ] .	In addition, recent preclinical studies have shown that dual inhibition of mTOR with rapamycin and Akt with perifosine prevents mTOR inhibition initiated Akt activation and significantly enhances antitumor effects in lung cancer [XREF_BIBR] and multiple myeloma [XREF_BIBR].	20	24	initiated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	20	21	23	24
The inhibition of mTOR by rapalogs increases AKT activity and promotes cell growth by phosphorylation of the upstream negative regulator of mTOR , the TSC1 and TSC2 complex [ XREF_BIBR ] .	The inhibition of mTOR by rapalogs increases AKT activity and promotes cell growth by phosphorylation of the upstream negative regulator of mTOR, the TSC1 and TSC2 complex [XREF_BIBR].	1	8	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	3	4	7	8
Moreover , BEZ235 , a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells , impaired viability at nanomolar concentrations .	Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations.	9	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	11	15	18	19
Activated AKT plays a pivotal role as well in the regulation of translation via phosphorylation and activation of the serine/threonine kinase mammalian target of rapamycin ( mTOR ) .	Activated AKT plays a pivotal role as well in the regulation of translation via phosphorylation and activation of the serine/threonine kinase mammalian target of rapamycin (mTOR).	0	27	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	26	27	1	2
However , T308 phosphorylation and downstream AKT signaling rapidly recover in the cells treated with mTOR kinase inhibitors [ XREF_BIBR , XREF_BIBR ] , and in Rictor , mLst8 , and mSin1 KO embryos and fibroblasts , AKT-T308 phosphorylation remains intact [ XREF_BIBR , XREF_BIBR ] indicating T308 and S473 phosphorylation can also occur independently .	However, T308 phosphorylation and downstream AKT signaling rapidly recover in the cells treated with mTOR kinase inhibitors [XREF_BIBR, XREF_BIBR], and in Rictor, mLst8, and mSin1 KO embryos and fibroblasts, AKT-T308 phosphorylation remains intact [XREF_BIBR, XREF_BIBR] indicating T308 and S473 phosphorylation can also occur independently.	6	17	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	15	16	6	7
Accordingly , treatment of these tumors with an AKT inhibitor and rapamycin uniformly resulted in abrogation of mTOR inhibition induced AKT activation in all tumors but failed to induce antitumor response in a subset .	Accordingly, treatment of these tumors with an AKT inhibitor and rapamycin uniformly resulted in abrogation of mTOR inhibition induced AKT activation in all tumors but failed to induce antitumor response in a subset.	17	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	17	18	20	21
Here , we discovered that inhibition of mTOR by RAD001 not only activates AKT but also leads to S184 Bax phosphorylation and inactivation in a lung cancer cell line and in tumor tissues from NSCLC patients treated with RAD001 ( XREF_FIG ) .	Here, we discovered that inhibition of mTOR by RAD001 not only activates AKT but also leads to S184 Bax phosphorylation and inactivation in a lung cancer cell line and in tumor tissues from NSCLC patients treated with RAD001 (XREF_FIG).	5	14	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	7	8	13	14
Further mechanistic studies also suggest a feedback loop within PI3K-Akt-mTOR pathway that mTOR and S6K inhibition induces feedback activation of Akt [ XREF_BIBR ] .	Further mechanistic studies also suggest a feedback loop within PI3K-Akt-mTOR pathway that mTOR and S6K inhibition induces feedback activation of Akt [XREF_BIBR].	12	22	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	12	13	20	21
Akt is subsequently activated through phosphorylation by intracellular kinases , 3-phosphoinoitide-dependent protein kinase 1 ( PDK1 ) and the rictor-mTORC2 ( mammalian target of rapamycin complex 2 ) , at positions Thr 308 and Ser 473 , respectively ( XREF_FIG ) .	Akt is subsequently activated through phosphorylation by intracellular kinases, 3-phosphoinoitide-dependent protein kinase 1 (PDK1) and the rictor-mTORC2 (mammalian target of rapamycin complex 2), at positions Thr 308 and Ser 473, respectively (XREF_FIG).	0	25	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	21	25	0	1
Moreover , persistent activation of hepatic mTOR signaling reduces AKT activity , subsequently inhibiting SREBP-1c expression and lipogenic responses under HFD conditions .	Moreover, persistent activation of hepatic mTOR signaling reduces AKT activity, subsequently inhibiting SREBP-1c expression and lipogenic responses under HFD conditions.	6	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	6	7	9	10
Moreover , inhibition of AKT induces activation of upstream RTK signaling pathways , such as HER3 [ XREF_BIBR ] , and mTOR inhibition causes activation of AKT signaling [ XREF_BIBR ] or MAPK pathway [ XREF_BIBR ] .	Moreover, inhibition of AKT induces activation of upstream RTK signaling pathways, such as HER3 [XREF_BIBR], and mTOR inhibition causes activation of AKT signaling [XREF_BIBR] or MAPK pathway [XREF_BIBR].	21	29	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	21	22	26	27
It remains possible that mTOR inhibition induces Akt activation by other unknown mechanisms , such as indirect activation of mTOR-rictor by auraptene , which require further elucidation .	It remains possible that mTOR inhibition induces Akt activation by other unknown mechanisms, such as indirect activation of mTOR-rictor by auraptene, which require further elucidation.	4	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	4	5	7	8
Since mTOR inhibition increases AKT activity by disrupting feedback inhibition [ XREF_BIBR , XREF_BIBR ] , vertical targeting of the PI3K-AKT-mTOR pathway has proven to be a promising approach in several cancer types [ XREF_BIBR - XREF_BIBR ] , with clinical trials ongoing [ XREF_BIBR ] .	Since mTOR inhibition increases AKT activity by disrupting feedback inhibition [XREF_BIBR, XREF_BIBR], vertical targeting of the PI3K-AKT-mTOR pathway has proven to be a promising approach in several cancer types [XREF_BIBR - XREF_BIBR], with clinical trials ongoing [XREF_BIBR].	1	5	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	1	2	4	5
A putative negative-feedback inhibition of Akt by mTOR was ruled out because previous research with mammary cells utilizing a complete AA mixture revealed no change in phosphorylation status of Akt after the addition of rapamycin [ XREF_BIBR ] .	A putative negative-feedback inhibition of Akt by mTOR was ruled out because previous research with mammary cells utilizing a complete AA mixture revealed no change in phosphorylation status of Akt after the addition of rapamycin [XREF_BIBR].	3	8	inhibition	Negative_activation_token_2_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	7	8	5	6
Mammalian target of rapamycin ( mTOR ) is a downstream target of Akt , and we hypothesized that irradiation activates mTOR signaling in both glioma and endothelial cells ( ECs ) and that radiosensitization results from inhibiting mTOR signaling .	Mammalian target of rapamycin (mTOR) is a downstream target of Akt, and we hypothesized that irradiation activates mTOR signaling in both glioma and endothelial cells (ECs) and that radiosensitization results from inhibiting mTOR signaling.	0	13	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	Akt	Akt	Akt	0	4	12	13
Dual inhibitors of PI3K and mTOR target the active sites of both holoenzymes to inhibit the pathway both upstream and downstream of AKT , thus avoiding the problem of AKT activation following abolition of the mTORC1-S6K-IRS-1 or S6K-mTORC2-AKT negative feedback loops .	Dual inhibitors of PI3K and mTOR target the active sites of both holoenzymes to inhibit the pathway both upstream and downstream of AKT, thus avoiding the problem of AKT activation following abolition of the mTORC1-S6K-IRS-1 or S6K-mTORC2-AKT negative feedback loops.	1	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	5	6	22	23
Since mTOR inhibition could activate AKT mediated survival , AKT inhibitors could present a class of drugs to be administered in combination with temsirolimus in order to enhance its effectiveness in vivo .	Since mTOR inhibition could activate AKT mediated survival, AKT inhibitors could present a class of drugs to be administered in combination with temsirolimus in order to enhance its effectiveness in vivo.	1	6	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	1	2	5	6
Consequently , mTOR inhibition enhances Akt activity , with the potential to promote cancer cell survival and chemoresistance .	Consequently, mTOR inhibition enhances Akt activity, with the potential to promote cancer cell survival and chemoresistance.	2	6	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	2	3	5	6
The activation of Akt in oxygen deprived cells may be due to mTOR inhibition , which eliminates mTOR induced feedback pathways that inhibit Akt activation by tyrosine kinase receptor and other Akt activation signals .	The activation of Akt in oxygen deprived cells may be due to mTOR inhibition, which eliminates mTOR induced feedback pathways that inhibit Akt activation by tyrosine kinase receptor and other Akt activation signals.	17	24	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	17	18	23	24
In contrast to ceramide induced autophagy , SK1 ( S1P )-induced autophagy is characterized by ( i ) the inhibition of mammalian target of rapamycin signaling independently of the Akt and protein kinase B signaling arm and ( ii ) the lack of robust accumulation of the autophagy protein Beclin 1 .	In contrast to ceramide induced autophagy, SK1 (S1P)-induced autophagy is characterized by (i) the inhibition of mammalian target of rapamycin signaling independently of the Akt and protein kinase B signaling arm and (ii) the lack of robust accumulation of the autophagy protein Beclin 1.	21	30	signaling	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Akt	Akt	Akt	21	25	29	30
Thus studying the energy sensor kinase mammalian target of rapamycin ( mTOR , ) the other major target of AKT ( Fingar and Blenis 2004 ) , and its role in osteoblast differentiation would be provocative .	Thus studying the energy sensor kinase mammalian target of rapamycin (mTOR,) the other major target of AKT (Fingar and Blenis 2004), and its role in osteoblast differentiation would be provocative.	6	20	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	AKT	AKT	AKT	6	10	19	20
The dual PI3K-mTOR inhibitors target the p110 subunit of PI3K as well as mTOR inhibiting the pathway both upstream and downstream of AKT .	The dual PI3K-mTOR inhibitors target the p110 subunit of PI3K as well as mTOR inhibiting the pathway both upstream and downstream of AKT.	4	23	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	13	14	22	23
There are reports indicate that several molecular mechanisms , such as Akt activation induced by mTOR inhibition , might account for the limited antitumor effects of mTOR inhibitors [ XREF_BIBR - XREF_BIBR ] .	There are reports indicate that several molecular mechanisms, such as Akt activation induced by mTOR inhibition, might account for the limited antitumor effects of mTOR inhibitors [XREF_BIBR - XREF_BIBR].	11	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Akt	Akt	Akt	15	16	11	12
Although the mechanism is unclear , herein , inhibition of mTOR by RAD001 little increased PI3K and AKT signalling in mesothelioma cell lines ( XREF_FIG ) , which can interpret this contradiction .	Although the mechanism is unclear, herein, inhibition of mTOR by RAD001 little increased PI3K and AKT signalling in mesothelioma cell lines (XREF_FIG), which can interpret this contradiction.	8	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	AKT	AKT	AKT	10	11	17	18
Many new agents that target the PI3K-AKT pathway , including PI3K , dual PI3K and mammalian target of rapamycin and catalytic domain AKT inhibitors , are now in various phases of clinical testing .	Many new agents that target the PI3K-AKT pathway, including PI3K, dual PI3K and mammalian target of rapamycin and catalytic domain AKT inhibitors, are now in various phases of clinical testing.	4	19	target	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	PI3K-AKT	PI3K-AKT	PI3K-AKT	15	19	6	7
Depletion of Mre11 or CtIP , antibody mediated inhibition of Mre11 , or small molecule inhibition of MRN using mirin results in metaphase chromosome alignment defects in Xenopus egg extracts .	Depletion of Mre11 or CtIP, antibody mediated inhibition of Mre11, or small molecule inhibition of MRN using mirin results in metaphase chromosome alignment defects in Xenopus egg extracts.	0	18	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	MRN	MRN	MRN	2	3	17	18
They also demonstrated that hyperphosphorylation of Mre11 inactivated the MRN complex , through dissociation from chromatin , enabling downregulation of DNA damage signalling during cell cycle checkpoint recovery following DNA repair .	They also demonstrated that hyperphosphorylation of Mre11 inactivated the MRN complex, through dissociation from chromatin, enabling downregulation of DNA damage signalling during cell cycle checkpoint recovery following DNA repair.	4	10	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	hyperphosphorylation of Mre11	mre11	MRN	MRN	mrn	6	7	9	10
Although the effects of these MRN inhibitors have not yet been studied at stressed and collapsed replication forks , we speculate that mirin and other MRE11 exonuclease inhibitors may allow engagement of the MRN complex on collapsed forks , while inhibiting its end-resection ability .	Although the effects of these MRN inhibitors have not yet been studied at stressed and collapsed replication forks, we speculate that mirin and other MRE11 exonuclease inhibitors may allow engagement of the MRN complex on collapsed forks, while inhibiting its end-resection ability.	25	34	allow	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MRE11	MRE11	MRE11	MRN	MRN	MRN	25	26	33	34
Ubiquitination of NBS1 by the ring finger protein RNF8 promotes optimal binding to DSBs , whereas MRE11 phosphorylation by Polo like kinase 1 ( Plk1 ) inhibits recruitment of the MRN complex to DSBs .	Ubiquitination of NBS1 by the ring finger protein RNF8 promotes optimal binding to DSBs, whereas MRE11 phosphorylation by Polo like kinase 1 (Plk1) inhibits recruitment of the MRN complex to DSBs.	16	31	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MRE11	MRE11 phosphorylation	mre11	MRN	MRN	mrn	16	17	30	31
The treatment with siPIH1D1 led to decreased levels of MRE11 and slight decrease of RAD50 and NBS1 in contrast to treatment with siLUC ( XREF_SUPPLEMENTARY ) .	The treatment with siPIH1D1 led to decreased levels of MRE11 and slight decrease of RAD50 and NBS1 in contrast to treatment with siLUC (XREF_SUPPLEMENTARY).	9	17	decrease	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MRE11	MRE11	MRE11	NBS1	NBS1	NBS1	9	10	16	17
Knockdown of NBS1 had no effect on the level of RAD50 or MRE11 , but knockdown of RAD50 also depleted cells of NBS1 , and knockdown of MRE11 depleted cells of all three MRN proteins .	Knockdown of NBS1 had no effect on the level of RAD50 or MRE11, but knockdown of RAD50 also depleted cells of NBS1, and knockdown of MRE11 depleted cells of all three MRN proteins.	25	34	depleted	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	MRN	MRN	MRN	27	28	33	34
Knockdown of MRE11 is known to reduce stability of the other MRN components , NBS1 and RAD50 .	Knockdown of MRE11 is known to reduce stability of the other MRN components, NBS1 and RAD50.	0	12	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	MRN	MRN	MRN	2	3	11	12
Conversely , Mre11 down-regulation by small interference RNA ( siRNA ) in HT29 cells inhibited Chk2 activation and down-regulated Nbs1 and Rad50 .	Conversely, Mre11 down-regulation by small interference RNA (siRNA) in HT29 cells inhibited Chk2 activation and down-regulated Nbs1 and Rad50.	2	21	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	Mre11	Mre11	Nbs1	Nbs1	Nbs1	2	3	19	20
Loss of Nbs1 or Mre11 is embryonic lethal [ XREF_BIBR , XREF_BIBR ] and mutations in NBS1 and MRE11 lead to the chromosomal instability disorders Njimegen breakage syndrome ( mutation in NBS ) and ataxia telangiectasia like disorder ( ATLD ; mutation in Mre11 ) .	Loss of Nbs1 or Mre11 is embryonic lethal [XREF_BIBR, XREF_BIBR] and mutations in NBS1 and MRE11 lead to the chromosomal instability disorders Njimegen breakage syndrome (mutation in NBS) and ataxia telangiectasia like disorder (ATLD; mutation in Mre11).	11	32	lead	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRE11	MRE11	MRE11	NBS	NBS	NBS	18	19	31	32
Mirin is an inhibitor of MRE11 exonuclease activity that also blocks MRN activation of ATM during dsDNA break repair [ XREF_BIBR , XREF_BIBR ] .	Mirin is an inhibitor of MRE11 exonuclease activity that also blocks MRN activation of ATM during dsDNA break repair [XREF_BIBR, XREF_BIBR].	5	12	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MRE11	MRE11	MRE11	MRN	MRN	MRN	5	6	11	12
Mutations in NBS1 , MRE11A , and RAD50 disrupting the functionality of MRN complex may lead to genome instability and carcinogenesis .	Mutations in NBS1, MRE11A, and RAD50 disrupting the functionality of MRN complex may lead to genome instability and carcinogenesis.	0	13	disrupting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MRE11A	MRE11A	MRE11A	MRN	MRN	MRN	4	5	12	13
Phosphorylation of Mre11 at SQ/TQ sites inactivates the MRN complex by facilitating its dissociation from chromatin , thus allowing down-regulation of DNA damage signaling and recovery from the checkpoint response .	Phosphorylation of Mre11 at SQ/TQ sites inactivates the MRN complex by facilitating its dissociation from chromatin, thus allowing down-regulation of DNA damage signaling and recovery from the checkpoint response.	0	9	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	Phosphorylation of Mre11	mre11	MRN	MRN	mrn	2	3	8	9
Phosphorylation of Mre11 at S649 and S688 inhibited loading of the MRN complex to damaged DNA , leading to both premature DNA damage checkpoint termination and inhibition of DNA repair .	Phosphorylation of Mre11 at S649 and S688 inhibited loading of the MRN complex to damaged DNA, leading to both premature DNA damage checkpoint termination and inhibition of DNA repair.	0	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	Phosphorylation of Mre11 at S649 and S688	mre11	MRN	MRN	mrn	2	3	11	12
The loss of either Rad50 or Mre11 triggers destabilization of the whole MRN complex and the disappearance of the other components .	The loss of either Rad50 or Mre11 triggers destabilization of the whole MRN complex and the disappearance of the other components.	1	13	triggers	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	loss of either Rad50 or Mre11	mre11	MRN	MRN	mrn	6	7	12	13
Phosphorylation of Mre11 SQ/TQ motif impairs DNA tethering and subsequent ATM activation .	Phosphorylation of Mre11 SQ/TQ motif impairs DNA tethering and subsequent ATM activation.	0	11	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	Phosphorylation of Mre11	mre11	ATM	ATM	atm	2	3	10	11
TRIP13 deficient spermatocytes also progress to an H1t positive stage if ATM activity is attenuated by hypomorphic mutations in Mre11 or Nbs1 or by elimination of the ATM-effector kinase CHK2 .	TRIP13 deficient spermatocytes also progress to an H1t positive stage if ATM activity is attenuated by hypomorphic mutations in Mre11 or Nbs1 or by elimination of the ATM-effector kinase CHK2.	11	21	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	19	20	11	12
Moreover , Mre11 depletion dramatically impairs the ATM ( Axatia telangiectasia mutated )-dependent response to DSBs .	Moreover, Mre11 depletion dramatically impairs the ATM (Axatia telangiectasia mutated)-dependent response to DSBs.	2	9	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	2	3	7	8
Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of Chk1 inhibition contributed , via synthetic lethality , to extreme sensitivity to irinotecan .	Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of Chk1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan.	9	16	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	9	10	15	16
Whereas phosphorylation of Mre11 at these residues is not required for DSB induced ATM activation , abrogation of Mre11 dephosphorylation impairs ATM signaling .	Whereas phosphorylation of Mre11 at these residues is not required for DSB induced ATM activation, abrogation of Mre11 dephosphorylation impairs ATM signaling.	18	22	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	Mre11 dephosphorylation	mre11	ATM	ATM	atm	18	19	21	22
Interestingly , the lack of either Sae2 or Mre11 nuclease activity enhances Tel1 and ATM activation at DSBs by increasing MRX persistence at DSBs XREF_BIBR XREF_BIBR , suggesting that Sae2 and Mre11 nuclease can inhibit Tel1 and ATM signaling activity .	Interestingly, the lack of either Sae2 or Mre11 nuclease activity enhances Tel1 and ATM activation at DSBs by increasing MRX persistence at DSBs XREF_BIBR XREF_BIBR, suggesting that Sae2 and Mre11 nuclease can inhibit Tel1 and ATM signaling activity.	8	15	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	8	9	14	15
However , it is also worth noting that both ATM and the Mre11 complex have central functions independent from one another as ATM is synthetically lethal with many hypomorphic mutations in the Mre11 complex , some of which do not impair ATM activation .	However, it is also worth noting that both ATM and the Mre11 complex have central functions independent from one another as ATM is synthetically lethal with many hypomorphic mutations in the Mre11 complex, some of which do not impair ATM activation.	32	42	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	32	33	41	42
Hypomorphic mutations in Mre11 complex alleles , or its depletion by viral proteins , impair ATM activation and the G2/M checkpoint .	Hypomorphic mutations in Mre11 complex alleles, or its depletion by viral proteins, impair ATM activation and the G2/M checkpoint.	3	16	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	3	4	15	16
Altogether , these data demonstrate that DNA damage induced phosphorylation of Mre11 is not required for ATM activation , however , abrogation of Mre11 dephosphorylation dramatically impairs ATM signaling .	Altogether, these data demonstrate that DNA damage induced phosphorylation of Mre11 is not required for ATM activation, however, abrogation of Mre11 dephosphorylation dramatically impairs ATM signaling.	23	28	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	Mre11 dephosphorylation	mre11	ATM	ATM	atm	23	24	27	28
The Mre11 ATLD1 allele impairs ATM activation , thus reducing the total pool of active ATM and potentially affecting all substrates .	The Mre11 ATLD1 allele impairs ATM activation, thus reducing the total pool of active ATM and potentially affecting all substrates.	1	6	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mre11	Mre11	Mre11	ATM	ATM	ATM	1	2	5	6
We have shown that HGFL induced Ron activation in Kupffer cells induces Mefv ( pyrin ) and diminishes Lcn2 expression , which may promote the expression of anti-inflammatory genes while inhibiting genes involved in inflammation .	We have shown that HGFL induced Ron activation in Kupffer cells induces Mefv (pyrin) and diminishes Lcn2 expression, which may promote the expression of anti-inflammatory genes while inhibiting genes involved in inflammation.	4	7	induced	Positive_early_activation	Positive_activation	Negative_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	4	5	6	7
Moreover , after persistent Zt/g4 treatment , MSP induced RON activation was completely inhibited also the downstream pMAPK and pAkt activation was inhibited in 5637 cells .	Moreover, after persistent Zt/g4 treatment, MSP induced RON activation was completely inhibited also the downstream pMAPK and pAkt activation was inhibited in 5637 cells.	7	10	induced	Positive_early_activation	Positive_activation	Negative_activation	MSP	MSP	MSP	RON	RON	RON	7	8	9	10
Upon further analyses of downstream signaling targets of HGFL induced Ron activation , decreases in the activation of AKT and MAPK were observed in prostate tumors of HGFL-/- TRAMP+ mice compared to HGFL +/+ TRAMP+ mice .	Upon further analyses of downstream signaling targets of HGFL induced Ron activation, decreases in the activation of AKT and MAPK were observed in prostate tumors of HGFL-/- TRAMP+ mice compared to HGFL +/+ TRAMP+ mice.	6	11	induced	Positive_early_activation	Positive_activation	Positive_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	8	9	10	11
HGFL ablation decreased oncogenic Ron activation and delayed mammary tumor initiation .	HGFL ablation decreased oncogenic Ron activation and delayed mammary tumor initiation.	0	5	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	0	1	4	5
Result showed that after Zt/g4 treatment for 48 h , MSP induced RON activation was completely inhibited .	Result showed that after Zt/g4 treatment for 48 h, MSP induced RON activation was completely inhibited.	10	13	induced	Positive_early_activation	Positive_activation	Negative_activation	MSP	MSP	MSP	RON	RON	RON	10	11	12	13
RONDelta85 has the inhibitory effect on MSP induced RON signaling events [ XREF_BIBR ] .	RONDelta85 has the inhibitory effect on MSP induced RON signaling events [XREF_BIBR].	4	12	induced	Positive_early_activation	Positive_activation	Positive_activation	MSP	MSP	MSP	RON	RON	RON	6	7	8	9
Further , HGFL induced Ron signaling may inhibit Lcn2 ( a proinflammatory protein ) induction by LPS , which may further reduce Kupffer cell associated proinflammatory cytokine production as well as decrease immune cell infiltration to the area of injury .	Further, HGFL induced Ron signaling may inhibit Lcn2 (a proinflammatory protein) induction by LPS, which may further reduce Kupffer cell associated proinflammatory cytokine production as well as decrease immune cell infiltration to the area of injury.	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	2	3	4	5
Although HGFL induced Ron activation diminishes LPS induced increases in inflammatory cytokine secretion by macrophages , the significance of moderate induction of the proinflammatory cytokines immediately after Ron activation is not known .	Although HGFL induced Ron activation diminishes LPS induced increases in inflammatory cytokine secretion by macrophages, the significance of moderate induction of the proinflammatory cytokines immediately after Ron activation is not known.	1	4	induced	Positive_early_activation	Positive_activation	Negative_activation	HGFL	HGFL	HGFL	Ron	Ron	Ron	1	2	3	4
Other pathways may be involved , for example , phosphatidylinositol 3-kinase ( PI3K ) , mammalian target of rapamycin ( mTOR ) , mitogen activated protein kinase ( MAPK ) and protein kinase B ( PKB and Akt ) , which have already been well characterized in leukemia models .	Other pathways may be involved, for example, phosphatidylinositol 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen activated protein kinase (MAPK) and protein kinase B (PKB and Akt), which have already been well characterized in leukemia models.	15	34	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	protein kinase B	protein kinase B	protein kinase B	15	19	31	34
Ketamine increases mammalian target of rapamycin complex 1 ( mTORC1 ) signaling , via activation of protein kinase B ( PKB or Akt ) and ERK .	Ketamine increases mammalian target of rapamycin complex 1 (mTORC1) signaling, via activation of protein kinase B (PKB or Akt) and ERK.	2	19	signaling	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	protein kinase B	protein kinase B	protein kinase B	2	6	16	19
The current study involved structural computational biology approaches to explore compounds from a diverse pool of naphthoquinone analogs that can inhibit key cancer signaling proteins phosphoinositide 3-kinase ( PI3K ) , protein kinase B , PKB ( AKT ) , and mammalian target of rapamycin ( mTOR ) .	The current study involved structural computational biology approaches to explore compounds from a diverse pool of naphthoquinone analogs that can inhibit key cancer signaling proteins phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT), and mammalian target of rapamycin (mTOR).	17	47	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	protein kinase B	protein kinase B	protein kinase B	46	47	31	34
Active TGF-beta1 production was inhibited by the MMP-2 shRNA construct but not the control irrelevant shRNA ( XREF_FIG , top panel ) .	Active TGF-beta1 production was inhibited by the MMP-2 shRNA construct but not the control irrelevant shRNA (XREF_FIG, top panel).	1	9	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	MMP-2	MMP-2	MMP-2	TGF-beta1	TGF-beta1	TGF-beta1	7	8	1	2
The inhibitory mechanisms through which doxycycline ( decreased release of active TGF-beta from LAP by MMP-2 and -9 ) and losartan ( decreased expression of TGF-beta ) are distinct but both result in less TGF-beta signaling .	The inhibitory mechanisms through which doxycycline (decreased release of active TGF-beta from LAP by MMP-2 and -9) and losartan (decreased expression of TGF-beta) are distinct but both result in less TGF-beta signaling.	7	17	decreased	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	MMP-2	MMP-2	MMP-2	LAP	LAP	LAP	15	16	13	14
MMP-2 , but not MMP-3 or -9 siRNA , blocked removal of the LAP and release of biologically active TGF-beta .	MMP-2, but not MMP-3 or -9 siRNA, blocked removal of the LAP and release of biologically active TGF-beta.	0	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MMP-2	MMP-2	MMP-2	LAP	LAP	LAP	0	1	13	14
Conversely , deletion or mutation of Lamin A/C alters mechanical actin dynamics and interferes with MKL1 mediated serum response factor ( SRF ) activity [ XREF_BIBR ] .	Conversely, deletion or mutation of Lamin A/C alters mechanical actin dynamics and interferes with MKL1 mediated serum response factor (SRF) activity [XREF_BIBR].	13	20	mediated	Positive_early_activation	Positive_activation	Positive_activation	MKL1	MKL1	MKL1	serum response factor	serum response factor	serum response factor	15	16	17	20
The activity of Srf exhibited a positive correlation with the stiffness , as judged by the expression of Mkl1 mediated Srf targets such as Acta2 , consistent with a previous report 40 .	The activity of Srf exhibited a positive correlation with the stiffness, as judged by the expression of Mkl1 mediated Srf targets such as Acta2, consistent with a previous report 40.	16	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	Mkl1	Mkl1	Mkl1	Srf	Srf	Srf	18	19	20	21
MMP-9 is known to degrade a variety of proteins , including aggrecan , collagen , elastin , fibronectin , galectin-3 , IL-1beta , laminin , SPARC , as well as activate TGF-beta1 by processing the latent TGF-beta binding protein [ XREF_BIBR , XREF_BIBR ] .	MMP-9 is known to degrade a variety of proteins, including aggrecan, collagen, elastin, fibronectin, galectin-3, IL-1beta, laminin, SPARC, as well as activate TGF-beta1 by processing the latent TGF-beta binding protein [XREF_BIBR, XREF_BIBR].	0	32	degrade	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MMP-9	MMP-9	MMP-9	TGF-beta1	TGF-beta1	TGF-beta1	0	1	31	32
CMT-3 posttreatment increased TIMP-1 level and thereby inhibited MMP-9 , which in turn decreased TGF-beta1 and caspase-3 signaling pathways and improved survivability in septic rats .	CMT-3 posttreatment increased TIMP-1 level and thereby inhibited MMP-9, which in turn decreased TGF-beta1 and caspase-3 signaling pathways and improved survivability in septic rats.	7	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MMP-9	MMP-9	MMP-9	TGF-beta1	TGF-beta1	TGF-beta1	8	9	14	15
Notably , the presence of anti-integrin alpha4 or beta2 neutralizing antibodies suppressed the mRNAs of Il-1beta , Il-6 , and Mmp-9 , and anti-integrin beta2 suppressed Tgf-beta1 .	Notably, the presence of anti-integrin alpha4 or beta2 neutralizing antibodies suppressed the mRNAs of Il-1beta, Il-6, and Mmp-9, and anti-integrin beta2 suppressed Tgf-beta1.	13	27	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mmp-9	Mmp-9	Mmp-9	Tgf-beta1	Tgf-beta1	Tgf-beta1	20	21	26	27
3.4 MIF triggered JNK activation is diminished in fibroblasts genetically deficient in Cd74 .	3.4 MIF triggered JNK activation is diminished in fibroblasts genetically deficient in Cd74.	0	13	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MIF	MIF	MIF	Cd74	Cd74	Cd74	1	2	12	13
Here we observed that MIF induced leukocyte adhesion and emigration in the microcirculation were reduced in CD74 -/- mice .	Here we observed that MIF induced leukocyte adhesion and emigration in the microcirculation were reduced in CD74 -/- mice.	4	18	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MIF	MIF	MIF	CD74	CD74	CD74	4	5	16	17
The MIF R87A-L88A-R89A triple mutant elicited a reduced cell migratory response in CXCR4 expressing JVM-3 lymphocytes compared to WT-MIF , but contrary to CXCR4 mediated signaling in the S. cerevisiae system the response was not completely abolished .	The MIF R87A-L88A-R89A triple mutant elicited a reduced cell migratory response in CXCR4 expressing JVM-3 lymphocytes compared to WT-MIF, but contrary to CXCR4 mediated signaling in the S. cerevisiae system the response was not completely abolished.	1	13	elicited	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	1	2	12	13
In another type of assay , we noticed that when added to the upper chamber of the Transwell system , MIF retains the RMS cells in the upper chamber and thus significantly inhibits chemotaxis of CXCR7 + RH18 and CXCR4 + RH30 cells in response to the SDF-1 gradient ( XREF_SUPPLEMENTARY ) .	In another type of assay, we noticed that when added to the upper chamber of the Transwell system, MIF retains the RMS cells in the upper chamber and thus significantly inhibits chemotaxis of CXCR7 + RH18 and CXCR4 + RH30 cells in response to the SDF-1 gradient (XREF_SUPPLEMENTARY).	20	42	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MIF	MIF	MIF	CXCR4	CXCR4	CXCR4	20	21	39	40
showing increased mammalian target of rapamycin signaling in Grb10 knockout islets is an early indication that the link has physiological significance .	showing increased mammalian target of rapamycin signaling in Grb10 knockout islets is an early indication that the link has physiological significance.	2	10	signaling	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	Grb10	Grb10	Grb10	2	6	8	9
Targeted deletion of the Grb10 gene in pancreas enhances beta-cell mass and insulin and IGF -1 and mTOR signaling in islets .	Targeted deletion of the Grb10 gene in pancreas enhances beta-cell mass and insulin and IGF -1 and mTOR signaling in islets.	0	18	Targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	Grb10	Grb10	Grb10	17	18	4	5
Currently , different inhibitors targeting eIF4F are in clinical trials which block the activation of eIF4E by Mnk1 or prevent the association of eIF4E with eIF4G at initiation complex XREF_BIBR .	Currently, different inhibitors targeting eIF4F are in clinical trials which block the activation of eIF4E by Mnk1 or prevent the association of eIF4E with eIF4G at initiation complex XREF_BIBR.	11	18	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Mnk1	Mnk1	Mnk1	eIF4E	eIF4E	eIF4E	17	18	15	16
A reduction in the level of CSN3 protein with small interfering RNA abrogated MLF1 induced G1 arrest and impaired the activation of p53 by genotoxic stress .	A reduction in the level of CSN3 protein with small interfering RNA abrogated MLF1 induced G1 arrest and impaired the activation of p53 by genotoxic stress.	13	23	impaired	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MLF1	MLF1	MLF1	p53	p53	p53	13	14	22	23
MLF1 is expressed in a wide variety of tissues , shuttles between the cytoplasm and the nucleus , and has also been shown to reduce proliferation by stabilizing the activity of TP53 by suppressing its E3 ubiquitin ligase , COP1 [ XREF_BIBR ] .	MLF1 is expressed in a wide variety of tissues, shuttles between the cytoplasm and the nucleus, and has also been shown to reduce proliferation by stabilizing the activity of TP53 by suppressing its E3 ubiquitin ligase, COP1 [XREF_BIBR].	0	32	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MLF1	MLF1 is expressed	mlf1	TP53	TP53	tp53	0	1	31	32
Deletion mutants of the N-terminal region of human MRAP which lack amino acids 1-24 or 1-35 are unable to promote MC2R trafficking to the cell surface suggesting that the N-terminal region plays a prominent role in receptor trafficking .	Deletion mutants of the N-terminal region of human MRAP which lack amino acids 1-24 or 1-35 are unable to promote MC2R trafficking to the cell surface suggesting that the N-terminal region plays a prominent role in receptor trafficking.	5	21	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MRAP	MRAP	MRAP	MC2R	MC2R	MC2R	8	9	20	21
These genes include DEPTOR and MNK2 which directly inhibit mTORC1 complex and eIF4E , respectively [ XREF_BIBR , XREF_BIBR ] .	These genes include DEPTOR and MNK2 which directly inhibit mTORC1 complex and eIF4E, respectively [XREF_BIBR, XREF_BIBR].	2	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MNK2	MNK2	MNK2	eIF4E	eIF4E	eIF4E	5	6	12	13
The recombinant active form of MMP-3 could degrade DMP-1 protein but not osteocalcin and osteopontin in vitro .	The recombinant active form of MMP-3 could degrade DMP-1 protein but not osteocalcin and osteopontin in vitro.	3	15	degrade	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MMP-3	MMP-3	MMP-3	osteopontin	osteopontin	osteopontin	5	6	14	15
Indeed , the Hippo pathway , via MOB1A activation of LATS1 tumor suppressor can negatively regulate cell proliferation by modulating cyclin A activity [ XREF_BIBR ] .	Indeed, the Hippo pathway, via MOB1A activation of LATS1 tumor suppressor can negatively regulate cell proliferation by modulating cyclin A activity [XREF_BIBR].	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	MOB1A	MOB1A	MOB1A	LATS1	LATS1	LATS1	7	8	10	11
This result also implied that the abundance of endogenous MRAP2 was not high enough to inhibit MC2R signaling substantially ; if it were , then the increased abundance of MRAP in transfected cells would compete with endogenous MRAP2 and increase the responsiveness of these cells to ACTH .	This result also implied that the abundance of endogenous MRAP2 was not high enough to inhibit MC2R signaling substantially; if it were, then the increased abundance of MRAP in transfected cells would compete with endogenous MRAP2 and increase the responsiveness of these cells to ACTH.	6	17	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MRAP2	MRAP2	MRAP2	MC2R	MC2R	MC2R	9	10	16	17
Myostatin negatively regulates skeletal muscle size by activating ACVR2B and initiating Smad2/3 signaling .	Myostatin negatively regulates skeletal muscle size by activating ACVR2B and initiating Smad2/3 signaling.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Myostatin	Myostatin	Myostatin	ACVR2B	ACVR2B	ACVR2B	0	1	8	9
Rapamacyn has been used to inhibit mTOR and enhance the memory T-cell differentiation , but mTOR is also expressed in other cells , such as dendritic cells , where the inhibition hampers the induction of the immune response acting as an immunosuppressive drug .	Rapamacyn has been used to inhibit mTOR and enhance the memory T-cell differentiation, but mTOR is also expressed in other cells, such as dendritic cells, where the inhibition hampers the induction of the immune response acting as an immunosuppressive drug.	5	19	inhibit	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	mTOR	mTOR is also expressed	mtor	mTOR	mTOR	mtor	15	16	6	7
Conversely , under starvation conditions , AMPK induced MTOR inhibition prevents MTOR from binding to ULK1 .	Conversely, under starvation conditions, AMPK induced MTOR inhibition prevents MTOR from binding to ULK1.	6	12	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	MTOR	AMPK induced MTOR	mtor	MTOR	MTOR	mtor	8	9	11	12
Considering the finding that AMP activated protein kinase ( AMPK ) and mammalian target of rapamycin ( mTOR ) are critical energy sensors that also have a role in autophagy regulation , 35 the effect of safingol on the phosphorylation of AMPK and mTOR was examined .	Considering the finding that AMP activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are critical energy sensors that also have a role in autophagy regulation, 35 the effect of safingol on the phosphorylation of AMPK and mTOR was examined.	4	18	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	17	18	12	16
These findings indicate that renin inhibition not only inhibited phosphorylation of mTOR but also attenuated activation of the mTOR pathway .	These findings indicate that renin inhibition not only inhibited phosphorylation of mTOR but also attenuated activation of the mTOR pathway.	4	19	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	renin inhibition not only inhibited phosphorylation of mTOR	mtor	mTOR	mTOR	mtor	11	12	18	19
Self-complementary adeno associated virus serotype 5 ( AAV5 ) was constructed to express green fluorescent protein ( GFP ) and a small interfering RNA ( siRNA ) targeting mammalian target of rapamycin ( mTOR ) .	Self-complementary adeno associated virus serotype 5 (AAV5) was constructed to express green fluorescent protein (GFP) and a small interfering RNA (siRNA) targeting mammalian target of rapamycin (mTOR).	23	34	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	33	34	28	32
For instance , the 5 '-adenosine monophosphate activated protein kinase ( AMPK ) and mammalian and mechanistic target of rapamycin ( mTOR ) signaling play significant roles in the development of these metabolic disorders .	For instance, the 5 '-adenosine monophosphate activated protein kinase (AMPK) and mammalian and mechanistic target of rapamycin (mTOR) signaling play significant roles in the development of these metabolic disorders.	6	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	21	22	16	20
Everolimus ( C 53 H 83 NO 14 ) is an efficient anti-cancer drug for breast cancer which targets mammalian target of rapamycin ( mTOR ) .	Everolimus (C 53 H 83 NO 14) is an efficient anti-cancer drug for breast cancer which targets mammalian target of rapamycin (mTOR).	16	25	targets	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	24	25	19	23
Alternatively , the mTOR binding partner proline rich Akt and PKB substrate 40kDa ( PRAS40 ) is directly phosphorylated by Akt which in turn leads to revoking of PRAS40 mediated inhibition of mTOR .	Alternatively, the mTOR binding partner proline rich Akt and PKB substrate 40kDa (PRAS40) is directly phosphorylated by Akt which in turn leads to revoking of PRAS40 mediated inhibition of mTOR.	3	33	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR binding partner proline rich Akt and PKB substrate 40kDa (PRAS40) is directly phosphorylated	mtor	mTOR	mTOR	mtor	3	4	32	33
First , we found that MTOR phosphorylation was decreased after 25 to 50J/cm 2 UVA exposure , suggesting the sensitivity of MTOR to UVA in contrast to the UVB radiation ) .	First, we found that MTOR phosphorylation was decreased after 25 to 50J/cm 2 UVA exposure, suggesting the sensitivity of MTOR to UVA in contrast to the UVB radiation).	5	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTOR	MTOR phosphorylation	mtor	MTOR	MTOR	mtor	5	6	21	22
Rapamycin , a mammalian target of rapamycin ( mTOR ) inhibitor , inhibits mTOR activity , eventually leading to cell cycle arrest at the G 1 phase XREF_BIBR .	Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, inhibits mTOR activity, eventually leading to cell cycle arrest at the G 1 phase XREF_BIBR.	3	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mTOR	3	7	13	14
There are several LTM related signaling pathways other than those mentioned in this review in other animals , such as N-methyl-D-aspartic acid ( NMDA ) receptor signaling , insulin receptor signaling , mitogen activated protein kinase ( MAPK ) signaling , and mechanistic target of rapamycin ( mTOR ) signaling .	There are several LTM related signaling pathways other than those mentioned in this review in other animals, such as N-methyl-D-aspartic acid (NMDA) receptor signaling, insulin receptor signaling, mitogen activated protein kinase (MAPK) signaling, and mechanistic target of rapamycin (mTOR) signaling.	32	48	activated	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	47	48	42	46
As predicted , overexpression of mTOR decreased autophagic flux ( Bmal1cDNA 0.32 +/- 0.02 vs. Bmal1cDNA plus mTOR 0.21 +/- 0.02 , p < 0.05 , n = 8 ; Figure XREF_FIG ) .	As predicted, overexpression of mTOR decreased autophagic flux (Bmal1cDNA 0.32 +/- 0.02 vs. Bmal1cDNA plus mTOR 0.21 +/- 0.02, p < 0.05, n = 8; Figure XREF_FIG).	3	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	overexpression of mTOR	mtor	mTOR	mTOR	mtor	5	6	17	18
Everolimus , a selective inhibitor of mammalian target of rapamycin ( mTOR ) , inhibits the downstream signalling events of the mTOR pathway .	Everolimus, a selective inhibitor of mammalian target of rapamycin (mTOR), inhibits the downstream signalling events of the mTOR pathway.	6	22	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mTOR	6	10	21	22
Pharmaceutic reagents that specifically target mammalian target of rapamycin ( mTOR ) have been approved by the Food and Drug Administration ( FDA ) of the United States for treating advanced renal cancer , progressive or metastatic pancreatic cancer , and breast cancer in post-menopausal women with estrogen receptor ( ER ) - or progesterone receptor ( PR )-positive and human epidermal growth factor receptor 2 ( HER2 )-negative lesions .	Pharmaceutic reagents that specifically target mammalian target of rapamycin (mTOR) have been approved by the Food and Drug Administration (FDA) of the United States for treating advanced renal cancer, progressive or metastatic pancreatic cancer, and breast cancer in post-menopausal women with estrogen receptor (ER) - or progesterone receptor (PR)-positive and human epidermal growth factor receptor 2 (HER2)-negative lesions.	1	11	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	10	11	5	9
A novel class of immunosuppressants that inhibit the kinase mammalian target of rapamycin ( mTOR ) , although not nephrotoxic themselves , enhance CI nephrotoxicity .	A novel class of immunosuppressants that inhibit the kinase mammalian target of rapamycin (mTOR), although not nephrotoxic themselves, enhance CI nephrotoxicity.	4	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	14	15	9	13
For advanced PNET , systemic treatment or targeted treatment has been implemented , such as somatostatin analogs , agents targeting the vascular endothelial growth factor ( VEGF ) signaling pathway and the mechanistic target of rapamycin ( mTOR ) .	For advanced PNET, systemic treatment or targeted treatment has been implemented, such as somatostatin analogs, agents targeting the vascular endothelial growth factor (VEGF) signaling pathway and the mechanistic target of rapamycin (mTOR).	18	38	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	37	38	32	36
Multiple agents that target vascular endothelial growth factor ( VEGF ) or mammalian target of rapamycin ( mTOR ) have been approved for treatment of RCC based on an improvement in progression-free survival ( PFS ) when compared with placebo or an active control [ 2 ] , [ 3 ] , [ 4 ] , [ 5 ] .	Multiple agents that target vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) have been approved for treatment of RCC based on an improvement in progression-free survival (PFS) when compared with placebo or an active control [2], [3], [4], [5].	1	18	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	17	18	12	16
Conversely , knockdown of integrin beta1 partially attenuated higher stiffness mediated stemness characteristics in HCC cells , and reversed the phosphorylation levels of Akt and mTOR , and expressions of p-4E-BP and SOX2 , suggesting that integrin beta1 may deliver higher stiffness signal into HCC cells and activate mTOR signaling pathway .	Conversely, knockdown of integrin beta1 partially attenuated higher stiffness mediated stemness characteristics in HCC cells, and reversed the phosphorylation levels of Akt and mTOR, and expressions of p-4E-BP and SOX2, suggesting that integrin beta1 may deliver higher stiffness signal into HCC cells and activate mTOR signaling pathway.	4	50	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	integrin beta1 partially attenuated higher stiffness mediated stemness characteristics in HCC cells, and reversed the phosphorylation levels of Akt and mTOR	mtor	mTOR	mTOR	mtor	25	26	48	49
Cancer therapies that simultaneously target activated mammalian target of rapamycin ( mTOR ) and cell metabolism are urgently needed .	Cancer therapies that simultaneously target activated mammalian target of rapamycin (mTOR) and cell metabolism are urgently needed.	1	12	target activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	11	12	6	10
In recent years , treatment options have improved significantly with the introduction of multiple agents that target vascular endothelial growth factor ( VEGF ) or mammalian target of rapamycin ( mTOR ) .	In recent years, treatment options have improved significantly with the introduction of multiple agents that target vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR).	14	31	target	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	30	31	25	29
To determine the pathways involved in autophagy induction , adenosine monophosphate activated protein kinase ( AMPK ) and the mechanistic target of rapamycin ( mTOR ) were also explored .	To determine the pathways involved in autophagy induction, adenosine monophosphate activated protein kinase (AMPK) and the mechanistic target of rapamycin (mTOR) were also explored.	10	25	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	24	25	19	23
For further mechanistic investigations , we found that MLN4924 treatment resulted in a remarkable decreased phosphorylation of mTOR , and reduced mTOR activity , as reflected by dose dependent inhibition of p70S6K and 4E-BP1 phosphorylation .	For further mechanistic investigations, we found that MLN4924 treatment resulted in a remarkable decreased phosphorylation of mTOR, and reduced mTOR activity, as reflected by dose dependent inhibition of p70S6K and 4E-BP1 phosphorylation.	8	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	MLN4924 treatment resulted in a remarkable decreased phosphorylation of mTOR	mtor	mTOR	mTOR	mtor	17	18	21	22
Single gene mutations in mammalian target of rapamycin ( mTOR ) signaling pathway are associated with the development of ASD and enhanced mTOR signaling plays a central role in directing immune responses towards allergy as well .	Single gene mutations in mammalian target of rapamycin (mTOR) signaling pathway are associated with the development of ASD and enhanced mTOR signaling plays a central role in directing immune responses towards allergy as well.	4	23	enhanced	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mTOR	4	8	22	23
Besides controlling carbohydrate and lipid metabolism , AMPK phosphorylates major mTOR signaling regulators like TSC2 , thus functioning to suppress mTOR signaling that governs anabolic responses , such as protein synthesis .	Besides controlling carbohydrate and lipid metabolism, AMPK phosphorylates major mTOR signaling regulators like TSC2, thus functioning to suppress mTOR signaling that governs anabolic responses, such as protein synthesis.	7	21	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	AMPK phosphorylates major mTOR	mtor	mTOR	mTOR	mtor	10	11	20	21
In addition , established cytostatic agents or new drugs targeting HER2 , angiogenesis , or mammalian target of Rapamycin ( mTOR ) have been combined to novel therapy strategies [ XREF_BIBR - XREF_BIBR ] .	In addition, established cytostatic agents or new drugs targeting HER2, angiogenesis, or mammalian target of Rapamycin (mTOR) have been combined to novel therapy strategies [XREF_BIBR - XREF_BIBR].	8	21	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of Rapamycin	mammalian target of Rapamycin	mammalian target of Rapamycin	20	21	15	19
Currently , there are two kinds of therapeutic agents applied in targeted therapy for RCC , ie , tyrosine kinase inhibitors ( TKIs ) targeting tumor angiogenesis and mammalian target of rapamycin ( mTOR ) inhibitors .	Currently, there are two kinds of therapeutic agents applied in targeted therapy for RCC, ie, tyrosine kinase inhibitors (TKIs) targeting tumor angiogenesis and mammalian target of rapamycin (mTOR) inhibitors.	12	34	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	33	34	28	32
Accordingly , we observed increased signal transducer and activator of transcription 3 ( STAT3 ) and mammalian target of rapamycin ( mTOR ) phosphorylation in tubules with preneoplastic phenotypes .	Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) phosphorylation in tubules with preneoplastic phenotypes.	4	24	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR) phosphorylation	mtor	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	21	22	16	20
One mechanism is that APN activated AMPK directly phosphorylates raptor , a constituent of the nutrient- and rapamycin sensitive mTOR complex 1 ( mTORC1 ) , thereby inhibiting mTOR activity .	One mechanism is that APN activated AMPK directly phosphorylates raptor, a constituent of the nutrient- and rapamycin sensitive mTOR complex 1 (mTORC1), thereby inhibiting mTOR activity.	4	29	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	APN activated AMPK directly phosphorylates raptor, a constituent of the nutrient- and rapamycin sensitive mTOR	mtor	mTOR	mTOR	mtor	19	20	28	29
Independently from SMAD4 expression , the exposure of cells to EGF chronic stimulation caused both increased ( Ser 2448 ) and decreased mTOR ( Ser 2481 ) phosphorylation , while p-beta-catenin was induced in BxPC3 but not in BxPC3-SMAD4+ cells .	Independently from SMAD4 expression, the exposure of cells to EGF chronic stimulation caused both increased (Ser 2448) and decreased mTOR (Ser 2481) phosphorylation, while p-beta-catenin was induced in BxPC3 but not in BxPC3-SMAD4+ cells.	21	28	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR (Ser 2481) phosphorylation	mtor	mTOR	mTOR	mtor	22	23	22	23
The KAA-HFD-induced activation of AMPK was associated with an increased protein expression of sirtuin 1 ( Sirt1 ) , decreased forkhead box protein O3a ( Foxo3a ) level , and suppression of mammalian target of rapamycin ( mTOR ) phosphorylation compared with the HFD fed mice .	The KAA-HFD-induced activation of AMPK was associated with an increased protein expression of sirtuin 1 (Sirt1), decreased forkhead box protein O3a (Foxo3a) level, and suppression of mammalian target of rapamycin (mTOR) phosphorylation compared with the HFD fed mice.	19	40	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin (mTOR) phosphorylation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	32	36	32	36
This decreases the interaction between upstream signaling modules localized near the plasma membrane and the lysosome associated mammalian target of rapamycin ( mTOR ) complex , preventing the activation of mTOR , which is required for new protein synthesis .	This decreases the interaction between upstream signaling modules localized near the plasma membrane and the lysosome associated mammalian target of rapamycin (mTOR) complex, preventing the activation of mTOR, which is required for new protein synthesis.	17	31	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mTOR	17	21	30	31
The induction of cell senescence appears to require cell cycle arrest and ongoing or even accelerated metabolic activity ( cell growth ) , particularly ribosome biogenesis that is known to be mediated by the mammalian target of rapamycin ( mTOR ) pathway .	The induction of cell senescence appears to require cell cycle arrest and ongoing or even accelerated metabolic activity (cell growth), particularly ribosome biogenesis that is known to be mediated by the mammalian target of rapamycin (mTOR) pathway.	25	40	mediated	Positive_activation_syntax_6_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mTOR	34	38	39	40
HIF-1alpha silencing also increased the expression of phospho-Akt , mTOR , and P70S6K and activated the mTOR signals significantly .	HIF-1alpha silencing also increased the expression of phospho-Akt, mTOR, and P70S6K and activated the mTOR signals significantly.	0	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	HIF-1alpha silencing also increased the expression of phospho-Akt, mTOR	mtor	mTOR	mTOR	mtor	9	10	16	17
The kinases AMP activated protein kinase ( AMPK ) and mammalian target of rapamycin ( mTOR ) are each linked to food intake regulation , but only mTOR had increased activity in KSR2 (-/-) mouse brain , and the ability of rapamycin to inhibit food intake in KSR2 (-/-) mice further implicated mTOR in this process .	The kinases AMP activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are each linked to food intake regulation, but only mTOR had increased activity in KSR2 (-/-) mouse brain, and the ability of rapamycin to inhibit food intake in KSR2 (-/-) mice further implicated mTOR in this process.	2	16	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	15	16	10	14
Loss of Fbxw7 during tumorigenesis leads to elevated steady-state expression of mTOR and enhanced mTOR signaling .	Loss of Fbxw7 during tumorigenesis leads to elevated steady-state expression of mTOR and enhanced mTOR signaling.	0	15	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	Loss of Fbxw7 during tumorigenesis leads to elevated steady-state expression of mTOR	mtor	mTOR	mTOR	mtor	11	12	14	15
Tuberin dependent stimulation of GTP hydrolysis of Rheb blocks phosphorylation of mTOR ( Ser 2448 ) , which antagonizes the mTOR signaling pathway .	Tuberin dependent stimulation of GTP hydrolysis of Rheb blocks phosphorylation of mTOR (Ser 2448), which antagonizes the mTOR signaling pathway.	0	22	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	Tuberin dependent stimulation of GTP hydrolysis of Rheb blocks phosphorylation of mTOR (Ser 2448	mtor	mTOR	mTOR	mtor	11	12	20	21
PI-103 , the first synthetic multitargeted compound which simultaneously inhibits PI3Kalpha and mammalian target of rapamycin ( mTOR ) shows high antitumor activity in glioma xenografts .	PI-103, the first synthetic multitargeted compound which simultaneously inhibits PI3Kalpha and mammalian target of rapamycin (mTOR) shows high antitumor activity in glioma xenografts.	0	18	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	17	18	12	16
B cell activation , CSR , and development into Ab secreting cells are effected by receptors that stimulate the mammalian target of rapamycin ( mTOR ) .	B cell activation, CSR, and development into Ab secreting cells are effected by receptors that stimulate the mammalian target of rapamycin (mTOR).	15	25	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	24	25	19	23
The adenosine monophosphate activated protein kinase ( AMPK ) complex and mammalian target of rapamycin ( mTOR ) are master regulators of cellular energy homeostasis .	The adenosine monophosphate activated protein kinase (AMPK) complex and mammalian target of rapamycin (mTOR) are master regulators of cellular energy homeostasis.	2	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	16	17	11	15
Mammalian target of rapamycin ( mTOR ) inhibitor suppresses cellular growth of RCC by blocking mTOR mediated signaling .	Mammalian target of rapamycin (mTOR) inhibitor suppresses cellular growth of RCC by blocking mTOR mediated signaling.	0	17	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	mTOR	mTOR	mTOR	0	4	15	16
For example , nutrients ( glucose and amino acids ) or inhibitors of phosphatidylinositol 3-kinase , AKT or mammalian target of rapamycin ( mTOR ) directly regulates AMP kinase or mTOR complex activities to ULK1 phosphorylation while not affecting ATG4 activity .	For example, nutrients (glucose and amino acids) or inhibitors of phosphatidylinositol 3-kinase, AKT or mammalian target of rapamycin (mTOR) directly regulates AMP kinase or mTOR complex activities to ULK1 phosphorylation while not affecting ATG4 activity.	18	32	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mTOR	18	22	30	31
Autophagy is regulated by various signaling pathways , and AMP activated protein kinase ( AMPK ) and mammalian target of rapamycin ( mTOR ) signaling pathways have emerged as the central checkpoints in the regulation of autophagy [ XREF_BIBR ] .	Autophagy is regulated by various signaling pathways, and AMP activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathways have emerged as the central checkpoints in the regulation of autophagy [XREF_BIBR].	9	23	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	22	23	17	21
One possibility is that PKA directly phosphorylates mTOR and inhibits mTOR kinase activity .	One possibility is that PKA directly phosphorylates mTOR and inhibits mTOR kinase activity.	4	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	PKA directly phosphorylates mTOR	mtor	mTOR	mTOR	mtor	7	8	10	11
Secondly , AMPK directly phosphorylates the mTOR binding partner raptor on 722 and 792 serine residues , which inactivates raptor and mTOR .	Secondly, AMPK directly phosphorylates the mTOR binding partner raptor on 722 and 792 serine residues, which inactivates raptor and mTOR.	2	22	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	AMPK directly phosphorylates the mTOR binding partner raptor on 722 and 792 serine residues	mtor	mTOR	mTOR	mtor	6	7	21	22
Temsirolimus , the specific small molecule inhibitor of the mammalian target of rapamycin ( mTOR ) , inhibits the PI3K and mTOR signaling pathway by binding to the mTORC1 complex ( mTOR and FK506 binding protein 12 ) [ XREF_BIBR , XREF_BIBR ] .	Temsirolimus, the specific small molecule inhibitor of the mammalian target of rapamycin (mTOR), inhibits the PI3K and mTOR signaling pathway by binding to the mTORC1 complex (mTOR and FK506 binding protein 12) [XREF_BIBR, XREF_BIBR].	9	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mTOR	9	13	21	22
The 5 '-adenosine monophosphate activated protein kinase ( AMPK ) and mammalian target of rapamycin ( mTOR ) appear to play a significant role in the intermediary metabolism of these diseases .	The 5 '-adenosine monophosphate activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) appear to play a significant role in the intermediary metabolism of these diseases.	3	17	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	16	17	11	15
The results ( XREF_FIG ) show that as expected , MTOR protein expression was blocked by the siRNA targeting Mtor , compared to non targeting siRNA ( XREF_FIG ) .	The results (XREF_FIG) show that as expected, MTOR protein expression was blocked by the siRNA targeting Mtor, compared to non targeting siRNA (XREF_FIG).	10	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTOR	MTOR protein expression	mtor	Mtor	Mtor	mtor	10	11	19	20
This activation triggers a cascade of signals that stimulates protein kinase B ( AKT ) and the mammalian Target of Rapamycin ( mTOR ) .	This activation triggers a cascade of signals that stimulates protein kinase B (AKT) and the mammalian Target of Rapamycin (mTOR).	6	23	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian Target of Rapamycin	mammalian Target of Rapamycin	mammalian Target of Rapamycin	22	23	17	21
The AMP activated protein kinase ( AMPK ) and mammalian target of rapamycin ( mTOR ) are two major short-term energy sensors for the rapid regulation of autophagy .	The AMP activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are two major short-term energy sensors for the rapid regulation of autophagy.	1	15	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	14	15	9	13
Leptin has been shown to be essential for development of naive T-cells [ XREF_BIBR ] and immature B-cells supporting intracellular activation of the mechanistic target of rapamycin complex 1 ( mTOR ) mediated processes .	Leptin has been shown to be essential for development of naive T-cells [XREF_BIBR] and immature B-cells supporting intracellular activation of the mechanistic target of rapamycin complex 1 (mTOR) mediated processes.	17	31	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	30	31	23	27
Here we show that adenovirus encodes two proteins that activate the mammalian target of rapamycin ( mTOR ) for viral replication , even under nutrient and growth factor limiting conditions .	Here we show that adenovirus encodes two proteins that activate the mammalian target of rapamycin (mTOR) for viral replication, even under nutrient and growth factor limiting conditions.	7	17	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	16	17	11	15
Also the pharmacokinetics of mTOR ( mechanistic target of rapamycin , mammalian target of rapamycin ) inhibitors , which are used as anti-cancer and immunosuppressive agents ( sirolimus , everolimus ) was shown to be influenced by polymorphisms in CYP3A4 and CYP3A5 genes .	Also the pharmacokinetics of mTOR (mechanistic target of rapamycin, mammalian target of rapamycin) inhibitors, which are used as anti-cancer and immunosuppressive agents (sirolimus, everolimus) was shown to be influenced by polymorphisms in CYP3A4 and CYP3A5 genes.	2	16	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	4	5	11	15
DDIT4 functions as an inhibitor of the mammalian target of rapamycin ( mTOR ) complex 1 ; activation of mTOR complex 1 is controlled by anabolic hormones including insulin XREF_BIBR .	DDIT4 functions as an inhibitor of the mammalian target of rapamycin (mTOR) complex 1; activation of mTOR complex 1 is controlled by anabolic hormones including insulin XREF_BIBR.	7	20	activation	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	mTOR	mTOR	mTOR	7	11	19	20
( 3 ) Mammalian target of rapamycin ( mTOR ) : testosterone activates the mTOR pathway [ XREF_BIBR ] and in turn the mTOR stimulate cellular growth and hypertrophy [ XREF_BIBR ] .	(3) Mammalian target of rapamycin (mTOR) : testosterone activates the mTOR pathway [XREF_BIBR] and in turn the mTOR stimulate cellular growth and hypertrophy [XREF_BIBR].	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	mTOR	mTOR	mTOR	3	7	14	15
Recently , however , mTOR inhibition immediately before Toll like receptor ligation has been found to exert proinflammatory effects on myeloid cells , notably enhanced IL-12p40 and p70 production .	Recently, however, mTOR inhibition immediately before Toll like receptor ligation has been found to exert proinflammatory effects on myeloid cells, notably enhanced IL-12p40 and p70 production.	4	28	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	p70	p70	p70	4	5	27	28
The authors suggest that metformin appears to have antiproliferative effects on the endometrium of estradiol or tamoxifen treated mice via inhibiting the mTOR mediated S6K1 activation .	The authors suggest that metformin appears to have antiproliferative effects on the endometrium of estradiol or tamoxifen treated mice via inhibiting the mTOR mediated S6K1 activation.	20	25	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	22	23	24	25
S6K1 is activated by growth factors such as insulin , and by mammalian target of rapamycin ( mTOR ) , which is itself regulated by amino acids .	S6K1 is activated by growth factors such as insulin, and by mammalian target of rapamycin (mTOR), which is itself regulated by amino acids.	0	16	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	S6K1	S6K1	S6K1	12	16	0	1
The P70 ribosomal protein S6 kinase 1 ( P70S6K1 ) is activated by the mammalian target of rapamycin ( mTORC1 ) and regulates proliferation , growth , and metabolism .	The P70 ribosomal protein S6 kinase 1 (P70S6K1) is activated by the mammalian target of rapamycin (mTORC1) and regulates proliferation, growth, and metabolism.	1	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	P70S6K1	P70S6K1	P70S6K1	14	18	8	9
Therefore , our findings support the notion that PD toxins induced activation of AMPK and inactivation of Akt may cooperatively result in suppression of mTOR mediated S6K1 and 4E-BP1 pathways , thereby leading to neuronal cell death in the context of PD .	Therefore, our findings support the notion that PD toxins induced activation of AMPK and inactivation of Akt may cooperatively result in suppression of mTOR mediated S6K1 and 4E-BP1 pathways, thereby leading to neuronal cell death in the context of PD.	22	29	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	24	25	26	27
Moreover , elimination of S6K1 activation by mTOR pathway inhibitor enhances the killing effects of the hedgehog pathway inhibitor .	Moreover, elimination of S6K1 activation by mTOR pathway inhibitor enhances the killing effects of the hedgehog pathway inhibitor.	4	9	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	7	8	4	5
Therefore , we propose that suppression of mTOR mediated S6K1 and 4E-BP1 pathways plays a crucial role in the pathogenesis of PD .	Therefore, we propose that suppression of mTOR mediated S6K1 and 4E-BP1 pathways plays a crucial role in the pathogenesis of PD.	5	12	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	7	8	9	10
Akt has been previously shown to activate mammalian target of rapamycin ( mTOR ) , which in turn activates p70S6 kinase to induce TIMP-3 upon TGF-beta stimulation [ XREF_BIBR ] .	Akt has been previously shown to activate mammalian target of rapamycin (mTOR), which in turn activates p70S6 kinase to induce TIMP-3 upon TGF-beta stimulation [XREF_BIBR].	7	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	p70S6 kinase	p70S6 kinase	p70S6 kinase	7	11	19	21
We observed that angiogenic stimulation of BM endothelial cells activates mTOR and engages its downstream pathways 4E-BP1 and S6K1 , which are inhibited by the mTOR specific blockers rapamycin and CCI-779 .	We observed that angiogenic stimulation of BM endothelial cells activates mTOR and engages its downstream pathways 4E-BP1 and S6K1, which are inhibited by the mTOR specific blockers rapamycin and CCI-779.	9	28	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	25	26	18	19
S6K1 ( p70 ribosomal S6 kinase 1 ) is activated by insulin and growth factors via the PI3K ( phosphoinositide 3-kinase ) and mTOR ( mammalian target of rapamycin ) signalling pathways .	S6K1 (p70 ribosomal S6 kinase 1) is activated by insulin and growth factors via the PI3K (phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin) signalling pathways.	0	29	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	S6K1	S6K1	S6K1	25	29	0	1
These findings indicate that inactivation of Akt duo to the PD toxins results in neuronal cell death via inhibition of mTOR mediated S6K1 and 4E-BP1 pathways .	These findings indicate that inactivation of Akt duo to the PD toxins results in neuronal cell death via inhibition of mTOR mediated S6K1 and 4E-BP1 pathways.	18	25	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	20	21	22	23
In the nervous system , inhibition of mTOR mediated p70S6K and 4E-BP1 signalling usually promotes neuronal apoptosis XREF_BIBR .	In the nervous system, inhibition of mTOR mediated p70S6K and 4E-BP1 signalling usually promotes neuronal apoptosis XREF_BIBR.	5	12	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	7	8	9	10
We found that ectopic expression of constitutively active Akt or dominant negative AMPKalpha , or inhibition of AMPKalpha with compound C partially prevented inhibition of mTOR mediated S6K1 and 4E-BP1 pathways and neuronal cell death triggered by 6-OHDA , MPP + or rotenone .	We found that ectopic expression of constitutively active Akt or dominant negative AMPKalpha, or inhibition of AMPKalpha with compound C partially prevented inhibition of mTOR mediated S6K1 and 4E-BP1 pathways and neuronal cell death triggered by 6-OHDA, MPP + or rotenone.	23	30	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	25	26	27	28
We then probed the contribution of these intermediates to IGF1 induced Kitl expression by using pathway specific inhibitors ( XREF_FIG ) : rhIGF1 stimulated Kitl expression was reduced by AKT Inhibitor X [ XREF_BIBR ] ; by rapamycin , which selectively inhibits the activation of p70S6K by MTOR complex 1 [ XREF_BIBR ] ; and by PD98059 , a selective MEK inhibitor [ XREF_BIBR ] .	We then probed the contribution of these intermediates to IGF1 induced Kitl expression by using pathway specific inhibitors (XREF_FIG) : rhIGF1 stimulated Kitl expression was reduced by AKT Inhibitor X [XREF_BIBR]; by rapamycin, which selectively inhibits the activation of p70S6K by MTOR complex 1 [XREF_BIBR]; and by PD98059, a selective MEK inhibitor [XREF_BIBR].	43	48	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	MTOR	MTOR	MTOR	p70S6K	p70S6K	p70S6K	47	48	45	46
After an 80-min incubation , we immunoblotted for GFP , to monitor GFP-FM4-hGH secretion , and the phosphorylated form of the S6 ribosomal protein , a downstream target of the mTOR activated p70 S6-kinase ( Chung etal , 1992 ) .	After an 80-min incubation, we immunoblotted for GFP, to monitor GFP-FM4-hGH secretion, and the phosphorylated form of the S6 ribosomal protein, a downstream target of the mTOR activated p70 S6-kinase (Chung etal, 1992).	27	33	activated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70	p70	p70	30	31	32	33
S 6 ribosomal kinase 1 ( S6K1 ) , which is activated by the mammalian target of rapamycin , is critical for cell growth .	S 6 ribosomal kinase 1 (S6K1), which is activated by the mammalian target of rapamycin, is critical for cell growth.	0	18	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	S 6 ribosomal kinase 1	S 6 ribosomal kinase 1	S 6 ribosomal kinase 1	14	18	0	5
While the physiological significance of rictor or mSin1 phosphorylation is under investigation , studies have revealed that S6K1 phosphorylates rictor ( Thr1135 ) , and rapamycin inhibition of this phosphorylation is by suppressing mTOR mediated S6K1 [ XREF_BIBR ] .	While the physiological significance of rictor or mSin1 phosphorylation is under investigation, studies have revealed that S6K1 phosphorylates rictor (Thr1135), and rapamycin inhibition of this phosphorylation is by suppressing mTOR mediated S6K1 [XREF_BIBR].	33	36	mediated	Positive_early_activation	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	33	34	35	36
Rapamycin is an mTOR dependent inhibitor of p70S6K that was used alone or in combination with the protease inhibitors to challenge the cells by stimulating autophagy above its basal activity level .	Rapamycin is an mTOR dependent inhibitor of p70S6K that was used alone or in combination with the protease inhibitors to challenge the cells by stimulating autophagy above its basal activity level.	3	8	inhibitor	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	3	4	7	8
In skeletal muscle , activation of Akt by IGF-1 stimulates protein translation through induction of mammalian target of rapamycin ( mTOR ) , which activates p70S6K and inactivates the inhibitor of translational initiation 4EBP1 , and GSK-3beta , which stimulates the initiation factor eIF2B .	In skeletal muscle, activation of Akt by IGF-1 stimulates protein translation through induction of mammalian target of rapamycin (mTOR), which activates p70S6K and inactivates the inhibitor of translational initiation 4EBP1, and GSK-3beta, which stimulates the initiation factor eIF2B.	15	26	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	p70S6K	p70S6K	p70S6K	15	19	25	26
One such target is p70S6k1 ( S6K1 ) , a serine/threonine kinase which is inactivated by the mTOR : FKBP12 : rapamycin complex , and which has been linked to translational control by virtue of its ability to phosphorylate the ribosomal protein S6 .	One such target is p70S6k1 (S6K1), a serine/threonine kinase which is inactivated by the mTOR : FKBP12 : rapamycin complex, and which has been linked to translational control by virtue of its ability to phosphorylate the ribosomal protein S6.	4	18	inactivated	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	17	18	6	7
The results underscore that activation of AMPK by the PD toxins contributes to neuronal cell death through inhibition of mTOR mediated S6K1 and 4E-BP1 pathways .	The results underscore that activation of AMPK by the PD toxins contributes to neuronal cell death through inhibition of mTOR mediated S6K1 and 4E-BP1 pathways.	17	24	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	19	20	21	22
Collectively , our results indicate that H 2 O 2 induced neuronal cell death at least in part through inhibition of mTOR mediated S6K1 and 4E-BP1/eIF4E pathways .	Collectively, our results indicate that H 2 O 2 induced neuronal cell death at least in part through inhibition of mTOR mediated S6K1 and 4E-BP1/eIF4E pathways.	19	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	21	22	23	24
Collectively , our findings support the notion that inhibition of mTOR mediated S6K1 and 4E-BP1 pathways are involved in neuronal cell death in the context of PD .	Collectively, our findings support the notion that inhibition of mTOR mediated S6K1 and 4E-BP1 pathways are involved in neuronal cell death in the context of PD.	8	15	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	10	11	12	13
Furthermore , cells expressing S6K1-ca , but not GFP , were also resistant to the PD toxins induced cleavages of caspase-3 ( XREF_FIG ) , suggesting that inhibition of mTOR mediated S6K1 pathway at least , in part , contributes to neuronal cell death in the PD models .	Furthermore, cells expressing S6K1-ca, but not GFP, were also resistant to the PD toxins induced cleavages of caspase-3 (XREF_FIG), suggesting that inhibition of mTOR mediated S6K1 pathway at least, in part, contributes to neuronal cell death in the PD models.	27	32	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	29	30	31	32
A recent study has hinted at this possibility , since disrupting mammalian mTor nuclear import was determined to impair downstream S6K1 activation .	A recent study has hinted at this possibility, since disrupting mammalian mTor nuclear import was determined to impair downstream S6K1 activation.	10	21	impair	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	mTor	mTor	mTor	S6K1	S6K1	S6K1	12	13	20	21
AKT induces activation of the mammalian target of rapamycin ( mTOR ) , which then activates S6K1 , ultimately stimulating protein synthesis .	AKT induces activation of the mammalian target of rapamycin (mTOR), which then activates S6K1, ultimately stimulating protein synthesis.	5	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	S6K1	S6K1	S6K1	5	9	16	17
Activation of AMPK and inactivation of Akt result in suppression of mTOR mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson ' s disease .	Activation of AMPK and inactivation of Akt result in suppression of mTOR mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson 's disease.	9	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	11	12	13	14
p70S6K itself is activated by 3-phosphoinositide-dependent protein kinase 1 ( PDK-1 ) and mammalian target of rapamycin ( mTOR ) kinase .	p70S6K itself is activated by 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and mammalian target of rapamycin (mTOR) kinase.	0	17	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	p70S6K	p70S6K	p70S6K	13	17	0	1
The findings support the notion that H 2 O 2 induces ROS contributing to suppression of mTOR mediated S6K1 and 4E-BP1 pathways , leading to neuronal cell death .	The findings support the notion that H 2 O 2 induces ROS contributing to suppression of mTOR mediated S6K1 and 4E-BP1 pathways, leading to neuronal cell death.	14	21	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	16	17	18	19
Mammalian target of rapamycin ( mTOR ) is known to phosphorylate and thereby activate p70 S6K1 .	Mammalian target of rapamycin (mTOR) is known to phosphorylate and thereby activate p70 S6K1.	0	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	p70 S6K1	p70 S6K1	p70 S6K1	0	4	14	16
The FRAP kinase inhibitor rapamycin and the DNA repair inhibitor aphidicolin significantly suppressed the UVB mediated increase in p70 ribosomal S6 kinase activity by 50-65 % and MMP-1 and MMP-3 protein levels by 34-68 % and 42-88 % compared with UVB irradiated fibroblasts .	The FRAP kinase inhibitor rapamycin and the DNA repair inhibitor aphidicolin significantly suppressed the UVB mediated increase in p70 ribosomal S6 kinase activity by 50-65% and MMP-1 and MMP-3 protein levels by 34-68% and 42-88% compared with UVB irradiated fibroblasts.	1	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRAP	FRAP	FRAP	p70	p70	p70	1	2	18	19
Knockout of the mTOR target S6K1 XREF_BIBR or long-term mTOR blockade by rapamycin treatment XREF_BIBR extends lifespan in mice .	Knockout of the mTOR target S6K1 XREF_BIBR or long-term mTOR blockade by rapamycin treatment XREF_BIBR extends lifespan in mice.	3	6	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	3	4	5	6
As seen in XREF_FIG baicalein significantly increases DDIT4 expression and inhibits activation of the mTOR targets S6K1 and S6 in both platinum sensitive and platinum resistant cell lines .	As seen in XREF_FIG baicalein significantly increases DDIT4 expression and inhibits activation of the mTOR targets S6K1 and S6 in both platinum sensitive and platinum resistant cell lines.	11	18	targets	Positive_activation_token_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	14	15	16	17
Originally , Dr. Krymskaya ' s group reported that the mTOR kinase inhibitor rapamycin selectively blocks the constitutive activation of S6K1 and proliferation of cells with mutated TSC2 from LAM patients .	Originally, Dr. Krymskaya 's group reported that the mTOR kinase inhibitor rapamycin selectively blocks the constitutive activation of S6K1 and proliferation of cells with mutated TSC2 from LAM patients.	10	22	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	10	11	20	21
Here , we show both activation of AMPK and inactivation of Akt in in vitro PD models , which contributes to suppression of mTOR mediated S6K1 and 4E-BP1 pathways and induction of neuronal cell death .	Here, we show both activation of AMPK and inactivation of Akt in in vitro PD models, which contributes to suppression of mTOR mediated S6K1 and 4E-BP1 pathways and induction of neuronal cell death.	21	28	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	23	24	25	26
In addition , p70S6K , which is a downstream signalling molecule of Akt , regulates protein synthesis and proliferation , and could be blocked by its upstream kinase mTOR 38 .	In addition, p70S6K, which is a downstream signalling molecule of Akt, regulates protein synthesis and proliferation, and could be blocked by its upstream kinase mTOR 38.	3	29	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	28	29	3	4
When mTOR is inhibited S6K1 does not inhibit IRS-1 .	When mTOR is inhibited S6K1 does not inhibit IRS-1.	1	5	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	1	2	4	5
As shown in XREF_FIG , increasing amounts of the mutant ( eIF3f 1-221 ) disrupted the activation of S6K1 by mTOR as evidenced by the decrease in both the S6K1 and rpS6 phosphorylation and an increase in hypophosphorylated form of S6K1 bound to eIF3f .	As shown in XREF_FIG, increasing amounts of the mutant (eIF3f 1-221) disrupted the activation of S6K1 by mTOR as evidenced by the decrease in both the S6K1 and rpS6 phosphorylation and an increase in hypophosphorylated form of S6K1 bound to eIF3f.	14	21	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	20	21	18	19
Together , the results indicate that the crosstalk between Ca 2+ signaling and mitochondrial H 2 O 2 is required for rotenone inhibition of mTOR mediated S6K1 and 4E-BP1 pathways .	Together, the results indicate that the crosstalk between Ca 2+ signaling and mitochondrial H 2 O 2 is required for rotenone inhibition of mTOR mediated S6K1 and 4E-BP1 pathways.	22	29	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	24	25	26	27
Inhibition of the mammalian target of rapamycin with 10 ng/ml rapamycin blocked S6K1 activation and proliferation of both lines .	Inhibition of the mammalian target of rapamycin with 10 ng/ml rapamycin blocked S6K1 activation and proliferation of both lines.	3	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	S6K1	S6K1	S6K1	3	7	12	13
PD toxins inactivates Akt , resulting in inhibition of mTOR mediated S6K1 and 4E-BP1 pathways , as well as cell death .	PD toxins inactivates Akt, resulting in inhibition of mTOR mediated S6K1 and 4E-BP1 pathways, as well as cell death.	7	14	mediated	Positive_early_activation	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K1	S6K1	S6K1	9	10	11	12
The total expression of mTOR was reduced in the miR-184 cohort , potentially inhibited the formation of the mTORC1 and therefore reducing the activity of S6K1 .	The total expression of mTOR was reduced in the miR-184 cohort, potentially inhibited the formation of the mTORC1 and therefore reducing the activity of S6K1.	2	26	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	expression of mTOR	mtor	S6K1	S6K1	s6k1	4	5	25	26
MG-2477 treatment also induced a sharp decrease in the phosphorylation of the mTOR targets p70 ribosomal protein S6 kinase and 4E-BP1 , revealing a potent inhibitory effect of MG-2477 treatment on Akt and mTOR signaling .	MG-2477 treatment also induced a sharp decrease in the phosphorylation of the mTOR targets p70 ribosomal protein S6 kinase and 4E-BP1, revealing a potent inhibitory effect of MG-2477 treatment on Akt and mTOR signaling.	9	22	targets	Positive_activation_token_1_verb	Positive_activation	Negative_activation	mTOR	phosphorylation of the mTOR	mtor	p70	p70	p70	12	13	14	15
With mTOR inhibition and down-regulation of p70S6K and 4E-BP1 , our data further depicted an essential role of RBM20 expression through activation of downstream effectors of mTOR signalling in the regulation of titin splicing ( depicted in XREF_FIG ) .	With mTOR inhibition and down-regulation of p70S6K and 4E-BP1, our data further depicted an essential role of RBM20 expression through activation of downstream effectors of mTOR signalling in the regulation of titin splicing (depicted in XREF_FIG).	1	8	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	1	2	6	7
mTOR suppression consequently inhibited the activation of mTOR downstream targets p70S6K and 4E-BP-1 .	mTOR suppression consequently inhibited the activation of mTOR downstream targets p70S6K and 4E-BP-1.	0	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	p70S6K	p70S6K	p70S6K	0	1	10	11
The microsomal triglyceride transport protein ( MTP ) inhibitor and antisense oligonucleotide against apolipoprotein B ( ApoB ) reduce the ApoB containing lipoprotein by blocking the hepatic very low density lipoprotein synthesis pathway .	The microsomal triglyceride transport protein (MTP) inhibitor and antisense oligonucleotide against apolipoprotein B (ApoB) reduce the ApoB containing lipoprotein by blocking the hepatic very low density lipoprotein synthesis pathway.	4	21	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	MTP	MTP	ApoB	ApoB	ApoB	6	7	20	21
These data indicate that niacin accelerates hepatic intracellular post-translational degradation of apoB by selectively reducing triglyceride synthesis ( through inhibiting both fatty acid synthesis and fatty acid esterification to produce TG ) without affecting ALLN-inhibitable protease- or MTP mediated intracellular apoB processing , resulting in decreased apoB secretion and hence lower circulating levels of the atherogenic lipoproteins .	These data indicate that niacin accelerates hepatic intracellular post-translational degradation of apoB by selectively reducing triglyceride synthesis (through inhibiting both fatty acid synthesis and fatty acid esterification to produce TG) without affecting ALLN-inhibitable protease- or MTP mediated intracellular apoB processing, resulting in decreased apoB secretion and hence lower circulating levels of the atherogenic lipoproteins.	33	41	mediated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MTP	MTP	MTP	apoB	apoB	apoB	37	38	40	41
Therefore , although the expression of apoB protein remains unchanged , low levels of MTP in the obese rat liver can reduce apoB secretion .	Therefore, although the expression of apoB protein remains unchanged, low levels of MTP in the obese rat liver can reduce apoB secretion.	12	23	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	levels of MTP	mtp	apoB	apoB	apob	14	15	22	23
Lipoprotein synthesis studies revealed that hepatic MTP ablation significantly reduces assembly and secretion of both apoB100 and apoB48 lipoproteins .	Lipoprotein synthesis studies revealed that hepatic MTP ablation significantly reduces assembly and secretion of both apoB100 and apoB48 lipoproteins.	6	18	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	MTP	MTP	apoB100	apoB100	apoB100	6	7	15	16
However , coexpression of MTP decreased the accessibility of apoB to exogenous trypsin by 2-fold for apoB72 and by 10-fold for apoB94 in isolated microsomes .	However, coexpression of MTP decreased the accessibility of apoB to exogenous trypsin by 2-fold for apoB72 and by 10-fold for apoB94 in isolated microsomes.	2	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	coexpression of MTP	mtp	apoB	apoB	apob	4	5	9	10
In this study , our data showed that DDX3 up-regulates MTP promoter and knockdown of DDX3 results in lipid accumulation and reduced ApoB secretion .	In this study, our data showed that DDX3 up-regulates MTP promoter and knockdown of DDX3 results in lipid accumulation and reduced ApoB secretion.	10	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	MTP	MTP	ApoB	ApoB	ApoB	10	11	22	23
Chemical inhibition of MTP dramatically inhibits HCVcc production , as well as genetic silencing of apolipoproteins apoE and apoB [ XREF_BIBR , XREF_BIBR ] .	Chemical inhibition of MTP dramatically inhibits HCVcc production, as well as genetic silencing of apolipoproteins apoE and apoB [XREF_BIBR, XREF_BIBR].	1	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	MTP	MTP	apoB	apoB	apoB	3	4	18	19
In humans , MTP deficiency blocks secretion of apoB containing lipoproteins , resulting in abetalipoproteinemia XREF_BIBR .	In humans, MTP deficiency blocks secretion of apoB containing lipoproteins, resulting in abetalipoproteinemia XREF_BIBR.	3	9	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	MTP	MTP	apoB	apoB	apoB	3	4	8	9
Inhibition in VLDL synthesis after MTP mediated ApoB lipidation results in accumulation of lipidated ApoB as crescents on the periphery of the LDs .	Inhibition in VLDL synthesis after MTP mediated ApoB lipidation results in accumulation of lipidated ApoB as crescents on the periphery of the LDs.	3	8	mediated	Positive_early_activation	Positive_activation	Negative_activation	MTP	MTP	MTP	ApoB	ApoB	ApoB	5	6	7	8
Lack of MTTP protein in pluripotent stem cell derived hepatocytes and cardiomyocytes abolishes apoB secretion and increases cell stress .	Lack of MTTP protein in pluripotent stem cell derived hepatocytes and cardiomyocytes abolishes apoB secretion and increases cell stress.	2	14	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTTP	MTTP	MTTP	apoB	apoB	apoB	2	3	13	14
If MTP is absent or is inactivated ApoB is targeted for ERAD regardless of whether the synthesis and secretion of LDLs and VLDLs are needed .	If MTP is absent or is inactivated ApoB is targeted for ERAD regardless of whether the synthesis and secretion of LDLs and VLDLs are needed.	1	8	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	MTP	MTP	ApoB	ApoB	ApoB	1	2	7	8
In summary , MTP lipid transfer activity does not appear to influence translocational status of apoB , but its inhibition is associated with an increased susceptibility to proteasome mediated degradation and reduced assembly and secretion of apoB lipoprotein particles .	In summary, MTP lipid transfer activity does not appear to influence translocational status of apoB, but its inhibition is associated with an increased susceptibility to proteasome mediated degradation and reduced assembly and secretion of apoB lipoprotein particles.	3	38	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	MTP	MTP	apoB	apoB	apoB	3	4	36	37
Because ApoB is synthesized constitutively , the 4-ONE-mediated loss of secretion and decrease in intracellular ApoB is likely due primarily to accelerated degradation of ApoB at a later step in the VLDL maturation and secretion pathway , and not due to ApoB degradation caused by failure of cotranslational lipidation by MTP .	Because ApoB is synthesized constitutively, the 4-ONE-mediated loss of secretion and decrease in intracellular ApoB is likely due primarily to accelerated degradation of ApoB at a later step in the VLDL maturation and secretion pathway, and not due to ApoB degradation caused by failure of cotranslational lipidation by MTP.	41	51	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	MTP	MTP	MTP	ApoB	ApoB	ApoB	50	51	41	42
Recent studies with heterozygous MTP knockout mice have suggested that half-normal levels of MTP in the liver reduce apoB secretion .	Recent studies with heterozygous MTP knockout mice have suggested that half-normal levels of MTP in the liver reduce apoB secretion.	11	19	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	levels of MTP	mtp	apoB	apoB	apob	13	14	18	19
This suggests that NDGA treatment results in the inhibition of VLDL biosynthesis downstream of MTP mediated lipidation of ApoB .	This suggests that NDGA treatment results in the inhibition of VLDL biosynthesis downstream of MTP mediated lipidation of ApoB.	11	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MTP	MTP	MTP	ApoB	ApoB	ApoB	14	15	18	19
Taken together , we provide compelling evidence that BMI1 decreases ETOP induced G2/M checkpoint activation via reducing NBS1 mediated ATM activation .	Taken together, we provide compelling evidence that BMI1 decreases ETOP induced G2/M checkpoint activation via reducing NBS1 mediated ATM activation.	16	20	mediated	Positive_early_activation	Positive_activation	Negative_activation	NBS1	NBS1	NBS1	ATM	ATM	ATM	17	18	19	20
A fragment of human Nbs1 spanning residues 401 to 754 was previously shown to suppress ATM activation and nuclear localization defects in NBS patient cells .	A fragment of human Nbs1 spanning residues 401 to 754 was previously shown to suppress ATM activation and nuclear localization defects in NBS patient cells.	1	16	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	4	5	15	16
Interestingly , shRNA mediated silencing of ATMIN , but not Nbs1 , attenuated 3TF induced ATM and p53 activation ( XREF_SUPPLEMENTARY ) .	Interestingly, shRNA mediated silencing of ATMIN, but not Nbs1, attenuated 3TF induced ATM and p53 activation (XREF_SUPPLEMENTARY).	4	18	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	10	11	15	16
In addition , HCV core protein was shown to interact with NBS1 and prevent formation of the MRN complex , which impairs ATM mediated repair of DSBs .	In addition, HCV core protein was shown to interact with NBS1 and prevent formation of the MRN complex, which impairs ATM mediated repair of DSBs.	17	23	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MRN	MRN	MRN	ATM	ATM	ATM	17	18	22	23
Notably , overexpression of the NBS1 ubiquitinationdeficient mutant inhibits ATM activation upon genotoxic stress .	Notably, overexpression of the NBS1 ubiquitinationdeficient mutant inhibits ATM activation upon genotoxic stress.	2	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NBS1	overexpression of the NBS1	nbs1	ATM	ATM	atm	5	6	9	10
Deletion of the C-terminal domain of Nbs1 also failed to activate ATM as evidenced by the lack of IR induced ATM phosphorylation at S1981 ( XREF_FIG G ) .	Deletion of the C-terminal domain of Nbs1 also failed to activate ATM as evidenced by the lack of IR induced ATM phosphorylation at S1981 (XREF_FIG G).	4	12	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	6	7	11	12
DNA-PKcs Inhibits the Activation of ATM by MRN and DNA in Vitro .	DNA-PKcs Inhibits the Activation of ATM by MRN and DNA in Vitro.	1	9	Activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	MRN	MRN	MRN	ATM	ATM	ATM	7	8	5	6
These data indicate that ATMIN , and not NBS , partially diminishes ATM dependent 53BP1 localization at sites of replicative stress .	These data indicate that ATMIN, and not NBS, partially diminishes ATM dependent 53BP1 localization at sites of replicative stress.	4	15	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NBS	NBS	NBS	ATM	ATM	ATM	8	9	12	13
In contrast , the Nbs1 Delta B allele does not impair ATM activation but reduces ATM activity on particular substrates ( e.g ., SMC1 ) , while not affecting others .	In contrast, the Nbs1 Delta B allele does not impair ATM activation but reduces ATM activity on particular substrates (e.g., SMC1), while not affecting others.	4	12	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	4	5	11	12
In vitro experiments already several years ago showed that mirin efficiently blocked direct activation of ATM by MRN , and the exonuclease activity of MRE11 , thus , abolished the IR induced G2/M checkpoint and HR [ XREF_BIBR ] .	In vitro experiments already several years ago showed that mirin efficiently blocked direct activation of ATM by MRN, and the exonuclease activity of MRE11, thus, abolished the IR induced G2/M checkpoint and HR [XREF_BIBR].	11	18	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	MRN	MRN	MRN	ATM	ATM	ATM	17	18	15	16
Our previous data , as well as additional data presented here , suggests that the Nbs1 DeltaB mutation does not strongly impair DSB end capture and ATM activation , but does compromise resection efficiency , as indicated by reduced S4/8 phosphorylation of RPA and lower SSA efficiency .	Our previous data, as well as additional data presented here, suggests that the Nbs1 DeltaB mutation does not strongly impair DSB end capture and ATM activation, but does compromise resection efficiency, as indicated by reduced S4/8 phosphorylation of RPA and lower SSA efficiency.	15	27	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Nbs1	Nbs1	Nbs1	ATM	ATM	ATM	15	16	26	27
Disruption of MRN function through mutation or viral infection causes defects in ATM localization and activation [ XREF_BIBR - XREF_BIBR ] .	Disruption of MRN function through mutation or viral infection causes defects in ATM localization and activation [XREF_BIBR - XREF_BIBR].	2	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	MRN	MRN	MRN	ATM	ATM	ATM	2	3	12	13
While loss of the activity of MRN activated ATM may enhance the mutagenic effects of anticancer treatments and hamper the DDR barrier against tumorigenesis , the inhibition of the OS activated ATM activity , which mediates oxidative defenses , might be efficacious in controlling malignant cell growth .	While loss of the activity of MRN activated ATM may enhance the mutagenic effects of anticancer treatments and hamper the DDR barrier against tumorigenesis, the inhibition of the OS activated ATM activity, which mediates oxidative defenses, might be efficacious in controlling malignant cell growth.	4	18	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	MRN	MRN	MRN	ATM	ATM	ATM	6	7	8	9
Based on these results we designed a smaller panel of 62 agents containing targeted compounds that effectively reduced STAT3 activity , including cyclin dependent kinase ( CDK ) , mammalian target of rapamycin ( mTOR ) , heat shock protein 90 ( Hsp90 ) , and Janus kinase ( JAK ) inhibitors .	Based on these results we designed a smaller panel of 62 agents containing targeted compounds that effectively reduced STAT3 activity, including cyclin dependent kinase (CDK), mammalian target of rapamycin (mTOR), heat shock protein 90 (Hsp90), and Janus kinase (JAK) inhibitors.	14	35	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	34	35	18	19
In CAIA mice , metformin treatment resulted in a significant improvement of arthritis score , with reduced bone destruction , inflammatory cytokines production , and RORgammat expressing T cells associated with the AMPK and mTOR mediated inhibition of STAT3 signaling .	In CAIA mice, metformin treatment resulted in a significant improvement of arthritis score, with reduced bone destruction, inflammatory cytokines production, and RORgammat expressing T cells associated with the AMPK and mTOR mediated inhibition of STAT3 signaling.	34	39	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	34	35	38	39
Mammalian target of rapamycin complex 1 ( mTORC1 ) activates STAT3 during hypoxia in renal cystadenoma cells , and promotes HIF-1alpha and VEGF expression [ XREF_BIBR ] .	Mammalian target of rapamycin complex 1 (mTORC1) activates STAT3 during hypoxia in renal cystadenoma cells, and promotes HIF-1alpha and VEGF expression [XREF_BIBR].	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	STAT3	STAT3	STAT3	0	4	10	11
Conversely , deletion of TSC2 , the key negative regulator of mTOR , diminished NF-kappaB but enhanced STAT3 activity and reversed this proinflammatory cytokine shift .	Conversely, deletion of TSC2, the key negative regulator of mTOR, diminished NF-kappaB but enhanced STAT3 activity and reversed this proinflammatory cytokine shift.	9	18	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	11	12	17	18
It is known that the mTOR signaling pathway can inhibit the inflammatory response in microglia and monocytes by reducing NF-kappaB activation and enhancing STAT3 activity and anti-inflammatory IL-10 production [ XREF_BIBR , XREF_BIBR ] , whereas inhibition of mTOR with or without rapamycin has reciprocal effects [ XREF_BIBR - XREF_BIBR ] .	It is known that the mTOR signaling pathway can inhibit the inflammatory response in microglia and monocytes by reducing NF-kappaB activation and enhancing STAT3 activity and anti-inflammatory IL-10 production [XREF_BIBR, XREF_BIBR], whereas inhibition of mTOR with or without rapamycin has reciprocal effects [XREF_BIBR - XREF_BIBR].	5	24	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	5	6	23	24
We included mammalian target of rapamycin ( mTOR ) and STAT3 that were previously reported to be under the influence of glutamine : glutamine can activate mTOR through phosphorylation on S2448 , XREF_BIBR and mTOR can in turn activate STAT3 by phosphorylation on S727 XREF_BIBR ( human sequences ) .	We included mammalian target of rapamycin (mTOR) and STAT3 that were previously reported to be under the influence of glutamine : glutamine can activate mTOR through phosphorylation on S2448, XREF_BIBR and mTOR can in turn activate STAT3 by phosphorylation on S727 XREF_BIBR (human sequences).	5	40	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	7	8	39	40
Mammalian target of rapamycin inhibition by rapamycin reduces both Stat3 activation in effector T cells and the frequency of IL-17-producing T cells in lupus patients .	Mammalian target of rapamycin inhibition by rapamycin reduces both Stat3 activation in effector T cells and the frequency of IL-17-producing T cells in lupus patients.	0	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	Stat3	Stat3	Stat3	0	4	9	10
The lack of mTOR was reported to cause potentially meaningful decreases of IL-4-induced STAT6 and IL-6-induced STAT3 .	The lack of mTOR was reported to cause potentially meaningful decreases of IL-4-induced STAT6 and IL-6-induced STAT3.	1	17	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	STAT3	STAT3	STAT3	3	4	16	17
Importantly , dual inhibition of PI3K and Akt and mTOR pathways targeted rictor and raptor in WM cells , even when cultured in presence of BMSCs which induced up-regulation of raptor but not rictor .	Importantly, dual inhibition of PI3K and Akt and mTOR pathways targeted rictor and raptor in WM cells, even when cultured in presence of BMSCs which induced up-regulation of raptor but not rictor.	9	15	targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	raptor	raptor	raptor	9	10	14	15
Enhancing mTOR targeted cancer therapy by preventing mTOR and raptor inhibition initiated , mTOR and rictor independent Akt activation .	Enhancing mTOR targeted cancer therapy by preventing mTOR and raptor inhibition initiated, mTOR and rictor independent Akt activation.	0	10	targeted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	raptor	raptor	raptor	1	2	9	10
The present study is the first to our knowledge to demonstrate that phosphorylation of mTOR Ser2481 was specifically inhibited in HCC cell lines harboring activated mTORC1 and Raptor when treated with nanomolar concentrations of mTORC1 inhibitors .	The present study is the first to our knowledge to demonstrate that phosphorylation of mTOR Ser2481 was specifically inhibited in HCC cell lines harboring activated mTORC1 and Raptor when treated with nanomolar concentrations of mTORC1 inhibitors.	12	28	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	mTOR	phosphorylation of mTOR Ser2481	mtor	Raptor	Raptor	raptor	14	15	27	28
Results of this study showed that inhibition of the mammalian target of rapamycin complex 1 ( mTORC1 ) pathway , by rapamycin or by small interfering RNA mediated targeting of raptor ( gene name , RPTOR ) , enhanced amniotic fluid stem cell differentiation toward a chondrocytic phenotype and increased their engrafting efficiency into cartilaginous structures .	Results of this study showed that inhibition of the mammalian target of rapamycin complex 1 (mTORC1) pathway, by rapamycin or by small interfering RNA mediated targeting of raptor (gene name, RPTOR), enhanced amniotic fluid stem cell differentiation toward a chondrocytic phenotype and increased their engrafting efficiency into cartilaginous structures.	9	33	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	raptor	raptor	raptor	9	13	30	31
However , the phosphomimetic mutation of all four sites to aspartate ( 4xD ) significantly impairs activation of SRF by myocardin , whereas the phosphodeficient mutation of all four sites to alanine ( 4xA ) has no effect .	However, the phosphomimetic mutation of all four sites to aspartate (4xD) significantly impairs activation of SRF by myocardin, whereas the phosphodeficient mutation of all four sites to alanine (4xA) has no effect.	15	21	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	myocardin	myocardin	myocardin	SRF	SRF	SRF	20	21	18	19
These data are in contrast with other studies in which Notch target genes have been reported to antagonize SRF ( serum response factor ) and myocardin , the main transcription regulators of VSMC gene expression and SMC differentiation [ XREF_BIBR , XREF_BIBR ] .	These data are in contrast with other studies in which Notch target genes have been reported to antagonize SRF (serum response factor) and myocardin, the main transcription regulators of VSMC gene expression and SMC differentiation [XREF_BIBR, XREF_BIBR].	4	30	antagonize	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	myocardin	myocardin	myocardin	SRF	SRF	SRF	25	26	18	19
In conclusion , our study is the first to investigate corpus cavernosum smooth muscle cells phenotypes in the early stages of cavernous injury model rats , and Myocd reversed phenotypic modulation by activating serum response factor .	In conclusion, our study is the first to investigate corpus cavernosum smooth muscle cells phenotypes in the early stages of cavernous injury model rats, and Myocd reversed phenotypic modulation by activating serum response factor.	27	36	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Myocd	Myocd	Myocd	serum response factor	serum response factor	serum response factor	27	28	33	36
It is unlikely that engagement of TRIF occurs at lower concentrations of TLR4 agonist than are required to engage MyD88 , because there was no statistically significant difference in the log ( EC 50 ) values of sLipid A for the TRIF dependent activating phosphorylation of IRF3 and the MyD88 dependent loss of IRAK1 ( XREF_FIG ) .	It is unlikely that engagement of TRIF occurs at lower concentrations of TLR4 agonist than are required to engage MyD88, because there was no statistically significant difference in the log (EC 50) values of sLipid A for the TRIF dependent activating phosphorylation of IRF3 and the MyD88 dependent loss of IRAK1 (XREF_FIG).	49	54	loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	MyD88	MyD88	MyD88	IRAK1	IRAK1	IRAK1	49	50	53	54
It is plausible that respiratory syncytial virus , which activates TLR2 signaling and influenza virus which activates MyD-88 dependent TLR signaling can deplete IRAK-1 and this may limit CXCL-10 production and excessive inflammation caused by these viruses .	It is plausible that respiratory syncytial virus, which activates TLR2 signaling and influenza virus which activates MyD-88 dependent TLR signaling can deplete IRAK-1 and this may limit CXCL-10 production and excessive inflammation caused by these viruses.	16	25	deplete	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	MyD-88	MyD-88	MyD-88	IRAK-1	IRAK-1	IRAK-1	17	18	23	24
One candidate that fits these data is MyD88 itself , as the alternate splice form MyD88 S inhibits IRAK activation downstream of MyD88 and upstream of IKK XREF_BIBR , XREF_BIBR , XREF_BIBR .	One candidate that fits these data is MyD88 itself, as the alternate splice form MyD88 S inhibits IRAK activation downstream of MyD88 and upstream of IKK XREF_BIBR, XREF_BIBR, XREF_BIBR.	15	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MyD88	MyD88	MyD88	IRAK	IRAK	IRAK	15	16	18	19
SGK1 is activated by the serine/threonine kinase mammalian target of rapamycin ( mTOR ) isoform mTORC2 .	SGK1 is activated by the serine/threonine kinase mammalian target of rapamycin (mTOR) isoform mTORC2.	0	11	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	SGK1	SGK1	SGK1	7	11	0	1
The mechanistic target of rapamycin complex 2 ( mTORC2 ) and Rictor ( RICT-1 ) modulate longevity by causing SGK-1 to inhibit the stress response transcription factor SKN-1 and Nrf in the intestine , shortening lifespan .	The mechanistic target of rapamycin complex 2 (mTORC2) and Rictor (RICT-1) modulate longevity by causing SGK-1 to inhibit the stress response transcription factor SKN-1 and Nrf in the intestine, shortening lifespan.	1	20	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	SGK-1	SGK-1	SGK-1	1	5	19	20
This pathway is known to regulate differentiation of Th17 cells by AKT activation of the Mechanistic Target of Rapamycin Complex 1 ( mTORC1 ) , thereby activating HIF-1alpha and S6K2 , as well as inhibiting Gfi1 XREF_BIBR XREF_BIBR XREF_BIBR .	This pathway is known to regulate differentiation of Th17 cells by AKT activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1), thereby activating HIF-1alpha and S6K2, as well as inhibiting Gfi1 XREF_BIBR XREF_BIBR XREF_BIBR.	15	30	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mechanistic Target of Rapamycin	Mechanistic Target of Rapamycin	Mechanistic Target of Rapamycin	S6K2	S6K2	S6K2	15	19	29	30
As a predominantly nuclear protein , S6K2 activation was facilitated by enhanced mTOR nuclear import with the tagging of an exogenous nuclear localization signal and diminished by enhanced mTOR nuclear export with the tagging of a nuclear export sequence .	As a predominantly nuclear protein, S6K2 activation was facilitated by enhanced mTOR nuclear import with the tagging of an exogenous nuclear localization signal and diminished by enhanced mTOR nuclear export with the tagging of a nuclear export sequence.	6	29	diminished	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	mTOR	mTOR	mTOR	S6K2	S6K2	S6K2	28	29	6	7
In our previous study , we found that depletion of hMYH disrupts ATR and Chk1 activation following hydroxyurea ( HU ) and ultraviolet treatment [ XREF_BIBR ] .	In our previous study, we found that depletion of hMYH disrupts ATR and Chk1 activation following hydroxyurea (HU) and ultraviolet treatment [XREF_BIBR].	8	15	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	hMYH	hMYH	hMYH	ATR	ATR	ATR	10	11	12	13
The siRNA induced knock-down of MyD88 prevented the LPS induced increase in IRAK4 activity in Caco-2 monolayers ( XREF_FIG ) .	The siRNA induced knock-down of MyD88 prevented the LPS induced increase in IRAK4 activity in Caco-2 monolayers (XREF_FIG).	3	13	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MyD88	MyD88	MyD88	IRAK4	IRAK4	IRAK4	5	6	12	13
Furthermore , both ML7 and BDM suppressed expression of MyoD and myogenin , induced p27 ( kip1 ) but not p21 ( cip1 ) , and inhibited differentiation .	Furthermore, both ML7 and BDM suppressed expression of MyoD and myogenin, induced p27 (kip1) but not p21 (cip1), and inhibited differentiation.	3	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MyoD	ML7 and BDM suppressed expression of MyoD	myod	p21	p21	p21	9	10	20	21
Downregulation of TIF2 using short hairpin RNA disrupted the AR loading to the PSA enhancer and subsequently inhibited AR activity .	Downregulation of TIF2 using short hairpin RNA disrupted the AR loading to the PSA enhancer and subsequently inhibited AR activity.	0	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TIF2	TIF2	TIF2	AR	AR	AR	2	3	18	19
Filamin-A ( FLNa ) interferes with AR interdomain interactions and competes with the co-activator transcriptional intermediary factor 2 ( TIF2 ) to specifically down-regulate AR function [ XREF_BIBR ] .	Filamin-A (FLNa) interferes with AR interdomain interactions and competes with the co-activator transcriptional intermediary factor 2 (TIF2) to specifically down-regulate AR function [XREF_BIBR].	17	25	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TIF2	TIF2	TIF2	AR	AR	AR	19	20	24	25
NCoR inhibition of AR resembles that of CKbetaBP2 and CRIF1 in that its AR inhibitory effect in the presence of R1881 can be reversed by TIF2 , suggesting competition between NCoR and TIF2 for binding sites on ligand activated AR .	NCoR inhibition of AR resembles that of CKbetaBP2 and CRIF1 in that its AR inhibitory effect in the presence of R1881 can be reversed by TIF2, suggesting competition between NCoR and TIF2 for binding sites on ligand activated AR.	13	26	reversed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	TIF2	TIF2	TIF2	AR	AR	AR	25	26	13	14
45 Downregulation of NCoA2 reduces AR target gene expression and inhibits proliferation of AR dependent and -independent prostate cancer cells , whereas it is believed that in AR positive cancer cells , high levels of androgens repress NCoA2 expression .	45 Downregulation of NCoA2 reduces AR target gene expression and inhibits proliferation of AR dependent and -independent prostate cancer cells, whereas it is believed that in AR positive cancer cells, high levels of androgens repress NCoA2 expression.	1	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NCoA2	NCoA2	NCoA2	AR	AR	AR	3	4	13	14
Knockdown of TIF-2 has been reported to inhibit androgen independent AR activation in C4-2 cells .	Knockdown of TIF-2 has been reported to inhibit androgen independent AR activation in C4-2 cells.	0	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TIF-2	TIF-2	TIF-2	AR	AR	AR	2	3	10	11
Furthermore , ARA70 was able to recover the COUP-TF II induced AR repression in a dose dependent manner ( XREF_FIG ) , and COUP-TF II was able to repress the ARA70 enhanced AR transactivation in a dose dependent manner ( XREF_FIG ) .	Furthermore, ARA70 was able to recover the COUP-TF II induced AR repression in a dose dependent manner (XREF_FIG), and COUP-TF II was able to repress the ARA70 enhanced AR transactivation in a dose dependent manner (XREF_FIG).	28	33	enhanced	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ARA70	ARA70	ARA70	AR	AR	AR	30	31	32	33
ARA70 overexpression reversed the AR down-regulatory effect on ERalpha signaling .	ARA70 overexpression reversed the AR down-regulatory effect on ERalpha signaling.	0	6	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ARA70	ARA70 overexpression	ara70	AR	AR	ar	0	1	4	5
As shown in both LNCaP and CWR22rv1 cells , knockdown of ARA70 by stably transfected ARA70-siRNA results in the reduction of the PSA induced AR transactivation ( XREF_FIG , lanes 9 vs 3 in LNCaP ; XREF_FIG lanes 7 vs 2 in CWR22rv1 ) , suggesting PSA might go through interaction with ARA70 to enhance its coactivity that results in the induction of AR transactivation .	As shown in both LNCaP and CWR22rv1 cells, knockdown of ARA70 by stably transfected ARA70-siRNA results in the reduction of the PSA induced AR transactivation (XREF_FIG, lanes 9 vs 3 in LNCaP; XREF_FIG lanes 7 vs 2 in CWR22rv1), suggesting PSA might go through interaction with ARA70 to enhance its coactivity that results in the induction of AR transactivation.	9	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ARA70	ARA70	ARA70	AR	AR	AR	11	12	24	25
Such a mechanism has been shown for Necdin , which sequesters EID-1 , an E1A like protein that inhibits MyoD by suppressing the acetyltransferase activity of its transcriptional co-activator p300 [ XREF_BIBR ] .	Such a mechanism has been shown for Necdin, which sequesters EID-1, an E1A like protein that inhibits MyoD by suppressing the acetyltransferase activity of its transcriptional co-activator p300 [XREF_BIBR].	5	14	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Necdin	Necdin	Necdin	EID-1	EID-1	EID-1	7	8	11	12
Necdin is mainly present in the cytoplasm of mature neurons and was reported to sequester EID1 in the cytoplasm , rendering EID1 less active in transcriptional repression because of its retention in the cytoplasm .	Necdin is mainly present in the cytoplasm of mature neurons and was reported to sequester EID1 in the cytoplasm, rendering EID1 less active in transcriptional repression because of its retention in the cytoplasm.	0	18	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Necdin	Necdin	Necdin	EID1	EID1	EID1	0	1	15	16
Filopodia downregulation could be due to the fact that Nck sequesters N-WASP from the Cdc42-GTP pathway , since Nck has a higher affinity to N-WASP [ XREF_BIBR ] .	Filopodia downregulation could be due to the fact that Nck sequesters N-WASP from the Cdc42-GTP pathway, since Nck has a higher affinity to N-WASP [XREF_BIBR].	9	12	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Nck	Nck	Nck	N-WASP	N-WASP	N-WASP	9	10	11	12
Downregulation of filopodia could be due to the fact that Nck sequesters N-WASP from the Cdc42-GTP pathway , as the former was shown to have a greater affinity to N-WASP than the latter .	Downregulation of filopodia could be due to the fact that Nck sequesters N-WASP from the Cdc42-GTP pathway, as the former was shown to have a greater affinity to N-WASP than the latter.	10	13	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Nck	Nck	Nck	N-WASP	N-WASP	N-WASP	10	11	12	13
Knockout of SRC-3 in these cells caused higher AR immunoreactivity , suggesting that the AH tumors in 3PEKOT mice might be more differentiated .	Knockout of SRC-3 in these cells caused higher AR immunoreactivity, suggesting that the AH tumors in 3PEKOT mice might be more differentiated.	0	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SRC-3	SRC-3	SRC-3	AR	AR	AR	2	3	8	9
Knockdown of SRC-1 and ACTR , but not SRC-2 , individually or in combination , decreased AR mRNA and protein expression .	Knockdown of SRC-1 and ACTR, but not SRC-2, individually or in combination, decreased AR mRNA and protein expression.	0	17	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ACTR	ACTR	ACTR	AR	AR	AR	4	5	16	17
Consistently , Nek2 expression level was unchanged upon depletion of Hec1 by two distinct Hec1 siRNAs ( XREF_FIG ) .	Consistently, Nek2 expression level was unchanged upon depletion of Hec1 by two distinct Hec1 siRNAs (XREF_FIG).	2	11	was unchanged upon depletion	Negative_activation_copula_1	Positive_activation	Negative_activation	Nek2	Nek2 expression level	nek2	Hec1	Hec1	hec1	2	3	10	11
A reason for this is the compensation of the loss of p62 by Nbr1 , which is a homologue of p62 .	A reason for this is the compensation of the loss of p62 by Nbr1, which is a homologue of p62.	6	18	loss	Negative_activation_token_2_noun	Positive_activation	Negative_activation	Nbr1	Nbr1	Nbr1	p62	p62	p62	13	14	11	12
Moreover , nicastrin deficiency reduces the levels of APH-1 , PEN-2 and PS1 fragments , and affects their intracellular trafficking .	Moreover, nicastrin deficiency reduces the levels of APH-1, PEN-2 and PS1 fragments, and affects their intracellular trafficking.	2	13	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	nicastrin	nicastrin	nicastrin	PS1	PS1	PS1	2	3	12	13
However , our experiments in which MVA was compared to MVA and K1L , a recombinant virus which does not induce IkappaBalpha degradation or nuclear translocation of p65 and RelA in infected cells , revealed that canonical NF-kappaB signaling via p65 and RelA is not required for the liberation of AA , the accumulation of COX-2 , or PGE 2 production by MVA infected C3HA cells .	However, our experiments in which MVA was compared to MVA and K1L, a recombinant virus which does not induce IkappaBalpha degradation or nuclear translocation of p65 and RelA in infected cells, revealed that canonical NF-kappaB signaling via p65 and RelA is not required for the liberation of AA, the accumulation of COX-2, or PGE 2 production by MVA infected C3HA cells.	21	30	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	21	22	29	30
The levels of p-IkappaBalpha increased after LPS stimulation whereas the levels of IkappaBalpha decreased , resulting in the translocation of NF-kappaB p65 into the nucleus .	The levels of p-IkappaBalpha increased after LPS stimulation whereas the levels of IkappaBalpha decreased, resulting in the translocation of NF-kappaB p65 into the nucleus.	10	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	levels of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	12	13	20	22
[ XREF_BIBR ] In normal cells , p65 of NF-kappaB is sequestered by IkappaBalpha in the cytoplasm .	[XREF_BIBR] In normal cells, p65 of NF-kappaB is sequestered by IkappaBalpha in the cytoplasm.	7	16	sequestered	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	13	14	7	8
Furthermore , treatment of both prostate cancer cells with BA decreased the phosphorylation of IkappaB kinase ( IKK ) alpha and I-kappa-B-alpha ( IkappaBalpha ) inhibiting the nuclear location of NF-kappaB and p65 causing cytosolic accumulation and resulting in its decreased nuclear binding .	Furthermore, treatment of both prostate cancer cells with BA decreased the phosphorylation of IkappaB kinase (IKK) alpha and I-kappa-B-alpha (IkappaBalpha) inhibiting the nuclear location of NF-kappaB and p65 causing cytosolic accumulation and resulting in its decreased nuclear binding.	21	33	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	23	24	32	33
Activation of the NF-kappaB canonical pathway requires IkappaB kinase ( IKK ) beta activation , phosphorylation of IkappaBalpha which sequesters the NF-kappaB p65 subunit in the cytoplasm , followed by phosphorylated IkappaBalpha destruction through the proteasome pathway and the release and nuclear translocation of p65 .	Activation of the NF-kappaB canonical pathway requires IkappaB kinase (IKK) beta activation, phosphorylation of IkappaBalpha which sequesters the NF-kappaB p65 subunit in the cytoplasm, followed by phosphorylated IkappaBalpha destruction through the proteasome pathway and the release and nuclear translocation of p65.	15	23	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	phosphorylation of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	17	18	21	23
We observed that genipin induced IkappaBalpha accumulation and reduced its phosphorylation , down-regulated IKKalpha and blocked the translocation of p65 into nuclear regions of TAMs .	We observed that genipin induced IkappaBalpha accumulation and reduced its phosphorylation, down-regulated IKKalpha and blocked the translocation of p65 into nuclear regions of TAMs.	3	20	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	genipin induced IkappaBalpha	ikappabalpha	p65	p65	p65	5	6	19	20
This evidence demonstrated that Tat competed for the binding of IkappaB-alpha to p65 and prevented the IkappaB-alpha repression of p65 .	This evidence demonstrated that Tat competed for the binding of IkappaB-alpha to p65 and prevented the IkappaB-alpha repression of p65.	16	20	repression	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	p65	p65	p65	16	17	19	20
XREF_BIBR , XREF_BIBR In our study , theaflavin inhibited LPS induced IkappaBalpha degradation and nuclear translocation of RelA in BMMs .	XREF_BIBR, XREF_BIBR In our study, theaflavin inhibited LPS induced IkappaBalpha degradation and nuclear translocation of RelA in BMMs.	7	18	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	theaflavin inhibited LPS induced IkappaBalpha	ikappabalpha	RelA	RelA	rela	11	12	17	18
Furthermore , wedelolactone upregulated the expression of IkappaBalpha and inhibited phosphonation and nuclear migration of p65 .	Furthermore, wedelolactone upregulated the expression of IkappaBalpha and inhibited phosphonation and nuclear migration of p65.	2	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	wedelolactone upregulated the expression of IkappaBalpha	ikappabalpha	p65	p65	p65	7	8	15	16
BA treatment decreases phosphorylation of IkappaBalpha at Ser32/36 , causing increased NF-kappaB and p65 level s in the cytosol ( XREF_FIG ) .	BA treatment decreases phosphorylation of IkappaBalpha at Ser32/36, causing increased NF-kappaB and p65 level s in the cytosol (XREF_FIG).	0	15	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	BA treatment decreases phosphorylation of IkappaBalpha	ikappabalpha	p65	p65	p65	5	6	13	14
Here we show that the bacterially expressed and purified carboxy-terminal region ( CTR ) of p105 abolishes the binding of p50 homodimers to a kappa B motif but minimally affects the binding of p65 homodimers and NF-kappa B. By contrast , MAD-3 inhibits the binding of p65 and NF-kappa B but not p50 .	Here we show that the bacterially expressed and purified carboxy-terminal region (CTR) of p105 abolishes the binding of p50 homodimers to a kappa B motif but minimally affects the binding of p65 homodimers and NF-kappa B. By contrast, MAD-3 inhibits the binding of p65 and NF-kappa B but not p50.	41	49	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MAD-3	MAD-3	MAD-3	p65	p65	p65	41	42	46	47
Resveratrol treatment also reduced nuclear factor-kappaB ( NF-kappaB ) activity , reduced phosphorylation levels of IkappaBalpha , and reduced nuclear translocation of the NF-kappaB subunit p65 .	Resveratrol treatment also reduced nuclear factor-kappaB (NF-kappaB) activity, reduced phosphorylation levels of IkappaBalpha, and reduced nuclear translocation of the NF-kappaB subunit p65.	0	26	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	Resveratrol treatment also reduced nuclear factor-kappaB (NF-kappaB) activity, reduced phosphorylation levels of IkappaBalpha	ikappabalpha	p65	p65	p65	15	16	25	26
In particular , IkappaBalpha can sequester p65 in the cytoplasm by masking the nuclear localization sequences thereby inhibiting its translocation into the nucleus [ XREF_BIBR , XREF_BIBR ] .	In particular, IkappaBalpha can sequester p65 in the cytoplasm by masking the nuclear localization sequences thereby inhibiting its translocation into the nucleus [XREF_BIBR, XREF_BIBR].	3	9	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	3	4	6	7
NF-kappaB activity is controlled by inhibitors of NF-kappaB ( such as IkappaBalpha which inhibits p65 and p50 dimers ) that keep NF-kappaB inactive in the cytoplasm .	NF-kappaB activity is controlled by inhibitors of NF-kappaB (such as IkappaBalpha which inhibits p65 and p50 dimers) that keep NF-kappaB inactive in the cytoplasm.	3	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	11	12	14	15
In the present studies neonatal PMN exhibited earlier IkappaBalpha degradation and prominent basal phosphorylation levels of p65 and RelA ( XREF_FIG ) , consistent with NF-kappaB activation status .	In the present studies neonatal PMN exhibited earlier IkappaBalpha degradation and prominent basal phosphorylation levels of p65 and RelA (XREF_FIG), consistent with NF-kappaB activation status.	8	19	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	8	9	18	19
On the other hand , it did not alter IkappaBalpha degradation or nuclear translocation of p65 .	On the other hand, it did not alter IkappaBalpha degradation or nuclear translocation of p65.	9	16	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	9	10	15	16
Mechanistically , IkappaBalpha blocks the association of ACTN4 and p65 in the cytosol .	Mechanistically, IkappaBalpha blocks the association of ACTN4 and p65 in the cytosol.	2	10	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	2	3	9	10
The NF and kappaB dimer p50 and p65 is normally sequestered in the cytosol by IkappaBalpha .	The NF and kappaB dimer p50 and p65 is normally sequestered in the cytosol by IkappaBalpha.	1	16	sequestered	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	15	16	7	8
Fourth , NF-kappaB inhibition either by overexpression of IkappaBalpha-SR or knockdown of p65 abolishes the ST80 and Bortezomib stimulated upregulation of BAG3 .	Fourth, NF-kappaB inhibition either by overexpression of IkappaBalpha-SR or knockdown of p65 abolishes the ST80 and Bortezomib stimulated upregulation of BAG3.	3	13	inhibition	Negative_activation_syntax_1_noun	Positive_activation	Negative_activation	IkappaBalpha-SR	overexpression of IkappaBalpha-SR	ikappabalpha-sr	p65	p65	p65	8	9	12	13
fAbeta 1-40 was found to induce upregulation in phosphorylation levels of IKKalpha and IKKbeta ( P < 0.001 , Figures XREF_FIG and XREF_FIG ) , decrease the levels of IkappaBalpha ( P < 0.001 , Figures XREF_FIG and XREF_FIG ) , and increase the NF-kappaB p65 distribution in nucleus ( P < 0.001 , Figures XREF_FIG and XREF_FIG ) .	fAbeta 1-40 was found to induce upregulation in phosphorylation levels of IKKalpha and IKKbeta (P < 0.001, Figures XREF_FIG and XREF_FIG), decrease the levels of IkappaBalpha (P < 0.001, Figures XREF_FIG and XREF_FIG), and increase the NF-kappaB p65 distribution in nucleus (P < 0.001, Figures XREF_FIG and XREF_FIG).	0	46	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	fAbeta 1-40 was found to induce upregulation in phosphorylation levels of IKKalpha and IKKbeta (P < 0.001, Figures XREF_FIG and XREF_FIG), decrease the levels of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	29	30	44	46
LPS induced IkappaBalpha degradation and increased levels of NF-kappaB p65 subunit in the nucleus .	LPS induced IkappaBalpha degradation and increased levels of NF-kappaB p65 subunit in the nucleus.	0	10	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	LPS induced IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	2	3	8	10
In contrast , JWH133 treatment inhibited the degradation and phosphorylation of IkappaB-alpha and decreased the levels of the p65 subunit of NF-kappaB in the nuclear extracts of the lung tissues .	In contrast, JWH133 treatment inhibited the degradation and phosphorylation of IkappaB-alpha and decreased the levels of the p65 subunit of NF-kappaB in the nuclear extracts of the lung tissues.	3	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB-alpha	JWH133 treatment inhibited the degradation and phosphorylation of IkappaB-alpha	ikappab-alpha	p65	p65	p65	11	12	18	19
IkappaBalpha sequesters p65 : p50 in the cytoplasm and is a confirmed target of miR-30e * [ XREF_BIBR ] .	IkappaBalpha sequesters p65 : p50 in the cytoplasm and is a confirmed target of miR-30e * [XREF_BIBR].	0	4	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	0	1	2	3
The increased level of IkappaBalpha degradation and translocation of p65 and p50 as a result of TPA stimulation were significantly suppressed by treatment with BVT948 ( XREF_FIG B ) .	The increased level of IkappaBalpha degradation and translocation of p65 and p50 as a result of TPA stimulation were significantly suppressed by treatment with BVT948 (XREF_FIG B).	4	14	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	4	5	9	10
Exposure to c-SWNTs decreased levels of IkappaBalpha and p65 in the cytoplasm at 7 and 30 days ( XREF_FIG ) , suggesting IkappaBalpha degradation and translocation of p65 proteins to the nucleus .	Exposure to c-SWNTs decreased levels of IkappaBalpha and p65 in the cytoplasm at 7 and 30 days (XREF_FIG), suggesting IkappaBalpha degradation and translocation of p65 proteins to the nucleus.	22	28	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	22	23	27	28
Thus , the IkappaBalpha independent degradation of RelA , triggered by gammaHV68 , offers a plausible interpretation for the apparent paradoxical effect of RelA and the IkappaBalpha super-suppressor on gammaHV68 lytic replication .	Thus, the IkappaBalpha independent degradation of RelA, triggered by gammaHV68, offers a plausible interpretation for the apparent paradoxical effect of RelA and the IkappaBalpha super-suppressor on gammaHV68 lytic replication.	3	8	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	3	4	7	8
IkappaBalpha inhibits NF-kappaB by sequestering p65 in the cytoplasm .	IkappaBalpha inhibits NF-kappaB by sequestering p65 in the cytoplasm.	0	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	0	1	5	6
Activation of the canonical NF-kappaB pathway occurs when the IKKbeta ( IkappaB kinase beta ) kinase phosphorylates IkappaBalpha causing its degradation and release of the p50 and p65 ( RelA ) heterodimer allowing for translocation to the nucleus where it regulates gene expression .	Activation of the canonical NF-kappaB pathway occurs when the IKKbeta (IkappaB kinase beta) kinase phosphorylates IkappaBalpha causing its degradation and release of the p50 and p65 (RelA) heterodimer allowing for translocation to the nucleus where it regulates gene expression.	9	31	causing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IKKbeta (IkappaB kinase beta) kinase phosphorylates IkappaBalpha	ikappabalpha	p65	p65	p65	17	18	27	28
Catalpol enhanced IkappaB-alpha and SOD1 levels , blocked nuclear NF-kappaB p65 expression during STC induced AP ( XREF_FIG ) , and induced degradation of NF-kappaB p65 ( as evident from the staining intensity ) in the nucleus , particularly at 12 h after STC injection ( XREF_FIG a-j ) .	Catalpol enhanced IkappaB-alpha and SOD1 levels, blocked nuclear NF-kappaB p65 expression during STC induced AP (XREF_FIG), and induced degradation of NF-kappaB p65 (as evident from the staining intensity) in the nucleus, particularly at 12 h after STC injection (XREF_FIG a-j).	0	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB-alpha	Catalpol enhanced IkappaB-alpha and SOD1 levels	ikappab-alpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	2	3	24	26
In the classical NF-kappaB pathway , the IkappaB kinase complex directly phosphorylates IkappaBalpha , which sequesters the NF and kappaB heterodimer p65 ( also known as RelA ) and p50 in the cytosol , leading to the ubiquitination and proteasomal degradation of IkappaBalpha [ XREF_BIBR , XREF_BIBR ] .	In the classical NF-kappaB pathway, the IkappaB kinase complex directly phosphorylates IkappaBalpha, which sequesters the NF and kappaB heterodimer p65 (also known as RelA) and p50 in the cytosol, leading to the ubiquitination and proteasomal degradation of IkappaBalpha [XREF_BIBR, XREF_BIBR].	7	22	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaB kinase complex directly phosphorylates IkappaBalpha	ikappabalpha	p65	p65	p65	12	13	21	22
This suggests that increased expression and phosphorylation of RelA occurs at the stage of the benign naevus , but IkappaB-alpha is able to sequester RelA in the cytoplasm and regulate RelA transcriptional transactivation .	This suggests that increased expression and phosphorylation of RelA occurs at the stage of the benign naevus, but IkappaB-alpha is able to sequester RelA in the cytoplasm and regulate RelA transcriptional transactivation.	19	29	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	RelA	RelA	RelA	19	20	24	25
IkappaB-alpha is subsequently ubiquitinated and then degraded , allowing the NF-kappaB p50 and p65 subunits to translocate to the nucleus [ XREF_BIBR ] .	IkappaB-alpha is subsequently ubiquitinated and then degraded, allowing the NF-kappaB p50 and p65 subunits to translocate to the nucleus [XREF_BIBR].	0	14	allowing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha is subsequently ubiquitinated	ikappab-alpha	p65	p65	p65	0	1	13	14
EGCG suppressed the TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha , thereby decreasing the phosphorylation and nuclear translocation of the NF-kappaB p65 subunit in HUVECs .	EGCG suppressed the TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, thereby decreasing the phosphorylation and nuclear translocation of the NF-kappaB p65 subunit in HUVECs.	0	21	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB-alpha	EGCG suppressed the TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha	ikappab-alpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	8	9	19	21
In this study , we demonstrated that knockdown of HMGB1 expression significantly inhibited the expression levels of NF-kappaB and p65 and VEGF-C , up-regulated IkappaBalpha expression , and suppressed the nuclear translocation and DNA binding activity of NF-kappaB and p65 , which indicated that HMGB1 might regulate VEGF-C expression in the development of BUC via the NF-kappaB signalling pathway .	In this study, we demonstrated that knockdown of HMGB1 expression significantly inhibited the expression levels of NF-kappaB and p65 and VEGF-C, up-regulated IkappaBalpha expression, and suppressed the nuclear translocation and DNA binding activity of NF-kappaB and p65, which indicated that HMGB1 might regulate VEGF-C expression in the development of BUC via the NF-kappaB signalling pathway.	9	42	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	HMGB1 expression significantly inhibited the expression levels of NF-kappaB and p65 and VEGF-C, up-regulated IkappaBalpha expression	ikappabalpha	p65	p65	p65	24	25	39	40
Knockdown of miR-10a decreases the expression of MAP3K7 and betaTRC , which upregulates phosphorylation of IkappaBalpha , causing more nuclear transport of NF-kappaB p65 and upregulation of the inflammatory cytokines such as MCP-1 , IL-6 , IL-8 , VCAM1 , and E-selectin ( SELE ) [ XREF_BIBR ] .	Knockdown of miR-10a decreases the expression of MAP3K7 and betaTRC, which upregulates phosphorylation of IkappaBalpha, causing more nuclear transport of NF-kappaB p65 and upregulation of the inflammatory cytokines such as MCP-1, IL-6, IL-8, VCAM1, and E-selectin (SELE) [XREF_BIBR].	5	24	causing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	expression of MAP3K7 and betaTRC, which upregulates phosphorylation of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	15	16	22	24
Furthermore , CI suppressed the production of prostaglandin E ( 2 , ) expression of cyclooxygenase type-2 ( COX-2 ) , blocked IkappaB-alpha degradation and activation of NF-kappaB p65 in BV-2 cells in a dose dependent manner .	Furthermore, CI suppressed the production of prostaglandin E (2,) expression of cyclooxygenase type-2 (COX-2), blocked IkappaB-alpha degradation and activation of NF-kappaB p65 in BV-2 cells in a dose dependent manner.	22	29	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	22	23	27	29
Pre-incubating the cells with 10 muM of the proteasome inhibitor MG-132 for 4 hr completely blocked IkappaBalpha degradation and nuclear translocation of p50 and p65 ( XREF_FIG ) .	Pre-incubating the cells with 10 muM of the proteasome inhibitor MG-132 for 4 hr completely blocked IkappaBalpha degradation and nuclear translocation of p50 and p65 (XREF_FIG).	16	25	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	16	17	24	25
In resting cells , cytoplasmic IkappaBalpha sequesters the canonical NFkappaB subunits p65 and p50 , preventing their nuclear translocation .	In resting cells, cytoplasmic IkappaBalpha sequesters the canonical NFkappaB subunits p65 and p50, preventing their nuclear translocation.	4	13	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	5	6	11	12
It was surprising that these investigators did not measure total IkappaBalpha degradation or inhibition of RelA nuclear localization by Klotho to buttress their suggestion of NF-kappaB canonical pathway inhibition by Klotho .	It was surprising that these investigators did not measure total IkappaBalpha degradation or inhibition of RelA nuclear localization by Klotho to buttress their suggestion of NF-kappaB canonical pathway inhibition by Klotho.	10	17	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	10	11	15	16
PEITC also suppressed LPS induced phosphorylation and degradation of IkBa and decreased nuclear translocation of p65 .	PEITC also suppressed LPS induced phosphorylation and degradation of IkBa and decreased nuclear translocation of p65.	0	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkBa	PEITC also suppressed LPS induced phosphorylation and degradation of IkBa	ikba	p65	p65	p65	9	10	15	16
While IkappaBalpha degradation and translocation of NF-kappaB p65 to nuclei were not significantly affected by either compound , the stability of eotaxin-1 mRNA was decreased with hetero-30-OH-GL .	While IkappaBalpha degradation and translocation of NF-kappaB p65 to nuclei were not significantly affected by either compound, the stability of eotaxin-1 mRNA was decreased with hetero-30-OH-GL.	1	8	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	1	2	6	8
Tylophorine reduced the IkappaBalpha protein level , and consequently p65 sequestered by IkappaBalpha was liberated and subjected to phosphorylation and NF-kappaB activation in TGEV infected ST cells .	Tylophorine reduced the IkappaBalpha protein level, and consequently p65 sequestered by IkappaBalpha was liberated and subjected to phosphorylation and NF-kappaB activation in TGEV infected ST cells.	9	16	sequestered	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	12	13	9	10
MaR1 caused an attenuation of TNF-alpha induced NF-kappaB activation in both cell types associated with inhibition of I-kappa Kinase ( IKK ) phosphorylation , IkappaB-alpha degradation and nuclear translocation of the NF- kappaB p65 subunit .	MaR1 caused an attenuation of TNF-alpha induced NF-kappaB activation in both cell types associated with inhibition of I-kappa Kinase (IKK) phosphorylation, IkappaB-alpha degradation and nuclear translocation of the NF- kappaB p65 subunit.	24	34	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	p65	p65	p65	24	25	33	34
Bcl-3 did not however modulate the classical IKK dependent signaling pathway per se , as it did not impair TNFalpha induced IkappaBalpha degradation or nuclear translocation of RelA , but instead delimited binding and access of RelA complexes to select regulatory gene regions , as shown here .	Bcl-3 did not however modulate the classical IKK dependent signaling pathway per se, as it did not impair TNFalpha induced IkappaBalpha degradation or nuclear translocation of RelA, but instead delimited binding and access of RelA complexes to select regulatory gene regions, as shown here.	19	28	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	TNFalpha induced IkappaBalpha	ikappabalpha	RelA	RelA	rela	21	22	27	28
Mutant construct for IkappaBalpha ( IkappaBalphaM ) XREF_BIBR or p100 ( p100M ) XREF_BIBR was transfected into LNCaP cells to block RelA : p50 dimer or RelB : p52 dimer nuclear translocation , respectively .	Mutant construct for IkappaBalpha (IkappaBalphaM) XREF_BIBR or p100 (p100M) XREF_BIBR was transfected into LNCaP cells to block RelA : p50 dimer or RelB : p52 dimer nuclear translocation, respectively.	1	22	block	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	3	4	21	22
Moreover , IKK-beta activation induces phosphorylation and degradation of IkappaBalpha , an event which targets NF-kappaB p65 to the nucleus , thereby enhancing NF-kappaB p65 transcriptional activity ( XREF_FIG ) .	Moreover, IKK-beta activation induces phosphorylation and degradation of IkappaBalpha, an event which targets NF-kappaB p65 to the nucleus, thereby enhancing NF-kappaB p65 transcriptional activity (XREF_FIG).	2	17	targets	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	IkappaBalpha	IKK-beta activation induces phosphorylation and degradation of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	9	10	15	17
The RHD also functions as a binding site for ankyrin repeats in the IkappaBalpha protein , which blocks the NF-kappaB p65 nuclear localization signal ( NLS ) .	The RHD also functions as a binding site for ankyrin repeats in the IkappaBalpha protein, which blocks the NF-kappaB p65 nuclear localization signal (NLS).	13	23	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	13	14	19	21
The target that was most highly predicted was inhibitor of kappa B alpha ( IkappaBalpha ) , a known regulator of NF-kappaB that sequesters the p65 subunit when inactive , but degrades and releases p65 subunit when the NF-kappaB pathway is activated [ XREF_BIBR ] .	The target that was most highly predicted was inhibitor of kappa B alpha (IkappaBalpha), a known regulator of NF-kappaB that sequesters the p65 subunit when inactive, but degrades and releases p65 subunit when the NF-kappaB pathway is activated [XREF_BIBR].	12	35	degrades	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	14	15	34	35
Following this phosphorylation , IkappaBalpha is ubiquitinated and then degraded by the proteasome , allowing p65 and p50 NF-kappaB heterodimers to translocate into the nucleus and mediate NF-kappaB activity XREF_BIBR .	Following this phosphorylation, IkappaBalpha is ubiquitinated and then degraded by the proteasome, allowing p65 and p50 NF-kappaB heterodimers to translocate into the nucleus and mediate NF-kappaB activity XREF_BIBR.	4	19	degraded	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha is ubiquitinated	ikappabalpha	p65	p65	p65	4	5	15	16
Though the RelA NES can mediate its export from the nucleus , IkappaBalpha and epsilon help reduce nuclear re-entry of RelA containing complexes by partially obscuring the nuclear localization signal .	Though the RelA NES can mediate its export from the nucleus, IkappaBalpha and epsilon help reduce nuclear re-entry of RelA containing complexes by partially obscuring the nuclear localization signal.	12	21	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	12	13	20	21
Our studies showed that ZY induced NF-kappaB activation in lung tissue and purified primary neutrophils by promoting IkappaB-alpha degradation and nuclear translocation of NF-kappaB p65 .	Our studies showed that ZY induced NF-kappaB activation in lung tissue and purified primary neutrophils by promoting IkappaB-alpha degradation and nuclear translocation of NF-kappaB p65.	17	25	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	17	18	23	25
Tat counteracts the IkappaB-alpha inhibition of p65 by competing the repressor binding .	Tat counteracts the IkappaB-alpha inhibition of p65 by competing the repressor binding.	3	7	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	p65	p65	p65	3	4	6	7
In order to gain further insight into the mechanism , AGE-BSA induced IkappaBalpha degradation and nuclear translocation of NF-kappaB p65 , p50 and Rel B have been studies in this report ( XREF_FIG and XREF_FIG ) .	In order to gain further insight into the mechanism, AGE-BSA induced IkappaBalpha degradation and nuclear translocation of NF-kappaB p65, p50 and Rel B have been studies in this report (XREF_FIG and XREF_FIG).	12	20	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	12	13	18	20
There was inhibition of TNFalpha induced degradation of IkBalpha protein thereby preventing p65 nuclear translocation .	There was inhibition of TNFalpha induced degradation of IkBalpha protein thereby preventing p65 nuclear translocation.	8	13	preventing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkBalpha protein	IkBalpha protein	IkBalpha protein	p65	p65	p65	8	10	12	13
The molecular process by which RelB activates euchromatin of selective genes is poorly understood , but it clearly plays a role in sustaining expression of IKB-alpha repressor of NF-kB RelA and p65 19 .	The molecular process by which RelB activates euchromatin of selective genes is poorly understood, but it clearly plays a role in sustaining expression of IKB-alpha repressor of NF-kB RelA and p65 19.	23	32	repressor	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IKB-alpha	expression of IKB-alpha	ikb-alpha	p65	p65	p65	25	26	31	32
Neither did AR increase the concentration of IkappaBalpha , which can sequester and inactivate RelA .	Neither did AR increase the concentration of IkappaBalpha, which can sequester and inactivate RelA.	5	15	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	7	8	14	15
Western blot analysis showed that compound 7 inhibited the LPS induced phosphorylation of IkappaBalpha and antagonized the LPS induced reduction of cytoplasmic NF-kappaB p65 and the increase of nuclear NF-kappaB p65 .	Western blot analysis showed that compound 7 inhibited the LPS induced phosphorylation of IkappaBalpha and antagonized the LPS induced reduction of cytoplasmic NF-kappaB p65 and the increase of nuclear NF-kappaB p65.	9	24	antagonized	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	LPS induced phosphorylation of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	13	14	22	24
Further , we analysed the Tat effect on the IkappaB-alpha repression of p65 transcriptional activity by transfecting p50 -/- p65 -/- MEFs with the NF-kappaB-Luc reporter together with expression vectors of p65 and IkappaB-alpha , in presence or absence of Tat .	Further, we analysed the Tat effect on the IkappaB-alpha repression of p65 transcriptional activity by transfecting p50 -/- p65 -/- MEFs with the NF-kappaB-Luc reporter together with expression vectors of p65 and IkappaB-alpha, in presence or absence of Tat.	9	14	repression	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	p65	p65	p65	9	10	12	13
E2 both 1 ) enhances expression of IkappaBalpha , a direct inhibitor of NFkappaB activation , thus accelerating a negative feedback loop in NFkappaB signaling , and 2 ) directly inhibits binding of NFkappaB p65 to the promoters of inflammatory genes , including MCP-1 and CINC-2beta , thereby inhibiting their expression .	E2 both 1) enhances expression of IkappaBalpha, a direct inhibitor of NFkappaB activation, thus accelerating a negative feedback loop in NFkappaB signaling, and 2) directly inhibits binding of NFkappaB p65 to the promoters of inflammatory genes, including MCP-1 and CINC-2beta, thereby inhibiting their expression.	5	35	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	expression of IkappaBalpha	ikappabalpha	NFkappaB p65	NFkappaB p65	nfkappab p65	7	8	33	35
Further observations revealed that Mat increased the protein levels of IkappaBalpha , and blocked the translocation of NF-kappaB p65 from the cytosol to the nucleus in the ischemic cortex and injured neurons and astrocytes induced by in vitro OGD .	Further observations revealed that Mat increased the protein levels of IkappaBalpha, and blocked the translocation of NF-kappaB p65 from the cytosol to the nucleus in the ischemic cortex and injured neurons and astrocytes induced by in vitro OGD.	4	19	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	Mat increased the protein levels of IkappaBalpha	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	10	11	17	19
Upon oxLDL stimulation , IkappaB-alpha is phosphorylated and subsequently degraded , which allows p65 to be liberated from IkB-alpha .	Upon oxLDL stimulation, IkappaB-alpha is phosphorylated and subsequently degraded, which allows p65 to be liberated from IkB-alpha.	4	16	degraded	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB-alpha	IkappaB-alpha is phosphorylated	ikappab-alpha	p65	p65	p65	4	5	13	14
In HCT116 cells , CAPE interfered with TNF-alpha dependent IkappaBalpha degradation and subsequent nuclear accumulation of p65 , which occurred by direct inhibition of inhibitory protein kappaB kinase ( IKK ) .	In HCT116 cells, CAPE interfered with TNF-alpha dependent IkappaBalpha degradation and subsequent nuclear accumulation of p65, which occurred by direct inhibition of inhibitory protein kappaB kinase (IKK).	9	19	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	9	10	16	17
Identical IkappaBalpha degradation and nuclear translocation of RelA for the three cell lines validated our assumption ( through 30 min after TNFalpha stimulation in XREF_FIG and XREF_SUPPLEMENTARY ) .	Identical IkappaBalpha degradation and nuclear translocation of RelA for the three cell lines validated our assumption (through 30 min after TNFalpha stimulation in XREF_FIG and XREF_SUPPLEMENTARY).	1	12	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	1	2	7	8
From one side IkappaBalpha negatively regulates the NF-kappaB subunit p65 and from the other p53 .	From one side IkappaBalpha negatively regulates the NF-kappaB subunit p65 and from the other p53.	2	10	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	3	4	9	10
Indeed , when in addition to pyruvate inhibiting PHDs , NADH aliments ROS production by Noxs , IkappaBalpha is ultimately degraded , releasing p65 from its inhibitory interaction with IkappaBalpha .	Indeed, when in addition to pyruvate inhibiting PHDs, NADH aliments ROS production by Noxs, IkappaBalpha is ultimately degraded, releasing p65 from its inhibitory interaction with IkappaBalpha.	17	24	degraded	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	17	18	23	24
CAPE decreased expression of cytosolic IkappaBalpha and increased nuclear translocation of p65 .	CAPE decreased expression of cytosolic IkappaBalpha and increased nuclear translocation of p65.	0	12	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	CAPE decreased expression of cytosolic IkappaBalpha	ikappabalpha	p65	p65	p65	5	6	11	12
The compound also decreased tumor necrosis factor-alpha , interleukin ( IL )-1beta , and IL-12 production ; inhibited the phosphorylation and degradation of IkappaB-alpha ; and blocked the nuclear translocation of p50 and p65 in mouse BV2 microglia induced by LPS .	The compound also decreased tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-12 production; inhibited the phosphorylation and degradation of IkappaB-alpha; and blocked the nuclear translocation of p50 and p65 in mouse BV2 microglia induced by LPS.	8	34	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB-alpha	interleukin (IL)-1beta, and IL-12 production; inhibited the phosphorylation and degradation of IkappaB-alpha	ikappab-alpha	p65	p65	p65	23	24	33	34
NF-kappaB inhibitor IkappaBalpha preferentially inhibits p65 and p50 dimers , whereas IkappaBepsilon controls p65 and c-Rel , and c-Rel activation also depends on the non redundant regulator IkappaBbeta [ XREF_BIBR - XREF_BIBR ] , and the protease activities of MALT1 [ XREF_BIBR ] .	NF-kappaB inhibitor IkappaBalpha preferentially inhibits p65 and p50 dimers, whereas IkappaBepsilon controls p65 and c-Rel, and c-Rel activation also depends on the non redundant regulator IkappaBbeta [XREF_BIBR - XREF_BIBR], and the protease activities of MALT1 [XREF_BIBR].	0	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	2	3	5	6
Our results suggest that IkappaBalpha sequesters not only p65 but also RPS3 in the cytoplasm .	Our results suggest that IkappaBalpha sequesters not only p65 but also RPS3 in the cytoplasm.	4	11	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	4	5	8	9
Under basal conditions , IkappaBalpha sequesters the NF-kappaB transcription factor heterodimer ( p50 and p65 ) in the cytoplasm .	Under basal conditions, IkappaBalpha sequesters the NF-kappaB transcription factor heterodimer (p50 and p65) in the cytoplasm.	4	15	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	4	5	14	15
This indicates that the IkappaBalpha-SR was able to attenuate p65 transcriptional activity without compromising its overall expression .	This indicates that the IkappaBalpha-SR was able to attenuate p65 transcriptional activity without compromising its overall expression.	3	11	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha-SR	IkappaBalpha-SR	IkappaBalpha-SR	p65	p65	p65	4	5	9	10
Furthermore , DXM inhibited LPS induced IkappaBalpha degradation and nuclear translocation of p65 .	Furthermore, DXM inhibited LPS induced IkappaBalpha degradation and nuclear translocation of p65.	2	13	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	DXM inhibited LPS induced IkappaBalpha	ikappabalpha	p65	p65	p65	6	7	12	13
Upon stimulation by cytokines or UV radiation , IkappaBalpha is phosphorylated , ubiquitinated , and degraded , releasing NF-kappaB p50 and p65 to translocate to the nucleus and transactivate target genes .	Upon stimulation by cytokines or UV radiation, IkappaBalpha is phosphorylated, ubiquitinated, and degraded, releasing NF-kappaB p50 and p65 to translocate to the nucleus and transactivate target genes.	8	22	degraded	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha is phosphorylated	ikappabalpha	p65	p65	p65	8	9	21	22
In wild-type CHBP , but not the C156S mutant transduced cells , both IkappaBalpha degradation and nuclear translocation of p65 were blocked ( XREF_SUPPLEMENTARY ) .	In wild-type CHBP, but not the C156S mutant transduced cells, both IkappaBalpha degradation and nuclear translocation of p65 were blocked (XREF_SUPPLEMENTARY).	13	20	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	13	14	19	20
We found that SIRT1 strongly suppressed p65 acetylation at K310 and phosphorylation at Ser 536 , and that SIRT1 increased IkappaBalpha expression in cytosol , and decreased the nuclear translocation NF-kappaB p65 , and consequently decreased NF-kappaB to kappaB binding , which agrees with previous reports .	We found that SIRT1 strongly suppressed p65 acetylation at K310 and phosphorylation at Ser 536, and that SIRT1 increased IkappaBalpha expression in cytosol, and decreased the nuclear translocation NF-kappaB p65, and consequently decreased NF-kappaB to kappaB binding, which agrees with previous reports.	18	32	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	SIRT1 increased IkappaBalpha expression	ikappabalpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	20	21	30	32
The role of IkappaBalpha is to sequester RelA and other NF-kappaB members in the cytoplasm , thereby preventing NF-kappaB transcriptional activation [ XREF_BIBR ] .	The role of IkappaBalpha is to sequester RelA and other NF-kappaB members in the cytoplasm, thereby preventing NF-kappaB transcriptional activation [XREF_BIBR].	1	11	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	3	4	7	8
This occurred at the transcriptional level , since the gingerol compounds decreased LPS induced IkappaB-alpha degradation , prevented nuclear translocation of NF-kappaB p65 and reduced NF-kappaB activity in a concentration dependent manner .	This occurred at the transcriptional level, since the gingerol compounds decreased LPS induced IkappaB-alpha degradation, prevented nuclear translocation of NF-kappaB p65 and reduced NF-kappaB activity in a concentration dependent manner.	9	23	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaB-alpha	gingerol compounds decreased LPS induced IkappaB-alpha	ikappab-alpha	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	14	15	21	23
Sanguinarine blocked the tumor necrosis factor induced phosphorylation and degradation of IkappaBalpha , an inhibitory subunit of NF-kappaB , and inhibited translocation of p65 subunit to the nucleus .	Sanguinarine blocked the tumor necrosis factor induced phosphorylation and degradation of IkappaBalpha, an inhibitory subunit of NF-kappaB, and inhibited translocation of p65 subunit to the nucleus.	0	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	Sanguinarine blocked the tumor necrosis factor induced phosphorylation and degradation of IkappaBalpha	ikappabalpha	p65	p65	p65	11	12	23	24
The present study showed that PMS1077 inhibited TNF-alpha induced phosphorylation and degradation of IkappaB-alpha and TNF-alpha induced translocation of p65 to the nucleus .	The present study showed that PMS1077 inhibited TNF-alpha induced phosphorylation and degradation of IkappaB-alpha and TNF-alpha induced translocation of p65 to the nucleus.	5	20	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaB-alpha	PMS1077 inhibited TNF-alpha induced phosphorylation and degradation of IkappaB-alpha	ikappab-alpha	p65	p65	p65	13	14	19	20
E2F-1 degradation could allow NF-kappaB to re-activate IkappaBalpha , which in turn could restore RelA to a cytoplasmic localization .	E2F-1 degradation could allow NF-kappaB to re-activate IkappaBalpha, which in turn could restore RelA to a cytoplasmic localization.	6	15	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	7	8	14	15
Moreover , African Swine Fever Virus encodes a homolog to IkappaBalpha that sequesters p65 in the cytoplasm following IkappaBalpha degradation XREF_BIBR .	Moreover, African Swine Fever Virus encodes a homolog to IkappaBalpha that sequesters p65 in the cytoplasm following IkappaBalpha degradation XREF_BIBR.	6	14	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	10	11	13	14
In addition , we hypothesized that pre-transcriptional mechanisms might be involved and observed that pre-exposure with IL-1beta strongly reduced flagellin induced IkappaBalpha degradation and nuclear translocation of p65 upon re-stimulation .	In addition, we hypothesized that pre-transcriptional mechanisms might be involved and observed that pre-exposure with IL-1beta strongly reduced flagellin induced IkappaBalpha degradation and nuclear translocation of p65 upon re-stimulation.	19	28	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	IkappaBalpha	flagellin induced IkappaBalpha	ikappabalpha	p65	p65	p65	21	22	27	28
XREF_BIBR Overexpression of the IkappaBalpha superrepressor with an adenoviral vector markedly inhibited translocation of p50 and p65 into the nucleus in PASMCs from IPAH patients ( with the -254 G allele ) and significantly inhibited TNF-alpha-mediated upregulation of TRPC6 ( XREF_FIG ) .	XREF_BIBR Overexpression of the IkappaBalpha superrepressor with an adenoviral vector markedly inhibited translocation of p50 and p65 into the nucleus in PASMCs from IPAH patients (with the -254 G allele) and significantly inhibited TNF-alpha-mediated upregulation of TRPC6 (XREF_FIG).	1	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	Overexpression of the IkappaBalpha	ikappabalpha	p65	p65	p65	4	5	16	17
Furthermore , we found that PPP3CC knockdown significantly increased the expression of p-IkappaBalpha ( XREF_FIG ) and enhanced the activity of p65 in PPC cells ( XREF_FIG ) , while overexpression of PPP3CC resulted in decreased p-IkappaBalpha expression ( XREF_FIG ) and reduced p65 activity in CRPC cells ( XREF_FIG ) .	Furthermore, we found that PPP3CC knockdown significantly increased the expression of p-IkappaBalpha (XREF_FIG) and enhanced the activity of p65 in PPC cells (XREF_FIG), while overexpression of PPP3CC resulted in decreased p-IkappaBalpha expression (XREF_FIG) and reduced p65 activity in CRPC cells (XREF_FIG).	5	22	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p-IkappaBalpha	PPP3CC knockdown significantly increased the expression of p-IkappaBalpha	p-ikappabalpha	p65	p65	p65	12	13	21	22
The canonical pathway triggers IkappaBalpha degradation , which enables RelA and cRel containing complexes to translocate to the nucleus , including RelA : p50 , cRel : p50 , RelA : RelA and cRel : cRel dimers .	The canonical pathway triggers IkappaBalpha degradation, which enables RelA and cRel containing complexes to translocate to the nucleus, including RelA : p50, cRel : p50, RelA : RelA and cRel : cRel dimers.	4	12	enables	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	4	5	9	10
Furthermore , the IkappaBalpha-SR blocked the ability of RelA to enhance GAL4-REL transactivation ( XREF_FIG ) .	Furthermore, the IkappaBalpha-SR blocked the ability of RelA to enhance GAL4-REL transactivation (XREF_FIG).	2	9	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha-SR	IkappaBalpha-SR	IkappaBalpha-SR	RelA	RelA	RelA	3	4	8	9
As shown in XREF_FIG A , B , pre-treatment with 1 and 2 for 12 h , at the indicated concentrations , significantly inhibited LPS induced phosphorylation and degradation of IkappaB-alpha , thereby preventing the translocation of p65 into the nucleus .	As shown in XREF_FIG A, B, pre-treatment with 1 and 2 for 12 h, at the indicated concentrations, significantly inhibited LPS induced phosphorylation and degradation of IkappaB-alpha, thereby preventing the translocation of p65 into the nucleus.	24	38	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaB-alpha	LPS induced phosphorylation and degradation of IkappaB-alpha	ikappab-alpha	p65	p65	p65	30	31	37	38
NF-kappaB family genes ( REL , RELA ( p65 ) , and RELB ) and IkappaB family genes ( NFKBIA ( the inhibitor of RELA ) , NFKBIE ( inhibitor of REL ) and NFKB1 ( p105 , precursor of p50 ) ) shared similar transcription patterns , an early upregulation at 4-10 hours was followed by a decrease at 48-96 hours .	NF-kappaB family genes (REL, RELA (p65), and RELB) and IkappaB family genes (NFKBIA (the inhibitor of RELA), NFKBIE (inhibitor of REL) and NFKB1 (p105, precursor of p50)) shared similar transcription patterns, an early upregulation at 4-10 hours was followed by a decrease at 48-96 hours.	17	34	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	NFKBIA	NFKBIA	NFKBIA	RELA	RELA	RELA	19	20	24	25
In contrast , the expression of Bcl2 , XIAP and IkappaBalpha mRNA stimulated by cisplatin or mitomycin C treatment were unaffected by depletion of either p65 , p50 or BRCA1 ( XREF_FIG ) , indicating that activation by these damagers in our system is independent of p65 and p50 the most abundant NF and kappaB complex .	In contrast, the expression of Bcl2, XIAP and IkappaBalpha mRNA stimulated by cisplatin or mitomycin C treatment were unaffected by depletion of either p65, p50 or BRCA1 (XREF_FIG), indicating that activation by these damagers in our system is independent of p65 and p50 the most abundant NF and kappaB complex.	4	34	were unaffected by depletion	Negative_activation_copula_1	Positive_activation	Negative_activation	IkappaBalpha	expression of Bcl2, XIAP and IkappaBalpha	ikappabalpha	p65	p65	p65	10	11	25	26
Taken together , these findings indicate that IkappaBalpha ( DeltaN ) specifically represses signal dependent activation of nuclear RelA and c-Rel , which are normally induced during thymic selection and T cell activation .	Taken together, these findings indicate that IkappaBalpha (DeltaN) specifically represses signal dependent activation of nuclear RelA and c-Rel, which are normally induced during thymic selection and T cell activation.	7	20	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	RelA	RelA	RelA	7	8	18	19
3.1.4 IkappaBalpha SR prevents p65 , but not p50 , binding to IL-1beta responsive gene promoters .	3.1.4 IkappaBalpha SR prevents p65, but not p50, binding to IL-1beta responsive gene promoters.	0	8	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	1	2	4	5
Following phosphorylation , IkappaBalpha becomes ubiquitinated by an E3 ligase complex consisting of beta transducing repeat containing protein ( beta-TrCP ) and is subsequently degraded by the proteasome , thus releasing p65 and p50 into the nucleus and allowing transcription to occur .	Following phosphorylation, IkappaBalpha becomes ubiquitinated by an E3 ligase complex consisting of beta transducing repeat containing protein (beta-TrCP) and is subsequently degraded by the proteasome, thus releasing p65 and p50 into the nucleus and allowing transcription to occur.	3	33	degraded	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p65	p65	p65	3	4	31	32
Loss of p75NTR may allow for the increased binding of necdin to TrkA , facilitating , in turn , activation of TrkA by NGF .	Loss of p75NTR may allow for the increased binding of necdin to TrkA, facilitating, in turn, activation of TrkA by NGF.	14	24	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	23	24	21	22
In line with in vivo evidence concerning the potential initial role of basal forebrain degeneration in AD onset and progression , these results help to clarify the important issue concerning the causal role of the loss in NGF stimulated TrkA mediated signaling in the activation of the pathogenetic amyloid cascade , suggesting that NGF deprivation is actually able to directly and locally trigger the amyloidogenic APP processing in responsive cholinergic enriched basal forebrain neurons .	In line with in vivo evidence concerning the potential initial role of basal forebrain degeneration in AD onset and progression, these results help to clarify the important issue concerning the causal role of the loss in NGF stimulated TrkA mediated signaling in the activation of the pathogenetic amyloid cascade, suggesting that NGF deprivation is actually able to directly and locally trigger the amyloidogenic APP processing in responsive cholinergic enriched basal forebrain neurons.	35	41	stimulated	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	loss in NGF	ngf	TrkA	TrkA	trka	37	38	39	40
In contrast , expression of either dynamin1ab-EGFP phosphomimetic mutant ( Ser774/778-Glu ) ( XREF_FIG ) or the non phosphorylatable dynamin1ab EGFP mutant ( Ser774/778-Ala ) ( XREF_FIG ) significantly reduced NGF mediated TrkA internalization in cell bodies to 39 % and 50 % , respectively , when compared to neurons expressing wild-type dynamin1ab-EGFP ( XREF_FIG ) .	In contrast, expression of either dynamin1ab-EGFP phosphomimetic mutant (Ser774/778-Glu) (XREF_FIG) or the non phosphorylatable dynamin1ab EGFP mutant (Ser774/778-Ala) (XREF_FIG) significantly reduced NGF mediated TrkA internalization in cell bodies to 39% and 50%, respectively, when compared to neurons expressing wild-type dynamin1ab-EGFP (XREF_FIG).	29	33	mediated	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	30	31	32	33
XREF_BIBR , XREF_BIBR Moreover , in presence of p75 receptors , lower NGF concentrations are needed to elicit TrkA dependent responses in neurons .	XREF_BIBR, XREF_BIBR Moreover, in presence of p75 receptors, lower NGF concentrations are needed to elicit TrkA dependent responses in neurons.	12	20	elicit	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	18	19
NGF and TRAIL inhibits TrkA SH-SY5Y tumourigenic growth in vitro .	NGF and TRAIL inhibits TrkA SH-SY5Y tumourigenic growth in vitro.	0	5	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	4	5
We now report that NGF induced activation of trkA receptors in isolated ovarian thecal cells disrupts cell to cell communication by affecting the functional integrity of gap junctions .	We now report that NGF induced activation of trkA receptors in isolated ovarian thecal cells disrupts cell to cell communication by affecting the functional integrity of gap junctions.	4	9	induced	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	trkA	trkA	trkA	4	5	8	9
NGF ( 100ng/ml for 1-6h ) did not reduce cFLIP mRNA or protein expression in TrkA SH-SY5Y cells nor induce cFLIP degradation ( XREF_FIG ) , suggesting an alternative mechanism for sensitization to TRAIL induced apoptosis .	NGF (100ng/ml for 1-6h) did not reduce cFLIP mRNA or protein expression in TrkA SH-SY5Y cells nor induce cFLIP degradation (XREF_FIG), suggesting an alternative mechanism for sensitization to TRAIL induced apoptosis.	0	19	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	15	16
The inhibitory actions of K252a on NGF induced Trk activity were also been confirmed in PC12-cells treated with 200nM of K252a [ XREF_BIBR ] .	The inhibitory actions of K252a on NGF induced Trk activity were also been confirmed in PC12-cells treated with 200nM of K252a [XREF_BIBR].	4	9	induced	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	Trk	Trk	Trk	6	7	8	9
Suppression of NGF induced TrkA signaling may be another mechanism by which Nogo inhibits neurite growth .	Suppression of NGF induced TrkA signaling may be another mechanism by which Nogo inhibits neurite growth.	0	5	induced	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	4	5
Few studies have reported that pro NGF inhibits NGF mediated TrkA activation in PC12 cells XREF_BIBR .	Few studies have reported that pro NGF inhibits NGF mediated TrkA activation in PC12 cells XREF_BIBR.	7	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	10	11
Further , proNGF showed an inhibitory effect on NGF mediated TrkA activation in PC12 cells [ XREF_BIBR ] .	Further, proNGF showed an inhibitory effect on NGF mediated TrkA activation in PC12 cells [XREF_BIBR].	6	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	10	11
In NGF dependent sympathetic neurons , the receptor mediated die-back axon degeneration pathway ( also known as developmental axon degeneration ) is initiated by the loss of NGF mediated TrkA survival signaling , activation of the p75 neurotrophin receptor , or DR6 , which stimulate the dual leucine zipper kinase ( DLK )/JNK kinases and the BH3 family members Puma , BimEL , and Harakiri ( Hrk ) , which subsequently compromise mitochondrial function by the activation of Bax , caspase-3 and caspase-6 , and calpains .	In NGF dependent sympathetic neurons, the receptor mediated die-back axon degeneration pathway (also known as developmental axon degeneration) is initiated by the loss of NGF mediated TrkA survival signaling, activation of the p75 neurotrophin receptor, or DR6, which stimulate the dual leucine zipper kinase (DLK)/JNK kinases and the BH3 family members Puma, BimEL, and Harakiri (Hrk), which subsequently compromise mitochondrial function by the activation of Bax, caspase-3 and caspase-6, and calpains.	25	31	mediated	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	27	28	29	30
The NGF induced TrkA internalization was slightly inhibited in the presence of Cu 2+ and Zn 2+ ions , whereas the metal ions elicited the NGF ( 1-14 )-induced internalization of TrkA and no significant differences were found in the weak Ac-NGF ( 1-14 )-induced receptor internalization .	The NGF induced TrkA internalization was slightly inhibited in the presence of Cu 2+ and Zn 2+ ions, whereas the metal ions elicited the NGF (1-14)-induced internalization of TrkA and no significant differences were found in the weak Ac-NGF (1-14)-induced receptor internalization.	0	4	induced	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	1	2	3	4
Interestingly , this cell death can be reverted if TrkA inactivation during hypoxia is suppressed by the addition of NGF .	Interestingly, this cell death can be reverted if TrkA inactivation during hypoxia is suppressed by the addition of NGF.	9	20	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	19	20	9	10
Thus , this colocalization transiently decreased by 5 minutes of NGF stimulation , likely due to NGF induced TrkA internalization , and increased subsequently to reach a maximum after 60 minutes of exposure to NGF .	Thus, this colocalization transiently decreased by 5 minutes of NGF stimulation, likely due to NGF induced TrkA internalization, and increased subsequently to reach a maximum after 60 minutes of exposure to NGF.	5	19	induced	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	16	17	18	19
The combination of NGF plus TRAIL inhibited TrkA SH-SY5Y tumourigenicity by > 95 % , more than expected , considering that NGF plus TRAIL induced no more than 70 % cell death in a temporary sensitization effect .	The combination of NGF plus TRAIL inhibited TrkA SH-SY5Y tumourigenicity by> 95%, more than expected, considering that NGF plus TRAIL induced no more than 70% cell death in a temporary sensitization effect.	1	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	7	8
Hence , the action of Cbl on TrkA limits NGF signalling within the cells .	Hence, the action of Cbl on TrkA limits NGF signalling within the cells.	7	10	limits	Negative_activation_token_1_noun	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	9	10	7	8
Expression of a Rab7 dominant negative mutant in NGF stimulated PC12 cells determines endosomal accumulation of TrkA and augmented TrkA signaling , leading to the increase of downstream effects , such as phosphorylation of Erk1/2 , up-regulation of growth associated protein 43 ( GAP43 ) and strongly enhancing neurite outgrowth in response to limited NGF stimulations [ XREF_BIBR ] .	Expression of a Rab7 dominant negative mutant in NGF stimulated PC12 cells determines endosomal accumulation of TrkA and augmented TrkA signaling, leading to the increase of downstream effects, such as phosphorylation of Erk1/2, up-regulation of growth associated protein 43 (GAP43) and strongly enhancing neurite outgrowth in response to limited NGF stimulations [XREF_BIBR].	6	17	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	16	17
NGF is released from target cells , binds to and activates its high-affinity receptor TrkA on the neuron , and is internalized into the responsive neuron .	NGF is released from target cells, binds to and activates its high-affinity receptor TrkA on the neuron, and is internalized into the responsive neuron.	0	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	0	1	14	15
SgG2 increases NGF mediated axonal growth , blocking retrograde transport of TrkA , resulting in an accumulation of high levels of phosphorylated TrkA at the nerve endings .	SgG2 increases NGF mediated axonal growth, blocking retrograde transport of TrkA, resulting in an accumulation of high levels of phosphorylated TrkA at the nerve endings.	2	12	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	2	3	11	12
Upon inhibition of protein synthesis by puromycin , NGF induced TrkA degradation indeed was faster in PC12-shNEAP cells in comparison to that in PC12-pSuper control cells .	Upon inhibition of protein synthesis by puromycin, NGF induced TrkA degradation indeed was faster in PC12-shNEAP cells in comparison to that in PC12-pSuper control cells.	8	11	induced	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	10	11
When NGF is co-applied with the kinase inhibitor K252a to inhibit Trk , but not p75 signaling , cells fired predominantly in a phasic pattern .	When NGF is co-applied with the kinase inhibitor K252a to inhibit Trk, but not p75 signaling, cells fired predominantly in a phasic pattern.	1	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	Trk	Trk	Trk	1	2	11	12
Pretreatment with indomethacin attenuated NGF facilitated weight bearing asymmetry and reversed OA induced ipsilateral TrkA mRNA up-regulation .	Pretreatment with indomethacin attenuated NGF facilitated weight bearing asymmetry and reversed OA induced ipsilateral TrkA mRNA up-regulation.	4	16	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	14	15
Since TrkA endocytosis is a pre-requisite for its retrograde transport [ XREF_BIBR , XREF_BIBR ] , this could explain the blockage of NGF mediated TrkA retrograde transport caused by SgG2 .	Since TrkA endocytosis is a pre-requisite for its retrograde transport [XREF_BIBR, XREF_BIBR], this could explain the blockage of NGF mediated TrkA retrograde transport caused by SgG2.	20	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	22	23	24	25
TRAF4 knockdown also suppressed NGF stimulated TrkA downstream p38 MAPK activation and invasion associated gene expression .	TRAF4 knockdown also suppressed NGF stimulated TrkA downstream p38 MAPK activation and invasion associated gene expression.	3	12	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	4	5	6	7
Although much is known about the mechanisms regulating retrograde survival signaling to the nucleus , how target derived NGF activates TrkA receptors in nerve terminals to induce axonal outgrowth remains unclear .	Although much is known about the mechanisms regulating retrograde survival signaling to the nucleus, how target derived NGF activates TrkA receptors in nerve terminals to induce axonal outgrowth remains unclear.	17	21	activates	Positive_activation_token_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	18	19	20	21
Target derived neurotrophins like nerve growth factor ( NGF ) mediate biological effects by binding to and activating Trk neurotrophin receptors at nerve terminals .	Target derived neurotrophins like nerve growth factor (NGF) mediate biological effects by binding to and activating Trk neurotrophin receptors at nerve terminals.	0	20	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	Trk	Trk	Trk	8	9	18	19
Short term treatment of PC12 cells with ceramide analogues also resulted in reduced NGF stimulated TrkA activation , suggesting that p75 mediated increases in sphingomyelinase activity may contribute to this modulatory effect .	Short term treatment of PC12 cells with ceramide analogues also resulted in reduced NGF stimulated TrkA activation, suggesting that p75 mediated increases in sphingomyelinase activity may contribute to this modulatory effect.	12	16	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	13	14	15	16
ADAMTS-4-mediated reduction in NGF release by astrocytes may contribute to neurodegeneration in ADAMTS-4-treated SOD1 G93A mice by preventing TrkA signaling in surviving motoneurons .	ADAMTS-4-mediated reduction in NGF release by astrocytes may contribute to neurodegeneration in ADAMTS-4-treated SOD1 G93A mice by preventing TrkA signaling in surviving motoneurons.	3	19	contribute	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	3	4	18	19
Given that NGF exerts trophic effects via TrkA binding , it was expected that L5/LOX -1 would interfere with NGF induced neuronal differentiation by disrupting TrkA .	Given that NGF exerts trophic effects via TrkA binding, it was expected that L5/LOX -1 would interfere with NGF induced neuronal differentiation by disrupting TrkA.	19	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	19	20	25	26
It is important to note that many have investigated the molecular components of sensory neurite growth in relation to neuroregeneration and synaptogenesis in the nervous system , primarily targeting NGF induced TrkA activation which in turns leads to neurite growth [ XREF_BIBR ] .	It is important to note that many have investigated the molecular components of sensory neurite growth in relation to neuroregeneration and synaptogenesis in the nervous system, primarily targeting NGF induced TrkA activation which in turns leads to neurite growth [XREF_BIBR].	28	32	induced	Positive_early_activation	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	29	30	31	32
This may be because tanezumab specifically inhibits the activation of TrkA by NGF [ XREF_BIBR , XREF_BIBR ] , rather than blocking the cyclooxygenase pathways [ XREF_BIBR ] .	This may be because tanezumab specifically inhibits the activation of TrkA by NGF [XREF_BIBR, XREF_BIBR], rather than blocking the cyclooxygenase pathways [XREF_BIBR].	8	13	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	12	13	10	11
Deletion of PKCdelta using siRNA in human synovial cells selectively upregulated expression of NGF and TrkA , brain derived nerve growth factor and Substance P ( tachykinin ; TAC1 ) -- downstream targets of the NGF and TrkA axis XREF_BIBR XREF_BIBR ( see online supplementary figure S1A , B ) .	Deletion of PKCdelta using siRNA in human synovial cells selectively upregulated expression of NGF and TrkA, brain derived nerve growth factor and Substance P (tachykinin; TAC1) -- downstream targets of the NGF and TrkA axis XREF_BIBR XREF_BIBR (see online supplementary figure S1A, B).	2	40	targets	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	NGF	PKCdelta using siRNA in human synovial cells selectively upregulated expression of NGF	ngf	TrkA	TrkA	trka	13	14	37	38
This is due therefore , to inhibition of NGF induced TrkA and p75 NTR exit from lipid rafts by Cav-1 .	This is due therefore, to inhibition of NGF induced TrkA and p75 NTR exit from lipid rafts by Cav-1.	6	14	induced	Positive_early_activation	Positive_activation	Negative_activation	NGF	NGF	NGF	TrkA	TrkA	TrkA	8	9	10	11
RelB is sequestered in the cytosol by the p100 molecule .	RelB is sequestered in the cytosol by the p100 molecule.	0	9	sequestered	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	8	9	0	1
Because p100 is a specific inhibitor of RelB , this finding explained why RelB was not detected in the active nuclear NF and kappaB complex ( XREF_FIG ) .	Because p100 is a specific inhibitor of RelB, this finding explained why RelB was not detected in the active nuclear NF and kappaB complex (XREF_FIG).	1	8	is a specific inhibitor	Negative_activation_copula_1	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	1	2	7	8
For the non canonical pathway , RelB is sequestered in the cytosol by p100 .	For the non canonical pathway, RelB is sequestered in the cytosol by p100.	6	14	sequestered	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	13	14	6	7
Our immunoprecipitation analyses indicated that p100 sequesters RelB to curtail this late acting RelB : p50 response in WT cells ( XREF_SUPPLEMENTARY ) XREF_BIBR .	Our immunoprecipitation analyses indicated that p100 sequesters RelB to curtail this late acting RelB : p50 response in WT cells (XREF_SUPPLEMENTARY) XREF_BIBR.	5	8	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	5	6	7	8
Interestingly , the p52 deficiency also attenuated the binding of RelB to the Ifnb promoter ( XREF_FIG ) , a finding that was consistent with the requirement of partner proteins for the DNA binding function of RelB .	Interestingly, the p52 deficiency also attenuated the binding of RelB to the Ifnb promoter (XREF_FIG), a finding that was consistent with the requirement of partner proteins for the DNA binding function of RelB.	3	11	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p52	p52	p52	RelB	RelB	RelB	3	4	10	11
This activates RelB dimers because p100 is the main inhibitor of RelB .	This activates RelB dimers because p100 is the main inhibitor of RelB.	5	12	is the main inhibitor	Negative_activation_copula_1	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	5	6	11	12
For example , if BCR mediated production of p100 exceeds BAFFR induced p100 processing , then excess p100 could sequester RELB or block the action of RELA , thereby decreasing the levels of functional NF-kappaB heterodimers .	For example, if BCR mediated production of p100 exceeds BAFFR induced p100 processing, then excess p100 could sequester RELB or block the action of RELA, thereby decreasing the levels of functional NF-kappaB heterodimers.	15	22	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	p100	p100	RELB	RELB	RELB	17	18	20	21
p100 , encoded by the Nf-b2 gene , is known to inhibit RelB .	p100, encoded by the Nf-b2 gene, is known to inhibit RelB.	0	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	0	1	12	13
The RelB gene locates on chromosome 19q13.32 , and encodes messenger ribonucleic acid from 11 exons , producing a protein of 579 amino acids.17 The RelB protein is very labile and normally sequestered in the cytoplasm by p100 .	The RelB gene locates on chromosome 19q13.32, and encodes messenger ribonucleic acid from 11 exons, producing a protein of 579 amino acids.17 The RelB protein is very labile and normally sequestered in the cytoplasm by p100.	25	38	sequestered	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	37	38	25	26
p100 is the main inhibitor of RelB and nuclear p52-RelB complexes control genes that are predominantly involved in adaptive immunity and lymphoid organ development XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	p100 is the main inhibitor of RelB and nuclear p52-RelB complexes control genes that are predominantly involved in adaptive immunity and lymphoid organ development XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	7	is the main inhibitor	Negative_activation_copula_1	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	0	1	6	7
RelB and c-Rel , unlike RelA , are also inducible gene products , and the newly synthesized RelB and c-Rel may be sequestered immediately by p100 and p105 to prevent the activation of the RelB- or c-Rel-containing complexes .	RelB and c-Rel, unlike RelA, are also inducible gene products, and the newly synthesized RelB and c-Rel may be sequestered immediately by p100 and p105 to prevent the activation of the RelB- or c-Rel-containing complexes.	22	37	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB-	RelB-	RelB-	25	26	34	35
Its cytosolic control is not affected by stimuli that lead to RelA nuclear translocation , and RelB nuclear localization is prevented by p100 , but not by p105 or IkappaBalpha .	Its cytosolic control is not affected by stimuli that lead to RelA nuclear translocation, and RelB nuclear localization is prevented by p100, but not by p105 or IkappaBalpha.	16	23	prevented	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	22	23	16	17
NIK is required for the processing of the NF-kappaB2 p100 precursor to p52 and since the COOH-terminal domain of p100 specifically inhibits RelB function , lack of RelB DNA binding in the absence of functional NIK most likely is due to defective processing of the inhibitory p100 precursor .	NIK is required for the processing of the NF-kappaB2 p100 precursor to p52 and since the COOH-terminal domain of p100 specifically inhibits RelB function, lack of RelB DNA binding in the absence of functional NIK most likely is due to defective processing of the inhibitory p100 precursor.	17	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	19	20	22	23
Although , all antibodies raised against p52 also recognise p100 , DNA binding is expected to be mainly due to p52 since p100 is known to act as an IkappaB like molecule and sequester p52 and RelB in the cytoplasm [ XREF_BIBR , XREF_BIBR ] .	Although, all antibodies raised against p52 also recognise p100, DNA binding is expected to be mainly due to p52 since p100 is known to act as an IkappaB like molecule and sequester p52 and RelB in the cytoplasm [XREF_BIBR, XREF_BIBR].	22	37	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	22	23	36	37
RelB is sequestered in the cytosol by p100 that is processed to p52 , which releases p52 and RelB heterodimers , which then translocate to the nucleus [ XREF_BIBR ] .	RelB is sequestered in the cytosol by p100 that is processed to p52, which releases p52 and RelB heterodimers, which then translocate to the nucleus [XREF_BIBR].	0	10	sequestered	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	7	8	0	1
In line with this , unprocessed p100 is known to specifically sequester and inhibit RelB XREF_BIBR , leading to a severe signalling defect .	In line with this, unprocessed p100 is known to specifically sequester and inhibit RelB XREF_BIBR, leading to a severe signalling defect.	5	15	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	6	7	14	15
The released NIK phosphorylates IKK alpha , which in turn phosphorylates the p100 that sequesters the NF-kappaB family member RelB in the cytoplasm .	The released NIK phosphorylates IKK alpha, which in turn phosphorylates the p100 that sequesters the NF-kappaB family member RelB in the cytoplasm.	4	22	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	IKK alpha, which in turn phosphorylates the p100	p100	RelB	RelB	relb	12	13	19	20
Mechanistically , TNF inactivated NIK in LTbetaR stimulated cells and induced the synthesis of Nfkb2 mRNA encoding p100 ; these together potently accumulated unprocessed p100 , which attenuated the RelB activity as inhibitory IkappaBdelta .	Mechanistically, TNF inactivated NIK in LTbetaR stimulated cells and induced the synthesis of Nfkb2 mRNA encoding p100; these together potently accumulated unprocessed p100, which attenuated the RelB activity as inhibitory IkappaBdelta.	22	30	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	24	25	29	30
Further , TNF has been shown to induce p100 , which in return inhibits RelB : : p50 complexes XREF_BIBR .	Further, TNF has been shown to induce p100, which in return inhibits RelB : : p50 complexes XREF_BIBR.	7	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	8	9	14	15
While inhibition of RelB by p100 is relieved by cleavage of p100 into p52 , p100 has recently been shown to aggregate and act as an inhibitor of p50 : p65 .	While inhibition of RelB by p100 is relieved by cleavage of p100 into p52, p100 has recently been shown to aggregate and act as an inhibitor of p50 : p65.	1	6	inhibition	Negative_activation_token_2_noun	Positive_activation	Negative_activation	p100	p100	p100	RelB	RelB	RelB	5	6	3	4
Overexpression of p50 completely blocked the IL-1beta-induced recruitment of p65 to the proximal kappaB site within the CCL20 gene promoter region ( XREF_FIG ) .	Overexpression of p50 completely blocked the IL-1beta-induced recruitment of p65 to the proximal kappaB site within the CCL20 gene promoter region (XREF_FIG).	0	10	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p50	Overexpression of p50	p50	p65	p65	p65	2	3	9	10
TNF induced RelB : p50 and NFkappaB dimer suppresses apoptosis independent of RelA .	TNF induced RelB : p50 and NFkappaB dimer suppresses apoptosis independent of RelA.	4	13	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p50	p50	p50	RelA	RelA	RelA	4	5	12	13
Mutations in the -41 NF-kappaB site attenuated the p50 mediated suppression of the p65 transactivation of the FN promoter .	Mutations in the -41 NF-kappaB site attenuated the p50 mediated suppression of the p65 transactivation of the FN promoter.	7	14	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p50	p50	p50	p65	p65	p65	8	9	13	14
Nfkb1 SSAA mutation reduced activation of p50 and RelA after both BCR and CD40 stimulation .	Nfkb1 SSAA mutation reduced activation of p50 and RelA after both BCR and CD40 stimulation.	0	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Nfkb1	Nfkb1	Nfkb1	RelA	RelA	RelA	0	1	8	9
Noteworthy , co-transfection of p50 completely blocked cytokine and p65 dependent induction .	Noteworthy, co-transfection of p50 completely blocked cytokine and p65 dependent induction.	2	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p50	p50	p50	p65	p65	p65	4	5	9	10
Cotransfection of p50 completely blocked p65 mediated induction .	Cotransfection of p50 completely blocked p65 mediated induction.	0	7	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p50	p50	p50	p65	p65	p65	2	3	5	6
Excess p50 downregulates p65 , thus suggesting that a p50 homodimer may modulate transcription in place of the p50 and p65 heterodimer that activates transcription of NF-kappaB-related genes 24 .	Excess p50 downregulates p65, thus suggesting that a p50 homodimer may modulate transcription in place of the p50 and p65 heterodimer that activates transcription of NF-kappaB-related genes 24.	0	4	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p50	p50	p50	p65	p65	p65	1	2	3	4
Given that p105 functions as an IkappaB for RELA and c-REL , it is conceivable that the loss of p105 in the Nfkappab1 -/- mice leads to enhanced RELA and c-REL activity in B cells that promote chronic disease pathogenesis .	Given that p105 functions as an IkappaB for RELA and c-REL, it is conceivable that the loss of p105 in the Nfkappab1 -/- mice leads to enhanced RELA and c-REL activity in B cells that promote chronic disease pathogenesis.	17	36	leads	Positive_activation_syntax_7_verb	Positive_activation	Positive_activation	p105	loss of p105	p105	RELA	RELA	rela	19	20	28	29
Both p50 and RelA nuclear translocations and binding activities were reduced by Nfkb1 SSAA mutation after 4-h CD40L stimulation .	Both p50 and RelA nuclear translocations and binding activities were reduced by Nfkb1 SSAA mutation after 4-h CD40L stimulation.	1	14	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Nfkb1	Nfkb1	Nfkb1	RelA	RelA	RelA	12	13	3	4
These results suggest that , in this model system , p105 acts as an I kappa B to sequester p50 and p65 in the cytoplasm and that Tax by inhibiting I kappa B activity of p105 , enhances nuclear localization of p50 and p65 .	These results suggest that, in this model system, p105 acts as an I kappa B to sequester p50 and p65 in the cytoplasm and that Tax by inhibiting I kappa B activity of p105, enhances nuclear localization of p50 and p65.	10	22	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p105	p105	p105	p65	p65	p65	10	11	21	22
Thus , the major effects of Nfkb1 SSAA mutation in FM B cells were to reduce the early activation of canonical NF-kappaB subunits p50 and RelA , after stimulation of either BCR or CD40 , and the late activation of c-Rel after prolonged BCR cross linking .	Thus, the major effects of Nfkb1 SSAA mutation in FM B cells were to reduce the early activation of canonical NF-kappaB subunits p50 and RelA, after stimulation of either BCR or CD40, and the late activation of c-Rel after prolonged BCR cross linking.	6	26	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Nfkb1	Nfkb1	Nfkb1	RelA	RelA	RelA	6	7	25	26
The NICD translocates to the nucleus as part of a coactivator complex that targets CSL ( CBF1 , suppressor of hairless , Lag-2 ) DNA binding proteins .	The NICD translocates to the nucleus as part of a coactivator complex that targets CSL (CBF1, suppressor of hairless, Lag-2) DNA binding proteins.	0	18	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NICD	NICD translocates to the nucleus	nicd	CBF1	CBF1	cbf1	1	2	16	17
NICD would be required to sequester RBP-Jkappa away from Ptf1a in order to prevent the promotion of the acinar fate in this lineage .	NICD would be required to sequester RBP-Jkappa away from Ptf1a in order to prevent the promotion of the acinar fate in this lineage.	0	7	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NICD	NICD	NICD	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	0	1	6	7
Notably , lack of Notch1 and Notch2 receptors in Th9 cells inhibited the binding of both RBP-Jkappa and Smad3 to the Il9 promoter , suggesting that Notch downstream signaling is required for physical interaction of Smad3 with the Il9 promoter ( XREF_FIG ) .	Notably, lack of Notch1 and Notch2 receptors in Th9 cells inhibited the binding of both RBP-Jkappa and Smad3 to the Il9 promoter, suggesting that Notch downstream signaling is required for physical interaction of Smad3 with the Il9 promoter (XREF_FIG).	4	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Notch1	Notch1	Notch1	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	4	5	16	17
In neural precursor cells and vascular progenitors , NICD inhibits beta-catenin activity directly by forming a Notch , beta , catenin , and Rbp-J complex to prevent beta-catenin from binding its target sites [ XREF_BIBR ] .	In neural precursor cells and vascular progenitors, NICD inhibits beta-catenin activity directly by forming a Notch, beta, catenin, and Rbp-J complex to prevent beta-catenin from binding its target sites [XREF_BIBR].	8	24	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NICD	NICD	NICD	Rbp-J	Rbp-J	Rbp-J	8	9	23	24
H-89 , PP1 , U0126 and Stattic pre-treatment significantly inhibited the forskolin induced Nm23 protein expression , suggesting the possible involvement of c-Src , ERK and STAT3 in cAMP induced upregulation of Nm23 , respectively .	H-89, PP1, U0126 and Stattic pre-treatment significantly inhibited the forskolin induced Nm23 protein expression, suggesting the possible involvement of c-Src, ERK and STAT3 in cAMP induced upregulation of Nm23, respectively.	0	33	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Nm23	H-89, PP1, U0126 and Stattic pre-treatment significantly inhibited the forskolin induced Nm23 protein expression	nm23	Nm23	Nm23	nm23	13	14	32	33
NMac1 decreased the Km value of Nm23-H1 for substrate UDP without affecting Vmax .	NMac1 decreased the Km value of Nm23-H1 for substrate UDP without affecting Vmax.	0	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NMac1	NMac1	NMac1	Nm23-H1	Nm23-H1	Nm23-H1	0	1	6	7
Furthermore , oncogenic YAP1 activation occurs as a consequence of a loss in NF2 dependent inactivation of LATS1 ( a key inhibitor of YAP1 ) , and decreased LATS1 activity has also been associated with glioma progression .	Furthermore, oncogenic YAP1 activation occurs as a consequence of a loss in NF2 dependent inactivation of LATS1 (a key inhibitor of YAP1), and decreased LATS1 activity has also been associated with glioma progression.	13	21	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	NF2	NF2	NF2	LATS1	LATS1	LATS1	13	14	17	18
They also indicate that inhibition of Notch1 signaling by DAPT causes HIF-1alpha down-regulation , probably by PHD2 up-regulation .	They also indicate that inhibition of Notch1 signaling by DAPT causes HIF-1alpha down-regulation, probably by PHD2 up-regulation.	6	12	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Notch1	Notch1	Notch1	HIF-1alpha	HIF-1alpha	HIF-1alpha	6	7	11	12
This NRG1 dependent protective effect was abolished upon antibody mediated blockade of ErbB3 .	This NRG1 dependent protective effect was abolished upon antibody mediated blockade of ErbB3.	0	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	1	2	12	13
Inhibition of cell viability by BMS777607 could be rescued by NRG1 dependent activation of HER3 , suggesting an escape mechanism by tumor microenvironment .	Inhibition of cell viability by BMS777607 could be rescued by NRG1 dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment.	10	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	HER3	HER3	HER3	10	11	14	15
We found that NRG1 induced ErbB3 down-regulation was significantly decreased in SIMPLE depleted Schwann cells compared with the control cells ( XREF_FIG ) , which indicates that SIMPLE is required for NRG1 induced lysosomal degradation of ErbB3 .	We found that NRG1 induced ErbB3 down-regulation was significantly decreased in SIMPLE depleted Schwann cells compared with the control cells (XREF_FIG), which indicates that SIMPLE is required for NRG1 induced lysosomal degradation of ErbB3.	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	3	4	5	6
PTPN13 interacted with the cytoplasmic tail of Necl-2 , similar to the interaction with Necl-4 , and thereby inhibited the heregulin induced ErbB3 and ErbB2 signaling and ErbB4 activity [ XREF_BIBR , XREF_BIBR ] .	PTPN13 interacted with the cytoplasmic tail of Necl-2, similar to the interaction with Necl-4, and thereby inhibited the heregulin induced ErbB3 and ErbB2 signaling and ErbB4 activity [XREF_BIBR, XREF_BIBR].	19	25	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB3	ErbB3	ErbB3	20	21	22	23
MM-111 targets the HER2 and HER3 heterodimer with specificity and avidity by docking onto HER2 and subsequently binding to HER3 and blocking Heregulin induced activation of HER3 , therefore , it is more effective at inhibiting HER3 activation than a HER2 or HER3 monoclonal antibody ( trastuzumab and pertuzumab ) and TKI ( lapatinib ) .	MM-111 targets the HER2 and HER3 heterodimer with specificity and avidity by docking onto HER2 and subsequently binding to HER3 and blocking Heregulin induced activation of HER3, therefore, it is more effective at inhibiting HER3 activation than a HER2 or HER3 monoclonal antibody (trastuzumab and pertuzumab) and TKI (lapatinib).	21	27	induced	Positive_early_activation	Positive_activation	Negative_activation	Heregulin	Heregulin	Heregulin	HER3	HER3	HER3	22	23	26	27
We demonstrate here for the first time that the ErbB3/4 ligand Heregulin ( HRG ) reduced both ErbB2 and ErbB3 mRNA and protein levels in human breast cancer cell lines .	We demonstrate here for the first time that the ErbB3/4 ligand Heregulin (HRG) reduced both ErbB2 and ErbB3 mRNA and protein levels in human breast cancer cell lines.	8	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Heregulin	Heregulin	Heregulin	ErbB3	ErbB3	ErbB3	11	12	19	20
hMENA 11a silencing impaired the NRG-1-mediated activation of HER3 in HER2 overexpressing breast cancer cell lines , suggesting that NRG-1 was no longer able to activate HER3 in cells lacking hMENA 11a .	hMENA 11a silencing impaired the NRG-1-mediated activation of HER3 in HER2 overexpressing breast cancer cell lines, suggesting that NRG-1 was no longer able to activate HER3 in cells lacking hMENA 11a.	19	27	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	NRG-1	NRG-1	NRG-1	HER3	HER3	HER3	19	20	26	27
The Nielsen group , who investigated MM-111 , found that trastuzumab , lapatinib , and pertuzumab were not effective at inhibiting heregulin induced HER3 activation in HER2+ BC cells [ XREF_BIBR ] .	The Nielsen group, who investigated MM-111, found that trastuzumab, lapatinib, and pertuzumab were not effective at inhibiting heregulin induced HER3 activation in HER2+ BC cells [XREF_BIBR].	20	24	induced	Positive_early_activation	Positive_activation	Negative_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	21	22	23	24
In this context , the observation reported here , that HCV sways surface expression of the different family members of the ErbB family by NRG1 dependent down-regulation of ErbB3 is of particular interest since the resulting up-regulation of EGFR and ErbB2 ( XREF_FIG ) may be in advantage for the viral life cycle .	In this context, the observation reported here, that HCV sways surface expression of the different family members of the ErbB family by NRG1 dependent down-regulation of ErbB3 is of particular interest since the resulting up-regulation of EGFR and ErbB2 (XREF_FIG) may be in advantage for the viral life cycle.	24	29	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	24	25	28	29
Aptamers against recombinant heregulin 3 ( HER3 ) RTK have been recently isolated and shown to inhibit the heregulin induced activation of the HER3 and HER2 dimer [ XREF_BIBR ] .	Aptamers against recombinant heregulin 3 (HER3) RTK have been recently isolated and shown to inhibit the heregulin induced activation of the HER3 and HER2 dimer [XREF_BIBR].	17	26	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	18	19	23	24
Because kinase-inactive HER3 is not presently an amenable target for forthcoming HER TKIs , molecular approaches that can efficiently block heregulin triggered HER3 transactivation or nucleocytoplasmic trafficking of heregulin might offer novel strategies with which to manage HER driven breast cancer disease .	Because kinase-inactive HER3 is not presently an amenable target for forthcoming HER TKIs, molecular approaches that can efficiently block heregulin triggered HER3 transactivation or nucleocytoplasmic trafficking of heregulin might offer novel strategies with which to manage HER driven breast cancer disease.	19	23	triggered	Positive_activation_token_1_verb	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	20	21	22	23
In addition , SIMPLE is also required for efficient attenuation of ERK1/2 signaling downstream of NRG1 activated ErbB2 and ErbB3 receptors .	In addition, SIMPLE is also required for efficient attenuation of ERK1/2 signaling downstream of NRG1 activated ErbB2 and ErbB3 receptors.	12	20	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	ErbB3	ErbB3	ErbB3	15	16	19	20
This result indicated that pertuzumab inhibited as well as decreased NRG1 induced HER3 activation ligand induced HER signalling in these cells .	This result indicated that pertuzumab inhibited as well as decreased NRG1 induced HER3 activation ligand induced HER signalling in these cells.	9	14	induced	Positive_early_activation	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	HER3	HER3	HER3	10	11	12	13
The bispecific antibody MM-111 forms a trimeric complex with HER2 and HER3 , effectively inhibiting the HER2 and HER3 oncogenic unit and heregulin induced HER3 activation , showing antitumor activity [ XREF_BIBR ] .	The bispecific antibody MM-111 forms a trimeric complex with HER2 and HER3, effectively inhibiting the HER2 and HER3 oncogenic unit and heregulin induced HER3 activation, showing antitumor activity [XREF_BIBR].	22	25	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	HER3	HER3	HER3	22	23	24	25
As shown in XREF_FIG , ANP pretreatment markedly diminished the cGMP responses of wild-type GC-A to a subsequent stimulation with 10 nm ANP .	As shown in XREF_FIG, ANP pretreatment markedly diminished the cGMP responses of wild-type GC-A to a subsequent stimulation with 10 nm ANP.	5	15	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	5	6	14	15
NPR-A , but not NPR-C , mRNA levels were reduced in a dose dependent fashion by ANP .	NPR-A, but not NPR-C, mRNA levels were reduced in a dose dependent fashion by ANP.	0	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	16	17	0	1
Here , we used a more direct sequential immunoprecipitation-western blot assay to demonstrate that long-term ANP exposure increases NPR-A degradation in primary , immortalized , and transfected cells .	Here, we used a more direct sequential immunoprecipitation-western blot assay to demonstrate that long-term ANP exposure increases NPR-A degradation in primary, immortalized, and transfected cells.	15	19	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	15	16	18	19
These findings provided direct evidence that treatment of cells with unlabeled ANP accelerates the disappearance of surface receptors , indicating that ANP dependent down-regulation of GC-A and NPRA involves the internalization of the receptor [ XREF_BIBR ] .	These findings provided direct evidence that treatment of cells with unlabeled ANP accelerates the disappearance of surface receptors, indicating that ANP dependent down-regulation of GC-A and NPRA involves the internalization of the receptor [XREF_BIBR].	21	27	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	21	22	25	26
We recently found that ANP increases GC-A degradation in a variety of cell lines and that the internalization rate of GC-A is dramatically affected by cellular environment , which may explain the disparate results of previous investigators ( Dickey et al ., submitted for publication ) .	We recently found that ANP increases GC-A degradation in a variety of cell lines and that the internalization rate of GC-A is dramatically affected by cellular environment, which may explain the disparate results of previous investigators (Dickey et al., submitted for publication).	4	7	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	4	5	6	7
These findings provided direct evidence that treatment of cells with unlabeled ANP accelerates the disappearance of surface receptors , indicating that ANP dependent down-regulation of GC-A and NPRA involves internalization of the receptor .	These findings provided direct evidence that treatment of cells with unlabeled ANP accelerates the disappearance of surface receptors, indicating that ANP dependent down-regulation of GC-A and NPRA involves internalization of the receptor.	21	28	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ANP	ANP	ANP	NPRA	NPRA	NPRA	21	22	27	28
However , as described in the next section , ANP pretreatment markedly reduced the responsiveness of GC-A to subsequent ANP stimulation , indicating homologous desensitization of the receptor .	However, as described in the next section, ANP pretreatment markedly reduced the responsiveness of GC-A to subsequent ANP stimulation, indicating homologous desensitization of the receptor.	9	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	9	10	16	17
ANP has been shown to downregulate ANP-A and -B receptors and cGMP response in various tissues .	ANP has been shown to downregulate ANP-A and -B receptors and cGMP response in various tissues.	0	9	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANP	ANP	ANP	ANP-A	ANP-A	ANP-A	0	1	6	7
However , 1-h ANP exposures did not significantly reduce NPR-A concentrations in any cell line .	However, 1-h ANP exposures did not significantly reduce NPR-A concentrations in any cell line.	3	10	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ANP	ANP	ANP	NPR-A	NPR-A	NPR-A	3	4	9	10
Even more , ANP stimulated GC-A activity in lung cell membranes was reduced by more than 80 % .	Even more, ANP stimulated GC-A activity in lung cell membranes was reduced by more than 80%.	3	6	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ANP	ANP	ANP	GC-A	GC-A	GC-A	3	4	5	6
Tamoxifen inhibited the activation of GC-A by atrial natriuretic factor ( ANF ) .	Tamoxifen inhibited the activation of GC-A by atrial natriuretic factor (ANF).	3	10	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	atrial natriuretic factor	atrial natriuretic factor	atrial natriuretic factor	GC-A	GC-A	GC-A	7	10	5	6
Blockade of ErbB2 activation by heregulin neutralizing antibodies and by AG879 resulted in prevention of cell cycle re-entry .	Blockade of ErbB2 activation by heregulin neutralizing antibodies and by AG879 resulted in prevention of cell cycle re-entry.	2	7	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	5	6	2	3
For example , the ErbB ligands EGF , transforming growth factor alpha , betacellulin , and heregulin have been shown to rescue from or attenuate the antiproliferative effect of HER2 antibodies .	For example, the ErbB ligands EGF, transforming growth factor alpha, betacellulin, and heregulin have been shown to rescue from or attenuate the antiproliferative effect of HER2 antibodies.	13	30	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	heregulin	heregulin	heregulin	HER2	HER2	HER2	16	17	29	30
Catenin dissociation from VE-cadherin was enhanced by Heregulin beta1 ( P < .05 ) stimulation and decreased by trastuzumab ( P < .05 ) blockade of HER2 signaling in cancer cells .	Catenin dissociation from VE-cadherin was enhanced by Heregulin beta1 (P <.05) stimulation and decreased by trastuzumab (P <.05) blockade of HER2 signaling in cancer cells.	5	27	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Heregulin	Heregulin	Heregulin	HER2	HER2	HER2	7	8	26	27
Nonirradiated A30 BT has potency comparable to that of unmodified A30 with respect to the inhibition of NRG1 induced activation of ERBB2 and ERBB3 signaling ( see the XREF_SUPPLEMENTARY ) .	Nonirradiated A30 BT has potency comparable to that of unmodified A30 with respect to the inhibition of NRG1 induced activation of ERBB2 and ERBB3 signaling (see the XREF_SUPPLEMENTARY).	15	24	induced	Positive_early_activation	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	ERBB2	ERBB2	ERBB2	17	18	21	22
We investigated here whether Necl-4 ( also termed TSLL2 , IGSF4C , SynCAM4 , or CADM4 ) [ XREF_BIBR - XREF_BIBR ] also regulated the contact inhibition of cell movement and proliferation , because it binds protein-tyrosine phosphatase , non receptor type 13 ( PTPN13 , also termed PTP-BL , PTP-BAS , PTP-L1 , or FAP1 ) , a putative tumor suppressor , through the cytoplasmic region of Necl-4 , and inhibits the heregulin induced activation of the ErbB2 and ErbB3 signaling through PTPN13 and the phorbol ester induced disassembly of hemidesmosomes [ XREF_BIBR ] .	We investigated here whether Necl-4 (also termed TSLL2, IGSF4C, SynCAM4, or CADM4) [XREF_BIBR - XREF_BIBR] also regulated the contact inhibition of cell movement and proliferation, because it binds protein-tyrosine phosphatase, non receptor type 13 (PTPN13, also termed PTP-BL, PTP-BAS, PTP-L1, or FAP1), a putative tumor suppressor, through the cytoplasmic region of Necl-4, and inhibits the heregulin induced activation of the ErbB2 and ErbB3 signaling through PTPN13 and the phorbol ester induced disassembly of hemidesmosomes [XREF_BIBR].	72	81	induced	Positive_early_activation	Positive_activation	Positive_activation	heregulin	heregulin	heregulin	ErbB2	ErbB2	ErbB2	73	74	78	79
Previous studies have shown that Nrg1 induced activation causes ErbB3 endocytosis and subsequent degradation by the lysosome in MCF7 breast tumor cells , although the ErbB3 degradation occurs at a slower rate than that of ErbB1 [ XREF_BIBR , XREF_BIBR ] Furthermore , our recent work has revealed that , in response to Nrg1 binding , ErbB3 in Schwann cells can undergo endocytic degradation , which is associated with the termination of Nrg1 activated ErbB2 and ErbB3 receptor signaling [ XREF_BIBR , XREF_BIBR ] .	Previous studies have shown that Nrg1 induced activation causes ErbB3 endocytosis and subsequent degradation by the lysosome in MCF7 breast tumor cells, although the ErbB3 degradation occurs at a slower rate than that of ErbB1 [XREF_BIBR, XREF_BIBR] Furthermore, our recent work has revealed that, in response to Nrg1 binding, ErbB3 in Schwann cells can undergo endocytic degradation, which is associated with the termination of Nrg1 activated ErbB2 and ErbB3 receptor signaling [XREF_BIBR, XREF_BIBR].	70	78	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Nrg1	Nrg1	Nrg1	ErbB2	ErbB2	ErbB2	72	73	74	75
In addition , the Heregulin mediated induction of Notch1 activity was reduced by the GSI in MCF-10A and ErbB2 and SKBR3 cells .	In addition, the Heregulin mediated induction of Notch1 activity was reduced by the GSI in MCF-10A and ErbB2 and SKBR3 cells.	3	19	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Heregulin	Heregulin	Heregulin	ErbB2	ErbB2	ErbB2	4	5	18	19
Our results also demonstrate that NRG-1 attenuated ECM mortality is associated the activation of ErbB4 and AKT and inactivation of STAT3 signaling pathways .	Our results also demonstrate that NRG-1 attenuated ECM mortality is associated the activation of ErbB4 and AKT and inactivation of STAT3 signaling pathways.	5	16	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NRG-1	NRG-1	NRG-1	ErbB4	ErbB4	ErbB4	5	6	14	15
We demonstrate that heregulin induced HER4 activity inhibits cell proliferation and delays G ( 2 )/M progression of breast cancer cells .	We demonstrate that heregulin induced HER4 activity inhibits cell proliferation and delays G (2)/M progression of breast cancer cells.	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	heregulin	heregulin	heregulin	HER4	HER4	HER4	3	4	5	6
These data are consistent with the idea that reduced levels of NRG-1 in NRG-1 +/- mice are only partly effective to stimulate ErbB4 signaling in response to TPS .	These data are consistent with the idea that reduced levels of NRG-1 in NRG-1 +/- mice are only partly effective to stimulate ErbB4 signaling in response to TPS.	9	23	stimulate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NRG-1	levels of NRG-1	nrg-1	ErbB4	ErbB4	erbb4	11	12	22	23
Recently , we demonstrated that the lack of NRG1 processing in BACE1 knockouts reduces postsynaptic function of ErbB4 , a receptor for NRG1 .	Recently, we demonstrated that the lack of NRG1 processing in BACE1 knockouts reduces postsynaptic function of ErbB4, a receptor for NRG1.	8	20	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	8	9	17	18
To characterize the interaction between Iressa and ErbB4 in greater detail and to test whether Iressa inhibits the activation of ErbB4 by Nrg1 , ErbB4 was immunoprecipitated from PC12-ErbB4-GFP cells after a short exposure to Nrg1 with or without Iressa treatment .	To characterize the interaction between Iressa and ErbB4 in greater detail and to test whether Iressa inhibits the activation of ErbB4 by Nrg1, ErbB4 was immunoprecipitated from PC12-ErbB4-GFP cells after a short exposure to Nrg1 with or without Iressa treatment.	16	23	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Nrg1	Nrg1	Nrg1	ErbB4	ErbB4	ErbB4	22	23	20	21
Trk inhibition did not alter NRG1 induced ErbB4 activation .	Trk inhibition did not alter NRG1 induced ErbB4 activation.	4	8	induced	Positive_early_activation	Positive_activation	Positive_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	5	6	7	8
Taken together , these results indicate that spironolactone serves as an inhibitor of NRG1 mediated ERBB4 signaling .	Taken together, these results indicate that spironolactone serves as an inhibitor of NRG1 mediated ERBB4 signaling.	11	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	ERBB4	ERBB4	ERBB4	13	14	15	16
The ability of DISC1 to regulate excitatory-inhibitory synapse formation by cortical interneurons depends on its inhibitory effect on NRG1 induced ERBB4 activation and signaling , ultimately effecting the spiking interneuron-pyramidal neuron circuit .	The ability of DISC1 to regulate excitatory-inhibitory synapse formation by cortical interneurons depends on its inhibitory effect on NRG1 induced ERBB4 activation and signaling, ultimately effecting the spiking interneuron-pyramidal neuron circuit.	16	21	induced	Positive_early_activation	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	ERBB4	ERBB4	ERBB4	18	19	20	21
Recently , it has been shown that the absence of NRG1 processing in BACE1 -/- mice decreased postsynaptic function of ErbB4 , a receptor for NRG1 [ XREF_BIBR ] .	Recently, it has been shown that the absence of NRG1 processing in BACE1 -/- mice decreased postsynaptic function of ErbB4, a receptor for NRG1 [XREF_BIBR].	10	23	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	10	11	20	21
The anti-NRG1 antibody used in this study both stabilizes full length NRG1 and blocks NRG1 mediated ErbB4 activation .	The anti-NRG1 antibody used in this study both stabilizes full length NRG1 and blocks NRG1 mediated ErbB4 activation.	13	17	mediated	Positive_early_activation	Positive_activation	Negative_activation	NRG1	NRG1	NRG1	ErbB4	ErbB4	ErbB4	14	15	16	17
To test this , we analyzed the time course of BDNF and NT4 induced TrkB degradation using a surface biotinylation degradation assay .	To test this, we analyzed the time course of BDNF and NT4 induced TrkB degradation using a surface biotinylation degradation assay.	8	15	induced	Positive_early_activation	Positive_activation	Negative_activation	NT4	NT4	NT4	TrkB	TrkB	TrkB	12	13	14	15
Moreover , recombinant NTF4 with the most frequent mutation , p.Arg206Trp , caused a decreased activation of TrkB [ XREF_BIBR ] .	Moreover, recombinant NTF4 with the most frequent mutation, p.Arg206Trp, caused a decreased activation of TrkB [XREF_BIBR].	2	19	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NTF4	NTF4	NTF4	TrkB	TrkB	TrkB	3	4	17	18
NPM1 is involved in ribosome biogenesis and centrosome duplication , and modulates the activity of the TP53 and CDKN2A tumor suppressors .	NPM1 is involved in ribosome biogenesis and centrosome duplication, and modulates the activity of the TP53 and CDKN2A tumor suppressors.	0	20	modulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NPM1	NPM1	NPM1	CDKN2A	CDKN2A	CDKN2A	0	1	18	19
A recent study using mouse embryonic stem ( ES ) cells engineered to express the three Trk receptors has shown that TrkA and TrkC but not TrkB instruct developing neurons to die , and the death of neurons is prevented by the addition of their ligands , NGF or NT-3 , respectively [ XREF_BIBR ] , indicating an important role for NGF and TrKA and NT-3 and TrkC signaling in cell number control and the modeling of developing sympathetic and sensory neurons .	A recent study using mouse embryonic stem (ES) cells engineered to express the three Trk receptors has shown that TrkA and TrkC but not TrkB instruct developing neurons to die, and the death of neurons is prevented by the addition of their ligands, NGF or NT-3, respectively [XREF_BIBR], indicating an important role for NGF and TrKA and NT-3 and TrkC signaling in cell number control and the modeling of developing sympathetic and sensory neurons.	39	68	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	49	50	67	68
Current studies report that NT-3 and TrkC expression was significantly elevated in normal colon tissues than in primary CRC tissues and CRC cells but NT-3 treatment of colon cancer cells ectopically expressing TrkC inhibits the tumor suppressor activity of TrkC .	Current studies report that NT-3 and TrkC expression was significantly elevated in normal colon tissues than in primary CRC tissues and CRC cells but NT-3 treatment of colon cancer cells ectopically expressing TrkC inhibits the tumor suppressor activity of TrkC.	24	40	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NT-3	NT-3	NT-3	TrkC	TrkC	TrkC	24	25	39	40
In a separate study , in vivo administration of the proteasome inhibitor Velcade prevented burn induced loss of muscle mass determined at 48 h. Finally , administration of the glucocorticoid receptor antagonist RU-486 did not prevent burn induced atrophy of the gastrocnemius or the associated elevation in atrogin-1 , MuRF-1 , or polyUb .	In a separate study, in vivo administration of the proteasome inhibitor Velcade prevented burn induced loss of muscle mass determined at 48 h. Finally, administration of the glucocorticoid receptor antagonist RU-486 did not prevent burn induced atrophy of the gastrocnemius or the associated elevation in atrogin-1, MuRF-1, or polyUb.	29	52	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	atrogin-1	atrogin-1	atrogin-1	29	31	47	48
Conceivably , resistance mechanisms to BRAF inhibition like IGF-1R XREF_BIBR , COT XREF_BIBR , NRAS XREF_BIBR , or PDGFRbeta XREF_BIBR could also provide alternate survival pathways in the context of c-Met inhibition .	Conceivably, resistance mechanisms to BRAF inhibition like IGF-1R XREF_BIBR, COT XREF_BIBR, NRAS XREF_BIBR, or PDGFRbeta XREF_BIBR could also provide alternate survival pathways in the context of c-Met inhibition.	5	15	inhibition	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	NRAS	NRAS	NRAS	BRAF	BRAF	BRAF	14	15	5	6
Melanomas escape inhibition of BRAF via upregulation of alternative pathways including upregulation of PDGFRbeta receptor tyrosine kinase , N-RAS mediated reactivation of the MAPK pathway or activation mutations in MEK1 downstream of BRAF [ XREF_BIBR , XREF_BIBR ] .	Melanomas escape inhibition of BRAF via upregulation of alternative pathways including upregulation of PDGFRbeta receptor tyrosine kinase, N-RAS mediated reactivation of the MAPK pathway or activation mutations in MEK1 downstream of BRAF [XREF_BIBR, XREF_BIBR].	2	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	N-RAS	N-RAS	N-RAS	BRAF	BRAF	BRAF	18	19	4	5
Indeed , transient transfection and chromatin immunoprecipitation verified that SHP strongly repressed PPARalpha mediated transactivation .	Indeed, transient transfection and chromatin immunoprecipitation verified that SHP strongly repressed PPARalpha mediated transactivation.	9	14	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SHP	SHP	SHP	PPARalpha	PPARalpha	PPARalpha	9	10	12	13
Here we demonstrate that the alternative Nrp2 splice form , s 9 Nrp2 B , potently sequesters VEGF-C and inhibits binding to Nrp2 .	Here we demonstrate that the alternative Nrp2 splice form, s 9 Nrp2 B, potently sequesters VEGF-C and inhibits binding to Nrp2.	6	18	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Nrp2	Nrp2	Nrp2	VEGF-C	VEGF-C	VEGF-C	6	7	17	18
These results suggest that Nr1d1 up-regulation is able to suppress Nr2e3 associated retinal degeneration by redirecting the biological networks that modulate photoreceptor development and function .	These results suggest that Nr1d1 up-regulation is able to suppress Nr2e3 associated retinal degeneration by redirecting the biological networks that modulate photoreceptor development and function.	4	11	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Nr1d1	Nr1d1	Nr1d1	Nr2e3	Nr2e3	Nr2e3	4	5	10	11
NPY also inhibits lipolysis in 3T3-L1 cells , mediated by NPY1R ( Park etal .	NPY also inhibits lipolysis in 3T3-L1 cells, mediated by NPY1R (Park etal.	0	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NPY	NPY	NPY	NPY1R	NPY1R	NPY1R	0	1	10	11
XREF_BIBR Antagonists for receptor NPY2r block NPY induced endothelial cell migration that may occur in early organogenesis .	XREF_BIBR Antagonists for receptor NPY2r block NPY induced endothelial cell migration that may occur in early organogenesis.	1	7	block	Negative_activation_token_1_noun	Positive_activation	Negative_activation	NPY	NPY	NPY	NPY2r	NPY2r	NPY2r	6	7	4	5
Netrin-1 induces axon growth cone collapse of mouse cerebellum external granule layer ( EGL ) cells , and the knockdown of DSCAM or UNC5C by specific shRNAs or blocking their signaling by overexpressing dominant negative mutants suppresses netrin-1-induced growth cone collapse .	Netrin-1 induces axon growth cone collapse of mouse cerebellum external granule layer (EGL) cells, and the knockdown of DSCAM or UNC5C by specific shRNAs or blocking their signaling by overexpressing dominant negative mutants suppresses netrin-1-induced growth cone collapse.	0	24	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Netrin-1	Netrin-1	Netrin-1	UNC5C	UNC5C	UNC5C	0	1	23	24
So , NUMB could increase to prevent the degradation of p53 by HDM2 .	So, NUMB could increase to prevent the degradation of p53 by HDM2.	2	11	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	NUMB	NUMB	NUMB	p53	p53	p53	2	3	10	11
Together , these results suggest that knockdown of NUMB promotes EMT by modulating p53 stability in MCF10A cells .	Together, these results suggest that knockdown of NUMB promotes EMT by modulating p53 stability in MCF10A cells.	6	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NUMB	NUMB	NUMB	p53	p53	p53	8	9	13	14
In normal human mammary epithelial cells and breast cancer cells expressing wild-type p53 , NUMB suppressed EMT by stabilizing p53 .	In normal human mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53.	14	20	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NUMB	NUMB	NUMB	p53	p53	p53	14	15	19	20
Numb is required to prevent p53 dependent senescence following skeletal muscle injury .	Numb is required to prevent p53 dependent senescence following skeletal muscle injury.	0	7	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Numb	Numb	Numb	p53	p53	p53	0	1	5	6
Loss of Numb could enable breast cancer cells to bypass the p53 tumor suppressor response .	Loss of Numb could enable breast cancer cells to bypass the p53 tumor suppressor response.	0	14	enable	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Loss of Numb	numb	p53	p53	p53	2	3	11	12
The cell fate determinant Numb is frequently downregulated in human breast cancers ( BCs ) , resulting in p53 inactivation and an aggressive disease course .	The cell fate determinant Numb is frequently downregulated in human breast cancers (BCs), resulting in p53 inactivation and an aggressive disease course.	3	19	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Numb	Numb	Numb	p53	p53	p53	4	5	18	19
Although Numb deficient satellite cells exhibit myostatin dependent proliferative defects [ XREF_BIBR ] , Numb is also able to prevent p53 dependent senescence during muscle repair [ XREF_BIBR ] .	Although Numb deficient satellite cells exhibit myostatin dependent proliferative defects [XREF_BIBR], Numb is also able to prevent p53 dependent senescence during muscle repair [XREF_BIBR].	14	22	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Numb	Numb	Numb	p53	p53	p53	14	15	20	21
In addition , Numb has recently been shown to prevent degradation of the tumor suppressor p53 [ XREF_BIBR ] .	In addition, Numb has recently been shown to prevent degradation of the tumor suppressor p53 [XREF_BIBR].	3	16	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Numb	Numb	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	3	4	13	16
In this scenario , the absence of Numb is expected to impair p53 stabilization but not to alter T-cell specification , as previous data have shown , 9 as loss of p53 apparently does not affect thymocyte development .	In this scenario, the absence of Numb is expected to impair p53 stabilization but not to alter T-cell specification, as previous data have shown, 9 as loss of p53 apparently does not affect thymocyte development.	5	13	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Numb	Numb	Numb	p53	p53	p53	7	8	12	13
In normal mammary epithelial cells and breast cancer cells expressing wild-type p53 , NUMB suppressed EMT by stabilizing p53 .	In normal mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53.	13	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NUMB	NUMB	NUMB	p53	p53	p53	13	14	18	19
NUMB suppresses EMT by stabilizing p53 in human mammary epithelial cells .	NUMB suppresses EMT by stabilizing p53 in human mammary epithelial cells.	0	6	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NUMB	NUMB	NUMB	p53	p53	p53	0	1	5	6
Second , NUMB was stimulated as an adaptive response to HDM2 overexpression to balance the effects of HDM2 , which is p53 can be inhibited by HDM2 and NUMB can protect p53 from the inhibition of HDM2 XREF_BIBR , XREF_BIBR .	Second, NUMB was stimulated as an adaptive response to HDM2 overexpression to balance the effects of HDM2, which is p53 can be inhibited by HDM2 and NUMB can protect p53 from the inhibition of HDM2 XREF_BIBR, XREF_BIBR.	17	29	inhibited	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	NUMB	NUMB	NUMB	p53	p53	p53	28	29	21	22
In leukemia and breast cancer , Numb inhibits growth by stabilizing p53 and inhibiting Notch [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In leukemia and breast cancer, Numb inhibits growth by stabilizing p53 and inhibiting Notch [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Numb	Numb	Numb	p53	p53	p53	6	7	11	12
Loss of Numb induces a p53 dependent senescence .	Loss of Numb induces a p53 dependent senescence.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Numb	Loss of Numb	numb	p53	p53	p53	2	3	5	6
Together , these results suggest that loss of TrkA in pancreatic tissues causes the defects in glucose homeostasis and insulin secretion in Pdx1-Cre ; TrkA f/f mice .	Together, these results suggest that loss of TrkA in pancreatic tissues causes the defects in glucose homeostasis and insulin secretion in Pdx1-Cre; TrkA f/f mice.	6	26	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkA	loss of TrkA	trka	TrkA	TrkA	trka	8	9	24	25
A partial knockdown of TrkA expression increased the ratio of p75NTR : TrkA ( XREF_FIG and XREF_FIG ) .	A partial knockdown of TrkA expression increased the ratio of p75NTR : TrkA (XREF_FIG and XREF_FIG).	4	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TrkA	TrkA expression	trka	TrkA	TrkA	trka	4	5	12	13
The addition of LAR wedge peptide inhibited LAR co-immunoprecipitation with TrkA , augmented NGF induced activation of TrkA , ERK , and AKT , and in the absence of exogenous NGF , induced activation of TrkA , ERK , and AKT .	The addition of LAR wedge peptide inhibited LAR co-immunoprecipitation with TrkA, augmented NGF induced activation of TrkA, ERK, and AKT, and in the absence of exogenous NGF, induced activation of TrkA, ERK, and AKT.	3	40	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkA	LAR wedge peptide inhibited LAR co-immunoprecipitation with TrkA, augmented NGF induced activation of TrkA	trka	TrkA	TrkA	trka	17	18	35	36
The TrkA R685A mutation prevented receptor binding to PTP1B and suppressed PTP1B induced TrkA dephosphorylation , but did not disrupt TrkA kinase activity or downstream signaling ( XREF_SUPPLEMENTARY ) .	The TrkA R685A mutation prevented receptor binding to PTP1B and suppressed PTP1B induced TrkA dephosphorylation, but did not disrupt TrkA kinase activity or downstream signaling (XREF_SUPPLEMENTARY).	1	22	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TrkA	TrkA R685A mutation prevented receptor binding to PTP1B and suppressed PTP1B induced TrkA dephosphorylation	trka	TrkA	TrkA	trka	1	2	20	21
We found that patients with SGS showed increased TrkB expression , decreased p75 NTR / TrkB ratio , and decreased p75 NTR expression when compared to those with CPS .	We found that patients with SGS showed increased TrkB expression, decreased p75 NTR / TrkB ratio, and decreased p75 NTR expression when compared to those with CPS.	8	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TrkB	TrkB expression	trkb	TrkB	TrkB	trkb	8	9	15	16
The effect of TrkB knockdown in CFs was rescued by co-expression of the TrkB miRNA resistant form of TrkB tagged with mOrange driven by the MSCV ( TrkB-Res ) .	The effect of TrkB knockdown in CFs was rescued by co-expression of the TrkB miRNA resistant form of TrkB tagged with mOrange driven by the MSCV (TrkB-Res).	8	19	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkB	co-expression of the TrkB	trkb	TrkB	TrkB	trkb	13	14	18	19
In Neurog2 single mutant mice , there is an initial loss of TrkC + , TrkB + and Ret + mechanoreceptors , although the loss of TrkC + and TrkB + neurons is later compensated by neurons formed from Neurog1 expressing precursors [ XREF_BIBR ] .	In Neurog2 single mutant mice, there is an initial loss of TrkC +, TrkB + and Ret + mechanoreceptors, although the loss of TrkC + and TrkB + neurons is later compensated by neurons formed from Neurog1 expressing precursors [XREF_BIBR].	7	16	is an initial loss	Negative_activation_copula_1	Positive_activation	Negative_activation	TrkB	loss of TrkC +, TrkB	trkb	TrkB	TrkB	trkb	15	16	15	16
Interestingly , the amount of TrkB in the Golgi membrane enriched fraction was significantly increased in ARHGAP33 KO mice ( P = 0.0017 ; XREF_FIG ) , suggesting impaired TrkB trafficking at the Golgi apparatus .	Interestingly, the amount of TrkB in the Golgi membrane enriched fraction was significantly increased in ARHGAP33 KO mice (P = 0.0017; XREF_FIG), suggesting impaired TrkB trafficking at the Golgi apparatus.	3	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TrkB	amount of TrkB	trkb	TrkB	TrkB	trkb	5	6	29	30
We found that the effects of BDNF on APE1 levels and protection of cortical neurons against oxidative DNA damage ( menadione ) were completely abolished when TrkB levels were selectively reduced using TrkB shRNA .	We found that the effects of BDNF on APE1 levels and protection of cortical neurons against oxidative DNA damage (menadione) were completely abolished when TrkB levels were selectively reduced using TrkB shRNA.	26	33	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TrkB	TrkB levels	trkb	TrkB	TrkB	trkb	26	27	32	33
By contrast , both acute NtsR1 and D1R antagonism abolished LHA Nts induced suppression of feeding in Nts Cre ; NtsR1 ++ mice , implying obligatory , overlapping roles for Nts and DA in this process .	By contrast, both acute NtsR1 and D1R antagonism abolished LHA Nts induced suppression of feeding in Nts Cre; NtsR1 ++ mice, implying obligatory, overlapping roles for Nts and DA in this process.	10	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Nts	Nts	Nts	NtsR1	NtsR1	NtsR1	11	12	20	21
These data suggest that activation of LHA Nts neurons promotes locomotor activity , energy expenditure and NtsR1 dependent suppression of feeding to promote weight loss .	These data suggest that activation of LHA Nts neurons promotes locomotor activity, energy expenditure and NtsR1 dependent suppression of feeding to promote weight loss.	7	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Nts	Nts	Nts	NtsR1	NtsR1	NtsR1	7	8	16	17
In this model Numb negatively regulates Notch , Akt1 and Itch , and each pathway further affects defined downstream signaling .	In this model Numb negatively regulates Notch, Akt1 and Itch, and each pathway further affects defined downstream signaling.	3	11	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Numb	Numb	Numb	Itch	Itch	Itch	3	4	10	11
XREF_BIBR - XREF_BIBR NUMB is also able to directly inhibit NOTCH by recruiting Itch for polyubiquitination and degradation of Notch proteins .	XREF_BIBR - XREF_BIBR NUMB is also able to directly inhibit NOTCH by recruiting Itch for polyubiquitination and degradation of Notch proteins.	2	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NUMB	NUMB	NUMB	Itch	Itch	Itch	3	4	13	14
Loss of STK11 function in these cells would reduce its phosphorylation of NUAK1 at Thr 211 and thus deactivate the p53 regulated brake on cell cycle progression .	Loss of STK11 function in these cells would reduce its phosphorylation of NUAK1 at Thr 211 and thus deactivate the p53 regulated brake on cell cycle progression.	2	21	deactivate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	NUAK1	STK11 function in these cells would reduce its phosphorylation of NUAK1 at Thr 211	nuak1	p53	p53	p53	12	13	20	21
Finally , we observed a dose dependent OT stimulation of cell proliferation associated with OTR activation that was completely abolished by the selective OT antagonist .	Finally, we observed a dose dependent OT stimulation of cell proliferation associated with OTR activation that was completely abolished by the selective OT antagonist.	14	24	abolished	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	OT	OT	OT	OTR	OTR	OTR	23	24	14	15
In line with this , a low dose of the selective oxytocin antagonist desGlyDTyrOVT blocks the rescue effect of TGOT only in the Oxtr ( +/-) genotype , whereas the less selective antagonist SR49059 blocks rescue in both genotypes .	In line with this, a low dose of the selective oxytocin antagonist desGlyDTyrOVT blocks the rescue effect of TGOT only in the Oxtr (+/-) genotype, whereas the less selective antagonist SR49059 blocks rescue in both genotypes.	11	24	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	oxytocin	oxytocin	oxytocin	Oxtr	Oxtr	Oxtr	11	12	23	24
Continuous oxytocin infusion from Day 13 blocked the rise in uterine oxytocin receptor concentrations which normally precedes oestrus .	Continuous oxytocin infusion from Day 13 blocked the rise in uterine oxytocin receptor concentrations which normally precedes oestrus.	1	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	1	2	11	13
We have previously found that OT down-regulates OTR in the non pregnant rat myometrium , but this therefore does not appear to take place at the level of mRNA production .	We have previously found that OT down-regulates OTR in the non pregnant rat myometrium, but this therefore does not appear to take place at the level of mRNA production.	5	13	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	OT	OT	OT	OTR	OTR	OTR	5	6	7	8
Since cloprostenol , a PGF-2 alpha analogue , overcame the antiluteolytic action of oxytocin , it is suggested that continuous oxytocin treatment may inhibit uterine production of PGF-2 alpha , possibly by down regulating the uterine oxytocin receptor .	Since cloprostenol, a PGF-2 alpha analogue, overcame the antiluteolytic action of oxytocin, it is suggested that continuous oxytocin treatment may inhibit uterine production of PGF-2 alpha, possibly by down regulating the uterine oxytocin receptor.	20	38	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	20	21	36	38
Addition of oxytocin or progesterone , which reduce oxytocin receptor bindingin vivo , also lowered oxytocin receptor bindingin vitro in the absence of any effect on PKC .	Addition of oxytocin or progesterone, which reduce oxytocin receptor bindingin vivo, also lowered oxytocin receptor bindingin vitro in the absence of any effect on PKC.	0	17	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	oxytocin	oxytocin	oxytocin	oxytocin receptor	oxytocin receptor	oxytocin receptor	2	3	15	17
Our data suggest , that IL-1beta indirectly increases OT secretion in primary cultures of human decidua in a time dependent fashion through the production of prostaglandins through COX-2 and that this increase in OT peptide may secondarily down-regulate the OTR and its signalling cascade .	Our data suggest, that IL-1beta indirectly increases OT secretion in primary cultures of human decidua in a time dependent fashion through the production of prostaglandins through COX-2 and that this increase in OT peptide may secondarily down-regulate the OTR and its signalling cascade.	33	43	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	OT	OT	OT	OTR	OTR	OTR	33	34	39	40
Gestational cocaine treatment in rat dams results in decreased oxytocin ( OT ) levels , up-regulated oxytocin receptor ( OTR ) binding density and decreased receptor affinity in the whole amygdala , all concomitant with a significant increase in maternal aggression on postpartum day six .	Gestational cocaine treatment in rat dams results in decreased oxytocin (OT) levels, up-regulated oxytocin receptor (OTR) binding density and decreased receptor affinity in the whole amygdala, all concomitant with a significant increase in maternal aggression on postpartum day six.	9	18	up-regulated	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	OT	OT	OT	oxytocin receptor	oxytocin receptor	oxytocin receptor	11	12	16	18
We found four genes , lis-1 , cap-1 , cap-2 , and dli-1 , that when depleted by RNAi significantly suppressed dhc-1 ( or195ts ) lethality , cytoskeletal defects , and DHC localization in the germline and early embryo .	We found four genes, lis-1, cap-1, cap-2, and dli-1, that when depleted by RNAi significantly suppressed dhc-1 (or195ts) lethality, cytoskeletal defects, and DHC localization in the germline and early embryo.	3	32	suppressed	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	lis-1	lis-1	lis-1	dhc-1	dhc-1	dhc-1	5	6	21	22
These results suggest that dli-1 and lis-1 suppress dhc-1 ( or195ts ) by a similar mechanism .	These results suggest that dli-1 and lis-1 suppress dhc-1 (or195ts) by a similar mechanism.	4	10	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	lis-1	lis-1	lis-1	dhc-1	dhc-1	dhc-1	6	7	8	9
RNAi mediated knockdown of lis-1 in wild-type animals , similar to the lis-1 ( null ) , caused DHC-1 to become cytoplasmic .	RNAi mediated knockdown of lis-1 in wild-type animals, similar to the lis-1 (null), caused DHC-1 to become cytoplasmic.	2	19	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	lis-1	lis-1	lis-1	DHC-1	DHC-1	DHC-1	4	5	18	19
Therefore , OSR1 haploinsufficiency may cause decreased pNKCC1 abundance in testes and mature spermatozoa , thereby contributing to male subfertility .	Therefore, OSR1 haploinsufficiency may cause decreased pNKCC1 abundance in testes and mature spermatozoa, thereby contributing to male subfertility.	2	8	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	OSR1	OSR1	OSR1	pNKCC1	pNKCC1	pNKCC1	2	3	7	8
Depletion of either WNK1 or OXSR1 also reduced NKCC1 activity , suggesting that WNK1 and OSR1 are required for NKCC1 function .	Depletion of either WNK1 or OXSR1 also reduced NKCC1 activity, suggesting that WNK1 and OSR1 are required for NKCC1 function.	0	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	OXSR1	OXSR1	OXSR1	NKCC1	NKCC1	NKCC1	5	6	8	9
Furthermore , there was a strong inhibition of PAK1 ( P < .05 ) , Limk1 ( P < .01 ) , and cofilin ( P < .01 ) phosphorylation on uPAR knockdown .	Furthermore, there was a strong inhibition of PAK1 (P <.05), Limk1 (P <.01), and cofilin (P <.01) phosphorylation on uPAR knockdown.	3	30	was a strong inhibition	Negative_activation_copula_1	Positive_activation	Negative_activation	PAK1	PAK1 (P <.05), Limk1 (P <.01), and cofilin (P <.01) phosphorylation	pak1	Limk1	Limk1	limk1	8	9	15	16
Interestingly , both ROCK isoforms and PAK1 , an activator of LIMK1 by phosphorylation , expectedly reduced LIMK1 activity under condition A 1.28 fold ( n = 4 ) and activated it significantly under condition B 1.335-fold ( n = 4 ) [ XREF_FIG B ( v ) , C ] .	Interestingly, both ROCK isoforms and PAK1, an activator of LIMK1 by phosphorylation, expectedly reduced LIMK1 activity under condition A 1.28 fold (n = 4) and activated it significantly under condition B 1.335-fold (n = 4) [XREF_FIG B (v), C].	4	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PAK1	PAK1	PAK1	LIMK1	LIMK1	LIMK1	6	7	17	18
PAK1 depletion inhibited the accumulation of p-LIMK and p-p41-ARC in the context of RHOJ overexpression ( XREF_FIG ) , indicating that RHOJ activates PAK1 in order to phosphorylate these downstream targets .	PAK1 depletion inhibited the accumulation of p-LIMK and p-p41-ARC in the context of RHOJ overexpression (XREF_FIG), indicating that RHOJ activates PAK1 in order to phosphorylate these downstream targets.	0	8	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	p-LIMK	p-LIMK	p-LIMK	0	1	6	7
Their study demonstrated PAK1 kinase activity contributes to nuclear localization and signaling of beta-catenin , whereas our data shows that inhibition of PAK1 promotes beta-catenin activity in cell adhesion at the membrane .	Their study demonstrated PAK1 kinase activity contributes to nuclear localization and signaling of beta-catenin, whereas our data shows that inhibition of PAK1 promotes beta-catenin activity in cell adhesion at the membrane.	20	25	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PAK1	PAK1	PAK1	beta-catenin	beta-catenin	beta-catenin	22	23	24	25
A functional relation between PAK1 and beta-catenin has been established by inhibiting PAK1 in tumour cells : small interfering RNA ( siPAK1 ) and KD-PAK1 significantly reduced beta-catenin and cyclin D1 at the protein level .	A functional relation between PAK1 and beta-catenin has been established by inhibiting PAK1 in tumour cells : small interfering RNA (siPAK1) and KD-PAK1 significantly reduced beta-catenin and cyclin D1 at the protein level.	19	30	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	KD-PAK1	KD-PAK1	KD-PAK1	beta-catenin	beta-catenin	beta-catenin	24	25	27	28
For example , phosphorylation of protein kinase p90RSK by several MAPK proteins can inhibit tuberous sclerosis-2 ( TSC2 ) ( on Ser 1796 and Ser 939 ) , and activation of raptor ( Ser 719 ) , eIF4B ( Ser 422 ) , and rpS6 ( Ser 235/236 ) , to promote protein translation .	For example, phosphorylation of protein kinase p90RSK by several MAPK proteins can inhibit tuberous sclerosis-2 (TSC2) (on Ser 1796 and Ser 939), and activation of raptor (Ser 719), eIF4B (Ser 422), and rpS6 (Ser 235/236), to promote protein translation.	3	39	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p90RSK	phosphorylation of protein kinase p90RSK	p90rsk	eIF4B	eIF4B	eif4b	7	8	37	38
Pak1 depletion suppressed the accumulation of Plk1 induced by RhoJ overexpression ( XREF_FIG ) , consistent with a role for Pak1 in activating Plk1 .	Pak1 depletion suppressed the accumulation of Plk1 induced by RhoJ overexpression (XREF_FIG), consistent with a role for Pak1 in activating Plk1.	0	7	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	Plk1	Plk1	Plk1	0	1	6	7
Suppression of Pak1 Morphant Phenotype with Activated Mek .	Suppression of Pak1 Morphant Phenotype with Activated Mek.	2	8	Activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Pak1	Pak1	Pak1	Mek	Mek	Mek	2	3	7	8
Knockdown of Pak1 in endometrial cancer cells reduced cell proliferation and down-regulated cyclin D1 , ERalpha and PR .	Knockdown of Pak1 in endometrial cancer cells reduced cell proliferation and down-regulated cyclin D1, ERalpha and PR.	0	16	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Pak1	Pak1	Pak1	ERalpha	ERalpha	ERalpha	2	3	15	16
Moreover , cell-cell junctions were found to be inhibited by PAK1 induced Snail activation , promoting dissemination of cancer cells by inducing epithelial mesenchymal transition ( EMT ) [ XREF_BIBR , XREF_BIBR ] .	Moreover, cell-cell junctions were found to be inhibited by PAK1 induced Snail activation, promoting dissemination of cancer cells by inducing epithelial mesenchymal transition (EMT) [XREF_BIBR, XREF_BIBR].	8	13	induced	Positive_early_activation	Positive_activation	Positive_activation	PAK1	PAK1	PAK1	Snail	Snail	Snail	10	11	12	13
Complete loss of Lis1 or Ndel1 using hGFAP- and Tamoxifen-Cre induced Lis1 and Ndel1 conditional knock-out mice resulted in the total inhibition of movement and impaired formation of leading processes in the developing neocortex .	Complete loss of Lis1 or Ndel1 using hGFAP- and Tamoxifen-Cre induced Lis1 and Ndel1 conditional knock-out mice resulted in the total inhibition of movement and impaired formation of leading processes in the developing neocortex.	1	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Lis1	loss of Lis1	lis1	Ndel1	Ndel1	ndel1	3	4	13	14
Replacement of the OSM AB loop within OSM ' s binding site III with that of LIF abrogated OSMR activation , measured as STAT3 phosphorylation at Tyr 705 , but did not compromise LIFR activation .	Replacement of the OSM AB loop within OSM 's binding site III with that of LIF abrogated OSMR activation, measured as STAT3 phosphorylation at Tyr 705, but did not compromise LIFR activation.	3	19	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	OSM	OSM	OSM	OSMR	OSMR	OSMR	3	4	18	19
Knockdown of PAFAH1B2 strongly reduced Abeta secretion from human cells , and this effect was confirmed in primary cells derived from PAFAH1B2 knock-out mice .	Knockdown of PAFAH1B2 strongly reduced Abeta secretion from human cells, and this effect was confirmed in primary cells derived from PAFAH1B2 knock-out mice.	0	6	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PAFAH1B2	PAFAH1B2	PAFAH1B2	Abeta	Abeta	Abeta	2	3	5	6
Representative images show that mutation of the coiled-coil domain of PALB2 disrupted the assembly of PALB2 and RAD51 foci in EUFA1341 cells ( XREF_FIG ) .	Representative images show that mutation of the coiled-coil domain of PALB2 disrupted the assembly of PALB2 and RAD51 foci in EUFA1341 cells (XREF_FIG).	8	18	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	10	11	17	18
Based on these findings , we suggest that both RAD51 and DMC1 expression and TEX15-, BRCA1-, BRCA2- and PALB2 mediated RAD51 and DMC1 loading onto sites of DSBs were disrupted in SCARKO and EGF transgenic testes .	Based on these findings, we suggest that both RAD51 and DMC1 expression and TEX15-, BRCA1-, BRCA2- and PALB2 mediated RAD51 and DMC1 loading onto sites of DSBs were disrupted in SCARKO and EGF transgenic testes.	12	23	mediated	Positive_early_activation	Positive_activation	Negative_activation	PALB2	PALB2	PALB2	RAD51	RAD51	RAD51	18	19	20	21
In contrast , Pericentrin NE localization was partially reduced by Pcm1 depletion as previously shown [ XREF_BIBR , XREF_BIBR ] .	In contrast, Pericentrin NE localization was partially reduced by Pcm1 depletion as previously shown [XREF_BIBR, XREF_BIBR].	3	11	reduced	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Pcm1	Pcm1	Pcm1	Pericentrin	Pericentrin	Pericentrin	10	11	3	4
Loss of PCM-1 leads to reduced targeting of centrin , pericentrin , and ninein to centrosomes in cycling cells and compromises primary cilia assembly .	Loss of PCM-1 leads to reduced targeting of centrin, pericentrin, and ninein to centrosomes in cycling cells and compromises primary cilia assembly.	0	11	leads to	Positive_activation_nested_syntax_2_verb	Positive_activation	Negative_activation	PCM-1	Loss of PCM-1	pcm-1	pericentrin	pericentrin	pericentrin	2	3	10	11
PAK2 deletion leads to cerebral hemorrhage in redhead zebrafish and this defect is rescued by endothelial specific expression of PAK2 , demonstrating the important role of PAK2 in brain vessels XREF_BIBR .	PAK2 deletion leads to cerebral hemorrhage in redhead zebrafish and this defect is rescued by endothelial specific expression of PAK2, demonstrating the important role of PAK2 in brain vessels XREF_BIBR.	13	27	rescued	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PAK2	expression of PAK2	pak2	PAK2	PAK2	pak2	19	20	26	27
Thus , mutations in PALB2 disrupt BRCA2 tumor suppression function and predispose carriers to similar cancers .	Thus, mutations in PALB2 disrupt BRCA2 tumor suppression function and predispose carriers to similar cancers.	2	9	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PALB2	PALB2	PALB2	BRCA2	BRCA2	BRCA2	4	5	6	7
Mutation of the PH domain of PDK1 inhibits the full activation of Akt , which prevents the activation of downstream pathways [ XREF_BIBR ] .	Mutation of the PH domain of PDK1 inhibits the full activation of Akt, which prevents the activation of downstream pathways [XREF_BIBR].	4	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	6	7	12	13
In contrast , in cell lines lacking activating PI3KCA mutations , partial inhibition of Akt signaling synergized with camptothecin or etoposide , but higher A-443654 or MK-2206 concentrations ( > 80 % inhibition of Akt signaling ) or PDK1 siRNA antagonized the topoisomerase poisons by diminishing DNA synthesis , a process that contributes to effective DNA damage and killing by these agents .	In contrast, in cell lines lacking activating PI3KCA mutations, partial inhibition of Akt signaling synergized with camptothecin or etoposide, but higher A-443654 or MK-2206 concentrations (> 80% inhibition of Akt signaling) or PDK1 siRNA antagonized the topoisomerase poisons by diminishing DNA synthesis, a process that contributes to effective DNA damage and killing by these agents.	32	39	inhibition	Negative_activation_syntax_7_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	38	39	34	35
Rapamycin and S6K inhibitors reduce cardiac ischemic remodeling and cardiomyocyte apoptosis through PDK1 dependent activation of the Akt pathway 111 .	Rapamycin and S6K inhibitors reduce cardiac ischemic remodeling and cardiomyocyte apoptosis through PDK1 dependent activation of the Akt pathway 111.	12	18	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	12	13	17	18
Inhibition of c-Jun reduces PDK1 expression and attenuates Akt and PKC activity , which can be restored by exogenous PDK1 .	Inhibition of c-Jun reduces PDK1 expression and attenuates Akt and PKC activity, which can be restored by exogenous PDK1.	8	20	restored	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	19	20	8	9
Akt is the only known PH domain containing PDPK1 target and PDPK1 has to be localized to the plasma membrane to activate Akt through binding of its PH domain to PtdIns ( 3,4,5 ) P 3 .	Akt is the only known PH domain containing PDPK1 target and PDPK1 has to be localized to the plasma membrane to activate Akt through binding of its PH domain to PtdIns (3,4,5) P 3.	8	23	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	PDPK1	PDPK1	PDPK1	Akt	Akt	Akt	8	9	22	23
Akt signalling is also decreased by a Rictor dependent , PDK1 independent mechanism .	Akt signalling is also decreased by a Rictor dependent, PDK1 independent mechanism.	0	12	decreased	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	10	11	0	1
Immunodepletion of PDK1 or Raptor reduced Akt at Thr 308 significantly .	Immunodepletion of PDK1 or Raptor reduced Akt at Thr 308 significantly.	0	7	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	2	3	6	7
Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway , stimulated proapoptotic p38 MAPK pathway , and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes .	Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes.	0	10	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	2	3	9	10
Thus , combination with PDK1 mediated Akt inhibition sensitizes MDA-MB-231 cells to tamoxifen .	Thus, combination with PDK1 mediated Akt inhibition sensitizes MDA-MB-231 cells to tamoxifen.	2	7	mediated	Positive_early_activation	Positive_activation	Negative_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	4	5	6	7
It can also be noted that the ASK1 protein has a mutually inhibitory relationship with the kinase PDK , XREF_BIBR which inhibits AKT XREF_BIBR and thereby reduces the chances of cell survival in response to oxidative stress .	It can also be noted that the ASK1 protein has a mutually inhibitory relationship with the kinase PDK, XREF_BIBR which inhibits AKT XREF_BIBR and thereby reduces the chances of cell survival in response to oxidative stress.	13	23	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	PDK	PDK	PDK	AKT	AKT	AKT	17	18	22	23
40 In line with this , induction of PDK1 activity decreases apoptosis by activating Akt .	40 In line with this, induction of PDK1 activity decreases apoptosis by activating Akt.	8	15	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	8	9	14	15
Genetic mutation of the PH domain of PDK1 inhibits Akt , leading to glucose and insulin intolerance , indicating the critical role played by PtdIns ( 3,4,5 ) P 3 in glucose homeostasis [ XREF_BIBR ] .	Genetic mutation of the PH domain of PDK1 inhibits Akt, leading to glucose and insulin intolerance, indicating the critical role played by PtdIns (3,4,5) P 3 in glucose homeostasis [XREF_BIBR].	5	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	PDK1	PDK1	Akt	Akt	Akt	7	8	9	10
PTEN loss causes accumulation of PtdIns ( 3,4,5 ) P3 , with recruitment and activation of AKT mediated by PDK1 ; PDK1 phosphorylates AKT at the critical residue Thr308 , whereas the Ser473 residue of AKT is a substrate of mammalian target of rapamycin 2 complex ( mTORC2 ) .	PTEN loss causes accumulation of PtdIns (3,4,5) P3, with recruitment and activation of AKT mediated by PDK1; PDK1 phosphorylates AKT at the critical residue Thr308, whereas the Ser473 residue of AKT is a substrate of mammalian target of rapamycin 2 complex (mTORC2).	12	20	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	PDK1	PDK1	PDK1	AKT	AKT	AKT	19	20	16	17
To discern mechanisms for long-term GRK5 mediated PDGFRbeta desensitization pertinent to SMC proliferation and migration , we tested whether GRK5 could augment PDGFRbeta ubiquitination , a process that triggers PDGFRbeta degradation in the lysosome .	To discern mechanisms for long-term GRK5 mediated PDGFRbeta desensitization pertinent to SMC proliferation and migration, we tested whether GRK5 could augment PDGFRbeta ubiquitination, a process that triggers PDGFRbeta degradation in the lysosome.	19	30	triggers	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	PDGFRbeta	GRK5 could augment PDGFRbeta ubiquitination	pdgfrbeta	PDGFRbeta	PDGFRbeta	pdgfrbeta	22	23	29	30
The GRK2 dependent serine phosphorylation of PDGFRbeta reduces Tyr autophosphorylation and allosteric activation of Galpha i , as well as the association of PDGFRbeta with the Na + / H + exchanger regulatory factor .	The GRK2 dependent serine phosphorylation of PDGFRbeta reduces Tyr autophosphorylation and allosteric activation of Galpha i, as well as the association of PDGFRbeta with the Na + / H + exchanger regulatory factor.	1	26	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDGFRbeta	GRK2 dependent serine phosphorylation of PDGFRbeta	pdgfrbeta	PDGFRbeta	PDGFRbeta	pdgfrbeta	6	7	23	24
The above data taken together indicate that RTX treatment not only mediates a significant attenuation of PDGFRalpha and PDGFRbeta expression on spindle like cells , but also associates with a decrease in PDGFRbeta phosphorylation ( activation ) status .	The above data taken together indicate that RTX treatment not only mediates a significant attenuation of PDGFRalpha and PDGFRbeta expression on spindle like cells, but also associates with a decrease in PDGFRbeta phosphorylation (activation) status.	30	34	decrease	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	PDGFRbeta	PDGFRbeta phosphorylation	pdgfrbeta	PDGFRbeta	PDGFRbeta	pdgfrbeta	32	33	32	33
17 Our study reveals a novel mechanism by which GRK5 alters PDGFRbeta signaling : enhancing PDGFRbeta ubiquitination , which enhances PDGFRbeta degradation .	17 Our study reveals a novel mechanism by which GRK5 alters PDGFRbeta signaling : enhancing PDGFRbeta ubiquitination, which enhances PDGFRbeta degradation.	15	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PDGFRbeta	PDGFRbeta ubiquitination	pdgfrbeta	PDGFRbeta	PDGFRbeta	pdgfrbeta	15	16	20	21
There was loss of PDGFR-alpha and gain of PDGFR-beta in somatotropinomas .	There was loss of PDGFR-alpha and gain of PDGFR-beta in somatotropinomas.	1	10	was loss	Negative_activation_copula_1	Positive_activation	Negative_activation	PDGFR-beta	loss of PDGFR-alpha and gain of PDGFR-beta	pdgfr-beta	PDGFR-beta	PDGFR-beta	pdgfr-beta	8	9	8	9
Furthermore , LDE225 in combination with vemurafenib down-regulated PDGFRalpha expression and inhibited ERK and AKT activation in the BRAF-I sensitive and resistant melanoma cells .	Furthermore, LDE225 in combination with vemurafenib down-regulated PDGFRalpha expression and inhibited ERK and AKT activation in the BRAF-I sensitive and resistant melanoma cells.	2	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDGFRalpha	LDE225 in combination with vemurafenib down-regulated PDGFRalpha expression	pdgfralpha	ERK	ERK	erk	8	9	12	13
Furthermore , PDGFRalpha down-regulation by the Shh-I LDE225 in combination with vemurafenib enhances tumor growth inhibition in vitro and in vivo and decreases ERK and AKT activation in both sensitive and resistant cell lines .	Furthermore, PDGFRalpha down-regulation by the Shh-I LDE225 in combination with vemurafenib enhances tumor growth inhibition in vitro and in vivo and decreases ERK and AKT activation in both sensitive and resistant cell lines.	2	26	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDGFRalpha	PDGFRalpha	PDGFRalpha	ERK	ERK	ERK	2	3	23	24
The HGF-up-regulated Axl and PDGFR-alpha could be inhibited by PD98059 , supporting the involvement of MEK and ERK 1/2 signaling in this transactivation event .	The HGF-up-regulated Axl and PDGFR-alpha could be inhibited by PD98059, supporting the involvement of MEK and ERK 1/2 signaling in this transactivation event.	2	19	supporting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PDGFR-alpha	PDGFR-alpha	PDGFR-alpha	ERK 1/2	ERK 1/2	ERK 1/2	4	5	17	19
In KIT-mutant GIST , inhibition of PDGFRA disrupts a KIT-ERK-ETV1-KIT signaling loop by inhibiting ERK activation .	In KIT-mutant GIST, inhibition of PDGFRA disrupts a KIT-ERK-ETV1-KIT signaling loop by inhibiting ERK activation.	4	15	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PDGFRA	PDGFRA	PDGFRA	ERK	ERK	ERK	6	7	14	15
SHP-2 regulates the expression of the PDGFRbeta , and thus levels of PDGFRbeta are downregulated in mutant fibroblasts lacking SHP-2 XREF_BIBR .	SHP-2 regulates the expression of the PDGFRbeta, and thus levels of PDGFRbeta are downregulated in mutant fibroblasts lacking SHP-2 XREF_BIBR.	10	20	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDGFRbeta	levels of PDGFRbeta	pdgfrbeta	SHP-2	SHP-2	shp-2	12	13	19	20
The small interference RNA mediated down-regulation of PDK1 attenuated maximum MEK and MAPK activities but could not prolong MAPK signaling duration .	The small interference RNA mediated down-regulation of PDK1 attenuated maximum MEK and MAPK activities but could not prolong MAPK signaling duration.	5	13	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	PDK1	PDK1	MEK	MEK	MEK	7	8	10	11
To further verify the pro survival liaisons between PDK1 and RSK1/2 , we tested whether PDK1 may suppress apoptosis by regulating the active overexpressed RSK1 .	To further verify the pro survival liaisons between PDK1 and RSK1/2, we tested whether PDK1 may suppress apoptosis by regulating the active overexpressed RSK1.	15	25	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDK1	PDK1	PDK1	RSK1	RSK1	RSK1	15	16	24	25
Knockdown of PDK1 protein levels by lentiviral expression of PDK1 siRNA produced comparable decreases in PKCdelta activity ( not shown ) .	Knockdown of PDK1 protein levels by lentiviral expression of PDK1 siRNA produced comparable decreases in PKCdelta activity (not shown).	0	16	produced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PDK1	Knockdown of PDK1 protein levels by lentiviral expression of PDK1	pdk1	PKCdelta	PKCdelta	pkcdelta	9	10	15	16
Interestingly , the potent PDGFRB and FGFR1 inhibitor PD-161570 and PD-166285 strongly reduced the kinase activity of TGFBR1 and SRC with similar potency to their reported targets .	Interestingly, the potent PDGFRB and FGFR1 inhibitor PD-161570 and PD-166285 strongly reduced the kinase activity of TGFBR1 and SRC with similar potency to their reported targets.	2	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PDGFRB	PDGFRB	PDGFRB	SRC	SRC	SRC	4	5	19	20
Consistent with this observation , phosphorylation of AKT , the canonical substrate of PDGFA activated PDGFRalpha [ XREF_BIBR - XREF_BIBR ] , was reduced in both Alk5 Dermo1 lung homogenates and isolated primary Alk5 Dermo1 mesenchymal cells .	Consistent with this observation, phosphorylation of AKT, the canonical substrate of PDGFA activated PDGFRalpha [XREF_BIBR - XREF_BIBR], was reduced in both Alk5 Dermo1 lung homogenates and isolated primary Alk5 Dermo1 mesenchymal cells.	11	17	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	PDGFA	PDGFA	PDGFA	PDGFRalpha	PDGFRalpha	PDGFRalpha	13	14	15	16
Mechanistic studies suggest that liganded PR represses ER activity by interfering with its ability to interact productively with the transcriptional machinery , a process known as quenching .	Mechanistic studies suggest that liganded PR represses ER activity by interfering with its ability to interact productively with the transcriptional machinery, a process known as quenching.	4	8	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	5	6	7	8
For instance it is not always appreciated that PR can inhibit ER transcriptional activity [ XREF_BIBR , XREF_BIBR ] .	For instance it is not always appreciated that PR can inhibit ER transcriptional activity [XREF_BIBR, XREF_BIBR].	8	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	8	9	11	12
Since stromal PR has been implicated to suppress epithelial ER activity , we further asked whether stromal PR expression is downregulated in the COUP-TFII conditional mutants .	Since stromal PR has been implicated to suppress epithelial ER activity, we further asked whether stromal PR expression is downregulated in the COUP-TFII conditional mutants.	1	10	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	2	3	9	10
In the MDA-MB-361 model system of EGFRvIII induced estrogen-independence , tamoxifen-resistance , ERalpha protein levels were reduced , although not substantially , and a more pronounced reduction in PgR protein levels ( XREF_FIG ) .	In the MDA-MB-361 model system of EGFRvIII induced estrogen-independence, tamoxifen-resistance, ERalpha protein levels were reduced, although not substantially, and a more pronounced reduction in PgR protein levels (XREF_FIG).	7	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PgR	PgR protein levels	pgr	ERalpha protein	ERalpha protein	eralpha protein	28	29	12	14
In promoter interference assays PR represses ER transcriptional activity predominantly through PR-A .	In promoter interference assays PR represses ER transcriptional activity predominantly through PR-A.	4	8	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	4	5	6	7
In breast cancer models , numerous ER target genes require PR expression ( i.e ., via scaffolding actions in ER/PR complexes ) for optimal estrogen responsiveness in the absence of exogenously added progesterone [ XREF_BIBR ] , while PR can dominantly repress or modify ER actions as part of ER/PR complexes when both ligands ( i.e ., estrogen and progesterone agonists or antagonists ) are combined [ XREF_BIBR , XREF_BIBR ] .	In breast cancer models, numerous ER target genes require PR expression (i.e., via scaffolding actions in ER/PR complexes) for optimal estrogen responsiveness in the absence of exogenously added progesterone [XREF_BIBR], while PR can dominantly repress or modify ER actions as part of ER/PR complexes when both ligands (i.e., estrogen and progesterone agonists or antagonists) are combined [XREF_BIBR, XREF_BIBR].	38	45	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	38	39	44	45
In addition , the failure of MMTV-neu-expressing tumor cells to form normal mammary structures by themselves would be impaired by the absence of PR + and ERalpha + progeny .	In addition, the failure of MMTV-neu-expressing tumor cells to form normal mammary structures by themselves would be impaired by the absence of PR + and ERalpha + progeny.	18	28	impaired	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ERalpha	ERalpha	ERalpha	23	24	26	27
In contrast , it has been reported that P 4 inhibits E 2 beta reduced neointimal proliferation [ XREF_BIBR ] and decreases ER and P 4 receptor ( PR ) expression in human uterine vascular endothelium [ XREF_BIBR ] , which consequently attenuates E 2 beta induced angiogenic responses [ XREF_BIBR , XREF_BIBR ] .	In contrast, it has been reported that P 4 inhibits E 2 beta reduced neointimal proliferation [XREF_BIBR] and decreases ER and P 4 receptor (PR) expression in human uterine vascular endothelium [XREF_BIBR], which consequently attenuates E 2 beta induced angiogenic responses [XREF_BIBR, XREF_BIBR].	14	29	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	28	29	22	23
Our results illuminate how PR may indirectly impede ER action by reducing the bioavailability of translational molecules needed for tumor growth .	Our results illuminate how PR may indirectly impede ER action by reducing the bioavailability of translational molecules needed for tumor growth.	4	9	impede	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	4	5	8	9
These data indicate that PR ligands can transdominantly suppress estrogen receptor signaling and stimulation of uterine leiomyoma cell growth .	These data indicate that PR ligands can transdominantly suppress estrogen receptor signaling and stimulation of uterine leiomyoma cell growth.	4	11	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	estrogen receptor	estrogen receptor	estrogen receptor	4	5	9	11
These results suggest that liganded PR transdominantly suppresses ER signaling in leiomyoma .	These results suggest that liganded PR transdominantly suppresses ER signaling in leiomyoma.	4	9	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	5	6	8	9
In addition , overexpression of FOXC1 reduced expression of PR , IRS1 , and XBP1 ( downstream target of ERalpha ) and significantly reduced luciferase activity caused by E2 using ERE luciferase reporter assay .	In addition, overexpression of FOXC1 reduced expression of PR, IRS1, and XBP1 (downstream target of ERalpha) and significantly reduced luciferase activity caused by E2 using ERE luciferase reporter assay.	3	20	target	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	PR	overexpression of FOXC1 reduced expression of PR	pr	ERalpha	ERalpha	eralpha	9	10	19	20
Immunohistochemistry was used to determine the protein expressions of proliferating cell nuclear antigen ( PCNA ) , inhibiting apoptosis gene Bcl-2 , estrogen receptor ( ER ) , and progesterone receptor ( PR ) .	Immunohistochemistry was used to determine the protein expressions of proliferating cell nuclear antigen (PCNA), inhibiting apoptosis gene Bcl-2, estrogen receptor (ER), and progesterone receptor (PR).	12	33	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	estrogen receptor	estrogen receptor	estrogen receptor	32	33	22	24
Although suppression of oxidant repressed genes was not shown to be associated with ERBB2 over-expression , there was an enrichment of oxidant induced genes among the ERBB2 over-expressing ER positive breast tumors , suggesting that elevated oxidative stress is associated with ERBB2 overexpression and may contribute to the loss of PR co-expression seen in ERBB2 overexpressing ER positive breast cancers .	Although suppression of oxidant repressed genes was not shown to be associated with ERBB2 over-expression, there was an enrichment of oxidant induced genes among the ERBB2 over-expressing ER positive breast tumors, suggesting that elevated oxidative stress is associated with ERBB2 overexpression and may contribute to the loss of PR co-expression seen in ERBB2 overexpressing ER positive breast cancers.	50	59	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR co-expression	pr	ER	ER	er	50	51	56	57
At the biochemical level , there is a loss of estrogen receptor ( ERalpha ) and progesterone receptor ( PR ) in the luminal and glandular epithelium [ XREF_BIBR ] , together with a marked reduction of the polymorphic mucin , Muc-1 expression [ XREF_BIBR ] .	At the biochemical level, there is a loss of estrogen receptor (ERalpha) and progesterone receptor (PR) in the luminal and glandular epithelium [XREF_BIBR], together with a marked reduction of the polymorphic mucin, Muc-1 expression [XREF_BIBR].	6	18	is a loss	Negative_activation_copula_1	Positive_activation	Negative_activation	progesterone receptor	loss of estrogen receptor (ERalpha) and progesterone receptor	progesterone receptor	estrogen receptor	estrogen receptor	estrogen receptor	16	18	10	12
At the biochemical level , there is a loss of estrogen receptor ( ERalpha ) and progesterone receptor ( PR ) in the luminal epithelium [ XREF_BIBR ] together with a marked reduction of the polymorphic mucin , Muc-1 expression [ XREF_BIBR ] .	At the biochemical level, there is a loss of estrogen receptor (ERalpha) and progesterone receptor (PR) in the luminal epithelium [XREF_BIBR] together with a marked reduction of the polymorphic mucin, Muc-1 expression [XREF_BIBR].	6	18	is a loss	Negative_activation_copula_1	Positive_activation	Negative_activation	progesterone receptor	loss of estrogen receptor (ERalpha) and progesterone receptor	progesterone receptor	estrogen receptor	estrogen receptor	estrogen receptor	16	18	10	12
In addition , joint activation of ER and PR antagonized ER regulated oncogenic processes in five tumor explants treated ex vivo for 24 hours ( XREF_FIG ) .	In addition, joint activation of ER and PR antagonized ER regulated oncogenic processes in five tumor explants treated ex vivo for 24 hours (XREF_FIG).	4	11	antagonized	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	8	9	10	11
In previous studies of primary luminal cancers , we showed that the ER + PR + population suppresses mitosis of the ER - PR - subpopulation [ XREF_BIBR ] .	In previous studies of primary luminal cancers, we showed that the ER + PR + population suppresses mitosis of the ER - PR - subpopulation [XREF_BIBR].	13	23	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	14	15	21	22
In addition , because high-dose anti-estrogen treatment has been shown to inhibit ER and PR negative breast cancer cells , we compared the anti-proliferative activity of MIF to that of the anti-estrogen 4-hydroxytamoxifen ( TAM ) or combination hormonal therapy ( MIF + TAM ) .	In addition, because high-dose anti-estrogen treatment has been shown to inhibit ER and PR negative breast cancer cells, we compared the anti-proliferative activity of MIF to that of the anti-estrogen 4-hydroxytamoxifen (TAM) or combination hormonal therapy (MIF + TAM).	9	21	inhibit	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	14	15	12	13
Furthermore , PRL and TGFalpha in combination blocked the mitogenic effects of estrogen , dramatically reduced progesterone receptor levels , and diminished ERalpha down-regulation in response to circulating estrogen levels , in contrast to the other genotypes .	Furthermore, PRL and TGFalpha in combination blocked the mitogenic effects of estrogen, dramatically reduced progesterone receptor levels, and diminished ERalpha down-regulation in response to circulating estrogen levels, in contrast to the other genotypes.	2	23	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	progesterone receptor	PRL and TGFalpha in combination blocked the mitogenic effects of estrogen, dramatically reduced progesterone receptor levels	progesterone receptor	ERalpha	ERalpha	eralpha	16	18	22	23
On the opposite , the presence of the PR antagonist may interfere with the ability of PR to interact with ER , thus antagonizing the function of both ER and PR .	On the opposite, the presence of the PR antagonist may interfere with the ability of PR to interact with ER, thus antagonizing the function of both ER and PR.	8	30	antagonizing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PR	PR	PR	ER	ER	ER	8	9	28	29
There is a loss of ERalpha and PR in the luminal and glandular epithelium , among other significant endometrial changes .	There is a loss of ERalpha and PR in the luminal and glandular epithelium, among other significant endometrial changes.	1	8	is a loss	Negative_activation_copula_1	Positive_activation	Negative_activation	PR	loss of ERalpha and PR	pr	ERalpha	ERalpha	eralpha	7	8	5	6
Knock-down of hVPS34 also reduced expression Beclin-1 , VPS15 and UV-RAG ( XREF_FIG ) .	Knock-down of hVPS34 also reduced expression Beclin-1, VPS15 and UV-RAG (XREF_FIG).	0	12	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	hVPS34	hVPS34	hVPS34	Beclin-1	Beclin-1	Beclin-1	2	3	6	7
These data indicate that Vps34 functions upstream of the Peg3 and Beclin 1 complex as loss of Peg3 did not abrogate Peg3 or Beclin 1 induction , via decorin , in a manner similar to loss of Vps34 .	These data indicate that Vps34 functions upstream of the Peg3 and Beclin 1 complex as loss of Peg3 did not abrogate Peg3 or Beclin 1 induction, via decorin, in a manner similar to loss of Vps34.	4	25	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Vps34	Vps34	Vps34	Beclin 1	Beclin 1	Beclin 1	4	5	23	25
At least in certain cell types , such as HT-29 human colon carcinoma cells , enforced Bcl-2 expression decreases the amount of class III PI3K and Vps34 that coimmuno-precipitates with Bcl-2 and decreases Beclin 1 associated class III PI3K activity .	At least in certain cell types, such as HT-29 human colon carcinoma cells, enforced Bcl-2 expression decreases the amount of class III PI3K and Vps34 that coimmuno-precipitates with Bcl-2 and decreases Beclin 1 associated class III PI3K activity.	18	35	decreases	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Vps34	Vps34	Vps34	Beclin 1	Beclin 1	Beclin 1	26	27	33	35
PIAS4 prevents unusual RIF1 and 53BP1 nuclear bodies .	PIAS4 prevents unusual RIF1 and 53BP1 nuclear bodies.	0	7	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PIAS4	PIAS4	PIAS4	53BP1	53BP1	53BP1	0	1	5	6
Therefore , we propose that PIAS4 activity is required to suppress the formation of 53BP1 and RIF1 nuclear bodies .	Therefore, we propose that PIAS4 activity is required to suppress the formation of 53BP1 and RIF1 nuclear bodies.	5	18	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PIAS4	PIAS4	PIAS4	53BP1	53BP1	53BP1	5	6	14	15
We report here that overexpression of PEX6 can suppress the phenotypes of certain PEX1 deficient cells , that overexpression of PEX1 can suppress the phenotypes of certain PEX6 deficient cells , and that these instances of suppression are allele specific and require partial activity of the mutated gene .	We report here that overexpression of PEX6 can suppress the phenotypes of certain PEX1 deficient cells, that overexpression of PEX1 can suppress the phenotypes of certain PEX6 deficient cells, and that these instances of suppression are allele specific and require partial activity of the mutated gene.	4	15	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PEX6	overexpression of PEX6	pex6	PEX1	PEX1	pex1	6	7	13	14
Additionally , mutations in the Pex6 N2 peptide ( V245A and T246A ) decreased the apparent affinity of Pex1 and Pex6 for Pex15 1-309 from 0.6 to 2muM as judged by the concentration dependent inhibition of Pex1 and Pex6 ATPase activity .	Additionally, mutations in the Pex6 N2 peptide (V245A and T246A) decreased the apparent affinity of Pex1 and Pex6 for Pex15 1-309 from 0.6 to 2muM as judged by the concentration dependent inhibition of Pex1 and Pex6 ATPase activity.	5	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pex6	Pex6	Pex6	Pex1	Pex1	Pex1	5	6	18	19
Knockdown of Vps34 did not impair SopB dependent activation of Akt , indicating that the Class III PI3-kinase does not contribute to SopB mediated Akt activation ( XREF_FIG ) .	Knockdown of Vps34 did not impair SopB dependent activation of Akt, indicating that the Class III PI3-kinase does not contribute to SopB mediated Akt activation (XREF_FIG).	0	11	impair	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Vps34	Vps34	Vps34	Akt	Akt	Akt	2	3	10	11
Additionally , we found PICK1 inhibits ASIC1 mediated SOCE through an effect of calcineurin to dephosphorylate the channel .	Additionally, we found PICK1 inhibits ASIC1 mediated SOCE through an effect of calcineurin to dephosphorylate the channel.	4	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PICK1	PICK1	PICK1	ASIC1	ASIC1	ASIC1	4	5	6	7
This is typical of tumor cell lines that are sensitive to AKT inhibition , including the three other PIK3CA mutant ( T47D , MCF7 , MDA-453 ) and two PTEN mutant ( ZR-75-1 , LNCaP ) tumor cell lines .	This is typical of tumor cell lines that are sensitive to AKT inhibition, including the three other PIK3CA mutant (T47D, MCF7, MDA-453) and two PTEN mutant (ZR-75-1, LNCaP) tumor cell lines.	11	19	inhibition	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	18	19	11	12
In the 081110 neurosphere line , Akt activity was slightly reduced by both PIK3CA and PIK3R1 knockdown .	In the 081110 neurosphere line, Akt activity was slightly reduced by both PIK3CA and PIK3R1 knockdown.	6	16	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	13	14	6	7
Inactivation of either p110alpha or p110beta reduces PtdIns ( 3,4,5 ) P 3 and Akt activation upon PTEN loss in MEFs .	Inactivation of either p110alpha or p110beta reduces PtdIns (3,4,5) P 3 and Akt activation upon PTEN loss in MEFs.	0	15	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p110alpha	p110alpha	p110alpha	Akt	Akt	Akt	3	4	14	15
As a single agent , the p110alpha specific inhibitor BYL719 reduced tumor growth and P-Akt in iPIK3.iCre tumors without effecting P-PDK1 .	As a single agent, the p110alpha specific inhibitor BYL719 reduced tumor growth and P-Akt in iPIK3.iCre tumors without effecting P-PDK1.	5	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p110alpha	p110alpha	p110alpha	P-Akt	P-Akt	P-Akt	6	7	14	15
The PI3K-AKT pathway can be deregulated by activating mutations in the PIK3CA gene ( p110 subunit ) , by inactivation ( often by epigenetic mechanisms ) of the phosphatase and tensin homolog ( PTEN ) gene , or by activation of AKT [ XREF_BIBR , XREF_BIBR ] .	The PI3K-AKT pathway can be deregulated by activating mutations in the PIK3CA gene (p110 subunit), by inactivation (often by epigenetic mechanisms) of the phosphatase and tensin homolog (PTEN) gene, or by activation of AKT [XREF_BIBR, XREF_BIBR].	1	12	deregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PIK3CA	PIK3CA	PIK3CA	PI3K-AKT	PI3K-AKT	PI3K-AKT	11	12	1	2
Similar to what was seen with EZN4150 , downregulation of p110alpha by two independent siRNA sequences ( si38 and si39 ) reduced P-Akt , as compared to a control siRNA sequence .	Similar to what was seen with EZN4150, downregulation of p110alpha by two independent siRNA sequences (si38 and si39) reduced P-Akt, as compared to a control siRNA sequence.	8	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p110alpha	p110alpha	p110alpha	P-Akt	P-Akt	P-Akt	10	11	22	23
However , depletion of PIK3CA profoundly reduced PIP 3 production ( XREF_FIG ) , yet under these conditions , robust AKT activity is observed .	However, depletion of PIK3CA profoundly reduced PIP 3 production (XREF_FIG), yet under these conditions, robust AKT activity is observed.	2	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	4	5	20	21
Thus , p110beta is responsible for the rebound in PIP 3 levels and the reaccumulation of AKT phosphorylation in HER2 amplified cancers treated with a p110alpha specific inhibitor .	Thus, p110beta is responsible for the rebound in PIP 3 levels and the reaccumulation of AKT phosphorylation in HER2 amplified cancers treated with a p110alpha specific inhibitor.	16	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	25	26	16	17
It is possible that the increased autophagy upon p85alpha knockdown could result from reduced expression of p110alpha and consequent inhibition of Akt and mTOR .	It is possible that the increased autophagy upon p85alpha knockdown could result from reduced expression of p110alpha and consequent inhibition of Akt and mTOR.	16	23	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	p110alpha	p110alpha	p110alpha	Akt	Akt	Akt	16	17	21	22
PI3Kalpha inhibits apoptotic cell death by activating Akt , which also suppresses pathological signalling cascades .	PI3Kalpha inhibits apoptotic cell death by activating Akt, which also suppresses pathological signalling cascades.	0	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	Akt	Akt	Akt	0	1	7	8
In an accompanying manuscript , Costa et al ., show complementary results with a selective inhibitor of PI3Kalpha , which inhibits Akt and mTOR signaling in tumors with RTK activation or PI3K mutation , but not in those with PTEN inactivation .	In an accompanying manuscript, Costa et al., show complementary results with a selective inhibitor of PI3Kalpha, which inhibits Akt and mTOR signaling in tumors with RTK activation or PI3K mutation, but not in those with PTEN inactivation.	15	24	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	Akt	Akt	Akt	17	18	21	22
also reported that shRNAs of PIK3CB , but not PIK3CA , inactivated AKT and decreased cell viability of U251 cells .	also reported that shRNAs of PIK3CB, but not PIK3CA, inactivated AKT and decreased cell viability of U251 cells.	3	13	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PIK3CA	PIK3CA	PIK3CA	AKT	AKT	AKT	9	10	12	13
We also confirmed specific suppression of Akt activation in both PC9 and PC9 and ER1 cells when treated with PIK3CA siRNA ( XREF_FIG ) .	We also confirmed specific suppression of Akt activation in both PC9 and PC9 and ER1 cells when treated with PIK3CA siRNA (XREF_FIG).	6	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	Akt	Akt	Akt	19	20	6	7
Ablation of p110beta but not p110alpha inhibits downstream AKT signaling resulting in reduced tumorogenesis in these models .	Ablation of p110beta but not p110alpha inhibits downstream AKT signaling resulting in reduced tumorogenesis in these models.	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p110alpha	p110alpha	p110alpha	AKT	AKT	AKT	5	6	8	9
The N-terminal SH2 domain ( nSH2 ) in combination with the iSH2 domain is the minimal construct of p85alpha required to inhibit the activity of p110alpha .	The N-terminal SH2 domain (nSH2) in combination with the iSH2 domain is the minimal construct of p85alpha required to inhibit the activity of p110alpha.	16	26	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	18	19	25	26
The mutually exclusive binding of nSH2-p85alpha to p110alpha or to the p YXXM peptide , as shown in XREF_FIG indicates that the activation is through relieving the autoinhibition of p110alpha , which is impeded by the regulatory p85alpha .	The mutually exclusive binding of nSH2-p85alpha to p110alpha or to the p YXXM peptide, as shown in XREF_FIG indicates that the activation is through relieving the autoinhibition of p110alpha, which is impeded by the regulatory p85alpha.	27	38	impeded	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	37	38	29	30
However , the nSH2 domain of the p85alpha subunit inhibits the basal kinase activity of p110alpha , suggesting that the activation mechanism of PI3Kalpha includes a relief of this autoinhibition .	However, the nSH2 domain of the p85alpha subunit inhibits the basal kinase activity of p110alpha, suggesting that the activation mechanism of PI3Kalpha includes a relief of this autoinhibition.	7	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	7	8	15	16
Interestingly , p85alpha down-regulated Myr-p110alpha activity in yeast ( XREF_FIG C ) , suggesting that the inhibitory effect performed by the regulatory subunits in the absence of tyrosine phosphorylated receptors could be reproduced in the yeast system .	Interestingly, p85alpha down-regulated Myr-p110alpha activity in yeast (XREF_FIG C), suggesting that the inhibitory effect performed by the regulatory subunits in the absence of tyrosine phosphorylated receptors could be reproduced in the yeast system.	2	5	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p85alpha	p85alpha	p85alpha	Myr-p110alpha	Myr-p110alpha	Myr-p110alpha	2	3	4	5
In addition , p85alpha inhibits the basal activity of p110alpha and can negatively regulate signal transduction , as shown for insulin and GM-CSF receptor signaling .	In addition, p85alpha inhibits the basal activity of p110alpha and can negatively regulate signal transduction, as shown for insulin and GM-CSF receptor signaling.	3	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	3	4	9	10
Because the inter-SH2 domain of p85alpha is involved in p85alpha - p110 heterodimerization [ XREF_BIBR ] , it is possible that the p85alpha Delta434_475 mutant inefficiently inhibits its cognate partner p110 ( p110delta in the hematopoietic cells and p110alpha in muscle and other tissues ) , leading to elevated PI3K signaling .	Because the inter-SH2 domain of p85alpha is involved in p85alpha - p110 heterodimerization [XREF_BIBR], it is possible that the p85alpha Delta434_475 mutant inefficiently inhibits its cognate partner p110 (p110delta in the hematopoietic cells and p110alpha in muscle and other tissues), leading to elevated PI3K signaling.	22	39	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	22	23	38	39
The catalytic activity of p110alpha depends on association with the cell membrane and access to stores of the membrane bound PIP 2 substrate , and inhibition of p110alpha by p85alpha activity involves separation from the cell membrane .	The catalytic activity of p110alpha depends on association with the cell membrane and access to stores of the membrane bound PIP 2 substrate, and inhibition of p110alpha by p85alpha activity involves separation from the cell membrane.	25	30	inhibition	Negative_activation_token_2_noun	Positive_activation	Negative_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	29	30	27	28
Phosphorylation of p85alpha S652 by PKC [ XREF_BIBR ] ( as well as p85alpha S608 by p110alpha ) has been reported to decrease PI3Kalpha activity .	Phosphorylation of p85alpha S652 by PKC [XREF_BIBR] (as well as p85alpha S608 by p110alpha) has been reported to decrease PI3Kalpha activity.	0	24	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p85alpha	Phosphorylation of p85alpha S652	p85alpha	PI3Kalpha	PI3Kalpha	pi3kalpha	2	3	23	24
Given that an iSH2-cSH2 fragment of p85alpha binds but does not inhibit p110alpha , the mechanisms of activation by the C-terminal SH2 domain must be different .	Given that an iSH2-cSH2 fragment of p85alpha binds but does not inhibit p110alpha, the mechanisms of activation by the C-terminal SH2 domain must be different.	4	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	6	7	12	13
Thus , in the insulin sensitive tissues of the p85alpha -/- animal there are decreased p110alpha and p110beta catalytic subunits and in p110alpha +/- and p110beta +/- heterozygotes there is ~ 50 % decrease in p85 expression in liver and muscle .	Thus, in the insulin sensitive tissues of the p85alpha -/- animal there are decreased p110alpha and p110beta catalytic subunits and in p110alpha +/- and p110beta +/- heterozygotes there is ~ 50% decrease in p85 expression in liver and muscle.	9	33	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p85alpha	p85alpha	p85alpha	p110alpha	p110alpha	p110alpha	9	10	22	23
Consistent with this , a high membrane potential enhances the anterograde transport of mitochondria and also promotes the proteolysis of PINK1 FL into DeltaN-PINK1 , thereby inhibiting Parkin dependent mitophagy of active mitochondria .	Consistent with this, a high membrane potential enhances the anterograde transport of mitochondria and also promotes the proteolysis of PINK1 FL into DeltaN-PINK1, thereby inhibiting Parkin dependent mitophagy of active mitochondria.	20	29	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	20	21	27	28
Patient Mutations in PINK1 and Parkin Disrupt PINK1 and Parkin Pathway at Distinct Steps .	Patient Mutations in PINK1 and Parkin Disrupt PINK1 and Parkin Pathway at Distinct Steps.	1	8	Disrupt	Negative_activation_token_1_noun	Positive_activation	Negative_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	7	8	5	6
Further , PINK1 downregulation did not disrupt the Parkin and Beclin1 interaction suggesting SESN2 mediated Parkin-Beclin1 interaction was PINK1 independent .	Further, PINK1 downregulation did not disrupt the Parkin and Beclin1 interaction suggesting SESN2 mediated Parkin-Beclin1 interaction was PINK1 independent.	2	9	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	2	3	8	9
This phenotype requires both Parkin ( XREF_FIG ) and PINK1 ( XREF_FIG ) expression and the loss of the inner mitochondrial membrane potential ( XREF_FIG ) , indicating that it occurs upon mitophagy induction downstream of PINK1 induced Parkin translocation to mitochondria .	This phenotype requires both Parkin (XREF_FIG) and PINK1 (XREF_FIG) expression and the loss of the inner mitochondrial membrane potential (XREF_FIG), indicating that it occurs upon mitophagy induction downstream of PINK1 induced Parkin translocation to mitochondria.	33	39	induced	Positive_early_activation	Positive_activation	Negative_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	36	37	38	39
We can not rule out that PINK1 may actively prevent mitochondrial damage and dysfunction , in addition to its signaling role in the PINK1 and Parkin pathway .	We can not rule out that PINK1 may actively prevent mitochondrial damage and dysfunction, in addition to its signaling role in the PINK1 and Parkin pathway.	6	26	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	6	7	25	26
In Drosphila models a loss of Parkin or Pink1 results in extensive mitochondrial fusion , a phenotype rescued by overexpression of the fission GTPase Drp1 .	In Drosphila models a loss of Parkin or Pink1 results in extensive mitochondrial fusion, a phenotype rescued by overexpression of the fission GTPase Drp1.	4	9	loss	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	Pink1	Pink1	Pink1	Parkin	Parkin	Parkin	8	9	6	7
PINK1 arrested mitochondrial motility in wildtype but not Parkin -/- mice or Parkin RNAi flies .	PINK1 arrested mitochondrial motility in wildtype but not Parkin -/- mice or Parkin RNAi flies.	0	14	arrested	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	0	1	8	9
The preceding experiments suggested a model in which Ser156 of Miro is phosphorylated by PINK1 , which triggers Parkin dependent degradation of Miro by the proteasome .	The preceding experiments suggested a model in which Ser156 of Miro is phosphorylated by PINK1, which triggers Parkin dependent degradation of Miro by the proteasome.	12	20	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	14	15	18	19
Interestingly , the ubiquitin chains generated by Parkin are major targets of PINK1 phosphorylation , allowing Parkin retention on mitochondria , providing a feed forward mechanism to promote mitophagy [ XREF_BIBR , XREF_BIBR ] .	Interestingly, the ubiquitin chains generated by Parkin are major targets of PINK1 phosphorylation, allowing Parkin retention on mitochondria, providing a feed forward mechanism to promote mitophagy [XREF_BIBR, XREF_BIBR].	12	17	allowing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PINK1	PINK1 phosphorylation	pink1	Parkin	Parkin	parkin	12	13	16	17
Since we now report that S nitrosylation of PINK1 inhibits the PINK1 and Parkin dependent mitophagy pathway , our findings suggest that formation of SNO-PINK1 could mediate this disruption in mitophagy , resulting in neuronal cell death and thus modeling disease pathogenesis in PD .	Since we now report that S nitrosylation of PINK1 inhibits the PINK1 and Parkin dependent mitophagy pathway, our findings suggest that formation of SNO-PINK1 could mediate this disruption in mitophagy, resulting in neuronal cell death and thus modeling disease pathogenesis in PD.	6	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PINK1	PINK1	PINK1	Parkin	Parkin	Parkin	8	9	13	14
XREF_BIBR To our knowledge , this is the first study to demonstrate that PINK1 induced PARK2 translocation indeed suppresses the mitochondrial fusion rate .	XREF_BIBR To our knowledge, this is the first study to demonstrate that PINK1 induced PARK2 translocation indeed suppresses the mitochondrial fusion rate.	13	16	induced	Positive_early_activation	Positive_activation	Negative_activation	PINK1	PINK1	PINK1	PARK2	PARK2	PARK2	13	14	15	16
We reasoned that the abolishment of the phosphorylation of PINK1 or Parkin might fail to activate the PINK1 and Parkin pathway by disrupting the Parkin recruitment to the OMM and/or causing impairment of Parkin activity .	We reasoned that the abolishment of the phosphorylation of PINK1 or Parkin might fail to activate the PINK1 and Parkin pathway by disrupting the Parkin recruitment to the OMM and/or causing impairment of Parkin activity.	7	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PINK1	phosphorylation of PINK1	pink1	Parkin	Parkin	parkin	9	10	33	34
EBNA-3C also mediates the degradation of the retinoblastoma protein through an SCF cellular ubiquitin ligase , upregulates aurora kinase B transcription , increases aurora kinase B protein stability by reducing ubiquitylation of aurora kinase B and attenuates H2AX expression , stabilizes Pim-1 and Pim-1-mediated proteasomal degradation of the cell cycle inhibitor p21 and WAF1 , promoting cell proliferation , upregulates TCL1A and ITGA4 , downregulates JAG1 and NCALD and cooperates with EBNA-3A in repressing Bim , a proapoptotic Bcl-2 family protein .	EBNA-3C also mediates the degradation of the retinoblastoma protein through an SCF cellular ubiquitin ligase, upregulates aurora kinase B transcription, increases aurora kinase B protein stability by reducing ubiquitylation of aurora kinase B and attenuates H2AX expression, stabilizes Pim-1 and Pim-1-mediated proteasomal degradation of the cell cycle inhibitor p21 and WAF1, promoting cell proliferation, upregulates TCL1A and ITGA4, downregulates JAG1 and NCALD and cooperates with EBNA-3A in repressing Bim, a proapoptotic Bcl-2 family protein.	41	54	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Pim-1	Pim-1	Pim-1	WAF1	WAF1	WAF1	41	42	53	54
Interestingly , EBNA3C also facilitated the nuclear localization of Pim-1 , and promotes EBV induced cell proliferation by regulating Pim-1 mediated degradation of p21 and WAF1 .	Interestingly, EBNA3C also facilitated the nuclear localization of Pim-1, and promotes EBV induced cell proliferation by regulating Pim-1 mediated degradation of p21 and WAF1.	18	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Pim-1	Pim-1	Pim-1	p21	p21	p21	19	20	23	24
Our study demonstrated that EBNA3C significantly induces Pim-1 mediated proteosomal degradation of p21 .	Our study demonstrated that EBNA3C significantly induces Pim-1 mediated proteosomal degradation of p21.	6	13	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Pim-1	Pim-1	Pim-1	p21	p21	p21	7	8	12	13
Our results also support this finding showing that EBNA3C induced Pim-1 mediated downregulation of p21 which is also related to the inhibition of intrinsic apoptotic pathway in EBV transformed cells .	Our results also support this finding showing that EBNA3C induced Pim-1 mediated downregulation of p21 which is also related to the inhibition of intrinsic apoptotic pathway in EBV transformed cells.	8	15	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Pim-1	EBNA3C induced Pim-1	pim-1	p21	p21	p21	10	11	14	15
p21 is inhibited by PIM-1 in other cancer types , but its expression patterns in HCC are currently unclear .	p21 is inhibited by PIM-1 in other cancer types, but its expression patterns in HCC are currently unclear.	0	8	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PIM-1	PIM-1	PIM-1	p21	p21	p21	4	5	0	1
The knockdown of PIM1 induced nuclear localization of p21 and RUNX3 .	The knockdown of PIM1 induced nuclear localization of p21 and RUNX3.	1	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PIM1	PIM1	PIM1	p21	p21	p21	3	4	8	9
However , use of a novel dual PI3Kalpha and mTOR inhibitor , PI-103 , effectively and independently blocked activation of both PI3K and mTOR in vGPCR expressing endothelial cells .	However, use of a novel dual PI3Kalpha and mTOR inhibitor, PI-103, effectively and independently blocked activation of both PI3K and mTOR in vGPCR expressing endothelial cells.	2	24	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	mTOR	mTOR	mTOR	7	8	23	24
Finally , the PI3Kalpha selective inhibitor BYL-719 did not inhibit mTOR ( IC 50 > 10muM ) , and thus was used as a good chemical probe to test the influence of mTOR on TRF1 foci formation .	Finally, the PI3Kalpha selective inhibitor BYL-719 did not inhibit mTOR (IC 50> 10muM), and thus was used as a good chemical probe to test the influence of mTOR on TRF1 foci formation.	2	28	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3Kalpha	PI3Kalpha	PI3Kalpha	mTOR	mTOR	mTOR	3	4	10	11
On the other hand , down-regulating PKM2 activates AMPK and inhibits STAT3 , correlated with THP sensitivity .	On the other hand, down-regulating PKM2 activates AMPK and inhibits STAT3, correlated with THP sensitivity.	5	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	6	7	11	12
Interestingly , knockdown of PKM2 substantially decreased the assembly of the oligo protein complex and assembly of stat3 in the complex ( the weak supershift ) ( XREF_FIG ) , while expression of HA-PKM2 increased assembled complex and assembly of stat3 in the complex ( XREF_FIG ) .	Interestingly, knockdown of PKM2 substantially decreased the assembly of the oligo protein complex and assembly of stat3 in the complex (the weak supershift) (XREF_FIG), while expression of HA-PKM2 increased assembled complex and assembly of stat3 in the complex (XREF_FIG).	31	43	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HA-PKM2	expression of HA-PKM2	ha-pkm2	stat3	stat3	stat3	33	34	40	41
XREF_BIBR The same compounds may also lead to the inhibition of PKM2 mediated STAT3 activation , potentially representing a useful therapeutic tool to help hitting the uncontrolled growth of those highly glycolytic tumors that display both STAT3 activation and dimeric PKM2 .	XREF_BIBR The same compounds may also lead to the inhibition of PKM2 mediated STAT3 activation, potentially representing a useful therapeutic tool to help hitting the uncontrolled growth of those highly glycolytic tumors that display both STAT3 activation and dimeric PKM2.	9	14	mediated	Positive_early_activation	Positive_activation	Negative_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	11	12	13	14
PKM2 siRNA treatment significantly reduced the pSTAT3 and STAT3 ( P < 0.05 ) and pERK and ERK ( P < 0.05 ) ratios .	PKM2 siRNA treatment significantly reduced the pSTAT3 and STAT3 (P < 0.05) and pERK and ERK (P < 0.05) ratios.	0	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKM2	PKM2	PKM2	pSTAT3	pSTAT3	pSTAT3	0	1	6	7
While other players of the PKM2 specific sumoylation still have to be identified , this reveals yet another regulatory mechanism where PIAS balances nuclear targeting of PKM2 , PKM2 mediated STAT3 transactivation and STAT3 inhibition .	While other players of the PKM2 specific sumoylation still have to be identified, this reveals yet another regulatory mechanism where PIAS balances nuclear targeting of PKM2, PKM2 mediated STAT3 transactivation and STAT3 inhibition.	24	31	mediated	Positive_activation_syntax_3a_verb	Positive_activation	Positive_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	26	27	30	31
These results indicated that down-regulation of PKM2 inhibits STAT3 activation .	These results indicated that down-regulation of PKM2 inhibits STAT3 activation.	4	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKM2	PKM2	PKM2	STAT3	STAT3	STAT3	6	7	8	9
On this basis , one might hypothesize that , like Thr 58 mutation , a decrease in Pin1 activity should potentiate the oncogenic action of Myc : this putative tumor suppressive effect of Pin1 might be further reinforced by its positive action on p53 [ XREF_BIBR , XREF_BIBR ] , a key suppressor of Myc induced lymphomagenesis [ XREF_BIBR ] .	On this basis, one might hypothesize that, like Thr 58 mutation, a decrease in Pin1 activity should potentiate the oncogenic action of Myc : this putative tumor suppressive effect of Pin1 might be further reinforced by its positive action on p53 [XREF_BIBR, XREF_BIBR], a key suppressor of Myc induced lymphomagenesis [XREF_BIBR].	17	26	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Pin1	Pin1	Pin1	Myc	Myc	Myc	17	18	25	26
Although Pin1 promotes c-Myc degradation in normal cells , this activity is uncoupled in cancer cells where both proteins have oncogenic activities and are overexpressed , and Pin1 functions only as a c-Myc co-activator .	Although Pin1 promotes c-Myc degradation in normal cells, this activity is uncoupled in cancer cells where both proteins have oncogenic activities and are overexpressed, and Pin1 functions only as a c-Myc co-activator.	1	4	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Pin1	Pin1	Pin1	c-Myc	c-Myc	c-Myc	1	2	3	4
PIN1 is able to promote the degradation of c-Myc and cyclin E with the mediation of the FBXW7 E3 ligase , thus providing the evidence that it acts as a tumor suppressor .	PIN1 is able to promote the degradation of c-Myc and cyclin E with the mediation of the FBXW7 E3 ligase, thus providing the evidence that it acts as a tumor suppressor.	0	11	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PIN1	PIN1	PIN1	c-Myc	c-Myc	c-Myc	0	1	8	9
Pin1 silencing in lymphomas retarded disease progression in mice , making Pin1 an attractive therapeutic target in Myc driven tumors .	Pin1 silencing in lymphomas retarded disease progression in mice, making Pin1 an attractive therapeutic target in Myc driven tumors.	0	18	target	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	Pin1	Pin1	Pin1	Myc	Myc	Myc	0	1	17	18
An early example is human Pin1 downregulation of c-Myc .	An early example is human Pin1 downregulation of c-Myc.	5	9	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Pin1	Pin1	Pin1	c-Myc	c-Myc	c-Myc	5	6	8	9
The lack of PI3Kgamma attenuated the activation of Akt and protein kinase B and extracellular signal regulated kinase 1/2 signaling pathways in cardiac myocytes in response to isoproterenol .	The lack of PI3Kgamma attenuated the activation of Akt and protein kinase B and extracellular signal regulated kinase 1/2 signaling pathways in cardiac myocytes in response to isoproterenol.	1	12	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	3	4	8	9
XREF_FIG shows that isolated PI3Kdelta KD or isolated PI3Kgamma KD failed to block IL-6-induced AKT activation ; however combined PI3Kdeltagamma KD completely blocks IL-6-induced AKT activation .	XREF_FIG shows that isolated PI3Kdelta KD or isolated PI3Kgamma KD failed to block IL-6-induced AKT activation; however combined PI3Kdeltagamma KD completely blocks IL-6-induced AKT activation.	5	15	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	AKT	AKT	AKT	8	9	14	15
PI3Kgamma knockdown with specific siRNAs resulted in a dramatic decrease in the activation of Akt and mTOR in endothelial cells expressing vGPCR ( XREF_FIG ) , while knockdown of PI3Kalpha or PI3Kbeta had only a limited effect .	PI3Kgamma knockdown with specific siRNAs resulted in a dramatic decrease in the activation of Akt and mTOR in endothelial cells expressing vGPCR (XREF_FIG), while knockdown of PI3Kalpha or PI3Kbeta had only a limited effect.	0	16	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	0	1	14	15
Furthermore , these data suggest that PI3Kgamma directly inhibits GSK-3 independently of Akt .	Furthermore, these data suggest that PI3Kgamma directly inhibits GSK-3 independently of Akt.	6	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PI3Kgamma	PI3Kgamma	PI3Kgamma	Akt	Akt	Akt	6	7	12	13
VPS15 allosterically inhibits the VPS34 lipid kinase .	VPS15 allosterically inhibits the VPS34 lipid kinase.	0	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VPS15	VPS15	VPS15	VPS34	VPS34	VPS34	0	1	4	5
For instance , the query related to an interaction between PI3K ( PIK3CA ) and AKT ( AKT1 ) in Omnipath returns an activation of AKT1 by PIK3CA from four databases ( SignaLink3 , Laudanna_effects , Wang , Signor ) , and an inhibition of AKT1 by PIK3CA from one database ( Laudanna_effects ) .	For instance, the query related to an interaction between PI3K (PIK3CA) and AKT (AKT1) in Omnipath returns an activation of AKT1 by PIK3CA from four databases (SignaLink3, Laudanna_effects, Wang, Signor), and an inhibition of AKT1 by PIK3CA from one database (Laudanna_effects).	21	43	activation	Positive_activation_token_2_noun	Positive_activation	Positive_activation	PIK3CA	PIK3CA	PIK3CA	AKT1	AKT1	AKT1	27	28	25	26
In concert with these results , the knockdown of Pim-1 impairs IL-6 production and augments apoptosis by interfering RelA and p65 activation .	In concert with these results, the knockdown of Pim-1 impairs IL-6 production and augments apoptosis by interfering RelA and p65 activation.	7	21	augments	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Pim-1	Pim-1	Pim-1	p65	p65	p65	9	10	20	21
Given the differential abundance and tissue distribution of the p85 related regulatory subunits , we examined whether three human regulatory subunits , p85alpha , p85beta , and p55gamma , could downregulate human p110beta via their cSH2 domains .	Given the differential abundance and tissue distribution of the p85 related regulatory subunits, we examined whether three human regulatory subunits, p85alpha, p85beta, and p55gamma, could downregulate human p110beta via their cSH2 domains.	20	36	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p85alpha	p85alpha	p85alpha	p110beta	p110beta	p110beta	22	23	32	33
RTKs activate PI3K signaling by releasing p85alpha and beta mediated inhibition of p110 subunits ; lack of inhibition of p110beta by p85alpha and beta may thus contribute to the diminished stimulation of p110beta signaling by RTKs .	RTKs activate PI3K signaling by releasing p85alpha and beta mediated inhibition of p110 subunits; lack of inhibition of p110beta by p85alpha and beta may thus contribute to the diminished stimulation of p110beta signaling by RTKs.	17	23	inhibition	Negative_activation_token_2_noun	Positive_activation	Negative_activation	p85alpha	p85alpha	p85alpha	p110beta	p110beta	p110beta	21	22	19	20
Knockdown of p110alpha reduces Rac1 and RhoA activity .	Knockdown of p110alpha reduces Rac1 and RhoA activity.	0	7	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Rac1	Rac1	Rac1	2	3	4	5
In our study , the depletion of p110alpha using siRNA significantly inhibited the activation of Rac1 by H 2 S , whereas p110beta siRNA , p110gamma siRNA and p110delta siRNA had no effect on the activation of Rac1 .	In our study, the depletion of p110alpha using siRNA significantly inhibited the activation of Rac1 by H 2 S, whereas p110beta siRNA, p110gamma siRNA and p110delta siRNA had no effect on the activation of Rac1.	5	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p110alpha	p110alpha	p110alpha	Rac1	Rac1	Rac1	7	8	15	16
By reprobing the blots with anti-p21 antibody to check the levels of p21 in each of the samples , we found that cells that are transfected with wild type Pim-2 appear to have an increase in the steady state level of p21 , while the kinase dead Pim-2 seems to inhibit the accumulation of p21 as compared to the empty vector control in vivo which suggests that phosphorylation leads to stabilization of p21 .	By reprobing the blots with anti-p21 antibody to check the levels of p21 in each of the samples, we found that cells that are transfected with wild type Pim-2 appear to have an increase in the steady state level of p21, while the kinase dead Pim-2 seems to inhibit the accumulation of p21 as compared to the empty vector control in vivo which suggests that phosphorylation leads to stabilization of p21.	44	55	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pim-2	Pim-2	Pim-2	p21	p21	p21	47	48	54	55
Likewise , down-regulation of PIN1 decreases NOTCH1 transcriptional activity , which in turn abrogates tumour growth in vivo [ XREF_BIBR ] .	Likewise, down-regulation of PIN1 decreases NOTCH1 transcriptional activity, which in turn abrogates tumour growth in vivo [XREF_BIBR].	2	8	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PIN1	PIN1	PIN1	NOTCH1	NOTCH1	NOTCH1	4	5	6	7
Two main approaches have been used to block uPA : inhibition of its catalytic activity by selective low-molecular-weight inhibitors and prevention of uPA from binding to uPAR by using antagonistic peptides or antibodies .	Two main approaches have been used to block uPA : inhibition of its catalytic activity by selective low-molecular-weight inhibitors and prevention of uPA from binding to uPAR by using antagonistic peptides or antibodies.	7	27	block	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	22	23	26	27
Consequently , uPA mediated uPAR internalization was reduced by 80 % in the presence of TNF-alpha or IL-1beta ( P < 0.05 ) .	Consequently, uPA mediated uPAR internalization was reduced by 80% in the presence of TNF-alpha or IL-1beta (P < 0.05).	2	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	2	3	4	5
Binding of u-PA sharply decreased on SMC exposure to phosphatidylinositol specific phospholipase C , confirming the glycan phospholipid cell anchorage of u-PAR .	Binding of u-PA sharply decreased on SMC exposure to phosphatidylinositol specific phospholipase C, confirming the glycan phospholipid cell anchorage of u-PAR.	0	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	u-PA	u-PA	u-PA	u-PAR	u-PAR	u-PAR	2	3	21	22
These results indicate that the endogenous uPA : PAI-1 complexes readily internalize and specifically promote partial lysosomal targeting of uPAR in migratory HT1080 cells .	These results indicate that the endogenous uPA : PAI-1 complexes readily internalize and specifically promote partial lysosomal targeting of uPAR in migratory HT1080 cells.	4	23	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	6	7	19	20
Taking together , these findings indicate that up-regulation of PAI-1 and down-regulation of uPA by berberine may inactivate uPAR and its downstream signaling , which in turn suppresses inflammation associated migration and invasion of HCC cells .	Taking together, these findings indicate that up-regulation of PAI-1 and down-regulation of uPA by berberine may inactivate uPAR and its downstream signaling, which in turn suppresses inflammation associated migration and invasion of HCC cells.	9	27	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	13	14	18	19
Soluble uPAR was lower in supernatant from U937 on unmodified or RGD modified sIPNs than those from TCPS or PEG-only hydrogels ( p < 0.001 , XREF_FIG ) Addition of 10 IU exogenous uPA significantly lowered soluble uPAR in supernatant from U937 on TCPS and PEG-only hydrogels .	Soluble uPAR was lower in supernatant from U937 on unmodified or RGD modified sIPNs than those from TCPS or PEG-only hydrogels (p < 0.001, XREF_FIG) Addition of 10 IU exogenous uPA significantly lowered soluble uPAR in supernatant from U937 on TCPS and PEG-only hydrogels.	32	38	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	33	34	37	38
The identification of uPA and uPAR signaling in hemangiosarcomas has led to the development of a novel therapeutic approach targeting uPAR .	The identification of uPA and uPAR signaling in hemangiosarcomas has led to the development of a novel therapeutic approach targeting uPAR.	3	21	led	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	3	4	20	21
uPAR modulated monocyte migration was accelerated by uPA and was suppressed by amino terminal fragment of uPA dependent .	uPAR modulated monocyte migration was accelerated by uPA and was suppressed by amino terminal fragment of uPA dependent.	0	17	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	uPA	uPA	uPA	uPAR	uPAR	uPAR	16	17	0	1
Down-regulation of the expression of the uPA decreases interaction of the uPAR and integrins of the vitronectin receptor of the ECM XREF_BIBR .	Down-regulation of the expression of the uPA decreases interaction of the uPAR and integrins of the vitronectin receptor of the ECM XREF_BIBR.	3	12	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	uPA	expression of the uPA	upa	uPAR	uPAR	upar	6	7	11	12
Van Vugt et al demonstrated that Plk1 blocks Chk2 activation even in the presence of active ATM during mitosis [ XREF_BIBR ] .	Van Vugt et al demonstrated that Plk1 blocks Chk2 activation even in the presence of active ATM during mitosis [XREF_BIBR].	6	9	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	Chk2	Chk2	Chk2	6	7	8	9
In the normal G2/M transition , PLK1 inhibits CHEK2 and TP53BP1 .	In the normal G2/M transition, PLK1 inhibits CHEK2 and TP53BP1.	6	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK1	PLK1	PLK1	CHEK2	CHEK2	CHEK2	6	7	8	9
To test the hypothesis that Plk1 kinase activity could inhibit Chk2 as part of the mechanism of checkpoint inactivation , we first examined whether the activity of Plk1 could be responsible for the inability of DNA damage to activate Chk2 during mitosis ( XREF_FIG ) .	To test the hypothesis that Plk1 kinase activity could inhibit Chk2 as part of the mechanism of checkpoint inactivation, we first examined whether the activity of Plk1 could be responsible for the inability of DNA damage to activate Chk2 during mitosis (XREF_FIG).	5	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	Chk2	Chk2	Chk2	5	6	10	11
If the mitotic cells were treated with the Plk1 inhibitor , however , a marked elevation of Chk2 kinase activity was seen after DNA damage , consistent with a model where Plk1 kinase activity suppresses Chk2 activity during mitosis .	If the mitotic cells were treated with the Plk1 inhibitor, however, a marked elevation of Chk2 kinase activity was seen after DNA damage, consistent with a model where Plk1 kinase activity suppresses Chk2 activity during mitosis.	31	36	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	Chk2	Chk2	Chk2	31	32	35	36
Therefore , Plk1 phosphorylation may negatively regulate the interaction of Cep55 with the midbody component MKlp1 in anaphase cells and could provide an inhibitory signal preventing premature abscission factor recruitment .	Therefore, Plk1 phosphorylation may negatively regulate the interaction of Cep55 with the midbody component MKlp1 in anaphase cells and could provide an inhibitory signal preventing premature abscission factor recruitment.	2	11	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1 phosphorylation	plk1	Cep55	Cep55	cep55	2	3	10	11
Degradation of PLK1 at the end of karyokinesis allows the localization of CEP55 to the midbody and the later completion of abscission .	Degradation of PLK1 at the end of karyokinesis allows the localization of CEP55 to the midbody and the later completion of abscission.	0	13	allows	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK1	PLK1	PLK1	CEP55	CEP55	CEP55	2	3	12	13
Integrin signaling via FAK-Src controls cytokinetic abscission by decelerating PLK1 degradation and subsequent recruitment of CEP55 at the midbody .	Integrin signaling via FAK-Src controls cytokinetic abscission by decelerating PLK1 degradation and subsequent recruitment of CEP55 at the midbody.	9	16	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	PLK1	PLK1	PLK1	CEP55	CEP55	CEP55	9	10	15	16
Inhibition of Plk1 caused Cep55 to translocate to the midbody prematurely and resulted in abscission failure , presumably due to aberrant midbody architecture and the inability to properly target ESCRT-III components to the midbody 11 .	Inhibition of Plk1 caused Cep55 to translocate to the midbody prematurely and resulted in abscission failure, presumably due to aberrant midbody architecture and the inability to properly target ESCRT-III components to the midbody 11.	0	5	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	Cep55	Cep55	Cep55	2	3	4	5
PLK1 phosphorylation negatively regulates the interaction of Cep-55 with MKLP1 : only when PLK1 is degraded at the end of mitosis can Cep-55 interact with MKLP1 and accumulate in the midbody , allowing the initiation of abscission [ XREF_BIBR ] .	PLK1 phosphorylation negatively regulates the interaction of Cep-55 with MKLP1 : only when PLK1 is degraded at the end of mitosis can Cep-55 interact with MKLP1 and accumulate in the midbody, allowing the initiation of abscission [XREF_BIBR].	0	8	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK1	PLK1 phosphorylation	plk1	Cep-55	Cep-55	cep-55	0	1	7	8
Two such factors could be CHMP4B -- which has been described to localize to the midbody immediately before abscission [ XREF_BIBR ] -- and Cep55 , whose interaction with MKLP1 is inhibited by Plk1 phosphorylation until late in cytokinesis [ XREF_BIBR ] .	Two such factors could be CHMP4B -- which has been described to localize to the midbody immediately before abscission [XREF_BIBR] -- and Cep55, whose interaction with MKLP1 is inhibited by Plk1 phosphorylation until late in cytokinesis [XREF_BIBR].	5	35	inhibited	Negative_regulation_syntax_2_verb	Positive_activation	Negative_regulation	Plk1	Plk1 phosphorylation	plk1	Cep55	Cep55, whose interaction with MKLP1	cep55	33	34	24	25
Plk1 activity appears to be a limiting factor because over-expression of Plk1 accelerates the onset of cyclin A2 and B1 degradation , even though in somatic cells Plk1 activity is not required for the APC/C to target cyclin A2 at NEBD XREF_BIBR , XREF_BIBR .	Plk1 activity appears to be a limiting factor because over-expression of Plk1 accelerates the onset of cyclin A2 and B1 degradation, even though in somatic cells Plk1 activity is not required for the APC/C to target cyclin A2 at NEBD XREF_BIBR, XREF_BIBR.	9	20	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	over-expression of Plk1	plk1	B1	B1	b1	11	12	19	20
It has been reported that PLK1 inhibition efficiently arrested cells in mitosis by preventing cyclin B1 degradation at anaphase 15 .	It has been reported that PLK1 inhibition efficiently arrested cells in mitosis by preventing cyclin B1 degradation at anaphase 15.	5	16	arrested	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK1	PLK1	PLK1	B1	B1	B1	5	6	15	16
CCNB1 suppression by si-PLK1 encapsulated in YSK-MEND was also observed in the in vivo experiments .	CCNB1 suppression by si-PLK1 encapsulated in YSK-MEND was also observed in the in vivo experiments.	0	4	suppression	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	si-PLK1	si-PLK1	si-PLK1	CCNB1	CCNB1	CCNB1	3	4	0	1
Depletion of AURKA and AURKB , blocking PLK1 and shRNA suppression of CCNB1 retards tumour growth and increases chemosensitivity XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Depletion of AURKA and AURKB, blocking PLK1 and shRNA suppression of CCNB1 retards tumour growth and increases chemosensitivity XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	7	13	suppression	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	PLK1	PLK1	PLK1	CCNB1	CCNB1	CCNB1	7	8	12	13
However , we also discovered that Plk1 inhibition causes activation of the beta-catenin pathway and increased ex-pression of c-Myc , eventually resulting in resistance to Plk1 inhibition .	However, we also discovered that Plk1 inhibition causes activation of the beta-catenin pathway and increased ex-pression of c-Myc, eventually resulting in resistance to Plk1 inhibition.	6	19	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	c-Myc	c-Myc	c-Myc	6	7	18	19
Inhibitors of PLK1 , such as BI 6727 or BI2356 , preferentially induce potent apoptosis of Myc overexpressing tumor cells and synergistically potentiate the therapeutic efficacies of BCL-2 antagonists .	Inhibitors of PLK1, such as BI 6727 or BI2356, preferentially induce potent apoptosis of Myc overexpressing tumor cells and synergistically potentiate the therapeutic efficacies of BCL-2 antagonists.	0	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK1	PLK1	PLK1	Myc	Myc	Myc	2	3	16	17
The synergistic down regulation of Aurora-A ( AURKA and STK6 ) and Polo like kinase1 ( PLK1 ) , within the combination ( blue ) module may also further potentiate decreased MYC stability .	The synergistic down regulation of Aurora-A (AURKA and STK6) and Polo like kinase1 (PLK1), within the combination (blue) module may also further potentiate decreased MYC stability.	12	32	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK1	PLK1	PLK1	MYC	MYC	MYC	16	17	31	32
Mutation of one of the two residues involved in the docking of Plk1 to FoxM1 resulted in only a partial decrease in Plk1 enhanced FoxM1 transcriptional activity ( T596A , 55 % ; S678A , 30 % ) .	Mutation of one of the two residues involved in the docking of Plk1 to FoxM1 resulted in only a partial decrease in Plk1 enhanced FoxM1 transcriptional activity (T596A, 55%; S678A, 30%).	20	26	enhanced	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	FoxM1	FoxM1	FoxM1	22	23	24	25
Moreover , expression of kinase-active Plk1 , but not a kinase-dead Plk1 mutant , reduced the interaction of FoxM1 with Rb in co-immunoprecepitation experiments ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Moreover, expression of kinase-active Plk1, but not a kinase-dead Plk1 mutant, reduced the interaction of FoxM1 with Rb in co-immunoprecepitation experiments (XREF_FIG and XREF_SUPPLEMENTARY).	2	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	expression of kinase-active Plk1	plk1	FoxM1	FoxM1	foxm1	5	6	18	19
First , rapid downregulation of PLK1 ( evident 6 hours posttreatment ) likely results in reduced FOXM1 activation .	First, rapid downregulation of PLK1 (evident 6 hours posttreatment) likely results in reduced FOXM1 activation.	3	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK1	PLK1	PLK1	FOXM1	FOXM1	FOXM1	5	6	16	17
In this study , we show that down-regulation of PLCgamma1 expression severely impairs activation of the small GTP binding protein Rac and cell invasion in breast cancer cell lines and U87 in vitro .	In this study, we show that down-regulation of PLCgamma1 expression severely impairs activation of the small GTP binding protein Rac and cell invasion in breast cancer cell lines and U87 in vitro.	9	30	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PLCgamma1	PLCgamma1 expression	plcgamma1	Rac	Rac	rac	9	10	20	21
The combination of PLK1 overexpression and BI2536 treatment did not prevent alpha-syn expressing cells from developing pSer129 positive aggregates , despite the toxicity associated with BI2536 treatment ( XREF_FIG ) .	The combination of PLK1 overexpression and BI2536 treatment did not prevent alpha-syn expressing cells from developing pSer129 positive aggregates, despite the toxicity associated with BI2536 treatment (XREF_FIG).	3	13	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK1	PLK1 overexpression	plk1	alpha-syn	alpha-syn	alpha-syn	3	4	11	12
In this study , we show that Plk1 phosphorylation on MISP negatively regulates the cortical recruitment of p150 glued .	In this study, we show that Plk1 phosphorylation on MISP negatively regulates the cortical recruitment of p150 glued.	7	19	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1 phosphorylation	plk1	p150 glued	p150 glued	p150 glued	7	8	17	19
On the contrary , neither the phospholipase D 1 ( PLD1 ) nor the PLD2 inhibition is able to modulate the early ERK1/2 activation induced by LPS in RPE cells .	On the contrary, neither the phospholipase D 1 (PLD1) nor the PLD2 inhibition is able to modulate the early ERK1/2 activation induced by LPS in RPE cells.	14	23	modulate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PLD2	PLD2	PLD2	ERK1/2	ERK1/2	ERK1/2	14	15	22	23
Plk1 treatment partly inhibited the filament forming ability of vimentin , so that some Plk1 treated vimentin was recovered from the supernatant fraction ( XREF_FIG D ) .	Plk1 treatment partly inhibited the filament forming ability of vimentin, so that some Plk1 treated vimentin was recovered from the supernatant fraction (XREF_FIG D).	0	10	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	vimentin	vimentin	vimentin	0	1	9	10
As appreciable central spindle localization of isolated BRCT domains can occur in Plk1 inhibited cells expressing phosphomimetic HsCyk-4 , Plk1 may also function to relieve Ect2 autoinhibition XREF_BIBR .	As appreciable central spindle localization of isolated BRCT domains can occur in Plk1 inhibited cells expressing phosphomimetic HsCyk-4, Plk1 may also function to relieve Ect2 autoinhibition XREF_BIBR.	12	18	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk1	Plk1	Plk1	HsCyk-4	HsCyk-4	HsCyk-4	12	13	17	18
Thus , suppression of TIP47 does not cause trafficking defects of MPR300 or MPR46 .	Thus, suppression of TIP47 does not cause trafficking defects of MPR300 or MPR46.	2	13	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TIP47	TIP47	TIP47	MPR300	MPR300	MPR300	4	5	11	12
The single stranded DNA binding protein POT1 serves to restrict telomerase access to telomeric substrates both in vivo and in vitro [ XREF_BIBR , XREF_BIBR ] .	The single stranded DNA binding protein POT1 serves to restrict telomerase access to telomeric substrates both in vivo and in vitro [XREF_BIBR, XREF_BIBR].	0	11	restrict	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	6	7	10	11
Depletion of POT1 or TPP1 , or overexpression of a POT1 variant with a deletion in the DNA binding domain ( POT1DeltaOB ) , each leads to telomere elongation by telomerase , indicating that POT1 and TPP1 prevent telomerase action at telomeres .	Depletion of POT1 or TPP1, or overexpression of a POT1 variant with a deletion in the DNA binding domain (POT1DeltaOB), each leads to telomere elongation by telomerase, indicating that POT1 and TPP1 prevent telomerase action at telomeres.	34	39	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	34	35	38	39
Most hPot1 OB-fold mutations inhibit telomerase activity in vitro but promote telomere elongation in vivo .	Most hPot1 OB-fold mutations inhibit telomerase activity in vitro but promote telomere elongation in vivo.	0	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	hPot1	hPot1	hPot1	telomerase	telomerase	telomerase	1	2	5	6
Human POT1 , however , inhibits telomerase through sequestration of the 3 ' end of the substrate but it does not perturb telomere extension once telomerase has gained access to the DNA end .	Human POT1, however, inhibits telomerase through sequestration of the 3 ' end of the substrate but it does not perturb telomere extension once telomerase has gained access to the DNA end.	0	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	1	2	6	7
hPOT1 has been shown to inhibit telomerase activity in vitro by competing for access to the 3 ' end of G rich ss telomeric DNA 42 .	hPOT1 has been shown to inhibit telomerase activity in vitro by competing for access to the 3 ' end of G rich ss telomeric DNA 42.	0	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	hPOT1	hPOT1	hPOT1	telomerase	telomerase	telomerase	0	1	6	7
POT1 , the putative human ortholog of Cdc13p inhibits telomerase activity in vitro when bound to the 3 ' end of a telomeric oligonucleotide substrate .	POT1, the putative human ortholog of Cdc13p inhibits telomerase activity in vitro when bound to the 3 ' end of a telomeric oligonucleotide substrate.	0	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	0	1	9	10
POT1 inhibits telomerase elongation in vitro by preventing substrate access XREF_BIBR , XREF_BIBR .	POT1 inhibits telomerase elongation in vitro by preventing substrate access XREF_BIBR, XREF_BIBR.	0	3	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	0	1	2	3
Whereas hPOT1 inhibited telomerase activity on some DNA substrates , it actually stimulated the extension of other telomeric oligonucleotides .	Whereas hPOT1 inhibited telomerase activity on some DNA substrates, it actually stimulated the extension of other telomeric oligonucleotides.	1	4	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	hPOT1	hPOT1	hPOT1	telomerase	telomerase	telomerase	1	2	3	4
TPP1 directly recruits telomerase to telomeres to enable telomere elongation , while POT1 negatively regulates telomere length by modulating telomerase access to telomeres through physical interaction of its highly conserved oligonucleotide and oligosaccharide binding ( OB ) folds with the ss G-overhang XREF_BIBR - XREF_BIBR .	TPP1 directly recruits telomerase to telomeres to enable telomere elongation, while POT1 negatively regulates telomere length by modulating telomerase access to telomeres through physical interaction of its highly conserved oligonucleotide and oligosaccharide binding (OB) folds with the ss G-overhang XREF_BIBR - XREF_BIBR.	12	20	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	12	13	19	20
In the case of the mammalian system , in the absence of TPP1 , POT1 alone inhibits telomerase activity in vitro XREF_BIBR , XREF_BIBR .	In the case of the mammalian system, in the absence of TPP1, POT1 alone inhibits telomerase activity in vitro XREF_BIBR, XREF_BIBR.	14	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	14	15	17	18
Furthermore , studies in mice show POT1 loss induces telomerase independent extension of the G rich strand presumably through resection of the complementary C rich strand .	Furthermore, studies in mice show POT1 loss induces telomerase independent extension of the G rich strand presumably through resection of the complementary C rich strand.	6	11	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	6	7	9	10
Consistent with a role in chromosome end capping , Pot1 prevents access of telomerase to the 3 '-end and protects against exonucleolytic degradation .	Consistent with a role in chromosome end capping, Pot1 prevents access of telomerase to the 3 '-end and protects against exonucleolytic degradation.	9	19	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pot1	Pot1	Pot1	telomerase	telomerase	telomerase	9	10	13	14
POT1 prevents telomerase accessing an intact telomere complex but after hetero-dimerization with TPP1 , it allows telomerase to become active at telomeres and to extend the 3 ' overhang in late S-phase .	POT1 prevents telomerase accessing an intact telomere complex but after hetero-dimerization with TPP1, it allows telomerase to become active at telomeres and to extend the 3 ' overhang in late S-phase.	0	3	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	0	1	2	3
The combination of POT1 relative depletion and short 3 ' overhangs may then prevent telomerase from efficiently working on its substrate .	The combination of POT1 relative depletion and short 3 ' overhangs may then prevent telomerase from efficiently working on its substrate.	3	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	3	4	14	15
Our results indicate that POT-1 and POT-2 play independent roles in suppressing a telomerase independent telomere maintenance pathway but may function together to repress telomerase .	Our results indicate that POT-1 and POT-2 play independent roles in suppressing a telomerase independent telomere maintenance pathway but may function together to repress telomerase.	4	25	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT-1	POT-1	POT-1	telomerase	telomerase	telomerase	4	5	24	25
However , as POT1 is a competitive inhibitor of telomerase , telomerase in SAA patients should have a greater opportunity to elongate telomeres .	However, as POT1 is a competitive inhibitor of telomerase, telomerase in SAA patients should have a greater opportunity to elongate telomeres.	3	10	is a competitive inhibitor	Negative_activation_copula_1	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	3	4	9	10
Since POT1 forms a heterodimer with TPP1 , and together modulates telomerase processivity XREF_BIBR , XREF_BIBR , we postulated that the hPOT1 OB-fold mutations are unable to limit telomerase access to the ss telomeric DNA .	Since POT1 forms a heterodimer with TPP1, and together modulates telomerase processivity XREF_BIBR, XREF_BIBR, we postulated that the hPOT1 OB-fold mutations are unable to limit telomerase access to the ss telomeric DNA.	21	29	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	hPOT1	hPOT1	hPOT1	telomerase	telomerase	telomerase	21	22	28	29
Thus , depending on its location relative to the DNA 3 '-end , hPOT1 can either inhibit telomerase action or form a preferred substrate for telomerase .	Thus, depending on its location relative to the DNA 3 '-end, hPOT1 can either inhibit telomerase action or form a preferred substrate for telomerase.	13	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	hPOT1	hPOT1	hPOT1	telomerase	telomerase	telomerase	13	14	17	18
The binding of the recombinant POT1 with the telomere oligonucleotide inhibits the binding of telomerase .	The binding of the recombinant POT1 with the telomere oligonucleotide inhibits the binding of telomerase.	1	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	5	6	14	15
In vitro telomerase extension is inhibited by the presence of Pot1 and can be restored when the Pot1 binding site is moved away from the 3 ' end .	In vitro telomerase extension is inhibited by the presence of Pot1 and can be restored when the Pot1 binding site is moved away from the 3 ' end.	0	14	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Pot1	Pot1	Pot1	telomerase	telomerase	telomerase	10	11	2	3
The basic model of functional interaction of telomerase with shelterins postulates a TRFs ' control at TTAGGG repeats , which would regulate POT1 binding to the G-tail , and , in turn , POT1 would restrict telomerase access and telomere elongation .	The basic model of functional interaction of telomerase with shelterins postulates a TRFs ' control at TTAGGG repeats, which would regulate POT1 binding to the G-tail, and, in turn, POT1 would restrict telomerase access and telomere elongation.	33	37	restrict	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	33	34	36	37
In addition to its role in end-protection , Pot1 limits the ability of telomerase to extend the 3 ' overhang .	In addition to its role in end-protection, Pot1 limits the ability of telomerase to extend the 3 ' overhang.	8	14	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pot1	Pot1	Pot1	telomerase	telomerase	telomerase	8	9	13	14
This is achieved through multiple mechanisms , including regulation of telomerase expression and activity , sequestering of telomeres , and coating of telomeres with telomere binding proteins such as POT1 , which presumably serves to block telomerase access .	This is achieved through multiple mechanisms, including regulation of telomerase expression and activity, sequestering of telomeres, and coating of telomeres with telomere binding proteins such as POT1, which presumably serves to block telomerase access.	26	37	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	29	30	36	37
Transgenic pot-1 : : mCherry repressed telomerase in pot-1 mutants .	Transgenic pot-1 : : mCherry repressed telomerase in pot-1 mutants.	0	7	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	pot-1	pot-1	pot-1	telomerase	telomerase	telomerase	1	2	6	7
Similarly , when localized to the 3 ' end , hPOT1 alone inhibits human telomerase in vitro .	Similarly, when localized to the 3 ' end, hPOT1 alone inhibits human telomerase in vitro.	10	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	hPOT1	hPOT1	hPOT1	telomerase	telomerase	telomerase	10	11	14	15
Additionally , human Pot1 ( hPOT1 ) inhibits telomerase activity in vitro , presumably by sequestering the 3 ' ssDNA overhang that telomerase requires as a substrate .	Additionally, human Pot1 (hPOT1) inhibits telomerase activity in vitro, presumably by sequestering the 3 ' ssDNA overhang that telomerase requires as a substrate.	2	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pot1	Pot1	Pot1	telomerase	telomerase	telomerase	3	4	8	9
POT1 blocks telomerase from acting by binding to the 3 ' end of telomeric DNA .	POT1 blocks telomerase from acting by binding to the 3 ' end of telomeric DNA.	0	3	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	0	1	2	3
These findings suggest that while the majority of hPot1 OB-fold mutants were able to inhibit telomerase activity in an in vitro assay , in long term passaging experiments all displayed increased telomere length elongation similar to the hPot1 mutant human tumors XREF_BIBR - XREF_BIBR or cells expressing the hPot1 DeltaOB mutant which is unable to negatively regulate telomerase access to telomeres 44 .	These findings suggest that while the majority of hPot1 OB-fold mutants were able to inhibit telomerase activity in an in vitro assay, in long term passaging experiments all displayed increased telomere length elongation similar to the hPot1 mutant human tumors XREF_BIBR - XREF_BIBR or cells expressing the hPot1 DeltaOB mutant which is unable to negatively regulate telomerase access to telomeres 44.	48	58	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	hPot1	hPot1	hPot1	telomerase	telomerase	telomerase	48	49	57	58
Minimally , telomerase extension is inhibited by the presence of Pot1 in vitro , presumably by physically preventing access to the 3 ' overhang substrate .	Minimally, telomerase extension is inhibited by the presence of Pot1 in vitro, presumably by physically preventing access to the 3 ' overhang substrate.	2	11	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Pot1	Pot1	Pot1	telomerase	telomerase	telomerase	10	11	2	3
However , increased loading of POT1 along the overhang seems to block telomerase accessibility to the 3 '-OH substrate .	However, increased loading of POT1 along the overhang seems to block telomerase accessibility to the 3 '-OH substrate.	3	13	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	5	6	12	13
Cdc13p and human POT1 both inhibit telomerase activity in vitro by binding DNA and occluding access of telomerase to its substrate [ and this work ] .	Cdc13p and human POT1 both inhibit telomerase activity in vitro by binding DNA and occluding access of telomerase to its substrate [and this work].	0	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	3	4	6	7
When the telomeric strand ends in the sequence 3 '-TAG , POT1 tucks the end into a binding pocket and inhibits telomerase activity in vitro .	When the telomeric strand ends in the sequence 3 '-TAG, POT1 tucks the end into a binding pocket and inhibits telomerase activity in vitro.	11	22	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	11	12	21	22
Depending on its position on telomeric ssDNA , POT1 can either positively and negatively regulate telomerase .	Depending on its position on telomeric ssDNA, POT1 can either positively and negatively regulate telomerase.	8	16	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	8	9	15	16
In human cells , POT1 negatively regulates telomerase action at the telomere by binding directly to , and possibly concealing the 3 ' DNA terminus .	In human cells, POT1 negatively regulates telomerase action at the telomere by binding directly to, and possibly concealing the 3 ' DNA terminus.	4	8	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	4	5	7	8
These two events occur simultaneously at the beginning of SAA and could explain why telomeres in SAA patients are shortened despite a reduction in POT1 mediated telomerase inhibition .	These two events occur simultaneously at the beginning of SAA and could explain why telomeres in SAA patients are shortened despite a reduction in POT1 mediated telomerase inhibition.	22	27	mediated	Positive_early_activation	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	24	25	26	27
In vitro , Pot1 inhibits telomerase activity by sequestering the 3 ' ssDNA overhang that telomerase requires as a substrate , presumably through a simple competition event , suggesting that its intrinsic nature is to restrict access of telomerase to the overhang .	In vitro, Pot1 inhibits telomerase activity by sequestering the 3 ' ssDNA overhang that telomerase requires as a substrate, presumably through a simple competition event, suggesting that its intrinsic nature is to restrict access of telomerase to the overhang.	1	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pot1	Pot1	Pot1	telomerase	telomerase	telomerase	3	4	5	6
Because POT1 OB-fold mutants can not bind to telomeric ssDNA to repress telomerase access , telomerase is able to greatly lengthen telomeres ( XREF_FIG ) .	Because POT1 OB-fold mutants can not bind to telomeric ssDNA to repress telomerase access, telomerase is able to greatly lengthen telomeres (XREF_FIG).	1	13	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	1	2	12	13
As part of the shelterin complex POT1 also restricts access of telomerase to chromosome ends .	As part of the shelterin complex POT1 also restricts access of telomerase to chromosome ends.	5	12	restricts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	POT1	POT1	POT1	telomerase	telomerase	telomerase	6	7	11	12
Wip1 in turn deactivates Chk2 by means of dephosphorylation [ XREF_BIBR ] ( interaction 25 ) .	Wip1 in turn deactivates Chk2 by means of dephosphorylation [XREF_BIBR] (interaction 25).	0	5	deactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wip1	Wip1	Wip1	Chk2	Chk2	Chk2	0	1	4	5
( XREF_FIG ) could be expanded to include other regulators of p53 , such as the checkpoint kinase 2 ( CHK2 ) , which like ATM , activates p53 and is inhibited by Wip1 , in addition to being activated by ATM itself .	(XREF_FIG) could be expanded to include other regulators of p53, such as the checkpoint kinase 2 (CHK2), which like ATM, activates p53 and is inhibited by Wip1, in addition to being activated by ATM itself.	16	34	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Wip1	Wip1	Wip1	checkpoint kinase 2	checkpoint kinase 2	checkpoint kinase 2	33	34	16	19
Protein phosphatase 2A and Wip1 decreased CHK2 kinase activity and protein stability through T68 dephosphorylation .	Protein phosphatase 2A and Wip1 decreased CHK2 kinase activity and protein stability through T68 dephosphorylation.	2	8	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wip1	Wip1	Wip1	CHK2	CHK2	CHK2	4	5	6	7
In HCT15 colorectal cancer cells corrected for functional Chk2 activity , Wip1 overexpression suppressed the contribution of Chk2 to the G2/M DNA damage checkpoint .	In HCT15 colorectal cancer cells corrected for functional Chk2 activity, Wip1 overexpression suppressed the contribution of Chk2 to the G2/M DNA damage checkpoint.	11	18	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wip1	Wip1 overexpression	wip1	Chk2	Chk2	chk2	11	12	17	18
Previous experiments in which global Notch signaling was eliminated by the removal of Pofut1 or RBP-Jkappa in oocytes suggest that Notch signaling is not required through any of the four mammalian Notch receptors until after gastrulation [ XREF_BIBR , XREF_BIBR ] .	Previous experiments in which global Notch signaling was eliminated by the removal of Pofut1 or RBP-Jkappa in oocytes suggest that Notch signaling is not required through any of the four mammalian Notch receptors until after gastrulation [XREF_BIBR, XREF_BIBR].	5	15	eliminated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Pofut1	Pofut1	Pofut1	Notch	Notch	Notch	13	14	5	6
Our results strongly suggest that reduction of these ligand-receptor interactions was only due to decreased POFUT1 mediated O fucosylation of NOTCH receptors , because the relative quantity ( RQ ) of NOTCH receptors expressed at the cell surface was unaffected in Pofut1 cax and cax SCDMs , as also previously observed in mouse C2C12 myogenic cell knockdown for Pofut1 [ XREF_BIBR ] .	Our results strongly suggest that reduction of these ligand-receptor interactions was only due to decreased POFUT1 mediated O fucosylation of NOTCH receptors, because the relative quantity (RQ) of NOTCH receptors expressed at the cell surface was unaffected in Pofut1 cax and cax SCDMs, as also previously observed in mouse C2C12 myogenic cell knockdown for Pofut1 [XREF_BIBR].	12	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	POFUT1	POFUT1	POFUT1	NOTCH	NOTCH	NOTCH	15	16	20	21
Together , these results reflect the reduction in Notch signalling , induced by decreased Pofut1 expression in Pofut1 cax and cax SCDMs .	Together, these results reflect the reduction in Notch signalling, induced by decreased Pofut1 expression in Pofut1 cax and cax SCDMs.	8	16	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Pofut1	Pofut1 expression	pofut1	Notch	Notch	notch	14	15	8	9
Whereas loss of POFUT1 mediated Notch modification appears to block all Notch activity , reduced POFUT1 levels in embryos homozygous for the Pofut1 cax allele affects predominantly and consistently anterior-posterior somite patterning .	Whereas loss of POFUT1 mediated Notch modification appears to block all Notch activity, reduced POFUT1 levels in embryos homozygous for the Pofut1 cax allele affects predominantly and consistently anterior-posterior somite patterning.	1	6	mediated	Positive_early_activation	Positive_activation	Negative_activation	POFUT1	POFUT1	POFUT1	Notch	Notch	Notch	3	4	5	6
ACTH injections inhibit food intake in wild-type zebrafish but not in fish lacking functional MC4R .	ACTH injections inhibit food intake in wild-type zebrafish but not in fish lacking functional MC4R.	0	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ACTH	ACTH	ACTH	MC4R	MC4R	MC4R	0	1	14	15
Several residues of the hMC4R have been identified to be involved in NDP-MSH-induced receptor activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , However , substitution of Trp with DNaI ( 2 ) in -gamma-MSH [ Pro 5 , DNaI ( 2 ' ) 8 ] - gamma-MSH resulted in a significantly reduced MC4R activation but not for hMC1R .	Several residues of the hMC4R have been identified to be involved in NDP-MSH-induced receptor activation [XREF_BIBR, XREF_BIBR, XREF_BIBR], However, substitution of Trp with DNaI (2) in -gamma-MSH [Pro 5, DNaI (2 ') 8] - gamma-MSH resulted in a significantly reduced MC4R activation but not for hMC1R.	47	55	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	gamma-MSH	gamma-MSH	gamma-MSH	MC4R	MC4R	MC4R	47	48	53	54
As shown in Figure XREF_FIG B , NDP-MSH and alpha-MSH decreased the signaling of WT MC4R by approximately 50 % .	As shown in Figure XREF_FIG B, NDP-MSH and alpha-MSH decreased the signaling of WT MC4R by approximately 50%.	7	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	9	10	15	16
On the other hand , activation of the anorexigenic alpha-MSH and CART neurons inhibits food intake via activation of MC4R by alpha-MSH .	On the other hand, activation of the anorexigenic alpha-MSH and CART neurons inhibits food intake via activation of MC4R by alpha-MSH.	13	22	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC4R	MC4R	MC4R	21	22	19	20
Although we can not formally exclude that the impact of the K45R and K46R mutations might not only influence the acetylation of K45 and K46 , but also impair the kinase activity irrespective of these modifications , these results taken together indicate that in vitro acetylation of PLK4 at positions K45 and K46 , or mutation of these residues to R45 and R46 , inhibits PLK4 kinase activity .	Although we can not formally exclude that the impact of the K45R and K46R mutations might not only influence the acetylation of K45 and K46, but also impair the kinase activity irrespective of these modifications, these results taken together indicate that in vitro acetylation of PLK4 at positions K45 and K46, or mutation of these residues to R45 and R46, inhibits PLK4 kinase activity.	45	67	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK4	acetylation of PLK4 at positions K45 and K46	plk4	PLK4	PLK4	plk4	47	48	65	66
Thus , our data suggest that KAT2A/2B dependent acetylation of PLK4 in the kinase domain is required to limit kinase activity of PLK4 , perhaps primarily during S phase after PLK4 has acted to initiate centriole formation , to avoid subsequent rounds of centriole formation and centrosome overamplification .	Thus, our data suggest that KAT2A/2B dependent acetylation of PLK4 in the kinase domain is required to limit kinase activity of PLK4, perhaps primarily during S phase after PLK4 has acted to initiate centriole formation, to avoid subsequent rounds of centriole formation and centrosome overamplification.	6	23	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK4	KAT2A/2B dependent acetylation of PLK4	plk4	PLK4	PLK4	plk4	10	11	22	23
Expression of Plk4 WT -EYFP , but not Plk4 KD -EYFP , reduced the stability of Plk4 KD -Myc , demonstrating that Plk4 can promote self-destruction through intermolecular phosphorylation ( XREF_FIG ) .	Expression of Plk4 WT -EYFP, but not Plk4 KD -EYFP, reduced the stability of Plk4 KD -Myc, demonstrating that Plk4 can promote self-destruction through intermolecular phosphorylation (XREF_FIG).	0	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Plk4	Expression of Plk4	plk4	Plk4	Plk4	plk4	2	3	16	17
In conclusion , two different PPAR-alpha ligands ( Wy-14643 and BM-17.0744 ) inhibited cellular LPL activity in cultured cardiomyocytes by a posttranscriptional and posttranslational mechanism .	In conclusion, two different PPAR-alpha ligands (Wy-14643 and BM-17.0744) inhibited cellular LPL activity in cultured cardiomyocytes by a posttranscriptional and posttranslational mechanism.	5	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PPAR-alpha	PPAR-alpha	PPAR-alpha	LPL	LPL	LPL	5	6	14	15
Furthermore , the absence of PPARalpha may attenuate LPL activity in the subendothelial space of the vessel wall and decrease atherosclerosis .	Furthermore, the absence of PPARalpha may attenuate LPL activity in the subendothelial space of the vessel wall and decrease atherosclerosis.	3	9	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PPARalpha	PPARalpha	PPARalpha	LPL	LPL	LPL	5	6	8	9
For example , PPARgamma inhibits proinflammatory transcription factors , nuclear factor-kappaB ( NF-kappaB ) [ XREF_BIBR ] , and activator protein 1 ( AP-1 ) [ XREF_BIBR ] .	For example, PPARgamma inhibits proinflammatory transcription factors, nuclear factor-kappaB (NF-kappaB) [XREF_BIBR], and activator protein 1 (AP-1) [XREF_BIBR].	3	22	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	activator protein 1	activator protein 1	activator protein 1	3	4	19	22
After receiving liver-protective treatment , activated PPAR-gamma downregulated signal transducer and activator of transcription , nuclear factor-kappaB and activator protein-1 signaling pathways , oxidative stress and the inflammatory response were reduced , and liver injury was lessened .	After receiving liver-protective treatment, activated PPAR-gamma downregulated signal transducer and activator of transcription, nuclear factor-kappaB and activator protein-1 signaling pathways, oxidative stress and the inflammatory response were reduced, and liver injury was lessened.	5	21	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	activator protein-1	activator protein-1	activator protein-1	6	7	18	20
These results support the notion that alpha-dystroglycan hypoglycosylation is the consequence of Notch inactivation , produced by the reduced activity of POGLUT1 in the case of our patients .	These results support the notion that alpha-dystroglycan hypoglycosylation is the consequence of Notch inactivation, produced by the reduced activity of POGLUT1 in the case of our patients.	12	22	produced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	POGLUT1	POGLUT1	POGLUT1	Notch	Notch	Notch	21	22	12	13
Knockdown of mouse Poglut1 decreases Notch signaling in C2C12 cells , but does not strongly affect the levels of cell surface Notch protein or the binding of NOTCH to its ligand ; instead , like the Drosophila protein , POGLUT1 dependent modification appears to affect mouse Notch activity at a step between ligand binding and S3 cleavage of NOTCH [ XREF_BIBR ] .	Knockdown of mouse Poglut1 decreases Notch signaling in C2C12 cells, but does not strongly affect the levels of cell surface Notch protein or the binding of NOTCH to its ligand; instead, like the Drosophila protein, POGLUT1 dependent modification appears to affect mouse Notch activity at a step between ligand binding and S3 cleavage of NOTCH [XREF_BIBR].	0	6	decreases	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Poglut1	Poglut1	Poglut1	Notch	Notch	Notch	3	4	5	6
Despite these morphological similarities , the expression of a Notch target gene in the somites , Uncx4.1 , appeared normal in the paraxial mesoderm of Crumbs2 mutants ( XREF_SUPPLEMENTARY ) , whereas it is not expressed in Poglut1 wsnp embryos , confirming that the Notch pathway is blocked by the absence of POGLUT1 but not the absence of CRUMBS2 .	Despite these morphological similarities, the expression of a Notch target gene in the somites, Uncx4.1, appeared normal in the paraxial mesoderm of Crumbs2 mutants (XREF_SUPPLEMENTARY), whereas it is not expressed in Poglut1 wsnp embryos, confirming that the Notch pathway is blocked by the absence of POGLUT1 but not the absence of CRUMBS2.	44	53	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	POGLUT1	POGLUT1	POGLUT1	Notch	Notch	Notch	52	53	44	45
In growth inhibition experiments , alphaMSH significantly reduced growth of wild type MC1R transfected cells , but had no effect on cells transfected with variant MC1R .	In growth inhibition experiments, alphaMSH significantly reduced growth of wild type MC1R transfected cells, but had no effect on cells transfected with variant MC1R.	5	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	alphaMSH	alphaMSH	alphaMSH	MC1R	MC1R	MC1R	5	6	12	13
It means that lower concentration of alpha-MSH is required to induce ligands dependent activation of MC1R in O. rhodostigmatus than in other frogs .	It means that lower concentration of alpha-MSH is required to induce ligands dependent activation of MC1R in O. rhodostigmatus than in other frogs.	4	16	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	6	7	15	16
The binding of the former activates the MC1R and stimulates synthesis of the black to brown eumelanin , while antagonism of alpha-MSH by agouti signaling protein suppresses MC1R activity and results in the production of yellow to red pheomelanin ( Gantz and Fong 2003 ) .	The binding of the former activates the MC1R and stimulates synthesis of the black to brown eumelanin, while antagonism of alpha-MSH by agouti signaling protein suppresses MC1R activity and results in the production of yellow to red pheomelanin (Gantz and Fong 2003).	19	28	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	alpha-MSH	alpha-MSH	alpha-MSH	MC1R	MC1R	MC1R	21	22	27	28
Correspondingly , the p53 target gene products p21 and Mdm2 were somewhat increased by Wip1 inhibition in U2OS cells but not in MCF-7 cells .	Correspondingly, the p53 target gene products p21 and Mdm2 were somewhat increased by Wip1 inhibition in U2OS cells but not in MCF-7 cells.	5	15	increased	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Wip1	Wip1	Wip1	Mdm2	Mdm2	Mdm2	14	15	9	10
This suggests that inhibition of WIP1 can potentiate cytotoxic effects of doxorubicin and the MDM2 antagonist nutlin-3 .	This suggests that inhibition of WIP1 can potentiate cytotoxic effects of doxorubicin and the MDM2 antagonist nutlin-3.	3	16	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	WIP1	WIP1	WIP1	MDM2	MDM2	MDM2	5	6	14	15
In a rat genetic model of PD , PLK2 overexpression reduces intraneuronal human alpha-synuclein accumulation , suppresses dopaminergic neurodegeneration , and reverses hemiparkinsonian motor impairments induced by alpha-synuclein overexpression .	In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human alpha-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by alpha-synuclein overexpression.	8	14	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PLK2	PLK2 overexpression	plk2	alpha-synuclein	alpha-synuclein	alpha-synuclein	8	9	13	14
Phosphorylation of a-Syn Ser 129 by Polo-like-kinase 2 in vitro reduced the ability of a-Syn to inhibit TH or activate PP2A , identifying a novel regulatory role for Ser 129 on a-Syn .	Phosphorylation of a-Syn Ser 129 by Polo-like-kinase 2 in vitro reduced the ability of a-Syn to inhibit TH or activate PP2A, identifying a novel regulatory role for Ser 129 on a-Syn.	0	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Polo-like-kinase 2	Phosphorylation of a-Syn Ser 129 by Polo-like-kinase 2	polo-like-kinase 2	a-Syn	a-Syn	a-syn	6	8	14	15
We directly compared the effects that each beta-arrestin has on loss of MCHR1 from the cell surface of BHK-570 cells treated with MCH for 30min in XREF_FIG .	We directly compared the effects that each beta-arrestin has on loss of MCHR1 from the cell surface of BHK-570 cells treated with MCH for 30min in XREF_FIG.	10	24	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	MCH	MCH	MCH	MCHR1	MCHR1	MCHR1	22	23	12	13
Pofut1 point-mutations that disrupt O-fucosyltransferase activity destabilize the protein and abolish Notch1 signaling during mouse somitogenesis .	Pofut1 point-mutations that disrupt O-fucosyltransferase activity destabilize the protein and abolish Notch1 signaling during mouse somitogenesis.	0	12	abolish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pofut1	Pofut1	Pofut1	Notch1	Notch1	Notch1	0	1	11	12
As shown in XREF_FIG , siSIRT3 decreased the baseline protein level of SOD2 and reduced the induction of SOD2 by PGC-1alpha ( XREF_FIG ) .	As shown in XREF_FIG, siSIRT3 decreased the baseline protein level of SOD2 and reduced the induction of SOD2 by PGC-1alpha (XREF_FIG).	14	22	induction	Positive_activation_token_2_noun	Positive_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	SOD2	SOD2	SOD2	20	21	18	19
Interestingly , administration of gamma-MSH reverses salt sensitive hypertension in PC2 KO but not in MC3-R KO mice , suggesting that gamma-MSH can regulate Na + balance and blood pressure by acting through MC3-R [ XREF_BIBR ] .	Interestingly, administration of gamma-MSH reverses salt sensitive hypertension in PC2 KO but not in MC3-R KO mice, suggesting that gamma-MSH can regulate Na + balance and blood pressure by acting through MC3-R [XREF_BIBR].	2	17	reverses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	gamma-MSH	gamma-MSH	gamma-MSH	MC3-R	MC3-R	MC3-R	4	5	15	16
Akt mediates PPP2CA silencing induced activation of beta-catenin and NF-kappaB .	Akt mediates PPP2CA silencing induced activation of beta-catenin and NF-kappaB.	2	9	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PPP2CA	PPP2CA	PPP2CA	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
Akt mediated PPP2CA loss induced nuclear accumulation of beta-catenin and NF-kappaB through inactivation of Gsk3-beta and IkappaB-alpha , respectively .	Akt mediated PPP2CA loss induced nuclear accumulation of beta-catenin and NF-kappaB through inactivation of Gsk3-beta and IkappaB-alpha, respectively.	0	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PPP2CA	Akt mediated PPP2CA	ppp2ca	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
The parous hypermethylation of PPP2CA , which suggests a lower expression in parous women , supports the idea of decreased beta-catenin .	The parous hypermethylation of PPP2CA, which suggests a lower expression in parous women, supports the idea of decreased beta-catenin.	2	21	supports	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PPP2CA	hypermethylation of PPP2CA	ppp2ca	beta-catenin	beta-catenin	beta-catenin	4	5	20	21
In contrast , the knockdown of NIPP1 caused EZH2 to be hypophosphorylated .	In contrast, the knockdown of NIPP1 caused EZH2 to be hypophosphorylated.	4	9	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	NIPP1	NIPP1	NIPP1	EZH2	EZH2	EZH2	6	7	8	9
The loss of NIPP1 or PP1 reduces the targeting of EZH2 .	The loss of NIPP1 or PP1 reduces the targeting of EZH2.	1	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NIPP1	loss of NIPP1	nipp1	EZH2	EZH2	ezh2	3	4	10	11
The PP2a proapoptotic function is also mediated by direct dephosphorylation of specific proteins : PP2a both inactivates the antiapoptotic Bcl-2 and activates the proapoptotic factor Bad ( XREF_FIG ) .	The PP2a proapoptotic function is also mediated by direct dephosphorylation of specific proteins : PP2a both inactivates the antiapoptotic Bcl-2 and activates the proapoptotic factor Bad (XREF_FIG).	14	21	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PP2a	PP2a	PP2a	Bcl-2	Bcl-2	Bcl-2	14	15	19	20
Direct inhibition of calcineurin with FK506 XREF_BIBR , XREF_BIBR , cyclosporine A ( CsA ) XREF_BIBR , XREF_BIBR , or RNAi mediated depletion of the calcineurin catalytic subunit ( PPP3CB ) was also sufficient to block TFEB activation by AD , suggesting small-molecule inhibition of PTPMT1 activates TFEB via mobilization of calcineurin catalytic activity .	Direct inhibition of calcineurin with FK506 XREF_BIBR, XREF_BIBR, cyclosporine A (CsA) XREF_BIBR, XREF_BIBR, or RNAi mediated depletion of the calcineurin catalytic subunit (PPP3CB) was also sufficient to block TFEB activation by AD, suggesting small-molecule inhibition of PTPMT1 activates TFEB via mobilization of calcineurin catalytic activity.	15	37	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PPP3CB	PPP3CB	PPP3CB	TFEB	TFEB	TFEB	29	30	36	37
CnA is a direct target of miR499 and miR499 inhibits cardiomyocyte apoptosis through the suppression of CnA mediated Drp1 , thereby decreasing Drp1 mediated activation of mitochondrial fission .	CnA is a direct target of miR499 and miR499 inhibits cardiomyocyte apoptosis through the suppression of CnA mediated Drp1, thereby decreasing Drp1 mediated activation of mitochondrial fission.	14	19	mediated	Positive_early_activation	Positive_activation	Negative_activation	CnA	CnA	CnA	Drp1	Drp1	Drp1	16	17	18	19
Consistently , in our study , the Sirt1 content in SV cells was also activated due to resveratrol treatment , which was absent in AMPKalpha1 KO cells ; in addition , AMPKalpha1 deficiency dramatically reduced Sirt1 content .	Consistently, in our study, the Sirt1 content in SV cells was also activated due to resveratrol treatment, which was absent in AMPKalpha1 KO cells; in addition, AMPKalpha1 deficiency dramatically reduced Sirt1 content.	31	36	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	AMPKalpha1	AMPKalpha1	AMPKalpha1	Sirt1	Sirt1	Sirt1	31	32	35	36
Knockdown of AMPKalpha1 significantly decreased ( P < 0.001 ) PGC-1alpha expression and levels in Abcd1-KO mice mixed glial cells ( XREF_FIG ) .	Knockdown of AMPKalpha1 significantly decreased (P < 0.001) PGC-1alpha expression and levels in Abcd1-KO mice mixed glial cells (XREF_FIG).	0	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	AMPKalpha1	AMPKalpha1	AMPKalpha1	PGC-1alpha	PGC-1alpha	PGC-1alpha	2	3	10	11
It is also notable that depletion of PKAcalpha did not completely inhibit HSF1 ( XREF_FIG ) .	It is also notable that depletion of PKAcalpha did not completely inhibit HSF1 (XREF_FIG).	5	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKAcalpha	PKAcalpha	PKAcalpha	HSF1	HSF1	HSF1	7	8	12	13
Linking their control of both receptor tyrosine kinases and GPCRs , PKCalpha has recently been shown to mediate a feedback inhibition of the EGF receptor transactivation induced by G q -coupled receptor agonists .	Linking their control of both receptor tyrosine kinases and GPCRs, PKCalpha has recently been shown to mediate a feedback inhibition of the EGF receptor transactivation induced by G q -coupled receptor agonists.	11	25	mediate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCalpha	PKCalpha	PKCalpha	EGF receptor	EGF receptor	EGF receptor	11	12	23	25
Previously , we mentioned that EGFR signaling is negatively regulated by PKCalpha .	Previously, we mentioned that EGFR signaling is negatively regulated by PKCalpha.	5	12	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PKCalpha	PKCalpha	PKCalpha	EGFR	EGFR	EGFR	11	12	5	6
Inhibition of EGFR activation by PKCalpha has been noted in a number of systems and was also seen following re-expression of the isozyme in CRC cells ( XREF_SUPPLEMENTARY ) .	Inhibition of EGFR activation by PKCalpha has been noted in a number of systems and was also seen following re-expression of the isozyme in CRC cells (XREF_SUPPLEMENTARY).	2	6	activation	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	EGFR	EGFR	EGFR	5	6	2	3
These results have been taken as evidence that stoichiometric PKCalpha autophosphorylation at the hydrophobic motif can tonically inhibit PKCalpha actions at membranes under some conditions .	These results have been taken as evidence that stoichiometric PKCalpha autophosphorylation at the hydrophobic motif can tonically inhibit PKCalpha actions at membranes under some conditions.	9	19	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCalpha	PKCalpha autophosphorylation	pkcalpha	PKCalpha	PKCalpha	pkcalpha	9	10	18	19
Western blot analysis showed expression of PKC-alpha , -betaI , -delta , -eta , and -zeta in RAW cells ; down-regulation of PKC-alpha , -betaI , and -delta , but not -eta , was seen after long-term TPA treatment , indicating the possible involvement of one or all of PKC-alpha , -betaI , and -delta , but not -eta , in LPS mediated effects .	Western blot analysis showed expression of PKC-alpha, -betaI, -delta, -eta, and -zeta in RAW cells; down-regulation of PKC-alpha, -betaI, and -delta, but not -eta, was seen after long-term TPA treatment, indicating the possible involvement of one or all of PKC-alpha, -betaI, and -delta, but not -eta, in LPS mediated effects.	4	24	down-regulation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	PKC-alpha	expression of PKC-alpha	pkc-alpha	PKC-alpha	PKC-alpha	pkc-alpha	6	7	22	23
It has been previously shown in an ischemic stroke model that inhibiting PKCalpha increases the tight junction proteins ZO-1 , occludin , and VE-Cadherin [ XREF_BIBR ] .	It has been previously shown in an ischemic stroke model that inhibiting PKCalpha increases the tight junction proteins ZO-1, occludin, and VE-Cadherin [XREF_BIBR].	11	21	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCalpha	PKCalpha	PKCalpha	occludin	occludin	occludin	12	13	20	21
In mouse muscle and adipose tissues , knockout of Prkca ( encoding PKCalpha ) enhances IRS1 and PIK3 --> AKT and aPKC signalling , as well as glucose transport [ XREF_BIBR ] .	In mouse muscle and adipose tissues, knockout of Prkca (encoding PKCalpha) enhances IRS1 and PIK3 --> AKT and aPKC signalling, as well as glucose transport [XREF_BIBR].	7	28	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Prkca	Prkca	Prkca	IRS1	IRS1	IRS1	9	10	15	16
Moreover , pretreatment of the cells with the protein kinase C ( PKC ) inhibitors GF-109203X and RO-31-8220 and down-regulation of PKCalpha by prolonged treatment with 4beta-phorbol 12-myristate 13-acetate inhibited the H2O2 stimulated PLD2 activity , which points to the involvement of PKCalpha .	Moreover, pretreatment of the cells with the protein kinase C (PKC) inhibitors GF-109203X and RO-31-8220 and down-regulation of PKCalpha by prolonged treatment with 4beta-phorbol 12-myristate 13-acetate inhibited the H2O2 stimulated PLD2 activity, which points to the involvement of PKCalpha.	17	34	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCalpha	PKCalpha	PKCalpha	PLD2	PLD2	PLD2	21	22	33	34
PKC-alpha and -delta siRNA attenuated PKD activity , whereas overexpression of PKC-alpha and -delta enhanced PKD activity .	PKC-alpha and -delta siRNA attenuated PKD activity, whereas overexpression of PKC-alpha and -delta enhanced PKD activity.	0	6	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKC-alpha	PKC-alpha	PKC-alpha	PKD	PKD	PKD	0	1	5	6
Significantly , high levels of PKCepsilon , as seen in melanoma cells , block ATF2 nuclear export and function at the mitochondria , thereby attenuating apoptosis following exposure to genotoxic stress .	Significantly, high levels of PKCepsilon, as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria, thereby attenuating apoptosis following exposure to genotoxic stress.	3	24	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	levels of PKCepsilon	pkcepsilon	ATF2	ATF2	atf2	5	6	14	15
PKCepsilon phosphorylation negatively regulates ATF2 mitochondrial localization .	PKCepsilon phosphorylation negatively regulates ATF2 mitochondrial localization.	0	6	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	PKCepsilon phosphorylation	pkcepsilon	ATF2	ATF2	atf2	0	1	4	5
Consistently , siRNA mediated knockdown of PKCepsilon ( XREF_SUPPLEMENTARY ) promoted mitochondrial localization of ATF2 ( XREF_FIG ) , while overexpression of a constitutively active form of PKCepsilon , attenuated ATF2 accumulation at mitochondria following ETO treatment ( XREF_FIG ) .	Consistently, siRNA mediated knockdown of PKCepsilon (XREF_SUPPLEMENTARY) promoted mitochondrial localization of ATF2 (XREF_FIG), while overexpression of a constitutively active form of PKCepsilon, attenuated ATF2 accumulation at mitochondria following ETO treatment (XREF_FIG).	4	16	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	PKCepsilon	PKCepsilon	ATF2	ATF2	ATF2	6	7	14	15
PKCepsilon may play an indirect role in the metabolic changes that contribute to cancer development and/or progression , as suggested by the observation that elevated PKCepsilon activity antagonizes the HK1 and VDAC1 perturbing function of ATF2 .	PKCepsilon may play an indirect role in the metabolic changes that contribute to cancer development and/or progression, as suggested by the observation that elevated PKCepsilon activity antagonizes the HK1 and VDAC1 perturbing function of ATF2.	25	36	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	PKCepsilon	PKCepsilon	ATF2	ATF2	ATF2	25	26	35	36
Elevated levels of PKCepsilon , found in the more advanced metastatic melanomas , prevent the nuclear-to-mitochondrial translocation of ATF2 that enable its tumor suppressor function .	Elevated levels of PKCepsilon, found in the more advanced metastatic melanomas, prevent the nuclear-to-mitochondrial translocation of ATF2 that enable its tumor suppressor function.	1	19	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	levels of PKCepsilon	pkcepsilon	ATF2	ATF2	atf2	3	4	18	19
Hence , partial inhibition of PKCepsilon is expected to allow partial nuclear retention of ATF2 , whereas ATF2 T52A is largely excluded from the nuclei .	Hence, partial inhibition of PKCepsilon is expected to allow partial nuclear retention of ATF2, whereas ATF2 T52A is largely excluded from the nuclei.	3	15	allow	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	PKCepsilon	PKCepsilon	ATF2	ATF2	ATF2	5	6	14	15
Constitutively high PKCepsilon expression and activity , as seen in melanomas , attenuates ATF2 mitochondrial function and enhances its nuclear transcriptional activity , consistent with its oncogenic activity .	Constitutively high PKCepsilon expression and activity, as seen in melanomas, attenuates ATF2 mitochondrial function and enhances its nuclear transcriptional activity, consistent with its oncogenic activity.	2	15	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	PKCepsilon expression	pkcepsilon	ATF2	ATF2	atf2	2	3	13	14
These findings suggest that elevated PKCepsilon levels in melanoma cells inhibit ATF2 localization and function at the mitochondria , thereby attenuating its role in promoting cell death following genotoxic stress .	These findings suggest that elevated PKCepsilon levels in melanoma cells inhibit ATF2 localization and function at the mitochondria, thereby attenuating its role in promoting cell death following genotoxic stress.	5	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	PKCepsilon levels	pkcepsilon	ATF2	ATF2	atf2	5	6	11	12
However , co-expression of IL-32beta and PKCdelta reduced the H 2 O 2 -induced apoptosis in the presence of PKCdelta , implying that IL-32beta attenuates PKCdelta induced apoptosis under oxidative stress .	However, co-expression of IL-32beta and PKCdelta reduced the H 2 O 2 -induced apoptosis in the presence of PKCdelta, implying that IL-32beta attenuates PKCdelta induced apoptosis under oxidative stress.	2	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCdelta	co-expression of IL-32beta and PKCdelta	pkcdelta	PKCdelta	PKCdelta	pkcdelta	6	7	19	20
It has been reported that phosphorylation of PKCdelta at Y311 is important for downregulation of PKCdelta by activated Src but not by phorbol esters [ XREF_BIBR ] .	It has been reported that phosphorylation of PKCdelta at Y311 is important for downregulation of PKCdelta by activated Src but not by phorbol esters [XREF_BIBR].	5	16	is important for downregulation	Negative_activation_copula_1	Positive_activation	Negative_activation	PKCdelta	phosphorylation of PKCdelta at Y311	pkcdelta	PKCdelta	PKCdelta	pkcdelta	7	8	15	16
Anacardic acid suppressed paraquat induced PKCdelta proteolytic cleavage by 33 % and NaBu increased the cleavage of PKCdelta by 30 % .	Anacardic acid suppressed paraquat induced PKCdelta proteolytic cleavage by 33% and NaBu increased the cleavage of PKCdelta by 30%.	0	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	Anacardic acid suppressed paraquat induced PKCdelta	pkcdelta	PKCdelta	PKCdelta	pkcdelta	5	6	17	18
Inhibition of PKCepsilon , however , markedly increased phosphorylation of PKCdelta at Thr 505 and promoted translocation of PKCdelta to the cardiac mitochondria ( XREF_FIG ) .	Inhibition of PKCepsilon, however, markedly increased phosphorylation of PKCdelta at Thr 505 and promoted translocation of PKCdelta to the cardiac mitochondria (XREF_FIG).	2	19	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCdelta	PKCepsilon, however, markedly increased phosphorylation of PKCdelta at Thr 505	pkcdelta	PKCdelta	PKCdelta	pkcdelta	10	11	18	19
XREF_BIBR , XREF_BIBR Specifically , PKCepsilon has been shown to reverse TRPV1 desensitization by capsaicin through rephosphorylation of the channel at S800 .	XREF_BIBR, XREF_BIBR Specifically, PKCepsilon has been shown to reverse TRPV1 desensitization by capsaicin through rephosphorylation of the channel at S800.	5	12	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	5	6	11	12
Antagonists of PKCepsilon and PKA prevented sensitization of TRPV1 Ca2+ signals and currents in HEK 293 cells , and suppressed thermal hyperalgesia in mice .	Antagonists of PKCepsilon and PKA prevented sensitization of TRPV1 Ca2+ signals and currents in HEK 293 cells, and suppressed thermal hyperalgesia in mice.	0	10	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	2	3	8	9
Effect of PKCepsilon inhibition on AITC- and propofol induced restoration of TRPV1 sensitivity to agonist stimulation in cultured TRPA1-TRPV1 co-transfectedF-11 cells .	Effect of PKCepsilon inhibition on AITC- and propofol induced restoration of TRPV1 sensitivity to agonist stimulation in cultured TRPA1-TRPV1 co-transfectedF-11 cells.	2	12	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	PKCepsilon	PKCepsilon	TRPV1	TRPV1	TRPV1	2	3	11	12
Similarly , in human breast cancer cell lines in which ErbB2 is overexpressed , depletion of PKCdelta suppresses proliferation , Src , and ERK activation .	Similarly, in human breast cancer cell lines in which ErbB2 is overexpressed, depletion of PKCdelta suppresses proliferation, Src, and ERK activation.	14	21	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Src	Src	Src	16	17	20	21
PKCdelta appears to drive proliferation through formation of an active ErbB2/PKCdelta/Src signaling complex , as depletion of PKCdelta disrupts association of Src with the ErbB2 receptor .	PKCdelta appears to drive proliferation through formation of an active ErbB2/PKCdelta/Src signaling complex, as depletion of PKCdelta disrupts association of Src with the ErbB2 receptor.	15	22	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	Src	Src	Src	17	18	21	22
Finally , mutagenesis studies show that single residue substitutions in PKCdelta at Y311F or T505A prevent the Src dependent acquisition of cTnI-T 144 kinase activity .	Finally, mutagenesis studies show that single residue substitutions in PKCdelta at Y311F or T505A prevent the Src dependent acquisition of cTnI-T 144 kinase activity.	8	19	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCdelta	PKCdelta	PKCdelta	Src	Src	Src	10	11	17	18
We show that PKCdelta activation impairs neuronal mitochondrial morphology and increases neuronal cell death , at least in part , by inducing Drp1 dependent fission and fragmentation of the mitochondria under oxidative stress conditions ( XREF_FIG ) .	We show that PKCdelta activation impairs neuronal mitochondrial morphology and increases neuronal cell death, at least in part, by inducing Drp1 dependent fission and fragmentation of the mitochondria under oxidative stress conditions (XREF_FIG).	3	24	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCdelta	PKCdelta	PKCdelta	Drp1	Drp1	Drp1	3	4	22	23
We examined the effect of PKCdelta inhibition on thrombin induced activation of PKD and CPI-17 .	We examined the effect of PKCdelta inhibition on thrombin induced activation of PKD and CPI-17.	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCdelta	PKCdelta	PKCdelta	PKD	PKD	PKD	5	6	12	13
In conditions of hypoxia which activates PKCepsilon in heart and in the lens , the PKCepsilon , in the heart , is translocated to plasma membranes XREF_BIBR , XREF_BIBR , XREF_BIBR and phosphorylates and inhibits Cx43 gap junctions , XREF_BIBR , XREF_BIBR to prevent the propagation of apoptotic signal .	In conditions of hypoxia which activates PKCepsilon in heart and in the lens, the PKCepsilon, in the heart, is translocated to plasma membranes XREF_BIBR, XREF_BIBR, XREF_BIBR and phosphorylates and inhibits Cx43 gap junctions, XREF_BIBR, XREF_BIBR to prevent the propagation of apoptotic signal.	14	37	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKCepsilon	PKCepsilon, in the heart, is translocated to plasma membranes	pkcepsilon	Cx43	Cx43	cx43	15	16	35	36
PRKD1 expression levels also decreased following PRKD1 siRNA transfection as compared to levels observed in association with transfection of control siRNA .	PRKD1 expression levels also decreased following PRKD1 siRNA transfection as compared to levels observed in association with transfection of control siRNA.	0	8	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PRKD1	PRKD1 expression levels	prkd1	PRKD1	PRKD1	prkd1	0	1	6	7
Dysregulated beta-catenin signaling , excessive chemokine production and macrophage infiltration are often seen in PKD models XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	Dysregulated beta-catenin signaling, excessive chemokine production and macrophage infiltration are often seen in PKD models XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	0	15	Dysregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKD	PKD	PKD	beta-catenin	beta-catenin	beta-catenin	14	15	1	2
Having established that loss of PrKD1 expression increases nuclear beta-catenin through loss of T120 phosphorylation , we next evaluated whether T120 mutant beta catenin could influence PrKD1 expression .	Having established that loss of PrKD1 expression increases nuclear beta-catenin through loss of T120 phosphorylation, we next evaluated whether T120 mutant beta catenin could influence PrKD1 expression.	5	10	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PrKD1	PrKD1 expression	prkd1	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
Furthermore , Lck has been shown to co-precipitate with and directly phosphorylate PKCtheta , and Lck dependent phosphorylation of PKCtheta enhances the membrane targeting and activation of PKCtheta .	Furthermore, Lck has been shown to co-precipitate with and directly phosphorylate PKCtheta, and Lck dependent phosphorylation of PKCtheta enhances the membrane targeting and activation of PKCtheta.	15	28	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PKCtheta	Lck dependent phosphorylation of PKCtheta	pkctheta	PKCtheta	PKCtheta	pkctheta	19	20	27	28
Desumoylation did not affect the catalytic activity of PKC-theta but inhibited the association of CD28 with PKC-theta and filamin A and impaired the assembly of a mature immunological synapse and central co-accumulation of PKC-theta and CD28 .	Desumoylation did not affect the catalytic activity of PKC-theta but inhibited the association of CD28 with PKC-theta and filamin A and impaired the assembly of a mature immunological synapse and central co-accumulation of PKC-theta and CD28.	0	35	impaired	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PKC-theta	Desumoylation did not affect the catalytic activity of PKC-theta	pkc-theta	PKC-theta	PKC-theta	pkc-theta	8	9	33	34
Presenilin 1 Negatively Regulates beta-Catenin/T Cell Factor and Lymphoid Enhancer Factor-1 Signaling Independently of beta-Amyloid Precursor Protein and Notch Processing .	Presenilin 1 Negatively Regulates beta-Catenin/T Cell Factor and Lymphoid Enhancer Factor-1 Signaling Independently of beta-Amyloid Precursor Protein and Notch Processing.	0	19	Negatively Regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Presenilin 1	Presenilin 1	Presenilin 1	Notch	Notch	Notch	0	2	18	19
Unlike wt PS1 and some of its clinical mutants , all three PS1 artificial mutants decreased cleavage of Notch S3-site , suggesting that these artificial mutations may trigger conformational changes at the substrate docking and catalytic site that cause alteration of substrate specificity and inhibition pattern .	Unlike wt PS1 and some of its clinical mutants, all three PS1 artificial mutants decreased cleavage of Notch S3-site, suggesting that these artificial mutations may trigger conformational changes at the substrate docking and catalytic site that cause alteration of substrate specificity and inhibition pattern.	10	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PS1	PS1	PS1	Notch	Notch	Notch	12	13	18	19
Our main findings include ( i ) raised levels of DLL1 , which is a soluble Notch ligand with potential inhibiting effect on Notch signaling , ( ii ) down-regulation of PSEN1 and RBPJ ( SCZ ) , potentially impairing intracellular Notch signaling , and ( iii ) up-regulation of RFNG mRNA , which may inhibit ligand-receptor interactions , further impairing Notch signaling .	Our main findings include (i) raised levels of DLL1, which is a soluble Notch ligand with potential inhibiting effect on Notch signaling, (ii) down-regulation of PSEN1 and RBPJ (SCZ), potentially impairing intracellular Notch signaling, and (iii) up-regulation of RFNG mRNA, which may inhibit ligand-receptor interactions, further impairing Notch signaling.	29	42	impairing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PSEN1	PSEN1	PSEN1	Notch	Notch	Notch	31	32	41	42
Since then several studies have confirmed that many PSEN1 and PSEN2 mutations cause reduced NOTCH cleavage , decreased formation of the AICD fragment , and reduced processing of other gamma-secretase substrates such as N-cadherin [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Since then several studies have confirmed that many PSEN1 and PSEN2 mutations cause reduced NOTCH cleavage, decreased formation of the AICD fragment, and reduced processing of other gamma-secretase substrates such as N-cadherin [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	7	25	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PSEN1	PSEN1	PSEN1	NOTCH	NOTCH	NOTCH	8	9	14	15
In this study , a Notch downstream target Hes1 decreased in PS1 deficient NSCs , which was consistent with a previous report that PS1 deficiency caused the dysfunction of gamma-secretase and thereby blocks Notch signaling 43 .	In this study, a Notch downstream target Hes1 decreased in PS1 deficient NSCs, which was consistent with a previous report that PS1 deficiency caused the dysfunction of gamma-secretase and thereby blocks Notch signaling 43.	23	34	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PS1	PS1	PS1	Notch	Notch	Notch	23	24	33	34
We conclude that RNA interference of PS1 or Notch1 can block Notch signaling and consequently induce growth inhibition of HeLa cells .	We conclude that RNA interference of PS1 or Notch1 can block Notch signaling and consequently induce growth inhibition of HeLa cells.	4	12	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PS1	PS1	PS1	Notch	Notch	Notch	6	7	11	12
Thus , Notch signaling in the developing embryonic brain is more effectively suppressed by inactivation of both PS1 and PS2 in neural progenitor cells than in PS1-null mice [ XREF_BIBR ] .	Thus, Notch signaling in the developing embryonic brain is more effectively suppressed by inactivation of both PS1 and PS2 in neural progenitor cells than in PS1-null mice [XREF_BIBR].	2	19	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PS1	PS1	PS1	Notch	Notch	Notch	17	18	2	3
In parallel , mice rendered haploinsufficient in gamma-secretase presenilin-1 ( Psen1 ) , which inhibits downstream Notch activation , display almost-absent terminal osteoblast differentiation .	In parallel, mice rendered haploinsufficient in gamma-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation.	8	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Psen1	Psen1	Psen1	Notch	Notch	Notch	10	11	16	17
We report here that specific mutations in the N terminus , loop , or C terminus of PS1 all increase the production of Abeta ( 42 ) but cause inhibition of both epsilon-secretase cleavage of APP and S3-cleavage of Notch .	We report here that specific mutations in the N terminus, loop, or C terminus of PS1 all increase the production of Abeta (42) but cause inhibition of both epsilon-secretase cleavage of APP and S3-cleavage of Notch.	5	40	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PS1	PS1	PS1	Notch	Notch	Notch	17	18	39	40
Mutations in the gamma-secretase genes NCSTN , PSENEN , and PSEN1 impairing the Notch signaling in hair follicles have been found in some HS patients .	Mutations in the gamma-secretase genes NCSTN, PSENEN, and PSEN1 impairing the Notch signaling in hair follicles have been found in some HS patients.	0	14	impairing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PSEN1	PSEN1	PSEN1	Notch	Notch	Notch	10	11	13	14
Removal of both presenilin-1 ( encoded by Psen1 ) and presenilin-2 ( encoded by Psen2 ) completely abolishes NICD production .	Removal of both presenilin-1 (encoded by Psen1) and presenilin-2 (encoded by Psen2) completely abolishes NICD production.	0	19	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	presenilin-1	presenilin-1	presenilin-1	NICD	NICD	NICD	3	4	18	19
These results support the hypothesis that PS1 deficiency blocks neuronal Notch1 processing and signaling .	These results support the hypothesis that PS1 deficiency blocks neuronal Notch1 processing and signaling.	6	11	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PS1	PS1	PS1	Notch1	Notch1	Notch1	6	7	10	11
Notch1 signaling , assessed by measuring the activity of CBF1 , a downstream transcription factor , was impaired but not abolished by the PS1 aspartate mutations or gamma-secretase inhibitors .	Notch1 signaling, assessed by measuring the activity of CBF1, a downstream transcription factor, was impaired but not abolished by the PS1 aspartate mutations or gamma-secretase inhibitors.	0	25	abolished	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PS1	PS1	PS1	Notch1	Notch1	Notch1	23	24	0	1
These results provide insights for further study on PS1 mediated reduction of Notch 1 and APP processing for the treatment of Alzheimer ' s disease .	These results provide insights for further study on PS1 mediated reduction of Notch 1 and APP processing for the treatment of Alzheimer 's disease.	8	14	reduction	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	PS1	PS1	PS1	Notch 1	Notch 1	Notch 1	8	9	12	14
While it is important to study PS1 mediated reduction of Notch 1 and APP processing for the treatment of Alzheimer ' s disease , we do not know whether SP600125 would repress PS1 expression and gamma-secretase activity in vivo in adult mouse brains .	While it is important to study PS1 mediated reduction of Notch 1 and APP processing for the treatment of Alzheimer 's disease, we do not know whether SP600125 would repress PS1 expression and gamma-secretase activity in vivo in adult mouse brains.	6	12	reduction	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	PS1	PS1	PS1	Notch 1	Notch 1	Notch 1	6	7	10	12
Furthermore , we found that DNA-PKcs deficiency does not reduce apoptosis , tissue atrophy , or p53 activation in late generation mTerc (-/-) tissues but rather moderately exacerbates germ cell apoptosis and testicular degeneration .	Furthermore, we found that DNA-PKcs deficiency does not reduce apoptosis, tissue atrophy, or p53 activation in late generation mTerc (-/-) tissues but rather moderately exacerbates germ cell apoptosis and testicular degeneration.	5	17	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	p53	p53	p53	5	6	16	17
Our findings reported here help to clarify these pathways by showing that Artemis and DNA-PKcs function antagonistically to regulate the activation of p53 in response to oxidative stress derived from oxidative phosphorylation .	Our findings reported here help to clarify these pathways by showing that Artemis and DNA-PKcs function antagonistically to regulate the activation of p53 in response to oxidative stress derived from oxidative phosphorylation.	14	24	antagonistically	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	p53	p53	p53	14	15	22	23
Inhibition of DNA-PKcs induces an amplified p53 response .	Inhibition of DNA-PKcs induces an amplified p53 response.	0	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	p53	p53	p53	2	3	6	7
For example , loss of DNA-PKcs promotes a p53 dependent checkpoint in ATM sufficient thymocytes , but severely impairs p53 dependent apoptosis in ATM -/- thymocytes ( XREF_FIG ) .	For example, loss of DNA-PKcs promotes a p53 dependent checkpoint in ATM sufficient thymocytes, but severely impairs p53 dependent apoptosis in ATM -/- thymocytes (XREF_FIG).	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	DNA-PKcs	loss of DNA-PKcs	dna-pkcs	p53	p53	p53	5	6	8	9
Thus , DNA-PKcs deficiency selectively disrupts p53 dependent apoptosis but not cell-cycle arrest .	Thus, DNA-PKcs deficiency selectively disrupts p53 dependent apoptosis but not cell-cycle arrest.	2	8	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	p53	p53	p53	2	3	6	7
It is also possible that DNA-PKcs prevents WRN from dissociating from the DNA substrate , and that this interaction stimulates the processivity of WRN helicase .	It is also possible that DNA-PKcs prevents WRN from dissociating from the DNA substrate, and that this interaction stimulates the processivity of WRN helicase.	5	8	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	5	6	7	8
Serine/threonine phosphorylation of WRN by DNA-PKcs and tyrosine phosphorylation by c-Abl kinase , in vitro , inhibit the WRN exonuclease and helicase .	Serine/threonine phosphorylation of WRN by DNA-PKcs and tyrosine phosphorylation by c-Abl kinase, in vitro, inhibit the WRN exonuclease and helicase.	1	19	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	phosphorylation of WRN by DNA-PKcs and tyrosine	dna-pkcs	WRN	WRN	wrn	5	6	18	19
Thus , DNA-PKcs does not inhibit WRN exonuclease .	Thus, DNA-PKcs does not inhibit WRN exonuclease.	2	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	2	3	6	7
It appears that proteins responsible for D-NHEJ are deregulated by BCR and ABL : nuclear DNA-PKcs was downregulated , whereas Ligase IV , Artemis and XLF were upregulated by BCR and ABL kinase , but XRCC4 , Ku70 and Ku80 were not changed , which may affect the activity of WRN .	It appears that proteins responsible for D-NHEJ are deregulated by BCR and ABL : nuclear DNA-PKcs was downregulated, whereas Ligase IV, Artemis and XLF were upregulated by BCR and ABL kinase, but XRCC4, Ku70 and Ku80 were not changed, which may affect the activity of WRN.	14	51	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	WRN	WRN	WRN	15	16	50	51
XREF_BIBR DNA-PKcs deficiency impairs the functions of the Artemis nuclease that is required for the resolution of coding joint hairpins during V ( D ) J recombination , a prerequisite for the subsequent repair of coding joints by non homologous end joining ( NHEJ ) pathways .	XREF_BIBR DNA-PKcs deficiency impairs the functions of the Artemis nuclease that is required for the resolution of coding joint hairpins during V (D) J recombination, a prerequisite for the subsequent repair of coding joints by non homologous end joining (NHEJ) pathways.	1	9	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	1	2	8	9
These interactions suggest that DNA-PKcs may limit the activity of Artemis to an end within the context of an aligned end-pair , and physical association with ligase IV may promote a trial ligation of the ends after each cycle of processing .	These interactions suggest that DNA-PKcs may limit the activity of Artemis to an end within the context of an aligned end-pair, and physical association with ligase IV may promote a trial ligation of the ends after each cycle of processing.	4	11	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Artemis	Artemis	Artemis	4	5	10	11
In addition , downregulation of DNA-PKcs suppressed the activity of the Akt and NF-kappaB pathway .	In addition, downregulation of DNA-PKcs suppressed the activity of the Akt and NF-kappaB pathway.	3	14	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	Akt	Akt	Akt	5	6	11	12
Since there was a small reduction in the phosphorylation of AKT Ser473 in DLD-1 cells treated with siRNA against DNA-PKcs , an increase in radiation sensitivity was expected .	Since there was a small reduction in the phosphorylation of AKT Ser473 in DLD-1 cells treated with siRNA against DNA-PKcs, an increase in radiation sensitivity was expected.	10	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	AKT	AKT	AKT	19	20	10	11
To determine whether the levels of Ku and DNA-PKcs in HeLa nuclear extracts would be sufficient to block TDP1 mediated processing , Western blots were performed with various quantities of nuclear extract and of purified recombinant Ku and DNA-PKcs ( XREF_SUPPLEMENTARY ) .	To determine whether the levels of Ku and DNA-PKcs in HeLa nuclear extracts would be sufficient to block TDP1 mediated processing, Western blots were performed with various quantities of nuclear extract and of purified recombinant Ku and DNA-PKcs (XREF_SUPPLEMENTARY).	4	19	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	levels of Ku and DNA-PKcs	dna-pkcs	TDP1	TDP1	tdp1	8	9	18	19
Ku and DNA-PKcs inhibited TDP1 mediated processing of 3 '-phosphoglycolate double-strand break termini , and in the absence of ATP , ends sequestered by Ku plus DNA-PKcs were completely refractory to TDP1 .	Ku and DNA-PKcs inhibited TDP1 mediated processing of 3 '-phosphoglycolate double-strand break termini, and in the absence of ATP, ends sequestered by Ku plus DNA-PKcs were completely refractory to TDP1.	0	6	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	TDP1	TDP1	TDP1	2	3	4	5
Similarly , the DNA-PKcs inhibitor NU7441 also increases I-SceI-induced mNHEJ to the same level in both ATM -/- H2AX -/- H2AX cells and ATM -/- H2AX -/- EV cells , in both of which H2AX dependent NHEJ is inactivated , substantiating the previous observation that DNA-PKcs suppresses H2AX independent mNHEJ ( XREF_SUPPLEMENTARY ) .	Similarly, the DNA-PKcs inhibitor NU7441 also increases I-SceI-induced mNHEJ to the same level in both ATM -/- H2AX -/- H2AX cells and ATM -/- H2AX -/- EV cells, in both of which H2AX dependent NHEJ is inactivated, substantiating the previous observation that DNA-PKcs suppresses H2AX independent mNHEJ (XREF_SUPPLEMENTARY).	45	49	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DNA-PKcs	DNA-PKcs	DNA-PKcs	H2AX	H2AX	H2AX	45	46	47	48
Moreover , the ability of prolactin to activate nuclear PKC was inhibited totally by a monoclonal antibody to the rat liver prolactin receptor , implicating a prolactin receptor mediated activation process .	Moreover, the ability of prolactin to activate nuclear PKC was inhibited totally by a monoclonal antibody to the rat liver prolactin receptor, implicating a prolactin receptor mediated activation process.	3	30	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	prolactin	prolactin	prolactin	prolactin receptor	prolactin receptor	prolactin receptor	5	6	26	28
These data suggest that inhibition of Ptch by Shh is able to induce nuclear localisation of Ccnb1 that mirrors the effect of Ptch inactivation 20 , independent of Smo signaling , consistent with activation of non canonical Hh signaling .	These data suggest that inhibition of Ptch by Shh is able to induce nuclear localisation of Ccnb1 that mirrors the effect of Ptch inactivation 20, independent of Smo signaling, consistent with activation of non canonical Hh signaling.	4	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ptch	Ptch	Ptch	Ccnb1	Ccnb1	Ccnb1	6	7	16	17
To examine whether the PI3K and Akt pathway regulates endoglin shedding , HUVEC were infected with adenoviruses encoding phosphatase and tensin homolog ( PTEN ) , the phosphatase that inhibits PI3K signalling ( AdPTEN ) or inactive PTEN ( AdPTEN dn ) 32 .	To examine whether the PI3K and Akt pathway regulates endoglin shedding, HUVEC were infected with adenoviruses encoding phosphatase and tensin homolog (PTEN), the phosphatase that inhibits PI3K signalling (AdPTEN) or inactive PTEN (AdPTEN dn) 32.	18	40	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	PTEN	PTEN	PTEN	18	22	37	38
XIAP ( X Linked Inhibitor of Apoptosis ) , an anti-apoptotic protein , is involved in mono- and poly-ubiquitination of PTEN and knockdown of XIAP prevented nuclear translocation of PTEN .	XIAP (X Linked Inhibitor of Apoptosis), an anti-apoptotic protein, is involved in mono- and poly-ubiquitination of PTEN and knockdown of XIAP prevented nuclear translocation of PTEN.	18	30	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	poly-ubiquitination of PTEN	pten	PTEN	PTEN	pten	20	21	29	30
Endogenous phosphorylation of certain Pten residues , such as Serine 380 , can inhibit Pten activity and permit Akt driven proliferation XREF_BIBR XREF_BIBR .	Endogenous phosphorylation of certain Pten residues, such as Serine 380, can inhibit Pten activity and permit Akt driven proliferation XREF_BIBR XREF_BIBR.	1	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pten	phosphorylation of certain Pten residues, such as Serine 380	pten	Pten	Pten	pten	4	5	14	15
Moreover , we demonstrated that AFP promotes the ubiquitination of PTEN and accelerates PTEN degradation .	Moreover, we demonstrated that AFP promotes the ubiquitination of PTEN and accelerates PTEN degradation.	5	14	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	AFP promotes the ubiquitination of PTEN	pten	PTEN	PTEN	pten	10	11	13	14
Leptin promotes phosphorylation of PTEN at multiple sites in the C-terminal region and thus inhibiting the phosphatase activity of PTEN .	Leptin promotes phosphorylation of PTEN at multiple sites in the C-terminal region and thus inhibiting the phosphatase activity of PTEN.	0	20	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	Leptin promotes phosphorylation of PTEN	pten	PTEN	PTEN	pten	4	5	19	20
8 NEDD4-1 catalyzes PTEN polyubiquitination and degradation decreasing the cytoplasmic PTEN in carcinogenesis .	8 NEDD4-1 catalyzes PTEN polyubiquitination and degradation decreasing the cytoplasmic PTEN in carcinogenesis.	1	12	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	NEDD4-1 catalyzes PTEN polyubiquitination	pten	PTEN	PTEN	pten	3	4	10	11
The acetyltransferase P300 and CBP associated factor ( PCAF ) has been demonstrated to acetylate PTEN at Lys125 and Lys128 sites , which , in turn , negatively regulate PTEN catalytic activity .	The acetyltransferase P300 and CBP associated factor (PCAF) has been demonstrated to acetylate PTEN at Lys125 and Lys128 sites, which, in turn, negatively regulate PTEN catalytic activity.	2	31	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	P300 and CBP associated factor (PCAF) has been demonstrated to acetylate PTEN at Lys125 and Lys128	pten	PTEN	PTEN	pten	15	16	29	30
We found that decreased PTEN protein levels in C32TG cells overexpressing PTEN correlated with a decrease in the levels of CDC2 tyrosine 15 phosphorylation .	We found that decreased PTEN protein levels in C32TG cells overexpressing PTEN correlated with a decrease in the levels of CDC2 tyrosine 15 phosphorylation.	4	12	overexpressing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN protein levels	pten	PTEN	PTEN	pten	4	5	11	12
We applied PTEN targeting siRNA ( si-PTEN ) to successfully knockdown PTEN expression as indicated by decreased PTEN expression and increased AKT phosphorylation .	We applied PTEN targeting siRNA (si-PTEN) to successfully knockdown PTEN expression as indicated by decreased PTEN expression and increased AKT phosphorylation.	2	7	targeting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN	PTEN	si-PTEN	si-PTEN	si-PTEN	2	3	6	7
Stimulation of RPTPbeta polymerization results in increased tyrosine phosphorylation of PTEN that inhibits PTEN activity , thereby leading to enhanced AKT stimulation .	Stimulation of RPTPbeta polymerization results in increased tyrosine phosphorylation of PTEN that inhibits PTEN activity, thereby leading to enhanced AKT stimulation.	7	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	tyrosine phosphorylation of PTEN	pten	PTEN	PTEN	pten	10	11	13	14
Collectively , the data support the concept that reduced SMC PTEN expression promotes SMC dedifferentiation and PTEN is depleted during atherosclerosis progression .	Collectively, the data support the concept that reduced SMC PTEN expression promotes SMC dedifferentiation and PTEN is depleted during atherosclerosis progression.	10	17	promotes	Positive_activation_syntax_5_verb	Positive_activation	Negative_activation	PTEN	PTEN expression	pten	PTEN	PTEN	pten	10	11	16	17
As phosphorylation of PTEN by LKB1 inhibits the function of PTEN [ XREF_BIBR , XREF_BIBR ] , and as 4-HNE inhibits LKB1 [ XREF_BIBR , XREF_BIBR ] , high 4-HNE would result in high autophagy ( branch 3 in XREF_FIG ) .	As phosphorylation of PTEN by LKB1 inhibits the function of PTEN [XREF_BIBR, XREF_BIBR], and as 4-HNE inhibits LKB1 [XREF_BIBR, XREF_BIBR], high 4-HNE would result in high autophagy (branch 3 in XREF_FIG).	1	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	phosphorylation of PTEN	pten	PTEN	PTEN	pten	3	4	10	11
Thus , phosphorylation of PTEN at Ser 370 is adequate to inhibit PTEN lipid phosphatase activity and increase PtdIns ( 3,4,5 ) P 3 in N29/4 cells but is not sufficient per se for efficacious transmission of the leptin signal to F-actin .	Thus, phosphorylation of PTEN at Ser 370 is adequate to inhibit PTEN lipid phosphatase activity and increase PtdIns (3,4,5) P 3 in N29/4 cells but is not sufficient per se for efficacious transmission of the leptin signal to F-actin.	2	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	phosphorylation of PTEN at Ser 370	pten	PTEN	PTEN	pten	4	5	12	13
A well-known PTEN regulator CK2 is over-expressed and hyper-activated in CLL and CK2 blockade decreased PTEN phosphorylation , restoring PTEN activity .	A well-known PTEN regulator CK2 is over-expressed and hyper-activated in CLL and CK2 blockade decreased PTEN phosphorylation, restoring PTEN activity.	12	20	restoring	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	CK2 blockade decreased PTEN phosphorylation	pten	PTEN	PTEN	pten	15	16	19	20
PTEN is a negative regulator of the PI3K and Akt pathway , and PTEN phosphorylation by ROCK1 stimulates PTEN phosphatase activity [ XREF_BIBR ] .	PTEN is a negative regulator of the PI3K and Akt pathway, and PTEN phosphorylation by ROCK1 stimulates PTEN phosphatase activity [XREF_BIBR].	13	22	stimulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PTEN phosphorylation	pten	PTEN	PTEN	pten	13	14	18	19
Simultaneously , intermedin increased phosphatase and tensin homolog ( PTEN ) protein levels by increasing PTEN phosphorylation and inhibiting ubiquitin mediated PTEN degradation .	Simultaneously, intermedin increased phosphatase and tensin homolog (PTEN) protein levels by increasing PTEN phosphorylation and inhibiting ubiquitin mediated PTEN degradation.	15	22	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN phosphorylation	pten	PTEN	PTEN	pten	15	16	21	22
Also , EF24 activated the phosphorylated PTEN and marginally up-regulated total PTEN expression through the inhibition of ubiquitin mediated PTEN degradation .	Also, EF24 activated the phosphorylated PTEN and marginally up-regulated total PTEN expression through the inhibition of ubiquitin mediated PTEN degradation.	2	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	EF24 activated the phosphorylated PTEN and marginally up-regulated total PTEN expression	pten	PTEN	PTEN	pten	11	12	19	20
XIAP knockdown reduces constitutive mono- and polyubiquitination of PTEN , increases PTEN protein levels , and prevents nuclear accumulation of PTEN .	XIAP knockdown reduces constitutive mono- and polyubiquitination of PTEN, increases PTEN protein levels, and prevents nuclear accumulation of PTEN.	0	14	increases	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	PTEN	XIAP knockdown reduces constitutive mono- and polyubiquitination of PTEN	pten	PTEN	PTEN protein levels	pten	8	9	11	12
In many human tumors , there is loss of function or mutations in PTEN .	In many human tumors, there is loss of function or mutations in PTEN.	6	14	is loss	Negative_activation_copula_1	Positive_activation	Negative_activation	PTEN	loss of function or mutations in PTEN	pten	PTEN	PTEN	pten	13	14	13	14
The study further showed that treatment of mice with rosiglitazone , an activator of PPARgamma , could largely restore PTEN levels and attenuate PH suggesting the involvement of PTEN in the progression of vascular remodeling .	The study further showed that treatment of mice with rosiglitazone, an activator of PPARgamma, could largely restore PTEN levels and attenuate PH suggesting the involvement of PTEN in the progression of vascular remodeling.	14	29	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PPARgamma, could largely restore PTEN levels	pten	PTEN	PTEN	pten	19	20	28	29
Coexpression of PTEN with activated Src reduces the stability of PTEN .	Coexpression of PTEN with activated Src reduces the stability of PTEN.	0	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	Coexpression of PTEN	pten	PTEN	PTEN	pten	2	3	10	11
We further unveiled that PRL3 activated Akt signaling by dephosphorylating phosphatase and tensin homolog at tyrosine residue , thus reducing phosphatase and tensin homolog protein .	We further unveiled that PRL3 activated Akt signaling by dephosphorylating phosphatase and tensin homolog at tyrosine residue, thus reducing phosphatase and tensin homolog protein.	4	24	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	phosphatase and tensin homolog	PRL3 activated Akt signaling by dephosphorylating phosphatase and tensin homolog at tyrosine residue	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	10	14	20	24
These data suggest that phosphorylation of the PTEN tail suppresses the activity of PTEN by controlling the recruitment of PTEN into the PTEN associated complex .	These data suggest that phosphorylation of the PTEN tail suppresses the activity of PTEN by controlling the recruitment of PTEN into the PTEN associated complex.	4	20	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	phosphorylation of the PTEN	pten	PTEN	PTEN	pten	7	8	19	20
A recent study indicates that PS down regulates miR-17 , -20 a , -106 a , and -106 b while increasing PTEN levels and apoptosis in prostate cancer cells , in that PS reverses PTEN by regulating these miRs [ XREF_BIBR ] .	A recent study indicates that PS down regulates miR-17, -20 a, -106 a, and -106 b while increasing PTEN levels and apoptosis in prostate cancer cells, in that PS reverses PTEN by regulating these miRs [XREF_BIBR].	21	35	reverses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN levels	pten	PTEN	PTEN	pten	21	22	34	35
PTEN phosphorylation at Ser380 , Ser385 , Thr382 , and Thr383 reduces its phosphatase activity by moving PTEN from the intracellular membrane level to the cytosol .	PTEN phosphorylation at Ser380, Ser385, Thr382, and Thr383 reduces its phosphatase activity by moving PTEN from the intracellular membrane level to the cytosol.	0	22	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN phosphorylation at Ser380	pten	PTEN	PTEN	pten	0	1	17	18
In all , co-expression of PDZK1 and PTEN-wt can reduce the level of PTEN phosphorylation and increase the tumor suppressor function of PTEN .	In all, co-expression of PDZK1 and PTEN-wt can reduce the level of PTEN phosphorylation and increase the tumor suppressor function of PTEN.	3	23	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	co-expression of PDZK1 and PTEN-wt can reduce the level of PTEN phosphorylation	pten	PTEN	PTEN	pten	13	14	22	23
E2F3 , MCL-1 , EZH2 , MTDH , and PTEN were downregulated by miR-26a and the PTEN ( phosphatase and tensin homolog ) protein was also reduced after miR-26a overexpression .	E2F3, MCL-1, EZH2, MTDH, and PTEN were downregulated by miR-26a and the PTEN (phosphatase and tensin homolog) protein was also reduced after miR-26a overexpression.	0	26	downregulated	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	PTEN	PTEN	PTEN	18	22	9	10
Having shown that reexpression of catalytically dead PTEN suppresses invasion in PTEN null cancer cells , we tested whether cells endogenously expressing a PTEN mutant that lacks lipid phosphatase activity would be more invasive after PTEN knockdown .	Having shown that reexpression of catalytically dead PTEN suppresses invasion in PTEN null cancer cells, we tested whether cells endogenously expressing a PTEN mutant that lacks lipid phosphatase activity would be more invasive after PTEN knockdown.	3	14	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	reexpression of catalytically dead PTEN	pten	PTEN	PTEN	pten	7	8	11	12
Although a previous study suggested that the phosphorylation of PTEN at S370 and S380 inhibits certain PTEN functions , how these phosphorylation events affect enzymatic activity is unclear XREF_BIBR .	Although a previous study suggested that the phosphorylation of PTEN at S370 and S380 inhibits certain PTEN functions, how these phosphorylation events affect enzymatic activity is unclear XREF_BIBR.	7	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	phosphorylation of PTEN at S370 and S380	pten	PTEN	PTEN	pten	9	10	16	17
In addition , leptin enhanced phosphorylation of the lipid phosphatase PTEN which inhibits PTEN function and elevates PtdIns ( 3,4,5 ) P ( 3 ) levels .	In addition, leptin enhanced phosphorylation of the lipid phosphatase PTEN which inhibits PTEN function and elevates PtdIns (3,4,5) P (3) levels.	3	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	leptin enhanced phosphorylation of the lipid phosphatase PTEN	pten	PTEN	PTEN	pten	10	11	13	14
Taken together , these results indicate that E2 induces PTEN phosphorylation , increases PTEN protein stability and decreases PTEN lipid phosphatase activity .	Taken together, these results indicate that E2 induces PTEN phosphorylation, increases PTEN protein stability and decreases PTEN lipid phosphatase activity.	7	21	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	E2 induces PTEN phosphorylation	pten	PTEN	PTEN	pten	9	10	18	19
It is known that phosphorylation of PTEN at the C-terminal tail suppresses the activity of PTEN .	It is known that phosphorylation of PTEN at the C-terminal tail suppresses the activity of PTEN.	4	16	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	phosphorylation of PTEN	pten	PTEN	PTEN	pten	6	7	15	16
We showed previously that phosphorylation of the PTEN tail negatively regulates PTEN activity .	We showed previously that phosphorylation of the PTEN tail negatively regulates PTEN activity.	4	12	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	phosphorylation of the PTEN	pten	PTEN	PTEN	pten	7	8	11	12
Phosphorylation of PTEN at these residues is known to suppress the activity of PTEN .	Phosphorylation of PTEN at these residues is known to suppress the activity of PTEN.	0	14	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	Phosphorylation of PTEN	pten	PTEN	PTEN	pten	2	3	13	14
Phosphorylation of PTEN on its C-terminal tail has also been shown to negatively regulate PTEN activity at the protein levels .	Phosphorylation of PTEN on its C-terminal tail has also been shown to negatively regulate PTEN activity at the protein levels.	0	15	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	Phosphorylation of PTEN	pten	PTEN	PTEN	pten	2	3	14	15
The HECT-domain protein neural precursor cell expressed , developmentally down-regulated 4-1 ( NEDD4-1 ) has been identified as the E3 ligase that catalyzes PTEN polyubiquitylation and triggers proteasomal degradation of PTEN .	The HECT-domain protein neural precursor cell expressed, developmentally down-regulated 4-1 (NEDD4-1) has been identified as the E3 ligase that catalyzes PTEN polyubiquitylation and triggers proteasomal degradation of PTEN.	19	31	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	E3 ligase that catalyzes PTEN polyubiquitylation	pten	PTEN	PTEN	pten	23	24	30	31
Nedd4-1 is an HECT E3 ubiquitin ligase that is known to ubiquitinate the tumor suppressor pTEN and causes proteasomal degradation and nuclear translocation of pTEN [ XREF_BIBR , XREF_BIBR ] .	Nedd4-1 is an HECT E3 ubiquitin ligase that is known to ubiquitinate the tumor suppressor pTEN and causes proteasomal degradation and nuclear translocation of pTEN [XREF_BIBR, XREF_BIBR].	0	28	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	pTEN	Nedd4-1 is an HECT E3 ubiquitin ligase that is known to ubiquitinate the tumor suppressor pTEN	pten	pTEN	pTEN	pten	15	16	24	25
In addition to the key players mentioned above , FSS also upregulates endothelial microRNA-21 which suppresses its target gene phosphatase and tensin homolog ( PTEN ) , contributing to increased eNOS phosphorylation and NO production .	In addition to the key players mentioned above, FSS also upregulates endothelial microRNA-21 which suppresses its target gene phosphatase and tensin homolog (PTEN), contributing to increased eNOS phosphorylation and NO production.	15	25	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN	PTEN	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	24	25	19	23
Phosphatase and tensin homolog deleted on chromosome ten ( PTEN ) has been shown to inactivate the phosphatidylinositol 3-kinase ( PI3K )/Akt signaling pathway and the absence of PTEN elevates tau aggregation [ XREF_BIBR , XREF_BIBR ] .	Phosphatase and tensin homolog deleted on chromosome ten (PTEN) has been shown to inactivate the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and the absence of PTEN elevates tau aggregation [XREF_BIBR, XREF_BIBR].	0	29	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	PTEN	PTEN	PTEN	0	4	28	29
First , expression of normal PTEN effectively repressed motility of PTEN expressing U87MG cells , but had no effect on cocultured non-PTEN-expressing U87MG cells .	First, expression of normal PTEN effectively repressed motility of PTEN expressing U87MG cells, but had no effect on cocultured non-PTEN-expressing U87MG cells.	2	11	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	expression of normal PTEN	pten	PTEN	PTEN	pten	5	6	10	11
Therefore , inhibition of the PTEN phosphorylation by the Casein kinase 2 results in enhanced PTEN activity and a subsequent suppression in AKT function .	Therefore, inhibition of the PTEN phosphorylation by the Casein kinase 2 results in enhanced PTEN activity and a subsequent suppression in AKT function.	5	16	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN phosphorylation	pten	PTEN	PTEN	pten	5	6	15	16
There was loss of PTEN with staining in less than 20 % of tumor cells .	There was loss of PTEN with staining in less than 20% of tumor cells.	1	5	was loss	Negative_activation_copula_1	Positive_activation	Negative_activation	PTEN	loss of PTEN	pten	PTEN	PTEN	pten	4	5	4	5
As shown above , by competitively inhibiting CK2 kinase activity , TBB reduced CK2 mediated PTEN phosphorylation and restored PTEN protein turnover rate ( XREF_SUPPLEMENTARY ) to reflect its physiologically reduced mRNA levels in GXP GBMs ( XREF_SUPPLEMENTARY ) .	As shown above, by competitively inhibiting CK2 kinase activity, TBB reduced CK2 mediated PTEN phosphorylation and restored PTEN protein turnover rate (XREF_SUPPLEMENTARY) to reflect its physiologically reduced mRNA levels in GXP GBMs (XREF_SUPPLEMENTARY).	11	22	restored	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	TBB reduced CK2 mediated PTEN phosphorylation	pten	PTEN	PTEN	pten	15	16	19	20
This effect of leptin requires NMDAR activation and is associated with an increase in cytoplasmic PtdIns ( 3,4,5 ) P 3 levels through enhanced phosphorylation of the lipid phosphatase PTEN ( phosphatase and tensin homologue deleted on chromosome 10 ) , which inhibits PTEN function [ XREF_BIBR ] .	This effect of leptin requires NMDAR activation and is associated with an increase in cytoplasmic PtdIns (3,4,5) P 3 levels through enhanced phosphorylation of the lipid phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10), which inhibits PTEN function [XREF_BIBR].	24	44	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	phosphorylation of the lipid phosphatase PTEN	pten	PTEN	PTEN	pten	29	30	43	44
As shown in XREF_SUPPLEMENTARY , the stable expression of the miR-130 family molecules upregulated PTEN phosphorylation at Ser 380 consistent with the increased Akt phosphorylation levels ( XREF_FIG ) , indicating miR-130 family suppresses PTEN activation .	As shown in XREF_SUPPLEMENTARY, the stable expression of the miR-130 family molecules upregulated PTEN phosphorylation at Ser 380 consistent with the increased Akt phosphorylation levels (XREF_FIG), indicating miR-130 family suppresses PTEN activation.	7	35	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	expression of the miR-130 family molecules upregulated PTEN phosphorylation	pten	PTEN	PTEN	pten	14	15	34	35
It was demonstrated that the lncRNA phosphatase and tensin homolog ( PTEN ) pseudogene1 ( PTENpg1 ) sequesters various PTEN targeting miRNAs , thereby indirectly regulating the PTEN mRNA level .	It was demonstrated that the lncRNA phosphatase and tensin homolog (PTEN) pseudogene1 (PTENpg1) sequesters various PTEN targeting miRNAs, thereby indirectly regulating the PTEN mRNA level.	4	20	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	PTEN	PTEN	PTEN	6	10	19	20
A previous study suggested that the induction of p-PTEN induces a loss of PTEN activity , resulting in the activation of the AKT signaling pathway .	A previous study suggested that the induction of p-PTEN induces a loss of PTEN activity, resulting in the activation of the AKT signaling pathway.	6	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p-PTEN	p-PTEN	p-PTEN	PTEN	PTEN	PTEN	8	9	13	14
While some findings indicate that phosphorylation of PTEN improves stability but reduces PTEN function , others have shown that the loss of phospho-PTEN in migrating cells leads to the activation of Akt [ XREF_BIBR ] .	While some findings indicate that phosphorylation of PTEN improves stability but reduces PTEN function, others have shown that the loss of phospho-PTEN in migrating cells leads to the activation of Akt [XREF_BIBR].	5	13	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	phosphorylation of PTEN	pten	PTEN	PTEN	pten	7	8	12	13
In conclusion , our findings indicate that PTEN overexpression and lithium treatment cooperate to reduce the malignancy of CRC cells and highlight lithium and PTEN as potential candidates for studies to identify new therapeutic approaches for CRC treatment .	In conclusion, our findings indicate that PTEN overexpression and lithium treatment cooperate to reduce the malignancy of CRC cells and highlight lithium and PTEN as potential candidates for studies to identify new therapeutic approaches for CRC treatment.	7	25	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN overexpression	pten	PTEN	PTEN	pten	7	8	24	25
Recent findings from Hamamoto ' s group showed that SMYD2 mediated PTEN methylation at lysine 313 increased phosphorylation at serine 380 of PTEN , consequently inactivated PTEN and activated AKT activity and promoted cell growth and proliferation XREF_BIBR .	Recent findings from Hamamoto 's group showed that SMYD2 mediated PTEN methylation at lysine 313 increased phosphorylation at serine 380 of PTEN, consequently inactivated PTEN and activated AKT activity and promoted cell growth and proliferation XREF_BIBR.	9	30	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	SMYD2 mediated PTEN methylation at lysine 313 increased phosphorylation at serine 380 of PTEN	pten	PTEN	PTEN	pten	22	23	26	27
XREF_BIBR , XREF_BIBR In our current study , we find that PTEN expression is negatively regulated by TGFbeta , possibly via its inhibition of the PTEN promoter .	XREF_BIBR, XREF_BIBR In our current study, we find that PTEN expression is negatively regulated by TGFbeta, possibly via its inhibition of the PTEN promoter.	11	26	inhibition	Negative_activation_syntax_6_noun	Positive_activation	Negative_activation	PTEN	PTEN expression is negatively regulated by TGFbeta	pten	PTEN	PTEN	pten	11	12	25	26
In addition to the above mentioned proteins , FSS also upregulates endothelial microRNA-21 which suppresses its target gene phosphatase and tensin homolog ( PTEN ) , contributing to increased eNOS phosphorylation and NO production .	In addition to the above mentioned proteins, FSS also upregulates endothelial microRNA-21 which suppresses its target gene phosphatase and tensin homolog (PTEN), contributing to increased eNOS phosphorylation and NO production.	14	24	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN	PTEN	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	23	24	18	22
Inhibition of PTEN phosphorylation by the CK2 inhibitor 5,6-dichloro-1-beta-d-ribofuranosyl-benzimidazole also diminished the PTEN protein content .	Inhibition of PTEN phosphorylation by the CK2 inhibitor 5,6-dichloro-1-beta-d-ribofuranosyl-benzimidazole also diminished the PTEN protein content.	0	14	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	Inhibition of PTEN phosphorylation by the CK2 inhibitor	pten	PTEN	PTEN	pten	2	3	12	13
As PRL-3 decreased the expression of PTEN and increased the ratio of p-PTEN and PTEN to a greater extent in the SGC7901 cells , we chose the SGC7901 GC cell line to perform the next experiment .	As PRL-3 decreased the expression of PTEN and increased the ratio of p-PTEN and PTEN to a greater extent in the SGC7901 cells, we chose the SGC7901 GC cell line to perform the next experiment.	1	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	PRL-3 decreased the expression of PTEN	pten	p-PTEN	p-PTEN	p-pten	6	7	12	13
More and more studies have shown that a loss of phosphatase and tensin homolog ( PTEN ) expression is associated with TKI resistance .	More and more studies have shown that a loss of phosphatase and tensin homolog (PTEN) expression is associated with TKI resistance.	8	18	loss	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog (PTEN) expression	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	10	14	10	14
The up-regulated PTEN expression can be inhibited by PPARgamma antagonist suggesting the up-regulated PTEN gene and protein expressions were mediated by PPARgamma signalling .	The up-regulated PTEN expression can be inhibited by PPARgamma antagonist suggesting the up-regulated PTEN gene and protein expressions were mediated by PPARgamma signalling.	2	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN expression	pten	PTEN	PTEN	pten	2	3	13	14
PTEN ( phosphatase and tensin homologue deleted from chromosome 10 ) is known to exert phosphatase activity by binding to E-cadherin complexes via beta-catenin , and recent studies suggest that phosphorylation of the PTEN C-terminus tail might cause loss of this PTEN phosphatase activity .	PTEN (phosphatase and tensin homologue deleted from chromosome 10) is known to exert phosphatase activity by binding to E-cadherin complexes via beta-catenin, and recent studies suggest that phosphorylation of the PTEN C-terminus tail might cause loss of this PTEN phosphatase activity.	30	43	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	phosphorylation of the PTEN	pten	PTEN	PTEN	pten	33	34	41	42
Phosphorylation of PTEN at S380 prevents PTEN from binding to its PDZ domain containing partners , such as the p85 subunit of PI3K , and localizing to the plasma membrane [ XREF_BIBR ] .	Phosphorylation of PTEN at S380 prevents PTEN from binding to its PDZ domain containing partners, such as the p85 subunit of PI3K, and localizing to the plasma membrane [XREF_BIBR].	0	7	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	Phosphorylation of PTEN at S380	pten	PTEN	PTEN	pten	2	3	6	7
Contrary to previous findings , there was no consistent loss of PTEN in these primary MCL cells ( XREF_FIG ) .	Contrary to previous findings, there was no consistent loss of PTEN in these primary MCL cells (XREF_FIG).	6	16	was no consistent loss	Negative_activation_copula_1	Positive_activation	Negative_activation	PTEN	loss of PTEN	pten	PTEN	PTEN	pten	11	12	11	12
Since PTEN is a RPTPbeta substrate , this resulted in increased tyrosine phosphorylation of PTEN which attenuated PTEN enzymatic activity thereby leading to increased AKT phosphorylation .	Since PTEN is a RPTPbeta substrate, this resulted in increased tyrosine phosphorylation of PTEN which attenuated PTEN enzymatic activity thereby leading to increased AKT phosphorylation.	11	19	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	tyrosine phosphorylation of PTEN	pten	PTEN	PTEN	pten	14	15	17	18
There was complete loss of PTEN in 13/111 , 12 % of all cases .	There was complete loss of PTEN in 13/111, 12% of all cases.	1	6	was complete loss	Negative_activation_copula_1	Positive_activation	Negative_activation	PTEN	loss of PTEN	pten	PTEN	PTEN	pten	5	6	5	6
In the present study , we found that AFP promotes the ubiquitination of PTEN and may accelerate the degradation of PTEN via proteasome .	In the present study, we found that AFP promotes the ubiquitination of PTEN and may accelerate the degradation of PTEN via proteasome.	8	22	accelerate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	AFP promotes the ubiquitination of PTEN	pten	PTEN	PTEN	pten	13	14	20	21
Phosphorylation of PTEN ' s unstructured C-terminal tail reduces PTEN activity , and this result was interpreted as a blockage of PTEN ' s membrane binding interface through this tail .	Phosphorylation of PTEN 's unstructured C-terminal tail reduces PTEN activity, and this result was interpreted as a blockage of PTEN 's membrane binding interface through this tail.	0	14	reduces	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	PTEN	Phosphorylation of PTEN	pten	PTEN	PTEN	pten	2	3	9	10
In this study , we have found that expression of Rak , a PTEN interacting protein , strongly correlated with PTEN protein levels in breast cancer tissues , and we demonstrated that Rak positively regulates PTEN protein stability through phosphorylation of PTEN on Tyr 336 , which in turn prevents PTEN from ubiquitination and degradation .	In this study, we have found that expression of Rak, a PTEN interacting protein, strongly correlated with PTEN protein levels in breast cancer tissues, and we demonstrated that Rak positively regulates PTEN protein stability through phosphorylation of PTEN on Tyr 336, which in turn prevents PTEN from ubiquitination and degradation.	39	54	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	phosphorylation of PTEN on Tyr 336	pten	PTEN	PTEN	pten	41	42	50	51
Chen and colleagues reported that ETS positive cancers that lose PTEN exhibit partial restoration of androgen receptor transcription resulting in early-onset invasive prostate cancer , in contrast to the suppression of androgen receptor when there is loss of PTEN in ETS negative samples .	Chen and colleagues reported that ETS positive cancers that lose PTEN exhibit partial restoration of androgen receptor transcription resulting in early-onset invasive prostate cancer, in contrast to the suppression of androgen receptor when there is loss of PTEN in ETS negative samples.	35	42	is loss	Negative_activation_copula_1	Positive_activation	Negative_activation	PTEN	loss of PTEN	pten	PTEN	PTEN	pten	38	39	38	39
Notably , 20 % ( 74/367 ) of the discordant cases ( loss of PTEN protein expression by IHC and normal PTEN by FISH analysis ) showed heterogeneous PTEN protein loss in some , but not all , sampled tumor glands , compared to only 11 % ( 121/1087 ) of cases with PTEN IHC loss overall which showed heterogeneous PTEN loss .	Notably, 20% (74/367) of the discordant cases (loss of PTEN protein expression by IHC and normal PTEN by FISH analysis) showed heterogeneous PTEN protein loss in some, but not all, sampled tumor glands, compared to only 11% (121/1087) of cases with PTEN IHC loss overall which showed heterogeneous PTEN loss.	10	24	loss	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	PTEN	PTEN protein expression by IHC	pten	PTEN	PTEN	pten	14	15	21	22
Polyubiquitination of PTEN results in decreased protein stability leading to PTEN degradation by proteasome mediated decay mechanisms [ XREF_BIBR ] , whereas monoubiquitination of PTEN on Lys13 and Lys289 promotes the nuclear transport of PTEN [ XREF_BIBR , XREF_BIBR ] .	Polyubiquitination of PTEN results in decreased protein stability leading to PTEN degradation by proteasome mediated decay mechanisms [XREF_BIBR], whereas monoubiquitination of PTEN on Lys13 and Lys289 promotes the nuclear transport of PTEN [XREF_BIBR, XREF_BIBR].	22	38	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTEN	monoubiquitination of PTEN on Lys13 and Lys289	pten	PTEN	PTEN	pten	24	25	34	35
Recent studies have shown that loss of Pten expression represses androgen action in Pten knockout mice XREF_BIBR , XREF_BIBR .	Recent studies have shown that loss of Pten expression represses androgen action in Pten knockout mice XREF_BIBR, XREF_BIBR.	7	15	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pten	Pten expression	pten	Pten	Pten	pten	7	8	13	14
Hes1 can inhibit PTEN effectively via binding to its promoter , PTEN transcription will increase when shRNA silence of Hes1 is performed .	Hes1 can inhibit PTEN effectively via binding to its promoter, PTEN transcription will increase when shRNA silence of Hes1 is performed.	2	15	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN transcription	pten	PTEN	PTEN	pten	11	12	3	4
However , Adv-GFP-wtFRNK gene transfer substantially reduced FAK , PYK2 and paxillin phosphorylation ( n = 4 animals ) , indicating that FRNK overexpression early in the course of balloon injury can inhibit both FAK and PYK2 activation and downstream signaling in vivo .	However, Adv-GFP-wtFRNK gene transfer substantially reduced FAK, PYK2 and paxillin phosphorylation (n = 4 animals), indicating that FRNK overexpression early in the course of balloon injury can inhibit both FAK and PYK2 activation and downstream signaling in vivo.	22	37	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	FRNK overexpression	frnk	FAK	FAK	fak	22	23	34	35
Exogenous FRNK expression abrogates the enhanced FAK activation and cell migration in primary IPF lung fibroblasts .	Exogenous FRNK expression abrogates the enhanced FAK activation and cell migration in primary IPF lung fibroblasts.	1	7	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	FRNK expression	frnk	FAK	FAK	fak	1	2	6	7
We previously reported that the noncatalytic carboxyl-terminal protein binding domain of focal adhesion kinase ( FAK ) is expressed as a separate protein termed FAK related nonkinase ( FRNK ) and that ectopic expression of FRNK can attenuate FAK activity and integrin dependent signaling ( A. Richardson and J. T. Parsons , Nature 380:538-540, 1996 ) .	We previously reported that the noncatalytic carboxyl-terminal protein binding domain of focal adhesion kinase (FAK) is expressed as a separate protein termed FAK related nonkinase (FRNK) and that ectopic expression of FRNK can attenuate FAK activity and integrin dependent signaling (A. Richardson and J. T. Parsons, Nature 380:538-540, 1996).	33	39	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	expression of FRNK	frnk	FAK	FAK	fak	35	36	38	39
Interestingly , using a tamoxifen inducible , Cre mediated FAK deletion model to inactivate FAK from endothelium of blood vessels in adult mice , it was noted that the loss of FAK function is not lethal due to the functional compensation of Pyk2 ( FAK related protein proline rich tyrosine kinase 2 ) in which endothelial cells in blood vessels in adult mice , it was noted that the loss of FAK function or cultured endothelial cells have the adaptive capacity of switching to Pyk2 dependent signaling to maintain the lost FAK function .	Interestingly, using a tamoxifen inducible, Cre mediated FAK deletion model to inactivate FAK from endothelium of blood vessels in adult mice, it was noted that the loss of FAK function is not lethal due to the functional compensation of Pyk2 (FAK related protein proline rich tyrosine kinase 2) in which endothelial cells in blood vessels in adult mice, it was noted that the loss of FAK function or cultured endothelial cells have the adaptive capacity of switching to Pyk2 dependent signaling to maintain the lost FAK function.	7	15	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	Cre mediated FAK	fak	FAK	FAK	fak	9	10	14	15
These results suggest that the localization of FAK to FAs is required for its participation in antiviral signaling and that FRNK expression acts in a dominant negative manner to attenuate FAK mediated innate immune signaling .	These results suggest that the localization of FAK to FAs is required for its participation in antiviral signaling and that FRNK expression acts in a dominant negative manner to attenuate FAK mediated innate immune signaling.	20	31	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	FRNK expression	frnk	FAK	FAK	fak	20	21	30	31
siRNA was used to down-regulate total FAK protein while dominant negative , kinase deficient FAK was expressed to block FAK signaling .	siRNA was used to down-regulate total FAK protein while dominant negative, kinase deficient FAK was expressed to block FAK signaling.	9	20	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK was expressed	fak	FAK	FAK	fak	14	15	19	20
Interestingly , XREF_BIBR observed an unexpected enhancement of soft agar colony formation in v-Src-transformed cells lacking FAK that was subsequently prevented by FAK reexpression , suggesting the possibility that FAK may play a negative regulatory role in transformation .	Interestingly, XREF_BIBR observed an unexpected enhancement of soft agar colony formation in v-Src-transformed cells lacking FAK that was subsequently prevented by FAK reexpression, suggesting the possibility that FAK may play a negative regulatory role in transformation.	15	24	prevented	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FAK	FAK reexpression	fak	FAK	FAK	fak	22	23	16	17
The results suggest that FRNK limits growth and survival signaling pathways by binding directly to FAK in an inhibitory complex , and this inhibition is relieved by phosphorylation of FRNK at S217 .	The results suggest that FRNK limits growth and survival signaling pathways by binding directly to FAK in an inhibitory complex, and this inhibition is relieved by phosphorylation of FRNK at S217.	4	32	relieved	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FRNK	phosphorylation of FRNK at S217	frnk	FRNK	FRNK	frnk	29	30	4	5
XREF_BIBR also observed stimulation of I Cl , swell in neonatal rat myocytes when FAK was inhibited by overexpression of FRNK , an endogenous FAK inhibitor .	XREF_BIBR also observed stimulation of I Cl, swell in neonatal rat myocytes when FAK was inhibited by overexpression of FRNK, an endogenous FAK inhibitor.	14	25	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FRNK	overexpression of FRNK	frnk	FAK	FAK	fak	20	21	14	15
Akt IV inhibitor reduced Akt and FAK phosphorylation by 84 +/-6% and 54 +/-3% respectively ( n = 4 , p < 0.001 each ) and blocked pressure activation of FAK and Akt .	Akt IV inhibitor reduced Akt and FAK phosphorylation by 84 +/-6% and 54 +/-3% respectively (n = 4, p < 0.001 each) and blocked pressure activation of FAK and Akt.	0	32	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	Akt IV inhibitor reduced Akt and FAK phosphorylation	fak	FAK	FAK	fak	6	7	30	31
In addition , PTEN dephosphorylates Y397 FAK , which decreases FAK activity .	In addition, PTEN dephosphorylates Y397 FAK, which decreases FAK activity.	3	11	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	PTEN dephosphorylates Y397 FAK	fak	FAK	FAK	fak	6	7	10	11
Similarly , expression of FRNK , an alternatively spliced variant corresponding to the C-terminal portion of FAK , inhibits FAK activation by displacing FAK from the focal adhesion [ XREF_BIBR , XREF_BIBR ] .	Similarly, expression of FRNK, an alternatively spliced variant corresponding to the C-terminal portion of FAK, inhibits FAK activation by displacing FAK from the focal adhesion [XREF_BIBR, XREF_BIBR].	2	20	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	expression of FRNK	frnk	FAK	FAK	fak	4	5	19	20
The ability of these sequences in FRNK to suppress proapoptotic signals in FAT should enable FRNK to be expressed in a regulated fashion and to modulate certain functions of FAK -- for instance cell spreading -- without killing the cells in which it is expressed .	The ability of these sequences in FRNK to suppress proapoptotic signals in FAT should enable FRNK to be expressed in a regulated fashion and to modulate certain functions of FAK -- for instance cell spreading -- without killing the cells in which it is expressed.	4	34	modulate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FRNK	FRNK to suppress proapoptotic signals in FAT should enable FRNK to be expressed	frnk	FAK	FAK	fak	6	7	29	30
Interestingly , it was previously reported that a point mutation in FAK Y925 phosphorylation disrupted FAK ability to promote VEGF expression XREF_BIBR .	Interestingly, it was previously reported that a point mutation in FAK Y925 phosphorylation disrupted FAK ability to promote VEGF expression XREF_BIBR.	11	16	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK Y925 phosphorylation	fak	FAK	FAK	fak	11	12	15	16
In this study , we have shown that FAK is highly phosphorylated in primary Ewing sarcoma tumor samples and that downregulation of FAK by short hairpin RNA and treatment with a FAK selective kinase inhibitor , PF-562271 , impaired growth and colony formation in Ewing sarcoma cell lines .	In this study, we have shown that FAK is highly phosphorylated in primary Ewing sarcoma tumor samples and that downregulation of FAK by short hairpin RNA and treatment with a FAK selective kinase inhibitor, PF-562271, impaired growth and colony formation in Ewing sarcoma cell lines.	8	23	downregulation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	FAK	FAK is highly phosphorylated	fak	FAK	FAK	fak	8	9	22	23
It is interesting that FAK was only degraded by FAK-CD in the presence of neurofibromin in Nf1 +/+ MEF cells , and that neurofibromin co-localizes with FAK around the nucleus .	It is interesting that FAK was only degraded by FAK-CD in the presence of neurofibromin in Nf1 +/+ MEF cells, and that neurofibromin co-localizes with FAK around the nucleus.	4	10	degraded	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FAK-CD	FAK-CD	FAK-CD	FAK	FAK	FAK	9	10	4	5
We have shown that over-expression of FRNK inhibits FAK localization to focal adhesion complexes and promotes endothelial apoptosis .	We have shown that over-expression of FRNK inhibits FAK localization to focal adhesion complexes and promotes endothelial apoptosis.	4	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	over-expression of FRNK	frnk	FAK	FAK	fak	6	7	8	9
Inhibition of FAK by overexpression of FRNK ( Focal adhesion kinase -- Related Non Kinase ) and Src by PP2 significantly reduced migration of prostate cancer cells underlying the importance of FAK and Src signaling in cell motility .	Inhibition of FAK by overexpression of FRNK (Focal adhesion kinase -- Related Non Kinase) and Src by PP2 significantly reduced migration of prostate cancer cells underlying the importance of FAK and Src signaling in cell motility.	0	17	Inhibition	Negative_activation_token_2_noun	Positive_activation	Negative_activation	FRNK	overexpression of FRNK	frnk	FAK	FAK	fak	6	7	2	3
Furthermore , re-expression of FAK may restore the motile phenotypes in FAK negative cells .	Furthermore, re-expression of FAK may restore the motile phenotypes in FAK negative cells.	2	13	restore	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	re-expression of FAK	fak	FAK	FAK	fak	4	5	11	12
FTY720 led to tyrosine dephosphorylation of the focal adhesion kinase ( FAK ) and inhibited the protective FAK and PI3K pathway leading to an activation of caspase 6 .	FTY720 led to tyrosine dephosphorylation of the focal adhesion kinase (FAK) and inhibited the protective FAK and PI3K pathway leading to an activation of caspase 6.	0	20	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FTY720 led to tyrosine dephosphorylation of the focal adhesion kinase (FAK	fak	FAK	FAK	fak	11	12	17	18
Collectively , these data indicate that embryonic cardiac development is exquisitely sensitive to FRNK expression ( and a reduction in FAK activity ) , whereas further postnatal development is FAK independent .	Collectively, these data indicate that embryonic cardiac development is exquisitely sensitive to FRNK expression (and a reduction in FAK activity), whereas further postnatal development is FAK independent.	13	21	reduction	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	FRNK	FRNK expression	frnk	FAK	FAK	fak	13	14	20	21
Previously , we and other groups showed that activation of ErbB family members EGFR , ErbB2 , ErbB3 , and ErbB4 , as well as IGF-1 receptor , induces Tyr dephosphorylation of FAK , p130Cas , and paxillin ; inactivation of FAK ; and increased tumor cell motility , invasion , and metastasis .	Previously, we and other groups showed that activation of ErbB family members EGFR, ErbB2, ErbB3, and ErbB4, as well as IGF-1 receptor, induces Tyr dephosphorylation of FAK, p130Cas, and paxillin; inactivation of FAK; and increased tumor cell motility, invasion, and metastasis.	10	42	inactivation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	FAK	ErbB family members EGFR, ErbB2, ErbB3, and ErbB4, as well as IGF-1 receptor, induces Tyr dephosphorylation of FAK	fak	FAK	FAK	fak	32	33	41	42
Interestingly , Erk activity prevents paxillin from binding FAK as Erk phosphorylates FAK at Ser910 blocking the interaction of FAK with paxillin [ XREF_BIBR ] .	Interestingly, Erk activity prevents paxillin from binding FAK as Erk phosphorylates FAK at Ser910 blocking the interaction of FAK with paxillin [XREF_BIBR].	10	20	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	Erk phosphorylates FAK at Ser910	fak	FAK	FAK	fak	12	13	19	20
We show that inhibition of FAK signalling by expression of FAK or FAK siRNA did not affect cell proliferation or survival in SCC40 and SCC38 cells .	We show that inhibition of FAK signalling by expression of FAK or FAK siRNA did not affect cell proliferation or survival in SCC40 and SCC38 cells.	5	13	signalling	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	FAK	expression of FAK	fak	FAK	FAK	fak	10	11	5	6
Taken together , these data suggest the novel concept that FAK Tyr ( 407 ) phosphorylation negatively regulates the enzymatic and biological activities of FAK .	Taken together, these data suggest the novel concept that FAK Tyr (407) phosphorylation negatively regulates the enzymatic and biological activities of FAK.	10	25	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK Tyr (407) phosphorylation	fak	FAK	FAK	fak	10	11	24	25
These results were corroborated by a later study where FAK activity was down-regulated by CM specific overexpression of FRNK 110 .	These results were corroborated by a later study where FAK activity was down-regulated by CM specific overexpression of FRNK 110.	9	19	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FRNK	overexpression of FRNK	frnk	FAK	FAK	fak	18	19	9	10
FRNK expression mediated by Ad-FRNK abrogated the increased FAK activation ( as detected by decreased Y397 phosphorylation of FAK ) in IPF lung fibroblasts ( n = 2 ) , and also slightly decreased FAK activation in normal lung fibroblasts ( NHL , n = 2 ) ( XREF_FIG ) .	FRNK expression mediated by Ad-FRNK abrogated the increased FAK activation (as detected by decreased Y397 phosphorylation of FAK) in IPF lung fibroblasts (n = 2), and also slightly decreased FAK activation in normal lung fibroblasts (NHL, n = 2) (XREF_FIG).	0	9	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	FRNK expression	frnk	FAK	FAK	fak	0	1	8	9
Our current data show that FAK inhibition with AdFAK-CD in neuroblastoma cells results in a loss of FAK ( Y397 ) phosphorylation and decreased neuroblastoma cell survival .	Our current data show that FAK inhibition with AdFAK-CD in neuroblastoma cells results in a loss of FAK (Y397) phosphorylation and decreased neuroblastoma cell survival.	15	22	loss	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	FAK	FAK (Y397) phosphorylation	fak	FAK	FAK	fak	17	18	17	18
The most important that both microarray data and TaqMan Real-time PCR array data demonstrate significantly decreased expression of FAK in FAKsiRNA cell lines compared to the control group , and these data together with decreased tumorigenesis in vivo support the critical role of FAK signaling in breast tumorigenesis .	The most important that both microarray data and TaqMan Real-time PCR array data demonstrate significantly decreased expression of FAK in FAKsiRNA cell lines compared to the control group, and these data together with decreased tumorigenesis in vivo support the critical role of FAK signaling in breast tumorigenesis.	16	44	support	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	expression of FAK	fak	FAK	FAK	fak	18	19	43	44
We also demonstrated that the dominant negative FAK protein , FAK-CD caused significant detachment and degradation of FAK in Nf1 +/+ MEF cells but not in Nf1 +/+ MEF cells .	We also demonstrated that the dominant negative FAK protein, FAK-CD caused significant detachment and degradation of FAK in Nf1 +/+ MEF cells but not in Nf1 +/+ MEF cells.	8	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK-CD	FAK-CD	FAK-CD	FAK	FAK	FAK	10	11	17	18
Indeed , we found that expression of FRNK ( or inactivation of FAK ) promotes p38 activity and regulates expression of the p38 dependent cell cycle modifier , p27 kip and that pharmacological inhibition of p38 restores DNA synthesis in FRNK expressing cells .	Indeed, we found that expression of FRNK (or inactivation of FAK) promotes p38 activity and regulates expression of the p38 dependent cell cycle modifier, p27 kip and that pharmacological inhibition of p38 restores DNA synthesis in FRNK expressing cells.	5	13	inactivation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	FRNK	expression of FRNK	frnk	FAK	FAK	fak	7	8	12	13
Transient FRNK expression in human 293 cells inhibited exogenous MMP-2 promoter activity and overexpression of wild-type but not catalytically-inactive ( Ala 404 ) MMP-2 rescued v-Src-stimulated Matrigel invasion in the presence of FRNK .	Transient FRNK expression in human 293 cells inhibited exogenous MMP-2 promoter activity and overexpression of wild-type but not catalytically-inactive (Ala 404) MMP-2 rescued v-Src-stimulated Matrigel invasion in the presence of FRNK.	1	33	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	FRNK expression	frnk	FRNK	FRNK	frnk	1	2	32	33
FAK signaling is negatively regulated by expression of a FAK variant containing the C-terminal noncatalytic domain , termed FAK related nonkinase ( FRNK ) , which is autonomously or selectively expressed in several cell types and functions as a dominant negative inhibitor of FAK .	FAK signaling is negatively regulated by expression of a FAK variant containing the C-terminal noncatalytic domain, termed FAK related nonkinase (FRNK), which is autonomously or selectively expressed in several cell types and functions as a dominant negative inhibitor of FAK.	0	10	negatively regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	FAK	expression of a FAK	fak	FAK	FAK	fak	9	10	0	1
TAE226 ( 2.5 muM ) inhibited pFAK expression in a time dependent manner did not inhibit total FAK .	TAE226 (2.5 muM) inhibited pFAK expression in a time dependent manner did not inhibit total FAK.	6	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	pFAK	pFAK expression	pfak	FAK	FAK	fak	6	7	17	18
We recently reported that FAK Tyr 407 phosphorylation negatively regulates the enzymatic and biological activities of FAK , unlike phosphorylation of other tyrosine residues .	We recently reported that FAK Tyr 407 phosphorylation negatively regulates the enzymatic and biological activities of FAK, unlike phosphorylation of other tyrosine residues.	4	17	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK Tyr 407 phosphorylation	fak	FAK	FAK	fak	4	5	16	17
Furthermore , ectopic expression of FRNK causes dephosphorylation of FAK at Tyr 397 and blocks FAK mediated fibroblast migration , and overexpression of wild-type FAK in CHO and African monkey kidney cell line COS cells resulted in increased cell migration .	Furthermore, ectopic expression of FRNK causes dephosphorylation of FAK at Tyr 397 and blocks FAK mediated fibroblast migration, and overexpression of wild-type FAK in CHO and African monkey kidney cell line COS cells resulted in increased cell migration.	3	16	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	expression of FRNK causes dephosphorylation of FAK at Tyr 397	fak	FAK	FAK	fak	9	10	15	16
Taken together , the data showed that the two methodological approaches , expression of FRNK and siRNA against FAK , inhibited FAK mediated signalling pathways in HNSCC derived cells , and were suitable tools to address the question as to whether FAK is involved in HNSCC progression .	Taken together, the data showed that the two methodological approaches, expression of FRNK and siRNA against FAK, inhibited FAK mediated signalling pathways in HNSCC derived cells, and were suitable tools to address the question as to whether FAK is involved in HNSCC progression.	12	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	expression of FRNK	frnk	FAK	FAK	fak	14	15	21	22
Among them , mechanisms involved in phosphatase mediated dephosphorylation of FAK could be implicated , as already demonstrated Moreover , our results , while highlighting the importance of FAK phosphorylation in the control of FAK and paxillin interactions , clearly show that FAK phosphorylation at Tyr 925 is not sufficient to block localization of FAK to FAs , as previously suggested .	Among them, mechanisms involved in phosphatase mediated dephosphorylation of FAK could be implicated, as already demonstrated Moreover, our results, while highlighting the importance of FAK phosphorylation in the control of FAK and paxillin interactions, clearly show that FAK phosphorylation at Tyr 925 is not sufficient to block localization of FAK to FAs, as previously suggested.	42	55	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK phosphorylation at Tyr 925	fak	FAK	FAK	fak	42	43	54	55
Moreover , in these conditions LMW-PTP causes FAK dephosphorylation , thus preventing the activation of FAK downstream pathways .	Moreover, in these conditions LMW-PTP causes FAK dephosphorylation, thus preventing the activation of FAK downstream pathways.	5	17	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	LMW-PTP causes FAK dephosphorylation	fak	FAK	FAK	fak	7	8	15	16
Knockdown of FAK function either with a FAK anti-sense morpholino or by expression of FRNK , a dominant negative FAK isoform , blocks all aspects of the response to BDNF , including the acceleration of point contact dynamics .	Knockdown of FAK function either with a FAK anti-sense morpholino or by expression of FRNK, a dominant negative FAK isoform, blocks all aspects of the response to BDNF, including the acceleration of point contact dynamics.	0	15	Knockdown	Negative_activation_syntax_1_noun	Positive_activation	Negative_activation	FRNK	expression of FRNK	frnk	FAK	FAK	fak	14	15	2	3
Expression of FAK related nonkinase , kinase deficient Src , or the Src homology 3 domain of p130 ( cas ) , which respectively serve as dominant negative versions of FAK , Src , and p130 ( cas ) , apparently reversed the transformed phenotypes of FAK overexpressed cells upon HGF stimulation .	Expression of FAK related nonkinase, kinase deficient Src, or the Src homology 3 domain of p130 (cas), which respectively serve as dominant negative versions of FAK, Src, and p130 (cas), apparently reversed the transformed phenotypes of FAK overexpressed cells upon HGF stimulation.	0	48	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	Expression of FAK	fak	FAK	FAK	fak	2	3	46	47
In contrast , the specific PtdIns 3-kinase inhibitor LY294002 induced apoptosis and markedly decreased p125 ( FAK ) expression and increased FAK proteolysis but had little effect on Y861 phosphorylation .	In contrast, the specific PtdIns 3-kinase inhibitor LY294002 induced apoptosis and markedly decreased p125 (FAK) expression and increased FAK proteolysis but had little effect on Y861 phosphorylation.	5	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	FAK	PtdIns 3-kinase inhibitor LY294002 induced apoptosis and markedly decreased p125 (FAK) expression	fak	FAK	FAK	fak	16	17	21	22
In conclusion , this study supports the importance of FAK signaling for 3-D VSMC invasion into fibrin hydrogels , and it provides proof of concept that GFP-FRNK overexpression can disrupt FAK signaling and limit VSMC invasion under these conditions .	In conclusion, this study supports the importance of FAK signaling for 3-D VSMC invasion into fibrin hydrogels, and it provides proof of concept that GFP-FRNK overexpression can disrupt FAK signaling and limit VSMC invasion under these conditions.	26	31	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	GFP-FRNK	GFP-FRNK overexpression	gfp-frnk	FAK	FAK	fak	26	27	30	31
As expected , immunofluorescence staining for the c-myc and FRNK fusion protein and activated FAK ( using a Y 397 phospho-FAK-specific antibody ) showed that transient expression of FRNK , in ~ 10 % of the total cell population ( unpublished data ) , suppressed FAK activity ( XREF_FIG D , left , and XREF_FIG E ) .	As expected, immunofluorescence staining for the c-myc and FRNK fusion protein and activated FAK (using a Y 397 phospho-FAK-specific antibody) showed that transient expression of FRNK, in ~ 10% of the total cell population (unpublished data), suppressed FAK activity (XREF_FIG D, left, and XREF_FIG E).	26	46	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	expression of FRNK	frnk	FAK	FAK	fak	28	29	45	46
Inhibition of FAK activation ( by forced exogenous FRNK expression ) abrogates the increased cell migration in IPF lung fibroblasts .	Inhibition of FAK activation (by forced exogenous FRNK expression) abrogates the increased cell migration in IPF lung fibroblasts.	0	10	Inhibition	Negative_activation_syntax_1_noun	Positive_activation	Negative_activation	FRNK	FRNK expression	frnk	FAK	FAK	fak	8	9	2	3
Tyrosine phosphorylation of focal adhesion kinase ( FAK ) family members FAK and PYK2 was significantly reduced by dasatinib , and select inhibitors for these kinases PF431396 , which inhibits both FAK and PYK2 , and PF573228 , which only inhibits FAK and not PYK2 , significantly reduced matrix contraction by transdifferentiated Muller cells .	Tyrosine phosphorylation of focal adhesion kinase (FAK) family members FAK and PYK2 was significantly reduced by dasatinib, and select inhibitors for these kinases PF431396, which inhibits both FAK and PYK2, and PF573228, which only inhibits FAK and not PYK2, significantly reduced matrix contraction by transdifferentiated Muller cells.	0	44	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	Tyrosine phosphorylation of focal adhesion kinase (FAK	fak	FAK	FAK	fak	7	8	41	42
FAK-CD caused complete degradation of FAK in both Nf1 +/+ MEF cells , while FAK was present in Nf1 - / - MEF cells ( XREF_FIG ) .	FAK-CD caused complete degradation of FAK in both Nf1 +/+ MEF cells, while FAK was present in Nf1 - / - MEF cells (XREF_FIG).	0	6	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK-CD	FAK-CD	FAK-CD	FAK	FAK	FAK	0	1	5	6
Exogenous expression of FRNK has been widely used as a dominant negative mutant to inhibit FAK signalling ( Schlaepfer et al , 2004 ) .	Exogenous expression of FRNK has been widely used as a dominant negative mutant to inhibit FAK signalling (Schlaepfer et al, 2004).	1	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	expression of FRNK	frnk	FAK	FAK	fak	3	4	15	16
Consistent with the invasion results , overexpression of FRNK , a kinase negative mutant ( Arg454 FAK ) , and a Src binding mutant ( Phe397 FAK ) inhibited the accumulation of FAK at the bacterial entry site .	Consistent with the invasion results, overexpression of FRNK, a kinase negative mutant (Arg454 FAK), and a Src binding mutant (Phe397 FAK) inhibited the accumulation of FAK at the bacterial entry site.	6	33	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	overexpression of FRNK	frnk	FAK	FAK	fak	8	9	32	33
Moreover , FRNK expression also disrupts the formation of v , Src , and FAK complex , which , in turn , inhibits p130Cas activity and reduces the v-Src-stimulated ERK and JNK kinase activation , leading to impair v-Src-mediated cell invasion and metastasis [ XREF_BIBR ] .	Moreover, FRNK expression also disrupts the formation of v, Src, and FAK complex, which, in turn, inhibits p130Cas activity and reduces the v-Src-stimulated ERK and JNK kinase activation, leading to impair v-Src-mediated cell invasion and metastasis [XREF_BIBR].	2	15	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	FRNK expression	frnk	FAK	FAK	fak	2	3	14	15
FAK phosphorylation is blocked by botulinum C3 exoenzyme , placing FAK downstream of RhoA .	FAK phosphorylation is blocked by botulinum C3 exoenzyme, placing FAK downstream of RhoA.	0	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK phosphorylation	fak	FAK	FAK	fak	0	1	10	11
It is well known that FRNK overexpression inhibits FAK activation ; however , the effect of downregulation of FRNK expression on FAK activation has not been studied before .	It is well known that FRNK overexpression inhibits FAK activation; however, the effect of downregulation of FRNK expression on FAK activation has not been studied before.	5	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	FRNK overexpression	frnk	FAK	FAK	fak	5	6	8	9
HU-210 instead phosphorylates FAK related nonkinase ( FRNK ) , which inhibits FAK activity , in a CB1 receptor dependent manner [ XREF_BIBR - XREF_BIBR ] .	HU-210 instead phosphorylates FAK related nonkinase (FRNK), which inhibits FAK activity, in a CB1 receptor dependent manner [XREF_BIBR - XREF_BIBR].	2	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	phosphorylates FAK	fak	FAK	FAK	fak	3	4	12	13
This subcellular translocation response was transient , as there was a complete loss of FAK in focal adhesions within 60 min ( XREF_FIG B ) .	This subcellular translocation response was transient, as there was a complete loss of FAK in focal adhesions within 60 min (XREF_FIG B).	9	17	was a complete loss	Negative_activation_copula_1	Positive_activation	Negative_activation	FAK	loss of FAK	fak	FAK	FAK	fak	14	15	14	15
Overexpression of exogenous FRNK inhibits FAK activation ( determined by Y397 phosphorylation of FAK ) initiated by integrin receptor engagement with extracellular matrix proteins or by growth factors [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Overexpression of exogenous FRNK inhibits FAK activation (determined by Y397 phosphorylation of FAK) initiated by integrin receptor engagement with extracellular matrix proteins or by growth factors [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	6	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	Overexpression of exogenous FRNK	frnk	FAK	FAK	fak	3	4	5	6
To determine if FRNK expression could specifically inhibit Pyk2 and FAK-CT function in promoting FAK -/ - haptotactic motility , FRNK or S-1034 FRNK was transiently expressed along with a lacZ reporter in CA3 cells ( XREF_FIG B ) .	To determine if FRNK expression could specifically inhibit Pyk2 and FAK-CT function in promoting FAK -/ - haptotactic motility, FRNK or S-1034 FRNK was transiently expressed along with a lacZ reporter in CA3 cells (XREF_FIG B).	3	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	FRNK expression	frnk	FAK-CT	FAK-CT	fak-ct	3	4	10	11
Transfection of the rat CA1 area with small interfering RNA against galectin-3 facilitated fear memory and increased phosphorylated focal adhesion kinase ( FAK ) levels , effects that were blocked by co-transfection of the FAK phosphorylation defective mutant Flag FAKY397F .	Transfection of the rat CA1 area with small interfering RNA against galectin-3 facilitated fear memory and increased phosphorylated focal adhesion kinase (FAK) levels, effects that were blocked by co-transfection of the FAK phosphorylation defective mutant Flag FAKY397F.	22	36	blocked	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	FAK	FAK phosphorylation	fak	FAK	FAK	fak	34	35	22	23
Interestingly , MMP-2 overexpression in FRNK expressing cells rescued FRNK inhibition of cell invasion .	Interestingly, MMP-2 overexpression in FRNK expressing cells rescued FRNK inhibition of cell invasion.	2	10	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	FRNK	MMP-2 overexpression in FRNK expressing	frnk	FRNK	FRNK	frnk	5	6	9	10
Interestingly , several recent studies have indicated that p38 may function at the G 2 / M checkpoint to block cardiomyocyte cell cycle progression and we recently showed that expression of FRNK ( or inactivation of FAK ) promotes p38 activity and regulates expression of the p38 dependent cell cycle modifier , p27 kip .	Interestingly, several recent studies have indicated that p38 may function at the G 2 / M checkpoint to block cardiomyocyte cell cycle progression and we recently showed that expression of FRNK (or inactivation of FAK) promotes p38 activity and regulates expression of the p38 dependent cell cycle modifier, p27 kip.	29	37	inactivation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	FRNK	expression of FRNK	frnk	FAK	FAK	fak	31	32	36	37
Inhibition of FAK mediated signalling by expression of FRNK or siRNA against FAK .	Inhibition of FAK mediated signalling by expression of FRNK or siRNA against FAK.	3	13	mediated	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	FRNK	expression of FRNK	frnk	FAK	FAK	fak	8	9	12	13
Because the increased migration of vascular SMCs in response to extracellular matrix proteins and growth factors contributes to neointima formation , our results show that FAK inhibition by FRNK expression may provide a novel approach to regulate abnormal vascular SMC migration in vivo .	Because the increased migration of vascular SMCs in response to extracellular matrix proteins and growth factors contributes to neointima formation, our results show that FAK inhibition by FRNK expression may provide a novel approach to regulate abnormal vascular SMC migration in vivo.	25	30	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	FRNK	FRNK expression	frnk	FAK	FAK	fak	28	29	25	26
This binding recruits a protein-Tyr phosphatase ( PTP ) , PTP-PEST , which dephosphorylates FAK at Y397 and subsequently inhibits FAK activity .	This binding recruits a protein-Tyr phosphatase (PTP), PTP-PEST, which dephosphorylates FAK at Y397 and subsequently inhibits FAK activity.	5	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	phosphatase (PTP), PTP-PEST, which dephosphorylates FAK at Y397	fak	FAK	FAK	fak	14	15	20	21
Moreover , Western blot analysis for the protein tyrosine kinase , PYK2 , demonstrated that FAK Mo did not disrupt the translation of this closely related FAK family member ( XREF_FIG ) .	Moreover, Western blot analysis for the protein tyrosine kinase, PYK2, demonstrated that FAK Mo did not disrupt the translation of this closely related FAK family member (XREF_FIG).	15	28	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK	FAK	FAK	FAK	FAK	15	16	26	27
Knockdown of beta-arrestin using siRNA decreased both PTH induced PTH1R endocytosis ( XREF_FIG ) and PTH signaling downstream phosphorylation of ERK ( XREF_FIG ) .	Knockdown of beta-arrestin using siRNA decreased both PTH induced PTH1R endocytosis (XREF_FIG) and PTH signaling downstream phosphorylation of ERK (XREF_FIG).	5	10	induced	Positive_early_activation	Positive_activation	Negative_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	7	8	9	10
Thus , PTHR degradation induced by PTH ( 7-34 ) is due to proteosomal degradation .	Thus, PTHR degradation induced by PTH (7-34) is due to proteosomal degradation.	2	7	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	6	7	2	3
PTHR internalization is necessary for PTHR degradation induced by PTH ( 7-34 ) ( XREF_FIG ) .	PTHR internalization is necessary for PTHR degradation induced by PTH (7-34) (XREF_FIG).	5	14	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	9	10	5	6
Importantly , the potent PTHR1 antagonist PTH ( 7-34 ) alone had no significant effect on the proliferation of 5TGM1 myeloma cells at any dose tested ( XREF_FIG ) .	Importantly, the potent PTHR1 antagonist PTH (7-34) alone had no significant effect on the proliferation of 5TGM1 myeloma cells at any dose tested (XREF_FIG).	2	11	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	6	7	4	5
This action may forestall PTH resistance and downregulation of the PTH1R .	This action may forestall PTH resistance and downregulation of the PTH1R.	4	11	resistance	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	4	5	10	11
These findings support a key role of internalization on the PTHR degradative process triggered by PTH ( 7-34 ) .	These findings support a key role of internalization on the PTHR degradative process triggered by PTH (7-34).	10	17	triggered	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	15	16	10	11
To determine whether the reduced PTHR signaling following H 2 O 2 treatment was caused by PTH oxidation , we pre-incubated the NNT-PTH peptide with H 2 O 2 .	To determine whether the reduced PTHR signaling following H 2 O 2 treatment was caused by PTH oxidation, we pre-incubated the NNT-PTH peptide with H 2 O 2.	5	17	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	16	17	5	6
Furthermore , overexpression of USP2 in ROS cells rescued PTHR degradation induced by PTH ( 7-34 ) ( XREF_FIG ) .	Furthermore, overexpression of USP2 in ROS cells rescued PTHR degradation induced by PTH (7-34) (XREF_FIG).	9	18	induced	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	13	14	9	10
Furthermore , Western blot analysis showed that the PTH induced increase in levels of pSmad2 , ACAN , and CCN2 seen in NP tissue was diminished in the PTH1R KO mice .	Furthermore, Western blot analysis showed that the PTH induced increase in levels of pSmad2, ACAN, and CCN2 seen in NP tissue was diminished in the PTH1R KO mice.	7	30	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	8	9	28	29
7 Agents that block activation of PTHR1 by PTH or PTHrP could , in principle , restore normal levels of blood calcium and ameliorate the associated symptoms .	7 Agents that block activation of PTHR1 by PTH or PTHrP could, in principle, restore normal levels of blood calcium and ameliorate the associated symptoms.	3	10	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	8	9	6	7
Strikingly , the combination of bortezomib and the PTHR1 antagonist PTH ( 7-34 ) completely abrogated the beneficial effect of bortezomib treatment ( p = 0.04 on day +30 ) ( XREF_FIG ) .	Strikingly, the combination of bortezomib and the PTHR1 antagonist PTH (7-34) completely abrogated the beneficial effect of bortezomib treatment (p = 0.04 on day +30) (XREF_FIG).	3	11	antagonist	Negative_activation_token_1_noun	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	10	11	8	9
We observed that shRNA induced knockdown of Eps15 mRNA blocked the PTH ( 7-34 )-stimulated decrease of total PTHR abundance in CHO-N10-R3 ( XREF_FIG ) .	We observed that shRNA induced knockdown of Eps15 mRNA blocked the PTH (7-34)-stimulated decrease of total PTHR abundance in CHO-N10-R3 (XREF_FIG).	11	19	decrease	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	11	12	18	19
These findings suggest that PTH ( 7-34 ) preferentially reduces PTHR abundance .	These findings suggest that PTH (7-34) preferentially reduces PTHR abundance.	4	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	4	5	10	11
However , PTH ( 7-34 ) , which does not activate the PTHR but promotes receptor internalization , down-regulates the PTHR by a ubiquitin sensitive pathway .	However, PTH (7-34), which does not activate the PTHR but promotes receptor internalization, down-regulates the PTHR by a ubiquitin sensitive pathway.	2	21	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	2	3	20	21
PTH ( 1-84 ) did not induce PTHR degradation ( XREF_FIG ) .	PTH (1-84) did not induce PTHR degradation (XREF_FIG).	0	8	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	0	1	7	8
Although it has been shown that 24-48 hour PTH ( 1-34 ) treatment downregulates total PTHR in opossum kidney cells , we did not observe significant effects of PTH ( 1-34 ) on PTHR protein levels .	Although it has been shown that 24-48 hour PTH (1-34) treatment downregulates total PTHR in opossum kidney cells, we did not observe significant effects of PTH (1-34) on PTHR protein levels.	6	19	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR	PTHR	PTHR	8	9	15	16
Consistent with these results , cell-surface biotinylation showed that PTH decreased endogenous cell-surface LRP6 significantly at 30 minutes in UMR106 cells ( XREF_FIG ) , but not in PTH1R deficient OC59 cells ( XREF_SUPPLEMENTARY ) .	Consistent with these results, cell-surface biotinylation showed that PTH decreased endogenous cell-surface LRP6 significantly at 30 minutes in UMR106 cells (XREF_FIG), but not in PTH1R deficient OC59 cells (XREF_SUPPLEMENTARY).	9	29	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	9	10	28	29
In contrast to results from a previous study showing that PTH1R is down-regulated by PTH in cultured osteoblasts XREF_BIBR , PTH1R was slightly increased by intermittent PTH treatment in vivo as measured by IHC and Western blot analysis .	In contrast to results from a previous study showing that PTH1R is down-regulated by PTH in cultured osteoblasts XREF_BIBR, PTH1R was slightly increased by intermittent PTH treatment in vivo as measured by IHC and Western blot analysis.	10	15	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTH1R	PTH1R	PTH1R	14	15	10	11
PTH and PTHrP have been reported to down-regulate the PTHR1 at the mRNA level but AP-1 regulation of the PTHR1 promoter has not been described .	PTH and PTHrP have been reported to down-regulate the PTHR1 at the mRNA level but AP-1 regulation of the PTHR1 promoter has not been described.	0	10	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTH	PTH	PTH	PTHR1	PTHR1	PTHR1	0	1	9	10
Similarly , in MDA-MB-231 cells , Brk knockdown did not appreciably alter AKT activity in response to HGF , but increased AKT activity following EGF .	Similarly, in MDA-MB-231 cells, Brk knockdown did not appreciably alter AKT activity in response to HGF, but increased AKT activity following EGF.	6	22	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Brk	Brk	Brk	AKT	AKT	AKT	6	7	21	22
PTK6 mediated inhibition of AKT and MAPK prosurvival signaling pathways appears important , as disruption of Ptk6 led to increased activation of AKT and ERK1/2 and impaired apoptosis in irradiated mice [ XREF_BIBR ] .	PTK6 mediated inhibition of AKT and MAPK prosurvival signaling pathways appears important, as disruption of Ptk6 led to increased activation of AKT and ERK1/2 and impaired apoptosis in irradiated mice [XREF_BIBR].	0	6	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	0	1	4	5
In the mouse small intestine , we previously showed that PTK6 negatively regulates AKT and ERK1/2 activity after irradiation , but we were unable to detect differences in activation of these signaling proteins in wild type and Ptk6 -/- colons after AOM injection .	In the mouse small intestine, we previously showed that PTK6 negatively regulates AKT and ERK1/2 activity after irradiation, but we were unable to detect differences in activation of these signaling proteins in wild type and Ptk6 -/- colons after AOM injection.	10	16	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	10	11	13	14
Ectopic expression of membrane targeted active PTK6 promoted epithelial-mesenchymal transition in part by enhancing activation of AKT , thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer .	Ectopic expression of membrane targeted active PTK6 promoted epithelial-mesenchymal transition in part by enhancing activation of AKT, thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer.	1	17	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	expression of membrane targeted active PTK6	ptk6	AKT	AKT	akt	6	7	16	17
These results are consistent with our previous report that Brk inhibits AKT in selected ( nontransformed ) cell lines [ XREF_BIBR ] and studies in Sik-knockout mice , which display increased AKT activity in tissues that normally express Sik , the mouse homolog of Brk [ XREF_BIBR ] .	These results are consistent with our previous report that Brk inhibits AKT in selected (nontransformed) cell lines [XREF_BIBR] and studies in Sik-knockout mice, which display increased AKT activity in tissues that normally express Sik, the mouse homolog of Brk [XREF_BIBR].	9	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Brk	Brk	Brk	AKT	AKT	AKT	9	10	11	12
Furthermore , it has been demonstrated that PTK6 directly inactivated the protein kinase Akt in a manner that led to increased nuclear accumulation of FoxO1 [ XREF_BIBR ] , a transcription factor known to regulate inflammatory responses in epithelial cells [ XREF_BIBR ] .	Furthermore, it has been demonstrated that PTK6 directly inactivated the protein kinase Akt in a manner that led to increased nuclear accumulation of FoxO1 [XREF_BIBR], a transcription factor known to regulate inflammatory responses in epithelial cells [XREF_BIBR].	7	14	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTK6	PTK6	PTK6	Akt	Akt	Akt	7	8	13	14
More recent studies in PTK6 knockout mice also suggest that Brk inhibits Akt in differentiating murine intestinal epithelial cells [ XREF_BIBR , XREF_BIBR ] .	More recent studies in PTK6 knockout mice also suggest that Brk inhibits Akt in differentiating murine intestinal epithelial cells [XREF_BIBR, XREF_BIBR].	10	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Brk	Brk	Brk	Akt	Akt	Akt	10	11	12	13
Together these studies suggest that Brk signals differently during normal development relative to cancer progression ; Brk may function to limit Akt activity in normal cells or when growth factors are low , but this fails to occur in cancer cells , where Brk may somehow amplify growth factor dependent signaling inputs to PI3K and Akt pathway activation ( XREF_FIG ) .	Together these studies suggest that Brk signals differently during normal development relative to cancer progression; Brk may function to limit Akt activity in normal cells or when growth factors are low, but this fails to occur in cancer cells, where Brk may somehow amplify growth factor dependent signaling inputs to PI3K and Akt pathway activation (XREF_FIG).	5	22	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Brk	Brk	Brk	Akt	Akt	Akt	5	6	21	22
Brk also appears to inhibit basal AKT activity in selected nontumorigenic cell line models , such as COS-1 cells , but not in T47D breast cancer cells [ XREF_BIBR ] .	Brk also appears to inhibit basal AKT activity in selected nontumorigenic cell line models, such as COS-1 cells, but not in T47D breast cancer cells [XREF_BIBR].	0	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Brk	Brk	Brk	AKT	AKT	AKT	0	1	6	7
In concordance with these studies , we found increased levels of activated AKT in the intestines of the Ptk6 null mice , indicating that one function of PTK6 in normal nondividing epithelial cells is to suppress AKT to promote growth inhibition as cells differentiate XREF_BIBR .	In concordance with these studies, we found increased levels of activated AKT in the intestines of the Ptk6 null mice, indicating that one function of PTK6 in normal nondividing epithelial cells is to suppress AKT to promote growth inhibition as cells differentiate XREF_BIBR.	25	38	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	27	28	36	37
Knockdown of PTK6 decreases proliferation in breast cancer cell lines ( Harvey and Crompton , 2003 ) and blocks activity of a GTPase , of ERK5 ( extracellular signal regulated kinase ) and p38 mitogen activated protein kinase ( MAPK ) , but not Akt ( Mitchell et al , 1994 ; Barker et al , 1997 ; Llor et al , 1999 ; Born et al , 2005 ; Ostrander et al , 2007 ) .	Knockdown of PTK6 decreases proliferation in breast cancer cell lines (Harvey and Crompton, 2003) and blocks activity of a GTPase, of ERK5 (extracellular signal regulated kinase) and p38 mitogen activated protein kinase (MAPK), but not Akt (Mitchell et al, 1994; Barker et al, 1997; Llor et al, 1999; Born et al, 2005; Ostrander et al, 2007).	0	46	blocks	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	PTK6	PTK6	Akt	Akt	Akt	2	3	44	45
This observation is consistent with previous findings that PTK6 is known to inhibit the activity of the serine/threonine kinase Akt in a manner that promotes FoxO1 accumulation in the nucleus [ XREF_BIBR ] .	This observation is consistent with previous findings that PTK6 is known to inhibit the activity of the serine/threonine kinase Akt in a manner that promotes FoxO1 accumulation in the nucleus [XREF_BIBR].	8	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTK6	PTK6	PTK6	Akt	Akt	Akt	8	9	19	20
The ability of PTK6 to inhibit both AKT signaling [ XREF_BIBR , XREF_BIBR ] and the Wnt pathway [ XREF_BIBR , XREF_BIBR ] could contribute to its growth suppressive activities in vivo .	The ability of PTK6 to inhibit both AKT signaling [XREF_BIBR, XREF_BIBR] and the Wnt pathway [XREF_BIBR, XREF_BIBR] could contribute to its growth suppressive activities in vivo.	1	8	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	3	4	7	8
Although PTK6 negatively regulates AKT signaling in normal tissues in vivo , it may enhance AKT signaling in breast cancer cells .	Although PTK6 negatively regulates AKT signaling in normal tissues in vivo, it may enhance AKT signaling in breast cancer cells.	1	5	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	1	2	4	5
Knockdown of PTK6 in the PC3 human prostate cancer cell line disrupts FAK and AKT activation and promotes anoikis , which can be rescued by exogenous expression of FAK .	Knockdown of PTK6 in the PC3 human prostate cancer cell line disrupts FAK and AKT activation and promotes anoikis, which can be rescued by exogenous expression of FAK.	0	15	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	PTK6	PTK6	PTK6	AKT	AKT	AKT	2	3	14	15
XREF_BIBR , XREF_BIBR The findings that glucocorticoids oppose the FAK and ERK pathway through activation of Pyk2 raise the possibility that Pyk2 could be inhibited to increase the mechanoresponsive FAK signaling .	XREF_BIBR, XREF_BIBR The findings that glucocorticoids oppose the FAK and ERK pathway through activation of Pyk2 raise the possibility that Pyk2 could be inhibited to increase the mechanoresponsive FAK signaling.	21	30	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pyk2	Pyk2	Pyk2	FAK	FAK	FAK	21	22	29	30
Thus , compensatory changes in Pyk2 levels are independent of the means to inactivate FAK and may reflect differences in cell origin or transformation .	Thus, compensatory changes in Pyk2 levels are independent of the means to inactivate FAK and may reflect differences in cell origin or transformation.	5	15	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pyk2	Pyk2 levels	pyk2	FAK	FAK	fak	5	6	14	15
Activated Pyk2 may compete with FAK for binding partners and thereby decrease the FAK promoted pro survival signal in cells XREF_BIBR , XREF_BIBR .	Activated Pyk2 may compete with FAK for binding partners and thereby decrease the FAK promoted pro survival signal in cells XREF_BIBR, XREF_BIBR.	1	14	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pyk2	Pyk2	Pyk2	FAK	FAK	FAK	1	2	13	14
Nevertheless , it is conceivable that other FRNK effects , including its regulation of both the ERK1/2 and the phosphatidylinositol 3-kinase/Akt pathways that are involved in AngII induced VSMC protein synthesis , could be mediated by its inhibition of PYK2 .	Nevertheless, it is conceivable that other FRNK effects, including its regulation of both the ERK1/2 and the phosphatidylinositol 3-kinase/Akt pathways that are involved in AngII induced VSMC protein synthesis, could be mediated by its inhibition of PYK2.	7	40	mediated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	PYK2	PYK2	PYK2	FRNK	FRNK	FRNK	39	40	7	8
Importantly , the expression of homologous Pyk-2 was not increased and was even decreased in MCF-7-Tet-ON-FAK cells indicating FAK independent regulation of Pyk-2 in MCF-7 cells .	Importantly, the expression of homologous Pyk-2 was not increased and was even decreased in MCF-7-Tet-ON-FAK cells indicating FAK independent regulation of Pyk-2 in MCF-7 cells.	3	20	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pyk-2	expression of homologous Pyk-2	pyk-2	FAK	FAK	fak	6	7	18	19
This effect is specific for Pyk2 as expression of the Pyk2 FERM domain does not inhibit FAK [ XREF_BIBR ] .	This effect is specific for Pyk2 as expression of the Pyk2 FERM domain does not inhibit FAK [XREF_BIBR].	7	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pyk2	expression of the Pyk2	pyk2	FAK	FAK	fak	10	11	16	17
In the present study , it was used at concentrations 5nM and 16nM to block FAK alone and FAK and Pyk2 together in glioma cells .	In the present study, it was used at concentrations 5nM and 16nM to block FAK alone and FAK and Pyk2 together in glioma cells.	7	21	block	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Pyk2	Pyk2	Pyk2	FAK	FAK	FAK	20	21	15	16
Pyk2 expression was inhibited by the introduction of Pyk2 siRNA in PC12 cells to investigate the function of Pyk2 in ionomycin induced neurotransmitter release .	Pyk2 expression was inhibited by the introduction of Pyk2 siRNA in PC12 cells to investigate the function of Pyk2 in ionomycin induced neurotransmitter release.	0	9	inhibited	Negative_regulation_syntax_2_verb	Positive_activation	Positive_regulation	Pyk2	Pyk2	pyk2	Pyk2	Pyk2 expression	pyk2	8	9	0	1
In addition , expression of the Pyk2 FERM domain inhibits the ability of Pyk2 to augment ANF secretion ; this is correlated with reduced Pyk2 autophosphorylation .	In addition, expression of the Pyk2 FERM domain inhibits the ability of Pyk2 to augment ANF secretion; this is correlated with reduced Pyk2 autophosphorylation.	3	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pyk2	expression of the Pyk2	pyk2	Pyk2	Pyk2	pyk2	6	7	13	14
As expected , chelation of intracellular calcium abrogated phosphorylation of Pyk2 in response to pUS28 signaling and prevented Pyk2 activation in Ad-Trans controls ( data not shown ) .	As expected, chelation of intracellular calcium abrogated phosphorylation of Pyk2 in response to pUS28 signaling and prevented Pyk2 activation in Ad-Trans controls (data not shown).	6	19	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pyk2	calcium abrogated phosphorylation of Pyk2	pyk2	Pyk2	Pyk2	pyk2	10	11	18	19
However , the mechanism of action of dynamin on Pyk2 , whether dynamin promotes the dephosphorylation of Pyk2 Y402 , or alternatively prevents Pyk2 from being phosphorylated , and the downstream effects on signaling in OCs is unknown .	However, the mechanism of action of dynamin on Pyk2, whether dynamin promotes the dephosphorylation of Pyk2 Y402, or alternatively prevents Pyk2 from being phosphorylated, and the downstream effects on signaling in OCs is unknown.	12	24	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Pyk2	dynamin promotes the dephosphorylation of Pyk2 Y402	pyk2	Pyk2	Pyk2	pyk2	17	18	23	24
The modest inhibition of Pyk2 phosphorylation is consistent with the ability of Src to activate Pyk2 , and suggests feedback amplification of Pyk2 activation by Src .	The modest inhibition of Pyk2 phosphorylation is consistent with the ability of Src to activate Pyk2, and suggests feedback amplification of Pyk2 activation by Src.	4	16	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Pyk2	Pyk2 phosphorylation	pyk2	Pyk2	Pyk2	pyk2	4	5	15	16
Indeed , overexpression of the PYK2 FERM domain ( in the absence of calmodulin overexpression ) inhibited the activation of full-length PYK2 by forming a complex with the inactive enzyme [ Riggs , 2011 # 7050 ] .	Indeed, overexpression of the PYK2 FERM domain (in the absence of calmodulin overexpression) inhibited the activation of full-length PYK2 by forming a complex with the inactive enzyme [Riggs, 2011 # 7050].	2	22	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PYK2	overexpression of the PYK2	pyk2	PYK2	PYK2	pyk2	5	6	21	22
The ability of PTP1B knockdown to confer resistance to dasatinib ( XREF_FIG and XREF_SUPPLEMENTARY ) suggests PTP1B may augment Src signaling in RCC cells by channeling inputs from upstream oncogenes , including Ras .	The ability of PTP1B knockdown to confer resistance to dasatinib (XREF_FIG and XREF_SUPPLEMENTARY) suggests PTP1B may augment Src signaling in RCC cells by channeling inputs from upstream oncogenes, including Ras.	3	20	augment	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	3	4	19	20
In addition , these effects were also seen in Src expressing cells treated with an inhibitor of PTP1B ( XREF_FIG ) .	In addition, these effects were also seen in Src expressing cells treated with an inhibitor of PTP1B (XREF_FIG).	9	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	17	18	9	10
PTP1B targets the negative regulatory site of Src ( phosphotyrosine 529 ) , paxillin and p130Cas at peripheral cell-matrix adhesions .	PTP1B targets the negative regulatory site of Src (phosphotyrosine 529), paxillin and p130Cas at peripheral cell-matrix adhesions.	0	15	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	0	1	7	8
It is interesting to note that overexpression of wild-type PTP1B decreases the phosphotyrosine content of Src , without an apparent alteration of the phenotype .	It is interesting to note that overexpression of wild-type PTP1B decreases the phosphotyrosine content of Src, without an apparent alteration of the phenotype.	6	16	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTP1B	overexpression of wild-type PTP1B	ptp1b	Src	Src	src	9	10	15	16
Src kinase activation was increased by LPS and Src activity was significantly inhibited by PTP-1B pretreatment .	Src kinase activation was increased by LPS and Src activity was significantly inhibited by PTP-1B pretreatment.	0	15	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	PTP-1B	PTP-1B	PTP-1B	Src	Src	Src	14	15	0	1
However , recent in vitro data , carried out in a 3D cell culture setting , indicate that PTP1B mediated Src activation is a prime target in ErbB2 ( Neu )-induced human breast cancer cells [ XREF_BIBR ] .	However, recent in vitro data, carried out in a 3D cell culture setting, indicate that PTP1B mediated Src activation is a prime target in ErbB2 (Neu)-induced human breast cancer cells [XREF_BIBR].	18	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	18	19	20	21
Regarding these substrates , it is at least theoretically plausible that the reported in vivo effects of PTP1B loss on ErbB2 driven breast cancer can be explained in terms of failure to activate Src .	Regarding these substrates, it is at least theoretically plausible that the reported in vivo effects of PTP1B loss on ErbB2 driven breast cancer can be explained in terms of failure to activate Src.	17	34	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTP1B	PTP1B	PTP1B	Src	Src	Src	17	18	33	34
pSrc stainings revealed that the Src activation resulting from Ret expression was , however , unaffected by Fak ( Fig XREF_FIG H ) , indicating that Fak blocks the mitogenic effect of Ret downstream of Src activation .	pSrc stainings revealed that the Src activation resulting from Ret expression was, however, unaffected by Fak (Fig XREF_FIG H), indicating that Fak blocks the mitogenic effect of Ret downstream of Src activation.	26	36	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Fak	Fak	Fak	Ret	Ret	Ret	26	27	32	33
FAK suppresses RET in different fly epithelia .	FAK suppresses RET in different fly epithelia.	0	6	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK	FAK	RET	RET	RET	0	1	2	3
The N-terminal domain of FAK , but not its kinase activity , is required to suppress RET .	The N-terminal domain of FAK, but not its kinase activity, is required to suppress RET.	2	17	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK	FAK	RET	RET	RET	4	5	16	17
To gain insight into the mechanism by which FAK suppresses RET signalling , we co-expressed dRET CA and different dFAK mutant isoforms in the eye ( schematised in XREF_FIG ) .	To gain insight into the mechanism by which FAK suppresses RET signalling, we co-expressed dRET CA and different dFAK mutant isoforms in the eye (schematised in XREF_FIG).	8	11	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK	FAK	RET	RET	RET	8	9	10	11
FAK impairs MAPK signalling downstream of RET .	FAK impairs MAPK signalling downstream of RET.	0	7	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK	FAK	RET	RET	RET	0	1	6	7
To further test whether FAK can inhibit RET signalling we combined dRET and dFAK in different imaginal discs using the GMR-gal4 , dpp-gal4 and ptc-gal4 drivers .	To further test whether FAK can inhibit RET signalling we combined dRET and dFAK in different imaginal discs using the GMR-gal4, dpp-gal4 and ptc-gal4 drivers.	4	8	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	FAK	FAK	FAK	RET	RET	RET	4	5	7	8
XREF_BIBR - XREF_BIBR More recently , we also demonstrated that curcumin inhibits colon cancer cell migration through physical interaction with and activation of PTPN1 tyrosine phosphatase to reduce the abnormally hyperphosphorylated and hyperactive form of cortactin , a protein implicated in cancer motility and tumor invasiveness .	XREF_BIBR - XREF_BIBR More recently, we also demonstrated that curcumin inhibits colon cancer cell migration through physical interaction with and activation of PTPN1 tyrosine phosphatase to reduce the abnormally hyperphosphorylated and hyperactive form of cortactin, a protein implicated in cancer motility and tumor invasiveness.	23	38	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTPN1	PTPN1	PTPN1	cortactin	cortactin	cortactin	23	24	35	36
We found that eGFP-PTP1B-HA expression in both MDA-MB-231 and MTLn3 cells decreased cortactin tyrosine 421 phosphorylation at invadopodia relative to cells expressing eGFP alone ( XREF_FIG ; XREF_SUPPLEMENTARY ) , and eGFP-PTP1B-HA expression in MTLn3 cells significantly reduced the number of mature invadopodia per cell relative to eGFP alone ( XREF_SUPPLEMENTARY ) .	We found that eGFP-PTP1B-HA expression in both MDA-MB-231 and MTLn3 cells decreased cortactin tyrosine 421 phosphorylation at invadopodia relative to cells expressing eGFP alone (XREF_FIG; XREF_SUPPLEMENTARY), and eGFP-PTP1B-HA expression in MTLn3 cells significantly reduced the number of mature invadopodia per cell relative to eGFP alone (XREF_SUPPLEMENTARY).	3	13	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	eGFP-PTP1B-HA	eGFP-PTP1B-HA expression	egfp-ptp1b-ha	cortactin	cortactin	cortactin	3	4	12	13
However , immunofluorescence analysis and cell surface biotinylation in HCT119 cells treated with DMSO or curcumin showed that PTPN1 inhibition did not restore the cellular localization of pTyr 421 or total cortactin , respectively ( XREF_FIG ) .	However, immunofluorescence analysis and cell surface biotinylation in HCT119 cells treated with DMSO or curcumin showed that PTPN1 inhibition did not restore the cellular localization of pTyr 421 or total cortactin, respectively (XREF_FIG).	18	32	restore	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	PTPN1	PTPN1	PTPN1	cortactin	cortactin	cortactin	18	19	31	32
In the nucleus , PTK6 can inhibit proliferation by negatively regulating activity of the RNA binding protein Sam68 and inhibiting beta-catenin transcription XREF_BIBR , XREF_BIBR .	In the nucleus, PTK6 can inhibit proliferation by negatively regulating activity of the RNA binding protein Sam68 and inhibiting beta-catenin transcription XREF_BIBR, XREF_BIBR.	4	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTK6	PTK6	PTK6	Sam68	Sam68	Sam68	4	5	17	18
Expression of Brk was also found to negatively regulate the RNA binding function of Sam68 [ XREF_BIBR ] .	Expression of Brk was also found to negatively regulate the RNA binding function of Sam68 [XREF_BIBR].	0	16	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Brk	Expression of Brk	brk	Sam68	Sam68	sam68	2	3	14	15
More intriguingly , gene inactivation of RPTPalpha not only delays spreading on FN but also impairs activation of Src family kinases .	More intriguingly, gene inactivation of RPTPalpha not only delays spreading on FN but also impairs activation of Src family kinases.	4	20	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RPTPalpha	RPTPalpha	RPTPalpha	Src	Src	Src	6	7	18	19
Downregulation of the transmembrane PTPa has been proven to inhibit Src kinase activity and induce apoptosis in CRC cells [ XREF_BIBR ] .	Downregulation of the transmembrane PTPa has been proven to inhibit Src kinase activity and induce apoptosis in CRC cells [XREF_BIBR].	0	12	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTPa	PTPa	PTPa	Src	Src	Src	4	5	10	11
20 Inhibition of COX-2 in dendritic cells derived from mediastinal lymph nodes caused increased Th2 differentiation and IL-4 production , which was directly related to impaired Treg cell differentiation and immune tolerance .	20 Inhibition of COX-2 in dendritic cells derived from mediastinal lymph nodes caused increased Th2 differentiation and IL-4 production, which was directly related to impaired Treg cell differentiation and immune tolerance.	1	18	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	COX-2	COX-2	COX-2	IL-4	IL-4	IL-4	3	4	17	18
Although loss of PTPN6 has been shown to enhance JAK3 and STAT3 signaling in ALK positive anaplastic large-cell lymphoma , 59 the roles of PTPN6 in TNBC are not yet understood .	Although loss of PTPN6 has been shown to enhance JAK3 and STAT3 signaling in ALK positive anaplastic large-cell lymphoma, 59 the roles of PTPN6 in TNBC are not yet understood.	1	12	enhance	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	PTPN6	loss of PTPN6	ptpn6	JAK3	JAK3	jak3	3	4	9	10
XREF_BIBR - XREF_BIBR A recent study has suggested that ERK phosphorylation of Non Receptor Tyrosine Phosphatase 5 ( PTPN5 ) prevents BAK activation by preventing dephosphorylation of the molecule at tyrosine 108 ( a necessary but not sufficient event for BAK activation ) .	XREF_BIBR - XREF_BIBR A recent study has suggested that ERK phosphorylation of Non Receptor Tyrosine Phosphatase 5 (PTPN5) prevents BAK activation by preventing dephosphorylation of the molecule at tyrosine 108 (a necessary but not sufficient event for BAK activation).	2	38	prevents	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	PTPN5	PTPN5	PTPN5	BAK	BAK	BAK	18	19	21	22
SHP-2 knock-down significantly reduced the proliferation rate of IEC-6 and KRAS cells without severely affecting proliferation of control cells .	SHP-2 knock-down significantly reduced the proliferation rate of IEC-6 and KRAS cells without severely affecting proliferation of control cells.	0	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SHP-2	SHP-2	SHP-2	KRAS	KRAS	KRAS	0	1	10	11
Future work should test whether PTEN stabilizes and/or sequesters PPM1A in HaCaT after TGF-beta treatment , as illustrated in Model 8 .	Future work should test whether PTEN stabilizes and/or sequesters PPM1A in HaCaT after TGF-beta treatment, as illustrated in Model 8.	5	11	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PTEN	PTEN	PTEN	PPM1A	PPM1A	PPM1A	5	6	9	10
Pak1 also acts downstream in the Src and Fak pathway , as an effector for the small GTPase Rac1 Loss of Pak1 , induced by siRNA , expression of dominant negative alleles , gene-disruption , or small molecule inhibitors , has been shown to block transformation in vitro by oncogenic forms of Kras , ErbB2 , and KSHV .	Pak1 also acts downstream in the Src and Fak pathway, as an effector for the small GTPase Rac1 Loss of Pak1, induced by siRNA, expression of dominant negative alleles, gene-disruption, or small molecule inhibitors, has been shown to block transformation in vitro by oncogenic forms of Kras, ErbB2, and KSHV.	18	22	Loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	18	19	21	22
Knockdown of Rac1 protein levels with specific siRNA ( XREF_FIG ) significantly reduced activation of both Pak1 and Pak2 in papilloma cells ( * : p < 0.05 ) , as well as levels of COX-2 as previously described .	Knockdown of Rac1 protein levels with specific siRNA (XREF_FIG) significantly reduced activation of both Pak1 and Pak2 in papilloma cells (* : p < 0.05), as well as levels of COX-2 as previously described.	2	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Rac1	Rac1 protein levels	rac1	Pak1	Pak1	pak1	2	3	16	17
Furthermore , transfection of dominant negative Cdc42 and Rac1 inhibited 12-HETE-induced PAK1 , strongly suggesting that Cdc42 and Rac1 are the upstream activators of 12-HETE-induced PAK1 activation .	Furthermore, transfection of dominant negative Cdc42 and Rac1 inhibited 12-HETE-induced PAK1, strongly suggesting that Cdc42 and Rac1 are the upstream activators of 12-HETE-induced PAK1 activation.	2	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	8	9	11	12
Conversely , cells transfected with either PDGFRbeta or Pak1 siRNA or treated with an inhibitor of Rac1 ( NSC23766 ) or N-myristoyltransferase-1 ( Tris-dipalladium ) are unable to activate Rac1 or Pak1 in response to PDGF , and consequently , are unable to undergo PDGF mediated cell migration .	Conversely, cells transfected with either PDGFRbeta or Pak1 siRNA or treated with an inhibitor of Rac1 (NSC23766) or N-myristoyltransferase-1 (Tris-dipalladium) are unable to activate Rac1 or Pak1 in response to PDGF, and consequently, are unable to undergo PDGF mediated cell migration.	8	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Rac1	Rac1	Rac1	Pak1	Pak1	Pak1	16	17	8	9
More recently , it was shown that Rac1 inhibits MLC phosphorylation in melanoma cells , however , in this study WAVE2 mediated this effect rather than PAK1 , 2 or 3 11 .	More recently, it was shown that Rac1 inhibits MLC phosphorylation in melanoma cells, however, in this study WAVE2 mediated this effect rather than PAK1, 2 or 3 11.	7	27	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rac1	Rac1	Rac1	PAK1	PAK1	PAK1	7	8	26	27
These observations strongly indicate that Rabex-5 mediates the subcellular targeting of Rab5A .	These observations strongly indicate that Rabex-5 mediates the subcellular targeting of Rab5A.	5	12	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5A	Rab5A	Rab5A	5	6	11	12
The VPS9 domain of Rabex-5 is sufficient to mediate targeting of Rab5A .	The VPS9 domain of Rabex-5 is sufficient to mediate targeting of Rab5A.	2	12	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rabex-5	Rabex-5	Rabex-5	Rab5A	Rab5A	Rab5A	4	5	11	12
Rabaptin-5 contains two Rab5 binding sites required for binding Rab5 in early endosomes in a GTP dependent manner , and immunodepletion of rabaptin-5 strongly inhibits Rab5 dependent early endosome fusion .	Rabaptin-5 contains two Rab5 binding sites required for binding Rab5 in early endosomes in a GTP dependent manner, and immunodepletion of rabaptin-5 strongly inhibits Rab5 dependent early endosome fusion.	20	29	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	rabaptin-5	rabaptin-5	rabaptin-5	Rab5	Rab5	Rab5	22	23	25	26
Hypoxia inducible factor ( HIF ) has also shown to repress RABEP1 transcription , which lead to impaired Rab5 mediated endosome fusion and prolonged EGF receptor half-life [ XREF_BIBR ] .	Hypoxia inducible factor (HIF) has also shown to repress RABEP1 transcription, which lead to impaired Rab5 mediated endosome fusion and prolonged EGF receptor half-life [XREF_BIBR].	0	19	lead	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	RABEP1	Hypoxia inducible factor (HIF) has also shown to repress RABEP1 transcription	rabep1	Rab5	Rab5	rab5	11	12	18	19
As a result , Rac is sequestered , thereby inactivating PAK and leading to the collapse of the actin based cytoskeleton .	As a result, Rac is sequestered, thereby inactivating PAK and leading to the collapse of the actin based cytoskeleton.	4	11	sequestered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rac	Rac	Rac	PAK	PAK	PAK	4	5	10	11
We provide evidence that Rac1 and Cdc42 but not Rho activity is downregulated by AZA1 in prostate cancer cells and that combined Rac1 and Cdc42 inhibition suppresses cell proliferation and activation of PAK and AKT and signaling pathways affecting the downstream cell cycle regulator Cyclin D1 and the pro apoptotic protein BAD .	We provide evidence that Rac1 and Cdc42 but not Rho activity is downregulated by AZA1 in prostate cancer cells and that combined Rac1 and Cdc42 inhibition suppresses cell proliferation and activation of PAK and AKT and signaling pathways affecting the downstream cell cycle regulator Cyclin D1 and the pro apoptotic protein BAD.	21	37	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rac1	Rac1	Rac1	PAK	PAK	PAK	22	23	32	33
313 In contrast with this observation , in a Phase I dose escalation study of the combination AZD7762 plus irinotecan in subjects with advanced solid tumors , one patient with metastatic small-cell cancer bearing a hypomorphic mutation in RAD50 ( and consequent attenuation of the ATM signaling ) displayed a complete and durable response .	313 In contrast with this observation, in a Phase I dose escalation study of the combination AZD7762 plus irinotecan in subjects with advanced solid tumors, one patient with metastatic small-cell cancer bearing a hypomorphic mutation in RAD50 (and consequent attenuation of the ATM signaling) displayed a complete and durable response.	36	46	attenuation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	RAD50	RAD50	RAD50	ATM	ATM	ATM	38	39	45	46
Although we found that ING1b is required for Rad18 dependent PCNA-Ub , we also observed that co-KD of ING1b and Rad18 further reduced PCNA-Ub and sensitized cells to UV compared to ING1b and Rad18 KD alone .	Although we found that ING1b is required for Rad18 dependent PCNA-Ub, we also observed that co-KD of ING1b and Rad18 further reduced PCNA-Ub and sensitized cells to UV compared to ING1b and Rad18 KD alone.	16	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rad18	Rad18	Rad18	PCNA-Ub	PCNA-Ub	PCNA-Ub	20	21	23	24
Following DNA damage , such as that caused by UV and MMS , monoubiquitins are conjugated to PCNA arrested at the lesion-site by RAD6 and RAD18 and recruit bypass-polymerases [ XREF_BIBR , XREF_BIBR ] .	Following DNA damage, such as that caused by UV and MMS, monoubiquitins are conjugated to PCNA arrested at the lesion-site by RAD6 and RAD18 and recruit bypass-polymerases [XREF_BIBR, XREF_BIBR].	15	28	arrested	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	RAD18	RAD18	RAD18	PCNA	PCNA	PCNA	25	26	17	18
In addition , we found that coexpression of the Rac-1 N17 dominant inhibitory mutant dramatically diminishes JNK and SAPK stimulation by Vav , as well as reduces the focus forming ability of Vav in NIH3T3 murine fibroblasts .	In addition, we found that coexpression of the Rac-1 N17 dominant inhibitory mutant dramatically diminishes JNK and SAPK stimulation by Vav, as well as reduces the focus forming ability of Vav in NIH3T3 murine fibroblasts.	6	19	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rac-1	coexpression of the Rac-1	rac-1	SAPK	SAPK	sapk	9	10	18	19
Rad50 exhibits ATP dependent double stranded DNA binding and negatively regulates Mre11 endonucleolytic activity in yeast , prompting speculation that it regulates functional activity of the Mre11 complex .	Rad50 exhibits ATP dependent double stranded DNA binding and negatively regulates Mre11 endonucleolytic activity in yeast, prompting speculation that it regulates functional activity of the Mre11 complex.	0	13	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rad50	Rad50	Rad50	Mre11	Mre11	Mre11	0	1	11	12
This result is consistent with a previous study showing that depletion of Rad1 from egg extract did not perturb chromatin association of TopBP1 ; however , pol-alpha hyperloading was not examined in this previous study .	This result is consistent with a previous study showing that depletion of Rad1 from egg extract did not perturb chromatin association of TopBP1; however, pol-alpha hyperloading was not examined in this previous study.	10	23	perturb	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Rad1	Rad1	Rad1	TopBP1	TopBP1	TopBP1	12	13	22	23
Curcumin is also shown to inhibit Raf-1 [ XREF_BIBR , XREF_BIBR ] which also reduces MEK signalling ( MAPK ) from yet another point in the MAPK pathway as seen in Figures XREF_FIG and XREF_FIG .	Curcumin is also shown to inhibit Raf-1 [XREF_BIBR, XREF_BIBR] which also reduces MEK signalling (MAPK) from yet another point in the MAPK pathway as seen in Figures XREF_FIG and XREF_FIG.	6	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	6	7	15	16
NRAS or CRAF depletion by RNA interference ( RNAi ) blocked MEK and ERK activation by PLX4720 and 885-A in NRAS mutant cells ( XREF_FIG B and 1C ) and we show that 885-A activated CRAF in these cells ( XREF_FIG D ) .	NRAS or CRAF depletion by RNA interference (RNAi) blocked MEK and ERK activation by PLX4720 and 885-A in NRAS mutant cells (XREF_FIG B and 1C) and we show that 885-A activated CRAF in these cells (XREF_FIG D).	2	14	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	2	3	11	12
Tumor progression despite continued trametinib treatment suggests that alternative pathways activated by CRAF fusions in vivo permit tumor growth despite MEK inhibition .	Tumor progression despite continued trametinib treatment suggests that alternative pathways activated by CRAF fusions in vivo permit tumor growth despite MEK inhibition.	10	21	activated	Positive_activation_syntax_3_verb	Positive_activation	Negative_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	12	13	20	21
Akt activation , through the deletion of PTEN , can result in the phosphorylation and inactivation of Raf-1 thus decreasing downstream signaling of MEK and ERK which then leads to the loss of cellular differentiation [ XREF_BIBR , XREF_BIBR ] .	Akt activation, through the deletion of PTEN, can result in the phosphorylation and inactivation of Raf-1 thus decreasing downstream signaling of MEK and ERK which then leads to the loss of cellular differentiation [XREF_BIBR, XREF_BIBR].	13	25	decreasing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	phosphorylation and inactivation of Raf-1	raf-1	MEK	MEK	mek	17	18	23	24
Phosphorylation of Raf-1 on Ser 259 by PI 3 kinase target Akt kinase inhibits MEK and Erk pathway .	Phosphorylation of Raf-1 on Ser 259 by PI 3 kinase target Akt kinase inhibits MEK and Erk pathway.	0	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	Phosphorylation of Raf-1 on Ser 259	raf-1	MEK	MEK	mek	2	3	14	15
Strikingly , Raf-1 activation by Salp15 leads to mitogen activated protein kinase kinase ( MEK )-dependent decrease of IL-6 and TNF-alpha mRNA stability and impaired nucleosome remodeling at the IL-12p35 promoter .	Strikingly, Raf-1 activation by Salp15 leads to mitogen activated protein kinase kinase (MEK)-dependent decrease of IL-6 and TNF-alpha mRNA stability and impaired nucleosome remodeling at the IL-12p35 promoter.	2	16	leads	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	2	3	14	15
For example , binding of rocaglamide ( 1 ) to PHBs 1 and 2 was shown to block their interaction with C-Raf , thus inhibiting C-Raf mediated MEK and ERK signaling .	For example, binding of rocaglamide (1) to PHBs 1 and 2 was shown to block their interaction with C-Raf, thus inhibiting C-Raf mediated MEK and ERK signaling.	24	30	mediated	Positive_early_activation	Positive_activation	Negative_activation	C-Raf	C-Raf	C-Raf	MEK	MEK	MEK	25	26	27	28
Knockdown of either NRAS or CRAF abrogated activation of MEK and ERK by 885-A , as seen in Figure 1B .	Knockdown of either NRAS or CRAF abrogated activation of MEK and ERK by 885-A, as seen in Figure 1B.	0	11	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	5	6	9	10
Inhibition of Raf1 , mitogen activated protein kinase kinase ( MAPKK and MEK ) and p38 MAPK with , respectively , GW 5074 , PD 98059 and SB 203580 and downregulation of protein kinase C ( PKC ) with phorbol-12 ,13-dibutyrate ( 100 nM for 24 h ) prevented inhibition of NHE activity by IFN-gamma ( 0.5 and 24 h exposure ) .	Inhibition of Raf1, mitogen activated protein kinase kinase (MAPKK and MEK) and p38 MAPK with, respectively, GW 5074, PD 98059 and SB 203580 and downregulation of protein kinase C (PKC) with phorbol-12,13-dibutyrate (100 nM for 24 h) prevented inhibition of NHE activity by IFN-gamma (0.5 and 24 h exposure).	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf1	Raf1	Raf1	MEK	MEK	MEK	2	3	12	13
But PI 3 kinase and Akt mediated phosphorylation of Raf-1 at Ser 259 negatively regulates MEK and Erk .	But PI 3 kinase and Akt mediated phosphorylation of Raf-1 at Ser 259 negatively regulates MEK and Erk.	5	17	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	Akt mediated phosphorylation of Raf-1 at Ser 259	raf-1	MEK	MEK	mek	9	10	15	16
Whereas plasma membrane targeting of Raf-1 activates the classical MEK > ERK ( MAPK ) cascade but does not protect cells , mitochondrial targeting of Raf-1 protects cells XREF_BIBR .	Whereas plasma membrane targeting of Raf-1 activates the classical MEK> ERK (MAPK) cascade but does not protect cells, mitochondrial targeting of Raf-1 protects cells XREF_BIBR.	3	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	5	6	9	10
As reported in Figure 2B , silencing CRAF reversed MEK activation upon treatment with the RAF inhibitors GDC-0879 and PLX4720 .	As reported in Figure 2B, silencing CRAF reversed MEK activation upon treatment with the RAF inhibitors GDC-0879 and PLX4720.	6	10	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	7	8	9	10
Raf kinase inhibitor protein ( RKIP ) inhibits activation of MEK by Raf-1 and its downstream signal transduction , resulting in blocking the MAP kinase pathway .	Raf kinase inhibitor protein (RKIP) inhibits activation of MEK by Raf-1 and its downstream signal transduction, resulting in blocking the MAP kinase pathway.	7	17	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	12	13	10	11
PD098059 was identified initially to inhibit the unphosphorylated form of MEK1 and a constitutively active mutant of MEK1 , and subsequently to inhibit the activation of MEK by c-Raf or MEK kinase 1 but not the activation of MAPK kinase 4 by MEK kinase 1 .	PD098059 was identified initially to inhibit the unphosphorylated form of MEK1 and a constitutively active mutant of MEK1, and subsequently to inhibit the activation of MEK by c-Raf or MEK kinase 1 but not the activation of MAPK kinase 4 by MEK kinase 1.	24	31	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	c-Raf	c-Raf	c-Raf	MEK	MEK	MEK	28	29	26	27
Inhibition of Raf-1 , mitogen activated protein kinase kinase ( MAPKK and MEK ) , p38 MAPK and STAT1 with , respectively , GW 5074 , PD 98059 , SB 203580 and epigallocatechin gallate prevented inhibition of Na ( + )-K ( + )-ATPase activity by IFN-gamma .	Inhibition of Raf-1, mitogen activated protein kinase kinase (MAPKK and MEK), p38 MAPK and STAT1 with, respectively, GW 5074, PD 98059, SB 203580 and epigallocatechin gallate prevented inhibition of Na (+)-K (+)-ATPase activity by IFN-gamma.	0	13	activated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	2	3	12	13
Pin1 overexpression in cardiomyocytes induce Raf-1 phosphorylation which is a factor upstream from MEK , and attenuates kinase activities , thereby inhibiting the MEK pathway .	Pin1 overexpression in cardiomyocytes induce Raf-1 phosphorylation which is a factor upstream from MEK, and attenuates kinase activities, thereby inhibiting the MEK pathway.	0	24	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	Pin1 overexpression in cardiomyocytes induce Raf-1 phosphorylation	raf-1	MEK	MEK	mek	5	6	23	24
In this situation , amino acids target and inhibit the activity of the Raf-1 kinase , which downregulates the downstream MEK1/2 [ MAPK ( mitogen activated protein kinase )/ERK kinase 1/2 ] and ERK1/2 ( extracellular signal regulated kinase 1/2 ) kinases and autophagy activity .	In this situation, amino acids target and inhibit the activity of the Raf-1 kinase, which downregulates the downstream MEK1/2 [MAPK (mitogen activated protein kinase)/ERK kinase 1/2] and ERK1/2 (extracellular signal regulated kinase 1/2) kinases and autophagy activity.	13	22	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MEK1/2	MEK1/2	MEK1/2	13	14	20	21
Disruption of CRAF mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors .	Disruption of CRAF mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors.	0	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	CRAF	CRAF	CRAF	MEK	MEK	MEK	2	3	4	5
Cross talk between AKT and MEK and ERK pathways in muscle and breast cancer cells involved AKT mediated inactivation of Raf-1 repressing MEK pathway [ XREF_BIBR ; XREF_BIBR ] .	Cross talk between AKT and MEK and ERK pathways in muscle and breast cancer cells involved AKT mediated inactivation of Raf-1 repressing MEK pathway [XREF_BIBR; XREF_BIBR].	18	23	repressing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	Raf-1	Raf-1	MEK	MEK	MEK	20	21	22	23
Phosphorylation of Raf-1 on S259 by PKA inhibits Raf-1 kinase activity and its downstream signaling , resulting in inhibition of ERK .	Phosphorylation of Raf-1 on S259 by PKA inhibits Raf-1 kinase activity and its downstream signaling, resulting in inhibition of ERK.	0	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	Phosphorylation of Raf-1 on S259	raf-1	Raf-1	Raf-1	raf-1	2	3	8	9
Interestingly , even at a concentration of 10muM , dabrafenib induced a robust stimulation of CRAF signaling independent of light- or RAS mediated CRAF dimer formation in serum starved HEK293T cells expressing wild-type CRAF or the light-insensitive CRAF-CIBN protein .	Interestingly, even at a concentration of 10muM, dabrafenib induced a robust stimulation of CRAF signaling independent of light- or RAS mediated CRAF dimer formation in serum starved HEK293T cells expressing wild-type CRAF or the light-insensitive CRAF-CIBN protein.	15	25	signaling	Positive_regulation_syntax_3_noun	Positive_activation	Positive_regulation	CRAF	CRAF	craf	CRAF	RAS mediated CRAF	craf	15	16	23	24
In mesangial cells , PDE3 and PDE4 inhibitors increase cAMP levels and activate PKA to a similar extent , but only PDE3 inhibitors block phosphorylation of Raf-1 on serine 338 and suppress Raf-1 kinase activity and ERK activation .	In mesangial cells, PDE3 and PDE4 inhibitors increase cAMP levels and activate PKA to a similar extent, but only PDE3 inhibitors block phosphorylation of Raf-1 on serine 338 and suppress Raf-1 kinase activity and ERK activation.	21	34	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	PDE3 inhibitors block phosphorylation of Raf-1 on serine 338	raf-1	Raf-1	Raf-1	raf-1	26	27	32	33
Here , we show that Raf-1 dephosphorylation , primarily at epidermal growth factor ( EGF )-induced sites , abolishes Raf-1 kinase activity .	Here, we show that Raf-1 dephosphorylation, primarily at epidermal growth factor (EGF)-induced sites, abolishes Raf-1 kinase activity.	5	21	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Raf-1	Raf-1 dephosphorylation	raf-1	Raf-1	Raf-1	raf-1	5	6	19	20
Accordingly , although cRaf S259 phosphorylation by Akt inhibited cRaf activity , phosphorylation of cRaf S338 by an unknown kinase promoting its interaction with adaptor protein 14-3-3 prevailed over the inhibitory effect of Akt , and was necessary for the stable activation of cRaf .	Accordingly, although cRaf S259 phosphorylation by Akt inhibited cRaf activity, phosphorylation of cRaf S338 by an unknown kinase promoting its interaction with adaptor protein 14-3-3 prevailed over the inhibitory effect of Akt, and was necessary for the stable activation of cRaf.	3	10	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	cRaf	cRaf S259 phosphorylation	craf	cRaf	cRaf	craf	3	4	9	10
Consistently , RASSF5 and RASSF1 ( the founding member of the RASSF family ) can suppress MST1 activation both in vitro and in mammalian cells .	Consistently, RASSF5 and RASSF1 (the founding member of the RASSF family) can suppress MST1 activation both in vitro and in mammalian cells.	2	17	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RASSF1	RASSF1	RASSF1	MST1	MST1	MST1	4	5	16	17
Overexpression of RASSF1A or Nore1A inhibits MST1 activation , but coexpression of these RASSF proteins with Ras enhanced MST1 activity XREF_BIBR .	Overexpression of RASSF1A or Nore1A inhibits MST1 activation, but coexpression of these RASSF proteins with Ras enhanced MST1 activity XREF_BIBR.	0	7	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RASSF1A	Overexpression of RASSF1A	rassf1a	MST1	MST1	mst1	2	3	6	7
Nevertheless , dietary phospholipids containing high levels of DHA and EPA ( PL5 diet ) induced cephalic ( 8.5 % ) and vertebral column deformities ( 35.3 % ) adversely affecting fish growth and survival ; moreover , a down-regulation of retinoid X receptor alpha ( RXRalpha ) , retinoic acid receptor alpha , retinoic acid receptor gamma and bone morphogenetic protein-4 genes was also noted in PL5 dietary group at day 16 .	Nevertheless, dietary phospholipids containing high levels of DHA and EPA (PL5 diet) induced cephalic (8.5%) and vertebral column deformities (35.3%) adversely affecting fish growth and survival; moreover, a down-regulation of retinoid X receptor alpha (RXRalpha), retinoic acid receptor alpha, retinoic acid receptor gamma and bone morphogenetic protein-4 genes was also noted in PL5 dietary group at day 16.	39	58	down-regulation	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	retinoic acid receptor gamma	retinoic acid receptor gamma	retinoic acid receptor gamma	retinoid X receptor alpha	retinoid X receptor alpha	retinoid X receptor alpha	54	58	41	45
Using ~ 300 nM MEK1 as a substrate , PD98059 inhibited the activation of MEK1 by C-RAF with an IC 50 of 2-7 microM [ XREF_BIBR ] .	Using ~ 300 nM MEK1 as a substrate, PD98059 inhibited the activation of MEK1 by C-RAF with an IC 50 of 2-7 microM [XREF_BIBR].	10	17	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	C-RAF	C-RAF	C-RAF	MEK1	MEK1	MEK1	16	17	14	15
The interaction between RASSF1A and MST2 had already been described by Avruch ' s group [ XREF_BIBR , XREF_BIBR ] which indicated that RASSF1A prevented MST2 activation .	The interaction between RASSF1A and MST2 had already been described by Avruch 's group [XREF_BIBR, XREF_BIBR] which indicated that RASSF1A prevented MST2 activation.	23	26	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RASSF1A	RASSF1A	RASSF1A	MST2	MST2	MST2	23	24	25	26
Rheb directly binds and selectively activates the multiprotein complex 1 of mammalian target of rapamycin ( mTORC1 ) , which in turn mediates many cellular functions , such as protein translation 8 .	Rheb directly binds and selectively activates the multiprotein complex 1 of mammalian target of rapamycin (mTORC1), which in turn mediates many cellular functions, such as protein translation 8.	0	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	11	15
TSC1/2 is a GTPase activating protein complex that maintains Rheb ( Ras homologue enriched in brain ) in an inactive form , thereby causing mTOR inhibition XREF_BIBR XREF_BIBR XREF_BIBR .	TSC1/2 is a GTPase activating protein complex that maintains Rheb (Ras homologue enriched in brain) in an inactive form, thereby causing mTOR inhibition XREF_BIBR XREF_BIBR XREF_BIBR.	8	25	causing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	9	10	24	25
In the normal state , the hamartin and tuberin complex activates the protein Rheb , which inhibits mTOR .	In the normal state, the hamartin and tuberin complex activates the protein Rheb, which inhibits mTOR.	10	18	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	13	14	17	18
In contrast to the Ras/MEK/ERK pathway mediated Bim upregulation that is responsible for tipifarnib induced killing of malignant lymphoid cells , inhibition of Rheb induced mTOR signaling followed by dose dependent upregulation of Bax and Puma occurred in acute myelogenous leukemia cell lines undergoing tipifarnib induced apoptosis .	In contrast to the Ras/MEK/ERK pathway mediated Bim upregulation that is responsible for tipifarnib induced killing of malignant lymphoid cells, inhibition of Rheb induced mTOR signaling followed by dose dependent upregulation of Bax and Puma occurred in acute myelogenous leukemia cell lines undergoing tipifarnib induced apoptosis.	21	26	induced	Positive_early_activation	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	23	24	25	26
XREF_BIBR - XREF_BIBR Finally , AMP activated protein kinase ( AMPK ) phosphorylates TSC2 and stabilizes the TSC1 and TSC2 complex , thereby inhibiting Rheb mediated activation of mTOR .	XREF_BIBR - XREF_BIBR Finally, AMP activated protein kinase (AMPK) phosphorylates TSC2 and stabilizes the TSC1 and TSC2 complex, thereby inhibiting Rheb mediated activation of mTOR.	23	29	mediated	Positive_early_activation	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	24	25	28	29
TSC2 encodes the tuberin protein and TSC1 encodes the hamartin protein , which combine to form a heterodimer that acts as a GTPase activating protein complex on Rheb , a Ras family GTPase that in turn inhibits mTOR activity .	TSC2 encodes the tuberin protein and TSC1 encodes the hamartin protein, which combine to form a heterodimer that acts as a GTPase activating protein complex on Rheb, a Ras family GTPase that in turn inhibits mTOR activity.	23	38	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	27	28	37	38
The exosome mediated mechanisms may also operate in the cells of angiomyolipoma ( AML ) , which develops as a result of mutations in TSC1 and TSC2 genes in TSC patients , because we observed the reactivation of mammalian target of rapamycin and Notch pathways , driven by the delivery of Rheb and Notch1 esRNA , in AML cells depleted of Rheb that were treated with the exosomes purified from AML cells with the constitutively high Rheb levels .	The exosome mediated mechanisms may also operate in the cells of angiomyolipoma (AML), which develops as a result of mutations in TSC1 and TSC2 genes in TSC patients, because we observed the reactivation of mammalian target of rapamycin and Notch pathways, driven by the delivery of Rheb and Notch1 esRNA, in AML cells depleted of Rheb that were treated with the exosomes purified from AML cells with the constitutively high Rheb levels.	38	54	driven	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	51	52	38	42
Lastly , nutrient stress also induces a p38 kinase and p38 regulated kinase ( PRAK ) pathway that phosphorylates Rheb on S130 to inhibit Rheb nucleotide binding and thus mTOR activity XREF_BIBR .	Lastly, nutrient stress also induces a p38 kinase and p38 regulated kinase (PRAK) pathway that phosphorylates Rheb on S130 to inhibit Rheb nucleotide binding and thus mTOR activity XREF_BIBR.	7	31	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	p38 kinase and p38 regulated kinase (PRAK) pathway that phosphorylates Rheb on S130	rheb	mTOR	mTOR	mtor	19	20	29	30
TSC1 and TSC2 complex dissociates Ras homolog enriched in brain ( Rheb ) from mTOR , thus inhibits mTOR activation .	TSC1 and TSC2 complex dissociates Ras homolog enriched in brain (Rheb) from mTOR, thus inhibits mTOR activation.	5	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	mTOR	mTOR	mTOR	5	10	18	19
The protein products of TSC1 , hamartin and TSC2 , tuberin , inhibit Ras homolog enriched in the brain ( Rheb ) that activates mammalian target of rapamycin ( mTOR ) complex 1 ( mTORC1 ) .	The protein products of TSC1, hamartin and TSC2, tuberin, inhibit Ras homolog enriched in the brain (Rheb) that activates mammalian target of rapamycin (mTOR) complex 1 (mTORC1).	18	28	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	20	21	24	28
Furthermore , proteasome inhibition with MG132 restored the expression of Rheb and increased mTOR activity , resulting in an increased viability of H2O2 treated cells .	Furthermore, proteasome inhibition with MG132 restored the expression of Rheb and increased mTOR activity, resulting in an increased viability of H2O2 treated cells.	2	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	proteasome inhibition with MG132 restored the expression of Rheb	rheb	mTOR	mTOR	mtor	10	11	13	14
It should be noted that mTOR is inhibited by both Rheb dependent and independent mechanisms XREF_BIBR , XREF_BIBR .	It should be noted that mTOR is inhibited by both Rheb dependent and independent mechanisms XREF_BIBR, XREF_BIBR.	5	17	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	10	11	5	6
Suppression of TSC2 activates the GTP binding protein Ras homologue enriched in brain ( Rheb ) , which upregulates mTOR XREF_BIBR .	Suppression of TSC2 activates the GTP binding protein Ras homologue enriched in brain (Rheb), which upregulates mTOR XREF_BIBR.	12	20	upregulates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	14	15	19	20
Growth factor deprivation leads to inactivation of Akt protein kinase , activation of tuberous sclerosis 1/2 ( TSC1/2 ) , and inactivation of Rheb , thus attenuated Rheb activation of mTOR XREF_BIBR .	Growth factor deprivation leads to inactivation of Akt protein kinase, activation of tuberous sclerosis 1/2 (TSC1/2), and inactivation of Rheb, thus attenuated Rheb activation of mTOR XREF_BIBR.	27	31	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	27	28	30	31
RHEB positively regulates mammalian target of rapamycin ( mTOR ) .	RHEB positively regulates mammalian target of rapamycin (mTOR).	0	7	positively regulates	Positive_activation_syntax_1b_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	3	7
Hamartin and tuberin , the protein products of TSC1 and TSC2 , respectively , form a functional heterodimer that negatively regulates cell growth via tuberin ' s GTPase Activating Protein activity toward the small GTPase Rheb , which in turn activates the mechanistic target of rapamycin complex 1 ( mTORC1 ) .	Hamartin and tuberin, the protein products of TSC1 and TSC2, respectively, form a functional heterodimer that negatively regulates cell growth via tuberin 's GTPase Activating Protein activity toward the small GTPase Rheb, which in turn activates the mechanistic target of rapamycin complex 1 (mTORC1).	30	46	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	35	36	42	46
AMPK phosphorylates and activates the tuberous sclerosis complex that , in turn , phosphorylates the Ras homolog enriched in brain small GTPase , preventing activation of mTOR [ XREF_BIBR ] .	AMPK phosphorylates and activates the tuberous sclerosis complex that, in turn, phosphorylates the Ras homolog enriched in brain small GTPase, preventing activation of mTOR [XREF_BIBR].	13	28	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ras homolog enriched in brain	phosphorylates the Ras homolog enriched in brain	ras homolog enriched in brain	mTOR	mTOR	mtor	15	20	26	27
RHEB GTP activates mTOR ( mammalian target of rapamycin ) .	RHEB GTP activates mTOR (mammalian target of rapamycin).	0	9	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RHEB	RHEB	RHEB	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	5	9
At the molecular level , the protein products of TSC1 , hamartin and TSC2 , tuberin , form a heterodimer that inhibits Ras homologue enriched in the brain ( Rheb ) XREF_BIBR , a small G protein that activates mammalian target of rapamycin ( mTOR ) complex 1 ( mTORC1 ) .	At the molecular level, the protein products of TSC1, hamartin and TSC2, tuberin, form a heterodimer that inhibits Ras homologue enriched in the brain (Rheb) XREF_BIBR, a small G protein that activates mammalian target of rapamycin (mTOR) complex 1 (mTORC1).	29	43	activates	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	29	30	39	43
Rheb in turn directly regulates the mammalian target of rapamycin complex 1 ( mTORC1 ) in the PI3K/Akt/mTOR pathway [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Rheb in turn directly regulates the mammalian target of rapamycin complex 1 (mTORC1) in the PI3K/Akt/mTOR pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	10	directly regulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	6	10
mTOR is inhibited upon withdrawal of growth factors , such as insulin or insulin like growth factors , by a cascade of phosphorylation reactions involving Class I PI3K , Akt , TSC1 and TSC2 , and Rheb .	mTOR is inhibited upon withdrawal of growth factors, such as insulin or insulin like growth factors, by a cascade of phosphorylation reactions involving Class I PI3K, Akt, TSC1 and TSC2, and Rheb.	0	37	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Rheb	phosphorylation reactions involving Class I PI3K, Akt, TSC1 and TSC2, and Rheb	rheb	mTOR	mTOR	mtor	36	37	0	1
Uninhibited Rheb then activates mTOR , which then regulates three key components involved in translation initiation : eIF4E , eIF4G , and S6 kinase ( S6K ) [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Uninhibited Rheb then activates mTOR, which then regulates three key components involved in translation initiation : eIF4E, eIF4G, and S6 kinase (S6K) [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	1	2	4	5
According to our results , the mTOR activation was stimulated by PI3K and AKT dependent inhibition of TSC1/2 complex and RHEB .	According to our results, the mTOR activation was stimulated by PI3K and AKT dependent inhibition of TSC1/2 complex and RHEB.	6	21	stimulated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	RHEB	RHEB	RHEB	mTOR	mTOR	mTOR	20	21	6	7
Hamartin and tuberin physically interact to form a complex , which , through the GAP activity of tuberin , inactivates the small G protein Rheb , thereby relieving Rheb mediated mTOR inhibition .	Hamartin and tuberin physically interact to form a complex, which, through the GAP activity of tuberin, inactivates the small G protein Rheb, thereby relieving Rheb mediated mTOR inhibition.	28	31	mediated	Positive_early_activation	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	28	29	30	31
At the molecular level , tuberin interacts with hamartin [ XREF_BIBR , XREF_BIBR ] and functions as a GTPase activating protein ( GAP ) for the small GTPase Rheb ( Ras homologue enriched in brain ) , decreasing Rheb induced activation of mTOR signaling [ XREF_BIBR - XREF_BIBR ] .	At the molecular level, tuberin interacts with hamartin [XREF_BIBR, XREF_BIBR] and functions as a GTPase activating protein (GAP) for the small GTPase Rheb (Ras homologue enriched in brain), decreasing Rheb induced activation of mTOR signaling [XREF_BIBR - XREF_BIBR].	38	45	induced	Positive_early_activation	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	38	39	42	43
TSC2 encodes in its COOH terminus a GTPase activating protein ( GAP ) for small GTPase Rheb ( Ras homologue enriched in brain ) , whose activity antagonizes mTOR signaling .	TSC2 encodes in its COOH terminus a GTPase activating protein (GAP) for small GTPase Rheb (Ras homologue enriched in brain), whose activity antagonizes mTOR signaling.	9	29	antagonizes	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	16	17	28	29
Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR , whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability .	Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability.	8	20	antagonized	Negative_activation_syntax_6_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	18	19	10	11
Autophagy is moderately activated during prolonged ischemia through activation of AMPK and GSK-3 beta and inhibition of Rheb , which inhibit mTOR activity XREF_BIBR , XREF_BIBR , XREF_BIBR .	Autophagy is moderately activated during prolonged ischemia through activation of AMPK and GSK-3 beta and inhibition of Rheb, which inhibit mTOR activity XREF_BIBR, XREF_BIBR, XREF_BIBR.	13	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	17	18	21	22
In addition , Rheb regulates 4EBP1 binding to mTORC1 and reduces mTOR activity by controlling the association of mTOR with mTORC1 through FKBP38 .	In addition, Rheb regulates 4EBP1 binding to mTORC1 and reduces mTOR activity by controlling the association of mTOR with mTORC1 through FKBP38.	3	12	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	3	4	11	12
We demonstrate that Rheb GTPase ( Ras homolog enriched in brain ) , which induces mammalian target of rapamycin ( mTOR ) activity , is a physiological regulator of BACE1 stability and activity .	We demonstrate that Rheb GTPase (Ras homolog enriched in brain), which induces mammalian target of rapamycin (mTOR) activity, is a physiological regulator of BACE1 stability and activity.	3	19	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	3	4	15	19
Indeed , co-expression of Rheb was able to partially rescue the inhibition of mTOR by LY294002 , but not by PI-103 ( or rapamycin ) , confirming that PI-103 blocks S6 phosphorylation in these cells by direct inhibition of mTOR ( XREF_FIG ) .	Indeed, co-expression of Rheb was able to partially rescue the inhibition of mTOR by LY294002, but not by PI-103 (or rapamycin), confirming that PI-103 blocks S6 phosphorylation in these cells by direct inhibition of mTOR (XREF_FIG).	2	14	rescue	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	co-expression of Rheb	rheb	mTOR	mTOR	mtor	4	5	13	14
15 Rheb in its active form activates mammalian target of rapamycin complex 1 ( mTORC1 ) , a key regulator of protein translation , metabolism and cell proliferation .	15 Rheb in its active form activates mammalian target of rapamycin complex 1 (mTORC1), a key regulator of protein translation, metabolism and cell proliferation.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	1	2	7	11
Inactivating mutations in Tsc1 or Tsc2 result in the accumulation of the GTP bound form of Rheb , which activates mammalian target of rapamycin complex 1 ( mTORC1 ) XREF_BIBR .	Inactivating mutations in Tsc1 or Tsc2 result in the accumulation of the GTP bound form of Rheb, which activates mammalian target of rapamycin complex 1 (mTORC1) XREF_BIBR.	14	24	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	16	17	20	24
TSC2 exists in a complex with TSC1 in cells , and the TSC1/2 complex inhibits the mTOR activator Rheb 43 .	TSC2 exists in a complex with TSC1 in cells, and the TSC1/2 complex inhibits the mTOR activator Rheb 43.	14	19	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	18	19	16	17
RheB activates the mechanistic target of rapamycin ( mTOR ) , a serine/threonine kinase involved in the formation of two complexes , mTORC1 and mTORC2 .	RheB activates the mechanistic target of rapamycin (mTOR), a serine/threonine kinase involved in the formation of two complexes, mTORC1 and mTORC2.	0	7	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RheB	RheB	RheB	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	0	1	3	7
Akt phosphorylated tuberin is inactive , leading to increased Rheb activity , and Rheb is an activator of mammalian target of rapamycin ( mTOR ) , which controls protein synthesis and cell growth by activating a 70-kD ribosomal S6 kinase ( S6K1 ) and inhibiting the elongation initiation factor 4E binding protein 1 ( 4EBP1 ) .	Akt phosphorylated tuberin is inactive, leading to increased Rheb activity, and Rheb is an activator of mammalian target of rapamycin (mTOR), which controls protein synthesis and cell growth by activating a 70-kD ribosomal S6 kinase (S6K1) and inhibiting the elongation initiation factor 4E binding protein 1 (4EBP1).	13	22	is an activator	Positive_activation_copula_1	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	13	14	18	22
Tuberin is phosphorylated by AKT in response to PI3K signaling , and this phosphorylation inhibits tuberin mediated repression of Rheb , activating mTOR signaling to increase protein synthesis .	Tuberin is phosphorylated by AKT in response to PI3K signaling, and this phosphorylation inhibits tuberin mediated repression of Rheb, activating mTOR signaling to increase protein synthesis.	13	23	activating	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	phosphorylation inhibits tuberin mediated repression of Rheb	rheb	mTOR	mTOR	mtor	19	20	22	23
The GDP bound form of Rheb inhibits mTor , whereas the GTP bound form stimulates the enzyme .	The GDP bound form of Rheb inhibits mTor, whereas the GTP bound form stimulates the enzyme.	3	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTor	mTor	mTor	5	6	7	8
Moreover , f-BRAF-driven NSC proliferation results from tuberin and Rheb mediated mammalian target of rapamycin ( mTOR ) hyperactivation , leading to S6-kinase-dependent degradation of p27 .	Moreover, f-BRAF-driven NSC proliferation results from tuberin and Rheb mediated mammalian target of rapamycin (mTOR) hyperactivation, leading to S6-kinase-dependent degradation of p27.	5	15	mediated	Positive_early_activation	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	9	10	11	15
The small G protein Rheb activates the mechanistic target of rapamycin complex 1 ( mTORC1 ) in response to growth factor signals .	The small G protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals.	0	11	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rheb	Rheb	Rheb	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	4	5	7	11
Full-length TSC2 protein interacts with TSC1 to inhibit the activation of mTOR by Rheb .	Full-length TSC2 protein interacts with TSC1 to inhibit the activation of mTOR by Rheb.	7	14	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	13	14	11	12
Accordingly , mTOR activity is exquisitely sensitive to cell energy status , sensed through a complex circuitry involving the AMP activated kinase , a serine threonine kinase activated by the reduction of intracellular ATP and the increase of AMP and ATP ratio [ XREF_BIBR ] Phosphorylation of the TSC1 and TSC2 complex by AMPK and the consequent inactivation of the GTPase Rheb , an upstream activator of mTOR , profoundly inhibits mTOR signaling , thereby reducing protein synthesis and promoting cell survival under nutrient restriction [ XREF_BIBR ] .	Accordingly, mTOR activity is exquisitely sensitive to cell energy status, sensed through a complex circuitry involving the AMP activated kinase, a serine threonine kinase activated by the reduction of intracellular ATP and the increase of AMP and ATP ratio [XREF_BIBR] Phosphorylation of the TSC1 and TSC2 complex by AMPK and the consequent inactivation of the GTPase Rheb, an upstream activator of mTOR, profoundly inhibits mTOR signaling, thereby reducing protein synthesis and promoting cell survival under nutrient restriction [XREF_BIBR].	61	72	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	mTOR	mTOR	mTOR	61	62	71	72
All renin parameters including renin activity , active and total renin content in plasma were significantly suppressed following AngII infusion , which was unaffected by ONO treatment ( XREF_FIG ) .	All renin parameters including renin activity, active and total renin content in plasma were significantly suppressed following AngII infusion, which was unaffected by ONO treatment (XREF_FIG).	1	19	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	AngII	AngII	AngII	1	2	18	19
Benazepril did not alter mean arterial pressure , markedly increased plasma renin activity , reduced plasma angiotensin II , and caused a nonsignificant reduction in plasma norepinephrine .	Benazepril did not alter mean arterial pressure, markedly increased plasma renin activity, reduced plasma angiotensin II, and caused a nonsignificant reduction in plasma norepinephrine.	11	18	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	11	12	16	18
Firstly , marked increases in plasma renin levels are accompanied by marked decreases in plasma angiotensinogen levels , thereby attenuating any effect of increased renin levels on Ang I levels in blood .	Firstly, marked increases in plasma renin levels are accompanied by marked decreases in plasma angiotensinogen levels, thereby attenuating any effect of increased renin levels on Ang I levels in blood.	6	29	attenuating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin levels	renin	Ang I	Ang I	ang i	6	7	27	29
It acts at the point of activation of the renin-angiotensin-aldosterone system , or renin system , inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin converting enzyme ( ACE ) and ACE independent pathways .	It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin converting enzyme (ACE) and ACE independent pathways.	16	26	inhibiting	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	25	26	22	24
Renin has long been recognized as a preferred site for blockade of the renin-angiotensin-aldosterone system because it prevents conversion of angiotensinogen to angiotensin I. Aliskiren binds to the active site of the renin molecule , blocking angiotensinogen cleavage , thus , preventing the formation of angiotensin I. Clinical studies have demonstrated at least equivalent or superior blood pressure lowering efficacy compared with existing drugs with a favorable side effect profile .	Renin has long been recognized as a preferred site for blockade of the renin-angiotensin-aldosterone system because it prevents conversion of angiotensinogen to angiotensin I. Aliskiren binds to the active site of the renin molecule, blocking angiotensinogen cleavage, thus, preventing the formation of angiotensin I. Clinical studies have demonstrated at least equivalent or superior blood pressure lowering efficacy compared with existing drugs with a favorable side effect profile.	32	37	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	32	33	36	37
Overall renal functional response to exercise remained unchanged , possibly because of inhibition of renin mediated angiotensin II generation and cyclo-oxygenase-1 mediated thromboxane A 2 synthesis .	Overall renal functional response to exercise remained unchanged, possibly because of inhibition of renin mediated angiotensin II generation and cyclo-oxygenase-1 mediated thromboxane A 2 synthesis.	12	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	14	15	16	18
Aliskiren is an orally-active , nonpeptidic , direct inhibitor of renin which simultaneously reduces angiotensin I , angiotensin II and plasma renin activity ( PRA ) .	Aliskiren is an orally-active, nonpeptidic, direct inhibitor of renin which simultaneously reduces angiotensin I, angiotensin II and plasma renin activity (PRA).	8	24	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	10	11	17	19
Inhibition of ACE-I prevents the formation of angiotensin II , a potent vasoconstrictor while renin inhibition prevents the formation of angiotensin I , the precursor of angiotensin II [ XREF_BIBR ] .	Inhibition of ACE-I prevents the formation of angiotensin II, a potent vasoconstrictor while renin inhibition prevents the formation of angiotensin I, the precursor of angiotensin II [XREF_BIBR].	14	24	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	14	15	20	22
Increased renin and/or angiotensin II in the blood passing through the placental anastomoses may , by an endocrine action , suppress renin synthesis in the recipient kidney , thereby increasing renal blood flow and causing polyuria and polyhydramnios .	Increased renin and/or angiotensin II in the blood passing through the placental anastomoses may, by an endocrine action, suppress renin synthesis in the recipient kidney, thereby increasing renal blood flow and causing polyuria and polyhydramnios.	0	21	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	1	2	3	5
As PAC is dependent upon both angiotensinogen production by the liver and angiotensinogen degradation by renin , the decrease in PAC observed in hyperthyroidism could be due to an increase in plasma renin concentration , which would overcome the increased synthesis of liver angiotensinogen observed in these animals .	As PAC is dependent upon both angiotensinogen production by the liver and angiotensinogen degradation by renin, the decrease in PAC observed in hyperthyroidism could be due to an increase in plasma renin concentration, which would overcome the increased synthesis of liver angiotensinogen observed in these animals.	10	16	degradation	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	15	16	12	13
Angiotensin II ( Ang II ) , the product of sequential degradation of angiotensinogen by renin and ACE , increases BP by mechanisms that include ( i ) vasoconstriction via AT1R in the vasculature and via increasing sympathetic tone and the release of arginine vasopressin , ( ii ) modulation of renal sodium and water reabsorption by stimulating renal AT1R , the production and release of aldosterone from the adrenal glands , or the sensation of thirst in the central nervous system .	Angiotensin II (Ang II), the product of sequential degradation of angiotensinogen by renin and ACE, increases BP by mechanisms that include (i) vasoconstriction via AT1R in the vasculature and via increasing sympathetic tone and the release of arginine vasopressin, (ii) modulation of renal sodium and water reabsorption by stimulating renal AT1R, the production and release of aldosterone from the adrenal glands, or the sensation of thirst in the central nervous system.	11	17	degradation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	15	16	13	14
Angiotensin II ( Ang II ) , the product of sequential degradation of angiotensinogen by renin and ACE and the final effector of the RAS system , increases blood pressure by mechanisms that include ( i ) vasoconstriction via AT1R activation in the vasculature and via increasing sympathetic tone and the release of arginine vasopressin , ( ii ) modulation of renal sodium and water reabsorption by stimulating renal AT1R , the production and release of aldosterone from the adrenal glands , or the sensation of thirst in the central nervous system .	Angiotensin II (Ang II), the product of sequential degradation of angiotensinogen by renin and ACE and the final effector of the RAS system, increases blood pressure by mechanisms that include (i) vasoconstriction via AT1R activation in the vasculature and via increasing sympathetic tone and the release of arginine vasopressin, (ii) modulation of renal sodium and water reabsorption by stimulating renal AT1R, the production and release of aldosterone from the adrenal glands, or the sensation of thirst in the central nervous system.	11	21	degradation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	15	16	13	14
Ang II , the product of sequential degradation of angiotensinogen by renin and ACE and the final effector of the RAS , increases blood pressure by mechanisms that include ( i ) vasoconstriction via AT1R activation in the vasculature as well as increasing sympathetic tone and the release of arginine vasopressin , ( ii ) modulation of renal sodium and water reabsorption by stimulating renal AT1R , the production and release of aldosterone from the adrenal glands , or the sensation of thirst in the central nervous system .	Ang II, the product of sequential degradation of angiotensinogen by renin and ACE and the final effector of the RAS, increases blood pressure by mechanisms that include (i) vasoconstriction via AT1R activation in the vasculature as well as increasing sympathetic tone and the release of arginine vasopressin, (ii) modulation of renal sodium and water reabsorption by stimulating renal AT1R, the production and release of aldosterone from the adrenal glands, or the sensation of thirst in the central nervous system.	7	17	degradation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	11	12	9	10
The major angiotensin I generating activity of rat brain extracts has a pH optimum different from that of renal renin and is not inhibited by renin specific antibody .	The major angiotensin I generating activity of rat brain extracts has a pH optimum different from that of renal renin and is not inhibited by renin specific antibody.	0	27	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	25	26	2	4
Thus , a sustained renin inhibition by Ro 42-5892 , as indicated by increased plasma active renin levels , induces a much shorter fall in plasma Ang I and II apparently because of a rise in renin secretion .	Thus, a sustained renin inhibition by Ro 42-5892, as indicated by increased plasma active renin levels, induces a much shorter fall in plasma Ang I and II apparently because of a rise in renin secretion.	4	28	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	Ang I	Ang I	Ang I	4	5	26	28
In contrast however , total plasma renin and prorenin was significantly decreased ( P < 0.05 ) in all animals that received AngII ( XREF_FIG ) .	In contrast however, total plasma renin and prorenin was significantly decreased (P < 0.05) in all animals that received AngII (XREF_FIG).	4	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	AngII	AngII	AngII	6	7	22	23
ASO against AGT reduces intact AGT and des ( AngI ) AGT , leading to reductions of total AGT , whereas renin inhibition increases intact AGT and reduces des ( AngI ) AGT with no changes of total plasma AGT .	ASO against AGT reduces intact AGT and des (AngI) AGT, leading to reductions of total AGT, whereas renin inhibition increases intact AGT and reduces des (AngI) AGT with no changes of total plasma AGT.	21	35	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	AGT	AGT	AGT	21	22	32	33
Human renin mRNA was not suppressed by nonpressor angiotensin II and was paradoxically increased 1.9-fold by pressor angiotensin II.	Human renin mRNA was not suppressed by nonpressor angiotensin II and was paradoxically increased 1.9-fold by pressor angiotensin II.	1	10	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	angiotensin II	angiotensin II	angiotensin II	1	2	8	10
As captopril increases prorenin and active renin levels but prevents the formation of Ang II , our study excludes angiotensin independent effects of prorenin and supports angiotensin dependent effects of prorenin in the pathogenesis of polyarteritis nodosa .	As captopril increases prorenin and active renin levels but prevents the formation of Ang II, our study excludes angiotensin independent effects of prorenin and supports angiotensin dependent effects of prorenin in the pathogenesis of polyarteritis nodosa.	1	15	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	captopril increases prorenin and active renin levels	renin	Ang II	Ang II	ang ii	6	7	13	15
It is known that binding of prorenin to the M6PR results in degradation of renin preventing further ANG I generation [ XREF_BIBR ] .	It is known that binding of prorenin to the M6PR results in degradation of renin preventing further ANG I generation [XREF_BIBR].	12	19	preventing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	ANG I	ANG I	ANG I	14	15	17	19
A recent study in obese mice fed with a high fat diet demonstrated that systemic inhibition of renin via aliskiren elicited a decline of adipose Ang I and Ang II , visceral adiposity and plasma leptin .	A recent study in obese mice fed with a high fat diet demonstrated that systemic inhibition of renin via aliskiren elicited a decline of adipose Ang I and Ang II, visceral adiposity and plasma leptin.	15	30	elicited	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	Ang II	Ang II	Ang II	17	18	28	30
AngII significantly increased mean arterial blood pressure ( +14 +/- 4 mmHg ) and plasma aldosterone by 79 % ( +149 +/- 17 pg mL (-1) ) and reduced plasma renin activity and sodium excretion ( -41 +/- 16 mIU L (-1) and -46 +/- 6 micromol min (-1) respectively ) .	AngII significantly increased mean arterial blood pressure (+14 +/- 4 mmHg) and plasma aldosterone by 79% (+149 +/- 17 pg mL (-1)) and reduced plasma renin activity and sodium excretion (-41 +/- 16 mIU L (-1) and -46 +/- 6 micromol min (-1) respectively).	0	31	increased	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	renin	renin	renin	AngII	AngII	AngII	30	31	0	1
Inhibition of angiotensin-II production by renin and/or CAP drugs greatly restored the oxidative stress due to MI/R damage in mitochondria , cytosol , and plasma , as evident from decreased total oxidants and increased levels of antioxidants ( p < 0.001 vs. MI/R ; XREF_FIG XREF_FIG XREF_FIG - XREF_FIG ) .	Inhibition of angiotensin-II production by renin and/or CAP drugs greatly restored the oxidative stress due to MI/R damage in mitochondria, cytosol, and plasma, as evident from decreased total oxidants and increased levels of antioxidants (p < 0.001 vs. MI/R; XREF_FIG XREF_FIG XREF_FIG - XREF_FIG).	2	8	production	Positive_activation_syntax_2_noun	Positive_activation	Positive_activation	renin	renin	renin	angiotensin-II	angiotensin-II	angiotensin-II	5	6	2	3
The reduction in mRNA levels for renin and neprilysin in the medulla may reflect feedback inhibition by Ang-( 1-7 ) as these enzymes would be involved in the formation of the peptide , although the reduction in renin would tend to reduce Ang II as well .	The reduction in mRNA levels for renin and neprilysin in the medulla may reflect feedback inhibition by Ang-(1-7) as these enzymes would be involved in the formation of the peptide, although the reduction in renin would tend to reduce Ang II as well.	35	44	reduce	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	renin	renin	renin	Ang II	Ang II	Ang II	37	38	42	44
In the medulla oblongata , angiotensinogen mRNA was reduced only by the higher renin dose .	In the medulla oblongata, angiotensinogen mRNA was reduced only by the higher renin dose.	5	14	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	13	14	5	6
We postulate that renin ( or des-angiotensin I-angiotensinogen ) inhibits the angiotensinogen release rate , whereas angiotensin II stimulates it .	We postulate that renin (or des-angiotensin I-angiotensinogen) inhibits the angiotensinogen release rate, whereas angiotensin II stimulates it.	3	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	3	4	11	12
It blinds to the S1/S3 pocket at the active site of renin molecule thus preventing the conversion of angiotensinogen to Ang I. Aliskiren is a potent inhibitor of renin with an IC 50 ( concentration inhibiting 50 % of activity ) of 0.6 nmol/L .	It blinds to the S1/S3 pocket at the active site of renin molecule thus preventing the conversion of angiotensinogen to Ang I. Aliskiren is a potent inhibitor of renin with an IC 50 (concentration inhibiting 50% of activity) of 0.6 nmol/L.	11	19	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	11	12	18	19
Ang II , the product of sequential degradation of angiotensinogen by renin and ACE , and the final effector of the RAS system , increases blood pressure by : ( 1 ) vasoconstriction via AT1R activation , increased sympathetic tone and the release of arginine vasopressin ; and ( 2 ) modulation of renal sodium and water reabsorption by stimulating renal AT1R , the production and release of aldosterone or the sensation of thirst in the central nervous system .	Ang II, the product of sequential degradation of angiotensinogen by renin and ACE, and the final effector of the RAS system, increases blood pressure by : (1) vasoconstriction via AT1R activation, increased sympathetic tone and the release of arginine vasopressin; and (2) modulation of renal sodium and water reabsorption by stimulating renal AT1R, the production and release of aldosterone or the sensation of thirst in the central nervous system.	7	18	degradation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	renin	renin	renin	angiotensinogen	angiotensinogen	angiotensinogen	11	12	9	10
Plasma renin activity was reduced , that of angiotensin I converting enzyme was augmented , and plasma aldosterone concentrations were unchanged .	Plasma renin activity was reduced, that of angiotensin I converting enzyme was augmented, and plasma aldosterone concentrations were unchanged.	1	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	renin	renin	renin	angiotensin I	angiotensin I	angiotensin I	1	2	8	10
Ret is a potent activator of both PI3K and Akt and Ras and ERK , and the loss of cell bodies , axons , and reduced cell size in DAT-Ret mice suggest possible defects in PI3K and Akt and/or Ras and ERK signaling .	Ret is a potent activator of both PI3K and Akt and Ras and ERK, and the loss of cell bodies, axons, and reduced cell size in DAT-Ret mice suggest possible defects in PI3K and Akt and/or Ras and ERK signaling.	0	42	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ret	Ret	Ret	ERK	ERK	ERK	0	1	41	42
The stable transfection of RET mutated TPC-1 cell line with vector for the overexpression of let-7f inhibited the MAPK activation and reduced cell proliferation .	The stable transfection of RET mutated TPC-1 cell line with vector for the overexpression of let-7f inhibited the MAPK activation and reduced cell proliferation.	2	19	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RET	RET	RET	MAPK	MAPK	MAPK	4	5	18	19
The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK : substitution of the tyrosine 1062 of Ret , the Shc binding site , for phenylalanine abrogates ERK but not JNK activation .	The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK : substitution of the tyrosine 1062 of Ret, the Shc binding site, for phenylalanine abrogates ERK but not JNK activation.	22	42	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ret	Ret	Ret	ERK	ERK	ERK	28	29	38	39
Based on these findings , it was concluded that the coexpression of MYC-RET and GFP-ShcD downregulated ERK and AKT signal transduction in GDNF treated cells .	Based on these findings, it was concluded that the coexpression of MYC-RET and GFP-ShcD downregulated ERK and AKT signal transduction in GDNF treated cells.	10	20	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MYC-RET	coexpression of MYC-RET	myc-ret	ERK	ERK	erk	12	13	16	17
Furthermore , we established RET as a molecular marker for response to TKI treatment by demonstrating that only RET positive breast tumors reduced ERK1/2 activation in response to TKI treatment .	Furthermore, we established RET as a molecular marker for response to TKI treatment by demonstrating that only RET positive breast tumors reduced ERK1/2 activation in response to TKI treatment.	18	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RET	RET	RET	ERK1/2	ERK1/2	ERK1/2	18	19	23	24
Moreover , only two RET variants ( p. ( Ala756Val ) and p. ( Tyr1062Cys ) ) resulted in reduced ERK activation .	Moreover, only two RET variants (p. (Ala756Val) and p. (Tyr1062Cys)) resulted in reduced ERK activation.	4	22	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	RET	RET	RET	ERK	ERK	ERK	4	5	20	21
Previous studies have revealed that RET activates the Raf and MEK and PI3K and Akt downstream signaling pathways , which in turn phosphorylate and activate ERK1/2 and mammalian target of rapamycin ( mTOR ) proteins , respectively .	Previous studies have revealed that RET activates the Raf and MEK and PI3K and Akt downstream signaling pathways, which in turn phosphorylate and activate ERK1/2 and mammalian target of rapamycin (mTOR) proteins, respectively.	5	28	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	ERK1/2	ERK1/2	ERK1/2	5	6	25	26
RET knockdown inhibits tumor growth in vivo , and mechanically , RET activates ERK or AKT signaling to promote transformation associated phenotypes , including perineural invasion via activation of p70S6 kinase XREF_BIBR .	RET knockdown inhibits tumor growth in vivo, and mechanically, RET activates ERK or AKT signaling to promote transformation associated phenotypes, including perineural invasion via activation of p70S6 kinase XREF_BIBR.	11	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET	RET	ERK	ERK	ERK	11	12	13	14
However , depletion of RhoA with shRNA could attenuate MC-3129-mediated ROCK1 activation .	However, depletion of RhoA with shRNA could attenuate MC-3129-mediated ROCK1 activation.	2	11	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	4	5	10	11
To determine whether ROCK1 activity was necessary for Beclin1 interaction , cells were treated with a well established Rho kinase inhibitor , Y27632 , and endogenous ROCK1 or Beclin1 was pulled down in the presence or absence of HBSS .	To determine whether ROCK1 activity was necessary for Beclin1 interaction, cells were treated with a well established Rho kinase inhibitor, Y27632, and endogenous ROCK1 or Beclin1 was pulled down in the presence or absence of HBSS.	3	20	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	18	19	3	4
The pathways involved in the effects of ROCK knockdown in glioblastoma cells were analyzed using Western blot analysis to determine the protein expression levels of phosphoLimK , phosphoRac1 and cdc42 , cyclin D1 , Akt1 , phosphoAkt , beta1-integrin , beta-catenin , phosphoERK1/2 , and RhoA in cells with a stable ROCK1 and ROCK2 knockdown as well as in glioma cells treated with 100muM of Rho kinase inhibitor .	The pathways involved in the effects of ROCK knockdown in glioblastoma cells were analyzed using Western blot analysis to determine the protein expression levels of phosphoLimK, phosphoRac1 and cdc42, cyclin D1, Akt1, phosphoAkt, beta1-integrin, beta-catenin, phosphoERK1/2, and RhoA in cells with a stable ROCK1 and ROCK2 knockdown as well as in glioma cells treated with 100muM of Rho kinase inhibitor.	47	67	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	65	66	51	52
Depletion of RhoA with shRNA attenuated MC-3129-mediated ROCK1 activation .	Depletion of RhoA with shRNA attenuated MC-3129-mediated ROCK1 activation.	0	8	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	2	3	7	8
Recent study from our laboratory also showed that RhoA deletion up-regulates the activity of its downstream effector ROCK1 in peritoneal macrophages , and that this effect depends on non apoptotic Caspase-3 .	Recent study from our laboratory also showed that RhoA deletion up-regulates the activity of its downstream effector ROCK1 in peritoneal macrophages, and that this effect depends on non apoptotic Caspase-3.	8	20	up-regulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RhoA	RhoA	RhoA	ROCK1	ROCK1	ROCK1	8	9	17	18
Treatment by Rho kinase inhibitor or genetic deletion of ROCK1 rescued the mouse apoptotic phenotype with partial improvement of cardiac functions .	Treatment by Rho kinase inhibitor or genetic deletion of ROCK1 rescued the mouse apoptotic phenotype with partial improvement of cardiac functions.	2	10	inhibitor	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Rho	Rho	Rho	ROCK1	ROCK1	ROCK1	2	3	9	10
Overexpression of p65 is thought to limit the availability of CBP for Nrf2 complex formation , prioritizing transcription of the kappaB driven genes .	Overexpression of p65 is thought to limit the availability of CBP for Nrf2 complex formation, prioritizing transcription of the kappaB driven genes.	0	11	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p65	Overexpression of p65	p65	CBP	CBP	cbp	2	3	10	11
Importantly , AR could also repress gene activation by AP1 and RelA through sequestration of CREB binding protein [ XREF_BIBR ; XREF_BIBR ] .	Importantly, AR could also repress gene activation by AP1 and RelA through sequestration of CREB binding protein [XREF_BIBR; XREF_BIBR].	5	18	repress	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	RelA	RelA	RelA	CREB binding protein	CREB binding protein	CREB binding protein	11	12	15	18
Taken together , these results suggest that the benefits of RET are associated with increased autophagy activity and reduced apoptosis of muscle cells by modulating IGF-1 and its receptors , the Akt and mTOR and Akt and FOXO3a signaling pathways in aged skeletal muscles .	Taken together, these results suggest that the benefits of RET are associated with increased autophagy activity and reduced apoptosis of muscle cells by modulating IGF-1 and its receptors, the Akt and mTOR and Akt and FOXO3a signaling pathways in aged skeletal muscles.	8	35	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RET	RET	RET	Akt	Akt	Akt	10	11	31	32
Ret inhibition blocks the feed-forward loop by down-regulating Ret levels , as well as decreasing activity of Fak , an integrator of IL6-Ret signalling .	Ret inhibition blocks the feed-forward loop by down-regulating Ret levels, as well as decreasing activity of Fak, an integrator of IL6-Ret signalling.	0	20	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ret	Ret	Ret	Fak	Fak	Fak	0	1	17	18
Here , we show that the Ret tyrosine kinase is also degraded by autophagy in cancer cells with altered and reduced FAK signalling , preventing its binding to FAK at integrin adhesions .	Here, we show that the Ret tyrosine kinase is also degraded by autophagy in cancer cells with altered and reduced FAK signalling, preventing its binding to FAK at integrin adhesions.	6	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Ret	Ret	Ret	FAK	FAK	FAK	6	7	21	22
Previous reports state that RET binds to the FERM domain of FAK , an interaction that results in transactivation of both proteins [ XREF_BIBR ] , and that RET is degraded by autophagy in cancer cells with altered and reduced FAK signalling , preventing RET binding to FAK at focal adhesions [ XREF_BIBR ] .	Previous reports state that RET binds to the FERM domain of FAK, an interaction that results in transactivation of both proteins [XREF_BIBR], and that RET is degraded by autophagy in cancer cells with altered and reduced FAK signalling, preventing RET binding to FAK at focal adhesions [XREF_BIBR].	28	41	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RET	RET	RET	FAK	FAK	FAK	28	29	40	41
RET transcription was suppressed by CD133 in NB cells and glial cell line derived neurotrophic factor treatment failed to induce RET in CD133 expressing cells ; RET overexpression rescued CD133 related inhibition of neurite elongation .	RET transcription was suppressed by CD133 in NB cells and glial cell line derived neurotrophic factor treatment failed to induce RET in CD133 expressing cells; RET overexpression rescued CD133 related inhibition of neurite elongation.	0	22	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RET	RET transcription was suppressed by CD133 in NB cells and glial cell line derived neurotrophic factor	ret	RET	RET	ret	0	1	20	21
PKCalpha , in turn , causes RET phosphorylation and downregulates RET tyrosine kinase and downstream signaling , thus functioning as a negative feedback loop to modulate RET activity .	PKCalpha, in turn, causes RET phosphorylation and downregulates RET tyrosine kinase and downstream signaling, thus functioning as a negative feedback loop to modulate RET activity.	0	12	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RET	PKCalpha, in turn, causes RET phosphorylation	ret	RET	RET	ret	6	7	10	11
In addition , the NF-kappaB inhibitor , BAY 11-7082 , p65 knockdown , or Tax defective for NF-kappaB activation each reduced Tax mediated EGR1 upregulation , further confirming the importance of NF-kappaB activation in EGR1 expression .	In addition, the NF-kappaB inhibitor, BAY 11-7082, p65 knockdown, or Tax defective for NF-kappaB activation each reduced Tax mediated EGR1 upregulation, further confirming the importance of NF-kappaB activation in EGR1 expression.	10	24	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p65	p65	p65	EGR1	EGR1	EGR1	10	11	23	24
Moreover , p65 knockdown impaired Tax- and M47 Tax induced EGR1 mediated transcriptional activity .	Moreover, p65 knockdown impaired Tax- and M47 Tax induced EGR1 mediated transcriptional activity.	2	11	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p65	p65	p65	EGR1	EGR1	EGR1	2	3	10	11
In a pancreatic cancer cell line , Reelin inhibits cell migration via its high affinity receptors ApoER2 and VLDLR and intracellular adaptor protein Dab1 XREF_BIBR .	In a pancreatic cancer cell line, Reelin inhibits cell migration via its high affinity receptors ApoER2 and VLDLR and intracellular adaptor protein Dab1 XREF_BIBR.	7	24	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Reelin	Reelin	Reelin	VLDLR	VLDLR	VLDLR	7	8	18	19
We observed that Reelin treatment decreased the immunoprecipitation of VLDLR with each of the binding partners identified here , GluA1 , RasGRF1 , and CamKIIalpha .	We observed that Reelin treatment decreased the immunoprecipitation of VLDLR with each of the binding partners identified here, GluA1, RasGRF1, and CamKIIalpha.	3	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Reelin	Reelin	Reelin	VLDLR	VLDLR	VLDLR	3	4	9	10
The present review focuses on experimental and clinical studies evaluating the two principal approaches to renin inhibition , namely direct renin inhibition with aliskiren and inhibition of the ( pro ) renin receptor .	The present review focuses on experimental and clinical studies evaluating the two principal approaches to renin inhibition, namely direct renin inhibition with aliskiren and inhibition of the (pro) renin receptor.	20	33	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	renin	renin	renin	renin receptor	renin receptor	renin receptor	20	21	31	33
Inhibition of Rho with C3 exotoxin and a dominant negative Rho adenovirus and inhibition of ROCK with Y-27632 inhibited Cch stimulated PLD1 activity , increased protein secretion , and decreased ERK activity .	Inhibition of Rho with C3 exotoxin and a dominant negative Rho adenovirus and inhibition of ROCK with Y-27632 inhibited Cch stimulated PLD1 activity, increased protein secretion, and decreased ERK activity.	10	22	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rho	Rho	Rho	PLD1	PLD1	PLD1	10	11	21	22
The N-terminal 43-amino-acid region of p65 , which is required to interact with Sp1 , is essential to repress the Sp1 mediated transactivation .	The N-terminal 43-amino-acid region of p65, which is required to interact with Sp1, is essential to repress the Sp1 mediated transactivation.	3	22	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p65	p65	p65	Sp1	Sp1	Sp1	5	6	20	21
However , the exogenous expression of RBM15 or its deletion mutants did not cause mRNA export inhibition or excessive accumulation of poly ( A ) + RNA or DBP5 at the nuclear envelope ( data not shown ) , and hence there is no evidence to support an indirect stimulation .	However, the exogenous expression of RBM15 or its deletion mutants did not cause mRNA export inhibition or excessive accumulation of poly (A) + RNA or DBP5 at the nuclear envelope (data not shown), and hence there is no evidence to support an indirect stimulation.	4	29	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RBM15	expression of RBM15	rbm15	DBP5	DBP5	dbp5	6	7	28	29
Downregulation of Rheb , either by siRNA knockdown or TSC2 overexpression , reduces mitogen stimulated PLD1 activation .	Downregulation of Rheb, either by siRNA knockdown or TSC2 overexpression, reduces mitogen stimulated PLD1 activation.	0	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Rheb	Rheb	Rheb	PLD1	PLD1	PLD1	2	3	15	16
Alternatively , pRb inhibition of Id2 has been suggested to potentiate MyoD activity .	Alternatively, pRb inhibition of Id2 has been suggested to potentiate MyoD activity.	2	12	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	pRb	pRb	pRb	MyoD	MyoD	MyoD	2	3	11	12
Ubiquitylation of RIP1 blocks the complex formation to induce activation of caspase-8 , and instead induces NF-kappaB activation [ XREF_BIBR ] .	Ubiquitylation of RIP1 blocks the complex formation to induce activation of caspase-8, and instead induces NF-kappaB activation [XREF_BIBR].	0	12	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIP1	Ubiquitylation of RIP1	rip1	caspase-8	caspase-8	caspase-8	2	3	11	12
16-20 Loss of cIAP1 and cIAP2 leads to diminished ubiquitylation of RIPK1 and activates caspase-8 .	16-20 Loss of cIAP1 and cIAP2 leads to diminished ubiquitylation of RIPK1 and activates caspase-8.	1	15	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	Loss of cIAP1 and cIAP2 leads to diminished ubiquitylation of RIPK1	ripk1	caspase-8	caspase-8	caspase-8	11	12	14	15
Notably , genetic ablation of RIPK1 kinase activity also abrogated YopJ induced cleavage of caspase-8 and caspase-3 ( XREF_FIG ) .	Notably, genetic ablation of RIPK1 kinase activity also abrogated YopJ induced cleavage of caspase-8 and caspase-3 (XREF_FIG).	5	18	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	5	6	14	15
CYLD deficiency leads to hyperubiquitinated RIPK1 in the necrosome and impaired phosphorylation of RIPK1 and RIPK3 , thereby blocking caspase-8 activation .	CYLD deficiency leads to hyperubiquitinated RIPK1 in the necrosome and impaired phosphorylation of RIPK1 and RIPK3, thereby blocking caspase-8 activation.	0	20	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	CYLD deficiency leads to hyperubiquitinated RIPK1 in the necrosome and impaired phosphorylation of RIPK1	ripk1	caspase-8	caspase-8	caspase-8	13	14	19	20
Toll like receptors 3 and 4 can directly activate RIP3 via TRIF , a RHIM containing protein.16 Moreover , RIP1 may even antagonize necrosis by activating caspase 8 , the strong inhibitor of RIP3 mediated necrosis signalling .	Toll like receptors 3 and 4 can directly activate RIP3 via TRIF, a RHIM containing protein.16 Moreover, RIP1 may even antagonize necrosis by activating caspase 8, the strong inhibitor of RIP3 mediated necrosis signalling.	19	28	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIP1	RIP1	RIP1	caspase 8	caspase 8	caspase 8	19	20	26	28
The BIR3 domains of cIAP1 and cIAP2 bind the kinase RIP1 , while their E3 ligase activity mediates ubiquitination of RIP1 , stimulating NF-kappaB activation and suppressing activation of caspase-8 [ XREF_BIBR ] .	The BIR3 domains of cIAP1 and cIAP2 bind the kinase RIP1, while their E3 ligase activity mediates ubiquitination of RIP1, stimulating NF-kappaB activation and suppressing activation of caspase-8 [XREF_BIBR].	8	31	suppressing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	10	11	29	30
Deficiency of RIP1 negated induction of IL-8 secretion as well as induction of caspase-8 activity .	Deficiency of RIP1 negated induction of IL-8 secretion as well as induction of caspase-8 activity.	0	14	negated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	2	3	13	14
Interestingly , we observed that silencing of RIPK1 by shRNA in RCC cells caused caspase-8 and PARP1 cleavage ( XREF_SUPPLEMENTARY ) , indicating apoptotic death .	Interestingly, we observed that silencing of RIPK1 by shRNA in RCC cells caused caspase-8 and PARP1 cleavage (XREF_SUPPLEMENTARY), indicating apoptotic death.	5	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	7	8	14	15
To confirm that RIPK1 inhibition rescued Caspase8 depleted cells , we knocked down RIPK1 using siRNA instead of chemical inhibition with NEC1 .	To confirm that RIPK1 inhibition rescued Caspase8 depleted cells, we knocked down RIPK1 using siRNA instead of chemical inhibition with NEC1.	3	7	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	Caspase8	Caspase8	Caspase8	3	4	6	7
Recent evidence indicates that FADD and caspase-8 deficiency can be rescued by RIP3 and RIP1 deletion .	Recent evidence indicates that FADD and caspase-8 deficiency can be rescued by RIP3 and RIP1 deletion.	4	15	rescued	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	14	15	6	7
Accordingly , depletion of Ripk1 by RNAi completely abolished CASP8 and MYO7A proximity signals ( XREF_FIG , compare d ( ii ) and d ( iii ) with d ( iv ) ) .	Accordingly, depletion of Ripk1 by RNAi completely abolished CASP8 and MYO7A proximity signals (XREF_FIG, compare d (ii) and d (iii) with d (iv)).	2	13	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Ripk1	Ripk1	Ripk1	CASP8	CASP8	CASP8	4	5	9	10
Deletion of either Ripk1 or Ripk3 rescues embryonic lethality associated with the global knockout of FADD and Casp8 in mice , but not FLIP XREF_BIBR , XREF_BIBR , XREF_BIBR .	Deletion of either Ripk1 or Ripk3 rescues embryonic lethality associated with the global knockout of FADD and Casp8 in mice, but not FLIP XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	23	rescues	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ripk1	Ripk1	Ripk1	Casp8	Casp8	Casp8	3	4	17	18
We show that genetic deletion of Ripk1 licenses TRADD to complex with FADD-caspase-8 and activates caspase-8 during development .	We show that genetic deletion of Ripk1 licenses TRADD to complex with FADD-caspase-8 and activates caspase-8 during development.	6	16	activates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Ripk1	Ripk1	Ripk1	caspase-8	caspase-8	caspase-8	6	7	15	16
To determine whether A20 , TRAF2 and RIP1 inhibit caspase-8 cleavage in the complex , we conducted knockdown experiments by transfecting in TRAIL resistant cell lines with small interfering RNA ( siRNA ) specific to A20 , RIP1 and TRAF2 .	To determine whether A20, TRAF2 and RIP1 inhibit caspase-8 cleavage in the complex, we conducted knockdown experiments by transfecting in TRAIL resistant cell lines with small interfering RNA (siRNA) specific to A20, RIP1 and TRAF2.	3	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	7	8	9	10
Knockdown of RIP1 abolishes formation of this complex and subsequent activation of caspase-8 and -3 , mitochondrial perturbations and apoptosis .	Knockdown of RIP1 abolishes formation of this complex and subsequent activation of caspase-8 and -3, mitochondrial perturbations and apoptosis.	0	13	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	caspase-8	caspase-8	caspase-8	2	3	12	13
Both RIP-1 interference and BAY11-7082 significantly suppressed caspase-8 and caspase-3 activity ( XREF_FIG ) , and promoted cell apoptosis ( XREF_FIG ) .	Both RIP-1 interference and BAY11-7082 significantly suppressed caspase-8 and caspase-3 activity (XREF_FIG), and promoted cell apoptosis (XREF_FIG).	1	10	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIP-1	RIP-1	RIP-1	caspase-8	caspase-8	caspase-8	1	2	7	8
Knockdown of RIPK1 effectively suppressed activation of caspase-8 in poly I : C treated cells .	Knockdown of RIPK1 effectively suppressed activation of caspase-8 in poly I : C treated cells.	0	8	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RIPK1	RIPK1	RIPK1	caspase-8	caspase-8	caspase-8	2	3	7	8
The RIPK1 kinase inhibitor Nec-1 failed to reverse the enhanced caspase 8 activation by the RIPK3 inhibitor ( XREF_SUPPLEMENTARY ) .	The RIPK1 kinase inhibitor Nec-1 failed to reverse the enhanced caspase 8 activation by the RIPK3 inhibitor (XREF_SUPPLEMENTARY).	1	12	reverse	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	caspase 8	caspase 8	caspase 8	1	2	10	12
However , RIPK1 ablation could not prevent the death of NEMO deficient hepatocytes showing that kinase independent scaffolding properties of RIPK1 are required to prevent hepatocyte apoptosis .	However, RIPK1 ablation could not prevent the death of NEMO deficient hepatocytes showing that kinase independent scaffolding properties of RIPK1 are required to prevent hepatocyte apoptosis.	2	12	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	NEMO	NEMO	NEMO	2	3	10	11
Remarkably , combined LPC specific deficiency of RIPK1 and TRADD , but not of TRADD alone , prevented hepatocyte apoptosis and HCC development in NEMO LPC-KO animals .	Remarkably, combined LPC specific deficiency of RIPK1 and TRADD, but not of TRADD alone, prevented hepatocyte apoptosis and HCC development in NEMO LPC-KO animals.	5	26	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	NEMO	NEMO	NEMO	7	8	24	25
RIPK1 Kinase Activity Dependent Death of IECs Causes Colitis and Paneth Cell Loss in NEMO IEC-KO Mice .	RIPK1 Kinase Activity Dependent Death of IECs Causes Colitis and Paneth Cell Loss in NEMO IEC-KO Mice.	0	16	Causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	NEMO	NEMO	NEMO	0	1	14	15
However , RIPK1 ablation in LPC using RIPK1 floxed mice could not prevent the death of NEMO deficient hepatocytes showing that kinase independent platform properties of RIPK1 are required to prevent hepatocyte apoptosis ( this was prevented with the additional deletion of TRADD ) 113 .	However, RIPK1 ablation in LPC using RIPK1 floxed mice could not prevent the death of NEMO deficient hepatocytes showing that kinase independent platform properties of RIPK1 are required to prevent hepatocyte apoptosis (this was prevented with the additional deletion of TRADD) 113.	2	18	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	NEMO	NEMO	NEMO	2	3	16	17
Therefore , lack of RIPK1 kinase activity but not the absence of RIPK1 protein prevented hepatocyte apoptosis and HCC development in NEMO LPC-KO mice .	Therefore, lack of RIPK1 kinase activity but not the absence of RIPK1 protein prevented hepatocyte apoptosis and HCC development in NEMO LPC-KO mice.	4	23	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	NEMO	NEMO	NEMO	4	5	21	22
The demonstration that the inflammation in the SHARPIN deficient and IEC specific NEMO deficient mouse strains can be reversed by a kinase-inactive allele of RIPK1 provides formal proof that TNF driven cell death can cause inflammation when the early checkpoint is disrupted [ XREF_BIBR , XREF_BIBR ] .	The demonstration that the inflammation in the SHARPIN deficient and IEC specific NEMO deficient mouse strains can be reversed by a kinase-inactive allele of RIPK1 provides formal proof that TNF driven cell death can cause inflammation when the early checkpoint is disrupted [XREF_BIBR, XREF_BIBR].	10	25	reversed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	NEMO	NEMO	NEMO	24	25	12	13
One possibility may be that since RIP1 and NEMO are binding partners , the loss of RIP1 may allow NEMO to now bind to another molecule that is strongly pro apoptotic .	One possibility may be that since RIP1 and NEMO are binding partners, the loss of RIP1 may allow NEMO to now bind to another molecule that is strongly pro apoptotic.	14	22	allow	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	loss of RIP1	rip1	NEMO	NEMO	nemo	16	17	19	20
EGFR degradation was slowed by RIN1 silencing , enhanced by RIN1 overexpression and accelerated by RIN1 localization to the plasma membrane .	EGFR degradation was slowed by RIN1 silencing, enhanced by RIN1 overexpression and accelerated by RIN1 localization to the plasma membrane.	0	6	slowed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	RIN1	RIN1	RIN1	EGFR	EGFR	EGFR	5	6	0	1
XREF_BIBR Overexpression of RIN1 in HeLa cells increased RAB5 activity and enhanced EGFR degradation compared with control cells , while silencing endogenous RIN1 had the opposite effect .	XREF_BIBR Overexpression of RIN1 in HeLa cells increased RAB5 activity and enhanced EGFR degradation compared with control cells, while silencing endogenous RIN1 had the opposite effect.	1	13	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RIN1	Overexpression of RIN1	rin1	EGFR	EGFR	egfr	3	4	12	13
After siRab25 and AG1478 treatment , RIN1 induced EGFR signaling was inhibited , as evidenced by the decreased expression of p-EGFR , p-AKT and p-ERK in NC65-RIN1 cells .	After siRab25 and AG1478 treatment, RIN1 induced EGFR signaling was inhibited, as evidenced by the decreased expression of p-EGFR, p-AKT and p-ERK in NC65-RIN1 cells.	6	9	induced	Positive_early_activation	Positive_activation	Negative_activation	RIN1	RIN1	RIN1	EGFR	EGFR	EGFR	6	7	8	9
We observed that overexpression of Rin1 accelerates EGFR degradation in EGF stimulated cells .	We observed that overexpression of Rin1 accelerates EGFR degradation in EGF stimulated cells.	3	8	accelerates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Rin1	overexpression of Rin1	rin1	EGFR	EGFR	egfr	5	6	7	8
Surprisingly , inhibition of RIPK1 kinase activity by Nec-1 treatment significantly rescued the cell death in Tak1- and Ripk3-double-deficient BMDMs and Tak1 and Ripk3- and caspase activity deficient BMDMs .	Surprisingly, inhibition of RIPK1 kinase activity by Nec-1 treatment significantly rescued the cell death in Tak1- and Ripk3-double-deficient BMDMs and Tak1 and Ripk3- and caspase activity deficient BMDMs.	4	19	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	Tak1-	Tak1-	Tak1-	4	5	16	17
For Tak1 iKO and d iKO macrophages , we additionally treated with necrostatin-1 ( Nec-1 ) , an inhibitor of receptor interacting protein 1 ( RIP1 ) , which is known to block Tak1 deficient macrophage death XREF_BIBR .	For Tak1 iKO and d iKO macrophages, we additionally treated with necrostatin-1 (Nec-1), an inhibitor of receptor interacting protein 1 (RIP1), which is known to block Tak1 deficient macrophage death XREF_BIBR.	18	37	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RIP1	RIP1	RIP1	Tak1	Tak1	Tak1	25	26	33	34
We used necrostatin 1 ( Nec-1 ) , a well established RIPK1 kinase inhibitor , and found that inhibition of RIPK1 effectively restored cell viability of Tak1 deficient macrophages .	We used necrostatin 1 (Nec-1), a well established RIPK1 kinase inhibitor, and found that inhibition of RIPK1 effectively restored cell viability of Tak1 deficient macrophages.	18	28	restored	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK1	RIPK1	RIPK1	Tak1	Tak1	Tak1	20	21	26	27
Here we show that ZNRF4 induces K48 linked ubiquitination of RIP2 and promotes RIP2 degradation .	Here we show that ZNRF4 induces K48 linked ubiquitination of RIP2 and promotes RIP2 degradation.	4	14	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RIP2	ZNRF4 induces K48 linked ubiquitination of RIP2	rip2	RIP2	RIP2	rip2	10	11	13	14
Inactivation of the ATP binding site of RIPK2 through genetic disruption of key amino acid residues ( K38 , K47 , D164 ) or by chemical inhibition decreased full-length RIPK2 levels , decreased autophosphorylation and prevented RIPK2 mediated cellular activation or apoptosis XREF_BIBR , XREF_BIBR .	Inactivation of the ATP binding site of RIPK2 through genetic disruption of key amino acid residues (K38, K47, D164) or by chemical inhibition decreased full-length RIPK2 levels, decreased autophosphorylation and prevented RIPK2 mediated cellular activation or apoptosis XREF_BIBR, XREF_BIBR.	3	39	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RIPK2	ATP binding site of RIPK2 through genetic disruption of key amino acid residues (K38, K47, D164) or by chemical inhibition decreased full-length RIPK2 levels	ripk2	RIPK2	RIPK2	ripk2	29	30	36	37
RLN2 induced cell invasion was significantly decreased by transfection of relaxin receptor 1 ( RXFP1 ) siRNAs .	RLN2 induced cell invasion was significantly decreased by transfection of relaxin receptor 1 (RXFP1) siRNAs.	0	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RLN2	RLN2	RLN2	RXFP1	RXFP1	RXFP1	0	1	14	15
Corroborating with its role in targeting RAD18 to DNA damage induced foci , RNF8 depletion also significantly reduced the accumulation of RAD18 to chromatin fraction after IR ( XREF_FIG ) .	Corroborating with its role in targeting RAD18 to DNA damage induced foci, RNF8 depletion also significantly reduced the accumulation of RAD18 to chromatin fraction after IR (XREF_FIG).	13	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RNF8	RNF8	RNF8	RAD18	RAD18	RAD18	13	14	21	22
57 ROCK2 can phosphorylate and thereby inactivate CRMP2 , but the finding of increased CRMP2 levels after ROCK2 downregulation was surprising .	57 ROCK2 can phosphorylate and thereby inactivate CRMP2, but the finding of increased CRMP2 levels after ROCK2 downregulation was surprising.	0	8	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ROCK2	ROCK2	ROCK2	CRMP2	CRMP2	CRMP2	1	2	7	8
37 ROCK2 has been shown to phosphorylate and thereby inactivate CRMP2 .	37 ROCK2 has been shown to phosphorylate and thereby inactivate CRMP2.	0	11	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ROCK2	ROCK2	ROCK2	CRMP2	CRMP2	CRMP2	1	2	10	11
However , consistent with Rho kinase inhibitor fasudil treatment , genetic deletion of ROCK1 was not able to completely rescue Rnd3 deficiency mediated cardiac dysfunction ( XREF_FIG ) .	However, consistent with Rho kinase inhibitor fasudil treatment, genetic deletion of ROCK1 was not able to completely rescue Rnd3 deficiency mediated cardiac dysfunction (XREF_FIG).	11	21	rescue	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ROCK1	ROCK1	ROCK1	Rnd3	Rnd3	Rnd3	13	14	20	21
Rnd3 activity itself is inhibited by ROCK1 dependent phosphorylation on multiple sites , which induces its translocation from the membrane to the cytosol and reduces its ability to induce loss of stress fibers .	Rnd3 activity itself is inhibited by ROCK1 dependent phosphorylation on multiple sites, which induces its translocation from the membrane to the cytosol and reduces its ability to induce loss of stress fibers.	0	9	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	ROCK1	ROCK1 dependent phosphorylation	rock1	Rnd3	Rnd3	rnd3	6	7	0	1
However , RSK1 , the best characterized cytoplasmic ERK1/2 substrate , does not down-regulate ERalpha in our models .	However, RSK1, the best characterized cytoplasmic ERK1/2 substrate, does not down-regulate ERalpha in our models.	2	15	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RSK1	RSK1	RSK1	ERalpha	ERalpha	ERalpha	2	3	14	15
The finding that YB-1 over-expression ensures p300 stability is further supported by a significant decrease in HAT activity following siRNA mediated inhibition of YB-1 or its upstream kinases RSK1 and RSK2 ( XREF_SUPPLEMENTARY ) .	The finding that YB-1 over-expression ensures p300 stability is further supported by a significant decrease in HAT activity following siRNA mediated inhibition of YB-1 or its upstream kinases RSK1 and RSK2 (XREF_SUPPLEMENTARY).	20	32	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RSK1	RSK1	RSK1	YB-1	YB-1	YB-1	28	29	23	24
Rock1 and Daam1 , whose products were reported to negatively regulate Sox9 , were found to be miR-335 targets .	Rock1 and Daam1, whose products were reported to negatively regulate Sox9, were found to be miR-335 targets.	0	18	negatively regulate	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Rock1	Rock1	Rock1	Sox9	Sox9	Sox9	0	1	11	12
We performed immunoprecipitation with an anti-Parkin antibody in WT and RPA32- or RPA70- depleted HEK293T cells ectopically expressing Myc-NBS1 , and found that RPA deficiency did not affect the interaction between Parkin and NBS1 ( XREF_SUPPLEMENTARY ) .	We performed immunoprecipitation with an anti-Parkin antibody in WT and RPA32- or RPA70- depleted HEK293T cells ectopically expressing Myc-NBS1, and found that RPA deficiency did n't affect the interaction between Parkin and NBS1 (XREF_SUPPLEMENTARY).	10	21	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RPA32-	RPA32-	RPA32-	Myc-NBS1	Myc-NBS1	Myc-NBS1	10	11	18	19
Knock-down of RPGR reduced Rab8 targeting to primary cilia in vitro 35 .	Knock-down of RPGR reduced Rab8 targeting to primary cilia in vitro 35.	0	5	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RPGR	RPGR	RPGR	Rab8	Rab8	Rab8	2	3	4	5
Of note , and similarly to what has been obtained for RPAP4 and GPN1 , silencing of RPAP2 causes accumulation of the largest RNAPII subunits POLR2A and POLR2B in the cytoplasm , whereas the smaller subunits can reach the nuclear space ( data not shown ) .	Of note, and similarly to what has been obtained for RPAP4 and GPN1, silencing of RPAP2 causes accumulation of the largest RNAPII subunits POLR2A and POLR2B in the cytoplasm, whereas the smaller subunits can reach the nuclear space (data not shown).	15	27	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RPAP2	RPAP2	RPAP2	POLR2A	POLR2A	POLR2A	17	18	25	26
The expression responsive targets of Ror2 overexpression in MCF-7 induced a Ror2 and Wnt module of the non canonical Wnt signaling pathway .	The expression responsive targets of Ror2 overexpression in MCF-7 induced a Ror2 and Wnt module of the non canonical Wnt signaling pathway.	5	14	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Ror2	Ror2 overexpression	ror2	Ror2	Ror2	ror2	5	6	11	12
9 RhoA and ROCK1 , its effector kinase , inhibit Akt activation by enhancing PTEN activity .	9 RhoA and ROCK1, its effector kinase, inhibit Akt activation by enhancing PTEN activity.	1	15	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ROCK1	ROCK1	ROCK1	PTEN	PTEN	PTEN	3	4	14	15
Studies in mice with deficiencies in the downstream effectors of IGF-R signaling , including mTOR inhibition by rapamycin and S6K1 , demonstrate the central role of in-tracellular mitogenic pathways downstream of IGF-I in regulating lifespan and stress resistance while simultaneously reducing tumor growth ; in agreement with our yeast studies .	Studies in mice with deficiencies in the downstream effectors of IGF-R signaling, including mTOR inhibition by rapamycin and S6K1, demonstrate the central role of in-tracellular mitogenic pathways downstream of IGF-I in regulating lifespan and stress resistance while simultaneously reducing tumor growth; in agreement with our yeast studies.	14	20	inhibition	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	19	20	14	15
Expression of phospho-S6K1 and S6K1 downstream target protein S6 was also evaluated by growth factor stimulation and NVP-BEZ235 blocked the mTOR activity in both cell lines , suggesting that NVP-BEZ235 is an effective antagonist of mTOR .	Expression of phospho-S6K1 and S6K1 downstream target protein S6 was also evaluated by growth factor stimulation and NVP-BEZ235 blocked the mTOR activity in both cell lines, suggesting that NVP-BEZ235 is an effective antagonist of mTOR.	0	21	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	phospho-S6K1	Expression of phospho-S6K1	phospho-s6k1	mTOR	mTOR	mtor	2	3	20	21
Treatment with anisomycin or UV stimulated p38 and mTOR signaling in Tsc1 +/+ as well as in Tsc2 +/+ cells and inhibition of p38 by either SB203580 or BIRB796 strongly reduced mTOR activation as shown by diminished phosphorylation of p70S6K or S6 ( XREF_FIG ) .	Treatment with anisomycin or UV stimulated p38 and mTOR signaling in Tsc1 +/+ as well as in Tsc2 +/+ cells and inhibition of p38 by either SB203580 or BIRB796 strongly reduced mTOR activation as shown by diminished phosphorylation of p70S6K or S6 (XREF_FIG).	30	43	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p70S6K	phosphorylation of p70S6K	p70s6k	mTOR	mTOR	mtor	39	40	31	32
We therefore examined the ability of WISP1 to modulate the phosphorylation of AMP activated protein kinase ( AMPK ) , which can inhibit mTOR activity [ XREF_BIBR , XREF_BIBR ] , tuberous sclerosis complex 2 ( TSC2 ) , that also blocks mTOR activity [ XREF_BIBR ] , and Akt1 and p70S6K .	We therefore examined the ability of WISP1 to modulate the phosphorylation of AMP activated protein kinase (AMPK), which can inhibit mTOR activity [XREF_BIBR, XREF_BIBR], tuberous sclerosis complex 2 (TSC2), that also blocks mTOR activity [XREF_BIBR], and Akt1 and p70S6K.	15	52	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	51	52	23	24
Now that aberrant activation of mTOR and p70S6K pathway plays an important role in tumorigenesis and phosphorylated p70S6K by mTOR has higher activity to promote translation than p70S6K [ XREF_BIBR , XREF_BIBR ] , we speculated the combination of mTOR inhibitor and p70S6K siRNA could inhibit mTOR and p70S6K pathway at the most extent and thus inhibit tumor growth better .	Now that aberrant activation of mTOR and p70S6K pathway plays an important role in tumorigenesis and phosphorylated p70S6K by mTOR has higher activity to promote translation than p70S6K [XREF_BIBR, XREF_BIBR], we speculated the combination of mTOR inhibitor and p70S6K siRNA could inhibit mTOR and p70S6K pathway at the most extent and thus inhibit tumor growth better.	42	49	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	42	43	46	47
For example , reduced phosphorylation of S6K1 supports inhibition of mTOR .	For example, reduced phosphorylation of S6K1 supports inhibition of mTOR.	4	11	supports	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	S6K1	phosphorylation of S6K1	s6k1	mTOR	mTOR	mtor	6	7	10	11
Building on these results , we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels which increases CAD activation by upregulating its substrate availability and also by increasing its phosphorylation by S6K1 through the mammalian target of Rapamycin ( mTOR ) pathway .	Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels which increases CAD activation by upregulating its substrate availability and also by increasing its phosphorylation by S6K1 through the mammalian target of Rapamycin (mTOR) pathway.	28	39	increasing	Positive_activation_syntax_3_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mammalian target of Rapamycin	mammalian target of Rapamycin	mammalian target of Rapamycin	32	33	35	39
Activated mTOR phosphorylates at least two targets , p70S6K and 4E-BP1 , which in turn activates p70S6K and inhibits 4E-BP1 .	Activated mTOR phosphorylates at least two targets, p70S6K and 4E-BP1, which in turn activates p70S6K and inhibits 4E-BP1.	0	10	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	8	9	1	2
While SFN inhibits PDGF induced phosphorylation of p70S6K and 4E-BP1 ( downstream targets of mTOR ) , it does not affect ERK or Akt phosphorylation .	While SFN inhibits PDGF induced phosphorylation of p70S6K and 4E-BP1 (downstream targets of mTOR), it does not affect ERK or Akt phosphorylation.	1	15	targets	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p70S6K	SFN inhibits PDGF induced phosphorylation of p70S6K	p70s6k	mTOR	mTOR	mtor	7	8	14	15
Activated mTOR phosphorylates its two major targets , S6K1 and 4E-BP1 , which play a key role in myogenesis .	Activated mTOR phosphorylates its two major targets, S6K1 and 4E-BP1, which play a key role in myogenesis.	0	13	Activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mTOR	mTOR	mTOR	8	9	1	2
S6K1 is a downstream target of the mammalian target of rapamycin ( mTOR ) protein , which regulates the autophagy pathway [ XREF_BIBR ] and is a mechanism target for regulation of cell size [ XREF_BIBR ] .	S6K1 is a downstream target of the mammalian target of rapamycin (mTOR) protein, which regulates the autophagy pathway [XREF_BIBR] and is a mechanism target for regulation of cell size [XREF_BIBR].	0	11	is a downstream target	Positive_activation_copula_1	Positive_activation	Positive_activation	S6K1	S6K1	S6K1	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	7	11
To study the downstream targets of the mTOR pathway , 5637 and T24 cell lines were treated with triple siRNAs ( p70S6K , S6K , and eIF4E ) or the mTOR inhibitor rapamycin ( XREF_FIG ) .	To study the downstream targets of the mTOR pathway, 5637 and T24 cell lines were treated with triple siRNAs (p70S6K, S6K, and eIF4E) or the mTOR inhibitor rapamycin (XREF_FIG).	7	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	p70S6K	p70S6K	p70S6K	mTOR	mTOR	mTOR	21	22	7	8
The mTOR-insensitive S6K1 fully suppressed Everolimus induced elevation in p-ERK and p-AKT , a PI3K target , and partially recovered p-S6 .	The mTOR-insensitive S6K1 fully suppressed Everolimus induced elevation in p-ERK and p-AKT, a PI3K target, and partially recovered p-S6.	0	21	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	S6K1	S6K1	S6K1	p-S6	p-S6	p-S6	2	3	20	21
Deficiency in MSK1 and MSK2 prevented the binding of phosphorylated transcription factors CREB and ATF1 to the promoters of the genes encoding interleukin 10 and DUSP1 .	Deficiency in MSK1 and MSK2 prevented the binding of phosphorylated transcription factors CREB and ATF1 to the promoters of the genes encoding interleukin 10 and DUSP1.	0	15	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MSK2	MSK2	MSK2	ATF1	ATF1	ATF1	4	5	14	15
The results indicated that the TNFalpha stimulated Gli1 activity and expression of Gli target genes were impeded by S6K1 knock-down ( XREF_FIG ) .	The results indicated that the TNFalpha stimulated Gli1 activity and expression of Gli target genes were impeded by S6K1 knock-down (XREF_FIG).	7	19	impeded	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	S6K1	S6K1	S6K1	Gli1	Gli1	Gli1	18	19	7	8
In addition , S6K1 was able to partially rescue ERalpha knockdown .	In addition, S6K1 was able to partially rescue ERalpha knockdown.	3	10	rescue	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	S6K1	S6K1	S6K1	ERalpha	ERalpha	ERalpha	3	4	9	10
In addition , we show by ChIP experiments that MSK1 as well as MAPK inhibition abolishes binding of p65 , of its coactivator CBP , and of MSK1 itself to the kappaB intronic enhancer site of the SCF gene .	In addition, we show by ChIP experiments that MSK1 as well as MAPK inhibition abolishes binding of p65, of its coactivator CBP, and of MSK1 itself to the kappaB intronic enhancer site of the SCF gene.	9	19	abolishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MSK1	MSK1	MSK1	p65	p65	p65	9	10	18	19
This suggests the presence of syndecan-4 inhibits Rac1 activity at the contact , although where syndecan-4 is localised in the neural crest or how it inhibits Rac1 activity has not yet been identified .	This suggests the presence of syndecan-4 inhibits Rac1 activity at the contact, although where syndecan-4 is localised in the neural crest or how it inhibits Rac1 activity has not yet been identified.	3	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	5	6	7	8
Unlike Par3 targeting of the Rac GEF Tiam1 to the leading edge to locally activate Rac XREF_BIBR , syndecan-4 suppresses Rac activation except at the leading edge of the cell to promote directionally persistent cell migration .	Unlike Par3 targeting of the Rac GEF Tiam1 to the leading edge to locally activate Rac XREF_BIBR, syndecan-4 suppresses Rac activation except at the leading edge of the cell to promote directionally persistent cell migration.	18	21	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	syndecan-4	syndecan-4	syndecan-4	Rac	Rac	Rac	18	19	20	21
By analyzing the activity of the small GTPases using in vivo FRET imaging we showed that PCP signaling activates RhoA , while syndecan-4 inhibits Rac , both at the back of the neural crest cell .	By analyzing the activity of the small GTPases using in vivo FRET imaging we showed that PCP signaling activates RhoA, while syndecan-4 inhibits Rac, both at the back of the neural crest cell.	22	29	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	syndecan-4	syndecan-4	syndecan-4	Rac	Rac	Rac	22	23	24	25
However , the constitutively low Rac1 activity of the Y188L mutant MEFs suggests that although PKCalpha allows activation , other features of syndecan-4 suppress Rac1 activity in the absence of ligand engagement .	However, the constitutively low Rac1 activity of the Y188L mutant MEFs suggests that although PKCalpha allows activation, other features of syndecan-4 suppress Rac1 activity in the absence of ligand engagement.	20	25	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	22	23	24	25
Thus , syndecan-4 restricts Rac activation to generate a dominant lamella to drive directionally persistent fibroblast migration in response to linear fibrils in the extracellular matrix .	Thus, syndecan-4 restricts Rac activation to generate a dominant lamella to drive directionally persistent fibroblast migration in response to linear fibrils in the extracellular matrix.	2	5	restricts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	syndecan-4	syndecan-4	syndecan-4	Rac	Rac	Rac	2	3	4	5
As in mouse embryonic fibroblasts migrating on cell derived matrix XREF_BIBR , syndecan-4 via PKC restricts Rac activation to the leading edge for directionally persistent neural crest cell migration in vitro and in vivo XREF_BIBR .	As in mouse embryonic fibroblasts migrating on cell derived matrix XREF_BIBR, syndecan-4 via PKC restricts Rac activation to the leading edge for directionally persistent neural crest cell migration in vitro and in vivo XREF_BIBR.	12	17	restricts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	syndecan-4	syndecan-4	syndecan-4	Rac	Rac	Rac	12	13	16	17
It has already been suggested that SDC4 is necessary to suppress Rac1 activity ; however the suggested regulatory mechanism was characterized in stress conditions [ XREF_BIBR - XREF_BIBR ] .	It has already been suggested that SDC4 is necessary to suppress Rac1 activity; however the suggested regulatory mechanism was characterized in stress conditions [XREF_BIBR - XREF_BIBR].	6	12	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SDC4	SDC4	SDC4	Rac1	Rac1	Rac1	6	7	11	12
In this context , the proteoglycan Syndecan-4 , which is required for directional migration of neural crest cells , downregulates Rac1 activation to control the direction of cell protrusion development [ XREF_BIBR ] .	In this context, the proteoglycan Syndecan-4, which is required for directional migration of neural crest cells, downregulates Rac1 activation to control the direction of cell protrusion development [XREF_BIBR].	4	21	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Syndecan-4	Syndecan-4	Syndecan-4	Rac1	Rac1	Rac1	6	7	20	21
In the present study we report that , compared with wild type cells , fibronectin-adherent syndecan-4-null fibroblasts showed enhanced lamellipodia and increased Rac1 activity that could be down-regulated by re-expression of syndecan-4 in the mutant cells .	In the present study we report that, compared with wild type cells, fibronectin-adherent syndecan-4-null fibroblasts showed enhanced lamellipodia and increased Rac1 activity that could be down-regulated by re-expression of syndecan-4 in the mutant cells.	22	32	down-regulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	syndecan-4	re-expression of syndecan-4	syndecan-4	Rac1	Rac1	rac1	31	32	22	23
Instead the syndecan-4 null cells showed an overall enhanced Rac1 activity , implicating a negative regulatory role of syndecan-4 in modulating Rac1 activation , 37 that is , the engagement of syndecan-4 by matrix ligands would initiate a decrease in Rac1 activity with the eventual progression toward RhoA activation .	Instead the syndecan-4 null cells showed an overall enhanced Rac1 activity, implicating a negative regulatory role of syndecan-4 in modulating Rac1 activation, 37 that is, the engagement of syndecan-4 by matrix ligands would initiate a decrease in Rac1 activity with the eventual progression toward RhoA activation.	29	41	initiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	syndecan-4	syndecan-4	syndecan-4	Rac1	Rac1	Rac1	31	32	40	41
The mechanism by which syndecan-4 limits Rac activation resembles a mechanism used by the integrin alpha 4 -paxillin-Arf GAP ( GTPase activating protein ) complex to inhibit Rac activation around the periphery of migrating epithelial like CHO cells XREF_BIBR .	The mechanism by which syndecan-4 limits Rac activation resembles a mechanism used by the integrin alpha 4 -paxillin-Arf GAP (GTPase activating protein) complex to inhibit Rac activation around the periphery of migrating epithelial like CHO cells XREF_BIBR.	4	7	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	syndecan-4	syndecan-4	syndecan-4	Rac	Rac	Rac	4	5	6	7
Syndecan-4 , via PKC , restricts Rac activity to the leading edge of fibroblasts migrating on cell derived matrices .	Syndecan-4, via PKC, restricts Rac activity to the leading edge of fibroblasts migrating on cell derived matrices.	0	7	restricts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Syndecan-4	Syndecan-4	Syndecan-4	Rac	Rac	Rac	0	1	6	7
Reduction of Notch signaling in sdc3 -/- SCs is directly due to Syndecan-3 loss because ectopic expression of Syndecan-3 in sdc3 -/- SCs rescues activation of the Notch reporter CSL-Luc ( XREF_FIG ) .	Reduction of Notch signaling in sdc3 -/- SCs is directly due to Syndecan-3 loss because ectopic expression of Syndecan-3 in sdc3 -/- SCs rescues activation of the Notch reporter CSL-Luc (XREF_FIG).	16	29	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Syndecan-3	expression of Syndecan-3	syndecan-3	Notch	Notch	notch	18	19	27	28
The absence of Syndecan-3 impairs Notch signaling , altering SC homeostasis and affecting skeletal muscle regeneration .	The absence of Syndecan-3 impairs Notch signaling, altering SC homeostasis and affecting skeletal muscle regeneration.	1	6	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Syndecan-3	Syndecan-3	Syndecan-3	Notch	Notch	Notch	3	4	5	6
Indeed , SAV1 SARAH alone ( SAV1 incrementN268 ) blocked MST2 activation in vitro ( XREF_FIG ) .	Indeed, SAV1 SARAH alone (SAV1 incrementN268) blocked MST2 activation in vitro (XREF_FIG).	2	11	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	2	3	10	11
SAV1 SARAH disrupts this homodimerization of MST2 SARAH , and is expected to block MST2 activation .	SAV1 SARAH disrupts this homodimerization of MST2 SARAH, and is expected to block MST2 activation.	0	15	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SAV1	SAV1	SAV1	MST2	MST2	MST2	0	1	14	15
11 Neutralizing antibodies for the Sema3C receptors NRP1 and NRP2 block Sema3C effects on rodent DAx .	11 Neutralizing antibodies for the Sema3C receptors NRP1 and NRP2 block Sema3C effects on rodent DAx.	9	12	block	Negative_activation_token_1_noun	Positive_activation	Negative_activation	Sema3C	Sema3C	Sema3C	NRP2	NRP2	NRP2	11	12	9	10
These observations are consistent with previous studies demonstrating that : ( a ) P-selectin has a 50-fold higher affinity for PSGL-1 than does E-selectin ; ( b ) prolonged digestion of PSGL-1 with neuraminidase is required to fully eliminate recognition of P-selectin ; and ( c ) one or more of the amino-terminal tyrosines within the anionic polypeptide region plays an important role in PSGL-1 amino terminus recognition of P-selectin , but plays a lesser , if any , role in recognition of E-selectin under static conditions .	These observations are consistent with previous studies demonstrating that : (a) P-selectin has a 50-fold higher affinity for PSGL-1 than does E-selectin; (b) prolonged digestion of PSGL-1 with neuraminidase is required to fully eliminate recognition of P-selectin; and (c) one or more of the amino-terminal tyrosines within the anionic polypeptide region plays an important role in PSGL-1 amino terminus recognition of P-selectin, but plays a lesser, if any, role in recognition of E-selectin under static conditions.	29	42	eliminate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	PSGL-1	PSGL-1	PSGL-1	P-selectin	P-selectin	P-selectin	31	32	41	42
These results demonstrate that SEMA3F exerts a potent antilymphangiogenic and metastasis suppressor function in HNSCC , and that SEMA3F may also inhibit growth of a subset of HNSCC expressing NRP2 .	These results demonstrate that SEMA3F exerts a potent antilymphangiogenic and metastasis suppressor function in HNSCC, and that SEMA3F may also inhibit growth of a subset of HNSCC expressing NRP2.	18	30	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SEMA3F	SEMA3F	SEMA3F	NRP2	NRP2	NRP2	18	19	29	30
SCAND1 is thus likely to act as a regulator of MZF1 activity , in agreement with the hypothesis that SCAND1 could decrease MZF1 mediated signaling by altering its affinity for DNA targets ( 12 ) .	SCAND1 is thus likely to act as a regulator of MZF1 activity, in agreement with the hypothesis that SCAND1 could decrease MZF1 mediated signaling by altering its affinity for DNA targets (12).	19	24	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SCAND1	SCAND1	SCAND1	MZF1	MZF1	MZF1	19	20	22	23
In the absence of ligand , the Shh receptor Ptch represses the activity of Smo , while binding of Shh to Ptch relieves this blockade .	In the absence of ligand, the Shh receptor Ptch represses the activity of Smo, while binding of Shh to Ptch relieves this blockade.	7	15	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Smo	Smo	Smo	7	8	14	15
SHH protein decreases , SMO localization changes to the neuronal cell surface , and anterograde transport stops .	SHH protein decreases, SMO localization changes to the neuronal cell surface, and anterograde transport stops.	0	6	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SHH	SHH	SHH	SMO	SMO	SMO	0	1	4	5
In the absence of the hedgehog ligands ( Desert Hedgehog ( DHH ) , Indian Hedgehog ( IHH ) , and Sonic Hedgehog ( SHH ) ) , the Patched-1 ( PTCH1 ) and Patched-2 ( PTCH2 ) receptors , inhibit Smoothened ( SMO ) , the main effector of signaling , which is located in vesicles in the cytoplasm [ XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	In the absence of the hedgehog ligands (Desert Hedgehog (DHH), Indian Hedgehog (IHH), and Sonic Hedgehog (SHH)), the Patched-1 (PTCH1) and Patched-2 (PTCH2) receptors, inhibit Smoothened (SMO), the main effector of signaling, which is located in vesicles in the cytoplasm [XREF_BIBR, XREF_BIBR] (XREF_FIG).	22	54	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SHH	SHH	SHH	SMO	SMO	SMO	24	25	43	44
When the feedback loop is broken , as in figure XREF_FIG , Shh signalling causes rapid suppression of Ptc1 to low levels and growth of Smo and Gli1 to high levels .	When the feedback loop is broken, as in figure XREF_FIG, Shh signalling causes rapid suppression of Ptc1 to low levels and growth of Smo and Gli1 to high levels.	12	27	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Smo	Smo	Smo	12	13	25	26
Although Shh activates SMO and synaptamide inhibits the same pathway downregulating PTCH1 and Shh , our results suggest that Shh regulation of synaptamide mediated axon growth does not require activation of canonical Hedgehog signaling .	Although Shh activates SMO and synaptamide inhibits the same pathway downregulating PTCH1 and Shh, our results suggest that Shh regulation of synaptamide mediated axon growth does not require activation of canonical Hedgehog signaling.	1	6	activates	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	SMO	SMO	SMO	1	2	3	4
In 2012 the patient had further evidence of widespread metastasis with immunohistochemical evidence of SHH activation , and started on palliative chemotherapy with cycles of metronomic chemotherapy including celebrex , vismodegib ( a SHH signaling inhibitor that targets the SMO receptor ) and alternating etoposide and temozolomide .	In 2012 the patient had further evidence of widespread metastasis with immunohistochemical evidence of SHH activation, and started on palliative chemotherapy with cycles of metronomic chemotherapy including celebrex, vismodegib (a SHH signaling inhibitor that targets the SMO receptor) and alternating etoposide and temozolomide.	33	40	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SHH	SHH	SHH	SMO	SMO	SMO	33	34	39	40
For example , vismodegib ( GDC-0449 ) , an Shh pathway inhibitor targeting Smo , triggers the rapid regression of an MB patient ' s metastatic tumors , but it is soon followed by relapse due to mutations in Smo causing therapeutic resistance.7 , 8 Molecular classification can also guide the reduced treatment of medulloblastoma patients with less aggressive disease .	For example, vismodegib (GDC-0449), an Shh pathway inhibitor targeting Smo, triggers the rapid regression of an MB patient 's metastatic tumors, but it is soon followed by relapse due to mutations in Smo causing therapeutic resistance.7, 8 Molecular classification can also guide the reduced treatment of medulloblastoma patients with less aggressive disease.	9	14	targeting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Smo	Smo	Smo	9	10	13	14
In mice , Sufu is a major negative regulator of Shh , signaling downstream of Smo XREF_BIBR , XREF_BIBR .	In mice, Sufu is a major negative regulator of Shh, signaling downstream of Smo XREF_BIBR, XREF_BIBR.	8	16	signaling	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Smo	Smo	Smo	10	11	15	16
Cholesterol supplementation also restored the GLI response of BM15.766-treated Shh-LIGHT2 cells stimulated with SHH and rescued the reduced SHH induced SMO cilia localization .	Cholesterol supplementation also restored the GLI response of BM15.766-treated Shh-LIGHT2 cells stimulated with SHH and rescued the reduced SHH induced SMO cilia localization.	16	22	induced	Positive_early_activation	Positive_activation	Negative_activation	SHH	SHH	SHH	SMO	SMO	SMO	18	19	20	21
We further tested whether the impact of Notch activity on Shh induced Smo localization was limited to NIH 3T3 cells or more broadly applicable to other cell types including human NPCs , primary mouse embryonic fibroblasts ( MEFs ) , and C2C12 mouse myoblasts .	We further tested whether the impact of Notch activity on Shh induced Smo localization was limited to NIH 3T3 cells or more broadly applicable to other cell types including human NPCs, primary mouse embryonic fibroblasts (MEFs), and C2C12 mouse myoblasts.	8	13	induced	Positive_early_activation	Positive_activation	Negative_activation	Shh	Shh	Shh	Smo	Smo	Smo	10	11	12	13
When Shh ligand is not present , the Shh receptor Patched-1 actively represses Smo and leads to processing of full-length Gliinto its shorter , repressor form .	When Shh ligand is not present, the Shh receptor Patched-1 actively represses Smo and leads to processing of full-length Gliinto its shorter, repressor form.	8	14	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Smo	Smo	Smo	8	9	13	14
Inhibitors of the SHH signaling pathway are currently being developed to mainly target SMO or its upstream sites .	Inhibitors of the SHH signaling pathway are currently being developed to mainly target SMO or its upstream sites.	3	17	target	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SHH	SHH	SHH	SMO	SMO	SMO	3	4	13	14
Shh also inhibits the processing and degradation of Gli2 , with Gli2 being rapidly degraded in the absence of Shh .	Shh also inhibits the processing and degradation of Gli2, with Gli2 being rapidly degraded in the absence of Shh.	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	0	1	8	9
SHH signaling prevents the proteolysis of GLI2 and GLI3 and promotes their localization to the nucleus , where they regulate the expression of numerous target genes [ XREF_BIBR - XREF_BIBR ] .	SHH signaling prevents the proteolysis of GLI2 and GLI3 and promotes their localization to the nucleus, where they regulate the expression of numerous target genes [XREF_BIBR - XREF_BIBR].	0	8	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SHH	SHH	SHH	GLI2	GLI2	GLI2	0	1	6	7
Shh signaling suppresses Gli2 and Gli3 processing and converts them into activators , Gli2 A and Gli3 A , in a concentration dependent manner .	Shh signaling suppresses Gli2 and Gli3 processing and converts them into activators, Gli2 A and Gli3 A, in a concentration dependent manner.	0	6	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	0	1	3	4
Gli2 is downregulated by Shh signalling in the neural tube .	Gli2 is downregulated by Shh signalling in the neural tube.	0	5	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	4	5	0	1
Modulation of Gli protein activity is the downstream consequence of the Shh pathway , since the presence of Shh ligand acts to inhibit cleavage of Gli3 and suppress the processing and degradation of Gli2 .	Modulation of Gli protein activity is the downstream consequence of the Shh pathway, since the presence of Shh ligand acts to inhibit cleavage of Gli3 and suppress the processing and degradation of Gli2.	18	34	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Gli2	Gli2	Gli2	18	19	33	34
Finally , it appears that SHH signaling inhibits Nurr1 independently of the PI3K and AKt pathway ( XREF_FIG ) .	Finally, it appears that SHH signaling inhibits Nurr1 independently of the PI3K and AKt pathway (XREF_FIG).	5	15	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SHH	SHH	SHH	AKt	AKt	AKt	5	6	14	15
We next examined whether activation of Akt and Shh pathways blocks anti-proliferative effects of embelin by using constitutively active Akt and Shh protein , respectively .	We next examined whether activation of Akt and Shh pathways blocks anti-proliferative effects of embelin by using constitutively active Akt and Shh protein, respectively.	6	22	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Shh	Shh	Shh	Akt	Akt	Akt	8	9	19	20
Knockdown of SHH gene inhibits the activation of the PI3K and Akt pathway .	Knockdown of SHH gene inhibits the activation of the PI3K and Akt pathway.	2	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SHH	SHH	SHH	Akt	Akt	Akt	2	3	11	12
Sema4D may also inhibit plexinB1 expressed in the same cell by cis inhibition as described in ephrin , Notch and Sema6A and plexinA4 signaling systems XREF_BIBR .	Sema4D may also inhibit plexinB1 expressed in the same cell by cis inhibition as described in ephrin, Notch and Sema6A and plexinA4 signaling systems XREF_BIBR.	0	14	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sema4D	Sema4D	Sema4D	plexinB1	plexinB1	plexinB1	0	1	4	5
An involvement of other ErbB family members appears unlikely because dominant negative mutants of ErbB-1 , ErbB-3 , or ErbB-4 have no effect on Sema4D induced activation of plexin-B1 .	An involvement of other ErbB family members appears unlikely because dominant negative mutants of ErbB-1, ErbB-3, or ErbB-4 have no effect on Sema4D induced activation of plexin-B1.	22	29	induced	Positive_early_activation	Positive_activation	Negative_activation	Sema4D	Sema4D	Sema4D	plexin-B1	plexin-B1	plexin-B1	24	25	28	29
Under oxygen deprivation conditions , however , HIPK2 phosphorylation of Siah2 is reduced , which increases Siah2 activity and results in the stabilization of HIF-1alpha and increased transcription of hypoxia responsive genes .	Under oxygen deprivation conditions, however, HIPK2 phosphorylation of Siah2 is reduced, which increases Siah2 activity and results in the stabilization of HIF-1alpha and increased transcription of hypoxia responsive genes.	7	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Siah2	HIPK2 phosphorylation of Siah2	siah2	HIF-1alpha	HIF-1alpha	hif-1alpha	10	11	24	25
Because the prolyl hydroxylation of HIF1alpha is a prerequisite for its recognition by the von Hippel-Lindau protein ( pVHL ) and subsequent proteasomal degradation , the Siah2 mediated degradation of PHD relieves HIF1alpha from degradation and thus stabilizes HIF1alpha [ XREF_BIBR ] .	Because the prolyl hydroxylation of HIF1alpha is a prerequisite for its recognition by the von Hippel-Lindau protein (pVHL) and subsequent proteasomal degradation, the Siah2 mediated degradation of PHD relieves HIF1alpha from degradation and thus stabilizes HIF1alpha [XREF_BIBR].	26	33	relieves	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Siah2	Siah2	Siah2	HIF1alpha	HIF1alpha	HIF1alpha	26	27	32	33
Furthermore , coimmunoprecipitation experiments demonstrate that CIN85 overexpression limits the ability of Cbl to bind suppressor of TCR signaling 1 ( Sts1 ) , a negative regulator of Cbl functions , while CIN85 knockdown favors the formation of Cbl and Sts1 complexes .	Furthermore, coimmunoprecipitation experiments demonstrate that CIN85 overexpression limits the ability of Cbl to bind suppressor of TCR signaling 1 (Sts1), a negative regulator of Cbl functions, while CIN85 knockdown favors the formation of Cbl and Sts1 complexes.	6	26	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CIN85	CIN85 overexpression	cin85	Cbl	Cbl	cbl	6	7	12	13
So far as the role of Bif-1 in mitochondrial apoptosis is concerned some reports suggest that Bif-1 activates Bax and loss of Bif-1 suppresses apoptosis XREF_BIBR , XREF_BIBR , while others believe that Bax activates Bif-1 oligomerization XREF_BIBR and oligomeric Bif-1 can cause lipid membrane vesiculation , thus helps apoptosis .	So far as the role of Bif-1 in mitochondrial apoptosis is concerned some reports suggest that Bif-1 activates Bax and loss of Bif-1 suppresses apoptosis XREF_BIBR, XREF_BIBR, while others believe that Bax activates Bif-1 oligomerization XREF_BIBR and oligomeric Bif-1 can cause lipid membrane vesiculation, thus helps apoptosis.	16	23	activates	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Bif-1	Bif-1	Bif-1	Bax	Bax	Bax	16	17	18	19
Although downregulation of SENP1 decreased the transcriptional activity of HIF-1alpha , the viability of disc cells showed no significant loss under hypoxia .	Although downregulation of SENP1 decreased the transcriptional activity of HIF-1alpha, the viability of disc cells showed no significant loss under hypoxia.	1	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SENP1	SENP1	SENP1	HIF-1alpha	HIF-1alpha	HIF-1alpha	3	4	9	10
In order to determine whether the TGF-beta stimulatory effect was mediated by Smad3 , we repeated the experiment in SMCs with Smad3 activity blocked by a specific inhibitor , SIS3 , or increased Smad3 expression using an adenovirus .	In order to determine whether the TGF-beta stimulatory effect was mediated by Smad3, we repeated the experiment in SMCs with Smad3 activity blocked by a specific inhibitor, SIS3, or increased Smad3 expression using an adenovirus.	21	35	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Smad3	Smad3 expression	smad3	Smad3	Smad3	smad3	33	34	21	22
Thus , the use of these inhibitors , by giving virtually identical results has demonstrated not only that acrolein induced cell loss and VEGF regulation proceeds not only through a TGFbetaRI mediated pathway , but specifically through a TGFbetaRI receptor mediated Smad3 pathway , negating the possibility of non TGFbetaRI activated Smad3 activation which has been shown to occur in osteoblastic cells in response to parathyroid hormone .	Thus, the use of these inhibitors, by giving virtually identical results has demonstrated not only that acrolein induced cell loss and VEGF regulation proceeds not only through a TGFbetaRI mediated pathway, but specifically through a TGFbetaRI receptor mediated Smad3 pathway, negating the possibility of non TGFbetaRI activated Smad3 activation which has been shown to occur in osteoblastic cells in response to parathyroid hormone.	38	52	negating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	TGFbetaRI receptor mediated Smad3	smad3	Smad3	Smad3	smad3	41	42	51	52
Previously it was shown that inactive unphosphorylated Smad3 is bound to proteins such as SARA ( Smad anchor for receptor activation ) in the cytoplasm and that phosphorylation of Smad3 by the type I receptor decreases its affinity for SARA thus allowing Smad3 to interact with the Co-Smad Smad4 before entering the nucleus [ XREF_BIBR ] .	Previously it was shown that inactive unphosphorylated Smad3 is bound to proteins such as SARA (Smad anchor for receptor activation) in the cytoplasm and that phosphorylation of Smad3 by the type I receptor decreases its affinity for SARA thus allowing Smad3 to interact with the Co-Smad Smad4 before entering the nucleus [XREF_BIBR].	27	44	allowing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	phosphorylation of Smad3	smad3	Smad3	Smad3	smad3	29	30	42	43
This result indicates that S418 phosphorylation does not perturb the intrinsic transactivating ability of Smad3 but attenuates Smad3 activity by lowering its protein stability in the presence of TGF-beta .	This result indicates that S418 phosphorylation does not perturb the intrinsic transactivating ability of Smad3 but attenuates Smad3 activity by lowering its protein stability in the presence of TGF-beta.	5	18	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	phosphorylation does not perturb the intrinsic transactivating ability of Smad3	smad3	Smad3	Smad3	smad3	14	15	17	18
We explored the possibility that higher Smad3 levels may abrogate the effect of cAMP on Smad3 activity by overexpressing Smad3 in 2D cultured cells .	We explored the possibility that higher Smad3 levels may abrogate the effect of cAMP on Smad3 activity by overexpressing Smad3 in 2D cultured cells.	6	20	abrogate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Smad3 levels	smad3	Smad3	Smad3	smad3	6	7	19	20
42 Overexpression of both Smad2 and Smad3 blocks the spontaneous maturation of Smad3 deficient chondrocytes .	42 Overexpression of both Smad2 and Smad3 blocks the spontaneous maturation of Smad3 deficient chondrocytes.	1	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Overexpression of both Smad2 and Smad3	smad3	Smad3	Smad3	smad3	6	7	12	13
Cdk4 and Cdk2 phosphorylate Smad3 and inhibit Smad3 antiproliferative function , providing negative feedback control .	Cdk4 and Cdk2 phosphorylate Smad3 and inhibit Smad3 antiproliferative function, providing negative feedback control.	0	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Cdk4 and Cdk2 phosphorylate Smad3	smad3	Smad3	Smad3	smad3	4	5	7	8
p38MAPK inhibitors ( SB203580 ) can attenuate TGF-beta1-induced Smad3 expression and suppress the activation of smad3 .	p38MAPK inhibitors (SB203580) can attenuate TGF-beta1-induced Smad3 expression and suppress the activation of smad3.	0	16	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	p38MAPK inhibitors (SB203580) can attenuate TGF-beta1-induced Smad3 expression	smad3	smad3	smad3	smad3	8	9	15	16
Loss of CTGF can attenuate effects of TGF-beta1 by decreasing SMAD3 expression , which consequently attenuates TGF-beta1 and SMAD3 signaling .	Loss of CTGF can attenuate effects of TGF-beta1 by decreasing SMAD3 expression, which consequently attenuates TGF-beta1 and SMAD3 signaling.	10	19	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SMAD3	SMAD3 expression	smad3	SMAD3	SMAD3	smad3	10	11	18	19
The cyclinD1CDK4 and cyclinECDK2 kinases were shown to repress small mothers against decapentaplegic ( Smad3 )-mediated G1 arrest by phosphorylation of the Smad3 protein in the MCF7 cells , [ XREF_BIBR XREF_BIBR ] whereas the Smad3 , as one of the important effectors in the TGFbeta signaling pathway , is triggered by gemcitabine in this cell line .	The cyclinD1CDK4 and cyclinECDK2 kinases were shown to repress small mothers against decapentaplegic (Smad3)-mediated G1 arrest by phosphorylation of the Smad3 protein in the MCF7 cells, [XREF_BIBR XREF_BIBR] whereas the Smad3, as one of the important effectors in the TGFbeta signaling pathway, is triggered by gemcitabine in this cell line.	14	23	arrest	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	Smad3	phosphorylation of the Smad3	smad3	Smad3	Smad3	smad3	22	23	14	15
It has been demonstrated that the activation of ANP/cGMP/PKG signaling phosphorylates Smad3 and disrupts TGF-beta1-induced nuclear translocation of pSmad3 and later downstream events , including myofibroblast transformation and the proliferation and expression of extracellular matrix molecules [ XREF_BIBR , XREF_BIBR ] .	It has been demonstrated that the activation of ANP/cGMP/PKG signaling phosphorylates Smad3 and disrupts TGF-beta1-induced nuclear translocation of pSmad3 and later downstream events, including myofibroblast transformation and the proliferation and expression of extracellular matrix molecules [XREF_BIBR, XREF_BIBR].	8	22	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	ANP/cGMP/PKG signaling phosphorylates Smad3	smad3	pSmad3	pSmad3	psmad3	11	12	18	19
In contrast , cdk mediated phosphorylation of Smad3 reduces Smad3 transcriptional activity and antiproliferative function .	In contrast, cdk mediated phosphorylation of Smad3 reduces Smad3 transcriptional activity and antiproliferative function.	3	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	cdk mediated phosphorylation of Smad3	smad3	Smad3	Smad3	smad3	7	8	9	10
SIS3 is an inhibitor of the phosphorylation of Smad3 XREF_BIBR , which also reduced p-Smad3 and collagen I in C3a treated HRGECs .	SIS3 is an inhibitor of the phosphorylation of Smad3 XREF_BIBR, which also reduced p-Smad3 and collagen I in C3a treated HRGECs.	6	17	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad3	phosphorylation of Smad3	smad3	p-Smad3	p-Smad3	p-smad3	8	9	14	15
Once phosphorylated , YAP translocates from the nucleus to the cytoplasm and takes along with it Smad3 , thereby reducing TGFbeta and Smad3 dependent transcription XREF_BIBR , XREF_BIBR .	Once phosphorylated, YAP translocates from the nucleus to the cytoplasm and takes along with it Smad3, thereby reducing TGFbeta and Smad3 dependent transcription XREF_BIBR, XREF_BIBR.	4	23	reducing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	translocates from the nucleus to the cytoplasm and takes along with it Smad3	smad3	Smad3	Smad3	smad3	16	17	22	23
One such factor was Smad3 , as Socs3 has been shown to bind phosphorylated Smad3 ( P-Smad3 ) in LPS activated macrophages , preventing the nuclear translocation of P-Smad3 .	One such factor was Smad3, as Socs3 has been shown to bind phosphorylated Smad3 (P-Smad3) in LPS activated macrophages, preventing the nuclear translocation of P-Smad3.	13	29	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	phosphorylated Smad3	smad3	P-Smad3	P-Smad3	p-smad3	14	15	28	29
Smad3 phosphorylation is also reduced by the antioxidant ebselen , suggesting the involvement of redox dependent mechanisms in the activation of Smad3 and consequently the mediation of oxidant and antioxidant imbalance and IL-6 release .	Smad3 phosphorylation is also reduced by the antioxidant ebselen, suggesting the involvement of redox dependent mechanisms in the activation of Smad3 and consequently the mediation of oxidant and antioxidant imbalance and IL-6 release.	0	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Smad3 phosphorylation	smad3	Smad3	Smad3	smad3	0	1	21	22
We have mapped Smurf2 induced Smad3 ubiquitination sites to lysine residues at the MH2 domain , and demonstrate that Smad3 ubiquitination inhibits the formation of Smad3 complexes .	We have mapped Smurf2 induced Smad3 ubiquitination sites to lysine residues at the MH2 domain, and demonstrate that Smad3 ubiquitination inhibits the formation of Smad3 complexes.	19	26	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Smad3 ubiquitination	smad3	Smad3	Smad3	smad3	19	20	25	26
When the cells are subjected to activation of TGF-beta signaling and PKC signaling , PKC phosphorylation of Smad3 abrogates binding and transcriptional activity of Smad3 leading to suppression of TGF-beta response .	When the cells are subjected to activation of TGF-beta signaling and PKC signaling, PKC phosphorylation of Smad3 abrogates binding and transcriptional activity of Smad3 leading to suppression of TGF-beta response.	14	25	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	PKC phosphorylation of Smad3	smad3	Smad3	Smad3	smad3	17	18	24	25
These results demonstrate that inhibiting TGF-beta signaling with SB-431542 blocks phosphorylation of Smad2 and Smad3 and prevents nuclear translocation of p-Smad2 and p-Smad3 , which ultimately interrupts bladder smooth muscle formation .	These results demonstrate that inhibiting TGF-beta signaling with SB-431542 blocks phosphorylation of Smad2 and Smad3 and prevents nuclear translocation of p-Smad2 and p-Smad3, which ultimately interrupts bladder smooth muscle formation.	5	26	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	TGF-beta signaling with SB-431542 blocks phosphorylation of Smad2 and Smad3	smad3	p-Smad3	p-Smad3	p-smad3	14	15	22	23
This observation demonstrates that loss of SMAD3 induces remarkable inflammatory responses in Smad3 -/- mice after CaCl 2 treatment .	This observation demonstrates that loss of SMAD3 induces remarkable inflammatory responses in Smad3 -/- mice after CaCl 2 treatment.	4	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SMAD3	loss of SMAD3	smad3	Smad3	Smad3	smad3	6	7	12	13
5-HT also caused Smad3 phosphorylation and ketanserin diminished 5-HT-induced Smad3 activation .	5-HT also caused Smad3 phosphorylation and ketanserin diminished 5-HT-induced Smad3 activation.	3	10	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Smad3 phosphorylation	smad3	Smad3	Smad3	smad3	3	4	9	10
XREF_FIG shows that DN-Smad3 significantly suppressed Smad3 dependent induction , although complete inhibition was not achieved .	XREF_FIG shows that DN-Smad3 significantly suppressed Smad3 dependent induction, although complete inhibition was not achieved.	3	8	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	DN-Smad3	DN-Smad3	DN-Smad3	Smad3	Smad3	Smad3	3	4	6	7
Then JNK mediated linker phosphorylation of Smad3 inactivated cytostatic Smad3 signaling and facilitated hepatocarciongenesis [ XREF_BIBR ] .	Then JNK mediated linker phosphorylation of Smad3 inactivated cytostatic Smad3 signaling and facilitated hepatocarciongenesis [XREF_BIBR].	4	10	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	phosphorylation of Smad3	smad3	Smad3	Smad3	smad3	6	7	9	10
Activin induced phosphorylation of Smad3 and the truncated Smad3 isoform was blocked by both follistatin and siRNA mediated knockdown of Smad3 .	Activin induced phosphorylation of Smad3 and the truncated Smad3 isoform was blocked by both follistatin and siRNA mediated knockdown of Smad3.	0	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Activin induced phosphorylation of Smad3	smad3	Smad3	Smad3	smad3	4	5	20	21
TGFbeta activates smad2 which diminishes TGFbeta1 and smad3 signalling , including phosphorylation , nuclear translocation and the binding of smad3 to the Col1 promoter , leading to augmented collagen synthesis 23 , 24 .	TGFbeta activates smad2 which diminishes TGFbeta1 and smad3 signalling, including phosphorylation, nuclear translocation and the binding of smad3 to the Col1 promoter, leading to augmented collagen synthesis 23, 24.	5	20	signalling	Positive_activation_syntax_noun_Hearst	Positive_activation	Positive_activation	smad3	phosphorylation, nuclear translocation and the binding of smad3	smad3	smad3	smad3	smad3	19	20	7	8
It has been reported that phosphorylation of the SMAD3 linker region by CDK2 and CDK4 inhibits SMAD3 transcriptional activity XREF_BIBR - XREF_BIBR .	It has been reported that phosphorylation of the SMAD3 linker region by CDK2 and CDK4 inhibits SMAD3 transcriptional activity XREF_BIBR - XREF_BIBR.	5	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMAD3	phosphorylation of the SMAD3	smad3	SMAD3	SMAD3	smad3	8	9	16	17
A subsequent study revealed that Smad3 sumoylation mediated by PIASy causes decreased DNA binding affinity of Smad3 , which is responsible for the suppression of TGF-beta signaling .	A subsequent study revealed that Smad3 sumoylation mediated by PIASy causes decreased DNA binding affinity of Smad3, which is responsible for the suppression of TGF-beta signaling.	5	20	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Smad3 sumoylation	smad3	Smad3	Smad3	smad3	5	6	16	17
SIRT1 overexpression was specifically located at the striatum and , as expected , induced a decrease in the deacetylation levels of SIRT1 substrate -- Forkhead box protein O1 -- in the striatum ( XREF_FIG ) .	SIRT1 overexpression was specifically located at the striatum and, as expected, induced a decrease in the deacetylation levels of SIRT1 substrate -- Forkhead box protein O1 -- in the striatum (XREF_FIG).	0	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1 overexpression	sirt1	Forkhead box protein O1	Forkhead box protein O1	forkhead box protein o1	0	1	24	28
In contrast , other work has shown in cell culture that SIRT1 may repress the activity of FoxO1 , FoxO3a , and FoxO4 , suggesting that cellular longevity may benefit from reduction in FoxO protein generated apoptosis XREF_BIBR .	In contrast, other work has shown in cell culture that SIRT1 may repress the activity of FoxO1, FoxO3a, and FoxO4, suggesting that cellular longevity may benefit from reduction in FoxO protein generated apoptosis XREF_BIBR.	11	19	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	FoxO1	FoxO1	FoxO1	11	12	17	18
Thus our data showed that Sirt1 inhibition mediated activation of FoxO1 occurs in both PC3 and PC3-p53 cells , irrespective of their p53 status .	Thus our data showed that Sirt1 inhibition mediated activation of FoxO1 occurs in both PC3 and PC3-p53 cells, irrespective of their p53 status.	5	11	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	Sirt1	Sirt1	Sirt1	FoxO1	FoxO1	FoxO1	5	6	10	11
Consistent with anti-inflammatory and chemopreventative actions , a key observation of this study is that APO10LA supplementation induced SIRT1 protein expression and increased deacetylation of SIRT1 targets ( NF-kappaB p65 and FoxO1 ; XREF_FIG ) .	Consistent with anti-inflammatory and chemopreventative actions, a key observation of this study is that APO10LA supplementation induced SIRT1 protein expression and increased deacetylation of SIRT1 targets (NF-kappaB p65 and FoxO1; XREF_FIG).	15	32	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	APO10LA supplementation induced SIRT1 protein expression	sirt1	FoxO1	FoxO1	foxo1	18	19	31	32
XREF_BIBR In contrast , other work has shown in cell culture that Sirt1 may repress the activity of FoxO1 , FoxO3a and FoxO4 , suggesting that cellular longevity may benefit from reduction in FoxO protein generated apoptosis .	XREF_BIBR In contrast, other work has shown in cell culture that Sirt1 may repress the activity of FoxO1, FoxO3a and FoxO4, suggesting that cellular longevity may benefit from reduction in FoxO protein generated apoptosis.	12	22	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt1	Sirt1	Sirt1	FoxO1	FoxO1	FoxO1	12	13	18	19
Because FOXO1 deacetylation decreases its stability [ XREF_BIBR ] , Sirt1 overexpression decreased total FOXO1 protein in vitro .	Because FOXO1 deacetylation decreases its stability [XREF_BIBR], Sirt1 overexpression decreased total FOXO1 protein in vitro.	10	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt1	Sirt1 overexpression	sirt1	FOXO1	FOXO1	foxo1	10	11	14	15
In pig preadipocytes , SIRT1 may inhibit FOXO1 or other genes associated with pig adipocyte development .	In pig preadipocytes, SIRT1 may inhibit FOXO1 or other genes associated with pig adipocyte development.	4	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	4	5	7	8
During fasting , increased SIRT1 expression represses FOXO1 activity through increased deacetylation .	During fasting, increased SIRT1 expression represses FOXO1 activity through increased deacetylation.	4	8	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1 expression	sirt1	FOXO1	FOXO1	foxo1	4	5	7	8
In contrast , other reports have shown in cell culture that SIRT1 may repress the activity of FoxO1 , FoxO3a and FoxO4 , suggesting that cellular longevity may benefit from reduction in FoxO-protein-generated apoptosis [ XREF_BIBR ] .	In contrast, other reports have shown in cell culture that SIRT1 may repress the activity of FoxO1, FoxO3a and FoxO4, suggesting that cellular longevity may benefit from reduction in FoxO-protein-generated apoptosis [XREF_BIBR].	11	21	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	FoxO1	FoxO1	FoxO1	11	12	17	18
For example , overexpression of SIRT1 in the hypothalamus prevents FoxO1 from promoting hyperphagia and body weight gain [ XREF_BIBR ] .	For example, overexpression of SIRT1 in the hypothalamus prevents FoxO1 from promoting hyperphagia and body weight gain [XREF_BIBR].	3	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	overexpression of SIRT1	sirt1	FoxO1	FoxO1	foxo1	5	6	10	11
XREF_BIBR In contrast , other work has shown in cell culture that Sirt1 may repress the activity of FoxO1 , FoxO3a , and FoxO4 , suggesting that cellular longevity may benefit from reduction in FoxO protein generated apoptosis .	XREF_BIBR In contrast, other work has shown in cell culture that Sirt1 may repress the activity of FoxO1, FoxO3a, and FoxO4, suggesting that cellular longevity may benefit from reduction in FoxO protein generated apoptosis.	12	20	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt1	Sirt1	Sirt1	FoxO1	FoxO1	FoxO1	12	13	18	19
The degree of Sirt1 overexpression achieved in MEFs via infection with adenovirus encoding the Cre recombinase was sufficient to decrease the level of FoxO1 protein in the nucleus without affecting the FoxO1 protein level in the cytoplasm of DKI MEFs ( XREF_FIG d ) .	The degree of Sirt1 overexpression achieved in MEFs via infection with adenovirus encoding the Cre recombinase was sufficient to decrease the level of FoxO1 protein in the nucleus without affecting the FoxO1 protein level in the cytoplasm of DKI MEFs (XREF_FIG d).	3	24	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt1	Sirt1 overexpression	sirt1	FoxO1	FoxO1	foxo1	3	4	23	24
We demonstrated HG induced reduction in SIRT1 lead to increased oxidative stress mediated through FOXO1 which was prevented by SIRT1 activation .	We demonstrated HG induced reduction in SIRT1 lead to increased oxidative stress mediated through FOXO1 which was prevented by SIRT1 activation.	12	20	prevented	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	19	20	14	15
Other work has shown that Sirt1 may repress the activity of FoxO1 , FoxO3a , and FoxO4 , illustrating that cellular longevity may benefit from reduction in FoxO protein generated apoptosis XREF_BIBR .	Other work has shown that Sirt1 may repress the activity of FoxO1, FoxO3a, and FoxO4, illustrating that cellular longevity may benefit from reduction in FoxO protein generated apoptosis XREF_BIBR.	5	13	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt1	Sirt1	Sirt1	FoxO1	FoxO1	FoxO1	5	6	11	12
In contrast , other work has shown in cell culture that SIRT1 may repress the activity of FoxO1 , FoxO3a , and FoxO4 , suggesting that increased cellular survival and lifespan may benefit from reduction in FoxO proteins .	In contrast, other work has shown in cell culture that SIRT1 may repress the activity of FoxO1, FoxO3a, and FoxO4, suggesting that increased cellular survival and lifespan may benefit from reduction in FoxO proteins.	11	19	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	FoxO1	FoxO1	FoxO1	11	12	17	18
Over-expression of SIRT1 in theses regions of the hypothalamus prevents the forkhead transcription factor FoxO1 from promoting hyperphagia and body weight gain 73 .	Over-expression of SIRT1 in theses regions of the hypothalamus prevents the forkhead transcription factor FoxO1 from promoting hyperphagia and body weight gain 73.	0	15	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	Over-expression of SIRT1	sirt1	FoxO1	FoxO1	foxo1	2	3	14	15
These deleterious effects are associated with inhibition of Sirt1 mediated activation of forkhead box protein O1 ( FOXO1 ) and O3 ( FOXO3 ) , which are responsible for the transcription of antioxidant enzymes , such as superoxide dismutase and catalases [ XREF_BIBR - XREF_BIBR ] .	These deleterious effects are associated with inhibition of Sirt1 mediated activation of forkhead box protein O1 (FOXO1) and O3 (FOXO3), which are responsible for the transcription of antioxidant enzymes, such as superoxide dismutase and catalases [XREF_BIBR - XREF_BIBR].	8	16	mediated	Positive_early_activation	Positive_activation	Positive_activation	Sirt1	Sirt1	Sirt1	forkhead box protein O1	forkhead box protein O1	forkhead box protein O1	8	9	12	16
Further studies revealed that FOXO1 and beta-catenin pathway activity was downregulated by SIRT1 and eventually resulted in inhibition of target genes , including the proapoptotic gene Bcell lymphoma-2 interacting mediator of cell death , DNA repair gene growth arrest and DNA damage inducible protein 45 and the OB differentiation suppressor gene peroxisome proliferator activated receptor ( PPAR )-gamma .	Further studies revealed that FOXO1 and beta-catenin pathway activity was downregulated by SIRT1 and eventually resulted in inhibition of target genes, including the proapoptotic gene Bcell lymphoma-2 interacting mediator of cell death, DNA repair gene growth arrest and DNA damage inducible protein 45 and the OB differentiation suppressor gene peroxisome proliferator activated receptor (PPAR)-gamma.	4	13	downregulated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	12	13	4	5
On the other hand , overexpression of Sirt1 decreases , whereas knockdown of Sirt1 increases , an acetylated form of FoxO1 ( XREF_FIG ) .	On the other hand, overexpression of Sirt1 decreases, whereas knockdown of Sirt1 increases, an acetylated form of FoxO1 (XREF_FIG).	5	22	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt1	overexpression of Sirt1	sirt1	FoxO1	FoxO1	foxo1	7	8	20	21
For example , over-expression of SIRT1 in the hypothalamus prevents FoxO1 from promoting hyperphagia and body weight gain [ XREF_BIBR ] .	For example, over-expression of SIRT1 in the hypothalamus prevents FoxO1 from promoting hyperphagia and body weight gain [XREF_BIBR].	3	11	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	over-expression of SIRT1	sirt1	FoxO1	FoxO1	foxo1	5	6	10	11
FOXO1 and TORC2 , which have been reported to promote gluconeogenesis , are repressed by SIRT1 , resulting in decreased hepatic glucose production and improved glucose tolerance XREF_BIBR , XREF_BIBR .	FOXO1 and TORC2, which have been reported to promote gluconeogenesis, are repressed by SIRT1, resulting in decreased hepatic glucose production and improved glucose tolerance XREF_BIBR, XREF_BIBR.	0	24	repressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	FOXO1	FOXO1	FOXO1	15	16	0	1
On the one hand , decreased SIRT1 activity downregulates PGC-1alpha protein , thus decreasing SOD2 protein expression .	On the one hand, decreased SIRT1 activity downregulates PGC-1alpha protein, thus decreasing SOD2 protein expression.	6	11	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha protein	PGC-1alpha protein	PGC-1alpha protein	6	7	9	11
In p25 transgenic mice , which overexpress the cdk5 activating human p25 protein and exhibit tau hyperphosphorylation and neurodegeneration , 37 injection of the Sirt1 activating polyphenol resveratrol resulted in less hippocampal degeneration , less cognitive deficit , and reduced acetylation of Sirt1 substrates PGC-1alpha and p53 .	In p25 transgenic mice, which overexpress the cdk5 activating human p25 protein and exhibit tau hyperphosphorylation and neurodegeneration, 37 injection of the Sirt1 activating polyphenol resveratrol resulted in less hippocampal degeneration, less cognitive deficit, and reduced acetylation of Sirt1 substrates PGC-1alpha and p53.	24	46	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt1	Sirt1	Sirt1	PGC-1alpha	PGC-1alpha	PGC-1alpha	24	25	44	45
QEF increased protein expression levels of Klotho and SIRT1 , and decreased that of PGC-1alpha in the hippocampus .	QEF increased protein expression levels of Klotho and SIRT1, and decreased that of PGC-1alpha in the hippocampus.	0	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	QEF increased protein expression levels of Klotho and SIRT1	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	8	9	14	15
Thus , in response to low nutritional availability increased SIRT1 and activated AMPK inhibit hepatic fat accumulation by suppressing SREBP1 mediated lipogenesis and enhancing PGC-1alpha mediated oxidation , respectively XREF_BIBR ; XREF_BIBR .	Thus, in response to low nutritional availability increased SIRT1 and activated AMPK inhibit hepatic fat accumulation by suppressing SREBP1 mediated lipogenesis and enhancing PGC-1alpha mediated oxidation, respectively XREF_BIBR; XREF_BIBR.	9	25	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	9	10	24	25
We hypothesized that downregulation of hepatic SIRT1 signaling in G6Pase-alpha-deficient livers impairs PGC-1alpha activity , leading to mitochondrial dysfunction .	We hypothesized that downregulation of hepatic SIRT1 signaling in G6Pase-alpha-deficient livers impairs PGC-1alpha activity, leading to mitochondrial dysfunction.	6	13	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	6	7	12	13
XREF_BIBR - XREF_BIBR Ethanol mediated SIRT1 inhibition may directly perturb PGC-1alpha and PPAR signaling .	XREF_BIBR - XREF_BIBR Ethanol mediated SIRT1 inhibition may directly perturb PGC-1alpha and PPAR signaling.	3	13	perturb	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	Ethanol mediated SIRT1	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	5	6	10	11
PGC-1alpha deficiency decreases SIRT1 and catalase expression , and increases p53 levels in PGC-1alpha +/- / ApoE -/- mice .	PGC-1alpha deficiency decreases SIRT1 and catalase expression, and increases p53 levels in PGC-1alpha +/- / ApoE -/- mice.	0	14	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	PGC-1alpha deficiency decreases SIRT1 and catalase expression	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	3	4	13	14
Our findings that SIRT1 activation decreases PGC-1alpha coactivator activity and that inhibition or knockdown of SIRT1 increases PGC-1alpha activity are in keeping with data reported by Finkel ' s group XREF_BIBR .	Our findings that SIRT1 activation decreases PGC-1alpha coactivator activity and that inhibition or knockdown of SIRT1 increases PGC-1alpha activity are in keeping with data reported by Finkel 's group XREF_BIBR.	11	18	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	15	16	17	18
Calorie restriction or exercise also increases tissue NAD+ content thereby activates SIRT1 , which then activates PGC-1alpha through deacetylation [ XREF_BIBR ] .	Calorie restriction or exercise also increases tissue NAD+ content thereby activates SIRT1, which then activates PGC-1alpha through deacetylation [XREF_BIBR].	10	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	11	12	16	17
Besides , we find MeCP2 leads to reduced PGC-1alpha , which can be activated by SIRT1 [ XREF_BIBR , XREF_BIBR ] .	Besides, we find MeCP2 leads to reduced PGC-1alpha, which can be activated by SIRT1 [XREF_BIBR, XREF_BIBR].	5	19	activated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	15	16	8	9
In addition , SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate .	In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate.	3	9	modulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	3	4	8	9
They are important regulators of energy metabolism controlling the gluconeogenic genes and hepatic glucose output through PGC-1alpha deacetylation ( and hence the gluconeogenesis and glycolitic pathway ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] ; in addition , SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate [ XREF_BIBR ] .	They are important regulators of energy metabolism controlling the gluconeogenic genes and hepatic glucose output through PGC-1alpha deacetylation (and hence the gluconeogenesis and glycolitic pathway) [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR]; in addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate [XREF_BIBR].	40	46	modulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	40	41	45	46
were instrumental in driving SIRT1-PGC-1alpha research forward , there are two often overlooked observations from their study , which suggest that in certain situations , SIRT1 may negatively regulate PGC-1alpha and mitochondrial function .	were instrumental in driving SIRT1-PGC-1alpha research forward, there are two often overlooked observations from their study, which suggest that in certain situations, SIRT1 may negatively regulate PGC-1alpha and mitochondrial function.	25	32	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	25	26	29	30
To regulate glycolysis , SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate [ XREF_BIBR ] .	To regulate glycolysis, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate [XREF_BIBR].	4	10	modulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	9	10
This is also consistent with observations showing that overexpression of SIRT1 in muscle cells downregulates PGC-1alpha .	This is also consistent with observations showing that overexpression of SIRT1 in muscle cells downregulates PGC-1alpha.	8	16	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	overexpression of SIRT1	sirt1	PGC-1alpha	PGC-1alpha	pgc-1alpha	10	11	15	16
Moreover , this ER stress activation is associated with a decrease in the intracellular levels of Sirt1 , which subsequently represses PGC1alpha and leads to mitochondrial dysfunctions including the loss of mitochondrial membrane potential and accumulation of ROS associated with apoptosis .	Moreover, this ER stress activation is associated with a decrease in the intracellular levels of Sirt1, which subsequently represses PGC1alpha and leads to mitochondrial dysfunctions including the loss of mitochondrial membrane potential and accumulation of ROS associated with apoptosis.	14	23	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt1	levels of Sirt1	sirt1	PGC1alpha	PGC1alpha	pgc1alpha	16	17	21	22
When cotransfected with Smurf1 , Smad7 substantially downregulated BMPR1a and beta-catenin steady-state protein levels ( XREF_FIG ) .	When cotransfected with Smurf1, Smad7 substantially downregulated BMPR1a and beta-catenin steady-state protein levels (XREF_FIG).	5	11	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
It has been proposed that Smad7 selectively downregulates the mobile pool of beta-catenin while it upregulates the pool of beta-catenin that interacts with E-cadherin [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It has been proposed that Smad7 selectively downregulates the mobile pool of beta-catenin while it upregulates the pool of beta-catenin that interacts with E-cadherin [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	13	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	5	6	12	13
Another mechanistic possibility could be dysregulation of Wnt and beta-catenin signaling , as Smad7 was revealed to antagonize Wnt and beta-catenin signaling by accelerating beta-catenin degradation such that skin differentiation was shifted from forming hair follicles to sebaceous glands [ XREF_BIBR ] .	Another mechanistic possibility could be dysregulation of Wnt and beta-catenin signaling, as Smad7 was revealed to antagonize Wnt and beta-catenin signaling by accelerating beta-catenin degradation such that skin differentiation was shifted from forming hair follicles to sebaceous glands [XREF_BIBR].	13	25	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	13	14	24	25
Transgenic overexpression of Smad7 in the mouse skin disrupts hair follicle morphogenesis and induces premature sebaceous gland development by antagonizing Wnt and beta-catenin signaling [ XREF_BIBR ] .	Transgenic overexpression of Smad7 in the mouse skin disrupts hair follicle morphogenesis and induces premature sebaceous gland development by antagonizing Wnt and beta-catenin signaling [XREF_BIBR].	1	25	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	overexpression of Smad7	smad7	beta-catenin	beta-catenin	beta-catenin	3	4	22	23
Smad7 promotes myelination by blocking the BMP and beta-catenin negative regulatory pathways .	Smad7 promotes myelination by blocking the BMP and beta-catenin negative regulatory pathways.	0	11	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	0	1	8	9
Forced expression of Smad7 not only inhibits BMP signaling in OPCs , but also leads to the downregulation of beta-catenin levels through a mechanism involving Smad7 and its cognate E3 ubiquitin ligase Smurf1 , suggesting that Smad7 can block both the BMP and beta-catenin negative regulatory pathways for oligodendrocyte differentiation .	Forced expression of Smad7 not only inhibits BMP signaling in OPCs, but also leads to the downregulation of beta-catenin levels through a mechanism involving Smad7 and its cognate E3 ubiquitin ligase Smurf1, suggesting that Smad7 can block both the BMP and beta-catenin negative regulatory pathways for oligodendrocyte differentiation.	36	44	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	36	37	43	44
Expression of Smad7 was negatively regulated by miR-17-5p ; Smad7 expression inactivated NF-kappaB and Wnt and beta catenin pathways .	Expression of Smad7 was negatively regulated by miR-17-5p; Smad7 expression inactivated NF-kappaB and Wnt and beta catenin pathways.	9	18	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	Smad7 expression	smad7	beta catenin	beta catenin	beta catenin	9	10	16	18
Other studies have shown that SMAD7 degrades beta-catenin signaling , altering the Wnt signaling pathway which is a central element in CRC .	Other studies have shown that SMAD7 degrades beta-catenin signaling, altering the Wnt signaling pathway which is a central element in CRC.	5	8	degrades	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMAD7	SMAD7	SMAD7	beta-catenin	beta-catenin	beta-catenin	5	6	7	8
We observed that Smad7 promotes accumulation of beta-catenin in PC-3U cells , whereas Smad7 was reported to cause degradation of beta-catenin in keratinocytes .	We observed that Smad7 promotes accumulation of beta-catenin in PC-3U cells, whereas Smad7 was reported to cause degradation of beta-catenin in keratinocytes.	3	10	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
Suppression of Smad7 by short interfering RNA ( siRNA ) resulted in a reduced phosphorylation of p38 and prevented to some extent TGFbeta induced accumulation of beta-catenin ( XREF_FIG ) .	Suppression of Smad7 by short interfering RNA (siRNA) resulted in a reduced phosphorylation of p38 and prevented to some extent TGFbeta induced accumulation of beta-catenin (XREF_FIG).	0	28	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	2	3	26	27
XREF_BIBR Smad interacting protein-1 ( Sip1 ; Zeb2 ) activates Smad7 that antagonizes the bone morphogenetic protein ( BMP ) and Wnt and beta-catenin signaling pathways pivotal for the development of astrocytes .	XREF_BIBR Smad interacting protein-1 (Sip1; Zeb2) activates Smad7 that antagonizes the bone morphogenetic protein (BMP) and Wnt and beta-catenin signaling pathways pivotal for the development of astrocytes.	9	25	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	10	11	23	24
Smad7 was also reported to negatively regulate Wnt and beta-catenin signaling , while beta-catenin stabilization inhibits oligodendrocyte myelination .	Smad7 was also reported to negatively regulate Wnt and beta-catenin signaling, while beta-catenin stabilization inhibits oligodendrocyte myelination.	0	10	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	0	1	9	10
Meanwhile , restoration of SMAD7 expression effectively eliminated the miR-17-5p-enhanced , beta-catenin reporter gene activity ( XREF_FIG ) .	Meanwhile, restoration of SMAD7 expression effectively eliminated the miR-17-5p-enhanced, beta-catenin reporter gene activity (XREF_FIG).	4	13	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMAD7	SMAD7 expression	smad7	beta-catenin	beta-catenin	beta-catenin	4	5	11	12
For instance , according on the results of other studies , SMAD7 degrades beta-catenin signaling that alters the Wnt signaling pathway which has a central role in CRC .	For instance, according on the results of other studies, SMAD7 degrades beta-catenin signaling that alters the Wnt signaling pathway which has a central role in CRC.	11	14	degrades	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMAD7	SMAD7	SMAD7	beta-catenin	beta-catenin	beta-catenin	11	12	13	14
Finally , although its relationship to GSK3beta pathway remains unknown , Smad7 , an antagonist for TGFbetasignaling also induces beta-catenin degradation through Smurf2 in keratinocytes .	Finally, although its relationship to GSK3beta pathway remains unknown, Smad7, an antagonist for TGFbetasignaling also induces beta-catenin degradation through Smurf2 in keratinocytes.	11	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	beta-catenin	beta-catenin	beta-catenin	11	12	19	20
In addition , SMAD7 directly interferes with the TNF receptor associated factors ( TRAF ) , TAK1 , and TAB2/3 complex , resulting in the inhibition of NF-kappaB signaling , and diminishes beta-catenin protein by recruiting SMURF1 .	In addition, SMAD7 directly interferes with the TNF receptor associated factors (TRAF), TAK1, and TAB2/3 complex, resulting in the inhibition of NF-kappaB signaling, and diminishes beta-catenin protein by recruiting SMURF1.	3	33	diminishes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMAD7	SMAD7	SMAD7	beta-catenin	beta-catenin	beta-catenin	3	4	32	33
Our findings suggested that SIRT1 inactivated the Akt pathway in a SIRT1 deacetylase dependent manner by CCF-NLs .	Our findings suggested that SIRT1 inactivated the Akt pathway in a SIRT1 deacetylase dependent manner by CCF-NLs.	4	8	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	4	5	7	8
In conclusion , our findings demonstrated that adipogenesis of porcine preadipocytes was balanced by positive regulation of Akt2 and negative regulation of Sirt1 through crosstalk between C/EBPalpha and insulin stimulated PI3K and Akt pathways .	In conclusion, our findings demonstrated that adipogenesis of porcine preadipocytes was balanced by positive regulation of Akt2 and negative regulation of Sirt1 through crosstalk between C/EBPalpha and insulin stimulated PI3K and Akt pathways.	20	33	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt1	Sirt1	Sirt1	Akt	Akt	Akt	22	23	32	33
Lysine acetylation inhibits IRS2 activity and SIRT1 dependent deacetylation increases its activity , and thereby increasing the activity of Akt .	Lysine acetylation inhibits IRS2 activity and SIRT1 dependent deacetylation increases its activity, and thereby increasing the activity of Akt.	6	20	increasing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	SIRT1 dependent deacetylation	sirt1	Akt	Akt	akt	6	7	19	20
Rui-Hong Wang et al found that hepatic SIRT1 deficiency in mice can impair mTorc2 and Akt signaling leading to oxidative damage and insulin resistance [ XREF_BIBR ] .	Rui-Hong Wang et al found that hepatic SIRT1 deficiency in mice can impair mTorc2 and Akt signaling leading to oxidative damage and insulin resistance [XREF_BIBR].	7	16	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	7	8	15	16
These findings indicate that HT regulates the autophagy of VAFs through SIRT1 mediated Akt and mTOR suppression and then inhibits the inflammatory response of VAFs .	These findings indicate that HT regulates the autophagy of VAFs through SIRT1 mediated Akt and mTOR suppression and then inhibits the inflammatory response of VAFs.	9	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	11	12	13	14
Indeed , previous literature has suggested that SIRT1 activation in myoblasts has been shown to inhibit Akt and leucine evoked increases in mTOR [ XREF_BIBR ] .	Indeed, previous literature has suggested that SIRT1 activation in myoblasts has been shown to inhibit Akt and leucine evoked increases in mTOR [XREF_BIBR].	7	19	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	7	8	16	17
Further study found that HT regulated autophagy through SIRT1 mediated Akt and mTOR suppression in VAFs .	Further study found that HT regulated autophagy through SIRT1 mediated Akt and mTOR suppression in VAFs.	6	13	mediated	Positive_early_activation	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	8	9	10	11
Numerous studies have reported the protective effect of ginkgolide B against ischemic stroke by increasing sirt1 ( silent mating type information regulation 2 homolog-1 ) expression , suppresses NF-kappaB , inhibits PI3K and Akt pathway and TLR-4 / NF-kappaB , up-regulates heme oxygenase 1 , anti-apoptotic protein expression , and erythropoietin secretion .	Numerous studies have reported the protective effect of ginkgolide B against ischemic stroke by increasing sirt1 (silent mating type information regulation 2 homolog-1) expression, suppresses NF-kappaB, inhibits PI3K and Akt pathway and TLR-4 / NF-kappaB, up-regulates heme oxygenase 1, anti-apoptotic protein expression, and erythropoietin secretion.	3	34	inhibits	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	sirt1	sirt1	sirt1	Akt	Akt	Akt	15	16	33	34
It is demonstrated that loss of SIRT1 promotes activation of the oncogenic AKT pathway to mediate XPC down-regulation where mutation of the E2F site in the XPC promoter abolished the effect of SIRT1 inhibition and AKT activation , suggesting that inhibition of SIRT1 down-regulates XPC transcription by activating an AKT dependent E2F pathway [ XREF_BIBR ] .	It is demonstrated that loss of SIRT1 promotes activation of the oncogenic AKT pathway to mediate XPC down-regulation where mutation of the E2F site in the XPC promoter abolished the effect of SIRT1 inhibition and AKT activation, suggesting that inhibition of SIRT1 down-regulates XPC transcription by activating an AKT dependent E2F pathway [XREF_BIBR].	4	13	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	SIRT1	loss of SIRT1	sirt1	AKT	AKT	akt	6	7	12	13
XREF_BIBR , XREF_BIBR It has been proposed that SIRT1 inactivates the Akt pathway in a SIRT1 deacetylase dependent manner ; thus , SIRT1 acts as a deacetylase for the tumor suppressor PTEN , XREF_BIBR a known negative regulator for the phosphatidylinositol 3-kinase ( PI3K )/Akt pathway , which is a key oncogenic pathway that promotes cell growth and survival .	XREF_BIBR, XREF_BIBR It has been proposed that SIRT1 inactivates the Akt pathway in a SIRT1 deacetylase dependent manner; thus, SIRT1 acts as a deacetylase for the tumor suppressor PTEN, XREF_BIBR a known negative regulator for the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is a key oncogenic pathway that promotes cell growth and survival.	8	12	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	Akt	Akt	Akt	8	9	11	12
One possible model is that SIRT1 may be inhibiting ERalpha , PI 3 K or AKT activation directly .	One possible model is that SIRT1 may be inhibiting ERalpha, PI 3 K or AKT activation directly.	5	16	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	AKT	AKT	AKT	5	6	15	16
SIRT1 represses estrogen independent activation of AKT .	SIRT1 represses estrogen independent activation of AKT.	0	7	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT1	SIRT1	SIRT1	AKT	AKT	AKT	0	1	6	7
Smad2 phosphorylation at the linker region inhibits nuclear accumulation of Smad2 without interfering with TGF-beta-induced phosphorylation of its COOH-tail .	Smad2 phosphorylation at the linker region inhibits nuclear accumulation of Smad2 without interfering with TGF-beta-induced phosphorylation of its COOH-tail.	0	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad2	Smad2 phosphorylation	smad2	Smad2	Smad2	smad2	0	1	10	11
Each dose of losartan after bilateral cavernous nerve injury significantly attenuated the up-regulated expression of fibronectin ( p < 0.01 ) , pSMAD2 ( p < 0.05 ) and thrombospondin-1 ( p < 0.05 ) , and up-regulated total SMAD2 ( p < 0.05 ) .	Each dose of losartan after bilateral cavernous nerve injury significantly attenuated the up-regulated expression of fibronectin (p < 0.01), pSMAD2 (p < 0.05) and thrombospondin-1 (p < 0.05), and up-regulated total SMAD2 (p < 0.05).	3	41	up-regulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pSMAD2	losartan after bilateral cavernous nerve injury significantly attenuated the up-regulated expression of fibronectin (p < 0.01), pSMAD2	psmad2	SMAD2	SMAD2	smad2	22	23	39	40
Recent data from myeloma cells found that phosphorylation of Smad2 at the T8 site by CDK2 prevented Smad2 from linking with the co-Smad , Smad4 , thus inhibiting Smad dependent transcriptional activity .	Recent data from myeloma cells found that phosphorylation of Smad2 at the T8 site by CDK2 prevented Smad2 from linking with the co-Smad, Smad4, thus inhibiting Smad dependent transcriptional activity.	7	18	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad2	phosphorylation of Smad2	smad2	Smad2	Smad2	smad2	9	10	17	18
Smad2 phosphorylation at the linker region inhibits the nuclear accumulation of Smad2 without interfering with the TGF-beta-induced phosphorylation of its COOH-tail .	Smad2 phosphorylation at the linker region inhibits the nuclear accumulation of Smad2 without interfering with the TGF-beta-induced phosphorylation of its COOH-tail.	0	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad2	Smad2 phosphorylation	smad2	Smad2	Smad2	smad2	0	1	11	12
Besides , we also found that p21 activated kinase 2 ( PAK2 ) can directly phosphorylate Smad2 at Ser417 , which interferes with the TbetaRI-Smad2 association and thus blocks TGF-beta-induced Smad2 activation and signaling [ XREF_BIBR ] .	Besides, we also found that p21 activated kinase 2 (PAK2) can directly phosphorylate Smad2 at Ser417, which interferes with the TbetaRI-Smad2 association and thus blocks TGF-beta-induced Smad2 activation and signaling [XREF_BIBR].	6	31	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad2	p21 activated kinase 2 (PAK2) can directly phosphorylate Smad2 at Ser417	smad2	Smad2	Smad2	smad2	16	17	30	31
Activated downstream of ROS , MINK1 phosphorylated SMAD2 at T324 and inhibited the activation of SMAD2 .	Activated downstream of ROS, MINK1 phosphorylated SMAD2 at T324 and inhibited the activation of SMAD2.	5	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMAD2	MINK1 phosphorylated SMAD2 at T324	smad2	SMAD2	SMAD2	smad2	7	8	15	16
The data presented here demonstrate that lysine fatty acylation helps to target TNF-alpha to the lysosomes for degradation and at the same time decrease its localization in the recycling endosome ( XREF_FIG ) , which explains why Sirt6 KO cells have decreased TNF-alpha secretion .	The data presented here demonstrate that lysine fatty acylation helps to target TNF-alpha to the lysosomes for degradation and at the same time decrease its localization in the recycling endosome (XREF_FIG), which explains why Sirt6 KO cells have decreased TNF-alpha secretion.	37	43	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt6	Sirt6	Sirt6	TNF-alpha	TNF-alpha	TNF-alpha	37	38	42	43
In addition , assessment of the levels of TNF-alpha , IL-1beta , and IL-10 by ELISA in the heart homogenate of control and pSIRT6 injected mice after TAC or sham surgery showed that SIRT6 significantly attenuated the TAC induced upregulation of TNF-alpha and IL-1beta and the downregulation of IL-10 , suggesting that the effect of SIRT6 was mediated by the modulation of inflammatory factors .	In addition, assessment of the levels of TNF-alpha, IL-1beta, and IL-10 by ELISA in the heart homogenate of control and pSIRT6 injected mice after TAC or sham surgery showed that SIRT6 significantly attenuated the TAC induced upregulation of TNF-alpha and IL-1beta and the downregulation of IL-10, suggesting that the effect of SIRT6 was mediated by the modulation of inflammatory factors.	33	43	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT6	SIRT6	SIRT6	TNF-alpha	TNF-alpha	TNF-alpha	33	34	41	42
Both SIRT6 WT and G60A expression decreased TNFalpha lysine fatty acylation ( XREF_FIG ) , while none of the other mutants did .	Both SIRT6 WT and G60A expression decreased TNFalpha lysine fatty acylation (XREF_FIG), while none of the other mutants did.	1	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT6	SIRT6	SIRT6	TNFalpha	TNFalpha	TNFalpha	1	2	7	8
This suggested that the TNF-alpha localization in the recycling endosomes was decreased by Sirt6 KO , most likely due to the increased localization of TNF-alpha in the lysosomes .	This suggested that the TNF-alpha localization in the recycling endosomes was decreased by Sirt6 KO, most likely due to the increased localization of TNF-alpha in the lysosomes.	4	14	decreased	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Sirt6	Sirt6	Sirt6	TNF-alpha	TNF-alpha	TNF-alpha	13	14	4	5
In Smad4 deleted cells , phospho-Smad3 , Smad1 and Smad5 are all increased and Smad3 deletion abrogates Smad4 loss associated inflammation .	In Smad4 deleted cells, phospho-Smad3, Smad1 and Smad5 are all increased and Smad3 deletion abrogates Smad4 loss associated inflammation.	14	18	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Smad3	Smad3	Smad4	Smad4	Smad4	14	15	17	18
In addition to regulating SOD2 , SIRT3 also reduces oxidative stress by modulating the activity of isocitrate dehydrogenase 2 ( IDH2 ) , a mitochondrial enzyme that generates the reducing agent NADPH [ XREF_BIBR ] .	In addition to regulating SOD2, SIRT3 also reduces oxidative stress by modulating the activity of isocitrate dehydrogenase 2 (IDH2), a mitochondrial enzyme that generates the reducing agent NADPH [XREF_BIBR].	6	25	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	6	7	20	21
A significant decrease in IDH2 activity was detected ( XREF_FIG ) in the livers of mitochondria lacking Sirt3 , suggesting that loss of Sirt3 decreases IDH2 activity in vivo .	A significant decrease in IDH2 activity was detected (XREF_FIG) in the livers of mitochondria lacking Sirt3, suggesting that loss of Sirt3 decreases IDH2 activity in vivo.	21	26	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sirt3	loss of Sirt3	sirt3	IDH2	IDH2	idh2	23	24	25	26
SIRT3 suppresses the cellular production of deleterious ROS , via deacetylation and the activation of MnSOD and isocitrate dehydrogenase 2 ( IDH2 ) .	SIRT3 suppresses the cellular production of deleterious ROS, via deacetylation and the activation of MnSOD and isocitrate dehydrogenase 2 (IDH2).	0	22	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SIRT3	SIRT3	SIRT3	IDH2	IDH2	IDH2	0	1	21	22
We induced these cells to migrate to fibronectin in the absence ( mock ) and presence of Slit2 , and found that Slit2 inhibited the motility of cells expressing Robo4 , but not Robo4 ED-TM ( XREF_FIG ) .	We induced these cells to migrate to fibronectin in the absence (mock) and presence of Slit2, and found that Slit2 inhibited the motility of cells expressing Robo4, but not Robo4 ED-TM (XREF_FIG).	22	34	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Slit2	Slit2	Slit2	Robo4	Robo4	Robo4	22	23	33	34
More recently , investigators have demonstrated that in retinal and choroidal vascular pathologies , slit2 inhibited vascular permeability and neovascularization were abrogated in Robo4 deficient mice .	More recently, investigators have demonstrated that in retinal and choroidal vascular pathologies, slit2 inhibited vascular permeability and neovascularization were abrogated in Robo4 deficient mice.	14	25	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	slit2	slit2	slit2	Robo4	Robo4	Robo4	14	15	23	24
SLIT2 , which is a ligand for ROBO receptors , inhibits ARF6 activation in endothelial cells by stimulating ARF6 GAP activity in a ROBO4 dependent manner .	SLIT2, which is a ligand for ROBO receptors, inhibits ARF6 activation in endothelial cells by stimulating ARF6 GAP activity in a ROBO4 dependent manner.	0	25	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SLIT2	SLIT2	SLIT2	ROBO4	ROBO4	ROBO4	0	1	23	24
Additionally , SMAD3 was linked to four downregulated members of the NOTCH pathway and three upregulated genes : JUN , SQSTM1 and IL1F7 .	Additionally, SMAD3 was linked to four downregulated members of the NOTCH pathway and three upregulated genes : JUN, SQSTM1 and IL1F7.	2	12	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SMAD3	SMAD3	SMAD3	NOTCH	NOTCH	NOTCH	2	3	11	12
Interestingly , Smad3 activation directly antagonizes the Notch signalling pathway , which is known to regulate satellite cell quiescence and self-renewal .	Interestingly, Smad3 activation directly antagonizes the Notch signalling pathway, which is known to regulate satellite cell quiescence and self-renewal.	2	9	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Smad3	Smad3	Notch	Notch	Notch	2	3	7	8
TGF-beta-mediated Smurf2 promoter activation was inhibited by Smad7 or an activin receptor like kinase 5 inhibitor but not by dominant negative Smad or disruption of Smad binding elements in the promoter .	TGF-beta-mediated Smurf2 promoter activation was inhibited by Smad7 or an activin receptor like kinase 5 inhibitor but not by dominant negative Smad or disruption of Smad binding elements in the promoter.	1	11	inhibited	Negative_activation_syntax_4_verb	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	Smurf2	Smurf2	Smurf2	7	8	1	2
The degradation of Smurf2 by Smad7 leads to loss of inhibition of TGF-beta signaling .	The degradation of Smurf2 by Smad7 leads to loss of inhibition of TGF-beta signaling.	1	6	degradation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	Smurf2	Smurf2	Smurf2	5	6	3	4
Smad7 inhibits TGF-beta signaling by transfering Smurf1 and Smurf2 to the plasma membrane , which triggers the proteasomal destruction of TGF-beta receptors .	Smad7 inhibits TGF-beta signaling by transfering Smurf1 and Smurf2 to the plasma membrane, which triggers the proteasomal destruction of TGF-beta receptors.	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad7	Smad7	Smad7	Smurf2	Smurf2	Smurf2	0	1	8	9
As a consequence , a reduction in Smad2 expression or activation would increase the ability of Smad4 to bind Smad3 on the SBEs of target gene promoters .	As a consequence, a reduction in Smad2 expression or activation would increase the ability of Smad4 to bind Smad3 on the SBEs of target gene promoters.	7	17	increase	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad2	Smad2 expression	smad2	Smad4	Smad4	smad4	7	8	16	17
Using pharmacological and genetic approaches in cultured C2C12 myoblasts and in MuSCs , we demonstrated that Tcf/Lef activity during quiescence depended not on beta-catenin but on the transforming growth factor-beta ( TGF-beta ) effector and transcriptional coactivator Smad3 , which colocalized with Lef1 at canonical Wnt responsive elements and directly interacted with Lef1 specifically in G 0 Depletion of Smad3 , but not beta-catenin , reduced Lef1 occupancy at target promoters , Tcf/Lef target gene expression , and self-renewal of myoblasts .	Using pharmacological and genetic approaches in cultured C2C12 myoblasts and in MuSCs, we demonstrated that Tcf/Lef activity during quiescence depended not on beta-catenin but on the transforming growth factor-beta (TGF-beta) effector and transcriptional coactivator Smad3, which colocalized with Lef1 at canonical Wnt responsive elements and directly interacted with Lef1 specifically in G 0 Depletion of Smad3, but not beta-catenin, reduced Lef1 occupancy at target promoters, Tcf/Lef target gene expression, and self-renewal of myoblasts.	33	67	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad3	Smad3, which colocalized with Lef1 at canonical Wnt responsive elements and directly interacted with Lef1	smad3	Lef1	Lef1	lef1	37	38	66	67
Mutation of the Smad4 binding motif completely abolished transcriptional activation , whereas mutation or deletion of the Smad1 recognition sequence inhibited Smad1 and Smad4 responsiveness .	Mutation of the Smad4 binding motif completely abolished transcriptional activation, whereas mutation or deletion of the Smad1 recognition sequence inhibited Smad1 and Smad4 responsiveness.	17	24	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Smad1	Smad1	Smad1	Smad4	Smad4	Smad4	17	18	23	24
Downregulation of BAF60c expression prevents MyoD access to the chromatin and the proper loading of an active myogenic transcriptosome preventing the expression of hundreds of myogenic genes .	Downregulation of BAF60c expression prevents MyoD access to the chromatin and the proper loading of an active myogenic transcriptosome preventing the expression of hundreds of myogenic genes.	2	6	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAF60c	BAF60c expression	baf60c	MyoD	MyoD	myod	2	3	5	6
XREF_BIBR Furthermore , genome wide ChIP ( ChIP on ChIP ) showed that RNAi mediated downregulation of BAF60c expression prevents the recruitment of MyoD to most of its target genes impairing their transcription .	XREF_BIBR Furthermore, genome wide ChIP (ChIP on ChIP) showed that RNAi mediated downregulation of BAF60c expression prevents the recruitment of MyoD to most of its target genes impairing their transcription.	17	24	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAF60c	BAF60c expression	baf60c	MyoD	MyoD	myod	17	18	23	24
The most successful approaches that have been clinically validated so far include the targeting of the BRD4-NUT fusion transcript in NUT-midline carcinoma by BET ( Bromodomain Extra-Terminal ) inhibitors , and the use of EZH2 ( Enhancer of Zest Homolog 2 ) inhibitors in SMARCB1 deficient malignant rhabdoid tumors and SMARCA4 deficient ovarian small cell carcinomas .	The most successful approaches that have been clinically validated so far include the targeting of the BRD4-NUT fusion transcript in NUT-midline carcinoma by BET (Bromodomain Extra-Terminal) inhibitors, and the use of EZH2 (Enhancer of Zest Homolog 2) inhibitors in SMARCB1 deficient malignant rhabdoid tumors and SMARCA4 deficient ovarian small cell carcinomas.	11	55	inhibitors	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	SMARCA4	SMARCA4	SMARCA4	SMARCB1	SMARCB1	SMARCB1	50	51	44	45
In addition , we found that knockdown of SMG1 also caused the upregulation of Upf1 and Upf2 proteins , which was confirmed by different target sequences of siRNA .	In addition, we found that knockdown of SMG1 also caused the upregulation of Upf1 and Upf2 proteins, which was confirmed by different target sequences of siRNA.	6	17	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SMG1	SMG1	SMG1	Upf1	Upf1	Upf1	8	9	14	15
Furthermore , BRG1 depletion using RNA interference abrogated the ability of TERT to hyperactivate TOP-FLASH reporter plasmids in HeLa cells ( XREF_FIG ) .	Furthermore, BRG1 depletion using RNA interference abrogated the ability of TERT to hyperactivate TOP-FLASH reporter plasmids in HeLa cells (XREF_FIG).	2	12	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	BRG1	BRG1	BRG1	TERT	TERT	TERT	2	3	11	12
Similarly , Src kinase inhibitor SU6656 ( perhaps , in part by inhibiting EGFR transactivation ) has also been shown to attenuate the activation of Ras-Erk1/2 and PI-3K and Akt cascades and is currently used in preclinical studies .	Similarly, Src kinase inhibitor SU6656 (perhaps, in part by inhibiting EGFR transactivation) has also been shown to attenuate the activation of Ras-Erk1/2 and PI-3K and Akt cascades and is currently used in preclinical studies.	2	30	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Akt	Akt	Akt	2	3	29	30
Addition of a Src TKI partially blocked PI3K and AKT and restored sensitivity to lapatinib .	Addition of a Src TKI partially blocked PI3K and AKT and restored sensitivity to lapatinib.	3	10	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	AKT	AKT	AKT	3	4	9	10
Targeting eEF-2K impairs basal Akt activity mediated by c-Src .	Targeting eEF-2K impairs basal Akt activity mediated by c-Src.	4	9	mediated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	8	9	4	5
Moreover , we provide evidence that the inhibition of SRC may activate RAS , AKT and ERK1/2 in the cancer cells analysed .	Moreover, we provide evidence that the inhibition of SRC may activate RAS, AKT and ERK1/2 in the cancer cells analysed.	7	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SRC	SRC	SRC	AKT	AKT	AKT	9	10	14	15
Moreover , FAK overexpression was able to enhance HGF elicited signals , leading to sustained activation of ERK , JNK , and AKT , which could be prevented by the expression of the Src homology 3 domain of p130 ( cas ) .	Moreover, FAK overexpression was able to enhance HGF elicited signals, leading to sustained activation of ERK, JNK, and AKT, which could be prevented by the expression of the Src homology 3 domain of p130 (cas).	7	40	prevented	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Src	expression of the Src	src	AKT	AKT	akt	33	34	22	23
Of course , Src has been reported to inhibit apoptosis by activating the PI3k and Akt pathway , which protects cells against proapoptotic stimuli through the phosphorylation and inactivation of death accelerators , such as Bad , Bax , and caspase-9 .	Of course, Src has been reported to inhibit apoptosis by activating the PI3k and Akt pathway, which protects cells against proapoptotic stimuli through the phosphorylation and inactivation of death accelerators, such as Bad, Bax, and caspase-9.	3	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Akt	Akt	Akt	3	4	15	16
Bromocriptine caused protein kinase B ( Akt ) activation in PC12-D2R cells and the inhibition of either phosphoinositide ( PI ) 3-kinase , epidermal growth factor receptor ( EGFR ) , or c-Src eliminated the Akt activation and the cytoprotective effects of bromocriptine against oxidative stress .	Bromocriptine caused protein kinase B (Akt) activation in PC12-D2R cells and the inhibition of either phosphoinositide (PI) 3-kinase, epidermal growth factor receptor (EGFR), or c-Src eliminated the Akt activation and the cytoprotective effects of bromocriptine against oxidative stress.	32	36	eliminated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	32	33	35	36
Thus , we showed that downregulation of ROCK1 by miR-199a and b-5p lowered FAK and Src activity that subsequently reduced PI3K and AKT signaling , thereby suppressing HCC metastasis .	Thus, we showed that downregulation of ROCK1 by miR-199a and b-5p lowered FAK and Src activity that subsequently reduced PI3K and AKT signaling, thereby suppressing HCC metastasis.	15	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	AKT	AKT	AKT	15	16	22	23
Inhibition of Src with PP2 { 4-amino-5-( 4-chlorophenyl )-7-( t-butyl ) pyrazolo [ 3,4-d ] pyrimidine } and a DN-Src ( dominant negative Src ) construct prevented the activation of Akt , JAK ( Janus kinase ) and STAT3 .	Inhibition of Src with PP2 {4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine} and a DN-Src (dominant negative Src) construct prevented the activation of Akt, JAK (Janus kinase) and STAT3.	0	31	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	Akt	Akt	Akt	2	3	30	31
Although c-Src is an important adapter protein to mediate ER signaling pathways in MCF-7 :5 C cells , blockade of c-Src was insufficient to abolish the degradation of Akt by E 2 ( XREF_SUPPLEMENTARY ) .	Although c-Src is an important adapter protein to mediate ER signaling pathways in MCF-7 :5 C cells, blockade of c-Src was insufficient to abolish the degradation of Akt by E 2 (XREF_SUPPLEMENTARY).	18	29	abolish	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	20	21	28	29
Further , we inhibited the Src activity in EBV transformed cells using the Src specific inhibitor PP2 , and results show that Src inactivation markedly impairs Akt activity ( XREF_FIG ) .	Further, we inhibited the Src activity in EBV transformed cells using the Src specific inhibitor PP2, and results show that Src inactivation markedly impairs Akt activity (XREF_FIG).	22	27	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Akt	Akt	Akt	22	23	26	27
EXPRESSION OF THE Src */CasSD ATTENUATES THE PRO SURVIVAL PI3K and Akt PATHWAY AND INCREASES ERalpha LEVELS .	EXPRESSION OF THE Src */CasSD ATTENUATES THE PRO SURVIVAL PI3K and Akt PATHWAY AND INCREASES ERalpha LEVELS.	0	12	ATTENUATES	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	EXPRESSION OF THE Src	src	Akt	Akt	akt	3	4	11	12
More specifically , T3E dependent inhibition of Src induced Akt activation contributed to suppression of cell survival under hypoxia , and the reduction of fibrinolytic factors such as plasminogen activator-1 ( PAI-1 ) via the decrease of hypoxia inducible factor-2alpha by T3E led to inhibition of hypoxic invasion .	More specifically, T3E dependent inhibition of Src induced Akt activation contributed to suppression of cell survival under hypoxia, and the reduction of fibrinolytic factors such as plasminogen activator-1 (PAI-1) via the decrease of hypoxia inducible factor-2alpha by T3E led to inhibition of hypoxic invasion.	5	10	induced	Positive_early_activation	Positive_activation	Negative_activation	Src	Src	Src	Akt	Akt	Akt	7	8	9	10
Effects of Src Inhibition on Ouabain Induced Activation of Akt and Increase in the Level of Protein Synthesis in Adult Mouse Cardiac Myocytes .	Effects of Src Inhibition on Ouabain Induced Activation of Akt and Increase in the Level of Protein Synthesis in Adult Mouse Cardiac Myocytes.	2	11	Induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Akt	Akt	Akt	2	3	9	10
The action of trastuzumab is dependent on HER-2 signaling through Src hyperactivation , which further inhibits PTEN and its downstream PI3K and AKT signaling in cell proliferation .	The action of trastuzumab is dependent on HER-2 signaling through Src hyperactivation, which further inhibits PTEN and its downstream PI3K and AKT signaling in cell proliferation.	10	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	AKT	AKT	AKT	10	11	22	23
While c-Src inhibition mediates PI3K and Akt signaling upstream , our group examined the role of PI3K inhibition in MTC .	While c-Src inhibition mediates PI3K and Akt signaling upstream, our group examined the role of PI3K inhibition in MTC.	1	7	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	1	2	6	7
Subsequently , MPP inhibited the phospho protein levels of Syk and Src , which are upstream signaling enzymes that activate AKT ( XREF_FIG ) .	Subsequently, MPP inhibited the phospho protein levels of Syk and Src, which are upstream signaling enzymes that activate AKT (XREF_FIG).	2	22	activate	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	Src	MPP inhibited the phospho protein levels of Syk and Src	src	AKT	AKT	akt	11	12	20	21
Gas6 treated endothelial cells were transfected with small interfering RNA ( siRNA ) for Axl , caveolin-1 , c-Src , and Akt or treated with pharmacological inhibitors of c-Src and ERK1/2 .	Gas6 treated endothelial cells were transfected with small interfering RNA (siRNA) for Axl, caveolin-1, c-Src, and Akt or treated with pharmacological inhibitors of c-Src and ERK1/2.	14	30	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	28	29	21	22
Our results demonstrated for the first time evidence that in chondrocytes , IKK-inhibitor ( BMS ) , IGF-1 or/and PDGF-bb can suppress IL-1beta-induced NF-kappaB activation and apoptosis , and this may be mediated through c-Src dependent suppression of PI-3K and Akt , revealed by using pharmacological inhibitors PP1 , wortmannin and SH-5 , respectively .	Our results demonstrated for the first time evidence that in chondrocytes, IKK-inhibitor (BMS), IGF-1 or/and PDGF-bb can suppress IL-1beta-induced NF-kappaB activation and apoptosis, and this may be mediated through c-Src dependent suppression of PI-3K and Akt, revealed by using pharmacological inhibitors PP1, wortmannin and SH-5, respectively.	34	41	suppression	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	Akt	Akt	Akt	34	35	40	41
Thus the Src */CasSD effectively reduces the activation of the PI3K and Akt pathway , and this attenuation may , in part , be responsible for the increase in ERalpha levels .	Thus the Src */CasSD effectively reduces the activation of the PI3K and Akt pathway, and this attenuation may, in part, be responsible for the increase in ERalpha levels.	2	13	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Akt	Akt	Akt	2	3	12	13
As expected , SHP2 knockdown diminishes the dephosphorylation of Paxillin pY118 and Src pY527 , and attenuates ERK1/2 , AKT and S6K activation after HGF stimulation , and the alterations on these signaling molecules are more obvious compared to those without HGF stimulation in Figure XREF_FIG .	As expected, SHP2 knockdown diminishes the dephosphorylation of Paxillin pY118 and Src pY527, and attenuates ERK1/2, AKT and S6K activation after HGF stimulation, and the alterations on these signaling molecules are more obvious compared to those without HGF stimulation in Figure XREF_FIG.	3	22	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	SHP2 knockdown diminishes the dephosphorylation of Paxillin pY118 and Src	src	AKT	AKT	akt	12	13	19	20
We showed that downregulation of SRC attenuates p38 and AKT signaling that was activated by irradiation .	We showed that downregulation of SRC attenuates p38 and AKT signaling that was activated by irradiation.	3	10	attenuates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SRC	SRC	SRC	AKT	AKT	AKT	5	6	9	10
We showed that Src inhibition resulted in a decrease in the activation of PDK-1 and Akt .	We showed that Src inhibition resulted in a decrease in the activation of PDK-1 and Akt.	3	16	activation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	Src	Src	Src	Akt	Akt	Akt	3	4	15	16
The Src kinase inhibitor dasatinib decreases HER3 and PI3K and Akt activity , implicating Src a possible downstream pathway to resistance .	The Src kinase inhibitor dasatinib decreases HER3 and PI3K and Akt activity, implicating Src a possible downstream pathway to resistance.	1	11	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Akt	Akt	Akt	1	2	10	11
Akt activation was inhibited by the Src tyrosine kinase inhibitor PP2 , and removal of extracellular calcium .	Akt activation was inhibited by the Src tyrosine kinase inhibitor PP2, and removal of extracellular calcium.	0	10	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Src	Src	Src	Akt	Akt	Akt	6	7	0	1
Preclinical data suggests that Src inhibition may enhance the efficacy of the EGFR tyrosine kinase inhibitor gefitinib as well as the anti-EGFR monoclonal antibody cetuximab .	Preclinical data suggests that Src inhibition may enhance the efficacy of the EGFR tyrosine kinase inhibitor gefitinib as well as the anti-EGFR monoclonal antibody cetuximab.	4	16	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	EGFR	EGFR	EGFR	4	5	12	13
Further , Src activity antagonizes the proteolysis of EGFR via Cbl activation [ XREF_BIBR ] .	Further, Src activity antagonizes the proteolysis of EGFR via Cbl activation [XREF_BIBR].	2	13	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	EGFR	EGFR	EGFR	2	3	8	9
In particular , Kv1.2 is suppressed by the tyrosine kinase PYK2 and EGFr and Kv1.5 is suppressed by Src , as well as by activation of several growth factor receptors .	In particular, Kv1.2 is suppressed by the tyrosine kinase PYK2 and EGFr and Kv1.5 is suppressed by Src, as well as by activation of several growth factor receptors.	12	19	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Src	Src	Src	EGFr	EGFr	EGFr	18	19	12	13
LPC activated Src-kinase and protein kinase C ( PKC ) , and both Src kinase inhibitor PP-2 and PKC inhibitor inhibited the activation of EGFR by LPC .	LPC activated Src-kinase and protein kinase C (PKC), and both Src kinase inhibitor PP-2 and PKC inhibitor inhibited the activation of EGFR by LPC.	13	25	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	EGFR	EGFR	EGFR	13	14	24	25
Src and Ras oncogenes inhibit apoptosis of gallbladder carcinoma ( GBC ) cells by activating the epidermal growth factor receptor ( EGFR ) signaling pathway [ XREF_BIBR ] .	Src and Ras oncogenes inhibit apoptosis of gallbladder carcinoma (GBC) cells by activating the epidermal growth factor receptor (EGFR) signaling pathway [XREF_BIBR].	0	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	0	1	16	20
Having demonstrated that Src inhibition restored TKI sensitivity to WT EGFR expressing NSCLC cells , we investigated whether phosphorylation of Y845-EGFR , a Tyr phosphorylation site canonically linked to Src activity , plays a role in generating the TKI resistant phenotype observed during CS exposure .	Having demonstrated that Src inhibition restored TKI sensitivity to WT EGFR expressing NSCLC cells, we investigated whether phosphorylation of Y845-EGFR, a Tyr phosphorylation site canonically linked to Src activity, plays a role in generating the TKI resistant phenotype observed during CS exposure.	3	11	restored	Positive_activation_syntax_7_verb	Positive_activation	Negative_activation	Src	Src	Src	EGFR	EGFR	EGFR	3	4	10	11
Further , Src activity antagonizes the function of Cbl and inhibits EGFR proteolysis [ XREF_BIBR ] .	Further, Src activity antagonizes the function of Cbl and inhibits EGFR proteolysis [XREF_BIBR].	2	12	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	EGFR	EGFR	EGFR	2	3	11	12
Inhibition of HER2 alone is ineffective due to the sustained Src mediated EGFR activation , which is reflected by high levels of pAkt and pMAPK in resistant cells after lapatinib treatment .	Inhibition of HER2 alone is ineffective due to the sustained Src mediated EGFR activation, which is reflected by high levels of pAkt and pMAPK in resistant cells after lapatinib treatment.	10	13	mediated	Positive_early_activation	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	10	11	12	13
The Src family kinase inhibitor PP1 , overexpression of kinase-inactive c-Src , or chelation of intracellular Ca ( 2+ ) attenuated EGF-R transactivation .	The Src family kinase inhibitor PP1, overexpression of kinase-inactive c-Src, or chelation of intracellular Ca (2+) attenuated EGF-R transactivation.	7	22	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	overexpression of kinase-inactive c-Src	c-src	EGF-R	EGF-R	egf-r	10	11	21	22
Further , analysis of signaling pathways revealed that pAXL Y779 , pMET Y1349 , and pEGFR Y1173 were inhibited by the SRC targeting compound MPCD84111 .	Further, analysis of signaling pathways revealed that pAXL Y779, pMET Y1349, and pEGFR Y1173 were inhibited by the SRC targeting compound MPCD84111.	15	22	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	SRC	SRC	SRC	pEGFR	pEGFR	pEGFR	21	22	15	16
In contrast , blocking FXR activation increases Src ( Tyr416 ) phosphorylation , which in turn activates EGFR and post-receptor ERK1/2 signaling , thereby resulting in increased cell proliferation and tumor growth ( XREF_FIG ) .	In contrast, blocking FXR activation increases Src (Tyr416) phosphorylation, which in turn activates EGFR and post-receptor ERK1/2 signaling, thereby resulting in increased cell proliferation and tumor growth (XREF_FIG).	6	21	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src (Tyr416) phosphorylation	src	EGFR	EGFR	egfr	7	8	17	18
To investigate whether Src activity was important for HBEGF induced invadopodium function , Src activity was inhibited in HBEGF expressing MTLn3 ErbB1 and MDA-MB 231 transductants by treatment with 20uM SrcI1 , a Src inhibitor .	To investigate whether Src activity was important for HBEGF induced invadopodium function, Src activity was inhibited in HBEGF expressing MTLn3 ErbB1 and MDA-MB 231 transductants by treatment with 20uM SrcI1, a Src inhibitor.	13	25	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	ErbB1	ErbB1	ErbB1	13	14	21	22
Src kinase inhibitor PP1 and Src siRNA blocked IGF-I-induced activation of EGFR and ERK1/2 .	Src kinase inhibitor PP1 and Src siRNA blocked IGF-I-induced activation of EGFR and ERK1/2.	5	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	EGFR	EGFR	EGFR	5	6	11	12
EGFR inhibition requires the Y394 site and is modulated by Src .	EGFR inhibition requires the Y394 site and is modulated by Src.	0	11	modulated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Src	Src	Src	EGFR	EGFR	EGFR	10	11	0	1
For example , activation of the Src tyr kinase can induce ER degradation .	For example, activation of the Src tyr kinase can induce ER degradation.	6	12	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	ER	ER	ER	6	7	11	12
Furthermore , our study showed that the Src kinase inhibitor PP2 completely blocks ER stress and EMT induced by VCP inhibition in lung adenocarcinoma cells .	Furthermore, our study showed that the Src kinase inhibitor PP2 completely blocks ER stress and EMT induced by VCP inhibition in lung adenocarcinoma cells.	7	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	ER	ER	ER	7	8	13	14
We were also able to rescue the Akt and JNK activation following treatment with EerI by PP2 indicating Src kinase inhibitors PP2 can be used to block the ER stress and its associated EMT in lung adenocarcinoma cells .	We were also able to rescue the Akt and JNK activation following treatment with EerI by PP2 indicating Src kinase inhibitors PP2 can be used to block the ER stress and its associated EMT in lung adenocarcinoma cells.	18	29	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	ER	ER	ER	18	19	28	29
Conditional deletion of Src significantly increased the survival of Lgr5Cre ER ; Apc fl/fl and Apc Min/+ ( Min ) mice ( Fig XREF_FIG and B , respectively ) .	Conditional deletion of Src significantly increased the survival of Lgr5Cre ER; Apc fl/fl and Apc Min/+ (Min) mice (Fig XREF_FIG and B, respectively).	1	11	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	ER	ER	ER	3	4	10	11
SRC kinase inhibitor PP2 blocks ER stress and EMT in lung adenocarcinoma cells .	SRC kinase inhibitor PP2 blocks ER stress and EMT in lung adenocarcinoma cells.	0	6	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SRC	SRC	SRC	ER	ER	ER	0	1	5	6
Loss of C-Terminal SRC Kinase Mediates Estrogen Independent Growth of ER + Breast Cancer Cells .	Loss of C-Terminal SRC Kinase Mediates Estrogen Independent Growth of ER + Breast Cancer Cells.	3	14	Mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SRC	SRC	SRC	ER	ER	ER	3	4	10	11
The importance of the tyrosine motif in the cooperativity between SRC1 and TDG was demonstrated by the fact that substitution of Y1 and Y3 of SRC1 prevented stimulation of ERalpha activity by TDG and SRC1 ( XREF_FIG ) .	The importance of the tyrosine motif in the cooperativity between SRC1 and TDG was demonstrated by the fact that substitution of Y1 and Y3 of SRC1 prevented stimulation of ERalpha activity by TDG and SRC1 (XREF_FIG).	21	30	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SRC1	SRC1	SRC1	ERalpha	ERalpha	ERalpha	25	26	29	30
Src siRNA impaired ligand activated ER alpha loss in BT-20 cells .	Src siRNA impaired ligand activated ER alpha loss in BT-20 cells.	0	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	ER	ER	ER	0	1	5	6
Coexpression of SRC-1 reversed the ability of the estrogen receptor to squelch activation by hPR .	Coexpression of SRC-1 reversed the ability of the estrogen receptor to squelch activation by hPR.	0	10	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SRC-1	Coexpression of SRC-1	src-1	estrogen receptor	estrogen receptor	estrogen receptor	2	3	8	10
FMO3 knockdown also increased the activation of c-Src ( XREF_FIG ) , which has also recently been linked to saturated fatty acid induced ER stress and inflammatory signaling .	FMO3 knockdown also increased the activation of c-Src (XREF_FIG), which has also recently been linked to saturated fatty acid induced ER stress and inflammatory signaling.	5	24	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	c-Src	c-Src	c-Src	ER	ER	ER	7	8	23	24
Dasatinib ( Sprycel ( R ) , Bristol-Myers Squibb , formerly known as BMS-354825 ) is a TKI with rather promiscuous inhibitory activity that includes SRC family kinases , which inhibits ABL1 approximately 300 times more potently than imatinib [ XREF_BIBR ] .	Dasatinib (Sprycel (R), Bristol-Myers Squibb, formerly known as BMS-354825) is a TKI with rather promiscuous inhibitory activity that includes SRC family kinases, which inhibits ABL1 approximately 300 times more potently than imatinib [XREF_BIBR].	25	32	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SRC	SRC	SRC	ABL1	ABL1	ABL1	25	26	31	32
One interesting trend that becomes apparent from analyzing these data is that inhibitors that are selective for Abl over Src show activation state dependent inhibition of Abl , while non selective compounds show little or no phospho-dependence .	One interesting trend that becomes apparent from analyzing these data is that inhibitors that are selective for Abl over Src show activation state dependent inhibition of Abl, while non selective compounds show little or no phospho-dependence.	19	27	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Src	Src	Src	Abl	Abl	Abl	19	20	26	27
We then asked whether either EGFR or c-Src , known to be recruited to and contribute to full activation of the ErbB receptors could be responsible for phosphorylating c-Abl on Y488 and hence negatively regulate the activation of c-Abl by Mig6 .	We then asked whether either EGFR or c-Src, known to be recruited to and contribute to full activation of the ErbB receptors could be responsible for phosphorylating c-Abl on Y488 and hence negatively regulate the activation of c-Abl by Mig6.	5	39	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	c-Abl	c-Abl	c-Abl	7	8	38	39
Moreover , treatment of Src transformed cells with the Abl kinase blocker GNF-2 did not affect Abl protein levels , but reduced Abl kinase activity by over 90 % and , consequently reduced Robo1 expression by about 50 % .	Moreover, treatment of Src transformed cells with the Abl kinase blocker GNF-2 did not affect Abl protein levels, but reduced Abl kinase activity by over 90% and, consequently reduced Robo1 expression by about 50%.	2	24	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Abl	Abl	Abl	4	5	22	23
Because Src and Abl are structurally homologous , the dual Src and Abl TKI bosutinib ( SKI-606 ) can also inhibit Abl [ XREF_BIBR ] .	Because Src and Abl are structurally homologous, the dual Src and Abl TKI bosutinib (SKI-606) can also inhibit Abl [XREF_BIBR].	8	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Abl	Abl	Abl	10	11	21	22
The catalytic activity of Src is inhibited by phosphorylated-CagA , leading to tyrosine dephosphorylation of the actin binding proteins cortactin , ezrin , and vinculin , which ultimately results in cellular rearrangements and elongation .	The catalytic activity of Src is inhibited by phosphorylated-CagA, leading to tyrosine dephosphorylation of the actin binding proteins cortactin, ezrin, and vinculin, which ultimately results in cellular rearrangements and elongation.	2	28	leading	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	ezrin	ezrin	ezrin	4	5	21	22
Additionally , we present a dual SRC and DDR2 inhibitor , compound 5 , which suppresses DDR2 mutated lung cancer models .	Additionally, we present a dual SRC and DDR2 inhibitor, compound 5, which suppresses DDR2 mutated lung cancer models.	3	17	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SRC	SRC	SRC	DDR2	DDR2	DDR2	6	7	16	17
Fyn ' s phosphorylation of p120 at Y112 diminishes p120 ' s association with RhoA such that RhoA is no longer inhibited ( its activity rises ) , whereas Src phosphorylation of p120-catenin on Y217 and Y228 has the opposite effect , since Src enhances p120 ' s interaction to further inhibit RhoA .	Fyn 's phosphorylation of p120 at Y112 diminishes p120 's association with RhoA such that RhoA is no longer inhibited (its activity rises), whereas Src phosphorylation of p120-catenin on Y217 and Y228 has the opposite effect, since Src enhances p120 's interaction to further inhibit RhoA.	9	51	enhances	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Src	Src	Src	p120	p120	p120	43	44	45	46
Btk dependent phosphorylation of BAP-135 is abolished by mutations that impair activation of Btk by Src related kinases .	Btk dependent phosphorylation of BAP-135 is abolished by mutations that impair activation of Btk by Src related kinases.	11	17	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Src	Src	Src	Btk	Btk	Btk	15	16	13	14
Mechanistically , Sox4 ablation reduced activation of AKT and beta-catenin , leading to an attenuated invasive phenotype .	Mechanistically, Sox4 ablation reduced activation of AKT and beta-catenin, leading to an attenuated invasive phenotype.	2	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Sox4	Sox4	Sox4	beta-catenin	beta-catenin	beta-catenin	2	3	9	10
Furthermore , Src kinase inhibitor 3-( 4-chlorophenyl ) 1-( 1,1-dimethylethyl )-1H-pyrazolo [ 3,4-d ] pyrimidin-4-amine ( PP2 , 30 min ) decreased the NR2B and NR2A * ratio in mature mLGI1 ( XREF_FIG ) and immature wild-type ( XREF_FIG ) mice compared to their non treated counterparts .	Furthermore, Src kinase inhibitor 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo [3,4-d] pyrimidin-4-amine (PP2, 30 min) decreased the NR2B and NR2A * ratio in mature mLGI1 (XREF_FIG) and immature wild-type (XREF_FIG) mice compared to their non treated counterparts.	2	26	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	NR2A	NR2A	NR2A	2	3	25	26
As expected , DA as well as Src shRNA ( validated in XREF_SUPPLEMENTARY ) decreased FAK pTyr 925 levels and DA had no additional effect in cells treated with Src shRNA ( XREF_FIG ) .	As expected, DA as well as Src shRNA (validated in XREF_SUPPLEMENTARY) decreased FAK pTyr 925 levels and DA had no additional effect in cells treated with Src shRNA (XREF_FIG).	7	16	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	7	8	15	16
It is intriguing that the inhibition of Src by PP1 enhanced the overall FAK activation under HSS .	It is intriguing that the inhibition of Src by PP1 enhanced the overall FAK activation under HSS.	5	14	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	7	8	13	14
Together with the reduced sensitivity to Src inhibition of FAK stabilization in FAs by Cav1Y14D compared with wild-type Cav1 , this indicates that pY14Cav1 recruitment to FAs regulates the order and structure of these cellular domains .	Together with the reduced sensitivity to Src inhibition of FAK stabilization in FAs by Cav1Y14D compared with wild-type Cav1, this indicates that pY14Cav1 recruitment to FAs regulates the order and structure of these cellular domains.	6	10	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	6	7	9	10
Previously , it was reported that CSK binds to paxillin in focal adhesions in fibroblasts and epithelial cells and triggers Src inactivation and subsequent downregulation of FAK activation XREF_BIBR , XREF_BIBR .	Previously, it was reported that CSK binds to paxillin in focal adhesions in fibroblasts and epithelial cells and triggers Src inactivation and subsequent downregulation of FAK activation XREF_BIBR, XREF_BIBR.	20	28	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	20	21	26	27
FAK [ i ] inhibited FAK Y397 to a greater extent than Src [ i ] , and in agreement with studies showing that a reduction in FAK Y397 does not affect p130Cas phosphorylation , Src [ i ] inhibited the Src substrates paxillin Y118 and p130Cas Y249 to a greater extent than FAK [ i ] , which suggests that FAK [ i ] and Src [ i ] specifically inhibit FAK and Src , respectively .	FAK [i] inhibited FAK Y397 to a greater extent than Src [i], and in agreement with studies showing that a reduction in FAK Y397 does not affect p130Cas phosphorylation, Src [i] inhibited the Src substrates paxillin Y118 and p130Cas Y249 to a greater extent than FAK [i], which suggests that FAK [i] and Src [i] specifically inhibit FAK and Src, respectively.	61	74	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	66	67	72	73
Genetic ablation or pharmacological inhibition of Src or Syk impairs platelet spreading and FAK activation , indicating that these responses are dependent on integrin activation of Src and Syk .	Genetic ablation or pharmacological inhibition of Src or Syk impairs platelet spreading and FAK activation, indicating that these responses are dependent on integrin activation of Src and Syk.	1	14	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	6	7	13	14
Imatinib treatment did not inhibit VEGF induced tyrosine phosphorylation of Src family kinases ( XREF_SUPPLEMENTARY ) or downstream phosphorylation of the Src targets FAK and paxillin [ XREF_BIBR , XREF_BIBR ] ( XREF_SUPPLEMENTARY ) , demonstrating that Abl kinase activity is not required for Src activation .	Imatinib treatment did not inhibit VEGF induced tyrosine phosphorylation of Src family kinases (XREF_SUPPLEMENTARY) or downstream phosphorylation of the Src targets FAK and paxillin [XREF_BIBR, XREF_BIBR] (XREF_SUPPLEMENTARY), demonstrating that Abl kinase activity is not required for Src activation.	0	25	targets	Positive_activation_token_1_verb	Positive_activation	Positive_activation	Src	Imatinib treatment did not inhibit VEGF induced tyrosine phosphorylation of Src family kinases (XREF_SUPPLEMENTARY) or downstream phosphorylation of the Src	src	FAK	FAK	fak	21	22	23	24
We presume that constitutive activation of Src in polyamine depleted cells may prevent dynamic turnover of FAK during migration .	We presume that constitutive activation of Src in polyamine depleted cells may prevent dynamic turnover of FAK during migration.	4	17	prevent	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	6	7	16	17
This autophagic targeting of Src allows these FAK deficient cancer cells to deal with elevated levels of active Src kinase that is not spatially controlled by its tethering partner FAK XREF_BIBR .	This autophagic targeting of Src allows these FAK deficient cancer cells to deal with elevated levels of active Src kinase that is not spatially controlled by its tethering partner FAK XREF_BIBR.	2	10	allows	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	4	5	7	8
Src inhibition resulted in a decrease in FAK Y576 , paxillin Y118 , and p130Cas Y249 ; however , these phosphosites and total pY were all further reduced upon combined FAK and Src inhibition that also reduced FAK Y397 ( XREF_FIG ) .	Src inhibition resulted in a decrease in FAK Y576, paxillin Y118, and p130Cas Y249; however, these phosphosites and total pY were all further reduced upon combined FAK and Src inhibition that also reduced FAK Y397 (XREF_FIG).	32	38	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	32	33	37	38
The effects of FAK knockdown by siRNA or Src kinases inhibitor PP2 , with or without anti-HSP90 antibody , on PC3 cell invasion were also evaluated .	The effects of FAK knockdown by siRNA or Src kinases inhibitor PP2, with or without anti-HSP90 antibody, on PC3 cell invasion were also evaluated.	1	11	knockdown	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	8	9	3	4
Expression of a Src dominant negative mutant ( Y418F-Src ) also did not completely inhibit FAK activation ( XREF_FIG , left panels ) .	Expression of a Src dominant negative mutant (Y418F-Src) also did not completely inhibit FAK activation (XREF_FIG, left panels).	0	16	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Expression of a Src	src	FAK	FAK	fak	3	4	15	16
Pharmacological interventions indicate that in 3D matrices , cells deficient in FAK or kinase activity behave similarly to wild-type cells treated with inhibitors of Src activity or actomyosin-contractility .	Pharmacological interventions indicate that in 3D matrices, cells deficient in FAK or kinase activity behave similarly to wild-type cells treated with inhibitors of Src activity or actomyosin-contractility.	11	25	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	24	25	11	12
In addition , inhibition of Src by PP2 treatment did not further decrease the paxillin phosphorylation by blebbistatin but curiously restored some blebbistatin induced FAK inactivation ( XREF_FIG ) .	In addition, inhibition of Src by PP2 treatment did not further decrease the paxillin phosphorylation by blebbistatin but curiously restored some blebbistatin induced FAK inactivation (XREF_FIG).	3	25	restored	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	5	6	24	25
Knockdown of Src suppressed LiCl elicited movement and the level of FAK Pi-Tyr861 , which could be reversed by siRNA resistant Src .	Knockdown of Src suppressed LiCl elicited movement and the level of FAK Pi-Tyr861, which could be reversed by siRNA resistant Src.	11	22	reversed	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src	Src	FAK	FAK	FAK	21	22	11	12
Further , a Src family kinases inhibitor , PP2 , suppressed GRe and PHGPx mRNA by inactivation of FAK and c-Src in HL-60 and FAK cells .	Further, a Src family kinases inhibitor, PP2, suppressed GRe and PHGPx mRNA by inactivation of FAK and c-Src in HL-60 and FAK cells.	10	25	suppressed	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	FAK	FAK	FAK	20	21	24	25
This adhesion induced Src activation is also abolished in FAK -/- fibroblasts , which can be restored only by wild-type FAK , but not kinase-dead FAK ( XREF_FIG ) .	This adhesion induced Src activation is also abolished in FAK -/- fibroblasts, which can be restored only by wild-type FAK, but not kinase-dead FAK (XREF_FIG).	3	27	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	3	4	25	26
In HMSCs pretreated with PF228 , the increase of Src ECFP and FRET ratio was completely inhibited , indicating the FAK activity is an upstream signal necessary for Src activation .	In HMSCs pretreated with PF228, the increase of Src ECFP and FRET ratio was completely inhibited, indicating the FAK activity is an upstream signal necessary for Src activation.	9	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	FAK	FAK	FAK	9	10	20	21
Src kinase family inhibitor CGP77675 blocked STAT3 and STAT1 activation by H2O2 in a concentration dependent manner .	Src kinase family inhibitor CGP77675 blocked STAT3 and STAT1 activation by H2O2 in a concentration dependent manner.	0	9	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	STAT3	STAT3	STAT3	0	1	6	7
Inhibition of PKA ( KT-5720 , 1muM , 15min ) or suppression of Src ( Src inhibitor-1 , 1muM , 15min ) prevented the activation of STAT3 , as assessed by the nuclear accumulation of STAT3 , of WT cardiomyocytes .	Inhibition of PKA (KT-5720, 1muM, 15min) or suppression of Src (Src inhibitor-1, 1muM, 15min) prevented the activation of STAT3, as assessed by the nuclear accumulation of STAT3, of WT cardiomyocytes.	11	27	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	STAT3	STAT3	STAT3	13	14	26	27
Recently , it was reported that prolonged inhibition of Src causes reactivation of Stat3 and tumor cell survival through altered JAK and Stat3 interaction .	Recently, it was reported that prolonged inhibition of Src causes reactivation of Stat3 and tumor cell survival through altered JAK and Stat3 interaction.	7	17	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Stat3	Stat3	Stat3	9	10	13	14
c-Src inhibition leads to JAK dependent STAT3 activation in vitro and in vivo .	c-Src inhibition leads to JAK dependent STAT3 activation in vitro and in vivo.	0	7	leads	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	0	1	6	7
We hypothesized that c-Src inhibition could activate STAT3 by inducing a homeostatic feedback loop , contributing to c-Src inhibitor resistance .	We hypothesized that c-Src inhibition could activate STAT3 by inducing a homeostatic feedback loop, contributing to c-Src inhibitor resistance.	3	8	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	3	4	7	8
This is the first report that GA inhibits Src mediated Stat3 signaling contributing to the TKI resistance in lung cancer .	This is the first report that GA inhibits Src mediated Stat3 signaling contributing to the TKI resistance in lung cancer.	7	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	Src	Src	Src	Stat3	Stat3	Stat3	8	9	10	11
In cell lines from head and neck squamous cell cancers , squamous cell carcinoma of the skin ( unpublished data ) , and mesothelioma sustained c-Src inhibition also resulted in STAT3 reactivation .	In cell lines from head and neck squamous cell cancers, squamous cell carcinoma of the skin (unpublished data), and mesothelioma sustained c-Src inhibition also resulted in STAT3 reactivation.	25	32	reactivation	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	STAT3	STAT3	STAT3	25	26	30	31
Our data showed that IS increased the phosphorylation of JAK2 and AKT and decreased the phosphorylation of Src , while Src activation could not reverse IS induced decrease of pSTAT3 ( right ) .	Our data showed that IS increased the phosphorylation of JAK2 and AKT and decreased the phosphorylation of Src, while Src activation could not reverse IS induced decrease of pSTAT3 (right).	15	31	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	phosphorylation of Src	src	pSTAT3	pSTAT3	pstat3	17	18	29	30
Interestingly , inhibition of c-Src slightly increased Stat3 activation .	Interestingly, inhibition of c-Src slightly increased Stat3 activation.	2	8	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	Stat3	Stat3	Stat3	4	5	7	8
The inhibition of Src family kinases leads to changes in cell morphology due to missing activation of the Src interacting partners FAK , paxillin , p130Cas as well as STAT3 and STAT5 .	The inhibition of Src family kinases leads to changes in cell morphology due to missing activation of the Src interacting partners FAK, paxillin, p130Cas as well as STAT3 and STAT5.	3	31	leads	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	STAT3	STAT3	STAT3	3	4	29	30
The Src kinase inhibitor SU6656 suppressed IFN-gamma activation of Stat3 in both wild-type and Stat1-/- fibroblasts .	The Src kinase inhibitor SU6656 suppressed IFN-gamma activation of Stat3 in both wild-type and Stat1-/- fibroblasts.	1	10	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Stat3	Stat3	Stat3	1	2	9	10
Mechanistically , we demonstrated that GA suppression of Src mediated Stat3 signaling is important for the anti-tumorigenic effect in TKIR lung cancer .	Mechanistically, we demonstrated that GA suppression of Src mediated Stat3 signaling is important for the anti-tumorigenic effect in TKIR lung cancer.	6	11	mediated	Positive_early_activation	Positive_activation	Negative_activation	Src	Src	Src	Stat3	Stat3	Stat3	8	9	10	11
Finally , as expected , the SHP2 dependent activation of Src accounts for an increase in STAT3 activation in PAH-PASMCs as either SHP2 knockdown by siRNA or the Src inhibitor PP2 ( 4-amino-5-( 4-chlorophenyl )-7-( t-butyl ) pyrazolo [ 3,4-d ] pyrimidine ) significantly decreases STAT3 activation in PAH-PASMCs .	Finally, as expected, the SHP2 dependent activation of Src accounts for an increase in STAT3 activation in PAH-PASMCs as either SHP2 knockdown by siRNA or the Src inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine) significantly decreases STAT3 activation in PAH-PASMCs.	10	46	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	STAT3	STAT3	STAT3	10	11	45	46
First , Src dependent p130 Cas phosphorylation is reduced causing the consequent drastic decrement of Rac1 activation .	First, Src dependent p130 Cas phosphorylation is reduced causing the consequent drastic decrement of Rac1 activation.	2	16	causing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Rac1	Rac1	Rac1	2	3	15	16
Furthermore , addition NC to cells significantly decreases PDGF induced phosphorylation of c-Src , FAK , MAPKs , activation of RhoA , Rac1 and AP-1 transcriptional activity .	Furthermore, addition NC to cells significantly decreases PDGF induced phosphorylation of c-Src, FAK, MAPKs, activation of RhoA, Rac1 and AP-1 transcriptional activity.	3	23	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	c-Src	NC to cells significantly decreases PDGF induced phosphorylation of c-Src	c-src	Rac1	Rac1	rac1	12	13	22	23
As shown in XREF_FIG A , KD Src blocked Vav2 dependent Rac activation .	As shown in XREF_FIG A, KD Src blocked Vav2 dependent Rac activation.	6	12	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Rac	Rac	Rac	7	8	11	12
Down-regulation of Src by siRNA reduced activation of Rac1 and therefore Nox2 generated ROS XREF_BIBR .	Down-regulation of Src by siRNA reduced activation of Rac1 and therefore Nox2 generated ROS XREF_BIBR.	0	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Rac1	Rac1	Rac1	2	3	8	9
Gelsolin can be inhibited by its Src dependent phosphorylation on tyr 438 and/or it ' s binding to PIP 2 , two processes that occur during sperm capacitation .	Gelsolin can be inhibited by its Src dependent phosphorylation on tyr 438 and/or it 's binding to PIP 2, two processes that occur during sperm capacitation.	0	12	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Src	Src dependent phosphorylation on tyr 438	src	Gelsolin	Gelsolin	gelsolin	6	7	0	1
XREF_BIBR In addition , we found that activation of PKA and Src caused F-actin formation , which was inhibited by inhibiting Src activity , XREF_BIBR suggesting that activation of Src causes gelsolin inhibition and an increase in F-actin .	XREF_BIBR In addition, we found that activation of PKA and Src caused F-actin formation, which was inhibited by inhibiting Src activity, XREF_BIBR suggesting that activation of Src causes gelsolin inhibition and an increase in F-actin.	27	32	causes	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Src	Src	Src	gelsolin	gelsolin	gelsolin	29	30	31	32
XREF_BIBR These results confirm our hypothesis that gelsolin is inhibited during capacitation due to its binding to PIP 2 and tyr phosphorylation by Src .	XREF_BIBR These results confirm our hypothesis that gelsolin is inhibited during capacitation due to its binding to PIP 2 and tyr phosphorylation by Src.	7	24	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Src	Src	Src	gelsolin	gelsolin	gelsolin	23	24	7	8
We also found that Src homology-2 domain containing phosphatase ( SHP-2 ) is higher in TIL than in PBL , tightly correlates with PD-1 expression , and negatively regulates STAT1 and T-bet activation .	We also found that Src homology-2 domain containing phosphatase (SHP-2) is higher in TIL than in PBL, tightly correlates with PD-1 expression, and negatively regulates STAT1 and T-bet activation.	4	32	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	STAT1	STAT1	STAT1	4	5	29	30
PLCgamma isoforms are downstream targets of Src tyrosine kinase activity , and previous studies have indicated that PLCgamma1 can be activated by Src tyrosine kinase dependent phosphorylation after Ang II induced AT 1 R stimulation in smooth muscle cells .	PLCgamma isoforms are downstream targets of Src tyrosine kinase activity, and previous studies have indicated that PLCgamma1 can be activated by Src tyrosine kinase dependent phosphorylation after Ang II induced AT 1 R stimulation in smooth muscle cells.	17	27	activated	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	Src	Src tyrosine kinase dependent phosphorylation	src	PLCgamma1	PLCgamma1	plcgamma1	22	23	17	18
In rat hepatoma ( HTC ) cells , H ( 2 ) O ( 2 ) elicited a transient increase in tyrosine phosphorylation of phospholipase Cgamma1 ( PLCgamma1 ) that was blocked by PP2 , a Src family protein kinases inhibitor .	In rat hepatoma (HTC) cells, H (2) O (2) elicited a transient increase in tyrosine phosphorylation of phospholipase Cgamma1 (PLCgamma1) that was blocked by PP2, a Src family protein kinases inhibitor.	19	40	blocked	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	Src	Src	Src	PLCgamma1	PLCgamma1	PLCgamma1	36	37	27	28
Inhibition of a Src family tyrosine kinase by PP2 appears to alleviate this tyrosine kinase mediated inhibition of Raf-1 and allow activating modification ( s ) of Raf-1 to proceed .	Inhibition of a Src family tyrosine kinase by PP2 appears to alleviate this tyrosine kinase mediated inhibition of Raf-1 and allow activating modification (s) of Raf-1 to proceed.	3	29	allow activating	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Raf-1	Raf-1	Raf-1	3	4	27	28
In NIH 3T3 , SRC inhibition by PP2 appears to prevent RAF-1 negative regulation , thus leading to an increase of pERK1/2 levels in an RAS independent manner .	In NIH 3T3, SRC inhibition by PP2 appears to prevent RAF-1 negative regulation, thus leading to an increase of pERK1/2 levels in an RAS independent manner.	4	13	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SRC	SRC	SRC	RAF-1	RAF-1	RAF-1	4	5	11	12
Second , we found that neither basolateral 250 nM nor basolateral 2 microM PP2 , a high-affinity inhibitor for the Src family that also inhibits the Bcr-Abl sTK as well as the Kit RTK , reduces the CO ( 2 )-stimulated increase in J ( HCO ( 3 ) ) .	Second, we found that neither basolateral 250 nM nor basolateral 2 microM PP2, a high-affinity inhibitor for the Src family that also inhibits the Bcr-Abl sTK as well as the Kit RTK, reduces the CO (2)-stimulated increase in J (HCO (3)).	20	33	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	Kit	Kit	Kit	20	21	32	33
Restoring the Src kinase binding sites in KIT-F7 alone or together with the PI3Kinase binding site restored KIT induced signals as well as co-signals with WT EpoR , although restoring the Src kinase binding sites along with the PLC-gamma binding site repressed both KIT induced signaling as well as co-signaling with WT EpoR .	Restoring the Src kinase binding sites in KIT-F7 alone or together with the PI3Kinase binding site restored KIT induced signals as well as co-signals with WT EpoR, although restoring the Src kinase binding sites along with the PLC-gamma binding site repressed both KIT induced signaling as well as co-signaling with WT EpoR.	31	44	repressed	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Src	Src	Src	KIT	KIT	KIT	31	32	43	44
The inhibition of c-Src caused a persistent downregulation of P-Stat5 , but only a transient inhibition of P-Stat3 .	The inhibition of c-Src caused a persistent downregulation of P-Stat5, but only a transient inhibition of P-Stat3.	1	10	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	c-Src	c-Src	c-Src	P-Stat5	P-Stat5	P-Stat5	3	4	9	10
However , pSTAT5 was more efficiently and consistently inhibited by the SRC and ABLi , dasatinib , ( p = 0.0254 ) or by the A10 anti-CRLF2 mAb ( p = 0.0357 ) .	However, pSTAT5 was more efficiently and consistently inhibited by the SRC and ABLi, dasatinib, (p = 0.0254) or by the A10 anti-CRLF2 mAb (p = 0.0357).	2	19	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	SRC	SRC	SRC	pSTAT5	pSTAT5	pSTAT5	11	12	2	3
Src family tyrosine kinase ( SFK ) inhibitor PP2 could suppress the trafficking of NR2B containing NMDAR to the membrane [ XREF_BIBR ] .	Src family tyrosine kinase (SFK) inhibitor PP2 could suppress the trafficking of NR2B containing NMDAR to the membrane [XREF_BIBR].	0	15	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	NR2B	NR2B	NR2B	0	1	14	15
Although flow induced Cas phosphorylation was inhibited by kinase-inactive Src , PYK2 activation induced by flow was not inhibited by overexpression of kinase-inactive Src .	Although flow induced Cas phosphorylation was inhibited by kinase-inactive Src, PYK2 activation induced by flow was not inhibited by overexpression of kinase-inactive Src.	11	24	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Src	overexpression of kinase-inactive Src	src	PYK2	PYK2	pyk2	23	24	11	12
Pyk2 activation was completely abrogated in PI3KbetaKD , but not in PI3KgammaKD platelets , and was strongly inhibited by Src kinases and phospholipase C inhibitors , and by BAPTA-AM .	Pyk2 activation was completely abrogated in PI3KbetaKD, but not in PI3KgammaKD platelets, and was strongly inhibited by Src kinases and phospholipase C inhibitors, and by BAPTA-AM.	0	20	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Src	Src	Src	Pyk2	Pyk2	Pyk2	19	20	0	1
Src signaling is abnormal in PKD , and a recent study has indicated that inhibition of Src produces clinical benefits in PKD .	Src signaling is abnormal in PKD, and a recent study has indicated that inhibition of Src produces clinical benefits in PKD.	14	22	produces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Src	Src	Src	PKD	PKD	PKD	16	17	21	22
Activated Src rescues RACK1 inhibited growth of HT-29 cells .	Activated Src rescues RACK1 inhibited growth of HT-29 cells.	0	4	rescues	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Src	Src	Src	RACK1	RACK1	RACK1	1	2	3	4
Consistent with this hypothesis is the observation that IL-27 induces both pSTAT3 and pSTAT1 mediating T cell inhibition , and loss of STAT1 abrogates the suppressive effects of IL-27 by limiting the development of pSTAT-1 : pSTAT-3 heterodimers ( Fowler , Peters and Kuchroo , unpublished observations ) .	Consistent with this hypothesis is the observation that IL-27 induces both pSTAT3 and pSTAT1 mediating T cell inhibition, and loss of STAT1 abrogates the suppressive effects of IL-27 by limiting the development of pSTAT-1 : pSTAT-3 heterodimers (Fowler, Peters and Kuchroo, unpublished observations).	20	39	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	loss of STAT1	stat1	pSTAT-1	pSTAT-1	pstat-1	22	23	34	35
In mouse embryonic fibroblasts , it was found that ERK mediates STAT1 phosphorylation at S727 and increases proteasomal degradation of STAT1 [ XREF_BIBR ] .	In mouse embryonic fibroblasts, it was found that ERK mediates STAT1 phosphorylation at S727 and increases proteasomal degradation of STAT1 [XREF_BIBR].	9	22	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	ERK mediates STAT1 phosphorylation at S727	stat1	STAT1	STAT1	stat1	11	12	20	21
We provided evidence that protein STAT1 does not get phosphorylated on tyrosine 701 , impeding IFN-gamma-induced- JAK and STAT1 pathway in NOD fibroblasts .	We provided evidence that protein STAT1 does not get phosphorylated on tyrosine 701, impeding IFN-gamma-induced- JAK and STAT1 pathway in NOD fibroblasts.	4	19	impeding	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	STAT1 does not get phosphorylated on tyrosine 701	stat1	STAT1	STAT1	stat1	5	6	18	19
Hypomethylated STAT1 binds to the inhibitory Protein Inhibitor of Activated STAT ( PIAS1 ) , which prevents STAT1 from activating ISG transcription .	Hypomethylated STAT1 binds to the inhibitory Protein Inhibitor of Activated STAT (PIAS1), which prevents STAT1 from activating ISG transcription.	0	18	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	Hypomethylated STAT1 binds to the inhibitory Protein Inhibitor of Activated STAT	stat1	STAT1	STAT1	stat1	1	2	17	18
OSM induced phosphorylation of STAT1 , and treatment of adipocytes with JAK3 inhibitor WHI-P131 or MEK inhibitor U0126 , but not with JAK2 inhibitor AG490 , prevented the activation of STAT1 .	OSM induced phosphorylation of STAT1, and treatment of adipocytes with JAK3 inhibitor WHI-P131 or MEK inhibitor U0126, but not with JAK2 inhibitor AG490, prevented the activation of STAT1.	0	31	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	OSM induced phosphorylation of STAT1	stat1	STAT1	STAT1	stat1	4	5	30	31
Tissue arrays of liver biopsies were used to study the expression of STAT1 , STAT2 , STAT5 and PIAS1 ( protein inhibitor of activated STAT1 ) .	Tissue arrays of liver biopsies were used to study the expression of STAT1, STAT2, STAT5 and PIAS1 (protein inhibitor of activated STAT1).	10	25	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	STAT1	expression of STAT1	stat1	STAT1	STAT1	stat1	12	13	24	25
PRMT1 catalyzes methylation of STAT1 XREF_BIBR as well as of PIAS1 ( protein inhibitor of activated STAT1 ) XREF_BIBR .	PRMT1 catalyzes methylation of STAT1 XREF_BIBR as well as of PIAS1 (protein inhibitor of activated STAT1) XREF_BIBR.	0	17	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	STAT1	PRMT1 catalyzes methylation of STAT1	stat1	STAT1	STAT1	stat1	4	5	16	17
Impaired STAT1 methylation may cause enhanced complex formation between protein inhibitor of activated STAT1 ( PIAS1 ) and STAT1 , which competes with STAT1 binding to DNA ( XREF_FIG ) .	Impaired STAT1 methylation may cause enhanced complex formation between protein inhibitor of activated STAT1 (PIAS1) and STAT1, which competes with STAT1 binding to DNA (XREF_FIG).	1	18	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	STAT1 methylation	stat1	STAT1	STAT1	stat1	1	2	13	14
However , PTP inhibition had no impact on the ARBE mediated inhibition of IFN-gamma-induced STAT1 phosphorylation ( XREF_FIG , XREF_SUPPLEMENTARY ) .	However, PTP inhibition had no impact on the ARBE mediated inhibition of IFN-gamma-induced STAT1 phosphorylation (XREF_FIG, XREF_SUPPLEMENTARY).	10	16	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	STAT1 phosphorylation	stat1	STAT1	STAT1	stat1	14	15	14	15
Stat1 phosphorylation in neurons also correlated with increased expression of total Stat1 protein , suggesting that low basal levels of Stat1 expression may limit the initial Stat1 dependent response to IFNgamma in neurons .	Stat1 phosphorylation in neurons also correlated with increased expression of total Stat1 protein, suggesting that low basal levels of Stat1 expression may limit the initial Stat1 dependent response to IFNgamma in neurons.	20	28	limit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Stat1	Stat1 expression	stat1	Stat1	Stat1	stat1	20	21	26	27
Therefore , JEV NS5 does not block the induction of IFN , but activates a cellular PTP to dephosphorylate STAT1 and Tyk2 , thus preventing the nuclear translocation of STAT1 .	Therefore, JEV NS5 does not block the induction of IFN, but activates a cellular PTP to dephosphorylate STAT1 and Tyk2, thus preventing the nuclear translocation of STAT1.	18	30	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	dephosphorylate STAT1	stat1	STAT1	STAT1	stat1	19	20	29	30
SUMOylation of STAT1 on K703 by PIAS1 inhibits its activation and also inhibits the formation of STAT1 nuclear paracrystalline arrays , which makes tyrosine phosphorylated STAT1 more susceptible to inactivation by nuclear phosphatases .	SUMOylation of STAT1 on K703 by PIAS1 inhibits its activation and also inhibits the formation of STAT1 nuclear paracrystalline arrays, which makes tyrosine phosphorylated STAT1 more susceptible to inactivation by nuclear phosphatases.	0	19	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	SUMOylation of STAT1 on K703	stat1	STAT1	STAT1	stat1	2	3	16	17
Dephosphorylation of STAT1 at Try701 blocks carrier mediated nuclear accumulation of STAT1 [ XREF_BIBR ] but does not affect the carrier independent import of unphosphorylated STAT1 , which occurs via direct binding to nucleoporins [ XREF_BIBR ] .	Dephosphorylation of STAT1 at Try701 blocks carrier mediated nuclear accumulation of STAT1 [XREF_BIBR] but does not affect the carrier independent import of unphosphorylated STAT1, which occurs via direct binding to nucleoporins [XREF_BIBR].	0	13	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	Dephosphorylation of STAT1	stat1	STAT1	STAT1	stat1	2	3	11	12
In mouse embryonic fibroblasts , it has been described that ERK mediates phosphorylation of STAT1 at the serine 727 residue and increases proteasomal degradation of STAT1 [ XREF_BIBR ] .	In mouse embryonic fibroblasts, it has been described that ERK mediates phosphorylation of STAT1 at the serine 727 residue and increases proteasomal degradation of STAT1 [XREF_BIBR].	10	27	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	ERK mediates phosphorylation of STAT1 at the serine 727	stat1	STAT1	STAT1	stat1	14	15	25	26
XREF_BIBR , XREF_BIBR STAT1 acetylation at lysine ( K ) 410 and K413 negatively regulates its activity by impeding DNA binding and promoting an anti-parallel conformation of STAT1 dimers that facilitates Y701 dephosphorylation .	XREF_BIBR, XREF_BIBR STAT1 acetylation at lysine (K) 410 and K413 negatively regulates its activity by impeding DNA binding and promoting an anti-parallel conformation of STAT1 dimers that facilitates Y701 dephosphorylation.	3	28	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	STAT1 acetylation at lysine	stat1	STAT1	STAT1	stat1	3	4	27	28
However , densitometric analysis of western blot data from primary microglial cells in Figure XREF_FIG and XREF_FIG reveals that apigenin significantly reduces STAT1 phosphorylation at tyrosine residue 701 ( p < 0.01 ) and luteolin significantly reduces STAT1 phosphorylation at serine residue 727 ( p < 0.01 ) .	However, densitometric analysis of western blot data from primary microglial cells in Figure XREF_FIG and XREF_FIG reveals that apigenin significantly reduces STAT1 phosphorylation at tyrosine residue 701 (p < 0.01) and luteolin significantly reduces STAT1 phosphorylation at serine residue 727 (p < 0.01).	36	43	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	STAT1 phosphorylation at serine residue 727	stat1	STAT1	STAT1	stat1	37	38	37	38
To confirm the role of STAT1 in SAMHD1 expression , we further analyzed the expression of SAMHD1 induced by IFN-alpha in MARC-145 and HEK293 cells , in which the STAT1 expression was silenced by shRNA targeting STAT1 gene .	To confirm the role of STAT1 in SAMHD1 expression, we further analyzed the expression of SAMHD1 induced by IFN-alpha in MARC-145 and HEK293 cells, in which the STAT1 expression was silenced by shRNA targeting STAT1 gene.	29	37	targeting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	STAT1 expression	stat1	STAT1	STAT1	stat1	29	30	36	37
HCV core prevents phosphorylation of STAT1 in response to IFN-alpha XREF_BIBR and NS5A prevents translocation of pSTAT1 to the nucleus XREF_BIBR .	HCV core prevents phosphorylation of STAT1 in response to IFN-alpha XREF_BIBR and NS5A prevents translocation of pSTAT1 to the nucleus XREF_BIBR.	3	17	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	phosphorylation of STAT1	stat1	pSTAT1	pSTAT1	pstat1	5	6	16	17
As shown in XREF_FIG , the knockdown of AIM2 expression in BPH-1 cells increased steady-state levels of STAT1 and potentiated IFN-gamma-induced activation of STAT1 .	As shown in XREF_FIG, the knockdown of AIM2 expression in BPH-1 cells increased steady-state levels of STAT1 and potentiated IFN-gamma-induced activation of STAT1.	8	24	potentiated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	AIM2 expression in BPH-1 cells increased steady-state levels of STAT1	stat1	STAT1	STAT1	stat1	17	18	23	24
Overexpression of STAT1 via stable transfection enhances IFN-gamma activation of STAT1 , but surprisingly attenuates IFN-alpha activation of STAT1 , STAT2 and STAT3 without affecting Janus kinase activation .	Overexpression of STAT1 via stable transfection enhances IFN-gamma activation of STAT1, but surprisingly attenuates IFN-alpha activation of STAT1, STAT2 and STAT3 without affecting Janus kinase activation.	0	11	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	Overexpression of STAT1	stat1	STAT1	STAT1	stat1	2	3	10	11
We also observed , in presence of TGFbeta1 , an inhibition of IFNgamma induced pSTAT1 tyr that could depended on TGFbeta1 induced decrease of total STAT1 .	We also observed, in presence of TGFbeta1, an inhibition of IFNgamma induced pSTAT1 tyr that could depended on TGFbeta1 induced decrease of total STAT1.	12	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	pSTAT1	IFNgamma induced pSTAT1	pstat1	STAT1	STAT1	stat1	14	15	25	26
Although cisplatin increased serine phosphorylation of STAT1 in wild-type mice and diminished STAT3 expression in wild-type and STAT1 -/- mice , gentamicin increased tyrosine phosphorylation of STAT3 in STAT1 -/- mice .	Although cisplatin increased serine phosphorylation of STAT1 in wild-type mice and diminished STAT3 expression in wild-type and STAT1 -/- mice, gentamicin increased tyrosine phosphorylation of STAT3 in STAT1 -/- mice.	1	19	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	cisplatin increased serine phosphorylation of STAT1	stat1	STAT1	STAT1	stat1	6	7	17	18
A phosphorylation acetylation switch is involved in regulation of STAT1 signaling , such that STAT1 acetylation by CBP facilitates its dephosphorylation by TCP45 phosphatase and thereby suppresses the STAT1 signaling .	A phosphorylation acetylation switch is involved in regulation of STAT1 signaling, such that STAT1 acetylation by CBP facilitates its dephosphorylation by TCP45 phosphatase and thereby suppresses the STAT1 signaling.	14	29	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	STAT1 acetylation	stat1	STAT1	STAT1	stat1	14	15	28	29
However , pharmacological inhibition of p38 MAP kinase cascade signaling did not alter either STAT1 expression or IFNgamma mediated STAT1 phosphorylation in hippocampal neurons ( XREF_FIG ) , supporting a STAT1 independent role for p38 MAP kinase signaling in IFNgamma signaling .	However, pharmacological inhibition of p38 MAP kinase cascade signaling did not alter either STAT1 expression or IFNgamma mediated STAT1 phosphorylation in hippocampal neurons (XREF_FIG), supporting a STAT1 independent role for p38 MAP kinase signaling in IFNgamma signaling.	17	32	supporting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT1	IFNgamma mediated STAT1 phosphorylation	stat1	STAT1	STAT1	stat1	19	20	30	31
These results suggest that sumoylation of STAT1 does not prevent STAT1 dimerization and are consistent with the results that conjugated SUMO moiety affects the interaction between STAT1 and DNA through steric hindrance .	These results suggest that sumoylation of STAT1 does not prevent STAT1 dimerization and are consistent with the results that conjugated SUMO moiety affects the interaction between STAT1 and DNA through steric hindrance.	4	11	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	sumoylation of STAT1	stat1	STAT1	STAT1	stat1	6	7	10	11
Nevertheless , through a chromatin immunoprecipitation ( ChIP ) assay with the anti-STAT1 antibody , we also showed that OSM induced STAT1 binding to SLUG promoter around this region ; the binding level ( enrichment ) of STAT1 on SLUG promoter was positively correlated with overexpressing or knockdown STAT1 .	Nevertheless, through a chromatin immunoprecipitation (ChIP) assay with the anti-STAT1 antibody, we also showed that OSM induced STAT1 binding to SLUG promoter around this region; the binding level (enrichment) of STAT1 on SLUG promoter was positively correlated with overexpressing or knockdown STAT1.	32	49	knockdown	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT1	level (enrichment) of STAT1	stat1	STAT1	STAT1	stat1	37	38	48	49
Conversely , PTP inhibitor pervanadate reversed CK mediated STAT3 inactivation and cleavages of caspase-3 and PARP .	Conversely, PTP inhibitor pervanadate reversed CK mediated STAT3 inactivation and cleavages of caspase-3 and PARP.	2	15	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	STAT3	PTP inhibitor pervanadate reversed CK mediated STAT3	stat3	caspase-3	caspase-3	caspase-3	8	9	13	14
Deletion of Stat3 in Jak2V617F knock-in mice significantly increased the HSC enriched LSK compartment ( Lin - Sca1 + c-kit + ) and its subsets including long-term HSC ( LT-HSC ; Lin - Sca1 + c-kit + CD34 - CD135 - ) , short-term HSC ( ST-HSC ; Lin - Sca1 + c-kit + CD34 + CD135 - ) , and multi-potent progenitors ( MPP ; Lin - Sca1 + c-kit + CD34 + CD135 + ) in the BM and spleens .	Deletion of Stat3 in Jak2V617F knock-in mice significantly increased the HSC enriched LSK compartment (Lin - Sca1 + c-kit +) and its subsets including long-term HSC (LT-HSC; Lin - Sca1 + c-kit + CD34 - CD135 -), short-term HSC (ST-HSC; Lin - Sca1 + c-kit + CD34 + CD135 -), and multi-potent progenitors (MPP; Lin - Sca1 + c-kit + CD34 + CD135 +) in the BM and spleens.	0	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Stat3	Stat3	Stat3	Sca1	Sca1	Sca1	2	3	17	18
Actual prevention of STAT3 phosphorylation reduced the ligation induced Sca-1 elevation .	Actual prevention of STAT3 phosphorylation reduced the ligation induced Sca-1 elevation.	3	10	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT3	STAT3 phosphorylation	stat3	Sca-1	Sca-1	sca-1	3	4	9	10
Resveratrol treatment alone increased TNF-alpha , TNF-alpha R1 , NF-kappaB , SIRT-1 , STAT1 and STAT3 mRNA levels and decreased caspase 3 protein levels .	Resveratrol treatment alone increased TNF-alpha, TNF-alpha R1, NF-kappaB, SIRT-1, STAT1 and STAT3 mRNA levels and decreased caspase 3 protein levels.	0	22	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT3	Resveratrol treatment alone increased TNF-alpha, TNF-alpha R1, NF-kappaB, SIRT-1, STAT1 and STAT3 mRNA levels	stat3	caspase 3	caspase 3	caspase 3	15	16	20	22
In addition , DMBA induced caspase-3 activity was significantly increased by inhibition of STAT3 or AKT in TC-PTP-deficient keratinocytes in comparison to DMBA-only control ( XREF_FIG ; a , b , c ) .	In addition, DMBA induced caspase-3 activity was significantly increased by inhibition of STAT3 or AKT in TC-PTP-deficient keratinocytes in comparison to DMBA-only control (XREF_FIG; a, b, c).	5	15	increased	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	STAT3	STAT3	STAT3	caspase-3	caspase-3	caspase-3	13	14	5	6
We found that expression of STAT3-CA inhibited the cleavage of both caspase-3 and PARP , as well as DNA fragmentation triggered by PHA-665752 ( XREF_FIG ) .	We found that expression of STAT3-CA inhibited the cleavage of both caspase-3 and PARP, as well as DNA fragmentation triggered by PHA-665752 (XREF_FIG).	3	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT3-CA	expression of STAT3-CA	stat3-ca	caspase-3	caspase-3	caspase-3	5	6	11	12
ChIP analyses were consistent with reduced gene expression levels of Sca-1 in epidermal cells treated with the Stat3 selective inhibitor , STA-21 .	ChIP analyses were consistent with reduced gene expression levels of Sca-1 in epidermal cells treated with the Stat3 selective inhibitor, STA-21.	8	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	Stat3	Stat3	Stat3	Sca-1	Sca-1	Sca-1	17	18	10	11
LLL12 also inhibited STAT3 phosphorylation and induced caspase-3 cleavage in the ALDH + / CD44 + / CD24 - subpopulation of MDA-MB-231 and SUM159 ( XREF_FIG ) .	LLL12 also inhibited STAT3 phosphorylation and induced caspase-3 cleavage in the ALDH + / CD44 + / CD24 - subpopulation of MDA-MB-231 and SUM159 (XREF_FIG).	0	8	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT3	LLL12 also inhibited STAT3 phosphorylation	stat3	caspase-3	caspase-3	caspase-3	3	4	7	8
Additionally , HN activated STAT3 phosphorylation and inhibited caspase-3 activation .	Additionally, HN activated STAT3 phosphorylation and inhibited caspase-3 activation.	2	9	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT3	HN activated STAT3 phosphorylation	stat3	caspase-3	caspase-3	caspase-3	4	5	8	9
Furthermore , immunohistochemistry revealed that the expression of p-STAT3 and VEGF was suppressed and cleaved caspase 3 was activated in tumor sections isolated from PROS treated group mice compared to untreated control .	Furthermore, immunohistochemistry revealed that the expression of p-STAT3 and VEGF was suppressed and cleaved caspase 3 was activated in tumor sections isolated from PROS treated group mice compared to untreated control.	6	18	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p-STAT3	expression of p-STAT3	p-stat3	caspase 3	caspase 3	caspase 3	8	9	15	17
Reduction in STAT3 phosphorylation at tyrosine residue 705 could cause activation of caspase-9 and caspase-3 , while apoptotic signaling could be mediated via activation of the cell death initiator procaspase-9 , whereas activated caspase-9 in turn cleaves executioner caspase-3 .	Reduction in STAT3 phosphorylation at tyrosine residue 705 could cause activation of caspase-9 and caspase-3, while apoptotic signaling could be mediated via activation of the cell death initiator procaspase-9, whereas activated caspase-9 in turn cleaves executioner caspase-3.	2	15	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT3	STAT3 phosphorylation at tyrosine residue 705	stat3	caspase-3	caspase-3	caspase-3	2	3	14	15
Moreover , STAT3 , and not other inhibitors , completely abrogated the anti-apoptotic effect and expression of caspase3 in decidual gammadelta T cells induced by recombinant human TSLP .	Moreover, STAT3, and not other inhibitors, completely abrogated the anti-apoptotic effect and expression of caspase3 in decidual gammadelta T cells induced by recombinant human TSLP.	2	18	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT3	STAT3	STAT3	caspase3	caspase3	caspase3	2	3	17	18
In contrast , a constitutively active STAT3 attenuated caspase-3 cleavage induced by sorafenib alone and combined with TRAIL .	In contrast, a constitutively active STAT3 attenuated caspase-3 cleavage induced by sorafenib alone and combined with TRAIL.	3	9	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT3	STAT3	STAT3	caspase-3	caspase-3	caspase-3	6	7	8	9
Blockade of active STAT3 increases caspase-3 activity and increases cardiomyocyte apoptosis following myocardial I/R injury XREF_BIBR .	Blockade of active STAT3 increases caspase-3 activity and increases cardiomyocyte apoptosis following myocardial I/R injury XREF_BIBR.	0	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT3	STAT3	STAT3	caspase-3	caspase-3	caspase-3	3	4	5	6
It was reported that reduction in STAT3 phosphorylation at tyrosine 705 residue could cause activation of caspase-9 and caspase-3 .	It was reported that reduction in STAT3 phosphorylation at tyrosine 705 residue could cause activation of caspase-9 and caspase-3.	6	19	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT3	STAT3 phosphorylation at tyrosine 705	stat3	caspase-3	caspase-3	caspase-3	6	7	18	19
Unlike WT STAT2 , but as predicted , hybrid STAT2 did not inhibit the nuclear import of activated STAT1 , which accumulated strongly in the nucleus upon IFN-gamma treatment ( XREF_FIG , panels 3 and 4 ) .	Unlike WT STAT2, but as predicted, hybrid STAT2 did not inhibit the nuclear import of activated STAT1, which accumulated strongly in the nucleus upon IFN-gamma treatment (XREF_FIG, panels 3 and 4).	8	21	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	9	10	18	19
Recombinant STAT2 , like the endogenous STAT2 , inhibited STAT1 nuclear accumulation ( XREF_FIG , panels 1 and 2 ) , in agreement with a previous observation by Julkunen and colleagues [ XREF_BIBR ] .	Recombinant STAT2, like the endogenous STAT2, inhibited STAT1 nuclear accumulation (XREF_FIG, panels 1 and 2), in agreement with a previous observation by Julkunen and colleagues [XREF_BIBR].	0	11	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	1	2	9	10
STAT2 Inhibits the Nuclear Import Specifically of STAT1 in Multiple Signaling Pathways .	STAT2 Inhibits the Nuclear Import Specifically of STAT1 in Multiple Signaling Pathways.	0	11	Inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	0	1	7	8
Latent STAT2 Inhibits the IFN-gamma-Induced Nuclear Import and DNA Binding of STAT1 .	Latent STAT2 Inhibits the IFN-gamma-Induced Nuclear Import and DNA Binding of STAT1.	0	12	Inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	1	2	11	12
Restoration of IFN-gamma unresponsiveness of hybrid STAT2 by introducing the SH2 domain inactivating mutation R602L [ XREF_BIBR ] , on the other hand , restored STAT1 inhibition ( XREF_FIG , panels 5 and 6 ) .	Restoration of IFN-gamma unresponsiveness of hybrid STAT2 by introducing the SH2 domain inactivating mutation R602L [XREF_BIBR], on the other hand, restored STAT1 inhibition (XREF_FIG, panels 5 and 6).	3	26	restored	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	6	7	25	26
In contrast , cell culture experiments have demonstrated that the divergent murine STAT2 protein fails to support STAT1 targeting .	In contrast, cell culture experiments have demonstrated that the divergent murine STAT2 protein fails to support STAT1 targeting.	12	18	support	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT2	STAT2	STAT2	STAT1	STAT1	STAT1	12	13	17	18
Very recently it has been reported that in primary mouse adipocytes , PKA associates with and phosphorylates AMPKalpha1 at Ser173 to restrict Thr172 phosphorylation and thus activation of AMPKalpha1 by LKB1 kinase in response to lipolytic signals 63 .	Very recently it has been reported that in primary mouse adipocytes, PKA associates with and phosphorylates AMPKalpha1 at Ser173 to restrict Thr172 phosphorylation and thus activation of AMPKalpha1 by LKB1 kinase in response to lipolytic signals 63.	26	31	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	LKB1	LKB1	LKB1	AMPKalpha1	AMPKalpha1	AMPKalpha1	30	31	28	29
Here , we report that in primary mouse adipocytes , PKA associates with and phosphorylates AMPKalpha1 at Ser 173 to impede threonine ( Thr 172 ) phosphorylation and thus activation of AMPKalpha1 by LKB1 in response to lipolytic signals .	Here, we report that in primary mouse adipocytes, PKA associates with and phosphorylates AMPKalpha1 at Ser 173 to impede threonine (Thr 172) phosphorylation and thus activation of AMPKalpha1 by LKB1 in response to lipolytic signals.	20	35	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	LKB1	LKB1	LKB1	AMPKalpha1	AMPKalpha1	AMPKalpha1	33	34	31	32
The downregulation of C/EBPalpha and SREBP1 by P. miliaceum L. may reduce fatty acid synthesis as well as PPARgamma activity , which may result in the inhibition of adipogenesis by blocking adipocyte differentiation .	The downregulation of C/EBPalpha and SREBP1 by P. miliaceum L. may reduce fatty acid synthesis as well as PPARgamma activity, which may result in the inhibition of adipogenesis by blocking adipocyte differentiation.	1	19	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SREBP1	SREBP1	SREBP1	PPARgamma	PPARgamma	PPARgamma	5	6	18	19
The phosphoryl transfer step in SRPK1 is very fast and does not limit turnover of the SR protein SRSF1 .	The phosphoryl transfer step in SRPK1 is very fast and does not limit turnover of the SR protein SRSF1.	3	19	limit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1	SRPK1	SRSF1	SRSF1	SRSF1	5	6	18	19
Inhibition of SRPK1 activity with small molecule inhibitors or RNA interference ( RNAi ) knockdown of SRPK1 expression has been reported to block the phosphorylation and nuclear shuttling of SRSF1 , switching the ratio of VEGF-A splicing to decrease the pro angiogenic VEGF-A xxx and increase the anti-angiogenic VEGF-A xxx b isoforms [ XREF_BIBR , XREF_BIBR ] .	Inhibition of SRPK1 activity with small molecule inhibitors or RNA interference (RNAi) knockdown of SRPK1 expression has been reported to block the phosphorylation and nuclear shuttling of SRSF1, switching the ratio of VEGF-A splicing to decrease the pro angiogenic VEGF-A xxx and increase the anti-angiogenic VEGF-A xxx b isoforms [XREF_BIBR, XREF_BIBR].	16	30	block	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	SRPK1	SRPK1 expression	srpk1	SRSF1	SRSF1	srsf1	16	17	29	30
SRPK1 inhibition and block of SRSF1 function , thus enhancing distal splice site selection , results in an increased proportion of VEGF-A xxx b ( XREF_FIG ) .	SRPK1 inhibition and block of SRSF1 function, thus enhancing distal splice site selection, results in an increased proportion of VEGF-A xxx b (XREF_FIG).	0	6	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	SRPK1	SRPK1	SRPK1	SRSF1	SRSF1	SRSF1	0	1	5	6
The acetylation of both proteins appears to be essential for the IL-4-induced signal transduction cascade , because inhibition of CBP and p300 by the viral wild-type E1A oncoprotein abrogated acetylation of both histones and STAT6 and strongly suppressed transcriptional activation of the 15-LOX-1 gene .	The acetylation of both proteins appears to be essential for the IL-4-induced signal transduction cascade, because inhibition of CBP and p300 by the viral wild-type E1A oncoprotein abrogated acetylation of both histones and STAT6 and strongly suppressed transcriptional activation of the 15-LOX-1 gene.	19	43	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	STAT6	CBP and p300 by the viral wild-type E1A oncoprotein abrogated acetylation of both histones and STAT6	stat6	15-LOX-1	15-LOX-1	15-lox-1	34	35	42	43
Consistent with our hypothesis that inhibiting NUAK1 will lead to increased association of PP1beta MYPT1 and PLK1 , the authors of that study observed that shRNA mediated knockdown of LKB1 , that would be expected to inhibit NUAK1 activity , promoted the association of MYPT1 and PLK1 [ XREF_BIBR ] .	Consistent with our hypothesis that inhibiting NUAK1 will lead to increased association of PP1beta MYPT1 and PLK1, the authors of that study observed that shRNA mediated knockdown of LKB1, that would be expected to inhibit NUAK1 activity, promoted the association of MYPT1 and PLK1 [XREF_BIBR].	27	38	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	LKB1	LKB1	NUAK1	NUAK1	NUAK1	29	30	37	38
NUAK1 ( NUAK family SnF1 like kinase-1 ) and NUAK2 protein kinases are activated by the LKB1 tumour suppressor and have been implicated in regulating multiple processes such as cell survival , senescence , adhesion and polarity .	NUAK1 (NUAK family SnF1 like kinase-1) and NUAK2 protein kinases are activated by the LKB1 tumour suppressor and have been implicated in regulating multiple processes such as cell survival, senescence, adhesion and polarity.	0	22	activated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	LKB1	LKB1	LKB1	NUAK1	NUAK1	NUAK1	16	17	0	1
Because LKB1 deficiency is expected to functionally inactivate both SIK2 and SAD-A , a powerful mechanism must be activated upon LKB1 deletion that can compensate for these losses and lead to a net enhancement of insulin secretion .	Because LKB1 deficiency is expected to functionally inactivate both SIK2 and SAD-A, a powerful mechanism must be activated upon LKB1 deletion that can compensate for these losses and lead to a net enhancement of insulin secretion.	1	12	inactivate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LKB1	LKB1	LKB1	SAD-A	SAD-A	SAD-A	1	2	11	12
Phosphorylation of Syk on Y346 disrupts Syk autoinhibitory intramolecular interactions between the interdomain B sequences and the kinase domain of Syk ; moreover , binding of SH2 containing proteins to phosphorylated Y346 on Syk has been proposed to help stabilize the active conformation of the kinase .	Phosphorylation of Syk on Y346 disrupts Syk autoinhibitory intramolecular interactions between the interdomain B sequences and the kinase domain of Syk; moreover, binding of SH2 containing proteins to phosphorylated Y346 on Syk has been proposed to help stabilize the active conformation of the kinase.	0	21	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Syk	Phosphorylation of Syk on Y346	syk	Syk	Syk	syk	2	3	20	21
In support of this model , reduction of endogenous Syk expression did not inhibit phosphorylation of activated FcgammaRIIA in monocytes [ XREF_BIBR ] but reduced downstream tyrosine phosphorylation and phagocytosis was observed in Syk deficient macrophages [ XREF_BIBR ] .	In support of this model, reduction of endogenous Syk expression did not inhibit phosphorylation of activated FcgammaRIIA in monocytes [XREF_BIBR] but reduced downstream tyrosine phosphorylation and phagocytosis was observed in Syk deficient macrophages [XREF_BIBR].	9	35	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Syk	Syk expression	syk	Syk	Syk	syk	9	10	33	34
In the present work , we generated Syk flox and flox / LysM-Cre mice and performed the majority of experiments with primary macrophages derived from bone marrow in which Syk expression was reduced by 60-70 % , to study the role of Syk in transcriptional regulation .	In the present work, we generated Syk flox and flox / LysM-Cre mice and performed the majority of experiments with primary macrophages derived from bone marrow in which Syk expression was reduced by 60-70%, to study the role of Syk in transcriptional regulation.	29	43	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Syk	Syk expression	syk	Syk	Syk	syk	29	30	42	43
Blocking Syk activation by kinase inhibitors or RNAi reduced Syk phosphorylation , lysosomal destabilization , ROS production , and caspase-1 activation in Ceacam1 -/- neutrophils .	Blocking Syk activation by kinase inhibitors or RNAi reduced Syk phosphorylation, lysosomal destabilization, ROS production, and caspase-1 activation in Ceacam1 -/- neutrophils.	0	11	Blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Syk	Syk phosphorylation	syk	Syk	Syk	syk	9	10	1	2
M-CSF induced Syk phosphorylation is abolished in Syk-/- pre-osteoclasts expressing kinase-inactive Syk ( XREF_FIG ) .	M-CSF induced Syk phosphorylation is abolished in Syk-/- pre-osteoclasts expressing kinase-inactive Syk (XREF_FIG).	0	13	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Syk	M-CSF induced Syk phosphorylation	syk	Syk	Syk	syk	2	3	11	12
Exposing DCs isolated from the gut of uninfected mice to HES quickly and selectively inhibits Syk and CLEC expression further supporting the supposition that Hpb deactivates Syk signaling in gut DCs .	Exposing DCs isolated from the gut of uninfected mice to HES quickly and selectively inhibits Syk and CLEC expression further supporting the supposition that Hpb deactivates Syk signaling in gut DCs.	15	27	deactivates	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Syk	Syk and CLEC expression	syk	Syk	Syk	syk	15	16	26	27
Our initial model ( A ) incorporated the continuous presence of a simple abundant generic phosphatase that is able to dephosphorylate Syk on Y525 , thereby restricting the ability of Syk ( and therefore of the GPVI receptor ) to signal downstream .	Our initial model (A) incorporated the continuous presence of a simple abundant generic phosphatase that is able to dephosphorylate Syk on Y525, thereby restricting the ability of Syk (and therefore of the GPVI receptor) to signal downstream.	15	31	restricting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Syk	phosphatase that is able to dephosphorylate Syk on Y525	syk	Syk	Syk	syk	21	22	30	31
UBASH3B/STS-1/TULA-2 is a highly active protein tyrosine phosphatase ; its major target appears to be a specific regulatory site of protein tyrosine kinases of the Syk family , dephosphorylation of which inhibits Syk and Zap-70 kinases and suppresses receptor signaling mediated by these kinases .	UBASH3B/STS-1/TULA-2 is a highly active protein tyrosine phosphatase; its major target appears to be a specific regulatory site of protein tyrosine kinases of the Syk family, dephosphorylation of which inhibits Syk and Zap-70 kinases and suppresses receptor signaling mediated by these kinases.	25	35	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Syk	Syk family, dephosphorylation	syk	Syk	Syk	syk	25	26	32	33
While the activation of LKB1 and AMPK by Sirt1 involves deacetylation of LKB1 , it remains to be determined whether the deacetylation of PTP1B , Syk , or another unknown component ( s ) underlies the Sirt1 inhibition of PTP1B and Syk .	While the activation of LKB1 and AMPK by Sirt1 involves deacetylation of LKB1, it remains to be determined whether the deacetylation of PTP1B, Syk, or another unknown component (s) underlies the Sirt1 inhibition of PTP1B and Syk.	21	42	underlies	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Syk	deacetylation of PTP1B, Syk	syk	Syk	Syk	syk	25	26	41	42
Thus , our results revealed that deficiency in MST1 kinase suppressed the activation of FOXO3a regulated genes in atrophic muscles , indicating that the activity of this transcription factor was differentially modulated in WT and MST1 deficient atrophic muscles .	Thus, our results revealed that deficiency in MST1 kinase suppressed the activation of FOXO3a regulated genes in atrophic muscles, indicating that the activity of this transcription factor was differentially modulated in WT and MST1 deficient atrophic muscles.	8	16	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MST1	MST1	MST1	FOXO3a	FOXO3a	FOXO3a	8	9	14	15
A reporter assay revealed that MST1 induced FoxO3 transactivation was completely inhibited by co-transfection with BRAF V600E .	A reporter assay revealed that MST1 induced FoxO3 transactivation was completely inhibited by co-transfection with BRAF V600E.	5	8	induced	Positive_early_activation	Positive_activation	Negative_activation	MST1	MST1	MST1	FoxO3	FoxO3	FoxO3	5	6	7	8
Furthermore , MST1 induced FoxO3 transactivation was also repressed by BRAF V600E , indicating that BRAF V600E inhibits the RASSF1A-MST1-FoxO3 pathway ( XREF_FIG ) .	Furthermore, MST1 induced FoxO3 transactivation was also repressed by BRAF V600E, indicating that BRAF V600E inhibits the RASSF1A-MST1-FoxO3 pathway (XREF_FIG).	2	5	induced	Positive_early_activation	Positive_activation	Negative_activation	MST1	MST1	MST1	FoxO3	FoxO3	FoxO3	2	3	4	5
The inhibition of RASSF1A or MST1 induced FoxO3 transactivation and nuclear translocation by BRAF V600E led to the hypothesis that BRAF V600E might regulate FoxO3 transactivation via a MST1 dependent pathway .	The inhibition of RASSF1A or MST1 induced FoxO3 transactivation and nuclear translocation by BRAF V600E led to the hypothesis that BRAF V600E might regulate FoxO3 transactivation via a MST1 dependent pathway.	1	8	induced	Positive_early_activation	Positive_activation	Negative_activation	MST1	MST1	MST1	FoxO3	FoxO3	FoxO3	5	6	7	8
Supporting this idea , immunofluorescence studies revealed not only the BRAF V600E -mediated inhibition of MST1 induced FoxO3 nuclear translocation , but also a direct interaction between MST1 and BRAF V600E , which was confirmed through IP assays that demonstrated that BRAF V600E binds to the C-terminal dimerization domain of MST1 .	Supporting this idea, immunofluorescence studies revealed not only the BRAF V600E -mediated inhibition of MST1 induced FoxO3 nuclear translocation, but also a direct interaction between MST1 and BRAF V600E, which was confirmed through IP assays that demonstrated that BRAF V600E binds to the C-terminal dimerization domain of MST1.	13	19	induced	Positive_early_activation	Positive_activation	Negative_activation	MST1	MST1	MST1	FoxO3	FoxO3	FoxO3	15	16	17	18
These reporter assays indicated that increased levels of MST1 could prevent BRAF V600E -induced FoxO3 inactivation .	These reporter assays indicated that increased levels of MST1 could prevent BRAF V600E -induced FoxO3 inactivation.	6	15	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MST1	levels of MST1	mst1	FoxO3	FoxO3	foxo3	8	9	14	15
In addition , over-expression of MST1 prevented BRAF V600E -induced FoxO3 inactivation .	In addition, over-expression of MST1 prevented BRAF V600E -induced FoxO3 inactivation.	3	11	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MST1	over-expression of MST1	mst1	FoxO3	FoxO3	foxo3	5	6	10	11
Enforced expression of a kinase-inactive MST1 mutant ( K59R ) , which inhibits MST1 activity in vivo , 33 blocked binding of MST1 to the PSA promoter ( XREF_FIG ) , suggesting that efficient association of MST1 with chromatin may require kinase activity .	Enforced expression of a kinase-inactive MST1 mutant (K59R), which inhibits MST1 activity in vivo, 33 blocked binding of MST1 to the PSA promoter (XREF_FIG), suggesting that efficient association of MST1 with chromatin may require kinase activity.	1	14	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MST1	expression of a kinase-inactive MST1	mst1	MST1	MST1	mst1	5	6	13	14
XREF_BIBR , XREF_BIBR Interestingly , the protein phosphatase PHLPP , which dephosphorylates Akt [ Ser473 ] 95 and thereby interferes with the ability of Akt to phosphorylate and negatively regulate Foxo , 96 also promotes the dephosphorylation of MST1 [ Thr387 ] , thus enhancing MST1 catalyzed FOXO activation .	XREF_BIBR, XREF_BIBR Interestingly, the protein phosphatase PHLPP, which dephosphorylates Akt [Ser473] 95 and thereby interferes with the ability of Akt to phosphorylate and negatively regulate Foxo, 96 also promotes the dephosphorylation of MST1 [Thr387], thus enhancing MST1 catalyzed FOXO activation.	7	46	enhancing	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	MST1	phosphatase PHLPP, which dephosphorylates Akt [Ser473] 95 and thereby interferes with the ability of Akt to phosphorylate and negatively regulate Foxo, 96 also promotes the dephosphorylation of MST1 [Thr387	mst1	MST1	MST1	mst1	38	39	45	46
Phosphorylation of MST1 by Akt prevents caspase mediated cleavage of MST1 and hence prevents activation of MST1 [ XREF_BIBR ] .	Phosphorylation of MST1 by Akt prevents caspase mediated cleavage of MST1 and hence prevents activation of MST1 [XREF_BIBR].	0	18	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	MST1	Phosphorylation of MST1	mst1	MST1	MST1	mst1	2	3	16	17
Conversely , Abl mediated phosphorylation of Mst2 at Y81 disrupts the c , Raf , and Mst2 heterodimer and enhances Mst2 homodimerization and activity [ XREF_BIBR ] .	Conversely, Abl mediated phosphorylation of Mst2 at Y81 disrupts the c, Raf, and Mst2 heterodimer and enhances Mst2 homodimerization and activity [XREF_BIBR].	2	21	enhances	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mst2	Abl mediated phosphorylation of Mst2 at Y81	mst2	Mst2	Mst2	mst2	6	7	20	21
However , the livers of Sik3 -/- mice possessed activated AMPK and an enhanced gluconeogenic program ( XREF_FIG ) , suggesting that loss of LKB1 causes a deficiency of SIK3 and subsequent AMPK resistance .	However, the livers of Sik3 -/- mice possessed activated AMPK and an enhanced gluconeogenic program (XREF_FIG), suggesting that loss of LKB1 causes a deficiency of SIK3 and subsequent AMPK resistance.	22	33	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	LKB1	loss of LKB1	lkb1	SIK3	SIK3	sik3	24	25	29	30
In cultured hippocampal neurons , overexpression of LKB1 induces multiple axons and RNAi depletion of LKB1 or its subunit STRAD block axonal differentiation XREF_BIBR .	In cultured hippocampal neurons, overexpression of LKB1 induces multiple axons and RNAi depletion of LKB1 or its subunit STRAD block axonal differentiation XREF_BIBR.	5	20	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	LKB1	overexpression of LKB1	lkb1	STRAD	STRAD	strad	7	8	19	20
Because SYK kinase activity is required for activation of SLP65 , BCR-ABL1/LYN/CBL-induced proteasomal degradation of SYK also prevents further activation of the SLP65 tumor suppressor .	Because SYK kinase activity is required for activation of SLP65, BCR-ABL1/LYN/CBL-induced proteasomal degradation of SYK also prevents further activation of the SLP65 tumor suppressor.	13	24	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SYK	SYK	SYK	SLP65	SLP65	SLP65	15	16	22	23
This RASSF1A and MST2 promoted LATS1 activity is targeted toward YAP1 [ XREF_BIBR ] , resulting in increased pS127-YAP [ XREF_BIBR ] and decreased YAP-TEAD oncogenic behavior [ XREF_BIBR , XREF_BIBR ] .	This RASSF1A and MST2 promoted LATS1 activity is targeted toward YAP1 [XREF_BIBR], resulting in increased pS127-YAP [XREF_BIBR] and decreased YAP-TEAD oncogenic behavior [XREF_BIBR, XREF_BIBR].	1	6	promoted	Positive_activation_token_1_verb	Positive_activation	Negative_activation	MST2	MST2	MST2	LATS1	LATS1	LATS1	3	4	5	6
Since Syk is reported to participate in the activation of signaling through PI3K , Btk , and Ras , we further examined which pathways downstream of Syk contributed to the ADE of VSV-EBOV GP infection using specific inhibitors of PI3K ( LY294002 ) , Btk ( LFM-A13 ) , and Ras ( Manumycin A ) ( XREF_FIG ) .	Since Syk is reported to participate in the activation of signaling through PI3K, Btk, and Ras, we further examined which pathways downstream of Syk contributed to the ADE of VSV-EBOV GP infection using specific inhibitors of PI3K (LY294002), Btk (LFM-A13), and Ras (Manumycin A) (XREF_FIG).	23	46	contributed	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Syk	Syk	Syk	Btk	Btk	Btk	26	27	44	45
Because the TP53 tumor suppressor gene is frequently mutated in human pancreatic cancer ( 40 %-70% ) XREF_BIBR and LKB1 is down-regulated in around 20 % of PDAC , we hypothesized that loss of Lkb1 mediated p53 and p21 induction might be able to circumvent the need for p53 mutation in human PDAC and thus should not be down-regulated in those tumors with p53 mutation .	Because the TP53 tumor suppressor gene is frequently mutated in human pancreatic cancer (40%-70%) XREF_BIBR and LKB1 is down-regulated in around 20% of PDAC, we hypothesized that loss of Lkb1 mediated p53 and p21 induction might be able to circumvent the need for p53 mutation in human PDAC and thus should not be down-regulated in those tumors with p53 mutation.	32	39	mediated	Positive_early_activation	Positive_activation	Negative_activation	Lkb1	Lkb1	Lkb1	p53	p53	p53	34	35	36	37
Our finding that TBK1 stimulated AKT degradation led us to examine whether these phosphorylation sites regulate TBK1 stability .	Our finding that TBK1 stimulated AKT degradation led us to examine whether these phosphorylation sites regulate TBK1 stability.	3	6	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	3	4	5	6
One study using conditional TBK1 -/- in CD4 + T cells ( Tbk1 fl/fl : CD4-Cre mice ) and stimulation with TCR and CD28 , suggested that basal TBK1 is required for constitutive AKT turnover to prevent hyperactivation of AKT upon T cell activation .	One study using conditional TBK1 -/- in CD4 + T cells (Tbk1 fl/fl : CD4-Cre mice) and stimulation with TCR and CD28, suggested that basal TBK1 is required for constitutive AKT turnover to prevent hyperactivation of AKT upon T cell activation.	27	40	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	28	29	39	40
TBK1 also induced the proteolytic degradation of exogenously expressed AKT but did not affect the co-transfected control protein GFP ( XREF_SUPPLEMENTARY ) .	TBK1 also induced the proteolytic degradation of exogenously expressed AKT but did not affect the co-transfected control protein GFP (XREF_SUPPLEMENTARY).	0	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	0	1	9	10
Moreover , a small-molecule inhibitor of TBK1 , MRT67307 , efficiently inhibited the AKT degradation ( XREF_FIG ) .	Moreover, a small-molecule inhibitor of TBK1, MRT67307, efficiently inhibited the AKT degradation (XREF_FIG).	4	14	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	6	7	13	14
The primary target of TBK1 appears to be AKT , since TBK1 promotes ubiquitin dependent degradation of AKT in a manner that depends on a previously defined TBK1 phosphorylation site within AKT , S378 .	The primary target of TBK1 appears to be AKT, since TBK1 promotes ubiquitin dependent degradation of AKT in a manner that depends on a previously defined TBK1 phosphorylation site within AKT, S378.	11	18	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	11	12	17	18
VMH specific inhibition of TBK-1 in mice with diet induced obesity impaired glucose metabolism and AKT activation .	VMH specific inhibition of TBK-1 in mice with diet induced obesity impaired glucose metabolism and AKT activation.	2	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK-1	TBK-1	TBK-1	AKT	AKT	AKT	4	5	15	16
We next employed a transient transfection model to see whether overexpressed TBK1 was able to induce AKT degradation .	We next employed a transient transfection model to see whether overexpressed TBK1 was able to induce AKT degradation.	10	17	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	11	12	16	17
Concordant with the consequence of siRNA and shRNA mediated TBK1 depletion , a 24-hour exposure to Compound II inhibited AKT pathway activation and survival in multiple cancer cell lines at doses close to those affecting IRF-3 nuclear localization ( XREF_FIG ) .	Concordant with the consequence of siRNA and shRNA mediated TBK1 depletion, a 24-hour exposure to Compound II inhibited AKT pathway activation and survival in multiple cancer cell lines at doses close to those affecting IRF-3 nuclear localization (XREF_FIG).	9	21	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	9	10	19	20
TBK1 depletion slightly decreased AKT activation in SBcl2 , WM1366 and SKMel2 cells in response to insulin stimulation but no effect was observed in WM1361A and WM1346 cells .	TBK1 depletion slightly decreased AKT activation in SBcl2, WM1366 and SKMel2 cells in response to insulin stimulation but no effect was observed in WM1361A and WM1346 cells.	0	5	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	0	1	4	5
We have obtained biochemical evidence that the serine 378 phosphorylation site of AKT is crucial for TBK1 stimulated AKT degradation .	We have obtained biochemical evidence that the serine 378 phosphorylation site of AKT is crucial for TBK1 stimulated AKT degradation.	16	19	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	AKT	AKT	AKT	16	17	18	19
In addition , Mst1 also impeded virus induced activation of TANK binding kinase 1 ( TBK1 ) , further attenuating IRF3 activation .	In addition, Mst1 also impeded virus induced activation of TANK binding kinase 1 (TBK1), further attenuating IRF3 activation.	8	21	attenuating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	15	16	20	21
PPM1B phosphatase activity is required for its inhibitory effect on RIG-I-CARD-, MAVS- and TBK1 induced IRF3 activation and IFNbeta gene expression .	PPM1B phosphatase activity is required for its inhibitory effect on RIG-I-CARD-, MAVS- and TBK1 induced IRF3 activation and IFNbeta gene expression.	8	16	induced	Positive_early_activation	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	13	14	15	16
This results in a strong inhibition of both RIG-I- and TBK1 mediated IRF3 dependent IFN and ISG promoter activities .	This results in a strong inhibition of both RIG-I- and TBK1 mediated IRF3 dependent IFN and ISG promoter activities.	5	14	mediated	Positive_early_activation	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	10	11	12	13
Furthermore , inhibition of TBK1 and genetic inactivation of IRF3 blocked the IFN response but not cell death ( XREF_FIG ) , indicating that cell death is not linked to either cytokines or IRF3 dependent cell death pathways described in other systems .	Furthermore, inhibition of TBK1 and genetic inactivation of IRF3 blocked the IFN response but not cell death (XREF_FIG), indicating that cell death is not linked to either cytokines or IRF3 dependent cell death pathways described in other systems.	4	10	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	4	5	9	10
The viral proteins that target TBK1 act by either blocking activation of TBK1 by MAVS or by inhibiting activation of IRF3 by TBK1 .	The viral proteins that target TBK1 act by either blocking activation of TBK1 by MAVS or by inhibiting activation of IRF3 by TBK1.	17	23	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	22	23	20	21
Following engagement of various TLR and RLR signaling , IRF3 is activated by Inhibitor of kappaB kinase ( IKK ) family kinases TANK binding kinase 1 ( TBK1 ) and IKKepsilon through Ser/Thr phosphorylation .	Following engagement of various TLR and RLR signaling, IRF3 is activated by Inhibitor of kappaB kinase (IKK) family kinases TANK binding kinase 1 (TBK1) and IKKepsilon through Ser/Thr phosphorylation.	9	28	activated	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	27	28	9	10
In addition , TBK1 -/- fibroblasts showed impaired response to poly ( I : C ) as demonstrated by delayed induction of IFN-beta and IFN inducible genes , and diminished IRF-3 dimerization .	In addition, TBK1 -/- fibroblasts showed impaired response to poly (I : C) as demonstrated by delayed induction of IFN-beta and IFN inducible genes, and diminished IRF-3 dimerization.	3	31	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IRF-3	IRF-3	IRF-3	3	4	30	31
The Ser/Thr protein phosphatase , Mg 2+ / Mn 2+ -dependent ( PPM ) 1B acts as a TBK1 phosphatase to inhibit IRF3 activation , while PPM1A targets both TBK1 and IKKepsilon and MAVS for dephosphorylation to negatively regulate the antiviral response XREF_BIBR , XREF_BIBR .	The Ser/Thr protein phosphatase, Mg 2+ / Mn 2+ -dependent (PPM) 1B acts as a TBK1 phosphatase to inhibit IRF3 activation, while PPM1A targets both TBK1 and IKKepsilon and MAVS for dephosphorylation to negatively regulate the antiviral response XREF_BIBR, XREF_BIBR.	18	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	18	19	22	23
The Vaccinia virus protein C6 binds TBK1 adaptor proteins ( TANK , NAP1 , and SINTBAD ) , thereby inhibiting the activation of IRF3 and IRF7 [ XREF_BIBR ] , and the Gn protein of hantaviruses disrupts the formation of TBK1 complexes , thereby blocking downstream responses [ XREF_BIBR ] .	The Vaccinia virus protein C6 binds TBK1 adaptor proteins (TANK, NAP1, and SINTBAD), thereby inhibiting the activation of IRF3 and IRF7 [XREF_BIBR], and the Gn protein of hantaviruses disrupts the formation of TBK1 complexes, thereby blocking downstream responses [XREF_BIBR].	6	27	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IRF3	IRF3	IRF3	6	7	23	24
Deletion of either Tab1 or Tab2 impaired LPS induced migration shift of TAK1 , suggesting some impairment of TAK1 activation in response to LPS ( XREF_FIG , top panels ) .	Deletion of either Tab1 or Tab2 impaired LPS induced migration shift of TAK1, suggesting some impairment of TAK1 activation in response to LPS (XREF_FIG, top panels).	0	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Tab1	Tab1	Tab1	TAK1	TAK1	TAK1	3	4	12	13
TAK1 activity is also subject to regulation by a feedback loop in which p38alpha MAPK suppresses the activation of TAK1 by phosphorylation of TAB1 at Ser423 and Thr431 .	TAK1 activity is also subject to regulation by a feedback loop in which p38alpha MAPK suppresses the activation of TAK1 by phosphorylation of TAB1 at Ser423 and Thr431.	17	27	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	TAB1	phosphorylation of TAB1 at Ser423	tab1	TAK1	TAK1	tak1	23	24	19	20
Single deletion of Tab1 or Tab2 does not cause any abnormalities in the epidermis and intestinal epithelium but double deletion of Tab1 and Tab2 phenocopies Tak1 deficiency XREF_BIBR , suggesting that TAB1 and TAB2 redundantly function in TAK1 regulation in these tissues .	Single deletion of Tab1 or Tab2 does not cause any abnormalities in the epidermis and intestinal epithelium but double deletion of Tab1 and Tab2 phenocopies Tak1 deficiency XREF_BIBR, suggesting that TAB1 and TAB2 redundantly function in TAK1 regulation in these tissues.	1	27	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Tab1	Tab1	Tab1	Tak1	Tak1	Tak1	3	4	25	26
Ablation of both TAB1 and TAB2 diminished the activity of TAK1 in vivo and causes accumulation of ROS in the epithelial tissues .	Ablation of both TAB1 and TAB2 diminished the activity of TAK1 in vivo and causes accumulation of ROS in the epithelial tissues.	0	12	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TAB1	TAB1	TAB1	TAK1	TAK1	TAK1	3	4	10	11
Inhibition of the TAB1 phosphatase DUSP14 also blocked TAB1 dephosphorylation and reduced TAK1 activation .	Inhibition of the TAB1 phosphatase DUSP14 also blocked TAB1 dephosphorylation and reduced TAK1 activation.	3	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1 phosphatase DUSP14 also blocked TAB1 dephosphorylation	tab1	TAK1	TAK1	tak1	3	4	12	13
Double deficiency of Tab1 and Tab2 abolished TAK1 activity in the epidermis in vivo , which caused TNF induced cell death and tissue damage resembling the phenotypes of TAK1 deficiency XREF_BIBR .	Double deficiency of Tab1 and Tab2 abolished TAK1 activity in the epidermis in vivo, which caused TNF induced cell death and tissue damage resembling the phenotypes of TAK1 deficiency XREF_BIBR.	1	8	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tab1	Tab1	Tab1	TAK1	TAK1	TAK1	3	4	7	8
We show that Tab1 deficiency greatly reduces TAK1 activity in the epidermis .	We show that Tab1 deficiency greatly reduces TAK1 activity in the epidermis.	3	8	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tab1	Tab1	Tab1	TAK1	TAK1	TAK1	3	4	7	8
This suggests that TAB2 mediates deactivation of TAK1 .	This suggests that TAB2 mediates deactivation of TAK1.	3	8	mediates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	3	4	7	8
These results suggest that TAB2 and TAB3 negatively regulate autophagy independently of TAK1 activity .	These results suggest that TAB2 and TAB3 negatively regulate autophagy independently of TAK1 activity.	4	13	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	4	5	12	13
TAB2 deficiency caused reduced TAK1 activity , resulting in abnormal capillary blood vessels , similar to the compound deficiency of TAK1 and TNF signaling .	TAB2 deficiency caused reduced TAK1 activity, resulting in abnormal capillary blood vessels, similar to the compound deficiency of TAK1 and TNF signaling.	0	5	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TAB2	TAB2	TAB2	TAK1	TAK1	TAK1	0	1	4	5
Depletion of TAB1 or mutation of P2Y 1 ubiquitination sites inhibits p38 MAPK activation .	Depletion of TAB1 or mutation of P2Y 1 ubiquitination sites inhibits p38 MAPK activation.	0	13	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	TAB1	TAB1	p38 MAPK	p38 MAPK	p38 MAPK	2	3	11	13
In addition , siRNA knockdown and rescue studies indicated that expression of siRNA resistant TAB1 WT was sufficient to restore p38 activation in response to thrombin , whereas the TAB1 P412A mutant was not .	In addition, siRNA knockdown and rescue studies indicated that expression of siRNA resistant TAB1 WT was sufficient to restore p38 activation in response to thrombin, whereas the TAB1 P412A mutant was not.	10	21	restore	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TAB1	expression of siRNA resistant TAB1	tab1	p38	p38	p38	14	15	20	21
Consequently , TAB-1 expression antagonizes the downstream activity of p38 kinase induced by MKK3 and attenuates interleukin-1beta-induced inflammatory gene induction in cardiomyocytes .	Consequently, TAB-1 expression antagonizes the downstream activity of p38 kinase induced by MKK3 and attenuates interleukin-1beta-induced inflammatory gene induction in cardiomyocytes.	2	10	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TAB-1	TAB-1 expression	tab-1	p38	p38	p38	2	3	9	10
Co-depletion of TAB1 and TAB2 caused a marked inhibition of thrombin dependent p38 activation ( XREF_FIG , lanes 1-4 ) .	Co-depletion of TAB1 and TAB2 caused a marked inhibition of thrombin dependent p38 activation (XREF_FIG, lanes 1-4).	0	13	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TAB1	TAB1	TAB1	p38	p38	p38	2	3	12	13
Amlexanox increased phosphorylation of TBK1 on Ser172 in 3T3-L1 adipocytes , and blocked polyinosinic : polycytidylic acid ( poly I : C )-stimulated phosphorylation of interferon responsive factor-3 ( IRF3 ) , a presumed substrate of IKKepsilon and TBK1 27 ( XREF_FIG ) .	Amlexanox increased phosphorylation of TBK1 on Ser172 in 3T3-L1 adipocytes, and blocked polyinosinic : polycytidylic acid (poly I : C)-stimulated phosphorylation of interferon responsive factor-3 (IRF3), a presumed substrate of IKKepsilon and TBK1 27 (XREF_FIG).	0	37	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	Amlexanox increased phosphorylation of TBK1 on Ser172	tbk1	IKKepsilon	IKKepsilon	ikkepsilon	4	5	36	37
This HTS revealed that 227 compounds in this library inhibited TBK1 at a concentration of 10 microM and 57 compounds inhibited IKKepsilon , including several compounds that inhibited these enzymes at sub-micromolar concentrations ( XREF_FIG ) .	This HTS revealed that 227 compounds in this library inhibited TBK1 at a concentration of 10 microM and 57 compounds inhibited IKKepsilon, including several compounds that inhibited these enzymes at sub-micromolar concentrations (XREF_FIG).	10	22	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TBK1	TBK1	TBK1	IKKepsilon	IKKepsilon	IKKepsilon	10	11	21	22
In addition , the blockade of ERK1/2 activation negated the catalytic activity of IKKalpha , but not that of IKKbeta , whereas silencing NAK by specific siRNA abrogated the IKKbeta activity in TPA treated cells .	In addition, the blockade of ERK1/2 activation negated the catalytic activity of IKKalpha, but not that of IKKbeta, whereas silencing NAK by specific siRNA abrogated the IKKbeta activity in TPA treated cells.	22	30	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	NAK	NAK	NAK	IKKbeta	IKKbeta	IKKbeta	23	24	29	30
The enhanced JNK and IkappaB kinase activation in DUSP14 deficient T cells was attenuated by TAB1 short hairpin RNA knockdown .	The enhanced JNK and IkappaB kinase activation in DUSP14 deficient T cells was attenuated by TAB1 short hairpin RNA knockdown.	0	19	attenuated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TAB1	TAB1	TAB1	JNK	JNK	JNK	15	16	2	3
The TARBP2 sequestration is known to restrict the availability of Dicer enzyme leading to modification of microRNA processing .	The TARBP2 sequestration is known to restrict the availability of Dicer enzyme leading to modification of microRNA processing.	1	11	restrict	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TARBP2	TARBP2	TARBP2	Dicer	Dicer	Dicer	1	2	10	11
This suggests that BFA blocks EGFR recycling and thus shortens EGF dependent receptor signalling , whereas TGFalpha shortens receptor signalling and thus blocks EGFR downregulation .	This suggests that BFA blocks EGFR recycling and thus shortens EGF dependent receptor signalling, whereas TGFalpha shortens receptor signalling and thus blocks EGFR downregulation.	16	24	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	16	17	23	24
Treatment of highly enriched cultures of cortical astrocytes with dibutyryl cAMP accelerated the TGFalpha induced internalization and subsequent functional inactivation of epidermal growth factor ( EGF ) receptor by transiently inhibiting EGF receptor mRNA synthesis .	Treatment of highly enriched cultures of cortical astrocytes with dibutyryl cAMP accelerated the TGFalpha induced internalization and subsequent functional inactivation of epidermal growth factor (EGF) receptor by transiently inhibiting EGF receptor mRNA synthesis.	12	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFalpha	TGFalpha	TGFalpha	EGF receptor	EGF receptor	EGF receptor	13	14	31	33
Addition of a neutralizing monoclonal antibody versus transforming growth factor alpha ( TGFalpha ) had no effect on the primary activation of either the EGFR or the MAPK and JNK pathways after irradiation but abolished the secondary activation of EGFR , MAPK , and JNK .	Addition of a neutralizing monoclonal antibody versus transforming growth factor alpha (TGFalpha) had no effect on the primary activation of either the EGFR or the MAPK and JNK pathways after irradiation but abolished the secondary activation of EGFR, MAPK, and JNK.	0	44	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	12	13	39	40
In the present study , neutralizing TGFalpha abolished the paclitaxel induced activation of EGFR , and paclitaxel may stimulate release of TGFalpha to activate the EGFR pathway .	In the present study, neutralizing TGFalpha abolished the paclitaxel induced activation of EGFR, and paclitaxel may stimulate release of TGFalpha to activate the EGFR pathway.	5	14	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	6	7	13	14
Likewise it inhibits TGFalpha induced pEGFR and pERK 1/2 with IC50 values of 0.03 and 0.16 mug/ml respectively .	Likewise it inhibits TGFalpha induced pEGFR and pERK 1/2 with IC50 values of 0.03 and 0.16 mug/ml respectively.	2	7	induced	Positive_early_activation	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	pEGFR	pEGFR	pEGFR	3	4	5	6
Both TAPI-1 , a TNF-alpha converting enzyme ( TACE ) inhibitor , and TGF-alpha neutralizing antibody could inhibit the activation of EGFR and the generation of TNF-alpha mRNA after LPS treatment .	Both TAPI-1, a TNF-alpha converting enzyme (TACE) inhibitor, and TGF-alpha neutralizing antibody could inhibit the activation of EGFR and the generation of TNF-alpha mRNA after LPS treatment.	13	22	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	13	14	21	22
Similarly , AG1024 and SU6656 inhibited basal and IGF2 induced phosphorylation of c-SRC and EGFR , and SU6656 reduced TGFalpha induced EGFR activity in tamoxifen resistant T47D cells .	Similarly, AG1024 and SU6656 inhibited basal and IGF2 induced phosphorylation of c-SRC and EGFR, and SU6656 reduced TGFalpha induced EGFR activity in tamoxifen resistant T47D cells.	18	22	induced	Positive_early_activation	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	19	20	21	22
A statistical analysis performed for data given in XREF_FIG A and B shows significant reductions of PKB and Akt and EGFR in cells treated with TGFalpha ( exemplary tested for 10ng/ml ) in the presence of CpG-1-PTO or nCpG-5-PTO , respectively ( XREF_FIG C and D ) .	A statistical analysis performed for data given in XREF_FIG A and B shows significant reductions of PKB and Akt and EGFR in cells treated with TGFalpha (exemplary tested for 10ng/ml) in the presence of CpG-1-PTO or nCpG-5-PTO, respectively (XREF_FIG C and D).	14	26	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	25	26	20	21
77 Transfection of HIF-2alpha siRNA into HCC cells was shown to downregulate the expression of VEGF , cyclin D1 , HIF-2alpha and TGF-alpha , inhibiting the activation of EGFR .	77 Transfection of HIF-2alpha siRNA into HCC cells was shown to downregulate the expression of VEGF, cyclin D1, HIF-2alpha and TGF-alpha, inhibiting the activation of EGFR.	3	29	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-alpha	HIF-2alpha siRNA into HCC cells was shown to downregulate the expression of VEGF, cyclin D1, HIF-2alpha and TGF-alpha	tgf-alpha	EGFR	EGFR	egfr	22	23	28	29
More importantly , suppression of TGF-alpha and EGFR signaling , through prophylactic administration of potent and highly selective inhibitors of ligand induced EGFR activation , completely prevented both high-P- and low-Ca-induced parathyroid hyperplasia as well as TGF-alpha self upregulation .	More importantly, suppression of TGF-alpha and EGFR signaling, through prophylactic administration of potent and highly selective inhibitors of ligand induced EGFR activation, completely prevented both high-P- and low-Ca-induced parathyroid hyperplasia as well as TGF-alpha self upregulation.	5	23	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	5	6	22	23
TGF-alpha did not induce significant EGFR degradation ( XREF_FIG ) .	TGF-alpha did not induce significant EGFR degradation (XREF_FIG).	0	6	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	0	1	5	6
TGFalpha induced more robust EGFR recycling than EGF and TGFalpha induced EGFR recycling was also reduced by AKTVIII treatment ( XREF_FIG ) .	TGFalpha induced more robust EGFR recycling than EGF and TGFalpha induced EGFR recycling was also reduced by AKTVIII treatment (XREF_FIG).	5	12	induced	Positive_early_activation	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	9	10	11	12
Neutralization of TGF-alpha Blocks Both EGFR Transactivation and ERK Signaling .	Neutralization of TGF-alpha Blocks Both EGFR Transactivation and ERK Signaling.	0	6	Blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-alpha	TGF-alpha	TGF-alpha	EGFR	EGFR	EGFR	2	3	5	6
In addition , we have shown that the functionally distinct EGFR ligands , EGF and transforming growth factor-alpha ( TGFalpha ) , exert differing effects on EGFR downregulation and hence on the duration of ErbB2 co-activation : high concentrations of EGF initially cause prolonged EGFR activation associated with ErbB2 heterodimerisation , followed by eventual EGFR downregulation and signal cessation ; whereas TGFalpha fails to downregulate EGFR , leading to sustained signalling ( Gulliford et al , 1997 ; Ouyang et al , 1999a ) .	In addition, we have shown that the functionally distinct EGFR ligands, EGF and transforming growth factor-alpha (TGFalpha), exert differing effects on EGFR downregulation and hence on the duration of ErbB2 co-activation : high concentrations of EGF initially cause prolonged EGFR activation associated with ErbB2 heterodimerisation, followed by eventual EGFR downregulation and signal cessation; whereas TGFalpha fails to downregulate EGFR, leading to sustained signalling (Gulliford et al, 1997; Ouyang et al, 1999a).	61	66	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	61	62	65	66
Similarly , in T47D-R cells , AG1024 and SU6656 inhibited basal and IGF-II-induced phosphorylation of c-SRC and EGFR , and SU6656 reduced TGFalpha induced EGFR activity .	Similarly, in T47D-R cells, AG1024 and SU6656 inhibited basal and IGF-II-induced phosphorylation of c-SRC and EGFR, and SU6656 reduced TGFalpha induced EGFR activity.	21	25	induced	Positive_early_activation	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	22	23	24	25
Treatment of cells with silymarin , genistein or EGCG at 100-200 microM resulted in a complete inhibition of TGFalpha caused activation of erbB1 followed by a moderate to strong inhibition ( 10-90 % ) of Shc activation without an alteration in their protein levels .	Treatment of cells with silymarin, genistein or EGCG at 100-200 microM resulted in a complete inhibition of TGFalpha caused activation of erbB1 followed by a moderate to strong inhibition (10-90%) of Shc activation without an alteration in their protein levels.	16	23	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	erbB1	erbB1	erbB1	18	19	22	23
As a result , TGFalpha does not cause significant degradation and down-regulation of EGFR .	As a result, TGFalpha does not cause significant degradation and down-regulation of EGFR.	4	14	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFalpha	TGFalpha	TGFalpha	EGFR	EGFR	EGFR	4	5	13	14
Treatment of serum starved cells with silymarin resulted in a significant inhibition of transforming growth factor alpha mediated activation of erbB1 but no change in its protein levels .	Treatment of serum starved cells with silymarin resulted in a significant inhibition of transforming growth factor alpha mediated activation of erbB1 but no change in its protein levels.	11	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	transforming growth factor alpha	transforming growth factor alpha	transforming growth factor alpha	erbB1	erbB1	erbB1	13	17	20	21
By quantitative real-time PCR analysis and immunostaining , LAP treatment also abrogates the upregulation of cutaneous TGF-beta1 and connective tissue growth factor mRNAs and type I collagen synthesis in Scl GVHD .	By quantitative real-time PCR analysis and immunostaining, LAP treatment also abrogates the upregulation of cutaneous TGF-beta1 and connective tissue growth factor mRNAs and type I collagen synthesis in Scl GVHD.	8	22	abrogates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LAP	LAP	LAP	TGF-beta1	TGF-beta1	TGF-beta1	8	9	16	17
This latent complex is inactive because LAP prevents mature TGF-beta1 from binding to its receptor .	This latent complex is inactive because LAP prevents mature TGF-beta1 from binding to its receptor.	6	10	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LAP	LAP	LAP	TGF-beta1	TGF-beta1	TGF-beta1	6	7	9	10
Thus , elevated serum TGF-beta1 levels are associated with osteosclerosis , and conversely , decreased serum TGF-beta1 with osteopenia .	Thus, elevated serum TGF-beta1 levels are associated with osteosclerosis, and conversely, decreased serum TGF-beta1 with osteopenia.	4	17	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1 levels	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	4	5	16	17
Omegaven ( R ) ( 1/10-1/1000 ) dose-dependently inhibited the LPS induced TGFbeta1 and MMP-9 release ( XREF_FIG ) and decreased basal TGFbeta1 and MMP-9 secretion in human monocytes .	Omegaven (R) (1/10-1/1000) dose-dependently inhibited the LPS induced TGFbeta1 and MMP-9 release (XREF_FIG) and decreased basal TGFbeta1 and MMP-9 secretion in human monocytes.	10	28	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFbeta1	LPS induced TGFbeta1	tgfbeta1	TGFbeta1	TGFbeta1	tgfbeta1	12	13	22	23
The authors concluded that LAP inhibits the portion of known TGF-beta1 signals that result in fibrosis , but that TGF-beta1 likely signaled through other pathways to mediate inflammation .	The authors concluded that LAP inhibits the portion of known TGF-beta1 signals that result in fibrosis, but that TGF-beta1 likely signaled through other pathways to mediate inflammation.	4	26	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LAP	LAP	LAP	TGF-beta1	TGF-beta1	TGF-beta1	4	5	10	11
Latent TGF-beta1 has no biological activity because LAP prevents mature TGF-beta1 to bind to its receptor .	Latent TGF-beta1 has no biological activity because LAP prevents mature TGF-beta1 to bind to its receptor.	7	12	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LAP	LAP	LAP	TGF-beta1	TGF-beta1	TGF-beta1	7	8	10	11
TGF-beta1 can inhibit LAP induced monocyte chemotaxis .	TGF-beta1 can inhibit LAP induced monocyte chemotaxis.	0	4	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	LAP	LAP	LAP	0	1	3	4
The importance of TSP1 mediated TGF-beta 1 activation is supported by the observation that collagen gel contraction , an in vitro model for wound contraction , was enhanced by addition of TSP1 , with a concordant increase in active TGF-beta 1 , and reduced by antibody mediated functional knockdown of either TSP1 or TGF-beta 1 .	The importance of TSP1 mediated TGF-beta 1 activation is supported by the observation that collagen gel contraction, an in vitro model for wound contraction, was enhanced by addition of TSP1, with a concordant increase in active TGF-beta 1, and reduced by antibody mediated functional knockdown of either TSP1 or TGF-beta 1.	3	55	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta 1	TSP1 mediated TGF-beta 1	tgf-beta 1	TGF-beta 1	TGF-beta 1	tgf-beta 1	5	7	53	55
The results showed that E-cadherin and SnoN expression in NRK52Es decreased significantly , but poly-ubiquitination of SnoN , TGF-beta1 , alpha-SMA , FN , Arkadia , p-Smad2 and p-Smad3 expression significantly increased due to high glucose stimulation , which could be almost completely reversed by OM , suggesting that OM may alleviate EMT induced by high glucose via upregulating SnoN expression and inhibiting TGF-beta1 and Smad signaling pathway activation .	The results showed that E-cadherin and SnoN expression in NRK52Es decreased significantly, but poly-ubiquitination of SnoN, TGF-beta1, alpha-SMA, FN, Arkadia, p-Smad2 and p-Smad3 expression significantly increased due to high glucose stimulation, which could be almost completely reversed by OM, suggesting that OM may alleviate EMT induced by high glucose via upregulating SnoN expression and inhibiting TGF-beta1 and Smad signaling pathway activation.	14	68	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	poly-ubiquitination of SnoN, TGF-beta1	tgf-beta1	TGF-beta1	TGF-beta1	tgf-beta1	18	19	63	64
We found that recombinant LAP and recombinant soluble betaglycan decrease the active form of TGF-beta1 , measured by ELISA , in a dose dependent manner in a cell-free system .	We found that recombinant LAP and recombinant soluble betaglycan decrease the active form of TGF-beta1, measured by ELISA, in a dose dependent manner in a cell-free system.	3	15	decrease	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LAP	LAP	LAP	TGF-beta1	TGF-beta1	TGF-beta1	4	5	14	15
This same microarray analysis also found that the mRNA level of a TGFbeta1 regulated gene , betaig-h3 , was reduced in EBNA1 ' s presence , indicating EBNA1 might impair TGFbeta1 signaling .	This same microarray analysis also found that the mRNA level of a TGFbeta1 regulated gene, betaig-h3, was reduced in EBNA1 's presence, indicating EBNA1 might impair TGFbeta1 signaling.	9	31	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFbeta1	level of a TGFbeta1	tgfbeta1	TGFbeta1	TGFbeta1	tgfbeta1	12	13	30	31
2 The increased expression and activation of TGF-beta1 by NO may occur via the S nitrosation of LAP , preventing the ability of LAP to bind to and hence inactivate TGF-beta1 .	2 The increased expression and activation of TGF-beta1 by NO may occur via the S nitrosation of LAP, preventing the ability of LAP to bind to and hence inactivate TGF-beta1.	5	24	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	LAP	LAP	LAP	7	8	23	24
The different changes of mRNA expression level of TGF-beta 1 and IL-6 in wound tissue result in low production and decreased activity of TGF-beta 1 and IL-6 , which lower the reparative ability of wound tissue .	The different changes of mRNA expression level of TGF-beta 1 and IL-6 in wound tissue result in low production and decreased activity of TGF-beta 1 and IL-6, which lower the reparative ability of wound tissue.	6	29	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta 1	level of TGF-beta 1	tgf-beta 1	TGF-beta 1	TGF-beta 1	tgf-beta 1	8	10	23	25
Furthermore , ICC assay showed TGF-beta1 also decreased the proportions of ALK5 + leukocytes in both PBL and HKL ( XREF_FIG ) , implying that ALK5 degradation and endocytosis was induced by TGF-beta1 .	Furthermore, ICC assay showed TGF-beta1 also decreased the proportions of ALK5 + leukocytes in both PBL and HKL (XREF_FIG), implying that ALK5 degradation and endocytosis was induced by TGF-beta1.	5	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	5	6	11	12
TGF-beta1 reduced the proportion of ALK5 + leukocytes in PBL and HKL .	TGF-beta1 reduced the proportion of ALK5 + leukocytes in PBL and HKL.	0	11	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	0	1	5	6
Using the six-well plate approach , cells were treated with SB431542 ( an inhibitor of TGF-beta receptor ALK5 ) or human TGF-beta1 during dedifferentiation .	Using the six-well plate approach, cells were treated with SB431542 (an inhibitor of TGF-beta receptor ALK5) or human TGF-beta1 during dedifferentiation.	8	23	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	21	22	17	18
It is consistent with the observation that TGF-beta1 decreased the number of ALK5 + leukocytes in PBL and HKL , revealing a negative regulation of TGF-beta1 signaling at the receptor level .	It is consistent with the observation that TGF-beta1 decreased the number of ALK5 + leukocytes in PBL and HKL, revealing a negative regulation of TGF-beta1 signaling at the receptor level.	7	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	ALK5	ALK5	ALK5	7	8	12	13
Disruption of the expression of TGF-beta1 by antisense TGF-beta1 mRNA restores localization of TbetaRII at the PCT cell surface , indicating a ligand induced impediment in receptor trafficking .	Disruption of the expression of TGF-beta1 by antisense TGF-beta1 mRNA restores localization of TbetaRII at the PCT cell surface, indicating a ligand induced impediment in receptor trafficking.	3	14	restores	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	expression of TGF-beta1	tgf-beta1	TbetaRII	TbetaRII	tbetarii	5	6	13	14
Thus , VASP knockdown inhibits TGF-beta1 downregulation of TbetaRII , which may be another mechanism for the increase of total TbetaRII of VASP knockdown HSCs .	Thus, VASP knockdown inhibits TGF-beta1 downregulation of TbetaRII, which may be another mechanism for the increase of total TbetaRII of VASP knockdown HSCs.	5	14	downregulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaRII	TbetaRII	TbetaRII	5	6	8	9
We found that TGF-beta1 downregulated TbetaRII and TbetaRIII ( and not only TbetaRIII ) in oral CAFs and in NFs .	We found that TGF-beta1 downregulated TbetaRII and TbetaRIII (and not only TbetaRIII) in oral CAFs and in NFs.	3	12	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaRII	TbetaRII	TbetaRII	3	4	5	6
TbetaRII positive SW-13 cell growth was inhibited by exogenous human TGF-beta1 ( hTGF-beta1 ) in a dose dependent manner .	TbetaRII positive SW-13 cell growth was inhibited by exogenous human TGF-beta1 (hTGF-beta1) in a dose dependent manner.	0	18	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaRII	TbetaRII	TbetaRII	10	11	0	1
Exogenous TGF-beta1 could downregulate both TbetaRII and TbetaRIII in oral CAFs and in NFs .	Exogenous TGF-beta1 could downregulate both TbetaRII and TbetaRIII in oral CAFs and in NFs.	0	7	downregulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta1	TGF-beta1	TGF-beta1	TbetaRII	TbetaRII	TbetaRII	1	2	5	6
TET2 binds and activates WT1 target genes by increasing the 5hmC levels at the promoter regions of these specific sites in normal HSC , and therefore TET2 inhibits leukemia proliferation in a WT1 dependent manner [ XREF_BIBR ] .	TET2 binds and activates WT1 target genes by increasing the 5hmC levels at the promoter regions of these specific sites in normal HSC, and therefore TET2 inhibits leukemia proliferation in a WT1 dependent manner [XREF_BIBR].	26	34	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TET2	TET2	TET2	WT1	WT1	WT1	26	27	32	33
Taken together , our results suggest that TET2 negatively regulates leukemia cell proliferation in a WT1 dependent manner and that this tumor suppressor function of TET2 is inactivated by multiple AML associated TET2 mutations that lost its binding with WT1 ( XREF_FIG ) .	Taken together, our results suggest that TET2 negatively regulates leukemia cell proliferation in a WT1 dependent manner and that this tumor suppressor function of TET2 is inactivated by multiple AML associated TET2 mutations that lost its binding with WT1 (XREF_FIG).	7	17	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TET2	TET2	TET2	WT1	WT1	WT1	7	8	15	16
TET2 inhibits leukemia cell proliferation in a WT1 dependent manner .	TET2 inhibits leukemia cell proliferation in a WT1 dependent manner.	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TET2	TET2	TET2	WT1	WT1	WT1	0	1	7	8
The functional relevance of WT1 recrutied TET2 is further supported by the finding that TET2 inhibits leukemia cell proliferation in a WT1 dependent manner .	The functional relevance of WT1 recrutied TET2 is further supported by the finding that TET2 inhibits leukemia cell proliferation in a WT1 dependent manner.	14	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TET2	TET2	TET2	WT1	WT1	WT1	14	15	21	22
TGF-beta2 did not inhibit mineralization of ALK5 deficient calvarial cells ( XREF_FIG ) , suggesting that differentiating osteoblasts become 16 mature independent of TGF-beta signaling .	TGF-beta2 did not inhibit mineralization of ALK5 deficient calvarial cells (XREF_FIG), suggesting that differentiating osteoblasts become 16 mature independent of TGF-beta signaling.	0	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta2	TGF-beta2	TGF-beta2	ALK5	ALK5	ALK5	0	1	6	7
They found that Tgfb2 , Tgfbr1 , or Tak1 haploinsufficiency disrupted TbetaRI and TbetaRIII mediated signaling and rescued the craniofacial anomalies in Tgfbr2 mutant mice , suggesting that modulation of TGF-beta signaling may be beneficial for the prevention of congenital craniofacial birth defects .	They found that Tgfb2, Tgfbr1, or Tak1 haploinsufficiency disrupted TbetaRI and TbetaRIII mediated signaling and rescued the craniofacial anomalies in Tgfbr2 mutant mice, suggesting that modulation of TGF-beta signaling may be beneficial for the prevention of congenital craniofacial birth defects.	3	17	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tgfb2	Tgfb2	Tgfb2	TbetaRI	TbetaRI	TbetaRI	3	4	11	12
Strikingly , Tgfb2 , Tgfbr1 ( also known as Alk5 ) , or Tak1 haploinsufficiency disrupted TbetaRI and TbetaRIII mediated signaling and rescued craniofacial deformities in Tgfbr2 mutant mice , indicating that activation of this noncanonical TGF-beta signaling pathway was responsible for craniofacial malformations in Tgfbr2 mutant mice .	Strikingly, Tgfb2, Tgfbr1 (also known as Alk5), or Tak1 haploinsufficiency disrupted TbetaRI and TbetaRIII mediated signaling and rescued craniofacial deformities in Tgfbr2 mutant mice, indicating that activation of this noncanonical TGF-beta signaling pathway was responsible for craniofacial malformations in Tgfbr2 mutant mice.	2	22	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tgfb2	Tgfb2	Tgfb2	TbetaRI	TbetaRI	TbetaRI	2	3	16	17
Importantly , however , the expression of the obligate co-receptor Cripto specifically by male germ cells should theoretically restrict Nodal signaling to this population .	Importantly, however, the expression of the obligate co-receptor Cripto specifically by male germ cells should theoretically restrict Nodal signaling to this population.	5	20	restrict	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Cripto	expression of the obligate co-receptor Cripto	cripto	Nodal	Nodal	nodal	10	11	19	20
We showed that CRIPTO shed by PGAP6 was active as a Nodal coreceptor and that PGAP6 mediated release of CRIPTO reduced Nodal signaling in cells on which CRIPTO was expressed .	We showed that CRIPTO shed by PGAP6 was active as a Nodal coreceptor and that PGAP6 mediated release of CRIPTO reduced Nodal signaling in cells on which CRIPTO was expressed.	17	22	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	CRIPTO	CRIPTO	CRIPTO	Nodal	Nodal	Nodal	19	20	21	22
Luciferase assays confirmed that E2F1 activity was reduced by low TFDP1 levels .	Luciferase assays confirmed that E2F1 activity was reduced by low TFDP1 levels.	4	12	reduced	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TFDP1	TFDP1 levels	tfdp1	E2F1	E2F1	e2f1	10	11	4	5
TFDP3 has a high sequence homology with TFDP1 , which can inhibit E2F1 function by competing with TFDP1 to bind to E2F1 and affect the process of cell cycle .	TFDP3 has a high sequence homology with TFDP1, which can inhibit E2F1 function by competing with TFDP1 to bind to E2F1 and affect the process of cell cycle.	5	13	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TFDP1	TFDP1	TFDP1	E2F1	E2F1	E2F1	7	8	12	13
Next , we asked if there was a correlation between TET2 mediated OGT targeting and the targeted gene transcription levels .	Next, we asked if there was a correlation between TET2 mediated OGT targeting and the targeted gene transcription levels.	8	19	mediated	Positive_early_activation	Positive_activation	Positive_activation	TET2	TET2	TET2	OGT	OGT	OGT	10	11	12	13
Loss of TET2 in ESCs prevents the association of OGT with chromatin , and overexpression of TET2 increases the level of chromatin bound OGT .	Loss of TET2 in ESCs prevents the association of OGT with chromatin, and overexpression of TET2 increases the level of chromatin bound OGT.	0	10	prevents	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TET2	Loss of TET2	tet2	OGT	OGT	ogt	2	3	9	10
However , levels of active TGF-beta2 were reduced , suggesting the involvement of t-flavanone in the activation pathway of TGF-beta2 .	However, levels of active TGF-beta2 were reduced, suggesting the involvement of t-flavanone in the activation pathway of TGF-beta2.	2	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta2	levels of active TGF-beta2	tgf-beta2	TGF-beta2	TGF-beta2	tgf-beta2	5	6	19	20
However , MK2206 failed to block the effect of high KLF4 or expression of exogenous TCL1 ( XREF_FIG A and 7B ) , showing that KLF4 induced TCL1 reduces the mitochondrial content independent of the AKT signaling pathway .	However, MK2206 failed to block the effect of high KLF4 or expression of exogenous TCL1 (XREF_FIG A and 7B), showing that KLF4 induced TCL1 reduces the mitochondrial content independent of the AKT signaling pathway.	25	37	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TCL1	KLF4 induced TCL1	tcl1	AKT	AKT	akt	27	28	35	36
Interestingly , other studies have inhibited TGFbeta receptor kinase activity , which reduced SMAD3 activity , and observed elevated claudin-5 expression .	Interestingly, other studies have inhibited TGFbeta receptor kinase activity, which reduced SMAD3 activity, and observed elevated claudin-5 expression.	6	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	6	7	13	14
Loss-of-function of BMP signalling in mouse cartilage impairs chondrogenesis XREF_BIBR - XREF_BIBR , and the TGF-beta pathway promotes chondrogenesis by enabling Smad3 to form an active transcriptional complex with CBP and p300 and the chondrogenic master regulator , Sox9 33 .	Loss-of-function of BMP signalling in mouse cartilage impairs chondrogenesis XREF_BIBR - XREF_BIBR, and the TGF-beta pathway promotes chondrogenesis by enabling Smad3 to form an active transcriptional complex with CBP and p300 and the chondrogenic master regulator, Sox9 33.	15	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	15	16	21	22
TGF-beta significantly reduced Smad3 mRNA , whereas LCM had only marginal effect .	TGF-beta significantly reduced Smad3 mRNA, whereas LCM had only marginal effect.	0	4	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	3	4
Finally , we compared wild-type IRF3 and IRF3 5SD for their effects on TGF-beta target genes , and measured basal , i.e. autocrine TGF-beta-dependent , and TGF-beta-induced mRNA expression of Smad7 , p15 Ink4B and p21 Cip1 , three direct Smad3 targets that are induced by TGF-beta , and c-Myc , which is directly repressed by Smad3 in response to autocrine or added TGF-beta .	Finally, we compared wild-type IRF3 and IRF3 5SD for their effects on TGF-beta target genes, and measured basal, i.e. autocrine TGF-beta-dependent, and TGF-beta-induced mRNA expression of Smad7, p15 Ink4B and p21 Cip1, three direct Smad3 targets that are induced by TGF-beta, and c-Myc, which is directly repressed by Smad3 in response to autocrine or added TGF-beta.	40	47	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	46	47	40	41
In the case of Smad3 , the E239A mutation also abolished the phosphorylation by the TGFbeta type I receptor ( ALK5 ) .	In the case of Smad3, the E239A mutation also abolished the phosphorylation by the TGFbeta type I receptor (ALK5).	2	18	abolished	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	15	16	4	5
In those reports , mechanisms of Sirt1 ' s antifibrotic effects were explained by suppression of both cyclooxygenase 2 expression [ XREF_BIBR ] and activation of TGFbeta induced Smad3 [ XREF_BIBR ] , both of which are recognized as classical pathogenic factors in diabetic nephropathy .	In those reports, mechanisms of Sirt1 's antifibrotic effects were explained by suppression of both cyclooxygenase 2 expression [XREF_BIBR] and activation of TGFbeta induced Smad3 [XREF_BIBR], both of which are recognized as classical pathogenic factors in diabetic nephropathy.	24	30	induced	Positive_early_activation	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	26	27	28	29
Also , TGF-beta mAb decreased activation of pSMAD2 , pSMAD3 and pSTAT3 .	Also, TGF-beta mAb decreased activation of pSMAD2, pSMAD3 and pSTAT3.	2	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	pSMAD3	pSMAD3	pSMAD3	2	3	9	10
Indeed , TGFbeta has even been shown to inhibit the expression of Smad3 [ XREF_BIBR ] further suggesting that Smad3 can counteract Smad2 activities in some systems .	Indeed, TGFbeta has even been shown to inhibit the expression of Smad3 [XREF_BIBR] further suggesting that Smad3 can counteract Smad2 activities in some systems.	2	14	inhibit	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	TGFbeta	TGFbeta	tgfbeta	Smad3	expression of Smad3	smad3	2	3	12	13
Further evidence reveals that MBD3 knockdown up-regulates expression of TGF-beta , and then activates p-Smad2 and p-Smad3 , while MBD3 overexpression results in downregulation of TGF-beta , p-Smad2 , and p-Smad3 .	Further evidence reveals that MBD3 knockdown up-regulates expression of TGF-beta, and then activates p-Smad2 and p-Smad3, while MBD3 overexpression results in downregulation of TGF-beta, p-Smad2, and p-Smad3.	4	17	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	MBD3 knockdown up-regulates expression of TGF-beta	tgf-beta	p-Smad3	p-Smad3	p-smad3	9	10	16	17
XREF_BIBR , XREF_BIBR Additionally , TGF-beta inhibits differentiation of naive CD8 + T cells to cytotoxic CD8 + T cells independently of Smad3 .	XREF_BIBR, XREF_BIBR Additionally, TGF-beta inhibits differentiation of naive CD8 + T cells to cytotoxic CD8 + T cells independently of Smad3.	5	23	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	5	6	22	23
In contrast , TGFbeta induced SMAD3 binding was typically diminished along the gene upon calcipotriol treatment ( XREF_FIG , top 2 tracks , and independently validated by ChIP-qPCR , XREF_FIG ) .	In contrast, TGFbeta induced SMAD3 binding was typically diminished along the gene upon calcipotriol treatment (XREF_FIG, top 2 tracks, and independently validated by ChIP-qPCR, XREF_FIG).	3	6	induced	Positive_early_activation	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	3	4	5	6
TGF-beta activated Smad3 proteins repress C/EBP dependent transcriptional activation of genes critical for adipogenesis [ XREF_BIBR ] .	TGF-beta activated Smad3 proteins repress C/EBP dependent transcriptional activation of genes critical for adipogenesis [XREF_BIBR].	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	2	3
These antifibrogenic activities result from inhibition of the nuclear translocation of TGFbeta activated smad3 by smad6 downstream of BMP7 activated smad5 .	These antifibrogenic activities result from inhibition of the nuclear translocation of TGFbeta activated smad3 by smad6 downstream of BMP7 activated smad5.	9	19	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	smad3	smad3	smad3	11	12	13	14
How TTK downregulates KLF5 remains unknown , but could be related to TGF-beta signaling , as TGF-beta downregulates KLF5 28 and TTK inhibition reduced the activation of SMAD3 by TGF-beta , potentially impacting the assembly of the transcriptional complex for KLF5 or altering the cellular localization and function of KLF5 .	How TTK downregulates KLF5 remains unknown, but could be related to TGF-beta signaling, as TGF-beta downregulates KLF5 28 and TTK inhibition reduced the activation of SMAD3 by TGF-beta, potentially impacting the assembly of the transcriptional complex for KLF5 or altering the cellular localization and function of KLF5.	23	30	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	29	30	27	28
PPAR-gamma ligands repress TGFbeta induced myofibroblast differentiation and activation by targeting the PI3K and Akt and Smad3 pathways , respectively .	PPAR-gamma ligands repress TGFbeta induced myofibroblast differentiation and activation by targeting the PI3K and Akt and Smad3 pathways, respectively.	3	17	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	3	4	16	17
TGF-beta and Smad3 signaling activity was completely abrogated by TGF-beta receptor1 inhibitor SB431542 but increasing amount of ERG relieved the inhibitory activity of TGF-beta and Smad3 .	TGF-beta and Smad3 signaling activity was completely abrogated by TGF-beta receptor1 inhibitor SB431542 but increasing amount of ERG relieved the inhibitory activity of TGF-beta and Smad3.	2	12	abrogated	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	9	10	2	3
Our study demonstrated that co-expression of p53 had a restrictive effect on Smad3 dependent transcriptional activity in cells not treated with TGFbeta ( XREF_FIG ) .	Our study demonstrated that co-expression of p53 had a restrictive effect on Smad3 dependent transcriptional activity in cells not treated with TGFbeta (XREF_FIG).	10	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	21	22	12	13
Recent studies suggest that TGF-beta suppresses neoplastic cell development by employing Smad3 protein to repress the gene of human telomerase reverse transcriptase ( hTERT ) .	Recent studies suggest that TGF-beta suppresses neoplastic cell development by employing Smad3 protein to repress the gene of human telomerase reverse transcriptase (hTERT).	4	12	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	4	5	11	12
alpha-SMA induction and Smad3 nuclear localization were blocked by the TGFbeta type I receptor ( TbetaRI , otherwise known as Alk5 ) inhibitor SB43154 , while AEC derived from Nkx2.1-Cre ; Alk5 flox/KO mice did not undergo EMT on collagen , consistent with a requirement for signaling via Alk5 in collagen induced EMT .	alpha-SMA induction and Smad3 nuclear localization were blocked by the TGFbeta type I receptor (TbetaRI, otherwise known as Alk5) inhibitor SB43154, while AEC derived from Nkx2.1-Cre; Alk5 flox/KO mice did not undergo EMT on collagen, consistent with a requirement for signaling via Alk5 in collagen induced EMT.	3	11	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	10	11	3	4
In contrast to Smad4 , Smad3 as well as Smad7 associate with PIASy , stimulating sumoylation of Smad3 and suppressing TGFbeta mediated Smad3 activation .	In contrast to Smad4, Smad3 as well as Smad7 associate with PIASy, stimulating sumoylation of Smad3 and suppressing TGFbeta mediated Smad3 activation.	19	23	mediated	Positive_early_activation	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	20	21	22	23
Moreover , treatment of NHDF with the selective SRC inhibitor SU6656 resulted in significantly reduced TGFbeta induced SMAD3 nuclear translocation , when compared to DMSO treated cells .	Moreover, treatment of NHDF with the selective SRC inhibitor SU6656 resulted in significantly reduced TGFbeta induced SMAD3 nuclear translocation, when compared to DMSO treated cells.	14	19	induced	Positive_early_activation	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	15	16	17	18
Preventing loss of TbetaRII by over-expression restores TGF-beta activation of Smad 3 , and therefore protects against ROS inhibition of type I procollagen gene expression [ XREF_BIBR , XREF_BIBR ] .	Preventing loss of TbetaRII by over-expression restores TGF-beta activation of Smad 3, and therefore protects against ROS inhibition of type I procollagen gene expression [XREF_BIBR, XREF_BIBR].	7	12	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad 3	Smad 3	Smad 3	7	8	10	12
This down-regulation of Smad3 by TGF-beta treatment did not appear to result from shortening of the half-life of Smad3 mRNA .	This down-regulation of Smad3 by TGF-beta treatment did not appear to result from shortening of the half-life of Smad3 mRNA.	1	6	down-regulation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	5	6	3	4
Furthermore , TGF-beta failed to repress MMP-1 promoter activity in Smad3 deficient murine embryonic fibroblasts .	Furthermore, TGF-beta failed to repress MMP-1 promoter activity in Smad3 deficient murine embryonic fibroblasts.	2	14	repress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	2	3	10	11
Pretreatment with TGFbeta type II receptor antisense oligonucleotide resulted in a trend toward a lower TGFbeta induced pSmad3 .	Pretreatment with TGFbeta type II receptor antisense oligonucleotide resulted in a trend toward a lower TGFbeta induced pSmad3.	8	18	induced	Positive_early_activation	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	pSmad3	pSmad3	pSmad3	15	16	17	18
This inhibitory effect was probably mediated by blocking TGF-beta induced Smad3 activation [ XREF_BIBR ] .	This inhibitory effect was probably mediated by blocking TGF-beta induced Smad3 activation [XREF_BIBR].	8	11	induced	Positive_early_activation	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	8	9	10	11
Conversely , TGFbeta neutralisation reversed the LSMCM mediated SMAD3 elevation ( XREF_FIG ) .	Conversely, TGFbeta neutralisation reversed the LSMCM mediated SMAD3 elevation (XREF_FIG).	2	9	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	2	3	8	9
TGF-beta and IL-2 treatment enhanced co-immunoprecipitation of Smad3 and Stat5 with Tet1 and Tet2 in T cells while TGF-beta and IL-2 neutralizing antibody attenuated the co-immunoprecipitation of Smad3 and Stat5 with Tet1 and Tet2 in Treg cells ( XREF_FIG ) .	TGF-beta and IL-2 treatment enhanced co-immunoprecipitation of Smad3 and Stat5 with Tet1 and Tet2 in T cells while TGF-beta and IL-2 neutralizing antibody attenuated the co-immunoprecipitation of Smad3 and Stat5 with Tet1 and Tet2 in Treg cells (XREF_FIG).	0	9	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	0	1	7	8
However , TGFbeta mediated Smad3 activation could limit later Stat3 activation in hepatocytes independent of alterations in IL6 induction as Stat3 activation is strongly and significantly increased at 42hr post-pHx in Smad3 -/- livers when compared to similarly treated wild type mice .	However, TGFbeta mediated Smad3 activation could limit later Stat3 activation in hepatocytes independent of alterations in IL6 induction as Stat3 activation is strongly and significantly increased at 42hr post-pHx in Smad3 -/- livers when compared to similarly treated wild type mice.	2	26	mediated	Positive_early_activation	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	2	3	4	5
Phospho-SMAD3 ( S423 and S425 ) chromatin immunoprecipitation ( CHIP ) in NHDF treated with PTP4A1 ASO showed significantly reduced TGFbeta induced SMAD3 occupancy on the COL1A2 promoter compared with Cntrl ASO treated cells .	Phospho-SMAD3 (S423 and S425) chromatin immunoprecipitation (CHIP) in NHDF treated with PTP4A1 ASO showed significantly reduced TGFbeta induced SMAD3 occupancy on the COL1A2 promoter compared with Cntrl ASO treated cells.	17	23	induced	Positive_early_activation	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	SMAD3	SMAD3	SMAD3	20	21	22	23
The inhibitor did not reduce activation of Smad3 by TGFbeta , ruling out an off-target effect on TGFbetaR activation ( Supplemental Figure S4A ) .	The inhibitor did not reduce activation of Smad3 by TGFbeta, ruling out an off-target effect on TGFbetaR activation (Supplemental Figure S4A).	4	10	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	9	10	7	8
As part of the numerous transcriptional changes necessary for EMT , TGFbeta initiated Smad3 signaling results in remodeling of the redox environment and decreased nucleophilic tone .	As part of the numerous transcriptional changes necessary for EMT, TGFbeta initiated Smad3 signaling results in remodeling of the redox environment and decreased nucleophilic tone.	11	14	initiated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	11	12	13	14
We hypothesized that PPARgamma agonists inhibit transforming growth factor ( TGF ) beta1 activation of TGFbeta receptor ( TGFbetaR ) -1 signaling in quiescent stellate cells , thereby abrogating Smad3 dependent induction of extracellular matrix ( ECM ) genes , such as PAI-1 and collagen-1alphaI .	We hypothesized that PPARgamma agonists inhibit transforming growth factor (TGF) beta1 activation of TGFbeta receptor (TGFbetaR) -1 signaling in quiescent stellate cells, thereby abrogating Smad3 dependent induction of extracellular matrix (ECM) genes, such as PAI-1 and collagen-1alphaI.	15	31	abrogating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	15	16	29	30
In summary , we find evidence for decreased Smad3 RNA expression and a trend toward decreased SMAD3 activation by TGF-beta in the striatum of HD knock-in mice , though any changes in SMAD3 protein are subtle .	In summary, we find evidence for decreased Smad3 RNA expression and a trend toward decreased SMAD3 activation by TGF-beta in the striatum of HD knock-in mice, though any changes in SMAD3 protein are subtle.	16	22	activation	Positive_activation_syntax_2_noun	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	SMAD3	SMAD3	SMAD3	19	20	16	17
Interestingly , we also noted that TGFbeta decreased Smad3 mRNA by > 80 % after 24h , suggesting the presence of a negative feedback loop .	Interestingly, we also noted that TGFbeta decreased Smad3 mRNA by> 80% after 24h, suggesting the presence of a negative feedback loop.	6	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	6	7	8	9
XREF_BIBR - XREF_BIBR Of particular interest , HCV core protein interacts with Smad3 and consequently inhibits TGFbeta induced Smad3 transcriptional activity .	XREF_BIBR - XREF_BIBR Of particular interest, HCV core protein interacts with Smad3 and consequently inhibits TGFbeta induced Smad3 transcriptional activity.	15	20	induced	Positive_early_activation	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	Smad3	Smad3	Smad3	16	17	18	19
Furthermore , TGF-beta suppressed the PGC-1alpha luciferase reporter in 3T3-L1 cells , whereas , TGF-beta was unable to repress the promoter in 3T3-L1 cells expressing shSmad3 ( XREF_FIG ) indicating that TGF-beta represses the PGC-1alpha promoter in a Smad3 dependent manner .	Furthermore, TGF-beta suppressed the PGC-1alpha luciferase reporter in 3T3-L1 cells, whereas, TGF-beta was unable to repress the promoter in 3T3-L1 cells expressing shSmad3 (XREF_FIG) indicating that TGF-beta represses the PGC-1alpha promoter in a Smad3 dependent manner.	31	40	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Smad3	Smad3	Smad3	31	32	38	39
This inhibits Tiam1 mediated Rac activation suppressing migration and invasion .	This inhibits Tiam1 mediated Rac activation suppressing migration and invasion.	1	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	2	3	4	5
XREF_BIBR Together , this suggests that the observed reduction in cell migration associated with Tiam1 mediated Rac1 activation might be a consequence of stronger cell-cell contacts through inhibiting IQGAP1 binding to beta-catenin .	XREF_BIBR Together, this suggests that the observed reduction in cell migration associated with Tiam1 mediated Rac1 activation might be a consequence of stronger cell-cell contacts through inhibiting IQGAP1 binding to beta-catenin.	12	17	mediated	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	14	15	16	17
Downregulation of Tiam1 with 100 microM NSC-23766 inhibited activation of Rac1 and migration of AT2 cells , suggesting its involvement in repair mechanisms of AT2 cells subjected to mechanical strain .	Downregulation of Tiam1 with 100 microM NSC-23766 inhibited activation of Rac1 and migration of AT2 cells, suggesting its involvement in repair mechanisms of AT2 cells subjected to mechanical strain.	0	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	2	3	10	11
Coexpression of Bcr , but not a GAP-dead Bcr mutant ( Bcr-GD ) , inhibited both Tiam1 induced Rac1 activation ( XREF_SUPPLEMENTARY ) and autophosphorylation of Pak ( XREF_FIG ) , a Rac1 effector that regulates spine morphogenesis .	Coexpression of Bcr, but not a GAP-dead Bcr mutant (Bcr-GD), inhibited both Tiam1 induced Rac1 activation (XREF_SUPPLEMENTARY) and autophosphorylation of Pak (XREF_FIG), a Rac1 effector that regulates spine morphogenesis.	14	19	induced	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	16	17	18	19
Collectively , these results show that Tiam1 induced Rac activity impedes TJ assembly in MDCKII cells , consistent with the findings of Chen and Macara 8 .	Collectively, these results show that Tiam1 induced Rac activity impedes TJ assembly in MDCKII cells, consistent with the findings of Chen and Macara 8.	6	9	induced	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	6	7	8	9
Tiam1 helps restrict the activity of Rac to dendritic spines via its interaction with the PDZ protein Par3 , and Tiam1 scaffolding is also important for coupling upstream signals to downstream signaling events .	Tiam1 helps restrict the activity of Rac to dendritic spines via its interaction with the PDZ protein Par3, and Tiam1 scaffolding is also important for coupling upstream signals to downstream signaling events.	0	7	restrict	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	6	7
Since the EHop-016 inhibitor was developed to block the association of Vav1 with Rac1 and , to a lesser extent , the activation of Rac1 by Tiam1 , we wanted to determine if either of these GEFs was involved in regulating phagocytosis in TM-1 cells .	Since the EHop-016 inhibitor was developed to block the association of Vav1 with Rac1 and, to a lesser extent, the activation of Rac1 by Tiam1, we wanted to determine if either of these GEFs was involved in regulating phagocytosis in TM-1 cells.	7	27	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	26	27	24	25
Tiam1 induced Rac activity impedes TJ assembly .	Tiam1 induced Rac activity impedes TJ assembly.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	0	1	2	3
The interaction of Tiam1 with PAR3 serves to spatially restrict Rac1 activation and localize cytoskeletal remodeling .	The interaction of Tiam1 with PAR3 serves to spatially restrict Rac1 activation and localize cytoskeletal remodeling.	1	11	restrict	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	3	4	10	11
XREF_BIBR This suggests that Tiam1 , in the absence of ECM signaling interference , might function predominantly to inhibit Rac1 driven cell migration and invasion .	XREF_BIBR This suggests that Tiam1, in the absence of ECM signaling interference, might function predominantly to inhibit Rac1 driven cell migration and invasion.	4	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	4	5	19	20
Upon inhibition of PI3-kinase , the Tiam1 mediated Rac activation decreased on both the motility suppressing fibronectin and the motility promoting collagen I substrate .	Upon inhibition of PI3-kinase, the Tiam1 mediated Rac activation decreased on both the motility suppressing fibronectin and the motility promoting collagen I substrate.	5	9	mediated	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	6	7	8	9
Either talin1 or Tiam1 depletion reduced the Rac1 activation before seeding , suggesting that a talin and Tiam1 complex contributes to the basal Rac1 activity .	Either talin1 or Tiam1 depletion reduced the Rac1 activation before seeding, suggesting that a talin and Tiam1 complex contributes to the basal Rac1 activity.	1	8	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	3	4	7	8
Knockdown of Tiam1 suppressed adhesion dependent Rac1 activation ( Supplemental Figure S5B ) .	Knockdown of Tiam1 suppressed adhesion dependent Rac1 activation (Supplemental Figure S5B).	0	7	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	2	3	6	7
In addition to U251 cells , when we used another glioma LN229 cells that express DOCK180 at a higher level than U251 cells for Rac1 activation , either DOCK180 or Tiam1 depletion attenuated adhesion induced Rac1 activation to a similar degree ( unpublished data ) .	In addition to U251 cells, when we used another glioma LN229 cells that express DOCK180 at a higher level than U251 cells for Rac1 activation, either DOCK180 or Tiam1 depletion attenuated adhesion induced Rac1 activation to a similar degree (unpublished data).	30	36	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	30	31	35	36
Thus , there is a strong possibility that this mechanism may be responsible for our findings that Tiam1 siRNA decreased Rac1 activity and blocked the ability of fasudil to increase Rac1 activity while Tiam2 siRNA decreased Rac1 activity but failed to block the increase of Rac1 activity by fasudil ( XREF_FIG ) .	Thus, there is a strong possibility that this mechanism may be responsible for our findings that Tiam1 siRNA decreased Rac1 activity and blocked the ability of fasudil to increase Rac1 activity while Tiam2 siRNA decreased Rac1 activity but failed to block the increase of Rac1 activity by fasudil (XREF_FIG).	17	21	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	17	18	20	21
Furthermore , functional inactivation of either Tiam1 or Vav2 appears to attenuate sustained activation of Rac1 and its downstream signaling events [ activation of stress kinases ] under conditions of metabolic stress .	Furthermore, functional inactivation of either Tiam1 or Vav2 appears to attenuate sustained activation of Rac1 and its downstream signaling events [activation of stress kinases] under conditions of metabolic stress.	3	16	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	15	16
Analysis of Rac activation in MDCK-f3 cells coexpressing FLTiam1 and Deltap85 gave a decrease of Tiam1 mediated Rac activation by two- to threefold by Deltap85 on a fibronectin as well as on a collagen I substrate ( data not shown ) , consistent with the findings using the PI3-kinase inhibitors .	Analysis of Rac activation in MDCK-f3 cells coexpressing FLTiam1 and Deltap85 gave a decrease of Tiam1 mediated Rac activation by two- to threefold by Deltap85 on a fibronectin as well as on a collagen I substrate (data not shown), consistent with the findings using the PI3-kinase inhibitors.	13	18	mediated	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	15	16	17	18
Based on these findings , these authors concluded that nm23-H1 plays a negative modulatory role in the Tiam1 induced activation of Rac1 [ XREF_BIBR ] .	Based on these findings, these authors concluded that nm23-H1 plays a negative modulatory role in the Tiam1 induced activation of Rac1 [XREF_BIBR].	14	23	induced	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	17	18	21	22
The finding that both Tiam1 and constitutively active RacL61C40 could rescue the spreading defect of Tiam1-/- keratinocytes suggests that this defect is caused by impaired Tiam1 mediated Rac signaling toward the actin cytoskeleton .	The finding that both Tiam1 and constitutively active RacL61C40 could rescue the spreading defect of Tiam1-/- keratinocytes suggests that this defect is caused by impaired Tiam1 mediated Rac signaling toward the actin cytoskeleton.	22	28	mediated	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	25	26	27	28
Furthermore , knockdown of TIAM1 , the Rac1 activating GEF , or Rac1 itself also reduced viral replication .	Furthermore, knockdown of TIAM1, the Rac1 activating GEF, or Rac1 itself also reduced viral replication.	2	13	activating	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TIAM1	TIAM1	TIAM1	Rac1	Rac1	Rac1	4	5	12	13
We report an intriguing mechanism by which the inhibition of ROCK1 indirectly diminishes the activity of upstream RhoA through the stimulation of Tiam1 induced Rac1 activity .	We report an intriguing mechanism by which the inhibition of ROCK1 indirectly diminishes the activity of upstream RhoA through the stimulation of Tiam1 induced Rac1 activity.	20	25	induced	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	22	23	24	25
Both Tiam1 and V12Rac1 can rescue the defects of Tiam1-/- keratinocytes , indicating that these deficiencies are caused by impaired Tiam1 mediated Rac activation .	Both Tiam1 and V12Rac1 can rescue the defects of Tiam1-/- keratinocytes, indicating that these deficiencies are caused by impaired Tiam1 mediated Rac activation.	17	23	mediated	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	20	21	22	23
Expression of catalytically active Tiam1 , but not inactive Tiam1 , rescues the apoptosis susceptibility of Tiam1-KO keratinocytes , indicating that this defect is caused by impaired Tiam1 mediated Rac activation .	Expression of catalytically active Tiam1, but not inactive Tiam1, rescues the apoptosis susceptibility of Tiam1-KO keratinocytes, indicating that this defect is caused by impaired Tiam1 mediated Rac activation.	24	30	mediated	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	27	28	29	30
Down-regulation of Tiam1 inhibited Rac1 activity , cell adhesion , and migration [ XREF_BIBR ] .	Down-regulation of Tiam1 inhibited Rac1 activity, cell adhesion, and migration [XREF_BIBR].	0	5	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	2	3	4	5
Knockdown of Tiam1 , a close homolog of STEF , reduced dbcAMP induced Rac1 activation by half .	Knockdown of Tiam1, a close homolog of STEF, reduced dbcAMP induced Rac1 activation by half.	0	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	2	3	13	14
The impaired Tiam1 mediated Rac activity leads to decreased levels of intracellular reactive oxygen speicies ( ROS ) , which , in turn , blocks ERK phosphorylation and activation [ XREF_BIBR ] .	The impaired Tiam1 mediated Rac activity leads to decreased levels of intracellular reactive oxygen speicies (ROS), which, in turn, blocks ERK phosphorylation and activation [XREF_BIBR].	2	5	mediated	Positive_early_activation	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	2	3	4	5
Loss of the Rac activator Tiam1 , or the downstream WAVE complex component CYFIP1 , can contribute to cell migration , invasion , and metastasis , suggesting that suppression of major regulators of lamellipodia formation can lead to increased metastatic potential .	Loss of the Rac activator Tiam1, or the downstream WAVE complex component CYFIP1, can contribute to cell migration, invasion, and metastasis, suggesting that suppression of major regulators of lamellipodia formation can lead to increased metastatic potential.	0	13	activator	Positive_activation_token_1_noun	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac	Rac	Rac	5	6	3	4
For example , although downregulation of Tiam1 significantly inhibited nerve growth factor ( NGF )-dependent Rac1 activation and neurite outgrowth , Tiam1 phosphorylation was not observed in response to NGF whereas Tiam1 is phosphorylated by TrkB following BDNF stimulation .	For example, although downregulation of Tiam1 significantly inhibited nerve growth factor (NGF)-dependent Rac1 activation and neurite outgrowth, Tiam1 phosphorylation was not observed in response to NGF whereas Tiam1 is phosphorylated by TrkB following BDNF stimulation.	4	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	6	7	15	16
Importantly , both Tiam1 depleted cells in culture and Rac1 deficient epithelial cells invivo escape the mitotic arrest induced by Eg5 suppression .	Importantly, both Tiam1 depleted cells in culture and Rac1 deficient epithelial cells invivo escape the mitotic arrest induced by Eg5 suppression.	2	10	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tiam1	Tiam1	Tiam1	Rac1	Rac1	Rac1	3	4	9	10
In these cells TLR4 ligands caused MyD88 dependent suppression of anti-fibrotic microRNAs ( miR29a and miR29b ) combined with downregulation of the TGF-beta pseudo-receptor BAMBI , resulting in augmented TGF-beta signalling intensity XREF_BIBR .	In these cells TLR4 ligands caused MyD88 dependent suppression of anti-fibrotic microRNAs (miR29a and miR29b) combined with downregulation of the TGF-beta pseudo-receptor BAMBI, resulting in augmented TGF-beta signalling intensity XREF_BIBR.	3	8	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	6	7
Rab26 silencing not only modulated the surface levels of TLR4 but also activated the TLR4 downstream intermediates MyD88 , TRAF6 and NF-kappaB p65 .	Rab26 silencing not only modulated the surface levels of TLR4 but also activated the TLR4 downstream intermediates MyD88, TRAF6 and NF-kappaB p65.	0	22	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	Rab26 silencing not only modulated the surface levels of TLR4	tlr4	MyD88	MyD88	myd88	9	10	17	18
TLR4 deficiency in the cells decreased FA induced augmentation of MyD88 , phospho-p38 , and LPL , suggesting that TLR4 may modulate FA induced lipid metabolism in cardiomyocytes .	TLR4 deficiency in the cells decreased FA induced augmentation of MyD88, phospho-p38, and LPL, suggesting that TLR4 may modulate FA induced lipid metabolism in cardiomyocytes.	0	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	10	11
In EAC breast tumor bearing mice , APS can decrease the tumor weigh , increase immune organ indexes through activation of TLR4 mediated MyD88 dependent signaling pathway [ XREF_BIBR ] .	In EAC breast tumor bearing mice, APS can decrease the tumor weigh, increase immune organ indexes through activation of TLR4 mediated MyD88 dependent signaling pathway [XREF_BIBR].	19	24	mediated	Positive_early_activation	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	21	22	23	24
HO-1 protects liver against I/R injury by inhibiting TLR2 and TLR4 triggered MyD88- and TRIF dependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats .	HO-1 protects liver against I/R injury by inhibiting TLR2 and TLR4 triggered MyD88- and TRIF dependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats.	7	14	triggered	Positive_activation_token_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	10	11	12	13
Further studies indicated that ischemia reperfusion induced liver damage could be improved by inhibiting TLR4 triggered MyD88 and TRIF- dependent pathways .	Further studies indicated that ischemia reperfusion induced liver damage could be improved by inhibiting TLR4 triggered MyD88 and TRIF- dependent pathways.	13	18	triggered	Positive_activation_token_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	14	15	16	17
Furthermore , the group found that melatonin attenuated the TLR4 induced MyD88- and TRIF dependent signaling pathways in rats with ovarian cancer [ XREF_BIBR ] .	Furthermore, the group found that melatonin attenuated the TLR4 induced MyD88- and TRIF dependent signaling pathways in rats with ovarian cancer [XREF_BIBR].	8	16	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	9	10	11	12
These results indicate that dLOS induced TLR4 activation triggers MyD88- and TRIF dependent signaling pathways , though much lower in activity when compared with LPS .	These results indicate that dLOS induced TLR4 activation triggers MyD88- and TRIF dependent signaling pathways, though much lower in activity when compared with LPS.	6	18	triggers	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88-	MyD88-	MyD88-	6	7	9	10
mTOR inhibition restores TLR4 mediated MyD88 dependent TNFalpha release in HIV+ AM .	mTOR inhibition restores TLR4 mediated MyD88 dependent TNFalpha release in HIV+ AM.	3	8	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	3	4	5	6
Hence , from all that mentioned above , the pretreatment with anti-TLR4 mAb inhibited the expressions of TLR4 , decreased the secretion of MyD88 thereby suppressing the activation of NF-kappaBeta , which reduced the inflammatory response to sepsis associated ARDS .	Hence, from all that mentioned above, the pretreatment with anti-TLR4 mAb inhibited the expressions of TLR4, decreased the secretion of MyD88 thereby suppressing the activation of NF-kappaBeta, which reduced the inflammatory response to sepsis associated ARDS.	15	32	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	expressions of TLR4	tlr4	MyD88	MyD88	myd88	17	18	23	24
Under these conditions , TLR4 mediated MyD88 dependent events were inhibited by CMEP-NQ , including the association of MyD88 with IRAK1 , phosphorylation of IRAK1 , TAK1 , and MAPKs ( ERK , JNK and p38 MAPK ) , and activation of NF-kappaB and AP-1 .	Under these conditions, TLR4 mediated MyD88 dependent events were inhibited by CMEP-NQ, including the association of MyD88 with IRAK1, phosphorylation of IRAK1, TAK1, and MAPKs (ERK, JNK and p38 MAPK), and activation of NF-kappaB and AP-1.	4	8	mediated	Positive_early_activation	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	4	5	6	7
In another study , miR-145 was found to target MAL , which is the bridging adaptor between TLR2- and TLR4 mediated MyD88 dependent signaling [ XREF_BIBR ] .	In another study, miR-145 was found to target MAL, which is the bridging adaptor between TLR2- and TLR4 mediated MyD88 dependent signaling [XREF_BIBR].	19	23	mediated	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	19	20	21	22
Compared with mammals , the lack of TLR4 ortholog in some fish species leads us to hypothesize that mechanism of LPS recognition in fish may be different from mammals , and zebrafish TLR4 orthologs negatively regulates the MyD88 dependent signaling pathway post LPS stimulation XREF_BIBR .	Compared with mammals, the lack of TLR4 ortholog in some fish species leads us to hypothesize that mechanism of LPS recognition in fish may be different from mammals, and zebrafish TLR4 orthologs negatively regulates the MyD88 dependent signaling pathway post LPS stimulation XREF_BIBR.	32	44	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	32	33	37	38
Lysakova-Devine et al showed that viral inhibitory peptide of TLR4 specifically inhibited TLR4 by directly targeting MyD88 adaptor like and TRIF related adaptor molecule 30 .	Lysakova-Devine et al showed that viral inhibitory peptide of TLR4 specifically inhibited TLR4 by directly targeting MyD88 adaptor like and TRIF related adaptor molecule 30.	7	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	9	10	16	17
In contrast , IgG 1 levels in TLR4 and MyD88 knockout mice are significantly reduced , indicating TLR4 and MyD88 are essential for IgG 1 production .	In contrast, IgG 1 levels in TLR4 and MyD88 knockout mice are significantly reduced, indicating TLR4 and MyD88 are essential for IgG 1 production.	7	20	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	7	8	19	20
Our results show that LPS signaled via a TLR4- and MyD88 independent manner in fish , and , surprisingly , that the zebrafish TLR4 orthologs negatively regulated the MyD88 dependent signaling pathway .	Our results show that LPS signaled via a TLR4- and MyD88 independent manner in fish, and, surprisingly, that the zebrafish TLR4 orthologs negatively regulated the MyD88 dependent signaling pathway.	23	31	negatively regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	23	24	28	29
In this study , RC-101 , a variant of the humanized theta-defensin RC-1 , blocked TLR4 mediated gene expression in mouse and human macrophages in response to LPS , targeting both MyD88- and TRIF dependent pathways .	In this study, RC-101, a variant of the humanized theta-defensin RC-1, blocked TLR4 mediated gene expression in mouse and human macrophages in response to LPS, targeting both MyD88- and TRIF dependent pathways.	4	35	targeting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	RC-101, a variant of the humanized theta-defensin RC-1, blocked TLR4 mediated gene expression	tlr4	MyD88-	MyD88-	myd88-	15	16	31	32
This difference is consistent with the lack of evidence showing that LPS induced activity of MyD88s inhibits MyD88 mediated TLR4 pathway in human cells .	This difference is consistent with the lack of evidence showing that LPS induced activity of MyD88s inhibits MyD88 mediated TLR4 pathway in human cells.	16	20	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	MyD88 mediated TLR4	tlr4	MyD88	MyD88	myd88	19	20	17	18
TLR4 induces tumor growth and inhibits paclitaxel activity in MyD88 positive human ovarian carcinoma in vitro .	TLR4 induces tumor growth and inhibits paclitaxel activity in MyD88 positive human ovarian carcinoma in vitro.	0	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	MyD88	MyD88	MyD88	0	1	9	10
We currently show that transient focal ischemia in adult rats induces TLR2 and TLR4 expression within hours and shRNA mediated knockdown of TLR2 and TLR4 alone and in combination decreases the infarct size and swelling .	We currently show that transient focal ischemia in adult rats induces TLR2 and TLR4 expression within hours and shRNA mediated knockdown of TLR2 and TLR4 alone and in combination decreases the infarct size and swelling.	11	25	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4 expression	tlr4	TLR4	TLR4	tlr4	13	14	24	25
CLI-095 , also known as TAK-242 , is a cyclohexene derivative that suppresses TLR4 signaling mediated by the intracellular domain of TLR4 , whereas siRNA gene silencing effectively down-regulates overall TLR4 protein expression , which thus reduces TLR4 signaling through both intracellular and extracellular domains .	CLI-095, also known as TAK-242, is a cyclohexene derivative that suppresses TLR4 signaling mediated by the intracellular domain of TLR4, whereas siRNA gene silencing effectively down-regulates overall TLR4 protein expression, which thus reduces TLR4 signaling through both intracellular and extracellular domains.	30	38	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4 protein expression	tlr4	TLR4	TLR4	tlr4	30	31	37	38
We previously demonstrated that TLR4 expression levels and activity ( Myd88 as a marker ) are increased in brainstem of MI induced heart failure , and that blockade of brain angiotensin II type 1 receptor decreased brain TLR4 with the attenuation of LV remodeling and sympathoexcitaion XREF_BIBR .	We previously demonstrated that TLR4 expression levels and activity (Myd88 as a marker) are increased in brainstem of MI induced heart failure, and that blockade of brain angiotensin II type 1 receptor decreased brain TLR4 with the attenuation of LV remodeling and sympathoexcitaion XREF_BIBR.	4	38	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4 expression levels	tlr4	TLR4	TLR4	tlr4	4	5	37	38
Then , the observed suppression of the increase in TLR4 expression in the kidneys of rats fed with (-)-epicatechin could be due to : i ) a prevention of the LPS induced upregulation of TLR4 , as was suggested by dietary administration of a flavonoid rich supplement XREF_BIBR , and/or ii ) a stimulation of TLR4 degradation , as was shown to occur with the addition of epigallocatechin gallate to LPS treated adipocytes XREF_BIBR .	Then, the observed suppression of the increase in TLR4 expression in the kidneys of rats fed with (-)-epicatechin could be due to : i) a prevention of the LPS induced upregulation of TLR4, as was suggested by dietary administration of a flavonoid rich supplement XREF_BIBR, and/or ii) a stimulation of TLR4 degradation, as was shown to occur with the addition of epigallocatechin gallate to LPS treated adipocytes XREF_BIBR.	9	35	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4 expression	tlr4	TLR4	TLR4	tlr4	9	10	34	35
Ibudilast was studied here as it is known to have MIF inhibitor and toll like receptor 4 ( TLR4 ) inhibitor mechanisms of action for neuropathic pain reversal 64 beyond its action as a PDE inhibitor .	Ibudilast was studied here as it is known to have MIF inhibitor and toll like receptor 4 (TLR4) inhibitor mechanisms of action for neuropathic pain reversal 64 beyond its action as a PDE inhibitor.	11	21	inhibitor	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	toll like receptor 4	toll like receptor 4	toll like receptor 4	18	19	13	17
TLR4 mRNA expression was inhibited by IL-4 as early as 6 h but the effect was lost by 24 h. Surface expression of TLR4 was inhibited by IL-4 at 12 and 24 h , but returned to baseline at 48 h. IL-4 inhibited activity of the TLR4 promoter as early as 6 h , but , like the mRNA , these effects were transient .	TLR4 mRNA expression was inhibited by IL-4 as early as 6 h but the effect was lost by 24 h. Surface expression of TLR4 was inhibited by IL-4 at 12 and 24 h, but returned to baseline at 48 h. IL-4 inhibited activity of the TLR4 promoter as early as 6 h, but, like the mRNA, these effects were transient.	0	47	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4 mRNA expression	tlr4	TLR4	TLR4	tlr4	0	1	46	47
The effect of rosiglitazone as the ligand of peroxisome proliferator activated receptor gamma ( PPARgamma ) inhibiting the TLR4 expression in ischemic lobes in partial hepatic ischemia and reperfusion injury ( IRI ) in BALB/C mice and the action of rosiglitazone inhibiting the TLR4 receptor mediated inherent immune response were investigated .	The effect of rosiglitazone as the ligand of peroxisome proliferator activated receptor gamma (PPARgamma) inhibiting the TLR4 expression in ischemic lobes in partial hepatic ischemia and reperfusion injury (IRI) in BALB/C mice and the action of rosiglitazone inhibiting the TLR4 receptor mediated inherent immune response were investigated.	8	44	inhibiting	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	TLR4	peroxisome proliferator activated receptor gamma (PPARgamma) inhibiting the TLR4 expression	tlr4	TLR4	TLR4	tlr4	18	19	43	44
Our results suggest that magnolol exerts an anti-inflammatory property by down-regulated the expression of TLR4 up-regulated by LPS , thereby attenuating TLR4 mediated the activation of NF-kappaB and MAPK signaling and the release of pro inflammatory cytokines .	Our results suggest that magnolol exerts an anti-inflammatory property by down-regulated the expression of TLR4 up-regulated by LPS, thereby attenuating TLR4 mediated the activation of NF-kappaB and MAPK signaling and the release of pro inflammatory cytokines.	12	22	attenuating	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	expression of TLR4	tlr4	TLR4	TLR4	tlr4	14	15	21	22
GMFG knockdown delayed LPS induced TLR4 internalization and caused prolonged TLR4 retention at the early endosome , suggesting that TLR4 transport from early to late endosomes is interrupted , which may contribute to enhanced LPS induced TLR4 signaling .	GMFG knockdown delayed LPS induced TLR4 internalization and caused prolonged TLR4 retention at the early endosome, suggesting that TLR4 transport from early to late endosomes is interrupted, which may contribute to enhanced LPS induced TLR4 signaling.	3	11	caused	Positive_activation_syntax_5_verb	Positive_activation	Positive_activation	TLR4	LPS induced TLR4	tlr4	TLR4	TLR4	tlr4	5	6	10	11
In vitro experiments reveal that OA-NO2 suppresses LPS induced TLR4 signalling , inhibitor of kappaB ( IkappaBalpha ) phosphorylation and ubiquitination , phosphorylation of the IkappaB kinase ( IKK ) , impairing the recruitment of the TLR4 and TNF receptor associated factor 6 ( TRAF6 ) to the lipid rafts compartments .	In vitro experiments reveal that OA-NO2 suppresses LPS induced TLR4 signalling, inhibitor of kappaB (IkappaBalpha) phosphorylation and ubiquitination, phosphorylation of the IkappaB kinase (IKK), impairing the recruitment of the TLR4 and TNF receptor associated factor 6 (TRAF6) to the lipid rafts compartments.	5	39	impairing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	OA-NO2 suppresses LPS induced TLR4 signalling, inhibitor of kappaB (IkappaBalpha) phosphorylation	tlr4	TLR4	TLR4	tlr4	9	10	36	37
, have shown that blocking the endosomal-lysosomal TLR4 trafficking in macrophages causes a decreased TLR4 degradation and an increased plasma membrane TLR4 expression , which leads to a more robust inflammatory response to LPS , similar to what we have observed in CF cells .	, have shown that blocking the endosomal-lysosomal TLR4 trafficking in macrophages causes a decreased TLR4 degradation and an increased plasma membrane TLR4 expression, which leads to a more robust inflammatory response to LPS, similar to what we have observed in CF cells.	4	23	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4 expression	tlr4	TLR4	TLR4	tlr4	21	22	7	8
MiR-145 , a TGF-beta signaling target , decreases miR-20a expression and upregulates TbetaRII through c-Myc .	MiR-145, a TGF-beta signaling target, decreases miR-20a expression and upregulates TbetaRII through c-Myc.	3	13	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGF-beta	TGF-beta	TGF-beta	TbetaRII	TbetaRII	TbetaRII	3	4	12	13
TGFbeta robustly downregulated TbetaRII after 6 and 24 hours of incubation ( XREF_TABLE ) .	TGFbeta robustly downregulated TbetaRII after 6 and 24 hours of incubation (XREF_TABLE).	0	4	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	TbetaRII	TbetaRII	TbetaRII	0	1	3	4
We thus conclude that miR-17-92 cluster could inhibit TGFB pathway induced proliferation inhibition and collagen synthesis in PMCs by directly targeting TGFBR2 , SMAD2 , and SMAD4 .	We thus conclude that miR-17-92 cluster could inhibit TGFB pathway induced proliferation inhibition and collagen synthesis in PMCs by directly targeting TGFBR2, SMAD2, and SMAD4.	8	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TGFB	TGFB	TGFB	TGFBR2	TGFBR2	TGFBR2	8	9	21	22
To determine the effect of heterozygous loss of Tgfbr2 on cell proliferation , clonal and heterogeneous fibroblasts were treated with TGF-beta and analyzed for changes in 3 [ H ] thymidine incorporation .	To determine the effect of heterozygous loss of Tgfbr2 on cell proliferation, clonal and heterogeneous fibroblasts were treated with TGF-beta and analyzed for changes in 3 [H] thymidine incorporation.	6	21	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Tgfbr2	Tgfbr2	Tgfbr2	20	21	8	9
Interestingly , TGF-beta treatment upregulated BAMBI mRNA in glomerular endothelial cells and downregulated TbetaR-II , perhaps as a negative feedback loop .	Interestingly, TGF-beta treatment upregulated BAMBI mRNA in glomerular endothelial cells and downregulated TbetaR-II, perhaps as a negative feedback loop.	2	14	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	TbetaR-II	TbetaR-II	TbetaR-II	2	3	13	14
TGF-beta strongly induced reporter activity in WT stromal cells but TGF-beta induced reporter activity was strongly suppressed in Tgfbr2 KO stromal cells ( XREF_FIG ) .	TGF-beta strongly induced reporter activity in WT stromal cells but TGF-beta induced reporter activity was strongly suppressed in Tgfbr2 KO stromal cells (XREF_FIG).	10	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	Tgfbr2	Tgfbr2	Tgfbr2	10	11	18	19
Experimentally , TGF-beta signalling in fibroblasts was modulated using a TGF-beta ligand and inhibitor or through lentiviral short hairpin RNA mediated TGFBR2 specific knockdown .	Experimentally, TGF-beta signalling in fibroblasts was modulated using a TGF-beta ligand and inhibitor or through lentiviral short hairpin RNA mediated TGFBR2 specific knockdown.	2	23	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	TGFBR2	TGFBR2	TGFBR2	2	3	21	22
It was also of interest that the DTH+ phenotype was associated with the inhibitory member of the TGF-beta super-signaling pathway SMAD7 , which will inhibit TGFBR2 mediated signaling events .	It was also of interest that the DTH+ phenotype was associated with the inhibitory member of the TGF-beta super-signaling pathway SMAD7, which will inhibit TGFBR2 mediated signaling events.	17	28	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	TGFBR2	TGFBR2	TGFBR2	17	18	25	26
Also , the ex vivo effects of TGFbeta on hepatoblasts , and on our earlier in vivo data on the role of TGFbeta in biliary differentiation , lead to the suggestion that TGFbeta promotes biliary differentiation of hepatoblasts and induces repression of TbetaRII .	Also, the ex vivo effects of TGFbeta on hepatoblasts, and on our earlier in vivo data on the role of TGFbeta in biliary differentiation, lead to the suggestion that TGFbeta promotes biliary differentiation of hepatoblasts and induces repression of TbetaRII.	32	43	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFbeta	TGFbeta	TGFbeta	TbetaRII	TbetaRII	TbetaRII	32	33	42	43
The suppressed canonical TGF-beta signaling in the aortic endothelium is modulated by both hypercholesterolemia and dietary trans fats , increasing the localization of TbetaR-I and TbetaR-II in lipid rafts / caveolae in the aortic endothelium of these mice but not in control mice [ XREF_BIBR , XREF_BIBR ] .	The suppressed canonical TGF-beta signaling in the aortic endothelium is modulated by both hypercholesterolemia and dietary trans fats, increasing the localization of TbetaR-I and TbetaR-II in lipid rafts / caveolae in the aortic endothelium of these mice but not in control mice [XREF_BIBR, XREF_BIBR].	3	26	modulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGF-beta	TGF-beta	TGF-beta	TbetaR-II	TbetaR-II	TbetaR-II	3	4	25	26
In addition , ALK5 activated Smad3 repressed the transcriptional activity of SF-1 and LRH-1 as well as Nur77 ( data not shown ) .	In addition, ALK5 activated Smad3 repressed the transcriptional activity of SF-1 and LRH-1 as well as Nur77 (data not shown).	3	6	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	3	4	5	6
Upon treatment , SMAD activation was reduced to control levels , indicating that TbetaRI blocks canonical SMAD3 signaling in patient SSCT fibroblasts .	Upon treatment, SMAD activation was reduced to control levels, indicating that TbetaRI blocks canonical SMAD3 signaling in patient SSCT fibroblasts.	13	17	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TbetaRI	TbetaRI	TbetaRI	SMAD3	SMAD3	SMAD3	13	14	16	17
Accordingly , lack of TbetaRI sumoylation decreases TGF-beta-induced Smad2 and Smad3 activation , and TGF-beta-induced transcription of target genes .	Accordingly, lack of TbetaRI sumoylation decreases TGF-beta-induced Smad2 and Smad3 activation, and TGF-beta-induced transcription of target genes.	4	11	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TbetaRI	TbetaRI sumoylation	tbetari	Smad3	Smad3	smad3	4	5	10	11
Tgfbr1 haploinsufficiency impairs Smad2 and Smad3 signaling .	Tgfbr1 haploinsufficiency impairs Smad2 and Smad3 signaling.	0	6	impairs	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tgfbr1	Tgfbr1	Tgfbr1	Smad3	Smad3	Smad3	0	1	5	6
TGFBR1 and TGFBR2 rescued the miR-130a-3p-mediated reduction in the mRNA and protein expression levels of Smad2 and Smad3 ( XREF_FIG ) .	TGFBR1 and TGFBR2 rescued the miR-130a-3p-mediated reduction in the mRNA and protein expression levels of Smad2 and Smad3 (XREF_FIG).	0	18	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFBR1	TGFBR1	TGFBR1	Smad3	Smad3	Smad3	0	1	17	18
ALK5 activated Smad3 represses Nur77 transactivation .	ALK5 activated Smad3 represses Nur77 transactivation.	0	3	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	0	1	2	3
We demonstrate that ALK5 activated Smad3 inhibits the transactivation of Nur77 through the inhibition of Nur77 binding to DNA , resulting in decreased expression of steroidogenic genes .	We demonstrate that ALK5 activated Smad3 inhibits the transactivation of Nur77 through the inhibition of Nur77 binding to DNA, resulting in decreased expression of steroidogenic genes.	3	6	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	3	4	5	6
Taken together , these results suggest that ALK5 activated Smad3 , downstream of TGF-beta1 signaling , inhibits Nur77 transactivation .	Taken together, these results suggest that ALK5 activated Smad3, downstream of TGF-beta1 signaling, inhibits Nur77 transactivation.	7	16	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	7	8	9	10
The coexpression of Smad3 with ALK5 ( TD ) , but not ALK5 ( WT ) and ALK5 ( KR ) , further inhibited Nur77 transactivation ( XREF_FIG ) , suggesting that ALK5 activated Smad3 represses Nur77 transactivation .	The coexpression of Smad3 with ALK5 (TD), but not ALK5 (WT) and ALK5 (KR), further inhibited Nur77 transactivation (XREF_FIG), suggesting that ALK5 activated Smad3 represses Nur77 transactivation.	32	35	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ALK5	ALK5	ALK5	Smad3	Smad3	Smad3	32	33	34	35
This may be because the TLR4 mediated fibrogenic response , such as the up-regulation of Timp-1 and the down-regulation of Bambi , is not inhibited in TRIF -/- HSCs .	This may be because the TLR4 mediated fibrogenic response, such as the up-regulation of Timp-1 and the down-regulation of Bambi, is not inhibited in TRIF -/- HSCs.	4	28	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	5	6	26	27
Previous work provided evidence indicating that resveratrol acts by specifically inhibiting the TLR4 mediated TRIF dependent pathway , without affecting the MyD88 dependent pathway .	Previous work provided evidence indicating that resveratrol acts by specifically inhibiting the TLR4 mediated TRIF dependent pathway, without affecting the MyD88 dependent pathway.	10	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	12	13	14	15
Thus , the WALK11.3 peptide showed specific inhibition of TLR4 mediated TRIF dependent signaling .	Thus, the WALK11.3 peptide showed specific inhibition of TLR4 mediated TRIF dependent signaling.	7	13	mediated	Positive_early_activation	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	9	10	11	12
Dexmedetomidine preconditioning inhibited the expression of TLR4 and NF-kappaB and increased that of TRIF .	Dexmedetomidine preconditioning inhibited the expression of TLR4 and NF-kappaB and increased that of TRIF.	0	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR4	Dexmedetomidine preconditioning inhibited the expression of TLR4	tlr4	TRIF	TRIF	trif	6	7	13	14
TAK-242 inhibits the TLR4 induced TRIF signaling pathway as well as the MyD88 dependent pathway [ XREF_BIBR ] .	TAK-242 inhibits the TLR4 induced TRIF signaling pathway as well as the MyD88 dependent pathway [XREF_BIBR].	2	7	induced	Positive_early_activation	Positive_activation	Positive_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	3	4	5	6
In HSCs , activated TLR4 signaling downregulates TGF-beta pseudoreceptor BMP and activin membrane bound inhibitor ( BAMBI ) , resulting in enhancement of TGF-beta signaling , whereas BAMBI downregulation is dependent on MyD88 but not TRIF [ XREF_BIBR , XREF_BIBR ] .	In HSCs, activated TLR4 signaling downregulates TGF-beta pseudoreceptor BMP and activin membrane bound inhibitor (BAMBI), resulting in enhancement of TGF-beta signaling, whereas BAMBI downregulation is dependent on MyD88 but not TRIF [XREF_BIBR, XREF_BIBR].	4	37	downregulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR4	TLR4	TLR4	TRIF	TRIF	TRIF	4	5	35	36
TGFBR1 and TGFBR2 rescued the miR-130a-3p-mediated reductions in the mRNA and protein expression levels of Smad2 , Smad3 , Col-1 , and Col-4 .	TGFBR1 and TGFBR2 rescued the miR-130a-3p-mediated reductions in the mRNA and protein expression levels of Smad2, Smad3, Col-1, and Col-4.	0	22	rescued	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TGFBR1	TGFBR1	TGFBR1	Smad2	Smad2	Smad2	0	1	15	16
SB431542 inhibits the kinase activity of TGFbeta specific receptor ALK5 thereby blocking SMAD2 signaling but spares SMAD1/5/8 signaling used by BMPs 54 .	SB431542 inhibits the kinase activity of TGFbeta specific receptor ALK5 thereby blocking SMAD2 signaling but spares SMAD1/5/8 signaling used by BMPs 54.	4	13	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ALK5	ALK5	ALK5	SMAD2	SMAD2	SMAD2	9	10	12	13
Alternatively , Lyp may serve to dephosphorylate an inhibitor of TLR signaling , thereby promoting TLR responses , and Lyp620W may be more effective at turning off this inhibitory pathway .	Alternatively, Lyp may serve to dephosphorylate an inhibitor of TLR signaling, thereby promoting TLR responses, and Lyp620W may be more effective at turning off this inhibitory pathway.	2	16	promoting	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	Lyp may serve to dephosphorylate an inhibitor of TLR	tlr	TLR	TLR	tlr	10	11	15	16
On differentiating monocytes , IVIg promotes the acquisition of altered transcriptional and cytokine profiles , reduces TLR expression and signaling , and upregulates negative regulators of TLR initiated intracellular signaling .	On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR initiated intracellular signaling.	4	27	upregulates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR	IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression	tlr	TLR	TLR	tlr	16	17	26	27
In both glial cell types , LPS stimulation upregulated pro inflammatory cytokines , TLR 2 and TLR 3 gene expression but down-regulated other TLR genes .	In both glial cell types, LPS stimulation upregulated pro inflammatory cytokines, TLR 2 and TLR 3 gene expression but down-regulated other TLR genes.	6	24	down-regulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR	LPS stimulation upregulated pro inflammatory cytokines, TLR 2 and TLR 3 gene expression	tlr	TLR	TLR	tlr	16	17	23	24
Macrophages deficient in CD11b have reduced TLR induced degradation of MyD88 and TRIF resulting in enhanced activation of NFkappaB and other TLR dependent pathways and inflammatory cytokine production .	Macrophages deficient in CD11b have reduced TLR induced degradation of MyD88 and TRIF resulting in enhanced activation of NFkappaB and other TLR dependent pathways and inflammatory cytokine production.	6	13	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	6	7	12	13
For example , SARM negatively regulates TRIF dependent TLRs signaling XREF_BIBR , and Integrin CD11b negatively regulates TLR induced inflammatory responses by targeting MyD88 and TRIF for degradation XREF_BIBR .	For example, SARM negatively regulates TRIF dependent TLRs signaling XREF_BIBR, and Integrin CD11b negatively regulates TLR induced inflammatory responses by targeting MyD88 and TRIF for degradation XREF_BIBR.	17	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	17	18	25	26
Sterile alpha and Toll and IL-1R motif containing 1 ( SARM1 ) negatively regulates TRIF dependent TLR signaling in mammals .	Sterile alpha and Toll and IL-1R motif containing 1 (SARM1) negatively regulates TRIF dependent TLR signaling in mammals.	12	17	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TLR	TLR	TLR	TRIF	TRIF	TRIF	16	17	14	15
Using MAPPIT analysis , the conserved proline 125 mutant of MAL and TIRAP was reported to prevent MAL and TIRAP homodimerization , heterodimerization with MyD88 and interaction of MyD88 with TLR4 [ XREF_BIBR ] suggesting its role for the abrogated TLR signaling .	Using MAPPIT analysis, the conserved proline 125 mutant of MAL and TIRAP was reported to prevent MAL and TIRAP homodimerization, heterodimerization with MyD88 and interaction of MyD88 with TLR4 [XREF_BIBR] suggesting its role for the abrogated TLR signaling.	8	32	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	12	13	28	29
In the other individuals , IgG dependent , adaptive immunity to LTA operates as a somatic modifier , selectively rescuing the inborn error of TIRAP , which disrupts TLR2-, TIRAP-, and MyD88 dependent innate immunity to LTA and staphylococci .	In the other individuals, IgG dependent, adaptive immunity to LTA operates as a somatic modifier, selectively rescuing the inborn error of TIRAP, which disrupts TLR2-, TIRAP-, and MyD88 dependent innate immunity to LTA and staphylococci.	22	34	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TIRAP	TIRAP	TIRAP	MyD88	MyD88	MyD88	24	25	31	32
We used an inducible Cre-loxP system driven by a Myh11 promoter XREF_BIBR to delete SMC specific Tgfbr1 ( Tgfbr1 iko ) , Tgfbr2 ( Tgfbr2 iko ) , or both Tgfbr1 and Tgfbr2 ( Tgfbr1 iko .	We used an inducible Cre-loxP system driven by a Myh11 promoter XREF_BIBR to delete SMC specific Tgfbr1 (Tgfbr1 iko), Tgfbr2 (Tgfbr2 iko), or both Tgfbr1 and Tgfbr2 (Tgfbr1 iko.	1	25	driven	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Tgfbr2	Tgfbr2	Tgfbr2	Tgfbr1	Tgfbr1	Tgfbr1	22	23	16	17
Similarly , suppression of TNF induced AKT activation by curcumin was also abrogated by glutathione .	Similarly, suppression of TNF induced AKT activation by curcumin was also abrogated by glutathione.	2	7	induced	Positive_early_activation	Positive_activation	Negative_activation	TNF	TNF	TNF	AKT	AKT	AKT	4	5	6	7
Increased levels of Tumor Necrosis Factor alpha ( TNF-alpha ) have been shown to suppress the AKT and mTOR ( mammalian target of rapamyosin ) pathway , a crucial pathway for regulating skeletal muscle hypertrophy and thereby increase muscle catabolism [ XREF_BIBR - XREF_BIBR ] .	Increased levels of Tumor Necrosis Factor alpha (TNF-alpha) have been shown to suppress the AKT and mTOR (mammalian target of rapamyosin) pathway, a crucial pathway for regulating skeletal muscle hypertrophy and thereby increase muscle catabolism [XREF_BIBR - XREF_BIBR].	1	25	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tumor Necrosis Factor	levels of Tumor Necrosis Factor	tumor necrosis factor	AKT	AKT	akt	3	6	16	17
The anti-tumorigenic cytokine TNF-alpha can inhibit GSK-3beta activity by stimulating Akt to phosphorylate GSK-3beta at S9 in renal carcinoma cells ( RCC ) .	The anti-tumorigenic cytokine TNF-alpha can inhibit GSK-3beta activity by stimulating Akt to phosphorylate GSK-3beta at S9 in renal carcinoma cells (RCC).	0	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	3	4	10	11
The inhibition of TNFalpha induced AKT activation often leads to the activation of TNFalpha mediated apoptosis .	The inhibition of TNFalpha induced AKT activation often leads to the activation of TNFalpha mediated apoptosis.	1	6	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	3	4	5	6
Our observation that Sulindac and TNFalpha combination synergistically induced apoptosis and inhibited AKT activation suggested that AKT activity might be critical for their induction of apoptosis .	Our observation that Sulindac and TNFalpha combination synergistically induced apoptosis and inhibited AKT activation suggested that AKT activity might be critical for their induction of apoptosis.	5	13	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	5	6	12	13
In this study , we reveal a novel function of API-1 in regulation of c-FLIP levels and tumor necrosis factor related apoptosis inducing ligand ( TRAIL )-induced apoptosis , independent of Akt inhibition .	In this study, we reveal a novel function of API-1 in regulation of c-FLIP levels and tumor necrosis factor related apoptosis inducing ligand (TRAIL)-induced apoptosis, independent of Akt inhibition.	17	32	inducing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	Akt	Akt	Akt	17	20	31	32
We analyzed whether overexpression of constitutively active AKT reversed D11 mediated inhibition of NF-kappaB in cells treated with TNFalpha .	We analyzed whether overexpression of constitutively active AKT reversed D11 mediated inhibition of NF-kappaB in cells treated with TNFalpha.	3	19	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	18	19	7	8
Transfection of RXRalpha siRNA in A549 cells , which reduced both the full-length RXRalpha and tRXRalpha expression , abolished the inhibitory effect of N-6 on TNFalpha induced AKT activation .	Transfection of RXRalpha siRNA in A549 cells, which reduced both the full-length RXRalpha and tRXRalpha expression, abolished the inhibitory effect of N-6 on TNFalpha induced AKT activation.	23	28	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	25	26	27	28
In one study , enhanced gene expression of IL-6 and decreased levels of insulin signaling pathway and Akt pathway was observed when enterocytes were treated with TNF-alpha XREF_BIBR .	In one study, enhanced gene expression of IL-6 and decreased levels of insulin signaling pathway and Akt pathway was observed when enterocytes were treated with TNF-alpha XREF_BIBR.	17	27	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	26	27	17	18
Furthermore , PI3K and Akt inhibition significantly promoted the proliferation potential of NP cells treated with TNF-alpha ( XREF_FIG ) , whereas there was no significant difference in cell viability before and after inhibiting the activation of the PI3K and Akt pathway ( XREF_SUPPLEMENTARY ) .	Furthermore, PI3K and Akt inhibition significantly promoted the proliferation potential of NP cells treated with TNF-alpha (XREF_FIG), whereas there was no significant difference in cell viability before and after inhibiting the activation of the PI3K and Akt pathway (XREF_SUPPLEMENTARY).	2	18	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	16	17	4	5
In addition , inhibiting AKT phosphorylation in cultured normal human keratinocytes treated with TNF-alpha in the presence of a PI3K inhibitor resulted in a significant decrease in NF-kappaB phosphorylation with an increase in apoptotic cells .	In addition, inhibiting AKT phosphorylation in cultured normal human keratinocytes treated with TNF-alpha in the presence of a PI3K inhibitor resulted in a significant decrease in NF-kappaB phosphorylation with an increase in apoptotic cells.	4	14	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	AKT	AKT	AKT	13	14	4	5
TNF-alpha is also reported to suppress the Akt and mTOR pathway [ XREF_BIBR ] , promoting muscle catabolism , oxidative stress , and nitric acid production [ XREF_BIBR , XREF_BIBR ] .	TNF-alpha is also reported to suppress the Akt and mTOR pathway [XREF_BIBR], promoting muscle catabolism, oxidative stress, and nitric acid production [XREF_BIBR, XREF_BIBR].	0	10	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	0	1	7	8
For example , elevated levels of tumor necrosis factor alpha ( TNF-alpha ) were found to increase muscle catabolism by suppressing the Akt and mammalian target of rapamycin ( mTOR ) pathway .	For example, elevated levels of tumor necrosis factor alpha (TNF-alpha) were found to increase muscle catabolism by suppressing the Akt and mammalian target of rapamycin (mTOR) pathway.	4	25	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor necrosis factor	levels of tumor necrosis factor	tumor necrosis factor	Akt	Akt	akt	6	9	22	23
The detailed molecular mechanism underlying this enhancement of doxorubicin induced cell death by TNFalpha remains unclear , but since TNFalpha was found to elicit an increase in early JNK and p53 signaling and a loss of late AKT signaling , interplay between these pathways may be implicated in the observed enhancement of cell death .	The detailed molecular mechanism underlying this enhancement of doxorubicin induced cell death by TNFalpha remains unclear, but since TNFalpha was found to elicit an increase in early JNK and p53 signaling and a loss of late AKT signaling, interplay between these pathways may be implicated in the observed enhancement of cell death.	19	38	elicit	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	19	20	37	38
Firstly , TNF-alpha can attenuate PI3K and Akt dependent cell survival signalling through phosphorylation of IRS-1 at Serine 307 [ XREF_BIBR ] and activation of p38 MAPK and I-kappaB kinase beta ( IKKbeta ) [ XREF_BIBR ] .	Firstly, TNF-alpha can attenuate PI3K and Akt dependent cell survival signalling through phosphorylation of IRS-1 at Serine 307 [XREF_BIBR] and activation of p38 MAPK and I-kappaB kinase beta (IKKbeta) [XREF_BIBR].	2	11	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	2	3	7	8
Similarly , suppression of TNF induced Akt ( a serine/threonine kinase ) activation by curcumin was also countered by GSH .	Similarly, suppression of TNF induced Akt (a serine/threonine kinase) activation by curcumin was also countered by GSH.	2	17	induced	Positive_early_activation	Positive_activation	Negative_activation	TNF	TNF	TNF	Akt	Akt	Akt	4	5	6	7
Consistently , compound 30 showed a better effect on the inhibition of TNFalpha induced AKT activation .	Consistently, compound 30 showed a better effect on the inhibition of TNFalpha induced AKT activation.	10	15	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	12	13	14	15
The conformational change of tRXRalpha induced by N-6 disrupted the interaction of tRXRalpha and p85alpha , leading to the inhibition of TNFalpha induced AKT activation .	The conformational change of tRXRalpha induced by N-6 disrupted the interaction of tRXRalpha and p85alpha, leading to the inhibition of TNFalpha induced AKT activation.	19	24	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	21	22	23	24
In addition , TNF-alpha might also promote autophagy by inhibiting activation of the Akt pathway .	In addition, TNF-alpha might also promote autophagy by inhibiting activation of the Akt pathway.	3	14	promote	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	3	4	13	14
Intraplantar carrageenan induced a prolonged increase in P-Akt , presumably mediated via PI-3K activation , which was blocked by TNF antagonism .	Intraplantar carrageenan induced a prolonged increase in P-Akt, presumably mediated via PI-3K activation, which was blocked by TNF antagonism.	2	20	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	P-Akt	P-Akt	P-Akt	19	20	7	8
Inhibition of TNFalpha induced AKT activation by Sulindac and analogs in cancer cells led to a shift of TNFalpha signaling from survival to death .	Inhibition of TNFalpha induced AKT activation by Sulindac and analogs in cancer cells led to a shift of TNFalpha signaling from survival to death.	0	5	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	2	3	4	5
Immunoblotting showed that K-80003 was much more effective than Sulindac in inhibiting RA- and TNFalpha induced AKT activation ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Immunoblotting showed that K-80003 was much more effective than Sulindac in inhibiting RA- and TNFalpha induced AKT activation (XREF_FIG and XREF_SUPPLEMENTARY).	11	17	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	14	15	16	17
The role of tRXRalpha in triptolide inhibition of TNF induced AKT activation was then determined by studying the effect of triptolide on TNFalpha induced tRXRalpha interaction with p85alpha , an event that leads to activation of the PI3K and AKT pathway XREF_BIBR .	The role of tRXRalpha in triptolide inhibition of TNF induced AKT activation was then determined by studying the effect of triptolide on TNFalpha induced tRXRalpha interaction with p85alpha, an event that leads to activation of the PI3K and AKT pathway XREF_BIBR.	6	11	induced	Positive_early_activation	Positive_activation	Negative_activation	TNF	TNF	TNF	AKT	AKT	AKT	8	9	10	11
As shown in XREF_FIG , TNF-alpha induced Akt activation in a time dependent manner and alpha-tomatine suppressed this activation as effectively as Akt inhibitor VIII with no significant effect on the expression of total Akt protein .	As shown in XREF_FIG, TNF-alpha induced Akt activation in a time dependent manner and alpha-tomatine suppressed this activation as effectively as Akt inhibitor VIII with no significant effect on the expression of total Akt protein.	5	8	induced	Positive_early_activation	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	5	6	7	8
Artesunate reduced methacholine induced airway hyper-responsiveness , suppressed pulmonary inflammation cell recruitment and IL-4 , IL-8 , IL-13 and TNF-alpha levels , selectively inhibited PI3Kdelta and Akt pathway , and restored HDAC2 activity .	Artesunate reduced methacholine induced airway hyper-responsiveness, suppressed pulmonary inflammation cell recruitment and IL-4, IL-8, IL-13 and TNF-alpha levels, selectively inhibited PI3Kdelta and Akt pathway, and restored HDAC2 activity.	2	27	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	methacholine induced airway hyper-responsiveness, suppressed pulmonary inflammation cell recruitment and IL-4, IL-8, IL-13 and TNF-alpha levels	tnf-alpha	Akt	Akt	akt	19	20	26	27
TNF-alpha induces C2C12 myotube apoptosis and atrophy XREF_BIBR and also inactivates the PI-3K and Akt signaling pathway and induces L6 myotube atrophy XREF_BIBR .	TNF-alpha induces C2C12 myotube apoptosis and atrophy XREF_BIBR and also inactivates the PI-3K and Akt signaling pathway and induces L6 myotube atrophy XREF_BIBR.	0	16	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	0	1	14	15
In comparison , processing of Nrg1 type III by ADAM17 ( or TNF-alpha converting enzyme , TACE ) generates an NTF that attenuates erbB receptor signaling and inhibits Akt activation , indicating its role as a negative regulator of the axonal Nrg1 signaling .	In comparison, processing of Nrg1 type III by ADAM17 (or TNF-alpha converting enzyme, TACE) generates an NTF that attenuates erbB receptor signaling and inhibits Akt activation, indicating its role as a negative regulator of the axonal Nrg1 signaling.	18	29	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	NTF	NTF	NTF	Akt	Akt	Akt	20	21	28	29
In support of this conclusion , we showed that knocking down RXRalpha expression by RXRalpha siRNA impaired its inhibitory effects on basal and TNFalpha induced AKT activation ( XREF_FIG ) , while overexpression of tRXRalpha resulted in an enhancement ( XREF_FIG ) .	In support of this conclusion, we showed that knocking down RXRalpha expression by RXRalpha siRNA impaired its inhibitory effects on basal and TNFalpha induced AKT activation (XREF_FIG), while overexpression of tRXRalpha resulted in an enhancement (XREF_FIG).	16	26	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	23	24	25	26
CF31 inhibition of TNFalpha activation of AKT also results in TNFalpha dependent activation of caspase-8 and apoptosis .	CF31 inhibition of TNFalpha activation of AKT also results in TNFalpha dependent activation of caspase-8 and apoptosis.	3	7	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	3	4	6	7
Additionally , TNF-alpha antagonizes the insulin and Akt signal transduction , thus leading to activation of FOXO1 , which is capable of mediating a transcriptional activation role in response to TNF-alpha on CCL20 gene expression in HepG2 cells and promotes lymphocyte chemotaxis .	Additionally, TNF-alpha antagonizes the insulin and Akt signal transduction, thus leading to activation of FOXO1, which is capable of mediating a transcriptional activation role in response to TNF-alpha on CCL20 gene expression in HepG2 cells and promotes lymphocyte chemotaxis.	2	39	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	2	3	7	8
Our observation that Sulindac and TNFalpha synergistically inhibit tRXRalpha dependent AKT activation provides insight into the crosstalk between retinoid receptor and TNFalpha signaling pathways .	Our observation that Sulindac and TNFalpha synergistically inhibit tRXRalpha dependent AKT activation provides insight into the crosstalk between retinoid receptor and TNFalpha signaling pathways.	3	11	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	5	6	10	11
The interaction of the LxxLL like motif in p85alpha with the coactivator binding groove of tRXRalpha is biologically relevant as TNFalpha induced activation of AKT in cells transfected with tRXRalpha and p85alpha was inhibited by cotransfection of BCR but not BCR mutant , similar to the inhibitory effect of K-80003 ( XREF_SUPPLEMENTARY ) .	The interaction of the LxxLL like motif in p85alpha with the coactivator binding groove of tRXRalpha is biologically relevant as TNFalpha induced activation of AKT in cells transfected with tRXRalpha and p85alpha was inhibited by cotransfection of BCR but not BCR mutant, similar to the inhibitory effect of K-80003 (XREF_SUPPLEMENTARY).	20	26	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	20	21	24	25
Several previous studies have confirmed that TNF-alpha at the elevated level can increase catabolism in skeletal muscle by suppressing Akt and mTOR pathway [ XREF_BIBR ] .	Several previous studies have confirmed that TNF-alpha at the elevated level can increase catabolism in skeletal muscle by suppressing Akt and mTOR pathway [XREF_BIBR].	6	24	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	6	7	19	20
Thus , the inhibitory effect of N-6 on TNFalpha induced AKT activation might rely on its disruption of the interaction of tRXRalpha with p85alpha .	Thus, the inhibitory effect of N-6 on TNFalpha induced AKT activation might rely on its disruption of the interaction of tRXRalpha with p85alpha.	6	11	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	8	9	10	11
As the possible mechanisms , gamma2pf activated ERK and p38 MAPK but inactivated Akt in HUVECs .	As the possible mechanisms, gamma2pf activated ERK and p38 MAPK but inactivated Akt in HUVECs.	5	14	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	gamma2pf	gamma2pf	gamma2pf	Akt	Akt	Akt	5	6	13	14
These results suggested that PL-PTX may be associated with ovarian cancer metastasis , which is mediated by the TNF induced inhibition of the ERK and AKT signaling pathway .	These results suggested that PL-PTX may be associated with ovarian cancer metastasis, which is mediated by the TNF induced inhibition of the ERK and AKT signaling pathway.	18	27	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	TNF	TNF	TNF	AKT	AKT	AKT	18	19	25	26
Therefore , PL-PTX is more efficient compared with PTX in inhibiting tumor growth in vivo by mediating the ERK and AKT signaling inhibited by TNF .	Therefore, PL-PTX is more efficient compared with PTX in inhibiting tumor growth in vivo by mediating the ERK and AKT signaling inhibited by TNF.	18	25	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	AKT	AKT	AKT	24	25	20	21
Finally , because TNF activated AKT targets NFkappaB , which is a well-known mediator of TNF responses [ XREF_BIBR - XREF_BIBR ] that control SC fate [ XREF_BIBR ] , and because NFkappaB can target AKT [ XREF_BIBR , XREF_BIBR ] , evidencing a cross-talk between these pathways [ XREF_BIBR , XREF_BIBR ] , we used the NFkappaB inhibitor BAY 11-7082 in combination with TNF to form melanospheres .	Finally, because TNF activated AKT targets NFkappaB, which is a well-known mediator of TNF responses [XREF_BIBR - XREF_BIBR] that control SC fate [XREF_BIBR], and because NFkappaB can target AKT [XREF_BIBR, XREF_BIBR], evidencing a cross-talk between these pathways [XREF_BIBR, XREF_BIBR], we used the NFkappaB inhibitor BAY 11-7082 in combination with TNF to form melanospheres.	3	7	activated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	3	4	5	6
To functionally inhibit and activate potential signaling pathways , we utilized LY29400 and IGF -1 ( a specific inhibitor and activator , respectively , of the PI3K and Akt pathway ) and PDTC and TNF-alpha ( a specific inhibitor and activator , respectively , of NF-kappaB signaling ) .	To functionally inhibit and activate potential signaling pathways, we utilized LY29400 and IGF -1 (a specific inhibitor and activator, respectively, of the PI3K and Akt pathway) and PDTC and TNF-alpha (a specific inhibitor and activator, respectively, of NF-kappaB signaling).	13	35	inhibitor	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	34	35	28	29
However , when cells were cotreated with either K-8008 or K-8012 , the TNFalpha induced AKT activation was suppressed in a dose dependent manner ( XREF_FIG ) .	However, when cells were cotreated with either K-8008 or K-8012, the TNFalpha induced AKT activation was suppressed in a dose dependent manner (XREF_FIG).	12	16	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	13	14	15	16
Moreover , IGF-1 administration restored the activation of Akt and p70 S6 kinase ( S6K ) suppressed by higher concentration of TNF-alpha ( 10ng/mL ) challenge .	Moreover, IGF-1 administration restored the activation of Akt and p70 S6 kinase (S6K) suppressed by higher concentration of TNF-alpha (10ng/mL) challenge.	8	23	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	Akt	Akt	Akt	21	22	8	9
These data demonstrate that PI3K and AKT inactivation stimulated melanoma GFP high cell differentiation , suggesting that TNF suppresses their commitment to the differentiation fate by activating AKT , consequently preventing asymmetric self-renewal and promoting symmetric self-renewal of GFP high melanoma SCs .	These data demonstrate that PI3K and AKT inactivation stimulated melanoma GFP high cell differentiation, suggesting that TNF suppresses their commitment to the differentiation fate by activating AKT, consequently preventing asymmetric self-renewal and promoting symmetric self-renewal of GFP high melanoma SCs.	17	28	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	AKT	AKT	AKT	17	18	27	28
The fact that Sulindac and TNFalpha synergistically inhibit AKT activation in cancer cells implies that TNFalpha and probably other cytokines can prime cancer cells for their responsiveness to RXRalpha ligands such as Sulindac by converting AKT activation from a RXRalpha independent to a RXRalpha dependent manner .	The fact that Sulindac and TNFalpha synergistically inhibit AKT activation in cancer cells implies that TNFalpha and probably other cytokines can prime cancer cells for their responsiveness to RXRalpha ligands such as Sulindac by converting AKT activation from a RXRalpha independent to a RXRalpha dependent manner.	3	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	5	6	8	9
The TNF induced activation of AKT and S6K1 could be blocked by Torin-1 and PP242 ( XREF_FIG B ) , two specific inhibitors of both mTORC1 and mTORC2 functions , indicating that TNF specifically activates AKT and S6K1 via mTOR .	The TNF induced activation of AKT and S6K1 could be blocked by Torin-1 and PP242 (XREF_FIG B), two specific inhibitors of both mTORC1 and mTORC2 functions, indicating that TNF specifically activates AKT and S6K1 via mTOR.	32	39	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	AKT	AKT	AKT	32	33	35	36
The results showed that gamma2pf weakly activated ERK and p38 MAPK but inactivated Akt in HUVECs ( XREF_SUPPLEMENTARY ) .	The results showed that gamma2pf weakly activated ERK and p38 MAPK but inactivated Akt in HUVECs (XREF_SUPPLEMENTARY).	4	14	inactivated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	gamma2pf	gamma2pf	gamma2pf	Akt	Akt	Akt	4	5	13	14
Inhibition of Mcl-1 by EGCG triggered caspase 3 activity in RA synovial fibroblasts , which was mediated via down-regulation of the TNFalpha induced Akt and NF-kappaB pathways .	Inhibition of Mcl-1 by EGCG triggered caspase 3 activity in RA synovial fibroblasts, which was mediated via down-regulation of the TNFalpha induced Akt and NF-kappaB pathways.	18	26	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	Akt	Akt	Akt	21	22	23	24
The pro inflammatory cytokines IL-1beta and TNFalpha have been shown to induce apoptosis by inhibiting the activity of AKT .	The pro inflammatory cytokines IL-1beta and TNFalpha have been shown to induce apoptosis by inhibiting the activity of AKT.	4	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	AKT	AKT	AKT	6	7	18	19
MTX , SSZ , infliximab , and IL-4 each inhibited the expression of RANKL in RA FLS in a dose dependent manner , and also increased the secretion of OPG in RA FLS supernatants .	MTX, SSZ, infliximab, and IL-4 each inhibited the expression of RANKL in RA FLS in a dose dependent manner, and also increased the secretion of OPG in RA FLS supernatants.	0	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	MTX, SSZ, infliximab, and IL-4 each inhibited the expression of RANKL	rankl	OPG	OPG	opg	13	14	29	30
The lowered serum estrogen concentrations decrease the expression of ERalpha , ERbeta and OPG , raise the expression of RANKL of condylar cartilage and reduce the proportion of OPG and RANKL .	The lowered serum estrogen concentrations decrease the expression of ERalpha, ERbeta and OPG, raise the expression of RANKL of condylar cartilage and reduce the proportion of OPG and RANKL.	3	30	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	estrogen concentrations decrease the expression of ERalpha, ERbeta and OPG, raise the expression of RANKL	rankl	OPG	OPG	opg	19	20	28	29
Meanwhile , dexamethasone dose-dependently ( 10 -6 M-10 -4 M ) increased GILZ and RANKL expression and reduced ALP , OPG and OC , but the pattern of mRNA expression was reversed when icariin was added .	Meanwhile, dexamethasone dose-dependently (10 -6 M-10 -4 M) increased GILZ and RANKL expression and reduced ALP, OPG and OC, but the pattern of mRNA expression was reversed when icariin was added.	2	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	dexamethasone dose-dependently (10 -6 M-10 -4 M) increased GILZ and RANKL expression	rankl	OPG	OPG	opg	14	15	20	21
PTH simultaneously stimulates RANK-L expression and inhibits OPG production [ XREF_BIBR , XREF_BIBR ] .	PTH simultaneously stimulates RANK-L expression and inhibits OPG production [XREF_BIBR, XREF_BIBR].	0	8	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANK-L	PTH simultaneously stimulates RANK-L expression	rank-l	OPG	OPG	opg	3	4	7	8
MyD88 deficiency markedly inhibited RANKL expression after LPS stimulation and increased OPG messenger RNA ( mRNA ) production .	MyD88 deficiency markedly inhibited RANKL expression after LPS stimulation and increased OPG messenger RNA (mRNA) production.	0	13	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	MyD88 deficiency markedly inhibited RANKL expression	rankl	OPG	OPG	opg	4	5	11	12
In summary , our study showed that ( i ) exogenous IL-17 induced autocrine IL-17 production , IFN-gamma synthesis , and RANKL expression on blood neutrophils from nonarthritic mice and these effects were inhibited upon simultaneous TLR2 stimulation ; ( ii ) Ly6G + CD11b + cells from arthritic group produced IL-17 , IFN-gamma , and OPG spontaneously and expressed RANKL ; ( iii ) TLR2 increased IL-17-mediated RANKL expression and inhibited OPG secretion by neutrophils from arthritic mice .	In summary, our study showed that (i) exogenous IL-17 induced autocrine IL-17 production, IFN-gamma synthesis, and RANKL expression on blood neutrophils from nonarthritic mice and these effects were inhibited upon simultaneous TLR2 stimulation; (ii) Ly6G + CD11b + cells from arthritic group produced IL-17, IFN-gamma, and OPG spontaneously and expressed RANKL; (iii) TLR2 increased IL-17-mediated RANKL expression and inhibited OPG secretion by neutrophils from arthritic mice.	65	73	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	TLR2 increased IL-17-mediated RANKL expression	rankl	OPG	OPG	opg	68	69	72	73
Dasatinib significantly increased the activity of ALP and the level of calcium deposition in MSC cultured with DAG after , respectively , 7 and 14 days ; it upregulated the expression of BSP and OPN genes independently of DAG ; and it markedly downregulated the expression of RANKL gene and protein ( decrease in RANKL and OPG ratio ) , the key factor that stimulates osteoclast differentiation and activity .	Dasatinib significantly increased the activity of ALP and the level of calcium deposition in MSC cultured with DAG after, respectively, 7 and 14 days; it upregulated the expression of BSP and OPN genes independently of DAG; and it markedly downregulated the expression of RANKL gene and protein (decrease in RANKL and OPG ratio), the key factor that stimulates osteoclast differentiation and activity.	45	57	decrease	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	RANKL	expression of RANKL	rankl	OPG	OPG	opg	47	48	56	57
cPTH increased the expression of RANKL mRNA and lowered that of OPG mRNA in SCs from T cell replete mice but not in those from nude mice .	cPTH increased the expression of RANKL mRNA and lowered that of OPG mRNA in SCs from T cell replete mice but not in those from nude mice.	0	12	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	cPTH increased the expression of RANKL	rankl	OPG	OPG	opg	5	6	11	12
Interestingly , although in vivo studies indicate that the increased RANKL and OPG ratio is attributable to decreased OPG in individual osteocytes , with RANKL remaining unchanged , in vitro studies have shown it to be a result of a simultaneous decrease in OPG and increase in RANKL .	Interestingly, although in vivo studies indicate that the increased RANKL and OPG ratio is attributable to decreased OPG in individual osteocytes, with RANKL remaining unchanged, in vitro studies have shown it to be a result of a simultaneous decrease in OPG and increase in RANKL.	8	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	10	11	18	19
The reduction in OPG may be due to the following reasons : OPG is a decoy for RANKL , as reduced RANKL may cause less activation of OPG , so the ratio of RANKL and OPG critically determines osteoclast formation ; or there are other negative regulatory mechanisms of RANK signaling that have been described that inhibit osteoclastogenesis , such as IFN-beta , which mediates a feedback mechanism that blocks further c-fos-dependent activity XREF_BIBR .	The reduction in OPG may be due to the following reasons : OPG is a decoy for RANKL, as reduced RANKL may cause less activation of OPG, so the ratio of RANKL and OPG critically determines osteoclast formation; or there are other negative regulatory mechanisms of RANK signaling that have been described that inhibit osteoclastogenesis, such as IFN-beta, which mediates a feedback mechanism that blocks further c-fos-dependent activity XREF_BIBR.	20	28	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	21	22	27	28
RANKL signaling can be inhibited using OPG , OPG-mimetics , RANK fragments , or monoclonal antibodies against RANKL or RANK .	RANKL signaling can be inhibited using OPG, OPG-mimetics, RANK fragments, or monoclonal antibodies against RANKL or RANK.	0	15	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	0	1	6	7
RANKL enhanced activation of osteoclasts was attenuated in the castration+ OPG group .	RANKL enhanced activation of osteoclasts was attenuated in the castration+ OPG group.	0	11	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	0	1	10	11
Although Rankl upregulation in osteocytes in the unloaded condition might increase bone resorption by reducing Opg release from osteocytes to the bone surface , the upregulation of Rankl in osteocytes by unloading is inconsistently observed .	Although Rankl upregulation in osteocytes in the unloaded condition might increase bone resorption by reducing Opg release from osteocytes to the bone surface, the upregulation of Rankl in osteocytes by unloading is inconsistently observed.	1	16	increase	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Rankl	Rankl	Rankl	Opg	Opg	Opg	1	2	15	16
Consistent with previous work , SCD-O cells displayed increased RankL with concomitantly decreased Opg in response to 1,25 ( OH ) 2 D 3 exposure .	Consistent with previous work, SCD-O cells displayed increased RankL with concomitantly decreased Opg in response to 1,25 (OH) 2 D 3 exposure.	7	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RankL	RankL	RankL	Opg	Opg	Opg	9	10	13	14
Compounds such as parathyroid hormone , 1alpha ,25-( OH ) 2 D 3 , prostaglandin E 2 , and dexamethasone stimulate RANKL expression and inhibit OPG production , thereby causing increased osteoclastogenesis , whereas 17beta-estradiol increases OPG and decreases RANKL , reducing osteoclastogenesis .	Compounds such as parathyroid hormone, 1alpha,25-(OH) 2 D 3, prostaglandin E 2, and dexamethasone stimulate RANKL expression and inhibit OPG production, thereby causing increased osteoclastogenesis, whereas 17beta-estradiol increases OPG and decreases RANKL, reducing osteoclastogenesis.	14	26	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	prostaglandin E 2, and dexamethasone stimulate RANKL expression	rankl	OPG	OPG	opg	21	22	25	26
DOK3 positively regulates osteoblast expression of RANKL and represses OPG thereby providing additional osteoblast regulation of osteoclastogenesis .	DOK3 positively regulates osteoblast expression of RANKL and represses OPG thereby providing additional osteoblast regulation of osteoclastogenesis.	0	11	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	DOK3 positively regulates osteoblast expression of RANKL	rankl	OPG	OPG	opg	6	7	9	10
Methotrexate significantly downregulates synovial expression of RANKL and RANK and decreases the RANKL and OPG ratio .	Methotrexate significantly downregulates synovial expression of RANKL and RANK and decreases the RANKL and OPG ratio.	0	15	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	Methotrexate significantly downregulates synovial expression of RANKL	rankl	OPG	OPG	opg	6	7	14	15
Estrogen inhibits expression of RANKL on osteoblasts , stromal cells , and lymphocytes , and increases production of osteoprotegerin ( OPG ) , an inhibitor of RANK signaling XREF_BIBR .	Estrogen inhibits expression of RANKL on osteoblasts, stromal cells, and lymphocytes, and increases production of osteoprotegerin (OPG), an inhibitor of RANK signaling XREF_BIBR.	0	24	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	Estrogen inhibits expression of RANKL	rankl	osteoprotegerin	osteoprotegerin	osteoprotegerin	4	5	18	19
TLR2 engagement increased IL-17 and IFN-gamma production , potentiated IL-17-mediated RANKL expression , and inhibited OPG secretion .	TLR2 engagement increased IL-17 and IFN-gamma production, potentiated IL-17-mediated RANKL expression, and inhibited OPG secretion.	0	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	TLR2 engagement increased IL-17 and IFN-gamma production, potentiated IL-17-mediated RANKL expression	rankl	OPG	OPG	opg	10	11	15	16
All OPG mediated effects could be prevented by RANKL antibodies or RANKL-siRNA transfection and MAPK inhibitor PD98059 reduced the stimulatory effect of OPG on integrin alphav expression .	All OPG mediated effects could be prevented by RANKL antibodies or RANKL-siRNA transfection and MAPK inhibitor PD98059 reduced the stimulatory effect of OPG on integrin alphav expression.	0	17	prevented	Negative_activation_syntax_6_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	8	9	1	2
We first evidenced that FVIII.vWF complex inhibited RANKL induced osteoclastogenesis and enhanced the inhibitory effect of OPG .	We first evidenced that FVIII.vWF complex inhibited RANKL induced osteoclastogenesis and enhanced the inhibitory effect of OPG.	7	17	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	7	8	16	17
We also observed that 30 days of T3 treatment increased RANK and RANKL mRNA expression ( 2.5- and 2.6-fold ) and decreased OPG mRNA ( 50 % ) expression in the femur of WT mice , but not in the femur of KO mice ( XREF_FIG ) .	We also observed that 30 days of T3 treatment increased RANK and RANKL mRNA expression (2.5- and 2.6-fold) and decreased OPG mRNA (50%) expression in the femur of WT mice, but not in the femur of KO mice (XREF_FIG).	7	23	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	T3 treatment increased RANK and RANKL mRNA expression	rankl	OPG	OPG	opg	12	13	22	23
Accordingly , in Ovx bones there was reduced OPG and increased RANKL expression .	Accordingly, in Ovx bones there was reduced OPG and increased RANKL expression.	7	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL expression	rankl	OPG	OPG	opg	11	12	8	9
The results indicated that TF-SB decreased the protein expression of PTHrP and RANKL , but promoted OPG .	The results indicated that TF-SB decreased the protein expression of PTHrP and RANKL, but promoted OPG.	4	17	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	TF-SB decreased the protein expression of PTHrP and RANKL	rankl	OPG	OPG	opg	12	13	16	17
RANKL , and subsequent RANK pathway activation , may be blocked by RANKL soluble decoy receptor osteoprotegerin ( OPG ) , which is secreted by mature osteoblasts and stromal cells .	RANKL, and subsequent RANK pathway activation, may be blocked by RANKL soluble decoy receptor osteoprotegerin (OPG), which is secreted by mature osteoblasts and stromal cells.	0	23	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	osteoprotegerin	osteoprotegerin	osteoprotegerin	0	1	16	17
Whilst we know that TRAIL and RANKL inhibit the OPG assay ( personal communication ) no data is available on binding to such complexes for the sRANKL assay kit .	Whilst we know that TRAIL and RANKL inhibit the OPG assay (personal communication) no data is available on binding to such complexes for the sRANKL assay kit.	4	10	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	6	7	9	10
Moreover , miR-106b inhibitor treatment suppressed RANK ligand ( RANKL ) expression , increased osteoprotegerin ( OPG ) expression and reduced the RANKL : OPG ratio in CIA mice .	Moreover, miR-106b inhibitor treatment suppressed RANK ligand (RANKL) expression, increased osteoprotegerin (OPG) expression and reduced the RANKL : OPG ratio in CIA mice.	7	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	9	10	24	25
The balance between the osteoclast promoting RANKL and the osteoclast inhibiting OPG can regulate the number and activity of osteoclasts .	The balance between the osteoclast promoting RANKL and the osteoclast inhibiting OPG can regulate the number and activity of osteoclasts.	6	12	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	6	7	11	12
This analysis revealed that cPTH increased the expression of RANKL mRNA ( XREF_FIG ) and lowered that of OPG mRNA ( XREF_FIG ) in SCs from WT mice but not in those from TNF-/- mice .	This analysis revealed that cPTH increased the expression of RANKL mRNA (XREF_FIG) and lowered that of OPG mRNA (XREF_FIG) in SCs from WT mice but not in those from TNF-/- mice.	4	19	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	cPTH increased the expression of RANKL	rankl	OPG	OPG	opg	9	10	18	19
Thus , ATRA increased the mRNA and protein expression of RANKL and transiently decreased the RANKL inhibitor osteoprotegerin ( OPG ) at the mRNA level with no effect on OPG protein .	Thus, ATRA increased the mRNA and protein expression of RANKL and transiently decreased the RANKL inhibitor osteoprotegerin (OPG) at the mRNA level with no effect on OPG protein.	2	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	ATRA increased the mRNA and protein expression of RANKL	rankl	osteoprotegerin	osteoprotegerin	osteoprotegerin	10	11	17	18
This is suggested to be mediated partly through the reduction of OPG expression and increase of RANKL expression , which reduces the OPG and RANKL ratio , suppressing excessive bone formation .	This is suggested to be mediated partly through the reduction of OPG expression and increase of RANKL expression, which reduces the OPG and RANKL ratio, suppressing excessive bone formation.	16	25	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	RANKL expression	rankl	OPG	OPG	opg	16	17	22	23
Collectively , these results suggested that LA suppressed RANKL over-expression and enhanced the decreased OPG expression , OPG and RANKL ratio and ALP activity induced by DEX partly by inhibiting the NOX4 , NF-kappaB , and JNK pathways and activating the PI3K and AKT pathway .	Collectively, these results suggested that LA suppressed RANKL over-expression and enhanced the decreased OPG expression, OPG and RANKL ratio and ALP activity induced by DEX partly by inhibiting the NOX4, NF-kappaB, and JNK pathways and activating the PI3K and AKT pathway.	6	16	enhanced	Positive_regulation_syntax_1_verb	Positive_activation	Negative_regulation	RANKL	LA suppressed RANKL over-expression	rankl	OPG	OPG expression	opg	8	9	14	15
The results indicated that DXM significantly elevated the expression of RANKL , and significantly reduced the RANKL and OPG ratio .	The results indicated that DXM significantly elevated the expression of RANKL, and significantly reduced the RANKL and OPG ratio.	4	19	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	DXM significantly elevated the expression of RANKL	rankl	OPG	OPG	opg	10	11	18	19
This analysis revealed that cPTH increased the expression of RANKL mRNA and lowered that of OPG mRNA in SCs from control mice but not in those from PPR T cells -/- mice ( XREF_FIG ) , thus indicating that one mechanism by which PPR signaling in T cells increases SC osteoclastogenic activity is by regulating their production of osteoclastogenic cytokines .	This analysis revealed that cPTH increased the expression of RANKL mRNA and lowered that of OPG mRNA in SCs from control mice but not in those from PPR T cells -/- mice (XREF_FIG), thus indicating that one mechanism by which PPR signaling in T cells increases SC osteoclastogenic activity is by regulating their production of osteoclastogenic cytokines.	4	16	lowered	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	cPTH increased the expression of RANKL	rankl	OPG	OPG	opg	9	10	15	16
In contrast , in lumbar vertebra ( mostly composed of cancellous bone ) , only RANKL is decreased resulting in reduced RANKL and OPG ratio .	In contrast, in lumbar vertebra (mostly composed of cancellous bone), only RANKL is decreased resulting in reduced RANKL and OPG ratio.	14	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	OPG	OPG	OPG	15	16	23	24
TLR2 engagement potentiated the IL-17-mediated RANKL expression only on neutrophils from arthritic mice and inhibited OPG secretion in cell cultures at the same time .	TLR2 engagement potentiated the IL-17-mediated RANKL expression only on neutrophils from arthritic mice and inhibited OPG secretion in cell cultures at the same time.	0	16	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	TLR2 engagement potentiated the IL-17-mediated RANKL expression	rankl	OPG	OPG	opg	5	6	15	16
TNFR2 also induces TRAF2 degradation .	TNFR2 also induces TRAF2 degradation.	0	4	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	0	1	3	4
Binding of TNFR2 by TNF on T cells induces cIAP-1 dependent degradation of TRAF2 XREF_BIBR , resulting in the activation of the alternative NF-kappaB pathway XREF_BIBR .	Binding of TNFR2 by TNF on T cells induces cIAP-1 dependent degradation of TRAF2 XREF_BIBR, resulting in the activation of the alternative NF-kappaB pathway XREF_BIBR.	0	14	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	2	3	13	14
In addition , TNFR2 mediated degradation of TRAF2 and ASK1 is severely impaired in cIAP1 deficient B cells .	In addition, TNFR2 mediated degradation of TRAF2 and ASK1 is severely impaired in cIAP1 deficient B cells.	3	12	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	3	4	7	8
Here we show that TRAF2 depletion by TNFR2 is a negative feedback for NF-kB activation which has an important effect on TNFR1 signalling , resulting in the increased cytotoxicity induced by this receptor .	Here we show that TRAF2 depletion by TNFR2 is a negative feedback for NF-kB activation which has an important effect on TNFR1 signalling, resulting in the increased cytotoxicity induced by this receptor.	4	8	depletion	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	7	8	4	5
Moreover , when both receptors are co-expressed together with TRAF2 , TNFR2 also induces TRAF2 degradation , indicating that at high concentrations of both TNFR1 and TNFR2 the biological effects shown occur at low levels of TRAF2 ( Fig XREF_FIG , lower panel ) .	Moreover, when both receptors are co-expressed together with TRAF2, TNFR2 also induces TRAF2 degradation, indicating that at high concentrations of both TNFR1 and TNFR2 the biological effects shown occur at low levels of TRAF2 (Fig XREF_FIG, lower panel).	11	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	11	12	14	15
When TNFR1 and TNFR2 are coactivated , TNFR2 induces TRAF2 degradation thus affecting the formation of TNFR1 signalling complex , preventing the binding of cIAP1 and cIAP2 to TNFR1 which finally enhance its apoptotic potential .	When TNFR1 and TNFR2 are coactivated, TNFR2 induces TRAF2 degradation thus affecting the formation of TNFR1 signalling complex, preventing the binding of cIAP1 and cIAP2 to TNFR1 which finally enhance its apoptotic potential.	7	10	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	7	8	9	10
In vitro studies showed that NF-kappaB activation leads to production of TRAF1 , which blocks TNFR2 mediated degradation of TRAF2 .	In vitro studies showed that NF-kappaB activation leads to production of TRAF1, which blocks TNFR2 mediated degradation of TRAF2.	14	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	15	16	19	20
More recently it has been shown that TNFR2 and other receptors belonging to the TNFR superfamily induce TRAF2 degradation [ XREF_BIBR , XREF_BIBR ] .	More recently it has been shown that TNFR2 and other receptors belonging to the TNFR superfamily induce TRAF2 degradation [XREF_BIBR, XREF_BIBR].	7	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	7	8	17	18
When TNFR1 and TNFR2 were activated simultaneously , TNFR2 induced TRAF2 degradation and the subsequent decrease in NF-kappaB activation resulted in an enhancement of cytotoxicity triggered by TNFR1 XREF_BIBR , XREF_BIBR .	When TNFR1 and TNFR2 were activated simultaneously, TNFR2 induced TRAF2 degradation and the subsequent decrease in NF-kappaB activation resulted in an enhancement of cytotoxicity triggered by TNFR1 XREF_BIBR, XREF_BIBR.	8	11	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	8	9	10	11
Indeed , the TRAF2 dependent TNFRs 4-1BB and GITR have been shown to prolong CD8 T cell survival in the lung during influenza infection , thus TNFR2 dependent loss of TRAF2 may contribute to a decrease in survival signaling through these receptors [ XREF_BIBR , XREF_BIBR ] .	Indeed, the TRAF2 dependent TNFRs 4-1BB and GITR have been shown to prolong CD8 T cell survival in the lung during influenza infection, thus TNFR2 dependent loss of TRAF2 may contribute to a decrease in survival signaling through these receptors [XREF_BIBR, XREF_BIBR].	26	31	loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	26	27	30	31
Alternatively , RIP may also serve as a c-IAP-1 substrate and TNFR2 induced thymocyte cell death might involve the degradation of both RIP and TRAF2 .	Alternatively, RIP may also serve as a c-IAP-1 substrate and TNFR2 induced thymocyte cell death might involve the degradation of both RIP and TRAF2.	9	25	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	11	12	24	25
In contrast , TNFR2 signaling induces TRAF2 degradation to induce the alternate NF-kappaB pathway [ XREF_BIBR ] and here we have shown that CD8 intrinsic TNF and TNFR2 signaling potentiates contraction of the CD8 T cell response in the lung after viral clearance .	In contrast, TNFR2 signaling induces TRAF2 degradation to induce the alternate NF-kappaB pathway [XREF_BIBR] and here we have shown that CD8 intrinsic TNF and TNFR2 signaling potentiates contraction of the CD8 T cell response in the lung after viral clearance.	3	7	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	3	4	6	7
TRAF1 was shown to rescue a cIAP2-binding-defective mutant of TRAF2 and was able to inhibit TNFR2 induced proteosomal degradation of TRAF2 .	TRAF1 was shown to rescue a cIAP2-binding-defective mutant of TRAF2 and was able to inhibit TNFR2 induced proteosomal degradation of TRAF2.	14	21	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	15	16	20	21
The structure of the TRAF1 : TRAF2 : cIAP2 may also explain how TRAF1 can inhibit TNFR2 induced proteasomal degradation of TRAF2 .	The structure of the TRAF1 : TRAF2 : cIAP2 may also explain how TRAF1 can inhibit TNFR2 induced proteasomal degradation of TRAF2.	15	22	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	16	17	21	22
Previous work has implicated cIAP1 in the ubiquitylation and proteasomal degradation of TRAF2 by TNF-R2 , and cIAP2 can ubiquitylate and degrade TRAF1 .	Previous work has implicated cIAP1 in the ubiquitylation and proteasomal degradation of TRAF2 by TNF-R2, and cIAP2 can ubiquitylate and degrade TRAF1.	3	15	degradation	Negative_activation_token_2_noun	Positive_activation	Negative_activation	TNF-R2	TNF-R2	TNF-R2	TRAF2	TRAF2	TRAF2	14	15	12	13
TRAF2 depletion by TNFR2 is responsible for the enhancement of cytotoxicity driven by TNFR1 .	TRAF2 depletion by TNFR2 is responsible for the enhancement of cytotoxicity driven by TNFR1.	0	4	depletion	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	3	4	0	1
Then , TRAF2 degradation induced by TNFR2 contributes to inhibition of NF-kappaB and TRAF2 dependent JNK signaling , but TNFR2 is still able to activate a TRAF2 independent JNK pathway , which is responsible for TNFR2 dependent cell death in some cell types .	Then, TRAF2 degradation induced by TNFR2 contributes to inhibition of NF-kappaB and TRAF2 dependent JNK signaling, but TNFR2 is still able to activate a TRAF2 independent JNK pathway, which is responsible for TNFR2 dependent cell death in some cell types.	19	29	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	19	20	26	27
However , recent evidence indicates that TNFR2 also signals to induce TRAF2 degradation .	However, recent evidence indicates that TNFR2 also signals to induce TRAF2 degradation.	6	12	signals	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	6	7	11	12
c-IAP1 was identified as the ubiquitin protein ligase for ASK1 ubiquitination , and studies with primary B cells from c-IAP1 knock-out animals revealed that c-IAP1 is required for TNFR2 induced TRAF2 and ASK1 degradation .	c-IAP1 was identified as the ubiquitin protein ligase for ASK1 ubiquitination, and studies with primary B cells from c-IAP1 knock-out animals revealed that c-IAP1 is required for TNFR2 induced TRAF2 and ASK1 degradation.	26	33	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	28	29	30	31
Analysis of total cell lysates revealed that TNFR2 stimulation triggered robust ( JJN3 , AMO1 and KMS11 ) to moderate ( RPMI8226 , KMS-12-BM , INA6 and OPM2 ) TRAF2 degradation in 7 of the 10 investigated cell lines ( XREF_FIG ) .	Analysis of total cell lysates revealed that TNFR2 stimulation triggered robust (JJN3, AMO1 and KMS11) to moderate (RPMI8226, KMS-12-BM, INA6 and OPM2) TRAF2 degradation in 7 of the 10 investigated cell lines (XREF_FIG).	7	30	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	7	8	29	30
In primary T cells , the TNFR2 dependent degradation of TRAF2 results in activation of the alternative NF-kappaB pathway [ XREF_BIBR ] .	In primary T cells, the TNFR2 dependent degradation of TRAF2 results in activation of the alternative NF-kappaB pathway [XREF_BIBR].	6	11	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	6	7	10	11
We have also shown that TRAF2 depletion by TNFR2 negatively affects NF-kB activation ( Fig XREF_FIG ) .	We have also shown that TRAF2 depletion by TNFR2 negatively affects NF-kB activation (Fig XREF_FIG).	5	9	depletion	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	TNFR2	TNFR2	TNFR2	TRAF2	TRAF2	TRAF2	8	9	5	6
Additionally , marked RANKL induced RANK immunofluorescence staining in Raw 264.7 cells was attenuated by cilostazol and rSIRT1 , and both attenuations were prevented by sirtinol .	Additionally, marked RANKL induced RANK immunofluorescence staining in Raw 264.7 cells was attenuated by cilostazol and rSIRT1, and both attenuations were prevented by sirtinol.	2	7	induced	Positive_early_activation	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	3	4	5	6
Catabolic effects of RANKL are inhibited by OPG , thereby preventing the activation of its receptor RANK .	Catabolic effects of RANKL are inhibited by OPG, thereby preventing the activation of its receptor RANK.	1	17	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	3	4	16	17
Osteoblasts also express osteoprotegerin , a soluble decoy receptor for RANKL , which can inhibit the activation of RANK by RANKL .	Osteoblasts also express osteoprotegerin, a soluble decoy receptor for RANKL, which can inhibit the activation of RANK by RANKL.	14	21	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	20	21	18	19
Additionally , osteoblasts express osteoprotegerin- ( OPG ) , a soluble decoy receptor for RANKL , which inhibits activation of RANK by RANKL .	Additionally, osteoblasts express osteoprotegerin- (OPG), a soluble decoy receptor for RANKL, which inhibits activation of RANK by RANKL.	17	23	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	22	23	20	21
This decreased or absent expression of RANKL in the tumor cells may allow RANK , which is normally expressed as a receptor on the cell surface , to target RANKL present on the cell surface of normal osteoblasts and stromal cells of the bone .	This decreased or absent expression of RANKL in the tumor cells may allow RANK, which is normally expressed as a receptor on the cell surface, to target RANKL present on the cell surface of normal osteoblasts and stromal cells of the bone.	4	28	allow	Positive_regulation_syntax_1_verb	Positive_activation	Positive_regulation	RANKL	expression of RANKL	rankl	RANK	RANK, which is normally expressed	rank	6	7	13	14
This cell-to-cell contact can be inhibited by osteoprotegerin ( OPG ) , a soluble cytokine in the TNF receptor superfamily which is expressed and released by stromal cells and osteoblasts and which blocks the activation of RANK by RANKL due to its affinity to RANKL .	This cell-to-cell contact can be inhibited by osteoprotegerin (OPG), a soluble cytokine in the TNF receptor superfamily which is expressed and released by stromal cells and osteoblasts and which blocks the activation of RANK by RANKL due to its affinity to RANKL.	32	39	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	38	39	36	37
RANKL antibody can directly block RANKL and RANK signal pathway , which is an efficient therapy to inhibit bone absorption associated with implant wearing particles .	RANKL antibody can directly block RANKL and RANK signal pathway, which is an efficient therapy to inhibit bone absorption associated with implant wearing particles.	0	9	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	0	1	7	8
Sinomenine decreased the expression of RANKL stimulated osteoclastic specific genes and RANK and TRAF6 .	Sinomenine decreased the expression of RANKL stimulated osteoclastic specific genes and RANK and TRAF6.	3	13	stimulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	RANKL	expression of RANKL	rankl	RANK	RANK	rank	5	6	11	12
Their results show that RANK plays an insignificant role in the protection of podocytes and that RANKL reduces podocyte apoptosis independently of RANK .	Their results show that RANK plays an insignificant role in the protection of podocytes and that RANKL reduces podocyte apoptosis independently of RANK.	16	23	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	16	17	22	23
OPG binds RANKL as a decoy receptor , inhibiting the activation of RANK by RANKL and preventing the differentiation of bone marrow precursor ( monocyte and macrophage ) cells to osteoclasts -- cells that are central in the process of bone resorption [ XREF_BIBR ] .	OPG binds RANKL as a decoy receptor, inhibiting the activation of RANK by RANKL and preventing the differentiation of bone marrow precursor (monocyte and macrophage) cells to osteoclasts -- cells that are central in the process of bone resorption [XREF_BIBR].	8	15	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	14	15	12	13
The localized expression of RANKL in the MZ may , therefore , restrict the effects of RANK signaling to DCs in this specific niche and may even have a role in retention of RANK + DCs , thus favoring the activation of mCTLs and not the priming of naive Tcells by migratory DCs .	The localized expression of RANKL in the MZ may, therefore, restrict the effects of RANK signaling to DCs in this specific niche and may even have a role in retention of RANK + DCs, thus favoring the activation of mCTLs and not the priming of naive Tcells by migratory DCs.	2	17	restrict	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	expression of RANKL	rankl	RANK	RANK	rank	4	5	16	17
Denosumab suppresses osteoclast formation in humans by binding to RANKL , which in turn inhibits RANK activation ; immunoassays showed denosumab to be specific for human RANKL .	Denosumab suppresses osteoclast formation in humans by binding to RANKL, which in turn inhibits RANK activation; immunoassays showed denosumab to be specific for human RANKL.	1	16	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	9	10	15	16
By binding RANKL , denosumab prevents the interaction of RANKL with RANK on osteoclasts and reversibly inhibits osteoclast mediated bone resorption .	By binding RANKL, denosumab prevents the interaction of RANKL with RANK on osteoclasts and reversibly inhibits osteoclast mediated bone resorption.	0	13	prevents	Negative_activation_syntax_3_verb	Positive_activation	Negative_activation	RANKL	RANKL	RANKL	RANK	RANK	RANK	2	3	11	12
Therefore , on HIV-1 exposure , amines prevent the surface access of an intracellular pool of TRAIL thus inhibiting the pro killer activity of HIV activated pDC .	Therefore, on HIV-1 exposure, amines prevent the surface access of an intracellular pool of TRAIL thus inhibiting the pro killer activity of HIV activated pDC.	14	22	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	killer	killer	killer	16	17	21	22
Functional studies showed that TRAIL blocking antibody , exogenous soluble TRAIL and soluble DR5 drastically reduce radiation induced apoptosis and that membrane bound TRAIL mediated pro apoptotic signaling is dependent on modulation of TRAIL shedding .	Functional studies showed that TRAIL blocking antibody, exogenous soluble TRAIL and soluble DR5 drastically reduce radiation induced apoptosis and that membrane bound TRAIL mediated pro apoptotic signaling is dependent on modulation of TRAIL shedding.	4	15	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	4	5	13	14
In the present study , TRAIL treatment in INS-1 cells upregulated DcR1 and downregulated DR5 without altering the expression of DcR2 and DR4 .	In the present study, TRAIL treatment in INS-1 cells upregulated DcR1 and downregulated DR5 without altering the expression of DcR2 and DR4.	5	15	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	14	15
Thus , the GGTI-298 and TRAIL combination induces a DR5 dependent Akt inhibition .	Thus, the GGTI-298 and TRAIL combination induces a DR5 dependent Akt inhibition.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	9	10
Thus , the GGTI-298 and TRAIL combination induces a DR5 dependent IkappaBalpha degradation or NF-kappaB activation .	Thus, the GGTI-298 and TRAIL combination induces a DR5 dependent IkappaBalpha degradation or NF-kappaB activation.	3	12	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	5	6	9	10
showed that TRAIL can co-recruit DcR2 with DR5 , producing a heteromeric , inactive receptor complex , thus equally inhibiting DR5 function but in a ligand dependent manner .	showed that TRAIL can co-recruit DcR2 with DR5, producing a heteromeric, inactive receptor complex, thus equally inhibiting DR5 function but in a ligand dependent manner.	2	21	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	2	3	20	21
Cell death with 2DG+ TRAIL was attenuated by approximately 25 % in the absence of DR5 , but remained significantly greater than when treated with TRAIL alone ( XREF_FIG ) .	Cell death with 2DG+ TRAIL was attenuated by approximately 25% in the absence of DR5, but remained significantly greater than when treated with TRAIL alone (XREF_FIG).	13	28	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	DR5	DR5	DR5	25	26	15	16
This reduced cFLIP recruitment and increased caspase-8 recruitment to TRAIL activated DR4 containing death receptor complexes , resulting in the cleavage and activation of caspase-8 and subsequent caspase-3-mediated apoptosis .	This reduced cFLIP recruitment and increased caspase-8 recruitment to TRAIL activated DR4 containing death receptor complexes, resulting in the cleavage and activation of caspase-8 and subsequent caspase-3-mediated apoptosis.	3	12	activated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	9	10	11	12
Recent studies already support this hypothesis , reporting hyperthermia to enhance apoptosis induced by TRAIL or the DR4 targeting mapatumumab in colon cancer cells in vitro and in vivo XREF_BIBR , XREF_BIBR .	Recent studies already support this hypothesis, reporting hyperthermia to enhance apoptosis induced by TRAIL or the DR4 targeting mapatumumab in colon cancer cells in vitro and in vivo XREF_BIBR, XREF_BIBR.	12	19	induced	Positive_activation_syntax_2_verb	Positive_activation	Positive_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	14	15	17	18
In summary , combined treatment of LA and TRAIL increased cytotoxicity and the sub-G1 population in A549 and H1299 NSCLCs , induced apoptosis by cleavage of PARP , and inhibited pro caspases 8/9/3 , Bcl-2 , and XIAP , and activated DR4 in A549 and H1299 cells .	In summary, combined treatment of LA and TRAIL increased cytotoxicity and the sub-G1 population in A549 and H1299 NSCLCs, induced apoptosis by cleavage of PARP, and inhibited pro caspases 8/9/3, Bcl-2, and XIAP, and activated DR4 in A549 and H1299 cells.	4	46	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	8	9	41	42
It is intriguing to note that enforced expression of caveolin results in de-sensitization of cells towards TRAIL as engagement of TRAIL with its respective receptor DR4 reduces the localization of DR4 in caveolae and results in its internalization .	It is intriguing to note that enforced expression of caveolin results in de-sensitization of cells towards TRAIL as engagement of TRAIL with its respective receptor DR4 reduces the localization of DR4 in caveolae and results in its internalization.	18	31	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	20	21	30	31
We observed that DR4 expression was reduced in all samples treated with wortmannin and TRAIL , regardless of the androgen status .	We observed that DR4 expression was reduced in all samples treated with wortmannin and TRAIL, regardless of the androgen status.	3	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	TRAIL	TRAIL	TRAIL	DR4	DR4	DR4	14	15	3	4
In experiments not shown , we verified the APRIL blocking activity of TACI-Ig using cell lines that exhibit a modest proliferative response to recombinant APRIL .	In experiments not shown, we verified the APRIL blocking activity of TACI-Ig using cell lines that exhibit a modest proliferative response to recombinant APRIL.	8	13	blocking activity	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	APRIL	APRIL	APRIL	TACI-Ig	TACI-Ig	TACI-Ig	8	9	12	13
It blocks the activation of TACI by APRIL and BLyS .	It blocks the activation of TACI by APRIL and BLyS.	1	9	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	APRIL	APRIL	APRIL	TACI	TACI	TACI	7	8	5	6
APRIL blocking TACI-Ig activity was assessed in vitro by its ability to block APRIL induced IgA production in mouse IgD + B cells ( data not shown ) .	APRIL blocking TACI-Ig activity was assessed in vitro by its ability to block APRIL induced IgA production in mouse IgD + B cells (data not shown).	0	5	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	APRIL	APRIL	APRIL	TACI-Ig	TACI-Ig	TACI-Ig	0	1	2	3
p110alpha suppression with siRNA strongly reduced TNF induced endothelial permeability ( XREF_FIG ) , whereas a small decrease was observed for p110gamma but not p110delta- or p110beta depleted cells .	p110alpha suppression with siRNA strongly reduced TNF induced endothelial permeability (XREF_FIG), whereas a small decrease was observed for p110gamma but not p110delta- or p110beta depleted cells.	6	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNF	TNF	TNF	p110delta-	p110delta-	p110delta-	6	7	24	25
The FADD and FAS genes , linked with the apoptotic death pathway , were perturbed by CSA , DTL and ETM , as well as TNFRSF10A by CSA .	The FADD and FAS genes, linked with the apoptotic death pathway, were perturbed by CSA, DTL and ETM, as well as TNFRSF10A by CSA.	1	26	perturbed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TNFRSF10A	TNFRSF10A	TNFRSF10A	FADD	FADD	FADD	25	26	1	2
24 As depicted in Figure XREF_FIG F and XREF_FIG G , ox-LDL , IL-6 , or TNFalpha significantly reduced the levels of GCH1 protein in endothelial cells or in cells treated with the control antagomir , consistent with other reports .	24 As depicted in Figure XREF_FIG F and XREF_FIG G, ox-LDL, IL-6, or TNFalpha significantly reduced the levels of GCH1 protein in endothelial cells or in cells treated with the control antagomir, consistent with other reports.	11	23	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	GCH1	GCH1	GCH1	16	17	22	23
By amplifying BAFF-R cleavage from centrocytes , BAFF excess might impair B-cell selection and high affinity Ab maturation .	By amplifying BAFF-R cleavage from centrocytes, BAFF excess might impair B-cell selection and high affinity Ab maturation.	2	11	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	BAFF	BAFF	BAFF	BAFF-R	BAFF-R	BAFF-R	7	8	2	3
Upon transfection of cells with NleE and subsequent stimulation by IL-1beta or TNF-alpha , the variable NF-kappaB components p65 and c-Rel were prevented from translocating into the nucleus , and release of IL-8 was greatly reduced as a result ( XREF_FIG ) .	Upon transfection of cells with NleE and subsequent stimulation by IL-1beta or TNF-alpha, the variable NF-kappaB components p65 and c-Rel were prevented from translocating into the nucleus, and release of IL-8 was greatly reduced as a result (XREF_FIG).	8	23	prevented	Negative_activation_syntax_4_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	c-Rel	c-Rel	c-Rel	12	13	20	21
In the CNS , LIGHT was shown to negatively regulate axon growth of nodose sensory neurons by activating the HVEM receptor [ XREF_BIBR ] .	In the CNS, LIGHT was shown to negatively regulate axon growth of nodose sensory neurons by activating the HVEM receptor [XREF_BIBR].	4	20	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	LIGHT	LIGHT	LIGHT	HVEM	HVEM	HVEM	4	5	19	20
Nuclear p53 can promote autophagy by interacting with sestrins 1/2 , but in the cytosolic compartment p53 inhibits autophagy by activating Bax .	Nuclear p53 can promote autophagy by interacting with sestrins 1/2, but in the cytosolic compartment p53 inhibits autophagy by activating Bax.	16	22	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	16	17	21	22
We demonstrated that DNA supercoiling strongly enhanced the level of mutp53 mediated repression of the BAX and MSP and MST1 promoters .	We demonstrated that DNA supercoiling strongly enhanced the level of mutp53 mediated repression of the BAX and MSP and MST1 promoters.	8	20	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	mutp53	level of mutp53	mutp53	BAX	BAX	bax	10	11	15	16
HDAC inhibition suppressed p53 dependent activation of Bax , thus preventing post-mitochondrial events , including cleavage of Caspase-9 and Caspase-3 [ XREF_BIBR ] .	HDAC inhibition suppressed p53 dependent activation of Bax, thus preventing post-mitochondrial events, including cleavage of Caspase-9 and Caspase-3 [XREF_BIBR].	3	8	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	3	4	7	8
Reverse transcription-polymerase chain reaction and western blot analysis were used to detect the levels of mRNA and proteins of p53 upregulated modulator of apoptosis ( PUMA ) , Bax and Bcl-2 .	Reverse transcription-polymerase chain reaction and western blot analysis were used to detect the levels of mRNA and proteins of p53 upregulated modulator of apoptosis (PUMA), Bax and Bcl-2.	17	29	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	19	20	28	29
Moreover , PX-478 alone upregulated p53 expression and reduced the bcl2 and BAX ratio under hypoxia , but not under oxia .	Moreover, PX-478 alone upregulated p53 expression and reduced the bcl2 and BAX ratio under hypoxia, but not under oxia.	2	13	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	PX-478 alone upregulated p53 expression	p53	BAX	BAX	bax	5	6	12	13
Using a panel of well characterized Arg175 p53 mutants we found that only mutants ( Tyr175 , Trp175 , Asp175 and Phe175 ) which have completely lost their ability to transactivate repress wild-type p53 stimulated Bax , p21 and PG13 promoter constructs .	Using a panel of well characterized Arg175 p53 mutants we found that only mutants (Tyr175, Trp175, Asp175 and Phe175) which have completely lost their ability to transactivate repress wild-type p53 stimulated Bax, p21 and PG13 promoter constructs.	31	41	stimulated	Positive_activation_token_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	33	34	35	36
Bcl-2 and p53 inhibited the interaction between full length activated Bax and nucleophosmin .	Bcl-2 and p53 inhibited the interaction between full length activated Bax and nucleophosmin.	0	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	2	3	10	11
A shorter p53 40-59 peptide with phosphorylated Ser 46 activated BAX in the presence of Pin1 and its P47S mutation , a p53 polymorphism with reduced pro apoptotic activity , abrogated BAX activation ( XREF_FIG ) .	A shorter p53 40-59 peptide with phosphorylated Ser 46 activated BAX in the presence of Pin1 and its P47S mutation, a p53 polymorphism with reduced pro apoptotic activity, abrogated BAX activation (XREF_FIG).	0	32	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	BAX	BAX	BAX	2	3	31	32
Downregulation of miR-214 increased p53 protein expression and decreased the Bcl-2 and Bax signaling pathway of TSCC Tca8113 cells .	Downregulation of miR-214 increased p53 protein expression and decreased the Bcl-2 and Bax signaling pathway of TSCC Tca8113 cells.	2	14	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	miR-214 increased p53 protein expression	p53	Bax	Bax	bax	4	5	12	13
At first , we investigated the effect of DNA topology on mutp53 repression of the BAX promoter region , as described for hot spot mutp53 proteins by XREF_BIBR .	At first, we investigated the effect of DNA topology on mutp53 repression of the BAX promoter region, as described for hot spot mutp53 proteins by XREF_BIBR.	11	17	repression	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	mutp53	mutp53	mutp53	BAX	BAX	BAX	11	12	15	16
Inhibition of gankyrin increased P53 mRNA levels and subsequently upregulated CDKN1A ( p21Waf1 and Cip1 ) and BAX transcripts , which are direct transcriptional targets of p53 .	Inhibition of gankyrin increased P53 mRNA levels and subsequently upregulated CDKN1A (p21Waf1 and Cip1) and BAX transcripts, which are direct transcriptional targets of p53.	2	18	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	P53	gankyrin increased P53 mRNA levels	p53	BAX	BAX	bax	4	5	17	18
The p53 protein was decreased pro survival Bcl-2 proteins and elevated pro apoptosis Bax protein expression [ XREF_BIBR , XREF_BIBR ] .	The p53 protein was decreased pro survival Bcl-2 proteins and elevated pro apoptosis Bax protein expression [XREF_BIBR, XREF_BIBR].	1	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	1	2	13	14
We found that BRP can promote the expression of p53 and the further activation of Caspase-3 , and down-regulate Bcl-2 and Bax ratio as shown by Western blot analysis .	We found that BRP can promote the expression of p53 and the further activation of Caspase-3, and down-regulate Bcl-2 and Bax ratio as shown by Western blot analysis.	3	22	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	BRP can promote the expression of p53	p53	Bax	Bax	bax	9	10	21	22
Silencing of MAGE-A in HMCL and primary patient cells did not impair cell cycle regulation , but it did result in apoptosis through p53 dependent activation of Bax and Bak genes and by repression of survivin through p53 dependent and independent mechanisms .	Silencing of MAGE-A in HMCL and primary patient cells did not impair cell cycle regulation, but it did result in apoptosis through p53 dependent activation of Bax and Bak genes and by repression of survivin through p53 dependent and independent mechanisms.	23	30	activation	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	23	24	27	28
P53 can down-regulate BCL-2 and BAX to promote apoptosis .	P53 can down-regulate BCL-2 and BAX to promote apoptosis.	0	6	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	P53	P53	P53	BAX	BAX	BAX	0	1	5	6
Thus , p53 enhances the myocyte renin-angiotensin-system and decreases the Bcl-2 and Bax ratio in the cells , triggering apoptosis .	Thus, p53 enhances the myocyte renin-angiotensin-system and decreases the Bcl-2 and Bax ratio in the cells, triggering apoptosis.	2	13	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	2	3	12	13
Knockdown of p53 significantly reversed the induction of Bax and Bak as well as the downregulation of Bcl-2 caused by LL-37 ( XREF_FIG ) .	Knockdown of p53 significantly reversed the induction of Bax and Bak as well as the downregulation of Bcl-2 caused by LL-37 (XREF_FIG).	0	10	reversed	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	2	3	8	9
Using gene targeted mice , we show that the tumor suppressor p53 mediates Bax transcriptional induction after PD related complex I blockade in vivo , but it does not participate in Bax mitochondrial translocation in this model , either by a transcription independent mechanism or through the induction of BH3-only proteins Puma or Noxa .	Using gene targeted mice, we show that the tumor suppressor p53 mediates Bax transcriptional induction after PD related complex I blockade in vivo, but it does not participate in Bax mitochondrial translocation in this model, either by a transcription independent mechanism or through the induction of BH3-only proteins Puma or Noxa.	9	15	mediates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	Bax	Bax	Bax	9	12	13	14
However , the overexpression of miR-214 reduced the anticancer effect of cantharidin on the proliferation and apoptosis of TSCC Tca8113 cells , inhibited p53 protein expression , and increased the Bcl-2 and Bax signaling pathway .	However, the overexpression of miR-214 reduced the anticancer effect of cantharidin on the proliferation and apoptosis of TSCC Tca8113 cells, inhibited p53 protein expression, and increased the Bcl-2 and Bax signaling pathway.	3	34	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	overexpression of miR-214 reduced the anticancer effect of cantharidin on the proliferation and apoptosis of TSCC Tca8113 cells, inhibited p53 protein expression	p53	Bax	Bax	bax	23	24	32	33
Thus , the two direct p53 transcriptional targets Noxa and Puma can mediate the pro apoptotic activity of Bax and Bak , and thereby promote apoptosis .	Thus, the two direct p53 transcriptional targets Noxa and Puma can mediate the pro apoptotic activity of Bax and Bak, and thereby promote apoptosis.	5	20	mediate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	18	19
Knockdown of p53 inhibits up-regulation of p21 and BAX .	Knockdown of p53 inhibits up-regulation of p21 and BAX.	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	2	3	8	9
The tumor suppressor p53 can directly activate Bax and downregulate Bcl-2 , in the absence of other proteins , to permeabilize mitochondria and engage the apoptotic program .	The tumor suppressor p53 can directly activate Bax and downregulate Bcl-2, in the absence of other proteins, to permeabilize mitochondria and engage the apoptotic program.	1	8	directly activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	Bax	Bax	Bax	1	4	7	8
A further investigation also confirmed that AChE deficiency down-regulated p53 induction and phosphorylation at serine 15 , and decreased the Bax and Bcl -2 ratio during I/R .	A further investigation also confirmed that AChE deficiency down-regulated p53 induction and phosphorylation at serine 15, and decreased the Bax and Bcl -2 ratio during I/R.	6	24	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	AChE deficiency down-regulated p53 induction and phosphorylation at serine	p53	Bax	Bax	bax	9	10	20	21
Our data further showed that MPTP induced BAX up-regulation is dependent on dopaminergic p53 function as evidenced by the fact that selective depletion of p53 in DA neurons abolished BAX induction by MPTP treatment .	Our data further showed that MPTP induced BAX up-regulation is dependent on dopaminergic p53 function as evidenced by the fact that selective depletion of p53 in DA neurons abolished BAX induction by MPTP treatment.	22	30	abolished	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	24	25	29	30
p38 inhibition also abolished the p53 dependent induction of the proapoptotic Bax and Bak activator Puma , whereas inhibiting syncytial apoptosis ( XREF_FIG E ) .	p38 inhibition also abolished the p53 dependent induction of the proapoptotic Bax and Bak activator Puma, whereas inhibiting syncytial apoptosis (XREF_FIG E).	5	15	induction	Positive_activation_syntax_3_noun	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	5	6	11	12
p53 siRNA significantly increased local provasculogenic factors ( hypoxia inducible factor 1 alpha , stromal cell derived factor 1 alpha , and vascular endothelial growth factor ; P < = 0.05 ) and decreased local proapoptotic factors ( p53 , PUMA , and Bax ; P < = 0.05 ) .	p53 siRNA significantly increased local provasculogenic factors (hypoxia inducible factor 1 alpha, stromal cell derived factor 1 alpha, and vascular endothelial growth factor; P < = 0.05) and decreased local proapoptotic factors (p53, PUMA, and Bax; P < = 0.05).	0	46	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	0	1	43	44
Phosphorylation of the tumor suppressor protein p53 by Chk2 may lead to upregulation of Bax , an apoptosis promoting event .	Phosphorylation of the tumor suppressor protein p53 by Chk2 may lead to upregulation of Bax, an apoptosis promoting event.	0	17	lead to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	p53	Phosphorylation of the tumor suppressor protein p53	p53	Bax	Bax	bax	6	7	14	15
Inhibition of NF-kappaB with IKSR ( XREF_FIG C ) or SN50 , as well as inhibition of p53 with cyclic pifithrin-alpha ( XREF_FIG D ) all inhibited the activation of Bax and Bak .	Inhibition of NF-kappaB with IKSR (XREF_FIG C) or SN50, as well as inhibition of p53 with cyclic pifithrin-alpha (XREF_FIG D) all inhibited the activation of Bax and Bak.	15	32	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	17	18	30	31
The TP53 specific inhibitor pifithrin-alpha ( PFT-alpha ) blocked induction of autophagic proteins including DNA Damage Regulated Autophagy Modulator1 ( DRAM1 ) , LC3-II and beclin1 and apoptotic proteins including TP53 upregulated modulator of apoptosis ( PUMA ) and BAX .	The TP53 specific inhibitor pifithrin-alpha (PFT-alpha) blocked induction of autophagic proteins including DNA Damage Regulated Autophagy Modulator1 (DRAM1), LC3-II and beclin1 and apoptotic proteins including TP53 upregulated modulator of apoptosis (PUMA) and BAX.	1	40	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TP53	TP53	TP53	BAX	BAX	BAX	1	2	39	40
Both 15d-PGJ ( 2 )-induced apoptosis and the induction of p21 ( Waf1 ) and Bax can be abolished by p53 small interfering RNA but not by peroxisome proliferator activated receptor gamma inhibitors .	Both 15d-PGJ (2)-induced apoptosis and the induction of p21 (Waf1) and Bax can be abolished by p53 small interfering RNA but not by peroxisome proliferator activated receptor gamma inhibitors.	1	22	abolished	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	20	21	15	16
Inhibition of Chk1 kills tetraploid cells via p38 dependent activation of p53 ( see also Ignacio Toledo , Matilde Murga and Oscar Fernandez-Capetillo , in this issue ) followed by p53 mediated activation of Bax and Bak driven apoptosis .	Inhibition of Chk1 kills tetraploid cells via p38 dependent activation of p53 (see also Ignacio Toledo, Matilde Murga and Oscar Fernandez-Capetillo, in this issue) followed by p53 mediated activation of Bax and Bak driven apoptosis.	30	38	mediated	Positive_early_activation	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	30	31	34	35
We demonstrated that inactivation of p53 by p53 specific siRNA significantly inhibits the expression of p53 targeted genes ( i.e. p21 and Bax ) and alleviated alcohol induced cell cycle arrest ( XREF_FIG ) .	We demonstrated that inactivation of p53 by p53 specific siRNA significantly inhibits the expression of p53 targeted genes (i.e. p21 and Bax) and alleviated alcohol induced cell cycle arrest (XREF_FIG).	3	23	targeted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53 by p53 specific siRNA significantly inhibits the expression of p53	p53	Bax	Bax	bax	5	6	22	23
Puma induction in growth factor or glucose withdrawal was dependent on p53 in cell lines and in activated primary T lymphocytes because p53 deficiency suppressed Puma induction and delayed Bax and caspase activation , DNA fragmentation , and loss of clonogenic survival .	Puma induction in growth factor or glucose withdrawal was dependent on p53 in cell lines and in activated primary T lymphocytes because p53 deficiency suppressed Puma induction and delayed Bax and caspase activation, DNA fragmentation, and loss of clonogenic survival.	22	30	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	22	23	29	30
Thus , the loss of wild-type p53 leads to both genomic instability and resistance to PCD by activating Bax and Bak ( pro apoptotic factors ) from the mitochondria , which prevents the cell death process from occurring [ XREF_BIBR , XREF_BIBR ] .	Thus, the loss of wild-type p53 leads to both genomic instability and resistance to PCD by activating Bax and Bak (pro apoptotic factors) from the mitochondria, which prevents the cell death process from occurring [XREF_BIBR, XREF_BIBR].	3	24	leads	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	loss of wild-type p53	p53	Bax	Bax	bax	6	7	18	19
Alpha lipoic acid suppressed proliferating cell nuclear antigen ( PCNA ) and p53 expression , induced apoptosis , upregulated proapoptotic protein Bax .	Alpha lipoic acid suppressed proliferating cell nuclear antigen (PCNA) and p53 expression, induced apoptosis, upregulated proapoptotic protein Bax.	0	22	upregulated	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	Alpha lipoic acid suppressed proliferating cell nuclear antigen (PCNA) and p53 expression	p53	Bax	Bax	bax	12	13	21	22
Although Cd increased the gene expression of BAX in p53-knockdown cells , the expression levels of BAX when treated with Cd and p53 siRNA were lower than that of BAX when treated with Cd and control siRNA ( XREF_FIG ) .	Although Cd increased the gene expression of BAX in p53-knockdown cells, the expression levels of BAX when treated with Cd and p53 siRNA were lower than that of BAX when treated with Cd and control siRNA (XREF_FIG).	14	23	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	p53	p53	p53	BAX	BAX	BAX	22	23	16	17
Upregulation of P53 significantly decreased the Bcl-2 and Bax ratio that induced the release of cytochrome C from the mitochondria which in turn caused upregulation of caspase-3 .	Upregulation of P53 significantly decreased the Bcl-2 and Bax ratio that induced the release of cytochrome C from the mitochondria which in turn caused upregulation of caspase-3.	0	9	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	P53	P53	P53	Bax	Bax	Bax	2	3	8	9
Inhibition of PP1 , but not PP2A , with okadaic acid induced the p53 target Bax and , consequently , apoptosis in rabbit lens epithelial cells [ XREF_BIBR ] .	Inhibition of PP1, but not PP2A, with okadaic acid induced the p53 target Bax and, consequently, apoptosis in rabbit lens epithelial cells [XREF_BIBR].	11	16	target	Positive_activation_token_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bax	Bax	Bax	13	14	15	16
These data suggest nuclear p53 suppresses invasion by inducing Bax , which then binds to complex-I and inhibits ROS production .	These data suggest nuclear p53 suppresses invasion by inducing Bax, which then binds to complex-I and inhibits ROS production.	3	17	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	4	5	9	10
In a rat model of post-ischemic acute stroke , TH treatment reduced cerebral infarction while limiting cell death through modulation of the p53 targets Bax and BCl2 [ XREF_BIBR ] .	In a rat model of post-ischemic acute stroke, TH treatment reduced cerebral infarction while limiting cell death through modulation of the p53 targets Bax and BCl2 [XREF_BIBR].	19	28	targets	Positive_activation_token_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	22	23	24	25
Moreover , 10 and 20 mug/mL Sal B reduced the expression levels of p53 , increased the Bcl-2 and Bax ratio and inhibited the caspase-3 activity in ox-LDL-treated HUVECs ( P < 0.05 ) .	Moreover, 10 and 20 mug/mL Sal B reduced the expression levels of p53, increased the Bcl-2 and Bax ratio and inhibited the caspase-3 activity in ox-LDL-treated HUVECs (P < 0.05).	6	20	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	Sal B reduced the expression levels of p53	p53	Bax	Bax	bax	13	14	19	20
What is known is that the transcriptional blockade of p53 by alpha-amanitin induces p53 mitochondrial localisation and Bax accumulation , and activation in mitochondria .	What is known is that the transcriptional blockade of p53 by alpha-amanitin induces p53 mitochondrial localisation and Bax accumulation, and activation in mitochondria.	7	18	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	Bax	Bax	Bax	9	10	17	18
However , it is notable that the extent of maturation achieved in this setting was marginal compared with that achieved with LPS stimulation and out of proportion with the amount of circulating TNF-alpha and consequent down-regulation of the TNF-RI on DCs ( XREF_FIG and Fig .	However, it is notable that the extent of maturation achieved in this setting was marginal compared with that achieved with LPS stimulation and out of proportion with the amount of circulating TNF-alpha and consequent down-regulation of the TNF-RI on DCs (XREF_FIG and Fig.	32	39	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNF-RI	TNF-RI	TNF-RI	32	33	38	39
TNFalpha+ DXMb exposed cultures demonstrated significant upregulation in anti-apoptotic Bcl-2 and Bcl-xl genes and downregulation in pro apoptotic Bax gene expression ; DXMb treatment of TNFalpha explants also lowered the Bax and Bcl -2 ratio and inhibited TNFR1 upregulation .	TNFalpha+ DXMb exposed cultures demonstrated significant upregulation in anti-apoptotic Bcl-2 and Bcl-xl genes and downregulation in pro apoptotic Bax gene expression; DXMb treatment of TNFalpha explants also lowered the Bax and Bcl -2 ratio and inhibited TNFR1 upregulation.	25	38	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	25	26	37	38
Wild-type TNF induces TNFR2 and Etk and activates both ASK1 and Etk but does not down-regulate TNFR1 .	Wild-type TNF induces TNFR2 and Etk and activates both ASK1 and Etk but does not down-regulate TNFR1.	0	17	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	1	2	16	17
Applying affinity maturation and re-engineering of humanized variable domains , we generated a monovalent Fab derivative ( 13.7 ) of ATROSAB that exhibited increased binding to TNFR1 and superior inhibition of TNF mediated TNFR1 activation , while lacking any agonistic activity even in the presence of cross linking antibodies .	Applying affinity maturation and re-engineering of humanized variable domains, we generated a monovalent Fab derivative (13.7) of ATROSAB that exhibited increased binding to TNFR1 and superior inhibition of TNF mediated TNFR1 activation, while lacking any agonistic activity even in the presence of cross linking antibodies.	29	34	mediated	Positive_early_activation	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	31	32	33	34
The combination of TNFalpha plus Abeta42 treatment of middle-age neurons slightly decreased the TNFR1 : TNFR2 mRNA ratio relative to Abeta alone , but the same combination treatment of old neurons produced a large decline in the TNFR1 : TNFR2 ratio .	The combination of TNFalpha plus Abeta42 treatment of middle-age neurons slightly decreased the TNFR1 : TNFR2 mRNA ratio relative to Abeta alone, but the same combination treatment of old neurons produced a large decline in the TNFR1 : TNFR2 ratio.	1	18	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	3	4	13	14
TNF-alpha also reduces the barrier function of IECs in IBD by inducing TNFR1 mediated IEC apoptosis XREF_BIBR and increasing the permeability of TJ through TNFR2 signaling XREF_BIBR .	TNF-alpha also reduces the barrier function of IECs in IBD by inducing TNFR1 mediated IEC apoptosis XREF_BIBR and increasing the permeability of TJ through TNFR2 signaling XREF_BIBR.	0	13	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	0	1	12	13
TNF conjugated to phycoerythrin ( TNF-PE ) also reacted with a small population of thymocytes and was found to specifically block binding of the TNF-R2 mAb and not the TNF-R1 mAb , implicating preferential binding of TNF-PE to TNF-R2 .	TNF conjugated to phycoerythrin (TNF-PE) also reacted with a small population of thymocytes and was found to specifically block binding of the TNF-R2 mAb and not the TNF-R1 mAb, implicating preferential binding of TNF-PE to TNF-R2.	0	30	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	TNF-R1	TNF-R1	TNF-R1	0	1	29	30
XREF_BIBR , XREF_BIBR Moreover , priming cells for a few hours with TWEAK results in depletion of the Triton X-100 soluble cytosolic pool of TRAF2-cIAP1/2 complexes and reduced TNF induced TNFR1 associated ubiquitination of RIP1 , which , as mentioned before , is mediated by the cIAPs .	XREF_BIBR, XREF_BIBR Moreover, priming cells for a few hours with TWEAK results in depletion of the Triton X-100 soluble cytosolic pool of TRAF2-cIAP1/2 complexes and reduced TNF induced TNFR1 associated ubiquitination of RIP1, which, as mentioned before, is mediated by the cIAPs.	27	31	induced	Positive_early_activation	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	28	29	30	31
For example , TNF-alpha is known to inhibit insulin signaling in adipose tissue , and deletion of TNF-alpha , or the TNF receptor , TNFR1 , in both genetic ( TNFR1 ) and high-fat diet induced ( TNFR1 and TNF-alpha ) obese mice results in greater insulin sensitivity .	For example, TNF-alpha is known to inhibit insulin signaling in adipose tissue, and deletion of TNF-alpha, or the TNF receptor, TNFR1, in both genetic (TNFR1) and high-fat diet induced (TNFR1 and TNF-alpha) obese mice results in greater insulin sensitivity.	3	31	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	3	4	30	31
TNF-alpha downregulated TNFR1 mRNA ( XREF_FIG ) and total cellular protein levels as measured by semi-quantitative RT-PCR and ELISA respectively ( XREF_FIG ) .	TNF-alpha downregulated TNFR1 mRNA (XREF_FIG) and total cellular protein levels as measured by semi-quantitative RT-PCR and ELISA respectively (XREF_FIG).	0	3	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	0	1	2	3
These results suggest that TNFalpha production , in response to EBV latency III infection , creates the synthetic requirement for cFLIP to block TNFR1 driven programed cell death .	These results suggest that TNFalpha production, in response to EBV latency III infection, creates the synthetic requirement for cFLIP to block TNFR1 driven programed cell death.	4	24	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	4	5	23	24
However , TNF-alpha down-regulates TNFR1 and TNFR2 receptors which would be predicted to down-regulate TNF-alpha mediated activation of this transcription factor .	However, TNF-alpha down-regulates TNFR1 and TNFR2 receptors which would be predicted to down-regulate TNF-alpha mediated activation of this transcription factor.	2	7	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	2	3	4	5
As a TNFR1 antagonist , it reduced cytotoxicity mediated by TNF-alpha in L929 fibroblasts and effectively inhibited the combination between TNF-alpha with TNFR1 in surface plasmon resonance analysis .	As a TNFR1 antagonist, it reduced cytotoxicity mediated by TNF-alpha in L929 fibroblasts and effectively inhibited the combination between TNF-alpha with TNFR1 in surface plasmon resonance analysis.	8	25	mediated	Positive_activation_syntax_3_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	10	11	22	23
Unlabeled TNF inhibited > 95 % of the specific binding of a Gaussia princeps luciferase ( GpL ) fusion protein of TNF to TNFR1 and TNFR2 and blocked binding of soluble GpL fusion proteins of TNFR1 and TNFR2 to membrane TNF expressing cells to > 95 % , too .	Unlabeled TNF inhibited> 95% of the specific binding of a Gaussia princeps luciferase (GpL) fusion protein of TNF to TNFR1 and TNFR2 and blocked binding of soluble GpL fusion proteins of TNFR1 and TNFR2 to membrane TNF expressing cells to> 95%, too.	0	37	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	1	2	35	36
Here we studied the influence of TNF and TNF receptors ( TNFR ) on intercellular adhesion molecule-1 ( ICAM-1 ) and macrophage influx following chronic constrictive injury ( CCI ) in mice by three different paradigms : ( 1 ) C57BL and Wld mice with delayed TNF up-regulation , ( 2 ) in vivo inhibition of TNFR1 and TNFR2 by neutralizing antibodies , and ( 3 ) three different types of mice with a genetic deficiency for TNFR .	Here we studied the influence of TNF and TNF receptors (TNFR) on intercellular adhesion molecule-1 (ICAM-1) and macrophage influx following chronic constrictive injury (CCI) in mice by three different paradigms : (1) C57BL and Wld mice with delayed TNF up-regulation, (2) in vivo inhibition of TNFR1 and TNFR2 by neutralizing antibodies, and (3) three different types of mice with a genetic deficiency for TNFR.	46	58	inhibition	Negative_activation_syntax_7_noun	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	46	47	56	57
In addition , we also found that TNFalpha could slightly induce IKKbeta degradation and potently trigger the degradation of TNFR1 as well as IkappaBalpha upon 1-hour treatment of TNFalpha .	In addition, we also found that TNFalpha could slightly induce IKKbeta degradation and potently trigger the degradation of TNFR1 as well as IkappaBalpha upon 1-hour treatment of TNFalpha.	7	20	trigger	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	7	8	19	20
Acute but Not Chronic TNF Induces a TNFR1 Dependent Loss of Paneth Cell Populations .	Acute but Not Chronic TNF Induces a TNFR1 Dependent Loss of Paneth Cell Populations.	0	9	Induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	4	5	7	8
173 The opposite approach is required for the TNFalpha pathway , where biologics have been developed to block TNFalpha itself or TNFR1 , preventing downstream activation of the NF-kappaB pathway and/or apoptosis induction and providing effective treatment for a number of inflammatory diseases , including SLE , rheumatoid arthritis and septic shock .	173 The opposite approach is required for the TNFalpha pathway, where biologics have been developed to block TNFalpha itself or TNFR1, preventing downstream activation of the NF-kappaB pathway and/or apoptosis induction and providing effective treatment for a number of inflammatory diseases, including SLE, rheumatoid arthritis and septic shock.	8	36	block	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	8	9	21	22
In this context , a selective inhibition of TNF induced TNFR1 but not TNFR2 signaling activity holds great promises to overcome undesired effects observed with less specific TNF antagonists currently used in clinic .	In this context, a selective inhibition of TNF induced TNFR1 but not TNFR2 signaling activity holds great promises to overcome undesired effects observed with less specific TNF antagonists currently used in clinic.	6	16	induced	Positive_early_activation	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR1	TNFR1	TNFR1	8	9	10	11
However , TRAF2 is not degraded in the context of TNFalpha triggered TNFR1 signaling , although both TRAF2 and cIAP1 are recruited to the TNFR1 complex .	However, TRAF2 is not degraded in the context of TNFalpha triggered TNFR1 signaling, although both TRAF2 and cIAP1 are recruited to the TNFR1 complex.	8	13	triggered	Positive_activation_token_1_verb	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	TNFR1	TNFR1	TNFR1	10	11	12	13
In the MLE-15 cells , TNF-alpha exposure suppresses cellular TNFR1 content ( data not shown ) .	In the MLE-15 cells, TNF-alpha exposure suppresses cellular TNFR1 content (data not shown).	5	10	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF-alpha	TNF-alpha	TNF-alpha	TNFR1	TNFR1	TNFR1	5	6	9	10
The inhibition of glycolysis can also be achieved by p53 dependent transcriptional activation of synthesis of cytochrome C oxidative 2 , resulting in enhanced mitochondrial respiration .	The inhibition of glycolysis can also be achieved by p53 dependent transcriptional activation of synthesis of cytochrome C oxidative 2, resulting in enhanced mitochondrial respiration.	7	18	activation	Positive_activation_syntax_7_noun	Positive_activation	Positive_activation	p53	p53	p53	cytochrome C	cytochrome C	cytochrome C	9	10	16	18
Bcl-x ( L ) and/or mutated p53 inhibit the apoptotic process by preventing the mitochondrial release of cytochrome c and/or activation of execution caspases .	Bcl-x (L) and/or mutated p53 inhibit the apoptotic process by preventing the mitochondrial release of cytochrome c and/or activation of execution caspases.	6	19	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	6	7	17	19
Moreover , EMR exposure increased the levels of p53 protein and p53 target gene expression , promoted cytochrome c release from mitochondrion , and increased caspase-3 activity .	Moreover, EMR exposure increased the levels of p53 protein and p53 target gene expression, promoted cytochrome c release from mitochondrion, and increased caspase-3 activity.	2	19	promoted	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	EMR exposure increased the levels of p53 protein and p53 target gene expression	p53	cytochrome c	cytochrome c	cytochrome c	11	12	17	19
In this study , western blot analysis revealed that repeated ethanol treatment decreased the expression of steroidogenic acute regulatory protein ( StAR ) , 3b-hydroxysteroid dehydrogenase ( 3b-HSD ) and 17b-hydroxysteroid dehydrogenase ( 17b-HSD ) ; increased the expression of active caspase-3 , p53 , Fas and Fas-L ; and led to up-regulation of Bax and Bcl -2 ratio and translocation of cytochrome c from mitochondria to cytosol in testis .	In this study, western blot analysis revealed that repeated ethanol treatment decreased the expression of steroidogenic acute regulatory protein (StAR), 3b-hydroxysteroid dehydrogenase (3b-HSD) and 17b-hydroxysteroid dehydrogenase (17b-HSD); increased the expression of active caspase-3, p53, Fas and Fas-L; and led to up-regulation of Bax and Bcl -2 ratio and translocation of cytochrome c from mitochondria to cytosol in testis.	10	64	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	p53	ethanol treatment decreased the expression of steroidogenic acute regulatory protein (StAR), 3b-hydroxysteroid dehydrogenase (3b-HSD) and 17b-hydroxysteroid dehydrogenase (17b-HSD); increased the expression of active caspase-3, p53	p53	cytochrome c	cytochrome c	cytochrome c	43	44	62	64
p53 binds to and inhibits antiapoptotic members of the Bcl-2 family that reside in the mitochondrial surface , such as Bcl-2 or Bcl-xL , resulting in increased mitochondrial membrane permeability , the release of mitochondrial cytochrome c into the cytosol , and the initiation of the apoptotic caspase cascade .	p53 binds to and inhibits antiapoptotic members of the Bcl-2 family that reside in the mitochondrial surface, such as Bcl-2 or Bcl-xL, resulting in increased mitochondrial membrane permeability, the release of mitochondrial cytochrome c into the cytosol, and the initiation of the apoptotic caspase cascade.	0	37	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	0	1	35	37
In the mitochondria , p53 also induces loss of mitochondrial membrane potential , cytochrome c release and caspase-3 activation , triggering apoptosis .	In the mitochondria, p53 also induces loss of mitochondrial membrane potential, cytochrome c release and caspase-3 activation, triggering apoptosis.	4	15	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	4	5	13	15
In addition , ASA could led to a loss in the mitochondrial out membrane potential , up-regulate p53 , phosphorylated p53 and Bax , down-regulate Bcl-2 , release cytochrome c from the mitochondria to the cytoplasm , and activate caspase-9 and caspase-3 in A549 cells , which revealed that ASA could also induce apoptosis through the mitochondria mediated pathway .	In addition, ASA could led to a loss in the mitochondrial out membrane potential, up-regulate p53, phosphorylated p53 and Bax, down-regulate Bcl-2, release cytochrome c from the mitochondria to the cytoplasm, and activate caspase-9 and caspase-3 in A549 cells, which revealed that ASA could also induce apoptosis through the mitochondria mediated pathway.	17	30	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	17	18	28	30
Importantly , at early stages of neural differentiation , p53 was actively translocated to mitochondria and attenuated mitochondrial oxidative stress , cytochrome c release , and mitophagy .	Importantly, at early stages of neural differentiation, p53 was actively translocated to mitochondria and attenuated mitochondrial oxidative stress, cytochrome c release, and mitophagy.	9	23	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53 was actively translocated to mitochondria	p53	cytochrome c	cytochrome c	cytochrome c	9	10	21	23
The inhibitory effect of HMGA1 on p53 induced cytochrome c release was further confirmed by analyzing mitochondrial and cytosolic fractions isolated from wild-type and MEFs null for the hmga1 gene after UV irradiation .	The inhibitory effect of HMGA1 on p53 induced cytochrome c release was further confirmed by analyzing mitochondrial and cytosolic fractions isolated from wild-type and MEFs null for the hmga1 gene after UV irradiation.	4	10	induced	Positive_early_activation	Positive_activation	Negative_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	6	7	8	10
Western blot analysis revealed that repeated ethanol treatment decreased the expression of steroidogenic acute regulatory protein ( StAR ) , 3 beta-hydroxysteroid dehydrogenase ( 3beta-HSD ) and 17 beta-hydroxysteroid dehydrogenase ( 17beta-HSD ) ; increased the expression of active caspase-3 , p53 , Fas and Fas-L ; and led to up-regulation of Bax and Bcl -2 ratio and translocation of cytochrome c from mitochondria to cytosol in testis .	Western blot analysis revealed that repeated ethanol treatment decreased the expression of steroidogenic acute regulatory protein (StAR), 3 beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17beta-HSD); increased the expression of active caspase-3, p53, Fas and Fas-L; and led to up-regulation of Bax and Bcl -2 ratio and translocation of cytochrome c from mitochondria to cytosol in testis.	6	62	led to	Positive_activation_nested_syntax_2_verb	Positive_activation	Positive_activation	p53	ethanol treatment decreased the expression of steroidogenic acute regulatory protein (StAR), 3 beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17beta-HSD); increased the expression of active caspase-3, p53	p53	cytochrome c	cytochrome c	cytochrome c	41	42	60	62
In contrast , XREF_BIBR demonstrated that TP53 could be translocated to mitochondria and attenuate oxidative stress , mitophagy , and cytochrome c release during neuronal differentiation .	In contrast, XREF_BIBR demonstrated that TP53 could be translocated to mitochondria and attenuate oxidative stress, mitophagy, and cytochrome c release during neuronal differentiation.	6	22	attenuate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TP53	TP53 could be translocated to mitochondria	tp53	cytochrome c	cytochrome c	cytochrome c	6	7	20	22
Inactivation of p53 blocks cytochrome c release and caspase-9 activation .	Inactivation of p53 blocks cytochrome c release and caspase-9 activation.	0	6	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	2	3	4	6
The addition of the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone ( zVAD-fmk ) directly after transduction almost completely prevented p53 induced apoptotic cell death but did not inhibit mitochondrial cytochrome c release .	The addition of the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) directly after transduction almost completely prevented p53 induced apoptotic cell death but did not inhibit mitochondrial cytochrome c release.	18	30	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	18	19	28	30
Apoptotic induction by GATPT was shown to be mediated in a p53 dependent manner and loss of p53 impaired the release of cytochrome c from mitochondria to cytosol .	Apoptotic induction by GATPT was shown to be mediated in a p53 dependent manner and loss of p53 impaired the release of cytochrome c from mitochondria to cytosol.	13	24	impaired	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	17	18	22	24
In MEFs , zVAD-fmk increased p53 dependent loss of DeltaPsim , cytochrome c release and caspase-9 activity .	In MEFs, zVAD-fmk increased p53 dependent loss of DeltaPsim, cytochrome c release and caspase-9 activity.	5	13	loss	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	p53	p53	p53	cytochrome c	cytochrome c	cytochrome c	5	6	11	13
In addition , EGCG attenuated TNFalpha mediated down-regulation of TNFalpha receptor 1 ( TNFR1 ) , but not TNFR2 .	In addition, EGCG attenuated TNFalpha mediated down-regulation of TNFalpha receptor 1 (TNFR1), but not TNFR2.	5	19	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	5	6	18	19
NFkappaB inhibition had little effect on IL-6 + TNFalpha induced TNFR2 , but did inhibit induction of endogenous IL-6 and TNFR2 in cells treated with TNFalpha alone .	NFkappaB inhibition had little effect on IL-6 + TNFalpha induced TNFR2, but did inhibit induction of endogenous IL-6 and TNFR2 in cells treated with TNFalpha alone.	2	14	induced	Positive_early_activation	Positive_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	8	9	10	11
Additionally , by inducing macrophage secretion of IL-10 , pathogenic mycobacteria may also limit apoptosis since IL-10 inhibits TNFalpha expression and increases release of soluble TNFR2 to neutralize TNFalpha activity [ XREF_BIBR ] .	Additionally, by inducing macrophage secretion of IL-10, pathogenic mycobacteria may also limit apoptosis since IL-10 inhibits TNFalpha expression and increases release of soluble TNFR2 to neutralize TNFalpha activity [XREF_BIBR].	16	26	increases	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TNFalpha	IL-10 inhibits TNFalpha expression	tnfalpha	TNFR2	TNFR2	tnfr2	18	19	25	26
Moreover , blockade of bioactive IL-6 in ascites , but not TNF , also decreased the level of TNFR2 expression in both CD4 + and CD8 + T cells as well as Teff and Tregs , with the most prominent effect found on Tregs , overall increasing the ratio of TNFR2 + Teffs to TNFR2 + Tregs .	Moreover, blockade of bioactive IL-6 in ascites, but not TNF, also decreased the level of TNFR2 expression in both CD4 + and CD8 + T cells as well as Teff and Tregs, with the most prominent effect found on Tregs, overall increasing the ratio of TNFR2 + Teffs to TNFR2 + Tregs.	2	51	increasing	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	11	12	50	51
Furthermore , effects of combined inhibition of STAT3 and NFkappaB on basal or IL-6 + TNFalpha induced TNFR2 was not significantly different than the inhibitory effect of cucurbitacin alone .	Furthermore, effects of combined inhibition of STAT3 and NFkappaB on basal or IL-6 + TNFalpha induced TNFR2 was not significantly different than the inhibitory effect of cucurbitacin alone.	5	21	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	15	16	17	18
Basal and IL-6 + TNFalpha induced TNFR2 were decreased by pharmacological STAT3 inhibition .	Basal and IL-6 + TNFalpha induced TNFR2 were decreased by pharmacological STAT3 inhibition.	0	8	induced	Positive_early_activation	Positive_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	TNFR2	TNFR2	TNFR2	4	5	6	7
Deficiency in TNF or TNFR1 abrogated TNFR2 induced expression of A20 and significantly reduced upregulation of IL-6 , IL-1beta , and TRAF1 .	Deficiency in TNF or TNFR1 abrogated TNFR2 induced expression of A20 and significantly reduced upregulation of IL-6, IL-1beta, and TRAF1.	0	7	abrogated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	2	3	6	7
TNF induced proMMP9 production , as measured by zymography , was significantly blocked and inhibited by TNF receptor 1 ( TNFRSF1A ) antibody , NFKB activation inhibitor ( NFKBAI ) , and MAPK1/3 ( ERK ) inhibitor ( U0126 ) ( P < 0.01 ) , but not by TNF receptor 2 ( TNFRSF1B ) antibody , MAPK14 ( p38 MAPK ) inhibitor ( SB203580 ) , and MAPK8/9/10 ( JNK ) inhibitor ( SP600125 ) .	TNF induced proMMP9 production, as measured by zymography, was significantly blocked and inhibited by TNF receptor 1 (TNFRSF1A) antibody, NFKB activation inhibitor (NFKBAI), and MAPK1/3 (ERK) inhibitor (U0126) (P < 0.01), but not by TNF receptor 2 (TNFRSF1B) antibody, MAPK14 (p38 MAPK) inhibitor (SB203580), and MAPK8/9/10 (JNK) inhibitor (SP600125).	12	55	blocked	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFRSF1B	TNFRSF1B	TNFRSF1B	16	17	53	54
During BCG induced pleurisy , transmembrane TNF on M-MDSC restricts proliferation of CD4 T cells via interaction with lymphocyte expressed TNFR2 .	During BCG induced pleurisy, transmembrane TNF on M-MDSC restricts proliferation of CD4 T cells via interaction with lymphocyte expressed TNFR2.	5	21	restricts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	6	7	20	21
TNF blockade during sustained acute disease prevents ongoing lesion progression and severe clinical disability and promotes repair independent of TNFR2 .	TNF blockade during sustained acute disease prevents ongoing lesion progression and severe clinical disability and promotes repair independent of TNFR2.	0	20	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TNF	TNF	TNF	TNFR2	TNFR2	TNFR2	0	1	19	20
In contrast , OA treatment of p53 silenced cells inhibited BAK conformational change following DNA damage ( XREF_FIG 10A ) .	In contrast, OA treatment of p53 silenced cells inhibited BAK conformational change following DNA damage (XREF_FIG 10A).	4	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	BAK	BAK	BAK	6	7	10	11
We found that p53 siRNA efficiently prevented AIF and endoG release as well as Bak activation in HCT116 Bax KO and MCF-7 cells .	We found that p53 siRNA efficiently prevented AIF and endoG release as well as Bak activation in HCT116 Bax KO and MCF-7 cells.	3	15	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	p53	p53	p53	Bak	Bak	Bak	3	4	14	15
Summarizing , these experiments established proof-of-principle that several BH3-only proteins and p53 , when expressed simultaneously , can instigate apoptosis in the absence of BAX and with significantly reduced BAK in HCT116 cells .	Summarizing, these experiments established proof-of-principle that several BH3-only proteins and p53, when expressed simultaneously, can instigate apoptosis in the absence of BAX and with significantly reduced BAK in HCT116 cells.	9	32	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	p53	p53	p53	BAK	BAK	BAK	11	12	29	30
ASPP2 inhibits L-OHP-induced cell autophagy in a p53 independent manner .	ASPP2 inhibits L-OHP-induced cell autophagy in a p53 independent manner.	0	9	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	0	1	7	8
These results suggested that ASPP2 inhibited L-OHP-induced cell autophagy independent of p53 .	These results suggested that ASPP2 inhibited L-OHP-induced cell autophagy independent of p53.	4	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	4	5	11	12
In our MY1H system , the decrease in positive signal from transactivation of GAL4AD-p53 requires the interaction of LTAg or 53BP2 with GAL4AD-p53 : LTAg and 53BP2 prevent the DNA binding of p53 in vivo , thereby leading to decreased activation potential .	In our MY1H system, the decrease in positive signal from transactivation of GAL4AD-p53 requires the interaction of LTAg or 53BP2 with GAL4AD-p53 : LTAg and 53BP2 prevent the DNA binding of p53 in vivo, thereby leading to decreased activation potential.	24	33	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	53BP2	53BP2	53BP2	p53	p53	p53	26	27	32	33
Alternatively , ectopic expression of either ASPP1 or ASPP2 enhances p53 dependent apoptosis , and depletion of ASPP1 and/or ASPP2 suppresses the ability of p53 to induce apoptosis .	Alternatively, ectopic expression of either ASPP1 or ASPP2 enhances p53 dependent apoptosis, and depletion of ASPP1 and/or ASPP2 suppresses the ability of p53 to induce apoptosis.	15	25	suppresses	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	19	20	24	25
The expression of ASPP1 and ASPP2 is frequently downregulated in human breast tumours ( Samuels-Lev et al , 2001 ) and tumour cell lines ( Liu et al , 2005 ) expressing wild-type p53 , suggesting that there is a selective advantage for loss of ASPP1 and ASPP2 expression in human breast tumours expressing wild-type p53 .	The expression of ASPP1 and ASPP2 is frequently downregulated in human breast tumours (Samuels-Lev et al, 2001) and tumour cell lines (Liu et al, 2005) expressing wild-type p53, suggesting that there is a selective advantage for loss of ASPP1 and ASPP2 expression in human breast tumours expressing wild-type p53.	1	34	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ASPP2	expression of ASPP1 and ASPP2	aspp2	p53	p53	p53	5	6	33	34
First , as discussed above , previous studies have already proven that LTAg and 53BP2 inhibit DNA binding of p53 by binding to and masking p53 ' s DNA binding domain .	First, as discussed above, previous studies have already proven that LTAg and 53BP2 inhibit DNA binding of p53 by binding to and masking p53 's DNA binding domain.	12	20	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	53BP2	53BP2	53BP2	p53	p53	p53	14	15	19	20
Both LTAg and 53BP2 inhibit wild-type p53 function through a protein protein interaction at the DNA binding domain of p53 , thereby preventing p53 from binding to its consensus DNA target site .	Both LTAg and 53BP2 inhibit wild-type p53 function through a protein protein interaction at the DNA binding domain of p53, thereby preventing p53 from binding to its consensus DNA target site.	1	7	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	53BP2	53BP2	53BP2	p53	p53	p53	3	4	6	7
How attenuation of ASPP2 expression modulates p53 dependent and/or p53 independent pathways in acute leukemia remains to be elucidated .	How attenuation of ASPP2 expression modulates p53 dependent and/or p53 independent pathways in acute leukemia remains to be elucidated.	3	7	modulates	Positive_activation_token_1_verb	Positive_activation	Negative_activation	ASPP2	ASPP2 expression	aspp2	p53	p53	p53	3	4	6	7
Once inside host cells , CagA interacts with ASPP2 , which specifically stimulates p53 mediated apoptosis and reverses its pro apoptotic function to promote ASPP2 dependent degradation of p53 .	Once inside host cells, CagA interacts with ASPP2, which specifically stimulates p53 mediated apoptosis and reverses its pro apoptotic function to promote ASPP2 dependent degradation of p53.	24	29	degradation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	ASPP2	ASPP2	ASPP2	p53	p53	p53	24	25	28	29
Nevertheless , these data suggest that TRAF2 inhibits caspase-8 activation by recruiting cIAP1 ( and possibly also cIAP2 ) to the TNFR1 complex following TNFalpha stimulation .	Nevertheless, these data suggest that TRAF2 inhibits caspase-8 activation by recruiting cIAP1 (and possibly also cIAP2) to the TNFR1 complex following TNFalpha stimulation.	6	17	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF2	TRAF2	TRAF2	cIAP1	cIAP1	cIAP1	6	7	12	13
When treated with LBW242 , TRAF2 cko-/- MEFs were resistant to SM induced degradation of cIAP1 .	When treated with LBW242, TRAF2 cko-/- MEFs were resistant to SM induced degradation of cIAP1.	5	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF2	TRAF2	TRAF2	cIAP1	cIAP1	cIAP1	5	6	15	16
14 Although all three SMs triggered depletion of endogenous cIAP1 in WT mouse embryonic fibroblasts ( MEFs ) ( XREF_FIG ) , TRAF2 -/- MEFs were refractory to rapid SM induced degradation of cIAP1 .	14 Although all three SMs triggered depletion of endogenous cIAP1 in WT mouse embryonic fibroblasts (MEFs) (XREF_FIG), TRAF2 -/- MEFs were refractory to rapid SM induced degradation of cIAP1.	22	34	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF2	TRAF2	TRAF2	cIAP1	cIAP1	cIAP1	22	23	33	34
TRAF1-/- dendritic cells show attenuated responses to secondary stimulation by TRAF2 dependent factors and increased stimulus dependent TRAF2 degradation .	TRAF1-/- dendritic cells show attenuated responses to secondary stimulation by TRAF2 dependent factors and increased stimulus dependent TRAF2 degradation.	0	18	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF1-/-	TRAF1-/-	TRAF1-/-	TRAF2	TRAF2	TRAF2	0	1	17	18
The observation that TRAF1 can either activate or inhibit the NF-kappa B pathway and the fact that it influences the oligomerization of TRAF2 indicates that relative levels of IKK2 , TRAF1 and TRAF2 may be important for regulation of NF-kappa B activity .	The observation that TRAF1 can either activate or inhibit the NF-kappa B pathway and the fact that it influences the oligomerization of TRAF2 indicates that relative levels of IKK2, TRAF1 and TRAF2 may be important for regulation of NF-kappa B activity.	3	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	3	4	22	23
While TRAF-2/3/5/6 activate downstream signaling , TRAF-1 inactivates TRAF-2 by direct binding and is considered an inhibitory TRAF .	While TRAF-2/3/5/6 activate downstream signaling, TRAF-1 inactivates TRAF-2 by direct binding and is considered an inhibitory TRAF.	6	14	inactivates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF-1	TRAF-1	TRAF-1	TRAF-2	TRAF-2	TRAF-2	6	7	8	9
As we found that only TRAF2 that is capable of raft translocation can bind to Filamin and that TRAF1 can disrupt the interaction of TRAF2 and Filamin ( XREF_FIG ) , it appears that cytoskeletal trafficking of TRAF2 is a consequence of raft translocation .	As we found that only TRAF2 that is capable of raft translocation can bind to Filamin and that TRAF1 can disrupt the interaction of TRAF2 and Filamin (XREF_FIG), it appears that cytoskeletal trafficking of TRAF2 is a consequence of raft translocation.	18	28	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF1	TRAF1	TRAF1	TRAF2	TRAF2	TRAF2	18	19	24	25
XREF_BIBR , XREF_BIBR The finding that loss of either cIAP1/2 or Traf2 can activate RIP1 suggests that these proteins normally function to keep RIP1 inactive .	XREF_BIBR, XREF_BIBR The finding that loss of either cIAP1/2 or Traf2 can activate RIP1 suggests that these proteins normally function to keep RIP1 inactive.	6	15	activate	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Traf2	loss of either cIAP1/2 or Traf2	traf2	RIP1	RIP1	rip1	11	12	14	15
These data raise the possibility that TRAF2 limits the access of RIP1 to complex II , and that the lack of TRAF2 allows potentiated RIP1 recruitment and subsequent caspase-8 activation , which is similar to the cIAP deficiency as previously reported [ XREF_BIBR ] .	These data raise the possibility that TRAF2 limits the access of RIP1 to complex II, and that the lack of TRAF2 allows potentiated RIP1 recruitment and subsequent caspase-8 activation, which is similar to the cIAP deficiency as previously reported [XREF_BIBR].	6	12	limits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF2	TRAF2	TRAF2	RIP1	RIP1	RIP1	6	7	11	12
In comparison to caspase-8 activity induced by TNF alone or TNF + CHX in Sharpin deficient HaCaT cells , TRADD deficiency significantly suppressed caspase-8 activation ( XREF_FIG ) .	In comparison to caspase-8 activity induced by TNF alone or TNF + CHX in Sharpin deficient HaCaT cells, TRADD deficiency significantly suppressed caspase-8 activation (XREF_FIG).	19	24	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRADD	TRADD	TRADD	caspase-8	caspase-8	caspase-8	19	20	23	24
Here we showed that deletion TRADD largely blocked PARP cleavage , caspase 8 activation , GAPDH release , and cell death induced by 5z-7 plus TNFalpha , indicating a critical role for TRADD in regulating both apoptotic and necroptotic signaling ( XREF_FIG ) .	Here we showed that deletion TRADD largely blocked PARP cleavage, caspase 8 activation, GAPDH release, and cell death induced by 5z-7 plus TNFalpha, indicating a critical role for TRADD in regulating both apoptotic and necroptotic signaling (XREF_FIG).	4	13	blocked	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRADD	TRADD	TRADD	caspase 8	caspase 8	caspase 8	5	6	11	13
First , we quantified Mad2 levels at unattached KTs in control and Tpr depleted cells overexpressing GFP-Mad2 by immunofluorescence microscopy upon MT depolymerization with nocodazole ( XREF_FIG and S1 J ) .	First, we quantified Mad2 levels at unattached KTs in control and Tpr depleted cells overexpressing GFP-Mad2 by immunofluorescence microscopy upon MT depolymerization with nocodazole (XREF_FIG and S1 J).	3	17	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tpr	Tpr	Tpr	GFP-Mad2	GFP-Mad2	GFP-Mad2	12	13	16	17
Next , we quantified the mitotic duration after nocodazole treatment in Tpr depleted cells overexpressing GFP-Mad2 and found a significant rescue of mitotic duration relative to parental cells depleted of Tpr ( 15.8 +/- 7.6 h vs. 11.7 +/- 7.1 h ; n = 115 cells , P < 0.01 ; XREF_FIG ) .	Next, we quantified the mitotic duration after nocodazole treatment in Tpr depleted cells overexpressing GFP-Mad2 and found a significant rescue of mitotic duration relative to parental cells depleted of Tpr (15.8 +/- 7.6 h vs. 11.7 +/- 7.1 h; n = 115 cells, P < 0.01; XREF_FIG).	3	16	depleted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tpr	Tpr	Tpr	GFP-Mad2	GFP-Mad2	GFP-Mad2	11	12	15	16
cIAP1/2 interacting protein TRAF2 ( TNF receptor associated factor 2 ) prevented the Vgl-4-driven nuclear localization of cIAP2 .	cIAP1/2 interacting protein TRAF2 (TNF receptor associated factor 2) prevented the Vgl-4-driven nuclear localization of cIAP2.	0	18	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF2	TRAF2	TRAF2	cIAP2	cIAP2	cIAP2	3	4	17	18
35 Inhibition of Traf2 may cause defective TAK1 signaling that in turn promotes necroptosis .	35 Inhibition of Traf2 may cause defective TAK1 signaling that in turn promotes necroptosis.	1	8	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Traf2	Traf2	Traf2	TAK1	TAK1	TAK1	3	4	7	8
Overall , our current findings predict that BBR is a potential candidate for therapeutic targeting of TLR4 and TRAF2 mediated ASK1 activation in inflammatory and in RA pathogenesis possibly through post-transcriptional gene silencing via miR-23a .	Overall, our current findings predict that BBR is a potential candidate for therapeutic targeting of TLR4 and TRAF2 mediated ASK1 activation in inflammatory and in RA pathogenesis possibly through post-transcriptional gene silencing via miR-23a.	14	21	mediated	Positive_early_activation	Positive_activation	Positive_activation	TRAF2	TRAF2	TRAF2	ASK1	ASK1	ASK1	18	19	20	21
NF-kappaB activation by LMP1 ( 1-231 ) is likely to be mediated by TRAF1 and TRAF2 heteroaggregates since TRAF1 is unique among the TRAFs in coactivating NF-kappaB with LMP1 ( 1-231 ) , a TRAF2 dominant negative mutant can block LMP1 ( 1-231 )-mediated NF-kappaB activation as well as TRAF1 coactivation , and 30 % of TRAF2 is associated with TRAF1 in EBV transformed B cells .	NF-kappaB activation by LMP1 (1-231) is likely to be mediated by TRAF1 and TRAF2 heteroaggregates since TRAF1 is unique among the TRAFs in coactivating NF-kappaB with LMP1 (1-231), a TRAF2 dominant negative mutant can block LMP1 (1-231)-mediated NF-kappaB activation as well as TRAF1 coactivation, and 30% of TRAF2 is associated with TRAF1 in EBV transformed B cells.	33	50	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF2	TRAF2	TRAF2	TRAF1	TRAF1	TRAF1	34	35	49	50
Our data indicate that TSC1 inhibits Rac1 and TSC2 blocks this activity of TSC1 .	Our data indicate that TSC1 inhibits Rac1 and TSC2 blocks this activity of TSC1.	6	14	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSC2	TSC2	TSC2	TSC1	TSC1	TSC1	8	9	13	14
41 Fisetin caused inhibition of the phosphorylation of TSC2 and increase in the protein expression of TSC2 consistent with the fact that Akt phosphorylates TSC2 and disrupts the TSC1 and TSC2complex , leading to activation of mTOR .	41 Fisetin caused inhibition of the phosphorylation of TSC2 and increase in the protein expression of TSC2 consistent with the fact that Akt phosphorylates TSC2 and disrupts the TSC1 and TSC2complex, leading to activation of mTOR.	1	30	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSC2	Fisetin caused inhibition of the phosphorylation of TSC2 and increase in the protein expression of TSC2 consistent with the fact that Akt phosphorylates TSC2	tsc2	TSC1	TSC1	tsc1	24	25	28	29
Phosphorylation of raptor and TSC2 , as downstream effectors of the ROS-AMPK axis , reduced mTORC1 activity since i ) raptor phosphorylation at Ser 722 and Ser 792 can promote its binding to 14-3-3 , which would attenuate the Ser Thr kinase function of mTOR [ XREF_BIBR ] ; and ii ) stimulatory phosphorylation of TSC2 at Ser 1387 can enhance the TSC2 and TSC1 tuberous sclerosis complex activity , which is a negative regulator of mTORC1 [ XREF_BIBR ] .	Phosphorylation of raptor and TSC2, as downstream effectors of the ROS-AMPK axis, reduced mTORC1 activity since i) raptor phosphorylation at Ser-722 and Ser-792 can promote its binding to 14-3-3, which would attenuate the Ser Thr kinase function of mTOR [XREF_BIBR]; and ii) stimulatory phosphorylation of TSC2 at Ser 1387 can enhance the TSC2 and TSC1 tuberous sclerosis complex activity, which is a negative regulator of mTORC1 [XREF_BIBR].	0	68	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSC2	Phosphorylation of raptor and TSC2	tsc2	TSC1	TSC1	tsc1	4	5	64	65
Furthermore , because oligomerization of the hamartin carboxyl-terminal coiled coil domain was inhibited by the presence of tuberin , we propose that tuberin acts as a chaperone , preventing hamartin self aggregation .	Furthermore, because oligomerization of the hamartin carboxyl-terminal coiled coil domain was inhibited by the presence of tuberin, we propose that tuberin acts as a chaperone, preventing hamartin self aggregation.	22	31	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	tuberin	tuberin	tuberin	hamartin	hamartin	hamartin	22	23	29	30
However , phosphorylation of TSC2 by Akt , extracellular signal regulated kinases ( ERK ) , RSK1 , AMPK , or glycogen synthase kinase -3 beta ( GSK-3beta ) may be more important to block TSC1 and TSC2 activity .	However, phosphorylation of TSC2 by Akt, extracellular signal regulated kinases (ERK), RSK1, AMPK, or glycogen synthase kinase -3 beta (GSK-3beta) may be more important to block TSC1 and TSC2 activity.	2	38	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSC2	phosphorylation of TSC2	tsc2	TSC1	TSC1	tsc1	4	5	35	36
Phosphorylation of TSC2 by Akt disrupts the TSC1 and TSC2 complex and the subcellular localization of TSC1 and TSC2 as well as its function as tumor suppressor genes ( 28-30 ) .	Phosphorylation of TSC2 by Akt disrupts the TSC1 and TSC2 complex and the subcellular localization of TSC1 and TSC2 as well as its function as tumor suppressor genes (28-30).	0	11	disrupts	Negative_regulation_syntax_1_verb	Positive_activation	Negative_regulation	TSC2	Phosphorylation of TSC2 by Akt	tsc2	TSC1	TSC1 and TSC2 complex	tsc1	2	3	7	8
As expected , in sucrose density fractions , both transient ( XREF_FIG ) and stable ( XREF_SUPPLEMENTARY ) knockdown of TSC2 caused a complete shift of TSC1 to fractions of intermediate density ( XREF_FIG and XREF_SUPPLEMENTARY ) , and TSC1 knockdown had the same effect on the fractionation of TSC2 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	As expected, in sucrose density fractions, both transient (XREF_FIG) and stable (XREF_SUPPLEMENTARY) knockdown of TSC2 caused a complete shift of TSC1 to fractions of intermediate density (XREF_FIG and XREF_SUPPLEMENTARY), and TSC1 knockdown had the same effect on the fractionation of TSC2 (XREF_FIG and XREF_SUPPLEMENTARY).	18	27	caused	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TSC2	TSC2	TSC2	TSC1	TSC1	TSC1	20	21	26	27
XREF_BIBR , XREF_BIBR Phosphorylation of TSC2 at serine 939 by DAPK1 disrupts the dimerization of TSC1 with TSC2 , leading to increased cell growth and protein synthesis , and thereby maintaining a homeostatic balance between survival and death signaling .	XREF_BIBR, XREF_BIBR Phosphorylation of TSC2 at serine 939 by DAPK1 disrupts the dimerization of TSC1 with TSC2, leading to increased cell growth and protein synthesis, and thereby maintaining a homeostatic balance between survival and death signaling.	3	16	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSC2	Phosphorylation of TSC2 at serine 939	tsc2	TSC1	TSC1	tsc1	5	6	15	16
Akt induced phosphorylation of the tumour suppressor TSC2 ( also known as tuberin ) causes the dissociation of TSC2 and TSC1 ( also known as hamartin ) , relieving their inhibition of mTOR kinase .	Akt induced phosphorylation of the tumour suppressor TSC2 (also known as tuberin) causes the dissociation of TSC2 and TSC1 (also known as hamartin), relieving their inhibition of mTOR kinase.	0	21	causes	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSC2	Akt induced phosphorylation of the tumour suppressor TSC2	tsc2	TSC1	TSC1	tsc1	7	8	20	21
In our model , TSC1 inhibits Rac1 , and TSC2 blocks this activity of TSC1 that is a prerequisite to the activation of Rac1 and the subsequent inhibition of Rho ; this , in turn , promotes stress fiber disassembly and focal adhesion remodeling ( XREF_FIG ) .	In our model, TSC1 inhibits Rac1, and TSC2 blocks this activity of TSC1 that is a prerequisite to the activation of Rac1 and the subsequent inhibition of Rho; this, in turn, promotes stress fiber disassembly and focal adhesion remodeling (XREF_FIG).	9	15	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSC2	TSC2	TSC2	TSC1	TSC1	TSC1	9	10	14	15
Combining with the inverse relevance of miR-146b-5p and TRAF6 expressions in the glioma specimens , our results indicated that TRAF6 overexpression induced by miR-146b-5p downexpression promoted the cell proliferation and inhibited apoptosis in malignant gliomas by activating TAK1 pathway and then accelerating the phosphorylated dissociation of IkappaBalpha from p65 : p50 , which enhanced our comprehension of the molecular mechanism of glioma malignant progression and suggested that miR-146b-5p could be potentially applied in the treatment of malignant gliomas .	Combining with the inverse relevance of miR-146b-5p and TRAF6 expressions in the glioma specimens, our results indicated that TRAF6 overexpression induced by miR-146b-5p downexpression promoted the cell proliferation and inhibited apoptosis in malignant gliomas by activating TAK1 pathway and then accelerating the phosphorylated dissociation of IkappaBalpha from p65 : p50, which enhanced our comprehension of the molecular mechanism of glioma malignant progression and suggested that miR-146b-5p could be potentially applied in the treatment of malignant gliomas.	19	38	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF6	TRAF6 overexpression	traf6	TAK1	TAK1	tak1	19	20	37	38
Depletion of TRAF2 , TRAF3 , and TRAF6 by lentivirus mediated transduction of short hairpin ( sh ) RNAs produced similar results : CD40 induced MEKK1 activation was barely detected in TRAF2 deficient cells , whereas TRAF6 depletion prevented TAK1 activation ( XREF_FIG ) .	Depletion of TRAF2, TRAF3, and TRAF6 by lentivirus mediated transduction of short hairpin (sh) RNAs produced similar results : CD40 induced MEKK1 activation was barely detected in TRAF2 deficient cells, whereas TRAF6 depletion prevented TAK1 activation (XREF_FIG).	36	40	prevented	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	36	37	39	40
Analysis of the upstream kinases revealed that Tak1 activation was selectively augmented by Traf6 overexpression but suppressed by Traf6 ablation ( XREF_FIG ) , whereas negligible effects were observed on the phosphorylation levels of Tbk1 , Ask1 , Pi3k , Ilk and Fak in response to hypertrophic stresses ( XREF_SUPPLEMENTARY ) .	Analysis of the upstream kinases revealed that Tak1 activation was selectively augmented by Traf6 overexpression but suppressed by Traf6 ablation (XREF_FIG), whereas negligible effects were observed on the phosphorylation levels of Tbk1, Ask1, Pi3k, Ilk and Fak in response to hypertrophic stresses (XREF_SUPPLEMENTARY).	7	19	suppressed	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	Traf6	Traf6	Traf6	Tak1	Tak1	Tak1	18	19	7	8
Collectively , our results suggest that even though TRAF6 is an upstream activator of TAK1 in many signaling cascades , inactivation of TAK1 , but not TRAF6 , regulates adipocyte survival , energy expenditure , and HFD induced obesity in mice .	Collectively, our results suggest that even though TRAF6 is an upstream activator of TAK1 in many signaling cascades, inactivation of TAK1, but not TRAF6, regulates adipocyte survival, energy expenditure, and HFD induced obesity in mice.	8	18	is an upstream activator	Positive_activation_copula_1	Positive_activation	Positive_activation	TRAF6	TRAF6	TRAF6	TAK1	TAK1	TAK1	8	9	14	15
On the other hand , K48 linked ubiquitination of TRAF6 promotes proteasomal degradation of TRAF6 , thereby limiting an innate immune response .	On the other hand, K48 linked ubiquitination of TRAF6 promotes proteasomal degradation of TRAF6, thereby limiting an innate immune response.	5	15	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF6	K48 linked ubiquitination of TRAF6	traf6	TRAF6	TRAF6	traf6	9	10	14	15
TSLP enhanced Th2 cytokine secretion in vitro by targeting TSLPR on antigen specific T cells .	TSLP enhanced Th2 cytokine secretion in vitro by targeting TSLPR on antigen specific T cells.	0	10	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	0	1	9	10
Mouse derived immature dendritic cells and T lymphocytes were co-cultured in vitro , which were divided into 4 groups ( TSLP stimulation group , TSLP stimulation and its receptor blocking group , ovalbumin stimulation group and ovalbumin stimulation and TSLP receptor blocking group ) .	Mouse derived immature dendritic cells and T lymphocytes were co-cultured in vitro, which were divided into 4 groups (TSLP stimulation group, TSLP stimulation and its receptor blocking group, ovalbumin stimulation group and ovalbumin stimulation and TSLP receptor blocking group).	20	41	blocking	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSLP	TSLP	TSLP	TSLP receptor	TSLP receptor	TSLP receptor	20	21	39	41
Importantly , TSLP treatment failed to inhibit TSLPR kd -SW1116 derived tumor growth , which was accompanied by similar tumor necrotic areas and apoptotic responses to those in control group without TSLP treatment .	Importantly, TSLP treatment failed to inhibit TSLPR kd -SW1116 derived tumor growth, which was accompanied by similar tumor necrotic areas and apoptotic responses to those in control group without TSLP treatment.	2	9	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	2	3	7	8
Finally , using a xenograft mouse model , we demonstrated that peritumoral administration of TSLP greatly reduced tumor growth accompanied with extensive tumor apoptotic response , which was abolished by tumor cell specific knockdown of TSLPR .	Finally, using a xenograft mouse model, we demonstrated that peritumoral administration of TSLP greatly reduced tumor growth accompanied with extensive tumor apoptotic response, which was abolished by tumor cell specific knockdown of TSLPR.	12	36	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TSLP	TSLP	TSLP	TSLPR	TSLPR	TSLPR	14	15	35	36
Incubation of Tu167 cells with TYK2 specific siRNA led to decreased STAT3 activation ; TYK2 depletion also decreased STAT3 reactivation after dasatinib exposure .	Incubation of Tu167 cells with TYK2 specific siRNA led to decreased STAT3 activation; TYK2 depletion also decreased STAT3 reactivation after dasatinib exposure.	14	19	decreased	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	TYK2	TYK2	TYK2	STAT3	STAT3	STAT3	14	15	18	19
FHL2 is , therefore , an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6 mediated RANK signaling .	FHL2 is, therefore, an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6 mediated RANK signaling.	12	16	mediated	Positive_early_activation	Positive_activation	Negative_activation	TRAF6	TRAF6	TRAF6	RANK	RANK	RANK	13	14	15	16
FHL2 inhibits TRAF6 induced NF-kappaB activity in wild-type osteoclast precursors and , in keeping with its role as a suppressor of TRAF6 mediated RANK signaling , TRAF6 and RANK association is enhanced in FHL2-/- osteoclasts .	FHL2 inhibits TRAF6 induced NF-kappaB activity in wild-type osteoclast precursors and, in keeping with its role as a suppressor of TRAF6 mediated RANK signaling, TRAF6 and RANK association is enhanced in FHL2-/- osteoclasts.	19	24	mediated	Positive_early_activation	Positive_activation	Negative_activation	TRAF6	TRAF6	TRAF6	RANK	RANK	RANK	21	22	23	24
TRAF6 deficiency selectively blocks RANK mediated canonical NF-kappaB activation in IECs .	TRAF6 deficiency selectively blocks RANK mediated canonical NF-kappaB activation in IECs.	0	8	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TRAF6	TRAF6	TRAF6	RANK	RANK	RANK	0	1	4	5
Surprisingly , the reduction of Mad2 caused by the loss of Mps1 in ald B4-2 mutant is enough to remove the spindle checkpoint in response to colchicine , but it does not lead to rapid anaphase onset and mitotic exit , in contrast to the loss of Mad2 alone in the mad2 EY mutant , instead it shows significantly delayed progression between prophase to metaphase and metaphase to telophase by about 3 and 1.5 min , respectively ( XREF_TABLE ) .	Surprisingly, the reduction of Mad2 caused by the loss of Mps1 in ald B4-2 mutant is enough to remove the spindle checkpoint in response to colchicine, but it does not lead to rapid anaphase onset and mitotic exit, in contrast to the loss of Mad2 alone in the mad2 EY mutant, instead it shows significantly delayed progression between prophase to metaphase and metaphase to telophase by about 3 and 1.5 min, respectively (XREF_TABLE).	3	12	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	Mps1	loss of Mps1	mps1	Mad2	Mad2	mad2	11	12	5	6
In addition , depletion of Mps1 prevents Mad1 and Mad2 localization to the kinetochore [ 25 ] .	In addition, depletion of Mps1 prevents Mad1 and Mad2 localization to the kinetochore [25].	3	10	prevents	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Mps1	Mps1	Mad2	Mad2	Mad2	5	6	9	10
Persistent autophosphorylation of Mps1 causes a decreased kinetochore localization of BubR1 and Mad2 .	Persistent autophosphorylation of Mps1 causes a decreased kinetochore localization of BubR1 and Mad2.	1	13	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Mps1	autophosphorylation of Mps1	mps1	Mad2	Mad2	mad2	3	4	12	13
Notably , the lack of Tyk2 is known to selectively impair the transcription of only a subset of virally induced IFNAR1 responsive genes XREF_BIBR .	Notably, the lack of Tyk2 is known to selectively impair the transcription of only a subset of virally induced IFNAR1 responsive genes XREF_BIBR.	3	21	impair	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Tyk2	Tyk2	Tyk2	IFNAR1	IFNAR1	IFNAR1	5	6	20	21
In the absence of ubiquitination , this motif is masked by associated TYK2 , thereby preventing basal endocytosis and degradation of IFNAR1 .	In the absence of ubiquitination, this motif is masked by associated TYK2, thereby preventing basal endocytosis and degradation of IFNAR1.	9	22	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	TYK2	TYK2	TYK2	IFNAR1	IFNAR1	IFNAR1	12	13	21	22
Interestingly , SENP2 and UBC9-DN overexpression both strongly decreased FOXL2 transactivation on the reporters pSODluc-3340 and Per2-luc ( XREF_FIG ) .	Interestingly, SENP2 and UBC9-DN overexpression both strongly decreased FOXL2 transactivation on the reporters pSODluc-3340 and Per2-luc (XREF_FIG).	2	10	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	UBC9-DN	UBC9-DN overexpression	ubc9-dn	FOXL2	FOXL2	foxl2	4	5	9	10
Expression of degradation resistant Mps1 proteins rescues prometaphase accumulation in Chk2 deficient cells .	Expression of degradation resistant Mps1 proteins rescues prometaphase accumulation in Chk2 deficient cells.	0	12	rescues	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Mps1	Expression of degradation resistant Mps1	mps1	Chk2	Chk2	chk2	4	5	10	11
KAP1 was able to block nucleolar sequestration of MDM2 by ARF XREF_BIBR .	KAP1 was able to block nucleolar sequestration of MDM2 by ARF XREF_BIBR.	0	9	block	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	KAP1	KAP1	KAP1	MDM2	MDM2	MDM2	0	1	8	9
Taken together , our results show that the inhibition of Mps1 kinase together with the exposure to clinically relevant doses of taxanes enhances CIN in BRCA1 -/-; TP53 -/- mammary tumours .	Taken together, our results show that the inhibition of Mps1 kinase together with the exposure to clinically relevant doses of taxanes enhances CIN in BRCA1 -/-; TP53 -/- mammary tumours.	10	30	enhances	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Mps1	Mps1	Mps1	TP53	TP53	TP53	10	11	27	28
Because VEGFA reduces the number of surface VEGFR2 when applied alone , we wanted to test whether it would reduce the number of surface receptors after their numbers were increased by prior treatment with sunitinib .	Because VEGFA reduces the number of surface VEGFR2 when applied alone, we wanted to test whether it would reduce the number of surface receptors after their numbers were increased by prior treatment with sunitinib.	1	8	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	1	2	7	8
Although KDR or VEGFR2 , analogous to FLT1 , is also subject to extracellular and intracellular cleavage , VEGF-A does not inhibit KDR cleavage .	Although KDR or VEGFR2, analogous to FLT1, is also subject to extracellular and intracellular cleavage, VEGF-A does not inhibit KDR cleavage.	18	23	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	18	19	22	23
[ XREF_BIBR - XREF_BIBR ] Most of these inhibitors act by sequestering VEGF-A and only a few specifically disrupt VEGF and VEGFR2 signaling .	[XREF_BIBR - XREF_BIBR] Most of these inhibitors act by sequestering VEGF-A and only a few specifically disrupt VEGF and VEGFR2 signaling.	12	22	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	12	13	21	22
We further demonstrate that both the wild-type and mutant forms of VEGFR-3 could form heterodimers with VEGFR-2 , and decreased the level of phospho-VEGFR-2 and the downstream phospho-Erk1/2 in endothelial cells when they were treated with VEGF-A .	We further demonstrate that both the wild-type and mutant forms of VEGFR-3 could form heterodimers with VEGFR-2, and decreased the level of phospho-VEGFR-2 and the downstream phospho-Erk1/2 in endothelial cells when they were treated with VEGF-A.	21	37	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	phospho-VEGFR-2	phospho-VEGFR-2	phospho-VEGFR-2	36	37	23	24
Blocking VEGF-A activation of VEGFR2 is sufficient to suppress lymphangiogenesis .	Blocking VEGF-A activation of VEGFR2 is sufficient to suppress lymphangiogenesis.	1	5	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	1	2	4	5
In this study we find that alterations in VEGF-A and VEGFR2 activation , as evidenced both by inhibition of VEGFR2 by VEGF-A 165 b ( Bates etal .	In this study we find that alterations in VEGF-A and VEGFR2 activation, as evidenced both by inhibition of VEGFR2 by VEGF-A 165 b (Bates etal.	14	23	inhibition	Negative_activation_token_2_noun	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	21	22	19	20
In HemECs , both VEGF-A 165 a and VEGF-A 165 b induced a reduction of VEGFR2 over time .	In HemECs, both VEGF-A 165 a and VEGF-A 165 b induced a reduction of VEGFR2 over time.	3	16	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	4	5	15	16
ENG deletion alters VEGFA induced VEGFR2 kinetics and downstream signalling .	ENG deletion alters VEGFA induced VEGFR2 kinetics and downstream signalling.	2	6	induced	Positive_early_activation	Positive_activation	Positive_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	3	4	5	6
Through blocking activation of VEGFR-2 by VEGF-A and the other VEGF ligands , ramucirumab inhibits the angiogenesis pathways involved in the development and progression of gastric cancer .	Through blocking activation of VEGFR-2 by VEGF-A and the other VEGF ligands, ramucirumab inhibits the angiogenesis pathways involved in the development and progression of gastric cancer.	1	11	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	6	7	4	5
VEGFA treatment reduces the number of cell surface VEGFR2 on sunitinib treatment .	VEGFA treatment reduces the number of cell surface VEGFR2 on sunitinib treatment.	0	11	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	0	1	8	9
VEGF-A , VEGFR-1 , or VEGFR-2 was inhibited by antisense oligodeoxynucleotides ( ODNs ) in vivo and by a VEGF-A neutralizing antibody or VEGFR-2 inhibitor in vitro .	VEGF-A, VEGFR-1, or VEGFR-2 was inhibited by antisense oligodeoxynucleotides (ODNs) in vivo and by a VEGF-A neutralizing antibody or VEGFR-2 inhibitor in vitro.	0	20	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	19	20	5	6
Others have demonstrated that the lack of Nrp-1 signalling promotes VEGFR2 degradation 23 , and that VEGF-A 165 b , which does not bind to Nrp-1 11 , promotes VEGFR2 degradation and/or prevents recycling of the receptor .	Others have demonstrated that the lack of Nrp-1 signalling promotes VEGFR2 degradation 23, and that VEGF-A 165 b, which does not bind to Nrp-1 11, promotes VEGFR2 degradation and/or prevents recycling of the receptor.	16	30	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-A	VEGF-A 165 b, which does not bind to Nrp-1 11	vegf-a	VEGFR2	VEGFR2	vegfr2	16	17	29	30
VEGF-A 165 b inhibits canonical VEGF-A signaling by competitive interference with the interaction of pro angiogenic isoforms with the VEGFR2 and NRP1 receptor complex thereby preventing full downstream signaling of VEGFR2 .	VEGF-A 165 b inhibits canonical VEGF-A signaling by competitive interference with the interaction of pro angiogenic isoforms with the VEGFR2 and NRP1 receptor complex thereby preventing full downstream signaling of VEGFR2.	0	31	preventing	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	30	31
Moreover , pharmacological inhibitors of VEGFR2 ( indolin and dihyroindol , 5 microM ) , and a receptor tyrosine kinase inhibitor ( PD173074 , 5 microM ) , almost completely inhibited VEGF-A induced Src phosphorylation at Tyr 416 , the autophosphorylation site necessary for Src activation , suggesting VEGF-A induces VEGFR2 dependent Src activation ( XREF_FIG ) .	Moreover, pharmacological inhibitors of VEGFR2 (indolin and dihyroindol, 5 microM), and a receptor tyrosine kinase inhibitor (PD173074, 5 microM), almost completely inhibited VEGF-A induced Src phosphorylation at Tyr 416, the autophosphorylation site necessary for Src activation, suggesting VEGF-A induces VEGFR2 dependent Src activation (XREF_FIG).	47	51	induces	Positive_activation_token_1_verb	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	48	49	50	51
VEGFA treatment reduces the number of surface VEGFR2 .	VEGFA treatment reduces the number of surface VEGFR2.	0	8	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	0	1	7	8
As shown in XREF_FIG , VEGFA treatment after sunitinib treatment , which increases the number of surface VEGFR2 , causes a dramatic decrease in the number of surface VEGFR2 .	As shown in XREF_FIG, VEGFA treatment after sunitinib treatment, which increases the number of surface VEGFR2, causes a dramatic decrease in the number of surface VEGFR2.	5	29	causes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFA	VEGFA	VEGFA	VEGFR2	VEGFR2	VEGFR2	5	6	28	29
Importantly , VEGF-A 165 b suppression via incubation with the neutralizing antibody increased VEGFR-2 p ( Y951 )/VEGFR-2 ratio ( p = 0.02 ) ( XREF_FIG ) .	Importantly, VEGF-A 165 b suppression via incubation with the neutralizing antibody increased VEGFR-2 p (Y951)/VEGFR-2 ratio (p = 0.02) (XREF_FIG).	2	14	increased	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-2	VEGFR-2	VEGFR-2	2	3	13	14
To determine whether mesonephric cells positive for KDR-LacZ were affected by VEGFA signal transduction inhibition , E11 KDR-LacZ mouse testis organ cultures were treated with VEGFR-TKI , a VEGFA receptor tyrosine kinase antagonist , which inhibits both KDR and FLT1 .	To determine whether mesonephric cells positive for KDR-LacZ were affected by VEGFA signal transduction inhibition, E11 KDR-LacZ mouse testis organ cultures were treated with VEGFR-TKI, a VEGFA receptor tyrosine kinase antagonist, which inhibits both KDR and FLT1.	28	39	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGFA	VEGFA	VEGFA	KDR	KDR	KDR	28	29	37	38
The anti-proliferative and anti-angiogenic effects of VEGF-A 165 b may be attributed to the fact that VEGF-A 165 b is a weak agonist of VEGFR2 and ameliorates VEGF-A 165 a mediated VEGFR2 activation and downstream signalling , promoting the degradation of VEGFR2 11 , 23 as well as lack of DLL4 induction , an important factor in the establishment of endothelial tip cells .	The anti-proliferative and anti-angiogenic effects of VEGF-A 165 b may be attributed to the fact that VEGF-A 165 b is a weak agonist of VEGFR2 and ameliorates VEGF-A 165 a mediated VEGFR2 activation and downstream signalling, promoting the degradation of VEGFR2 11, 23 as well as lack of DLL4 induction, an important factor in the establishment of endothelial tip cells.	16	44	promoting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	16	17	41	42
VEGF-A 165 stimulation promoted VEGFR2 degradation over a short time period ( 2-4 h ) , with VEGFR2 levels reduced by ~ 60 % after 2 h ( XREF_FIG ) .	VEGF-A 165 stimulation promoted VEGFR2 degradation over a short time period (2-4 h), with VEGFR2 levels reduced by ~ 60% after 2 h (XREF_FIG).	0	5	promoted	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR2	VEGFR2	VEGFR2	0	1	4	5
VEGF-A treatment in phase 2 , after the priming with BMP4 and GSK-3betaI , resulted in around 15 % VEC + of the total number of cells , but the total KDR + cell ratio was lower in cultures treated with VEGF-A alone than with DAPT alone .	VEGF-A treatment in phase 2, after the priming with BMP4 and GSK-3betaI, resulted in around 15% VEC + of the total number of cells, but the total KDR + cell ratio was lower in cultures treated with VEGF-A alone than with DAPT alone.	29	42	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	KDR	KDR	KDR	41	42	31	32
Importantly , HIMF significantly increased lung VEGF-A expression and downregulated VEGFR2 in a HIF-1alpha-dependent manner .	Importantly, HIMF significantly increased lung VEGF-A expression and downregulated VEGFR2 in a HIF-1alpha-dependent manner.	2	11	downregulated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-A	HIMF significantly increased lung VEGF-A expression	vegf-a	VEGFR2	VEGFR2	vegfr2	6	7	10	11
Furthermore , the abnormal embryos showed p53 staining in the remaining cells , suggesting loss of HAUSP caused accumulation of p53 ( XREF_FIG ) .	Furthermore, the abnormal embryos showed p53 staining in the remaining cells, suggesting loss of HAUSP caused accumulation of p53 (XREF_FIG).	14	22	caused	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	HAUSP	loss of HAUSP	hausp	p53	p53	p53	16	17	20	21
Furthermore , HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes .	Furthermore, HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes.	2	6	elevates	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	2	3	5	6
Overexpression of TSPYL5 suppresses p53 function and its target genes by regulating ubiquitin specific protease 7 ( USP7 ) that cause p53 degradation .	Overexpression of TSPYL5 suppresses p53 function and its target genes by regulating ubiquitin specific protease 7 (USP7) that cause p53 degradation.	14	22	cause	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	p53	p53	p53	17	18	21	22
By either mechanism , our results establish that USP7 modulates the repressive H3K9me3 mark by protecting SUV39H1 from MDM2 mediated degradation and blocking aberrant p53 transactivation of target genes in unstressed p53 wt cells .	By either mechanism, our results establish that USP7 modulates the repressive H3K9me3 mark by protecting SUV39H1 from MDM2 mediated degradation and blocking aberrant p53 transactivation of target genes in unstressed p53 wt cells.	8	25	modulates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	USP7	USP7	USP7	p53	p53	p53	8	9	24	25
Collectively , we have demonstrated that inhibition of USP7 by a small-molecule inhibitor P22077 can result in reactivation of p53 and consequently inhibit tumor growth .	Collectively, we have demonstrated that inhibition of USP7 by a small-molecule inhibitor P22077 can result in reactivation of p53 and consequently inhibit tumor growth.	6	20	result in reactivation	Positive_activation_syntax_8_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	p53	p53	p53	8	9	19	20
For example , expression of EBNA1 but not a USP7 binding mutant of EBNA1 was shown to reduce the accumulation of p53 in response to DNA damage in U2OS cells [ XREF_BIBR ] .	For example, expression of EBNA1 but not a USP7 binding mutant of EBNA1 was shown to reduce the accumulation of p53 in response to DNA damage in U2OS cells [XREF_BIBR].	3	22	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	expression of EBNA1 but not a USP7	usp7	p53	p53	p53	9	10	21	22
Notably , selective dual inhibitors of USP7 and USP47 have been synthesized and induced accumulation of p53 and apoptosis in human cancer cell lines [ XREF_BIBR ] .	Notably, selective dual inhibitors of USP7 and USP47 have been synthesized and induced accumulation of p53 and apoptosis in human cancer cell lines [XREF_BIBR].	4	18	synthesized	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	p53	p53	p53	6	7	16	17
Compound 1 , a selective inhibitor of USP7 and USP47 with moderate potency , demonstrates inhibition of USP7 in cells and induces elevated p53 and apoptosis in cancer cell lines .	Compound 1, a selective inhibitor of USP7 and USP47 with moderate potency, demonstrates inhibition of USP7 in cells and induces elevated p53 and apoptosis in cancer cell lines.	5	25	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	p53	p53	p53	7	8	23	24
For example , expression of EBNA1 but not a USP7 binding mutant of EBNA1 in U2OS cells was shown to reduce the accumulation of p53 in response to DNA damage and subsequent apoptosis [ XREF_BIBR ] .	For example, expression of EBNA1 but not a USP7 binding mutant of EBNA1 in U2OS cells was shown to reduce the accumulation of p53 in response to DNA damage and subsequent apoptosis [XREF_BIBR].	3	25	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	expression of EBNA1 but not a USP7	usp7	p53	p53	p53	9	10	24	25
More recently , it has been shown that a small molecule inhibitor of HAUSP , HBX41108 , stabilizes p53 and induces p53 dependent apoptosis in cancer cell lines that retain wild-type p53 [ XREF_BIBR ] .	More recently, it has been shown that a small molecule inhibitor of HAUSP, HBX41108, stabilizes p53 and induces p53 dependent apoptosis in cancer cell lines that retain wild-type p53 [XREF_BIBR].	11	23	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	13	14	21	22
The inhibition of USP7 with HBX 41,108 , a DUB to Hdm2 has shown to induce p53 dependent apoptosis with an IC in sub-micro-molar concentrations .	The inhibition of USP7 with HBX 41,108, a DUB to Hdm2 has shown to induce p53 dependent apoptosis with an IC in sub-micro-molar concentrations.	1	18	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	p53	p53	p53	3	4	16	17
Thus , inhibiting HAUSP by small compound interference has been proposed as a rational therapeutic strategy to activate p53 in p53 wild type tumors .	Thus, inhibiting HAUSP by small compound interference has been proposed as a rational therapeutic strategy to activate p53 in p53 wild type tumors.	2	19	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	3	4	18	19
As p53 can antagonize the anti-apoptotic effects of Bcl-2 and Bcl-xL [ XREF_BIBR ] , USP7 may inhibit the Bcl-2 and Bcl-xL anti-apoptotic effect by negatively regulating p53 .	As p53 can antagonize the anti-apoptotic effects of Bcl-2 and Bcl-xL [XREF_BIBR], USP7 may inhibit the Bcl-2 and Bcl-xL anti-apoptotic effect by negatively regulating p53.	15	28	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	p53	p53	p53	15	16	27	28
Hence , inhibition of Usp7 is thought to inactivate Mdm2 and thereby activate p53 , resulting in inhibition of cell cycle progression and tumor cell apoptosis .	Hence, inhibition of Usp7 is thought to inactivate Mdm2 and thereby activate p53, resulting in inhibition of cell cycle progression and tumor cell apoptosis.	2	14	activate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Usp7	Usp7	Usp7	p53	p53	p53	4	5	13	14
Increased ARF-BP1 and Mule degradation causes p53 stabilization , which is antagonized by the DUBs USP7 and USP4 .	Increased ARF-BP1 and Mule degradation causes p53 stabilization, which is antagonized by the DUBs USP7 and USP4.	6	17	antagonized	Negative_activation_syntax_2_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	p53	p53	p53	15	16	6	7
Here , we show that inhibitors of HAUSP and Nutlin-3 can synergistically activate p53 function and induce p53 dependent apoptosis in human cancer cells .	Here, we show that inhibitors of HAUSP and Nutlin-3 can synergistically activate p53 function and induce p53 dependent apoptosis in human cancer cells.	5	19	induce	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	7	8	17	18
As p53 is activated by genotoxic stress and has a key role in genotoxic stress induced cell death , we reasoned that pharmacological inhibition of USP7 activity would potentiate p53 activity and result in increased chemosensitivity .	As p53 is activated by genotoxic stress and has a key role in genotoxic stress induced cell death, we reasoned that pharmacological inhibition of USP7 activity would potentiate p53 activity and result in increased chemosensitivity.	25	30	potentiate	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	p53	p53	p53	25	26	29	30
Although several Daxx interacting proteins are involved in critical cellular pathways regarding P53 degradation , such as ubiquitin-specific-processing protease 7 ( USP7 ) and mouse double minute 2 ( Mdm2 ) [ XREF_BIBR , XREF_BIBR ] , it is still unclear whether Daxx has any role in tumorigenicity of OSCC .	Although several Daxx interacting proteins are involved in critical cellular pathways regarding P53 degradation, such as ubiquitin-specific-processing protease 7 (USP7) and mouse double minute 2 (Mdm2) [XREF_BIBR, XREF_BIBR], it is still unclear whether Daxx has any role in tumorigenicity of OSCC.	12	20	degradation	Negative_activation_syntax_noun_Hearst	Positive_activation	Negative_activation	ubiquitin-specific-processing protease 7	ubiquitin-specific-processing protease 7	ubiquitin-specific-processing protease 7	P53	P53	P53	17	20	12	13
In addition , HAUSP dependent stabilization of Mdm2 and Mdmx might enhance degradation of p53 by the Mdm2 and Mdmx heterodimer .	In addition, HAUSP dependent stabilization of Mdm2 and Mdmx might enhance degradation of p53 by the Mdm2 and Mdmx heterodimer.	3	15	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	HAUSP	HAUSP	HAUSP	p53	p53	p53	3	4	14	15
On a related note , sVEGFR-3 can not only bind VEGFR-3 but also acts as a trap for VEGF-C , which blocks VEGFR-3 signaling [ XREF_BIBR , XREF_BIBR ] .	On a related note, sVEGFR-3 can not only bind VEGFR-3 but also acts as a trap for VEGF-C, which blocks VEGFR-3 signaling [XREF_BIBR, XREF_BIBR].	16	23	blocks	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	18	19	22	23
The downregulation of VEGFR2 by VEGF 165 and the downregulation of VEGFR2 and VEGFR3 by VEGF-C is consistent with the ligand induced internalization and degradation exhibited by tyrosine kinase receptors [ XREF_BIBR , XREF_BIBR ] .	The downregulation of VEGFR2 by VEGF 165 and the downregulation of VEGFR2 and VEGFR3 by VEGF-C is consistent with the ligand induced internalization and degradation exhibited by tyrosine kinase receptors [XREF_BIBR, XREF_BIBR].	9	16	downregulation	Negative_activation_syntax_2_noun	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	15	16	13	14
Using cell-by-cell analysis , we characterize such variability in receptor densities across the endothelial cells and find that in addition to regulating receptor density , elevated VEGF 165 levels increase the heterogeneity of VEGFR1 surface density while decreasing the heterogeneity of VEGFR2 surface density , while VEGF-C decreases the heterogeneity of VEGFR2 and VEGFR3 surface densities ( XREF_FIG ) .	Using cell-by-cell analysis, we characterize such variability in receptor densities across the endothelial cells and find that in addition to regulating receptor density, elevated VEGF 165 levels increase the heterogeneity of VEGFR1 surface density while decreasing the heterogeneity of VEGFR2 surface density, while VEGF-C decreases the heterogeneity of VEGFR2 and VEGFR3 surface densities (XREF_FIG).	46	55	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR3	VEGFR3	VEGFR3	46	47	53	54
VEGF-C neutralizing antibody ( VGX-100 ) inhibits VEGFR-2 and VEGFR-3 , thereby blocking both angiogenesis and lymphangiogenesis .	VEGF-C neutralizing antibody (VGX-100) inhibits VEGFR-2 and VEGFR-3, thereby blocking both angiogenesis and lymphangiogenesis.	0	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	0	1	9	10
First we tested the timing and concentration-dependence of VEGF-C down-regulation of VEGFR-3 .	First we tested the timing and concentration-dependence of VEGF-C down-regulation of VEGFR-3.	8	12	down-regulation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	8	9	11	12
We have shown that VEGF-C down-regulates VEGFR-3 protein and mRNA expression in LECs and vECs in vitro in a time- and concentration dependent manner .	We have shown that VEGF-C down-regulates VEGFR-3 protein and mRNA expression in LECs and vECs in vitro in a time- and concentration dependent manner.	4	7	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	6	7
Our findings indicate that VEGF-C down-regulates VEGFR-3 in lymphatic endothelial cells through VEGFR-3 kinase activation and , in part , via lysosomal degradation .	Our findings indicate that VEGF-C down-regulates VEGFR-3 in lymphatic endothelial cells through VEGFR-3 kinase activation and, in part, via lysosomal degradation.	4	10	down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	4	5	6	7
Here , we demonstrate that VEGF-C , -D , and -C156S , but not VEGF-A , down-regulate VEGFR-3 .	Here, we demonstrate that VEGF-C, -D, and -C156S, but not VEGF-A, down-regulate VEGFR-3.	5	18	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	5	6	17	18
Therapeutic VEGF-C administration restored lymphangiogenesis following inhibition of VEGFR-3 but did not increase lymphangiogenesis following inhibition of IF .	Therapeutic VEGF-C administration restored lymphangiogenesis following inhibition of VEGFR-3 but did not increase lymphangiogenesis following inhibition of IF.	1	9	restored	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	1	2	8	9
VEGF-C Down-regulates VEGFR-3 Protein and mRNA Expression in LECs and vECs .	VEGF-C Down-regulates VEGFR-3 Protein and mRNA Expression in LECs and vECs.	0	3	Down-regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	0	1	2	3
Moreover , VEGFR-3 was present in the cell lysate prior to but not following stimulation with VEGF-C ( XREF_FIG , left lanes ) , indicating that VEGF-C induces intracellular degradation of VEGFR-3 .	Moreover, VEGFR-3 was present in the cell lysate prior to but not following stimulation with VEGF-C (XREF_FIG, left lanes), indicating that VEGF-C induces intracellular degradation of VEGFR-3.	26	32	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	26	27	31	32
Robo4 is required for Slit2N to inhibit the activation of VEGFR-3 by VEGF-C .	Robo4 is required for Slit2N to inhibit the activation of VEGFR-3 by VEGF-C.	6	13	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	12	13	10	11
The extremely transient nature of these increases ( depleted by 30 minutes post-stimulation ) , compared to the long time scale over which VEGF-C induces VEGFR-3 degradation ( 6-24 hours ) suggests that these two effects are likely unrelated .	The extremely transient nature of these increases (depleted by 30 minutes post-stimulation), compared to the long time scale over which VEGF-C induces VEGFR-3 degradation (6-24 hours) suggests that these two effects are likely unrelated.	23	26	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	23	24	25	26
VEGF-C alone decreased cell surface VEGFR-3 by about 50 % after 15 and 30minutes incubation .	VEGF-C alone decreased cell surface VEGFR-3 by about 50% after 15 and 30minutes incubation.	0	6	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-3	VEGFR-3	VEGFR-3	0	1	5	6
Expression of a carboxy-terminal fragment of Vav2 decreased the elevation of Rac1 activity induced by epidermal growth factor , consistent with Vav2 mediating activation of Rac1 downstream from growth factor receptors .	Expression of a carboxy-terminal fragment of Vav2 decreased the elevation of Rac1 activity induced by epidermal growth factor, consistent with Vav2 mediating activation of Rac1 downstream from growth factor receptors.	4	12	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	6	7	11	12
Mechanistically , NEDD9 promotes mesenchymal migration via VAV2 dependent Rac1 activation , and depletion of VAV2 impairs the ability of NEDD9 to activate Rac1 .	Mechanistically, NEDD9 promotes mesenchymal migration via VAV2 dependent Rac1 activation, and depletion of VAV2 impairs the ability of NEDD9 to activate Rac1.	13	24	impairs	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	VAV2	VAV2	VAV2	Rac1	Rac1	Rac1	15	16	23	24
Previously , we found that vav2 , a Rac GEF , regulated P2Y 2 R mediated Rac1 activation , by demonstrating that expression of dominant negative vav2 inhibits Rac1 activity in UTP treated 1321N1 cells expressing the P2Y 2 R [ XREF_BIBR ] .	Previously, we found that vav2, a Rac GEF, regulated P2Y 2 R mediated Rac1 activation, by demonstrating that expression of dominant negative vav2 inhibits Rac1 activity in UTP treated 1321N1 cells expressing the P2Y 2 R [XREF_BIBR].	22	29	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	vav2	expression of dominant negative vav2	vav2	Rac1	Rac1	rac1	26	27	28	29
Transfection of shRNA-Vav2 attenuated this enhanced Rac activity by the FF diet in glomeruli ( shRNA-Vav2 vs. control under an FF diet ) .	Transfection of shRNA-Vav2 attenuated this enhanced Rac activity by the FF diet in glomeruli (shRNA-Vav2 vs. control under an FF diet).	0	7	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	shRNA-Vav2	shRNA-Vav2	shRNA-Vav2	Rac	Rac	Rac	2	3	6	7
Because decreased expression of Vav2 ( an activator of Rac1 ) could not explain the increased Rac1 activation in double-KD versus CGNL1 (-) cells , we focused on MgcRacGAP , a GAP that is ~ 30-fold more active against Rac1 and Cdc42 than RhoA .	Because decreased expression of Vav2 (an activator of Rac1) could not explain the increased Rac1 activation in double-KD versus CGNL1 (-) cells, we focused on MgcRacGAP, a GAP that is ~ 30-fold more active against Rac1 and Cdc42 than RhoA.	2	10	activator	Positive_activation_syntax_7_noun	Positive_activation	Negative_activation	Vav2	expression of Vav2	vav2	Rac1	Rac1	rac1	4	5	9	10
When the involvement of other GEFs was examined , depletion of Vav2 , mainly expressed in U251 cells among the three Vav isoforms ( unpublished data ) , attenuated Rac1 activation , but to a slightly lesser extent than Tiam1 depletion .	When the involvement of other GEFs was examined, depletion of Vav2, mainly expressed in U251 cells among the three Vav isoforms (unpublished data), attenuated Rac1 activation, but to a slightly lesser extent than Tiam1 depletion.	9	30	attenuated	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	Rac1	Rac1	Rac1	11	12	29	30
Studies involving inducible VEGF-A gene inactivation or administration of soluble ( s ) forms of the receptor Flt-1 to inhibit VEGF-A function have established that VEGF-A continues to be critically important during post-natal growth and organ development [ XREF_BIBR ] .	Studies involving inducible VEGF-A gene inactivation or administration of soluble (s) forms of the receptor Flt-1 to inhibit VEGF-A function have established that VEGF-A continues to be critically important during post-natal growth and organ development [XREF_BIBR].	3	18	inactivation	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	Flt-1	Flt-1	Flt-1	3	4	17	18
VEGF-A inhibition of FLT1 cleavage is not dependent on FLT1 tyrosine kinase activity or the intracellular FLT1 residues .	VEGF-A inhibition of FLT1 cleavage is not dependent on FLT1 tyrosine kinase activity or the intracellular FLT1 residues.	0	4	inhibition	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	FLT1	FLT1	FLT1	0	1	3	4
In WATs , SPARC might also limit the activation of VEGFR-1 by VEGF-A , and thereby promote angiogenesis , during adipogenesis .	In WATs, SPARC might also limit the activation of VEGFR-1 by VEGF-A, and thereby promote angiogenesis, during adipogenesis.	6	13	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	VEGF-A	VEGF-A	VEGF-A	VEGFR-1	VEGFR-1	VEGFR-1	12	13	10	11
Interestingly , whereas overexpression of Atg1 led to phosphorylation and reduced gel migration of Atg13 as previously shown , ADUK overexpression did not effect the migration properties of Atg13 ( XREF_FIG , input ) .	Interestingly, whereas overexpression of Atg1 led to phosphorylation and reduced gel migration of Atg13 as previously shown, ADUK overexpression did not effect the migration properties of Atg13 (XREF_FIG, input).	3	15	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Atg1	overexpression of Atg1	atg1	Atg13	Atg13	atg13	5	6	14	15
Furthermore , they showed that Atg1 overexpression suppressed the autophagy defective phenotype in the Deltaapg13 and atg13 strain , indicating a linkage between Atg1 and Atg13 [ XREF_BIBR ] .	Furthermore, they showed that Atg1 overexpression suppressed the autophagy defective phenotype in the Deltaapg13 and atg13 strain, indicating a linkage between Atg1 and Atg13 [XREF_BIBR].	5	17	suppressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Atg1	Atg1 overexpression	atg1	atg13	atg13	atg13	5	6	16	17
The degradation of ULK1 induces the instability ATG13 and the degradation of BECLIN 1 induces the instability of ATG14L .	The degradation of ULK1 induces the instability ATG13 and the degradation of BECLIN 1 induces the instability of ATG14L.	1	8	induces	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	ULK1	ULK1	ULK1	ATG13	ATG13	ATG13	3	4	7	8
Expression of dominant negative Atg1 in fat bodies of fed larvae reduced the amount of slower mobility forms of endogenous Atg13 , and in starved larvae practically eliminated all Atg13 high forms ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	Expression of dominant negative Atg1 in fat bodies of fed larvae reduced the amount of slower mobility forms of endogenous Atg13, and in starved larvae practically eliminated all Atg13 high forms (XREF_FIG; XREF_SUPPLEMENTARY).	0	21	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Atg1	Expression of dominant negative Atg1	atg1	Atg13	Atg13	atg13	4	5	20	21
In line with our interaction data , co-expression of Atg1 decreased the mobility of Atg13 fragments containing the C-terminus ( XREF_FIG ) , suggesting that Atg1phosphorylated these fragments .	In line with our interaction data, co-expression of Atg1 decreased the mobility of Atg13 fragments containing the C-terminus (XREF_FIG), suggesting that Atg1phosphorylated these fragments.	7	15	decreased	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Atg1	co-expression of Atg1	atg1	Atg13	Atg13	atg13	9	10	14	15
This evidence strongly suggests that RAP80 sequesters BRCA1 from the edge of DSBs and fine-tunes the HR promoting function of BRCA1 .	This evidence strongly suggests that RAP80 sequesters BRCA1 from the edge of DSBs and fine-tunes the HR promoting function of BRCA1.	5	14	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	5	6	7	8
A possible model is that the HP1 interacting BRCA1 and BARD1 complex reinforces DNA end resection and HR , and BRCA1 , Abraxas , and RAP80 complex sequesters the resection thereafter by recruiting BRCA1 from the HP1 interacting complex ( XREF_SUPPLEMENTARY ) .	A possible model is that the HP1 interacting BRCA1 and BARD1 complex reinforces DNA end resection and HR, and BRCA1, Abraxas, and RAP80 complex sequesters the resection thereafter by recruiting BRCA1 from the HP1 interacting complex (XREF_SUPPLEMENTARY).	25	34	sequesters	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	25	26	33	34
RAP80 represses HR by blocking DNA end-resection and sequestering BRCA1 .	RAP80 represses HR by blocking DNA end-resection and sequestering BRCA1.	0	10	represses	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	0	1	9	10
It was suggested that RAP80 complexes contribute to a process that down-modulates BRCA1 homologous recombination function and thereby suppressing exaggerated BRCA1 driven HR .	It was suggested that RAP80 complexes contribute to a process that down-modulates BRCA1 homologous recombination function and thereby suppressing exaggerated BRCA1 driven HR.	4	21	suppressing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	4	5	20	21
In contrast , suppressing BRCA1 driven HR by RAP80 can occur in cells with intact BRCA1 .	In contrast, suppressing BRCA1 driven HR by RAP80 can occur in cells with intact BRCA1.	3	10	driven	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	RAP80	RAP80	RAP80	BRCA1	BRCA1	BRCA1	8	9	4	5
VIPHyb , in which the first six C-terminal amino acids were replaced with the neurotensin sequence , is a broad spectrum VIP antagonist inhibiting human and mouse VPAC1 , VPAC2 , and PAC1 receptors .	VIPHyb, in which the first six C-terminal amino acids were replaced with the neurotensin sequence, is a broad spectrum VIP antagonist inhibiting human and mouse VPAC1, VPAC2, and PAC1 receptors.	21	33	inhibiting	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	21	22	27	28
Another VIP antagonist , PG 97-269 , selectively inhibits only VPAC1 receptors .	Another VIP antagonist, PG 97-269, selectively inhibits only VPAC1 receptors.	1	11	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	1	2	10	11
Our findings reveal that absence of VIP expression induces resistance to colitis in our DSS induced murine model , as well as VIP antagonism that inhibits VIP and VPAC1 signaling , thus leading to a suppression of colonic mucosa inflammation and damage .	Our findings reveal that absence of VIP expression induces resistance to colitis in our DSS induced murine model, as well as VIP antagonism that inhibits VIP and VPAC1 signaling, thus leading to a suppression of colonic mucosa inflammation and damage.	22	29	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	22	23	28	29
It is also possible that other receptors are activated by VIP to suppress the glial component of the VPAC1 receptor mediated response , such as VPAC1 and VPAC2 receptor splice variants .	It is also possible that other receptors are activated by VIP to suppress the glial component of the VPAC1 receptor mediated response, such as VPAC1 and VPAC2 receptor splice variants.	8	21	suppress	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	10	11	18	19
Consistently , by activating VPAC1 receptors and cAMP and PKA signaling , VIP reduced the slow AHP current and the tonic potassium current which regulates the excitability of hippocampal and cortical pyramidal neurons .	Consistently, by activating VPAC1 receptors and cAMP and PKA signaling, VIP reduced the slow AHP current and the tonic potassium current which regulates the excitability of hippocampal and cortical pyramidal neurons.	4	14	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VIP	VIP	VIP	VPAC1	VPAC1	VPAC1	12	13	4	5
USP7 also negatively regulates the stability of MDM2 .	USP7 also negatively regulates the stability of MDM2.	0	8	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	MDM2	MDM2	MDM2	0	1	7	8
Interestingly , severe ablation of USP7 expression diminished Mdm2 but increased Poleta ( XREF_FIG ) .	Interestingly, severe ablation of USP7 expression diminished Mdm2 but increased Poleta (XREF_FIG).	5	9	diminished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	USP7 expression	usp7	Mdm2	Mdm2	mdm2	5	6	8	9
XREF_BIBR HAUSP antagonizes the action of MDM2 on P53 .	XREF_BIBR HAUSP antagonizes the action of MDM2 on P53.	0	7	antagonizes	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	HAUSP	HAUSP	HAUSP	MDM2	MDM2	MDM2	1	2	6	7
25 USP7 deficiency in mouse embryonic fibroblasts ( MEFs ) greatly reduces the half-life of MDM2 and activates p53 .	25 USP7 deficiency in mouse embryonic fibroblasts (MEFs) greatly reduces the half-life of MDM2 and activates p53.	1	16	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	USP7	USP7	USP7	MDM2	MDM2	MDM2	1	2	15	16
Furthermore , overexpressing USP28 inhibited FBXW7-185aa-induced c-Myc turnover ( XREF_FIG ) .	Furthermore, overexpressing USP28 inhibited FBXW7-185aa-induced c-Myc turnover (XREF_FIG).	2	7	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	USP28	USP28	USP28	c-Myc	c-Myc	c-Myc	3	4	6	7
In addition , nickel and hypoxia exposure decreased USP28 , a c-myc de-ubiquitinating enzyme , contributing to a higher steady state level of c-myc ubiquitination and promoting c-myc degradation .	In addition, nickel and hypoxia exposure decreased USP28, a c-myc de-ubiquitinating enzyme, contributing to a higher steady state level of c-myc ubiquitination and promoting c-myc degradation.	8	28	promoting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	USP28	USP28	USP28	c-myc	c-myc	c-myc	8	9	27	28
In addition , nickel and hypoxia exposure decreased USP28 , a c-Myc de-ubiquitinating enzyme , contributing to a higher steady state level of c-Myc ubiquitination and promoting c-Myc degradation .	In addition, nickel and hypoxia exposure decreased USP28, a c-Myc de-ubiquitinating enzyme, contributing to a higher steady state level of c-Myc ubiquitination and promoting c-Myc degradation.	8	28	promoting	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	USP28	USP28	USP28	c-Myc	c-Myc	c-Myc	8	9	27	28
Our biochemical data also reveal that Atg14L and UVRAG compete for the same binding site within the Beclin 1 coiled-coil domain and readily disrupt the Beclin 1 homodimer to form a heterodimeric Beclin 1-Atg14L or -UVRAG complex because they bind to Beclin 1 with higher affinity than Beclin 1 ' s self association .	Our biochemical data also reveal that Atg14L and UVRAG compete for the same binding site within the Beclin 1 coiled-coil domain and readily disrupt the Beclin 1 homodimer to form a heterodimeric Beclin 1-Atg14L or -UVRAG complex because they bind to Beclin 1 with higher affinity than Beclin 1 's self association.	6	27	disrupt	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	UVRAG	UVRAG	UVRAG	Beclin 1	Beclin 1	Beclin 1	8	9	25	27
UVRAG disrupts this Beclin 1 dimer interface and thus UVRAG-Beclin 1 heterodimers are assembled , which presumably cause the activation of autophagy .	UVRAG disrupts this Beclin 1 dimer interface and thus UVRAG-Beclin 1 heterodimers are assembled, which presumably cause the activation of autophagy.	0	6	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	UVRAG	UVRAG	UVRAG	Beclin 1	Beclin 1	Beclin 1	0	1	3	5
Moreover , coimmunoprecipitation assays show that UVRAG substantially reduces Beclin1 dimerization in vivo .	Moreover, coimmunoprecipitation assays show that UVRAG substantially reduces Beclin1 dimerization in vivo.	6	10	reduces	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	UVRAG	UVRAG	UVRAG	Beclin1	Beclin1	Beclin1	6	7	9	10
Further , while in vitro ITC studies indicate that UVRAG , which heterodimerizes via the BECN1 CCD , disrupts the BECN1 homodimer ; over-expression of the UVRAG CCD in cell culture diminishes , but does not abolish homo-oligomerization .	Further, while in vitro ITC studies indicate that UVRAG, which heterodimerizes via the BECN1 CCD, disrupts the BECN1 homodimer; over-expression of the UVRAG CCD in cell culture diminishes, but does not abolish homo-oligomerization.	9	21	disrupts	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	UVRAG	UVRAG	UVRAG	BECN1	BECN1	BECN1	9	10	20	21
Vav1 deficient mice exhibit substantial defects in T cell development , marked by a block at the DN3 stage and dramatically reduced activities of ERKs and PLC- gamma1 XREF_BIBR , XREF_BIBR , critical downstream mediators of Vav signaling in response to TCR stimulation .	Vav1 deficient mice exhibit substantial defects in T cell development, marked by a block at the DN3 stage and dramatically reduced activities of ERKs and PLC- gamma1 XREF_BIBR, XREF_BIBR, critical downstream mediators of Vav signaling in response to TCR stimulation.	0	25	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Vav1	Vav1	Vav1	ERKs	ERKs	ERKs	0	1	24	25
Mutations in the Dbl homology , pleckstrin homology , or cysteine rich domains of Vav1Y3F abolished Rac1 or ERK activation in the absence of EGF and blocked the migration promoting activity of Vav1Y3F .	Mutations in the Dbl homology, pleckstrin homology, or cysteine rich domains of Vav1Y3F abolished Rac1 or ERK activation in the absence of EGF and blocked the migration promoting activity of Vav1Y3F.	12	19	abolished	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Vav1Y3F	Vav1Y3F	Vav1Y3F	ERK	ERK	ERK	14	15	18	19
Reynolds described the pathway through which our predicted-target Vav1 activates MEK and ERK signaling via Ras XREF_BIBR .	Reynolds described the pathway through which our predicted-target Vav1 activates MEK and ERK signaling via Ras XREF_BIBR.	6	13	activates	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav1	Vav1	Vav1	ERK	ERK	ERK	8	9	12	13
In contrast , the absence of Vav1 reduced ERK activation and exocytosis of cytotoxic granules that allow NK cells to lyse their targets .	In contrast, the absence of Vav1 reduced ERK activation and exocytosis of cytotoxic granules that allow NK cells to lyse their targets.	4	9	reduced	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Vav1	Vav1	Vav1	ERK	ERK	ERK	6	7	8	9
Given the structural similarity of Vav1 and Vav2 and the involvement of Vav2 downstream of EGFR as a regulator of Rho GTPases , we explored the potential Cbl interaction with and regulation of Vav2 function as a paradigm to understanding the biological impact of Cbl mediated negative regulation of EGFR signaling pathways in a physiologically relevant setting .	Given the structural similarity of Vav1 and Vav2 and the involvement of Vav2 downstream of EGFR as a regulator of Rho GTPases, we explored the potential Cbl interaction with and regulation of Vav2 function as a paradigm to understanding the biological impact of Cbl mediated negative regulation of EGFR signaling pathways in a physiologically relevant setting.	33	51	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Vav2	Vav2	Vav2	EGFR	EGFR	EGFR	33	34	49	50
Knockdown of Vav2 in HeLa cells enhanced EGFR degradation and reduced cell proliferation .	Knockdown of Vav2 in HeLa cells enhanced EGFR degradation and reduced cell proliferation.	0	8	enhanced	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Vav2	Vav2	Vav2	EGFR	EGFR	EGFR	2	3	7	8
Both Vav2 Y172 phosphorylation and RhoA activation were blocked by the EGFR inhibitor AG1478 and prevented in MC overexpressing kinase inactive EGFR .	Both Vav2 Y172 phosphorylation and RhoA activation were blocked by the EGFR inhibitor AG1478 and prevented in MC overexpressing kinase inactive EGFR.	1	22	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Vav2	Vav2 Y172 phosphorylation	vav2	EGFR	EGFR	egfr	1	2	21	22
This type of reagent would not block activation of VEGFR-2 by VEGF-C or VEGF-D , however , bispecific antibodies that bind both VEGFR-2 and VEGFR-3 ( Jimenez et al , 2005 ) could possibly be used for this purpose .	This type of reagent would not block activation of VEGFR-2 by VEGF-C or VEGF-D, however, bispecific antibodies that bind both VEGFR-2 and VEGFR-3 (Jimenez et al, 2005) could possibly be used for this purpose.	6	18	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	VEGF-C	VEGF-C	VEGF-C	VEGFR-2	VEGFR-2	VEGFR-2	11	12	9	10
p27 (-/-) cells treated with KIS siRNA grow and progress to S/G ( 2 ) similar to control treated cells , implicating p27 ( Kip1 ) as the critical target for KIS .	p27 (-/-) cells treated with KIS siRNA grow and progress to S/G (2) similar to control treated cells, implicating p27 (Kip1) as the critical target for KIS.	0	6	treated with	Positive_activation_surface_treated_with	Positive_activation	Negative_activation	KIS	KIS	KIS	p27	p27	p27	5	6	0	1
By inhibiting Akt , trastuzumab can inhibit KIS expression and therefore inhibit KIS induced nuclear export of p27 .	By inhibiting Akt, trastuzumab can inhibit KIS expression and therefore inhibit KIS induced nuclear export of p27.	4	18	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	KIS	trastuzumab can inhibit KIS expression	kis	p27	p27	p27	7	8	17	18
It is quite reasonable that the UHMK1 kinase promotes cell proliferation by repressing the cyclin dependent kinase ( CDK ) inhibitor p27Kip1 through phosphorylation and then activating CDK in G1 phase XREF_BIBR , XREF_BIBR , XREF_BIBR .	It is quite reasonable that the UHMK1 kinase promotes cell proliferation by repressing the cyclin dependent kinase (CDK) inhibitor p27Kip1 through phosphorylation and then activating CDK in G1 phase XREF_BIBR, XREF_BIBR, XREF_BIBR.	6	22	promotes	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	UHMK1	UHMK1	UHMK1	p27Kip1	p27Kip1	p27Kip1	6	7	21	22
USP9x shRNA delivery significantly inhibits TGF-beta-induced SMAD4 nuclear retention and eliminates PA promotion of TGF-beta-induced SMAD4 nuclear retention .	USP9x shRNA delivery significantly inhibits TGF-beta-induced SMAD4 nuclear retention and eliminates PA promotion of TGF-beta-induced SMAD4 nuclear retention.	0	17	eliminates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	USP9x	USP9x	USP9x	SMAD4	SMAD4	SMAD4	0	1	15	16
The phosphorylation of Ser1027 in ULK2 by PKA decreases the autophagic activity ( and the apoptosis ) of ULK2 , by promoting not only dissociation of Atg13 and FIP200 from ULK2 but also the nuclear localization of ULK2 ( XREF_FIG , right ) .	The phosphorylation of Ser1027 in ULK2 by PKA decreases the autophagic activity (and the apoptosis) of ULK2, by promoting not only dissociation of Atg13 and FIP200 from ULK2 but also the nuclear localization of ULK2 (XREF_FIG, right).	1	28	decreases	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ULK2	phosphorylation of Ser1027 in ULK2	ulk2	Atg13	Atg13	atg13	5	6	26	27
Moreover , pathogenic VCPs show impaired migration to mitochondria , and the exogenous pathogenic VCP expression partially inhibits Npl4 and p47 localization to mitochondria .	Moreover, pathogenic VCPs show impaired migration to mitochondria, and the exogenous pathogenic VCP expression partially inhibits Npl4 and p47 localization to mitochondria.	14	21	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VCP	VCP expression	vcp	Npl4	Npl4	npl4	14	15	18	19
Tumor cell derived sULBP2 as opposed to cell bound ULBP2 does not down-regulate NKG2D on NK cells .	Tumor cell derived sULBP2 as opposed to cell bound ULBP2 does not down-regulate NKG2D on NK cells.	9	14	down-regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ULBP2	ULBP2	ULBP2	NKG2D	NKG2D	NKG2D	9	10	13	14
Moreover , Wnt1 knockdown induced the cytoplasmic accumulation of beta-catenin in breast cancer cells ( XREF_SUPPLEMENTARY ) .	Moreover, Wnt1 knockdown induced the cytoplasmic accumulation of beta-catenin in breast cancer cells (XREF_SUPPLEMENTARY).	2	10	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	2	3	9	10
Wnt1 and beta-catenin depletion and overexpression of nuclear beta-catenin , together with TCF binding sites activation demonstrated that ABCB1 is positively regulated by the canonical pathway of Wnt signaling .	Wnt1 and beta-catenin depletion and overexpression of nuclear beta-catenin, together with TCF binding sites activation demonstrated that ABCB1 is positively regulated by the canonical pathway of Wnt signaling.	0	15	depletion	Negative_activation_syntax_3_noun	Positive_activation	Negative_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	0	1	8	9
BMP-4 also activated beta-catenin , which was blocked by Smad4 and Wnt1 siRNAs .	BMP-4 also activated beta-catenin, which was blocked by Smad4 and Wnt1 siRNAs.	2	12	blocked	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	11	12	3	4
In this context , miR-122-5p targets the Wnt1 suppressing activation of the Wnt and beta-catenin pathway 28 .	In this context, miR-122-5p targets the Wnt1 suppressing activation of the Wnt and beta-catenin pathway 28.	7	15	activation	Positive_activation_syntax_3_noun	Positive_activation	Negative_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	7	8	14	15
Silencing Frizzled6 did not have a significant impact on VEGF- or Wnt1 induced beta-catenin activation ( XREF_FIG ) .	Silencing Frizzled6 did not have a significant impact on VEGF- or Wnt1 induced beta-catenin activation (XREF_FIG).	7	14	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	11	12	13	14
In normal cells , downregulation of Wnt-1 signaling degrades beta-catenin in the Axin-APC protein complex by GSK-3beta .	In normal cells, downregulation of Wnt-1 signaling degrades beta-catenin in the Axin-APC protein complex by GSK-3beta.	6	14	degrades	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt-1	Wnt-1	Wnt-1	beta-catenin	beta-catenin	beta-catenin	6	7	9	10
As shown in Figure XREF_FIG , while SD ( 48 h ) , 6-OHDA ( 25 muM ) , or MPP + ( 25 muM ) exposures resulted in a dramatic decrease of beta-catenin transcript ( A ) and protein ( B ) , the preventive application of Wnt1 , while inactive , per se , efficiently reversed beta-catenin downregulation , both at a mRNA and protein levels .	As shown in Figure XREF_FIG, while SD (48 h), 6-OHDA (25 muM), or MPP + (25 muM) exposures resulted in a dramatic decrease of beta-catenin transcript (A) and protein (B), the preventive application of Wnt1, while inactive, per se, efficiently reversed beta-catenin downregulation, both at a mRNA and protein levels.	46	59	reversed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt1	Wnt1	Wnt1	beta-catenin	beta-catenin	beta-catenin	48	49	58	59
Our results showed decreased expression of beta-catenin and pGSK3beta when MSCs were treated with Wnt10b siRNA compared to the control ( P < 0.05 ) and this effect was not reversed by concurrent treatment with CoPP .	Our results showed decreased expression of beta-catenin and pGSK3beta when MSCs were treated with Wnt10b siRNA compared to the control (P < 0.05) and this effect was not reversed by concurrent treatment with CoPP.	4	15	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Wnt10b	Wnt10b	Wnt10b	beta-catenin	beta-catenin	beta-catenin	14	15	6	7
Knockdown of Wnt10B expression inhibits the Wnt and beta-catenin signaling pathway and cancer cell stemness .	Knockdown of Wnt10B expression inhibits the Wnt and beta-catenin signaling pathway and cancer cell stemness.	2	10	inhibits	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	Wnt10B	Wnt10B expression	wnt10b	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
Moreover , MAT2A suppressed Wnt10b expression and further inhibited Wnt and beta-catenin signaling to promote adipogenesis .	Moreover, MAT2A suppressed Wnt10b expression and further inhibited Wnt and beta-catenin signaling to promote adipogenesis.	4	12	inhibited	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt10b	Wnt10b expression	wnt10b	beta-catenin	beta-catenin	beta-catenin	4	5	11	12
Thus , it is probable that a loss in the BCL11B gene attenuates the COUP-TFII-mediated suppression of Wnt10b gene expression , thereby activating the Wnt and beta-catenin signaling pathway .	Thus, it is probable that a loss in the BCL11B gene attenuates the COUP-TFII-mediated suppression of Wnt10b gene expression, thereby activating the Wnt and beta-catenin signaling pathway.	17	28	activating	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt10b	Wnt10b gene expression	wnt10b	beta-catenin	beta-catenin	beta-catenin	17	18	26	27
Expression of wnt11 the mostly likely Fzd7 ligand in the foregut , was unchanged by depletion of Sdc4 , Fzd7 , Fn1 or Szl ( XREF_SUPPLEMENTARY ) .	Expression of wnt11 the mostly likely Fzd7 ligand in the foregut, was unchanged by depletion of Sdc4, Fzd7, Fn1 or Szl (XREF_SUPPLEMENTARY).	0	20	was unchanged by depletion	Negative_activation_copula_1	Positive_activation	Negative_activation	wnt11	Expression of wnt11	wnt11	Fzd7	Fzd7	fzd7	2	3	19	20
Loss of Fmi function at sites of Fz7 accumulation therefore causes cells to separate faster , suggesting that Fmi contributes to Wnt11 induced Fz7 accumulation control of cell contact persistence .	Loss of Fmi function at sites of Fz7 accumulation therefore causes cells to separate faster, suggesting that Fmi contributes to Wnt11 induced Fz7 accumulation control of cell contact persistence.	19	25	induced	Positive_early_activation	Positive_activation	Positive_activation	Wnt11	Wnt11	Wnt11	Fz7	Fz7	Fz7	21	22	23	24
Depletion of WNK1 from HeLa cells by using small interfering RNA reduces OSR1 kinase activity .	Depletion of WNK1 from HeLa cells by using small interfering RNA reduces OSR1 kinase activity.	0	14	reduces	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	OSR1	OSR1	OSR1	2	3	12	13
They also showed that OXSR1 was phosphorylated in a WNK1 dependent manner and that depletion of WNK1 from HeLa cells with small interfering RNA reduced OXSR1 kinase activity .	They also showed that OXSR1 was phosphorylated in a WNK1 dependent manner and that depletion of WNK1 from HeLa cells with small interfering RNA reduced OXSR1 kinase activity.	14	27	reduced	Negative_activation_syntax_1_verb	Positive_activation	Positive_activation	WNK1	WNK1	WNK1	OXSR1	OXSR1	OXSR1	16	17	25	26
Since p53 is stabilized by phosphorylation , we tested if downregulation of VRK1 would also prevent accumulation of p53 in response to UV treatment .	Since p53 is stabilized by phosphorylation, we tested if downregulation of VRK1 would also prevent accumulation of p53 in response to UV treatment.	10	19	prevent	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	VRK1	VRK1	VRK1	p53	p53	p53	12	13	18	19
In addition , either Wnt10a-siRNA3 or LGK-974 may inhibit the viability of SKOV3 ; however , there was no synergic effect exhibited between siRNA3 and LGK-974 ( XREF_FIG ) , suggesting that Wnt and beta-catenin signaling is inhibited by Wnt10a siRNA .	In addition, either Wnt10a-siRNA3 or LGK-974 may inhibit the viability of SKOV3; however, there was no synergic effect exhibited between siRNA3 and LGK-974 (XREF_FIG), suggesting that Wnt and beta-catenin signaling is inhibited by Wnt10a siRNA.	32	40	inhibited	Negative_activation_syntax_2_verb	Positive_activation	Positive_activation	Wnt10a	Wnt10a	Wnt10a	beta-catenin	beta-catenin	beta-catenin	39	40	34	35
Further , selectively blocking Wnt1 induced Lrp6 signaling may benefit patients with symptoms of skeletal overgrowth from recessive SOST mutations as well as dominant LRP5 HBM mutations .	Further, selectively blocking Wnt1 induced Lrp6 signaling may benefit patients with symptoms of skeletal overgrowth from recessive SOST mutations as well as dominant LRP5 HBM mutations.	3	7	induced	Positive_early_activation	Positive_activation	Negative_activation	Wnt1	Wnt1	Wnt1	Lrp6	Lrp6	Lrp6	4	5	6	7
As ROR2 is reported to mediate the WNT5A dependent inhibition of beta-catenin-TCF-regulated genes in human embryonic cells [ XREF_BIBR , XREF_BIBR ] , we tested whether WNT5A mediated the canonical Wnt dependent role of aberrant epigenetic ROR2 repression in colon cancer .	As ROR2 is reported to mediate the WNT5A dependent inhibition of beta-catenin-TCF-regulated genes in human embryonic cells [XREF_BIBR, XREF_BIBR], we tested whether WNT5A mediated the canonical Wnt dependent role of aberrant epigenetic ROR2 repression in colon cancer.	26	37	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	WNT5A	WNT5A	WNT5A	ROR2	ROR2	ROR2	26	27	36	37
In addition to its oncogenic roles in cancers , Wnt5a also has been found to inhibit canonical Wnt and beta-catenin signaling in a Ror2 dependent manner and has a tumor suppressor role in several cancer types , such as colorectal cancer ( CRC ) [ XREF_BIBR ] , thyroid cancer [ XREF_BIBR ] , and maybe breast cancers as well [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition to its oncogenic roles in cancers, Wnt5a also has been found to inhibit canonical Wnt and beta-catenin signaling in a Ror2 dependent manner and has a tumor suppressor role in several cancer types, such as colorectal cancer (CRC) [XREF_BIBR], thyroid cancer [XREF_BIBR], and maybe breast cancers as well [XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	27	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt5a	Wnt5a	Wnt5a	Ror2	Ror2	Ror2	9	10	23	24
While previously somewhat paradoxical , it is now clear that in the former role , Wnt5a expression may inhibit uncontrolled Wnt and beta-catenin signaling in the presence of Ror2 , whereas in the latter , Wnt5a could promote canonical Wnt signaling when Fz4 and LRP5 are expressed .	While previously somewhat paradoxical, it is now clear that in the former role, Wnt5a expression may inhibit uncontrolled Wnt and beta-catenin signaling in the presence of Ror2, whereas in the latter, Wnt5a could promote canonical Wnt signaling when Fz4 and LRP5 are expressed.	15	29	inhibit	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt5a	Wnt5a expression	wnt5a	Ror2	Ror2	ror2	15	16	28	29
ROR2 was strongly decreased in cells treated with siRNA against Wnt5A compared with scramble treated or lipofectamine treated cells ( P < 0.001 ) .	ROR2 was strongly decreased in cells treated with siRNA against Wnt5A compared with scramble treated or lipofectamine treated cells (P < 0.001).	0	11	treated with	Positive_activation_surface_treated_with	Positive_activation	Positive_activation	Wnt5A	Wnt5A	Wnt5A	ROR2	ROR2	ROR2	10	11	0	1
Specifically , Wnt5a was reported to promote GSK3beta independent degradation of beta-catenin in the regulation of limb development .	Specifically, Wnt5a was reported to promote GSK3beta independent degradation of beta-catenin in the regulation of limb development.	2	9	promote	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt5a	Wnt5a	Wnt5a	GSK3beta	GSK3beta	GSK3beta	2	3	7	8
Interestingly , non canonical signaling has been shown to exert an antagonistic effect on canonical signaling , with Wnt5a promoting GSK3beta independent degradation of beta-catenin [ XREF_BIBR ] and competing with Wnt3a for binding to the receptor complex [ XREF_BIBR ] .	Interestingly, non canonical signaling has been shown to exert an antagonistic effect on canonical signaling, with Wnt5a promoting GSK3beta independent degradation of beta-catenin [XREF_BIBR] and competing with Wnt3a for binding to the receptor complex [XREF_BIBR].	7	29	promoting	Positive_activation_token_1_verb	Positive_activation	Negative_activation	Wnt5a	Wnt5a	Wnt5a	GSK3beta	GSK3beta	GSK3beta	18	19	20	21
However , upon pre-treatment of the cells with GO6983 , rWnt5A was less efficient at decreasing ROR1 , suggesting that PKC is required for the Wnt5A mediated degradation of ROR1 ( XREF_FIG , XREF_SUPPLEMENTARY , GO + rWnt5A ) .	However, upon pre-treatment of the cells with GO6983, rWnt5A was less efficient at decreasing ROR1, suggesting that PKC is required for the Wnt5A mediated degradation of ROR1 (XREF_FIG, XREF_SUPPLEMENTARY, GO + rWnt5A).	22	31	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt5A	Wnt5A	Wnt5A	ROR1	ROR1	ROR1	25	26	29	30
In agreement with earlier studies , 13 Wnt5a did not enhance the proliferation of ROR1 negative TCL1-leukemia cells co-cultured with HeLa CD154 cells and IL-4/10 ( XREF_SUPPLEMENTARY ) , indicating a dependency on ROR1 for this effect .	In agreement with earlier studies, 13 Wnt5a did not enhance the proliferation of ROR1 negative TCL1-leukemia cells co-cultured with HeLa CD154 cells and IL-4/10 (XREF_SUPPLEMENTARY), indicating a dependency on ROR1 for this effect.	6	17	enhance	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt5a	Wnt5a	Wnt5a	ROR1	ROR1	ROR1	7	8	14	15
We show that Wnt5A can signal to increase the proteasomal degradation of ROR1 , such that ROR1 is decreased during invasion .	We show that Wnt5A can signal to increase the proteasomal degradation of ROR1, such that ROR1 is decreased during invasion.	3	13	signal	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt5A	Wnt5A	Wnt5A	ROR1	ROR1	ROR1	3	4	12	13
Over-expression of Wnt5a antagonized RA mediated down-regulation of Myf5 and MyoD in C2C12 cells .	Over-expression of Wnt5a antagonized RA mediated down-regulation of Myf5 and MyoD in C2C12 cells.	0	11	antagonized	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt5a	Over-expression of Wnt5a	wnt5a	MyoD	MyoD	myod	2	3	10	11
Thus , overexpression of Wnt5a in C2C12 myoblasts partially blocked RA induced down-regulation of Myf5 and MyoD in differentiated C2C12 cells .	Thus, overexpression of Wnt5a in C2C12 myoblasts partially blocked RA induced down-regulation of Myf5 and MyoD in differentiated C2C12 cells.	2	17	blocked	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt5a	overexpression of Wnt5a	wnt5a	MyoD	MyoD	myod	4	5	16	17
Wnt3a treatment transiently disrupted the Dvl-1 and Smad1 interaction coincident with nuclear accumulation of beta-catenin .	Wnt3a treatment transiently disrupted the Dvl-1 and Smad1 interaction coincident with nuclear accumulation of beta-catenin.	0	9	disrupted	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Wnt3a	Wnt3a	Wnt3a	Dvl-1	Dvl-1	Dvl-1	0	1	5	6
Consistent with the biochemical evidence that WNT3A does not induce marked LRP6 internalization , WNT3A did not visibly reduce LRP6 staining at the surfaces of MEF cells examined by confocal fluorescence microscopy ( XREF_FIG ) .	Consistent with the biochemical evidence that WNT3A does not induce marked LRP6 internalization, WNT3A did not visibly reduce LRP6 staining at the surfaces of MEF cells examined by confocal fluorescence microscopy (XREF_FIG).	14	20	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	WNT3A	WNT3A	WNT3A	LRP6	LRP6	LRP6	14	15	19	20
Wnt3a induced LRP6 activation was dramatically reduced by ( P ) RR siRNA-treatment ( XREF_FIG ) , compared with the cells treated with scrambled siRNA .	Wnt3a induced LRP6 activation was dramatically reduced by (P) RR siRNA-treatment (XREF_FIG), compared with the cells treated with scrambled siRNA.	0	3	induced	Positive_early_activation	Positive_activation	Negative_activation	Wnt3a	Wnt3a	Wnt3a	LRP6	LRP6	LRP6	0	1	2	3
Also , the in vitro studies showed that the LRP5 mutations C913fs and L1149Q alter Wnt signaling activity , as indicated by impaired activation of LRP5 by Wnt3a .	Also, the in vitro studies showed that the LRP5 mutations C913fs and L1149Q alter Wnt signaling activity, as indicated by impaired activation of LRP5 by Wnt3a.	20	28	activation	Positive_activation_token_2_noun	Positive_activation	Negative_activation	Wnt3a	Wnt3a	Wnt3a	LRP5	LRP5	LRP5	27	28	25	26
In colon cancer , the reduction of YAP1 expression triggered hyperactivity of the Wnt and beta-catenin pathway , supporting the link between Hippo and YAP1 signaling and the Wnt and beta-catenin pathway [ XREF_BIBR ] .	In colon cancer, the reduction of YAP1 expression triggered hyperactivity of the Wnt and beta-catenin pathway, supporting the link between Hippo and YAP1 signaling and the Wnt and beta-catenin pathway [XREF_BIBR].	7	16	triggered	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	YAP1	YAP1 expression	yap1	beta-catenin	beta-catenin	beta-catenin	7	8	15	16
YAP1 recruits beta-TRCP to the beta-catenin destruction complex in the absence of WNT , and thus , reduce the cytoplasm beta-catenin retention .	YAP1 recruits beta-TRCP to the beta-catenin destruction complex in the absence of WNT, and thus, reduce the cytoplasm beta-catenin retention.	0	21	reduce	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	YAP1	YAP1	YAP1	beta-catenin	beta-catenin	beta-catenin	0	1	20	21
On the other hand , YAP1 silencing resulted in both CTNNB1 and beta-catenin increase and beta-catenin nuclear expression .	On the other hand, YAP1 silencing resulted in both CTNNB1 and beta-catenin increase and beta-catenin nuclear expression.	5	14	increase	Positive_activation_syntax_results_in	Positive_activation	Negative_activation	YAP1	YAP1	YAP1	beta-catenin	beta-catenin	beta-catenin	5	6	12	13
YAP1 silencing increases CTNNB1 and Beta-Catenin regardless of DVL2 mRNA expression .	YAP1 silencing increases CTNNB1 and Beta-Catenin regardless of DVL2 mRNA expression.	0	6	increases	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	YAP1	YAP1	YAP1	Beta-Catenin	Beta-Catenin	Beta-Catenin	0	1	5	6
Remarkably under stress conditions , the expression of exogenous XBP1 repressed splicing of endogenous XBP1 mRNA without repressing the activation of PERK .	Remarkably under stress conditions, the expression of exogenous XBP1 repressed splicing of endogenous XBP1 mRNA without repressing the activation of PERK.	6	15	repressed	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	XBP1	expression of exogenous XBP1	xbp1	XBP1	XBP1	xbp1	9	10	14	15
Levels of the XBP1 targets ERdj4 and EDEM1 were reduced in Xbp1 +/- mice , an effect that was more pronounced in ethanol fed compared to control fed mice .	Levels of the XBP1 targets ERdj4 and EDEM1 were reduced in Xbp1 +/- mice, an effect that was more pronounced in ethanol fed compared to control fed mice.	0	16	targets	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	XBP1	Levels of the XBP1	xbp1	Xbp1	Xbp1	xbp1	3	4	11	12
The results showed that XBP-1 protein level of H929 cells was inhibited effectively by the PLL3.7 lentiviral vector mediated expression xbp-1 shRNA .	The results showed that XBP-1 protein level of H929 cells was inhibited effectively by the PLL3.7 lentiviral vector mediated expression xbp-1 shRNA.	4	21	mediated	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	XBP-1	XBP-1 protein level of H929 cells was inhibited effectively by the PLL3.7	xbp-1	xbp-1	xbp-1	xbp-1	4	5	20	21
Considering that Xxylt1 can negatively regulate Notch activation 102 , this may suggest a novel pathway changes to comprise Notch activation in the tumorigenesis of these cancer types .	Considering that Xxylt1 can negatively regulate Notch activation 102, this may suggest a novel pathway changes to comprise Notch activation in the tumorigenesis of these cancer types.	0	12	negatively regulate	Negative_activation_syntax_5_verb	Positive_activation	Negative_activation	Xxylt1	Xxylt1	Xxylt1	Notch	Notch	Notch	2	3	6	7
Although much work needs to be done , considering that XXYLT1 can negatively regulate Notch signaling 9 , our findings suggest that Notch-inhibitory xylosylation by XXYLT1 may play an important role in Notch related tumorigenesis in specific cancer types , for example , lung squamous cell carcinoma .	Although much work needs to be done, considering that XXYLT1 can negatively regulate Notch signaling 9, our findings suggest that Notch-inhibitory xylosylation by XXYLT1 may play an important role in Notch related tumorigenesis in specific cancer types, for example, lung squamous cell carcinoma.	10	15	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	XXYLT1	XXYLT1	XXYLT1	Notch	Notch	Notch	10	11	14	15
Because XXYLT1 negatively regulates Notch 9 , and Notch aberrations have been linked to myeloid cancers 31 and squamous cell carcinoma of lung 32 , head and neck squamous cell carcinoma 33 , we wondered if the enzyme XXYLT1 is implicated in cancer .	Because XXYLT1 negatively regulates Notch 9, and Notch aberrations have been linked to myeloid cancers 31 and squamous cell carcinoma of lung 32, head and neck squamous cell carcinoma 33, we wondered if the enzyme XXYLT1 is implicated in cancer.	1	5	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	XXYLT1	XXYLT1	XXYLT1	Notch	Notch	Notch	1	2	4	5
Xylosylation by the retaining glycosyltransferase ( GT ) XXYLT1 negatively regulates Notch activation 9 .	Xylosylation by the retaining glycosyltransferase (GT) XXYLT1 negatively regulates Notch activation 9.	8	12	negatively regulates	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	XXYLT1	XXYLT1	XXYLT1	Notch	Notch	Notch	8	9	11	12
DNA-PKcs deficiency caused a DSB repair defect that was , unexpectedly , suppressed by KU70 disruption .	DNA-PKcs deficiency caused a DSB repair defect that was, unexpectedly, suppressed by KU70 disruption.	0	15	caused	Positive_activation_syntax_2_verb	Positive_activation	Negative_activation	KU70	KU70	KU70	DNA-PKcs	DNA-PKcs	DNA-PKcs	14	15	0	1
These results demonstrate how Yap1 supports degradation of p73 via Runx and how it plays an opposite role in response to DNA damage .	These results demonstrate how Yap1 supports degradation of p73 via Runx and how it plays an opposite role in response to DNA damage.	4	10	supports	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	Yap1	Yap1	Yap1	p73	p73	p73	4	5	8	9
As expected , silencing Lats1/2 can activate YAP1 , indicated by nuclear translocation of YAP1 , enhanced transcription of CTGF and CYR61 , and increased transcriptional activity of TEAD4 ( XREF_SUPPLEMENTARY ) .	As expected, silencing Lats1/2 can activate YAP1, indicated by nuclear translocation of YAP1, enhanced transcription of CTGF and CYR61, and increased transcriptional activity of TEAD4 (XREF_SUPPLEMENTARY).	7	30	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	YAP1	YAP1, indicated by nuclear translocation of YAP1, enhanced transcription	yap1	TEAD4	TEAD4	tead4	7	8	28	29
A more likely explanation of the poor potency of mXCL1 for mXCR1 could be that either the extra N-terminal methionine or the lack of glycosylation of the E. Coli produced recombinant murine lymphotactin prevented proper activation of the murine but not the human lymphotactin receptor .	A more likely explanation of the poor potency of mXCL1 for mXCR1 could be that either the extra N-terminal methionine or the lack of glycosylation of the E. Coli produced recombinant murine lymphotactin prevented proper activation of the murine but not the human lymphotactin receptor.	30	45	prevented	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	lymphotactin	lymphotactin	lymphotactin	lymphotactin receptor	lymphotactin receptor	lymphotactin receptor	32	33	43	45
This result may be explained by a compensatory mechanism , by which ADAMTS13 synthesis is increased due to the marked elevation in VWF plasma levels , keeping VWF and ADAMTS13 antigen ratio unchanged .	This result may be explained by a compensatory mechanism, by which ADAMTS13 synthesis is increased due to the marked elevation in VWF plasma levels, keeping VWF and ADAMTS13 antigen ratio unchanged.	12	31	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	12	13	27	28
ADAMTS13 deficiency causes accumulation of unusually large von Willebrand factor molecules , which cross-link platelets in the circulation or on the endothelial surface .	ADAMTS13 deficiency causes accumulation of unusually large von Willebrand factor molecules, which cross-link platelets in the circulation or on the endothelial surface.	0	10	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	0	1	7	10
Consistent with its partial inhibition of VWF-ADAMTS13 interactions in binding assays , mAb508 reduced ADAMTS13 mediated VWF degradation in a vortex based degradation assay by 48 +/- 10 % .	Consistent with its partial inhibition of VWF-ADAMTS13 interactions in binding assays, mAb508 reduced ADAMTS13 mediated VWF degradation in a vortex based degradation assay by 48 +/- 10%.	13	17	mediated	Positive_early_activation	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	14	15	16	17
In malaria , endothelial cell activation with increased circulating amounts of active and ultra-large VWF , together with reduced VWF inactivation by ADAMTS13 , may result in intravascular platelet aggregation , thrombocytopenia , and microvascular disease .	In malaria, endothelial cell activation with increased circulating amounts of active and ultra-large VWF, together with reduced VWF inactivation by ADAMTS13, may result in intravascular platelet aggregation, thrombocytopenia, and microvascular disease.	19	23	inactivation	Negative_activation_syntax_2_noun	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	22	23	19	20
We propose that this novel VWF C-terminal binding site may participate as the initial step of a multistep interaction ultimately leading to proteolysis of VWF by ADAMTS13 .	We propose that this novel VWF C-terminal binding site may participate as the initial step of a multistep interaction ultimately leading to proteolysis of VWF by ADAMTS13.	20	27	leading	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	26	27	24	25
This VWF deficiency is believed to contribute to the bleeding diathesis of patients on LVAD support and is caused by excessive VWF cleavage by the metalloprotease ADAMTS-13 under high shear stress .	This VWF deficiency is believed to contribute to the bleeding diathesis of patients on LVAD support and is caused by excessive VWF cleavage by the metalloprotease ADAMTS-13 under high shear stress.	1	27	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	26	27	1	2
The formation of proteolytic cleavage product of VWF by ADAMTS13 in the citrated plasma is time- ( XREF_FIG ) and concentration- ( XREF_FIG ) dependent with the maximal cleavage products detected with 1 mul of plasma in a total of 20 mul reaction volume after 60 minutes of vortex at 2,500 rpm using the MixMate PCR mixer .	The formation of proteolytic cleavage product of VWF by ADAMTS13 in the citrated plasma is time- (XREF_FIG) and concentration- (XREF_FIG) dependent with the maximal cleavage products detected with 1 mul of plasma in a total of 20 mul reaction volume after 60 minutes of vortex at 2,500 rpm using the MixMate PCR mixer.	5	13	product	Positive_activation_token_2_noun	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	9	10	7	8
Systemic inflammation complicating advanced cirrhosis is accompanied by reduced activity of ADAMTS13 promoting a prothrombotic function of VWF , which can be employed to predict clinical outcome .	Systemic inflammation complicating advanced cirrhosis is accompanied by reduced activity of ADAMTS13 promoting a prothrombotic function of VWF, which can be employed to predict clinical outcome.	9	24	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	11	12	17	18
Deficiency of ADAMTS-13 promotes VWF induced platelet aggregation , which can result in thrombotic thrombocytopenic purpura [ XREF_BIBR ] .	Deficiency of ADAMTS-13 promotes VWF induced platelet aggregation, which can result in thrombotic thrombocytopenic purpura [XREF_BIBR].	0	5	promotes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	2	3	4	5
Seven other mAbs against VWF including SZ129 and SZ130 ( two mAbs against VWF A1 ) , SZ29 ( another mAb against VWF A2 ) , SZ123 and SZ125 ( two mAbs against VWF A3 ) and 1C1E7 and 75H4B12 ( two mAbs against VWF D'D3 ) exhibited no effects on ADAMTS13 mediated VWF proteolysis under either shear stress or denaturing conditions .	Seven other mAbs against VWF including SZ129 and SZ130 (two mAbs against VWF A1), SZ29 (another mAb against VWF A2), SZ123 and SZ125 (two mAbs against VWF A3) and 1C1E7 and 75H4B12 (two mAbs against VWF D'D3) exhibited no effects on ADAMTS13 mediated VWF proteolysis under either shear stress or denaturing conditions.	47	54	mediated	Positive_early_activation	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	51	52	53	54
Idiopathic TTP is a rare hematological emergency ( four cases per million ) driven by an inhibitory autoantibody to the ADAMTS13 metalloproteinase causing the accumulation of unusually large von Willebrand factor multimers .	Idiopathic TTP is a rare hematological emergency (four cases per million) driven by an inhibitory autoantibody to the ADAMTS13 metalloproteinase causing the accumulation of unusually large von Willebrand factor multimers.	20	31	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	20	21	28	31
Other key features of these studies have documented the rapid disappearance of the ultra high molecular weight VWF multimers and the coincident demonstration of ADAMTS13 mediated proteolytic fragments of VWF within 15 minutes of product infusion .	Other key features of these studies have documented the rapid disappearance of the ultra high molecular weight VWF multimers and the coincident demonstration of ADAMTS13 mediated proteolytic fragments of VWF within 15 minutes of product infusion.	22	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	24	25	29	30
Lack of ADAMTS-13 activity causes increased concentrations of high molecular weight von Willebrand factor forms and increased platelet aggregation .	Lack of ADAMTS-13 activity causes increased concentrations of high molecular weight von Willebrand factor forms and increased platelet aggregation.	2	14	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	von Willebrand factor	von Willebrand factor	von Willebrand factor	2	3	11	14
They suggested that a binding site in the C-terminal region ( D4CK ) of VWF is constitutively exposed and participates at the initial step of a multi-step interaction , ultimately leading to proteolysis of VWF by ADAMTS13 .	They suggested that a binding site in the C-terminal region (D4CK) of VWF is constitutively exposed and participates at the initial step of a multi-step interaction, ultimately leading to proteolysis of VWF by ADAMTS13.	30	37	leading	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	36	37	34	35
VWF multimeric size is modulated by ADAMTS-13 , which cleaves in the VWF A2 domain , thus reducing both the molecular weight and platelet tethering function .	VWF multimeric size is modulated by ADAMTS-13, which cleaves in the VWF A2 domain, thus reducing both the molecular weight and platelet tethering function.	0	9	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	VWF	VWF	VWF	6	7	0	1
ADAMTS13 -/- mice had increased VWF release , with accumulation at inflamed colonic sites .	ADAMTS13 -/- mice had increased VWF release, with accumulation at inflamed colonic sites.	0	6	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	0	1	5	6
Our data also demonstrate the direct correlation between anti-arterial thrombotic activity of ADAMTS13 ( or variants ) ( XREF_FIG and XREF_FIG ) and its VWF-cleavage activity under fluid shear stress ( XREF_FIG , XREF_FIG , and XREF_TABLE ) , suggesting the critical role of ADAMTS13 mediated VWF proteolysis in modulation of arterial thrombosis .	Our data also demonstrate the direct correlation between anti-arterial thrombotic activity of ADAMTS13 (or variants) (XREF_FIG and XREF_FIG) and its VWF-cleavage activity under fluid shear stress (XREF_FIG, XREF_FIG, and XREF_TABLE), suggesting the critical role of ADAMTS13 mediated VWF proteolysis in modulation of arterial thrombosis.	42	47	mediated	Positive_early_activation	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	44	45	46	47
The second category includes mechanisms that do not initiate clotting by themselves but may promote clotting propagation by shifting coagulation balance : increased level , activity or longevity of pro coagulant factors , decreased concentration or function of the anti-coagulant molecules , decreased fibrinolysis , ADAMTS13 , increased vWF [ XREF_BIBR ] .	The second category includes mechanisms that do not initiate clotting by themselves but may promote clotting propagation by shifting coagulation balance : increased level, activity or longevity of pro coagulant factors, decreased concentration or function of the anti-coagulant molecules, decreased fibrinolysis, ADAMTS13, increased vWF [XREF_BIBR].	43	49	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	vWF	vWF	vWF	45	46	48	49
Interestingly , some evidence suggests that ADAMTS13 reduces disulfide bond activity , thereby preventing the covalent lateral association and increased platelet adherence of plasma VWF multimers under high shear stress XREF_BIBR .	Interestingly, some evidence suggests that ADAMTS13 reduces disulfide bond activity, thereby preventing the covalent lateral association and increased platelet adherence of plasma VWF multimers under high shear stress XREF_BIBR.	6	25	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	6	7	24	25
Deletion of the C-terminal TSP1 and CUB domains of ADAMTS13 impairs the cleavage of large VWF multimers in vitro , increases vascular thrombosis in vivo , and yet increases the cleavage of peptide substrates such as FRETS-VWF73 .	Deletion of the C-terminal TSP1 and CUB domains of ADAMTS13 impairs the cleavage of large VWF multimers in vitro, increases vascular thrombosis in vivo, and yet increases the cleavage of peptide substrates such as FRETS-VWF73.	4	16	impairs	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	9	10	15	16
The mechanism of the protective effects of E2 on the cardiovascular system could be explained by the intracellular regulation of VWF produced by ADAMTS13 .	The mechanism of the protective effects of E2 on the cardiovascular system could be explained by the intracellular regulation of VWF produced by ADAMTS13.	18	24	produced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	23	24	20	21
The ADAMTS13 related increase in VWF length XREF_BIBR is known as thrombotic thrombocytopenic purpura and corresponds to a shifting of the representation cloud to the right in XREF_FIG , resulting in easier platelet activation and a tendency toward thrombosis .	The ADAMTS13 related increase in VWF length XREF_BIBR is known as thrombotic thrombocytopenic purpura and corresponds to a shifting of the representation cloud to the right in XREF_FIG, resulting in easier platelet activation and a tendency toward thrombosis.	1	7	increase	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	1	2	5	6
The dysregulation of ADAMTS 13 activity could promote massive release of high molecular weight multimers of von Willebrand factor ( VWF ) from endothelium and , as a consequence , could cause intravascular platelet aggregation .	The dysregulation of ADAMTS 13 activity could promote massive release of high molecular weight multimers of von Willebrand factor (VWF) from endothelium and, as a consequence, could cause intravascular platelet aggregation.	3	19	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS 13	ADAMTS 13	ADAMTS 13	von Willebrand factor	von Willebrand factor	von Willebrand factor	3	5	16	19
Among the related adamalysins with thrombospondin motifs ( ADAMTSs ) , the C-terminal domains of ADAMTS-4 and ADAMTS-5 have been shown to promote aggrecan cleavage , the C-terminal spacer domain of ADAMTS13 promotes cleavage of von Willebrand factor and C-terminal domains of ADAMTS-2 modulate processing of the N-terminal propeptide of procollagen .	Among the related adamalysins with thrombospondin motifs (ADAMTSs), the C-terminal domains of ADAMTS-4 and ADAMTS-5 have been shown to promote aggrecan cleavage, the C-terminal spacer domain of ADAMTS13 promotes cleavage of von Willebrand factor and C-terminal domains of ADAMTS-2 modulate processing of the N-terminal propeptide of procollagen.	29	38	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	31	32	35	38
In the normal state , circulating proteases , notably ADAMTS13 , degrade vWF into smaller multimers thereby reducing the thrombogenic propensity of vWF ; however , in sepsis this homeostatic function may go awry .	In the normal state, circulating proteases, notably ADAMTS13, degrade vWF into smaller multimers thereby reducing the thrombogenic propensity of vWF; however, in sepsis this homeostatic function may go awry.	6	13	degrade	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	vWF	vWF	vWF	9	10	12	13
The von Willebrand factor cleaving protease ( VWFCP ) modulates the von Willebrand factor ( VWF ) multimeric size in normal plasma .	The von Willebrand factor cleaving protease (VWFCP) modulates the von Willebrand factor (VWF) multimeric size in normal plasma.	1	18	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	von Willebrand factor cleaving protease	von Willebrand factor cleaving protease	von Willebrand factor cleaving protease	VWF	VWF	VWF	1	6	15	16
XREF_BIBR XREF_BIBR Generally , noncongenital TTP is secondary to autoantibody mediated reduction in activity of a disintegrin and metalloproteinase with thrombospondin domain 13 ( ADAMTS 13 ) , a metalloproteinase that degrades von Willebrand factor ( vWF ) .	XREF_BIBR XREF_BIBR Generally, noncongenital TTP is secondary to autoantibody mediated reduction in activity of a disintegrin and metalloproteinase with thrombospondin domain 13 (ADAMTS 13), a metalloproteinase that degrades von Willebrand factor (vWF).	11	35	degrades	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	ADAMTS 13	ADAMTS 13	ADAMTS 13	von Willebrand factor	von Willebrand factor	von Willebrand factor	24	26	32	35
ADAMTS13 primarily drives cleavage of the polymeric ultra-large molecular weight von Willebrand factor ( ULMW-vWF ) into multimeric vWF of smaller sizes within blood vessels XREF_BIBR , XREF_BIBR .	ADAMTS13 primarily drives cleavage of the polymeric ultra-large molecular weight von Willebrand factor (ULMW-vWF) into multimeric vWF of smaller sizes within blood vessels XREF_BIBR, XREF_BIBR.	0	13	drives	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	0	1	10	13
Lack of functional ADAMTS13 leads to ultralarge vWF multimers and predisposes to the formation of microvascular thrombi .	Lack of functional ADAMTS13 leads to ultralarge vWF multimers and predisposes to the formation of microvascular thrombi.	0	8	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	vWF	vWF	vWF	3	4	7	8
A possible mechanism is that low ADAMTS13 levels cause less fragmentation of vWF , resulting in more long vWF molecules that can activate platelets , thereby a higher RPR .	A possible mechanism is that low ADAMTS13 levels cause less fragmentation of vWF, resulting in more long vWF molecules that can activate platelets, thereby a higher RPR.	6	13	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13 levels	adamts13	vWF	vWF	vwf	6	7	12	13
ADAMTS13 , the specific von Willebrand factor ( VWF )-cleaving metalloprotease , prevents the spontaneous formation of platelet thrombi in the microcirculation by degrading the highly adhesive ultralarge VWF multimers into smaller forms .	ADAMTS13, the specific von Willebrand factor (VWF)-cleaving metalloprotease, prevents the spontaneous formation of platelet thrombi in the microcirculation by degrading the highly adhesive ultralarge VWF multimers into smaller forms.	0	29	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	0	1	28	29
ADAMTS13 modulates von Willebrand factor ( VWF ) platelet tethering function by proteolysis of the Tyr1605-Met1606 bond in the VWF A2 domain .	ADAMTS13 modulates von Willebrand factor (VWF) platelet tethering function by proteolysis of the Tyr1605-Met1606 bond in the VWF A2 domain.	0	5	modulates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	von Willebrand factor	von Willebrand factor	von Willebrand factor	0	1	2	5
Endothelial cell injury leads to enhanced cellular adhesion to the vessel wall , amplifying the inflammatory response and coagulation via ADAMTS13 mediated Von Willebrand factor cleavage , NETS and microparticles leading to the formation of microvascular thrombosis [ XREF_BIBR , XREF_BIBR ] .	Endothelial cell injury leads to enhanced cellular adhesion to the vessel wall, amplifying the inflammatory response and coagulation via ADAMTS13 mediated Von Willebrand factor cleavage, NETS and microparticles leading to the formation of microvascular thrombosis [XREF_BIBR, XREF_BIBR].	16	25	mediated	Positive_early_activation	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	Von Willebrand factor	Von Willebrand factor	Von Willebrand factor	20	21	22	25
ADAMTS13 variants truncated downstream of the spacer domain increases by two- to threefolds the activity of ADAMTS13 in cleaving abbreviated VWF peptides such as VWF73 ( D1596-R1668 ) , indicating that the distal part of ADAMTS13 enhances the cleavage of VWF multimers but hinders the cleavage of VWF73 [ XREF_BIBR ] .	ADAMTS13 variants truncated downstream of the spacer domain increases by two- to threefolds the activity of ADAMTS13 in cleaving abbreviated VWF peptides such as VWF73 (D1596-R1668), indicating that the distal part of ADAMTS13 enhances the cleavage of VWF multimers but hinders the cleavage of VWF73 [XREF_BIBR].	33	41	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	35	36	40	41
Similar to thrombotic thrombocytopenic purpura ( TTP ) , TAMOF is associated with decreased alpha disintegrin and metalloproteinase with thrombospondin motifs-13 ( ADAMTS-13 ) leading to increased circulating ultra-large von Willebrand factor ( vWF ) , platelet overconsumption , and organ failure secondary to vWF rich microvascular thromboses .	Similar to thrombotic thrombocytopenic purpura (TTP), TAMOF is associated with decreased alpha disintegrin and metalloproteinase with thrombospondin motifs-13 (ADAMTS-13) leading to increased circulating ultra-large von Willebrand factor (vWF), platelet overconsumption, and organ failure secondary to vWF rich microvascular thromboses.	20	32	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	von Willebrand factor	von Willebrand factor	von Willebrand factor	22	23	29	32
[ XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR ] Furthermore , there was increased plasma VWF and decreased ADAMTS13 levels in preeclampsia [ XREF_BIBR ] and diabetic nephropathy , with a negative correlation with estimated glomerular filtration rate .	[XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR] Furthermore, there was increased plasma VWF and decreased ADAMTS13 levels in preeclampsia [XREF_BIBR] and diabetic nephropathy, with a negative correlation with estimated glomerular filtration rate.	10	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13 levels	adamts13	VWF	VWF	vwf	15	16	12	13
Our results suggest that removal of the C-terminal TSP1 and CUB domains by FXIa and alpha-thrombin may limit ADAMTS13 mediated VWF inactivation in vivo .	Our results suggest that removal of the C-terminal TSP1 and CUB domains by FXIa and alpha-thrombin may limit ADAMTS13 mediated VWF inactivation in vivo.	17	21	mediated	Positive_early_activation	Negative_activation	Positive_activation	ADAMTS13	ADAMTS13	ADAMTS13	VWF	VWF	VWF	18	19	20	21
Recent evidence has demonstrated that supraphysiological shear stress from continuous-flow LVADs accelerates von Willebrand factor ( vWF ) metabolism by the action of a disintegrin and metalloproteinase with a thrombospondin type 1 motif , member 13 ( ADAMTS-13 ) ( the vWF protease ) .	Recent evidence has demonstrated that supraphysiological shear stress from continuous-flow LVADs accelerates von Willebrand factor (vWF) metabolism by the action of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) (the vWF protease).	11	38	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ADAMTS-13	ADAMTS-13	ADAMTS-13	von Willebrand factor	von Willebrand factor	von Willebrand factor	37	38	12	15
In addition to this mechanism , AgRP also acts as an agonist to increase K + efflux through inwardly rectifying potassium channel Kir7.1 , and produces a strong hyperpolarization in MC4R expressing neurons in the paraventricular nucleus of mice9 .	In addition to this mechanism, AgRP also acts as an agonist to increase K + efflux through inwardly rectifying potassium channel Kir7.1, and produces a strong hyperpolarization in MC4R expressing neurons in the paraventricular nucleus of mice9.	6	31	produces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	6	7	30	31
For example , a single dose of 100 pmol has been reported to produce a robust increase in food intake that persists for an entire week , and centrally administered AgRP has been shown to increase food intake in Mc4r -/- mice in a dose dependent manner .	For example, a single dose of 100 pmol has been reported to produce a robust increase in food intake that persists for an entire week, and centrally administered AgRP has been shown to increase food intake in Mc4r -/- mice in a dose dependent manner.	29	41	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AgRP	AgRP	AgRP	Mc4r	Mc4r	Mc4r	30	31	39	40
Acute activation of MC4R by central administration of alpha-MSH or the synthetic agonist MTII have been shown to suppress feeding and blockade of MC4R by AgRP ( see above ) or the synthetic antagonist SHU9119 have been shown to promote feeding [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Acute activation of MC4R by central administration of alpha-MSH or the synthetic agonist MTII have been shown to suppress feeding and blockade of MC4R by AgRP (see above) or the synthetic antagonist SHU9119 have been shown to promote feeding [XREF_BIBR, XREF_BIBR, XREF_BIBR].	18	26	blockade	Negative_activation_token_2_noun	Negative_activation	Positive_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	25	26	23	24
MC4R -/ - mice and mice treated with AgRP are resistant to lipopolysaccharide- or tumor induced cachexia , further supporting the role of MC4R in energy balance and body weight regulation .	MC4R -/ - mice and mice treated with AgRP are resistant to lipopolysaccharide- or tumor induced cachexia, further supporting the role of MC4R in energy balance and body weight regulation.	0	10	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	8	9	0	1
We investigated the role of AGRP and melanocortin signaling in ghrelin induced food intake by studying melanocortin 3 and 4 receptor knockout ( MC3R KO and MC4R KO ) mice .	We investigated the role of AGRP and melanocortin signaling in ghrelin induced food intake by studying melanocortin 3 and 4 receptor knockout (MC3R KO and MC4R KO) mice.	5	27	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AGRP	AGRP	AGRP	MC4R	MC4R	MC4R	5	6	26	27
It is also possible that once released , AgRP activates MC4R receptors within hypothalamic structures which stimulate VTA neurons with direct projections to the mPFC but not the NAcc .	It is also possible that once released, AgRP activates MC4R receptors within hypothalamic structures which stimulate VTA neurons with direct projections to the mPFC but not the NAcc.	8	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	8	9	10	11
Conversely , AgRP mediated a MC4R dependent increase in Tl + flux through Kir7.1 , with an EC 50 of 10 -8.6 M ( XREF_FIG ) .	Conversely, AgRP mediated a MC4R dependent increase in Tl + flux through Kir7.1, with an EC 50 of 10 -8.6 M (XREF_FIG).	2	7	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AgRP	AgRP	AgRP	MC4R	MC4R	MC4R	2	3	5	6
Increased NPY and AGRP neuronal activity increases feeding and promotes fat deposition via activation of NPY receptors and AGRP mediated inverse agonism of MC3R and MC4R .	Increased NPY and AGRP neuronal activity increases feeding and promotes fat deposition via activation of NPY receptors and AGRP mediated inverse agonism of MC3R and MC4R.	1	26	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AGRP	AGRP	AGRP	MC4R	MC4R	MC4R	3	4	25	26
In contrast , suppression of agrp expression reduces growth rate in a MC4R dependent manner during this period .	In contrast, suppression of agrp expression reduces growth rate in a MC4R dependent manner during this period.	5	14	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	agrp	agrp expression	agrp	MC4R	MC4R	mc4r	5	6	12	13
We show that inhibition of Crk signaling by Abl dependent phosphorylation , and positive signaling through Nck engagement , constitute the molecular mechanisms by which the cluster of c-Abl PxxP motifs inhibits lamellipodium and focal adhesion formation , and promotes formation of filopodia during cell attachment .	We show that inhibition of Crk signaling by Abl dependent phosphorylation, and positive signaling through Nck engagement, constitute the molecular mechanisms by which the cluster of c-Abl PxxP motifs inhibits lamellipodium and focal adhesion formation, and promotes formation of filopodia during cell attachment.	5	11	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Abl	Abl dependent phosphorylation	abl	Crk	Crk	crk	8	9	5	6
Our findings indicate that regulated protein degradation by the proteasome specifically controls cell death through regulation of Abl mediated Crk Tyr221 phosphorylation and assembly of the CAS-Crk signaling scaffold .	Our findings indicate that regulated protein degradation by the proteasome specifically controls cell death through regulation of Abl mediated Crk Tyr221 phosphorylation and assembly of the CAS-Crk signaling scaffold.	15	20	mediated	Positive_early_activation	Negative_activation	Positive_activation	Abl	Abl	Abl	Crk	Crk	Crk	17	18	19	20
Crk pY221 phosphorylation was partially impaired in imatinib treated HNSCC lines ( XREF_FIG ) and was further downregulated when combined with the Src inhibitor SU6656 ( XREF_SUPPLEMENTARY ) , suggesting that Crk is targeted by Src and Abl kinases in HNSCC .	Crk pY221 phosphorylation was partially impaired in imatinib treated HNSCC lines (XREF_FIG) and was further downregulated when combined with the Src inhibitor SU6656 (XREF_SUPPLEMENTARY), suggesting that Crk is targeted by Src and Abl kinases in HNSCC.	31	38	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Abl	Abl	Abl	Crk	Crk	Crk	37	38	31	32
Immunoblotting for the phosphorylated form of the ABL1 target CRKL confirmed ABL1 down-regulation as well as significantly reduced FN stimulated pPXN in ABL1 knockdown compared with control cells ( XREF_FIG ) .	Immunoblotting for the phosphorylated form of the ABL1 target CRKL confirmed ABL1 down-regulation as well as significantly reduced FN stimulated pPXN in ABL1 knockdown compared with control cells (XREF_FIG).	4	10	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ABL1	ABL1	ABL1	CRKL	CRKL	CRKL	7	8	9	10
In these experiments , four protein substrates were identified ( FLJ22795 , SH3YL1 , CRKL , ABI1 ) that were uniquely phosphorylated on arrays treated with the Abl protein kinase .	In these experiments, four protein substrates were identified (FLJ22795, SH3YL1, CRKL, ABI1) that were uniquely phosphorylated on arrays treated with the Abl protein kinase.	14	29	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Abl	Abl	Abl	CRKL	CRKL	CRKL	27	28	14	15
Preclinical studies demonstrate activated ABL1 kinase signalling in NUP214-ABL1 T-ALL analogous to that of Ph + and subsets of Ph like B-ALL , as well as in vitro inhibition of the ABL1 target phosphoproteins CrkL and STAT5 and increased cell death with dasatinib or nilotinib treatment .	Preclinical studies demonstrate activated ABL1 kinase signalling in NUP214-ABL1 T-ALL analogous to that of Ph + and subsets of Ph like B-ALL, as well as in vitro inhibition of the ABL1 target phosphoproteins CrkL and STAT5 and increased cell death with dasatinib or nilotinib treatment.	4	36	signalling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ABL1	ABL1	ABL1	CrkL	CrkL	CrkL	4	5	34	35
Supporting the idea that ABL2 can help convey VEGF164 induced VEGFR2 mediated permeability signaling , we show here that ABL1 knockdown or NRP1 does not completely abolish pCRKL induction , whereas the pharmacological VEGFR2 blockade with PTK/ZK or dual ABL1 and ABL2 blockade with Imatinib abrogated pCRKL and pSFK induction in response to VEGF164 in vitro .	Supporting the idea that ABL2 can help convey VEGF164 induced VEGFR2 mediated permeability signaling, we show here that ABL1 knockdown or NRP1 does not completely abolish pCRKL induction, whereas the pharmacological VEGFR2 blockade with PTK/ZK or dual ABL1 and ABL2 blockade with Imatinib abrogated pCRKL and pSFK induction in response to VEGF164 in vitro.	34	49	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ABL1	ABL1	ABL1	pCRKL	pCRKL	pCRKL	39	40	46	47
Otud7b binds to and deubiquitinates Zap70 , thereby preventing the interaction of Zap70 with the negative-regulatory phosphatases , Sts1 and Sts2 199 ( XREF_FIG ) .	Otud7b binds to and deubiquitinates Zap70, thereby preventing the interaction of Zap70 with the negative-regulatory phosphatases, Sts1 and Sts2 199 (XREF_FIG).	0	23	preventing	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Zap70	Otud7b binds to and deubiquitinates Zap70	zap70	Zap70	Zap70	zap70	5	6	12	13
In preclinical models it has been well established that engagement of CTLA4 leads to decreased phosphorylation of Lck and Zap70 XREF_BIBR , while CTLA4 knock out mice XREF_BIBR and humans with polymorphisms in CTLA4 that lead to decreased inhibitory function XREF_BIBR , have constitutively increased phosphorylation in Lck and Zap70 .	In preclinical models it has been well established that engagement of CTLA4 leads to decreased phosphorylation of Lck and Zap70 XREF_BIBR, while CTLA4 knock out mice XREF_BIBR and humans with polymorphisms in CTLA4 that lead to decreased inhibitory function XREF_BIBR, have constitutively increased phosphorylation in Lck and Zap70.	15	50	increased	Positive_activation_syntax_1_verb	Positive_activation	Positive_activation	Zap70	phosphorylation of Lck and Zap70	zap70	Zap70	Zap70	zap70	19	20	49	50
Recent studies suggest that ubiquitination of Zap70 may negatively regulate Zap70 activity by recruiting the protein tyrosine phosphatase Sts1 ( also called TULA-2 or Ubash3b ) and its homologue , Sts2 ( also called TULA or Ubash3a ) 196 ( XREF_FIG ) .	Recent studies suggest that ubiquitination of Zap70 may negatively regulate Zap70 activity by recruiting the protein tyrosine phosphatase Sts1 (also called TULA-2 or Ubash3b) and its homologue, Sts2 (also called TULA or Ubash3a) 196 (XREF_FIG).	4	11	negatively regulate	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	Zap70	ubiquitination of Zap70	zap70	Zap70	Zap70	zap70	6	7	10	11
Our results show that c-Abl not only targets Hdm2 , but also Hdmx , which together contribute to p53 activation in response to DNA damage .	Our results show that c-Abl not only targets Hdm2, but also Hdmx, which together contribute to p53 activation in response to DNA damage.	4	16	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-Abl	c-Abl	c-Abl	Hdm2	Hdm2	Hdm2	4	5	8	9
The Mdm2-p53 interaction is inhibited by stress induced phosphorylation of Ser395 and Tyr394 on Mdm2 by the kinases ATM and c-Abl , respectively [ XREF_BIBR , XREF_BIBR ] .	The Mdm2-p53 interaction is inhibited by stress induced phosphorylation of Ser395 and Tyr394 on Mdm2 by the kinases ATM and c-Abl, respectively [XREF_BIBR, XREF_BIBR].	7	21	induced	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	c-Abl	c-Abl	c-Abl	Mdm2	Mdm2	Mdm2	20	21	14	15
c-Abl mediates down-regulation of HDM2 , leading to an increase of p53 level .	c-Abl mediates down-regulation of HDM2, leading to an increase of p53 level.	0	5	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-Abl	c-Abl	c-Abl	HDM2	HDM2	HDM2	0	1	4	5
Quite intriguingly , phosphorylation of Parkin by cyclin dependent kinase 5 ( Cdk-5 ) , casein kinase 1 ( CK-1 ) and c-Abl modulates Parkin folding and/or activity [ XREF_BIBR - XREF_BIBR , XREF_BIBR ] .	Quite intriguingly, phosphorylation of Parkin by cyclin dependent kinase 5 (Cdk-5), casein kinase 1 (CK-1) and c-Abl modulates Parkin folding and/or activity [XREF_BIBR - XREF_BIBR, XREF_BIBR].	19	25	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-Abl	c-Abl	c-Abl	Parkin	Parkin	Parkin	22	23	24	25
Whereas overexpression of AKT1 restored AR knockdown induced ROS and TNFalpha/IL -6 mRNA expression decreasing .	Whereas overexpression of AKT1 restored AR knockdown induced ROS and TNFalpha/IL -6 mRNA expression decreasing.	1	6	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT1	overexpression of AKT1	akt1	AR	AR	ar	3	4	5	6
To test whether MST1 induction could suppress AR activation mediated by AKT1 signaling , we performed promoter reporter assays and showed that enforced MST1 expression antagonized AKT1 mediated androgen dependent and - independent AR activation ( XREF_FIG , left panel ) .	To test whether MST1 induction could suppress AR activation mediated by AKT1 signaling, we performed promoter reporter assays and showed that enforced MST1 expression antagonized AKT1 mediated androgen dependent and - independent AR activation (XREF_FIG, left panel).	7	12	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT1	AKT1	AKT1	AR	AR	AR	11	12	7	8
In a human uterine epithelial cell line , MUC1 release was induced by MT1-MMP in a TACE and ADAM17 independent way .	In a human uterine epithelial cell line, MUC1 release was induced by MT1-MMP in a TACE and ADAM17 independent way.	8	20	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ADAM17	ADAM17	ADAM17	MUC1	MUC1	MUC1	18	19	8	9
Short term activation of cells by phorbol esters , which increase TACE and ADAM17 mediated shedding without increasing cell surface TACE and ADAM17 concentrations [ XREF_BIBR ] , increased TACE and ADAM17 mediated shedding of MUC1 [ XREF_BIBR ] .	Short term activation of cells by phorbol esters, which increase TACE and ADAM17 mediated shedding without increasing cell surface TACE and ADAM17 concentrations [XREF_BIBR], increased TACE and ADAM17 mediated shedding of MUC1 [XREF_BIBR].	29	37	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TACE	TACE	TACE	MUC1	MUC1	MUC1	29	30	35	36
SARA based Smad binding aptamers and their expression in NMuMG epithelial cells resulted in a block of TGFbeta induced EMT and an inhibition of Smad3 activity XREF_BIBR .	SARA based Smad binding aptamers and their expression in NMuMG epithelial cells resulted in a block of TGFbeta induced EMT and an inhibition of Smad3 activity XREF_BIBR.	0	26	induced	Positive_activation_syntax_1_verb	Positive_activation	Negative_activation	SARA	SARA	SARA	Smad3	Smad3	Smad3	0	1	24	25
SARA , for example , can sequester inactive Smad2 and Smad3 in the cytoplasm .	SARA, for example, can sequester inactive Smad2 and Smad3 in the cytoplasm.	0	11	sequester	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	SARA	SARA	SARA	Smad3	Smad3	Smad3	0	1	10	11
Reporter assays show that GRG5 can enhance Six3 activity which is required for early eye development .	Reporter assays show that GRG5 can enhance Six3 activity which is required for early eye development.	4	8	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GRG5	GRG5	GRG5	Six3	Six3	Six3	4	5	7	8
ZIC1 and ZIC4 antagonize the transcriptional activity of Gli .	ZIC1 and ZIC4 antagonize the transcriptional activity of Gli.	0	9	antagonize	Negative_activation_syntax_1_verb	Positive_activation	Negative_activation	ZIC1	ZIC1	ZIC1	Gli	Gli	Gli	0	1	8	9
For example , amplification of the EGF receptor in breast cancer cells , or activation of Abl by the BCR-ABL translocation in chronic myelogenous leukemia , activates Src or Abl kinases and targets p27 for degradation XREF_BIBR , XREF_BIBR .	For example, amplification of the EGF receptor in breast cancer cells, or activation of Abl by the BCR-ABL translocation in chronic myelogenous leukemia, activates Src or Abl kinases and targets p27 for degradation XREF_BIBR, XREF_BIBR.	14	34	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Abl	Abl	Abl	p27	p27	p27	16	17	33	34
Moreover , Akt1 hyperactivation can also induce p27 dependent cellular senescence in vivo , which profoundly limits the ability of Akt1 to induce invasive prostate cancer [ XREF_BIBR ] .	Moreover, Akt1 hyperactivation can also induce p27 dependent cellular senescence in vivo, which profoundly limits the ability of Akt1 to induce invasive prostate cancer [XREF_BIBR].	2	10	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	p27	p27	p27	2	3	7	8
Why has there been so much confusion surrounding identity of the p27 residues ( s ) targeted by Akt1 ?	Why has there been so much confusion surrounding identity of the p27 residues (s) targeted by Akt1?	11	19	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	p27	p27	p27	18	19	11	12
Finally , we found that in cultured cells under physiologically relevant conditions such as oxidative stress or growth factor deprivation , endogenous Akt1 causes p27 accumulation by phosphorylating S10 .	Finally, we found that in cultured cells under physiologically relevant conditions such as oxidative stress or growth factor deprivation, endogenous Akt1 causes p27 accumulation by phosphorylating S10.	21	25	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	p27	p27	p27	22	23	24	25
To further confirm that Slug inhibited cell proliferation and tumor formation of cervical cancer cells by trans-suppressing Akt1 and p-Akt 1 through both the p21 and p27 proteins and the Wnt and beta-catenin signaling pathway , first of all , the recombinant Akt1 plasmid was transiently transfected in the SiHa-Slug and HeLa-shControl cells , in which high level of Slug expression trans-suppressed the expression of Akt1 and p-Akt 1 .	To further confirm that Slug inhibited cell proliferation and tumor formation of cervical cancer cells by trans-suppressing Akt1 and p-Akt 1 through both the p21 and p27 proteins and the Wnt and beta-catenin signaling pathway, first of all, the recombinant Akt1 plasmid was transiently transfected in the SiHa-Slug and HeLa-shControl cells, in which high level of Slug expression trans-suppressed the expression of Akt1 and p-Akt 1.	5	27	inhibited	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	p27	p27	p27	17	18	26	27
AKT1 null mammary epithelial tumor cells have also reduced proliferative capability with reduced cyclinD1 and increased p27 XREF_BIBR .	AKT1 null mammary epithelial tumor cells have also reduced proliferative capability with reduced cyclinD1 and increased p27 XREF_BIBR.	0	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT1	AKT1	AKT1	p27	p27	p27	0	1	16	17
Given our in vitro analysis suggesting Akt1 specificity can vary , it remains possible that Akt1 targets p27 residues other than/in addition to S10 in response to different physiological conditions .	Given our in vitro analysis suggesting Akt1 specificity can vary, it remains possible that Akt1 targets p27 residues other than/in addition to S10 in response to different physiological conditions.	15	18	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	p27	p27	p27	15	16	17	18
Taken together , these findings indicate that AKT1 induces caspase mediated cleavage of p27Kip1 , required for G1-S progression in FLT3-ITD cells .	Taken together, these findings indicate that AKT1 induces caspase mediated cleavage of p27Kip1, required for G1-S progression in FLT3-ITD cells.	7	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT1	AKT1	AKT1	p27Kip1	p27Kip1	p27Kip1	7	8	13	14
AKT1 induces caspase mediated cleavage of the CDK inhibitor p27Kip1 during cell cycle progression in leukemia cells transformed by FLT3-ITD .	AKT1 induces caspase mediated cleavage of the CDK inhibitor p27Kip1 during cell cycle progression in leukemia cells transformed by FLT3-ITD.	0	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT1	AKT1	AKT1	p27Kip1	p27Kip1	p27Kip1	0	1	9	10
Moreover , depletion of Akt1 in Brca1 Delta11 and Delta11 MEFs rescued nuclear staining of pChk1 , confirming effect of the Akt1 on pChk1 nuclear localization in Brca1 deficient cells .	Moreover, depletion of Akt1 in Brca1 Delta11 and Delta11 MEFs rescued nuclear staining of pChk1, confirming effect of the Akt1 on pChk1 nuclear localization in Brca1 deficient cells.	2	18	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	pChk1	pChk1	pChk1	4	5	15	16
Similar to the finding that AKT1 induced Chk1 pS280 results in an attenuation of Chk1 kinase activity , another study using melanoma cells found that inhibition of RSK1 or MEK results in a reduction in the amount of Chk1 pS280 and an increase in the amount of Chk1 kinase activity [ XREF_BIBR ] .	Similar to the finding that AKT1 induced Chk1 pS280 results in an attenuation of Chk1 kinase activity, another study using melanoma cells found that inhibition of RSK1 or MEK results in a reduction in the amount of Chk1 pS280 and an increase in the amount of Chk1 kinase activity [XREF_BIBR].	5	8	induced	Positive_early_activation	Negative_activation	Positive_activation	AKT1	AKT1	AKT1	Chk1	Chk1	Chk1	5	6	7	8
Conversely , overexpression of AKT1 significantly increased the mRNA of CHK1 .	Conversely, overexpression of AKT1 significantly increased the mRNA of CHK1.	2	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT1	overexpression of AKT1	akt1	CHK1	CHK1	chk1	4	5	10	11
These observations indicate that Akt1 induces cytoplasmic retention of Chk1 and Rad51 in Brca1 Delta11 and Delta11 MEFs .	These observations indicate that Akt1 induces cytoplasmic retention of Chk1 and Rad51 in Brca1 Delta11 and Delta11 MEFs.	4	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	Chk1	Chk1	Chk1	4	5	9	10
Consistent with mTOR regulation of CHK1 , expression of myr-AKT1 increased CHK1 in Rh30 cells , accompanied with increased pAKT-S473 and pGSK3beta-S9 .	Consistent with mTOR regulation of CHK1, expression of myr-AKT1 increased CHK1 in Rh30 cells, accompanied with increased pAKT-S473 and pGSK3beta-S9.	7	12	increased	Positive_activation_token_1_verb	Negative_activation	Positive_activation	myr-AKT1	expression of myr-AKT1	myr-akt1	CHK1	CHK1	chk1	9	10	11	12
Depletion of Akt1 rescued association of pChk1 and Rad51 , suggesting that these protein protein interactions are dependent on Akt1 .	Depletion of Akt1 rescued association of pChk1 and Rad51, suggesting that these protein protein interactions are dependent on Akt1.	0	8	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	pChk1	pChk1	pChk1	2	3	6	7
Knockdown of Akt1 significantly upregulated p21 promoter activity , and partially restored the CXCR2 mediated downregulation of p21 promoter activity .	Knockdown of Akt1 significantly upregulated p21 promoter activity, and partially restored the CXCR2 mediated downregulation of p21 promoter activity.	0	7	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt1	Akt1	Akt1	p21	p21	p21	2	3	5	6
gamma-Mangostin significantly downregulated mRNA expression of Akt1 and NFkappaB and upregulated p21 WAF1 and IkappaBalpha .	gamma-Mangostin significantly downregulated mRNA expression of Akt1 and NFkappaB and upregulated p21 WAF1 and IkappaBalpha.	0	13	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	gamma-Mangostin significantly downregulated mRNA expression of Akt1	akt1	p21 WAF1	p21 WAF1	p21 waf1	6	7	11	13
Silencing Mdm2 or Akt1 upregulated p21 expression , whereas Akt1 overexpression downregulated p21 at the promoter and protein levels in p53WT cells .	Silencing Mdm2 or Akt1 upregulated p21 expression, whereas Akt1 overexpression downregulated p21 at the promoter and protein levels in p53WT cells.	1	7	upregulated	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Akt1	Akt1	akt1	p21	p21 expression	p21	3	4	5	6
In addition , Akt1 and PKB enhances the stability and cytoplasmic localization of p21 and promotes cell survival by phosphorylation of p21 [ XREF_BIBR - XREF_BIBR ] .	In addition, Akt1 and PKB enhances the stability and cytoplasmic localization of p21 and promotes cell survival by phosphorylation of p21 [XREF_BIBR - XREF_BIBR].	3	15	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	p21	p21	p21	3	4	13	14
Protein kinase B directly regulates GSK3beta by phosphorylation of GSK3beta at amino acid serine 9 , thereby inactivating its kinase activity .	Protein kinase B directly regulates GSK3beta by phosphorylation of GSK3beta at amino acid serine 9, thereby inactivating its kinase activity.	0	6	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Protein kinase B	Protein kinase B	Protein kinase B	GSK3beta	GSK3beta	GSK3beta	0	3	5	6
In response to extracellular signals that activate the phosphatidylinositide 3-kinase ( PI3K ) pathway , protein kinase B ( AKT ) is activated triggering the inactivation of GSK3beta by phosphorylation of Ser9 [ XREF_BIBR ] .	In response to extracellular signals that activate the phosphatidylinositide 3-kinase (PI3K) pathway, protein kinase B (AKT) is activated triggering the inactivation of GSK3beta by phosphorylation of Ser9 [XREF_BIBR].	15	28	triggering	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	GSK3beta	GSK3beta	GSK3beta	15	18	27	28
In murine embryonic stem cells ( mESCs ) , Gsk3beta is inhibited by multiple mechanisms , including its inhibitory phosphorylation on serine 9 by protein kinase B ( Akt ) , a major effector of the canonical phosphatidylinositol 3-kinase ( PI3K ) pathway .	In murine embryonic stem cells (mESCs), Gsk3beta is inhibited by multiple mechanisms, including its inhibitory phosphorylation on serine 9 by protein kinase B (Akt), a major effector of the canonical phosphatidylinositol 3-kinase (PI3K) pathway.	9	27	inhibited	Negative_activation_syntax_4_verb	Negative_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	Gsk3beta	Gsk3beta	Gsk3beta	24	27	9	10
Shear induced GSK-3beta activation was mediated by Akt-1 activation as inhibition of Akt-1 phosphorylation inhibited the GSK-3beta response to a 5 min step flow ( XREF_SUPPLEMENTARY ) .	Shear induced GSK-3beta activation was mediated by Akt-1 activation as inhibition of Akt-1 phosphorylation inhibited the GSK-3beta response to a 5 min step flow (XREF_SUPPLEMENTARY).	2	8	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt-1	Akt-1	Akt-1	GSK-3beta	GSK-3beta	GSK-3beta	7	8	2	3
This novel mechanism explains how AKT1 promotes self-renewal by regulating the activity and localization of GSK3beta .	This novel mechanism explains how AKT1 promotes self-renewal by regulating the activity and localization of GSK3beta.	5	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT1	AKT1	AKT1	GSK3beta	GSK3beta	GSK3beta	5	6	15	16
Following activation , AKT-1 activates Rac-1 and eNOS , which may act in concert to induce actin dependent outward spreading of endothelial cells that increases endothelial barrier function in response to S1P .	Following activation, AKT-1 activates Rac-1 and eNOS, which may act in concert to induce actin dependent outward spreading of endothelial cells that increases endothelial barrier function in response to S1P.	3	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT-1	AKT-1	AKT-1	Rac-1	Rac-1	Rac-1	3	4	5	6
Hence we next wanted to determine whether Akt1 could modulate the activity of Rac and Pak in endothelial cells and fibroblasts .	Hence we next wanted to determine whether Akt1 could modulate the activity of Rac and Pak in endothelial cells and fibroblasts.	7	15	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	Rac	Rac	Rac	7	8	13	14
In addition , downregulation of RhoB induced Akt1 activation , which in turn activated Rac1 through the guanine-exchange factor Trio to control cell shape rearrangement .	In addition, downregulation of RhoB induced Akt1 activation, which in turn activated Rac1 through the guanine-exchange factor Trio to control cell shape rearrangement.	5	15	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	RhoB induced Akt1	akt1	Rac1	Rac1	rac1	7	8	14	15
Active Akt1 activates Bad through phospho-serine 136 in a Bad protein , while the activated Bad induces the fusion of anti-apoptotic BCL-2 and BCL-XL in order to inhibit neuronal apoptosis .	Active Akt1 activates Bad through phospho-serine 136 in a Bad protein, while the activated Bad induces the fusion of anti-apoptotic BCL-2 and BCL-XL in order to inhibit neuronal apoptosis.	0	4	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	Bad	Bad	Bad	1	2	3	4
Protein kinase B ( Akt )-dependent phosphorylation of Bad at serine 136 enhances the interaction of Bad with phosphopeptide binding proteins 14-3-3 which prevent the dimerization of Bad with Bcl-XL , inhibits the release of cytochrome c into the cytosol , and suppresses the activation of caspase-3 that ultimately increases neuronal survival .	Protein kinase B (Akt)-dependent phosphorylation of Bad at serine 136 enhances the interaction of Bad with phosphopeptide binding proteins 14-3-3 which prevent the dimerization of Bad with Bcl-XL, inhibits the release of cytochrome c into the cytosol, and suppresses the activation of caspase-3 that ultimately increases neuronal survival.	0	21	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Protein kinase B	Protein kinase B (Akt)-dependent phosphorylation of Bad at serine 136	protein kinase b	Bad	Bad	bad	0	3	16	17
An increase in Akt1 activity in cells induces 14-3-3zeta and sigma , p-Bad , and p-YAP , promoting cell survival , whereas decreasing Akt activity suppresses the same proteins and inhibits cell survival .	An increase in Akt1 activity in cells induces 14-3-3zeta and sigma, p-Bad, and p-YAP, promoting cell survival, whereas decreasing Akt activity suppresses the same proteins and inhibits cell survival.	3	13	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	p-Bad	p-Bad	p-Bad	3	4	12	13
Alternatively , ceramides inhibit protein kinase B , allowing the Foxo1 transcription factor to act at the nuclear level , repressing genes with nuclear PDX1 exclusion [ XREF_BIBR ] .	Alternatively, ceramides inhibit protein kinase B, allowing the Foxo1 transcription factor to act at the nuclear level, repressing genes with nuclear PDX1 exclusion [XREF_BIBR].	4	12	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	Foxo1	Foxo1	Foxo1	4	7	10	11
Over expression of AKT1 , which modulates FOXO1 activity , is frequently observed in pancreatic cancer , indicating a potential role of FOXO1 in regulation of cell cycle , proliferation and apoptosis during tumorigenesis XREF_BIBR - XREF_BIBR .	Over expression of AKT1, which modulates FOXO1 activity, is frequently observed in pancreatic cancer, indicating a potential role of FOXO1 in regulation of cell cycle, proliferation and apoptosis during tumorigenesis XREF_BIBR - XREF_BIBR.	1	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT1	expression of AKT1	akt1	FOXO1	FOXO1	foxo1	3	4	7	8
Using this approach , it is confirmed that Akt1 and PKBalpha is the preferred isoform sustaining adipocyte differentiation , but both Akt1 and PKBalpha and Akt2 and PKBbeta can indistinctly support insulin dependent FoxO1 ( forkhead box O1 ) nuclear exclusion .	Using this approach, it is confirmed that Akt1 and PKBalpha is the preferred isoform sustaining adipocyte differentiation, but both Akt1 and PKBalpha and Akt2 and PKBbeta can indistinctly support insulin dependent FoxO1 (forkhead box O1) nuclear exclusion.	21	40	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKBalpha	PKBalpha	PKBalpha	FoxO1	FoxO1	FoxO1	23	24	33	34
These results demonstrate that both Akt1 and Akt2 signalling modulate FoxO1 nuclear exclusion in response to insulin , as previously described [ XREF_BIBR ] .	These results demonstrate that both Akt1 and Akt2 signalling modulate FoxO1 nuclear exclusion in response to insulin, as previously described [XREF_BIBR].	4	12	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	FoxO1	FoxO1	FoxO1	5	6	10	11
XREF_BIBR Activation of Akt and protein kinase B results in the phosphorylation of FOXO , causing FOXO to remain localized in the cytoplasm .	XREF_BIBR Activation of Akt and protein kinase B results in the phosphorylation of FOXO, causing FOXO to remain localized in the cytoplasm.	3	18	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	FOXO	FOXO	FOXO	5	8	16	17
These observations suggest that the enhanced atherosclerosis observed in the Akt1 null mice could be mediated by decreased eNOS activity and increased FoxO transcriptional activation because this family of transcription factors are phosphorylated and inactivated by Akt .	These observations suggest that the enhanced atherosclerosis observed in the Akt1 null mice could be mediated by decreased eNOS activity and increased FoxO transcriptional activation because this family of transcription factors are phosphorylated and inactivated by Akt.	7	24	increased	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	FoxO	FoxO	FoxO	10	11	22	23
These data led us to hypothesize that Akt-1 may mediate the observed EZH2 induced phenotype .	These data led us to hypothesize that Akt-1 may mediate the observed EZH2 induced phenotype.	6	13	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt-1	Akt-1	Akt-1	EZH2	EZH2	EZH2	7	8	12	13
The programmed cell death 4 ( PDCD4 ) tumor suppressor is down-regulated in several malignancies , and the ( subcellular ) expression of its protein product is modulated by both oncomiR miR-21 and protein kinase B ( Akt ) .	The programmed cell death 4 (PDCD4) tumor suppressor is down-regulated in several malignancies, and the (subcellular) expression of its protein product is modulated by both oncomiR miR-21 and protein kinase B (Akt).	0	36	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	protein kinase B	protein kinase B	protein kinase B	PDCD4	PDCD4	PDCD4	33	36	6	7
AKT1 and AKT2 activation , which occurs during the early steps of myogenesis , induces KHSRP dismissal from H19 lncRNA and , as a consequence , myogenin mRNA is stabilized while KHSRP is repurposed to promote maturation of myogenic miRNAs , thus favoring myogenic differentiation 8 .	AKT1 and AKT2 activation, which occurs during the early steps of myogenesis, induces KHSRP dismissal from H19 lncRNA and, as a consequence, myogenin mRNA is stabilized while KHSRP is repurposed to promote maturation of myogenic miRNAs, thus favoring myogenic differentiation 8.	0	16	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT1	AKT1	AKT1	KHSRP	KHSRP	KHSRP	0	1	15	16
Although WISP1 has been shown in neurons to previously require PI 3-K and Akt1 to protect neurons against oxidative stress , we now show that the activation of PI 3-K and Akt1 are vital for WISP1 to modulate the activity of the forkhead transcription factor FoxO3a that can lead to apoptotic cell injury .	Although WISP1 has been shown in neurons to previously require PI 3-K and Akt1 to protect neurons against oxidative stress, we now show that the activation of PI 3-K and Akt1 are vital for WISP1 to modulate the activity of the forkhead transcription factor FoxO3a that can lead to apoptotic cell injury.	26	46	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	FoxO3a	FoxO3a	FoxO3a	31	32	45	46
Overall , our data indicate that Akt1 mediated affinity modulation of integrin beta 3 is necessary for transendothelial migration of prostate cancer cells .	Overall, our data indicate that Akt1 mediated affinity modulation of integrin beta 3 is necessary for transendothelial migration of prostate cancer cells.	6	14	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt1	Akt1	Akt1	integrin beta 3	integrin beta 3	integrin beta 3	6	7	11	14
Western blot analysis revealed that Ad-p53 and gefitinib in combination significantly downregulated the phosphorylation of protein kinase B ( p-Akt ) and upregulated caspase-9 and cleaved caspase-3 , while there were minimal effects on the expression of extracellular signal regulated kinase ( ERK ) and phosphorylation of ERK ( p-ERK ) .	Western blot analysis revealed that Ad-p53 and gefitinib in combination significantly downregulated the phosphorylation of protein kinase B (p-Akt) and upregulated caspase-9 and cleaved caspase-3, while there were minimal effects on the expression of extracellular signal regulated kinase (ERK) and phosphorylation of ERK (p-ERK).	5	24	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	protein kinase B	Ad-p53 and gefitinib in combination significantly downregulated the phosphorylation of protein kinase B	protein kinase b	caspase-9	caspase-9	caspase-9	15	18	23	24
AMD and DME inhibit Akt induced AR protein stability , contributing to observed lower levels of AR protein .	AMD and DME inhibit Akt induced AR protein stability, contributing to observed lower levels of AR protein.	4	8	induced	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	4	5	6	7
Phosphorylation of MAPK and Akt can also increase AR activation in low androgen and estrogen concentrations , as well as increase the neuroprotective activities of ERalpha and AR [ XREF_BIBR ] .	Phosphorylation of MAPK and Akt can also increase AR activation in low androgen and estrogen concentrations, as well as increase the neuroprotective activities of ERalpha and AR [XREF_BIBR].	0	9	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Phosphorylation of MAPK and Akt	akt	AR	AR	ar	4	5	8	9
The PI3K pathway appears to be critical in the development of CRPC : in vitro data suggest that overexpression and activation of AKT can trigger prostate cancer androgen escape via altered sensitivity and activation of AR ( Edwards and Bartlett , 2005 ) .	The PI3K pathway appears to be critical in the development of CRPC : in vitro data suggest that overexpression and activation of AKT can trigger prostate cancer androgen escape via altered sensitivity and activation of AR (Edwards and Bartlett, 2005).	18	39	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	overexpression and activation of AKT	akt	AR	AR	ar	22	23	35	36
Thus , Akt is a novel activator of AR required for HER-2 and neu signaling to androgen independent survival and growth of prostate cancer cells .	Thus, Akt is a novel activator of AR required for HER-2 and neu signaling to androgen independent survival and growth of prostate cancer cells.	2	9	is a novel activator	Positive_activation_copula_1	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	2	3	8	9
This regulatory loop is specific for PSA , does not involve known AR activators such as Src and AKT , and may contribute to AR signaling under conditions of increasing PSA levels in patients .	This regulatory loop is specific for PSA, does not involve known AR activators such as Src and AKT, and may contribute to AR signaling under conditions of increasing PSA levels in patients.	12	19	activators	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	18	19	12	13
MST1 was reported to inhibit AKT signaling , which is known to functionally intersect with and promote AR driven PSA promoter activation .	MST1 was reported to inhibit AKT signaling, which is known to functionally intersect with and promote AR driven PSA promoter activation.	5	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	5	6	17	18
We therefore determined whether MEK and ERK activation is required for AKT induced AR downregulation .	We therefore determined whether MEK and ERK activation is required for AKT induced AR downregulation.	11	14	induced	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	11	12	13	14
Two signaling transduction pathways , namely PI3K and AKT and JAK and STAT3 pathways , have been shown to activate AR in prostate cancer cells XREF_BIBR - XREF_BIBR .	Two signaling transduction pathways, namely PI3K and AKT and JAK and STAT3 pathways, have been shown to activate AR in prostate cancer cells XREF_BIBR - XREF_BIBR.	3	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	8	9	20	21
The PI3K inhibitor LY294002 completely blocked the basal and EGF stimulated Akt phosphorylation in LNCaP cells but did not prevent the marked decrease in AR protein in response to EGF ( XREF_FIG , left and middle ) .	The PI3K inhibitor LY294002 completely blocked the basal and EGF stimulated Akt phosphorylation in LNCaP cells but did not prevent the marked decrease in AR protein in response to EGF (XREF_FIG, left and middle).	1	25	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	PI3K inhibitor LY294002 completely blocked the basal and EGF stimulated Akt phosphorylation	akt	AR	AR	ar	11	12	24	25
In support of this notion , despite its insignificant effect on basal ERK1/2 activity , AKT overexpression induced significant AR downregulation in the FBS culture ( XREF_FIG ) .	In support of this notion, despite its insignificant effect on basal ERK1/2 activity, AKT overexpression induced significant AR downregulation in the FBS culture (XREF_FIG).	15	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT overexpression	akt	AR	AR	ar	15	16	19	20
Suppressing PI3K and Akt signaling with the pan-PI3K inhibitor LY294002 or exogenous expression of PTEN , a negative regulator of Akt activity , can reduce AR signaling .	Suppressing PI3K and Akt signaling with the pan-PI3K inhibitor LY294002 or exogenous expression of PTEN, a negative regulator of Akt activity, can reduce AR signaling.	3	26	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	3	4	25	26
Some investigators have found that Akt enhances AR activity , whereas others have reported that it inhibits AR activity [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	Some investigators have found that Akt enhances AR activity, whereas others have reported that it inhibits AR activity [XREF_BIBR; XREF_BIBR; XREF_BIBR].	5	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	5	6	7	8
Consistent with its effect on MEK and ERK , AKT overexpression augmented AR downregulation in the LNCaP c.s.FBS culture ( XREF_FIG ) .	Consistent with its effect on MEK and ERK, AKT overexpression augmented AR downregulation in the LNCaP c.s.FBS culture (XREF_FIG).	9	13	augmented	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT overexpression	akt	AR	AR	ar	9	10	12	13
It was also reported that the activation of PI3K and AKT pathway can suppress the AR activity in low passage LNCaP and enhance AR activity in high passage , hence suggesting modulation as cells evolve towards less responsive status [ XREF_BIBR ] .	It was also reported that the activation of PI3K and AKT pathway can suppress the AR activity in low passage LNCaP and enhance AR activity in high passage, hence suggesting modulation as cells evolve towards less responsive status [XREF_BIBR].	8	24	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	10	11	23	24
Blocking of the Akt pathway by a dominant negative Akt or an inhibitor LY294002 abrogates the HER-2 and neu induced AR signaling and cell survival and growth effects in the absence or presence of androgen .	Blocking of the Akt pathway by a dominant negative Akt or an inhibitor LY294002 abrogates the HER-2 and neu-induced AR signaling and cell survival and growth effects in the absence or presence of androgen.	3	21	abrogates	Negative_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Akt	Akt	akt	AR	neu-induced AR	ar	3	4	20	21
In prostate cancer , Akt upregulates AR activity , suggesting a mechanism of everolimus induced activation of AR .	In prostate cancer, Akt upregulates AR activity, suggesting a mechanism of everolimus induced activation of AR.	4	7	upregulates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	4	5	6	7
These results suggest that Akt is an activator of AR required for androgen independent survival and growth of PCa cells .	These results suggest that Akt is an activator of AR required for androgen independent survival and growth of PCa cells.	4	10	is an activator	Positive_activation_copula_1	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	4	5	9	10
Therefore , PTEN loss and increased AKT signaling inhibit HER kinases and consequently diminish AR activity ( XREF_FIG ) .	Therefore, PTEN loss and increased AKT signaling inhibit HER kinases and consequently diminish AR activity (XREF_FIG).	3	15	diminish	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	6	7	14	15
Moreover , inhibition of PI3K and Akt signaling inhibited enhanced migration and invasion in ACC-2 Ar cells ( XREF_FIG ) .	Moreover, inhibition of PI3K and Akt signaling inhibited enhanced migration and invasion in ACC-2 Ar cells (XREF_FIG).	4	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Ar	Ar	Ar	6	7	15	16
Given that current Akt and mTOR inhibitor drugs activate AR signaling while androgen ablation and AR antagonist drugs cross-induce Akt pathway through a reciprocal feedback regulatory loop , the inhibition of both Akt and AR signaling pathways by prolonged MSeA supplement suggests that combined use of MSeA with these drugs may mitigate their undesirable side effects and result in greater PCa risk reduction .	Given that current Akt and mTOR inhibitor drugs activate AR signaling while androgen ablation and AR antagonist drugs cross-induce Akt pathway through a reciprocal feedback regulatory loop, the inhibition of both Akt and AR signaling pathways by prolonged MSeA supplement suggests that combined use of MSeA with these drugs may mitigate their undesirable side effects and result in greater PCa risk reduction.	2	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	3	4	9	10
The inhibition of Akt in prostate cells abrogates HER-2 and neu induced AR signaling and cell survival and growth effects in the absence or presence of androgen XREF_BIBR .	The inhibition of Akt in prostate cells abrogates HER-2 and neu-induced AR signaling and cell survival and growth effects in the absence or presence of androgen XREF_BIBR.	1	13	abrogates	Negative_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Akt	Akt	akt	AR	neu-induced AR	ar	3	4	12	13
Inhibition of the MEK and Akt signaling pathways prevented AR trafficking .	Inhibition of the MEK and Akt signaling pathways prevented AR trafficking.	5	10	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	5	6	9	10
Mechanistic studies demonstrate that both Akt and ERK get activated upon PP2A inhibition and support the androgen independent growth of LNCaP cells in AR dependent and -independent manners .	Mechanistic studies demonstrate that both Akt and ERK get activated upon PP2A inhibition and support the androgen independent growth of LNCaP cells in AR dependent and -independent manners.	4	24	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	5	6	23	24
Moreover , PI3K-AKT and beta-catenin can cooperate to stimulate AR signaling in CRPC , and beta-catenin can interact directly with AR .	Moreover, PI3K-AKT and beta-catenin can cooperate to stimulate AR signaling in CRPC, and beta-catenin can interact directly with AR.	2	10	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	AR	AR	AR	2	3	9	10
Our results suggest that MEK and ERK activation is a downstream event of AKT activation , which is mediated by B-Raf and is partly required for AKT mediated AR downregulation .	Our results suggest that MEK and ERK activation is a downstream event of AKT activation, which is mediated by B-Raf and is partly required for AKT mediated AR downregulation.	26	29	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	26	27	28	29
Increased AKT function can alternatively upregulate androgen receptor signaling indirectly via activation of NFkB .	Increased AKT function can alternatively upregulate androgen receptor signaling indirectly via activation of NFkB.	1	8	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	androgen receptor	androgen receptor	androgen receptor	1	2	6	8
MEK and ERK activity is partly required for AKT mediated AR regulation .	MEK and ERK activity is partly required for AKT mediated AR regulation.	8	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	8	9	10	11
More importantly , PI3K-Akt signaling enhances AR activity and is involved in the induction of AR target genes , such as p21 ( WAF and CIP ) , a gene with anti-apoptosis activity and associated with androgen independent growth in human prostate cancer .	More importantly, PI3K-Akt signaling enhances AR activity and is involved in the induction of AR target genes, such as p21 (WAF and CIP), a gene with anti-apoptosis activity and associated with androgen independent growth in human prostate cancer.	3	7	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	AR	AR	AR	3	4	6	7
Although effective , the MEK1/2 specific inhibitor AZD6244 could not completely inhibit AKT mediated AR downregulation in the c.s.FBS culture ( XREF_FIG ) , indicating that the mechanisms underlying AKT mediated ERK1/2 and AR regulation may not entirely overlap .	Although effective, the MEK1/2 specific inhibitor AZD6244 could not completely inhibit AKT mediated AR downregulation in the c.s.FBS culture (XREF_FIG), indicating that the mechanisms underlying AKT mediated ERK1/2 and AR regulation may not entirely overlap.	11	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	12	13	14	15
Studies on the effect of the Akt mediated AR serines 213 and 791 phosphorylation on AR transcription yielded conflicting results demonstrating either repression or activation of AR function .	Studies on the effect of the Akt mediated AR serines 213 and 791 phosphorylation on AR transcription yielded conflicting results demonstrating either repression or activation of AR function.	3	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	6	7	8	9
These data suggest that Akt dependent activation of AR may occur in models of advanced PCa ; however , this relationship between Akt and AR was not assessed in LNCaP derived recurrent cell lines ( such as C4-2 and C4-2B ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	These data suggest that Akt dependent activation of AR may occur in models of advanced PCa; however, this relationship between Akt and AR was not assessed in LNCaP derived recurrent cell lines (such as C4-2 and C4-2B) [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	9	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	4	5	8	9
However , the Wnt and beta-catenin and PI3K and AKT pathways , which are both activated by MUC1-C [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] , have been shown to stimulate AR function in positive feed-forward loops that lead to androgen independent AR activation [ XREF_BIBR - XREF_BIBR ] .	However, the Wnt and beta-catenin and PI3K and AKT pathways, which are both activated by MUC1-C [XREF_BIBR, XREF_BIBR, XREF_BIBR], have been shown to stimulate AR function in positive feed-forward loops that lead to androgen independent AR activation [XREF_BIBR - XREF_BIBR].	7	32	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	9	10	31	32
Finally , addition of IGF inhibitors successfully masked the AR deficiency induced Akt activation , and inhibitions of Akt , IGF1 , and IGF2 pathways reversed the AR depletion effects on the adipogenesis process .	Finally, addition of IGF inhibitors successfully masked the AR deficiency induced Akt activation, and inhibitions of Akt, IGF1, and IGF2 pathways reversed the AR depletion effects on the adipogenesis process.	18	29	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	18	19	27	28
Moreover , the Akt and mTOR pathway can activate AR in the absence of androgen .	Moreover, the Akt and mTOR pathway can activate AR in the absence of androgen.	3	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	3	4	9	10
An earlier study showed that inhibition of Akt pathway abrogates the HER-2 and neu induced AR signaling activity XREF_BIBR .	An earlier study showed that inhibition of Akt pathway abrogates the HER-2 and neu-induced AR signaling activity XREF_BIBR.	7	18	abrogates	Negative_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Akt	Akt	akt	AR	neu-induced AR	ar	7	8	15	16
Combined activation of Akt and Erk pathways stimulates epithelial AR function and blocks apoptosis inducing paracrine signals from the stroma , leading to androgen independent cancer .	Combined activation of Akt and Erk pathways stimulates epithelial AR function and blocks apoptosis inducing paracrine signals from the stroma, leading to androgen independent cancer.	3	10	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	3	4	9	10
Previous studies suggest that PI3K and AKT and AR signaling pathways play complementary roles in maintaining PCa proliferation in low-androgen environments [ XREF_BIBR ] , and that activated PI3K and AKT signaling can contribute to the ligand independent and constitutive activation of the AR in CRPCa [ XREF_BIBR ] .	Previous studies suggest that PI3K and AKT and AR signaling pathways play complementary roles in maintaining PCa proliferation in low-androgen environments [XREF_BIBR], and that activated PI3K and AKT signaling can contribute to the ligand independent and constitutive activation of the AR in CRPCa [XREF_BIBR].	30	47	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	30	31	43	44
Previous studies in human PCa cell lines and mice models have suggested that inactivation of PTEN and PI3K and AKT activation can modulate AR activity and contribute to CRPC [ XREF_BIBR - XREF_BIBR ] .	Previous studies in human PCa cell lines and mice models have suggested that inactivation of PTEN and PI3K and AKT activation can modulate AR activity and contribute to CRPC [XREF_BIBR - XREF_BIBR].	19	24	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	19	20	23	24
Thus , in cells with high levels of GSK-3 activity , activation of Akt through inhibition of GSK-3 may increase AR activity .	Thus, in cells with high levels of GSK-3 activity, activation of Akt through inhibition of GSK-3 may increase AR activity.	11	21	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	13	14	20	21
Among these , ERK , IL-6 , AKT , NFKB , and E2F1 up-regulate AR .	Among these, ERK, IL-6, AKT, NFKB, and E2F1 up-regulate AR.	3	15	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	7	8	14	15
Additional experiments performed with viruses containing constitutively active ( Adeno-myrAkt ) or dominant negative ( Adeno-dnAkt ) forms of Akt demonstrated that Akt , a protein kinase whose activation is known to be inhibited by PTEN , mediated the observed antagonism between PTEN and AR transcriptional activity .	Additional experiments performed with viruses containing constitutively active (Adeno-myrAkt) or dominant negative (Adeno-dnAkt) forms of Akt demonstrated that Akt, a protein kinase whose activation is known to be inhibited by PTEN, mediated the observed antagonism between PTEN and AR transcriptional activity.	22	46	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	22	23	44	45
Since the AKT pathway modulates AR function and protects prostate cancer cells from apoptosis induced by AD , we investigated the contribution of this mechanism to the additive effects of edelfosine and AD .	Since the AKT pathway modulates AR function and protects prostate cancer cells from apoptosis induced by AD, we investigated the contribution of this mechanism to the additive effects of edelfosine and AD.	2	6	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	2	3	5	6
Akt regulates transcriptional activity of the androgen receptor ( AR ) , and our data show that Akt stimulated AR transcriptional activity is dependent on androgen binding to the AR .	Akt regulates transcriptional activity of the androgen receptor (AR), and our data show that Akt stimulated AR transcriptional activity is dependent on androgen binding to the AR.	17	21	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	17	18	19	20
The AKT pathway modulates AR function and protects prostate cancer cells from apoptosis induced by AD .	The AKT pathway modulates AR function and protects prostate cancer cells from apoptosis induced by AD.	1	5	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	1	2	4	5
Further , transfection of a constitutively active form of Akt ( pCMV-6-myr-Akt-HA ) , but not a control vector ( pCMV-HA ) , promoted AR transcriptional activity both in vehicle- and rapamycin treated cells ( XREF_FIG ) .	Further, transfection of a constitutively active form of Akt (pCMV-6-myr-Akt-HA), but not a control vector (pCMV-HA), promoted AR transcriptional activity both in vehicle- and rapamycin treated cells (XREF_FIG).	7	26	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	9	10	24	25
Although PI3K and Akt signaling promotes AR activity , examples of PTEN regulation of JNK signaling independently of Akt have been reported ; furthermore , JNK deficiency promotes androgen independent progenitor cell growth and metastatic PrCa more rapidly than PTEN deficiency alone .	Although PI3K and Akt signaling promotes AR activity, examples of PTEN regulation of JNK signaling independently of Akt have been reported; furthermore, JNK deficiency promotes androgen independent progenitor cell growth and metastatic PrCa more rapidly than PTEN deficiency alone.	1	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	3	4	6	7
Inhibition of Akt , however , does not fully attenuate p-XSC-mediated down-regulation of AR activity suggesting inhibition of AR signaling by p-XSC does not occur solely through alterations in the PI3K and Akt survival pathway .	Inhibition of Akt, however, does not fully attenuate p-XSC-mediated down-regulation of AR activity suggesting inhibition of AR signaling by p-XSC does not occur solely through alterations in the PI3K and Akt survival pathway.	0	14	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	2	3	13	14
Nevertheless , AKT-R25A could mediate AR downregulation , although not as efficiently as wild type AKT ( XREF_FIG ) , indicating that the canonical PH domain control is important but not necessary for AKT mediated AR regulation .	Nevertheless, AKT-R25A could mediate AR downregulation, although not as efficiently as wild type AKT (XREF_FIG), indicating that the canonical PH domain control is important but not necessary for AKT mediated AR regulation.	33	36	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	33	34	35	36
Furthermore , promoter reporter and ChIP experiments revealed that enforced MST1 antagonized AKT mediated AR activation and reduced binding of AR to its cognate DNA binding site .	Furthermore, promoter reporter and ChIP experiments revealed that enforced MST1 antagonized AKT mediated AR activation and reduced binding of AR to its cognate DNA binding site.	12	17	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	12	13	14	15
XREF_BIBR , XREF_BIBR - XREF_BIBR It is also known that MAPK , AKT , and STAT could activate AR signaling , and they also are involved in human hepatocarcinogenesis .	XREF_BIBR, XREF_BIBR - XREF_BIBR It is also known that MAPK, AKT, and STAT could activate AR signaling, and they also are involved in human hepatocarcinogenesis.	10	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	12	13	18	19
We next examined whether the PI3K and Akt or Ras/Raf/Erk pathways , both of which can modulate AR function , were required for the EGF- or heregulin-beta1-induced decrease in AR expression .	We next examined whether the PI3K and Akt or Ras/Raf/Erk pathways, both of which can modulate AR function, were required for the EGF- or heregulin-beta1-induced decrease in AR expression.	7	18	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	7	8	17	18
These observations suggest IGF-1 and Akt mediated inactivation of AR as potential therapy for SBMA .	These observations suggest IGF-1 and Akt mediated inactivation of AR as potential therapy for SBMA.	3	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	5	6	9	10
The phosphoinositide 3-kinase ( PI3K )/Akt pathway is constitutively active in LNCaP cells because of the loss of PTEN expression , and PI3K and AKT was shown to activate the AR signaling ( Wu et al , 1998 ; Li et al , 2001 ) .	The phosphoinositide 3-kinase (PI3K)/Akt pathway is constitutively active in LNCaP cells because of the loss of PTEN expression, and PI3K and AKT was shown to activate the AR signaling (Wu et al, 1998; Li et al, 2001).	22	31	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	24	25	30	31
In prostate cancer , Akt has been shown to modulate by phosphorylation the activity and stabilisation of the nuclear androgen receptor ( Lin et al , 2001 , 2002 ) .	In prostate cancer, Akt has been shown to modulate by phosphorylation the activity and stabilisation of the nuclear androgen receptor (Lin et al, 2001, 2002).	4	21	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	androgen receptor	androgen receptor	androgen receptor	4	5	19	21
Androgen mediated stimulation of mTORC2 and consecutive mTORC2 mediated activation of Akt inhibit FoxO1 activity XREF_BIBR and stimulate androgen receptor transcriptional activity XREF_BIBR .	Androgen mediated stimulation of mTORC2 and consecutive mTORC2 mediated activation of Akt inhibit FoxO1 activity XREF_BIBR and stimulate androgen receptor transcriptional activity XREF_BIBR.	7	20	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	mTORC2 mediated activation of Akt	akt	androgen receptor	androgen receptor	androgen receptor	11	12	18	20
Further , overexpression of kinase-dead Akt largely reversed isosilybin B mediated-AR degradation suggesting a critical role of Akt in AR degradation .	Further, overexpression of kinase-dead Akt largely reversed isosilybin B mediated-AR degradation suggesting a critical role of Akt in AR degradation.	2	20	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	overexpression of kinase-dead Akt	akt	AR	AR	ar	5	6	19	20
While we do not know the mechanism of Akt induced AR mRNA upregulation , we speculate that this might occur through Akt activation of NF- kappaB .	While we do not know the mechanism of Akt induced AR mRNA upregulation, we speculate that this might occur through Akt activation of NF- kappaB.	6	12	induced	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	8	9	10	11
For instance , it was reported that the PI3K and Akt pathway can suppress AR activity in androgen dependent LNCaP cells with low passage numbers , but enhances AR activity in LNCaP cells with high passage numbers .	For instance, it was reported that the PI3K and Akt pathway can suppress AR activity in androgen dependent LNCaP cells with low passage numbers, but enhances AR activity in LNCaP cells with high passage numbers.	8	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	AR	AR	AR	10	11	14	15
We propose that androgen independence emerges by means of epithelial-stromal competition , in which activation of Akt and Erk promotes AR activity in the prostate epithelium while counteracting antagonistic effects of the stroma .	We propose that androgen independence emerges by means of epithelial-stromal competition, in which activation of Akt and Erk promotes AR activity in the prostate epithelium while counteracting antagonistic effects of the stroma.	14	21	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	16	17	20	21
Interactions associated with a null strength , an extreme situation , can be removed from the model : it is the case for the activation of JNK by Rac and the activation of AR by AKT whose strengths are close to 0 ( k Rac --> JNK = 6.7e-05 , k AKT --> AR = 8.4e-04 ) .	Interactions associated with a null strength, an extreme situation, can be removed from the model : it is the case for the activation of JNK by Rac and the activation of AR by AKT whose strengths are close to 0 (k Rac --> JNK = 6.7e-05, k AKT --> AR = 8.4e-04).	31	36	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	35	36	33	34
Importantly , it has been found that Akt is an important activator of the AR , which is required for androgen independent survival and growth of prostate cancer cells [ XREF_BIBR ] .	Importantly, it has been found that Akt is an important activator of the AR, which is required for androgen independent survival and growth of prostate cancer cells [XREF_BIBR].	7	18	is an important activator	Positive_activation_copula_1	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	7	8	14	15
Although Wen and colleagues reported that activation of AKT upregulated AR transactivity [ XREF_BIBR ] , there have been conflicting reports that activation of AKT suppressed AR transactivity [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Although Wen and colleagues reported that activation of AKT upregulated AR transactivity [XREF_BIBR], there have been conflicting reports that activation of AKT suppressed AR transactivity [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	11	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	8	9	10	11
Therefore , Akt is an important activator of the AR , which is required for the androgen independent survival and growth of PCa cells .	Therefore, Akt is an important activator of the AR, which is required for the androgen independent survival and growth of PCa cells.	2	13	is an important activator	Positive_activation_copula_1	Negative_activation	Positive_activation	Akt	Akt	Akt	AR	AR	AR	2	3	9	10
The persistence of AR signaling may be driven by several mechanisms of resistance including AR splice variants , intra-tumoral production of androgens and activation of alternate pathways which support AR signalling , including the AKT and MEK pathways [ XREF_BIBR ] .	The persistence of AR signaling may be driven by several mechanisms of resistance including AR splice variants, intra-tumoral production of androgens and activation of alternate pathways which support AR signalling, including the AKT and MEK pathways [XREF_BIBR].	29	37	signalling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	AKT	AKT	AKT	AR	AR	AR	34	35	29	30
Food derived growth factors activate the oncogenic phosphoinositide-3-kinase and Akt signaling pathway , which increases androgen receptor transcriptional activity and de-represses FoxO1 suppressed target genes of follicular keratinocyte proliferation and sebaceous lipogenesis .	Food derived growth factors activate the oncogenic phosphoinositide-3-kinase and Akt signaling pathway, which increases androgen receptor transcriptional activity and de-represses FoxO1 suppressed target genes of follicular keratinocyte proliferation and sebaceous lipogenesis.	9	17	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	androgen receptor	androgen receptor	androgen receptor	9	10	15	17
This effect can at least partly be ascribed to activation of the important anti-apoptotic AKT target BAD , since beta1 integrin induced phosphorylation of BAD Ser136 was reduced after RICTOR knockdown ( XREF_FIG ) .	This effect can at least partly be ascribed to activation of the important anti-apoptotic AKT target BAD, since beta1 integrin induced phosphorylation of BAD Ser136 was reduced after RICTOR knockdown (XREF_FIG).	9	17	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	BAD	BAD	BAD	14	15	16	17
AKT can activate BAD by phosphorylation on Ser136 XREF_BIBR or activate NF-kappaB via regulating IkappaB kinase ( IKK ) XREF_BIBR , thus results in anti-apoptotic effects .	AKT can activate BAD by phosphorylation on Ser136 XREF_BIBR or activate NF-kappaB via regulating IkappaB kinase (IKK) XREF_BIBR, thus results in anti-apoptotic effects.	0	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	BAD	BAD	BAD	0	1	3	4
Here , we show that TWEAK stimulation results in Akt activation and phosphorylaton of the pro apoptotic protein BAD .	Here, we show that TWEAK stimulation results in Akt activation and phosphorylaton of the pro apoptotic protein BAD.	9	19	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	BAD	BAD	BAD	9	10	18	19
Down-regulated AKT leads to up-regulation of pro apoptotic protein Bax and Bad , which then activate the cleaved caspase-9 and caspase-3 , resulting in cell apoptosis via mitochondrial pathway .	Down-regulated AKT leads to up-regulation of pro apoptotic protein Bax and Bad, which then activate the cleaved caspase-9 and caspase-3, resulting in cell apoptosis via mitochondrial pathway.	0	12	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	Bad	Bad	Bad	1	2	11	12
XREF_BIBR - XREF_BIBR Once activated , AKT can target downstream modulators of apoptosis such as GSK3beta , IRS-1 ( insulin receptor substrate-1 ) , PDE-3B ( phosphodiesterase-3B ) , BAD , caspase-9 , Forkhead proteins , NF-kappaB , mTOR , nitric oxide synthase ( NOS ) , Raf protein kinase , and BRCA1 .	XREF_BIBR - XREF_BIBR Once activated, AKT can target downstream modulators of apoptosis such as GSK3beta, IRS-1 (insulin receptor substrate-1), PDE-3B (phosphodiesterase-3B), BAD, caspase-9, Forkhead proteins, NF-kappaB, mTOR, nitric oxide synthase (NOS), Raf protein kinase, and BRCA1.	6	30	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	BAD	BAD	BAD	6	7	29	30
NRG1 stimulation also triggered Bcl2 antagonist of cell death ( BAD ) phosphorylation of the Akt site on Ser 136 , an inhibitory modification that prevents BAD from triggering the mitochondrial apoptosis pathway [ XREF_BIBR ] .	NRG1 stimulation also triggered Bcl2 antagonist of cell death (BAD) phosphorylation of the Akt site on Ser 136, an inhibitory modification that prevents BAD from triggering the mitochondrial apoptosis pathway [XREF_BIBR].	0	27	prevents	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	Akt	NRG1 stimulation also triggered Bcl2 antagonist of cell death (BAD) phosphorylation of the Akt site on Ser 136	akt	BAD	BAD	bad	15	16	26	27
Neuroprotective pretreatments such as estradiol and ischemic preconditioning can reduce global ischemia induced cell death by activation of Akt and subsequent inactivation of its downstream target , the proapoptotic protein Bad .	Neuroprotective pretreatments such as estradiol and ischemic preconditioning can reduce global ischemia induced cell death by activation of Akt and subsequent inactivation of its downstream target, the proapoptotic protein Bad.	12	31	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bad	Bad	Bad	18	19	30	31
Mechanisms of PKB mediated Survival : The Good and the BAD .	Mechanisms of PKB mediated Survival : The Good and the BAD.	0	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKB	PKB	PKB	BAD	BAD	BAD	2	3	10	11
Akt inhibition by WT-Cts and PL-Cts variants also inhibits downstream FoxO1 and BAD .	Akt inhibition by WT-Cts and PL-Cts variants also inhibits downstream FoxO1 and BAD.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	BAD	BAD	BAD	0	1	12	13
Likewise , the highly increased expression of PDK1 and AKT in non cancerous patients causes the downregulation of BAD , which further leads to decreased apoptosis .	Likewise, the highly increased expression of PDK1 and AKT in non cancerous patients causes the downregulation of BAD, which further leads to decreased apoptosis.	5	22	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	expression of PDK1 and AKT	akt	BAD	BAD	bad	9	10	18	19
In particular , Akt promotes cell survival by preventing Bad from inhibiting the anti-apoptotic activity of Bcl-xL .	In particular, Akt promotes cell survival by preventing Bad from inhibiting the anti-apoptotic activity of Bcl-xL.	3	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bad	Bad	Bad	3	4	9	10
Furthermore , Akt activation mediated through phosphatidylinositol-3 kinase ( PI3K ) pathway has been reported to inhibit apoptosis by inhibiting caspase-9 and Bad .	Furthermore, Akt activation mediated through phosphatidylinositol-3 kinase (PI3K) pathway has been reported to inhibit apoptosis by inhibiting caspase-9 and Bad.	2	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bad	Bad	Bad	2	3	22	23
Regarding that AKT was reported to activate BAD and prevents caspase-3 from cleaving [ XREF_BIBR ] , we thereby illustrated the potential regulatory trend between MSI1 and AKT activation in response to chemotherapy .	Regarding that AKT was reported to activate BAD and prevents caspase-3 from cleaving [XREF_BIBR], we thereby illustrated the potential regulatory trend between MSI1 and AKT activation in response to chemotherapy.	1	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	BAD	BAD	BAD	2	3	7	8
Potential redox sensitive Akt activation by dopamine activates Bad and promotes cell death in melanocytes .	Potential redox sensitive Akt activation by dopamine activates Bad and promotes cell death in melanocytes.	3	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bad	Bad	Bad	3	4	8	9
Akt also promotes sequestration of Bad and suppresses the pro apoptotic activity of GSK-3beta .	Akt also promotes sequestration of Bad and suppresses the pro apoptotic activity of GSK-3beta.	0	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bad	Bad	Bad	0	1	5	6
It is therefore , possible that Pls mediated activation of AKT and ERK can inhibit caspase-9 probably by targeting Bad protein .	It is therefore, possible that Pls mediated activation of AKT and ERK can inhibit caspase-9 probably by targeting Bad protein.	6	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	Pls mediated activation of AKT	akt	Bad protein	Bad protein	bad protein	10	11	19	21
For example , the inhibition of the PI3-K and Akt -1 pathway down-regulated Bcl-XL , Mcl-1 , and Bad , while at the same time up-regulating Bax , whereas the inhibition of Fak up-regulated both Bax and Bak , down-regulated Bad , and did not affect the other Bcl-2 homologs analyzed .	For example, the inhibition of the PI3-K and Akt -1 pathway down-regulated Bcl-XL, Mcl-1, and Bad, while at the same time up-regulating Bax, whereas the inhibition of Fak up-regulated both Bax and Bak, down-regulated Bad, and did not affect the other Bcl-2 homologs analyzed.	9	19	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bad	Bad	Bad	9	10	18	19
AKT , a serine/threonine kinase , in turn modulates the activity of mTORC1 , BCL-2 ( BAD ) , FOXO , p53 , p27 , C-MYC , insulin like growth factors , and cyclin D1 , resulting in dysregulation of metabolism and protein synthesis , and cell growth , proliferation , and survival .	AKT, a serine/threonine kinase, in turn modulates the activity of mTORC1, BCL-2 (BAD), FOXO, p53, p27, C-MYC, insulin like growth factors, and cyclin D1, resulting in dysregulation of metabolism and protein synthesis, and cell growth, proliferation, and survival.	0	17	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	BAD	BAD	BAD	0	1	16	17
This pathway showed that ICAM2 induced tyrosine phosphorylation of ezrin and PI3K kinase membrane translocation , resulting in phosphatidylinositol-3 ,4,5 production , PDK-1 and AKT activation , and subsequent phosphorylation of AKT targets BAD , GSK3 , and FKHR .	This pathway showed that ICAM2 induced tyrosine phosphorylation of ezrin and PI3K kinase membrane translocation, resulting in phosphatidylinositol-3,4,5 production, PDK-1 and AKT activation, and subsequent phosphorylation of AKT targets BAD, GSK3, and FKHR.	29	38	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	phosphorylation of AKT	akt	BAD	BAD	bad	31	32	33	34
AKT promotes pro apoptotic BAD to be sequestered .	AKT promotes pro apoptotic BAD to be sequestered.	0	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	BAD	BAD	BAD	0	1	4	5
Akt kinase can directly regulate the action of Bad through phosphorylation of serine 136 .	Akt kinase can directly regulate the action of Bad through phosphorylation of serine 136.	0	9	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bad	Bad	Bad	0	1	8	9
The results also suggested that the inactivation of Bad mediated by Akt during the infection occurred gradually and was a time dependent process .	The results also suggested that the inactivation of Bad mediated by Akt during the infection occurred gradually and was a time dependent process.	6	12	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bad	Bad	Bad	11	12	8	9
AKT in turn modulates the activity of its downstream targets , mTOR , BAD , FOXO , p27 , c-MYC , and cyclin D1 and regulates cellular proliferation , metabolism , and survival [ XREF_BIBR ] .	AKT in turn modulates the activity of its downstream targets, mTOR, BAD, FOXO, p27, c-MYC, and cyclin D1 and regulates cellular proliferation, metabolism, and survival [XREF_BIBR].	0	25	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	BAD	BAD	BAD	0	1	13	14
Additionally , astaxanthin upregulates the phosphorylation of Akt and Bad , thus activating the Akt and Bad signaling pathway to dramatically decrease neuronal apoptosis in the early stages of brain damage [ XREF_BIBR ] .	Additionally, astaxanthin upregulates the phosphorylation of Akt and Bad, thus activating the Akt and Bad signaling pathway to dramatically decrease neuronal apoptosis in the early stages of brain damage [XREF_BIBR].	2	18	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	astaxanthin upregulates the phosphorylation of Akt	akt	Bad	Bad	bad	7	8	16	17
Further , isoflurane inhibited the phosphorylation of Akt and Bad , increased the expression of Bad , and downregulated Bcl-xL and Bad ratio ; whereas dexmedetomidine reversed those effects .	Further, isoflurane inhibited the phosphorylation of Akt and Bad, increased the expression of Bad, and downregulated Bcl-xL and Bad ratio; whereas dexmedetomidine reversed those effects.	2	16	increased	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Akt	isoflurane inhibited the phosphorylation of Akt	akt	Bad	expression of Bad	bad	7	8	15	16
We found that C225 increased the number of caspase-3-positive cells significantly , the mechanism may be that C225 against with EGFR blocked the PI3K pathway which reduced Akt phosphorylation ( Akt is an important protein molecule in PI3K pathway , it regulates caspase-9 , GSK-3beta , NF-kappaB , such as protein phosphorylation and ultimately controls cell survival and apoptosis ) and then activated caspase-9 and process of apoptosis using caspase-3 to cut DNA to complete the task of apoptosis .	We found that C225 increased the number of caspase-3-positive cells significantly, the mechanism may be that C225 against with EGFR blocked the PI3K pathway which reduced Akt phosphorylation (Akt is an important protein molecule in PI3K pathway, it regulates caspase-9, GSK-3beta, NF-kappaB, such as protein phosphorylation and ultimately controls cell survival and apoptosis) and then activated caspase-9 and process of apoptosis using caspase-3 to cut DNA to complete the task of apoptosis.	23	67	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	PI3K pathway which reduced Akt phosphorylation	akt	caspase-9	caspase-9	caspase-9	27	28	63	64
These pathways seem to be mediated by downstream MAPK , PI3K and Akt activation and inhibition of downstream Caspase-9 activation ( XREF_TABLE , Row 11 ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	These pathways seem to be mediated by downstream MAPK, PI3K and Akt activation and inhibition of downstream Caspase-9 activation (XREF_TABLE, Row 11) [XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	19	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Caspase-9	Caspase-9	Caspase-9	12	13	18	19
However , depletion of Akt did not reverse the inhibition of caspase-9 activation by infection .	However, depletion of Akt did not reverse the inhibition of caspase-9 activation by infection.	2	12	reverse	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	4	5	11	12
Akt modulates cell signaling by phosphorylation of several substrates and among them is caspase-9 , a protease that is activated in the apoptotic cell death pathway .	Akt modulates cell signaling by phosphorylation of several substrates and among them is caspase-9, a protease that is activated in the apoptotic cell death pathway.	0	16	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	0	1	13	14
Active Akt , a common mediator of cell survival signals , has been shown to inhibit apoptosis by attenuating activity of pro apoptotic factors Bad and caspase-9 .	Active Akt, a common mediator of cell survival signals, has been shown to inhibit apoptosis by attenuating activity of pro apoptotic factors Bad and caspase-9.	0	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	1	2	26	27
Wortmannin or LY294002 , two structurally dissimilar inhibitors of phosphatidylinositol 3 '-kinase ( PI-3 kinase ) , abolished both cisplatin induced Akt phosphorylation and Bad phosphorylation , and promoted cisplatin induced early and accelerated activation of caspase-3 and caspase-9 , but not of caspase-8 and caspase-1 , indicating that inhibition of the Akt and PKB phosphorylation pathway enhances the mitochondrial dependent activation of caspases .	Wortmannin or LY294002, two structurally dissimilar inhibitors of phosphatidylinositol 3 '-kinase (PI-3 kinase), abolished both cisplatin induced Akt phosphorylation and Bad phosphorylation, and promoted cisplatin induced early and accelerated activation of caspase-3 and caspase-9, but not of caspase-8 and caspase-1, indicating that inhibition of the Akt and PKB phosphorylation pathway enhances the mitochondrial dependent activation of caspases.	2	39	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	LY294002, two structurally dissimilar inhibitors of phosphatidylinositol 3 '-kinase (PI-3 kinase), abolished both cisplatin induced Akt phosphorylation	akt	caspase-9	caspase-9	caspase-9	21	22	38	39
Moreover , we also found that HC inhibited the phosphorylation of Akt and ERK1/2 which usually activated by IPoC in normal heart , induced excessive apoptosis by down-regulating Bcl-2 and up-regulating Bax , cytochrome c , caspase 9 and caspase 3 when compared with that in normal heart .	Moreover, we also found that HC inhibited the phosphorylation of Akt and ERK1/2 which usually activated by IPoC in normal heart, induced excessive apoptosis by down-regulating Bcl-2 and up-regulating Bax, cytochrome c, caspase 9 and caspase 3 when compared with that in normal heart.	6	38	up-regulating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	HC inhibited the phosphorylation of Akt	akt	caspase 9	caspase 9	caspase 9	11	12	36	38
These results suggest that inhibition of caspase-9 activation by Akt dependent phosphorylation is not generalized across species .	These results suggest that inhibition of caspase-9 activation by Akt dependent phosphorylation is not generalized across species.	6	12	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Akt	Akt dependent phosphorylation	akt	caspase-9	caspase-9	caspase-9	9	10	6	7
Phosphorylation of the oncogene product Akt was significantly reduced followed by decreased phosphorylation and increased processing of pro-caspase-9 on resveratrol treatment .	Phosphorylation of the oncogene product Akt was significantly reduced followed by decreased phosphorylation and increased processing of pro-caspase-9 on resveratrol treatment.	0	18	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Phosphorylation of the oncogene product Akt	akt	pro-caspase-9	pro-caspase-9	pro-caspase-9	5	6	17	18
Akt directly regulates caspase-9 activity and promotes cellular survival at post-mitochondrial level [ XREF_BIBR , XREF_BIBR ] .	Akt directly regulates caspase-9 activity and promotes cellular survival at post-mitochondrial level [XREF_BIBR, XREF_BIBR].	0	6	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	0	1	3	4
Conversely , the dominant negative form of Akt inhibited LIF induced increase in cell viability and suppression of caspase-9 activation .	Conversely, the dominant negative form of Akt inhibited LIF induced increase in cell viability and suppression of caspase-9 activation.	5	19	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	7	8	18	19
Finally , Akt was found to mediate exclusion of the exon 3,4,5,6 cassette of Casp9 via the phosphorylation state of the RNA splicing factor SRp30a via serines 199 , 201 , 227 and 234 .	Finally, Akt was found to mediate exclusion of the exon 3,4,5,6 cassette of Casp9 via the phosphorylation state of the RNA splicing factor SRp30a via serines 199, 201, 227 and 234.	2	18	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Casp9	Casp9	Casp9	2	3	14	15
In contrast , FKBP5 knockdown enhanced the proliferation of U251 cells , increased the phosphorylation of Akt significantly ( p < 0.05 ) , increased the expression of Bcl-2 and decreased the expression of Bax , and decreased the cleavage of caspase-9 and caspase-3 significantly ( p < 0.05 ) .	In contrast, FKBP5 knockdown enhanced the proliferation of U251 cells, increased the phosphorylation of Akt significantly (p < 0.05), increased the expression of Bcl-2 and decreased the expression of Bax, and decreased the cleavage of caspase-9 and caspase-3 significantly (p < 0.05).	3	43	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	FKBP5 knockdown enhanced the proliferation of U251 cells, increased the phosphorylation of Akt	akt	caspase-9	caspase-9	caspase-9	16	17	41	42
Akt have been reported to inhibit apoptosis by inhibiting caspase-9 activation XREF_BIBR .	Akt have been reported to inhibit apoptosis by inhibiting caspase-9 activation XREF_BIBR.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase-9	caspase-9	caspase-9	0	1	9	10
AKT promotes cell survival by controlling the activities of caspase-9 , Bax , and the mTOR pathway and protecting XIAP from degradation .	AKT promotes cell survival by controlling the activities of caspase-9, Bax, and the mTOR pathway and protecting XIAP from degradation.	0	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	caspase-9	caspase-9	caspase-9	0	1	9	10
Alternatively , activation of Akt by VP could prevent cell death by modulating the apoptotic process at the post-mitochondrial level , by directly inhibiting caspase 9 and 3 activation at a step after cytochrome c release .	Alternatively, activation of Akt by VP could prevent cell death by modulating the apoptotic process at the post-mitochondrial level, by directly inhibiting caspase 9 and 3 activation at a step after cytochrome c release.	2	28	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	caspase 9	caspase 9	caspase 9	4	5	24	26
Rg3 downregulates PI3K and Akt and inhibitor of apoptosis family of proteins , thereby allowing caspase 3 and caspase 9 to function XREF_BIBR .	Rg3 downregulates PI3K and Akt and inhibitor of apoptosis family of proteins, thereby allowing caspase 3 and caspase 9 to function XREF_BIBR.	1	21	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	caspase 9	caspase 9	caspase 9	4	5	18	20
Consistently , the Akt phosphorylation level was significantly decreased in MCF7-shGPR81 cells and increased the cleavage of poly ( ADP-ribose ) polymerase ( PARP ) and caspase-9 , markers of apoptosis , in MCF7-GPR81 cells .	Consistently, the Akt phosphorylation level was significantly decreased in MCF7-shGPR81 cells and increased the cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-9, markers of apoptosis, in MCF7-GPR81 cells.	3	34	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt phosphorylation level	akt	caspase-9	caspase-9	caspase-9	3	4	26	27
Akt phosphorylated at T308 , primarily targets TSC2 and PRAS40 leading to the activation of mTORC1 , S6K , and protein synthesis , while Akt phosphorylated at S473 was shown to target mainly the FoxO proteins and promote anti apoptotic and cell survival pathways .	Akt phosphorylated at T308, primarily targets TSC2 and PRAS40 leading to the activation of mTORC1, S6K, and protein synthesis, while Akt phosphorylated at S473 was shown to target mainly the FoxO proteins and promote anti apoptotic and cell survival pathways.	0	10	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt phosphorylated at T308	akt	PRAS40	PRAS40	pras40	0	1	9	10
AKT increases translational machinery to produce ribosomes and increases the protein synthesis rate by dual regulation of the GTPase activating protein ( GAP ) TSC2 and PRAS40 ( a proline rich AKT substrate of 40 KDa ) .	AKT increases translational machinery to produce ribosomes and increases the protein synthesis rate by dual regulation of the GTPase activating protein (GAP) TSC2 and PRAS40 (a proline rich AKT substrate of 40 KDa).	0	27	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	PRAS40	PRAS40	PRAS40	0	1	26	27
In the presence of Rheb and insulin , PRAS40 release is abolished by Akt inhibition without diminishing mTORC1 signaling .	In the presence of Rheb and insulin, PRAS40 release is abolished by Akt inhibition without diminishing mTORC1 signaling.	8	14	abolished	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	13	14	8	9
MLN0128 inhibited AKT phosphorylation at the mTORC2 site Ser473 and reduced phosphorylation of AKT substrates PRAS40 and GSK .	MLN0128 inhibited AKT phosphorylation at the mTORC2 site Ser473 and reduced phosphorylation of AKT substrates PRAS40 and GSK.	0	17	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	MLN0128 inhibited AKT phosphorylation at the mTORC2 site Ser473	akt	PRAS40	PRAS40	pras40	2	3	15	16
Our phosphoproteomics analysis coupled with studies using wortmannin to inhibit the PI3K and Akt pathway revealed that GH stimulates the phosphorylation of numerous proteins in the Akt-mTORC1 pathway , including : 1 ) Akt mediated TSC2 Ser939 phosphorylation , which suppresses TSC2 function and thus inhibits the activity of mTORC1 ; 2 ) Akt mediated PRAS40 Thr247 phosphorylation , which is thought to contribute to relief of PRAS40 dependent inhibition of mTORC1 ; and 3 ) mTOR as well as Erk1/2 mediated raptor Ser863 phosphorylation , which has been shown to promote multisite raptor phosphorylation and augment mTORC1 activity .	Our phosphoproteomics analysis coupled with studies using wortmannin to inhibit the PI3K and Akt pathway revealed that GH stimulates the phosphorylation of numerous proteins in the Akt-mTORC1 pathway, including : 1) Akt mediated TSC2 Ser939 phosphorylation, which suppresses TSC2 function and thus inhibits the activity of mTORC1; 2) Akt mediated PRAS40 Thr247 phosphorylation, which is thought to contribute to relief of PRAS40 dependent inhibition of mTORC1; and 3) mTOR as well as Erk1/2 mediated raptor Ser863 phosphorylation, which has been shown to promote multisite raptor phosphorylation and augment mTORC1 activity.	53	98	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	53	54	55	56
Recently , site directed mutagenesis and gene rescue studies showed that Akt mediated activation of PRAS40 via threonine 246 phosphorylation is both necessary and sufficient to cause exosome secretion , without affecting the ER/Golgi pathway [ XREF_BIBR ] .	Recently, site directed mutagenesis and gene rescue studies showed that Akt mediated activation of PRAS40 via threonine 246 phosphorylation is both necessary and sufficient to cause exosome secretion, without affecting the ER/Golgi pathway [XREF_BIBR].	11	19	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	11	12	15	16
By contrast , AKT inhibition greatly enhanced P-AKT , as predicted by this agent ' s mechanism of action , reduced P-PRAS40 , and had little or no effect on P-p70 S6K or P-4E-BP1 .	By contrast, AKT inhibition greatly enhanced P-AKT, as predicted by this agent 's mechanism of action, reduced P-PRAS40, and had little or no effect on P-p70 S6K or P-4E-BP1.	3	22	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	P-PRAS40	P-PRAS40	P-PRAS40	3	4	21	22
Site directed mutagenesis and gene rescue studies show that Akt mediated activation of PRAS40 via threonine 246 phosphorylation is both necessary and sufficient to cause exosome secretion without affecting the endoplasmic reticulum and Golgi pathway .	Site directed mutagenesis and gene rescue studies show that Akt mediated activation of PRAS40 via threonine 246 phosphorylation is both necessary and sufficient to cause exosome secretion without affecting the endoplasmic reticulum and Golgi pathway.	9	17	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	9	10	13	14
These effects were due to increased levels of pS473 -Akt ( P < 0.0001 ) and pS473 -Akt and total Akt ( both P < 0.0001 ) in ethanol exposed livers , increased pT246 -PRAS40 and Total PRAS40 in ethanol exposed livers ( P < 0.05 ) , and decreased pT246 -PRAS40 and pT246 -PRAS40 and Total PRAS40 in control livers ( both P < 0.0001 ) .	These effects were due to increased levels of pS473 -Akt (P < 0.0001) and pS473 -Akt and total Akt (both P < 0.0001) in ethanol exposed livers, increased pT246 -PRAS40 and Total PRAS40 in ethanol exposed livers (P < 0.05), and decreased pT246 -PRAS40 and pT246 -PRAS40 and Total PRAS40 in control livers (both P < 0.0001).	17	38	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	20	21	37	38
In excellent agreement with their work , correction of the E545K mutation in MCF-7 cells led to a selective loss of AKT phosphorylation and phosphorylation of AKT targets FOXO 1/3 and PRAS40 in both low and high serum conditions , but mTOR dependent signaling to p70S6K and EIF4EBP1 was not significantly affected .	In excellent agreement with their work, correction of the E545K mutation in MCF-7 cells led to a selective loss of AKT phosphorylation and phosphorylation of AKT targets FOXO 1/3 and PRAS40 in both low and high serum conditions, but mTOR dependent signaling to p70S6K and EIF4EBP1 was not significantly affected.	24	38	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	phosphorylation of AKT	akt	PRAS40	PRAS40	pras40	26	27	31	32
Physiologically , PRAS40 is activated by Pim1 and by phosphatidylinositol 3-kinase/Akt ( PI3K and Akt ) , which are further regulated by upstream tyrosine kinase receptor growth factors , including insulin like growth factor 1 [ XREF_BIBR ] .	Physiologically, PRAS40 is activated by Pim1 and by phosphatidylinositol 3-kinase/Akt (PI3K and Akt), which are further regulated by upstream tyrosine kinase receptor growth factors, including insulin like growth factor 1 [XREF_BIBR].	2	15	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	14	15	2	3
Another Akt target PRAS40 ( also known as Atk1s1 ) was upregulated in both KO mESCs ( XREF_FIG A ) .	Another Akt target PRAS40 (also known as Atk1s1) was upregulated in both KO mESCs (XREF_FIG A).	0	11	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	1	2	3	4
This disinhibition appears to explain the diminished response rate , especially through activation of the downstream Akt target PRAS40 .	This disinhibition appears to explain the diminished response rate, especially through activation of the downstream Akt target PRAS40.	12	19	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	16	17	18	19
Akt is the main regulator of phosphorylation at Thr246 and relieves PRAS40 mediated inhibition of mTORC1 [ XREF_BIBR , XREF_BIBR ] .	Akt is the main regulator of phosphorylation at Thr246 and relieves PRAS40 mediated inhibition of mTORC1 [XREF_BIBR, XREF_BIBR].	0	13	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	0	1	11	12
Our results showed that IL-24 wt expression reduced AKT mediated PRAS40 inactivation .	Our results showed that IL-24 wt expression reduced AKT mediated PRAS40 inactivation.	8	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	PRAS40	PRAS40	PRAS40	8	9	10	11
The PI3K-Akt survival pathway is the main pathway that PRAS40 is involved in ; PRAS40 is a substrate for Akt , but can also be activated by an Akt independent mechanisms .	The PI3K-Akt survival pathway is the main pathway that PRAS40 is involved in; PRAS40 is a substrate for Akt, but can also be activated by an Akt independent mechanisms.	14	30	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	PRAS40	PRAS40	PRAS40	28	29	14	15
AKT can also activate mTOR independently of TSC2 , via PRAS40 ( AKT1S1 ; proline rich AKT-substrate 40 kDa ) .	AKT can also activate mTOR independently of TSC2, via PRAS40 (AKT1S1; proline rich AKT-substrate 40 kDa).	0	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	AKT1S1	AKT1S1	AKT1S1	0	1	12	13
The kinase AKT can also target PRAS40 , which under conditions of low AKT activity inhibits mTOR activity by directly binding with Raptor .	The kinase AKT can also target PRAS40, which under conditions of low AKT activity inhibits mTOR activity by directly binding with Raptor.	0	15	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	PRAS40	PRAS40	PRAS40	2	3	6	7
We propose that Ser ( 87 ) of Bim ( EL ) is an important regulatory site that is targeted by Akt to attenuate the pro apoptotic function of Bim ( EL ) , thereby promoting cell survival .	We propose that Ser (87) of Bim (EL) is an important regulatory site that is targeted by Akt to attenuate the pro apoptotic function of Bim (EL), thereby promoting cell survival.	19	31	targeted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Bim	Bim	Bim	21	22	29	30
Furthermore , PP242 also completely abolished the effect of NaHS on the downstream Akt targets Bim and Bcl-2 ( XREF_FIG ) .	Furthermore, PP242 also completely abolished the effect of NaHS on the downstream Akt targets Bim and Bcl-2 (XREF_FIG).	13	16	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bim	Bim	Bim	13	14	15	16
AKT mediates BIM activation through two primary pathways : ( 1 ) AKT phosphorylates BIM directly and inhibits BIM activation XREF_BIBR , XREF_BIBR , or ( 2 ) AKT phosphorylates FOXO3A , leading to its cytoplasmic retention by 14-3-3 proteins .	AKT mediates BIM activation through two primary pathways : (1) AKT phosphorylates BIM directly and inhibits BIM activation XREF_BIBR, XREF_BIBR, or (2) AKT phosphorylates FOXO3A, leading to its cytoplasmic retention by 14-3-3 proteins.	0	3	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	BIM	BIM	BIM	0	1	2	3
It has been reported by several studies that Akt modulates Bim activation either directly or indirectly , resulting in cell death .	It has been reported by several studies that Akt modulates Bim activation either directly or indirectly, resulting in cell death.	8	11	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bim	Bim	Bim	8	9	10	11
Bim EL contains six proline directed S-P or T-P phosphorylation motifs for Erk and one phosphorylation site for Akt , Ser87 , which targets Bim for proteosomal degradation .	Bim EL contains six proline directed S-P or T-P phosphorylation motifs for Erk and one phosphorylation site for Akt, Ser87, which targets Bim for proteosomal degradation.	5	27	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bim	Bim	Bim	18	19	24	25
Akt mediates Bim activation via two primary pathways : Akt phosphorylates Bim directly and inhibits Bim activation ; Akt phosphorylates FOXO3A , leading to its cytoplasmic retention by 14-3-3 proteins .	Akt mediates Bim activation via two primary pathways : Akt phosphorylates Bim directly and inhibits Bim activation; Akt phosphorylates FOXO3A, leading to its cytoplasmic retention by 14-3-3 proteins.	0	3	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bim	Bim	Bim	0	1	2	3
Activation of PI3K and AKT signaling induces osteoblast growth via upregulation of mammalian target of rapamycin C1 ( mTORC1 ) expression , glucose uptake via upregulation of Glucose transporter type 4 ( GLUT4 ) translocation and cell survival via downregulation of FOXO1 , proapoptotic proteins like Bcl-2-associated death promoter ( BAD ) , Bcl-2-like protein 11 ( BIM ) and caspases .	Activation of PI3K and AKT signaling induces osteoblast growth via upregulation of mammalian target of rapamycin C1 (mTORC1) expression, glucose uptake via upregulation of Glucose transporter type 4 (GLUT4) translocation and cell survival via downregulation of FOXO1, proapoptotic proteins like Bcl-2-associated death promoter (BAD), Bcl-2-like protein 11 (BIM) and caspases.	2	56	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	Bcl-2-like protein 11	Bcl-2-like protein 11	Bcl-2-like protein 11	4	5	53	56
Recent studies have indicated that Akt modulates Bim activation either directly or indirectly .	Recent studies have indicated that Akt modulates Bim activation either directly or indirectly.	5	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Bim	Bim	Bim	5	6	7	8
Erlotinib treatment of HCC827 cells results in dephosphorylation of AKT and ERK , and induction of the proapoptotic protein BIM , as shown previously .	Erlotinib treatment of HCC827 cells results in dephosphorylation of AKT and ERK, and induction of the proapoptotic protein BIM, as shown previously.	0	20	induction	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	AKT	Erlotinib treatment of HCC827 cells results in dephosphorylation of AKT	akt	BIM	BIM	bim	9	10	19	20
Recent studies have indicated that AKT modulates BIM activation either directly or indirectly XREF_BIBR , XREF_BIBR .	Recent studies have indicated that AKT modulates BIM activation either directly or indirectly XREF_BIBR, XREF_BIBR.	5	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	BIM	BIM	BIM	5	6	7	8
As shown in XREF_FIG , SPHK1 inhibition decreased phosphorylation of Akt and FOXO3a and upregulated Bim , an overall response similar to RNAi knockdown of SPHK1 .	As shown in XREF_FIG, SPHK1 inhibition decreased phosphorylation of Akt and FOXO3a and upregulated Bim, an overall response similar to RNAi knockdown of SPHK1.	5	16	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	SPHK1 inhibition decreased phosphorylation of Akt	akt	Bim	Bim	bim	10	11	15	16
XREF_BIBR We found that the restoration of intracellular calcium in cystic cholangiocytes is associated with Akt activation and inhibition of B-Raf and Erk1/2 .	XREF_BIBR We found that the restoration of intracellular calcium in cystic cholangiocytes is associated with Akt activation and inhibition of B-Raf and Erk1/2.	15	22	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	B-Raf	B-Raf	B-Raf	15	16	20	21
Interestingly , treatment with single agent trametinib caused upregulation of AKT signaling in BRAF non V600E cells only , suggesting a potential escape mechanism for development of resistance to treatment with MEK inhibitor alone .	Interestingly, treatment with single agent trametinib caused upregulation of AKT signaling in BRAF non V600E cells only, suggesting a potential escape mechanism for development of resistance to treatment with MEK inhibitor alone.	10	16	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	BRAF	BRAF	BRAF	10	11	13	14
PLX4720 and BRAF siRNA leads to AKT signaling in BRAF V600E mutated and PTEN- melanoma cell lines .	PLX4720 and BRAF siRNA leads to AKT signaling in BRAF V600E-mutated and PTEN- melanoma cell lines.	6	10	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	BRAF	BRAF	BRAF	6	7	9	10
The BRAF p.V600E hotspot mutation is reported in 3 % of NSCLC and alters residues important in AKT mediated BRAF phosphorylation , suggesting that the disruption of AKT induced BRAF inhibition plays a role in malignant transformation XREF_BIBR , XREF_BIBR .	The BRAF p.V600E hotspot mutation is reported in 3% of NSCLC and alters residues important in AKT mediated BRAF phosphorylation, suggesting that the disruption of AKT induced BRAF inhibition plays a role in malignant transformation XREF_BIBR, XREF_BIBR.	25	30	induced	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	BRAF	BRAF	BRAF	27	28	29	30
Baseline AKT signaling in the BRAF WT cell lines was indicated by the constitutive phosphorylation of GSK3alpha ( S21 ) ( XREF_FIG ) .	Baseline AKT signaling in the BRAF WT cell lines was indicated by the constitutive phosphorylation of GSK3alpha (S21) (XREF_FIG).	1	8	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	BRAF	BRAF	BRAF	1	2	5	6
Three BRAF mutations identified in this study are novel , altering residues important in AKT mediated BRAF phosphorylation and suggesting that disruption of AKT induced BRAF inhibition can play a role in malignant transformation .	Three BRAF mutations identified in this study are novel, altering residues important in AKT mediated BRAF phosphorylation and suggesting that disruption of AKT induced BRAF inhibition can play a role in malignant transformation.	21	26	induced	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	BRAF	BRAF	BRAF	23	24	25	26
Moreover , AKT could promote activation of B-RAF via phosphorylation on Ser 445 , with ERK1/2 activation requiring androgen deprivation in androgen dependent PCa cells XREF_BIBR .	Moreover, AKT could promote activation of B-RAF via phosphorylation on Ser 445, with ERK1/2 activation requiring androgen deprivation in androgen dependent PCa cells XREF_BIBR.	2	9	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	B-RAF	B-RAF	B-RAF	2	3	7	8
In addition , it has been reported that disruption of intracellular calcium mobilization operated by calcium channel blockers was associated with decreased activity of Akt , a negative regulator of B-Raf , resulting in activation of the B-Raf and ERK pathway 66 .	In addition, it has been reported that disruption of intracellular calcium mobilization operated by calcium channel blockers was associated with decreased activity of Akt, a negative regulator of B-Raf, resulting in activation of the B-Raf and ERK pathway 66.	24	40	resulting in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	B-Raf	B-Raf	B-Raf	24	25	37	38
The pharmacologic activation by four different Trpv4 agonists restores intracellular calcium levels subsequently decreasing proliferation and cyst growth via a mechanism involving Akt activation and inhibition of B-Raf and Erk pathway .	The pharmacologic activation by four different Trpv4 agonists restores intracellular calcium levels subsequently decreasing proliferation and cyst growth via a mechanism involving Akt activation and inhibition of B-Raf and Erk pathway.	22	30	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	B-Raf	B-Raf	B-Raf	22	23	27	28
Interestingly , full Akt activation in Braf and Bcat-STA melanomas was only observed in a small subset of tumors and always in the context of relative decreases in melanocyte differentiation antigen expression ( XREF_FIG ) .	Interestingly, full Akt activation in Braf and Bcat-STA melanomas was only observed in a small subset of tumors and always in the context of relative decreases in melanocyte differentiation antigen expression (XREF_FIG).	3	9	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Braf	Braf	Braf	3	4	6	7
We speculated that the differential sub-cellular localization of Akt1 and Akt2 proteins within pro B cells may contribute to the specific regulation of FoxO1 by Akt2 .	We speculated that the differential sub-cellular localization of Akt1 and Akt2 proteins within pro B cells may contribute to the specific regulation of FoxO1 by Akt2.	17	26	contribute	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Akt2	Akt2	Akt2	FoxO1	FoxO1	FoxO1	25	26	23	24
Together , these data show that Akt2 specifically regulates FoxO1 phosphorylation in pro B cells and suggests that the selective localization of Akt2 to the B cell nucleus contributes to the specific regulation of FoxO1 by Akt2 .	Together, these data show that Akt2 specifically regulates FoxO1 phosphorylation in pro B cells and suggests that the selective localization of Akt2 to the B cell nucleus contributes to the specific regulation of FoxO1 by Akt2.	28	37	contributes	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Akt2	Akt2	Akt2	FoxO1	FoxO1	FoxO1	36	37	34	35
WT-AKT2 also reduced the binding of FOXO1 to the TIMP-1 promoter , whereas AKT2 shRNA increased the binding of FOXO1 to the TIMP-1 promoter ( XREF_FIG ) .	WT-AKT2 also reduced the binding of FOXO1 to the TIMP-1 promoter, whereas AKT2 shRNA increased the binding of FOXO1 to the TIMP-1 promoter (XREF_FIG).	13	20	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT2	AKT2	AKT2	FOXO1	FOXO1	FOXO1	13	14	19	20
ChIP analysis showed that WT-AKT2 reduced the binding of FOXO1 to the MMP-9 promoter , whereas AKT2 shRNA increased the binding of FOXO1 to the MMP-9 promoter ( XREF_FIG ) .	ChIP analysis showed that WT-AKT2 reduced the binding of FOXO1 to the MMP-9 promoter, whereas AKT2 shRNA increased the binding of FOXO1 to the MMP-9 promoter (XREF_FIG).	16	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT2	AKT2	AKT2	FOXO1	FOXO1	FOXO1	16	17	22	23
Taking these data in aggregate , we suggest that Akt2 promotes hepatic lipid accumulation and de novo lipogenesis independent of FoxA2 and FoxO1 .	Taking these data in aggregate, we suggest that Akt2 promotes hepatic lipid accumulation and de novo lipogenesis independent of FoxA2 and FoxO1.	9	23	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt2	Akt2	Akt2	FoxO1	FoxO1	FoxO1	9	10	22	23
We also found that phosphorylation by AKT1 and AKT2 promotes KHSRP dependent maturation of myomiRs in the early phases of myogenic differentiation of C2C12 cells 37 .	We also found that phosphorylation by AKT1 and AKT2 promotes KHSRP dependent maturation of myomiRs in the early phases of myogenic differentiation of C2C12 cells 37.	4	12	promotes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT2	AKT2	AKT2	KHSRP	KHSRP	KHSRP	8	9	10	11
On the other hand , knockdown of AKT3 with siRNA caused at least 50 % reduction of total AKT , phospho-AKT Ser473 , B-Raf , and phospho-mTOR Ser2448 as well as decreased phospho-AKT Thr308 in PC-3 cells .	On the other hand, knockdown of AKT3 with siRNA caused at least 50% reduction of total AKT, phospho-AKT Ser473, B-Raf, and phospho-mTOR Ser2448 as well as decreased phospho-AKT Thr308 in PC-3 cells.	5	24	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT3	AKT3	AKT3	B-Raf	B-Raf	B-Raf	7	8	23	24
Our observation indicated that overexpression of AKT3 augmented protein abundance of B-Raf , which promotes the proliferation of prostate cancer cells .	Our observation indicated that overexpression of AKT3 augmented protein abundance of B-Raf, which promotes the proliferation of prostate cancer cells.	4	14	augmented	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT3	overexpression of AKT3	akt3	B-Raf	B-Raf	b-raf	6	7	11	12
In vitro studies in breast cancer cell lines suggest that AKT1 mediated degradation of the pro invasion transcription factor NFAT and the tumour-suppressor tuberous sclerosis complex 2 ( TSC2 ) decreases , whereas AKT2 mediated up-regulation of pro invasive beta1-integrin promotes cell migration [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In vitro studies in breast cancer cell lines suggest that AKT1 mediated degradation of the pro invasion transcription factor NFAT and the tumour-suppressor tuberous sclerosis complex 2 (TSC2) decreases, whereas AKT2 mediated up-regulation of pro invasive beta1-integrin promotes cell migration [XREF_BIBR, XREF_BIBR, XREF_BIBR].	10	29	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	AKT1	AKT1	AKT1	TSC2	TSC2	TSC2	10	11	28	29
Loss of the tumor suppressor PTEN has been shown to activate mTORC1 via protein kinase B ( AKT ) , which inhibits TSC1 and TSC2 through phosphorylation [ XREF_BIBR ] .	Loss of the tumor suppressor PTEN has been shown to activate mTORC1 via protein kinase B (AKT), which inhibits TSC1 and TSC2 through phosphorylation [XREF_BIBR].	13	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	protein kinase B	protein kinase B	protein kinase B	TSC2	TSC2	TSC2	13	16	24	25
The authors also concluded that Akt2 increased the stability and nuclear localization of p27 , thus inhibiting cell cycle progression .	The authors also concluded that Akt2 increased the stability and nuclear localization of p27, thus inhibiting cell cycle progression.	5	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt2	Akt2	Akt2	p27	p27	p27	5	6	13	14
The most important gene changes with gain of function belonging to PanIN : RAS , EGFR , COX-2 , HGF , FADK , Notch , Wnt , Myb , CCKRB , BCL-6 , CXCR4 , AKT-2 , and the genes with loss of function promote pre-cancerous lesions : BRCA2 , PTEN , SMAD4 , p16 , p53 , p21 and WAF , p27 and CIP1 .	The most important gene changes with gain of function belonging to PanIN : RAS, EGFR, COX-2, HGF, FADK, Notch, Wnt, Myb, CCKRB, BCL-6, CXCR4, AKT-2, and the genes with loss of function promote pre-cancerous lesions : BRCA2, PTEN, SMAD4, p16, p53, p21 and WAF, p27 and CIP1.	13	63	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT-2	AKT-2	AKT-2	p27	p27	p27	35	36	62	63
The two isoforms of the Ser/Thr kinase GSK3 are primarily regulated by inhibitory phosphorylation at Ser21 in GSK3alpha and Ser9 in GSK3beta which is often mediated by Akt .	The two isoforms of the Ser/Thr kinase GSK3 are primarily regulated by inhibitory phosphorylation at Ser21 in GSK3alpha and Ser9 in GSK3beta which is often mediated by Akt.	10	28	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	27	28	21	22
Aspirin efficiently reversed the upregulation of beta-catenin and P-Akt expression and the TAC- or ANG II induced downregulation of GSK-3beta .	Aspirin efficiently reversed the upregulation of beta-catenin and P-Akt expression and the TAC- or ANG II induced downregulation of GSK-3beta.	6	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	P-Akt	P-Akt expression	p-akt	GSK-3beta	GSK-3beta	gsk-3beta	8	9	19	20
Interestingly , 5-HT 1A R has been reported to promote mitochondrial movement in axons of hippocampal neurons at 17 DIV , and this effect is mediated by the inhibition of GSK-3beta promoted by Akt .	Interestingly, 5-HT 1A R has been reported to promote mitochondrial movement in axons of hippocampal neurons at 17 DIV, and this effect is mediated by the inhibition of GSK-3beta promoted by Akt.	28	34	promoted	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	33	34	30	31
Akt also promotes cell survival by activating CREB , and promotes proliferation by activating mTOR and , indirectly , p70 ribosomal S6 kinase and GSK-3beta which contributes to cyclin D accumulation of cell cycle entry .	Akt also promotes cell survival by activating CREB, and promotes proliferation by activating mTOR and, indirectly, p70 ribosomal S6 kinase and GSK-3beta which contributes to cyclin D accumulation of cell cycle entry.	0	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	24	25
Based on these results , we confirmed that the knockdown of Pokemon in HepG2 cells suppressed the phosphorylation of ERK and Akt , thus activating GSK-3beta , which is the downstream target of Akt .	Based on these results, we confirmed that the knockdown of Pokemon in HepG2 cells suppressed the phosphorylation of ERK and Akt, thus activating GSK-3beta, which is the downstream target of Akt.	11	31	activating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Pokemon in HepG2 cells suppressed the phosphorylation of ERK and Akt	akt	GSK-3beta	GSK-3beta	gsk-3beta	21	22	25	26
However , rather than driving NF-kappaB activation through IKK phosphorylation , PI3K and Akt signaling serves to inactivate the inhibitory GSK3beta .	However, rather than driving NF-kappaB activation through IKK phosphorylation, PI3K and Akt signaling serves to inactivate the inhibitory GSK3beta.	11	21	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	13	14	20	21
For example , the Akt gene , which can directly regulate GSK3beta activity and downstream TCF/LEF signaling , is itself a schizophrenia risk gene and has been shown to be downregulated in postmortem brains of schizophrenia patients .	For example, the Akt gene, which can directly regulate GSK3beta activity and downstream TCF/LEF signaling, is itself a schizophrenia risk gene and has been shown to be downregulated in postmortem brains of schizophrenia patients.	4	12	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	11	12
Our present study demonstrated that activation of Akt and GSK3beta enhanced after SAH onset , administration of HS improved activation of Akt and GSK3beta , resultantly improving neuronal survival after SAH .	Our present study demonstrated that activation of Akt and GSK3beta enhanced after SAH onset, administration of HS improved activation of Akt and GSK3beta, resultantly improving neuronal survival after SAH.	5	24	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	7	8	23	24
During Helicobacter pylori infection , PKB mediated GSK-3beta inactivation plays an essential role in Wnt signaling activation and cell proliferation XREF_BIBR .	During Helicobacter pylori infection, PKB mediated GSK-3beta inactivation plays an essential role in Wnt signaling activation and cell proliferation XREF_BIBR.	5	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	PKB	PKB	PKB	GSK-3beta	GSK-3beta	GSK-3beta	5	6	7	8
As GSK-3beta has been revealed to phosphorylate tau , dysfunction of PI3K and AKT signaling causes GSK-3beta hyper-activity and directs to tau hyper-phosphorylation , an important event in AD pathogenesis [ XREF_BIBR ] .	As GSK-3beta has been revealed to phosphorylate tau, dysfunction of PI3K and AKT signaling causes GSK-3beta hyper-activity and directs to tau hyper-phosphorylation, an important event in AD pathogenesis [XREF_BIBR].	11	17	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	13	14	16	17
While inhibition of Akt and subsequent activation of GSK-3beta by phosphorylation at Tyr 216 ( p-Tyr 216 GSK-3beta ) phosphorylates tau , activation of Akt and inhibition of GSK-3beta by phosphorylation at Ser 9 ( p-Ser 9 GSK-3beta ) reduces tau phosphorylation .	While inhibition of Akt and subsequent activation of GSK-3beta by phosphorylation at Tyr 216 (p-Tyr 216 GSK-3beta) phosphorylates tau, activation of Akt and inhibition of GSK-3beta by phosphorylation at Ser 9 (p-Ser 9 GSK-3beta) reduces tau phosphorylation.	3	10	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	8	9
Marine lipopeptide Iturin A inhibits Akt mediated GSK3beta and FoxO3a signaling and triggers apoptosis in breast cancer .	Marine lipopeptide Iturin A inhibits Akt mediated GSK3beta and FoxO3a signaling and triggers apoptosis in breast cancer.	4	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	7	8
Given the above data , and taken together with current literature , we propose the model that activation of AKT by IL-8 exposure activates S6K which either directly , or via inactivation of GSK3beta , is able to augment translation of the pool of mRNA present for CAR Ex8 ( XREF_FIG ) .	Given the above data, and taken together with current literature, we propose the model that activation of AKT by IL-8 exposure activates S6K which either directly, or via inactivation of GSK3beta, is able to augment translation of the pool of mRNA present for CAR Ex8 (XREF_FIG).	17	34	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	19	20	33	34
We show that Aurora A kinase , which functions in centrosome activity and spindle assembly , is highly induced during reprogramming and inhibits Akt mediated inactivation of GSK3beta , resulting in compromised reprogramming efficiency .	We show that Aurora A kinase, which functions in centrosome activity and spindle assembly, is highly induced during reprogramming and inhibits Akt mediated inactivation of GSK3beta, resulting in compromised reprogramming efficiency.	22	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	23	24	27	28
GSK-3beta is a downstream target of the PI3K and Akt signaling pathway XREF_BIBR , XREF_BIBR , and PI3K and Akt inactivation increases GSK-3beta activity XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	GSK-3beta is a downstream target of the PI3K and Akt signaling pathway XREF_BIBR, XREF_BIBR, and PI3K and Akt inactivation increases GSK-3beta activity XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	19	24	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	19	20	22	23
The PTEN K254R mutant retained the ability to counter PI3K signaling as its expression in PTEN deficient human U87MG glioblastoma cells resulted in comparable decreases in phosphorylation of protein kinase B ( PKB ) ( also called Akt ) and of the PKB target GSK3beta , as did expression of wt PTEN ( XREF_SUPPLEMENTARY ) and in vitro , displayed equal phosphatase activity towards PI ( 3,4,5 ) P 3 ( XREF_SUPPLEMENTARY ) .	The PTEN K254R mutant retained the ability to counter PI3K signaling as its expression in PTEN deficient human U87MG glioblastoma cells resulted in comparable decreases in phosphorylation of protein kinase B (PKB) (also called Akt) and of the PKB target GSK3beta, as did expression of wt PTEN (XREF_SUPPLEMENTARY) and in vitro, displayed equal phosphatase activity towards PI (3,4,5) P 3 (XREF_SUPPLEMENTARY).	21	47	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PKB	PKB	PKB	GSK3beta	GSK3beta	GSK3beta	42	43	44	45
During LTD induction , Akt is dephosphorylated at Ser473 , enabling GSK3beta activation .	During LTD induction, Akt is dephosphorylated at Ser473, enabling GSK3beta activation.	4	12	enabling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt is dephosphorylated at Ser473	akt	GSK3beta	GSK3beta	gsk3beta	4	5	11	12
They show that inhibition of PI3-K and Akt induces a 40 % decrease of cyclin D1 half-life as a result of accumulation of the dephosphorylated and active form of GSK-3beta within the nucleus , where this kinase can phosphorylate cyclin D1 .	They show that inhibition of PI3-K and Akt induces a 40% decrease of cyclin D1 half-life as a result of accumulation of the dephosphorylated and active form of GSK-3beta within the nucleus, where this kinase can phosphorylate cyclin D1.	3	30	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	7	8	29	30
Thus BAD inactivates AKT , which may activate GSK-3beta ( XREF_FIG ) causing reduction of beta-catenin ( XREF_FIG ) .	Thus BAD inactivates AKT, which may activate GSK-3beta (XREF_FIG) causing reduction of beta-catenin (XREF_FIG).	2	17	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	3	4	8	9
PLZF caused an Akt mediated downregulation of GSK3beta and reduced the activity of MEK1/2 .	PLZF caused an Akt mediated downregulation of GSK3beta and reduced the activity of MEK1/2.	2	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	7	8
As the downstream effector kinase of Akt , p-GSK-3beta could be increased by the phosphorylation of Akt , and promote the survival of damaged neurons .	As the downstream effector kinase of Akt, p-GSK-3beta could be increased by the phosphorylation of Akt, and promote the survival of damaged neurons.	8	19	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	phosphorylation of Akt	akt	p-GSK-3beta	p-GSK-3beta	p-gsk-3beta	16	17	8	9
The PPP2R5D subunit regulates tau phosphorylation via Akt mediated GSK3beta activation .	The PPP2R5D subunit regulates tau phosphorylation via Akt mediated GSK3beta activation.	5	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	7	8	9	10
AKT activation could elevate GSK3beta phosp horylation , which in turn induces Wnt signaling activity and promotes EMT in human cancers .	AKT activation could elevate GSK3beta phosp horylation, which in turn induces Wnt signaling activity and promotes EMT in human cancers.	0	6	elevate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	0	1	4	5
Activation of the transcription factor SREBP1c , controlling the expression of ACC , is known to be linked to the AKT mediated inactivation of GSK-3beta .	Activation of the transcription factor SREBP1c, controlling the expression of ACC, is known to be linked to the AKT mediated inactivation of GSK-3beta.	17	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	20	21	24	25
The PI3K and Akt and PKG pathways may mediate GSK-3beta inactivation .	The PI3K and Akt and PKG pathways may mediate GSK-3beta inactivation.	3	10	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	9	10
The PI3K and AKT pathways has been reported to modulate the activity of GSK-3beta .	The PI3K and AKT pathways has been reported to modulate the activity of GSK-3beta.	1	14	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	3	4	13	14
Aberrant activation of Akt leads to increase the inactive GSK3beta , which is downstream target kinase of Akt in colorectal cancer .	Aberrant activation of Akt leads to increase the inactive GSK3beta, which is downstream target kinase of Akt in colorectal cancer.	1	15	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	9	10
In addition , activated MEK-ERK and AKT signaling also triggered a robust inactivation of GSK3beta , which would lead to stabilization of anti-apoptotic MCL1 ( XREF_FIG ) .	In addition, activated MEK-ERK and AKT signaling also triggered a robust inactivation of GSK3beta, which would lead to stabilization of anti-apoptotic MCL1 (XREF_FIG).	6	18	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	6	7	14	15
In addition , EMT is positively associated with aberrant activation of Wnt or the PI3K and Akt pathway , which activates GSK-3beta and stabilizes beta-catenin [ XREF_BIBR , XREF_BIBR ] .	In addition, EMT is positively associated with aberrant activation of Wnt or the PI3K and Akt pathway, which activates GSK-3beta and stabilizes beta-catenin [XREF_BIBR, XREF_BIBR].	14	22	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	16	17	21	22
Downregulation of PI3K and Akt signaling causes GSK-3beta activity increase and leads to Tau hyper-phosphorylation , the main component of NFT ( Hooper et al ., 2008 ; Freude et al ., 2009 ) .	Downregulation of PI3K and Akt signaling causes GSK-3beta activity increase and leads to Tau hyper-phosphorylation, the main component of NFT (Hooper et al., 2008; Freude et al., 2009).	2	9	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	4	5	7	8
The addition of LY294002 , a PI3K inhibitor , could suppress phosphorylation of Akt and CREB and activate GSK-3beta , resulting in abolishment of neuroprotective effects of rifampicin on cells exposed to rotenone .	The addition of LY294002, a PI3K inhibitor, could suppress phosphorylation of Akt and CREB and activate GSK-3beta, resulting in abolishment of neuroprotective effects of rifampicin on cells exposed to rotenone.	3	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	LY294002, a PI3K inhibitor, could suppress phosphorylation of Akt	akt	GSK-3beta	GSK-3beta	gsk-3beta	13	14	18	19
PI3K and AKT signaling pathway dysfunction causes GSK-3beta activity increase and leads to Tau hyper-phosphorylation , the main component of NFT [ XREF_BIBR ] .	PI3K and AKT signaling pathway dysfunction causes GSK-3beta activity increase and leads to Tau hyper-phosphorylation, the main component of NFT [XREF_BIBR].	2	9	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	2	3	7	8
To confirm the mechanism underlying the effect of baicalein on Cyr61 induced Akt activation and inhibition of GSK3beta activity , MCF-7 cells transiently transfected with Cyr61 , referred to as MCF-7-Cyr61 , were established ( XREF_SUPPLEMENTARY ) .	To confirm the mechanism underlying the effect of baicalein on Cyr61 induced Akt activation and inhibition of GSK3beta activity, MCF-7 cells transiently transfected with Cyr61, referred to as MCF-7-Cyr61, were established (XREF_SUPPLEMENTARY).	10	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Cyr61 induced Akt	akt	GSK3beta	GSK3beta	gsk3beta	12	13	17	18
PCDH20 inhibits Wnt signalling pathway through antagonizing ERK and Akt mediated activation of GSK-3beta .	PCDH20 inhibits Wnt signalling pathway through antagonizing ERK and Akt mediated activation of GSK-3beta.	7	14	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	9	10	13	14
Insights into mechanisms responsible for the proinflammatory and immune suppressive activities of Gr1 ( + ) CD11b ( + ) cells from aged mice have uncovered a defective PI3K-Akt signaling pathway , leading to a reduced Akt dependent inactivation of GSK3beta .	Insights into mechanisms responsible for the proinflammatory and immune suppressive activities of Gr1 (+) CD11b (+) cells from aged mice have uncovered a defective PI3K-Akt signaling pathway, leading to a reduced Akt dependent inactivation of GSK3beta.	36	41	inactivation	Negative_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	36	37	40	41
On the other hand , Akt could activate GSK3beta to manipulate cell cycle and glucose metabolism [ XREF_BIBR ] .	On the other hand, Akt could activate GSK3beta to manipulate cell cycle and glucose metabolism [XREF_BIBR].	5	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	8	9
Dominant negative Akt , but not dominant negative p70S6 kinase , inhibited GSK3beta phosphorylation induced by high glucose and high insulin , suggesting Akt but not p70S6 kinase was upstream of GSK3beta .	Dominant negative Akt, but not dominant negative p70S6 kinase, inhibited GSK3beta phosphorylation induced by high glucose and high insulin, suggesting Akt but not p70S6 kinase was upstream of GSK3beta.	0	32	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	31	32
This kinase and its regulator AKT are targets of palbociclib and GSK3beta phosphorylates beta-catenin , leading to beta-catenin degradation by the proteasome .	This kinase and its regulator AKT are targets of palbociclib and GSK3beta phosphorylates beta-catenin, leading to beta-catenin degradation by the proteasome.	1	12	are targets	Positive_activation_copula_1	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	5	6	11	12
The PI3K-AKT pathway modulates GSK-3beta activity 4 and accordingly , cells from patients with PIK3CA , PIK3R2 or AKT3 mutations similarly accumulated CCND2 .	The PI3K-AKT pathway modulates GSK-3beta activity 4 and accordingly, cells from patients with PIK3CA, PIK3R2 or AKT3 mutations similarly accumulated CCND2.	1	5	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	GSK-3beta	GSK-3beta	GSK-3beta	1	2	4	5
These results demonstrate that CO-induced GSK3beta inactivation is mediated by the PI3K and Akt signaling pathway and consequently modulates the TLR4 driven inflammatory response .	These results demonstrate that CO-induced GSK3beta inactivation is mediated by the PI3K and Akt signaling pathway and consequently modulates the TLR4 driven inflammatory response.	5	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	13	14	5	6
We observed that activating Akt by EGF promoted SCD1 mediated upregulation of p-GSK3beta and beta-catenin in T98G and U87 cell lines .	We observed that activating Akt by EGF promoted SCD1 mediated upregulation of p-GSK3beta and beta-catenin in T98G and U87 cell lines.	3	14	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p-GSK3beta	p-GSK3beta	p-GSK3beta	4	5	12	13
These results indicated that Akt mediated GSK-3beta inactivation also involves in ABT-263-induced Mcl-1 stabilization , possibly through regulating the phosphorylation of Mcl-1 Ser159 .	These results indicated that Akt mediated GSK-3beta inactivation also involves in ABT-263-induced Mcl-1 stabilization, possibly through regulating the phosphorylation of Mcl-1 Ser159.	4	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	4	5	6	7
PI3K and Akt is known to promote EMT by regulating the activity of GSK3beta , which targets Snail for degradation by suppressing NF-kappaB-dependent Snail expression [ XREF_BIBR , XREF_BIBR ] .	PI3K and Akt is known to promote EMT by regulating the activity of GSK3beta, which targets Snail for degradation by suppressing NF-kappaB-dependent Snail expression [XREF_BIBR, XREF_BIBR].	0	25	promote	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Akt	Akt	akt	GSK3beta	GSK3beta, which targets Snail for degradation by suppressing NF-kappaB-dependent Snail expression	gsk3beta	2	3	13	14
Here we show that inhibition of PI3-K and Akt induces a 40 % decrease of cyclin D1 half-life as a result of accumulation of the dephosphorylated and active form of GSK-3beta within the nucleus , where this kinase can phosphorylate cyclin D1 on Thr286 thereby promoting its nuclear export .	Here we show that inhibition of PI3-K and Akt induces a 40% decrease of cyclin D1 half-life as a result of accumulation of the dephosphorylated and active form of GSK-3beta within the nucleus, where this kinase can phosphorylate cyclin D1 on Thr286 thereby promoting its nuclear export.	4	31	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	8	9	30	31
The activation of PI3K and Akt and Ras might mediate the inactivation of GSK3beta [ XREF_BIBR ] .	The activation of PI3K and Akt and Ras might mediate the inactivation of GSK3beta [XREF_BIBR].	1	15	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	13	14
Although it is well known that Akt induces the inactivation of GSK-3beta via PI3K pathway , XREF_BIBR there are only a few reports concerning the TNF-alpha activation of Akt through its phosphorylation .	Although it is well known that Akt induces the inactivation of GSK-3beta via PI3K pathway, XREF_BIBR there are only a few reports concerning the TNF-alpha activation of Akt through its phosphorylation.	6	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	6	7	11	12
Together , these results demonstrate that EGFR dependent phosphorylation of ZNRF1 at Y103 promotes degradation of AKT and resultant activation of GSK3beta , which mediates oxidative stress induced neuronal apoptosis ( XREF_FIG ) .	Together, these results demonstrate that EGFR dependent phosphorylation of ZNRF1 at Y103 promotes degradation of AKT and resultant activation of GSK3beta, which mediates oxidative stress induced neuronal apoptosis (XREF_FIG).	16	24	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	16	17	21	22
High-Density Astrocyte Induced Neuroprotection against Propofol is partially through Akt Mediated GSK3beta Signaling .	High-Density Astrocyte Induced Neuroprotection against Propofol is partially through Akt Mediated GSK3beta Signaling.	7	12	Mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	9	10	11	12
Taken together , these results demonstrated that cypripedin suppresses the mesenchymal transition in lung cancer via inhibition of Akt , which in turn activates GSK-3beta and leads to Slug degradation .	Taken together, these results demonstrated that cypripedin suppresses the mesenchymal transition in lung cancer via inhibition of Akt, which in turn activates GSK-3beta and leads to Slug degradation.	16	28	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	18	19	24	25
Activation of TLR4 or inhibition of PI3K and AKT can activate GSK-3beta and vice versa .	Activation of TLR4 or inhibition of PI3K and AKT can activate GSK-3beta and vice versa.	2	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	8	9	11	12
Specifically we have determined that suppression of the AKT and GSK3beta pathway by either IGF-1 mediated AKT activation or pharmacological inhibition of GSK3beta does not affect the induction of JNK targets including P-c-Jun , P-ATF2 or ATF3 .	Specifically we have determined that suppression of the AKT and GSK3beta pathway by either IGF-1 mediated AKT activation or pharmacological inhibition of GSK3beta does not affect the induction of JNK targets including P-c-Jun, P-ATF2 or ATF3.	14	23	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	IGF-1 mediated AKT	akt	GSK3beta	GSK3beta	gsk3beta	16	17	22	23
Inactivation of Akt using inhibitors LY294002 and MK2206 could elevate the SCD1 inhibition mediated downregulation of p-GSK3beta and beta-catenin in T98G-R and U87-R cell lines .	Inactivation of Akt using inhibitors LY294002 and MK2206 could elevate the SCD1 inhibition mediated downregulation of p-GSK3beta and beta-catenin in T98G-R and U87-R cell lines.	0	18	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p-GSK3beta	p-GSK3beta	p-GSK3beta	2	3	16	17
Luteolin is able to inhibit IGF-1-induced activation of IGF-1R and Akt , and phosphorylation of the Akt targets p70S6K1 , GSK-3beta , and FKHR and FKHRL1 .	Luteolin is able to inhibit IGF-1-induced activation of IGF-1R and Akt, and phosphorylation of the Akt targets p70S6K1, GSK-3beta, and FKHR and FKHRL1.	13	21	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	phosphorylation of the Akt	akt	GSK-3beta	GSK-3beta	gsk-3beta	16	17	20	21
Moreover , the kinases GSK3beta and mTOR , modulated by PI-3K and Akt , can inhibit NFAT activity , suggesting a cross-talk between the calcium and growth factor signaling pathways .	Moreover, the kinases GSK3beta and mTOR, modulated by PI-3K and Akt, can inhibit NFAT activity, suggesting a cross-talk between the calcium and growth factor signaling pathways.	2	15	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	12	13	4	5
Akt also promotes protein synthesis by phosphorylating and inactivating GSK3beta , thus releasing the GSK3beta dependent inhibition of the eukariotic translation initiation factor 2B ( eIF2B ) .	Akt also promotes protein synthesis by phosphorylating and inactivating GSK3beta, thus releasing the GSK3beta dependent inhibition of the eukariotic translation initiation factor 2B (eIF2B).	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	9	10
Mechanistic studies have suggested that Akt mediated Gsk-3beta inactivation plays a role in Mcl-1 phosphorylation and stabilization XREF_BIBR , XREF_BIBR .	Mechanistic studies have suggested that Akt mediated Gsk-3beta inactivation plays a role in Mcl-1 phosphorylation and stabilization XREF_BIBR, XREF_BIBR.	5	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	Gsk-3beta	Gsk-3beta	Gsk-3beta	5	6	7	8
Akt activation , in turn , potentially activated MDM2 , leading to enhanced p53 ubiquitination and potential blockage of GSK3beta .	Akt activation, in turn, potentially activated MDM2, leading to enhanced p53 ubiquitination and potential blockage of GSK3beta.	0	20	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	19	20
For example , Akt drives GLUT ( glucose transporter ) plasma membrane translocation to normalize blood glucose and activates GSK-3beta ( glycogen synthase kinase-3beta ) to induce glycogen synthesis through the target of rapamycin complexes , including mTOR ( mammalian target of rapamycin ) , to control AMPK , energy metabolism , mitochondrial function , synaptic plasticity and memory .	For example, Akt drives GLUT (glucose transporter) plasma membrane translocation to normalize blood glucose and activates GSK-3beta (glycogen synthase kinase-3beta) to induce glycogen synthesis through the target of rapamycin complexes, including mTOR (mammalian target of rapamycin), to control AMPK, energy metabolism, mitochondrial function, synaptic plasticity and memory.	3	26	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	3	4	19	20
Similarly , co-transfected Akt-myr ( a constitutively active Akt mutant ) with PCDH20 could also antagonize the active Akt induced GSK-3beta inactivation and Wnt and beta-catenin signalling pathway activation .	Similarly, co-transfected Akt-myr (a constitutively active Akt mutant) with PCDH20 could also antagonize the active Akt induced GSK-3beta inactivation and Wnt and beta-catenin signalling pathway activation.	16	21	induced	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	18	19	20	21
Akt mediated GSK-3beta inactivation also involves in ABT-263-induced Mcl-1 stabilization .	Akt mediated GSK-3beta inactivation also involves in ABT-263-induced Mcl-1 stabilization.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	2	3
It has been suggested that Atoh1 mRNA transcription was facilitated by JNK in normal intestinal epithelium [ XREF_BIBR ] , whereas Atoh1 expression was mainly regulated via post-translational modification in CRC development and the activation of AKT could induce the inactivation of GSK3beta , which was involved in the ubiquitin-proteasomal degradation of Atoh1 in CRC cells [ XREF_BIBR , XREF_BIBR ] .	It has been suggested that Atoh1 mRNA transcription was facilitated by JNK in normal intestinal epithelium [XREF_BIBR], whereas Atoh1 expression was mainly regulated via post-translational modification in CRC development and the activation of AKT could induce the inactivation of GSK3beta, which was involved in the ubiquitin-proteasomal degradation of Atoh1 in CRC cells [XREF_BIBR, XREF_BIBR].	34	46	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	36	37	42	43
Thus increased MYCN levels via amplification or as the result of Akt mediated GSK-3beta inactivation would lead to DPYSL3 suppression in NB cells .	Thus increased MYCN levels via amplification or as the result of Akt mediated GSK-3beta inactivation would lead to DPYSL3 suppression in NB cells.	9	14	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	11	12	13	14
Furthermore , ABT-263 increased the protein stability of Mcl-1 through promoting ERK- and JNK induced phosphorylation of Mcl-1 Thr163 and increasing the Akt mediated inactivation of GSK-3beta .	Furthermore, ABT-263 increased the protein stability of Mcl-1 through promoting ERK- and JNK induced phosphorylation of Mcl-1 Thr163 and increasing the Akt mediated inactivation of GSK-3beta.	21	27	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	22	23	26	27
Inactivation of Akt triggers GSK-3beta activity through decreasing phosphorylation , which plays a key role in neuronal loss occurring in neurodegenerative diseases , such as PD [ XREF_BIBR , XREF_BIBR ] and AD [ XREF_BIBR ] .	Inactivation of Akt triggers GSK-3beta activity through decreasing phosphorylation, which plays a key role in neuronal loss occurring in neurodegenerative diseases, such as PD [XREF_BIBR, XREF_BIBR] and AD [XREF_BIBR].	0	5	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	4	5
Akt mediated GSK-3beta inactivation also played important role in preventing Mcl-1 protein degradation in the presence of ABT-263 .	Akt mediated GSK-3beta inactivation also played important role in preventing Mcl-1 protein degradation in the presence of ABT-263.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	0	1	2	3
Akt mediated inactivation of GSK3beta and FOXO after CD150 and CD180 stimulation suggests a pro survival role for these receptors in CLL B cells pathobiology , while cross-talk between CD180 and BCR can redirect signaling from pro survival to pro apoptotic pathways [ XREF_BIBR ] .	Akt mediated inactivation of GSK3beta and FOXO after CD150 and CD180 stimulation suggests a pro survival role for these receptors in CLL B cells pathobiology, while cross-talk between CD180 and BCR can redirect signaling from pro survival to pro apoptotic pathways [XREF_BIBR].	0	6	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	4	5
In response to growth factors , Akt is normally phosphorylated by a protein kinase named PDK1 ( 3-phosphoinositide-dependent protein kinase 1 ) , which activates the GSK3beta ( Glycogen synthase kinase 3 ) and mTOR signaling pathways .	In response to growth factors, Akt is normally phosphorylated by a protein kinase named PDK1 (3-phosphoinositide-dependent protein kinase 1), which activates the GSK3beta (Glycogen synthase kinase 3) and mTOR signaling pathways.	6	36	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt is normally phosphorylated by a protein kinase named PDK1	akt	GSK3beta	GSK3beta	gsk3beta	6	7	26	27
Moreover , SPH induced dephosphorylation of Akt at Ser ( 473 ) subsequently leads to the activation of GSK-3beta , caspase 3 , PARP cleavage , and ultimately apoptosis .	Moreover, SPH induced dephosphorylation of Akt at Ser (473) subsequently leads to the activation of GSK-3beta, caspase 3, PARP cleavage, and ultimately apoptosis.	2	28	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Akt	SPH induced dephosphorylation of Akt at Ser (473	akt	GSK-3beta	GSK-3beta	gsk-3beta	6	7	18	19
Levels of the AKT target GSK3beta were also reduced by deguelin , and p-GSK3beta ( lower band with the p-GSKalphabeta Ser 21,9 antibody used ) was undetectable already with 10 muM deguelin .	Levels of the AKT target GSK3beta were also reduced by deguelin, and p-GSK3beta (lower band with the p-GSKalphabeta Ser 21,9 antibody used) was undetectable already with 10 muM deguelin.	0	6	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	3	4	5	6
Defective AKT phosphorylation resulted in the activation of GSK-3beta , indicated by reduced pSer9 GSK-3beta compared with total GSK-3beta levels ( Fig XREF_FIG C and D ) .	Defective AKT phosphorylation resulted in the activation of GSK-3beta, indicated by reduced pSer9 GSK-3beta compared with total GSK-3beta levels (Fig XREF_FIG C and D).	1	9	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	AKT	AKT phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	1	2	8	9
As the protein expression profile detected in standard and basal medium treated samples showed a stronger accumulation of beta-catenin at late phase of Wnt3a stimulation , GSK3beta downregulation by simultaneous treatment with Wnt and growth factors is hypothesized to involve GSK3beta pools differently modulated by Akt .	As the protein expression profile detected in standard and basal medium treated samples showed a stronger accumulation of beta-catenin at late phase of Wnt3a stimulation, GSK3beta downregulation by simultaneous treatment with Wnt and growth factors is hypothesized to involve GSK3beta pools differently modulated by Akt.	40	46	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	45	46	40	41
Considering that Akt phosphorylation at T308 has the most pronounced effect on Akt activation , whereas phospho-S473 might stabilize or increase this initial Akt activation step , it is tempting to speculate that activation of Akt at T308 is sufficient to trigger GSK3beta activation at least to a certain extent .	Considering that Akt phosphorylation at T308 has the most pronounced effect on Akt activation, whereas phospho-S473 might stabilize or increase this initial Akt activation step, it is tempting to speculate that activation of Akt at T308 is sufficient to trigger GSK3beta activation at least to a certain extent.	33	43	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	35	36	42	43
Downregulation of GSK3beta activating tyrosine phosphorylation without change in Ser9-GSK3beta phosphorylation negates the involvement of Akt kinase mediated downstream GSK3beta inactivation .	Downregulation of GSK3beta activating tyrosine phosphorylation without change in Ser9-GSK3beta phosphorylation negates the involvement of Akt kinase mediated downstream GSK3beta inactivation.	15	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	15	16	19	20
In the absence of SPIN90 , however , interactions with Akt are lost , which leads to a concomitant sequestration of GSK3beta by activated Akt .	In the absence of SPIN90, however, interactions with Akt are lost, which leads to a concomitant sequestration of GSK3beta by activated Akt.	15	25	leads	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	24	25	21	22
In this study , we observed inactivation of Akt and activation of GSK-3beta in NLS treated PCa cells ( XREF_FIG ) , which suggest that inhibition of Akt signaling and activation of GSK-3beta partially contribute to the pro apoptotic and G1/S phase arrest activity of NLS in PCa cells .	In this study, we observed inactivation of Akt and activation of GSK-3beta in NLS treated PCa cells (XREF_FIG), which suggest that inhibition of Akt signaling and activation of GSK-3beta partially contribute to the pro apoptotic and G1/S phase arrest activity of NLS in PCa cells.	27	33	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	27	28	32	33
Furthermore , JNK downstream targets are not affected by AKT signaling independently of GSK3beta as their induction is not affected by AKT activation by IGF-1 ( XREF_FIG ) .	Furthermore, JNK downstream targets are not affected by AKT signaling independently of GSK3beta as their induction is not affected by AKT activation by IGF-1 (XREF_FIG).	9	14	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	9	10	13	14
Given that mTORC1 and GSK3beta are both targeted by Akt , but mTORC1 is activated whereas GSK3beta is inhibited by Akt dependent phosphorylation events , these results may appear contradictory .	Given that mTORC1 and GSK3beta are both targeted by Akt, but mTORC1 is activated whereas GSK3beta is inhibited by Akt dependent phosphorylation events, these results may appear contradictory.	2	10	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	9	10	4	5
Our results suggest that PCDH20 induces Erks and Akt mediated activation of GSK-3beta , which in turn inhibits Wnt and beta-catenin signalling and leads to inhibition of HCC growth and migration .	Our results suggest that PCDH20 induces Erks and Akt mediated activation of GSK-3beta, which in turn inhibits Wnt and beta-catenin signalling and leads to inhibition of HCC growth and migration.	8	23	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	8	9	12	13
The activation of PI3K and AKT negatively mediates GSK-3beta and affects glycogen synthesis .	The activation of PI3K and AKT negatively mediates GSK-3beta and affects glycogen synthesis.	1	9	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	5	6	8	9
Inhibition of tau phosphorylation through inactivation of GSK-3beta by Akt has been well described [ XREF_BIBR ] .	Inhibition of tau phosphorylation through inactivation of GSK-3beta by Akt has been well described [XREF_BIBR].	5	10	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	9	10	7	8
In addition , we found that overexpression of Akt enhances formation of an inactive form of GSK3beta ( phospho-GSK3beta ) and nuclear localization of NFATc1 , and that overexpression of a constitutively active form of GSK3beta attenuates osteoclast formation through downregulation of NFATc1 .	In addition, we found that overexpression of Akt enhances formation of an inactive form of GSK3beta (phospho-GSK3beta) and nuclear localization of NFATc1, and that overexpression of a constitutively active form of GSK3beta attenuates osteoclast formation through downregulation of NFATc1.	6	18	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	overexpression of Akt	akt	GSK3beta	GSK3beta	gsk3beta	8	9	16	17
Recent research also revealed that Akt mediates the binding of hexokinase 2 to the mitochondria by negatively regulating the activity of GSK3beta in the disease process .	Recent research also revealed that Akt mediates the binding of hexokinase 2 to the mitochondria by negatively regulating the activity of GSK3beta in the disease process.	5	22	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	5	6	21	22
ET-1 mainly used the mitogen activated protein kinase and phosphatidylinositol-3-kinase and AKT pathways to activate GSK3beta , whereas under ISO stimulation , only the phosphatidylinositol-3-kinase and AKT pathway was required to trigger the GSK3beta pathway .	ET-1 mainly used the mitogen activated protein kinase and phosphatidylinositol-3-kinase and AKT pathways to activate GSK3beta, whereas under ISO stimulation, only the phosphatidylinositol-3-kinase and AKT pathway was required to trigger the GSK3beta pathway.	26	34	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	26	27	33	34
Westernblot analysis revealed the levels of pAkt , pGSK3beta , p-BAD were decreased , whereas levels of cleaved caspase-3 were increased in gastrocnemius muscles from mice received 25-OHC , but not from mice that received 20-OHC , 22-OHC or control treatment ( XREF_FIG A ) , suggesting that inactivation of Akt and subsequent activation of GSK3beta led to Bad and caspase -3 mediated apoptosis .	Westernblot analysis revealed the levels of pAkt, pGSK3beta, p-BAD were decreased, whereas levels of cleaved caspase-3 were increased in gastrocnemius muscles from mice received 25-OHC, but not from mice that received 20-OHC, 22-OHC or control treatment (XREF_FIG A), suggesting that inactivation of Akt and subsequent activation of GSK3beta led to Bad and caspase -3 mediated apoptosis.	50	56	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	50	51	55	56
These in vitro and in vivo data together confirm the role of PI3K and Akt mediated GSK-3beta inactivation in EphB2 induced tau dephosphorylation .	These in vitro and in vivo data together confirm the role of PI3K and Akt mediated GSK-3beta inactivation in EphB2 induced tau dephosphorylation.	10	17	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	14	15	16	17
This is also in agreement with the findings that both PI3K and Akt promote NF-kappaB activity , because these signaling molecules inactivate GSK3beta .	This is also in agreement with the findings that both PI3K and Akt promote NF-kappaB activity, because these signaling molecules inactivate GSK3beta.	10	23	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	12	13	22	23
Sensitization of Cancer Cells through Reduction of Total Akt and Downregulation of Salinomycin Induced pAkt , pGSk3beta , pTSC2 , and p4EBP1 by Cotreatment with MK-2206 .	Sensitization of Cancer Cells through Reduction of Total Akt and Downregulation of Salinomycin Induced pAkt, pGSk3beta, pTSC2, and p4EBP1 by Cotreatment with MK-2206.	0	17	Induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	pGSk3beta	pGSk3beta	pGSk3beta	8	9	16	17
Overall , our data illustrate that during IL-7 signaling , AKT is activated which then prevents GSK3beta signaling and leads to reduced CD27 and CD28 loss .	Overall, our data illustrate that during IL-7 signaling, AKT is activated which then prevents GSK3beta signaling and leads to reduced CD27 and CD28 loss.	10	17	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	10	11	16	17
In conclusion , these findings suggest that inhibition of Akt signaling and activation of GSK-3beta partially contributes to the pro apoptotic effect of embelin in prostate cancer cells .	In conclusion, these findings suggest that inhibition of Akt signaling and activation of GSK-3beta partially contributes to the pro apoptotic effect of embelin in prostate cancer cells.	9	15	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	9	10	14	15
GSK3beta , identified in AIB1 immunoprecipitates in E2 treated MCF-7 cells ( XREF_SUPPLEMENTARY ) , can be activated by PI3K and AKT , and has also been shown to be a regulator of Wnt signaling ( see below ) .	GSK3beta, identified in AIB1 immunoprecipitates in E2 treated MCF-7 cells (XREF_SUPPLEMENTARY), can be activated by PI3K and AKT, and has also been shown to be a regulator of Wnt signaling (see below).	0	31	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	21	22	0	1
Moreover , Akt activation modulates GSK3beta activity , which regulates microtubule dynamics , neuritic growth , synaptogenesis , and synaptic plasticity .	Moreover, Akt activation modulates GSK3beta activity, which regulates microtubule dynamics, neuritic growth, synaptogenesis, and synaptic plasticity.	2	6	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	5	6
Under our experimental conditions , however , CK2-inhibition does not counteract the activities of Bcr-Abl , ERK1/2 nor that of Akt as demonstrated by the comparable phosphorylation extent of Akt Ser473 and Thr308 , and of Akt target GSK3beta Ser9 .	Under our experimental conditions, however, CK2-inhibition does not counteract the activities of Bcr-Abl, ERK1/2 nor that of Akt as demonstrated by the comparable phosphorylation extent of Akt Ser473 and Thr308, and of Akt target GSK3beta Ser9.	36	39	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	36	37	38	39
One should be cautious when estimating GSK3beta activity based on solely its S9 inhibitory phosphorylation because increases in substrate can override Akt mediated GSK3beta inhibition XREF_BIBR and can thus lead to erroneous conclusions .	One should be cautious when estimating GSK3beta activity based on solely its S9 inhibitory phosphorylation because increases in substrate can override Akt mediated GSK3beta inhibition XREF_BIBR and can thus lead to erroneous conclusions.	20	25	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	21	22	23	24
In conclusion , insulin and IGF-1 may alleviate cognitive impairment in PD via the inactivation of GSK3beta mediated by PI3K and Akt .	In conclusion, insulin and IGF-1 may alleviate cognitive impairment in PD via the inactivation of GSK3beta mediated by PI3K and Akt.	14	22	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	21	22	16	17
We also have shown that STZ causes insulin resistance and impairment on phosphoinositide 3-kinase ( PI3K ) activity in the Neuro-2a cells through protein kinase B ( Akt ) inactivation by S nitrosylation , which could upregulate GSK3-beta activity .	We also have shown that STZ causes insulin resistance and impairment on phosphoinositide 3-kinase (PI3K) activity in the Neuro-2a cells through protein kinase B (Akt) inactivation by S nitrosylation, which could upregulate GSK3-beta activity.	21	38	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3-beta	GSK3-beta	GSK3-beta	27	28	37	38
On the other hand , it has been shown that Plexin-B1 inactivates PI3K , dephosphorylates AKT and activates GSK-3beta through R-Ras GAP activity .	On the other hand, it has been shown that Plexin-B1 inactivates PI3K, dephosphorylates AKT and activates GSK-3beta through R-Ras GAP activity.	10	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	Plexin-B1 inactivates PI3K, dephosphorylates AKT	akt	GSK-3beta	GSK-3beta	gsk-3beta	15	16	18	19
Iturin A inhibits Akt mediated GSK3beta and FoxO3a signaling and triggers apoptosis in breast cancer .	Iturin A inhibits Akt mediated GSK3beta and FoxO3a signaling and triggers apoptosis in breast cancer.	2	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	3	4	5	6
The data of XREF_FIG supports the notion that there is constitutive Akt dependent mediation of GSK3beta activity .	The data of XREF_FIG supports the notion that there is constitutive Akt dependent mediation of GSK3beta activity.	11	16	mediation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	11	12	15	16
It has been shown that during glucose deprivation , attenuated PI3K and PKB signals activate GSK3beta , which targets Mcl-1 to the proteasome [ XREF_BIBR , XREF_BIBR ] .	It has been shown that during glucose deprivation, attenuated PI3K and PKB signals activate GSK3beta, which targets Mcl-1 to the proteasome [XREF_BIBR, XREF_BIBR].	10	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKB	PKB	PKB	GSK3beta	GSK3beta	GSK3beta	12	13	15	16
Consequently , PPARgamma PTEN mediated antagonism of AKT may reduce the inhibition of GSK3beta enhancing proteasomal degradation of beta-catenin , in agreement with other reports that have implicated PTEN as a negative regulator of beta-catenin by way of AKT and GSK3beta [ XREF_BIBR ] .	Consequently, PPARgamma PTEN mediated antagonism of AKT may reduce the inhibition of GSK3beta enhancing proteasomal degradation of beta-catenin, in agreement with other reports that have implicated PTEN as a negative regulator of beta-catenin by way of AKT and GSK3beta [XREF_BIBR].	5	14	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	7	8	13	14
Akt activation provides a powerful antiapoptotic signal and also mediates the inactivation of GSK3beta , stabilization of beta-catenin , and subsequent stimulation of beta-catenin-dependent transcription [ XREF_BIBR ] .	Akt activation provides a powerful antiapoptotic signal and also mediates the inactivation of GSK3beta, stabilization of beta-catenin, and subsequent stimulation of beta-catenin-dependent transcription [XREF_BIBR].	0	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	13	14
Sema4D induced down-regulation of R-Ras activity dephosphorylates PI3K and Akt and activates GSK3beta .	Sema4D induced down-regulation of R-Ras activity dephosphorylates PI3K and Akt and activates GSK3beta.	0	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Sema4D induced down-regulation of R-Ras activity dephosphorylates PI3K and Akt	akt	GSK3beta	GSK3beta	gsk3beta	9	10	12	13
Another Akt substrate GSK3beta is negatively modulated by Akt activity .	Another Akt substrate GSK3beta is negatively modulated by Akt activity.	0	9	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	8	9	3	4
However , down-regulation of Akt and DSH proteins by Phyllanthus could cause activation of GSK3beta and degradation of beta-catenin and c-myc .	However, down-regulation of Akt and DSH proteins by Phyllanthus could cause activation of GSK3beta and degradation of beta-catenin and c-myc.	4	16	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	4	5	14	15
37 In addition , overexpression of beta-arrestin-2 increases Akt mediated activation of GSK3beta in endometrial cancer cells .	37 In addition, overexpression of beta-arrestin-2 increases Akt mediated activation of GSK3beta in endometrial cancer cells.	8	16	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	8	9	12	13
We found that obatoclax provoked a time dependent increase of AKT mediated GSK3beta serine 9 phosphorylation ( p-GSK3beta ( S9 ) ) , indicating the inhibition of GSK3beta by obatoclax ( XREF_FIG B , upper three blots ) .	We found that obatoclax provoked a time dependent increase of AKT mediated GSK3beta serine 9 phosphorylation (p-GSK3beta (S9)), indicating the inhibition of GSK3beta by obatoclax (XREF_FIG B, upper three blots).	8	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	10	11	12	13
Reactive oxygen species mediate Cr ( VI )-induced carcinogenesis through PI3K and AKT dependent activation of GSK-3 beta and beta-catenin signaling .	Reactive oxygen species mediate Cr (VI)-induced carcinogenesis through PI3K and AKT dependent activation of GSK-3 beta and beta-catenin signaling.	10	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3 beta	GSK-3 beta	GSK-3 beta	12	13	16	18
Inhibition of Akt ( MK-2206 ) reversed the oxidant induced inactivation of GSK3beta ( XREF_FIG ) .	Inhibition of Akt (MK-2206) reversed the oxidant induced inactivation of GSK3beta (XREF_FIG).	0	14	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	2	3	12	13
Akt is known to directly regulate GSK3beta by phosphorylation of its inhibitory serine residue ( Ser 9 ) .	Akt is known to directly regulate GSK3beta by phosphorylation of its inhibitory serine residue (Ser 9).	0	7	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	6	7
Akt mediates its downstream effects via phosphorylation and inactivation of GSK3beta ser9 , with subsequently decreased phosphorylation of the GSK3beta target beta-catenin , resulting in increased beta-catenin nuclear translocation , binding to T-cell factor , and stimulation of gene expression related to cell proliferation and survival [ XREF_BIBR , XREF_BIBR ] .	Akt mediates its downstream effects via phosphorylation and inactivation of GSK3beta ser9, with subsequently decreased phosphorylation of the GSK3beta target beta-catenin, resulting in increased beta-catenin nuclear translocation, binding to T-cell factor, and stimulation of gene expression related to cell proliferation and survival [XREF_BIBR, XREF_BIBR].	0	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	10	11
Akt activation can sequentially activate the downstream mTOR complex1 ( mTORC1 ) and GSK3beta , both of which play important roles in cancer development .	Akt activation can sequentially activate the downstream mTOR complex1 (mTORC1) and GSK3beta, both of which play important roles in cancer development.	0	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	0	1	13	14
Interestingly , Akt phosphorylation on Ser473 and Thr308 was not altered ( XREF_FIG and D ) , suggesting that GSK-3beta inactivation and mTOR activation were not mediated by Akt .	Interestingly, Akt phosphorylation on Ser473 and Thr308 was not altered (XREF_FIG and D), suggesting that GSK-3beta inactivation and mTOR activation were not mediated by Akt.	19	29	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	28	29	19	20
Activation of AKT leads to phosphorylation and thus inactivation of GSK-3beta .	Activation of AKT leads to phosphorylation and thus inactivation of GSK-3beta.	0	11	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	2	3	10	11
Activation of Akt directly leads to phosphorylation and therefore inactivation of GSK-3beta , en route to unfavorable cardiac remodeling .	Activation of Akt directly leads to phosphorylation and therefore inactivation of GSK-3beta, en route to unfavorable cardiac remodeling.	0	12	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK-3beta	GSK-3beta	GSK-3beta	2	3	11	12
According to these findings , oncogenic signaling pathways related to AKT mediated GSK-3beta inactivation are speculated to be important for SHP2 activation as well as IFN-gamma hyporesponsiveness .	According to these findings, oncogenic signaling pathways related to AKT mediated GSK-3beta inactivation are speculated to be important for SHP2 activation as well as IFN-gamma hyporesponsiveness.	8	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK-3beta	GSK-3beta	GSK-3beta	10	11	12	13
These findings suggest that Akt and GSK-3beta pathway aberrations are a general finding in cells with mTORC1 disrupted by Raptor silencing and that Akt phosphorylation leads to functional activation of Akt and GSK-3beta signaling .	These findings suggest that Akt and GSK-3beta pathway aberrations are a general finding in cells with mTORC1 disrupted by Raptor silencing and that Akt phosphorylation leads to functional activation of Akt and GSK-3beta signaling.	23	33	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt phosphorylation	akt	GSK-3beta	GSK-3beta	gsk-3beta	23	24	32	33
Both the MEK-ERK and AKT pathways also inactivate BIM , an essential molecule for steroid induced cell death , and inhibit GSK3B , an important regulator of proapoptotic BIM .	Both the MEK-ERK and AKT pathways also inactivate BIM, an essential molecule for steroid induced cell death, and inhibit GSK3B, an important regulator of proapoptotic BIM.	4	25	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3B	GSK3B	GSK3B	4	5	21	22
The binding of FGF2 to its receptor ( FGFR1 ) induces several signalling cascades , such as MAPK mediated ERK activation and AKT mediated GSK3beta inactivation , both of which regulate cell survival .	The binding of FGF2 to its receptor (FGFR1) induces several signalling cascades, such as MAPK mediated ERK activation and AKT mediated GSK3beta inactivation, both of which regulate cell survival.	20	25	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	GSK3beta	GSK3beta	GSK3beta	22	23	24	25
The blunted activation of PI3K targets such as Akt and its downstream substrate GSK3beta in insulin perfused CIRKO hearts is consistent with the hypothesis that reduced PI3K signaling could contribute to mitochondrial dysfunction in CIRKO hearts .	The blunted activation of PI3K targets such as Akt and its downstream substrate GSK3beta in insulin perfused CIRKO hearts is consistent with the hypothesis that reduced PI3K signaling could contribute to mitochondrial dysfunction in CIRKO hearts.	2	18	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3beta	GSK3beta	GSK3beta	8	9	13	14
These data demonstrate that activation of AKT , either by PTEN deficiency or by overexpression of constitutively activated AKT , leads to nuclear exclusion of FOXO1 and FOXO3 in VSMC , which was associated with upregulation of Runx2 .	These data demonstrate that activation of AKT, either by PTEN deficiency or by overexpression of constitutively activated AKT, leads to nuclear exclusion of FOXO1 and FOXO3 in VSMC, which was associated with upregulation of Runx2.	14	28	leads	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	AKT	overexpression of constitutively activated AKT	akt	FOXO3	FOXO3	foxo3	18	19	27	28
Though IKKbeta remains active when v-Abl is inhibited ( as evidenced by NF-kappaB activation , see below ) , the loss of inhibitory AKT family phosphorylation may drive existing FoxO3a into the nucleus , resulting in TRAIL upregulation in the absence of a change in FoxO3a protein levels .	Though IKKbeta remains active when v-Abl is inhibited (as evidenced by NF-kappaB activation, see below), the loss of inhibitory AKT family phosphorylation may drive existing FoxO3a into the nucleus, resulting in TRAIL upregulation in the absence of a change in FoxO3a protein levels.	23	30	drive	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT family phosphorylation	akt	FoxO3a	FoxO3a	foxo3a	23	24	29	30
In this setting , PIM1 activated pPRAS40 , AKT activated pFOXO3a , and their complex formation with 14-3-3 could be key regulators of the radiation induced radioresistance in NSCLC cells .	In this setting, PIM1 activated pPRAS40, AKT activated pFOXO3a, and their complex formation with 14-3-3 could be key regulators of the radiation induced radioresistance in NSCLC cells.	8	11	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	pFOXO3a	pFOXO3a	pFOXO3a	8	9	10	11
In addition , AKT was able to increase the steady-state protein levels of both , the P34A mutant and wildtype FoxO3 ( XREF_FIG , HA- blot , compare lane 1 with 2 and lane 4 with 5 ) , while 14-3-3 affected wildtype FoxO3 but not the P34A mutant ( XREF_FIG , HA-blot , compare lane 1 with 3 and lane 4 with 6 ) .	In addition, AKT was able to increase the steady-state protein levels of both, the P34A mutant and wildtype FoxO3 (XREF_FIG, HA- blot, compare lane 1 with 2 and lane 4 with 5), while 14-3-3 affected wildtype FoxO3 but not the P34A mutant (XREF_FIG, HA-blot, compare lane 1 with 3 and lane 4 with 6).	3	48	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FoxO3	FoxO3	FoxO3	3	4	43	44
Overall these results demonstrate that productive HTLV-1 infection provides a survival and proliferative persistence advantage to infected CD4 + T cells , and is associated with AKT mediated inactivation of FOXO3a transcriptional activity .	Overall these results demonstrate that productive HTLV-1 infection provides a survival and proliferative persistence advantage to infected CD4 + T cells, and is associated with AKT mediated inactivation of FOXO3a transcriptional activity.	24	32	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	26	27	30	31
Collectively , these results demonstrate that Tax expression enhanced T cell longevity and activation , through the inhibition of FOXO3a transcriptional activity , mediated by AKT phosphorylation at S253 and Thr32 residues .	Collectively, these results demonstrate that Tax expression enhanced T cell longevity and activation, through the inhibition of FOXO3a transcriptional activity, mediated by AKT phosphorylation at S253 and Thr32 residues.	19	29	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT phosphorylation at S253	akt	FOXO3a	FOXO3a	foxo3a	25	26	19	20
Previous studies showed that treatment with the non steroidal anti-inflammatory drug sulindac sulfide reverses the PI3K and Akt mediated cytoplasmic accumulation of FoxO3a and restores its transcriptional activity in FRTL-5 cells [ XREF_BIBR ] ; The aforementioned results indicated that the activity of FRTL-5 cells was involved in the PI3K/Akt/FoxO3a pathway .	Previous studies showed that treatment with the non steroidal anti-inflammatory drug sulindac sulfide reverses the PI3K and Akt mediated cytoplasmic accumulation of FoxO3a and restores its transcriptional activity in FRTL-5 cells [XREF_BIBR]; The aforementioned results indicated that the activity of FRTL-5 cells was involved in the PI3K/Akt/FoxO3a pathway.	15	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	17	18	22	23
In Dex induced muscle atrophy , miR-1 overexpression suppresses HSP70 protein expression and reduces Akt phosphorylation , which enhances FoxO3 activation XREF_BIBR .	In Dex induced muscle atrophy, miR-1 overexpression suppresses HSP70 protein expression and reduces Akt phosphorylation, which enhances FoxO3 activation XREF_BIBR.	6	21	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	miR-1 overexpression suppresses HSP70 protein expression and reduces Akt phosphorylation	akt	FoxO3	FoxO3	foxo3	14	15	19	20
Our study revealed that alphaMSH could blunt the phosphorylation of Akt and JNK and specifically , Akt phosphorylation activates Foxo1 and Foxo3a , while JNK phosphorylation stimulates Foxo4 .	Our study revealed that alphaMSH could blunt the phosphorylation of Akt and JNK and specifically, Akt phosphorylation activates Foxo1 and Foxo3a, while JNK phosphorylation stimulates Foxo4.	16	22	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt phosphorylation	akt	Foxo3a	Foxo3a	foxo3a	16	17	21	22
In summary , these results indicate that the down-regulation of MIR2052HG can reduce ESR1 mRNA levels by promoting AKT mediated down-regulation of FOXO3 , which regulates ESR1 transcription .	In summary, these results indicate that the down-regulation of MIR2052HG can reduce ESR1 mRNA levels by promoting AKT mediated down-regulation of FOXO3, which regulates ESR1 transcription.	18	28	mediated	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	AKT	AKT	akt	FOXO3	FOXO3, which regulates ESR1 transcription	foxo3	18	19	22	23
Western blot analyses revealed that clozapine induced the phosphorylation of Akt and FoxO3a by the PI3K and Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a and the nuclear translocation of FoxO3a evoked by corticosterone .	Western blot analyses revealed that clozapine induced the phosphorylation of Akt and FoxO3a by the PI3K and Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a and the nuclear translocation of FoxO3a evoked by corticosterone.	5	35	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	clozapine induced the phosphorylation of Akt	akt	FoxO3a	FoxO3a	foxo3a	10	11	34	35
Consequently , pPRAS40 made a trimeric complex with 14-3-3 and AKT activated pFOXO3a , which then moved rapidly to the cytoplasm .	Consequently, pPRAS40 made a trimeric complex with 14-3-3 and AKT activated pFOXO3a, which then moved rapidly to the cytoplasm.	6	16	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	pFOXO3a	pFOXO3a	pFOXO3a	10	11	12	13
Following its recruitment to SHPS-1 , PDK1 was further activated via Tyr ( 373/376 ) phosphorylation , and this was required for a maximal increase in PDK1 kinase activity and AKT mediated FOXO3a Thr ( 32 ) phosphorylation .	Following its recruitment to SHPS-1, PDK1 was further activated via Tyr (373/376) phosphorylation, and this was required for a maximal increase in PDK1 kinase activity and AKT mediated FOXO3a Thr (32) phosphorylation.	24	33	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	30	31	32	33
Upregulation of FOXO3a and Par-4 were seen in WA treated tumors , suggesting abolition of AKT mediated signaling and reversion of the pro apoptotic function of the FOXO3a and Par-4 signaling axis in prostate cancer .	Upregulation of FOXO3a and Par-4 were seen in WA treated tumors, suggesting abolition of AKT mediated signaling and reversion of the pro apoptotic function of the FOXO3a and Par-4 signaling axis in prostate cancer.	13	31	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	15	16	27	28
Recent studies have found that transient downregulation of Akt signaling and activation of FOXO3a is required for mitotic progression in NIH 3T3 cells [ XREF_BIBR ] .	Recent studies have found that transient downregulation of Akt signaling and activation of FOXO3a is required for mitotic progression in NIH 3T3 cells [XREF_BIBR].	8	14	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	8	9	13	14
Further experiments demonstrated that Akt mediated FoxO3a ( forkhead box O3a ) nuclear translocation and the JNK ( c-Jun N-terminal kinase )/c-Jun pathway only partially trigger Puma induction and apoptosis , whereas dominant negative c-Jun expression with FoxO3a reduction completely inhibits Puma expression and cell death .	Further experiments demonstrated that Akt mediated FoxO3a (forkhead box O3a) nuclear translocation and the JNK (c-Jun N-terminal kinase)/c-Jun pathway only partially trigger Puma induction and apoptosis, whereas dominant negative c-Jun expression with FoxO3a reduction completely inhibits Puma expression and cell death.	4	25	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	4	5	6	7
Similarly , IkappaB kinase ( IKK ) and Akt ( PKB ) phosphorylate and cause proteolysis of FoxO3a [ XREF_BIBR , XREF_BIBR ] .	Similarly, IkappaB kinase (IKK) and Akt (PKB) phosphorylate and cause proteolysis of FoxO3a [XREF_BIBR, XREF_BIBR].	3	21	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	8	9	17	18
Collectively , our data support a model where both AKT and 14-3-3 positively regulate FoxO3 in addition to their established negative roles and that 14-3-3 availability could dictate the fate of phosphorylated FoxO3 toward degradation or recycling .	Collectively, our data support a model where both AKT and 14-3-3 positively regulate FoxO3 in addition to their established negative roles and that 14-3-3 availability could dictate the fate of phosphorylated FoxO3 toward degradation or recycling.	8	16	positively regulate	Positive_activation_syntax_1b_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FoxO3	FoxO3	FoxO3	9	10	14	15
Blockade of sPD-L1 secreted by the MSCs was able to partially restore levels of AKT phosphorylation and completely suppress the FOXO3 upregulation seen , back to that of control levels .	Blockade of sPD-L1 secreted by the MSCs was able to partially restore levels of AKT phosphorylation and completely suppress the FOXO3 upregulation seen, back to that of control levels.	2	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	sPD-L1 secreted by the MSCs was able to partially restore levels of AKT phosphorylation	akt	FOXO3	FOXO3	foxo3	14	15	20	21
One explanation for PKB hyperactivation might be that T-ALL cells frequently carry a heterozygous deletion of the PTEN gene locus [ XREF_BIBR ] , which leads to increased PI3K-PKB signaling and thereby inactivation of the PKB target FOXO3 in leukemia cells .	One explanation for PKB hyperactivation might be that T-ALL cells frequently carry a heterozygous deletion of the PTEN gene locus [XREF_BIBR], which leads to increased PI3K-PKB signaling and thereby inactivation of the PKB target FOXO3 in leukemia cells.	32	40	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PKB	PKB	PKB	FOXO3	FOXO3	FOXO3	35	36	37	38
In this study , overexpression of ALDH2 was associated with a suppression of phosphatase activity which leads to enhanced Akt and AMP activated protein kinase activities and regulation of their downstream targets Foxo3 transcription factor and caspase-3 .	In this study, overexpression of ALDH2 was associated with a suppression of phosphatase activity which leads to enhanced Akt and AMP activated protein kinase activities and regulation of their downstream targets Foxo3 transcription factor and caspase-3.	16	34	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo3	Foxo3	Foxo3	19	20	32	33
The combination of FW-04-806 and lapatinib showed synergistic reduction of HER2 expression and the downstream PI3K and Akt and Ras/MEK/ERK pathways , enhanced suppression of Akt mediated FOXO3a inactivation and augmented antitumor efficacy on SKBR3 xenografts with a favorable toxicity profile , suggesting its viability as a combination therapy for clinical studies in HER2+ breast cancer patients .	The combination of FW-04-806 and lapatinib showed synergistic reduction of HER2 expression and the downstream PI3K and Akt and Ras/MEK/ERK pathways, enhanced suppression of Akt mediated FOXO3a inactivation and augmented antitumor efficacy on SKBR3 xenografts with a favorable toxicity profile, suggesting its viability as a combination therapy for clinical studies in HER2+ breast cancer patients.	23	28	mediated	Positive_early_activation	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	25	26	27	28
In addition , AKT induced FoxO3a inactivation under TGFbeta stimulation caused mesangial cell survival XREF_BIBR .	In addition, AKT induced FoxO3a inactivation under TGFbeta stimulation caused mesangial cell survival XREF_BIBR.	3	6	induced	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	FoxO3a	FoxO3a	FoxO3a	3	4	5	6
First , Akt promotes nuclear exclusion of Foxo3a through direct phosphorylation at three consensus sites ( 32 Thr , 253 Ser , and 315 Ser ) , or via phosphorylation by its downstream effector IKKbeta .	First, Akt promotes nuclear exclusion of Foxo3a through direct phosphorylation at three consensus sites (32 Thr, 253 Ser, and 315 Ser), or via phosphorylation by its downstream effector IKKbeta.	2	29	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	2	3	7	8
Akt triggers inactivation and degradation of the FOXO transcription factors FoxO1 and FoxO3 , which are important for Treg suppressor function [ XREF_BIBR ] .	Akt triggers inactivation and degradation of the FOXO transcription factors FoxO1 and FoxO3, which are important for Treg suppressor function [XREF_BIBR].	0	16	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	0	1	12	13
Thus , hyperactivation of Akt in tumors relieves FoxO3a mediated repression of FoxM1 and propagates a tumorigenic phenotype .	Thus, hyperactivation of Akt in tumors relieves FoxO3a mediated repression of FoxM1 and propagates a tumorigenic phenotype.	2	10	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	4	5	8	9
Lapatinib induced inhibition of activated Akt enabled derepression of the transcription factor FOXO3a , which promotes ER signaling .	Lapatinib induced inhibition of activated Akt enabled derepression of the transcription factor FOXO3a, which promotes ER signaling.	2	15	enabled	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	5	6	12	13
PI3K-AKT signaling network ( XREF_FIG ) showed alterations of upstream regulators ( collagens , laminins , and integrins ) and signaling molecules ( PTEN , RAC , MAPK , and MTOR ) and downstream TFs ( FOXO3 and RBL2 ) .	PI3K-AKT signaling network (XREF_FIG) showed alterations of upstream regulators (collagens, laminins, and integrins) and signaling molecules (PTEN, RAC, MAPK, and MTOR) and downstream TFs (FOXO3 and RBL2).	0	38	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO3	FOXO3	FOXO3	0	1	36	37
Upon dephosphorylation by Akt , FOXO3a is activated and imports into the nucleus from cytoplasm , thereby preventing cell proliferation .	Upon dephosphorylation by Akt, FOXO3a is activated and imports into the nucleus from cytoplasm, thereby preventing cell proliferation.	1	8	activated	Positive_activation_syntax_4_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	3	4	5	6
Furthermore , TGF-beta is also shown to be a critical regulator of AKT activation in LSCs and control FOXO3a localization .	Furthermore, TGF-beta is also shown to be a critical regulator of AKT activation in LSCs and control FOXO3a localization.	12	19	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	12	13	18	19
Western blot analyses showed that venlafaxine induced the phosphorylation of Akt and FoxO3a by the PI3K and Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a , and the nuclear translocation of Foxo3a induced by corticosterone .	Western blot analyses showed that venlafaxine induced the phosphorylation of Akt and FoxO3a by the PI3K and Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a, and the nuclear translocation of Foxo3a induced by corticosterone.	5	29	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	venlafaxine induced the phosphorylation of Akt	akt	FoxO3a	FoxO3a	foxo3a	10	11	28	29
Since Akt activation is known to mediate cell survival via phosphorylation and inactivation of downstream proteins ( FoxO1 and FoxO3a ) , we estimated the phosphorylation status of FoxO1 and FoxO3a proteins following treatment with TRG in both serum containing and serum deprived media .	Since Akt activation is known to mediate cell survival via phosphorylation and inactivation of downstream proteins (FoxO1 and FoxO3a), we estimated the phosphorylation status of FoxO1 and FoxO3a proteins following treatment with TRG in both serum containing and serum deprived media.	1	20	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	1	2	19	20
Our lab has recently demonstrated that knockdown of either rictor or mSIN1 , two key structural components of mTORC2 , sensitizes keratinocytes to UVB induced apoptosis , and that this effect is dependent on AKT mediated FOXO3a regulation [ XREF_BIBR ] .	Our lab has recently demonstrated that knockdown of either rictor or mSIN1, two key structural components of mTORC2, sensitizes keratinocytes to UVB induced apoptosis, and that this effect is dependent on AKT mediated FOXO3a regulation [XREF_BIBR].	32	37	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	34	35	36	37
These authors proposed a model by which miR-1 inhibits the expression of HSP70 ( heat shock protein 70 ) protein , thereby reducing AKT phosphorylation and enhancing the activation of FOXO3 and atrophy related proteins .	These authors proposed a model by which miR-1 inhibits the expression of HSP70 (heat shock protein 70) protein, thereby reducing AKT phosphorylation and enhancing the activation of FOXO3 and atrophy related proteins.	12	32	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	HSP70 (heat shock protein 70) protein, thereby reducing AKT phosphorylation	akt	FOXO3	FOXO3	foxo3	23	24	30	31
In vitro , we found that stimulation with SS reversed PI3K and Akt driven inactivation of FOXO3 , resulting in its nuclear relocation and a combined induction of the antiproliferative FOXO target genes Gadd45alpha and p27 ( kip1 ) and the proapoptotic FOXO target gene Bim in benign ( FRTL-5 ) and malignant human thyrocytes ( FTC-133 ) .	In vitro, we found that stimulation with SS reversed PI3K and Akt driven inactivation of FOXO3, resulting in its nuclear relocation and a combined induction of the antiproliferative FOXO target genes Gadd45alpha and p27 (kip1) and the proapoptotic FOXO target gene Bim in benign (FRTL-5) and malignant human thyrocytes (FTC-133).	9	17	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO3	FOXO3	FOXO3	12	13	16	17
Skeletal muscle atrophy in these mice is initiated by the Akt pathway which suppresses protein synthesis and induces FoxO3 mediated expression of atrogenes ( e.g ., atrogin1 and MuRF1 ) .	Skeletal muscle atrophy in these mice is initiated by the Akt pathway which suppresses protein synthesis and induces FoxO3 mediated expression of atrogenes (e.g., atrogin1 and MuRF1).	10	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	10	11	18	19
Our data show that AKT overexpression increases the steady-state levels of FoxO3 protein in a manner dependent on AKT activity and its ability to bind FoxO3 .	Our data show that AKT overexpression increases the steady-state levels of FoxO3 protein in a manner dependent on AKT activity and its ability to bind FoxO3.	4	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT overexpression	akt	FoxO3	FoxO3	foxo3	4	5	11	12
In particular , SSc serum induced EPC apoptosis through the inhibition of Akt phosphorylation , which prevented FOXO3a degradation with consequent up-regulation of the pro apoptotic protein Bim [ XREF_BIBR ] .	In particular, SSc serum induced EPC apoptosis through the inhibition of Akt phosphorylation, which prevented FOXO3a degradation with consequent up-regulation of the pro apoptotic protein Bim [XREF_BIBR].	12	18	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	FOXO3a	FOXO3a	foxo3a	12	13	17	18
In the nucleus , FoxO3a can be dephosphorylated by PP2A , both at Akt and MST-1 sites , and Akt mediated re-phosphorylation could exclude FoxO3a from the nucleus .	In the nucleus, FoxO3a can be dephosphorylated by PP2A, both at Akt and MST-1 sites, and Akt mediated re-phosphorylation could exclude FoxO3a from the nucleus.	19	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	19	20	24	25
To further study survival signaling by NPMALK , we generated Ba/F3 cell lines with either inducible or constitutive expression of NPM-ALK and examined the regulation of the AKT target FOXO3a .	To further study survival signaling by NPMALK, we generated Ba/F3 cell lines with either inducible or constitutive expression of NPM-ALK and examined the regulation of the AKT target FOXO3a.	24	30	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	27	28	29	30
Expression of a dominant negative Akt in PC-3 cells induced FOXO3A nuclear accumulation and up regulation of MnSOD , a downstream target of FOXO3a .	Expression of a dominant negative Akt in PC-3 cells induced FOXO3A nuclear accumulation and up regulation of MnSOD, a downstream target of FOXO3a.	0	24	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Expression of a dominant negative Akt	akt	FOXO3a	FOXO3a	foxo3a	5	6	23	24
As expected , a constitutively active version of the protein kinase Akt significantly increased the cyto-plasmic localization of FoxO3-GFP .	As expected, a constitutively active version of the protein kinase Akt significantly increased the cyto-plasmic localization of FoxO3-GFP.	6	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3-GFP	FoxO3-GFP	FoxO3-GFP	11	12	18	19
XREF_BIBR A retrospective analysis demonstrated that the BRCA1 locus product , BRCA1-IRIS , silencing or inactivation using a novel inhibitory mimetic peptide could sensitize TNBC cells to low paclitaxel concentrations in vitro and in vivo , through inactivating two autocrine signaling loops involving EGFR-1 and EGFR3 that regulated AKT causing survivin degradation and Fork head box O3a ( FOXO3a ) upregulation .	XREF_BIBR A retrospective analysis demonstrated that the BRCA1 locus product, BRCA1-IRIS, silencing or inactivation using a novel inhibitory mimetic peptide could sensitize TNBC cells to low paclitaxel concentrations in vitro and in vivo, through inactivating two autocrine signaling loops involving EGFR-1 and EGFR3 that regulated AKT causing survivin degradation and Fork head box O3a (FOXO3a) upregulation.	47	60	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	48	49	58	59
Furthermore , repression of phosphor-PI3K and Akt could inhibit the localization of the FoxO3 and Smad4 transcription factor complex from the cytoplasm to the nucleus and then deactivate the Smad2/3 dependent signalling pathway [ XREF_BIBR ] , the activation of which has been proven responsible for the EndMT process of EPCs [ XREF_BIBR ] .	Furthermore, repression of phosphor-PI3K and Akt could inhibit the localization of the FoxO3 and Smad4 transcription factor complex from the cytoplasm to the nucleus and then deactivate the Smad2/3 dependent signalling pathway [XREF_BIBR], the activation of which has been proven responsible for the EndMT process of EPCs [XREF_BIBR].	2	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3	FoxO3	FoxO3	6	7	13	14
It must be noted that the same signal can theoretically cause cell and protein loss , as Akt can mediate the effects of FoxO3a on different events , such as autophagy and protein catabolism .	It must be noted that the same signal can theoretically cause cell and protein loss, as Akt can mediate the effects of FoxO3a on different events, such as autophagy and protein catabolism.	17	33	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	17	18	23	24
XREF_FIG , knockdown of Akt or FOXO3a gene expression by siRNA decreased the level of Akt and FOXO3a protein to 10.59 +/-0.55 and 14.51 +/-1.13 % , respectively , compared to control cells .	XREF_FIG, knockdown of Akt or FOXO3a gene expression by siRNA decreased the level of Akt and FOXO3a protein to 10.59 +/-0.55 and 14.51 +/-1.13%, respectively, compared to control cells.	4	18	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt or FOXO3a gene expression	akt	FOXO3a	FOXO3a	foxo3a	4	5	17	18
Mechanistically , based on current and our previous work on BC cells , 28 CCN5 interacts with integrin alpha6beta1 to suppress the PI3K and Akt signaling which then activates FOXO3a .	Mechanistically, based on current and our previous work on BC cells, 28 CCN5 interacts with integrin alpha6beta1 to suppress the PI3K and Akt signaling which then activates FOXO3a.	22	30	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	24	25	29	30
To determine whether the hyperphosphorylated form of Akt causes deregulation of FOXO3A , we undertook pharmacological and genetic approaches using PC-3 cells .	To determine whether the hyperphosphorylated form of Akt causes deregulation of FOXO3A, we undertook pharmacological and genetic approaches using PC-3 cells.	5	12	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO3A	FOXO3A	FOXO3A	7	8	11	12
XREF_BIBR , XREF_BIBR Here , we demonstrate that AKT activation inhibits the pro apoptotic function of Par-4 by suppressing FOXO3a activation in CRPC cells .	XREF_BIBR, XREF_BIBR Here, we demonstrate that AKT activation inhibits the pro apoptotic function of Par-4 by suppressing FOXO3a activation in CRPC cells.	8	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	8	9	19	20
Our data revealed that the protective effect of ZP2495 was related to FoxO3a activation mediated by the PI3K and Akt and AMPK pathways .	Our data revealed that the protective effect of ZP2495 was related to FoxO3a activation mediated by the PI3K and Akt and AMPK pathways.	12	20	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	19	20	12	13
Further reports have shown that under conditions of cytokine deprivation mediated cellular stress , AKT mediated activation of FOXO3A and subsequent transcriptional regulation by FOXO3A leads to cell cycle arrest and apoptosis XREF_BIBR , XREF_BIBR .	Further reports have shown that under conditions of cytokine deprivation mediated cellular stress, AKT mediated activation of FOXO3A and subsequent transcriptional regulation by FOXO3A leads to cell cycle arrest and apoptosis XREF_BIBR, XREF_BIBR.	14	19	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3A	FOXO3A	FOXO3A	14	15	18	19
All the aforesaid observations establish that CK2 is significantly responsible for AKT mediated inactivation of FOXO3a , and its subsequent nuclear expulsion through a revoked PML-PHLPP2 association .	All the aforesaid observations establish that CK2 is significantly responsible for AKT mediated inactivation of FOXO3a, and its subsequent nuclear expulsion through a revoked PML-PHLPP2 association.	11	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	11	12	15	16
FoxO3 activity is induced by the PI3K and AKT signaling cascade and inhibited by PGC-1alpha [ XREF_BIBR ; XREF_BIBR ; XREF_BIBR ] .	FoxO3 activity is induced by the PI3K and AKT signaling cascade and inhibited by PGC-1alpha [XREF_BIBR; XREF_BIBR; XREF_BIBR].	0	10	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FoxO3	FoxO3	FoxO3	8	9	0	1
In solid tumors , ONC201 caused late-stage induction of tumor necrosis factor related apoptosis inducing ligand ( TRAIL ) death receptor 5 ( DR5 ) and promoted the transcription of the TRAIL gene , the latter through activation of the transcription factor FOXO3a caused by late-stage inactivation of signaling by the kinases AKT and MAPK ( mitogen activated protein kinase ) .	In solid tumors, ONC201 caused late-stage induction of tumor necrosis factor related apoptosis inducing ligand (TRAIL) death receptor 5 (DR5) and promoted the transcription of the TRAIL gene, the latter through activation of the transcription factor FOXO3a caused by late-stage inactivation of signaling by the kinases AKT and MAPK (mitogen activated protein kinase).	37	56	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	52	53	42	43
The associated inactivation of Akt leads to the dephosphorylation and activation of the Akt targeted transcription factor FoxO3 .	The associated inactivation of Akt leads to the dephosphorylation and activation of the Akt targeted transcription factor FoxO3.	8	18	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	dephosphorylation and activation of the Akt	akt	FoxO3	FoxO3	foxo3	13	14	17	18
FOXO3a biological activity is mainly modulated via inhibitory phosphorylation by the PI3K and AKT and MEK and ERK pathways .	FOXO3a biological activity is mainly modulated via inhibitory phosphorylation by the PI3K and AKT and MEK and ERK pathways.	0	14	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	13	14	0	1
Our data indicated that the basal level of AKT was unable to phosphorylate FOXO3a or induce FOXO3a nuclear exclusion ( XREF_FIG ) .	Our data indicated that the basal level of AKT was unable to phosphorylate FOXO3a or induce FOXO3a nuclear exclusion (XREF_FIG).	6	18	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	level of AKT	akt	FOXO3a	FOXO3a	foxo3a	8	9	16	17
Chronic receptor activation results in the inhibition of the PI3K-AKT signaling pathway , which in turn activates the transcription factor FOXO3A , leading to the cell cycle arrest .	Chronic receptor activation results in the inhibition of the PI3K-AKT signaling pathway, which in turn activates the transcription factor FOXO3A, leading to the cell cycle arrest.	9	21	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO3A	FOXO3A	FOXO3A	9	10	20	21
Our data revealed that high glucose stimulates ROS accumulation and inhibits Akt which subsequently activated FoxO3a .	Our data revealed that high glucose stimulates ROS accumulation and inhibits Akt which subsequently activated FoxO3a.	10	16	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	11	12	15	16
As mention above , Akt activation induces binding of FoxO3a and 14-3-3 , which can affect the function of proapoptotic protein producing transcription factors such as Bim .	As mention above, Akt activation induces binding of FoxO3a and 14-3-3, which can affect the function of proapoptotic protein producing transcription factors such as Bim.	4	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	4	5	9	10
For instance , miR205 upregulates AKT dependent activation of FOXO3a in lung cancer cell via suppressing PTEN [ XREF_BIBR ] .	For instance, miR205 upregulates AKT dependent activation of FOXO3a in lung cancer cell via suppressing PTEN [XREF_BIBR].	5	13	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	5	6	9	10
Mechanistically , PI3K and Akt signaling mediated the NF-kappaB , FOXO3a , and p53 pathways .	Mechanistically, PI3K and Akt signaling mediated the NF-kappaB, FOXO3a, and p53 pathways.	2	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO3a	FOXO3a	FOXO3a	4	5	10	11
Other studies demonstrated that activated AKT induced FOXO3a accumulation in the cytoplasm from nucleus , whereas inhibition of AKT resulted in FOXO3a accumulation in the nucleus [ XREF_BIBR , XREF_BIBR ] .	Other studies demonstrated that activated AKT induced FOXO3a accumulation in the cytoplasm from nucleus, whereas inhibition of AKT resulted in FOXO3a accumulation in the nucleus [XREF_BIBR, XREF_BIBR].	4	8	induced	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	5	6	7	8
In summary , these studies demonstrate that UVB irradiation promotes the mTORC2 dependent cytoplasmic sequestration of FOXO3a , which is mediated by AKT .	In summary, these studies demonstrate that UVB irradiation promotes the mTORC2 dependent cytoplasmic sequestration of FOXO3a, which is mediated by AKT.	14	23	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	22	23	16	17
De novo HTLV-1 infection of CD4 + T cells or direct lentiviral mediated introduction of Tax led to AKT activation and AKT dependent inactivation of FOXO3a , via phosphorylation of residues Ser253 and Thr32 .	De novo HTLV-1 infection of CD4 + T cells or direct lentiviral mediated introduction of Tax led to AKT activation and AKT dependent inactivation of FOXO3a, via phosphorylation of residues Ser253 and Thr32.	18	26	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	18	19	25	26
Akt directly regulates the functions of FoxO3a through phosphorylation , leading to its accumulation in the cytoplasm .	Akt directly regulates the functions of FoxO3a through phosphorylation, leading to its accumulation in the cytoplasm.	0	7	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO3a	FoxO3a	FoxO3a	0	1	6	7
Moreover , Mst1 also inhibits Akt activation [ XREF_BIBR ] and prevents Akt mediated destabilization of Foxo1 and Foxo3 [ XREF_BIBR ] .	Moreover, Mst1 also inhibits Akt activation [XREF_BIBR] and prevents Akt mediated destabilization of Foxo1 and Foxo3 [XREF_BIBR].	11	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo3	Foxo3	Foxo3	12	13	18	19
Finally , adenoviral mediated expression of dominant negative AKT activated FKHRL1 and induced expression of Bim .	Finally, adenoviral mediated expression of dominant negative AKT activated FKHRL1 and induced expression of Bim.	4	11	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	expression of dominant negative AKT	akt	FKHRL1	FKHRL1	fkhrl1	8	9	10	11
In addition to mTOR pathway , the PI3K and AKT signaling also targeted the FOXO3a and p27kip1 pathway to suppress proliferation and induce cell cycle arrest [ XREF_BIBR ] .	In addition to mTOR pathway, the PI3K and AKT signaling also targeted the FOXO3a and p27kip1 pathway to suppress proliferation and induce cell cycle arrest [XREF_BIBR].	7	17	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3a	FOXO3a	FOXO3a	9	10	14	15
AKT activation upregulates the GATA-1 and FOXO3 transcriptional pathways with resulting inhibition of apoptosis , modulation of cell cycle and enhanced maturation of erythroid cells .	AKT activation upregulates the GATA-1 and FOXO3 transcriptional pathways with resulting inhibition of apoptosis, modulation of cell cycle and enhanced maturation of erythroid cells.	0	8	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO3	FOXO3	FOXO3	0	1	6	7
Furthermore , we find that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization .	Furthermore, we find that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization.	11	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo3a	Foxo3a	Foxo3a	11	12	17	18
Insulin and Akt promotes FoxO1 nuclear exclusion through phosphorylation of T24 , S253 , and S316 ( murine residues ) .	Insulin and Akt promotes FoxO1 nuclear exclusion through phosphorylation of T24, S253, and S316 (murine residues).	0	6	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	2	3	4	5
Although , the expression of insulin receptor was completely blocked , FoxO1 was translocated from the nucleus to the cytoplasm with the RGZ treatment , and thus it seems that there may be a direct mechanism in PPAR-gamma-induced FoxO1 nuclear exclusion rather than PI3K-Akt pathway mediated FoxO1 shuttling .	Although, the expression of insulin receptor was completely blocked, FoxO1 was translocated from the nucleus to the cytoplasm with the RGZ treatment, and thus it seems that there may be a direct mechanism in PPAR-gamma-induced FoxO1 nuclear exclusion rather than PI3K-Akt pathway mediated FoxO1 shuttling.	43	47	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FoxO1	FoxO1	FoxO1	43	44	46	47
The AKT target FOXO1 is reported to function primarily as a repressor of FSH genes , including Ccnd2 and Inha .	The AKT target FOXO1 is reported to function primarily as a repressor of FSH genes, including Ccnd2 and Inha.	0	7	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	1	2	3	4
XREF_BIBR In cell models of endometrial cancer , presensitization of cells to block Akt activation and foster transcription activity of FoxO1 enhances the effect of chemotherapy to limit tumor growth .	XREF_BIBR In cell models of endometrial cancer, presensitization of cells to block Akt activation and foster transcription activity of FoxO1 enhances the effect of chemotherapy to limit tumor growth.	13	21	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	13	14	20	21
The present study was designed to understand the role of Akt mediation of FOXO1A in response to Trastuzumab treatment and mechanisms of Trastuzumab actions in inhibiting the HER2 receptors and their downstream events .	The present study was designed to understand the role of Akt mediation of FOXO1A in response to Trastuzumab treatment and mechanisms of Trastuzumab actions in inhibiting the HER2 receptors and their downstream events.	10	20	mediation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO1A	FOXO1A	FOXO1A	10	11	13	14
Taken together with the data on Akt targeted FoxO1 and reversion results , the findings place Akt and PKC functions downstream from mTORC2 in T cells .	Taken together with the data on Akt targeted FoxO1 and reversion results, the findings place Akt and PKC functions downstream from mTORC2 in T cells.	4	11	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	6	7	8	9
Akt is known to trigger inactivation and degradation of the transcription factors Forkhead box O3 ( FoxO3 ) and FoxO1 [ XREF_BIBR ] , both of which are important for Treg function [ XREF_BIBR ] .	Akt is known to trigger inactivation and degradation of the transcription factors Forkhead box O3 (FoxO3) and FoxO1 [XREF_BIBR], both of which are important for Treg function [XREF_BIBR].	0	21	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	0	1	19	20
In contrast , Akt which is known to negatively regulate FOXO1 did not have a significant effect on RANKL induced FOXO1 nuclear localization two days after stimulation .	In contrast, Akt which is known to negatively regulate FOXO1 did not have a significant effect on RANKL induced FOXO1 nuclear localization two days after stimulation.	3	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	3	4	20	21
The PI3K and Akt pathway activates mTOR and forkhead box protein O1 ( FOXO1 ) and the MAPK and ERK cascade .	The PI3K and Akt pathway activates mTOR and forkhead box protein O1 (FOXO1) and the MAPK and ERK cascade.	1	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	forkhead box protein O1	forkhead box protein O1	forkhead box protein O1	3	4	8	12
A large amount of evidence suggests that inactivation of Akt and subsequent activation of the forkhead and winged helix family transcription factor Foxo1 , through suppression IRS1 and IRS2 in organs following hyperinsulinemia , metabolic inflammation , and over nutrition , may provide key mechanisms for the metabolic syndrome in humans .	A large amount of evidence suggests that inactivation of Akt and subsequent activation of the forkhead and winged helix family transcription factor Foxo1, through suppression IRS1 and IRS2 in organs following hyperinsulinemia, metabolic inflammation, and over nutrition, may provide key mechanisms for the metabolic syndrome in humans.	9	23	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	9	10	22	23
We further identify that AKT negatively regulates IL-9 induction in Th9 and Th17 cells by inhibiting Foxo1 functions .	We further identify that AKT negatively regulates IL-9 induction in Th9 and Th17 cells by inhibiting Foxo1 functions.	4	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Foxo1	Foxo1	Foxo1	4	5	16	17
siRNA mediated knockdown in HeLa and MCF7 cells showed that RICTOR-mTOR was required for phosphorylation of AKT Ser473 , and for efficient phosphorylation of the downstream AKT targets FOXO1 Thr24 and BAD Ser136 , in response to beta1 integrin stimulation .	siRNA mediated knockdown in HeLa and MCF7 cells showed that RICTOR-mTOR was required for phosphorylation of AKT Ser473, and for efficient phosphorylation of the downstream AKT targets FOXO1 Thr24 and BAD Ser136, in response to beta1 integrin stimulation.	26	29	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	26	27	28	29
Insulin stimulates activating phosphorylation events on Akt leading to subsequent phosphorylation of the Akt targets FOXO1 , FOXO3a , and TSC2 , the latter target of which leads to mTORC1 activation and phosphorylation of S6K1 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Insulin stimulates activating phosphorylation events on Akt leading to subsequent phosphorylation of the Akt targets FOXO1, FOXO3a, and TSC2, the latter target of which leads to mTORC1 activation and phosphorylation of S6K1 (XREF_FIG and XREF_SUPPLEMENTARY).	10	24	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	phosphorylation of the Akt	akt	FOXO1	FOXO1	foxo1	13	14	15	16
Interestingly , PTEN knockdown increased phosphorylation of Akt ( 2.4-2.6 ) and Foxo1 ( 2.6-2.8 ) , but diminished nuclear total Foxo1 ( 0.2-0.4 ) , compared with untreated or scramble siRNA treated WT controls ( 0.3-0.5 and 0.5-0.9 , 1.9-2.0 , respectively ) .	Interestingly, PTEN knockdown increased phosphorylation of Akt (2.4-2.6) and Foxo1 (2.6-2.8), but diminished nuclear total Foxo1 (0.2-0.4), compared with untreated or scramble siRNA treated WT controls (0.3-0.5 and 0.5-0.9, 1.9-2.0, respectively).	2	31	diminished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	PTEN knockdown increased phosphorylation of Akt	akt	Foxo1	Foxo1	foxo1	7	8	21	22
Thus , activation of PI3K and Akt appears to promote nuclear excursion of FoxO1 , thereby increasing the expression levels of these genes .	Thus, activation of PI3K and Akt appears to promote nuclear excursion of FoxO1, thereby increasing the expression levels of these genes.	2	14	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	6	7	13	14
The anti-adipogenic actions of FoxO1 appear to be under the control of insulin signaling as cells lacking either insulin receptor , or insulin receptor substrate or the insulin target AKT , have increased FoxO1 activity and impaired differentiation .	The anti-adipogenic actions of FoxO1 appear to be under the control of insulin signaling as cells lacking either insulin receptor, or insulin receptor substrate or the insulin target AKT, have increased FoxO1 activity and impaired differentiation.	15	34	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	29	30	33	34
In conclusion , co-overexpression of Akt and Ang-1 in MSC activated cell cycle progression by upregulation of miR-143 and stimulation of FoxO1 and Erk5 signaling .	In conclusion, co-overexpression of Akt and Ang-1 in MSC activated cell cycle progression by upregulation of miR-143 and stimulation of FoxO1 and Erk5 signaling.	3	24	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	co-overexpression of Akt	akt	FoxO1	FoxO1	foxo1	5	6	21	22
MicroRNA-21-mediated suppression of PTEN mRNA thus promotes PI3K and AKT signaling , which downregulates nuclear FoxO1 .	MicroRNA-21-mediated suppression of PTEN mRNA thus promotes PI3K and AKT signaling, which downregulates nuclear FoxO1.	7	16	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	9	10	15	16
Although AngII greatly reduced activating S473 and T308 Akt phosphorylation ( by 87 % and 67 % , respectively , P < 0.001 , Figure XREF_FIG A and B ) , as well as downstream Akt mediated FoxO1 and FoxO3a phosphorylation ( by 61 % , P < 0.001 , Figure XREF_FIG C ) , PP2Calpha knockdown did not reverse those reductions , and had no effect on basal Akt and FOXO phosphorylation .	Although AngII greatly reduced activating S473 and T308 Akt phosphorylation (by 87% and 67%, respectively, P < 0.001, Figure XREF_FIG A and B), as well as downstream Akt mediated FoxO1 and FoxO3a phosphorylation (by 61%, P < 0.001, Figure XREF_FIG C), PP2Calpha knockdown did not reverse those reductions, and had no effect on basal Akt and FOXO phosphorylation.	3	40	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	35	36	37	38
It is unclear why AKT targets p-FOXO1 more strongly than p-S6 in human retinoblastoma .	It is unclear why AKT targets p-FOXO1 more strongly than p-S6 in human retinoblastoma.	4	7	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p-FOXO1	p-FOXO1	p-FOXO1	4	5	6	7
It has been shown to block AKT mediated FOXO1 nuclear export and cell proliferation [ XREF_BIBR ] .	It has been shown to block AKT mediated FOXO1 nuclear export and cell proliferation [XREF_BIBR].	6	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	6	7	8	9
In response to insulin , Akt activation promotes nuclear exclusion of FoxO1 by phosphorylation , thereby blocking transcriptional regulation of gluconeogenic genes .	In response to insulin, Akt activation promotes nuclear exclusion of FoxO1 by phosphorylation, thereby blocking transcriptional regulation of gluconeogenic genes.	5	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	5	6	11	12
Elevated levels of Sox2 activate a Sox2 negative feedback loop that leads to increases in AKT activation , which , in turn , leads to increased pFoxO1 ( S253 ) that is sequestered in the cytoplasm and unable to bind the Sox2 gene .	Elevated levels of Sox2 activate a Sox2 negative feedback loop that leads to increases in AKT activation, which, in turn, leads to increased pFoxO1 (S253) that is sequestered in the cytoplasm and unable to bind the Sox2 gene.	15	27	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	pFoxO1	pFoxO1	pFoxO1	15	16	26	27
In support of this , Tsc1 Delta and Delta BMDMs display decreased IL-4-inducible Akt activation , as indicated by diminished P-Akt T308 and P-Akt S473 ( XREF_FIG ) and phosphorylation of the Akt targets FOXO1 and PRAS40 ( XREF_SUPPLEMENTARY ) .	In support of this, Tsc1 Delta and Delta BMDMs display decreased IL-4-inducible Akt activation, as indicated by diminished P-Akt T308 and P-Akt S473 (XREF_FIG) and phosphorylation of the Akt targets FOXO1 and PRAS40 (XREF_SUPPLEMENTARY).	29	38	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	phosphorylation of the Akt	akt	FOXO1	FOXO1	foxo1	32	33	34	35
XREF_BIBR Insulin regulates FoxO1 function through Akt mediated phosphorylation that causes FoxO1 relocation from the nucleus to the cytosol and results in decreased expression of FoxO1 regulated genes .	XREF_BIBR Insulin regulates FoxO1 function through Akt mediated phosphorylation that causes FoxO1 relocation from the nucleus to the cytosol and results in decreased expression of FoxO1 regulated genes.	6	12	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt mediated phosphorylation	akt	FoxO1	FoxO1	foxo1	6	7	11	12
Reduction of Akt phosphorylation caused by a decrease of IGF-1 in the elderly could activate FKHR , thus promoting the transcription of atrogin-1 and MuRF1 ( muscle ring-finger protein 1 ) .	Reduction of Akt phosphorylation caused by a decrease of IGF-1 in the elderly could activate FKHR, thus promoting the transcription of atrogin-1 and MuRF1 (muscle ring-finger protein 1).	2	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation	akt	FKHR	FKHR	fkhr	2	3	15	16
In fact , Brown et al [ XREF_BIBR ] suggest that mTORC2 in DC reduces the inflammatory response through phosphorylation of Akt and cytoplasmic retention of the transcription factor FoxO1 ( diminished S256 phosphorylation ) .	In fact, Brown et al [XREF_BIBR] suggest that mTORC2 in DC reduces the inflammatory response through phosphorylation of Akt and cytoplasmic retention of the transcription factor FoxO1 (diminished S256 phosphorylation).	19	30	retention	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	phosphorylation of Akt	akt	FoxO1	FoxO1	foxo1	21	22	29	30
After the binding of insulin to insulin receptor ( IR ) , Akt is activated , subsequently phosphorylating and excluding FoxO1 proteins from the nucleus to the cytoplasm , thus dampening its effects to promote glucose production [ XREF_BIBR ] , both in isolated hepatocytes [ XREF_BIBR ] and transgenic mouse models [ XREF_BIBR ] .	After the binding of insulin to insulin receptor (IR), Akt is activated, subsequently phosphorylating and excluding FoxO1 proteins from the nucleus to the cytoplasm, thus dampening its effects to promote glucose production [XREF_BIBR], both in isolated hepatocytes [XREF_BIBR] and transgenic mouse models [XREF_BIBR].	12	21	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	12	13	20	21
The Akt target FoxO1 represses cell cycling , enhances apoptosis , and has been identified as a regulator of T-bet and galectin-3 , proteins that promote Th1 cell responses .	The Akt target FoxO1 represses cell cycling, enhances apoptosis, and has been identified as a regulator of T-bet and galectin-3, proteins that promote Th1 cell responses.	0	14	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	1	2	3	4
Akt activation induced by E4-ORF1 expression alone was sufficient to promote the complete redistribution of FoxO1 to the cytosol , demonstrating that E4-ORF1 activation of Akt leads to functional regulation of FoxO1 but not on Glut4 ( XREF_FIG ) .	Akt activation induced by E4-ORF1 expression alone was sufficient to promote the complete redistribution of FoxO1 to the cytosol, demonstrating that E4-ORF1 activation of Akt leads to functional regulation of FoxO1 but not on Glut4 (XREF_FIG).	0	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	0	1	15	16
The present study and our published work XREF_BIBR demonstrated that APN activated JNK signaling and suppressed Akt signaling XREF_BIBR , all of which can activate FoxO1 .	The present study and our published work XREF_BIBR demonstrated that APN activated JNK signaling and suppressed Akt signaling XREF_BIBR, all of which can activate FoxO1.	16	26	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	16	17	25	26
Insulin , one of several anorexigenic hormones , inhibits food intake through AKT mediated FoxO1 inactivation in the hypothalamus XREF_BIBR .	Insulin, one of several anorexigenic hormones, inhibits food intake through AKT mediated FoxO1 inactivation in the hypothalamus XREF_BIBR.	10	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	FoxO1	FoxO1	FoxO1	12	13	14	15
Akt levels normally suppress both autophagy and ubiquitin mediated protein breakdown by supressing FoxO1 .	Akt levels normally suppress both autophagy and ubiquitin mediated protein breakdown by supressing FoxO1.	0	14	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt levels	akt	FoxO1	FoxO1	foxo1	0	1	13	14
BTNL2 blocks Akt mediated inactivation of Foxo1 , a transcription factor necessary for Foxp3 expression .	BTNL2 blocks Akt mediated inactivation of Foxo1, a transcription factor necessary for Foxp3 expression.	1	7	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	2	3	6	7
Such alternative explanations are particularly important as our biochemical analysis did not reveal changes in the activation of the two Akt targets FoxO1 and GSK3-beta .	Such alternative explanations are particularly important as our biochemical analysis did not reveal changes in the activation of the two Akt targets FoxO1 and GSK3-beta.	16	23	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	20	21	22	23
AKT phosphorylation promotes B cell survival by inactivating transcription factor FOXO1 3 .	AKT phosphorylation promotes B cell survival by inactivating transcription factor FOXO1 3.	0	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT phosphorylation	akt	FOXO1	FOXO1	foxo1	0	1	10	11
Mechanistically , Pten deletion induces PI3K and AKT mediated nuclear exclusion of Foxo1 and suppression of Notch signaling .	Mechanistically, Pten deletion induces PI3K and AKT mediated nuclear exclusion of Foxo1 and suppression of Notch signaling.	5	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	Foxo1	Foxo1	Foxo1	7	8	12	13
In this regard , Kamagate et al demonstrated that mice in a fed state downregulate MTP expression through Akt mediated FoxO1 inactivation .	In this regard, Kamagate et al demonstrated that mice in a fed state downregulate MTP expression through Akt mediated FoxO1 inactivation.	16	21	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	18	19	20	21
The mechanism by which PI3K regulates RAG is dependent on Akt mediated Foxo1 inactivation , preventing Foxo1 dependent expression of the Rag1/2 genes .	The mechanism by which PI3K regulates RAG is dependent on Akt mediated Foxo1 inactivation, preventing Foxo1 dependent expression of the Rag1/2 genes.	8	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	10	11	12	13
2 ) Akt inactivation activates Foxo1 resulting in heme deficiency , limiting mitochondrial cofactor biosynthesis and ATP production , as we observed in liver lacking both IRS1 and IRS2 .	2) Akt inactivation activates Foxo1 resulting in heme deficiency, limiting mitochondrial cofactor biosynthesis and ATP production, as we observed in liver lacking both IRS1 and IRS2.	2	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	2	3	5	6
Finally , LPS mediated Akt activation was diminished in Tsc1 Delta and Delta BMDMs , as evidenced by a defect in phosphorylation of Akt and the Akt target FOXO1 ( XREF_SUPPLEMENTARY ) .	Finally, LPS mediated Akt activation was diminished in Tsc1 Delta and Delta BMDMs, as evidenced by a defect in phosphorylation of Akt and the Akt target FOXO1 (XREF_SUPPLEMENTARY).	19	30	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	26	27	28	29
In our study , maternal chromium restriction impaired PI3K-Akt signaling , thus activating FoxO1 , resulting in excess hepatic glucose production .	In our study, maternal chromium restriction impaired PI3K-Akt signaling, thus activating FoxO1, resulting in excess hepatic glucose production.	8	14	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	FoxO1	FoxO1	FoxO1	8	9	13	14
To determine whether overexpression of Akt could rescue the phenotype of FoxO1 deficient cells , we infected si-CTR- and si-FoxO1-tranfected cells with constitutively active Akt .	To determine whether overexpression of Akt could rescue the phenotype of FoxO1 deficient cells, we infected si-CTR- and si-FoxO1-tranfected cells with constitutively active Akt.	3	13	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	overexpression of Akt	akt	FoxO1	FoxO1	foxo1	5	6	11	12
In addition to the inhibition of lipolysis via Akt dependent PDE3B activation in adipose tissue , these results further showed that astragaloside IV restrained hepatic gluconeogenesis through Akt mediated FoxO1 inactivation .	In addition to the inhibition of lipolysis via Akt dependent PDE3B activation in adipose tissue, these results further showed that astragaloside IV restrained hepatic gluconeogenesis through Akt mediated FoxO1 inactivation.	25	30	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	27	28	29	30
Conversely , silencing BRCA1-IRIS in ovarian cancer cell lines derepressed PTEN expression along with the antiapoptotic AKT targets FOXO1 and FOXO3a , suppressing survivin expression .	Conversely, silencing BRCA1-IRIS in ovarian cancer cell lines derepressed PTEN expression along with the antiapoptotic AKT targets FOXO1 and FOXO3a, suppressing survivin expression.	9	20	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	16	17	18	19
Unfortunately , growth of alveolar tumor cells in culture resulted in higher ENTPD5 expression levels than those observed in bronchiolar cells , enhanced Akt activation and high phosphorylation levels of the Akt targets FOXO1 and FOXO3a , which were maintained upon culture under low serum conditions ( XREF_SUPPLEMENTARY ) .	Unfortunately, growth of alveolar tumor cells in culture resulted in higher ENTPD5 expression levels than those observed in bronchiolar cells, enhanced Akt activation and high phosphorylation levels of the Akt targets FOXO1 and FOXO3a, which were maintained upon culture under low serum conditions (XREF_SUPPLEMENTARY).	24	39	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	31	32	33	34
However , loss of PTEN activates AKT , which in turn results in nuclear exclusion of FOXO1 and abolishes FOXO1 mediated inhibition of AR , thereby driving castration resistant progression of PCa .	However, loss of PTEN activates AKT, which in turn results in nuclear exclusion of FOXO1 and abolishes FOXO1 mediated inhibition of AR, thereby driving castration resistant progression of PCa.	5	21	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	6	7	19	20
In a study in umbilical veins , activation of the PI3K and Akt pathway in endothelial cells induces the deregulation of FoxO1 and subsequently inhibits the secretion of connective tissue growth factor ( CTGF ) , leading to the abnormal proliferation of endothelial cells .	In a study in umbilical veins, activation of the PI3K and Akt pathway in endothelial cells induces the deregulation of FoxO1 and subsequently inhibits the secretion of connective tissue growth factor (CTGF), leading to the abnormal proliferation of endothelial cells.	10	22	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	12	13	21	22
To differentiate the activities of nuclear Foxo1 and cytosolic Foxo1 induced by Akt activation , we inserted a complementary DNA fragment coding for a haemagglutinin ( HA )-tagged human Foxo1 mutant in which amino acids at the Akt phosphorylation sites were substituted with alanines 18 ( HA-hFoxo1 ( AAA ) ) , preceded by a loxP flanked ` neo-STOP ' cassette into the Rosa26 locus ( XREF_SUPPLEMENTARY ) .	To differentiate the activities of nuclear Foxo1 and cytosolic Foxo1 induced by Akt activation, we inserted a complementary DNA fragment coding for a haemagglutinin (HA)-tagged human Foxo1 mutant in which amino acids at the Akt phosphorylation sites were substituted with alanines 18 (HA-hFoxo1 (AAA)), preceded by a loxP flanked ` neo-STOP ' cassette into the Rosa26 locus (XREF_SUPPLEMENTARY).	1	13	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo1	Foxo1	Foxo1	12	13	9	10
Serum ( IGF-1 ) levels were lower in lumbar disc degeneration patients than those of healthy controls , and addition of IGF-1 to human NP SV40 cells induced Akt phosphorylation and then inactivated FoxO1 , leading to inhibition of MMP-3 transcription [ XREF_BIBR ] .	Serum (IGF-1) levels were lower in lumbar disc degeneration patients than those of healthy controls, and addition of IGF-1 to human NP SV40 cells induced Akt phosphorylation and then inactivated FoxO1, leading to inhibition of MMP-3 transcription [XREF_BIBR].	21	34	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	IGF-1 to human NP SV40 cells induced Akt phosphorylation	akt	FoxO1	FoxO1	foxo1	28	29	33	34
In the fasted state , increases in circulating glucagon first stimulate hepatic gluconeogenesis via the PKA mediated phosphorylation of CREB and the promotion of the CREB-CRTC2 axis , which is repressed by AMPK , while decreases in circulating insulin then increase gluconeogenic gene expression via the de-phosphorylation of the forkhead transcription factor FoxO1 reversing the repression of FoxO1 by Akt upon insulin activation .	In the fasted state, increases in circulating glucagon first stimulate hepatic gluconeogenesis via the PKA mediated phosphorylation of CREB and the promotion of the CREB-CRTC2 axis, which is repressed by AMPK, while decreases in circulating insulin then increase gluconeogenic gene expression via the de-phosphorylation of the forkhead transcription factor FoxO1 reversing the repression of FoxO1 by Akt upon insulin activation.	53	60	repression	Negative_activation_token_2_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	59	60	57	58
AKT inhibition of M22 or IGF-1-treated cultures was found to increase nuclear ( 1.4-fold , p = 0.026 ; 1.3-fold , p = 0.001 , respectively ) and decrease cytoplasmic ( 24.2 % , p = 0.001 ; 36 % , p = 0.004 , respectively ) FOXO1 localization .	AKT inhibition of M22 or IGF-1-treated cultures was found to increase nuclear (1.4-fold, p = 0.026; 1.3-fold, p = 0.001, respectively) and decrease cytoplasmic (24.2%, p = 0.001; 36%, p = 0.004, respectively) FOXO1 localization.	0	48	decrease	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO1	FOXO1	FOXO1	0	1	47	48
This suggests that MSTN may play an important role in LIPUS improving the T1DM induced muscle atrophy by the Akt independent increase in mTOR and inhibition of FoxO1 .	This suggests that MSTN may play an important role in LIPUS improving the T1DM induced muscle atrophy by the Akt independent increase in mTOR and inhibition of FoxO1.	14	28	induced	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	19	20	27	28
FOXO1 is not known to be a direct target of GSK3beta , but is targeted by both Akt and AMPK .	FOXO1 is not known to be a direct target of GSK3beta, but is targeted by both Akt and AMPK.	0	19	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO1	FOXO1	FOXO1	17	18	0	1
The effects of IGF-1 on skeletal muscle are mediated mainly by the PI3K and Akt pathway leading to the downstream activation of protein synthesis [ XREF_BIBR ] and inhibition of FOXO-1 , which regulates the expression of the rate limiting ubiquitin E3-ligases Murf-1 and MAFbx , thereby reducing proteosomal protein degradation [ XREF_BIBR , XREF_BIBR ] .	The effects of IGF-1 on skeletal muscle are mediated mainly by the PI3K and Akt pathway leading to the downstream activation of protein synthesis [XREF_BIBR] and inhibition of FOXO-1, which regulates the expression of the rate limiting ubiquitin E3-ligases Murf-1 and MAFbx, thereby reducing proteosomal protein degradation [XREF_BIBR, XREF_BIBR].	8	33	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO-1	FOXO-1	FOXO-1	14	15	30	31
Since phosphorylation of FoxO1 at Thr 24 and Ser 256 by Akt induces 14-3-3 binding and cytosolic translocation of FoxO1 XREF_BIBR , XREF_BIBR , we next examined whether transcriptional inactivation of FoxO1 induced by Lats2 activation is mediated by Akt .	Since phosphorylation of FoxO1 at Thr 24 and Ser 256 by Akt induces 14-3-3 binding and cytosolic translocation of FoxO1 XREF_BIBR, XREF_BIBR, we next examined whether transcriptional inactivation of FoxO1 induced by Lats2 activation is mediated by Akt.	1	20	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	phosphorylation of FoxO1 at Thr 24 and Ser 256 by Akt	akt	FoxO1	FoxO1	foxo1	11	12	19	20
Being a lipid phosphatase , PTEN can reduce PI-3 ,4,5-P 3 concentrations and suppress Akt phosphorylation and activation , which activates FOXO1 and increases glucose production in the liver [ XREF_BIBR , XREF_BIBR ] .	Being a lipid phosphatase, PTEN can reduce PI-3,4,5-P 3 concentrations and suppress Akt phosphorylation and activation, which activates FOXO1 and increases glucose production in the liver [XREF_BIBR, XREF_BIBR].	5	22	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	PTEN can reduce PI-3,4,5-P 3 concentrations and suppress Akt phosphorylation	akt	FOXO1	FOXO1	foxo1	14	15	21	22
In IL-7 treated Tsc1 KO naive CD8 + T cells , Bim L expression was dramatically increased which was consistent with absence of Akt mediated FoxO1 ( Thr24 ) and FoxO3a ( Thr32 ) phosphorylation , while no Bim L expression was detected in IL-7-treated WT naive CD8 + T cells , even though both cells expressed similar levels of Bim EL ( XREF_FIG ) .	In IL-7 treated Tsc1 KO naive CD8 + T cells, Bim L expression was dramatically increased which was consistent with absence of Akt mediated FoxO1 (Thr24) and FoxO3a (Thr32) phosphorylation, while no Bim L expression was detected in IL-7-treated WT naive CD8 + T cells, even though both cells expressed similar levels of Bim EL (XREF_FIG).	21	35	mediated	Positive_early_regulation	Negative_activation	Positive_regulation	Akt	Akt	akt	FoxO1	FoxO1 (Thr24) and FoxO3a (Thr32) phosphorylation	foxo1	23	24	25	26
Collectively , these results , although do not rule out the possibility that KRIT1 may control FoxO1 expression through an indirect modulation of SirT1 function , support the interpretation that KRIT1 , by preventing the Akt mediated inactivation and downregulation of FoxO1 , may favor the SirT1 and FoxO1 interaction , which , in turn , could promote the shifting of FoxO1 functions towards resistance to oxidative stress .	Collectively, these results, although do not rule out the possibility that KRIT1 may control FoxO1 expression through an indirect modulation of SirT1 function, support the interpretation that KRIT1, by preventing the Akt mediated inactivation and downregulation of FoxO1, may favor the SirT1 and FoxO1 interaction, which, in turn, could promote the shifting of FoxO1 functions towards resistance to oxidative stress.	34	42	mediated	Positive_activation_syntax_3a_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	35	36	41	42
In cell models of endometrial cancer , presensitization of cells to block Akt activation and foster transcription activity of FoxO1 enhances the effect of chemotherapy to limit tumor growth [ XREF_BIBR ] .	In cell models of endometrial cancer, presensitization of cells to block Akt activation and foster transcription activity of FoxO1 enhances the effect of chemotherapy to limit tumor growth [XREF_BIBR].	12	20	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	12	13	19	20
XREF_BIBR In cell models of endometrial cancer , pre-sensitization of cells to block Akt activation and foster transcription activity of FoxO1 enhances the effect of chemotherapy to limit tumor growth .	XREF_BIBR In cell models of endometrial cancer, pre-sensitization of cells to block Akt activation and foster transcription activity of FoxO1 enhances the effect of chemotherapy to limit tumor growth.	13	21	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	13	14	20	21
In particular , the PI3K-AKT pathway phosphorylates FOXO1a and targets the protein for destruction by the proteasome , and recent studies have suggested that AKT targets FOXO1a for degradation in ARMS derived cell lines .	In particular, the PI3K-AKT pathway phosphorylates FOXO1a and targets the protein for destruction by the proteasome, and recent studies have suggested that AKT targets FOXO1a for degradation in ARMS derived cell lines.	24	31	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO1a	FOXO1a	FOXO1a	24	25	26	27
This FOXO1 methylation prevented Akt mediated phosphorylation and augmented the ability of FOXO1 to induce target gene expression , including that of the proapoptotic gene bim .	This FOXO1 methylation prevented Akt mediated phosphorylation and augmented the ability of FOXO1 to induce target gene expression, including that of the proapoptotic gene bim.	1	13	augmented	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	FOXO1 methylation prevented Akt mediated phosphorylation	akt	FOXO1	FOXO1	foxo1	4	5	12	13
AKT Phosphorylation has been shown to mediate B cell survival by promoting FOXO1 degradation XREF_BIBR , XREF_BIBR .	AKT Phosphorylation has been shown to mediate B cell survival by promoting FOXO1 degradation XREF_BIBR, XREF_BIBR.	0	14	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT Phosphorylation	akt	FOXO1	FOXO1	foxo1	0	1	12	13
In addition , the observation that KRIT1 dependent prevention of Akt mediated inactivation and downregulation of FoxO1 may favor the interaction of FoxO1 with SirT1 raises the possibility that KRIT1 plays a role in promoting the shifting of FoxO1 functions away from apoptosis and towards resistance to oxidative stress .	In addition, the observation that KRIT1 dependent prevention of Akt mediated inactivation and downregulation of FoxO1 may favor the interaction of FoxO1 with SirT1 raises the possibility that KRIT1 plays a role in promoting the shifting of FoxO1 functions away from apoptosis and towards resistance to oxidative stress.	8	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	10	11	22	23
In cell models of endometrial cancer , pre-sensitization of cells to block Akt activation and foster transcription activity of FoxO1 enhances the effect of chemotherapy to limit tumor growth .	In cell models of endometrial cancer, pre-sensitization of cells to block Akt activation and foster transcription activity of FoxO1 enhances the effect of chemotherapy to limit tumor growth.	12	20	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	12	13	19	20
XREF_BIBR - XREF_BIBR It is tempting to speculate that reduced VLDL secretion in CGI-58 ASO treated mice XREF_BIBR might partially result from improved Akt mediated inactivation of FoxO1 .	XREF_BIBR - XREF_BIBR It is tempting to speculate that reduced VLDL secretion in CGI-58 ASO treated mice XREF_BIBR might partially result from improved Akt mediated inactivation of FoxO1.	20	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO1	FoxO1	FoxO1	23	24	27	28
PP2A inhibitors increased hepatic Akt phosphorylation and inhibited FoxO1 in vitro and in vivo , and suppressed gluconeogenesis in hepatocytes .	PP2A inhibitors increased hepatic Akt phosphorylation and inhibited FoxO1 in vitro and in vivo, and suppressed gluconeogenesis in hepatocytes.	0	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	PP2A inhibitors increased hepatic Akt phosphorylation	akt	FoxO1	FoxO1	foxo1	4	5	8	9
Constitutive Akt activation in prostate epithelium induces cellular features of senescence , including SA-beta-Gal ( senescence associated beta-galactosidase ) activity and increased p27 expression XREF_BIBR .	Constitutive Akt activation in prostate epithelium induces cellular features of senescence, including SA-beta-Gal (senescence associated beta-galactosidase) activity and increased p27 expression XREF_BIBR.	1	24	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27	p27	p27	1	2	22	23
Moreover , TGF-alpha increased cyclin D/CDK 4 and cyclin E/CDK 2 levels , while decreasing p21cip1 and waf1 and p27kip1 , which were blocked by the inhibition of Akt , mTOR and Notch .	Moreover, TGF-alpha increased cyclin D/CDK 4 and cyclin E/CDK 2 levels, while decreasing p21cip1 and waf1 and p27kip1, which were blocked by the inhibition of Akt, mTOR and Notch.	15	32	blocked	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27kip1	p27kip1	p27kip1	28	29	19	20
PD-1 inhibits Skp2 by inhibiting PIK3 and Akt and Ras/MEK/ERK signaling leading to increase of p27kip1 and inhibition of Cdk2 .	PD-1 inhibits Skp2 by inhibiting PIK3 and Akt and Ras/MEK/ERK signaling leading to increase of p27kip1 and inhibition of Cdk2.	7	19	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27kip1	p27kip1	p27kip1	7	8	15	16
Hcy induces dephosphorylation of Akt and FOXO3a and upregulates p27Kip1 in a time- and dose dependent manner .	Hcy induces dephosphorylation of Akt and FOXO3a and upregulates p27Kip1 in a time- and dose dependent manner.	0	10	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Hcy induces dephosphorylation of Akt	akt	p27Kip1	p27Kip1	p27kip1	4	5	9	10
Nuclear Akt directly inhibits the activity of CDK2-inhibitor p27 kip1 , whereas it indirectly inhibits the activity of anti-apoptotic molecules such as Bcl2 ( by increasing the activity of CDK2 ) .	Nuclear Akt directly inhibits the activity of CDK2-inhibitor p27 kip1, whereas it indirectly inhibits the activity of anti-apoptotic molecules such as Bcl2 (by increasing the activity of CDK2).	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27 kip1	p27 kip1	p27 kip1	1	2	8	10
The inability of BAFF alone to induce proliferation of WT B cells results from a failure to down-regulate p27 kip1 , a cyclin dependent kinase inhibitor which is negatively regulated by Akt either directly or via inhibition of the FOXO factors .	The inability of BAFF alone to induce proliferation of WT B cells results from a failure to down-regulate p27 kip1, a cyclin dependent kinase inhibitor which is negatively regulated by Akt either directly or via inhibition of the FOXO factors.	18	40	negatively regulated	Negative_activation_syntax_6_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27 kip1	p27 kip1	p27 kip1	31	32	18	20
Thus , in this context SAM68 depletion might lead to suppression of AKT phosphorylation and subsequent activation of FOXO factors , which in turn promote the upregulation of p21 ( Cip1 ) and p27 ( Kip1 ) ( XREF_FIG ) [ XREF_BIBR ] .	Thus, in this context SAM68 depletion might lead to suppression of AKT phosphorylation and subsequent activation of FOXO factors, which in turn promote the upregulation of p21 (Cip1) and p27 (Kip1) (XREF_FIG) [XREF_BIBR].	10	34	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	p27	p27	p27	12	13	33	34
This feedback PI3K and AKT activation would promote cytoplasmic p27 sequestration and p27 dependent tumor cell migration and metastasis .	This feedback PI3K and AKT activation would promote cytoplasmic p27 sequestration and p27 dependent tumor cell migration and metastasis.	4	10	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	4	5	9	10
Similarly , NPM-ALK can down-modulate , via PI3K-AKT , the inhibitory action of FOXO3a , upregulating Cyclin D2 and down-regulating p27 , and providing positive growth signals .	Similarly, NPM-ALK can down-modulate, via PI3K-AKT, the inhibitory action of FOXO3a, upregulating Cyclin D2 and down-regulating p27, and providing positive growth signals.	7	23	upregulating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	p27	p27	p27	7	8	20	21
Phosphorylation of AKT could upregulate cyclin D1 and downregulate the cyclin D kinase ( CDK ) inhibitors p21 and p27 , which promotes cell cycle progression .	Phosphorylation of AKT could upregulate cyclin D1 and downregulate the cyclin D kinase (CDK) inhibitors p21 and p27, which promotes cell cycle progression.	0	22	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	Phosphorylation of AKT	akt	p27	p27	p27	2	3	19	20
AKT Mediated p27 Downregulation in Murine and Human Cells in vitro is Dependent on T157 .	AKT Mediated p27 Downregulation in Murine and Human Cells in vitro is Dependent on T157.	0	3	Mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	0	1	2	3
The molecular mechanism for cell cycle arrest was shown to be dependent on increased Akt activation via overexpression of PRL-3 , followed by negative feedback regulation of the PI3K and Akt pathway and subsequent transcription of growth arresting genes ( specifically Foxo , p21 , and p27 ) ( XREF_FIG ) .	The molecular mechanism for cell cycle arrest was shown to be dependent on increased Akt activation via overexpression of PRL-3, followed by negative feedback regulation of the PI3K and Akt pathway and subsequent transcription of growth arresting genes (specifically Foxo, p21, and p27) (XREF_FIG).	14	47	arresting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	14	15	46	47
Akt upregulation can also promote cell growth by inactivating the negative cell cycle regulators p21 XREF_BIBR and p27 XREF_BIBR - XREF_BIBR .	Akt upregulation can also promote cell growth by inactivating the negative cell cycle regulators p21 XREF_BIBR and p27 XREF_BIBR - XREF_BIBR.	0	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27	p27	p27	0	1	17	18
We demonstrate that Hcy induces dephosphorylation of Akt and FKHRL1 and upregulates the cyclin dependent kinase inhibitors p27 ( kip1 ) in a time- and dose dependent manner .	We demonstrate that Hcy induces dephosphorylation of Akt and FKHRL1 and upregulates the cyclin dependent kinase inhibitors p27 (kip1) in a time- and dose dependent manner.	3	19	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Hcy induces dephosphorylation of Akt	akt	p27	p27	p27	7	8	17	18
These were associated with reduction in the phosphorylation of vascular endothelial growth factor receptor-2 Tyr951 , c-Kit Tyr568/570 , platelet derived growth factor receptor-beta Tyr1021 , and Akt Ser473 and Thr308 , down-regulation of positive cell cycle regulators , increased apoptosis , and up-regulation of p27 .	These were associated with reduction in the phosphorylation of vascular endothelial growth factor receptor-2 Tyr951, c-Kit Tyr568/570, platelet derived growth factor receptor-beta Tyr1021, and Akt Ser473 and Thr308, down-regulation of positive cell cycle regulators, increased apoptosis, and up-regulation of p27.	27	46	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27	p27	p27	27	28	45	46
Based on studies of the mammalian homologues of Sch9 and Sic1 ( AKT and p27 ) , however , this is likely to be the case -- AKT inhibits G 1 arrest in mammalian cells by inhibiting the activity of p27 .	Based on studies of the mammalian homologues of Sch9 and Sic1 (AKT and p27), however, this is likely to be the case -- AKT inhibits G 1 arrest in mammalian cells by inhibiting the activity of p27.	27	41	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	p27	p27	p27	27	28	40	41
The PI3 kinase and AKT pathway has been shown to increase degradation of the p27 cyclin dependent kinase inhibitor through phosphorylation of consensus AKT sites on p27 and SKP2 , and AKT driven proliferation may be checked by feedback mechanisms that increase p27 expression and induce senescence .	The PI3 kinase and AKT pathway has been shown to increase degradation of the p27 cyclin dependent kinase inhibitor through phosphorylation of consensus AKT sites on p27 and SKP2, and AKT driven proliferation may be checked by feedback mechanisms that increase p27 expression and induce senescence.	4	18	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	4	5	14	15
p27 phosphorylation at T157 in the p27 nuclear localization signal ( NLS ) by AKT is associated with sequestration in the cytoplasm due to 14-3-3 binding .	p27 phosphorylation at T157 in the p27 nuclear localization signal (NLS) by AKT is associated with sequestration in the cytoplasm due to 14-3-3 binding.	6	15	signal	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	14	15	6	7
Finally the subcellular localization of p27 Kip also has prognostic significance where high cytoplasmic p27 Kip1 , which is driven by activated Akt , is associated with poor outcome ( Liang et al ., 2002 ) .	Finally the subcellular localization of p27 Kip also has prognostic significance where high cytoplasmic p27 Kip1, which is driven by activated Akt, is associated with poor outcome (Liang et al., 2002).	14	23	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27 Kip1	p27 Kip1	p27 Kip1	22	23	14	16
Furthermore , protein levels and AKT phosphorylation diminution resulted in a p27 and p21 increase [ XREF_BIBR ] ( XREF_FIG ) .	Furthermore, protein levels and AKT phosphorylation diminution resulted in a p27 and p21 increase [XREF_BIBR] (XREF_FIG).	5	15	increase	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	AKT	AKT phosphorylation	akt	p27	p27	p27	5	6	11	12
For example , Akt targets and suppresses p27Kip1 , a direct inhibitor of CDK2 , which is then free and able to promote transcription and resultant cell proliferation [ XREF_BIBR ] , and inhibits the proapoptotic bcl-2 antagonist of cell death ( BAD ) , leading to its sequestration and eventual prevention of cell death [ XREF_BIBR ] .	For example, Akt targets and suppresses p27Kip1, a direct inhibitor of CDK2, which is then free and able to promote transcription and resultant cell proliferation [XREF_BIBR], and inhibits the proapoptotic bcl-2 antagonist of cell death (BAD), leading to its sequestration and eventual prevention of cell death [XREF_BIBR].	3	11	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27Kip1	p27Kip1	p27Kip1	3	4	7	8
The activated PI3-K and AKT pathway could enhance p27 destruction in human cancers [ XREF_BIBR ] .	The activated PI3-K and AKT pathway could enhance p27 destruction in human cancers [XREF_BIBR].	4	9	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	4	5	8	9
Although the molecular mechanisms that link EGFR inhibition to induction of p27KIP1 remain ill defined , it is conceivable that the combination of the sudden loss in the proliferative MAPK signaling and a sustained Akt pro survival activity resulting from the PTEN null status induces p27KIP1 in our system .	Although the molecular mechanisms that link EGFR inhibition to induction of p27KIP1 remain ill defined, it is conceivable that the combination of the sudden loss in the proliferative MAPK signaling and a sustained Akt pro survival activity resulting from the PTEN null status induces p27KIP1 in our system.	34	48	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27KIP1	p27KIP1	p27KIP1	34	35	45	46
53 In addition , Akt has been shown to block the cell cycle inhibitory action of p27 through its phosphorylation at the nuclear localization sequence and subsequent retention in the cytosol .	53 In addition, Akt has been shown to block the cell cycle inhibitory action of p27 through its phosphorylation at the nuclear localization sequence and subsequent retention in the cytosol.	4	17	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27	p27	p27	4	5	16	17
Nonetheless , the marked hyperplasia in response to doxycycline induction of AKT that occurs despite high levels of p27 indicate that AKT may be blocking the CDK2 inhibitory function of p27 by novel mechanisms that remain to be identified .	Nonetheless, the marked hyperplasia in response to doxycycline induction of AKT that occurs despite high levels of p27 indicate that AKT may be blocking the CDK2 inhibitory function of p27 by novel mechanisms that remain to be identified.	21	31	blocking	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	21	22	30	31
Also , the abundance of Beclin 1 and p27 in EBs was increased by PI3K and AKT , but not by ERK , inhibition ( XREF_FIG ) , indicating that the two pathways likely regulated autophagy and differentiation in heart progenitor cells via non redundant mechanisms .	Also, the abundance of Beclin 1 and p27 in EBs was increased by PI3K and AKT, but not by ERK, inhibition (XREF_FIG), indicating that the two pathways likely regulated autophagy and differentiation in heart progenitor cells via non redundant mechanisms.	3	17	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	16	17	8	9
Phosphorylation of C-terminal Thr198 by Akt promotes 14-3-3 binding and cytoplasmic localization of p27 Kip1 [ XREF_BIBR ] .	Phosphorylation of C-terminal Thr198 by Akt promotes 14-3-3 binding and cytoplasmic localization of p27 Kip1 [XREF_BIBR].	0	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Phosphorylation of C-terminal Thr198 by Akt	akt	p27 Kip1	p27 Kip1	p27 kip1	5	6	13	15
13 Cytoplasmic PTEN dephosphorylates AKT , upregulates p27 ( kip1 ) and induces apoptosis .	13 Cytoplasmic PTEN dephosphorylates AKT, upregulates p27 (kip1) and induces apoptosis.	2	9	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	PTEN dephosphorylates AKT	akt	p27	p27	p27	4	5	7	8
Nonetheless , these findings show that AKT driven proliferation in murine prostate epithelium is mediated by mechanisms that are independent of AKT mediated p27 downregulation .	Nonetheless, these findings show that AKT driven proliferation in murine prostate epithelium is mediated by mechanisms that are independent of AKT mediated p27 downregulation.	6	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	6	7	23	24
The cell cycle inhibitor p27 ( CDKN1B ) is a direct target of Akt , and Akt mediated p27 phosophorylation leads to p27 degradation 20 .	The cell cycle inhibitor p27 (CDKN1B) is a direct target of Akt, and Akt mediated p27 phosophorylation leads to p27 degradation 20.	16	19	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	p27	p27	p27	16	17	18	19
In addition , AKT can also inhibit and promote the degradation of p27 , a cyclin dependent kinase inhibitor that like p21 can arrest cells in G1-phase by binding and inhibiting G1-phase cyclin-cdk complexes .	In addition, AKT can also inhibit and promote the degradation of p27, a cyclin dependent kinase inhibitor that like p21 can arrest cells in G1-phase by binding and inhibiting G1-phase cyclin-cdk complexes.	3	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	3	4	12	13
Interestingly , these AKT mediated metabolic effects can be reversed by a SKP2 inhibitor , resulting in a p53 independent but p27 KIP1 -dependent senescence 88 .	Interestingly, these AKT mediated metabolic effects can be reversed by a SKP2 inhibitor, resulting in a p53 independent but p27 KIP1 -dependent senescence 88.	2	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27 KIP1	p27 KIP1	p27 KIP1	3	4	21	23
We found that cytoplasmic PTEN down-regulates phosphorylation of Akt and up-regulates p27 ( kip1 ) , whereas nuclear PTEN down-regulates cyclin D1 and prevents the phosphorylation of MAPK .	We found that cytoplasmic PTEN down-regulates phosphorylation of Akt and up-regulates p27 (kip1), whereas nuclear PTEN down-regulates cyclin D1 and prevents the phosphorylation of MAPK.	4	13	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	PTEN down-regulates phosphorylation of Akt	akt	p27	p27	p27	8	9	11	12
The mechanism involves in increased expression of cyclin D1 , cyclin E , CDK 2 , CDK 4 , and pRb , and decreased level of cyclin dependent kinases inhibitors p21 and p27 , which are blocked by the inhibitors of upstream signal molecules , MAPK and PI3K and Akt .	The mechanism involves in increased expression of cyclin D1, cyclin E, CDK 2, CDK 4, and pRb, and decreased level of cyclin dependent kinases inhibitors p21 and p27, which are blocked by the inhibitors of upstream signal molecules, MAPK and PI3K and Akt.	23	50	blocked	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27	p27	p27	49	50	32	33
AKT promotes the G1/S transition by antagonizing the accumulation of two G1/S transition inhibitors , p21 and p27 .	AKT promotes the G1/S transition by antagonizing the accumulation of two G1/S transition inhibitors, p21 and p27.	0	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	0	1	17	18
Furthermore inhibition of PI3K and Akt pathways can decrease MCL growth by inducing p27 Kip1 accumulation through Cks1 and Skp2 downregulation [ XREF_BIBR ] .	Furthermore inhibition of PI3K and Akt pathways can decrease MCL growth by inducing p27 Kip1 accumulation through Cks1 and Skp2 downregulation [XREF_BIBR].	3	15	decrease	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27 Kip1	p27 Kip1	p27 Kip1	5	6	13	15
On the other hand , inactivation of Akt by ZSTK474 led to increase of p27 and the consequent desphosphorylation of p-Rb , which might also be involved in the G1 arrest .	On the other hand, inactivation of Akt by ZSTK474 led to increase of p27 and the consequent desphosphorylation of p-Rb, which might also be involved in the G1 arrest.	5	18	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27	p27	p27	7	8	14	15
Akt upregulation can also promote cell growth by inactivating the negative cell cycle regulators p21 [ XREF_BIBR ] and p27 [ XREF_BIBR - XREF_BIBR ] .	Akt upregulation can also promote cell growth by inactivating the negative cell cycle regulators p21 [XREF_BIBR] and p27 [XREF_BIBR - XREF_BIBR].	0	21	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27	p27	p27	0	1	19	20
Expression of HIN-1 also inhibits Akt mediated retention of p27 in the cytoplasm .	Expression of HIN-1 also inhibits Akt mediated retention of p27 in the cytoplasm.	5	12	retention	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	p27	p27	p27	5	6	9	10
Akt also inhibits cyclin dependent kinase inhibitors p21 and p27 , limiting their transfer from cytoplasm to the nucleus , which is conducive to cell proliferation [ XREF_BIBR , XREF_BIBR ] .	Akt also inhibits cyclin dependent kinase inhibitors p21 and p27, limiting their transfer from cytoplasm to the nucleus, which is conducive to cell proliferation [XREF_BIBR, XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	0	1	9	10
Type I IFN is also required for the apoptosis resulting from infection induced activation of the TRIF associated receptors TLR3 and TLR4 , in part by suppressing Akt signaling and degradation of the CDK inhibitor p27 .	Type I IFN is also required for the apoptosis resulting from infection induced activation of the TRIF associated receptors TLR3 and TLR4, in part by suppressing Akt signaling and degradation of the CDK inhibitor p27.	27	36	signaling	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	p27	p27	p27	27	28	35	36
These findings indicate that IGF-1R and AKT inhibition can reduce apoptosis and increase long-term survival in p53 knockdown or null cells in a p27 dependent manner .	These findings indicate that IGF-1R and AKT inhibition can reduce apoptosis and increase long-term survival in p53 knockdown or null cells in a p27 dependent manner.	4	25	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	6	7	23	24
We show that 14-3-3sigma blocks Akt mediated acceleration of p27 ( Kip1 ) turnover rate .	We show that 14-3-3sigma blocks Akt mediated acceleration of p27 (Kip1) turnover rate.	5	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p27	p27	p27	5	6	9	10
Given that activated AKT can modulate p27 via SKP-2 , we asked if mTORC2 has a role in the regulation of the SKP-2 and p27 axis .	Given that activated AKT can modulate p27 via SKP-2, we asked if mTORC2 has a role in the regulation of the SKP-2 and p27 axis.	2	8	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27	p27	p27	3	4	6	7
PI3K and AKT pathway inhibition is associated with inhibition of caspase 3 inhibition limiting p27Kip1 cleavage .	PI3K and AKT pathway inhibition is associated with inhibition of caspase 3 inhibition limiting p27Kip1 cleavage.	2	15	limiting	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p27Kip1	p27Kip1	p27Kip1	2	3	14	15
A major form of regulation is Akt mediated phos phorylation of FOXO and nuclear exclusion in response to insulin or other growth factors .	A major form of regulation is Akt mediated phos phorylation of FOXO and nuclear exclusion in response to insulin or other growth factors.	2	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	6	7	11	12
For example , the hypophosphorylation of Akt leads to the activation of FoxO transcription factors that transcribe genes for free radical scavengers such as catalase and Mn-superoxide dismutase in addition to upregulating Gadd45a ( growth arrest and DNA damage response gene ) expression .	For example, the hypophosphorylation of Akt leads to the activation of FoxO transcription factors that transcribe genes for free radical scavengers such as catalase and Mn-superoxide dismutase in addition to upregulating Gadd45a (growth arrest and DNA damage response gene) expression.	4	14	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Akt	hypophosphorylation of Akt	akt	FoxO	FoxO	foxo	6	7	12	13
While nuclear AKT levels are positively regulated by Glc to support FOXO nuclear exclusion , JNK1/2 are activated in response to oxidative stress to promote FOXO nuclear import .	While nuclear AKT levels are positively regulated by Glc to support FOXO nuclear exclusion, JNK1/2 are activated in response to oxidative stress to promote FOXO nuclear import.	2	13	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT levels	akt	FOXO	FOXO	foxo	2	3	11	12
Pathways that are PI3K specific include Akt mediated inactivation of Foxo transcription factors and transcription independent regulation of glucose uptake and metabolism .	Pathways that are PI3K specific include Akt mediated inactivation of Foxo transcription factors and transcription independent regulation of glucose uptake and metabolism.	6	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	6	7	10	11
Thus , T cells responding in tumor microenvironments repressed mitochondrial biogenesis through repression of PGC1alpha , driven , in part , by chronic Akt activation and consequent repression of Foxo activity .	Thus, T cells responding in tumor microenvironments repressed mitochondrial biogenesis through repression of PGC1alpha, driven, in part, by chronic Akt activation and consequent repression of Foxo activity.	23	30	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	23	24	29	30
Akt controls protein synthesis via mTOR and protein degradation via transcription factors of the FoxO family .	Akt controls protein synthesis via mTOR and protein degradation via transcription factors of the FoxO family.	0	15	synthesis	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	0	1	14	15
Inactivation of the PI3K and Akt signaling pathway activates FoxO proteins and promotes longevity in worms and flies .	Inactivation of the PI3K and Akt signaling pathway activates FoxO proteins and promotes longevity in worms and flies.	5	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	5	6	9	10
It is well known that constitutive PI3K-AKT pathway activation causes downregulation of FOXO tumour suppressor functions in BRCA XREF_BIBR .	It is well known that constitutive PI3K-AKT pathway activation causes downregulation of FOXO tumour suppressor functions in BRCA XREF_BIBR.	6	15	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO	FOXO	FOXO	6	7	12	13
From these results we conclude that inhibition of PKB and subsequent activation of FoxO transcription factors mediates an antiproliferative effect of cAMP .	From these results we conclude that inhibition of PKB and subsequent activation of FoxO transcription factors mediates an antiproliferative effect of cAMP.	8	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PKB	PKB	PKB	FoxO	FoxO	FoxO	8	9	13	14
For example , in this study , we used LLC cells from ATCC , which take 28days to fully develop cachexia and induce MuRF1 up-regulation through Akt mediated FoxO activation .	For example, in this study, we used LLC cells from ATCC, which take 28days to fully develop cachexia and induce MuRF1 up-regulation through Akt mediated FoxO activation.	22	29	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	26	27	28	29
Akt phosphorylation also induces nuclear export of FOXO proteins through the nuclear pore complex , which is dependent on 14-3-3 chaperone proteins and the exportin receptor , chromosomal region maintenance protein 1 ( CRM1 ) [ XREF_BIBR , XREF_BIBR ] .	Akt phosphorylation also induces nuclear export of FOXO proteins through the nuclear pore complex, which is dependent on 14-3-3 chaperone proteins and the exportin receptor, chromosomal region maintenance protein 1 (CRM1) [XREF_BIBR, XREF_BIBR].	0	8	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt phosphorylation	akt	FOXO	FOXO	foxo	0	1	7	8
In particular , our results indicated that Akt targeted Foxo to control the downregulated IRGs , and Erk targeted a transcriptional cascade mediated through the IEGs to control the upregulated IRGs .	In particular, our results indicated that Akt targeted Foxo to control the downregulated IRGs, and Erk targeted a transcriptional cascade mediated through the IEGs to control the upregulated IRGs.	7	11	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	7	8	9	10
The conclusion is that one of the functions of CTLA-4 is to resolve inflammatory responses by signaling through B7 and overriding the nuclear exclusion of Foxo factors mediated by IKKbeta and/or Akt XREF_BIBR .	The conclusion is that one of the functions of CTLA-4 is to resolve inflammatory responses by signaling through B7 and overriding the nuclear exclusion of Foxo factors mediated by IKKbeta and/or Akt XREF_BIBR.	25	32	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	31	32	25	26
These FOXO regulatory pathways are triggered by the PI3K and AKT pathway which mediates cellular functions of proliferation and cell growth XREF_BIBR .	These FOXO regulatory pathways are triggered by the PI3K and AKT pathway which mediates cellular functions of proliferation and cell growth XREF_BIBR.	1	11	triggered	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	10	11	1	2
IGF-I stimulation and AKT overexpression promotes embryonic cardiomyocyte proliferation and cytoplasmic localization of FOXO .	IGF-I stimulation and AKT overexpression promotes embryonic cardiomyocyte proliferation and cytoplasmic localization of FOXO.	3	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT overexpression	akt	FOXO	FOXO	foxo	3	4	13	14
Akt also inhibits muscle proteolysis by repressing the action of the Forkhead box FOXO proteins and their targets , the muscle specific E3-ubiquitin ligases Muscle Atrophy F-Box ( MAFbx-atrogin ) and muscle Really Interesting New Gene ( RING )-finger protein 1 ( MuRF1 ) [ XREF_BIBR , XREF_BIBR ] .	Akt also inhibits muscle proteolysis by repressing the action of the Forkhead box FOXO proteins and their targets, the muscle specific E3-ubiquitin ligases Muscle Atrophy F-Box (MAFbx-atrogin) and muscle Really Interesting New Gene (RING)-finger protein 1 (MuRF1) [XREF_BIBR, XREF_BIBR].	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	0	1	13	14
Specifically , Akt inhibits FoxOs and causes consequent inactivation of FoxO signaling pathway , which can be clearly shown in the TF-Pathway map of PIK3CA H1047R samples .	Specifically, Akt inhibits FoxOs and causes consequent inactivation of FoxO signaling pathway, which can be clearly shown in the TF-Pathway map of PIK3CA H1047R samples.	2	12	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	2	3	10	11
Whereas mutation of Akt and PKB promotes the nuclear accumulation of DAF-16 and FoxO , mutation of eak genes increases nuclear DAF-16 and FoxO activity without influencing DAF-16 and FoxO subcellular localization .	Whereas mutation of Akt and PKB promotes the nuclear accumulation of DAF-16 and FoxO, mutation of eak genes increases nuclear DAF-16 and FoxO activity without influencing DAF-16 and FoxO subcellular localization.	1	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKB	PKB	PKB	FoxO	FoxO	FoxO	5	6	13	14
Generally speaking , the activation of survival and growth ERK and Akt signaling causes the retention of FOXO factors in the cytoplasm or degradation , and the stress and JNK pathway has been shown to phosphorylate 14-3-3 , releasing FOXO to enter the nucleus , inducing apoptosis.13 , 15 However , the upstream regulated network of FOXO-nm23-H1 transduction is complicated .	Generally speaking, the activation of survival and growth ERK and Akt signaling causes the retention of FOXO factors in the cytoplasm or degradation, and the stress and JNK pathway has been shown to phosphorylate 14-3-3, releasing FOXO to enter the nucleus, inducing apoptosis.13, 15 However, the upstream regulated network of FOXO-nm23-H1 transduction is complicated.	11	18	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	11	12	17	18
We next examined the effects of AKT on resveratrol induced FOXO activity in LNCaP cells ( XREF_FIG ) .	We next examined the effects of AKT on resveratrol induced FOXO activity in LNCaP cells (XREF_FIG).	4	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	6	7	10	11
Additionally , as hypophosphosrylation of Akt modulates the regulation of FOXO transcription factors XREF_BIBR , XREF_BIBR , we also observed that FOXO1 is upregulated in presence of p19 ( XREF_FIG ) .	Additionally, as hypophosphosrylation of Akt modulates the regulation of FOXO transcription factors XREF_BIBR, XREF_BIBR, we also observed that FOXO1 is upregulated in presence of p19 (XREF_FIG).	3	13	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	5	6	10	11
Regarding the mechanisms of regulation , activated AKT can negatively modulate gene expression by recruiting FoxO transcription factors from the nucleus to the cytoplasm .	Regarding the mechanisms of regulation, activated AKT can negatively modulate gene expression by recruiting FoxO transcription factors from the nucleus to the cytoplasm.	6	17	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	7	8	15	16
Constitutive PI3K-AKT pathway activation , a driver of breast cancer growth , causes down-regulation of FOXO tumor suppressor functions .	Constitutive PI3K-AKT pathway activation, a driver of breast cancer growth, causes down-regulation of FOXO tumor suppressor functions.	1	18	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	FOXO	FOXO	FOXO	1	2	15	16
FOXO polypeptides are regulated by phosphorylation [ XREF_BIBR , XREF_BIBR ] ; they are inhibited by the kinases Akt , Sgk , IKKbeta , CDK2 and TAK1 which all promote FOXO nuclear exit , usually mediated by binding of 14-3-3 and in some instances followed by ubiquitination and degradation [ XREF_BIBR ] .	FOXO polypeptides are regulated by phosphorylation [XREF_BIBR, XREF_BIBR]; they are inhibited by the kinases Akt, Sgk, IKKbeta, CDK2 and TAK1 which all promote FOXO nuclear exit, usually mediated by binding of 14-3-3 and in some instances followed by ubiquitination and degradation [XREF_BIBR].	14	35	promote	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	18	19	30	31
Unexpectedly co-misexpression of Trbl and Akt in the fat body led to a significant reduction in total FoxO levels ( XREF_FIG ) , suggesting that Trbl and Akt might act combinatorially to direct FoxO turnover .	Unexpectedly co-misexpression of Trbl and Akt in the fat body led to a significant reduction in total FoxO levels (XREF_FIG), suggesting that Trbl and Akt might act combinatorially to direct FoxO turnover.	25	34	direct	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	27	28	33	34
The dephosphorylation of AKT activate the regulator FOXO and then induced the activation of InR via a cellular feedback mechanism under azadirachtin stress .	The dephosphorylation of AKT activate the regulator FOXO and then induced the activation of InR via a cellular feedback mechanism under azadirachtin stress.	1	8	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	dephosphorylation of AKT	akt	FOXO	FOXO	foxo	3	4	7	8
During basal conditions , FOXO is targeted for phosphorylation by AKT , which results in reductions in transcriptional activity .	During basal conditions, FOXO is targeted for phosphorylation by AKT, which results in reductions in transcriptional activity.	4	13	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	10	11	4	5
The highly conserved genetic relationship between AKT and FoxO family members provides definitive proof of the vital regulatory interaction between AKT signaling and suppression of the FoxO transcriptional program .	The highly conserved genetic relationship between AKT and FoxO family members provides definitive proof of the vital regulatory interaction between AKT signaling and suppression of the FoxO transcriptional program.	20	28	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	20	21	26	27
FoxO transcriptional activity is negatively regulated through phosphorylation dependent nuclear exclusion of FoxO , which is mediated by PI3K and AKT and epidermal growth factor receptor ( EGFR ) signalling 53 .	FoxO transcriptional activity is negatively regulated through phosphorylation dependent nuclear exclusion of FoxO, which is mediated by PI3K and AKT and epidermal growth factor receptor (EGFR) signalling 53.	10	21	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FoxO	FoxO	FoxO	20	21	12	13
A similar mechanism has been described in C. elegans where hypophosphosrylation of Akt modulates the regulation of FOXO transcription factors XREF_BIBR , XREF_BIBR , causing G1/S arrest that leads to a reversible cellular quiescence state XREF_BIBR , XREF_BIBR .	A similar mechanism has been described in C. elegans where hypophosphosrylation of Akt modulates the regulation of FOXO transcription factors XREF_BIBR, XREF_BIBR, causing G1/S arrest that leads to a reversible cellular quiescence state XREF_BIBR, XREF_BIBR.	10	20	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	12	13	17	18
Moreover , we reported that the anti-proliferative effect of silencing Sam68 was accompanied with up-regulated expression of cyclin dependent kinase inhibitors , p21 ( Cip1 ) and p27 ( Kip1 ) , enhanced transactivation of FOXO factors ( FOXO4 ) , and dysreuglation of Akt and GSK-3beta signaling .	Moreover, we reported that the anti-proliferative effect of silencing Sam68 was accompanied with up-regulated expression of cyclin dependent kinase inhibitors, p21 (Cip1) and p27 (Kip1), enhanced transactivation of FOXO factors (FOXO4), and dysreuglation of Akt and GSK-3beta signaling.	32	47	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	44	45	35	36
These findings indicate that FoxO proteins were activated by the inactivation of Akt .	These findings indicate that FoxO proteins were activated by the inactivation of Akt.	4	13	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	12	13	4	5
Akt also blocks protein degradation by inhibiting Foxo family transcription factors , which regulate ubiquitin-proteasome pathway .	Akt also blocks protein degradation by inhibiting Foxo family transcription factors, which regulate ubiquitin-proteasome pathway.	0	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	0	1	7	8
AKT prevents proteolysis by repressing the FOXO family of transcription factors , and induces protein synthesis through the mTOR signaling pathway .	AKT prevents proteolysis by repressing the FOXO family of transcription factors, and induces protein synthesis through the mTOR signaling pathway.	0	13	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	0	1	6	7
Specifically , AKT inhibition or genetic interference with PDK-1-mediated AKT activation prevents the downregulation of FOXO target genes encoding proteins important for naive CD8 T cell trafficking : L-selectin ( CD62L ) , KLF2 , CC motif chemokine receptor 7 ( CCR7 ) , and sphingosine-1 phosphate receptor 1 ( S1P1 ) .	Specifically, AKT inhibition or genetic interference with PDK-1-mediated AKT activation prevents the downregulation of FOXO target genes encoding proteins important for naive CD8 T cell trafficking : L-selectin (CD62L), KLF2, CC motif chemokine receptor 7 (CCR7), and sphingosine-1 phosphate receptor 1 (S1P1).	2	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	2	3	15	16
Based on the current literature , Dsor1 never inhibits rolled and Akt never activates Foxo , making valid negative reference sets .	Based on the current literature, Dsor1 never inhibits rolled and Akt never activates Foxo, making valid negative reference sets.	9	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Foxo	Foxo	Foxo	11	12	14	15
Akt inhibits protein degradation by phosphorylating and thus repressing the transcription factors of the FoxO family , and stimulates protein synthesis via the mammalian target of rapamycin ( mTOR ) and glycogen synthase kinase 3beta ( GSK3beta ) [ XREF_BIBR ] .	Akt inhibits protein degradation by phosphorylating and thus repressing the transcription factors of the FoxO family, and stimulates protein synthesis via the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3beta (GSK3beta) [XREF_BIBR].	0	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	0	1	14	15
This is consistent with lapatinib inhibiting AKT and ERK signaling networks causing FOXO activation and c-Myc degradation , leading to RTK upregulation .	This is consistent with lapatinib inhibiting AKT and ERK signaling networks causing FOXO activation and c-Myc degradation, leading to RTK upregulation.	6	13	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	FOXO	FOXO	FOXO	6	7	12	13
Low PI3K and Akt activity allows FOXO function to be re-established , and programs the cell to express AID and commit to the GC B cell fate .	Low PI3K and Akt activity allows FOXO function to be re-established, and programs the cell to express AID and commit to the GC B cell fate.	3	7	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	3	4	6	7
PI3K and Akt independent mechanisms also have been shown to modulate FOXO activity .	PI3K and Akt independent mechanisms also have been shown to modulate FOXO activity.	0	12	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FOXO	FOXO	FOXO	2	3	11	12
Down-stimulation of Akt activates the forkhead box protein O ( FoxO ) family which increases atrogin-1 and MuRF-1 , two potent inducers of protein degradation [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Down-stimulation of Akt activates the forkhead box protein O (FoxO) family which increases atrogin-1 and MuRF-1, two potent inducers of protein degradation [XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO	FoxO	FoxO	2	3	10	11
These findings are consistent with the notion that the PI3K and AKT pathway targets p21 to confer antiapoptotic and prosurvival signals , resulting in increased S phase entry , growth promotion , and resistance to death signals [ XREF_BIBR ] .	These findings are consistent with the notion that the PI3K and AKT pathway targets p21 to confer antiapoptotic and prosurvival signals, resulting in increased S phase entry, growth promotion, and resistance to death signals [XREF_BIBR].	9	15	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p21	p21	p21	11	12	14	15
Akt activates beta-cell proliferation in a cdk4 dependent manner by inducing cyclin D1 , D2 and p21 Cip1 [ XREF_BIBR ] .	Akt activates beta-cell proliferation in a cdk4 dependent manner by inducing cyclin D1, D2 and p21 Cip1 [XREF_BIBR].	0	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21 Cip1	p21 Cip1	p21 Cip1	0	1	16	18
Here we show that IGF-I promotes muscle cell survival through Akt mediated induction of the cyclin dependent kinase inhibitor p21 .	Here we show that IGF-I promotes muscle cell survival through Akt mediated induction of the cyclin dependent kinase inhibitor p21.	10	20	induction	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	p21	p21	p21	10	11	19	20
In contrast , stimulation of AKT increases p21 ( Cip1 ) via inhibitory phosphorylation of GSK-3 .	In contrast, stimulation of AKT increases p21 (Cip1) via inhibitory phosphorylation of GSK-3.	3	13	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p21	p21	p21	5	6	7	8
Under this condition , we observed a great increase in p21 expression , that might be ascribed to the release of p21 gene negative regulation exerted by myc , or to AKT and mTOR signaling activation ( as previously shown , XREF_FIG ) , which has been shown to initiate p21 dependent senescence in particular conditions XREF_BIBR .	Under this condition, we observed a great increase in p21 expression, that might be ascribed to the release of p21 gene negative regulation exerted by myc, or to AKT and mTOR signaling activation (as previously shown, XREF_FIG), which has been shown to initiate p21 dependent senescence in particular conditions XREF_BIBR.	16	52	initiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p21	p21	p21	31	32	50	51
Excessive accumulation of p21 protein has also been reported to support tumor growth and to result from a post-translational mechanism by which Akt promotes p21 protein stability [ XREF_BIBR - XREF_BIBR ] .	Excessive accumulation of p21 protein has also been reported to support tumor growth and to result from a post-translational mechanism by which Akt promotes p21 protein stability [XREF_BIBR - XREF_BIBR].	22	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	22	23	24	25
Here we show that PI3K and AKT pathway activation in response to phosphatase and tensin homolog ( PTEN ) knockdown , mutant PI3K , catalytic , alpha polypeptide ( PIK3CA ) or activated AKT expression , promotes accumulation of p53 and p21 , increases cell size and induces senescence associated beta-galactosidase activity .	Here we show that PI3K and AKT pathway activation in response to phosphatase and tensin homolog (PTEN) knockdown, mutant PI3K, catalytic, alpha polypeptide (PIK3CA) or activated AKT expression, promotes accumulation of p53 and p21, increases cell size and induces senescence associated beta-galactosidase activity.	4	42	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p21	p21	p21	6	7	41	42
PI3-kinase and AKT cause an upregulation of p21 by suppressing GSK-3beta activity and activating mTOR in both cultured human urothelial carcinoma cells and mouse urothelial cells in vivo .	PI3-kinase and AKT cause an upregulation of p21 by suppressing GSK-3beta activity and activating mTOR in both cultured human urothelial carcinoma cells and mouse urothelial cells in vivo.	0	8	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p21	p21	p21	2	3	7	8
Overexpression of Akt activated p21 accelerated tumor onset and promoted lung metastasis in MMTV and neu mice , providing evidence that p21 , especially cytoplasmic phosphorylated p21 , has an oncogenic role in promoting mammary tumorigenesis and metastasis .	Overexpression of Akt activated p21 accelerated tumor onset and promoted lung metastasis in MMTV and neu mice, providing evidence that p21, especially cytoplasmic phosphorylated p21, has an oncogenic role in promoting mammary tumorigenesis and metastasis.	0	5	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Overexpression of Akt	akt	p21	p21	p21	2	3	4	5
This theoretical analysis shows that OLP and OSCC share two leader genes : TP53 and CDKN1A , involved in the PI3K signalling events mediated by AKT pathway .	This theoretical analysis shows that OLP and OSCC share two leader genes : TP53 and CDKN1A, involved in the PI3K signalling events mediated by AKT pathway.	8	26	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	CDKN1A	CDKN1A	CDKN1A	25	26	15	16
Moreover , our chemical obviously induced p21/WAF1/CIP1 ( Cyclin dependent kinase inhibitor 1A ) expression by releasing from Bcl-2 ( B-cell lymphoma-2 ) and by inhibition of AKT mediated p21 suppression .	Moreover, our chemical obviously induced p21/WAF1/CIP1 (Cyclin dependent kinase inhibitor 1A) expression by releasing from Bcl-2 (B-cell lymphoma-2) and by inhibition of AKT mediated p21 suppression.	25	30	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	p21	p21	p21	27	28	29	30
The PI3K and Akt that is activated by HER-2 and neu induces cytoplasmic localization of the CDK inhibitor p21 Waf1 and Cip1 .	The PI3K and Akt that is activated by HER-2 and neu induces cytoplasmic localization of the CDK inhibitor p21 Waf1 and Cip1.	1	22	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Cip1	Cip1	Cip1	3	4	21	22
In addition , we have demonstrated that the changes in p21 Cip induced by Akt have a significant impact on regulation of beta cell mass , proliferation and survival .	In addition, we have demonstrated that the changes in p21 Cip induced by Akt have a significant impact on regulation of beta cell mass, proliferation and survival.	10	15	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	14	15	10	11
The results here show that overexpression of Akt activated p21 accelerated the tumor onset and promoted lung metastasis in MMTV and neu mice , providing evidence that p21 , especially the cytoplasmic p21 , has an oncogenic role in promoting mammary tumorigenesis and metastasis .	The results here show that overexpression of Akt activated p21 accelerated the tumor onset and promoted lung metastasis in MMTV and neu mice, providing evidence that p21, especially the cytoplasmic p21, has an oncogenic role in promoting mammary tumorigenesis and metastasis.	5	15	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	overexpression of Akt	akt	p21	p21	p21	7	8	9	10
We also determined that AKT could not induce p21 or SAbetaGAL activity in BJ-T cells expressing SV40 large T antigen , consistent with the ability of SV40 large T antigen to repress p53 and retinoblastoma activity ( data not shown ) .	We also determined that AKT could not induce p21 or SAbetaGAL activity in BJ-T cells expressing SV40 large T antigen, consistent with the ability of SV40 large T antigen to repress p53 and retinoblastoma activity (data not shown).	4	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p21	p21	p21	4	5	8	9
Based on these observations , and on the results in XREF_FIG , we conclude that IGF activated signal transduction pathways control muscle cell survival by at least two mechanisms , one involving induction of MyoD mRNA and protein through PI3-kinase , with the subsequent stimulation of p21 expression , and the other through induction of p21 by Akt .	Based on these observations, and on the results in XREF_FIG, we conclude that IGF activated signal transduction pathways control muscle cell survival by at least two mechanisms, one involving induction of MyoD mRNA and protein through PI3-kinase, with the subsequent stimulation of p21 expression, and the other through induction of p21 by Akt.	31	58	induction	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	57	58	55	56
The Akt protein modulates cyclin dependent kinase inhibitors , p27 Kip and p21 Waf1 and Cip1 , that inhibit cell cycle progression .	The Akt protein modulates cyclin dependent kinase inhibitors, p27 Kip and p21 Waf1 and Cip1, that inhibit cell cycle progression.	1	16	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Cip1	Cip1	Cip1	1	2	15	16
We find that Akt induces p21 in myoblasts by a mechanism that does not require MyoD .	We find that Akt induces p21 in myoblasts by a mechanism that does not require MyoD.	3	7	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	3	4	5	6
The actinomycin D experiments show that the half-life of p21 Cip mRNA was significantly reduced in MIN6 caAkt cells supporting the concept that transcriptional regulation is the major mechanism by which p21 Cip RNA expression is increased by Akt .	The actinomycin D experiments show that the half-life of p21 Cip mRNA was significantly reduced in MIN6 caAkt cells supporting the concept that transcriptional regulation is the major mechanism by which p21 Cip RNA expression is increased by Akt.	31	39	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	38	39	31	32
P-AKT could promote the transition of p21 from the cell nucleus to the cytoplasm , where it can then exert its function in promoting cell proliferation .	P-AKT could promote the transition of p21 from the cell nucleus to the cytoplasm, where it can then exert its function in promoting cell proliferation.	0	7	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	P-AKT	P-AKT	P-AKT	p21	p21	p21	0	1	6	7
Thus , one could envision a feedback loop in which p21 mediated Akt activation further activates p21 cytoplasmic functions , thus perpetuating p38 suppression in order to turn off inflammatory reactions .	Thus, one could envision a feedback loop in which p21 mediated Akt activation further activates p21 cytoplasmic functions, thus perpetuating p38 suppression in order to turn off inflammatory reactions.	10	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	p21 mediated Akt	akt	p21	p21	p21	12	13	16	17
The combination of specific inhibitors of ERK1/2 , JNK or PI3K and Akt pathway and metformin further promoted cell apoptosis and the up-regulation of p21 , Bax , Bad , cleaved caspase-3 and -9 as well as the down-regulation of Bcl-2 mediated by metformin alone , but inhibition of p38 pathway exhibited the opposite results .	The combination of specific inhibitors of ERK1/2, JNK or PI3K and Akt pathway and metformin further promoted cell apoptosis and the up-regulation of p21, Bax, Bad, cleaved caspase-3 and -9 as well as the down-regulation of Bcl-2 mediated by metformin alone, but inhibition of p38 pathway exhibited the opposite results.	12	30	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	12	13	24	25
Akt could modulate transcriptional regulation of p21 Cip by regulation of these transcription factors .	Akt could modulate transcriptional regulation of p21 Cip by regulation of these transcription factors.	0	7	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	0	1	6	7
This process involves activation of JNK , which enhances the synthesis of p21 , combined with the activation of PKB , which inhibits p21 degradation .	This process involves activation of JNK, which enhances the synthesis of p21, combined with the activation of PKB, which inhibits p21 degradation.	17	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PKB	PKB	PKB	p21	p21	p21	19	20	23	24
Importantly , p21 Cip1 protein induced by Akt does not inhibit cyclin E-Cdk2 but rather promotes the assembly and activation of cyclin D1 and Cdk4 complex , which controls G1 to S phase progression and enhances cell cycling [ XREF_BIBR ] .	Importantly, p21 Cip1 protein induced by Akt does not inhibit cyclin E-Cdk2 but rather promotes the assembly and activation of cyclin D1 and Cdk4 complex, which controls G1 to S phase progression and enhances cell cycling [XREF_BIBR].	2	8	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21 Cip1	p21 Cip1	p21 Cip1	7	8	2	4
More importantly , homozygous deletion of PTEN in prostatic epithelium in mice induced premalignant lesions containing large numbers of senescent cells , which was accompanied by AKT activation and upregulation of p19 ARF , p53 and p21 WAF1 proteins .	More importantly, homozygous deletion of PTEN in prostatic epithelium in mice induced premalignant lesions containing large numbers of senescent cells, which was accompanied by AKT activation and upregulation of p19 ARF, p53 and p21 WAF1 proteins.	26	38	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	p21 WAF1	p21 WAF1	p21 WAF1	26	27	36	38
In addition , Akt may contribute to the induction of cell-cycle progression by regulating the Cdk inhibitors p27 KIP and p21 CIP [ XREF_BIBR ] .	In addition, Akt may contribute to the induction of cell-cycle progression by regulating the Cdk inhibitors p27 KIP and p21 CIP [XREF_BIBR].	3	21	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	3	4	20	21
Akt likely mediates cell migration at least partly by activating Rac and p21 activated protein kinase .	Akt likely mediates cell migration at least partly by activating Rac and p21 activated protein kinase.	0	13	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	0	1	12	13
A fuller understanding of the mechanisms by which p21 is upregulated by PI3-kinase and AKT signaling will allow potential therapeutic intervention to increase p21 expression in tumors that have lost it .	A fuller understanding of the mechanisms by which p21 is upregulated by PI3-kinase and AKT signaling will allow potential therapeutic intervention to increase p21 expression in tumors that have lost it.	8	15	upregulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	p21	p21	p21	14	15	8	9
Akt induced p21 can promote the assembly and activation of cyclin D1 and Cdk4 complex , triggering G1/S transition XREF_BIBR , XREF_BIBR .	Akt induced p21 can promote the assembly and activation of cyclin D1 and Cdk4 complex, triggering G1/S transition XREF_BIBR, XREF_BIBR.	0	4	induced	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	0	1	2	3
LRIG2 stimulated PI3K mediated AKT phosphorylation of serine 473 , causing MCL-1 downregulation and upregulation of BAK , BAX , and p21 .	LRIG2 stimulated PI3K mediated AKT phosphorylation of serine 473, causing MCL-1 downregulation and upregulation of BAK, BAX, and p21.	0	22	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	LRIG2 stimulated PI3K mediated AKT	akt	p21	p21	p21	4	5	21	22
Induction of dominan negative Akt by a replication deficient adenovirus blocked p21 and cyclin A synthesis , but had no effect on p27 .	Induction of dominan negative Akt by a replication deficient adenovirus blocked p21 and cyclin A synthesis, but had no effect on p27.	0	15	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21	p21	p21	4	5	11	12
Increased Nrf2 stability is dependent on the Akt mediated accumulation of p21 Cip1 and WAF1 and GSK-3 inhibition .	Increased Nrf2 stability is dependent on the Akt mediated accumulation of p21 Cip1 and WAF1 and GSK-3 inhibition.	4	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	p21 Cip1	p21 Cip1	p21 Cip1	7	8	11	13
Overexpression of Akt activated p21 accelerated the tumor onset and promoted lung metastasis in MMTV and neu mice , providing evidence that p21 , especially the cytoplasmic p21 has an oncogenic role in promoting mammary tumorigenesis and metastasis .	Overexpression of Akt activated p21 accelerated the tumor onset and promoted lung metastasis in MMTV and neu mice, providing evidence that p21, especially the cytoplasmic p21 has an oncogenic role in promoting mammary tumorigenesis and metastasis.	0	10	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Overexpression of Akt	akt	p21	p21	p21	2	3	4	5
Insulin and Akt signaling has been demonstrated to activate Rac1 [ XREF_BIBR ] , which controls nuclear localization of beta-catenin and activation of canonical Wnt signaling [ XREF_BIBR ] .	Insulin and Akt signaling has been demonstrated to activate Rac1 [XREF_BIBR], which controls nuclear localization of beta-catenin and activation of canonical Wnt signaling [XREF_BIBR].	0	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	2	3	9	10
Expression of the constitutively active Akt myr construct raised the basal level of Rac1 activation independent of P-Rex1 ( XREF_FIG ) .	Expression of the constitutively active Akt myr construct raised the basal level of Rac1 activation independent of P-Rex1 (XREF_FIG).	0	14	raised	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Expression of the constitutively active Akt	akt	Rac1	Rac1	rac1	5	6	13	14
Moreover , in this current report we also provided data that rac1 dependent activity was blocked by PI3kinase and Akt inhibition .	Moreover, in this current report we also provided data that rac1 dependent activity was blocked by PI3kinase and Akt inhibition.	11	20	blocked	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	rac1	rac1	rac1	19	20	11	12
Although Akt may be a downstream target of Rac1 , it is not critical for Tys mediated barrier improvement .	Although Akt may be a downstream target of Rac1, it is not critical for Tys mediated barrier improvement.	1	9	be a downstream target	Positive_activation_copula_1	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	1	2	8	9
Heterologous expression of P-Rex1 in COS phox cells potentiated fMet-Leu-Phe-induced Akt phosphorylation , whereas expression of a constitutively active form of Akt enhanced Rac1 activation .	Heterologous expression of P-Rex1 in COS phox cells potentiated fMet-Leu-Phe-induced Akt phosphorylation, whereas expression of a constitutively active form of Akt enhanced Rac1 activation.	19	24	enhanced	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	21	22	23	24
Thus these data suggest that the PI3K and Akt pathway is upstream of Rac1 and activates Rac1 , while the JNK pathway is downstream of Rac1 , and that the PI3K and Akt-Rac 1-JNK axis may have a significant role in the maintenance of gastric CSCs .	Thus these data suggest that the PI3K and Akt pathway is upstream of Rac1 and activates Rac1, while the JNK pathway is downstream of Rac1, and that the PI3K and Akt-Rac 1-JNK axis may have a significant role in the maintenance of gastric CSCs.	6	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	8	9	16	17
Furthermore , the activation of AKT that functions as a compensatory prosurvival mechanism in rat hepatocytes in response to oxidative stimuli , can suppress ROS production by inhibiting function of pro apoptotic , prooxidative Rac1 GTPase XREF_BIBR , which is necessary for activation of NOX2 .	Furthermore, the activation of AKT that functions as a compensatory prosurvival mechanism in rat hepatocytes in response to oxidative stimuli, can suppress ROS production by inhibiting function of pro apoptotic, prooxidative Rac1 GTPase XREF_BIBR, which is necessary for activation of NOX2.	3	36	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	Rac1	Rac1	Rac1	5	6	34	35
Rac1 activity was blocked by PI3kinase and Akt inhibition .	Rac1 activity was blocked by PI3kinase and Akt inhibition.	0	8	blocked	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	7	8	0	1
Taken together , these results suggest that Akt promotes cell motility downstream of Rac and Cdc42 in growth factor stimulated cells and in invasive PTEN deficient cells .	Taken together, these results suggest that Akt promotes cell motility downstream of Rac and Cdc42 in growth factor stimulated cells and in invasive PTEN deficient cells.	7	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac	Rac	Rac	7	8	13	14
Progesterone promotes Akt phosphorylation in the PI3K cascade and activates Rac1 associated NGF induced neurite outgrowth via the PI3K and MAPK cascades XREF_BIBR , XREF_BIBR .	Progesterone promotes Akt phosphorylation in the PI3K cascade and activates Rac1 associated NGF induced neurite outgrowth via the PI3K and MAPK cascades XREF_BIBR, XREF_BIBR.	0	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Progesterone promotes Akt phosphorylation	akt	Rac1	Rac1	rac1	2	3	10	11
Based on our previous studies demonstrating that AKT and mTOR growth regulation in Nf1 deficient astrocytes results from mTOR mediated Rac1 activation , we show that STAT3 activation is controlled by Rac1 activation downstream of mTOR in Nf1-/- mouse astrocytes and NF1 deficient human MPNST cells .	Based on our previous studies demonstrating that AKT and mTOR growth regulation in Nf1 deficient astrocytes results from mTOR mediated Rac1 activation, we show that STAT3 activation is controlled by Rac1 activation downstream of mTOR in Nf1-/- mouse astrocytes and NF1 deficient human MPNST cells.	7	21	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	Rac1	Rac1	Rac1	7	8	20	21
AKT signaling activated RAC1 through the RAC-GEF TIAM1 , while PKC signaling dampened expression of the endogenous RAC1 inhibitor , RHOGDI2 [ XREF_BIBR ] .	AKT signaling activated RAC1 through the RAC-GEF TIAM1, while PKC signaling dampened expression of the endogenous RAC1 inhibitor, RHOGDI2 [XREF_BIBR].	0	4	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	RAC1	RAC1	RAC1	0	1	3	4
Particularly , expression of constitutively active form of Rac enhances activation of Akt and expression of constitutively active form of Akt enhances activation of Rac .	Particularly, expression of constitutively active form of Rac enhances activation of Akt and expression of constitutively active form of Akt enhances activation of Rac.	10	25	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac	Rac	Rac	12	13	24	25
Pharmacological inhibition of PI3K ( Wortmannin ) , Akt ( HIMO ) and GSK3beta ( SB216763 ) abrogated the activation of Rac1 induced by PGE 2 in EP3alpha expressing , EP3beta expressing and WT VSMCs ( XREF_FIG ) .	Pharmacological inhibition of PI3K (Wortmannin), Akt (HIMO) and GSK3beta (SB216763) abrogated the activation of Rac1 induced by PGE 2 in EP3alpha expressing, EP3beta expressing and WT VSMCs (XREF_FIG).	1	22	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	8	9	21	22
Although Rac1 deletion caused a significant reduction in phospho-PAK1 , -AKT , and -ERK under serum stimulation , reconstitution of active PAK1 , but not AKT or MEK1 , was able to rescue the actin cytoskeleton and adhesion phenotypes of the Rac1 deficient cells .	Although Rac1 deletion caused a significant reduction in phospho-PAK1, -AKT, and -ERK under serum stimulation, reconstitution of active PAK1, but not AKT or MEK1, was able to rescue the actin cytoskeleton and adhesion phenotypes of the Rac1 deficient cells.	18	43	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	Rac1	Rac1	Rac1	25	26	41	42
CD44s transactivates the barrier enhancing S1P1 receptor within CEM which results in the serine/threonine kinase , Akt mediated activation of the Rac1 guanine nucleotide exchange factor , Tiam1 , and Rac1-GTP formation leading to cortical actin formation and strengthening of EC-EC contacts .	CD44s transactivates the barrier enhancing S1P1 receptor within CEM which results in the serine/threonine kinase, Akt mediated activation of the Rac1 guanine nucleotide exchange factor, Tiam1, and Rac1-GTP formation leading to cortical actin formation and strengthening of EC-EC contacts.	16	27	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	16	17	21	22
The mTORC2 substrate Akt did not affect RhoGDI2 dampening , but partially increased Rac1 activity through the Rac-GEF Tiam1 , thus partially rescuing cell invasion and motility .	The mTORC2 substrate Akt did not affect RhoGDI2 dampening, but partially increased Rac1 activity through the Rac-GEF Tiam1, thus partially rescuing cell invasion and motility.	0	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	3	4	13	14
Our data reveal that PAF stimulation results in migration of THP-1 , ND and DM monocytes through phosphorylation of AKT and GSK-3beta leading to Rac-1 activation .	Our data reveal that PAF stimulation results in migration of THP-1, ND and DM monocytes through phosphorylation of AKT and GSK-3beta leading to Rac-1 activation.	17	25	leading to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	AKT	phosphorylation of AKT	akt	Rac-1	Rac-1	rac-1	19	20	24	25
Furthermore , PI3K and AKT and PKB can activate Rac1 [ XREF_BIBR ] , which in turn triggers TIMP2 , MMP2 , and MMP9 pathway to promote cell invasion [ XREF_BIBR ] .	Furthermore, PI3K and AKT and PKB can activate Rac1 [XREF_BIBR], which in turn triggers TIMP2, MMP2, and MMP9 pathway to promote cell invasion [XREF_BIBR].	2	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKB	PKB	PKB	Rac1	Rac1	Rac1	6	7	9	10
The decreased PIP3 concentration would 1 ) fail to recruit and activate Akt ; 2 ) fail to activate Rac1 through the well recognized positive feedback loop , which in turn would 3 ) diminish the uncapping of actin filaments that is required for de novo actin assembly at the leading edge , which ultimately would 4 ) inhibit functional cell polarization and chemotaxis .	The decreased PIP3 concentration would 1) fail to recruit and activate Akt; 2) fail to activate Rac1 through the well recognized positive feedback loop, which in turn would 3) diminish the uncapping of actin filaments that is required for de novo actin assembly at the leading edge, which ultimately would 4) inhibit functional cell polarization and chemotaxis.	12	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	12	13	19	20
To address whether Rac1 activation is mediated by PI3K and Akt signaling pathway , LPS activated BV-2 cells were pretreated with wortmannin , which covalently inactivates the PI3K catalytic site , and with API-2 , an Akt inhibitor .	To address whether Rac1 activation is mediated by PI3K and Akt signaling pathway, LPS activated BV-2 cells were pretreated with wortmannin, which covalently inactivates the PI3K catalytic site, and with API-2, an Akt inhibitor.	3	12	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	10	11	3	4
Surprisingly , blockage of Akt and GSK3beta , which act downstream of PI3K , reduced Rac1 and RhoA activity in VSMCs without a detectable impact on Cdc42 and inhibited the reorientation of the MTOCs toward to directional migration , suggesting the involvement of Rac1 and RhoA in the microtubule rearrangement and cell polarity as described previously 46 .	Surprisingly, blockage of Akt and GSK3beta, which act downstream of PI3K, reduced Rac1 and RhoA activity in VSMCs without a detectable impact on Cdc42 and inhibited the reorientation of the MTOCs toward to directional migration, suggesting the involvement of Rac1 and RhoA in the microtubule rearrangement and cell polarity as described previously 46.	2	18	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	4	5	15	16
Akt signaling activates Rac1 through the Rac-GEF Tiam1 , while PKC signaling dampens expression of the endogenous Rac1 inhibitor , RhoGDI2 .	Akt signaling activates Rac1 through the Rac-GEF Tiam1, while PKC signaling dampens expression of the endogenous Rac1 inhibitor, RhoGDI2.	0	4	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	0	1	3	4
Therefore , these results suggest that positive feedback activation of Rac by Akt is important for full activation of Rac in addition to activation of Rac by synergistic activation of P-Rex1 through Gbetagamma and PI3K .	Therefore, these results suggest that positive feedback activation of Rac by Akt is important for full activation of Rac in addition to activation of Rac by synergistic activation of P-Rex1 through Gbetagamma and PI3K.	8	13	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac	Rac	Rac	12	13	10	11
PI3K and Akt may be upstream and activates Rac1 , while JNK may be downstream of Rac1 .	PI3K and Akt may be upstream and activates Rac1, while JNK may be downstream of Rac1.	0	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	2	3	8	9
Moreover , the inhibitors also reduced Rac1 activation in fMLF stimulated cells , suggesting a crosstalk between Akt and p-Rex1 activation of Rac1 .	Moreover, the inhibitors also reduced Rac1 activation in fMLF stimulated cells, suggesting a crosstalk between Akt and p-Rex1 activation of Rac1.	17	23	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	17	18	22	23
3 ) P-Akt activates Rac1 and Calpain , which enhances SOCE and in turn P-Akt .	3) P-Akt activates Rac1 and Calpain, which enhances SOCE and in turn P-Akt.	0	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	P-Akt	P-Akt	P-Akt	Rac1	Rac1	Rac1	2	3	4	5
XREF_BIBR , XREF_BIBR These studies suggest that AKT , ERK1/2 and NF-kappaB pro survival signalings are downstream targets of Rac1 .	XREF_BIBR, XREF_BIBR These studies suggest that AKT, ERK1/2 and NF-kappaB pro survival signalings are downstream targets of Rac1.	7	20	are downstream targets	Positive_activation_copula_1	Negative_activation	Positive_activation	AKT	AKT	AKT	Rac1	Rac1	Rac1	7	8	19	20
Insulin stimulated ( P < .05 ) phosphorylation of insulin receptor ( +320 % ) , and insulin receptor substrate-1 ( +140 % ) , Akt ( +177 % ) , glycogen-synthase kinase-beta3 ( +70 % ) , and endothelial nitric oxide synthase ( eNOS ; +100 % ) increased nitric oxide production and activated Ras related C3 botulinum toxin substrate 1 ( Rac1 ) .	Insulin stimulated (P <.05) phosphorylation of insulin receptor (+320%), and insulin receptor substrate-1 (+140%), Akt (+177%), glycogen-synthase kinase-beta3 (+70%), and endothelial nitric oxide synthase (eNOS; +100%) increased nitric oxide production and activated Ras related C3 botulinum toxin substrate 1 (Rac1).	7	64	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	phosphorylation of insulin receptor (+320%), and insulin receptor substrate-1 (+140%), Akt	akt	Rac1	Rac1	rac1	25	26	63	64
Subsequently , the signaling cascade from the EGF receptor ( EGFR ) to the Akt mediated activation of Rac1 is turned off , resulting in a decrease of endomembrane trafficking of TRPM6 to the apical surface and decreased Mg 2+ transport [ XREF_BIBR ] .	Subsequently, the signaling cascade from the EGF receptor (EGFR) to the Akt mediated activation of Rac1 is turned off, resulting in a decrease of endomembrane trafficking of TRPM6 to the apical surface and decreased Mg 2+ transport [XREF_BIBR].	14	19	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	14	15	18	19
These reports initially led to our hypothesis that both AKT and ERK1/2 were downstream targets of Rac1 in the response of pancreatic cancer cells to IR .	These reports initially led to our hypothesis that both AKT and ERK1/2 were downstream targets of Rac1 in the response of pancreatic cancer cells to IR.	8	19	were downstream targets	Positive_activation_copula_1	Negative_activation	Positive_activation	AKT	AKT	AKT	Rac1	Rac1	Rac1	9	10	16	17
TGF-beta1 treatment induced cytoskeleton reorganization , alpha-SMA expression , increased the phosphorylation of ERK , Smad2/3 , and AKT , and activated RhoA and Rac1 .	TGF-beta1 treatment induced cytoskeleton reorganization, alpha-SMA expression, increased the phosphorylation of ERK, Smad2/3, and AKT, and activated RhoA and Rac1.	0	25	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	TGF-beta1 treatment induced cytoskeleton reorganization, alpha-SMA expression, increased the phosphorylation of ERK, Smad2/3, and AKT	akt	Rac1	Rac1	rac1	18	19	24	25
Downregulation of RhoB also induced Akt activation which in turns activates Rac1 via the GEF Trio .	Downregulation of RhoB also induced Akt activation which in turns activates Rac1 via the GEF Trio.	5	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	5	6	11	12
In agreement , recent work demonstrated that constitutively active Akt induces Rac1 activity in SCs , and remodeling of the actin cytoskeleton is an essential prerequisite for membrane expansion during myelination .	In agreement, recent work demonstrated that constitutively active Akt induces Rac1 activity in SCs, and remodeling of the actin cytoskeleton is an essential prerequisite for membrane expansion during myelination.	8	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	9	10	11	12
Several studies showed that Rac1 activation was dependent on PI3K activity and that inhibitors of PI3K and Akt blocked Rac1 activation XREF_BIBR , XREF_BIBR .	Several studies showed that Rac1 activation was dependent on PI3K activity and that inhibitors of PI3K and Akt blocked Rac1 activation XREF_BIBR, XREF_BIBR.	13	21	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	17	18	19	20
This results in the serine/threonine kinase , Akt mediated activation of the Rac1 guanine nucleotide exchange factor , Tiam1 , and Rac1-GTP formation leading to cortical actin formation and strengthening of EC-EC contacts .	This results in the serine/threonine kinase, Akt mediated activation of the Rac1 guanine nucleotide exchange factor, Tiam1, and Rac1-GTP formation leading to cortical actin formation and strengthening of EC-EC contacts.	7	18	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	7	8	12	13
In line with this possibility , constitutive activation of Akt was shown to induce Rac1 activity in cultured SCs ( Domenech-Estevez et al ., 2016 ) .	In line with this possibility, constitutive activation of Akt was shown to induce Rac1 activity in cultured SCs (Domenech-Estevez et al., 2016).	7	15	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Rac1	Rac1	Rac1	9	10	14	15
These results indicate that AKT is suppressed by EZH2 inhibition , but does not mediate the anti-autophagy effects of EZH2 on VSMCs .	These results indicate that AKT is suppressed by EZH2 inhibition, but does not mediate the anti-autophagy effects of EZH2 on VSMCs.	4	20	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	4	5	19	20
As Akt pathway mediated the cytoplasmic localization of EZH2 , LY294002 was used to inhibit Akt pathway to see its effect on actin-filament-severing proteins .	As Akt pathway mediated the cytoplasmic localization of EZH2, LY294002 was used to inhibit Akt pathway to see its effect on actin-filament-severing proteins.	1	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	EZH2	EZH2	EZH2	1	2	8	9
This is in contrast to a recent study showing that in cancer cells , Akt induced pEzh2 S21 activates those genes lacking H3K27me3 modifications 24 .	This is in contrast to a recent study showing that in cancer cells, Akt induced pEzh2 S21 activates those genes lacking H3K27me3 modifications 24.	14	17	induced	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	pEzh2	pEzh2	pEzh2	14	15	16	17
Rapamycin inhibition of mTOR , a downstream effector of Akt pathway XREF_BIBR , XREF_BIBR , increased Eomes expression and reduced Id3 , suggesting that the mechanism of Ezh2 inhibition by Akt differs from mTOR dependent effects .	Rapamycin inhibition of mTOR, a downstream effector of Akt pathway XREF_BIBR, XREF_BIBR, increased Eomes expression and reduced Id3, suggesting that the mechanism of Ezh2 inhibition by Akt differs from mTOR dependent effects.	27	31	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Ezh2	Ezh2	Ezh2	30	31	27	28
XREF_BIBR , XREF_BIBR Recent studies have shown that EZH2 could promote cell cycle progression via affecting AKT pathway or cyclin expression and that EZH2 also be modulated by post-translational modifications through phosphorylation by AKT .	XREF_BIBR, XREF_BIBR Recent studies have shown that EZH2 could promote cell cycle progression via affecting AKT pathway or cyclin expression and that EZH2 also be modulated by post-translational modifications through phosphorylation by AKT.	23	34	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	33	34	23	24
Thus , to determine whether AKT mediated the anti-autophagy role of EZH2 in VSMCs , we treated AKT overexpressed VSMCs with EZH2 inhibitor UNC1999 , which in turn significantly increased AKT and decreased H3K27me2 and H3K27me3 were observed .	Thus, to determine whether AKT mediated the anti-autophagy role of EZH2 in VSMCs, we treated AKT overexpressed VSMCs with EZH2 inhibitor UNC1999, which in turn significantly increased AKT and decreased H3K27me2 and H3K27me3 were observed.	5	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	5	6	11	12
Our data indicate that EZH2 S21 phosphorylation is required for the EZH2-STAT3 interaction and the enhanced STAT3 activity , and AKT inhibition in vivo effectively abolished pS21 EZH2 .	Our data indicate that EZH2 S21 phosphorylation is required for the EZH2-STAT3 interaction and the enhanced STAT3 activity, and AKT inhibition in vivo effectively abolished pS21 EZH2.	20	28	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	20	21	27	28
EZH2 could activate AKT pathway and be promoted by AKT pathway .	EZH2 could activate AKT pathway and be promoted by AKT pathway.	0	10	promoted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	9	10	0	1
Of note , EZH2 abundance was also reduced by AKT and STAT3 inhibition ( XREF_SUPPLEMENTARY ) .	Of note, EZH2 abundance was also reduced by AKT and STAT3 inhibition (XREF_SUPPLEMENTARY).	3	12	reduced	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	9	10	3	4
The methylation state of the STAT3 gene was found to be mediated by Enhancer of zeste homolog 2 ( EZH2 ) , that participates in DNA methylation and which can be activated by Akt signaling [ XREF_BIBR ] .	The methylation state of the STAT3 gene was found to be mediated by Enhancer of zeste homolog 2 (EZH2), that participates in DNA methylation and which can be activated by Akt signaling [XREF_BIBR].	11	36	activated	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	EZH2	EZH2	EZH2	33	34	19	20
Furthermore , we uncovered that MEK-ERK1/2 , but not AMPKalpha , mTOR , or AKT signaling pathway , mediated the function of EZH2 on ACD of VSMCs .	Furthermore, we uncovered that MEK-ERK1/2, but not AMPKalpha, mTOR, or AKT signaling pathway, mediated the function of EZH2 on ACD of VSMCs.	14	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	14	15	22	23
Given that AKT is often hyperactive in EOC , it is possible that AKT directly regulates EZH2 in a PRC2 independent manner to activate certain genes in EOC .	Given that AKT is often hyperactive in EOC, it is possible that AKT directly regulates EZH2 in a PRC2 independent manner to activate certain genes in EOC.	13	23	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	13	14	16	17
To elucidate the downstream effectors of PI3K mediated regulation of HOXA gene expression , and considering that AKT mediates EZH2 histone methyltransferase activity in HeLa cells , we assessed whether the regulatory role of the PI3K pathway on HOXA9 expression could be linked to histone modifications .	To elucidate the downstream effectors of PI3K mediated regulation of HOXA gene expression, and considering that AKT mediates EZH2 histone methyltransferase activity in HeLa cells, we assessed whether the regulatory role of the PI3K pathway on HOXA9 expression could be linked to histone modifications.	16	22	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	EZH2	EZH2	EZH2	17	18	19	20
Therefore PI3K-AKT , inducing stabilization of the two KSRP target transcripts beta-catenin and PP2ACA , could enhance the cellular levels of beta-catenin protein operating a combinatorial positive control .	Therefore PI3K-AKT, inducing stabilization of the two KSRP target transcripts beta-catenin and PP2ACA, could enhance the cellular levels of beta-catenin protein operating a combinatorial positive control.	1	16	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	KSRP	KSRP	KSRP	1	2	8	9
AKT activation induces KSRP dismissal from H19 and , as a consequence , myogenin mRNA is stabilized while KSRP is repurposed to promote maturation of myogenic microRNAs , thus favoring myogenic differentiation .	AKT activation induces KSRP dismissal from H19 and, as a consequence, myogenin mRNA is stabilized while KSRP is repurposed to promote maturation of myogenic microRNAs, thus favoring myogenic differentiation.	0	4	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	KSRP	KSRP	KSRP	0	1	3	4
In order to select KSRP target transcripts whose expression is induced by PI3K-AKT activation , we performed a comparative analysis of the results of the two screenings .	In order to select KSRP target transcripts whose expression is induced by PI3K-AKT activation, we performed a comparative analysis of the results of the two screenings.	4	13	induced	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	KSRP	KSRP	KSRP	12	13	4	5
Indeed , phosphorylation of KSRP Serine 193 by Akt promotes nuclear accumulation of KSRP through interaction with 14-3-3zeta [ XREF_BIBR ] .	Indeed, phosphorylation of KSRP Serine 193 by Akt promotes nuclear accumulation of KSRP through interaction with 14-3-3zeta [XREF_BIBR].	2	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	phosphorylation of KSRP Serine 193 by Akt	akt	KSRP	KSRP	ksrp	8	9	13	14
Previous studies demonstrated that at least two signaling pathways , the MAPK p38 and the Akt and PKB , can target KSRP and modulate ARE mediated mRNA decay XREF_BIBR .	Previous studies demonstrated that at least two signaling pathways, the MAPK p38 and the Akt and PKB, can target KSRP and modulate ARE mediated mRNA decay XREF_BIBR.	12	22	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKB	PKB	PKB	KSRP	KSRP	KSRP	17	18	21	22
Control of the Drosha microprocessor by RNA binding proteins : KSRP activation by Akt .	Control of the Drosha microprocessor by RNA binding proteins : KSRP activation by Akt.	10	14	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	KSRP	KSRP	KSRP	13	14	10	11
In contrast to HuR , KSRP was reported to de-stabilize beta-catenin mRNA and provide a platform on which both Wnt stimulation and the PI3K and AKT pathway could trigger beta-catenin accumulation by counteracting the activity of KSRP .	In contrast to HuR, KSRP was reported to de-stabilize beta-catenin mRNA and provide a platform on which both Wnt stimulation and the PI3K and AKT pathway could trigger beta-catenin accumulation by counteracting the activity of KSRP.	23	37	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	KSRP	KSRP	KSRP	25	26	36	37
To verify this hypothesis , we systematically searched , among the AU rich transcriptome , for KSRP target transcripts whose expression was upregulated by PI3K-AKT signaling .	To verify this hypothesis, we systematically searched, among the AU rich transcriptome, for KSRP target transcripts whose expression was upregulated by PI3K-AKT signaling.	16	25	upregulated	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	PI3K-AKT	PI3K-AKT	PI3K-AKT	KSRP	KSRP	KSRP	24	25	16	17
Our data contradict a recent study that insulin stimulation or AKT activation increases interaction of KSRP with 14-3-3zeta , which renders KSRP restriction in the nucleus [ XREF_BIBR , XREF_BIBR ] .	Our data contradict a recent study that insulin stimulation or AKT activation increases interaction of KSRP with 14-3-3zeta, which renders KSRP restriction in the nucleus [XREF_BIBR, XREF_BIBR].	10	16	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	KSRP	KSRP	KSRP	10	11	15	16
The use of pharmacological inhibitors revealed that the modulation of Akt , mTOR and JNK phosphorylation was required for diosgenin induced FAS suppression .	The use of pharmacological inhibitors revealed that the modulation of Akt, mTOR and JNK phosphorylation was required for diosgenin induced FAS suppression.	10	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt, mTOR and JNK phosphorylation	akt	FAS	FAS	fas	10	11	21	22
We also show that Akt leads to the accumulation of nuclear SREBP-1 but not SREBP-2 , and that activation of SREBP is required for Akt induced activation of the FAS promoter .	We also show that Akt leads to the accumulation of nuclear SREBP-1 but not SREBP-2, and that activation of SREBP is required for Akt induced activation of the FAS promoter.	24	30	induced	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	FAS	FAS	FAS	24	25	29	30
PI3-kinase and Akt signaling is known to promote survival by down regulating Fas and death receptor signaling .	PI3-kinase and Akt signaling is known to promote survival by down regulating Fas and death receptor signaling.	0	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Fas	Fas	Fas	2	3	12	13
Tumor associated FAS and SREBP-1c are mainly induced by a growth factor activated PI3 and Akt signaling cascades which are amplified through mutations in signaling molecules such as PTEN , BCR-ABL , EGFR and HER2 and neu .	Tumor associated FAS and SREBP-1c are mainly induced by a growth factor activated PI3 and Akt signaling cascades which are amplified through mutations in signaling molecules such as PTEN, BCR-ABL, EGFR and HER2 and neu.	2	17	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FAS	FAS	FAS	15	16	2	3
The co-activation of Akt and p38 MAPK could synergistically regulate dynamics of FAs and rearrangement of cytoskeleton promoting HUMSCs chemotactic migration .	The co-activation of Akt and p38 MAPK could synergistically regulate dynamics of FAs and rearrangement of cytoskeleton promoting HUMSCs chemotactic migration.	3	14	synergistically regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FAs	FAs	FAs	3	4	12	13
Together with our previous results , these findings demonstrate that TRAF1 targets the ASK1 and JNK pro death pathway and the Akt pro survival pathway , which in turn induces Fas and FasL associated neuronal apoptosis in ischaemic stroke .	Together with our previous results, these findings demonstrate that TRAF1 targets the ASK1 and JNK pro death pathway and the Akt pro survival pathway, which in turn induces Fas and FasL associated neuronal apoptosis in ischaemic stroke.	21	33	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Fas	Fas	Fas	21	22	30	31
Here , we show that inhibition of both PI3K class IA and serine threonine kinase Akt in type II cells promoted the redistribution of CD95 into lipid rafts , DISC formation and the initiation of the apoptotic signal .	Here, we show that inhibition of both PI3K class IA and serine threonine kinase Akt in type II cells promoted the redistribution of CD95 into lipid rafts, DISC formation and the initiation of the apoptotic signal.	5	25	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	CD95	CD95	CD95	15	16	24	25
The enhanced cytotoxicity of this combination was associated with diminished Akt activation and marked down-regulation of Raf-1 , MEK1/2 , and mitogen activated protein kinase ( MAPK ) .	The enhanced cytotoxicity of this combination was associated with diminished Akt activation and marked down-regulation of Raf-1, MEK1/2, and mitogen activated protein kinase (MAPK).	10	23	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Raf-1	Raf-1	Raf-1	10	11	16	17
In addition , Akt reduction was also shown to inhibit MAP3Ks , ASK1 , and Raf-1 , molecules required for the activation of p38MAPK [ XREF_BIBR ] .	In addition, Akt reduction was also shown to inhibit MAP3Ks, ASK1, and Raf-1, molecules required for the activation of p38MAPK [XREF_BIBR].	3	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Raf-1	Raf-1	Raf-1	3	4	15	16
Erks are activated by PMA , albeit to a lesser extent , in PMA resistant cells ; this response occurs via a Raf-1 mediated pathway that is modulated by Akt and RKIP [ XREF_BIBR ] .	Erks are activated by PMA, albeit to a lesser extent, in PMA resistant cells; this response occurs via a Raf-1 mediated pathway that is modulated by Akt and RKIP [XREF_BIBR].	22	33	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Raf-1	Raf-1	Raf-1	29	30	22	23
Negative regulation of the activity of a kinase by other kinases can occur in the context of a negative feedback loop , as does the inhibition of MEK1 by ERK , or in the context of pathway cross talk , as exemplified by the down-regulation of Raf-1 by Akt or PKA .	Negative regulation of the activity of a kinase by other kinases can occur in the context of a negative feedback loop, as does the inhibition of MEK1 by ERK, or in the context of pathway cross talk, as exemplified by the down-regulation of Raf-1 by Akt or PKA.	41	50	down-regulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Akt	Akt	Akt	Raf-1	Raf-1	Raf-1	48	49	46	47
It has been known that AKT can negatively regulate MEK and ERK signaling by directly inhibiting C-Raf via Ser259 phosphorylation , which promotes Raf interaction with the inhibitory scaffold 14-3-3zeta [ XREF_BIBR , XREF_BIBR ] .	It has been known that AKT can negatively regulate MEK and ERK signaling by directly inhibiting C-Raf via Ser259 phosphorylation, which promotes Raf interaction with the inhibitory scaffold 14-3-3zeta [XREF_BIBR, XREF_BIBR].	5	19	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	C-Raf	C-Raf	C-Raf	5	6	16	17
The putative RAF-AKT crosstalk in M13MDA435-1 hybrid cells was further validated by Western Blot analysing RAF-1 phosphorylation at position S259 , which is consistent with AKT mediated RAF-1 inactivation [ XREF_BIBR ] .	The putative RAF-AKT crosstalk in M13MDA435-1 hybrid cells was further validated by Western Blot analysing RAF-1 phosphorylation at position S259, which is consistent with AKT mediated RAF-1 inactivation [XREF_BIBR].	25	28	mediated	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	RAF-1	RAF-1	RAF-1	25	26	27	28
Furthermore , the study showed that acute protection from A 1 AR activation is dependent on protein kinase C and Akt activation , whereas the delayed protection is dependent on Akt activation and induction of HSP27 .	Furthermore, the study showed that acute protection from A 1 AR activation is dependent on protein kinase C and Akt activation, whereas the delayed protection is dependent on Akt activation and induction of HSP27.	30	36	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	HSP27	HSP27	HSP27	30	31	35	36
Since Hsp27 can be activated by both MAPK and Akt pathways , it is possible that interactions between IGF-1 signaling and Hsp27 phospho activation function to promote castrate resistant progression .	Since Hsp27 can be activated by both MAPK and Akt pathways, it is possible that interactions between IGF-1 signaling and Hsp27 phospho activation function to promote castrate resistant progression.	1	10	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Hsp27	Hsp27	Hsp27	9	10	1	2
In contrast to the effects on human endothelial cells , sphinganine 1-phosphate failed to phosphorylate ERK MAPK , Akt and HSP27 and induce HSP27 in HK-2 ( human renal proximal tubule epithelial ) cells ( data not shown ) .	In contrast to the effects on human endothelial cells, sphinganine 1-phosphate failed to phosphorylate ERK MAPK, Akt and HSP27 and induce HSP27 in HK-2 (human renal proximal tubule epithelial) cells (data not shown).	10	24	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	sphinganine 1-phosphate failed to phosphorylate ERK MAPK, Akt	akt	HSP27	HSP27	hsp27	18	19	23	24
Therefore , it is reasonable to postulate that PI3K and AKT could mediate HSP27 related effects .	Therefore, it is reasonable to postulate that PI3K and AKT could mediate HSP27 related effects.	8	15	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	HSP27	HSP27	HSP27	10	11	13	14
While MK2 inhibition gave a strong reduction in the GA induced phosphorylation of Hsp27 , Akt inhibition did not prevent Hsp27 activation ( XREF_FIG ) .	While MK2 inhibition gave a strong reduction in the GA induced phosphorylation of Hsp27, Akt inhibition did not prevent Hsp27 activation (XREF_FIG).	15	21	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Hsp27	Hsp27	Hsp27	15	16	20	21
Acid significantly enhanced phosphorylation of Akt and MAPKs in HEMEC as well as inducing Hsp27 and Hsp70 .	Acid significantly enhanced phosphorylation of Akt and MAPKs in HEMEC as well as inducing Hsp27 and Hsp70.	0	16	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Acid significantly enhanced phosphorylation of Akt	akt	Hsp27	Hsp27	hsp27	5	6	14	15
PI3K and Akt mediates HSP27 induced resistance to apoptosis induced by melatonin .	PI3K and Akt mediates HSP27 induced resistance to apoptosis induced by melatonin.	0	5	mediates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	HSP27	HSP27	HSP27	2	3	4	5
Importantly , we reveal here that PTEN depletion and the concomitant sustained activation of AKT cause CHK1 to be sequestered in the cytoplasm .	Importantly, we reveal here that PTEN depletion and the concomitant sustained activation of AKT cause CHK1 to be sequestered in the cytoplasm.	12	17	cause	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	CHK1	CHK1	CHK1	14	15	16	17
In the context of DNA damage , loss of PTEN enables cells to bypass the normal G2/M checkpoint enforced by CHK1 as a result of Akt mediated CHK1 sequestration in the cytoplasm .	In the context of DNA damage, loss of PTEN enables cells to bypass the normal G2/M checkpoint enforced by CHK1 as a result of Akt mediated CHK1 sequestration in the cytoplasm.	23	28	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	CHK1	CHK1	CHK1	25	26	27	28
However , it is notable that inhibition of the aberrant kinases or the PI3K and Akt pathway more prominently reduced activation of Chk1 than its expression in these cells ( XREF_FIG , XREF_FIG , XREF_FIG , XREF_FIG , XREF_FIG ) .	However, it is notable that inhibition of the aberrant kinases or the PI3K and Akt pathway more prominently reduced activation of Chk1 than its expression in these cells (XREF_FIG, XREF_FIG, XREF_FIG, XREF_FIG, XREF_FIG).	13	23	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Chk1	Chk1	Chk1	15	16	22	23
However , the suggestion that AKT modulates Chk1 activity is controversial .	However, the suggestion that AKT modulates Chk1 activity is controversial.	5	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	Chk1	Chk1	Chk1	5	6	7	8
Activation of Akt suppresses the checkpoint by inhibiting the DNA damage response pathways , either ATM and Chk2 or ATR and Chk1 , depending on the cellular context .	Activation of Akt suppresses the checkpoint by inhibiting the DNA damage response pathways, either ATM and Chk2 or ATR and Chk1, depending on the cellular context.	0	22	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	Chk1	Chk1	Chk1	2	3	21	22
Thus , the PI3K and Akt pathway may enhance Chk1 activation also in hematopoietic cells under some circumstances , although under the conditions more relevant to treatment of leukemia its inhibition downregulated Chk1 activation and G2/M checkpoint to enhance apoptosis .	Thus, the PI3K and Akt pathway may enhance Chk1 activation also in hematopoietic cells under some circumstances, although under the conditions more relevant to treatment of leukemia its inhibition downregulated Chk1 activation and G2/M checkpoint to enhance apoptosis.	3	10	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Chk1	Chk1	Chk1	5	6	9	10
Loss of PTEN and subsequent activation of AKT impair Chk1 through phosphorylation , ubiquitination , and reduced nuclear localization to promote genomic instability in tumor cells [ XREF_BIBR ] .	Loss of PTEN and subsequent activation of AKT impair Chk1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells [XREF_BIBR].	5	10	impair	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	Chk1	Chk1	Chk1	7	8	9	10
Similarly , growth inhibition observed in PTEN depleted HK-2 cells is also relieved by MK-2206 treatment ( XREF_FIG ) , suggestive of an upstream role of PTEN loss mediated Akt activation in pSMAD3 dependent fibrotic responses .	Similarly, growth inhibition observed in PTEN depleted HK-2 cells is also relieved by MK-2206 treatment (XREF_FIG), suggestive of an upstream role of PTEN loss mediated Akt activation in pSMAD3 dependent fibrotic responses.	29	33	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	pSMAD3	pSMAD3	pSMAD3	29	30	32	33
Thus , it is the abrogation of SMAD3 mediated signaling by Akt that may influence the stability and proliferative capacity of Tie2-ECs .	Thus, it is the abrogation of SMAD3 mediated signaling by Akt that may influence the stability and proliferative capacity of Tie2-ECs.	7	12	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	SMAD3	SMAD3	SMAD3	11	12	7	8
Conversely , a reduced amount of IGF-1R diminished the levels of P-AKT , allowing dissociation and nuclear translocation of Smad3 and enhancement of the TGFbeta1 signaling pathway and fibrosis [ XREF_BIBR ] .	Conversely, a reduced amount of IGF-1R diminished the levels of P-AKT, allowing dissociation and nuclear translocation of Smad3 and enhancement of the TGFbeta1 signaling pathway and fibrosis [XREF_BIBR].	4	21	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	P-AKT	amount of IGF-1R diminished the levels of P-AKT	p-akt	Smad3	Smad3	smad3	11	12	19	20
Exactly how PI3K and Akt modulates Smad3 activation remains a question unanswered .	Exactly how PI3K and Akt modulates Smad3 activation remains a question unanswered.	2	7	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Smad3	Smad3	Smad3	4	5	6	7
Additionally , it is possible that Akt could mediate SMAD3 post-translationally via proteasomal targeting [ XREF_BIBR ] in ECs .	Additionally, it is possible that Akt could mediate SMAD3 post-translationally via proteasomal targeting [XREF_BIBR] in ECs.	6	10	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	SMAD3	SMAD3	SMAD3	6	7	9	10
Thus , the eupatolide mediated increase in AKT phosphorylation may enhance the degree of interaction between AKT and SMAD3 , which contributes to the inhibition of TGF-beta signal transduction .	Thus, the eupatolide mediated increase in AKT phosphorylation may enhance the degree of interaction between AKT and SMAD3, which contributes to the inhibition of TGF-beta signal transduction.	7	21	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT phosphorylation	akt	SMAD3	SMAD3	smad3	7	8	18	19
Akt activates apoptosis regulating kinase 1 ( Ask1 ) to promote apoptosis in response to ROS .	Akt activates apoptosis regulating kinase 1 (Ask1) to promote apoptosis in response to ROS.	0	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Ask1	Ask1	Ask1	0	1	7	8
The previously unrecognized relationship whereby blocking FOXO activity via direct inhibition or Akt activation activates JNK and c-JUN signaling is quite distinctive from prior reports that AKT inhibits JNK by inhibiting the JNK activating kinase ASK1 .	The previously unrecognized relationship whereby blocking FOXO activity via direct inhibition or Akt activation activates JNK and c-JUN signaling is quite distinctive from prior reports that AKT inhibits JNK by inhibiting the JNK activating kinase ASK1.	26	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT	AKT	ASK1	ASK1	ASK1	26	27	35	36
Silencing Akt by siRNA reduced the activation of ASK1 and p38 MAPK and cell apoptosis , whereas without nickel stimulation , siRNA Akt had no effect on the activation of ASK1 and p38 MAPK .	Silencing Akt by siRNA reduced the activation of ASK1 and p38 MAPK and cell apoptosis, whereas without nickel stimulation, siRNA Akt had no effect on the activation of ASK1 and p38 MAPK.	0	11	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	1	2	8	9
Our study demonstrates that nickel induced BEAS-2B cell apoptosis through the Akt mediated ASK1 and p38 pathway .	Our study demonstrates that nickel induced BEAS-2B cell apoptosis through the Akt mediated ASK1 and p38 pathway.	8	16	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	11	12	13	14
The present study demonstrates that nickel induced generation of ROS activated Akt , which activated ASK1 through Thr838 phosphorylation , leading to downstream activation of p38 MAPK , eventually causing cell apoptosis .	The present study demonstrates that nickel induced generation of ROS activated Akt, which activated ASK1 through Thr838 phosphorylation, leading to downstream activation of p38 MAPK, eventually causing cell apoptosis.	10	16	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	ASK1	ASK1	ASK1	11	12	15	16
However , further increase in Akt promotes accumulation of the inactive form of MST2 which sequesters Raf-1 from being activated by Ras via formation of the MST2-ERK complexes , thus resulting in suppressed ERK activity at high Akt levels ( Phase II , indicated in XREF_FIG b ) .	However, further increase in Akt promotes accumulation of the inactive form of MST2 which sequesters Raf-1 from being activated by Ras via formation of the MST2-ERK complexes, thus resulting in suppressed ERK activity at high Akt levels (Phase II, indicated in XREF_FIG b).	3	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	MST2	MST2	MST2	5	6	13	14
Small molecule inhibitors of PI3K and Akt or depletion of Akt activate MST2 .	Small molecule inhibitors of PI3K and Akt or depletion of Akt activate MST2.	2	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MST2	MST2	MST2	6	7	12	13
The second layer encompasses Akt , which can either promote or suppress MST2 activation and apoptosis depending on its activation profile .	The second layer encompasses Akt, which can either promote or suppress MST2 activation and apoptosis depending on its activation profile.	3	13	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	MST2	MST2	MST2	4	5	12	13
We also did not see significantly increased phosphorylation of the Akt targets GSK3alpha and beta in the rescued cells ( XREF_SUPPLEMENTARY ) .	We also did not see significantly increased phosphorylation of the Akt targets GSK3alpha and beta in the rescued cells (XREF_SUPPLEMENTARY).	7	18	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	phosphorylation of the Akt	akt	GSK3alpha	GSK3alpha	gsk3alpha	10	11	12	13
Enhanced Akt activity is further evidenced by increased phosphorylation levels of the Akt target GSK3alpha and beta ( serine 21/serine 9 ) in IWAT and muscle ( XREF_FIG G ) .	Enhanced Akt activity is further evidenced by increased phosphorylation levels of the Akt target GSK3alpha and beta (serine 21/serine 9) in IWAT and muscle (XREF_FIG G).	9	18	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3alpha	GSK3alpha	GSK3alpha	12	13	14	15
The data of XREF_FIG supports the idea that there is constitutive Akt dependent mediation of GSK3alpha activity .	The data of XREF_FIG supports the idea that there is constitutive Akt dependent mediation of GSK3alpha activity.	11	16	mediation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3alpha	GSK3alpha	GSK3alpha	11	12	15	16
Furthermore , the IL-8 expression increased and remained at high levels after 6h when Akt was inhibited to avoid GSK3alpha inhibition .	Furthermore, the IL-8 expression increased and remained at high levels after 6h when Akt was inhibited to avoid GSK3alpha inhibition.	14	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	GSK3alpha	GSK3alpha	GSK3alpha	14	15	19	20
ATP caused translocation of GLUT4myc-eGFP to the cell surface , mechanistically mediated by increased exocytosis involving AS160 and Rab8A reduced by dominant negative Akt or PI3Kgamma kinase dead mutants , and potentiated by myristoylated PI3Kgamma .	ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160 and Rab8A reduced by dominant negative Akt or PI3Kgamma kinase dead mutants, and potentiated by myristoylated PI3Kgamma.	14	28	reduced	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AS160	AS160	AS160	23	24	16	17
To address the apparent disconnect between Akt signaling and glucose utilization , the Akt targets AS160 ( involved in GLUT4 trafficking and glucose uptake ) and GSK3beta ( involved in regulation of glycogen synthesis ) were assessed in CBK and littermate CON hearts .	To address the apparent disconnect between Akt signaling and glucose utilization, the Akt targets AS160 (involved in GLUT4 trafficking and glucose uptake) and GSK3beta (involved in regulation of glycogen synthesis) were assessed in CBK and littermate CON hearts.	12	36	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AS160	AS160	AS160	13	14	15	16
Recent in vitro experiments using insulinoma cells demonstrated that the Akt target AS160 relates survival signals from Akt signaling [ XREF_BIBR ] .	Recent in vitro experiments using insulinoma cells demonstrated that the Akt target AS160 relates survival signals from Akt signaling [XREF_BIBR].	9	13	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	AS160	AS160	AS160	10	11	12	13
Stimulation of glucose transport in muscle involves activation of Akt and phosphorylation of Rab GTPase activating protein AS160 by Akt .	Stimulation of glucose transport in muscle involves activation of Akt and phosphorylation of Rab GTPase activating protein AS160 by Akt.	7	18	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt and phosphorylation	akt	AS160	AS160	as160	9	10	17	18
Under acute stress conditions , AKT promoted cell survival by inhibiting MST1 , but prolonged stress decreased AKT , which allowed pro apoptotic MST1 signaling .	Under acute stress conditions, AKT promoted cell survival by inhibiting MST1, but prolonged stress decreased AKT, which allowed pro apoptotic MST1 signaling.	5	12	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	MST1	MST1	MST1	5	6	11	12
PI3K and AKT were inhibited by LY294002 and triciribine ( AKT inhibitor ) led to lower levels of phosphorylation of GSK3 and FOXO1 , two well characterized AKT substrates and induced MST1 activation ( XREF_FIG and XREF_SUPPLEMENTARY ) .	PI3K and AKT were inhibited by LY294002 and triciribine (AKT inhibitor) led to lower levels of phosphorylation of GSK3 and FOXO1, two well characterized AKT substrates and induced MST1 activation (XREF_FIG and XREF_SUPPLEMENTARY).	0	32	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	MST1	MST1	MST1	2	3	31	32
Constitutively active ( CA ) Akt or CA IKKbeta blocks PDCD4 mediated inhibition and restores renal cancer cell migration and invasion .	Constitutively active (CA) Akt or CA IKKbeta blocks PDCD4 mediated inhibition and restores renal cancer cell migration and invasion.	1	14	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	PDCD4	PDCD4	PDCD4	5	6	10	11
Notably , enhanced AKT activation in Pdcd4 -/- ADSCs was accompanied by a marked increase in the expression of cyclinD1 , a main regulator of G1/S phase transition , XREF_BIBR , XREF_BIBR which was consistent with the changes of cell cycle in XREF_FIG ( XREF_FIG ) .	Notably, enhanced AKT activation in Pdcd4 -/- ADSCs was accompanied by a marked increase in the expression of cyclinD1, a main regulator of G1/S phase transition, XREF_BIBR, XREF_BIBR which was consistent with the changes of cell cycle in XREF_FIG (XREF_FIG).	3	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	Pdcd4	Pdcd4	Pdcd4	3	4	6	7
AKT and RSK can also target some of these PDCD4 sites ( XREF_FIG ) .	AKT and RSK can also target some of these PDCD4 sites (XREF_FIG).	0	10	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	PDCD4	PDCD4	PDCD4	0	1	9	10
We therefore hypothesized that the insulin and Akt pathway differentially modulates the co-repressor activity of NCoR1 at lipogenic and oxidative phosphorylation ( OxPhos )/ketogenic genes .	We therefore hypothesized that the insulin and Akt pathway differentially modulates the co-repressor activity of NCoR1 at lipogenic and oxidative phosphorylation (OxPhos)/ketogenic genes.	5	24	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	NCoR1	NCoR1	NCoR1	7	8	15	16
Thus , the fact that the transcriptional repressive activity of NCoR1 is enhanced in nutrient affluent conditions , which are usually associated with enhanced Akt and PKB phosphorylation , seems in conflict with the transcriptional de-repression mechanism of NCoR1 induced by Akt and PKB phosphorylation .	Thus, the fact that the transcriptional repressive activity of NCoR1 is enhanced in nutrient affluent conditions, which are usually associated with enhanced Akt and PKB phosphorylation, seems in conflict with the transcriptional de-repression mechanism of NCoR1 induced by Akt and PKB phosphorylation.	36	45	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt and PKB phosphorylation	akt	NCoR1	NCoR1	ncor1	41	42	38	39
On the basis of the mutations found in TAL1 positive T-ALL cases , such as the prevalence for PTEN deletions , we hypothesized that strong AKT activation could be required to drive the proliferation of TAL1 + cells .	On the basis of the mutations found in TAL1 positive T-ALL cases, such as the prevalence for PTEN deletions, we hypothesized that strong AKT activation could be required to drive the proliferation of TAL1 + cells.	25	37	drive	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	TAL1	TAL1	TAL1	25	26	35	36
Phosphorylations of Thr90 by Akt kinase and Ser122 by MAP kinase enhance transcriptional activity in TAL1 .	Phosphorylations of Thr90 by Akt kinase and Ser122 by MAP kinase enhance transcriptional activity in TAL1.	0	16	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Phosphorylations of Thr90 by Akt kinase and Ser122	akt	TAL1	TAL1	tal1	4	5	15	16
Most importantly , for the first time , we have discovered a novel reverse regulation within the traditional PTEN and AKT signaling pathway , whereby AKT induces GATA2 with consequent decreased PTEN transcription , likely germane in tumor invasion and metastases but not initiation .	Most importantly, for the first time, we have discovered a novel reverse regulation within the traditional PTEN and AKT signaling pathway, whereby AKT induces GATA2 with consequent decreased PTEN transcription, likely germane in tumor invasion and metastases but not initiation.	20	28	induces	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	GATA2	GATA2	GATA2	20	21	27	28
This finding was supported by the observations that activation of cAMP signaling inhibited Akt activity via Rap1A and that inhibition of PI3K and Akt with specific pharmacological inhibitors or by expressing dominant negative enzymes inhibited the MKK4 and JNK pathway and HDAC8 protein degradation .	This finding was supported by the observations that activation of cAMP signaling inhibited Akt activity via Rap1A and that inhibition of PI3K and Akt with specific pharmacological inhibitors or by expressing dominant negative enzymes inhibited the MKK4 and JNK pathway and HDAC8 protein degradation.	19	39	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	MKK4	MKK4	MKK4	23	24	36	37
It has also been reported that the PI3K and Akt cascade negatively regulates the JNK pathway in PC12 cells by inhibiting MLK3 to downregulate MKK-7 [ XREF_BIBR ] .	It has also been reported that the PI3K and Akt cascade negatively regulates the JNK pathway in PC12 cells by inhibiting MLK3 to downregulate MKK-7 [XREF_BIBR].	7	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	MLK3	MLK3	MLK3	9	10	21	22
However , Erk activation is enhanced only slightly , and there is no increase in Akt activation in PTP1B deficient cells .	However, Erk activation is enhanced only slightly, and there is no increase in Akt activation in PTP1B deficient cells.	15	20	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	PTP1B	PTP1B	PTP1B	15	16	18	19
These findings suggest that Akt mediated PGC-1alpha inactivation could be also involved in senescence in these cells .	These findings suggest that Akt mediated PGC-1alpha inactivation could be also involved in senescence in these cells.	4	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	PGC-1alpha	PGC-1alpha	PGC-1alpha	4	5	6	7
Here , we show that in Streptozotocin induced diabetic wild type mice , hypo phosphorylation of Akt , resulted in activation of Foxa2 transcription factor in the muscle .	Here, we show that in Streptozotocin induced diabetic wild type mice, hypo phosphorylation of Akt, resulted in activation of Foxa2 transcription factor in the muscle.	14	24	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Akt	phosphorylation of Akt	akt	Foxa2	Foxa2	foxa2	16	17	22	23
Inhibition of Akt phosphorylation by IRAK 1/4 inhibitor and the inability of LY294002 to inhibit IRAK1 - TRAF6 interaction suggested that there was a sequential activation of IRAK followed by PI 3-kinase activation in IL-1beta signaling in human CEC .	Inhibition of Akt phosphorylation by IRAK 1/4 inhibitor and the inability of LY294002 to inhibit IRAK1 - TRAF6 interaction suggested that there was a sequential activation of IRAK followed by PI 3-kinase activation in IL-1beta signaling in human CEC.	2	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt phosphorylation by IRAK	akt	IRAK1	IRAK1	irak1	2	3	15	16
These data reveal for the first time that HtrA2 and Omi is directly regulated by Akt and provide a mechanism by which Akt induces cell survival at post-mitochondrial level .	These data reveal for the first time that HtrA2 and Omi is directly regulated by Akt and provide a mechanism by which Akt induces cell survival at post-mitochondrial level.	8	16	directly regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Omi	Omi	Omi	15	16	10	11
ERK , Akt , and Jak2 mediate Gab2 induced HepG2 cell proliferation and migration .	ERK, Akt, and Jak2 mediate Gab2 induced HepG2 cell proliferation and migration.	0	8	mediate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Gab2	Gab2	Gab2	2	3	7	8
The cells expressing AMPK-alpha1 were serum starved , and some were then treated with IGF-1 to activate Akt .	The cells expressing AMPK-alpha1 were serum starved, and some were then treated with IGF-1 to activate Akt.	2	18	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Akt	Akt	Akt	AMPK-alpha1	AMPK-alpha1	AMPK-alpha1	17	18	3	4
This result is consistent with the observed lack of suppression of Akt ^ by Ban ( XREF_FIG ) and suggests that Mad may be targeted by Akt in the context of synaptogenesis .	This result is consistent with the observed lack of suppression of Akt ^ by Ban (XREF_FIG) and suggests that Mad may be targeted by Akt in the context of synaptogenesis.	21	27	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Mad	Mad	Mad	26	27	21	22
In addition , we documented the FoxO6 phosphorylation process , and showed how both Akt and Pak1 signaling modulated FoxO6 activities induced by LPS during aging by using HepG2 cells and aged rat livers .	In addition, we documented the FoxO6 phosphorylation process, and showed how both Akt and Pak1 signaling modulated FoxO6 activities induced by LPS during aging by using HepG2 cells and aged rat livers.	14	20	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	FoxO6	FoxO6	FoxO6	14	15	19	20
To determine whether AKT directed tuberin ' s subcellular localization , tuberin from membrane and cytosolic compartments of NIH3T3 cells treated with IGF-1 or EGF was immunoprecipitated and detected with a ( S/T ) phosphosubstrate antibody that recognizes the consensus phosphorylation site for AKT and RSK containing phospho-Ser and Thr with Arg at position -5 and -3 ( RXRXXpS/T ) .	To determine whether AKT directed tuberin 's subcellular localization, tuberin from membrane and cytosolic compartments of NIH3T3 cells treated with IGF-1 or EGF was immunoprecipitated and detected with a (S/T) phosphosubstrate antibody that recognizes the consensus phosphorylation site for AKT and RSK containing phospho-Ser and Thr with Arg at position -5 and -3 (RXRXXpS/T).	3	20	directed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	tuberin	tuberin	tuberin	3	4	5	6
The mTOR is an important molecule downstream of Akt , and is activated when Akt abrogates the suppressive action of tumor suppressor tuberin ( also known as tuberous sclerosis complex 1 , TSC1 ) on mTOR [ XREF_BIBR , XREF_BIBR ] .	The mTOR is an important molecule downstream of Akt, and is activated when Akt abrogates the suppressive action of tumor suppressor tuberin (also known as tuberous sclerosis complex 1, TSC1) on mTOR [XREF_BIBR, XREF_BIBR].	14	23	abrogates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	tuberin	tuberin	tuberin	14	15	22	23
Although it is clear that activation of AKT blocks tuberin inhibition of TOR signaling , the mechanism by which AKT inactivates this tumor suppressor is unknown .	Although it is clear that activation of AKT blocks tuberin inhibition of TOR signaling, the mechanism by which AKT inactivates this tumor suppressor is unknown.	5	10	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	tuberin	tuberin	tuberin	7	8	9	10
AKT inhibits TSC2 mediated inhibition of the mammalian target of rapamycin , or mTOR , functionality .	AKT inhibits TSC2 mediated inhibition of the mammalian target of rapamycin, or mTOR, functionality.	0	4	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	0	1	2	3
As it is a direct downstream target of PI-3K , Akt is a key oncogenic survival factor and can inactivate a broad panel of critical pro apoptotic molecules such as p38 MAPK , Bad , caspase-9 , the Forkhead transcription factor FKHRL1 , GSK3-beta , cell-cycle inhibitors p21 and p27 , and tumour suppressors p53 and TSC2 ( Zhou et al , 2001 ; Inoki et al , 2002 ; Blain and Massague , 2002 ; Liao and Hung , 2003 ) .	As it is a direct downstream target of PI-3K, Akt is a key oncogenic survival factor and can inactivate a broad panel of critical pro apoptotic molecules such as p38 MAPK, Bad, caspase-9, the Forkhead transcription factor FKHRL1, GSK3-beta, cell-cycle inhibitors p21 and p27, and tumour suppressors p53 and TSC2 (Zhou et al, 2001; Inoki et al, 2002; Blain and Massague, 2002; Liao and Hung, 2003).	10	57	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	10	11	56	57
Of interest , direct and paracrine AKT activation of the TSC2 and mTOR pathway has been shown to be necessary and sufficient for vGPCR oncogenesis .	Of interest, direct and paracrine AKT activation of the TSC2 and mTOR pathway has been shown to be necessary and sufficient for vGPCR oncogenesis.	6	13	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	6	7	10	11
Its activity is regulated by various stimuli ( XREF_FIG ) -- activators include nutrient redundancy as well as signaling from growth factor receptors which causes an Akt mediated relief of hamartin and tuberin ( TSC1/2 )-mediated mTORC1 inhibition .	Its activity is regulated by various stimuli (XREF_FIG) -- activators include nutrient redundancy as well as signaling from growth factor receptors which causes an Akt mediated relief of hamartin and tuberin (TSC1/2)-mediated mTORC1 inhibition.	25	33	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	tuberin	tuberin	tuberin	26	27	32	33
Moreover , Shh induced mouse medulloblastomas manifested Akt mediated TSC2 inactivation , and the mutant TSC2 allele synergized with aberrant Shh signaling to increase medulloblastoma incidence in mice .	Moreover, Shh induced mouse medulloblastomas manifested Akt mediated TSC2 inactivation, and the mutant TSC2 allele synergized with aberrant Shh signaling to increase medulloblastoma incidence in mice.	7	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	7	8	9	10
Within the phosphatidylinositide 3-kinase ( PI3K )/AKT signalling pathway , AKT directly phosphorylates TSC2 on four or five residues , revealing that TSC1 and TSC2 is directly regulated by AKT [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Within the phosphatidylinositide 3-kinase (PI3K)/AKT signalling pathway, AKT directly phosphorylates TSC2 on four or five residues, revealing that TSC1 and TSC2 is directly regulated by AKT [XREF_BIBR, XREF_BIBR, XREF_BIBR].	22	35	directly regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	29	30	24	25
We went on to show that neither blockade nor knockdown of Akt1 , 2 or 3 ( alone or in combination ) impacted proliferation or levels of p-mTOR and downstream targets , even in a setting where the canonical Akt targets Tsc2 and Gsk3 were potently inhibited .	We went on to show that neither blockade nor knockdown of Akt1, 2 or 3 (alone or in combination) impacted proliferation or levels of p-mTOR and downstream targets, even in a setting where the canonical Akt targets Tsc2 and Gsk3 were potently inhibited.	37	46	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	Tsc2	Tsc2	Tsc2	39	40	41	42
Our findings highlight the efficacy of late-onset DR in managing astrocytoma growth and suggest that DR may be an effective broad-spectrum inhibitor of Akt signaling in PTEN and TSC2 deficient astrocytomas .	Our findings highlight the efficacy of late-onset DR in managing astrocytoma growth and suggest that DR may be an effective broad-spectrum inhibitor of Akt signaling in PTEN and TSC2 deficient astrocytomas.	23	29	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	23	24	28	29
Although it is clear that growth factor induced activation of Akt blocks TSC1 and TSC2 inhibition of mTOR signaling [ XREF_BIBR - XREF_BIBR ] , the molecular mechanism by which Akt inhibits the function of TSC1 and TSC2 protein complex as a cell growth suppressor is still undefined .	Although it is clear that growth factor induced activation of Akt blocks TSC1 and TSC2 inhibition of mTOR signaling [XREF_BIBR - XREF_BIBR], the molecular mechanism by which Akt inhibits the function of TSC1 and TSC2 protein complex as a cell growth suppressor is still undefined.	8	15	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	10	11	14	15
Akt activates mTOR via phosphorylation and inhibition of the TSC2 subunit of the tuberous sclerosis complex ( TSC ) .	Akt activates mTOR via phosphorylation and inhibition of the TSC2 subunit of the tuberous sclerosis complex (TSC).	0	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	9	10
Akt triggers a network that positively regulates G1/S cell cycle progression through inactivation of GSK3beta , leading to increased cyclin D1 , and inhibition of Forkhead family transcription factors and the tumor suppressor tuberin ( TSC2 ) , leading to reduction of p27 ( Kip1 ) [ XREF_BIBR ] .	Akt triggers a network that positively regulates G1/S cell cycle progression through inactivation of GSK3beta, leading to increased cyclin D1, and inhibition of Forkhead family transcription factors and the tumor suppressor tuberin (TSC2), leading to reduction of p27 (Kip1) [XREF_BIBR].	0	38	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	tuberin	tuberin	tuberin	0	1	33	34
There is a marked reduction in Akt activation in Tsc2 (-/-) TP53 (-/-) and Tsc1 (-/-) cells in response to serum and PDGF , along with a reduction in cell ruffling .	There is a marked reduction in Akt activation in Tsc2 (-/-) TP53 (-/-) and Tsc1 (-/-) cells in response to serum and PDGF, along with a reduction in cell ruffling.	6	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Tsc2	Tsc2	Tsc2	6	7	9	10
PKB triggers a network that positively regulates G1/S cell cycle progression through inactivation of GSK3-beta , leading to increased cyclin D1 , and inhibition of Forkhead family transcription factors and the tumor suppressor tuberin ( TSC2 ) , leading to reduction of p27Kip1 .	PKB triggers a network that positively regulates G1/S cell cycle progression through inactivation of GSK3-beta, leading to increased cyclin D1, and inhibition of Forkhead family transcription factors and the tumor suppressor tuberin (TSC2), leading to reduction of p27Kip1.	0	38	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PKB	PKB	PKB	tuberin	tuberin	tuberin	0	1	33	34
Akt ( protein kinase B , PKB ) , a PH domain containing serine/threonine kinase , regulates growth factor signaling to stimulate glucose uptake , glycogen synthesis and protein synthesis by influencing the glycogen synthase kinase 3 ( GSK3 ) alpha/beta and tuberous sclerosis complex 2 ( TSC2 )-mTOR signaling pathways .	Akt (protein kinase B, PKB), a PH domain containing serine/threonine kinase, regulates growth factor signaling to stimulate glucose uptake, glycogen synthesis and protein synthesis by influencing the glycogen synthase kinase 3 (GSK3) alpha/beta and tuberous sclerosis complex 2 (TSC2)-mTOR signaling pathways.	0	50	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	47	48
Indeed , not only does loss of dystrophin affect synaptic transmission XREF_BIBR and has recently been found to cause susceptibility to malignant tumors in mice XREF_BIBR , it also affects activity of Akt XREF_BIBR , a kinase that directly regulates TSC2 .	Indeed, not only does loss of dystrophin affect synaptic transmission XREF_BIBR and has recently been found to cause susceptibility to malignant tumors in mice XREF_BIBR, it also affects activity of Akt XREF_BIBR, a kinase that directly regulates TSC2.	32	41	directly regulates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	32	33	40	41
Consistently , inhibition of mTORC1 and S6K signaling by a specific S6K1 inhibitor , S6K1-I 31 or mTORC1 inhibitor , rapamycin XREF_BIBR , XREF_BIBR , XREF_BIBR could still augment Akt activation in TSC2 -/- MEFs depleted of endogenous IRS-1 and/or Grb10 ( XREF_SUPPLEMENTARY ) , advocating that mTORC1 and S6K could exert its negative regulation of mTORC2 and Akt following PDGF or EGF stimulation through uncharacterized negative feedback loop ( s ) other than IRS-1 and Grb10 .	Consistently, inhibition of mTORC1 and S6K signaling by a specific S6K1 inhibitor, S6K1-I 31 or mTORC1 inhibitor, rapamycin XREF_BIBR, XREF_BIBR, XREF_BIBR could still augment Akt activation in TSC2 -/- MEFs depleted of endogenous IRS-1 and/or Grb10 (XREF_SUPPLEMENTARY), advocating that mTORC1 and S6K could exert its negative regulation of mTORC2 and Akt following PDGF or EGF stimulation through uncharacterized negative feedback loop (s) other than IRS-1 and Grb10.	29	34	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	29	30	32	33
It is generally believed that activation of PI3K and Akt stimulates the mTOR pathway by phosphorylating and inactivating the tumor suppressor protein tuberous sclerosis complex 2 ( TSC2 ) , which negatively regulates mTOR activity .	It is generally believed that activation of PI3K and Akt stimulates the mTOR pathway by phosphorylating and inactivating the tumor suppressor protein tuberous sclerosis complex 2 (TSC2), which negatively regulates mTOR activity.	5	32	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	9	10	27	28
Taken together , these data suggest that EGF activates mTORC1 in spinal cord astrocytes through Akt mediated Tuberin inactivation ( XREF_SUPPLEMENTARY ) .	Taken together, these data suggest that EGF activates mTORC1 in spinal cord astrocytes through Akt mediated Tuberin inactivation (XREF_SUPPLEMENTARY).	8	18	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	Tuberin	Tuberin	Tuberin	15	16	17	18
have shown that Akt does not promote release of TSC2 from TSC1 , but instead activates mTORC1 by causing dissociation of the TSC holocomplex from the lysosomal membrane where Rheb is located .	have shown that Akt does not promote release of TSC2 from TSC1, but instead activates mTORC1 by causing dissociation of the TSC holocomplex from the lysosomal membrane where Rheb is located.	3	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	3	4	9	10
Akt activates mTOR through ( i ) phosphorylation and inhibition of tuberous sclerosis complex 2 ( TSC2 ) , which inactivates the mTOR activating GTP binding protein Rheb , and/or ( ii ) phosphorylation of PRAS40 a member of mTORC1 , one of the two functional complexes of mTOR , which includes mLST8 and Gbl and the scaffold protein Raptor .	Akt activates mTOR through (i) phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which inactivates the mTOR activating GTP binding protein Rheb, and/or (ii) phosphorylation of PRAS40 a member of mTORC1, one of the two functional complexes of mTOR, which includes mLST8 and Gbl and the scaffold protein Raptor.	0	31	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	16	17
The protein kinase Akt activates mTOR via direct phosphorylation and inhibition of tuberous sclerosis complex 2 ( TSC2 ) , which is a negative regulator of mTOR XREF_BIBR .	The protein kinase Akt activates mTOR via direct phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which is a negative regulator of mTOR XREF_BIBR.	0	24	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	3	4	17	18
The downstream target of the insulin receptor signaling pathway Akt inhibits the TSC2 protein and allows Rheb-GTP to accumulate and to activate mTORC1 and thus amplifies the amino acid dependent activation .	The downstream target of the insulin receptor signaling pathway Akt inhibits the TSC2 protein and allows Rheb-GTP to accumulate and to activate mTORC1 and thus amplifies the amino acid dependent activation.	2	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	9	10	12	13
Further results reveal that influenza A virus H5N1 notably decreases the phosphorylation of the AKT kinase that downregulates the TSC2 .	Further results reveal that influenza A virus H5N1 notably decreases the phosphorylation of the AKT kinase that downregulates the TSC2.	7	20	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	H5N1 notably decreases the phosphorylation of the AKT	akt	TSC2	TSC2	tsc2	14	15	19	20
Enhanced ATP and AMP ratio stabilizes Akt , which targets TSC2 , PRAS40 ; this results in further activation of mTORC1 .	Enhanced ATP and AMP ratio stabilizes Akt, which targets TSC2, PRAS40; this results in further activation of mTORC1.	0	15	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	6	7	10	11
In MCF-7 cells expressing constitutively active myristoylated AKT ( myr-AKT ) , AKT phosphorylation inactivates TSC2 , with loss of TSC2 from the membrane and peroxisomal fractions and increased TSC2 in the cytosol ( XREF_FIG ) .	In MCF-7 cells expressing constitutively active myristoylated AKT (myr-AKT), AKT phosphorylation inactivates TSC2, with loss of TSC2 from the membrane and peroxisomal fractions and increased TSC2 in the cytosol (XREF_FIG).	12	18	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AKT	AKT phosphorylation	akt	TSC2	TSC2	tsc2	12	13	15	16
Consistent with the insulin resistant nature of Akt signaling in the Tsc2 -/- MEFs , removal of insulin from the differentiation mixture only mildly reduced intracellular triglyceride levels ( XREF_FIG ) .	Consistent with the insulin resistant nature of Akt signaling in the Tsc2 -/- MEFs, removal of insulin from the differentiation mixture only mildly reduced intracellular triglyceride levels (XREF_FIG).	7	12	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Tsc2	Tsc2	Tsc2	7	8	11	12
PIM and AKT can activate TSC2 directly [ XREF_BIBR ] or by controlling AMP : ATP ratio [ XREF_BIBR ] .	PIM and AKT can activate TSC2 directly [XREF_BIBR] or by controlling AMP : ATP ratio [XREF_BIBR].	0	6	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	2	3	5	6
Akt plasmid transfection and RNA interference supported Akt and tuberous sclerosis 2 ( TSC2 ) involvement in this process .	Akt plasmid transfection and RNA interference supported Akt and tuberous sclerosis 2 (TSC2) involvement in this process.	0	15	supported	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	13	14
In contrast to WT , antagonism of PI3K-Akt signaling in adult TSC2 +/- slices had no effect on the expression of LTD , nor did it restore rapamycin sensitivity ( XREF_FIG ) .	In contrast to WT, antagonism of PI3K-Akt signaling in adult TSC2 +/- slices had no effect on the expression of LTD, nor did it restore rapamycin sensitivity (XREF_FIG).	7	13	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PI3K-Akt	PI3K-Akt	PI3K-Akt	TSC2	TSC2	TSC2	7	8	11	12
AKT targets TSC2 , preventing it from inhibiting mTOR 25 .	AKT targets TSC2, preventing it from inhibiting mTOR 25.	0	3	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	0	1	2	3
AKT is known to activate mTOR via phosphorylation and inhibition of the TSC2 subunit of the tuberous sclerosis complex ( TSC ) .	AKT is known to activate mTOR via phosphorylation and inhibition of the TSC2 subunit of the tuberous sclerosis complex (TSC).	0	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	0	1	12	13
AKT activation triggered glycogen synthase kinase ( GSK3 ) and TSC2 downregulation via phosphorylation , and TSC2 inactivation facilitated phospho-mTOR and phospho-p70S6K upregulation .	AKT activation triggered glycogen synthase kinase (GSK3) and TSC2 downregulation via phosphorylation, and TSC2 inactivation facilitated phospho-mTOR and phospho-p70S6K upregulation.	0	11	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	0	1	10	11
Insulin stimulated Akt activation can also promote mTORC1 activity via direct phosphorylation and inhibition of TSC2 ,.	Insulin stimulated Akt activation can also promote mTORC1 activity via direct phosphorylation and inhibition of TSC2,.	2	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	2	3	15	16
We therefore used phospho specific antibodies to assess the modulation of Tsc2 by Akt and ERK1/2 in neurons stimulated with BDNF or ephrin-A1 .	We therefore used phospho specific antibodies to assess the modulation of Tsc2 by Akt and ERK1/2 in neurons stimulated with BDNF or ephrin-A1.	7	17	modulation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Tsc2	Tsc2	Tsc2	13	14	11	12
This releases ULK1/2 to activate FIP200 , a protein critical for autophagosome formation and autophagy initiation ; as an upstream effector of mTOR , Akt can activate mTOR via direct phosphorylation and inhibition of tuberous sclerosis complex 2 ( TSC2 ) , which is a negative regulator of mTOR .	This releases ULK1/2 to activate FIP200, a protein critical for autophagosome formation and autophagy initiation; as an upstream effector of mTOR, Akt can activate mTOR via direct phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which is a negative regulator of mTOR.	24	46	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	24	25	39	40
Akt activation in Tsc2 -/- p53 -/- MEFs was reduced due to impaired mTORC2 activity XREF_BIBR .	Akt activation in Tsc2 -/- p53 -/- MEFs was reduced due to impaired mTORC2 activity XREF_BIBR.	0	5	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	Tsc2	Tsc2	Tsc2	0	1	3	4
Akt activates mTORC1 by phosphorylating and thereby deactivating the negative regulator TSC2 .	Akt activates mTORC1 by phosphorylating and thereby deactivating the negative regulator TSC2.	0	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	0	1	11	12
A recent study showed that a combination of sirolimus and resveratrol , a polyphenol present in fruits and red wine , reduced sirolimus induced autophagy and prevented Akt activation and apoptosis of TSC2 deficient cells [ XREF_BIBR ] .	A recent study showed that a combination of sirolimus and resveratrol, a polyphenol present in fruits and red wine, reduced sirolimus induced autophagy and prevented Akt activation and apoptosis of TSC2 deficient cells [XREF_BIBR].	27	34	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	27	28	32	33
Physical sequestration of tuberin from its target Rheb suggested a mechanism whereby AKT modulated tuberin by partitioning it away from the membrane rather than altering its intrinsic GAP activity for Rheb .	Physical sequestration of tuberin from its target Rheb suggested a mechanism whereby AKT modulated tuberin by partitioning it away from the membrane rather than altering its intrinsic GAP activity for Rheb.	12	15	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	tuberin	tuberin	tuberin	12	13	14	15
To confirm that activation of AKT directed tuberin to the cytosol , MCF7 cells stably transfected with a constitutively active AKT ( myr-AKT ) were examined and found to contain more cytosolic tuberin relative to wild-type MCF7 cells ( XREF_FIG ) .	To confirm that activation of AKT directed tuberin to the cytosol, MCF7 cells stably transfected with a constitutively active AKT (myr-AKT) were examined and found to contain more cytosolic tuberin relative to wild-type MCF7 cells (XREF_FIG).	3	8	directed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	tuberin	tuberin	tuberin	5	6	7	8
Ras mediated activation of both , the PI3K and AKT pathway and the MEK and ERK pathway , can trigger downregulation of the function of tuberin to block the activities of mTOR and p70S6K .	Ras mediated activation of both, the PI3K and AKT pathway and the MEK and ERK pathway, can trigger downregulation of the function of tuberin to block the activities of mTOR and p70S6K.	7	26	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	tuberin	tuberin	tuberin	9	10	25	26
Importantly , the effect of NFkappaB was specific to AS160 as AKT target TSC2 T1462 phosphorylation was unaffected by NFkappaB inhibition ( XREF_FIG ) .	Importantly, the effect of NFkappaB was specific to AS160 as AKT target TSC2 T1462 phosphorylation was unaffected by NFkappaB inhibition (XREF_FIG).	11	14	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AKT	AKT	AKT	TSC2	TSC2	TSC2	11	12	13	14
In addition , similar to the function of Rictor to mTORC2 , mSin1 mediates Akt phosphorylation of FOXO3a [ XREF_BIBR ] , while other Akt targets TSC2 , GSK3 , and the TORC1 effectors , S6K and 4E-BP1 were unaffected .	In addition, similar to the function of Rictor to mTORC2, mSin1 mediates Akt phosphorylation of FOXO3a [XREF_BIBR], while other Akt targets TSC2, GSK3, and the TORC1 effectors, S6K and 4E-BP1 were unaffected.	23	39	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	24	25	26	27
As a control , inhibition of Akt significantly prevented insulin induced dissociation of TSC2 from lysosomes .	As a control, inhibition of Akt significantly prevented insulin induced dissociation of TSC2 from lysosomes.	4	14	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	TSC2	TSC2	TSC2	6	7	13	14
Tuberin translocation is mediated by AKT phosphorylation .	Tuberin translocation is mediated by AKT phosphorylation.	0	7	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AKT	AKT phosphorylation	akt	Tuberin	Tuberin	tuberin	5	6	0	1
Because ATM mediates activation of Akt in response to cellular stress , we additionally investigated its response to MTBITC .	Because ATM mediates activation of Akt in response to cellular stress, we additionally investigated its response to MTBITC.	1	7	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	1	2	5	6
Pharmacological inhibition of ATM has been shown to suppress Akt mediated pro survival signaling in cancer cells 26 .	Pharmacological inhibition of ATM has been shown to suppress Akt mediated pro survival signaling in cancer cells 26.	1	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	3	4	9	10
Since ATM can stimulate Akt activity in differentiated SH-SY5Y cells , it is conceivable that ATM inhibition may result in reduced cell survival .	Since ATM can stimulate Akt activity in differentiated SH-SY5Y cells, it is conceivable that ATM inhibition may result in reduced cell survival.	1	5	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	1	2	4	5
Moreover , ATM activated Akt , a pro survival signal , whose inhibition further enhanced ( S )-crizotinib-induced inhibition of GC cell growth and tumor growth in xenograft mice , and re-sensitized resistant GC cells to ( S )-crizotinib .	Moreover, ATM activated Akt, a pro survival signal, whose inhibition further enhanced (S)-crizotinib-induced inhibition of GC cell growth and tumor growth in xenograft mice, and re-sensitized resistant GC cells to (S)-crizotinib.	2	14	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	2	3	4	5
The new information provided by the study is that cell-line-dependent differences in the role of ATM in insulin signaling provide support for specific experimental models in which to study the role of ATM in insulin stimulated activation of Akt ( C2C12 and RD cells ) and to examine Akt independent effects of ATM ( L6 cells and mouse skeletal muscle ) in mediation of insulin ' s effects .	The new information provided by the study is that cell-line-dependent differences in the role of ATM in insulin signaling provide support for specific experimental models in which to study the role of ATM in insulin stimulated activation of Akt (C2C12 and RD cells) and to examine Akt independent effects of ATM (L6 cells and mouse skeletal muscle) in mediation of insulin 's effects.	30	43	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	32	33	38	39
It is particularly interesting that ATM mediated AKT activation may be a double edged sword , both increasing DNA repair to promote genomic integrity while at the same time increasing pro tumorigenic metabolism .	It is particularly interesting that ATM mediated AKT activation may be a double edged sword, both increasing DNA repair to promote genomic integrity while at the same time increasing pro tumorigenic metabolism.	5	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	ATM	ATM	ATM	AKT	AKT	AKT	5	6	7	8
ATM mediated Akt activation in response to insulin is possibly through PI3K , not mTOR or DNA-PK , in neuron like SH-SY5Y cells .	ATM mediated Akt activation in response to insulin is possibly through PI3K, not mTOR or DNA-PK, in neuron like SH-SY5Y cells.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	0	1	2	3
The blockade of ATM with KU55933 prevented the ( S )-crizotinib-induced Akt activation , a finding consistent with reports that ATM is a major regulator of full Akt activation , its inhibition correlated with suppression of Akt dependent pro survival signals in cancer cells 25 .	The blockade of ATM with KU55933 prevented the (S)-crizotinib-induced Akt activation, a finding consistent with reports that ATM is a major regulator of full Akt activation, its inhibition correlated with suppression of Akt dependent pro survival signals in cancer cells 25.	1	12	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	3	4	11	12
Notably , treatment of Atm -/- NSCs with SB203580 restored Akt activation and normal proliferation XREF_BIBR , which implies that in Atm -/- NSCs , Bmi-1 degradation may be accelerated by chronic p38 activation .	Notably, treatment of Atm -/- NSCs with SB203580 restored Akt activation and normal proliferation XREF_BIBR, which implies that in Atm -/- NSCs, Bmi-1 degradation may be accelerated by chronic p38 activation.	4	11	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Atm	Atm	Atm	Akt	Akt	Akt	4	5	10	11
Recent papers indicate that other DNA damage induced pathways such as the Mre11 and ATM activate AKT under genotoxic stress to promote survival .	Recent papers indicate that other DNA damage induced pathways such as the Mre11 and ATM activate AKT under genotoxic stress to promote survival.	8	17	activate	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	AKT	AKT	AKT	14	15	16	17
These results demonstrate that ATM mediates the Akt signaling and promotes cell survival in neuron like human SH-SY5Y cells , suggesting that impaired activation of Akt is the reason for neuronal degeneration in human A-T .	These results demonstrate that ATM mediates the Akt signaling and promotes cell survival in neuron like human SH-SY5Y cells, suggesting that impaired activation of Akt is the reason for neuronal degeneration in human A-T.	4	10	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	4	5	7	8
Given its ability to activate ATM , AMPK , and Akt -- which together play prominent roles in responsive to genotoxic , oxidative , and metabolic stress , are central regulators of fuel uptake , storage , and oxidation , and play key cardioprotective roles -- CQ can exert positive metabolic effects , even in cell types in which ATM does not activate AMPK or Akt .	Given its ability to activate ATM, AMPK, and Akt -- which together play prominent roles in responsive to genotoxic, oxidative, and metabolic stress, are central regulators of fuel uptake, storage, and oxidation, and play key cardioprotective roles -- CQ can exert positive metabolic effects, even in cell types in which ATM does not activate AMPK or Akt.	59	66	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	59	60	65	66
ATM Activates AKT .	ATM Activates AKT.	0	3	Activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	AKT	AKT	AKT	0	1	2	3
Moreover ATM pharmacological inhibition has been shown to inhibit AKT dependent prosurvival signal in cancer cells [ XREF_BIBR , XREF_BIBR ] .	Moreover ATM pharmacological inhibition has been shown to inhibit AKT dependent prosurvival signal in cancer cells [XREF_BIBR, XREF_BIBR].	1	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	AKT	AKT	AKT	1	2	9	10
Furthermore , it has demonstrated that ATM is necessary for full activation of Akt in response to insulin in Cos cells , and a role of ATM in insulin stimulated activation of Akt in cultured L6 myoblasts has been described .	Furthermore, it has demonstrated that ATM is necessary for full activation of Akt in response to insulin in Cos cells, and a role of ATM in insulin stimulated activation of Akt in cultured L6 myoblasts has been described.	24	33	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	26	27	32	33
We hypothesized that chloroquine and resveratrol , both known ATM activators , would also activate AMPK and Akt .	We hypothesized that chloroquine and resveratrol, both known ATM activators, would also activate AMPK and Akt.	9	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	9	10	17	18
Nevertheless , these findings appears in line with previous reports showing that ATM mediates full activation of Akt in response to insulin or DNA damage , XREF_BIBR - XREF_BIBR and that Akt may regulate Skp2 at both transcriptional and posttranscriptional levels .	Nevertheless, these findings appears in line with previous reports showing that ATM mediates full activation of Akt in response to insulin or DNA damage, XREF_BIBR - XREF_BIBR and that Akt may regulate Skp2 at both transcriptional and posttranscriptional levels.	12	19	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	12	13	17	18
Furthermore , several studies associate the lack of ATM mediated AKT signaling with neuronal degeneration [ XREF_BIBR - XREF_BIBR ] , and the possibility of a rescue mechanism promoted by Dexa is a very interesting prospect .	Furthermore, several studies associate the lack of ATM mediated AKT signaling with neuronal degeneration [XREF_BIBR - XREF_BIBR], and the possibility of a rescue mechanism promoted by Dexa is a very interesting prospect.	6	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	ATM	ATM	ATM	AKT	AKT	AKT	8	9	10	11
These results suggest that ATM mediated Akt activation in response to insulin involves PI3K , not mTOR or DNA-PK .	These results suggest that ATM mediated Akt activation in response to insulin involves PI3K, not mTOR or DNA-PK.	4	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	4	5	6	7
We found that Atm -/- NSCs , but not Atm +/+ NSCs , failed to activate Akt after exposure to H 2 O 2 ( data not shown ) , demonstrating that ATM is required for the activation of Akt .	We found that Atm -/- NSCs, but not Atm +/+ NSCs, failed to activate Akt after exposure to H 2 O 2 (data not shown), demonstrating that ATM is required for the activation of Akt.	3	17	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Atm	Atm	Atm	Akt	Akt	Akt	3	4	16	17
ATM activates AKT in response to DNA damage .	ATM activates AKT in response to DNA damage.	0	4	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	AKT	AKT	AKT	0	1	2	3
Inhibition of the ATM activity represses Akt activation , leading to reduced cell growth and induction of apoptosis in cancer cells with Akt overphosphorylated by insulin growth factor.25 However , it remains unknown whether ATM is involved in the regulation of the EGFR pathway in NSCLCs .	Inhibition of the ATM activity represses Akt activation, leading to reduced cell growth and induction of apoptosis in cancer cells with Akt overphosphorylated by insulin growth factor.25 However, it remains unknown whether ATM is involved in the regulation of the EGFR pathway in NSCLCs.	3	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	3	4	6	7
The opposite effect was observed upon DNA damage , when ATM activated AKT kinase phosphorylates Nup153 , an important nucleopore component , thus enhancing its interaction with EXP-5 and promoting the export of pre-miRNAs into the cytoplasm [ XREF_BIBR ] .	The opposite effect was observed upon DNA damage, when ATM activated AKT kinase phosphorylates Nup153, an important nucleopore component, thus enhancing its interaction with EXP-5 and promoting the export of pre-miRNAs into the cytoplasm [XREF_BIBR].	10	16	activated	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	ATM	ATM	atm	AKT	AKT kinase phosphorylates Nup153	akt	10	11	12	13
As shown in Figure XREF_FIG , the expression levels of p-Akt Ser473 and pGSK-3beta Ser9 were markedly decreased in cells treated with KU55933 , indicating that ATM may activate the Akt and GSK-3beta signaling .	As shown in Figure XREF_FIG, the expression levels of p-Akt Ser473 and pGSK-3beta Ser9 were markedly decreased in cells treated with KU55933, indicating that ATM may activate the Akt and GSK-3beta signaling.	26	33	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	26	27	30	31
Our results show that ATM is mainly responsible for nuclear response to DNA damage in undifferentiated SH-SY5Y cells , whereas ATM mediates the Akt signaling and promotes cell survival in neuronally differentiated SH-SY5Y cells .	Our results show that ATM is mainly responsible for nuclear response to DNA damage in undifferentiated SH-SY5Y cells, whereas ATM mediates the Akt signaling and promotes cell survival in neuronally differentiated SH-SY5Y cells.	20	26	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	20	21	23	24
Ataxia telangiectasia mutated ( ATM ) activates Akt kinase to phosphorylate Nup153 , a key component of the nucleopore , leading to enhanced interaction between Nup153 and Xpo5 and more efficient nuclear export of pre-miRNAs .	Ataxia telangiectasia mutated (ATM) activates Akt kinase to phosphorylate Nup153, a key component of the nucleopore, leading to enhanced interaction between Nup153 and Xpo5 and more efficient nuclear export of pre-miRNAs.	1	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	4	5	7	8
We further demonstrated that ATM mediated downregulation of protein phosphatase 2A activity caused activation of the AKT and cyclin D1 pathway after long-term FR .	We further demonstrated that ATM mediated downregulation of protein phosphatase 2A activity caused activation of the AKT and cyclin D1 pathway after long-term FR.	4	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	AKT	AKT	AKT	4	5	16	17
It was reported that ATM mediates full activation of Akt in response to insulin or DNA damage , XREF_BIBR - XREF_BIBR and several reports have demonstrated that Akt may regulate Skp2 function at both transcriptional and posttranscriptional levels .	It was reported that ATM mediates full activation of Akt in response to insulin or DNA damage, XREF_BIBR - XREF_BIBR and several reports have demonstrated that Akt may regulate Skp2 function at both transcriptional and posttranscriptional levels.	4	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Akt	Akt	Akt	4	5	9	10
In the example in Figure XREF_FIG , we see the genes ATM , CHK1 , CHK2 and MDM2 with the relationships : ATM activating CHK1 , CHK2 and MDM2 inhibiting p53 .	In the example in Figure XREF_FIG, we see the genes ATM, CHK1, CHK2 and MDM2 with the relationships : ATM activating CHK1, CHK2 and MDM2 inhibiting p53.	22	29	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	22	23	28	29
These two relationships are illustrated in Figure XREF_FIG where we see ATM activating CHK1 , CHK2 and MDM2 inhibiting p53 .	These two relationships are illustrated in Figure XREF_FIG where we see ATM activating CHK1, CHK2 and MDM2 inhibiting p53.	11	18	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	11	12	17	18
Therefore , further in-depth studies are needed to investigate the precise molecular mechanism of how ATM affects CKIdelta cellular localization , as well as how ATM and CKIdelta work synergistically to promote Mdm2 destruction following DNA damage .	Therefore, further in-depth studies are needed to investigate the precise molecular mechanism of how ATM affects CKIdelta cellular localization, as well as how ATM and CKIdelta work synergistically to promote Mdm2 destruction following DNA damage.	25	33	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	25	26	32	33
Consistent with previous studies , we found that inactivation of the Ataxia Telangiectasia Mutated ( ATM ) kinase , in turn , impaired DNA damage induced Mdm2 destruction .	Consistent with previous studies, we found that inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase, in turn, impaired DNA damage induced Mdm2 destruction.	11	27	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ataxia Telangiectasia Mutated	Ataxia Telangiectasia Mutated	Ataxia Telangiectasia Mutated	Mdm2	Mdm2	Mdm2	11	14	26	27
ATM and CHK1 kinases induced by genotoxic stress signals activate p53 by driving dissociation of MDM2 and MDM4 through phophorylation [ XREF_BIBR ] .	ATM and CHK1 kinases induced by genotoxic stress signals activate p53 by driving dissociation of MDM2 and MDM4 through phophorylation [XREF_BIBR].	0	17	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	0	1	15	16
ATM triggers the activation of p53 , Chk2 and indirectly a cytoplasmic form of Mdm2 - a natural inhibitor of p53 .	ATM triggers the activation of p53, Chk2 and indirectly a cytoplasmic form of Mdm2 - a natural inhibitor of p53.	0	15	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	0	1	14	15
Stabilization of p53 in response to DNA damage requires ATM mediated inactivation of the oncoprotein Mdm2 , a ubiquitin ligase that acts as a major negative regulator of p53 .	Stabilization of p53 in response to DNA damage requires ATM mediated inactivation of the oncoprotein Mdm2, a ubiquitin ligase that acts as a major negative regulator of p53.	8	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	oncoprotein Mdm2	oncoprotein Mdm2	oncoprotein Mdm2	9	10	14	16
However , ATM can further activate MDM2 at Ser395 allowing MDM2 self degradation [ XREF_BIBR ] .	However, ATM can further activate MDM2 at Ser395 allowing MDM2 self degradation [XREF_BIBR].	2	7	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	2	3	6	7
Our data provides direct , in vivo , evidence that DNA damage induced phosphorylation of Mdm2 at this single residue by ATM induces Mdm2 destabilization .	Our data provides direct, in vivo, evidence that DNA damage induced phosphorylation of Mdm2 at this single residue by ATM induces Mdm2 destabilization.	19	24	induces	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	21	22	23	24
Thus , by directly mediating or indirectly promoting post-translational modifications of both p53 and its negative regulator Mdm2 , ATM disrupts the p53-Mdm2 negative loop through different mechanisms , resulting in a rapid accumulation of p53 , especially in the nucleus .	Thus, by directly mediating or indirectly promoting post-translational modifications of both p53 and its negative regulator Mdm2, ATM disrupts the p53-Mdm2 negative loop through different mechanisms, resulting in a rapid accumulation of p53, especially in the nucleus.	9	21	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Mdm2	Mdm2	Mdm2	19	20	17	18
These results show how ATM mediated modifications of HDMX and HDM2 switch HDM2 E3 ubiquitin ligase activity away from p53 but toward HDMX and itself and illustrate how the substrate specificity of HDM2 E3 ligase activity is regulated .	These results show how ATM mediated modifications of HDMX and HDM2 switch HDM2 E3 ubiquitin ligase activity away from p53 but toward HDMX and itself and illustrate how the substrate specificity of HDM2 E3 ligase activity is regulated.	4	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	HDM2	HDM2	HDM2	4	5	12	13
In unstressed cells , degradation of p53 is rapid , while the degradation of MDM2 is slow ( delta MDM2 = 0.002 , k atm = ~ 0 , k atm : ATM induced accelerated degradation rate of MDM2 ) .	In unstressed cells, degradation of p53 is rapid, while the degradation of MDM2 is slow (delta MDM2 = 0.002, k atm = ~ 0, k atm : ATM induced accelerated degradation rate of MDM2).	32	39	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	MDM2	MDM2	MDM2	32	33	38	39
Exenatide , a GLP-1R agonist , is thought to potentially promote CM clearance by reducing postprandial levels of apoCIII , which inhibits lipoprotein lipase and hinders hepatic TRL clearance .	Exenatide, a GLP-1R agonist, is thought to potentially promote CM clearance by reducing postprandial levels of apoCIII, which inhibits lipoprotein lipase and hinders hepatic TRL clearance.	0	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoCIII	Exenatide, a GLP-1R agonist, is thought to potentially promote CM clearance by reducing postprandial levels of apoCIII	apociii	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	18	19	22	24
ApoCIII decreases TRL catabolism by inhibiting lipoprotein lipase activity and reducing ApoE dependent hepatic uptake of TRL and remnants .	ApoCIII decreases TRL catabolism by inhibiting lipoprotein lipase activity and reducing ApoE dependent hepatic uptake of TRL and remnants.	0	8	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoCIII	ApoCIII	ApoCIII	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	6	8
To test whether by chronically limiting lipoprotein lipase activity ApoC3 might also reduce topic and/or ectopic fat deposition , we grouped subjects into tertiles of triglyceride with progressively higher ApoC3 enrichment ( ApoC3 to triglycerides ratio ) and then compared body fat and serum alanine aminotransferase ( ALT ) concentration ( as a proxy for fatty liver ) .	To test whether by chronically limiting lipoprotein lipase activity ApoC3 might also reduce topic and/or ectopic fat deposition, we grouped subjects into tertiles of triglyceride with progressively higher ApoC3 enrichment (ApoC3 to triglycerides ratio) and then compared body fat and serum alanine aminotransferase (ALT) concentration (as a proxy for fatty liver).	6	13	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ApoC3	ApoC3	ApoC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	9	10	6	8
Indeed , apoC3 impairs the lipolysis of TRLs by inhibiting lipoprotein lipase and the hepatic uptake of TRLs by remnant receptors .	Indeed, apoC3 impairs the lipolysis of TRLs by inhibiting lipoprotein lipase and the hepatic uptake of TRLs by remnant receptors.	2	12	impairs	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	apoC3	apoC3	apoC3	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	2	3	10	12
Two apolipoproteins known to regulate VLDL lipolysis by lipoprotein lipase are apoC-II and apoC-III , which activate and inhibit lipoprotein lipase , respectively .	Two apolipoproteins known to regulate VLDL lipolysis by lipoprotein lipase are apoC-II and apoC-III, which activate and inhibit lipoprotein lipase, respectively.	11	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	apoC-III	apoC-III	apoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	13	14	19	21
This observation is surprising when considering the respective functions of apoC-II and apoC-III , which are to activate and inhibit lipoprotein lipase activity , respectively XREF_BIBR .	This observation is surprising when considering the respective functions of apoC-II and apoC-III, which are to activate and inhibit lipoprotein lipase activity, respectively XREF_BIBR.	8	22	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	apoC-III	apoC-III	apoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	12	13	20	22
This is consistent with previous observations that reduced apoC-III in TRL enhances LPL mediated lipolysis and receptor mediated clearance of TRL , thereby lowering plasma triglyceride levels .	This is consistent with previous observations that reduced apoC-III in TRL enhances LPL mediated lipolysis and receptor mediated clearance of TRL, thereby lowering plasma triglyceride levels.	8	13	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	apoC-III	apoC-III	apoC-III	LPL	LPL	LPL	8	9	12	13
Particularly , fibrates inhibit the expression of APOC-III thereby enhancing the LPL activity [ XREF_BIBR ] .	Particularly, fibrates inhibit the expression of APOC-III thereby enhancing the LPL activity [XREF_BIBR].	5	12	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	APOC-III	expression of APOC-III	apoc-iii	LPL	LPL	lpl	7	8	11	12
During this process , the C apolipoproteins including apo C-II , which activates lipoprotein lipase , and apo C-III , which inhibits this enzyme , as well as apo A-I and apo A-IV are transferred to high-density lipoproteins ( HDLs ) .	During this process, the C apolipoproteins including apo C-II, which activates lipoprotein lipase, and apo C-III, which inhibits this enzyme, as well as apo A-I and apo A-IV are transferred to high-density lipoproteins (HDLs).	12	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	apo C-III	apo C-III	apo C-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	17	19	13	15
FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II , very low-density lipoproteins receptor ( VLDL-R ) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III , which increases lipoprotein lipase activity .	FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity.	32	39	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	apolipoprotein C-III	apolipoprotein C-III	apolipoprotein C-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	32	34	37	39
APOCIII is synthesized in the liver and is thought to inhibit the clearance of TG rich lipoproteins by noncompetitively inhibiting LPL .	APOCIII is synthesized in the liver and is thought to inhibit the clearance of TG rich lipoproteins by noncompetitively inhibiting LPL.	0	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	APOCIII	APOCIII	APOCIII	LPL	LPL	LPL	0	1	20	21
ApoC-III is thought to slow the metabolism of chylomicrons and VLDL by inhibiting lipoprotein lipase and blocking the engagement of apoE and apoB-100 with their hepatic receptors .	ApoC-III is thought to slow the metabolism of chylomicrons and VLDL by inhibiting lipoprotein lipase and blocking the engagement of apoE and apoB-100 with their hepatic receptors.	0	15	slow	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ApoC-III	ApoC-III	ApoC-III	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	13	15
In this regard , ATM positively regulates CtIP activity in promoting DNA end resection 5 .	In this regard, ATM positively regulates CtIP activity in promoting DNA end resection 5.	4	8	positively regulates	Positive_activation_syntax_1b_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	CtIP	CtIP	CtIP	4	5	7	8
This resection is abrogated by inhibition of ATM signaling or depletion of CtIP [ XREF_BIBR ] .	This resection is abrogated by inhibition of ATM signaling or depletion of CtIP [XREF_BIBR].	7	14	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ATM	ATM	ATM	CtIP	CtIP	CtIP	7	8	12	13
The exact mechanism of ATM activation of CtIP to promote initial end resection is still not clear .	The exact mechanism of ATM activation of CtIP to promote initial end resection is still not clear.	4	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ATM	ATM	ATM	CtIP	CtIP	CtIP	4	5	7	8
For example , ATM deficiency inhibits resection by impairing CtIP activation 29 , but promotes resection via other nucleases by impairing inhibitory activities of H2AX , 53BP1 and , indirectly , Rif1 XREF_BIBR , XREF_BIBR ( XREF_FIG ) .	For example, ATM deficiency inhibits resection by impairing CtIP activation 29, but promotes resection via other nucleases by impairing inhibitory activities of H2AX, 53BP1 and, indirectly, Rif1 XREF_BIBR, XREF_BIBR (XREF_FIG).	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ATM	ATM	ATM	CtIP	CtIP	CtIP	3	4	9	10
Thus , the defect in CE and SE joining per se in the combined absence of H2AX and XLF may reflect H2AX functioning downstream of ATM activation at a DSB , both to promote joining , for example via an end tethering function , and also to specifically prevent end resection by ATM activated CtIP .	Thus, the defect in CE and SE joining per se in the combined absence of H2AX and XLF may reflect H2AX functioning downstream of ATM activation at a DSB, both to promote joining, for example via an end tethering function, and also to specifically prevent end resection by ATM activated CtIP.	48	55	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	CtIP	CtIP	CtIP	52	53	54	55
Tel1 and its mammalian homologue ATM stimulate resection initiation by activating MRX and CtIP .	Tel1 and its mammalian homologue ATM stimulate resection initiation by activating MRX and CtIP.	4	14	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	CtIP	CtIP	CtIP	5	6	13	14
It is not immediately clear why ATM would not be required for GCRs , because CtIP , which is activated by ATM , is required for GCRs XREF_BIBR .	It is not immediately clear why ATM would not be required for GCRs, because CtIP, which is activated by ATM, is required for GCRs XREF_BIBR.	15	24	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	CtIP	CtIP	CtIP	21	22	15	16
Furthermore , ATM inhibition from 40 to 48 hpi decreased levels of the hyper-phosphorylated form of CtIP ( XREF_SUPPLEMENTARY , compare lane 1 to 2 ) , an ATM and CDK dependent product XREF_BIBR .	Furthermore, ATM inhibition from 40 to 48 hpi decreased levels of the hyper-phosphorylated form of CtIP (XREF_SUPPLEMENTARY, compare lane 1 to 2), an ATM and CDK dependent product XREF_BIBR.	2	17	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	CtIP	CtIP	CtIP	2	3	16	17
Furthermore , we found that expression of Amot , but not AmotDeltaN , rescued aPKCzeta-ca cells from stratified growth in 2D cultures , which is consistent with this phenotype being driven by Yap1 activity and Amot sequestering Yap1 from the nucleus ( XREF_FIG ) .	Furthermore, we found that expression of Amot, but not AmotDeltaN, rescued aPKCzeta-ca cells from stratified growth in 2D cultures, which is consistent with this phenotype being driven by Yap1 activity and Amot sequestering Yap1 from the nucleus (XREF_FIG).	30	38	sequestering	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Amot	Amot	Amot	Yap1	Yap1	Yap1	35	36	37	38
Of importance , expression of Amot , but not AmotDeltaN , was able to restore Yap1 localization to cell junctions ( XREF_FIG ) , consistent with a role for Amot in sequestration of Yap1 at tight junctions in MDCK cells .	Of importance, expression of Amot, but not AmotDeltaN, was able to restore Yap1 localization to cell junctions (XREF_FIG), consistent with a role for Amot in sequestration of Yap1 at tight junctions in MDCK cells.	3	16	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Amot	expression of Amot	amot	Yap1	Yap1	yap1	5	6	15	16
In 2D cultures , expression of Amot , but not AmotDeltaN , was able to restore Yap1 exclusion from the nucleus ( XREF_FIG , and Supplemental Figure S7 , F and G ) .	In 2D cultures, expression of Amot, but not AmotDeltaN, was able to restore Yap1 exclusion from the nucleus (XREF_FIG, and Supplemental Figure S7, F and G).	4	17	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Amot	expression of Amot	amot	Yap1	Yap1	yap1	6	7	16	17
Although reexpression of Amot was sufficient to restore Yap1 at tight junctions , it did not restore the plasma membrane localization of Mst1/2 or Lats1/2 phosphorylation , indicating that loss of Mst1/2 from the plasma membrane and inactivation of Lats1/2 are upstream of loss of Amot expression .	Although reexpression of Amot was sufficient to restore Yap1 at tight junctions, it did not restore the plasma membrane localization of Mst1/2 or Lats1/2 phosphorylation, indicating that loss of Mst1/2 from the plasma membrane and inactivation of Lats1/2 are upstream of loss of Amot expression.	1	9	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Amot	reexpression of Amot	amot	Yap1	Yap1	yap1	3	4	8	9
AMOT promotes either YAP1 nuclear localization or cytoplasmic retention in different cancer types .	AMOT promotes either YAP1 nuclear localization or cytoplasmic retention in different cancer types.	0	5	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AMOT	AMOT	AMOT	YAP1	YAP1	YAP1	0	1	3	4
Despite the demonstrated modulation of beta-catenin by Wtx in BMPC differentiation , the two genes have distinct roles in later stages of osteogenesis .	Despite the demonstrated modulation of beta-catenin by Wtx in BMPC differentiation, the two genes have distinct roles in later stages of osteogenesis.	3	10	modulation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Wtx	Wtx	Wtx	beta-catenin	beta-catenin	beta-catenin	7	8	5	6
Cytoplasmic WTX physically associates with components of the beta-catenin destruction complex and inhibits Wnt signaling by enhancing the degradation of beta-catenin .	Cytoplasmic WTX physically associates with components of the beta-catenin destruction complex and inhibits Wnt signaling by enhancing the degradation of beta-catenin.	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	WTX	WTX	WTX	beta-catenin	beta-catenin	beta-catenin	1	2	20	21
The data also suggest that deregulation of Wnt / beta-catenin signaling by WTX gene mutation may be a rare event in the pathogenesis of colorectal , gastric , and hepatocellular carcinomas .	The data also suggest that deregulation of Wnt / beta-catenin signaling by WTX gene mutation may be a rare event in the pathogenesis of colorectal, gastric, and hepatocellular carcinomas.	9	14	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	WTX	WTX	WTX	beta-catenin	beta-catenin	beta-catenin	12	13	9	10
Inactivation of the Wnt antagonist WTX has been shown to induce beta-catenin activation and result in the accumulation of mesenchymal precursor cells in mice 23 , which also suggests that beta-catenin is indeed involved in epithelial-mesenchymal transition .	Inactivation of the Wnt antagonist WTX has been shown to induce beta-catenin activation and result in the accumulation of mesenchymal precursor cells in mice 23, which also suggests that beta-catenin is indeed involved in epithelial-mesenchymal transition.	0	12	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WTX	WTX	WTX	beta-catenin	beta-catenin	beta-catenin	5	6	11	12
Taken together , these data demonstrate that ERCC1 deficiency leads to increased NF-kappaB activity in both osteoblastic and osteoclastic cells , potentially through an ATM dependent increase in IKKgamma activity in response to unrepaired endogenous DNA damage .	Taken together, these data demonstrate that ERCC1 deficiency leads to increased NF-kappaB activity in both osteoblastic and osteoclastic cells, potentially through an ATM dependent increase in IKKgamma activity in response to unrepaired endogenous DNA damage.	24	29	increase	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ATM	ATM	ATM	IKKgamma	IKKgamma	IKKgamma	24	25	28	29
Two of the best characterized connections involve ATM dependent activation of NEMO , a regulatory subunit of the IKK complex , stimulating NF-kappaB activity 356 , 357 , 358 , 359 , 360 , and of NKG2D and DNAM-1 and CD226 ligands , two key players in innate imunity 361 , 362 , 363 .	Two of the best characterized connections involve ATM dependent activation of NEMO, a regulatory subunit of the IKK complex, stimulating NF-kappaB activity 356, 357, 358, 359, 360, and of NKG2D and DNAM-1 and CD226 ligands, two key players in innate imunity 361, 362, 363.	7	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ATM	ATM	ATM	NEMO	NEMO	NEMO	7	8	11	12
Silencing ATM expression significantly abrogated the activation of ATM at Ser 1981 , Chk1 at Ser 345 and Cdc25C at Ser 216 in curcumin treated cells and substantially prevented the cells from undergoing G2/M arrest and apoptosis .	Silencing ATM expression significantly abrogated the activation of ATM at Ser 1981, Chk1 at Ser 345 and Cdc25C at Ser 216 in curcumin treated cells and substantially prevented the cells from undergoing G2/M arrest and apoptosis.	1	20	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM expression	atm	Cdc25C	Cdc25C	cdc25c	1	2	18	19
Collectively , these data suggest that up-regulation of LETM1 induces sustained activation of proliferative signaling pathways , such as PDGF signal pathway by AKT induced YAP1 transactivation , resulting in aggressive thyroid cancer phenotypes .	Collectively, these data suggest that up-regulation of LETM1 induces sustained activation of proliferative signaling pathways, such as PDGF signal pathway by AKT induced YAP1 transactivation, resulting in aggressive thyroid cancer phenotypes.	21	26	induced	Positive_early_activation	Negative_activation	Positive_activation	AKT	AKT	AKT	YAP1	YAP1	YAP1	23	24	25	26
Interestingly , Aurora A kinase ( AURKA gene product ) has been previously shown to modulate full-length AR activity and thus represents a potential mechanism of positive feedback that may enhance AR signalling .	Interestingly, Aurora A kinase (AURKA gene product) has been previously shown to modulate full-length AR activity and thus represents a potential mechanism of positive feedback that may enhance AR signalling.	4	18	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AURKA	AURKA	AURKA	AR	AR	AR	6	7	17	18
However , RNAi knockdown of ATR does not prevent p53 activation in response to DNA damage , suggesting that the ATR mediated pathway may not be the primary mechanism of MDM2 regulation upon DNA damage .	However, RNAi knockdown of ATR does not prevent p53 activation in response to DNA damage, suggesting that the ATR mediated pathway may not be the primary mechanism of MDM2 regulation upon DNA damage.	19	31	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATR	ATR	ATR	MDM2	MDM2	MDM2	20	21	30	31
Hypoxia mimetic iron chelator deferroxamine promoted p53 accumulation in H9c2 myoblast cells by suppressing the Akt and MDM2 pathway , which was restored by ATR .	Hypoxia mimetic iron chelator deferroxamine promoted p53 accumulation in H9c2 myoblast cells by suppressing the Akt and MDM2 pathway, which was restored by ATR.	15	25	restored	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ATR	ATR	ATR	MDM2	MDM2	MDM2	24	25	17	18
While ASIP stimulates opposite effects , that is , de-differentiation of melanocytes , human melanoma and murine B16-F1 melanoma cells , and increases their migration in wound healing assays [ XREF_BIBR , XREF_BIBR ] , the effect of ASIP induced MC1R signaling on melanoma colonization in vivo is not known .	While ASIP stimulates opposite effects, that is, de-differentiation of melanocytes, human melanoma and murine B16-F1 melanoma cells, and increases their migration in wound healing assays [XREF_BIBR, XREF_BIBR], the effect of ASIP induced MC1R signaling on melanoma colonization in vivo is not known.	36	41	induced	Positive_early_activation	Negative_activation	Positive_activation	ASIP	ASIP	ASIP	MC1R	MC1R	MC1R	38	39	40	41
In that study , the authors suggest that ATM can cause upregulation of p63 not only through independent pathways , but also via a c-Abl-dependant pathway , perhaps explaining the trend towards a protective effect of imatinib found here ( XREF_FIG ) .	In that study, the authors suggest that ATM can cause upregulation of p63 not only through independent pathways, but also via a c-Abl-dependant pathway, perhaps explaining the trend towards a protective effect of imatinib found here (XREF_FIG).	8	14	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	p63	p63	p63	8	9	13	14
Taken together , the down-regulation of APIP and UACA expression suggests that the threshold to activate the apoptosome apparatus may be decreased in NSCLC cells due to the lack of APIP mediated suppression and UACA assisted Apaf-1 nuclear entry .	Taken together, the down-regulation of APIP and UACA expression suggests that the threshold to activate the apoptosome apparatus may be decreased in NSCLC cells due to the lack of APIP mediated suppression and UACA assisted Apaf-1 nuclear entry.	30	37	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	APIP	APIP	APIP	Apaf-1	Apaf-1	Apaf-1	30	31	36	37
In the absence of Wnt signaling , cytoplasmic beta-catenin is targeted for destruction by the APC , axin , and GSK3beta complex that phosphorylates beta-catenin and directs it to a destruction pathway .	In the absence of Wnt signaling, cytoplasmic beta-catenin is targeted for destruction by the APC, axin, and GSK3beta complex that phosphorylates beta-catenin and directs it to a destruction pathway.	7	22	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	APC	APC, axin, and GSK3beta complex	apc	beta-catenin	beta-catenin	beta-catenin	15	16	8	9
The expression of ALK fusion proteins induced delocalization of PSF from the nucleus to the cytoplasm and forced overexpression of PSF inhibited proliferation and induced apoptosis in cells expressing NPM and ALK .	The expression of ALK fusion proteins induced delocalization of PSF from the nucleus to the cytoplasm and forced overexpression of PSF inhibited proliferation and induced apoptosis in cells expressing NPM and ALK.	1	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ALK	expression of ALK	alk	PSF	PSF	psf	3	4	9	10
Nuclear accumulation of zyxin and activated Akt may represent a fundamental mechanism that facilitates nuclear-signal transduction and potentiates cell survival .	Nuclear accumulation of zyxin and activated Akt may represent a fundamental mechanism that facilitates nuclear-signal transduction and potentiates cell survival.	1	7	activated	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Akt	Akt	Akt	zyxin	zyxin	zyxin	6	7	3	4
We speculate that Akt mediated BRF1 activities are also involved in cav-1-induced VEGF , TGF-beta1 , and FGF2 mRNA stability .	We speculate that Akt mediated BRF1 activities are also involved in cav-1-induced VEGF, TGF-beta1, and FGF2 mRNA stability.	3	6	mediated	Positive_early_activation	Negative_activation	Positive_activation	Akt	Akt	Akt	BRF1	BRF1	BRF1	3	4	5	6
Our deletion and site directed mutagenesis experiments identified Serine 564 ( S564 ) as the dominant ATM targeted site of DAXX , and immunofluorescence experiments revealed localization of S564 phosphorylated DAXX to PML nuclear bodies .	Our deletion and site directed mutagenesis experiments identified Serine 564 (S564) as the dominant ATM targeted site of DAXX, and immunofluorescence experiments revealed localization of S564 phosphorylated DAXX to PML nuclear bodies.	7	21	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	DAXX	DAXX	DAXX	16	17	20	21
How the ATM and ATR mediated modification of Siah-1 affects TRF2 regulation remains to be determined .	How the ATM and ATR mediated modification of Siah-1 affects TRF2 regulation remains to be determined.	1	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ATM	ATM	ATM	Siah-1	Siah-1	Siah-1	2	3	8	9
Moreover , nitidine chloride downregulated Cyclin B1 , CDK1 and Bcl-2 , upregulated p27 and Bax , inactivated PARP , activated Caspase-3 in AML cells .	Moreover, nitidine chloride downregulated Cyclin B1, CDK1 and Bcl-2, upregulated p27 and Bax, inactivated PARP, activated Caspase-3 in AML cells.	8	17	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	10	11	15	16
In addition , formononetin increased the proportion of early apoptotic DU-145 cells , down-regulated the protein levels of Bcl-2 and up-regulated those of RASD1 and Bax .	In addition, formononetin increased the proportion of early apoptotic DU-145 cells, down-regulated the protein levels of Bcl-2 and up-regulated those of RASD1 and Bax.	3	26	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	formononetin increased the proportion of early apoptotic DU-145 cells, down-regulated the protein levels of Bcl-2	bcl-2	Bax	Bax	bax	18	19	25	26
MT1M group showed inhibited HepG2 proliferation , declined HepG2 apoptosis , enhanced Caspase-3 activity , reduced Bcl-2 protein level , and upregulated Bax protein compared with control ( p < 0.05 ) .	MT1M group showed inhibited HepG2 proliferation, declined HepG2 apoptosis, enhanced Caspase-3 activity, reduced Bcl-2 protein level, and upregulated Bax protein compared with control (p < 0.05).	0	23	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	MT1M group showed inhibited HepG2 proliferation, declined HepG2 apoptosis, enhanced Caspase-3 activity, reduced Bcl-2 protein level	bcl-2	Bax	Bax	bax	16	17	22	23
On the other hand , in some tissues including the human endometrium , the control of apoptosis has been associated to proteins related to the Bcl-2 family , like Bcl-2 that promotes cell survival and Bax which is an inducer of apoptosis [ XREF_BIBR , XREF_BIBR ] .	On the other hand, in some tissues including the human endometrium, the control of apoptosis has been associated to proteins related to the Bcl-2 family, like Bcl-2 that promotes cell survival and Bax which is an inducer of apoptosis [XREF_BIBR, XREF_BIBR].	22	39	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	29	30	35	36
Accumulation of Bcl-2 and Bcl-xL can protect cells from apoptosis , promote cell survival and accelerate tumor growth by sequestering pro apoptotic Bax .	Accumulation of Bcl-2 and Bcl-xL can protect cells from apoptosis, promote cell survival and accelerate tumor growth by sequestering pro apoptotic Bax.	0	23	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	22	23
As expected , TFF3 silencing decreased BCL2 expression and increased BAX expression XREF_BIBR - XREF_BIBR .	As expected, TFF3 silencing decreased BCL2 expression and increased BAX expression XREF_BIBR - XREF_BIBR.	3	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	TFF3 silencing decreased BCL2 expression	bcl2	BAX	BAX	bax	6	7	10	11
Recently , both Bcl-2 , which promotes cell survival , and Bax , which promotes cell death , have been implicated as major players in the control of apoptotic pathways , and it has been suggested that the ratio of Bcl-2 and Bax protein controls the relative susceptibility of cells to death stimuli .	Recently, both Bcl-2, which promotes cell survival, and Bax, which promotes cell death, have been implicated as major players in the control of apoptotic pathways, and it has been suggested that the ratio of Bcl-2 and Bax protein controls the relative susceptibility of cells to death stimuli.	2	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	11	12
These results indicate that HD downregulates Bcl-2 expression and upregulates Bax expression , and the expression ratio of Bax and Bcl -2 in the HD exposed BMSCs .	These results indicate that HD downregulates Bcl-2 expression and upregulates Bax expression, and the expression ratio of Bax and Bcl -2 in the HD exposed BMSCs.	4	12	upregulates	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Bcl-2	HD downregulates Bcl-2 expression	bcl-2	Bax	Bax expression	bax	6	7	10	11
In addition , AE-CB treatment could downregulate the protein level of Bcl-2 and upregulate the Bax , leading to the increase in the ratio of Bax to Bcl-2 in SMMC-7721 cells .	In addition, AE-CB treatment could downregulate the protein level of Bcl-2 and upregulate the Bax, leading to the increase in the ratio of Bax to Bcl-2 in SMMC-7721 cells.	3	16	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	AE-CB treatment could downregulate the protein level of Bcl-2	bcl-2	Bax	Bax	bax	11	12	15	16
In the late stage of endoreduplication , the effects of PTX-2 on different cancer cells involves : ( i ) down-regulation of anti-apoptotic Bcl-2 members and IAP family proteins ; ( ii ) up-regulation of pro apoptotic Bax protein and tumor necrosis factor related apoptosis inducing ligand ( TRAIL )-receptor 1/receptor 2 ( DR4 and DR5 ) ; and ( iii ) mitochondrial dysfunction .	In the late stage of endoreduplication, the effects of PTX-2 on different cancer cells involves : (i) down-regulation of anti-apoptotic Bcl-2 members and IAP family proteins; (ii) up-regulation of pro apoptotic Bax protein and tumor necrosis factor related apoptosis inducing ligand (TRAIL)-receptor 1/receptor 2 (DR4 and DR5); and (iii) mitochondrial dysfunction.	23	38	up-regulation	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	23	24	37	38
Metformin significantly down-regulated the expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulated the pro apoptotic protein Bax .	Metformin significantly down-regulated the expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulated the pro apoptotic protein Bax.	0	19	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Metformin significantly down-regulated the expression of the anti-apoptotic proteins Bcl-2	bcl-2	Bax	Bax	bax	9	10	18	19
45 For example , JNKs specifically phosphorylate BCL-2 , BIM and BMF which then activate BAX and BAK to initiate MOMP and apoptosis .	45 For example, JNKs specifically phosphorylate BCL-2, BIM and BMF which then activate BAX and BAK to initiate MOMP and apoptosis.	4	17	activate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	BCL-2	JNKs specifically phosphorylate BCL-2	bcl-2	BAX	BAX	bax	7	8	15	16
Sham group demonstrated basic expression of both Bcl-2 and Bax and IR induced downregulated Bcl-2 and upregulated Bax .	Sham group demonstrated basic expression of both Bcl-2 and Bax and IR induced downregulated Bcl-2 and upregulated Bax.	4	18	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of both Bcl-2	bcl-2	Bax	Bax	bax	7	8	17	18
A recent study has reported that Bcl-2 negatively regulates autophagy by inhibiting Bax and Bcl-2 homologous antagonist and killer ( Bak ) XREF_BIBR .	A recent study has reported that Bcl-2 negatively regulates autophagy by inhibiting Bax and Bcl-2 homologous antagonist and killer (Bak) XREF_BIBR.	6	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	12	13
Regarding the apoptosis related Bcl-2 family proteins , decreased levels of Bax and increased levels of Bcl-2 resulted in a downregulated Bax and Bcl -2 ratio in diabetic mice with DHM treatment .	Regarding the apoptosis related Bcl-2 family proteins, decreased levels of Bax and increased levels of Bcl-2 resulted in a downregulated Bax and Bcl -2 ratio in diabetic mice with DHM treatment.	11	17	increased	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Bcl-2	levels of Bcl-2	bcl-2	Bax	Bax	bax	16	17	11	12
These two proteins have opposing effects , with Bcl-2 serving to prolong cell survival and Bax acting as an accelerator of apoptosis [ XREF_BIBR - XREF_BIBR ] .	These two proteins have opposing effects, with Bcl-2 serving to prolong cell survival and Bax acting as an accelerator of apoptosis [XREF_BIBR - XREF_BIBR].	3	25	prolong	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	15	16
KLF4 overexpression resulted in upregulation Bax and down regulation Bcl-2 leading to increase in Bax : Bcl-2 ratio .	KLF4 overexpression resulted in upregulation Bax and down regulation Bcl-2 leading to increase in Bax : Bcl-2 ratio.	2	17	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	14	15
A role for Bim in apoptosis was proposed recently [ XREF_BIBR - XREF_BIBR ] ; it has been suggested that ER stress increases dephosphorylated Bim , which inhibits Bcl-2 , a pro survival protein , leading to Bax and Bak activation and cell death [ XREF_BIBR ] .	A role for Bim in apoptosis was proposed recently [XREF_BIBR - XREF_BIBR]; it has been suggested that ER stress increases dephosphorylated Bim, which inhibits Bcl-2, a pro survival protein, leading to Bax and Bak activation and cell death [XREF_BIBR].	28	40	leading to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	28	29	37	38
Puma and Noxa then inhibit the anti-apoptotic proteins Bcl-2 and Bcl-X L , thus allowing the pro apoptotic molecules Bax and Bak to multi-merize and to insert into the mitochondrial membrane .	Puma and Noxa then inhibit the anti-apoptotic proteins Bcl-2 and Bcl-X L, thus allowing the pro apoptotic molecules Bax and Bak to multi-merize and to insert into the mitochondrial membrane.	4	26	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	19	20
Anti-apoptotic Bcl-2 proteins reside on the outer mitochondrial membrane ( OMM ) and prevent apoptosis by inhibiting the activation of the pro apoptotic family members Bax and Bak .	Anti-apoptotic Bcl-2 proteins reside on the outer mitochondrial membrane (OMM) and prevent apoptosis by inhibiting the activation of the pro apoptotic family members Bax and Bak.	1	27	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	25	26
Bcl-2 knockdown , however , directly decreased Bcl-2 : Bax ratios and allowed caspase activation , shifting cells away from survival and towards apoptosis .	Bcl-2 knockdown, however, directly decreased Bcl-2 : Bax ratios and allowed caspase activation, shifting cells away from survival and towards apoptosis.	0	10	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	9	10
BIM is a proapoptotic BH3-only member of the BCL-2 family that activates BAX and neutralizes BCL2 like antiapoptotic proteins .	BIM is a proapoptotic BH3-only member of the BCL-2 family that activates BAX and neutralizes BCL2 like antiapoptotic proteins.	8	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	8	9	12	13
Oleandrin also down-regulated the expression of bcl-2 , but up-regulated bax , caspase-9 , Fas , FasL , caspase-8 and caspase-3 .	Oleandrin also down-regulated the expression of bcl-2, but up-regulated bax, caspase-9, Fas, FasL, caspase-8 and caspase-3.	0	20	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	Oleandrin also down-regulated the expression of bcl-2	bcl-2	bax	bax	bax	6	7	10	11
The localization of BCL2 to the ER membrane supports the concept that it regulates ER located BAX and BAK function .	The localization of BCL2 to the ER membrane supports the concept that it regulates ER located BAX and BAK function.	1	19	supports	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	3	4	16	17
In contrast , BCL-2 levels increased in the treated cultures with respect to the control cultures , resulting in the BAX and BCL -2 ratio dropping in both cell lines .	In contrast, BCL-2 levels increased in the treated cultures with respect to the control cultures, resulting in the BAX and BCL -2 ratio dropping in both cell lines.	3	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2 levels	bcl-2	BAX	BAX	bax	3	4	20	21
By mimicking BH3-only proteins ( such as NOXA , PUMA , BID , BAD , BIM ) , antiapoptotic BCL2 members can be sequestered , thus , allowing BAK and BAX to activate the intrinsic apoptotic pathway .	By mimicking BH3-only proteins (such as NOXA, PUMA, BID, BAD, BIM), antiapoptotic BCL2 members can be sequestered, thus, allowing BAK and BAX to activate the intrinsic apoptotic pathway.	19	32	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	19	20	30	31
Specifically , following METH exposure , Chop increases the expression of Bax and decreases the expression of Bcl-2 , which leads to an increased Bax and Bcl -2 ratio , thereby inducing the release of cyto c to initiate caspase cascades .	Specifically, following METH exposure, Chop increases the expression of Bax and decreases the expression of Bcl-2, which leads to an increased Bax and Bcl -2 ratio, thereby inducing the release of cyto c to initiate caspase cascades.	15	28	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	17	18	24	25
Interestingly , stable overexpression of Bcl-2 can lead to the upregulation of Bax and increased sensitivity to PDT ( Kim et al , 1999 ; Srivastava et al , 2001 ) .	Interestingly, stable overexpression of Bcl-2 can lead to the upregulation of Bax and increased sensitivity to PDT (Kim et al, 1999; Srivastava et al, 2001).	3	13	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	overexpression of Bcl-2	bcl-2	Bax	Bax	bax	5	6	12	13
TAT down-regulated the expression of mTOR signaling pathway and BCL-2 protein , and up-regulated proapoptotic protein BAX .	TAT down-regulated the expression of mTOR signaling pathway and BCL-2 protein, and up-regulated proapoptotic protein BAX.	0	17	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	TAT down-regulated the expression of mTOR signaling pathway and BCL-2	bcl-2	BAX	BAX	bax	9	10	16	17
PUMA is a pro apoptotic Bcl-2 family member that interacts with anti-apoptotic Bcl-2 family members to activate Bax and/or Bak .	PUMA is a pro apoptotic Bcl-2 family member that interacts with anti-apoptotic Bcl-2 family members to activate Bax and/or Bak.	5	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	17	18
Our results indicate that LSS significantly protects from apoptotic injury to the cells induced by Abeta 25-35 ( XREF_FIG , XREF_FIG and XREF_FIG ) , decreases mitochondria membrane potentials ( XREF_FIG ) , upregulates the expression of Bcl-2 protein , and downregulates the expressions of Bax protein and the ratio of Bcl-2 and Bax ( XREF_FIG ) , and inhibits the mRNA expression and nuclear translocation of NF-kappaBp65 ( XREF_FIG and XREF_FIG ) in Abeta 25-35 -treated PC12 cells .	Our results indicate that LSS significantly protects from apoptotic injury to the cells induced by Abeta 25-35 (XREF_FIG, XREF_FIG and XREF_FIG), decreases mitochondria membrane potentials (XREF_FIG), upregulates the expression of Bcl-2 protein, and downregulates the expressions of Bax protein and the ratio of Bcl-2 and Bax (XREF_FIG), and inhibits the mRNA expression and nuclear translocation of NF-kappaBp65 (XREF_FIG and XREF_FIG) in Abeta 25-35 -treated PC12 cells.	4	46	downregulates	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Bcl-2	LSS significantly protects from apoptotic injury to the cells induced by Abeta 25-35 (XREF_FIG, XREF_FIG and XREF_FIG), decreases mitochondria membrane potentials (XREF_FIG), upregulates the expression of Bcl-2	bcl-2	Bax	expressions of Bax	bax	37	38	45	46
RT-PCR was used to detect the mRNA expression of the apoptosis inhibiting gene of Bcl-2 and apoptosis promoting genes of P53 , Bax , and Bad .	RT-PCR was used to detect the mRNA expression of the apoptosis inhibiting gene of Bcl-2 and apoptosis promoting genes of P53, Bax, and Bad.	12	23	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	14	15	22	23
Silencing of GPAT1 expression decreased Bcl-2 expression , but increased Bax , cleaved caspase-9 , and cleaved caspase-3 expressions ( XREF_FIG ) .	Silencing of GPAT1 expression decreased Bcl-2 expression, but increased Bax, cleaved caspase-9, and cleaved caspase-3 expressions (XREF_FIG).	2	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	GPAT1 expression decreased Bcl-2 expression	bcl-2	Bax	Bax	bax	5	6	10	11
Downregulation of Bcl-2 by RNAi potentiated the redistribution of Bax and cytochrome c and reversed cisplatin-resistance .	Downregulation of Bcl-2 by RNAi potentiated the redistribution of Bax and cytochrome c and reversed cisplatin-resistance.	0	12	potentiated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	9	10
It is well known that Bax promotes apoptosis , and conversely , Bcl-2 inhibits apoptosis by blocking the release and oligomerization of Bax .	It is well known that Bax promotes apoptosis, and conversely, Bcl-2 inhibits apoptosis by blocking the release and oligomerization of Bax.	12	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	12	13	22	23
Bcl-2 family proteins are regulated by a variety of metabolic stresses to promote activation of Bax and Bak and cause cell death ( XREF_FIG ) .	Bcl-2 family proteins are regulated by a variety of metabolic stresses to promote activation of Bax and Bak and cause cell death (XREF_FIG).	0	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	15	16
BH3 ( Bcl-2 homology 3 )-only proteins of the Bcl-2 family activate Bax or Bak during apoptosis to promote the release of pro death factors sequestered in the mitochondrial intermembrane space .	BH3 (Bcl-2 homology 3)-only proteins of the Bcl-2 family activate Bax or Bak during apoptosis to promote the release of pro death factors sequestered in the mitochondrial intermembrane space.	9	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	9	10	12	13
Inactivation of antiapoptotic BCL-2 proteins in turn promotes BAX and BAK activation , leading to cleavage of caspase-9 and -3 and caspase dependent apoptosis .	Inactivation of antiapoptotic BCL-2 proteins in turn promotes BAX and BAK activation, leading to cleavage of caspase-9 and -3 and caspase dependent apoptosis.	3	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	3	4	8	9
The third BCL-2 subfamily of proteins , BH3-only molecules ( BH3s ) , promotes apoptosis by either activating BAX and BAK or inactivating BCL-2 and BCL-X L / MCL-1 .	The third BCL-2 subfamily of proteins, BH3-only molecules (BH3s), promotes apoptosis by either activating BAX and BAK or inactivating BCL-2 and BCL-X L / MCL-1.	2	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	2	3	18	19
Select BCL-2 homology domain 3 ( BH3 ) helices activate BAX directly by engaging an alpha1 and alpha6 trigger site .	Select BCL-2 homology domain 3 (BH3) helices activate BAX directly by engaging an alpha1 and alpha6 trigger site.	1	11	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	1	2	10	11
ABT-737 inhibits the interactions of Bcl-2 and Bax and Bcl-xL and Bak , thus allowing Bax and Bak to induce MOMP and apoptosis .	ABT-737 inhibits the interactions of Bcl-2 and Bax and Bcl-xL and Bak, thus allowing Bax and Bak to induce MOMP and apoptosis.	3	19	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	15	16
In addition , quercetin could down-regulate expression of bcl-2 , up-regulate Bax , but exerted no effect on the overall expression of Akt .	In addition, quercetin could down-regulate expression of bcl-2, up-regulate Bax, but exerted no effect on the overall expression of Akt.	3	12	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	quercetin could down-regulate expression of bcl-2	bcl-2	Bax	Bax	bax	8	9	11	12
This inactivation of antiapoptotic BCL-2 proteins promotes activation of BAX and BAK , cleavage of caspase-9 and -3 and caspase dependent apoptosis .	This inactivation of antiapoptotic BCL-2 proteins promotes activation of BAX and BAK, cleavage of caspase-9 and -3 and caspase dependent apoptosis.	4	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	4	5	9	10
Delivery of ANXA2 siRNA significantly downregulated the expression of P-gp , MRP1 and Bcl-2 , while markedly upregulated Bax in SGC7901 and DDP cells .	Delivery of ANXA2 siRNA significantly downregulated the expression of P-gp, MRP1 and Bcl-2, while markedly upregulated Bax in SGC7901 and DDP cells.	2	23	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	ANXA2 siRNA significantly downregulated the expression of P-gp, MRP1 and Bcl-2	bcl-2	Bax	Bax	bax	13	14	18	19
In the presence of VPA/HU , such tumor cells increase expression of the pro apoptotic BCL-2 family protein BIM , independent of wild-type p53 signaling and in the absence of increased expression of the p53 targets PUMA and BAX .	In the presence of VPA/HU, such tumor cells increase expression of the pro apoptotic BCL-2 family protein BIM, independent of wild-type p53 signaling and in the absence of increased expression of the p53 targets PUMA and BAX.	10	39	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	expression of the pro apoptotic BCL-2	bcl-2	BAX	BAX	bax	15	16	38	39
Functional activity of PUMA is initiated by protein targeting to the outer mitochondrial membrane where PUMA interacts with anti-apoptotic Bcl-2 family members inhibiting their suppression of Bax and Bak XREF_BIBR , XREF_BIBR .	Functional activity of PUMA is initiated by protein targeting to the outer mitochondrial membrane where PUMA interacts with anti-apoptotic Bcl-2 family members inhibiting their suppression of Bax and Bak XREF_BIBR, XREF_BIBR.	19	29	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	19	20	26	27
Induction of the intrinsic pathway of apoptosis is dictated by the release of pro apoptotic BH3-only activator proteins ( BIM , PUMA , BID ) from anti-apoptotic BCL-2 family members ( BCL-2 , BCL-x L , MCL-1 , BCL-w and A1 ) that in turn activate BAX and BAK leading to mitochondrial membrane permeabilization and cytochrome c release .	Induction of the intrinsic pathway of apoptosis is dictated by the release of pro apoptotic BH3-only activator proteins (BIM, PUMA, BID) from anti-apoptotic BCL-2 family members (BCL-2, BCL-x L, MCL-1, BCL-w and A1) that in turn activate BAX and BAK leading to mitochondrial membrane permeabilization and cytochrome c release.	27	49	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	27	28	46	47
Numerous studies have addressed three major mechanisms of IRF3 mediated apoptosis : ( i ) homodimers of IRF3 induce transcription of the BH3-only proteins Noxa and Puma , which antagonizes pro survival Bcl-2 proteins such as Mcl-1 and Bcl-xL to activate Bax and Bak and to damage mitochondria , leading to the release of cytochrome c which causes apoptosis .	Numerous studies have addressed three major mechanisms of IRF3 mediated apoptosis : (i) homodimers of IRF3 induce transcription of the BH3-only proteins Noxa and Puma, which antagonizes pro survival Bcl-2 proteins such as Mcl-1 and Bcl-xL to activate Bax and Bak and to damage mitochondria, leading to the release of cytochrome c which causes apoptosis.	32	43	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	32	33	41	42
Results indicate that BDA-366-treated Bcl2 but not Bcl2 alone enhanced the ability of Bax to bind to 6A7 antibody ( XREF_FIG , lane 4 vs. lanes 5-7 ) , indicating that BDA-366-treated Bcl2 can induce Bax conformational change leading to Bax activation .	Results indicate that BDA-366-treated Bcl2 but not Bcl2 alone enhanced the ability of Bax to bind to 6A7 antibody (XREF_FIG, lane 4 vs. lanes 5-7), indicating that BDA-366-treated Bcl2 can induce Bax conformational change leading to Bax activation.	31	37	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	32	33	35	36
Some findings indicate that Bax can bind to and be activated by the BH3-only proteins Bim , Puma or the proapoptotic Bcl-2 family protein tBid .	Some findings indicate that Bax can bind to and be activated by the BH3-only proteins Bim, Puma or the proapoptotic Bcl-2 family protein tBid.	4	24	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	21	22	4	5
Mechanistically , these treatments abrogate the RT induced BCL-2 expression and activate BAX to render apoptotic and tumor regressing effects .	Mechanistically, these treatments abrogate the RT induced BCL-2 expression and activate BAX to render apoptotic and tumor regressing effects.	6	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	RT induced BCL-2 expression	bcl-2	BAX	BAX	bax	8	9	12	13
Pro apoptotic BCL-2 proteins activate the BAX and BCL-2 homologous antagonist and killer ( BAK ) proteins to trigger MOMP , thereby causing cytochrome c release to drive programmed cell death 109 .	Pro apoptotic BCL-2 proteins activate the BAX and BCL-2 homologous antagonist and killer (BAK) proteins to trigger MOMP, thereby causing cytochrome c release to drive programmed cell death 109.	2	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	2	3	6	7
Combination therapy upregulated pro apoptotic Bax and down regulated anti-apoptotic Bcl-2 , the alterations that could increase Bax : Bcl-2 ratio to trigger mitochondria dependent caspase cascade , for ultimately increasing caspase-3 activation and activity for induction of apoptosis in the serum starved SH-SY5Y cells .	Combination therapy upregulated pro apoptotic Bax and down regulated anti-apoptotic Bcl-2, the alterations that could increase Bax : Bcl-2 ratio to trigger mitochondria dependent caspase cascade, for ultimately increasing caspase-3 activation and activity for induction of apoptosis in the serum starved SH-SY5Y cells.	8	18	increase	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	10	11	17	18
The result of RT-PCR analysis revealed that naringin down-regulated the mRNA expression levels of BCL-2 and up-regulated BAX , caspase-3 and cytochrome C.	The result of RT-PCR analysis revealed that naringin down-regulated the mRNA expression levels of BCL-2 and up-regulated BAX, caspase-3 and cytochrome C.	7	22	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	naringin down-regulated the mRNA expression levels of BCL-2	bcl-2	BAX	BAX	bax	14	15	17	18
Interestingly , LDFRT treatment in both cell lines with or without Paclitaxel down-regulated nuclear factor kappa B activity and BCL-2 protein expression and simultaneously up-regulated BAX protein .	Interestingly, LDFRT treatment in both cell lines with or without Paclitaxel down-regulated nuclear factor kappa B activity and BCL-2 protein expression and simultaneously up-regulated BAX protein.	2	26	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	LDFRT treatment in both cell lines with or without Paclitaxel down-regulated nuclear factor kappa B activity and BCL-2 protein expression	bcl-2	BAX	BAX	bax	19	20	25	26
6,7 Bax shuttling is also mediated by Bcl-2 and Mcl-1 , 6 but could additionally involve Bcl-2 protein independent mechanisms .	6,7 Bax shuttling is also mediated by Bcl-2 and Mcl-1, 6 but could additionally involve Bcl-2 protein independent mechanisms.	1	11	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	1	2
Bax and Bak are constitutively present in cells but , under apoptotic conditions , are activated by certain Bcl-2 family members belonging to the BH3-only group ( e.g ., Bid , Bim , and Puma ) .	Bax and Bak are constitutively present in cells but, under apoptotic conditions, are activated by certain Bcl-2 family members belonging to the BH3-only group (e.g., Bid, Bim, and Puma).	0	20	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	18	19	0	1
Deregulated BCL-2 and BCL-X L involved in GA induced oligomerization of BAX and BAK at the ER and apoptosis .	Deregulated BCL-2 and BCL-X L involved in GA induced oligomerization of BAX and BAK at the ER and apoptosis.	0	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	1	2	11	12
When driven along with Bax ( BA64III , BC57I ) using vg-GAL4 or twist-GAL4 Bcl-2 rescued Bax induced lethality whereas Bax 30-192 ( DBA8II , BC57I ) induced lethality was only marginally rescued .	When driven along with Bax (BA64III, BC57I) using vg-GAL4 or twist-GAL4 Bcl-2 rescued Bax induced lethality whereas Bax 30-192 (DBA8II, BC57I) induced lethality was only marginally rescued.	10	17	rescued	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	14	15	16	17
Overexpression of the anti-apoptotic Bcl-2 and Bcl-xL proteins in cancer cells inhibits apoptosis by blocking activation of BAX and/or BAK and confers cancer cells resistance to a variety of chemotherapeutic agents .	Overexpression of the anti-apoptotic Bcl-2 and Bcl-xL proteins in cancer cells inhibits apoptosis by blocking activation of BAX and/or BAK and confers cancer cells resistance to a variety of chemotherapeutic agents.	0	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of the anti-apoptotic Bcl-2	bcl-2	BAX	BAX	bax	4	5	17	18
Higher Bax and Bcl2 ratio , increased Bax oligomerication , and decreased MMP lead to the release of cytochrome c , a pro apoptotic protein that promotes caspase activation and initiation of mitochondria mediated apoptosis .	Higher Bax and Bcl2 ratio, increased Bax oligomerication, and decreased MMP lead to the release of cytochrome c, a pro apoptotic protein that promotes caspase activation and initiation of mitochondria mediated apoptosis.	3	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	3	4	7	8
Pro survival Bcl-2 proteins prevent apoptosis by inhibiting Bax and Bak .	Pro survival Bcl-2 proteins prevent apoptosis by inhibiting Bax and Bak.	2	10	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	8	9
We found that treatment of pancreatic cancer cells with pristimerin resulted in an increase in the expression of Bax protein and a decrease in the expression of Bcl-2 and Bcl-xL thereby increasing the ratios of Bax and Bcl -2 and Bax and Bcl-xL in favor of apoptosis .	We found that treatment of pancreatic cancer cells with pristimerin resulted in an increase in the expression of Bax protein and a decrease in the expression of Bcl-2 and Bcl-xL thereby increasing the ratios of Bax and Bcl -2 and Bax and Bcl-xL in favor of apoptosis.	25	36	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	27	28	35	36
Tq dose-dependently downregulated Bcl-2 mRNA expression and , as a result , increased Bax and Bcl -2 mRNA ratio .	Tq dose-dependently downregulated Bcl-2 mRNA expression and, as a result, increased Bax and Bcl -2 mRNA ratio.	0	18	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Tq dose-dependently downregulated Bcl-2 mRNA expression	bcl-2	Bax	Bax	bax	3	4	13	14
The Bcl-2 subfamily of BH3-only proteins can either inhibit the anti-apoptotic proteins or directly activate Bax or Bak .	The Bcl-2 subfamily of BH3-only proteins can either inhibit the anti-apoptotic proteins or directly activate Bax or Bak.	1	17	directly activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	15	16
It suggested that BPA can diminish the expression of Bcl-2 , increase the expression of Bax , and thus decrease the ratio of Bcl-2 and Bax .	It suggested that BPA can diminish the expression of Bcl-2, increase the expression of Bax, and thus decrease the ratio of Bcl-2 and Bax.	3	16	increase	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Bcl-2	BPA can diminish the expression of Bcl-2	bcl-2	Bax	expression of Bax	bax	9	10	15	16
Among the pro death members , Bak and Bax have been categorized as the last gateway of cytochrome c release , and their homo-oligomerization on the mitochondrial membrane is essential for release , while the anti-apoptotic Bcl-2 members prevent mitochondrial protein release by interacting with and inhibiting both Bak and Bax [ XREF_BIBR ] .	Among the pro death members, Bak and Bax have been categorized as the last gateway of cytochrome c release, and their homo-oligomerization on the mitochondrial membrane is essential for release, while the anti-apoptotic Bcl-2 members prevent mitochondrial protein release by interacting with and inhibiting both Bak and Bax [XREF_BIBR].	36	52	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	36	37	50	51
Furthermore , beta , beta-dimethylacrylshikonin down-regulated the mRNA and protein expression of Bcl-2 but up-regulated that of Bax .	Furthermore, beta,beta-dimethylacrylshikonin down-regulated the mRNA and protein expression of Bcl-2 but up-regulated that of Bax.	4	18	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	beta-dimethylacrylshikonin down-regulated the mRNA and protein expression of Bcl-2	bcl-2	Bax	Bax	bax	12	13	17	18
Multiple members of the BCL-2 family have been shown to modulate BAX mitochondrial localization .	Multiple members of the BCL-2 family have been shown to modulate BAX mitochondrial localization.	4	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	4	5	11	12
Results indicated that CrVI decreased ( P < 0.05 ) expression of Bcl-2 and Bcl-XL proteins , increased ( P < 0.05 ) total Bad and Bax proteins , and decreased ( P < 0.05 ) HSP70 and HSP90 proteins .	Results indicated that CrVI decreased (P < 0.05) expression of Bcl-2 and Bcl-XL proteins, increased (P < 0.05) total Bad and Bax proteins, and decreased (P < 0.05) HSP70 and HSP90 proteins.	10	27	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	12	13	26	27
However , Bcl-2 accelerates the shuttling of only Bax , and not that of Bak .	However, Bcl-2 accelerates the shuttling of only Bax, and not that of Bak.	2	9	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	8	9
The pro apoptotic Bcl-2 family member BIM is known to induce BAX activation .	The pro apoptotic Bcl-2 family member BIM is known to induce BAX activation.	3	12	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	3	4	11	12
By contrast , another model states that binding of all pro survival BCL-2 family proteins by BH3 only proteins is sufficient to activate BAX and BAK XREF_BIBR , XREF_BIBR .	By contrast, another model states that binding of all pro survival BCL-2 family proteins by BH3 only proteins is sufficient to activate BAX and BAK XREF_BIBR, XREF_BIBR.	7	26	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	12	13	23	24
Relevant to the neuroprotective effects of Bcl-2 in transgenic mSOD1 mice , overexpression of Bcl-2 increases the formation of Bcl-2 : Bax heterodimers , which abolish the Bax proapoptotic property .	Relevant to the neuroprotective effects of Bcl-2 in transgenic mSOD1 mice, overexpression of Bcl-2 increases the formation of Bcl-2 : Bax heterodimers, which abolish the Bax proapoptotic property.	12	22	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	overexpression of Bcl-2	bcl-2	Bax	Bax	bax	14	15	21	22
PUMA and and NOXA as well as Bad can inhibit anti-apoptotic members Bcl-2 and Bcl-Xl members where Bid and Bim can activate pro apoptotic members Bax and Bak [ XREF_BIBR - XREF_BIBR ] .	PUMA and and NOXA as well as Bad can inhibit anti-apoptotic members Bcl-2 and Bcl-Xl members where Bid and Bim can activate pro apoptotic members Bax and Bak [XREF_BIBR - XREF_BIBR].	12	29	activate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	12	13	25	26
In addition , overexpression of miR-302b-3p/302c- 3p/302d-3p can reduce the expression of ZEB1 , inhibit the expression of Bcl-2 and promote the expression BAX in EC at the RNA level and the protein level .	In addition, overexpression of miR-302b-3p/302c- 3p/302d-3p can reduce the expression of ZEB1, inhibit the expression of Bcl-2 and promote the expression BAX in EC at the RNA level and the protein level.	3	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	overexpression of miR-302b-3p/302c- 3p/302d-3p can reduce the expression of ZEB1, inhibit the expression of Bcl-2	bcl-2	BAX	BAX	bax	18	19	23	24
Glucocorticoid signaling increases the expression of the pro apoptotic Bcl-2 family member Bim , which can activate the pro apoptotic proteins Bax and Bak to disrupt mitochondrial membrane potential , resulting in the release of cytochrome c and other apoptogenic proteins [ XREF_BIBR ] .	Glucocorticoid signaling increases the expression of the pro apoptotic Bcl-2 family member Bim, which can activate the pro apoptotic proteins Bax and Bak to disrupt mitochondrial membrane potential, resulting in the release of cytochrome c and other apoptogenic proteins [XREF_BIBR].	4	25	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of the pro apoptotic Bcl-2	bcl-2	Bax	Bax	bax	9	10	21	22
BDA-366-treated Bcl-2 , rather than Bcl-2 alone , enhances the ability of Bax to bind to 6A7 antibody , whereas BDA-366 itself is not a Bax activator ( XREF_FIG ) .	BDA-366-treated Bcl-2, rather than Bcl-2 alone, enhances the ability of Bax to bind to 6A7 antibody, whereas BDA-366 itself is not a Bax activator (XREF_FIG).	0	13	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	12	13
LiCl combined with mitomycin C significantly down-regulated HMGB1 , MMP9 and Bcl-2 gene expression but significantly increased the level of Bax protein .	LiCl combined with mitomycin C significantly down-regulated HMGB1, MMP9 and Bcl-2 gene expression but significantly increased the level of Bax protein.	0	21	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	LiCl combined with mitomycin C significantly down-regulated HMGB1, MMP9 and Bcl-2 gene expression	bcl-2	Bax	Bax	bax	11	12	20	21
Anti-apoptotic Bcl-2 family proteins , which include Bcl-2 , Bcl-XL , and Mcl-1 , prevent apoptotic cell death by inhibiting the activation and channel formation of Bax and Bak .	Anti-apoptotic Bcl-2 family proteins, which include Bcl-2, Bcl-XL, and Mcl-1, prevent apoptotic cell death by inhibiting the activation and channel formation of Bax and Bak.	1	28	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	26	27
Other Bcl-2 family proteins , such as that those contain only one Bcl-2 homology domain 3 ( BH-3 ) , can also activate Bax by directly binding to Bax [ XREF_BIBR ] .	Other Bcl-2 family proteins, such as that those contain only one Bcl-2 homology domain 3 (BH-3), can also activate Bax by directly binding to Bax [XREF_BIBR].	1	24	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	23	24
Interestingly , forced expression of PCAF reduced Bcl-2 expression , upregulated BAX and repressed cell apoptosis .	Interestingly, forced expression of PCAF reduced Bcl-2 expression, upregulated BAX and repressed cell apoptosis.	3	12	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of PCAF reduced Bcl-2 expression	bcl-2	BAX	BAX	bax	7	8	11	12
However , the death inhibitory proteins Bcl-x ( L ) and Bcl-2 fail to rescue Bax delta mediated growth inhibition under conditions promoting respiration , although they bind Bax delta in the cell .	However, the death inhibitory proteins Bcl-x (L) and Bcl-2 fail to rescue Bax delta mediated growth inhibition under conditions promoting respiration, although they bind Bax delta in the cell.	6	16	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	11	12	15	16
Western blot analysis of Bax and Bcl-2 ( pro- and anti-apoptotic gene products , respectively ) indicated higher expression of Bax protein and no significant change in bcl-2 expression and accordingly increased the Bax and Bcl -2 ratio compared to control group , confirming the histological study .	Western blot analysis of Bax and Bcl-2 (pro- and anti-apoptotic gene products, respectively) indicated higher expression of Bax protein and no significant change in bcl-2 expression and accordingly increased the Bax and Bcl -2 ratio compared to control group, confirming the histological study.	2	37	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	33	34
In addition , DEA could down-regulate expression of Bcl-2 , up-regulate Bax and induced cytochrome c release .	In addition, DEA could down-regulate expression of Bcl-2, up-regulate Bax and induced cytochrome c release.	3	12	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	DEA could down-regulate expression of Bcl-2	bcl-2	Bax	Bax	bax	8	9	11	12
PUMA , a pro apoptotic BH3-only Bcl-2 family protein , promotes Bax and Bak and mitochondria dependent apoptosis in various cell types .	PUMA, a pro apoptotic BH3-only Bcl-2 family protein, promotes Bax and Bak and mitochondria dependent apoptosis in various cell types.	6	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	11	12
In addition , p-Akt and p-GSK3beta have been reported to upregulate the expression of Bcl-2 and Bcl-xL , and increase the Bcl-2 and Bax ratio .	In addition, p-Akt and p-GSK3beta have been reported to upregulate the expression of Bcl-2 and Bcl-xL, and increase the Bcl-2 and Bax ratio.	3	24	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	p-Akt and p-GSK3beta have been reported to upregulate the expression of Bcl-2	bcl-2	Bax	Bax	bax	14	15	23	24
Western blot analysis suggested that silence of TLR4 , MyD88 , ERK , JNK , and p38 decreased Bcl-2 expression level and increased Bax and cleaved caspase-3 expression levels , consistent with the FCM analysis results .	Western blot analysis suggested that silence of TLR4, MyD88, ERK, JNK, and p38 decreased Bcl-2 expression level and increased Bax and cleaved caspase-3 expression levels, consistent with the FCM analysis results.	9	24	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	MyD88, ERK, JNK, and p38 decreased Bcl-2 expression level	bcl-2	Bax	Bax	bax	18	19	23	24
Bcl-2 family proteins could either promote cell survival ( Bcl-2 and Bcl-XL ) or induce apoptosis ( Bax and Bad ) .	Bcl-2 family proteins could either promote cell survival (Bcl-2 and Bcl-XL) or induce apoptosis (Bax and Bad).	0	19	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	17	18
In mitochondrion dependent apoptosis , increase of bax and bcl-2 down-expression induce Bax relocation in the outer mitochondrial membrane .	In mitochondrion dependent apoptosis, increase of bax and bcl-2 down-expression induce Bax relocation in the outer mitochondrial membrane.	7	13	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	bcl-2 down-expression	bcl-2	Bax	Bax	bax	9	10	12	13
In response to apoptotic stimuli , the third Bcl-2 subfamily , BH3-only proteins , promote apoptosis by either activating Bax and Bak or inactivating Bcl-2 , Bcl-xL and Mcl-1 .	In response to apoptotic stimuli, the third Bcl-2 subfamily, BH3-only proteins, promote apoptosis by either activating Bax and Bak or inactivating Bcl-2, Bcl-xL and Mcl-1.	8	21	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	19	20
Moreover , HD downregulated the Bcl-2 expression , upregulated the Bax expression and the Bax and Bcl -2 ratio , promoted the disruption of MMP , induced the release of cytochrome c from mitochondria to cytosol , and increased the activity of caspase-3 in MSCs .	Moreover, HD downregulated the Bcl-2 expression, upregulated the Bax expression and the Bax and Bcl -2 ratio, promoted the disruption of MMP, induced the release of cytochrome c from mitochondria to cytosol, and increased the activity of caspase-3 in MSCs.	2	12	upregulated	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Bcl-2	HD downregulated the Bcl-2 expression	bcl-2	Bax	Bax expression	bax	5	6	10	11
These models included activation of Bax by an activator such as tBid , inhibition of the activator and Bax by Bcl-2 , and displacement of the activator in the activator and Bcl-2 complex by Bax .	These models included activation of Bax by an activator such as tBid, inhibition of the activator and Bax by Bcl-2, and displacement of the activator in the activator and Bcl-2 complex by Bax.	13	21	activator	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	20	21	18	19
The complexes also activates apoptosis via the mitochondrial pathway by down-regulating Bcl-2 and up-regulating of Bax .	The complexes also activates apoptosis via the mitochondrial pathway by down-regulating Bcl-2 and up-regulating of Bax.	3	16	activates	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	11	12	15	16
This process has been studied in some details [ XREF_BIBR ] ; glucocorticoid signaling increases the expression of the pro apoptotic Bcl-2 family member , which can activate the pro apoptotic proteins Bax and Bak to disrupt mitochondrial membrane potential , resulting in the release of cytochrome c and other apoptogenic proteins .	This process has been studied in some details [XREF_BIBR]; glucocorticoid signaling increases the expression of the pro apoptotic Bcl-2 family member, which can activate the pro apoptotic proteins Bax and Bak to disrupt mitochondrial membrane potential, resulting in the release of cytochrome c and other apoptogenic proteins.	16	36	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of the pro apoptotic Bcl-2	bcl-2	Bax	Bax	bax	21	22	32	33
Recent studies showed that LBP could increase Bcl-2 expression , decrease the expression of apoptotic Apaf-1 and caspase-3 in the spleen of mice and restore Bax and Bcl -2 ratio spermatogenic cells of rat [ XREF_BIBR , XREF_BIBR ] , suggesting that the mechanistic effect of LBP may be exerted on caspase mediated signaling cascades of apoptosis .	Recent studies showed that LBP could increase Bcl-2 expression, decrease the expression of apoptotic Apaf-1 and caspase-3 in the spleen of mice and restore Bax and Bcl -2 ratio spermatogenic cells of rat [XREF_BIBR, XREF_BIBR], suggesting that the mechanistic effect of LBP may be exerted on caspase mediated signaling cascades of apoptosis.	4	40	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	LBP could increase Bcl-2 expression	bcl-2	Bax	Bax	bax	7	8	25	26
At the molecular level , DEX decreased the levels of the pro apoptosis protein Bax , increased the levels of the anti-apoptosis protein Bcl-2 , thus increasing the Bcl-2 and Bax ratio , and inhibited caspase-3 activation .	At the molecular level, DEX decreased the levels of the pro apoptosis protein Bax, increased the levels of the anti-apoptosis protein Bcl-2, thus increasing the Bcl-2 and Bax ratio, and inhibited caspase-3 activation.	18	31	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	levels of the anti-apoptosis protein Bcl-2	bcl-2	Bax	Bax	bax	23	24	30	31
Thus we hypothesize that rhCNB reduces the expression of Bcl-2 and Bcl-xL so allowing Bax to accumulate in the OMM , and they also upregulate Bim to further activate Bax , which then triggers the mitochondria apoptosis pathway .	Thus we hypothesize that rhCNB reduces the expression of Bcl-2 and Bcl-xL so allowing Bax to accumulate in the OMM, and they also upregulate Bim to further activate Bax, which then triggers the mitochondria apoptosis pathway.	7	16	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	9	10	14	15
The GSH analogue , gamma-glutamylcysteinyl-ethyl ester , down-regulated Bax and p53 abundance but restored that of Bcl-2 , thereby increasing Bcl-2 and Bax .	The GSH analogue, gamma-glutamylcysteinyl-ethyl ester, down-regulated Bax and p53 abundance but restored that of Bcl-2, thereby increasing Bcl-2 and Bax.	14	23	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	16	17	22	23
BCL-2 homology 3 ( BH3 )-only members of the BCL-2 family either directly activate BAX and BAK and induce cytochrome C release or do so indirectly via antagonistic interaction with antiapoptotic members of the same family .	BCL-2 homology 3 (BH3)-only members of the BCL-2 family either directly activate BAX and BAK and induce cytochrome C release or do so indirectly via antagonistic interaction with antiapoptotic members of the same family.	0	18	directly activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	0	1	14	15
Interestingly , MK-AS also clearly downregulated the protein level of Bcl-2 , and upregulated p53 , Bax , and caspase-3 in the hepatocellular carcinoma tissue .	Interestingly, MK-AS also clearly downregulated the protein level of Bcl-2, and upregulated p53, Bax, and caspase-3 in the hepatocellular carcinoma tissue.	2	17	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	MK-AS also clearly downregulated the protein level of Bcl-2	bcl-2	Bax	Bax	bax	10	11	16	17
Since the anti-apoptotic family members , Bcl-2 and Bcl-XL are able to prevent the permeabilization of the outer mitochondrial membrane by directly inhibiting Bax and Bak , XREF_BIBR we first analyzed this potential beneficial effect in the CryAB R120G / Bcl-2 hearts .	Since the anti-apoptotic family members, Bcl-2 and Bcl-XL are able to prevent the permeabilization of the outer mitochondrial membrane by directly inhibiting Bax and Bak, XREF_BIBR we first analyzed this potential beneficial effect in the CryAB R120G / Bcl-2 hearts.	6	27	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	23	24
The findings from our study demonstrated that nicotine increased the expression of Bax and reduced the expression of Bcl-2 , which increased the Bax and Bcl -2 ratio in a dose dependent manner .	The findings from our study demonstrated that nicotine increased the expression of Bax and reduced the expression of Bcl-2, which increased the Bax and Bcl -2 ratio in a dose dependent manner.	16	27	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of Bcl-2	bcl-2	Bax	Bax	bax	18	19	23	24
Since GAPLINC can absorb miR-211 , which increases Bcl-2 , and Bcl-2 abrogation upregulates the apoptotic protein Bax , Bcl-2 , and Bax expressions were detected .	Since GAPLINC can absorb miR-211, which increases Bcl-2, and Bcl-2 abrogation upregulates the apoptotic protein Bax, Bcl-2, and Bax expressions were detected.	11	18	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	11	12	17	18
Moreover , HGF induced sequestration of Bax by Bcl-2 allows Bax to become inactive , thereby inhibiting apoptosis .	Moreover, HGF induced sequestration of Bax by Bcl-2 allows Bax to become inactive, thereby inhibiting apoptosis.	6	12	allows	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	10	11
In contrast , Bcl-2 prevents apoptosis by inhibiting the activity of Bax [ XREF_BIBR , XREF_BIBR ] .	In contrast, Bcl-2 prevents apoptosis by inhibiting the activity of Bax [XREF_BIBR, XREF_BIBR].	3	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	11	12
Under abnormal conditions , however , overexpressed Bcl-2 could dissociate Bax dimers and promote the formation of complexes of Bax and Bcl-2 , then inhibit cell apoptosis , and up-regulated Bax increases the number of Bax dimers and promote cell apoptosis .	Under abnormal conditions, however, overexpressed Bcl-2 could dissociate Bax dimers and promote the formation of complexes of Bax and Bcl-2, then inhibit cell apoptosis, and up-regulated Bax increases the number of Bax dimers and promote cell apoptosis.	6	29	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	19	20
Therefore , it appears that MOAP-1 may function similar to the canonical BH3-only proteins of the Bcl-2 family that are known to promote Bax activation and which are also inhibited by its anti-apoptotic family members .	Therefore, it appears that MOAP-1 may function similar to the canonical BH3-only proteins of the Bcl-2 family that are known to promote Bax activation and which are also inhibited by its anti-apoptotic family members.	16	24	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	16	17	23	24
The pathway of promoting apoptosis by Bax protein may be related to the anti-apoptotic protein Bcl-2 , which can cause Bax to lose its pro apoptotic effect .	The pathway of promoting apoptosis by Bax protein may be related to the anti-apoptotic protein Bcl-2, which can cause Bax to lose its pro apoptotic effect.	10	21	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	15	16	20	21
Antiapoptotic Bcl-2 proteins reside on the outer mitochondrial membrane ( OMM ) and prevent apoptosis by inhibiting the activation of the proapoptotic family members , Bax and Bak .	Antiapoptotic Bcl-2 proteins reside on the outer mitochondrial membrane (OMM) and prevent apoptosis by inhibiting the activation of the proapoptotic family members, Bax and Bak.	1	26	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	25	26
Precisely how BAX and BAK are activated by other Bcl-2 family proteins has been a source of intense research since their discovery .	Precisely how BAX and BAK are activated by other Bcl-2 family proteins has been a source of intense research since their discovery.	2	11	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	9	10	2	3
The mechanism of (-)-phenserine efficacy inhibiting the initiation of neuronal preprogramed cell death will be supported by the profile of anti-apoptotic , Bcl-2 , and pro apoptotic brain marked exosome BAX and activated Capsase-3 .	The mechanism of (-)-phenserine efficacy inhibiting the initiation of neuronal preprogramed cell death will be supported by the profile of anti-apoptotic, Bcl-2, and pro apoptotic brain marked exosome BAX and activated Capsase-3.	15	33	supported	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	22	23	30	31
In contrast , Bcl2 is a survival ( antiapoptotic ) gene and the dimer Bax and Bcl2 induces a neutralization of Bax and a loss of apoptosis .	In contrast, Bcl2 is a survival (antiapoptotic) gene and the dimer Bax and Bcl2 induces a neutralization of Bax and a loss of apoptosis.	14	22	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	16	17	21	22
These findings imply that a specific region in Bax confers an active propensity for apoptosis in mammalian cells and support the view that Bcl-2 may block death primarily by suppressing Bax activity .	These findings imply that a specific region in Bax confers an active propensity for apoptosis in mammalian cells and support the view that Bcl-2 may block death primarily by suppressing Bax activity.	23	31	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	23	24	30	31
Finally , NIR significantly rescued OGD induced suppression of p-Akt and Bcl-2 expression , and attenuated OGD induced upregulation of Bax , BAD and caspase-3 activation .	Finally, NIR significantly rescued OGD induced suppression of p-Akt and Bcl-2 expression, and attenuated OGD induced upregulation of Bax, BAD and caspase-3 activation.	2	25	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	NIR significantly rescued OGD induced suppression of p-Akt and Bcl-2 expression	bcl-2	Bax	Bax	bax	11	12	20	21
One possibility is the neutralization of anti-apoptotic Bcl2 family members that releases Bax from the anti and apoptotic complex and the other is for Bim to bind directly and activate Bax [ XREF_BIBR - XREF_BIBR ] .	One possibility is the neutralization of anti-apoptotic Bcl2 family members that releases Bax from the anti and apoptotic complex and the other is for Bim to bind directly and activate Bax [XREF_BIBR - XREF_BIBR].	7	34	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	7	8	30	31
Antioxidants antagonized Bcl-2 : INrf2 interaction , led to release and stabilization of Bcl-2 , increased Bcl-2 : Bax heterodimers and reduced apoptosis .	Antioxidants antagonized Bcl-2 : INrf2 interaction, led to release and stabilization of Bcl-2, increased Bcl-2 : Bax heterodimers and reduced apoptosis.	2	21	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	18	19
Our findings above reveal that the BDA-366-induced conformationally changed Bcl2 ( i.e. with exposed BH3 domain ) can activate Bax ( XREF_FIG and XREF_FIG ) .	Our findings above reveal that the BDA-366-induced conformationally changed Bcl2 (i.e. with exposed BH3 domain) can activate Bax (XREF_FIG and XREF_FIG).	5	23	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	9	10	19	20
XREF_BIBR , XREF_BIBR Bax activation is triggered by the transcriptional and posttranslational activation of Bcl-2 homology domain 3 ( BH3 )-only proteins that directly activate Bax and/or indirectly activate Bax by neutralizing the activity of anti-apoptotic Bcl-2 family proteins ( ' de-repression ' ) .	XREF_BIBR, XREF_BIBR Bax activation is triggered by the transcriptional and posttranslational activation of Bcl-2 homology domain 3 (BH3)-only proteins that directly activate Bax and/or indirectly activate Bax by neutralizing the activity of anti-apoptotic Bcl-2 family proteins (' de-repression ').	3	16	triggered	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	14	15	3	4
Although further investigations may shed light on this important issue , the data presented here , including the weak interaction of KSHV BCL-2 with BAX ( XREF_FIG A and XREF_SUPPLEMENTARY ) , suggest that viral BCL-2 homologues may not necessarily target both BAX and BAK to suppress apoptosis .	Although further investigations may shed light on this important issue, the data presented here, including the weak interaction of KSHV BCL-2 with BAX (XREF_FIG A and XREF_SUPPLEMENTARY), suggest that viral BCL-2 homologues may not necessarily target both BAX and BAK to suppress apoptosis.	35	44	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	35	36	42	43
At the core of the mitochondrial pathway is the process of mitochondrial outer membrane permeabilization ( MOMP ) mediated predominantly by the pro apoptotic BCL-2 family members , Bax and Bak , and inhibited by the anti-apoptotic BCL-2 family proteins .	At the core of the mitochondrial pathway is the process of mitochondrial outer membrane permeabilization (MOMP) mediated predominantly by the pro apoptotic BCL-2 family members, Bax and Bak, and inhibited by the anti-apoptotic BCL-2 family proteins.	18	30	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	Bax	Bax	Bax	24	25	28	29
The expression of bcl-2 was increased , bax and bcl -2 ratio and AI decreased in this group .	The expression of bcl-2 was increased, bax and bcl -2 ratio and AI decreased in this group.	1	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	expression of bcl-2	bcl-2	bax	bax	bax	3	4	7	8
To determine whether BDA-366 induces Bcl2 conformation change by exposure of its BH3 domain in tumor tissues and whether the BH3 domain exposed Bcl2 activates Bax , conformational changes in both Bcl2 and Bax were simultaneously analyzed by QD-IHF on the same tissue slide .	To determine whether BDA-366 induces Bcl2 conformation change by exposure of its BH3 domain in tumor tissues and whether the BH3 domain exposed Bcl2 activates Bax, conformational changes in both Bcl2 and Bax were simultaneously analyzed by QD-IHF on the same tissue slide.	22	26	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	23	24	25	26
The Bcl-2 family consists of both cell death promoters and preventers , including the anti-apoptotic proteins Bcl-2 , Bcl- xL , Mcl-1 , A1/Bfl -1 and Bcl-W , and the pro apoptotic members Bax , Bak , Bad , Bik , Bid , Hrk and Bok [ XREF_BIBR ] .	The Bcl-2 family consists of both cell death promoters and preventers, including the anti-apoptotic proteins Bcl-2, Bcl- xL, Mcl-1, A1/Bfl -1 and Bcl-W, and the pro apoptotic members Bax, Bak, Bad, Bik, Bid, Hrk and Bok [XREF_BIBR].	3	47	promoters	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	16	17	33	34
The canonical mitochondrial apoptosis pathway is induced by the multidomain proapoptotic BCL-2 family members BAX and BAK , 17 which control mitochondrial outer membrane permeabilization ( MOMP ) .	The canonical mitochondrial apoptosis pathway is induced by the multidomain proapoptotic BCL-2 family members BAX and BAK, 17 which control mitochondrial outer membrane permeabilization (MOMP).	6	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	11	12	14	15
To determine if changes in anti-apoptotic Bcl-2 protein expression activates Bax and Bak , we examined the levels of Bcl-2 , Bcl-x L , and Mcl-1 .	To determine if changes in anti-apoptotic Bcl-2 protein expression activates Bax and Bak, we examined the levels of Bcl-2, Bcl-x L, and Mcl-1.	6	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 protein expression	bcl-2	Bax	Bax	bax	6	7	10	11
Some Bcl-2 family members induce apoptosis ( Bax , Bad , Bid , and Bcl-X1 ) , whereas others inhibit apoptosis ( Bcl-2 and Bcl-X1 ) .	Some Bcl-2 family members induce apoptosis (Bax, Bad, Bid, and Bcl-X1), whereas others inhibit apoptosis (Bcl-2 and Bcl-X1).	1	14	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	7	8
This inactivation of anti-apoptotic BCL-2 family proteins in turn promotes activation of BAX and BAK , activation of caspase-9 and -3 and caspase dependent apoptosis .	This inactivation of anti-apoptotic BCL-2 family proteins in turn promotes activation of BAX and BAK, activation of caspase-9 and -3 and caspase dependent apoptosis.	4	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	4	5	12	13
BCL-2 and its closest homologues ( BCL-X L , BCL-W , MCL-1 and A1/BFL-1 ) promote cell survival by neutralising pro apoptotic relatives : BAX and BAK , and more distant relatives known as BH3-only proteins .	BCL-2 and its closest homologues (BCL-X L, BCL-W, MCL-1 and A1/BFL-1) promote cell survival by neutralising pro apoptotic relatives : BAX and BAK, and more distant relatives known as BH3-only proteins.	0	26	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	0	1	24	25
Our data showed that UCP2 enhanced MAPKs activation and reduced Bcl-2 expression , which can reduce Bax stimulated apoptotic events .	Our data showed that UCP2 enhanced MAPKs activation and reduced Bcl-2 expression, which can reduce Bax stimulated apoptotic events.	4	17	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	UCP2 enhanced MAPKs activation and reduced Bcl-2 expression	bcl-2	Bax	Bax	bax	10	11	16	17
Stable overexpression of Ran also markedly inhibited the phosphorylation of Bcl-2 by paclitaxel , and inhibited the translocation of Bax , the release of cytochrome c and activation of caspase-3 .	Stable overexpression of Ran also markedly inhibited the phosphorylation of Bcl-2 by paclitaxel, and inhibited the translocation of Bax, the release of cytochrome c and activation of caspase-3.	1	20	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	overexpression of Ran also markedly inhibited the phosphorylation of Bcl-2	bcl-2	Bax	Bax	bax	10	11	19	20
tBID then binds Bcl-2 allowing BAX to form a pore in the outer membrane of the mitochondria enabling the release of cytochrome c into the cytosol .	tBID then binds Bcl-2 allowing BAX to form a pore in the outer membrane of the mitochondria enabling the release of cytochrome c into the cytosol.	2	7	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	3	4	5	6
Both anti- and pro apoptotic Bcl-2 family members can respond to changes in glucose metabolism after cytokine withdrawal to promote Bax activation .	Both anti- and pro apoptotic Bcl-2 family members can respond to changes in glucose metabolism after cytokine withdrawal to promote Bax activation.	5	21	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	20	21
Pro apoptotic Bax promotes intrinsic apoptosis by forming oligomers in the mitochondrial outer membrane , facilitating the release of the apoptogenic molecules , whereas anti-apoptotic Bcl-2 blocks mitochondrial apoptosis by blocking the release and oligomerization of Bax XREF_BIBR .	Pro apoptotic Bax promotes intrinsic apoptosis by forming oligomers in the mitochondrial outer membrane, facilitating the release of the apoptogenic molecules, whereas anti-apoptotic Bcl-2 blocks mitochondrial apoptosis by blocking the release and oligomerization of Bax XREF_BIBR.	24	37	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	25	26	36	37
Increased expression of Bax but not Bcl-2 in hypoxic cerebral tissue thus increasing the Bax and Bcl -2 ratio in favor of hypoxia induced apoptosis has been reported .	Increased expression of Bax but not Bcl-2 in hypoxic cerebral tissue thus increasing the Bax and Bcl -2 ratio in favor of hypoxia induced apoptosis has been reported.	1	18	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of Bax but not Bcl-2	bcl-2	Bax	Bax	bax	6	7	14	15
The third Bcl-2 subfamily of proteins , BH3-only molecules ( BH3s ) , promotes apoptosis by either activating Bax and Bak or inactivating Bcl-2/Bcl-xL/Mcl-1 .	The third Bcl-2 subfamily of proteins, BH3-only molecules (BH3s), promotes apoptosis by either activating Bax and Bak or inactivating Bcl-2/Bcl-xL/Mcl-1.	2	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	18	19
10 For this purpose , caspase-8 cleaves the proapoptotic Bcl-2 protein BID to tBID ( truncated ) , which then activates BAX and BAK .	10 For this purpose, caspase-8 cleaves the proapoptotic Bcl-2 protein BID to tBID (truncated), which then activates BAX and BAK.	9	23	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	9	10	21	22
RCE-4 increased the expression of Bax and decreased the expression of Bcl-2 , thus augmenting the Bax and Bcl -2 ratio .	RCE-4 increased the expression of Bax and decreased the expression of Bcl-2, thus augmenting the Bax and Bcl -2 ratio.	0	20	augmenting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	RCE-4 increased the expression of Bax and decreased the expression of Bcl-2	bcl-2	Bax	Bax	bax	11	12	16	17
Nevertheless , a separate step , whereby a subclass of apoptotic Bcl-2 proteins such as Bim and Bid directly activate Bak and Bax , was proposed to be required for oligomerization XREF_BIBR - XREF_BIBR .	Nevertheless, a separate step, whereby a subclass of apoptotic Bcl-2 proteins such as Bim and Bid directly activate Bak and Bax, was proposed to be required for oligomerization XREF_BIBR - XREF_BIBR.	11	23	directly activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	11	12	22	23
By blocking polymerization of Bax , Bcl-2 suppresses apoptosis and contributes to drug resistance in cancer cells .	By blocking polymerization of Bax, Bcl-2 suppresses apoptosis and contributes to drug resistance in cancer cells.	2	10	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	4	5
The explanation for these contradictory results may lie in the fact that other members of the Bcl2 family modulate the function of Bcl2 and Bax and , hence , their relative expression and/or activity levels also affect the CLL cells susceptibility to apoptosis .	The explanation for these contradictory results may lie in the fact that other members of the Bcl2 family modulate the function of Bcl2 and Bax and, hence, their relative expression and/or activity levels also affect the CLL cells susceptibility to apoptosis.	16	25	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	16	17	24	25
The Bcl-2 acts as an anti-apoptotic protein to prevent permeabilization of the outer mitochondrial membrane by inhibiting the action of the pro apoptotic protein Bax [ XREF_BIBR ] .	The Bcl-2 acts as an anti-apoptotic protein to prevent permeabilization of the outer mitochondrial membrane by inhibiting the action of the pro apoptotic protein Bax [XREF_BIBR].	0	26	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	24	25
To confirm that these effects were not exclusively dependent on the A staple position , we documented that BCL-2 BH4 SAHB C also inhibited BIM SAHB A - and heat triggered BAX activation ( XREF_SUPPLEMENTARY ) .	To confirm that these effects were not exclusively dependent on the A staple position, we documented that BCL-2 BH4 SAHB C also inhibited BIM SAHB A - and heat triggered BAX activation (XREF_SUPPLEMENTARY).	18	32	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	18	19	31	32
It looks like that both Bax and Bcl-2 from imaging analysis showed a decrease as the increase of the concentration of AFB 1 and ST , but the ratio of Bax and Bcl-2 with a value from 1.37 to 2.88 in the treatment group is higher than the control group of 1.12 , supporting the pro apoptotic function of Bax and Bcl-2 to HepG2 cells upon exposed to mycotoxins .	It looks like that both Bax and Bcl-2 from imaging analysis showed a decrease as the increase of the concentration of AFB 1 and ST, but the ratio of Bax and Bcl-2 with a value from 1.37 to 2.88 in the treatment group is higher than the control group of 1.12, supporting the pro apoptotic function of Bax and Bcl-2 to HepG2 cells upon exposed to mycotoxins.	28	61	supporting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	32	33	59	60
We also discuss how the spatial regulation of Bcl-2 family preference for binding partners contributes to regulate Bax and Bak activation .	We also discuss how the spatial regulation of Bcl-2 family preference for binding partners contributes to regulate Bax and Bak activation.	8	20	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	8	9	17	18
Our results suggest that BCL-2 contains an intrinsic pro apoptotic activity and can induce apoptosis independent of BAX and BAK under specific conditions .	Our results suggest that BCL-2 contains an intrinsic pro apoptotic activity and can induce apoptosis independent of BAX and BAK under specific conditions.	4	19	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	4	5	17	18
Programmed cell death requires the activation of Bax and Bak ( the pro apoptotic effector proteins ) , which is proposed to occur by one of two mechanisms : the ' direct activation ' model , in which BH3-only proteins directly interact with Bax and Bak XREF_BIBR , and the ' indirect activation ' model , where the BH3-only proteins bind to the anti-apoptotic Bcl-2 proteins inducing the release of Bax and Bak XREF_BIBR .	Programmed cell death requires the activation of Bax and Bak (the pro apoptotic effector proteins), which is proposed to occur by one of two mechanisms : the ' direct activation ' model, in which BH3-only proteins directly interact with Bax and Bak XREF_BIBR, and the ' indirect activation ' model, where the BH3-only proteins bind to the anti-apoptotic Bcl-2 proteins inducing the release of Bax and Bak XREF_BIBR.	64	73	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	64	65	70	71
We have provided genetic evidence that BCL2 family members block autophagy by inhibiting BAX and BAK1 , but others have proposed they instead inhibit BECN1 .	We have provided genetic evidence that BCL2 family members block autophagy by inhibiting BAX and BAK1, but others have proposed they instead inhibit BECN1.	6	15	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BAX	BAX	BAX	6	7	13	14
ABC decreased Bcl-xl , increased Bax and Bim without affecting Bcl-2 , p-Bcl-2 , Bok , and Bad expression ( XREF_FIG ) .	ABC decreased Bcl-xl, increased Bax and Bim without affecting Bcl-2, p-Bcl-2, Bok, and Bad expression (XREF_FIG).	4	18	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p-Bcl-2	p-Bcl-2	p-Bcl-2	Bax	Bax	Bax	12	13	5	6
Despite numerous molecules being implicated in BAX activation in RGCs following axonal injury , the prodeath Bcl2 family members that activate BAX after axonal injury are not completely defined .	Despite numerous molecules being implicated in BAX activation in RGCs following axonal injury, the prodeath Bcl2 family members that activate BAX after axonal injury are not completely defined.	16	22	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	BAX	BAX	BAX	16	17	21	22
Pretreating NRCs with 10 microM GSRd prior to SI/R promoted Bcl-2 expression and inhibited Bax expression , increasing the Bcl-2 and Bax ratio ( XREF_FIG ) .	Pretreating NRCs with 10 microM GSRd prior to SI/R promoted Bcl-2 expression and inhibited Bax expression, increasing the Bcl-2 and Bax ratio (XREF_FIG).	8	22	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	SI/R promoted Bcl-2 expression	bcl-2	Bax	Bax	bax	10	11	21	22
It is well known that Bax promotes intrinsic apoptosis by forming oligomers in the mitochondrial outer membrane , participating in the release of apoptogenic molecules ; oppositely , Bcl-2 inhibits mitochondrial apoptosis by blocking the release and oligomerization of Bax .	It is well known that Bax promotes intrinsic apoptosis by forming oligomers in the mitochondrial outer membrane, participating in the release of apoptogenic molecules; oppositely, Bcl-2 inhibits mitochondrial apoptosis by blocking the release and oligomerization of Bax.	28	40	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	28	29	39	40
Sustained JNK activation aggravated caspase8 and mitochondria dependent death pathway , downregulated Bcl-2 expression and increased mitochondrial translocation of Bax .	Sustained JNK activation aggravated caspase8 and mitochondria dependent death pathway, downregulated Bcl-2 expression and increased mitochondrial translocation of Bax.	1	20	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	JNK activation aggravated caspase8 and mitochondria dependent death pathway, downregulated Bcl-2 expression	bcl-2	Bax	Bax	bax	12	13	19	20
In addition , ESC-3 treatment could downregulate the protein level of Bcl-2 and upregulate the Bax , leading to the increase in the ratio of Bax to Bcl-2 in Mz-ChA-1 cells .	In addition, ESC-3 treatment could downregulate the protein level of Bcl-2 and upregulate the Bax, leading to the increase in the ratio of Bax to Bcl-2 in Mz-ChA-1 cells.	3	16	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	ESC-3 treatment could downregulate the protein level of Bcl-2	bcl-2	Bax	Bax	bax	11	12	15	16
NDRG2 distinctively enhanced Bcl-2 expression and increased the Bcl-2 and Bax ratio , which decreased sensitivity of Hela cells to drug induced apoptosis .	NDRG2 distinctively enhanced Bcl-2 expression and increased the Bcl-2 and Bax ratio, which decreased sensitivity of Hela cells to drug induced apoptosis.	0	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	NDRG2 distinctively enhanced Bcl-2 expression	bcl-2	Bax	Bax	bax	3	4	10	11
Bcl-2 and Bax are two important regulators of the mitochondrial apoptotic signaling pathway XREF_BIBR , and Bcl-2 can prevent permeabilization of the outer mitochondrial membrane by inhibiting activation of Bax and Bak , leading to attenuation of the activation of caspase-9 and caspase-3 XREF_BIBR .	Bcl-2 and Bax are two important regulators of the mitochondrial apoptotic signaling pathway XREF_BIBR, and Bcl-2 can prevent permeabilization of the outer mitochondrial membrane by inhibiting activation of Bax and Bak, leading to attenuation of the activation of caspase-9 and caspase-3 XREF_BIBR.	16	31	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	16	17	29	30
This paper shows that ICG remarkably induced Bax expression and downregulated Bcl-2 expression , which in turn increased the Bax and Bcl -2 ratio after 3 minutes of exposure at 0.05 mg/ml , a common concentration still in use by some surgeons .	This paper shows that ICG remarkably induced Bax expression and downregulated Bcl-2 expression, which in turn increased the Bax and Bcl -2 ratio after 3 minutes of exposure at 0.05 mg/ml, a common concentration still in use by some surgeons.	4	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	ICG remarkably induced Bax expression and downregulated Bcl-2 expression	bcl-2	Bax	Bax	bax	11	12	19	20
RT-PCR demonstrated that caspase-3 and bax were significantly up-regulated in SW1990 cells treated with TL while bcl-2 mRNA was not .	RT-PCR demonstrated that caspase-3 and bax were significantly up-regulated in SW1990 cells treated with TL while bcl-2 mRNA was not.	3	17	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	bcl-2	bcl-2	bcl-2	bax	bax	bax	16	17	5	6
Although it is unclear how converted Bcl-2 activates Bax , it can be envisioned that the converted Bcl-2 with its BH3 domain exposed may act directly or indirectly on Bax , resulting in Bax activation and apoptosis .	Although it is unclear how converted Bcl-2 activates Bax, it can be envisioned that the converted Bcl-2 with its BH3 domain exposed may act directly or indirectly on Bax, resulting in Bax activation and apoptosis.	5	9	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	8	9
The Bcl-2 , when down-regulated , allows the activation of Bax and thus the formation of protein channels through which pro apoptotic factors such as cytochrome C are released into the cytosol , initiating the apoptotic cascade [ XREF_BIBR , XREF_BIBR ] .	The Bcl-2, when down-regulated, allows the activation of Bax and thus the formation of protein channels through which pro apoptotic factors such as cytochrome C are released into the cytosol, initiating the apoptotic cascade [XREF_BIBR, XREF_BIBR].	0	11	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	10	11
Furthermore , analysis of Bcl-2 family mediators of apoptosis , such as Bcl-2 , Bax and Bcl-XL , showed that depletion of CIAPIN1 could downregulate Bcl-2 , Bcl-XL and upregulate Bax in AdSiCIAPIN1 transduced cells , suggesting that the apoptotic effect of CIAPIN1 could be partly mediated by the Bcl-2 family ( XREF_FIG ) .	Furthermore, analysis of Bcl-2 family mediators of apoptosis, such as Bcl-2, Bax and Bcl-XL, showed that depletion of CIAPIN1 could downregulate Bcl-2, Bcl-XL and upregulate Bax in AdSiCIAPIN1 transduced cells, suggesting that the apoptotic effect of CIAPIN1 could be partly mediated by the Bcl-2 family (XREF_FIG).	4	31	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	30	31
Conversely , downregulation of Bcl-2 by small interfering RNA induced Bax and cytochrome c redistribution and reverse cisplatin-resistance .	Conversely, downregulation of Bcl-2 by small interfering RNA induced Bax and cytochrome c redistribution and reverse cisplatin-resistance.	2	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	10	11
BH3-only proteins antagonize the protective activity of Bcl-2 pro survival family members at the mitochondria and activate pro apoptotic Bax and Bak , which then induce mitochondrial outer membrane permeabilization ( MOMP ) and finally lead to the induction of the caspase cascade ( XREF_FIG ) .	BH3-only proteins antagonize the protective activity of Bcl-2 pro survival family members at the mitochondria and activate pro apoptotic Bax and Bak, which then induce mitochondrial outer membrane permeabilization (MOMP) and finally lead to the induction of the caspase cascade (XREF_FIG).	5	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	19	20
As phosphorylation of Bcl-2 and degradation of Mcl-1 and Bcl-X L allow activation of the apoptotic proteins Bax and Bak , 22 these data could explain the onset and extent of apoptosis in cells treated with CMPD1 .	As phosphorylation of Bcl-2 and degradation of Mcl-1 and Bcl-X L allow activation of the apoptotic proteins Bax and Bak, 22 these data could explain the onset and extent of apoptosis in cells treated with CMPD1.	1	19	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	phosphorylation of Bcl-2	bcl-2	Bax	Bax	bax	3	4	17	18
Moreover , the upregulated expression of BAX and the downregulated expression of Bcl-2 increased the ratio of BAX to Bcl-2 ( XREF_FIG ) .	Moreover, the upregulated expression of BAX and the downregulated expression of Bcl-2 increased the ratio of BAX to Bcl-2 (XREF_FIG).	10	18	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of Bcl-2	bcl-2	BAX	BAX	bax	12	13	17	18
In summary , our study for the first time demonstrated that inactivation of the two pro survival Bcl-2 family proteins , Bcl-xL and Mcl-1 , triggers Bax and Bak activation in the absence of the three direct activator BH3-only proteins , Bid , Bim , Puma , and the tumor suppressor p53 .	In summary, our study for the first time demonstrated that inactivation of the two pro survival Bcl-2 family proteins, Bcl-xL and Mcl-1, triggers Bax and Bak activation in the absence of the three direct activator BH3-only proteins, Bid, Bim, Puma, and the tumor suppressor p53.	17	29	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	17	18	26	27
By 24 h anoxic exposure , the expression of Bcl2 had increased to 110 +/-24% and Bax to 130 +/- 10 % of normoxia .	By 24 h anoxic exposure, the expression of Bcl2 had increased to 110 +/-24% and Bax to 130 +/- 10% of normoxia.	7	21	increased	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Bcl2	expression of Bcl2	bcl2	Bax	Bax	bax	9	10	16	17
Moreover , upon apoptotic stimuli , another Bcl-2 apoptosis promoting protein Bax undergoes a conformational change and translocates to mitochondria , where it oligomerizes and forms pores that allow the release of cytochrome c 32 .	Moreover, upon apoptotic stimuli, another Bcl-2 apoptosis promoting protein Bax undergoes a conformational change and translocates to mitochondria, where it oligomerizes and forms pores that allow the release of cytochrome c 32.	7	12	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	11	12
Mechanistic studies revealed that FBA-TPQ down-regulated MDM2 , E2F1 , Bcl-2 , PI3K proteins , up-regulated Fas , Bax , p53 and p-p 53 , ATM and p-ATM , gammaH2AX , and led to increased cleavage of caspases-3 , -8 and -9 both in vitro and in vivo [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Mechanistic studies revealed that FBA-TPQ down-regulated MDM2, E2F1, Bcl-2, PI3K proteins, up-regulated Fas, Bax, p53 and p-p 53, ATM and p-ATM, gammaH2AX, and led to increased cleavage of caspases-3, -8 and -9 both in vitro and in vivo [XREF_BIBR, XREF_BIBR, XREF_BIBR].	6	19	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	10	11	18	19
Phosphorylation of Bcl-2 following combination therapy appeared to promote Bax homodimerization and mitochondrial release of proapoptotic factors into the cytosol .	Phosphorylation of Bcl-2 following combination therapy appeared to promote Bax homodimerization and mitochondrial release of proapoptotic factors into the cytosol.	0	10	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Phosphorylation of Bcl-2	bcl-2	Bax	Bax	bax	2	3	9	10
The observation is consistent with a general expectation that viral BCL-2 would prefer to target BAX and BAK rather than the upstream BH3-only proteins [ XREF_BIBR ] .	The observation is consistent with a general expectation that viral BCL-2 would prefer to target BAX and BAK rather than the upstream BH3-only proteins [XREF_BIBR].	9	25	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	10	11	15	16
Further , there was increased BAX and decreased BCl-2 levels , incidence of mitochondrial membrane potential depolarization , release of cytochrome c into cytosol , caspase activation , PS externalization and cell death in BAY 11-7082 and MLN4924 treated platelets .	Further, there was increased BAX and decreased BCl-2 levels, incidence of mitochondrial membrane potential depolarization, release of cytochrome c into cytosol, caspase activation, PS externalization and cell death in BAY 11-7082 and MLN4924 treated platelets.	4	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCl-2	BCl-2 levels	bcl-2	BAX	BAX	bax	8	9	5	6
Inhibition of the Notch pathway via DAPT increased Bcl-2 expression , decreased Bax and cleaved caspase-3 levels and prevented HKC cell apoptosis .	Inhibition of the Notch pathway via DAPT increased Bcl-2 expression, decreased Bax and cleaved caspase-3 levels and prevented HKC cell apoptosis.	3	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Notch pathway via DAPT increased Bcl-2 expression	bcl-2	Bax	Bax	bax	8	9	12	13
Bad binds to the pro survival proteins Bcl-2 , Bcl-w and Bcl-xL , thus preventing their inhibition of Bak and/or Bax .	Bad binds to the pro survival proteins Bcl-2, Bcl-w and Bcl-xL, thus preventing their inhibition of Bak and/or Bax.	1	21	preventing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	7	8	20	21
Transfection of miR-629-5p mimic decreased the expression level of Bax ( XREF_FIG D ) , increased the expression level of Bcl-2 ( XREF_FIG D ) , and decreased the ratio of Bax to Bcl-2 than the mimic Con/5-FU group ( XREF_FIG E ) .	Transfection of miR-629-5p mimic decreased the expression level of Bax (XREF_FIG D), increased the expression level of Bcl-2 (XREF_FIG D), and decreased the ratio of Bax to Bcl-2 than the mimic Con/5-FU group (XREF_FIG E).	2	32	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	miR-629-5p mimic decreased the expression level of Bax (XREF_FIG D), increased the expression level of Bcl-2	bcl-2	Bax	Bax	bax	20	21	31	32
21 Because pBad promotes mitochondrial respiration and ATP production , whereas non pBad binds the anti-apoptotic partners Bcl-2 and Bcl-xL eliciting Bax and Bak activation , 36 the low pBad and Bad ratio found in R6/2 brain lysates suggests that Bad activity shifts from positive metabolic to negative apoptotic function in HD cells .	21 Because pBad promotes mitochondrial respiration and ATP production, whereas non pBad binds the anti-apoptotic partners Bcl-2 and Bcl-xL eliciting Bax and Bak activation, 36 the low pBad and Bad ratio found in R6/2 brain lysates suggests that Bad activity shifts from positive metabolic to negative apoptotic function in HD cells.	13	24	eliciting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	17	18	21	22
JNK activation has also been implicated in FFA induced hepatocyte lipoapoptosis by activation of proapoptotic BCL-2 proteins Bim and Bax , triggering the mitochondrial apoptotic pathway [ XREF_BIBR , XREF_BIBR ] .	JNK activation has also been implicated in FFA induced hepatocyte lipoapoptosis by activation of proapoptotic BCL-2 proteins Bim and Bax, triggering the mitochondrial apoptotic pathway [XREF_BIBR, XREF_BIBR].	8	20	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	Bax	Bax	Bax	15	16	19	20
EGCG abrogated the expression of anti-apoptotic Bcl-2 and Bcl-XL proteins and enhanced the levels of proapoptotic Bax proteins followed by caspase-3 activation [ XREF_BIBR ] .	EGCG abrogated the expression of anti-apoptotic Bcl-2 and Bcl-XL proteins and enhanced the levels of proapoptotic Bax proteins followed by caspase-3 activation [XREF_BIBR].	0	17	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	EGCG abrogated the expression of anti-apoptotic Bcl-2	bcl-2	Bax	Bax	bax	6	7	16	17
The anti-apoptotic protein Bcl-2 acts to prevent permeabilization of the outer mitochondrial membrane by inhibiting the action of the pro apoptotic protein Bax [ XREF_BIBR ] .	The anti-apoptotic protein Bcl-2 acts to prevent permeabilization of the outer mitochondrial membrane by inhibiting the action of the pro apoptotic protein Bax [XREF_BIBR].	0	24	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	22	23
In contrast , anti-apoptotic Bcl-2 blocks mitochondrial apoptosis by inhibiting the release and oligomerization of Bax [ Leibowitz and Yu , 2010 ] .	In contrast, anti-apoptotic Bcl-2 blocks mitochondrial apoptosis by inhibiting the release and oligomerization of Bax [Leibowitz and Yu, 2010].	3	16	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	4	5	15	16
Since ABT-737 functions as a sensitizer and BIM is critical for heat shock induced killing , the simplest explanation is that ABT-737 most likely liberated BIM from BCL-2 or BCL-X L , which in turn activated BAX and/or BAK .	Since ABT-737 functions as a sensitizer and BIM is critical for heat shock induced killing, the simplest explanation is that ABT-737 most likely liberated BIM from BCL-2 or BCL-X L, which in turn activated BAX and/or BAK.	27	38	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	27	28	36	37
However , Adv-bcl-2 administration significantly enhanced Bcl-2 and Bax ratio , decreased ischemia and reperfusion induced O ( 2 ) (-) amount , inhibited proximal and distal tubular apoptosis and improved renal function .	However, Adv-bcl-2 administration significantly enhanced Bcl-2 and Bax ratio, decreased ischemia and reperfusion induced O (2) (-) amount, inhibited proximal and distal tubular apoptosis and improved renal function.	2	9	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Adv-bcl-2	Adv-bcl-2	Adv-bcl-2	Bax	Bax	Bax	2	3	8	9
For example , the anti-apoptotic protein Bcl-2 inhibits Bax- and Bak mediated mitochondrial outer membrane integrity breakdown , whereas phosphorylation of Bcl-2 leads to activation of Bax and Bak , causing the release of cytotoxic proteins into the cytosol and triggering caspase activation XREF_BIBR .	For example, the anti-apoptotic protein Bcl-2 inhibits Bax- and Bak mediated mitochondrial outer membrane integrity breakdown, whereas phosphorylation of Bcl-2 leads to activation of Bax and Bak, causing the release of cytotoxic proteins into the cytosol and triggering caspase activation XREF_BIBR.	19	28	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	phosphorylation of Bcl-2	bcl-2	Bax	Bax	bax	21	22	26	27
As bax has been shown to be a downstream effector of the bcl-2-regulated pathway of apoptosis and the activation of bcl-2 can promote the release of bax , leading to activation of caspases XREF_BIBR , XREF_BIBR , we sought to examine whether there is an interaction between bcl-2 , bax , and capspase-3 .	As bax has been shown to be a downstream effector of the bcl-2-regulated pathway of apoptosis and the activation of bcl-2 can promote the release of bax, leading to activation of caspases XREF_BIBR, XREF_BIBR, we sought to examine whether there is an interaction between bcl-2, bax, and capspase-3.	18	27	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	bcl-2	bcl-2	bax	bax	bax	20	21	26	27
The proapoptotic activity of Bax and Bak is regulated by both Bcl-2 family members and BH3-only proteins ; Bcl-2 proteins keep Bax and Bak bound and sequestered , and it is only with the activation of BH3-only proteins and the dissociation of the Bcl-2 proteins that Bax and Bak will undergo conformational changes that will ( in the case of the cytosolic Bax ) induce their accumulation on the outer mitochondrial membrane and cause both Bax and Bak to oligomerize .	The proapoptotic activity of Bax and Bak is regulated by both Bcl-2 family members and BH3-only proteins; Bcl-2 proteins keep Bax and Bak bound and sequestered, and it is only with the activation of BH3-only proteins and the dissociation of the Bcl-2 proteins that Bax and Bak will undergo conformational changes that will (in the case of the cytosolic Bax) induce their accumulation on the outer mitochondrial membrane and cause both Bax and Bak to oligomerize.	43	77	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	43	44	75	76
In addition , JNK directly phosphorylates and inactivates the antiapoptotic Bcl-2 and Bcl-x L , thereby activating Bim and Bax [ XREF_BIBR ] .	In addition, JNK directly phosphorylates and inactivates the antiapoptotic Bcl-2 and Bcl-x L, thereby activating Bim and Bax [XREF_BIBR].	3	21	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	JNK directly phosphorylates and inactivates the antiapoptotic Bcl-2	bcl-2	Bax	Bax	bax	10	11	19	20
Inhibitory Bcl-2 family members sequester only BH3 and/or Bax and Bak proteins , thereby preventing their participation in proapoptotic complexes .	Inhibitory Bcl-2 family members sequester only BH3 and/or Bax and Bak proteins, thereby preventing their participation in proapoptotic complexes.	1	11	sequester	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	8	9
Furthermore , rapamycin and curcumin increased caspase 9 , 3 and 7 activity , decreased anti-apoptotic bcl-2 levels , and increased the pro apoptotic protein Bax .	Furthermore, rapamycin and curcumin increased caspase 9, 3 and 7 activity, decreased anti-apoptotic bcl-2 levels, and increased the pro apoptotic protein Bax.	2	26	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	rapamycin and curcumin increased caspase 9, 3 and 7 activity, decreased anti-apoptotic bcl-2 levels	bcl-2	Bax	Bax	bax	16	17	25	26
Furthermore , the Bax-Anti Bcl2 combination module ( XREF_FIG B ) driven by artificial hTERT promoter could specifically and effectively inhibit malignant phenotypes of BCa by reversing the ratio of Bcl2 and Bax XREF_BIBR .	Furthermore, the Bax-Anti Bcl2 combination module (XREF_FIG B) driven by artificial hTERT promoter could specifically and effectively inhibit malignant phenotypes of BCa by reversing the ratio of Bcl2 and Bax XREF_BIBR.	4	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	Bax	Bax	Bax	4	5	32	33
Significantly , antiapoptotic bcl-2 family members prevent apoptosis by inhibiting Bax conformational change .	Significantly, antiapoptotic bcl-2 family members prevent apoptosis by inhibiting Bax conformational change.	3	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	Bax	Bax	Bax	3	4	10	11
Meanwhile , Bcl-2 inhibits apoptosis by blocking Bax activation and thus preventing mitochondrial outer membrane permeabilization and the subsequent release of cytochrome c.	Meanwhile, Bcl-2 inhibits apoptosis by blocking Bax activation and thus preventing mitochondrial outer membrane permeabilization and the subsequent release of cytochrome c.	2	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	2	3	7	8
Pro cell death Bcl-2 proteins either neutralize pro survival family members or directly promote the activation of Bax and Bak resulting in mitochondria instability and the release of apoptosis inducing proteins such as cytochrome C , SMAC/Diablo and AIF .	Pro cell death Bcl-2 proteins either neutralize pro survival family members or directly promote the activation of Bax and Bak resulting in mitochondria instability and the release of apoptosis inducing proteins such as cytochrome C, SMAC/Diablo and AIF.	3	19	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	17	18
Activated Bid interacts with Bax , a pro apoptotic member of the Bcl-2 family , inducing Bax to dimerize in the outer mitochondrial membrane and initiate release of proteins that promote cell death , including cytochrome c , Apoptosis Inducing Factor ( AIF ) and Second Mediator of Apoptotic Cell death ( SMAC , also known as Diablo ) .	Activated Bid interacts with Bax, a pro apoptotic member of the Bcl-2 family, inducing Bax to dimerize in the outer mitochondrial membrane and initiate release of proteins that promote cell death, including cytochrome c, Apoptosis Inducing Factor (AIF) and Second Mediator of Apoptotic Cell death (SMAC, also known as Diablo).	12	17	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	12	13	16	17
This is consistent with previous data indicating that antagonism of Bcl-2 family members alone is insufficient to activate Bax .	This is consistent with previous data indicating that antagonism of Bcl-2 family members alone is insufficient to activate Bax.	10	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	10	11	18	19
Western blot analysis also revealed that 3-NC down-regulated the expression of anti-apoptotic protein Bcl2 and up-regulated pro apoptotic protein Bax , in all of the cell lines .	Western blot analysis also revealed that 3-NC down-regulated the expression of anti-apoptotic protein Bcl2 and up-regulated pro apoptotic protein Bax, in all of the cell lines.	6	26	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	3-NC down-regulated the expression of anti-apoptotic protein Bcl2	bcl2	Bax	Bax	bax	13	14	19	20
From [ XREF_FIG ] , it is evident that downregulation of antiapoptotic Bcl-2 caused an increase in the proapoptotic Bcl-2 and Bax ratio in the MCF-7 cell line after exposure to the sponge extract , suggesting that Bcl-2 participated in the sponge extract induced apoptosis in breast cancer cells .	From [XREF_FIG], it is evident that downregulation of antiapoptotic Bcl-2 caused an increase in the proapoptotic Bcl-2 and Bax ratio in the MCF-7 cell line after exposure to the sponge extract, suggesting that Bcl-2 participated in the sponge extract induced apoptosis in breast cancer cells.	9	22	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	12	13	21	22
BAX and BAK activation can be triggered by BH3-only proapoptotic BCL-2 family members such as BID and BIM , PUMA , BAD and NOXA .	BAX and BAK activation can be triggered by BH3-only proapoptotic BCL-2 family members such as BID and BIM, PUMA, BAD and NOXA.	0	12	triggered	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	10	11	0	1
Our current results revealed that , under chronic cerebral hypoperfusion , baclofen could simultaneously increase the expression of Bcl-2 and Bax ( especially for Bcl-2 ) by promoting the phosphorylation of ERK ( as described below ) XREF_BIBR XREF_BIBR , but up-regulate Bcl-2 and Bax ratio , which might both inhibit autophagy and down-regulate cleaved caspase-3 XREF_BIBR XREF_BIBR XREF_BIBR .	Our current results revealed that, under chronic cerebral hypoperfusion, baclofen could simultaneously increase the expression of Bcl-2 and Bax (especially for Bcl-2) by promoting the phosphorylation of ERK (as described below) XREF_BIBR XREF_BIBR, but up-regulate Bcl-2 and Bax ratio, which might both inhibit autophagy and down-regulate cleaved caspase-3 XREF_BIBR XREF_BIBR XREF_BIBR.	11	45	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	baclofen could simultaneously increase the expression of Bcl-2	bcl-2	Bax	Bax	bax	18	19	44	45
A further layer of control is regulated by pro apoptotic BH3-only Bcl-2 proteins that can activate BAX and BAK directly or indirectly through inhibition of anti-apoptotic Bcl-2 family proteins [ XREF_BIBR ] .	A further layer of control is regulated by pro apoptotic BH3-only Bcl-2 proteins that can activate BAX and BAK directly or indirectly through inhibition of anti-apoptotic Bcl-2 family proteins [XREF_BIBR].	11	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	11	12	16	17
Bax upregulation and Bcl-2 downregulation increases the Bax to Bcl-2 ratio ; this may be directly associated with cytochrome c release .	Bax upregulation and Bcl-2 downregulation increases the Bax to Bcl-2 ratio; this may be directly associated with cytochrome c release.	3	8	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	3	4	7	8
It was speculated that rapid Bcl-2 phosphorylation initially promotes cell survival by inducing autophagy by releasing beclin 1 which has low affinity for Bcl-2 but when autophagy fails to keep cells alive , Bcl-2 phosphorylation triggers apoptosis by dissociating Bax from the complex [ XREF_BIBR ] .	It was speculated that rapid Bcl-2 phosphorylation initially promotes cell survival by inducing autophagy by releasing beclin 1 which has low affinity for Bcl-2 but when autophagy fails to keep cells alive, Bcl-2 phosphorylation triggers apoptosis by dissociating Bax from the complex [XREF_BIBR].	33	40	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 phosphorylation	bcl-2	Bax	Bax	bax	33	34	39	40
This is in stark contrast to our reported knockdown experiments showing that concurrent KD of Bcl-2 , Bcl-x L and Mcl-1 is sufficient to induce autoactivation of BAX and BAK and apoptosis in QKO cells XREF_BIBR .	This is in stark contrast to our reported knockdown experiments showing that concurrent KD of Bcl-2, Bcl-x L and Mcl-1 is sufficient to induce autoactivation of BAX and BAK and apoptosis in QKO cells XREF_BIBR.	15	31	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	15	16	27	28
miR-27a overexpression rescued hMVICs from TNF-alpha-induced inflammatory injury , as cell viability and BrdU incorporation were increased , apoptotic cell rate was decreased , Bcl-2 was up-regulated , Bax and cleaved caspase-3/9 were down-regulated , and the release of IL-1beta , IL-6 , and MMP-9 was reduced when miR-27a was overexpressed .	miR-27a overexpression rescued hMVICs from TNF-alpha-induced inflammatory injury, as cell viability and BrdU incorporation were increased, apoptotic cell rate was decreased, Bcl-2 was up-regulated, Bax and cleaved caspase-3/9 were down-regulated, and the release of IL-1beta, IL-6, and MMP-9 was reduced when miR-27a was overexpressed.	24	30	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	24	25	28	29
Here we show that the BH3-only Bcl-2 family members , Dp5 and Hrk and Bim , are induced upstream of the Bax checkpoint in neuronal apoptosis in a manner that shows significant dependence on JNK signaling .	Here we show that the BH3-only Bcl-2 family members, Dp5 and Hrk and Bim, are induced upstream of the Bax checkpoint in neuronal apoptosis in a manner that shows significant dependence on JNK signaling.	6	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	6	7	21	22
The Bcl-2 homology domain 3 only ( BH3-only ) protein Bid activates Bax and Bak to mediate the release of cytochrome c into cytosol .	The Bcl-2 homology domain 3 only (BH3-only) protein Bid activates Bax and Bak to mediate the release of cytochrome c into cytosol.	1	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	12	13
In the GLN supplemented group Bax mRNA has increased by 19 % and caspase-3 mRNA by 30 % and Bcl-2 mRNA decreased by 33 % .	In the GLN supplemented group Bax mRNA has increased by 19% and caspase-3 mRNA by 30% and Bcl-2 mRNA decreased by 33%.	5	20	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	19	20	5	6
Tetracaine not only resulted in caspase-3 , caspase-8 and caspase-9 activation and disruption of MTP but also downregulated Bcl-2 and Bcl-xL and upregulated Bad and Bax , along with the upregulation of cytoplasmic cytochrome c ( Cyt .	Tetracaine not only resulted in caspase-3, caspase-8 and caspase-9 activation and disruption of MTP but also downregulated Bcl-2 and Bcl-xL and upregulated Bad and Bax, along with the upregulation of cytoplasmic cytochrome c (Cyt.	17	34	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	18	19	25	26
Bax activation by wortmannin was prevented by Bcl-2 overexpression ( A-375-Bcl-2 ; XREF_FIG ) , proving Bax suppression by Bcl-2 in wortmannin and TRAIL induced apoptosis .	Bax activation by wortmannin was prevented by Bcl-2 overexpression (A-375-Bcl-2; XREF_FIG), proving Bax suppression by Bcl-2 in wortmannin and TRAIL induced apoptosis.	0	9	prevented	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	Bax	Bax	bax	7	8	0	1
The pro apoptotic Bax protein expression increased in ethanol fed WT as well as ALR deficient mice as compared to respective pair fed mice ; anti-apoptotic Bcl2 expression did not change in either phenotype upon ethanol feeding causing an increased Bax and Bcl2 ratio ( XREF_FIG ) .	The pro apoptotic Bax protein expression increased in ethanol fed WT as well as ALR deficient mice as compared to respective pair fed mice; anti-apoptotic Bcl2 expression did not change in either phenotype upon ethanol feeding causing an increased Bax and Bcl2 ratio (XREF_FIG).	26	45	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2 expression	bcl2	Bax	Bax	bax	26	27	40	41
Beyond its function in cell migration , Bcl-wav was found to act as a pro apoptotic Bcl-2 member inducing Bax and Bak dependent cell death .	Beyond its function in cell migration, Bcl-wav was found to act as a pro apoptotic Bcl-2 member inducing Bax and Bak dependent cell death.	16	24	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	16	17	19	20
Bcl-2 simultaneously increases time the down-regulation of Bax , which can increase the level of ERK phosphorylation .	Bcl-2 simultaneously increases time the down-regulation of Bax, which can increase the level of ERK phosphorylation.	0	17	increases	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Bcl-2	Bcl-2	bcl-2	Bax	Bax, which can increase the level of ERK phosphorylation	bax	0	1	7	8
Consistently , dihydromyricetin downregulates Bcl-2 expression and increases Bax and Bcl -2 ratio through upregulation of p53 signaling pathway in HepG2 cells [ XREF_BIBR ] .	Consistently, dihydromyricetin downregulates Bcl-2 expression and increases Bax and Bcl -2 ratio through upregulation of p53 signaling pathway in HepG2 cells [XREF_BIBR].	2	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	dihydromyricetin downregulates Bcl-2 expression	bcl-2	Bax	Bax	bax	4	5	8	9
During apoptosis , upregulation of pro apoptotic Bcl-2 members such as BIM ( so called BH3-only proteins ) overwhelms anti-apoptotic Bcl-2 function and activates BAX and BAK triggering mitochondrial outer membrane permeabilisation and cell death 2 .	During apoptosis, upregulation of pro apoptotic Bcl-2 members such as BIM (so called BH3-only proteins) overwhelms anti-apoptotic Bcl-2 function and activates BAX and BAK triggering mitochondrial outer membrane permeabilisation and cell death 2.	7	27	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	BAX	BAX	BAX	7	8	24	25
The increase of caspase-8 , 9 , 3 activities revealed that caspase was a key mediator of the apoptotic pathway induced by grifolin , and the underexpression of Bcl-2 and up-regulation of Bax resulted in the increase of Bax : Bcl-2 ratio , suggesting that Bcl-2 family involved in the control of apoptosis .	The increase of caspase-8, 9, 3 activities revealed that caspase was a key mediator of the apoptotic pathway induced by grifolin, and the underexpression of Bcl-2 and up-regulation of Bax resulted in the increase of Bax : Bcl-2 ratio, suggesting that Bcl-2 family involved in the control of apoptosis.	26	39	increase	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Bcl-2	underexpression of Bcl-2	bcl-2	Bax	Bax	bax	28	29	38	39
The BH3-only members of the Bcl-2 family either activate Bax and Bak or inhibit antiapoptotic proteins such as Bcl-XL andMcl-1 .	The BH3-only members of the Bcl-2 family either activate Bax and Bak or inhibit antiapoptotic proteins such as Bcl-XL andMcl-1.	5	11	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	5	6	9	10
Dephosphorylation of Bad results its translocation to the outer mitochondrial membrane that permits it to bind to anti-apoptotic protein Bcl 2 family proteins , Bcl 2 or Bcl-xL , which allows pro apoptotic protein Bax to promote apoptosis .	Dephosphorylation of Bad results its translocation to the outer mitochondrial membrane that permits it to bind to anti-apoptotic protein Bcl 2 family proteins, Bcl 2 or Bcl-xL, which allows pro apoptotic protein Bax to promote apoptosis.	15	36	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl 2	Bcl 2	Bcl 2	Bax	Bax	Bax	24	26	34	35
Bcl-2 was upregulated ( p < 0.05 ) in HSIL and Bax in SCC when compared with benign cervical squamous epithelium .	Bcl-2 was upregulated (p < 0.05) in HSIL and Bax in SCC when compared with benign cervical squamous epithelium.	0	12	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	11	12
Bcl-2 homologues promote survival in great part by counteracting pro apoptotic counterparts , Bax and Bak and their upstream effectors the BH3-only proteins .	Bcl-2 homologues promote survival in great part by counteracting pro apoptotic counterparts, Bax and Bak and their upstream effectors the BH3-only proteins.	0	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	0	1	13	14
The antiapoptotic proteins of the BCL-2 family promote cell survival by preventing activation of the pro apoptotic proteins BAX and BAK , which are responsible for the initiation of the mitochondrial apoptosis pathway [ XREF_BIBR , XREF_BIBR ] .	The antiapoptotic proteins of the BCL-2 family promote cell survival by preventing activation of the pro apoptotic proteins BAX and BAK, which are responsible for the initiation of the mitochondrial apoptosis pathway [XREF_BIBR, XREF_BIBR].	5	24	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	5	6	18	19
ABPPk treatment , in a dose dependent manner , antagonized OGD induced down-regulation of Bcl-2 and Bcl-xL and OGD induced up-regulation of Bax , and significant reversing effects of ABPPk were achieved by 3 doses ( 0.04 , 0.2 and 1.0 microg/ml ) for Bcl-xL expression , 1 dose ( 1.0 microg/ml ) for Bcl-2 expression , and 2 doses ( 0.2 and 1.0 microg/ml ) for Bax expression ( XREF_FIG ) .	ABPPk treatment, in a dose dependent manner, antagonized OGD induced down-regulation of Bcl-2 and Bcl-xL and OGD induced up-regulation of Bax, and significant reversing effects of ABPPk were achieved by 3 doses (0.04, 0.2 and 1.0 microg/ml) for Bcl-xL expression, 1 dose (1.0 microg/ml) for Bcl-2 expression, and 2 doses (0.2 and 1.0 microg/ml) for Bax expression (XREF_FIG).	12	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	14	15	22	23
In contrast , in the CD4 + CD25 high T cells cultured with RAPA , the expression levels of anti-apoptotic Bcl-2 and Bcl-xL increased significantly ( p < 0.001 ) , resulting in the Bcl-2 and Bax and Bcl-xL and Bax ratios of 1/2 .6 and 1/1 .2 , respectively ( XREF_FIG ) .	In contrast, in the CD4 + CD25 high T cells cultured with RAPA, the expression levels of anti-apoptotic Bcl-2 and Bcl-xL increased significantly (p < 0.001), resulting in the Bcl-2 and Bax and Bcl-xL and Bax ratios of 1/2.6 and 1/1.2, respectively (XREF_FIG).	17	37	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	levels of anti-apoptotic Bcl-2	bcl-2	Bax	Bax	bax	20	21	36	37
The protein B-cell lymphoma and leukemia 2 ( Bcl-2 ) [ XREF_BIBR ] , which is very sensitive to any damage in mitochondrial content , activates Bax proteins which in turn open pores in the mitochondrial membrane inducing cytochrome C to get out of the mitochondrial membrane and bind to apoptotic protease activating factor-1 ( Apaf-1 ) which is present in the cytosol .	The protein B-cell lymphoma and leukemia 2 (Bcl-2) [XREF_BIBR], which is very sensitive to any damage in mitochondrial content, activates Bax proteins which in turn open pores in the mitochondrial membrane inducing cytochrome C to get out of the mitochondrial membrane and bind to apoptotic protease activating factor-1 (Apaf-1) which is present in the cytosol.	3	54	activates	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Bcl-2	Bcl-2	bcl-2	Bax	Bax proteins which in turn open pores in the mitochondrial membrane inducing cytochrome C to get out of the mitochondrial membrane and bind to apoptotic protease activating factor-1	bax	8	9	26	27
The Bcl-2 family proteins , by selective binding , either act as antiapoptotic factors ( Bcl-XL ) or can also promote apoptosis ( Bax , Bad ) .	The Bcl-2 family proteins, by selective binding, either act as antiapoptotic factors (Bcl-XL) or can also promote apoptosis (Bax, Bad).	0	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	1	2	23	24
The antiapoptotic BCL-2 proteins inhibit apoptosis by inhibiting proapoptotic BCL-2 family proteins BAX and BAK .	The antiapoptotic BCL-2 proteins inhibit apoptosis by inhibiting proapoptotic BCL-2 family proteins BAX and BAK.	2	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	2	3	12	13
The results of the present study suggest that down-regulation of Bcl-2 expression may trigger activation of caspase-3 and Bax in cardiomyocytes during I/R , resulting in cell death .	The results of the present study suggest that down-regulation of Bcl-2 expression may trigger activation of caspase-3 and Bax in cardiomyocytes during I/R, resulting in cell death.	10	19	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 expression	bcl-2	Bax	Bax	bax	10	11	18	19
Overexpression of miR-27a rescued hMVICs from TNF-alpha-induced inflammatory injury , as cell viability and BrdU incorporation were increased , apoptotic cell rate was decreased , Bcl-2 was up-regulated , Bax and cleaved caspase-3/9 were down-regulated , and the release of IL-1beta , IL-6 , and MMP-9 were reduced .	Overexpression of miR-27a rescued hMVICs from TNF-alpha-induced inflammatory injury, as cell viability and BrdU incorporation were increased, apoptotic cell rate was decreased, Bcl-2 was up-regulated, Bax and cleaved caspase-3/9 were down-regulated, and the release of IL-1beta, IL-6, and MMP-9 were reduced.	25	31	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	25	26	29	30
As shown in XREF_FIG , the anti-apoptotic Bcl-2 proteins , Bcl-2 and Bcl-xl , were downregulated while the pro apoptotic Bcl-2 proteins , Bax and cleaved caspase-3 , were upregulated after overexpression of miR-495 .	As shown in XREF_FIG, the anti-apoptotic Bcl-2 proteins, Bcl-2 and Bcl-xl, were downregulated while the pro apoptotic Bcl-2 proteins, Bax and cleaved caspase-3, were upregulated after overexpression of miR-495.	20	30	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	20	21	23	24
In addition , our results indicate that this phenomenon stems from a novel mechanism involving two levels of cooperation between Bcl-2 family proteins : ( 1 ) quercetin mediates Mcl-1 down-regulation and activates Bax ; and ( 2 ) Mcl-1 regulates quercetin mediated Bax activation .	In addition, our results indicate that this phenomenon stems from a novel mechanism involving two levels of cooperation between Bcl-2 family proteins : (1) quercetin mediates Mcl-1 down-regulation and activates Bax; and (2) Mcl-1 regulates quercetin mediated Bax activation.	20	34	activates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	20	21	33	34
In addition , treatment of breast and prostate cancer cells with WEV+ NP or WEV alone revealed that the combination of WEV with NP robustly decreased the phosphorylation of AKT , ERK , and IkappaBalpha ; decreased the expression of cyclin D1 , surviving , and the antiapoptotic Bcl-2 family members Bcl-2 , Bcl-XL , and Mcl-1 ; markedly increased the expression of cyclin B1 and the proapoptotic Bcl-2 family members Bak , Bax , and Bim ; altered the mitochondrial membrane potential ; and subsequently sensitized tumor cells to growth arrest .	In addition, treatment of breast and prostate cancer cells with WEV+NP or WEV alone revealed that the combination of WEV with NP robustly decreased the phosphorylation of AKT, ERK, and IkappaBalpha; decreased the expression of cyclin D1, surviving, and the antiapoptotic Bcl-2 family members Bcl-2, Bcl-XL, and Mcl-1; markedly increased the expression of cyclin B1 and the proapoptotic Bcl-2 family members Bak, Bax, and Bim; altered the mitochondrial membrane potential; and subsequently sensitized tumor cells to growth arrest.	48	74	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bax	Bax	Bax	48	49	73	74
HT induced inhibition of Bcl-2 expression / induction of BAX lead to disruption of these associations , resulting in predominantly BAX homodimers , leading to apoptosis .	HT induced inhibition of Bcl-2 expression / induction of BAX lead to disruption of these associations, resulting in predominantly BAX homodimers, leading to apoptosis.	4	10	induction	Positive_activation_syntax_7_noun	Negative_activation	Negative_activation	Bcl-2	Bcl-2 expression	bcl-2	BAX	BAX	bax	4	5	9	10
The third BCL-2 subfamily , BH3-only proteins ( BIM , tBID , PUMA , BAD , NOXA , HRK ) that sense cellular stress and are strictly regulated through both transcriptional and posttranslational mechanisms , promote apoptosis by either activating BAX and BAK ( only for BIM , PUMA and tBID ) and/or inactivating BCL-2 , BCL-X L or MCL1 .	The third BCL-2 subfamily, BH3-only proteins (BIM, tBID, PUMA, BAD, NOXA, HRK) that sense cellular stress and are strictly regulated through both transcriptional and posttranslational mechanisms, promote apoptosis by either activating BAX and BAK (only for BIM, PUMA and tBID) and/or inactivating BCL-2, BCL-X L or MCL1.	2	50	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAX	BAX	BAX	2	3	40	41
Furthermore , BITC induced the down-regulation of Bcl-2 expression and induced up-regulation of Bax in A375.S2 cells .	Furthermore, BITC induced the down-regulation of Bcl-2 expression and induced up-regulation of Bax in A375.S2 cells.	2	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	BITC induced the down-regulation of Bcl-2 expression	bcl-2	Bax	Bax	bax	7	8	13	14
An increase in the Bax and Bcl2 ratio induces the release of cytochrome c followed by sequential activation of caspases and culminating with cell death [ XREF_BIBR ] .	An increase in the Bax and Bcl2 ratio induces the release of cytochrome c followed by sequential activation of caspases and culminating with cell death [XREF_BIBR].	4	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	6	7	12	14
BCL2 can enhance survival by sequestration of BH3-only proteins , including BIM and PUMA , which are important for BAX-BAK-mediated permeabilization of the mitochondrial membrane , facilitating subsequent release of cytochrome C and apoptosis .	BCL2 can enhance survival by sequestration of BH3-only proteins, including BIM and PUMA, which are important for BAX-BAK-mediated permeabilization of the mitochondrial membrane, facilitating subsequent release of cytochrome C and apoptosis.	0	32	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	cytochrome C	cytochrome C	cytochrome C	0	1	30	32
Bcl-2 , a membrane protein of primarily the outer membrane of mitochondria , appears to inhibit apoptosis by blocking the efflux of cytochrome c from mitochondria .	Bcl-2, a membrane protein of primarily the outer membrane of mitochondria, appears to inhibit apoptosis by blocking the efflux of cytochrome c from mitochondria.	0	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	22	24
For example , Bcl-2 inhibits apoptosis by inhibiting cytochrome c release and caspase activation , while Bax promotes apoptosis by inducing the release of cytochrome c , which then triggers the downstream apoptosis event [ XREF_BIBR ] .	For example, Bcl-2 inhibits apoptosis by inhibiting cytochrome c release and caspase activation, while Bax promotes apoptosis by inducing the release of cytochrome c, which then triggers the downstream apoptosis event [XREF_BIBR].	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	8	10
In addition , apoptosis induced by 3-BrPA and SCT was initiated by the upregulation of Bax and downregulation of Bcl-2 , which promote cytochromec release and subsequently activate caspase-9 and-3 , and ultimately execute mitochondria mediated apoptosis .	In addition, apoptosis induced by 3-BrPA and SCT was initiated by the upregulation of Bax and downregulation of Bcl-2, which promote cytochromec release and subsequently activate caspase-9 and-3, and ultimately execute mitochondria mediated apoptosis.	13	27	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochromec	cytochromec	cytochromec	19	20	23	24
Bim , a BH3-only Bcl-2 protein , initiates apoptosis by promoting the release of mitochondrial cytochrome C , which in turn activates caspase3 and eventually leads to apoptosis [ XREF_BIBR ] .	Bim, a BH3-only Bcl-2 protein, initiates apoptosis by promoting the release of mitochondrial cytochrome C, which in turn activates caspase3 and eventually leads to apoptosis [XREF_BIBR].	4	17	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	4	5	15	17
XREF_BIBR , XREF_BIBR Downregulation of Bcl-2 and upregulation of Bax can induce the release of cytochrome C from the mitochondria into the cytosol , triggering the activity of caspase-3 and -9 and eventually causing apoptosis .	XREF_BIBR, XREF_BIBR Downregulation of Bcl-2 and upregulation of Bax can induce the release of cytochrome C from the mitochondria into the cytosol, triggering the activity of caspase-3 and -9 and eventually causing apoptosis.	3	17	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	5	6	15	17
In Drosophila , the Bcl-2 homolog Debcl functions to promote mitochondrial cytochrome c release that , in turn , modulates Dark dependent activation of the initiator caspase Dronc .	In Drosophila, the Bcl-2 homolog Debcl functions to promote mitochondrial cytochrome c release that, in turn, modulates Dark dependent activation of the initiator caspase Dronc.	4	13	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	11	13
Another link could be Bid , a proapoptotic Bcl-2 family member that , following an activating cleavage event , translocates to mitochondria and mediates cytochrome c release and activation of caspase 9 .	Another link could be Bid, a proapoptotic Bcl-2 family member that, following an activating cleavage event, translocates to mitochondria and mediates cytochrome c release and activation of caspase 9.	8	26	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	24	26
In this review , we discuss the evidence that cytochrome c release is mediated by Bcl-2 family proteins in a process that involves only outer membrane permeability but leaves inner membrane energization , protein import function and the ultrastructure of mitochondria intact .	In this review, we discuss the evidence that cytochrome c release is mediated by Bcl-2 family proteins in a process that involves only outer membrane permeability but leaves inner membrane energization, protein import function and the ultrastructure of mitochondria intact.	9	17	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	9	11
Western blot analysis showed that PEITC promoted Bax expression and inhibited Bcl-2 expression associated with the disintegration of the outer mitochondrial membrane causing cytochrome c release , and activation of caspase-9 and -3 cascade leading to apoptosis .	Western blot analysis showed that PEITC promoted Bax expression and inhibited Bcl-2 expression associated with the disintegration of the outer mitochondrial membrane causing cytochrome c release, and activation of caspase-9 and -3 cascade leading to apoptosis.	5	25	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	PEITC promoted Bax expression and inhibited Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	23	25
The activation of the proapoptotic Bcl-2 family member Bax , induces permeabilization of the mitochondrial outer membrane and release of cytochrome c leading to caspase dependent apoptosis [ XREF_BIBR , XREF_BIBR ] .	The activation of the proapoptotic Bcl-2 family member Bax, induces permeabilization of the mitochondrial outer membrane and release of cytochrome c leading to caspase dependent apoptosis [XREF_BIBR, XREF_BIBR].	5	22	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	20	22
XREF_BIBR also found that apoptosis predominated in cardiomyocytes after reoxygenation through a mitochondrial apoptotic pathway , and that Bcl-2 prevented reoxygenation induced apoptosis by inhibiting the release of cytochrome c from mitochondria .	XREF_BIBR also found that apoptosis predominated in cardiomyocytes after reoxygenation through a mitochondrial apoptotic pathway, and that Bcl-2 prevented reoxygenation induced apoptosis by inhibiting the release of cytochrome c from mitochondria.	18	30	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	28	30
Thus , complex I blockade stimulates intramitochondrial ROS , which is released into cytosol and damage the DNA strands , and increases the releasable soluble pool of cyt c within the mitochondrial intermembrane space , whereas activation of pro cell death Bcl-2 family proteins is necessary to trigger neuronal death by increasing permeabilization of the outer mitochondrial membrane and releasing cytochrome c into the cytosol [ XREF_BIBR , XREF_BIBR ] .	Thus, complex I blockade stimulates intramitochondrial ROS, which is released into cytosol and damage the DNA strands, and increases the releasable soluble pool of cyt c within the mitochondrial intermembrane space, whereas activation of pro cell death Bcl-2 family proteins is necessary to trigger neuronal death by increasing permeabilization of the outer mitochondrial membrane and releasing cytochrome c into the cytosol [XREF_BIBR, XREF_BIBR].	41	62	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	41	42	60	62
Once the pro and antiapoptotic balance is disrupted , proapoptotic Bcl-2 proteins activate cytochrome c and second mitochondria derived activator of caspase release from the intermembrane space .	Once the pro and antiapoptotic balance is disrupted, proapoptotic Bcl-2 proteins activate cytochrome c and second mitochondria derived activator of caspase release from the intermembrane space.	10	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	13	15
In the intrinsic pathway , proapoptotic proteins of the BCL2 family induce permeabilization of the outer mitochondrial membrane and the release of cytochrome c that leads to activation of caspase-9 .	In the intrinsic pathway, proapoptotic proteins of the BCL2 family induce permeabilization of the outer mitochondrial membrane and the release of cytochrome c that leads to activation of caspase-9.	9	24	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	9	10	22	24
In conjunction with recent reports that caspase activation is maximal at acidic pH , these findings have led us to hypothesize that Bcl-2 may modulate cytochrome c release following oxidative stress by modifying the pH dependent activation of mitochondrial caspase activity .	In conjunction with recent reports that caspase activation is maximal at acidic pH, these findings have led us to hypothesize that Bcl-2 may modulate cytochrome c release following oxidative stress by modifying the pH dependent activation of mitochondrial caspase activity.	22	27	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	22	23	25	27
Sustained JNK activation is known to trigger apoptosis by regulating specific proteins of the B-cell lymphoma family 2 ( Bcl-2 ) , which activates the cytochrome C mediated apoptotic pathway .	Sustained JNK activation is known to trigger apoptosis by regulating specific proteins of the B-cell lymphoma family 2 (Bcl-2), which activates the cytochrome C mediated apoptotic pathway.	11	29	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	19	20	25	27
Multiple studies XREF_BIBR XREF_BIBR XREF_BIBR have suggested that downregulation of mitochondrial Bcl-2 destabilises the integrity of the mitochondrial outer membrane and enhances the release of cytochrome c from mitochondria , leading to activation of the caspase mediated apoptosis pathway .	Multiple studies XREF_BIBR XREF_BIBR XREF_BIBR have suggested that downregulation of mitochondrial Bcl-2 destabilises the integrity of the mitochondrial outer membrane and enhances the release of cytochrome c from mitochondria, leading to activation of the caspase mediated apoptosis pathway.	8	27	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	11	12	25	27
BID , a pro apoptotic Bcl-2 family member , promotes cytochrome c release during apoptosis initiated by CD95L or TNF .	BID, a pro apoptotic Bcl-2 family member, promotes cytochrome c release during apoptosis initiated by CD95L or TNF.	5	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	10	12
Inhibitory Bcl-2 family members like Bcl-2 and Mcl-1 keep Bak and Bax in their monomeric inactive form and thereby prevent cytochrome c release and apoptosis induction XREF_BIBR , XREF_BIBR .	Inhibitory Bcl-2 family members like Bcl-2 and Mcl-1 keep Bak and Bax in their monomeric inactive form and thereby prevent cytochrome c release and apoptosis induction XREF_BIBR, XREF_BIBR.	1	22	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	20	22
XREF_BIBR - XREF_BIBR Moreover , previous studies showed that Bcl-2 protein family members mediate the release of cytochrome c in the context of apoptotic stimuli .	XREF_BIBR - XREF_BIBR Moreover, previous studies showed that Bcl-2 protein family members mediate the release of cytochrome c in the context of apoptotic stimuli.	9	19	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	9	10	17	19
Bax promotes apoptosis by the release of cytochrome c from mitochondria and downstream activation of caspases , while Bcl-2 inhibits cell apoptosis by restraining the pro apoptotic effects of Bax and blocking the release of cytochrome c [ XREF_BIBR , XREF_BIBR ] .	Bax promotes apoptosis by the release of cytochrome c from mitochondria and downstream activation of caspases, while Bcl-2 inhibits cell apoptosis by restraining the pro apoptotic effects of Bax and blocking the release of cytochrome c [XREF_BIBR, XREF_BIBR].	18	37	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	35	37
This is emphasized by several studies demonstrating that SEVO pre- and postconditioning decrease ischemia induced apoptosis [ XREF_BIBR ] by reduced activation of caspase-3 and caspase-9 mediated by phosphorylation of Akt and extracellular signal related kinases [ XREF_BIBR ] , as well as less release of cytochrome c and caspase-3 activation mediated by increased Bcl-2 expression and activation of NF-kappaB [ XREF_BIBR ] .	This is emphasized by several studies demonstrating that SEVO pre- and postconditioning decrease ischemia induced apoptosis [XREF_BIBR] by reduced activation of caspase-3 and caspase-9 mediated by phosphorylation of Akt and extracellular signal related kinases [XREF_BIBR], as well as less release of cytochrome c and caspase-3 activation mediated by increased Bcl-2 expression and activation of NF-kappaB [XREF_BIBR].	46	56	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	54	55	46	48
For example , the anti-apoptotic molecules Bcl-2 and Bcl-xL oppose apoptosis by facilitating the blockade of the channels responsible for release of cytochrome c. Conversely , by mechanisms that are not fully understood , pro apoptotic Bcl-2 family members such as Bax , Bad , Bak , and Bid promote apoptosis by opening the channels and allowing cytochrome c to escape into the cytosol .	For example, the anti-apoptotic molecules Bcl-2 and Bcl-xL oppose apoptosis by facilitating the blockade of the channels responsible for release of cytochrome c. Conversely, by mechanisms that are not fully understood, pro apoptotic Bcl-2 family members such as Bax, Bad, Bak, and Bid promote apoptosis by opening the channels and allowing cytochrome c to escape into the cytosol.	36	59	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	36	37	57	59
On the outer mitochondrial membrane p53 interacts pro apoptotic and anti-apoptotic members of the Bcl-2 family of cell death regulators , including BAD , BAK , BCL2 , and BCLXL , enabling oligomerization of pro apoptotic members and subsequent cytochrome c release .	On the outer mitochondrial membrane p53 interacts pro apoptotic and anti-apoptotic members of the Bcl-2 family of cell death regulators, including BAD, BAK, BCL2, and BCLXL, enabling oligomerization of pro apoptotic members and subsequent cytochrome c release.	14	41	enabling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	14	15	39	41
Signal transduction studies showed that Dox markedly decreased mitochondrial membrane potential , disturbed Bcl-2 family protein balance , enhanced cytochrome c release in the cytosol , increased levels of Apaf1 , caspase-9/3/8 , FAS , cleaved PARP protein and ultimately led to apoptotic cell death .	Signal transduction studies showed that Dox markedly decreased mitochondrial membrane potential, disturbed Bcl-2 family protein balance, enhanced cytochrome c release in the cytosol, increased levels of Apaf1, caspase-9/3/8, FAS, cleaved PARP protein and ultimately led to apoptotic cell death.	13	21	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	19	21
However , proapoptotic Bcl-2 family proteins such as Bax which is upregulated by p53 can activate apoptosis by releasing cytochrome c ( cyt-c ) from mitochondria , where Apaf-1 activation takes place [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	However, proapoptotic Bcl-2 family proteins such as Bax which is upregulated by p53 can activate apoptosis by releasing cytochrome c (cyt-c) from mitochondria, where Apaf-1 activation takes place [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	19	21
The anti-apoptotic protein Bcl-2 prevents apoptosis by maintaining the mitochondrial transmembrane potential and blocking the release of cytochrome c , whereas the pro apoptotic protein Bax stimulates apoptosis by collapsing the mitochondrial membrane potential , leading to increased cytochrome c release .	The anti-apoptotic protein Bcl-2 prevents apoptosis by maintaining the mitochondrial transmembrane potential and blocking the release of cytochrome c, whereas the pro apoptotic protein Bax stimulates apoptosis by collapsing the mitochondrial membrane potential, leading to increased cytochrome c release.	0	19	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	17	19
In our studies , we found the increased expression of Bax ( pro apoptotic ) , decreased expression of Bcl-2 ( anti-apoptotic ) as well as activated mitochondrial dependent pathways via reduced mitochondrial membrane potential , enhanced cytochrome C , increased expression of caspase 9 and caspase 3 in the cytosol and cleavage of PARP in STZ induced diabetic nephropathy .	In our studies, we found the increased expression of Bax (pro apoptotic), decreased expression of Bcl-2 (anti-apoptotic) as well as activated mitochondrial dependent pathways via reduced mitochondrial membrane potential, enhanced cytochrome C, increased expression of caspase 9 and caspase 3 in the cytosol and cleavage of PARP in STZ induced diabetic nephropathy.	8	39	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	expression of Bax (pro apoptotic), decreased expression of Bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome c	19	20	37	39
Overexpression of B cell lymphoma gene 2 ( Bcl-2 ) inhibited TRAIL induced release of cytochrome c , changes in MMP , and apoptosis .	Overexpression of B cell lymphoma gene 2 (Bcl-2) inhibited TRAIL induced release of cytochrome c, changes in MMP, and apoptosis.	0	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Overexpression of B cell lymphoma gene 2 (Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	15	17
Caspase-8 is also able to truncate and activate Bcl-2 interacting domain ( BID ) , a pro apoptotic member of Bcl-2 family , subsequently initiating cytochrome C release and apoptosis [ XREF_BIBR ] .	Caspase-8 is also able to truncate and activate Bcl-2 interacting domain (BID), a pro apoptotic member of Bcl-2 family, subsequently initiating cytochrome C release and apoptosis [XREF_BIBR].	8	27	initiating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	8	9	25	27
The pro death Bcl-2 family protein , Bid , mediates this pathway by inducing mitochondrial releases of cytochrome c and other apoptotic factors .	The pro death Bcl-2 family protein, Bid, mediates this pathway by inducing mitochondrial releases of cytochrome c and other apoptotic factors.	3	19	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	17	19
The Bcl-2 protein prevents apoptosis by maintaining the incrementpsi M and blocking the release of cytochrome c , whereas the Bax protein stimulates apoptosis by collapsing the incrementpsi M , leading to increased cytochrome c release .	The Bcl-2 protein prevents apoptosis by maintaining the incrementpsi M and blocking the release of cytochrome c, whereas the Bax protein stimulates apoptosis by collapsing the incrementpsi M, leading to increased cytochrome c release.	1	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	15	17
The BCL2 family of proteins can induce or inhibit the release of cytochrome c into the cytosol through pro- or anti-apoptotic members respectively .	The BCL2 family of proteins can induce or inhibit the release of cytochrome c into the cytosol through pro- or anti-apoptotic members respectively.	1	14	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	cytochrome c	cytochrome c	cytochrome c	1	2	12	14
Bad is a Ca2 +-sensitive pro apoptotic Bcl-2 protein , which on activation translocates from cytosol to mitochondria to initiate cytochrome c release .	Bad is a Ca2 +-sensitive pro apoptotic Bcl-2 protein, which on activation translocates from cytosol to mitochondria to initiate cytochrome c release.	7	22	initiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	20	22
Through direct interaction with the voltage dependent anion channel ( VDAC ) , proapoptotic members of the Bcl-2 family such as Bax and Bak induce apoptogenic cytochrome c release in isolated mitochondria , whereas BH3-only proteins such as Bid and Bik do not directly target the VDAC to induce cytochrome c release .	Through direct interaction with the voltage dependent anion channel (VDAC), proapoptotic members of the Bcl-2 family such as Bax and Bak induce apoptogenic cytochrome c release in isolated mitochondria, whereas BH3-only proteins such as Bid and Bik do not directly target the VDAC to induce cytochrome c release.	17	28	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	17	18	26	28
In particular , stable expression of the herpesvirus saimiri Bcl-2 protein in Jurkat lymphocytes has been shown to prevent loss of mitochondrial membrane potential , cytochrome c release , and caspase-3 activation after ligation of the Fas receptor 14 .	In particular, stable expression of the herpesvirus saimiri Bcl-2 protein in Jurkat lymphocytes has been shown to prevent loss of mitochondrial membrane potential, cytochrome c release, and caspase-3 activation after ligation of the Fas receptor 14.	9	27	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	9	10	25	27
It is generally contended that the anti-apoptotic members of the Bcl-2 family work to prevent cytochrome c release by stabilizing the mitochondrial membrane barrier function and the pro apoptotic members tend to induce cytochrome c release by permeabilizing the mitochondrial membrane [ XREF_BIBR , XREF_BIBR ] .	It is generally contended that the anti-apoptotic members of the Bcl-2 family work to prevent cytochrome c release by stabilizing the mitochondrial membrane barrier function and the pro apoptotic members tend to induce cytochrome c release by permeabilizing the mitochondrial membrane [XREF_BIBR, XREF_BIBR].	10	35	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	33	35
The chemotherapeutic properties of Curcumin , the major constituent of turmeric powder , have been reported as inducing lung cancer cell death through Bax up regulation and Bcl-2 , Bcl-XL down regulation , causing AIF and cytochrome c release .	The chemotherapeutic properties of Curcumin, the major constituent of turmeric powder, have been reported as inducing lung cancer cell death through Bax up regulation and Bcl-2, Bcl-XL down regulation, causing AIF and cytochrome c release.	25	38	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	27	28	36	38
Our results clearly show that beta-elemene induced caspase-3 , -7 and -9 activities , decreased Bcl-2 expression , caused cytochrome c release and increased the levels of cleaved caspase-9 and poly ( ADP-ribose ) polymerase in NSCLC cells .	Our results clearly show that beta-elemene induced caspase-3, -7 and -9 activities, decreased Bcl-2 expression, caused cytochrome c release and increased the levels of cleaved caspase-9 and poly (ADP-ribose) polymerase in NSCLC cells.	5	21	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	beta-elemene induced caspase-3, -7 and -9 activities, decreased Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	19	21
The proapoptotic members of Bcl-2 family such as Bax , Bad , and Bak initiate the release of cytochrome c , but antiapoptotic members of this family such as bcl-2 and bcl-xl antagonize it .	The proapoptotic members of Bcl-2 family such as Bax, Bad, and Bak initiate the release of cytochrome c, but antiapoptotic members of this family such as bcl-2 and bcl-xl antagonize it.	4	20	initiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	18	20
Bcl-2 BH3 failed to induce cytochrome c release , even in wild-type cells .	Bcl-2 BH3 failed to induce cytochrome c release, even in wild-type cells.	0	7	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Imbalanced Bcl-2 family members , such as pro apoptotic Bcl-2-associated X protein ( Bax ) , Bcl-2-associated agonist of cell death , and BH3 interacting domain death agonist and antiapoptotic Bcl-2 , induce mitochondrial membrane permeabilization , cytochrome c release , and initiator caspase-9 activation , followed by effector caspase-3 activation , resulting in apoptosis .	Imbalanced Bcl-2 family members, such as pro apoptotic Bcl-2-associated X protein (Bax), Bcl-2-associated agonist of cell death, and BH3 interacting domain death agonist and antiapoptotic Bcl-2, induce mitochondrial membrane permeabilization, cytochrome c release, and initiator caspase-9 activation, followed by effector caspase-3 activation, resulting in apoptosis.	1	39	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	37	39
These results indicate that polyamines regulate PP2A activity , and inhibition of PP2A in response to polyamine depletion increases steady state levels of Bad and Bcl-2 proteins and their phosphorylation and thereby prevents cytochrome c release , caspase-9 , and caspase-3 activation .	These results indicate that polyamines regulate PP2A activity, and inhibition of PP2A in response to polyamine depletion increases steady state levels of Bad and Bcl-2 proteins and their phosphorylation and thereby prevents cytochrome c release, caspase-9, and caspase-3 activation.	12	35	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	PP2A in response to polyamine depletion increases steady state levels of Bad and Bcl-2 proteins and their phosphorylation	bcl-2	cytochrome c	cytochrome c	cytochrome c	25	26	33	35
Caspase cleavage of Bcl-2 and Bcl-x L has been reported to promote release of cytochrome c from lipid vesicles and from mitochondria XREF_BIBR , XREF_BIBR .	Caspase cleavage of Bcl-2 and Bcl-x L has been reported to promote release of cytochrome c from lipid vesicles and from mitochondria XREF_BIBR, XREF_BIBR.	3	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	14	16
In Apaf1 -/- mice , vice versa , Bax and Bak and other Bcl-2 family members enable cytochrome c release in response to developmental signals from surrounding tissues ; the mitochondria start their depolarization program and autophagy sustains cell survival until metabolites for energy production are totally consumed and secondary cellular destruction takes place .	In Apaf1 -/- mice, vice versa, Bax and Bak and other Bcl-2 family members enable cytochrome c release in response to developmental signals from surrounding tissues; the mitochondria start their depolarization program and autophagy sustains cell survival until metabolites for energy production are totally consumed and secondary cellular destruction takes place.	13	19	enable	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	17	19
The pro apoptotic Bcl-2 members promote cytochrome c release [ XREF_BIBR ] ,, while anti-apoptotic Bcl-2 proteins such as Bcl-2 , Bcl-xL , and Mcl-1 protect mitochondrial integrity [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	The pro apoptotic Bcl-2 members promote cytochrome c release [XREF_BIBR],, while anti-apoptotic Bcl-2 proteins such as Bcl-2, Bcl-xL, and Mcl-1 protect mitochondrial integrity [XREF_BIBR, XREF_BIBR - XREF_BIBR].	3	8	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	6	8
NO induced apoptosis in E1A expressing cells did not require expression Bak or Bax , indicating that NO induced caspase-2-mediated mitochondrial injury does not proceed through the activities of typical , proapoptotic Bcl-2 family members that induce mitochondrial cytochrome C release .	NO induced apoptosis in E1A expressing cells did not require expression Bak or Bax, indicating that NO induced caspase-2-mediated mitochondrial injury does not proceed through the activities of typical, proapoptotic Bcl-2 family members that induce mitochondrial cytochrome C release.	32	40	induce	Positive_activation_syntax_3a_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	32	33	38	40
In this study , we have further investigated the anticancer effects of 5-AcTMF on CL1-5 non small cell lung cancer cells ( NSCLC ) both in vitro and in vivo and demonstrated that 5-AcTMF effectively inhibited cancer cell proliferation , induced G2/M-phase arrest associated with cdc2 and CDC25c and increased in the apoptotic cells associated with caspase activation , down regulation of Bcl-2 , XIAP and Survivn , inducing release of cytochrome c into the cytosol and disruption of mitochondrial membrane potential .	In this study, we have further investigated the anticancer effects of 5-AcTMF on CL1-5 non small cell lung cancer cells (NSCLC) both in vitro and in vivo and demonstrated that 5-AcTMF effectively inhibited cancer cell proliferation, induced G2/M-phase arrest associated with cdc2 and CDC25c and increased in the apoptotic cells associated with caspase activation, down regulation of Bcl-2, XIAP and Survivn, inducing release of cytochrome c into the cytosol and disruption of mitochondrial membrane potential.	60	73	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	62	63	71	73
An increase in the Bax and Bcl2 ratio leads to release of cytochrome c followed by stepwise activation of caspases leading to cell death .	An increase in the Bax and Bcl2 ratio leads to release of cytochrome c followed by stepwise activation of caspases leading to cell death.	4	14	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	6	7	12	14
Consistent with the decreased expression of Bcl-2 ( XREF_FIG ) , which is an integral membrane protein located mainly on the outer mitochondrial membrane that inhibits apoptosis , cytochrome c was transferred from the mitochondrial intermembrane space to the cytoplasm ( XREF_FIG ) .	Consistent with the decreased expression of Bcl-2 (XREF_FIG), which is an integral membrane protein located mainly on the outer mitochondrial membrane that inhibits apoptosis, cytochrome c was transferred from the mitochondrial intermembrane space to the cytoplasm (XREF_FIG).	4	30	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	Bcl-2	expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	28	30
Bcl-2 is well known to prevent apoptosis by blocking the cyotosolic release of cytochrome c from mitochondria [ XREF_BIBR ] .	Bcl-2 is well known to prevent apoptosis by blocking the cyotosolic release of cytochrome c from mitochondria [XREF_BIBR].	0	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
Numerous studies have demonstrated that the oncoprotein Bcl-2 can inhibit apoptosis by inhibiting the release of cytochrome c and can also modulate oxidant induced apoptosis [ XREF_BIBR ] .	Numerous studies have demonstrated that the oncoprotein Bcl-2 can inhibit apoptosis by inhibiting the release of cytochrome c and can also modulate oxidant induced apoptosis [XREF_BIBR].	5	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	16	18
As shown in XREF_FIG , the results revealed that AT-I induced up-regulation of proapoptotic protein Bax and down-regulation of anti-apoptotic protein Bcl-2 , which could increase cytochrome C and AIF in the cytosol , and then activated the cytosolic caspase-9 .	As shown in XREF_FIG, the results revealed that AT-I induced up-regulation of proapoptotic protein Bax and down-regulation of anti-apoptotic protein Bcl-2, which could increase cytochrome C and AIF in the cytosol, and then activated the cytosolic caspase-9.	15	28	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	21	22	26	28
Studies with fibroblasts have shown that JNK activation and the pro apoptotic protein Bax , a Bcl2 family member [ XREF_BIBR ] , are sufficient to cause the caspase independent release of cytochrome c , which leads to apoptosis .	Studies with fibroblasts have shown that JNK activation and the pro apoptotic protein Bax, a Bcl2 family member [XREF_BIBR], are sufficient to cause the caspase independent release of cytochrome c, which leads to apoptosis.	16	34	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	16	17	32	34
Through direct interaction with the voltage dependent anion channel ( VDAC ) , proapoptotic Bcl-2 family members such as Bax and Bak induce apoptogenic mitochondrial cytochrome c release and membrane potential ( Deltapsi ) loss in isolated mitochondria .	Through direct interaction with the voltage dependent anion channel (VDAC), proapoptotic Bcl-2 family members such as Bax and Bak induce apoptogenic mitochondrial cytochrome c release and membrane potential (Deltapsi) loss in isolated mitochondria.	14	27	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	14	15	25	27
Both cytochrome c release and caspase activation triggered by p38 MAPK activation and Bcl-2 phosphorylation are absent in embryonic fibroblasts from p38alpha knock-out mice ( p38alpha (-/-) MEF ) , whereas they occur within 12 h of serum withdrawal in p38alpha ( +/+ ) MEF ; moreover , they can be prevented by p38 MAPK inhibitors and are not associated with the synthesis of the proapoptotic proteins Bax and Fas .	Both cytochrome c release and caspase activation triggered by p38 MAPK activation and Bcl-2 phosphorylation are absent in embryonic fibroblasts from p38alpha knock-out mice (p38alpha (-/-) MEF), whereas they occur within 12 h of serum withdrawal in p38alpha (+/+) MEF; moreover, they can be prevented by p38 MAPK inhibitors and are not associated with the synthesis of the proapoptotic proteins Bax and Fas.	1	15	triggered	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 phosphorylation	bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	1	3
Bax inhibition and Bcl-2 activation suppress release of cytochrome c from mitochondria that prevents cleavage of caspase-3 .	Bax inhibition and Bcl-2 activation suppress release of cytochrome c from mitochondria that prevents cleavage of caspase-3.	3	10	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	8	10
After the gene p53 was translocated to the nucleus , expression of p53 was increased , and the Bcl-2 family genes were activated , triggering the collapse of the mitochondrial membrane potential , cytochrome c release , activation of caspase-9 and caspase-3 , and , ultimately , cell death via apoptosis .	After the gene p53 was translocated to the nucleus, expression of p53 was increased, and the Bcl-2 family genes were activated, triggering the collapse of the mitochondrial membrane potential, cytochrome c release, activation of caspase-9 and caspase-3, and, ultimately, cell death via apoptosis.	18	35	triggering	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	33	35
p53 can be activated upon oxidative stress and initiates apoptosis through binding to mitochondrial Bcl-2 , displacing Bax , which induces apoptosis and cytochrome C release from the mitochondria .	p53 can be activated upon oxidative stress and initiates apoptosis through binding to mitochondrial Bcl-2, displacing Bax, which induces apoptosis and cytochrome C release from the mitochondria.	3	25	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	14	15	23	25
29 Bcl-2 can prevent apoptosis by blocking the release of cytochrome c from mitochondria 30 and inhibiting the activation of caspase-3 .	29 Bcl-2 can prevent apoptosis by blocking the release of cytochrome c from mitochondria 30 and inhibiting the activation of caspase-3.	0	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	10	12
To investigate if the release of Cytochrome C mediated by mutSOD1 and Bcl-2 was accompanied by structural alterations of the mitochondria , we analyzed mitochondrial morphology by transmission electron microscopy in HEK293T cells co-transfected with mutSOD1 and Bcl-2 or control cells co-transfected with mutSOD1 + control plasmid or Bcl-2 + SOD1-WT .	To investigate if the release of Cytochrome C mediated by mutSOD1 and Bcl-2 was accompanied by structural alterations of the mitochondria, we analyzed mitochondrial morphology by transmission electron microscopy in HEK293T cells co-transfected with mutSOD1 and Bcl-2 or control cells co-transfected with mutSOD1 + control plasmid or Bcl-2 + SOD1-WT.	6	13	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Cytochrome C	Cytochrome C	Cytochrome C	12	13	6	8
Bcl-2 inhibits apoptosis by reducing the release of cytochrome c ( cyto C ) XREF_BIBR , leading to a reduction in the release of caspase 9 and caspase 3 .	Bcl-2 inhibits apoptosis by reducing the release of cytochrome c (cyto C) XREF_BIBR, leading to a reduction in the release of caspase 9 and caspase 3.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
Bcl-2 blocks apoptosis via the mitochondrial pathway by inhibiting the release of cytochrome C from the mitochondria , thus preventing the cascade of events that results in compromise of the mitochondrial outer membrane potential , which in turn leads to caspase-9 activation and subsequent apoptosis [ XREF_BIBR ] .	Bcl-2 blocks apoptosis via the mitochondrial pathway by inhibiting the release of cytochrome C from the mitochondria, thus preventing the cascade of events that results in compromise of the mitochondrial outer membrane potential, which in turn leads to caspase-9 activation and subsequent apoptosis [XREF_BIBR].	0	14	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	12	14
Overexpression of Bcl-2 prevents the initiation of apoptosis by blocking the efflux of cytochrome c from the mitochondria [ XREF_BIBR ] .	Overexpression of Bcl-2 prevents the initiation of apoptosis by blocking the efflux of cytochrome c from the mitochondria [XREF_BIBR].	0	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	13	15
Bcl-2 family proteins promote the release of cytochrome c and change the permeability of the mitochondrial membrane [ XREF_BIBR ] .	Bcl-2 family proteins promote the release of cytochrome c and change the permeability of the mitochondrial membrane [XREF_BIBR].	0	9	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	7	9
Bcl2 blocks a major apoptotic pathway by inhibiting the release of cytochrome C from the mitochondria , thereby preventing caspase induced apoptosis .	Bcl2 blocks a major apoptotic pathway by inhibiting the release of cytochrome C from the mitochondria, thereby preventing caspase induced apoptosis.	0	13	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl2	Bcl2	Bcl2	cytochrome C	cytochrome C	cytochrome C	0	1	11	13
Finally , consistent with the finding that activated PKC-delta triggers the redistribution and activation of Bax , a Bcl-2 family protein that can directly induce cytochrome c release and downstream apoptotic cascade , we observed markedly increased levels of Bax in brain slices exposed to misfolded PrP .	Finally, consistent with the finding that activated PKC-delta triggers the redistribution and activation of Bax, a Bcl-2 family protein that can directly induce cytochrome c release and downstream apoptotic cascade, we observed markedly increased levels of Bax in brain slices exposed to misfolded PrP.	18	27	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	25	27
Bcl-2 , an anti-apoptotic protein , is the central regulator of the mitochondrial outer membrane permeability and promotes the release of the cytochrome c XREF_BIBR .	Bcl-2, an anti-apoptotic protein, is the central regulator of the mitochondrial outer membrane permeability and promotes the release of the cytochrome c XREF_BIBR.	0	24	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	22	24
The cognate siRNA knockdowns Bcl-2 and promotes the release of cytochrome c from mitochondria .	The cognate siRNA knockdowns Bcl-2 and promotes the release of cytochrome c from mitochondria.	0	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	10	12
Bcl-2 family members regulate the ability of Bak and Bax to permeabilize the mitochondrial outer membrane and initiate cytochrome c release into the cytosol XREF_BIBR .	Bcl-2 family members regulate the ability of Bak and Bax to permeabilize the mitochondrial outer membrane and initiate cytochrome c release into the cytosol XREF_BIBR.	0	20	initiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	18	20
In particular , Bax , a Bcl-2 family member protein , moves from the cytosol to the mitochondria , inducing cytochrome c release .	In particular, Bax, a Bcl-2 family member protein, moves from the cytosol to the mitochondria, inducing cytochrome c release.	6	22	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	20	22
The available data imply that in the coral , as in mammals , multi-domain Bcl-2 proteins modulate release of cytochrome c from mitochondria , allowing the assembly of the apoptosome , which also contains APAF-1 and the apoptotic initiator , caspase-9 .	The available data imply that in the coral, as in mammals, multi-domain Bcl-2 proteins modulate release of cytochrome c from mitochondria, allowing the assembly of the apoptosome, which also contains APAF-1 and the apoptotic initiator, caspase-9.	14	21	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	14	15	19	21
The elevated ratio of Bax and Bak : Bcl-2 and Bcl-xL would cause the MMP loss and cytochrome c release , which might be intimately associated with the activation of caspase-9 .	The elevated ratio of Bax and Bak : Bcl-2 and Bcl-xL would cause the MMP loss and cytochrome c release, which might be intimately associated with the activation of caspase-9.	2	25	cause	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	17	19
Downregulation and phosphorylation of Bcl-2 as well as upregulation of Bad may induce depolarization of mitochondria and subsequent translocation of cytochrome c into the cytosol .	Downregulation and phosphorylation of Bcl-2 as well as upregulation of Bad may induce depolarization of mitochondria and subsequent translocation of cytochrome c into the cytosol.	0	22	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	phosphorylation of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	20	22
In addition , Bcl-2 overexpression strongly blocked KATOIII cell apoptosis by inhibiting the cytochrome c release from mitochondria and caspase-3 activation .	In addition, Bcl-2 overexpression strongly blocked KATOIII cell apoptosis by inhibiting the cytochrome c release from mitochondria and caspase-3 activation.	3	15	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	13	15
Furthermore , in experimental tissue culture studies in tumors suggested that , high levels of anti-apoptotic protein Bcl-2 which are located in the outer mitochondrial membrane impair the mitochondrial membrane potential by reducing the release of cytochrome C and inhibit influx of various chemotherapeutic agents across the cell membrane .	Furthermore, in experimental tissue culture studies in tumors suggested that, high levels of anti-apoptotic protein Bcl-2 which are located in the outer mitochondrial membrane impair the mitochondrial membrane potential by reducing the release of cytochrome C and inhibit influx of various chemotherapeutic agents across the cell membrane.	13	38	impair	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	levels of anti-apoptotic protein Bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome c	17	18	36	38
p73 activates the transcription of Bax and Bcl-2 , causing the release of cytochrome c from the mitochondria .	p73 activates the transcription of Bax and Bcl-2, causing the release of cytochrome c from the mitochondria.	0	15	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	p73 activates the transcription of Bax and Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	13	15
ANG increases Bcl-2 protein level , stimulates cytochrome c release and decreases caspase activity .	ANG increases Bcl-2 protein level, stimulates cytochrome c release and decreases caspase activity.	0	9	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	ANG increases Bcl-2 protein level	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	7	9
Increased Bax and decreased Bcl-2 expression can stimulate the release of cytochrome c from the mitochondria , which activates caspase-9 .	Increased Bax and decreased Bcl-2 expression can stimulate the release of cytochrome c from the mitochondria, which activates caspase-9.	4	13	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	11	13
In contrast , Bcl-2 proteins can prevent apoptosis by blocking the release of cytochrome c from mitochondria [ XREF_BIBR - XREF_BIBR ] .	In contrast, Bcl-2 proteins can prevent apoptosis by blocking the release of cytochrome c from mitochondria [XREF_BIBR - XREF_BIBR].	3	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	13	15
Galactosylated artemisinin exhibits great antitumor activities , which may be ralated to triggering cytochrome C apoptotic pathway which mediated by BCL-2 family .	Galactosylated artemisinin exhibits great antitumor activities, which may be ralated to triggering cytochrome C apoptotic pathway which mediated by BCL-2 family.	13	21	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	cytochrome C	cytochrome C	cytochrome C	20	21	13	15
Mitochondrial Bax interacts with other Bcl-2 family proteins , which triggers cytochrome c release ( XREF_FIG ) .	Mitochondrial Bax interacts with other Bcl-2 family proteins, which triggers cytochrome c release (XREF_FIG).	5	13	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	11	13
A low Bcl-2 to Bax ratio can induce DeltaPsim collapse , the release of cytochrome c , and subsequent apoptosis .	A low Bcl-2 to Bax ratio can induce DeltaPsim collapse, the release of cytochrome c, and subsequent apoptosis.	0	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	14	16
BAX and BCL-2 activate caspases by promoting the release of cytochrome C from mitochondrion .	BAX and BCL-2 activate caspases by promoting the release of cytochrome C from mitochondrion.	0	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	cytochrome C	cytochrome C	cytochrome C	2	3	10	12
XREF_BIBR In the mitochondria dependent pathway ( intrinsic pathway ) , the increased pro apoptotic members of Bcl-2 family of protein , such as Bax , induce the release of cytochrome c into the cytosol via the opening of the outer mitochondrial membrane .	XREF_BIBR In the mitochondria dependent pathway (intrinsic pathway), the increased pro apoptotic members of Bcl-2 family of protein, such as Bax, induce the release of cytochrome c into the cytosol via the opening of the outer mitochondrial membrane.	17	32	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	17	18	30	32
Bcl-2 antagonizes Bax by reducing cytochrome c release .	Bcl-2 antagonizes Bax by reducing cytochrome c release.	0	7	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	5	7
Using permeabilized PC60 cells overexpressing Bcl-2 as a result of gene transfection , we analyzed the effect of Bcl-2 on CAF induced MMD and cytochrome c release .	Using permeabilized PC60 cells overexpressing Bcl-2 as a result of gene transfection, we analyzed the effect of Bcl-2 on CAF induced MMD and cytochrome c release.	16	26	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	24	26
Numerous studies have demonstrated that the oncoprotein Bcl-2 can inhibit apoptosis by inhibiting the release of cytochrome c and can also modulate oxidant induced apoptosis .	Numerous studies have demonstrated that the oncoprotein Bcl-2 can inhibit apoptosis by inhibiting the release of cytochrome c and can also modulate oxidant induced apoptosis.	5	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	16	18
We asked if bcl-2 depletion not only leads to selective permeation of the outer mitochondrial membrane ( MOMP ) favoring cytochrome c release and programmed cell death , but also favors opening of the mitochondrial permeability transition pore ( MPTP ) .	We asked if bcl-2 depletion not only leads to selective permeation of the outer mitochondrial membrane (MOMP) favoring cytochrome c release and programmed cell death, but also favors opening of the mitochondrial permeability transition pore (MPTP).	3	22	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	20	22
The proapoptotic members of the BCL2 family , such as BAX , BAK , and BAD , activate the release of cytochrome C from mitochondria , while antiapoptotic members of the same family , BCL-2 and BCLX L , antagonize it .	The proapoptotic members of the BCL2 family, such as BAX, BAK, and BAD, activate the release of cytochrome C from mitochondria, while antiapoptotic members of the same family, BCL-2 and BCLX L, antagonize it.	5	23	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	cytochrome C	cytochrome C	cytochrome C	5	6	21	23
Bcl-2 is able to inhibit apoptosis by blocking the release of cytochrome C , while Bid can induce the release of cytochrome C after truncation XREF_BIBR .	Bcl-2 is able to inhibit apoptosis by blocking the release of cytochrome C, while Bid can induce the release of cytochrome C after truncation XREF_BIBR.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	11	13
Over-expression of Bcl-2 has been shown to prevent apoptosis by blocking the release of cytochrome c from mitochondria XREF_BIBR .	Over-expression of Bcl-2 has been shown to prevent apoptosis by blocking the release of cytochrome c from mitochondria XREF_BIBR.	0	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Over-expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	14	16
Bcl-2 then increased the release of cytochrome C into the cytoplasm and induced the cleavage of caspase-9 , caspase-3 , and PARP .	Bcl-2 then increased the release of cytochrome C into the cytoplasm and induced the cleavage of caspase-9, caspase-3, and PARP.	0	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	6	8
Moreover , FK18 increased Akt phosphorylation under both normoxic and OGD conditions , attenuated mitochondrial translocation of the proapoptotic protein Bad , up-regulated the expression of Bcl-2 and Bax , and inhibited the release of cytochrome c from the mitochondria into the cytoplasm .	Moreover, FK18 increased Akt phosphorylation under both normoxic and OGD conditions, attenuated mitochondrial translocation of the proapoptotic protein Bad, up-regulated the expression of Bcl-2 and Bax, and inhibited the release of cytochrome c from the mitochondria into the cytoplasm.	2	37	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	FK18 increased Akt phosphorylation under both normoxic and OGD conditions, attenuated mitochondrial translocation of the proapoptotic protein Bad, up-regulated the expression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	26	27	35	37
ER targeted Bcl-2 inhibited mitochondrial membrane depolarization and cytochrome c release in MDS erythroid precursors undergoing apoptosis , indicating a role for the ER in the death pathway , upstream of the mitochondria .	ER targeted Bcl-2 inhibited mitochondrial membrane depolarization and cytochrome c release in MDS erythroid precursors undergoing apoptosis, indicating a role for the ER in the death pathway, upstream of the mitochondria.	2	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	8	10
During stroke associated apoptosis , cytosolic c-Jun N-terminal Kinases ( JNKs ) and Bcl-2 family proteins translocate towards mitochondria and promote cytochrome c release by interacting with the outer mitochondrion membrane associated proteins .	During stroke associated apoptosis, cytosolic c-Jun N-terminal Kinases (JNKs) and Bcl-2 family proteins translocate towards mitochondria and promote cytochrome c release by interacting with the outer mitochondrion membrane associated proteins.	13	23	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	21	23
A prime example are the bcl-2 family proteins such as Bad and Bax whose activation and mitochondrial translocation are shown to induce cytochrome c release following apoptotic stimuli after cerebral ischemia XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	A prime example are the bcl-2 family proteins such as Bad and Bax whose activation and mitochondrial translocation are shown to induce cytochrome c release following apoptotic stimuli after cerebral ischemia XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	5	24	induce	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	22	24
On the other hand , Bcl-2 , an anti-apoptotic member , can be sequestered in mitochondria , inhibiting the release of cytochrome c and preventing apoptosis .	On the other hand, Bcl-2, an anti-apoptotic member, can be sequestered in mitochondria, inhibiting the release of cytochrome c and preventing apoptosis.	5	23	sequestered	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	21	23
The Bcl-2 TMD peptides promoted mitochondrial outer membrane permeabilization ( MOMP ) and cytochrome c release from isolated mitochondria and different cell lines .	The Bcl-2 TMD peptides promoted mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release from isolated mitochondria and different cell lines.	1	15	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	13	15
An increasing number of studies have shown that bcl-2 family members , particularly bcl-2 , may inhibit apoptosis by blocking cytochrome c release and inhibiting caspase-3 and -9 activation but not that of caspase-12 .	An increasing number of studies have shown that bcl-2 family members, particularly bcl-2, may inhibit apoptosis by blocking cytochrome c release and inhibiting caspase-3 and -9 activation but not that of caspase-12.	8	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	20	22
The cells treated with 50microM of curcumin , 30.91 microM ( NEC-1 ) , 20.70 microM ( NEC-2 ) and 16.86 microM ( NEC-3 ) showed enhanced activation of p53 and elevated bax and Bcl2 expression ( NEC-3 ) , increased cytochrome-c in cytosol ( NEC-2 ) confirming the enhanced cytotoxicity .	The cells treated with 50microM of curcumin, 30.91 microM (NEC-1), 20.70 microM (NEC-2) and 16.86 microM (NEC-3) showed enhanced activation of p53 and elevated bax and Bcl2 expression (NEC-3), increased cytochrome-c in cytosol (NEC-2) confirming the enhanced cytotoxicity.	34	42	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2 expression	bcl2	cytochrome-c	cytochrome-c	cytochrome-c	34	35	41	42
Phosphorylation of Bcl-2 inactivates its antiapoptotic effect and triggers the release of cytochrome c , then activating caspase-3 which induced early apoptosis [ XREF_BIBR , XREF_BIBR ] .	Phosphorylation of Bcl-2 inactivates its antiapoptotic effect and triggers the release of cytochrome c, then activating caspase-3 which induced early apoptosis [XREF_BIBR, XREF_BIBR].	0	14	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Phosphorylation of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	12	14
In the human colon cancer cells HCT116 , deoxycholic acid ( DCA ) induces apoptosis via the mitochondrial pathway by triggering the release of mitochondrial factors such as cytochrome c. To elucidate if Bax , a proapoptotic member of the Bcl-2 family known to trigger cytochrome c release in response to various types of apoptotic stimuli , is involved in DCA induced apoptosis in HCT116 cells , we analyzed DCA induced apoptosis in Bax-knockout ( Bax (-/-) ) HCT116 cells .	In the human colon cancer cells HCT116, deoxycholic acid (DCA) induces apoptosis via the mitochondrial pathway by triggering the release of mitochondrial factors such as cytochrome c. To elucidate if Bax, a proapoptotic member of the Bcl-2 family known to trigger cytochrome c release in response to various types of apoptotic stimuli, is involved in DCA induced apoptosis in HCT116 cells, we analyzed DCA induced apoptosis in Bax-knockout (Bax (-/-)) HCT116 cells.	40	47	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	40	41	45	47
XREF_BIBR , XREF_BIBR A low ratio of Bcl-2 to Bax can induce caspase activation , the release of cytochrome c , and subsequently apoptosis .	XREF_BIBR, XREF_BIBR A low ratio of Bcl-2 to Bax can induce caspase activation, the release of cytochrome c, and subsequently apoptosis.	5	20	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	18	20
In contrast , the pro apoptotic members of the Bcl-2 family , such as Bax and Bak , can stimulate release of mitochondrial cytochrome c and trigger activation of the initiator and executioner caspases .	In contrast, the pro apoptotic members of the Bcl-2 family, such as Bax and Bak, can stimulate release of mitochondrial cytochrome c and trigger activation of the initiator and executioner caspases.	9	25	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	9	10	23	25
Bcl-2 inhibits cell apoptosis by reducing the release of mitochondrial cytochrome c in order to inhibit the activation of caspase-3 .	Bcl-2 inhibits cell apoptosis by reducing the release of mitochondrial cytochrome c in order to inhibit the activation of caspase-3.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	10	12
Bcl-2 family proteins are involved in intrinsic apoptosis pathway ; therefore , the downregulation of Bcl-2 and Bax ratio promotes the release of cytochrome c from the mitochondria to the cytoplasm under oxidative stress and then induces the forming of an apoptosome containing APAF-1 , cytochrome c , and procaspase-9 .	Bcl-2 family proteins are involved in intrinsic apoptosis pathway; therefore, the downregulation of Bcl-2 and Bax ratio promotes the release of cytochrome c from the mitochondria to the cytoplasm under oxidative stress and then induces the forming of an apoptosome containing APAF-1, cytochrome c, and procaspase-9.	15	25	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	23	25
There were increased amounts of Evans blue , apoptotic proteins ( caspase-3 , -8 , and -9 and cytochrome C ) , and decreased anti-apoptotic proteins ( bcl-2 ) after 2-3 weeks of infection .	There were increased amounts of Evans blue, apoptotic proteins (caspase-3, -8, and -9 and cytochrome C), and decreased anti-apoptotic proteins (bcl-2) after 2-3 weeks of infection.	2	28	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome C	27	28	18	20
Furthermore , Bim ( also known as Bcl-2-related ovarian death gene ) promotes apoptosis by binding with anti-apoptotic Bcl-2 family members thereby inducing mitochondrial release of cytochrome c , which subsequently activates caspase-9 , caspase-3 and death effector molecules [ XREF_BIBR ] .	Furthermore, Bim (also known as Bcl-2-related ovarian death gene) promotes apoptosis by binding with anti-apoptotic Bcl-2 family members thereby inducing mitochondrial release of cytochrome c, which subsequently activates caspase-9, caspase-3 and death effector molecules [XREF_BIBR].	18	28	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	26	28
When cells were stimulated by apoptosis signals , Bcl-2 was released from the membrane to allow the release of cytochrome C into cytoplasm .	When cells were stimulated by apoptosis signals, Bcl-2 was released from the membrane to allow the release of cytochrome C into cytoplasm.	8	21	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	8	9	19	21
This may be because BCL-2 can promote cytochrome C release by mitochondria and increase caspase protease activated by cytochrome C , thus weakening its inhibitory effect on cell apoptosis .	This may be because BCL-2 can promote cytochrome C release by mitochondria and increase caspase protease activated by cytochrome C, thus weakening its inhibitory effect on cell apoptosis.	4	9	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	cytochrome C	cytochrome C	cytochrome C	4	5	7	9
Previous reports have shown that p53 is up-regulated while BCL2 is down-regulated to induce CYCS release from the mitochondrion , which further activates CASP9 and CASP3 to encourage cell apoptosis .	Previous reports have shown that p53 is up-regulated while BCL2 is down-regulated to induce CYCS release from the mitochondrion, which further activates CASP9 and CASP3 to encourage cell apoptosis.	9	15	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	CYCS	CYCS	CYCS	9	10	14	15
Bcl-2 blocks the increased permeability of the mitochondrial membrane and prevents the release of cytochrome C 31 .	Bcl-2 blocks the increased permeability of the mitochondrial membrane and prevents the release of cytochrome C 31.	0	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	14	16
Bcl-2 antisense delivered with this strategy significantly induced more cell death , apoptosis , and cytochrome c release in MCF-7/E6 than in MCF-7 , but did not affect Fas level in both cells and activated caspase-8 equally .	Bcl-2 antisense delivered with this strategy significantly induced more cell death, apoptosis, and cytochrome c release in MCF-7/E6 than in MCF-7, but did not affect Fas level in both cells and activated caspase-8 equally.	0	27	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	15	17
Among the extrinsic pathway , caspase-8 cleaves the Bcl-2 related protein Bid , which in turn induces cytochrome c release from mitochondria and caspase-3 activation , likewise resulting in apoptosis [ XREF_BIBR , XREF_BIBR ] .	Among the extrinsic pathway, caspase-8 cleaves the Bcl-2 related protein Bid, which in turn induces cytochrome c release from mitochondria and caspase-3 activation, likewise resulting in apoptosis [XREF_BIBR, XREF_BIBR].	8	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	17	19
Western analysis of the tumor lysates indicated that , similar to prostate cancer cells in vitro , treatment with simvastatin significantly impaired phosphorylation of Bad ( p < 0.01 ) , decreased protein levels of Bcl-2 and Bcl-xL ( p < 0.01 and p < 0.001 , respectively ) , increased release of cytochrome C from the mitochondria to cytosol ( p < 0.05 ) as well as increased protein expressions of BimL and BimS , cleaved caspase 9 and cleaved caspase 3 ( p < 0.05 ) , compared to saline treated controls .	Western analysis of the tumor lysates indicated that, similar to prostate cancer cells in vitro, treatment with simvastatin significantly impaired phosphorylation of Bad (p < 0.01), decreased protein levels of Bcl-2 and Bcl-xL (p < 0.01 and p < 0.001, respectively), increased release of cytochrome C from the mitochondria to cytosol (p < 0.05) as well as increased protein expressions of BimL and BimS, cleaved caspase 9 and cleaved caspase 3 (p < 0.05), compared to saline treated controls.	22	55	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	phosphorylation of Bad (p < 0.01), decreased protein levels of Bcl-2	bcl-2	cytochrome C	cytochrome C	cytochrome c	35	36	53	55
This redirection requires functional ER signaling and is mediated by a depletion of Bcl-2 and an induction of Bax and Bak , manifesting in cytochrome C release and PARP cleavage .	This redirection requires functional ER signaling and is mediated by a depletion of Bcl-2 and an induction of Bax and Bak, manifesting in cytochrome C release and PARP cleavage.	8	26	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	13	14	24	26
Among these the anti-apoptotic proteins , Bfl-1 and Bcl-2 were upregulated , preventing the release of cytochrome c from the mitochondria and the downstream activation of caspases .	Among these the anti-apoptotic proteins, Bfl-1 and Bcl-2 were upregulated, preventing the release of cytochrome c from the mitochondria and the downstream activation of caspases.	6	18	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	16	18
While Bcl-2 inhibits the formation of the apoptosome by blocking the release of cytochrome c from mitochondria , BIRC3 inhibits apoptosis by interacting with the tumor necrosis factor ( TNF ) receptor associated factors TRAF1 and TRAF2 [ XREF_BIBR ] .	While Bcl-2 inhibits the formation of the apoptosome by blocking the release of cytochrome c from mitochondria, BIRC3 inhibits apoptosis by interacting with the tumor necrosis factor (TNF) receptor associated factors TRAF1 and TRAF2 [XREF_BIBR].	1	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	13	15
Neurotrophin withdrawal pathways converge on the pro apoptotic Bcl-2 family member Bax , which causes cytochrome c release from mitochondria [ XREF_BIBR , XREF_BIBR ] .	Neurotrophin withdrawal pathways converge on the pro apoptotic Bcl-2 family member Bax, which causes cytochrome c release from mitochondria [XREF_BIBR, XREF_BIBR].	8	17	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	15	17
Bcl-2 disrupts the proapoptotic proteins of Bax and acts as channel proteins in the mitochondrial membrane to prevent the mitochondrial release of Cytochrome c for induction of caspase cascade and apoptosis XREF_BIBR , XREF_BIBR .	Bcl-2 disrupts the proapoptotic proteins of Bax and acts as channel proteins in the mitochondrial membrane to prevent the mitochondrial release of Cytochrome c for induction of caspase cascade and apoptosis XREF_BIBR, XREF_BIBR.	0	24	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Cytochrome c	Cytochrome c	Cytochrome c	0	1	22	24
The Bcl-2 protein family are important regulators of caspase-9 activation , where the Bcl-2 and Bax ratio in the mitochondria modulate the level of cytochrome c release after apoptotic stimuli ( Adams and Cory , 1998 ; Hengartner , 2000 ) .	The Bcl-2 protein family are important regulators of caspase-9 activation, where the Bcl-2 and Bax ratio in the mitochondria modulate the level of cytochrome c release after apoptotic stimuli (Adams and Cory, 1998; Hengartner, 2000).	13	26	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	24	26
31 More studies have elaborated that Bcl-2 preserves the mitochondrial membrane and inhibits the release of internal calcium into the cytoplasm , whereas Bax is processed on the outer mitochondrial membrane and regulates the release of cytochrome c. XREF_BIBR , XREF_BIBR The reasons are that Bcl-2 family proteins activated the intrinsic apoptotic pathway causing mitochondrial cytochrome c to be released into the cytosol .	31 More studies have elaborated that Bcl-2 preserves the mitochondrial membrane and inhibits the release of internal calcium into the cytoplasm, whereas Bax is processed on the outer mitochondrial membrane and regulates the release of cytochrome c. XREF_BIBR, XREF_BIBR The reasons are that Bcl-2 family proteins activated the intrinsic apoptotic pathway causing mitochondrial cytochrome c to be released into the cytosol.	45	57	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	45	46	55	57
The pro apoptotic effector BCL-2 proteins BAK ( BCL-2 antagonist killer 1 ) and BAX ( BCL-2 associated x protein ) homo-oligomerize into proteolipid pores within the OMM and are required to promote mitochondrial outer membrane permeabilization ( MOMP ) and cytochrome c release .	The pro apoptotic effector BCL-2 proteins BAK (BCL-2 antagonist killer 1) and BAX (BCL-2 associated x protein) homo-oligomerize into proteolipid pores within the OMM and are required to promote mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release.	0	43	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	4	5	41	43
Moreover , cynaroside moderated H ( 2 ) O ( 2 ) -induced disruption of mitochondrial membrane potential , increased the expression of anti-apoptotic protein Bcl-2 while decreased the expression of pro apoptotic protein Bax , and thereby inhibited the release of apoptogenic factors ( cytochrome c and smac/Diablo ) from mitochondria in H9c2 cells .	Moreover, cynaroside moderated H (2) O (2) -induced disruption of mitochondrial membrane potential, increased the expression of anti-apoptotic protein Bcl-2 while decreased the expression of pro apoptotic protein Bax, and thereby inhibited the release of apoptogenic factors (cytochrome c and smac/Diablo) from mitochondria in H9c2 cells.	2	47	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	cynaroside moderated H (2) O (2) -induced disruption of mitochondrial membrane potential, increased the expression of anti-apoptotic protein Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	25	26	45	47
We hypothesized that mtHK2 might prevent the OMM permeabilization and cytochrome c release mediated by proapoptotic Bcl2 family members .	We hypothesized that mtHK2 might prevent the OMM permeabilization and cytochrome c release mediated by proapoptotic Bcl2 family members.	10	18	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	16	17	10	12
Taken together , these results show three mechanisms by which Bcl-2 may mediate endothelial cell cytoprotection independently of cytochrome c release : ( a ) increased survivin expression , ( b ) inhibition of p53 accumulation , and ( c ) inhibition of p38 MAPK .	Taken together, these results show three mechanisms by which Bcl-2 may mediate endothelial cell cytoprotection independently of cytochrome c release : (a) increased survivin expression, (b) inhibition of p53 accumulation, and (c) inhibition of p38 MAPK.	10	20	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	18	20
Bcl-2 related proteins appear to modulate the release of Cytochrome c XREF_BIBR .	Bcl-2 related proteins appear to modulate the release of Cytochrome c XREF_BIBR.	0	11	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Cytochrome c	Cytochrome c	Cytochrome c	0	1	9	11
The pro apoptotic factor Bax has been reported to form heterodimers with the anti-apoptotic factor Bcl-2 , which consequently induce cytochrome c release and accelerate apoptosis [ XREF_BIBR ] .	The pro apoptotic factor Bax has been reported to form heterodimers with the anti-apoptotic factor Bcl-2, which consequently induce cytochrome c release and accelerate apoptosis [XREF_BIBR].	9	22	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	20	22
The pro apoptotic proteins in the Bcl-2 family , including Bax and Bak , normally act on the mitochondrial membrane to promote permeabilization and release of cytochrome C and reactive oxygen species , which are important signals in the apoptosis cascade .	The pro apoptotic proteins in the Bcl-2 family, including Bax and Bak, normally act on the mitochondrial membrane to promote permeabilization and release of cytochrome C and reactive oxygen species, which are important signals in the apoptosis cascade.	6	28	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	6	7	26	28
Bcl-2 family proteins such as Bax stimulate apoptosis by promoting the release of cytochrome c from mitochondria .	Bcl-2 family proteins such as Bax stimulate apoptosis by promoting the release of cytochrome c from mitochondria.	0	15	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
Since Bcl-2 family antagonists are expected to induce cytochrome c release and apoptosis in a Bax and Bak dependent manner [ XREF_BIBR ] , the specificity of UMI-77 was tested using wild type ( WT ) murine embryonic fibroblasts ( MEF ) and double knockout ( DKO ) cells , deficient in both Bax and Bak .	Since Bcl-2 family antagonists are expected to induce cytochrome c release and apoptosis in a Bax and Bak dependent manner [XREF_BIBR], the specificity of UMI-77 was tested using wild type (WT) murine embryonic fibroblasts (MEF) and double knockout (DKO) cells, deficient in both Bax and Bak.	1	10	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	8	10
Therefore , downregulation or upregulation of Bcl-2 or p53 , respectively , in ETBO treated cancer cells could promote the release of mitochondrial cytochrome c and activate the caspase cascade ; p53 activation can trigger cytochrome c release into the cytoplasm via the Bcl-2-mediated pathway , and the released cytochrome c activates caspase-3 .	Therefore, downregulation or upregulation of Bcl-2 or p53, respectively, in ETBO treated cancer cells could promote the release of mitochondrial cytochrome c and activate the caspase cascade; p53 activation can trigger cytochrome c release into the cytoplasm via the Bcl-2-mediated pathway, and the released cytochrome c activates caspase-3.	2	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	23	25
XREF_BIBR ) in their study investigated that overexpression of BCL2 prevents the initiation of the cellular apoptotic programme by blocking the release of cytochrome c from mitochondria .	XREF_BIBR) in their study investigated that overexpression of BCL2 prevents the initiation of the cellular apoptotic programme by blocking the release of cytochrome c from mitochondria.	7	25	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	overexpression of BCL2	bcl2	cytochrome c	cytochrome c	cytochrome c	9	10	23	25
The imbalance of Bcl-2 and Bax can induce the release of cytochrome c from the mitochondria , which can bind with the Apaf-1 and pro-caspase-9 to form apoptosome .	The imbalance of Bcl-2 and Bax can induce the release of cytochrome c from the mitochondria, which can bind with the Apaf-1 and pro-caspase-9 to form apoptosome.	1	13	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	11	13
In a different apoptotic pathway , Calp2 causes fragmentation of Bcl-xL ( Bcl2l1 ) and Bcl2 in addition to cleavage of Bax to increase the Bax and bcl2 ratio , a step that mediates cytochrome C release , activates Casp3 and initiates the apoptotic execution .	In a different apoptotic pathway, Calp2 causes fragmentation of Bcl-xL (Bcl2l1) and Bcl2 in addition to cleavage of Bax to increase the Bax and bcl2 ratio, a step that mediates cytochrome C release, activates Casp3 and initiates the apoptotic execution.	25	36	mediates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	bcl2	bcl2	bcl2	cytochrome C	cytochrome C	cytochrome C	27	28	34	36
Members of the Bcl-2 family , which includes Bcl-xL and A1/Bfl-1 , can inhibit this process by blocking the release of cytochrome c from mitochondria .	Members of the Bcl-2 family, which includes Bcl-xL and A1/Bfl-1, can inhibit this process by blocking the release of cytochrome c from mitochondria.	3	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	21	23
Bcl-2 family pro apoptotic proteins promote cell death by inducing mitochondrial damage , cytochrome c release , and subsequent caspase activation , and the Bcl-2 family of anti-apoptotic proteins inhibit apoptosis by preventing the release of cytochrome c ; however , the mechanism by which parasites utilize this method of apoptotic inhibition has not been elucidated .	Bcl-2 family pro apoptotic proteins promote cell death by inducing mitochondrial damage, cytochrome c release, and subsequent caspase activation, and the Bcl-2 family of anti-apoptotic proteins inhibit apoptosis by preventing the release of cytochrome c; however, the mechanism by which parasites utilize this method of apoptotic inhibition has not been elucidated.	0	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	13	15
This idea is also supported by the observations that overexpression of the anti-apoptotic gene Bcl-2 increases hair cell survival , and that Bcl-2 functions to block mitochondrial apoptosis by inhibiting cytochrome c release .	This idea is also supported by the observations that overexpression of the anti-apoptotic gene Bcl-2 increases hair cell survival, and that Bcl-2 functions to block mitochondrial apoptosis by inhibiting cytochrome c release.	22	32	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	22	23	30	32
Signal transduction studies showed that Dox markedly decreased mitochondrial membrane potential , disturbed Bcl-2 family protein balance , enhanced cytochrome c release in the cytosol , increased levels of Apaf1 , caspase-9/3 , cleaved PARP protein and ultimately led to apoptotic cell death .	Signal transduction studies showed that Dox markedly decreased mitochondrial membrane potential, disturbed Bcl-2 family protein balance, enhanced cytochrome c release in the cytosol, increased levels of Apaf1, caspase-9/3, cleaved PARP protein and ultimately led to apoptotic cell death.	13	21	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	19	21
Overexpression of Bcl-2 or Bcl-XL inhibits apoptosis by suppressing the generation of reactive oxygen species ( ROS ) , preventing an increase in the permeability and blocking the release of cytochrome c [ XREF_BIBR ] .	Overexpression of Bcl-2 or Bcl-XL inhibits apoptosis by suppressing the generation of reactive oxygen species (ROS), preventing an increase in the permeability and blocking the release of cytochrome c [XREF_BIBR].	0	33	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	30	32
Proapoptotic Bcl-2 family members , such as Bax , promote release of cytochrome c from mitochondria , leading to caspase activation and cell death .	Proapoptotic Bcl-2 family members, such as Bax, promote release of cytochrome c from mitochondria, leading to caspase activation and cell death.	1	14	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	12	14
Bcl-2 is specifically considered as an important antiapoptotic protein and has been shown to prevent apoptosis by blocking cytochrome C release from mitochondria [ XREF_BIBR , XREF_BIBR ] .	Bcl-2 is specifically considered as an important antiapoptotic protein and has been shown to prevent apoptosis by blocking cytochrome C release from mitochondria [XREF_BIBR, XREF_BIBR].	0	20	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	18	20
On the mechanistic level , classical anti-apoptotic Bcl-2 family members ( BAK , BAD , BID , BAX , BCL-XL , MCL-1 ) modulate apoptosis by preserving mitochondrial membrane integrity and preventing the release of cytochrome C , the caspase cascade and the apoptotic program .	On the mechanistic level, classical anti-apoptotic Bcl-2 family members (BAK, BAD, BID, BAX, BCL-XL, MCL-1) modulate apoptosis by preserving mitochondrial membrane integrity and preventing the release of cytochrome C, the caspase cascade and the apoptotic program.	7	37	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	7	8	35	37
The altered expression of Bcl-2 family member proteins triggered the release of cytochrome-C and activation of initiator capsase 9 followed by activation of effector caspase 3 .	The altered expression of Bcl-2 family member proteins triggered the release of cytochrome-C and activation of initiator capsase 9 followed by activation of effector caspase 3.	4	14	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome-C	cytochrome-C	cytochrome-C	4	5	12	13
Bcl-2 inhibits apoptosis by inhibiting the release of cytochrome c and the activation of caspase-9 in E1A transfected cells .	Bcl-2 inhibits apoptosis by inhibiting the release of cytochrome c and the activation of caspase-9 in E1A transfected cells.	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
Our data indicated an increase in p53 and Bax expression and a decrease in Bcl2 expression , which resulted in a reduction in the DeltaPsim and increased cytochrome c release into the cytosol .	Our data indicated an increase in p53 and Bax expression and a decrease in Bcl2 expression, which resulted in a reduction in the DeltaPsim and increased cytochrome c release into the cytosol.	14	29	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2 expression	bcl2	cytochrome c	cytochrome c	cytochrome c	14	15	27	29
The overexpression of Bcl-2 or Bcl-XL results in the inhibition of cytochrome c release and termination of the apoptotic response , whereas the overexpression of Bax or its Bcl-2 homologous domain 3 promotes cytochrome c release .	The overexpression of Bcl-2 or Bcl-XL results in the inhibition of cytochrome c release and termination of the apoptotic response, whereas the overexpression of Bax or its Bcl-2 homologous domain 3 promotes cytochrome c release.	1	35	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	overexpression of Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	33	35
We also demonstrated that Akt inhibits apoptosis and cytochrome c release induced by several proapoptotic Bcl-2 family members .	We also demonstrated that Akt inhibits apoptosis and cytochrome c release induced by several proapoptotic Bcl-2 family members.	6	17	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	15	16	8	10
Pro apoptotic members of Bcl-2 family ( Bax , Bak etc. ) induce the release of cytochrome c and cause mitochondrial dysfunction .	Pro apoptotic members of Bcl-2 family (Bax, Bak etc.) induce the release of cytochrome c and cause mitochondrial dysfunction.	4	18	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	16	18
XREF_BIBR In addition , Bcl-2 family proteins , including Bax , Bad , Bid , Bcl-2 , and Bcl-xL , located on the mitochondrial membrane can alter the permeability of the mitochondrial membrane and trigger the release of cytochrome c or caspases , thus activating the post-mitochondrial caspase cascade and leading to apoptotic cell death .	XREF_BIBR In addition, Bcl-2 family proteins, including Bax, Bad, Bid, Bcl-2, and Bcl-xL, located on the mitochondrial membrane can alter the permeability of the mitochondrial membrane and trigger the release of cytochrome c or caspases, thus activating the post-mitochondrial caspase cascade and leading to apoptotic cell death.	4	40	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	38	40
The findings revealed that the TalphaPcZn-PDT treatment of LoVo cells resulted in the induction of apoptosis , the formation of p38 MAPK and caspase -9 complexes , the activation of p38 MAPK , caspase-9 , caspase-3 and Bid , the downregulation of Bcl-2 , the reduction of mitochondrial membrane potential ( DeltaPsim ) , the upregulation of Bax and the release of apoptosis inducing factor ( AIF ) and cytochrome c ( Cyto c ) .	The findings revealed that the TalphaPcZn-PDT treatment of LoVo cells resulted in the induction of apoptosis, the formation of p38 MAPK and caspase -9 complexes, the activation of p38 MAPK, caspase-9, caspase-3 and Bid, the downregulation of Bcl-2, the reduction of mitochondrial membrane potential (DeltaPsim), the upregulation of Bax and the release of apoptosis inducing factor (AIF) and cytochrome c (Cyto c).	40	71	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	42	43	69	71
Bcl-2 and BHRF1 suppress the mitochondrial pathway by preventing loss of mitochondrial membrane depolarization and inhibiting the release of cytochrome c and apoptosis inducing factor into the cytosol 29 .	Bcl-2 and BHRF1 suppress the mitochondrial pathway by preventing loss of mitochondrial membrane depolarization and inhibiting the release of cytochrome c and apoptosis inducing factor into the cytosol 29.	0	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	19	21
The change of pro apoptotic Bcl-2 family members such as Bax could also cause the release of cytochrome c and other pro apoptotic mitochondrial factors during cell apoptosis 32 .	The change of pro apoptotic Bcl-2 family members such as Bax could also cause the release of cytochrome c and other pro apoptotic mitochondrial factors during cell apoptosis 32.	5	19	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	17	19
Taken together , these findings suggest that proapoptotic Bcl-2 family proteins , including Bax and Bak , induce the mitochondrial PT and cytochrome c release by interacting with the PT pores .	Taken together, these findings suggest that proapoptotic Bcl-2 family proteins, including Bax and Bak, induce the mitochondrial PT and cytochrome c release by interacting with the PT pores.	8	24	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	22	24
It has been reported that a low Bcl-2 to Bax ratio can cause DeltaPsim collapse , the release of cytochrome c , and subsequent apoptosis [ XREF_BIBR ] .	It has been reported that a low Bcl-2 to Bax ratio can cause DeltaPsim collapse, the release of cytochrome c, and subsequent apoptosis [XREF_BIBR].	5	21	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	7	8	19	21
Here we report that in cells or with isolated mitochondria , pro apoptotic Bcl-2 proteins cause the release of cytochrome c , Smac/Diablo and HtrA2 and Omi but not endonuclease G ( EndoG ) and apoptosis inducing factor ( AIF ) .	Here we report that in cells or with isolated mitochondria, pro apoptotic Bcl-2 proteins cause the release of cytochrome c, Smac/Diablo and HtrA2 and Omi but not endonuclease G (EndoG) and apoptosis inducing factor (AIF).	13	21	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	13	14	19	21
The presence of Bax and Bcl-2 also caused the release of cytochrome c in the mitochondria , the results of which are concordant with those of Zhang et al .	The presence of Bax and Bcl-2 also caused the release of cytochrome c in the mitochondria, the results of which are concordant with those of Zhang et al.	1	13	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	11	13
Bcl-2 and Bax also play very important roles in mitochondrial pathway , the down-regulation of Bcl-2 and the up-regulation of Bax can induce the release of cytochrome-C ( cytosol ) from mitochondria , trigger the activity of caspase-3 and -9 and finally cause cell apoptosis .	Bcl-2 and Bax also play very important roles in mitochondrial pathway, the down-regulation of Bcl-2 and the up-regulation of Bax can induce the release of cytochrome-C (cytosol) from mitochondria, trigger the activity of caspase-3 and -9 and finally cause cell apoptosis.	13	28	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome-C	cytochrome-C	cytochrome-C	15	16	26	27
In the present study , we showed that beta , beta-dimethylacrylshikonin down-regulated the expression of XIAP , cIAP-2 and Bcl-2 and up-regulated the expression of Bak and Bax , and caused the loss of mitochondrial membrane potential and release of cytochrome c in SGC-7901 cells , consistent with mitochondria dependent apoptosis .	In the present study, we showed that beta,beta-dimethylacrylshikonin down-regulated the expression of XIAP, cIAP-2 and Bcl-2 and up-regulated the expression of Bak and Bax, and caused the loss of mitochondrial membrane potential and release of cytochrome c in SGC-7901 cells, consistent with mitochondria dependent apoptosis.	8	42	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	beta,beta-dimethylacrylshikonin down-regulated the expression of XIAP, cIAP-2 and Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	19	20	40	42
This Bcl-2 and Bcl-x L mediated retention of mitochondrial cytochrome c [ XREF_BIBR , XREF_BIBR ] is caused by inhibition of Bax channel forming activity in the outer mitochondrial membrane [ XREF_BIBR ] or by modulation mitochondrial membrane potential and volume homeostasis [ XREF_BIBR ] .	This Bcl-2 and Bcl-x L mediated retention of mitochondrial cytochrome c [XREF_BIBR, XREF_BIBR] is caused by inhibition of Bax channel forming activity in the outer mitochondrial membrane [XREF_BIBR] or by modulation mitochondrial membrane potential and volume homeostasis [XREF_BIBR].	1	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	9	11
Cytochrome c from the mitochondria , mediated by Bax and Bcl2 , has been implicated in ER stress associated apoptosis [ XREF_BIBR ] .	Cytochrome c from the mitochondria, mediated by Bax and Bcl2, has been implicated in ER stress associated apoptosis [XREF_BIBR].	0	11	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	Cytochrome c	Cytochrome c	Cytochrome c	10	11	0	2
The chemotherapeutic properties of curcumin have been reported as inducing lung cancer cell death through Bax upregulation and Bcl-2 , Bcl-XL downregulation , causing AIF and cytochrome c release [ XREF_BIBR ] .	The chemotherapeutic properties of curcumin have been reported as inducing lung cancer cell death through Bax upregulation and Bcl-2, Bcl-XL downregulation, causing AIF and cytochrome c release [XREF_BIBR].	16	28	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	26	28
The intrinsic pathway is mediated by Bcl-2 family proteins causing release of cytochrome c from mitochondria leading to activation of caspase-9 via formation of the cytosolic apoptosome complex with Apaf-1 .	The intrinsic pathway is mediated by Bcl-2 family proteins causing release of cytochrome c from mitochondria leading to activation of caspase-9 via formation of the cytosolic apoptosome complex with Apaf-1.	6	14	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	12	14
It is also possible that the pro apoptotic members of Bcl-2 family induce the release of cytochrome c and other apoptotic factors ( Smac/Diablo homologue , and Omi ) into the cytosol from the mitochondria , whereas the anti-apoptotic members inhibit the releases of these factors XREF_BIBR .	It is also possible that the pro apoptotic members of Bcl-2 family induce the release of cytochrome c and other apoptotic factors (Smac/Diablo homologue, and Omi) into the cytosol from the mitochondria, whereas the anti-apoptotic members inhibit the releases of these factors XREF_BIBR.	10	18	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	16	18
Proapoptotic Bcl-2 homology 3-only protein Bim plays an important role in Bax and Bak mediated cytochrome c release and apoptosis .	Proapoptotic Bcl-2 homology 3-only protein Bim plays an important role in Bax and Bak mediated cytochrome c release and apoptosis.	1	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	15	17
The anti-apoptotic Bcl-2 members repress apoptosis by blocking the release of cytochrome c whereas the pro apoptotic members promote apoptosis .	The anti-apoptotic Bcl-2 members repress apoptosis by blocking the release of cytochrome c whereas the pro apoptotic members promote apoptosis.	2	13	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	2	3	11	13
Bcl-2 suppresses apoptosis by inhibiting the release of cytochrome c from the mitochondria into the cytoplasm .	Bcl-2 suppresses apoptosis by inhibiting the release of cytochrome c from the mitochondria into the cytoplasm.	0	10	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	8	10
In apoptosis , the Bcl-2 family protein Bax ( and Bak ) also inserts into the mitochondrial outer membrane to form a permeation pore that allows the release of cytochrome c from the intermembrane space to the cytoplasm .	In apoptosis, the Bcl-2 family protein Bax (and Bak) also inserts into the mitochondrial outer membrane to form a permeation pore that allows the release of cytochrome c from the intermembrane space to the cytoplasm.	4	31	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	29	31
In this scenario , the increased ratio of pro apoptotic Bcl-2 family members to anti-apoptotic Bcl-2 family members induces the release of cytochrome c which binds to Apaf-1 , leading to activation of procaspase-9 and subsequent activation of procaspase-3 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In this scenario, the increased ratio of pro apoptotic Bcl-2 family members to anti-apoptotic Bcl-2 family members induces the release of cytochrome c which binds to Apaf-1, leading to activation of procaspase-9 and subsequent activation of procaspase-3 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	10	24	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	10	11	22	24
In addition , investigators have shown that Bcl-2 gene family is known to modulate the permeability of the mitochondrial membrane and the release of cytochrome C [ XREF_BIBR ] .	In addition, investigators have shown that Bcl-2 gene family is known to modulate the permeability of the mitochondrial membrane and the release of cytochrome C [XREF_BIBR].	7	27	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	7	8	24	26
The Bcl-2 gene within the mitochondria can promote mitochondrial membrane stability , and block MPT opening and inhibiting cytochrome c release , thereby inhibiting the apoptosis of cells .	The Bcl-2 gene within the mitochondria can promote mitochondrial membrane stability, and block MPT opening and inhibiting cytochrome c release, thereby inhibiting the apoptosis of cells.	1	20	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	1	2	18	20
Bcl-2 and Bcl-x ( L ) inhibit apoptosis , in part by blocking the release of cytochrome c from mitochondria .	Bcl-2 and Bcl-x (L) inhibit apoptosis, in part by blocking the release of cytochrome c from mitochondria.	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	0	1	16	18
The BCL-2 family of proteins at the mitochondrial outer membrane mediate apoptosis by controlling the release of cytochrome c from the mitochondrial intermembrane space , which triggers the caspase protease activation in cytosol XREF_BIBR .	The BCL-2 family of proteins at the mitochondrial outer membrane mediate apoptosis by controlling the release of cytochrome c from the mitochondrial intermembrane space, which triggers the caspase protease activation in cytosol XREF_BIBR.	1	19	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	1	2	17	19
By binding several proapoptotic or antiapoptotic Bcl-2 family members ( all containing a BH3 domain ) , Bcl-2 fine-tunes mitochondrial membrane dynamics and triggers the release of cytochrome c and other apoptosis effectors from mitochondria .	By binding several proapoptotic or antiapoptotic Bcl-2 family members (all containing a BH3 domain), Bcl-2 fine-tunes mitochondrial membrane dynamics and triggers the release of cytochrome c and other apoptosis effectors from mitochondria.	17	29	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	17	18	27	29
Proapoptotic Bcl2 proteins promote apoptosis by inducing the release of mitochondrial cytochrome c into the cytoplasm , leading to caspase activation .	Proapoptotic Bcl2 proteins promote apoptosis by inducing the release of mitochondrial cytochrome c into the cytoplasm, leading to caspase activation.	1	13	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	cytochrome c	cytochrome c	cytochrome c	1	2	11	13
Concomitant administration of SP600125 , a selective JNK inhibitor , or aminoguanidine ( AG ) , a selected inducible nitric oxide synthase ( iNOS ) inhibitor , effectively diminished BCL-2 phosphorylation , suppressed cytochrome c release from mitochondria and caspase activation , and significantly prevented ctx induced muscle cell apoptosis .	Concomitant administration of SP600125, a selective JNK inhibitor, or aminoguanidine (AG), a selected inducible nitric oxide synthase (iNOS) inhibitor, effectively diminished BCL-2 phosphorylation, suppressed cytochrome c release from mitochondria and caspase activation, and significantly prevented ctx induced muscle cell apoptosis.	19	35	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	nitric oxide synthase (iNOS) inhibitor, effectively diminished BCL-2 phosphorylation	bcl-2	cytochrome c	cytochrome c	cytochrome c	29	30	33	35
Ceramide treatment of isolated mitochondria leads to the activation of a mitochondrial protein phosphatase ( PP2A ) , which dephosphorylates the antiapoptotic Bcl-2 ( Ruvolo et al , 1999 ) and causes cytochrome c release ( Ghafourifar et al , 1999 ) .	Ceramide treatment of isolated mitochondria leads to the activation of a mitochondrial protein phosphatase (PP2A), which dephosphorylates the antiapoptotic Bcl-2 (Ruvolo et al, 1999) and causes cytochrome c release (Ghafourifar et al, 1999).	13	34	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	phosphatase (PP2A), which dephosphorylates the antiapoptotic Bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	22	23	32	34
Low levels of Bcl-2 and increased levels of BAK promote the release of cytochrome c from the mitochondria triggering the activation of caspases that regulate the induction and execution of apoptosis 46 .	Low levels of Bcl-2 and increased levels of BAK promote the release of cytochrome c from the mitochondria triggering the activation of caspases that regulate the induction and execution of apoptosis 46.	3	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 and increased levels	bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	13	15
Furthermore , atenolol suppressed TNF-alpha expression , JNK , p38 MAPK and CaMKII phosphorylation , increased Bcl-2 expression , and inhibited cytochrome c release and cardiomyocyte apoptosis in the myocardium of endotoxemic mice .	Furthermore, atenolol suppressed TNF-alpha expression, JNK, p38 MAPK and CaMKII phosphorylation, increased Bcl-2 expression, and inhibited cytochrome c release and cardiomyocyte apoptosis in the myocardium of endotoxemic mice.	2	23	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	atenolol suppressed TNF-alpha expression, JNK, p38 MAPK and CaMKII phosphorylation, increased Bcl-2 expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	16	17	21	23
Numerous proapoptotic members of the Bcl-2 family may induce cytochrome c release ; however , tBID may initiate release of almost all mitochondrial cytochrome c into the cytosol at a very low concentration compared with others .	Numerous proapoptotic members of the Bcl-2 family may induce cytochrome c release; however, tBID may initiate release of almost all mitochondrial cytochrome c into the cytosol at a very low concentration compared with others.	5	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	9	11
Previous studies have shown that the anti-apoptotic protein Bcl-2 is converted into a potent pro apoptotic factor and may enhance cell death by amplifying the caspase cascade and that the cleavage of Bcl-2 by caspase-3 into a 22-kDa fragment induces mitochondrial cytochrome c release XREF_BIBR .	Previous studies have shown that the anti-apoptotic protein Bcl-2 is converted into a potent pro apoptotic factor and may enhance cell death by amplifying the caspase cascade and that the cleavage of Bcl-2 by caspase-3 into a 22-kDa fragment induces mitochondrial cytochrome c release XREF_BIBR.	30	44	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	32	33	41	43
Bid is truncated by caspase-8 , translocates to mitochondria , and interacts with other Bcl-2 family proteins , which causes cytochrome c release followed by apoptotic cell death [ XREF_BIBR ] .	Bid is truncated by caspase-8, translocates to mitochondria, and interacts with other Bcl-2 family proteins, which causes cytochrome c release followed by apoptotic cell death [XREF_BIBR].	14	22	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	14	15	20	22
Bcl-2 is known to suppress apoptosis by inhibiting the release of cytochrome C from the mitochondria to the cytosol .	Bcl-2 is known to suppress apoptosis by inhibiting the release of cytochrome C from the mitochondria to the cytosol.	0	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome C	cytochrome C	cytochrome C	0	1	11	13
Proapoptotic members of the Bcl-2 family , including Bax , Bak , and Bid , directly trigger the mitochondrial release of apoptogenic cytochrome c and apoptosis inducing factor into the cytoplasm .	Proapoptotic members of the Bcl-2 family, including Bax, Bak, and Bid, directly trigger the mitochondrial release of apoptogenic cytochrome c and apoptosis inducing factor into the cytoplasm.	4	24	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	22	24
These signals result in the increase of mitochondrial proapoptotic Bcl-2 levels and decrease of mitochondrial antiapoptotic Bcl-2 members , which subsequently increase cytochrome c release from mitocondria .	These signals result in the increase of mitochondrial proapoptotic Bcl-2 levels and decrease of mitochondrial antiapoptotic Bcl-2 members, which subsequently increase cytochrome c release from mitocondria.	16	24	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	16	17	22	24
The pro apoptotic members of Bcl-2 family induce release of mitochondrial cytochrome c into cytosol , which eventually leads to caspase-3 activation through constitution of apoptosome complex with Apaf-1 and caspase-9 XREF_BIBR .	The pro apoptotic members of Bcl-2 family induce release of mitochondrial cytochrome c into cytosol, which eventually leads to caspase-3 activation through constitution of apoptosome complex with Apaf-1 and caspase-9 XREF_BIBR.	5	13	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	5	6	11	13
Bad promotes apoptosis by displacing Bax , another Bcl-2 family member , from binding to Bcl-2 and Bcl-xL , causing cytochrome c release from mitochondria [ XREF_BIBR ] .	Bad promotes apoptosis by displacing Bax, another Bcl-2 family member, from binding to Bcl-2 and Bcl-xL, causing cytochrome c release from mitochondria [XREF_BIBR].	8	22	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	8	9	20	22
Insertion of Bax , but not Bcl-2 and Delta34 , into mitochondria triggered a rapid release of cytochrome c from the mitochondria .	Insertion of Bax, but not Bcl-2 and Delta34, into mitochondria triggered a rapid release of cytochrome c from the mitochondria.	0	19	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	6	7	17	19
Bad is a pro apoptotic ( BH3-only ) member of the bcl-2 family that antagonizes the anti-apoptosis proteins bcl-2 , bcl-xl and bcl-2 , allowing activation of bax and bak oligomers and release of cytochrome c from the mitochondria .	Bad is a pro apoptotic (BH3-only) member of the bcl-2 family that antagonizes the anti-apoptosis proteins bcl-2, bcl-xl and bcl-2, allowing activation of bax and bak oligomers and release of cytochrome c from the mitochondria.	15	36	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	bcl-2	bcl-2	cytochrome c	cytochrome c	cytochrome c	18	19	34	36
The repression of eIF2alpha phosphorylation by exendin-4 and forskolin may restore Bcl-2 expression and thus prevent cytochrome C release and caspase 3 activation by salubrinal and CPA , but they have little effect on palmitate induced apoptosis .	The repression of eIF2alpha phosphorylation by exendin-4 and forskolin may restore Bcl-2 expression and thus prevent cytochrome C release and caspase 3 activation by salubrinal and CPA, but they have little effect on palmitate induced apoptosis.	1	18	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	repression of eIF2alpha phosphorylation by exendin-4 and forskolin may restore Bcl-2 expression	bcl-2	cytochrome C	cytochrome C	cytochrome c	11	12	16	18
Pro- and anti-apoptotic Bcl-2 family proteins play an important role in regulating the intrinsic apoptotic pathway and in particular Bax , a principal effector pro apoptotic Bcl-2 family member plays an important role in H/R induced apoptosis by regulating release of cytochrome c XREF_BIBR .	Pro- and anti-apoptotic Bcl-2 family proteins play an important role in regulating the intrinsic apoptotic pathway and in particular Bax, a principal effector pro apoptotic Bcl-2 family member plays an important role in H/R induced apoptosis by regulating release of cytochrome c XREF_BIBR.	0	43	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	41	43
Alternatively , in contrast to normally structured Bcl-2 which forms low conductance channels to maintain physiological mitochondrial Deltapsi , conformationally altered Bcl-2 may change its channel activity and dysregulate mitochondria bioenergetics ultimately causing Cytochrome C release .	Alternatively, in contrast to normally structured Bcl-2 which forms low conductance channels to maintain physiological mitochondrial Deltapsi, conformationally altered Bcl-2 may change its channel activity and dysregulate mitochondria bioenergetics ultimately causing Cytochrome C release.	19	35	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Cytochrome C	Cytochrome C	Cytochrome C	21	22	33	35
One proposal is that pro apoptotic BCL-2 family members , such as tBID , BAX and BAK , promote formation of specific cytochrome c release channels in the mitochondrial outer membrane [ XREF_BIBR , XREF_BIBR ] .	One proposal is that pro apoptotic BCL-2 family members, such as tBID, BAX and BAK, promote formation of specific cytochrome c release channels in the mitochondrial outer membrane [XREF_BIBR, XREF_BIBR].	6	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	6	7	22	24
Similar to loss of both Bax and Bak , cells without MK-STYX expression are unable to release cytochrome c. Proapoptotic members of the BCL-2 family ( Bax , Bid , and Bim ) are unable to trigger cytochrome c release in MK-STYX-depleted cells , placing the apoptotic deficiency at the level of mitochondrial outer membrane permeabilization ( MOMP ) .	Similar to loss of both Bax and Bak, cells without MK-STYX expression are unable to release cytochrome c. Proapoptotic members of the BCL-2 family (Bax, Bid, and Bim) are unable to trigger cytochrome c release in MK-STYX-depleted cells, placing the apoptotic deficiency at the level of mitochondrial outer membrane permeabilization (MOMP).	23	39	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	cytochrome c	cytochrome c	cytochrome c	23	24	37	39
The release of Bcl-2 during ischemia-reperfusion injury has been proven to prevent apoptosis by blocking the release of cytochrome c from the mitochondria and ameliorating the activation of caspase-3 [ XREF_BIBR , XREF_BIBR ] .	The release of Bcl-2 during ischemia-reperfusion injury has been proven to prevent apoptosis by blocking the release of cytochrome c from the mitochondria and ameliorating the activation of caspase-3 [XREF_BIBR, XREF_BIBR].	1	20	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	cytochrome c	cytochrome c	cytochrome c	3	4	18	20
GS treatment also decreased bcl-2 gene expression , followed by mitochondrial swelling , increased cytochrome c release , and caspase activation .	GS treatment also decreased bcl-2 gene expression, followed by mitochondrial swelling, increased cytochrome c release, and caspase activation.	4	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bcl-2	bcl-2 gene expression	bcl-2	cytochrome c	cytochrome c	cytochrome c	4	5	14	16
These proteins are cleaved-caspase3 known as the executioner of apoptosis , Bax which also activates apoptosis and Bcl-2 as a blocker of apoptosis in cells .	These proteins are cleaved-caspase3 known as the executioner of apoptosis, Bax which also activates apoptosis and Bcl-2 as a blocker of apoptosis in cells.	9	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	11	12	17	18
Moreover , CHC treatment resulted in decreased expression of Bax and concomitant increase of Bcl-2 , as was revealed by western-blot analysis .	Moreover, CHC treatment resulted in decreased expression of Bax and concomitant increase of Bcl-2, as was revealed by western-blot analysis.	9	15	increase	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	9	10	14	15
In agreement with this model , activation of Bax by E2F1 could , in part , induce the re-distribution of the Bcl-2 members through increasing of BimL levels .	In agreement with this model, activation of Bax by E2F1 could, in part, induce the re-distribution of the Bcl-2 members through increasing of BimL levels.	6	22	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	8	9	21	22
Spirulina extract ( 1mug/mL ) , considerably inhibited increased ROS and RNS levels , reduction in cytochrome c release , raise in mitochondrial membrane potential , decreased the over expression of proapoptotic protein Bax and suppressed the Bax and Bcl2 ratio with induced apoptosis without affecting cell viability .	Spirulina extract (1mug/mL), considerably inhibited increased ROS and RNS levels, reduction in cytochrome c release, raise in mitochondrial membrane potential, decreased the over expression of proapoptotic protein Bax and suppressed the Bax and Bcl2 ratio with induced apoptosis without affecting cell viability.	16	40	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	cytochrome c release, raise in mitochondrial membrane potential, decreased the over expression of proapoptotic protein Bax	bax	Bcl2	Bcl2	bcl2	33	34	39	40
Both Bax activation and Bcl-2 protection support the involvement of the Bcl-2 family proteins in 2DG toxicity in these cells .	Both Bax activation and Bcl-2 protection support the involvement of the Bcl-2 family proteins in 2DG toxicity in these cells.	1	13	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	1	2	11	12
SI/R treatment decreased Bcl-2 ( an anti-apoptotic protein ) expression , and increased Bax ( a pro apoptotic protein ) expression , decreasing the Bcl-2 and Bax ratio ( XREF_FIG ) .	SI/R treatment decreased Bcl-2 (an anti-apoptotic protein) expression, and increased Bax (a pro apoptotic protein) expression, decreasing the Bcl-2 and Bax ratio (XREF_FIG).	0	27	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	SI/R treatment decreased Bcl-2 (an anti-apoptotic protein) expression, and increased Bax (a pro apoptotic protein) expression	bax	Bcl-2	Bcl-2	bcl-2	13	14	24	25
In the context of apoptosis , CtBPs act as co-repressors at several pro apoptotic Bcl-2 family member gene promoters , such as Bax and the Bcl-2 homology-3 domain ( BH3 )-only proteins , Noxa , Bik , Bim , and Bmf .	In the context of apoptosis, CtBPs act as co-repressors at several pro apoptotic Bcl-2 family member gene promoters, such as Bax and the Bcl-2 homology-3 domain (BH3)-only proteins, Noxa, Bik, Bim, and Bmf.	14	23	promoters	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	22	23	14	15
XREF_BIBR In experimental models of obstructive nephropathy decreasing levels of Bcl-2 and increasing levels of Bax have correlated with progressive apoptotic cell death .	XREF_BIBR In experimental models of obstructive nephropathy decreasing levels of Bcl-2 and increasing levels of Bax have correlated with progressive apoptotic cell death.	10	16	increasing	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Bax	levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	15	16	10	11
In addition , silibinin reduced the expression of pro apoptotic Bax and ameliorated AGE induced suppression of Bcl-2 protein synthesis .	In addition, silibinin reduced the expression of pro apoptotic Bax and ameliorated AGE induced suppression of Bcl-2 protein synthesis.	6	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	expression of pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	17	18
PRD treatment significantly downregulated the expression of bax and caspase-3 mRNA ( P < 0.01 ) , but significantly increased bcl-2 mRNA expression and bcl-2 mRNA and bax mRNA ratio in diabetic rat retinas ( P < 0.01 ; XREF_FIG , XREF_TABLE ) .	PRD treatment significantly downregulated the expression of bax and caspase-3 mRNA (P < 0.01), but significantly increased bcl-2 mRNA expression and bcl-2 mRNA and bax mRNA ratio in diabetic rat retinas (P < 0.01; XREF_FIG, XREF_TABLE).	0	23	increased	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	bax	PRD treatment significantly downregulated the expression of bax	bax	bcl-2	bcl-2 mRNA expression	bcl-2	7	8	20	21
After WDR79 was knocked down , the expression of Bcl-2 significantly decreased , whereas Bax protein expression markedly increased , resulting in a low Bcl-2 and Bax ratio in both cell lines tested .	After WDR79 was knocked down, the expression of Bcl-2 significantly decreased, whereas Bax protein expression markedly increased, resulting in a low Bcl-2 and Bax ratio in both cell lines tested.	14	31	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax protein expression	bax	Bcl-2	Bcl-2	bcl-2	14	15	24	25
XREF_BIBR reported that heat stress induced the mRNA and protein expression of BAX in LLC-PK1 cells , significantly increasing the ratio of Bcl-2 and BAX XREF_BIBR .	XREF_BIBR reported that heat stress induced the mRNA and protein expression of BAX in LLC-PK1 cells, significantly increasing the ratio of Bcl-2 and BAX XREF_BIBR.	3	25	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	heat stress induced the mRNA and protein expression of BAX	bax	Bcl-2	Bcl-2	bcl-2	12	13	22	23
The suppression of MYCN expression increased the levels of Bax and decreased the levels of Bcl-2 and cyclin D1 proteins in cell derived tumour xenografts .	The suppression of MYCN expression increased the levels of Bax and decreased the levels of Bcl-2 and cyclin D1 proteins in cell derived tumour xenografts.	3	19	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	MYCN expression increased the levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	9	10	15	16
LPS significantly increased the myocardial Bax expression and slightly decreased Bcl-2 expression ; quercetin pretreatment decreased Bax expression to the control level and significantly lowered Bax and Bcl -2 ratio as compared with the LPS group .	LPS significantly increased the myocardial Bax expression and slightly decreased Bcl-2 expression; quercetin pretreatment decreased Bax expression to the control level and significantly lowered Bax and Bcl -2 ratio as compared with the LPS group.	0	12	decreased	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Bax	LPS significantly increased the myocardial Bax expression	bax	Bcl-2	Bcl-2 expression	bcl-2	5	6	10	11
Whereas low doses induced p21/Cip1/Waf1 and HDM2 , high doses induced only GADD45 and BAX increasing the BAX : BCL-2 ratio .	Whereas low doses induced p21/Cip1/Waf1 and HDM2, high doses induced only GADD45 and BAX increasing the BAX : BCL-2 ratio.	10	20	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	BAX	BAX	BCL-2	BCL-2	BCL-2	14	15	19	20
Bcl-2 inhibits apoptosis by preventing the release of cytochrome c whereas , Bax induces apoptosis by dimerizing and inactivating the anti-apoptotic Bcl-2 proteins and enhancing cytochrome c release .	Bcl-2 inhibits apoptosis by preventing the release of cytochrome c whereas, Bax induces apoptosis by dimerizing and inactivating the anti-apoptotic Bcl-2 proteins and enhancing cytochrome c release.	12	22	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	12	13	21	22
DNA breaks occurred within 6 h and levels of Bax mRNA significantly increased within the infarcted hemisphere , indicating a shift in the gene expression ratio of Bcl-2 to Bax .	DNA breaks occurred within 6 h and levels of Bax mRNA significantly increased within the infarcted hemisphere, indicating a shift in the gene expression ratio of Bcl-2 to Bax.	9	28	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	9	10	27	28
Here , we shows that in the cultured human brain microvascular endothelial cells ( HBMEC ) , we found that venlafaxine protects methylglyoxal ( MGO )-induced cell injury , and the venlafaxine significant reduction in the level of reactive oxygen species , down-regulated expression of pro apoptotic activated caspase-3 and Bax , increased BDNF release and expression of anti-apoptotic Bcl-2 in the cultured HBMEC .	Here, we shows that in the cultured human brain microvascular endothelial cells (HBMEC), we found that venlafaxine protects methylglyoxal (MGO)-induced cell injury, and the venlafaxine significant reduction in the level of reactive oxygen species, down-regulated expression of pro apoptotic activated caspase-3 and Bax, increased BDNF release and expression of anti-apoptotic Bcl-2 in the cultured HBMEC.	43	60	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	expression of pro apoptotic activated caspase-3 and Bax	bax	Bcl-2	Bcl-2	bcl-2	50	51	59	60
We found that STIP knockdown in NSCLC cells increased the expression of Bax and decreased that of Bcl-2 , resulting in a significant elevation in the Bcl-2 and Bax ratio .	We found that STIP knockdown in NSCLC cells increased the expression of Bax and decreased that of Bcl-2, resulting in a significant elevation in the Bcl-2 and Bax ratio.	3	18	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	STIP knockdown in NSCLC cells increased the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	12	13	17	18
Therefore , the increased Bax levels and the reduced Bcl2 levels caused high Bax and Bcl2 ratios ( greater than 1 ) in a time dependent manner , indicating DN induced apoptosis via regulation of the Bcl-2 family protein mediated mitochondrial pathway .	Therefore, the increased Bax levels and the reduced Bcl2 levels caused high Bax and Bcl2 ratios (greater than 1) in a time dependent manner, indicating DN induced apoptosis via regulation of the Bcl-2 family protein mediated mitochondrial pathway.	4	16	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax levels	bax	Bcl2	Bcl2	bcl2	4	5	15	16
Even though Bax and Bcl-2 belong to the same family , Bax can not only antagonize the inhibitory effect of Bcl-2 on cell apoptosis , but also directly act on cells to facilitate apoptosis .	Even though Bax and Bcl-2 belong to the same family, Bax can not only antagonize the inhibitory effect of Bcl-2 on cell apoptosis, but also directly act on cells to facilitate apoptosis.	11	28	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	11	12	20	21
The western blot analyses results demonstrated that in cells that expressed stable levels of Siva 1 , the protein levels of cleaved caspase-3 increased 1.96-fold ( P = 0.0016 ) , cleaved caspase-9 increased 2.03-fold ( P = 0.0002 ) , Bax increased 2.02-fold ( P = 0.0005 ) and Bcl-2 decreased by 44 % ( P = 0.0004 ) ( XREF_FIG ) .	The western blot analyses results demonstrated that in cells that expressed stable levels of Siva 1, the protein levels of cleaved caspase-3 increased 1.96-fold (P = 0.0016), cleaved caspase-9 increased 2.03-fold (P = 0.0002), Bax increased 2.02-fold (P = 0.0005) and Bcl-2 decreased by 44% (P = 0.0004) (XREF_FIG).	41	51	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	41	42	50	51
In the upstream , MAA increased the expression of Bax , decreased the expression of Bcl-2 , and augmented the Bax and Bcl -2 ratio .	In the upstream, MAA increased the expression of Bax, decreased the expression of Bcl-2, and augmented the Bax and Bcl -2 ratio.	4	16	decreased	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	Bax	MAA increased the expression of Bax	bax	Bcl-2	expression of Bcl-2	bcl-2	9	10	15	16
The tumor-suppressor molecule p53 can promote mitochondrial damage via its activity as a transcription factor for pro apoptotic proteins like p53 upregulated modulator of apoptosis ( PUMA ) , Phorbol-12-Myristate-13-Acetate-Induced Protein 1 ( PMAIP1 also known as Noxa ) , and Bcl-2 associated X protein ( Bax ) , all of which are involved in mitochondrial outer-membrane permeabilization and apoptosis .	The tumor-suppressor molecule p53 can promote mitochondrial damage via its activity as a transcription factor for pro apoptotic proteins like p53 upregulated modulator of apoptosis (PUMA), Phorbol-12-Myristate-13-Acetate-Induced Protein 1 (PMAIP1 also known as Noxa), and Bcl-2 associated X protein (Bax), all of which are involved in mitochondrial outer-membrane permeabilization and apoptosis.	21	47	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	46	47	41	42
Bax and Bcl-2 genes belong to the same gene family and Bax can both antagonize the inhibitory effect of Bcl-2 on cell apoptosis as well as act directly on the cells to promote tumor cell apoptosis .	Bax and Bcl-2 genes belong to the same gene family and Bax can both antagonize the inhibitory effect of Bcl-2 on cell apoptosis as well as act directly on the cells to promote tumor cell apoptosis.	11	20	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	11	12	19	20
This report suggests that Bax over-expression could accelerate apoptotic cell death by counteracting the ability of Bcl-2 to inhibit apoptosis .	This report suggests that Bax over-expression could accelerate apoptotic cell death by counteracting the ability of Bcl-2 to inhibit apoptosis.	4	17	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax over-expression	bax	Bcl-2	Bcl-2	bcl-2	4	5	16	17
Cell survival is dependent , in part , upon the ratio of Bax , which promotes apoptosis , to Bcl-2 , which protects cells from apoptosis [ XREF_BIBR ] .	Cell survival is dependent, in part, upon the ratio of Bax, which promotes apoptosis, to Bcl-2, which protects cells from apoptosis [XREF_BIBR].	10	22	promotes	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	12	13	19	20
Bax promotes apoptosis by binding to and antagonizing the anti-apoptotic Bcl-2 protein where a substantial decrease of this protein was clearly observed in this study .	Bax promotes apoptosis by binding to and antagonizing the anti-apoptotic Bcl-2 protein where a substantial decrease of this protein was clearly observed in this study.	0	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	10	11
In contrast to Bcl-2 , Bax , which heterodimerises with Bcl-2 to control the level of apoptotic susceptibility , is downregulated in SCLC and upregulated in NSCLC , resulting in a ratio of Bcl-2 : Bax of > 1 in 95 % of SCLC and 25 % of NSCLC prone to resistance to apoptosis [ XREF_BIBR ] .	In contrast to Bcl-2, Bax, which heterodimerises with Bcl-2 to control the level of apoptotic susceptibility, is downregulated in SCLC and upregulated in NSCLC, resulting in a ratio of Bcl-2 : Bax of> 1 in 95% of SCLC and 25% of NSCLC prone to resistance to apoptosis [XREF_BIBR].	5	34	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	5	6	33	34
As expected , decreased levels of Bcl-2 and increased levels of Bax were detected in the HMGB1 shRNA transfected colorectal cancer cells , and the Bax and Bcl -2 ratio was increased in HMGB1 shRNA transfected cells .	As expected, decreased levels of Bcl-2 and increased levels of Bax were detected in the HMGB1 shRNA transfected colorectal cancer cells, and the Bax and Bcl -2 ratio was increased in HMGB1 shRNA transfected cells.	6	12	increased	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Bax	levels of Bax	bax	Bcl-2	Bcl-2	bcl-2	11	12	6	7
The combination of these agents most effectively induced apoptosis in both cell lines by inhibiting Bcl-2 and increasing Bax : Bcl-2 ratio to release mitochondrial pro apoptotic molecules , suppressing anti-apoptotic survival factors such as NF-kappaB , N-Myc , and survivin , and activating extrinsic and intrinsic caspase pathways .	The combination of these agents most effectively induced apoptosis in both cell lines by inhibiting Bcl-2 and increasing Bax : Bcl-2 ratio to release mitochondrial pro apoptotic molecules, suppressing anti-apoptotic survival factors such as NF-kappaB, N-Myc, and survivin, and activating extrinsic and intrinsic caspase pathways.	14	21	increasing	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	18	19	15	16
The results indicate that at 24 h , MXC increased Bcl-xL and Bax mRNA levels and increased the ratio of Bax and Bcl2 .	The results indicate that at 24 h, MXC increased Bcl-xL and Bax mRNA levels and increased the ratio of Bax and Bcl2.	8	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	MXC increased Bcl-xL and Bax mRNA levels	bax	Bcl2	Bcl2	bcl2	12	13	22	23
Therefore , we examined the expression of the Bcl-X and Bax genes , which are known to synergize and antagonize Bcl-2 , respectively .	Therefore, we examined the expression of the Bcl-X and Bax genes, which are known to synergize and antagonize Bcl-2, respectively.	5	21	synergize	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	expression of the Bcl-X and Bax	bax	Bcl-2	Bcl-2	bcl-2	10	11	20	21
It is concluded that CZBG combined with Dox can enhance the apoptosis rate in K562 and A02 cells , down-regulate the expression of BCL-2 and up-regulate the expression of BAX , thereby , can reverse the multidrug resistance of K562 and A02 cells by decreasing the ratio of BCL-2 and BAX .	It is concluded that CZBG combined with Dox can enhance the apoptosis rate in K562 and A02 cells, down-regulate the expression of BCL-2 and up-regulate the expression of BAX, thereby, can reverse the multidrug resistance of K562 and A02 cells by decreasing the ratio of BCL-2 and BAX.	27	50	reverse	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAX	expression of BAX	bax	BCL-2	BCL-2	bcl-2	29	30	48	49
Mechanistically , Bax promotes cell death by directly binding and antagonizing pro survival Bcl-2 [ XREF_BIBR ] , and it also induces apoptosis by itself through its direct channel forming activity in mitochondria and activation of caspase pathway [ XREF_BIBR * , XREF_BIBR * * ] .	Mechanistically, Bax promotes cell death by directly binding and antagonizing pro survival Bcl-2 [XREF_BIBR], and it also induces apoptosis by itself through its direct channel forming activity in mitochondria and activation of caspase pathway [XREF_BIBR *, XREF_BIBR **].	2	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	2	3	13	14
Bax antagonizes the apoptosis inhibitory effect of Bcl-2 gene and directly promotes cell apoptosis by interaction with cells .	Bax antagonizes the apoptosis inhibitory effect of Bcl-2 gene and directly promotes cell apoptosis by interaction with cells.	0	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	7	8
Further study by co-transfection experiments indicated that Bid but not Bax ( both were pro apoptotic proteins of Bcl-2 family ) blocked the inhibitory effect of Bcl-2 on Fas mediated apoptosis .	Further study by co-transfection experiments indicated that Bid but not Bax (both were pro apoptotic proteins of Bcl-2 family) blocked the inhibitory effect of Bcl-2 on Fas mediated apoptosis.	7	27	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	10	11	26	27
On the other hand Bax , a proapototic protein , has been reported to mediate the opposite effect of Bcl2 protein .	On the other hand Bax, a proapototic protein, has been reported to mediate the opposite effect of Bcl2 protein.	4	20	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl2	Bcl2	Bcl2	4	5	19	20
Meanwhile , knockdown of TDP-43 attenuated the expression of the proapoptotic proteins Bax and Cytochrome c , elevated the anti-apoptotic protein Bcl-2 , and suppressed the activation of caspase 3 in H 2 O 2 -induced RGC-5 cells .	Meanwhile, knockdown of TDP-43 attenuated the expression of the proapoptotic proteins Bax and Cytochrome c, elevated the anti-apoptotic protein Bcl-2, and suppressed the activation of caspase 3 in H 2 O 2 -induced RGC-5 cells.	4	22	elevated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	TDP-43 attenuated the expression of the proapoptotic proteins Bax	bax	Bcl-2	Bcl-2	bcl-2	12	13	21	22
BAX promotes apoptosis by binding to and antagonizing the action of BCL-2 protein , resulting in release of cytochrome c and activation of caspases to induce apoptosis .	BAX promotes apoptosis by binding to and antagonizing the action of BCL-2 protein, resulting in release of cytochrome c and activation of caspases to induce apoptosis.	0	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	BAX	BAX	BCL-2	BCL-2	BCL-2	0	1	11	12
Besides , TSN significantly downregulated the expression of Bax and upregulated Bcl-2 ( P < 0.05 ) .	Besides, TSN significantly downregulated the expression of Bax and upregulated Bcl-2 (P < 0.05).	2	13	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	TSN significantly downregulated the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	8	9	11	12
Our results suggest that dysregulated expression of Bcl2 and Bax , which leads to a high Bcl2 and Bax ratio in leukemic cells , contributes to the pathogenesis and clinical course of CLL .	Our results suggest that dysregulated expression of Bcl2 and Bax, which leads to a high Bcl2 and Bax ratio in leukemic cells, contributes to the pathogenesis and clinical course of CLL.	5	22	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Bax	expression of Bcl2 and Bax	bax	Bcl2	Bcl2	bcl2	9	10	16	17
XREF_BIBR However , the apoptosis regulator Bax promotes apoptosis by binding to and antagonizing the Bcl-2 protein .	XREF_BIBR However, the apoptosis regulator Bax promotes apoptosis by binding to and antagonizing the Bcl-2 protein.	4	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	apoptosis regulator Bax	apoptosis regulator Bax	apoptosis regulator Bax	Bcl-2	Bcl-2	Bcl-2	4	7	15	16
Bax is an apoptosis promoter of Bcl-2 family , under the influence of apoptotic stimuli , such as oxidative stress , Bax could cause the release of cytochrome C and stimulate programmed cell death .	Bax is an apoptosis promoter of Bcl-2 family, under the influence of apoptotic stimuli, such as oxidative stress, Bax could cause the release of cytochrome C and stimulate programmed cell death.	6	30	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	21	22	6	7
If the DNA can not be repaired , p53 can induce Bax activation and downregulation of Bcl-2 , causing apoptosis [ XREF_BIBR , XREF_BIBR ] .	If the DNA can not be repaired, p53 can induce Bax activation and downregulation of Bcl-2, causing apoptosis [XREF_BIBR, XREF_BIBR].	11	17	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	11	12	16	17
Moreover , nicorandil significantly inhibited the hypoxia induced changes in Bax and Bcl-2 expression , and concomitant increased Bax and decreased Bcl-2 immunoreactivity in mitochondria .	Moreover, nicorandil significantly inhibited the hypoxia induced changes in Bax and Bcl-2 expression, and concomitant increased Bax and decreased Bcl-2 immunoreactivity in mitochondria.	2	22	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	nicorandil significantly inhibited the hypoxia induced changes in Bax and Bcl-2 expression	bax	Bcl-2	Bcl-2	bcl-2	10	11	21	22
As an anti-apoptotic effector , Bcl-2 could form a two-polymer with Bax to inhibit apoptosis , while Bax could increase the effect of Bcl-2 to promote apoptosis .	As an anti-apoptotic effector, Bcl-2 could form a two-polymer with Bax to inhibit apoptosis, while Bax could increase the effect of Bcl-2 to promote apoptosis.	17	24	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	17	18	23	24
A possible hypothesis is that the action of WT1 on the BAX promoter down regulates BAX gene expression , thereby allowing BCL-2 to repress apoptosis .	A possible hypothesis is that the action of WT1 on the BAX promoter down regulates BAX gene expression, thereby allowing BCL-2 to repress apoptosis.	15	23	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	BAX gene expression	bax	BCL-2	BCL-2	bcl-2	15	16	21	22
In concert with these findings , Western blot analysis showed a decreased expression of bcl-2 and increased levels of Bax and caspase-3 in C6 cells treated by panaxydol .	In concert with these findings, Western blot analysis showed a decreased expression of bcl-2 and increased levels of Bax and caspase-3 in C6 cells treated by panaxydol.	14	21	increased	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Bax	levels of Bax	bax	bcl-2	bcl-2	bcl-2	19	20	14	15
It has been implicated in activation of the intrinsic apoptosis pathway by shifting the balance of the multifunctional B-cell lymphoma-2 ( Bcl-2 ) family away from Bcl-2 survival signaling towards induction of proapoptotic factors such as Bax and PUMA ( p53 upregulated modulator of apoptosis ) , which contribute to caspase cascade activation .	It has been implicated in activation of the intrinsic apoptosis pathway by shifting the balance of the multifunctional B-cell lymphoma-2 (Bcl-2) family away from Bcl-2 survival signaling towards induction of proapoptotic factors such as Bax and PUMA (p53 upregulated modulator of apoptosis), which contribute to caspase cascade activation.	26	38	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	36	37	26	27
PTHrP downregulated expression of proapoptotic Bax and PUMA and upregulated antiapoptotic Bcl-2 and Bcl-xl .	PTHrP downregulated expression of proapoptotic Bax and PUMA and upregulated antiapoptotic Bcl-2 and Bcl-xl.	0	13	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	PTHrP downregulated expression of proapoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	5	6	11	12
In addition to reactive oxygen species scavenging activity in Dex induced splenocytes , BA administration up-regulated antioxidant enzymes , decreased lipid peroxidation , restored mitochondrial function , decreased the expression of pro apoptotic protein Bax , prevented the decline of anti-apoptotic protein Bcl-2 , inhibited caspase-9 and caspase-3 activation , and improved cell survival .	In addition to reactive oxygen species scavenging activity in Dex induced splenocytes, BA administration up-regulated antioxidant enzymes, decreased lipid peroxidation, restored mitochondrial function, decreased the expression of pro apoptotic protein Bax, prevented the decline of anti-apoptotic protein Bcl-2, inhibited caspase-9 and caspase-3 activation, and improved cell survival.	13	43	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	BA administration up-regulated antioxidant enzymes, decreased lipid peroxidation, restored mitochondrial function, decreased the expression of pro apoptotic protein Bax	bax	Bcl-2	Bcl-2	bcl-2	34	35	42	43
A surexpression of bax in several cell lines allows to counteract the effect of bcl-2 .	A surexpression of bax in several cell lines allows to counteract the effect of bcl-2.	1	15	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bax	surexpression of bax	bax	bcl-2	bcl-2	bcl-2	3	4	14	15
We observed that TQ inhibited tumor cell growth in vitro , where treatment with TQ arrested the cell cycle in G1 by upregulating p21 and downregulating cyclinD1 and CDK2 expression ; moreover , TQ induced apoptosis by decreasing expression of Bcl-2 and increasing expression of Bax .	We observed that TQ inhibited tumor cell growth in vitro, where treatment with TQ arrested the cell cycle in G1 by upregulating p21 and downregulating cyclinD1 and CDK2 expression; moreover, TQ induced apoptosis by decreasing expression of Bcl-2 and increasing expression of Bax.	40	46	increasing	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Bax	expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	45	46	40	41
Consistent with this effect , alpha-mangostin also attenuated high-glucose induced up-regulation of both cleaved caspase-3 and Bax ( proapoptotic proteins ) and high-glucose induced down-regulation of Bcl-2 ( an anti-apoptotic protein ) .	Consistent with this effect, alpha-mangostin also attenuated high-glucose induced up-regulation of both cleaved caspase-3 and Bax (proapoptotic proteins) and high-glucose induced down-regulation of Bcl-2 (an anti-apoptotic protein).	10	30	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	16	17	26	27
XREF_BIBR , XREF_BIBR , XREF_BIBR Herein , AT-MNPs downregulated Bcl2- and BclXL expression levels , whereas Bax and Bad were significantly upregulated , increasing the ratio of Bax : Bcl2 and thus contributing to apoptosis , which was in line with TUNEL and flow cytometry results in NSCLC cells .	XREF_BIBR, XREF_BIBR, XREF_BIBR Herein, AT-MNPs downregulated Bcl2- and BclXL expression levels, whereas Bax and Bad were significantly upregulated, increasing the ratio of Bax : Bcl2 and thus contributing to apoptosis, which was in line with TUNEL and flow cytometry results in NSCLC cells.	16	30	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl2	Bcl2	Bcl2	16	17	29	30
Unexpectedly , treatment with erlotinib did not reduce the Bax mRNA expression , erlotinib suppressed Bax protein up-regulation and reversed Bcl-2 mRNA and protein down-regulation in the kidney tissue of CP-N rats .	Unexpectedly, treatment with erlotinib did not reduce the Bax mRNA expression, erlotinib suppressed Bax protein up-regulation and reversed Bcl-2 mRNA and protein down-regulation in the kidney tissue of CP-N rats.	9	21	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	Bax mRNA expression, erlotinib suppressed	bax	Bcl-2	Bcl-2	bcl-2	9	10	20	21
Furthermore , farnesol treatment reduced the expression of Bax and antagonized LPS induced decrease in anti-apoptotic Bcl-2 .	Furthermore, farnesol treatment reduced the expression of Bax and antagonized LPS induced decrease in anti-apoptotic Bcl-2.	2	17	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	farnesol treatment reduced the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	8	9	16	17
H/R treatment dramatically reduced Bcl-2 and Bcl-XL , increased Bax and Bak expression and decreased the ratio of Bcl-2 and Bax .	H/R treatment dramatically reduced Bcl-2 and Bcl-XL, increased Bax and Bak expression and decreased the ratio of Bcl-2 and Bax.	0	20	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	H/R treatment dramatically reduced Bcl-2 and Bcl-XL, increased Bax and Bak expression	bax	Bcl-2	Bcl-2	bcl-2	9	10	18	19
The results revealed that knockdown of TRIM24 increased the protein levels of p53 , Bax , and Caspase-8 , and decreased Bcl-2 and Survivin ( XREF_FIG ) .	The results revealed that knockdown of TRIM24 increased the protein levels of p53, Bax, and Caspase-8, and decreased Bcl-2 and Survivin (XREF_FIG).	6	25	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	TRIM24 increased the protein levels of p53, Bax	bax	Bcl-2	Bcl-2	bcl-2	14	15	21	22
Together , these cell-free and cell based studies demonstrate that NuBCP-9 induces Bax activation in a Bcl-2 dependent manner and that the loop and BH3 regions of Bcl-2 are crucial .	Together, these cell-free and cell based studies demonstrate that NuBCP-9 induces Bax activation in a Bcl-2 dependent manner and that the loop and BH3 regions of Bcl-2 are crucial.	12	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	12	13	16	17
Several years earlier , van Delft et al demonstrated that 6 putative mimetics killed BAX and BAK deficient mouse embryonic fibroblasts ( MEF ) implying they were not directly targeting BCL2 proteins .	Several years earlier, van Delft et al demonstrated that 6 putative mimetics killed BAX and BAK deficient mouse embryonic fibroblasts (MEF) implying they were not directly targeting BCL2 proteins.	14	31	targeting	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	BAX	BAX	BAX	BCL2	BCL2	BCL2	14	15	30	31
Moreover , western blotting analysis revealed that knockdown of TRIM24 increased the protein levels of p53 , Bax , and Caspase-8 , and decreased Bcl-2 , Survivin , Cyclin D1 , and CDK4 .	Moreover, western blotting analysis revealed that knockdown of TRIM24 increased the protein levels of p53, Bax, and Caspase-8, and decreased Bcl-2, Survivin, Cyclin D1, and CDK4.	9	32	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	TRIM24 increased the protein levels of p53, Bax	bax	Bcl-2	Bcl-2	bcl-2	17	18	24	25
In addition , naringenin induced loss of mitochondrial membrane potential and increased Bax and decreased Bcl-2 proteins in PC3 cells , but not LNCaP cells .	In addition, naringenin induced loss of mitochondrial membrane potential and increased Bax and decreased Bcl-2 proteins in PC3 cells, but not LNCaP cells.	3	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	naringenin induced loss of mitochondrial membrane potential and increased Bax	bax	Bcl-2	Bcl-2	bcl-2	12	13	15	16
MiR-132 overexpression significantly down-regulated the expressions of Bax , cytochrome c , and caspase-9 , but up-regulated BCl-2 .	MiR-132 overexpression significantly down-regulated the expressions of Bax, cytochrome c, and caspase-9, but up-regulated BCl-2.	0	18	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	MiR-132 overexpression significantly down-regulated the expressions of Bax	bax	BCl-2	BCl-2	bcl-2	7	8	17	18
Increased level of Bax leads to the combination of Bcl-2 , low concentration of Bcl-2 in the cell , and activation of cell apoptosis [ XREF_BIBR ] .	Increased level of Bax leads to the combination of Bcl-2, low concentration of Bcl-2 in the cell, and activation of cell apoptosis [XREF_BIBR].	1	10	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Bax	level of Bax	bax	Bcl-2	Bcl-2	bcl-2	3	4	9	10
In vitro studies showed that treatment of triple negative breast cancer ( TNBC ) MDA-MB-231 cells with Se-PFPs ( 1 ) inhibited cell growth dose-dependently by arresting cells at G2 phase via inhibiting CDC25C-CyclinB1 and CDC2 pathway ; ( 2 ) caused apoptosis associated with increased p53 , Bax , Puma and Noxa , decreased Bcl2 , increased Bax and Bcl2 ratio and increased activities of caspases 3/9 , suggesting its effect on p53 mediated cytochrome c-caspase pathway .	In vitro studies showed that treatment of triple negative breast cancer (TNBC) MDA-MB-231 cells with Se-PFPs (1) inhibited cell growth dose-dependently by arresting cells at G2 phase via inhibiting CDC25C-CyclinB1 and CDC2 pathway; (2) caused apoptosis associated with increased p53, Bax, Puma and Noxa, decreased Bcl2, increased Bax and Bcl2 ratio and increased activities of caspases 3/9, suggesting its effect on p53 mediated cytochrome c-caspase pathway.	48	63	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl2	Bcl2	Bcl2	48	49	60	61
SP600125 , a specific inhibitor of JNK MAPK , markedly promoted the expression of Bax and inhibited the Bcl-2 and Bax ratio .	SP600125, a specific inhibitor of JNK MAPK, markedly promoted the expression of Bax and inhibited the Bcl-2 and Bax ratio.	0	21	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	SP600125, a specific inhibitor of JNK MAPK, markedly promoted the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	14	15	18	19
Together , these data establish that Bax and Bak do not mediate the effects of Bcl-2 or Bcl-x L in beta-cell function and further distinguish the physiological effects of Bcl inhibition from Bax and Bak dependent apoptotic events .	Together, these data establish that Bax and Bak do not mediate the effects of Bcl-2 or Bcl-x L in beta-cell function and further distinguish the physiological effects of Bcl inhibition from Bax and Bak dependent apoptotic events.	6	18	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	6	7	15	16
Studies have shown Bax , Bad , Bak promote the release of cytochrome c , while bcl-2 and Bcl-X L delays this response and promote cell survival .	Studies have shown Bax, Bad, Bak promote the release of cytochrome c, while bcl-2 and Bcl-X L delays this response and promote cell survival.	3	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	bcl-2	bcl-2	bcl-2	3	4	16	17
The results indicated that , on the one hand , YAP promoted cell growth and invasion but LATS1 reduced them not only by decreasing YAP , CTGF , PCNA , MMP-2 , MMP-9 , CyclinD1 , Bcl-2 and increasing Bax and p-YAP expression , but also through inhibiting nuclear transfer of YAP .	The results indicated that, on the one hand, YAP promoted cell growth and invasion but LATS1 reduced them not only by decreasing YAP, CTGF, PCNA, MMP-2, MMP-9, CyclinD1, Bcl-2 and increasing Bax and p-YAP expression, but also through inhibiting nuclear transfer of YAP.	23	40	increasing	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	39	40	36	37
The present study revealed that MVA treatment upregulated the expression of Bcl-2 , while downregulating the expression of Bax , which increased the Bcl-2 and Bax ratio and inhibited HMC apoptosis .	The present study revealed that MVA treatment upregulated the expression of Bcl-2, while downregulating the expression of Bax, which increased the Bcl-2 and Bax ratio and inhibited HMC apoptosis.	16	28	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	18	19	23	24
Ido1 can prevent uterine stromal cells proliferation and enhance the expression of the Bax gene and increase the Bax and Bcl2 ratio under in vitro decidualization .	Ido1 can prevent uterine stromal cells proliferation and enhance the expression of the Bax gene and increase the Bax and Bcl2 ratio under in vitro decidualization.	0	21	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Ido1 can prevent uterine stromal cells proliferation and enhance the expression of the Bax	bax	Bcl2	Bcl2	bcl2	13	14	20	21
Bax promotes apoptosis by binding to and antagonizing the Bcl-2 protein XREF_BIBR .	Bax promotes apoptosis by binding to and antagonizing the Bcl-2 protein XREF_BIBR.	0	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	9	10
Cap pretreatment significantly attenuated generation of reactive oxygen species , inhibited mPTP opening and caspase-3 activation , downregulated Bax , upregulated 14-3-3eta and Bcl-2 , and ultimately reduced apoptosis in H9c2 cells that underwent A/R .	Cap pretreatment significantly attenuated generation of reactive oxygen species, inhibited mPTP opening and caspase-3 activation, downregulated Bax, upregulated 14-3-3eta and Bcl-2, and ultimately reduced apoptosis in H9c2 cells that underwent A/R.	17	24	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	18	19	23	24
MiR-503 and miR-497 target the anti-apoptotic Bcl-2 gene to reverse CDDP resistance XREF_BIBR - XREF_BIBR , and conversely miR-21 decreases expression of anti-apoptotic Bax and increases pro apoptotic Bcl-2 resulting in re-acquiring CDDP sensitivity XREF_BIBR .	MiR-503 and miR-497 target the anti-apoptotic Bcl-2 gene to reverse CDDP resistance XREF_BIBR - XREF_BIBR, and conversely miR-21 decreases expression of anti-apoptotic Bax and increases pro apoptotic Bcl-2 resulting in re-acquiring CDDP sensitivity XREF_BIBR.	18	29	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	miR-21 decreases expression of anti-apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	23	24	28	29
XREF_BIBR - XREF_BIBR Previous studies have also demonstrated that PF ( 10 mg/kg ) reduced infarct size in ischemia and reperfusion injury rat , improved the hemodynamic parameters , decreased Caspase-3 and Bax expressions , but upregulated Bcl-2 in the left ventricles ( LVs ) .	XREF_BIBR - XREF_BIBR Previous studies have also demonstrated that PF (10 mg/kg) reduced infarct size in ischemia and reperfusion injury rat, improved the hemodynamic parameters, decreased Caspase-3 and Bax expressions, but upregulated Bcl-2 in the left ventricles (LVs).	9	38	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	PF (10 mg/kg) reduced infarct size in ischemia and reperfusion injury rat, improved the hemodynamic parameters, decreased Caspase-3 and Bax expressions	bax	Bcl-2	Bcl-2	bcl-2	32	33	37	38
The highest dose significantly decreased the apoptotic protein Bax and all doses stimulated anti-apoptotic Bcl-2 after 4 weeks of treatment .	The highest dose significantly decreased the apoptotic protein Bax and all doses stimulated anti-apoptotic Bcl-2 after 4 weeks of treatment.	5	15	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	8	9	14	15
Protein kinase C ( PKC ) phosphorylates BCL2 protein and BAX modulates BCL2 dimerization .	Protein kinase C (PKC) phosphorylates BCL2 protein and BAX modulates BCL2 dimerization.	8	13	modulates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	BAX	BAX	BAX	BCL2	BCL2	BCL2	10	11	12	13
IL-7 prolongs T cell survival through induction of the anti-apoptotic factors Bcl-2 and Bcl-xL as well as inhibition of the pro apoptotic factors Bad and Bax XREF_BIBR .	IL-7 prolongs T cell survival through induction of the anti-apoptotic factors Bcl-2 and Bcl-xL as well as inhibition of the pro apoptotic factors Bad and Bax XREF_BIBR.	6	26	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	25	26	11	12
Bcl-2 is capable of inhibiting apoptosis , while BAX promotes cell death by countering the effect of BCL-2 .	Bcl-2 is capable of inhibiting apoptosis, while BAX promotes cell death by countering the effect of BCL-2.	8	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	BAX	BAX	BCL-2	BCL-2	BCL-2	8	9	17	18
Ultimately , our findings confirmed that resveratrol caused overexpression of BAX , decreased the expression of BCL2 , and induced apoptosis in dose- and time dependent manners via regulation of anti-apoptotic and pro apoptotic proteins of the BCL-2 family .	Ultimately, our findings confirmed that resveratrol caused overexpression of BAX, decreased the expression of BCL2, and induced apoptosis in dose- and time dependent manners via regulation of anti-apoptotic and pro apoptotic proteins of the BCL-2 family.	6	38	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	resveratrol caused overexpression of BAX	bax	BCL-2	BCL-2	bcl-2	10	11	37	38
The E3 ligase parkin , which is known to trigger mitochondria specific autophagy , ubiquitylates BAX K128 and targets the pro apoptotic BCL-2 protein for proteasomal degradation .	The E3 ligase parkin, which is known to trigger mitochondria specific autophagy, ubiquitylates BAX K128 and targets the pro apoptotic BCL-2 protein for proteasomal degradation.	3	23	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	parkin, which is known to trigger mitochondria specific autophagy, ubiquitylates BAX K128	bax	BCL-2	BCL-2	bcl-2	15	16	22	23
BH3-only proteins are firstly upregulated or activated by cytotoxic injury during the mitochondrial pathway , and subsequently activate and oligomerize Bax , which leads the oligomerized Bcl-2 family members , Bax and Bak , to induce the release of cytochrome c from the mitochondria into the cytosol .	BH3-only proteins are firstly upregulated or activated by cytotoxic injury during the mitochondrial pathway, and subsequently activate and oligomerize Bax, which leads the oligomerized Bcl-2 family members, Bax and Bak, to induce the release of cytochrome c from the mitochondria into the cytosol.	17	28	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	20	21	26	27
BAX ( Bcl-2-associated X protein ) , a member of the BCL-2 protein family , promotes cell apoptosis by binding to and antagonizing the BCL-2 protein .	BAX (Bcl-2-associated X protein), a member of the BCL-2 protein family, promotes cell apoptosis by binding to and antagonizing the BCL-2 protein.	0	25	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	BAX	BAX	BCL-2	BCL-2	BCL-2	0	1	24	25
Western blot analysis was performed to examine the levels of p53 upregulated modulator of apoptosis ( PUMA ) , BCL2 , apoptosis regulator ( Bcl-2 ) and BCL2 associated X , apoptosis regulator ( Bax ) in A549 cells .	Western blot analysis was performed to examine the levels of p53 upregulated modulator of apoptosis (PUMA), BCL2, apoptosis regulator (Bcl-2) and BCL2 associated X, apoptosis regulator (Bax) in A549 cells.	11	35	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	BCL2	BCL2	BCL2	34	35	27	28
Furthermore , LY-15 effectively inhibited the B16 cell migration , increased the expressions levels of caspase-3 , caspase-9 and the pro apoptotic Bax , and reduced that of the anti-apoptotic Bcl-2 .	Furthermore, LY-15 effectively inhibited the B16 cell migration, increased the expressions levels of caspase-3, caspase-9 and the pro apoptotic Bax, and reduced that of the anti-apoptotic Bcl-2.	2	31	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	LY-15 effectively inhibited the B16 cell migration, increased the expressions levels of caspase-3, caspase-9 and the pro apoptotic Bax	bax	Bcl-2	Bcl-2	bcl-2	22	23	30	31
Overexpression of Bax promotes cell death ; conversely , Bcl-2 functions as a suppressor of apoptosis .	Overexpression of Bax promotes cell death; conversely, Bcl-2 functions as a suppressor of apoptosis.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Overexpression of Bax	bax	Bcl-2	Bcl-2	bcl-2	2	3	9	10
The results from total kidney homogenates support those from the immunohistology , namely , Bax increases in transplanted kidneys and Bcl-2 in the PARP inhibitor treated transplanted kidneys ( XREF_FIG ) .	The results from total kidney homogenates support those from the immunohistology, namely, Bax increases in transplanted kidneys and Bcl-2 in the PARP inhibitor treated transplanted kidneys (XREF_FIG).	14	21	increases	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	14	15	20	21
Furthermore , we also analyzed the mRNA expression of caspase-3 in the neuronal tissues of rats and the protein expressions of Bax and Bcl-2 in PC12 cells , our results show that Abeta 25-35 significantly increased the expression of caspase-3 in the brain tissues of the AD rats compared to that of the control rats , while LSS significantly reduced the expressions of caspase-3 mRNA and Bax protein , meantime , increased the protein expression of Bcl-2 and the ratio of Bcl-2 and Bax .	Furthermore, we also analyzed the mRNA expression of caspase-3 in the neuronal tissues of rats and the protein expressions of Bax and Bcl-2 in PC12 cells, our results show that Abeta 25-35 significantly increased the expression of caspase-3 in the brain tissues of the AD rats compared to that of the control rats, while LSS significantly reduced the expressions of caspase-3 mRNA and Bax protein, meantime, increased the protein expression of Bcl-2 and the ratio of Bcl-2 and Bax.	61	77	increased	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Bax	expressions of caspase-3 mRNA and Bax	bax	Bcl-2	expression of Bcl-2	bcl-2	66	67	76	77
Western blot analysis indicated that BMF silencing markedly increased the expression of Bax , caspase-3 and p27 , and decreased that of Bcl-2 in ESCC cells ( XREF_FIG ) .	Western blot analysis indicated that BMF silencing markedly increased the expression of Bax, caspase-3 and p27, and decreased that of Bcl-2 in ESCC cells (XREF_FIG).	5	23	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bax	BMF silencing markedly increased the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	12	13	22	23
Furthermore , active Bax also elicited the Bcl-2 conformational alteration .	Furthermore, active Bax also elicited the Bcl-2 conformational alteration.	2	9	elicited	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	3	4	7	8
Irisin administration significantly downregulated the Bax and caspase-3 expression and upregulated the Bcl-2 protein .	Irisin administration significantly downregulated the Bax and caspase-3 expression and upregulated the Bcl-2 protein.	0	13	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Irisin administration significantly downregulated the Bax and caspase-3 expression	bax	Bcl-2	Bcl-2	bcl-2	5	6	12	13
In addition to beta-catenin , we also examined the role of pro survival protein Bax , a key anti-survival factor , can promote apoptosis by binding to and antagonizing pro survival Bcl-2 proteins such as Bcl-2 or Bcl-xL [ XREF_BIBR ] .	In addition to beta-catenin, we also examined the role of pro survival protein Bax, a key anti-survival factor, can promote apoptosis by binding to and antagonizing pro survival Bcl-2 proteins such as Bcl-2 or Bcl-xL [XREF_BIBR].	9	32	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	14	15	31	32
Upon formation of this protein protein complex , Bax also prevented the binding of antimycin A 2 ( a known inhibitory ligand of Bcl-2 ) to the Bcl-2 protein , as fluorescence spectroscopy experiments showed .	Upon formation of this protein protein complex, Bax also prevented the binding of antimycin A 2 (a known inhibitory ligand of Bcl-2) to the Bcl-2 protein, as fluorescence spectroscopy experiments showed.	8	24	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	8	9	23	24
[ XREF_BIBR XREF_BIBR ] Furthermore , several studies have reported a reduction of apoptosis by H/R via altering the expression of Bcl-2 and/or Bax protein , thus increasing the ratio of Bcl-2 and Bax protein prevents the progression of apoptosis in myocardium after HR .	[XREF_BIBR XREF_BIBR] Furthermore, several studies have reported a reduction of apoptosis by H/R via altering the expression of Bcl-2 and/or Bax protein, thus increasing the ratio of Bcl-2 and Bax protein prevents the progression of apoptosis in myocardium after HR.	23	34	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	23	24	31	32
Further , proapoptotic BAX was upregulated as well as anti-apoptotic proteins Bcl-2 , Bcl-xL and Mcl-1 were downregulated in MDA-MB-231 and MCF-7 cells treated with Iturin A in time dependent manner .	Further, proapoptotic BAX was upregulated as well as anti-apoptotic proteins Bcl-2, Bcl-xL and Mcl-1 were downregulated in MDA-MB-231 and MCF-7 cells treated with Iturin A in time dependent manner.	2	15	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	BAX	BAX	Bcl-2	Bcl-2	Bcl-2	3	4	11	12
Pro apoptotic gene , Bax was up-regulated and down-regulation of the Bcl-2 and Bax ratio , suggesting that Bcl-2 family involved in the control of apoptosis .	Pro apoptotic gene, Bax was up-regulated and down-regulation of the Bcl-2 and Bax ratio, suggesting that Bcl-2 family involved in the control of apoptosis.	4	14	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	4	5	11	12
Explicitly , HG medium increases Bax expression , but does not modulate Bcl-2 .	Explicitly, HG medium increases Bax expression, but does not modulate Bcl-2.	2	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	HG medium increases Bax expression	bax	Bcl-2	Bcl-2	bcl-2	5	6	12	13
Data on Bcl-2 and Bax were supported by immunofluorescence for Bcl-2 and activated Bax .	Data on Bcl-2 and Bax were supported by immunofluorescence for Bcl-2 and activated Bax.	8	14	activated	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	13	14	10	11
We also found that MXC increases Bax ( 48 and 96 h ) , increases Bcl2 ( 96 h ) , and decreases Bax and Bcl2 ratios ( 96 h ) at later time points .	We also found that MXC increases Bax (48 and 96 h), increases Bcl2 (96 h), and decreases Bax and Bcl2 ratios (96 h) at later time points.	4	22	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl2	Bcl2	Bcl2	6	7	15	16
Bax promotes apoptosis by binding to and antagonizing the Bcl-2 protein ( Kumar et al ., 2013 ) .	Bax promotes apoptosis by binding to and antagonizing the Bcl-2 protein (Kumar et al., 2013).	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	9	10
The deregulation of crypt cellular proliferation in the colon of the AOM injected rats was associated with ( Bcl-2 and Bax > 1 ) , while the upregulation of Bax in A. ilicifolius treatment groups caused a change in the Bcl-2 and Bax ratio value which was reserved to ( Bcl-2 and Bax < 1 ) ( XREF_FIG ) .	The deregulation of crypt cellular proliferation in the colon of the AOM injected rats was associated with (Bcl-2 and Bax> 1), while the upregulation of Bax in A. ilicifolius treatment groups caused a change in the Bcl-2 and Bax ratio value which was reserved to (Bcl-2 and Bax < 1) (XREF_FIG).	27	57	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	29	30	40	41
MOMP is induced by pro apoptotic Bcl-2 family members , Bax and Bak , and inhibited by anti-apoptotic members Bcl-2 , Bcl-xL and Mcl-1 .	MOMP is induced by pro apoptotic Bcl-2 family members, Bax and Bak, and inhibited by anti-apoptotic members Bcl-2, Bcl-xL and Mcl-1.	2	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	10	11	19	20
Compelling evidences have been demonstrated that Bax is the activator of caspase-3 and Bcl-2 is the inhibitor of caspase-3 .	Compelling evidences have been demonstrated that Bax is the activator of caspase-3 and Bcl-2 is the inhibitor of caspase-3.	6	14	is the activator	Positive_activation_copula_1	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	6	7	13	14
The apoptosis regulator BAX promotes apoptosis by binding to and antagonizing the Bcl-2 protein .	The apoptosis regulator BAX promotes apoptosis by binding to and antagonizing the Bcl-2 protein.	1	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	apoptosis regulator BAX	apoptosis regulator BAX	apoptosis regulator BAX	Bcl-2	Bcl-2	Bcl-2	1	4	12	13
It was found that there was increased BcL2 but decreased BAX transcript abundance .	It was found that there was increased BcL2 but decreased BAX transcript abundance.	6	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAX	BAX	BAX	BcL2	BcL2	BcL2	10	11	7	8
Apoptosis is regulated , among others , by the Bax and Bcl2 ratio [ XREF_BIBR , XREF_BIBR ] , where Bax promotes apoptosis by binding to and antagonizing the anti-apoptotic Bcl-2 protein .	Apoptosis is regulated, among others, by the Bax and Bcl2 ratio [XREF_BIBR, XREF_BIBR], where Bax promotes apoptosis by binding to and antagonizing the anti-apoptotic Bcl-2 protein.	20	31	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	20	21	30	31
Our study revealed that rAGAP upregulated the expression of Bax and caused simultaneous downregulation of Bcl-2 , thereby decreasing the Bcl-2 and Bax ratio .	Our study revealed that rAGAP upregulated the expression of Bax and caused simultaneous downregulation of Bcl-2, thereby decreasing the Bcl-2 and Bax ratio.	4	16	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	rAGAP upregulated the expression of Bax	bax	Bcl-2	Bcl-2	bcl-2	9	10	15	16
Bax , not only antagonizes the inhibitory effects of Bcl-2 on cell apoptosis , but also directly promotes tumor cell apoptosis .	Bax, not only antagonizes the inhibitory effects of Bcl-2 on cell apoptosis, but also directly promotes tumor cell apoptosis.	0	17	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	Bax	Bax	Bcl-2	Bcl-2	Bcl-2	0	1	9	10
Downregulation of Bcl-2 and the overexpression of Bax by QUE-NL supported the involvement of Bcl-2 family proteins upstream of C6 glioma cell death .	Downregulation of Bcl-2 and the overexpression of Bax by QUE-NL supported the involvement of Bcl-2 family proteins upstream of C6 glioma cell death.	5	16	supported	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bax	overexpression of Bax	bax	Bcl-2	Bcl-2	bcl-2	7	8	14	15
BAK is activated by a subclass of proapoptotic BCL-2 proteins which share an amphipathic alpha helical BH3 domain ( BH3-only proteins ) XREF_BIBR , XREF_BIBR .	BAK is activated by a subclass of proapoptotic BCL-2 proteins which share an amphipathic alpha helical BH3 domain (BH3-only proteins) XREF_BIBR, XREF_BIBR.	0	9	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAK	BAK	BAK	8	9	0	1
The BCL-2 homology ( BH ) 3-only protein BID activates BAK to perform this function .	The BCL-2 homology (BH) 3-only protein BID activates BAK to perform this function.	1	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAK	BAK	BAK	1	2	10	11
Melphalan induced caspase-8 activation , however , did not lead to Bid cleavage , indicating that Bak activation in response to melphalan was mediated by a different Bcl-2 family protein ( s ) .	Melphalan induced caspase-8 activation, however, did not lead to Bid cleavage, indicating that Bak activation in response to melphalan was mediated by a different Bcl-2 family protein (s).	16	29	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	27	28	16	17
Since 2DG also sensitizes cancer cells to Bcl-2 antagonists such as ABT , addition of a Bcl-2 antagonist to 2DG treated cells mechanically activates Bak , circumventing the usual signal transduction cascades required for Bak activation .	Since 2DG also sensitizes cancer cells to Bcl-2 antagonists such as ABT, addition of a Bcl-2 antagonist to 2DG treated cells mechanically activates Bak, circumventing the usual signal transduction cascades required for Bak activation.	16	31	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	16	17	24	25
P53 antagonizes the antiapoptotic activities of Bcl-2 , Bcl-xl and Mcl-1 thus , allowing proapoptoticBax , Bak and Bid to trigger apoptosis [ XREF_BIBR , XREF_BIBR ] .	P53 antagonizes the antiapoptotic activities of Bcl-2, Bcl-xl and Mcl-1 thus, allowing proapoptoticBax, Bak and Bid to trigger apoptosis [XREF_BIBR, XREF_BIBR].	1	20	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	6	7	16	17
Therefore , in MODE 1 repression ( sequestration of the direct activator ) BAK remains inactive while in MODE 2 repression , BAK is activated and sequestered by anti-apoptotic BCL-2 proteins ( XREF_FIG ) .	Therefore, in MODE 1 repression (sequestration of the direct activator) BAK remains inactive while in MODE 2 repression, BAK is activated and sequestered by anti-apoptotic BCL-2 proteins (XREF_FIG).	22	30	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BAK	BAK	BAK	29	30	22	23
In addition , Bcl-2 has been shown to activate Bak to induce C16 ceramide accumulation [ XREF_BIBR , XREF_BIBR ] .	In addition, Bcl-2 has been shown to activate Bak to induce C16 ceramide accumulation [XREF_BIBR, XREF_BIBR].	3	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Bak	Bak	Bak	3	4	9	10
Genetic evidence that Bid is required for Bak and Bax dependent apoptosis caused by Bcl-xL deficiency and biochemical evidence that full-length Bid is inactive for displacing Bak or Bax from Bcl-xL together suggest that tBid is produced in wild-type liver .	Genetic evidence that Bid is required for Bak and Bax dependent apoptosis caused by Bcl-xL deficiency and biochemical evidence that full-length Bid is inactive for displacing Bak or Bax from Bcl-xL together suggest that tBid is produced in wild-type liver.	7	15	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	14	15	9	10
On the other hand , the indirect model would suggest that the inactivation of Mcl-1 and Bcl-xL by Noxa may cause these two proteins to release Bax or Bak , allowing homo-oligomerization and activation of Bax and Bak , which would subsequently damage the mitochondria XREF_BIBR , XREF_BIBR .	On the other hand, the indirect model would suggest that the inactivation of Mcl-1 and Bcl-xL by Noxa may cause these two proteins to release Bax or Bak, allowing homo-oligomerization and activation of Bax and Bak, which would subsequently damage the mitochondria XREF_BIBR, XREF_BIBR.	12	28	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	16	17	26	27
Unlike wild-type DJ-1 , DJ-1 ( L166P ) fails to stabilize Bcl-X L , but it dissociates Bax from Bcl-X L that leading Bax enrichment in outer mitochondrial membrane and subsequently triggers cell death in response to UV irradiation .	Unlike wild-type DJ-1, DJ-1 (L166P) fails to stabilize Bcl-X L, but it dissociates Bax from Bcl-X L that leading Bax enrichment in outer mitochondrial membrane and subsequently triggers cell death in response to UV irradiation.	19	24	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-X L	Bcl-X L	Bcl-X L	Bax	Bax	Bax	19	21	23	24
How might this view of Bcl-xL function jibe with the long-held view that Bcl-xL directly suppresses apoptosis by inhibiting Bax and Bak mediated cytochrome c release ?	How might this view of Bcl-xL function jibe with the long-held view that Bcl-xL directly suppresses apoptosis by inhibiting Bax and Bak mediated cytochrome c release?	13	20	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	13	14	19	20
Ceramide has been shown to regulate Bcl-x alternative splicing to decrease Bcl-xL level [ XREF_BIBR ] , and to mediate Bak and Bax function in the intrinsic apoptosis pathway [ XREF_BIBR - XREF_BIBR ] .	Ceramide has been shown to regulate Bcl-x alternative splicing to decrease Bcl-xL level [XREF_BIBR], and to mediate Bak and Bax function in the intrinsic apoptosis pathway [XREF_BIBR - XREF_BIBR].	6	23	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-x	Bcl-x alternative splicing to decrease Bcl-xL level	bcl-x	Bax	Bax	bax	6	7	22	23
Most importantly , our data show that Bcl-xL promotes the dissociation of Bax from the membrane in the absence of any additional component .	Most importantly, our data show that Bcl-xL promotes the dissociation of Bax from the membrane in the absence of any additional component.	7	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	7	8	12	13
Treatment of JN-DSRCT-1 cells with MG-132 , a proteasome specific inhibitor , also resulted in the induction of apoptosis through a similar increase in the Bax : Bcl-xL ratio specifically caused by inhibiting Bax degradation and turnover .	Treatment of JN-DSRCT-1 cells with MG-132, a proteasome specific inhibitor, also resulted in the induction of apoptosis through a similar increase in the Bax : Bcl-xL ratio specifically caused by inhibiting Bax degradation and turnover.	27	34	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	27	28	33	34
WhenBcl-xL tot = 2.4 x 10 5 ( with Bad tot = 2 x 10 5 ) , dephosphorylated Bad is not able to displace Bax from its complex with Bcl-x L : high abundance of Bcl-x L allows it to restrain whole Bad u and whole Bax at the same time .	WhenBcl-xL tot = 2.4 x 10 5 (with Bad tot = 2 x 10 5), dephosphorylated Bad is not able to displace Bax from its complex with Bcl-x L : high abundance of Bcl-x L allows it to restrain whole Bad u and whole Bax at the same time.	36	48	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bax	Bax	Bax	36	38	47	48
Also , increasing the ratio of mitochondrial Bax and Bcl-xL induces Bax activation and cytochrome c release from mitochondria in the presence of a BH3-only protein , tBid , in a cell-free system XREF_BIBR .	Also, increasing the ratio of mitochondrial Bax and Bcl-xL induces Bax activation and cytochrome c release from mitochondria in the presence of a BH3-only protein, tBid, in a cell-free system XREF_BIBR.	4	12	induces	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	9	10	11	12
49 A third possibility is that the simultaneous inactivation of Bcl-xL and Mcl-1 causes the release of some positive regulator ( s ) of Bax and Bak activation .	49 A third possibility is that the simultaneous inactivation of Bcl-xL and Mcl-1 causes the release of some positive regulator (s) of Bax and Bak activation.	8	27	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	10	11	24	25
We therefore demonstrate that direct increase in the ratio of mitochondrial Bax and Bcl-XL can induce Bax activation in the p53- and Bcl-2-negative leukemic cells .	We therefore demonstrate that direct increase in the ratio of mitochondrial Bax and Bcl-XL can induce Bax activation in the p53- and Bcl-2-negative leukemic cells.	8	17	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	13	14	16	17
The increased ratio of Bax and Bcl-XL in K/Bax mitochondria led to an increased conformationally changed Bax , formation of the homo-multimer of Bax-Bax , and a reduced hetero-dimerization of Bax-Bcl-XL .	The increased ratio of Bax and Bcl-XL in K/Bax mitochondria led to an increased conformationally changed Bax, formation of the homo-multimer of Bax-Bax, and a reduced hetero-dimerization of Bax-Bcl-XL.	2	28	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	6	7	16	17
The inhibitory effect of Bcl-xL on vinblastine induced apoptosis in KB-3 cells may also be due to effects on Bax , as we have previously shown that Bcl-xL overexpression blocks conformational changes and oligomerization of Bax in vinblastine treated KB-3 cells .	The inhibitory effect of Bcl-xL on vinblastine induced apoptosis in KB-3 cells may also be due to effects on Bax, as we have previously shown that Bcl-xL overexpression blocks conformational changes and oligomerization of Bax in vinblastine treated KB-3 cells.	27	37	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL overexpression	bcl-xl	Bax	Bax	bax	27	28	35	36
This phenomenon seems to be a common feature of anti-apoptotic Bcl-2 family members as an over-abundance of Bcl-xL was also recently shown to induce both Bax accumulation and functional activation at the mitochondria .	This phenomenon seems to be a common feature of anti-apoptotic Bcl-2 family members as an over-abundance of Bcl-xL was also recently shown to induce both Bax accumulation and functional activation at the mitochondria.	15	26	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	17	18	25	26
In contrast to wt Bax , Bcl-x L over-expression did not detectably increase the retrotranslocation of Bax 1-2/L-6 in a 660 s time frame ( XREF_FIG ) .	In contrast to wt Bax, Bcl-x L over-expression did not detectably increase the retrotranslocation of Bax 1-2/L-6 in a 660 s time frame (XREF_FIG).	6	17	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-x L	Bcl-x L over-expression	bcl-x l	Bax	Bax	bax	6	8	16	17
Interestingly , the 3DDS dimerization of Bax mediated by detergents and BH3 peptides and Bcl-xL in an alkaline condition or elevated temperature were recently discovered XREF_BIBR XREF_BIBR XREF_BIBR .	Interestingly, the 3DDS dimerization of Bax mediated by detergents and BH3 peptides and Bcl-xL in an alkaline condition or elevated temperature were recently discovered XREF_BIBR XREF_BIBR XREF_BIBR.	4	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	14	15	6	7
Although Bcl-xL regulation of neurite outgrowth via DR6 is still under investigation , we also find that depletion of Bcl-xL using the RNAi approach activates pro apoptotic Bax .	Although Bcl-xL regulation of neurite outgrowth via DR6 is still under investigation, we also find that depletion of Bcl-xL using the RNAi approach activates pro apoptotic Bax.	17	28	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	19	20	27	28
By inhibiting BH3-only proteins or by directly binding Bax ( multi-BH pro apoptotic Bcl-2 homolog ) , Bcl-x L can prevent homo-oligomerization of Bax that otherwise leads to mitochondrial outer membrane permeability ( MOMP ) .	By inhibiting BH3-only proteins or by directly binding Bax (multi-BH pro apoptotic Bcl-2 homolog), Bcl-x L can prevent homo-oligomerization of Bax that otherwise leads to mitochondrial outer membrane permeability (MOMP).	17	24	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bax	Bax	Bax	17	19	23	24
Increased BAX and Bcl-XL ratio was noted with a maximum of 10 fold induced BAX and 2 fold reduced Bcl-XL in CS-DS coated DOX loaded PLGA-PVA-NP treated MCF-7- DOX-R cells .	Increased BAX and Bcl-XL ratio was noted with a maximum of 10 fold induced BAX and 2 fold reduced Bcl-XL in CS-DS coated DOX loaded PLGA-PVA-NP treated MCF-7- DOX-R cells.	3	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-XL	Bcl-XL	Bcl-XL	BAX	BAX	BAX	3	4	14	15
Bcl-xL rescues autophagy in bax expressing cells .	Bcl-xL rescues autophagy in bax expressing cells.	0	6	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	bax	bax	bax	0	1	4	5
BH3-only members ( Bad , Bid , Noxa , Puma ) are pro apoptotic and can modulate the conformation of Bax and Bak1 to sensitize this channel , possibly by exposing its membrane insertion domain , or they serve as decoys for Bcl-x L that allow Bax to form pores in the OMM .	BH3-only members (Bad, Bid, Noxa, Puma) are pro apoptotic and can modulate the conformation of Bax and Bak1 to sensitize this channel, possibly by exposing its membrane insertion domain, or they serve as decoys for Bcl-x L that allow Bax to form pores in the OMM.	42	48	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-x L	Bcl-x L	Bcl-x L	Bax	Bax	Bax	42	44	46	47
To investigate whether Bcl-xL promotes metastasis of Bax and Bak DKO cells in vivo , we performed an experimental tail vein metastasis assay .	To investigate whether Bcl-xL promotes metastasis of Bax and Bak DKO cells in vivo, we performed an experimental tail vein metastasis assay.	3	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	3	4	7	8
FOXO3 can promote Bim translocation to the mitochondria and knockdown of anti-apoptotic protein Bcl-xL , which can modulate Bax mediated mitochondrial cell death .	FOXO3 can promote Bim translocation to the mitochondria and knockdown of anti-apoptotic protein Bcl-xL, which can modulate Bax mediated mitochondrial cell death.	7	19	modulate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	13	14	18	19
The closest BCL-2 relatives ( BCL-X L , BCL-W , MCL-1 , A1/BFL -1 and , in humans , BCL-B ) promote cell survival , but BAX and BAK ( and possibly BOK ) instead promote cell death , as do distant relatives termed BH3-only proteins , because their only homology to BCL-2 ( or each other ) is the BH3 domain , through which they engage multi-BH domain relatives .	The closest BCL-2 relatives (BCL-X L, BCL-W, MCL-1, A1/BFL -1 and, in humans, BCL-B) promote cell survival, but BAX and BAK (and possibly BOK) instead promote cell death, as do distant relatives termed BH3-only proteins, because their only homology to BCL-2 (or each other) is the BH3 domain, through which they engage multi-BH domain relatives.	5	32	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-X L	BCL-X L	BCL-X L	BAX	BAX	BAX	5	7	26	27
Once Bcl-xL was displaced and Bad allows Bax to act , the event following this would be the release of cytochrome c from mitochondria .	Once Bcl-xL was displaced and Bad allows Bax to act, the event following this would be the release of cytochrome c from mitochondria.	1	9	allows	Positive_activation_syntax_3a_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	1	2	7	8
Hence , p21 protects against hyperoxia by delaying the loss of Bcl-X L that sequesters Bak and Bax .	Hence, p21 protects against hyperoxia by delaying the loss of Bcl-X L that sequesters Bak and Bax.	9	18	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-X L	loss of Bcl-X L	bcl-x l	Bax	Bax	bax	11	13	17	18
Dephosphorylated Bad forms a heterodimer with the anti-apoptotic BCL2 family members Bcl-2 and Bcl-xL , which allows Bax and Bak to aggregate and initiate apoptosis [ XREF_BIBR ] .	Dephosphorylated Bad forms a heterodimer with the anti-apoptotic BCL2 family members Bcl-2 and Bcl-xL, which allows Bax and Bak to aggregate and initiate apoptosis [XREF_BIBR].	2	23	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	13	14	17	18
Monitoring the expression of B-cell CCL and Lymphoma 2 ( Bcl-2 ) family members and their role in apoptosis induction after treatment with WEV or WEV+ NP revealed that the combination of WEV with NP robustly decreased the expression of the anti-apoptotic effectors Bcl-2 , Bcl XL and Mcl-1 ; conversely increased the expression of the pro apoptotic effectors Bak , Bax and Bim ; and altered the mitochondrial membrane potential in MM cells .	Monitoring the expression of B-cell CCL and Lymphoma 2 (Bcl-2) family members and their role in apoptosis induction after treatment with WEV or WEV+NP revealed that the combination of WEV with NP robustly decreased the expression of the anti-apoptotic effectors Bcl-2, Bcl XL and Mcl-1; conversely increased the expression of the pro apoptotic effectors Bak, Bax and Bim; and altered the mitochondrial membrane potential in MM cells.	45	62	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl XL	Bcl XL	Bcl XL	Bax	Bax	Bax	45	47	61	62
The constitutive balanced ratio of Bax and Bcl-XL in K562 mitochondria allowed the formation of active Bax and cytochrome c release from mitochondria in the presence of a BH3-only protein , tBid , in a cell-free system .	The constitutive balanced ratio of Bax and Bcl-XL in K562 mitochondria allowed the formation of active Bax and cytochrome c release from mitochondria in the presence of a BH3-only protein, tBid, in a cell-free system.	3	20	allowed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	7	8	16	17
Deamidation of Bcl-xL might be induced in order to translocate Bax to the mitochondria .	Deamidation of Bcl-xL might be induced in order to translocate Bax to the mitochondria.	0	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	2	3	10	11
Several BH3 peptides relieved the inhibition of BAX caused by the antiapoptotic BCL-XL and/or MCL-1 proteins and some of them display specificity for either BCL-XL or MCL-1 .	Several BH3 peptides relieved the inhibition of BAX caused by the antiapoptotic BCL-XL and/or MCL-1 proteins and some of them display specificity for either BCL-XL or MCL-1.	5	13	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	BCL-XL	BCL-XL	BCL-XL	BAX	BAX	BAX	12	13	7	8
Bad , a member of Bcl 2 family has been found to be the first protein that initiates apoptosis by displacing Bcl 2 or Bcl-xL which allows Bax to oligomerize and create pores on the mitochondrial membrane to release cytochrome c into the cytosol XREF_BIBR , XREF_BIBR .	Bad, a member of Bcl 2 family has been found to be the first protein that initiates apoptosis by displacing Bcl 2 or Bcl-xL which allows Bax to oligomerize and create pores on the mitochondrial membrane to release cytochrome c into the cytosol XREF_BIBR, XREF_BIBR.	20	28	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	24	25	27	28
The overall fold of Bcl-xL induced by the detergent OM reveals a domain swapped dimer ( XREF_FIG ) conformation , which is topologically identical to that reported for 3DDS Bax dimers induced by OM XREF_BIBR and Bcl-xL exposed to an alkaline pH ( pH 10 ) XREF_BIBR .	The overall fold of Bcl-xL induced by the detergent OM reveals a domain swapped dimer (XREF_FIG) conformation, which is topologically identical to that reported for 3DDS Bax dimers induced by OM XREF_BIBR and Bcl-xL exposed to an alkaline pH (pH 10) XREF_BIBR.	29	37	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	36	37	29	30
Moreover , we show that cBid activates Bax without affecting its assembly , while Bcl-xL induces the dissociation of Bax oligomers .	Moreover, we show that cBid activates Bax without affecting its assembly, while Bcl-xL induces the dissociation of Bax oligomers.	14	20	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	14	15	19	20
OnabotA treated rats showed a reduced epithelial staining of Bcl-xL and a consistently increased Bax and Caspase-3 staining when compared with saline treated animals .	OnabotA treated rats showed a reduced epithelial staining of Bcl-xL and a consistently increased Bax and Caspase-3 staining when compared with saline treated animals.	7	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	9	10	14	15
Previous work has shown that the death inhibiting family members Bcl-2 and Bcl-xL form heterodimers with the death promoting homologue Bax and that certain site directed mutants of Bcl-2 and Bcl-xL lose both biological activity and the ability to bind Bax .	Previous work has shown that the death inhibiting family members Bcl-2 and Bcl-xL form heterodimers with the death promoting homologue Bax and that certain site directed mutants of Bcl-2 and Bcl-xL lose both biological activity and the ability to bind Bax.	12	21	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	12	13	20	21
In fact , Fluorescence Loss In Photobleaching ( FLIP ) experiments revealed that Bcl-xL increased mitochondrial Bax off rates , without any detectable competition between Bax and Bcl-xL for MOM binding , proving that Bax effectively retrotranslocates from the mitochondria to the cytosol , when inactivated .	In fact, Fluorescence Loss In Photobleaching (FLIP) experiments revealed that Bcl-xL increased mitochondrial Bax off rates, without any detectable competition between Bax and Bcl-xL for MOM binding, proving that Bax effectively retrotranslocates from the mitochondria to the cytosol, when inactivated.	13	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	13	14	16	17
Therefore , the same experiment was performed using 20 nM Bcl-XL , a concentration at which Bcl-XL competes less efficiently with Bax for binding to tBid , allowing some Bax to become membrane bound .	Therefore, the same experiment was performed using 20 nM Bcl-XL, a concentration at which Bcl-XL competes less efficiently with Bax for binding to tBid, allowing some Bax to become membrane bound.	16	31	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-XL	Bcl-XL	Bcl-XL	Bax	Bax	Bax	16	17	29	30
Treatment of MCF-7 cells with ASDO resulted in a rapid depletion of mitochondrial membrane potential and release of cytochrome c and Smac/Diablo through up-regulation of Bax , Bad and PUMA expression and down-regulation of Bcl-xl expression .	Treatment of MCF-7 cells with ASDO resulted in a rapid depletion of mitochondrial membrane potential and release of cytochrome c and Smac/Diablo through up-regulation of Bax, Bad and PUMA expression and down-regulation of Bcl-xl expression.	23	35	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Bcl-xl	expression and down-regulation of Bcl-xl	bcl-xl	Bax	Bax	bax	34	35	25	26
A similar observation was made in yeast , where the co-expression of Bax and Bcl-xL induced a greater mitochondrial localization of Bax than when it was expressed alone XREF_BIBR .	A similar observation was made in yeast, where the co-expression of Bax and Bcl-xL induced a greater mitochondrial localization of Bax than when it was expressed alone XREF_BIBR.	10	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	co-expression of Bax and Bcl-xL	bcl-xl	Bax	Bax	bax	14	15	21	22
GM-CSF or IL-5 signaling up-regulate Bcl-xL expression and inhibit caspase activation by suppressing the function of proapoptotic Bax .	GM-CSF or IL-5 signaling up-regulate Bcl-xL expression and inhibit caspase activation by suppressing the function of proapoptotic Bax.	0	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-xL	GM-CSF or IL-5 signaling up-regulate Bcl-xL expression	bcl-xl	Bax	Bax	bax	5	6	17	18
Our findings demonstrate that no additional components are necessary for Bcl-xL-mediated retro translocation of Bax , which , based on our data , might be driven by Bcl-xL homo-dimerization in solution .	Our findings demonstrate that no additional components are necessary for Bcl-xL-mediated retro translocation of Bax, which, based on our data, might be driven by Bcl-xL homo-dimerization in solution.	12	28	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	27	28	14	15
This sequestration of Bcl-xL will trigger Bax activation only upon a death stimulus as we and others have previously reported .	This sequestration of Bcl-xL will trigger Bax activation only upon a death stimulus as we and others have previously reported.	1	7	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	3	4	6	7
Bcl-xL modulates Bax via different mechanisms : ( i ) Bcl-xL inhibits Bax activation by sequestering tBid ; XREF_BIBR , XREF_BIBR ( ii ) Bcl-xL reduces the oligomerization state of Bax within membranes ; 78 and ( iii ) Bcl-xL decreases the membrane bound population of Bax .	Bcl-xL modulates Bax via different mechanisms : (i) Bcl-xL inhibits Bax activation by sequestering tBid; XREF_BIBR, XREF_BIBR (ii) Bcl-xL reduces the oligomerization state of Bax within membranes; 78 and (iii) Bcl-xL decreases the membrane bound population of Bax.	0	5	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	0	1	2	3
The histogram in XREF_FIG shows a shift in the brightness distribution towards lower values of fluorescence intensity , suggesting a decrease in the oligomeric state of Bax particles promoted by Bcl-xL .	The histogram in XREF_FIG shows a shift in the brightness distribution towards lower values of fluorescence intensity, suggesting a decrease in the oligomeric state of Bax particles promoted by Bcl-xL.	26	31	promoted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	Bax	Bax	Bax	30	31	26	27
Indeed , KSHV was previously shown to downregulate autophagy , apoptosis and cell death using its viral FLIP and BCL-2 proteins that target autophagy related proteins ATG3 and BECN1 , respectively .	Indeed, KSHV was previously shown to downregulate autophagy, apoptosis and cell death using its viral FLIP and BCL-2 proteins that target autophagy related proteins ATG3 and BECN1, respectively.	19	29	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BECN1	BECN1	BECN1	19	20	28	29
VMP1 releases Bcl-2 from Beclin 1 , driving Beclin 1 into the autophagy pathway .	VMP1 releases Bcl-2 from Beclin 1, driving Beclin 1 into the autophagy pathway.	0	10	driving	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	2	3	8	10
Phosphorylation of BCL2 by MAPK8 and JNK1 stimulates dissociation of the BECN1 and BCL2 complex and allows BECN1 to associate with the PtdIns3K complex I , thereby inducing autophagy .	Phosphorylation of BCL2 by MAPK8 and JNK1 stimulates dissociation of the BECN1 and BCL2 complex and allows BECN1 to associate with the PtdIns3K complex I, thereby inducing autophagy.	0	15	stimulates	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	BCL2	Phosphorylation of BCL2 by MAPK8	bcl2	BECN1	BECN1 and BCL2 complex	becn1	2	3	11	12
Therefore , both Bcl-2 and caspase-9 could activate the release of Beclin-1 [ XREF_BIBR , XREF_BIBR ] .	Therefore, both Bcl-2 and caspase-9 could activate the release of Beclin-1 [XREF_BIBR, XREF_BIBR].	2	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	3	4	11	12
JNK1 mediated phosphorylation of Bcl-2 in response to nutrient starvation causes dissociation of Beclin-1 from this complex to initiate autophagosome signaling and influence apoptosis .	JNK1 mediated phosphorylation of Bcl-2 in response to nutrient starvation causes dissociation of Beclin-1 from this complex to initiate autophagosome signaling and influence apoptosis.	0	14	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	JNK1 mediated phosphorylation of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	4	5	13	14
Bcl-2 could target Beclin 1 dependent autophagic pathway via its inhibitory interaction with the autophagic marker Beclin 1 .	Bcl-2 could target Beclin 1 dependent autophagic pathway via its inhibitory interaction with the autophagic marker Beclin 1.	0	5	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	0	1	3	5
JNK1 mediated phosphorylation of BCL-2 leads to release of BECLIN1 and activation of autophagy .	JNK1 mediated phosphorylation of BCL-2 leads to release of BECLIN1 and activation of autophagy.	0	13	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	JNK1 mediated phosphorylation of BCL-2	bcl-2	BECLIN1	BECLIN1	beclin1	4	5	9	10
In our study , downregulation of Bcl-2 by metformin treatment and Stat3 inactivation leads to liberated or induced Beclin-1 and Atg5 , thereby triggering autophagy .	In our study, downregulation of Bcl-2 by metformin treatment and Stat3 inactivation leads to liberated or induced Beclin-1 and Atg5, thereby triggering autophagy.	4	20	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	6	7	18	19
97 Moreover , JNK phosphorylation of Bcl-2 results in Beclin 1 activation by promoting the dissociation of Beclin 1 from Bcl-2 .	97 Moreover, JNK phosphorylation of Bcl-2 results in Beclin 1 activation by promoting the dissociation of Beclin 1 from Bcl-2.	3	12	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Bcl-2	JNK phosphorylation of Bcl-2	bcl-2	Beclin 1	Beclin 1	beclin 1	6	7	9	11
Phosphorylation of Bcl-2 causes the separation of Beclin1 from Bcl-2 .	Phosphorylation of Bcl-2 causes the separation of Beclin1 from Bcl-2.	0	8	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Phosphorylation of Bcl-2	bcl-2	Beclin1	Beclin1	beclin1	2	3	7	8
150 Owing to the BH3 domain possessed by Beclin1 , both Bnip3L and Bnip3 compete with Beclin 1 for binding to Bcl2 , which upon their increased expression releases Beclin 1 , causing induction of autophagy .	150 Owing to the BH3 domain possessed by Beclin1, both Bnip3L and Bnip3 compete with Beclin 1 for binding to Bcl2, which upon their increased expression releases Beclin 1, causing induction of autophagy.	14	31	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	Bcl2	Bcl2	Beclin 1	Beclin 1	Beclin 1	21	22	29	31
Therefore , it is plausible that cellular Bcl-2 overexpression and viral Bcl-2s disrupt the tumor suppressor activity of the autophagy pathway by blocking the Beclin 1 function .	Therefore, it is plausible that cellular Bcl-2 overexpression and viral Bcl-2s disrupt the tumor suppressor activity of the autophagy pathway by blocking the Beclin 1 function.	7	26	disrupt	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2 overexpression	bcl-2	Beclin 1	Beclin 1	beclin 1	7	8	24	26
JNK phosphorylation of BCL-2 activates Beclin-1 resulting in increased autophagy .	JNK phosphorylation of BCL-2 activates Beclin-1 resulting in increased autophagy.	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	JNK phosphorylation of BCL-2	bcl-2	Beclin-1	Beclin-1	beclin-1	3	4	5	6
The autophagy promoting function of Beclin-1 is influenced by the antiapoptotic protein Bcl-2 ; in fact , when Beclin-1 is bound to Bcl-2 , autophagy is inhibited ; instead , the dissociation from Bcl-2 allows Beclin-1 to interact with PI3K and III complex , and to activate autophagy .	The autophagy promoting function of Beclin-1 is influenced by the antiapoptotic protein Bcl-2; in fact, when Beclin-1 is bound to Bcl-2, autophagy is inhibited; instead, the dissociation from Bcl-2 allows Beclin-1 to interact with PI3K and III complex, and to activate autophagy.	31	36	allows	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	33	34	35	36
The dissociation of Beclin 1 from BCL-2 allows Beclin 1 to form a complex with VPS34 , an essential component of the autophagy machinery , to initiate phagophore formation .	The dissociation of Beclin 1 from BCL-2 allows Beclin 1 to form a complex with VPS34, an essential component of the autophagy machinery, to initiate phagophore formation.	1	11	allows	Positive_activation_token_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	Beclin 1	Beclin 1	Beclin 1	6	7	8	10
It is reported that phosphorylation of Bcl-2 leads to the dissociation of the Bcl-2 and Beclin-1 complex , allowing Beclin-1 to complex with Vps34 triggering the initiation of autophagosome formation [ XREF_BIBR ; XREF_BIBR ] ; a process that incorporates LC3-II and several Atg related proteins .	It is reported that phosphorylation of Bcl-2 leads to the dissociation of the Bcl-2 and Beclin-1 complex, allowing Beclin-1 to complex with Vps34 triggering the initiation of autophagosome formation [XREF_BIBR; XREF_BIBR]; a process that incorporates LC3-II and several Atg related proteins.	4	20	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	phosphorylation of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	6	7	19	20
JNK activation has been shown to induce Bcl-2 phosphorylation , disrupt the Bcl-2 and Beclin 1 complex , and promote the release of Beclin 1 to induce autophagy XREF_BIBR .	JNK activation has been shown to induce Bcl-2 phosphorylation, disrupt the Bcl-2 and Beclin 1 complex, and promote the release of Beclin 1 to induce autophagy XREF_BIBR.	0	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	JNK activation has been shown to induce Bcl-2 phosphorylation	bcl-2	Beclin 1	Beclin 1	beclin 1	7	8	23	25
As well , the targeting of Beclin-1 by Bcl-2 represents the crucial point to understand the mechanism of autophagy regulation .	As well, the targeting of Beclin-1 by Bcl-2 represents the crucial point to understand the mechanism of autophagy regulation.	4	9	targeting	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	8	9	6	7
These effects of BCL2 on starvation induced Beclin 1 S90 phosphorylation and autophagy were not due to a blockade of MK2 and MK3 activation , as levels of phospho-HSP27 increased similarly during starvation in HeLa and control , HeLa and BCL2 and HeLa and BCL2 AAA cells .	These effects of BCL2 on starvation induced Beclin 1 S90 phosphorylation and autophagy were not due to a blockade of MK2 and MK3 activation, as levels of phospho-HSP27 increased similarly during starvation in HeLa and control, HeLa and BCL2 and HeLa and BCL2 AAA cells.	1	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	Beclin 1	Beclin 1	Beclin 1	3	4	7	9
When the interaction between the BH3 domain of Beclin 1 and the BH3 binding domain of Bcl-2/X L is stimulated , Bcl-2 acts to enhance homodimerization of Beclin 1 by stabilizing dimerization of their CCD in an anti-parallel orientation .	When the interaction between the BH3 domain of Beclin 1 and the BH3 binding domain of Bcl-2/X L is stimulated, Bcl-2 acts to enhance homodimerization of Beclin 1 by stabilizing dimerization of their CCD in an anti-parallel orientation.	21	29	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	21	22	27	29
Relieving the inhibition of BECN1 by Bcl-2 or Bcl-X L displacement allows for the activation of a PI3 Kinase called vacuolar protein sorting 34 ( VPS34 ) , resulting in the nucleation of an isolation membrane .	Relieving the inhibition of BECN1 by Bcl-2 or Bcl-X L displacement allows for the activation of a PI3 Kinase called vacuolar protein sorting 34 (VPS34), resulting in the nucleation of an isolation membrane.	2	10	inhibition	Negative_activation_token_2_noun	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	BECN1	BECN1	BECN1	6	7	4	5
We have also demonstrated that the binding of the VMP1-AtgD domain to the Beclin 1 BH3 motif promotes the displacement of Bcl-2 , a negative regulator of autophagy , driving Beclin 1 to the autophagic pathway .	We have also demonstrated that the binding of the VMP1-AtgD domain to the Beclin 1 BH3 motif promotes the displacement of Bcl-2, a negative regulator of autophagy, driving Beclin 1 to the autophagic pathway.	21	32	driving	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	21	22	30	32
Moreover , after transfection of Hep1-6 cells with a plasmid encoding Bcl-2 , we observed that Bcl-2 overexpression rescued the colocalization of Bcl-2 and Beclin-1 in the cytoplasm and inhibited autophagy ( XREF_SUPPLEMENTARY ) .	Moreover, after transfection of Hep1-6 cells with a plasmid encoding Bcl-2, we observed that Bcl-2 overexpression rescued the colocalization of Bcl-2 and Beclin-1 in the cytoplasm and inhibited autophagy (XREF_SUPPLEMENTARY).	16	25	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 overexpression	bcl-2	Beclin-1	Beclin-1	beclin-1	16	17	24	25
At a minimum , given the central role of Beclin 1 and autophagy in intracellular pathogen degradation ( xenophagy ) , and activation of innate and adaptive immunity , it seems likely that viral Bcl-2 targeting of the Beclin 1 function may contribute to gamma-herpesvirus pathogenesis .	At a minimum, given the central role of Beclin 1 and autophagy in intracellular pathogen degradation (xenophagy), and activation of innate and adaptive immunity, it seems likely that viral Bcl-2 targeting of the Beclin 1 function may contribute to gamma-herpesvirus pathogenesis.	34	40	targeting	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	34	35	38	40
Recent studies have shown that in cells undergoing nutrient deprivation- or ceramide induced autophagy , JNK1 phosphorylates serine 70 on Bcl-2 , promoting disruption of Bcl-2 and Beclin-1 complexes , and liberating Beclin-1 to promote autophagy [ XREF_BIBR , XREF_BIBR ] .	Recent studies have shown that in cells undergoing nutrient deprivation- or ceramide induced autophagy, JNK1 phosphorylates serine 70 on Bcl-2, promoting disruption of Bcl-2 and Beclin-1 complexes, and liberating Beclin-1 to promote autophagy [XREF_BIBR, XREF_BIBR].	15	34	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	JNK1 phosphorylates serine 70 on Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	20	21	32	33
In response to amino acid deprivation or ceramide treatment , the phosphorylation of Bcl-2 by JNK1 leads to reduced interaction between Bcl-2 and Beclin 1 , which in turn triggers autophagy [ XREF_BIBR , XREF_BIBR ] .	In response to amino acid deprivation or ceramide treatment, the phosphorylation of Bcl-2 by JNK1 leads to reduced interaction between Bcl-2 and Beclin 1, which in turn triggers autophagy [XREF_BIBR, XREF_BIBR].	11	29	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Bcl-2	phosphorylation of Bcl-2	bcl-2	Beclin 1	Beclin 1	beclin 1	13	14	23	25
Another miRNA , MIR205 inhibits BCL2 expression , thus modulating a key negative regulator of BECN1 function in autophagy [ XREF_BIBR ] .	Another miRNA, MIR205 inhibits BCL2 expression, thus modulating a key negative regulator of BECN1 function in autophagy [XREF_BIBR].	3	16	modulating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	MIR205 inhibits BCL2 expression	bcl2	BECN1	BECN1	becn1	5	6	15	16
More and more researches support presupposition that BCL-2 can inhibit autophagy by repressing Beclin-1 .	More and more researches support presupposition that BCL-2 can inhibit autophagy by repressing Beclin-1.	7	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	Beclin-1	Beclin-1	Beclin-1	7	8	13	14
TRAF2 dependent activation of IRE1 and c-Jun JNK reportedly result in the phosphorylation of Bcl-2 , allowing the dissociation of Beclin-1 , activation of the PI3K complex and autophagy [ XREF_BIBR , XREF_BIBR ] .	TRAF2 dependent activation of IRE1 and c-Jun JNK reportedly result in the phosphorylation of Bcl-2, allowing the dissociation of Beclin-1, activation of the PI3K complex and autophagy [XREF_BIBR, XREF_BIBR].	0	21	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	TRAF2 dependent activation of IRE1 and c-Jun JNK reportedly result in the phosphorylation of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	14	15	20	21
For example , XREF_BIBR showed that early after starvation , low levels of multisite Bcl-2 phosphorylation result in increased dissociation of the Bcl-2-Beclin 1 complex and increased Beclin 1 dependent autophagy , which may be an attempt to promote cell survival .	For example, XREF_BIBR showed that early after starvation, low levels of multisite Bcl-2 phosphorylation result in increased dissociation of the Bcl-2-Beclin 1 complex and increased Beclin 1 dependent autophagy, which may be an attempt to promote cell survival.	14	29	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 phosphorylation	bcl-2	Beclin 1	Beclin 1	beclin 1	14	15	27	29
A detailed understanding of BECN1 interactions with cellular and viral BCL2 proteins recently enabled development of a potent , yet very specific , cell penetrating peptide , designed to disrupt viral BCL2-BECN1 interactions , and induce autophagy in cultured cells , without affecting normal regulation of BECN1 mediated by cellular BCL2 proteins .	A detailed understanding of BECN1 interactions with cellular and viral BCL2 proteins recently enabled development of a potent, yet very specific, cell penetrating peptide, designed to disrupt viral BCL2-BECN1 interactions, and induce autophagy in cultured cells, without affecting normal regulation of BECN1 mediated by cellular BCL2 proteins.	44	51	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	BECN1	BECN1	BECN1	50	51	46	47
Treatment with the IP 3 R antagonist or physiological induction of autophagy by nutrient starvation disrupts the interaction between IP 3 R and Beclin 1 , which is an interaction that is abolished by Bcl-2 knockdown or enhanced by Bcl-2 overexpression .	Treatment with the IP 3 R antagonist or physiological induction of autophagy by nutrient starvation disrupts the interaction between IP 3 R and Beclin 1, which is an interaction that is abolished by Bcl-2 knockdown or enhanced by Bcl-2 overexpression.	15	41	enhanced	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 overexpression	bcl-2	Beclin 1	Beclin 1	beclin 1	39	40	23	25
BCL2 antiapoptotic proteins , which are regulated by XBP-1 ( S ) can block autophagy by inhibiting BECN1 .	BCL2 antiapoptotic proteins, which are regulated by XBP-1 (S) can block autophagy by inhibiting BECN1.	0	18	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL2	BCL2	BCL2	BECN1	BECN1	BECN1	0	1	17	18
JNK can also activate autophagy through phosphorylation of BCL-2 [ XREF_BIBR ] or by c-Jun dependent up-regulation of Beclin-1 expression [ XREF_BIBR ] , while its pharmacological inhibition blocks autophagic flux and increases apoptosis [ XREF_BIBR ] .	JNK can also activate autophagy through phosphorylation of BCL-2 [XREF_BIBR] or by c-Jun dependent up-regulation of Beclin-1 expression [XREF_BIBR], while its pharmacological inhibition blocks autophagic flux and increases apoptosis [XREF_BIBR].	3	21	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	BCL-2	activate autophagy through phosphorylation of BCL-2 [XREF_BIBR] or by c-Jun	bcl-2	Beclin-1	Beclin-1	beclin-1	8	9	18	19
Bcl-2 protein interacts with Beclin-1 and inhibits autophagy by suppressing the formation of PI3K , III , and Beclin-1 complex .	Bcl-2 protein interacts with Beclin-1 and inhibits autophagy by suppressing the formation of PI3K, III, and Beclin-1 complex.	0	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin-1	Beclin-1	Beclin-1	0	1	18	19
Bcl-2 inhibits autophagy when bound to Beclin 1 and downregulates Beclin 1 , which is associated with the outcomes of patients in the present study .	Bcl-2 inhibits autophagy when bound to Beclin 1 and downregulates Beclin 1, which is associated with the outcomes of patients in the present study.	0	15	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	0	1	10	12
JNK-1 phosphorylates Bcl-2 , which allows Beclin-1 to dissociate from Bcl-2 and activate autophagy XREF_BIBR .	JNK-1 phosphorylates Bcl-2, which allows Beclin-1 to dissociate from Bcl-2 and activate autophagy XREF_BIBR.	0	12	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	JNK-1 phosphorylates Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	2	3	6	7
Recently , we have shown that in nutrient deprivation conditions C-Jun N-terminal kinase mediated Bcl-2 phosphorylation inhibits its interaction with Beclin 1 and increases Beclin 1 dependent autophagy .	Recently, we have shown that in nutrient deprivation conditions C-Jun N-terminal kinase mediated Bcl-2 phosphorylation inhibits its interaction with Beclin 1 and increases Beclin 1 dependent autophagy.	10	26	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	C-Jun N-terminal kinase mediated Bcl-2 phosphorylation	bcl-2	Beclin 1	Beclin 1	beclin 1	14	15	24	26
This mechanism of MAPK8 signaling is mediated by BCL2 ( B cell leukemia/lymphoma 2 ) phosphorylation ( on Thr69 , Ser70 , and Ser87 ) that disrupts the interaction of BCL2 with BECN1 ( beclin 1 , autophagy related ) and initiates BECN1 dependent autophagy [ 5 ] .	This mechanism of MAPK8 signaling is mediated by BCL2 (B cell leukemia/lymphoma 2) phosphorylation (on Thr69, Ser70, and Ser87) that disrupts the interaction of BCL2 with BECN1 (beclin 1, autophagy related) and initiates BECN1 dependent autophagy [5].	6	44	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	mediated by BCL2 (B cell leukemia/lymphoma 2) phosphorylation (on Thr69, Ser70, and Ser87) that disrupts the interaction of BCL2	bcl2	BECN1	BECN1	becn1	8	9	42	43
Moreover , the activation of JNK signaling during oxidative stress leads to the phosphorylation of Bcl-2 , which causes Beclin 1 to dissociate from the Vps34 complex and results in the activation of autophagy .	Moreover, the activation of JNK signaling during oxidative stress leads to the phosphorylation of Bcl-2, which causes Beclin 1 to dissociate from the Vps34 complex and results in the activation of autophagy.	13	28	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	phosphorylation of Bcl-2	bcl-2	Beclin 1	Beclin 1	beclin 1	15	16	19	21
The antiapoptotic BCL2 family members were shown to contribute to autophagy by binding to the BH3 domain of BECN1 , thereby preventing BECN1 from initiating autophagy .	The antiapoptotic BCL2 family members were shown to contribute to autophagy by binding to the BH3 domain of BECN1, thereby preventing BECN1 from initiating autophagy.	2	23	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	BECN1	BECN1	BECN1	2	3	22	23
Phosphorylation of Beclin1 by DAP-kinase [ XREF_BIBR ] , phosphorylation of Bcl2 by the JNK pathway [ XREF_BIBR ] or the activation by Bif-1 [ XREF_BIBR ] weaken these interactions and activate Beclin1 .	Phosphorylation of Beclin1 by DAP-kinase [XREF_BIBR], phosphorylation of Bcl2 by the JNK pathway [XREF_BIBR] or the activation by Bif-1 [XREF_BIBR] weaken these interactions and activate Beclin1.	9	33	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	phosphorylation of Bcl2	bcl2	Beclin1	Beclin1	beclin1	11	12	32	33
Activation of JNK1 has been shown to lead to Bcl-2 phosphorylation causing release of Beclin 1 from Bcl-2-Beclin 1 complexes , resulting in autophagy induction XREF_BIBR .	Activation of JNK1 has been shown to lead to Bcl-2 phosphorylation causing release of Beclin 1 from Bcl-2-Beclin 1 complexes, resulting in autophagy induction XREF_BIBR.	9	16	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 phosphorylation	bcl-2	Beclin 1	Beclin 1	beclin 1	9	10	14	16
Moreover , c-Jun N-terminal kinase 1 ( JNK1 ) also induces BCL-2 phosphorylation , triggering the dissociation of BECLIN 1 from BCL-2 , and is linked to autophagy induction under starvation conditions in non cardiac cells [ XREF_BIBR ] .	Moreover, c-Jun N-terminal kinase 1 (JNK1) also induces BCL-2 phosphorylation, triggering the dissociation of BECLIN 1 from BCL-2, and is linked to autophagy induction under starvation conditions in non cardiac cells [XREF_BIBR].	2	20	triggering	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	c-Jun N-terminal kinase 1 (JNK1) also induces BCL-2 phosphorylation	bcl-2	BECLIN 1	BECLIN 1	beclin 1	11	12	18	20
Release of BCL-2 allows BECLIN 1 to form a complex with VPS34 and VPS15 to initiate formation of the phagophore [ XREF_BIBR ] .	Release of BCL-2 allows BECLIN 1 to form a complex with VPS34 and VPS15 to initiate formation of the phagophore [XREF_BIBR].	0	7	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BECLIN 1	BECLIN 1	BECLIN 1	2	3	4	6
Recently , it was reported that JNK mediated phosphorylation of Bcl-2 causes its release of Beclin-1 , thereby allowing autophagy to proceed [ XREF_BIBR ] .	Recently, it was reported that JNK mediated phosphorylation of Bcl-2 causes its release of Beclin-1, thereby allowing autophagy to proceed [XREF_BIBR].	6	16	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	JNK mediated phosphorylation of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	10	11	15	16
Another pathway that is regulated after starvation in cells is an increase in Beclin-1 activity mediated by JNK phosphorylation of Bcl-2 , which in its unphosphorylated state binds and inhibits Beclin-1 .	Another pathway that is regulated after starvation in cells is an increase in Beclin-1 activity mediated by JNK phosphorylation of Bcl-2, which in its unphosphorylated state binds and inhibits Beclin-1.	13	29	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-2	phosphorylation of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	20	21	13	14
Multisite phosphorylation of Bcl-2 in its nonstructural loop ( Thr 69 , Ser 70 , Ser 87 ) by c-Jun N-terminal kinase 1 ( JNK1 ) also promotes dissociation of Beclin 1 from Bcl-2 that results in induction of autophagy [ XREF_BIBR , XREF_BIBR ] .	Multisite phosphorylation of Bcl-2 in its nonstructural loop (Thr 69, Ser 70, Ser 87) by c-Jun N-terminal kinase 1 (JNK1) also promotes dissociation of Beclin 1 from Bcl-2 that results in induction of autophagy [XREF_BIBR, XREF_BIBR].	1	32	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	phosphorylation of Bcl-2	bcl-2	Beclin 1	Beclin 1	beclin 1	3	4	30	32
A key autophagic target of FOXO3 is Bnip3 , a member of the BH3-only family of proteins which have been shown to promote autophagy by relieving the inhibition of Beclin 1 by Bcl-2 [ XREF_BIBR ] .	A key autophagic target of FOXO3 is Bnip3, a member of the BH3-only family of proteins which have been shown to promote autophagy by relieving the inhibition of Beclin 1 by Bcl-2 [XREF_BIBR].	27	34	inhibition	Negative_activation_token_2_noun	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Beclin 1	Beclin 1	Beclin 1	32	33	29	31
8 BCL-2 dissociation also allows BECLIN-1 activation by AMBRA1 .	8 BCL-2 dissociation also allows BECLIN-1 activation by AMBRA1.	1	6	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-2	BCL-2	BCL-2	BECLIN-1	BECLIN-1	BECLIN-1	1	2	5	6
Recent studies showed that JNK mediated phosphorylation of Bcl2 caused its release of Beclin1 , thereby allowing autophagy to proceed [ XREF_BIBR ] .	Recent studies showed that JNK mediated phosphorylation of Bcl2 caused its release of Beclin1, thereby allowing autophagy to proceed [XREF_BIBR].	4	14	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	JNK mediated phosphorylation of Bcl2	bcl2	Beclin1	Beclin1	beclin1	8	9	13	14
The phosphorylation of the anti-apoptotic BCL2 at the ER by JNK stimulates autophagy by modulating the activity of Beclin1 .	The phosphorylation of the anti-apoptotic BCL2 at the ER by JNK stimulates autophagy by modulating the activity of Beclin1.	1	19	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	phosphorylation of the anti-apoptotic BCL2	bcl2	Beclin1	Beclin1	beclin1	5	6	18	19
Additionally , BNIP3 can activate macroautophagy through its interaction with BCL2 , which causes the release of BECN1from BCL2 and promotes BECN1 mediated autophagosome synthesis [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Additionally, BNIP3 can activate macroautophagy through its interaction with BCL2, which causes the release of BECN1from BCL2 and promotes BECN1 mediated autophagosome synthesis [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	22	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL2	BCL2	BCL2	BECN1	BECN1	BECN1	10	11	21	22
However , parkin monoubiquitination of Bcl2 enhances the ability of Bcl2 to bind beclin 1 and suppress autophagy , and RNAi knockdown of parkin increases the LC3-II band in 293 , SH-SY5Y , and primary neuron cultures [ XREF_BIBR ] .	However, parkin monoubiquitination of Bcl2 enhances the ability of Bcl2 to bind beclin 1 and suppress autophagy, and RNAi knockdown of parkin increases the LC3-II band in 293, SH-SY5Y, and primary neuron cultures [XREF_BIBR].	2	15	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2	parkin monoubiquitination of Bcl2	bcl2	beclin 1	beclin 1	beclin 1	5	6	13	15
These data suggest that the downregulation of Bcl-2 expression promotes the release of Beclin-1 from Bcl-2-Beclin-1 complexes ; the released Beclin-1 then initiates ASPP2 induced autophagy , which induces apoptosis in hepatoma cells with ASPP2 overexpression .	These data suggest that the downregulation of Bcl-2 expression promotes the release of Beclin-1 from Bcl-2-Beclin-1 complexes; the released Beclin-1 then initiates ASPP2 induced autophagy, which induces apoptosis in hepatoma cells with ASPP2 overexpression.	7	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 expression	bcl-2	Beclin-1	Beclin-1	beclin-1	7	8	13	14
Phosphorylation of Bcl-2 by JNK 41 causes the release of beclin-1 , 42 which can exert its pro autophagic role .	Phosphorylation of Bcl-2 by JNK 41 causes the release of beclin-1, 42 which can exert its pro autophagic role.	0	12	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Phosphorylation of Bcl-2	bcl-2	beclin-1	beclin-1	beclin-1	2	3	10	11
For example , the anti-apoptotic proteins BCL-2 and BCL-X L which are over-expressed in certain lymphomas and carcinomas , prevent the induction of autophagy by binding to and inhibiting Beclin-1 .	For example, the anti-apoptotic proteins BCL-2 and BCL-X L which are over-expressed in certain lymphomas and carcinomas, prevent the induction of autophagy by binding to and inhibiting Beclin-1.	3	30	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-2	BCL-2	BCL-2	Beclin-1	Beclin-1	Beclin-1	6	7	29	30
Phosphorylation of Bcl-2 by Jun N-terminal protein kinase 1 ( JNK1 ) dissociates the complex and enables Beclin-1 to stimulate autophagy [ XREF_BIBR ] .	Phosphorylation of Bcl-2 by Jun N-terminal protein kinase 1 (JNK1) dissociates the complex and enables Beclin-1 to stimulate autophagy [XREF_BIBR].	0	18	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Phosphorylation of Bcl-2	bcl-2	Beclin-1	Beclin-1	beclin-1	2	3	17	18
Bcl-2 phosphorylation resulted in increased dissociation of the Bcl-2-Beclin 1 complex and increased Beclin 1 dependent autophagy .	Bcl-2 phosphorylation resulted in increased dissociation of the Bcl-2-Beclin 1 complex and increased Beclin 1 dependent autophagy.	0	15	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2 phosphorylation	bcl-2	Beclin 1	Beclin 1	beclin 1	0	1	13	15
It has been demonstrated that CHOP expression increases the expression levels of ATG5 and BH3-only protein , in addition to reducing the expression levels of Bcl-2 , which contributes to beclin-1 releasing from Bcl-2 .	It has been demonstrated that CHOP expression increases the expression levels of ATG5 and BH3-only protein, in addition to reducing the expression levels of Bcl-2, which contributes to beclin-1 releasing from Bcl-2.	23	31	contributes	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Bcl-2	levels of Bcl-2	bcl-2	beclin-1	beclin-1	beclin-1	25	26	30	31
Axin 2 is an essential element of this pathway , is highly expressed in OPCs and negatively regulates the Wnt signaling pathway by promoting beta-catenin degradation .	Axin 2 is an essential element of this pathway, is highly expressed in OPCs and negatively regulates the Wnt signaling pathway by promoting beta-catenin degradation.	0	25	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Axin 2	Axin 2 is an essential element of this pathway, is highly expressed	axin 2	beta-catenin	beta-catenin	beta-catenin	0	2	24	25
However , exogenous Wnt6 did not enhance Axin2 mRNA levels or induce beta-catenin accumulation .	However, exogenous Wnt6 did not enhance Axin2 mRNA levels or induce beta-catenin accumulation.	3	13	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Axin2	Wnt6 did not enhance Axin2 mRNA levels	axin2	beta-catenin	beta-catenin	beta-catenin	7	8	12	13
AZ1366 stabilized Axin-1 in a dose dependent manner ( XREF_FIG ) , and provided a corresponding decrease in the mRNA level of multiple beta-catenin dependent targets , including Survivin , c-Myc and Axin2 , albeit with different dose-dependencies ( XREF_FIG ) .	AZ1366 stabilized Axin-1 in a dose dependent manner (XREF_FIG), and provided a corresponding decrease in the mRNA level of multiple beta-catenin dependent targets, including Survivin, c-Myc and Axin2, albeit with different dose-dependencies (XREF_FIG).	23	33	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	32	33	23	24
Thus , we evaluated the status of beta-catenin-dependent transcription in nasal epithelia from Cby -/- mice and age matched controls using quantitative PCR for the direct beta-catenin targets Axin2 and CyclinD1 .	Thus, we evaluated the status of beta-catenin-dependent transcription in nasal epithelia from Cby -/- mice and age matched controls using quantitative PCR for the direct beta-catenin targets Axin2 and CyclinD1.	20	30	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	28	29	26	27
Because axin-2 is transcriptionally induced following reception of Wnt and beta-catenin signal , to further monitor the activation of Wnt signaling in frontal and parietal bones , we used axin-2 lacZ/+ mice in which a lacZ reporter gene has been inserted into the Wnt target gene axin-2 .	Because axin-2 is transcriptionally induced following reception of Wnt and beta-catenin signal, to further monitor the activation of Wnt signaling in frontal and parietal bones, we used axin-2 lacZ/+ mice in which a lacZ reporter gene has been inserted into the Wnt target gene axin-2.	1	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	axin-2	axin-2	axin-2	beta-catenin	beta-catenin	beta-catenin	1	2	10	11
Notably , the known Wnt and beta-catenin downstream targets such as Klf2 , Tfcp2l1 , Klf4 , Axin2 , Fgf5 , Cdx2 , Lef1 , Gata2 , Sall3 , and Dkk1 were induced by GSK3beta inhibition but not by GSK3alpha inhibition ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Notably, the known Wnt and beta-catenin downstream targets such as Klf2, Tfcp2l1, Klf4, Axin2, Fgf5, Cdx2, Lef1, Gata2, Sall3, and Dkk1 were induced by GSK3beta inhibition but not by GSK3alpha inhibition (XREF_FIG and XREF_SUPPLEMENTARY).	6	18	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	17	18	6	7
These observations show that GEN-27 inhibits p65 nuclear translocation , which leads to the increased expression of CDX2 , APC , AXIN2 and p-beta-catenin ( S37 ) , decreased nuclear translocation of beta-catenin , resulting in the down-regulation of beta-catenin target genes .	These observations show that GEN-27 inhibits p65 nuclear translocation, which leads to the increased expression of CDX2, APC, AXIN2 and p-beta-catenin (S37), decreased nuclear translocation of beta-catenin, resulting in the down-regulation of beta-catenin target genes.	6	33	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	p65 nuclear translocation, which leads to the increased expression of CDX2, APC, AXIN2	axin2	beta-catenin	beta-catenin	beta-catenin	21	22	32	33
When target genes of Wnt and beta-catenin signaling such as cyclin D1 and Axin2 , were upregulated , expression of Irs1 , but not that of Irs2 or IR , was significantly elevated .	When target genes of Wnt and beta-catenin signaling such as cyclin D1 and Axin2, were upregulated, expression of Irs1, but not that of Irs2 or IR, was significantly elevated.	4	14	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	13	14	6	7
Administration of 4-OHT results in the translocation of DeltaNbeta-catenin-ERT2 into the nucleus , as confirmed by immunocytochemistry staining and immuno blotting ( XREF_FIG ) , and activates the Wnt and beta-catenin signalling pathway , as indicated by the increased expression of Wnt and beta-catenin targets Axin2 and Cdx1 ( XREF_FIG ) .	Administration of 4-OHT results in the translocation of DeltaNbeta-catenin-ERT2 into the nucleus, as confirmed by immunocytochemistry staining and immuno blotting (XREF_FIG), and activates the Wnt and beta-catenin signalling pathway, as indicated by the increased expression of Wnt and beta-catenin targets Axin2 and Cdx1 (XREF_FIG).	26	49	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	45	46	43	44
In conclusion , WNT and beta-catenin signal activation mediated by the methylation of SFRP4 , MCC , and AXIN2 may make different contributions to colorectal neoplasia between the serrated and conventional routes .	In conclusion, WNT and beta-catenin signal activation mediated by the methylation of SFRP4, MCC, and AXIN2 may make different contributions to colorectal neoplasia between the serrated and conventional routes.	5	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	AXIN2	methylation of SFRP4, MCC, and AXIN2	axin2	beta-catenin	beta-catenin	beta-catenin	18	19	5	6
Under physiological conditions , Axin2 protein negatively regulates this signaling pathway by promoting the degradation of beta-catenin even in the presence of Wnt , possibly through a GSK3 mediated mechanism that is critical for oligodendrocyte differentiation 7 .	Under physiological conditions, Axin2 protein negatively regulates this signaling pathway by promoting the degradation of beta-catenin even in the presence of Wnt, possibly through a GSK3 mediated mechanism that is critical for oligodendrocyte differentiation 7.	4	17	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	4	5	16	17
CTNNB1 encodes beta-catenin , which is the central downstream mediator of canonical WNT signalling , which forms a complex with lymphoid enhancer factor/T cell factor ( LEF and TCF ) transcription factors to modulate target gene expression [ XREF_BIBR ] , whereas PTEN , APC , AXIN2 , AKT3 and NHERF1 gene products modulate beta-catenin activity .	CTNNB1 encodes beta-catenin, which is the central downstream mediator of canonical WNT signalling, which forms a complex with lymphoid enhancer factor/T cell factor (LEF and TCF) transcription factors to modulate target gene expression [XREF_BIBR], whereas PTEN, APC, AXIN2, AKT3 and NHERF1 gene products modulate beta-catenin activity.	42	55	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	46	47	54	55
Axin2 and conductin mediated feedback promotes beta-catenin destruction in Wnt stimulated cells .	Axin2 and conductin mediated feedback promotes beta-catenin destruction in Wnt stimulated cells.	0	7	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
Furthermore , the levels of Axin2 mRNA were increased 2.8-fold ( n = 12 MMTV-Wnt1 , n = 11 MMTV-Wnt1 ; MMTV-Wnt5a p-value < 0.05 , REST ; XREF_FIG ) in double transgenic mice , suggesting an increase in overall Wnt and beta-catenin signaling in the presence of Wnt5a in vivo .	Furthermore, the levels of Axin2 mRNA were increased 2.8-fold (n = 12 MMTV-Wnt1, n = 11 MMTV-Wnt1; MMTV-Wnt5a p-value < 0.05, REST; XREF_FIG) in double transgenic mice, suggesting an increase in overall Wnt and beta-catenin signaling in the presence of Wnt5a in vivo.	5	43	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	5	6	42	43
Our results showed that GEN-27 increased expressions of adenomatous polyposis coli ( APC ) and axis inhibition protein 2 ( AXIN2 ) , and reduced beta-catenin nuclear localization , which resulted from the inhibition of NF-kappaB and p65 nuclear localization and up-regulation of caudal related homeobox transcription factor 2 ( CDX2 ) .	Our results showed that GEN-27 increased expressions of adenomatous polyposis coli (APC) and axis inhibition protein 2 (AXIN2), and reduced beta-catenin nuclear localization, which resulted from the inhibition of NF-kappaB and p65 nuclear localization and up-regulation of caudal related homeobox transcription factor 2 (CDX2).	4	27	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	GEN-27 increased expressions of adenomatous polyposis coli (APC) and axis inhibition protein 2 (AXIN2	axin2	beta-catenin	beta-catenin	beta-catenin	20	21	25	26
We confirmed that the beta-catenin pathway is indeed activated in PC9M2 cells by determination of enhanced phosphorylation of Akt and GSK3alpha , cytoplasmic localization of beta-catenin and activation of Axin2 gene transcription .	We confirmed that the beta-catenin pathway is indeed activated in PC9M2 cells by determination of enhanced phosphorylation of Akt and GSK3alpha, cytoplasmic localization of beta-catenin and activation of Axin2 gene transcription.	4	32	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Axin2	Axin2 gene transcription	axin2	beta-catenin	beta-catenin	beta-catenin	29	30	4	5
Although , this line will be used more extensively in the future , an important inherent limitation of the Axin2 LacZ line is the corresponding up-regulation of endogenous Wnt signaling , since the Axin related protein , AXIN2 , modulates beta-catenin stability .	Although, this line will be used more extensively in the future, an important inherent limitation of the Axin2 LacZ line is the corresponding up-regulation of endogenous Wnt signaling, since the Axin related protein, AXIN2, modulates beta-catenin stability.	35	41	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	37	38	40	41
Axin-2 shRNA mediated activation of Wnt and beta-catenin signaling improved behavioral functions and protected the nigralDAergic neurons by increasing mitochondrial functionality in parkinsonian rats .	Axin-2 shRNA mediated activation of Wnt and beta-catenin signaling improved behavioral functions and protected the nigralDAergic neurons by increasing mitochondrial functionality in parkinsonian rats.	0	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Axin-2	Axin-2	Axin-2	beta-catenin	beta-catenin	beta-catenin	0	1	7	8
Axin2 - a target of canonical beta-catenin 24 - was diminished in aortas deficient for LRP6 , while Klf5 - a target of noncanonical Wnt signaling like OPN XREF_BIBR , XREF_BIBR -- was upregulated along with the progenitor marker Sca1 27 ( XREF_FIG ) .	Axin2 - a target of canonical beta-catenin 24 - was diminished in aortas deficient for LRP6, while Klf5 - a target of noncanonical Wnt signaling like OPN XREF_BIBR, XREF_BIBR -- was upregulated along with the progenitor marker Sca1 27 (XREF_FIG).	0	10	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
Axin2 , one of the negative regulators of Wnt-beta-catenin , is expressed at higher levels in OPCs than in OLs and induces beta-catenin degradation .	Axin2, one of the negative regulators of Wnt-beta-catenin, is expressed at higher levels in OPCs than in OLs and induces beta-catenin degradation.	0	23	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2, one of the negative regulators of Wnt-beta-catenin, is expressed	axin2	beta-catenin	beta-catenin	beta-catenin	0	1	22	23
Some of these patterns are Wnt and beta-catenin signalling dependent , as exposure to Chi from 48 to 72h AA leads to a clear increase in Nodal , Lefty1 and Wnt3a , as well as in the Wnt and beta-catenin targets Axin2 , Dkk and cripto ( XREF_FIG ) .	Some of these patterns are Wnt and beta-catenin signalling dependent, as exposure to Chi from 48 to 72h AA leads to a clear increase in Nodal, Lefty1 and Wnt3a, as well as in the Wnt and beta-catenin targets Axin2, Dkk and cripto (XREF_FIG).	20	42	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	41	42	39	40
beta-catenin , the key effector of canonical Wnt signaling , can be phosphorylated and primed for proteasomal degradation by a destruction complex ( DC ) including the glykogen synthase kinase 3 beta ( GSK3beta ) and axin 2 , which triggers beta-catenin inactivation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	beta-catenin, the key effector of canonical Wnt signaling, can be phosphorylated and primed for proteasomal degradation by a destruction complex (DC) including the glykogen synthase kinase 3 beta (GSK3beta) and axin 2, which triggers beta-catenin inactivation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	21	42	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	axin 2	axin 2	axin 2	beta-catenin	beta-catenin	beta-catenin	36	38	41	42
Pericentral hepatocytes show active Wnt and beta-catenin signaling as demonstrated by pericentral specific expression of Wnt and beta-catenin targets Axin2 , glutamine synthetase ( GS ) , and cytochrome P450 enzymes CYP2E1 and CYP1A2 ( XREF_FIG ) .	Pericentral hepatocytes show active Wnt and beta-catenin signaling as demonstrated by pericentral specific expression of Wnt and beta-catenin targets Axin2, glutamine synthetase (GS), and cytochrome P450 enzymes CYP2E1 and CYP1A2 (XREF_FIG).	13	20	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	19	20	17	18
HIV clade B Tat , in primary progenitor derived astrocytes ( PDAs ) and U87MG cells , inhibited Wnt and beta-catenin signaling as demonstrated by its inhibition of active beta-catenin , TOPflash reporter activity , and Axin-2 ( a downstream target of Wnt and beta-catenin signaling ) .	HIV clade B Tat, in primary progenitor derived astrocytes (PDAs) and U87MG cells, inhibited Wnt and beta-catenin signaling as demonstrated by its inhibition of active beta-catenin, TOPflash reporter activity, and Axin-2 (a downstream target of Wnt and beta-catenin signaling).	26	45	target	Positive_activation_syntax_7_noun	Negative_activation	Negative_activation	Axin-2	Axin-2	Axin-2	beta-catenin	beta-catenin	beta-catenin	36	37	44	45
Of some interest , they did show that overexpression of a truncated AXIN2 protein , predicted to result from the frameshifts , promoted beta-catenin accumulation in cells in culture , consistent with a possible gain-of-function role for the truncated AXIN2 protein .	Of some interest, they did show that overexpression of a truncated AXIN2 protein, predicted to result from the frameshifts, promoted beta-catenin accumulation in cells in culture, consistent with a possible gain-of-function role for the truncated AXIN2 protein.	8	24	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AXIN2	overexpression of a truncated AXIN2	axin2	beta-catenin	beta-catenin	beta-catenin	12	13	23	24
In both cases we observed a significant increase in the proportion of cells expressing the BAT-gal reporter ( XREF_FIG ) and the endogenous Wnt and beta-catenin target Axin2 ( XREF_FIG ) after 24 hours , confirming successful activation of the pathway .	In both cases we observed a significant increase in the proportion of cells expressing the BAT-gal reporter (XREF_FIG) and the endogenous Wnt and beta-catenin target Axin2 (XREF_FIG) after 24 hours, confirming successful activation of the pathway.	16	28	target	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	27	28	25	26
Moreover , Wtx deficiency causes delays in the closure of the cranial suture whereas beta-catenin activation driven by Axin2 deficiency has the opposite phenotype , indicating that Wtx has functions that are independent of beta-catenin regulation in osteoblast differentiation .	Moreover, Wtx deficiency causes delays in the closure of the cranial suture whereas beta-catenin activation driven by Axin2 deficiency has the opposite phenotype, indicating that Wtx has functions that are independent of beta-catenin regulation in osteoblast differentiation.	14	19	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	18	19	14	15
Further , inhibition of Wnt activation by Dkk1 did not block activation of the beta-catenin target Axin2 in Notch activated cells , whereas Dkk1 did block Wnt3a induced Axin2 , thereby confirming Wnt independent activation of beta-catenin by Notch .	Further, inhibition of Wnt activation by Dkk1 did not block activation of the beta-catenin target Axin2 in Notch activated cells, whereas Dkk1 did block Wnt3a induced Axin2, thereby confirming Wnt independent activation of beta-catenin by Notch.	11	17	target	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	16	17	14	15
We first confirmed that Wnt3a and increasing concentrations of BIO induce Axin2 expression to activate Wnt and beta-catenin signaling ( XREF_FIG ) .	We first confirmed that Wnt3a and increasing concentrations of BIO induce Axin2 expression to activate Wnt and beta-catenin signaling (XREF_FIG).	4	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Axin2	Wnt3a and increasing concentrations of BIO induce Axin2 expression	axin2	beta-catenin	beta-catenin	beta-catenin	11	12	17	18
Accordingly , the direct Wnt and beta-catenin targets Axin2 and the canonical Wnt pathway receptor Fzd1 were up-regulated .	Accordingly, the direct Wnt and beta-catenin targets Axin2 and the canonical Wnt pathway receptor Fzd1 were up-regulated.	4	17	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	8	9	6	7
Additionally , because Axin2 is a component of the beta-catenin destruction complex , the high AXIN2 levels may result in reduced Wnt and beta-catenin signaling .	Additionally, because Axin2 is a component of the beta-catenin destruction complex, the high AXIN2 levels may result in reduced Wnt and beta-catenin signaling.	15	25	signaling	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	AXIN2	AXIN2 levels	axin2	beta-catenin	beta-catenin	beta-catenin	15	16	23	24
In addition , Wnt and beta-catenin signaling promotes the POU3F2 branch during CI but not during PE phase ( XREF_SUPPLEMENTARY ) , and consistent with this we observe the mid and hindbrain Wnt and beta-catenin targets AXIN2 and TNFRSF19 ( XREF_SUPPLEMENTARY , ) selectively expressed in the minor D12 progenitor cluster D12_P_S100A11 ( XREF_FIG , P < .01 , Fisher ' s exact test ) ; both of these insights together confirm the biological significance of our discovered cell types and suggest that the origin of the mid-hindbrain POU3F2 branch can occur during early neurodevelopment prior to the bifurcation at D26 ( XREF_FIG ) .	In addition, Wnt and beta-catenin signaling promotes the POU3F2 branch during CI but not during PE phase (XREF_SUPPLEMENTARY), and consistent with this we observe the mid and hindbrain Wnt and beta-catenin targets AXIN2 and TNFRSF19 (XREF_SUPPLEMENTARY,) selectively expressed in the minor D12 progenitor cluster D12_P_S100A11 (XREF_FIG, P <.01, Fisher 's exact test); both of these insights together confirm the biological significance of our discovered cell types and suggest that the origin of the mid-hindbrain POU3F2 branch can occur during early neurodevelopment prior to the bifurcation at D26 (XREF_FIG).	34	102	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	36	37	34	35
Thus , the lack of Axin2 induction correlates with the lesser capacity of L4 to induce a free pool of beta-catenin .	Thus, the lack of Axin2 induction correlates with the lesser capacity of L4 to induce a free pool of beta-catenin.	5	21	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	5	6	20	21
Mutations in APC , CTNNB1 , AXIN1 or AXIN2 cause impairment in the beta-catenin degradation pathway and result in accumulation of beta-catenin in a wide range of human cancers .	Mutations in APC, CTNNB1, AXIN1 or AXIN2 cause impairment in the beta-catenin degradation pathway and result in accumulation of beta-catenin in a wide range of human cancers.	0	15	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	8	9	13	14
In the absence of an activating signal , phosphorylation of beta-catenin by glycogen synthase kinase 3 ( GSK3 ) acting in conjunction with adenomatous polyposis coli and axin and conductin causes beta-catenin to interact with the beta-transducin repeat containing protein which results in its ubiquitination and degradation .	In the absence of an activating signal, phosphorylation of beta-catenin by glycogen synthase kinase 3 (GSK3) acting in conjunction with adenomatous polyposis coli and axin and conductin causes beta-catenin to interact with the beta-transducin repeat containing protein which results in its ubiquitination and degradation.	25	32	causes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	conductin	conductin	conductin	beta-catenin	beta-catenin	beta-catenin	29	30	31	32
17 Consistently , increased expression of beta-catenin targets Axin2 , C-Myc , Jag1 and CD44 is observed , suggesting beta-catenin transcriptional activity is induced in the Pten-null livers ( XREF_FIG ) .	17 Consistently, increased expression of beta-catenin targets Axin2, C-Myc, Jag1 and CD44 is observed, suggesting beta-catenin transcriptional activity is induced in the Pten-null livers (XREF_FIG).	6	14	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	8	9	6	7
We observed that dsRed2+ EpiSCs were modestly enriched , and Sox1-GFP + EpiSCs were slightly depleted , for the beta-catenin target Axin2 ( supplementary material Fig .	We observed that dsRed2+ EpiSCs were modestly enriched, and Sox1-GFP + EpiSCs were slightly depleted, for the beta-catenin target Axin2 (supplementary material Fig.	15	24	target	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	21	22	19	20
Interestingly , targeting the MNK-eIF4E axis decreased the expression of p-MNK1 and p-eIF4E and the mRNA and protein expression of factors downstream of beta-catenin signaling including c-Myc , cyclin D1 , MMP-7 , and Axin2 , but increased the expression of beta-catenin , which was inconsistent with IHC data and previous results .	Interestingly, targeting the MNK-eIF4E axis decreased the expression of p-MNK1 and p-eIF4E and the mRNA and protein expression of factors downstream of beta-catenin signaling including c-Myc, cyclin D1, MMP-7, and Axin2, but increased the expression of beta-catenin, which was inconsistent with IHC data and previous results.	23	35	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	34	35	23	24
Decreased available Axin2 protein reduces elimination of beta-catenin , allowing beta-catenin to translocate to the nucleus where it stimulates the transcription of various target genes .	Decreased available Axin2 protein reduces elimination of beta-catenin, allowing beta-catenin to translocate to the nucleus where it stimulates the transcription of various target genes.	2	8	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Axin2	Axin2	Axin2	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
In addition , we also determined the mRNA levels of Fgf21 ( a tyrosine kinase receptor ligand that inhibits osteoblastogenesis [ XREF_BIBR ] and Axin2 ( a target of the Wnt and beta-CATENIN pathway downstream of GSK3 ) .	In addition, we also determined the mRNA levels of Fgf21 (a tyrosine kinase receptor ligand that inhibits osteoblastogenesis [XREF_BIBR] and Axin2 (a target of the Wnt and beta-CATENIN pathway downstream of GSK3).	8	33	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	Axin2	Axin2	Axin2	beta-CATENIN	beta-CATENIN	beta-CATENIN	24	25	32	33
The general absence of nuclear beta-catenin in RMS tissue may also explain i ) the low levels of the widely recognized target of WNT and beta-catenin signaling AXIN2 in clinical samples and ii ) the lack of correlation between beta-catenin and CTNNB1 and LEF1 and LEF1 expression levels .	The general absence of nuclear beta-catenin in RMS tissue may also explain i) the low levels of the widely recognized target of WNT and beta-catenin signaling AXIN2 in clinical samples and ii) the lack of correlation between beta-catenin and CTNNB1 and LEF1 and LEF1 expression levels.	2	28	signaling	Positive_activation_token_1_noun	Negative_activation	Positive_activation	AXIN2	AXIN2	AXIN2	beta-catenin	beta-catenin	beta-catenin	27	28	25	26
Second , together with JNK1/2 phosphorylation , events pointing to autophagy activation such as BIM and BECLIN1 and BCL2 and BECLIN1 dissociation and SQSTM1 and p62 degradation were observed .	Second, together with JNK1/2 phosphorylation, events pointing to autophagy activation such as BIM and BECLIN1 and BCL2 and BECLIN1 dissociation and SQSTM1 and p62 degradation were observed.	11	21	activation	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	BIM	BIM	BIM	BCL2	BCL2	BCL2	14	15	18	19
Bim S -Bad BH3 F19A has little appreciable in vitro affinity for Mcl-1 ( 3B ) or Bcl-w ( IC 50 > 10muM in both cases ) and only targets to the mitochondria in the presence of Bcl-x L but not other Bcl-2 family members ( XREF_SUPPLEMENTARY ) .	Bim S -Bad BH3 F19A has little appreciable in vitro affinity for Mcl-1 (3B) or Bcl-w (IC 50> 10muM in both cases) and only targets to the mitochondria in the presence of Bcl-x L but not other Bcl-2 family members (XREF_SUPPLEMENTARY).	0	44	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	42	43
We show that this synergism is mediated by the pro apoptotic factor BIM , which is dephosphorylated as a result of MEK inhibition , allowing it to bind to and neutralize MCL-1 , thereby enhancing BCL-2 and BCL-XL inhibitor induced cell death .	We show that this synergism is mediated by the pro apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2 and BCL-XL inhibitor induced cell death.	6	36	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BIM	BIM, which is dephosphorylated	bim	BCL-2	BCL-2	bcl-2	12	13	35	36
Bim activates the proapoptotic Bcl-2 protein Bax in the mitochondria to release cytochrome C into the cytosol , which in turn initiates a downstream caspase program leading to apoptosis [ XREF_BIBR , XREF_BIBR ] .	Bim activates the proapoptotic Bcl-2 protein Bax in the mitochondria to release cytochrome C into the cytosol, which in turn initiates a downstream caspase program leading to apoptosis [XREF_BIBR, XREF_BIBR].	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	4	5
Bim and Puma appear to activate the mitochondrial pathway by interacting with and neutralizing the anti-apoptotic Bcl-2 homolog Bcl-x L , and inhibition of JNK prevented Bim and Puma induction , interaction with Bcl-x L , and induction of apoptosis .	Bim and Puma appear to activate the mitochondrial pathway by interacting with and neutralizing the anti-apoptotic Bcl-2 homolog Bcl-x L, and inhibition of JNK prevented Bim and Puma induction, interaction with Bcl-x L, and induction of apoptosis.	0	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	16	17
Using knockout mouse models and RNAi mediated gene silencing in cell lines , our group and others had demonstrated the importance of the mitochondrial apoptotic pathway in ER stress induced cell death , particularly the role of the pro apoptotic BH3-only BCL-2 family members , BIM and PUMA .	Using knockout mouse models and RNAi mediated gene silencing in cell lines, our group and others had demonstrated the importance of the mitochondrial apoptotic pathway in ER stress induced cell death, particularly the role of the pro apoptotic BH3-only BCL-2 family members, BIM and PUMA.	29	47	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BIM	BIM	BIM	BCL-2	BCL-2	BCL-2	45	46	41	42
Previous works limited themselves to the response of the Bcl-2 family induced by activators tBid and Bim solely .	Previous works limited themselves to the response of the Bcl-2 family induced by activators tBid and Bim solely.	9	17	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	16	17	9	10
Bim and Puma mediate cell death by negatively regulating the activity of pro survival Bcl-2 family members 23 .	Bim and Puma mediate cell death by negatively regulating the activity of pro survival Bcl-2 family members 23.	0	16	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	14	15
First , we took advantage of Bim +/- Bcl-2 -/- mice , as loss of a single allele of Bim has previously been shown to prevent the early lethality and kidney disease of Bcl-2 deficiency .	First, we took advantage of Bim +/- Bcl-2 -/- mice, as loss of a single allele of Bim has previously been shown to prevent the early lethality and kidney disease of Bcl-2 deficiency.	17	34	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	19	20	33	34
One possibility is that the absence of Bim allows Bcl-2 lo cells the opportunity to survive , since a major function of Bcl-2 is to restrain Bim .	One possibility is that the absence of Bim allows Bcl-2 lo cells the opportunity to survive, since a major function of Bcl-2 is to restrain Bim.	5	11	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	7	8	9	10
A hydrocarbon stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity , blocked inhibitory antiapoptotic interactions , directly triggered proapoptotic activity , and induced dose responsive and BH3 sequence specific cell death of hematologic cancer cells .	A hydrocarbon stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity, blocked inhibitory antiapoptotic interactions, directly triggered proapoptotic activity, and induced dose responsive and BH3 sequence specific cell death of hematologic cancer cells.	7	14	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BIM	BIM	BIM	BCL-2	BCL-2	BCL-2	7	8	12	13
Following an apoptotic-stress event , BIM translocates to the mitochondria and initiates the mitochondrial cell death pathway by either directly activating BAX like proteins or indirectly binding pro survival BCL-2 family members , thereby releasing the BAX like proteins XREF_BIBR , XREF_BIBR .	Following an apoptotic-stress event, BIM translocates to the mitochondria and initiates the mitochondrial cell death pathway by either directly activating BAX like proteins or indirectly binding pro survival BCL-2 family members, thereby releasing the BAX like proteins XREF_BIBR, XREF_BIBR.	5	31	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BIM	BIM translocates to the mitochondria	bim	BCL-2	BCL-2	bcl-2	5	6	29	30
In particular , the increased expression of the pro apoptotic member Bim in T cells after cytokine deprival relieves the inhibitory effect anti-apoptotic Bcl-2 and Bcl-xL exert on Bax and Bak .	In particular, the increased expression of the pro apoptotic member Bim in T cells after cytokine deprival relieves the inhibitory effect anti-apoptotic Bcl-2 and Bcl-xL exert on Bax and Bak.	11	25	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	11	12	23	24
In response to different stimuli , Bcl2L11 is produced and can induce apoptosis by inactivating anti-apoptotic Bcl2 proteins and activating BAX-BAK1 [ XREF_BIBR , XREF_BIBR ] .	In response to different stimuli, Bcl2L11 is produced and can induce apoptosis by inactivating anti-apoptotic Bcl2 proteins and activating BAX-BAK1 [XREF_BIBR, XREF_BIBR].	6	17	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl2L11	Bcl2L11	Bcl2L11	Bcl2	Bcl2	Bcl2	6	7	16	17
Bim is classically thought to promote apoptosis by neutralizing pro survival Bcl-2 proteins .	Bim is classically thought to promote apoptosis by neutralizing pro survival Bcl-2 proteins.	0	12	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	11	12
Furthermore , it was shown recently that the human Bcl-2 family protein BAX is activated by binding of the helical BIM SAHB peptide on the 1-6 face of the protein .	Furthermore, it was shown recently that the human Bcl-2 family protein BAX is activated by binding of the helical BIM SAHB peptide on the 1-6 face of the protein.	7	22	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BIM	BIM	BIM	Bcl-2	Bcl-2	Bcl-2	20	21	9	10
Curcumin upregulates the p53 modulator of apoptosis ( PUMA ) and Noxa , which , in turn , activates the proapoptotic multi-domain Bcl-2 family members Bax , Bim , and Bak and downregulates Bcl-2 and Bcl-xl .	Curcumin upregulates the p53 modulator of apoptosis (PUMA) and Noxa, which, in turn, activates the proapoptotic multi-domain Bcl-2 family members Bax, Bim, and Bak and downregulates Bcl-2 and Bcl-xl.	4	28	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	27	28	22	23
The activation of Bim can induce BCL2 associated X ( Bax ) expression , thus increasing cell apoptosis via the mitochondrial pathways .	The activation of Bim can induce BCL2 associated X (Bax) expression, thus increasing cell apoptosis via the mitochondrial pathways.	1	7	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	BCL2	BCL2	BCL2	3	4	6	7
We used real-time PCR to examine their expressions in splenic MOG specific CD4 T cells from animals 9 days after EAE induction , and we found that the expression of the pro apoptotic Bim was increased in Id2 deficient CD4 T cells but not Bcl-2 ( XREF_FIG ) .	We used real-time PCR to examine their expressions in splenic MOG specific CD4 T cells from animals 9 days after EAE induction, and we found that the expression of the pro apoptotic Bim was increased in Id2 deficient CD4 T cells but not Bcl-2 (XREF_FIG).	28	46	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	expression of the pro apoptotic Bim	bim	Bcl-2	Bcl-2	bcl-2	33	34	44	45
Sodium arsenite induces apoptosis in PC12 cells by activating the stress activated p38 MAP kinase and the pro apoptotic Bcl-2 family protein Bim ( EL ) .	Sodium arsenite induces apoptosis in PC12 cells by activating the stress activated p38 MAP kinase and the pro apoptotic Bcl-2 family protein Bim (EL).	11	24	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	22	23	19	20
Bim activates pro apoptotic proteins Bcl-2 associated X protein ( Bax ) and Bcl-2 homologous antagonist and killer ( Bak ) , which in-turn exert their apoptotic activities with other pro apoptotic and anti-apoptotic Bcl-2 family proteins .	Bim activates pro apoptotic proteins Bcl-2 associated X protein (Bax) and Bcl-2 homologous antagonist and killer (Bak), which in-turn exert their apoptotic activities with other pro apoptotic and anti-apoptotic Bcl-2 family proteins.	0	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	5	6
Because loss of a single Bim allele prevents the lethality and kidney disease of Bcl-2 deficiency , we reasoned that Bim +/-Bcl-2-/- mice could be used to determine whether Bcl-2 is required for T cell survival in vivo when Bim expression is reduced by 50 % .	Because loss of a single Bim allele prevents the lethality and kidney disease of Bcl-2 deficiency, we reasoned that Bim +/-Bcl-2-/- mice could be used to determine whether Bcl-2 is required for T cell survival in vivo when Bim expression is reduced by 50%.	5	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	5	6	14	15
Bid and Bim ) enabling them to bind and regulate anti-apoptotic Bcl-2 proteins .	Bid and Bim) enabling them to bind and regulate anti-apoptotic Bcl-2 proteins.	0	12	enabling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	2	3	11	12
In colon cancer cells , Bim induction , though not required , likely potentiates PUMA dependent apoptosis by antagonizing anti-apoptotic Bcl-2 family proteins including Mcl-1 , whose levels remain high after treatment .	In colon cancer cells, Bim induction, though not required, likely potentiates PUMA dependent apoptosis by antagonizing anti-apoptotic Bcl-2 family proteins including Mcl-1, whose levels remain high after treatment.	5	22	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	5	6	20	21
Following detection of cellular stress induced by conditions such as growth factor withdrawal , irradiation , or cytotoxic chemicals , Bim mediates apoptosis by driving activation of Bcl-2 family death effector molecules and subsequent disruption of the outer mitochondrial membrane , cytochrome C release , apoptosome complex assembly , pro caspase 9 cleavage , and apoptosis .	Following detection of cellular stress induced by conditions such as growth factor withdrawal, irradiation, or cytotoxic chemicals, Bim mediates apoptosis by driving activation of Bcl-2 family death effector molecules and subsequent disruption of the outer mitochondrial membrane, cytochrome C release, apoptosome complex assembly, pro caspase 9 cleavage, and apoptosis.	20	31	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	20	21	27	28
The removal of one bim allele rescues the renal phenotype and survival of bcl-2 -/- mice , whereas loss of both bim alleles further corrects the hypopigmentation phenotype .	The removal of one bim allele rescues the renal phenotype and survival of bcl-2 -/- mice, whereas loss of both bim alleles further corrects the hypopigmentation phenotype.	4	15	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	bim	bim	bim	bcl-2	bcl-2	bcl-2	4	5	13	14
Mechanistically , G-Rg1 promoted the phosphorylation of Akt and FoxO3a and led to the cytoplasmic translocation of FoxO3a , which in turn suppressed FoxO3a modulated expression of proapoptotic Bim and elevated the ratio of Bcl-2 to Bax .	Mechanistically, G-Rg1 promoted the phosphorylation of Akt and FoxO3a and led to the cytoplasmic translocation of FoxO3a, which in turn suppressed FoxO3a modulated expression of proapoptotic Bim and elevated the ratio of Bcl-2 to Bax.	17	35	elevated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	FoxO3a, which in turn suppressed FoxO3a modulated expression of proapoptotic Bim	bim	Bcl-2	Bcl-2	bcl-2	28	29	34	35
This may occur through several mechanisms including decreased RNA expression , increased anti-apoptotic BCL2 family member expression , or alterations in the BIM splicing machinery .	This may occur through several mechanisms including decreased RNA expression, increased anti-apoptotic BCL2 family member expression, or alterations in the BIM splicing machinery.	11	24	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BIM	BIM	BIM	BCL2	BCL2	BCL2	22	23	13	14
T cell deletion can also occur in the periphery where autoreactive T cells die by apoptosis dependent on the pro survival BCL-2 antagonist BIM and triggered by the death receptor FAS .	T cell deletion can also occur in the periphery where autoreactive T cells die by apoptosis dependent on the pro survival BCL-2 antagonist BIM and triggered by the death receptor FAS.	16	24	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	BIM	BIM	BIM	BCL-2	BCL-2	BCL-2	23	24	21	22
Bim eventually activates pro apoptotic Bcl-2 family members ( BAX or BAK ) to induce apoptosis .	Bim eventually activates pro apoptotic Bcl-2 family members (BAX or BAK) to induce apoptosis.	0	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-2	Bcl-2	Bcl-2	0	1	5	6
Nevertheless , BCL-X L expression did not restore the organelle localization of BAK in ZP114 cells ( XREF_FIG , lanes 7 and 8 ) , suggesting that BCL-X L did not function redundantly with VDAC2 with respect to the organelle localization of BAK .	Nevertheless, BCL-X L expression did not restore the organelle localization of BAK in ZP114 cells (XREF_FIG, lanes 7 and 8), suggesting that BCL-X L did not function redundantly with VDAC2 with respect to the organelle localization of BAK.	2	13	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-X L	BCL-X L expression	bcl-x l	BAK	BAK	bak	2	4	12	13
Cotransfection of Bcl-X L and Bak caused no change in Bak localization ( XREF_FIG D ) .	Cotransfection of Bcl-X L and Bak caused no change in Bak localization (XREF_FIG D).	2	11	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-X L	Bcl-X L	Bcl-X L	Bak	Bak	Bak	2	4	10	11
Strikingly , increased levels of Bcl-xL accelerate Bak retrotranslocation into the cytosol and increase the cytosolic pools of overexpressed and endogenous Bak .	Strikingly, increased levels of Bcl-xL accelerate Bak retrotranslocation into the cytosol and increase the cytosolic pools of overexpressed and endogenous Bak.	3	22	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	levels of Bcl-xL	bcl-xl	Bak	Bak	bak	5	6	21	22
Interestingly , an equimolar concentration of n/c BID and BCL-xL ( 100 nM ) induced BAK BH4 cleavage by calpain in the absence of MOMP , consistent with MODE 2 inhibition .	Interestingly, an equimolar concentration of n/c BID and BCL-xL (100 nM) induced BAK BH4 cleavage by calpain in the absence of MOMP, consistent with MODE 2 inhibition.	4	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-xL	BCL-xL	BCL-xL	BAK	BAK	BAK	9	10	15	16
Overexpression of antiapoptotic BCL-2 family members BCL-X L and MCL-1 restores peroxisome formation in ZP114 cells ( XREF_FIG ) even though the localization of BAK is not altered ( XREF_FIG ) , suggesting that some BCL-X L and MCL-1 may target to peroxisomes to inhibit BAK , at least upon overexpression .	Overexpression of antiapoptotic BCL-2 family members BCL-X L and MCL-1 restores peroxisome formation in ZP114 cells (XREF_FIG) even though the localization of BAK is not altered (XREF_FIG), suggesting that some BCL-X L and MCL-1 may target to peroxisomes to inhibit BAK, at least upon overexpression.	35	48	target	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BCL-X L	BCL-X L	BCL-X L	BAK	BAK	BAK	35	37	45	46
XREF_BIBR , XREF_BIBR ABT-737 , a small-molecule inhibitor of BCL-2 , BCL-X L and BCL-W , induces apoptosis in a BAX- and BAK dependent manner .	XREF_BIBR, XREF_BIBR ABT-737, a small-molecule inhibitor of BCL-2, BCL-X L and BCL-W, induces apoptosis in a BAX- and BAK dependent manner.	11	24	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BCL-X L	BCL-X L	BCL-X L	BAK	BAK	BAK	11	13	22	23
COX-2 is upregulated in MDA-MB-231 and RR10 cells compared with in MDA-MB-231 cells , and silencing of COX-2 expression by shRNA in MDA-MB-231 and RR10 cells decreases the expression of Bcl-2 and Bcl-XL , but increases the proapoptotic protein BAK , leading to the increased apoptosis following treatment with gamma irradiation in comparison with those in control cells .	COX-2 is upregulated in MDA-MB-231 and RR10 cells compared with in MDA-MB-231 cells, and silencing of COX-2 expression by shRNA in MDA-MB-231 and RR10 cells decreases the expression of Bcl-2 and Bcl-XL, but increases the proapoptotic protein BAK, leading to the increased apoptosis following treatment with gamma irradiation in comparison with those in control cells.	17	40	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-XL	COX-2 expression by shRNA in MDA-MB-231 and RR10 cells decreases the expression of Bcl-2 and Bcl-XL	bcl-xl	BAK	BAK	bak	32	33	39	40
In GC resistant cell lines , this effect was mediated , at least in part , by inhibition of Akt and affecting downstream Akt targets such as Bad , a proapoptotic Bcl-2 family member , and the X linked inhibitor of apoptosis protein ( XIAP ) .	In GC resistant cell lines, this effect was mediated, at least in part, by inhibition of Akt and affecting downstream Akt targets such as Bad, a proapoptotic Bcl-2 family member, and the X linked inhibitor of apoptosis protein (XIAP).	24	33	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	27	28	31	32
Taken together , CD and VOSL treatment can up-regulate the expression of p53 , down-regulate the phosphorylation levels of BID and BAD and increase the ratio of BAX to BCL-2 , to trigger the mitochondrial dependent apoptotic pathway .	Taken together, CD and VOSL treatment can up-regulate the expression of p53, down-regulate the phosphorylation levels of BID and BAD and increase the ratio of BAX to BCL-2, to trigger the mitochondrial dependent apoptotic pathway.	3	30	increase	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	BAD	CD and VOSL treatment can up-regulate the expression of p53, down-regulate the phosphorylation levels of BID and BAD	bad	BCL-2	BCL-2	bcl-2	21	22	29	30
In prostate cancer cells , ErbB2 and HER2 activates ERK to phosphorylate and deactivate Bad , which is then in turn unable to deactivate the anti-apoptotic proteins Bcl-2 and Bcl-X L.	In prostate cancer cells, ErbB2 and HER2 activates ERK to phosphorylate and deactivate Bad, which is then in turn unable to deactivate the anti-apoptotic proteins Bcl-2 and Bcl-X L.	11	30	deactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	phosphorylate and deactivate Bad	bad	Bcl-2	Bcl-2	bcl-2	14	15	27	28
This leads to sequestering of Bcl2 by Bad , which inhibits its downstream anti-apoptotic activity .	This leads to sequestering of Bcl2 by Bad, which inhibits its downstream anti-apoptotic activity.	1	10	sequestering	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl2	Bcl2	Bcl2	7	8	5	6
14-3-3zeta was found to play a major role in anti-apoptosis by directly binding with Akt phosphorylated Bad , a pro apoptotic protein , at one or more serine sites , thereby blocking the inhibition of Bcl-2 by Bad XREF_BIBR .	14-3-3zeta was found to play a major role in anti-apoptosis by directly binding with Akt phosphorylated Bad, a pro apoptotic protein, at one or more serine sites, thereby blocking the inhibition of Bcl-2 by Bad XREF_BIBR.	14	36	blocking	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	Akt phosphorylated Bad, a pro apoptotic protein, at one or more serine	bad	Bcl-2	Bcl-2	bcl-2	16	17	35	36
ABT-737 , and the orally bioavailable derivative ABT-263 , are mimetics based on the pro apoptotic BH3-only protein Bad , which selectively target Bcl-2 , Bcl-xL and Bcl-w , but do not inhibit Mcl-1 .	ABT-737, and the orally bioavailable derivative ABT-263, are mimetics based on the pro apoptotic BH3-only protein Bad, which selectively target Bcl-2, Bcl-xL and Bcl-w, but do not inhibit Mcl-1.	17	32	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	18	19	23	24
Akt inhibits apoptosis by four main mechanisms : ( 1 ) phosphorylation and inactivation of BAD , which normally binds to and inactivates antiapoptotic Bcl 2 and Bcl XL , a critical step in the activation of the caspase protease pathway .	Akt inhibits apoptosis by four main mechanisms : (1) phosphorylation and inactivation of BAD, which normally binds to and inactivates antiapoptotic Bcl 2 and Bcl XL, a critical step in the activation of the caspase protease pathway.	11	28	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BAD	phosphorylation and inactivation of BAD	bad	Bcl 2	Bcl 2	bcl 2	15	16	24	26
This idea is also supported by the observations that integrins promote cell survival after injury and apoptotic insults through stimulation of the PI3K-Akt pathway which leads to phosphorylation of the pro apoptotic protein , BAD , thereby enhancing the anti-apoptotic effects of Bcl-2 ( Gilcrease , 2006 ) .	This idea is also supported by the observations that integrins promote cell survival after injury and apoptotic insults through stimulation of the PI3K-Akt pathway which leads to phosphorylation of the pro apoptotic protein, BAD, thereby enhancing the anti-apoptotic effects of Bcl-2 (Gilcrease, 2006).	22	43	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAD	PI3K-Akt pathway which leads to phosphorylation of the pro apoptotic protein, BAD	bad	Bcl-2	Bcl-2	bcl-2	34	35	42	43
This hormone protects neurons in the peripheral nervous system from apoptosis by activating the PI3K and Akt pathway , which in turn phosphorylates Bad and activates Bcl 2 , an anti-apoptotic protein that interferes with the activation of caspases [ XREF_BIBR - XREF_BIBR ] .	This hormone protects neurons in the peripheral nervous system from apoptosis by activating the PI3K and Akt pathway, which in turn phosphorylates Bad and activates Bcl 2, an anti-apoptotic protein that interferes with the activation of caspases [XREF_BIBR - XREF_BIBR].	14	31	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	PI3K and Akt pathway, which in turn phosphorylates Bad	bad	Bcl 2	Bcl 2	bcl 2	23	24	26	28
Protein Bad binds and inactivate inhibitors of apoptosis Bcl-2 and Bcl-XL .	Protein Bad binds and inactivate inhibitors of apoptosis Bcl-2 and Bcl-XL.	0	10	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	Bad	Bad	Bcl-2	Bcl-2	Bcl-2	1	2	8	9
Moreover , mice ablated for the anti-apoptotic protein Bcl-2 , which is activated by Akt phosphorylation of BAD at S136 ( Datta etal , 1997 ) , exhibit severe manifestation of cystic kidney disease ( Veis etal , 1993 ) .	Moreover, mice ablated for the anti-apoptotic protein Bcl-2, which is activated by Akt phosphorylation of BAD at S136 (Datta etal, 1997), exhibit severe manifestation of cystic kidney disease (Veis etal, 1993).	5	27	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BAD	phosphorylation of BAD at S136	bad	Bcl-2	Bcl-2	bcl-2	17	18	8	9
The phosphorylation of BAD protein by phospho-Akt promotes its association with 14-3-3 protein and allows Bcl-2 to act as an anti-apoptotic factor and promote survival .	The phosphorylation of BAD protein by phospho-Akt promotes its association with 14-3-3 protein and allows Bcl-2 to act as an anti-apoptotic factor and promote survival.	1	23	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAD protein	phosphorylation of BAD protein	bad protein	Bcl-2	Bcl-2	bcl-2	3	5	15	16
Translocation of Bad to the mitochondrial membrane eliminates the inhibitory effects of Bcl2 on Bax .	Translocation of Bad to the mitochondrial membrane eliminates the inhibitory effects of Bcl2 on Bax.	0	13	eliminates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	Translocation of Bad to the mitochondrial membrane	bad	Bcl2	Bcl2	bcl2	2	3	12	13
BAD is known to promote cell death by antagonizing anti-death BCL-2 proteins , but a number of studies clearly show that BAD has a normal physiological role in healthy cells .	BAD is known to promote cell death by antagonizing anti-death BCL-2 proteins, but a number of studies clearly show that BAD has a normal physiological role in healthy cells.	0	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAD	BAD	BAD	BCL-2	BCL-2	BCL-2	0	1	10	11
The phosphorylation of BAD enables BCL2 to act as an anti-apoptotic factor and promote cell survival [ XREF_BIBR ] .	The phosphorylation of BAD enables BCL2 to act as an anti-apoptotic factor and promote cell survival [XREF_BIBR].	1	6	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAD	phosphorylation of BAD	bad	BCL2	BCL2	bcl2	3	4	5	6
In contrast , the BAD mimetic ABT-199 , which specifically targets BCL-2 , induced the activation of BAX within two hours in sensitive patient cells , consistent with the direct inhibitory mode of action of this drug .	In contrast, the BAD mimetic ABT-199, which specifically targets BCL-2, induced the activation of BAX within two hours in sensitive patient cells, consistent with the direct inhibitory mode of action of this drug.	4	12	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAD	BAD	BAD	BCL-2	BCL-2	BCL-2	4	5	11	12
For instance , inhibiting the AKT mediated phosphorylation of Bad would limit its sequestration and promote Bcl-2 activation leading to apoptosis .	For instance, inhibiting the AKT mediated phosphorylation of Bad would limit its sequestration and promote Bcl-2 activation leading to apoptosis.	5	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	AKT mediated phosphorylation of Bad	bad	Bcl-2	Bcl-2	bcl-2	9	10	16	17
The ERK and Akt pathway can phosphorylate Bad , which allows Bcl-2 to form homodimers that result in the generation of an antiapoptotic response .	The ERK and Akt pathway can phosphorylate Bad, which allows Bcl-2 to form homodimers that result in the generation of an antiapoptotic response.	1	13	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	ERK and Akt pathway can phosphorylate Bad	bad	Bcl-2	Bcl-2	bcl-2	7	8	11	12
We subsequently demonstrate that Fallopian tube biopsies from smokers exhibit evidence of an anti-apoptotic profile ( reduced BAD , increased BCL2 ) , a trend towards increased cellular proliferation and decreased cell death , and structural changes in epithelial cell surface structure .	We subsequently demonstrate that Fallopian tube biopsies from smokers exhibit evidence of an anti-apoptotic profile (reduced BAD, increased BCL2), a trend towards increased cellular proliferation and decreased cell death, and structural changes in epithelial cell surface structure.	17	21	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BAD	BAD	BAD	BCL2	BCL2	BCL2	17	18	20	21
Raf-1 , one of the downstream targets of Ras , has been reported to activate bcl-2 through displacement and/or phosphorylation of Bad .	Raf-1, one of the downstream targets of Ras, has been reported to activate bcl-2 through displacement and/or phosphorylation of Bad.	14	22	activate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Bad	phosphorylation of Bad	bad	bcl-2	bcl-2	bcl-2	21	22	15	16
The ERK pathway phosphorylates Bad , which promotes Bcl-2 to form homodimers to bind Bax and inhibit its activation .	The ERK pathway phosphorylates Bad, which promotes Bcl-2 to form homodimers to bind Bax and inhibit its activation.	1	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	ERK pathway phosphorylates Bad	bad	Bcl-2	Bcl-2	bcl-2	4	5	8	9
Enhancement of p-Bad could induce the release of Bcl-2 from Bcl-2 and Bad dimmer .	Enhancement of p-Bad could induce the release of Bcl-2 from Bcl-2 and Bad dimmer.	0	9	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p-Bad	p-Bad	p-Bad	Bcl-2	Bcl-2	Bcl-2	2	3	8	9
When unphosphorylated , active Bad induces apoptosis by sequestering anti-apoptotic members of the Bcl2 family ( e.g ., Bcl2 and BclXL ) , permitting aggregation of pro apoptotic members ( e.g ., Bax and Bak ) .	When unphosphorylated, active Bad induces apoptosis by sequestering anti-apoptotic members of the Bcl2 family (e.g., Bcl2 and BclXL), permitting aggregation of pro apoptotic members (e.g., Bax and Bak).	3	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	Bad	Bad	Bcl2	Bcl2	Bcl2	4	5	13	14
Besides , AKT phosphorylates BAD , which no longer interacts with Bcl-2 ( anti-apoptotic members of the bcl-2 family ) , resulting in Bcl-2 activation .	Besides, AKT phosphorylates BAD, which no longer interacts with Bcl-2 (anti-apoptotic members of the bcl-2 family), resulting in Bcl-2 activation.	3	25	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	BAD	phosphorylates BAD	bad	Bcl-2	Bcl-2	bcl-2	4	5	23	24
Since the inactivation of p-Bad via its dephosphorylation induces Bcl-2 down-regulation leading to apoptosis XREF_BIBR , the state of p-Bad was examined in response to Antho 50 treatment .	Since the inactivation of p-Bad via its dephosphorylation induces Bcl-2 down-regulation leading to apoptosis XREF_BIBR, the state of p-Bad was examined in response to Antho 50 treatment.	2	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p-Bad	p-Bad	p-Bad	Bcl-2	Bcl-2	Bcl-2	4	5	9	10
ERK1/2 activation through active Ras and PKA has also been shown to block cytochrome c release through Bad mediated Bcl-xL inhibition [ XREF_BIBR ] .	ERK1/2 activation through active Ras and PKA has also been shown to block cytochrome c release through Bad mediated Bcl-xL inhibition [XREF_BIBR].	15	20	mediated	Positive_early_activation	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-xL	Bcl-xL	Bcl-xL	17	18	19	20
Mechanistically , shRNA mediated suppression of BAD or hnRNP A1 that , in turn , leads to Bcl-xL but not Bcl-2 downregulation , allowed us to determine that inhibition of Bcl-xL and restoration of BAD activity mostly accounts for the apoptosis induced in CD34 + CML-BC progenitors by the Bcl-xL and Bcl2 antagonist ABT-263 and mTORC1/2 inhibitor PP242 , respectively ( XREF_FIG ) .	Mechanistically, shRNA mediated suppression of BAD or hnRNP A1 that, in turn, leads to Bcl-xL but not Bcl-2 downregulation, allowed us to determine that inhibition of Bcl-xL and restoration of BAD activity mostly accounts for the apoptosis induced in CD34 + CML-BC progenitors by the Bcl-xL and Bcl2 antagonist ABT-263 and mTORC1/2 inhibitor PP242, respectively (XREF_FIG).	6	18	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	BAD	BAD	BAD	Bcl-xL	Bcl-xL	Bcl-xL	6	7	17	18
Isoflurane , not sevoflurane at the equivalent dose , induced significant neuroapoptosis , decreased the levels of phospho-Akt and phospho-Bad proteins , increased the expression of Bad protein and reduced the ratio of Bcl-xL and Bad in the hippocampus .	Isoflurane, not sevoflurane at the equivalent dose, induced significant neuroapoptosis, decreased the levels of phospho-Akt and phospho-Bad proteins, increased the expression of Bad protein and reduced the ratio of Bcl-xL and Bad in the hippocampus.	0	35	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad protein	Isoflurane, not sevoflurane at the equivalent dose, induced significant neuroapoptosis, decreased the levels of phospho-Akt and phospho-Bad proteins, increased the expression of Bad protein	bad protein	Bcl-xL	Bcl-xL	bcl-xl	26	28	33	34
Decreased Bad and Bcl-XL binding induced by rapamycin can render Bad less able to suppress the antiapoptotic function of Bcl-XL .	Decreased Bad and Bcl-XL binding induced by rapamycin can render Bad less able to suppress the antiapoptotic function of Bcl-XL.	10	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bad	Bad	Bad	Bcl-XL	Bcl-XL	Bcl-XL	10	11	19	20
KG-1a and MV4.11 cells also retained some capacity to respond to BAD-BH3 , likely due to residual BCL-X L , which is targeted by BAD , but not by ABT-199 .	KG-1a and MV4.11 cells also retained some capacity to respond to BAD-BH3, likely due to residual BCL-X L, which is targeted by BAD, but not by ABT-199.	17	25	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BAD	BAD	BAD	BCL-X L	BCL-X L	BCL-X L	24	25	17	19
Similarly , mTORC2 at mitochondria could help ensure efficient coupling of Akt phosphorylation to downstream targets like Bad , Bim , or Bcl-XL , which are themselves located at the mitochondria , thereby directly linking mTORC2 with cell survival as proposed earlier .	Similarly, mTORC2 at mitochondria could help ensure efficient coupling of Akt phosphorylation to downstream targets like Bad, Bim, or Bcl-XL, which are themselves located at the mitochondria, thereby directly linking mTORC2 with cell survival as proposed earlier.	6	27	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Bad	Bad	Bad	Bcl-XL	Bcl-XL	Bcl-XL	17	18	22	23
Phosphorylation of Bad by Akt leads to the binding of Bad with the cytosolic protein 14-3-3 to release Bcl-x L and allows Akt to block apoptosis [ XREF_BIBR ] .	Phosphorylation of Bad by Akt leads to the binding of Bad with the cytosolic protein 14-3-3 to release Bcl-x L and allows Akt to block apoptosis [XREF_BIBR].	0	20	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bad	Phosphorylation of Bad	bad	Bcl-x L	Bcl-x L	bcl-x l	2	3	18	20
Thus , it appears that Bcl-w activates complex-I by binding to Bax and promoting the release of Bax from complex-I .	Thus, it appears that Bcl-w activates complex-I by binding to Bax and promoting the release of Bax from complex-I.	5	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-w	Bcl-w	Bcl-w	Bax	Bax	Bax	5	6	17	18
Down-regulation of Bcl-w activates Bax and Bak , and then induces apoptosis XREF_BIBR , XREF_BIBR .	Down-regulation of Bcl-w activates Bax and Bak, and then induces apoptosis XREF_BIBR, XREF_BIBR.	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-w	Bcl-w	Bcl-w	Bax	Bax	Bax	2	3	4	5
We concluded from these data that Bim and Bmf activate apoptotic pathways by functionally sequestering Mcl-1 and Bcl-X L , respectively .	We concluded from these data that Bim and Bmf activate apoptotic pathways by functionally sequestering Mcl-1 and Bcl-X L, respectively.	6	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-X L	Bcl-X L	Bcl-X L	6	7	17	19
Thus , both decreasing expression of Bcl-xL and increasing expression of Bim were involved in beta-cell apoptosis induced by KD of IRS2 .	Thus, both decreasing expression of Bcl-xL and increasing expression of Bim were involved in beta-cell apoptosis induced by KD of IRS2.	6	12	increasing	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Bim	expression of Bim	bim	Bcl-xL	Bcl-xL	bcl-xl	11	12	6	7
Bcl-xL , in its anti-apoptotic role , enhances VDAC conductance after a cell death stimulus to enhance ATP release .	Bcl-xL, in its anti-apoptotic role, enhances VDAC conductance after a cell death stimulus to enhance ATP release.	0	9	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	VDAC	VDAC	VDAC	0	1	8	9
Bcl-xL expression sustains OMM permeability under these conditions , and increases the VDAC gating potential in reconstituted preparations [ XREF_BIBR ] .	Bcl-xL expression sustains OMM permeability under these conditions, and increases the VDAC gating potential in reconstituted preparations [XREF_BIBR].	0	14	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL expression	bcl-xl	VDAC	VDAC	vdac	0	1	12	13
In fact , whereas the BH4 domain of Bcl-XL is able to selectively target and inhibit the N-terminal domain of VDAC1 , the BH4 domain of Bcl-2 is uniquely involved in inhibiting the IP 3 Rs .	In fact, whereas the BH4 domain of Bcl-XL is able to selectively target and inhibit the N-terminal domain of VDAC1, the BH4 domain of Bcl-2 is uniquely involved in inhibiting the IP 3 Rs.	6	21	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-XL	Bcl-XL	Bcl-XL	VDAC1	VDAC1	VDAC1	8	9	20	21
As stated above , Bcl-xL increases the conductance of VDAC to release ATP from mitochondria in both cancer cells and squiid synapse .	As stated above, Bcl-xL increases the conductance of VDAC to release ATP from mitochondria in both cancer cells and squiid synapse.	4	10	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xL	Bcl-xL	Bcl-xL	VDAC	VDAC	VDAC	4	5	9	10
In addition , via its BH4 domain , Bcl-XL at MAMs can also target VDAC1 XREF_BIBR , and inhibition of VDAC1 by Bcl-XL prevents mitochondrial Ca 2+ overload and protects against apoptosis XREF_BIBR .	In addition, via its BH4 domain, Bcl-XL at MAMs can also target VDAC1 XREF_BIBR, and inhibition of VDAC1 by Bcl-XL prevents mitochondrial Ca 2+ overload and protects against apoptosis XREF_BIBR.	8	15	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-XL	Bcl-XL	Bcl-XL	VDAC1	VDAC1	VDAC1	8	9	14	15
Indeed , some reports shows that VDAC closure is a sort of anti-apoptotic signal , as demonstrate , for example , by the role of hexokinases or gelsolin ; on the opposite side , VDAC closure has been also shown to enhance cell death through apoptosis , given that Bcl-XL , an anti-apoptotic Bcl-2 family member , triggers VDAC opening and , in parallel , some apoptotic stimuli such as serum deprivation , reduces OMM permeability .	Indeed, some reports shows that VDAC closure is a sort of anti-apoptotic signal, as demonstrate, for example, by the role of hexokinases or gelsolin; on the opposite side, VDAC closure has been also shown to enhance cell death through apoptosis, given that Bcl-XL, an anti-apoptotic Bcl-2 family member, triggers VDAC opening and, in parallel, some apoptotic stimuli such as serum deprivation, reduces OMM permeability.	49	59	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-XL	Bcl-XL	Bcl-XL	VDAC	VDAC	VDAC	49	50	58	59
In conclusion , we have found that desflurane activated NF-kappaB during the preconditioning period , inhibited excessive activation of NF-kappaB in reperfusion , up-regulated Bcl-2 and c-IAP1 expression and inhibited SMAC release and caspase-3 cleavage after A/R injury .	In conclusion, we have found that desflurane activated NF-kappaB during the preconditioning period, inhibited excessive activation of NF-kappaB in reperfusion, up-regulated Bcl-2 and c-IAP1 expression and inhibited SMAC release and caspase-3 cleavage after A/R injury.	7	31	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Bcl-2	desflurane activated NF-kappaB during the preconditioning period, inhibited excessive activation of NF-kappaB in reperfusion, up-regulated Bcl-2 and c-IAP1 expression	bcl-2	SMAC	SMAC	smac	24	25	30	31
Thus , mitochondria and associated Bcl-2 and Bcl-x ( L ) proteins may play a functional role in death receptor induced apoptosis by modulating the release of Smac .	Thus, mitochondria and associated Bcl-2 and Bcl-x (L) proteins may play a functional role in death receptor induced apoptosis by modulating the release of Smac.	2	28	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Smac	Smac	Smac	5	6	27	28
This increased the processing of caspase-8 and Bcl-2 interacting domain ( BID ) , augmented cytosolic accumulation of the prodeath molecules cytochrome-c , Smac and Omi , as well as led to increased activity of caspase-3 and apoptosis .	This increased the processing of caspase-8 and Bcl-2 interacting domain (BID), augmented cytosolic accumulation of the prodeath molecules cytochrome-c, Smac and Omi, as well as led to increased activity of caspase-3 and apoptosis.	5	25	augmented	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Bcl-2	Bcl-2	Smac	Smac	Smac	7	8	23	24
Desflurane preconditioning up-regulated the expression of c-IAP1 and Bcl-2 , blocked the cleavage of caspase-3 and reduced SMAC release , and decreased the cell death of HUVECs after A/R .	Desflurane preconditioning up-regulated the expression of c-IAP1 and Bcl-2, blocked the cleavage of caspase-3 and reduced SMAC release, and decreased the cell death of HUVECs after A/R.	0	18	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-2	Desflurane preconditioning up-regulated the expression of c-IAP1 and Bcl-2	bcl-2	SMAC	SMAC	smac	8	9	17	18
Beclin 1 independent activation of autophagy was also found in Hela cells treated with Z18 ( a Bcl-X L / Bcl-2 inhibitor ) 32 and midbrain primary dopaminergic neurons intoxicated with MPP + 33 .	Beclin 1 independent activation of autophagy was also found in Hela cells treated with Z18 (a Bcl-X L / Bcl-2 inhibitor) 32 and midbrain primary dopaminergic neurons intoxicated with MPP + 33.	0	19	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Bcl-X L	Bcl-X L	Bcl-X L	Beclin 1	Beclin 1	Beclin 1	17	19	0	2
Beclin 1 defects caused by the overexpression of Bcl-xL may facilitate tumor malignant differentiation , which results in a more aggressive cancer cell phenotype and poor prognosis of hepatocellular carcinoma .	Beclin 1 defects caused by the overexpression of Bcl-xL may facilitate tumor malignant differentiation, which results in a more aggressive cancer cell phenotype and poor prognosis of hepatocellular carcinoma.	0	9	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bcl-xL	overexpression of Bcl-xL	bcl-xl	Beclin 1	Beclin 1	beclin 1	8	9	0	2
Linalool decreased mitochondrial oxygen consumption rate , increased the expression of Bax and Bak , reduced the expression of Bcl-2 and Bcl-xl , and increased the activities of caspase 3 and caspase 9 , leading to increase of apoptosis .	Linalool decreased mitochondrial oxygen consumption rate, increased the expression of Bax and Bak, reduced the expression of Bcl-2 and Bcl-xl, and increased the activities of caspase 3 and caspase 9, leading to increase of apoptosis.	0	33	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bcl-xl	Linalool decreased mitochondrial oxygen consumption rate, increased the expression of Bax and Bak, reduced the expression of Bcl-2 and Bcl-xl	bcl-xl	caspase 9	caspase 9	caspase 9	21	22	31	33
Engagement of the BH3 domain alone must suffice , because addition of a Bim BH3 peptide to lysates induced a change in the membrane association of Bcl-w indistinguishable from that observed in cells induced to die ( compare XREF_FIG and XREF_FIG ) .	Engagement of the BH3 domain alone must suffice, because addition of a Bim BH3 peptide to lysates induced a change in the membrane association of Bcl-w indistinguishable from that observed in cells induced to die (compare XREF_FIG and XREF_FIG).	13	27	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-w	Bcl-w	Bcl-w	13	14	26	27
XREF_BIBR In our earlier report on Bcl-w using the same model applied presently , we found that Bcl-w was targeted by Bim during seizure induced neuronal death and Bcl-w deficiency led to significantly enhanced hippocampal damage from seizures .	XREF_BIBR In our earlier report on Bcl-w using the same model applied presently, we found that Bcl-w was targeted by Bim during seizure induced neuronal death and Bcl-w deficiency led to significantly enhanced hippocampal damage from seizures.	17	22	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Bim	Bim	Bim	Bcl-w	Bcl-w	Bcl-w	21	22	17	18
The antiapoptotic effect of VP is mediated by V1 receptors and involves phosphorylation ( leading to inactivation ) of the pro apoptotic protein Bad .	The antiapoptotic effect of VP is mediated by V1 receptors and involves phosphorylation (leading to inactivation) of the pro apoptotic protein Bad.	2	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VP	VP	VP	Bad	Bad	Bad	4	5	23	24
Accordingly , our data demonstrated upregulation and activation of TP53 as a result of AURKB inhibition which suggests that AURKB contributes to MYCN mediated repression of TP53 function in neuroblastoma .	Accordingly, our data demonstrated upregulation and activation of TP53 as a result of AURKB inhibition which suggests that AURKB contributes to MYCN mediated repression of TP53 function in neuroblastoma.	14	27	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AURKB	AURKB	AURKB	TP53	TP53	TP53	14	15	26	27
The silencer of death domains ( SODD ) has been proposed to prevent constitutive signaling of tumor necrosis factor receptor 1 ( TNFR1 ) in the absence of ligand .	The silencer of death domains (SODD) has been proposed to prevent constitutive signaling of tumor necrosis factor receptor 1 (TNFR1) in the absence of ligand.	0	22	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	silencer of death domains	silencer of death domains	silencer of death domains	tumor necrosis factor receptor 1	tumor necrosis factor receptor 1	tumor necrosis factor receptor 1	1	5	16	21
The work presented here demonstrates the importance of a CpG rich 109bp segment in the transactivation of the ER promoter by BRCA1 in two transformed non tumorigenic human mammary epithelial cell lines .	The work presented here demonstrates the importance of a CpG rich 109bp segment in the transactivation of the ER promoter by BRCA1 in two transformed non tumorigenic human mammary epithelial cell lines.	18	23	promoter	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	21	22	18	19
Moreover , MTA1 and HDAC complex recruited to the ERE of BRCA1 promoter in an ER alpha dependent manner .	Moreover, MTA1 and HDAC complex recruited to the ERE of BRCA1 promoter in an ER alpha dependent manner.	11	16	promoter	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	11	12	15	16
Using an E2 responsive construct carrying the key positive regulatory element of the BRCA1 promoter upstream of the luciferase gene [ XREF_BIBR , XREF_BIBR ] , we found that TCDD , PCB # 138 , PCB # 153 , and PCB # 180 can downregulate the basal as well as the E2 induced BRCA1 promoter activity in both the ER positive cell line ( MCF-7 ( BUS ) ) and in the ER negative cell line ( MDA-MB-231 ) .	Using an E2 responsive construct carrying the key positive regulatory element of the BRCA1 promoter upstream of the luciferase gene [XREF_BIBR, XREF_BIBR], we found that TCDD, PCB # 138, PCB # 153, and PCB # 180 can downregulate the basal as well as the E2 induced BRCA1 promoter activity in both the ER positive cell line (MCF-7 (BUS)) and in the ER negative cell line (MDA-MB-231).	29	72	promoter activity	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	BRCA1	TCDD, PCB # 138, PCB # 153, and PCB # 180 can downregulate the basal as well as the E2 induced BRCA1	brca1	ER	ER	er	53	54	59	60
It has been reported that ICI182780 inhibited E2 induced BRCA1 mRNA induction in ER positive cells .	It has been reported that ICI182780 inhibited E2 induced BRCA1 mRNA induction in ER positive cells.	5	15	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	BRCA1	ICI182780 inhibited E2 induced BRCA1	brca1	ER	ER	er	9	10	13	14
BRCA1 underexpression also enhanced estrogen inducible ER-alpha activity in a PI3K and Akt dependent manner .	BRCA1 underexpression also enhanced estrogen inducible ER-alpha activity in a PI3K and Akt dependent manner.	0	7	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1 underexpression	brca1	ER-alpha	ER-alpha	er-alpha	0	1	6	7
We found that underexpression of BRCA1 caused ligand independent activation of ER-alpha that was mediated through phosphatidylinositol-3 kinase ( PI3K )/c-Akt signaling .	We found that underexpression of BRCA1 caused ligand independent activation of ER-alpha that was mediated through phosphatidylinositol-3 kinase (PI3K)/c-Akt signaling.	3	19	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	underexpression of BRCA1	brca1	ER-alpha	ER-alpha	er-alpha	5	6	11	12
XREF_BIBR Cyclin D binding also increased ER-alpha transactivation , presumably allowed by BRCA1 .	XREF_BIBR Cyclin D binding also increased ER-alpha transactivation, presumably allowed by BRCA1.	6	13	allowed	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	12	13	6	7
Thus the two BRCA1 missense mutations could not promote the estrogen receptor signaling pathway for familial breast and ovarian carcinogenesis .	Thus the two BRCA1 missense mutations could not promote the estrogen receptor signaling pathway for familial breast and ovarian carcinogenesis.	3	13	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	3	4	10	12
A novel domain of cyclin D1 , predicted to form a helix-loop-helix structure , was required for binding to ERalpha and for rescue of BRCA1 mediated ERalpha transcriptional repression .	A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ERalpha and for rescue of BRCA1 mediated ERalpha transcriptional repression.	22	27	mediated	Positive_early_activation	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	24	25	26	27
To determine if the induction of ER promoter activity by BRCA1 was seen at the level of the endogenous gene ( i.e. at the mRNA level ) , we performed RT-PCR on extracts isolated following transfection with BRCA1 or pRK7 .	To determine if the induction of ER promoter activity by BRCA1 was seen at the level of the endogenous gene (i.e. at the mRNA level), we performed RT-PCR on extracts isolated following transfection with BRCA1 or pRK7.	6	11	promoter activity	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	10	11	6	7
Thus , our work showed that the two BRCA1 missense mutations failed to promote the estrogen receptor signaling pathway in breast and ovarian carcinogenesis .	Thus, our work showed that the two BRCA1 missense mutations failed to promote the estrogen receptor signaling pathway in breast and ovarian carcinogenesis.	8	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	8	9	15	17
Recently , studies have suggested this tissue specificity may be linked to inhibition of estrogen receptor alpha ( ERalpha ) transcriptional activation by BRCA1 .	Recently, studies have suggested this tissue specificity may be linked to inhibition of estrogen receptor alpha (ERalpha) transcriptional activation by BRCA1.	18	24	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	23	24	18	19
BRCA1 ( but not BRCA2 ) siRNA caused a modest increase in E2 stimulated ER-alpha activity .	BRCA1 (but not BRCA2) siRNA caused a modest increase in E2 stimulated ER-alpha activity.	0	15	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	0	1	14	15
Our study concludes that the two BRCA1 missense mutations failed to promote the estrogen receptor signaling pathway in familial breast and ovarian carcinogenesis .	Our study concludes that the two BRCA1 missense mutations failed to promote the estrogen receptor signaling pathway in familial breast and ovarian carcinogenesis.	6	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	6	7	13	15
To determine if wild type BRCA1 could induce activity of the ER promoter , we performed a series of transient transfections with ER promoter segments linked to a luciferase reporter .	To determine if wild type BRCA1 could induce activity of the ER promoter, we performed a series of transient transfections with ER promoter segments linked to a luciferase reporter.	3	12	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	5	6	11	12
These data suggest BRCA1 does not directly regulate ER turnover in breast cancer cells .	These data suggest BRCA1 does not directly regulate ER turnover in breast cancer cells.	3	9	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	3	4	8	9
BRCA1 has been shown to target ERalpha for monoubiquitylation 66 .	BRCA1 has been shown to target ERalpha for monoubiquitylation 66.	0	7	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	0	1	6	7
The BRD7 gene was included as an additional candidate gene for TNBC because BRD7 is required for the BRCA1 mediated transcriptional regulation of the estrogen receptor XREF_BIBR .	The BRD7 gene was included as an additional candidate gene for TNBC because BRD7 is required for the BRCA1 mediated transcriptional regulation of the estrogen receptor XREF_BIBR.	15	26	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	18	19	24	26
For example , the insulin like growth factor 1 receptor ( IGF1R ) gene is a downstream target for BRCA1 , as wild-type BRCA1 expression suppresses promoter activity and endogenous IGF1R levels [ XREF_BIBR ] ; BRCA1 can lead to degradation of the progesterone receptor by counteracting the action of progesterone ; multiple mechanisms are involved in BRCA1 mediated estrogen receptor repression [ XREF_BIBR , XREF_BIBR ] .	For example, the insulin like growth factor 1 receptor (IGF1R) gene is a downstream target for BRCA1, as wild-type BRCA1 expression suppresses promoter activity and endogenous IGF1R levels [XREF_BIBR]; BRCA1 can lead to degradation of the progesterone receptor by counteracting the action of progesterone; multiple mechanisms are involved in BRCA1 mediated estrogen receptor repression [XREF_BIBR, XREF_BIBR].	55	61	mediated	Positive_early_activation	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	57	58	59	61
Addition of BRCA1 but not Mutant # 1 to E2 induced ERalpha in the presence of SUMO-1 and Ubc9 resulted in the degradation of ERalpha suggesting BRCA1 to be a putative SUMO-1 and Ubc9 dependent E3 ubiquitin ligase for ERalpha .	Addition of BRCA1 but not Mutant # 1 to E2 induced ERalpha in the presence of SUMO-1 and Ubc9 resulted in the degradation of ERalpha suggesting BRCA1 to be a putative SUMO-1 and Ubc9 dependent E3 ubiquitin ligase for ERalpha.	0	12	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	2	3	11	12
Thus , BRCA1 ( but not BRCA2 or control ) siRNA significantly reversed the genistein mediated inhibition of E2 stimulated ER-alpha activity ( P < 0.001 ) .	Thus, BRCA1 (but not BRCA2 or control) siRNA significantly reversed the genistein mediated inhibition of E2 stimulated ER-alpha activity (P < 0.001).	2	21	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	2	3	20	21
Figure XREF_FIG illustrates that although BRCA1 induces the production of ER mRNA in MCF10A cells , the levels are still much lower than in an ER positive cell line .	Figure XREF_FIG illustrates that although BRCA1 induces the production of ER mRNA in MCF10A cells, the levels are still much lower than in an ER positive cell line.	5	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	5	6	10	11
For example , BRCA1 has been shown to modulate transcriptional activity of estrogen receptor ERalpha , which could explain why BRCA1 mutations mainly lead to cancers in estrogen responsive tissues such as breast and ovary .	For example, BRCA1 has been shown to modulate transcriptional activity of estrogen receptor ERalpha, which could explain why BRCA1 mutations mainly lead to cancers in estrogen responsive tissues such as breast and ovary.	3	14	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	3	4	12	14
BRD7 can bind to BRCA1 in breast cancer cells , which is required for the BRCA1 mediated transcriptional regulation of the estrogen receptor ( ER ) , suggesting a close relationship between BRD7 and breast cancer development 9 .	BRD7 can bind to BRCA1 in breast cancer cells, which is required for the BRCA1 mediated transcriptional regulation of the estrogen receptor (ER), suggesting a close relationship between BRD7 and breast cancer development 9.	12	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	estrogen receptor	estrogen receptor	estrogen receptor	15	16	21	23
By contrast , it was also shown that BRCA1 may induce an increased transcriptional activity of ER-alpha by upregulation of p300 expression , a coactivator of ER-alpha .	By contrast, it was also shown that BRCA1 may induce an increased transcriptional activity of ER-alpha by upregulation of p300 expression, a coactivator of ER-alpha.	8	17	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	8	9	16	17
Of note , transient transfection of BRCA1 in MCF10A cells was not sufficient to induce ER mRNA to the level of an ER positive cell line .	Of note, transient transfection of BRCA1 in MCF10A cells was not sufficient to induce ER mRNA to the level of an ER positive cell line.	4	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	6	7	15	16
Since progesterone receptors ( PRA and PRB ) are also target genes that are up-regulated by ER-alpha , one might predict that BRCA1 represses the PR pathway by inhibiting ER-alpha activity .	Since progesterone receptors (PRA and PRB) are also target genes that are up-regulated by ER-alpha, one might predict that BRCA1 represses the PR pathway by inhibiting ER-alpha activity.	22	30	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	22	23	29	30
Together , these results show that decreased expression of BRCA1 modulates ER mediated transcription and abrogated Tam suppression of endogenous ER target genes .	Together, these results show that decreased expression of BRCA1 modulates ER mediated transcription and abrogated Tam suppression of endogenous ER target genes.	7	22	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	expression of BRCA1	brca1	ER	ER	er	9	10	20	21
Here , we found that transient transfection of a BRCA1 amino acid 1-302 expression vector ( DN-BRCA1 ) partially rescued the inhibition of E2 stimulated ER-alpha activity by I3C alone , genistein alone , or the combination of I3C plus genistein ( P < 0.001 ) ( data not shown ) .	Here, we found that transient transfection of a BRCA1 amino acid 1-302 expression vector (DN-BRCA1) partially rescued the inhibition of E2 stimulated ER-alpha activity by I3C alone, genistein alone, or the combination of I3C plus genistein (P < 0.001) (data not shown).	9	26	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	9	10	25	26
Nevertheless , upregulation of ER-alpha signaling by BRCA1 also is incongruent with the novel finding that BRCA1 mutation linked ER negative breast cancer cells may be derived from either ER positive or ER negative luminal progenitor cells .	Nevertheless, upregulation of ER-alpha signaling by BRCA1 also is incongruent with the novel finding that BRCA1 mutation linked ER negative breast cancer cells may be derived from either ER positive or ER negative luminal progenitor cells.	4	8	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER-alpha	ER-alpha	ER-alpha	7	8	4	5
The breast cancer and ovarian susceptibility gene 1 ( BRCA1 ) has been shown to inhibit ERalpha signaling by repressing the AF-2 domain of ERalpha , which is linked to the ligand binding domain .	The breast cancer and ovarian susceptibility gene 1 (BRCA1) has been shown to inhibit ERalpha signaling by repressing the AF-2 domain of ERalpha, which is linked to the ligand binding domain.	2	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BRCA1	BRCA1	BRCA1	ERalpha	ERalpha	ERalpha	9	10	16	17
Supporting this theory , Hosey and colleagues [ XREF_BIBR ] have shown that transfection of the wild-type BRCA1 gene into HCC1937 cells , an ER- breast cancer cell line homozygous for the BRCA1 mutation , restores ER production .	Supporting this theory, Hosey and colleagues [XREF_BIBR] have shown that transfection of the wild-type BRCA1 gene into HCC1937 cells, an ER- breast cancer cell line homozygous for the BRCA1 mutation, restores ER production.	17	37	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BRCA1	BRCA1	BRCA1	ER	ER	ER	17	18	36	37
Knockdown of survivin expression by siRNA increased the activation of caspase 3 , induced podocyte apoptosis and remarkable rearrangement of actin cytoskeleton .	Knockdown of survivin expression by siRNA increased the activation of caspase 3, induced podocyte apoptosis and remarkable rearrangement of actin cytoskeleton.	2	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin expression	survivin	caspase 3	caspase 3	caspase 3	2	3	10	12
Berberine inhibited Nuclear Factor kappa-B ( NF-kappaB ) activity , reduced the expression of cyclin D1 and survivin , induced phosphorylation of p53 and increased caspase-3 cleavage in vitro .	Berberine inhibited Nuclear Factor kappa-B (NF-kappaB) activity, reduced the expression of cyclin D1 and survivin, induced phosphorylation of p53 and increased caspase-3 cleavage in vitro.	0	26	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	Berberine inhibited Nuclear Factor kappa-B (NF-kappaB) activity, reduced the expression of cyclin D1 and survivin	survivin	caspase-3	caspase-3	caspase-3	17	18	25	26
Survivin , a member of the inhibitor-of-apoptosis family , inhibits apoptosis by blocking caspase-3 and -7 activation .	Survivin, a member of the inhibitor-of-apoptosis family, inhibits apoptosis by blocking caspase-3 and -7 activation.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	13	14
Survivin blocks apoptosis by targeting the terminal effector caspase-3 and caspase-7 ( Adida et al , 1998 ; Tamm et al , 1998 ) whereas stimulation of ceramide may be one of the molecular basis for the anti-apoptotic effect of COX-2 ( Chan et al , 1998 ) .	Survivin blocks apoptosis by targeting the terminal effector caspase-3 and caspase-7 (Adida et al, 1998; Tamm et al, 1998) whereas stimulation of ceramide may be one of the molecular basis for the anti-apoptotic effect of COX-2 (Chan et al, 1998).	0	12	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	8	9
Utilizing a cell-free system in which caspase-3 was activated in eosinophil cytosolic extracts by addition of cytochrome c and immunodepletion of cIAP-2 or survivin resulted in accelerated caspase activation .	Utilizing a cell-free system in which caspase-3 was activated in eosinophil cytosolic extracts by addition of cytochrome c and immunodepletion of cIAP-2 or survivin resulted in accelerated caspase activation.	6	24	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	23	24	6	7
Exposure of T24 cells to costunolide was also associated with increased expression of Bax , down-regulation of Bcl-2 , survivin and significant activation of caspase-3 , and its downstream target PARP .	Exposure of T24 cells to costunolide was also associated with increased expression of Bax, down-regulation of Bcl-2, survivin and significant activation of caspase-3, and its downstream target PARP.	17	25	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	19	20	24	25
Survivin is a member of the inhibitor of apoptosis protein ( IAP ) family and inhibits apoptosis by suppressing the activity of caspase-3 , -7 , and -9 [ XREF_BIBR ] .	Survivin is a member of the inhibitor of apoptosis protein (IAP) family and inhibits apoptosis by suppressing the activity of caspase-3, -7, and -9 [XREF_BIBR].	0	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	0	1	22	23
Furthermore , survivin is a potent inactivator of caspase-9 and caspase-3 and is regulated via the Akt and mTOR signaling pathway .	Furthermore, survivin is a potent inactivator of caspase-9 and caspase-3 and is regulated via the Akt and mTOR signaling pathway.	2	13	is a potent inactivator	Negative_activation_copula_1	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	2	3	10	11
Our results showed that YM155 downregulated survivin expression without affecting XIAP and induced cleavage of caspase 3 , caspase 9 and caspase 8 .	Our results showed that YM155 downregulated survivin expression without affecting XIAP and induced cleavage of caspase 3, caspase 9 and caspase 8.	4	21	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	YM155 downregulated survivin expression	survivin	caspase 3	caspase 3	caspase 3	6	7	15	17
It has been indicated that NAIP contrasts apoptosis by inhibition of the executioner caspase-3 and caspase-7 [ XREF_BIBR ] while survivin has been shown to modulate the executioner caspase-3 [ XREF_BIBR ] .	It has been indicated that NAIP contrasts apoptosis by inhibition of the executioner caspase-3 and caspase-7 [XREF_BIBR] while survivin has been shown to modulate the executioner caspase-3 [XREF_BIBR].	20	30	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	20	21	28	29
Therefore , this set of observations further confirmed that survivin negatively modulated Casp3 activity in transfected CGCs .	Therefore, this set of observations further confirmed that survivin negatively modulated Casp3 activity in transfected CGCs.	9	13	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	survivin	survivin	Casp3	Casp3	Casp3	9	10	12	13
Conversely , in the cytoplasm , Survivin blocks intrinsic and extrinsic apoptosis by directly inhibiting caspase-3 and -7 , as well as interfering with caspase-9 XREF_BIBR .	Conversely, in the cytoplasm, Survivin blocks intrinsic and extrinsic apoptosis by directly inhibiting caspase-3 and -7, as well as interfering with caspase-9 XREF_BIBR.	6	17	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	6	7	15	16
Moreover , survivin may prevent cell apoptosis by inhibiting caspase-3 activation .	Moreover, survivin may prevent cell apoptosis by inhibiting caspase-3 activation.	2	10	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	2	3	9	10
33 In our study , baicalein significantly inhibited the expression of survivin and decreased the expression of survivin activated caspase-3 .	33 In our study, baicalein significantly inhibited the expression of survivin and decreased the expression of survivin activated caspase-3.	15	20	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	expression of survivin	survivin	caspase-3	caspase-3	caspase-3	17	18	19	20
The survivin inhibits the cell apoptosis by inhibiting apoptotic factors , caspase-3 and -7 activity directly .	The survivin inhibits the cell apoptosis by inhibiting apoptotic factors, caspase-3 and -7 activity directly.	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	1	2	11	12
ICG-001-mediated downregulation of survivin expression enhanced caspase-3 activity and apoptosis , which was rescued by overexpression of wild type but not mutant ( C84A ) survivin .	ICG-001-mediated downregulation of survivin expression enhanced caspase-3 activity and apoptosis, which was rescued by overexpression of wild type but not mutant (C84A) survivin.	3	7	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	survivin expression	survivin	caspase-3	caspase-3	caspase-3	3	4	6	7
Mechanistically , knockdown of IKKbeta or NF-kappaB decreases the expression of Survivin , an important anti-apoptotic protein and NF-kappaB target gene , and induces caspase-3 cleavage .	Mechanistically, knockdown of IKKbeta or NF-kappaB decreases the expression of Survivin, an important anti-apoptotic protein and NF-kappaB target gene, and induces caspase-3 cleavage.	4	25	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	IKKbeta or NF-kappaB decreases the expression of Survivin	survivin	caspase-3	caspase-3	caspase-3	11	12	24	25
As shown in XREF_FIG , depletion of survivin by siRNA not only significantly increased TRAIL induced apoptotic cell death but also remarkably increased caspase-3 activation compared with the control siRNA .	As shown in XREF_FIG, depletion of survivin by siRNA not only significantly increased TRAIL induced apoptotic cell death but also remarkably increased caspase-3 activation compared with the control siRNA.	5	24	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	7	8	23	24
Downregulation of survivin by siRNA clearly induced caspase-9 and caspase-3 cleavage in PANC-1 cells , as revealed by the Western blot analysis as expected ( XREF_FIG ) .	Downregulation of survivin by siRNA clearly induced caspase-9 and caspase-3 cleavage in PANC-1 cells, as revealed by the Western blot analysis as expected (XREF_FIG).	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	2	3	9	10
Survivin inhibits apoptosis , and downregulation of survivin triggers caspase-9 and caspase-3 activation , leading to the induction of apoptotic cell death .	Survivin inhibits apoptosis, and downregulation of survivin triggers caspase-9 and caspase-3 activation, leading to the induction of apoptotic cell death.	5	12	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	survivin	survivin	caspase-3	caspase-3	caspase-3	7	8	11	12
The down-regulation of FLIP , XIAP and Survivin induced by RGZ can activate caspase-3 , whereby induced apoptosis and proliferation inhibition in myeloma cells .	The down-regulation of FLIP, XIAP and Survivin induced by RGZ can activate caspase-3, whereby induced apoptosis and proliferation inhibition in myeloma cells.	1	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Survivin	Survivin	Survivin	caspase-3	caspase-3	caspase-3	7	8	13	14
Our data show that Fbw1a , which normally targets beta-catenin for degradation , works together with p300 to enhance the transcriptional activity of beta-catenin , whereas other F-box and WD40 proteins do not .	Our data show that Fbw1a, which normally targets beta-catenin for degradation, works together with p300 to enhance the transcriptional activity of beta-catenin, whereas other F-box and WD40 proteins do not.	4	24	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Fbw1a	Fbw1a	Fbw1a	beta-catenin	beta-catenin	beta-catenin	4	5	23	24
Biochemical studies have suggested that beta-TrCP targets the oncogenic protein beta-catenin for ubiquitination and followed by proteasome degradation .	Biochemical studies have suggested that beta-TrCP targets the oncogenic protein beta-catenin for ubiquitination and followed by proteasome degradation.	5	12	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
In addition , while ectopic beta-TrCP expression enhanced TZD facilitated beta-catenin ablation , its siRNA mediated knockdown protected cells from this degradation .	In addition, while ectopic beta-TrCP expression enhanced TZD facilitated beta-catenin ablation, its siRNA mediated knockdown protected cells from this degradation.	5	11	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-TrCP	beta-TrCP expression	beta-trcp	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
Another F-box protein , beta-TrCp1 and Fbw1a , has been shown to enhance the ability of beta-catenin to activate transcription through cooperating with the co-activator p300 in addition to targeting beta-catenin for degradation 30 .	Another F-box protein, beta-TrCp1 and Fbw1a, has been shown to enhance the ability of beta-catenin to activate transcription through cooperating with the co-activator p300 in addition to targeting beta-catenin for degradation 30.	2	17	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Fbw1a	Fbw1a	Fbw1a	beta-catenin	beta-catenin	beta-catenin	6	7	16	17
This interaction resulted in disassociating beta-catenin from the binding of beta-TrCP leading to increase beta-catenin stability .	This interaction resulted in disassociating beta-catenin from the binding of beta-TrCP leading to increase beta-catenin stability.	8	15	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	10	11	14	15
Negative feed-back regulation should be facilitated by BTRC dependent degradation of CTNNB1 , whereas MYC was proposed to enhance the transcription of IGF2BP1 , suggesting a positive feed-back loop [ XREF_BIBR ] .	Negative feed-back regulation should be facilitated by BTRC dependent degradation of CTNNB1, whereas MYC was proposed to enhance the transcription of IGF2BP1, suggesting a positive feed-back loop [XREF_BIBR].	7	12	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	BTRC	BTRC	BTRC	CTNNB1	CTNNB1	CTNNB1	7	8	11	12
This plasma membrane localized protein aggregate , which is sometimes referred to as the ' Wnt signalosome ' , inactivates a cytoplasmic destruction machinery consisting of casein kinase 1 , glycogen synthase kinase 3 ( Gsk3 ) , axis inhibitor ( Axin ) , adenomatosis polyposis coli and the E3 ubiquitin ligase beta-Trcp ( Btrc ) , causing beta-catenin stabilization and transcriptional activation of Wnt targets .	This plasma membrane localized protein aggregate, which is sometimes referred to as the ' Wnt signalosome ', inactivates a cytoplasmic destruction machinery consisting of casein kinase 1, glycogen synthase kinase 3 (Gsk3), axis inhibitor (Axin), adenomatosis polyposis coli and the E3 ubiquitin ligase beta-Trcp (Btrc), causing beta-catenin stabilization and transcriptional activation of Wnt targets.	52	59	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Btrc	Btrc	Btrc	beta-catenin	beta-catenin	beta-catenin	54	55	58	59
In XREF_BIBR , BTRC has been experimentally verified to inhibit the beta-catenin ( CTNNB1 ) pathway that is upregulated after insults such as seizures and promotes adult neurogenesis ( BTRC ---> CTNNB1 ) .	In XREF_BIBR, BTRC has been experimentally verified to inhibit the beta-catenin (CTNNB1) pathway that is upregulated after insults such as seizures and promotes adult neurogenesis (BTRC ---> CTNNB1).	3	32	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BTRC	BTRC	BTRC	CTNNB1	CTNNB1	CTNNB1	3	4	31	32
In summary , cells treated with IGFBP-3 have higher amounts of active destruction complex as demonstrated by the increased degradation of beta-catenin mediated by beta-TrCP .	In summary, cells treated with IGFBP-3 have higher amounts of active destruction complex as demonstrated by the increased degradation of beta-catenin mediated by beta-TrCP.	19	25	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-catenin	beta-catenin	beta-catenin	24	25	21	22
Our results has uncovered a previously unrealized role of GSK3beta Y216 phosphorylation : it triggers GSK3beta recruitment of beta-TrCP and subsequent GSK3beta monoubiquitination by beta-TrCP , an event required for Wnt induced inhibition of beta-catenin degradation , thus identifying phosphorylation of GSK3beta Y216 as an ' activator ' of the Wnt and beta-catenin pathway .	Our results has uncovered a previously unrealized role of GSK3beta Y216 phosphorylation : it triggers GSK3beta recruitment of beta-TrCP and subsequent GSK3beta monoubiquitination by beta-TrCP, an event required for Wnt induced inhibition of beta-catenin degradation, thus identifying phosphorylation of GSK3beta Y216 as an ' activator ' of the Wnt and beta-catenin pathway.	18	35	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-TrCP	beta-TrCP and subsequent GSK3beta monoubiquitination	beta-trcp	beta-catenin	beta-catenin	beta-catenin	18	19	34	35
beta-TrCP Is a Target of the Wnt and beta-Catenin Pathway and Up-regulates NF-kappaB and Down-regulates Wnt and beta-Catenin Signaling .	beta-TrCP Is a Target of the Wnt and beta-Catenin Pathway and Up-regulates NF-kappaB and Down-regulates Wnt and beta-Catenin Signaling.	0	18	Up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-TrCP	beta-TrCP	beta-TrCP	beta-Catenin	beta-Catenin	beta-Catenin	0	1	17	18
Survivin suppresses mitochondrial apoptosis by inhibiting caspase-9 activities in concert with the caspase inhibitor , XIAP [ XREF_BIBR ] .	Survivin suppresses mitochondrial apoptosis by inhibiting caspase-9 activities in concert with the caspase inhibitor, XIAP [XREF_BIBR].	0	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Survivin	Survivin	Survivin	caspase-9	caspase-9	caspase-9	0	1	6	7
Specifically , in all four tested cell lines depletion of SRSF2 resulted in decreased expression of proapoptotic : caspase-9a , Smac3 ( a splice variant of SMAC/DIABLO that counteracts caspase-9 inhibition ) , surv-2B ( a splice variant of BIRC5 and survivin that activates caspase-9 ) , BimS and Bimalpha3 , as well as MCL-1S .	Specifically, in all four tested cell lines depletion of SRSF2 resulted in decreased expression of proapoptotic : caspase-9a, Smac3 (a splice variant of SMAC/DIABLO that counteracts caspase-9 inhibition), surv-2B (a splice variant of BIRC5 and survivin that activates caspase-9), BimS and Bimalpha3, as well as MCL-1S.	37	45	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BIRC5	BIRC5	BIRC5	caspase-9	caspase-9	caspase-9	39	40	44	45
Previous studies suggest that survivin enhances tumor cell survival primarily through the inhibition of apoptosis , presumably by direct and indirect binding to caspase-9 .	Previous studies suggest that survivin enhances tumor cell survival primarily through the inhibition of apoptosis, presumably by direct and indirect binding to caspase-9.	4	24	enhances	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	survivin	survivin	survivin	caspase-9	caspase-9	caspase-9	4	5	23	24
Moreover , PTER-ITC significantly decreased expression of survivin , which blocks caspase-9 and -3 , thereby inhibiting apoptosis .	Moreover, PTER-ITC significantly decreased expression of survivin, which blocks caspase-9 and -3, thereby inhibiting apoptosis.	2	13	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	survivin	PTER-ITC significantly decreased expression of survivin	survivin	caspase-9	caspase-9	caspase-9	7	8	11	12
The effects of abstinence and relapse on PKA and CaMKI mediated p-synapsin I Ser9 in the NAc are shown in XREF_FIG .	The effects of abstinence and relapse on PKA and CaMKI mediated p-synapsin I Ser9 in the NAc are shown in XREF_FIG.	3	18	mediated	Positive_early_activation	Negative_activation	Positive_activation	CaMKI	CaMKI	CaMKI	p-synapsin I	p-synapsin I	p-synapsin I	9	10	11	13
The finding that PKA , but not ERK MAP kinase , activation in the dmPFC is necessary for abstinence induced augmentation of p-CREB and p-GluA1 Ser845 in the dmPFC , and PKA and CaMKI mediated p-synapsin I Ser9 in the NAc , suggests that there is a biphasic alteration in PFC signaling that shifts from ERK dependence during early withdrawal to PKA dependence during more prolonged abstinence .	The finding that PKA, but not ERK MAP kinase, activation in the dmPFC is necessary for abstinence induced augmentation of p-CREB and p-GluA1 Ser845 in the dmPFC, and PKA and CaMKI mediated p-synapsin I Ser9 in the NAc, suggests that there is a biphasic alteration in PFC signaling that shifts from ERK dependence during early withdrawal to PKA dependence during more prolonged abstinence.	31	37	mediated	Positive_early_activation	Negative_activation	Positive_activation	CaMKI	CaMKI	CaMKI	p-synapsin I	p-synapsin I	p-synapsin I	33	34	35	37
Bub1 promotes the assembly of a subset of these proteins , Mad2 , BubR1 and Bub3 , and Cdc20 , into the SAC effector , the mitotic checkpoint complex ( MCC ) , which targets the anaphase promoting complex and cyclosome ( APC/C ) to inhibit its ability to promote mitotic exit .	Bub1 promotes the assembly of a subset of these proteins, Mad2, BubR1 and Bub3, and Cdc20, into the SAC effector, the mitotic checkpoint complex (MCC), which targets the anaphase promoting complex and cyclosome (APC/C) to inhibit its ability to promote mitotic exit.	0	19	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bub1	Bub1	Bub1	Cdc20	Cdc20	Cdc20	0	1	18	19
Active Aurora B then phosphorylates ATM , which then phosphorylates gamma-H2AX and Bub1 at kinetochores , promoting the accumulation of Mad2 and Cdc20 .	Active Aurora B then phosphorylates ATM, which then phosphorylates gamma-H2AX and Bub1 at kinetochores, promoting the accumulation of Mad2 and Cdc20.	5	23	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bub1	ATM, which then phosphorylates gamma-H2AX and Bub1	bub1	Cdc20	Cdc20	cdc20	12	13	22	23
Addition of both KEN-box peptides did not inhibit Bub1 mediated phosphoryation of Cdc20 or Cdc20N .	Addition of both KEN-box peptides did not inhibit Bub1 mediated phosphoryation of Cdc20 or Cdc20N.	7	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Bub1	Bub1	Bub1	Cdc20	Cdc20	Cdc20	8	9	12	13
In these cases , beta-TrCP targets a variety of cellular growth and survival inhibitors including IkappaB ( inhibitor of kappaB ) family members ( NF-kappaB signaling pathway ) , BimEL ( extra-long isoform of Bim ) and Pdcd4 ( programmed cell death 4 ) .	In these cases, beta-TrCP targets a variety of cellular growth and survival inhibitors including IkappaB (inhibitor of kappaB) family members (NF-kappaB signaling pathway), BimEL (extra-long isoform of Bim) and Pdcd4 (programmed cell death 4).	4	39	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-TrCP	beta-TrCP	beta-TrCP	Pdcd4	Pdcd4	Pdcd4	4	5	37	38
The increase in PDCD4 was not associated with any changes in S6K1 activation , but the abundance of beta transducing repeat containing protein ( beta-TrCP ) , the ubiquitin ligase that targets PDCD4 for degradation , increased .	The increase in PDCD4 was not associated with any changes in S6K1 activation, but the abundance of beta transducing repeat containing protein (beta-TrCP), the ubiquitin ligase that targets PDCD4 for degradation, increased.	22	34	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	beta-TrCP	beta-TrCP	beta-TrCP	PDCD4	PDCD4	PDCD4	24	25	32	33
Whether beta-TrCP too can target PDCD4 for degradation in a phosphorylation independent manner remains to be demonstrated .	Whether beta-TrCP too can target PDCD4 for degradation in a phosphorylation independent manner remains to be demonstrated.	1	6	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-TrCP	beta-TrCP	beta-TrCP	PDCD4	PDCD4	PDCD4	1	2	5	6
The latter finding , together with the evidence that concomitant downregulation of p53 by RNAi only partially rescued cell growth inhibition and reduced , but not abrogated completely , apoptosis induced by Apollon knockdown in ZR75.1 cells , led us to hypothesise that Apollon downregulation can also directly or indirectly activate caspase-3 by a p53 independent signal ( XREF_FIG ) .	The latter finding, together with the evidence that concomitant downregulation of p53 by RNAi only partially rescued cell growth inhibition and reduced, but not abrogated completely, apoptosis induced by Apollon knockdown in ZR75.1 cells, led us to hypothesise that Apollon downregulation can also directly or indirectly activate caspase-3 by a p53 independent signal (XREF_FIG).	43	56	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Apollon	Apollon	Apollon	caspase-3	caspase-3	caspase-3	43	44	51	52
Furthermore , there was a concomitant up-regulation of active caspase-3 and decreased expression of BRUCE ( an inhibitor of apoptosis protein ) .	Furthermore, there was a concomitant up-regulation of active caspase-3 and decreased expression of BRUCE (an inhibitor of apoptosis protein).	3	17	was a concomitant up-regulation	Positive_activation_copula_1	Negative_activation	Positive_activation	BRUCE	expression of BRUCE	bruce	caspase-3	caspase-3	caspase-3	14	15	9	10
BNIP3 can suppress mTOR by binding to and inhibiting Rheb , and subsequently induce autophagy .	BNIP3 can suppress mTOR by binding to and inhibiting Rheb, and subsequently induce autophagy.	0	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BNIP3	BNIP3	BNIP3	Rheb	Rheb	Rheb	0	1	9	10
Hypoxia inducible proapoptotic protein BNIP3 ( BCL2 and adenovirus E1B 19-kDa-protein-interacting protein 3 ) also inhibits mTORC1 by directly associating with and inhibiting Rheb .	Hypoxia inducible proapoptotic protein BNIP3 (BCL2 and adenovirus E1B 19-kDa-protein-interacting protein 3) also inhibits mTORC1 by directly associating with and inhibiting Rheb.	0	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	BNIP3	BNIP3	BNIP3	Rheb	Rheb	Rheb	4	5	23	24
Thus , it appears to be reasonable that Nbk blocks the inhibitory function of Bcl-x L on Bak , but the antiapoptotic Mcl-1 is capable of backing up and still keeping Bak in check as a second restraint .	Thus, it appears to be reasonable that Nbk blocks the inhibitory function of Bcl-x L on Bak, but the antiapoptotic Mcl-1 is capable of backing up and still keeping Bak in check as a second restraint.	8	16	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Nbk	Nbk	Nbk	Bcl-x L	Bcl-x L	Bcl-x L	8	9	14	16
Furthermore , Smad3 is targeted for degradation by ROC1-SCF Fbw1a , and this is dependent on TGFbeta .	Furthermore, Smad3 is targeted for degradation by ROC1-SCF Fbw1a, and this is dependent on TGFbeta.	2	10	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Fbw1a	Fbw1a	Fbw1a	Smad3	Smad3	Smad3	9	10	2	3
Ultimately , PER phosphorylation by DBT and CKI at S47 forms a binding site for the E3 ubiquitin ligase SLIMB and beta-TrCP , which targets PER for degradation via the ubiquitin-proteasome pathway [ XREF_BIBR ] .	Ultimately, PER phosphorylation by DBT and CKI at S47 forms a binding site for the E3 ubiquitin ligase SLIMB and beta-TrCP, which targets PER for degradation via the ubiquitin-proteasome pathway [XREF_BIBR].	13	27	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-TrCP	beta-TrCP	beta-TrCP	PER	PER	PER	21	22	25	26
145 One proposed mechanism of enhanced XIAP activity involves co-expression of survivin , another IAP family member , which can bind to SMAC to block SMAC mediated inhibition of XIAP .	145 One proposed mechanism of enhanced XIAP activity involves co-expression of survivin, another IAP family member, which can bind to SMAC to block SMAC mediated inhibition of XIAP.	9	27	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	survivin	co-expression of survivin	survivin	SMAC	SMAC	smac	11	12	25	26
XREF_BIBR BIRC3 inactivating mutations and a fraction of BIRC3 deletions cause a truncation of the C-terminal RING domain of the BIRC3 protein , essential for ubiquitination , and the following proteasome degradation , of MAP3K14 , and drives constitutive non canonical NF-kappaB activation ( XREF_FIG ) .	XREF_BIBR BIRC3 inactivating mutations and a fraction of BIRC3 deletions cause a truncation of the C-terminal RING domain of the BIRC3 protein, essential for ubiquitination, and the following proteasome degradation, of MAP3K14, and drives constitutive non canonical NF-kappaB activation (XREF_FIG).	1	35	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	BIRC3	BIRC3	BIRC3	MAP3K14	MAP3K14	MAP3K14	1	2	34	35
cIAP-2 and XIAP potently suppress apoptosis by directly inhibiting caspase-3 , caspase-7 , and caspase-9 activity [ XREF_BIBR , XREF_BIBR ] .	cIAP-2 and XIAP potently suppress apoptosis by directly inhibiting caspase-3, caspase-7, and caspase-9 activity [XREF_BIBR, XREF_BIBR].	0	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cIAP-2	cIAP-2	cIAP-2	caspase-9	caspase-9	caspase-9	0	1	14	15
Overexpression of RUNX3 increased cIAP2 expression in A2780s cells , whereas inhibition of RUNX3 decreased cIAP2 expression and potentiated carboplatin induced decrease of cIAP2 in A2780cp cells .	Overexpression of RUNX3 increased cIAP2 expression in A2780s cells, whereas inhibition of RUNX3 decreased cIAP2 expression and potentiated carboplatin induced decrease of cIAP2 in A2780cp cells.	13	24	potentiated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cIAP2	RUNX3 decreased cIAP2 expression	ciap2	cIAP2	cIAP2	ciap2	15	16	23	24
Hence , caspase-3 mediated PARP cleavage following exposure to 6-OHDA appears independent of CB and CD alterations .	Hence, caspase-3 mediated PARP cleavage following exposure to 6-OHDA appears independent of CB and CD alterations.	2	5	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	2	3	4	5
Subsequently , active caspase-3 mediated the cleavage of PARP to account for DNA fragmentation as well as other morphological and biochemical changes during apoptosis .	Subsequently, active caspase-3 mediated the cleavage of PARP to account for DNA fragmentation as well as other morphological and biochemical changes during apoptosis.	2	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	3	4	8	9
Caspase 3 activation induces PARP cleavage , DNA fragmentation and ultimately kills the cells by apoptosis .	Caspase 3 activation induces PARP cleavage, DNA fragmentation and ultimately kills the cells by apoptosis.	0	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase 3	Caspase 3	Caspase 3	PARP	PARP	PARP	0	2	4	5
JQ1 activated caspase-3 and caspase-9 expression and induced PARP cleavage as well as cytochrome c release into the cytoplasm from mitochondria .	JQ1 activated caspase-3 and caspase-9 expression and induced PARP cleavage as well as cytochrome c release into the cytoplasm from mitochondria.	0	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	JQ1 activated caspase-3 and caspase-9 expression	caspase-3	PARP	PARP	parp	2	3	8	9
Caspase-3 promotes apoptosis by cleaving PARP , and cleavage of PARP by caspases is considered a hallmark of apoptosis [ XREF_BIBR ] .	Caspase-3 promotes apoptosis by cleaving PARP, and cleavage of PARP by caspases is considered a hallmark of apoptosis [XREF_BIBR].	0	6	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	0	1	5	6
The programmed cell death induced by these agents involved CPP32 mediated PARP cleavage and DNA fragmentation .	The programmed cell death induced by these agents involved CPP32 mediated PARP cleavage and DNA fragmentation.	8	12	mediated	Positive_early_activation	Negative_activation	Positive_activation	CPP32	CPP32	CPP32	PARP	PARP	PARP	9	10	11	12
Since caspase-3 plays a crucial role in apoptotic cell death by cleaving poly ( ADP-ribose ) polymerase ( PARP ) to suppress the DNA repair pathway [ XREF_BIBR ] , we tested the potential involvement of caspase-3 in apicularen A induced cell death by measuring caspase-3 activity and the PARP cleavage .	Since caspase-3 plays a crucial role in apoptotic cell death by cleaving poly (ADP-ribose) polymerase (PARP) to suppress the DNA repair pathway [XREF_BIBR], we tested the potential involvement of caspase-3 in apicularen A induced cell death by measuring caspase-3 activity and the PARP cleavage.	34	50	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	36	37	49	50
PARP cleavage is catalyzed by activated Caspase-3 which prevents PARP mediated DNA repair processes .	PARP cleavage is catalyzed by activated Caspase-3 which prevents PARP mediated DNA repair processes.	0	8	catalyzed	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	6	7	0	1
PARP can also be used as a marker for apoptosis , since activation of apoptosis leads to cleavage of full-length PARP ( 113 kDa ) by Caspase-3 and -7 into two smaller fragments ( 89 and 24 kDa ) ; the 113 kDa and 89 kDa forms are readily distinguished by Western blot analysis XREF_BIBR , XREF_BIBR .	PARP can also be used as a marker for apoptosis, since activation of apoptosis leads to cleavage of full-length PARP (113 kDa) by Caspase-3 and -7 into two smaller fragments (89 and 24 kDa); the 113 kDa and 89 kDa forms are readily distinguished by Western blot analysis XREF_BIBR, XREF_BIBR.	15	28	leads	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	26	27	20	21
293T cells transfected with lacZ control , ELMOD1 and TMCO1 expression plasmids were then analysed by Western blotting with an antibody raised against the caspase-3 target PARP , which showed PARP cleavage in the cells transfected with the ELMOD1 and TMCO1 expression plasmids but not in the cells transfected with the control expression plasmid .	293T cells transfected with lacZ control, ELMOD1 and TMCO1 expression plasmids were then analysed by Western blotting with an antibody raised against the caspase-3 target PARP, which showed PARP cleavage in the cells transfected with the ELMOD1 and TMCO1 expression plasmids but not in the cells transfected with the control expression plasmid.	21	29	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	24	25	26	27
The DEVD peptide was originally identified from the caspase cleavage site within PARP , a DNA repair enzyme , targeted by caspase-3 during apoptosis 27 .	The DEVD peptide was originally identified from the caspase cleavage site within PARP, a DNA repair enzyme, targeted by caspase-3 during apoptosis 27.	5	22	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	21	22	12	13
Following JHMV infection , we observed the cleavage of procaspase 3 ( 35 kDa ) into its active form ( 17 kDa ) , in combination with cleavage of the caspase 3 target PARP , and muted expression of Bcl2 , a member of the anti-apoptotic Bcl-x family of proteins , confirming previous reports XREF_BIBR - XREF_BIBR that in vitro JHMV triggers apoptosis within infected oligodendrocyte cultures ( XREF_FIG ) .	Following JHMV infection, we observed the cleavage of procaspase 3 (35 kDa) into its active form (17 kDa), in combination with cleavage of the caspase 3 target PARP, and muted expression of Bcl2, a member of the anti-apoptotic Bcl-x family of proteins, confirming previous reports XREF_BIBR - XREF_BIBR that in vitro JHMV triggers apoptosis within infected oligodendrocyte cultures (XREF_FIG).	27	37	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	30	32	33	34
Altogether these data indicate that the induction of apoptosis by these new derivatives is associated with Bcl-2 down-regulation and caspase-3 activation that in turn stimulated PARP cleavage .	Altogether these data indicate that the induction of apoptosis by these new derivatives is associated with Bcl-2 down-regulation and caspase-3 activation that in turn stimulated PARP cleavage.	19	26	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	19	20	25	26
Caspase-3 , represents a convergence point between the two routes , and in turn induces PARP cleavage , chromosomal DNA breaks and finally the breakdown of the cell into apoptotic bodies XREF_BIBR .	Caspase-3, represents a convergence point between the two routes, and in turn induces PARP cleavage, chromosomal DNA breaks and finally the breakdown of the cell into apoptotic bodies XREF_BIBR.	0	16	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	0	1	15	16
PARP is targeted for cleavage at Asp214 by activated caspase-3 and is a sensitive measure of committed apoptotic signaling [ XREF_BIBR ] .	PARP is targeted for cleavage at Asp214 by activated caspase-3 and is a sensitive measure of committed apoptotic signaling [XREF_BIBR].	0	10	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	9	10	0	1
Immunoblot analysis of lysates from cells treated with alpha-hemolysin showed no evidence of caspase-3 activation or cleavage of PARP , both of which could be induced in the THP-1 cells by treatment with Staurosporine ( which is known to activate apoptosis ) ( XREF_FIG ) .	Immunoblot analysis of lysates from cells treated with alpha-hemolysin showed no evidence of caspase-3 activation or cleavage of PARP, both of which could be induced in the THP-1 cells by treatment with Staurosporine (which is known to activate apoptosis) (XREF_FIG).	13	25	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	13	14	18	19
Apoptosis was mediated by cleavage of the receptor proximal caspase FLICE and MACH ( caspase-8 ) and the downstream caspase CPP32 ( caspase-3 , Apopain ) resulting in cleavage of the prototype caspase substrate PARP .	Apoptosis was mediated by cleavage of the receptor proximal caspase FLICE and MACH (caspase-8) and the downstream caspase CPP32 (caspase-3, Apopain) resulting in cleavage of the prototype caspase substrate PARP.	2	35	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CPP32	CPP32	CPP32	PARP	PARP	PARP	20	21	34	35
Further , activation of caspase-3 led to cleavage of its target proteins PARP-1 and ICAD , which resulted in apoptotic DNA damage .	Further, activation of caspase-3 led to cleavage of its target proteins PARP-1 and ICAD, which resulted in apoptotic DNA damage.	2	17	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	4	5	12	13
Finally , the lethality induced by mifepristone in all cell lines , without apparent distinction of platinum-sensitivities , was associated with another marker of apoptotic death , the cleavage of the caspase-3 target PARP from the full length 116 kDa form to a 89 kDa fragment [ XREF_BIBR ] .	Finally, the lethality induced by mifepristone in all cell lines, without apparent distinction of platinum-sensitivities, was associated with another marker of apoptotic death, the cleavage of the caspase-3 target PARP from the full length 116 kDa form to a 89 kDa fragment [XREF_BIBR].	28	34	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	31	32	33	34
The activation of caspase-3 induced PARP cleavage .	The activation of caspase-3 induced PARP cleavage.	1	6	induced	Positive_early_activation	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	3	4	5	6
Our results showed that TCS dose-dependently activated caspase-8 and caspase-9 , each at the apex of its pathway , following which came caspase-3 activation and cleavage of PARP ( XREF_FIG ) .	Our results showed that TCS dose-dependently activated caspase-8 and caspase-9, each at the apex of its pathway, following which came caspase-3 activation and cleavage of PARP (XREF_FIG).	22	29	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	22	23	27	28
The catalytic domain can be efficiently cleaved from DNA binding domain by interleukin-1 converting enzyme ( ICE )-like caspases ( mainly caspase 3 ) , resulting in cleavage of PARP.50 , 51 The cleavage facilitates cellular disassembly and serves as a marker of cell apoptosis , and the amount of cleaved PARP ( c-PARP ) can be used to assess the propensity of cells to apoptosis.52 Caspase 3 is one of the key executioners of apoptosis , which is either partially or totally responsible for the proteolytic cleavage of PARP.53 Activation of caspase 3 requires proteolytic processing of its inactive zymogen into activated p17 and p21 fragments , and the amount of cleaved caspase 3 ( c-Casp3 ) is a quantitative index of apoptosis induction.50 Our data showed increased expression of both c-PARP and c-Casp3 , indicating a caspase3 activated PARP cleavage in response to TB induced apoptosis .	The catalytic domain can be efficiently cleaved from DNA binding domain by interleukin-1 converting enzyme (ICE)-like caspases (mainly caspase 3), resulting in cleavage of PARP.50, 51 The cleavage facilitates cellular disassembly and serves as a marker of cell apoptosis, and the amount of cleaved PARP (c-PARP) can be used to assess the propensity of cells to apoptosis.52 Caspase 3 is one of the key executioners of apoptosis, which is either partially or totally responsible for the proteolytic cleavage of PARP.53 Activation of caspase 3 requires proteolytic processing of its inactive zymogen into activated p17 and p21 fragments, and the amount of cleaved caspase 3 (c-Casp3) is a quantitative index of apoptosis induction.50 Our data showed increased expression of both c-PARP and c-Casp3, indicating a caspase3 activated PARP cleavage in response to TB induced apoptosis.	138	147	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	caspase3	caspase3	caspase3	PARP	PARP	PARP	138	139	140	141
The activation of aspartate specific cysteine protease ( caspase ) represents a crucial step in the induction of drug induced apoptosis , with the cleavage of PARP by caspase-3 considered one of the hallmarks of apoptosis .	The activation of aspartate specific cysteine protease (caspase) represents a crucial step in the induction of drug induced apoptosis, with the cleavage of PARP by caspase-3 considered one of the hallmarks of apoptosis.	19	29	induced	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	28	29	26	27
Western blotting assay revealed that delta-T3 increased the expression levels of cell cycle inhibitors ( p21 , p27 ) , pro apoptotic protein ( Bax ) and suppressed expression levels of cell cycle protein ( Cyclin D1 ) , anti-apoptotic proteins ( Bcl-2 , Bcl-x L and Mcl-1 ) , resulting in the Caspase-3 activation and cleavage of PARP .	Western blotting assay revealed that delta-T3 increased the expression levels of cell cycle inhibitors (p21, p27), pro apoptotic protein (Bax) and suppressed expression levels of cell cycle protein (Cyclin D1), anti-apoptotic proteins (Bcl-2, Bcl-x L and Mcl-1), resulting in the Caspase-3 activation and cleavage of PARP.	53	59	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	53	54	58	59
Caspase-3 activation and cleavage of PARP-1 were found to be late event as they appeared by 24 h and proceeded the alteration in Bax and Bcl -2 levels .	Caspase-3 activation and cleavage of PARP-1 were found to be late event as they appeared by 24 h and proceeded the alteration in Bax and Bcl -2 levels.	0	6	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP-1	PARP-1	PARP-1	0	1	5	6
Caspase 3 induces fragmentation of PARP protein and this modification blocks the ability of PARP to repair damaged DNA [ XREF_BIBR ] .	Caspase 3 induces fragmentation of PARP protein and this modification blocks the ability of PARP to repair damaged DNA [XREF_BIBR].	0	6	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase 3	Caspase 3	Caspase 3	PARP	PARP	PARP	0	2	5	6
Thereafter , caspase-3 is activated , which increases PARP cleavage .	Thereafter, caspase-3 is activated, which increases PARP cleavage.	2	9	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	2	3	8	9
Activated caspase-9 can cleave and activate caspase-3 , 6 and 7 , inducing PARP cleavage and apoptosis [ XREF_BIBR , XREF_BIBR ] .	Activated caspase-9 can cleave and activate caspase-3, 6 and 7, inducing PARP cleavage and apoptosis [XREF_BIBR, XREF_BIBR].	3	14	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	6	7	13	14
Moreover , palmitate significantly stimulated caspase-3 activation and proteolytic cleavage of PARP in cardiomyocytes ( XREF_FIG ) .	Moreover, palmitate significantly stimulated caspase-3 activation and proteolytic cleavage of PARP in cardiomyocytes (XREF_FIG).	5	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	5	6	11	12
Data showed that translocated YopE 1-138 -tBID triggered CASP3 ( XREF_FIG ) and PARP ( XREF_FIG ) cleavage , CASP3 activation ( XREF_FIG ) and massive cell death ( XREF_FIG ) .	Data showed that translocated YopE 1-138 -tBID triggered CASP3 (XREF_FIG) and PARP (XREF_FIG) cleavage, CASP3 activation (XREF_FIG) and massive cell death (XREF_FIG).	7	20	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CASP3	CASP3	CASP3	PARP	PARP	PARP	19	20	13	14
Caspase-3 activation has been suggested to activate PARP and induce apoptosis , which is also related to ROS production .	Caspase-3 activation has been suggested to activate PARP and induce apoptosis, which is also related to ROS production.	0	8	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	0	1	7	8
The two initiator caspases crosstalk via Bid prompting caspase-3 mediated PARP cleavage and HKM apoptosis ( XREF_FIG ) .	The two initiator caspases crosstalk via Bid prompting caspase-3 mediated PARP cleavage and HKM apoptosis (XREF_FIG).	7	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	8	9	10	11
To comprehensively find mechanistic insight into the role of TMEM40 in regulating BCa cell proliferation and apoptosis , we measured the alteration of proliferation related signals ( p53 , p21 , c-MYC , cyclin D1 ) and apoptosis related proteins ( p53 , activated caspase-3 , activated caspase-9 , activated PARP ) by western blotting .	To comprehensively find mechanistic insight into the role of TMEM40 in regulating BCa cell proliferation and apoptosis, we measured the alteration of proliferation related signals (p53, p21, c-MYC, cyclin D1) and apoptosis related proteins (p53, activated caspase-3, activated caspase-9, activated PARP) by western blotting.	43	51	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	44	45	50	51
In line with established features of mitochondrial apoptosis , STM modulated Bcl-2 family proteins , dissipated MMP , and induced caspase-3 activation and cleavage of PARP in A549 lung cancer cells in a dose dependent manner .	In line with established features of mitochondrial apoptosis, STM modulated Bcl-2 family proteins, dissipated MMP, and induced caspase-3 activation and cleavage of PARP in A549 lung cancer cells in a dose dependent manner.	20	26	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	20	21	25	26
Caspase-3 promotes apoptosis by cleaving PARP in endothelial cells .	Caspase-3 promotes apoptosis by cleaving PARP in endothelial cells.	0	6	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	0	1	5	6
In Hela cells , 2,3-dehydrosilybin , at 25 and 50 muM , activated the cleavage of caspase 3 , caspase 9 and significantly induced PARP cleavage .	In Hela cells, 2,3-dehydrosilybin, at 25 and 50 muM, activated the cleavage of caspase 3, caspase 9 and significantly induced PARP cleavage.	14	25	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	16	18	24	25
EFV treatment did not cause caspase-3 activation or cleavage of PARP ( XREF_FIG ) .	EFV treatment did not cause caspase-3 activation or cleavage of PARP (XREF_FIG).	5	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	5	6	10	11
Activation of caspase-3 and caspase-7 induces the proteolytic cleavage of PARP to its signature 85-kDa fragment .	Activation of caspase-3 and caspase-7 induces the proteolytic cleavage of PARP to its signature 85-kDa fragment.	0	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	2	3	10	11
Moreover , the caspase-3 induced PARP-1 fragmentation coinciding with the increase of caspase-3 activity was detected solely in the target organ and exclusively in hepatocytes undergoing apoptosis .	Moreover, the caspase-3 induced PARP-1 fragmentation coinciding with the increase of caspase-3 activity was detected solely in the target organ and exclusively in hepatocytes undergoing apoptosis.	2	6	induced	Positive_early_activation	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	3	4	5	6
PARP cleavage is catalyzed by activated caspase-3 which prevents PARP mediated DNA repair processes XREF_BIBR .	PARP cleavage is catalyzed by activated caspase-3 which prevents PARP mediated DNA repair processes XREF_BIBR.	0	8	catalyzed	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	6	7	0	1
In the current study treatment of SW480 cells with morin resulted in caspase 3 mediated PARP cleavage by the activation both extrinsic as well as intrinsic pathways of apoptosis which was ascertained by using the downstream caspase 3 inhibitor .	In the current study treatment of SW480 cells with morin resulted in caspase 3 mediated PARP cleavage by the activation both extrinsic as well as intrinsic pathways of apoptosis which was ascertained by using the downstream caspase 3 inhibitor.	10	16	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	12	14	15	16
Also , increased caspase-3 activity mediated ICAD cleavage and PARP fragmention .	Also, increased caspase-3 activity mediated ICAD cleavage and PARP fragmention.	3	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	3	4	9	10
Therefore , the inhibition of caspase-3 induced by Infliximab could inhibit PARG activity and prevent PARP inactivation thus exacerbating PAR accumulation at all cell layers of retinal explants .	Therefore, the inhibition of caspase-3 induced by Infliximab could inhibit PARG activity and prevent PARP inactivation thus exacerbating PAR accumulation at all cell layers of retinal explants.	3	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	5	6	15	16
Our results suggest that : ( a ) Pc 4-PDT is effective in the treatment of SW480 human colon cancer xenografts independent of p53 status ; ( b ) PARP cleavage may be mediated by caspase-9 and caspase-3 activation in the Pc 4-PDT-treated tumors ; and ( c ) p38 phosphorylation may be a trigger of apoptosis in response to PDT in vivo in this tumor model .	Our results suggest that : (a) Pc 4-PDT is effective in the treatment of SW480 human colon cancer xenografts independent of p53 status; (b) PARP cleavage may be mediated by caspase-9 and caspase-3 activation in the Pc 4-PDT-treated tumors; and (c) p38 phosphorylation may be a trigger of apoptosis in response to PDT in vivo in this tumor model.	29	38	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	37	38	29	30
In addition to using sub-G1 accumulation and Annexin V staining , caspase 3 activation ( cleavage ) and PARP cleavage which is catalyzed by caspase 3 were then monitored by immunoblotting as another apoptotic indication .	In addition to using sub-G1 accumulation and Annexin V staining, caspase 3 activation (cleavage) and PARP cleavage which is catalyzed by caspase 3 were then monitored by immunoblotting as another apoptotic indication.	18	26	catalyzed	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	24	26	18	19
Caspase-3 , for example , promotes cleavage of PARP1 ( poly ( ADP-ribose ) polymerase 1 ) and internucleosomal DNA fragmentation , one of the hallmarks of apoptosis [ XREF_BIBR ] .	Caspase-3, for example, promotes cleavage of PARP1 (poly (ADP-ribose) polymerase 1) and internucleosomal DNA fragmentation, one of the hallmarks of apoptosis [XREF_BIBR].	0	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP1	PARP1	PARP1	0	1	8	9
However , caspase-3 driven cleavage of PARP-1 , a characteristic feature of apoptotic commitment , was observed in WM793 and FEMX , but not in LOX cells ( XREF_FIG ) resulting in pronounced apoptosis for WM793 and FEMX cells , but only G2/M arrest for resistant LOX cells 24 h after treatment ( XREF_FIG ) .	However, caspase-3 driven cleavage of PARP-1, a characteristic feature of apoptotic commitment, was observed in WM793 and FEMX, but not in LOX cells (XREF_FIG) resulting in pronounced apoptosis for WM793 and FEMX cells, but only G2/M arrest for resistant LOX cells 24 h after treatment (XREF_FIG).	2	16	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	2	3	6	7
Under our experimental conditions , we observed that mild hypoxia promoted cell death through caspase-3 activation in the inner retina ( INL and GCL ) and PARP activation through the whole retina .	Under our experimental conditions, we observed that mild hypoxia promoted cell death through caspase-3 activation in the inner retina (INL and GCL) and PARP activation through the whole retina.	14	27	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	14	15	26	27
Finally , downregulation of GLIPR1 in A549 and DDP cells was discovered significantly increased the cleaved PARP , a DNA repair enzyme , and cleaved caspase-3 , a pro apoptotic protein .	Finally, downregulation of GLIPR1 in A549 and DDP cells was discovered significantly increased the cleaved PARP, a DNA repair enzyme, and cleaved caspase-3, a pro apoptotic protein.	13	30	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	25	26	16	17
Caspase-3 mediates the nuclear enzyme PARP through proteolytic cleavage , which then plays an important role in apoptotic cells .	Caspase-3 mediates the nuclear enzyme PARP through proteolytic cleavage, which then plays an important role in apoptotic cells.	0	6	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	0	1	5	6
Activated caspase-9 activates caspase-3 and caspase-7 , which in turn induces PARP cleavage .	Activated caspase-9 activates caspase-3 and caspase-7, which in turn induces PARP cleavage.	0	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	3	4	11	12
Caspase 9 is an initiator caspase , and once it gets activated , it activates caspase 3 and this causes the proteolysis of PARP .	Caspase 9 is an initiator caspase, and once it gets activated, it activates caspase 3 and this causes the proteolysis of PARP.	15	24	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	15	17	23	24
The anti-tumor effects of the compound were further confirmed with caspase-3 activation and degradation of PARP .	The anti-tumor effects of the compound were further confirmed with caspase-3 activation and degradation of PARP.	10	16	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	10	11	15	16
Considering the fact that the caspase-3 mediated PARP-1 cleavage occurred only in 60 % of animals tested between 20 and 40 h , it becomes obvious that the cellular response in vivo to the same trigger ( s ) strongly varies and may depend on a variety of intrinsic factors .	Considering the fact that the caspase-3 mediated PARP-1 cleavage occurred only in 60% of animals tested between 20 and 40 h, it becomes obvious that the cellular response in vivo to the same trigger (s) strongly varies and may depend on a variety of intrinsic factors.	4	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	5	6	7	8
Further , inhibition of the upstream activator of caspase 3 , caspase 9 , suppressed 6MP induced PARP cleavage ( XREF_FIG ) .	Further, inhibition of the upstream activator of caspase 3, caspase 9, suppressed 6MP induced PARP cleavage (XREF_FIG).	6	18	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	8	10	17	18
Consistent with the protective effects of Vitamin C against drug induced apoptosis , Vitamin C blocked fenretinide induced activation of Caspase 3 ( i.e ., inhibited pro Caspase cleavage ) and suppressed cleavage of PARP in the RS4 ; 11 cells ( XREF_FIG ) .	Consistent with the protective effects of Vitamin C against drug induced apoptosis, Vitamin C blocked fenretinide induced activation of Caspase 3 (i.e., inhibited pro Caspase cleavage) and suppressed cleavage of PARP in the RS4; 11 cells (XREF_FIG).	13	35	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase 3	Vitamin C blocked fenretinide induced activation of Caspase 3	caspase 3	PARP	PARP	parp	20	22	34	35
This agent also downregulated the expression of STAT3 regulated cyclin D1 , Bcl-xL , and VEGF , activated caspase-3 , induced PARP cleavage , and increased the sub-G1 population of MM cells .	This agent also downregulated the expression of STAT3 regulated cyclin D1, Bcl-xL, and VEGF, activated caspase-3, induced PARP cleavage, and increased the sub-G1 population of MM cells.	10	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	18	19	21	22
Of note , Noxa knockdown accelerated reduction in cell viability caused by serum starvation , which was largely due to induction of apoptosis as shown by caspase-3 activation and cleavage of its substrate PARP .	Of note, Noxa knockdown accelerated reduction in cell viability caused by serum starvation, which was largely due to induction of apoptosis as shown by caspase-3 activation and cleavage of its substrate PARP.	26	34	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	26	27	33	34
The activation of caspase-3 induces PARP cleavage , chromosomal DNA break and finally the occurrence of apoptosis [ XREF_BIBR ] .	The activation of caspase-3 induces PARP cleavage, chromosomal DNA break and finally the occurrence of apoptosis [XREF_BIBR].	1	6	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	3	4	5	6
However , the simultaneous administration of caspase-3 and -7 inhibitor ( Z-VAD-FMK ) with nocodazole prevented PARP1 loss in G2 arrested cells , thus suggesting that nocodazole induced PARP1 cleavage by caspases .	However, the simultaneous administration of caspase-3 and -7 inhibitor (Z-VAD-FMK) with nocodazole prevented PARP1 loss in G2 arrested cells, thus suggesting that nocodazole induced PARP1 cleavage by caspases.	4	17	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP1	PARP1	PARP1	6	7	16	17
The integrity of caspase-3 mediated PARP1 cleavage in Molt-3 cells was verified by UV exposure ( data not shown ) .	The integrity of caspase-3 mediated PARP1 cleavage in Molt-3 cells was verified by UV exposure (data not shown).	1	6	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP1	PARP1	PARP1	3	4	5	6
Both PARP proteolysis and the proapoptotic effects of the protease are inhibited by nanomolar concentrations of a selective inhibitor of apopain ( CPP32 ) , while an inhibitor of IL-1 beta converting enzyme is much less effective , requiring micromolar concentrations for the inhibition of the isolated protease .	Both PARP proteolysis and the proapoptotic effects of the protease are inhibited by nanomolar concentrations of a selective inhibitor of apopain (CPP32), while an inhibitor of IL-1 beta converting enzyme is much less effective, requiring micromolar concentrations for the inhibition of the isolated protease.	1	22	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	apopain	apopain	apopain	PARP	PARP	PARP	20	21	1	2
We used a minimal protein construct comprising PARP-1 ' s flexibly linked N-terminal zinc fingers F1F2 ( XREF_FIG B ) , corresponding to the naturally occurring caspase-3 cleavage product of PARP-1 .	We used a minimal protein construct comprising PARP-1 's flexibly linked N-terminal zinc fingers F1F2 (XREF_FIG B), corresponding to the naturally occurring caspase-3 cleavage product of PARP-1.	26	31	product	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	26	27	30	31
The introduction of caspase-3 gene in PKCdelta over-expressing cells ( MCF-7/cas-3/PKCdelta ) significantly enhanced the cleavage of the PKCdelta , caspase-3 , and PARP cleavage in the presence of TRAIL when compared to untreated cells ( XREF_FIG ) .	The introduction of caspase-3 gene in PKCdelta over-expressing cells (MCF-7/cas-3/PKCdelta) significantly enhanced the cleavage of the PKCdelta, caspase-3, and PARP cleavage in the presence of TRAIL when compared to untreated cells (XREF_FIG).	3	24	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	3	4	23	24
An early transient rupture in nuclear protein was recently shown to be required for apoptosis to proceed in cancer cells XREF_BIBR , and this event results from the cleavage of poly ( ADP-ribose ) polymerase ( PARP ) , which is catalyzed by caspase-3 .	An early transient rupture in nuclear protein was recently shown to be required for apoptosis to proceed in cancer cells XREF_BIBR, and this event results from the cleavage of poly (ADP-ribose) polymerase (PARP), which is catalyzed by caspase-3.	34	44	catalyzed	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	43	44	36	37
These results were consistent with the findings of previous study that caspase-3 led to PARP to cleavage and consequently caused the progression of OA with cell apoptosis and death [ XREF_BIBR ] .	These results were consistent with the findings of previous study that caspase-3 led to PARP to cleavage and consequently caused the progression of OA with cell apoptosis and death [XREF_BIBR].	11	19	led	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	11	12	14	15
Dieckol attenuated the expression of alpha-SMA and TGF-beta1 , increased sub-G1 phase population , and induced caspase-3 activation and cleavages of PARP in HSCs .	Dieckol attenuated the expression of alpha-SMA and TGF-beta1, increased sub-G1 phase population, and induced caspase-3 activation and cleavages of PARP in HSCs.	16	22	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	16	17	21	22
Caspase-3 plays key roles in the execution of apoptotic pathways , and as the end point of both intrinsic and extrinsic pathways , cleaved caspase-3 activates PARP and induces apoptosis [ XREF_BIBR , XREF_BIBR ] .	Caspase-3 plays key roles in the execution of apoptotic pathways, and as the end point of both intrinsic and extrinsic pathways, cleaved caspase-3 activates PARP and induces apoptosis [XREF_BIBR, XREF_BIBR].	23	28	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	24	25	26	27
We found that SN-38 had modest effect on PARP , and caspase-3 and gefitinib significantly increased the cleavage of PARP and caspase-3 caused by SN-38 in HepG2 and Bel-7402 cells ( XREF_FIG ) .	We found that SN-38 had modest effect on PARP, and caspase-3 and gefitinib significantly increased the cleavage of PARP and caspase-3 caused by SN-38 in HepG2 and Bel-7402 cells (XREF_FIG).	11	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	11	12	19	20
When a cell initiates apoptosis , PARP is targeted by caspase 3 and caspase 7 , and is cleaved , rendering the enzyme inactive .	When a cell initiates apoptosis, PARP is targeted by caspase 3 and caspase 7, and is cleaved, rendering the enzyme inactive.	6	18	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	10	12	6	7
The detected increase of caspase-3 , in addition to the in vitro observed increased PARP cleavage , suggest that the effect of ceritinib on cell viability is mediated by caspase dependent apoptosis [ XREF_BIBR ] .	The detected increase of caspase-3, in addition to the in vitro observed increased PARP cleavage, suggest that the effect of ceritinib on cell viability is mediated by caspase dependent apoptosis [XREF_BIBR].	2	15	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	4	5	14	15
Pro-caspase-3 is cleaved to form active caspase-3 , which targets and cleaves PARP1 , driving the cells further into becoming apoptotic [ XREF_BIBR , XREF_BIBR ] .	Pro-caspase-3 is cleaved to form active caspase-3, which targets and cleaves PARP1, driving the cells further into becoming apoptotic [XREF_BIBR, XREF_BIBR].	5	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP1	PARP1	PARP1	6	7	12	13
Cellular apoptosis was evaluated by multiple techniques such as DNA fragmentation ( XREF_FIG ) , caspase-3 induced AMC production ( XREF_FIG ) and PARP cleavage ( XREF_FIG ) .	Cellular apoptosis was evaluated by multiple techniques such as DNA fragmentation (XREF_FIG), caspase-3 induced AMC production (XREF_FIG) and PARP cleavage (XREF_FIG).	15	24	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	15	16	23	24
Altogether these data indicate that the induction of apoptosis by 4e is associated with Bcl-2 down regulation and caspase-3 activation , which in turn stimulates PARP cleavage .	Altogether these data indicate that the induction of apoptosis by 4e is associated with Bcl-2 down regulation and caspase-3 activation, which in turn stimulates PARP cleavage.	16	26	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	18	19	25	26
One of the most significant underlying mechanism is a highly cancer cell specific induction of caspase-3 mediated cleavage of PARP .	One of the most significant underlying mechanism is a highly cancer cell specific induction of caspase-3 mediated cleavage of PARP.	13	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	15	16	19	20
Since PARP cleavage is promoted by the effector Caspase-3 , these data confirm that apoptotic cell death was delayed after transfection with siPERK followed by ER stress .	Since PARP cleavage is promoted by the effector Caspase-3, these data confirm that apoptotic cell death was delayed after transfection with siPERK followed by ER stress.	1	9	promoted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	8	9	1	2
The activation of caspase-3 induces the cleavage of PARP , a well-known substrate of caspase-3 .	The activation of caspase-3 induces the cleavage of PARP, a well-known substrate of caspase-3.	1	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	3	4	8	9
To determine whether this sub-G 1 / G 0 population constituted apoptotic cells , Molt4-hyg cells were treated with 75 muM farnesol and at different time points cells were analyzed for the induction of several apoptotic markers , including the cysteine proteases , caspase-9 and caspase-3 , and the caspase-3 target PARP-1 .	To determine whether this sub-G 1 / G 0 population constituted apoptotic cells, Molt4-hyg cells were treated with 75 muM farnesol and at different time points cells were analyzed for the induction of several apoptotic markers, including the cysteine proteases, caspase-9 and caspase-3, and the caspase-3 target PARP-1.	32	52	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	49	50	51	52
The potential of CMPP to inhibit cellular growth in MD-MB-486 breast cancer cells and MV3 melanoma cells was largely due to induction of caspase dependent apoptosis , as confirmed by caspase-3 activation and cleavage of its substrate PARP .	The potential of CMPP to inhibit cellular growth in MD-MB-486 breast cancer cells and MV3 melanoma cells was largely due to induction of caspase dependent apoptosis, as confirmed by caspase-3 activation and cleavage of its substrate PARP.	30	38	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	30	31	37	38
The activity of caspase 3 to cleave the synthetic substrate in vitro and PARP in vivo is blocked by a specific inhibitor of caspase 3 .	The activity of caspase 3 to cleave the synthetic substrate in vitro and PARP in vivo is blocked by a specific inhibitor of caspase 3.	1	25	blocked	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	23	25	13	14
The inhibitor of caspase-3 blocked PARP-1 cleavage activity and protected against MEF induced apoptotic cell death .	The inhibitor of caspase-3 blocked PARP-1 cleavage activity and protected against MEF induced apoptotic cell death.	1	7	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	3	4	5	6
Next , PARP cleavage , triggered by caspase-3 activation during apoptotic processes , and apoptosis related Bcl-2 family proteins were also detected when macrophages were treated with ox-LDL TG and metformin ( 0.5 mM ) .	Next, PARP cleavage, triggered by caspase-3 activation during apoptotic processes, and apoptosis related Bcl-2 family proteins were also detected when macrophages were treated with ox-LDL TG and metformin (0.5 mM).	2	8	triggered	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	7	8	2	3
Finally , we found that the decrease in cell viability was due , at least in part , to an induction of apoptosis , as cleavage of the caspase 3 target PARP was observed in TAT-DI1-treated A549 cells ( XREF_FIG ) .	Finally, we found that the decrease in cell viability was due, at least in part, to an induction of apoptosis, as cleavage of the caspase 3 target PARP was observed in TAT-DI1-treated A549 cells (XREF_FIG).	25	33	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	28	30	31	32
Interestingly , the activation of caspase-3 also induced the PARP cleavage .	Interestingly, the activation of caspase-3 also induced the PARP cleavage.	3	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	5	6	9	10
Inhibition of CPP32 like proteinases by Ac-Asp-Glu-Val-Asp-aldehyde but not by Ac-Tyr-Val-Ala-Asp-aldehyde prevents CPP32 , PARP and p59Fyn cleavage indicating that CPP32 or CPP32 like proteinases are responsible for the cleavage of p59Fyn .	Inhibition of CPP32 like proteinases by Ac-Asp-Glu-Val-Asp-aldehyde but not by Ac-Tyr-Val-Ala-Asp-aldehyde prevents CPP32, PARP and p59Fyn cleavage indicating that CPP32 or CPP32 like proteinases are responsible for the cleavage of p59Fyn.	0	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CPP32	CPP32	CPP32	PARP	PARP	PARP	2	3	14	15
Our data showed increased expression of Caspase-3 and simultaneous increase in PARP-1 cleavage over the time period of 24-72 h with all the three treatments ( XREF_FIG ) .	Our data showed increased expression of Caspase-3 and simultaneous increase in PARP-1 cleavage over the time period of 24-72 h with all the three treatments (XREF_FIG).	6	12	increase	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP-1	PARP-1	PARP-1	6	7	11	12
Caspase 3 cleavage is an early event in many forms of programmed cell death and leads to the induction of PARP cleavage XREF_BIBR , XREF_BIBR .	Caspase 3 cleavage is an early event in many forms of programmed cell death and leads to the induction of PARP cleavage XREF_BIBR, XREF_BIBR.	0	22	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Caspase 3	Caspase 3	Caspase 3	PARP	PARP	PARP	0	2	20	21
Then caspase 3 was activated and cleaved PARP , inducing apoptosis .	Then caspase 3 was activated and cleaved PARP, inducing apoptosis.	1	8	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	1	3	7	8
Second , caspase-3 and PARP are viewed as key enforcers of apoptosis , and activated caspase-3 can further decompose its critical downstream substrate PARP and ultimately lead to apoptosis [ XREF_BIBR , XREF_BIBR ] .	Second, caspase-3 and PARP are viewed as key enforcers of apoptosis, and activated caspase-3 can further decompose its critical downstream substrate PARP and ultimately lead to apoptosis [XREF_BIBR, XREF_BIBR].	2	24	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	2	3	23	24
To further elucidate the link between OX 1 R and apoptosis , we used Western blotting technique to semi-quantify pancreatic tissue levels of OX 1 R protein and the apoptotic marker PARP polymerase , a DNA repair enzyme which is targeted by active caspase 3 during apoptosis .	To further elucidate the link between OX 1 R and apoptosis, we used Western blotting technique to semi-quantify pancreatic tissue levels of OX 1 R protein and the apoptotic marker PARP polymerase, a DNA repair enzyme which is targeted by active caspase 3 during apoptosis.	31	46	targeted	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	43	45	31	32
Caspase-3 primarily activates PARP ; however , studies have additionally indicated that caspase-6 and caspase-7 are also able to cause PARP cleavage .	Caspase-3 primarily activates PARP; however, studies have additionally indicated that caspase-6 and caspase-7 are also able to cause PARP cleavage.	0	4	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	0	1	3	4
The executioner caspase-3 is activated by autolytic cleavage and catalyzes the proteolysis and inactivation of the DNA repair enzyme poly-( ADP-ribose )-polymerase 1 ( PARP1 ) [ XREF_BIBR ] .	The executioner caspase-3 is activated by autolytic cleavage and catalyzes the proteolysis and inactivation of the DNA repair enzyme poly-(ADP-ribose)-polymerase 1 (PARP1) [XREF_BIBR].	0	27	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP1	PARP1	PARP1	2	3	24	25
The resulting activation of caspase-3 then triggers an irreversible cell death program in the nucleus [ XREF_BIBR , XREF_BIBR ] , and this involve the inactivation of PARP and DNA-PK , two key enzymes involved in the homeostatic maintenance of genomic integrity [ XREF_BIBR , XREF_BIBR ] .	The resulting activation of caspase-3 then triggers an irreversible cell death program in the nucleus [XREF_BIBR, XREF_BIBR], and this involve the inactivation of PARP and DNA-PK, two key enzymes involved in the homeostatic maintenance of genomic integrity [XREF_BIBR, XREF_BIBR].	2	29	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	4	5	27	28
FCP induce caspase-3 activation and subsequent cleavage of PARP in A549 cells .	FCP induce caspase-3 activation and subsequent cleavage of PARP in A549 cells.	2	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	2	3	8	9
Caspase-3 which is frequently activated protease in cellular apoptosis causes PARP cleavage in late apoptosis ( Ola et al ., 2011 ) .	Caspase-3 which is frequently activated protease in cellular apoptosis causes PARP cleavage in late apoptosis (Ola et al., 2011).	0	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	0	1	10	11
Western blotting analyses confirmed the mitochondrial involvement revealing the activation of the intrinsic pathway followed by caspase-3 activation and cleavage of PARP-1 .	Western blotting analyses confirmed the mitochondrial involvement revealing the activation of the intrinsic pathway followed by caspase-3 activation and cleavage of PARP-1.	16	22	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP-1	PARP-1	PARP-1	16	17	21	22
To obtain biochemical evidence for the protective effect of UII in DOX induced apoptosis , we investigated the caspase-3 activation and cleavage of PARP in HUVECs after PI3K inhibitor ( LY294002 ) , or an ERK inhibitor ( U0126 ) treatment ( XREF_FIG and XREF_FIG ) .	To obtain biochemical evidence for the protective effect of UII in DOX induced apoptosis, we investigated the caspase-3 activation and cleavage of PARP in HUVECs after PI3K inhibitor (LY294002), or an ERK inhibitor (U0126) treatment (XREF_FIG and XREF_FIG).	18	24	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	18	19	23	24
Reversely , caspase-3 and -9 inhibitors also blocked the DMNQ-S17 induced caspase-3 activation and PARP cleavage in U937 cells .	Reversely, caspase-3 and -9 inhibitors also blocked the DMNQ-S17 induced caspase-3 activation and PARP cleavage in U937 cells.	2	15	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	2	3	14	15
Our results revealed that oxaliplatin induced significant apoptosis at 1 muM , and that this was accompanied by downregulation of the anti-apoptotic protein , Bcl-2 , and up-regulation of the pro apoptotic responses of Bax expression , p53 activation , and caspase 3 directed PARP cleavage .	Our results revealed that oxaliplatin induced significant apoptosis at 1 muM, and that this was accompanied by downregulation of the anti-apoptotic protein, Bcl-2, and up-regulation of the pro apoptotic responses of Bax expression, p53 activation, and caspase 3 directed PARP cleavage.	32	45	directed	Positive_activation_token_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	41	43	44	45
Presumably , if enough CPP32 mediated destruction of PARP occurs before the action of PARP tips the balance to proliferation , apoptosis will occur , abrogating a potential tumour .	Presumably, if enough CPP32 mediated destruction of PARP occurs before the action of PARP tips the balance to proliferation, apoptosis will occur, abrogating a potential tumour.	3	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CPP32	CPP32	CPP32	PARP	PARP	PARP	4	5	8	9
In these experiments , apoptosis was detected by assaying for the cleavage of the caspase-3 target PARP .	In these experiments, apoptosis was detected by assaying for the cleavage of the caspase-3 target PARP.	11	17	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	14	15	16	17
Therefore , PARP cleavage could be mediated by either caspase-3 or caspase-6 in the AAV2 infected MDA-MB-468 cells .	Therefore, PARP cleavage could be mediated by either caspase-3 or caspase-6 in the AAV2 infected MDA-MB-468 cells.	2	11	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	9	10	2	3
Coincidently , caspase-3 activation and cleavage of PARP were not detected .	Coincidently, caspase-3 activation and cleavage of PARP were not detected.	2	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	2	3	7	8
Since caspase activity contributes to the overall apoptotic morphology by cleavage of various cellular substrates , we examined the effect of ACS treatment on caspase-3 activation and proteolytic cleavage of PARP using western blotting .	Since caspase activity contributes to the overall apoptotic morphology by cleavage of various cellular substrates, we examined the effect of ACS treatment on caspase-3 activation and proteolytic cleavage of PARP using western blotting.	24	31	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	24	25	30	31
Moreover , our results showed that overexpression of HLJ1 enhances PARP cleavage caused by caspase-3 activity in CL1-5 exposed to UV irradiation , X irradiation or drugs , even though HLJ1 overexpression has no apparent effect on drug induced apoptosis .	Moreover, our results showed that overexpression of HLJ1 enhances PARP cleavage caused by caspase-3 activity in CL1-5 exposed to UV irradiation, X irradiation or drugs, even though HLJ1 overexpression has no apparent effect on drug induced apoptosis.	10	15	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	14	15	10	11
XREF_BIBR PARP , as one of the essential substrates , was activated by caspase-3 and caspase-7 , which promoted the DNA strand breaks .	XREF_BIBR PARP, as one of the essential substrates, was activated by caspase-3 and caspase-7, which promoted the DNA strand breaks.	0	18	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	13	14	1	2
Overexpression of MCL-1 in MM.1 S led to resistance to GSK126 inducing apoptosis , while silencing MCL-1 by siRNA increased sensitivity of MM.1 S cells to GSK126 inducing apoptosis as reflected by increase in specific cleavage of PARP and activated caspase-3 .	Overexpression of MCL-1 in MM.1 S led to resistance to GSK126 inducing apoptosis, while silencing MCL-1 by siRNA increased sensitivity of MM.1 S cells to GSK126 inducing apoptosis as reflected by increase in specific cleavage of PARP and activated caspase-3.	35	41	activated	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	40	41	37	38
Active caspase-9 then activates caspase-3 , which in turn cleaves substrates such as inhibitor of caspase activated DNase ( ICAD ) and PARP , leading to nucelosomal DNA fragmentation and thus apoptosis .	Active caspase-9 then activates caspase-3, which in turn cleaves substrates such as inhibitor of caspase activated DNase (ICAD) and PARP, leading to nucelosomal DNA fragmentation and thus apoptosis.	3	23	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	4	5	22	23
Furthermore , a Western blot analysis demonstrated that active caspase 3 induced PARP cleavage ( XREF_FIG E ) .	Furthermore, a Western blot analysis demonstrated that active caspase 3 induced PARP cleavage (XREF_FIG E).	8	13	induced	Positive_early_activation	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	9	11	12	13
This cleavage was mirrored by that shown by the caspase-3 target PARP , a classic indicator of apoptosis ( XREF_FIG , left ) .	This cleavage was mirrored by that shown by the caspase-3 target PARP, a classic indicator of apoptosis (XREF_FIG, left).	6	12	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	9	10	11	12
Caspase 3 activation is a common step of the apoptotic signaling pathway and caspase 3 mediated PARP cleavage precipitates cell apoptosis XREF_BIBR .	Caspase 3 activation is a common step of the apoptotic signaling pathway and caspase 3 mediated PARP cleavage precipitates cell apoptosis XREF_BIBR.	6	17	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	13	15	16	17
Surprisingly , we noticed that caspase 3 mediated PARP cleavage continuously increased even after ANE induced necrosis was initiated ( XREF_FIG 4 ) .	Surprisingly, we noticed that caspase 3 mediated PARP cleavage continuously increased even after ANE induced necrosis was initiated (XREF_FIG 4).	5	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	5	7	8	9
To investigate how caspase-3 activation during VCA induced apoptosis induces cleavages of PARP , the expression of PARP and the pattern of caspase-3 activation in HL-60 cells were investigated .	To investigate how caspase-3 activation during VCA induced apoptosis induces cleavages of PARP, the expression of PARP and the pattern of caspase-3 activation in HL-60 cells were investigated.	3	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	3	4	12	13
In addition , western blot analysis revealed fragmentation of PARP induced by an increase in activated caspase-3 after alpha-LA treatment .	In addition, western blot analysis revealed fragmentation of PARP induced by an increase in activated caspase-3 after alpha-LA treatment.	7	19	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	16	17	9	10
Consistent with the tumor promoting role of tNOX suggested by many previous studies , oxaliplatin treated MKN45 and TMK-1 cells showed no down-regulation of tNOX at both translational and transcriptional levels ( in fact , some up-regulation of tNOX was observed in TMK-1 cells ) , increased expression of survivin ( an anti-apoptotic factor ) , and no evidence of caspase 3 directed PARP cleavage .	Consistent with the tumor promoting role of tNOX suggested by many previous studies, oxaliplatin treated MKN45 and TMK-1 cells showed no down-regulation of tNOX at both translational and transcriptional levels (in fact, some up-regulation of tNOX was observed in TMK-1 cells), increased expression of survivin (an anti-apoptotic factor), and no evidence of caspase 3 directed PARP cleavage.	58	64	directed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	60	62	63	64
Co-expression of ASK2 and ASK1 stabilized these two proteins and reduced starvation induced caspase-3 activation and degradation of PARP .	Co-expression of ASK2 and ASK1 stabilized these two proteins and reduced starvation induced caspase-3 activation and degradation of PARP.	13	19	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	13	14	18	19
Caspase-3 mediated PARP cleavage into a molecular weight of 89 kDa is considered a hallmark of apoptosis .	Caspase-3 mediated PARP cleavage into a molecular weight of 89 kDa is considered a hallmark of apoptosis.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP	PARP	PARP	0	1	2	3
We found that APA induced cleavage of caspases-3 , -8 and -9 and also resulted in PARP cleavage , another apoptosis related event , possibly catalyzed by caspase-3 .	We found that APA induced cleavage of caspases-3, -8 and -9 and also resulted in PARP cleavage, another apoptosis related event, possibly catalyzed by caspase-3.	16	28	catalyzed	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	27	28	16	17
Caspase 3 mediated PARP cleavage has been considered as a hallmark of apoptosis .	Caspase 3 mediated PARP cleavage has been considered as a hallmark of apoptosis.	0	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	Caspase 3	Caspase 3	Caspase 3	PARP	PARP	PARP	0	2	3	4
This correlated with induction of substantial apoptosis as indicated by an increase in the sub-G1 cell population and caspase-3 induced PARP cleavage .	This correlated with induction of substantial apoptosis as indicated by an increase in the sub-G1 cell population and caspase-3 induced PARP cleavage.	11	21	induced	Positive_early_activation	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	18	19	20	21
Furthermore , activation of caspase-8 ( extrinsic pathway ) and -9 ( intrinsic pathway ) stimulates caspase-3 , which in turn induces PARP cleavage XREF_BIBR .	Furthermore, activation of caspase-8 (extrinsic pathway) and -9 (intrinsic pathway) stimulates caspase-3, which in turn induces PARP cleavage XREF_BIBR.	15	24	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	16	17	22	23
The activated caspase 3 then induced PARP activation leading to apoptotic responses at the DNA level .	The activated caspase 3 then induced PARP activation leading to apoptotic responses at the DNA level.	0	7	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	PARP	PARP	PARP	2	4	6	7
PARP cleavage to form a 85 kDa fragment of PARP mediated by caspase-3 is often associated with apoptosis and has been served as one hallmark of apoptosis and caspase activation .	PARP cleavage to form a 85 kDa fragment of PARP mediated by caspase-3 is often associated with apoptosis and has been served as one hallmark of apoptosis and caspase activation.	7	13	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PARP	PARP	PARP	12	13	9	10
In fact , PARP-1 cleavage , which was mediated by active Caspase-3 , occurred in limited cases of apoptosis .	In fact, PARP-1 cleavage, which was mediated by active Caspase-3, occurred in limited cases of apoptosis.	3	12	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	PARP-1	PARP-1	PARP-1	11	12	3	4
However , loss or inhibition of either FADD or CASP8 induces RIP1- and RIP3 dependent necroptosis , an alternative cell death pathway [ XREF_BIBR ] .	However, loss or inhibition of either FADD or CASP8 induces RIP1- and RIP3 dependent necroptosis, an alternative cell death pathway [XREF_BIBR].	2	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CASP8	loss or inhibition of either FADD or CASP8	casp8	RIP1-	RIP1-	rip1-	9	10	11	12
Activation of caspase-8 induces cleavage of RIPK1 and RIPK3 and promotes complex II into a pro apoptosis state .	Activation of caspase-8 induces cleavage of RIPK1 and RIPK3 and promotes complex II into a pro apoptosis state.	0	8	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	2	3	6	7
XREF_BIBR , XREF_BIBR Intriguingly , such switch may not operate in all cell types , as demonstrated by the fact that Ripk1 -/- intestinal epithelial cells are fully rescued by the concomitant absence of Casp8 ( Peter Vandenabeele , personal communication ) .	XREF_BIBR, XREF_BIBR Intriguingly, such switch may not operate in all cell types, as demonstrated by the fact that Ripk1 -/- intestinal epithelial cells are fully rescued by the concomitant absence of Casp8 (Peter Vandenabeele, personal communication).	21	37	rescued	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Casp8	Casp8	Casp8	Ripk1	Ripk1	Ripk1	34	35	21	22
In complex IIb and ripoptosome , homodimeric caspase-8 initiates apoptosis by cleaving RIPK1 and disassembling complex IIb and ripoptosome .	In complex IIb and ripoptosome, homodimeric caspase-8 initiates apoptosis by cleaving RIPK1 and disassembling complex IIb and ripoptosome.	6	13	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	7	8	12	13
When caspase-8 activity is inhibited , preventing cleavage of RIP1 , RIP1 positively activates a necrotic ( necroptosis ) pathway XREF_BIBR .	When caspase-8 activity is inhibited, preventing cleavage of RIP1, RIP1 positively activates a necrotic (necroptosis) pathway XREF_BIBR.	1	10	preventing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	1	2	9	10
We hypothesized that caspase-8 activation would induce similar RIPK1 and RIPK3 cleavage in LeTx treated apoptotic macrophages .	We hypothesized that caspase-8 activation would induce similar RIPK1 and RIPK3 cleavage in LeTx treated apoptotic macrophages.	3	13	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	3	4	8	9
Normally , caspase 8 triggers apoptosis by cleaving RIP1 to inhibit the pro survival actions derived from NF-kappaB signaling , and the pro apoptotic protein Bid to generate a truncated form ( tBid ) for inducing cytochrome c release and apoptosome formation .	Normally, caspase 8 triggers apoptosis by cleaving RIP1 to inhibit the pro survival actions derived from NF-kappaB signaling, and the pro apoptotic protein Bid to generate a truncated form (tBid) for inducing cytochrome c release and apoptosome formation.	2	9	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 8	caspase 8	caspase 8	RIP1	RIP1	RIP1	2	4	8	9
Caspase-8 induces the exogenous apoptosis and deactivates the necroptosis by inhibiting the activity of RIPK3 and RIPK1 .	Caspase-8 induces the exogenous apoptosis and deactivates the necroptosis by inhibiting the activity of RIPK3 and RIPK1.	0	17	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-8	Caspase-8	Caspase-8	RIPK1	RIPK1	RIPK1	0	1	16	17
While cleavage of RIPK1 and RIPK3 by caspase-8 prevents necroptosis and elicits apoptosis , caspase-8 inactivation promotes the engagement of RIPK1 and RIPK3 to the effector mechanisms of necroptosis [ XREF_BIBR ] .	While cleavage of RIPK1 and RIPK3 by caspase-8 prevents necroptosis and elicits apoptosis, caspase-8 inactivation promotes the engagement of RIPK1 and RIPK3 to the effector mechanisms of necroptosis [XREF_BIBR].	14	22	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	14	15	20	21
If CYCLD relieves RIP1 ubiquitination , complex II a formation is promoted , and then , caspase-8 activates the cleavage of RIP1 and RIP3 .	If CYCLD relieves RIP1 ubiquitination, complex II a formation is promoted, and then, caspase-8 activates the cleavage of RIP1 and RIP3.	16	23	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	16	17	21	22
These results suggest that caspase 8 cleavage of RIPK1 may induce a conformational change in RIPK1 , subsequently allowing greater accessibility to the HRV 3C cleavage site .	These results suggest that caspase 8 cleavage of RIPK1 may induce a conformational change in RIPK1, subsequently allowing greater accessibility to the HRV 3C cleavage site.	4	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	4	6	15	16
In either the TRADD/FADD/caspase -8 or the RIP1/FADD/caspase -8 complex , caspase-8 is activated , which in turn cleaves RIP1 and RIP3 , and induces cell apoptosis .	In either the TRADD/FADD/caspase -8 or the RIP1/FADD/caspase -8 complex, caspase-8 is activated, which in turn cleaves RIP1 and RIP3, and induces cell apoptosis.	11	21	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	11	12	19	20
As caspase 8 mediated cleavage of RIPK1 is an early apoptotic event 26 , HRV may be able to limit the progression of apoptosis to its effector phase through cleavage of the pro apoptotic , caspase 8 generated RIPK1 cleavage product .	As caspase 8 mediated cleavage of RIPK1 is an early apoptotic event 26, HRV may be able to limit the progression of apoptosis to its effector phase through cleavage of the pro apoptotic, caspase 8 generated RIPK1 cleavage product.	1	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	1	3	6	7
As described in section 6 , RIPK1- and RIPK-3-mediated necroptosis drives increased mortality during TNF induced SIRS an effect that could be blocked by the presence of caspase-8 , which promoted RIPK1 and/or RIPK3 cleavage and inhibited necroptosis .	As described in section 6, RIPK1- and RIPK-3-mediated necroptosis drives increased mortality during TNF induced SIRS an effect that could be blocked by the presence of caspase-8, which promoted RIPK1 and/or RIPK3 cleavage and inhibited necroptosis.	25	36	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	27	28	31	32
cFLIP deficient [ XREF_BIBR ] or RIP1 deficient mice [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] die during development but are fully rescued by the combined elimination of apoptotic ( Casp8 or FADD ) and necroptotic ( RIP3 or MLKL ) machinery .	cFLIP deficient [XREF_BIBR] or RIP1 deficient mice [XREF_BIBR, XREF_BIBR, XREF_BIBR] die during development but are fully rescued by the combined elimination of apoptotic (Casp8 or FADD) and necroptotic (RIP3 or MLKL) machinery.	6	32	rescued	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Casp8	Casp8	Casp8	RIP1	RIP1	RIP1	30	31	6	7
XREF_BIBR , XREF_BIBR Inhibition of endogenous caspase-8 mediated-cleavage of RIP1 is essential for maximal execution of death receptor mediated programmed necrosis .	XREF_BIBR, XREF_BIBR Inhibition of endogenous caspase-8 mediated-cleavage of RIP1 is essential for maximal execution of death receptor mediated programmed necrosis.	6	10	mediated-cleavage	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIP1	RIP1	RIP1	6	7	9	10
Caspase-8 deficiency in mouse embryos triggers chronic RIPK1 dependent activation of inflammatory genes , independently of RIPK3 .	Caspase-8 deficiency in mouse embryos triggers chronic RIPK1 dependent activation of inflammatory genes, independently of RIPK3.	0	9	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	RIPK1	RIPK1	RIPK1	0	1	7	8
Interestingly , data from in vitro protease assays strongly suggest that cleavage of RIPK1 by 3C protease can occur downstream of caspase 8 mediated RIPK1 cleavage .	Interestingly, data from in vitro protease assays strongly suggest that cleavage of RIPK1 by 3C protease can occur downstream of caspase 8 mediated RIPK1 cleavage.	18	25	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	21	23	24	25
However , it still remains to be elucidated how and where caspase-8 and -10 activate RIPK1 to initiate the phosphorylation of IkappaBalpha .	However, it still remains to be elucidated how and where caspase-8 and -10 activate RIPK1 to initiate the phosphorylation of IkappaBalpha.	11	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	11	12	15	16
Our model thus predicts that TNF induced necrosis could occur despite CASP8 mediated cleavage of RIP1 .	Our model thus predicts that TNF induced necrosis could occur despite CASP8 mediated cleavage of RIP1.	9	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CASP8	CASP8	CASP8	RIP1	RIP1	RIP1	11	12	15	16
Necroptotic signaling is also suppressed by caspase 8 mediated cleavage of RIPK1 and/or CYLD .	Necroptotic signaling is also suppressed by caspase 8 mediated cleavage of RIPK1 and/or CYLD.	4	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	6	8	11	12
The delicate balance between RIPK1 and RIPK3 stabilization and caspase 8 driven RIPK1 and RIPK3 cleavage seems to function as the switch between apoptosis and necrosis .	The delicate balance between RIPK1 and RIPK3 stabilization and caspase 8 driven RIPK1 and RIPK3 cleavage seems to function as the switch between apoptosis and necrosis.	2	18	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	9	11	12	13
82 The detrimental effect of necroptosis in sepsis is blocked by the presence of caspase 8 , which promotes RIPK1 and/or RIPK3 cleavage and inhibits necroptosis .	82 The detrimental effect of necroptosis in sepsis is blocked by the presence of caspase 8, which promotes RIPK1 and/or RIPK3 cleavage and inhibits necroptosis.	12	24	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	14	16	19	20
The cleavage of RIPK1 remained caspase-8 dependent as caspase-8 inhibition by z-IETD-fmk prevented the RIPK1 cleavage under normal and acidic conditions ( XREF_FIG ) .	The cleavage of RIPK1 remained caspase-8 dependent as caspase-8 inhibition by z-IETD-fmk prevented the RIPK1 cleavage under normal and acidic conditions (XREF_FIG).	8	15	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	8	9	14	15
In addition , because it lacks the death effector domain ( DED ) that recruits caspase 8 , FADD-DD might promote programmed necrosis by inhibiting caspase 8 mediated RIP1 and RIP3 cleavage ( XREF_FIG ) .	In addition, because it lacks the death effector domain (DED) that recruits caspase 8, FADD-DD might promote programmed necrosis by inhibiting caspase 8 mediated RIP1 and RIP3 cleavage (XREF_FIG).	24	31	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase 8	caspase 8	caspase 8	RIP1	RIP1	RIP1	25	27	28	29
The caspase 8 mediated RIPK1 cleavage product has a pro apoptotic function , and further cleavage of this pro apoptotic cleavage product by HRV 3C may provide a mechanism by which HRV limits apoptosis .	The caspase 8 mediated RIPK1 cleavage product has a pro apoptotic function, and further cleavage of this pro apoptotic cleavage product by HRV 3C may provide a mechanism by which HRV limits apoptosis.	0	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase 8	caspase 8	caspase 8	RIPK1	RIPK1	RIPK1	1	3	4	5
Caspase-8 targets the deubiquitinase CYLD preventing RIPK1 initiation of necroptosis .	Caspase-8 targets the deubiquitinase CYLD preventing RIPK1 initiation of necroptosis.	0	7	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Caspase-8	Caspase-8	Caspase-8	RIPK1	RIPK1	RIPK1	0	1	6	7
Thus , inhibition of caspase 8 mediated RIP1 cleavage is crucial to ensure the phosphorylation and activation of downstream RIP1 and RIP3 substrates ( XREF_FIG ) .	Thus, inhibition of caspase 8 mediated RIP1 cleavage is crucial to ensure the phosphorylation and activation of downstream RIP1 and RIP3 substrates (XREF_FIG).	2	8	mediated	Positive_early_activation	Negative_activation	Negative_activation	caspase 8	caspase 8	caspase 8	RIP1	RIP1	RIP1	4	6	7	8
Caspase-8 deletion inhibited proteolytic cleavage of RIP1 , resulting in the formation of FADD-RIP1-RIP3 kinase complexes required for the programmed necrosis and premature activation of NF-kappaB and JNK [ XREF_BIBR , XREF_BIBR ] .	Caspase-8 deletion inhibited proteolytic cleavage of RIP1, resulting in the formation of FADD-RIP1-RIP3 kinase complexes required for the programmed necrosis and premature activation of NF-kappaB and JNK [XREF_BIBR, XREF_BIBR].	0	7	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Caspase-8	Caspase-8	Caspase-8	RIP1	RIP1	RIP1	0	1	6	7
Activation of caspase-8 by Dex could induce cleavage of RIPK1 and RIPK3 and formation of the complex II which contains RIPK1 , RIPK3 , caspase-8 and FADD and leads to apoptosis .	Activation of caspase-8 by Dex could induce cleavage of RIPK1 and RIPK3 and formation of the complex II which contains RIPK1, RIPK3, caspase-8 and FADD and leads to apoptosis.	0	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-8	caspase-8	caspase-8	RIPK1	RIPK1	RIPK1	2	3	9	10
As a comparison trypsin mediated detachment resulted in a time dependent cell death , paralleled by caspase-3 activation and suppression of ERK , PKB and Ikappa-B phosphoyrylation at 24 h or later after detachment .	As a comparison trypsin mediated detachment resulted in a time dependent cell death, paralleled by caspase-3 activation and suppression of ERK, PKB and Ikappa-B phosphoyrylation at 24 h or later after detachment.	16	26	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PKB	PKB	PKB	16	17	23	24
Overall , the results of the present study suggest that ClC-2 activation induced by GDM inhibits myelin development and cell apoptosis in white matter , which is associated with caspase-3 mediated PI3K-Akt pathway .	Overall, the results of the present study suggest that ClC-2 activation induced by GDM inhibits myelin development and cell apoptosis in white matter, which is associated with caspase-3 mediated PI3K-Akt pathway.	27	32	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	PI3K-Akt	PI3K-Akt	PI3K-Akt	29	30	31	32
In addition , TIPE-2 treatment increased the expression levels of caspase-3 and caspase-8 ( XREF_FIG ) , and upregulated PI3K and AKT in tumor tissues ( XREF_FIG ) .	In addition, TIPE-2 treatment increased the expression levels of caspase-3 and caspase-8 (XREF_FIG), and upregulated PI3K and AKT in tumor tissues (XREF_FIG).	3	22	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	TIPE-2 treatment increased the expression levels of caspase-3	caspase-3	AKT	AKT	akt	10	11	21	22
Pretreatment of ovarian cancer cells and their whole cell lysate with tetrapeptide inhibitors of caspases in vitro significantly decreased Akt cleavage induced by cisplatin and exogenous active caspase-3 .	Pretreatment of ovarian cancer cells and their whole cell lysate with tetrapeptide inhibitors of caspases in vitro significantly decreased Akt cleavage induced by cisplatin and exogenous active caspase-3.	19	28	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	Akt	Akt	Akt	27	28	19	20
These cumulative data suggest that the increased oxidative stress followed by caspase 3 mediated AKT cleavage may be a mechanism by which the activation of this survival pathway is censored in cervical cancer cell lines by forced expression of OGDHL .	These cumulative data suggest that the increased oxidative stress followed by caspase 3 mediated AKT cleavage may be a mechanism by which the activation of this survival pathway is censored in cervical cancer cell lines by forced expression of OGDHL.	11	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	AKT	AKT	AKT	11	13	14	15
Furthermore , aortic banding induced activation of Src , mitogen activated protein kinases , and Akt was blunted by Sca-1 overexpression and enhanced by Sca-1 deficiency .	Furthermore, aortic banding induced activation of Src, mitogen activated protein kinases, and Akt was blunted by Sca-1 overexpression and enhanced by Sca-1 deficiency.	15	25	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Sca-1	Sca-1	Sca-1	Akt	Akt	Akt	24	25	15	16
Furthermore , we confirmed that caspase 3 mediated AKT cleavage through in vitro caspase 3 assay in SiHa and CaSki cell lines by using SiHa and CaSki whole cell lysate in the presence of recombinant caspase 3 with or without caspase 3 inhibitor ( DEVD-FMK ) at different time points ( data not shown ) .	Furthermore, we confirmed that caspase 3 mediated AKT cleavage through in vitro caspase 3 assay in SiHa and CaSki cell lines by using SiHa and CaSki whole cell lysate in the presence of recombinant caspase 3 with or without caspase 3 inhibitor (DEVD-FMK) at different time points (data not shown).	5	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	AKT	AKT	AKT	5	7	8	9
For example , active caspase-3 may trigger Akt activation and protection from apoptosis by proteolytic cleavage of RasGAP to a N-terminal fragment XREF_BIBR .	For example, active caspase-3 may trigger Akt activation and protection from apoptosis by proteolytic cleavage of RasGAP to a N-terminal fragment XREF_BIBR.	3	8	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	Akt	Akt	Akt	4	5	7	8
Moreover , the addition of caspase 3 or ROS inhibitors in the presence of OGDHL increased AKT signaling and cervical cancer cell proliferation .	Moreover, the addition of caspase 3 or ROS inhibitors in the presence of OGDHL increased AKT signaling and cervical cancer cell proliferation.	3	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	AKT	AKT	AKT	5	7	16	17
Since the Sca1 controlled RasC activity promotes the activation of PKB and PKBR1 through regulation of TORC2 , PKB and PKBR1 mediated phosphorylation of Sca1 suggests the presence of a regulatory feedback mechanism .	Since the Sca1 controlled RasC activity promotes the activation of PKB and PKBR1 through regulation of TORC2, PKB and PKBR1 mediated phosphorylation of Sca1 suggests the presence of a regulatory feedback mechanism.	1	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sca1	Sca1	Sca1	PKB	PKB	PKB	2	3	10	11
To determine whether caspase-3 mediates Akt phosphory lation , cells were pre-treated with z-DEVD-fmk , a specific caspase-3 inhibitor .	To determine whether caspase-3 mediates Akt phosphory lation, cells were pre-treated with z-DEVD-fmk, a specific caspase-3 inhibitor.	3	7	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	Akt	Akt	Akt	3	4	5	6
Although it is unknown whether this process is also associated with the role of caspase-3 in LTD , overall it appears that caspase-3 activation can modulate LTP and LTD differentially by modulating the Akt and GSK-3beta pathway and that caspase-3 activation is essential for normal synaptic function .	Although it is unknown whether this process is also associated with the role of caspase-3 in LTD, overall it appears that caspase-3 activation can modulate LTP and LTD differentially by modulating the Akt and GSK-3beta pathway and that caspase-3 activation is essential for normal synaptic function.	22	36	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	Akt	Akt	Akt	22	23	33	34
Meanwhile , survivin , Bcl-2 , and caspase-3 were the downstream target of Akt , which were related with proliferation and apoptosis [ XREF_BIBR , XREF_BIBR ] .	Meanwhile, survivin, Bcl-2, and caspase-3 were the downstream target of Akt, which were related with proliferation and apoptosis [XREF_BIBR, XREF_BIBR].	2	17	were the downstream target	Positive_activation_copula_1	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	Akt	Akt	Akt	7	8	13	14
Here we showed that Sca-1 activated Akt possibly through the PDGFR-beta pathway .	Here we showed that Sca-1 activated Akt possibly through the PDGFR-beta pathway.	4	7	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sca-1	Sca-1	Sca-1	Akt	Akt	Akt	4	5	6	7
However , following the constraints of Additional file XREF_SUPPLEMENTARY : Table 10S , we can complete the composite model with such reactions as Bid truncation by caspase-2 and PARP cleavage triggered by caspase-7 .	However, following the constraints of Additional file XREF_SUPPLEMENTARY : Table 10S, we can complete the composite model with such reactions as Bid truncation by caspase-2 and PARP cleavage triggered by caspase-7.	26	33	triggered	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-7	caspase-7	caspase-7	PARP	PARP	PARP	32	33	28	29
Based on our observation that caspase 7 is activated in MCF-7 cells following exposure to resveratrol , we propose that PARP cleavage is mediated primarily by caspase-7 .	Based on our observation that caspase 7 is activated in MCF-7 cells following exposure to resveratrol, we propose that PARP cleavage is mediated primarily by caspase-7.	20	27	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-7	caspase-7	caspase-7	PARP	PARP	PARP	26	27	20	21
An activation of caspase-7 induces the proteolytic cleavage of PARP , and since the cleavage of PARP was observed , this indicates that caspase-7 was activated .	An activation of caspase-7 induces the proteolytic cleavage of PARP, and since the cleavage of PARP was observed, this indicates that caspase-7 was activated.	1	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-7	caspase-7	caspase-7	PARP	PARP	PARP	3	4	9	10
Activated caspase-9 then activates downstream caspase-3 and/or caspase-7 , which in turn induces PARP cleavage .	Activated caspase-9 then activates downstream caspase-3 and/or caspase-7, which in turn induces PARP cleavage.	0	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-7	caspase-7	caspase-7	PARP	PARP	PARP	7	8	13	14
The Western blot analysis demonstrated that SAMC dramatically activated caspase-7 by increasing the cleaved caspase-7 level , which in turn led to the cleaved PARP in both MCF-7 and MDA-MB-231 cells .	The Western blot analysis demonstrated that SAMC dramatically activated caspase-7 by increasing the cleaved caspase-7 level, which in turn led to the cleaved PARP in both MCF-7 and MDA-MB-231 cells.	6	25	led	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	caspase-7	SAMC dramatically activated caspase-7 by increasing the cleaved caspase-7 level	caspase-7	PARP	PARP	parp	14	15	24	25
15 The possible role of caspase-7 in the regulation of hypoxia induced apoptosis as well as the relationship between caspase-7 and the PARP cleavage that is known to occur in ADRP retinas 16 have been recently investigated .	15 The possible role of caspase-7 in the regulation of hypoxia induced apoptosis as well as the relationship between caspase-7 and the PARP cleavage that is known to occur in ADRP retinas 16 have been recently investigated.	3	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-7	caspase-7	caspase-7	PARP	PARP	PARP	5	6	22	23
We have previously used confocal imaging to conclude that EGFR internalization in these cells was not impaired by Cbl and Cbl-b knockdown but these analyses were not quantitative .	We have previously used confocal imaging to conclude that EGFR internalization in these cells was not impaired by Cbl and Cbl-b knockdown but these analyses were not quantitative.	9	21	impaired	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Cbl-b	Cbl-b	Cbl-b	EGFR	EGFR	EGFR	20	21	9	10
Furthermore , combined knockdown of Cbl and Cbl-b in immortal human mammary epithelial cells was shown to be more efficient than Cbl knockdown alone at reducing the ligand induced degradation of EGFR .	Furthermore, combined knockdown of Cbl and Cbl-b in immortal human mammary epithelial cells was shown to be more efficient than Cbl knockdown alone at reducing the ligand induced degradation of EGFR.	3	32	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cbl-b	Cbl-b	Cbl-b	EGFR	EGFR	EGFR	7	8	31	32
Previous studies revealed that Cbl-b increases the sensitivity of gastric cancer cells by enhancing the epidermal growth factor receptor ( EGFR ) and mitochondria mediated signaling pathways in gastric cancer [ XREF_BIBR ] .	Previous studies revealed that Cbl-b increases the sensitivity of gastric cancer cells by enhancing the epidermal growth factor receptor (EGFR) and mitochondria mediated signaling pathways in gastric cancer [XREF_BIBR].	4	19	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cbl-b	Cbl-b	Cbl-b	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	4	5	15	19
Knockdown studies of Cbl-b directly showed that loss of Cbl-b led to chemoresistance to 5-FU , as well as enhanced activation of EGFR , ERK and Akt signaling .	Knockdown studies of Cbl-b directly showed that loss of Cbl-b led to chemoresistance to 5-FU, as well as enhanced activation of EGFR, ERK and Akt signaling.	7	27	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Cbl-b	loss of Cbl-b	cbl-b	EGFR	EGFR	egfr	9	10	22	23
These results indicated that Cbl-b enhanced the chemosensitivity of gastric cancer cells to 5-FU through the regulation of levels of active ( phosphorylated ) EGFR , ERK and Akt .	These results indicated that Cbl-b enhanced the chemosensitivity of gastric cancer cells to 5-FU through the regulation of levels of active (phosphorylated) EGFR, ERK and Akt.	4	28	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cbl-b	Cbl-b	Cbl-b	EGFR	EGFR	EGFR	4	5	24	25
Since Cbl proteins are negative regulators of EGFR signaling , Cbl-b may promote 5-FU chemosensitivity in gastric cancer cells by regulating the level of EGFR survival signaling .	Since Cbl proteins are negative regulators of EGFR signaling, Cbl-b may promote 5-FU chemosensitivity in gastric cancer cells by regulating the level of EGFR survival signaling.	10	26	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cbl-b	Cbl-b	Cbl-b	EGFR	EGFR	EGFR	10	11	24	25
It should be noted , however , that out results do not rule out the possibility that a residual pool of c-Cbl and Cbl-b is sufficient to support EGFR endocytosis or that Cbl-c could facilitate EGFR endocytosis .	It should be noted, however, that out results do not rule out the possibility that a residual pool of c-Cbl and Cbl-b is sufficient to support EGFR endocytosis or that Cbl-c could facilitate EGFR endocytosis.	19	29	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cbl-b	Cbl-b	Cbl-b	EGFR	EGFR	EGFR	23	24	28	29
XREF_BIBR Gelsolin has been implicated in apoptosis with caspase-3 activation producing an N-terminal gelsolin fragment ( N-Gelsolin ) with un regulated actin filament severing capacity .	XREF_BIBR Gelsolin has been implicated in apoptosis with caspase-3 activation producing an N-terminal gelsolin fragment (N-Gelsolin) with un regulated actin filament severing capacity.	8	14	producing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	gelsolin	gelsolin	gelsolin	8	9	13	14
Clearly , the underlying molecular mechanism of gelsolin fragmentation induced by caspase-3 contributes to actin cytoskeletal collapse and nucleolysis XREF_BIBR , which mediate , in part , the morphologic changes of apoptosis and also a mechanistic role for actin severing protein in the apoptotic caspase initiated cascade .	Clearly, the underlying molecular mechanism of gelsolin fragmentation induced by caspase-3 contributes to actin cytoskeletal collapse and nucleolysis XREF_BIBR, which mediate, in part, the morphologic changes of apoptosis and also a mechanistic role for actin severing protein in the apoptotic caspase initiated cascade.	7	12	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	gelsolin	gelsolin	gelsolin	11	12	7	8
Other work has demonstrated that the cleavage of caspase-3 activates gelsolin which has F-actin severing properties [ XREF_BIBR ] .	Other work has demonstrated that the cleavage of caspase-3 activates gelsolin which has F-actin severing properties [XREF_BIBR].	6	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	gelsolin	gelsolin	gelsolin	8	9	10	11
In the same experimental conditions IFNalpha induced also gelsolin cleavage that occurred together with caspase-3 activation and release of cytochrome c. All these effects were antagonized by the exposure of IFNalpha treated KB to 10 nM EGF for the last 12 h. Moreover , the specific inhibition of caspase-3 with 20 microM DEVD completely abrogated apoptosis and gelsolin cleavage induced by IFNalpha .	In the same experimental conditions IFNalpha induced also gelsolin cleavage that occurred together with caspase-3 activation and release of cytochrome c. All these effects were antagonized by the exposure of IFNalpha treated KB to 10 nM EGF for the last 12 h. Moreover, the specific inhibition of caspase-3 with 20 microM DEVD completely abrogated apoptosis and gelsolin cleavage induced by IFNalpha.	46	58	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	gelsolin	gelsolin	gelsolin	48	49	57	58
Additionally , we found that the calpain inhibitor MDL28170 , which inhibits both capn1 and capn2 , failed to block the generation of cp-A/1 .	Additionally, we found that the calpain inhibitor MDL28170, which inhibits both capn1 and capn2, failed to block the generation of cp-A/1.	6	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	calpain inhibitor	calpain inhibitor	calpain inhibitor	capn2	capn2	capn2	6	8	15	16
Earlier we have shown that an equimolar mixture of calpastatin subdomains A and C ( 19 amino acids each ) strongly activates m-calpain in vitro .	Earlier we have shown that an equimolar mixture of calpastatin subdomains A and C (19 amino acids each) strongly activates m-calpain in vitro.	9	23	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	calpastatin	calpastatin	calpastatin	m-calpain	m-calpain	m-calpain	9	10	22	23
However , calpain inhibitor II , a close structural analog which blocks m-calpain , had no salutary effect .	However, calpain inhibitor II, a close structural analog which blocks m-calpain, had no salutary effect.	2	13	blocks	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	calpain inhibitor	calpain inhibitor	calpain inhibitor	m-calpain	m-calpain	m-calpain	2	4	12	13
This system consists of mu-calpain and m-calpain activated by Ca 2+ ions and endogenous calpain inhibitor - calpastatin .	This system consists of mu-calpain and m-calpain activated by Ca 2+ ions and endogenous calpain inhibitor - calpastatin.	2	18	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	calpastatin	calpastatin	calpastatin	m-calpain	m-calpain	m-calpain	17	18	6	7
When m-calpain was blocked by the specific calpain inhibitor MDL 28170 , it was found that the satellite cells show defects in cell cycle stage regulation , prevention of Myo-D accumulation in the nucleus in the G 1 phase and enhancement of Myf5 expression [ XREF_BIBR ] .	When m-calpain was blocked by the specific calpain inhibitor MDL 28170, it was found that the satellite cells show defects in cell cycle stage regulation, prevention of Myo-D accumulation in the nucleus in the G 1 phase and enhancement of Myf5 expression [XREF_BIBR].	1	9	blocked	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	calpain inhibitor	calpain inhibitor	calpain inhibitor	m-calpain	m-calpain	m-calpain	7	9	1	2
In this study , we followed the alphaII-spectrin breakdown reactions catalyzed by caspase-3 that yield SBDP150 and SBDP120 .	In this study, we followed the alphaII-spectrin breakdown reactions catalyzed by caspase-3 that yield SBDP150 and SBDP120.	7	14	catalyzed	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	alphaII-spectrin	alphaII-spectrin	alphaII-spectrin	12	13	7	8
Caspase-3 mediated alphaII-spectrin proteolysis results in the release of a 120kDa spectrin breakdown product ( SBDP120 ) , known to occur in conditions with cell death .	Caspase-3 mediated alphaII-spectrin proteolysis results in the release of a 120kDa spectrin breakdown product (SBDP120), known to occur in conditions with cell death.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	alphaII-spectrin	alphaII-spectrin	alphaII-spectrin	0	1	2	3
Caspase-3 mediated alphaII-spectrin proteolysis results in the release of SBDP120 and SBDP150 fragments XREF_BIBR , XREF_BIBR .	Caspase-3 mediated alphaII-spectrin proteolysis results in the release of SBDP120 and SBDP150 fragments XREF_BIBR, XREF_BIBR.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	Caspase-3	Caspase-3	Caspase-3	alphaII-spectrin	alphaII-spectrin	alphaII-spectrin	0	1	2	3
A conclusion from these studies was that caspase-3 mediates Abeta inhibition of LTP by inducing cleavage of Akt1 , a negative suppressor of GSK-3 , and subsequent increase in the pool of active GSK-3beta , detected as a decrease in the levels of p-GSK-3 ( Ser 9 ) .	A conclusion from these studies was that caspase-3 mediates Abeta inhibition of LTP by inducing cleavage of Akt1, a negative suppressor of GSK-3, and subsequent increase in the pool of active GSK-3beta, detected as a decrease in the levels of p-GSK-3 (Ser 9).	7	18	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	Akt1	Akt1	Akt1	7	8	17	18
Compared to controls , DDM stimulated cell expansion , reduced apoptotic marker caspase 3 , increased cell survival marker Akt1 and enhanced mineralised matrix deposition as determined by mineral deposition and increased expression of bone related markers , alkaline phosphatase and osteopontin .	Compared to controls, DDM stimulated cell expansion, reduced apoptotic marker caspase 3, increased cell survival marker Akt1 and enhanced mineralised matrix deposition as determined by mineral deposition and increased expression of bone related markers, alkaline phosphatase and osteopontin.	9	20	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase 3	caspase 3	caspase 3	Akt1	Akt1	Akt1	12	14	19	20
Activated IR directly phosphorylates tyrosine residues on several substrates including insulin receptor substrate ( IRS ) protein 1-4 , Shc , Grb-2-assocated protein ( Gab1 ) , Dock1 , Cbl , and APS adaptor proteins , all of which provide specific docking sites for other signaling proteins containing SH2 domains , leading to activation of both Ras --> MAP kinases and PI-3K --> Akt signaling cascades [ XREF_BIBR ] .	Activated IR directly phosphorylates tyrosine residues on several substrates including insulin receptor substrate (IRS) protein 1-4, Shc, Grb-2-assocated protein (Gab1), Dock1, Cbl, and APS adaptor proteins, all of which provide specific docking sites for other signaling proteins containing SH2 domains, leading to activation of both Ras --> MAP kinases and PI-3K --> Akt signaling cascades [XREF_BIBR].	0	30	Activated	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Cbl	Cbl	cbl	IR	IR directly phosphorylates tyrosine residues on several substrates including insulin receptor substrate	ir	29	30	1	2
Given that H 2 O 2 is a potent inducer of myocyte death that is released as a result of IR injury , it may account for the c-Cbl activation and myocyte death in the early IR injury .	Given that H 2 O 2 is a potent inducer of myocyte death that is released as a result of IR injury, it may account for the c-Cbl activation and myocyte death in the early IR injury.	28	37	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	c-Cbl	c-Cbl	c-Cbl	IR	IR	IR	28	29	36	37
Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes .	Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes.	0	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CaMKIV	Expression of active CaMKIV	camkiv	HDAC4	HDAC4	hdac4	3	4	7	8
Defects in the tumour suppressor protein Cbl , an E3-ubiquitin ligase , also slow the degradation of Kit and Flt3 , and prolong the activation of Akt , resulting in mastocytosis and myelo-proliferative disease XREF_BIBR XREF_BIBR XREF_BIBR .	Defects in the tumour suppressor protein Cbl, an E3-ubiquitin ligase, also slow the degradation of Kit and Flt3, and prolong the activation of Akt, resulting in mastocytosis and myelo-proliferative disease XREF_BIBR XREF_BIBR XREF_BIBR.	0	20	slow	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cbl	Cbl	Cbl	Flt3	Flt3	Flt3	6	7	19	20
During apoptosis , caspase-3 mediated cleavage removes the extreme N-terminal and C-terminal regions of LEDGF and p75 , abrogating its stress survival functions [ XREF_BIBR ] .	During apoptosis, caspase-3 mediated cleavage removes the extreme N-terminal and C-terminal regions of LEDGF and p75, abrogating its stress survival functions [XREF_BIBR].	3	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	caspase-3	caspase-3	caspase-3	LEDGF	LEDGF	LEDGF	3	4	14	15
The Cby driven cytoplasmic accumulation of beta-catenin has been reported to induce an unfolded protein response .	The Cby driven cytoplasmic accumulation of beta-catenin has been reported to induce an unfolded protein response.	0	11	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
It is , therefore , somewhat puzzling to find that Akt phosphorylation of Cby facilitates its interaction with 14-3-3 and triggers the cytoplasmic sequestration of beta-catenin , thereby attenuating beta-catenin signaling .	It is, therefore, somewhat puzzling to find that Akt phosphorylation of Cby facilitates its interaction with 14-3-3 and triggers the cytoplasmic sequestration of beta-catenin, thereby attenuating beta-catenin signaling.	10	26	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cby	Akt phosphorylation of Cby	cby	beta-catenin	beta-catenin	beta-catenin	13	14	25	26
To elucidate if the nuclear cytoplasmic shuttling of Cby modulates beta-catenin subcellular distribution , we examined beta-catenin localization after coexpression with the cytoplasmic CbyDeltaNLS2 or nuclear CbyL21A/L24A/L27A mutant .	To elucidate if the nuclear cytoplasmic shuttling of Cby modulates beta-catenin subcellular distribution, we examined beta-catenin localization after coexpression with the cytoplasmic CbyDeltaNLS2 or nuclear CbyL21A/L24A/L27A mutant.	6	12	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	8	9	10	11
Upon phosphorylation of Cby serine 20 by Akt kinase , Cby and 14-3-3 form a stable trimolecular complex with beta-catenin , and cooperate to promote cytoplasmic localization of beta-catenin , leading to down-regulation of beta-catenin-mediated transcriptional activation .	Upon phosphorylation of Cby serine 20 by Akt kinase, Cby and 14-3-3 form a stable trimolecular complex with beta-catenin, and cooperate to promote cytoplasmic localization of beta-catenin, leading to down-regulation of beta-catenin-mediated transcriptional activation.	10	29	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	10	11	28	29
To investigate whether endogenous Cby modulates beta-catenin localization , we generated HEK293 cell lines stably expressing shRNA against Cby or negative control scrambled shRNA .	To investigate whether endogenous Cby modulates beta-catenin localization, we generated HEK293 cell lines stably expressing shRNA against Cby or negative control scrambled shRNA.	3	7	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	4	5	6	7
Taken together , our results indicate that Cby negatively modulates endogenous beta-catenin signaling in SW480 cells .	Taken together, our results indicate that Cby negatively modulates endogenous beta-catenin signaling in SW480 cells.	7	12	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	7	8	11	12
Intriguingly , Cby and 14-3-3 collaborate to promote cytoplasmic localization of beta-catenin .	Intriguingly, Cby and 14-3-3 collaborate to promote cytoplasmic localization of beta-catenin.	2	12	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
Our results , therefore , suggest that inhibition of beta-catenin signaling by Cby involves at least two distinct molecular mechanisms ( XREF_FIG ) ; i.e ., competing with Tcf/Lef transcription factors for binding to beta-catenin in the nucleus and facilitating nuclear export of beta-catenin via interaction with 14-3-3 upon its phosphorylation by Akt .	Our results, therefore, suggest that inhibition of beta-catenin signaling by Cby involves at least two distinct molecular mechanisms (XREF_FIG); i.e., competing with Tcf/Lef transcription factors for binding to beta-catenin in the nucleus and facilitating nuclear export of beta-catenin via interaction with 14-3-3 upon its phosphorylation by Akt.	9	13	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	12	13	9	10
In such a cell context , as in other cell types , CBY1 driven cytoplasmic re-location of beta-catenin activates UPR , which , in turn , induced the BCL2 interacting mediator of cell death ( BIM ) , hence contributing to the execution phase of apoptotic death [ XREF_BIBR ] .	In such a cell context, as in other cell types, CBY1 driven cytoplasmic re-location of beta-catenin activates UPR, which, in turn, induced the BCL2 interacting mediator of cell death (BIM), hence contributing to the execution phase of apoptotic death [XREF_BIBR].	12	18	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CBY1	CBY1	CBY1	beta-catenin	beta-catenin	beta-catenin	12	13	17	18
CBY1 down-modulation associated with BCR-ABL1 TK promotes beta-catenin retention within the nuclear compartment and transcriptional activation .	CBY1 down-modulation associated with BCR-ABL1 TK promotes beta-catenin retention within the nuclear compartment and transcriptional activation.	0	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CBY1	CBY1	CBY1	beta-catenin	beta-catenin	beta-catenin	0	1	7	8
Ablation of Cby results in elevation of Wnt and beta-catenin signaling in the lung .	Ablation of Cby results in elevation of Wnt and beta-catenin signaling in the lung.	0	10	results in elevation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Cby	Cby	Cby	beta-catenin	beta-catenin	beta-catenin	2	3	9	10
CDK1 mediated Bcl-2 serine 70 phosphorylation enhances its pro apoptotic function , whereas CDK1 mediated Bad serine 128 phosphorylation promotes apoptosis .	CDK1 mediated Bcl-2 serine 70 phosphorylation enhances its pro apoptotic function, whereas CDK1 mediated Bad serine 128 phosphorylation promotes apoptosis.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	CDK1	CDK1	CDK1	Bcl-2	Bcl-2	Bcl-2	0	1	2	3
We propose a model in which activation of Cdc2 initiates the release of Bora into the cytoplasm where it can bind and activate Aurora-A .	We propose a model in which activation of Cdc2 initiates the release of Bora into the cytoplasm where it can bind and activate Aurora-A.	6	14	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdc2	Cdc2	Cdc2	Bora	Bora	Bora	8	9	13	14
According to the proposed mechanism , Cdk1 causes BORA to exit from the nucleus and binds reversibly with Plk1 .	According to the proposed mechanism, Cdk1 causes BORA to exit from the nucleus and binds reversibly with Plk1.	6	15	causes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	BORA	BORA	BORA	6	7	8	9
Activation of Aurora-A requires Bora which is also activated by Cdk1 .	Activation of Aurora-A requires Bora which is also activated by Cdk1.	3	11	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Bora	Bora	Bora	10	11	4	5
Moreover , our genetic and pharmacological rescue analysis provided evidence that the effect of ZDHHC8 on axon growth is mediated in part via Cdc42 dependent modulation of Akt and Gsk3beta signaling in the tip of the axon .	Moreover, our genetic and pharmacological rescue analysis provided evidence that the effect of ZDHHC8 on axon growth is mediated in part via Cdc42 dependent modulation of Akt and Gsk3beta signaling in the tip of the axon.	23	30	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Gsk3beta	Gsk3beta	Gsk3beta	23	24	29	30
The effect of ZDHHC8 is mediated in part via Cdc42 dependent modulation of Akt and Gsk3beta signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3beta activity during postnatal brain development .	The effect of ZDHHC8 is mediated in part via Cdc42 dependent modulation of Akt and Gsk3beta signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3beta activity during postnatal brain development.	9	16	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Cdc42	Cdc42	Cdc42	Gsk3beta	Gsk3beta	Gsk3beta	9	10	15	16
Recent experiments in somatic cell extracts indicate that Wee1 activity might be stimulated by phosphorylation by low Cdk1 levels and inhibited by high levels , suggesting a more complicated control mechanism .	Recent experiments in somatic cell extracts indicate that Wee1 activity might be stimulated by phosphorylation by low Cdk1 levels and inhibited by high levels, suggesting a more complicated control mechanism.	8	19	stimulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Cdk1	Cdk1 levels	cdk1	Wee1	Wee1	wee1	17	18	8	9
We first carried out an analysis of the mechanism by which mitotic Cdk1 and cyclin stimulates activation of Wee1 .	We first carried out an analysis of the mechanism by which mitotic Cdk1 and cyclin stimulates activation of Wee1.	11	19	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	12	13	18	19
The Swe1 response to phosphorylation by Cdk1 in budding yeast is biphasic in that Wee1 is initially activated by Clb and Cdk1 phosphorylation , with stabilization of the Swe1 and Cdk complex , before being eventually inactivated and dissociated [ XREF_BIBR ] .	The Swe1 response to phosphorylation by Cdk1 in budding yeast is biphasic in that Wee1 is initially activated by Clb and Cdk1 phosphorylation, with stabilization of the Swe1 and Cdk complex, before being eventually inactivated and dissociated [XREF_BIBR].	13	23	initially activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Cdk1	Cdk1 phosphorylation	cdk1	Wee1	Wee1	wee1	21	22	14	15
These results strongly suggest that an insufficient amount of Cdc2 and continuous activation of Wee1 B are the cause of meiotic failure of small oocytes in pigs .	These results strongly suggest that an insufficient amount of Cdc2 and continuous activation of Wee1 B are the cause of meiotic failure of small oocytes in pigs.	9	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	9	10	14	15
By contrast , when RO-3306 blocked the phosphorylation of WEE1 by CDK1 , it also suppressed the phosphorylation of CDK1 by WEE1 on Y15 , arguing for activation of WEE1 mediated by CDK1 .	By contrast, when RO-3306 blocked the phosphorylation of WEE1 by CDK1, it also suppressed the phosphorylation of CDK1 by WEE1 on Y15, arguing for activation of WEE1 mediated by CDK1.	27	33	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CDK1	CDK1	CDK1	WEE1	WEE1	WEE1	32	33	29	30
We present evidence that down-regulation of Cdk1 activates Wee1 and Myt1 kinases and inhibits Cdc25 phosphatase during the M to G1 transition .	We present evidence that down-regulation of Cdk1 activates Wee1 and Myt1 kinases and inhibits Cdc25 phosphatase during the M to G1 transition.	4	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	6	7	8	9
Cks mediates Cdk1 directed Wee1 activity at mitotic entry .	Cks mediates Cdk1 directed Wee1 activity at mitotic entry.	1	5	directed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	2	3	4	5
Knockdown of CDK1 rescued the WEE1 depletion phenotype ( XREF_FIG ) , with no visible effects on the cell cycle .	Knockdown of CDK1 rescued the WEE1 depletion phenotype (XREF_FIG), with no visible effects on the cell cycle.	0	7	rescued	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	WEE1	WEE1	WEE1	2	3	5	6
Recently , studies have shown that the p34Cdc2 targeting Wee1 kinase contains a caspase-3 cleavage site .	Recently, studies have shown that the p34Cdc2 targeting Wee1 kinase contains a caspase-3 cleavage site.	6	11	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p34Cdc2	p34Cdc2	p34Cdc2	Wee1	Wee1	Wee1	7	8	9	10
Mitotic entry is controlled by the antagonising effect on Cdc2 activation of Wee1 kinase and Cdc25 phosphatase .	Mitotic entry is controlled by the antagonising effect on Cdc2 activation of Wee1 kinase and Cdc25 phosphatase.	9	13	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	9	10	12	13
To assess the effects of xHsl7 on Cdc2 directed Wee1 kinase activity , we took interphase Xenopus cytosol ( lacking membranes and thus devoid of Myt1 ) as a source of robust Wee1 kinase activity and either immunodepleted endogenous xHsl7 or supplemented the extract with excess recombinant xHsl7 ( which , like excess xHsl7 RNA , was able to accelerate mitotic entry in cycling extracts ) .	To assess the effects of xHsl7 on Cdc2 directed Wee1 kinase activity, we took interphase Xenopus cytosol (lacking membranes and thus devoid of Myt1) as a source of robust Wee1 kinase activity and either immunodepleted endogenous xHsl7 or supplemented the extract with excess recombinant xHsl7 (which, like excess xHsl7 RNA, was able to accelerate mitotic entry in cycling extracts).	1	11	directed	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	7	8	9	10
The DNA damage checkpoint , a pivotal target of WEE1 by CDC2 phosphorylation , stalls the cell cycle and protects cancer cells from death in response to unrepaired DNA lesions [ XREF_BIBR , XREF_BIBR ] .	The DNA damage checkpoint, a pivotal target of WEE1 by CDC2 phosphorylation, stalls the cell cycle and protects cancer cells from death in response to unrepaired DNA lesions [XREF_BIBR, XREF_BIBR].	7	13	target	Positive_activation_token_2_noun	Negative_activation	Positive_activation	CDC2	CDC2 phosphorylation	cdc2	WEE1	WEE1	wee1	11	12	9	10
Thus , we sought to determine the relative contribution of WEE1 targets CDK1 and CDK2 to the combinatorial activity of AZD1775 and cytarabine .	Thus, we sought to determine the relative contribution of WEE1 targets CDK1 and CDK2 to the combinatorial activity of AZD1775 and cytarabine.	8	14	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	CDK1	CDK1	CDK1	WEE1	WEE1	WEE1	12	13	10	11
Bifurcation analysis shows that when the spatiotemporal regulation is coupled to the positive feedback loops ( active Cdc2 promotes its activator , Cdc25 , and suppress its inhibitor , Wee1 ) , the mitosis promoting factor ( MPF ) exhibits a bistable steady-state relationship with the cell size .	Bifurcation analysis shows that when the spatiotemporal regulation is coupled to the positive feedback loops (active Cdc2 promotes its activator, Cdc25, and suppress its inhibitor, Wee1), the mitosis promoting factor (MPF) exhibits a bistable steady-state relationship with the cell size.	16	30	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdc2	Cdc2	Cdc2	Wee1	Wee1	Wee1	17	18	29	30
Cdk1 also activates Wee1 in human cells , which suggests that this mechanism is conserved .	Cdk1 also activates Wee1 in human cells, which suggests that this mechanism is conserved.	0	4	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	0	1	3	4
During M/G 1 transition down-regulation of Cdk1 activates Wee1 and Myt1 kinases and inhibits Cdc25 phosphatases XREF_BIBR .	During M/G 1 transition down-regulation of Cdk1 activates Wee1 and Myt1 kinases and inhibits Cdc25 phosphatases XREF_BIBR.	4	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Wee1	Wee1	Wee1	6	7	8	9
The role of Cdk2 could be to target p27 directly via phosphorylation or indirectly by influencing the activity of E2F or substrate specificity of the ubiquitin ligase .	The role of Cdk2 could be to target p27 directly via phosphorylation or indirectly by influencing the activity of E2F or substrate specificity of the ubiquitin ligase.	1	22	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	Cdk2	Cdk2	p27	p27	p27	3	4	8	9
Thus , depletion of Cdk2 in Skp2 -/- cells led to an overall inactivation of the cell cycle machinery and senescence , but restored p27 turnover to normal rates ( XREF_FIG ) , indicating the regulation of p27 stability by Skp2 independent pathways in the absence of Cdk2 .	Thus, depletion of Cdk2 in Skp2 -/- cells led to an overall inactivation of the cell cycle machinery and senescence, but restored p27 turnover to normal rates (XREF_FIG), indicating the regulation of p27 stability by Skp2 independent pathways in the absence of Cdk2.	2	25	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	Cdk2	Cdk2	p27	p27	p27	4	5	24	25
Phosphorylation of p27 ( Thr187 ) by CDK2 causes p27 protein to bind with ubiquitin ligase ( SCF-SKP2 ) that leads to 26S proteosome degradation [ XREF_BIBR ] .	Phosphorylation of p27 (Thr187) by CDK2 causes p27 protein to bind with ubiquitin ligase (SCF-SKP2) that leads to 26S proteosome degradation [XREF_BIBR].	0	10	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	Phosphorylation of p27 (Thr187) by CDK2	cdk2	p27	p27	p27	7	8	9	10
Indeed , the inactivation of Cdk4 or Cdk2 induces relocation of free p27 to Cdk2 or Cdc2 complexes respectively , which affects their activity .	Indeed, the inactivation of Cdk4 or Cdk2 induces relocation of free p27 to Cdk2 or Cdc2 complexes respectively, which affects their activity.	3	18	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	Cdk2	Cdk2	p27	p27	p27	7	8	12	13
These results indicate that ALS significantly downregulates the expression of CDC2 , cyclin B1 , and CDK2 but upregulates p21 Waf1 and Cip1 , p27 Kip1 , and p53 in both PANC-1 and BxPC-3 cells , which contributes , at least in part , to the observed cell cycle arrest phenomenon in both cell lines .	These results indicate that ALS significantly downregulates the expression of CDC2, cyclin B1, and CDK2 but upregulates p21 Waf1 and Cip1, p27 Kip1, and p53 in both PANC-1 and BxPC-3 cells, which contributes, at least in part, to the observed cell cycle arrest phenomenon in both cell lines.	4	26	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	ALS significantly downregulates the expression of CDC2, cyclin B1, and CDK2	cdk2	p27 Kip1	p27 Kip1	p27 kip1	16	17	24	26
Cdk2 is the main target of p27 ( refs 2 , 3 ) and therefore we hypothesized that loss of Cdk2 activity should modify the p27 (-/-) mouse phenotype .	Cdk2 is the main target of p27 (refs 2, 3) and therefore we hypothesized that loss of Cdk2 activity should modify the p27 (-/-) mouse phenotype.	0	8	is the main target	Positive_activation_copula_1	Negative_activation	Positive_activation	Cdk2	Cdk2	Cdk2	p27	p27	p27	0	1	6	7
The increased cdk2 activity also led to an early proteasomal degradation of p27 ( Kip1 ) that could be reversed by HBx specific RNA interference and blocked by a chemical inhibitor of cdk2 or the T187A mutant of p27 .	The increased cdk2 activity also led to an early proteasomal degradation of p27 (Kip1) that could be reversed by HBx specific RNA interference and blocked by a chemical inhibitor of cdk2 or the T187A mutant of p27.	12	33	blocked	Negative_activation_syntax_6_verb	Negative_activation	Positive_activation	cdk2	cdk2	cdk2	Kip1	Kip1	Kip1	32	33	14	15
Here , we demonstrated that NDRG2 enhanced the expression of the positive cell cycle proteins Cdk2 , cyclin B and cyclin D and down-regulated the negative cell cycle regulator p27 during proliferation .	Here, we demonstrated that NDRG2 enhanced the expression of the positive cell cycle proteins Cdk2, cyclin B and cyclin D and down-regulated the negative cell cycle regulator p27 during proliferation.	5	30	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	NDRG2 enhanced the expression of the positive cell cycle proteins Cdk2	cdk2	p27	p27	p27	15	16	29	30
Western blot analysis showed that H2A.Z.1 knockdown suppressed the expression of CDK4 , CDK6 , cyclin D1 and CDK2 , and simultaneously induced p21 WAF1 and Cip1 and p27 Kip1 in both SNU-449 and SK-Hep-1 cells .	Western blot analysis showed that H2A.Z.1 knockdown suppressed the expression of CDK4, CDK6, cyclin D1 and CDK2, and simultaneously induced p21 WAF1 and Cip1 and p27 Kip1 in both SNU-449 and SK-Hep-1 cells.	5	30	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	H2A.Z.1 knockdown suppressed the expression of CDK4, CDK6, cyclin D1 and CDK2	cdk2	p27 Kip1	p27 Kip1	p27 kip1	18	19	28	30
Paradoxically , however , the main phenotypes of p27null mice , namely , increased body size , organ hyperplasia , pituitary tumors , and retinal dysplasia , are not rescued by concomitant deletion of Cdk2 , thus suggesting that these p27 null phenotypes are not primarily caused by uncontrolled CDK2 activity .	Paradoxically, however, the main phenotypes of p27null mice, namely, increased body size, organ hyperplasia, pituitary tumors, and retinal dysplasia, are not rescued by concomitant deletion of Cdk2, thus suggesting that these p27 null phenotypes are not primarily caused by uncontrolled CDK2 activity.	40	50	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	p27	p27	p27	49	50	40	41
TGFbeta modulates cell proliferation by controlling the expression of cell cycle regulating factors , including Cyclin Dependent Kinases ( CDKs ) like p15 , p21 , and p27 and cell cycle promoters like cMYC , cyclin D2 , CDK2 , and cyclin E. TGFbeta also promotes T naive cell differentiation into Treg cells by inducing FOXP3 expression , or into Th17 cells in the presence of IL-6 ( XREF_FIG ) .	TGFbeta modulates cell proliferation by controlling the expression of cell cycle regulating factors, including Cyclin Dependent Kinases (CDKs) like p15, p21, and p27 and cell cycle promoters like cMYC, cyclin D2, CDK2, and cyclin E. TGFbeta also promotes T naive cell differentiation into Treg cells by inducing FOXP3 expression, or into Th17 cells in the presence of IL-6 (XREF_FIG).	27	39	promoters	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	p27	p27	p27	38	39	27	28
These results are consistent with the inhibition of Cdk2 phosphorylation by 4a or 16a causing nuclear retention of p27 Kip1 ( XREF_FIG ) .	These results are consistent with the inhibition of Cdk2 phosphorylation by 4a or 16a causing nuclear retention of p27 Kip1 (XREF_FIG).	8	20	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Cdk2	Cdk2 phosphorylation by 4a	cdk2	p27 Kip1	p27 Kip1	p27 kip1	8	9	18	20
Cotransfection of dominant negative CDK2 and RhoA ( 63 ) inhibited RhoA ( 63 )-induced cyclin E/CDK2 activity and p27 ( Kip ) degradation .	Cotransfection of dominant negative CDK2 and RhoA (63) inhibited RhoA (63)-induced cyclin E/CDK2 activity and p27 (Kip) degradation.	0	23	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	p27	p27	p27	4	5	19	20
The observation that CDK2 knock-out was not able to rescue the phenotype of p27 null mice indirectly supports our work .	The observation that CDK2 knock-out was not able to rescue the phenotype of p27 null mice indirectly supports our work.	3	15	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	p27	p27	p27	3	4	13	14
There had been reports that the down-regulation of p27kip1 protein caused by the activation of CDK2 protein was related to trastuzumab resistance of breast cancer XREF_BIBR XREF_BIBR , indicating it might be one another mechanism involved in the trastuzumab resistance in gastric cancer .	There had been reports that the down-regulation of p27kip1 protein caused by the activation of CDK2 protein was related to trastuzumab resistance of breast cancer XREF_BIBR XREF_BIBR, indicating it might be one another mechanism involved in the trastuzumab resistance in gastric cancer.	8	16	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	p27kip1	p27kip1	p27kip1	15	16	8	9
It is thus possible that , in the absence of p21 and persistent Chk1 activity , Cdc25A upregulation caused by Cdk2 depletion eventually results in entry into mitosis despite initial efficient G2 arrest 13 .	It is thus possible that, in the absence of p21 and persistent Chk1 activity, Cdc25A upregulation caused by Cdk2 depletion eventually results in entry into mitosis despite initial efficient G2 arrest 13.	16	21	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	Cdc25A	Cdc25A	Cdc25A	20	21	16	17
Both Cdk2 and cdc25A are G1 phase specific genes and Cdk2 is the target of Cdc25A .	Both Cdk2 and cdc25A are G1 phase specific genes and Cdk2 is the target of Cdc25A.	8	16	is the target	Positive_activation_copula_1	Negative_activation	Positive_activation	Cdk2	Cdk2	Cdk2	Cdc25A	Cdc25A	Cdc25A	10	11	15	16
Separase is eventually activated by proteolysis of securin or the cyclin B subunit of Cdk1 , which in both cases is mediated by a ubiquitin protein ligase named anaphase promoting complex or cyclosome ( APC/C ) and its cofactor Cdc20 [ XREF_BIBR , XREF_BIBR ] .	Separase is eventually activated by proteolysis of securin or the cyclin B subunit of Cdk1, which in both cases is mediated by a ubiquitin protein ligase named anaphase promoting complex or cyclosome (APC/C) and its cofactor Cdc20 [XREF_BIBR, XREF_BIBR].	0	21	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Separase	Separase	Separase	14	15	0	1
In this work , we show that in budding yeast Cdk1 activates Separase ( Esp1 in yeast ) through phosphorylation to trigger anaphase onset .	In this work, we show that in budding yeast Cdk1 activates Separase (Esp1 in yeast) through phosphorylation to trigger anaphase onset.	10	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Separase	Separase	Separase	10	11	12	13
Thus , when kinetochores come under tension and chromosomes biorient on mitotic or meiotic spindles , the SAC is turned off and Cdk1 is permitted to activate APC/C Cdc20 and thereby trigger its own demise as well as separase activation .	Thus, when kinetochores come under tension and chromosomes biorient on mitotic or meiotic spindles, the SAC is turned off and Cdk1 is permitted to activate APC/C Cdc20 and thereby trigger its own demise as well as separase activation.	22	39	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	separase	separase	separase	22	23	38	39
Although phosphorylation itself triggers aggregation , recent work has shown that stable binding of Cdk1 and Cyclin B1 to Separase prevents aggregation [ XREF_BIBR ] , indicating that Cdk1 also promotes Separase activity in vertebrates .	Although phosphorylation itself triggers aggregation, recent work has shown that stable binding of Cdk1 and Cyclin B1 to Separase prevents aggregation [XREF_BIBR], indicating that Cdk1 also promotes Separase activity in vertebrates.	28	32	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Separase	Separase	Separase	28	29	31	32
The inactivation of Cdk1 will activate separase and then trigger cohesin degradation , and ultimately initiates the final separation of sister chromatids 25 .	The inactivation of Cdk1 will activate separase and then trigger cohesin degradation, and ultimately initiates the final separation of sister chromatids 25.	1	7	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	separase	separase	separase	3	4	6	7
The proximity between the Cdk1 phosphorylation site and the Akt phosphorylation site on FOXO1 ( seven residues apart ) immediately suggested a mechanism by which Cdk1 might activate FOXO1 .	The proximity between the Cdk1 phosphorylation site and the Akt phosphorylation site on FOXO1 (seven residues apart) immediately suggested a mechanism by which Cdk1 might activate FOXO1.	25	29	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	FOXO1	FOXO1	FOXO1	25	26	28	29
Overexpression of FO1-6nls in prostate cancer ( PCa ) cells not only blocked CDK1 induced cytoplasmic localization of FOXO1 but also augmented FOXO1 ' s transcriptional activity .	Overexpression of FO1-6nls in prostate cancer (PCa) cells not only blocked CDK1 induced cytoplasmic localization of FOXO1 but also augmented FOXO1 's transcriptional activity.	13	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK1	CDK1	CDK1	FOXO1	FOXO1	FOXO1	13	14	18	19
Given that CDK1 and cyclin B1 are often overexpressed in human cancers including PCa , our findings suggest that aberrant activation of CDK1 may contribute to tumorigenesis by promoting cell proliferation and survival via phosphorylation and inhibition of FOXO1 .	Given that CDK1 and cyclin B1 are often overexpressed in human cancers including PCa, our findings suggest that aberrant activation of CDK1 may contribute to tumorigenesis by promoting cell proliferation and survival via phosphorylation and inhibition of FOXO1.	20	39	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK1	CDK1	CDK1	FOXO1	FOXO1	FOXO1	22	23	38	39
JNK controlled Cdk1 activity modulates full interaction of Ezh2 to the E3 ligase Smurf2 through multiple threonine phosphorylation sites within Ezh2 .	JNK controlled Cdk1 activity modulates full interaction of Ezh2 to the E3 ligase Smurf2 through multiple threonine phosphorylation sites within Ezh2.	2	13	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Ezh2	Ezh2	Ezh2	2	3	8	9
Cdk1 modulates Ezh2 and survival of erythroblasts .	Cdk1 modulates Ezh2 and survival of erythroblasts.	0	6	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	Ezh2	Ezh2	Ezh2	0	1	2	3
On the other hand , CDC2 ( CDK1 ) and CDK2 have been shown to activate EZH2 by phosphorylation of its Thr350 residue [ XREF_BIBR - XREF_BIBR ] .	On the other hand, CDC2 (CDK1) and CDK2 have been shown to activate EZH2 by phosphorylation of its Thr350 residue [XREF_BIBR - XREF_BIBR].	5	17	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDC2	CDC2	CDC2	EZH2	EZH2	EZH2	5	6	16	17
CDK1 Activates Foxo as a Key Check in the Cell Cycle .	CDK1 Activates Foxo as a Key Check in the Cell Cycle.	0	5	Activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK1	CDK1	CDK1	Foxo	Foxo	Foxo	0	1	2	3
The effect of this modification on FoxO1 localization and activity is controversial with CDK1 reported to cause nuclear localization and transcriptional activation , and CDK2 reported to cause cytoplasmic localization and inhibition of FoxO1 .	The effect of this modification on FoxO1 localization and activity is controversial with CDK1 reported to cause nuclear localization and transcriptional activation, and CDK2 reported to cause cytoplasmic localization and inhibition of FoxO1.	24	34	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	FoxO1	FoxO1	FoxO1	24	25	33	34
Removal of cdc2 from mitotic cell extracts by immunoprecipitation causes a concomitant depletion of RB kinase activity .	Removal of cdc2 from mitotic cell extracts by immunoprecipitation causes a concomitant depletion of RB kinase activity.	0	16	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	cdc2	cdc2	cdc2	RB	RB	RB	2	3	14	15
Suppression of Tpr and CDK1 Increases Virus Replication While Blockade of ATM , p53 , and Vimentin Reducing Virus Replication .	Suppression of Tpr and CDK1 Increases Virus Replication While Blockade of ATM, p53, and Vimentin Reducing Virus Replication.	2	17	Blockade	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	Vimentin	Vimentin	Vimentin	4	5	16	17
We propose that Cdk1 phosphorylation induces Plk1 mediated reorganization of vimentin filaments ( XREF_FIG C ) .	We propose that Cdk1 phosphorylation induces Plk1 mediated reorganization of vimentin filaments (XREF_FIG C).	3	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1 phosphorylation	cdk1	vimentin	vimentin	vimentin	3	4	10	11
Whether p21 can also inhibit CDK1 dependent phosphorylation of SAMHD1 and block HIV-1 replication by reducing CDK1 mediated SAMHD1 inactivation will be an important aspect of future studies .	Whether p21 can also inhibit CDK1 dependent phosphorylation of SAMHD1 and block HIV-1 replication by reducing CDK1 mediated SAMHD1 inactivation will be an important aspect of future studies.	15	19	mediated	Positive_early_activation	Negative_activation	Positive_activation	CDK1	CDK1	CDK1	SAMHD1	SAMHD1	SAMHD1	16	17	18	19
Previous work showed that these threonines were targets of p34 cdc2 and MAP kinases known to reduce the ability of mammalian MAP4 to bind MTs in HeLa cells .	Previous work showed that these threonines were targets of p34 cdc2 and MAP kinases known to reduce the ability of mammalian MAP4 to bind MTs in HeLa cells.	9	22	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p34 cdc2	p34 cdc2	p34 cdc2	MAP4	MAP4	MAP4	9	11	21	22
Next , to investigate whether Cdk1 mediates the effects of PTHrP on chondrocyte proliferation and differentiation , we designed an experiment based on an organ culture system , since alpha1 ( II ) Cdk1f/f mice were not viable and the basal expression level of PTHrP in the cartilage was too low XREF_BIBR to reliably detect its possible downregulation in alpha1 ( II ) Cdk1f/f mice .	Next, to investigate whether Cdk1 mediates the effects of PTHrP on chondrocyte proliferation and differentiation, we designed an experiment based on an organ culture system, since alpha1 (II) Cdk1f/f mice were not viable and the basal expression level of PTHrP in the cartilage was too low XREF_BIBR to reliably detect its possible downregulation in alpha1 (II) Cdk1f/f mice.	5	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk1	Cdk1	Cdk1	PTHrP	PTHrP	PTHrP	5	6	10	11
These data indicate that two upstream stimuli , active Ras and active Cdc2 , utilize different MAPKKKs to activate MEK1 and p42 MAPK .	These data indicate that two upstream stimuli, active Ras and active Cdc2, utilize different MAPKKKs to activate MEK1 and p42 MAPK.	6	22	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdc2	Cdc2	Cdc2	MEK1	MEK1	MEK1	12	13	19	20
Inhibition of ATR results in CDK1 independent downregulation of RRM1 and RRM2 .	Inhibition of ATR results in CDK1 independent downregulation of RRM1 and RRM2.	5	12	downregulation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	CDK1	CDK1	CDK1	RRM2	RRM2	RRM2	5	6	11	12
Rb pathway defects include gain-of-function mutations of the cyclin dependent kinase cdk4 and cyclin D , which activates Rb through phosphorylation , and loss-of-function mutations of p16 and Rb .	Rb pathway defects include gain-of-function mutations of the cyclin dependent kinase cdk4 and cyclin D, which activates Rb through phosphorylation, and loss-of-function mutations of p16 and Rb.	5	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cdk4	cdk4	cdk4	Rb	Rb	Rb	11	12	18	19
In the early G1 phase , the cyclin D1 and CDK4 complex partially activates pRb by phosphorylation , resulting in the inhibition of pRb function ; in the late G1 phase , CDK2 complexed with cyclin E further phosphorylates pRb to complete its inactivation and allows the cell to enter the S phase .	In the early G1 phase, the cyclin D1 and CDK4 complex partially activates pRb by phosphorylation, resulting in the inhibition of pRb function; in the late G1 phase, CDK2 complexed with cyclin E further phosphorylates pRb to complete its inactivation and allows the cell to enter the S phase.	10	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	pRb	pRb	pRb	10	11	14	15
Overexpression of cdk2 and cdk4 but not a dominant negative cdk2 rescued Rb mediated downregulation of telomerase activity .	Overexpression of cdk2 and cdk4 but not a dominant negative cdk2 rescued Rb mediated downregulation of telomerase activity.	0	14	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cdk4	Overexpression of cdk2 and cdk4	cdk4	Rb	Rb	rb	4	5	12	13
As a result , the CDK4 protein is constantly activated promoting the Rb pathway and subsequent cellular division .	As a result, the CDK4 protein is constantly activated promoting the Rb pathway and subsequent cellular division.	5	13	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	5	6	12	13
p16ink4 and p15ink4 are tumor suppressor proteins keeping Cdk4 inactive , which enables Rb to hold E2Fs as inactive and to arrest cell cycle at G1 phase .	p16ink4 and p15ink4 are tumor suppressor proteins keeping Cdk4 inactive, which enables Rb to hold E2Fs as inactive and to arrest cell cycle at G1 phase.	7	14	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk4	Cdk4	Cdk4	Rb	Rb	Rb	8	9	13	14
Palbociclib ( PD 0332991 ) , a potent and selective inhibitor of CDK4 and CDK6 , inhibits proliferation of several Rb positive cancer cell lines and xenograft models .	Palbociclib (PD 0332991), a potent and selective inhibitor of CDK4 and CDK6, inhibits proliferation of several Rb positive cancer cell lines and xenograft models.	10	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	Rb	Rb	Rb	12	13	20	21
E2F family deregulation especially occurs in recurrent neuroblastomas and tumor derived cell lines , presumably caused by upregulation of factors , such as CDK4 , that inhibit the RB1 tumor suppressor [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	E2F family deregulation especially occurs in recurrent neuroblastomas and tumor derived cell lines, presumably caused by upregulation of factors, such as CDK4, that inhibit the RB1 tumor suppressor [XREF_BIBR, XREF_BIBR, XREF_BIBR].	12	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	RB1	RB1	RB1	23	24	28	29
Here , we have shown that IKKbeta can upregulate CDK4 mediated phopshorylation of pRb through phosphorylating and inactivating P16 , indicating that activation of IKKbeta also plays important roles in modulating the pRb pathway .	Here, we have shown that IKKbeta can upregulate CDK4 mediated phopshorylation of pRb through phosphorylating and inactivating P16, indicating that activation of IKKbeta also plays important roles in modulating the pRb pathway.	8	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	pRb	pRb	pRb	9	10	13	14
CDK4 is associated with D-type cyclins to promote cell-cycle entry and progression through G 1 by inactivating the retinoblastoma protein Rb .	CDK4 is associated with D-type cyclins to promote cell-cycle entry and progression through G 1 by inactivating the retinoblastoma protein Rb.	0	20	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	0	1	18	20
CDK4 and 6 phosphorylate the Rb ( retinoblastoma protein ) [ XREF_BIBR , XREF_BIBR ] and cause Rb to release the E2F transcription factor which can then activate genes essential for G1-S transition and S-phase [ XREF_BIBR ] .	CDK4 and 6 phosphorylate the Rb (retinoblastoma protein) [XREF_BIBR, XREF_BIBR] and cause Rb to release the E2F transcription factor which can then activate genes essential for G1-S transition and S-phase [XREF_BIBR].	0	18	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4 and 6 phosphorylate the Rb	cdk4	Rb	Rb	rb	0	1	17	18
For example , the RB1 pathway is inactivated in all glioblastoma tumors but is caused either by somatic RB1 mutations , CDKN2A/B mutations , or CDK4 amplification XREF_BIBR .	For example, the RB1 pathway is inactivated in all glioblastoma tumors but is caused either by somatic RB1 mutations, CDKN2A/B mutations, or CDK4 amplification XREF_BIBR.	4	27	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	RB1	RB1	RB1	25	26	4	5
Finally , we also assessed by immunoprecipitation the ability of E2F-4 transcription factors to associate with the Cdk4 activated pRb family member p107 .	Finally, we also assessed by immunoprecipitation the ability of E2F-4 transcription factors to associate with the Cdk4 activated pRb family member p107.	16	22	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk4	Cdk4	Cdk4	pRb	pRb	pRb	17	18	19	20
Indeed , two families of endogenous CDKIs were found to function operationally as tumor suppressors : i ) The WAF1/CIP/KIP family of CDKIs ( p21 , p27 and p57 ) appear to inhibit the activity of all major CDKs , while the INK4 family of CDKIs ( p16 , p15 , p18 and p19 ) more specifically inhibit the cyclin D dependent kinases CDK4 and CDK6 , which phosphorylate and inactivate the pRb suppressor in early G1 .	Indeed, two families of endogenous CDKIs were found to function operationally as tumor suppressors : i) The WAF1/CIP/KIP family of CDKIs (p21, p27 and p57) appear to inhibit the activity of all major CDKs, while the INK4 family of CDKIs (p16, p15, p18 and p19) more specifically inhibit the cyclin D dependent kinases CDK4 and CDK6, which phosphorylate and inactivate the pRb suppressor in early G1.	30	73	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	pRb	pRb	pRb	63	64	72	73
Modest selectivity between Cdks is exhibited by some compounds , and Cdk4 selective inhibitors block pRb ( + ) cells in the G ( 1 )-phase of the cell division cycle .	Modest selectivity between Cdks is exhibited by some compounds, and Cdk4 selective inhibitors block pRb (+) cells in the G (1)-phase of the cell division cycle.	11	19	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk4	Cdk4	Cdk4	pRb	pRb	pRb	11	12	15	16
The knockdown of cyclin D1 or CDK4 reduced p-Rb levels markedly ( XREF_FIG ) .	The knockdown of cyclin D1 or CDK4 reduced p-Rb levels markedly (XREF_FIG).	1	12	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	p-Rb	p-Rb	p-Rb	6	7	8	9
By contrast , assessment of the CDK4 and cyclin D1 complex and measurement of its kinase activity are entirely congruent with the proliferative response , and suggest that CDK4 compensated for diminished CDK2 activity to inactivate pRb and promote cell cycle progression ( XREF_FIG ) .	By contrast, assessment of the CDK4 and cyclin D1 complex and measurement of its kinase activity are entirely congruent with the proliferative response, and suggest that CDK4 compensated for diminished CDK2 activity to inactivate pRb and promote cell cycle progression (XREF_FIG).	28	37	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	pRb	pRb	pRb	28	29	36	37
In addition , Cdk4 dependent activation of pRb , which is important for cell cycle arrest , did not significantly change ( XREF_FIG ) .	In addition, Cdk4 dependent activation of pRb, which is important for cell cycle arrest, did not significantly change (XREF_FIG).	3	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Cdk4	Cdk4	Cdk4	pRb	pRb	pRb	3	4	7	8
Additionally the Cdkn1b gene product p27 Kip1 , which is functionally and structurally related to p21 , was shown to inhibit both Cdk4 and Cdk2 thereby promoting pRb activity [ XREF_BIBR , XREF_BIBR ] .	Additionally the Cdkn1b gene product p27 Kip1, which is functionally and structurally related to p21, was shown to inhibit both Cdk4 and Cdk2 thereby promoting pRb activity [XREF_BIBR, XREF_BIBR].	21	28	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk4	Cdk4	Cdk4	pRb	pRb	pRb	22	23	27	28
To induce immortalization , cells were introduced with the telomerase catalytic subunit hTERT , and both the p53 and pRB pathways were perturbed by p53 knockdown and over-expression of CyclinD and CDK4 chimera , respectively , giving rise to an immortal cell line designated as EP ( XREF_FIG ) .	To induce immortalization, cells were introduced with the telomerase catalytic subunit hTERT, and both the p53 and pRB pathways were perturbed by p53 knockdown and over-expression of CyclinD and CDK4 chimera, respectively, giving rise to an immortal cell line designated as EP (XREF_FIG).	19	32	perturbed	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	pRB	pRB	pRB	31	32	19	20
Gain-of-function mutations in CDK4 are seen , in GBM , activating the RB pathway .	Gain-of-function mutations in CDK4 are seen, in GBM, activating the RB pathway.	1	13	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	RB	RB	RB	3	4	12	13
Verification showed that CDK4 knockdown inhibited hormone independent growth and reduced P-Rb levels in 6/6 ER+ breast cancer cell lines ( XREF_FIG , XREF_SUPPLEMENTARY ; confirmed using an independent CDK4 siRNA , data not shown ) .	Verification showed that CDK4 knockdown inhibited hormone independent growth and reduced P-Rb levels in 6/6 ER+ breast cancer cell lines (XREF_FIG, XREF_SUPPLEMENTARY; confirmed using an independent CDK4 siRNA, data not shown).	3	12	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	P-Rb	P-Rb	P-Rb	3	4	11	12
A different study indicates that overexpression of wild type CDK2 enhanced the hormone dependent activity of exogenous PR-B or PR-A .	A different study indicates that overexpression of wild type CDK2 enhanced the hormone dependent activity of exogenous PR-B or PR-A.	5	19	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	overexpression of wild type CDK2	cdk2	PR-B	PR-B	pr-b	9	10	17	18
Our results suggest that Ad induced cyclin E activates CDK2 that targets the transcriptional repressor pRb to generate a cellular environment for viral productive replication .	Our results suggest that Ad induced cyclin E activates CDK2 that targets the transcriptional repressor pRb to generate a cellular environment for viral productive replication.	8	16	targets	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	pRb	pRb	pRb	9	10	15	16
Inhibition of CDK2 by the siRNA repressed the pCDK2 T160 , phospho-pRb S612 , and cyclin EL induced by Adwt infection ( XREF_FIG , comparing lane 1 with 2 and lane 3 with 4 ) .	Inhibition of CDK2 by the siRNA repressed the pCDK2 T160, phospho-pRb S612, and cyclin EL induced by Adwt infection (XREF_FIG, comparing lane 1 with 2 and lane 3 with 4).	0	12	repressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	phospho-pRb	phospho-pRb	phospho-pRb	2	3	11	12
The two cyclin E forms differ functionally in that cyclin E , but not cyclin Es , is able to complex with cdk2 , to activate the histone H1 , pRb and p107 in vitro kinase activity of cdk2 and to rescue a triple CLN mutation in S. cerevisiae .	The two cyclin E forms differ functionally in that cyclin E, but not cyclin Es, is able to complex with cdk2, to activate the histone H1, pRb and p107 in vitro kinase activity of cdk2 and to rescue a triple CLN mutation in S. cerevisiae.	25	41	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cdk2	cdk2	cdk2	pRb	pRb	pRb	38	39	30	31
By analogy with our fibroblast data , this effect could be a reflection of elevated CDK2 activity potentiating the growth of Rb -/- tumor cells .	By analogy with our fibroblast data, this effect could be a reflection of elevated CDK2 activity potentiating the growth of Rb -/- tumor cells.	15	24	potentiating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	Rb	Rb	Rb	15	16	21	22
It is generally accepted that CDK2 promotes G1/S transition by phosphorylating and thereby inactivating Rb , resulting in the activation of E2F transcription factors , as these events take place in the nucleus , cytoplasmic mislocalization of CDK2 would render it inactive in promoting cell cycle progression .	It is generally accepted that CDK2 promotes G1/S transition by phosphorylating and thereby inactivating Rb, resulting in the activation of E2F transcription factors, as these events take place in the nucleus, cytoplasmic mislocalization of CDK2 would render it inactive in promoting cell cycle progression.	5	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	Rb	Rb	Rb	5	6	14	15
These three lines of evidence support the hypothesis that Ad induced cyclin EL activates CDK2 , which targets the transcriptional suppressor pRb , controlling cellular and viral gene expression for productive viral replication ( XREF_FIG ) .	These three lines of evidence support the hypothesis that Ad induced cyclin EL activates CDK2, which targets the transcriptional suppressor pRb, controlling cellular and viral gene expression for productive viral replication (XREF_FIG).	13	22	targets	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	CDK2	CDK2	CDK2	pRb	pRb	pRb	14	15	21	22
Intriguingly , the knockdown of both CDK4 and CDK6 , but not CDK2 , allowed RB to become the most hypophosphorylated form and converted the SN38 sensitive cells to a resistant state .	Intriguingly, the knockdown of both CDK4 and CDK6, but not CDK2, allowed RB to become the most hypophosphorylated form and converted the SN38 sensitive cells to a resistant state.	3	17	allowed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	RB	RB	RB	12	13	15	16
In cells with low levels of the cyclin dependent kinase inhibitor , p27 , overexpression of activated Cdk2 induces hormone independent activation of PR and this hormone independent activation is blocked by mutation of Ser 400 , a PR phosphorylation site [ XREF_BIBR ] .	In cells with low levels of the cyclin dependent kinase inhibitor, p27, overexpression of activated Cdk2 induces hormone independent activation of PR and this hormone independent activation is blocked by mutation of Ser 400, a PR phosphorylation site [XREF_BIBR].	14	24	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	overexpression of activated Cdk2	cdk2	PR	PR	pr	17	18	23	24
Interestingly , expression of the constitutively active CDK-2 also induced hormone independent activation of WT PR measured using a PR responsive luciferase reporter whereas the basal activity of the Ser400Ala mutant was unaffected .	Interestingly, expression of the constitutively active CDK-2 also induced hormone independent activation of WT PR measured using a PR responsive luciferase reporter whereas the basal activity of the Ser400Ala mutant was unaffected.	2	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK-2	expression of the constitutively active CDK-2	cdk-2	PR	PR	pr	7	8	15	16
PR was unresponsive to activated CDK2 in breast cancer cells with elevated p27 , and RNA interference knock-down of p27 partially restored CDK2 induced ligand independent PR activation .	PR was unresponsive to activated CDK2 in breast cancer cells with elevated p27, and RNA interference knock-down of p27 partially restored CDK2 induced ligand independent PR activation.	22	27	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	PR	PR	PR	22	23	26	27
A similar interaction occurs between PARP-1 and PR : PARP-1 binding of PR , as well as hormone activated CDK2 induced PR PARylation , acts to stimulate cancer cell proliferation .	A similar interaction occurs between PARP-1 and PR : PARP-1 binding of PR, as well as hormone activated CDK2 induced PR PARylation, acts to stimulate cancer cell proliferation.	18	22	induced	Positive_early_activation	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	PR	PR	PR	19	20	21	22
Inhibition of Cdk2 activity abolishes progesterone dependent activation of PR target genes in part through inhibition of PR dependent recruitment of steroid receptor coactivator 1 ( SRC-1 ) and subsequent histone H4 acetylation at the target promoter .	Inhibition of Cdk2 activity abolishes progesterone dependent activation of PR target genes in part through inhibition of PR dependent recruitment of steroid receptor coactivator 1 (SRC-1) and subsequent histone H4 acetylation at the target promoter.	2	11	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	Cdk2	Cdk2	PR	PR	PR	2	3	9	10
Ser400 is a substrate for Cdk2 and expression of constitutively active Cdk2 enhances PR activity in the absence or presence of hormone .	Ser400 is a substrate for Cdk2 and expression of constitutively active Cdk2 enhances PR activity in the absence or presence of hormone.	7	14	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	expression of constitutively active Cdk2	cdk2	PR	PR	pr	11	12	13	14
Basal PR transcriptional activity occurred independently of progestins , was increased by activated CDK2 , and attenuated by RU486 .	Basal PR transcriptional activity occurred independently of progestins, was increased by activated CDK2, and attenuated by RU486.	0	16	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CDK2	CDK2	CDK2	PR	PR	PR	13	14	1	2
In some contexts , constitutively active Cdk2 stimulates basal PR activity [ XREF_BIBR ] and heregulin can activate PR [ XREF_BIBR ] .	In some contexts, constitutively active Cdk2 stimulates basal PR activity [XREF_BIBR] and heregulin can activate PR [XREF_BIBR].	5	20	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	Cdk2	Cdk2	PR	PR	PR	6	7	18	19
In reporter gene assays , cyclin A2 overexpression enhanced PR activity while inhibition of Cdk2 activity using the chemical inhibitor roscovitine or Cdk2 siRNA strongly inhibited PR activity .	In reporter gene assays, cyclin A2 overexpression enhanced PR activity while inhibition of Cdk2 activity using the chemical inhibitor roscovitine or Cdk2 siRNA strongly inhibited PR activity.	14	27	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	Cdk2	Cdk2	PR	PR	PR	14	15	26	27
This increase was not seen in the cyclin D overexpressing MCF7-CD1 cells , where transfection of cdk4 siRNA was not sufficient to enhance Smad3 activity .	This increase was not seen in the cyclin D overexpressing MCF7-CD1 cells, where transfection of cdk4 siRNA was not sufficient to enhance Smad3 activity.	16	24	enhance	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	cdk4	cdk4	cdk4	Smad3	Smad3	Smad3	16	17	23	24
Moreover , CDK4 activates Smad3 through phosphorylation , then phosphorylated Smad3 suppresses Id-1 expression .	Moreover, CDK4 activates Smad3 through phosphorylation, then phosphorylated Smad3 suppresses Id-1 expression.	2	5	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK4	CDK4	CDK4	Smad3	Smad3	Smad3	2	3	4	5
Since phosphorylation of Cdh1 and Fzr by CDK2 : cyclin E inhibits APC Cdh1 and Fzr activity [ XREF_BIBR ] , oscillations of APC Cdh1 and Fzr activity appear to be driven by periodic inactivation of Cdh1 and Fzr by CDK2 : cyclin E [ XREF_BIBR , XREF_BIBR ] .	Since phosphorylation of Cdh1 and Fzr by CDK2 : cyclin E inhibits APC Cdh1 and Fzr activity [XREF_BIBR], oscillations of APC Cdh1 and Fzr activity appear to be driven by periodic inactivation of Cdh1 and Fzr by CDK2 : cyclin E [XREF_BIBR, XREF_BIBR].	1	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDK2	phosphorylation of Cdh1 and Fzr by CDK2	cdk2	Fzr	Fzr	fzr	7	8	15	16
XREF_BIBR , XREF_BIBR Low Cyclin E : Cdk2 activity allows high APC ( Fzr ) activity , which in turn , degrades mitotic cyclins and Geminin , thereby allowing assembly of preRCs .	XREF_BIBR, XREF_BIBR Low Cyclin E : Cdk2 activity allows high APC (Fzr) activity, which in turn, degrades mitotic cyclins and Geminin, thereby allowing assembly of preRCs.	7	15	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	Cdk2	Cdk2	Fzr	Fzr	Fzr	7	8	13	14
Of critical importance is the fact that Cdk2 * Cyclin E inactivates Fzr , suggesting that APC * Fzr oscillations are driven by periodic inhibition of Fzr by Cdk2 * Cyclin E.	Of critical importance is the fact that Cdk2 * Cyclin E inactivates Fzr, suggesting that APC * Fzr oscillations are driven by periodic inhibition of Fzr by Cdk2 * Cyclin E.	21	29	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Cdk2	Cdk2	Cdk2	Fzr	Fzr	Fzr	28	29	26	27
Despite the increased tyrosine phosphorylation of Cdk2 in embryos overexpressing Wee1 , Cdk2 kinase activity was not repressed .	Despite the increased tyrosine phosphorylation of Cdk2 in embryos overexpressing Wee1, Cdk2 kinase activity was not repressed.	3	11	overexpressing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk2	tyrosine phosphorylation of Cdk2	cdk2	Wee1	Wee1	wee1	6	7	10	11
Moreover , ectopic expression of cyclin D1 and Cdk4 can stimulate the Brca1 promoter in an E2F dependent manner , and this is inhibited by coexpression of the p16 ( INK4a ) cyclin dependent kinase inhibitor .	Moreover, ectopic expression of cyclin D1 and Cdk4 can stimulate the Brca1 promoter in an E2F dependent manner, and this is inhibited by coexpression of the p16 (INK4a) cyclin dependent kinase inhibitor.	3	13	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk4	expression of cyclin D1 and Cdk4	cdk4	Brca1	Brca1	brca1	8	9	12	13
Since cyclinE and Cdk2 is involved in the regulation of the cell cycle progression from G2 to M phase , inhibition of Sirt2 deacetylase activity mediated by cyclinE and Cdk2 might be a requirement for the cell cycle progression from G2 to M phase [ XREF_BIBR ] .	Since cyclinE and Cdk2 is involved in the regulation of the cell cycle progression from G2 to M phase, inhibition of Sirt2 deacetylase activity mediated by cyclinE and Cdk2 might be a requirement for the cell cycle progression from G2 to M phase [XREF_BIBR].	22	30	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Cdk2	Cdk2	Cdk2	Sirt2	Sirt2	Sirt2	29	30	22	23
However , the protein level and enzyme activity of phospho-p38 MAPK in siRNA-S100A9 vectors groups presented no substantial changes compared with the other two groups Reduced S100A9 up-regulates the cell cycle related proteins p21 and p27 causing the inactivation of CDK2 and CDK4 .	However, the protein level and enzyme activity of phospho-p38 MAPK in siRNA-S100A9 vectors groups presented no substantial changes compared with the other two groups Reduced S100A9 up-regulates the cell cycle related proteins p21 and p27 causing the inactivation of CDK2 and CDK4.	28	42	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	33	34	40	41
XREF_BIBR The translocation of Id2 in cells with mutated polycystins is linked to downregulation of p21 leading to increase of CDK2 activity and cell cycle progression .	XREF_BIBR The translocation of Id2 in cells with mutated polycystins is linked to downregulation of p21 leading to increase of CDK2 activity and cell cycle progression.	13	21	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	15	16	20	21
p21 overexpression upregulated CDK2 and cyclin E , and CDK2 and cyclin E downregulation were rescued by p21 overexpressing in tigecycline treated cells .	p21 overexpression upregulated CDK2 and cyclin E, and CDK2 and cyclin E downregulation were rescued by p21 overexpressing in tigecycline treated cells.	9	19	rescued	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p21	p21 overexpressing	p21	CDK2	CDK2	cdk2	17	18	9	10
The overexpression of p21 Cip1 and Waf1 or p27 Kip1 , CKIs that target Cdk2 , also abrogated staurosporine- and , to a lesser degree , TNF-alpha-induced chromatin condensation ( XREF_FIG and XREF_FIG A , and data not shown ) .	The overexpression of p21 Cip1 and Waf1 or p27 Kip1, CKIs that target Cdk2, also abrogated staurosporine- and, to a lesser degree, TNF-alpha-induced chromatin condensation (XREF_FIG and XREF_FIG A, and data not shown).	1	15	target	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	p21 Cip1	overexpression of p21 Cip1	p21 cip1	Cdk2	Cdk2	cdk2	3	5	14	15
CDK4 T172 Phosphorylation Is Central in a CDK7 Dependent Bidirectional CDK4 and CDK2 Interplay Mediated by p21 Phosphorylation at the Restriction Point .	CDK4 T172 Phosphorylation Is Central in a CDK7 Dependent Bidirectional CDK4 and CDK2 Interplay Mediated by p21 Phosphorylation at the Restriction Point.	12	18	Mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p21	p21 Phosphorylation	p21	CDK2	CDK2	cdk2	16	17	12	13
p21 negatively regulates cell cycle progression by inhibiting CDK2 and CDK4 and blocks DNA replication by binding to PCNA [ XREF_BIBR ] .	p21 negatively regulates cell cycle progression by inhibiting CDK2 and CDK4 and blocks DNA replication by binding to PCNA [XREF_BIBR].	0	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	0	1	8	9
At the same time , the expression levels of P16 and P21 were significantly reduced , thus weakening the inhibition of CDK2 , CDK4 , and CDK6 .	At the same time, the expression levels of P16 and P21 were significantly reduced, thus weakening the inhibition of CDK2, CDK4, and CDK6.	7	26	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	P21	levels of P16 and P21	p21	CDK2	CDK2	cdk2	11	12	21	22
Among these , the Cdk inhibitor ( CKI ) p21 WAF1 acts to arrest the cell cycle by inhibiting Cdk2 and cyclin E and Cdk2 and cyclin A.	Among these, the Cdk inhibitor (CKI) p21 WAF1 acts to arrest the cell cycle by inhibiting Cdk2 and cyclin E and Cdk2 and cyclin A.	9	22	arrest	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 WAF1	p21 WAF1	p21 WAF1	Cdk2	Cdk2	Cdk2	9	11	19	20
Since CDK2 , and not CDK4 or CDK6 , is the major driving force for cell cycle progression in ES cells XREF_BIBR , decreased inhibition of CDK2 by p21 and p27 should accelerate cell proliferation .	Since CDK2, and not CDK4 or CDK6, is the major driving force for cell cycle progression in ES cells XREF_BIBR, decreased inhibition of CDK2 by p21 and p27 should accelerate cell proliferation.	23	30	inhibition	Negative_activation_token_2_noun	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	28	29	26	27
These effects were antagonized by pharmacological inhibition of CDKN2C and CDKN1A targets CDK2 and CDK4 in vitro .	These effects were antagonized by pharmacological inhibition of CDKN2C and CDKN1A targets CDK2 and CDK4 in vitro.	6	14	targets	Positive_activation_token_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK2	CDK2	CDK2	10	11	12	13
These results suggest that an increase in p21 and p27 protein causes increased binding with CDK2 and inhibition of CDK2 activity .	These results suggest that an increase in p21 and p27 protein causes increased binding with CDK2 and inhibition of CDK2 activity.	7	20	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	7	8	19	20
Simvastatin reversed the down-regulation of p21 protein expression and decreased CDK4 and CDK2 kinase activities .	Simvastatin reversed the down-regulation of p21 protein expression and decreased CDK4 and CDK2 kinase activities.	0	14	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	Simvastatin reversed the down-regulation of p21 protein expression	p21	CDK2	CDK2	cdk2	5	6	12	13
49 As CDKN1A inhibits both G1 and G2 cell cycle phase progression by binding to and inhibiting CDK2 and CDK1 , 50 our observation that KLF6-wt mediates G2 arrest in BTSC23 cells is also consistent with the induction of CDKN1A by KLF6 .	49 As CDKN1A inhibits both G1 and G2 cell cycle phase progression by binding to and inhibiting CDK2 and CDK1, 50 our observation that KLF6-wt mediates G2 arrest in BTSC23 cells is also consistent with the induction of CDKN1A by KLF6.	2	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	CDK2	CDK2	CDK2	2	3	17	18
We conclude that phosphorylation of p21 by Cdk2 limits the effectiveness of p21 to inhibit Cdk2 , which is the mechanism for continued cisplatin cytotoxicity even after the induction of a protective protein .	We conclude that phosphorylation of p21 by Cdk2 limits the effectiveness of p21 to inhibit Cdk2, which is the mechanism for continued cisplatin cytotoxicity even after the induction of a protective protein.	3	20	limits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	phosphorylation of p21	p21	Cdk2	Cdk2	cdk2	5	6	15	16
Displacement of p21 Cip1 from active cyclin D1/CDK4 complexes allows p21 Cip1 to bind and inhibit CDK2 activity , thereby inhibiting progression through G 1 and into S phase ( Sherr and Roberts , 2004 ) .	Displacement of p21 Cip1 from active cyclin D1/CDK4 complexes allows p21 Cip1 to bind and inhibit CDK2 activity, thereby inhibiting progression through G 1 and into S phase (Sherr and Roberts, 2004).	2	17	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21 Cip1	p21 Cip1	p21 Cip1	CDK2	CDK2	CDK2	2	4	16	17
Two CDK inhibitors , p21 and p27 , are known to inhibit CDK2 kinase activity during G1 cell cycle progression .	Two CDK inhibitors, p21 and p27, are known to inhibit CDK2 kinase activity during G1 cell cycle progression.	2	14	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	4	5	12	13
Cell cycle progression is governed by cyclin dependent kinases ( Cdks ) , and p21 slows or halts cell cycle progression by inhibiting Cdk2 .	Cell cycle progression is governed by cyclin dependent kinases (Cdks), and p21 slows or halts cell cycle progression by inhibiting Cdk2.	14	24	slows	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	14	15	23	24
Inhibitors of cyclin dependent kinase ( cdk ) , p21 and p27 , inhibit cdk2 and cdk4/6 , thereby inhibiting progression through G1 and S phases [ XREF_BIBR ] .	Inhibitors of cyclin dependent kinase (cdk), p21 and p27, inhibit cdk2 and cdk4/6, thereby inhibiting progression through G1 and S phases [XREF_BIBR].	0	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	cdk2	cdk2	cdk2	9	10	14	15
In our model , two double negative feedback loops control p21 expression : ( i ) phosphorylation by CDK2 targets p21 for Skp2 dependent degradation XREF_BIBR XREF_BIBR , while high levels of p21 inhibit CDK2 activity XREF_BIBR ; and ( ii ) PCNA in active replication complexes ( aRCs ) recruits CRL4 Cdt2 to degrade p21 , while p21 can bind to PCNA interfering with its function as a processivity factor during DNA replication XREF_BIBR XREF_BIBR .	In our model, two double negative feedback loops control p21 expression : (i) phosphorylation by CDK2 targets p21 for Skp2 dependent degradation XREF_BIBR XREF_BIBR, while high levels of p21 inhibit CDK2 activity XREF_BIBR; and (ii) PCNA in active replication complexes (aRCs) recruits CRL4 Cdt2 to degrade p21, while p21 can bind to PCNA interfering with its function as a processivity factor during DNA replication XREF_BIBR XREF_BIBR.	16	22	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	20	21	18	19
Meanwhile , the reduction of cellular iron stabilizes HIF-1alpha , increases p21 expression , and inhibits CDK2 enzymatic activity either indirectly by suppressing mRNA production or directly through p21 mediated inhibition .	Meanwhile, the reduction of cellular iron stabilizes HIF-1alpha, increases p21 expression, and inhibits CDK2 enzymatic activity either indirectly by suppressing mRNA production or directly through p21 mediated inhibition.	6	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	iron stabilizes HIF-1alpha, increases p21 expression	p21	CDK2	CDK2	cdk2	11	12	16	17
An increase in the expression level of p21 has been found to inhibit E2F mediated transcription by disrupting the cdk2 containing E2F and p130 complex [ XREF_BIBR ] .	An increase in the expression level of p21 has been found to inhibit E2F mediated transcription by disrupting the cdk2 containing E2F and p130 complex [XREF_BIBR].	5	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	level of p21	p21	cdk2	cdk2	cdk2	7	8	19	20
Enforced expression of CDK4 may therefore overcome a gamma-irradiation-induced G1 arrest through the titration of the CDK inhibitor p21 allowing both CDK4 and CDK2 to remain active .	Enforced expression of CDK4 may therefore overcome a gamma-irradiation-induced G1 arrest through the titration of the CDK inhibitor p21 allowing both CDK4 and CDK2 to remain active.	13	25	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	18	19	23	24
To test whether an increase in p21 protein at the end of the previous cell cycle causes cells to enter the CDK2 low state after mitosis , we added TMP to asynchronous cultures and selected for analysis only those cells that were in G2 or M when TMP was added .	To test whether an increase in p21 protein at the end of the previous cell cycle causes cells to enter the CDK2 low state after mitosis, we added TMP to asynchronous cultures and selected for analysis only those cells that were in G2 or M when TMP was added.	6	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	6	7	21	22
Additionally , by inhibiting CDK2 , p21 inhibits the induction of CDC2 and CCNB1 indirectly , as the expression of these genes at the G1/S transition is mediated by the NF-Y transcription factor following its phosphorylation by CDK2 .	Additionally, by inhibiting CDK2, p21 inhibits the induction of CDC2 and CCNB1 indirectly, as the expression of these genes at the G1/S transition is mediated by the NF-Y transcription factor following its phosphorylation by CDK2.	3	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	6	7	4	5
CDK2 emerge cells show initially high levels of p21 that then decay around the time that CDK2 activity turns back on ( XREF_FIG , green ) , consistent with the notion that a decay in p21 enables a rise in CDK2 activity .	CDK2 emerge cells show initially high levels of p21 that then decay around the time that CDK2 activity turns back on (XREF_FIG, green), consistent with the notion that a decay in p21 enables a rise in CDK2 activity.	33	41	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	35	36	40	41
Low level of p21 in G2 allows immediate building up of the CDK2 activity following mitotic exit and results in continuous proliferation .	Low level of p21 in G2 allows immediate building up of the CDK2 activity following mitotic exit and results in continuous proliferation.	1	13	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	level of p21	p21	CDK2	CDK2	cdk2	3	4	12	13
Sequestration of p21 waf1 and cip1 and p27 kip1 in cyclin D complexes , combined with decreased expression of p21 waf1 and cip1 ( see XREF_FIG ) , relieves inhibition of cdk2 ( Roberts 1999 ) ( see XREF_FIG ) , allowing inactivation of pocket proteins and progression through the cell cycle .	Sequestration of p21 waf1 and cip1 and p27 kip1 in cyclin D complexes, combined with decreased expression of p21 waf1 and cip1 (see XREF_FIG), relieves inhibition of cdk2 (Roberts 1999) (see XREF_FIG), allowing inactivation of pocket proteins and progression through the cell cycle.	0	37	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	cip1	cip1	cip1	cdk2	cdk2	cdk2	5	6	31	32
Both results are in agreement with our findings of pCDK2 T160 as a gatekeeper , as CDK2 phosphorylation is a downstream process of both Cyclin D1 : CDK4 activation and p21 mediated nuclear import of CDK2 .	Both results are in agreement with our findings of pCDK2 T160 as a gatekeeper, as CDK2 phosphorylation is a downstream process of both Cyclin D1 : CDK4 activation and p21 mediated nuclear import of CDK2.	28	36	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	30	31	35	36
Similarly , pERK was also necessary for pSMAD2 phosphorylation , as well as p21 upregulation and repression of CDK2 ( XREF_FIG ) .	Similarly, pERK was also necessary for pSMAD2 phosphorylation, as well as p21 upregulation and repression of CDK2 (XREF_FIG).	8	20	upregulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p21	phosphorylation, as well as p21	p21	CDK2	CDK2	cdk2	13	14	18	19
We hypothesized that the observed G1-S arrest after irradiation was regulated by p21 mediated Cdk2 down-regulation .	We hypothesized that the observed G1-S arrest after irradiation was regulated by p21 mediated Cdk2 down-regulation.	10	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	12	13	14	15
In addition , phosphorylation of p21 ( Cip1 ) at Thr 145 decreases the binding of the cyclin dependent kinases Cdk2 and Cdk4 to p21 ( Cip1 ) and attenuates the Cdk2 inhibitory activity of p21 ( Cip1 ) .	In addition, phosphorylation of p21 (Cip1) at Thr 145 decreases the binding of the cyclin dependent kinases Cdk2 and Cdk4 to p21 (Cip1) and attenuates the Cdk2 inhibitory activity of p21 (Cip1).	3	22	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cip1	phosphorylation of p21 (Cip1) at Thr 145	cip1	Cdk2	Cdk2	cdk2	7	8	20	21
HDACi also decreased the levels of phosphorylated retinoblastoma ( Rb ) , which was regulated by p21 mediated Cdk2 and Cdk4 activity , suggesting that the upregulated p21 might work through the Rb-E2F pathway to inhibit cystic epithelial cell proliferation .	HDACi also decreased the levels of phosphorylated retinoblastoma (Rb), which was regulated by p21 mediated Cdk2 and Cdk4 activity, suggesting that the upregulated p21 might work through the Rb-E2F pathway to inhibit cystic epithelial cell proliferation.	14	21	mediated	Positive_early_activation	Negative_activation	Positive_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	16	17	18	19
We determined that KIF7 depletion from MLE15 cells accelerates entry into S phase in part through increased cyclin d1 expression , increased CDK2 activity , and reduced expression of the cell cycle inhibitor p21 ( XREF_FIG ) .	We determined that KIF7 depletion from MLE15 cells accelerates entry into S phase in part through increased cyclin d1 expression, increased CDK2 activity, and reduced expression of the cell cycle inhibitor p21 (XREF_FIG).	21	35	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	33	34	22	23
XREF_BIBR - XREF_BIBR Our laboratory found that cisplatin induced kidney cell death was dependent on Cdk2 activation , and inhibition of Cdk2 by p21 , dominant negative ( DN )-Cdk2 , or chemical inhibitors such as roscovitine or purvalanol protected kidney cells from cisplatin induced apoptosis both in vitro and in vivo .	XREF_BIBR - XREF_BIBR Our laboratory found that cisplatin induced kidney cell death was dependent on Cdk2 activation, and inhibition of Cdk2 by p21, dominant negative (DN)-Cdk2, or chemical inhibitors such as roscovitine or purvalanol protected kidney cells from cisplatin induced apoptosis both in vitro and in vivo.	19	33	inhibition	Negative_activation_token_2_noun	Negative_activation	Negative_activation	p21	p21	p21	Cdk2	Cdk2	Cdk2	23	24	21	22
Transcriptional targets of p53 , MDM2 and p21 , have been shown to inhibit CDK2 activity and contribute to p53 dependent cell cycle arrest XREF_BIBR .	Transcriptional targets of p53, MDM2 and p21, have been shown to inhibit CDK2 activity and contribute to p53 dependent cell cycle arrest XREF_BIBR.	1	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK2	CDK2	CDK2	7	8	14	15
p53 is essential to prevent immature escaping from cell cycle G2 checkpoint arrest through p21 mediated cdk2 inactivation , and this leads to inhibition of cdk2 dependent NF-Y phosphorylation and NF-Y dependent transcription of the cell cycle G2-regulatory genes , including cdc2 and cyclin B.	p53 is essential to prevent immature escaping from cell cycle G2 checkpoint arrest through p21 mediated cdk2 inactivation, and this leads to inhibition of cdk2 dependent NF-Y phosphorylation and NF-Y dependent transcription of the cell cycle G2-regulatory genes, including cdc2 and cyclin B.	12	17	mediated	Positive_early_activation	Negative_activation	Positive_activation	p21	p21	p21	cdk2	cdk2	cdk2	14	15	16	17
We propose that during TNFalpha induced apoptosis , PKCdelta mediated phosphorylation of p21 ( WAF1 and CIP1 ) at ( 146 ) Ser attenuates the Cdk2 binding of p21 ( WAF1 and CIP1 ) and thereby upregulates Cdk2 activity .	We propose that during TNFalpha induced apoptosis, PKCdelta mediated phosphorylation of p21 (WAF1 and CIP1) at (146) Ser attenuates the Cdk2 binding of p21 (WAF1 and CIP1) and thereby upregulates Cdk2 activity.	8	26	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	PKCdelta mediated phosphorylation of p21 (WAF1 and CIP1) at (146) Ser	p21	Cdk2	Cdk2	cdk2	12	13	25	26
Addition of PD98059 and SB202190 , inhibitors of ERK and p38 , respectively , decreased vanadate induced S phase arrest , reduced p21 levels , restored activation of p-cdk2 , and decreased p53 activity .	Addition of PD98059 and SB202190, inhibitors of ERK and p38, respectively, decreased vanadate induced S phase arrest, reduced p21 levels, restored activation of p-cdk2, and decreased p53 activity.	15	29	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	vanadate induced S phase arrest, reduced p21 levels	p21	p-cdk2	p-cdk2	p-cdk2	22	23	28	29
The sequestration of p21 by CDK4-cyclin D and CDK6-cyclin D may also promote oncogenesis by freeing CDK2 from inhibitory p21 .	The sequestration of p21 by CDK4-cyclin D and CDK6-cyclin D may also promote oncogenesis by freeing CDK2 from inhibitory p21.	1	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK2	CDK2	CDK2	3	4	16	17
1 In late G 1 , after the cell has committed to the next round of cell division , p27 is eliminated via SCF Skp2 to allow activation of Cdk1 and Cdk2 and , consequently , promote progression through the subsequent phases of the cell cycle .	1 In late G 1, after the cell has committed to the next round of cell division, p27 is eliminated via SCF Skp2 to allow activation of Cdk1 and Cdk2 and, consequently, promote progression through the subsequent phases of the cell cycle.	19	36	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	19	20	31	32
Anti-estrogens , such as tamoxifen , antagonise estrogen induced ERalpha transactivation of cyclin D1 , resulting in reduced CDK4/6 activity , p27 Kip1 -mediated inhibition of CDK2 and growth arrest .	Anti-estrogens, such as tamoxifen, antagonise estrogen induced ERalpha transactivation of cyclin D1, resulting in reduced CDK4/6 activity, p27 Kip1 -mediated inhibition of CDK2 and growth arrest.	21	29	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Positive_activation	p27 Kip1	p27 Kip1	p27 Kip1	CDK2	CDK2	CDK2	21	23	26	27
Whereas p18 Ink4c is a specific inhibitor of Cdk4 and Cdk6 , p27 Kip1 preferentially targets cyclin E- and A dependent Cdk2 , which acts later in G1 phase to help guide the G1 to S-phase transition .	Whereas p18 Ink4c is a specific inhibitor of Cdk4 and Cdk6, p27 Kip1 preferentially targets cyclin E- and A dependent Cdk2, which acts later in G1 phase to help guide the G1 to S-phase transition.	12	30	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27 Kip1	p27 Kip1	p27 Kip1	Cdk2	Cdk2	Cdk2	12	14	21	22
Cells that have passed beta selection differ from the preceding cells by several criteria , including hyperphosphorylation of Rb , increased expression of cyclins A and B , down-regulation of p27 , increased CDK2 activity , an induction of cdc2 activity , and progression through DNA synthesis .	Cells that have passed beta selection differ from the preceding cells by several criteria, including hyperphosphorylation of Rb, increased expression of cyclins A and B, down-regulation of p27, increased CDK2 activity, an induction of cdc2 activity, and progression through DNA synthesis.	28	34	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	CDK2	CDK2	CDK2	30	31	33	34
In resting CCL39 fibroblasts and IEC-6 intestinal epithelial cells , protein levels of p27 ( Kip1 ) were elevated but dramatically decreased on serum stimulation , along with hyperphosphorylation of pRb and increased CDK2 activity .	In resting CCL39 fibroblasts and IEC-6 intestinal epithelial cells, protein levels of p27 (Kip1) were elevated but dramatically decreased on serum stimulation, along with hyperphosphorylation of pRb and increased CDK2 activity.	11	34	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	levels of p27	p27	CDK2	CDK2	cdk2	13	14	33	34
Thus , sequestration of p27 ( KIP1 ) by cyclin D1/Cdk4 resulted in activation of Cdk2 in vitro .	Thus, sequestration of p27 (KIP1) by cyclin D1/Cdk4 resulted in activation of Cdk2 in vitro.	2	16	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	4	5	15	16
CD40 also induces downregulation of the cell cycle inhibitor p27 through a PI3K dependent manner , and the LMP1 lymphoma cells also had decreased levels of p27 with phosphorylation of Rb and increased Cdk2 ( XREF_FIG C ) [ XREF_BIBR ] .	CD40 also induces downregulation of the cell cycle inhibitor p27 through a PI3K dependent manner, and the LMP1 lymphoma cells also had decreased levels of p27 with phosphorylation of Rb and increased Cdk2 (XREF_FIG C) [XREF_BIBR].	18	39	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	LMP1 lymphoma cells also had decreased levels of p27	p27	Cdk2	Cdk2	cdk2	26	27	33	34
In addition to the direct activation of CDK4 , CCND3 can further promote cell proliferation by the sequestration of p27 and indirect activation of CDK2 and CCNE , which might explain why high p27 expression ( probably sequestered by CCND3 ) is an adverse prognostic factor in DLBCL .	In addition to the direct activation of CDK4, CCND3 can further promote cell proliferation by the sequestration of p27 and indirect activation of CDK2 and CCNE, which might explain why high p27 expression (probably sequestered by CCND3) is an adverse prognostic factor in DLBCL.	19	26	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p27	p27	p27	CDK2	CDK2	CDK2	19	20	24	25
The data demonstrate that p27 ( Kip1 ) differentially regulates the activity of cdk4 and cdk2 during terminal erythroid differentiation and suggests a switching mechanism whereby cdk4 functions to sequester p27 ( Kip1 ) until a specified time in differentiation when cdk2 kinase activity is targeted by p27 ( Kip1 ) to elicit G ( 1 ) growth arrest .	The data demonstrate that p27 (Kip1) differentially regulates the activity of cdk4 and cdk2 during terminal erythroid differentiation and suggests a switching mechanism whereby cdk4 functions to sequester p27 (Kip1) until a specified time in differentiation when cdk2 kinase activity is targeted by p27 (Kip1) to elicit G (1) growth arrest.	41	52	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p27	p27	p27	cdk2	cdk2	cdk2	47	48	41	42
An equally interesting possibility is that p27 more directly regulates the transcriptional activity of MYC ( also in a CDK2 and Ser-62-independent manner ) .	An equally interesting possibility is that p27 more directly regulates the transcriptional activity of MYC (also in a CDK2 and Ser-62-independent manner).	6	22	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	CDK2	CDK2	CDK2	6	7	19	20
Such a reduced model also avoids unnecessary complications that might arise from the need to properly model the Cdk2 binding step , which involves p27 induced Cdk2 remodeling but does not contribute to the rapid association phase .	Such a reduced model also avoids unnecessary complications that might arise from the need to properly model the Cdk2 binding step, which involves p27 induced Cdk2 remodeling but does not contribute to the rapid association phase.	24	31	induced	Positive_early_activation	Negative_activation	Positive_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	24	25	26	27
Simultaneously , p27 is upregulated , which also can downregulate the expression CDK2 .	Simultaneously, p27 is upregulated, which also can downregulate the expression CDK2.	2	13	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	CDK2	CDK2	CDK2	2	3	12	13
However , since cytoplasmic p27 re-expression only partially rescued apoptosis in p27 knockdown cells , it is likely that both p27 functions ( apoptosis suppression in the cytoplasm and CDK2 inhibition in the nucleus ) play roles in modulating apoptotic responses to lapatinib treatment Although the mechanisms by which cytoplasmic p27 blocks apoptosis are unknown , this appears to be a widespread feature of cancer cells , and related findings have been reported in mitogen depleted MCF7 breast cancer cells [ XREF_BIBR ] and in U87-MG glioma cells , that express abundant cytoplasmic p27 .	However, since cytoplasmic p27 re-expression only partially rescued apoptosis in p27 knockdown cells, it is likely that both p27 functions (apoptosis suppression in the cytoplasm and CDK2 inhibition in the nucleus) play roles in modulating apoptotic responses to lapatinib treatment Although the mechanisms by which cytoplasmic p27 blocks apoptosis are unknown, this appears to be a widespread feature of cancer cells, and related findings have been reported in mitogen depleted MCF7 breast cancer cells [XREF_BIBR] and in U87-MG glioma cells, that express abundant cytoplasmic p27.	20	30	suppression	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	p27	p27	p27	CDK2	CDK2	CDK2	20	21	29	30
In times of cell stress , p27 Kip1 can prevent apoptosis by directly inhibiting Cdk2 activation and downstream activity of the pro apoptotic factor Bax .	In times of cell stress, p27 Kip1 can prevent apoptosis by directly inhibiting Cdk2 activation and downstream activity of the pro apoptotic factor Bax.	6	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 Kip1	p27 Kip1	p27 Kip1	Cdk2	Cdk2	Cdk2	6	8	14	15
Phosphorylation of p27 on Y88 partially reactivates Cdk2 within the p27/Cdk2/cyclin A ternary complex [ XREF_BIBR ] while phosphorylation of p21 on Y77 does not ( this study ) .	Phosphorylation of p27 on Y88 partially reactivates Cdk2 within the p27/Cdk2/cyclin A ternary complex [XREF_BIBR] while phosphorylation of p21 on Y77 does not (this study).	0	8	reactivates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	Phosphorylation of p27 on Y88	p27	Cdk2	Cdk2	cdk2	2	3	7	8
It is believed that p27 translocated to the cytoplasm initiates its degradation and activates CDK2 and can enhance import of cyclin D to the nucleus [ XREF_BIBR ] resulting in the loss of functionality of p27 in cytoplasm .	It is believed that p27 translocated to the cytoplasm initiates its degradation and activates CDK2 and can enhance import of cyclin D to the nucleus [XREF_BIBR] resulting in the loss of functionality of p27 in cytoplasm.	4	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	CDK2	CDK2	CDK2	4	5	14	15
Tyrosine phosphorylation of p27 by BCR-ABL ( Y74 , Y88 , Y89 ) or Src family kinases ( Y88 and Y74 ) impairs the CDK2 inhibitory action of p27 .	Tyrosine phosphorylation of p27 by BCR-ABL (Y74, Y88, Y89) or Src family kinases (Y88 and Y74) impairs the CDK2 inhibitory action of p27.	0	26	impairs	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	Tyrosine phosphorylation of p27	p27	CDK2	CDK2	cdk2	3	4	24	25
Up-regulated p27 increases the inhibition to cdk2 and reduces the proliferation of NSPCs .	Up-regulated p27 increases the inhibition to cdk2 and reduces the proliferation of NSPCs.	0	8	increases	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	p27	p27	p27	cdk2	cdk2	cdk2	1	2	6	7
Activated Src has been shown to initially phosphorylate p27 enabling the activation of the CDK2 complex .	Activated Src has been shown to initially phosphorylate p27 enabling the activation of the CDK2 complex.	7	15	enabling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	phosphorylate p27	p27	CDK2	CDK2	cdk2	8	9	14	15
p27 kip1 has been shown to negatively regulate the transition from G1 to S phase by inhibiting the activity of CDK2 .	p27 kip1 has been shown to negatively regulate the transition from G1 to S phase by inhibiting the activity of CDK2.	0	21	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p27 kip1	p27 kip1	p27 kip1	CDK2	CDK2	CDK2	0	2	20	21
For this reason , p27 is degraded timely , before the onset of cells into S phase , preventing unwanted Cdk2 inhibition .	For this reason, p27 is degraded timely, before the onset of cells into S phase, preventing unwanted Cdk2 inhibition.	4	21	degraded	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	4	5	20	21
One such inhibitor , p27 that belongs to Kip and Cip family , potently inhibits CDK2 kinase activity in G0 and early G1 phase and leads to cell-cycle arrest XREF_BIBR .	One such inhibitor, p27 that belongs to Kip and Cip family, potently inhibits CDK2 kinase activity in G0 and early G1 phase and leads to cell-cycle arrest XREF_BIBR.	2	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	CDK2	CDK2	CDK2	4	5	15	16
Based on our present study , which demonstrates substantial p27 induction and p27 dependent inhibition of CDK2 by DAP , it is appropriate for the p53/p21/p27 axis to assume greater prominence and become a new focus of attention in checkpoint response to DNA damage .	Based on our present study, which demonstrates substantial p27 induction and p27 dependent inhibition of CDK2 by DAP, it is appropriate for the p53/p21/p27 axis to assume greater prominence and become a new focus of attention in checkpoint response to DNA damage.	9	17	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p27	p27	p27	CDK2	CDK2	CDK2	9	10	16	17
Immunodepletion of p27 increased CDK2- and cyclin E associated kinase activities .	Immunodepletion of p27 increased CDK2- and cyclin E associated kinase activities.	0	7	increased	Positive_activation_token_1_verb	Negative_activation	Positive_activation	p27	p27	p27	CDK2-	CDK2-	CDK2-	2	3	4	5
By inhibiting Cdk2 , p27 prevents cell proliferation .	By inhibiting Cdk2, p27 prevents cell proliferation.	1	6	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	Cdk2	Cdk2	Cdk2	4	5	2	3
Like our experimental results , either Cdh1 or p27 ablation caused early CDK2 activation at reduced cyclin E1 levels , suggesting that their dynamics could be similar .	Like our experimental results, either Cdh1 or p27 ablation caused early CDK2 activation at reduced cyclin E1 levels, suggesting that their dynamics could be similar.	8	13	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	CDK2	CDK2	CDK2	8	9	12	13
Both p21 and p27 can promote activation of Cdk4 and cyclin D , by assisting with complex assembly and translocation to the nucleus ; Association of Cdk4 with p27 depends on phosphorylation of the latter by growth factor dependent kinases .	Both p21 and p27 can promote activation of Cdk4 and cyclin D, by assisting with complex assembly and translocation to the nucleus; Association of Cdk4 with p27 depends on phosphorylation of the latter by growth factor dependent kinases.	0	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	Cdk4	Cdk4	Cdk4	1	2	8	9
p27 kip1 and other cdk inhibitors of the p21 family might also promote the association of cdk4 with cyclins D.	p27 kip1 and other cdk inhibitors of the p21 family might also promote the association of cdk4 with cyclins D.	8	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	cdk4	cdk4	cdk4	8	9	16	17
Furthermore , in vitro kinase assays using purified proteins demonstrated that the addition of p21 and waf1 to cyclin D2/cdk4 increased the kinase activity of cdk4 .	Furthermore, in vitro kinase assays using purified proteins demonstrated that the addition of p21 and waf1 to cyclin D2/cdk4 increased the kinase activity of cdk4.	12	26	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	cdk4	cdk4	cdk4	14	15	25	26
Overexpressed Cdk4 in epithelial cells induces a dramatic upregulation of p16 ( INK4a ) and milder upregulation of p53 and p21 ( WAF1 ) , which become unresponsive to UV irradiation .	Overexpressed Cdk4 in epithelial cells induces a dramatic upregulation of p16 (INK4a) and milder upregulation of p53 and p21 (WAF1), which become unresponsive to UV irradiation.	0	23	Overexpressed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WAF1	WAF1	WAF1	Cdk4	Cdk4	Cdk4	22	23	1	2
However , p21 and p27 were also shown to promote the assembly of active kinase CDK4 or CDK6 complexes whereas they inhibits CDK2 activity XREF_BIBR .	However, p21 and p27 were also shown to promote the assembly of active kinase CDK4 or CDK6 complexes whereas they inhibits CDK2 activity XREF_BIBR.	2	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK4	CDK4	CDK4	2	3	15	16
In addition , selective inhibition of Kv1.3 significantly increased expression level of p21 ( Waf1 and Cip1 ) and significantly decreased the expression level of Cdk4 and cyclin D3 .	In addition, selective inhibition of Kv1.3 significantly increased expression level of p21 (Waf1 and Cip1) and significantly decreased the expression level of Cdk4 and cyclin D3.	6	28	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	Kv1.3 significantly increased expression level of p21	p21	Cdk4	Cdk4	cdk4	12	13	25	26
Having expected that p14ARF would induce G1 as well as G2/M arrest , but also knowing from our CDK4 IP experiments that p14ARF induced p21 may be enhancing CDK4 activity , we were curious if p14ARF was functioning to maintain a certain percentage of cells in G1 rather than inducing indiscriminate arrest .	Having expected that p14ARF would induce G1 as well as G2/M arrest, but also knowing from our CDK4 IP experiments that p14ARF induced p21 may be enhancing CDK4 activity, we were curious if p14ARF was functioning to maintain a certain percentage of cells in G1 rather than inducing indiscriminate arrest.	22	29	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p14ARF induced p21	p21	CDK4	CDK4	cdk4	24	25	28	29
In this report we demonstrate that the CDK inhibitors p21 ( CIP ) , p27 ( KIP ) , and p57 ( KIP2 ) all promote the association of cdk4 with the D-type cyclins .	In this report we demonstrate that the CDK inhibitors p21 (CIP), p27 (KIP), and p57 (KIP2) all promote the association of cdk4 with the D-type cyclins.	6	30	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	cdk4	cdk4	cdk4	9	10	29	30
Biochemical analyses on CARF induced molecular signaling revealed that in p53-null cells , it caused transcriptional repression of p21 ( WAF1 ) leading to increase in CDK4 , CDK6 , pRb and E2F1 resulting in continued cell cycle progression .	Biochemical analyses on CARF induced molecular signaling revealed that in p53-null cells, it caused transcriptional repression of p21 (WAF1) leading to increase in CDK4, CDK6, pRb and E2F1 resulting in continued cell cycle progression.	18	32	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WAF1	WAF1	WAF1	CDK4	CDK4	CDK4	20	21	26	27
The accumulation of p53 in the nucleus induces the PTEN- and p21 mediated downregulation of cyclin D1 and CDK4 .	The accumulation of p53 in the nucleus induces the PTEN- and p21 mediated downregulation of cyclin D1 and CDK4.	9	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK4	CDK4	CDK4	11	12	18	19
This finding confirms those of previous studies that increased PAK4 expression in the early G1 phase reduces p21 levels , and thus abrogates CDK4 and CDK6 activity .	This finding confirms those of previous studies that increased PAK4 expression in the early G1 phase reduces p21 levels, and thus abrogates CDK4 and CDK6 activity.	9	26	abrogates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	PAK4 expression in the early G1 phase reduces p21 levels	p21	CDK4	CDK4	cdk4	17	18	23	24
Under certain specific conditions , p21 can promote the kinase activities of CDK4 and CDK6 , thus , promoting the cells to pass stage G1 ; p21 can inhibit the activity of CDK2 and thus , inhibit the phosphorylation of the CDK2 dependent RB protein , and the unphosphorylated RB can bind with the transcription factor E2F1 and thus , inhibit its transcriptional activity ; therefore , p21 inhibits CDK2 and eventually inhibits the transcription of the gene necessary for the E2F1 dependent G1/S transformation , leading to stage G1/S arrest .	Under certain specific conditions, p21 can promote the kinase activities of CDK4 and CDK6, thus, promoting the cells to pass stage G1; p21 can inhibit the activity of CDK2 and thus, inhibit the phosphorylation of the CDK2 dependent RB protein, and the unphosphorylated RB can bind with the transcription factor E2F1 and thus, inhibit its transcriptional activity; therefore, p21 inhibits CDK2 and eventually inhibits the transcription of the gene necessary for the E2F1 dependent G1/S transformation, leading to stage G1/S arrest.	5	14	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK4	CDK4	CDK4	5	6	12	13
Through its binding to PCNA , p21 inhibits replication by blocking the ability of PCNA to stimulate DNA polymerases [ XREF_BIBR ] , and leads to cell growth arrest in the mitotic cycle [ XREF_BIBR ] .	Through its binding to PCNA, p21 inhibits replication by blocking the ability of PCNA to stimulate DNA polymerases [XREF_BIBR], and leads to cell growth arrest in the mitotic cycle [XREF_BIBR].	6	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	6	7	14	15
The resultant amino acid substitution from aspartate to glycine may have vital implication in PCNA mediated cell cycle regulation by p21 ( waf1 and cip1 ) .	The resultant amino acid substitution from aspartate to glycine may have vital implication in PCNA mediated cell cycle regulation by p21 (waf1 and cip1).	12	21	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	20	21	14	15
Given that high p21 expression is often associated with lower PCNA abundance , our findings are suggestive of a global growth inhibitory mechanism involving p21 mediated PCNA suppression .	Given that high p21 expression is often associated with lower PCNA abundance, our findings are suggestive of a global growth inhibitory mechanism involving p21 mediated PCNA suppression.	23	27	mediated	Positive_early_activation	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	24	25	26	27
In eukaryotes , p21 targets PCNA , the eukaryotic analog of the beta subunit , to promote replication arrest after DNA damage [ XREF_BIBR ] .	In eukaryotes, p21 targets PCNA, the eukaryotic analog of the beta subunit, to promote replication arrest after DNA damage [XREF_BIBR].	3	16	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	3	4	5	6
Previous studies have shown that UV induced binding of p21 ( WAF1 ) to PCNA through the PCNA interacting protein ( PIP ) domain in p21 ( WAF1 ) promotes a switch from DNA replication to DNA repair by altering the PCNA protein complex .	Previous studies have shown that UV induced binding of p21 (WAF1) to PCNA through the PCNA interacting protein (PIP) domain in p21 (WAF1) promotes a switch from DNA replication to DNA repair by altering the PCNA protein complex.	23	43	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	25	26	41	42
Following cytoplasmic relocation of PAX6 , we observed a cell cycle arrest via p21 mediated PCNA downregulation ( Figs XREF_FIG & XREF_FIG ) .	Following cytoplasmic relocation of PAX6, we observed a cell cycle arrest via p21 mediated PCNA downregulation (Figs XREF_FIG & XREF_FIG).	11	16	mediated	Positive_early_activation	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	13	14	15	16
It has been proposed that this binding of p21 WAF-1 directs PCNA towards inhibition of DNA replication without affecting NER [ XREF_BIBR ] and that Tax can prevent this pathway by its capacity to inhibit p53 transcriptional activities [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	It has been proposed that this binding of p21 WAF-1 directs PCNA towards inhibition of DNA replication without affecting NER [XREF_BIBR] and that Tax can prevent this pathway by its capacity to inhibit p53 transcriptional activities [XREF_BIBR, XREF_BIBR, XREF_BIBR].	8	13	directs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	8	9	11	12
Downregulation of p21 by miR-17-5p in turn promotes PCNA ( proliferating cell nuclear antigen ) activity , where p21 is a negative regulator of PCNA and thus ERalpha promotes breast cancer cell cycle progression and proliferation in p21/PCNA/E2F1 dependent pathway [ XREF_BIBR ] .	Downregulation of p21 by miR-17-5p in turn promotes PCNA (proliferating cell nuclear antigen) activity, where p21 is a negative regulator of PCNA and thus ERalpha promotes breast cancer cell cycle progression and proliferation in p21/PCNA/E2F1 dependent pathway [XREF_BIBR].	0	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	2	3	8	9
Upon activation , p21 disrupts cell-cycle progression by binding to and inhibiting both cyclin dependent kinase-cyclin complexes and proliferating cell nuclear antigen .	Upon activation, p21 disrupts cell-cycle progression by binding to and inhibiting both cyclin dependent kinase-cyclin complexes and proliferating cell nuclear antigen.	3	22	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	3	4	18	22
The inhibition of CTNNA3 by miR-425 in turn resulted in increased PCNA , decreased p21 Cip1 and Waf1 and Akt activation , as well as the increased MMP-9 .	The inhibition of CTNNA3 by miR-425 in turn resulted in increased PCNA, decreased p21 Cip1 and Waf1 and Akt activation, as well as the increased MMP-9.	8	16	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21 Cip1	p21 Cip1	p21 Cip1	PCNA	PCNA	PCNA	14	16	11	12
P21 can also attenuate cell growth by inhibiting proliferating cell nuclear antigen ( PCNA ) , a replication protein which acts as a processivity factor for DNA polymerase , via protein protein interaction [ XREF_BIBR ] .	P21 can also attenuate cell growth by inhibiting proliferating cell nuclear antigen (PCNA), a replication protein which acts as a processivity factor for DNA polymerase, via protein protein interaction [XREF_BIBR].	0	12	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	P21	P21	P21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	0	1	8	12
The carboxyl end of p21 WAF1 and CIP1 mediates the PCNA binding and activity of DNA polymerase delta ( Chen et al , 1995 ; Luo et al , 1995 ; Nakanishi et al , 1995 ; Warbrick et al , 1995 ) .	The carboxyl end of p21 WAF1 and CIP1 mediates the PCNA binding and activity of DNA polymerase delta (Chen et al, 1995; Luo et al, 1995; Nakanishi et al, 1995; Warbrick et al, 1995).	4	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21 WAF1	p21 WAF1	p21 WAF1	PCNA	PCNA	PCNA	4	6	10	11
p21 Waf modulates cell-cycle progression by forming a complex with cyclins , cyclin dependent protein kinases , and PCNA .	p21 Waf modulates cell-cycle progression by forming a complex with cyclins, cyclin dependent protein kinases, and PCNA.	0	19	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	0	1	18	19
However , p21 can also directly inhibit DNA synthesis by binding to and inhibiting PCNA ( proliferating cell nuclear antigen ) [ XREF_BIBR ] .	However, p21 can also directly inhibit DNA synthesis by binding to and inhibiting PCNA (proliferating cell nuclear antigen) [XREF_BIBR].	2	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	2	3	14	15
Increased glycolysis in HL-60R cells is affected by the p21 peptide targeting cytosolic PCNA .	Increased glycolysis in HL-60R cells is affected by the p21 peptide targeting cytosolic PCNA.	9	14	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	9	10	13	14
p21 inhibits cell cycle progression by binding to and inhibiting the function of cyclin dependent kinases and proliferating cell nuclear antigen .	p21 inhibits cell cycle progression by binding to and inhibiting the function of cyclin dependent kinases and proliferating cell nuclear antigen.	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	0	1	17	21
In addition , p21 inhibits long patch BER by inhibiting PCNA directed stimulation of flap endonuclease 1 ( FEN1 ) , DNA ligase I , and poldelta [ XREF_BIBR ] .	In addition, p21 inhibits long patch BER by inhibiting PCNA directed stimulation of flap endonuclease 1 (FEN1), DNA ligase I, and poldelta [XREF_BIBR].	3	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	PCNA	PCNA	PCNA	3	4	10	11
XREF_BIBR Indeed p21 is a known inhibitor of the short-gap filling activity of proliferating cell nuclear antigen ( PCNA ) during DNA repair , and p21 down-regulation has been shown to play a role in efficient PCNA ubiquitylation after UV irradiation and thus promotes PCNA dependent repair .	XREF_BIBR Indeed p21 is a known inhibitor of the short-gap filling activity of proliferating cell nuclear antigen (PCNA) during DNA repair, and p21 down-regulation has been shown to play a role in efficient PCNA ubiquitylation after UV irradiation and thus promotes PCNA dependent repair.	25	46	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	25	26	44	45
To confirm that the inhibitory effect of the p21 antagonist on DNA synthesis was PCNA dependent , in a separate experiment increasing concentrations of PCNA were added to the cell extract treated with the p21 based peptide to rescue the DNA synthesis .	To confirm that the inhibitory effect of the p21 antagonist on DNA synthesis was PCNA dependent, in a separate experiment increasing concentrations of PCNA were added to the cell extract treated with the p21 based peptide to rescue the DNA synthesis.	22	35	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	p21	p21	p21	PCNA	PCNA	PCNA	34	35	24	25
The cyclin kinase inhibitor p21 and WAF1 is regulated by p53 dependent or independent pathways and inhibits the action of proliferating cell nuclear antigen ( PCNA ) .	The cyclin kinase inhibitor p21 and WAF1 is regulated by p53 dependent or independent pathways and inhibits the action of proliferating cell nuclear antigen (PCNA).	4	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WAF1	WAF1	WAF1	proliferating cell nuclear antigen	proliferating cell nuclear antigen	proliferating cell nuclear antigen	6	7	20	24
Since several in vitro studies demonstrate that CDKN1A ( formerly known as p21 ) down-regulates replication by inhibiting PCNA , and since CDKN1A can retard progression of cells through S phase in vivo , the question arises whether CDKN1A is involved in the S-phase damage sensing pathway .	Since several in vitro studies demonstrate that CDKN1A (formerly known as p21) down-regulates replication by inhibiting PCNA, and since CDKN1A can retard progression of cells through S phase in vivo, the question arises whether CDKN1A is involved in the S-phase damage sensing pathway.	7	19	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CDKN1A	CDKN1A	CDKN1A	PCNA	PCNA	PCNA	7	8	18	19
The difference in net proliferation did not appear to be explainable by cell loss because of apoptosis , and indeed there was a concomitant increase in Myt1 and CDC2 as well as p21 , with a decrease in cyclin E2 ( XREF_FIG ) .	The difference in net proliferation did not appear to be explainable by cell loss because of apoptosis, and indeed there was a concomitant increase in Myt1 and CDC2 as well as p21, with a decrease in cyclin E2 (XREF_FIG).	21	33	was a concomitant increase	Positive_activation_copula_1	Negative_activation	Positive_activation	p21	p21	p21	CDC2	CDC2	CDC2	32	33	28	29
While p21 promotes a G2/M checkpoint by inactivating cdc2 , to establish a G1/S checkpoint p21 inactivates cdk2 .	While p21 promotes a G2/M checkpoint by inactivating cdc2, to establish a G1/S checkpoint p21 inactivates cdk2.	1	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	cdc2	cdc2	cdc2	1	2	8	9
Cdc2 is inhibited simultaneously by three transcriptional targets of p53 , Gadd45 , p21 , and 14-3-3 sigma .	Cdc2 is inhibited simultaneously by three transcriptional targets of p53, Gadd45, p21, and 14-3-3 sigma.	0	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdc2	Cdc2	Cdc2	13	14	0	1
Therefore , a strong G2 cell-cycle arrest is detected in RAD51 overexpressing cells , which occurs through p21 mediated CDK1 inactivation .	Therefore, a strong G2 cell-cycle arrest is detected in RAD51 overexpressing cells, which occurs through p21 mediated CDK1 inactivation.	15	20	mediated	Positive_early_activation	Negative_activation	Positive_activation	p21	p21	p21	CDK1	CDK1	CDK1	17	18	19	20
XREF_BIBR Our results demonstrated that TPX2 silencing led to protein deregulation of CDK1 , cyclin B , securin , separase , and aurora A protein ; by contrast , p21 mRNA and protein were upregulated .	XREF_BIBR Our results demonstrated that TPX2 silencing led to protein deregulation of CDK1, cyclin B, securin, separase, and aurora A protein; by contrast, p21 mRNA and protein were upregulated.	7	30	led	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK1	CDK1	CDK1	29	30	12	13
Inhibition of phosphatidylinositol 3-kinase ( PI3K )/Akt with LY294002 ( LY ) and p38 kinase with SB203580 ( SB ) , respectively , decreased berberine induced p53 and p21 expression and restored cell proliferation and expression of cyclin B1 , cdc2 , cdc25c , and pRb cell cycle progression proteins .	Inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt with LY294002 (LY) and p38 kinase with SB203580 (SB), respectively, decreased berberine induced p53 and p21 expression and restored cell proliferation and expression of cyclin B1, cdc2, cdc25c, and pRb cell cycle progression proteins.	2	41	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	phosphatidylinositol 3-kinase (PI3K)/Akt with LY294002 (LY) and p38 kinase with SB203580 (SB), respectively, decreased berberine induced p53 and p21 expression	p21	cdc2	cdc2	cdc2	28	29	40	41
Targeted knockout CDK2 demonstrates that CDK2 is not necessary for the inhibitory effect of p21 on cell cycle ; and p21 can also inhibit the activity of CDK1 kinase , thus , rendering the arrest of cell cycle in the G2/M stage .	Targeted knockout CDK2 demonstrates that CDK2 is not necessary for the inhibitory effect of p21 on cell cycle; and p21 can also inhibit the activity of CDK1 kinase, thus, rendering the arrest of cell cycle in the G2/M stage.	20	28	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	CDK1	CDK1	CDK1	20	21	27	28
To further delineate the underlying mechanism of EZH2 silencing on modulation of the cell cycle , the expression of p53 and p21 , which upregulate Cdc2 and cyclin B1 , was analyzed with western blotting .	To further delineate the underlying mechanism of EZH2 silencing on modulation of the cell cycle, the expression of p53 and p21, which upregulate Cdc2 and cyclin B1, was analyzed with western blotting.	17	28	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	expression of p53 and p21	p21	Cdc2	Cdc2	cdc2	21	22	25	26
A combination of in vivo and in vitro experiments have identified a large number of kinases including Protein Kinase A , Protein Kinase C , Calcium Calmodulin Kinase , p21 activated Kinase , Cdc2 Kinase , Rho-Kinase , Aurora-B , Polo like Kinase and AKT Kinase which phosphorylate one or more of the 41 sites in vimentin identified to date .	A combination of in vivo and in vitro experiments have identified a large number of kinases including Protein Kinase A, Protein Kinase C, Calcium Calmodulin Kinase, p21 activated Kinase, Cdc2 Kinase, Rho-Kinase, Aurora-B, Polo like Kinase and AKT Kinase which phosphorylate one or more of the 41 sites in vimentin identified to date.	29	34	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	Cdc2	Cdc2	Cdc2	29	30	33	34
R box dependent repression requires p21 and waf1 , and overexpression of p21 and waf1 also represses the cdc2 promoter .	R box dependent repression requires p21 and waf1, and overexpression of p21 and waf1 also represses the cdc2 promoter.	10	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	waf1	overexpression of p21 and waf1	waf1	cdc2	cdc2	cdc2	14	15	18	19
The CDK1 activity was modulated by cytosolic p21 , and G-Rg3 restored the p21 expression level that had been suppressed by HCV core protein ( XREF_FIG ) .	The CDK1 activity was modulated by cytosolic p21, and G-Rg3 restored the p21 expression level that had been suppressed by HCV core protein (XREF_FIG).	1	8	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p21	p21	p21	CDK1	CDK1	CDK1	7	8	1	2
Here we show , using an inducible p53 expression system , that wild-type p53 overexpression in EJ bladder carcinoma cells , which have lost functional p53 , triggers the rapid onset of G1 and G2/M growth arrest associated with p21 up-regulation and repression of mitotic cyclins ( cyclin A and B ) and cdc2 .	Here we show, using an inducible p53 expression system, that wild-type p53 overexpression in EJ bladder carcinoma cells, which have lost functional p53, triggers the rapid onset of G1 and G2/M growth arrest associated with p21 up-regulation and repression of mitotic cyclins (cyclin A and B) and cdc2.	39	54	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p21	p21	p21	cdc2	cdc2	cdc2	39	40	53	54
P53 and p21 were reported to block cells at G2 phase by inhibiting Cdc2 XREF_BIBR .	P53 and p21 were reported to block cells at G2 phase by inhibiting Cdc2 XREF_BIBR.	0	14	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdc2	Cdc2	Cdc2	2	3	13	14
p21 does not interfere with the dephosphorylation of two inhibitory phosphorylation sites on Cdc2 , Thr ( 14 ) and Tyr ( 15 ) , indicating that p21 targets a different event in Cdc2 activation as the well described DNA damage checkpoint pathway involving Chk1 and Cdc25C .	p21 does not interfere with the dephosphorylation of two inhibitory phosphorylation sites on Cdc2, Thr (14) and Tyr (15), indicating that p21 targets a different event in Cdc2 activation as the well described DNA damage checkpoint pathway involving Chk1 and Cdc25C.	27	34	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	Cdc2	Cdc2	Cdc2	27	28	33	34
Elimination of p21 ( Cip1 ) rescues Cdk1 activity and prevents premature mitotic exit in Aurora B deficient cells .	Elimination of p21 (Cip1) rescues Cdk1 activity and prevents premature mitotic exit in Aurora B deficient cells.	0	8	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	Cdk1	Cdk1	Cdk1	2	3	7	8
Cdc2 is inhibited simultaneously by three transcriptional targets of p53 , Gadd45 , p21 , and 14-3-3sigma [ XREF_BIBR ] .	Cdc2 is inhibited simultaneously by three transcriptional targets of p53, Gadd45, p21, and 14-3-3sigma [XREF_BIBR].	0	14	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p21	p21	p21	Cdc2	Cdc2	Cdc2	13	14	0	1
p16INK4A inhibits the G1-S transition by blocking the activity of cyclin dependent kinases 4 and 6 ( CDK4 and CDK6 ) that phosphorylate and inactivate the Rb tumor suppressor [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	p16INK4A inhibits the G1-S transition by blocking the activity of cyclin dependent kinases 4 and 6 (CDK4 and CDK6) that phosphorylate and inactivate the Rb tumor suppressor [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16INK4A	p16INK4A	p16INK4A	CDK4	CDK4	CDK4	0	1	17	18
The fact that p16 ( INK4A ) and flavopiridol negate Cdk4 mediated suppression of yeast cell growth implies that this simple system can be used as a screen for identifying Cdk4 specific antagonists which may mimic p16 ( INK4A ) in the cancer cell cycle .	The fact that p16 (INK4A) and flavopiridol negate Cdk4 mediated suppression of yeast cell growth implies that this simple system can be used as a screen for identifying Cdk4 specific antagonists which may mimic p16 (INK4A) in the cancer cell cycle.	3	12	negate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p16	p16	p16	Cdk4	Cdk4	Cdk4	3	4	10	11
Alterations in p16 INK4A cause an inability to regulate CDK4 and the G1/S transition , leading to an uninhibited cell cycle progression that mimics the Rb mutation phenotype .	Alterations in p16 INK4A cause an inability to regulate CDK4 and the G1/S transition, leading to an uninhibited cell cycle progression that mimics the Rb mutation phenotype.	2	13	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p16 INK4A	p16 INK4A	p16 INK4A	CDK4	CDK4	CDK4	2	4	9	10
This fits with what is known about RB signaling in GBM , which can be deactivated by inactivation of RB1 itself ( through mutation or deletion ) , by activation of CDK4 ( a CDK that inhibits RB1 activity ) through amplification , or by inactivation of the CDK inhibitor p16 , which is encoded by CDKN2A , through deletion or mutation .	This fits with what is known about RB signaling in GBM, which can be deactivated by inactivation of RB1 itself (through mutation or deletion), by activation of CDK4 (a CDK that inhibits RB1 activity) through amplification, or by inactivation of the CDK inhibitor p16, which is encoded by CDKN2A, through deletion or mutation.	29	54	activation	Positive_activation_syntax_1_noun	Negative_activation	Negative_activation	p16	p16	p16	CDK4	CDK4	CDK4	50	51	31	32
Overexpression of its product , p16 , has been shown to block the transition through the G1/S phase of the cell cycle in a pRb dependent fashion by inhibiting the cyclin D dependent kinases cdk4 and cdk6 .	Overexpression of its product, p16, has been shown to block the transition through the G1/S phase of the cell cycle in a pRb dependent fashion by inhibiting the cyclin D dependent kinases cdk4 and cdk6.	3	36	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16	p16	cdk4	cdk4	cdk4	5	6	34	35
The CDKN2A gene is frequently mutated or deleted in melanoma tumors , leading to a release in the inhibition of cyclin dependent kinases CDK4 and CDK6 , causing a progression from G1 to S-phase and increased cell cycle activity and proliferation .	The CDKN2A gene is frequently mutated or deleted in melanoma tumors, leading to a release in the inhibition of cyclin dependent kinases CDK4 and CDK6, causing a progression from G1 to S-phase and increased cell cycle activity and proliferation.	1	27	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDKN2A	CDKN2A	CDKN2A	CDK4	CDK4	CDK4	1	2	23	24
The INK4a gene encodes another type of CDK inhibitor , p16 INK4a , which specifically binds to and inactivates D-type CDKs , CDK4 and CDK6 [ XREF_BIBR ] .	The INK4a gene encodes another type of CDK inhibitor, p16 INK4a, which specifically binds to and inactivates D-type CDKs, CDK4 and CDK6 [XREF_BIBR].	10	26	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p16 INK4a	p16 INK4a	p16 INK4a	CDK4	CDK4	CDK4	10	12	22	23
XREF_BIBR Loss-of-function mutations in CDKN2A cause increased CDK4 activity and a predispostion to malignant melanoma .	XREF_BIBR Loss-of-function mutations in CDKN2A cause increased CDK4 activity and a predispostion to malignant melanoma.	4	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDKN2A	CDKN2A	CDKN2A	CDK4	CDK4	CDK4	4	5	7	8
The CDK inhibitory proteins , p16 ink4a and p15 ink4b ( hereafter p16 and p15 ) , bind to and inhibit CDK4 and 6 , respectively , via their ankyrin repeats [ XREF_BIBR , XREF_BIBR ] .	The CDK inhibitory proteins, p16 ink4a and p15 ink4b (hereafter p16 and p15), bind to and inhibit CDK4 and 6, respectively, via their ankyrin repeats [XREF_BIBR, XREF_BIBR].	5	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p16 ink4a	p16 ink4a	p16 ink4a	CDK4	CDK4	CDK4	5	7	21	22
p16 Ink4a slows cell cycle progression by inhibiting the G1 cyclin dependent kinase Cdk4 XREF_BIBR , and Cdk4 is bound and positively regulated by Pax6 in cortical stem cells .	p16 Ink4a slows cell cycle progression by inhibiting the G1 cyclin dependent kinase Cdk4 XREF_BIBR, and Cdk4 is bound and positively regulated by Pax6 in cortical stem cells.	0	14	slows	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16 Ink4a	p16 Ink4a	p16 Ink4a	Cdk4	Cdk4	Cdk4	0	2	13	14
Low expression of p16 induces high CDK4 activity ( because p16 is a specific CDK4 inhibitor ) , which promotes progression from the G1 phase to the S phase .	Low expression of p16 induces high CDK4 activity (because p16 is a specific CDK4 inhibitor), which promotes progression from the G1 phase to the S phase.	1	7	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p16	expression of p16	p16	CDK4	CDK4	cdk4	3	4	6	7
By inhibiting CDK4 and CDK6 , p16 impedes cell cycle progression from G1 to S phase and acts as a tumor suppressor that has been implicated in the prevention of cancers , notably gliomas [ XREF_BIBR , XREF_BIBR ] .	By inhibiting CDK4 and CDK6, p16 impedes cell cycle progression from G1 to S phase and acts as a tumor suppressor that has been implicated in the prevention of cancers, notably gliomas [XREF_BIBR, XREF_BIBR].	1	17	impedes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p16	p16	p16	CDK4	CDK4	CDK4	6	7	2	3
Bmi-1 negatively controls the expression of the p16 gene ; p16 expression is one of the hallmarks of cellular senescence and inhibits the activity of CDK4 , which is the key enzyme in the G 1 -S transformation during cell division , preventing the cells from entering S phase .	Bmi-1 negatively controls the expression of the p16 gene; p16 expression is one of the hallmarks of cellular senescence and inhibits the activity of CDK4, which is the key enzyme in the G 1 -S transformation during cell division, preventing the cells from entering S phase.	10	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p16	p16 expression	p16	CDK4	CDK4	cdk4	10	11	25	26
In particular , the cell cycle promoting function of cyclin dependent kinase 6 ( CDK6 ) which associates with cyclin D and targets the retinoblastoma protein to allow passage through the G1/S phase restriction point has been shown to have functional relationships with TGFbeta1 and MYC .	In particular, the cell cycle promoting function of cyclin dependent kinase 6 (CDK6) which associates with cyclin D and targets the retinoblastoma protein to allow passage through the G1/S phase restriction point has been shown to have functional relationships with TGFbeta1 and MYC.	7	26	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	14	15	24	26
The p38-MAPK pathway upregulates p16 , which prevents Cdk4- or Cdk6 mediated pRb inactivation .	The p38-MAPK pathway upregulates p16, which prevents Cdk4- or Cdk6 mediated pRb inactivation.	8	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	Cdk6	Cdk6	Cdk6	pRb	pRb	pRb	10	11	12	13
Therefore , the phenotypic differences that exist between p107 -/- p130 -/- and p107 -/- Rb -/- mice and Cdk6 and Ccnd1 double transgenic mice are enhanced chondrocyte proliferation and the lack of chondrocyte apoptosis in p107 -/- p130 -/- and p107 -/- Rb -/- mice .	Therefore, the phenotypic differences that exist between p107 -/- p130 -/- and p107 -/- Rb -/- mice and Cdk6 and Ccnd1 double transgenic mice are enhanced chondrocyte proliferation and the lack of chondrocyte apoptosis in p107 -/- p130 -/- and p107 -/- Rb -/- mice.	4	45	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk6	Cdk6	Cdk6	Rb	Rb	Rb	19	20	43	44
15 CDK6 forms a complex with cyclin-D and targets the retinoblastoma protein , allowing passage through the G 1 / S phase restriction point .	15 CDK6 forms a complex with cyclin-D and targets the retinoblastoma protein, allowing passage through the G 1 / S phase restriction point.	0	12	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	1	2	10	12
As a second barrier to proliferation , p16 Ink4a prevents CDK4- and CDK6 mediated inactivation of RB to block cell cycle progression ( XREF_FIG ) .	As a second barrier to proliferation, p16 Ink4a prevents CDK4- and CDK6 mediated inactivation of RB to block cell cycle progression (XREF_FIG).	12	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	RB	RB	RB	12	13	16	17
CDK6 activates cyclin D1 and the cyclin D1 and CDK6 complex activates pRB and E2F which controls the cell cycle progression from the mid-G1 to S phase .	CDK6 activates cyclin D1 and the cyclin D1 and CDK6 complex activates pRB and E2F which controls the cell cycle progression from the mid-G1 to S phase.	0	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	pRB	pRB	pRB	0	1	12	13
Overexpression of CDK6 and Cyclin D1 reversed miR-218-mediated inhibition of pRB and E2F1 signaling and attenuated the miR-218-induced cell cycle arrest .	Overexpression of CDK6 and Cyclin D1 reversed miR-218-mediated inhibition of pRB and E2F1 signaling and attenuated the miR-218-induced cell cycle arrest.	0	13	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	Overexpression of CDK6	cdk6	pRB	pRB	prb	2	3	10	11
CDK6 mediated G1/S transition requires its kinase substrate RB ; thus , RB gene status is the primary determinant of the tumor response to the G1 kinase inhibition XREF_BIBR , XREF_BIBR .	CDK6 mediated G1/S transition requires its kinase substrate RB; thus, RB gene status is the primary determinant of the tumor response to the G1 kinase inhibition XREF_BIBR, XREF_BIBR.	0	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	RB	RB	RB	0	1	8	9
In addition , we show EBNA3C coupled with Cyclin D1 and CDK6 complex significantly abolishes the growth suppressive function of pRb in Saos-2 cells .	In addition, we show EBNA3C coupled with Cyclin D1 and CDK6 complex significantly abolishes the growth suppressive function of pRb in Saos-2 cells.	11	23	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	pRb	pRb	pRb	11	12	20	21
Neither Rb1 nor Runx1 deletion restored T-leukemogenesis in the K43M background ( XREF_SUPPLEMENTARY ) , despite efficient deletion of the Runx1 fl/fl allele by the ICN-CRE retrovirus in a Cdk6 WT background ( XREF_SUPPLEMENTARY ) .	Neither Rb1 nor Runx1 deletion restored T-leukemogenesis in the K43M background (XREF_SUPPLEMENTARY), despite efficient deletion of the Runx1 fl/fl allele by the ICN-CRE retrovirus in a Cdk6 WT background (XREF_SUPPLEMENTARY).	0	31	restored	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Cdk6	Cdk6	Cdk6	Rb1	Rb1	Rb1	29	30	1	2
Consequently , KSHV infected cells can avoid Rb induced cell cycle arrest by the v , cyclin , and CDK6 complex XREF_BIBR , XREF_BIBR .	Consequently, KSHV infected cells can avoid Rb induced cell cycle arrest by the v, cyclin, and CDK6 complex XREF_BIBR, XREF_BIBR.	6	21	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	Rb	Rb	Rb	19	20	7	8
Cdk5 modulates the retinoblastoma protein ( Rb )/E2F pathway by phosphorylating Rb [ XREF_BIBR ] , thereby promoting cancer cell proliferation as in MTC [ XREF_BIBR ] .	Cdk5 modulates the retinoblastoma protein (Rb)/E2F pathway by phosphorylating Rb [XREF_BIBR], thereby promoting cancer cell proliferation as in MTC [XREF_BIBR].	0	5	modulates	Positive_activation_syntax_3a_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	0	1	3	5
Thus , Cdk5 may contribute meaningfully to the progression of some forms of MTC by inactivating Rb and enabling the expression of the E2F target genes , Cdk2 and Cyclin A ( XREF_FIG ) .	Thus, Cdk5 may contribute meaningfully to the progression of some forms of MTC by inactivating Rb and enabling the expression of the E2F target genes, Cdk2 and Cyclin A (XREF_FIG).	2	17	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	Rb	Rb	Rb	2	3	16	17
Indeed , inhibiting Cdk5 activity in mouse and human MTC cells by treatment with CP681301 decreased phospho-Ser807/811 Rb in a dose dependent manner and stopped cell growth ( XREF_FIG ; XREF_SUPPLEMENTARY ; XREF_FIG ; XREF_SUPPLEMENTARY ) .	Indeed, inhibiting Cdk5 activity in mouse and human MTC cells by treatment with CP681301 decreased phospho-Ser807/811 Rb in a dose dependent manner and stopped cell growth (XREF_FIG; XREF_SUPPLEMENTARY; XREF_FIG; XREF_SUPPLEMENTARY).	3	18	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	Rb	Rb	Rb	3	4	17	18
However , blocking all CDK activity by pan-CDK inhibitor , Olomoucine , effectively blocked HIV and MDM induced formation of ppRb serine795 at 4 hours ( XREF_FIG ) , suggesting that a member of the CDK family other than CDK5 targets pRb at serine795 .	However, blocking all CDK activity by pan-CDK inhibitor, Olomoucine, effectively blocked HIV and MDM induced formation of ppRb serine795 at 4 hours (XREF_FIG), suggesting that a member of the CDK family other than CDK5 targets pRb at serine795.	37	43	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	CDK5	CDK5	CDK5	pRb	pRb	pRb	39	40	41	42
To determine whether CDK5 targets pRb at serine795 , which is in close vicinity of serine807/811 site , we examined pRb phosphorylation at this site in HIV-MDM- treated neurons , pre-incubated with Roscovitine .	To determine whether CDK5 targets pRb at serine795, which is in close vicinity of serine807/811 site, we examined pRb phosphorylation at this site in HIV-MDM- treated neurons, pre-incubated with Roscovitine.	1	7	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	CDK5	CDK5	CDK5	pRb	pRb	pRb	3	4	5	6
Nevertheless , Cdk5 did not modulate Notch or Rb1 in Cdk5 knockdown cells .	Nevertheless, Cdk5 did not modulate Notch or Rb1 in Cdk5 knockdown cells.	2	9	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	Rb1	Rb1	Rb1	2	3	8	9
The discovery by Firestein and colleagues XREF_BIBR showing significant RB1 and CDK8 copy number gains in colorectal cancers is especially intriguing given the evidence that CDK8 is an important modulator of both beta-catenin and E2F1 .	The discovery by Firestein and colleagues XREF_BIBR showing significant RB1 and CDK8 copy number gains in colorectal cancers is especially intriguing given the evidence that CDK8 is an important modulator of both beta-catenin and E2F1.	25	35	is an important modulator	Positive_activation_copula_1	Negative_activation	Positive_activation	CDK8	CDK8	CDK8	E2F1	E2F1	E2F1	25	26	34	35
CDK8 and E2F1 both present at the MYC promoter , CDK8 suppresses the E2F1 dependent inhibition of beta-catenin-mediated transcription [ XREF_BIBR ] .	CDK8 and E2F1 both present at the MYC promoter, CDK8 suppresses the E2F1 dependent inhibition of beta-catenin-mediated transcription [XREF_BIBR].	0	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK8	CDK8	CDK8	E2F1	E2F1	E2F1	0	1	13	14
CDK8 has also been reported to attenuate E2F1 inhibition of beta-catenin [ XREF_BIBR ] .	CDK8 has also been reported to attenuate E2F1 inhibition of beta-catenin [XREF_BIBR].	0	8	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK8	CDK8	CDK8	E2F1	E2F1	E2F1	0	1	7	8
Subsequent biochemical analysis revealed that CDK8 kinase activity could suppress the inhibitory effect of E2F1 on beta-catenin-dependent transcription .	Subsequent biochemical analysis revealed that CDK8 kinase activity could suppress the inhibitory effect of E2F1 on beta-catenin-dependent transcription.	5	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK8	CDK8	CDK8	E2F1	E2F1	E2F1	5	6	14	15
In a consequent genetic screen for upstream regulators of E2F1 , CDK8 was identified as a potent E2F1 suppressor , and biochemical analyses revealed that CDK8 kinase activity was required to suppress the inhibitory effect of E2F1 on beta-catenin-dependent transcription .	In a consequent genetic screen for upstream regulators of E2F1, CDK8 was identified as a potent E2F1 suppressor, and biochemical analyses revealed that CDK8 kinase activity was required to suppress the inhibitory effect of E2F1 on beta-catenin-dependent transcription.	25	37	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK8	CDK8	CDK8	E2F1	E2F1	E2F1	25	26	36	37
Moreover , expression of CDK8 , but not CDK8KD , suppressed the inhibitory effect of E2F1 on the pTopFLASH reporter ( XREF_FIG ) .	Moreover, expression of CDK8, but not CDK8KD, suppressed the inhibitory effect of E2F1 on the pTopFLASH reporter (XREF_FIG).	2	16	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK8	expression of CDK8	cdk8	E2F1	E2F1	e2f1	4	5	15	16
p16INK4a , a cell cycle inhibitor that inhibits cyclin dependent kinase 4 ( cdk4 ) and cdk6 , has been found as the tumor suppressor gene and is frequently deleted , methylated or mutated in many malignancies .	p16INK4a, a cell cycle inhibitor that inhibits cyclin dependent kinase 4 (cdk4) and cdk6, has been found as the tumor suppressor gene and is frequently deleted, methylated or mutated in many malignancies.	0	29	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	p16INK4a	p16INK4a	p16INK4a	cdk6	cdk6	cdk6	0	1	16	17
On the contrary , knockdown of NgBR in Bel/5FU cells increased p53 and p21 protein levels and consequently decreased CDK6 , CyclinD1 , and phosphorylated Rb protein levels as compared to the control Bel/5FU NS cells .	On the contrary, knockdown of NgBR in Bel/5FU cells increased p53 and p21 protein levels and consequently decreased CDK6, CyclinD1, and phosphorylated Rb protein levels as compared to the control Bel/5FU NS cells.	6	21	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	NgBR in Bel/5FU cells increased p53 and p21 protein levels	p21	CDK6	CDK6	cdk6	13	14	19	20
p21 dependent inhibition of cell cycle progression from G 1 to S phase is mediated by inhibition of Cdk4/( and Cdk6 )/D-type cyclin complexes , and Cdk2 and cyclin E ( and cyclin A ) complexes XREF_BIBR , XREF_BIBR .	p21 dependent inhibition of cell cycle progression from G 1 to S phase is mediated by inhibition of Cdk4/(and Cdk6)/D-type cyclin complexes, and Cdk2 and cyclin E (and cyclin A) complexes XREF_BIBR, XREF_BIBR.	0	24	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Cdk6	Cdk6)/D-type cyclin complexes	cdk6	p21	p21	p21	20	21	0	1
We found that CDK6 could significantly increase p21 promoter activity .	We found that CDK6 could significantly increase p21 promoter activity.	3	9	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	p21	p21	p21	3	4	7	8
We observed that knocking down expression of CDK4 decreased expression of CCND1 , CDK6 , and E2F1 yet upregulated p21 .	We observed that knocking down expression of CDK4 decreased expression of CCND1, CDK6, and E2F1 yet upregulated p21.	9	20	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	expression of CCND1, CDK6	cdk6	p21	p21	p21	13	14	19	20
To study the molecular mechanism of CDK6 regulation of p21 expression , a luciferase reporter assay was performed to analyze whether CDK6 enhanced the p21 promoter activity .	To study the molecular mechanism of CDK6 regulation of p21 expression, a luciferase reporter assay was performed to analyze whether CDK6 enhanced the p21 promoter activity.	21	26	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK6	CDK6	CDK6	p21	p21	p21	21	22	24	25
In addition to mediating p53 dependent G1 arrest , the p21 protein has been reported to inhibit progression through the S phase to the G2 phase and the G2/M transition by suppressing the activities of the CDK1/2-cyclin A and CDK1-cyclin B1 complexes , respectively , in a p53 independent manner XREF_BIBR .	In addition to mediating p53 dependent G1 arrest, the p21 protein has been reported to inhibit progression through the S phase to the G2 phase and the G2/M transition by suppressing the activities of the CDK1/2-cyclin A and CDK1-cyclin B1 complexes, respectively, in a p53 independent manner XREF_BIBR.	10	41	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p21	p21	p21	B1	B1	B1	10	11	40	41
Thus , full-length p21 Cip1/Waf1/Sic1 does not cause cyclin B1 to accumulate in the nucleus by inhibiting cyclin A/CDK kinase activity .	Thus, full-length p21 Cip1/Waf1/Sic1 does not cause cyclin B1 to accumulate in the nucleus by inhibiting cyclin A/CDK kinase activity.	3	10	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p21	p21	p21	B1	B1	B1	3	4	9	10
CDKN2B is a tumor suppressor gene that encodes both p15 INK4B , which modulates CDK4 and CDK6 , and prevents cyclin D activation .	CDKN2B is a tumor suppressor gene that encodes both p15 INK4B, which modulates CDK4 and CDK6, and prevents cyclin D activation.	9	16	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p15 INK4B	p15 INK4B	p15 INK4B	CDK4	CDK4	CDK4	9	11	14	15
Additionally , myricetin treatment resulted in the up-regulation of Thr14 and Tyr15 phosphorylated ( inactive ) Cdc2 and p27 , and the down-regulation of CDK7 kinase protein , as well as CDK7 mediated Thr161 phosphorylated ( active ) Cdc2 .	Additionally, myricetin treatment resulted in the up-regulation of Thr14 and Tyr15 phosphorylated (inactive) Cdc2 and p27, and the down-regulation of CDK7 kinase protein, as well as CDK7 mediated Thr161 phosphorylated (active) Cdc2.	12	39	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	phosphorylated (inactive) Cdc2 and p27, and the down-regulation of CDK7 kinase protein, as well as CDK7	p27	Cdc2	Cdc2	cdc2	18	19	38	39
Together these results suggest that the carboxyl-terminal domain of p27 may activate CDC2 kinase activity in vivo during G2/M and that this effect may be regulated by serine/threonine phosphorylation .	Together these results suggest that the carboxyl-terminal domain of p27 may activate CDC2 kinase activity in vivo during G2/M and that this effect may be regulated by serine/threonine phosphorylation.	7	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p27	p27	p27	CDC2	CDC2	CDC2	9	10	12	13
To determine if knockdown of Cdk5 is sufficient to inhibit the proliferative capacity of Cdk5r1 , we used siRNA mediated Cdk5 knockdown in the INS-1 832/13 beta-cell line .	To determine if knockdown of Cdk5 is sufficient to inhibit the proliferative capacity of Cdk5r1, we used siRNA mediated Cdk5 knockdown in the INS-1 832/13 beta-cell line.	3	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	Cdk5r1	Cdk5r1	Cdk5r1	5	6	14	15
CDK5RAP2 encodes the centrosomal protein CDK5RAP2 , which was originally identified in a yeast-two-hybrid screen of rat brain libraries to interact with the neuronal Cdk5 activator CDK5R1 .	CDK5RAP2 encodes the centrosomal protein CDK5RAP2, which was originally identified in a yeast-two-hybrid screen of rat brain libraries to interact with the neuronal Cdk5 activator CDK5R1.	20	27	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	CDK5R1	CDK5R1	CDK5R1	24	25	26	27
Here we delineate a complex consisting of the AMPK related kinase SIK2 , the CDK5 activator CDK5R1 and p35 , and the E3 ligase PJA2 essential for beta cell functional compensation .	Here we delineate a complex consisting of the AMPK related kinase SIK2, the CDK5 activator CDK5R1 and p35, and the E3 ligase PJA2 essential for beta cell functional compensation.	5	17	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	CDK5	CDK5	CDK5	CDK5R1	CDK5R1	CDK5R1	14	15	16	17
In short-term animals , CDK5 knockdown showed reduction of CDK5 , reversed Tau aggregation , and improved spatial memory compared to scrambled treated old 3xTg-AD mice .	In short-term animals, CDK5 knockdown showed reduction of CDK5, reversed Tau aggregation, and improved spatial memory compared to scrambled treated old 3xTg-AD mice.	4	13	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CDK5	CDK5	CDK5	Tau	Tau	Tau	4	5	12	13
In contrast , in cultured cells where there is endogenous protein kinase ( s ) phosphorylating Ser202 strongly , Cdk5 can no longer target the Thr205 of tau with Ser202 phosphorylation .	In contrast, in cultured cells where there is endogenous protein kinase (s) phosphorylating Ser202 strongly, Cdk5 can no longer target the Thr205 of tau with Ser202 phosphorylation.	19	28	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	tau	tau	tau	19	20	27	28
Detailed interaction studies further revealed that the AR NH ( 2 )-terminal domain interacting with CAK was essential for the CAK induced AR transactivation .	Detailed interaction studies further revealed that the AR NH (2)-terminal domain interacting with CAK was essential for the CAK induced AR transactivation.	19	23	induced	Positive_early_activation	Negative_activation	Positive_activation	CAK	CAK	CAK	AR	AR	AR	20	21	22	23
XREF_BIBR AR interacts strongly with XPB and XPD , and weakly with CDK7 , which eventually enhances AR transactivation by phosphorylating AR at S515 .	XREF_BIBR AR interacts strongly with XPB and XPD, and weakly with CDK7, which eventually enhances AR transactivation by phosphorylating AR at S515.	10	24	enhances	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	CDK7	CDK7	cdk7	AR	phosphorylating AR at S515	ar	12	13	21	22
Over-expression of cdk7 in AR negative cell lines enhanced AR activity in transient assays , thus implicating the alterations in the general transcription machinery as a putative means to alter AR activity .	Over-expression of cdk7 in AR negative cell lines enhanced AR activity in transient assays, thus implicating the alterations in the general transcription machinery as a putative means to alter AR activity.	0	10	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cdk7	Over-expression of cdk7	cdk7	AR	AR	ar	2	3	9	10
This effect occurs through p16 related promotion of the MDM2 mRNA turnover via the p16INK4A downstream effectors miR-141 and miR-146b-5p , which bind specific sites at the 3 ' untranslated region of the MDM2 mRNA .	This effect occurs through p16 related promotion of the MDM2 mRNA turnover via the p16INK4A downstream effectors miR-141 and miR-146b-5p, which bind specific sites at the 3 ' untranslated region of the MDM2 mRNA.	4	11	promotion	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	p16	p16	p16	MDM2	MDM2	MDM2	4	5	9	10
XREF_BIBR Since p16 INK4a negatively regulates CDK4 and p14 ARF ( p19 ARF in mice ) inhibits MDM2 , blocking rapid ubiquitin mediated decay of p53 , simultaneous inactivation of both genes by a homozygous deletion dysregulates both the RB1 pathway and the p53 pathway .	XREF_BIBR Since p16 INK4a negatively regulates CDK4 and p14 ARF (p19 ARF in mice) inhibits MDM2, blocking rapid ubiquitin mediated decay of p53, simultaneous inactivation of both genes by a homozygous deletion dysregulates both the RB1 pathway and the p53 pathway.	2	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p16 INK4a	p16 INK4a	p16 INK4a	MDM2	MDM2	MDM2	2	4	17	18
Ectopic expression of p16 leads to G1 arrest in NP-9 cells by redistributing p21 and p27 CKIs and inhibiting cyclin dependent kinase CDK2 activity .	Ectopic expression of p16 leads to G1 arrest in NP-9 cells by redistributing p21 and p27 CKIs and inhibiting cyclin dependent kinase CDK2 activity.	1	23	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p16	expression of p16	p16	CDK2	CDK2	cdk2	3	4	22	23
Silencing p16 did neither rescue G1-S arrest nor inhibit Cdk2 down-regulation ( XREF_SUPPLEMENTARY ) .	Silencing p16 did neither rescue G1-S arrest nor inhibit Cdk2 down-regulation (XREF_SUPPLEMENTARY).	0	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p16	p16	p16	Cdk2	Cdk2	Cdk2	1	2	9	10
We have identified a specific phosphorylation site on mammalian Pak1 , T212 , which is targeted by the neuronal p35 and Cdk5 kinase .	We have identified a specific phosphorylation site on mammalian Pak1, T212, which is targeted by the neuronal p35 and Cdk5 kinase.	2	22	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	Pak1	Pak1	Pak1	21	22	9	10
It has been suggested that Cdk5 allows PAK1 to switch from an active to an inactive state and thereby mediate a rapid and dynamic regulation of the actin cytoskeleton , thus facilitating dendritic spine formation .	It has been suggested that Cdk5 allows PAK1 to switch from an active to an inactive state and thereby mediate a rapid and dynamic regulation of the actin cytoskeleton, thus facilitating dendritic spine formation.	5	19	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	PAK1	PAK1	PAK1	5	6	7	8
To perform these diverse functions , Cdk5 displays extensive crosstalks with various regulatory pathways including mitogen activated protein kinase-receptor tyrosine kinases , c-Jun N-terminal kinase 3 , phosphoinositol-3-kinase and protein kinase B and glycogen synthase kinase 3beta signaling pathways .	To perform these diverse functions, Cdk5 displays extensive crosstalks with various regulatory pathways including mitogen activated protein kinase-receptor tyrosine kinases, c-Jun N-terminal kinase 3, phosphoinositol-3-kinase and protein kinase B and glycogen synthase kinase 3beta signaling pathways.	6	26	activated	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Cdk5	Cdk5	Cdk5	c-Jun N-terminal kinase 3	c-Jun N-terminal kinase 3	c-Jun N-terminal kinase 3	6	7	22	26
Alternatively , CDK7 mediated activation of POLR2A occurs in a tumor cell context dependent manner .	Alternatively, CDK7 mediated activation of POLR2A occurs in a tumor cell context dependent manner.	2	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	CDK7	CDK7	CDK7	POLR2A	POLR2A	POLR2A	2	3	6	7
Subsequent studies by Tang et al showed that Cdk5 phosphorylation induces MEF2 destabilization by greatly enhancing caspase dependent cleavage of MEF2A and D.	Subsequent studies by Tang et al showed that Cdk5 phosphorylation induces MEF2 destabilization by greatly enhancing caspase dependent cleavage of MEF2A and D.	8	22	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cdk5	Cdk5 phosphorylation	cdk5	MEF2A	MEF2A	mef2a	8	9	20	21
We found that although MAML1 , p300 and CDK8 enhanced Notch activity when co-expressed alone with Notch , they more potently enhanced Notch transcription in each other ' s presence compared to Notch alone ( XREF_FIG ) suggesting a synergy ( p < 0.0001 ) .	We found that although MAML1, p300 and CDK8 enhanced Notch activity when co-expressed alone with Notch, they more potently enhanced Notch transcription in each other 's presence compared to Notch alone (XREF_FIG) suggesting a synergy (p < 0.0001).	4	11	enhanced	Positive_activation_token_1_verb	Negative_activation	Positive_activation	CDK8	CDK8	CDK8	Notch	Notch	Notch	8	9	10	11
This down-regulation of c-FLIP alone allowed TRAIL to induce caspase-8 activation ( XREF_FIG ) .	This down-regulation of c-FLIP alone allowed TRAIL to induce caspase-8 activation (XREF_FIG).	1	10	allowed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	9	10
c-FLIP modulates caspase 8 and , by inhibiting its activation due to the lack of connection with the receiver , there is a block to the FAS activation of apoptosis by its extrinsic pathway .	c-FLIP modulates caspase 8 and, by inhibiting its activation due to the lack of connection with the receiver, there is a block to the FAS activation of apoptosis by its extrinsic pathway.	0	7	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	0	1	2	4
Caspase-8 activity is detectable in DC and is increased by IL-4 induction of c-FLIP .	Caspase-8 activity is detectable in DC and is increased by IL-4 induction of c-FLIP.	0	14	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	Caspase-8	Caspase-8	Caspase-8	13	14	0	1
c-FLIP may contribute to RAF inhibitor resistance by preventing caspase 8 activation induced by RAF inhibitor .	c-FLIP may contribute to RAF inhibitor resistance by preventing caspase 8 activation induced by RAF inhibitor.	0	11	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	0	1	9	11
The cellular FLICE-inhibitory protein ( c-FLIP ) , which is vastly homologous to caspase 8 but lacks enzymatic activity , can also associate with the DISC , blocking activation of caspase 8 through competition for binding sites .	The cellular FLICE-inhibitory protein (c-FLIP), which is vastly homologous to caspase 8 but lacks enzymatic activity, can also associate with the DISC, blocking activation of caspase 8 through competition for binding sites.	1	32	blocking	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	cellular FLICE-inhibitory protein	cellular FLICE-inhibitory protein	cellular FLICE-inhibitory protein	caspase 8	caspase 8	caspase 8	1	4	30	32
Alternatively , caspase 8 activation caused by the down-regulation of c-FLIP at the transcriptional or posttranslational levels underlies the mode of action of some TRAIL sensitizers [ XREF_BIBR ] .	Alternatively, caspase 8 activation caused by the down-regulation of c-FLIP at the transcriptional or posttranslational levels underlies the mode of action of some TRAIL sensitizers [XREF_BIBR].	2	11	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	10	11	2	4
XREF_BIBR Alternative antiapoptotic approaches may prove more fruitful , such as using the c-FLIP short-form which does not activate caspase 8 , XREF_BIBR introducing the viral caspase inhibitor CrmA XREF_BIBR or by using siRNA against the Fas receptor .	XREF_BIBR Alternative antiapoptotic approaches may prove more fruitful, such as using the c-FLIP short-form which does not activate caspase 8, XREF_BIBR introducing the viral caspase inhibitor CrmA XREF_BIBR or by using siRNA against the Fas receptor.	13	37	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	13	14	19	21
Cycloheximide is the protein synthesis inhibitor activates the caspase-8 by inhibiting the c-Flip , a physiological inhibitor of caspase-8 .	Cycloheximide is the protein synthesis inhibitor activates the caspase-8 by inhibiting the c-Flip, a physiological inhibitor of caspase-8.	6	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-Flip	c-Flip	c-Flip	caspase-8	caspase-8	caspase-8	12	13	8	9
Coactivation of CD21 and BCR in human tonsillar B cells decreased Fas expression upon CD40 stimulus , increase the levels of anti-apoptotic Flip and Bcl-2 ( but not BCL-xl ) and reduced caspase-8 cleavage when compared to BCR activation alone However activation of mouse B cells by recombinant antigen fused with C3d 3 resulted in only an increase in expression level of FLIP but not Bcl-2 .	Coactivation of CD21 and BCR in human tonsillar B cells decreased Fas expression upon CD40 stimulus, increase the levels of anti-apoptotic Flip and Bcl-2 (but not BCL-xl) and reduced caspase-8 cleavage when compared to BCR activation alone However activation of mouse B cells by recombinant antigen fused with C3d 3 resulted in only an increase in expression level of FLIP but not Bcl-2.	2	33	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Flip	CD21 and BCR in human tonsillar B cells decreased Fas expression upon CD40 stimulus, increase the levels of anti-apoptotic Flip	flip	caspase-8	caspase-8	caspase-8	22	23	32	33
Caspase-1 and -2 can non catalytically activate NF-kappaB , caspase-8 can be activated by c-FLIP L , a catalytically inactive caspase , and functional caspase-12 exists in two catalytically inactive forms ( for review see ) .	Caspase-1 and -2 can non catalytically activate NF-kappaB, caspase-8 can be activated by c-FLIP L, a catalytically inactive caspase, and functional caspase-12 exists in two catalytically inactive forms (for review see).	9	15	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	14	15	9	10
Low levels of cFLIP allow caspase-8 homodimers to form , and apoptosis ensues [ XREF_BIBR ] .	Low levels of cFLIP allow caspase-8 homodimers to form, and apoptosis ensues [XREF_BIBR].	1	6	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	levels of cFLIP	cflip	caspase-8	caspase-8	caspase-8	3	4	5	6
Knockdown of the c-FLIP gene triggers spontaneous caspase-8 and -9-dependent apoptosis in MCF-7 breast cancer cells .	Knockdown of the c-FLIP gene triggers spontaneous caspase-8 and -9-dependent apoptosis in MCF-7 breast cancer cells.	3	15	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	7	8
Many researches have addressed this issue and put forward several possible mechanisms including the non functional binding to death decoy receptor 1 or 2 ( DcR1 , 2 ) , reduced Caspase expression , dysfunctions of death receptor 4 ( DR4 ) and death receptor 5 ( DR5 ) or overexpression of anti-apoptotic proteins cellular FLICE inhibitory protein ( cFLIP ) , Mcl-1 , Bcl2 , etc [ XREF_BIBR , XREF_BIBR ] .	Many researches have addressed this issue and put forward several possible mechanisms including the non functional binding to death decoy receptor 1 or 2 (DcR1, 2), reduced Caspase expression, dysfunctions of death receptor 4 (DR4) and death receptor 5 (DR5) or overexpression of anti-apoptotic proteins cellular FLICE inhibitory protein (cFLIP), Mcl-1, Bcl2, etc [XREF_BIBR, XREF_BIBR].	30	60	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	FLICE	FLICE	FLICE	59	60	55	56
Upregulation of c-FLIP ( L ) protein , an inhibitor of apoptosis induced by tumor necrosis factor related apoptosis inducing ligand ( TRAIL ) , correspond with inhibition of ATRA induced ( autocrine TRAIL mediated ) caspase-8 activation and apoptosis .	Upregulation of c-FLIP (L) protein, an inhibitor of apoptosis induced by tumor necrosis factor related apoptosis inducing ligand (TRAIL), correspond with inhibition of ATRA induced (autocrine TRAIL mediated) caspase-8 activation and apoptosis.	0	37	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	36	37
RIP-1 or c-FLIP L siRNA markedly induced cell apoptosis and enhanced caspase-8 and caspase-3 activities .	RIP-1 or c-FLIP L siRNA markedly induced cell apoptosis and enhanced caspase-8 and caspase-3 activities.	2	14	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	11	12
Increased expression of cFLIP may cause the caspase-8 signal transduction pathway to be inhibited and stop the cascade reaction such that apoptosis of CC cells would be inhibited .	Increased expression of cFLIP may cause the caspase-8 signal transduction pathway to be inhibited and stop the cascade reaction such that apoptosis of CC cells would be inhibited.	1	10	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	expression of cFLIP	cflip	caspase-8	caspase-8	caspase-8	3	4	7	8
c-FLIP S and c-FLIP R both inhibit death signaling at the DISC , by inhibiting caspase-8 activation .	c-FLIP S and c-FLIP R both inhibit death signaling at the DISC, by inhibiting caspase-8 activation.	0	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	15	16
The lower level of caspase-8 activity we observed in DC grown with only GM-CSF likely reflected the reduced levels of c-FLIP , as we have observed that deletion of c-FLIP in T cells or mouse embryonic fibroblasts results in loss of active caspase-8 [ XREF_BIBR ] , whereas increased c-FLIP augments caspase-8 activity [ XREF_BIBR ] .	The lower level of caspase-8 activity we observed in DC grown with only GM-CSF likely reflected the reduced levels of c-FLIP, as we have observed that deletion of c-FLIP in T cells or mouse embryonic fibroblasts results in loss of active caspase-8 [XREF_BIBR], whereas increased c-FLIP augments caspase-8 activity [XREF_BIBR].	48	52	augments	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	49	50	51	52
We supposed that NAE inhibition could lead to decreased participation of c-FLIP in the DISC , thereby promoting caspase-8 processing .	We supposed that NAE inhibition could lead to decreased participation of c-FLIP in the DISC, thereby promoting caspase-8 processing.	9	19	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	11	12	18	19
However , it has also been shown that cFLIP mediates activation of full-length caspase-8 at the DISC , which in turn results in caspase-8-induced cleavage of cFLIP .	However, it has also been shown that cFLIP mediates activation of full-length caspase-8 at the DISC, which in turn results in caspase-8-induced cleavage of cFLIP.	8	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	8	9	13	14
However , at physiological expression levels , c-FLIP L appears to support the enzymatic activity of caspase-8 in the heterodimer complex with caspase-8 .	However, at physiological expression levels, c-FLIP L appears to support the enzymatic activity of caspase-8 in the heterodimer complex with caspase-8.	7	17	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	7	8	16	17
This TRAIL induced pro apoptotic cross talk is mediated by SHP protein tyrosine phosphatase ( s ) and the non receptor tyrosine kinase c-Src , depends upon TrkAIII de-phosphorylation , and TrkAIII binding and sequester of cFLIP , which increases the caspase-8 to cFLIP ratio at activated death receptors , inducing delayed caspase dependent apoptosis .	This TRAIL induced pro apoptotic cross talk is mediated by SHP protein tyrosine phosphatase (s) and the non receptor tyrosine kinase c-Src, depends upon TrkAIII de-phosphorylation, and TrkAIII binding and sequester of cFLIP, which increases the caspase-8 to cFLIP ratio at activated death receptors, inducing delayed caspase dependent apoptosis.	34	42	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	36	37	41	42
Hence , the synergistic effect of CDK9 inhibition and TRAIL is due to a dual mechanism : downregulation of cFlip enables caspase-8 activation at the DISC and downregulation of Mcl-1 facilitates activation of the mitochondrial apoptosis pathway for enhanced caspase-9 and , ultimately , caspase-3 activation .	Hence, the synergistic effect of CDK9 inhibition and TRAIL is due to a dual mechanism : downregulation of cFlip enables caspase-8 activation at the DISC and downregulation of Mcl-1 facilitates activation of the mitochondrial apoptosis pathway for enhanced caspase-9 and, ultimately, caspase-3 activation.	17	22	enables	Positive_activation_token_1_verb	Negative_activation	Positive_activation	cFlip	cFlip	cFlip	caspase-8	caspase-8	caspase-8	19	20	21	22
echanisms include overexpression of the inhibitor of caspase-8 activation c-FLIP , hypermethylation of caspase-8 , reduced cell surface TRAIL receptor expression , overexpression of anti-apoptotic Bcl-2 family members such as Bcl-XL or Mcl-1 , loss of pro apoptotic Bax , and overexpression of the inhibitor of apoptosis ( IAP ) family members .	echanisms include overexpression of the inhibitor of caspase-8 activation c-FLIP, hypermethylation of caspase-8, reduced cell surface TRAIL receptor expression, overexpression of anti-apoptotic Bcl-2 family members such as Bcl-XL or Mcl-1, loss of pro apoptotic Bax, and overexpression of the inhibitor of apoptosis (IAP) family members.	5	11	activation	Positive_activation_token_1_noun	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	9	10	7	8
Cellular FLICE-inhibitory protein ( c-FLIP ) is an inhibitor of caspase-8 and is required for macrophage survival .	Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor of caspase-8 and is required for macrophage survival.	0	11	is an inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Cellular FLICE-inhibitory protein	Cellular FLICE-inhibitory protein	Cellular FLICE-inhibitory protein	caspase-8	caspase-8	caspase-8	0	3	10	11
Importantly , down-regulation of c-FLIP serves to further enhance caspase-8 activation , which sustains the ER-stress/JNK/CHOP/DR5 amplifying loop .	Importantly, down-regulation of c-FLIP serves to further enhance caspase-8 activation, which sustains the ER-stress/JNK/CHOP/DR5 amplifying loop.	2	10	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	4	5	9	10
As already reported in other experimental models , XREF_BIBR , XREF_BIBR we verified that c-FLIP ablation in MEFs enhanced the basal caspase-8 activity ( XREF_FIG ) , which was restored by both the specific caspase-8 inhibitor zIETD and c-FLIP L re-introduction ( XREF_FIG ) .	As already reported in other experimental models, XREF_BIBR, XREF_BIBR we verified that c-FLIP ablation in MEFs enhanced the basal caspase-8 activity (XREF_FIG), which was restored by both the specific caspase-8 inhibitor zIETD and c-FLIP L re-introduction (XREF_FIG).	21	40	restored	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	38	39	21	22
Sustained JNK activation may promote TNFalpha induced apoptosis via JNK mediated activation of E3 ubiquitin ligase Itch that ubiquitinates cFLIP , leading to its proteasomal degradation and , subsequently , enhanced caspase-8 activation .	Sustained JNK activation may promote TNFalpha induced apoptosis via JNK mediated activation of E3 ubiquitin ligase Itch that ubiquitinates cFLIP, leading to its proteasomal degradation and, subsequently, enhanced caspase-8 activation.	1	32	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	JNK activation may promote TNFalpha induced apoptosis via JNK mediated activation of E3 ubiquitin ligase Itch that ubiquitinates cFLIP	cflip	caspase-8	caspase-8	caspase-8	19	20	31	32
Moreover , CLARP augmented the killing ability of caspase-8 and FADD and MORT -1 in mammalian cells .	Moreover, CLARP augmented the killing ability of caspase-8 and FADD and MORT -1 in mammalian cells.	2	10	augmented	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CLARP	CLARP	CLARP	caspase-8	caspase-8	caspase-8	2	3	8	9
As a catalytically inactive homolog of caspase-8 , a proapoptotic initiator caspase , c-FLIP blocks apoptosis by binding to and inhibiting caspase-8 .	As a catalytically inactive homolog of caspase-8, a proapoptotic initiator caspase, c-FLIP blocks apoptosis by binding to and inhibiting caspase-8.	13	22	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	13	14	21	22
In vitro mechanistic studies using CVB3 infection of mouse embryonic fibroblasts ( MEF ) further revealed that c-FLIP L promoted caspase-8 activation and interferon production , whereas c-FLIP S and v-FLIPs did the opposite .	In vitro mechanistic studies using CVB3 infection of mouse embryonic fibroblasts (MEF) further revealed that c-FLIP L promoted caspase-8 activation and interferon production, whereas c-FLIP S and v-FLIPs did the opposite.	17	21	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	17	18	20	21
It was reported that cellular FLICE-inhibitory protein ( c-FLIP ) , as a protease-dead Caspase-8 homologue , can suppress the activation of Caspase-8 and thereby inhibit Caspase-8-mediated apoptosis [ XREF_BIBR , XREF_BIBR ] .	It was reported that cellular FLICE-inhibitory protein (c-FLIP), as a protease-dead Caspase-8 homologue, can suppress the activation of Caspase-8 and thereby inhibit Caspase-8-mediated apoptosis [XREF_BIBR, XREF_BIBR].	6	23	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	Caspase-8	Caspase-8	Caspase-8	8	9	22	23
Consistent with these results , the overexpression of the Bcl-2 family member Bcl-x ( L ) or the caspase-8 modulator c-FLIP ( L ) markedly prevented FD-891-induced apoptosis .	Consistent with these results, the overexpression of the Bcl-2 family member Bcl-x (L) or the caspase-8 modulator c-FLIP (L) markedly prevented FD-891-induced apoptosis.	0	24	modulator	Positive_activation_token_1_noun	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	20	21	18	19
c-Flip proteins usually suppress apoptosis by inhibiting caspase-8 activation through a heterodimerization process .	c-Flip proteins usually suppress apoptosis by inhibiting caspase-8 activation through a heterodimerization process.	0	8	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Flip	c-Flip	c-Flip	caspase-8	caspase-8	caspase-8	0	1	7	8
At low expression levels , which are probably found in most cells , c-FLIP L enhances the caspase-8 activation .	At low expression levels, which are probably found in most cells, c-FLIP L enhances the caspase-8 activation.	13	18	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	13	14	17	18
We recently reported that an apoptotic inhibitory complex ( AIC ) comprised of DR5 , FADD , caspase-8 , and c-FLIP L exists in MCF-7 cells , and the absence of c-FLIP L from this complex induces ligand independent caspase-8 activation in the death inducing signaling complex ( DISC ) , leading to apoptosis [ XREF_BIBR ] .	We recently reported that an apoptotic inhibitory complex (AIC) comprised of DR5, FADD, caspase-8, and c-FLIP L exists in MCF-7 cells, and the absence of c-FLIP L from this complex induces ligand independent caspase-8 activation in the death inducing signaling complex (DISC), leading to apoptosis [XREF_BIBR].	31	40	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	31	32	39	40
Upon activation , JNK phosphorylates Itch ( a E3 related ligase ) and accelerates the decay of c-FLIP L , which augments caspase 8 activity and allows apoptosis to proceed ( Gao et al , 2004 ; Chang et al , 2006 ) .	Upon activation, JNK phosphorylates Itch (a E3 related ligase) and accelerates the decay of c-FLIP L, which augments caspase 8 activity and allows apoptosis to proceed (Gao et al, 2004; Chang et al, 2006).	17	24	augments	Positive_activation_syntax_3a_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	17	18	22	24
Nonetheless , evidence exists suggesting that rather than preventing apoptosis , c-FLIP L can activate caspase 8 at the DISC , leading to increased basal levels of apoptosis in T cells engineered to express high levels of c-FLIP L.	Nonetheless, evidence exists suggesting that rather than preventing apoptosis, c-FLIP L can activate caspase 8 at the DISC, leading to increased basal levels of apoptosis in T cells engineered to express high levels of c-FLIP L.	11	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	11	12	15	17
42 CFLAR ( c-FLIP ) inhibits apoptosis by blocking the activation of caspase-8 .	42 CFLAR (c-FLIP) inhibits apoptosis by blocking the activation of caspase-8.	1	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	3	4	12	13
Cellular FLICE-inhibitory protein ( c-FLIP ) has a higher affinity for the DISC than caspase-8 and inhibits processing of caspase-8 and induction of apoptosis via the death receptor pathway at high levels of expression .	Cellular FLICE-inhibitory protein (c-FLIP) has a higher affinity for the DISC than caspase-8 and inhibits processing of caspase-8 and induction of apoptosis via the death receptor pathway at high levels of expression.	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Cellular FLICE-inhibitory protein	Cellular FLICE-inhibitory protein	Cellular FLICE-inhibitory protein	caspase-8	caspase-8	caspase-8	0	3	19	20
The knockdown of cFLIP reversed the acquired sorafenib resistance by activating caspase-8 and inhibiting activated ERS in the sorafenib resistant HCC cells .	The knockdown of cFLIP reversed the acquired sorafenib resistance by activating caspase-8 and inhibiting activated ERS in the sorafenib resistant HCC cells.	1	12	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	3	4	11	12
The TNF-alpha death-receptor extrinsic pathway involves caspase 8 activation , which is inhibited by cellular FLICE-inhibitory protein ( cFLIP ) ; thus , cFLIP siRNA was employed in our studies .	The TNF-alpha death-receptor extrinsic pathway involves caspase 8 activation, which is inhibited by cellular FLICE-inhibitory protein (cFLIP); thus, cFLIP siRNA was employed in our studies.	6	19	inhibited	Negative_activation_syntax_6_verb	Negative_activation	Negative_activation	cFLIP	cFLIP	cFLIP	caspase 8	caspase 8	caspase 8	18	19	6	8
Heat shock protein ( HSP ) 27 protects the cell by controlling apoptosis and immune reactions , and c-FLIP ( cellular-FLICE inhibitory protein ) inhibits apoptosis by inhibiting caspase-8 activity .	Heat shock protein (HSP) 27 protects the cell by controlling apoptosis and immune reactions, and c-FLIP (cellular-FLICE inhibitory protein) inhibits apoptosis by inhibiting caspase-8 activity.	18	29	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	18	19	28	29
Short c-FLIP isoforms could block caspase-8 activation upon overexpression , whereas the long isoform , c-FLIP L , can both block and accelerate caspase-8 activation .	Short c-FLIP isoforms could block caspase-8 activation upon overexpression, whereas the long isoform, c-FLIP L, can both block and accelerate caspase-8 activation.	1	24	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	1	2	23	24
c-FLIP L can accelerate caspase-8 activation , whereas c-FLIP R/S inhibits it .	c-FLIP L can accelerate caspase-8 activation, whereas c-FLIP R/S inhibits it.	0	5	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	4	5
Another question that was unclear for a number of years is whether c-FLIP L could indeed activate caspase-8 at the DISC .	Another question that was unclear for a number of years is whether c-FLIP L could indeed activate caspase-8 at the DISC.	12	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	12	13	17	18
c-FLIP L -mediated activation of caspase-8 depends on procaspase-8 : c-FLIP L heterodimerization , resulting in localized enzymatic activity in the absence of proteolytic cleavage of either caspase-8 or c-FLIP L ( XREF_FIG and XREF_FIG ) .	c-FLIP L -mediated activation of caspase-8 depends on procaspase-8 : c-FLIP L heterodimerization, resulting in localized enzymatic activity in the absence of proteolytic cleavage of either caspase-8 or c-FLIP L (XREF_FIG and XREF_FIG).	0	6	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	5	6
Mechanistically , c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase mediated processing of the ER shaping protein reticulon-4 ( RTN4 ) that was corrected by re-introduction of c-FLIP L and caspase inhibition , resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition .	Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase mediated processing of the ER shaping protein reticulon-4 (RTN4) that was corrected by re-introduction of c-FLIP L and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition.	2	10	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	8	9
Both c-FLIP ( L ) and c-FLIP ( S ) suppress apoptosis by inhibiting Caspase-8 activation , although at different levels of pro-Caspase-8 processing .	Both c-FLIP (L) and c-FLIP (S) suppress apoptosis by inhibiting Caspase-8 activation, although at different levels of pro-Caspase-8 processing.	0	15	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	Caspase-8	Caspase-8	Caspase-8	1	2	14	15
c-FLIP may inhibit or promote T cell death as previous data demonstrate that the c-FLIP L isoform can promote or inhibit caspase 8 activation while the c-FLIP S isoform promotes or inhibit T cell death when overexpressed .	c-FLIP may inhibit or promote T cell death as previous data demonstrate that the c-FLIP L isoform can promote or inhibit caspase 8 activation while the c-FLIP S isoform promotes or inhibit T cell death when overexpressed.	14	23	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	14	15	21	23
c-FLIP L was shown to promote caspase 8 activation at low expression levels and inhibit caspase 8 activation at high expression levels .	c-FLIP L was shown to promote caspase 8 activation at low expression levels and inhibit caspase 8 activation at high expression levels.	0	8	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	0	1	6	8
The interaction between Mib1 and cFLIP decreases the association of caspase-8 with cFLIP , which activates caspase-8 and induces cell death .	The interaction between Mib1 and cFLIP decreases the association of caspase-8 with cFLIP, which activates caspase-8 and induces cell death.	6	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	12	13	16	17
Active caspase 8 generated from an efficient DISC can be inhibited by high levels of c-FLIP , antagonizing caspase 8 activation .	Active caspase 8 generated from an efficient DISC can be inhibited by high levels of c-FLIP, antagonizing caspase 8 activation.	0	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	c-FLIP	levels of c-FLIP	c-flip	caspase 8	caspase 8	caspase 8	15	16	1	3
These findings were consistent in three independent experiments , and confirmed the requirement of caspase-8 to induce IFN-beta production during CVB3 infection , restoration with non cleavable caspase-8 D387A restored caspase-8 activity , which was augmented by c-FLIP L and reduced by c-FLIP S ( XREF_FIG ) .	These findings were consistent in three independent experiments, and confirmed the requirement of caspase-8 to induce IFN-beta production during CVB3 infection, restoration with non cleavable caspase-8 D387A restored caspase-8 activity, which was augmented by c-FLIP L and reduced by c-FLIP S (XREF_FIG).	30	38	augmented	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	37	38	30	31
c-FLIP ( L ) can heterodimerize with and activate caspase-8 through an activation loop in the C terminus of c-FLIP ( L ) .	c-FLIP (L) can heterodimerize with and activate caspase-8 through an activation loop in the C terminus of c-FLIP (L).	0	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	9	10
It should be noted , however , that the long isoform of c-FLIP is also able to activate caspase-8 within the DISC [ XREF_BIBR , XREF_BIBR ] by mere dimerization in the absence of proteolytic activity [ XREF_BIBR ] .	It should be noted, however, that the long isoform of c-FLIP is also able to activate caspase-8 within the DISC [XREF_BIBR, XREF_BIBR] by mere dimerization in the absence of proteolytic activity [XREF_BIBR].	10	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	12	13	18	19
In this manner , c-FLIP isoforms may either promote caspase-8 activation , or limit its activity to prevent apoptosis .	In this manner, c-FLIP isoforms may either promote caspase-8 activation, or limit its activity to prevent apoptosis.	4	10	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	4	5	9	10
XREF_BIBR Although c-FLIP L has been described in most reports as an inhibitor of caspase-8 activation in DISC , some other studies show that c-FLIP L can activate the caspase-8 .	XREF_BIBR Although c-FLIP L has been described in most reports as an inhibitor of caspase-8 activation in DISC, some other studies show that c-FLIP L can activate the caspase-8.	24	30	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	24	25	29	30
We identified cFLIP upregulation that may promote caspase 8 mediated degradation of CYLD , and other necrosome components , as a possible mechanism abrogating Mtb ' s capacity to coopt necroptotic signaling .	We identified cFLIP upregulation that may promote caspase 8 mediated degradation of CYLD, and other necrosome components, as a possible mechanism abrogating Mtb 's capacity to coopt necroptotic signaling.	2	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	caspase 8	caspase 8	caspase 8	2	3	7	9
Besides caspase-8 and -10 , the catalytically inactive homolog of caspase-8 , cFLIP has been found to be present at the DISC and has been shown to enhance caspase-8 activity forming heterodimers with the enzyme .	Besides caspase-8 and -10, the catalytically inactive homolog of caspase-8, cFLIP has been found to be present at the DISC and has been shown to enhance caspase-8 activity forming heterodimers with the enzyme.	10	29	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	12	13	28	29
c-FLIP also heterodimerizes with and activates caspase-8 , resulting in increased death of T cells and a selection of a T helper 2 cytokine profile .	c-FLIP also heterodimerizes with and activates caspase-8, resulting in increased death of T cells and a selection of a T helper 2 cytokine profile.	0	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	6	7
Down-regulated and low levels of c-FLIP are thought to promote caspase-8 activation , whereas in high concentrations c-FLIP may compete for binding , reduce caspase-8 activity and the cell ' s susceptibility to apoptosis [ XREF_BIBR , XREF_BIBR ] .	Down-regulated and low levels of c-FLIP are thought to promote caspase-8 activation, whereas in high concentrations c-FLIP may compete for binding, reduce caspase-8 activity and the cell 's susceptibility to apoptosis [XREF_BIBR, XREF_BIBR].	3	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	levels of c-FLIP	c-flip	caspase-8	caspase-8	caspase-8	5	6	10	11
Moreover , c-FLIP even promotes caspase 8 activation in these cells .	Moreover, c-FLIP even promotes caspase 8 activation in these cells.	2	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	2	3	5	7
The long c-FLIP isoform , c-FLIP L , and the short c-FLIP isoform , c-FLIP R , inhibited MAPK induction by blocking caspase-8 processing at the DISC .	The long c-FLIP isoform, c-FLIP L, and the short c-FLIP isoform, c-FLIP R, inhibited MAPK induction by blocking caspase-8 processing at the DISC.	2	23	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	2	3	22	23
This study shows the power of systems biology approaches for identifying novel genes that regulate drug resistance and identifies SART1 as a previously unidentified regulator of c-FLIP and drug induced activation of caspase-8 .	This study shows the power of systems biology approaches for identifying novel genes that regulate drug resistance and identifies SART1 as a previously unidentified regulator of c-FLIP and drug induced activation of caspase-8.	24	33	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	26	27	32	33
c-FLIP S completely inhibits caspase-8 processing , whereas c-FLIP L allows partial processing of caspase-8 .	c-FLIP S completely inhibits caspase-8 processing, whereas c-FLIP L allows partial processing of caspase-8.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	0	1	4	5
The cellular FLICE inhibitory protein ( c-FLIP ) , which is homologous to caspase-8 but lacks the enzymatic activity , can also associate with the DISC , blocking activation of caspase-8 through competition for binding sites .	The cellular FLICE inhibitory protein (c-FLIP), which is homologous to caspase-8 but lacks the enzymatic activity, can also associate with the DISC, blocking activation of caspase-8 through competition for binding sites.	4	31	blocking	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase-8	caspase-8	caspase-8	6	7	30	31
This promotes complexing between phosphorylated TrkAIII , SHP and c-Src , leading to SHP mediated TrkAIII de-phosphorylation and the sequester cFLIP , which increases the caspase-8 to cFLIP ratio recruited to activated TRAIL-receptors , explaining the delay in caspase cleavage and apoptosis via the extrinsic pathway .	This promotes complexing between phosphorylated TrkAIII, SHP and c-Src, leading to SHP mediated TrkAIII de-phosphorylation and the sequester cFLIP, which increases the caspase-8 to cFLIP ratio recruited to activated TRAIL-receptors, explaining the delay in caspase cleavage and apoptosis via the extrinsic pathway.	20	34	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	20	21	25	26
Survivin , as the most representative caspase inhibitor factors , block apoptosis by interacting with CASP9 activated fragment , while another apoptotic inhibitor , c-FLIP , reduces the cleavage of CASP8 and 9 .	Survivin, as the most representative caspase inhibitor factors, block apoptosis by interacting with CASP9 activated fragment, while another apoptotic inhibitor, c-FLIP, reduces the cleavage of CASP8 and 9.	22	32	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	CASP8	CASP8	CASP8	24	25	30	31
Consistent with previous publications [ XREF_BIBR , XREF_BIBR ] , cFLIP overexpression did not completely inhibit caspase-8 activation and RIP1 processing in response to TRAIL stimulation , indicating that cFLIP allows moderate activation of caspase-8 .	Consistent with previous publications [XREF_BIBR, XREF_BIBR], cFLIP overexpression did not completely inhibit caspase-8 activation and RIP1 processing in response to TRAIL stimulation, indicating that cFLIP allows moderate activation of caspase-8.	29	35	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	cFLIP	cFLIP	cFLIP	caspase-8	caspase-8	caspase-8	29	30	34	35
17 c-FLIP L modulates caspase 8 activation within membrane complexes called death inducing signaling complexes comprised of death receptors and adapter proteins such as Fas associated death domain ( FADD ) .	17 c-FLIP L modulates caspase 8 activation within membrane complexes called death inducing signaling complexes comprised of death receptors and adapter proteins such as Fas associated death domain (FADD).	1	6	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	1	2	4	6
As TCR signaling induces caspase 8 activation and c-FLIP can either promote or inhibit caspase 8 activation , and c-FLIP deficient T cells have been found to have increased apoptosis following TCR stimulation in a Rag chimeric mutant model , we tested what roles c-FLIP might play after TCR stimulation of mature T cells in an ER-cre inducible system .	As TCR signaling induces caspase 8 activation and c-FLIP can either promote or inhibit caspase 8 activation, and c-FLIP deficient T cells have been found to have increased apoptosis following TCR stimulation in a Rag chimeric mutant model, we tested what roles c-FLIP might play after TCR stimulation of mature T cells in an ER-cre inducible system.	6	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-FLIP	c-FLIP	c-FLIP	caspase 8	caspase 8	caspase 8	8	9	14	16
Therefore , 14-3-3 gamma is important for Chk1 mediated Cdc25A turnover via the ubiquitin-proteasome pathway .	Therefore, 14-3-3 gamma is important for Chk1 mediated Cdc25A turnover via the ubiquitin-proteasome pathway.	5	10	mediated	Positive_early_activation	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	7	8	9	10
Chk1 and SCF betaTRCP mediate Cdc25A turnover in the S and G2 phases of cell division .	Chk1 and SCF betaTRCP mediate Cdc25A turnover in the S and G2 phases of cell division.	0	6	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	0	1	5	6
This could be explained by the fact that , although MUS81 depletion significantly reduced DNA damage produced by Chk1 inhibition or depletion , it did not reverse the stabilisation of Cdc25A caused by Chk1 inactivation ( XREF_SUPPLEMENTARY ) .	This could be explained by the fact that, although MUS81 depletion significantly reduced DNA damage produced by Chk1 inhibition or depletion, it did not reverse the stabilisation of Cdc25A caused by Chk1 inactivation (XREF_SUPPLEMENTARY).	28	34	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	33	34	30	31
Addition of SCH 900776 decreased the cytarabine induced Chk1 autophosphorylation at Ser 296 and prevented Cdc25A downregulation ( XREF_FIG , lanes 7-10 vs. lane 6 ) , suggesting that SCH 900776 was disrupting the replication checkpoint .	Addition of SCH 900776 decreased the cytarabine induced Chk1 autophosphorylation at Ser 296 and prevented Cdc25A downregulation (XREF_FIG, lanes 7-10 vs. lane 6), suggesting that SCH 900776 was disrupting the replication checkpoint.	2	16	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	SCH 900776 decreased the cytarabine induced Chk1 autophosphorylation	chk1	Cdc25A	Cdc25A	cdc25a	8	9	15	16
5-FU confers S-phase arrest through Chk1 mediated Cdc25A proteolysis leading to inhibition of Cdk2 .	5-FU confers S-phase arrest through Chk1 mediated Cdc25A proteolysis leading to inhibition of Cdk2.	1	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	5	6	7	8
In response to various stresses , Cdc25A becomes hyperphosphorylated by a several stress dependent kinases including p38 , Chk1 , and Chk2 , subsequently targeting Cdc25A for degradation via ubiquitin mediated proteolysis .	In response to various stresses, Cdc25A becomes hyperphosphorylated by a several stress dependent kinases including p38, Chk1, and Chk2, subsequently targeting Cdc25A for degradation via ubiquitin mediated proteolysis.	14	27	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	18	19	25	26
CDC25A is also a downstream target of Chk1 mediated checkpoint pathway : activation of Chk1 by DNA damaging conditions targets CDC25A for proteasome degradation , which prevents cells with chromosomal abnormalities from progressing through the cell cycle XREF_BIBR , XREF_BIBR , XREF_BIBR .	CDC25A is also a downstream target of Chk1 mediated checkpoint pathway : activation of Chk1 by DNA damaging conditions targets CDC25A for proteasome degradation, which prevents cells with chromosomal abnormalities from progressing through the cell cycle XREF_BIBR, XREF_BIBR, XREF_BIBR.	12	23	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	CDC25A	CDC25A	CDC25A	14	15	20	21
These were accompanied by elevated p53 activity and decreased abundance of CDC25A , which is targeted for degradation by CHK1 and required for the G2-M phase transition .	These were accompanied by elevated p53 activity and decreased abundance of CDC25A, which is targeted for degradation by CHK1 and required for the G2-M phase transition.	9	21	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CHK1	CHK1	CHK1	CDC25A	CDC25A	CDC25A	19	20	11	12
Thus , the physiological replication checkpoint is activated transiently at the MBT by developmental cues , and activated Chk1 , only together with an unknown kinase , targets Cdc25A for degradation to ensure later development .	Thus, the physiological replication checkpoint is activated transiently at the MBT by developmental cues, and activated Chk1, only together with an unknown kinase, targets Cdc25A for degradation to ensure later development.	18	32	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	18	19	28	29
Here , we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase promoting Cdc25A phosphatase , prevented ionizing radiation ( IR )-induced degradation of Cdc25A , and caused radioresistant DNA synthesis ( RDS ) .	Here, we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase promoting Cdc25A phosphatase, prevented ionizing radiation (IR)-induced degradation of Cdc25A, and caused radioresistant DNA synthesis (RDS).	8	21	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	11	12	20	21
Chk1 targeting of Cdc25A for destruction is also conserved to mammals [ XREF_BIBR ] .	Chk1 targeting of Cdc25A for destruction is also conserved to mammals [XREF_BIBR].	0	5	targeting	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	0	1	3	4
Chk1 targets CDC25A , CDC25B and CDC25C and down regulates their phosphatase activity whereas Chk2 targets CDC25A for ubiquitin mediated degradation at the intra-S phase checkpoint [ XREF_BIBR ] .	Chk1 targets CDC25A, CDC25B and CDC25C and down regulates their phosphatase activity whereas Chk2 targets CDC25A for ubiquitin mediated degradation at the intra-S phase checkpoint [XREF_BIBR].	0	9	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	CDC25A	CDC25A	CDC25A	0	1	2	3
On the other hand , Chk1 also targets Cdc25A , which is the phosphatase that counteracts Wee1 mediated phosphorylations on CDKs .	On the other hand, Chk1 also targets Cdc25A, which is the phosphatase that counteracts Wee1 mediated phosphorylations on CDKs.	5	13	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	5	6	8	9
The CHK1 target CDC25A was also found to be rapidly degraded , indicative of checkpoint activation .	The CHK1 target CDC25A was also found to be rapidly degraded, indicative of checkpoint activation.	0	10	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	CHK1	CHK1	CHK1	CDC25A	CDC25A	CDC25A	1	2	3	4
Upon activation , CHK1 targets Cdc25A for degradation which dampens the activity of cyclin dependent kinase 2 ( CDK2 )/cyclin complexes slowing down DNA synthesis 4 .	Upon activation, CHK1 targets Cdc25A for degradation which dampens the activity of cyclin dependent kinase 2 (CDK2)/cyclin complexes slowing down DNA synthesis 4.	1	7	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	CHK1	CHK1	CHK1	Cdc25A	Cdc25A	Cdc25A	3	4	5	6
In U2OS cells , Chk1 phosphorylates Cdc25A at multiple sites and inhibition of Chk1 results in a marked accumulation of Cdc25A , suggesting that phosphorylation by Chk1 targets Cdc25A for degradation [ XREF_BIBR - XREF_BIBR ] .	In U2OS cells, Chk1 phosphorylates Cdc25A at multiple sites and inhibition of Chk1 results in a marked accumulation of Cdc25A, suggesting that phosphorylation by Chk1 targets Cdc25A for degradation [XREF_BIBR - XREF_BIBR].	24	34	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	26	27	28	29
CHK1 targets CDC25A to ubiquitin mediated degradation [ XREF_BIBR ] .	CHK1 targets CDC25A to ubiquitin mediated degradation [XREF_BIBR].	0	5	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	CHK1	CHK1	CHK1	CDC25A	CDC25A	CDC25A	0	1	2	3
For instance , in Xenopus , Cdc25 must also be inactivated to slow the cell cycle at the MBT , including the Cdc25A isoform , which seems to be targeted for degradation by Chk1 phosphorylation [ XREF_BIBR ] .	For instance, in Xenopus, Cdc25 must also be inactivated to slow the cell cycle at the MBT, including the Cdc25A isoform, which seems to be targeted for degradation by Chk1 phosphorylation [XREF_BIBR].	22	36	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Chk1	Chk1 phosphorylation	chk1	Cdc25A	Cdc25A	cdc25a	33	34	22	23
Conversely , treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine induced S-phase accumulation , decreased Cdc25A degradation , and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis .	Conversely, treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine induced S-phase accumulation, decreased Cdc25A degradation, and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis.	13	27	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	13	14	26	27
Cdc25A is also targeted for IR dependent degradation by Chk1 XREF_BIBR , which is activated after phosphorylation by ATR on residues S317 and S345 XREF_BIBR , XREF_BIBR .	Cdc25A is also targeted for IR dependent degradation by Chk1 XREF_BIBR, which is activated after phosphorylation by ATR on residues S317 and S345 XREF_BIBR, XREF_BIBR.	0	10	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	9	10	0	1
Since the Cdc25A protein profile in vpr expressing cells showed similar pattern to normal cells , it suggests that Vpr has little or no effect on Chk1 mediated Cdc25A protein production or degradation .	Since the Cdc25A protein profile in vpr expressing cells showed similar pattern to normal cells, it suggests that Vpr has little or no effect on Chk1 mediated Cdc25A protein production or degradation.	24	30	mediated	Positive_early_activation	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	26	27	28	29
As shown in Figure XREF_FIG , depletion of Chk1 completely abolished HU mediated Cdc25A degradation .	As shown in Figure XREF_FIG, depletion of Chk1 completely abolished HU mediated Cdc25A degradation.	6	14	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	8	9	13	14
We have also shown that CHIR-124 treatment can restore the level of cdc25A protein , which is normally targeted by Chk1 for degradation following DNA damage , indicating that Chk1 signaling is suppressed in the presence of CHIR-124 .	We have also shown that CHIR-124 treatment can restore the level of cdc25A protein, which is normally targeted by Chk1 for degradation following DNA damage, indicating that Chk1 signaling is suppressed in the presence of CHIR-124.	12	21	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	cdc25A	cdc25A	cdc25A	20	21	12	13
The simultaneous depletion of Chk1 and Chk2 inhibited Cdc25A degradation , induced premature mitotic entry and enhanced cytotoxicity in response to FdUrd and gemcitabine to a similar extent as Chk1 depletion alone .	The simultaneous depletion of Chk1 and Chk2 inhibited Cdc25A degradation, induced premature mitotic entry and enhanced cytotoxicity in response to FdUrd and gemcitabine to a similar extent as Chk1 depletion alone.	2	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	4	5	8	9
Knockdown of Cdc6 also led to increased levels of the Chk1 target Cdc25A , before and after IR treatment ( XREF_SUPPLEMENTARY ) .	Knockdown of Cdc6 also led to increased levels of the Chk1 target Cdc25A, before and after IR treatment (XREF_SUPPLEMENTARY).	7	13	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25A	Cdc25A	Cdc25A	10	11	12	13
By using RNA interference to specifically deplete cells of Chk1 , we demonstrate that Chk1 mediates the down-regulation of endogenous CDC25A , which occurs upon induction of CK2beta expression .	By using RNA interference to specifically deplete cells of Chk1, we demonstrate that Chk1 mediates the down-regulation of endogenous CDC25A, which occurs upon induction of CK2beta expression.	14	23	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	CDC25A	CDC25A	CDC25A	14	15	20	21
XREF_BIBR , XREF_BIBR The biological necessity for Csk mediated Src regulation is highlighted in mouse gene knockout studies , where deletion of Csk leads to early stage embryonic death and severe neural tube defects .	XREF_BIBR, XREF_BIBR The biological necessity for Csk mediated Src regulation is highlighted in mouse gene knockout studies, where deletion of Csk leads to early stage embryonic death and severe neural tube defects.	5	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	7	8	9	10
The inhibition of c-Src activity promoted by PTEN and Csk would collaborate with TC-PTP to terminate this pathway , which is required to recycle Cx43 [ XREF_BIBR ] .	The inhibition of c-Src activity promoted by PTEN and Csk would collaborate with TC-PTP to terminate this pathway, which is required to recycle Cx43 [XREF_BIBR].	3	10	promoted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	c-Src	c-Src	c-Src	9	10	3	4
This data suggests that Csk expression may also modulate Src independent pathways or SYF cells may express other kinases that are closely related to SFKs and are regulated by Csk .	This data suggests that Csk expression may also modulate Src independent pathways or SYF cells may express other kinases that are closely related to SFKs and are regulated by Csk.	4	22	modulate	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Csk	Csk expression	csk	Src	Src independent pathways or SYF cells may express	src	4	5	9	10
Knock-down of CSK expression reversed the inhibition of Src activation by isorhamnetin .	Knock-down of CSK expression reversed the inhibition of Src activation by isorhamnetin.	2	9	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CSK	CSK expression	csk	Src	Src	src	2	3	8	9
XREF_BIBR The activation of STAT92E in Csk -/- clones is likely due to upregulation of Src kinases in the absence of negative regulation by Csk ( as opposed to Csk dependent activation of Dome or Hop ) , but this has not been formally shown .	XREF_BIBR The activation of STAT92E in Csk -/- clones is likely due to upregulation of Src kinases in the absence of negative regulation by Csk (as opposed to Csk dependent activation of Dome or Hop), but this has not been formally shown.	13	25	upregulation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	24	25	15	16
We confirmed that haploinsufficiency of Csk increased the active form of Src in Csk +/- mice aorta .	We confirmed that haploinsufficiency of Csk increased the active form of Src in Csk +/- mice aorta.	3	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	5	6	11	12
These results indicate that Cbp is required for the Csk mediated inactivation of c-Src and may control the promotion of malignancy in NSCLC tumors that are characterized by c-Src upregulation .	These results indicate that Cbp is required for the Csk mediated inactivation of c-Src and may control the promotion of malignancy in NSCLC tumors that are characterized by c-Src upregulation.	8	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	c-Src	c-Src	c-Src	9	10	13	14
Dissociation of Csk relieves Src kinases inhibition , enabling TCR downstream signaling pathways .	Dissociation of Csk relieves Src kinases inhibition, enabling TCR downstream signaling pathways.	0	6	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	2	3	4	5
These results suggest that the loss of IGF-I downstream mitogenic signaling in differentiating 3T3-L1 cells is due to a change in IGF-I activation of c-Src and CSK may mediate the inactivation of c-Src by IGF-I in 3T3-L1 adipogenesis .	These results suggest that the loss of IGF-I downstream mitogenic signaling in differentiating 3T3-L1 cells is due to a change in IGF-I activation of c-Src and CSK may mediate the inactivation of c-Src by IGF-I in 3T3-L1 adipogenesis.	26	33	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CSK	CSK	CSK	c-Src	c-Src	c-Src	26	27	32	33
13 This lack of Csk mediated Src regulation is more pronounced in the filasterean Capsaspora owczarzaki , which represents a sister group to metazoans and choanoflagellates .	13 This lack of Csk mediated Src regulation is more pronounced in the filasterean Capsaspora owczarzaki, which represents a sister group to metazoans and choanoflagellates.	2	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	4	5	6	7
The molecular basis of the specificity of Csk targeting the Src tail appears to involve both local and long-range interactions and illustrates the complexity of selective targeting in post-translational modification .	The molecular basis of the specificity of Csk targeting the Src tail appears to involve both local and long-range interactions and illustrates the complexity of selective targeting in post-translational modification.	5	11	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	7	8	10	11
Depletion of CSK increased the activation of Src detected by increased Y416 autophosphorylation ( XREF_FIG ) .	Depletion of CSK increased the activation of Src detected by increased Y416 autophosphorylation (XREF_FIG).	0	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CSK	CSK	CSK	Src	Src	Src	2	3	7	8
Csk is probably involved in the downregulation of TCR signaling by C-terminal tyrosine phosphorylation of Lck and Fyn , but the mechanism whereby Csk targets these Src family members is not known .	Csk is probably involved in the downregulation of TCR signaling by C-terminal tyrosine phosphorylation of Lck and Fyn, but the mechanism whereby Csk targets these Src family members is not known.	23	28	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	23	24	26	27
However , Src activity is not directly regulated through phosphorylation of Tyr527 by Csk , and a subtle decrease in Csk activity is not believed to contribute to regulation of Src activity because of the excess amount of expression of Csk .	However, Src activity is not directly regulated through phosphorylation of Tyr527 by Csk, and a subtle decrease in Csk activity is not believed to contribute to regulation of Src activity because of the excess amount of expression of Csk.	2	14	directly regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	13	14	2	3
PRL-3 activates Src signaling XREF_BIBR , XREF_BIBR , XREF_BIBR by reducing the synthesis of protein , Csk , an inhibitor of the pathway XREF_BIBR , XREF_BIBR and upregulation of PRL1 activates the Src kinase through increased Tyr416 phosphorylation and cell migration XREF_BIBR .	PRL-3 activates Src signaling XREF_BIBR, XREF_BIBR, XREF_BIBR by reducing the synthesis of protein, Csk, an inhibitor of the pathway XREF_BIBR, XREF_BIBR and upregulation of PRL1 activates the Src kinase through increased Tyr416 phosphorylation and cell migration XREF_BIBR.	2	31	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	16	17	2	3
In addition , Cox activity was also correlated with c-Src kinase activity , decreasing when Src was down-regulated by the expression of Csk WT or the dominant negative Src KD , and increasing when Src activity was up-regulated by the expression of Csk KD .	In addition, Cox activity was also correlated with c-Src kinase activity, decreasing when Src was down-regulated by the expression of Csk WT or the dominant negative Src KD, and increasing when Src activity was up-regulated by the expression of Csk KD.	34	43	up-regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Csk	expression of Csk	csk	Src	Src	src	42	43	34	35
We revealed that activation of D 1 Rs by DA promptly upregulates the AC/cAMP/PKA cascade leading to PKA dependent Csk Ser 364 phosphorylation and activation , and Csk induced Src Tyr 527 phosphorylation in neurites .	We revealed that activation of D 1 Rs by DA promptly upregulates the AC/cAMP/PKA cascade leading to PKA dependent Csk Ser 364 phosphorylation and activation, and Csk induced Src Tyr 527 phosphorylation in neurites.	27	30	induced	Positive_early_activation	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	27	28	29	30
Conversely , Csk KD acts as a dominant negative molecule against endogenous Csk , increasing Src kinase activity and bone resorbing activity in osteoclasts .	Conversely, Csk KD acts as a dominant negative molecule against endogenous Csk, increasing Src kinase activity and bone resorbing activity in osteoclasts.	2	17	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Src	Src	Src	2	3	15	16
Here , we show that T CM and T EM possess differential constitutive Lck activities , driven in part by differential regulation by Shp-1 and Csk .	Here, we show that T CM and T EM possess differential constitutive Lck activities, driven in part by differential regulation by Shp-1 and Csk.	13	26	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Lck	Lck	Lck	25	26	13	14
By controlling the fraction of active Lck , Csk can also modulate the activation threshold and affinity discrimination of T cells .	By controlling the fraction of active Lck, Csk can also modulate the activation threshold and affinity discrimination of T cells.	3	12	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Lck	Lck	Lck	8	9	6	7
Upon T cell activation , PAG is dephosphorylated and Csk is removed from the plasma membrane to allow Lck activation .	Upon T cell activation, PAG is dephosphorylated and Csk is removed from the plasma membrane to allow Lck activation.	9	19	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Lck	Lck	Lck	9	10	18	19
Here we provide evidence that alpha/beta T cell development in the absence of Csk is also independent of gamma and delta TCR expression and that no other substrate of Csk is sufficient to drive T cell development in the absence of Lck and Fyn .	Here we provide evidence that alpha/beta T cell development in the absence of Csk is also independent of gamma and delta TCR expression and that no other substrate of Csk is sufficient to drive T cell development in the absence of Lck and Fyn.	27	43	drive	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Lck	Lck	Lck	29	30	41	42
Phosphorylation of Cdc25C on S287 by Chk1 causes Cdc25C to bind 14-3-3 protein , sequestering Cdc25C in the cytosol .	Phosphorylation of Cdc25C on S287 by Chk1 causes Cdc25C to bind 14-3-3 protein, sequestering Cdc25C in the cytosol.	4	9	causes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	6	7	8	9
Recent studies showed that Chk1 , a serine threonine kinase , is critical for G2/M arrest in response to DNA damage and is also known to modulate Cdc25C .	Recent studies showed that Chk1, a serine threonine kinase, is critical for G2/M arrest in response to DNA damage and is also known to modulate Cdc25C.	4	28	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	Cdc25C	Cdc25C	Cdc25C	4	5	27	28
Activated Chk1 induces CDC25C to be phosphorylated at Ser216 site and to be combined with 14-3-3sigma , which makes CDC25C deactivated , finally leads inhibition of MPF activity and G2/M phase arrest to repair DNA damage or induce cell apoptosis [ XREF_BIBR ] .	Activated Chk1 induces CDC25C to be phosphorylated at Ser216 site and to be combined with 14-3-3sigma, which makes CDC25C deactivated, finally leads inhibition of MPF activity and G2/M phase arrest to repair DNA damage or induce cell apoptosis [XREF_BIBR].	0	4	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	CDC25C	CDC25C	CDC25C	1	2	3	4
Chk1 activates cdc25c phosphatase by phosphorylation which subsequently inhibits CDK2 activity [ XREF_BIBR , XREF_BIBR ] .	Chk1 activates cdc25c phosphatase by phosphorylation which subsequently inhibits CDK2 activity [XREF_BIBR, XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	cdc25c	cdc25c	cdc25c	0	1	2	3
hMYH disrupted cells decreased the phosphorylation of Chk1 upon HU or UV treatment and increased the phosphorylation of Cdk2 and the amount of Cdc25A , but not Cdc25C .	hMYH disrupted cells decreased the phosphorylation of Chk1 upon HU or UV treatment and increased the phosphorylation of Cdk2 and the amount of Cdc25A, but not Cdc25C.	0	28	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	hMYH disrupted cells decreased the phosphorylation of Chk1	chk1	Cdc25C	Cdc25C	cdc25c	7	8	27	28
CSNK1A1 E98 mutations increase beta-catenin activity thereby providing selective growth advantage .	CSNK1A1 E98 mutations increase beta-catenin activity thereby providing selective growth advantage.	0	5	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CSNK1A1	CSNK1A1	CSNK1A1	beta-catenin	beta-catenin	beta-catenin	0	1	4	5
In mice , the inactivation of casein kinase 1 alpha ( Csnk1a1 ) promotes the cytoplasmatic and nuclear accumulation of beta catenin which stimulates the transcription of Wnt signaling target genes .	In mice, the inactivation of casein kinase 1 alpha (Csnk1a1) promotes the cytoplasmatic and nuclear accumulation of beta catenin which stimulates the transcription of Wnt signaling target genes.	7	26	promotes	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Csnk1a1	Csnk1a1	csnk1a1	beta catenin	beta catenin which stimulates the transcription	beta catenin	11	12	20	22
Csnk1a1 -/- Mx1Cre + cells transduced with CSNK1A1 E98V cDNA , compared to cells expressing the wild-type cDNA , had increased nuclear beta-catenin accumulation by immunofluorescence , and higher beta-catenin accumulation by intracellular flow cytometry ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Csnk1a1 -/- Mx1Cre + cells transduced with CSNK1A1 E98V cDNA, compared to cells expressing the wild-type cDNA, had increased nuclear beta-catenin accumulation by immunofluorescence, and higher beta-catenin accumulation by intracellular flow cytometry (XREF_FIG and XREF_SUPPLEMENTARY).	0	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csnk1a1	Csnk1a1	Csnk1a1	beta-catenin	beta-catenin	beta-catenin	0	1	22	23
In a mouse model , ablation of Csnk1a1 caused the accumulation of beta-catenin in the cytoplasm and nucleus activating many Wnt target genes although no tumor formation was observed .	In a mouse model, ablation of Csnk1a1 caused the accumulation of beta-catenin in the cytoplasm and nucleus activating many Wnt target genes although no tumor formation was observed.	5	13	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csnk1a1	Csnk1a1	Csnk1a1	beta-catenin	beta-catenin	beta-catenin	7	8	12	13
For instance , CKIalpha inhibits the pathway by promoting beta-catenin degradation through the phosphorylation of beta-catenin ' s Ser45 , while CKIdelta and epsilon activates the pathway , possibly by destabilizing the beta-catenin degradation complex [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	For instance, CKIalpha inhibits the pathway by promoting beta-catenin degradation through the phosphorylation of beta-catenin 's Ser45, while CKIdelta and epsilon activates the pathway, possibly by destabilizing the beta-catenin degradation complex [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	19	inhibits	Negative_regulation_syntax_1_verb	Negative_activation	Positive_regulation	CKIalpha	CKIalpha	ckialpha	beta-catenin	phosphorylation of beta-catenin 's Ser45	beta-catenin	3	4	15	16
Csnk1a1 -/+ Mx1Cre + hematopoietic cells , transplanted into WT mice , had increased nuclear beta-catenin accumulation by immunohistochemistry ( XREF_SUPPLEMENTARY ) and by intracellular flow cytometry ( XREF_FIG ) .	Csnk1a1 -/+ Mx1Cre + hematopoietic cells, transplanted into WT mice, had increased nuclear beta-catenin accumulation by immunohistochemistry (XREF_SUPPLEMENTARY) and by intracellular flow cytometry (XREF_FIG).	0	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Csnk1a1	Csnk1a1	Csnk1a1	beta-catenin	beta-catenin	beta-catenin	0	1	15	16
Transcriptional dysregulation of Wnt and beta-catenin signaling by CHD8 in NSCs has also been reported previously XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Transcriptional dysregulation of Wnt and beta-catenin signaling by CHD8 in NSCs has also been reported previously XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	10	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	8	9	5	6
Many of the top genes from recent exome studies are novel candidates for ASD and ID , including the strongest overall association : CHD8 , an ATP dependent chromodomain helicase that directly regulates CTNNB1 [ XREF_BIBR ] as well as the p53 pathway [ XREF_BIBR ] .	Many of the top genes from recent exome studies are novel candidates for ASD and ID, including the strongest overall association : CHD8, an ATP dependent chromodomain helicase that directly regulates CTNNB1 [XREF_BIBR] as well as the p53 pathway [XREF_BIBR].	21	42	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CHD8	CHD8	CHD8	CTNNB1	CTNNB1	CTNNB1	23	24	33	34
Indeed , as macrocephaly was also noted in 12 ASD patients with CHD8 mutations , and as CHD8 is known to repress WNT and beta-catenin targets , it seems likely that imbalance of WNT and beta-catenin signalling is a key mechanism leading to the opposing micro- versus macrocephaly phenotypes in NBS , CSS and Weaver ' s syndrome XREF_BIBR , XREF_BIBR , XREF_BIBR .	Indeed, as macrocephaly was also noted in 12 ASD patients with CHD8 mutations, and as CHD8 is known to repress WNT and beta-catenin targets, it seems likely that imbalance of WNT and beta-catenin signalling is a key mechanism leading to the opposing micro- versus macrocephaly phenotypes in NBS, CSS and Weaver 's syndrome XREF_BIBR, XREF_BIBR, XREF_BIBR.	17	25	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	17	18	24	25
Here we show that CHD8 promotes the association of beta-catenin and histone H1 , with formation of the trimeric complex on chromatin being required for inhibition of beta-catenin-dependent transactivation .	Here we show that CHD8 promotes the association of beta-catenin and histone H1, with formation of the trimeric complex on chromatin being required for inhibition of beta-catenin-dependent transactivation.	4	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	4	5	9	10
Additionally , EZH2 and BAF complexes have opposing roles in chromatin regulation and are both linked to WNT and beta-catenin signalling , like CHD8 , so comparing their involvement in neurodevelopmental mechanisms will be informative .	Additionally, EZH2 and BAF complexes have opposing roles in chromatin regulation and are both linked to WNT and beta-catenin signalling, like CHD8, so comparing their involvement in neurodevelopmental mechanisms will be informative.	19	24	signalling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	CHD8	CHD8	CHD8	beta-catenin	beta-catenin	beta-catenin	23	24	19	20
CHD8 also has an important role in development , is highly expressed during early embryogenesis and appears to modulate WNT and beta-catenin signaling through interaction and downregulation of response genes .	CHD8 also has an important role in development, is highly expressed during early embryogenesis and appears to modulate WNT and beta-catenin signaling through interaction and downregulation of response genes.	0	22	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CHD8	CHD8 also has an important role in development, is highly expressed	chd8	beta-catenin	beta-catenin	beta-catenin	0	1	21	22
The protein kinase Chk1 is phosphorylated in response to DNA damage in an ATM- and ATR dependent manner , and activated Chk1 down-regulates TLK1 transiently through phosphorylation at S695 8 .	The protein kinase Chk1 is phosphorylated in response to DNA damage in an ATM- and ATR dependent manner, and activated Chk1 down-regulates TLK1 transiently through phosphorylation at S695 8.	21	24	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Chk1	Chk1	Chk1	TLK1	TLK1	TLK1	21	22	23	24
Direct Chk1 induced inhibition of TLK1 is transient , and TLK1 activity returns to baseline levels later in the damage response .	Direct Chk1 induced inhibition of TLK1 is transient, and TLK1 activity returns to baseline levels later in the damage response.	0	12	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Chk1	Chk1	Chk1	TLK1	TLK1	TLK1	1	2	10	11
Our data suggest that Jab1 antagonizes TGF-beta function by inducing degradation of Smad4 through a distinct degradation pathway .	Our data suggest that Jab1 antagonizes TGF-beta function by inducing degradation of Smad4 through a distinct degradation pathway.	4	13	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Jab1	Jab1	Jab1	Smad4	Smad4	Smad4	4	5	12	13
By degrading Smad4 or Smad7 , Jab1 can repress or increase TGF-beta and BMP signaling , respectively , in vitro .	By degrading Smad4 or Smad7, Jab1 can repress or increase TGF-beta and BMP signaling, respectively, in vitro.	1	10	repress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Jab1	Jab1	Jab1	Smad4	Smad4	Smad4	6	7	2	3
Thus , CD4 + T cells activated in the mLNs and expressing mainly IFN-gamma in the setting of TAC induced nonischemic HF adhere to CFB and induce CFB transition to profibrotic myofibroblasts .	Thus, CD4 + T cells activated in the mLNs and expressing mainly IFN-gamma in the setting of TAC induced nonischemic HF adhere to CFB and induce CFB transition to profibrotic myofibroblasts.	20	28	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HF	HF	HF	CFB	CFB	CFB	21	22	27	28
Examples for such negative regulatory mechanisms involve the tyrosine phosphatases SHP-1 and SHIP in FcepsilonRI- mediated mast cell activation XREF_BIBR , XREF_BIBR , the Cbl family ubiquitin ligases , which facilitate degradation or internalization of the activated FcepsilonRI signaling components 5 , and the inhibitory kinase Csk , which phosphorylates and thereby inactivates the FcepsilonRI proximal kinases Lyn and Fyn 1 .	Examples for such negative regulatory mechanisms involve the tyrosine phosphatases SHP-1 and SHIP in FcepsilonRI- mediated mast cell activation XREF_BIBR, XREF_BIBR, the Cbl family ubiquitin ligases, which facilitate degradation or internalization of the activated FcepsilonRI signaling components 5, and the inhibitory kinase Csk, which phosphorylates and thereby inactivates the FcepsilonRI proximal kinases Lyn and Fyn 1.	10	59	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Csk	Csk	Csk	Lyn	Lyn	Lyn	46	47	57	58
Global Identification of Phosphorylation Sites of Tau Catalyzed by Chk1 and Chk2 Using LC-MS 3 .	Global Identification of Phosphorylation Sites of Tau Catalyzed by Chk1 and Chk2 Using LC-MS 3.	6	12	Catalyzed	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Chk2	Chk2	Chk2	Tau	Tau	Tau	11	12	6	7
Inflammatory markers IL6 and CRP were both increased by feeding HF chow and this was blunted by exercise .	Inflammatory markers IL6 and CRP were both increased by feeding HF chow and this was blunted by exercise.	2	11	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	HF	HF	HF	CRP	CRP	CRP	10	11	4	5
Notwithstanding the pleiotropic effects of resveratrol on proliferation , our ability to match CSNK1E suppression with two compounds that subsequently proved to be inhibitors of beta-catenin activity further supports the hypothesis that CSNK1E functions in breast cancer cells to promote beta-catenin signaling .	Notwithstanding the pleiotropic effects of resveratrol on proliferation, our ability to match CSNK1E suppression with two compounds that subsequently proved to be inhibitors of beta-catenin activity further supports the hypothesis that CSNK1E functions in breast cancer cells to promote beta-catenin signaling.	32	41	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CSNK1E	CSNK1E	CSNK1E	beta-catenin	beta-catenin	beta-catenin	32	33	40	41
Loss of CSNK1E Function Abrogates beta-Catenin Activity .	Loss of CSNK1E Function Abrogates beta-Catenin Activity.	2	6	Abrogates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CSNK1E	CSNK1E	CSNK1E	beta-Catenin	beta-Catenin	beta-Catenin	2	3	5	6
To validate the observation from the beta-catenin reporter screen , that CSNK1E is required for beta-catenin activity , we used the same two CSNK1E specific shRNA sequences that we tested above in an independent beta-catenin reporter assay and observed that suppression of CSNK1E reduces beta-catenin transcriptional activity by more than two-fold ( XREF_FIG ) .	To validate the observation from the beta-catenin reporter screen, that CSNK1E is required for beta-catenin activity, we used the same two CSNK1E specific shRNA sequences that we tested above in an independent beta-catenin reporter assay and observed that suppression of CSNK1E reduces beta-catenin transcriptional activity by more than two-fold (XREF_FIG).	40	46	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CSNK1E	CSNK1E	CSNK1E	beta-catenin	beta-catenin	beta-catenin	42	43	44	45
Thus , our data suggest that CKIepsilon modulates Wnt and beta-catenin and Fz/PCP signaling pathways via kinase dependent and -independent mechanisms .	Thus, our data suggest that CKIepsilon modulates Wnt and beta-catenin and Fz/PCP signaling pathways via kinase dependent and -independent mechanisms.	6	11	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CKIepsilon	CKIepsilon	CKIepsilon	beta-catenin	beta-catenin	beta-catenin	6	7	10	11
ATM phosphorylates CKIdelta to possibly regulate its ability to interact with , and subsequently promote Mdm2 destruction .	ATM phosphorylates CKIdelta to possibly regulate its ability to interact with, and subsequently promote Mdm2 destruction.	0	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CKIdelta	ATM phosphorylates CKIdelta	ckidelta	Mdm2	Mdm2	mdm2	2	3	15	16
Instead , the reduction of P-Smad3 and total Smad3 caused by CKIgamma2 overexpression could be rescued by pretreating the cells with the proteasome inhibitor , MG-132 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Instead, the reduction of P-Smad3 and total Smad3 caused by CKIgamma2 overexpression could be rescued by pretreating the cells with the proteasome inhibitor, MG-132 (XREF_FIG and XREF_SUPPLEMENTARY).	5	13	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CKIgamma2	CKIgamma2 overexpression	ckigamma2	P-Smad3	P-Smad3	p-smad3	11	12	5	6
It was previously showed that ectopically expressed , constitutively active chimeras between Wnt8 and Fz1 or overexpression of Wnt10b in pre-adipocytes and MSCs increased the levels of beta-catenin and inhibited adipogenesis by blocking the induction of the key transcription factors PPARG and CEBPA [ XREF_BIBR ] .	It was previously showed that ectopically expressed, constitutively active chimeras between Wnt8 and Fz1 or overexpression of Wnt10b in pre-adipocytes and MSCs increased the levels of beta-catenin and inhibited adipogenesis by blocking the induction of the key transcription factors PPARG and CEBPA [XREF_BIBR].	18	42	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	Wnt10b in pre-adipocytes and MSCs increased the levels of beta-catenin	beta-catenin	PPARG	PPARG	pparg	27	28	40	41
Another report has shown that deregulated APC and beta-catenin indirectly induced aberrant PPARgamma overexpression [ XREF_BIBR ] , explaining previous experimental data in APC Min /+ mice showing a promoting effect of PPARgamma on carcinogenesis [ XREF_BIBR ] .	Another report has shown that deregulated APC and beta-catenin indirectly induced aberrant PPARgamma overexpression [XREF_BIBR], explaining previous experimental data in APC Min /+ mice showing a promoting effect of PPARgamma on carcinogenesis [XREF_BIBR].	6	14	induced	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma overexpression	ppargamma	8	9	12	13
We found that high glucose stimulated miR-27a expression , which , by negatively targeting PPARgamma , activated beta-catenin signaling as evidenced by upregulation of beta-catenin target genes , snail1 and alpha-smooth muscle actin ( alpha-SMA ) and downregulation of podocyte specific markers podocin and synaptopodin .	We found that high glucose stimulated miR-27a expression, which, by negatively targeting PPARgamma, activated beta-catenin signaling as evidenced by upregulation of beta-catenin target genes, snail1 and alpha-smooth muscle actin (alpha-SMA) and downregulation of podocyte specific markers podocin and synaptopodin.	13	18	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	17	18	14	15
When cultures were grown in presence of indomethacin , which accelerates the rate of adipogenesis , twice daily LIV failed to inhibit adipogenesis , while HMS was efficacious causing reductions in adiponectin , PPARgamma and increasing beta-catenin ( XREF_FIG ) .	When cultures were grown in presence of indomethacin, which accelerates the rate of adipogenesis, twice daily LIV failed to inhibit adipogenesis, while HMS was efficacious causing reductions in adiponectin, PPARgamma and increasing beta-catenin (XREF_FIG).	29	38	increasing	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	36	37	33	34
XREF_BIBR , XREF_BIBR , XREF_BIBR A recent study of the mechanism of Wnt and beta-catenin-induced osteoblastogenesis revealed that Wnt and beta-catenin signaling allows activation of transcription factors important in osteoblastogenesis by suppressing CCAAT and enhancer binding protein alpha ( C/EBPa ) and peroxisome proliferator activated receptor gamma ( PPARgamma ) .	XREF_BIBR, XREF_BIBR, XREF_BIBR A recent study of the mechanism of Wnt and beta-catenin-induced osteoblastogenesis revealed that Wnt and beta-catenin signaling allows activation of transcription factors important in osteoblastogenesis by suppressing CCAAT and enhancer binding protein alpha (C/EBPa) and peroxisome proliferator activated receptor gamma (PPARgamma).	18	47	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	peroxisome proliferator activated receptor gamma	peroxisome proliferator activated receptor gamma	peroxisome proliferator activated receptor gamma	20	21	42	47
Myeloid specific PTEN ablation promotes beta-catenin , which in turn activates PPARgamma and Jagged-1 and Notch signaling , leading to augmented Foxp3 + Treg induction while inhibited RORgammat and IL-17A in IR triggered liver inflammation .	Myeloid specific PTEN ablation promotes beta-catenin, which in turn activates PPARgamma and Jagged-1 and Notch signaling, leading to augmented Foxp3 + Treg induction while inhibited RORgammat and IL-17A in IR triggered liver inflammation.	4	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	5	6	11	12
Activation of Wnt signaling and accumulation of beta-catenin stimulates osteoblastogenesis and suppresses adipogenesis by suppressing PPARgamma and C/EBPalpha .	Activation of Wnt signaling and accumulation of beta-catenin stimulates osteoblastogenesis and suppresses adipogenesis by suppressing PPARgamma and C/EBPalpha.	3	17	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	7	8	15	16
In numerous tissues , canonical WNT and beta-catenin pathway activation induces inactivation of PPARgamma , while PPARgamma activation induces inhibition of canonical WNT and beta-catenin signaling .	In numerous tissues, canonical WNT and beta-catenin pathway activation induces inactivation of PPARgamma, while PPARgamma activation induces inhibition of canonical WNT and beta-catenin signaling.	7	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	7	8	13	14
For instance , it has been shown , in colon cancer cells , that beta-catenin targets PPAR-gamma activity by increasing PPAR-gamma protein levels XREF_BIBR .	For instance, it has been shown, in colon cancer cells, that beta-catenin targets PPAR-gamma activity by increasing PPAR-gamma protein levels XREF_BIBR.	14	17	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	PPAR-gamma	PPAR-gamma	PPAR-gamma	14	15	16	17
However , knockdown of beta-catenin in PTEN deficient macrophages inhibited PPARgamma and Jagged-1 and Notch , which led to reduced Foxp3 + Tregs .	However, knockdown of beta-catenin in PTEN deficient macrophages inhibited PPARgamma and Jagged-1 and Notch, which led to reduced Foxp3 + Tregs.	2	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	4	5	10	11
In the current study , the enhancement of protein and gene expression of beta-catenin induced by MIR may have mediated the activation of transcription factors such as RUNX2 , and the downregulation of PPARgamma , thus biasing BMSC differentiation away from adipogenesis and towards osteoblastogenesis .	In the current study, the enhancement of protein and gene expression of beta-catenin induced by MIR may have mediated the activation of transcription factors such as RUNX2, and the downregulation of PPARgamma, thus biasing BMSC differentiation away from adipogenesis and towards osteoblastogenesis.	11	34	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-catenin	expression of beta-catenin	beta-catenin	PPARgamma	PPARgamma	ppargamma	13	14	33	34
It has been previously shown that Sparc influences adipogenesis in a beta-catenin dependent manner XREF_BIBR and PPARgamma activity is modulated by beta-catenin XREF_BIBR .	It has been previously shown that Sparc influences adipogenesis in a beta-catenin dependent manner XREF_BIBR and PPARgamma activity is modulated by beta-catenin XREF_BIBR.	16	22	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	21	22	16	17
Second , myeloid specific PTEN knockout promoted beta-catenin activation , which in turn induced PPARgamma activation , increased anti-inflammatory M2 macrophage differentiation and decreased pro inflammatory cytokines .	Second, myeloid specific PTEN knockout promoted beta-catenin activation, which in turn induced PPARgamma activation, increased anti-inflammatory M2 macrophage differentiation and decreased pro inflammatory cytokines.	7	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	7	8	14	15
It is interesting to investigate that whether beta-catenin mediates the restoration of PPARgamma by evodiamine in PDGF-BB-stimulated VSMCs .	It is interesting to investigate that whether beta-catenin mediates the restoration of PPARgamma by evodiamine in PDGF-BB-stimulated VSMCs.	7	13	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	7	8	12	13
XREF_BIBR - XREF_BIBR XREF_FIG shows a graphic representation of beta-catenin signaling mediated PPARgamma and Nrf2 regulation in the presence or absence of Wnt .	XREF_BIBR - XREF_BIBR XREF_FIG shows a graphic representation of beta-catenin signaling mediated PPARgamma and Nrf2 regulation in the presence or absence of Wnt.	9	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	beta-catenin	beta-catenin	beta-catenin	PPARgamma	PPARgamma	PPARgamma	9	10	12	13
It is well known that the Wnt and beta-catenin signaling reduces adipogenesis by blocking induction of PPAR-gamma and C/EBP-alpha 7 .	It is well known that the Wnt and beta-catenin signaling reduces adipogenesis by blocking induction of PPAR-gamma and C/EBP-alpha 7.	6	18	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	beta-catenin	beta-catenin	beta-catenin	PPAR-gamma	PPAR-gamma	PPAR-gamma	8	9	16	17
Evidence that p120 could direct nuclear localization of Kaiso was obtained by overexpressing p120 in Trp53 Delta and Delta -4 cells , which resulted in high cytoplasmic p120 and a reduction in nuclear Kaiso ( XREF_FIG ) .	Evidence that p120 could direct nuclear localization of Kaiso was obtained by overexpressing p120 in Trp53 Delta and Delta -4 cells, which resulted in high cytoplasmic p120 and a reduction in nuclear Kaiso (XREF_FIG).	2	9	direct	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	2	3	8	9
Luciferase reporter assay data confirmed that knockdown of p120ctn expression significantly reversed promoter regulatory effects of Kaiso .	Luciferase reporter assay data confirmed that knockdown of p120ctn expression significantly reversed promoter regulatory effects of Kaiso.	8	17	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p120ctn	p120ctn expression	p120ctn	Kaiso	Kaiso	kaiso	8	9	16	17
Also , Kaiso and p120ctn expression increased in cells at the wound border of an injured HCAEC monolayer to enhance wound closure 39 , indicating a protective effect of Kaiso in wounded endothelial cells .	Also, Kaiso and p120ctn expression increased in cells at the wound border of an injured HCAEC monolayer to enhance wound closure 39, indicating a protective effect of Kaiso in wounded endothelial cells.	4	30	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p120ctn	p120ctn expression	p120ctn	Kaiso	Kaiso	kaiso	4	5	29	30
In several contexts , Kaiso is negatively modulated by p120 or is positively modulated by delta-catenin 108 ( which was recently implicated in the modulation of chromatin in severe autism 152 ) .	In several contexts, Kaiso is negatively modulated by p120 or is positively modulated by delta-catenin 108 (which was recently implicated in the modulation of chromatin in severe autism 152).	4	13	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	9	10	4	5
A similar role has been described for p120-catenin , which can relieve Kaiso dependent transcriptional repression in the nucleus XREF_BIBR XREF_BIBR .	A similar role has been described for p120-catenin, which can relieve Kaiso dependent transcriptional repression in the nucleus XREF_BIBR XREF_BIBR.	5	15	relieve	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p120-catenin	p120-catenin	p120-catenin	Kaiso	Kaiso	Kaiso	7	8	12	13
It is unlikely that the complex binds to the Kaiso binding regions because p120 promotes dissociation of Kaiso from DNA .	It is unlikely that the complex binds to the Kaiso binding regions because p120 promotes dissociation of Kaiso from DNA.	13	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	13	14	17	18
The notion that the p120 and Kaiso signaling activated by p120 siRNA was facilitated by destabilization of microtubules is supported by the finding that p120 is capable of regulating microtubule dynamics in a cadherin independent manner XREF_BIBR .	The notion that the p120 and Kaiso signaling activated by p120 siRNA was facilitated by destabilization of microtubules is supported by the finding that p120 is capable of regulating microtubule dynamics in a cadherin independent manner XREF_BIBR.	4	11	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	10	11	6	7
P120ctn is the major binding partner of Kaiso and has been reported to promote the dissociation of Kaiso from KBS , thus relieving Kaiso mediated transcriptional repression XREF_BIBR , XREF_BIBR , XREF_BIBR .	P120ctn is the major binding partner of Kaiso and has been reported to promote the dissociation of Kaiso from KBS, thus relieving Kaiso mediated transcriptional repression XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	P120ctn	P120ctn	P120ctn	Kaiso	Kaiso	Kaiso	0	1	17	18
These modes of Kaiso modulation by p120 can open attractive perspectives in linking events on cell membrane and changes in nuclear gene expression .	These modes of Kaiso modulation by p120 can open attractive perspectives in linking events on cell membrane and changes in nuclear gene expression.	3	7	modulation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	p120	p120	p120	Kaiso	Kaiso	Kaiso	6	7	3	4
In Xenopus laevis , we demonstrate that Wnt signals result in Frodo mediated stabilization of p120-catenin , which , in turn , promotes Kaiso sequestration or removal from the nucleus .	In Xenopus laevis, we demonstrate that Wnt signals result in Frodo mediated stabilization of p120-catenin, which, in turn, promotes Kaiso sequestration or removal from the nucleus.	13	24	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p120-catenin	p120-catenin	p120-catenin	Kaiso	Kaiso	Kaiso	15	16	23	24
Here , we describe that Wnt induced p120-catenin phosphorylation at Ser268 and Ser269 also enhances its binding to the transcriptional factor Kaiso , preventing Kaiso mediated inhibition of the beta-catenin-Tcf-4 transcriptional complex .	Here, we describe that Wnt induced p120-catenin phosphorylation at Ser268 and Ser269 also enhances its binding to the transcriptional factor Kaiso, preventing Kaiso mediated inhibition of the beta-catenin-Tcf-4 transcriptional complex.	5	22	enhances	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	p120-catenin	Wnt induced p120-catenin phosphorylation at Ser268	p120-catenin	Kaiso	Kaiso	kaiso	7	8	21	22
Inhibitor of beta-catenin and TCF ( ICAT ) inhibits beta-catenin transcriptional activity by competing with T-cell factor and lymphoid enhancer factor .	Inhibitor of beta-catenin and TCF (ICAT) inhibits beta-catenin transcriptional activity by competing with T-cell factor and lymphoid enhancer factor.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	6	7	9	10
As expected , the overexpression of ICAT induced marked upregulation of mesenchymal marker vimentin and snail but downregulation of epithelial marker E-cadherin and beta-catenin in SiHa cells .	As expected, the overexpression of ICAT induced marked upregulation of mesenchymal marker vimentin and snail but downregulation of epithelial marker E-cadherin and beta-catenin in SiHa cells.	4	24	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ICAT	overexpression of ICAT	icat	beta-catenin	beta-catenin	beta-catenin	6	7	23	24
Inhibition of beta-catenin in chondrocytes by expressing ICAT ( Inhibitor of beta-catenin and TCF ) , a Wnt inhibitor , resulted in delayed skeletal growth postnatally with decreased proliferative and hypertrophic zones [ XREF_BIBR ] .	Inhibition of beta-catenin in chondrocytes by expressing ICAT (Inhibitor of beta-catenin and TCF), a Wnt inhibitor, resulted in delayed skeletal growth postnatally with decreased proliferative and hypertrophic zones [XREF_BIBR].	6	18	Inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	7	8	11	12
In addition , intracellular inhibitors of Wnt and beta-catenin signaling such as ICAT ( inhibitor of beta-catenin and TCF/LEF ) antagonize protein protein interactions between beta-catenin and nuclear transcription factor complexes bound to DNA 48 ( XREF_FIG ) .	In addition, intracellular inhibitors of Wnt and beta-catenin signaling such as ICAT (inhibitor of beta-catenin and TCF/LEF) antagonize protein protein interactions between beta-catenin and nuclear transcription factor complexes bound to DNA 48 (XREF_FIG).	6	13	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ICAT	ICAT	ICAT	beta-catenin	beta-catenin	beta-catenin	12	13	8	9
To further investigate this hypothesis , we demonstrated that siRNA mediated knockdown of CTNNBIP1 inhibited CTNNBIP1 production , which markedly increased beta-catenin activity .	To further investigate this hypothesis, we demonstrated that siRNA mediated knockdown of CTNNBIP1 inhibited CTNNBIP1 production, which markedly increased beta-catenin activity.	15	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CTNNBIP1	CTNNBIP1	CTNNBIP1	beta-catenin	beta-catenin	beta-catenin	15	16	21	22
Beta-catenin interacting protein one ( CTNNBIP1 ) negatively regulates the Wnt pathway by inhibiting the interaction of beta-catenin with Tcf4 and repressing beta-catenin-Tcf4-mediated transactivation XREF_BIBR .	Beta-catenin interacting protein one (CTNNBIP1) negatively regulates the Wnt pathway by inhibiting the interaction of beta-catenin with Tcf4 and repressing beta-catenin-Tcf4-mediated transactivation XREF_BIBR.	0	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CTNNBIP1	CTNNBIP1	CTNNBIP1	beta-catenin	beta-catenin	beta-catenin	5	6	17	18
Re-expression of alphaE-catenin in alphaE-catenin -/- cells rescued the cytoplasmic localization of Yap1 ( XREF_SUPPLEMENTARY ) .	Re-expression of alphaE-catenin in alphaE-catenin -/- cells rescued the cytoplasmic localization of Yap1 (XREF_SUPPLEMENTARY).	0	14	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	alphaE-catenin	Re-expression of alphaE-catenin	alphae-catenin	Yap1	Yap1	yap1	2	3	12	13
XREF_BIBR As a dimer , XREF_BIBR Smac targets both the BIR2 and BIR3 domains in XIAP concurrently and prevents the inhibition of XIAP not only to caspase-9 but also to caspase-3/-7.	XREF_BIBR As a dimer, XREF_BIBR Smac targets both the BIR2 and BIR3 domains in XIAP concurrently and prevents the inhibition of XIAP not only to caspase-9 but also to caspase-3/-7.	5	23	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	6	7	22	23
Although SMAC mimetics were originally designed to target XIAP , we found that AZD5582 preferentially degrades cIAP-1 and cIAP-2 .	Although SMAC mimetics were originally designed to target XIAP, we found that AZD5582 preferentially degrades cIAP-1 and cIAP-2.	1	9	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	1	2	8	9
Indeed , Puma induction triggered Smac release from the mitochondria and Smac induced distraction of XIAP from caspase-3 to result in the initial activation of caspase-3 .	Indeed, Puma induction triggered Smac release from the mitochondria and Smac induced distraction of XIAP from caspase-3 to result in the initial activation of caspase-3.	5	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac release from the mitochondria	smac	XIAP	XIAP	xiap	5	6	15	16
However , the release of mitochondrial Smac can antagonize the inhibition of XIAP .	However, the release of mitochondrial Smac can antagonize the inhibition of XIAP.	3	13	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	6	7	12	13
Structure based strategy has been employed to develop monovalent Smac mimetics designed to mimic the Smac AVPI binding motif and so target the XIAP BIR3 domain .	Structure based strategy has been employed to develop monovalent Smac mimetics designed to mimic the Smac AVPI binding motif and so target the XIAP BIR3 domain.	9	25	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	9	10	23	24
While the XIAP BIR3 protein effectively inhibits the activity of caspase-9 and caspase-3/-7, these Smac mimetics dose-dependently antagonize the inhibition of XIAP to caspase activity ( XREF_FIG ) .	While the XIAP BIR3 protein effectively inhibits the activity of caspase-9 and caspase-3/-7, these Smac mimetics dose-dependently antagonize the inhibition of XIAP to caspase activity (XREF_FIG).	14	22	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	14	15	21	22
Because most of monovalent Smac mimetics have been designed to target the BIR3 domain of XIAP , our data suggest that for the design of more effective monovalent Smac mimetics , their potency against XIAP BIR2 domain needs to be improved .	Because most of monovalent Smac mimetics have been designed to target the BIR3 domain of XIAP, our data suggest that for the design of more effective monovalent Smac mimetics, their potency against XIAP BIR2 domain needs to be improved.	4	16	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	4	5	15	16
Thus , it is not surprising that small-molecule Smac mimetics also target other IAP proteins , in addition to XIAP .	Thus, it is not surprising that small-molecule Smac mimetics also target other IAP proteins, in addition to XIAP.	8	20	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	8	9	19	20
5 Upon its release from the mitochondria into the cytosol , Smac triggers caspase-3 activation by neutralizing XIAP .	5 Upon its release from the mitochondria into the cytosol, Smac triggers caspase-3 activation by neutralizing XIAP.	11	18	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	11	12	17	18
Hence , this high-resolution crystal structure clearly shows that bivalent Smac mimetic 3 induces dimerization of XIAP BIR3 and provides a structural basis for high-affinity interaction .	Hence, this high-resolution crystal structure clearly shows that bivalent Smac mimetic 3 induces dimerization of XIAP BIR3 and provides a structural basis for high-affinity interaction.	9	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	10	11	16	17
Smac also suppresses the inhibitory activity of XIAP toward caspase-3 by cooperatively interacting with the BIR3 and BIR2 domains of XIAP .	Smac also suppresses the inhibitory activity of XIAP toward caspase-3 by cooperatively interacting with the BIR3 and BIR2 domains of XIAP.	0	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	0	1	7	8
Some studies reported that IAP proteins , such as XIAP , c-IAP1 , c-IAP2 and Apollon , degraded Smac through the ubiquitin pathway , while others reported that Smac promoted the degradation of survivin , cIAP1 , cIAP2 , but not XIAP and livin .	Some studies reported that IAP proteins, such as XIAP, c-IAP1, c-IAP2 and Apollon, degraded Smac through the ubiquitin pathway, while others reported that Smac promoted the degradation of survivin, cIAP1, cIAP2, but not XIAP and livin.	28	43	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	28	29	41	42
The results suggest that XIAP targeting by Smac agonists or XIAP-siRNA can be used as a synergistic strategy for cellular immunotherapy of Hodgkin lymphoma .	The results suggest that XIAP targeting by Smac agonists or XIAP-siRNA can be used as a synergistic strategy for cellular immunotherapy of Hodgkin lymphoma.	4	8	targeting	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	7	8	4	5
The precise mechanism by which Smac antagonizes the inhibition of XIAP to caspase-3/-7 is not completely clear .	The precise mechanism by which Smac antagonizes the inhibition of XIAP to caspase-3/-7 is not completely clear.	5	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	5	6	10	11
SMAC is a dimer and interacts with its four N-terminal amino acid residues ( AVPI ) with XIAP to abrogate XIAP mediated inhibition of caspases-3 and -9 leading to dissociation of bound caspases from XIAP .	SMAC is a dimer and interacts with its four N-terminal amino acid residues (AVPI) with XIAP to abrogate XIAP mediated inhibition of caspases-3 and -9 leading to dissociation of bound caspases from XIAP.	0	22	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	0	1	20	21
7 In its homodimer form , Smac protein binds concurrently to both the BIR2 and BIR3 domains of XIAP using two AVPI binding motifs and nullifies the inhibition of XIAP to caspase-9 and caspase-3/7 .	7 In its homodimer form, Smac protein binds concurrently to both the BIR2 and BIR3 domains of XIAP using two AVPI binding motifs and nullifies the inhibition of XIAP to caspase-9 and caspase-3/7.	6	30	nullifies	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	6	7	29	30
It was subsequently shown that dimeric SMAC protein concurrently interacts with both the BIR2 and BIR3 domains in XIAP , blocking the inhibition of XIAP BIR3 to caspase-9 activity , as well as the inhibition of XIAP BIR2 domain to caspase-3/-7 activity [ XREF_BIBR ] .	It was subsequently shown that dimeric SMAC protein concurrently interacts with both the BIR2 and BIR3 domains in XIAP, blocking the inhibition of XIAP BIR3 to caspase-9 activity, as well as the inhibition of XIAP BIR2 domain to caspase-3/-7 activity [XREF_BIBR].	6	25	blocking	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	6	7	24	25
While endogenous SMAC effectively targets c-IAP1 , c-IAP2 , and XIAP for degradation , SMAC mimetics or non SMAC IAP antagonists can be engineered to have more specificity towards certain IAPs over others .	While endogenous SMAC effectively targets c-IAP1, c-IAP2, and XIAP for degradation, SMAC mimetics or non SMAC IAP antagonists can be engineered to have more specificity towards certain IAPs over others.	1	11	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	2	3	10	11
Based upon their expected mode of action , Smac mimetics should antagonize the inhibition of XIAP BIR3 to caspase-9 by binding to the same site where caspase-9 binds .	Based upon their expected mode of action, Smac mimetics should antagonize the inhibition of XIAP BIR3 to caspase-9 by binding to the same site where caspase-9 binds.	8	16	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	8	9	15	16
The treatment of Smac mimetic did not affect the levels of XIAP , survivin , or Smac , but induced a complete dissociation of Smac and XIAP within 24 h in HNSCC cells ( XREF_FIG ) .	The treatment of Smac mimetic did not affect the levels of XIAP, survivin, or Smac, but induced a complete dissociation of Smac and XIAP within 24 h in HNSCC cells (XREF_FIG).	1	27	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	3	4	26	27
For example , Smac mimetics , small molecules which are under clinical development , mimic endogenous Smac/DIABLO and inhibit the inhibitors of apoptosis ( IAP ) proteins cIAP1/2 and XIAP , triggering TNF-alpha-dependent apoptosis .	For example, Smac mimetics, small molecules which are under clinical development, mimic endogenous Smac/DIABLO and inhibit the inhibitors of apoptosis (IAP) proteins cIAP1/2 and XIAP, triggering TNF-alpha-dependent apoptosis.	3	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	3	4	29	30
Additionally , SMAC mimetic targeting of XIAP prevents it from binding to caspase-3 , -7 , or -9 , thereby allowing caspase activation and apoptotic cell death to occur .	Additionally, SMAC mimetic targeting of XIAP prevents it from binding to caspase-3, -7, or -9, thereby allowing caspase activation and apoptotic cell death to occur.	2	7	targeting	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	2	3	6	7
Diablo Promotes Apoptosis by Removing Miha and Xiap from Processed Caspase 9 .	Diablo Promotes Apoptosis by Removing Miha and Xiap from Processed Caspase 9.	0	8	Promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Diablo	Diablo	Diablo	Xiap	Xiap	Xiap	0	1	7	8
43 The same study suggested that concurrent targeting of both XIAP and cIAP1 BIR3 by Smac mimetics may be required for effective inhibition of cell growth and induction of apoptosis in cancer cells .	43 The same study suggested that concurrent targeting of both XIAP and cIAP1 BIR3 by Smac mimetics may be required for effective inhibition of cell growth and induction of apoptosis in cancer cells.	7	16	targeting	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	15	16	10	11
In a recent report , in vitro treatment of HIV infected central memory T-cells with 3 SMAC mimetics ( birinapant , GDC-0152 and emblin ) targeting XIAP activity successfully induced a significant dose dependent increase in apoptosis [ XREF_BIBR ] .	In a recent report, in vitro treatment of HIV infected central memory T-cells with 3 SMAC mimetics (birinapant, GDC-0152 and emblin) targeting XIAP activity successfully induced a significant dose dependent increase in apoptosis [XREF_BIBR].	16	27	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	XIAP	XIAP	XIAP	16	17	26	27
The use of Smac mimetics in this setting may restore the XIAP and Smac balance , in turn restoring apoptosis and leading to improved patient outcomes .	The use of Smac mimetics in this setting may restore the XIAP and Smac balance, in turn restoring apoptosis and leading to improved patient outcomes.	3	14	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	3	4	11	12
However , since Smac alone was sufficient to promote caspase-3 activity in vitro by inactivating XIAP , we proposed the existence of a death receptor induced , Smac dependent and apoptosome independent pathway .	However, since Smac alone was sufficient to promote caspase-3 activity in vitro by inactivating XIAP, we proposed the existence of a death receptor induced, Smac dependent and apoptosome independent pathway.	3	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	3	4	15	16
The downregulation of IAPs by Smac 066 was confirmed in our Western blot analysis , where we observed decreased levels of cIAP1 , cIAP2 , and XIAP only in RA-FLS extracts treated with monomeric Smac 066 .	The downregulation of IAPs by Smac 066 was confirmed in our Western blot analysis, where we observed decreased levels of cIAP1, cIAP2, and XIAP only in RA-FLS extracts treated with monomeric Smac 066.	19	35	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	34	35	26	27
While the XIAP BIR3 protein effectively inhibits the activity of caspase-3/-7, these Smac mimetics dose-dependently antagonize the inhibition of XIAP to caspase activity .	While the XIAP BIR3 protein effectively inhibits the activity of caspase-3/-7, these Smac mimetics dose-dependently antagonize the inhibition of XIAP to caspase activity.	12	20	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	12	13	19	20
While monovalent Smac mimetics can potently antagonize the inhibition of XIAP BIR3 protein to the activity of caspase 9 , they are much less effective in antagonizing the inhibition of caspase-9 and 3 by XIAP protein containing both BIR2 and BIR3 domains .	While monovalent Smac mimetics can potently antagonize the inhibition of XIAP BIR3 protein to the activity of caspase 9, they are much less effective in antagonizing the inhibition of caspase-9 and 3 by XIAP protein containing both BIR2 and BIR3 domains.	2	12	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	XIAP	XIAP	XIAP	2	3	10	11
Having established that there is a Wnt3A induced LRP6 down-regulation and Wnt and LRP6 signaling decay after Wnt3A treatment , we then investigated the effects of Dkk1 on Wnt3A induced LRP6 down-regulation .	Having established that there is a Wnt3A induced LRP6 down-regulation and Wnt and LRP6 signaling decay after Wnt3A treatment, we then investigated the effects of Dkk1 on Wnt3A induced LRP6 down-regulation.	24	31	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	26	27	30	31
We found that treatment with Filipin III , an inhibitor of caveolae mediated endocytosis , induced LRP6 accumulation , enhanced Dkk1 induced LRP6 stabilization , and blocked Wnt3A induced LRP6 down-regulation in HT1080 LRP6 cells ( XREF_FIG ) .	We found that treatment with Filipin III, an inhibitor of caveolae mediated endocytosis, induced LRP6 accumulation, enhanced Dkk1 induced LRP6 stabilization, and blocked Wnt3A induced LRP6 down-regulation in HT1080 LRP6 cells (XREF_FIG).	20	23	induced	Positive_early_activation	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	20	21	22	23
Like RSpo1 , RSpo2-4 antagonize DKK1 activity by interfering with DKK1 mediated LRP6 and Kremen association .	Like RSpo1, RSpo2-4 antagonize DKK1 activity by interfering with DKK1 mediated LRP6 and Kremen association.	8	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	10	11	12	13
In addition , Dkk1 bridges Lrp6 and another transmembrane protein , Kremen , inducing endocytosis of Lrp6 .	In addition, Dkk1 bridges Lrp6 and another transmembrane protein, Kremen, inducing endocytosis of Lrp6.	3	17	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	Lrp6	Lrp6	Lrp6	3	4	16	17
It has been postulated that RSPO binds to Kremen and blocks DKK1 induced internalization of LRP6 XREF_BIBR .	It has been postulated that RSPO binds to Kremen and blocks DKK1 induced internalization of LRP6 XREF_BIBR.	11	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	11	12	15	16
There was still about 60 % LRP6 remaining after the cells were treated with Dkk1 for 9 h ( XREF_FIG ) .	There was still about 60% LRP6 remaining after the cells were treated with Dkk1 for 9 h (XREF_FIG).	1	19	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	14	15	6	7
It has been shown that RSPO1 stimulates Wnt and beta-catenin signaling by preventing DKK1 and Kremen- or RNF43 and ZNRF3 mediated turnover of LRP6 on the cell surface XREF_BIBR , XREF_BIBR .	It has been shown that RSPO1 stimulates Wnt and beta-catenin signaling by preventing DKK1 and Kremen- or RNF43 and ZNRF3 mediated turnover of LRP6 on the cell surface XREF_BIBR, XREF_BIBR.	13	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	13	14	23	24
These results suggest that Dkk1 induces the internalization of LRP6 to suppress its phosphorylation in the lipid raft and allows subsequent recycling of LRP6 so that it can be reused for signaling .	These results suggest that Dkk1 induces the internalization of LRP6 to suppress its phosphorylation in the lipid raft and allows subsequent recycling of LRP6 so that it can be reused for signaling.	4	24	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	4	5	23	24
DKK-1 has been reported to induce the internalization of LRP6 .	DKK-1 has been reported to induce the internalization of LRP6.	0	10	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DKK-1	DKK-1	DKK-1	LRP6	LRP6	LRP6	0	1	9	10
This causes either LRP6 activation in the case of Wnt3a or signal attenuation by Dkk-1 .	This causes either LRP6 activation in the case of Wnt3a or signal attenuation by Dkk-1.	3	15	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Dkk-1	Dkk-1	Dkk-1	LRP6	LRP6	LRP6	14	15	3	4
Dkk1 acts on cell surface to induce LRP6 accumulation .	Dkk1 acts on cell surface to induce LRP6 accumulation.	0	8	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	0	1	7	8
Dkk-1-induced clathrin endocytosis of LRP6 is consistent with the observation that Kremen1 co-localizes with clathrin but not caveolin on cell surface , and its cytosolic tail participates in clathrin mediated endocytosis by engaging AP-2 complex , with the D 466 XXXLV motif identified being the responsible sorting element for Dkk-1 mediated LRP6 down-regulation .	Dkk-1-induced clathrin endocytosis of LRP6 is consistent with the observation that Kremen1 co-localizes with clathrin but not caveolin on cell surface, and its cytosolic tail participates in clathrin mediated endocytosis by engaging AP-2 complex, with the D 466 XXXLV motif identified being the responsible sorting element for Dkk-1 mediated LRP6 down-regulation.	47	52	mediated	Positive_early_activation	Negative_activation	Positive_activation	Dkk-1	Dkk-1	Dkk-1	LRP6	LRP6	LRP6	49	50	51	52
However , while both DKK1 and Dab2 inhibit Wnt and beta-catenin signalling by promoting LRP6 internalization through the clathrin pathway , their inhibitory actions differ in several important aspects : ( 1 ) whereas Dab2 interacts with LRP6 ' s intracellular domain , DKK1 interacts with the extracellular domain of LRP6 ; ( 2 ) mere expression of DKK1 in cells induces internalization of LRP6 , whereas Dab2 expression has no effect on basal or Wnt3A induced LRP6 internalization .	However, while both DKK1 and Dab2 inhibit Wnt and beta-catenin signalling by promoting LRP6 internalization through the clathrin pathway, their inhibitory actions differ in several important aspects : (1) whereas Dab2 interacts with LRP6 's intracellular domain, DKK1 interacts with the extracellular domain of LRP6; (2) mere expression of DKK1 in cells induces internalization of LRP6, whereas Dab2 expression has no effect on basal or Wnt3A induced LRP6 internalization.	3	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	4	5	14	15
A study now suggests that Krms , in the absence of Dkk1 , potentiate Wnt signaling by maintaining LRP5 and LRP6 at the plasma membrane .	A study now suggests that Krms, in the absence of Dkk1, potentiate Wnt signaling by maintaining LRP5 and LRP6 at the plasma membrane.	9	21	potentiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	11	12	20	21
DKK1 was previously shown to induce the internalization and recycling of LRP6 via a Clathrin dependent mechanism XREF_BIBR , XREF_BIBR .	DKK1 was previously shown to induce the internalization and recycling of LRP6 via a Clathrin dependent mechanism XREF_BIBR, XREF_BIBR.	0	17	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	0	1	11	12
In the present study , we found that transfected Dkk1 induces LRP6 accumulation while inhibiting Wnt and LRP6 signaling .	In the present study, we found that transfected Dkk1 induces LRP6 accumulation while inhibiting Wnt and LRP6 signaling.	8	12	induces	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	9	10	11	12
Dkk-1 can form a ternary complex with Krm2 and LRP6 and induce rapid endocytosis and removal of LRP6 from the plasma membrane XREF_BIBR , XREF_BIBR .	Dkk-1 can form a ternary complex with Krm2 and LRP6 and induce rapid endocytosis and removal of LRP6 from the plasma membrane XREF_BIBR, XREF_BIBR.	0	18	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk-1	Dkk-1	Dkk-1	LRP6	LRP6	LRP6	0	1	17	18
DKK-1 inhibits Wnt signaling by disrupting the binding of LRP6 to the Wnt and FZD ligand and receptor complex [ XREF_BIBR ] .	DKK-1 inhibits Wnt signaling by disrupting the binding of LRP6 to the Wnt and FZD ligand and receptor complex [XREF_BIBR].	0	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DKK-1	DKK-1	DKK-1	LRP6	LRP6	LRP6	0	1	9	10
DKK1 or Wnt3A also fails to induce internalization of endogenous LRP6 XREF_BIBR , XREF_BIBR .	DKK1 or Wnt3A also fails to induce internalization of endogenous LRP6 XREF_BIBR, XREF_BIBR.	0	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	0	1	10	11
Previous studies have demonstrated that Dkk1 promotes LRP6 internalization and degradation when it forms a ternary complex with the cell surface receptor Kremen .	Previous studies have demonstrated that Dkk1 promotes LRP6 internalization and degradation when it forms a ternary complex with the cell surface receptor Kremen.	5	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	5	6	7	8
DKK-1 induces the internalization of LRP6 XREF_BIBR and LGK974 inhibits porcupine , a transmembrane protein located on the endoplasmic reticulum XREF_BIBR , while LPS acts on cell surface Toll like receptor 4 XREF_BIBR .	DKK-1 induces the internalization of LRP6 XREF_BIBR and LGK974 inhibits porcupine, a transmembrane protein located on the endoplasmic reticulum XREF_BIBR, while LPS acts on cell surface Toll like receptor 4 XREF_BIBR.	0	6	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DKK-1	DKK-1	DKK-1	LRP6	LRP6	LRP6	0	1	5	6
Curiously , the Wnt inhibitor Dkk1 also triggers an internalization of LRP6 through clathrin mediated endocytosis [ XREF_BIBR , XREF_BIBR ] .	Curiously, the Wnt inhibitor Dkk1 also triggers an internalization of LRP6 through clathrin mediated endocytosis [XREF_BIBR, XREF_BIBR].	2	12	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	5	6	11	12
When it interacts with Kremen1/2 , Dkk1 promotes LRP6 degradation XREF_BIBR - XREF_BIBR .	When it interacts with Kremen1/2, Dkk1 promotes LRP6 degradation XREF_BIBR - XREF_BIBR.	6	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	6	7	8	9
Dkk1 , on the other hand , induces internalization of LRP6 in a clathrin dependent manner and inhibits beta-cat activities .	Dkk1, on the other hand, induces internalization of LRP6 in a clathrin dependent manner and inhibits beta-cat activities.	0	17	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	LRP6	LRP6	LRP6	0	1	10	11
Inhibiting the activity of extracellular LRP6 antagonists such as DKK1 can also potentiate Wnt signaling XREF_BIBR .	Inhibiting the activity of extracellular LRP6 antagonists such as DKK1 can also potentiate Wnt signaling XREF_BIBR.	5	10	antagonists	Negative_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	DKK1	DKK1	DKK1	LRP6	LRP6	LRP6	9	10	5	6
The Smac mimetic LCL-161 , which targets cIAP1 and cIAP2 for degradation , modestly altered hair cell responses to aminoglycosides , with differing responses for neomycin and gentamicin .	The Smac mimetic LCL-161, which targets cIAP1 and cIAP2 for degradation, modestly altered hair cell responses to aminoglycosides, with differing responses for neomycin and gentamicin.	1	11	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	1	2	7	8
As such , rather than promoting tumor cell survival in the tumor microenvironment , TNF and LT-alpha may become cytotoxic in the presence of SMAC mimetics targeting cIAP1 and cIAP2 .	As such, rather than promoting tumor cell survival in the tumor microenvironment, TNF and LT-alpha may become cytotoxic in the presence of SMAC mimetics targeting cIAP1 and cIAP2.	24	29	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	cIAP1	cIAP1	cIAP1	24	25	27	28
Mechanistic studies have demonstrated that these monovalent and bivalent SMAC mimetics activate the E3 ubiquitin ligase activity of cIAP1 and cIAP2 that induce autoubiquitylation and degradation of cIAPs [ XREF_BIBR , XREF_BIBR ] .	Mechanistic studies have demonstrated that these monovalent and bivalent SMAC mimetics activate the E3 ubiquitin ligase activity of cIAP1 and cIAP2 that induce autoubiquitylation and degradation of cIAPs [XREF_BIBR, XREF_BIBR].	9	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	cIAP1	cIAP1	cIAP1	9	10	18	19
The Smac mimetic LCL-161 , which targets cIAP1 and cIAP2 for degradation and leads to caspase activation , modestly sensitized hair cells to gentamicin damage , with 10 muM LCL reducing hair cell survival by 18.4 % over gentamicin only .	The Smac mimetic LCL-161, which targets cIAP1 and cIAP2 for degradation and leads to caspase activation, modestly sensitized hair cells to gentamicin damage, with 10 muM LCL reducing hair cell survival by 18.4% over gentamicin only.	1	9	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	1	2	7	8
It has been well documented that Smac mimetic BV6 specifically targets cIAP1 and cIAP2 proteins to induce apoptosis through activating the TNFalpha signaling pathway [ XREF_BIBR , XREF_BIBR ] .	It has been well documented that Smac mimetic BV6 specifically targets cIAP1 and cIAP2 proteins to induce apoptosis through activating the TNFalpha signaling pathway [XREF_BIBR, XREF_BIBR].	6	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	cIAP1	cIAP1	cIAP1	6	7	11	12
An example of this phenomenon includes chronic lymphocytic leukemia ( CLL ) cells that are especially resistant to SMAC mimetics targeting cIAP1 and cIAP2 activity [ XREF_BIBR ] .	An example of this phenomenon includes chronic lymphocytic leukemia (CLL) cells that are especially resistant to SMAC mimetics targeting cIAP1 and cIAP2 activity [XREF_BIBR].	18	26	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	cIAP1	cIAP1	cIAP1	18	19	21	22
Birinapant is a novel bivalent peptidomimetic of SMAC , shown to preferentially target cIAP1 , relative to cIAP2 and XIAP .	Birinapant is a novel bivalent peptidomimetic of SMAC, shown to preferentially target cIAP1, relative to cIAP2 and XIAP.	5	15	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	cIAP1	cIAP1	cIAP1	7	8	13	14
In addition , in metastatic human colon and breast cancer cells , BIRC2 is the molecular target of ceramide , and the Smac mimetic , BV6 , targets BIRC2 to induce apoptosis via the TNFalpha signaling pathway [ XREF_BIBR , XREF_BIBR ] .	In addition, in metastatic human colon and breast cancer cells, BIRC2 is the molecular target of ceramide, and the Smac mimetic, BV6, targets BIRC2 to induce apoptosis via the TNFalpha signaling pathway [XREF_BIBR, XREF_BIBR].	21	29	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	BIRC2	BIRC2	BIRC2	22	23	28	29
Birinapant is a novel dimeric SMAC mimetic designed to specifically target cIAP1 and cIAP2 for degradation , resulting in a switch in TNFR signaling ; activation of TNFR upon binding of TNF-alpha in the presence of cIAP1 and cIAP2 leads to NF-kappaB activation and increased cell proliferation .	Birinapant is a novel dimeric SMAC mimetic designed to specifically target cIAP1 and cIAP2 for degradation, resulting in a switch in TNFR signaling; activation of TNFR upon binding of TNF-alpha in the presence of cIAP1 and cIAP2 leads to NF-kappaB activation and increased cell proliferation.	2	17	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	cIAP1	cIAP1	cIAP1	5	6	11	12
SMAC deficiency increased cIAP1 and cIAP2 expression , intestinal proliferation , and promoted p65 activation in APC Min/+ mice .	SMAC deficiency increased cIAP1 and cIAP2 expression, intestinal proliferation, and promoted p65 activation in APC Min/+ mice.	0	9	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	cIAP1	cIAP1	cIAP1	0	1	3	4
Targeted depletion of cIAP-1 by SMAC mimetics in conjunction with TRAIL may be beneficial for the treatment of human hepatobiliary malignancies .	Targeted depletion of cIAP-1 by SMAC mimetics in conjunction with TRAIL may be beneficial for the treatment of human hepatobiliary malignancies.	1	6	depletion	Negative_activation_token_2_noun	Negative_activation	Negative_activation	SMAC	SMAC	SMAC	cIAP-1	cIAP-1	cIAP-1	5	6	3	4
These bivalent SMAC mimetics are made up of two monovalent units linked by a chemical structure [ XREF_BIBR ] and have been shown to promote the dimerization of the BIR2-BIR3 domains of c-IAP1 , as well as BIR3 constructs of XIAP [ XREF_BIBR ] .	These bivalent SMAC mimetics are made up of two monovalent units linked by a chemical structure [XREF_BIBR] and have been shown to promote the dimerization of the BIR2-BIR3 domains of c-IAP1, as well as BIR3 constructs of XIAP [XREF_BIBR].	2	33	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	c-IAP1	c-IAP1	c-IAP1	2	3	32	33
To determine whether the mechanism by which Smac targets c-IAP1 for degradation was related to CD30 induced degradation of c-IAP1 , we used a mature cytosolic version of Smac that bypasses mitochondria [ XREF_BIBR ] .	To determine whether the mechanism by which Smac targets c-IAP1 for degradation was related to CD30 induced degradation of c-IAP1, we used a mature cytosolic version of Smac that bypasses mitochondria [XREF_BIBR].	7	13	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Smac	Smac	Smac	c-IAP1	c-IAP1	c-IAP1	7	8	9	10
Equal expression of both factors revealed a decrease in Dlx2 activation of the full-length Msx2 promoter from 20- to 5-fold ( XREF_FIG ) .	Equal expression of both factors revealed a decrease in Dlx2 activation of the full-length Msx2 promoter from 20- to 5-fold (XREF_FIG).	9	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Dlx2	Dlx2	Dlx2	Msx2	Msx2	Msx2	9	10	14	15
The full-length Lef-1 cDNA containing the betaBD activated the Msx2 promoter at ~ 6-fold and co-expression of Dlx2 synergistically activated the Msx2 promoter at ~ 40-fold in CHO cells ( XREF_FIG ) .	The full-length Lef-1 cDNA containing the betaBD activated the Msx2 promoter at ~ 6-fold and co-expression of Dlx2 synergistically activated the Msx2 promoter at ~ 40-fold in CHO cells (XREF_FIG).	15	22	synergistically activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dlx2	co-expression of Dlx2	dlx2	Msx2	Msx2	msx2	17	18	21	22
Dlx2 activation of Msx2 was demonstrated using three promoter constructs linked to the luciferase gene ( XREF_FIG ) .	Dlx2 activation of Msx2 was demonstrated using three promoter constructs linked to the luciferase gene (XREF_FIG).	0	4	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Dlx2	Dlx2	Dlx2	Msx2	Msx2	Msx2	0	1	3	4
Dlx2 and Lef-1 synergistically activate the Msx2 promoter .	Dlx2 and Lef-1 synergistically activate the Msx2 promoter.	0	7	synergistically activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dlx2	Dlx2	Dlx2	Msx2	Msx2	Msx2	0	1	6	7
Dlx2 activates the Msx2 promoter in several cell lines and binds DNA as a monomer and dimer .	Dlx2 activates the Msx2 promoter in several cell lines and binds DNA as a monomer and dimer.	0	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dlx2	Dlx2	Dlx2	Msx2	Msx2	Msx2	0	1	3	4
Dlx2 activated the full-length Msx2 promoter at ~ 20-fold in CHO cells ( XREF_FIG ) .	Dlx2 activated the full-length Msx2 promoter at ~ 20-fold in CHO cells (XREF_FIG).	0	5	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dlx2	Dlx2	Dlx2	Msx2	Msx2	Msx2	0	1	4	5
The synergistic activation of the Msx2 promoter by Dlx2 and Lef-1 FL was decreased from ~ 38-fold without Msx2 to 28-fold ( 1.25 mug Msx2 ) , 17-fold ( 2.5 mug Msx2 ) and 9-fold ( 3.75 mug Msx2 ) .	The synergistic activation of the Msx2 promoter by Dlx2 and Lef-1 FL was decreased from ~ 38-fold without Msx2 to 28-fold (1.25 mug Msx2), 17-fold (2.5 mug Msx2) and 9-fold (3.75 mug Msx2).	5	11	promoter	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Dlx2	Dlx2	Dlx2	Msx2	Msx2	Msx2	8	9	5	6
Thus , Dlx2 and Lef-1 interact to synergistically activate Msx2 ; Msx2 can attenuate Dlx2 activation or directly repress Msx2 promoter activity .	Thus, Dlx2 and Lef-1 interact to synergistically activate Msx2; Msx2 can attenuate Dlx2 activation or directly repress Msx2 promoter activity.	2	10	synergistically activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dlx2	Dlx2	Dlx2	Msx2	Msx2	Msx2	2	3	9	10
The activation levels were decreased however , the relative activation of the Msx2 promoter by Dlx2 and Lef-1 were similar .	The activation levels were decreased however, the relative activation of the Msx2 promoter by Dlx2 and Lef-1 were similar.	12	17	promoter	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Dlx2	Dlx2	Dlx2	Msx2	Msx2	Msx2	15	16	12	13
Following mitogenic stimulation , DEPTOR is targeted for degradation by betaTrCP , resulting in mTOR activation and cell proliferation 31 - 33 .	Following mitogenic stimulation, DEPTOR is targeted for degradation by betaTrCP, resulting in mTOR activation and cell proliferation 31 - 33.	4	15	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	4	5	14	15
Alcohol supplementation inhibited MTOR signaling by down-regulating pMTOR and increasing expression of Deptor , which promotes MTOR degradation ( XREF_TABLE ) .	Alcohol supplementation inhibited MTOR signaling by down-regulating pMTOR and increasing expression of Deptor, which promotes MTOR degradation (XREF_TABLE).	10	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Deptor	expression of Deptor	deptor	MTOR	MTOR	mtor	12	13	16	17
Loss of Deptor leads to activation of mTOR targets and AKT , whereas overexpression inhibits mTORC1 but activates PI3K-I-AKT signalling .	Loss of Deptor leads to activation of mTOR targets and AKT, whereas overexpression inhibits mTORC1 but activates PI3K-I-AKT signalling.	0	8	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Deptor	Loss of Deptor	deptor	mTOR	mTOR	mtor	2	3	7	8
This is likely because p38gamma and p38delta act through the mTOR modulator DEPTOR , so that the lack of p38gamma and p38delta results only in partial inhibition of mTOR activity .	This is likely because p38gamma and p38delta act through the mTOR modulator DEPTOR, so that the lack of p38gamma and p38delta results only in partial inhibition of mTOR activity.	7	13	modulator	Positive_activation_token_1_noun	Negative_activation	Positive_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	12	13	10	11
Taken together , we would like to propose the following ( XREF_FIG ) that builds upon the model proposal shown in the study by Cai et al : under normal conditions , mTOR activity is modulated by DEPTOR .	Taken together, we would like to propose the following (XREF_FIG) that builds upon the model proposal shown in the study by Cai et al : under normal conditions, mTOR activity is modulated by DEPTOR.	32	38	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	37	38	32	33
We recently reported that an adaptor called DEP domain containing mTOR interacting protein ( DEPTOR ) that is known to modulate mTOR signaling [ XREF_BIBR ] has marked effects on EC activation responses [ XREF_BIBR ] .	We recently reported that an adaptor called DEP domain containing mTOR interacting protein (DEPTOR) that is known to modulate mTOR signaling [XREF_BIBR] has marked effects on EC activation responses [XREF_BIBR].	12	22	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	14	15	21	22
Thus , we concluded from these results that blockade of neddylation have inhibitory effects on DCs , which were induced by Deptor accumulation driven mTOR signaling inactivation .	Thus, we concluded from these results that blockade of neddylation have inhibitory effects on DCs, which were induced by Deptor accumulation driven mTOR signaling inactivation.	21	26	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Deptor	Deptor	Deptor	mTOR	mTOR	mTOR	21	22	24	25
Our findings provide new systems-level insights into the complexity of mTOR signalling contributed by DEPTOR .	Our findings provide new systems-level insights into the complexity of mTOR signalling contributed by DEPTOR.	10	15	contributed	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	14	15	10	11
These results indicate that TGFbeta induces a deptor independent rapid activation of mTOR ; however , expression of collagen I ( alpha2 ) requires deptor mediated activation of mTOR induced by prolonged TGFbeta treatment ( XREF_FIG , XREF_FIG and XREF_FIG ) .	These results indicate that TGFbeta induces a deptor independent rapid activation of mTOR; however, expression of collagen I (alpha2) requires deptor mediated activation of mTOR induced by prolonged TGFbeta treatment (XREF_FIG, XREF_FIG and XREF_FIG).	24	29	mediated	Positive_early_activation	Negative_activation	Positive_activation	deptor	deptor	deptor	mTOR	mTOR	mTOR	24	25	28	29
Rapid DEPTOR destruction may underlie activation of mTOR kinase activity when cells are shifted from unfavorable to favorable environments .	Rapid DEPTOR destruction may underlie activation of mTOR kinase activity when cells are shifted from unfavorable to favorable environments.	1	9	underlie	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DEPTOR	DEPTOR	DEPTOR	mTOR	mTOR	mTOR	1	2	7	8
The cleaved DFF45 fragments dissociate from DFF40 , allowing DFF40 to oligomerize to form a large functional complex that cleaves DNA by introducing double strand breaks .	The cleaved DFF45 fragments dissociate from DFF40, allowing DFF40 to oligomerize to form a large functional complex that cleaves DNA by introducing double strand breaks.	2	11	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DFF45	DFF45	DFF45	DFF40	DFF40	DFF40	2	3	9	10
Upon apoptosis induction , DFF45 is cleaved by caspases to allow DFF40 activation .	Upon apoptosis induction, DFF45 is cleaved by caspases to allow DFF40 activation.	4	12	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DFF45	DFF45	DFF45	DFF40	DFF40	DFF40	4	5	11	12
XREF_BIBR DFFA has been postulated to stabilize the synthesis of DFFB , XREF_BIBR , XREF_BIBR or mediate the correct folding and chromatin localization of DFFB .	XREF_BIBR DFFA has been postulated to stabilize the synthesis of DFFB, XREF_BIBR, XREF_BIBR or mediate the correct folding and chromatin localization of DFFB.	0	25	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DFFA	DFFA	DFFA	DFFB	DFFB	DFFB	1	2	24	25
During apoptosis , DFF-40 and CAD is activated by caspase-3-mediated cleavage of DFF45 and ICAD .	During apoptosis, DFF-40 and CAD is activated by caspase-3-mediated cleavage of DFF45 and ICAD.	3	14	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	DFF45	DFF45	DFF45	DFF-40	DFF-40	DFF-40	12	13	3	4
During apoptosis , Caspase-3 and Caspase-7-mediated cleavage of DFF45 induces the release and activation of DFF40 , leading to the generation of double stranded breaks in inter-nucleosomal chromatin regions and chromatin condensation [ XREF_BIBR ] .	During apoptosis, Caspase-3 and Caspase-7-mediated cleavage of DFF45 induces the release and activation of DFF40, leading to the generation of double stranded breaks in inter-nucleosomal chromatin regions and chromatin condensation [XREF_BIBR].	6	16	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DFF45	DFF45	DFF45	DFF40	DFF40	DFF40	8	9	15	16
The cleaved DFF45 dissociates from DFF40 , inducing the oligomerization of DFF40 that has DNase activity .	The cleaved DFF45 dissociates from DFF40, inducing the oligomerization of DFF40 that has DNase activity.	0	12	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DFF45	DFF45	DFF45	DFF40	DFF40	DFF40	2	3	11	12
Altogether , these results demonstrated that the SMAC mimetic BV6 is indeed able to suppress the inhibitory effect of cIAP2 on full maturation of caspase-3 complexes and thereby promote microglial cell death ( XREF_FIG ) .	Altogether, these results demonstrated that the SMAC mimetic BV6 is indeed able to suppress the inhibitory effect of cIAP2 on full maturation of caspase-3 complexes and thereby promote microglial cell death (XREF_FIG).	7	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAC	SMAC	SMAC	cIAP2	cIAP2	cIAP2	7	8	19	20
These results indicated that in BMP2 stimulated osteoprogenitors the Wnt3a dependent inhibition of ALP is partially abrogated by Dkk1 and -2 .	These results indicated that in BMP2 stimulated osteoprogenitors the Wnt3a dependent inhibition of ALP is partially abrogated by Dkk1 and -2.	9	20	abrogated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	18	19	9	10
As a result , the Polymerization of and MAP-2 and NF-H induced by Abeta25-35 could be significantly inhibited by Wnt3a ( 40ng/ml ) , however enhanced by Dkk1 ( 100ng/ml ) .	As a result, the Polymerization of and MAP-2 and NF-H induced by Abeta25-35 could be significantly inhibited by Wnt3a (40ng/ml), however enhanced by Dkk1 (100ng/ml).	17	29	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	27	28	19	20
To address this question , we assessed the effects of DKK1 on CFZ induced ALP activity in the absence or presence of Wnt3a ( as positive control for indicating function of DKK1 ) in the differentiation medium for primary MSCs from two patients with MM .	To address this question, we assessed the effects of DKK1 on CFZ induced ALP activity in the absence or presence of Wnt3a (as positive control for indicating function of DKK1) in the differentiation medium for primary MSCs from two patients with MM.	8	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	10	11	22	23
Interestingly , DKK1 potentiated Wnt3a induced exosomes secretion , whilst DKK1 challenge alone did not stimulate exosomes release .	Interestingly, DKK1 potentiated Wnt3a induced exosomes secretion, whilst DKK1 challenge alone did not stimulate exosomes release.	2	5	potentiated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	2	3	4	5
Dkk1 abrogates the suppressive effect of Wnt3a on M-CSF production in BMP2 stimulated cells .	Dkk1 abrogates the suppressive effect of Wnt3a on M-CSF production in BMP2 stimulated cells.	0	7	abrogates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	0	1	6	7
When used concurrently with Wnt3a , however , Dkk-1 blocked the inhibitory effect of Wnt3a .	When used concurrently with Wnt3a, however, Dkk-1 blocked the inhibitory effect of Wnt3a.	8	15	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk-1	Dkk-1	Dkk-1	Wnt3a	Wnt3a	Wnt3a	8	9	14	15
Dkk1 prevents Wnt3a mediated inhibition of VCAM-1 .	Dkk1 prevents Wnt3a mediated inhibition of VCAM-1.	0	4	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	0	1	2	3
In fact , DKK1 potentiated Wnt3a induced exosome release as measured by the presence of beta-actin in the 100000xg fraction , which provides a surrogate measure for total exosomal protein .	In fact, DKK1 potentiated Wnt3a induced exosome release as measured by the presence of beta-actin in the 100000xg fraction, which provides a surrogate measure for total exosomal protein.	3	6	potentiated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	3	4	5	6
As shown in XREF_FIG , after a 3- day treatment , more proliferating cells were observed in cultures treated with Wnt3a ( XREF_FIG ) , and fewer proliferating cells in cultures treated with DKK1 ( XREF_FIG ) , as compared to the control cultures ( XREF_FIG ) .	As shown in XREF_FIG, after a 3- day treatment, more proliferating cells were observed in cultures treated with Wnt3a (XREF_FIG), and fewer proliferating cells in cultures treated with DKK1 (XREF_FIG), as compared to the control cultures (XREF_FIG).	18	35	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	DKK1	DKK1	DKK1	Wnt3a	Wnt3a	Wnt3a	33	34	20	21
In this circumstance , soluble Dkk1 prevented Wnt3a mediated inhibition of VCAM-1 on the GFP - cell population .	In this circumstance, soluble Dkk1 prevented Wnt3a mediated inhibition of VCAM-1 on the GFP - cell population.	4	9	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	5	6	7	8
Western blot assays also demonstrated that Wnt3a overexpressing cells treated with Dkk1 had higher expression of E-cadherin and lower expression of vimentin , Snail , and Twist compared with untreated cells .	Western blot assays also demonstrated that Wnt3a overexpressing cells treated with Dkk1 had higher expression of E-cadherin and lower expression of vimentin, Snail, and Twist compared with untreated cells.	6	12	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Dkk1	Dkk1	Dkk1	Wnt3a	Wnt3a	Wnt3a	11	12	6	7
It has been shown that the tumor suppressor CYLD targets TRAF6 for deubiquitination to terminate TLR triggered activation of NF-kappaB XREF_BIBR XREF_BIBR .	It has been shown that the tumor suppressor CYLD targets TRAF6 for deubiquitination to terminate TLR triggered activation of NF-kappaB XREF_BIBR XREF_BIBR.	5	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	TRAF6	TRAF6	TRAF6	8	9	10	11
CYLD has been shown to target TRAF6 , TRAF2 , and NEMO for deubiquitination , thus presumably reduced their activities in NF-kappaB activation .	CYLD has been shown to target TRAF6, TRAF2, and NEMO for deubiquitination, thus presumably reduced their activities in NF-kappaB activation.	0	7	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CYLD	CYLD	CYLD	TRAF6	TRAF6	TRAF6	0	1	6	7
Our data thus suggests that CYLD inhibits NF-kappaB by targeting TRAF6 and 7 .	Our data thus suggests that CYLD inhibits NF-kappaB by targeting TRAF6 and 7.	5	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	TRAF6	TRAF6	TRAF6	5	6	10	11
It has been demonstrated that the deubiquitinating enzymes A20 and CYLD inhibit NF-kappaB signaling by targeting TRAF6 upstream of IKK , while the deubiquitinating protein DUBA inhibits type I interferon activity by targeting TRAF3 .	It has been demonstrated that the deubiquitinating enzymes A20 and CYLD inhibit NF-kappaB signaling by targeting TRAF6 upstream of IKK, while the deubiquitinating protein DUBA inhibits type I interferon activity by targeting TRAF3.	8	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	TRAF6	TRAF6	TRAF6	10	11	16	17
40 RANKL stimulated osteoclastogenesis potently induces the expression of CYLD , and the accumulated CYLD targets TRAF6 by interacting with the adaptor protein , p62 .	40 RANKL stimulated osteoclastogenesis potently induces the expression of CYLD, and the accumulated CYLD targets TRAF6 by interacting with the adaptor protein, p62.	2	18	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	CYLD	CYLD	CYLD	TRAF6	TRAF6	TRAF6	14	15	16	17
The deubiquitinating enzymes A20 and CYLD inhibit NF-kappaB signaling by targeting TRAF6 upstream of IKK , while a recent report shows that CUEDC2 inhibits IKK activity by recruiting a phosphatase PP1 and keeps IKK in an inactivated status .	The deubiquitinating enzymes A20 and CYLD inhibit NF-kappaB signaling by targeting TRAF6 upstream of IKK, while a recent report shows that CUEDC2 inhibits IKK activity by recruiting a phosphatase PP1 and keeps IKK in an inactivated status.	3	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CYLD	CYLD	CYLD	TRAF6	TRAF6	TRAF6	5	6	11	12
As shown in XREF_FIG A549 cells depleted of DAPK2 have reduced DAPK1 phosphorylated on S308 , which is an inactivating phosphorylation event that modulates DAPK1 activity .	As shown in XREF_FIG A549 cells depleted of DAPK2 have reduced DAPK1 phosphorylated on S308, which is an inactivating phosphorylation event that modulates DAPK1 activity.	10	25	modulates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	DAPK1	DAPK1 phosphorylated on S308	dapk1	DAPK1	DAPK1	dapk1	11	12	24	25
ERK phosphorylates DAPK at Ser734 , thereby increasing DAPK catalytic activity both in vitro and in vivo [ XREF_BIBR ] .	ERK phosphorylates DAPK at Ser734, thereby increasing DAPK catalytic activity both in vitro and in vivo [XREF_BIBR].	0	18	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DAPK	ERK phosphorylates DAPK at Ser734	dapk	DAPK	DAPK	dapk	2	3	8	9
Hypermethylation of the DAPK promoter region induces DAPK deficiency and this has been confirmed as a common phenomenon in B-cell malignancies , such as follicular lymphoma , diffuse large B-cell lymphoma , and Burkitt ' s lymphoma .	Hypermethylation of the DAPK promoter region induces DAPK deficiency and this has been confirmed as a common phenomenon in B-cell malignancies, such as follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt 's lymphoma.	0	8	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DAPK	Hypermethylation of the DAPK	dapk	DAPK	DAPK	dapk	3	4	7	8
This indicates that DAPK could be activated by NMDA receptor mediated calcium flux , activation of calcineurin , and subsequent DAPK dephosphorylation .	This indicates that DAPK could be activated by NMDA receptor mediated calcium flux, activation of calcineurin, and subsequent DAPK dephosphorylation.	3	22	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	DAPK	NMDA receptor mediated calcium flux, activation of calcineurin, and subsequent DAPK dephosphorylation	dapk	DAPK	DAPK	dapk	20	21	3	4
Conversely , application of NMDA receptor antagonist or removal of extracellular Ca 2+ inhibits DAPK1 dephosphorylation at pS 308 and inactivates DAPK1 ( XREF_FIG , see also XREF_SUPPLEMENTARY ) .	Conversely, application of NMDA receptor antagonist or removal of extracellular Ca 2+ inhibits DAPK1 dephosphorylation at pS 308 and inactivates DAPK1 (XREF_FIG, see also XREF_SUPPLEMENTARY).	4	23	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DAPK1	NMDA receptor antagonist or removal of extracellular Ca 2+ inhibits DAPK1 dephosphorylation	dapk1	DAPK1	DAPK1	dapk1	14	15	21	22
Instead , it has been suggested that Daxx mediates Fas- and TGF-beta-induced cell death through Ask1-Jnk activation [ XREF_BIBR , XREF_BIBR ] .	Instead, it has been suggested that Daxx mediates Fas- and TGF-beta-induced cell death through Ask1-Jnk activation [XREF_BIBR, XREF_BIBR].	7	13	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Daxx	Daxx	Daxx	Fas-	Fas-	Fas-	7	8	9	10
Daxx has been reported to mediate the Fas and JNK dependent signals in the cytoplasm .	Daxx has been reported to mediate the Fas and JNK dependent signals in the cytoplasm.	0	11	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Daxx	Daxx	Daxx	Fas	Fas	Fas	0	1	7	8
A subsequent study showed that although DAXX specifically enhances FAS function , the human homolog of DAXX ( hDAXX ) does not bind FAS and instead is found in the nucleus , where it localizes to promyelocytic leukemia protein ( PML ) oncogenic domains ( PODs ) [ XREF_BIBR ] .	A subsequent study showed that although DAXX specifically enhances FAS function, the human homolog of DAXX (hDAXX) does not bind FAS and instead is found in the nucleus, where it localizes to promyelocytic leukemia protein (PML) oncogenic domains (PODs) [XREF_BIBR].	6	10	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DAXX	DAXX	DAXX	FAS	FAS	FAS	6	7	9	10
Downregulation of DAB2IP could activate the ERK and Akt pathways and was correlated with the expression of epithelial-mesenchymal transition markers , such as E-cadherin and vimentin .	Downregulation of DAB2IP could activate the ERK and Akt pathways and was correlated with the expression of epithelial-mesenchymal transition markers, such as E-cadherin and vimentin.	0	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DAB2IP	DAB2IP	DAB2IP	Akt	Akt	Akt	2	3	8	9
These data showed that downregulation of DAB2IP could activate ERK or Akt in the presence of DAB2IP siRNA to knock down endogenous DAB2IP levels in bladder cancer cell lines .	These data showed that downregulation of DAB2IP could activate ERK or Akt in the presence of DAB2IP siRNA to knock down endogenous DAB2IP levels in bladder cancer cell lines.	4	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DAB2IP	DAB2IP	DAB2IP	Akt	Akt	Akt	6	7	11	12
Thus , DAB2IP suppresses growth and metastasis of NPC probably by targeting PI3K and Akt pathway , and may act as a hopeful therapeutic target for NPC .	Thus, DAB2IP suppresses growth and metastasis of NPC probably by targeting PI3K and Akt pathway, and may act as a hopeful therapeutic target for NPC.	2	19	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DAB2IP	DAB2IP	DAB2IP	Akt	Akt	Akt	2	3	14	15
Here we review recent progress on the structural and functional characterization of P58IPK , and discuss the possible mechanisms by which P58IPK modulates PKR and induces tumorigenesis in view of present knowledge of TPR proteins and molecular chaperones .	Here we review recent progress on the structural and functional characterization of P58IPK, and discuss the possible mechanisms by which P58IPK modulates PKR and induces tumorigenesis in view of present knowledge of TPR proteins and molecular chaperones.	21	25	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	P58IPK	P58IPK	P58IPK	PKR	PKR	PKR	21	22	23	24
However , Dlx5 completely reverses Msx2 repression of the OC promoter .	However, Dlx5 completely reverses Msx2 repression of the OC promoter.	2	6	reverses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Dlx5	Dlx5	Dlx5	Msx2	Msx2	Msx2	2	3	5	6
Finally , Dlx5 reverses Msx2 inhibition of OC promoter activation by FGF2 and forskolin .	Finally, Dlx5 reverses Msx2 inhibition of OC promoter activation by FGF2 and forskolin.	2	5	reverses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Dlx5	Dlx5	Dlx5	Msx2	Msx2	Msx2	2	3	4	5
However , depletion of Smac could not rescue the remarkable downregulation of SIRT1 and survivin by RSV and CFZ combination treatment .	However, depletion of Smac could n't rescue the remarkable downregulation of SIRT1 and survivin by RSV and CFZ combination treatment.	2	15	rescue	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Smac	Smac	Smac	survivin	survivin	survivin	4	5	14	15
It was found that MA treatment increased the protein expression of Smac and decreased the protein levels of c-IAP1 , c-IAP2 , X linked inhibitor of apoptosis protein ( XIAP ) and Survivin in a dose dependent manner .	It was found that MA treatment increased the protein expression of Smac and decreased the protein levels of c-IAP1, c-IAP2, X linked inhibitor of apoptosis protein (XIAP) and Survivin in a dose dependent manner.	4	37	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smac	MA treatment increased the protein expression of Smac	smac	Survivin	Survivin	survivin	11	12	32	33
Interestingly , BTICs produce desert hedgehog ( DHH ) ligand , enabling a paracrine DHH and Ptch2 signaling cascade that culminates in vascular leakage and increased angiogenic potential .	Interestingly, BTICs produce desert hedgehog (DHH) ligand, enabling a paracrine DHH and Ptch2 signaling cascade that culminates in vascular leakage and increased angiogenic potential.	5	18	enabling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DHH	DHH	DHH	Ptch2	Ptch2	Ptch2	7	8	16	17
Interestingly , BTICs produce desert hedgehog ( DHH ) ligand , enabling a paracrine DHH and Ptch2 signaling cascade that conveys elevated permeability and angiogenesis .	Interestingly, BTICs produce desert hedgehog (DHH) ligand, enabling a paracrine DHH and Ptch2 signaling cascade that conveys elevated permeability and angiogenesis.	5	18	enabling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DHH	DHH	DHH	Ptch2	Ptch2	Ptch2	7	8	16	17
Importantly , phosphorylation of DAPK2 by AMPK enhances DAPK2 ' s ability to phosphorylate Beclin-1 , and depletion of DAPK2 reduces autophagy in response to AMPK activation .	Importantly, phosphorylation of DAPK2 by AMPK enhances DAPK2 's ability to phosphorylate Beclin-1, and depletion of DAPK2 reduces autophagy in response to AMPK activation.	2	13	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DAPK2	phosphorylation of DAPK2	dapk2	DAPK2	DAPK2	dapk2	4	5	8	9
XREF_BIBR , XREF_BIBR Indeed , our previous study has shown that DAB2IP can modulate AR activities and PCa cell growth .	XREF_BIBR, XREF_BIBR Indeed, our previous study has shown that DAB2IP can modulate AR activities and PCa cell growth.	11	15	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DAB2IP	DAB2IP	DAB2IP	AR	AR	AR	11	12	14	15
Previously , we reported that DAB2IP modulated androgen receptor activation in the development of castration resistant PCa ; however , its direct action on the failure of androgen deprivation therapy ( ADT ) remains largely unknown .	Previously, we reported that DAB2IP modulated androgen receptor activation in the development of castration resistant PCa; however, its direct action on the failure of androgen deprivation therapy (ADT) remains largely unknown.	5	9	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DAB2IP	DAB2IP	DAB2IP	androgen receptor	androgen receptor	androgen receptor	5	6	7	9
Knockdown of Dpr1 by RNA interference up-regulates endogenous Dvl2 protein .	Knockdown of Dpr1 by RNA interference up-regulates endogenous Dvl2 protein.	0	9	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Dpr1	Dpr1	Dpr1	Dvl2	Dvl2	Dvl2	2	3	8	9
Specifically , DPR1 enhances the interaction of Dvl2 with the Von Hippel-Lindau tumor suppressor ( pVHL ) , an E3 ubiquitin ligase component , resulting in Dvl2 ubiquitination and degradation in lysosomes 25 .	Specifically, DPR1 enhances the interaction of Dvl2 with the Von Hippel-Lindau tumor suppressor (pVHL), an E3 ubiquitin ligase component, resulting in Dvl2 ubiquitination and degradation in lysosomes 25.	2	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DPR1	DPR1	DPR1	Dvl2	Dvl2	Dvl2	2	3	7	8
Interestingly , coexpression of MKK7 and CYLD restored the nuclear presence of Bcl3 in melanoma tissues ( XREF_SUPPLEMENTARY ) .	Interestingly, coexpression of MKK7 and CYLD restored the nuclear presence of Bcl3 in melanoma tissues (XREF_SUPPLEMENTARY).	2	13	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CYLD	coexpression of MKK7 and CYLD	cyld	Bcl3	Bcl3	bcl3	6	7	12	13
The regulation of TRAF2 signaling by CYLD was identified by screening an RNAi library targeting DUBs for ones that attenuate NFkappaB activation [ XREF_BIBR ] and through a two-hybrid screen for proteins that interact with the regulatory subunit of the IkappaB kinase complex that could also bind to TRAF2 [ XREF_BIBR ] .	The regulation of TRAF2 signaling by CYLD was identified by screening an RNAi library targeting DUBs for ones that attenuate NFkappaB activation [XREF_BIBR] and through a two-hybrid screen for proteins that interact with the regulatory subunit of the IkappaB kinase complex that could also bind to TRAF2 [XREF_BIBR].	3	7	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	CYLD	CYLD	CYLD	TRAF2	TRAF2	TRAF2	6	7	3	4
19 We conclude that DAB2IP can modulate STAT3 activation and reprograms its target gene expression ( i.e ., survivin , Bcl-2 and Bax ) , which will shift the balance from pro apoptotic to anti-apoptotic activities under androgen depleted condition .	19 We conclude that DAB2IP can modulate STAT3 activation and reprograms its target gene expression (i.e., survivin, Bcl-2 and Bax), which will shift the balance from pro apoptotic to anti-apoptotic activities under androgen depleted condition.	4	8	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DAB2IP	DAB2IP	DAB2IP	STAT3	STAT3	STAT3	4	5	7	8
Mammals express three HH family members , Sonic hedgehog ( SHH ) , Desert hedgehog ( DHH ) , and Indian hedgehog ( IHH ) , whose binding to their receptor Patched1 ( PTCH1 ) relieves PTCH1 mediated repression of Smoothened ( SMO ) activity .	Mammals express three HH family members, Sonic hedgehog (SHH), Desert hedgehog (DHH), and Indian hedgehog (IHH), whose binding to their receptor Patched1 (PTCH1) relieves PTCH1 mediated repression of Smoothened (SMO) activity.	14	38	relieves	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	DHH	DHH	DHH	PTCH1	PTCH1	PTCH1	16	17	36	37
We postulate , therefore , that cellular Dab2 levels modulate Wnt and beta-catenin signalling by regulating the endocytic fate of the LRP6 receptor .	We postulate, therefore, that cellular Dab2 levels modulate Wnt and beta-catenin signalling by regulating the endocytic fate of the LRP6 receptor.	7	22	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dab2	Dab2 levels	dab2	LRP6	LRP6	lrp6	7	8	21	22
We previously found that human pancreatic cancer cells frequently lost DUSP6 expression , which could induce constitutively active MAPK1 , and the loss was associated with hypermethylation of the CpG cluster region of intron 1 of DUSP6 .	We previously found that human pancreatic cancer cells frequently lost DUSP6 expression, which could induce constitutively active MAPK1, and the loss was associated with hypermethylation of the CpG cluster region of intron 1 of DUSP6.	10	19	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DUSP6	DUSP6 expression	dusp6	MAPK1	MAPK1	mapk1	10	11	18	19
By profiling of gene expressions associated with downregulation of MAPK1 induced by exogenous overexpression of DUSP6 in pancreatic cancer cells , we found that AURKA and STK15 , the gene encoding Aurora-A kinase , which plays key roles in cellular mitosis , was among the downregulated genes along with its related genes , which included AURKB , TPX2 and CENPA .	By profiling of gene expressions associated with downregulation of MAPK1 induced by exogenous overexpression of DUSP6 in pancreatic cancer cells, we found that AURKA and STK15, the gene encoding Aurora-A kinase, which plays key roles in cellular mitosis, was among the downregulated genes along with its related genes, which included AURKB, TPX2 and CENPA.	7	16	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	DUSP6	overexpression of DUSP6	dusp6	MAPK1	MAPK1	mapk1	15	16	9	10
DUSP1 dephosphorylates ERK in the nucleus and allows its trafficking to the cytoplasm [ XREF_BIBR ] , while DUSP6 causes the cytoplasmic retention of ERK2 [ XREF_BIBR ] .	DUSP1 dephosphorylates ERK in the nucleus and allows its trafficking to the cytoplasm [XREF_BIBR], while DUSP6 causes the cytoplasmic retention of ERK2 [XREF_BIBR].	18	26	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DUSP6	DUSP6	DUSP6	ERK2	ERK2	ERK2	18	19	24	25
Mutational and kinetic study shows that the 334 FNFM 337 motif in the MKP3 catalytic domain is essential for MKP3 mediated ERK2 inactivation and is responsible for ERK2 mediated MKP3 activation .	Mutational and kinetic study shows that the 334 FNFM 337 motif in the MKP3 catalytic domain is essential for MKP3 mediated ERK2 inactivation and is responsible for ERK2 mediated MKP3 activation.	19	22	mediated	Positive_early_activation	Negative_activation	Positive_activation	MKP3	MKP3	MKP3	ERK2	ERK2	ERK2	19	20	21	22
This surprising result was first shown by Kholodenko and co-workers in their computational studies of the distributive dual phosphorylation and dephosphosphorylation of the ERK2 mitogen activated protein kinase ( MAPK ) kinase by the MAPK kinase MEK1 and the MAPK phosphatase MKP3 [ XREF_BIBR ] .	This surprising result was first shown by Kholodenko and co-workers in their computational studies of the distributive dual phosphorylation and dephosphosphorylation of the ERK2 mitogen activated protein kinase (MAPK) kinase by the MAPK kinase MEK1 and the MAPK phosphatase MKP3 [XREF_BIBR].	23	42	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MKP3	MKP3	MKP3	ERK2	ERK2	ERK2	41	42	23	24
Dyrk1A promoted tau E10 inclusion , whereas 9G8 inhibited E10 inclusion , and these actions were variable , depending on the cell types .	Dyrk1A promoted tau E10 inclusion, whereas 9G8 inhibited E10 inclusion, and these actions were variable, depending on the cell types.	0	4	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dyrk1A	Dyrk1A	Dyrk1A	tau	tau	tau	0	1	2	3
Coexpression of mnb enhanced Tau toxicity and resulted in a more severe phenotype with smaller eyes ( GMR > mnb+ Tau in XREF_FIG A and B ) .	Coexpression of mnb enhanced Tau toxicity and resulted in a more severe phenotype with smaller eyes (GMR> mnb+ Tau in XREF_FIG A and B).	0	5	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mnb	Coexpression of mnb	mnb	Tau	Tau	tau	2	3	4	5
Up-regulation of Dyrk1A as in Down syndrome could lead to neurofibrillary degeneration by shifting the alternative splicing of Tau exon 10 to an increase in the ratio of 3R-tau/4R-tau .	Up-regulation of Dyrk1A as in Down syndrome could lead to neurofibrillary degeneration by shifting the alternative splicing of Tau exon 10 to an increase in the ratio of 3R-tau/4R-tau.	0	19	lead	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dyrk1A	Dyrk1A	Dyrk1A	Tau	Tau	Tau	2	3	18	19
However , unlike in COS7 cells , overexpression of active Dyrk1A , but not dead Dyrk1A K188R , promoted tau E10 inclusion .	However, unlike in COS7 cells, overexpression of active Dyrk1A, but not dead Dyrk1A K188R, promoted tau E10 inclusion.	7	21	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dyrk1A	overexpression of active Dyrk1A	dyrk1a	tau	tau	tau	10	11	19	20
Dyrk1A itself promoted tau E10 inclusion , whereas 9G8 inhibited E10 inclusion , and these actions were variable depending on the cell types .	Dyrk1A itself promoted tau E10 inclusion, whereas 9G8 inhibited E10 inclusion, and these actions were variable depending on the cell types.	0	5	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dyrk1A	Dyrk1A	Dyrk1A	tau	tau	tau	0	1	3	4
Interestingly , we found that Dyrk1A itself , without being co-transfected with 9G8 , promoted tau E10 inclusion , and this action was dependent on the kinase activity because no promotion of E10 inclusion was observed with the inactive Dyrk1A K188R .	Interestingly, we found that Dyrk1A itself, without being co-transfected with 9G8, promoted tau E10 inclusion, and this action was dependent on the kinase activity because no promotion of E10 inclusion was observed with the inactive Dyrk1A K188R.	5	23	promoted	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Dyrk1A	Dyrk1A	Dyrk1A	tau	tau	tau	5	6	15	16
Moreover , maximal induction of CL100 mRNA and a CL100 like activity did not trigger inactivation of p42mapk , which was sustained at a high level after stimulation of PC12 cells with nerve growth factor , PAE cells with serum , or Swiss 3T3 cells with PDGF .	Moreover, maximal induction of CL100 mRNA and a CL100 like activity did not trigger inactivation of p42mapk, which was sustained at a high level after stimulation of PC12 cells with nerve growth factor, PAE cells with serum, or Swiss 3T3 cells with PDGF.	5	21	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CL100	CL100	CL100	p42mapk	p42mapk	p42mapk	5	6	17	18
In contrast , knockdown of the nuclear inducible MKPs , DUSP1 and -2 , did not affect ppERK2 responses but increased and decreased ERK2-GFP N : C localization , respectively ( XREF_FIG ) .	In contrast, knockdown of the nuclear inducible MKPs, DUSP1 and -2, did not affect ppERK2 responses but increased and decreased ERK2-GFP N : C localization, respectively (XREF_FIG).	3	24	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	DUSP1	DUSP1	DUSP1	ERK2-GFP	ERK2-GFP	ERK2-GFP	10	11	23	24
Overexpression of DUSP1 , -2 , or -4 prevented ERK2 activation , but only DUSP2 and -4 caused ERK2-GFP nuclear accumulation or could be immunoprecipitated with ERK2 .	Overexpression of DUSP1, -2, or -4 prevented ERK2 activation, but only DUSP2 and -4 caused ERK2-GFP nuclear accumulation or could be immunoprecipitated with ERK2.	0	20	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DUSP1	Overexpression of DUSP1	dusp1	ERK2-GFP	ERK2-GFP	erk2-gfp	2	3	18	19
Overexpression of DUSP26 suppresses p53 ' onco-suppressive ' function in response to genotoxic stress .	Overexpression of DUSP26 suppresses p53 ' onco-suppressive ' function in response to genotoxic stress.	0	6	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	DUSP26	Overexpression of DUSP26	dusp26	p53	p53	p53	2	3	4	5
Of them , dual-specificity protein phosphatase 26 ( DUSP26 ) , which inhibits mitogen activated protein kinase ( MAPK ) and p53 tumor suppressor and is known to be overexpressed in anaplastic thyroid carcinoma , was inhibited by ethyl-3 ,4-dephostatin in a concentration dependent manner .	Of them, dual-specificity protein phosphatase 26 (DUSP26), which inhibits mitogen activated protein kinase (MAPK) and p53 tumor suppressor and is known to be overexpressed in anaplastic thyroid carcinoma, was inhibited by ethyl-3,4-dephostatin in a concentration dependent manner.	3	36	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	DUSP26	DUSP26	DUSP26	p53	p53	p53	8	9	21	22
Furthermore , Dyrk1A , the closest family member to Mirk and Dyrk1B , has been found to phosphorylate FoxO1 at ser329 , a novel in vivo phosphorylation site , and mediates cellular localization of FoxO1 in immortalized cells .	Furthermore, Dyrk1A, the closest family member to Mirk and Dyrk1B, has been found to phosphorylate FoxO1 at ser329, a novel in vivo phosphorylation site, and mediates cellular localization of FoxO1 in immortalized cells.	2	36	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dyrk1A	Dyrk1A, the closest family member to Mirk and Dyrk1B, has been found to phosphorylate FoxO1 at ser329	dyrk1a	FoxO1	FoxO1	foxo1	2	3	34	35
It has been reported that FOXO transcription factors can be targeted by DYRK kinases XREF_BIBR .	It has been reported that FOXO transcription factors can be targeted by DYRK kinases XREF_BIBR.	5	14	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	DYRK	DYRK	DYRK	FOXO	FOXO	FOXO	12	13	5	6
Dyrk1A promotes food intake via direct phosphorylation and activation of SIRT1 , which in return deacytylates and activates FOXO .	Dyrk1A promotes food intake via direct phosphorylation and activation of SIRT1, which in return deacytylates and activates FOXO.	0	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Dyrk1A	Dyrk1A	Dyrk1A	FOXO	FOXO	FOXO	0	1	18	19
In vivo experiments examining the loss-of-function of the MAP kinase phosphatase 1 ( MKP-1 ) , which deactivates JNK1 , show reduced dendritic arborization of cortical pyramidal neurons , as well as impaired axonal branching 35 .	In vivo experiments examining the loss-of-function of the MAP kinase phosphatase 1 (MKP-1), which deactivates JNK1, show reduced dendritic arborization of cortical pyramidal neurons, as well as impaired axonal branching 35.	5	19	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MKP-1	loss-of-function of the MAP kinase phosphatase 1 (MKP-1	mkp-1	JNK1	JNK1	jnk1	13	14	18	19
Moreover , this study suggests an ERK independent induction of CL100 following stimulation of SAPK and p38 MAP kinase .	Moreover, this study suggests an ERK independent induction of CL100 following stimulation of SAPK and p38 MAP kinase.	10	18	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	CL100	CL100	CL100	SAPK	SAPK	SAPK	10	11	14	15
We speculate that the antiapoptotic effects of DUSP4 in ECs exposed to Ang-1 may be mediated through selective inhibition of DUSP4 induced SAPK and JNK activation .	We speculate that the antiapoptotic effects of DUSP4 in ECs exposed to Ang-1 may be mediated through selective inhibition of DUSP4 induced SAPK and JNK activation.	18	25	induced	Positive_early_activation	Negative_activation	Negative_activation	DUSP4	DUSP4	DUSP4	SAPK	SAPK	SAPK	20	21	22	23
DLC1 down-regulation induces AMBRA1 dependent autophagy .	DLC1 down-regulation induces AMBRA1 dependent autophagy.	0	5	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DLC1	DLC1	DLC1	AMBRA1	AMBRA1	AMBRA1	0	1	3	4
None of the siRNAs had a measurable effect on whole-cell ppERK2 levels in unstimulated cells ( XREF_FIG , left panel ) , but siRNAs to DUSP3 , -5 , and -10 significantly reduced the ERK2-GFP N : C ratio , and DUSP2 and -7 siRNAs increased ERK2-GFP nuclear localization under basal conditions ( XREF_FIG , right panel ) .	None of the siRNAs had a measurable effect on whole-cell ppERK2 levels in unstimulated cells (XREF_FIG, left panel), but siRNAs to DUSP3, -5, and -10 significantly reduced the ERK2-GFP N : C ratio, and DUSP2 and -7 siRNAs increased ERK2-GFP nuclear localization under basal conditions (XREF_FIG, right panel).	23	48	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DUSP2	DUSP2	DUSP2	ERK2-GFP	ERK2-GFP	ERK2-GFP	41	42	46	47
We further analysed the levels of p-AKT ( Ser473 ) and p-FOXO3A ( Ser253 ) in CAL 27 cell line treated with DYRK1A siRNA .	We further analysed the levels of p-AKT (Ser473) and p-FOXO3A (Ser253) in CAL 27 cell line treated with DYRK1A siRNA.	4	23	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	DYRK1A	DYRK1A	DYRK1A	p-FOXO3A	p-FOXO3A	p-FOXO3A	22	23	11	12
12-O-Tetradecanoylphorbol-13-acetate ( TPA )-induced Erk1/2 activation in human prostate cancer PC-3 cells is a paradigm of diacylglycerol induced EGFR transactivation in androgen independent prostate cancer .	12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced Erk1/2 activation in human prostate cancer PC-3 cells is a paradigm of diacylglycerol induced EGFR transactivation in androgen independent prostate cancer.	4	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	EGFR	EGFR	EGFR	4	5	18	19
Notably , protection from EGF induced degradation and inhibition of EGF induced intracellular redistribution afforded by GH were both prevented by a MEK1 inhibitor , suggesting a role for GH induced ERK activation in regulating the trafficking itinerary of the EGF stimulated EGFR .	Notably, protection from EGF induced degradation and inhibition of EGF induced intracellular redistribution afforded by GH were both prevented by a MEK1 inhibitor, suggesting a role for GH induced ERK activation in regulating the trafficking itinerary of the EGF stimulated EGFR.	29	43	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	GH induced ERK	erk	EGFR	EGFR	egfr	31	32	42	43
From these data , we concluded that Erk activation , but not Akt activation , downstream of EGFR is required for differentiation of K5 + K19 - hMECs in MEGM medium .	From these data, we concluded that Erk activation, but not Akt activation, downstream of EGFR is required for differentiation of K5 + K19 - hMECs in MEGM medium.	7	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Erk	Erk	Erk	EGFR	EGFR	EGFR	7	8	17	18
Even though the mechanism of LPA- and ET-1-induced MAPK activation in EGFR transfected SK-N-MC cells remains to be determined definitively , our results provide strong evidence that the EGFR links these GPCRs to MAPK activation .	Even though the mechanism of LPA- and ET-1-induced MAPK activation in EGFR transfected SK-N-MC cells remains to be determined definitively, our results provide strong evidence that the EGFR links these GPCRs to MAPK activation.	8	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	8	9	11	12
Importantly , IR and TR cells were attenuated the classical EGFR membrane signaling including downstream ERK1/2 and AKT pathways ( XREF_FIG ) and were more sensitive to Y211F CPPP treatment than the parental cells ( XREF_FIG ) , suggesting that the Y211F CPPP has the potential to treat the IR or TR TNBC patients .	Importantly, IR and TR cells were attenuated the classical EGFR membrane signaling including downstream ERK1/2 and AKT pathways (XREF_FIG) and were more sensitive to Y211F CPPP treatment than the parental cells (XREF_FIG), suggesting that the Y211F CPPP has the potential to treat the IR or TR TNBC patients.	10	20	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	15	16	10	11
Activation of this signaling pathway is connected to NO stimulated overall tyrosine phosphorylation that also involves the transactivation of the EGF receptor mediated by ERK1/2 .	Activation of this signaling pathway is connected to NO stimulated overall tyrosine phosphorylation that also involves the transactivation of the EGF receptor mediated by ERK1/2.	8	25	mediated	Positive_regulation_syntax_2_verb	Negative_activation	Positive_regulation	ERK1/2	ERK1/2	erk1/2	EGF receptor	NO stimulated overall tyrosine phosphorylation that also involves the transactivation of the EGF receptor	egf receptor	24	25	20	22
Studies by our group and others found that in many BRAF-mutant CRCs , RAF inhibitor induced reductions in MAPK signaling lead to inactivation of negative feedback signals downstream of ERK , allowing epidermal growth factor receptor ( EGFR ) to reactivate MAPK through RAS and CRAF XREF_BIBR ( XREF_FIG ) .	Studies by our group and others found that in many BRAF-mutant CRCs, RAF inhibitor induced reductions in MAPK signaling lead to inactivation of negative feedback signals downstream of ERK, allowing epidermal growth factor receptor (EGFR) to reactivate MAPK through RAS and CRAF XREF_BIBR (XREF_FIG).	18	36	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	18	19	32	36
While MAPK , PI3K and AKT and the STAT pathways have been shown to be the major signaling cascades activated by EGFR and mediate EGFR oncogenic signaling , the molecular mechanism of active mutant EGFR driving NSCLC growth remains elusive .	While MAPK, PI3K and AKT and the STAT pathways have been shown to be the major signaling cascades activated by EGFR and mediate EGFR oncogenic signaling, the molecular mechanism of active mutant EGFR driving NSCLC growth remains elusive.	1	26	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	1	2	24	25
JWH-015 inhibited EMT in NSCLC cells A549 and also reversed the mesenchymal nature of CALU-1 cells by downregulation of EGFR signaling targets like ERK and STAT3 .	JWH-015 inhibited EMT in NSCLC cells A549 and also reversed the mesenchymal nature of CALU-1 cells by downregulation of EGFR signaling targets like ERK and STAT3.	19	25	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	23	24	19	20
We determined that ERK but not PI3K or RalGEF activation of HMEC16C cells supports anchorage independent proliferation independent of EGFR activation .	We determined that ERK but not PI3K or RalGEF activation of HMEC16C cells supports anchorage independent proliferation independent of EGFR activation.	3	20	supports	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	3	4	19	20
In this study , we focus on the mechanism of attenuated ERK signaling and present evidence suggesting that the mechanism of attenuated ERK signaling in EGFR overexpressing cells is a sequestration of ERKs at the cell membrane in EGFR containing complexes .	In this study, we focus on the mechanism of attenuated ERK signaling and present evidence suggesting that the mechanism of attenuated ERK signaling in EGFR overexpressing cells is a sequestration of ERKs at the cell membrane in EGFR containing complexes.	22	27	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	22	23	25	26
Notably , VRAC is the target of several regulatory mechanisms activated by osmotic cell swelling ; among these , are EGFR activation and phosphorylation by PI3K , src and ERK .	Notably, VRAC is the target of several regulatory mechanisms activated by osmotic cell swelling; among these, are EGFR activation and phosphorylation by PI3K, src and ERK.	20	30	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	29	30	20	21
Then , the EGFR dependent activation of AKT and other downstream substrates , such as ERK , might contribute to cell resistance to AZD8055 .	Then, the EGFR dependent activation of AKT and other downstream substrates, such as ERK, might contribute to cell resistance to AZD8055.	3	16	activation	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	15	16	3	4
IGF1R activates EGFR downstream signaling including PI3K and AKT and MAPK and ERK pathways to bypass the inhibited EGFR .	IGF1R activates EGFR downstream signaling including PI3K and AKT and MAPK and ERK pathways to bypass the inhibited EGFR.	2	13	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	10	11	2	3
NPV-BEZ235 enhances ERK activation independently of EGFR , HER2 , insulin receptor and IGF-1 receptor .	NPV-BEZ235 enhances ERK activation independently of EGFR, HER2, insulin receptor and IGF-1 receptor.	2	14	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	2	3	6	7
ERK ( 1/2 ) phosphorylation induced by stimulation of either 5-HT ( 2B ) or 5-HT ( 2C ) receptors was mediated by epidermal growth factor ( EGF ) receptor transactivation ( Peng et al ., this issue ) , shown by the inhibitory effect of AG1478 , an inhibitor of the EGF receptor tyrosine kinase , and GM6001 , an inhibitor of Zn dependent metalloproteinases , and thus of 5-HT ( 2B ) receptor mediated EGF receptor agonist release .	ERK (1/2) phosphorylation induced by stimulation of either 5-HT (2B) or 5-HT (2C) receptors was mediated by epidermal growth factor (EGF) receptor transactivation (Peng et al., this issue), shown by the inhibitory effect of AG1478, an inhibitor of the EGF receptor tyrosine kinase, and GM6001, an inhibitor of Zn dependent metalloproteinases, and thus of 5-HT (2B) receptor mediated EGF receptor agonist release.	0	79	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK (1/2) phosphorylation	erk	EGF receptor	EGF receptor	egf receptor	0	1	76	78
Sulindac metabolites block EGF induced phosphorylation of EGFR and ERK1/2 , downregulate total EGFR protein , and induce apoptotic cell death .	Sulindac metabolites block EGF induced phosphorylation of EGFR and ERK1/2, downregulate total EGFR protein, and induce apoptotic cell death.	0	14	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	Sulindac metabolites block EGF induced phosphorylation of EGFR and ERK1/2	erk1/2	EGFR	EGFR	egfr	9	10	13	14
Previous studies have shown that EGFR signaling mediated by the MEK and ERK and PI3K and AKT pathways is essential for RPE cell proliferation and survival [ XREF_BIBR ] .	Previous studies have shown that EGFR signaling mediated by the MEK and ERK and PI3K and AKT pathways is essential for RPE cell proliferation and survival [XREF_BIBR].	5	13	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	12	13	5	6
Collectively , these data indicate that ERK activity , by phosphorylation of a threonine residue in the EGFR juxtamembrane cytoplasmic domain , modulates EGFR trafficking and signaling .	Collectively, these data indicate that ERK activity, by phosphorylation of a threonine residue in the EGFR juxtamembrane cytoplasmic domain, modulates EGFR trafficking and signaling.	6	24	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	6	7	23	24
However , in the current study , ERK was activated downstream rather than upstream of EGFR .	However, in the current study, ERK was activated downstream rather than upstream of EGFR.	7	16	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	7	8	15	16
Then we measured the activation of EGFR and its downstream signaling , the phosphorylation levels of EGFR , AKT and ERK1/2 were increased in the TAZ rescued HDAC9-knockdown cells and xenograft tumors .	Then we measured the activation of EGFR and its downstream signaling, the phosphorylation levels of EGFR, AKT and ERK1/2 were increased in the TAZ rescued HDAC9-knockdown cells and xenograft tumors.	4	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	levels of EGFR, AKT and ERK1/2	erk1/2	EGFR	EGFR	egfr	20	21	6	7
Several over-expressed genes located in regions of amplification play roles in constitutive KRAS activation ( PTGS2 and COX2 ) , enhanced transactivation of the EGFR ( RGS2 ) , enhanced invasive potential ( ECM1 ) , and MAPK and ERK activation ( PTGS2 and COX2 ) .	Several over-expressed genes located in regions of amplification play roles in constitutive KRAS activation (PTGS2 and COX2), enhanced transactivation of the EGFR (RGS2), enhanced invasive potential (ECM1), and MAPK and ERK activation (PTGS2 and COX2).	21	40	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	39	40	24	25
It has been described that carvedilol , which is used for certain cardiovascular diseases , blocks the deleterious effects mediated by beta1AR and also presents and additional cardioprotective effect mediated by MAPK activation through a beta-arrestin and EGFR transactivation pathway .	It has been described that carvedilol, which is used for certain cardiovascular diseases, blocks the deleterious effects mediated by beta1AR and also presents and additional cardioprotective effect mediated by MAPK activation through a beta-arrestin and EGFR transactivation pathway.	29	39	mediated	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	31	32	37	38
Upon ligand binding , EGFR signaling is mediated by the MAPK and PI3K and Akt pathways .	Upon ligand binding, EGFR signaling is mediated by the MAPK and PI3K and Akt pathways.	4	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	10	11	4	5
We also clarified that the activated EGFR and ERK pathway by PNN could also be inhibited by ERK blocker .	We also clarified that the activated EGFR and ERK pathway by PNN could also be inhibited by ERK blocker.	4	18	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	17	18	6	7
As expected , the loss of MAPK protein strongly reduced the potency of EGFR signaling ; MAPK phosphorylation induced by treatment of an S2 cell line that stably expresses the EGFR ( D2F ;) with media conditioned by cells expressing Spi was strongly reduced in cells treated with mago RNAi ( XREF_FIG ) .	As expected, the loss of MAPK protein strongly reduced the potency of EGFR signaling; MAPK phosphorylation induced by treatment of an S2 cell line that stably expresses the EGFR (D2F;) with media conditioned by cells expressing Spi was strongly reduced in cells treated with mago RNAi (XREF_FIG).	6	14	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	6	7	13	14
We found that USP8 mutated PAs have a higher incidence of EGFR expression , increased EGFR protein abundance and activation of downstream Erk1/2 , indicating that USP8 mutations enhance EGFR signaling in tumors .	We found that USP8 mutated PAs have a higher incidence of EGFR expression, increased EGFR protein abundance and activation of downstream Erk1/2, indicating that USP8 mutations enhance EGFR signaling in tumors.	14	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	EGFR	EGFR	EGFR	22	23	15	16
Furthermore , the inhibitory effect of DEX was associated with shorter ERK activation ( XREF_FIG ) , probably due to simultaneous induction of inhibitors of both EGFR and ERK ( ERRFI1 and DUSP1 , respectively ) .	Furthermore, the inhibitory effect of DEX was associated with shorter ERK activation (XREF_FIG), probably due to simultaneous induction of inhibitors of both EGFR and ERK (ERRFI1 and DUSP1, respectively).	11	32	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	11	12	26	27
Inhibition of either ERK or AKT activation is sufficient to prevent EGFR activation and cell proliferation .	Inhibition of either ERK or AKT activation is sufficient to prevent EGFR activation and cell proliferation.	0	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	3	4	11	12
The sensitivity to growth inhibition by Gefitinib has been associated with dependence on protein kinase B/AKT ( Akt ) and extracellular signal regulated kinase 1/2 ( ERK1/2 ) activation in response to EGFR signaling for survival and proliferation and extent of EGF induced down-regulation of cell surface EGFR XREF_BIBR .	The sensitivity to growth inhibition by Gefitinib has been associated with dependence on protein kinase B/AKT (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) activation in response to EGFR signaling for survival and proliferation and extent of EGF induced down-regulation of cell surface EGFR XREF_BIBR.	26	48	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	26	27	47	48
Taken together , these findings suggest that LIFR expression and cetuximab chemosensitivity may affect the downstream of EGFR signalling mediated by MAPK as well as PI3K and Akt and JAK and STAT3 pathways .	Taken together, these findings suggest that LIFR expression and cetuximab chemosensitivity may affect the downstream of EGFR signalling mediated by MAPK as well as PI3K and Akt and JAK and STAT3 pathways.	17	22	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	21	22	17	18
BRAF V600E inhibition suppresses MAPK signaling , which in turn downregulates the EGFR phosphatase PTPN9 , resulting in sustained EGFR phosphorylation and enhanced EGFR activity .	BRAF V600E inhibition suppresses MAPK signaling, which in turn downregulates the EGFR phosphatase PTPN9, resulting in sustained EGFR phosphorylation and enhanced EGFR activity.	4	14	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	4	5	12	13
Src and EGFR were both activated by PGE2 , which in turn increased the phosphorylation levels of p44/42 MAPK .	Src and EGFR were both activated by PGE2, which in turn increased the phosphorylation levels of p44/42 MAPK.	0	19	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAPK	PGE2, which in turn increased the phosphorylation levels of p44/42 MAPK	mapk	EGFR	EGFR	egfr	18	19	2	3
Based on this strong correlation , we utilized the QCM-D to demonstrate that this dynamic focal-adhesion restructuring is regulated temporally by the downstream pathways of EGFR signaling such as the PI3K , MAPK and ERK , and PLC pathways .	Based on this strong correlation, we utilized the QCM-D to demonstrate that this dynamic focal-adhesion restructuring is regulated temporally by the downstream pathways of EGFR signaling such as the PI3K, MAPK and ERK, and PLC pathways.	25	35	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	34	35	25	26
Canonical Smad3 signaling and ERK and Sp1 signaling pathways mediate TGF-beta-induced EGFR upregulation .	Canonical Smad3 signaling and ERK and Sp1 signaling pathways mediate TGF-beta-induced EGFR upregulation.	4	12	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	4	5	11	12
Also in support a MAPK independent effect , knockdown of KSR1 did not enhance the effects of the dual EGFR and HER2 small molecule inhibitor ( XREF_SUPPLEMENTARY ) .	Also in support a MAPK independent effect, knockdown of KSR1 did not enhance the effects of the dual EGFR and HER2 small molecule inhibitor (XREF_SUPPLEMENTARY).	4	26	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	4	5	19	20
The MAPK signaling pathway lies downstream of EGFR and accepts the signal transmission of EGFR .	The MAPK signaling pathway lies downstream of EGFR and accepts the signal transmission of EGFR.	1	15	accepts	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	1	2	14	15
Although the role of Shoc2 on ERK activation in the EGFR signaling pathway has been described XREF_BIBR , XREF_BIBR , XREF_BIBR , we found the same behavior for Shoc2 in other cell systems and for other RTK dependent signaling routes , such as fibroblast growth factor-receptor ( FGFR ) and tropomyosin related kinase ( Trk ) families .	Although the role of Shoc2 on ERK activation in the EGFR signaling pathway has been described XREF_BIBR, XREF_BIBR, XREF_BIBR, we found the same behavior for Shoc2 in other cell systems and for other RTK dependent signaling routes, such as fibroblast growth factor-receptor (FGFR) and tropomyosin related kinase (Trk) families.	6	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	6	7	10	11
Downstream EGFR signaling by ERK , but not PI3K or PKC , mediated the gefitinib response .	Downstream EGFR signaling by ERK, but not PI3K or PKC, mediated the gefitinib response.	1	5	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	4	5	1	2
Next , we determined the levels of activation and the effect of EGFR inhibition on the canonical EGFR signaling pathways driven by MAPK and PI3K-Akt .	Next, we determined the levels of activation and the effect of EGFR inhibition on the canonical EGFR signaling pathways driven by MAPK and PI3K-Akt.	17	24	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	22	23	17	18
Additionally , because ERK signalling has been implicated in beta cell integrity and function , and MIG6 suppressed EGFR signalling ( including ERK phosphorylation ) , we investigated whether MIG6 suppresses the downstream effectors of ERK .	Additionally, because ERK signalling has been implicated in beta cell integrity and function, and MIG6 suppressed EGFR signalling (including ERK phosphorylation), we investigated whether MIG6 suppresses the downstream effectors of ERK.	18	24	signalling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK phosphorylation	erk	EGFR	EGFR	egfr	22	23	18	19
Considering the key importance of ERK1/2 signaling in EGFR dependent cellular functions and published data that EGFR/ERK1/2 signaling is critical for maintaining colonic claudin-2 expression , we further determined if HDACi dependent decrease in claudin-2 expression can be rescued by simply activating the ERK1/2 signaling .	Considering the key importance of ERK1/2 signaling in EGFR dependent cellular functions and published data that EGFR/ERK1/2 signaling is critical for maintaining colonic claudin-2 expression, we further determined if HDACi dependent decrease in claudin-2 expression can be rescued by simply activating the ERK1/2 signaling.	5	14	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	5	6	8	9
These findings indicate that Src and Pyk2 act upstream of the EGF-R and that the majority of Ang II induced ERK phosphorylation is dependent on trans-activation of the EGF-R .	These findings indicate that Src and Pyk2 act upstream of the EGF-R and that the majority of Ang II induced ERK phosphorylation is dependent on trans-activation of the EGF-R.	17	29	is dependent on trans-activation	Positive_activation_copula_1	Negative_activation	Positive_activation	ERK	Ang II induced ERK phosphorylation	erk	EGF-R	EGF-R	egf-r	20	21	28	29
Overall , these data indicate that ERK1/2 phosphorylation mediates EGFR induced hypertrophic and lysosomal phenotypes in NAGLU depleted H9C2 .	Overall, these data indicate that ERK1/2 phosphorylation mediates EGFR induced hypertrophic and lysosomal phenotypes in NAGLU depleted H9C2.	6	10	mediates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2 phosphorylation	erk1/2	EGFR	EGFR	egfr	6	7	9	10
As with other GPCRs , ERK activity is increased distal to beta1AR dependent EGFR transactivation and , along with enhanced Akt activation , this mechanism promotes cardiomyocyte survival XREF_BIBR , XREF_BIBR , XREF_BIBR , while in cardiac fibroblasts , beta2AR mediated transactivation leads to increased DNA synthesis and mitogenesis 15 .	As with other GPCRs, ERK activity is increased distal to beta1AR dependent EGFR transactivation and, along with enhanced Akt activation, this mechanism promotes cardiomyocyte survival XREF_BIBR, XREF_BIBR, XREF_BIBR, while in cardiac fibroblasts, beta2AR mediated transactivation leads to increased DNA synthesis and mitogenesis 15.	5	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	5	6	13	14
In UMSCC81B cells , EGFR and downstream signalling such as Akt and GSK-3beta and Erk were constitutively activated in the absence of FBS and EGF , whereas in 81B-Fb cells , only Erk was activated .	In UMSCC81B cells, EGFR and downstream signalling such as Akt and GSK-3beta and Erk were constitutively activated in the absence of FBS and EGF, whereas in 81B-Fb cells, only Erk was activated.	4	15	signalling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Erk	Erk	Erk	EGFR	EGFR	EGFR	14	15	4	5
CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma .	CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma.	0	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	2	3	7	8
One of the main reasons for primary resistance to EGFR-TKIs is that there are alternative mechanisms for persistent activation of EGFR downstream signaling , including both the RAS and ERK and phosphoinositide 3-kinase ( PI3K )/Akt kinase pathways [ XREF_BIBR ] .	One of the main reasons for primary resistance to EGFR-TKIs is that there are alternative mechanisms for persistent activation of EGFR downstream signaling, including both the RAS and ERK and phosphoinositide 3-kinase (PI3K)/Akt kinase pathways [XREF_BIBR].	20	32	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	29	30	20	21
These results indicate that Akt and Erk are the downstream targets of EGFR , ErbB2 and ErbB4 .	These results indicate that Akt and Erk are the downstream targets of EGFR, ErbB2 and ErbB4.	4	16	are the downstream targets	Positive_activation_copula_1	Negative_activation	Positive_activation	Erk	Erk	Erk	EGFR	EGFR	EGFR	6	7	12	13
In addition , ERK or AKT activation is essential for EGFR activation because ERK or AKT inhibitor blocks EGFR activation following UVB radiation , indicating that EGFR/AKT/ERK pathways form a regulatory loop and converge into cell cycle progression following UVB radiation .	In addition, ERK or AKT activation is essential for EGFR activation because ERK or AKT inhibitor blocks EGFR activation following UVB radiation, indicating that EGFR/AKT/ERK pathways form a regulatory loop and converge into cell cycle progression following UVB radiation.	13	19	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	13	14	18	19
In summary , the improved suppression of MAPK signaling and the substantial tumor regressions observed in our xenograft studies support the evaluation of combined RAF and EGFR inhibition in clinical trials for patients with BRAF mutant CRC .	In summary, the improved suppression of MAPK signaling and the substantial tumor regressions observed in our xenograft studies support the evaluation of combined RAF and EGFR inhibition in clinical trials for patients with BRAF mutant CRC.	7	27	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	7	8	26	27
Concomitant inhibition of EGFR and MEK was an effective therapeutic strategy in models of EGFR TKI resistance driven by MAPK pathway activation .	Concomitant inhibition of EGFR and MEK was an effective therapeutic strategy in models of EGFR TKI resistance driven by MAPK pathway activation.	14	21	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	19	20	14	15
We further determined the involvement of ERK1/2 and STAT3 signaling in EGFR signaling in vivo during LPS induced AKI mice model .	We further determined the involvement of ERK1/2 and STAT3 signaling in EGFR signaling in vivo during LPS induced AKI mice model.	6	12	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	6	7	11	12
These specific inhibitors not only blocked EGF stimulated EGFR autophosphorylation but also targeted EGFR signaling including MAPK and Akt pathways .	These specific inhibitors not only blocked EGF stimulated EGFR autophosphorylation but also targeted EGFR signaling including MAPK and Akt pathways.	13	19	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	16	17	13	14
5 PI3K-Akt and MAPK ( ERK1/2 ) are two major downstream effectors of EGFR activation , and it is known that PI3K-Akt activation is closely related to cell survival and migration , 29 and that ERK1/2 signaling pathway activation triggers cell proliferation .	5 PI3K-Akt and MAPK (ERK1/2) are two major downstream effectors of EGFR activation, and it is known that PI3K-Akt activation is closely related to cell survival and migration, 29 and that ERK1/2 signaling pathway activation triggers cell proliferation.	13	40	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	35	36	13	14
This ligand independent and constitutive EGFRwt signaling is termed non canonical EGFR signaling because it does not involve activation of canonical EGFR signals such as ERK and Akt .	This ligand independent and constitutive EGFRwt signaling is termed non canonical EGFR signaling because it does not involve activation of canonical EGFR signals such as ERK and Akt.	21	27	signals	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	25	26	21	22
Moreover , a recent study in a model of colitis associated colon cancer showed that ginseng reduced levels of phospho-active EGFR and phospho-active ErbB2 as well as ERK , a down stream effector of EGFR , indicating ginseng could suppress EGFR signals in colonic tumorigenesis [ XREF_BIBR ] .	Moreover, a recent study in a model of colitis associated colon cancer showed that ginseng reduced levels of phospho-active EGFR and phospho-active ErbB2 as well as ERK, a down stream effector of EGFR, indicating ginseng could suppress EGFR signals in colonic tumorigenesis [XREF_BIBR].	17	41	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	levels of phospho-active EGFR and phospho-active ErbB2 as well as ERK	erk	EGFR	EGFR	egfr	27	28	40	41
Akt and ERK signaling pathways also mediated HGF [ XREF_BIBR , XREF_BIBR ] , TGF-beta [ XREF_BIBR , XREF_BIBR ] , and EGFR [ XREF_BIBR , XREF_BIBR ] inducing EMT .	Akt and ERK signaling pathways also mediated HGF [XREF_BIBR, XREF_BIBR], TGF-beta [XREF_BIBR, XREF_BIBR], and EGFR [XREF_BIBR, XREF_BIBR] inducing EMT.	0	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	2	3	22	23
Consistent with these observations , we found that ERK1/2 and PI3K and AKT pathways mediated the effects of EGF and EGFR signals on the expression and activation of MMP-9 in GBM .	Consistent with these observations, we found that ERK1/2 and PI3K and AKT pathways mediated the effects of EGF and EGFR signals on the expression and activation of MMP-9 in GBM.	8	21	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	8	9	20	21
As examples , GRK2 recruitment to ligand bound EGFR increases Erk 1/2 activation , while GRK2 mediated phosphorylation of PDGFR reduces tyrosine kinase activity .	As examples, GRK2 recruitment to ligand bound EGFR increases Erk 1/2 activation, while GRK2 mediated phosphorylation of PDGFR reduces tyrosine kinase activity.	8	12	increases	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Erk 1/2	Erk 1/2	Erk 1/2	EGFR	EGFR	EGFR	10	12	8	9
In addition , data suggest that inhibition of MAPK and PKC-delta signaling pathways should abrogate cell migration and invasion in EGFR overexpressing human breast cancer cells .	In addition, data suggest that inhibition of MAPK and PKC-delta signaling pathways should abrogate cell migration and invasion in EGFR overexpressing human breast cancer cells.	8	21	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	8	9	20	21
Previous studies showed that PTH increases the expression and the activity of epidermal growth factor receptor ( EGFR ) in osteoblasts , and activation of ERK1/2 by PTH in osteoblasts was demonstrated to induce the proteolytical release of EGFR ligands and EGFR transactivation .	Previous studies showed that PTH increases the expression and the activity of epidermal growth factor receptor (EGFR) in osteoblasts, and activation of ERK1/2 by PTH in osteoblasts was demonstrated to induce the proteolytical release of EGFR ligands and EGFR transactivation.	23	42	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	25	26	41	42
Furthermore , ouabain appeared to activate Erk1/2 and Akt signaling independent of EGFR .	Furthermore, ouabain appeared to activate Erk1/2 and Akt signaling independent of EGFR.	6	13	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	EGFR	EGFR	EGFR	6	7	12	13
Sox9 induction occurs through ligand stimulated activation of epidermal growth factor receptor ( EGFR ) and subsequent MAPK pathway activation .	Sox9 induction occurs through ligand stimulated activation of epidermal growth factor receptor (EGFR) and subsequent MAPK pathway activation.	5	19	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	17	18	8	12
Consistent with a role of Cav-1 in the ERK1/2 mediated EGFR signalling pathway that regulates ENaC , we have found that the ability of EGF to trigger phosphorylation of ERK1/2 was inhibited by an siRNA directed against Cav-1 ( XREF_FIG ) .	Consistent with a role of Cav-1 in the ERK1/2 mediated EGFR signalling pathway that regulates ENaC, we have found that the ability of EGF to trigger phosphorylation of ERK1/2 was inhibited by an siRNA directed against Cav-1 (XREF_FIG).	5	12	mediated	Positive_early_activation	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	8	9	10	11
In contrast to their proposed model for gonadotropins , our findings show that the induction of AKT and ERK phosphorylation by thyrostimulin in NIH : OVCAR-3 cells is mainly through transactivation of EGFR ( XREF_FIG ) .	In contrast to their proposed model for gonadotropins, our findings show that the induction of AKT and ERK phosphorylation by thyrostimulin in NIH : OVCAR-3 cells is mainly through transactivation of EGFR (XREF_FIG).	14	34	is mainly through transactivation	Positive_activation_copula_1	Negative_activation	Positive_activation	ERK	induction of AKT and ERK phosphorylation by thyrostimulin	erk	EGFR	EGFR	egfr	18	19	32	33
Since we showed that AKT , but not ERK , is the major mediator of EGFR in regulating the CSC phenotype , our results provide the rationale for targeting AKT to overcome gefitinib resistance conferred by either EGFR mutations or by EGFR independent activation of AKT such as c-Met amplification , ErbB3 overexpression , or loss of PTEN .	Since we showed that AKT, but not ERK, is the major mediator of EGFR in regulating the CSC phenotype, our results provide the rationale for targeting AKT to overcome gefitinib resistance conferred by either EGFR mutations or by EGFR independent activation of AKT such as c-Met amplification, ErbB3 overexpression, or loss of PTEN.	4	17	is the major mediator	Positive_activation_copula_1	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	8	9	15	16
It has been shown that c-Src is implicated in various downstream signaling pathways associated with EGFR dependent signaling such as MAPK and STAT5 pathways .	It has been shown that c-Src is implicated in various downstream signaling pathways associated with EGFR dependent signaling such as MAPK and STAT5 pathways.	15	23	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	20	21	15	16
HGF activates MET , expressed on tumor cells , and drives resistance to EGFR targeted therapy by triggering ERK and PI3K and AKT pro survival signaling and by promoting epithelial-mesenchymal transition [ XREF_BIBR ] .	HGF activates MET, expressed on tumor cells, and drives resistance to EGFR targeted therapy by triggering ERK and PI3K and AKT pro survival signaling and by promoting epithelial-mesenchymal transition [XREF_BIBR].	11	28	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	18	19	13	14
In turn , inhibition of the MAPK pathway reduces ligand mediated EGFR endocytosis , suggesting a potential feedback of elevated ERK activity on EGFR endocytosis .	In turn, inhibition of the MAPK pathway reduces ligand mediated EGFR endocytosis, suggesting a potential feedback of elevated ERK activity on EGFR endocytosis.	6	12	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	6	7	11	12
These effects are mediated by PPARgamma induced nongenomic transactivation of the epidermal growth factor receptor and downstream extracellular signal regulated kinases ( ERK ) .	These effects are mediated by PPARgamma induced nongenomic transactivation of the epidermal growth factor receptor and downstream extracellular signal regulated kinases (ERK).	6	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	22	23	11	15
Ligand mediated EGFR signaling such as either PI3K and AKT or RAS and ERK pathway regulates various cellular processes including cell survival , death , growth , proliferation , and motility XREF_BIBR .	Ligand mediated EGFR signaling such as either PI3K and AKT or RAS and ERK pathway regulates various cellular processes including cell survival, death, growth, proliferation, and motility XREF_BIBR.	2	14	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	13	14	2	3
Several of signaling pathways can be triggered by EGF and EGFR activation including the MEK and ERK pathways .	Several of signaling pathways can be triggered by EGF and EGFR activation including the MEK and ERK pathways.	8	17	activation	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	16	17	10	11
Also , inhibition of the HhP , both pharmacologically and genetically , augmented the EGFR driven phenotype by increasing activation of both MEK and ERK and PI3K and AKT .	Also, inhibition of the HhP, both pharmacologically and genetically, augmented the EGFR driven phenotype by increasing activation of both MEK and ERK and PI3K and AKT.	12	25	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	24	25	14	15
In the phase I monotherapy study EGF10004 , inhibition of phosphorylated AKT and MAPK ( downstream targets of HER-2 and EGFR ) at day 21 were also associated with clinical responses .	In the phase I monotherapy study EGF10004, inhibition of phosphorylated AKT and MAPK (downstream targets of HER-2 and EGFR) at day 21 were also associated with clinical responses.	10	21	targets	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	13	14	20	21
Our data suggested that LATS2 can suppress ERK signaling in EGFR wild-type lung adenocarcinoma cell lines with high basal LATS2 expression .	Our data suggested that LATS2 can suppress ERK signaling in EGFR wild-type lung adenocarcinoma cell lines with high basal LATS2 expression.	7	11	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	7	8	10	11
By analyzing the ERK activation kinetics in the ind expressing cell and in the middle of the ERK activation domain , we found that ERK activation in Egfr heterozygous embryos follows the same kinetics as in wild type embryos in both domains ( XREF_SUPPLEMENTARY ) .	By analyzing the ERK activation kinetics in the ind expressing cell and in the middle of the ERK activation domain, we found that ERK activation in Egfr heterozygous embryos follows the same kinetics as in wild type embryos in both domains (XREF_SUPPLEMENTARY).	24	29	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	Egfr	Egfr	Egfr	24	25	27	28
Inhibition of ERK also abolished AKT and EGFR activation .	Inhibition of ERK also abolished AKT and EGFR activation.	0	8	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	2	3	7	8
An interesting outcome of our study was that although ERK and Akt activation upon cholinergic stimulus both require EGFR activity , only ERK activation is fully dependent on the MMP mediated extracellular pathway of EGFR activation , whereas MMP inhibition only partially inhibits the basal and stimulated Akt activity ( XREF_FIG ) .	An interesting outcome of our study was that although ERK and Akt activation upon cholinergic stimulus both require EGFR activity, only ERK activation is fully dependent on the MMP mediated extracellular pathway of EGFR activation, whereas MMP inhibition only partially inhibits the basal and stimulated Akt activity (XREF_FIG).	22	35	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	22	23	34	35
Endophilin B1 decreased also sustained EGFR downstream signaling such as Erk1/2 phosphorylation in response to EGF stimulation and promoted prostate cancer cell proliferation which is EGF independent .	Endophilin B1 decreased also sustained EGFR downstream signaling such as Erk1/2 phosphorylation in response to EGF stimulation and promoted prostate cancer cell proliferation which is EGF independent.	5	12	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Erk1/2	Erk1/2 phosphorylation	erk1/2	EGFR	EGFR	egfr	10	11	5	6
There are conflicting reports on the role of MAPK signaling in EGFRvIII expressing models where some studies report activation and others fail to suggest a role .	There are conflicting reports on the role of MAPK signaling in EGFRvIII expressing models where some studies report activation and others fail to suggest a role.	8	12	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFRvIII	EGFRvIII	EGFRvIII	8	9	11	12
Our results indicate that in addition to its EGFR effector function , the ERK pathway also contributes to corneal epithelial wound healing by regulating ADAM17 activity , HB-EGF shedding , and EGFR activation .	Our results indicate that in addition to its EGFR effector function, the ERK pathway also contributes to corneal epithelial wound healing by regulating ADAM17 activity, HB-EGF shedding, and EGFR activation.	13	32	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	13	14	31	32
Furthermore , studies in our lab have shown that MEK and ERK inhibition can reverse TGFalpha and EGFR mediated repression of Sox9 expression [ XREF_BIBR ] .	Furthermore, studies in our lab have shown that MEK and ERK inhibition can reverse TGFalpha and EGFR mediated repression of Sox9 expression [XREF_BIBR].	9	18	reverse	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	11	12	17	18
XREF_BIBR , XREF_BIBR To identify the intracellular pathway ( s ) participating in the activation of EGFR , we showed in the present study that ERK1/2 mediates HB-EGF shedding and EGFR activation in response to wounding , ATP , and LPA .	XREF_BIBR, XREF_BIBR To identify the intracellular pathway (s) participating in the activation of EGFR, we showed in the present study that ERK1/2 mediates HB-EGF shedding and EGFR activation in response to wounding, ATP, and LPA.	25	31	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	25	26	30	31
BCRP reduced intracellular gefitinib levels and attenuated inhibitory activities of gefitinib to EGF dependent EGFR signalings including downstream MAPK and Akt pathways in gefitinib sensitive PC-9 cells .	BCRP reduced intracellular gefitinib levels and attenuated inhibitory activities of gefitinib to EGF dependent EGFR signalings including downstream MAPK and Akt pathways in gefitinib sensitive PC-9 cells.	14	26	signalings	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	18	19	14	15
This results in highly enhanced and prolonged EGFR signaling , including ERK and AKT activation , which also correlates with cancer progression .	This results in highly enhanced and prolonged EGFR signaling, including ERK and AKT activation, which also correlates with cancer progression.	7	12	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	11	12	7	8
In conclusion , our results suggest that ERK1/2 mediates HB-EGF shedding and subsequent EGFR transactivation in response to a variety of stimuli including wounding and GPCR ligands via regulating phosphorylation and activation of ADAM17 .	In conclusion, our results suggest that ERK1/2 mediates HB-EGF shedding and subsequent EGFR transactivation in response to a variety of stimuli including wounding and GPCR ligands via regulating phosphorylation and activation of ADAM17.	7	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	7	8	13	14
Here we provide evidence that in the COS-7 cell model EGFR transactivation via the muscarinic M2 receptor ( M2R ) is independent of MMPs and results in an incomplete EGFR signalling including ERK and Akt but not PLCgamma1 .	Here we provide evidence that in the COS-7 cell model EGFR transactivation via the muscarinic M2 receptor (M2R) is independent of MMPs and results in an incomplete EGFR signalling including ERK and Akt but not PLCgamma1.	29	37	signalling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	32	33	29	30
[ XREF_BIBR ] Several signaling molecules may participate in EGFR activation such as phosphatidylinositol-3 kinase ( PI3K ) , extracellular signal regulated kinase ( ERK ) , mitogen activated protein kinase ( MAPK ) , etc. [ XREF_BIBR XREF_BIBR ] [ XREF_FIG ] .	[XREF_BIBR] Several signaling molecules may participate in EGFR activation such as phosphatidylinositol-3 kinase (PI3K), extracellular signal regulated kinase (ERK), mitogen activated protein kinase (MAPK), etc. [XREF_BIBR XREF_BIBR] [XREF_FIG].	9	23	activation	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	extracellular signal regulated kinase	extracellular signal regulated kinase	extracellular signal regulated kinase	EGFR	EGFR	EGFR	19	23	9	10
For example , in Sprouty ( hSpry ) regulation of Ras and MAPK mediated EGFR signaling , EGFR induces hSpry2 expression but hSpry2 inhibits EGFR function ( negative feedback ) ; however , hSpry2 also promotes EGFR activity by preventing Cbl dependent EGFR inhibition ( positive feedback ) .	For example, in Sprouty (hSpry) regulation of Ras and MAPK mediated EGFR signaling, EGFR induces hSpry2 expression but hSpry2 inhibits EGFR function (negative feedback); however, hSpry2 also promotes EGFR activity by preventing Cbl dependent EGFR inhibition (positive feedback).	10	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	EGFR	EGFR	EGFR	12	13	14	15
A deletion of ETS2 in mice results in a phenotype similar to a deletion of the RAS and ERK activator EGFR , and a deletion of both ETS1 and ETS2 in mouse embryonic fibroblasts inhibits HrasG12V transformation , but it is not known what cis-regulatory sequences mediate these effects .	A deletion of ETS2 in mice results in a phenotype similar to a deletion of the RAS and ERK activator EGFR, and a deletion of both ETS1 and ETS2 in mouse embryonic fibroblasts inhibits HrasG12V transformation, but it is not known what cis-regulatory sequences mediate these effects.	13	21	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	18	19	20	21
For example , Ras and ERK mediated EGFR signaling can regulate cell growth and transformation .	For example, Ras and ERK mediated EGFR signaling can regulate cell growth and transformation.	1	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	5	6	7	8
Gefitinib promptly suppressed the EGFR downstream signaling including Akt and ERK1/2 in TKIS cells but showed modest effect in TKIR cells .	Gefitinib promptly suppressed the EGFR downstream signaling including Akt and ERK1/2 in TKIS cells but showed modest effect in TKIR cells.	4	11	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	EGFR	EGFR	EGFR	10	11	4	5
Loss of Holn1 function in the holn1 c07150 mutants , as well as reduced ERK signaling in EGFR t1 and ERK/rl 10a mutants , impaired the wound healing process .	Loss of Holn1 function in the holn1 c07150 mutants, as well as reduced ERK signaling in EGFR t1 and ERK/rl 10a mutants, impaired the wound healing process.	14	18	signaling	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	EGFR	EGFR	EGFR	14	15	17	18
Sorafenib inhibited catC T421M in vitro ( XREF_SUPPLEMENTARY ) and induced ERK signaling in cells expressing catC T421M ( XREF_FIG ) , demonstrating that this mutant is capable of inhibitor induced MEK and ERK activation .	Sorafenib inhibited catC T421M in vitro (XREF_SUPPLEMENTARY) and induced ERK signaling in cells expressing catC T421M (XREF_FIG), demonstrating that this mutant is capable of inhibitor induced MEK and ERK activation.	11	34	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	11	12	31	32
In this study , we present data suggesting that ERK1c , but not ERK1/2 , might be the mediator of the MEK induced Golgi fragmentation during mitosis .	In this study, we present data suggesting that ERK1c, but not ERK1/2, might be the mediator of the MEK induced Golgi fragmentation during mitosis.	9	22	be the mediator	Positive_activation_copula_1	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MEK	MEK	MEK	13	14	21	22
Activated Raf-1 phosphorylates and activates MAPK and ERK kinase Mek ) , thus initiating the Mek --> MAP kinase cascade , which ultimately results in the phosphorylation and activation of transcription factors by MAP kinase .	Activated Raf-1 phosphorylates and activates MAPK and ERK kinase Mek), thus initiating the Mek --> MAP kinase cascade, which ultimately results in the phosphorylation and activation of transcription factors by MAP kinase.	1	19	initiating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	Raf-1 phosphorylates and activates MAPK and ERK	erk	Mek	Mek	mek	7	8	15	16
XREF_BIBR identified TPL2 as a MAPK pathway agonist that activates MEK independent of RAF signaling and drives resistance to RAF inhibition in melanoma , we hypothesized that TPL2 might be upregulated in B16BR cells .	XREF_BIBR identified TPL2 as a MAPK pathway agonist that activates MEK independent of RAF signaling and drives resistance to RAF inhibition in melanoma, we hypothesized that TPL2 might be upregulated in B16BR cells.	5	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	5	6	10	11
An inhibitor of the MAPK activator MEK , PD 098059 , effectively blocked ATP- and 2-chloroadenosine-induced DNA synthesis , thereby indicating that the ERK and MAPK cascade mediates mitogenic signaling by P2 and P1 purinergic receptors in human fetal astrocytes .	An inhibitor of the MAPK activator MEK, PD 098059, effectively blocked ATP- and 2-chloroadenosine-induced DNA synthesis, thereby indicating that the ERK and MAPK cascade mediates mitogenic signaling by P2 and P1 purinergic receptors in human fetal astrocytes.	1	7	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	4	5	6	7
However , autophagy induction was attenuated but not completely suppressed by indirect inhibition of ERK in the presence of the aforementioned MEK1/2 specific inhibitors ( results not shown ) .	However, autophagy induction was attenuated but not completely suppressed by indirect inhibition of ERK in the presence of the aforementioned MEK1/2 specific inhibitors (results not shown).	9	22	suppressed	Negative_activation_syntax_3_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK1/2	MEK1/2	MEK1/2	14	15	21	22
The ERK activator MEK was reported to regulate JNK activity in rat intestine cell line ( IEC-6 ) and in human astrocyte cell line ( U-251 ) [ XREF_BIBR , XREF_BIBR ] .	The ERK activator MEK was reported to regulate JNK activity in rat intestine cell line (IEC-6) and in human astrocyte cell line (U-251) [XREF_BIBR, XREF_BIBR].	0	7	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	1	2	3	4
We next examined whether the inability of ERK to accumulate in the nucleus of nonadherent tet-MEK *-3T3 cells , induced to express active MEK , corresponded to inefficient phosphorylation of a nuclear target .	We next examined whether the inability of ERK to accumulate in the nucleus of nonadherent tet-MEK *-3T3 cells, induced to express active MEK, corresponded to inefficient phosphorylation of a nuclear target.	5	24	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	7	8	23	24
ERK1/2 are unique targets of MEK , making MEK an interesting target for anticancer therapeutics .	ERK1/2 are unique targets of MEK, making MEK an interesting target for anticancer therapeutics.	0	6	are unique targets	Positive_activation_copula_1	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MEK	MEK	MEK	0	1	5	6
Although basal phosphorylated ERK is minimal in mouse spinal cords without noxious stimuli , we investigated whether expression of the DN MEK transgene would alter basal ERK activation in the DN MEK mice .	Although basal phosphorylated ERK is minimal in mouse spinal cords without noxious stimuli, we investigated whether expression of the DN MEK transgene would alter basal ERK activation in the DN MEK mice.	26	32	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	26	27	31	32
ERK can be activated by Ref mediated MEK signaling .	ERK can be activated by Ref mediated MEK signaling.	0	8	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	0	1	7	8
Activated MEK in turn phosphorylates ERK on a tyrosine and threonine residue within its T-Loop , such that it subsequently targets its nuclear and non nuclear substrates .	Activated MEK in turn phosphorylates ERK on a tyrosine and threonine residue within its T-Loop, such that it subsequently targets its nuclear and non nuclear substrates.	0	16	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	phosphorylates ERK on a tyrosine and threonine residue	erk	MEK	MEK	mek	5	6	1	2
Interestingly , LiCl pretreatment enhanced LPS induced MEK1/2 phosphorylation unlike ERK ( data not shown ) suggesting that Li ' s effect on LPS induced ERK likely occurs below MEK1/2 and potentially via a protein that could directly affect ERK .	Interestingly, LiCl pretreatment enhanced LPS induced MEK1/2 phosphorylation unlike ERK (data not shown) suggesting that Li 's effect on LPS induced ERK likely occurs below MEK1/2 and potentially via a protein that could directly affect ERK.	27	40	potentially	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK1/2	MEK1/2	MEK1/2	39	40	29	30
Melatonin is effective in preventing the ischemic brain injury induced down-regulation of Raf-1 , MEK1/2 and ERK1/2 phosphorylation 57 , suggesting that the activation of Raf/MEK/ERK cascade can be mediated by Melatonin .	Melatonin is effective in preventing the ischemic brain injury induced down-regulation of Raf-1, MEK1/2 and ERK1/2 phosphorylation 57, suggesting that the activation of Raf/MEK/ERK cascade can be mediated by Melatonin.	9	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2 phosphorylation	erk1/2	MEK1/2	MEK1/2	mek1/2	16	17	14	15
In addition , pharmacologic inhibition of the Erk activator Mek in zebrafish results in defective cranio-facial development , outflow tract blockage in the heart with concomitant pericardial edema , and increased vascular permeability .	In addition, pharmacologic inhibition of the Erk activator Mek in zebrafish results in defective cranio-facial development, outflow tract blockage in the heart with concomitant pericardial edema, and increased vascular permeability.	4	11	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Erk	Erk	Erk	Mek	Mek	Mek	7	8	9	10
However , suppression of this pathway by blocking FGF receptor activity or by more direct disruption of MAPK signalling using a small molecule inhibitor of the MAPK activator MEK , uncouples this differentiation signal and shifts the balance in favour of ES cell self-renewal .	However, suppression of this pathway by blocking FGF receptor activity or by more direct disruption of MAPK signalling using a small molecule inhibitor of the MAPK activator MEK, uncouples this differentiation signal and shifts the balance in favour of ES cell self-renewal.	23	29	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	26	27	28	29
We previously reported that SCH772984 , an ERK 1/2 inhibitor , effectively suppressed MAPK pathway signaling and cell proliferation in BRAF , MEK , and concurrent BRAF and MEK inhibitor resistant tumor models .	We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK, and concurrent BRAF and MEK inhibitor resistant tumor models.	13	23	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	13	14	22	23
We then combined CHIR with blockade of the Erk pathway , initially using inhibitors of both the Erk activating enzymes MEK1/2 , and of the fibroblast growth factor ( FGF ) receptor .	We then combined CHIR with blockade of the Erk pathway, initially using inhibitors of both the Erk activating enzymes MEK1/2, and of the fibroblast growth factor (FGF) receptor.	13	21	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk	Erk	Erk	MEK1/2	MEK1/2	MEK1/2	17	18	20	21
Activated MEK phosphorylates ERK1/2 , which in turn phosphorylates transcription factors that control a number of proliferative and anti-apoptotic targets .	Activated MEK phosphorylates ERK1/2, which in turn phosphorylates transcription factors that control a number of proliferative and anti-apoptotic targets.	0	8	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	phosphorylates ERK1/2	erk1/2	MEK	MEK	mek	3	4	1	2
The contribution of ERK1/2 to CD24 induced motility and invasion was examined using a specific inhibitor of the upstream ERK1/2 activator MEK1/2 ( U0126 ) .	The contribution of ERK1/2 to CD24 induced motility and invasion was examined using a specific inhibitor of the upstream ERK1/2 activator MEK1/2 (U0126).	15	23	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MEK1/2	MEK1/2	MEK1/2	19	20	21	22
Erk1/2 is a target of Mek and the activity of Erk1/2 required activation of the upstream kinase Mek .	Erk1/2 is a target of Mek and the activity of Erk1/2 required activation of the upstream kinase Mek.	0	6	is a target	Positive_activation_copula_1	Negative_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	Mek	Mek	Mek	0	1	5	6
PD98059 has been shown to inhibit activation of MEK targets including ERK1/2 [ XREF_BIBR ] .	PD98059 has been shown to inhibit activation of MEK targets including ERK1/2 [XREF_BIBR].	8	13	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MEK	MEK	MEK	11	12	8	9
We investigated the effects of transformation on serum and growth factor stimulation of Erk1 and Erk2 , and show that stimulation of these MAP kinases , as well as the Erk activator Mek , is delayed in oncogene transformed cells .	We investigated the effects of transformation on serum and growth factor stimulation of Erk1 and Erk2, and show that stimulation of these MAP kinases, as well as the Erk activator Mek, is delayed in oncogene transformed cells.	20	35	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Erk	Erk	Erk	Mek	Mek	Mek	30	31	32	33
Activated MEK subsequently phosphorylates ERK , which translocates to the nucleus where it activates multiple transcription factors .	Activated MEK subsequently phosphorylates ERK, which translocates to the nucleus where it activates multiple transcription factors.	0	7	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	phosphorylates ERK	erk	MEK	MEK	mek	4	5	1	2
Activated MEK activates ERK , which induces several proliferative and survival processes , one of which is activation of the cyclin D and CDK4/6 complex ( discussed above ) upon translocation to the nucleus .	Activated MEK activates ERK, which induces several proliferative and survival processes, one of which is activation of the cyclin D and CDK4/6 complex (discussed above) upon translocation to the nucleus.	0	17	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	3	4	1	2
While AKT stimulates mTOR pathway through PRAS40 and further activates p70S6 , S6 , and 4E-BP1 , PDK1 may play a role in activating MEK mediated MAPK pathway , where PDK1 interacts with and activates MEK and also p90RSK to activate the MAPK signaling pathway .	While AKT stimulates mTOR pathway through PRAS40 and further activates p70S6, S6, and 4E-BP1, PDK1 may play a role in activating MEK mediated MAPK pathway, where PDK1 interacts with and activates MEK and also p90RSK to activate the MAPK signaling pathway.	24	38	activates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	MAPK	MEK mediated MAPK	mapk	MEK	MEK	mek	26	27	35	36
Finally , the ability of TPO to induce the IEX-1 gene expression was inhibited by U0126 , a specific inhibitor of the ERKs activator MEK and AML1 transcriptional activity was shown to be modulated by TPO through ERK dependent phosphorylation .	Finally, the ability of TPO to induce the IEX-1 gene expression was inhibited by U0126, a specific inhibitor of the ERKs activator MEK and AML1 transcriptional activity was shown to be modulated by TPO through ERK dependent phosphorylation.	19	28	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERKs	ERKs	ERKs	MEK	MEK	MEK	22	23	24	25
Activated MEK then directly phosphorylates a conserved tyrosine and threonine residue in the kinase activation loop of ERK XREF_BIBR .	Activated MEK then directly phosphorylates a conserved tyrosine and threonine residue in the kinase activation loop of ERK XREF_BIBR.	0	18	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	17	18	1	2
MEK1/2 activation , like ERK , was not increased in CIA .	MEK1/2 activation, like ERK, was not increased in CIA.	0	5	activation	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK1/2	MEK1/2	MEK1/2	4	5	0	1
To explore the role of MAPK activation on PGI 2 and cAMP production by BK and IGF-1 in VSMC , cells were pretreated for 30 min with PD 98059 ( 20 muM , NEN-Biolabs , Beverly , MA ) , a specific cell permeable inhibitor of the MAPK activator MEK followed by BK ( 10 -8 M ) or IGF-1 ( 10 -8 M ) stimulation for 10 min .	To explore the role of MAPK activation on PGI 2 and cAMP production by BK and IGF-1 in VSMC, cells were pretreated for 30 min with PD 98059 (20 muM, NEN-Biolabs, Beverly, MA), a specific cell permeable inhibitor of the MAPK activator MEK followed by BK (10 -8 M) or IGF-1 (10 -8 M) stimulation for 10 min.	44	50	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	47	48	49	50
Additional signaling proteins that appear to participate in the regulation of PKCtheta cellular localization and function include the ERK activating MEK kinase , phosphatidylinositol 3-kinase ( PI3K ) and Vav .	Additional signaling proteins that appear to participate in the regulation of PKCtheta cellular localization and function include the ERK activating MEK kinase, phosphatidylinositol 3-kinase (PI3K) and Vav.	16	21	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	18	19	20	21
To demonstrate that the appearance of p59 Lck indeed depends on Erk mediated phosphorylation , T cells were stimulated with iAbs for 30 min in the presence or absence of U0126 or MEK Inhibitor I , inhibitors of the Erk activator MEK .	To demonstrate that the appearance of p59 Lck indeed depends on Erk mediated phosphorylation, T cells were stimulated with iAbs for 30 min in the presence or absence of U0126 or MEK Inhibitor I, inhibitors of the Erk activator MEK.	36	42	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Erk	Erk	Erk	MEK	MEK	MEK	39	40	41	42
Since RNF2 overexpression was studied in the context of activated MAPK signaling ( due to BRAF V600E mutation ) , which is known to activate MEK , we asked whether phosphorylation of RNF2 by MEK may be important for its role in gene activation in the context of melanoma .	Since RNF2 overexpression was studied in the context of activated MAPK signaling (due to BRAF V600E mutation), which is known to activate MEK, we asked whether phosphorylation of RNF2 by MEK may be important for its role in gene activation in the context of melanoma.	10	26	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	10	11	25	26
Mutated NRAS triggers the MAPK signaling cascade through activation of RAF , which in turn activates MEK , thereby triggering ERK phosphorylation and cellular proliferation .	Mutated NRAS triggers the MAPK signaling cascade through activation of RAF, which in turn activates MEK, thereby triggering ERK phosphorylation and cellular proliferation.	4	24	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	4	5	16	17
Although not a screen hit , MEK target ERK showed up-regulated expression with a trend to increased activation in RCC4B20 cells .	Although not a screen hit, MEK target ERK showed up-regulated expression with a trend to increased activation in RCC4B20 cells.	6	9	target	Positive_activation_token_1_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	8	9	6	7
Activated MEK in turn phosphorylates ERK resulting in its translocation to nucleus .	Activated MEK in turn phosphorylates ERK resulting in its translocation to nucleus.	0	6	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	phosphorylates ERK	erk	MEK	MEK	mek	5	6	1	2
Therefore , the reduction in spinal ERK activation in the DN MEK mice is not due to reduced number of unmyelinated peripheral fibers .	Therefore, the reduction in spinal ERK activation in the DN MEK mice is not due to reduced number of unmyelinated peripheral fibers.	6	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	6	7	11	12
The classical MAPK cascade leads from the Ras kinases to the MAPKK MEK1/2 .	The classical MAPK cascade leads from the Ras kinases to the MAPKK MEK1/2.	2	13	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK1/2	MEK1/2	MEK1/2	2	3	12	13
No changes were apparent at 1 or 2 days , but at 7 days , the protein expression of cyclins A , B1 , C , D1 , E , and the phosphorylated form of MAPK signaler MEK ( P-MEK1/2 ) decreased at 500 and 1000muM concentrations ( XREF_FIG ) .	No changes were apparent at 1 or 2 days, but at 7 days, the protein expression of cyclins A, B1, C, D1, E, and the phosphorylated form of MAPK signaler MEK (P-MEK1/2) decreased at 500 and 1000muM concentrations (XREF_FIG).	33	39	signaler	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	35	36	37	38
The ERK activator MEK , which possesses a NES-sequence , was apparently not involved in nuclear export , as it did not seem to enter the nucleus .	The ERK activator MEK, which possesses a NES-sequence, was apparently not involved in nuclear export, as it did not seem to enter the nucleus.	0	13	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	1	2	3	4
Potential ERK independent roles of somatic MEK1 mutants in melanoma pathogenesis would further support the combined BRAF and MEK inhibition therapeutic approach .	Potential ERK independent roles of somatic MEK1 mutants in melanoma pathogenesis would further support the combined BRAF and MEK inhibition therapeutic approach.	1	21	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	1	2	18	19
However , in DC , Ser380/386 phosphorylation was resistant to inhibition of the Erk1/2 activating kinases MEK1/2 by PD184352 and could be fully blocked only when the p38 MAP kinase inhibitor BIRB0796 was also included ( XREF_FIG ) .	However, in DC, Ser380/386 phosphorylation was resistant to inhibition of the Erk1/2 activating kinases MEK1/2 by PD184352 and could be fully blocked only when the p38 MAP kinase inhibitor BIRB0796 was also included (XREF_FIG).	10	17	activating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Erk1/2	Erk1/2	Erk1/2	MEK1/2	MEK1/2	MEK1/2	13	14	16	17
We investigated the role of ERK in sleep dependent ODP consolidation by inhibiting the ERK activating enzyme MEK in V1 ( via U0126 ) during post-MD sleep .	We investigated the role of ERK in sleep dependent ODP consolidation by inhibiting the ERK activating enzyme MEK in V1 (via U0126) during post-MD sleep.	12	18	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	14	15	17	18
PD 98059 , an inhibitor of the ERK activator MEK ( mitogen activated protein kinase kinase ) and bisindolylmaleimide I , an inhibitor of PKC activation , each blocked aldosterone stimulated hypertrophy .	PD 98059, an inhibitor of the ERK activator MEK (mitogen activated protein kinase kinase) and bisindolylmaleimide I, an inhibitor of PKC activation, each blocked aldosterone stimulated hypertrophy.	4	10	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	7	8	9	10
As shown in XREF_FIG and XREF_FIG , intrahippocampal infusion of fluoxetine into P15 mice caused a significant increase in PSD95 expression and synaptogenesis and this effect was eliminated upon inhibition of the Erk activator MEK with U0126 and PKCalpha with Ro 31-8220 .	As shown in XREF_FIG and XREF_FIG, intrahippocampal infusion of fluoxetine into P15 mice caused a significant increase in PSD95 expression and synaptogenesis and this effect was eliminated upon inhibition of the Erk activator MEK with U0126 and PKCalpha with Ro 31-8220.	29	35	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Erk	Erk	Erk	MEK	MEK	MEK	32	33	34	35
As shown in XREF_FIG A , inhibitors of the ERK activator MEK ( PD98059 ) , or PI-3K ( wortmannin ) were each able to reverse the antiapoptotic effect of alpha M beta 2 clustering with either 19c F ( ab ' ) 2 or rhICAM-1 coated beads ( XREF_FIG A ) .	As shown in XREF_FIG A, inhibitors of the ERK activator MEK (PD98059), or PI-3K (wortmannin) were each able to reverse the antiapoptotic effect of alpha M beta 2 clustering with either 19c F (ab ') 2 or rhICAM-1 coated beads (XREF_FIG A).	6	13	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	9	10	11	12
Taken together , our results suggest that phosphorylated alphaB crystallin may inhibit the RAS that causes inactivation of ERK1/2 ( a downstream target of the raf-1 and MEK1/2 pathways ) .	Taken together, our results suggest that phosphorylated alphaB crystallin may inhibit the RAS that causes inactivation of ERK1/2 (a downstream target of the raf-1 and MEK1/2 pathways).	16	28	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MEK1/2	MEK1/2	MEK1/2	18	19	27	28
Immunoblot analysis revealed strong and consistent FGF2 induced , FGFR dependent phosphorylation of ERK1/2 , the upstream MAPK kinases 1 and 2 ( MEK1/2 ) , and FGFR substrate 2alpha ( FRS2alpha ) , which is the primary adaptor involved in FGFR induced MEK and ERK activation .	Immunoblot analysis revealed strong and consistent FGF2 induced, FGFR dependent phosphorylation of ERK1/2, the upstream MAPK kinases 1 and 2 (MEK1/2), and FGFR substrate 2alpha (FRS2alpha), which is the primary adaptor involved in FGFR induced MEK and ERK activation.	9	46	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	FGFR dependent phosphorylation of ERK1/2	erk1/2	MEK	MEK	mek	13	14	43	44
Approximately 40 % of cutaneous melanoma patients have tumors with an activating mutation in the BRAF gene ( BRAF V600E/K ) , which activates the MAPK pathway via a phosphorylation cascade that activates MEK and ERK [ XREF_BIBR ] .	Approximately 40% of cutaneous melanoma patients have tumors with an activating mutation in the BRAF gene (BRAF V600E/K), which activates the MAPK pathway via a phosphorylation cascade that activates MEK and ERK [XREF_BIBR].	25	37	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	25	26	33	34
Raf phosphorylates MAPK and ERK kinase ( MEK ) and MEK activates the extracellular-signal-regulated kinase ( ERK ) in the MEK and ERK pathway .	Raf phosphorylates MAPK and ERK kinase (MEK) and MEK activates the extracellular-signal-regulated kinase (ERK) in the MEK and ERK pathway.	1	23	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	phosphorylates MAPK	mapk	MEK	MEK	mek	2	3	20	21
Treatment with PD-98059 ( an inhibitor specific to the ERK1/2 activator MEK1/2 ) significantly suppressed the phosphorylation of MLCK , suggesting a role for ERK1/2 in regulating the activity of MLCK .	Treatment with PD-98059 (an inhibitor specific to the ERK1/2 activator MEK1/2) significantly suppressed the phosphorylation of MLCK, suggesting a role for ERK1/2 in regulating the activity of MLCK.	6	12	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MEK1/2	MEK1/2	MEK1/2	9	10	11	12
Actually , co-treatment of C2C12 muscle cells with insulin and PD98059 decreased expression of P-T202 and Y204 ERK1/2 ( specific target of MEK ) at the same , and during following days ( 3-5 ) .	Actually, co-treatment of C2C12 muscle cells with insulin and PD98059 decreased expression of P-T202 and Y204 ERK1/2 (specific target of MEK) at the same, and during following days (3-5).	12	33	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	ERK1/2	expression of P-T202 and Y204 ERK1/2	erk1/2	MEK	MEK	mek	17	18	22	23
It is unlikely that the decrease in basal hippocampal ERK activity could produce decreased nociception in the DN MEK mice .	It is unlikely that the decrease in basal hippocampal ERK activity could produce decreased nociception in the DN MEK mice.	9	19	produce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	9	10	18	19
To confirm a role for MAPK signaling in patients with relapsed ALL , we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse .	To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse.	16	24	target	Positive_activation_token_1_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK1/2	MEK1/2	MEK1/2	21	22	19	20
Activated Mek , in turn , phosphorylates extracellular signal regulated kinase ( Erk ) , which can also be phosphorylated on one or both residues .	Activated Mek, in turn, phosphorylates extracellular signal regulated kinase (Erk), which can also be phosphorylated on one or both residues.	0	11	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	extracellular signal regulated kinase	phosphorylates extracellular signal regulated kinase	extracellular signal regulated kinase	Mek	Mek	mek	7	11	1	2
Mek1/2 is the chief regulatory step of the Erk1/2 signaling pathway and all endogenous activators of the Erk signaling pathway targets Mek1/2 .	Mek1/2 is the chief regulatory step of the Erk1/2 signaling pathway and all endogenous activators of the Erk signaling pathway targets Mek1/2.	17	22	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk	Erk	Erk	Mek1/2	Mek1/2	Mek1/2	17	18	21	22
Our results reveal that signaling by ERK and its upstream kinase MEK in the VMH mediates the leptin induced increase in glucose utilization and its insulin sensitivity both in the whole body and in red-type skeletal muscle through activation of MCR in the VMH .	Our results reveal that signaling by ERK and its upstream kinase MEK in the VMH mediates the leptin induced increase in glucose utilization and its insulin sensitivity both in the whole body and in red-type skeletal muscle through activation of MCR in the VMH.	4	15	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	6	7	11	12
The cells were then treated with 10mM U0126 ( Beyotime , Shanghai , China ) , a MAPK and ERK kinase inhibitor that inhibits MEK1/2 for downregulation of expression of P-ERK for 72h .	The cells were then treated with 10mM U0126 (Beyotime, Shanghai, China), a MAPK and ERK kinase inhibitor that inhibits MEK1/2 for downregulation of expression of P-ERK for 72h.	19	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK1/2	MEK1/2	MEK1/2	19	20	24	25
IQ motif containing GTPase activating protein 1 ( IQGAP1 ) is a MAPK scaffold that directly regulates the activation of RAF , MEK , and extracellular signalling regulated kinases ( ERKs ) [ XREF_BIBR ] .	IQ motif containing GTPase activating protein 1 (IQGAP1) is a MAPK scaffold that directly regulates the activation of RAF, MEK, and extracellular signalling regulated kinases (ERKs) [XREF_BIBR].	12	23	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	12	13	22	23
Treatment with exogenous MMP-7 has been reported to induce activation by phosphorylation of Akt and ERK1/2 ( p44/42 MAPK [ mitogen activated protein kinase ] ) , as well as epithelial growth factor receptor ( EGFR ) and MEK .	Treatment with exogenous MMP-7 has been reported to induce activation by phosphorylation of Akt and ERK1/2 (p44/42 MAPK [mitogen activated protein kinase]), as well as epithelial growth factor receptor (EGFR) and MEK.	9	39	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	ERK1/2	phosphorylation of Akt and ERK1/2	erk1/2	MEK	MEK	mek	15	16	38	39
And these five MEK inhibitors could down regulate ERK phosphorylation ( a downstream target of MEK ) in Drosophila cells .	And these five MEK inhibitors could down regulate ERK phosphorylation (a downstream target of MEK) in Drosophila cells.	8	16	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	ERK	ERK phosphorylation	erk	MEK	MEK	mek	8	9	15	16
Here we report that PDK1 promotes MAPK activation in a MEK dependent manner .	Here we report that PDK1 promotes MAPK activation in a MEK dependent manner.	6	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	6	7	10	11
These results are consistent with the hypothesis that ERK and mTOR signaling interact at multiple levels to regulate tumor growth in vivo , and support the testing of MEK plus mTOR inhibitor combinations in pancreatic cancer patients .	These results are consistent with the hypothesis that ERK and mTOR signaling interact at multiple levels to regulate tumor growth in vivo, and support the testing of MEK plus mTOR inhibitor combinations in pancreatic cancer patients.	8	29	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	8	9	28	29
The mitogen activated protein kinase , MEK , and its effector , ERK , is one such RTK downstream target .	The mitogen activated protein kinase, MEK, and its effector, ERK, is one such RTK downstream target.	1	13	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	12	13	6	7
In HEK293 cells , we also examined several other MAP kinases including JNK ( phosphorylated by SEK1 or MKK4 ) , p38 MAPK ( target of MKK3 , MKK6 , and SEK ) and Erk ( target of MEK ) since they had been directly or indirectly implicated in several other studies regarding calcium mediated autophagy regulation XREF_BIBR .	In HEK293 cells, we also examined several other MAP kinases including JNK (phosphorylated by SEK1 or MKK4), p38 MAPK (target of MKK3, MKK6, and SEK) and Erk (target of MEK) since they had been directly or indirectly implicated in several other studies regarding calcium mediated autophagy regulation XREF_BIBR.	10	47	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	Erk	Erk	Erk	MEK	MEK	MEK	34	35	38	39
19 Interestingly , irradiation of p53- and p21 deficient HCT116 cells in the presence of U0126 , an inhibitor of the ERK1/2 activating kinases MEK1/2 , protected them from apoptosis , as evidenced microscopically ( not shown ) and by inhibition of caspase-3-like DEVDase activity ( XREF_FIG ) .	19 Interestingly, irradiation of p53- and p21 deficient HCT116 cells in the presence of U0126, an inhibitor of the ERK1/2 activating kinases MEK1/2, protected them from apoptosis, as evidenced microscopically (not shown) and by inhibition of caspase-3-like DEVDase activity (XREF_FIG).	18	25	activating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MEK1/2	MEK1/2	MEK1/2	21	22	24	25
Preincubation of cultured pachytene spermatocytes with PD98059 ( a selective inhibitor of ERK activating kinases MEK1/2 ) completely blocks the ability of OA to induce chromosome condensation and progression to meiotic metaphases .	Preincubation of cultured pachytene spermatocytes with PD98059 (a selective inhibitor of ERK activating kinases MEK1/2) completely blocks the ability of OA to induce chromosome condensation and progression to meiotic metaphases.	10	16	activating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK1/2	MEK1/2	MEK1/2	12	13	15	16
As expected , we found that MEKi alone resulted in a reduction in ERK1/2 phosphorylation ( the immediate downstream target of MEK1/2 ) , in both mouse and human CD8 + T cells .	As expected, we found that MEKi alone resulted in a reduction in ERK1/2 phosphorylation (the immediate downstream target of MEK1/2), in both mouse and human CD8 + T cells.	13	22	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2 phosphorylation	erk1/2	MEK1/2	MEK1/2	mek1/2	13	14	21	22
Phosphorylation of in MAPK pathway signaling molecules c-Raf , MEK1/2 , ERK1/2 , and p90RSK was determined by Western blot .	Phosphorylation of in MAPK pathway signaling molecules c-Raf, MEK1/2, ERK1/2, and p90RSK was determined by Western blot.	0	10	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	Phosphorylation of in MAPK	mapk	MEK1/2	MEK1/2	mek1/2	3	4	9	10
The TNFalpha induced activation of ERK1/2 was specifically prevented by compound PD 98059 a specific inhibitor of the MAP kinase kinase MEK1/2 .	The TNFalpha induced activation of ERK1/2 was specifically prevented by compound PD 98059 a specific inhibitor of the MAP kinase kinase MEK1/2.	1	22	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	TNFalpha induced activation of ERK1/2	erk1/2	MEK1/2	MEK1/2	mek1/2	5	6	21	22
Combined treatment with DTT and U0126 , an inhibitor of ERK upstream activators mitogen activated protein kinase ( MAPK ) kinase1 and 2 ( MEK1/2 ) , blocked autophagy flux in HeLa cells .	Combined treatment with DTT and U0126, an inhibitor of ERK upstream activators mitogen activated protein kinase (MAPK) kinase1 and 2 (MEK1/2), blocked autophagy flux in HeLa cells.	10	25	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK1/2	MEK1/2	MEK1/2	10	11	24	25
Although a similar feedback increase in MEK phosphorylation has been previously reported , our current finding is unique since MEK hyperactivation was induced by an abrogation of ERK1/2 expression , and not by a downregulation of ERK1/2 phosphorylation as observed in other studies [ XREF_BIBR , XREF_BIBR ] .	Although a similar feedback increase in MEK phosphorylation has been previously reported, our current finding is unique since MEK hyperactivation was induced by an abrogation of ERK1/2 expression, and not by a downregulation of ERK1/2 phosphorylation as observed in other studies [XREF_BIBR, XREF_BIBR].	19	29	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2 expression	erk1/2	MEK	MEK	mek	27	28	19	20
ANG II significantly increased aldosterone release , and this effect was inhibited by the LO inhibitor baicalein , as well as a specific p38 MAPK inhibitor , SB202190 , but not by PD098059 , a specific inhibitor of the ERK activator MEK .	ANG II significantly increased aldosterone release, and this effect was inhibited by the LO inhibitor baicalein, as well as a specific p38 MAPK inhibitor, SB202190, but not by PD098059, a specific inhibitor of the ERK activator MEK.	36	42	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK	MEK	MEK	39	40	41	42
To determine whether the Erk activation was associated with the inhibitory effect of GGF , co-cultures were treated with GGF along with increasing concentrations of U0126 , a specific inhibitor of Erk activator Mek1/2 , and maintained under myelinating condition .	To determine whether the Erk activation was associated with the inhibitory effect of GGF, co-cultures were treated with GGF along with increasing concentrations of U0126, a specific inhibitor of Erk activator Mek1/2, and maintained under myelinating condition.	29	34	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Erk	Erk	Erk	Mek1/2	Mek1/2	Mek1/2	31	32	33	34
Previous studies demonstrated that BRAFV600E establishes a high level of ERK directed transcriptional output and MEK dependent negative feedback of growth factor-receptor ( GF-R ) signaling , whereas activated oncogenic RTKs do not .	Previous studies demonstrated that BRAFV600E establishes a high level of ERK directed transcriptional output and MEK dependent negative feedback of growth factor-receptor (GF-R) signaling, whereas activated oncogenic RTKs do not.	8	25	directed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	level of ERK	erk	MEK	MEK	mek	10	11	15	16
The currently known MAPKs have been assigned to six groups , ERK1/2 , cJun N-terminal kinase ( JNK ) 1/2/3 , p38alpha/beta/gamma/delta , ERK5 , NLK , and ERK3alpha and beta , and constitute the bottom part of a set of three-step signaling cascades which generally consist of upstream MAPK activating kinases ( MAPKK or MEK and MKK ) and MKK activating kinases .	The currently known MAPKs have been assigned to six groups, ERK1/2, cJun N-terminal kinase (JNK) 1/2/3, p38alpha/beta/gamma/delta, ERK5, NLK, and ERK3alpha and beta, and constitute the bottom part of a set of three-step signaling cascades which generally consist of upstream MAPK activating kinases (MAPKK or MEK and MKK) and MKK activating kinases.	46	56	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK	MEK	MEK	49	50	55	56
However , several positive and negative feedback loops within the core kinase module ( Raf , MEK , and ERK ) triggered by active MEK or ERK , respectively , were reported .	However, several positive and negative feedback loops within the core kinase module (Raf, MEK, and ERK) triggered by active MEK or ERK, respectively, were reported.	12	27	triggered	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	26	27	16	17
Our results indicate that the strength and duration of the nuclear ERK activation signal that is initially induced by ERK kinase ( MEK ) are determined at least in part by modulation of the phosphatase activity of PP2A-B56gamma1 through two independent pathways .	Our results indicate that the strength and duration of the nuclear ERK activation signal that is initially induced by ERK kinase (MEK) are determined at least in part by modulation of the phosphatase activity of PP2A-B56gamma1 through two independent pathways.	13	23	induced	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	19	20	22	23
Genetic deletion of Erk1/2 or pharmacological targeting of MEK1/2 results in supraphysiological activity of the ERK5 pathway .	Genetic deletion of Erk1/2 or pharmacological targeting of MEK1/2 results in supraphysiological activity of the ERK5 pathway.	3	9	targeting	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	MEK1/2	MEK1/2	MEK1/2	3	4	8	9
In hUCB-MSCs , the expression levels of ERK1/2 and Mitogen Activated Protein Kinase Kinase 1/2 ( MAP2K1/2 or MEK1/2 ) did not change after the knockdown of REX1 .	In hUCB-MSCs, the expression levels of ERK1/2 and Mitogen Activated Protein Kinase Kinase 1/2 (MAP2K1/2 or MEK1/2) did not change after the knockdown of REX1.	5	19	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	levels of ERK1/2	erk1/2	MEK1/2	MEK1/2	mek1/2	7	8	18	19
AZD6244 and ARRY-142886 , a novel , orally active , potent , selective , and ATP-uncompetitive MAP and ERK kinase ( MEK ) 1/2 inhibitor , targets the crucial MEK kinase in the RAS and ERK signaling pathway .	AZD6244/ARRY-142886, a novel, orally active, potent, selective, and ATP-uncompetitive MAP and ERK kinase (MEK) 1/2 inhibitor, targets the crucial MEK kinase in the RAS and ERK signaling pathway.	18	30	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	18	19	29	30
Therefore , EPA and DHA seem to modulate MAPK activation upstream and downstream of MEK1/2 .	Therefore, EPA and DHA seem to modulate MAPK activation upstream and downstream of MEK1/2.	8	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK1/2	MEK1/2	MEK1/2	8	9	14	15
It further set out to characterize the hypothetical role of nuclear-export signal ( NES )-dependent relocation of ERK after nuclear entry and the potential involvement of the ERK activator MEK .	It further set out to characterize the hypothetical role of nuclear-export signal (NES)-dependent relocation of ERK after nuclear entry and the potential involvement of the ERK activator MEK.	24	30	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	27	28	29	30
Instead , the cutaneous toxicities associated with these RAF inhibitors have been attributed to paradoxical ERK activation , in which BRAF-wild-type cells paradoxically activate MEK and ERK activity through increased CRAF activation .	Instead, the cutaneous toxicities associated with these RAF inhibitors have been attributed to paradoxical ERK activation, in which BRAF-wild-type cells paradoxically activate MEK and ERK activity through increased CRAF activation.	15	27	activate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK	MEK	MEK	15	16	24	25
Phosphorylation of 4EBP1 by mTORC1 leads to its dissociation from eIF4E and allows eIF4E to form an active initiation complex at the 5 ' end of mRNAs .	Phosphorylation of 4EBP1 by mTORC1 leads to its dissociation from eIF4E and allows eIF4E to form an active initiation complex at the 5 ' end of mRNAs.	0	15	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	Phosphorylation of 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	2	3	13	14
In particular , the hyperphosphorylation of 4E-BP1 , via mTORC1 kinase activity , stimulates the release of eukaryotic initiation factor 4E ( eIF4E ) from 4E-BP1 , therefore allowing eIF4E to bind with eIF4G and eIF4A to form the eIF4F translation initiation complex [ XREF_BIBR ] .	In particular, the hyperphosphorylation of 4E-BP1, via mTORC1 kinase activity, stimulates the release of eukaryotic initiation factor 4E (eIF4E) from 4E-BP1, therefore allowing eIF4E to bind with eIF4G and eIF4A to form the eIF4F translation initiation complex [XREF_BIBR].	4	21	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	hyperphosphorylation of 4E-BP1	4e-bp1	eukaryotic initiation factor 4E	eukaryotic initiation factor 4E	eukaryotic initiation factor 4e	6	7	17	21
Because 4EBP1 modulates eIF4E activity , our results highlight the importance of incorporating a joint analysis of eIF4E and 4EBP1 mRNAs in HNSCC patient care decisions .	Because 4EBP1 modulates eIF4E activity, our results highlight the importance of incorporating a joint analysis of eIF4E and 4EBP1 mRNAs in HNSCC patient care decisions.	1	4	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	1	2	3	4
The hyperphosphorylation of 4E-BP1 by PTX increased the association of eIF-4E with eIF-4G , whereas cotreatment with purvalanol A inhibited the association of eIF-4E with eIF-4G in PTX treated cells .	The hyperphosphorylation of 4E-BP1 by PTX increased the association of eIF-4E with eIF-4G, whereas cotreatment with purvalanol A inhibited the association of eIF-4E with eIF-4G in PTX treated cells.	1	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	hyperphosphorylation of 4E-BP1	4e-bp1	eIF-4E	eIF-4E	eif-4e	3	4	10	11
Activated mTOR phosphorylates 4EBP1 , relieving its repression of eIF4E , allowing Cap dependent translation initiation ( XREF_FIG ) .	Activated mTOR phosphorylates 4EBP1, relieving its repression of eIF4E, allowing Cap dependent translation initiation (XREF_FIG).	0	10	relieving	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	phosphorylates 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	3	4	9	10
Phosphorylation of 4E-BP1 can increase translation by derepressing the 4E-BP-mediated inhibition of eIF4E , a key translation initiation factor .	Phosphorylation of 4E-BP1 can increase translation by derepressing the 4E-BP-mediated inhibition of eIF4E, a key translation initiation factor.	0	18	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	Phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	2	3	12	13
When mTORC1 phosphorylates 4EBP-1 , 4EBP-1 detaches from eIF4E , increases the formation of the eIF4F complex and improves protein synthesis rate .	When mTORC1 phosphorylates 4EBP-1, 4EBP-1 detaches from eIF4E, increases the formation of the eIF4F complex and improves protein synthesis rate.	2	18	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP-1	phosphorylates 4EBP-1, 4EBP-1	4ebp-1	eIF4F	eIF4F	eif4f	5	6	15	16
This time course corresponded very well with the change in TLK1B expression after IR and suggests that the translation of TLK1B is induced by an increase in 4E-BP1 phosphorylation resulting in an increase in free eIF4E .	This time course corresponded very well with the change in TLK1B expression after IR and suggests that the translation of TLK1B is induced by an increase in 4E-BP1 phosphorylation resulting in an increase in free eIF4E.	22	36	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	27	28	35	36
IFNlambda inducible phosphorylation and activation of RSK1 results in its dissociation from 4E-BP1 at the same time that 4E-BP1 dissociates from eIF4E to allow formation of eIF4F and initiation of cap dependent translation .	IFNlambda inducible phosphorylation and activation of RSK1 results in its dissociation from 4E-BP1 at the same time that 4E-BP1 dissociates from eIF4E to allow formation of eIF4F and initiation of cap dependent translation.	18	28	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4F	eIF4F	eIF4F	18	19	26	27
To the extent that the pathway enables LPS activated macrophages to carry out essential protein translation , it likely works in concert with complementary LPS induced mechanisms that enhance translation initiation , such as mTOR induced phosphorylation of 4E-BP1 , which activates the initiation factor eIF4E 24 .	To the extent that the pathway enables LPS activated macrophages to carry out essential protein translation, it likely works in concert with complementary LPS induced mechanisms that enhance translation initiation, such as mTOR induced phosphorylation of 4E-BP1, which activates the initiation factor eIF4E 24.	34	46	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	mTOR induced phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	38	39	45	46
The p-4E-BP1 loses its ability to bind to eIF4E and allows the eIF4E complex to bind to the cap structure of mRNA , subsequently initiating the protein translation .	The p-4E-BP1 loses its ability to bind to eIF4E and allows the eIF4E complex to bind to the cap structure of mRNA, subsequently initiating the protein translation.	0	13	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p-4E-BP1	p-4E-BP1	p-4E-BP1	eIF4E	eIF4E	eIF4E	1	2	12	13
The eIF4E pathway is a target for cancer therapy with drugs that either inhibit eIF4E activity indirectly ( mTOR inhibitors that reduce 4E-BP1 phosphorylation thereby inhibiting eIF4E ( Smolewski , 2006 ) ) , or directly ( by binding to/reducing expression of eIF4E ( Graff et al , 2008 ) ) .	The eIF4E pathway is a target for cancer therapy with drugs that either inhibit eIF4E activity indirectly (mTOR inhibitors that reduce 4E-BP1 phosphorylation thereby inhibiting eIF4E (Smolewski, 2006)), or directly (by binding to/reducing expression of eIF4E (Graff et al, 2008)).	18	28	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	mTOR inhibitors that reduce 4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	22	23	26	27
However , phosphorylation of 4E-BP1 leads to reduced eIF4E binding and therefore reduced inhibition of eIF4E activity .	However, phosphorylation of 4E-BP1 leads to reduced eIF4E binding and therefore reduced inhibition of eIF4E activity.	2	16	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	4	5	15	16
The phosphorylation of 4E-BP1 promotes cap dependent translation by releasing eIF4E , while rpS6 phosphorylation increases ribosome biogenesis by enhancing the translation of ribosomal proteins .	The phosphorylation of 4E-BP1 promotes cap dependent translation by releasing eIF4E, while rpS6 phosphorylation increases ribosome biogenesis by enhancing the translation of ribosomal proteins.	1	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	3	4	10	11
IGF-I stimulated protein synthesis , augmented phosphorylation of 4E-BP1 and promoted the dissociation of eIF4E from 4E-BP1 .	IGF-I stimulated protein synthesis, augmented phosphorylation of 4E-BP1 and promoted the dissociation of eIF4E from 4E-BP1.	0	15	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	IGF-I stimulated protein synthesis, augmented phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	8	9	14	15
While inactivation of the repressor 4E-BP1 can modulate eIF4E availability , its ability to regulate translation depends upon its overall abundance .	While inactivation of the repressor 4E-BP1 can modulate eIF4E availability, its ability to regulate translation depends upon its overall abundance.	1	9	modulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	5	6	8	9
Phosphorylation of 4E-BP1 by mTORC1 results in the release of eIF4E , thus increasing eIF4E availability for cap dependent mRNA translation XREF_BIBR - XREF_BIBR .	Phosphorylation of 4E-BP1 by mTORC1 results in the release of eIF4E, thus increasing eIF4E availability for cap dependent mRNA translation XREF_BIBR - XREF_BIBR.	0	15	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	2	3	14	15
4EBP1 phosphorylation results in release of the inhibition of eIF4E and enables the formation of eIF4F complex .	4EBP1 phosphorylation results in release of the inhibition of eIF4E and enables the formation of eIF4F complex.	0	16	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	4EBP1 phosphorylation	4ebp1	eIF4F	eIF4F	eif4f	0	1	15	16
Phosphorylation of 4E-BP1 by mTORC1 , results in 4E-BP1/eIF4E dissociation allowing eIF4E to bind eIF4G and activate mRNA translation .	Phosphorylation of 4E-BP1 by mTORC1, results in 4E-BP1/eIF4E dissociation allowing eIF4E to bind eIF4G and activate mRNA translation.	0	13	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	2	3	11	12
Subsequently , phosphorylation and inactivation of eIF4EBP-1 promotes protein translation by allowing eIF4E to interact with other cap binding elements to generate an active translation initiation complex [ XREF_BIBR ] .	Subsequently, phosphorylation and inactivation of eIF4EBP-1 promotes protein translation by allowing eIF4E to interact with other cap binding elements to generate an active translation initiation complex [XREF_BIBR].	2	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	eIF4EBP-1	phosphorylation and inactivation of eIF4EBP-1	eif4ebp-1	eIF4E	eIF4E	eif4e	6	7	12	13
These results strongly suggest that disrupted 4E-BP1 function could contribute to eIF4F mediated tumor formation .	These results strongly suggest that disrupted 4E-BP1 function could contribute to eIF4F mediated tumor formation.	6	12	contribute	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4F	eIF4F	eIF4F	6	7	11	12
However , upon its mTOR mediated phosphorylation , 4E-BP1 dissociates thereby allowing eIF-4E to bind to the eIF-4F complex and translation increases [ XREF_BIBR , XREF_BIBR ] .	However, upon its mTOR mediated phosphorylation, 4E-BP1 dissociates thereby allowing eIF-4E to bind to the eIF-4F complex and translation increases [XREF_BIBR, XREF_BIBR].	8	14	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF-4E	eIF-4E	eIF-4E	8	9	12	13
It has been shown that dephosphorylation of 4E-BP1 triggers the sequestration of eIF4E and inhibits cap dependent translation .	It has been shown that dephosphorylation of 4E-BP1 triggers the sequestration of eIF4E and inhibits cap dependent translation.	5	13	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	dephosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	7	8	12	13
The phosphorylation of 4EBP1 prevents its inhibition of eIF4E , which also stimulates translation XREF_BIBR .	The phosphorylation of 4EBP1 prevents its inhibition of eIF4E, which also stimulates translation XREF_BIBR.	1	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	phosphorylation of 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	3	4	8	9
Phosphorylation of 4E-BP1 at Ser65 , which causes the greatest reduction in binding affinity to eIF4E , was reduced , yet total 4E-BP1 was increased by ~ 2.2-fold , in placentas from 3100 m , as compared with sea-level controls ( XREF_FIG A , B ) .	Phosphorylation of 4E-BP1 at Ser65, which causes the greatest reduction in binding affinity to eIF4E, was reduced, yet total 4E-BP1 was increased by ~ 2.2-fold, in placentas from 3100 m, as compared with sea-level controls (XREF_FIG A, B).	0	16	causes	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	4E-BP1	Phosphorylation of 4E-BP1 at Ser65	4e-bp1	eIF4E	eIF4E	eif4e	2	3	15	16
In arthropods , SINV infection led to the activation of the PI3K-Akt-TOR pathway which contributed to an uptick in translation through TOR activation of 4E-BP1 , which activates eIF4E , a protein necessary for cap dependent translation .	In arthropods, SINV infection led to the activation of the PI3K-Akt-TOR pathway which contributed to an uptick in translation through TOR activation of 4E-BP1, which activates eIF4E, a protein necessary for cap dependent translation.	22	36	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	24	25	28	29
It is possible that IFNs compete with growth factors for the use of the same signaling elements required for initiation of cap dependent translation ( i.e. inactivation of 4E-BP1 and subsequent activation of the eIF4E complex ) downstream of activation of the PI 3K/Akt pathway .	It is possible that IFNs compete with growth factors for the use of the same signaling elements required for initiation of cap dependent translation (i.e. inactivation of 4E-BP1 and subsequent activation of the eIF4E complex) downstream of activation of the PI 3K/Akt pathway.	28	35	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	28	29	34	35
Phosphorylation of 4E-BP1 by mTORC1 induces the release of eIF4E ( eukaryotic translation initiation factor 4E ) from 4E-BP1 and the subsequent formation of eIF4F ( translation initiation factor 4F ) complex .	Phosphorylation of 4E-BP1 by mTORC1 induces the release of eIF4E (eukaryotic translation initiation factor 4E) from 4E-BP1 and the subsequent formation of eIF4F (translation initiation factor 4F) complex.	0	25	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Phosphorylation of 4E-BP1	4e-bp1	eIF4F	eIF4F	eif4f	2	3	24	25
This inhibition is associated with the increased phosphorylation of eukaryotic initiation factor ( eIF2 ) alpha , increased association of eIF4E with the inhibitory eIF4E binding protein ( 4E-BP1 ) , and specific cleavages of eIF4B and eIF2alpha .	This inhibition is associated with the increased phosphorylation of eukaryotic initiation factor (eIF2) alpha, increased association of eIF4E with the inhibitory eIF4E binding protein (4E-BP1), and specific cleavages of eIF4B and eIF2alpha.	17	29	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	28	29	20	21
Phosphorylation of 4E-BP1 leads to its dissociation from eIF4E , allowing active eIF4E to bind eIF4G during translation initiation complex formation .	Phosphorylation of 4E-BP1 leads to its dissociation from eIF4E, allowing active eIF4E to bind eIF4G during translation initiation complex formation.	0	14	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	2	3	12	13
AKT also acts on the mammalian target of rapamycin ( mTOR ) , a multi-domain Serine/Threonine kinase that phosphorylates eukaryotic initiation factor 4E binding protein 1 ( 4EBP1 ) , which inactivates eIF4E , allowing initiation of translation .	AKT also acts on the mammalian target of rapamycin (mTOR), a multi-domain Serine/Threonine kinase that phosphorylates eukaryotic initiation factor 4E binding protein 1 (4EBP1), which inactivates eIF4E, allowing initiation of translation.	5	33	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4EBP1	mammalian target of rapamycin (mTOR), a multi-domain Serine/Threonine kinase that phosphorylates eukaryotic initiation factor 4E binding protein 1 (4EBP1	4ebp1	eIF4E	eIF4E	eif4e	27	28	32	33
Phosphorylation of 4E-BP1 by mTOR induces the dissociation of eukaryotic initiation factor 4E from 4E-BP1 , which enhances the cap dependent initiation of mRNA translation .	Phosphorylation of 4E-BP1 by mTOR induces the dissociation of eukaryotic initiation factor 4E from 4E-BP1, which enhances the cap dependent initiation of mRNA translation.	0	13	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Phosphorylation of 4E-BP1	4e-bp1	eukaryotic initiation factor 4E	eukaryotic initiation factor 4E	eukaryotic initiation factor 4e	2	3	9	13
The phosphorylation and consequent release of 4E-BP1 enables eIF4E to engage in protein translation .	The phosphorylation and consequent release of 4E-BP1 enables eIF4E to engage in protein translation.	4	9	enables	Positive_activation_token_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	6	7	8	9
To confirm that BAPTA-AM and calmodulin regulate Mcl-1 through mTORC1 pathway , we overexpressed 4E-BP1 target eIF4E ( eukaryotic translation Initiation Factor 4E ) .	To confirm that BAPTA-AM and calmodulin regulate Mcl-1 through mTORC1 pathway, we overexpressed 4E-BP1 target eIF4E (eukaryotic translation Initiation Factor 4E).	13	20	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	14	15	16	17
The phosphorylation of 4E-BP1 causes the release of eIF4E that can then bind to eIF4G to assemble translation initiation complex ( XREF_FIG ) .	The phosphorylation of 4E-BP1 causes the release of eIF4E that can then bind to eIF4G to assemble translation initiation complex (XREF_FIG).	1	9	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	3	4	8	9
This response is mediated by mTOR and is believed to result from 4EBP1 phosphorylation , which allows eIF4E to bind eIF4G .	This response is mediated by mTOR and is believed to result from 4EBP1 phosphorylation, which allows eIF4E to bind eIF4G.	12	19	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	4EBP1 phosphorylation	4ebp1	eIF4E	eIF4E	eif4e	12	13	17	18
Removal of 4E-BP1 and 2 relieves eIF4E suppression and provides an opportunity to study cellular and molecular mechanisms underlying the impact of mTORC1 , via 4E-BPs , on nociception .	Removal of 4E-BP1 and 2 relieves eIF4E suppression and provides an opportunity to study cellular and molecular mechanisms underlying the impact of mTORC1, via 4E-BPs, on nociception.	0	7	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	2	3	6	7
Because rapamycin decreases 4E-BP1 phosphorylation , thereby decreasing the availability of eIF4E , we assessed the effect of eIF4E siRNA on SCD1 expression in MDA-MB-468 cells .	Because rapamycin decreases 4E-BP1 phosphorylation, thereby decreasing the availability of eIF4E, we assessed the effect of eIF4E siRNA on SCD1 expression in MDA-MB-468 cells.	1	12	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	rapamycin decreases 4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	3	4	11	12
When mTOR activity is low , 4E-BP1 is hypophosphorylated which allows it to bind efficiently to eIF4E and block translation initiation whereas when mTOR activity is high , 4E-BP1 is phosphorylated causing it to release eIF4E , thus allowing cap dependent translation to begin [ XREF_BIBR ] .	When mTOR activity is low, 4E-BP1 is hypophosphorylated which allows it to bind efficiently to eIF4E and block translation initiation whereas when mTOR activity is high, 4E-BP1 is phosphorylated causing it to release eIF4E, thus allowing cap dependent translation to begin [XREF_BIBR].	28	36	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1 is phosphorylated	4e-bp1	eIF4E	eIF4E	eif4e	28	29	35	36
mTORC1 also phosphorylates 4EBP1 promoting dissociation of eIF4E from 4EBP1 , thus relieving the inhibitory effect of 4EBP1 on eIF4E dependent translation initiation , which again ultimately leads to increased translation of mRNAs .	mTORC1 also phosphorylates 4EBP1 promoting dissociation of eIF4E from 4EBP1, thus relieving the inhibitory effect of 4EBP1 on eIF4E dependent translation initiation, which again ultimately leads to increased translation of mRNAs.	0	8	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	mTORC1 also phosphorylates 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	3	4	7	8
At late time following IR , UPP mediated degradation of 4E-BP1 is inhibited , which consequently promotes the sequestration of eIF4E and blocks cap dependent protein synthesis XREF_BIBR .	At late time following IR, UPP mediated degradation of 4E-BP1 is inhibited, which consequently promotes the sequestration of eIF4E and blocks cap dependent protein synthesis XREF_BIBR.	8	21	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	10	11	20	21
Insulin elicits phosphorylation of 4E-BP1 and its release from eIF4E , allowing eIF4E to form initiation factor complexes .	Insulin elicits phosphorylation of 4E-BP1 and its release from eIF4E, allowing eIF4E to form initiation factor complexes.	0	14	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Insulin elicits phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	4	5	12	13
mTORC1 mediated phosphorylation of 4E-BP1 activates eIF4E , which leads to increased translation of mRNAs for pro tumorigenic genes .	mTORC1 mediated phosphorylation of 4E-BP1 activates eIF4E, which leads to increased translation of mRNAs for pro tumorigenic genes.	0	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	mTORC1 mediated phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	4	5	6	7
Upon phosphorylation by mTORC1 , 4E-BP1 is released from eIF4E , allowing eIF4E to bind to eIF4G to form the eIF4F-cap binding complex .	Upon phosphorylation by mTORC1, 4E-BP1 is released from eIF4E, allowing eIF4E to bind to eIF4G to form the eIF4F-cap binding complex.	5	14	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	5	6	12	13
Phosphorylation of 4E-BP1 by mTORC1 relieves its inhibition of the eIF4E translation initiation factor , allowing translation to proceed [ XREF_BIBR ] .	Phosphorylation of 4E-BP1 by mTORC1 relieves its inhibition of the eIF4E translation initiation factor, allowing translation to proceed [XREF_BIBR].	0	13	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	2	3	10	11
mTORC1 mediated 4E-BP1 phosphorylation induces the dissociation of 4E-BP1 from the eukaryotic initiation factor 4E ( eIF4E ) , thus allowing the assembly of the eIF4F complex to initiate cap dependent mRNA translation .	mTORC1 mediated 4E-BP1 phosphorylation induces the dissociation of 4E-BP1 from the eukaryotic initiation factor 4E (eIF4E), thus allowing the assembly of the eIF4F complex to initiate cap dependent mRNA translation.	0	26	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	mTORC1 mediated 4E-BP1 phosphorylation induces the dissociation of 4E-BP1	4e-bp1	eIF4F	eIF4F	eif4f	8	9	25	26
Phosphorylation of 4E-BP1 leads to dissociation and activation of eIF4E , which mediates classic cap dependent translation .	Phosphorylation of 4E-BP1 leads to dissociation and activation of eIF4E, which mediates classic cap dependent translation.	0	12	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	4E-BP1	Phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	2	3	9	10
XREF_BIBR The mechanistic and mammalian target of rapamycin ( mTOR ) complex 1 ( mTORC1 ) stimulates assembly of the eIF4F complex by phosphorylating and inactivating the 4E binding proteins ( 4E-BP1 , 2 and 3 ) which otherwise prevent eIF4E : eIF4G interaction and thereby eIF4F complex assembly .	XREF_BIBR The mechanistic and mammalian target of rapamycin (mTOR) complex 1 (mTORC1) stimulates assembly of the eIF4F complex by phosphorylating and inactivating the 4E binding proteins (4E-BP1, 2 and 3) which otherwise prevent eIF4E : eIF4G interaction and thereby eIF4F complex assembly.	14	41	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	mTORC1) stimulates assembly of the eIF4F complex by phosphorylating and inactivating the 4E binding proteins (4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	31	32	40	41
Leucine dependent hyperphosphorylation of 4E-BP1 increased the availability of eIF4E to form the active eIF4G.eIF4E complex .	Leucine dependent hyperphosphorylation of 4E-BP1 increased the availability of eIF4E to form the active eIF4G.eIF4E complex.	0	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Leucine dependent hyperphosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	4	5	9	10
Increasing cAMP promotes PHAS-I dephosphorylation and increases binding to eIF-4E .	Increasing cAMP promotes PHAS-I dephosphorylation and increases binding to eIF-4E.	1	10	increases	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	PHAS-I	cAMP promotes PHAS-I dephosphorylation	phas-i	eIF-4E	eIF-4E	eif-4e	3	4	9	10
When activated , mTOR phosphorylates the downstream target proteins , S6K1 and 4EBP1 , leading to the dissociation of eIF4E * 4EBP1 and the formation of the active eIF4G * eIF4E complex which enhances translation initiation .	When activated, mTOR phosphorylates the downstream target proteins, S6K1 and 4EBP1, leading to the dissociation of eIF4E * 4EBP1 and the formation of the active eIF4G * eIF4E complex which enhances translation initiation.	8	31	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	12	13	30	31
4E-BP1 is released from eIF4E after phosphorylation , allowing eIF4E to assemble with other translation initiation factors to initiate cap dependent translation [ XREF_BIBR ] .	4E-BP1 is released from eIF4E after phosphorylation, allowing eIF4E to assemble with other translation initiation factors to initiate cap dependent translation [XREF_BIBR].	0	11	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	0	1	9	10
This induces a conformational change in 4E-BP1 allowing the release of eIF4E , freeing it to associate with eIF4G leading to recruitment of ribosomes and activation of translation .	This induces a conformational change in 4E-BP1 allowing the release of eIF4E, freeing it to associate with eIF4G leading to recruitment of ribosomes and activation of translation.	1	12	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	6	7	11	12
Results from pull-down assay using 7-methyl-GTP Sepharose 4B beads indicated that PEITC treatment reduced cap bound eIF4E , confirming that increased 4E-BP1 expression and inhibition of 4E-BP1 phosphorylation indeed reduced the availability of eIF4E for translation initiation .	Results from pull-down assay using 7-methyl-GTP Sepharose 4B beads indicated that PEITC treatment reduced cap bound eIF4E, confirming that increased 4E-BP1 expression and inhibition of 4E-BP1 phosphorylation indeed reduced the availability of eIF4E for translation initiation.	26	34	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	26	27	33	34
The ( hyper ) phosphorylation of 4E-BP1 reduces its affinity for eIF4E , allows eIF4E to bind eIF4G to form the eIF4F complex and the cap dependent translation .	The (hyper) phosphorylation of 4E-BP1 reduces its affinity for eIF4E, allows eIF4E to bind eIF4G to form the eIF4F complex and the cap dependent translation.	4	16	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	6	7	14	15
In the presence of Akt activation , the mTORC1 complex is formed and downstream p70S6K and 4E-BP1 are phosphorylated , allowing the dissociation of eIF-4E , ribosome biogenesis and protein synthesis .	In the presence of Akt activation, the mTORC1 complex is formed and downstream p70S6K and 4E-BP1 are phosphorylated, allowing the dissociation of eIF-4E, ribosome biogenesis and protein synthesis.	14	30	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1 are phosphorylated	4e-bp1	eIF-4E	eIF-4E	eif-4e	16	17	24	25
Phosphorylation of 4E-BP1 causes it to release eIF4E to function in mRNA translation .	Phosphorylation of 4E-BP1 causes it to release eIF4E to function in mRNA translation.	0	8	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	2	3	7	8
A phosphorylation of 4E-BP1 leads to the release of eIF4E and the initiation of translation , which seems to be decreased with OSI-906 treatment in non transformed as well as transformed BALB/c cells .	A phosphorylation of 4E-BP1 leads to the release of eIF4E and the initiation of translation, which seems to be decreased with OSI-906 treatment in non transformed as well as transformed BALB/c cells.	1	10	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	4E-BP1	phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	3	4	9	10
TOR dependent phosphorylation of 4E-BP1 causes the dissociation of 4E , BP1 , and eIF4E complex to activate the translation machinery , and the FMRP function is also regulated by the TOR pathway through the phosphorylation of the ribosomal protein S6 kinase .	TOR dependent phosphorylation of 4E-BP1 causes the dissociation of 4E, BP1, and eIF4E complex to activate the translation machinery, and the FMRP function is also regulated by the TOR pathway through the phosphorylation of the ribosomal protein S6 kinase.	2	15	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	4	5	14	15
The phosphorylation of 4EBP1 leads to a reduction of the inhibitory binding to eIF4E .	The phosphorylation of 4EBP1 leads to a reduction of the inhibitory binding to eIF4E.	1	14	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	4EBP1	phosphorylation of 4EBP1	4ebp1	eIF4E	eIF4E	eif4e	3	4	13	14
Insulin also increased the phosphorylation of PHAS-I ( phosphorylated heat- and acid-stable protein ) and promoted the dissociation of the PHAS-I * eIF-4E complex .	Insulin also increased the phosphorylation of PHAS-I (phosphorylated heat- and acid-stable protein) and promoted the dissociation of the PHAS-I * eIF-4E complex.	0	23	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHAS-I	Insulin also increased the phosphorylation of PHAS-I	phas-i	eIF-4E	eIF-4E	eif-4e	6	7	22	23
In muscle , but not liver , GH increased eIF2B activity and 4E-BP1 phosphorylation in both the fasted and fed state and increased the association of eIF4E with eIF4G in the fed state .	In muscle, but not liver, GH increased eIF2B activity and 4E-BP1 phosphorylation in both the fasted and fed state and increased the association of eIF4E with eIF4G in the fed state.	7	27	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	GH increased eIF2B activity and 4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	12	13	26	27
Hyperphosphorylation of 4E-BP1 by the mTORC1 complex reduces its affinity to eIF4E allowing eIF4E to direct ribsosomes to initiate mRNA translation whereas hypophosphorylation of 4E-BP1 enhances its affinity to eIF4E resulting in inhibition of mRNA translation .	Hyperphosphorylation of 4E-BP1 by the mTORC1 complex reduces its affinity to eIF4E allowing eIF4E to direct ribsosomes to initiate mRNA translation whereas hypophosphorylation of 4E-BP1 enhances its affinity to eIF4E resulting in inhibition of mRNA translation.	22	30	enhances	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	4E-BP1	hypophosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	24	25	29	30
As a control for cap disassembly , Huh7 cells were treated with Torin1 , an mTOR inhibitor that blocks 4E-BP1 phosphorylation and thereby lowers the availability of eIF4E for translation .	As a control for cap disassembly, Huh7 cells were treated with Torin1, an mTOR inhibitor that blocks 4E-BP1 phosphorylation and thereby lowers the availability of eIF4E for translation.	12	29	lowers	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	4E-BP1	Torin1, an mTOR inhibitor that blocks 4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	19	20	27	28
In muscle of nonseptic control mice , the IGF-I pellet increased 4E-BP1 phosphorylation and caused redistribution of eIF4E from 4E-BP1 to eIF4G .	In muscle of nonseptic control mice, the IGF-I pellet increased 4E-BP1 phosphorylation and caused redistribution of eIF4E from 4E-BP1 to eIF4G.	8	18	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	IGF-I pellet increased 4E-BP1 phosphorylation	4e-bp1	eIF4E	eIF4E	eif4e	11	12	17	18
As a consequence , both the increased total expression of 4E-BP1 and the decreased phosphorylation of 4E-BP1 at Thr 37/46 will promote binding of eIF4E resulting in inhibition of cap dependent translation initiation in the IUGR placenta .	As a consequence, both the increased total expression of 4E-BP1 and the decreased phosphorylation of 4E-BP1 at Thr 37/46 will promote binding of eIF4E resulting in inhibition of cap dependent translation initiation in the IUGR placenta.	8	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	expression of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	10	11	24	25
The resulting detachment of 4EBP1 from an inactive 4EBP1 * eIF4E complex allows eIF4E to form an active complex with eIF4G , thereby activating translation initiation .	The resulting detachment of 4EBP1 from an inactive 4EBP1 * eIF4E complex allows eIF4E to form an active complex with eIF4G, thereby activating translation initiation.	2	15	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	4EBP1	4EBP1	eIF4E	eIF4E	eIF4E	4	5	13	14
In addition , mTORC1 phosphorylates 4E-BP1 thereby inhibiting its repression of eIF4E , which leads to enhanced initiation of translation .	In addition, mTORC1 phosphorylates 4E-BP1 thereby inhibiting its repression of eIF4E, which leads to enhanced initiation of translation.	3	14	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	mTORC1 phosphorylates 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	5	6	11	12
When phosphorylated , 4E-BP1 loses that affinity and separates from eIF4E , thereby allowing eIF4E to function in cap dependent mRNA translation .	When phosphorylated, 4E-BP1 loses that affinity and separates from eIF4E, thereby allowing eIF4E to function in cap dependent mRNA translation.	3	16	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	3	4	14	15
Dissociation of 4E-BP1 from eIF-4E enables eIF-4E to initiate translation .	Dissociation of 4E-BP1 from eIF-4E enables eIF-4E to initiate translation.	0	7	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF-4E	eIF-4E	eIF-4E	2	3	6	7
The phosphorylation of the initiation factor 4E-BP1 on Ser65 was also enhanced , increasing the availability of functional eukaryotic initiation factor 4E ( eIF4E ) .	The phosphorylation of the initiation factor 4E-BP1 on Ser65 was also enhanced, increasing the availability of functional eukaryotic initiation factor 4E (eIF4E).	1	22	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	phosphorylation of the initiation factor 4E-BP1 on Ser65	4e-bp1	eukaryotic initiation factor 4E	eukaryotic initiation factor 4E	eukaryotic initiation factor 4e	6	7	18	22
Phosphorylation of 4E-BP1 by mTORC1 increases the availability of eIF4E .	Phosphorylation of 4E-BP1 by mTORC1 increases the availability of eIF4E.	0	10	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	Phosphorylation of 4E-BP1	4e-bp1	eIF4E	eIF4E	eif4e	2	3	9	10
The mTORC1 complex is formed and downstream p70 S6K and 4E-BP1 are phosphorylated , allowing the dissociation of eIF-4E , ribosome biogenesis and protein synthesis .	The mTORC1 complex is formed and downstream p70 S6K and 4E-BP1 are phosphorylated, allowing the dissociation of eIF-4E, ribosome biogenesis and protein synthesis.	8	24	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1 are phosphorylated	4e-bp1	eIF-4E	eIF-4E	eif-4e	10	11	18	19
Phosphorylation of 4EBP1 by mTOR causes the release eIF-4E , which then acts to initiate cap dependent protein translation .	Phosphorylation of 4EBP1 by mTOR causes the release eIF-4E, which then acts to initiate cap dependent protein translation.	0	14	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4EBP1	Phosphorylation of 4EBP1	4ebp1	eIF-4E	eIF-4E	eif-4e	2	3	8	9
4E-BP1 dissociation allows eIF4E to sequentially associate with eIF4G , a scaffold protein that recruits an array of other translation initiation factors to form the eIF4F complex to promote translation initiation .	4E-BP1 dissociation allows eIF4E to sequentially associate with eIF4G, a scaffold protein that recruits an array of other translation initiation factors to form the eIF4F complex to promote translation initiation.	0	6	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	4E-BP1	4E-BP1	4E-BP1	eIF4E	eIF4E	eIF4E	0	1	3	4
Our results are consistent with the previous finding that Notch activation increases transcriptional activity of p53 , resulting in up-regulation of p21 mediated by ERK in cancer cells 29 .	Our results are consistent with the previous finding that Notch activation increases transcriptional activity of p53, resulting in up-regulation of p21 mediated by ERK in cancer cells 29.	19	27	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	24	25	21	22
At the molecular level , Rottlerin hampered the NFkB activation process , causing loss of cyclin D1 and promoting , in a PKCdelta dependent pathway , ERK activation , which , in turn induced the cell cycle inhibitor p21 Cip1 and Kip1 .	At the molecular level, Rottlerin hampered the NFkB activation process, causing loss of cyclin D1 and promoting, in a PKCdelta dependent pathway, ERK activation, which, in turn induced the cell cycle inhibitor p21 Cip1 and Kip1.	26	40	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	p21 Cip1	p21 Cip1	p21 Cip1	26	27	38	40
Inhibition of EGFR , PI3K ( phosphoinositide 3-kinase ; kinases required for Rac activation by HRG ) or MEK [ MAPK ( mitogen activated protein kinase )/ERK ( extracellular-signal-regulated kinase ) kinase ] also blocked the up-regulation of cyclin D1 and p21 ( Cip1 ) by HRG .	Inhibition of EGFR, PI3K (phosphoinositide 3-kinase; kinases required for Rac activation by HRG) or MEK [MAPK (mitogen activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] also blocked the up-regulation of cyclin D1 and p21 (Cip1) by HRG.	2	42	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21	p21	p21	20	21	41	42
Given the recent finding that the mitogen activated protein kinase ( MAPK ) pathway can cause p21 induction and arrest cells , we examined the involvement of this pathway for p21 and p15 induction by TGF-beta .	Given the recent finding that the mitogen activated protein kinase (MAPK) pathway can cause p21 induction and arrest cells, we examined the involvement of this pathway for p21 and p15 induction by TGF-beta.	9	17	cause	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21	p21	p21	11	12	16	17
In SKBR3 cells , strong activation of MEK and ERK pathway by PMA causes induction of p21 and cell cycle arrest .	In SKBR3 cells, strong activation of MEK and ERK pathway by PMA causes induction of p21 and cell cycle arrest.	7	20	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	9	10	16	17
EGFR mediated induction of enterocyte proliferation requires MAPK dependent increase in p21 ( waf1 and cip1 ) expression in intestinal epithelial cells .	EGFR mediated induction of enterocyte proliferation requires MAPK dependent increase in p21 (waf1 and cip1) expression in intestinal epithelial cells.	7	15	increase	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21	p21	p21	7	8	11	12
This is one of the key mechanisms whereby cells can adapt to stress induced by amino acid deprivation as sustained Erk activation increases p21 ( cip1 and waf1 ) which blocks cell cycle progression and contributes to activation of the GCN2-eIF2alpha-ATF4 survival pathway XREF_BIBR - XREF_BIBR .	This is one of the key mechanisms whereby cells can adapt to stress induced by amino acid deprivation as sustained Erk activation increases p21 (cip1 and waf1) which blocks cell cycle progression and contributes to activation of the GCN2-eIF2alpha-ATF4 survival pathway XREF_BIBR - XREF_BIBR.	20	27	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk	Erk	Erk	cip1	cip1	cip1	20	21	25	26
p21Cip and WAF1 , an important regulator of cell proliferation , is induced by both p53- and extracellular signal regulated kinase ( ERK ) pathways .	p21Cip and WAF1, an important regulator of cell proliferation, is induced by both p53- and extracellular signal regulated kinase (ERK) pathways.	0	21	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	extracellular signal regulated kinase	extracellular signal regulated kinase	extracellular signal regulated kinase	WAF1	WAF1	WAF1	17	21	2	3
Based on these findings , we propose that a ROCK mediated signal is involved in interfering with the process of ERK mediated p21 ( Cip1 and Waf1 ) induction in PMA induced proapoptotic TF-1 and D2 cells .	Based on these findings, we propose that a ROCK mediated signal is involved in interfering with the process of ERK mediated p21 (Cip1 and Waf1) induction in PMA induced proapoptotic TF-1 and D2 cells.	18	31	mediated	Positive_early_activation	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	20	21	22	23
Evidence for the role of beta-catenin in VPA induced activation of the ERK-p21 Cip and WAF1 pathway , and subsequent effects on differentiation and inhibition of proliferation in NPCs , was seen in the reduction of the effects of VPA , including ERK activation and induction of p21 Cip and WAF1 and Tuj1 , following siRNA mediated beta-catenin knockdown .	Evidence for the role of beta-catenin in VPA induced activation of the ERK-p21 Cip and WAF1 pathway, and subsequent effects on differentiation and inhibition of proliferation in NPCs, was seen in the reduction of the effects of VPA, including ERK activation and induction of p21 Cip and WAF1 and Tuj1, following siRNA mediated beta-catenin knockdown.	42	48	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	42	43	47	48
In this study , we evaluated the proliferative behavior of PMA treated MCF-7 breast cancer cell and found that : PMA induced growth arrest and inhibited cell death ; PMA activated ERKs , which , in turn , induced p21 ; and inhibitors of ERK ( PD98059 ) and PKC ( GF109203X ) prevented p21 induction and abolished the PMA survival effect .	In this study, we evaluated the proliferative behavior of PMA treated MCF-7 breast cancer cell and found that : PMA induced growth arrest and inhibited cell death; PMA activated ERKs, which, in turn, induced p21; and inhibitors of ERK (PD98059) and PKC (GF109203X) prevented p21 induction and abolished the PMA survival effect.	42	55	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	44	45	54	55
There is also evidence that the MEK and Erk pathway is activated by the Type III IFN receptor and mediates IFNlambda dependent activation of the kinase RSK1 and downstream upregulation of p21 WAF1 and CIP1 , suggesting a mechanism for the generation of IFNlambda- inducible growth inhibitory responses .	There is also evidence that the MEK and Erk pathway is activated by the Type III IFN receptor and mediates IFNlambda dependent activation of the kinase RSK1 and downstream upregulation of p21 WAF1 and CIP1, suggesting a mechanism for the generation of IFNlambda- inducible growth inhibitory responses.	6	35	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk	Erk	Erk	CIP1	CIP1	CIP1	8	9	34	35
ERK can activate p15 , p16 and p21 to arrest the cell cycle , or cooperate with the PI3K-mTOR pathway to suppress p27 and allow activity of cyclinE and cdk2 complexes and Rb phosphorylation to promote cell cycle entry .	ERK can activate p15, p16 and p21 to arrest the cell cycle, or cooperate with the PI3K-mTOR pathway to suppress p27 and allow activity of cyclinE and cdk2 complexes and Rb phosphorylation to promote cell cycle entry.	0	8	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	0	1	7	8
Overall , the TsA activated ERK pathway plays an important role in cell cycle arrest and apoptosis through the ERK dependent induction of p21 in Ras related human cancer cells .	Overall, the TsA activated ERK pathway plays an important role in cell cycle arrest and apoptosis through the ERK dependent induction of p21 in Ras related human cancer cells.	19	25	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	19	20	23	24
Moreover , blockade of the activity of c-SRC , ERK1/2 , or NFkappaB prevented FA induced increases in TP53 , CDKN1A and CDKN1B protein .	Moreover, blockade of the activity of c-SRC, ERK1/2, or NFkappaB prevented FA induced increases in TP53, CDKN1A and CDKN1B protein.	5	21	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	CDKN1A	CDKN1A	CDKN1A	9	10	20	21
Our previous studies described overexpression of the platelet derived growth factor receptor ( PDGFR ) in association with metastatic MB , and demonstrated that PDGFR promotes migration through ERK dependent activation of p21 protein ( Cdc42 and Rac )-activated kinase 1 ( Pak1 ) signaling [ XREF_BIBR , XREF_BIBR ] .	Our previous studies described overexpression of the platelet derived growth factor receptor (PDGFR) in association with metastatic MB, and demonstrated that PDGFR promotes migration through ERK dependent activation of p21 protein (Cdc42 and Rac)-activated kinase 1 (Pak1) signaling [XREF_BIBR, XREF_BIBR].	28	33	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	28	29	32	33
ROS activate ERK and p38 , which in turn upregulate p21 and cdc2 and cause degradation of cdc25C , leading to cell growth arrest at the G ( 2 )/M phase .	ROS activate ERK and p38, which in turn upregulate p21 and cdc2 and cause degradation of cdc25C, leading to cell growth arrest at the G (2)/M phase.	1	14	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	2	3	10	11
We propose that excess HA produced by HAS3 has the two-fold effect of increasing E-cadherin homotypic interaction and suppressing S-phase entry , as well as elevating unliganded EGF receptor , sustained ERK activation and elevation of p21 and p27 protein .	We propose that excess HA produced by HAS3 has the two-fold effect of increasing E-cadherin homotypic interaction and suppressing S-phase entry, as well as elevating unliganded EGF receptor, sustained ERK activation and elevation of p21 and p27 protein.	31	39	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	31	32	36	37
For example , in SKBr3 breast cancer cells , PMA hyper-activates the MEK and MAPK pathway , thus inducing p21 and cell cycle arrest .	For example, in SKBr3 breast cancer cells, PMA hyper-activates the MEK and MAPK pathway, thus inducing p21 and cell cycle arrest.	12	23	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21	p21	p21	14	15	19	20
Increased phosphorylation of JNK 31 , 32 , and p38MAPKs 33 is normally associated with induction of apoptosis , whereas ERK1/2 primarily plays a role in cell proliferation instead of apoptosis 34 , Researcher has demonstrated that persistent over-activation of ERK1/2 induces cell cycle arrest by stabilizing the p21 complex 35 .	Increased phosphorylation of JNK 31, 32, and p38MAPKs 33 is normally associated with induction of apoptosis, whereas ERK1/2 primarily plays a role in cell proliferation instead of apoptosis 34, Researcher has demonstrated that persistent over-activation of ERK1/2 induces cell cycle arrest by stabilizing the p21 complex 35.	38	49	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	p21	p21	p21	40	41	48	49
This mechanism appears particularly pertinent to the anti-mitogenic effects of NO , sodium salicylate and relaxin , all of which elicit ERK 1/2 -dependent up-regulation of p21 waf1 and cip1 and p27 kip1 to inhibit mitogenesis .	This mechanism appears particularly pertinent to the anti-mitogenic effects of NO, sodium salicylate and relaxin, all of which elicit ERK 1/2 -dependent up-regulation of p21 waf1 and cip1 and p27 kip1 to inhibit mitogenesis.	21	32	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK 1/2	ERK 1/2	ERK 1/2	cip1	cip1	cip1	21	23	29	30
Remarkably , MEK and ERK activity was necessary for mortalin depletion to induce p21 ( CIP1 ) expression in B-Raf ( V600E )-transformed cancer cells regardless of their p53 status .	Remarkably, MEK and ERK activity was necessary for mortalin depletion to induce p21 (CIP1) expression in B-Raf (V600E)-transformed cancer cells regardless of their p53 status.	2	29	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	4	5	13	14
Pretreatment of the cells with PD98059 abolished the magnolol induced upregulation of p21 protein , suggesting the involvement of an ERK pathway in the magnolol induced upregulation of p21 in COLO-205 cells .	Pretreatment of the cells with PD98059 abolished the magnolol induced upregulation of p21 protein, suggesting the involvement of an ERK pathway in the magnolol induced upregulation of p21 in COLO-205 cells.	20	29	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	20	21	28	29
As it was investigated in detail in SKBR3 cells [ XREF_BIBR ] , PMA activates the MEK and ERK pathway , which in turn induces both p21 and cyclin D1 , causing G1 and G2 cell cycle arrest .	As it was investigated in detail in SKBR3 cells [XREF_BIBR], PMA activates the MEK and ERK pathway, which in turn induces both p21 and cyclin D1, causing G1 and G2 cell cycle arrest.	16	29	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	18	19	26	27
Taken together , our data suggest that VES induces activation of PKC and PKC dependent hypophosphorylation of retinoblastoma protein , which results in induction of apoptosis , and that VES induced early activation of ERK and ERK dependent induction of p21 ( WAF1 ) are not required for apoptosis .	Taken together, our data suggest that VES induces activation of PKC and PKC dependent hypophosphorylation of retinoblastoma protein, which results in induction of apoptosis, and that VES induced early activation of ERK and ERK dependent induction of p21 (WAF1) are not required for apoptosis.	34	42	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	34	35	40	41
Furthermore , potent activation of PKCs resulted in robust Erk activation and elevation of p21 ( CIP1 ) .	Furthermore, potent activation of PKCs resulted in robust Erk activation and elevation of p21 (CIP1).	9	16	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Erk	Erk	Erk	p21	p21	p21	9	10	14	15
Our data argue that MAPK signaling increased p21 promoter activity via multiple transcription factors , which alone were insufficient for a robust prolonged increase in p21 protein levels in primary hepatocytes , and that to increase p21 protein levels also required enhanced stabilization of p21 mRNA and p21 protein .	Our data argue that MAPK signaling increased p21 promoter activity via multiple transcription factors, which alone were insufficient for a robust prolonged increase in p21 protein levels in primary hepatocytes, and that to increase p21 protein levels also required enhanced stabilization of p21 mRNA and p21 protein.	4	9	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21	p21	p21	4	5	7	8
Our results show that downregulation of Erk1/2 significantly inhibits degradation of p53 ( p < .01 ) induced by H. pylori and activates transcriptional targets p53 , p21 and PUMA ( XREF_SUPPLEMENTARY ) .	Our results show that downregulation of Erk1/2 significantly inhibits degradation of p53 (p <.01) induced by H. pylori and activates transcriptional targets p53, p21 and PUMA (XREF_SUPPLEMENTARY).	4	28	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	p21	p21	p21	6	7	27	28
MAPK dependent induction of p21 ( Cip1 ) was also necessary for G1 phase progression , although its degradation by the proteasome was required for S phase entry .	MAPK dependent induction of p21 (Cip1) was also necessary for G1 phase progression, although its degradation by the proteasome was required for S phase entry.	0	5	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21	p21	p21	0	1	4	5
Here , we hypothesized that ROS generated in response to TPA inhibit Erk1/2 directed phosphatase activity , which leads to an increase phosphorylation of Erk1/2 to signal p21 WAF1 and Cip1 -mediated growth arrest in ML-1 cells .	Here, we hypothesized that ROS generated in response to TPA inhibit Erk1/2 directed phosphatase activity, which leads to an increase phosphorylation of Erk1/2 to signal p21 WAF1 and Cip1 -mediated growth arrest in ML-1 cells.	5	33	signal	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk1/2	ROS generated in response to TPA inhibit Erk1/2 directed phosphatase activity, which leads to an increase phosphorylation of Erk1/2	erk1/2	Cip1	Cip1	cip1	24	25	30	31
CT treatment of cells expressing the insert -ve , but not insert + ve hCTR , induced the phosphorylation of Erk1/2 MAPK , which persisted for at least 72 h. Treatment of cells expressing the insert -ve hCTR with the MAPK kinase ( MEK ) inhibitor , PD-98059 , inhibited the phosphorylation of Erk1/2 and abrogated the growth inhibitory effects of salmon CT , the accumulation of cells in G2 , and the associated induction of p21 ( WAF1 and CIP1 ) .	CT treatment of cells expressing the insert -ve, but not insert + ve hCTR, induced the phosphorylation of Erk1/2 MAPK, which persisted for at least 72 h. Treatment of cells expressing the insert -ve hCTR with the MAPK kinase (MEK) inhibitor, PD-98059, inhibited the phosphorylation of Erk1/2 and abrogated the growth inhibitory effects of salmon CT, the accumulation of cells in G2, and the associated induction of p21 (WAF1 and CIP1).	0	80	induction	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	Erk1/2	CT treatment of cells expressing the insert -ve, but not insert + ve hCTR, induced the phosphorylation of Erk1/2 MAPK, which persisted for at least 72 h. Treatment of cells expressing the insert -ve hCTR with the MAPK kinase (MEK) inhibitor, PD-98059, inhibited the phosphorylation of Erk1/2	erk1/2	p21	p21	p21	53	54	76	77
The above mentioned Erk1/2 mediated stabilization of p21 and CIP1 is also likely to be Matn2 dependent XREF_BIBR .	The above mentioned Erk1/2 mediated stabilization of p21 and CIP1 is also likely to be Matn2 dependent XREF_BIBR.	2	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	CIP1	CIP1	CIP1	3	4	9	10
Here , the transcription factor Myc and the cyclin dependent kinase inhibitor p21 are both activated by ERK [ XREF_BIBR , XREF_BIBR ] .	Here, the transcription factor Myc and the cyclin dependent kinase inhibitor p21 are both activated by ERK [XREF_BIBR, XREF_BIBR].	5	21	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	p21	p21	p21	17	18	12	13
Thus , it is likely that both p53 , activated ERK1/2 MAPK activate the p21 gene by binding to its promoter .	Thus, it is likely that both p53, activated ERK1/2 MAPK activate the p21 gene by binding to its promoter.	10	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2 MAPK	ERK1/2 MAPK	ERK1/2 MAPK	p21	p21	p21	10	12	14	15
In agreement with this hypothesis , prolonged MAPK signaling further increased p21 mRNA stability at 36 h , compared with the 8-h time point .	In agreement with this hypothesis, prolonged MAPK signaling further increased p21 mRNA stability at 36 h, compared with the 8-h time point.	7	13	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21	p21	p21	7	8	11	12
In contrast , TPA activated MAPK pathway causes p21WAF1 and CIP1 dependent growth arrest without apoptosis .	In contrast, TPA activated MAPK pathway causes p21WAF1 and CIP1 dependent growth arrest without apoptosis.	5	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	CIP1	CIP1	CIP1	5	6	10	11
In addition , both Smad- and Ras and MAPK mediated pathways target a proximal sequence of the p21 promoter that can recruit transcription factors of the Sp1 family together with Smads .	In addition, both Smad- and Ras and MAPK mediated pathways target a proximal sequence of the p21 promoter that can recruit transcription factors of the Sp1 family together with Smads.	8	18	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21	p21	p21	8	9	17	18
A hyperactivated ERK driven transcriptional induction of the cyclin dependent kinase inhibitor p21 and cyclin D1 triggers a massive accumulation of both cyclin D1 and p21 , leading to cell cycle arrest by p21 XREF_BIBR .	A hyperactivated ERK driven transcriptional induction of the cyclin dependent kinase inhibitor p21 and cyclin D1 triggers a massive accumulation of both cyclin D1 and p21, leading to cell cycle arrest by p21 XREF_BIBR.	0	16	driven	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	p21	p21	p21	2	3	12	13
Sustained ERK activation promotes the upregulation of p21 and cyclin D1 XREF_BIBR , XREF_BIBR , XREF_BIBR and activates caspase 3 , all of which have an important role in the late steps of physiological MK differentiation .	Sustained ERK activation promotes the upregulation of p21 and cyclin D1 XREF_BIBR, XREF_BIBR, XREF_BIBR and activates caspase 3, all of which have an important role in the late steps of physiological MK differentiation.	1	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	1	2	7	8
MAPK activation induced p21 cip-1 , which suppressed the levels of cyclin D1 that controls G 1 / S cell cycle transition .	MAPK activation induced p21 cip-1, which suppressed the levels of cyclin D1 that controls G 1 / S cell cycle transition.	0	4	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21	p21	p21	0	1	3	4
In addition , tyrosine phosphorylation of MAPK , MAPK dependent increase in p21 ( waf1 and cip1 ) , c-Myc , and c-Fos expression were found to be upstream events in growth factor induced crypt cell proliferation XREF_BIBR , XREF_BIBR , XREF_BIBR .	In addition, tyrosine phosphorylation of MAPK, MAPK dependent increase in p21 (waf1 and cip1), c-Myc, and c-Fos expression were found to be upstream events in growth factor induced crypt cell proliferation XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	13	increase	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	tyrosine phosphorylation of MAPK	mapk	p21	p21	p21	6	7	12	13
In some cases , ERK signaling induces p21 accumulation , as demonstrated in chondrocyte maturation [ XREF_BIBR ] .	In some cases, ERK signaling induces p21 accumulation, as demonstrated in chondrocyte maturation [XREF_BIBR].	4	8	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	4	5	7	8
PKCalpha is antiproliferative and causes G1 cell-cycle arrest associated with ERK activation and inhibition of p21 and p27 in the intestinal epithelial cells [ XREF_BIBR ] .	PKCalpha is antiproliferative and causes G1 cell-cycle arrest associated with ERK activation and inhibition of p21 and p27 in the intestinal epithelial cells [XREF_BIBR].	10	17	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	10	11	15	16
ERK1/2 inhibition by the MAPK inhibitor PD98059 also prevented p21 upregulation , whereas other cell cycle related proteins were not affected .	ERK1/2 inhibition by the MAPK inhibitor PD98059 also prevented p21 upregulation, whereas other cell cycle related proteins were not affected.	0	10	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	p21	p21	p21	0	1	9	10
It is clear that both inhibition of proliferation and differentiation of NPCs stimulated by VPA occur through the ERK pathway dependent induction of p21 Cip and WAF1 .	It is clear that both inhibition of proliferation and differentiation of NPCs stimulated by VPA occur through the ERK pathway dependent induction of p21 Cip and WAF1.	18	24	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	18	19	23	24
In NIH 3T3 cells , low levels of ERK signaling induce cyclin D1 to maximal level and stimulate proliferation , whereas higher levels of ERK signaling induce the cyclin dependent kinase inhibitor p21 Cip1 , which causes cell-cycle arrest [ XREF_BIBR , XREF_BIBR ] .	In NIH 3T3 cells, low levels of ERK signaling induce cyclin D1 to maximal level and stimulate proliferation, whereas higher levels of ERK signaling induce the cyclin dependent kinase inhibitor p21 Cip1, which causes cell-cycle arrest [XREF_BIBR, XREF_BIBR].	24	34	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	p21 Cip1	p21 Cip1	p21 Cip1	24	25	32	34
This interaction also promotes ERK1/2 signaling and transcription of p21 leading to tumor cell growth arrest [ XREF_BIBR ] as well as caspase-3 activation and induction of apoptosis [ XREF_BIBR ] .	This interaction also promotes ERK1/2 signaling and transcription of p21 leading to tumor cell growth arrest [XREF_BIBR] as well as caspase-3 activation and induction of apoptosis [XREF_BIBR].	4	10	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	p21	p21	p21	4	5	9	10
These results lets us to hypothesize that ERK1/2 mediate p21 down-regulation via p53 .	These results lets us to hypothesize that ERK1/2 mediate p21 down-regulation via p53.	7	10	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	p21	p21	p21	7	8	9	10
To ascertain whether the ERK pathway mediates p21 Cip and WAF1 induction and neuronal differentiation in response to VPA , we measured the effect of inhibition of the Ras-ERK pathway on the induction of p21 Cip and WAF1 and Tuj1 by VPA .	To ascertain whether the ERK pathway mediates p21 Cip and WAF1 induction and neuronal differentiation in response to VPA, we measured the effect of inhibition of the Ras-ERK pathway on the induction of p21 Cip and WAF1 and Tuj1 by VPA.	4	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	WAF1	WAF1	WAF1	4	5	10	11
The Western blot showed that exogenous IGFBP7 promoted phosphorylation of p38 ( MAPK ) , up-regulated expression of p21 ( CIP1 and WAF1 ) , and inhibited phosphorylation of Rb .	The Western blot showed that exogenous IGFBP7 promoted phosphorylation of p38 (MAPK), up-regulated expression of p21 (CIP1 and WAF1), and inhibited phosphorylation of Rb.	6	23	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	IGFBP7 promoted phosphorylation of p38 (MAPK	mapk	WAF1	WAF1	waf1	12	13	22	23
MAPK induces up-regulation of p21 cip in response to NGF-TrkA signaling in melanoma cells .	MAPK induces up-regulation of p21 cip in response to NGF-TrkA signaling in melanoma cells.	0	5	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	p21	p21	p21	0	1	4	5
The MEK and ERK intracellular signaling pathway upregulates p21 in response to stimulation by several factors including TGF-beta [ XREF_BIBR ] .	The MEK and ERK intracellular signaling pathway upregulates p21 in response to stimulation by several factors including TGF-beta [XREF_BIBR].	1	10	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	p21	p21	p21	3	4	8	9
Furthermore , knockdown of Eea1 but not of Erk1/2 significantly inhibited BRAF mediated stimulation of C2C12 cell migration ( XREF_FIG ) supporting our conclusion that signaling events downstream of MET necessary for limb muscle precursor migration rely on the translocation of BRAF into the nucleus and not on the activation of the ERK1/2 signaling cascade .	Furthermore, knockdown of Eea1 but not of Erk1/2 significantly inhibited BRAF mediated stimulation of C2C12 cell migration (XREF_FIG) supporting our conclusion that signaling events downstream of MET necessary for limb muscle precursor migration rely on the translocation of BRAF into the nucleus and not on the activation of the ERK1/2 signaling cascade.	2	13	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	BRAF	BRAF	BRAF	8	9	11	12
These cancers develop due to the paradoxical activation of MAPK signaling in BRAF wild-type cells with upstream activation of RAS when treated with BRAF inhibitors .	These cancers develop due to the paradoxical activation of MAPK signaling in BRAF wild-type cells with upstream activation of RAS when treated with BRAF inhibitors.	9	14	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	9	10	12	13
Although the currently available RAF inhibitors induce paradoxical hyperactivation of ERK signaling in BRAF wild-type cells that promotes cancer growth , a new class of inhibitors that does not cause this phenomenon has been developed .	Although the currently available RAF inhibitors induce paradoxical hyperactivation of ERK signaling in BRAF wild-type cells that promotes cancer growth, a new class of inhibitors that does not cause this phenomenon has been developed.	10	15	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	10	11	13	14
Western blot analyses indicated that combination treatment is associated with decreased MAPK and PI3K and mTOR signaling in the BRAF V600E cell lines , while combination treatment has no effect on MAPK signaling in BRAF wild-type or KRAS mutant cells ( XREF_FIG ) .	Western blot analyses indicated that combination treatment is associated with decreased MAPK and PI3K and mTOR signaling in the BRAF V600E cell lines, while combination treatment has no effect on MAPK signaling in BRAF wild-type or KRAS mutant cells (XREF_FIG).	31	35	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	31	32	34	35
However , as reported for other BRAF inhibitors , dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF ( RAF1 ) signalling , potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors .	However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors.	12	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	12	13	17	18
Preclinical evidence indicates vemurafenib and other RAF inhibitors induce proliferation of mutant-RAS tumors via paradoxical activation of RAS and ERK signaling in wild-type BRAF cells XREF_BIBR , XREF_BIBR .	Preclinical evidence indicates vemurafenib and other RAF inhibitors induce proliferation of mutant-RAS tumors via paradoxical activation of RAS and ERK signaling in wild-type BRAF cells XREF_BIBR, XREF_BIBR.	17	24	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	19	20	23	24
FDA approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K mutant melanoma , but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells .	FDA approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells.	28	33	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	BRAF	BRAF	BRAF	28	29	32	33
On one hand , there is a large body of evidence showing that MAPK activation in melanoma cells contributes to immunosuppression and BRAF and MEK inhibitors trigger melanoma specific immune responses , which are typically manifested by a rapid increase in tumour infiltrating lymphocytes ( TILs ) consisting mainly of cytotoxic T lymphocytes ( CTLs ) [ XREF_BIBR - XREF_BIBR ] .	On one hand, there is a large body of evidence showing that MAPK activation in melanoma cells contributes to immunosuppression and BRAF and MEK inhibitors trigger melanoma specific immune responses, which are typically manifested by a rapid increase in tumour infiltrating lymphocytes (TILs) consisting mainly of cytotoxic T lymphocytes (CTLs) [XREF_BIBR - XREF_BIBR].	13	23	contributes	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	13	14	22	23
MLN2480 inhibited MAPK pathway signaling in preclinical BRAF and RAS mutant melanoma and colorectal carcinoma models [ XREF_BIBR ] .	MLN2480 inhibited MAPK pathway signaling in preclinical BRAF and RAS mutant melanoma and colorectal carcinoma models [XREF_BIBR].	2	15	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	2	3	7	8
The increased MAPK signalingin BRaf inhibited cells decreases Akt activation .	The increased MAPK signalingin BRaf inhibited cells decreases Akt activation.	0	5	signalingin	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRaf	BRaf	BRaf	2	3	4	5
Secondary cutaneous malignancies are a well documented toxicity of vemurafenib , thought to be mediated by enhanced ERK signalling in BRAF wild-type , RAS-mutant cells .	Secondary cutaneous malignancies are a well documented toxicity of vemurafenib, thought to be mediated by enhanced ERK signalling in BRAF wild-type, RAS-mutant cells.	17	21	signalling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	17	18	20	21
Therefore , we assessed the phosphorylation status of MEK ( the immediate downstream kinase target of BRAF ) and ERK ( the kinase phosphorylated by active MEK ) , using antibodies that specifically recognize phosphorylated MEK and ERK .	Therefore, we assessed the phosphorylation status of MEK (the immediate downstream kinase target of BRAF) and ERK (the kinase phosphorylated by active MEK), using antibodies that specifically recognize phosphorylated MEK and ERK.	3	22	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	19	20	16	17
A year later , Kaplan and colleagues published corroborating evidence that PLX4720 paradoxically activated MEK1/2 > ERK1/2 signaling in BRAF WT cells .	A year later, Kaplan and colleagues published corroborating evidence that PLX4720 paradoxically activated MEK1/2> ERK1/2 signaling in BRAF WT cells.	16	21	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	BRAF	BRAF	BRAF	16	17	19	20
This observed effector T cell activation may be explained by paradoxical activation of MAPK signaling in BRAF wild-type cells through enhanced CRAF dimerization .	This observed effector T cell activation may be explained by paradoxical activation of MAPK signaling in BRAF wild-type cells through enhanced CRAF dimerization.	13	18	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	13	14	16	17
A new study reveals that rewiring of MAPK signaling in cells expressing mutant RAS includes ERK mediated BRAF inactivation and the concomitant activation of CRAF , partly through amplification by the phosphodiesterase 4 isoform .	A new study reveals that rewiring of MAPK signaling in cells expressing mutant RAS includes ERK mediated BRAF inactivation and the concomitant activation of CRAF, partly through amplification by the phosphodiesterase 4 isoform.	14	22	mediated	Positive_early_activation	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	15	16	17	18
PB is a potent inhibitor of monomeric BRAF V600E , but is unique because it induces minimal RAF priming and paradoxical ERK signaling activation in BRAF WT -expressing cells .	PB is a potent inhibitor of monomeric BRAF V600E, but is unique because it induces minimal RAF priming and paradoxical ERK signaling activation in BRAF WT -expressing cells.	21	28	signaling activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	21	22	25	26
However , dabrafenib can upregulate MAPK effector activation in BRAF wild-type melanoma [ XREF_BIBR ] .	However, dabrafenib can upregulate MAPK effector activation in BRAF wild-type melanoma [XREF_BIBR].	5	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	5	6	9	10
The continued MAPK dependency of BRAF inhibitor resistant melanomas led to the initiation of clinical trials to evaluate the BRAF and MEK inhibitor combination .	The continued MAPK dependency of BRAF inhibitor resistant melanomas led to the initiation of clinical trials to evaluate the BRAF and MEK inhibitor combination.	2	23	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	2	3	19	20
This specimen also exhibited robust MAPK pathway activation and elevated expression of B-RAF , C-RAF and COT relative to matched normal skin or B-RAF V600E cell lines ( XREF_SUPPLEMENTARY ) .	This specimen also exhibited robust MAPK pathway activation and elevated expression of B-RAF, C-RAF and COT relative to matched normal skin or B-RAF V600E cell lines (XREF_SUPPLEMENTARY).	5	16	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	B-RAF	B-RAF	B-RAF	5	6	12	13
Taken together , these data suggest that MAPK pathway activation in BRAF V600 mutant melanoma cells has a direct suppressive effect on the capacity of DC to activate T cells .	Taken together, these data suggest that MAPK pathway activation in BRAF V600 mutant melanoma cells has a direct suppressive effect on the capacity of DC to activate T cells.	7	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	7	8	11	12
Activated BRAF triggers MAPK signaling leading to melanocyte growth and proliferation ( XREF_FIG ) .	Activated BRAF triggers MAPK signaling leading to melanocyte growth and proliferation (XREF_FIG).	0	4	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	3	4	1	2
Reports indicate that BRAF inhibitors induce ERK signaling and increase growth in wild-type BRAF cells .	Reports indicate that BRAF inhibitors induce ERK signaling and increase growth in wild-type BRAF cells.	6	14	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	6	7	13	14
Here , we predict that RAF inhibitors can enhance T cell activation , based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells .	Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells.	22	27	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	22	23	25	26
They observed that PLX4720 inhibited ERK signaling in BRAF V600E cells , but they did not observe paradoxical MEK1/2 > ERK1/2 activation in BRAF WT lines .	They observed that PLX4720 inhibited ERK signaling in BRAF V600E cells, but they did not observe paradoxical MEK1/2> ERK1/2 activation in BRAF WT lines.	20	25	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	BRAF	BRAF	BRAF	20	21	23	24
Also consistent with this ERK dependent p15 induction , inhibition of ERK signaling by the MEK inhibitor U0126 blocked BRAF driven p15 induction ( XREF_SUPPLEMENTARY ) .	Also consistent with this ERK dependent p15 induction, inhibition of ERK signaling by the MEK inhibitor U0126 blocked BRAF driven p15 induction (XREF_SUPPLEMENTARY).	11	20	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	11	12	19	20
Conversely , the incidence of a number of cutaneous AEs , particularly development of SCC , was reduced with combination therapy due to blockade of paradoxical MAPK activation in BRAF wild-type cells through MEK inhibition [ 14 ] .	Conversely, the incidence of a number of cutaneous AEs, particularly development of SCC, was reduced with combination therapy due to blockade of paradoxical MAPK activation in BRAF wild-type cells through MEK inhibition [14].	26	31	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	26	27	29	30
These results corroborate with previous findings that mTORC1 activity is primarily regulated by ERK signaling in BRAF or MEK inhibitor sensitive melanomas .	These results corroborate with previous findings that mTORC1 activity is primarily regulated by ERK signaling in BRAF or MEK inhibitor sensitive melanomas.	13	21	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	13	14	16	17
While RAF inhibitors block ERK signaling in BRAF-mutant cells , they paradoxically enhance ERK signaling in BRAF wild-type cells in preclinical studies [ XREF_BIBR , XREF_BIBR ] .	While RAF inhibitors block ERK signaling in BRAF-mutant cells, they paradoxically enhance ERK signaling in BRAF wild-type cells in preclinical studies [XREF_BIBR, XREF_BIBR].	13	18	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	13	14	16	17
Also concerning is an acceleration of preexisting RAS mutant growths in the colon and appearance of RAS driven leukemias which are thought to arise due ERK activation in the adjacent wild type BRAF tissue ( reviewed in see also ) .	Also concerning is an acceleration of preexisting RAS mutant growths in the colon and appearance of RAS driven leukemias which are thought to arise due ERK activation in the adjacent wild type BRAF tissue (reviewed in see also).	25	33	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	25	26	32	33
They have been shown to inhibit the kinase activities of all three RAF family members in vitro and to activate ERK signaling in BRAF knockout cells with active RAS .	They have been shown to inhibit the kinase activities of all three RAF family members in vitro and to activate ERK signaling in BRAF knockout cells with active RAS.	20	25	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	20	21	23	24
Combining a BRAF inhibitor with a MEK inhibitor , which may block paradoxical MAPK activation in BRAF wild type ( skin ) cells , may lower the incidence of squamoproliferative eruptions .	Combining a BRAF inhibitor with a MEK inhibitor, which may block paradoxical MAPK activation in BRAF wild type (skin) cells, may lower the incidence of squamoproliferative eruptions.	13	17	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	13	14	16	17
Paradoxical activation of ERK signaling in BRAF wild-type tissues with BRAF inhibitors has been previously reported .	Paradoxical activation of ERK signaling in BRAF wild-type tissues with BRAF inhibitors has been previously reported.	3	8	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	3	4	6	7
XREF_BIBR , XREF_BIBR Furthermore , anti-BRAF monotherapy leads to secondary skin cancers in some cases due to paradoxical MAPK pathway activation in BRAF wild-type cells .	XREF_BIBR, XREF_BIBR Furthermore, anti-BRAF monotherapy leads to secondary skin cancers in some cases due to paradoxical MAPK pathway activation in BRAF wild-type cells.	18	24	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	18	19	22	23
In our study , we examined whether 17-AAG could inhibit PLX4032 enhanced ERK signaling in BRAF WT melanoma cells .	In our study, we examined whether 17-AAG could inhibit PLX4032 enhanced ERK signaling in BRAF WT melanoma cells.	12	18	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	12	13	15	16
We have gone on to show that as a consequence of ERK being constitutively activated in melanoma cell lines expressing oncogenic BRAF , MITF protein levels are lower in mutant BRAF melanoma cells than in melanocytes .	We have gone on to show that as a consequence of ERK being constitutively activated in melanoma cell lines expressing oncogenic BRAF, MITF protein levels are lower in mutant BRAF melanoma cells than in melanocytes.	9	22	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	11	12	21	22
Given the clinical utility of MAPK targeted therapy and the anticorrelative relationship of hotspot BRAF , RAS and loss-of-function NF1 mutations , we suspect that the framework generated by the TCGA study will be useful to guide personalised therapeutic decisions for cutaneous melanoma ( XREF_TABLE ) .	Given the clinical utility of MAPK targeted therapy and the anticorrelative relationship of hotspot BRAF, RAS and loss-of-function NF1 mutations, we suspect that the framework generated by the TCGA study will be useful to guide personalised therapeutic decisions for cutaneous melanoma (XREF_TABLE).	3	20	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	5	6	14	15
Also , the combination of MEK inhibitors and first generation BRAF inhibitors are better tolerated than the respective mono-therapies , because the paradoxical activation of MAPK signaling in BRAF wild-type tissues antagonizes the inhibitory functions of MEK inhibitors , and in turn limits this paradoxical activation XREF_BIBR .	Also, the combination of MEK inhibitors and first generation BRAF inhibitors are better tolerated than the respective mono-therapies, because the paradoxical activation of MAPK signaling in BRAF wild-type tissues antagonizes the inhibitory functions of MEK inhibitors, and in turn limits this paradoxical activation XREF_BIBR.	25	30	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	25	26	28	29
AMPK also abrogates ERK signaling in many cell types , and this effect has recently been linked to negative regulation of the upstream ERK activator BRaf ( XREF_FIG ) .	AMPK also abrogates ERK signaling in many cell types, and this effect has recently been linked to negative regulation of the upstream ERK activator BRaf (XREF_FIG).	19	27	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	BRaf	BRaf	BRaf	23	24	25	26
The authors proposed that the paradoxical ERK activation in BRAF wt cells may be a common event with ATP-competitive inhibitors of the BRAF kinase domain and showed that MEK inhibition blocks this paradoxical activation .	The authors proposed that the paradoxical ERK activation in BRAF wt cells may be a common event with ATP-competitive inhibitors of the BRAF kinase domain and showed that MEK inhibition blocks this paradoxical activation.	6	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	6	7	9	10
PAK1 has been shown to be particularly critical for MAPK activation in BRAF WT melanoma and in breast cancer by linking MET activation to MAPK signaling .	PAK1 has been shown to be particularly critical for MAPK activation in BRAF WT melanoma and in breast cancer by linking MET activation to MAPK signaling.	9	14	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	9	10	12	13
XREF_BIBR has found that low concentration of ERK alone can not reverse BRAF-inhibitor and MEK-inhibitor double resistance ( DDR , double-drugs-resistance ) unless co-targeting BRAF and MEK .	XREF_BIBR has found that low concentration of ERK alone can not reverse BRAF-inhibitor and MEK-inhibitor double resistance (DDR, double-drugs-resistance) unless co-targeting BRAF and MEK.	5	26	reverse	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	7	8	24	25
Intriguingly , increased MAPK signalingin BRaf inhibited cells is accompanied by significantly decreased Akt activation .	Intriguingly, increased MAPK signalingin BRaf inhibited cells is accompanied by significantly decreased Akt activation.	3	6	signalingin	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRaf	BRaf	BRaf	3	4	5	6
XREF_BIBR - XREF_BIBR This RAF inhibitor dependent activation of MAPK signaling in BRAF wild-type cells is termed paradoxical MAPK-pathway activation 15 and is driven by the formation of RAF dimers that lead to signaling through CRAF and consequently MAPK-pathway hyperactivation .	XREF_BIBR - XREF_BIBR This RAF inhibitor dependent activation of MAPK signaling in BRAF wild-type cells is termed paradoxical MAPK-pathway activation 15 and is driven by the formation of RAF dimers that lead to signaling through CRAF and consequently MAPK-pathway hyperactivation.	9	14	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	9	10	12	13
High basal level ERK1/2 activity is observed in more than 60 % ( combined KRAS and BRAF gene mutation frequency ) of colon cancers , thus targeting the BRAF signaling pathway may be an effective approach to control these highly malignant cancers .	High basal level ERK1/2 activity is observed in more than 60% (combined KRAS and BRAF gene mutation frequency) of colon cancers, thus targeting the BRAF signaling pathway may be an effective approach to control these highly malignant cancers.	3	30	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	BRAF	BRAF	BRAF	3	4	28	29
As BRAF is directly upstream from the MEK kinase , activating mutations in BRAF result in constitutively activated MEK with subsequent activation of the MAPK and ERK pathway .	As BRAF is directly upstream from the MEK kinase, activating mutations in BRAF result in constitutively activated MEK with subsequent activation of the MAPK and ERK pathway.	10	27	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	24	25	13	14
In many instances , these RTKs reactivate MEK and ERK signaling independently of BRAF , and in that way confer resistance to BRAF inhibitors .	In many instances, these RTKs reactivate MEK and ERK signaling independently of BRAF, and in that way confer resistance to BRAF inhibitors.	7	14	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	9	10	13	14
These results indicate that LCH cells can harbor additional genetic alterations in the RAS-RAF-MEK pathway which , in the case of MAP2K1 , may be responsible for ERK activation in a wild type BRAF setting .	These results indicate that LCH cells can harbor additional genetic alterations in the RAS-RAF-MEK pathway which, in the case of MAP2K1, may be responsible for ERK activation in a wild type BRAF setting.	27	34	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	27	28	33	34
In vitro testing indicated that sorafenib may lead to paradoxical ERK activation in both wild-type BRAF and fusion KIAA1549 : BRAF tumor cells as well as NF1 deficient cells , suggesting that BRAF inhibitors should only be used in BRAF V600E -mutant tumors [ XREF_BIBR ] .	In vitro testing indicated that sorafenib may lead to paradoxical ERK activation in both wild-type BRAF and fusion KIAA1549 : BRAF tumor cells as well as NF1 deficient cells, suggesting that BRAF inhibitors should only be used in BRAF V600E -mutant tumors [XREF_BIBR].	10	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	10	11	15	16
The discovery of BRAF mutations and MAPK pathway dependence of human cancers led to the therapeutic strategy targeting BRAF and MAPK pathway .	The discovery of BRAF mutations and MAPK pathway dependence of human cancers led to the therapeutic strategy targeting BRAF and MAPK pathway.	6	21	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	6	7	18	19
EGF induction of DUSP5 and FOS were also strongly attenuated by a MEK inhibitor ( trametinib ) , demonstrating that DUSP5 is a bone fide target of ERK signaling in KRAS and BRAF wild-type CRCcells .	EGF induction of DUSP5 and FOS were also strongly attenuated by a MEK inhibitor (trametinib), demonstrating that DUSP5 is a bone fide target of ERK signaling in KRAS and BRAF wild-type CRCcells.	27	34	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	BRAF	BRAF	BRAF	27	28	32	33
Importantly , SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors .	Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors.	5	16	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BRAF	BRAF	BRAF	5	6	11	12
In older animals levels of activated PERK were low and there was also no significant activation of eIF2alpha by PERK with sleep deprivation .	In older animals levels of activated PERK were low and there was also no significant activation of eIF2alpha by PERK with sleep deprivation.	15	22	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	19	20	17	18
These results demonstrate that deletion of one allele of Perk reduces p-eIF2alpha , pro apoptotic CHOP yet maintains or even increases vascularity , as determined by CD31 staining .	These results demonstrate that deletion of one allele of Perk reduces p-eIF2alpha, pro apoptotic CHOP yet maintains or even increases vascularity, as determined by CD31 staining.	7	12	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Perk	Perk	Perk	p-eIF2alpha	p-eIF2alpha	p-eIF2alpha	9	10	11	12
The unfolded protein response initiates endoplasmic reticulum stress that activates PERK , which subsequently activates eIF2alpha by phosphorylation .	The unfolded protein response initiates endoplasmic reticulum stress that activates PERK, which subsequently activates eIF2alpha by phosphorylation.	9	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	10	11	15	16
Interestingly , Hsp27 knockdown affects the three transmembrane ER stress sensors , namely PERK ( increase of p-eIF2-a , ATF-4 ) , IRE1 ( cleaved XBP1 ) and ATP-6 ( cleaved ATF-6 ) .	Interestingly, Hsp27 knockdown affects the three transmembrane ER stress sensors, namely PERK (increase of p-eIF2-a, ATF-4), IRE1 (cleaved XBP1) and ATP-6 (cleaved ATF-6).	10	28	increase	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	PERK	PERK	PERK	p-eIF2-a	p-eIF2-a	p-eIF2-a	13	14	17	18
As expected , it caused apoptosis in MCF-7 :5 C cells ( XREF_FIG ) and activated eukaryotic translation initiation factor-2alpha ( eIF2alpha ) ( XREF_FIG ) , which is activated by PERK .	As expected, it caused apoptosis in MCF-7 :5 C cells (XREF_FIG) and activated eukaryotic translation initiation factor-2alpha (eIF2alpha) (XREF_FIG), which is activated by PERK.	19	32	activated	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	31	32	21	22
By suppression of kinase PERK and PKR activity , and enhancement of phosphotase GADD34-PP1 activity , phosphor-eIF2alpha was reduced to low level at late infection times , resulting in robust protein synthesis throughout the infection course .	By suppression of kinase PERK and PKR activity, and enhancement of phosphotase GADD34-PP1 activity, phosphor-eIF2alpha was reduced to low level at late infection times, resulting in robust protein synthesis throughout the infection course.	1	19	reduced	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	phosphor-eIF2alpha	phosphor-eIF2alpha	phosphor-eIF2alpha	4	5	16	17
However , increased phosphorylation of PERK activated eIF2alpha was apparent only in Col10a1 p.N617K mice , which , together with the microarray data , supports our conclusion that Tg cog elicits a milder ER stress and , consequently , a milder phenotype than Col10a1 p.N617K .	However, increased phosphorylation of PERK activated eIF2alpha was apparent only in Col10a1 p.N617K mice, which, together with the microarray data, supports our conclusion that Tg cog elicits a milder ER stress and, consequently, a milder phenotype than Col10a1 p.N617K.	3	9	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PERK	phosphorylation of PERK	perk	eIF2alpha	eIF2alpha	eif2alpha	5	6	7	8
For example , in Abeta induced astrocytes , salubrinal inhibition of PERK and eIF2alpha dependent ER stress and exposure to the neurosteroid progesterone ( PG ) significantly suppressed neuroinflammation by down-regulating PERK and eIF2alpha signaling .	For example, in Abeta induced astrocytes, salubrinal inhibition of PERK and eIF2alpha dependent ER stress and exposure to the neurosteroid progesterone (PG) significantly suppressed neuroinflammation by down-regulating PERK and eIF2alpha signaling.	11	34	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	11	12	33	34
Consistent with p-PERK catalyzing formation of p-eIF2alpha , PERK knockdown inhibited formation of p-eIF2alpha ( XREF_FIG ) .	Consistent with p-PERK catalyzing formation of p-eIF2alpha, PERK knockdown inhibited formation of p-eIF2alpha (XREF_FIG).	8	15	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	p-eIF2alpha	p-eIF2alpha	p-eIF2alpha	8	9	13	14
Interestingly , several studies have reported the induction of autophagy by ER stress , notably after activation of eIF2alpha by PERK , thus linking autophagy to the UPR [ XREF_BIBR , XREF_BIBR ] .	Interestingly, several studies have reported the induction of autophagy by ER stress, notably after activation of eIF2alpha by PERK, thus linking autophagy to the UPR [XREF_BIBR, XREF_BIBR].	16	21	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	20	21	18	19
15 CHOP expression is mostly controlled by the eIF2alpha and ATF4 signaling branch , which is activated not only by the UPR sensor PERK but also by the kinases GCN2 , HRI , and PKR 2 that are non ER stress dependent .	15 CHOP expression is mostly controlled by the eIF2alpha and ATF4 signaling branch, which is activated not only by the UPR sensor PERK but also by the kinases GCN2, HRI, and PKR 2 that are non ER stress dependent.	5	24	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	23	24	8	9
The UPR acts to alleviate stress and restore ER function by blocking translation and promoting degradation of misfolded proteins through downstream effectors such as PERK activated eIF2alpha and IRE1alpha induced splicing of the X-box Binding Protein ( XBP1 ) 17 .	The UPR acts to alleviate stress and restore ER function by blocking translation and promoting degradation of misfolded proteins through downstream effectors such as PERK activated eIF2alpha and IRE1alpha induced splicing of the X-box Binding Protein (XBP1) 17.	21	29	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	24	25	26	27
As we know , PERK mediates its effects by phosphorylating ( inactivating ) eIF2alpha .	As we know, PERK mediates its effects by phosphorylating (inactivating) eIF2alpha.	4	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	4	5	13	14
Second , partial silencing of PERK by RNA interference downregulated p-eIF2alpha ( XREF_FIG ) , and PD407824 and AZD7762 elevated the expression level of p-PERK ( XREF_FIG ) .	Second, partial silencing of PERK by RNA interference downregulated p-eIF2alpha (XREF_FIG), and PD407824 and AZD7762 elevated the expression level of p-PERK (XREF_FIG).	3	12	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	p-eIF2alpha	p-eIF2alpha	p-eIF2alpha	5	6	10	11
We found that ATA induced phosphorylation and activation of PERK which , in turn , phosphorylated and activated the translation initiation factor eIF2alpha .	We found that ATA induced phosphorylation and activation of PERK which, in turn, phosphorylated and activated the translation initiation factor eIF2alpha.	3	23	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	ATA induced phosphorylation and activation of PERK	perk	eIF2alpha	eIF2alpha	eif2alpha	9	10	22	23
When overexpressing 4R tau in neurons , PERK activator treatment still increased pNRF2 , but not pEIF2A ( Fig XREF_FIG F and G ) , while PERK inhibitor treatment decreased pEIF2A but not pNRF2 .	When overexpressing 4R tau in neurons, PERK activator treatment still increased pNRF2, but not pEIF2A (Fig XREF_FIG F and G), while PERK inhibitor treatment decreased pEIF2A but not pNRF2.	7	33	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PERK	PERK	PERK	pEIF2A	pEIF2A	pEIF2A	7	8	30	31
PERK is activated by dimerization and autophosphorylation which further phosphorylate and activate the translation initiation factor eIF2alpha .	PERK is activated by dimerization and autophosphorylation which further phosphorylate and activate the translation initiation factor eIF2alpha.	0	17	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	0	1	16	17
PERK mediated eIF2alpha-P is the main UPR branch leading to general protein synthesis repression and facilitation of select mRNA translation .	PERK mediated eIF2alpha-P is the main UPR branch leading to general protein synthesis repression and facilitation of select mRNA translation.	0	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha-P	eIF2alpha-P	eIF2alpha-P	0	1	2	3
PERK activates eIF2a , and then the phosphorylated eIF2a induces the translation of ATF4 mRNA [ XREF_BIBR ] .	PERK activates eIF2a, and then the phosphorylated eIF2a induces the translation of ATF4 mRNA [XREF_BIBR].	0	3	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2a	eIF2a	eIF2a	0	1	2	3
PERK ( protein kinase R like endoplasmic reticulum kinase ) acts as one of the key sensors for the unfolded protein response and is known to activate eIF2alpha .	PERK (protein kinase R like endoplasmic reticulum kinase) acts as one of the key sensors for the unfolded protein response and is known to activate eIF2alpha.	0	28	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	0	1	27	28
We also demonstrated that CO induced ATF4 expression via the PERK mediated eIF2alpha pathway .	We also demonstrated that CO induced ATF4 expression via the PERK mediated eIF2alpha pathway.	7	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	10	11	12	13
In the PERK-eIF2alpha pathway , freed PERK spontaneously dimerizes and activates eIF2a S ( 51 ) phosphorylation .	In the PERK-eIF2alpha pathway, freed PERK spontaneously dimerizes and activates eIF2a S (51) phosphorylation.	5	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2a	eIF2a	eIF2a	6	7	11	12
PERK phosphorylation promotes release of Nrf2 from Keap1 and its translocation into the nucleus , independently of eIF2alpha .	PERK phosphorylation promotes release of Nrf2 from Keap1 and its translocation into the nucleus, independently of eIF2alpha.	0	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK phosphorylation	perk	eIF2alpha	eIF2alpha	eif2alpha	0	1	17	18
PERK activates eIF2alpha to increase ATF4 expression , which then binds to the promoter of GRP7832 to increase GRP78 and induce the reduction of nascent protein translation .	PERK activates eIF2alpha to increase ATF4 expression, which then binds to the promoter of GRP7832 to increase GRP78 and induce the reduction of nascent protein translation.	0	3	activates	Positive_activation_syntax_3a_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	0	1	2	3
Classically , PERK is activated in response to ER stress and then activates NRF2 , which protects cells from oxidative damage , and EIF2A , which in turn suppresses protein translation and activates ATF4 ( Fig XREF_FIG A ) .	Classically, PERK is activated in response to ER stress and then activates NRF2, which protects cells from oxidative damage, and EIF2A, which in turn suppresses protein translation and activates ATF4 (Fig XREF_FIG A).	2	37	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	EIF2A	EIF2A	EIF2A	2	3	23	24
Similarly , levels of ER stress markers such as PERK induced p-eIF2alpha , ATF6 and XBP1u are increased in extravillous cytotrophoblasts , decidual cells and macrophages in decidual tissues derived from pregnancies complicated by FGR with or without preeclampsia [ XREF_BIBR ] .	Similarly, levels of ER stress markers such as PERK induced p-eIF2alpha, ATF6 and XBP1u are increased in extravillous cytotrophoblasts, decidual cells and macrophages in decidual tissues derived from pregnancies complicated by FGR with or without preeclampsia [XREF_BIBR].	6	17	induced	Positive_early_activation	Negative_activation	Positive_activation	PERK	PERK	PERK	p-eIF2alpha	p-eIF2alpha	p-eIF2alpha	9	10	11	12
This can be attributed to the UPR response induced by PERK activation of eIF2alpha .	This can be attributed to the UPR response induced by PERK activation of eIF2alpha.	10	14	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	10	11	13	14
However , PERK induced activation of eIF2alpha is believed to occur exclusively upon the induction of ER stress [ XREF_BIBR ] .	However, PERK induced activation of eIF2alpha is believed to occur exclusively upon the induction of ER stress [XREF_BIBR].	2	7	induced	Positive_early_activation	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	2	3	6	7
PERK dimerization and trans-autophosphorylation leads to the activation of eIF2alpha by phosphorylation at Ser51 .	PERK dimerization and trans-autophosphorylation leads to the activation of eIF2alpha by phosphorylation at Ser51.	0	10	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PERK	PERK dimerization and trans-autophosphorylation	perk	eIF2alpha	eIF2alpha	eif2alpha	0	1	9	10
Activation of eIF2alpha by PERK leads to the inhibition of the translation initiation .	Activation of eIF2alpha by PERK leads to the inhibition of the translation initiation.	0	5	Activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	4	5	2	3
Genetic reduction of PERK or GCN2 lowers eIF2alpha-P , and protects against impaired LTP and spatial memory in a model of AD ( Ma etal .	Genetic reduction of PERK or GCN2 lowers eIF2alpha-P, and protects against impaired LTP and spatial memory in a model of AD (Ma etal.	1	8	lowers	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha-P	eIF2alpha-P	eIF2alpha-P	3	4	7	8
ATF4 expression is mediated by the PERK mediated eIF2alpha pathway and regulates FGF21 expression .	ATF4 expression is mediated by the PERK mediated eIF2alpha pathway and regulates FGF21 expression.	3	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	6	7	8	9
Activated PERK activates eIF-2alpha to suppress general protein translation but permit selective translation of the ATF4 transcription factor , which is known to induce ATG5 ( Autophagy related gene 5 ) and LC3B expression .	Activated PERK activates eIF-2alpha to suppress general protein translation but permit selective translation of the ATF4 transcription factor, which is known to induce ATG5 (Autophagy related gene 5) and LC3B expression.	0	33	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF-2alpha	eIF-2alpha	eIF-2alpha	1	2	3	4
Relative protein concentrations of the ER stress sensor PERK and the ER stress targets eIF2alpha and IkappaB in the liver of lactating and non lactating sows on day 20 of lactation .	Relative protein concentrations of the ER stress sensor PERK and the ER stress targets eIF2alpha and IkappaB in the liver of lactating and non lactating sows on day 20 of lactation.	2	16	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	8	9	14	15
It was observed that PERK activates eIF2alpha , ATF4 , and CHOP , causing apoptosis .	It was observed that PERK activates eIF2alpha, ATF4, and CHOP, causing apoptosis.	4	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	4	5	6	7
A second pathway is mediated by PERK , which activates p-eIF2alpha , which then activates CHOP .	A second pathway is mediated by PERK, which activates p-eIF2alpha, which then activates CHOP.	4	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	p-eIF2alpha	p-eIF2alpha	p-eIF2alpha	6	7	10	11
Next , because PERK mediated eIF2alpha signaling is one of three branches of the unfolded protein response , we tested modulators that are available for another branch , which requires ATF6 signaling .	Next, because PERK mediated eIF2alpha signaling is one of three branches of the unfolded protein response, we tested modulators that are available for another branch, which requires ATF6 signaling.	3	6	mediated	Positive_early_activation	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	3	4	5	6
Only acute palmitate treatment increased GRP78 ( 28 % , P < 0.05 ) , PERK ( 98 % , P < 0.01 ) , eIF-2A ( 35 % , P < 0.01 ) , IRE1a ( 60 % , P < 0.05 ) and TRAF2 ( 23 % , P < 0.05 ) protein content , and PERK phosphorylation ( 106 % , P < 0.001 ) , but did not elicit eIF-2A , IKK phosphorylation or increased XBP1 nuclear content .	Only acute palmitate treatment increased GRP78 (28%, P < 0.05), PERK (98%, P < 0.01), eIF-2A (35%, P < 0.01), IRE1a (60%, P < 0.05) and TRAF2 (23%, P < 0.05) protein content, and PERK phosphorylation (106%, P < 0.001), but did not elicit eIF-2A, IKK phosphorylation or increased XBP1 nuclear content.	2	81	elicit	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	palmitate treatment increased GRP78 (28%, P < 0.05), PERK (98%, P < 0.01), eIF-2A (35%, P < 0.01), IRE1a (60%, P < 0.05) and TRAF2 (23%, P < 0.05) protein content, and PERK phosphorylation	perk	eIF-2A	eIF-2A	eif-2a	15	16	73	74
While PERK activates eIF2alpha during UPR activation upon ER stress , other serine kinases such as general control nonderepressible 2 ( GCN2 ) can also phosphorylate eIF2alpha in response to other stresses including amino acid deprivation .	While PERK activates eIF2alpha during UPR activation upon ER stress, other serine kinases such as general control nonderepressible 2 (GCN2) can also phosphorylate eIF2alpha in response to other stresses including amino acid deprivation.	1	4	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	1	2	3	4
PERK induces p-eIF2alpha , which in turn suppresses global mRNA translation and favours apoptosis by increasing the translation of ATF4 .	PERK induces p-eIF2alpha, which in turn suppresses global mRNA translation and favours apoptosis by increasing the translation of ATF4.	0	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	p-eIF2alpha	p-eIF2alpha	p-eIF2alpha	0	1	2	3
PERK is known to activate the eIF2alpha and ATF4 pathway [ XREF_BIBR ] .	PERK is known to activate the eIF2alpha and ATF4 pathway [XREF_BIBR].	0	11	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	0	1	6	7
Therefore , these findings suggested that PERK dependent activation of eIF2alpha occurred specifically in advanced stages of 5XFAD mouse brains suffering from BACE1 elevations and was not affected by BACE1 haploinsufficiency .	Therefore, these findings suggested that PERK dependent activation of eIF2alpha occurred specifically in advanced stages of 5XFAD mouse brains suffering from BACE1 elevations and was not affected by BACE1 haploinsufficiency.	6	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PERK	PERK	PERK	eIF2alpha	eIF2alpha	eIF2alpha	6	7	10	11
IL-6 mediated the pathway of Janus kinase ( JAK ) , signal transducer and activator of transcription 3 ( STAT3 ) , and mitogen activated protein kinase ( MAPK ) , which induced androgen receptor mediated gene expression and eventually induced androgen independent growth of androgen dependent PCa cells [ XREF_BIBR ] .	IL-6 mediated the pathway of Janus kinase (JAK), signal transducer and activator of transcription 3 (STAT3), and mitogen activated protein kinase (MAPK), which induced androgen receptor mediated gene expression and eventually induced androgen independent growth of androgen dependent PCa cells [XREF_BIBR].	26	35	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	androgen receptor	androgen receptor	androgen receptor	28	29	33	35
( ii ) The phosphorylation of MAPK incurs IL-6 expression , and promotes AR production .	(ii) The phosphorylation of MAPK incurs IL-6 expression, and promotes AR production.	4	14	promotes	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	MAPK	phosphorylation of MAPK	mapk	AR	AR	ar	6	7	13	14
In the present study , we found that EGF could increase BCa cell growth , migration and invasion in the presence of AR under the low amount of androgen and EGF was able to potentiate AR transactivation through EGFR by activating PI3K and AKT and MAPK pathway at castration androgen level .	In the present study, we found that EGF could increase BCa cell growth, migration and invasion in the presence of AR under the low amount of androgen and EGF was able to potentiate AR transactivation through EGFR by activating PI3K and AKT and MAPK pathway at castration androgen level.	34	46	potentiate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	45	46	35	36
CD9 activates MAP kinase pathways [ XREF_BIBR - XREF_BIBR ] , which in turn may lead to AR activation by MAPK phosphorylation [ XREF_BIBR - XREF_BIBR ] .	CD9 activates MAP kinase pathways [XREF_BIBR - XREF_BIBR], which in turn may lead to AR activation by MAPK phosphorylation [XREF_BIBR - XREF_BIBR].	15	23	lead	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	MAPK	MAPK phosphorylation	mapk	AR	AR	ar	20	21	17	18
We therefore examined the kinetics of ERK1/2 signaling elicited by the WT or Del301-303 alpha 2B AR in Sp -/- and the corresponding Sp +/+ MEFs .	We therefore examined the kinetics of ERK1/2 signaling elicited by the WT or Del301-303 alpha 2B AR in Sp -/- and the corresponding Sp +/+ MEFs.	6	17	elicited	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	AR	AR	AR	6	7	16	17
We found that short-term inhibition of p42 and p44 MAPK activity either by a MAPK kinase inhibitor , U0126 , or by depletion of kinase with small interfering RNA caused target gene specific reductions in AR activity .	We found that short-term inhibition of p42 and p44 MAPK activity either by a MAPK kinase inhibitor, U0126, or by depletion of kinase with small interfering RNA caused target gene specific reductions in AR activity.	9	36	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	9	10	35	36
We found that sustained ERK1/2 activation using active Raf or MEK1/2 mutants is sufficient to induce AR downregulation at mRNA and protein levels in LNCaP .	We found that sustained ERK1/2 activation using active Raf or MEK1/2 mutants is sufficient to induce AR downregulation at mRNA and protein levels in LNCaP.	4	17	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	AR	AR	AR	4	5	16	17
ERK-1/2 mediated non genomic AR signaling .	ERK-1/2 mediated non genomic AR signaling.	0	5	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK-1/2	ERK-1/2	ERK-1/2	AR	AR	AR	0	1	4	5
Raf induced AR downregulation is mediated by MEK and ERK but MEK and ERK inhibition can not block long term androgen withdrawal induced AR downregulation in LNCaP cells .	Raf induced AR downregulation is mediated by MEK and ERK but MEK and ERK inhibition can not block long term androgen withdrawal induced AR downregulation in LNCaP cells.	11	24	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	AR	AR	AR	13	14	23	24
To determine if Erk signaling plays an important role in the regulation of EZH2 expression , Kras ( G12V ) + AR transduced PEB cells were treated with the Erk signaling inhibitor U0126 or EZH2 inhibitor DZNep ( control ) .	To determine if Erk signaling plays an important role in the regulation of EZH2 expression, Kras (G12V) + AR transduced PEB cells were treated with the Erk signaling inhibitor U0126 or EZH2 inhibitor DZNep (control).	16	32	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Erk	Erk	Erk	AR	AR	AR	29	30	21	22
Inhibitors of protein kinase A and C and MAPK down-regulated IL-6-induced AR activity .	Inhibitors of protein kinase A and C and MAPK down-regulated IL-6-induced AR activity.	4	12	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	8	9	11	12
An increased ERK activity may contribute to the tumorigenic effects of beta 2 AR and AGAP2 .	An increased ERK activity may contribute to the tumorigenic effects of beta 2 AR and AGAP2.	2	15	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	AR	AR	AR	2	3	13	14
We also examined the effects of these GPRC6A ligands on ERK activation in androgen receptor positive 22Rv1 and androgen receptor negative PC-3 cells ( XREF_FIG ) .	We also examined the effects of these GPRC6A ligands on ERK activation in androgen receptor positive 22Rv1 and androgen receptor negative PC-3 cells (XREF_FIG).	10	22	activation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	ERK	ERK	ERK	androgen receptor	androgen receptor	androgen receptor	10	11	18	20
These findings strongly suggest that the MAPK inactivates AR corepressors and thereby activates the AR signaling as an adaptive response .	These findings strongly suggest that the MAPK inactivates AR corepressors and thereby activates the AR signaling as an adaptive response.	5	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	6	7	14	15
MAPK pathway is frequently deregulated in metastatic PCa and CRPC and activates AR dependent transcription [ XREF_BIBR ] .	MAPK pathway is frequently deregulated in metastatic PCa and CRPC and activates AR dependent transcription [XREF_BIBR].	0	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	0	1	12	13
The Ras-Raf-mitogen-activated protein kinase ( MAPK ) pathway and c-Src , which are activated downstream of EGFR , may also enhance AR responses to low levels of androgen .	The Ras-Raf-mitogen-activated protein kinase (MAPK) pathway and c-Src, which are activated downstream of EGFR, may also enhance AR responses to low levels of androgen.	3	22	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	5	6	21	22
To further delineate the role of Galpha i in carvedilol induced betaAR signaling , we measured the level of ERK activation in beta 1 AR or beta 2 AR stable cells after removing Galpha i using CRISPR and Cas9 gene editing .	To further delineate the role of Galpha i in carvedilol induced betaAR signaling, we measured the level of ERK activation in beta 1 AR or beta 2 AR stable cells after removing Galpha i using CRISPR and Cas9 gene editing.	19	25	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	AR	AR	AR	19	20	24	25
AR activation by IL-6 is potentiated by STAT3 and MAPK pathways [ XREF_BIBR ] as evidenced by association of STAT3 with the AR , which occurs in an IL-6-dependent manner [ XREF_BIBR ] .	AR activation by IL-6 is potentiated by STAT3 and MAPK pathways [XREF_BIBR] as evidenced by association of STAT3 with the AR, which occurs in an IL-6-dependent manner [XREF_BIBR].	0	10	potentiated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	9	10	0	1
We previously reported feed-forward links between stress induced YB-1 to CLU activation in parallel with enhanced Akt and MAPK signaling which collectively support AR stability and activity during treatment with the AR antagonist enzalutamide ( Matsumoto etal , 2013 ) .	We previously reported feed-forward links between stress induced YB-1 to CLU activation in parallel with enhanced Akt and MAPK signaling which collectively support AR stability and activity during treatment with the AR antagonist enzalutamide (Matsumoto etal, 2013).	18	24	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	18	19	23	24
It should be noted ERK signaling can also enhance AR signaling , making it a particularly attractive therapeutic target in prostate cancer .	It should be noted ERK signaling can also enhance AR signaling, making it a particularly attractive therapeutic target in prostate cancer.	4	10	enhance	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	AR	AR	AR	4	5	9	10
However , it is likely that MEK inhibition also impinges on AR , as MAPK has been shown to augment AR function , and the inhibitor U0126 has been shown to reduce AR transcriptional activity in a target gene specific manner .	However, it is likely that MEK inhibition also impinges on AR, as MAPK has been shown to augment AR function, and the inhibitor U0126 has been shown to reduce AR transcriptional activity in a target gene specific manner.	14	21	augment	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	14	15	20	21
sFGL2 secretion by CD4 ( + ) T cells can be induced with TNF-alpha and IFN-gamma stimulation through MAPK signaling in renal allograft AR .	sFGL2 secretion by CD4 (+) T cells can be induced with TNF-alpha and IFN-gamma stimulation through MAPK signaling in renal allograft AR.	18	24	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	18	19	23	24
In DU145 cells , MAPK pathway is necessary for IL-6-induced , but not for androgen induced , activation of AR and expression of the latter ' s target genes .	In DU145 cells, MAPK pathway is necessary for IL-6-induced, but not for androgen induced, activation of AR and expression of the latter 's target genes.	4	21	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	4	5	19	20
In addition , PKC or MEK1/2 inhibition prevented ERK1/2 phosphorylation and antagonized AR mediated induction of NR4A2 and NR4A3 , suggesting the involvement of these kinases in AR to NR4A signaling .	In addition, PKC or MEK1/2 inhibition prevented ERK1/2 phosphorylation and antagonized AR mediated induction of NR4A2 and NR4A3, suggesting the involvement of these kinases in AR to NR4A signaling.	3	14	antagonized	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK1/2	PKC or MEK1/2 inhibition prevented ERK1/2 phosphorylation	erk1/2	AR	AR	ar	8	9	12	13
The activation of ERK1/2 through 17beta-estradiol triggered simultaneous association of endogenous androgen receptor , estrogen receptor alpha and Src .	The activation of ERK1/2 through 17beta-estradiol triggered simultaneous association of endogenous androgen receptor, estrogen receptor alpha and Src.	1	13	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	androgen receptor	androgen receptor	androgen receptor	3	4	11	13
In this study , we considered both the traditional hormone dependent and MAPK mediated AR activation .	In this study, we considered both the traditional hormone dependent and MAPK mediated AR activation.	5	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	12	13	14	15
Peptide growth factors that activate the signalling pathway of mitogen activated protein kinases ( MAPK ) stimulate AR activity in ligand independent or synergistic manner .	Peptide growth factors that activate the signalling pathway of mitogen activated protein kinases (MAPK) stimulate AR activity in ligand independent or synergistic manner.	2	18	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	14	15	17	18
Overexpression of AR in the MCF-7 breast cancer cell line , as postulated by Britton and colleagues , is thought to be due to cross talk between ERalpha and the EGFR and MAPK pathway , which leads to a self propogating autocrine growth-regulatory loop through ERalpha mediated development of AR [ XREF_BIBR ] .	Overexpression of AR in the MCF-7 breast cancer cell line, as postulated by Britton and colleagues, is thought to be due to cross talk between ERalpha and the EGFR and MAPK pathway, which leads to a self propogating autocrine growth-regulatory loop through ERalpha mediated development of AR [XREF_BIBR].	30	51	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	32	33	49	50
In addition , the extent of ERK activation in opto-beta 2 AR displayed a light-power-dependent relationship that was absent in untransfected HEK293 control cells ( XREF_SUPPLEMENTARY ) .	In addition, the extent of ERK activation in opto-beta 2 AR displayed a light-power-dependent relationship that was absent in untransfected HEK293 control cells (XREF_SUPPLEMENTARY).	6	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	AR	AR	AR	6	7	11	12
In another ligand independent manner without DHT , MAPK and STAT3 signal pathways can promote AR to translocate into nuclear XREF_BIBR .	In another ligand independent manner without DHT, MAPK and STAT3 signal pathways can promote AR to translocate into nuclear XREF_BIBR.	8	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	8	9	15	16
Mitogen activated protein kinases ( MAPK ) also modulate AR activity .	Mitogen activated protein kinases (MAPK) also modulate AR activity.	3	10	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	5	6	9	10
The Raf family of serine/threonine kinases and the MAP kinase ( MAPK ) pathway are heavily implicated in prostate cancer as activation of the Raf and MAPK pathway increases prostate cancer cell growth both AR dependent and -independent under in vitro conditions .	The Raf family of serine/threonine kinases and the MAP kinase (MAPK) pathway are heavily implicated in prostate cancer as activation of the Raf and MAPK pathway increases prostate cancer cell growth both AR dependent and -independent under in vitro conditions.	24	41	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	26	27	34	35
Several studies have demonstrated that MAPK can activate AR in the absence of hormone stimulation .	Several studies have demonstrated that MAPK can activate AR in the absence of hormone stimulation.	5	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	5	6	8	9
We next examined whether inhibition of the MAPK pathways could block the beta 3 AR dependent IL-6 production .	We next examined whether inhibition of the MAPK pathways could block the beta 3 AR dependent IL-6 production.	7	17	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	AR	AR	AR	7	8	14	15
of the MAPK activator Mek1 .	of the MAPK activator Mek1.	0	5	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	Mek1	Mek1	Mek1	2	3	4	5
In GECs that overexpress iPLA ( 2 ) gamma , complement mediated PGE ( 2 ) production was reduced by inhibitors of MAP and ERK kinase 1 ( MEK1 ) and p38 but not JNK .	In GECs that overexpress iPLA (2) gamma, complement mediated PGE (2) production was reduced by inhibitors of MAP and ERK kinase 1 (MEK1) and p38 but not JNK.	18	34	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK1	MEK1	MEK1	24	25	28	29
However , rIL-10 and RA rescued LPS mediated ERK activation in MEK1 deficient macrophages .	However, rIL-10 and RA rescued LPS mediated ERK activation in MEK1 deficient macrophages.	4	13	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	RA rescued LPS mediated ERK	erk	MEK1	MEK1	mek1	8	9	11	12
Activated MEK 1 and MEK 2 go on to phosphorylate and activate their respective substrates ERK 1 ( p44 MAPK ) and ERK2 ( p42 MAPK ) .	Activated MEK 1 and MEK 2 go on to phosphorylate and activate their respective substrates ERK 1 (p44 MAPK) and ERK2 (p42 MAPK).	0	20	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK 1	MEK 1	MEK 1	19	20	1	3
ERK1/2 activity is necessary for mortalin depletion to induce MEK1 upregulation in B-Raf V600E -transformed cancer cells .	ERK1/2 activity is necessary for mortalin depletion to induce MEK1 upregulation in B-Raf V600E -transformed cancer cells.	0	10	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MEK1	MEK1	MEK1	0	1	9	10
To test this possibility , we examined the effects of PD98059 , a specific inhibitor of the ERK1/2 activator MEK-1 , on this effect .	To test this possibility, we examined the effects of PD98059, a specific inhibitor of the ERK1/2 activator MEK-1, on this effect.	14	20	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MEK-1	MEK-1	MEK-1	17	18	19	20
Transfection with MEK1 was used as a positive control for activation , showing that LRRK2 activation of the ERK pathway was comparable in intensity to that of the specific ERK1/2 activator MEK1 ( XREF_FIG ) .	Transfection with MEK1 was used as a positive control for activation, showing that LRRK2 activation of the ERK pathway was comparable in intensity to that of the specific ERK1/2 activator MEK1 (XREF_FIG).	25	33	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MEK1	MEK1	MEK1	29	30	31	32
As seen with the somatic MEK2 mutations described above , doxycycline inducible expression of MEK1 mutations resulted in elevated MEK and ERK phosphyorylation , which was sustained in the presence of drug concentrations that inhibited MAPK signaling in A375 melanoma cells that overexpressed wild-type MEK1 ( XREF_FIG ) .	As seen with the somatic MEK2 mutations described above, doxycycline inducible expression of MEK1 mutations resulted in elevated MEK and ERK phosphyorylation, which was sustained in the presence of drug concentrations that inhibited MAPK signaling in A375 melanoma cells that overexpressed wild-type MEK1 (XREF_FIG).	35	45	overexpressed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MEK1	MEK1	MEK1	35	36	44	45
CDK5 has also been characterized to phosphorylate the ERK activating protein kinase MEK1 in the brain [ XREF_BIBR ] .	CDK5 has also been characterized to phosphorylate the ERK activating protein kinase MEK1 in the brain [XREF_BIBR].	0	17	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	CDK5 has also been characterized to phosphorylate the ERK	erk	MEK1	MEK1	mek1	8	9	12	13
This observation complies with results reported by others showing that a specific inhibitor of the ERK1/2 activator MEK1 blocked gastrin induced anti-apoptosis in AR42J cells [ XREF_BIBR ] .	This observation complies with results reported by others showing that a specific inhibitor of the ERK1/2 activator MEK1 blocked gastrin induced anti-apoptosis in AR42J cells [XREF_BIBR].	12	18	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MEK1	MEK1	MEK1	15	16	17	18
The function of the ERK pathway in bRG formation was tested by expressing the ERK activator Mek1 DD in the E14.5 mouse cortex through in utero electroporation .	The function of the ERK pathway in bRG formation was tested by expressing the ERK activator Mek1 DD in the E14.5 mouse cortex through in utero electroporation.	14	17	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	Mek1	Mek1	Mek1	14	15	16	17
Cells were treated with U0126 , a specific inhibitor of the ERK activating kinases MEK1 and MEK2 .	Cells were treated with U0126, a specific inhibitor of the ERK activating kinases MEK1 and MEK2.	8	16	activating	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK1	MEK1	MEK1	11	12	14	15
However , inhibition of the transient Erk1/2 activity with a specific mitogen activated protein kinase kinase 1 ( MEK-1 ) inhibitor PD 98059 prevented subsequent hypoxia induced proliferation at 18 h. Interestingly , inhibition of general matrix metalloproteinase ( MMP ) activity , using either doxycycline or GM 6001 , prevented both transient Erk1/2 activity and subsequent proliferation in response to hypoxia .	However, inhibition of the transient Erk1/2 activity with a specific mitogen activated protein kinase kinase 1 (MEK-1) inhibitor PD 98059 prevented subsequent hypoxia induced proliferation at 18 h. Interestingly, inhibition of general matrix metalloproteinase (MMP) activity, using either doxycycline or GM 6001, prevented both transient Erk1/2 activity and subsequent proliferation in response to hypoxia.	6	20	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	MEK-1	MEK-1	MEK-1	6	7	18	19
An increase in the activation of ERKs either by overexpressing MEK-1 or treatment of cells with R115777 caused an up-regulation in the levels of a cyclin dependent kinase ( cdk ) inhibitor , p21 ( cip1 and waf1 ) .	An increase in the activation of ERKs either by overexpressing MEK-1 or treatment of cells with R115777 caused an up-regulation in the levels of a cyclin dependent kinase (cdk) inhibitor, p21 (cip1 and waf1).	4	14	overexpressing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERKs	ERKs	ERKs	MEK-1	MEK-1	MEK-1	6	7	10	11
We suggest that Ser ( 407 ) and Thr ( 411 ) are novel residues of Mkk1 activated by these MAPK pathways .	We suggest that Ser (407) and Thr (411) are novel residues of Mkk1 activated by these MAPK pathways.	14	21	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	Mkk1	Mkk1	Mkk1	20	21	16	17
Following serum deprivation , ERK activation in Mek1 +/Y130C and Mek1 Y130C/- MEFs showed a more elevated trend than in Mek1 +/+ cells .	Following serum deprivation, ERK activation in Mek1 +/Y130C and Mek1 Y130C/- MEFs showed a more elevated trend than in Mek1 +/+ cells.	4	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	Mek1	Mek1	Mek1	4	5	7	8
Addition of either PD169316 ( a p38 inhibitor ) or SP600125 ( a JNK inhibitor ) induced formation of domes ( a phenomenon dependent on TJ barrier function ) and enhanced transepithelial electrical resistance , whereas U0126 ( an inhibitor of the ERK1/2 activators MEK1 and MEK2 ) had no significant effect .	Addition of either PD169316 (a p38 inhibitor) or SP600125 (a JNK inhibitor) induced formation of domes (a phenomenon dependent on TJ barrier function) and enhanced transepithelial electrical resistance, whereas U0126 (an inhibitor of the ERK1/2 activators MEK1 and MEK2) had no significant effect.	39	46	activators	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK1/2	ERK1/2	ERK1/2	MEK1	MEK1	MEK1	42	43	44	45
Pretreatment of collagen gel cultures with U0126 , a selective inhibitor of the ERK activators MEK1 and MEK2 [ XREF_BIBR ] , attenuated TGF-beta1-induced branching tubulogenesis in a dose dependent manner , a 63 % inhibition being observed at 20 muM .	Pretreatment of collagen gel cultures with U0126, a selective inhibitor of the ERK activators MEK1 and MEK2 [XREF_BIBR], attenuated TGF-beta1-induced branching tubulogenesis in a dose dependent manner, a 63% inhibition being observed at 20 muM.	10	19	activators	Positive_activation_token_1_verb	Negative_activation	Negative_activation	ERK	ERK	ERK	MEK1	MEK1	MEK1	13	14	15	16
MEK1 drives ERK1/2 activation and T cell proliferation .	MEK1 drives ERK1/2 activation and T cell proliferation.	0	3	drives	Positive_activation_token_1_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MEK1	MEK1	MEK1	2	3	0	1
In U373 , Chinese hamster ovary ( CHO ) , and INS-1 cells , MEK1 was activated by regulators of ERKs , while MEK2 was not .	In U373, Chinese hamster ovary (CHO), and INS-1 cells, MEK1 was activated by regulators of ERKs, while MEK2 was not.	14	21	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERKs	ERKs	ERKs	MEK1	MEK1	MEK1	20	21	14	15
In the present study , we examined the effects of SFN on PDGF induced activation of p70S6K versus 4E-BP1 ( downstream targets of mTOR ) , in conjunction with Akt ( a downstream target of PI 3-kinase ) and ERK1/2 ( a downstream target of MEK1 ) .	In the present study, we examined the effects of SFN on PDGF induced activation of p70S6K versus 4E-BP1 (downstream targets of mTOR), in conjunction with Akt (a downstream target of PI 3-kinase) and ERK1/2 (a downstream target of MEK1).	13	46	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MEK1	MEK1	MEK1	39	40	45	46
In contrast , LPS in the presence of RA or rIL-10 led to ERK activation independent of MEK1 .	In contrast, LPS in the presence of RA or rIL-10 led to ERK activation independent of MEK1.	13	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK1	MEK1	MEK1	13	14	17	18
Confirming drug potency , we observe that upon MEK specific inhibitors U0126 and AZD6244 phosphorylation of ERK1/2 -the target of MEK1- is blocked , while upon multi specific kinase inhibitor Sorafenib MEK1 phosphorylation decreases .	Confirming drug potency, we observe that upon MEK specific inhibitors U0126 and AZD6244 phosphorylation of ERK1/2 -the target of MEK1- is blocked, while upon multi specific kinase inhibitor Sorafenib MEK1 phosphorylation decreases.	11	21	target	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK1/2	U0126 and AZD6244 phosphorylation of ERK1/2	erk1/2	MEK1-	MEK1-	mek1-	16	17	20	21
Activated MEK1 catalyzes the phosphorylation of ERK on Thr183 and Tyr185 XREF_BIBR .	Activated MEK1 catalyzes the phosphorylation of ERK on Thr183 and Tyr185 XREF_BIBR.	0	11	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	phosphorylation of ERK on Thr183	erk	MEK1	MEK1	mek1	6	7	1	2
Here we characterize phosphorylation of the ERK activating protein kinase MEK1 by Cdk5 , ERK , and Cdk1 in vitro in intact mouse brain tissue and in the context of an animal behavioral paradigm of stress .	Here we characterize phosphorylation of the ERK activating protein kinase MEK1 by Cdk5, ERK, and Cdk1 in vitro in intact mouse brain tissue and in the context of an animal behavioral paradigm of stress.	3	28	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	phosphorylation of the ERK	erk	MEK1	MEK1	mek1	6	7	10	11
Of particular relevance , knock-out of the ERK activator MEK1 displaces late endosomes to the periphery [ XREF_BIBR , XREF_BIBR ] .	Of particular relevance, knock-out of the ERK activator MEK1 displaces late endosomes to the periphery [XREF_BIBR, XREF_BIBR].	4	10	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK1	MEK1	MEK1	7	8	9	10
Circumstantial evidence indicates that an ERK like protein may be the downstream target of MEK1 .	Circumstantial evidence indicates that an ERK like protein may be the downstream target of MEK1.	4	15	be the downstream target	Positive_activation_copula_1	Negative_activation	Positive_activation	ERK	ERK	ERK	MEK1	MEK1	MEK1	5	6	14	15
Alternately , increased ERK signaling can also target MITF for degradation .	Alternately, increased ERK signaling can also target MITF for degradation.	3	9	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MITF	MITF	MITF	3	4	8	9
Taken together , these data pre-emptively reveal a potentially significant mechanism of MAPK signaling mediated early acquired resistance to AURKA inhibition , which involves an upregulation of pERK and ERK and the associated downstream pro proliferative ( c-JUN , Cyclin D1 ) and anti-apoptotic ( MITF , Bcl-2 ) molecular signature ( XREF_FIG ) .	Taken together, these data pre-emptively reveal a potentially significant mechanism of MAPK signaling mediated early acquired resistance to AURKA inhibition, which involves an upregulation of pERK and ERK and the associated downstream pro proliferative (c-JUN, Cyclin D1) and anti-apoptotic (MITF, Bcl-2) molecular signature (XREF_FIG).	12	47	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	12	13	45	46
Our data are consistent with previous studies demonstrating that MITF degradation is stimulated by ERK dependent proteasomal degradation , although the mechanism is unclear .	Our data are consistent with previous studies demonstrating that MITF degradation is stimulated by ERK dependent proteasomal degradation, although the mechanism is unclear.	9	17	stimulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MITF	MITF	MITF	14	15	9	10
An additional key post-translational modification on MITF is its phosphorylation by MAPK , which subsequently targets MITF for ubiquitination and proteolysis .	An additional key post-translational modification on MITF is its phosphorylation by MAPK, which subsequently targets MITF for ubiquitination and proteolysis.	9	20	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	11	12	16	17
Altogether , these molecular changes suggested a MAPK signaling mediated program of MITF upregulation and associated resistance .	Altogether, these molecular changes suggested a MAPK signaling mediated program of MITF upregulation and associated resistance.	7	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	7	8	12	13
Conversely , ERK phosphorylation elicits transient activation of MITF followed by its proteasomal degradation .	Conversely, ERK phosphorylation elicits transient activation of MITF followed by its proteasomal degradation.	2	9	elicits	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK phosphorylation	erk	MITF	MITF	mitf	2	3	8	9
Activation of adenylyl cyclase induces cAMP and protein kinase A to activate CREB , and p38 and ERK MAPK pathways activate MITF .	Activation of adenylyl cyclase induces cAMP and protein kinase A to activate CREB, and p38 and ERK MAPK pathways activate MITF.	15	22	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK MAPK	ERK MAPK	ERK MAPK	MITF	MITF	MITF	17	19	21	22
As MITF expression can be reduced by histone deacetylase inhibitors ( HDACi ) [ XREF_BIBR ] , combined HDAC and MAPK inhibition was shown to prevent MITF driven resistance in melanoma cells [ XREF_BIBR ] .	As MITF expression can be reduced by histone deacetylase inhibitors (HDACi) [XREF_BIBR], combined HDAC and MAPK inhibition was shown to prevent MITF driven resistance in melanoma cells [XREF_BIBR].	20	27	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	20	21	26	27
Consistently , a ROS scavenger inhibited ERK phosphorylation and restored MITF degradation .	Consistently, a ROS scavenger inhibited ERK phosphorylation and restored MITF degradation.	3	11	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	ROS scavenger inhibited ERK phosphorylation	erk	MITF	MITF	mitf	6	7	10	11
The activated extracellular signal related kinase ERK and c-Jun N-terminal kinase JNK , the members of the MAPK family , upregulate the transcription activity or ubiquitin dependent degradation of MITF as a feedback mechanism of melanin production .	The activated extracellular signal related kinase ERK and c-Jun N-terminal kinase JNK, the members of the MAPK family, upregulate the transcription activity or ubiquitin dependent degradation of MITF as a feedback mechanism of melanin production.	5	30	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MITF	MITF	MITF	6	7	29	30
It has been recently shown that MAPK activation slows down mitochondrial oxidative metabolism by repressing the MITF and PGC1alpha pathway [ XREF_BIBR ] .	It has been recently shown that MAPK activation slows down mitochondrial oxidative metabolism by repressing the MITF and PGC1alpha pathway [XREF_BIBR].	6	21	slows	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	6	7	16	17
Oncogenic BRAF and ERK may both promote MITF activation and also enhance its degradation XREF_BIBR - XREF_BIBR .	Oncogenic BRAF and ERK may both promote MITF activation and also enhance its degradation XREF_BIBR - XREF_BIBR.	1	8	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MITF	MITF	MITF	3	4	7	8
The relationship between BRAF and MITF is poorly understood since oncogenic BRAF and the ERK pathway promotes MITF activation but also leads to its degradation .	The relationship between BRAF and MITF is poorly understood since oncogenic BRAF and the ERK pathway promotes MITF activation but also leads to its degradation.	14	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MITF	MITF	MITF	14	15	17	18
Moreover , the specific ERK pathway inhibitor , PD98059 , blocked the hypopigmentation effect of SPC , and abrogated the SPC mediated downregulation of MITF .	Moreover, the specific ERK pathway inhibitor, PD98059, blocked the hypopigmentation effect of SPC, and abrogated the SPC mediated downregulation of MITF.	4	25	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MITF	MITF	MITF	4	5	24	25
Phosphorylation of ERK activates MITF to stimulus melanin synthesis .	Phosphorylation of ERK activates MITF to stimulus melanin synthesis.	0	5	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	Phosphorylation of ERK	erk	MITF	MITF	mitf	2	3	4	5
We hypothesized that combined HDAC and MAPK inhibition might prevent cAMP and MITF driven resistance in melanoma cells .	We hypothesized that combined HDAC and MAPK inhibition might prevent cAMP and MITF driven resistance in melanoma cells.	6	13	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	6	7	12	13
It is known that MITF is targeted for degradation after its phosphorylation by Erk1/2 or Akt [ XREF_BIBR , XREF_BIBR ] .	It is known that MITF is targeted for degradation after its phosphorylation by Erk1/2 or Akt [XREF_BIBR, XREF_BIBR].	4	17	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Erk1/2	Erk1/2	Erk1/2	MITF	MITF	MITF	13	14	4	5
Anti-Melanogenic Activities of Heracleum moellendorffii via ERK1/2 Mediated MITF Downregulation .	Anti-Melanogenic Activities of Heracleum moellendorffii via ERK1/2 Mediated MITF Downregulation.	4	9	Mediated	Positive_early_activation	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	MITF	MITF	MITF	6	7	8	9
Treatment with PD98059 , an ERK pathway specific inhibitor , restored liposomal TMP induced reductions in melanin , abrogated reductions in tyrosinase activity , and downregulated MITF and tyrosinase protein .	Treatment with PD98059, an ERK pathway specific inhibitor, restored liposomal TMP induced reductions in melanin, abrogated reductions in tyrosinase activity, and downregulated MITF and tyrosinase protein.	5	29	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MITF	MITF	MITF	5	6	26	27
MAPK pathway modulates the transcription activity of MITF and plays important role in melanin synthesis [ XREF_BIBR , XREF_BIBR ] .	MAPK pathway modulates the transcription activity of MITF and plays important role in melanin synthesis [XREF_BIBR, XREF_BIBR].	0	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	0	1	7	8
ERK and AKT inhibitors attenuated the inhibition of MITF degradation by [ 6 ]-shogaol .	ERK and AKT inhibitors attenuated the inhibition of MITF degradation by [6]-shogaol.	0	9	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	MITF	MITF	MITF	0	1	8	9
Although MAPK signaling has been shown to promote MITF transcriptional activity through its phosphorylation , this post-translational modification also promotes MITF ' s proteasome mediated degradation .	Although MAPK signaling has been shown to promote MITF transcriptional activity through its phosphorylation, this post-translational modification also promotes MITF 's proteasome mediated degradation.	1	10	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	1	2	8	9
Activation of the p38 and ERK MAPK pathways activates MITF , which subsequently induces expression and activation of tyrosinase in zebrafish embryos and B16F10 cells [ XREF_BIBR ] .	Activation of the p38 and ERK MAPK pathways activates MITF, which subsequently induces expression and activation of tyrosinase in zebrafish embryos and B16F10 cells [XREF_BIBR].	5	19	activates	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	ERK MAPK	ERK MAPK	erk mapk	MITF	MITF, which subsequently induces expression and activation of tyrosinase	mitf	5	7	9	10
For example , SCF binds to the c-kit receptor , and MAPK family , ERK1/2 , JNK , and p38 , are activated in the melanocytes , thereby altering MITF activities and functions through phosphorylation or dephosphorylation .	For example, SCF binds to the c-kit receptor, and MAPK family, ERK1/2, JNK, and p38, are activated in the melanocytes, thereby altering MITF activities and functions through phosphorylation or dephosphorylation.	11	30	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	11	12	29	30
Notably , it has previously been reported that ERK is an important regulator of melanogenesis , as ERK phosphorylation induces MITF activation and its following degradation , and thus , inhibits melanin synthesis .	Notably, it has previously been reported that ERK is an important regulator of melanogenesis, as ERK phosphorylation induces MITF activation and its following degradation, and thus, inhibits melanin synthesis.	17	21	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK phosphorylation	erk	MITF	MITF	mitf	17	18	20	21
The MAPK mediated MITF degradation pathways activated by norartocarpetin have not been investigated yet .	The MAPK mediated MITF degradation pathways activated by norartocarpetin have not been investigated yet.	0	12	mediated	Positive_early_activation	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MITF	MITF	MITF	1	2	3	4
TGF-beta1 induced a significant delay in ERK activation and ERK induced down-regulation of Mitf XREF_BIBR .	TGF-beta1 induced a significant delay in ERK activation and ERK induced down-regulation of Mitf XREF_BIBR.	6	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	Mitf	Mitf	Mitf	6	7	13	14
LXRs are upregulated in melanocytes from perilesional skin of vitiligo patients [ XREF_BIBR ] , and LXR activation could inhibit the melanogenesis in human primary melanocytes and murine B16 melanoma cells by downregulating melanogenic enzymes through Ras- and ERK induced MITF degradation [ XREF_BIBR ] .	LXRs are upregulated in melanocytes from perilesional skin of vitiligo patients [XREF_BIBR], and LXR activation could inhibit the melanogenesis in human primary melanocytes and murine B16 melanoma cells by downregulating melanogenic enzymes through Ras- and ERK induced MITF degradation [XREF_BIBR].	32	41	induced	Positive_early_activation	Negative_activation	Positive_activation	ERK	ERK	ERK	MITF	MITF	MITF	38	39	40	41
By using and comparing HEK293T cells with and without stable expression of Flag tagged full-length PC1 , we found that either PKR knockdown or mutant K296R over-expression abolishes the down-regulation of P-eIF2alpha by WT PC1 .	By using and comparing HEK293T cells with and without stable expression of Flag tagged full-length PC1, we found that either PKR knockdown or mutant K296R over-expression abolishes the down-regulation of P-eIF2alpha by WT PC1.	21	32	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PKR	PKR	PKR	P-eIF2alpha	P-eIF2alpha	P-eIF2alpha	21	22	31	32
We tested an inhibitor of the cytosolic PKR ( PKRi ) , which had no effect on the eIF2alpha-P level in STHdh Q111/111 cells , nor on the Tun induced eIF2alpha-P , but did inhibit eIF2alpha phosphorylation cause by the PKR activator poly-I : C.	We tested an inhibitor of the cytosolic PKR (PKRi), which had no effect on the eIF2alpha-P level in STHdh Q111/111 cells, nor on the Tun induced eIF2alpha-P, but did inhibit eIF2alpha phosphorylation cause by the PKR activator poly-I : C.	3	31	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF2alpha-P	eIF2alpha-P	eIF2alpha-P	7	8	30	31
Also we did not find any significant differences in the level of eIF2alpha and phosphorylated eIF2alpha between 2HDD4 cells and naive cells , suggesting that the phosphorlyation of eIF2alpha mediated by PKR activation mainly functions on the host against HCV infection at the early phase of viral infection .	Also we did not find any significant differences in the level of eIF2alpha and phosphorylated eIF2alpha between 2HDD4 cells and naive cells, suggesting that the phosphorlyation of eIF2alpha mediated by PKR activation mainly functions on the host against HCV infection at the early phase of viral infection.	26	32	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	31	32	28	29
The UPR is a protective mechanism that is activated by phosphorylation of PKR like endoplasmic reticulum kinase ( PERK ) , inositol requiring enzyme-1 ( IRE-1 ) , and eukaryotic translation initiation factor 2alpha ( eIF2alpha ) .	The UPR is a protective mechanism that is activated by phosphorylation of PKR like endoplasmic reticulum kinase (PERK), inositol requiring enzyme-1 (IRE-1), and eukaryotic translation initiation factor 2alpha (eIF2alpha).	8	36	activated	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	PKR	phosphorylation of PKR	pkr	eIF2alpha	eIF2alpha	eif2alpha	12	13	35	36
The protein kinase PKR is activated by RNA with double stranded ( ds ) structure and subsequently impairs translation through phosphorylation of protein synthesis initiation factor eIF-2alpha .	The protein kinase PKR is activated by RNA with double stranded (ds) structure and subsequently impairs translation through phosphorylation of protein synthesis initiation factor eIF-2alpha.	0	27	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKR	PKR	PKR	eIF-2alpha	eIF-2alpha	eIF-2alpha	3	4	26	27
We further performed a longer kinetics over a few hours ( 0 , 4 , 6 , 8 , 12 and 24 h ) and found that HBx-siRNA promoted the phosphorylation of PKR until 6 h and enhanced the activation of eIF2-alpha until 12 h post-transfection ( XREF_FIG ) , while the scramble siRNA showed a weak activation of PKR ( XREF_FIG ) .	We further performed a longer kinetics over a few hours (0, 4, 6, 8, 12 and 24 h) and found that HBx-siRNA promoted the phosphorylation of PKR until 6 h and enhanced the activation of eIF2-alpha until 12 h post-transfection (XREF_FIG), while the scramble siRNA showed a weak activation of PKR (XREF_FIG).	27	42	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKR	HBx-siRNA promoted the phosphorylation of PKR	pkr	eIF2-alpha	eIF2-alpha	eif2-alpha	32	33	41	42
Free fatty acids stimulate autophagy through EIF2AK2 and PKR dependent activation of EIF2S1 and eIF2alpha , MAPK8 ( mitogen activated protein kinase 8 ) or inhibition of MTORC1 .	Free fatty acids stimulate autophagy through EIF2AK2 and PKR dependent activation of EIF2S1 and eIF2alpha, MAPK8 (mitogen activated protein kinase 8) or inhibition of MTORC1.	6	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	EIF2AK2	EIF2AK2	EIF2AK2	eIF2alpha	eIF2alpha	eIF2alpha	6	7	14	15
Thus , it is unlikely that P-eIF2alpha was induced by P-PKR in these cell lines .	Thus, it is unlikely that P-eIF2alpha was induced by P-PKR in these cell lines.	6	14	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	P-PKR	P-PKR	P-PKR	P-eIF2alpha	P-eIF2alpha	P-eIF2alpha	10	11	6	7
BACE1 translation may also be upregulated by oxidative stress via protein kinase R ( PKR ) , which promotes eIF2alpha mediated translational de-repression , and also activates JNK [ XREF_BIBR ] .	BACE1 translation may also be upregulated by oxidative stress via protein kinase R (PKR), which promotes eIF2alpha mediated translational de-repression, and also activates JNK [XREF_BIBR].	12	22	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	14	15	19	20
PKR inhibition reduces eIF2alpha activation in TD .	PKR inhibition reduces eIF2alpha activation in TD.	0	4	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PKR	PKR	PKR	eIF2alpha	eIF2alpha	eIF2alpha	0	1	3	4
This effect is caused by the reduction of the PKR ( protein kinase regulated by RNA ) activation and phoshorylation of the PKR-substrate eIF-2alpha mediated by the ectopic ADAR1 expression .	This effect is caused by the reduction of the PKR (protein kinase regulated by RNA) activation and phoshorylation of the PKR-substrate eIF-2alpha mediated by the ectopic ADAR1 expression.	6	24	activation	Positive_activation_syntax_7_noun	Negative_activation	Negative_activation	PKR	PKR	PKR	eIF-2alpha	eIF-2alpha	eIF-2alpha	9	10	23	24
Taken together , our data suggest that PC1 inhibits PKR phosphorylation through which it down-regulates the eIF2alpha activity .	Taken together, our data suggest that PC1 inhibits PKR phosphorylation through which it down-regulates the eIF2alpha activity.	7	17	down-regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PKR	PC1 inhibits PKR phosphorylation	pkr	eIF2alpha	eIF2alpha	eif2alpha	9	10	16	17
As already noted , other kinases capable of sensing cell stress , including GCN2 and interferon induced double stranded RNA dependent protein kinase R ( PKR ) , can also activate eIF2alpha in response to conditions like amino acid deprivation and viral infection .	As already noted, other kinases capable of sensing cell stress, including GCN2 and interferon induced double stranded RNA dependent protein kinase R (PKR), can also activate eIF2alpha in response to conditions like amino acid deprivation and viral infection.	21	33	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	protein kinase R	protein kinase R	protein kinase R	eIF2alpha	eIF2alpha	eIF2alpha	21	24	31	32
We therefore propose a model where prolonged ERK activation results in caspase-8 activation , leading to cleavage of BID to tBID , which facilitates Bax induced mitochondrial permeablization , caspase-9 activation , and cell death .	We therefore propose a model where prolonged ERK activation results in caspase-8 activation, leading to cleavage of BID to tBID, which facilitates Bax induced mitochondrial permeablization, caspase-9 activation, and cell death.	7	13	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	ERK	ERK	ERK	caspase-8	caspase-8	caspase-8	7	8	11	12
Next , we examined whether phosphorylation at the S387 residue by P-ERK modulates caspase-8 dimerization .	Next, we examined whether phosphorylation at the S387 residue by P-ERK modulates caspase-8 dimerization.	9	14	modulates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	P-ERK	P-ERK	P-ERK	caspase-8	caspase-8	caspase-8	11	12	13	14
Consistently , inhibition of ERK or JNK alone partially inhibited , whereas combined inhibition of ERK and JNK completely eliminated both caspase-1 and caspase-8 activation ( XREF_FIG ) .	Consistently, inhibition of ERK or JNK alone partially inhibited, whereas combined inhibition of ERK and JNK completely eliminated both caspase-1 and caspase-8 activation (XREF_FIG).	13	24	eliminated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	caspase-8	caspase-8	caspase-8	15	16	23	24
Furthermore , ERK activity can promote either intrinsic or extrinsic apoptotic pathways by inducing mitochondrial cytochrome c release or caspase-8 activation , permanent cell cycle arrest , and/or autophagic vacuolization [ XREF_BIBR ] .	Furthermore, ERK activity can promote either intrinsic or extrinsic apoptotic pathways by inducing mitochondrial cytochrome c release or caspase-8 activation, permanent cell cycle arrest, and/or autophagic vacuolization [XREF_BIBR].	2	20	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	caspase-8	caspase-8	caspase-8	2	3	19	20
We have demonstrated that Vpr induces ERK dependent activation of caspase-8 , leading to cleavage of BID to tBID , and ultimately , caspase-9 activation and apoptosis .	We have demonstrated that Vpr induces ERK dependent activation of caspase-8, leading to cleavage of BID to tBID, and ultimately, caspase-9 activation and apoptosis.	6	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	caspase-8	caspase-8	caspase-8	6	7	10	11
Recently , we found that fisetin also induces apoptotic cell death through the ERK1/2 mediated activation of the caspase-8 and caspase-3-dependent pathway in HeLa human cervical adenocarcinoma cells [ XREF_BIBR ] .	Recently, we found that fisetin also induces apoptotic cell death through the ERK1/2 mediated activation of the caspase-8 and caspase-3-dependent pathway in HeLa human cervical adenocarcinoma cells [XREF_BIBR].	13	19	mediated	Positive_early_activation	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	caspase-8	caspase-8	caspase-8	13	14	18	19
Accordingly , prolonged ERK stimulation activated caspase 8 and strongly potentiated Fas signaling .	Accordingly, prolonged ERK stimulation activated caspase 8 and strongly potentiated Fas signaling.	3	8	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	caspase 8	caspase 8	caspase 8	3	4	6	8
Combined ERK and JNK activation ( activated downstream of TPL2 ) were similarly required for NOD2 induced caspase-1 and caspase-8 activation ; rescuing ERK and JNK activation in TPL2 deficient MDMs restored early IL-1beta and IL-18 secretion and long-term secretion of additional cytokines .	Combined ERK and JNK activation (activated downstream of TPL2) were similarly required for NOD2 induced caspase-1 and caspase-8 activation; rescuing ERK and JNK activation in TPL2 deficient MDMs restored early IL-1beta and IL-18 secretion and long-term secretion of additional cytokines.	0	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	caspase-8	caspase-8	caspase-8	1	2	19	20
However , inhibition of ERK by PD98059 reversed oridonin induced cell death as well as the activation of caspase 8 , indicating that ERK mediated control occured upstream of caspase 8 .	However, inhibition of ERK by PD98059 reversed oridonin induced cell death as well as the activation of caspase 8, indicating that ERK mediated control occured upstream of caspase 8.	2	20	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	caspase 8	caspase 8	caspase 8	4	5	18	20
In conclusion , at least 2 pathways appear activated by cadmium in osteoblasts : a direct induction of caspase-8 followed by activation of caspase-3 and an indirect induction by phosphorylation of ERK1/2 , p38 , and JNK MAPK triggering activation of caspase-8 and -3 .	In conclusion, at least 2 pathways appear activated by cadmium in osteoblasts : a direct induction of caspase-8 followed by activation of caspase-3 and an indirect induction by phosphorylation of ERK1/2, p38, and JNK MAPK triggering activation of caspase-8 and -3.	29	43	triggering	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	phosphorylation of ERK1/2	erk1/2	caspase-8	caspase-8	caspase-8	31	32	41	42
In addition , MGRX mediated inhibition of [ Formula : see text ] 1 integrin attenuates ERK phosphorylation ( p-ERK ) , which up-regulates caspase-8 and Bax .	In addition, MGRX mediated inhibition of [Formula : see text] 1 integrin attenuates ERK phosphorylation (p-ERK), which up-regulates caspase-8 and Bax.	14	26	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	integrin attenuates ERK phosphorylation	erk	caspase-8	caspase-8	caspase-8	16	17	24	25
Similar to our findings Cagnol et al ., in their study reported that prolonged activation of ERK1/2 induces FADD independent caspase-8 activation and cell death [ XREF_BIBR ] .	Similar to our findings Cagnol et al., in their study reported that prolonged activation of ERK1/2 induces FADD independent caspase-8 activation and cell death [XREF_BIBR].	14	21	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	caspase-8	caspase-8	caspase-8	16	17	20	21
These findings reveal that prolonged ERK and MAPK stimulation results in caspase 8 activation and cell death .	These findings reveal that prolonged ERK and MAPK stimulation results in caspase 8 activation and cell death.	4	14	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	ERK	ERK	ERK	caspase 8	caspase 8	caspase 8	5	6	11	13
Our results clearly demonstrate that ASK1 , and Fas-p38 MAPK mediated caspase-8 dependent pathways are involved in apoptotic cell death provoked by the pore forming enterotoxin Nhe .	Our results clearly demonstrate that ASK1, and Fas-p38 MAPK mediated caspase-8 dependent pathways are involved in apoptotic cell death provoked by the pore forming enterotoxin Nhe.	5	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	caspase-8	caspase-8	caspase-8	9	10	11	12
Acute Eps15 inhibition in mammalian cell lines impairs EGFR and transferrin receptor endocytosis , but deletion of Eps15 in murine fibroblasts fails to affect these pathways , suggesting that other proteins can compensate for its prolonged absence .	Acute Eps15 inhibition in mammalian cell lines impairs EGFR and transferrin receptor endocytosis, but deletion of Eps15 in murine fibroblasts fails to affect these pathways, suggesting that other proteins can compensate for its prolonged absence.	1	12	impairs	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Eps15	Eps15	Eps15	EGFR	EGFR	EGFR	1	2	8	9
A molecular circuitry was proposed whereby EPS15 and EPS15R mediate internalization of activated EGFR to stimulate receptor recycling , therefore responding to mitogenic signalling of EGF [ XREF_BIBR ] .	A molecular circuitry was proposed whereby EPS15 and EPS15R mediate internalization of activated EGFR to stimulate receptor recycling, therefore responding to mitogenic signalling of EGF [XREF_BIBR].	6	14	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	EPS15	EPS15	EPS15	EGFR	EGFR	EGFR	6	7	13	14
Indeed , the interaction of EPS15 and EGFR is reduced in SPOPL depleted cells ( XREF_FIG ) , while the interaction of EPS15 and HRS is stabilized ( XREF_FIG ) , consistent with the idea that EPS15 ubiquitination promotes EGFR stabilization .	Indeed, the interaction of EPS15 and EGFR is reduced in SPOPL depleted cells (XREF_FIG), while the interaction of EPS15 and HRS is stabilized (XREF_FIG), consistent with the idea that EPS15 ubiquitination promotes EGFR stabilization.	36	40	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	EPS15	EPS15 ubiquitination	eps15	EGFR	EGFR	egfr	36	37	39	40
Silencing of EPS15 expression reduces the endocytosis of EGFR and transferrin moderately 68 .	Silencing of EPS15 expression reduces the endocytosis of EGFR and transferrin moderately 68.	2	10	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	EPS15	EPS15 expression	eps15	EGFR	EGFR	egfr	2	3	8	9
Finally , we investigated why loss of SPOPL mediated ubiquitination of EPS15 increased EGFR degradation in lysosomes .	Finally, we investigated why loss of SPOPL mediated ubiquitination of EPS15 increased EGFR degradation in lysosomes.	5	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	EPS15	loss of SPOPL mediated ubiquitination of EPS15	eps15	EGFR	EGFR	egfr	11	12	13	14
It should be noted , however , that the described Eps15 mediated internalization of the EGFR is not the only mechanism for EGFR internalization .	It should be noted, however, that the described Eps15 mediated internalization of the EGFR is not the only mechanism for EGFR internalization.	8	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Eps15	Eps15	Eps15	EGFR	EGFR	EGFR	10	11	15	16
In this paper , we have investigated the function of Eps15 in the ligand induced endocytosis of the EGF receptor .	In this paper, we have investigated the function of Eps15 in the ligand induced endocytosis of the EGF receptor.	8	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Eps15	Eps15	Eps15	EGF receptor	EGF receptor	EGF receptor	10	11	18	20
Importantly , although reexpression of myc-Eps15 in siRNA treated cells did not rescue the inhibited EGFR degradation , reintroducing low levels of Eps15b to these cells did ( XREF_FIG ) .	Importantly, although reexpression of myc-Eps15 in siRNA treated cells did not rescue the inhibited EGFR degradation, reintroducing low levels of Eps15b to these cells did (XREF_FIG).	3	16	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myc-Eps15	reexpression of myc-Eps15	myc-eps15	EGFR	EGFR	egfr	5	6	15	16
Interestingly , PTPN3 mediated tyrosine dephosphorylation of Eps15 promotes EGFR for lipid raft mediated endocytosis and lysosomal degradation .	Interestingly, PTPN3 mediated tyrosine dephosphorylation of Eps15 promotes EGFR for lipid raft mediated endocytosis and lysosomal degradation.	2	13	promotes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Eps15	PTPN3 mediated tyrosine dephosphorylation of Eps15	eps15	EGFR	EGFR	egfr	7	8	9	10
CSB stimulates the AP site incision activity of APE1 on normal ( i.e. fully paired ) and bubble AP-DNA substrates , with the latter being more pronounced ( up to 6-fold ) .	CSB stimulates the AP site incision activity of APE1 on normal (i.e. fully paired) and bubble AP-DNA substrates, with the latter being more pronounced (up to 6-fold).	0	19	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CSB	CSB	CSB	APE1	APE1	APE1	0	1	8	9
We next examined whether CSB could stimulate the endonuclease activity of a truncated APE1 protein lacking the first 29 amino acid residues ( i.e. Delta29APE1 ) .	We next examined whether CSB could stimulate the endonuclease activity of a truncated APE1 protein lacking the first 29 amino acid residues (i.e. Delta29APE1).	4	14	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CSB	CSB	CSB	APE1	APE1	APE1	4	5	13	14
Interestingly , it was found that the incision activity of APE1 was more pronounced when the AP site was located in a transcription bubble , suggesting that CSB may preferentially stimulate APE1 activity in regions of active transcription .	Interestingly, it was found that the incision activity of APE1 was more pronounced when the AP site was located in a transcription bubble, suggesting that CSB may preferentially stimulate APE1 activity in regions of active transcription.	27	32	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CSB	CSB	CSB	APE1	APE1	APE1	27	28	31	32
Notably , addition of ATP did not affect the CSB stimulation of APE1 ( XREF_FIG C ) .	Notably, addition of ATP did not affect the CSB stimulation of APE1 (XREF_FIG C).	9	15	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	CSB	CSB	CSB	APE1	APE1	APE1	9	10	12	13
We also found that CSB stimulates APE1 AP site incision activity on abasic site containing DNA substrates -- in an ATP independent , species specific manner ( no activation of E. coli endonuclease IV was observed by CSB ) -- likely via a direct interaction with the N-terminal ' REF-1 region ' of APE1 .	We also found that CSB stimulates APE1 AP site incision activity on abasic site containing DNA substrates -- in an ATP independent, species specific manner (no activation of E. coli endonuclease IV was observed by CSB) -- likely via a direct interaction with the N-terminal ' REF-1 region ' of APE1.	4	10	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CSB	CSB	CSB	APE1	APE1	APE1	4	5	6	7
Furthermore , CSB is able to stimulate Ape1 AP site incision XREF_BIBR and elongation of RNA polymerase I XREF_BIBR in an ATP independent manner , indicating ATP independent functions of CSB in DNA repair and transcription .	Furthermore, CSB is able to stimulate Ape1 AP site incision XREF_BIBR and elongation of RNA polymerase I XREF_BIBR in an ATP independent manner, indicating ATP independent functions of CSB in DNA repair and transcription.	2	8	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CSB	CSB	CSB	Ape1	Ape1	Ape1	2	3	7	8
In addition , CSB stimulates the AP site incision activity of APE1 in an ATP independent manner .	In addition, CSB stimulates the AP site incision activity of APE1 in an ATP independent manner.	3	16	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CSB	CSB	CSB	APE1	APE1	APE1	3	4	11	12
The phosphorylation of eEF2 at threonine ( Thr ) 56 by eEF2K causes eEF2 to release from the ribosome , halting translation elongation of most proteins [ XREF_BIBR , XREF_BIBR ] .	The phosphorylation of eEF2 at threonine (Thr) 56 by eEF2K causes eEF2 to release from the ribosome, halting translation elongation of most proteins [XREF_BIBR, XREF_BIBR].	9	14	causes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	11	12	13	14
S6K also phosphorylates and inhibits the eukaryotic elongation factor 2 ( eEF2 ) kinase ( eEF2K ) , thereby relieving the inhibition of eEF2 by eEF2K and enhancing translation elongation [ XREF_BIBR , XREF_BIBR ] .	S6K also phosphorylates and inhibits the eukaryotic elongation factor 2 (eEF2) kinase (eEF2K), thereby relieving the inhibition of eEF2 by eEF2K and enhancing translation elongation [XREF_BIBR, XREF_BIBR].	19	26	inhibition	Negative_activation_token_2_noun	Negative_activation	Positive_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	25	26	23	24
S6K1 also plays a key role in translational elongation , phosphorylating eukaryotic elongation factor 2 kinase ( eEF2K ) , allowing eEF2 to continue translational elongation .	S6K1 also plays a key role in translational elongation, phosphorylating eukaryotic elongation factor 2 kinase (eEF2K), allowing eEF2 to continue translational elongation.	0	23	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	eukaryotic elongation factor 2 kinase	S6K1 also plays a key role in translational elongation, phosphorylating eukaryotic elongation factor 2 kinase	eukaryotic elongation factor 2 kinase	eEF2	eEF2	eef2	11	16	21	22
eEF2K negatively regulates translation elongation by repressing eukaryotic elongation factor 2 ( eEF2 ) .	eEF2K negatively regulates translation elongation by repressing eukaryotic elongation factor 2 (eEF2).	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF2K	eEF2K	eEF2K	elongation factor 2	elongation factor 2	elongation factor 2	0	1	8	11
eEF-2K inhibits translation by phosphorylating , and thereby blocking the ability of elongation factor 2 ( eEF-2 ) to bind the ribosome .	eEF-2K inhibits translation by phosphorylating, and thereby blocking the ability of elongation factor 2 (eEF-2) to bind the ribosome.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	eEF-2K	eEF-2K	eEF-2K	elongation factor 2	elongation factor 2	elongation factor 2	0	1	12	15
We observed that inhibition of expression of eEF2K abolished the increase of phospho-eEF2 induced by RPS19 depletion , indicating that eEF2K is indeed responsible for the phosphorylation of eEF2 in this setting .	We observed that inhibition of expression of eEF2K abolished the increase of phospho-eEF2 induced by RPS19 depletion, indicating that eEF2K is indeed responsible for the phosphorylation of eEF2 in this setting.	5	13	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	eEF2K	expression of eEF2K	eef2k	phospho-eEF2	phospho-eEF2	phospho-eef2	7	8	12	13
Importantly , suppression of eEF2K and subsequent reactivation of eEF2 significantly increases the rate of protein synthesis rates in cooled cells [ XREF_BIBR ] , consistent with the concept that elongation is a major regulatory node under specific pathophysiological conditions [ XREF_BIBR , XREF_BIBR ] .	Importantly, suppression of eEF2K and subsequent reactivation of eEF2 significantly increases the rate of protein synthesis rates in cooled cells [XREF_BIBR], consistent with the concept that elongation is a major regulatory node under specific pathophysiological conditions [XREF_BIBR, XREF_BIBR].	4	10	reactivation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	eEF2K	eEF2K	eEF2K	eEF2	eEF2	eEF2	4	5	9	10
Only one of the 4 siRNAs targeting the Eukaryotic Elongation Factor-2 Kinase ( EEF2K ) resulted in increased tetraploidy indicating an off-target effect .	Only one of the 4 siRNAs targeting the Eukaryotic Elongation Factor-2 Kinase (EEF2K) resulted in increased tetraploidy indicating an off-target effect.	1	14	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	EEF2K	EEF2K	EEF2K	Elongation Factor-2	Elongation Factor-2	Elongation Factor-2	13	14	9	11
We have thus uncovered a previously unknown mechanism of down-regulation of Cic activity by Mnb and Wap , which operates independently from the ERK mediated control of Cic .	We have thus uncovered a previously unknown mechanism of down-regulation of Cic activity by Mnb and Wap, which operates independently from the ERK mediated control of Cic.	19	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	Cic	Cic	Cic	23	24	27	28
These effects are consistent with the model , where anteriorly localized Bcd acts as a competitive inhibitor of MAPK mediated Cic downregulation .	These effects are consistent with the model, where anteriorly localized Bcd acts as a competitive inhibitor of MAPK mediated Cic downregulation.	16	21	mediated	Positive_early_activation	Negative_activation	Negative_activation	MAPK	MAPK	MAPK	Cic	Cic	Cic	18	19	20	21
Since growth factor stimulation can promote ERK mediated CIC suppression XREF_BIBR - XREF_BIBR , we monitored nuclear CIC expression with time-lapse microscopy in H1975 M1 cells expressing CIC-GFP during epidermal growth factor ( EGF )-stimulated ERK activation .	Since growth factor stimulation can promote ERK mediated CIC suppression XREF_BIBR - XREF_BIBR, we monitored nuclear CIC expression with time-lapse microscopy in H1975 M1 cells expressing CIC-GFP during epidermal growth factor (EGF)-stimulated ERK activation.	5	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	ERK	ERK	ERK	CIC	CIC	CIC	6	7	8	9
These data suggest that ERK mediated CIC suppression de-represses the ETV4-MMP24 axis to enhance metastasis in LAs with hyperactive MAPK signaling , augmenting the role of CIC in NSCLC progression beyond those tumors with genetically altered CIC .	These data suggest that ERK mediated CIC suppression de-represses the ETV4-MMP24 axis to enhance metastasis in LAs with hyperactive MAPK signaling, augmenting the role of CIC in NSCLC progression beyond those tumors with genetically altered CIC.	4	7	mediated	Positive_early_activation	Negative_activation	Negative_activation	ERK	ERK	ERK	CIC	CIC	CIC	4	5	6	7
Furthermore , we found that Cic , a transcriptional repressor that is degraded as a consequence of its phosphorylation by MAPK 24 , is significantly downregulated at the ventral side of the embryo ( data not shown ) , supporting the notion that the ventrally activated MAPK contributes to DV patterning .	Furthermore, we found that Cic, a transcriptional repressor that is degraded as a consequence of its phosphorylation by MAPK 24, is significantly downregulated at the ventral side of the embryo (data not shown), supporting the notion that the ventrally activated MAPK contributes to DV patterning.	5	25	degraded	Negative_activation_syntax_6_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	Cic	Cic	Cic	20	21	5	6
Since MAPK signaling mediated suppression of CIC is a predominant mode of CIC inactivation in LA , we stratified TCGA LAs by K-Ras mutant versus K-Ras wild-type , yielding 79 DE genes ( absolute log2 fold change > 0.79 , FDR < 0.10 ) ( XREF_SUPPLEMENTARY ) .	Since MAPK signaling mediated suppression of CIC is a predominant mode of CIC inactivation in LA, we stratified TCGA LAs by K-Ras mutant versus K-Ras wild-type, yielding 79 DE genes (absolute log2 fold change> 0.79, FDR < 0.10) (XREF_SUPPLEMENTARY).	1	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	CIC	CIC	CIC	1	2	12	13
These data indicate that MAPK mediated FGFR1 signaling plays an important role in the regulation of brachyury .	These data indicate that MAPK mediated FGFR1 signaling plays an important role in the regulation of brachyury.	4	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	FGFR1	FGFR1	FGFR1	4	5	6	7
Altered gene expression patterns support activation of several oncogenic signaling pathways in the aggressive subgroup including fibroblast growth factor receptor ( FGFR ) signaling ( upregulation of FGF1 and FGFR1 , downregulation of SPRY4 and SPRED2 ) , MAPK and PI3K signaling ( upregulation of HRAS and NRAS , downregulation of PTEN ) , and deregulation of small G proteins with a focus on Rap1 family members ( upregulation of SIPA1 , downregulation of RapGEF1 and RapGEF2 ) , mitosis effectors ( AURKA , INCENP ) and invasion and adhesion regulation ( ITGAV , MMP9 , MMP19 ) .	Altered gene expression patterns support activation of several oncogenic signaling pathways in the aggressive subgroup including fibroblast growth factor receptor (FGFR) signaling (upregulation of FGF1 and FGFR1, downregulation of SPRY4 and SPRED2), MAPK and PI3K signaling (upregulation of HRAS and NRAS, downregulation of PTEN), and deregulation of small G proteins with a focus on Rap1 family members (upregulation of SIPA1, downregulation of RapGEF1 and RapGEF2), mitosis effectors (AURKA, INCENP) and invasion and adhesion regulation (ITGAV, MMP9, MMP19).	25	41	upregulation	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	FGFR1	FGFR1	FGFR1	38	39	29	30
These data demonstrate that MAPK mediates the regulation of FGFR1 in brachyury activation .	These data demonstrate that MAPK mediates the regulation of FGFR1 in brachyury activation.	4	12	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	FGFR1	FGFR1	FGFR1	4	5	9	10
However , the exact cellular and molecular mechanisms linking the anti-differentiation effect and the notch pathway in MAPK signaling the under activation of FGFR1 remain to be investigated .	However, the exact cellular and molecular mechanisms linking the anti-differentiation effect and the notch pathway in MAPK signaling the under activation of FGFR1 remain to be investigated.	15	24	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	FGFR1	FGFR1	FGFR1	17	18	23	24
We found that BGJ398 , an FGFR inhibitor , effectively inhibited phosphorylation of FGFR1 and MEK and ERK signaling in FGFR1 amplified breast cancer without affecting tumor cell proliferation .	We found that BGJ398, an FGFR inhibitor, effectively inhibited phosphorylation of FGFR1 and MEK and ERK signaling in FGFR1 amplified breast cancer without affecting tumor cell proliferation.	17	21	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	FGFR1	FGFR1	FGFR1	17	18	20	21
Interestingly , inhibition of MAPK and PLCgamma pathways , but not PI3K and Akt pathways , blocked FGFR1 stimulation of FGF23-promoter activity in cultured osteoblasts .	Interestingly, inhibition of MAPK and PLCgamma pathways, but not PI3K and Akt pathways, blocked FGFR1 stimulation of FGF23-promoter activity in cultured osteoblasts.	4	18	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	FGFR1	FGFR1	FGFR1	4	5	17	18
Thus , it can be concluded that ENPP1 inhibits IR by blocking the conformational change of IR upon insulin binding .	Thus, it can be concluded that ENPP1 inhibits IR by blocking the conformational change of IR upon insulin binding.	7	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ENPP1	ENPP1	ENPP1	IR	IR	IR	7	8	9	10
In addition to the catalytic activity of ENPP1 , ENPP1 has been found to modulate insulin receptor activity and glucose homeostasis ( reviewed in 57 ) .	In addition to the catalytic activity of ENPP1, ENPP1 has been found to modulate insulin receptor activity and glucose homeostasis (reviewed in 57).	9	17	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ENPP1	ENPP1	ENPP1	insulin receptor	insulin receptor	insulin receptor	9	10	15	17
Ectonucleotide pyrophosphatase ( ENPP1 ) negatively modulates insulin receptor activation and plays a role in insulin signaling , insulin secretion , and glucose metabolism [ XREF_BIBR - XREF_BIBR ] .	Ectonucleotide pyrophosphatase (ENPP1) negatively modulates insulin receptor activation and plays a role in insulin signaling, insulin secretion, and glucose metabolism [XREF_BIBR - XREF_BIBR].	1	9	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ENPP1	ENPP1	ENPP1	insulin receptor	insulin receptor	insulin receptor	3	4	7	9
An additional finding of this study , which is entirely novel , is that ENPP1 expression induces defective IR activation , reduced insulin secretion upon stimulation of both glucose and glyburide , and increased susceptibility to apoptosis in pancreatic beta-cells ; also in most of these circumstances , the Q121 variant behaves as a gain of function aminoacid substitution .	An additional finding of this study, which is entirely novel, is that ENPP1 expression induces defective IR activation, reduced insulin secretion upon stimulation of both glucose and glyburide, and increased susceptibility to apoptosis in pancreatic beta-cells; also in most of these circumstances, the Q121 variant behaves as a gain of function aminoacid substitution.	14	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ENPP1	ENPP1 expression	enpp1	IR	IR	ir	14	15	18	19
Therefore , the results of our study support the new hypothesis that inheritance of the common genetic variant ENPP1 K121Q , a gain of function on the ENPP1 induced insulin receptor inhibition XREF_BIBR , would predispose individuals to decreased ability in forming mature adipocyte when storage of excessive energy intake is needed .	Therefore, the results of our study support the new hypothesis that inheritance of the common genetic variant ENPP1 K121Q, a gain of function on the ENPP1 induced insulin receptor inhibition XREF_BIBR, would predispose individuals to decreased ability in forming mature adipocyte when storage of excessive energy intake is needed.	24	32	induced	Positive_early_activation	Negative_activation	Positive_activation	ENPP1	ENPP1	ENPP1	insulin receptor	insulin receptor	insulin receptor	27	28	29	31
The fact that HGF is highly expressed in the case of H23 cells strengthens our claims that ERK induces positive regulation of GAB1 for associating with P85-PI3K via HGF mediation under normal conditions , disruption of which deactivates PI3K and AKT pathway XREF_BIBR XREF_BIBR .	The fact that HGF is highly expressed in the case of H23 cells strengthens our claims that ERK induces positive regulation of GAB1 for associating with P85-PI3K via HGF mediation under normal conditions, disruption of which deactivates PI3K and AKT pathway XREF_BIBR XREF_BIBR.	17	23	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	GAB1	GAB1	GAB1	17	18	22	23
In contrast with some cell systems , but consistent with some others , this did not occur through enhanced MAPK pathway activation , supporting the likelihood that MAPK mediation of Gab1 mitogenic signaling is cell specific .	In contrast with some cell systems, but consistent with some others, this did not occur through enhanced MAPK pathway activation, supporting the likelihood that MAPK mediation of Gab1 mitogenic signaling is cell specific.	27	32	mediation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	Gab1	Gab1	Gab1	27	28	30	31
The negative feedback loop involves the negative effect of Akt on Raf1 ; the positive feedback loop is mediated by PI3K activated Gab1 that strengths the MAPK activation via Rac and PAK .	The negative feedback loop involves the negative effect of Akt on Raf1; the positive feedback loop is mediated by PI3K activated Gab1 that strengths the MAPK activation via Rac and PAK.	21	27	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	Gab1	Gab1	Gab1	26	27	22	23
Myocardial EPO content was restored after EPO treatment , which in turn recruited signal transducer and activator of transcription ( STAT ) 3 protein and induced ERK signaling downstream of Jak2 , which increased arginase II levels and suppressed HSP90 expression , respectively .	Myocardial EPO content was restored after EPO treatment, which in turn recruited signal transducer and activator of transcription (STAT) 3 protein and induced ERK signaling downstream of Jak2, which increased arginase II levels and suppressed HSP90 expression, respectively.	14	41	signaling	Positive_regulation_syntax_7_noun	Negative_activation	Positive_regulation	ERK	ERK	erk	Jak2	Jak2, which increased arginase II levels and suppressed HSP90 expression	jak2	26	27	30	31
Inhibition of TK or JAK2 activities blocked magnolol induced phosphorylation of MEK and ERK , again supporting the upstream role of JAK2 .	Inhibition of TK or JAK2 activities blocked magnolol induced phosphorylation of MEK and ERK, again supporting the upstream role of JAK2.	2	22	supporting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK	TK or JAK2 activities blocked magnolol induced phosphorylation of MEK and ERK	erk	JAK2	JAK2	jak2	13	14	21	22
When zebrafish embryos were treated with an ERK signaling inhibitor prior to artery --- vein specification , runx1 and myb expression in the dorsal aorta decreased ; however , when treated with an ERK signaling inhibitor after artery --- vein specification but before EHT , runx1 and myb expression increased .	When zebrafish embryos were treated with an ERK signaling inhibitor prior to artery --- vein specification, runx1 and myb expression in the dorsal aorta decreased; however, when treated with an ERK signaling inhibitor after artery --- vein specification but before EHT, runx1 and myb expression increased.	17	35	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	ERK	ERK	ERK	myb	myb	myb	33	34	19	20
Here , we identified three MYB proteins , MYB30 , MYB55 , and MYB110 , which are transcriptionally induced by the MAMP-treatment , MAPK activation , and pathogen inoculation .	Here, we identified three MYB proteins, MYB30, MYB55, and MYB110, which are transcriptionally induced by the MAMP-treatment, MAPK activation, and pathogen inoculation.	5	24	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MYB	MYB	MYB	23	24	5	6
Based on the apparent importance of enhanced IL-3-dependent RAS and MAPK signaling in MYB KD/KD K11bL cells and the conserved MYB dependent expression of SPRY2 in both mouse and human progenitor cells , we reasoned that SPRY2 is pivotal to the way in which IL-3 can influence stem cell characteristics of myeloid progenitors .	Based on the apparent importance of enhanced IL-3-dependent RAS and MAPK signaling in MYB KD/KD K11bL cells and the conserved MYB dependent expression of SPRY2 in both mouse and human progenitor cells, we reasoned that SPRY2 is pivotal to the way in which IL-3 can influence stem cell characteristics of myeloid progenitors.	10	16	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	MYB	MYB	MYB	10	11	13	14
Furthermore , inhibition of the EGFR pathway strongly reduced hypodia induced HDAC6 deacetylase activity , whereas parallel inhibition of TGFbeta signaling had no effect .	Furthermore, inhibition of the EGFR pathway strongly reduced hypodia induced HDAC6 deacetylase activity, whereas parallel inhibition of TGFbeta signaling had no effect.	5	13	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	EGFR	EGFR	EGFR	HDAC6	HDAC6	HDAC6	5	6	11	12
Although it is possible that EGFR directly activates Smad3 , our results indicating that EGFR is activated by hypoxia and that inhibition of EGFR strongly reduced hypoxia induced HDAC6 deacetylase activity are consistent with a mechanism whereby EGFR activates HDAC6 , which in turn induces tubulin deacetylase activity that facilitates Smad3 activation and nuclear translocation .	Although it is possible that EGFR directly activates Smad3, our results indicating that EGFR is activated by hypoxia and that inhibition of EGFR strongly reduced hypoxia induced HDAC6 deacetylase activity are consistent with a mechanism whereby EGFR activates HDAC6, which in turn induces tubulin deacetylase activity that facilitates Smad3 activation and nuclear translocation.	37	44	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	EGFR	EGFR	EGFR	HDAC6	HDAC6	HDAC6	37	38	39	40
Several studies suggest that excessive signaling through B-RAF and MAPK promotes BAD ( BCL-2 antagonist of cell death ) phosphorylation and inactivation , and decreased BMF ( BCL-2 modifying factor ) and PUMA expression , and all these events lead to abrogated BAK and BAX activation , MOMP , and apoptosis .	Several studies suggest that excessive signaling through B-RAF and MAPK promotes BAD (BCL-2 antagonist of cell death) phosphorylation and inactivation, and decreased BMF (BCL-2 modifying factor) and PUMA expression, and all these events lead to abrogated BAK and BAX activation, MOMP, and apoptosis.	5	19	promotes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	BAD	BAD	BAD	9	10	11	12
Our findings demonstrate that ( i ) PKR , Ser/Thr kinase , phosphorylates its new substrate Cdc2 at the Tyr 4 residue , ( ii ) PKR mediated Tyr 4 phosphorylation facilitates Cdc2 ubiquitination and proteosomal degradation , ( iii ) unphosphorylated Tyr 4 prevents Cdc2 ubiquitination , and ( iv ) downstream from p53 , PKR has a crucial role in G2 arrest and triggers Cdc2 downregulation under genotoxic conditions .	Our findings demonstrate that (i) PKR, Ser/Thr kinase, phosphorylates its new substrate Cdc2 at the Tyr 4 residue, (ii) PKR mediated Tyr 4 phosphorylation facilitates Cdc2 ubiquitination and proteosomal degradation, (iii) unphosphorylated Tyr 4 prevents Cdc2 ubiquitination, and (iv) downstream from p53, PKR has a crucial role in G2 arrest and triggers Cdc2 downregulation under genotoxic conditions.	56	67	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKR	PKR	PKR	Cdc2	Cdc2	Cdc2	56	57	66	67
Moreover , activation of PKR with poly ( I : C ) induced an increase of CDK1 ( Fig XREF_FIG ) .	Moreover, activation of PKR with poly (I : C) induced an increase of CDK1 (Fig XREF_FIG).	2	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKR	PKR	PKR	CDK1	CDK1	CDK1	4	5	16	17
XREF_BIBR , XREF_BIBR EGFR homodimerization and heterodimerization with other EGFR family members leads to enhanced tyrosine kinase activity of the receptor complexes and activation of multiple signaling pathways , such as mitogen activated protein kinase ( MAPK ) , p38 MAPK , phosphatidylinositol 3 '-kinase ( PI3K ) , Src , Crk and Nck .	XREF_BIBR, XREF_BIBR EGFR homodimerization and heterodimerization with other EGFR family members leads to enhanced tyrosine kinase activity of the receptor complexes and activation of multiple signaling pathways, such as mitogen activated protein kinase (MAPK), p38 MAPK, phosphatidylinositol 3 '-kinase (PI3K), Src, Crk and Nck.	3	52	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	EGFR	EGFR	EGFR	Crk	Crk	Crk	3	4	51	52
However , as activated EGFR also phosphorylates Crk at the negative regulatory tyrosine Y221 , the relative stoichiometry of phosphorylation at Y251 and Y221 might be critical as a high pY251 and pY221 ratio on Crk typically induced by activated EGFR could favor Abl activation , and may resolve the issue of when Abl induces a tumor suppressing signal versus a tumor promoting signal .	However, as activated EGFR also phosphorylates Crk at the negative regulatory tyrosine Y221, the relative stoichiometry of phosphorylation at Y251 and Y221 might be critical as a high pY251 and pY221 ratio on Crk typically induced by activated EGFR could favor Abl activation, and may resolve the issue of when Abl induces a tumor suppressing signal versus a tumor promoting signal.	30	41	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	EGFR	EGFR	EGFR	Crk	Crk	Crk	40	41	35	36
DYRK1B has also been proposed to promote CCND1 turnover , but was reported to phosphorylate Thr ( 288 ) rather than Thr ( 286 ) .	DYRK1B has also been proposed to promote CCND1 turnover, but was reported to phosphorylate Thr (288) rather than Thr (286).	0	14	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	DYRK1B	DYRK1B	DYRK1B	CCND1	CCND1	CCND1	0	1	7	8
Furthermore , RNA interference mediated knockdown of epsin 1 was found to inhibit internalization of the EGFR , while having no effect on endocytosis of the transferrin receptor .	Furthermore, RNA interference mediated knockdown of epsin 1 was found to inhibit internalization of the EGFR, while having no effect on endocytosis of the transferrin receptor.	5	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	epsin 1	epsin 1	epsin 1	EGFR	EGFR	EGFR	7	9	16	17
AMPK dependent phosphorylation of eEF2K on Ser 398 leads to activation of eEF2K in response to genotoxic stress .	AMPK dependent phosphorylation of eEF2K on Ser 398 leads to activation of eEF2K in response to genotoxic stress.	0	14	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	eEF2K	AMPK dependent phosphorylation of eEF2K on Ser 398	eef2k	eEF2K	eEF2K	eef2k	4	5	12	13
An EID-1 ( E1A like inhibitor of differentiation-1 ) inhibits differentiation by blocking the histone acetyltransferase activity of p300 .	An EID-1 (E1A like inhibitor of differentiation-1) inhibits differentiation by blocking the histone acetyltransferase activity of p300.	0	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	EID-1	EID-1	EID-1	p300	p300	p300	1	2	18	19
Impairment of Mig-6 attenuation of EGFR family signaling may lead to increased cell proliferation and tumor formation .	Impairment of Mig-6 attenuation of EGFR family signaling may lead to increased cell proliferation and tumor formation.	2	7	attenuation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Mig-6	Mig-6	Mig-6	EGFR	EGFR	EGFR	2	3	5	6
In addition to inhibiting EGFR catalytic activity , MIG6 increases EGFR internalization and trafficking to the lysosome [ XREF_BIBR ] , even for EGFR mutants that are not trafficked by CBL mediated endocytosis [ XREF_BIBR ] .	In addition to inhibiting EGFR catalytic activity, MIG6 increases EGFR internalization and trafficking to the lysosome [XREF_BIBR], even for EGFR mutants that are not trafficked by CBL mediated endocytosis [XREF_BIBR].	8	11	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	8	9	10	11
We hypothesized that global KO of Mig-6 in mice would increase EGFR signaling and disrupt cartilage and subchondral bone homeostasis , leading to severe damage to the cartilage and subchondral bone after ligament and meniscus injury .	We hypothesized that global KO of Mig-6 in mice would increase EGFR signaling and disrupt cartilage and subchondral bone homeostasis, leading to severe damage to the cartilage and subchondral bone after ligament and meniscus injury.	4	12	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mig-6	Mig-6	Mig-6	EGFR	EGFR	EGFR	6	7	11	12
Thus , MIG6 may promote a reduction in beta cell mass by antagonising EGFR signalling .	Thus, MIG6 may promote a reduction in beta cell mass by antagonising EGFR signalling.	2	14	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	2	3	13	14
However , these cartilage specific Mig6 KO mice also revealed a more complex phenotype where loss of MIG6 and subsequent activation of EGFR signaling has an early anabolic effect on cartilage .	However, these cartilage specific Mig6 KO mice also revealed a more complex phenotype where loss of MIG6 and subsequent activation of EGFR signaling has an early anabolic effect on cartilage.	17	23	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	17	18	22	23
More recently , Mig-6 was shown to induce EGFR endocytosis and lysosomal degradation in glioblastoma cells via direct interaction with the SNARE protein STX8 [ XREF_BIBR ] .	More recently, Mig-6 was shown to induce EGFR endocytosis and lysosomal degradation in glioblastoma cells via direct interaction with the SNARE protein STX8 [XREF_BIBR].	3	9	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mig-6	Mig-6	Mig-6	EGFR	EGFR	EGFR	3	4	8	9
We hypothesized that in cells with high EGFR expression , downregulation of ERRFI1 would enhance EGFR signaling and thus increase AKT activity while , on the other hand , in EGFR-low cells , ERRFI1 would interact with AKT and decrease AKT activity .	We hypothesized that in cells with high EGFR expression, downregulation of ERRFI1 would enhance EGFR signaling and thus increase AKT activity while, on the other hand, in EGFR-low cells, ERRFI1 would interact with AKT and decrease AKT activity.	10	16	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERRFI1	ERRFI1	ERRFI1	EGFR	EGFR	EGFR	12	13	15	16
We also investigated MIG6 mediated cytokine induced desensitisation of EGFR signalling and the DNA damage repair response in 832/13 INS-1 beta cells .	We also investigated MIG6 mediated cytokine induced desensitisation of EGFR signalling and the DNA damage repair response in 832/13 INS-1 beta cells.	3	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	3	4	9	10
In conflict with our findings , a prior biochemical study found that Y394 phosphorylation diminishes the ability of Mig6 to inhibit EGFR 33 .	In conflict with our findings, a prior biochemical study found that Y394 phosphorylation diminishes the ability of Mig6 to inhibit EGFR 33.	13	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	phosphorylation diminishes the ability of Mig6	mig6	EGFR	EGFR	egfr	18	19	21	22
The Mig6 mediated reduction of EGFR occurs concomitantly with a TGFbeta induced EMT associated kinase switch of tumor cells to an AKT activated EGFR independent state .	The Mig6 mediated reduction of EGFR occurs concomitantly with a TGFbeta induced EMT associated kinase switch of tumor cells to an AKT activated EGFR independent state.	0	25	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	1	2	23	24
This might be due to the fact that ERRFI1 depletion increases EGFR activity , and downstream PI3K-AKT activity 34 , 35 and activated AKT creates a cage in the ATP bound form to prevent its access to phosphatases 36 .	This might be due to the fact that ERRFI1 depletion increases EGFR activity, and downstream PI3K-AKT activity 34, 35 and activated AKT creates a cage in the ATP bound form to prevent its access to phosphatases 36.	8	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ERRFI1	ERRFI1	ERRFI1	EGFR	EGFR	EGFR	8	9	11	12
These results suggest that tyrosine kinase catalyzed phosphorylation of Mig6 likely represents a feedback mechanism to antagonize its inhibition of EGFR ( XREF_FIG ) .	These results suggest that tyrosine kinase catalyzed phosphorylation of Mig6 likely represents a feedback mechanism to antagonize its inhibition of EGFR (XREF_FIG).	7	22	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Mig6	phosphorylation of Mig6	mig6	EGFR	EGFR	egfr	9	10	20	21
In agreement with such a model , Mig-6 promotes EGFR internalization , results in receptor degradation , leading to attenuation of ERK activity .	In agreement with such a model, Mig-6 promotes EGFR internalization, results in receptor degradation, leading to attenuation of ERK activity.	7	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mig-6	Mig-6	Mig-6	EGFR	EGFR	EGFR	7	8	9	10
MIG6 inhibits EGFR kinase activity and promotes WT EGFR trafficking to the degradation pathway .	MIG6 inhibits EGFR kinase activity and promotes WT EGFR trafficking to the degradation pathway.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	0	1	2	3
Mig-6 ablation in the thyroid gland in vivo increases EGFR and ERK activity but decreases NF-kappaB activity .	Mig-6 ablation in the thyroid gland in vivo increases EGFR and ERK activity but decreases NF-kappaB activity.	0	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mig-6	Mig-6	Mig-6	EGFR	EGFR	EGFR	0	1	9	10
Mig6 was proposed to inhibit EGFR signaling by direct binding to EGFR and ErbB2 -- by suppressing the EGFR kinase activity -- and by a receptor distal mechanism .	Mig6 was proposed to inhibit EGFR signaling by direct binding to EGFR and ErbB2 -- by suppressing the EGFR kinase activity -- and by a receptor distal mechanism.	0	6	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	0	1	5	6
Several interesting genes such as the transcriptional repressor HESX1 , a negative regulator of EGFR signaling ERRFI1 and the lymphoid specific helicase HELLS were repressed by SNF5 .	Several interesting genes such as the transcriptional repressor HESX1, a negative regulator of EGFR signaling ERRFI1 and the lymphoid specific helicase HELLS were repressed by SNF5.	12	22	signaling	Positive_activation_token_1_noun	Negative_activation	Positive_activation	ERRFI1	ERRFI1	ERRFI1	EGFR	EGFR	EGFR	16	17	14	15
Kinetic modeling based on EGFR endocytosis experiments performed on lung adenocarcinoma cells expressing WT and mutant ( Del 746-750 ) EGFRs have suggested that MIG6 promotes wild-type EGFR , but not mutant EGFR internalization .	Kinetic modeling based on EGFR endocytosis experiments performed on lung adenocarcinoma cells expressing WT and mutant (Del 746-750) EGFRs have suggested that MIG6 promotes wild-type EGFR, but not mutant EGFR internalization.	24	33	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	24	25	27	28
Moreover , MIG6 mediates ERBB receptor sorting to late endosomes by binding to syntaxin 8 , thus promoting ERBB lysosomal degradation [ XREF_BIBR ] .	Moreover, MIG6 mediates ERBB receptor sorting to late endosomes by binding to syntaxin 8, thus promoting ERBB lysosomal degradation [XREF_BIBR].	2	5	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MIG6	MIG6	MIG6	ERBB	ERBB	ERBB	2	3	4	5
Tyrosine Phosphorylation of Mig6 Reduces its Inhibition of the Epidermal Growth Factor Receptor .	Tyrosine Phosphorylation of Mig6 Reduces its Inhibition of the Epidermal Growth Factor Receptor.	0	13	Reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Mig6	Tyrosine Phosphorylation of Mig6	mig6	Epidermal Growth Factor Receptor	Epidermal Growth Factor Receptor	epidermal growth factor receptor	3	4	9	13
Immunoblotting data showed that basal EGFR level was not significantly affected in an unstimulated environment by Mig6 depletion , despite the fact that EGFR phosporylation was strongly enhanced by Mig6 depletion after ligand stimulation ( XREF_FIG ) .	Immunoblotting data showed that basal EGFR level was not significantly affected in an unstimulated environment by Mig6 depletion, despite the fact that EGFR phosporylation was strongly enhanced by Mig6 depletion after ligand stimulation (XREF_FIG).	23	30	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Mig6	Mig6	Mig6	EGFR	EGFR	EGFR	29	30	23	24
Accordingly , MIG6 down-regulation in thyroid cancer cells and papillary carcinoma enhances EGFR , ERBB2 and MET activity .	Accordingly, MIG6 down-regulation in thyroid cancer cells and papillary carcinoma enhances EGFR, ERBB2 and MET activity.	2	17	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MIG6	MIG6	MIG6	EGFR	EGFR	EGFR	2	3	12	13
As mentioned previously , ERRFI1 is known to work as a negative feedback regulator of the ERBB RTK pathway , so attenuated ERRFI1 might increase the ERBB RTK pathway and lead to increased cell growth .	As mentioned previously, ERRFI1 is known to work as a negative feedback regulator of the ERBB RTK pathway, so attenuated ERRFI1 might increase the ERBB RTK pathway and lead to increased cell growth.	22	30	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERRFI1	ERRFI1	ERRFI1	ERBB	ERBB	ERBB	22	23	26	27
Erythromycin and other macrolides exert anti-inflammatory activity by attenuation of both TNFalpha-IKKbeta and ERK1/2 signalling XREF_BIBR , XREF_BIBR , thus increasing the inhibitory effect of TSC1 and TSC2 towards Rheb .	Erythromycin and other macrolides exert anti-inflammatory activity by attenuation of both TNFalpha-IKKbeta and ERK1/2 signalling XREF_BIBR, XREF_BIBR, thus increasing the inhibitory effect of TSC1 and TSC2 towards Rheb.	13	28	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	TSC2	TSC2	TSC2	13	14	27	28
The anti-EGFR antibody was more efficient than rapamycin in reducing reactivity to HMB45 , the proliferation rate , and in controlling ERK activation in human TSC2 -/- ASM cells .	The anti-EGFR antibody was more efficient than rapamycin in reducing reactivity to HMB45, the proliferation rate, and in controlling ERK activation in human TSC2 -/- ASM cells.	21	28	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	21	22	25	26
Intensive activation of the Ras-ERK1/2 pathway can also stimulate mTOR activity by ERK1/2 and RSK signalling to the tuberous sclerosis complex 2 ( TSC2 ) , which is sensitive to different growth factors and stress signals [ XREF_BIBR ] .	Intensive activation of the Ras-ERK1/2 pathway can also stimulate mTOR activity by ERK1/2 and RSK signalling to the tuberous sclerosis complex 2 (TSC2), which is sensitive to different growth factors and stress signals [XREF_BIBR].	8	28	stimulate	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	TSC2	TSC2	TSC2	12	13	23	24
We also show that EphA receptor activation by ephrin-A ligands in neurons leads to inhibition of ERK1/2 kinase activity and decreased inhibition of Tsc2 by ERK1/2 .	We also show that EphA receptor activation by ephrin-A ligands in neurons leads to inhibition of ERK1/2 kinase activity and decreased inhibition of Tsc2 by ERK1/2.	20	26	inhibition	Negative_activation_token_2_noun	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Tsc2	Tsc2	Tsc2	25	26	23	24
Our data suggests the intriguing possibility that ERK mediated TSC2 inactivation is required along with mTOR dependent phosphorylation of S6 to sustain high levels of pS6 in HSC and HPC .	Our data suggests the intriguing possibility that ERK mediated TSC2 inactivation is required along with mTOR dependent phosphorylation of S6 to sustain high levels of pS6 in HSC and HPC.	7	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	7	8	9	10
Basal ERK1/2 phosphorylation and DHPG induced increases in ERK1/2 phosphorylation are unaltered in Tsc2 +/- mice ( XREF_FIG ) .	Basal ERK1/2 phosphorylation and DHPG induced increases in ERK1/2 phosphorylation are unaltered in Tsc2 +/- mice (XREF_FIG).	1	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2 phosphorylation	erk1/2	Tsc2	Tsc2	tsc2	1	2	13	14
This differs from the phosphorylation induced by insulin , indicating that MEK and ERK signalling targets distinct sites in TSC2 .	This differs from the phosphorylation induced by insulin, indicating that MEK and ERK signalling targets distinct sites in TSC2.	11	20	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	13	14	19	20
In this pathway , EphA activation leads to inhibition of ERK activity , which activates Tsc2 , which in turn inactivates the GTP binding protein Rheb .	In this pathway, EphA activation leads to inhibition of ERK activity, which activates Tsc2, which in turn inactivates the GTP binding protein Rheb.	10	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	Tsc2	Tsc2	Tsc2	10	11	15	16
Our finding that pharmacological inhibition of ERK inhibits GSK3beta activity in Tsc2 -/- cells suggests that modulation of ERK may be leveraged to regulate GSK3beta activity in multiple pathological conditions characterized by mTORC1 hyperactivation and insulin insensitivity .	Our finding that pharmacological inhibition of ERK inhibits GSK3beta activity in Tsc2 -/- cells suggests that modulation of ERK may be leveraged to regulate GSK3beta activity in multiple pathological conditions characterized by mTORC1 hyperactivation and insulin insensitivity.	4	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	Tsc2	Tsc2	Tsc2	6	7	11	12
Since the Ras and MAPK pathway has been found to induce mTORC1 activation via phosphorylation and inactivation of tuberin ( TSC2 ) at its serine 664 residue , 15 we assessed whether the same mechanism applies to liver cancer ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	Since the Ras and MAPK pathway has been found to induce mTORC1 activation via phosphorylation and inactivation of tuberin (TSC2) at its serine 664 residue, 15 we assessed whether the same mechanism applies to liver cancer (XREF_FIG; XREF_SUPPLEMENTARY).	2	20	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	tuberin	tuberin	tuberin	4	5	18	19
It appears Merlin does not regulate mTORC1 via the established PI3K-Akt or MAPK and ERK mediated TSC2 inactivation , and may instead regulate TSC and mTOR signaling in a novel fashion .	It appears Merlin does not regulate mTORC1 via the established PI3K-Akt or MAPK and ERK mediated TSC2 inactivation, and may instead regulate TSC and mTOR signaling in a novel fashion.	14	22	mediated	Positive_early_activation	Negative_activation	Positive_activation	ERK	ERK	ERK	TSC2	TSC2	TSC2	14	15	16	17
Finally , as polyubiquitination is now known to be involved in several cellular processes that do not imply proteasomal degradation , including control of transcription factor activity XREF_BIBR , XREF_BIBR , we examined whether MAFbx increased MyoD turnover in atrophic myotubes .	Finally, as polyubiquitination is now known to be involved in several cellular processes that do not imply proteasomal degradation, including control of transcription factor activity XREF_BIBR, XREF_BIBR, we examined whether MAFbx increased MyoD turnover in atrophic myotubes.	34	37	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	34	35	36	37
we present evidence that MyoD is targeted by Atrogin1 and MAFbx ( MAFbx ) in skeletal muscle atrophy .	we present evidence that MyoD is targeted by Atrogin1 and MAFbx (MAFbx) in skeletal muscle atrophy.	4	11	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	10	11	4	5
The nuclear localization of MAFbx during muscle atrophy and the loss of MyoD immuno staining lead us to investigate whether MyoD could be targeted by MAFbx in response to different experimental conditions previously shown to induce atrophy of C2C12 myotubes .	The nuclear localization of MAFbx during muscle atrophy and the loss of MyoD immuno staining lead us to investigate whether MyoD could be targeted by MAFbx in response to different experimental conditions previously shown to induce atrophy of C2C12 myotubes.	20	27	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	25	26	20	21
The Leibovitch group has also reported that MAFbx targets MyoD for proteolysis and most recently , the inhibition of this process prevented muscle atrophy .	The Leibovitch group has also reported that MAFbx targets MyoD for proteolysis and most recently, the inhibition of this process prevented muscle atrophy.	5	21	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	7	8	9	10
Knockdown of MAFbx in these myotubes prevented by more than 50 % the degradation of MyoD while a control shRNAi did not impair its degradation ( XREF_FIG ) .	Knockdown of MAFbx in these myotubes prevented by more than 50% the degradation of MyoD while a control shRNAi did not impair its degradation (XREF_FIG).	0	26	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	2	3	15	16
MAFbx has been shown to target and degrade MyoD , myogenin , and Eif3f , and degradation of any of these proteins reduces myotube diameters .	MAFbx has been shown to target and degrade MyoD, myogenin, and Eif3f, and degradation of any of these proteins reduces myotube diameters.	0	13	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	0	1	8	9
Several genes associated with Fbxo32 ( Atrogin-1 ) induced protein degradation ( via the ubiquitin-proteasome pathway ) were downregulated - Fbxo32 , Foxo1 , Myod1 , and Hdac5 [ XREF_BIBR , XREF_BIBR ] .	Several genes associated with Fbxo32 (Atrogin-1) induced protein degradation (via the ubiquitin-proteasome pathway) were downregulated - Fbxo32, Foxo1, Myod1, and Hdac5 [XREF_BIBR, XREF_BIBR].	1	25	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Atrogin-1	Atrogin-1	Atrogin-1	Myod1	Myod1	Myod1	6	7	24	25
On the other hand , atrogin-1 has been shown to target MyoD , the regulator of myogenesis , and eIF-e , the eukaryotic initiation factor of protein synthesis , suggesting that its main role is the regulation of protein synthesis .	On the other hand, atrogin-1 has been shown to target MyoD, the regulator of myogenesis, and eIF-e, the eukaryotic initiation factor of protein synthesis, suggesting that its main role is the regulation of protein synthesis.	5	19	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	atrogin-1	atrogin-1	atrogin-1	MyoD	MyoD	MyoD	5	6	11	12
We previously showed that MAFbx mediates MyoD proteolysis in vitro .	We previously showed that MAFbx mediates MyoD proteolysis in vitro.	4	7	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	4	5	6	7
A previous report demonstrated that atrogin-1 targets MyoD for its degradation through the ubiquitin proteasome mediated system XREF_BIBR .	A previous report demonstrated that atrogin-1 targets MyoD for its degradation through the ubiquitin proteasome mediated system XREF_BIBR.	5	15	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	atrogin-1	atrogin-1	atrogin-1	MyoD	MyoD	MyoD	5	6	7	8
These results suggest that the targeting of MyoD by MAFbx may be a major event to suppress the complex role of MyoD in plasticity and homeostasis in skeletal muscle .	These results suggest that the targeting of MyoD by MAFbx may be a major event to suppress the complex role of MyoD in plasticity and homeostasis in skeletal muscle.	5	10	targeting	Positive_activation_token_2_noun	Negative_activation	Positive_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	9	10	7	8
Atrogin-1 , a muscle specific E3 ligase , targets MyoD for degradation through the ubiquitin-proteasome-mediated system .	Atrogin-1, a muscle specific E3 ligase, targets MyoD for degradation through the ubiquitin-proteasome-mediated system.	0	11	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Atrogin-1	Atrogin-1	Atrogin-1	MyoD	MyoD	MyoD	0	1	9	10
Here we present evidence that MAFbx targets MyoD for degradation in several models of skeletal muscle atrophy .	Here we present evidence that MAFbx targets MyoD for degradation in several models of skeletal muscle atrophy.	3	9	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MAFbx	MAFbx	MAFbx	MyoD	MyoD	MyoD	5	6	7	8
By targeting MyoD for degradation , Atrogin-1 can inhibit differentiation in myoblasts .	By targeting MyoD for degradation, Atrogin-1 can inhibit differentiation in myoblasts.	1	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Atrogin-1	Atrogin-1	Atrogin-1	MyoD	MyoD	MyoD	6	7	2	3
FBXO11 also targets CDT2 for degradation , but the relevant targets in these other tissues remain unknown 54 , 55 .	FBXO11 also targets CDT2 for degradation, but the relevant targets in these other tissues remain unknown 54, 55.	0	5	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	CDT2	CDT2	CDT2	0	1	3	4
CDT2 is also targeted for degradation by FBXO11 , and it is overexpressed and/or amplified in Ewing sarcomas , breast , liver , and gastrointestinal cancers , suggesting that CDT2 is oncogenic XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR .	CDT2 is also targeted for degradation by FBXO11, and it is overexpressed and/or amplified in Ewing sarcomas, breast, liver, and gastrointestinal cancers, suggesting that CDT2 is oncogenic XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR.	0	8	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	CDT2	CDT2	CDT2	7	8	0	1
Inhibition of CDT2 degradation by FBXO11 depletion or expression of the stable CDT2 ( T464D ) mutant in cells deprived of serum or treated with TGFbeta resulted in a consistent decrease in SET8 levels ; however , the effect on other CDT2 substrates ( CDT1 and p21 ) was less consistent ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Inhibition of CDT2 degradation by FBXO11 depletion or expression of the stable CDT2 (T464D) mutant in cells deprived of serum or treated with TGFbeta resulted in a consistent decrease in SET8 levels; however, the effect on other CDT2 substrates (CDT1 and p21) was less consistent (XREF_FIG, XREF_SUPPLEMENTARY).	5	16	depletion	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	CDT2	CDT2	CDT2	5	6	12	13
The depletion of FBXO11 significantly increased the t1/2 of Cdt2 protein to > 5 hr ( XREF_FIG ) .	The depletion of FBXO11 significantly increased the t1/2 of Cdt2 protein to> 5 hr (XREF_FIG).	1	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	3	4	9	10
We also observed that expression of FBXO11 induced the appearance of high molecular weight species of CDT2 , which are likely ubiquitylated forms of CDT2 ( XREF_SUPPLEMENTARY ) .	We also observed that expression of FBXO11 induced the appearance of high molecular weight species of CDT2, which are likely ubiquitylated forms of CDT2 (XREF_SUPPLEMENTARY).	4	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	expression of FBXO11	fbxo11	CDT2	CDT2	cdt2	6	7	16	17
We hypothesized that in the absence of FBXO11 mediated destabilization of Cdt2 , Set8 is not induced during the 12-20 hr window and this is responsible for the increase of P-Smad2 and N-cadherin .	We hypothesized that in the absence of FBXO11 mediated destabilization of Cdt2, Set8 is not induced during the 12-20 hr window and this is responsible for the increase of P-Smad2 and N-cadherin.	5	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	7	8	11	12
Depletion of FBXO11 by all four siRNAs induced an increase in both the steady state levels and stability of CDT2 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Depletion of FBXO11 by all four siRNAs induced an increase in both the steady state levels and stability of CDT2 (XREF_FIG and XREF_SUPPLEMENTARY).	0	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	CDT2	CDT2	CDT2	2	3	19	20
FBXO11 promotes cellular migration by downregulating Cdt2 and thus upregulating Set8 .	FBXO11 promotes cellular migration by downregulating Cdt2 and thus upregulating Set8.	0	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	0	1	6	7
Because FBXO11 promotes the degradation of other proteins in addition to Cdt2 , we analyzed whether these effects of FBXO11-depletion resulted from the specific stabilization of Cdt2 .	Because FBXO11 promotes the degradation of other proteins in addition to Cdt2, we analyzed whether these effects of FBXO11-depletion resulted from the specific stabilization of Cdt2.	1	12	promotes	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	1	2	11	12
Thus , the increase of Cdt2 by si-FBXO11 was not due to off-target effect of the si-RNA .	Thus, the increase of Cdt2 by si-FBXO11 was not due to off-target effect of the si-RNA.	3	8	increase	Positive_activation_token_2_noun	Negative_activation	Positive_activation	si-FBXO11	si-FBXO11	si-FBXO11	Cdt2	Cdt2	Cdt2	7	8	5	6
Further experiments in HeLa and U2OS cells however , demonstrated that only the depletion of FBXO11 by multiple siRNA oligonucleotides reproducibly increased endogenous Cdt2 ( XREF_FIG , and data not shown ) or ectopic Cdt2 proteins ( XREF_FIG , lanes 1-4 ) .	Further experiments in HeLa and U2OS cells however, demonstrated that only the depletion of FBXO11 by multiple siRNA oligonucleotides reproducibly increased endogenous Cdt2 (XREF_FIG, and data not shown) or ectopic Cdt2 proteins (XREF_FIG, lanes 1-4).	13	35	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	Cdt2	Cdt2	Cdt2	15	16	23	24
FBXO11 was reported to target the BCL6 oncoprotein [ XREF_BIBR ] .	FBXO11 was reported to target the BCL6 oncoprotein [XREF_BIBR].	0	7	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	0	1	6	7
FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas .	FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas.	0	7	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	0	1	2	3
FBX011 ( F-box only protein 11 ) is a component of the SCF ubiquitin ligase complex , targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas [ XREF_BIBR ] .	FBX011 (F-box only protein 11) is a component of the SCF ubiquitin ligase complex, targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas [XREF_BIBR].	0	23	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBX011	FBX011	FBX011	BCL6	BCL6	BCL6	0	1	18	19
Notably , FBXO11 targets BCL6 , a repressor of the cell cycle regulator p53 , for degradation .	Notably, FBXO11 targets BCL6, a repressor of the cell cycle regulator p53, for degradation.	2	5	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	2	3	4	5
It has been recently reported that FBXO11 targets the BCL-6 oncoprotein for ubiquitylation and subsequent degradation .	It has been recently reported that FBXO11 targets the BCL-6 oncoprotein for ubiquitylation and subsequent degradation.	6	10	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	BCL-6	BCL-6	BCL-6	6	7	9	10
FBXO11 targets the BCL6 oncoprotein for degradation , and in B-cells , FBXO11 mutation directly corresponds with stabilization of BCL6 115 .	FBXO11 targets the BCL6 oncoprotein for degradation, and in B-cells, FBXO11 mutation directly corresponds with stabilization of BCL6 115.	0	4	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	0	1	3	4
Depletion of FBXO11 by both shRNAs induced an increase in the steady-state levels and stability of BCL6 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Depletion of FBXO11 by both shRNAs induced an increase in the steady-state levels and stability of BCL6 (XREF_FIG and XREF_SUPPLEMENTARY).	0	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	2	3	16	17
FBXO11 has also been shown to target the oncoprotein BCL6 ( B cell lymphoma 6 ) for degradation .	FBXO11 has also been shown to target the oncoprotein BCL6 (B cell lymphoma 6) for degradation.	0	17	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	0	1	9	10
Somatic mutations of the BCL6 ubiquitin ligase FBXO11 can enhance the half-life of BCL6 protein in DLBCL .	Somatic mutations of the BCL6 ubiquitin ligase FBXO11 can enhance the half-life of BCL6 protein in DLBCL.	1	14	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	BCL6	BCL6	BCL6	7	8	13	14
We show that FBXO11 promotes the neddylation of p53 both in vitro and in vivo .	We show that FBXO11 promotes the neddylation of p53 both in vitro and in vivo.	3	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	3	4	8	9
Moreover , overexpression of FBXO11 substantially promoted p53 neddylation in MCF7 cells ( XREF_FIG ) , which correlated with decreased p53 transcriptional activity ( XREF_FIG ) .	Moreover, overexpression of FBXO11 substantially promoted p53 neddylation in MCF7 cells (XREF_FIG), which correlated with decreased p53 transcriptional activity (XREF_FIG).	2	8	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	overexpression of FBXO11	fbxo11	p53	p53	p53	4	5	7	8
FBXO11 is also known to promote the neddylation of amino acids localized in the C-terminus of p53 .	FBXO11 is also known to promote the neddylation of amino acids localized in the C-terminus of p53.	0	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	0	1	16	17
Furthermore , FBXO11 promotes the neddylation of p53 both in vivo and in vitro and thus inhibits its function of transcription .	Furthermore, FBXO11 promotes the neddylation of p53 both in vivo and in vitro and thus inhibits its function of transcription.	2	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	2	3	7	8
It has been shown that FBXO11 promotes the neddylation of p53 at Lys320 and Lys321 .	It has been shown that FBXO11 promotes the neddylation of p53 at Lys320 and Lys321.	5	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	5	6	10	11
Some studies have presented that FBXO11 promotes the neddylation of p53 both on two lysines , Lys 320 and Lys 321 to suppress p53 function [ XREF_BIBR ] .	Some studies have presented that FBXO11 promotes the neddylation of p53 both on two lysines, Lys 320 and Lys 321 to suppress p53 function [XREF_BIBR].	5	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	5	6	10	11
The increased chemosensitivity could be mediated by miR-621-dependent downregulation of FBXO11 , resulting in enhanced p53 transactivity and increased apoptosis upon chemotherapy .	The increased chemosensitivity could be mediated by miR-621-dependent downregulation of FBXO11, resulting in enhanced p53 transactivity and increased apoptosis upon chemotherapy.	5	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	10	11	15	16
In breast cancer , FBXO11 may promote primary tumor growth and suppress apoptosis in response to cytotoxic chemotherapy by inhibiting p53 activity in those cancer cells harboring functional p53 , whereas it could repress metastasis via degrading SNAIL in p53 mutated cancer cells at late stages of breast cancer .	In breast cancer, FBXO11 may promote primary tumor growth and suppress apoptosis in response to cytotoxic chemotherapy by inhibiting p53 activity in those cancer cells harboring functional p53, whereas it could repress metastasis via degrading SNAIL in p53 mutated cancer cells at late stages of breast cancer.	4	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FBXO11	FBXO11	FBXO11	p53	p53	p53	4	5	20	21
We confirmed that digoxin or ouabain treatment induced ERK activation in both the STK11 mutant cell lines and their STK11 restored derivatives ( XREF_FIG and XREF_SUPPLEMENTARY ) .	We confirmed that digoxin or ouabain treatment induced ERK activation in both the STK11 mutant cell lines and their STK11 restored derivatives (XREF_FIG and XREF_SUPPLEMENTARY).	8	16	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	ERK	ERK	ERK	STK11	STK11	STK11	8	9	13	14
In addition , the Raf and Erk pathway promotes inactivation of LKB1 and subsequently AMPK , thereby preventing beta oxidation [ XREF_BIBR ] and decreasing the available mitochondrial acetyl-CoA pool .	In addition, the Raf and Erk pathway promotes inactivation of LKB1 and subsequently AMPK, thereby preventing beta oxidation [XREF_BIBR] and decreasing the available mitochondrial acetyl-CoA pool.	4	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk	Erk	Erk	LKB1	LKB1	LKB1	6	7	11	12
The LKB1 and AMPK pathway is negatively activated by ERK in AML cells , and ERK is activated in the 50 % of AML cases with mutations in intracellular signal transduction pathways .	The LKB1 and AMPK pathway is negatively activated by ERK in AML cells, and ERK is activated in the 50% of AML cases with mutations in intracellular signal transduction pathways.	1	12	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	LKB1	LKB1	LKB1	9	10	1	2
ERK1/2 mediates electric field induced activation of LKB1 .	ERK1/2 mediates electric field induced activation of LKB1.	0	8	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	LKB1	LKB1	LKB1	0	1	7	8
SAD and MAPK ( Par-1 ) kinases are other downstream targets of LKB1 and mainly expressed in the brain .	SAD and MAPK (Par-1) kinases are other downstream targets of LKB1 and mainly expressed in the brain.	0	13	are other downstream targets	Positive_activation_copula_1	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	LKB1	LKB1	LKB1	2	3	12	13
p38 and MAPK signaling mediates LKB1 regulation of MMP-1 .	p38 and MAPK signaling mediates LKB1 regulation of MMP-1.	0	6	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK	MAPK	MAPK	LKB1	LKB1	LKB1	2	3	5	6
To confirm that the UTRs of Emi1 were enhancing APC and Cdh1 activation solely through mitosis specific translational repression , rather than through an alternative mechanism , for example by stimulating specific mRNA localization , we sought to confer mitosis specific translational repression on Emi1 mRNA independently of the Emi1 UTRs .	To confirm that the UTRs of Emi1 were enhancing APC and Cdh1 activation solely through mitosis specific translational repression, rather than through an alternative mechanism, for example by stimulating specific mRNA localization, we sought to confer mitosis specific translational repression on Emi1 mRNA independently of the Emi1 UTRs.	4	12	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Emi1	Emi1	Emi1	Cdh1	Cdh1	Cdh1	6	7	11	12
Phosphorylation of Emi1 causes it to release Cdc20 and Cdh1 .	Phosphorylation of Emi1 causes it to release Cdc20 and Cdh1.	0	10	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Emi1	Phosphorylation of Emi1	emi1	Cdh1	Cdh1	cdh1	2	3	9	10
In CyclinE depleted cells , Emi1 accumulates first , leading toAPC/C Cdh1 inactivation and subsequent accumulation of CyclinA .	In CyclinE depleted cells, Emi1 accumulates first, leading toAPC/C Cdh1 inactivation and subsequent accumulation of CyclinA.	5	12	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Emi1	Emi1	Emi1	Cdh1	Cdh1	Cdh1	5	6	11	12
Similar to Cdh1 that directly targets cyclins and is inhibited by early mitotic inhibitor 1 ( Emi1 ) in animals XREF_BIBR , CCS52A has also been demonstrated to be inhibited by ULTRAVIOLET-B-INSENSITIVE4 ( UVI4 ) and GIGAS CELL1 ( GIG1 )/OMISSION OF SECOND DIVISION1 ( OSD1 ) and to target CYCA2 ; 3 for regulating endoreduplication in Arabidopsis XREF_BIBR XREF_BIBR XREF_BIBR .	Similar to Cdh1 that directly targets cyclins and is inhibited by early mitotic inhibitor 1 (Emi1) in animals XREF_BIBR, CCS52A has also been demonstrated to be inhibited by ULTRAVIOLET-B-INSENSITIVE4 (UVI4) and GIGAS CELL1 (GIG1)/OMISSION OF SECOND DIVISION1 (OSD1) and to target CYCA2; 3 for regulating endoreduplication in Arabidopsis XREF_BIBR XREF_BIBR XREF_BIBR.	0	15	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	early mitotic inhibitor 1	early mitotic inhibitor 1	early mitotic inhibitor 1	Cdh1	Cdh1	Cdh1	11	15	2	3
Absence of AKT or ERK1/2 activation could underlie the lack of frank local cancer induction or metastatic spread in Nkx3.1 : Tsc1 DKO mice .	Absence of AKT or ERK1/2 activation could underlie the lack of frank local cancer induction or metastatic spread in Nkx3.1 : Tsc1 DKO mice.	2	23	underlie	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Tsc1	Tsc1	Tsc1	4	5	21	22
Interestingly , in animal models of ASD , it has recently been reported that ERK promotes increased dendritic complexity in Tsc1 null neurons , and reducing ERK signaling rescued dendritic defects [ XREF_BIBR ] .	Interestingly, in animal models of ASD, it has recently been reported that ERK promotes increased dendritic complexity in Tsc1 null neurons, and reducing ERK signaling rescued dendritic defects [XREF_BIBR].	14	22	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK	ERK	ERK	Tsc1	Tsc1	Tsc1	14	15	20	21
FBXW7 targets CCDC6 for proteasomal degradation during mitotic arrest .	FBXW7 targets CCDC6 for proteasomal degradation during mitotic arrest.	0	5	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	FBXW7	FBXW7	FBXW7	CCDC6	CCDC6	CCDC6	0	1	2	3
Moreover , FBXW7 mediated CCDC6 degradation is impaired in response to DNA damage .	Moreover, FBXW7 mediated CCDC6 degradation is impaired in response to DNA damage.	2	5	mediated	Positive_early_activation	Negative_activation	Positive_activation	FBXW7	FBXW7	FBXW7	CCDC6	CCDC6	CCDC6	2	3	4	5
Mutagenesis of BCR Tyr 177 to Phe completely abolished FES induced BCR binding to the GRB2 SH2 domain , identifying Tyr 177 as an additional phosphorylation site for FES .	Mutagenesis of BCR Tyr 177 to Phe completely abolished FES induced BCR binding to the GRB2 SH2 domain, identifying Tyr 177 as an additional phosphorylation site for FES.	9	12	induced	Positive_early_activation	Negative_activation	Positive_activation	FES	FES	FES	BCR	BCR	BCR	9	10	11	12
Once Sos1 is switched OFF , all proteins downstream of Sos1 are also eventually switched OFF , including both ERK1/2 and p90RSK , which feeds back to allow Sos1 , and its associated Rac1 activating complex to be switched ON again .	Once Sos1 is switched OFF, all proteins downstream of Sos1 are also eventually switched OFF, including both ERK1/2 and p90RSK, which feeds back to allow Sos1, and its associated Rac1 activating complex to be switched ON again.	14	38	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK1/2	ERK1/2	ERK1/2	Sos1	Sos1	Sos1	19	20	28	29
Several reports have demonstrated that FBW7 can also target nuclear Notch1 and Notch4 for ubiquitination and can suppress Notch signaling ; however , the detailed biochemical nature and the in vivo physiological relevance in development and cell transformation of this interaction remain unknown .	Several reports have demonstrated that FBW7 can also target nuclear Notch1 and Notch4 for ubiquitination and can suppress Notch signaling; however, the detailed biochemical nature and the in vivo physiological relevance in development and cell transformation of this interaction remain unknown.	5	17	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FBW7	FBW7	FBW7	Notch4	Notch4	Notch4	5	6	12	13
At all concentrations tested , follistatin , a functional inhibitor of myostatin , completely blocked the inhibitory effect of myostatin ( 40 nM ) on glucose uptake by BeWo cells ( 0.4 nM , P < 0.05 ) .	At all concentrations tested, follistatin, a functional inhibitor of myostatin, completely blocked the inhibitory effect of myostatin (40 nM) on glucose uptake by BeWo cells (0.4 nM, P < 0.05).	5	22	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	5	6	19	20
Interestingly , investigations by Gregorevic and colleagues suggest Follistatin mediated Myostatin independent muscle hypertrophy by SMAD 1/3 and mTOR suggesting a strong involvement of Follistatin on BMP7 activation XREF_BIBR , XREF_BIBR .	Interestingly, investigations by Gregorevic and colleagues suggest Follistatin mediated Myostatin independent muscle hypertrophy by SMAD 1/3 and mTOR suggesting a strong involvement of Follistatin on BMP7 activation XREF_BIBR, XREF_BIBR.	8	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	Follistatin	Follistatin	Follistatin	Myostatin	Myostatin	Myostatin	8	9	10	11
As shown in XREF_FIG expression of myostatin mRNA was not significantly altered in the PCA animals treated with follistatin .	As shown in XREF_FIG expression of myostatin mRNA was not significantly altered in the PCA animals treated with follistatin.	6	19	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	18	19	6	7
When myostatin is genetically deleted or inhibited by transgenic expression of the myostatin binding protein follistatin , there is a more profound increase in muscle mass and both hypertrophy and hyperplasia of fibers is observed XREF_BIBR , XREF_BIBR .	When myostatin is genetically deleted or inhibited by transgenic expression of the myostatin binding protein follistatin, there is a more profound increase in muscle mass and both hypertrophy and hyperplasia of fibers is observed XREF_BIBR, XREF_BIBR.	1	16	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	follistatin	expression of the myostatin binding protein follistatin	follistatin	myostatin	myostatin	myostatin	15	16	1	2
In addition , follistatin , but not the mutant follistatin , was able to induce muscle hypertrophy in Mstn -/- mice , suggesting that blockade of the activins , but not of GDF11 , could contribute to muscle hypertrophy in the absence of GDF8 .	In addition, follistatin, but not the mutant follistatin, was able to induce muscle hypertrophy in Mstn -/- mice, suggesting that blockade of the activins, but not of GDF11, could contribute to muscle hypertrophy in the absence of GDF8.	3	20	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	follistatin	follistatin	follistatin	Mstn	Mstn	Mstn	3	4	18	19
Follistatin antagonize myostatin inhibitory activity by direct protein interaction .	Follistatin antagonize myostatin inhibitory activity by direct protein interaction.	0	4	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	2	3
XREF_BIBR Therefore , one may postulate that a reduced expression of FNDC5 leads to a reduced expression of follistatin ( inhibitor of myostatin ) , which eventually caused a reduction in muscle mass -- a phenomenon often observed in heart failure .	XREF_BIBR Therefore, one may postulate that a reduced expression of FNDC5 leads to a reduced expression of follistatin (inhibitor of myostatin), which eventually caused a reduction in muscle mass -- a phenomenon often observed in heart failure.	9	27	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	follistatin	expression of FNDC5 leads to a reduced expression of follistatin	follistatin	myostatin	myostatin	myostatin	18	19	22	23
Both follistatin and GASPs inhibit the activities of GDF11 and myostatin ; accordingly , follistatin ( Fst )-heterozygous 47 and Gasp1-null or Gasp2-null 48 mice have smaller muscles and increased GDF11 and myostatin bioactivity .	Both follistatin and GASPs inhibit the activities of GDF11 and myostatin; accordingly, follistatin (Fst)-heterozygous 47 and Gasp1-null or Gasp2-null 48 mice have smaller muscles and increased GDF11 and myostatin bioactivity.	0	11	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	myostatin	myostatin	myostatin	1	2	10	11
Although the use of the deacetylase inhibitors to increase the levels of follistatin ( an antagonist of myostatin ) has not lead to any positive results in the treatment of cachexia in experimental animals [ XREF_BIBR , XREF_BIBR ] , the use of the activin receptor extracellular domain/Fc fusion protein ( ACVR2B-Fc ) has been shown to be effective in the treatment of muscle wasting in tumor bearing animals [ XREF_BIBR ] .	Although the use of the deacetylase inhibitors to increase the levels of follistatin (an antagonist of myostatin) has not lead to any positive results in the treatment of cachexia in experimental animals [XREF_BIBR, XREF_BIBR], the use of the activin receptor extracellular domain/Fc fusion protein (ACVR2B-Fc) has been shown to be effective in the treatment of muscle wasting in tumor bearing animals [XREF_BIBR].	10	18	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	follistatin	levels of follistatin	follistatin	myostatin	myostatin	myostatin	12	13	17	18
Follistatin antagonizes myostatin mediated inhibition of myogenesis [ XREF_BIBR ] .	Follistatin antagonizes myostatin mediated inhibition of myogenesis [XREF_BIBR].	0	4	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Follistatin	Follistatin	Follistatin	myostatin	myostatin	myostatin	0	1	2	3
However , although a number of such markers have been proposed , e.g ., lower cortisol levels , increased heart rate dynamics shortly after the traumatic event or increased circulating PACAP or other vulnerability factors , such as polymorphism of the 5-HT transporter ( see above ) or of FkBP5 , a co-chaperone that modulates the glucocorticoid receptor ( GR ) , none qualify so far as a prognostic tool with sufficiently high accuracy .	However, although a number of such markers have been proposed, e.g., lower cortisol levels, increased heart rate dynamics shortly after the traumatic event or increased circulating PACAP or other vulnerability factors, such as polymorphism of the 5-HT transporter (see above) or of FkBP5, a co-chaperone that modulates the glucocorticoid receptor (GR), none qualify so far as a prognostic tool with sufficiently high accuracy.	34	58	modulates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	FkBP5	FkBP5	FkBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	49	50	56	58
FKBP4 is a functional antagonist of FKBP5 , modulating glucocorticoid receptor function .	FKBP4 is a functional antagonist of FKBP5, modulating glucocorticoid receptor function.	4	11	modulating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	6	7	9	11
FK506 binding protein 5 gene ( FKBP5 ) modulates glucocorticoid receptor activity .	FK506 binding protein 5 gene (FKBP5) modulates glucocorticoid receptor activity.	2	11	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	6	7	9	11
FKBP5 is a negative modulator of the glucocorticoid receptor , and the methylation of specific intronic regions of its gene has been shown to modulate the receptor activity by interfering with the FKBP5 ultra-short feedback loop .	FKBP5 is a negative modulator of the glucocorticoid receptor, and the methylation of specific intronic regions of its gene has been shown to modulate the receptor activity by interfering with the FKBP5 ultra-short feedback loop.	0	9	is a negative modulator	Positive_activation_copula_1	Negative_activation	Positive_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	0	1	7	9
The other primary series of studies exploring gene-by-environment effects examined FKBP5 , a protein that modulates the glucocorticoid receptor ( GR ) .	The other primary series of studies exploring gene-by-environment effects examined FKBP5, a protein that modulates the glucocorticoid receptor (GR).	9	19	modulates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	10	11	17	19
As already discussed , FKBP5 modulates glucocorticoid receptor activity .	As already discussed, FKBP5 modulates glucocorticoid receptor activity.	4	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	4	5	6	8
The FKBP5 gene product modulates glucocorticoid receptor function and has been previously associated with differential hippocampal structure , function , and affect disorder risk .	The FKBP5 gene product modulates glucocorticoid receptor function and has been previously associated with differential hippocampal structure, function, and affect disorder risk.	1	7	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	1	2	5	7
As described earlier , FKBP5 modulates glucocorticoid receptor activity .	As described earlier, FKBP5 modulates glucocorticoid receptor activity.	4	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	4	5	6	8
The FKBP5 genotypes associated with suicidal events in this study have been reported by others to cause the greatest degree of glucocorticoid receptor subsensitivity .	The FKBP5 genotypes associated with suicidal events in this study have been reported by others to cause the greatest degree of glucocorticoid receptor subsensitivity.	1	23	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FKBP5	FKBP5	FKBP5	glucocorticoid receptor	glucocorticoid receptor	glucocorticoid receptor	1	2	21	23
There is also a close relationship between FOXO proteins and PGC1alpha , as FOXO1 and FOXO3 have been shown to increase PGC1alpha activity , and PGC1alpha itself can augment the transcriptional activity of FOXO3 .	There is also a close relationship between FOXO proteins and PGC1alpha, as FOXO1 and FOXO3 have been shown to increase PGC1alpha activity, and PGC1alpha itself can augment the transcriptional activity of FOXO3.	13	22	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FOXO1	FOXO1	FOXO1	PGC1alpha	PGC1alpha	PGC1alpha	13	14	21	22
Furthermore , nuclear form of FoxO1 induces PGC-1alpha , UCP1 , SOD2 [ XREF_BIBR ] as well as ATGL gene transcription [ XREF_BIBR ] .	Furthermore, nuclear form of FoxO1 induces PGC-1alpha, UCP1, SOD2 [XREF_BIBR] as well as ATGL gene transcription [XREF_BIBR].	3	13	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FoxO1	FoxO1	FoxO1	PGC-1alpha	PGC-1alpha	PGC-1alpha	5	6	7	8
Although FOXO1 can be synergized by PGC-1alpha ( Puigserver etal .	Although FOXO1 can be synergized by PGC-1alpha (Puigserver etal.	1	8	synergized	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FOXO1	FOXO1	FOXO1	PGC-1alpha	PGC-1alpha	PGC-1alpha	1	2	6	7
reported that the synergistic growth inhibition mediated by FHIT and wt p53 in NSCLC cells is due to the stabilization and accumulation of p53 as a result of FHIT mediated down-regulation of MDM2 .	reported that the synergistic growth inhibition mediated by FHIT and wt p53 in NSCLC cells is due to the stabilization and accumulation of p53 as a result of FHIT mediated down-regulation of MDM2.	26	33	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FHIT	FHIT	FHIT	MDM2	MDM2	MDM2	28	29	32	33
In lung cancer cells , it was shown that FHIT ( fragile histidine triad gene ) mediates MDM2 inactivation .	In lung cancer cells, it was shown that FHIT (fragile histidine triad gene) mediates MDM2 inactivation.	9	18	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FHIT	FHIT	FHIT	MDM2	MDM2	MDM2	9	10	17	18
Furthermore , we found that this synergistic inhibition of tumor cell growth corresponded with the FHIT mediated inactivation of MDM2 , which thereby blocked the association of MDM2 with p53 , thus stabilizing the p53 protein .	Furthermore, we found that this synergistic inhibition of tumor cell growth corresponded with the FHIT mediated inactivation of MDM2, which thereby blocked the association of MDM2 with p53, thus stabilizing the p53 protein.	14	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FHIT	FHIT	FHIT	MDM2	MDM2	MDM2	15	16	19	20
Interestingly , inhibition of GDF11 signalling by follistatin substantially enhances muscle derived stem cell proliferation .	Interestingly, inhibition of GDF11 signalling by follistatin substantially enhances muscle derived stem cell proliferation.	4	8	signalling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	follistatin	follistatin	follistatin	GDF11	GDF11	GDF11	7	8	4	5
Inhibition of activin receptor signaling or blockade of activin A and GDF11 by the endogenous protein follistatin overcame this resistance .	Inhibition of activin receptor signaling or blockade of activin A and GDF11 by the endogenous protein follistatin overcame this resistance.	6	17	blockade	Negative_activation_syntax_2_noun	Negative_activation	Negative_activation	follistatin	follistatin	follistatin	GDF11	GDF11	GDF11	16	17	11	12
Finally , NS5A interacts with FKBP8 and can disrupt FKBP8 mediated mTOR regulation , while also stabilizing interaction with Hsp90 [ XREF_BIBR ] .	Finally, NS5A interacts with FKBP8 and can disrupt FKBP8 mediated mTOR regulation, while also stabilizing interaction with Hsp90 [XREF_BIBR].	8	12	mediated	Positive_early_activation	Negative_activation	Positive_activation	FKBP8	FKBP8	FKBP8	mTOR	mTOR	mTOR	9	10	11	12
Five of these genes -PTEN , AGPAT1 , PRKAA1 , FKBP8 and MAP4K3- were found to act upstream of mTOR complexes , and could modulate mTOR signalling .	Five of these genes -PTEN, AGPAT1, PRKAA1, FKBP8 and MAP4K3- were found to act upstream of mTOR complexes, and could modulate mTOR signalling.	4	26	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FKBP8	FKBP8	FKBP8	mTOR	mTOR	mTOR	10	11	25	26
FKBP12 may not be a direct substrate of TbetaR-I but possibly modulates the TbetaR-I function through its interaction with the regulatory domain of the kinase .	FKBP12 may not be a direct substrate of TbetaR-I but possibly modulates the TbetaR-I function through its interaction with the regulatory domain of the kinase.	0	14	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FKBP12	FKBP12	FKBP12	TbetaR-I	TbetaR-I	TbetaR-I	0	1	13	14
Fragile Histidine Triad ( FHIT ) Suppresses Proliferation and Promotes Apoptosis in Cholangiocarcinoma Cells by Blocking PI3K-Akt Pathway .	Fragile Histidine Triad (FHIT) Suppresses Proliferation and Promotes Apoptosis in Cholangiocarcinoma Cells by Blocking PI3K-Akt Pathway.	2	17	Suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	FHIT	FHIT	FHIT	PI3K-Akt	PI3K-Akt	PI3K-Akt	4	5	16	17
Our present study demonstrates that ectopic expression of Foxa2 positively regulates Lmx1a , Otx2 and other key transcription factors responsible for DA neuron development , and negatively regulates transcription factors related to glial cell development ( XREF_FIG ) .	Our present study demonstrates that ectopic expression of Foxa2 positively regulates Lmx1a, Otx2 and other key transcription factors responsible for DA neuron development, and negatively regulates transcription factors related to glial cell development (XREF_FIG).	6	18	positively regulates	Positive_activation_syntax_1b_verb	Negative_activation	Positive_activation	Foxa2	expression of Foxa2	foxa2	Otx2	Otx2	otx2	8	9	13	14
Our current studies clearly indicate a role of GFRP in modulation of both basal and laminar shear stimulated GTPCH-1 activity in human endothelial cells .	Our current studies clearly indicate a role of GFRP in modulation of both basal and laminar shear stimulated GTPCH-1 activity in human endothelial cells.	6	19	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GFRP	GFRP	GFRP	GTPCH-1	GTPCH-1	GTPCH-1	8	9	18	19
In animals , the GTPCHI feedback regulatory protein ( GFRP ) binds GTPCHI to mediate feed-forward activation of GTPCHI activity in the presence of phenylalanine , whereas it induces feedback inhibition of enzyme activity in the presence of biopterin .	In animals, the GTPCHI feedback regulatory protein (GFRP) binds GTPCHI to mediate feed-forward activation of GTPCHI activity in the presence of phenylalanine, whereas it induces feedback inhibition of enzyme activity in the presence of biopterin.	7	19	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GFRP	GFRP	GFRP	GTPCHI	GTPCHI	GTPCHI	9	10	18	19
Our results also reveal a novel mechanism for GFRP modulation of GTPCH-1 activity , by inhibiting its phosphorylation .	Our results also reveal a novel mechanism for GFRP modulation of GTPCH-1 activity, by inhibiting its phosphorylation.	8	12	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	GFRP	GFRP	GFRP	GTPCH-1	GTPCH-1	GTPCH-1	8	9	11	12
Recombinant human GFRP stimulated recombinant human GTP cyclohydrolase I in the presence of phenylalanine and mediated feedback inhibition by tetrahydrobiopterin .	Recombinant human GFRP stimulated recombinant human GTP cyclohydrolase I in the presence of phenylalanine and mediated feedback inhibition by tetrahydrobiopterin.	0	15	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GFRP	GFRP	GFRP	GTP cyclohydrolase I	GTP cyclohydrolase I	GTP cyclohydrolase I	2	3	6	9
The complex structure suggests that phenylalanine induced GTPCHI x GFRP complex formation enhances GTPCHI activity by locking the enzyme in the active state .	The complex structure suggests that phenylalanine induced GTPCHI x GFRP complex formation enhances GTPCHI activity by locking the enzyme in the active state.	6	14	enhances	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	GFRP	GFRP	GFRP	GTPCHI	GTPCHI	GTPCHI	9	10	13	14
GFRP also mediates feed-forward stimulation of GTP cyclohydrolase I activity by phenylalanine at subsaturating GTP levels .	GFRP also mediates feed-forward stimulation of GTP cyclohydrolase I activity by phenylalanine at subsaturating GTP levels.	0	9	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GFRP	GFRP	GFRP	GTP cyclohydrolase I	GTP cyclohydrolase I	GTP cyclohydrolase I	0	1	6	9
The P -3 Asp side chain at the C-terminus of CFTR significantly limits its affinity for CAL , which targets CFTR to the lysosome , but not for NHERF1 and NHERF2 , which functionally stabilize CFTR at the apical membrane ( XREF_TABLE ) .	The P -3 Asp side chain at the C-terminus of CFTR significantly limits its affinity for CAL, which targets CFTR to the lysosome, but not for NHERF1 and NHERF2, which functionally stabilize CFTR at the apical membrane (XREF_TABLE).	12	21	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	16	17	20	21
In parallel , several publications have shown that PIST may direct an associated membrane protein ( namely the CFTR ) towards lysosomal degradation XREF_BIBR , XREF_BIBR , XREF_BIBR .	In parallel, several publications have shown that PIST may direct an associated membrane protein (namely the CFTR) towards lysosomal degradation XREF_BIBR, XREF_BIBR, XREF_BIBR.	8	19	direct	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIST	PIST	PIST	CFTR	CFTR	CFTR	8	9	18	19
The cystic fibrosis transmembrane conductance regulator ( CFTR )-interacting protein , CFTR associated ligand ( CAL ) down-regulates total and cell surface CFTR by targeting CFTR for degradation in the lysosome .	The cystic fibrosis transmembrane conductance regulator (CFTR)-interacting protein, CFTR associated ligand (CAL) down-regulates total and cell surface CFTR by targeting CFTR for degradation in the lysosome.	13	23	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	15	16	22	23
More recently , Pelaseyed and Hansson [ XREF_BIBR ] elucidated the modulated down-expression of CFTR through over-expression of GOPC , which directs CFTR for degradation .	More recently, Pelaseyed and Hansson [XREF_BIBR] elucidated the modulated down-expression of CFTR through over-expression of GOPC, which directs CFTR for degradation.	16	24	directs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GOPC	over-expression of GOPC	gopc	CFTR	CFTR	cftr	18	19	22	23
As shown in XREF_FIG , silencing of MARCH2 inhibited the degradation of CFTR by CAL .	As shown in XREF_FIG, silencing of MARCH2 inhibited the degradation of CFTR by CAL.	8	15	degradation	Negative_activation_token_2_noun	Negative_activation	Positive_activation	CAL	CAL	CAL	CFTR	CFTR	CFTR	14	15	12	13
With the use of an antisense approach , reduced Gadd45 expression attenuated the suppression of Cdc2 and Cyclin B1 activity in UV irradiated human cells .	With the use of an antisense approach, reduced Gadd45 expression attenuated the suppression of Cdc2 and Cyclin B1 activity in UV irradiated human cells.	9	19	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Gadd45	Gadd45 expression	gadd45	Cdc2	Cdc2	cdc2	9	10	15	16
Glypican-3 induces oncogenicity by preventing IGF-1R degradation , a process that can be blocked by Grb10 .	Glypican-3 induces oncogenicity by preventing IGF-1R degradation, a process that can be blocked by Grb10.	5	16	blocked	Negative_activation_syntax_6_verb	Negative_activation	Positive_activation	Grb10	Grb10	Grb10	IGF-1R	IGF-1R	IGF-1R	15	16	5	6
In addition to inhibiting insulin receptor and IGF1R kinase activity by directly binding to the receptors , GRB10 can also negatively regulate insulin and IGF1 signaling by mediating insulin receptor and IGF1R degradation through ubiquitination .	In addition to inhibiting insulin receptor and IGF1R kinase activity by directly binding to the receptors, GRB10 can also negatively regulate insulin and IGF1 signaling by mediating insulin receptor and IGF1R degradation through ubiquitination.	17	32	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GRB10	GRB10	GRB10	IGF1R	IGF1R	IGF1R	17	18	31	32
We propose that activated Gli3 physically targets the MED12 interface within Mediator in order to functionally reverse Mediator dependent suppression of Shh target gene transcription .	We propose that activated Gli3 physically targets the MED12 interface within Mediator in order to functionally reverse Mediator dependent suppression of Shh target gene transcription.	3	9	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Gli3	Gli3	Gli3	MED12	MED12	MED12	4	5	8	9
The hedgehog signaling effector , Gli3 , targets Med12 through its activation domain and has been proposed to act by reversing the transcriptional repression caused by the Med12 module XREF_BIBR .	The hedgehog signaling effector, Gli3, targets Med12 through its activation domain and has been proposed to act by reversing the transcriptional repression caused by the Med12 module XREF_BIBR.	3	9	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Gli3	Gli3	Gli3	Med12	Med12	Med12	5	6	8	9
In addition , the mice became hyperinsulinemic owing to high levels of insulin resistance , which demonstrates that Meg1 and Grb10 also modulates the insulin receptor cascade negatively in vivo .	In addition, the mice became hyperinsulinemic owing to high levels of insulin resistance, which demonstrates that Meg1 and Grb10 also modulates the insulin receptor cascade negatively in vivo.	18	26	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Grb10	Grb10	Grb10	insulin receptor	insulin receptor	insulin receptor	20	21	24	26
Further , through qRT-PCR analysis , we confirmed that GATA2 -/- hESCs failed to activate SPI1 upon co-culture with OP9 .	Further, through qRT-PCR analysis, we confirmed that GATA2 -/- hESCs failed to activate SPI1 upon co-culture with OP9.	9	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GATA2	GATA2	GATA2	SPI1	SPI1	SPI1	9	10	15	16
GATA2 -/- hESCs failed to express SPI1 upon in vitro hematopoiesis through co-culturing with OP9 , and GATA2 has been reported to directly target and activate the SPI1 locus in mouse HPCs through two conserved regions [ XREF_BIBR ] .	GATA2 -/- hESCs failed to express SPI1 upon in vitro hematopoiesis through co-culturing with OP9, and GATA2 has been reported to directly target and activate the SPI1 locus in mouse HPCs through two conserved regions [XREF_BIBR].	17	28	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GATA2	GATA2	GATA2	SPI1	SPI1	SPI1	17	18	27	28
GRK2 is known to promote FPR1 internalization through phosphorylation 13 .	GRK2 is known to promote FPR1 internalization through phosphorylation 13.	0	6	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GRK2	GRK2	GRK2	FPR1	FPR1	FPR1	0	1	5	6
After SCF induced KIT dimerization and activation of its intrinsic kinase activity , phosphorylated tyrosine residues recruit SH2-domain containing proteins , including cytosolic adaptors SHC and GRB2 , SFKs ( LYN and FYN ) , PLCgamma , and PI3K .	After SCF induced KIT dimerization and activation of its intrinsic kinase activity, phosphorylated tyrosine residues recruit SH2-domain containing proteins, including cytosolic adaptors SHC and GRB2, SFKs (LYN and FYN), PLCgamma, and PI3K.	2	27	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GRB2	GRB2	GRB2	KIT	KIT	KIT	26	27	3	4
Dendritic Tau targets Fyn kinase to postsynaptic density , where Fyn facilitates stabilization of a complex triggering downstream excitotoxic signaling [ XREF_BIBR ] .	Dendritic Tau targets Fyn kinase to postsynaptic density, where Fyn facilitates stabilization of a complex triggering downstream excitotoxic signaling [XREF_BIBR].	1	4	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Fyn	Fyn	Fyn	Tau	Tau	Tau	3	4	1	2
Cordycepin reduced beta-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3beta , indicating that cordycepin suppressed beta-catenin stability is mediated by the activation of GSK-3beta .	Cordycepin reduced beta-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3beta, indicating that cordycepin suppressed beta-catenin stability is mediated by the activation of GSK-3beta.	2	15	restored	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	14	15	2	3
After IR injury , compared with control , p-beta-catenin and beta-catenin increased by 2.6-fold ( p < 0.001 ) , and p-GSK3beta and GSK3beta was decreased by 0.7-fold ( p = 0.036 ) .	After IR injury, compared with control, p-beta-catenin and beta-catenin increased by 2.6-fold (p < 0.001), and p-GSK3beta and GSK3beta was decreased by 0.7-fold (p = 0.036).	8	25	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	p-beta-catenin	p-beta-catenin	p-beta-catenin	23	24	8	9
DISC1 knockdown increased p-GSK3beta levels , and decreased beta-catenin and Cyclin D1 , while DISC1 upregulation produced the opposite results .	DISC1 knockdown increased p-GSK3beta levels, and decreased beta-catenin and Cyclin D1, while DISC1 upregulation produced the opposite results.	0	11	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p-GSK3beta	DISC1 knockdown increased p-GSK3beta levels	p-gsk3beta	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
Time course experiments revealed that PGE2 treatment resulted in increased phosphorylation of beta-catenin ( S675 ) and GSK3beta ( S9 ) , events that promote beta-catenin stabilization .	Time course experiments revealed that PGE2 treatment resulted in increased phosphorylation of beta-catenin (S675) and GSK3beta (S9), events that promote beta-catenin stabilization.	5	26	promote	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	GSK3beta	PGE2 treatment resulted in increased phosphorylation of beta-catenin (S675) and GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	17	18	25	26
Apart from reusing Dvl from autophagic degradation , mTORC1 inactivation of GSK3beta by S6K blocks the beta-catenin degradation .	Apart from reusing Dvl from autophagic degradation, mTORC1 inactivation of GSK3beta by S6K blocks the beta-catenin degradation.	9	17	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	11	12	16	17
Inactivated GSK3beta allows beta catenin to escape phosphorylation dependent proteosomal degradation , thereby promoting beta-catenin-mediated gene transcription XREF_BIBR .	Inactivated GSK3beta allows beta catenin to escape phosphorylation dependent proteosomal degradation, thereby promoting beta-catenin-mediated gene transcription XREF_BIBR.	0	5	allows	Positive_activation_token_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta catenin	beta catenin	beta catenin	1	2	3	5
BIO treatment downregulated the activity of GSK-3beta , upregulated and transported beta-catenin to the nucleus in CRC cells .	BIO treatment downregulated the activity of GSK-3beta, upregulated and transported beta-catenin to the nucleus in CRC cells.	4	14	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	11	12
However , in addition to its effects on mood stabilisation , lithium also inhibits glycogen synthase kinase-3beta ( GSK-3beta ) , which upregulates canonical Wnt and beta-catenin cell signalling [ XREF_BIBR ] .	However, in addition to its effects on mood stabilisation, lithium also inhibits glycogen synthase kinase-3beta (GSK-3beta), which upregulates canonical Wnt and beta-catenin cell signalling [XREF_BIBR].	16	28	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	18	19	26	27
Furthermore , IQUB overexpression or knockdown combined with treatment of Licl or MG-132 showed that IQUB activated Akt to promote GSK3beta phosphorylation , which in turn activated Wnt and beta-catenin signaling pathway in breast cancer cells .	Furthermore, IQUB overexpression or knockdown combined with treatment of Licl or MG-132 showed that IQUB activated Akt to promote GSK3beta phosphorylation, which in turn activated Wnt and beta-catenin signaling pathway in breast cancer cells.	20	31	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	20	21	29	30
Other research has shown that E-cadherin disassembly and concomitant inactivation of GSK-3beta that induces beta-catenin triggered NF-kappaB-dependent up-regulation of iNOS in hepatocytes .	Other research has shown that E-cadherin disassembly and concomitant inactivation of GSK-3beta that induces beta-catenin triggered NF-kappaB-dependent up-regulation of iNOS in hepatocytes.	6	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	11	12	14	15
LiCl , a potent inhibitor of Glycogen Synthase Kinase 3beta ( GSK3beta ) activity , abrogated the IL-6-induced inhibition of wild-type beta-catenin .	LiCl, a potent inhibitor of Glycogen Synthase Kinase 3beta (GSK3beta) activity, abrogated the IL-6-induced inhibition of wild-type beta-catenin.	0	22	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	11	12	21	22
For example , GSK-3beta is required for normal development and inhibits the canonical Wnt pathway by promoting the degradation of beta-catenin XREF_BIBR .	For example, GSK-3beta is required for normal development and inhibits the canonical Wnt pathway by promoting the degradation of beta-catenin XREF_BIBR.	3	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	20	21
Although Gsk3beta alone is able to modulate the Wnt and beta-catenin signaling , in some cases , inactivation of Gsk3beta does not necessarily lead to Wnt and beta-catenin signaling up-regulation .	Although Gsk3beta alone is able to modulate the Wnt and beta-catenin signaling, in some cases, inactivation of Gsk3beta does not necessarily lead to Wnt and beta-catenin signaling up-regulation.	1	11	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	1	2	10	11
Inhibition of AKT1/2 , but not GSK3beta , also blocked beta-catenin localization ( XREF_FIG ) , further indicating that dynamic HMW PEGDA/HA hydrogels mechanically induce sarcomere formation and regulate calcium handling via AKT and possibly Wnts .	Inhibition of AKT1/2, but not GSK3beta, also blocked beta-catenin localization (XREF_FIG), further indicating that dynamic HMW PEGDA/HA hydrogels mechanically induce sarcomere formation and regulate calcium handling via AKT and possibly Wnts.	0	11	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	6	7	10	11
Dishevelled prevents beta-catenin degradation by interfering with the interaction of beta-catenin with the degradation mediating Axin , APC , and GSK3beta complex .	Dishevelled prevents beta-catenin degradation by interfering with the interaction of beta-catenin with the degradation mediating Axin, APC, and GSK3beta complex.	1	21	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	20	21	2	3
49 IGF pathway activation may enhance Wnt and beta-catenin signaling , as Akt mediated phosphorylation and inactivation of GSK3beta enhances beta-catenin stability .	49 IGF pathway activation may enhance Wnt and beta-catenin signaling, as Akt mediated phosphorylation and inactivation of GSK3beta enhances beta-catenin stability.	12	21	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	Akt mediated phosphorylation and inactivation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	18	19	20	21
To further clarify the effects of LY , APO , and DPI on Wnt and beta-catenin signaling , the GSK3beta S9 phosphorylation , allowing accumulation of beta-catenin , was evaluated [ XREF_BIBR ] .	To further clarify the effects of LY, APO, and DPI on Wnt and beta-catenin signaling, the GSK3beta S9 phosphorylation, allowing accumulation of beta-catenin, was evaluated [XREF_BIBR].	19	27	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta S9 phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	19	20	26	27
These strands of evidence all support the inference that there is a strain responsive Wnt and LRP5 independent pathway in which beta-catenin is activated by PI3K and AKT mediated GSK-3beta suppression .	These strands of evidence all support the inference that there is a strain responsive Wnt and LRP5 independent pathway in which beta-catenin is activated by PI3K and AKT mediated GSK-3beta suppression.	21	30	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	AKT mediated GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	29	30	21	22
Our findings therefore suggest that constitutive , AKT mediated phosphorylation of GSK3beta on Ser 9 in BMDMs can promote beta-catenin accumulation and probably help in keeping a tonic survival status of the macrophage ( see model in XREF_SUPPLEMENTARY ) .	Our findings therefore suggest that constitutive, AKT mediated phosphorylation of GSK3beta on Ser 9 in BMDMs can promote beta-catenin accumulation and probably help in keeping a tonic survival status of the macrophage (see model in XREF_SUPPLEMENTARY).	7	20	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	AKT mediated phosphorylation of GSK3beta on Ser 9	gsk3beta	beta-catenin	beta-catenin	beta-catenin	11	12	19	20
The enhanced recruitment of GSK-3beta to the plasma membrane by free Gbetagamma and the subsequent phosphorylation of LRP6 at the PPPS/TP sites could be one of the reasons for the involvement of PKA in GPCR activated beta-catenin signaling .	The enhanced recruitment of GSK-3beta to the plasma membrane by free Gbetagamma and the subsequent phosphorylation of LRP6 at the PPPS/TP sites could be one of the reasons for the involvement of PKA in GPCR activated beta-catenin signaling.	2	37	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	recruitment of GSK-3beta to the plasma membrane	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	36	37
As beta-catenin turnover is triggered by GSK-3beta , a well known target of AKT , we made beta-catenin signaling a focal point of our investigation .	As beta-catenin turnover is triggered by GSK-3beta, a well known target of AKT, we made beta-catenin signaling a focal point of our investigation.	1	11	triggered	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	1	2
Activation of frizzled receptors by Wnt ligands disrupts the APC complex and inhibits GSK-3beta activity causing an accumulation of unphosphorylated ( i.e ., activated ) beta-catenin , which promotes its nuclear localization and subsequent regulation of target gene expression [ XREF_BIBR ] .	Activation of frizzled receptors by Wnt ligands disrupts the APC complex and inhibits GSK-3beta activity causing an accumulation of unphosphorylated (i.e., activated) beta-catenin, which promotes its nuclear localization and subsequent regulation of target gene expression [XREF_BIBR].	13	28	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	13	14	25	26
In primary human brain micro-vascular endothelial cells , de-phosphorylation of GSK-3beta at tyrosine 216 decreased the GSK3 mediated inhibition of beta-catenin .	In primary human brain micro-vascular endothelial cells, de-phosphorylation of GSK-3beta at tyrosine 216 decreased the GSK3 mediated inhibition of beta-catenin.	8	21	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	de-phosphorylation of GSK-3beta at tyrosine 216	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	10	11	20	21
Next , with the help of Gbp ( microarray reports a 4-fold increase of Gbp2 ) , Gsk-3beta is inhibited , which in turn inhibits beta-catenin .	Next, with the help of Gbp (microarray reports a 4-fold increase of Gbp2), Gsk-3beta is inhibited, which in turn inhibits beta-catenin.	17	26	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Gsk-3beta	Gsk-3beta	Gsk-3beta	beta-catenin	beta-catenin	beta-catenin	17	18	25	26
Akt phosphorylates and inactivates GSK3beta , allowing beta-catenin , a downstream effector of Wnt pathway to translocate into the nucleus where it binds to TCF-4 .	Akt phosphorylates and inactivates GSK3beta, allowing beta-catenin, a downstream effector of Wnt pathway to translocate into the nucleus where it binds to TCF-4.	0	16	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	Akt phosphorylates and inactivates GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	4	5	7	8
One pathway for inactivation of GSK3beta is by phosphorylation at serine 9 , originally described for insulin signaling through Akt and protein kinase B. Studies in non skeletal tissues have described beta-catenin activation mediated by phosphorylation of GSK3beta by Akt downstream of signaling through heterotrimeric G protein coupled receptors [ XREF_BIBR ; XREF_BIBR ] , a possibility which will certainly have implications for the skeleton .	One pathway for inactivation of GSK3beta is by phosphorylation at serine 9, originally described for insulin signaling through Akt and protein kinase B. Studies in non skeletal tissues have described beta-catenin activation mediated by phosphorylation of GSK3beta by Akt downstream of signaling through heterotrimeric G protein coupled receptors [XREF_BIBR; XREF_BIBR], a possibility which will certainly have implications for the skeleton.	31	38	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	37	38	31	32
CHIR is a highly specific GSK3 inhibitor that inhibits GSK3beta mediated beta-catenin degradation 28 .	CHIR is a highly specific GSK3 inhibitor that inhibits GSK3beta mediated beta-catenin degradation 28.	8	12	mediated	Positive_early_activation	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	9	10	11	12
beta-catenin is upregulated by the AKT and GSK3beta pathway , which thereby triggers the cell cycle by enhancing cyclin D1 expression XREF_BIBR .	beta-catenin is upregulated by the AKT and GSK3beta pathway, which thereby triggers the cell cycle by enhancing cyclin D1 expression XREF_BIBR.	0	8	upregulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	0	1
Inhibition of GSK-3beta leads to an accumulation of beta-catenin by decreasing the interaction of beta-catenin with APC , which targets beta-catenin for degradation .	Inhibition of GSK-3beta leads to an accumulation of beta-catenin by decreasing the interaction of beta-catenin with APC, which targets beta-catenin for degradation.	0	15	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	14	15
GSK-3beta prevented activation of the Wnt pathway by inhibiting beta-catenin activation .	GSK-3beta prevented activation of the Wnt pathway by inhibiting beta-catenin activation.	0	10	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	9	10
The Wnt binds to its co-receptors of Frizzled to activate Dsh , which recruits glycogen synthase kinase-3 beta ( GSK-3beta ) , promoting beta-catenin nuclear translocation and downstream gene expression , such as c-Myc .	The Wnt binds to its co-receptors of Frizzled to activate Dsh, which recruits glycogen synthase kinase-3 beta (GSK-3beta), promoting beta-catenin nuclear translocation and downstream gene expression, such as c-Myc.	17	24	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	19	20	23	24
Ordinarily , glycogen synthase kinase 3beta ( GSK-3beta ) constitutively phosphorylates and thereby targets beta-Catenin for degradation through the ubiquitin mediated proteosomal pathway .	Ordinarily, glycogen synthase kinase 3beta (GSK-3beta) constitutively phosphorylates and thereby targets beta-Catenin for degradation through the ubiquitin mediated proteosomal pathway.	5	15	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-Catenin	beta-Catenin	beta-Catenin	7	8	14	15
Upon TGF-beta stimulation , GSK-3beta is phosphorylated and inactivated , allowing beta-catenin to translocate to the nucleus , where it activates transcription of genes involved in myofibroblastic differentiation .	Upon TGF-beta stimulation, GSK-3beta is phosphorylated and inactivated, allowing beta-catenin to translocate to the nucleus, where it activates transcription of genes involved in myofibroblastic differentiation.	4	13	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta is phosphorylated	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	11	12
These suggest that HDAC is not involved in the recovery effect of VPA on ADP proliferation and that VPA recovers the inhibitory effects of DEX via increasing the phosphorylation of Ser ( 9 ) on GSK-3beta and following up-regulation of beta-catenin pathway .	These suggest that HDAC is not involved in the recovery effect of VPA on ADP proliferation and that VPA recovers the inhibitory effects of DEX via increasing the phosphorylation of Ser (9) on GSK-3beta and following up-regulation of beta-catenin pathway.	35	41	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	35	36	40	41
Our data demonstrated that DAX1 is overexpressed in cervical cancer , and that it promotes cell growth and tumorigenicity through activating Wnt and beta-catenin pathway mediated by GSK3beta .	Our data demonstrated that DAX1 is overexpressed in cervical cancer, and that it promotes cell growth and tumorigenicity through activating Wnt and beta-catenin pathway mediated by GSK3beta.	21	28	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	27	28	23	24
Under basal conditions , cytosolic beta-catenin levels are kept low due to glycogen synthase kinase-3 beta ( GSK3beta )-mediated phosphorylation that targets beta-catenin for degradation .	Under basal conditions, cytosolic beta-catenin levels are kept low due to glycogen synthase kinase-3 beta (GSK3beta)-mediated phosphorylation that targets beta-catenin for degradation.	12	24	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta (GSK3beta)-mediated phosphorylation	glycogen synthase kinase-3 beta	beta-catenin	beta-catenin	beta-catenin	12	16	22	23
Given that beta-catenin is targeted for degradation via phosphorylation of its serine ( Ser33/37/45 ) and threonine ( Thr41 ) residues by GSK-3beta , XREF_BIBR , XREF_BIBR we measured the levels of beta-catenin and phospho-beta-catenin in cholangiocarcinoma cells with or without miR-26a overexpression .	Given that beta-catenin is targeted for degradation via phosphorylation of its serine (Ser33/37/45) and threonine (Thr41) residues by GSK-3beta, XREF_BIBR, XREF_BIBR we measured the levels of beta-catenin and phospho-beta-catenin in cholangiocarcinoma cells with or without miR-26a overexpression.	2	26	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	22	23	2	3
Conventional PKC ( cPKC ) specific inhibitor GO6976 was found to abolish LPA induced GSK3beta phosphorylation and strongly inhibited nuclear accumulation of beta-catenin ( XREF_FIG ) .	Conventional PKC (cPKC) specific inhibitor GO6976 was found to abolish LPA induced GSK3beta phosphorylation and strongly inhibited nuclear accumulation of beta-catenin (XREF_FIG).	1	24	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	PKC (cPKC) specific inhibitor GO6976 was found to abolish LPA induced GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	14	15	22	23
GSK-3beta phosphorylation decreases the degradation of beta-catenin in the proteasome .	GSK-3beta phosphorylation decreases the degradation of beta-catenin in the proteasome.	0	9	decreases	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	6	7
The inactivation of GSK-3beta , specifically through tyrosine 216 dephosphorylation , increased beta-catenin , which is an important factor in maintaining BBB integrity [ XREF_BIBR , XREF_BIBR ] .	The inactivation of GSK-3beta, specifically through tyrosine 216 dephosphorylation, increased beta-catenin, which is an important factor in maintaining BBB integrity [XREF_BIBR, XREF_BIBR].	1	18	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	12	13
ABCB1 reduction was mainly triggered by an enhanced Glycogen Synthase Kinase 3 ( GSK3beta ) activation , which decreased beta-catenin nuclear abundance .	ABCB1 reduction was mainly triggered by an enhanced Glycogen Synthase Kinase 3 (GSK3beta) activation, which decreased beta-catenin nuclear abundance.	13	21	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	13	14	19	20
The N-terminal phosphorylation of GSK-3beta , phosphorylation of beta-catenin at S552 and S675 , and the induction of KLF5 collectively activate beta-catenin .	The N-terminal phosphorylation of GSK-3beta, phosphorylation of beta-catenin at S552 and S675, and the induction of KLF5 collectively activate beta-catenin.	2	22	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	phosphorylation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	21	22
Axin is a rate limiting component in Wnt signaling , being maintained at low steady-state protein levels yet required for efficient targeting of beta-catenin by Gsk3b [ XREF_BIBR , XREF_BIBR ] .	Axin is a rate limiting component in Wnt signaling, being maintained at low steady-state protein levels yet required for efficient targeting of beta-catenin by Gsk3b [XREF_BIBR, XREF_BIBR].	21	29	targeting	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Gsk3b	Gsk3b	Gsk3b	beta-catenin	beta-catenin	beta-catenin	25	26	23	24
SOX2 can bind beta-catenin , a key mediator of canonical Wnt signaling , and directly induce expression of the negative regulators APC and GSK3beta , which promote beta-catenin degradation .	SOX2 can bind beta-catenin, a key mediator of canonical Wnt signaling, and directly induce expression of the negative regulators APC and GSK3beta, which promote beta-catenin degradation.	0	28	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	SOX2 can bind beta-catenin, a key mediator of canonical Wnt signaling, and directly induce expression of the negative regulators APC and GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	23	24	27	28
Under these conditions , the inhibition of GSK-3beta and consequent activation of Wnt and beta-Catenin pathway has been shown to contribute to mES cell self-renewal XREF_BIBR , XREF_BIBR .	Under these conditions, the inhibition of GSK-3beta and consequent activation of Wnt and beta-Catenin pathway has been shown to contribute to mES cell self-renewal XREF_BIBR, XREF_BIBR.	7	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-Catenin	beta-Catenin	beta-Catenin	7	8	14	15
Thus , inactivated GSK-3beta , which is phosphorylated at its Ser9 , inhibits this proteasomal degradation of beta-catenin .	Thus, inactivated GSK-3beta, which is phosphorylated at its Ser9, inhibits this proteasomal degradation of beta-catenin.	3	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta, which is phosphorylated at its Ser9	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	17	18
XREF_BIBR On the contrary , phosphorylation of GSK3beta rescues beta-catenin from this destructive phosphorylation , leading to cytosolic accumulation of non phosphorylated beta-catenin .	XREF_BIBR On the contrary, phosphorylation of GSK3beta rescues beta-catenin from this destructive phosphorylation, leading to cytosolic accumulation of non phosphorylated beta-catenin.	5	10	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
These findings suggest that LPA stimulation of LR-MSCs leads GSK3beta phosphorylation which inhibits beta-catenin degradation and leads to beta-catenin pathway activation .	These findings suggest that LPA stimulation of LR-MSCs leads GSK3beta phosphorylation which inhibits beta-catenin degradation and leads to beta-catenin pathway activation.	4	20	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	LPA stimulation of LR-MSCs leads GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	9	10	18	19
Our data indicated that Wnt and beta-catenin signaling pathway can be activated by GSK3beta antagonists LiCl or SB216763 in PC12 cells .	Our data indicated that Wnt and beta-catenin signaling pathway can be activated by GSK3beta antagonists LiCl or SB216763 in PC12 cells.	6	14	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	13	14	6	7
Moreover , Akt regulates adipogenesis via the phosphorylation and inactivation of substrates , such as GSK3beta , which directly regulates PPARgamma , C/EBPbeta , C/EBPalpha and beta-catenin XREF_BIBR , XREF_BIBR .	Moreover, Akt regulates adipogenesis via the phosphorylation and inactivation of substrates, such as GSK3beta, which directly regulates PPARgamma, C/EBPbeta, C/EBPalpha and beta-catenin XREF_BIBR, XREF_BIBR.	4	27	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	15	16	26	27
The proteasomal degradation of beta-catenin mediated by GSK-3beta and the destruction complex is the central step in the canonical WNT signaling pathway .	The proteasomal degradation of beta-catenin mediated by GSK-3beta and the destruction complex is the central step in the canonical WNT signaling pathway.	2	11	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	4	5
To determine the mechanisms involved , TLR4 inhibited the phosphorylation of the upstream inhibitory kinase GSK3beta , causing beta-catenin degradation and subsequently a decrease in proliferation and repair .	To determine the mechanisms involved, TLR4 inhibited the phosphorylation of the upstream inhibitory kinase GSK3beta, causing beta-catenin degradation and subsequently a decrease in proliferation and repair.	6	19	causing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	TLR4 inhibited the phosphorylation of the upstream inhibitory kinase GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	15	16	18	19
XREF_FIG shows that without LiCl , an inhibitor of GSK-3beta , oleandrin was able to suppress the activities of Wnt and beta-catenin signaling by downregulating the TOP and FOP flash ratio in a concentration dependent manner ( 25 nM or 50 nM vs. control : P = 0.017 or P = 0.001 , 25 nM vs. 50 nM : P = 0.043 ) .	XREF_FIG shows that without LiCl, an inhibitor of GSK-3beta, oleandrin was able to suppress the activities of Wnt and beta-catenin signaling by downregulating the TOP and FOP flash ratio in a concentration dependent manner (25 nM or 50 nM vs. control : P = 0.017 or P = 0.001, 25 nM vs. 50 nM : P = 0.043).	7	22	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	9	10	21	22
In addition , phosphorylation of GSK-3beta at serine 9 residue decreases its activity and also causes cytoplasmic stabilization and nuclear translocation of beta-catenin resulting in T-cell factor-( TCF )/lymphoid enhancer factor ( LEF )-dependent transcriptional activation of target genes such as cyclin D1 and c-Myc .	In addition, phosphorylation of GSK-3beta at serine 9 residue decreases its activity and also causes cytoplasmic stabilization and nuclear translocation of beta-catenin resulting in T-cell factor-(TCF)/lymphoid enhancer factor (LEF)-dependent transcriptional activation of target genes such as cyclin D1 and c-Myc.	3	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	phosphorylation of GSK-3beta at serine 9	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	22	23
Because phosphorylation of glycogen synthase kinase-3beta ( GSK-3beta ) inhibits beta-catenin degradation , we further evaluated the effects of ANG II and ANG II plus pyr on p-ser9-GSK-3beta levels .	Because phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) inhibits beta-catenin degradation, we further evaluated the effects of ANG II and ANG II plus pyr on p-ser9-GSK-3beta levels.	1	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	phosphorylation of glycogen synthase kinase-3beta (GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	10	11
Phosphorylation of GSK3beta has been shown to mediate beta-catenin activation through inhibition of beta-catenin degradation complex .	Phosphorylation of GSK3beta has been shown to mediate beta-catenin activation through inhibition of beta-catenin degradation complex.	0	9	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	Phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
GSK3beta regulates soluble , cystosolic , beta-catenin expression by promoting its proteasomal degradation , while phosphorylation in S9 of GSK3beta mediates beta-catenin stabilization [ XREF_BIBR ] .	GSK3beta regulates soluble, cystosolic, beta-catenin expression by promoting its proteasomal degradation, while phosphorylation in S9 of GSK3beta mediates beta-catenin stabilization [XREF_BIBR].	17	22	mediates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	19	20	21	22
ColX expressing chondrocytes were detected in Col2a1-Smurf2 transgenic mice which might represent a mechanism of Smurf2 induced OA that Smurf2 mainly induced ubiquitination of GSK-3beta and its proteasomal degradation , and hence upregulation of beta-catenin [ XREF_BIBR ] .	ColX expressing chondrocytes were detected in Col2a1-Smurf2 transgenic mice which might represent a mechanism of Smurf2 induced OA that Smurf2 mainly induced ubiquitination of GSK-3beta and its proteasomal degradation, and hence upregulation of beta-catenin [XREF_BIBR].	0	36	upregulation	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	GSK-3beta	ColX expressing chondrocytes were detected in Col2a1-Smurf2 transgenic mice which might represent a mechanism of Smurf2 induced OA that Smurf2 mainly induced ubiquitination of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	24	25	34	35
GSK3beta serine 9 phosphorylation is known to render the kinase inactive leading to non phophorylation of its substrate beta-catenin and thus prevents beta-catenin protein degradation by proteosome .	GSK3beta serine 9 phosphorylation is known to render the kinase inactive leading to non phophorylation of its substrate beta-catenin and thus prevents beta-catenin protein degradation by proteosome.	0	24	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	0	1	22	23
Further analysis showed that LiCl mediated inactivation of the kinase GSK-3beta increased beta-catenin membrane ruffle staining ; this correlated with a faster rate of recruitment and not increased membrane retention of beta-catenin .	Further analysis showed that LiCl mediated inactivation of the kinase GSK-3beta increased beta-catenin membrane ruffle staining; this correlated with a faster rate of recruitment and not increased membrane retention of beta-catenin.	6	32	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	10	11	31	32
Figure XREF_FIG shows that without CHIR-99021 , an inhibitor of GSK-3beta , resveratrol was able to suppress Wnt and beta-catenin signaling by down-regulating the TOP and FOP flash ratio in a concentration dependent manner ( P < 0.05 ) .	Figure XREF_FIG shows that without CHIR-99021, an inhibitor of GSK-3beta, resveratrol was able to suppress Wnt and beta-catenin signaling by down-regulating the TOP and FOP flash ratio in a concentration dependent manner (P < 0.05).	8	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	10	11	19	20
GSK3beta is recruited to MCAM and phosphorylated at Ser9 by p38MAPK which renders GSK3beta kinase inactive leaving its substrate beta-catenin non phophorylated and thus preventing beta-catenin protein degradation by proteosome .	GSK3beta is recruited to MCAM and phosphorylated at Ser9 by p38MAPK which renders GSK3beta kinase inactive leaving its substrate beta-catenin non phophorylated and thus preventing beta-catenin protein degradation by proteosome.	13	27	preventing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	13	14	25	26
The induction of the phosphorylation of GSK-3beta inhibits its activity and allows beta-catenin to translocate to the nucleus and interact with T-cell factor and lymphocyte enhancer binding factor ( TCF/LEF ) to regulate the transcription of target genes .	The induction of the phosphorylation of GSK-3beta inhibits its activity and allows beta-catenin to translocate to the nucleus and interact with T-cell factor and lymphocyte enhancer binding factor (TCF/LEF) to regulate the transcription of target genes.	4	14	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	phosphorylation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	12	13
SGK3 promotes liver CSCs through beta-catenin accumulation by GSK3beta .	SGK3 promotes liver CSCs through beta-catenin accumulation by GSK3beta.	1	9	promotes	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	8	9	5	6
In gastric cancer , activated AKT induces the in activation of GSK-3beta , thereby activating Wnt and beta-catenin signaling [ XREF_BIBR ] .	In gastric cancer, activated AKT induces the in activation of GSK-3beta, thereby activating Wnt and beta-catenin signaling [XREF_BIBR].	9	20	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	11	12	17	18
Role of GSK-3beta and Wnt3a on STRAP induced stabilization of beta-catenin .	Role of GSK-3beta and Wnt3a on STRAP induced stabilization of beta-catenin.	0	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	10	11
Our data show that NDRG2 introduction into SW620 cells induces a decrease in GSK-3beta phosphorylation , which increases its kinase activity ( XREF_FIG ) and subsequently induces beta-catenin downregulation ( XREF_FIG and XREF_FIG ) .	Our data show that NDRG2 introduction into SW620 cells induces a decrease in GSK-3beta phosphorylation, which increases its kinase activity (XREF_FIG) and subsequently induces beta-catenin downregulation (XREF_FIG and XREF_FIG).	4	28	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	NDRG2 introduction into SW620 cells induces a decrease in GSK-3beta phosphorylation	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	13	14	27	28
Knockdown of GSK3alpha or GSK3beta individually does not increase beta-catenin and offers a conceptual resolution to targeting GSK3 : paralog selective inhibition .	Knockdown of GSK3alpha or GSK3beta individually does not increase beta-catenin and offers a conceptual resolution to targeting GSK3 : paralog selective inhibition.	0	10	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	4	5	9	10
During chronic lithium treatment , GSK-3beta is inactivated , preventing beta-catenin degradation , and thus increasing protein expression .	During chronic lithium treatment, GSK-3beta is inactivated, preventing beta-catenin degradation, and thus increasing protein expression.	5	11	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	10	11
Here we report that in osteoblastic ROS 17/2 .8 cells and primary osteoblast cultures , a single short period of dynamic mechanical strain , as well as the glycogen synthase kinase-3beta ( GSK-3beta ) inhibitor LiCl , increased nuclear accumulation of activated beta-catenin and stimulated TCF/LEF reporter activity .	Here we report that in osteoblastic ROS 17/2.8 cells and primary osteoblast cultures, a single short period of dynamic mechanical strain, as well as the glycogen synthase kinase-3beta (GSK-3beta) inhibitor LiCl, increased nuclear accumulation of activated beta-catenin and stimulated TCF/LEF reporter activity.	30	43	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	32	33	42	43
Importantly , the WNT and GSK3beta axis has recently been shown to activate intracellular signaling independent of beta-catenin stabilization .	Importantly, the WNT and GSK3beta axis has recently been shown to activate intracellular signaling independent of beta-catenin stabilization.	5	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	5	6	17	18
XREF_BIBR , XREF_BIBR , XREF_BIBR In this study , it was found that GSK-3beta could mediate beta-catenin and NF-kappaB signaling through the regulation of translocation of beta-catenin and p65 to the nucleus .	XREF_BIBR, XREF_BIBR, XREF_BIBR In this study, it was found that GSK-3beta could mediate beta-catenin and NF-kappaB signaling through the regulation of translocation of beta-catenin and p65 to the nucleus.	13	19	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	13	14	16	17
Additionally , 655-nm red light + LED enhanced the expression of beta-catenin , p-GSK3beta , and Lef1 , signaling molecules of the Wnt and beta-catenin pathway , in the hair matrix .	Additionally, 655-nm red light + LED enhanced the expression of beta-catenin, p-GSK3beta, and Lef1, signaling molecules of the Wnt and beta-catenin pathway, in the hair matrix.	9	25	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p-GSK3beta	expression of beta-catenin, p-GSK3beta	p-gsk3beta	beta-catenin	beta-catenin	beta-catenin	13	14	24	25
Downstream signaling of IGF-I can phosphorylate and inactivate GSK-3beta , thereby enhancing beta-catenin protein .	Downstream signaling of IGF-I can phosphorylate and inactivate GSK-3beta, thereby enhancing beta-catenin protein.	5	13	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	phosphorylate and inactivate GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	8	9	12	13
BIO , an inhibitor of the negative regulator GSK3beta , leads to target gene expression by stabilizing beta-catenin from the degradation complex XREF_BIBR XREF_BIBR , whereas JW74 stabilizes AXIN , a component of the beta-catenin degradation complex , eventually causing beta-catenin degradation XREF_BIBR .	BIO, an inhibitor of the negative regulator GSK3beta, leads to target gene expression by stabilizing beta-catenin from the degradation complex XREF_BIBR XREF_BIBR, whereas JW74 stabilizes AXIN, a component of the beta-catenin degradation complex, eventually causing beta-catenin degradation XREF_BIBR.	3	18	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	8	9	17	18
Signaling events that activate Disheveled ( Dvl ) phosphorylate GSK3beta and inhibit this cytostolic degradation machinery and promote stabilization of beta-catenin .	Signaling events that activate Disheveled (Dvl) phosphorylate GSK3beta and inhibit this cytostolic degradation machinery and promote stabilization of beta-catenin.	6	21	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	Dvl) phosphorylate GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	9	10	20	21
The canonical Wnt and beta-catenin pathway is initiated by binding of Wnts ( eg , Wnt3a ) to the cell surface molecules LRP5/6 and Frizzled ( FZD ) , resulting in the release of cytoplasmic beta-catenin from a protein complex consisting of Axin1/2 , APC , casein kinase 1 ( CK1 ) , and glycogen synthase kinase 3beta ( GSK3beta ) XREF_BIBR .	The canonical Wnt and beta-catenin pathway is initiated by binding of Wnts (eg, Wnt3a) to the cell surface molecules LRP5/6 and Frizzled (FZD), resulting in the release of cytoplasmic beta-catenin from a protein complex consisting of Axin1/2, APC, casein kinase 1 (CK1), and glycogen synthase kinase 3beta (GSK3beta) XREF_BIBR.	4	61	initiated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	59	60	4	5
We have found that Wnt induced long-term beta-catenin stabilization is mediated by GSK3beta monoubiquitination through suppressing beta-catenin recruitment of beta-TrCP .	We have found that Wnt induced long-term beta-catenin stabilization is mediated by GSK3beta monoubiquitination through suppressing beta-catenin recruitment of beta-TrCP.	7	14	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta monoubiquitination	gsk3beta	beta-catenin	beta-catenin	beta-catenin	12	13	7	8
Wnt pathway activation ( e.g ., through Frizzled receptor ) leads to GSK-3beta phosphorylation , which subsequently inhibits beta-catenin degradation by the APC-complex XREF_BIBR , XREF_BIBR .	Wnt pathway activation (e.g., through Frizzled receptor) leads to GSK-3beta phosphorylation, which subsequently inhibits beta-catenin degradation by the APC-complex XREF_BIBR, XREF_BIBR.	0	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	Wnt pathway activation (e.g., through Frizzled receptor) leads to GSK-3beta phosphorylation	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	12	13	18	19
Sodium ferulate could intensify GSK-3beta , which caused beta-catenin decline and Notch transcriptional arrest .	Sodium ferulate could intensify GSK-3beta, which caused beta-catenin decline and Notch transcriptional arrest.	3	9	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	8	9
In contrast , a reduction in HG mediated caspase-3 cleavage and cell apoptosis was observed to inhibit GSK-3beta activation or increase in nuclear beta-catenin via transfection of Wnt4 or Wnt5a or stable beta-catenin ( S33Y ) [ XREF_BIBR ] .	In contrast, a reduction in HG mediated caspase-3 cleavage and cell apoptosis was observed to inhibit GSK-3beta activation or increase in nuclear beta-catenin via transfection of Wnt4 or Wnt5a or stable beta-catenin (S33Y) [XREF_BIBR].	17	32	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	17	18	23	24
Here , we investigated whether glycogen synthase kinase 3beta ( GSK3beta ) inhibitors , which mimic the action of WNT molecules , could be used in PHHs to activate the beta-catenin pathway to study CYP expression .	Here, we investigated whether glycogen synthase kinase 3beta (GSK3beta) inhibitors, which mimic the action of WNT molecules, could be used in PHHs to activate the beta-catenin pathway to study CYP expression.	8	31	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	10	11	30	31
Inactivation of GSK-3beta , in turn , prevents the degradation of beta-catenin by the proteasome .	Inactivation of GSK-3beta, in turn, prevents the degradation of beta-catenin by the proteasome.	0	12	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
AEG-1 interacts with Gsk-3beta and CKIdeltato activate Wnt and beta-catenin .	AEG-1 interacts with Gsk-3beta and CKIdeltato activate Wnt and beta-catenin.	3	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Gsk-3beta	Gsk-3beta	Gsk-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	9	10
Moreover , the accumulation of Wnt-1 and beta-catenin in the ovaries indicated that ZEA activated the Wnt-1 and beta-catenin pathway , mediated by ERs and GSK-3beta .	Moreover, the accumulation of Wnt-1 and beta-catenin in the ovaries indicated that ZEA activated the Wnt-1 and beta-catenin pathway, mediated by ERs and GSK-3beta.	16	26	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	25	26	18	19
Inactivation of GSK-3beta , specifically through serine 9 phosphorylation and tyrosine 216 dephosphorylation , increased beta-Catenin , an important factor in maintaining the BBB .	Inactivation of GSK-3beta, specifically through serine 9 phosphorylation and tyrosine 216 dephosphorylation, increased beta-Catenin, an important factor in maintaining the BBB.	0	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-Catenin	beta-Catenin	beta-Catenin	2	3	15	16
GSK-3beta itself has many biological functions , yet its inhibition is well known to constitutively stimulate the canonical Wnt and beta-Catenin pathway XREF_BIBR .	GSK-3beta itself has many biological functions, yet its inhibition is well known to constitutively stimulate the canonical Wnt and beta-Catenin pathway XREF_BIBR.	0	22	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-Catenin	beta-Catenin	beta-Catenin	0	1	20	21
Thereby , Gsk3beta is inactivated , causing a stabilization of beta-catenin .	Thereby, Gsk3beta is inactivated, causing a stabilization of beta-catenin.	2	11	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	2	3	10	11
Since WISP1 phosphorylates GSK3beta , and activates beta-catenin and TCF/LEF [ XREF_BIBR ] , it is plausible that Ang-II-induced WISP1 may regulate its own expression , and its perpetual expression may mediate Ang-II ' s pro growth effects .	Since WISP1 phosphorylates GSK3beta, and activates beta-catenin and TCF/LEF [XREF_BIBR], it is plausible that Ang-II-induced WISP1 may regulate its own expression, and its perpetual expression may mediate Ang-II 's pro growth effects.	1	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	WISP1 phosphorylates GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
Furthermore , when the WNT and beta-catenin pathway was activated in chondrocytic cells by WNT3a or SB216763 , which inhibits the phosphorylation of GSK3beta , the mRNA levels of aggrecan and col2a1 were decreased , whereas that of mmp13 was increased .	Furthermore, when the WNT and beta-catenin pathway was activated in chondrocytic cells by WNT3a or SB216763, which inhibits the phosphorylation of GSK3beta, the mRNA levels of aggrecan and col2a1 were decreased, whereas that of mmp13 was increased.	6	24	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	WNT3a or SB216763, which inhibits the phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	23	24	6	7
Phosphorylation of GSK3beta inhibits this function and allows beta-catenin to accumulate in the cytosol and translocate into the nucleus to activate gene transcription .	Phosphorylation of GSK3beta inhibits this function and allows beta-catenin to accumulate in the cytosol and translocate into the nucleus to activate gene transcription.	0	15	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	Phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
Reduced phosphorylation of GSK3beta ( S9 ) prolongs GSK3beta activation [ XREF_BIBR ] and decreases beta-catenin protein stability .	Reduced phosphorylation of GSK3beta (S9) prolongs GSK3beta activation [XREF_BIBR] and decreases beta-catenin protein stability.	1	17	decreases	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	phosphorylation of GSK3beta (S9	gsk3beta	beta-catenin	beta-catenin	beta-catenin	3	4	15	16
beta-catenin is activated by the non phosphorylated form of GSK3beta .	beta-catenin is activated by the non phosphorylated form of GSK3beta.	0	10	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	9	10	0	1
Free ( non cadherin associated ) beta-catenin associates in another complex , containing the proteins adenomatous polyposis coli ( APC ) , axin , and glycogen synthase 3beta ( GSK3beta ) , which targets beta-catenin for degradation .	Free (non cadherin associated) beta-catenin associates in another complex, containing the proteins adenomatous polyposis coli (APC), axin, and glycogen synthase 3beta (GSK3beta), which targets beta-catenin for degradation.	27	36	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	29	30	34	35
Second , we utilized an N-terminally truncated mutant form of beta-catenin ( DeltaNbeta-catenin ) , which can not be targeted by Gsk3beta for degradation XREF_BIBR .	Second, we utilized an N-terminally truncated mutant form of beta-catenin (DeltaNbeta-catenin), which can not be targeted by Gsk3beta for degradation XREF_BIBR.	8	24	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	21	22	10	11
A likely molecule linking the PI3-K pathway to the Wnt signalling pathway may be GSK-3 beta , that normally targets beta-catenin for proteasome mediated degradation .	A likely molecule linking the PI3-K pathway to the Wnt signalling pathway may be GSK-3 beta, that normally targets beta-catenin for proteasome mediated degradation.	14	22	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3 beta	GSK-3 beta	GSK-3 beta	beta-catenin	beta-catenin	beta-catenin	14	16	20	21
DKK-1 , a specific inhibitor of Wnt signaling pathway , can downregulate the phosphorylation of GSK-3beta and promote degradation of beta-catenin , so the quantity of beta-catenin that is transported into the nucleus is reduced in immunofluorescence .	DKK-1, a specific inhibitor of Wnt signaling pathway, can downregulate the phosphorylation of GSK-3beta and promote degradation of beta-catenin, so the quantity of beta-catenin that is transported into the nucleus is reduced in immunofluorescence.	0	21	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	DKK-1, a specific inhibitor of Wnt signaling pathway, can downregulate the phosphorylation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	15	16	20	21
It has been reported that activated AMPK induces the phosphorylation of GSK-3beta and increases the nuclear accumulation of beta-catenin , leading to the induction of EMT and increased migration and metastatic competency of lung cancer cells .	It has been reported that activated AMPK induces the phosphorylation of GSK-3beta and increases the nuclear accumulation of beta-catenin, leading to the induction of EMT and increased migration and metastatic competency of lung cancer cells.	6	19	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	AMPK induces the phosphorylation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	11	12	18	19
But beta-catenin inhibition was significantly reduced by GSK3beta RNA interference or GSK3beta inhibitor lithium chloride and proteasome inhibitor MG132 .	But beta-catenin inhibition was significantly reduced by GSK3beta RNA interference or GSK3beta inhibitor lithium chloride and proteasome inhibitor MG132.	1	9	reduced	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	1	2
Activation of Dvl leads to the inhibition of glycogen synthase kinase 3beta ( GSK-3beta ) preventing beta-catenin degradation by the protein complexes consisting of GSK-3beta , axin , and adenomatous polyposis coli ( APC ) [ XREF_BIBR ] .	Activation of Dvl leads to the inhibition of glycogen synthase kinase 3beta (GSK-3beta) preventing beta-catenin degradation by the protein complexes consisting of GSK-3beta, axin, and adenomatous polyposis coli (APC) [XREF_BIBR].	11	17	preventing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	13	14	16	17
In the absence of Wnt signaling , the level of beta-catenin is kept low through degradation of cytoplasmic beta-catenin , which is targeted for phosphorylation and ubiquitination at Ser33/Ser37/Thr41 by GSK3beta bound to a scaffolding complex of axin and adenomatous polyposis coli ( APC ) protein .	In the absence of Wnt signaling, the level of beta-catenin is kept low through degradation of cytoplasmic beta-catenin, which is targeted for phosphorylation and ubiquitination at Ser33/Ser37/Thr41 by GSK3beta bound to a scaffolding complex of axin and adenomatous polyposis coli (APC) protein.	15	31	targeted	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	30	31	18	19
In quiescent cells beta-catenin is sequestered in a multi protein complex , including axin , adenomatous polyposis coli ( APC ) and glycogen synthase kinase-3beta ( GSK-3beta ) , that targets beta-catenin for phosphorylation , ubiquitination and proteosomal degradation [ XREF_BIBR , XREF_BIBR ] .	In quiescent cells beta-catenin is sequestered in a multi protein complex, including axin, adenomatous polyposis coli (APC) and glycogen synthase kinase-3beta (GSK-3beta), that targets beta-catenin for phosphorylation, ubiquitination and proteosomal degradation [XREF_BIBR, XREF_BIBR].	24	38	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	26	27	31	32
Inactivation of glycogen synthase kinase-3beta ( GSK-3beta ) by phosphorylation enhances nuclear accumulation of beta-catenin [ XREF_BIBR ] .	Inactivation of glycogen synthase kinase-3beta (GSK-3beta) by phosphorylation enhances nuclear accumulation of beta-catenin [XREF_BIBR].	4	16	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	14	15
Similarly , GSK3beta antagonist SB216763 was used to activate Wnt and beta-catenin pathway to see its effect on rotenone induced cell injury .	Similarly, GSK3beta antagonist SB216763 was used to activate Wnt and beta-catenin pathway to see its effect on rotenone induced cell injury.	2	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
In the absence of Wnt activation , GSK3beta targets beta-catenin for degradation , but upon cWnt activation , GSK3beta is inhibited and results in accumulation of beta-catenin and activation of downstream targets .	In the absence of Wnt activation, GSK3beta targets beta-catenin for degradation, but upon cWnt activation, GSK3beta is inhibited and results in accumulation of beta-catenin and activation of downstream targets.	2	16	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
beta-Catenin is phosphorylated by GSK3beta and undergoes proteasomal degradation while phosphorylation of GSK3beta inactivates it and allows nuclear translocation of beta-catenin .	beta-Catenin is phosphorylated by GSK3beta and undergoes proteasomal degradation while phosphorylation of GSK3beta inactivates it and allows nuclear translocation of beta-catenin.	10	21	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	12	13	20	21
GSK-3beta insufficiency or inhibition of proteasome function up-regulates beta-catenin and reduces PPAR gamma in PASMCs .	GSK-3beta insufficiency or inhibition of proteasome function up-regulates beta-catenin and reduces PPAR gamma in PASMCs.	0	9	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	8	9
In the presence of Wnt , GSK-3beta is phosphorylated and inhibited , thus preventing targeting of beta-catenin for degradation .	In the presence of Wnt, GSK-3beta is phosphorylated and inhibited, thus preventing targeting of beta-catenin for degradation.	6	17	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta is phosphorylated	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	16	17
The results showed that reconstitution of the GSK3beta KO/GSK3alpha KD MEFs with WT Flag-GSK3alpha or Flag-GSK3alpha Y279E , but not GSK3alpha Y279F mutant restored Wnt induced accumulation of beta-catenin ( XREF_FIG ) .	The results showed that reconstitution of the GSK3beta KO/GSK3alpha KD MEFs with WT Flag-GSK3alpha or Flag-GSK3alpha Y279E, but not GSK3alpha Y279F mutant restored Wnt induced accumulation of beta-catenin (XREF_FIG).	7	30	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	28	29
The Wnt signaling dependent phosphorylation of GSK-3beta inhibits its kinase activity , thereby preventing degradation of beta-catenin by GSK-3beta .	The Wnt signaling dependent phosphorylation of GSK-3beta inhibits its kinase activity, thereby preventing degradation of beta-catenin by GSK-3beta.	13	19	degradation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	18	19	16	17
As mentioned previously , GSK3-beta has also been implicated as an HBx target to promote beta-catenin stabilization .	As mentioned previously, GSK3-beta has also been implicated as an HBx target to promote beta-catenin stabilization.	4	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3-beta	GSK3-beta	GSK3-beta	beta-catenin	beta-catenin	beta-catenin	4	5	15	16
All our results reveal that estrogen and ERalpha blocked metastatic function of HA22T cells by modulating GSK3beta and betaTrCP expression and further enhanced beta-catenin degradation and suppressed its downstream target genes .	All our results reveal that estrogen and ERalpha blocked metastatic function of HA22T cells by modulating GSK3beta and betaTrCP expression and further enhanced beta-catenin degradation and suppressed its downstream target genes.	5	24	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	estrogen and ERalpha blocked metastatic function of HA22T cells by modulating GSK3beta and betaTrCP expression	gsk3beta	beta-catenin	beta-catenin	beta-catenin	16	17	23	24
These findings provide evidence that GSK-3beta modulates delta-catenin and beta-catenin stability through a similar regulatory pathway and that altering delta-catenin expression levels in neurons effects beta-catenin and GSK-3beta interactions and beta-catenin ubiquitination and turnover .	These findings provide evidence that GSK-3beta modulates delta-catenin and beta-catenin stability through a similar regulatory pathway and that altering delta-catenin expression levels in neurons effects beta-catenin and GSK-3beta interactions and beta-catenin ubiquitination and turnover.	5	18	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
Akt can phosphorylate and inactivate GSK-3beta , thereby facilitating cellular stabilization and increased concentrations of beta-catenin [ XREF_BIBR ] .	Akt can phosphorylate and inactivate GSK-3beta, thereby facilitating cellular stabilization and increased concentrations of beta-catenin [XREF_BIBR].	0	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	Akt can phosphorylate and inactivate GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	15	16
Thus , we conclude that Akt phosphorylation is the first step that occurs upon gal-3 silencing , which subsequently downregulates GSK-3beta phosphorylation and induces beta-catenin degradation .	Thus, we conclude that Akt phosphorylation is the first step that occurs upon gal-3 silencing, which subsequently downregulates GSK-3beta phosphorylation and induces beta-catenin degradation.	14	25	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	gal-3 silencing, which subsequently downregulates GSK-3beta phosphorylation	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	20	21	24	25
Inhibition of miR-155 increased GSK-3beta expression , attenuated Wnt and beta-catenin signaling pathway , weakened proliferation and invasion , and facilitated apoptosis in renal carcinoma cells .	Inhibition of miR-155 increased GSK-3beta expression, attenuated Wnt and beta-catenin signaling pathway, weakened proliferation and invasion, and facilitated apoptosis in renal carcinoma cells.	2	12	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	miR-155 increased GSK-3beta expression	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	10	11
The results showed that short term stimulation of HIEC cells with R-spondin 1 and Wnt-3a +/-SB-216763 , a glycogen synthase kinase 3beta ( GSK3beta ) inhibitor , induced beta-catenin and TCF activity and expression of the WNT target genes , cyclin D2 and LGR5 .	The results showed that short term stimulation of HIEC cells with R-spondin 1 and Wnt-3a +/-SB-216763, a glycogen synthase kinase 3beta (GSK3beta) inhibitor, induced beta-catenin and TCF activity and expression of the WNT target genes, cyclin D2 and LGR5.	21	31	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	23	24	28	29
Reduced GSK-3beta stabilizes and prevents beta-catenin from proteasomal degradation , allowing unphosphorylated beta-catenin to translocate to the nucleus for activation of developmentally important genes such as VEGF , bcl2 , survivin , tight junctions ( TJ ) .	Reduced GSK-3beta stabilizes and prevents beta-catenin from proteasomal degradation, allowing unphosphorylated beta-catenin to translocate to the nucleus for activation of developmentally important genes such as VEGF, bcl2, survivin, tight junctions (TJ).	0	6	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	1	2	5	6
In turn , inactivation of GSK-3beta promoted beta-catenin stabilization and signaling [ XREF_BIBR ] .	In turn, inactivation of GSK-3beta promoted beta-catenin stabilization and signaling [XREF_BIBR].	3	8	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	7	8
Further , inactivation of GSK-3beta can upregulate beta-catenin during gastrin [ XREF_BIBR ] and TNF-alpha [ XREF_BIBR ] induced EMT of cancer cells .	Further, inactivation of GSK-3beta can upregulate beta-catenin during gastrin [XREF_BIBR] and TNF-alpha [XREF_BIBR] induced EMT of cancer cells.	2	8	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	7	8
Cellular stimulation by Wnt or lithium chloride ( LiCl ) inactivates glycogen synthase kinase-3beta ( GSK-3beta ) , causing nuclear accumulation of beta-catenin and transactivation of genes that transform cells .	Cellular stimulation by Wnt or lithium chloride (LiCl) inactivates glycogen synthase kinase-3beta (GSK-3beta), causing nuclear accumulation of beta-catenin and transactivation of genes that transform cells.	13	24	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	15	16	22	23
Aberrant beta-catenin upregulation mediated by GSK-3beta was observed in the Hepa1-6 spheroids .	Aberrant beta-catenin upregulation mediated by GSK-3beta was observed in the Hepa1-6 spheroids.	1	6	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	1	2
In the PI3K/Akt/GSK-3beta signaling pathway , Akt regulated adipogenesis via the phosphorylation and inactivation of substrates , such as GSK-3beta , which directly regulated beta-catenin .	In the PI3K/Akt/GSK-3beta signaling pathway, Akt regulated adipogenesis via the phosphorylation and inactivation of substrates, such as GSK-3beta, which directly regulated beta-catenin.	8	25	directly regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	19	20	24	25
Suppression of UBE2T also inhibits gastric tumor invasion and metastasis via the WNT signal pathway by inhibiting WNT5A and WNT7B , which in turn promotes GSK3B expression , activates beta-Catenin , and inhibits the key oncogene c-Myc .	Suppression of UBE2T also inhibits gastric tumor invasion and metastasis via the WNT signal pathway by inhibiting WNT5A and WNT7B, which in turn promotes GSK3B expression, activates beta-Catenin, and inhibits the key oncogene c-Myc.	17	30	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3B	WNT5A and WNT7B, which in turn promotes GSK3B expression	gsk3b	beta-Catenin	beta-Catenin	beta-catenin	25	26	29	30
Nevertheless , PCB 153 had no effect on phosphorylation of glycogen synthase kinase-3beta ( GSK-3beta ) , which is supposed to target beta-catenin for its proteasomal degradation .	Nevertheless, PCB 153 had no effect on phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), which is supposed to target beta-catenin for its proteasomal degradation.	8	23	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	phosphorylation of glycogen synthase kinase-3beta (GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	14	15	22	23
Cucurbitacin B induced apoptosis and caused the growth inhibition of breast cancer cells through the reduction of the Wnt associated proteins and the inhibition of GSK-3 beta mediated beta-Catenin to the nucleus [ XREF_BIBR ] .	Cucurbitacin B induced apoptosis and caused the growth inhibition of breast cancer cells through the reduction of the Wnt associated proteins and the inhibition of GSK-3 beta mediated beta-Catenin to the nucleus [XREF_BIBR].	25	29	mediated	Positive_early_activation	Negative_activation	Negative_activation	GSK-3 beta	GSK-3 beta	GSK-3 beta	beta-Catenin	beta-Catenin	beta-Catenin	25	27	28	29
Both CK1alpha and GSK-3beta are known to target beta-catenin for proteasomal degradation via combined phosphorylation at key serine and threonine residues of beta-catenin XREF_BIBR .	Both CK1alpha and GSK-3beta are known to target beta-catenin for proteasomal degradation via combined phosphorylation at key serine and threonine residues of beta-catenin XREF_BIBR.	1	11	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
In conclusion , we see that RNA binding protein RBM3 induces stemness in colorectal cancer cells through a mechanism involving suppression of GSK3beta activity thereby enhancing beta-catenin signaling .	In conclusion, we see that RNA binding protein RBM3 induces stemness in colorectal cancer cells through a mechanism involving suppression of GSK3beta activity thereby enhancing beta-catenin signaling.	22	27	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	22	23	26	27
The luciferase reporter system studies affirmed the direct regulation of miR-452 on the 3 '-UTR of the GSK3beta , which activate the Wnt and beta-catenin signaling .	The luciferase reporter system studies affirmed the direct regulation of miR-452 on the 3 '-UTR of the GSK3beta, which activate the Wnt and beta-catenin signaling.	14	25	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	17	18	24	25
In this study , we investigated beta-catenin and NF-kappaB signaling through regulation of glycogen synthase kinase 3beta activity ( GSK-3beta , which modulates beta-catenin and NF-kappaB signaling ) using a specific inhibitor LiCl and a phosphatidylinositol 3-kinase ( PI3K ) inhibitor LY 294002 .	In this study, we investigated beta-catenin and NF-kappaB signaling through regulation of glycogen synthase kinase 3beta activity (GSK-3beta, which modulates beta-catenin and NF-kappaB signaling) using a specific inhibitor LiCl and a phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002.	17	26	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	19	20	23	24
GSK3beta antagonists are thought to modulate cWnt signaling by preventing the formation of a functional beta-catenin destruction complex .	GSK3beta antagonists are thought to modulate cWnt signaling by preventing the formation of a functional beta-catenin destruction complex.	0	17	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	0	1	15	16
Interestingly , despite the inhibition of GSK-3beta , we observed a decrease in the total levels of beta-catenin in stable Dsc2 knockdown cells , suggesting that Akt mediated GSK-3beta inhibition may promote the nuclear redistribution of beta-catenin and enhance beta-catenin-dependent transcription without inducing stabilization of total beta-catenin protein levels .	Interestingly, despite the inhibition of GSK-3beta, we observed a decrease in the total levels of beta-catenin in stable Dsc2 knockdown cells, suggesting that Akt mediated GSK-3beta inhibition may promote the nuclear redistribution of beta-catenin and enhance beta-catenin-dependent transcription without inducing stabilization of total beta-catenin protein levels.	26	37	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	Akt mediated GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	28	29	36	37
It is thus intriguing to determine if Gsk3beta modulates the activity of Wnt and beta-catenin signaling , and if Wnt and beta-catenin signaling is involved in palate development .	It is thus intriguing to determine if Gsk3beta modulates the activity of Wnt and beta-catenin signaling, and if Wnt and beta-catenin signaling is involved in palate development.	7	15	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	7	8	14	15
Concomitantly , Wnt signaling promotes inactivation of GSK3beta causing beta-catenin to accumulate in the cytoplasm .	Concomitantly, Wnt signaling promotes inactivation of GSK3beta causing beta-catenin to accumulate in the cytoplasm.	5	10	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
Fibulin-5 impedes Wnt and beta-catenin signaling by inhibiting extracellular signal regulated kinase ( ERK ) to activate glycogen synthase kinase-3 beta ( GSK3beta ) , which downregulates beta-catenin and prevents its nuclear accumulation , leading to suppression of MMP-7 and c-Myc expression .	Fibulin-5 impedes Wnt and beta-catenin signaling by inhibiting extracellular signal regulated kinase (ERK) to activate glycogen synthase kinase-3 beta (GSK3beta), which downregulates beta-catenin and prevents its nuclear accumulation, leading to suppression of MMP-7 and c-Myc expression.	17	28	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta	beta-catenin	beta-catenin	beta-catenin	17	21	27	28
Both CDK5 and GSK3beta can modulate beta-catenin signaling ; this regulation is complex , however , and depends on other kinases to prime the substrate as well as scaffolding proteins to successfully link the kinase with the substrate XREF_BIBR .	Both CDK5 and GSK3beta can modulate beta-catenin signaling; this regulation is complex, however, and depends on other kinases to prime the substrate as well as scaffolding proteins to successfully link the kinase with the substrate XREF_BIBR.	1	7	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	6	7
In a recent report , decreased GSK3beta phosphorylation promoted GSK3beta activation and degradation of beta-catenin [ XREF_BIBR ] .	In a recent report, decreased GSK3beta phosphorylation promoted GSK3beta activation and degradation of beta-catenin [XREF_BIBR].	6	16	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	6	7	14	15
Furthermore , beta-catenin protein was decreased by inhibition of phosphorylation of GSK3beta via mTORC1 activation .	Furthermore, beta-catenin protein was decreased by inhibition of phosphorylation of GSK3beta via mTORC1 activation.	2	14	decreased	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	11	12	2	3
These findings reveal that while RBM3 overexpression results in phosphorylation of GSK3beta , thereby attenuating beta-catenin degradation , this is only a partial mechanism and there is an as yet unknown role that RBM3 plays in modulatingbeta-catenin signaling .	These findings reveal that while RBM3 overexpression results in phosphorylation of GSK3beta, thereby attenuating beta-catenin degradation, this is only a partial mechanism and there is an as yet unknown role that RBM3 plays in modulatingbeta-catenin signaling.	5	16	attenuating	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	RBM3 overexpression results in phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	11	12	15	16
The accumulation of beta-catenin ( a GSK3beta target ) in the kidney of Irs2 -/- mice ( Fig XREF_FIG ) suggests that increased phosphorylation of GSK3beta leads to reduced GSK3beta kinase activity in the kidney , facilitating beta-catenin accumulation .	The accumulation of beta-catenin (a GSK3beta target) in the kidney of Irs2 -/- mice (Fig XREF_FIG) suggests that increased phosphorylation of GSK3beta leads to reduced GSK3beta kinase activity in the kidney, facilitating beta-catenin accumulation.	23	38	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	25	26	37	38
LANA interacts with GSK-3beta , an important modulator of the Wnt signaling pathway , leading to the accumulation of the beta-catenin and subsequent upregulation of Tcf/Lef regulated genes .	LANA interacts with GSK-3beta, an important modulator of the Wnt signaling pathway, leading to the accumulation of the beta-catenin and subsequent upregulation of Tcf/Lef regulated genes.	3	21	leading to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	20	21
We also observed an increase in phosphorylation of the inhibitory Ser 9 residue of GSK-3beta , which has been proposed to enhance beta-catenin signaling by promoting the accumulation of beta-catenin protein levels , in a manner analogous to Wnt mediated GSK-3beta inactivation .	We also observed an increase in phosphorylation of the inhibitory Ser 9 residue of GSK-3beta, which has been proposed to enhance beta-catenin signaling by promoting the accumulation of beta-catenin protein levels, in a manner analogous to Wnt mediated GSK-3beta inactivation.	6	36	enhance	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	GSK-3beta	phosphorylation of the inhibitory Ser 9 residue of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin protein levels	beta-catenin	14	15	29	30
20 This unusual mechanism makes them counterintuitive at first glance , for example , the strong phosphorylation of GSK3beta in B1I4 will actually lead to activation of beta-catenin .	20 This unusual mechanism makes them counterintuitive at first glance, for example, the strong phosphorylation of GSK3beta in B1I4 will actually lead to activation of beta-catenin.	16	28	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	18	19	27	28
Pyk2 inhibition results in suppression of Wnt signaling through the acceleration of beta-catenin degradation caused by GSK3beta activation [ XREF_BIBR ] .	Pyk2 inhibition results in suppression of Wnt signaling through the acceleration of beta-catenin degradation caused by GSK3beta activation [XREF_BIBR].	12	19	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	16	17	12	13
SULF2 expression also increased phosphorylation of the anti-apoptotic Akt substrate GSK3beta and stimulated Wnt and beta-catenin signalling .	SULF2 expression also increased phosphorylation of the anti-apoptotic Akt substrate GSK3beta and stimulated Wnt and beta-catenin signalling.	0	16	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	SULF2 expression also increased phosphorylation of the anti-apoptotic Akt substrate GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	10	11	15	16
In GIST , PI3K and Akt is constitutively activated , which promotes phosphorylation and inactivation of GSK3beta , allowing stabilization of the beta-catenin destruction complex .	In GIST, PI3K and Akt is constitutively activated, which promotes phosphorylation and inactivation of GSK3beta, allowing stabilization of the beta-catenin destruction complex.	3	24	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	PI3K and Akt is constitutively activated, which promotes phosphorylation and inactivation of GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	16	17	22	23
beta-catenin is targeted for degradation upon phosphorylation by GSK3beta XREF_BIBR .	beta-catenin is targeted for degradation upon phosphorylation by GSK3beta XREF_BIBR.	0	9	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	8	9	0	1
Pharmacological inhibition of GSK-3beta with CHIR-99021 or overexpression of beta-catenin reversed cordycepin induced reduction of cell viability , downregulation of beta-catenin and MGMT , increase of apoptosis and reduction of TMZ resistance .	Pharmacological inhibition of GSK-3beta with CHIR-99021 or overexpression of beta-catenin reversed cordycepin induced reduction of cell viability, downregulation of beta-catenin and MGMT, increase of apoptosis and reduction of TMZ resistance.	1	22	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	20	21
In normal cells , constitutively active GSK3beta negatively regulates Wnt and beta-catenin signaling via phosphorylation induced degradation of beta-catenin , thus limiting beta-catenin expression and activation of Wnt and beta-catenin signaling .	In normal cells, constitutively active GSK3beta negatively regulates Wnt and beta-catenin signaling via phosphorylation induced degradation of beta-catenin, thus limiting beta-catenin expression and activation of Wnt and beta-catenin signaling.	5	19	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	6	7	18	19
Both CK1alpha and GSK-3beta are known to target beta-catenin for proteasomal degradation via combined phosphorylation at key residues of beta-catenin XREF_BIBR .	Both CK1alpha and GSK-3beta are known to target beta-catenin for proteasomal degradation via combined phosphorylation at key residues of beta-catenin XREF_BIBR.	1	11	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
When phosphorylated in the Ser9 residue , GSK-3beta is inactivated , increasing the stabilized unphosphorylated state of beta-CATENIN [ XREF_BIBR ] .	When phosphorylated in the Ser9 residue, GSK-3beta is inactivated, increasing the stabilized unphosphorylated state of beta-CATENIN [XREF_BIBR].	7	19	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-CATENIN	beta-CATENIN	beta-CATENIN	7	8	17	18
In early passage MSCs expressing SIRT1 , resveratrol decreased ERK and GSK-3beta phosphorylation , suppressing beta-catenin activity .	In early passage MSCs expressing SIRT1, resveratrol decreased ERK and GSK-3beta phosphorylation, suppressing beta-catenin activity.	7	16	suppressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	resveratrol decreased ERK and GSK-3beta phosphorylation	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	11	12	15	16
Due to its kinase activity , GSK-3beta is able to target cyclin D1 and beta-catenin [ XREF_BIBR ] [ XREF_BIBR ] for ubiquitin dependent proteasomal degradation .	Due to its kinase activity, GSK-3beta is able to target cyclin D1 and beta-catenin [XREF_BIBR] [XREF_BIBR] for ubiquitin dependent proteasomal degradation.	6	19	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	14	15
Our study further demonstrates that increased RBM3 expression affects GSK3beta activity thereby enhancing beta-catenin signaling .	Our study further demonstrates that increased RBM3 expression affects GSK3beta activity thereby enhancing beta-catenin signaling.	9	14	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	9	10	13	14
Thus , inactivating GSK-3beta potentiates wnt and beta-catenin signaling and so promotes proliferation .	Thus, inactivating GSK-3beta potentiates wnt and beta-catenin signaling and so promotes proliferation.	2	11	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	7	8
In other groups of diabetic rats , the Wnt and beta-catenin pathway was activated by the inhibition of its negative regulator GSK-3beta .	In other groups of diabetic rats, the Wnt and beta-catenin pathway was activated by the inhibition of its negative regulator GSK-3beta.	8	22	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	21	22	10	11
Inactivation of GSK-3beta increases not only the stability of CREB for IL-10 production but also enhances the activity of beta-catenin and Mcl-1 for cell growth and survival XREF_BIBR , XREF_BIBR .	Inactivation of GSK-3beta increases not only the stability of CREB for IL-10 production but also enhances the activity of beta-catenin and Mcl-1 for cell growth and survival XREF_BIBR, XREF_BIBR.	0	21	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	19	20
By contrast , when Akt is inactivated , GSK3beta can cause a beta-catenin breakdown through the phosphorylation of beta-catenin , which inhibits the Wnt pathway [ XREF_BIBR , XREF_BIBR ] .	By contrast, when Akt is inactivated, GSK3beta can cause a beta-catenin breakdown through the phosphorylation of beta-catenin, which inhibits the Wnt pathway [XREF_BIBR, XREF_BIBR].	8	13	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	8	9	12	13
Coincidentally , exogenous bFGF mediated stimulation of fibroblasts apparently activated the PI3K and JNK pathway , which in turn phosphorylated GSK3beta and positively regulates beta-catenin shuttling between the cytoplasm and the nucleus .	Coincidentally, exogenous bFGF mediated stimulation of fibroblasts apparently activated the PI3K and JNK pathway, which in turn phosphorylated GSK3beta and positively regulates beta-catenin shuttling between the cytoplasm and the nucleus.	3	25	positively regulates	Positive_activation_syntax_1b_verb	Negative_activation	Positive_activation	GSK3beta	bFGF mediated stimulation of fibroblasts apparently activated the PI3K and JNK pathway, which in turn phosphorylated GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	20	21	24	25
Ectopic expression of a dominant negative form of GSK-3beta in FLT3-ITD-expressing cells activated beta-catenin and blocked the downregulation of the TCF and beta-catenin transcriptional activity induced by inhibition of FLT3 kinase .	Ectopic expression of a dominant negative form of GSK-3beta in FLT3-ITD-expressing cells activated beta-catenin and blocked the downregulation of the TCF and beta-catenin transcriptional activity induced by inhibition of FLT3 kinase.	6	24	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	8	9	22	23
Wnt3a acts to oppose the ability of the Dishevelled3 ( Dvl3 ) and KSRP complex to destabilize Ctnnb1 mRNA , as well as degradation of beta-catenin , which is catalyzed by GSK3beta phosphorylation .	Wnt3a acts to oppose the ability of the Dishevelled3 (Dvl3) and KSRP complex to destabilize Ctnnb1 mRNA, as well as degradation of beta-catenin, which is catalyzed by GSK3beta phosphorylation.	23	33	catalyzed	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	31	32	25	26
The absence of Gsk3beta does not alter the Wnt and beta-catenin signaling , suggesting that Gsk3beta could also mediate a signaling pathway independent of Wnt and beta-catenin signaling during palate development .	The absence of Gsk3beta does not alter the Wnt and beta-catenin signaling, suggesting that Gsk3beta could also mediate a signaling pathway independent of Wnt and beta-catenin signaling during palate development.	15	27	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	15	16	26	27
Thus , adenomatous polyposis coli ( APC ) , AXIN and glycogen synthase kinase-3beta ( GSK-3beta ) form a beta-catenin destruction complex and mediate the proteasomal beta-catenin degradation [ XREF_BIBR ] .	Thus, adenomatous polyposis coli (APC), AXIN and glycogen synthase kinase-3beta (GSK-3beta) form a beta-catenin destruction complex and mediate the proteasomal beta-catenin degradation [XREF_BIBR].	13	27	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	15	16	26	27
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Recently , some studies have found that GSK 3beta could modulate both NF-kappaB and beta-catenin activity through phosphorylation or transcriptional regulation .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Recently, some studies have found that GSK 3beta could modulate both NF-kappaB and beta-catenin activity through phosphorylation or transcriptional regulation.	16	24	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK 3beta	GSK 3beta	GSK 3beta	beta-catenin	beta-catenin	beta-catenin	16	18	23	24
Mutations in APC , Axin , GSK-3beta , beta-catenin and TCF may trigger Wnt signaling activation and beta-catenin upregulation , thus promoting CRC .	Mutations in APC, Axin, GSK-3beta, beta-catenin and TCF may trigger Wnt signaling activation and beta-catenin upregulation, thus promoting CRC.	0	18	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	17	18
As active beta-catenin moves into the nucleus and binds to transcription factors to initiate gene expression , including Cyclin D1 and c-Myc , the inactive form of p-GSK-3beta inhibits degradation of beta-catenin and promotes tumor development [ XREF_BIBR ] .	As active beta-catenin moves into the nucleus and binds to transcription factors to initiate gene expression, including Cyclin D1 and c-Myc, the inactive form of p-GSK-3beta inhibits degradation of beta-catenin and promotes tumor development [XREF_BIBR].	25	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p-GSK-3beta	p-GSK-3beta	p-GSK-3beta	beta-catenin	beta-catenin	beta-catenin	27	28	31	32
Our analyses revealed a novel interaction of CARMA1 with beta-catenin and its destruction complex consisting of CK1alpha , GSK3beta , APC and AXIN that promotes beta-catenin stabilization .	Our analyses revealed a novel interaction of CARMA1 with beta-catenin and its destruction complex consisting of CK1alpha, GSK3beta, APC and AXIN that promotes beta-catenin stabilization.	14	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	18	19	25	26
Phosphorylation of GSK3beta at serine 9 inactivates this kinase activity and causes stabilization and nuclear localization of beta-catenin from the plasma membrane to the cytoplasm and the nucleus , where the latter acts as a transcription cofactor for developmentally regulated genes .	Phosphorylation of GSK3beta at serine 9 inactivates this kinase activity and causes stabilization and nuclear localization of beta-catenin from the plasma membrane to the cytoplasm and the nucleus, where the latter acts as a transcription cofactor for developmentally regulated genes.	0	21	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	Phosphorylation of GSK3beta at serine 9	gsk3beta	beta-catenin	beta-catenin	beta-catenin	2	3	17	18
GSK-3beta suppresses HCC cell dissociation in vitro by upregulating epithelial junction proteins and inhibiting Wnt and beta-catenin signaling pathway .	GSK-3beta suppresses HCC cell dissociation in vitro by upregulating epithelial junction proteins and inhibiting Wnt and beta-catenin signaling pathway.	0	18	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	0	1	16	17
In colorectal cancers , RBM3 enhances Wnt and beta-catenin signaling mediated by inactivation of GSK3beta [ XREF_BIBR ] .	In colorectal cancers, RBM3 enhances Wnt and beta-catenin signaling mediated by inactivation of GSK3beta [XREF_BIBR].	6	16	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	14	15	8	9
The cytosolic Axin , APC , and GSK3beta complex targets beta-catenin for degradation via phosphorylation of Ser/Thr residues , first by the priming kinase , casein kinase-1 at Ser45 , and subsequently by GSK3beta at Ser33/37/Thr41 , and SB2 is annotated as an inhibitor of GSK3beta .	The cytosolic Axin, APC, and GSK3beta complex targets beta-catenin for degradation via phosphorylation of Ser/Thr residues, first by the priming kinase, casein kinase-1 at Ser45, and subsequently by GSK3beta at Ser33/37/Thr41, and SB2 is annotated as an inhibitor of GSK3beta.	7	12	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	7	8	10	11
MCSF induced phosphorylation of Ser9 in GSK3beta , which reduces GSK3beta kinase activity and therefore promotes beta-catenin stability .	MCSF induced phosphorylation of Ser9 in GSK3beta, which reduces GSK3beta kinase activity and therefore promotes beta-catenin stability.	1	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	6	7	16	17
To further investigate whether activation of GSK3beta could induce altered beta-catenin activity in the auditory cortex , western blot analysis revealed that the protein level of p-beta-catenin ( ser 33 , 37 Thr 41 ) was increased in the 4-month-old d-gal and 16-month-old d-gal rats compared with the corresponding NS rats ( P < 0.01 ) while total beta-catenin protein expression was markedly decreased ( P < 0.01 ) .	To further investigate whether activation of GSK3beta could induce altered beta-catenin activity in the auditory cortex, western blot analysis revealed that the protein level of p-beta-catenin (ser 33, 37 Thr 41) was increased in the 4-month-old d-gal and 16-month-old d-gal rats compared with the corresponding NS rats (P < 0.01) while total beta-catenin protein expression was markedly decreased (P < 0.01).	4	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	6	7	10	11
Together , these studies support a model in which mechanically induced GSK3beta inactivation and activation of Akt promotes mobilization of beta-catenin from a membrane sequestered pool that accumulates in the cytoplasm and subsequently translocates to the nucleus where it regulates the expression of mechanically responsive genes .	Together, these studies support a model in which mechanically induced GSK3beta inactivation and activation of Akt promotes mobilization of beta-catenin from a membrane sequestered pool that accumulates in the cytoplasm and subsequently translocates to the nucleus where it regulates the expression of mechanically responsive genes.	11	21	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	11	12	20	21
Interestingly , we also found that co-inhibition of GSK-3beta and GEF-H1 or GSK-3beta and ROCK produced equivalent inhibitory effects on LPS induced disruption of beta-catenin and ZO-1 .	Interestingly, we also found that co-inhibition of GSK-3beta and GEF-H1 or GSK-3beta and ROCK produced equivalent inhibitory effects on LPS induced disruption of beta-catenin and ZO-1.	6	26	produced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	8	9	24	25
Previous reports suggested that activated Akt phosphorylates GSK3beta and inhibits degradation of beta-catenin [ XREF_BIBR XREF_BIBR ] .	Previous reports suggested that activated Akt phosphorylates GSK3beta and inhibits degradation of beta-catenin [XREF_BIBR XREF_BIBR].	5	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	Akt phosphorylates GSK3beta	gsk3beta	beta-catenin	beta-catenin	beta-catenin	7	8	12	13
Further , phosphorylation at the ser 33/37/Thr41 residue which is linked to degradation of beta -catenin mediated by GSK-3beta was found to be reduced in the P-MSCs .	Further, phosphorylation at the ser 33/37/Thr41 residue which is linked to degradation of beta -catenin mediated by GSK-3beta was found to be reduced in the P-MSCs.	14	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta -catenin	beta -catenin	beta -catenin	18	19	14	16
Besides , the phosphorylation of GSK-3beta , which inactivates beta-catenin degradation , was inhibited by ASP treatment ( XREF_FIG ) .	Besides, the phosphorylation of GSK-3beta, which inactivates beta-catenin degradation, was inhibited by ASP treatment (XREF_FIG).	3	10	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	phosphorylation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
GSK3beta , axin , and APC are negative regulators of the Wnt signaling pathway and the complex requires all of these constituents to initiate the destruction of beta-catenin .	GSK3beta, axin, and APC are negative regulators of the Wnt signaling pathway and the complex requires all of these constituents to initiate the destruction of beta-catenin.	0	28	initiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	0	1	27	28
In contrast , in late passage MSCs , which did not express SIRT1 , resveratrol increased ERK and GSK-3beta phosphorylation , activating beta-catenin .	In contrast, in late passage MSCs, which did not express SIRT1, resveratrol increased ERK and GSK-3beta phosphorylation, activating beta-catenin.	14	23	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	resveratrol increased ERK and GSK-3beta phosphorylation	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	18	19	22	23
More specifically , FGF19 increases GSK3beta phosphorylation and activates beta-catenin , leading to the activation of beta-catenin and TCF4 regulated transcription in colon cancer cells [ XREF_BIBR ] .	More specifically, FGF19 increases GSK3beta phosphorylation and activates beta-catenin, leading to the activation of beta-catenin and TCF4-regulated transcription in colon cancer cells [XREF_BIBR].	3	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	FGF19 increases GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	5	6	9	10
The expression of a constitutively active mutated form of GSK3beta activated beta-catenin and TCF signaling to comparable levels to those induced by LPA , and protected against apoptosis in differentiating H19-7 cells .	The expression of a constitutively active mutated form of GSK3beta activated beta-catenin and TCF signaling to comparable levels to those induced by LPA, and protected against apoptosis in differentiating H19-7 cells.	7	14	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	9	10	11	12
Results have shown that EZH2 promotes cell proliferation and tumor formation in CC via the epigenetic silencing of GSK-3beta , which activates Wnt and beta-catenin .	Results have shown that EZH2 promotes cell proliferation and tumor formation in CC via the epigenetic silencing of GSK-3beta, which activates Wnt and beta-catenin.	16	25	activates	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	18	19	24	25
Since inactivation of GSK-3beta would inhibit degradation of beta-catenin ( XREF_SUPPLEMENTARY ) , these data imply that a decrease in PTEN levels would transcriptionally activate MMP7 via GSK-3beta-beta-catenin-TCF pathway .	Since inactivation of GSK-3beta would inhibit degradation of beta-catenin (XREF_SUPPLEMENTARY), these data imply that a decrease in PTEN levels would transcriptionally activate MMP7 via GSK-3beta-beta-catenin-TCF pathway.	1	10	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
In addition , we found that 6-gingerol induced phosphorylations of glycogen synthase kinase-3beta ( GSK-3beta ) , and promoted the nuclear accumulation of beta-catenin .	In addition, we found that 6-gingerol induced phosphorylations of glycogen synthase kinase-3beta (GSK-3beta), and promoted the nuclear accumulation of beta-catenin.	6	24	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	6-gingerol induced phosphorylations of glycogen synthase kinase-3beta (GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	14	15	23	24
This , in turn , induces GSK-3beta phosphorylation , which suppresses beta-catenin degradation .	This, in turn, induces GSK-3beta phosphorylation, which suppresses beta-catenin degradation.	6	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	11	12
In addition , GSK-3beta increased to decompose the role of beta-catenin by Cf-GP .	In addition, GSK-3beta increased to decompose the role of beta-catenin by Cf-GP.	3	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	10	11
In cardiomyocytes , one possible mechanism for YAP induced activation of beta-catenin is the elevation of IGF1R expression and subsequent activation of AKT and inhibition of GSK3beta , which could then cause beta-catenin accumulation and nuclear enrichment 17 .	In cardiomyocytes, one possible mechanism for YAP induced activation of beta-catenin is the elevation of IGF1R expression and subsequent activation of AKT and inhibition of GSK3beta, which could then cause beta-catenin accumulation and nuclear enrichment 17.	20	33	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	26	27	32	33
Additionally , DISC1 knockdown increased p-GSK3beta expression and decreased that of beta-catenin and Cyclin D1 , while DISC1 upregulation produced the opposite results .	Additionally, DISC1 knockdown increased p-GSK3beta expression and decreased that of beta-catenin and Cyclin D1, while DISC1 upregulation produced the opposite results.	2	14	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p-GSK3beta	DISC1 knockdown increased p-GSK3beta expression	p-gsk3beta	beta-catenin	beta-catenin	beta-catenin	5	6	11	12
Phosphorylation of GSK3b at Serine 9 by a protein complex comprised of PRKG2 and Axin1 causes increased beta-catenin ( CTNNB1 ) activity and increased hypertrophy of growth plate chondrocytes [ XREF_BIBR ] .	Phosphorylation of GSK3b at Serine 9 by a protein complex comprised of PRKG2 and Axin1 causes increased beta-catenin (CTNNB1) activity and increased hypertrophy of growth plate chondrocytes [XREF_BIBR].	0	28	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3b	Phosphorylation of GSK3b at Serine 9	gsk3b	beta-catenin	beta-catenin	beta-catenin	2	3	17	18
In subsequent studies , we also found that Se-Met activated the signaling pathway of PI3K and Akt , and thereby inhibited the GSK3beta activity , which would further activated the beta-catenin and Cyclin-D signaling pathway and promote NSC proliferation .	In subsequent studies, we also found that Se-Met activated the signaling pathway of PI3K and Akt, and thereby inhibited the GSK3beta activity, which would further activated the beta-catenin and Cyclin-D signaling pathway and promote NSC proliferation.	22	34	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	22	23	30	31
Activation of Wnt signaling leads to disheveled mediated inhibition of GSK-3beta allowing beta-catenin to activate transcription of Wnt and beta-catenin responsive genes .	Activation of Wnt signaling leads to disheveled mediated inhibition of GSK-3beta allowing beta-catenin to activate transcription of Wnt and beta-catenin responsive genes.	8	14	allowing	Positive_activation_token_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	10	11	12	13
Administration of nimbolide inhibited PI3K and Akt signalling with consequent activation of GSK-3beta thereby inducing trafficking of beta-catenin away from the nucleus and enhancing the expression of miR-126 and let-7 .	Administration of nimbolide inhibited PI3K and Akt signalling with consequent activation of GSK-3beta thereby inducing trafficking of beta-catenin away from the nucleus and enhancing the expression of miR-126 and let-7.	10	18	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	12	13	17	18
As shown in XREF_FIG , silymarin mediated proteasomal degradation of beta-catenin was observed in DMSO pretreated cells , while inhibition of GSK3beta attenuated silymarin induced downregulation of beta-catenin in both HCT116 and SW480 cells .	As shown in XREF_FIG, silymarin mediated proteasomal degradation of beta-catenin was observed in DMSO pretreated cells, while inhibition of GSK3beta attenuated silymarin induced downregulation of beta-catenin in both HCT116 and SW480 cells.	19	28	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	21	22	27	28
The local inactivation of GSK-3beta also seems to cause accumulation of beta-catenin .	The local inactivation of GSK-3beta also seems to cause accumulation of beta-catenin.	2	12	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	11	12
It is likely that PKC , a downstream effector of PLCgamma2 , phosphorylates and thus inactivates GSK3beta , a kinase that targets beta-catenin for ubiquitination and subsequent proteasomal degradation .	It is likely that PKC, a downstream effector of PLCgamma2, phosphorylates and thus inactivates GSK3beta, a kinase that targets beta-catenin for ubiquitination and subsequent proteasomal degradation.	15	28	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	16	17	22	23
In the cell , beta-catenin presence is regulated by Wnt ; in the absence of Wnt , beta-catenin is targeted by GSK-3beta for degradation , but the activation of the signaling pathway by Wnt reduces beta-catenin degradation , causing it to accumulate and translocate into the nucleus where it activates TCF and LEF1 transcription factors that bind to Wnt target genes .	In the cell, beta-catenin presence is regulated by Wnt; in the absence of Wnt, beta-catenin is targeted by GSK-3beta for degradation, but the activation of the signaling pathway by Wnt reduces beta-catenin degradation, causing it to accumulate and translocate into the nucleus where it activates TCF and LEF1 transcription factors that bind to Wnt target genes.	17	23	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	21	22	17	18
We found that knockdown of DDAH1 in the GC cells increased the levels of Wnt1 , enhanced phosphorylation of GSK-3beta at Ser9 , and reduced the phosphorylated forms of beta-catenin ( Ser33/37/Thr41 ) .	We found that knockdown of DDAH1 in the GC cells increased the levels of Wnt1, enhanced phosphorylation of GSK-3beta at Ser9, and reduced the phosphorylated forms of beta-catenin (Ser33/37/Thr41).	5	31	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	DDAH1 in the GC cells increased the levels of Wnt1, enhanced phosphorylation of GSK-3beta at Ser9	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	19	20	29	30
These results suggest that Gsk3beta may modulate Wnt and beta-catenin signaling function during palate development .	These results suggest that Gsk3beta may modulate Wnt and beta-catenin signaling function during palate development.	4	11	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	4	5	9	10
Inactivation of GSK-3beta stimulates beta-catenin , which in turn potentially regulates GSC differentiation and tumor progression via regulation of Notch pathway [ XREF_BIBR , XREF_BIBR ] .	Inactivation of GSK-3beta stimulates beta-catenin, which in turn potentially regulates GSC differentiation and tumor progression via regulation of Notch pathway [XREF_BIBR, XREF_BIBR].	0	10	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
The increase in beta-catenin due to PAK1 overexpression in H1355 and H23 cells occurred via an increase in GSK3beta phosphorylation at Serine 9 , which increased the beta-catenin protein stability .	The increase in beta-catenin due to PAK1 overexpression in H1355 and H23 cells occurred via an increase in GSK3beta phosphorylation at Serine 9, which increased the beta-catenin protein stability.	18	29	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta phosphorylation at Serine	gsk3beta	beta-catenin	beta-catenin	beta-catenin	18	19	27	28
The result indicated that the degradation of beta-catenin caused by down regulation of p-GSK3beta failed to enter the nucleus , resulting in the decreased expression of key osteogenesis gene was alleviated by S3 after HLS .	The result indicated that the degradation of beta-catenin caused by down regulation of p-GSK3beta failed to enter the nucleus, resulting in the decreased expression of key osteogenesis gene was alleviated by S3 after HLS.	5	20	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	p-GSK3beta	p-GSK3beta	p-GSK3beta	beta-catenin	beta-catenin	beta-catenin	13	14	7	8
These results showed that NDRG2 diminishes the phosphorylation of GSK-3beta , which enhances its kinase activity , and subsequently down-regulates beta-catenin in SW620 cells .	These results showed that NDRG2 diminishes the phosphorylation of GSK-3beta, which enhances its kinase activity, and subsequently down-regulates beta-catenin in SW620 cells.	4	21	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	NDRG2 diminishes the phosphorylation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	9	10	20	21
The other GSK3beta target beta-catenin is considered to be a major oncoprotein and a mediator of conventional Wnt and beta-catenin pathway [ XREF_BIBR ] .	The other GSK3beta target beta-catenin is considered to be a major oncoprotein and a mediator of conventional Wnt and beta-catenin pathway [XREF_BIBR].	0	11	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	4	5
DNAJB6 with Heat Shock Cognate 40 ( HSC40 ) can recruit PP2A to GSK3beta where it can directly dephosphorylate S9 and activate GSK3beta , which targets more beta-catenin for destruction .	DNAJB6 with Heat Shock Cognate 40 (HSC40) can recruit PP2A to GSK3beta where it can directly dephosphorylate S9 and activate GSK3beta, which targets more beta-catenin for destruction.	21	28	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	22	23	27	28
Silencing SFRP1 , GSK3beta and TLE3 disrupted the repression efficacy of the miR-744-regulated Wnt / beta-catenin activity ( XREF_SUPPLEMENTARY and Fig .	Silencing SFRP1, GSK3beta and TLE3 disrupted the repression efficacy of the miR-744-regulated Wnt / beta-catenin activity (XREF_SUPPLEMENTARY and Fig.	1	16	disrupted	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	3	4	15	16
Under physiologic conditions , glycogen synthase kinase 3beta ( GSK-3beta ) constitutively phosphorylates and targets beta-catenin for degradation through the ubiquitin-proteasome pathway .	Under physiologic conditions, glycogen synthase kinase 3beta (GSK-3beta) constitutively phosphorylates and targets beta-catenin for degradation through the ubiquitin-proteasome pathway.	7	17	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	9	10	15	16
Differently , in the current study , we found that PDE1 inhibition reduced GSK3beta phosphorylation ( activated GSK3beta ) and promoted beta-catenin degradation via GSK3beta dependent phosphorylation of beta-catenin .	Differently, in the current study, we found that PDE1 inhibition reduced GSK3beta phosphorylation (activated GSK3beta) and promoted beta-catenin degradation via GSK3beta dependent phosphorylation of beta-catenin.	10	22	promoted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	PDE1 inhibition reduced GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	13	14	21	22
In the cytosol , Axin1/2 , APC and GSK-3beta can inhibit Wnt signaling by promoting beta-catenin degradation 6 .	In the cytosol, Axin1/2, APC and GSK-3beta can inhibit Wnt signaling by promoting beta-catenin degradation 6.	4	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	8	9	15	16
The localization of beta-catenin , which is involved in cell proliferation , and mediated by GSK-3beta activation was also demonstrated .	The localization of beta-catenin, which is involved in cell proliferation, and mediated by GSK-3beta activation was also demonstrated.	1	16	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	15	16	3	4
DIF-1 activated glycogen synthase kinase-3beta ( GSK-3beta ) and inhibition of GSK-3beta attenuated the DIF-1-induced beta-catenin degradation , indicating the involvement of GSK-3beta in this effect .	DIF-1 activated glycogen synthase kinase-3beta (GSK-3beta) and inhibition of GSK-3beta attenuated the DIF-1-induced beta-catenin degradation, indicating the involvement of GSK-3beta in this effect.	4	16	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	15	16
The glycogen synthase kinase-3beta ( GSK3beta ) , reported to mediate beta-catenin and Wnt signalling [ XREF_BIBR , XREF_BIBR ] , also showed a reduced intensity of labelling in the cytoplasm of ZP3-KO oocytes ( XREF_FIG ) .	The glycogen synthase kinase-3beta (GSK3beta), reported to mediate beta-catenin and Wnt signalling [XREF_BIBR, XREF_BIBR], also showed a reduced intensity of labelling in the cytoplasm of ZP3-KO oocytes (XREF_FIG).	3	18	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	5	6	11	12
To address these shortcomings , the authors have taken a novel approach using chromatin immunoprecipitation enriched material annealed to microarrays ( ChIP-chip ) targeting genes in fetal brain tissue bound by beta-catenin , a transcription factor that is directly regulated by GSK3beta .	To address these shortcomings, the authors have taken a novel approach using chromatin immunoprecipitation enriched material annealed to microarrays (ChIP-chip) targeting genes in fetal brain tissue bound by beta-catenin, a transcription factor that is directly regulated by GSK3beta.	29	42	directly regulated	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	41	42	31	32
Furthermore , Glycogen Synthase Kinase-3beta ( GSK3-beta ) inhibition XREF_BIBR , lithium XREF_BIBR , XREF_BIBR or Wnt3a XREF_BIBR , all of which activate Wnt and beta-catenin signalling , exert neuroprotective effects in SCI .	Furthermore, Glycogen Synthase Kinase-3beta (GSK3-beta) inhibition XREF_BIBR, lithium XREF_BIBR, XREF_BIBR or Wnt3a XREF_BIBR, all of which activate Wnt and beta-catenin signalling, exert neuroprotective effects in SCI.	4	26	activate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	GSK3-beta	GSK3-beta	GSK3-beta	beta-catenin	beta-catenin	beta-catenin	6	7	25	26
By promoting degradation of beta-catenin , GSK-3beta effectively prevents intranuclear accumulation of beta-catenin and subsequent gene transcription XREF_BIBR .	By promoting degradation of beta-catenin, GSK-3beta effectively prevents intranuclear accumulation of beta-catenin and subsequent gene transcription XREF_BIBR.	2	9	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	6	7	4	5
It also attenuated GnRH-II induced trans-activation of a beta-catenin-dependent reporter gene , most likely because GSK3beta phosphorylation promotes translocation of beta-catenin to the nucleus .	It also attenuated GnRH-II induced trans-activation of a beta-catenin-dependent reporter gene, most likely because GSK3beta phosphorylation promotes translocation of beta-catenin to the nucleus.	15	21	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	15	16	20	21
We demonstrate that lack of Gadd45a not only prevents DeltaNp63alpha suppression and GSK3beta dephosphorylation but also prevents free cytoplasmic beta-catenin degradation after UV irradiation .	We demonstrate that lack of Gadd45a not only prevents DeltaNp63alpha suppression and GSK3beta dephosphorylation but also prevents free cytoplasmic beta-catenin degradation after UV irradiation.	5	20	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	Gadd45a not only prevents DeltaNp63alpha suppression and GSK3beta dephosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	12	13	19	20
To regulate gene expression , Akt phosphorylates GSK3beta at serine 9 , resulting in GSK3beta inactivation thus preventing proteasomal degradation of betacatenin ( XREF_FIG ) .	To regulate gene expression, Akt phosphorylates GSK3beta at serine 9, resulting in GSK3beta inactivation thus preventing proteasomal degradation of betacatenin (XREF_FIG).	14	23	preventing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	betacatenin	betacatenin	betacatenin	14	15	21	22
Inhibition of GSK-3beta decreased the pool of beta-catenin that was targeted for proteasomal degradation .	Inhibition of GSK-3beta decreased the pool of beta-catenin that was targeted for proteasomal degradation.	0	8	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	2	3	7	8
Mutations in the proteins of APC , axin , GSK-3beta , and CKI complex prevent proteasomal degradation of beta-catenin , thereby leading to translocation of beta-catenin into the nucleus and activation of beta-catenin and Tcf dependent transcription .	Mutations in the proteins of APC, axin, GSK-3beta, and CKI complex prevent proteasomal degradation of beta-catenin, thereby leading to translocation of beta-catenin into the nucleus and activation of beta-catenin and Tcf dependent transcription.	3	19	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	9	10	18	19
Less active GSK3beta enhanced activation of Wnt and beta-catenin pathway and resultant WISP1 expression ; in turn , increased WISP1 expression further led to phosphorylation and inactivation of GSK3beta , which eventuated in a strong positive feedback loop of WISP1 expression and concomitant refractory radioresistance .	Less active GSK3beta enhanced activation of Wnt and beta-catenin pathway and resultant WISP1 expression; in turn, increased WISP1 expression further led to phosphorylation and inactivation of GSK3beta, which eventuated in a strong positive feedback loop of WISP1 expression and concomitant refractory radioresistance.	0	9	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
GSK3beta phosphorylation leads to activation of the Wnt and beta-catenin pathway .	GSK3beta phosphorylation leads to activation of the Wnt and beta-catenin pathway.	0	10	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta phosphorylation	gsk3beta	beta-catenin	beta-catenin	beta-catenin	0	1	9	10
Phosphorylation and inactivation of GSK-3beta prevents beta-catenin degradation and results in cytosolic accumulation and eventual nuclear translocation of beta-catenin .	Phosphorylation and inactivation of GSK-3beta prevents beta-catenin degradation and results in cytosolic accumulation and eventual nuclear translocation of beta-catenin.	0	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	Phosphorylation and inactivation of GSK-3beta	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	4	5	6	7
XREF_BIBR , XREF_BIBR These results suggest that Akt and Gsk3beta axis mediated beta-catenin activation in islets may regulate beta-cell growth and function in c-Kit Wv/+ mice .	XREF_BIBR, XREF_BIBR These results suggest that Akt and Gsk3beta axis mediated beta-catenin activation in islets may regulate beta-cell growth and function in c-Kit Wv/+ mice.	7	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Gsk3beta	Gsk3beta	Gsk3beta	beta-catenin	beta-catenin	beta-catenin	9	10	12	13
Suppression of STAT3 attenuates the risk of GSK3beta inhibition induced beta-Catenin and Wnt activation by xanthatin .	Suppression of STAT3 attenuates the risk of GSK3beta inhibition induced beta-Catenin and Wnt activation by xanthatin.	7	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	beta-Catenin	beta-Catenin	beta-Catenin	7	8	10	11
LiCl has been reported to activate the Wnt pathway targets by inhibiting Gsk3b , a kinase that targets Ctnnb1 for degradation XREF_BIBR , XREF_BIBR .	LiCl has been reported to activate the Wnt pathway targets by inhibiting Gsk3b, a kinase that targets Ctnnb1 for degradation XREF_BIBR, XREF_BIBR.	11	21	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Gsk3b	Gsk3b	Gsk3b	Ctnnb1	Ctnnb1	Ctnnb1	12	13	18	19
In the absence of Wnt signaling , beta-catenin is targeted for degradation via ubiquitination by GSK3-beta .	In the absence of Wnt signaling, beta-catenin is targeted for degradation via ubiquitination by GSK3-beta.	7	16	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3-beta	GSK3-beta	GSK3-beta	beta-catenin	beta-catenin	beta-catenin	15	16	7	8
CDK5 can bind to beta-catenin and regulate its interaction with scaffolding molecules XREF_BIBR , XREF_BIBR , XREF_BIBR , while increased GSK3beta can target beta-catenin for degradation XREF_BIBR .	CDK5 can bind to beta-catenin and regulate its interaction with scaffolding molecules XREF_BIBR, XREF_BIBR, XREF_BIBR, while increased GSK3beta can target beta-catenin for degradation XREF_BIBR.	19	24	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	20	21	23	24
Further , degradation of beta-catenin induced by GSK-3beta phosphorylation is not a general mechanism but is cell type dependent [ XREF_BIBR ] .	Further, degradation of beta-catenin induced by GSK-3beta phosphorylation is not a general mechanism but is cell type dependent [XREF_BIBR].	2	9	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	beta-catenin	beta-catenin	beta-catenin	7	8	4	5
The GSK-3beta inactivation leads to increase in total beta-catenin protein and its consequent nuclear localization leading to increase in MnSOD enzyme activity .	The GSK-3beta inactivation leads to increase in total beta-catenin protein and its consequent nuclear localization leading to increase in MnSOD enzyme activity.	1	9	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	1	2	8	9
Both CK1alpha and GSK-3beta are known to target beta-catenin for proteasomal degradation via combined phosphorylation at key residues of beta-catenin .	Both CK1alpha and GSK-3beta are known to target beta-catenin for proteasomal degradation via combined phosphorylation at key residues of beta-catenin.	1	11	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
The Wnt binds to its co-receptors of Frizzled to activate Dsh , which recruits glycogen synthase kinase-3 beta ( GSK-3b ) , promoting beta-catenin nuclear translocation and downstream gene expression [ XREF_BIBR ] .	The Wnt binds to its co-receptors of Frizzled to activate Dsh, which recruits glycogen synthase kinase-3 beta (GSK-3b), promoting beta-catenin nuclear translocation and downstream gene expression [XREF_BIBR].	17	24	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3b	GSK-3b	GSK-3b	beta-catenin	beta-catenin	beta-catenin	19	20	23	24
Furthermore CK1epsilon is known to phosphorylate adenomatosis polyposis coli ( APC ) together with GSK3beta which leads to an increased affinity of APC to beta-catenin causing a transfer of beta-catenin from axin to APC .	Furthermore CK1epsilon is known to phosphorylate adenomatosis polyposis coli (APC) together with GSK3beta which leads to an increased affinity of APC to beta-catenin causing a transfer of beta-catenin from axin to APC.	5	25	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	14	15	24	25
For instance , Wnt signaling activation can occur through phosphorylation of the negative regulatory elements glycogen synthase kinase 3 beta ( GSK3beta ) , which in turn causes beta-catenin protein stabilization [ XREF_BIBR ] .	For instance, Wnt signaling activation can occur through phosphorylation of the negative regulatory elements glycogen synthase kinase 3 beta (GSK3beta), which in turn causes beta-catenin protein stabilization [XREF_BIBR].	19	30	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	21	22	28	29
In this pathway , glycogen synthase kinase-3beta ( GSK3beta ) down-regulates transduction of the canonical Wnt signal by promoting degradation of beta-catenin .	In this pathway, glycogen synthase kinase-3beta (GSK3beta) down-regulates transduction of the canonical Wnt signal by promoting degradation of beta-catenin.	6	22	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	beta-catenin	beta-catenin	beta-catenin	8	9	21	22
Because phosphorylation of GSK3beta on S9 inhibits its activity and prevents the targeting of beta-catenin for degradation , whole cell lysates were examined for both total GSK3beta and phosphorylated GSK3beta at S9 levels following Huaier treatment .	Because phosphorylation of GSK3beta on S9 inhibits its activity and prevents the targeting of beta-catenin for degradation, whole cell lysates were examined for both total GSK3beta and phosphorylated GSK3beta at S9 levels following Huaier treatment.	1	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	phosphorylation of GSK3beta on S9	gsk3beta	beta-catenin	beta-catenin	beta-catenin	3	4	14	15
According to the results of this experiment and other experiments , HSF-1 could be phosphorylated by p-GSK3beta , and p-GSK3beta may accelerate HSP70 production partially by activating HSF-1 during the experimental conditions , thus serving a protective function .	According to the results of this experiment and other experiments, HSF-1 could be phosphorylated by p-GSK3beta, and p-GSK3beta may accelerate HSP70 production partially by activating HSF-1 during the experimental conditions, thus serving a protective function.	19	28	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p-GSK3beta	p-GSK3beta	p-GSK3beta	HSF-1	HSF-1	HSF-1	19	20	27	28
Overexpression of GSK-3beta impaired heat shock induced activation of HSF-1 , and also reduced HSP-70 production , which was partially restored by the GSK-3beta inhibitor lithium .	Overexpression of GSK-3beta impaired heat shock induced activation of HSF-1, and also reduced HSP-70 production, which was partially restored by the GSK-3beta inhibitor lithium.	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	Overexpression of GSK-3beta	gsk-3beta	HSF-1	HSF-1	hsf-1	2	3	9	10
For example , a member of this pathway , GSK-3beta , is a negative regulator of HSF1 and phosphorylation of GSK3beta by Akt activates HSF1 and Hsp70 XREF_BIBR .	For example, a member of this pathway, GSK-3beta, is a negative regulator of HSF1 and phosphorylation of GSK3beta by Akt activates HSF1 and Hsp70 XREF_BIBR.	18	27	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	phosphorylation of GSK3beta	gsk3beta	HSF1	HSF1	hsf1	20	21	24	25
The phosphorylation of GSK3beta serves a critical role during the cardioprotection in diabetic rats , and p-GSK3beta may accelerate HSP70 production partially by activating HSF-1 during myocardial ischemic and reperfusion injury .	The phosphorylation of GSK3beta serves a critical role during the cardioprotection in diabetic rats, and p-GSK3beta may accelerate HSP70 production partially by activating HSF-1 during myocardial ischemic and reperfusion injury.	16	25	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p-GSK3beta	p-GSK3beta	p-GSK3beta	HSF-1	HSF-1	HSF-1	16	17	24	25
Phosphorylation of GSK-3beta blocks the GSK-3 inactivation of HSF-1 and thereby increases activity of HSF-1 .	Phosphorylation of GSK-3beta blocks the GSK-3 inactivation of HSF-1 and thereby increases activity of HSF-1.	0	9	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	Phosphorylation of GSK-3beta	gsk-3beta	HSF-1	HSF-1	hsf-1	2	3	8	9
This regulation might rely on the fact that the activation of AKT inhibited GSK-3beta [ XREF_BIBR ] , and the inhibition of GSK-3beta could activate HSF1 .	This regulation might rely on the fact that the activation of AKT inhibited GSK-3beta [XREF_BIBR], and the inhibition of GSK-3beta could activate HSF1.	20	26	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	HSF1	HSF1	HSF1	22	23	25	26
Concordantly , p-GSK3beta accelerated HSP70 production partially by activating HSF-1 during myocardial ischemia .	Concordantly, p-GSK3beta accelerated HSP70 production partially by activating HSF-1 during myocardial ischemia.	2	10	accelerated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p-GSK3beta	p-GSK3beta	p-GSK3beta	HSF-1	HSF-1	HSF-1	2	3	9	10
In contrast , overexpression of a dominant negative GSK3beta led to increased proteolytic cleavage of CREBH in hepatocytes during the circadian cycle ( XREF_FIG ) , thus supporting a regulatory role of AKT-GSK3beta signaling in BMAL1 controlled CREBH cleavage .	In contrast, overexpression of a dominant negative GSK3beta led to increased proteolytic cleavage of CREBH in hepatocytes during the circadian cycle (XREF_FIG), thus supporting a regulatory role of AKT-GSK3beta signaling in BMAL1 controlled CREBH cleavage.	3	38	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	overexpression of a dominant negative GSK3beta	gsk3beta	BMAL1	BMAL1	bmal1	8	9	35	36
GSK3beta may also modulate CLOCK , BMAL1 , and REV-ERBalpha .	GSK3beta may also modulate CLOCK, BMAL1, and REV-ERBalpha.	0	7	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	BMAL1	BMAL1	BMAL1	0	1	6	7
In particular , phosphorylation by CKIdelta and epsilon targets Per1-3 and Cry1-2 proteins for degradation and regulates their nuclear translocation , AMPK targets Cry1-2 proteins , and GSK3beta targets Arntl .	In particular, phosphorylation by CKIdelta and epsilon targets Per1-3 and Cry1-2 proteins for degradation and regulates their nuclear translocation, AMPK targets Cry1-2 proteins, and GSK3beta targets Arntl.	27	30	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Arntl	Arntl	Arntl	27	28	29	30
Previous studies have shown that upregulation of GSK-3beta activity can activate Bax , c-jun and the caspases family , in normal histiocytes and various tumor cells [ XREF_BIBR XREF_BIBR ] , resulting in cell apoptosis .	Previous studies have shown that upregulation of GSK-3beta activity can activate Bax, c-jun and the caspases family, in normal histiocytes and various tumor cells [XREF_BIBR XREF_BIBR], resulting in cell apoptosis.	7	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	c-jun	c-jun	c-jun	7	8	13	14
GSK3beta directly modulates the activity of transcription factors , activator protein 1 ( AP-1 ) and nuclear factor-kappaB ( NF-kappaB ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	GSK3beta directly modulates the activity of transcription factors, activator protein 1 (AP-1) and nuclear factor-kappaB (NF-kappaB) [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	12	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	activator protein 1	activator protein 1	activator protein 1	0	1	9	12
While GRK5 potentiates the nuclear localisation of aSyn , PLKs modulate the shuttling of the protein between the nucleus and cytoplasm .	While GRK5 potentiates the nuclear localisation of aSyn, PLKs modulate the shuttling of the protein between the nucleus and cytoplasm.	1	8	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GRK5	GRK5	GRK5	aSyn	aSyn	aSyn	1	2	7	8
While G protein coupled receptor kinase 5 ( GRK5 ) promotes the nuclear localization of aSyn , PLK2 and 3 modulate the shuttling of the protein between the nucleus and cytoplasm .	While G protein coupled receptor kinase 5 (GRK5) promotes the nuclear localization of aSyn, PLK2 and 3 modulate the shuttling of the protein between the nucleus and cytoplasm.	2	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GRK5	GRK5	GRK5	aSyn	aSyn	aSyn	8	9	15	16
When compared to the kinase substrate databases described above , 16 proteins were known AKT substrates ( Supplementary Data 7 ) including well studied molecules in AKT signaling such as GSK3A , GSK3B , AKT1S1 , EPHA2 and PFKFB2 .	When compared to the kinase substrate databases described above, 16 proteins were known AKT substrates (Supplementary Data 7) including well studied molecules in AKT signaling such as GSK3A, GSK3B, AKT1S1, EPHA2 and PFKFB2.	26	38	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	GSK3A	GSK3A	GSK3A	AKT	AKT	AKT	30	31	26	27
6 Neurotrophin dependent inactivation of GSK-3beta increases adenomatous polyposis coli ( APC ) 75 or collapsin response mediator protein-2 ( CRMP-2 ) 76 stabilization of microtubules and increases axon elongation in developing neurites .	6 Neurotrophin dependent inactivation of GSK-3beta increases adenomatous polyposis coli (APC) 75 or collapsin response mediator protein-2 (CRMP-2) 76 stabilization of microtubules and increases axon elongation in developing neurites.	3	19	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	collapsin response mediator protein-2	collapsin response mediator protein-2	collapsin response mediator protein-2	5	6	15	19
In addition , these complexes also mediate activation of GSK-3beta , which promotes CRMP2 mediated microtubule stabilization .	In addition, these complexes also mediate activation of GSK-3beta, which promotes CRMP2 mediated microtubule stabilization.	7	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	CRMP2	CRMP2	CRMP2	9	10	13	14
The present study demonstrated that chronic treatment with ethanol enhanced the rewarding effects of morphine by up-regulating functional changes in mu-opioid receptor , mediated by GRK2 .	The present study demonstrated that chronic treatment with ethanol enhanced the rewarding effects of morphine by up-regulating functional changes in mu-opioid receptor, mediated by GRK2.	20	26	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GRK2	GRK2	GRK2	mu-opioid receptor	mu-opioid receptor	mu-opioid receptor	25	26	20	22
These results suggest that homologous desensitization of rat mu-opioid receptors results from the activation of GRK2 and that a cluster of Ser/Thr residues ( Thr354Ser355Ser356Thr357 ) at the intracellular carboxyl tail plays an important role in GRK2 mediated mu-opioid receptor desensitization .	These results suggest that homologous desensitization of rat mu-opioid receptors results from the activation of GRK2 and that a cluster of Ser/Thr residues (Thr354Ser355Ser356Thr357) at the intracellular carboxyl tail plays an important role in GRK2 mediated mu-opioid receptor desensitization.	34	40	mediated	Positive_early_activation	Negative_activation	Positive_activation	GRK2	GRK2	GRK2	mu-opioid receptor	mu-opioid receptor	mu-opioid receptor	36	37	38	40
Our findings thus suggest that Thr ( 308 ) is a major residue involved in GRK6 mediated desensitization of BLT1 signaling .	Our findings thus suggest that Thr (308) is a major residue involved in GRK6 mediated desensitization of BLT1 signaling.	13	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GRK6	GRK6	GRK6	BLT1	BLT1	BLT1	15	16	19	20
Previous studies have reported that GSK3beta targets KLF5 for proteosomal degradation , 19 which is in concordance with GSK3beta altering the stability of many of its substrates .	Previous studies have reported that GSK3beta targets KLF5 for proteosomal degradation, 19 which is in concordance with GSK3beta altering the stability of many of its substrates.	3	12	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	KLF5	KLF5	KLF5	5	6	7	8
A rat CRMP4 triple alanine substitution mutant ( L-CRMP4-AAA-V5 ) for the three carboxy terminal phospho-residues targeted by GSK3beta ( Thr622 , Thr627 , Ser631 ) fails to undergo phosphorylation in response to nocodazole establishing the specificity of the antibody for phospho-CRMP4 ( XREF_SUPPLEMENTARY ) .	A rat CRMP4 triple alanine substitution mutant (L-CRMP4-AAA-V5) for the three carboxy terminal phospho-residues targeted by GSK3beta (Thr622, Thr627, Ser631) fails to undergo phosphorylation in response to nocodazole establishing the specificity of the antibody for phospho-CRMP4 (XREF_SUPPLEMENTARY).	0	28	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	CRMP4	CRMP4	CRMP4	18	19	2	3
We found that GSK3beta inhibits MAML1 transcriptional activity by directly targeting the N-terminal domain of MAML1 .	We found that GSK3beta inhibits MAML1 transcriptional activity by directly targeting the N-terminal domain of MAML1.	3	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	GSK3beta	GSK3beta	MAML1	MAML1	MAML1	3	4	5	6
As opposed to GRK2 which appeared specific for agonist dependent MC1R signaling , GRK6 also impaired constitutive signaling and promoted MC1R internalization , most likely by phosphorylation of the C-terminal Thr308 and Ser316 .	As opposed to GRK2 which appeared specific for agonist dependent MC1R signaling, GRK6 also impaired constitutive signaling and promoted MC1R internalization, most likely by phosphorylation of the C-terminal Thr308 and Ser316.	13	21	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GRK6	GRK6	GRK6	MC1R	MC1R	MC1R	13	14	20	21
Cotreatment with proteosome inhibitor bortezomib or MG-132 and inhibition of GSK-3beta ( that is involved in regulating MCL-1 stability ) did not reverse the suppression of MCL-1 detected upon cotreatment with ritonavir and metformin ( data not shown ) .	Cotreatment with proteosome inhibitor bortezomib or MG-132 and inhibition of GSK-3beta (that is involved in regulating MCL-1 stability) did not reverse the suppression of MCL-1 detected upon cotreatment with ritonavir and metformin (data not shown).	6	27	reverse	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	MCL-1	MCL-1	MCL-1	10	11	26	27
Intriguingly , it appeared that silencing of GSK-3alpha somehow favored whereas silencing of GSK-3beta protected against BZ induced AKT and , even more , MCL-1 degradation .	Intriguingly, it appeared that silencing of GSK-3alpha somehow favored whereas silencing of GSK-3beta protected against BZ induced AKT and, even more, MCL-1 degradation.	11	25	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	MCL-1	MCL-1	MCL-1	13	14	24	25
Furthermore , GSK-3beta causes Mcl-1 destabilization to induce the cathepsin D mediated activation of caspase-8 and Bid in ceramide- or etoposide induced apoptosis .	Furthermore, GSK-3beta causes Mcl-1 destabilization to induce the cathepsin D mediated activation of caspase-8 and Bid in ceramide- or etoposide induced apoptosis.	2	5	causes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	2	3	4	5
In the present study , we show that GSK-3beta and caspase-2 cause Mcl-1 destabilization followed by LMP and cathepsin D mediated caspase-8 activation in lysosomal-mitochondrial axis mediated apoptosis induced by either the ceramide analogue C 2 -ceramide or the topoisomerase II inhibitor etoposide .	In the present study, we show that GSK-3beta and caspase-2 cause Mcl-1 destabilization followed by LMP and cathepsin D mediated caspase-8 activation in lysosomal-mitochondrial axis mediated apoptosis induced by either the ceramide analogue C 2 -ceramide or the topoisomerase II inhibitor etoposide.	8	13	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	8	9	12	13
We further showed that GSK-3beta and caspase-2 synergistically induced Mcl-1 destabilization followed by LMP .	We further showed that GSK-3beta and caspase-2 synergistically induced Mcl-1 destabilization followed by LMP.	4	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	4	5	9	10
Importantly , GSK3beta phosphorylation prevents the phosphorylation dependent degradation of Mcl-1 , which is required for survival throughout B cell development .	Importantly, GSK3beta phosphorylation prevents the phosphorylation dependent degradation of Mcl-1, which is required for survival throughout B cell development.	2	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta phosphorylation	gsk3beta	Mcl-1	Mcl-1	mcl-1	2	3	10	11
In conclusion , our study demonstrates that ZA treatment triggers ROS and GSK-3beta activation , which further causes Mcl-1 downregulation and mitochondrial damage and results in apoptosis of osteoclast precursor cells .	In conclusion, our study demonstrates that ZA treatment triggers ROS and GSK-3beta activation, which further causes Mcl-1 downregulation and mitochondrial damage and results in apoptosis of osteoclast precursor cells.	10	19	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	12	13	18	19
These results indicated that p-Akt-mediated phosphorylation of GSK-3beta promotes the DCA induced Mcl-1 stabilization .	These results indicated that p-Akt-mediated phosphorylation of GSK-3beta promotes the DCA induced Mcl-1 stabilization.	5	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	phosphorylation of GSK-3beta	gsk-3beta	Mcl-1	Mcl-1	mcl-1	7	8	12	13
Propofol activated GSK-3beta and inhibiting GSK-3beta prevented Mcl-1 destabilization , MTP loss , and lysosomal and mitochondrial apoptosis .	Propofol activated GSK-3beta and inhibiting GSK-3beta prevented Mcl-1 destabilization, MTP loss, and lysosomal and mitochondrial apoptosis.	2	8	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	5	6	7	8
Activation of GSK-3beta results in Mcl-1 degradation , while inactivation of GSK-3beta causes accumulation of Mcl-1 promoting chemo-resistance in a Mcl-1 dependent manner .	Activation of GSK-3beta results in Mcl-1 degradation, while inactivation of GSK-3beta causes accumulation of Mcl-1 promoting chemo-resistance in a Mcl-1 dependent manner.	9	16	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	11	12	15	16
These results demonstrate that activation of GSK-3beta and caspase-2 mediate Mcl-1 destabilization in ceramide treated apoptotic cells .	These results demonstrate that activation of GSK-3beta and caspase-2 mediate Mcl-1 destabilization in ceramide treated apoptotic cells.	4	11	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	6	7	10	11
During cell apoptosis , activated GSK-3beta causes Mcl-1 down-regulation through a mechanism involving phosphorylation followed by proteasome mediated degradation [ XREF_BIBR ] .	During cell apoptosis, activated GSK-3beta causes Mcl-1 down-regulation through a mechanism involving phosphorylation followed by proteasome mediated degradation [XREF_BIBR].	4	8	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	5	6	7	8
Other studies have demonstrated that GSK-3beta function is important in Mcl-1 degradation because AKT mediated phosphorylation of GSK-3beta enhances Mcl-1 stability .	Other studies have demonstrated that GSK-3beta function is important in Mcl-1 degradation because AKT mediated phosphorylation of GSK-3beta enhances Mcl-1 stability.	13	20	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	AKT mediated phosphorylation of GSK-3beta	gsk-3beta	Mcl-1	Mcl-1	mcl-1	17	18	19	20
GSK-3beta activation causes Mcl-1 downregulation , facilitating neutrophil apoptosis , as demonstrated in our previous studies .	GSK-3beta activation causes Mcl-1 downregulation, facilitating neutrophil apoptosis, as demonstrated in our previous studies.	0	4	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Mcl-1	Mcl-1	Mcl-1	0	1	3	4
GSK3beta has been shown to increase Mcl-1 instability through phosphorylation on Ser 140 .	GSK3beta has been shown to increase Mcl-1 instability through phosphorylation on Ser 140.	0	7	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Mcl-1	Mcl-1	Mcl-1	0	1	6	7
Moreover , our data suggest that GSK-3alpha might control AKT protein turnover , while GSK-3beta could modulate MCL-1 protein stability .	Moreover, our data suggest that GSK-3alpha might control AKT protein turnover, while GSK-3beta could modulate MCL-1 protein stability.	14	19	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	MCL-1 protein	MCL-1 protein	MCL-1 protein	14	15	17	19
Moreover , SHP competed with HDAC4 for an influence over Runx2 transactivity ( see XREF_FIG ) , and inhibition of endogenous HDAC4 increased Runx2 transactivity ( see XREF_FIG ) , demonstrating that HDAC4 is a substantial corepressor of Runx2 .	Moreover, SHP competed with HDAC4 for an influence over Runx2 transactivity (see XREF_FIG), and inhibition of endogenous HDAC4 increased Runx2 transactivity (see XREF_FIG), demonstrating that HDAC4 is a substantial corepressor of Runx2.	18	24	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	21	22	23	24
It is reported that HDAC4 repressed chondrocyte hypertrophy by binding to and inhibiting Runx2 transcriptional activity in the chondrocytes of an embryonic chick [ XREF_BIBR ] .	It is reported that HDAC4 repressed chondrocyte hypertrophy by binding to and inhibiting Runx2 transcriptional activity in the chondrocytes of an embryonic chick [XREF_BIBR].	4	15	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	4	5	13	14
RUNX2 is activated by MEF2 and both MEF2 and RUNX2 are targeted by HDAC4 [ XREF_BIBR ] .	RUNX2 is activated by MEF2 and both MEF2 and RUNX2 are targeted by HDAC4 [XREF_BIBR].	7	15	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	HDAC4	HDAC4	HDAC4	RUNX2	RUNX2	RUNX2	13	14	9	10
Thus , the collected evidences suggest that HDAC4 may target both MEF2 and Runx2 to regulate chondrocytes hypertrophy independently .	Thus, the collected evidences suggest that HDAC4 may target both MEF2 and Runx2 to regulate chondrocytes hypertrophy independently.	7	14	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	7	8	13	14
This resulted in an increase of the HDAC2 : HDAC4 ratio , which then induced RUNX2 and ultimately resulted in increased expression of MMP13 , ADAMTS4 , and ADAMTS5 .	This resulted in an increase of the HDAC2 : HDAC4 ratio, which then induced RUNX2 and ultimately resulted in increased expression of MMP13, ADAMTS4, and ADAMTS5.	9	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HDAC4	HDAC4	HDAC4	RUNX2	RUNX2	RUNX2	9	10	15	16
HDAC4 overexpression inhibits chondrocyte hypertrophy and skeletal development by repressing the Runx2 and MEF2c transcription factors .	HDAC4 overexpression inhibits chondrocyte hypertrophy and skeletal development by repressing the Runx2 and MEF2c transcription factors.	0	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4 overexpression	hdac4	Runx2	Runx2	runx2	0	1	11	12
Hdac4 is expressed in prehypertrophic and hypertrophic zones of the growth plate and represses hypertrophy by binding to and blocking Runx2 activity [ XREF_BIBR ] .	Hdac4 is expressed in prehypertrophic and hypertrophic zones of the growth plate and represses hypertrophy by binding to and blocking Runx2 activity [XREF_BIBR].	0	21	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hdac4	Hdac4 is expressed	hdac4	Runx2	Runx2	runx2	0	1	20	21
The reason behind these differences might be that HDAC4 could modulate Runx2 activity , and Runx2 gene and protein can be upregulated due to the inhibition of HDAC4 by LMK-235 .	The reason behind these differences might be that HDAC4 could modulate Runx2 activity, and Runx2 gene and protein can be upregulated due to the inhibition of HDAC4 by LMK-235.	8	12	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	8	9	11	12
The result suggested that down regulation of HDAC4 by nBGC-treatment would allow Runx2 to bind its responsive region of the osteoblast differentiation gene ( s ) DNA , thus enhancing osteoblast differentiation .	The result suggested that down regulation of HDAC4 by nBGC-treatment would allow Runx2 to bind its responsive region of the osteoblast differentiation gene (s) DNA, thus enhancing osteoblast differentiation.	5	14	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	7	8	12	13
HDAC4 negatively regulates chondrocyte hypertrophy by inhibiting Runx2 , a critical transcription factor for chondrocyte hypertrophy .	HDAC4 negatively regulates chondrocyte hypertrophy by inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy.	0	12	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	0	1	7	8
Up-regulation of HDAC4 increased chondrogenesis as well as suppressing hypertrophy by inhibiting RUNX2 and MEF2C .	Up-regulation of HDAC4 increased chondrogenesis as well as suppressing hypertrophy by inhibiting RUNX2 and MEF2C.	0	14	suppressing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	RUNX2	RUNX2	RUNX2	2	3	12	13
Role of miRNA-140 in cartilage formation and maintenance via histone deacetylase-4 suppression ( a known repressor of RUNX-2 ) has been shown .	Role of miRNA-140 in cartilage formation and maintenance via histone deacetylase-4 suppression (a known repressor of RUNX-2) has been shown.	9	18	repressor	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	histone deacetylase-4	histone deacetylase-4	histone deacetylase-4	RUNX-2	RUNX-2	RUNX-2	9	11	17	18
One class II HDAC , HDAC4 , prevents chondrocyte hypertrophy in part by inhibiting the activity of the transcription factor Runx2 , a master gene of skeletogenesis , in proliferating chondrocytes .	One class II HDAC, HDAC4, prevents chondrocyte hypertrophy in part by inhibiting the activity of the transcription factor Runx2, a master gene of skeletogenesis, in proliferating chondrocytes.	1	24	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	5	6	20	21
Runx2 promoter assay results showed that inhibition of Runx2 promoter activity by HDAC4 occurs in a dose dependent manner in chondrocytes ( XREF_FIG ) and caspase-2 and 3 inhibitors further enhance HDAC4 repression on Runx2 promoter activity ( XREF_FIG ) .	Runx2 promoter assay results showed that inhibition of Runx2 promoter activity by HDAC4 occurs in a dose dependent manner in chondrocytes (XREF_FIG) and caspase-2 and 3 inhibitors further enhance HDAC4 repression on Runx2 promoter activity (XREF_FIG).	8	13	promoter activity	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	HDAC4	HDAC4	HDAC4	Runx2	Runx2	Runx2	12	13	8	9
In the current study , western blotting revealed that the CXCL5 and CXCR2 axis increased the phosphorylation of GSK-3beta ( Ser9 ) and stimulated the nuclear translocation of Snail in NPC cells .	In the current study, western blotting revealed that the CXCL5 and CXCR2 axis increased the phosphorylation of GSK-3beta (Ser9) and stimulated the nuclear translocation of Snail in NPC cells.	10	29	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	CXCL5 and CXCR2 axis increased the phosphorylation of GSK-3beta (Ser9	gsk-3beta	Snail	Snail	snail	18	19	28	29
Snail accumulation was mediated by Akt and GSK3beta signaling , which was activated by a modulation in the expression of the mTOR inhibitor DEPTOR .	Snail accumulation was mediated by Akt and GSK3beta signaling, which was activated by a modulation in the expression of the mTOR inhibitor DEPTOR.	0	8	mediated	Positive_activation_syntax_4_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Snail	Snail	Snail	7	8	0	1
The Akt and GSK-3beta signaling pathway can modulate stability of Snail [ XREF_BIBR , XREF_BIBR ] .	The Akt and GSK-3beta signaling pathway can modulate stability of Snail [XREF_BIBR, XREF_BIBR].	3	14	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	3	4	10	11
Although consistent , at this point we can not be sure whether the phosphorylation and inactivation of GSK3beta by myrAkt directly causes Snail induction or if Snail is regulated through an alternative pathway .	Although consistent, at this point we can not be sure whether the phosphorylation and inactivation of GSK3beta by myrAkt directly causes Snail induction or if Snail is regulated through an alternative pathway.	13	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	phosphorylation and inactivation of GSK3beta	gsk3beta	Snail	Snail	snail	17	18	22	23
Previous studies have mentioned that AKT and GSK-3beta signaling pathway can modulate the stability of Snail [ XREF_BIBR , XREF_BIBR ] .	Previous studies have mentioned that AKT and GSK-3beta signaling pathway can modulate the stability of Snail [XREF_BIBR, XREF_BIBR].	7	19	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	7	8	15	16
Therefore , it is possible to hypothesize that bFGF antibody upregulates E-cadherin expression in LLC , primarily by inactivating AKT , resulting in GSK3-beta activation and degradation of Snail .	Therefore, it is possible to hypothesize that bFGF antibody upregulates E-cadherin expression in LLC, primarily by inactivating AKT, resulting in GSK3-beta activation and degradation of Snail.	23	29	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	GSK3-beta	GSK3-beta	GSK3-beta	Snail	Snail	Snail	23	24	28	29
We discovered that the underlying mechanism , by which OLA1 regulates EMT , is related to OLA1 ' s inhibitory effect on GSK3beta , and the GSK3beta mediated Snail and E-cadherin signaling .	We discovered that the underlying mechanism, by which OLA1 regulates EMT, is related to OLA1 's inhibitory effect on GSK3beta, and the GSK3beta mediated Snail and E-cadherin signaling.	25	31	mediated	Positive_early_activation	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Snail	Snail	Snail	26	27	28	29
SNAI1 exclusion from the nucleus and proteosomal degradation is mediated through its phosphorylation by GSK3beta XREF_BIBR and at this point it is unclear if a connection between both phosphorylation pathways exists .	SNAI1 exclusion from the nucleus and proteosomal degradation is mediated through its phosphorylation by GSK3beta XREF_BIBR and at this point it is unclear if a connection between both phosphorylation pathways exists.	0	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	SNAI1	SNAI1	SNAI1	14	15	0	1
In contrast , knockdown of SYNJ2BP expression through shRNA ( shSYNJ2BP # 1 , # 2 , and # 3 ) reduced GSK3beta phosphorylation and increased the transportation of SNAI1 from the nucleus to the cytoplasm for degradation .	In contrast, knockdown of SYNJ2BP expression through shRNA (shSYNJ2BP # 1, # 2, and # 3) reduced GSK3beta phosphorylation and increased the transportation of SNAI1 from the nucleus to the cytoplasm for degradation.	5	30	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK3beta	SYNJ2BP expression through shRNA (shSYNJ2BP # 1, # 2, and # 3) reduced GSK3beta phosphorylation	gsk3beta	SNAI1	SNAI1	snai1	22	23	29	30
It has been shown that GSK-3beta seems to negatively regulate EMT by inhibiting the transcription factor Snail , a well-known EMT activator and E-cadherin suppressor [ XREF_BIBR ] .	It has been shown that GSK-3beta seems to negatively regulate EMT by inhibiting the transcription factor Snail, a well-known EMT activator and E-cadherin suppressor [XREF_BIBR].	5	26	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GSK-3beta	GSK-3beta	GSK-3beta	Snail	Snail	Snail	5	6	16	17
Increased GSK-3beta phosphorylation induces Snail accumulation .	Increased GSK-3beta phosphorylation induces Snail accumulation.	1	5	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta phosphorylation	gsk-3beta	Snail	Snail	snail	1	2	4	5
As shown in XREF_FIG , co-transfection GSK3beta with tau constructs and treatment of thapsigargin increased the interaction of tau with sorcin , indicating that fibrillogenic tau species preferentially associates with sorcin .	As shown in XREF_FIG, co-transfection GSK3beta with tau constructs and treatment of thapsigargin increased the interaction of tau with sorcin, indicating that fibrillogenic tau species preferentially associates with sorcin.	5	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	tau	tau	tau	6	7	18	19
There is also some evidence that GSK3beta activity can accelerate the aggregation of tau when introduced into some tau transgenic mice , 76 although in certain mice the introduction of GSK3beta actually resulted in less aggregation .	There is also some evidence that GSK3beta activity can accelerate the aggregation of tau when introduced into some tau transgenic mice, 76 although in certain mice the introduction of GSK3beta actually resulted in less aggregation.	6	14	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	tau	tau	tau	6	7	13	14
Once active , GSK-3beta promotes multimodal neurodegeneration by eliciting pro apoptotic pathways via caspase-3 , tau cleavage , and the subsequent aggregation of cleaved tau .	Once active, GSK-3beta promotes multimodal neurodegeneration by eliciting pro apoptotic pathways via caspase-3, tau cleavage, and the subsequent aggregation of cleaved tau.	3	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	tau	tau	tau	3	4	15	16
A 75 % decrease in the levels of GSK3beta reduced pTau by 11 % ; although this is a significant reduction , we note that it is less than the 15 % achieved by CDK5 reduction under the same conditions , unlike what was observed in the KOis under basal conditions .	A 75% decrease in the levels of GSK3beta reduced pTau by 11%; although this is a significant reduction, we note that it is less than the 15% achieved by CDK5 reduction under the same conditions, unlike what was observed in the KOis under basal conditions.	6	11	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	levels of GSK3beta	gsk3beta	pTau	pTau	ptau	8	9	10	11
GSK3beta mediated Tau toxicity is enhanced by S404A .	GSK3beta mediated Tau toxicity is enhanced by S404A.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Tau	Tau	Tau	0	1	2	3
In order to examine whether human GSK3beta ( hGSK3beta ) could also enhance Tau mediated toxicity in Drosophila , we first confirmed that hGSK3beta was capable of phosphorylating human Tau in Drosophila cells .	In order to examine whether human GSK3beta (hGSK3beta) could also enhance Tau mediated toxicity in Drosophila, we first confirmed that hGSK3beta was capable of phosphorylating human Tau in Drosophila cells.	5	14	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Tau	Tau	Tau	6	7	13	14
Furthermore , inhibition of PP1 and GSK3beta , downstream targets of CaN , prevents BDNF transport defects independent of tau .	Furthermore, inhibition of PP1 and GSK3beta, downstream targets of CaN, prevents BDNF transport defects independent of tau.	2	20	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	tau	tau	tau	6	7	19	20
GSK3beta expression can increase the toxicity of some but not all phosphorylation resistant forms of Tau , suggesting an interplay between Tau phosphorylation status and further kinase dependent components .	GSK3beta expression can increase the toxicity of some but not all phosphorylation resistant forms of Tau, suggesting an interplay between Tau phosphorylation status and further kinase dependent components.	0	16	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta expression	gsk3beta	Tau	Tau	tau	0	1	15	16
Here , we describe a new model in which adenovirus mediated gene expression of tau , DeltaMEKK , JNK3 , and GSK-3beta in COS-7 cells produces most of the pathological phosphorylation epitopes of tau including AT100 .	Here, we describe a new model in which adenovirus mediated gene expression of tau, DeltaMEKK, JNK3, and GSK-3beta in COS-7 cells produces most of the pathological phosphorylation epitopes of tau including AT100.	12	35	produces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	expression of tau, DeltaMEKK, JNK3, and GSK-3beta	gsk-3beta	tau	tau	tau	21	22	33	34
Although one other study is consistent with ours in showing that decreasing GSK-3beta activity leads to increased levels of insoluble tau oligomers XREF_BIBR , many other studies , mostly in rodent models , have conversely found that increasing GSK-3beta activity promotes tau aggregation XREF_BIBR XREF_BIBR XREF_BIBR , and that inhibition of GSK-3beta reduces insoluble tau XREF_BIBR XREF_BIBR .	Although one other study is consistent with ours in showing that decreasing GSK-3beta activity leads to increased levels of insoluble tau oligomers XREF_BIBR, many other studies, mostly in rodent models, have conversely found that increasing GSK-3beta activity promotes tau aggregation XREF_BIBR XREF_BIBR XREF_BIBR, and that inhibition of GSK-3beta reduces insoluble tau XREF_BIBR XREF_BIBR.	49	56	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	tau	tau	tau	51	52	54	55
The GSK3beta ( glycogen synthase kinase 3 beta ) inhibitor , alsterpaullone , was found to suppress toxicity of tau in a concentration dependent manner [ XREF_BIBR ] .	The GSK3beta (glycogen synthase kinase 3 beta) inhibitor, alsterpaullone, was found to suppress toxicity of tau in a concentration dependent manner [XREF_BIBR].	1	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	tau	tau	tau	1	2	19	20
Similarly , Hdac8 deletion significantly decreased p53 targets induction by 22d ( XREF_FIG ) .	Similarly, Hdac8 deletion significantly decreased p53 targets induction by 22d (XREF_FIG).	2	8	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Hdac8	Hdac8	Hdac8	p53	p53	p53	2	3	6	7
HDAC inhibitors and knockdown of HDAC8 decrease the level of wild-type p53 protein and transcript .	HDAC inhibitors and knockdown of HDAC8 decrease the level of wild-type p53 protein and transcript.	1	12	decrease	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	HDAC8	HDAC8	HDAC8	p53	p53	p53	5	6	11	12
This study elucidates a HDAC8 mediated p53 inactivating mechanism promoting LSC activity , and highlights HDAC8 inhibition as a promising approach to selectively target inv ( 16 ) + LSCs .	This study elucidates a HDAC8 mediated p53 inactivating mechanism promoting LSC activity, and highlights HDAC8 inhibition as a promising approach to selectively target inv (16) + LSCs.	2	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	HDAC8	HDAC8	HDAC8	p53	p53	p53	4	5	6	7
In this study , we uncovered a HDAC8 mediated post-translational p53 inactivating mechanism underlying CM associated LSC transformation and maintenance .	In this study, we uncovered a HDAC8 mediated post-translational p53 inactivating mechanism underlying CM associated LSC transformation and maintenance.	6	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HDAC8	HDAC8	HDAC8	p53	p53	p53	7	8	10	11
Altogether , these results indicate that Hdac8 functions to modulate p53 activity to ensure LT-HSC maintenance and cell survival under stress .	Altogether, these results indicate that Hdac8 functions to modulate p53 activity to ensure LT-HSC maintenance and cell survival under stress.	6	11	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Hdac8	Hdac8	Hdac8	p53	p53	p53	6	7	10	11
HDAC8 knockdown inhibits the ability of HoxA5 to activate the p53 promoter via decreasing HoxA5 expression .	HDAC8 knockdown inhibits the ability of HoxA5 to activate the p53 promoter via decreasing HoxA5 expression.	0	11	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HDAC8	HDAC8	HDAC8	p53	p53	p53	0	1	10	11
Mechanistically , we demonstrate that Hdac8 protein interacts with the p53 protein and modulates p53 activity via deacetylation .	Mechanistically, we demonstrate that Hdac8 protein interacts with the p53 protein and modulates p53 activity via deacetylation.	5	15	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Hdac8	Hdac8	Hdac8	p53	p53	p53	5	6	14	15
Granzyme A ( GzmA ) triggers cell death with apoptotic features by targeting the endoplasmic reticulum associated SET complex , which contains the GzmA activated DNase NM23-H1 , its inhibitor SET , and Ape1 .	Granzyme A (GzmA) triggers cell death with apoptotic features by targeting the endoplasmic reticulum associated SET complex, which contains the GzmA activated DNase NM23-H1, its inhibitor SET, and Ape1.	22	31	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	GzmA	GzmA	GzmA	SET	SET	SET	23	24	30	31
Furthermore , data supporting the association of Nm23-H1 as a constituent of the SET complex , a macromolecular complex , which is associated with the endoplasmic reticulum and is targeted by Granzyme-A during cytotoxic T lymphocyte induced apoptosis was presented by the Lieberman group [ XREF_BIBR ] .	Furthermore, data supporting the association of Nm23-H1 as a constituent of the SET complex, a macromolecular complex, which is associated with the endoplasmic reticulum and is targeted by Granzyme-A during cytotoxic T lymphocyte induced apoptosis was presented by the Lieberman group [XREF_BIBR].	13	32	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Granzyme-A	Granzyme-A	Granzyme-A	SET	SET	SET	31	32	13	14
Granzyme A could also target SET complex in endoplasmic reticulum which in turn induces DNA damage [ XREF_BIBR , XREF_BIBR ] .	Granzyme A could also target SET complex in endoplasmic reticulum which in turn induces DNA damage [XREF_BIBR, XREF_BIBR].	0	6	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Granzyme A	Granzyme A	Granzyme A	SET	SET	SET	0	2	5	6
Granzyme A can directly target the SET complex in ER for proteolysis .	Granzyme A can directly target the SET complex in ER for proteolysis.	0	7	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Granzyme A	Granzyme A	Granzyme A	SET	SET	SET	0	2	6	7
Therefore , HDAC4 activity appears under regulation of PKD to modulate Mef2 target genes in response to obestatin in human cells .	Therefore, HDAC4 activity appears under regulation of PKD to modulate Mef2 target genes in response to obestatin in human cells.	2	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HDAC4	HDAC4	HDAC4	Mef2	Mef2	Mef2	2	3	11	12
Specifically , miR1 promotes myogenesis by inhibiting the expression of Hdac4 , which can block Mef2 [ XREF_BIBR ] .	Specifically, miR1 promotes myogenesis by inhibiting the expression of Hdac4, which can block Mef2 [XREF_BIBR].	2	17	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hdac4	miR1 promotes myogenesis by inhibiting the expression of Hdac4	hdac4	Mef2	Mef2	mef2	10	11	15	16
Published studies have demonstrated a vital role of miR-1 in inhibiting HDAC4 , which suppresses Mef2 , and elevated Mef2 further activates the expression of miR-1 , thereby forming an auto-regulatory loop to maintain the myogenic program .	Published studies have demonstrated a vital role of miR-1 in inhibiting HDAC4, which suppresses Mef2, and elevated Mef2 further activates the expression of miR-1, thereby forming an auto-regulatory loop to maintain the myogenic program.	3	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	HDAC4	HDAC4	HDAC4	Mef2	Mef2	Mef2	11	12	15	16
Second , miR-143 promotes slow fibres by targeting HDAC4 , repressing its expression , and HDAC4 inhibits slow muscle gene expression by repressing MEF2C , an essential transcription factor of muscle development [ XREF_BIBR ] .	Second, miR-143 promotes slow fibres by targeting HDAC4, repressing its expression, and HDAC4 inhibits slow muscle gene expression by repressing MEF2C, an essential transcription factor of muscle development [XREF_BIBR].	15	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDAC4	HDAC4	HDAC4	MEF2C	MEF2C	MEF2C	15	16	23	24
We propose the following model : In contrast to results in immune cells , where GSK-3beta phosphorylates three serine residues in the N-terminal SP2 domain and thus terminates DNA binding of NFAT , we show that specific phosphorylation of the SP2 region of NFATc2 by GSK-3beta induces NFATc2 protein stability in the nucleus of pancreatic cancer cells ( XREF_FIG ) .	We propose the following model : In contrast to results in immune cells, where GSK-3beta phosphorylates three serine residues in the N-terminal SP2 domain and thus terminates DNA binding of NFAT, we show that specific phosphorylation of the SP2 region of NFATc2 by GSK-3beta induces NFATc2 protein stability in the nucleus of pancreatic cancer cells (XREF_FIG).	43	49	induces	Positive_activation_token_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	NFATc2	NFATc2	NFATc2	45	46	47	48
Inhibition of GSK-3beta , in turn , promotes NFATc2 inhibition and degradation in cancer cells .	Inhibition of GSK-3beta, in turn, promotes NFATc2 inhibition and degradation in cancer cells.	0	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	NFATc2	NFATc2	NFATc2	2	3	8	9
Phosphorylation of GSK-3beta enhances pNFH and axonal growth .	Phosphorylation of GSK-3beta enhances pNFH and axonal growth.	0	7	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	Phosphorylation of GSK-3beta	gsk-3beta	pNFH	pNFH	pnfh	2	3	4	5
GSK-3 alpha and GSK-3 beta induce a partial retardation of a proportion of the transfected NF-H , but only cdk-5 alters the rate of electrophoretic migration to that of NF-H from brain .	GSK-3 alpha and GSK-3 beta induce a partial retardation of a proportion of the transfected NF-H, but only cdk-5 alters the rate of electrophoretic migration to that of NF-H from brain.	3	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3 beta	GSK-3 beta	GSK-3 beta	NF-H	NF-H	NF-H	3	5	15	16
Thus , Hdac1 depletion may prolong inflammatory signals in IEC-6 cells , by insuring a selective time dependent maintenance of NF-kappaB p65 and C/EBPbeta activation .	Thus, Hdac1 depletion may prolong inflammatory signals in IEC-6 cells, by insuring a selective time dependent maintenance of NF-kappaB p65 and C/EBPbeta activation.	2	22	prolong	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Hdac1	Hdac1	Hdac1	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	2	3	20	22
In this study , we examined the effects of administering EGCG to MRL-Fas ( lpr ) mice with autoimmune sialadenitis on the levels of AQP5 , activated NF-kappaB p65 subunit , activated PKA , activated c-Jun N-terminal kinase ( JNK ) ( an activator of NF-kappaB ) , inhibitor kappaB ( IkappaB ) and histone deacetylase 1 ( HDAC1 ) ( an inhibitor of NF-kappaB ) .	In this study, we examined the effects of administering EGCG to MRL-Fas (lpr) mice with autoimmune sialadenitis on the levels of AQP5, activated NF-kappaB p65 subunit, activated PKA, activated c-Jun N-terminal kinase (JNK) (an activator of NF-kappaB), inhibitor kappaB (IkappaB) and histone deacetylase 1 (HDAC1) (an inhibitor of NF-kappaB).	26	62	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HDAC1	HDAC1	HDAC1	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	58	59	27	29
The recently reported feedback inhibition of PHLPP degradation by Akt mediated GSK-3beta inactivation adds complexity to the evolving paradigm .	The recently reported feedback inhibition of PHLPP degradation by Akt mediated GSK-3beta inactivation adds complexity to the evolving paradigm.	4	12	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Positive_activation	GSK-3beta	Akt mediated GSK-3beta	gsk-3beta	PHLPP	PHLPP	phlpp	11	12	6	7
15 In many cases , these repressors function as a complex and require transcriptional repression by removing an acetyl group from the histones of the MyoD target gene promoters that is primarily mediated by histone deacetylase 1 ( HDAC1 ) .	15 In many cases, these repressors function as a complex and require transcriptional repression by removing an acetyl group from the histones of the MyoD target gene promoters that is primarily mediated by histone deacetylase 1 (HDAC1).	25	37	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	histone deacetylase 1	histone deacetylase 1	histone deacetylase 1	MyoD	MyoD	MyoD	34	37	25	26
The stability of free alpha-globin might equally be increased though elevation of AHSP , 63 the alpha-hemoglobin stabilizing protein whose expression is increased in iron deficiency .	The stability of free alpha-globin might equally be increased though elevation of AHSP, 63 the alpha-hemoglobin stabilizing protein whose expression is increased in iron deficiency.	1	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	alpha-globin	alpha-globin	alpha-globin	alpha-hemoglobin stabilizing protein	alpha-hemoglobin stabilizing protein	alpha-hemoglobin stabilizing protein	4	5	16	19
HERC2 is known to target XPA and BRCA1 for degradation and a mechanism whereby it is involved in DNA repair and cell cycle regulation .	HERC2 is known to target XPA and BRCA1 for degradation and a mechanism whereby it is involved in DNA repair and cell cycle regulation.	0	7	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HERC2	HERC2	HERC2	XPA	XPA	XPA	0	1	5	6
Curcumin has been proposed to decrease Abeta production by inhibiting GSK3beta mediated PS1 activation , and curcumin downregulates presenilin 1 protein in a dose dependent manner to regulate gamma-secretase function .	Curcumin has been proposed to decrease Abeta production by inhibiting GSK3beta mediated PS1 activation, and curcumin downregulates presenilin 1 protein in a dose dependent manner to regulate gamma-secretase function.	10	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	PS1	PS1	PS1	10	11	12	13
In summary , our results indicate that inhibition of GSK-3beta reduces myocardin transcriptional activity , suggesting a role for GSK-3beta in myocardin transcriptional activity and smooth muscle differentiation .	In summary, our results indicate that inhibition of GSK-3beta reduces myocardin transcriptional activity, suggesting a role for GSK-3beta in myocardin transcriptional activity and smooth muscle differentiation.	7	13	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK-3beta	GSK-3beta	GSK-3beta	myocardin	myocardin	myocardin	9	10	11	12
These sites are targeted by the CK2 and GSK3beta [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] , preventing proteasomal degradation of PTEN [ XREF_BIBR ] .	These sites are targeted by the CK2 and GSK3beta [XREF_BIBR, XREF_BIBR - XREF_BIBR], preventing proteasomal degradation of PTEN [XREF_BIBR].	8	23	preventing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	PTEN	PTEN	PTEN	8	9	21	22
Therefore , by removing the suppression of Mef2 and CAMTA2 , the loss of Hdac5 or Hdac9 augments the stress induced cardiac hypertrophy .	Therefore, by removing the suppression of Mef2 and CAMTA2, the loss of Hdac5 or Hdac9 augments the stress induced cardiac hypertrophy.	5	18	augments	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Hdac5	loss of Hdac5	hdac5	Mef2	Mef2	mef2	14	15	7	8
miR-2861 targets Hdac5 , which is a transcriptional corepressor that antagonizes Runx2 mediated bone formation 71 and , therefore , miR-2861 epigenetically promotes osteoblast differentiation by Hdac5 repression .	miR-2861 targets Hdac5, which is a transcriptional corepressor that antagonizes Runx2 mediated bone formation 71 and, therefore, miR-2861 epigenetically promotes osteoblast differentiation by Hdac5 repression.	0	22	antagonizes	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Hdac5	Hdac5	Hdac5	Runx2	Runx2	Runx2	2	3	11	12
These data were consistent with Smk mediated inactivation of Akt ( XREF_FIG ) and GSK3beta ( data not shown ) , since activation of Akt and GSK3beta signalling has been reported to promote SerP of MUC1-CT [ XREF_BIBR ] .	These data were consistent with Smk mediated inactivation of Akt (XREF_FIG) and GSK3beta (data not shown), since activation of Akt and GSK3beta signalling has been reported to promote SerP of MUC1-CT [XREF_BIBR].	24	37	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	MUC1-CT	MUC1-CT	MUC1-CT	26	27	35	36
Since GSK3beta targets Smad1 for degradation , Wnt signaling additionally stabilizes Smad1 , thus enhancing BMP signaling [ XREF_BIBR ] , and promotes Wnt cooperation with BMP signaling .	Since GSK3beta targets Smad1 for degradation, Wnt signaling additionally stabilizes Smad1, thus enhancing BMP signaling [XREF_BIBR], and promotes Wnt cooperation with BMP signaling.	0	10	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	GSK3beta	GSK3beta	GSK3beta	Smad1	Smad1	Smad1	1	2	3	4
This confirms our preceding observations , using an anti-sense strategy XREF_BIBR , XREF_BIBR , that depletion of Hsp27 stimulates caspase-3 activity and apoptosis of HeLa cells ( XREF_FIG ) .	This confirms our preceding observations, using an anti-sense strategy XREF_BIBR, XREF_BIBR, that depletion of Hsp27 stimulates caspase-3 activity and apoptosis of HeLa cells (XREF_FIG).	15	20	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	caspase-3	caspase-3	caspase-3	17	18	19	20
Hsp27 downregulation in mouse oocytes dramatically increased the activitied caspase 8 and caspase 3 , while caspase 9 and cytochrome c activities did not change .	Hsp27 downregulation in mouse oocytes dramatically increased the activitied caspase 8 and caspase 3, while caspase 9 and cytochrome c activities did not change.	0	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Hsp27	Hsp27	Hsp27	caspase 3	caspase 3	caspase 3	0	1	12	14
As a result of siRNA transfection , the Hsp27 gene was silenced by ~ 50 % but did not cause a statistically significant change in caspase-3 activation .	As a result of siRNA transfection, the Hsp27 gene was silenced by ~ 50% but did not cause a statistically significant change in caspase-3 activation.	8	26	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Hsp27	Hsp27	Hsp27	caspase-3	caspase-3	caspase-3	8	9	25	26
Hsp27 silencing also blocked caspase-3 activation .	Hsp27 silencing also blocked caspase-3 activation.	0	5	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Hsp27	Hsp27	Hsp27	caspase-3	caspase-3	caspase-3	0	1	4	5
Moreover , soluble epoxide hydrolase inhibitor Trans-4-[ 4-( 3-adamantan-1-ylureido )-cyclohexyloxy ]-benzoic acid , commonly known as t-AUCB , inhibits HSP27 activation , which can increase caspase-3 activities leading to apoptosis in glioblastoma cells [ XREF_BIBR ] .	Moreover, soluble epoxide hydrolase inhibitor Trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid, commonly known as t-AUCB, inhibits HSP27 activation, which can increase caspase-3 activities leading to apoptosis in glioblastoma cells [XREF_BIBR].	19	26	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HSP27	HSP27	HSP27	caspase-3	caspase-3	caspase-3	19	20	25	26
MK2 inactivation or inhibition of MK2 or Hsp27 expression increases caspase-3 and PARP cleavage and DNA breaks and therefore cell death .	MK2 inactivation or inhibition of MK2 or Hsp27 expression increases caspase-3 and PARP cleavage and DNA breaks and therefore cell death.	0	12	increases	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Hsp27	MK2 inactivation or inhibition of MK2 or Hsp27 expression	hsp27	caspase-3	caspase-3	caspase-3	7	8	10	11
We also found that silencing Hsp27 using OGX-427 ( data not shown ) or siRNA in PC-3 cells treated with or without IGF-1 increased sub G0 fraction ( XREF_FIG ) and caspase 3 activity ( XREF_FIG ) .	We also found that silencing Hsp27 using OGX-427 (data not shown) or siRNA in PC-3 cells treated with or without IGF-1 increased sub G0 fraction (XREF_FIG) and caspase 3 activity (XREF_FIG).	4	33	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	caspase 3	caspase 3	caspase 3	5	6	31	33
It is known that Hsp27 can inhibit apoptosis by inhibiting caspase 9 , through the interaction with cytochrome c and prevention of the formation of the apoptosome complex , and caspase 3 , through interacting with pro caspase 3 molecules XREF_BIBR , XREF_BIBR .	It is known that Hsp27 can inhibit apoptosis by inhibiting caspase 9, through the interaction with cytochrome c and prevention of the formation of the apoptosome complex, and caspase 3, through interacting with pro caspase 3 molecules XREF_BIBR, XREF_BIBR.	4	32	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hsp27	Hsp27	Hsp27	caspase 3	caspase 3	caspase 3	4	5	30	32
According to the results , it was found that RA and quercetin effectively silenced Hsp27 and both agents induced apoptosis by activating the caspase-3 pathway .	According to the results, it was found that RA and quercetin effectively silenced Hsp27 and both agents induced apoptosis by activating the caspase-3 pathway.	14	24	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Hsp27	Hsp27	Hsp27	caspase-3	caspase-3	caspase-3	14	15	23	24
By a physical association , GRIM-19 augmented HTRA2 driven XIAP cleavage [ XREF_BIBR ] .	By a physical association, GRIM-19 augmented HTRA2 driven XIAP cleavage [XREF_BIBR].	6	10	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HTRA2	HTRA2	HTRA2	XIAP	XIAP	XIAP	7	8	9	10
Once released , HtrA2 promotes caspases activation by direct binding to XIAP and attenuates XIAP inhibition of caspases .	Once released, HtrA2 promotes caspases activation by direct binding to XIAP and attenuates XIAP inhibition of caspases.	3	15	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	3	4	14	15
As the pro apoptotic effects of Zn 2+ -chelation treatment have been reported to be mediated via caspase 3 activation and inhibited by XIAP [ XREF_BIBR ] Omi and HtrA2 activation may be expected to enhance the apoptotic effects of Zn 2+ -chelation by sequestering XIAP .	As the pro apoptotic effects of Zn 2+ -chelation treatment have been reported to be mediated via caspase 3 activation and inhibited by XIAP [XREF_BIBR] Omi and HtrA2 activation may be expected to enhance the apoptotic effects of Zn 2+ -chelation by sequestering XIAP.	29	46	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HtrA2	HtrA2	HtrA2	XIAP	XIAP	XIAP	29	30	45	46
XREF_BIBR HtrA2 and Omi is identified as a proapoptosis mitochondrial protein that is released from mitochondria and directly binds to and inhibits the caspase-inhibitory activity of XIAP .	XREF_BIBR HtrA2 and Omi is identified as a proapoptosis mitochondrial protein that is released from mitochondria and directly binds to and inhibits the caspase-inhibitory activity of XIAP.	1	27	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Omi	Omi	Omi	XIAP	XIAP	XIAP	3	4	26	27
Alternatively , Hhip might modulate Shh signaling by sequestering it away from other receptors [ XREF_BIBR ] .	Alternatively, Hhip might modulate Shh signaling by sequestering it away from other receptors [XREF_BIBR].	2	6	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	2	3	5	6
Moreover , studies of the talpid 3 chick mutant , which is due to a mutation in the centrosomal gene , KIAA0586 , resulting in failure of primary ciliogeneisis and abnormal Gli3 cleavage XREF_BIBR , XREF_BIBR , demonstrated abnormal lens development and ectopic lenses , as well as limb and craniofacial defects XREF_BIBR , XREF_BIBR Similarly in Xenopus , modulating Shh activity by knock-down or over-expression of the antagonist , hedgehog interacting protein ( Hip ) , resulted in abnormal eye development , including lens defects XREF_BIBR .	Moreover, studies of the talpid 3 chick mutant, which is due to a mutation in the centrosomal gene, KIAA0586, resulting in failure of primary ciliogeneisis and abnormal Gli3 cleavage XREF_BIBR, XREF_BIBR, demonstrated abnormal lens development and ectopic lenses, as well as limb and craniofacial defects XREF_BIBR, XREF_BIBR Similarly in Xenopus, modulating Shh activity by knock-down or over-expression of the antagonist, hedgehog interacting protein (Hip), resulted in abnormal eye development, including lens defects XREF_BIBR.	59	73	modulating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	hedgehog interacting protein	hedgehog interacting protein	hedgehog interacting protein	Shh	Shh	Shh	70	73	60	61
Shh signalling has also been implicated in the regeneration of a lens from the dorsal surface of the iris in the adult newt , with inhibition of Shh signalling by a cyclopamine analogue or hedgehog interacting protein ( HIP ) abrogating lens regeneration XREF_BIBR .	Shh signalling has also been implicated in the regeneration of a lens from the dorsal surface of the iris in the adult newt, with inhibition of Shh signalling by a cyclopamine analogue or hedgehog interacting protein (HIP) abrogating lens regeneration XREF_BIBR.	27	37	signalling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	hedgehog interacting protein	hedgehog interacting protein	hedgehog interacting protein	Shh	Shh	Shh	34	37	27	28
The influence of Shh on foetal TEC development was confirmed when WT FTOC were treated with recombinant Hhip , a Hh binding protein that neutralizes endogenous Hh proteins in the cultures .	The influence of Shh on foetal TEC development was confirmed when WT FTOC were treated with recombinant Hhip, a Hh binding protein that neutralizes endogenous Hh proteins in the cultures.	1	22	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	17	18	3	4
Blocking Shh signaling by expressing Shh antagonist Hhip in the oral ectoderm caused loss of anterior pituitary markers Gata2 and brn4 ( Pou3f4 ) , and a smaller pituitary .	Blocking Shh signaling by expressing Shh antagonist Hhip in the oral ectoderm caused loss of anterior pituitary markers Gata2 and brn4 (Pou3f4), and a smaller pituitary.	4	11	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Hhip	Hhip	Hhip	Shh	Shh	Shh	7	8	5	6
Altered HHIP levels may well lead to enhanced Shh signaling , and we speculate consequent similar corollaries as we have reported here .	Altered HHIP levels may well lead to enhanced Shh signaling, and we speculate consequent similar corollaries as we have reported here.	1	9	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	HHIP	HHIP levels	hhip	Shh	Shh	shh	1	2	8	9
Mutation of the residue phosphorylated by HIPK2 prevented UV- and HIPK2 directed CtBP clearance .	Mutation of the residue phosphorylated by HIPK2 prevented UV- and HIPK2 directed CtBP clearance.	8	13	directed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HIPK2	HIPK2	HIPK2	CtBP	CtBP	CtBP	10	11	12	13
Conversely , tumor suppressors , such as HIPK2 , Ink4a and Arf , and APC , target CtBP1 degradation to induce apoptosis XREF_BIBR .	Conversely, tumor suppressors, such as HIPK2, Ink4a and Arf, and APC, target CtBP1 degradation to induce apoptosis XREF_BIBR.	3	18	suppressors	Negative_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	HIPK2	HIPK2	HIPK2	CtBP1	CtBP1	CtBP1	7	8	17	18
There is evidence to suggest that Id2 targets E2A proteins , proven regulators of alpha-SMA XREF_BIBR and Id1 targets HEB as demonstrated by Li et al XREF_BIBR This would suggest a pivotal ; role for both Id1 and 2 in regulating epithelial phenotype in these cells .	There is evidence to suggest that Id2 targets E2A proteins, proven regulators of alpha-SMA XREF_BIBR and Id1 targets HEB as demonstrated by Li et al XREF_BIBR This would suggest a pivotal; role for both Id1 and 2 in regulating epithelial phenotype in these cells.	12	20	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Id1	Id1	Id1	HEB	HEB	HEB	17	18	19	20
Over-expression of Id1 leads to tubular cell dedifferentiation characterized by loss of E-cadherin and ZO-1 , as previously reported , 17 which is largely mediated by Id1 driven sequestration of transcription factor HEB in the nucleus .	Over-expression of Id1 leads to tubular cell dedifferentiation characterized by loss of E-cadherin and ZO-1, as previously reported, 17 which is largely mediated by Id1 driven sequestration of transcription factor HEB in the nucleus.	24	35	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Id1	Id1	Id1	HEB	HEB	HEB	26	27	32	33
Upon ligand mediated DDR1 kinase activation , Notch1 was activated , bound to DDR1 , and activated canonical Notch1 targets , including Hes1 and Hey2 .	Upon ligand mediated DDR1 kinase activation, Notch1 was activated, bound to DDR1, and activated canonical Notch1 targets, including Hes1 and Hey2.	18	25	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Hey2	Hey2	Hey2	Notch1	Notch1	Notch1	24	25	18	19
In addition , silencing RhoE expression in SCC028 cells resulted in a significant suppression of Notch1 target Hey2 promoter activity when compared to cells transfected with a control siRNA ( XREF_FIG ) .	In addition, silencing RhoE expression in SCC028 cells resulted in a significant suppression of Notch1 target Hey2 promoter activity when compared to cells transfected with a control siRNA (XREF_FIG).	15	19	target	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Hey2	Hey2	Hey2	Notch1	Notch1	Notch1	17	18	15	16
The function of Fih-1 on Mib is probably to stabilize the folding structure of Mib , as Fih-1 was found to stabilize the folding of AND through hydroxylation XREF_BIBR , and , thereby , further enhance Notch activation .	The function of Fih-1 on Mib is probably to stabilize the folding structure of Mib, as Fih-1 was found to stabilize the folding of AND through hydroxylation XREF_BIBR, and, thereby, further enhance Notch activation.	17	37	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Fih-1	Fih-1	Fih-1	Notch	Notch	Notch	17	18	36	37
Factor inhibiting HIF1 ( FIH-1 ) can also inhibit the activity of Notch , suggesting an additional level of interaction between the two pathways [ XREF_BIBR ] .	Factor inhibiting HIF1 (FIH-1) can also inhibit the activity of Notch, suggesting an additional level of interaction between the two pathways [XREF_BIBR].	2	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	FIH-1	FIH-1	FIH-1	Notch	Notch	Notch	4	5	12	13
Id proteins act by antagonizing the DNA binding of activating E proteins and Id2 has been postulated to repress pDC development by suppressing HEB and E2A as overexpression of these factors in haematopoietic progenitors led to enhanced pDC development .	Id proteins act by antagonizing the DNA binding of activating E proteins and Id2 has been postulated to repress pDC development by suppressing HEB and E2A as overexpression of these factors in haematopoietic progenitors led to enhanced pDC development.	13	25	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Id2	Id2	Id2	HEB	HEB	HEB	13	14	23	24
Knockdown of Id2 and Id3 by siRNA restored MyoD dependent activation of the myogenic program in RP58 -/- 10T1/2 fibroblasts ( XREF_FIG ) leading to the formation of multinucleated myotubes ( XREF_SUPPLEMENTARY ) .	Knockdown of Id2 and Id3 by siRNA restored MyoD dependent activation of the myogenic program in RP58 -/- 10T1/2 fibroblasts (XREF_FIG) leading to the formation of multinucleated myotubes (XREF_SUPPLEMENTARY).	0	10	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Id2	Id2	Id2	MyoD	MyoD	MyoD	2	3	8	9
Thus , our current working hypothesis is that RA induces expression of HIC1 to promote cellular quiescence and dormancy in the intestinal microenvironment , possibly by regulating Myc dependent processes including metabolism and proliferation .	Thus, our current working hypothesis is that RA induces expression of HIC1 to promote cellular quiescence and dormancy in the intestinal microenvironment, possibly by regulating Myc dependent processes including metabolism and proliferation.	8	29	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	HIC1	RA induces expression of HIC1	hic1	Myc	Myc	myc	12	13	27	28
In adult homeostatic muscle , quiescent satellite cells express Notch -1 , -2 , and -3 as well as high levels of the Notch and Rbpj targets Hey1 , HeyL , and Hes1 , thereby reflecting high Notch activity .	In adult homeostatic muscle, quiescent satellite cells express Notch -1, -2, and -3 as well as high levels of the Notch and Rbpj targets Hey1, HeyL, and Hes1, thereby reflecting high Notch activity.	20	28	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Hey1	Hey1	Hey1	Rbpj	Rbpj	Rbpj	27	28	25	26
The study involved the Ras-ERK and the IRS-PKB pathways , mediating the mitogenic and metabolic effects of insulin , respectively , and found no significant difference in the expression , basal activity , or insulin activation of IRS-1 and PKB between PCOS subjects and controls [ XREF_BIBR ] .	The study involved the Ras-ERK and the IRS-PKB pathways, mediating the mitogenic and metabolic effects of insulin, respectively, and found no significant difference in the expression, basal activity, or insulin activation of IRS-1 and PKB between PCOS subjects and controls [XREF_BIBR].	34	39	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	34	35	37	38
Insulin stimulated insulin receptor substrate 1 ( IRS-1 ) associated PI-3K activity has been shown to be decreased in adipocytes of type 2 diabetic subjects [ XREF_BIBR ] .	Insulin stimulated insulin receptor substrate 1 (IRS-1) associated PI-3K activity has been shown to be decreased in adipocytes of type 2 diabetic subjects [XREF_BIBR].	0	7	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	0	1	2	6
In association with shRNA mediated IRS-2 depletion and diminished insulin activation of aPKC in liver , insulin activation of IRS-1 and PI3K ( XREF_FIG ) and aPKC ( XREF_FIG ) improved in muscle in GK-diabetic rats .	In association with shRNA mediated IRS-2 depletion and diminished insulin activation of aPKC in liver, insulin activation of IRS-1 and PI3K (XREF_FIG) and aPKC (XREF_FIG) improved in muscle in GK-diabetic rats.	16	28	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	16	17	19	20
Overexpression of TRB3 ( 4-fold ) in tibialis anterior muscles by direct DNA injection significantly inhibited insulin stimulated IRS1 Tyr 612 phosphorylation compared to empty vector injected muscles ( XREF_FIG ) , whereas insulin stimulated Akt Thr 308 and Akt Ser 473 phosphorylation tended to decrease with TRB3 overexpression ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Overexpression of TRB3 (4-fold) in tibialis anterior muscles by direct DNA injection significantly inhibited insulin stimulated IRS1 Tyr 612 phosphorylation compared to empty vector injected muscles (XREF_FIG), whereas insulin stimulated Akt Thr 308 and Akt Ser 473 phosphorylation tended to decrease with TRB3 overexpression (XREF_FIG and XREF_SUPPLEMENTARY).	15	19	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	16	17	18	19
The results indicate that the signal for interaction of IRS1 and p85 was enhanced upon insulin stimulation in the PPP1R12A immunoprecipitates ( XREF_FIG ) and clearly confirmed the insulin stimulated association of PPP1R12A , IRS1 , and p85 .	The results indicate that the signal for interaction of IRS1 and p85 was enhanced upon insulin stimulation in the PPP1R12A immunoprecipitates (XREF_FIG) and clearly confirmed the insulin stimulated association of PPP1R12A, IRS1, and p85.	26	35	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	28	29	34	35
Chronic insulin treatment induced the large ( 86 % ) down-regulation of IRS-1 and the modest ( 36 % ) up-regulation of SHIP2 .	Chronic insulin treatment induced the large (86%) down-regulation of IRS-1 and the modest (36%) up-regulation of SHIP2.	1	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	12	13
Our present studies support previous reported data which demonstrate that Ang II inhibited the insulin induced activation of IRS-1 ( Tyr608 ) and Akt ( Ser473 ) in VSMC .	Our present studies support previous reported data which demonstrate that Ang II inhibited the insulin induced activation of IRS-1 (Tyr608) and Akt (Ser473) in VSMC.	13	25	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	14	15	18	19
This cytokine dramatically impairs insulin stimulation of IRS-1 XREF_BIBR , XREF_BIBR .	This cytokine dramatically impairs insulin stimulation of IRS-1 XREF_BIBR, XREF_BIBR.	4	8	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	7	8
In addition , C ( 2 ) and C ( 6 ) ceramides , but not C ( 2 ) D ( inactive ) ceramide or vehicle , inhibited insulin stimulated signaling downstream of the IR and IRS-1 .	In addition, C (2) and C (6) ceramides, but not C (2) D (inactive) ceramide or vehicle, inhibited insulin stimulated signaling downstream of the IR and IRS-1.	28	38	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	29	30	37	38
The extent of phosphorylation of p70 S6K at Thr 389 , and S6 proteins ( the downstream effectors of p70 S6K ) at Ser 240/244 was greater in cells overexpressing IRS-1 than in the control cells treated with or without insulin .	The extent of phosphorylation of p70 S6K at Thr 389, and S6 proteins (the downstream effectors of p70 S6K) at Ser 240/244 was greater in cells overexpressing IRS-1 than in the control cells treated with or without insulin.	29	41	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	40	41	30	31
Similarly , insulin mediated IRS-1 associated with the p85 regulatory subunit of phosphatidylinositol 3-kinase was increased by R-ALA ( 317 % ) and ET ( 319 % ) and to the greatest extent ( 435 % ) ( all P < 0.05 ) by the combination treatment .	Similarly, insulin mediated IRS-1 associated with the p85 regulatory subunit of phosphatidylinositol 3-kinase was increased by R-ALA (317%) and ET (319%) and to the greatest extent (435%) (all P < 0.05) by the combination treatment.	2	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	2	3	4	5
Y-27632 upregulated insulin stimulated IRS-1 and Akt activation in pre-adipocytes 19 .	Y-27632 upregulated insulin stimulated IRS-1 and Akt activation in pre-adipocytes 19.	1	7	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	2	3	4	5
However , we identified the p85 |-> and beta subunits of PI 3-K , a well known insulin stimulated binding partner of IRS-1 , in the basal samples with 0 +/- 0 and 11 +/- 2 assigned spectra , respectively , while in the insulin stimulated samples these proteins were identified with 8 +/-1 and 74 +/-15 assigned spectra , respectively , indicating increased association of IRS-1 and p85 upon insulin stimulation ( n = 5 , XREF_TABLE ) .	However, we identified the p85 |-> and beta subunits of PI 3-K, a well known insulin stimulated binding partner of IRS-1, in the basal samples with 0 +/- 0 and 11 +/- 2 assigned spectra, respectively, while in the insulin stimulated samples these proteins were identified with 8 +/-1 and 74 +/-15 assigned spectra, respectively, indicating increased association of IRS-1 and p85 upon insulin stimulation (n = 5, XREF_TABLE).	12	23	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	17	18	22	23
Moreover , HFI did not induce insulin resistance in the skeletal muscle of female and OVX rats but impaired the insulin stimulated glucose transport activity in the skeletal muscle of male rats , which was accompanied by lower insulin stimulated IRS-1 Tyr 989 ( 44 % ) , Akt Ser 473 ( 30 % ) , and AS160 Ser 588 ( 43 % ) , and increases in insulin stimulated IRS-1 Ser 307 ( 78 % ) , JNK Thr 183 / Tyr 185 ( 69 % ) , and p38 MAPK Thr 180 / Tyr 182 ( 81 % ) .	Moreover, HFI did not induce insulin resistance in the skeletal muscle of female and OVX rats but impaired the insulin stimulated glucose transport activity in the skeletal muscle of male rats, which was accompanied by lower insulin stimulated IRS-1 Tyr 989 (44%), Akt Ser 473 (30%), and AS160 Ser 588 (43%), and increases in insulin stimulated IRS-1 Ser 307 (78%), JNK Thr 183 / Tyr 185 (69%), and p38 MAPK Thr 180 / Tyr 182 (81%).	38	99	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	38	39	40	41
However , at 11 weeks of CR ( 7 % weight loss ) , insulin stimulated skeletal muscle phosphoTyr IRS1 , and phosphoSer473 Akt and PKB content increased , whereas phosphoTyr183 JNK content decreased , compared with baseline in both diet groups .	However, at 11 weeks of CR (7% weight loss), insulin stimulated skeletal muscle phosphoTyr IRS1, and phosphoSer473 Akt and PKB content increased, whereas phosphoTyr183 JNK content decreased, compared with baseline in both diet groups.	14	20	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	14	15	19	20
We conclude that LbetaT2 cells express IRS proteins and that insulin treatment results in activation of IRS-1 by tyrosine phosphorylation at an appropriate regulatory site .	We conclude that LbetaT2 cells express IRS proteins and that insulin treatment results in activation of IRS-1 by tyrosine phosphorylation at an appropriate regulatory site.	10	17	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	10	11	16	17
Cells pre-exposed to low-dose testosterone had significantly increased insulin induced mTOR-Ser 2448 and S6K-Thr 389 phosphorylation ( p < 0.05 ) , and further increased insulin induced IRS-1 Ser 636/639 phosphorylation ( p = 0.042 ) compared to control cells .	Cells pre-exposed to low-dose testosterone had significantly increased insulin induced mTOR-Ser 2448 and S6K-Thr 389 phosphorylation (p < 0.05), and further increased insulin induced IRS-1 Ser 636/639 phosphorylation (p = 0.042) compared to control cells.	25	28	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	25	26	27	28
The levels of insulin signaling molecules IRS-1 and GLUT-4 were assessed in ILP treated L6 myotubes by immunoblot analysis of cytoplasmic and plasma membrane fractions respectively .	The levels of insulin signaling molecules IRS-1 and GLUT-4 were assessed in ILP treated L6 myotubes by immunoblot analysis of cytoplasmic and plasma membrane fractions respectively.	1	8	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	levels of insulin	insulin	IRS-1	IRS-1	irs-1	3	4	6	7
The expression levels of the insulin signaling molecules pIRS-1 and IRS-1 , pIRS-2 and IRS-2 , Akt , PI3K , and pAkt and Akt were measured by western blot in livers from both the OF and NF groups .	The expression levels of the insulin signaling molecules pIRS-1 and IRS-1, pIRS-2 and IRS-2, Akt, PI3K, and pAkt and Akt were measured by western blot in livers from both the OF and NF groups.	2	23	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	levels of the insulin	insulin	pIRS-1	pIRS-1	pirs-1	5	6	8	9
However , insulin mediated IRS-1 and MAPK cascade activation contributes to growth in the adult .	However, insulin mediated IRS-1 and MAPK cascade activation contributes to growth in the adult.	2	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	2	3	4	5
Overexpression of calmodulin in Chinese hamster ovary cells reduced the tyrosine phosphorylation of IRS-1 induced by insulin , with a concomitant decrease in insulin stimulated association of IRS-1 with the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase .	Overexpression of calmodulin in Chinese hamster ovary cells reduced the tyrosine phosphorylation of IRS-1 induced by insulin, with a concomitant decrease in insulin stimulated association of IRS-1 with the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase.	21	28	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	23	24	27	28
In this signaling pathway ( XREF_FIG and XREF_FIG ) , insulin binding of the IR at the cell surface activates IRS-1 intracellularly , which in turn activates phosphatidylinositol-3-kinase ( PI3K ) and then Akt , which inhibits many downstream molecules , including the apoptosis inducing molecules BAD and caspase-9 , forkhead box containing transcription factors of the O family ( FoxO1 and FoxO3 ) , glycogen synthase kinase-3 ( GSK-3 ) , and the mammalian target-of and rapamycin complex 1 ( mTORC1 ) [ XREF_BIBR , XREF_BIBR ] .	In this signaling pathway (XREF_FIG and XREF_FIG), insulin binding of the IR at the cell surface activates IRS-1 intracellularly, which in turn activates phosphatidylinositol-3-kinase (PI3K) and then Akt, which inhibits many downstream molecules, including the apoptosis inducing molecules BAD and caspase-9, forkhead box containing transcription factors of the O family (FoxO1 and FoxO3), glycogen synthase kinase-3 (GSK-3), and the mammalian target-of and rapamycin complex 1 (mTORC1) [XREF_BIBR, XREF_BIBR].	10	26	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	10	11	20	21
In differentiated L6 myotubes , activation of S6K1 for as little as 1hr , inhibits insulin stimulated IRS-1 associated PI3K activity [ XREF_BIBR ] .	In differentiated L6 myotubes, activation of S6K1 for as little as 1hr, inhibits insulin stimulated IRS-1 associated PI3K activity [XREF_BIBR].	14	18	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	15	16	17	18
In skeletal muscle , insulin increased the activation of IR , IRS-1 , PI 3-kinase , PKB and S6 and stimulated protein synthesis .	In skeletal muscle, insulin increased the activation of IR, IRS-1, PI 3-kinase, PKB and S6 and stimulated protein synthesis.	4	20	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	11	12
Similar results were observed in T2D patients Although tyrosine phosphorylation of IRS1 was similar in TH and B6 without insulin , in contrast to B6 derived adipocytes , insulin at 10 and 50 nM failed to stimulate IRS1 tyrosine phophorylation in TH adipocytes ( XREF_SUPPLEMENTARY ) .	Similar results were observed in T2D patients Although tyrosine phosphorylation of IRS1 was similar in TH and B6 without insulin, in contrast to B6 derived adipocytes, insulin at 10 and 50 nM failed to stimulate IRS1 tyrosine phophorylation in TH adipocytes (XREF_SUPPLEMENTARY).	28	39	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	28	29	37	38
Indeed , while no insulin activation of IRS1 was evident in DM myotubes , in CTR muscle cells insulin stimulation induced an increase in IRS1 phosphorylation over time ( CTR vs DM1 p = 0.01 ; CTR vs DM2 p = 0.01 ) .	Indeed, while no insulin activation of IRS1 was evident in DM myotubes, in CTR muscle cells insulin stimulation induced an increase in IRS1 phosphorylation over time (CTR vs DM1 p = 0.01; CTR vs DM2 p = 0.01).	4	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	4	5	7	8
Supporting this hypothesis , a genetic variant near IRS1 , that is associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1 associated PI-3K activity in human skeletal muscle biopsies , is associated with type 2 diabetes , insulin resistance and hyperinsulinemia XREF_BIBR .	Supporting this hypothesis, a genetic variant near IRS1, that is associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1 associated PI-3K activity in human skeletal muscle biopsies, is associated with type 2 diabetes, insulin resistance and hyperinsulinemia XREF_BIBR.	22	26	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	22	23	25	26
It has been reported that short-term exercise training increased insulin stimulated PI3K activity , but other studies have reported that insulin stimulated IRS1 associated PI3K activity is unchanged or reduced after training .	It has been reported that short-term exercise training increased insulin stimulated PI3K activity, but other studies have reported that insulin stimulated IRS1 associated PI3K activity is unchanged or reduced after training.	20	27	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	20	21	22	23
Insulin ( 10nM ) was used to stimulate insulin signaling ( insulin receptor substrate ( IRS-1 ) and Akt ) for 3min .	Insulin (10nM) was used to stimulate insulin signaling (insulin receptor substrate (IRS-1) and Akt) for 3min.	0	18	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	15	16
With respect to compound 2 we did not observe any InsR beta degradation by Western blot whereas the effect on insulin driven phospho-IRS-1 was less conclusive ( data not shown ) .	With respect to compound 2 we did not observe any InsR beta degradation by Western blot whereas the effect on insulin driven phospho-IRS-1 was less conclusive (data not shown).	18	23	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	phospho-IRS-1	phospho-IRS-1	phospho-IRS-1	20	21	22	23
As a consequence , insulin activation of IRS-1 and IRS-1-associated PI3-kinase activity is inhibited , resulting in a decrease in insulin stimulated glucose transport activity [ XREF_BIBR ] .	As a consequence, insulin activation of IRS-1 and IRS-1-associated PI3-kinase activity is inhibited, resulting in a decrease in insulin stimulated glucose transport activity [XREF_BIBR].	4	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	7	8
6 Although basal ratios of p-ERK and ERK were reduced in the aortas of Insr +/- Irs1 +/- Apoe -/- mice , insulin stimulation resulted in significantly increased pERK and ERK ratio of insulin stimulated pERKs in Insr +/- Irs1 +/- Apoe -/- aortas compared with Insr +/+ Irs1 +/+ Apoe -/- aortas ( XREF_FIG ) .	6 Although basal ratios of p-ERK and ERK were reduced in the aortas of Insr +/- Irs1 +/- Apoe -/- mice, insulin stimulation resulted in significantly increased pERK and ERK ratio of insulin stimulated pERKs in Insr +/- Irs1 +/- Apoe -/- aortas compared with Insr +/+ Irs1 +/+ Apoe -/- aortas (XREF_FIG).	28	41	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	Irs1	Irs1	Irs1	33	34	39	40
Our study further found that high concentrations of insulin decreases the miR-145 expression , upregulates IRS1 , and promotes cell proliferation .	Our study further found that high concentrations of insulin decreases the miR-145 expression, upregulates IRS1, and promotes cell proliferation.	6	16	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	8	9	15	16
Furthermore , we found that mutation of tyrosines 1172 and 1222 totally prevents the insulin induced association of IRS-1 with the SH2 domains of PTP2C , demonstrating that both tyrosines 1172 and 1222 are key elements in the binding sites for the SH2 domains of PTP2C .	Furthermore, we found that mutation of tyrosines 1172 and 1222 totally prevents the insulin induced association of IRS-1 with the SH2 domains of PTP2C, demonstrating that both tyrosines 1172 and 1222 are key elements in the binding sites for the SH2 domains of PTP2C.	13	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	14	15	18	19
Similar data were obtained on endogenous IRS-1 phosphorylation when cells were treated with IGF-1 instead of insulin ( data not shown ) .	Similar data were obtained on endogenous IRS-1 phosphorylation when cells were treated with IGF-1 instead of insulin (data not shown).	6	17	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	16	17	6	7
We first investigate the effect of Ang II on insulin induced activation of IRS-1 and Akt in culture rat aortic VSMC .	We first investigate the effect of Ang II on insulin induced activation of IRS-1 and Akt in culture rat aortic VSMC.	7	15	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	9	10	13	14
[ Also note , in STZ-diabetic rats , insulin activation of PKB and IRS-1 and PI3K are markedly impaired , but , in contrast , activation of aPKC and IRS-2 and PI3K are fully conserved ; unpublished observations ; MP Sajan , ML Standaert , RV Farese ] .	[Also note, in STZ-diabetic rats, insulin activation of PKB and IRS-1 and PI3K are markedly impaired, but, in contrast, activation of aPKC and IRS-2 and PI3K are fully conserved; unpublished observations; MP Sajan, ML Standaert, RV Farese].	8	14	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	13	14
We have investigated the role of PI 3-kinase and mTOR in the degradation of IRS-1 induced by insulin .	We have investigated the role of PI 3-kinase and mTOR in the degradation of IRS-1 induced by insulin.	12	18	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	17	18	14	15
Interestingly , in Ptpn11 knockout liver , insulin stimulated IRS1 phospho-S307 ( hS312 ) increases , contrary to the inhibitory function of S307 phosphorylation in cultured cells [ XREF_BIBR ] .	Interestingly, in Ptpn11 knockout liver, insulin stimulated IRS1 phospho-S307 (hS312) increases, contrary to the inhibitory function of S307 phosphorylation in cultured cells [XREF_BIBR].	7	14	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	7	8	9	10
Neither high glucose plus insulin nor GlcN plus insulin prevented acute insulin stimulation ( approximately 20-fold ) of insulin receptor substrate 1 associated phosphatidylinositol ( PI ) -3 kinase .	Neither high glucose plus insulin nor GlcN plus insulin prevented acute insulin stimulation (approximately 20-fold) of insulin receptor substrate 1 associated phosphatidylinositol (PI) -3 kinase.	6	22	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	8	9	18	22
Insulin and IGF-1 stimulate the mTOR pathway by activating the insulin receptor substrate-1 and the phosphatidylinositol-3-kinase and Akt signaling pathway .	Insulin and IGF-1 stimulate the mTOR pathway by activating the insulin receptor substrate-1 and the phosphatidylinositol-3-kinase and Akt signaling pathway.	0	13	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	0	1	10	13
The improvement in muscle insulin sensitivity we observed in vivo is explained by enhanced cellular insulin signaling ( increased insulin stimulated IRS-1 tyrosine and Akt and PKB serine phosphorylation ) detected after 7 % weight loss but not after 48 h of CR .	The improvement in muscle insulin sensitivity we observed in vivo is explained by enhanced cellular insulin signaling (increased insulin stimulated IRS-1 tyrosine and Akt and PKB serine phosphorylation) detected after 7% weight loss but not after 48 h of CR.	16	28	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	19	20	21	22
We also studied the effect of preoperative feeding on postoperative insulin stimulated insulin receptor substrate-1 ( IRS-1 )-associated phosphatidylinositol ( PI ) 3-kinase activity in both Wistar rats and genetically non-insulin-dependent diabetic Goto-Kakazaki rats ( GK rats ) .	We also studied the effect of preoperative feeding on postoperative insulin stimulated insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity in both Wistar rats and genetically non-insulin-dependent diabetic Goto-Kakazaki rats (GK rats).	7	15	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	10	11	12	15
Ser307 phosphorylation of IRS-1 was not observed when the cells were treated with insulin alone .	Ser307 phosphorylation of IRS-1 was not observed when the cells were treated with insulin alone.	1	14	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	13	14	3	4
Bitter melon can also improve insulin sensitivity by increasing insulin stimulated insulin receptor substrate-1 ( IRS1 ) tyrosine phosphorylation in high-fat diet fed mice and rats [ XREF_BIBR , XREF_BIBR ] .	Bitter melon can also improve insulin sensitivity by increasing insulin stimulated insulin receptor substrate-1 (IRS1) tyrosine phosphorylation in high-fat diet fed mice and rats [XREF_BIBR, XREF_BIBR].	4	14	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	9	10	11	14
On examining two lines of Tg mice identified by Southern blot , the transgene product was expressed in skeletal muscle , liver , and adipose tissues , and insulin induced association of insulin receptor substrate 1 with endogenous SHP-2 was inhibited , confirming that DeltaPTP has a dominant negative property .	On examining two lines of Tg mice identified by Southern blot, the transgene product was expressed in skeletal muscle, liver, and adipose tissues, and insulin induced association of insulin receptor substrate 1 with endogenous SHP-2 was inhibited, confirming that DeltaPTP has a dominant negative property.	28	36	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	28	29	32	36
Ang II did not enhance insulin induced insulin receptor substrate-1 ( IRS-1 ) phosporylation or phosphatidylinositol3 ( PI-3 ) kinase activity , but did enhance insulin induced mitogen activated protein ( MAP ) kinase activity .	Ang II did not enhance insulin induced insulin receptor substrate-1 (IRS-1) phosporylation or phosphatidylinositol3 (PI-3) kinase activity, but did enhance insulin induced mitogen activated protein (MAP) kinase activity.	4	10	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	5	6	7	10
Combined thiazolidinedione-metformin treatment was remarkably effective in improving submaximal and maximal activation of all examined signalling factors required during insulin stimulated glucose transport , i.e. IR , IRS-1 and PI3K , aPKC and PKBbeta and Akt2 in skeletal muscles of type 2 diabetic patients .	Combined thiazolidinedione-metformin treatment was remarkably effective in improving submaximal and maximal activation of all examined signalling factors required during insulin stimulated glucose transport, i.e. IR, IRS-1 and PI3K, aPKC and PKBbeta and Akt2 in skeletal muscles of type 2 diabetic patients.	17	29	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	19	20	27	28
Acute administration of Ang II inhibits the insulin stimulated association of IRS-1 with p85 , which subsequently activates Akt mediating the metabolic effects of insulin [ XREF_BIBR ] .	Acute administration of Ang II inhibits the insulin stimulated association of IRS-1 with p85, which subsequently activates Akt mediating the metabolic effects of insulin [XREF_BIBR].	5	12	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	11	12
We found that , although insulin signaling was impaired in muscle , insulin activation of IRS-1 and PI3K , IRS-2 and PI3K , protein kinase B , and aPKC was largely intact in liver and that rosiglitazone improved insulin signaling to aPKC in muscle by improving responsiveness to PI-3 ,4,5-( PO4 ) 3 .	We found that, although insulin signaling was impaired in muscle, insulin activation of IRS-1 and PI3K, IRS-2 and PI3K, protein kinase B, and aPKC was largely intact in liver and that rosiglitazone improved insulin signaling to aPKC in muscle by improving responsiveness to PI-3,4,5-(PO4) 3.	12	28	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	12	13	15	16
In contrast , either hepatic Irs1 or Irs2 mediated suppression of HGP by intracerebroventricular insulin infusion .	In contrast, either hepatic Irs1 or Irs2 mediated suppression of HGP by intracerebroventricular insulin infusion.	3	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	Irs1	Irs1	Irs1	14	15	5	6
Insulin increased insulin receptor substrate-1 ( IRS-1 )-associated phosphoinositide ( PI ) 3-kinase activity threefold , and adrenaline did not influence basal or insulin stimulated PI 3-kinase activity .	Insulin increased insulin receptor substrate-1 (IRS-1)-associated phosphoinositide (PI) 3-kinase activity threefold, and adrenaline did not influence basal or insulin stimulated PI 3-kinase activity.	0	6	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	0	1	2	5
Although 10 nM insulin failed to prevent the HG induced degradation of IRS1 in CHO/IR cells ( sensitive to insulin ) , it did prevent HG induced IRS1 degradation to a modest extent in CHO cells ( less sensitive to insulin ; XREF_FIG , panels 1 and 3 , lanes e-f versus lanes a-d ) .	Although 10 nM insulin failed to prevent the HG induced degradation of IRS1 in CHO/IR cells (sensitive to insulin), it did prevent HG induced IRS1 degradation to a modest extent in CHO cells (less sensitive to insulin; XREF_FIG, panels 1 and 3, lanes e-f versus lanes a-d).	1	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	3	4	12	13
For example , OGT regulates insulin signaling through O GlcNAcylation of several important insulin signaling molecules , e.g ., IRS-1 , PI3K , PDK1 , and AKT1 , leading to attenuation of insulin signaling responses in glycogen synthesis , activation of gluconeogenic genes and glucose transporter GLUT4 translocation , thus contributing to insulin resistance in type II diabetes [ XREF_BIBR , XREF_BIBR ] .	For example, OGT regulates insulin signaling through O GlcNAcylation of several important insulin signaling molecules, e.g., IRS-1, PI3K, PDK1, and AKT1, leading to attenuation of insulin signaling responses in glycogen synthesis, activation of gluconeogenic genes and glucose transporter GLUT4 translocation, thus contributing to insulin resistance in type II diabetes [XREF_BIBR, XREF_BIBR].	9	20	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	13	14	19	20
Mstn significantly reduced basal and insulin induced IRS-1 tyrosine ( Tyr495 ) phosphorylation , and expression and activation of PI3K , associated with diminished AKT phosphorylation and elevated GSK3beta phosphorylation at Ser9 .	Mstn significantly reduced basal and insulin induced IRS-1 tyrosine (Tyr495) phosphorylation, and expression and activation of PI3K, associated with diminished AKT phosphorylation and elevated GSK3beta phosphorylation at Ser9.	3	8	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	5	6	7	8
The serine at codon 83 has a relevant effect on the formation of the IRS-1 and p85alpha PI3K complex as demonstrated by the reduced ability of the p85A and the high efficiency of the p85D mutant to induce an insulin mediated IRS-1 and p85alpha PI3K colocalization of IRS-1 and the formation of cytosolic foci .	The serine at codon 83 has a relevant effect on the formation of the IRS-1 and p85alpha PI3K complex as demonstrated by the reduced ability of the p85A and the high efficiency of the p85D mutant to induce an insulin mediated IRS-1 and p85alpha PI3K colocalization of IRS-1 and the formation of cytosolic foci.	37	45	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	39	40	41	42
Depletion of CUL7 by siRNA in C2C12 myotubes led to enhanced activation of downstream pathways of the insulin receptor , cellular glucose uptake upon insulin stimulation , and impaired insulin triggered proteasomal degradation of IRS1 .	Depletion of CUL7 by siRNA in C2C12 myotubes led to enhanced activation of downstream pathways of the insulin receptor, cellular glucose uptake upon insulin stimulation, and impaired insulin triggered proteasomal degradation of IRS1.	28	35	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	29	30	34	35
In conclusion , the results of the present study demonstrated that insulin induced IRS-1 and SHP2 association can be regulated in insulin sensitive tissues of animal models of insulin resistance and may have a role in the control of AKT phosphorylation , which may be implicated in the control of glucose metabolism .	In conclusion, the results of the present study demonstrated that insulin induced IRS-1 and SHP2 association can be regulated in insulin sensitive tissues of animal models of insulin resistance and may have a role in the control of AKT phosphorylation, which may be implicated in the control of glucose metabolism.	11	16	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	11	12	13	14
Pituitaries responded to insulin through insulin receptor substrate ( IRS ) 2 but not IRS1 , whereas in the ovary , both IRS1 and IRS2 were activated by insulin .	Pituitaries responded to insulin through insulin receptor substrate (IRS) 2 but not IRS1, whereas in the ovary, both IRS1 and IRS2 were activated by insulin.	21	29	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	28	29	22	23
Concurrently , defects in insulin induced IRS-1 associated PI3K activity is also found in skeletal muscle of type 2 diabetic humans [ XREF_BIBR ] .	Concurrently, defects in insulin induced IRS-1 associated PI3K activity is also found in skeletal muscle of type 2 diabetic humans [XREF_BIBR].	2	12	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	6	7
C/EBPalpha also regulates the expression of several other genes required for insulin stimulated glucose uptake , including the insulin receptor itself , as well the signaling intermediate IRS-1 XREF_BIBR .	C/EBPalpha also regulates the expression of several other genes required for insulin stimulated glucose uptake, including the insulin receptor itself, as well the signaling intermediate IRS-1 XREF_BIBR.	9	28	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	11	12	27	28
Unlike previously reported T2D risk loci , which predominantly associate with impaired beta cell function , the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French , Danish and Finnish participants from population based cohorts ; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1 associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies .	Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1 associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.	55	59	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	55	56	58	59
Insulin induced insulin receptor substrate 1 tyrosine and protein kinase B serine phosphorylation were significantly reduced in the liver and muscle of fatty animals compared with their lean littermates .	Insulin induced insulin receptor substrate 1 tyrosine and protein kinase B serine phosphorylation were significantly reduced in the liver and muscle of fatty animals compared with their lean littermates.	0	6	induced	Positive_early_activation	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	0	1	2	6
In summary , the physiological stress associated with muscle damage impairs insulin stimulation of IRS-1 , PI 3-kinase , and Akt-kinase , presumably leading to decreased insulin mediated glucose uptake .	In summary, the physiological stress associated with muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase, presumably leading to decreased insulin mediated glucose uptake.	11	20	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	11	12	14	15
Oral administration of MID-00935 increased insulin induced IRS-1 , Akt , and Erk phosphorylation via increasing IRS-1 levels in the skeletal muscle of DIO mice .	Oral administration of MID-00935 increased insulin induced IRS-1, Akt, and Erk phosphorylation via increasing IRS-1 levels in the skeletal muscle of DIO mice.	5	12	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	5	6	7	8
As alluded to above , in rodent models of T2DM , whereas insulin activation of IRS-1 and PI3K and Akt is impaired in muscle and liver , and , whereas insulin activation of aPKC is impaired in muscle , insulin activation of hepatic IRS2 and PI3K and aPKC is conserved or heightened by hyperinsulinemia [ XREF_BIBR , XREF_BIBR ] .	As alluded to above, in rodent models of T2DM, whereas insulin activation of IRS-1 and PI3K and Akt is impaired in muscle and liver, and, whereas insulin activation of aPKC is impaired in muscle, insulin activation of hepatic IRS2 and PI3K and aPKC is conserved or heightened by hyperinsulinemia [XREF_BIBR, XREF_BIBR].	12	19	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	12	13	15	16
Taken together , the present findings indicate that , in MCF-7 breast cancer cells , high glucose and high insulin conditions promoted cell proliferation and invasion by upregulating IRS1 and activating the Ras/Raf/ERK pathway .	Taken together, the present findings indicate that, in MCF-7 breast cancer cells, high glucose and high insulin conditions promoted cell proliferation and invasion by upregulating IRS1 and activating the Ras/Raf/ERK pathway.	19	29	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	19	20	28	29
Insulin also activates the insulin receptor substrate-1 ( IRS-1 ) , which has been shown as up-regulated in HCC .	Insulin also activates the insulin receptor substrate-1 (IRS-1), which has been shown as up-regulated in HCC.	0	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	0	1	4	7
Ex vivo biochemical studies of mediobasal hypothalamic tissue revealed that insulin stimulated the association of insulin receptor substrate-1 with the p85alpha subunit of PI3K and also tyrosine phosphorylation of p42 and p44 subunits of MAPK in the hypothalamus .	Ex vivo biochemical studies of mediobasal hypothalamic tissue revealed that insulin stimulated the association of insulin receptor substrate-1 with the p85alpha subunit of PI3K and also tyrosine phosphorylation of p42 and p44 subunits of MAPK in the hypothalamus.	10	18	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	10	11	15	18
Insulin and Igf signalling is mediated vaitwo intracellular insulin receptor substrates ( Irs1 and Irs2 ) ; null mutations in either Irs1 or Irs2 result in peripheral insulin resistance but only Irs2 /- mice are incapable enhancing beta-cell replication to compensate for peripheral insulin resistance [ XREF_BIBR ] .	Insulin and Igf signalling is mediated vaitwo intracellular insulin receptor substrates (Irs1 and Irs2); null mutations in either Irs1 or Irs2 result in peripheral insulin resistance but only Irs2 /- mice are incapable enhancing beta-cell replication to compensate for peripheral insulin resistance [XREF_BIBR].	0	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	Irs1	Irs1	Irs1	0	1	12	13
In the report by Rung et al ., the risk allele was associated with a ~ 30 % decrease in IRS1 protein levels and decreased insulin induction of IRS1 associated phosphatidylinositol-3-OH kinase activity in skeletal muscle , suggesting an effect on the initial step of the insulin signaling cascade .	In the report by Rung et al., the risk allele was associated with a ~ 30% decrease in IRS1 protein levels and decreased insulin induction of IRS1 associated phosphatidylinositol-3-OH kinase activity in skeletal muscle, suggesting an effect on the initial step of the insulin signaling cascade.	25	29	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	25	26	28	29
TNFalpha also acts indirectly on the glucose uptake , by inducing the up-regulation of ganglioside GM3 , which is a member of the SLs family that has proven to inhibit both : the insulin mediated activation of insulin receptor substrate-1 ( IRS-1 ) and the expression of insulin receptors from the lipid rafts .	TNFalpha also acts indirectly on the glucose uptake, by inducing the up-regulation of ganglioside GM3, which is a member of the SLs family that has proven to inhibit both : the insulin mediated activation of insulin receptor substrate-1 (IRS-1) and the expression of insulin receptors from the lipid rafts.	33	40	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	33	34	37	40
Moreover , AII inhibits insulin stimulated IRS-1 and IRS-2-associated PI3-kinase activity .	Moreover, AII inhibits insulin stimulated IRS-1 and IRS-2-associated PI3-kinase activity.	3	10	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	6	7
Cold exposure alone promoted higher insulin induced tyrosine phosphorylation of the insulin receptors , IRS-1 , IRS-2 , and ERK , and higher insulin induced IRS-1 and IRS-2 and PI3-kinase association .	Cold exposure alone promoted higher insulin induced tyrosine phosphorylation of the insulin receptors, IRS-1, IRS-2, and ERK, and higher insulin induced IRS-1 and IRS-2 and PI3-kinase association.	8	30	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	23	24	25	26
Conversely , rapamycin inhibited S6K1 and rpS6 activation , and significantly improved insulin -stimulated activation of IRS-1 and MEK1/2 in KO mice .	Conversely, rapamycin inhibited S6K1 and rpS6 activation, and significantly improved insulin -stimulated activation of IRS-1 and MEK1/2 in KO mice.	12	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	12	13	16	17
The effect of imatinib on constitutive IRS-1 signaling in cancer cells might differ from that on insulin induced IRS-1 signaling in insulin target tissues .	The effect of imatinib on constitutive IRS-1 signaling in cancer cells might differ from that on insulin induced IRS-1 signaling in insulin target tissues.	14	19	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	16	17	18	19
Insulin increased total IRS1 protein in both B6 and TH mice in a concentration dependent manner , however , to a lesser degree in TH ( 25 % reduction in basal level and 40 % reduction after 10 nM insulin stimulation , XREF_SUPPLEMENTARY , western blot ) .	Insulin increased total IRS1 protein in both B6 and TH mice in a concentration dependent manner, however, to a lesser degree in TH (25% reduction in basal level and 40% reduction after 10 nM insulin stimulation, XREF_SUPPLEMENTARY, western blot).	0	4	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS1	IRS1	IRS1	0	1	3	4
Insulin stimulation of insulin receptor and insulin-receptor substrate-1 ( IRS-1 ) tyrosine phosphorylation as well as activation of phosphatidylinositol 3-kinase ( PI-3 kinase ) and Akt ( also known as protein kinase B , PKB ) were all substantially reduced with severe obesity .	Insulin stimulation of insulin receptor and insulin-receptor substrate-1 (IRS-1) tyrosine phosphorylation as well as activation of phosphatidylinositol 3-kinase (PI-3 kinase) and Akt (also known as protein kinase B, PKB) were all substantially reduced with severe obesity.	0	8	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	insulin-receptor substrate-1	insulin-receptor substrate-1	insulin-receptor substrate-1	0	1	6	8
In wild-type mice on an HFD , insulin failed to significantly increase activation of IR , IRS-1 , and Akt .	In wild-type mice on an HFD, insulin failed to significantly increase activation of IR, IRS-1, and Akt.	7	17	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	16	17
Because skeletal muscle is responsible for the majority of insulin stimulated glucose disposition and IRS-1 is a key element in regulating metabolic actions of insulin , a decline in IRS-1 transcription in skeletal muscle was used to explain the development of insulin resistance in peripheral tissue .	Because skeletal muscle is responsible for the majority of insulin stimulated glucose disposition and IRS-1 is a key element in regulating metabolic actions of insulin, a decline in IRS-1 transcription in skeletal muscle was used to explain the development of insulin resistance in peripheral tissue.	7	15	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	9	10	14	15
XREF_BIBR , XREF_BIBR Insulin stimulation of IRS-1 and -2 leads to activation of intracellular PI3K ( phosphoinositide 3-kinase ) and AKT and PKB ( protein kinase B ) pathways , which are intimately involved in mediating the metabolic effects of insulin .	XREF_BIBR, XREF_BIBR Insulin stimulation of IRS-1 and -2 leads to activation of intracellular PI3K (phosphoinositide 3-kinase) and AKT and PKB (protein kinase B) pathways, which are intimately involved in mediating the metabolic effects of insulin.	3	8	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	3	4	6	7
IRS1 , which is stimulated by insulin or insulin like growth factor-1 , then activates phosphoinositide 3-kinase , which in turn activates the AKT pathway , and cardiac hypertrophy and cardiac failure subsequently occur .	IRS1, which is stimulated by insulin or insulin like growth factor-1, then activates phosphoinositide 3-kinase, which in turn activates the AKT pathway, and cardiac hypertrophy and cardiac failure subsequently occur.	0	14	stimulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	6	7	0	1
The present work provides evidence for the involvement of a particular PP1 complex , PPP1R12A and PP1cdelta , in the insulin stimulated IRS1 signaling complex .	The present work provides evidence for the involvement of a particular PP1 complex, PPP1R12A and PP1cdelta, in the insulin stimulated IRS1 signaling complex.	3	24	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	20	21	22	23
Insulin treatment did not change the concentrations of insulin receptors or Shc but increased IRS-1 in the caveolin enriched fraction , possibly recruited from the cytosolic pool .	Insulin treatment did not change the concentrations of insulin receptors or Shc but increased IRS-1 in the caveolin enriched fraction, possibly recruited from the cytosolic pool.	0	15	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	14	15
A phospho specific antibody directed at Tyr612 of IRS1 ( a putative binding domain for the p85 subunit of phosphoinositide-3-kinase ) was used to examine the insulin stimulated activation of IRS1 .	A phospho specific antibody directed at Tyr612 of IRS1 (a putative binding domain for the p85 subunit of phosphoinositide-3-kinase) was used to examine the insulin stimulated activation of IRS1.	25	31	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	26	27	30	31
These findings suggest that high glucose and high insulin conditions promoted the proliferation and invasion of MCF-7 cells by upregulating IRS1 and activating the Ras/Raf/ERK pathway .	These findings suggest that high glucose and high insulin conditions promoted the proliferation and invasion of MCF-7 cells by upregulating IRS1 and activating the Ras/Raf/ERK pathway.	8	21	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	8	9	20	21
53 We showed that MG53 disruption increased insulin elicited IRS-1 activation with an elevated IRS-1 protein level in mouse skeletal muscle , inducing skeletal muscle hypertrophy at least in the soleus , improving glucose tolerance even in regular diet fed mice and ameliorating HF/HS diet induced insulin resistance ( XREF_FIG and XREF_FIG ) .	53 We showed that MG53 disruption increased insulin elicited IRS-1 activation with an elevated IRS-1 protein level in mouse skeletal muscle, inducing skeletal muscle hypertrophy at least in the soleus, improving glucose tolerance even in regular diet fed mice and ameliorating HF/HS diet induced insulin resistance (XREF_FIG and XREF_FIG).	6	10	elicited	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	9	10
Signs of restored insulin responsiveness ( upregulation of IRS1 , INSIG2 , SREBF1 , and ZFP423 ) were apparent as early as 3 wk postpartum .	Signs of restored insulin responsiveness (upregulation of IRS1, INSIG2, SREBF1, and ZFP423) were apparent as early as 3 wk postpartum.	3	9	upregulation	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	3	4	8	9
Insulin induced IRS-1 and phosphatidylinositol 3 ( PI3 )-kinase ( but not IRS-2 and PI3-kinase ) association and serine Akt phosphorylation also increased ( 2.06- and 3.15-fold , respectively ) after training .	Insulin induced IRS-1 and phosphatidylinositol 3 (PI3)-kinase (but not IRS-2 and PI3-kinase) association and serine Akt phosphorylation also increased (2.06- and 3.15-fold, respectively) after training.	0	18	induced	Positive_early_activation	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	2	3
have demonstrated that insulin stimulated IRS1 associated PI 3-kinase activity is significantly reduced in liver of IRS2 -/- mice .	have demonstrated that insulin stimulated IRS1 associated PI 3-kinase activity is significantly reduced in liver of IRS2 -/- mice.	3	12	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	3	4	5	6
In the present study , we determined whether beta-arrestin-1 is involved in insulin induced insulin receptor substrate 1 ( IRS-1 ) degradation .	In the present study, we determined whether beta-arrestin-1 is involved in insulin induced insulin receptor substrate 1 (IRS-1) degradation.	10	19	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	12	13	14	18
Our overarching hypothesis was that high or low of insulin concentration may trigger the IRS-1 or 2 signaling and consequently activate FATP-2 & 5 mediated fatty acid transport , thus contributing to hepatic lipid accumulation .	Our overarching hypothesis was that high or low of insulin concentration may trigger the IRS-1 or 2 signaling and consequently activate FATP-2 & 5 mediated fatty acid transport, thus contributing to hepatic lipid accumulation.	9	17	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	9	10	14	15
However , S307 ( S312 in humans ) is the only site demonstrated to be required for insulin stimulated IRS-1 down-regulation .	However, S307 (S312 in humans) is the only site demonstrated to be required for insulin stimulated IRS-1 down-regulation.	15	20	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	17	18	19	20
Generally , IRS1 stimulated by insulin or IGF1 leads to the induction of a downstream PI3K-Akt or MAPK and ERK signaling cascade , which increases protein synthesis via translational activation to cellular growth [ XREF_BIBR , XREF_BIBR ] and promotes cell survival [ XREF_BIBR ] .	Generally, IRS1 stimulated by insulin or IGF1 leads to the induction of a downstream PI3K-Akt or MAPK and ERK signaling cascade, which increases protein synthesis via translational activation to cellular growth [XREF_BIBR, XREF_BIBR] and promotes cell survival [XREF_BIBR].	2	8	stimulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	5	6	2	3
Moreover , the insulin mediated induction of insulin receptor substrate-1 ( IRS-1 ) and glycogen synthase kinase-3beta ( GSK-3beta ) were also suppressed by wortmannin .	Moreover, the insulin mediated induction of insulin receptor substrate-1 (IRS-1) and glycogen synthase kinase-3beta (GSK-3beta) were also suppressed by wortmannin.	2	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	3	4	7	10
Upon examination of other targets of the insulin signaling pathway , we observed a marked reduction in insulin stimulated p-tyrosine ( p-Tyr ) ( insulin receptor beta-subunit and IRS-1 ) expression levels in E4orf1-Tg sWAT and liver tissues ( XREF_FIG C ) .	Upon examination of other targets of the insulin signaling pathway, we observed a marked reduction in insulin stimulated p-tyrosine (p-Tyr) (insulin receptor beta-subunit and IRS-1) expression levels in E4orf1-Tg sWAT and liver tissues (XREF_FIG C).	15	29	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	17	18	28	29
Fatty acid exposure decreased values for IRS-1 serine 312 phosphorylation as well as insulin stimulation of IRS-1 and Akt in cells from lean controls to values approximating those in myotubes from severely obese subjects ( XREF_FIG ) .	Fatty acid exposure decreased values for IRS-1 serine 312 phosphorylation as well as insulin stimulation of IRS-1 and Akt in cells from lean controls to values approximating those in myotubes from severely obese subjects (XREF_FIG).	13	18	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	13	14	16	17
In the present work , we have demonstrated that spectral counting is capable of detecting endogenous insulin stimulated IRS-1 complexes .	In the present work, we have demonstrated that spectral counting is capable of detecting endogenous insulin stimulated IRS-1 complexes.	14	19	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	16	17	18	19
Reconstitution of L-p110alpha KO livers with wild-type p110alpha resulted in a restoration of insulin stimulated IRS-1- and PY associated PI3K activity , as well as phosphorylation of Akt and PKB , GSK3beta , p70S6 kinase , and FoxO1 to normal or near-normal levels , whereas reconstitution with KD p110alpha had no effect ( XREF_FIG ) .	Reconstitution of L-p110alpha KO livers with wild-type p110alpha resulted in a restoration of insulin stimulated IRS-1- and PY associated PI3K activity, as well as phosphorylation of Akt and PKB, GSK3beta, p70S6 kinase, and FoxO1 to normal or near-normal levels, whereas reconstitution with KD p110alpha had no effect (XREF_FIG).	11	18	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1-	IRS-1-	IRS-1-	13	14	15	16
The results of the present study demonstrated that high glucose and high insulin conditions promoted the proliferation and invasion of MCF-7 breast cancer cells by upregulating IRS1 and activating the Ras/Raf/ERK pathway .	The results of the present study demonstrated that high glucose and high insulin conditions promoted the proliferation and invasion of MCF-7 breast cancer cells by upregulating IRS1 and activating the Ras/Raf/ERK pathway.	12	27	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	12	13	26	27
These results indicate that PPP1R12A and PP1cdelta are new members of the insulin stimulated IRS1 signaling complex , and the interaction of PPP1R12A and PP1cdelta with IRS1 is dependent on Akt and mTOR and raptor activation .	These results indicate that PPP1R12A and PP1cdelta are new members of the insulin stimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cdelta with IRS1 is dependent on Akt and mTOR and raptor activation.	9	16	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	12	13	14	15
Pro inflammatory cytokines , including IL-1beta , IL-6 , and TNF-alpha , can impair IRS-1 function by increasing its phosphorylation , thus preventing insulin mediated IRS-1 tyrosine phosphorylation XREF_BIBR .	Pro inflammatory cytokines, including IL-1beta, IL-6, and TNF-alpha, can impair IRS-1 function by increasing its phosphorylation, thus preventing insulin mediated IRS-1 tyrosine phosphorylation XREF_BIBR.	23	28	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	23	24	25	26
We found that , in liver as well as in muscle , whereas IRS-1 and PI3K activation by insulin was impaired , IRS-2 and PI3K was intact .	We found that, in liver as well as in muscle, whereas IRS-1 and PI3K activation by insulin was impaired, IRS-2 and PI3K was intact.	13	19	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	18	19	13	14
However , insulin stimulation of pIRS-1 measured as fold-change over basal phosphorylation was similar between volumes ( XREF_FIG ) .	However, insulin stimulation of pIRS-1 measured as fold-change over basal phosphorylation was similar between volumes (XREF_FIG).	2	6	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	pIRS-1	pIRS-1	pIRS-1	2	3	5	6
Ang II can also cause insulin resistance by interfering with the insulin stimulated increase in insulin receptor substrate 1 associated PI3K activity ( XREF_FIG ) .	Ang II can also cause insulin resistance by interfering with the insulin stimulated increase in insulin receptor substrate 1 associated PI3K activity (XREF_FIG).	8	19	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	11	12	15	19
We identified that miR-29 overexpression attenuates insulin signaling and expression of insulin receptor substrate 1 and phosphoinositide 3-kinase .	We identified that miR-29 overexpression attenuates insulin signaling and expression of insulin receptor substrate 1 and phosphoinositide 3-kinase.	6	15	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	6	7	11	15
First , pharmacological inhibition of IKKbeta via BMS-345541 did not potentiate insulin induced IRS1 ( insulin receptor substrate 1 ) tyrosine phosphorylation , PKB phosphorylation or 2-deoxyglucose uptake in differentiated 3T3-L1 adipocytes .	First, pharmacological inhibition of IKKbeta via BMS-345541 did not potentiate insulin induced IRS1 (insulin receptor substrate 1) tyrosine phosphorylation, PKB phosphorylation or 2-deoxyglucose uptake in differentiated 3T3-L1 adipocytes.	10	17	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	11	12	13	14
Compared with non pregnant control subjects , maximal insulin stimulated insulin receptor substrate 1 ( IRS-1 ) tyrosine phosphorylation was significantly lower by a mean 59 % in normal glucose tolerance and 62 % in gestational diabetes .	Compared with non pregnant control subjects, maximal insulin stimulated insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation was significantly lower by a mean 59% in normal glucose tolerance and 62% in gestational diabetes.	7	15	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	8	9	10	14
Both of the metal ions were also found to potentiate insulin mediated activation of IRS-1 .	Both of the metal ions were also found to potentiate insulin mediated activation of IRS-1.	10	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	10	11	14	15
SLs , such as GM 3 and ceramide are reported to inhibit insulin induced insulin receptor substrate-1 ( IRS-1 ) activation and Akt activation , respectively , and the subsequent trafficking of GLUT4 [ XREF_BIBR , XREF_BIBR ] .	SLs, such as GM 3 and ceramide are reported to inhibit insulin induced insulin receptor substrate-1 (IRS-1) activation and Akt activation, respectively, and the subsequent trafficking of GLUT4 [XREF_BIBR, XREF_BIBR].	11	30	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	12	13	14	17
Moreover , fADN attenuated insulin dependent activation of insulin receptor substrate-1 ( IRS-1 ) , as well as preventing the downstream activation of protein kinase B/Akt .	Moreover, fADN attenuated insulin dependent activation of insulin receptor substrate-1 (IRS-1), as well as preventing the downstream activation of protein kinase B/Akt.	4	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	4	5	8	11
Peripheral insulin resistance can also raise brain IRS-1 pS by decreasing clearance of brain Abeta , because insulin facilitates hepatic clearance of plasma Abeta [ XREF_BIBR ] , interference with which impairs brain clearance of that peptide [ XREF_BIBR ] .	Peripheral insulin resistance can also raise brain IRS-1 pS by decreasing clearance of brain Abeta, because insulin facilitates hepatic clearance of plasma Abeta [XREF_BIBR], interference with which impairs brain clearance of that peptide [XREF_BIBR].	1	8	raise	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	7	8
Exercise synergistically enhanced insulin stimulated insulin receptor substrate 1 associated phosphatidylinositol 3-kinase activity ( P < 0.05 ) and Akt Ser473 phosphorylation ( P < 0.05 ) in nondiabetic subjects but had little effect in diabetic subjects .	Exercise synergistically enhanced insulin stimulated insulin receptor substrate 1 associated phosphatidylinositol 3-kinase activity (P < 0.05) and Akt Ser473 phosphorylation (P < 0.05) in nondiabetic subjects but had little effect in diabetic subjects.	2	9	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	3	4	5	9
We have performed Western blot analysis to confirm the insulin stimulated interaction of IRS-1 with PPP1R12A and p85 .	We have performed Western blot analysis to confirm the insulin stimulated interaction of IRS-1 with PPP1R12A and p85.	7	14	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	9	10	13	14
PEDF effects may modulate vascular tone and blood pressure by JNK activation and reduced insulin dependent activation of IRS-1 and Akt [ XREF_BIBR , XREF_BIBR ] .	PEDF effects may modulate vascular tone and blood pressure by JNK activation and reduced insulin dependent activation of IRS-1 and Akt [XREF_BIBR, XREF_BIBR].	14	20	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	14	15	18	19
Insulin stimulated activations of IRS-1 , AKT and GSK3beta were significantly reduced in fibroblasts of LRP6 R611C mutation carriers compared to non carriers ( XREF_FIG ) .	Insulin stimulated activations of IRS-1, AKT and GSK3beta were significantly reduced in fibroblasts of LRP6 R611C mutation carriers compared to non carriers (XREF_FIG).	0	8	activations	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	4	5
Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 ( IRS-1 )-associated phosphatidylinositol 3-kinase ( PI3-kinase ) .	Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase).	15	25	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	15	16	22	23
Olanzapine has been found to attenuate phosphorylation of insulin like growth factor receptor ( IGF-R ) and IRS1 stimulated by insulin in wild-type fibroblast cells .	Olanzapine has been found to attenuate phosphorylation of insulin like growth factor receptor (IGF-R) and IRS1 stimulated by insulin in wild-type fibroblast cells.	5	24	stimulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	20	21	17	18
As expected , tyrosine phosphorylation of IRS1 was higher in STAMP2 expressing HepG2-HBx cells treated with insulin , compared to control vector transfected cells ( XREF_FIG ) .	As expected, tyrosine phosphorylation of IRS1 was higher in STAMP2 expressing HepG2-HBx cells treated with insulin, compared to control vector transfected cells (XREF_FIG).	4	17	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	16	17	6	7
In the present study , we investigated insulin induced IRS-1 and SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine kinase AKT and PKB in liver and muscle of three animal models of insulin resistance : STZ diabetes , epinephrine treated rats , and aging , which have alterations in IRS-1 tyrosine phosphorylation in common .	In the present study, we investigated insulin induced IRS-1 and SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine kinase AKT and PKB in liver and muscle of three animal models of insulin resistance : STZ diabetes, epinephrine treated rats, and aging, which have alterations in IRS-1 tyrosine phosphorylation in common.	7	47	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	9	10
Elevation in plasma free fatty acids levels increases intracellular fatty acyl-CoA and DAG which in turn activates PKCtheta in skeletal muscle which phosphorylates S307 on insulin stimulated insulin receptor substrate 1 ( IRS-1 ) resulting in reduced tyrosine phosphorylation and IRS-1-associated PI3-kinase activity [ XREF_BIBR - XREF_BIBR ] .	Elevation in plasma free fatty acids levels increases intracellular fatty acyl-CoA and DAG which in turn activates PKCtheta in skeletal muscle which phosphorylates S307 on insulin stimulated insulin receptor substrate 1 (IRS-1) resulting in reduced tyrosine phosphorylation and IRS-1-associated PI3-kinase activity [XREF_BIBR - XREF_BIBR].	12	32	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	DAG which in turn activates PKCtheta in skeletal muscle which phosphorylates S307 on insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	25	26	27	31
Insulin stimulated IRS-1 associated PI-3 kinase activities ( normalized for protein content ) were significantly greater in animals randomized to PMI 5011 ( XREF_FIG ) .	Insulin stimulated IRS-1 associated PI-3 kinase activities (normalized for protein content) were significantly greater in animals randomized to PMI 5011 (XREF_FIG).	0	15	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	2	3
Moreover , ERK1/2 activation induced by angiotensin II suppressed insulin sensitivity by inhibiting the insulin induced insulin receptor substrate 1 ( IRS-1 ) tyrosine phosphorylation and glucose uptake in vascular smooth muscle cells XREF_BIBR .	Moreover, ERK1/2 activation induced by angiotensin II suppressed insulin sensitivity by inhibiting the insulin induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and glucose uptake in vascular smooth muscle cells XREF_BIBR.	13	21	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	14	15	16	20
Interestingly , chronic GH treatment increased insulin stimulated association of IRS-1 with p85 and IRS-1-associated PI 3-kinase activity preferentially in the cytosol .	Interestingly, chronic GH treatment increased insulin stimulated association of IRS-1 with p85 and IRS-1-associated PI 3-kinase activity preferentially in the cytosol.	5	11	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	6	7	10	11
We observed a selective inhibition of insulin -induced activation of IRS-1 and Akt pathway while enhanced activation of MAPK , which is consistent with other studies shown in various insulin resistant state .	We observed a selective inhibition of insulin -induced activation of IRS-1 and Akt pathway while enhanced activation of MAPK, which is consistent with other studies shown in various insulin resistant state.	6	13	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	6	7	10	11
IRS-1 is activated by insulin via tyrosine phosphorylation of IRS-1 in the normal signaling pathway , but the Ser307 phosphorylation of IRS decreases its ability to phosphorylate tyrosine and can therefore cause insulin resistance [ XREF_BIBR - XREF_BIBR ] .	IRS-1 is activated by insulin via tyrosine phosphorylation of IRS-1 in the normal signaling pathway, but the Ser307 phosphorylation of IRS decreases its ability to phosphorylate tyrosine and can therefore cause insulin resistance [XREF_BIBR - XREF_BIBR].	0	7	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	0	1
The expression levels of insulin signaling molecules IRS-1 , Akt , eNOS , ERK1 and ERK2 , PKC-alpha , NFkappaB-p65 subunit and IkappaB-alpha in rat aortic endothelium were determined by immunohistochemistry and Western blot .	The expression levels of insulin signaling molecules IRS-1, Akt, eNOS, ERK1 and ERK2, PKC-alpha, NFkappaB-p65 subunit and IkappaB-alpha in rat aortic endothelium were determined by immunohistochemistry and Western blot.	2	22	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	levels of insulin	insulin	IRS-1	IRS-1	irs-1	4	5	7	8
In this model , insulin ( or IGF1 ) activates IRS-1 and the Akt pathway to enhance nutrient accumulation .	In this model, insulin (or IGF1) activates IRS-1 and the Akt pathway to enhance nutrient accumulation.	4	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	10	11
In addition , we found that AMPK inhibits insulin stimulation of IRS1 associated phosphatidylinositol 3-kinase activity , and that AMPK activates atypical protein kinase C and extracellular signal regulated kinase in the heart .	In addition, we found that AMPK inhibits insulin stimulation of IRS1 associated phosphatidylinositol 3-kinase activity, and that AMPK activates atypical protein kinase C and extracellular signal regulated kinase in the heart.	8	12	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	8	9	11	12
Strikingly , Insulin stimulated the association of IRS-1 and PI3-Kinase in the nucleus in a similar kinetics with the nuclear translocation of PI3-Kinase .	Strikingly, Insulin stimulated the association of IRS-1 and PI3-Kinase in the nucleus in a similar kinetics with the nuclear translocation of PI3-Kinase.	2	9	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	2	3	7	8
As noted above , far greater reductions in insulin responsiveness are seen below the IR in the AD brain beginning with IRS-1 , which is activated by insulin at only 10 % of normal levels in the hippocampal formation [ XREF_BIBR ] .	As noted above, far greater reductions in insulin responsiveness are seen below the IR in the AD brain beginning with IRS-1, which is activated by insulin at only 10% of normal levels in the hippocampal formation [XREF_BIBR].	11	28	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	27	28	21	22
Tunicamycin significantly impaired insulin stimulated IRS1 Tyr 612 and Akt Thr 308 phosphorylation by 67 % and 27 % , respectively ( XREF_FIG ) .	Tunicamycin significantly impaired insulin stimulated IRS1 Tyr 612 and Akt Thr 308 phosphorylation by 67% and 27%, respectively (XREF_FIG).	0	22	stimulated	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	3	4	5	6
High glucose and high insulin conditions promote MCF-7 cell proliferation and invasion by upregulating IRS1 and activating the Ras/Raf/ERK pathway .	High glucose and high insulin conditions promote MCF-7 cell proliferation and invasion by upregulating IRS1 and activating the Ras/Raf/ERK pathway.	4	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	4	5	14	15
However , it significantly potentiated the maximal insulin promoted BRET signal between hIR and Grb2 but not IRS1 .	However, it significantly potentiated the maximal insulin promoted BRET signal between hIR and Grb2 but not IRS1.	5	18	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	7	8	17	18
Inhibition of mTOR with rapamycin resulted in approximately 50 % inhibition of the insulin induced degradation of IRS-1 .	Inhibition of mTOR with rapamycin resulted in approximately 50% inhibition of the insulin induced degradation of IRS-1.	10	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	13	14	17	18
NButGT treatment , and the associated increases in O-GlcNAc levels , did not impair insulin stimulated activation of Akt , IRS1 , or FoxO1 in the liver while Akt activation was also not impaired in muscle or fat tissues ( XREF_FIG ) .	NButGT treatment, and the associated increases in O-GlcNAc levels, did not impair insulin stimulated activation of Akt, IRS1, or FoxO1 in the liver while Akt activation was also not impaired in muscle or fat tissues (XREF_FIG).	13	21	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	14	15	20	21
By contrast , insulin stimulated the PI 3-kinase cascade , inhibited apoptosis , and promoted replication of 32DIR cells expressing IRS-1 .	By contrast, insulin stimulated the PI 3-kinase cascade, inhibited apoptosis, and promoted replication of 32DIR cells expressing IRS-1.	3	21	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	3	4	20	21
Addition of leucine to the HFD almost completely rescued the insulin stimulation of IR , IRS-1 and AKT , returning them to levels similar to those in the CD mice ( XREF_FIG ) .	Addition of leucine to the HFD almost completely rescued the insulin stimulation of IR, IRS-1 and AKT, returning them to levels similar to those in the CD mice (XREF_FIG).	10	16	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	10	11	15	16
In fact , we found that exercise reduced insulin stimulated IRS-1 associated PI-3 kinase activity XREF_BIBR .	In fact, we found that exercise reduced insulin stimulated IRS-1 associated PI-3 kinase activity XREF_BIBR.	7	11	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	10	11
At the cellular level , insulin stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33 % lower ( P < 0.05 ) than that in the SHAM group and was associated with increased insulin stimulated IRS-1 Ser 307 and decreased Akt Ser 473 and AS160 Thr 642 phosphorylation and GLUT-4 expression .	At the cellular level, insulin stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33% lower (P < 0.05) than that in the SHAM group and was associated with increased insulin stimulated IRS-1 Ser 307 and decreased Akt Ser 473 and AS160 Thr 642 phosphorylation and GLUT-4 expression.	34	43	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	37	38	39	40
The same appears to be true in AD brains , where insulin induced IRS-1 activation is consistently reduced in tissues with significantly elevated levels of IRS-1 pS616 and IRS-1 pS636/639 , which are thus potential biomarkers of brain insulin resistance [ XREF_BIBR ] .	The same appears to be true in AD brains, where insulin induced IRS-1 activation is consistently reduced in tissues with significantly elevated levels of IRS-1 pS616 and IRS-1 pS636/639, which are thus potential biomarkers of brain insulin resistance [XREF_BIBR].	11	14	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	11	12	13	14
Insulin treatment ( 15-60 min ) caused the release of IRS-1 and IRS-2 from this complex ( high speed pellet ; HSP ) into the cytosol , whereas the level of tyrosyl phosphorylated IRS proteins remained constant .	Insulin treatment (15-60 min) caused the release of IRS-1 and IRS-2 from this complex (high speed pellet; HSP) into the cytosol, whereas the level of tyrosyl phosphorylated IRS proteins remained constant.	0	12	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	10	11
Dexamethasone markedly increased basal and insulin stimulated IRS-1 content 4 to 5-fold ( p < 0.01 ) .	Dexamethasone markedly increased basal and insulin stimulated IRS-1 content 4 to 5-fold (p < 0.01).	3	8	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	5	6	7	8
In that pathway ( XREF_FIG ) , insulin binding of the insulin receptor ( IR ) at the cell surface activates IRS-1 intracellularly , which in turn activates PI3K , then Akt and , finally , the many downstream targets of Akt , including mTOR [ XREF_BIBR , XREF_BIBR ] .	In that pathway (XREF_FIG), insulin binding of the insulin receptor (IR) at the cell surface activates IRS-1 intracellularly, which in turn activates PI3K, then Akt and, finally, the many downstream targets of Akt, including mTOR [XREF_BIBR, XREF_BIBR].	7	48	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	21	22
In the 7-day HS soleus , this was accompanied by increased ( 47 % ) insulin stimulated IRS-1 associated with the p85 subunit of PI3-kinase .	In the 7-day HS soleus, this was accompanied by increased (47%) insulin stimulated IRS-1 associated with the p85 subunit of PI3-kinase.	10	18	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	15	16	17	18
Contraction alone had little effect on PI 3-kinase activity , but contraction markedly blunted the insulin stimulated activation of IRS-1 and insulin receptor-immunoprecipitable PI 3-kinase .	Contraction alone had little effect on PI 3-kinase activity, but contraction markedly blunted the insulin stimulated activation of IRS-1 and insulin receptor-immunoprecipitable PI 3-kinase.	14	24	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	15	16	19	20
A recent study using cultured skeletal muscle from 10 PCOS patients and matched control subjects reported a 35 % significant increase in IRS-1 protein abundance in cultured skeletal muscle of PCOS patients , and the insulin stimulated IRS-1 associated PI3K activity was reduced in the PCOS patients XREF_BIBR .	A recent study using cultured skeletal muscle from 10 PCOS patients and matched control subjects reported a 35% significant increase in IRS-1 protein abundance in cultured skeletal muscle of PCOS patients, and the insulin stimulated IRS-1 associated PI3K activity was reduced in the PCOS patients XREF_BIBR.	34	42	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	35	36	37	38
To do so we measured IRS-1 tyrosine phosphorylation in cells treated with insulin in the absence or presence of ONOO -.	To do so we measured IRS-1 tyrosine phosphorylation in cells treated with insulin in the absence or presence of ONOO -.	5	13	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	12	13	5	6
To examine the effects of insulin on gluconeogenesis suppression as well as lipogenesis promotion in the livers of NAFLD patients , we selected key insulin signaling molecules , IRS-1 and IRS-2 , and key enzymes for gluconeogenesis , PEPCK and G6Pase , for glycolysis , GCK , and for lipogenesis , FAS .	To examine the effects of insulin on gluconeogenesis suppression as well as lipogenesis promotion in the livers of NAFLD patients, we selected key insulin signaling molecules, IRS-1 and IRS-2, and key enzymes for gluconeogenesis, PEPCK and G6Pase, for glycolysis, GCK, and for lipogenesis, FAS.	22	34	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	24	25	28	29
However , co-transfection with a plasmid directing the expression of rat IRS-1 fully restored insulin stimulated SRE-Luc activity in the IRS-1 antisense cell lines .	However, co-transfection with a plasmid directing the expression of rat IRS-1 fully restored insulin stimulated SRE-Luc activity in the IRS-1 antisense cell lines.	13	23	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	14	15	20	21
In conclusion , we have shown that ET-1 and cAMP may synergistically induce insulin resistance in adipocytes via inhibiting IRS-1 expression as well as insulin stimulated IRS-1 and IRS-2 activities .	In conclusion, we have shown that ET-1 and cAMP may synergistically induce insulin resistance in adipocytes via inhibiting IRS-1 expression as well as insulin stimulated IRS-1 and IRS-2 activities.	12	29	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	24	25	26	27
Immunoprecipitated lysates resolved by SDS-PAGE showed that nexilin and IRS1 are stably associated under basal conditions , however insulin stimulation elicited dissociation of the complex coincident with recruitment of p85alpha to IRS1 ( XREF_FIG ) .	Immunoprecipitated lysates resolved by SDS-PAGE showed that nexilin and IRS1 are stably associated under basal conditions, however insulin stimulation elicited dissociation of the complex coincident with recruitment of p85alpha to IRS1 (XREF_FIG).	18	33	elicited	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	18	19	31	32
Recently , Ser307Ala knock-in mice were found to be insulin resistant [ XREF_BIBR ] , suggesting that Ser307 phosphorylation may be important for insulin stimulated IRS-1 function , despite previous reports that phosphorylation at this site inhibits IRS-1 association with the IR [ XREF_BIBR ] .	Recently, Ser307Ala knock-in mice were found to be insulin resistant [XREF_BIBR], suggesting that Ser307 phosphorylation may be important for insulin stimulated IRS-1 function, despite previous reports that phosphorylation at this site inhibits IRS-1 association with the IR [XREF_BIBR].	21	26	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	23	24	25	26
We report here that the pathway also plays an important role in insulin induced subcellular redistribution of IRS-1 from the low-density microsomes ( LDM ) to the cytosol .	We report here that the pathway also plays an important role in insulin induced subcellular redistribution of IRS-1 from the low-density microsomes (LDM) to the cytosol.	10	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	12	13	17	18
Insulin induced significantly less activation of the IR --> IRS-1 --> PI3K --> Akt pathway in AD compared to healthy tissue in all brain areas our group has studied .	Insulin induced significantly less activation of the IR --> IRS-1 --> PI3K --> Akt pathway in AD compared to healthy tissue in all brain areas our group has studied.	0	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	9	10
Recent studies in L6 myotubes showed that , prior to its down-regulation by degradation , IRS-1 protein is acutely induced by insulin stimulation XREF_BIBR .	Recent studies in L6 myotubes showed that, prior to its down-regulation by degradation, IRS-1 protein is acutely induced by insulin stimulation XREF_BIBR.	15	23	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	21	22	15	16
In adipocytes and muscle cells , oxidative stress has been shown to disrupt subcellular redistribution of IRS-1 and PI 3-kinase induced by insulin treatment [ XREF_BIBR , XREF_BIBR ] .	In adipocytes and muscle cells, oxidative stress has been shown to disrupt subcellular redistribution of IRS-1 and PI 3-kinase induced by insulin treatment [XREF_BIBR, XREF_BIBR].	16	23	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	22	23	16	17
Although the insulin resistance of PCOS partially has a genetic substrate [ XREF_BIBR , XREF_BIBR ] , an increased androgenic activity could amplify insulin resistance as soon as testosterone in physiological concentrations enhanced the insulin induced IRS-1 serine 636/639 phosphorylation in differentiated rat skeletal muscle myotubes [ XREF_BIBR ] .	Although the insulin resistance of PCOS partially has a genetic substrate [XREF_BIBR, XREF_BIBR], an increased androgenic activity could amplify insulin resistance as soon as testosterone in physiological concentrations enhanced the insulin induced IRS-1 serine 636/639 phosphorylation in differentiated rat skeletal muscle myotubes [XREF_BIBR].	33	37	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	34	35	36	37
Inhibitors for phosphatidylinositol-3 kinase , mammalian target of rapamycin , and c-Jun amino-terminal kinase failed to block NO donor induced IRS-1 reduction , whereas these inhibitors prevented insulin stimulated IRS-1 decrease .	Inhibitors for phosphatidylinositol-3 kinase, mammalian target of rapamycin, and c-Jun amino-terminal kinase failed to block NO donor induced IRS-1 reduction, whereas these inhibitors prevented insulin stimulated IRS-1 decrease.	26	30	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	27	28	29	30
Nevertheless , we demonstrated here that in ZL hepatocytes of Ad-beta-gal group , insulin dose-dependently induces the levels of phospho-AKT ( Ser473 and Thr308 ) and IRS1 protein .	Nevertheless, we demonstrated here that in ZL hepatocytes of Ad-beta-gal group, insulin dose-dependently induces the levels of phospho-AKT (Ser473 and Thr308) and IRS1 protein.	13	27	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	13	14	26	27
Relevant to the question of divergent activation of PKB and aPKC during insulin action in diabetic liver , we found : ( a ) insulin increased IRS-1 and PI3K activity in Wistar non diabetic liver , but not in GK-diabetic liver ( XREF_FIG ) ; and ( b ) , in contrast , activation of IRS-2 and PI3K by insulin was , if anything , greater in GK-diabetic liver ( XREF_FIG ) .	Relevant to the question of divergent activation of PKB and aPKC during insulin action in diabetic liver, we found : (a) insulin increased IRS-1 and PI3K activity in Wistar non diabetic liver, but not in GK-diabetic liver (XREF_FIG); and (b), in contrast, activation of IRS-2 and PI3K by insulin was, if anything, greater in GK-diabetic liver (XREF_FIG).	24	29	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	24	25	26	27
Insulin stimulated IRS-1 and Akt Thr 308 phosphorylation were reduced by 44 and 52 % , respectively , in TgKO muscle ( XREF_FIG B ) .	Insulin stimulated IRS-1 and Akt Thr 308 phosphorylation were reduced by 44 and 52%, respectively, in TgKO muscle (XREF_FIG B).	0	5	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	2	3
Protein expression of other key insulin signaling molecules ( IRS-1 , the p85 subunit of PI 3-kinase , and Akt ) was unaltered after either treatment .	Protein expression of other key insulin signaling molecules (IRS-1, the p85 subunit of PI 3-kinase, and Akt) was unaltered after either treatment.	1	19	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	expression of other key insulin	insulin	IRS-1	IRS-1	irs-1	5	6	9	10
This short term insulin stimulation of IRS1 is also observed in human muscle .	This short term insulin stimulation of IRS1 is also observed in human muscle.	3	7	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	3	4	6	7
Presumably , the insulin induced redistribution of IRS-1 to the cytosol accounts for the phosphotyrosine immunoprecipitable PI 3-kinase activity detected in the cytosolic fraction from insulin treated cells , as shown above .	Presumably, the insulin induced redistribution of IRS-1 to the cytosol accounts for the phosphotyrosine immunoprecipitable PI 3-kinase activity detected in the cytosolic fraction from insulin treated cells, as shown above.	2	8	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	3	4	7	8
These results show that insulin can both stimulate and suppress IRS1 pS/pT at specific sites in healthy humans and diabetic patients , suggesting that the activation of both kinases and phosphatases on IRS1 is needed for proper insulin signaling .	These results show that insulin can both stimulate and suppress IRS1 pS/pT at specific sites in healthy humans and diabetic patients, suggesting that the activation of both kinases and phosphatases on IRS1 is needed for proper insulin signaling.	4	11	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	4	5	10	11
Since insulin activates eNOS through IRS1 and Akt pathway , we then investigated whether FABP4 have any effects on insulin stimulated IRS1 and Akt activation , which was monitored by phosphorylation at Tyr 989 and Ser 473 sites , respectively .	Since insulin activates eNOS through IRS1 and Akt pathway, we then investigated whether FABP4 have any effects on insulin stimulated IRS1 and Akt activation, which was monitored by phosphorylation at Tyr 989 and Ser 473 sites, respectively.	17	24	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	19	20	21	22
XREF_BIBR Insulin also activates insulin receptor substrate-1 ( IRS-1 ) , which is involved in cytokine signaling pathways and has been shown to be upregulated in HCC .	XREF_BIBR Insulin also activates insulin receptor substrate-1 (IRS-1), which is involved in cytokine signaling pathways and has been shown to be upregulated in HCC.	0	24	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	1	2	4	7
One possible mechanism suggests that decorin might suppress total IRS-1 levels insofar as that IGF-I and insulin induced IRS-1 downregulation is modulated by serine phosphorylation of IRS-1 residues .	One possible mechanism suggests that decorin might suppress total IRS-1 levels insofar as that IGF-I and insulin induced IRS-1 downregulation is modulated by serine phosphorylation of IRS-1 residues.	7	19	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	16	17	18	19
However , ET-1 treatment had no effect on insulin induced IRS-1 Tyr 612 phosphorylation , suggesting that the ET-1-mediated impairment noted on Akt phosphorylation and glucose transport is independent of PI3-kinase activation .	However, ET-1 treatment had no effect on insulin induced IRS-1 Tyr 612 phosphorylation, suggesting that the ET-1-mediated impairment noted on Akt phosphorylation and glucose transport is independent of PI3-kinase activation.	6	11	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	10	11
In addition , insulin stimulated IRS-1 Ser 312 was 55 % higher in the PCOS patients as compared to controls , even after controlling for the elevation in IRS-1 protein abundance in these subjects XREF_BIBR .	In addition, insulin stimulated IRS-1 Ser 312 was 55% higher in the PCOS patients as compared to controls, even after controlling for the elevation in IRS-1 protein abundance in these subjects XREF_BIBR.	3	6	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	3	4	5	6
Insulin stimulated IRS1 Tyr 612 and Akt Ser 473 phosphorylation was enhanced in BAT from TRB3KO mice compared to wild type mice ( XREF_FIG ) .	Insulin stimulated IRS1 Tyr 612 and Akt Ser 473 phosphorylation was enhanced in BAT from TRB3KO mice compared to wild type mice (XREF_FIG).	0	3	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS1	IRS1	IRS1	0	1	2	3
Although our study showed that AMPK activation enhanced insulin stimulated IRS1 associated PI3k activity and subsequent activation of Akt , this probably occurs through regulation of PI3K .	Although our study showed that AMPK activation enhanced insulin stimulated IRS1 associated PI3k activity and subsequent activation of Akt, this probably occurs through regulation of PI3K.	7	11	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	8	9	10	11
Because physical activity may modify the genetic effects on diabetes [ XREF_BIBR ] and enhance insulin activation of IRS1 associated phosphatidylinositol 3-kinase activity [ XREF_BIBR ] , we further examined the gene-physical activity interactions in relation to the risk of diabetes .	Because physical activity may modify the genetic effects on diabetes [XREF_BIBR] and enhance insulin activation of IRS1 associated phosphatidylinositol 3-kinase activity [XREF_BIBR], we further examined the gene-physical activity interactions in relation to the risk of diabetes.	15	19	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	15	16	18	19
These results indicate that CRL7 is critically involved in insulin triggered IRS1 regulation in skeletal muscle derived cells .	These results indicate that CRL7 is critically involved in insulin triggered IRS1 regulation in skeletal muscle derived cells.	7	12	triggered	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	9	10	11	12
For example , activation of insulin-receptor substrate-1 ( IRS-1 ) and PI3K by insulin , at supraphysiological concentrations that bind the IGF-IR , occurs to a greater extent when mammary epithelial cells are cultured on basement membrane compared with collagen I [ XREF_BIBR ] .	For example, activation of insulin-receptor substrate-1 (IRS-1) and PI3K by insulin, at supraphysiological concentrations that bind the IGF-IR, occurs to a greater extent when mammary epithelial cells are cultured on basement membrane compared with collagen I [XREF_BIBR].	3	14	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin-receptor substrate-1	insulin-receptor substrate-1	insulin-receptor substrate-1	13	14	5	7
The insulin receptors remained intact in the ovary , liver , and muscle in the PITIRKO mice ; therefore , insulin induced IRS1 signaling in these tissues closely resembles that seen in WT mice .	The insulin receptors remained intact in the ovary, liver, and muscle in the PITIRKO mice; therefore, insulin induced IRS1 signaling in these tissues closely resembles that seen in WT mice.	20	23	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	20	21	22	23
These results suggest that chronic treatment with acetoacetate selectively down-regulated the density of cell surface functional IR via lowering IR mRNA levels and IR synthesis , thereby retarding insulin induced activation of IRS-1 .	These results suggest that chronic treatment with acetoacetate selectively down-regulated the density of cell surface functional IR via lowering IR mRNA levels and IR synthesis, thereby retarding insulin induced activation of IRS-1.	28	33	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	28	29	32	33
The phosphorylation levels of insulin stimulated IRS-1 Ser 307 , Akt Ser 473 , and AS160 Thr 642 and the activity of p38 MAPK and SAPK and JNK in ANGII infused rats , when given access to running wheels , were normalized to the levels of the saline infusion group .	The phosphorylation levels of insulin stimulated IRS-1 Ser 307, Akt Ser 473, and AS160 Thr 642 and the activity of p38 MAPK and SAPK and JNK in ANGII infused rats, when given access to running wheels, were normalized to the levels of the saline infusion group.	2	7	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	levels of insulin	insulin	IRS-1	IRS-1	irs-1	4	5	6	7
Likewise , the 4-fold escalation in p-IRS-1 caused by insulin was also diminished by PG ( p < 0.05 ) ( XREF_FIG B ) .	Likewise, the 4-fold escalation in p-IRS-1 caused by insulin was also diminished by PG (p < 0.05) (XREF_FIG B).	4	10	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	p-IRS-1	p-IRS-1	p-IRS-1	9	10	6	7
By contrast , insulin stimulation of Irs1 (-/-) MEFs caused FoxO degradation , not only because Irs2 expression increased but also because Irs2 efficiently activated p110alpha --> Akt cascade .	By contrast, insulin stimulation of Irs1 (-/-) MEFs caused FoxO degradation, not only because Irs2 expression increased but also because Irs2 efficiently activated p110alpha --> Akt cascade.	3	8	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	Irs1	Irs1	Irs1	3	4	6	7
In conclusion , our study indicated that FTZ could decrease serum triglyceride , total cholesterol and fasting blood glucose and increase serum HDL-C , thereby reactivating the insulin stimulated IRS1 and PI3K pathway in insulin resistant HepG2 cells and up-regulating PI3K expression in adipose tissue .	In conclusion, our study indicated that FTZ could decrease serum triglyceride, total cholesterol and fasting blood glucose and increase serum HDL-C, thereby reactivating the insulin stimulated IRS1 and PI3K pathway in insulin resistant HepG2 cells and up-regulating PI3K expression in adipose tissue.	25	32	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	27	28	29	30
Maximal insulin stimulated IRS-1 associated PtdIns 3 '-kinase activit in these cells was 1-, 1.5-, 3-, and 3-fold , while insulin sensitivity , as determined by ED50 , was 1-, 2.5-, 10-, and 10-fold .	Maximal insulin stimulated IRS-1 associated PtdIns 3 '-kinase activit in these cells was 1-, 1.5-, 3-, and 3-fold, while insulin sensitivity, as determined by ED50, was 1-, 2.5-, 10-, and 10-fold.	0	14	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	3	4
In this study , we showed that Irs-2 could compensate for the defects of insulin signaling in Irs-1 deficient mice in insulin target tissues ( i.e ., liver and skeletal muscle ) , where the IRS-2 protein distribution and expression was found to be much higher than in wild type mice .	In this study, we showed that Irs-2 could compensate for the defects of insulin signaling in Irs-1 deficient mice in insulin target tissues (i.e., liver and skeletal muscle), where the IRS-2 protein distribution and expression was found to be much higher than in wild type mice.	14	18	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	Irs-1	Irs-1	Irs-1	14	15	17	18
Supported by the previous study of Moon et al ., it has been demonstrated that type 2 diabetic Otsuka Long-Evans Tokushima fatty ( OLETF ) rats fed with dietary rich MUFAs acquired from olive oil actually reduced hyperglycemia while improving skeletal muscle insulin sensitivity by conserving the insulin signaling IRS-1 and PI3K pathway and the translocation of GLUT4 to the plasma membrane , as compared with an SFAs rich diet [ XREF_BIBR ] .	Supported by the previous study of Moon et al., it has been demonstrated that type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats fed with dietary rich MUFAs acquired from olive oil actually reduced hyperglycemia while improving skeletal muscle insulin sensitivity by conserving the insulin signaling IRS-1 and PI3K pathway and the translocation of GLUT4 to the plasma membrane, as compared with an SFAs rich diet [XREF_BIBR].	45	55	signaling	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	47	48	49	50
In the OHC group , there was up-regulation of both an activator of insulin signaling IRS1 , and an inhibitor of insulin signaling pIRS2 .	In the OHC group, there was up-regulation of both an activator of insulin signaling IRS1, and an inhibitor of insulin signaling pIRS2.	11	16	signaling	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	13	14	15	16
However , the insulin signaling molecules insulin receptor substrate-1 ( IRS-1 ) and Akt were not affected by capsaicin .	However, the insulin signaling molecules insulin receptor substrate-1 (IRS-1) and Akt were not affected by capsaicin.	2	16	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	3	4	6	9
Insulin stimulates glucose uptake by binding to the insulin receptor and activating the IRS-1 , IRS-2 , PI3K , PDK , AKT , and/or PKC-zeta and PKC-lambda signaling pathway ( s ) .	Insulin stimulates glucose uptake by binding to the insulin receptor and activating the IRS-1, IRS-2, PI3K, PDK, AKT, and/or PKC-zeta and PKC-lambda signaling pathway (s).	0	21	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	13	14
Thus , inhibition of the Hsp90 family by GA or HA interrupts homodimerization of monomeric IR precursor in the ER and increases retention of monomeric IR precursor with CNX ; this event retards cell surface expression of IR and attenuates insulin induced activation of IRS-1 .	Thus, inhibition of the Hsp90 family by GA or HA interrupts homodimerization of monomeric IR precursor in the ER and increases retention of monomeric IR precursor with CNX; this event retards cell surface expression of IR and attenuates insulin induced activation of IRS-1.	40	45	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	40	41	44	45
It is important to note that insulin failed to significantly increase p-IRS-1 and IRS-1 ratio in vehicle treated burned mice , whereas p-IRS-1 and IRS-1 ratio was markedly increased by insulin in sham burned mice and FTI-277-treated burned mice ( XREF_FIG ) .	It is important to note that insulin failed to significantly increase p-IRS-1 and IRS-1 ratio in vehicle treated burned mice, whereas p-IRS-1 and IRS-1 ratio was markedly increased by insulin in sham burned mice and FTI-277-treated burned mice (XREF_FIG).	6	14	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	6	7	13	14
Treatment of control rats with BRL37344 led to higher insulin induced tyrosine phosphorylation of the insulin receptors , insulin receptor substrate ( IRS ) -1 and ERK , higher insulin induced IRS-1 and PI3-kinase association , and higher [ Ser ( 473 ) ] phosphorylation of Akt .	Treatment of control rats with BRL37344 led to higher insulin induced tyrosine phosphorylation of the insulin receptors, insulin receptor substrate (IRS) -1 and ERK, higher insulin induced IRS-1 and PI3-kinase association, and higher [Ser (473)] phosphorylation of Akt.	26	34	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	29	30	31	32
In summary , statin treatment improves insulin sensitivity in HFD fed rats by reversing the decrease in the insulin stimulated IRS-1 and phosphatidylinositol 3-kinase/Akt pathway in liver and muscle .	In summary, statin treatment improves insulin sensitivity in HFD fed rats by reversing the decrease in the insulin stimulated IRS-1 and phosphatidylinositol 3-kinase/Akt pathway in liver and muscle.	15	24	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	18	19	20	21
Overexpression of APPL1 DeltaCC had no stimulatory effect on the interaction of insulin stimulated IRS1 with IRbeta and Akt phosphorylation ( XREF_FIG ) , indicating that the binding of APPL1 to IRbeta is essential for the insulin sensitizing effect of APPL1 .	Overexpression of APPL1 DeltaCC had no stimulatory effect on the interaction of insulin stimulated IRS1 with IRbeta and Akt phosphorylation (XREF_FIG), indicating that the binding of APPL1 to IRbeta is essential for the insulin sensitizing effect of APPL1.	10	19	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	12	13	14	15
In the trauma only groups there was little consistent change in insulin induced P-IRS-1 ( Y612 : XREF_FIG ) .	In the trauma only groups there was little consistent change in insulin induced P-IRS-1 (Y612 : XREF_FIG).	9	15	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	P-IRS-1	P-IRS-1	P-IRS-1	11	12	13	14
A significant increase in insulin induced insulin receptor substrate 1 associated PI3K activation was also observed in LPL compared with LP islets .	A significant increase in insulin induced insulin receptor substrate 1 associated PI3K activation was also observed in LPL compared with LP islets.	2	10	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	4	5	6	10
The HSP is also enriched in IRS-1 , insulin stimulated tyrosyl phosphorylated IRS-1 and intracellular GLUT4 containing vesicles .	The HSP is also enriched in IRS-1, insulin stimulated tyrosyl phosphorylated IRS-1 and intracellular GLUT4 containing vesicles.	4	10	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	6	7
Moreover , insulin induced IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase activity are increased in islets of protein deficient rats .	Moreover, insulin induced IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase activity are increased in islets of protein deficient rats.	2	11	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1-	IRS-1-	IRS-1-	2	3	4	5
Insulin stimulated insulin receptor substrate 1 associated phosphatidylinositol 3-kinase and plasma membrane associated GLUT4 transporter were substantially increased with losartan treatment in burn injured animals ( 59 % above sham ) .	Insulin stimulated insulin receptor substrate 1 associated phosphatidylinositol 3-kinase and plasma membrane associated GLUT4 transporter were substantially increased with losartan treatment in burn injured animals (59% above sham).	0	6	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	0	1	2	6
NRVMs were infected with adenovirus expressing the gene encoding GFP , IRS1 , or IRS2 and then treated with insulin for 24 h before acute insulin stimulation for 0.5 h. Western blot analysis indicated that impaired Akt --> Foxo1 phosphorylation after chronic insulin exposure was largely prevented by overexpression of IRS1 or IRS2 ( XREF_FIG ) .	NRVMs were infected with adenovirus expressing the gene encoding GFP, IRS1, or IRS2 and then treated with insulin for 24 h before acute insulin stimulation for 0.5 h. Western blot analysis indicated that impaired Akt --> Foxo1 phosphorylation after chronic insulin exposure was largely prevented by overexpression of IRS1 or IRS2 (XREF_FIG).	8	22	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	19	20	11	12
Both of these abnormalities were associated with defects in insulin activation of insulin receptor substrate-1 and -2-associated phosphatidylinositol 3-kinase activity and a 2-fold increase in muscle and liver triglyceride content .	Both of these abnormalities were associated with defects in insulin activation of insulin receptor substrate-1 and -2-associated phosphatidylinositol 3-kinase activity and a 2-fold increase in muscle and liver triglyceride content.	9	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	9	10	12	15
Peripheral insulin resistance can also raise brain IRS-1 pS by decreasing clearance of brain Abeta because insulin facilitates hepatic clearance of plasma Abeta [ XREF_BIBR ] , interference with which impairs brain clearance of that peptide [ XREF_BIBR ] .	Peripheral insulin resistance can also raise brain IRS-1 pS by decreasing clearance of brain Abeta because insulin facilitates hepatic clearance of plasma Abeta [XREF_BIBR], interference with which impairs brain clearance of that peptide [XREF_BIBR].	1	8	raise	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	7	8
Treatment of high-fat fed mice with vildagliptin , a dipeptidyl peptidase-4 inhibitor ( anti-diabetic drug ) , also restored insulin induced neuronal IR , IRS1 , and Akt activation and long-term depression , improved brain mitochondrial dysfunction , and enhanced cognitive function measured by the Morris water maze test XREF_BIBR .	Treatment of high-fat fed mice with vildagliptin, a dipeptidyl peptidase-4 inhibitor (anti-diabetic drug), also restored insulin induced neuronal IR, IRS1, and Akt activation and long-term depression, improved brain mitochondrial dysfunction, and enhanced cognitive function measured by the Morris water maze test XREF_BIBR.	19	39	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	19	20	24	25
HFD reduced insulin stimulated IRS1 associated phosphatidylinositol 3 '-kinase activity and phosphorylation of protein kinase B , glycogen synthase kinase-3beta , endothelial nitric oxide synthase , and forkhead transcription factors by 40-60 % ( all p < 0.05 ) .	HFD reduced insulin stimulated IRS1 associated phosphatidylinositol 3 '-kinase activity and phosphorylation of protein kinase B, glycogen synthase kinase-3beta, endothelial nitric oxide synthase, and forkhead transcription factors by 40-60% (all p < 0.05).	1	5	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	2	3	4	5
( 4 ) Protein expression and TP with insulin stimulation of IRS-1 was negatively related to HOMA-IR in GDM group ( r =- 0.613 , -0.632 ; P < 0.01 ) , and TP with insulin stimulation was negatively related to HOMA-IR in normal pregnancy group ( r = -0.526 , P < 0.05 ) .	(4) Protein expression and TP with insulin stimulation of IRS-1 was negatively related to HOMA-IR in GDM group (r =- 0.613, -0.632; P < 0.01), and TP with insulin stimulation was negatively related to HOMA-IR in normal pregnancy group (r = -0.526, P < 0.05).	8	12	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	8	9	11	12
TNF-alpha results in insulin insensitivity , indirectly by stimulating stress hormone production and directly by sustained induction of SOCS-3 which decreases insulin induced insulin receptor substrate 1 ( IRS1 ) tyrosine phosphorylation and its association with the p85 , regulatory subunit of phosphatidylinositol-3 kinase ; and by negative regulation of PPAR gamma .	TNF-alpha results in insulin insensitivity, indirectly by stimulating stress hormone production and directly by sustained induction of SOCS-3 which decreases insulin induced insulin receptor substrate 1 (IRS1) tyrosine phosphorylation and its association with the p85, regulatory subunit of phosphatidylinositol-3 kinase; and by negative regulation of PPAR gamma.	20	28	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	21	22	23	27
Insulin activates the insulin receptor substrate-1 ( IRS-1 ) , and IRS-1-mediated signals may act as survival factors and protect against TGF-beta-induced apoptosis in HCC cell lines .	Insulin activates the insulin receptor substrate-1 (IRS-1), and IRS-1-mediated signals may act as survival factors and protect against TGF-beta-induced apoptosis in HCC cell lines.	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	0	1	3	6
Upon binding to the cell surface receptor , insulin activates its receptor tyrosine kinase , which phosphorylates and recruits insulin receptor ( IR ) substrates ( IRS ) 1 to 4 ( IRS1 , IRS4 ) , and other scaffold proteins , including SHC , CBL , APS , SH2B , GAB1 , and DOCK1 , that trigger downstream signaling cascades , including phosphatidylinositide 3-kinase ( PI-3K ) and mitogen activated protein kinases ( MAPKs ) .	Upon binding to the cell surface receptor, insulin activates its receptor tyrosine kinase, which phosphorylates and recruits insulin receptor (IR) substrates (IRS) 1 to 4 (IRS1, IRS4), and other scaffold proteins, including SHC, CBL, APS, SH2B, GAB1, and DOCK1, that trigger downstream signaling cascades, including phosphatidylinositide 3-kinase (PI-3K) and mitogen activated protein kinases (MAPKs).	8	34	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	8	9	32	33
After binding with its receptor , insulin activates IRS-1 through tyrosine phosphorylation , which initiates the association with the Gialpha-subunit .	After binding with its receptor, insulin activates IRS-1 through tyrosine phosphorylation, which initiates the association with the Gialpha-subunit.	6	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	6	7	8	9
It was recently shown that deletion of insulin receptors from podocytes decreased IRS1 associated PI3K activity which was followed by podocyte apoptosis and glomerulosclerosis [ XREF_BIBR ] .	It was recently shown that deletion of insulin receptors from podocytes decreased IRS1 associated PI3K activity which was followed by podocyte apoptosis and glomerulosclerosis [XREF_BIBR].	7	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	7	8	12	13
Although we have shown that the Csk Src homology 2 domain can bind to several tyrosine phosphorylated proteins , including pp125FAK and paxillin , a majority of protein which bound to Csk was IRS-1 when cells were stimulated by insulin .	Although we have shown that the Csk Src homology 2 domain can bind to several tyrosine phosphorylated proteins, including pp125FAK and paxillin, a majority of protein which bound to Csk was IRS-1 when cells were stimulated by insulin.	3	40	stimulated	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	39	40	33	34
As shown in XREF_FIG A , both insulin induced IRS1 associated PI 3-kinase activity and Akt and Foxo1 phosphorylation were significantly increased in resveratrol treated IRS2 -/- mice compared with untreated IRS2 deficient mice .	As shown in XREF_FIG A, both insulin induced IRS1 associated PI 3-kinase activity and Akt and Foxo1 phosphorylation were significantly increased in resveratrol treated IRS2 -/- mice compared with untreated IRS2 deficient mice.	4	10	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	7	8	9	10
Coincubation with the mTOR inhibitor , rapamycin , effectively inhibited the proteosomal degradation of IRS-1 caused by the chronic insulin treatment .	Coincubation with the mTOR inhibitor, rapamycin, effectively inhibited the proteosomal degradation of IRS-1 caused by the chronic insulin treatment.	12	20	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	19	20	14	15
In addition , insulin induced IRS-1 , Ser ( 307 ) , and Ser ( 636/639 ) phosphorylations were significantly suppressed in the raptor-DeltaC ( T )-overexpressing liver , whereas tyrosine phosphorylation of IRS-1 was increased .	In addition, insulin induced IRS-1, Ser (307), and Ser (636/639) phosphorylations were significantly suppressed in the raptor-DeltaC (T)-overexpressing liver, whereas tyrosine phosphorylation of IRS-1 was increased.	3	9	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	3	4	5	6
Insulin stimulated IRS-1 and IRS-2 signaling occurs mainly in the IM and shows different kinetics ; IRS-1-mediated signaling is more stable , whereas IRS-2-mediated signaling is more transient .	Insulin stimulated IRS-1 and IRS-2 signaling occurs mainly in the IM and shows different kinetics; IRS-1-mediated signaling is more stable, whereas IRS-2-mediated signaling is more transient.	0	5	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	2	3
In contrast , far greater reductions in insulin responsiveness are seen below the IR in the AD brain , as noted previously , beginning with IRS-1 , which is activated by insulin at only 10 % of normal levels in the HF [ XREF_BIBR ] .	In contrast, far greater reductions in insulin responsiveness are seen below the IR in the AD brain, as noted previously, beginning with IRS-1, which is activated by insulin at only 10% of normal levels in the HF [XREF_BIBR].	20	32	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	31	32	25	26
Activation of this pathway occurs due to the ability of insulin stimulated IRS1 to bind the GRB2 ( Grb2 ) protein in proliferating cells .	Activation of this pathway occurs due to the ability of insulin stimulated IRS1 to bind the GRB2 (Grb2) protein in proliferating cells.	8	13	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	10	11	12	13
In liver , insulin increased the activation of IR , IRS-1 , PI 3-kinase , PKB and S6 , but had no effect on protein synthesis .	In liver, insulin increased the activation of IR, IRS-1, PI 3-kinase, PKB and S6, but had no effect on protein synthesis.	3	20	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	3	4	10	11
Treatment of diabetic ( db/db ) mice with LG268 ( selective RXR ligand ) significantly increased insulin stimulated glucose transport in skeletal muscle , via increasing insulin stimulated insulin receptor substrate 1 ( IRS1 ) tyrosine phosphorylation and AKT phosphorylation [ XREF_BIBR ] .	Treatment of diabetic (db/db) mice with LG268 (selective RXR ligand) significantly increased insulin stimulated glucose transport in skeletal muscle, via increasing insulin stimulated insulin receptor substrate 1 (IRS1) tyrosine phosphorylation and AKT phosphorylation [XREF_BIBR].	16	33	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	16	17	28	32
In advanced stages , e.g ., in hepatocytes of type 2 diabetes ( T2D ) humans , insulin activation of insulin receptor substrate-1 ( IRS-1 ) and Akt fails , further increasing FoxO1 dependent gluconeogenic and lipogenic enzyme expression .	In advanced stages, e.g., in hepatocytes of type 2 diabetes (T2D) humans, insulin activation of insulin receptor substrate-1 (IRS-1) and Akt fails, further increasing FoxO1 dependent gluconeogenic and lipogenic enzyme expression.	17	23	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	17	18	20	23
MGO prevented the insulin dependent activation of the IRS1 and protein kinase Akt and endothelial nitric oxide synthase ( eNOS ) pathway , thereby blunting nitric oxide ( NO ) production , while extracellular signal regulated kinase ( ERK1/2 ) activation and endothelin-1 ( ET-1 ) release were increased by MGO in MAECs .	MGO prevented the insulin dependent activation of the IRS1 and protein kinase Akt and endothelial nitric oxide synthase (eNOS) pathway, thereby blunting nitric oxide (NO) production, while extracellular signal regulated kinase (ERK1/2) activation and endothelin-1 (ET-1) release were increased by MGO in MAECs.	3	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	3	4	8	9
We show that insulin activates IRS-1 , Akt and PKB , and is only a mild activator of the ERK signaling cascade .	We show that insulin activates IRS-1, Akt and PKB, and is only a mild activator of the ERK signaling cascade.	3	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	3	4	5	6
Again , pretreatment with PMA and ionomycin completely blocked insulin stimulated membrane localization of endogenous IRS1 protein ( XREF_SUPPLEMENTARY ) , indicating that intracellular Ca 2+ overload prevents membrane translocation of various PH domains by a common mechanism , potentially inhibiting interactions with PIPs .	Again, pretreatment with PMA and ionomycin completely blocked insulin stimulated membrane localization of endogenous IRS1 protein (XREF_SUPPLEMENTARY), indicating that intracellular Ca 2+ overload prevents membrane translocation of various PH domains by a common mechanism, potentially inhibiting interactions with PIPs.	8	16	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	9	10	15	16
Here we show that in COS-7 cells SOCS-3 decreases insulin induced insulin receptor substrate 1 ( IRS-1 ) tyrosine phosphorylation and its association with p85 , a regulatory subunit of phosphatidylinositol-3 kinase .	Here we show that in COS-7 cells SOCS-3 decreases insulin induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with p85, a regulatory subunit of phosphatidylinositol-3 kinase.	8	16	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	9	10	11	15
Insulin stimulated IRS-1 serine 632/635 phosphorylation and PI3K activity associated with IRS-1 or phosphotyrosine are impaired in skeletal muscle of ROCK1 deficient mice [ XREF_BIBR ] .	Insulin stimulated IRS-1 serine 632/635 phosphorylation and PI3K activity associated with IRS-1 or phosphotyrosine are impaired in skeletal muscle of ROCK1 deficient mice [XREF_BIBR].	0	3	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	2	3
In both muscles , the increase of insulin elicited IRS-1 , Akt and ERK1/2 activation was observed along with an elevation in the IRS-1 expression level in MG53 -/- mice , compared with MG53 +/+ mice ( XREF_FIG ) .	In both muscles, the increase of insulin elicited IRS-1, Akt and ERK1/2 activation was observed along with an elevation in the IRS-1 expression level in MG53 -/- mice, compared with MG53 +/+ mice (XREF_FIG).	5	14	elicited	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	9	10
No changes in the basal level or insulin stimulated levels of pIRS1 and total IRS1 ratio were observed ( data not shown ) .	No changes in the basal level or insulin stimulated levels of pIRS1 and total IRS1 ratio were observed (data not shown).	1	15	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	7	8	14	15
The insulin mediated interaction of IRS-1 with Grb2 was observed in PC12 but not in SK-N-BE ( 2 ) cells .	The insulin mediated interaction of IRS-1 with Grb2 was observed in PC12 but not in SK-N-BE (2) cells.	0	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	5	6
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR LBW infants are known to have adipocytes that demonstrate increased numbers of insulin receptors , glucose uptake , and basal and insulin stimulated insulin-receptor substrate 1 ( IRS-1 )-associated phosphatidylinositiol 3-kinase ( PI3K ) .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR LBW infants are known to have adipocytes that demonstrate increased numbers of insulin receptors, glucose uptake, and basal and insulin stimulated insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositiol 3-kinase (PI3K).	17	33	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin-receptor substrate 1	insulin-receptor substrate 1	insulin-receptor substrate 1	28	29	30	33
The results demonstrated that insulin induced IRS-1/PI 3-kinase association has a close correlation with IRS-1 tyrosine phosphorylation levels , but insulin induced IRS-1 and SHP2 association showed a modulation that did not parallel IRS-1 phosphorylation , with a tissue specific regulation in aging .	The results demonstrated that insulin induced IRS-1/PI 3-kinase association has a close correlation with IRS-1 tyrosine phosphorylation levels, but insulin induced IRS-1 and SHP2 association showed a modulation that did not parallel IRS-1 phosphorylation, with a tissue specific regulation in aging.	20	25	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	20	21	22	23
Expression of S6K-ED 3 E permitted the insulin sensitive stimulation of IRS-1 : S636/639 phosphorylation but abolished the TBC1D3 inhibitory effect .	Expression of S6K-ED 3 E permitted the insulin sensitive stimulation of IRS-1 : S636/639 phosphorylation but abolished the TBC1D3 inhibitory effect.	7	12	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	11	12
We have shown previously that liver specific deficiency of PTP1B enhanced insulin stimulated IRS1- and IRS2- associated p85alpha protein , without changes in p85alpha expression levels [ XREF_BIBR ] .	We have shown previously that liver specific deficiency of PTP1B enhanced insulin stimulated IRS1- and IRS2- associated p85alpha protein, without changes in p85alpha expression levels [XREF_BIBR].	10	16	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1-	IRS1-	IRS1-	11	12	13	14
These data suggested that insulin stimulates IRS-1 .	These data suggested that insulin stimulates IRS-1.	4	7	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	4	5	6	7
In contrast , the hepatic insulin signaling in the Irs1 -/- mice fed the HF diet was impaired , since Irs1 was absent and Irs2 signaling was suppressed by the hyperinsulinemia induced by the HF diet .	In contrast, the hepatic insulin signaling in the Irs1 -/- mice fed the HF diet was impaired, since Irs1 was absent and Irs2 signaling was suppressed by the hyperinsulinemia induced by the HF diet.	5	11	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	Irs1	Irs1	Irs1	5	6	9	10
The genetic variant causes reduced basal levels of IRS1 protein and decreased insulin induction of IRS1 associated phosphatidylinositol-3-hydroxykinase activity in human skeletal muscle biopsies [ XREF_BIBR ] .	The genetic variant causes reduced basal levels of IRS1 protein and decreased insulin induction of IRS1 associated phosphatidylinositol-3-hydroxykinase activity in human skeletal muscle biopsies [XREF_BIBR].	12	16	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	12	13	15	16
Insulin stimulation of IRS-1 immunoprecipitable phosphatidylinositol 3-kinase ( PI 3-kinase ) activity also was markedly lower in obese subjects compared with controls ( 10- vs 35-fold above basal , respectively ) .	Insulin stimulation of IRS-1 immunoprecipitable phosphatidylinositol 3-kinase (PI 3-kinase) activity also was markedly lower in obese subjects compared with controls (10- vs 35-fold above basal, respectively).	0	4	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	3	4
The same appears to be true in AD brains , where insulin induced IRS-1 activation is consistently reduced in tissues with significantly elevated levels of IRS-1 pS616 and IRS-1 pS636 , which are thus potential biomarkers of brain insulin resistance [ XREF_BIBR ] .	The same appears to be true in AD brains, where insulin induced IRS-1 activation is consistently reduced in tissues with significantly elevated levels of IRS-1 pS616 and IRS-1 pS636, which are thus potential biomarkers of brain insulin resistance [XREF_BIBR].	11	14	induced	Positive_early_activation	Negative_activation	Negative_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	11	12	13	14
Insulin signaling is initiated by the binding of insulin to the insulin receptor to activate IRS-1 , which subsequently activates PI3K ; the activation of PI3K results in the recruitment of GLUT4 to the cell surface [ XREF_BIBR ] .	Insulin signaling is initiated by the binding of insulin to the insulin receptor to activate IRS-1, which subsequently activates PI3K; the activation of PI3K results in the recruitment of GLUT4 to the cell surface [XREF_BIBR].	0	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	15	16
Enhanced increases in contraction stimulated AMPK Thr ( 172 ) phosphorylation and insulin stimulated IRS1 Ser ( 636/639 ) phosphorylation might be responsible for these opposing effects of leucine , respectively .	Enhanced increases in contraction stimulated AMPK Thr (172) phosphorylation and insulin stimulated IRS1 Ser (636/639) phosphorylation might be responsible for these opposing effects of leucine, respectively.	6	15	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	12	13	14	15
Other genes related with the adipose tissue are adiponectin , an insulin sensitizing protein that also promotes fatty acid oxidation , insulin receptor and insulin receptor substrate 1 ( IRS-1 ) , key proteins from the insulin signalling pathway , and cannabinoid receptor 1 ( CB1R ) and osteocalcin , which are related with energy metabolism .	Other genes related with the adipose tissue are adiponectin, an insulin sensitizing protein that also promotes fatty acid oxidation, insulin receptor and insulin receptor substrate 1 (IRS-1), key proteins from the insulin signalling pathway, and cannabinoid receptor 1 (CB1R) and osteocalcin, which are related with energy metabolism.	11	29	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate 1	insulin receptor substrate 1	insulin receptor substrate 1	11	12	24	28
Similar to previous findings in virus untreated GK-diabetic rats , insulin activation of aPKC ( XREF_FIG ) and IRS-1 and PI3K ( XREF_FIG ) , but not PKB ( XREF_FIG ) , was markedly impaired in muscles of adenoviral vector treated GK-diabetic rats .	Similar to previous findings in virus untreated GK-diabetic rats, insulin activation of aPKC (XREF_FIG) and IRS-1 and PI3K (XREF_FIG), but not PKB (XREF_FIG), was markedly impaired in muscles of adenoviral vector treated GK-diabetic rats.	10	20	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	10	11	18	19
Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function .	Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function.	6	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	6	7	8	9
Oxidative stress disrupts the insulin stimulated cellular redistribution of IRS1 and phosphoinositide 3-kinase required for efficient transduction of insulin signaling , GLUT4 translocation and glucose uptake [ XREF_BIBR ] .	Oxidative stress disrupts the insulin stimulated cellular redistribution of IRS1 and phosphoinositide 3-kinase required for efficient transduction of insulin signaling, GLUT4 translocation and glucose uptake [XREF_BIBR].	2	12	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	4	5	9	10
In the methionine- and choline deficient diet mouse model of steatohepatitis with CYP2E1 overexpression , insulin induced IRS-1 , IRS-2 , and Akt phosphorylation were similarly decreased .	In the methionine- and choline deficient diet mouse model of steatohepatitis with CYP2E1 overexpression, insulin induced IRS-1, IRS-2, and Akt phosphorylation were similarly decreased.	15	22	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	15	16	17	18
In contrast , phosphorylation at ser 302 may promote increased activation of IRS-1 by insulin in vitro .	In contrast, phosphorylation at ser 302 may promote increased activation of IRS-1 by insulin in vitro.	10	15	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	14	15	12	13
No significant difference was observed in relative p-IRS1 ( S612 ) levels , but interestingly hsf1 -/- mice exhibited a reduced basal and insulin stimulated ratio of p-IRS1 ( S636 and S639 )/total IRS1 compared to WT controls .	No significant difference was observed in relative p-IRS1 (S612) levels, but interestingly hsf1 -/- mice exhibited a reduced basal and insulin stimulated ratio of p-IRS1 (S636 and S639)/total IRS1 compared to WT controls.	23	28	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	p-IRS1	p-IRS1	p-IRS1	23	24	27	28
Interestingly , the JM domain separates insulin stimulated ROS metabolism , and insulin stimulated IRS-1 and IRS-2 activation .	Interestingly, the JM domain separates insulin stimulated ROS metabolism, and insulin stimulated IRS-1 and IRS-2 activation.	12	17	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	12	13	14	15
Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay .	Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay.	0	12	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	10	11	1	2
There were no differences in basal IRS-1 p and Akt 1 p as well as insulin stimulated IRS-1 p , Akt 1 p and Akt 2 p between LFD and BM groups except basal Akt 2 p content was significantly higher in BM than in LFD mice .	There were no differences in basal IRS-1 p and Akt 1 p as well as insulin stimulated IRS-1 p, Akt 1 p and Akt 2 p between LFD and BM groups except basal Akt 2 p content was significantly higher in BM than in LFD mice.	1	18	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	15	16	17	18
In the L-p110alpha KO mice , insulin stimulated IRS1 associated PI kinase activity was markedly blunted 7 .	In the L-p110alpha KO mice, insulin stimulated IRS1 associated PI kinase activity was markedly blunted 7.	6	15	stimulated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	6	7	8	9
Under insulin stimulated conditions , IRS-1 Ser 307 phosphorylation , expressed relative to total IRS-1 protein , was increased by 38 % and 64 % ( both p < 0.05 ) after 2-hr or 4-hr exposure to the oxidant stress , respectively ( XREF_FIG ) .	Under insulin stimulated conditions, IRS-1 Ser 307 phosphorylation, expressed relative to total IRS-1 protein, was increased by 38% and 64% (both p < 0.05) after 2-hr or 4-hr exposure to the oxidant stress, respectively (XREF_FIG).	0	18	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	1	2	5	6
Overexpression of beta 2 AR increases GRK2 expression that is associated with significant deficit of IRS1 activation and glucose uptake by insulin .	Overexpression of beta 2 AR increases GRK2 expression that is associated with significant deficit of IRS1 activation and glucose uptake by insulin.	15	22	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	21	22	15	16
Cells pre-exposed for 16 hours to low T concentrations ( 20 ng/mL ) had a significantly greater insulin induced IRS-1 Ser 636/639 phosphorylation compared to non T exposed ( control ) cells ( p = 0.042 , XREF_FIG ) following 30 minutes of exposure to 100 nM of insulin .	Cells pre-exposed for 16 hours to low T concentrations (20 ng/mL) had a significantly greater insulin induced IRS-1 Ser 636/639 phosphorylation compared to non T exposed (control) cells (p = 0.042, XREF_FIG) following 30 minutes of exposure to 100 nM of insulin.	13	20	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	17	18	19	20
Based on published evidence that during high-fat feeding in mice , reduced NO content in thoracic aorta precedes the onset of both hepatic inflammation ( increased NF-kappaB signaling ) and hepatic insulin resistance ( reduced insulin stimulated activation of IRS-1 / phosphatidylinositol 3-kinase/Akt ) , we first asked whether liver NO content declines prior to the onset of increased NF-kappaB signaling and Kupffer cell activation in this setting .	Based on published evidence that during high-fat feeding in mice, reduced NO content in thoracic aorta precedes the onset of both hepatic inflammation (increased NF-kappaB signaling) and hepatic insulin resistance (reduced insulin stimulated activation of IRS-1 / phosphatidylinositol 3-kinase/Akt), we first asked whether liver NO content declines prior to the onset of increased NF-kappaB signaling and Kupffer cell activation in this setting.	34	42	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	35	36	39	40
Glucose transportation is the speed limiting step of glucose metabolism and can be activated in the peripheral tissue by two different ways : ( 1 ) IRS-1 and PI3K signal transduction stimulated by insulin ; ( 2 ) activation of muscle contraction through AMPK [ XREF_BIBR ] .	Glucose transportation is the speed limiting step of glucose metabolism and can be activated in the peripheral tissue by two different ways : (1) IRS-1 and PI3K signal transduction stimulated by insulin; (2) activation of muscle contraction through AMPK [XREF_BIBR].	26	34	stimulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	33	34	26	27
Insulin stimulation of insulin receptors , IRS-1 , and PI3-K activation is clearly reduced in nonpancreatic cells carrying the Q121 variant .	Insulin stimulation of insulin receptors, IRS-1, and PI3-K activation is clearly reduced in nonpancreatic cells carrying the Q121 variant.	0	7	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	IRS-1	IRS-1	IRS-1	0	1	6	7
However , even in the absence of AA , insulin can still promote IRS-1 Ser 1101 phosphorylation by other kinases that remain to be fully characterized .	However, even in the absence of AA, insulin can still promote IRS-1 Ser 1101 phosphorylation by other kinases that remain to be fully characterized.	9	14	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	9	10	13	14
In vivo insulin infusion increased skeletal muscle insulin receptor substrate-1 ( IRS-1 ) tyrosine phosphorylation ( P = 0.01 ) and phosphatidylinositide 3-kinase ( PI 3-kinase ) activity ( phosphotyrosine and IRS-1 associated ) in control subjects ( P < 0.02 ) but not in IGT relatives ( NS ) .	In vivo insulin infusion increased skeletal muscle insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (P = 0.01) and phosphatidylinositide 3-kinase (PI 3-kinase) activity (phosphotyrosine and IRS-1 associated) in control subjects (P < 0.02) but not in IGT relatives (NS).	0	32	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	2	3	31	32
In contrast , imatinib did not inhibit insulin induced IRS-1 association with p85alpha or IRS-1-associated PI 3-kinase activity at any of the concentrations used in this study ( XREF_FIG ) .	In contrast, imatinib did not inhibit insulin induced IRS-1 association with p85alpha or IRS-1-associated PI 3-kinase activity at any of the concentrations used in this study (XREF_FIG).	6	10	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	7	8	9	10
Similarly , insulin stimulated association of IRS-1 and the P85 subunit of PI3K was enhanced in Ephx2-null and inhibitor treated mice resulting in increased phosphorylation of Ser473 and mitogen activated protein kinase ( MAPK ) .	Similarly, insulin stimulated association of IRS-1 and the P85 subunit of PI3K was enhanced in Ephx2-null and inhibitor treated mice resulting in increased phosphorylation of Ser473 and mitogen activated protein kinase (MAPK).	2	7	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS-1	IRS-1	IRS-1	2	3	6	7
Although high concentrations of insulin and HG individually lead to the degradation of IRS1 , insulin at low concentrations , for short periods of time , seems to inhibit HG induced degradation of IRS1 .	Although high concentrations of insulin and HG individually lead to the degradation of IRS1, insulin at low concentrations, for short periods of time, seems to inhibit HG induced degradation of IRS1.	15	34	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	IRS1	IRS1	IRS1	15	16	33	34
The increase in long-chain acyl-CoA , diacylglycerol , and lipid oxidation products will promote induction of insulin resistance though atypical protein kinase C activation and decreases insulin stimulated activity of insulin receptor substrate-1 associated phosphatidylinositol-3-kinase and subsequently reduce glucose uptake and storage .	The increase in long-chain acyl-CoA, diacylglycerol, and lipid oxidation products will promote induction of insulin resistance though atypical protein kinase C activation and decreases insulin stimulated activity of insulin receptor substrate-1 associated phosphatidylinositol-3-kinase and subsequently reduce glucose uptake and storage.	25	33	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	26	27	30	33
To elucidate the molecular mechanism of inactivation of insulin induced FOXO1 by the antioxidant betaine , we used HepG2 cells and the liver of db/db mice treated with betaine at a dose of 50 mg/kg/day for 3 weeks .	To elucidate the molecular mechanism of inactivation of insulin induced FOXO1 by the antioxidant betaine, we used HepG2 cells and the liver of db/db mice treated with betaine at a dose of 50 mg/kg/day for 3 weeks.	6	11	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	8	9	10	11
Insulin was able to antagonize the effect of BITC , since incubation with BITC in combination with insulin induced FOXO1 accumulation .	Insulin was able to antagonize the effect of BITC, since incubation with BITC in combination with insulin induced FOXO1 accumulation.	15	20	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	17	18	19	20
Recently , it has been shown that impaired cardiac insulin signaling FoxO1 mediated stimulates the beta-myosin heavy chain ( beta-MHC ) expression promoting cardiac dysfunction .	Recently, it has been shown that impaired cardiac insulin signaling FoxO1 mediated stimulates the beta-myosin heavy chain (beta-MHC) expression promoting cardiac dysfunction.	8	12	signaling	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	9	10	11	12
Our results reveal a complex network of genetic changes by which hepatic insulin resistance activates Foxo1 and dysregulates mitochondrial biogenesis and function .	Our results reveal a complex network of genetic changes by which hepatic insulin resistance activates Foxo1 and dysregulates mitochondrial biogenesis and function.	12	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	12	13	15	16
Leptin action was not altered in young Lepr DeltaIrs2 -mice , although insulin stimulated FoxO1 nuclear exclusion was reduced in Lepr DeltaIrs2 -mice .	Leptin action was not altered in young Lepr DeltaIrs2 -mice, although insulin stimulated FoxO1 nuclear exclusion was reduced in Lepr DeltaIrs2 -mice.	12	18	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	12	13	14	15
It was intriguing to find that insulin promoted FoxO1 nuclear exit and degradation ( XREF_FIG ) while FoxO1 potentiated myogenesis upon insulin treatment ( XREF_FIG ) .	It was intriguing to find that insulin promoted FoxO1 nuclear exit and degradation (XREF_FIG) while FoxO1 potentiated myogenesis upon insulin treatment (XREF_FIG).	6	10	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	6	7	8	9
For example , ChIP assays demonstrate that insulin stimulates the dissociation of FOXO1 from the G6Pase promoter [ XREF_BIBR , XREF_BIBR ] and global [ XREF_BIBR ] or liver specific [ XREF_BIBR ] disruption of the FOXO1 gene impairs the induction of G6Pase gene expression by fasting .	For example, ChIP assays demonstrate that insulin stimulates the dissociation of FOXO1 from the G6Pase promoter [XREF_BIBR, XREF_BIBR] and global [XREF_BIBR] or liver specific [XREF_BIBR] disruption of the FOXO1 gene impairs the induction of G6Pase gene expression by fasting.	7	13	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	7	8	12	13
We next performed MK-2206 dose response analyses of insulin induced FoxO1 regulation in our cell lines .	We next performed MK-2206 dose response analyses of insulin induced FoxO1 regulation in our cell lines.	6	11	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	8	9	10	11
Indeed , it has been shown that insulin induced FOXO1 is a master protein that turns on the expression of another key inflammatory cytokine , IL-1beta that also inhibits insulin signaling .	Indeed, it has been shown that insulin induced FOXO1 is a master protein that turns on the expression of another key inflammatory cytokine, IL-1beta that also inhibits insulin signaling.	7	13	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	7	8	9	10
Similar findings for insulin mediated shuttling of FoxO1 recently have been shown in MIN6 cells .	Similar findings for insulin mediated shuttling of FoxO1 recently have been shown in MIN6 cells.	1	8	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	3	4	7	8
Therefore , the insulin stimulated rescue of FoxO1 induced transrepression of PPARg might have been down-regulated in the adipocytes of the EG .	Therefore, the insulin stimulated rescue of FoxO1 induced transrepression of PPARg might have been down-regulated in the adipocytes of the EG.	2	8	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	3	4	7	8
Short-term LPS treatment did not change FoxO1 expression and distribution in the GT1-7 cells , nor insulin induced FoxO1 translocation from the nucleus to the cytoplasm .	Short-term LPS treatment did not change FoxO1 expression and distribution in the GT1-7 cells, nor insulin induced FoxO1 translocation from the nucleus to the cytoplasm.	16	19	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	16	17	18	19
They demonstrate that MTP is a target of the transcription factor FoxO1 and that excessive VLDL production associated with insulin resistance is caused by the inability of insulin to regulate FoxO1 transcriptional activation of MTP .	They demonstrate that MTP is a target of the transcription factor FoxO1 and that excessive VLDL production associated with insulin resistance is caused by the inability of insulin to regulate FoxO1 transcriptional activation of MTP.	22	32	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	27	28	30	31
Enhanced FoxO1 action parallels insulin resistance , which increases FoxO1 nuclear localization through reduced Akt phosphorylation of FoxO1 .	Enhanced FoxO1 action parallels insulin resistance, which increases FoxO1 nuclear localization through reduced Akt phosphorylation of FoxO1.	4	11	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	4	5	9	10
FOXO1 nuclear exclusion elicited by insulin or xenobiotics such as arsenite or copper ions was attenuated by DEM , suggesting that DEM interfered with nuclear export .	FOXO1 nuclear exclusion elicited by insulin or xenobiotics such as arsenite or copper ions was attenuated by DEM, suggesting that DEM interfered with nuclear export.	0	13	elicited	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	5	6	0	1
MK-2206 treatment inhibited insulin mediated FoxO1 nuclear exclusion in a dose dependent manner in cells expressing Akt1 WT or Akt2 WT .	MK-2206 treatment inhibited insulin mediated FoxO1 nuclear exclusion in a dose dependent manner in cells expressing Akt1 WT or Akt2 WT.	2	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	3	4	5	6
For instance , insulin activated PI3k ( phosphoinositide 3-kinase )-Akt pathway phosphorylates FoxO1 on T24 , S256 and S319 residues and this modification renders FoxO1 to be shuttled out of nucleus [ XREF_BIBR , XREF_BIBR ] .	For instance, insulin activated PI3k (phosphoinositide 3-kinase)-Akt pathway phosphorylates FoxO1 on T24, S256 and S319 residues and this modification renders FoxO1 to be shuttled out of nucleus [XREF_BIBR, XREF_BIBR].	3	19	activated	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	insulin	insulin	insulin	FoxO1	PI3k (phosphoinositide 3-kinase)-Akt pathway phosphorylates FoxO1 on T24, S256 and S319	foxo1	3	4	12	13
XREF_BIBR investigated the mechanism for this difference in the BA pool and found that in mice with normal physiology , insulin signaling activating FoxO1 maintains the production of 12 hydroxylated BAs by up-regulation of Cyp8b1 and normal FXR activity .	XREF_BIBR investigated the mechanism for this difference in the BA pool and found that in mice with normal physiology, insulin signaling activating FoxO1 maintains the production of 12 hydroxylated BAs by up-regulation of Cyp8b1 and normal FXR activity.	20	24	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	20	21	23	24
Overall , the results of this study indicate , that there are at least two main targets in insulin mediated myogenesis : notably transcriptional factor FOXO1 and GSK-3beta .	Overall, the results of this study indicate, that there are at least two main targets in insulin mediated myogenesis : notably transcriptional factor FOXO1 and GSK-3beta.	16	27	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	18	19	25	26
DEM induced nuclear accumulation overrode insulin induced nuclear exclusion of FoxO1a .	DEM induced nuclear accumulation overrode insulin induced nuclear exclusion of FoxO1a.	4	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1a	FoxO1a	FoxO1a	5	6	10	11
Both insulin signaling and glucose sensation can modulate the activity of the Foxo1 , a transcription factor that regulates the expression of beta cell characteristics .	Both insulin signaling and glucose sensation can modulate the activity of the Foxo1, a transcription factor that regulates the expression of beta cell characteristics.	1	16	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	Foxo1	Foxo1	Foxo1	1	2	12	13
In alphaXBPKD cells , nuclear FoxO1 was already decreased compared with control cells in the basal state , and insulin stimulation did not promote further exclusion of FoxO1 from the nucleus ( XREF_FIG ) .	In alphaXBPKD cells, nuclear FoxO1 was already decreased compared with control cells in the basal state, and insulin stimulation did not promote further exclusion of FoxO1 from the nucleus (XREF_FIG).	19	28	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	19	20	27	28
New studies investigating actions of the insulin targeted transcription factor FoxO1 may provide new insights for underlying mechanisms of advanced diabetic cardiomyopathy .	New studies investigating actions of the insulin targeted transcription factor FoxO1 may provide new insights for underlying mechanisms of advanced diabetic cardiomyopathy.	3	11	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	6	7	10	11
Through a serine/threonine protein kinase- ( AKT/PKB-) mediated phosphorylation , insulin causes nuclear exclusion of forkhead transcription factor 1 ( FOXO1 ) [ XREF_BIBR ] and forkhead transcription factor 2 ( FOXA2 ) that are both antiadipogenic transcription factors .	Through a serine/threonine protein kinase- (AKT/PKB-) mediated phosphorylation, insulin causes nuclear exclusion of forkhead transcription factor 1 (FOXO1) [XREF_BIBR] and forkhead transcription factor 2 (FOXA2) that are both antiadipogenic transcription factors.	10	31	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	10	11	20	21
Indeed , by activating Akt signaling cascade insulin mediates both mitochondrial fusion and FoxO1 nuclear exclusion .	Indeed, by activating Akt signaling cascade insulin mediates both mitochondrial fusion and FoxO1 nuclear exclusion.	6	15	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	7	8	13	14
As shown in XREF_FIG , phosphorylation of AKT and FOXO1 was clearly induced in cells treated with insulin for a relatively short periods ( 0-4h ) .	As shown in XREF_FIG, phosphorylation of AKT and FOXO1 was clearly induced in cells treated with insulin for a relatively short periods (0-4h).	5	22	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	17	18	9	10
These data show that insulin signaling through Akt2 promotes anabolic lipid metabolism independent of Foxa2 or FoxO1 and through pathways additional to the mTORC1 dependent activation of SREBP1c .	These data show that insulin signaling through Akt2 promotes anabolic lipid metabolism independent of Foxa2 or FoxO1 and through pathways additional to the mTORC1 dependent activation of SREBP1c.	4	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	4	5	16	17
InsR +/- enhanced hepatic fat content and impaired hepatic insulin signaling leading to Forkhead box protein O1 ( FoxO1 ) accumulation in MCD fed mice .	InsR +/- enhanced hepatic fat content and impaired hepatic insulin signaling leading to Forkhead box protein O1 (FoxO1) accumulation in MCD fed mice.	9	17	leading	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	Forkhead box protein O1	Forkhead box protein O1	Forkhead box protein O1	9	10	13	17
Thus , in hepatocytes as in other cell lines , all three FKHR PKB sites participate in insulin mediated inhibition of FKHR action and in insulin mediated accumulation of FKHR in cytoplasm .	Thus, in hepatocytes as in other cell lines, all three FKHR PKB sites participate in insulin mediated inhibition of FKHR action and in insulin mediated accumulation of FKHR in cytoplasm.	15	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FKHR	FKHR	FKHR	17	18	21	22
Examined in clonal alphaTC1-9 cells , insulin caused endogenous FoxO1 to translocate from the nucleus to the cytoplasm .	Examined in clonal alphaTC1-9 cells, insulin caused endogenous FoxO1 to translocate from the nucleus to the cytoplasm.	6	10	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	6	7	9	10
Furthermore , insulin increased p-FOXO1 by nearly threefold in CON livers but failed to do so in the IUGR livers ( XREF_FIG ) .	Furthermore, insulin increased p-FOXO1 by nearly threefold in CON livers but failed to do so in the IUGR livers (XREF_FIG).	2	14	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	p-FOXO1	p-FOXO1	p-FOXO1	2	3	4	5
A western-type diet can promote insulin resistance , which activates FoxO1 and FoxO3 early during the process of atherogenesis .	A western-type diet can promote insulin resistance, which activates FoxO1 and FoxO3 early during the process of atherogenesis.	5	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	5	6	10	11
The phosphorylation of FoxO1 by FA facilitated FoxO1 nuclear exclusion in a manner comparable to insulin induced FoxO1 translocation ( XREF_FIG ) .	The phosphorylation of FoxO1 by FA facilitated FoxO1 nuclear exclusion in a manner comparable to insulin induced FoxO1 translocation (XREF_FIG).	13	18	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	15	16	17	18
Our study is the first to demonstrate that insulin induces transcriptional inactivation of FOXO1 by its nuclear export via PI3K pathway in decidualizing endometrial stromal cells , as shown in other cell types [ XREF_BIBR ] .	Our study is the first to demonstrate that insulin induces transcriptional inactivation of FOXO1 by its nuclear export via PI3K pathway in decidualizing endometrial stromal cells, as shown in other cell types [XREF_BIBR].	8	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	8	9	13	14
In the present study , we attempted to elucidate the molecular modulation of antioxidant baicalin on the insulin induced FoxO1 inactivation .	In the present study, we attempted to elucidate the molecular modulation of antioxidant baicalin on the insulin induced FoxO1 inactivation.	8	20	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	17	18	19	20
Differently , high insulin levels mediate FoxO1 nuclear exclusion through its phosphorylation by Akt .	Differently, high insulin levels mediate FoxO1 nuclear exclusion through its phosphorylation by Akt.	3	8	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin levels	insulin	FoxO1	FoxO1	foxo1	3	4	6	7
XREF_BIBR Our results showed that 0.001 microM IGF-1 and 1microM insulin up-regulate p-Akt and p-FoxO1 at 15 and 30 minutes in human T-cells .	XREF_BIBR Our results showed that 0.001 microM IGF-1 and 1microM insulin up-regulate p-Akt and p-FoxO1 at 15 and 30 minutes in human T-cells.	7	15	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	p-FoxO1	p-FoxO1	p-FoxO1	10	11	14	15
At steady-state , insulin induced FoxO1 nuclear exclusion and GLUT4 translocation were similar in adipocytes expressing WT or MK-2206 resistant Akt mutants ( XREF_FIG A and XREF_FIG B ) .	At steady-state, insulin induced FoxO1 nuclear exclusion and GLUT4 translocation were similar in adipocytes expressing WT or MK-2206 resistant Akt mutants (XREF_FIG A and XREF_FIG B).	3	7	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	3	4	5	6
In fact , constitutive activation of this kinase in hepatocytes is sufficient to abrogate insulin mediated FOXO1 nuclear exclusion [ XREF_BIBR ] , suggesting the expected antagonistic relationship between these hormonal regulators of HGP .	In fact, constitutive activation of this kinase in hepatocytes is sufficient to abrogate insulin mediated FOXO1 nuclear exclusion [XREF_BIBR], suggesting the expected antagonistic relationship between these hormonal regulators of HGP.	13	18	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	14	15	16	17
We also demonstrate that PC derived exosomes can inhibit insulin and PI3K and Akt signalling , in which insulin induced FoxO1 nuclear exclusion is preserved and Glut4 trafficking is impaired .	We also demonstrate that PC derived exosomes can inhibit insulin and PI3K and Akt signalling, in which insulin induced FoxO1 nuclear exclusion is preserved and Glut4 trafficking is impaired.	18	22	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	18	19	20	21
Likewise , we have studied the insulin stimulated AKT and FOXO1 signalling , which could be involved in regulating proliferation and/or apoptosis in beta-cells downstream of PTP1B XREF_BIBR , XREF_BIBR .	Likewise, we have studied the insulin stimulated AKT and FOXO1 signalling, which could be involved in regulating proliferation and/or apoptosis in beta-cells downstream of PTP1B XREF_BIBR, XREF_BIBR.	4	11	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	6	7	10	11
Insulin dramatically reduced the FoxO1 nuclear level and the stability of FoxO1 protein [ XREF_BIBR , XREF_BIBR ] , suggesting that insulin triggered FoxO1 nuclear exclusion and protein degradation to reverse inhibited myogenesis by FoxO1 .	Insulin dramatically reduced the FoxO1 nuclear level and the stability of FoxO1 protein [XREF_BIBR, XREF_BIBR], suggesting that insulin triggered FoxO1 nuclear exclusion and protein degradation to reverse inhibited myogenesis by FoxO1.	21	25	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	21	22	23	24
Further investigation with chromatin immunoprecipitation , confocal microscopy , and Fluorescence Recovery After Photobleaching ( FRAP ) technology indicated a functional significance of this interaction , in both basal and insulin stimulated states , providing evidence that , by modulating FoxO1 transactivation , HMGA1 is essential for FoxO1 induced IGFBP1 gene expression , and thereby a critical modulator of insulin mediated FoxO1 regulation in the liver .	Further investigation with chromatin immunoprecipitation, confocal microscopy, and Fluorescence Recovery After Photobleaching (FRAP) technology indicated a functional significance of this interaction, in both basal and insulin stimulated states, providing evidence that, by modulating FoxO1 transactivation, HMGA1 is essential for FoxO1 induced IGFBP1 gene expression, and thereby a critical modulator of insulin mediated FoxO1 regulation in the liver.	57	62	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	59	60	61	62
The overexpression of miR-24 or shH2AX repressed insulin stimulated pIRS-1 ( Y632 ) , pAkt ( T308 ) , pAkt ( S473 ) and pFoxO1 ( S256 ) to similar degrees ( XREF_FIG ) .	The overexpression of miR-24 or shH2AX repressed insulin stimulated pIRS-1 (Y632), pAkt (T308), pAkt (S473) and pFoxO1 (S256) to similar degrees (XREF_FIG).	6	30	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	pFoxO1	pFoxO1	pFoxO1	7	8	24	25
Insulin signaling leads to a variety of progrowth , antiapoptotic responses , notably phosphorylation and nuclear exclusion of the closely related transcription factors forkhead transcription factor 01 ( FoxO1 ) , -3 , and -4 .	Insulin signaling leads to a variety of progrowth, antiapoptotic responses, notably phosphorylation and nuclear exclusion of the closely related transcription factors forkhead transcription factor 01 (FoxO1), -3, and -4.	0	34	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	FoxO1	FoxO1	FoxO1	0	1	28	29
In addition , insulin stimulation abrogated this difference , most likely due to insulin induced FOXO1 inactivation ( XREF_FIG ) .	In addition, insulin stimulation abrogated this difference, most likely due to insulin induced FOXO1 inactivation (XREF_FIG).	5	16	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	13	14	15	16
Insulin resistance renders macrophages more prone to cholesterol induced apoptosis by promoting nuclear localization of transcription factor FoxO1 .	Insulin resistance renders macrophages more prone to cholesterol induced apoptosis by promoting nuclear localization of transcription factor FoxO1.	0	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	FoxO1	FoxO1	FoxO1	0	1	17	18
Further downstream examination of the insulin signaling cascade revealed no difference in the insulin stimulated changes in FOXO1 or phospho-FOXO1 ( Ser 256 ) between the HET and WT groups ; whereas , total FOXO1 protein content was significantly elevated in the HET MTP mice in the basal state compared with WT ( p < 0.01 , XREF_FIG ) .	Further downstream examination of the insulin signaling cascade revealed no difference in the insulin stimulated changes in FOXO1 or phospho-FOXO1 (Ser 256) between the HET and WT groups; whereas, total FOXO1 protein content was significantly elevated in the HET MTP mice in the basal state compared with WT (p < 0.01, XREF_FIG).	10	19	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO1	FOXO1	FOXO1	13	14	17	18
HCV core protein inhibits insulin mediated FoxO1 translocation from the nucleus to the cytoplasm and subsequently reduces accumulation of FoxA2 in the nucleus [ XREF_BIBR ] .	HCV core protein inhibits insulin mediated FoxO1 translocation from the nucleus to the cytoplasm and subsequently reduces accumulation of FoxA2 in the nucleus [XREF_BIBR].	3	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	4	5	6	7
We tested the extent that impaired inactivation of FoxO1 by insulin was sufficient for glucose to promote increased serum VLDL .	We tested the extent that impaired inactivation of FoxO1 by insulin was sufficient for glucose to promote increased serum VLDL.	6	11	inactivation	Negative_activation_token_2_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO1	FoxO1	FoxO1	10	11	8	9
Insulin and Insulin like growth factor-1 can activate the phosphoinositide-3-kinase / Akt and FoxO1 pathway in T cells in vitro .	Insulin and Insulin like growth factor-1 can activate the phosphoinositide-3-kinase / Akt and FoxO1 pathway in T cells in vitro.	0	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	FoxO1	FoxO1	FoxO1	0	1	13	14
After feeding , rising levels of insulin promote the Akt mediated phosphorylation and subsequent nuclear exclusion of FoxO1 ; this leads to sharp reductions in Irf4 mRNA levels within hours .	After feeding, rising levels of insulin promote the Akt mediated phosphorylation and subsequent nuclear exclusion of FoxO1; this leads to sharp reductions in Irf4 mRNA levels within hours.	4	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	levels of insulin	insulin	FoxO1	FoxO1	foxo1	6	7	17	18
These results demonstrate that DNJ can increase hepatic insulin sensitivity via strengthening of the insulin stimulated PKB and GSK-3beta signal pathway and by modulating glucose metabolic enzymes in db/db mice .	These results demonstrate that DNJ can increase hepatic insulin sensitivity via strengthening of the insulin stimulated PKB and GSK-3beta signal pathway and by modulating glucose metabolic enzymes in db/db mice.	11	20	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	14	15	18	19
Moreover , insulin is well known to activate the Akt and GSK-3beta signaling pathway and thus inhibits the activity of GSK-3beta XREF_BIBR , XREF_BIBR .	Moreover, insulin is well known to activate the Akt and GSK-3beta signaling pathway and thus inhibits the activity of GSK-3beta XREF_BIBR, XREF_BIBR.	2	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	2	3	11	12
Insulin resistance leads to increase activation of GSK-3beta as well as other kinases due to combined effects of inhibiting PI3K-Akt and increased oxidative stress .	Insulin resistance leads to increase activation of GSK-3beta as well as other kinases due to combined effects of inhibiting PI3K-Akt and increased oxidative stress.	0	8	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	GSK-3beta	GSK-3beta	GSK-3beta	0	1	7	8
To further evaluate the role of GSK3beta in insulin signaling , the GSK3beta inhibitor lithium was used to mimic the consequences of insulin stimulated GSK3beta inactivation .	To further evaluate the role of GSK3beta in insulin signaling, the GSK3beta inhibitor lithium was used to mimic the consequences of insulin stimulated GSK3beta inactivation.	20	25	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	22	23	24	25
Our result showed that the expression level of pAkt Serine 473 and pGSK3beta were increased in NT control clone upon insulin stimulation , indicating that insulin could successfully activate Akt and GSK3beta in BEL7402 .	Our result showed that the expression level of pAkt Serine 473 and pGSK3beta were increased in NT control clone upon insulin stimulation, indicating that insulin could successfully activate Akt and GSK3beta in BEL7402.	25	32	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	25	26	31	32
Development of IR on chronic insulin treatment is accompanied by a decrease in insulin stimulation of Akt , p70S6K and GSK3beta , but does not affect MAPK mediated signaling pathways , a result mimicking that seen in muscle and adipocytes [ XREF_BIBR , XREF_BIBR ] .	Development of IR on chronic insulin treatment is accompanied by a decrease in insulin stimulation of Akt, p70S6K and GSK3beta, but does not affect MAPK mediated signaling pathways, a result mimicking that seen in muscle and adipocytes [XREF_BIBR, XREF_BIBR].	13	21	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	13	14	20	21
Since insulin and IGF -1 networks cross-talk with Wnt via GSK-3beta [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] , increased GSK-3beta activity caused by insulin and IGF -1 resistance could have further impaired Wnt signaling in juvenile cerebella .	Since insulin and IGF -1 networks cross-talk with Wnt via GSK-3beta [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR], increased GSK-3beta activity caused by insulin and IGF -1 resistance could have further impaired Wnt signaling in juvenile cerebella.	22	30	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	26	27	22	23
Reductions in insulin induced GSK3beta inhibition in the peripheral nerve may contribute to pathological changes in DN and warrant further investigation .	Reductions in insulin induced GSK3beta inhibition in the peripheral nerve may contribute to pathological changes in DN and warrant further investigation.	0	5	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	2	3	4	5
To assess the effect of HCV infection on insulin sensitivity , we examined the phosphorylation status of Akt and GSK3beta induced by insulin stimulation .	To assess the effect of HCV infection on insulin sensitivity, we examined the phosphorylation status of Akt and GSK3beta induced by insulin stimulation.	15	23	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	22	23	19	20
In this report , we found that insulin withdrawal triggered the activation of GSK-3beta , suggesting that GSK-3beta may play an important role in HCN cell death .	In this report, we found that insulin withdrawal triggered the activation of GSK-3beta, suggesting that GSK-3beta may play an important role in HCN cell death.	7	14	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	7	8	13	14
Insulin and IGF -1 resistance typically reduces Akt [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] , and increases GSK-3beta [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] activity .	Insulin and IGF -1 resistance typically reduces Akt [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR], and increases GSK-3beta [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] activity.	0	32	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	GSK-3beta	GSK-3beta	GSK-3beta	0	1	22	23
The results showed that the phospho-Akt ( p-Akt ) and phospho-GSK3beta ( p-GSK3beta ) in all three main insulin responsive tissues were greatly stimulated by insulin infusion ( XREF_FIG e-g ) .	The results showed that the phospho-Akt (p-Akt) and phospho-GSK3beta (p-GSK3beta) in all three main insulin responsive tissues were greatly stimulated by insulin infusion (XREF_FIG e-g).	5	26	stimulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	phospho-GSK3beta	phospho-GSK3beta	phospho-GSK3beta	25	26	10	11
The increase in GSK-3beta tyrosine phosphorylation corresponded directly to an increase in the association of Fyn tyrosine kinase with GSK-3beta , and Fyn immunoprecipitated from cells treated with insulin for 1 min phosphorylated GSK-3beta to a significantly greater extent than Fyn immunoprecipitated from control cells .	The increase in GSK-3beta tyrosine phosphorylation corresponded directly to an increase in the association of Fyn tyrosine kinase with GSK-3beta, and Fyn immunoprecipitated from cells treated with insulin for 1 min phosphorylated GSK-3beta to a significantly greater extent than Fyn immunoprecipitated from control cells.	17	29	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	28	29	19	20
In AD , brain insulin and IGF resistance reduces signaling through phosphoinositol-3-kinase ( PI3K ) , Akt , and Wnt and beta-catenin , and increases activation of GSK-3beta .	In AD, brain insulin and IGF resistance reduces signaling through phosphoinositol-3-kinase (PI3K), Akt, and Wnt and beta-catenin, and increases activation of GSK-3beta.	3	28	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	4	5	27	28
Downstream of AKT , glycogen synthase kinase-3 beta ( GSK3beta ) and ribosomal protein S6 ( pS6RP ) , which mediates the translational regulation through insulin were activated by insulin .	Downstream of AKT, glycogen synthase kinase-3 beta (GSK3beta) and ribosomal protein S6 (pS6RP), which mediates the translational regulation through insulin were activated by insulin.	4	30	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta	glycogen synthase kinase-3 beta	29	30	4	8
The protective effect of SphK1 was linked to its enhancement of insulin stimulated kinases Akt and GSK3beta .	The protective effect of SphK1 was linked to its enhancement of insulin stimulated kinases Akt and GSK3beta.	9	17	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	11	12	16	17
To examine possible molecular mechanisms for the preservation of islet beta-cell mass in Gsk-3beta +/- Irs2 -/- mice , islets from WT , Irs2 -/-, and Gsk-3beta +/- Irs2 -/- mice at 6 wk of age were examined by western blot analysis to assess insulin signaling upstream and downstream of Gsk-3beta .	To examine possible molecular mechanisms for the preservation of islet beta-cell mass in Gsk-3beta +/- Irs2 -/- mice, islets from WT, Irs2 -/-, and Gsk-3beta +/- Irs2 -/- mice at 6 wk of age were examined by western blot analysis to assess insulin signaling upstream and downstream of Gsk-3beta.	44	51	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	Gsk-3beta	Gsk-3beta	Gsk-3beta	44	45	50	51
Moreover , a small , but significant , portion of this oxidative stress induced insulin resistance is associated with a reduced insulin mediated suppression of the active form of GSK-3beta .	Moreover, a small, but significant, portion of this oxidative stress induced insulin resistance is associated with a reduced insulin mediated suppression of the active form of GSK-3beta.	17	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	21	22	29	30
Expression of GSK-3 was not influenced by dexamethasone treatment in muscles or adipocytes and insulin stimulated GSK-3beta Ser ( 9 ) phosphorylation was reduced in muscles only .	Expression of GSK-3 was not influenced by dexamethasone treatment in muscles or adipocytes and insulin stimulated GSK-3beta Ser (9) phosphorylation was reduced in muscles only.	14	17	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	14	15	16	17
We documented the HFCS induced alteration in the insulin signal transduction pathway , as shown by the impaired phosphorylation of IRS-1 protein as well as of the downstream key insulin signaling molecules , Akt , and GSK-3beta , an Akt substrate [ XREF_BIBR ] .	We documented the HFCS induced alteration in the insulin signal transduction pathway, as shown by the impaired phosphorylation of IRS-1 protein as well as of the downstream key insulin signaling molecules, Akt, and GSK-3beta, an Akt substrate [XREF_BIBR].	4	42	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	29	30	36	37
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR Insulin signaling causes inactivation of GSK-3beta ( S9 ) and GSK-3alpha ( S21 ) by activated Akt .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Insulin signaling causes inactivation of GSK-3beta (S9) and GSK-3alpha (S21) by activated Akt.	7	19	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	GSK-3beta	GSK-3beta	GSK-3beta	7	8	12	13
We find that insulin stimulated pGSK3beta and GSK3beta and pGSK3beta and beta-actin ( pSerine9 ) are reduced in SWELL1 KO adipocytes ( XREF_FIG ) , providing a molecular mechanism for the reduction in glycogen granules observed on EM ( XREF_FIG ) .	We find that insulin stimulated pGSK3beta and GSK3beta and pGSK3beta and beta-actin (pSerine9) are reduced in SWELL1 KO adipocytes (XREF_FIG), providing a molecular mechanism for the reduction in glycogen granules observed on EM (XREF_FIG).	3	16	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	3	4	7	8
We hypothesized that insulin stimulation and subsequent inactivation of GSK3beta allow cyclin D1 to form an active complex with CDK4 , promoting PGC-1alpha acetylation .	We hypothesized that insulin stimulation and subsequent inactivation of GSK3beta allow cyclin D1 to form an active complex with CDK4, promoting PGC-1alpha acetylation.	3	10	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	3	4	9	10
Insulin increased p-GSK3beta twofold in CON and IUGR livers ( XREF_FIG ) .	Insulin increased p-GSK3beta twofold in CON and IUGR livers (XREF_FIG).	0	3	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	p-GSK3beta	p-GSK3beta	p-GSK3beta	0	1	2	3
Exposure of cells to PC-TP inhibitors resulted in dose dependent , but insulin independent activation of Akt , p70-S6K and GSK3beta , which are key effectors of insulin signaling .	Exposure of cells to PC-TP inhibitors resulted in dose dependent, but insulin independent activation of Akt, p70-S6K and GSK3beta, which are key effectors of insulin signaling.	12	25	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	12	13	20	21
Furthermore , insulin stimulated PKB Ser ( 473 ) and Thr ( 308 ) and GSK-3beta Ser ( 9 ) phosphorylation were blocked by caffeine and theophylline .	Furthermore, insulin stimulated PKB Ser (473) and Thr (308) and GSK-3beta Ser (9) phosphorylation were blocked by caffeine and theophylline.	2	16	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	2	3	15	16
We then analyzed the effects of a HFD on the phosphorylation of key insulin signaling molecules , Akt , and its downstream signaling molecules GSK3beta and FOXO3 .	We then analyzed the effects of a HFD on the phosphorylation of key insulin signaling molecules, Akt, and its downstream signaling molecules GSK3beta and FOXO3.	10	26	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	phosphorylation of key insulin	insulin	GSK3beta	GSK3beta	gsk3beta	13	14	24	25
Together , these results demonstrate that ERK regulates insulin mediated GSK3beta activity independent of Akt and mTORC1 .	Together, these results demonstrate that ERK regulates insulin mediated GSK3beta activity independent of Akt and mTORC1.	7	16	mediated	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	8	9	10	11
In brain and neuron specific insulin receptor knockout mice , lack of insulin signaling in the brain activates GSK-3beta and leads to tau hyperphosphorylation XREF_BIBR .	In brain and neuron specific insulin receptor knockout mice, lack of insulin signaling in the brain activates GSK-3beta and leads to tau hyperphosphorylation XREF_BIBR.	12	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	12	13	18	19
Insulin experiment revealed that perioperative intranasal insulin administration could restore the surgery induced hippocampal neuroinflammation and hyperactivation of GSK-3beta , and prevent impairment in novel object recognition .	Insulin experiment revealed that perioperative intranasal insulin administration could restore the surgery induced hippocampal neuroinflammation and hyperactivation of GSK-3beta, and prevent impairment in novel object recognition.	6	19	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	6	7	18	19
These results support the assertion that insulin withdrawal induced death of HCN cells represents the genuine model of ACD in mammalian cells , and identify GSK-3beta as a critical regulator of ACD in HCN cells .	These results support the assertion that insulin withdrawal induced death of HCN cells represents the genuine model of ACD in mammalian cells, and identify GSK-3beta as a critical regulator of ACD in HCN cells.	6	26	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	6	7	25	26
Thus , insulin deficiency and resistance can induce abnormal activation of GSK3beta .	Thus, insulin deficiency and resistance can induce abnormal activation of GSK3beta.	2	12	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK3beta	GSK3beta	GSK3beta	2	3	11	12
The results showed that the insulin stimulated p-Akt and p-GSK3beta were not altered by salidroside in the skeletal muscle ( XREF_FIG ) .	The results showed that the insulin stimulated p-Akt and p-GSK3beta were not altered by salidroside in the skeletal muscle (XREF_FIG).	4	12	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	p-GSK3beta	p-GSK3beta	p-GSK3beta	5	6	9	10
On the other hand , the fact that AbetaPP oligomers inhibit neuronal insulin stimulated signals , blocking PI3 kinase activation of Akt , which leads to impaired survival signaling , increased activation of GSK-3beta , and resultant hyper-phosphorylation of tau , argues in favor of pursuing measures that reduce AbetaPP oligomer fibrillarization as a means of restoring brain insulin sensitivity .	On the other hand, the fact that AbetaPP oligomers inhibit neuronal insulin stimulated signals, blocking PI3 kinase activation of Akt, which leads to impaired survival signaling, increased activation of GSK-3beta, and resultant hyper-phosphorylation of tau, argues in favor of pursuing measures that reduce AbetaPP oligomer fibrillarization as a means of restoring brain insulin sensitivity.	11	34	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	GSK-3beta	GSK-3beta	GSK-3beta	12	13	33	34
Down regulation of the insulin signaling pathway increases C. elegans lifespan , stress tolerance , locomotory healthspan and resistance to proteotoxicity in a FOXO and DAF -16 dependent way XREF_BIBR .	Down regulation of the insulin signaling pathway increases C. elegans lifespan, stress tolerance, locomotory healthspan and resistance to proteotoxicity in a FOXO and DAF -16 dependent way XREF_BIBR.	4	24	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	4	5	23	24
We have also proposed that the shut-down of insulin signalling during diapause in C. pipiens activates the downstream FOXO , thus leading to the conspicuous hypertrophy of the fat body that is associated with the advent of diapause .	We have also proposed that the shut-down of insulin signalling during diapause in C. pipiens activates the downstream FOXO, thus leading to the conspicuous hypertrophy of the fat body that is associated with the advent of diapause.	8	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	8	9	18	19
Both insulin resistance and oxidative stress may promote the transcriptional activity of FOXO proteins , resulting in hyperglycemia and a further increased production of reactive oxygen species ( ROS ) XREF_BIBR .	Both insulin resistance and oxidative stress may promote the transcriptional activity of FOXO proteins, resulting in hyperglycemia and a further increased production of reactive oxygen species (ROS) XREF_BIBR.	1	13	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	1	2	12	13
The insulin signal acts through the insulin receptor to activate Akt to phosphorylate the FOXO transcription factor , thus barring FOXO from the nucleus .	The insulin signal acts through the insulin receptor to activate Akt to phosphorylate the FOXO transcription factor, thus barring FOXO from the nucleus.	1	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	1	2	20	21
Insulin signaling leads to the production of JH preventing FOXO activation and establishing a diapause phenotype .	Insulin signaling leads to the production of JH preventing FOXO activation and establishing a diapause phenotype.	0	10	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	FOXO	FOXO	FOXO	0	1	9	10
XREF_BIBR There is an association between increased oxidative stress and GDM as excessive oxidative stress decreases the phosphorylation of insulin stimulated Akt , glycogen synthase kinase 3 ( GSK-3 ) and forkhead box O ( FOXO ) 1alpha and alters the phosphorylation of MAPKs , including p38 , extracelluar signal regulated protein kinase and JNK , all of which have been reported to contribute to insulin resistance .	XREF_BIBR There is an association between increased oxidative stress and GDM as excessive oxidative stress decreases the phosphorylation of insulin stimulated Akt, glycogen synthase kinase 3 (GSK-3) and forkhead box O (FOXO) 1alpha and alters the phosphorylation of MAPKs, including p38, extracelluar signal regulated protein kinase and JNK, all of which have been reported to contribute to insulin resistance.	17	37	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	phosphorylation of insulin	insulin	FOXO	FOXO	foxo	19	20	35	36
They were also able to show that a shutdown in insulin signaling caused the activation of FOXO ( forkhead transcription factor ) , while the knock-down of FOXO resulted in the reduction of fat stores and a reduced life span in mosquitoes programmed for diapause .	They were also able to show that a shutdown in insulin signaling caused the activation of FOXO (forkhead transcription factor), while the knock-down of FOXO resulted in the reduction of fat stores and a reduced life span in mosquitoes programmed for diapause.	10	28	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	10	11	16	17
In addition , insulin could activate FOXO 1 , but inhibit MnSOD and CAT , and as a consequence enhancing ROS production .	In addition, insulin could activate FOXO 1, but inhibit MnSOD and CAT, and as a consequence enhancing ROS production.	3	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	3	4	6	7
Surprisingly , an analysis of insulin action mediated through the G6Pase and IGF binding protein-1 IRSs in the context of a heterologous thymidine kinase promoter reveals that signaling through the latter does not support the accepted model for insulin stimulated FOXO nuclear exclusion .	Surprisingly, an analysis of insulin action mediated through the G6Pase and IGF binding protein-1 IRSs in the context of a heterologous thymidine kinase promoter reveals that signaling through the latter does not support the accepted model for insulin stimulated FOXO nuclear exclusion.	33	42	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	38	39	40	41
Hence , decreased insulin signaling and signaling through a parallel daf-12 and NHR pathway converge to activate daf-16 and FOXO for the phenotypes seen in apl-1 ( yn5 ) mutants .	Hence, decreased insulin signaling and signaling through a parallel daf-12 and NHR pathway converge to activate daf-16 and FOXO for the phenotypes seen in apl-1 (yn5) mutants.	3	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	3	4	19	20
XREF_FIG demonstrates the complex signalling pathways through which oxidative stress and insulin can modulate FOXO activity to affect mitochondria .	XREF_FIG demonstrates the complex signalling pathways through which oxidative stress and insulin can modulate FOXO activity to affect mitochondria.	9	15	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	11	12	14	15
For example , FOXO is driven out of the nucleus by insulin as well as other growth factors [ XREF_BIBR ] and by Src signalling [ XREF_BIBR ] .	For example, FOXO is driven out of the nucleus by insulin as well as other growth factors [XREF_BIBR] and by Src signalling [XREF_BIBR].	3	17	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	11	12	3	4
FOXO is nuclear in cells devoid of growth factors , but upon insulin stimulation FOXO accumulates in the cytoplasm through AKT mediated phosphorylation As expected , RNAi mediated depletion of PI3K limited the insulin induced shift toward cytoplasmic FOXO .	FOXO is nuclear in cells devoid of growth factors, but upon insulin stimulation FOXO accumulates in the cytoplasm through AKT mediated phosphorylation As expected, RNAi mediated depletion of PI3K limited the insulin induced shift toward cytoplasmic FOXO.	12	15	stimulation	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	12	13	14	15
Insulin initiates a complex cascade of intracellular events , one of which is the phosphorylation and inactivation ( through nuclear export ) of members the Foxo family of transcription factors .	Insulin initiates a complex cascade of intracellular events, one of which is the phosphorylation and inactivation (through nuclear export) of members the Foxo family of transcription factors.	0	26	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	Foxo	Foxo	Foxo	0	1	25	26
The exception is that insulin addition reduced pEEA mRNA level that reflects the insulin induced FOXO mediated transcriptional reduction of 4E-BP .	The exception is that insulin addition reduced pEEA mRNA level that reflects the insulin induced FOXO mediated transcriptional reduction of 4E-BP.	12	16	induced	Positive_early_activation	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	13	14	15	16
Insulin and oxidative stress signals activate Foxo proteins in other hematopoietic cells , but the nature of the signals that drive Foxo3 activation or deactivation in DCs remains undefined .	Insulin and oxidative stress signals activate Foxo proteins in other hematopoietic cells, but the nature of the signals that drive Foxo3 activation or deactivation in DCs remains undefined.	0	7	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	Foxo	Foxo	Foxo	0	1	6	7
Knockdown of insulin ins-7 activity throughout the worm results in activation of DAF-16 and FOXO and extends lifespan , and intestine specific over-expression of ins-7 in young adults is toxic XREF_BIBR .	Knockdown of insulin ins-7 activity throughout the worm results in activation of DAF-16 and FOXO and extends lifespan, and intestine specific over-expression of ins-7 in young adults is toxic XREF_BIBR.	2	15	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	2	3	14	15
It is well established that insulin signaling causes functional inactivation the FOXO transcription factor DAF-16 and that many of the consequences of reduced insulin signaling seen in daf-2 mutants require daf-16 [ XREF_BIBR ] .	It is well established that insulin signaling causes functional inactivation the FOXO transcription factor DAF-16 and that many of the consequences of reduced insulin signaling seen in daf-2 mutants require daf-16 [XREF_BIBR].	5	14	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	5	6	11	12
Downregulation of the insulin signaling pathway increases C. elegans lifespan and locomotory healthspan in a FOXO and DAF-16-dependent manner XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Downregulation of the insulin signaling pathway increases C. elegans lifespan and locomotory healthspan in a FOXO and DAF-16-dependent manner XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	25	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	3	4	15	16
Here , we demonstrate that the Insulin and IGF-1-PI3K signaling pathway modulates the activity of the DAF-16 and FOXO transcription factor to promote the anterior migrations of the hermaphrodite specific neurons ( HSNs ) during embryogenesis of C. elegans .	Here, we demonstrate that the Insulin and IGF-1-PI3K signaling pathway modulates the activity of the DAF-16 and FOXO transcription factor to promote the anterior migrations of the hermaphrodite specific neurons (HSNs) during embryogenesis of C. elegans.	5	20	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Insulin	Insulin	Insulin	FOXO	FOXO	FOXO	6	7	18	19
A few of the identified compounds are known from previous work as having effects on glucose tolerance and insulin signaling , especially the PI3K inhibitors wortmannin and LY294002 , which cause insulin resistance and stimulate FOXO nuclear function ; the ATP dependent K + channel blocker repaglinide , which can mimic the effect of elevated glucose ; and the cAMP --> PKA agonists IBMX and forskolin .	A few of the identified compounds are known from previous work as having effects on glucose tolerance and insulin signaling, especially the PI3K inhibitors wortmannin and LY294002, which cause insulin resistance and stimulate FOXO nuclear function; the ATP dependent K + channel blocker repaglinide, which can mimic the effect of elevated glucose; and the cAMP --> PKA agonists IBMX and forskolin.	18	37	stimulate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	18	19	35	36
Insulin signaling restricts lifespan and stress resistance mainly by inhibiting nuclear localization of the conserved FOXO transcription factor DAF-16 .	Insulin signaling restricts lifespan and stress resistance mainly by inhibiting nuclear localization of the conserved FOXO transcription factor DAF-16.	0	18	restricts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Insulin	Insulin	Insulin	FOXO	FOXO	FOXO	0	1	15	16
Furthermore , the addition of insulin in vitro prevented the decrease in Akt and Foxo signaling induced by nutritional stress .	Furthermore, the addition of insulin in vitro prevented the decrease in Akt and Foxo signaling induced by nutritional stress.	3	15	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	Foxo	Foxo	Foxo	5	6	14	15
It has been well documented that insulin signaling and DNA modifications in FOXO affect longevity in humans XREF_BIBR , but little is known about the role and contribution of genes involved in immunity .	It has been well documented that insulin signaling and DNA modifications in FOXO affect longevity in humans XREF_BIBR, but little is known about the role and contribution of genes involved in immunity.	6	13	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	6	7	12	13
Lisa demonstrated that the insulin and IGF-1-PI3K signaling pathway modulates the activity of the DAF-16 and FoxO transcription factor to promote the anterior migrations of the hermaphrodite specific neurons during embryogenesis of C. elegans ( by signaling pathways that are conserved in humans ) .	Lisa demonstrated that the insulin and IGF-1-PI3K signaling pathway modulates the activity of the DAF-16 and FoxO transcription factor to promote the anterior migrations of the hermaphrodite specific neurons during embryogenesis of C. elegans (by signaling pathways that are conserved in humans).	3	18	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	4	5	16	17
However , insulin failed to activate the Akt --> FoxO cascade in Irs2 (-/-) MEFs because Irs1 expression was reduced in these cells , and p110alpha-PI 3-kinase was inefficiently activated during recruitment by Irs1 .	However, insulin failed to activate the Akt --> FoxO cascade in Irs2 (-/-) MEFs because Irs1 expression was reduced in these cells, and p110alpha-PI 3-kinase was inefficiently activated during recruitment by Irs1.	2	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	2	3	9	10
Both insulin resistance and oxidative stress stimulate back the transcriptional activity of FoxO proteins , inducing hyperglycemia and a further increased production of reactive oxygen species ( ROS ) closing the vicious circle XREF_BIBR .	Both insulin resistance and oxidative stress stimulate back the transcriptional activity of FoxO proteins, inducing hyperglycemia and a further increased production of reactive oxygen species (ROS) closing the vicious circle XREF_BIBR.	1	13	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FoxO	FoxO	FoxO	1	2	12	13
lin-14 ( lf ) does not extend lifespan without the critical downstream transcription factors of insulin signaling FOXO and DAF -16 or HSF-1 , suggesting that lin-14 modulates the level of insulin signaling , a well characterized mechanism for modulation of lifespan .	lin-14 (lf) does not extend lifespan without the critical downstream transcription factors of insulin signaling FOXO and DAF -16 or HSF-1, suggesting that lin-14 modulates the level of insulin signaling, a well characterized mechanism for modulation of lifespan.	13	18	signaling	Positive_activation_token_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	15	16	17	18
Mutations in the daf-2 insulin and IGF receptor gene cause an extension of lifespan and stress resistance by deregulating the function of the DAF-16 and FOXO transcription factor [ XREF_BIBR ] .	Mutations in the daf-2 insulin and IGF receptor gene cause an extension of lifespan and stress resistance by deregulating the function of the DAF-16 and FOXO transcription factor [XREF_BIBR].	0	27	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	4	5	25	26
XREF_BIBR In contrast , excess insulin and insulin like growth factor signaling accelerates cellular aging by negatively regulating FOXO transcription factors .	XREF_BIBR In contrast, excess insulin and insulin like growth factor signaling accelerates cellular aging by negatively regulating FOXO transcription factors.	4	20	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	5	6	18	19
Finally , lowered insulin signalling in wounded tissues themselves , as opposed to impaired vascular supply , may have an important role in the impaired wound healing in type 2 diabetes , and may imply that local up-regulation of insulin signalling or inhibition of FOXO is sufficient to effect an improvement .	Finally, lowered insulin signalling in wounded tissues themselves, as opposed to impaired vascular supply, may have an important role in the impaired wound healing in type 2 diabetes, and may imply that local up-regulation of insulin signalling or inhibition of FOXO is sufficient to effect an improvement.	39	45	signalling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	insulin	insulin	insulin	FOXO	FOXO	FOXO	39	40	44	45
This association leads to polyubiquitination of IKKgamma and phosphorylation of IKKbeta by TAK1 , activating IKKbeta .	This association leads to polyubiquitination of IKKgamma and phosphorylation of IKKbeta by TAK1, activating IKKbeta.	2	16	activating	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	IKKbeta	leads to polyubiquitination of IKKgamma and phosphorylation of IKKbeta by TAK1	ikkbeta	IKKbeta	IKKbeta	ikkbeta	10	11	15	16
Monoubiquitylated PKCepsilon interacts with a ubiquitin binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane , where PKCepsilon phosphorylates IKKbeta at Ser177 and activates IKKbeta .	Monoubiquitylated PKCepsilon interacts with a ubiquitin binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane, where PKCepsilon phosphorylates IKKbeta at Ser177 and activates IKKbeta.	24	32	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	PKCepsilon phosphorylates IKKbeta at Ser177	ikkbeta	IKKbeta	IKKbeta	ikkbeta	26	27	31	32
PKCepsilon phosphorylates IKKbeta at serine 177 , which activates IKKbeta .	PKCepsilon phosphorylates IKKbeta at serine 177, which activates IKKbeta.	0	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	PKCepsilon phosphorylates IKKbeta at serine 177	ikkbeta	IKKbeta	IKKbeta	ikkbeta	2	3	9	10
Given that TAK1 activates IKKbeta via phosphorylation of S177 in the activation loop of IKKbeta , phosphorylation of IKKbeta at S177 by PKCepsilon might activate IKKbeta , thereby inducing PKM2 expression .	Given that TAK1 activates IKKbeta via phosphorylation of S177 in the activation loop of IKKbeta, phosphorylation of IKKbeta at S177 by PKCepsilon might activate IKKbeta, thereby inducing PKM2 expression.	16	26	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	phosphorylation of IKKbeta at S177	ikkbeta	IKKbeta	IKKbeta	ikkbeta	18	19	25	26
Monoubiquitination of IKKbeta may modulate the phosphorylation status of IKKbeta at select C-terminal serines , which could play an important role in controlling IKKbeta signaling during chronic inflammation [ XREF_BIBR ] .	Monoubiquitination of IKKbeta may modulate the phosphorylation status of IKKbeta at select C-terminal serines, which could play an important role in controlling IKKbeta signaling during chronic inflammation [XREF_BIBR].	0	10	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	Monoubiquitination of IKKbeta	ikkbeta	IKKbeta	IKKbeta	ikkbeta	2	3	9	10
Moreover , PTP-PEST directly interacted with IkappaB kinase beta ( IKKbeta ) then inhibited IKKbeta phosphorylation at Ser ( 177/181 ) and Tyr ( 188/199 ) , and subsequently suppressed IKKbeta activation and kinase activity as well as downstream NF-kappaB activation , resulting in suppression of the TLR triggered innate immune response .	Moreover, PTP-PEST directly interacted with IkappaB kinase beta (IKKbeta) then inhibited IKKbeta phosphorylation at Ser (177/181) and Tyr (188/199), and subsequently suppressed IKKbeta activation and kinase activity as well as downstream NF-kappaB activation, resulting in suppression of the TLR triggered innate immune response.	8	23	inhibited	Negative_regulation_syntax_1_verb	Negative_activation	Negative_regulation	IKKbeta	IKKbeta	ikkbeta	IKKbeta	IKKbeta phosphorylation at Ser (177/181) and Tyr	ikkbeta	10	11	14	15
However , TAK1 only phosphorylates IKKbeta at Ser 177 , which is a priming event that enables IKKbeta to activate itself by phosphorylating Ser 181 .	However, TAK1 only phosphorylates IKKbeta at Ser 177, which is a priming event that enables IKKbeta to activate itself by phosphorylating Ser 181.	2	18	enables	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	IKKbeta	TAK1 only phosphorylates IKKbeta at Ser 177	ikkbeta	IKKbeta	IKKbeta	ikkbeta	5	6	17	18
PKCepsilon Phosphorylates IKKbeta at Ser177 and Activates IKKbeta .	PKCepsilon Phosphorylates IKKbeta at Ser177 and Activates IKKbeta.	0	8	Activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	PKCepsilon Phosphorylates IKKbeta at Ser177	ikkbeta	IKKbeta	IKKbeta	ikkbeta	2	3	7	8
As readily apparent , there was no reduction in IKKbeta protein in the SVF but a near complete loss of IKKbeta in adipocytes .	As readily apparent, there was no reduction in IKKbeta protein in the SVF but a near complete loss of IKKbeta in adipocytes.	5	22	was no reduction	Negative_activation_copula_1	Negative_activation	Negative_activation	IKKbeta	loss of IKKbeta	ikkbeta	IKKbeta protein	IKKbeta protein	ikkbeta protein	20	21	9	11
These results indicate that PKCepsilon phosphorylates IKKbeta at S177 and activates IKKbeta , which in turn induces PKM2 upregulation .	These results indicate that PKCepsilon phosphorylates IKKbeta at S177 and activates IKKbeta, which in turn induces PKM2 upregulation.	4	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	PKCepsilon phosphorylates IKKbeta at S177	ikkbeta	IKKbeta	IKKbeta	ikkbeta	6	7	11	12
PNPS-1 also could decrease the mRNA expression of Myd88 , TRAF6 , TIRAP , IRAKI , IKBKB , NFKB1 , NFKB2 and RelA in immature BMDCs determined by RT-PCR , and decreased the IKKbeta and P65 production in BMDCs determined by Western blot , and decreased the NF-kB P65 production determined by ELISA .	PNPS-1 also could decrease the mRNA expression of Myd88, TRAF6, TIRAP, IRAKI, IKBKB, NFKB1, NFKB2 and RelA in immature BMDCs determined by RT-PCR, and decreased the IKKbeta and P65 production in BMDCs determined by Western blot, and decreased the NF-kB P65 production determined by ELISA.	0	36	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKBKB	PNPS-1 also could decrease the mRNA expression of Myd88, TRAF6, TIRAP, IRAKI, IKBKB	ikbkb	IKKbeta	IKKbeta	ikkbeta	16	17	33	34
Vanillic acid treatment reversed the Abeta 1-42 -induced elevated expression of IKK-beta and NF-kappaB and reduced the activity of IKKbeta and NF-kappaB .	Vanillic acid treatment reversed the Abeta 1-42 -induced elevated expression of IKK-beta and NF-kappaB and reduced the activity of IKKbeta and NF-kappaB.	0	21	reduced	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKK-beta	Vanillic acid treatment reversed the Abeta 1-42 -induced elevated expression of IKK-beta	ikk-beta	IKKbeta	IKKbeta	ikkbeta	11	12	19	20
While the serine kinases IKKalpha and IKKbeta target the serines 32 and 36 of the IkappaBalpha protein , NEMO regulates the IKK complex activity through its binding to the carboxyl-terminal region of the IKKalpha and IKKbeta subunits , called the NEMO binding domain ( NBD ) .	While the serine kinases IKKalpha and IKKbeta target the serines 32 and 36 of the IkappaBalpha protein, NEMO regulates the IKK complex activity through its binding to the carboxyl-terminal region of the IKKalpha and IKKbeta subunits, called the NEMO binding domain (NBD).	4	16	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	6	7	15	16
IKK-beta , along with IKK-alpha and NEMO , mediate the phosphorlyation of IkappaB-alpha , a NF-kappaB inhibitory protein that masks the nuclear localization signal of NF-kappaB .	IKK-beta, along with IKK-alpha and NEMO, mediate the phosphorlyation of IkappaB-alpha, a NF-kappaB inhibitory protein that masks the nuclear localization signal of NF-kappaB.	0	17	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKK-beta	IKK-beta	IKK-beta	IkappaB-alpha	IkappaB-alpha	IkappaB-alpha	0	1	12	13
We also observed reduced levels of IkappaBalpha that coincided with an increased level of RelA protein in the nucleus in the absence of RANKL stimulation and at all time points tested in IKKbeta SSEE - compared with GFP- and IKKbeta WT -expressing cells , indicating that the constitutively activated form of IKKbeta induces continuous IkappaBalpha processing ( XREF_FIG ) .	We also observed reduced levels of IkappaBalpha that coincided with an increased level of RelA protein in the nucleus in the absence of RANKL stimulation and at all time points tested in IKKbeta SSEE - compared with GFP- and IKKbeta WT -expressing cells, indicating that the constitutively activated form of IKKbeta induces continuous IkappaBalpha processing (XREF_FIG).	49	55	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	51	52	54	55
Previous studies have shown that the mechanisms accounting for NF-kappaB signaling inhibition by OA-NO 2 are multifaceted , as OA-NO 2 ( a ) inhibits IKKbeta preventing the degradation of the inhibitor IkappaBalpha , ( b ) alkylate the NF-kappaB RelA protein at Cys38 to prevent DNA binding and ( c ) promote RelA polyubiquitination and proteasomal degradation 32 .	Previous studies have shown that the mechanisms accounting for NF-kappaB signaling inhibition by OA-NO 2 are multifaceted, as OA-NO 2 (a) inhibits IKKbeta preventing the degradation of the inhibitor IkappaBalpha, (b) alkylate the NF-kappaB RelA protein at Cys38 to prevent DNA binding and (c) promote RelA polyubiquitination and proteasomal degradation 32.	24	33	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	25	26	32	33
Expectedly , hepatic mRNA expression of Ikk2 and classical targets of NF-kB activation , namely IkBalpha , serum amyloid a1 ( Saa1 ) , intercellular adhesion molecule 1 ( Icam1 ) , Bcl-x , and Akt1 [ XREF_BIBR , XREF_BIBR ] were all significantly higher in 12-week-old male Liv-Ikk2ca mice than wild-type littermates .	Expectedly, hepatic mRNA expression of Ikk2 and classical targets of NF-kB activation, namely IkBalpha, serum amyloid a1 (Saa1), intercellular adhesion molecule 1 (Icam1), Bcl-x, and Akt1 [XREF_BIBR, XREF_BIBR] were all significantly higher in 12-week-old male Liv-Ikk2ca mice than wild-type littermates.	6	16	targets	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Ikk2	Ikk2	Ikk2	IkBalpha	IkBalpha	IkBalpha	6	7	15	16
A putative IKK2 small molecule inhibitor has now been developed ( SC-514 ) that has an IC50 value of 10-20 muM following IL-1beta stimulation , but does not completely block IkappaBalpha degradation at 30 M.	A putative IKK2 small molecule inhibitor has now been developed (SC-514) that has an IC50 value of 10-20 muM following IL-1beta stimulation, but does not completely block IkappaBalpha degradation at 30 M.	0	31	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	IKK2	IKK2	IKK2	IkappaBalpha	IkappaBalpha	IkappaBalpha	2	3	30	31
We also demonstrated that the DDA1 overexpression or knockdown with shDDA1 # 1 promoted or inhibited IKKbeta phosphorylation , thereby upregulating p-IkappaBalpha , which resulted in nuclear p65 translocation via degradation of p-IkappaBalpha , respectively .	We also demonstrated that the DDA1 overexpression or knockdown with shDDA1 # 1 promoted or inhibited IKKbeta phosphorylation, thereby upregulating p-IkappaBalpha, which resulted in nuclear p65 translocation via degradation of p-IkappaBalpha, respectively.	5	24	upregulating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	DDA1 overexpression or knockdown with shDDA1 # 1 promoted or inhibited IKKbeta phosphorylation	ikkbeta	p-IkappaBalpha	p-IkappaBalpha	p-ikappabalpha	16	17	21	22
Activation of NFkappaB requires the phosphorylation dependent degradation of IkappaBalpha , which is mediated by the IkappaBalpha kinase complex ( IKK ) , IKKalpha , IKKbeta , and IKKgamma ( NFkappaB essential modulator ) subunits .	Activation of NFkappaB requires the phosphorylation dependent degradation of IkappaBalpha, which is mediated by the IkappaBalpha kinase complex (IKK), IKKalpha, IKKbeta, and IKKgamma (NFkappaB essential modulator) subunits.	7	26	mediated	Positive_activation_syntax_6_verb	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	25	26	9	10
These results indicate the inhibitory effect of PHA-408 on IKK2 mediated IkappaBalpha degradation in vivo in lungs .	These results indicate the inhibitory effect of PHA-408 on IKK2 mediated IkappaBalpha degradation in vivo in lungs.	7	12	mediated	Positive_early_activation	Negative_activation	Positive_activation	IKK2	IKK2	IKK2	IkappaBalpha	IkappaBalpha	IkappaBalpha	9	10	11	12
Furthermore , exogenously expressed , catalytically inactive IKKbeta blocked TNF- but not IL-1-induced IkappaBalpha degradation in wild-type MEFs , and reconstitution of IKKalpha and beta double knockout cells with IKKalpha rescued IL-1- but not TNF induced NF-kappaB activation .	Furthermore, exogenously expressed, catalytically inactive IKKbeta blocked TNF- but not IL-1-induced IkappaBalpha degradation in wild-type MEFs, and reconstitution of IKKalpha and beta double knockout cells with IKKalpha rescued IL-1- but not TNF induced NF-kappaB activation.	6	14	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	7	8	13	14
The canonical IKKs IKKalpha and IKKbeta activate NF-kappaB via phosphorylation and subsequent degradation of the NF-kappaB inhibitory molecule IkappaBalpha .	The canonical IKKs IKKalpha and IKKbeta activate NF-kappaB via phosphorylation and subsequent degradation of the NF-kappaB inhibitory molecule IkappaBalpha.	3	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	5	6	18	19
Additionally , a constant basic IKKbeta mediated IkappaBalpha turnover exists in unstimulated cells XREF_BIBR , yielding in continuous NFkappaB dependent resynthesis of IkappaBalpha .	Additionally, a constant basic IKKbeta mediated IkappaBalpha turnover exists in unstimulated cells XREF_BIBR, yielding in continuous NFkappaB dependent resynthesis of IkappaBalpha.	2	9	mediated	Positive_early_activation	Negative_activation	Negative_activation	IKKbeta	IKKbeta	IKKbeta	IkappaBalpha	IkappaBalpha	IkappaBalpha	5	6	7	8
Down-regulated Akt activation by overexpressed SHIP-2 causes cell-cycle arrest [ XREF_BIBR ] .	Down-regulated Akt activation by overexpressed SHIP-2 causes cell-cycle arrest [XREF_BIBR].	1	6	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	SHIP-2	SHIP-2	SHIP-2	Akt	Akt	Akt	5	6	1	2
In contrast , the expression of a catalytically deficient mutant of SHIP2 or the proline rich domain of SHIP2 enhanced Akt activation .	In contrast, the expression of a catalytically deficient mutant of SHIP2 or the proline rich domain of SHIP2 enhanced Akt activation.	16	21	enhanced	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SHIP2	SHIP2	SHIP2	Akt	Akt	Akt	18	19	20	21
Overexpression of SHIP2 led to a decrease of the insulin dependent PIP3 production as well as Akt and PKB activation and MAPK stimulation .	Overexpression of SHIP2 led to a decrease of the insulin dependent PIP3 production as well as Akt and PKB activation and MAPK stimulation.	0	19	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	SHIP2	Overexpression of SHIP2	ship2	PKB	PKB	pkb	2	3	18	19
Furthermore , SHIP2 overexpression enhanced Akt activation , but Akt inhibition failed to influence SHIP2 induced phospho-JNK and VIM upregulation .	Furthermore, SHIP2 overexpression enhanced Akt activation, but Akt inhibition failed to influence SHIP2 induced phospho-JNK and VIM upregulation.	2	6	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHIP2	SHIP2 overexpression	ship2	Akt	Akt	akt	2	3	5	6
Auranofin downregulates the expression of IKK-beta and induces the nuclear translocation of FOXO3 protein in SKOV3 cells .	Auranofin downregulates the expression of IKK-beta and induces the nuclear translocation of FOXO3 protein in SKOV3 cells.	0	13	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKK-beta	Auranofin downregulates the expression of IKK-beta	ikk-beta	FOXO3	FOXO3	foxo3	5	6	12	13
In contrast , both knockdown and pharmacological inhibition of IKKbeta in these cells significantly reduced FoxO3a cytoplasmic sequestering and enhanced FoxO3a nuclear localisation , whereas IKKbeta overexpression was inhibitory ( 20 % increase in cytoplasmic retention , p < 0.01 ) .	In contrast, both knockdown and pharmacological inhibition of IKKbeta in these cells significantly reduced FoxO3a cytoplasmic sequestering and enhanced FoxO3a nuclear localisation, whereas IKKbeta overexpression was inhibitory (20% increase in cytoplasmic retention, p < 0.01).	7	22	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	FoxO3a	FoxO3a	FoxO3a	9	10	20	21
XREF_BIBR , XREF_BIBR Among these kinases , AKT , ERK , and IKKbeta promote FOXO3a ' s cytoplasmic retention and inactivate its function , XREF_BIBR - XREF_BIBR whereas p38 , MST1 , and AMPK promote FOXO3a ' s nuclear localization and activate its function as a transcription factor .	XREF_BIBR, XREF_BIBR Among these kinases, AKT, ERK, and IKKbeta promote FOXO3a 's cytoplasmic retention and inactivate its function, XREF_BIBR - XREF_BIBR whereas p38, MST1, and AMPK promote FOXO3a 's nuclear localization and activate its function as a transcription factor.	5	24	promote	Positive_activation_token_1_verb	Negative_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	FOXO3a	FOXO3a	FOXO3a	12	13	14	15
To demonstrate the requirement for IKKbeta activity in the Ub of FOXO3 , we did experiments with the IKKbeta inhibitor and showed that inhibition of IKKbeta activity abrogated the Ub of FOXO3 in 293T cells ( XREF_FIG ) , suggesting that the Ub of FOXO3 is dependent on IKKbeta activity .	To demonstrate the requirement for IKKbeta activity in the Ub of FOXO3, we did experiments with the IKKbeta inhibitor and showed that inhibition of IKKbeta activity abrogated the Ub of FOXO3 in 293T cells (XREF_FIG), suggesting that the Ub of FOXO3 is dependent on IKKbeta activity.	25	32	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	FOXO3	FOXO3	FOXO3	25	26	31	32
This IKK-beta-mediated tumorigenic mechanism is consistent with and supports our current finding that auranofin treatment can downregulate the expression of IKK-beta and promote FOXO3 nuclear localization to regulate the expression of its downstream target genes , resulting in the suppression of cell survival and growth and the promotion of cellular apoptosis in ovarian cancer cells .	This IKK-beta-mediated tumorigenic mechanism is consistent with and supports our current finding that auranofin treatment can downregulate the expression of IKK-beta and promote FOXO3 nuclear localization to regulate the expression of its downstream target genes, resulting in the suppression of cell survival and growth and the promotion of cellular apoptosis in ovarian cancer cells.	13	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IKK-beta	auranofin treatment can downregulate the expression of IKK-beta	ikk-beta	FOXO3	FOXO3	foxo3	20	21	23	24
The suppression of GLI signaling involves the ubiquitin regulated processing of GLI mediated by Numb and the HECT domain E3 ubiquitin ligase Itch [ XREF_BIBR ] .	The suppression of GLI signaling involves the ubiquitin regulated processing of GLI mediated by Numb and the HECT domain E3 ubiquitin ligase Itch [XREF_BIBR].	9	24	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Itch	Itch	Itch	GLI	GLI	GLI	22	23	11	12
The consequent activation of Itch , together with the recruitment of Gli1 through direct binding with Numb , allows Gli1 to enter into the complex , resulting in Gli1 ubiquitination and degradation .	The consequent activation of Itch, together with the recruitment of Gli1 through direct binding with Numb, allows Gli1 to enter into the complex, resulting in Gli1 ubiquitination and degradation.	2	21	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Itch	Itch	Itch	Gli1	Gli1	Gli1	4	5	19	20
Further , we have recently reported that PCAF induces the proteasome dependent degradation of Gli1 in response to genotoxic stress 29 , and described the ubiquitin dependent proteolysis of Gli1 mediated by Itch and Numb XREF_BIBR , XREF_BIBR .	Further, we have recently reported that PCAF induces the proteasome dependent degradation of Gli1 in response to genotoxic stress 29, and described the ubiquitin dependent proteolysis of Gli1 mediated by Itch and Numb XREF_BIBR, XREF_BIBR.	27	35	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Itch	Itch	Itch	Gli1	Gli1	Gli1	32	33	29	30
We found that HAUSP blocked Itch mediated degradation of Gli1 and Spop-Cul3-mediated degradation of Gli2 and Gli3 ( XREF_FIG , top panels ) without affecting Gli mRNA levels ( XREF_FIG , bottom panels ) .	We found that HAUSP blocked Itch mediated degradation of Gli1 and Spop-Cul3-mediated degradation of Gli2 and Gli3 (XREF_FIG, top panels) without affecting Gli mRNA levels (XREF_FIG, bottom panels).	4	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Itch	Itch	Itch	Gli1	Gli1	Gli1	5	6	9	10
Interestingly , we further found that IRF4 and IRF8 induce the gene encoding IRF5 , another IRF that is preferentially expressed in immune cells including macrophages ( see below ) .	Interestingly, we further found that IRF4 and IRF8 induce the gene encoding IRF5, another IRF that is preferentially expressed in immune cells including macrophages (see below).	6	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IRF4	IRF4	IRF4	IRF5	IRF5	IRF5	6	7	13	14
As a possible mechanism , we found that both IRF4 and IRF8 strongly induce Irf5 transcripts in Tot2 cells ( XREF_FIG ) .	As a possible mechanism, we found that both IRF4 and IRF8 strongly induce Irf5 transcripts in Tot2 cells (XREF_FIG).	8	15	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IRF4	IRF4	IRF4	Irf5	Irf5	Irf5	9	10	14	15
Negatively regulating IRFs include IRF4 that competitively inhibits IRF5 from binding to TLR , thereby inhibiting inflammatory responses .	Negatively regulating IRFs include IRF4 that competitively inhibits IRF5 from binding to TLR, thereby inhibiting inflammatory responses.	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IRF4	IRF4	IRF4	IRF5	IRF5	IRF5	4	5	8	9
In addition , Itch and AIP4 has now been shown to mediate polyubiquitylation dependent targeting of retrovirally expressed Notch1 ectodomain to lysosomes in the absence of ligand .	In addition, Itch and AIP4 has now been shown to mediate polyubiquitylation dependent targeting of retrovirally expressed Notch1 ectodomain to lysosomes in the absence of ligand.	3	19	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Itch	Itch	Itch	Notch1	Notch1	Notch1	3	4	18	19
As we know , ITCH is an anti-cancer protein targeting p63 , p73 , and Notch1 gene and usually involve in tumor formation and chemosensitivity [ XREF_BIBR ] .	As we know, ITCH is an anti-cancer protein targeting p63, p73, and Notch1 gene and usually involve in tumor formation and chemosensitivity [XREF_BIBR].	4	19	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ITCH	ITCH	ITCH	Notch1	Notch1	Notch1	4	5	15	16
In hematopoietic stem cells , Itch deficiency increases proliferation by stabilizing Notch1 signaling XREF_BIBR .	In hematopoietic stem cells, Itch deficiency increases proliferation by stabilizing Notch1 signaling XREF_BIBR.	5	13	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Itch	Itch	Itch	Notch1	Notch1	Notch1	5	6	11	12
Our previous studies showed that hCG down-regulates the IL1B induced increase of IL1R2 and IL1RN in ESCs and amplifies the IL1B induced increase of IL1R1 XREF_BIBR .	Our previous studies showed that hCG down-regulates the IL1B induced increase of IL1R2 and IL1RN in ESCs and amplifies the IL1B induced increase of IL1R1 XREF_BIBR.	7	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IL1B	IL1B	IL1B	IL1R2	IL1R2	IL1R2	8	9	12	13
Furthermore , IL-1beta induced shedding of IL-1R2 in vivo .	Furthermore, IL-1beta induced shedding of IL-1R2 in vivo.	2	8	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IL-1beta	IL-1beta	IL-1beta	IL-1R2	IL-1R2	IL-1R2	2	3	6	7
Despite a significant down-regulation of p38 MAPK ( i.e. MAPK12 ; -1.22-fold ; Figure XREF_FIG ) during IMI , the observed 13.9-fold up-regulation of IL1B and 38.9-fold up-regulation of IL1R2 probably overcame that response and also might have been sufficient to account for the fact that JAK1 expression was down-regulated ( -1.17-fold ; Figure XREF_FIG ) .	Despite a significant down-regulation of p38 MAPK (i.e. MAPK12; -1.22-fold; Figure XREF_FIG) during IMI, the observed 13.9-fold up-regulation of IL1B and 38.9-fold up-regulation of IL1R2 probably overcame that response and also might have been sufficient to account for the fact that JAK1 expression was down-regulated (-1.17-fold; Figure XREF_FIG).	24	30	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	IL1B	IL1B	IL1B	IL1R2	IL1R2	IL1R2	24	25	29	30
These data suggest that IKBKE induced FOXO3a mobility shift could result from IKBKE regulation of other kinase ( s ) in addition to Akt .	These data suggest that IKBKE induced FOXO3a mobility shift could result from IKBKE regulation of other kinase (s) in addition to Akt.	4	8	induced	Positive_early_activation	Negative_activation	Positive_activation	IKBKE	IKBKE	IKBKE	FOXO3a	FOXO3a	FOXO3a	4	5	6	7
XREF_FIG shows that constitutively active ( Myr )-IKBKE reduced whereas DN-IKBKE enhanced FOXO3a transcription activity .	XREF_FIG shows that constitutively active (Myr)-IKBKE reduced whereas DN-IKBKE enhanced FOXO3a transcription activity.	10	14	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DN-IKBKE	DN-IKBKE	DN-IKBKE	FOXO3a	FOXO3a	FOXO3a	10	11	12	13
Although this ubiquitin ligase has been reported to accelerate the degradation of MyoD , a myogenic transcription factor driving the transcription of myosin heavy chain ( MHC ) , IGF-I failed to blunt the reduction of MyoD and MHC caused by TNF-alpha and IFN-gamma .	Although this ubiquitin ligase has been reported to accelerate the degradation of MyoD, a myogenic transcription factor driving the transcription of myosin heavy chain (MHC), IGF-I failed to blunt the reduction of MyoD and MHC caused by TNF-alpha and IFN-gamma.	34	44	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	IFN-gamma	IFN-gamma	IFN-gamma	MyoD	MyoD	MyoD	43	44	36	37
To test this possibility , we transfected luciferase mRNAs containing the iNOS or the MyoD 5 ' UTR into myoblasts treated with or without IFNgamma and TNFalpha and assessed , using a luminometer , the effect of PatA on the translation of these two reporter mRNAs .	To test this possibility, we transfected luciferase mRNAs containing the iNOS or the MyoD 5 ' UTR into myoblasts treated with or without IFNgamma and TNFalpha and assessed, using a luminometer, the effect of PatA on the translation of these two reporter mRNAs.	9	26	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	IFNgamma	IFNgamma	IFNgamma	MyoD	MyoD	MyoD	24	25	14	15
The Id3 destructive and/or the TCF3 activating mutations lead to TCF3 activated transcription resulting in pro survival phosphoinositide 3-kinase ( PI3K ) signaling [ XREF_BIBR ] .	The Id3 destructive and/or the TCF3 activating mutations lead to TCF3 activated transcription resulting in pro survival phosphoinositide 3-kinase (PI3K) signaling [XREF_BIBR].	0	11	lead	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Id3	Id3	Id3	TCF3	TCF3	TCF3	1	2	10	11
This is in contrast to some reports indicating that inhibition of IKKbeta prevents IRS-1 Ser 307 ( equivalent to human IRS-1 Ser 312 ) phosphorylation in cultured HEPG2 , 3T3-L1 adipocytes , or embryonic kidney cells but is consistent with other observations that IKKbeta is disassociated from IRS-1 phosphorylation ( Steven E. Shoelson , Joslin Diabetes Center , Boston , MA , personal communication ) .	This is in contrast to some reports indicating that inhibition of IKKbeta prevents IRS-1 Ser 307 (equivalent to human IRS-1 Ser 312) phosphorylation in cultured HEPG2, 3T3-L1 adipocytes, or embryonic kidney cells but is consistent with other observations that IKKbeta is disassociated from IRS-1 phosphorylation (Steven E. Shoelson, Joslin Diabetes Center, Boston, MA, personal communication).	9	14	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	IKKbeta	IKKbeta	IKKbeta	IRS-1	IRS-1	IRS-1	11	12	13	14
All these observations suggest that Mib may not be Notch specific and can also work with other pathways , just as previously shown for another E3 ligase , Itch , which targets Notch receptor and links to TNF through JNK XREF_BIBR - XREF_BIBR .	All these observations suggest that Mib may not be Notch specific and can also work with other pathways, just as previously shown for another E3 ligase, Itch, which targets Notch receptor and links to TNF through JNK XREF_BIBR - XREF_BIBR.	26	33	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Itch	Itch	Itch	Notch	Notch	Notch	28	29	32	33
Our laboratory found that SHIP2 -/- fetal liver derived macrophages have augmented M-CSF-induced Akt1 activity .	Our laboratory found that SHIP2 -/- fetal liver derived macrophages have augmented M-CSF-induced Akt1 activity.	4	14	augmented	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHIP2	SHIP2	SHIP2	Akt1	Akt1	Akt1	4	5	13	14
An Antagonist Effect of Keap1 DeltaC on Keap1 Mediated Turnover of Nrf2 .	An Antagonist Effect of Keap1 DeltaC on Keap1 Mediated Turnover of Nrf2.	4	12	Mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	11	12
Suppression of Nrf2 by ENC1 is reminiscent of down-regulation of Nrf2 by Keap1 .	Suppression of Nrf2 by ENC1 is reminiscent of down-regulation of Nrf2 by Keap1.	6	13	down-regulation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	10	11
Keap1 mediates Nrf2 sequestration and degradation by assembling an E3 ubiquitin ligase with Cul3 and Rbx1 with the BTB domain in Keap1 via the Neh2 domain in Nrf2 to promote the poly-ubiquitization and degradation of Nrf2 .	Keap1 mediates Nrf2 sequestration and degradation by assembling an E3 ubiquitin ligase with Cul3 and Rbx1 with the BTB domain in Keap1 via the Neh2 domain in Nrf2 to promote the poly-ubiquitization and degradation of Nrf2.	0	3	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
Chemical modification of Keap1 with free aldehydes leads to its disassociation with Nrf2 , allowing Nrf2 to move into the nucleus 139 .	Chemical modification of Keap1 with free aldehydes leads to its disassociation with Nrf2, allowing Nrf2 to move into the nucleus 139.	1	17	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	15	16
Upon cellular stress , KEAP1 oxidation allows Nrf2 release and the subsequent activation of cellular defence genes carrying an ARE ( antioxidant response element ) in their promoter [ XREF_BIBR ] ( XREF_FIG ) .	Upon cellular stress, KEAP1 oxidation allows Nrf2 release and the subsequent activation of cellular defence genes carrying an ARE (antioxidant response element) in their promoter [XREF_BIBR] (XREF_FIG).	4	8	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	4	5	7	8
Based on available data , we hypothesize that the stress inducible binding of DPP3 to KEAP1 may sequester any free KEAP1 that is still available and capable of degrading NRF2 after stress thereby promoting NRF2 accumulation .	Based on available data, we hypothesize that the stress inducible binding of DPP3 to KEAP1 may sequester any free KEAP1 that is still available and capable of degrading NRF2 after stress thereby promoting NRF2 accumulation.	17	35	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	20	21	34	35
Under normal conditions , Keap1 anchors the Nrf2 transcription factor within the cytoplasm targeting it for ubiquitination and proteasomal degradation to maintain low levels of Nrf2 that mediate the constitutive expression of Nrf2 downstream genes .	Under normal conditions, Keap1 anchors the Nrf2 transcription factor within the cytoplasm targeting it for ubiquitination and proteasomal degradation to maintain low levels of Nrf2 that mediate the constitutive expression of Nrf2 downstream genes.	4	34	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	32	33
Nuclear localization experiments revealed that C506S mutation did not affect the retention of Nrf2 by INrf2 and Keap1 in the cytosol , or its release in response to antioxidants .	Nuclear localization experiments revealed that C506S mutation did not affect the retention of Nrf2 by INrf2 and Keap1 in the cytosol, or its release in response to antioxidants.	9	24	retention	Positive_activation_token_2_noun	Negative_activation	Positive_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	15	16	13	14
Third , while the presence and importance of NRF2 independent KEAP1 functions remain unknown , we and others have established that several KEAP1 interacting proteins drive NRF2 activation via a competitive binding mechanism .	Third, while the presence and importance of NRF2 independent KEAP1 functions remain unknown, we and others have established that several KEAP1 interacting proteins drive NRF2 activation via a competitive binding mechanism.	21	27	drive	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	22	23	26	27
However , with electrophilic or oxidative stress , Nrf2 and Keap1 disassociates , allowing Nrf2 to translocate to the nucleus and coordinate the stimulation of a battery of antioxidant and survival genes including Grx1 [ XREF_BIBR ] .	However, with electrophilic or oxidative stress, Nrf2 and Keap1 disassociates, allowing Nrf2 to translocate to the nucleus and coordinate the stimulation of a battery of antioxidant and survival genes including Grx1 [XREF_BIBR].	8	21	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	14	15
Under normal conditions , Nrf2 is bound in the cytosol by its repressor , kelch like ECH associated protein 1 ( Keap1 ) , which targets Nrf2 for ubiquitination and degradation .	Under normal conditions, Nrf2 is bound in the cytosol by its repressor, kelch like ECH associated protein 1 (Keap1), which targets Nrf2 for ubiquitination and degradation.	18	30	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	21	22	26	27
Nrf2 is sequestered in cytosol by an inhibitory protein Keap1 which causes its proteasomal degradation .	Nrf2 is sequestered in cytosol by an inhibitory protein Keap1 which causes its proteasomal degradation.	0	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	0	1
Keap1 , an E3 ubiquitin ligase , constantly targets Nrf2 for ubiquitination and subsequent degradation under unstressed conditions .	Keap1, an E3 ubiquitin ligase, constantly targets Nrf2 for ubiquitination and subsequent degradation under unstressed conditions.	0	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	9	10
Under normal conditions , Nrf2 is repressed by its association with Keap1 which targets Nrf2 for ubiquitination and proteasomal degradation .	Under normal conditions, Nrf2 is repressed by its association with Keap1 which targets Nrf2 for ubiquitination and proteasomal degradation.	6	19	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	14	15
Recently , XREF_BIBR reported that Nrf2 activation by 1,2-NQ was mediated by covalent modification and subsequent degradation of Keap1 .	Recently, XREF_BIBR reported that Nrf2 activation by 1,2-NQ was mediated by covalent modification and subsequent degradation of Keap1.	5	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	18	19	5	6
In addition , NMRs have markedly higher levels of cytoprotective NRF2 signaling activity due to the lower negative regulators of this signaling , such as Keap1 and betaTrCP .	In addition, NMRs have markedly higher levels of cytoprotective NRF2 signaling activity due to the lower negative regulators of this signaling, such as Keap1 and betaTrCP.	10	27	signaling activity	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	25	26	10	11
Often , Nrf2 is up-regulated in tumours of the head and neck , liver , lung , ovary and stomach through loss of its repression by Keap1 .	Often, Nrf2 is up-regulated in tumours of the head and neck, liver, lung, ovary and stomach through loss of its repression by Keap1.	2	27	up-regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	26	27	2	3
Keap1 causes Nrf2 to be degraded through the ubiquitin-proteasome pathway and thus ensures that Nrf2 is constitutively suppressed under unstressed conditions .	Keap1 causes Nrf2 to be degraded through the ubiquitin-proteasome pathway and thus ensures that Nrf2 is constitutively suppressed under unstressed conditions.	0	12	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
In defending the body from oxidative , inflammatory , or toxic stress , Keap1 negatively regulates Nrf2 by enhancing the rate of Nrf2 proteasomal degradation and alters its subcellular distribution .	In defending the body from oxidative, inflammatory, or toxic stress, Keap1 negatively regulates Nrf2 by enhancing the rate of Nrf2 proteasomal degradation and alters its subcellular distribution.	13	26	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	16	17
Under normal circumstances , Nrf2 is targeted for degradation by Keap1 .	Under normal circumstances, Nrf2 is targeted for degradation by Keap1.	4	11	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	4	5
Finally , the DLGex of Nrf2 is competitively displaced by phospho-p62 , which results in the dissociation of Nrf2 from Keap1 and robust activation of Nrf2 ( p62-Keap1-Nrf2 pathway ) .	Finally, the DLGex of Nrf2 is competitively displaced by phospho-p62, which results in the dissociation of Nrf2 from Keap1 and robust activation of Nrf2 (p62-Keap1-Nrf2 pathway).	20	28	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	25	26
It was initially thought that Keap1 inhibits Nrf2 by tethering the transcription factor in the cytoplasm and preventing its translocation to the nucleus [ XREF_BIBR ] before it was recognized that Keap1 serves to target Nrf2 for proteasomal degradation [ XREF_BIBR , XREF_BIBR ] .	It was initially thought that Keap1 inhibits Nrf2 by tethering the transcription factor in the cytoplasm and preventing its translocation to the nucleus [XREF_BIBR] before it was recognized that Keap1 serves to target Nrf2 for proteasomal degradation [XREF_BIBR, XREF_BIBR].	5	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	7	8
Another question that remains unanswered is whether MAPKs affect Keap1 mediated control of Nrf2 protein stability in vivo .	Another question that remains unanswered is whether MAPKs affect Keap1 mediated control of Nrf2 protein stability in vivo.	9	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	13	14
Furthermore , epigenetic modification in both Keap1 and Nrf2 can also activate Nrf2 as demonstrated in malignant glioma , colon cancer , and breast cancer .	Furthermore, epigenetic modification in both Keap1 and Nrf2 can also activate Nrf2 as demonstrated in malignant glioma, colon cancer, and breast cancer.	3	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	12	13
Exposure to xenobiotics and oxidants leads to the dissociation of Nrf2 from Keap1 , which allows the free Nrf2 to translocate to the nucleus where it heterodimerizes with c-Jun , an activator protein-1 ( AP-1 ) family protein .	Exposure to xenobiotics and oxidants leads to the dissociation of Nrf2 from Keap1, which allows the free Nrf2 to translocate to the nucleus where it heterodimerizes with c-Jun, an activator protein-1 (AP-1) family protein.	5	20	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	18	19
The electrophilic lipid peroxidation product , 4-hydroxy-2-nonenal ( HNE ) has been shown to modify Keap1 allowing Nrf2 to enter the nucleus .	The electrophilic lipid peroxidation product, 4-hydroxy-2-nonenal (HNE) has been shown to modify Keap1 allowing Nrf2 to enter the nucleus.	14	19	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	17	18
Third , Keap1 shRNA , mimicking miR-200a , activated Nrf2 and protected OB-6 cells from Dex .	Third, Keap1 shRNA, mimicking miR-200a, activated Nrf2 and protected OB-6 cells from Dex.	2	10	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	9	10
Disruption of endogenous Keap1 dimerization using BTB/POZ dominant negative proteins also inhibits the ability of Keap1 to retain Nrf2 in the cytoplasm .	Disruption of endogenous Keap1 dimerization using BTB/POZ dominant negative proteins also inhibits the ability of Keap1 to retain Nrf2 in the cytoplasm.	3	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	18	19
Sequestered by cytoplasmic Keap1 and targeted to proteasomal degradation in basal conditions , in case of oxidative stress Nrf2 detaches from Keap1 and translocates to the nucleus , where it heterodimerizes with one of the small Maf proteins .	Sequestered by cytoplasmic Keap1 and targeted to proteasomal degradation in basal conditions, in case of oxidative stress Nrf2 detaches from Keap1 and translocates to the nucleus, where it heterodimerizes with one of the small Maf proteins.	0	19	Sequestered	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	18	19
The competitive interaction with Keap1 increases Nrf2 regulated genes .	The competitive interaction with Keap1 increases Nrf2 regulated genes.	2	8	increases	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
Through target ID and validation , we have elucidated that pterisolic acid B activates the Nrf2 pathway by covalent modification of Cys171 within Keap1 , which inhibits Nrf2 degradation mediated by Keap1-Cul3 complexes .	Through target ID and validation, we have elucidated that pterisolic acid B activates the Nrf2 pathway by covalent modification of Cys171 within Keap1, which inhibits Nrf2 degradation mediated by Keap1-Cul3 complexes.	13	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	23	24	27	28
( 2 ) 3-Hydroxyanthranilic acid , a tryptophan kynurenine pathway metabolite , changes conformation of Keap1 , inducing the dissociation of Nrf2 and Keap1 , activating Nrf2 to enter the nucleus and induce expressions of antioxidant proteins ( such as HO-1 ) , thereby enhancing cellular antioxidant capacity .	(2) 3-Hydroxyanthranilic acid, a tryptophan kynurenine pathway metabolite, changes conformation of Keap1, inducing the dissociation of Nrf2 and Keap1, activating Nrf2 to enter the nucleus and induce expressions of antioxidant proteins (such as HO-1), thereby enhancing cellular antioxidant capacity.	13	23	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	21	22
Nrf2 normally resides in the cytoplasm , bound by its cytosolic inhibitor , Keap1 , which targets Nrf2 for proteosomal degradation .	Nrf2 normally resides in the cytoplasm, bound by its cytosolic inhibitor, Keap1, which targets Nrf2 for proteosomal degradation.	5	20	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	17	18
Keap1 , an E3-ubiquitin ligase , targets Nrf2 for ubiquitin dependent degradation , and is the major mechanism by which Nrf2 nuclear levels are tightly controlled in cells .	Keap1, an E3-ubiquitin ligase, targets Nrf2 for ubiquitin dependent degradation, and is the major mechanism by which Nrf2 nuclear levels are tightly controlled in cells.	0	8	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	7	8
In unstressed conditions , Nrf2 is constitutively synthesized and bound by Keap1 , which is a cysteine rich protein that targets Nrf2 for proteasomal degradation .	In unstressed conditions, Nrf2 is constitutively synthesized and bound by Keap1, which is a cysteine rich protein that targets Nrf2 for proteasomal degradation.	4	18	synthesized	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	4	5
In summary , Nrf2 is a very unstable protein under basal conditions because Keap1 is actively targeting Nrf2 for ubiquitination and degradation .	In summary, Nrf2 is a very unstable protein under basal conditions because Keap1 is actively targeting Nrf2 for ubiquitination and degradation.	13	21	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	17	18
In response to oxidative and electrophilic stress , key cysteine residues of KEAP1 are oxidised to allow NFE2L2 to dissociate from the ubiquitination activity of the complex .	In response to oxidative and electrophilic stress, key cysteine residues of KEAP1 are oxidised to allow NFE2L2 to dissociate from the ubiquitination activity of the complex.	10	19	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NFE2L2	NFE2L2	NFE2L2	12	13	17	18
Keap1 targets Nrf2 for ubiquitin conjugation and subsequent proteasome degradation in the cytoplasm by acting as a substrate adaptor for the Cul3 based E3 ubiquitin ligase complex .	Keap1 targets Nrf2 for ubiquitin conjugation and subsequent proteasome degradation in the cytoplasm by acting as a substrate adaptor for the Cul3 based E3 ubiquitin ligase complex.	0	22	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
In addition to mutation , hypermethylation of the KEAP1 promoter and NRF2 copy number amplifications promote NRF2 activity in lung , colon and prostate cancer .	In addition to mutation, hypermethylation of the KEAP1 promoter and NRF2 copy number amplifications promote NRF2 activity in lung, colon and prostate cancer.	5	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	hypermethylation of the KEAP1	keap1	NRF2	NRF2	nrf2	8	9	16	17
The demonstration that activation of Nrf2 by TBE-31 ameliorates NASH is consistent with several earlier reports in which pharmacologic activators of Nrf2 including baicalein , XREF_BIBR SFN , XREF_BIBR or Ezetimibe , XREF_BIBR or genetic activation of Nrf2 by expression of a hypomorphic Keap1 allele XREF_BIBR or hepatocyte specific knockout of Keap1 , XREF_BIBR inhibit NASH in rodents caused by an MCD diet or an HF diet .	The demonstration that activation of Nrf2 by TBE-31 ameliorates NASH is consistent with several earlier reports in which pharmacologic activators of Nrf2 including baicalein, XREF_BIBR SFN, XREF_BIBR or Ezetimibe, XREF_BIBR or genetic activation of Nrf2 by expression of a hypomorphic Keap1 allele XREF_BIBR or hepatocyte specific knockout of Keap1, XREF_BIBR inhibit NASH in rodents caused by an MCD diet or an HF diet.	35	49	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Keap1	expression of a hypomorphic Keap1	keap1	Nrf2	Nrf2	nrf2	43	44	37	38
We noted that KEAP1 , a substrate adaptor protein that targets NFE2L2 and NRF2 for ubiquitination and proteasomal degradation , was the only gene that scored highly in all four genome scale screens ( XREF_FIG and XREF_SUPPLEMENTARY ) .	We noted that KEAP1, a substrate adaptor protein that targets NFE2L2 and NRF2 for ubiquitination and proteasomal degradation, was the only gene that scored highly in all four genome scale screens (XREF_FIG and XREF_SUPPLEMENTARY).	3	23	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	3	4	13	14
The magnitude and duration of inducible Nrf2 signaling is delicately controlled at multiple levels by Keap1 , which targets Nrf2 for redox sensitive ubiquitin mediated degradation in the cytoplasm and exports Nrf2 from the nucleus .	The magnitude and duration of inducible Nrf2 signaling is delicately controlled at multiple levels by Keap1, which targets Nrf2 for redox sensitive ubiquitin mediated degradation in the cytoplasm and exports Nrf2 from the nucleus.	10	23	targets	Positive_activation_syntax_3a_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	19	20
Point mutations in Keap1 gene lead to non conservative amino acid substitutions in PrCa cells , novel transcriptional and posttranscriptional mechanisms of Keap1 inactivation , such as promoter CpG island hypermethylation and aberrant splicing of Keap1 in DU-145 cells , enhances Nrf2 activity and subsequently prevents cell sensitivity to radiation induced cell death .	Point mutations in Keap1 gene lead to non conservative amino acid substitutions in PrCa cells, novel transcriptional and posttranscriptional mechanisms of Keap1 inactivation, such as promoter CpG island hypermethylation and aberrant splicing of Keap1 in DU-145 cells, enhances Nrf2 activity and subsequently prevents cell sensitivity to radiation induced cell death.	3	42	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	41	42
Under no stress condition , Nrf2 controls basal expression of its target genes and is continually targeted by Keap1 for degradation catalyzed by the 26S proteasome via the ubiquitin dependent way [ XREF_BIBR ] .	Under no stress condition, Nrf2 controls basal expression of its target genes and is continually targeted by Keap1 for degradation catalyzed by the 26S proteasome via the ubiquitin dependent way [XREF_BIBR].	5	19	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	18	19	5	6
Under oxidative stress , MAPK and PKC pathways are activated to degrade Keap1 , the repressor of transcription factor Nrf2 , leading to the activation of Nrf2 and downstream antioxidant processes in the cell XREF_BIBR .	Under oxidative stress, MAPK and PKC pathways are activated to degrade Keap1, the repressor of transcription factor Nrf2, leading to the activation of Nrf2 and downstream antioxidant processes in the cell XREF_BIBR.	12	27	leading to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	26	27
A possible explanation for retention of some activity is that Keap1 independent activation of Nrf2 had occurred , for these vapor samples did induce the phosphorylation of ERK and phosphatidyl-inositol 3-kinase ( PI3K ) in BEAS-2B cells ( data not shown ) .	A possible explanation for retention of some activity is that Keap1 independent activation of Nrf2 had occurred, for these vapor samples did induce the phosphorylation of ERK and phosphatidyl-inositol 3-kinase (PI3K) in BEAS-2B cells (data not shown).	10	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	14	15
Under oxidative stress conditions , Nrf2 is induced at the protein level through redox sensitive modifications on critical cysteine residues in Keap1 , a component of an E3 ubiquitin ligase complex that targets Nrf2 for proteasomal degradation .	Under oxidative stress conditions, Nrf2 is induced at the protein level through redox sensitive modifications on critical cysteine residues in Keap1, a component of an E3 ubiquitin ligase complex that targets Nrf2 for proteasomal degradation.	19	36	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	21	22	33	34
At baseline , Nrf2 is maintained inactive in the cytoplasm by binding to Kelch like ECH associated protein 1 ( Keap1 ) , which targets Nrf2 for proteasomal degradation by serving as a binding adaptor to the Cul3 based E3 ubiquitin ligase complex [ XREF_BIBR ] .	At baseline, Nrf2 is maintained inactive in the cytoplasm by binding to Kelch like ECH associated protein 1 (Keap1), which targets Nrf2 for proteasomal degradation by serving as a binding adaptor to the Cul3 based E3 ubiquitin ligase complex [XREF_BIBR].	17	28	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	25	26
Nrf2 is sequestered in cytosol by an inhibitory protein Keap1 causing its proteosomal degradation [ XREF_BIBR ] .	Nrf2 is sequestered in cytosol by an inhibitory protein Keap1 causing its proteosomal degradation [XREF_BIBR].	0	10	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	0	1
Objective : We investigated the cross-regulations among NRF2 , NRF1 , and KEAP1 , a cullin-3-adapter protein that allows NRF2 to be ubiquinated and degraded by the proteasome complex , in arsenic induced antioxidant responses .	Objective : We investigated the cross-regulations among NRF2, NRF1, and KEAP1, a cullin-3-adapter protein that allows NRF2 to be ubiquinated and degraded by the proteasome complex, in arsenic induced antioxidant responses.	5	22	allows	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	12	13	19	20
Classically , modification of Keap1 cysteine residues by oxidative or electrophilic stress inhibits proteasomal degradation of Nrf2 30 .	Classically, modification of Keap1 cysteine residues by oxidative or electrophilic stress inhibits proteasomal degradation of Nrf2 30.	4	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	16	17
This may be due to compromised signaling through the Nrf2 pathway caused by increased abundance of Keap1 and Bach1 , which negatively regulate Nrf2 and the ARE , respectively .	This may be due to compromised signaling through the Nrf2 pathway caused by increased abundance of Keap1 and Bach1, which negatively regulate Nrf2 and the ARE, respectively.	9	18	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	9	10
KEAP1 releases NRF2 after exposure to ROS and thereby allows NRF2 accumulation .	KEAP1 releases NRF2 after exposure to ROS and thereby allows NRF2 accumulation.	0	11	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	10	11
Under normal conditions steadily expressed NRF2 protein is permanently targeted for ubiquitination and proteosomal degradation by the cytosolic protein KEAP1 .	Under normal conditions steadily expressed NRF2 protein is permanently targeted for ubiquitination and proteosomal degradation by the cytosolic protein KEAP1.	5	20	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	19	20	5	6
In the present study , Keap1 expression decreased as dietary valine levels increased up to a certain level in muscle , suggesting that the valine induced increase in the expression of antioxidant enzyme genes may be partly attributed to increased Nrf2 nuclear translocation caused by the down-regulation of Keap1 expression .	In the present study, Keap1 expression decreased as dietary valine levels increased up to a certain level in muscle, suggesting that the valine induced increase in the expression of antioxidant enzyme genes may be partly attributed to increased Nrf2 nuclear translocation caused by the down-regulation of Keap1 expression.	40	50	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1 expression	keap1	Nrf2	Nrf2	nrf2	48	49	40	41
Nrf2 is mainly regulated at the level of its protein stability by the cytosolic protein Keap1 , which functions as a substrate recruiting subunit of a Cullin3 E3 ubiquitin ligase to target Nrf2 for ubiquitination and subsequent degradation .	Nrf2 is mainly regulated at the level of its protein stability by the cytosolic protein Keap1, which functions as a substrate recruiting subunit of a Cullin3 E3 ubiquitin ligase to target Nrf2 for ubiquitination and subsequent degradation.	3	33	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	32	33
Collectively , these reports are suggesting that multiple cysteine residues of KEAP1 collectively contribute to transduce NRF2 signaling through conformational changes of KEAP1 .	Collectively, these reports are suggesting that multiple cysteine residues of KEAP1 collectively contribute to transduce NRF2 signaling through conformational changes of KEAP1.	9	17	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	11	12	16	17
In addition to activation by ROS , Nrf2 also can be activated by Keap1 independent phosphorylation .	In addition to activation by ROS, Nrf2 also can be activated by Keap1 independent phosphorylation.	7	16	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1 independent phosphorylation	keap1	Nrf2	Nrf2	nrf2	13	14	7	8
Release from Keap1 allows Nrf2 to translocate to the nucleus and activate antioxidants response elements which regulate many antioxidant genes .	Release from Keap1 allows Nrf2 to translocate to the nucleus and activate antioxidants response elements which regulate many antioxidant genes.	0	6	allows	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	4	5
In this line , depletion of SQSTM1 or KEAP1 modulated NFE2L2 activation and impaired the DHA mediated anti-inflammatory effects .	In this line, depletion of SQSTM1 or KEAP1 modulated NFE2L2 activation and impaired the DHA mediated anti-inflammatory effects.	4	11	modulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NFE2L2	NFE2L2	NFE2L2	8	9	10	11
These results demonstrate that miR-141 targets Keap1 to activate Nrf2 signaling , which protects RPEs and RGCs from UV radiation .	These results demonstrate that miR-141 targets Keap1 to activate Nrf2 signaling, which protects RPEs and RGCs from UV radiation.	4	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	9	10
Keap1 targets Nrf2 for ubiquitination and subsequent degradation by proteasome .	Keap1 targets Nrf2 for ubiquitination and subsequent degradation by proteasome.	0	7	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
Nrf2 is regulated by substrate adaptor protein Kelch like ECH associated protein 1 ( Keap1 ) that can target Nrf2 for ubiquitination and degradation by the proteasome .	Nrf2 is regulated by substrate adaptor protein Kelch like ECH associated protein 1 (Keap1) that can target Nrf2 for ubiquitination and degradation by the proteasome.	11	23	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	19	20
These results suggest that oxidation of Keap1 and subsequent activation of Nrf2 by parthenolide are essential for normal cell survival after radiation treatment .	These results suggest that oxidation of Keap1 and subsequent activation of Nrf2 by parthenolide are essential for normal cell survival after radiation treatment.	6	13	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	11	12
We have also identified a more potent natural product analogue J19-1 by semisynthesis and the subsequent biochemical evaluations revealed that J19-1 activates the Nrf2 pathway by covalently modifying Cys171 of keap1 , which inhibits Nrf2 degradation mediated by Keap1-Cul3 complexes .	We have also identified a more potent natural product analogue J19-1 by semisynthesis and the subsequent biochemical evaluations revealed that J19-1 activates the Nrf2 pathway by covalently modifying Cys171 of keap1, which inhibits Nrf2 degradation mediated by Keap1-Cul3 complexes.	28	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	keap1	keap1	keap1	Nrf2	Nrf2	Nrf2	30	31	34	35
In summary ( XREF_FIG ) , we propose that , under normal conditions , a single Keap1 protein is able to target multiple Nrf2 proteins for destruction via the ubiquitin-proteasome system .	In summary (XREF_FIG), we propose that, under normal conditions, a single Keap1 protein is able to target multiple Nrf2 proteins for destruction via the ubiquitin-proteasome system.	16	24	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	23	24
Darley-Usmar and coworkers have shown that HNE directly modifies Keap1 , which allows Nrf2 to avoid degradation and migrate to the nucleus where it can bind to EpRE elements in the promoters of the human GCLC and GCLM genes .	Darley-Usmar and coworkers have shown that HNE directly modifies Keap1, which allows Nrf2 to avoid degradation and migrate to the nucleus where it can bind to EpRE elements in the promoters of the human GCLC and GCLM genes.	8	18	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	13	14
Moreover , epigenetic modifications in Keap1 have also been shown to promote the accumulation of free Nrf2 in NSCLC tissue XREF_BIBR .	Moreover, epigenetic modifications in Keap1 have also been shown to promote the accumulation of free Nrf2 in NSCLC tissue XREF_BIBR.	3	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	16	17
PERK dependent phosphorylation triggers dissociation of Nrf2 and Keap1 complexes and allows subsequent Nrf2 nuclear import .	PERK dependent phosphorylation triggers dissociation of Nrf2 and Keap1 complexes and allows subsequent Nrf2 nuclear import.	2	15	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	phosphorylation triggers dissociation of Nrf2 and Keap1	keap1	Nrf2	Nrf2	nrf2	8	9	13	14
Nrf2 is targeted by Keap1 ( Kelch like ECH associated protein1 ) for ubiquitylation and proteasomal degradation under normal condition [ XREF_BIBR ] .	Nrf2 is targeted by Keap1 (Kelch like ECH associated protein1) for ubiquitylation and proteasomal degradation under normal condition [XREF_BIBR].	0	16	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	0	1
Many genes in each group are established NRF2 target genes , and included NQO1 and GCLM mRNAs ( consistent with our qRT-PCR results ) and other known NRF2 targets such as MAFG XREF_BIBR , KEAP1 XREF_BIBR , GSR XREF_BIBR , EPHX1 XREF_BIBR , TXNRD1 XREF_BIBR , PRDX1 XREF_BIBR and TXN XREF_BIBR , all of which were induced in response to L-SUL treatment in both PD and Control hONS cultures .	Many genes in each group are established NRF2 target genes, and included NQO1 and GCLM mRNAs (consistent with our qRT-PCR results) and other known NRF2 targets such as MAFG XREF_BIBR, KEAP1 XREF_BIBR, GSR XREF_BIBR, EPHX1 XREF_BIBR, TXNRD1 XREF_BIBR, PRDX1 XREF_BIBR and TXN XREF_BIBR, all of which were induced in response to L-SUL treatment in both PD and Control hONS cultures.	27	35	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	34	35	27	28
Under the basal condition , Nrf2 is compartmentalized in the cytoplasm and Nrf2 dependent transcription is repressed by a negative regulator Keap1 .	Under the basal condition, Nrf2 is compartmentalized in the cytoplasm and Nrf2 dependent transcription is repressed by a negative regulator Keap1.	7	22	repressed	Negative_activation_syntax_6_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	21	22	12	13
In cells cultured under homeostatic conditions , steady-state levels of Nrf2 are kept low because Keap1 , which serves as an adaptor protein for an E3 ubiquitin ligase , targets Nrf2 for ubiquitin dependent degradation by the proteasome [ XREF_BIBR - XREF_BIBR ] .	In cells cultured under homeostatic conditions, steady-state levels of Nrf2 are kept low because Keap1, which serves as an adaptor protein for an E3 ubiquitin ligase, targets Nrf2 for ubiquitin dependent degradation by the proteasome [XREF_BIBR - XREF_BIBR].	15	34	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	30	31
Nrf2 drives expression of genes in the oxidative response pathway , and NFEL2L mutations frequently disrupt binding to KEAP1 , which normally targets Nrf2 for degradation [ XREF_BIBR ] .	Nrf2 drives expression of genes in the oxidative response pathway, and NFEL2L mutations frequently disrupt binding to KEAP1, which normally targets Nrf2 for degradation [XREF_BIBR].	15	27	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	18	19	23	24
Magnified Nrf2 translation coupled with inhibited Keap1 mediated Nrf2 degradation could instantaneously elicit an effective antioxidant response .	Magnified Nrf2 translation coupled with inhibited Keap1 mediated Nrf2 degradation could instantaneously elicit an effective antioxidant response.	0	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	8	9
Oxidants , such as H 2 O 2 target cysteine residues in Keap1 allowing Nrf2 to escape Cul3 mediated degradation XREF_BIBR .	Oxidants, such as H 2 O 2 target cysteine residues in Keap1 allowing Nrf2 to escape Cul3 mediated degradation XREF_BIBR.	10	16	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	14	15
The interaction of Keap1 with Nrf2 under basal conditions directs Nrf2 for degradation by the ubiquitin-proteasomal system .	The interaction of Keap1 with Nrf2 under basal conditions directs Nrf2 for degradation by the ubiquitin-proteasomal system.	1	12	directs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	10	11
Together , the levels of the KEAP1 was not down-regulated in ROS Low cells , suggesting that the NRF2 constitutive activation in ROS Low cells is mediated through GRP78 and p-PERK signaling but not by KEAP1 down-regulation .	Together, the levels of the KEAP1 was not down-regulated in ROS Low cells, suggesting that the NRF2 constitutive activation in ROS Low cells is mediated through GRP78 and p-PERK signaling but not by KEAP1 down-regulation.	18	36	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	35	36	18	19
Consequently , cells transfected with mutant NFE2L2 were insensitive to KEAP1 mediated downregulation of NFE2L2 signalling .	Consequently, cells transfected with mutant NFE2L2 were insensitive to KEAP1 mediated downregulation of NFE2L2 signalling.	8	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NFE2L2	NFE2L2	NFE2L2	10	11	14	15
Despite the fact that Nrf2 mRNA is constitutively expressed , Keap1 targets Nrf2 for polyubiquitination and degradation , resulting in a short protein half-life .	Despite the fact that Nrf2 mRNA is constitutively expressed, Keap1 targets Nrf2 for polyubiquitination and degradation, resulting in a short protein half-life.	10	18	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	12	13
In the absence of stress , the transcription factor Nrf2 is retained in the cytoplasm through interaction with its inhibitor protein , Keap1 , which targets Nrf2 for ubiquitination and proteasomal degradation .	In the absence of stress, the transcription factor Nrf2 is retained in the cytoplasm through interaction with its inhibitor protein, Keap1, which targets Nrf2 for ubiquitination and proteasomal degradation.	20	31	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	26	27
Nrf2 is normally sequestered in the cytoplasm by the actin bound protein Keap1 , a substrate adaptor for an E3 ubiquitin ligase , which targets Nrf2 for rapid turnover [ XREF_BIBR ] .	Nrf2 is normally sequestered in the cytoplasm by the actin bound protein Keap1, a substrate adaptor for an E3 ubiquitin ligase, which targets Nrf2 for rapid turnover [XREF_BIBR].	10	30	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	25	26
Transfection of the Nrf2 or Keap1 expression plasmids successfully induced high expressions of human Nrf2 mRNA or Keap1 mRNA , respectively , in RAW 264.7 cells .	Transfection of the Nrf2 or Keap1 expression plasmids successfully induced high expressions of human Nrf2 mRNA or Keap1 mRNA, respectively, in RAW 264.7 cells.	5	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	14	15
Cell exposure to electrophilic and oxidative stress , however , releases NRF2 from the KEAP1 complex , which enables NRF2 to translocate to the nucleus and activate a battery of phase II cytoprotective genes by binding to the ARE [ XREF_BIBR ] .	Cell exposure to electrophilic and oxidative stress, however, releases NRF2 from the KEAP1 complex, which enables NRF2 to translocate to the nucleus and activate a battery of phase II cytoprotective genes by binding to the ARE [XREF_BIBR].	14	20	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	14	15	19	20
Nrf2 protein did not degrade , and sulforaphane as well as Keap1 siRNA still induced Nrf2 and Nrf2 dependent genes in the absence of DJ-1 .	Nrf2 protein did not degrade, and sulforaphane as well as Keap1 siRNA still induced Nrf2 and Nrf2 dependent genes in the absence of DJ-1.	11	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	15	16
The association of p62 with Keap1 allows Nrf2 to activate antioxidant gene expression [ XREF_BIBR ] .	The association of p62 with Keap1 allows Nrf2 to activate antioxidant gene expression [XREF_BIBR].	3	9	allows	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	7	8
These observations support the notion that cellular NRF2 levels are strictly regulated by two pathways through the protein degradation-repression mechanism : derepression from the KEAP1 based repression causes a rapid increase in NRF2 activity and induction of cellular defense mechanisms against electrophilic and oxidative insults , while beta-TrCP-based NRF2 degradation inhibits unnecessary NRF2 over-induction caused by KEAP1 inactivation .	These observations support the notion that cellular NRF2 levels are strictly regulated by two pathways through the protein degradation-repression mechanism : derepression from the KEAP1 based repression causes a rapid increase in NRF2 activity and induction of cellular defense mechanisms against electrophilic and oxidative insults, while beta-TrCP-based NRF2 degradation inhibits unnecessary NRF2 over-induction caused by KEAP1 inactivation.	52	57	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	56	57	52	53
This is the first time that the endogenous repressor Keap1 has been targeted to increase Nrf2 signaling in fibroblasts and proposes a new therapeutic strategy in combating ROS mishandling within diabetic wounds .	This is the first time that the endogenous repressor Keap1 has been targeted to increase Nrf2 signaling in fibroblasts and proposes a new therapeutic strategy in combating ROS mishandling within diabetic wounds.	6	20	targeted	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	15	16
The KEAP1 and NRF2 mutations associated with human cancers impair the Keap1 mediated repression of Nrf2 .	The KEAP1 and NRF2 mutations associated with human cancers impair the Keap1 mediated repression of Nrf2.	10	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	15	16
Stress induced oxidation of Keap1 cysteines allows Nrf2 to escape proteasomal targeting , dimerize with Maf1 , and induce transcription of target genes bearing antioxidant response elements ( ARE ) [ XREF_BIBR , XREF_BIBR ] .	Stress induced oxidation of Keap1 cysteines allows Nrf2 to escape proteasomal targeting, dimerize with Maf1, and induce transcription of target genes bearing antioxidant response elements (ARE) [XREF_BIBR, XREF_BIBR].	4	9	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	7	8
Upon normal homeostatic conditions , Nrf2 is repressed by its negative regulator Keap1 .	Upon normal homeostatic conditions, Nrf2 is repressed by its negative regulator Keap1.	5	13	repressed	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	5	6
Lack of p62 blocked CCCP induced Keap1 degradation and inhibited Nrf2 activation , and thereby increased the accumulation of ROS .	Lack of p62 blocked CCCP induced Keap1 degradation and inhibited Nrf2 activation, and thereby increased the accumulation of ROS.	2	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	p62 blocked CCCP induced Keap1	keap1	Nrf2	Nrf2	nrf2	6	7	10	11
Inactivation of KEAP1 strongly induces NRF2 , and this phenomenon is often observed in cancer cells ; cancer cells can thus acquire malignancy by perverting NRF2 activity .	Inactivation of KEAP1 strongly induces NRF2, and this phenomenon is often observed in cancer cells; cancer cells can thus acquire malignancy by perverting NRF2 activity.	0	6	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	2	3	5	6
Nuclear factor erythroid 2 related factor 2 ( NRF2 ) activates expression of cytoprotective proteins such as GCLC and enhances cancer cell survival , whereas KEAP1 inhibits NRF2 by mediating NRF2 degradation .	Nuclear factor erythroid 2 related factor 2 (NRF2) activates expression of cytoprotective proteins such as GCLC and enhances cancer cell survival, whereas KEAP1 inhibits NRF2 by mediating NRF2 degradation.	25	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	25	26	30	31
Importantly , the Keap1 mediated Nrf2 degradation can also be inhibited by small molecules , which are often electrophilic and act by modifying key Keap1 cysteine residues , particularly cysteine 151 [ XREF_BIBR ] .	Importantly, the Keap1 mediated Nrf2 degradation can also be inhibited by small molecules, which are often electrophilic and act by modifying key Keap1 cysteine residues, particularly cysteine 151 [XREF_BIBR].	2	6	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	5	6
Under the basal condition , Nrf2 dependent transcription is repressed by a negative regulator Keap1 .	Under the basal condition, Nrf2 dependent transcription is repressed by a negative regulator Keap1.	5	15	repressed	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	5	6
The sequestration of KEAP1 by p62 allows stabilization of NRF2 , which can then translocate to the nucleus and initiate target gene transcription .	The sequestration of KEAP1 by p62 allows stabilization of NRF2, which can then translocate to the nucleus and initiate target gene transcription.	1	19	allows	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	KEAP1	KEAP1	keap1	NRF2	NRF2, which can then translocate to the nucleus	nrf2	3	4	9	10
KEAP1 targets NRF2 for proteasomal degradation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	KEAP1 targets NRF2 for proteasomal degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	11	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	2	3
At baseline , the Nrf2 pathway is negatively regulated by Keap1 , a cytoplasmic regulatory protein that targets Nrf2 for proteasomal degradation through interaction with the Cullin-E3 ubiquitin ligase [ XREF_BIBR , XREF_BIBR ] .	At baseline, the Nrf2 pathway is negatively regulated by Keap1, a cytoplasmic regulatory protein that targets Nrf2 for proteasomal degradation through interaction with the Cullin-E3 ubiquitin ligase [XREF_BIBR, XREF_BIBR].	8	21	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	18	19
Keap1 targets the transcription factor Nrf2 , which regulates antioxidant genes , for proteasomal degradation .	Keap1 targets the transcription factor Nrf2, which regulates antioxidant genes, for proteasomal degradation.	0	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	5	6
It is hence likely that piceatannol modifies specific cysteine residues of Keap1 , which allows Nrf2 to translocate into the nucleus and bind to ARE , leading to enhancement of the expression of HO-1 .	It is hence likely that piceatannol modifies specific cysteine residues of Keap1, which allows Nrf2 to translocate into the nucleus and bind to ARE, leading to enhancement of the expression of HO-1.	9	24	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	15	16
Nrf2 protein degradation mechanisms may be mediated by Keap1 dependent and independent process .	Nrf2 protein degradation mechanisms may be mediated by Keap1 dependent and independent process.	0	12	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
XREF_BIBR , XREF_BIBR Nrf2 is tethered in the cytoplasm by the Keap1 protein under normal or unstressed conditions , 3 and Keap1 can target Nrf2 for ubiquitination by CUL3-ROC1 ligase and subsequent degradation by the proteasome .	XREF_BIBR, XREF_BIBR Nrf2 is tethered in the cytoplasm by the Keap1 protein under normal or unstressed conditions, 3 and Keap1 can target Nrf2 for ubiquitination by CUL3-ROC1 ligase and subsequent degradation by the proteasome.	19	26	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	21	22	24	25
As predicted for a redox sensor , mutation of this cysteine to serine blocks the capacity of Keap1 to detect alterations in intracellular redox status and to promote the dissociation of Keap1 : Nrf2 from CUL3 in response to oxidative stress .	As predicted for a redox sensor, mutation of this cysteine to serine blocks the capacity of Keap1 to detect alterations in intracellular redox status and to promote the dissociation of Keap1 : Nrf2 from CUL3 in response to oxidative stress.	15	35	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	33	34
Under conditions of oxidative stress , Keap1 dissociates , allowing Nrf2 to translocate to the nucleus and initiate transcription of genes containing an antioxidant response element .	Under conditions of oxidative stress, Keap1 dissociates, allowing Nrf2 to translocate to the nucleus and initiate transcription of genes containing an antioxidant response element.	6	12	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	10	11
In the Keap1 -/- liver , Nrf2 accumulates in the nucleus due to impaired Keap1 mediated Nrf2 degradation .	In the Keap1 -/- liver, Nrf2 accumulates in the nucleus due to impaired Keap1 mediated Nrf2 degradation.	7	17	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	16	17
In cells with FH deficiency , fumarate mediated succination of Keap1 elicits an Nrf2 response , maintaining constitutively high expression of Nrf2 targets [ XREF_BIBR - XREF_BIBR ] .	In cells with FH deficiency, fumarate mediated succination of Keap1 elicits an Nrf2 response, maintaining constitutively high expression of Nrf2 targets [XREF_BIBR - XREF_BIBR].	8	14	elicits	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	13	14
TGF-beta activity did not affect Keap1 mRNA levels , diminishing the likelihood that KEAP1 absence might underlie NRF2 stabilization .	TGF-beta activity did not affect Keap1 mRNA levels, diminishing the likelihood that KEAP1 absence might underlie NRF2 stabilization.	13	18	underlie	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	13	14	17	18
After its intake , Keap-1 expression was downregulated , promoting the translocation of Nrf2 to the nucleus and the expression of its driven target genes , NQO-1 and glutathione S-transferase P1 ( GST-P1 ) .	After its intake, Keap-1 expression was downregulated, promoting the translocation of Nrf2 to the nucleus and the expression of its driven target genes, NQO-1 and glutathione S-transferase P1 (GST-P1).	4	14	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap-1	Keap-1 expression	keap-1	Nrf2	Nrf2	nrf2	4	5	13	14
Keap1 shRNA induces Nrf2 stabilization in human osteoblastic cells .	Keap1 shRNA induces Nrf2 stabilization in human osteoblastic cells.	0	4	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
Oxidative stress can lead to modification of Keap1 cysteine residues , detaching Nrf2 from Keap1 , which prevents Nrf2 from proteosomal degradation and leads Nrf2 to translocate into the nucleus .	Oxidative stress can lead to modification of Keap1 cysteine residues, detaching Nrf2 from Keap1, which prevents Nrf2 from proteosomal degradation and leads Nrf2 to translocate into the nucleus.	11	25	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	24	25
Nrf2 is sequestered in the cytoplasm by the inhibitory protein Keap1 .	Nrf2 is sequestered in the cytoplasm by the inhibitory protein Keap1.	0	11	sequestered	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	0	1
Constitutive accumulation of NRF2 via a variety of mechanisms that disrupt KEAP1 mediated NRF2 degradation has been observed in various cancer types .	Constitutive accumulation of NRF2 via a variety of mechanisms that disrupt KEAP1 mediated NRF2 degradation has been observed in various cancer types.	10	14	mediated	Positive_early_activation	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	11	12	13	14
On the other hand , Nrf2 gene expression was not significantly affected ( XREF_FIG ) , but this does not preclude effects on Nrf2 activity , since the effect of Keap1 on Nrf2 is post-translational as Keap1 directs Nrf2 for proteasomal degradation .	On the other hand, Nrf2 gene expression was not significantly affected (XREF_FIG), but this does not preclude effects on Nrf2 activity, since the effect of Keap1 on Nrf2 is post-translational as Keap1 directs Nrf2 for proteasomal degradation.	36	41	directs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	36	37	38	39
Essentially all known inducers of phase 2 enzymes modify sulfhydryl groups , and covalent interactions with specific cysteine residues on Keap1 activate Nrf2 .	Essentially all known inducers of phase 2 enzymes modify sulfhydryl groups, and covalent interactions with specific cysteine residues on Keap1 activate Nrf2.	18	23	activate	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	22	23
Under normal conditions , Nrf2 is targeted for proteasomal degradation by INrf2 .	Under normal conditions, Nrf2 is targeted for proteasomal degradation by INrf2.	4	12	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	11	12	4	5
However , when oxidants or electrophiles are present , KEAP1 is inactivated , causing Nrf2 to accumulate and activate expression of its targets .	However, when oxidants or electrophiles are present, KEAP1 is inactivated, causing Nrf2 to accumulate and activate expression of its targets.	9	15	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	9	10	14	15
We demonstrated the potential binding between PhGs and the Keap1 activated Nrf2 and ARE pathway , and that PhGs with more glycosides had enhanced effects .	We demonstrated the potential binding between PhGs and the Keap1 activated Nrf2 and ARE pathway, and that PhGs with more glycosides had enhanced effects.	4	12	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	11	12
Nrf2 is largely regulated by Keap1 , which directs Nrf2 for proteasomal degradation .	Nrf2 is largely regulated by Keap1, which directs Nrf2 for proteasomal degradation.	3	12	directs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	9	10
Keap1 depletion induces Nrf2 stabilization followed by nuclear accumulation and target gene expression in VSMCs .	Keap1 depletion induces Nrf2 stabilization followed by nuclear accumulation and target gene expression in VSMCs.	0	4	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
The rate of Nrf2 degradation , measured under conditions where the majority of Nrf2 was not tethered , exhibited a T ( 1/2 ) of approximately 3 h. Over-expression of human INrf2 , KIAA0132 , blocked Nrf2 conjugation to the ubiquitin polymer and blocked Nrf2 degradation .	The rate of Nrf2 degradation, measured under conditions where the majority of Nrf2 was not tethered, exhibited a T (1/2) of approximately 3 h. Over-expression of human INrf2, KIAA0132, blocked Nrf2 conjugation to the ubiquitin polymer and blocked Nrf2 degradation.	28	37	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	INrf2	Over-expression of human INrf2	inrf2	Nrf2	Nrf2	nrf2	31	32	36	37
Nrf2 is normally sequestered in the cytoplasm by the actin bound protein Keap1 , a substrate adaptor for an E3 ubiquitin ligase , which targets Nrf2 for rapid turnover XREF_BIBR .	Nrf2 is normally sequestered in the cytoplasm by the actin bound protein Keap1, a substrate adaptor for an E3 ubiquitin ligase, which targets Nrf2 for rapid turnover XREF_BIBR.	10	29	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	25	26
Keap1 shRNA also activated Nrf2 and protected OB-6 cells from dexamethasone .	Keap1 shRNA also activated Nrf2 and protected OB-6 cells from dexamethasone.	0	5	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	4	5
Similarly to HIFalpha , under normal redox conditions , NRF2 is associated with a repressor protein , Kelch like ECH associated protein ( KEAP1 ) , which targets NRF2 for ubiquitination .	Similarly to HIFalpha, under normal redox conditions, NRF2 is associated with a repressor protein, Kelch like ECH associated protein (KEAP1), which targets NRF2 for ubiquitination.	21	30	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	23	24	28	29
One of the well established mechanisms is through Keap1 , an inhibitor that binds to and mediates a continual degradation of Nrf2 , and any modification of the key cysteine residues of Keap1 results in activation of Nrf2 .	One of the well established mechanisms is through Keap1, an inhibitor that binds to and mediates a continual degradation of Nrf2, and any modification of the key cysteine residues of Keap1 results in activation of Nrf2.	30	38	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	32	33	37	38
To gain a deeper understanding of the mechanism through which Nrf2 is targeted for ubiquitination by Keap1 , we recently developed a FLIM-FRET-based system in cells expressing Keap1-mCherry and EGFP-Nrf2 fusion proteins .	To gain a deeper understanding of the mechanism through which Nrf2 is targeted for ubiquitination by Keap1, we recently developed a FLIM-FRET-based system in cells expressing Keap1-mCherry and EGFP-Nrf2 fusion proteins.	10	17	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	10	11
In unstressed conditions , the Cullin3-adaptor protein KEAP1 constitutively targets NRF2 for ubiquitin conjugation and degradation by the proteasome .	In unstressed conditions, the Cullin3-adaptor protein KEAP1 constitutively targets NRF2 for ubiquitin conjugation and degradation by the proteasome.	4	15	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	7	8	10	11
Collectively , the results led to the hypothesis ( XREF_SUPPLEMENTARY ) that AI down regulates INrf2 transcripts that combined with higher ROS leads to increased Nrf2 and Nrf2 downstream cytoprotective proteins including detoxifying enzymes , antioxidants and efflux pumps .	Collectively, the results led to the hypothesis (XREF_SUPPLEMENTARY) that AI down regulates INrf2 transcripts that combined with higher ROS leads to increased Nrf2 and Nrf2 downstream cytoprotective proteins including detoxifying enzymes, antioxidants and efflux pumps.	15	27	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	15	16	25	26
At homoeostatic conditions , Keap1 [ XREF_BIBR ] , a substrate adaptor protein for cullin3-RING-box protein 1 ubiquitin ligase , continuously targets Nrf2 for ubiquitination and proteasomal degradation [ XREF_BIBR - XREF_BIBR ] , but loses this function in response to electrophiles and oxidants ( termed inducers ) , which chemically modify reactive cysteine sensors in Keap1 [ XREF_BIBR , XREF_BIBR ] .	At homoeostatic conditions, Keap1 [XREF_BIBR], a substrate adaptor protein for cullin3-RING-box protein 1 ubiquitin ligase, continuously targets Nrf2 for ubiquitination and proteasomal degradation [XREF_BIBR - XREF_BIBR], but loses this function in response to electrophiles and oxidants (termed inducers), which chemically modify reactive cysteine sensors in Keap1 [XREF_BIBR, XREF_BIBR].	4	31	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	22	23
Somatic mutations in Nrf2 or Keap1 can abolish Keap1 dependent degradation of Nrf2 , resulting in its accumulation and translocation to the nucleus to upregulate antioxidant response genes XREF_BIBR .	Somatic mutations in Nrf2 or Keap1 can abolish Keap1 dependent degradation of Nrf2, resulting in its accumulation and translocation to the nucleus to upregulate antioxidant response genes XREF_BIBR.	8	13	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	12	13
Under inflammatory and oxidative stress conditions , elevated ROS can enhance Keap1 oxidation causing release of Nrf2 .	Under inflammatory and oxidative stress conditions, elevated ROS can enhance Keap1 oxidation causing release of Nrf2.	11	17	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	16	17
Inactivation of KEAP1 by ROS activates NRF2 ( XREF_FIG ) .	Inactivation of KEAP1 by ROS activates NRF2 (XREF_FIG).	0	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	2	3	6	7
The corresponding changes in the mRNA levels of Kelch-like-ECH-associated protein 1 ( Keap1a and Keap1b ) and the inhibitor of kappaBalpha ( IkappaBalphaa and IkappaBalphab ) may contribute to regulate the transcriptional activity of Nrf2 and NF-kappaB , respectively .	The corresponding changes in the mRNA levels of Kelch-like-ECH-associated protein 1 (Keap1a and Keap1b) and the inhibitor of kappaBalpha (IkappaBalphaa and IkappaBalphab) may contribute to regulate the transcriptional activity of Nrf2 and NF-kappaB, respectively.	6	36	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Kelch-like-ECH-associated protein 1	levels of Kelch-like-ECH-associated protein 1	kelch-like-ech-associated protein 1	Nrf2	Nrf2	nrf2	8	11	34	35
Upon oxidative stress , dissociation of Keap1 from Nrf2 stabilizes Nrf2 and allows Nrf2 translocate to the nucleus to activate its target genes [ XREF_BIBR ] .	Upon oxidative stress, dissociation of Keap1 from Nrf2 stabilizes Nrf2 and allows Nrf2 translocate to the nucleus to activate its target genes [XREF_BIBR].	4	14	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	13	14
This is consistent with our hypothesis that modification of cysteine residues of KEAP1 by ROS causes NRF2 activation at day 8 of iPSC reprogramming .	This is consistent with our hypothesis that modification of cysteine residues of KEAP1 by ROS causes NRF2 activation at day 8 of iPSC reprogramming.	10	17	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	12	13	16	17
At day 2 , Keap1 expression was up-regulated , maintaining the decrease in the Nrf2 and Keap1 ratio , although the reduction seemed attenuating at day 2 .	At day 2, Keap1 expression was up-regulated, maintaining the decrease in the Nrf2 and Keap1 ratio, although the reduction seemed attenuating at day 2.	4	17	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1 expression	keap1	Nrf2	Nrf2	nrf2	4	5	14	15
Disruption of KEAP1 dependent degradation of NRF2 results in its accumulation and translocation to the nucleus , where it heterodimerizes with small musculoaponeurotic fibrosarcoma ( sMAF ) proteins and binds to the antioxidant response element ( ARE ) of target genes to activate their transcription [ XREF_BIBR ] .	Disruption of KEAP1 dependent degradation of NRF2 results in its accumulation and translocation to the nucleus, where it heterodimerizes with small musculoaponeurotic fibrosarcoma (sMAF) proteins and binds to the antioxidant response element (ARE) of target genes to activate their transcription [XREF_BIBR].	2	7	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	2	3	6	7
Moreover , dysfunctional and mutant inhibitor of Nrf2 ( INrf2 ) in human lung cancer cells failed to degrade Nrf2 , resulting in an increased Bcl-2 level and decreased etoposide- and UV/gamma radiation mediated DNA fragmentation .	Moreover, dysfunctional and mutant inhibitor of Nrf2 (INrf2) in human lung cancer cells failed to degrade Nrf2, resulting in an increased Bcl-2 level and decreased etoposide- and UV/gamma radiation mediated DNA fragmentation.	7	20	degrade	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	9	10	19	20
Upon modification of specific thiols , Keap1 allows Nrf2 to translocate into nucleus and activate the expression of a wide array of antioxidative metabolizing and detoxifying and many other genes by binding to the antioxidant response element ( ARE ) in their regulatory regions [ Structural Basis of KEAP1 Interactions with Nrf2 by Alex Bullock in this issue ] [ XREF_BIBR ] .	Upon modification of specific thiols, Keap1 allows Nrf2 to translocate into nucleus and activate the expression of a wide array of antioxidative metabolizing and detoxifying and many other genes by binding to the antioxidant response element (ARE) in their regulatory regions [Structural Basis of KEAP1 Interactions with Nrf2 by Alex Bullock in this issue] [XREF_BIBR].	6	14	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	8	9
XREF_BIBR , XREF_BIBR Keap1 targets Nrf2 for ubiquintination and proteasomal degradation by acting as a substrate adaptor protein for the cullin 3 dependent ubiquitin ligase .	XREF_BIBR, XREF_BIBR Keap1 targets Nrf2 for ubiquintination and proteasomal degradation by acting as a substrate adaptor protein for the cullin 3 dependent ubiquitin ligase.	0	10	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	5	6
We first confirmed that MMS promoted total protein accumulation and nuclear translocation of NRF2 ( XREF_FIG ) , agreeing with the classical mechanism involving the inhibition of KEAP1 mediated NRF2 degradation .	We first confirmed that MMS promoted total protein accumulation and nuclear translocation of NRF2 (XREF_FIG), agreeing with the classical mechanism involving the inhibition of KEAP1 mediated NRF2 degradation.	25	30	mediated	Positive_early_activation	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	27	28	29	30
XREF_BIBR , XREF_BIBR NRF2 is frequently activated by somatic mutations in KEAP1 in NSCLC , XREF_BIBR , XREF_BIBR and our analysis of the TCGA lung adenocarcinomas shows that the odds of a tumor having a KEAP1 mutation are increased more than sixfold among tumors with LKB1 loss .	XREF_BIBR, XREF_BIBR NRF2 is frequently activated by somatic mutations in KEAP1 in NSCLC, XREF_BIBR, XREF_BIBR and our analysis of the TCGA lung adenocarcinomas shows that the odds of a tumor having a KEAP1 mutation are increased more than sixfold among tumors with LKB1 loss.	0	12	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	11	12	3	4
Keap1 targets Nrf2 for ubiquitination and subsequent degradation by the 26S proteasome .	Keap1 targets Nrf2 for ubiquitination and subsequent degradation by the 26S proteasome.	0	7	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
Keap1 -/- mouse embryo fibroblasts ( MEFs ) constitutively overexpress Nrf2 and Nrf2 target genes and are characterized by low levels of intracellular reactive oxygen species ( ROS ) and a radiation resistant phenotype compared to wild-type MEFs [ XREF_BIBR ] .	Keap1 -/- mouse embryo fibroblasts (MEFs) constitutively overexpress Nrf2 and Nrf2 target genes and are characterized by low levels of intracellular reactive oxygen species (ROS) and a radiation resistant phenotype compared to wild-type MEFs [XREF_BIBR].	0	17	overexpress	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	10	11
Keap1 mediated negative regulation of Nrf2 prevents the unnecessary activation of Nrf2 under normal conditions .	Keap1 mediated negative regulation of Nrf2 prevents the unnecessary activation of Nrf2 under normal conditions.	0	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	11	12
These results suggest that substoichiometric Keap1 HNEylation ( 34 % , Figure XREF_FIG b ) is alone sufficient to block Nrf2 degradation .	These results suggest that substoichiometric Keap1 HNEylation (34%, Figure XREF_FIG b) is alone sufficient to block Nrf2 degradation.	5	21	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	20	21
However , aberrant activation of Nrf2 by keap1 somatic mutations may contribute to carcinogenesis and promote resistance to chemotherapy .	However, aberrant activation of Nrf2 by keap1 somatic mutations may contribute to carcinogenesis and promote resistance to chemotherapy.	3	9	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	keap1	keap1	keap1	Nrf2	Nrf2	Nrf2	7	8	5	6
Activation of Nrf2 by curcumin involves post-translational modifications that result in its release from Keap 1 , which normally targets Nrf2 for degradation , Nrf2 protein accumulation , and translocation to the nucleus .	Activation of Nrf2 by curcumin involves post-translational modifications that result in its release from Keap 1, which normally targets Nrf2 for degradation, Nrf2 protein accumulation, and translocation to the nucleus.	9	29	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap 1	Keap 1	Keap 1	Nrf2	Nrf2	Nrf2	14	16	20	21
NRF2 is normally sequestered and degraded in the cytoplasm by its negative regulator KEAP1 .	NRF2 is normally sequestered and degraded in the cytoplasm by its negative regulator KEAP1.	0	14	sequestered	Negative_activation_syntax_4_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	13	14	0	1
Multiple exogenous stimuli can induce the degradation of Keap1 , which allows Nrf2 to translocate to the nucleus where it can bind to the HO-1 promoter to induce expression [ XREF_BIBR ] .	Multiple exogenous stimuli can induce the degradation of Keap1, which allows Nrf2 to translocate to the nucleus where it can bind to the HO-1 promoter to induce expression [XREF_BIBR].	6	14	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	12	13
S alkylation of Keap1 causes the release of Nrf2 from Keap1 , permitting its escape from proteosomal degradation , nuclear translocation and induction of gene transcription [ XREF_BIBR , XREF_BIBR ] .	S alkylation of Keap1 causes the release of Nrf2 from Keap1, permitting its escape from proteosomal degradation, nuclear translocation and induction of gene transcription [XREF_BIBR, XREF_BIBR].	1	9	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	8	9
However , the nuclear influx of Nrf2 is still determined by the intensity of oxidative stress and Keap1 still modulates the redox-sensitivity of Nrf2 by controlling the availability of free Nrf2 proteins .	However, the nuclear influx of Nrf2 is still determined by the intensity of oxidative stress and Keap1 still modulates the redox-sensitivity of Nrf2 by controlling the availability of free Nrf2 proteins.	17	31	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	30	31
When cells are exposed to oxidative or electrophilic stress , modification of cysteine residues in Keap1 induces Nrf2 dissociation from Keap1 and subsequent nucleus translocation of Nrf2 .	When cells are exposed to oxidative or electrophilic stress, modification of cysteine residues in Keap1 induces Nrf2 dissociation from Keap1 and subsequent nucleus translocation of Nrf2.	13	18	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	17	18
Reaction of Cys151 with EPs is thus critical for inhibition of NRF2 degradation mediated by KEAP1 dependent degradation of NRF2 XREF_BIBR - XREF_BIBR .	Reaction of Cys151 with EPs is thus critical for inhibition of NRF2 degradation mediated by KEAP1 dependent degradation of NRF2 XREF_BIBR - XREF_BIBR.	11	17	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	15	16	11	12
While the number of tumors examined in this study is not sufficiently large to lead to a definitive conclusion , this study is the first to our knowledge to show that mutations and LOH in KEAP1 , as well as possibly other non-mutation-based mechanisms , enable high NRF2 activity in primary lung tumors .	While the number of tumors examined in this study is not sufficiently large to lead to a definitive conclusion, this study is the first to our knowledge to show that mutations and LOH in KEAP1, as well as possibly other non-mutation-based mechanisms, enable high NRF2 activity in primary lung tumors.	31	48	enable	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	35	36	47	48
Nuclear localization of Keap1 might serve to target Nrf2 to specific chromatin areas through the Keap1 BTB protein interaction domain .	Nuclear localization of Keap1 might serve to target Nrf2 to specific chromatin areas through the Keap1 BTB protein interaction domain.	1	9	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	8	9
It was shown that the down-regulation of Keap1 gene expression in murine lung promoted Nrf2 to move from cytoplasm to the nucleus , resulting in the enhancement of Cu/Zn-SOD and GPx mRNA expressions XREF_BIBR .	It was shown that the down-regulation of Keap1 gene expression in murine lung promoted Nrf2 to move from cytoplasm to the nucleus, resulting in the enhancement of Cu/Zn-SOD and GPx mRNA expressions XREF_BIBR.	7	15	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1 gene expression	keap1	Nrf2	Nrf2	nrf2	7	8	14	15
Oxidative and electrophilic stresses are sensed by Keap1 , which activates Nrf2 to achieve cytoprotection by regulating the expression of drug metabolizing and antioxidative stress enzymes and proteins .	Oxidative and electrophilic stresses are sensed by Keap1, which activates Nrf2 to achieve cytoprotection by regulating the expression of drug metabolizing and antioxidative stress enzymes and proteins.	5	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	11	12
The mechanism for this effect has been proposed to involve thiol dependent modulation of Keap1 , leading to loss of its ability to negatively regulate Nrf2 .	The mechanism for this effect has been proposed to involve thiol dependent modulation of Keap1, leading to loss of its ability to negatively regulate Nrf2.	12	26	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	25	26
In addition , the interaction of the Keap1 Kelch domain with p62 , an autophagy factor that functions in the clearance of poly-ubiquitinated complexes , activates Nrf2 through the disruption of binding via the lower affinity Keap1 binding site on Nrf2 .	In addition, the interaction of the Keap1 Kelch domain with p62, an autophagy factor that functions in the clearance of poly-ubiquitinated complexes, activates Nrf2 through the disruption of binding via the lower affinity Keap1 binding site on Nrf2.	7	27	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	26	27
One of the major functions of Keap1 is as a substrate adaptor protein to target Nrf2 to the Cul3 based E3 ubiquitin ligase for ubiquitination and subsequent degradation by the 26S proteasome .	One of the major functions of Keap1 is as a substrate adaptor protein to target Nrf2 to the Cul3 based E3 ubiquitin ligase for ubiquitination and subsequent degradation by the 26S proteasome.	4	16	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	15	16
Under basal conditions , NRF2 is bound to the repressor protein , KEAP1 , which targets NRF2 for degradation by the ubiquitin proteasome pathway .	Under basal conditions, NRF2 is bound to the repressor protein, KEAP1, which targets NRF2 for degradation by the ubiquitin proteasome pathway.	10	18	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	12	13	16	17
Under normal conditions , Nrf2 is targeted by Keap1 , which promotes Nrf2 proteasomal degradation via interactions with an ubiquitin ligase [ XREF_BIBR ] .	Under normal conditions, Nrf2 is targeted by Keap1, which promotes Nrf2 proteasomal degradation via interactions with an ubiquitin ligase [XREF_BIBR].	6	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	12	13
Moreover , it has been reported that CA exhibits an antioxidative property by binding to specific Keap1 cysteine residues , which in turn activates the Keap1 and Nrf2 pathway 19 .	Moreover, it has been reported that CA exhibits an antioxidative property by binding to specific Keap1 cysteine residues, which in turn activates the Keap1 and Nrf2 pathway 19.	16	28	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	27	28
Under normal conditions , Nrf2 is targeted by Keap1 , which promotes Nrf2 proteasomal degradation via interactions with an ubiquitin ligase .	Under normal conditions, Nrf2 is targeted by Keap1, which promotes Nrf2 proteasomal degradation via interactions with an ubiquitin ligase.	6	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	12	13
Elegant biochemical and molecular studies have yielded detailed mechanistic insights into how Nrf2 is inhibited by the ubiquitin ligase component Keap1 and how electrophilic compounds that bind specific Cys residues in Keap1 activate Nrf2 by relieving it from degradation [ XREF_BIBR , XREF_BIBR ] .	Elegant biochemical and molecular studies have yielded detailed mechanistic insights into how Nrf2 is inhibited by the ubiquitin ligase component Keap1 and how electrophilic compounds that bind specific Cys residues in Keap1 activate Nrf2 by relieving it from degradation [XREF_BIBR, XREF_BIBR].	26	34	activate	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	31	32	33	34
Specifically , it has been shown that tBHQ modifies the thiol groups of cysteine ( Cys ) -273 and Cys 288 on the Keap1 protein , which ultimately inhibits the repression of Nrf2 by Keap1 and facilitates Nrf2 signaling .	Specifically, it has been shown that tBHQ modifies the thiol groups of cysteine (Cys) -273 and Cys 288 on the Keap1 protein, which ultimately inhibits the repression of Nrf2 by Keap1 and facilitates Nrf2 signaling.	28	35	repression	Negative_activation_token_2_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	34	35	32	33
When administered to cultured cells , it reacts with cysteine 151 of Keap1 and thereby blocks Keap1 mediated Nrf2 degradation [ XREF_BIBR ] .	When administered to cultured cells, it reacts with cysteine 151 of Keap1 and thereby blocks Keap1 mediated Nrf2 degradation [XREF_BIBR].	15	19	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	16	17	18	19
With oxidative stress , Keap1 releases Nrf2 , which allows Nrf2 to translocate into the nucleus to activate the expression of anti-oxidant-related genes , such as NAD ( P ) H quinone oxidoreductase ( NQO1 ) , heme oxygenase 1 ( HO-1 ) , and glutamate cysteine ligases ( GCLM and GCLC ) 3 .	With oxidative stress, Keap1 releases Nrf2, which allows Nrf2 to translocate into the nucleus to activate the expression of anti-oxidant-related genes, such as NAD (P) H quinone oxidoreductase (NQO1), heme oxygenase 1 (HO-1), and glutamate cysteine ligases (GCLM and GCLC) 3.	4	12	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	10	11
These in vivo data highlight the fact that the formation of the closed conformation is of fundamental importance to the Keap1 mediated Nrf2 regulation .	These in vivo data highlight the fact that the formation of the closed conformation is of fundamental importance to the Keap1 mediated Nrf2 regulation.	17	23	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	22	23
Under non stimulated situations of low cellular ROS levels , Keap1 attaches to Nrf2 and directing Nrf2 to Cullin dependent E3 ubiquitin ligase proteosomal degradation .	Under non stimulated situations of low cellular ROS levels, Keap1 attaches to Nrf2 and directing Nrf2 to Cullin dependent E3 ubiquitin ligase proteosomal degradation.	10	17	directing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	16	17
Under normal conditions the levels of the Nrf2 protein in the cell are kept very low by its inhibitor ( Keap1 ) , which sequesters Nrf2 in the cytosol and facilitates its ubiquitination and proteasomal degradation .	Under normal conditions the levels of the Nrf2 protein in the cell are kept very low by its inhibitor (Keap1), which sequesters Nrf2 in the cytosol and facilitates its ubiquitination and proteasomal degradation.	18	26	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	25	26
For example , the redox regulation of Keap1 by oxidation of thiols cause activation of Nrf2 XREF_BIBR .	For example, the redox regulation of Keap1 by oxidation of thiols cause activation of Nrf2 XREF_BIBR.	5	16	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	15	16
And KD of Keap1 in 3T3-L1 cells results in activation of Nrf2 and an enhanced adipogenesis [ XREF_BIBR ] .	And KD of Keap1 in 3T3-L1 cells results in activation of Nrf2 and an enhanced adipogenesis [XREF_BIBR].	1	12	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	11	12
Until recently , it was not clear how KEAP1 oxidation enhances the stability of NRF2 since oxidized KEAP1 still interacts fully with the ETGE site and weakly with the DLG site .	Until recently, it was not clear how KEAP1 oxidation enhances the stability of NRF2 since oxidized KEAP1 still interacts fully with the ETGE site and weakly with the DLG site.	8	15	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	8	9	14	15
Real-time PCR revealed that Keap1 KD upregulated Nrf2 target genes , including Gclc , Gclm , Gstp1 , Gstp2 and Nqo1 in the glomerulus .	Real-time PCR revealed that Keap1 KD upregulated Nrf2 target genes, including Gclc, Gclm, Gstp1, Gstp2 and Nqo1 in the glomerulus.	4	9	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	7	8
At steady state , Nrf2 is kept inactive in the cytosol by its inhibitor protein Keap1 ( Kelch like ECH associated protein 1 ) , which targets Nrf2 for proteasomal degradation 2 .	At steady state, Nrf2 is kept inactive in the cytosol by its inhibitor protein Keap1 (Kelch like ECH associated protein 1), which targets Nrf2 for proteasomal degradation 2.	6	30	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	27	28
We propose that KEAP1 intermolecular disulfide formation via Cys ( 151 ) underlies the activation of NRF2 by reactive oxygen and nitrogen species .	We propose that KEAP1 intermolecular disulfide formation via Cys (151) underlies the activation of NRF2 by reactive oxygen and nitrogen species.	3	17	underlies	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	3	4	16	17
Conversely , downregulation of Keap1 decreased autophagy levels , increased Nrf2 activation , upregulated cytoprotective antioxidant gene expression , and caused accumulation of p62 , suggesting a feedback loop between ROS regulated Keap1-Nrf2 and Atg7 regulated autophagy .	Conversely, downregulation of Keap1 decreased autophagy levels, increased Nrf2 activation, upregulated cytoprotective antioxidant gene expression, and caused accumulation of p62, suggesting a feedback loop between ROS regulated Keap1-Nrf2 and Atg7 regulated autophagy.	2	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	10	11
ROS exposure causes cysteine modifications in KEAP1 , allowing newly translated NRF2 to evade ubiquitination and thus mediate activation of genes containing antioxidant response elements in their promoters .	ROS exposure causes cysteine modifications in KEAP1, allowing newly translated NRF2 to evade ubiquitination and thus mediate activation of genes containing antioxidant response elements in their promoters.	2	13	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	6	7	11	12
As opposed to the effect of Keap1 , which targets CncC for cullin 3 mediated proteasomal degradation in the cytoplasm , the inhibitory , acetylation dependent interaction between Fs ( 1 ) h and CncC presumably occurs in the nucleus where the BET protein resides ( XREF_FIG ) .	As opposed to the effect of Keap1, which targets CncC for cullin 3 mediated proteasomal degradation in the cytoplasm, the inhibitory, acetylation dependent interaction between Fs (1) h and CncC presumably occurs in the nucleus where the BET protein resides (XREF_FIG).	4	16	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	CncC	CncC	CncC	6	7	10	11
Nrf2 transcriptional activity depends on the dissociation of its repressor , Keap1 , who inhibits Nrf2 in the cytoplasm , orchestrating its ubiquitination and degradation XREF_BIBR .	Nrf2 transcriptional activity depends on the dissociation of its repressor, Keap1, who inhibits Nrf2 in the cytoplasm, orchestrating its ubiquitination and degradation XREF_BIBR.	9	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	15	16
Upon exposure to oxidative and electrophilic stressors , the redox sensitive cysteine residues in Keap1 are modified , allowing Nrf2 to dissociate from Nrf2 and Keap1 complex and escape degradation .	Upon exposure to oxidative and electrophilic stressors, the redox sensitive cysteine residues in Keap1 are modified, allowing Nrf2 to dissociate from Nrf2 and Keap1 complex and escape degradation.	12	21	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	19	20
Upon production of reactive oxygen species , Keap1 is degraded and allows Nrf2 to translocate to the nucleus to activate downstream antioxidant targets .	Upon production of reactive oxygen species, Keap1 is degraded and allows Nrf2 to translocate to the nucleus to activate downstream antioxidant targets.	7	14	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
However inhibition of Keap1 dependent degradation allows Nrf2 to translocate to the nucleus and activate transcription of antioxidant response element ( the cis acting promoter element , ARE ) containing genes [ XREF_BIBR ] .	However inhibition of Keap1 dependent degradation allows Nrf2 to translocate to the nucleus and activate transcription of antioxidant response element (the cis acting promoter element, ARE) containing genes [XREF_BIBR].	3	9	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	7	8
Keap1 promotes the elimination of Nrf2 , and further influences downstream mRNA expression of GCLC and GCLM after Nrf2 enters to the nucleolus .	Keap1 promotes the elimination of Nrf2, and further influences downstream mRNA expression of GCLC and GCLM after Nrf2 enters to the nucleolus.	0	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	5	6
Rather , Keap1 causes the rapid turnover of the Nrf2 transcription factor by assisting in Nrf2 ubiquitinylation ( resulting in rapid degradation by the 26S proteasome ) [ XREF_BIBR ] .	Rather, Keap1 causes the rapid turnover of the Nrf2 transcription factor by assisting in Nrf2 ubiquitinylation (resulting in rapid degradation by the 26S proteasome) [XREF_BIBR].	2	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	9	10
In contrast , silencing KEAP1 augmented protein accumulation of NRF2 under basal and iAs 3+ -exposed conditions , whereas the iAs 3+ -induced protein accumulation of NRF1 was attenuated in KEAP1-KD cells .	In contrast, silencing KEAP1 augmented protein accumulation of NRF2 under basal and iAs 3+ -exposed conditions, whereas the iAs 3+ -induced protein accumulation of NRF1 was attenuated in KEAP1-KD cells.	3	10	augmented	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	4	5	9	10
The blocking of these cysteine causes the loss of repression of Nrf2 by Keap1 and therefore Nrf2 becomes free and moves into the nucleus where it dimerizes with members of the small Maf family and binds to the electrophil response elements ( ARE ) located in the regulatory regions of cellular defense enzyme genes .	The blocking of these cysteine causes the loss of repression of Nrf2 by Keap1 and therefore Nrf2 becomes free and moves into the nucleus where it dimerizes with members of the small Maf family and binds to the electrophil response elements (ARE) located in the regulatory regions of cellular defense enzyme genes.	5	14	repression	Negative_activation_token_2_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	11	12
Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance .	Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance.	9	21	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	19	20
During acute oxidative stress , oxidized molecules modify multiple cysteine residues in Keap1 , causing Nrf2 to be released from connection with Keap1 .	During acute oxidative stress, oxidized molecules modify multiple cysteine residues in Keap1, causing Nrf2 to be released from connection with Keap1.	7	16	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	15	16
( ii ) The substrate adaptor function of Keap1 : once in the cytoplasm , Keap1 targets Nrf2 to the Cul3 containing E3 ubiquitin ligase for ubiquitination and degradation .	(ii) The substrate adaptor function of Keap1 : once in the cytoplasm, Keap1 targets Nrf2 to the Cul3 containing E3 ubiquitin ligase for ubiquitination and degradation.	6	20	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	17	18
Our data are consistent with ROS and KEAP1 mediated NRF2 activation , so we modulated NRF2 activity by genetic overexpression of KEAP1 .	Our data are consistent with ROS and KEAP1 mediated NRF2 activation, so we modulated NRF2 activity by genetic overexpression of KEAP1.	3	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	7	8	9	10
Since Keap1 shRNA induced Nrf2 stabilization in OB-6 cells , expressions of Nrf2 regulaed genes were also tested .	Since Keap1 shRNA induced Nrf2 stabilization in OB-6 cells, expressions of Nrf2 regulaed genes were also tested.	1	5	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	1	2	4	5
KEAP1 can target NRF2 , a master transcriptional factor for anti-oxidant genes , for cytoplasmic degradation .	KEAP1 can target NRF2, a master transcriptional factor for anti-oxidant genes, for cytoplasmic degradation.	0	15	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	3	4
Without stressors , Keap1 mediates the ubiquitinylation and subsequent proteolytic degradation of Nrf2 .	Without stressors, Keap1 mediates the ubiquitinylation and subsequent proteolytic degradation of Nrf2.	3	13	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	12	13
p65 RNAi alone had no effect on the cellular expression of Nrf2 , however , when co-transfected with Keap1 RNAi , p65 depletion was able to reverse the induction of Nrf2 caused by Keap1 depletion ( XREF_FIG ) .	p65 RNAi alone had no effect on the cellular expression of Nrf2, however, when co-transfected with Keap1 RNAi, p65 depletion was able to reverse the induction of Nrf2 caused by Keap1 depletion (XREF_FIG).	28	34	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	33	34	30	31
Knockdown of Keap1 induced Nrf2 accumulation and rescued cell viability and clonogenic survival to subsequent CCI-779 and CQ treatment ( XREF_FIG ) .	Knockdown of Keap1 induced Nrf2 accumulation and rescued cell viability and clonogenic survival to subsequent CCI-779 and CQ treatment (XREF_FIG).	0	5	induced	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	4	5
By contrast , both IF and western blot analyses revealed that Keap1 knock-down failed to prevent Nrf2 suppression by hypoglycemic exposure ( XREF_FIG ) , thus indicating the lack of functional role for Keap1 under these settings .	By contrast, both IF and western blot analyses revealed that Keap1 knock-down failed to prevent Nrf2 suppression by hypoglycemic exposure (XREF_FIG), thus indicating the lack of functional role for Keap1 under these settings.	11	17	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	16	17
Stress induced modification of cysteine residues in Keap1 causes the release of Nrf2 , which translocates from the cytosoplasm into the cell nucleus , where it binds to AREs in genes that encode antioxidant enzymes that protect the cell from the deleterious effects of ROS [ XREF_BIBR ] .	Stress induced modification of cysteine residues in Keap1 causes the release of Nrf2, which translocates from the cytosoplasm into the cell nucleus, where it binds to AREs in genes that encode antioxidant enzymes that protect the cell from the deleterious effects of ROS [XREF_BIBR].	5	15	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
In relation to this H 2 S has been shown to protect against cellular senescence and oxidative stress via S sulfhydration of Keap1 and resulting activation of Nrf2 .	In relation to this H 2 S has been shown to protect against cellular senescence and oxidative stress via S sulfhydration of Keap1 and resulting activation of Nrf2.	22	28	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	27	28
Under conditions of oxidative stress or electrophilic stimulation , the structure of Keap1 is changed , resulting in its disassociation from Nrf2 , thus activating Nrf2 .	Under conditions of oxidative stress or electrophilic stimulation, the structure of Keap1 is changed, resulting in its disassociation from Nrf2, thus activating Nrf2.	10	26	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	25	26
In non small cell lung cancer ( NSCLC ) , ATF4 overexpression can be caused by KEAP1 mediated activation of NRF2 or activation of the PI3K and mTOR signaling pathway .	In non small cell lung cancer (NSCLC), ATF4 overexpression can be caused by KEAP1 mediated activation of NRF2 or activation of the PI3K and mTOR signaling pathway.	16	29	mediated	Positive_early_activation	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	16	17	20	21
Moreover , 15d-PGJ2 may form adducts with Keap1 simultaneously causing dissociation of Nrf2 from complex [ XREF_BIBR ] .	Moreover, 15d-PGJ2 may form adducts with Keap1 simultaneously causing dissociation of Nrf2 from complex [XREF_BIBR].	4	13	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
In other species , considerable attention has been focused on regulation of the SKN-1 ortholog Nrf2 by the ubiquitin ligase and possible redox sensor Keap1 , which targets Nrf2 for degradation in the absence of stress XREF_BIBR , XREF_BIBR , XREF_BIBR .	In other species, considerable attention has been focused on regulation of the SKN-1 ortholog Nrf2 by the ubiquitin ligase and possible redox sensor Keap1, which targets Nrf2 for degradation in the absence of stress XREF_BIBR, XREF_BIBR, XREF_BIBR.	8	30	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	24	25	28	29
Upon exposure to electrophiles or other stressors , critical cysteine residues in Keap1 are modified allowing Nrf2 to be released without ubiquitination .	Upon exposure to electrophiles or other stressors, critical cysteine residues in Keap1 are modified allowing Nrf2 to be released without ubiquitination.	10	19	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	16	17
Hypermethylation of KEAP1 found in prostate cancer also stimulated the Nrf2 signal [ XREF_BIBR ] .	Hypermethylation of KEAP1 found in prostate cancer also stimulated the Nrf2 signal [XREF_BIBR].	0	11	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	Hypermethylation of KEAP1	keap1	Nrf2	Nrf2	nrf2	2	3	10	11
These compounds disrupt Keap1 mediated Nrf2 ubquitination , thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus , where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes .	These compounds disrupt Keap1 mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes.	2	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	5	6
Sulforaphane [ (-)-1-isothiocyanato-( 4R )-methylsulfinylbutane ] , a natural occurring isothiocyanate from cruciferous vegetables , strongly induces Nrf2 and ARE mediated transcription activation through inhibiting Keap1 mediated Nrf2 degradation [ XREF_BIBR ] .	Sulforaphane [(-)-1-isothiocyanato-(4R)-methylsulfinylbutane], a natural occurring isothiocyanate from cruciferous vegetables, strongly induces Nrf2 and ARE mediated transcription activation through inhibiting Keap1 mediated Nrf2 degradation [XREF_BIBR].	22	28	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	25	26	27	28
Keap1 targets Nrf2 to the Cullin3 E3 ligase complex for ubiquitination and subsequent degradation by the UPS .	Keap1 targets Nrf2 to the Cullin3 E3 ligase complex for ubiquitination and subsequent degradation by the UPS.	0	13	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
During oxidative stress several sensitive KEAP1 cysteines are oxidized resulting a loss of KEAP1 directed proteasomal degradation of NRF2 and increased proteasomal degradation of KEAP1 itself .	During oxidative stress several sensitive KEAP1 cysteines are oxidized resulting a loss of KEAP1 directed proteasomal degradation of NRF2 and increased proteasomal degradation of KEAP1 itself.	11	19	directed	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	loss of KEAP1	keap1	NRF2	NRF2	nrf2	13	14	18	19
These modifications ( which include adduct formation ) result in a conformational change of KEAP1 , thereby reversing the proteasomal degradation of NRF2 , which then becomes transcriptionally active [ XREF_FIG ] .	These modifications (which include adduct formation) result in a conformational change of KEAP1, thereby reversing the proteasomal degradation of NRF2, which then becomes transcriptionally active [XREF_FIG].	12	23	reversing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	14	15	22	23
Upon modification of specific thiols by insult , Keap1 allows Nrf2 to translocate into the nucleus to promote the expression of a wide array of cytoprotective genes by binding to ARE in regulatory regions [ XREF_BIBR ] .	Upon modification of specific thiols by insult, Keap1 allows Nrf2 to translocate into the nucleus to promote the expression of a wide array of cytoprotective genes by binding to ARE in regulatory regions [XREF_BIBR].	8	12	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	10	11
NRF2 expression is mainly regulated post-translationally via an adaptor for a Cul3 based E3 ubiquitin ligase , Keap1 [ XREF_BIBR , XREF_BIBR ] , although oncoproteins , such as K-Ras G12D and B-Raf V619E , induce Nrf2 mRNA accumulation to enhance basal NRF2 expression [ XREF_BIBR ] .	NRF2 expression is mainly regulated post-translationally via an adaptor for a Cul3 based E3 ubiquitin ligase, Keap1 [XREF_BIBR, XREF_BIBR], although oncoproteins, such as K-Ras G12D and B-Raf V619E, induce Nrf2 mRNA accumulation to enhance basal NRF2 expression [XREF_BIBR].	15	44	enhance	Positive_regulation_syntax_5_verb	Negative_activation	Positive_regulation	Keap1	Keap1	keap1	NRF2	NRF2 expression	nrf2	17	18	42	43
Under normal conditions , KEAP1 targets Nrf2 for proteasomal degradation [ XREF_BIBR , XREF_BIBR ] .	Under normal conditions, KEAP1 targets Nrf2 for proteasomal degradation [XREF_BIBR, XREF_BIBR].	4	13	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	4	5	6	7
Under basal conditions , Nrf2 is mainly localised to cytoplasm in a complex with the Kelch like ECH associated protein 1 ( Keap1 ) , an ubiquitin ligase substrate adaptor that targets Nrf2 for degradation 33 .	Under basal conditions, Nrf2 is mainly localised to cytoplasm in a complex with the Kelch like ECH associated protein 1 (Keap1), an ubiquitin ligase substrate adaptor that targets Nrf2 for degradation 33.	19	34	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	32	33
It could be proposed ( XREF_FIG ) that , at low concentrations , inducers are sensed first by the highly reactive cysteine residues of KEAP1 , activating the KEAP1 and NRF2 pathway .	It could be proposed (XREF_FIG) that, at low concentrations, inducers are sensed first by the highly reactive cysteine residues of KEAP1, activating the KEAP1 and NRF2 pathway.	22	31	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	24	25	30	31
Additionally , Keap1 independent activation of Nrf2 has been shown to be associated with resistance to EGFR-TKI despite expression of the wild-type EGFR gene in NSCLC cells [ XREF_BIBR ] .	Additionally, Keap1 independent activation of Nrf2 has been shown to be associated with resistance to EGFR-TKI despite expression of the wild-type EGFR gene in NSCLC cells [XREF_BIBR].	2	7	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	6	7
Keap1 still modulates the redox sensitivity of Nrf2 by controlling the availability of free Nrf2 proteins .	Keap1 still modulates the redox sensitivity of Nrf2 by controlling the availability of free Nrf2 proteins.	0	15	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	14	15
Biological effects of constitutive Nrf2 activation by Keap1 dysfunction due to mutations or low-level expression by hypermethylation have been reported previously [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Biological effects of constitutive Nrf2 activation by Keap1 dysfunction due to mutations or low-level expression by hypermethylation have been reported previously [XREF_BIBR, XREF_BIBR, XREF_BIBR].	4	8	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	4	5
At steady state , Keap1 acts as an adaptor for an E3 ubiquitin ligase , thereby targeting Nrf2 to the proteasome for degradation .	At steady state, Keap1 acts as an adaptor for an E3 ubiquitin ligase, thereby targeting Nrf2 to the proteasome for degradation.	4	18	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	17	18
KEAP1 was found to be succinated at multiple cysteine residues in Fh1 deficient , but not wild-type MEFs , and conversely repressed several NRF2 targets in wild-type , but not Fh1 deficient cells .	KEAP1 was found to be succinated at multiple cysteine residues in Fh1 deficient, but not wild-type MEFs, and conversely repressed several NRF2 targets in wild-type, but not Fh1 deficient cells.	0	24	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	0	1	23	24
At rest , Nrf2 is sequestered in the cytosol by Kelch like ECH associated protein 1 ( Keap1 ) ; however , during periods of oxidative stress , modifications to cysteine residues on Keap1 cause Nrf2 to be released and translocated to nucleus where it binds to the antioxidant response element ( ARE ) .	At rest, Nrf2 is sequestered in the cytosol by Kelch like ECH associated protein 1 (Keap1); however, during periods of oxidative stress, modifications to cysteine residues on Keap1 cause Nrf2 to be released and translocated to nucleus where it binds to the antioxidant response element (ARE).	31	36	cause	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	33	34	35	36
XREF_BIBR , XREF_BIBR Under basal conditions , Nrf2 is constantly targeted by Keap1 for ubiquination and proteasomal degradation and is , thus , kept in the cytoplasm and maintained at low levels ; under stressful conditions such as oxidative stress and inflammation or by external induction , Nrf2 is liberated from Keap1 dependent degradation and translocated into the nucleus to transcriptionally activate downstream ARE genes .	XREF_BIBR, XREF_BIBR Under basal conditions, Nrf2 is constantly targeted by Keap1 for ubiquination and proteasomal degradation and is, thus, kept in the cytoplasm and maintained at low levels; under stressful conditions such as oxidative stress and inflammation or by external induction, Nrf2 is liberated from Keap1 dependent degradation and translocated into the nucleus to transcriptionally activate downstream ARE genes.	7	19	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	7	8
As noted above , electrophilicity is the key chemical moiety to stimulate the Keap1 and Nrf2 system for inducing phase 2 enzymes , because electrophilic modification of the cysteine residues of Keap1 triggers dissociation of Nrf2 for nuclear translocation for its transcriptional activation .	As noted above, electrophilicity is the key chemical moiety to stimulate the Keap1 and Nrf2 system for inducing phase 2 enzymes, because electrophilic modification of the cysteine residues of Keap1 triggers dissociation of Nrf2 for nuclear translocation for its transcriptional activation.	29	36	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	31	32	35	36
It is not known , however , whether the thiol modification of Keap1 is enough to allow Nrf2 to localize to the nucleus .	It is not known, however, whether the thiol modification of Keap1 is enough to allow Nrf2 to localize to the nucleus.	10	19	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	17	18
With a half-life of only 20min , Nrf2 is constantly targeted for ubiquitination by Keap1 with consequential degradation via the proteasome .	With a half-life of only 20min, Nrf2 is constantly targeted for ubiquitination by Keap1 with consequential degradation via the proteasome.	7	15	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	7	8
The loss of Keap1 promoter DNA methylation eventually leads to overexpression of Keap1 resulting in Nrf2 suppression , because Keap1 is a negative regulator of Nrf2 .	The loss of Keap1 promoter DNA methylation eventually leads to overexpression of Keap1 resulting in Nrf2 suppression, because Keap1 is a negative regulator of Nrf2.	3	16	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1 promoter DNA methylation	keap1	Nrf2	Nrf2	nrf2	3	4	15	16
Moreover , the inhibition of mTORC1 by Sestrin2 is important for the p62 autophagy mediated breakdown of Kelch like ECH associated protein 1 ( Keap1 ) , the repressor molecule that directs Nrf2 to proteasomal degradation [ XREF_BIBR ] .	Moreover, the inhibition of mTORC1 by Sestrin2 is important for the p62 autophagy mediated breakdown of Kelch like ECH associated protein 1 (Keap1), the repressor molecule that directs Nrf2 to proteasomal degradation [XREF_BIBR].	21	33	directs	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	24	25	32	33
CUL3 encodes the ubiquitin ligase that KEAP1 uses to target NRF2 for proteasomal degradation XREF_BIBR , XREF_BIBR , XREF_BIBR .	CUL3 encodes the ubiquitin ligase that KEAP1 uses to target NRF2 for proteasomal degradation XREF_BIBR, XREF_BIBR, XREF_BIBR.	6	11	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	6	7	10	11
Here again we saw the uncertainty of the outcomes produced by epigenetic regulation of Keap1-Nrf2 signaling in cancers : while silencing of Nrf2 by DNA methylation is implicated in carcinogenesis , activation of Nrf2 signaling by hypermethylation of Keap1 promoter is also associated with tumor progression and resistance to therapies .	Here again we saw the uncertainty of the outcomes produced by epigenetic regulation of Keap1-Nrf2 signaling in cancers : while silencing of Nrf2 by DNA methylation is implicated in carcinogenesis, activation of Nrf2 signaling by hypermethylation of Keap1 promoter is also associated with tumor progression and resistance to therapies.	33	39	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Keap1	hypermethylation of Keap1	keap1	Nrf2	Nrf2	nrf2	38	39	33	34
To determine whether inhibition of Nrf2 mediated gene transcription by Keap1 is interfered by Keap1 DeltaC , both MHCC97H and HepG2 cell lines were co-transfected with the Keap1 or Keap1 DeltaC expression construct together with an ARE driven luciferase reporter .	To determine whether inhibition of Nrf2 mediated gene transcription by Keap1 is interfered by Keap1 DeltaC, both MHCC97H and HepG2 cell lines were co-transfected with the Keap1 or Keap1 DeltaC expression construct together with an ARE driven luciferase reporter.	3	11	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	5	6
The leading model posits that KEAP1 inactivation results in constitutive NFE2L2 transcriptional activation of antioxidant and pro survival genes .	The leading model posits that KEAP1 inactivation results in constitutive NFE2L2 transcriptional activation of antioxidant and pro survival genes.	5	13	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NFE2L2	NFE2L2	NFE2L2	5	6	10	11
Modification of the sensor protein Keap1 by electrophiles such as the isothiocyanate sulforaphane can direct Nrf2 accumulation in the nucleus and subsequent ARE activation .	Modification of the sensor protein Keap1 by electrophiles such as the isothiocyanate sulforaphane can direct Nrf2 accumulation in the nucleus and subsequent ARE activation.	0	16	direct	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	15	16
However , all current models propose that cysteine residues of KEAP1 are modified in response to oxidative stress , resulting in compromised function of the ubiquitin E3 ligase complex that effects proteasomal degradation of NRF2 and enhanced NRF2 stability .	However, all current models propose that cysteine residues of KEAP1 are modified in response to oxidative stress, resulting in compromised function of the ubiquitin E3 ligase complex that effects proteasomal degradation of NRF2 and enhanced NRF2 stability.	8	38	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	10	11	37	38
Oxidative stress impairs inhibition of Nrf2 by Keap1 XREF_BIBR .	Oxidative stress impairs inhibition of Nrf2 by Keap1 XREF_BIBR.	3	8	inhibition	Negative_activation_token_2_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	5	6
Under normal conditions , Nrf2 binds to the cytoskeleton associated protein Keap1 ( Kelch like ECH associated protein 1 ) which targets Nrf2 for proteasomal degradation .	Under normal conditions, Nrf2 binds to the cytoskeleton associated protein Keap1 (Kelch like ECH associated protein 1) which targets Nrf2 for proteasomal degradation.	9	25	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	22	23
It has been suggested that , under physiological conditions INrf2 targets Nrf2 for ubiquitin mediated degradation but electrophiles may trigger a switch of Cul3 dependent ubiquitination from Nrf2 to INrf2 resulting in ARE gene induction .	It has been suggested that, under physiological conditions INrf2 targets Nrf2 for ubiquitin mediated degradation but electrophiles may trigger a switch of Cul3 dependent ubiquitination from Nrf2 to INrf2 resulting in ARE gene induction.	9	13	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	INrf2	INrf2	INrf2	Nrf2	Nrf2	Nrf2	9	10	11	12
Under basal conditions , Nrf2 dependent transcription is repressed by its negative regulator Keap1 .	Under basal conditions, Nrf2 dependent transcription is repressed by its negative regulator Keap1.	4	14	repressed	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	4	5
In RCC , p62 is expressed and bound to Keap1 enabling Nrf2 activation .	In RCC, p62 is expressed and bound to Keap1 enabling Nrf2 activation.	5	12	enabling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	11	12
This finding is consistent with our observations that neither pharmacological inducers of Nrf2 nor genetic ablation of Keap1 can induce Nrf2 mediated responses in cortical neurons , because of the transcriptional repression of the Nrf2 gene itself .	This finding is consistent with our observations that neither pharmacological inducers of Nrf2 nor genetic ablation of Keap1 can induce Nrf2 mediated responses in cortical neurons, because of the transcriptional repression of the Nrf2 gene itself.	15	22	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	20	21
There are activating mutations in NRF2 and inactivating mutations in KEAP1 in human cancers , indicating that NRF2 can function as an oncogene and KEAP1 as a tumour suppressor gene XREF_BIBR , XREF_BIBR .	There are activating mutations in NRF2 and inactivating mutations in KEAP1 in human cancers, indicating that NRF2 can function as an oncogene and KEAP1 as a tumour suppressor gene XREF_BIBR, XREF_BIBR.	2	11	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	10	11	5	6
Oxidation induced conformational changes in Keap1 that lead to inhibition of the ubiquitin transfer to Nrf2 has been suggested as an alternative mechanism [ XREF_BIBR ] .	Oxidation induced conformational changes in Keap1 that lead to inhibition of the ubiquitin transfer to Nrf2 has been suggested as an alternative mechanism [XREF_BIBR].	3	16	lead	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	15	16
Interestingly , Keap1 knockout mice have increased accumulation of Nrf2 in the nuclear compartments of various tissues .	Interestingly, Keap1 knockout mice have increased accumulation of Nrf2 in the nuclear compartments of various tissues.	2	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	9	10
Activation of Nrf2 signaling by hypermethylation of Keap1 promoter is associated with tumor progression and resistance to therapies .	Activation of Nrf2 signaling by hypermethylation of Keap1 promoter is associated with tumor progression and resistance to therapies.	2	8	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Keap1	hypermethylation of Keap1	keap1	Nrf2	Nrf2	nrf2	7	8	2	3
Keap1 constantly targets Nrf2 for ubiquitination and subsequent 26S proteasomal degradation , maintaining Nrf2 at basal level .	Keap1 constantly targets Nrf2 for ubiquitination and subsequent 26S proteasomal degradation, maintaining Nrf2 at basal level.	0	4	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
Under normal conditions , Nrf2 is targeted by Keap1 , which promotes Nrf2 proteasomal degradation via interactions with ubiquitin ligase .	Under normal conditions, Nrf2 is targeted by Keap1, which promotes Nrf2 proteasomal degradation via interactions with ubiquitin ligase.	4	11	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	4	5
However , this biological difference could also be due to the fact that Keap1 not only targets Nrf2 for ubiquitination , but also IKKbeta , which is an activator of the NFkappaB-pathway .	However, this biological difference could also be due to the fact that Keap1 not only targets Nrf2 for ubiquitination, but also IKKbeta, which is an activator of the NFkappaB-pathway.	13	23	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	17	18
Keap1 constitutively targets Nrf2 for ubiquitination and proteasomal degradation , thereby maintaining Nrf2 signaling capacity at a low level .	Keap1 constitutively targets Nrf2 for ubiquitination and proteasomal degradation, thereby maintaining Nrf2 signaling capacity at a low level.	0	4	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
Moreover , the fact that Keap1 mediated Nrf2 degradation can be inhibited by a variety of electrophilic small molecules makes it a therapeutically attractive pathway for a variety of disorders XREF_BIBR .	Moreover, the fact that Keap1 mediated Nrf2 degradation can be inhibited by a variety of electrophilic small molecules makes it a therapeutically attractive pathway for a variety of disorders XREF_BIBR.	5	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	7	8
KEAP1 , a negative regulator of Nrf2 , mediates Nrf2 degradation XREF_BIBR .	KEAP1, a negative regulator of Nrf2, mediates Nrf2 degradation XREF_BIBR.	0	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	0	1	9	10
NRF2 levels are usually kept at low cellular levels by a physical interaction with KEAP1 , which targets NRF2 for degradation by the CUL3 E3 ubiquitin ligase [ XREF_BIBR , XREF_BIBR ] .	NRF2 levels are usually kept at low cellular levels by a physical interaction with KEAP1, which targets NRF2 for degradation by the CUL3 E3 ubiquitin ligase [XREF_BIBR, XREF_BIBR].	12	20	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	14	15	18	19
Chemical modification of the sensor cysteines of KEAP1 by inducers , such as sulforaphane , blocks the cycle of KEAP1 dependent NRF2 degradation .	Chemical modification of the sensor cysteines of KEAP1 by inducers, such as sulforaphane, blocks the cycle of KEAP1 dependent NRF2 degradation.	5	22	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	7	8	21	22
These results suggest that the absence of Keap1 constitutively activates Nrf2 , which then induces the phase 2 enzymes in neurons and induces increased resistance of cortical neurons to oxidative stress .	These results suggest that the absence of Keap1 constitutively activates Nrf2, which then induces the phase 2 enzymes in neurons and induces increased resistance of cortical neurons to oxidative stress.	5	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	10	11
Keap1 Cysteine 288 as a Potential Target for Diallyl Trisulfide Induced Nrf2 Activation .	Keap1 Cysteine 288 as a Potential Target for Diallyl Trisulfide Induced Nrf2 Activation.	0	12	Induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	11	12
Deletion of Neh2-NT or mutation of the DLG motif largely abolished the Keap1 mediated degradation of Nrf2 .	Deletion of Neh2-NT or mutation of the DLG motif largely abolished the Keap1 mediated degradation of Nrf2.	10	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	12	13	16	17
Constitutive activation of Nrf2 due to somatic mutations in Keap1 or Nrf2 that disrupt Keap1 mediated Nrf2 regulation is prominent in several types of human cancer cell lines and tumors [ XREF_BIBR - XREF_BIBR ] .	Constitutive activation of Nrf2 due to somatic mutations in Keap1 or Nrf2 that disrupt Keap1 mediated Nrf2 regulation is prominent in several types of human cancer cell lines and tumors [XREF_BIBR - XREF_BIBR].	13	17	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	16	17
A very recent report by Artaud-Macari et al XREF_BIBR demonstrated that NRF2 activation by KEAP1 siRNA introduction induces myofibroblasts dedifferentiation in lung fibroblasts from idiopathic pulmonary fibrosis patients , and SFN treatment suppresses TGFbeta1 stimulated alpha-SMA and COL expression in these cells .	A very recent report by Artaud-Macari et al XREF_BIBR demonstrated that NRF2 activation by KEAP1 siRNA introduction induces myofibroblasts dedifferentiation in lung fibroblasts from idiopathic pulmonary fibrosis patients, and SFN treatment suppresses TGFbeta1 stimulated alpha-SMA and COL expression in these cells.	11	16	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	14	15	11	12
In the 12h PUN treatment group , the Keap1 level significantly increased , while the Nrf2 level notably decreased , suggesting that the inhibitory effect of PUN ( 100muM ) on the Keap1-Nrf2 ubiquitination sustained no longer than 12h , as Keap1 rapidly accumulated and degraded Nrf2 protein , keeping Nrf2 at a low concentration .	In the 12h PUN treatment group, the Keap1 level significantly increased, while the Nrf2 level notably decreased, suggesting that the inhibitory effect of PUN (100muM) on the Keap1-Nrf2 ubiquitination sustained no longer than 12h, as Keap1 rapidly accumulated and degraded Nrf2 protein, keeping Nrf2 at a low concentration.	41	47	degraded	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	41	42	46	47
In clear renal cell carcinoma ( ccRCC ) , the epigenetic modulation of KEAP1 was shown to be the leading mechanism of KEAP1 deregulation ( 48.6 % ) , thus supporting a driver role of the KEAP1 and NRF2 axis in renal cancer .	In clear renal cell carcinoma (ccRCC), the epigenetic modulation of KEAP1 was shown to be the leading mechanism of KEAP1 deregulation (48.6%), thus supporting a driver role of the KEAP1 and NRF2 axis in renal cancer.	22	39	supporting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	22	23	38	39
Upon oxidative stress , Nrf2 is induced at protein levels through redox sensitive modifications on cysteine residues of Keap1 , a component of the E3 ubiquitin ligase that targets Nrf2 for ubiquitin dependent degradation .	Upon oxidative stress, Nrf2 is induced at protein levels through redox sensitive modifications on cysteine residues of Keap1, a component of the E3 ubiquitin ligase that targets Nrf2 for ubiquitin dependent degradation.	16	33	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	18	19	29	30
Inactivation of KEAP1 by oxidative stress or electrophilic chemicals allows NRF2 to activate transcription through binding to antioxidant response elements ( AREs ) and recruiting histone acetyltransferase CBP ( CREB binding protein ) .	Inactivation of KEAP1 by oxidative stress or electrophilic chemicals allows NRF2 to activate transcription through binding to antioxidant response elements (AREs) and recruiting histone acetyltransferase CBP (CREB binding protein).	0	27	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	2	3	10	11
Keap1 targets Nrf2 for ubiquitination and subsequent degradation by the 26S proteasome [ XREF_BIBR , XREF_BIBR ] .	Keap1 targets Nrf2 for ubiquitination and subsequent degradation by the 26S proteasome [XREF_BIBR, XREF_BIBR].	0	11	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
Quantitative real-time ( qRT )-PCR analysis confirmed that Keap1 specific HNEylation positively regulates Nrf2 transcriptional activity .	Quantitative real-time (qRT)-PCR analysis confirmed that Keap1 specific HNEylation positively regulates Nrf2 transcriptional activity.	8	15	positively regulates	Positive_activation_syntax_1b_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	13	14
Modification of specific Keap1 sulfhydryl groups appears to mediate the liberation of Nrf2 from Keap1 mediated ubiquitination .	Modification of specific Keap1 sulfhydryl groups appears to mediate the liberation of Nrf2 from Keap1 mediated ubiquitination.	3	13	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	12	13
While , the increase in VEGF expression is amplified via a positive feedback loop , where VEGF induced S nitrosylation of Keap1 promotes Nrf2 dependent HO-1 induction [ XREF_BIBR , XREF_BIBR ] .	While, the increase in VEGF expression is amplified via a positive feedback loop, where VEGF induced S nitrosylation of Keap1 promotes Nrf2 dependent HO-1 induction [XREF_BIBR, XREF_BIBR].	19	24	promotes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	21	22	23	24
Following translation , Nrf2 is targeted by a Keap1 homodimer in the cytosol , which facilitates binding of the Cullin-3 ( Cul3 )/RING box protein1 ( Rbx1 ) E3 ubiquitin ligase complex , consequently causing proteasomal degradation of Nrf2 [ XREF_BIBR ] ( XREF_FIG B ) .	Following translation, Nrf2 is targeted by a Keap1 homodimer in the cytosol, which facilitates binding of the Cullin-3 (Cul3)/RING box protein1 (Rbx1) E3 ubiquitin ligase complex, consequently causing proteasomal degradation of Nrf2 [XREF_BIBR] (XREF_FIG B).	3	9	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	3	4
Normally , Keap1 targets Nrf2 for ubiquitylation , leading to its proteasomal degradation [ XREF_BIBR ] .	Normally, Keap1 targets Nrf2 for ubiquitylation, leading to its proteasomal degradation [XREF_BIBR].	0	6	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	4	5
It acts as a Michael acceptor for reactive Cys residues on Keap1 en route to activating Nrf2 .	It acts as a Michael acceptor for reactive Cys residues on Keap1 en route to activating Nrf2.	1	17	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	16	17
Therefore the pool of Keap1 remains locked into association with existing Nrf2 via the high affinity ETGE site , allowing more de novo Nrf2 to escape Keap1 capture and proceed directly to the nucleus [ XREF_BIBR ] .	Therefore the pool of Keap1 remains locked into association with existing Nrf2 via the high affinity ETGE site, allowing more de novo Nrf2 to escape Keap1 capture and proceed directly to the nucleus [XREF_BIBR].	2	29	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	23	24
While somatic mutations in Nrf2 and Keap1 genes are rare in PDAC [ XREF_BIBR ] , a dysregulated Nrf2 and Keap1 system may allow persistent Nrf2 activation , and thus represent an important mechanism by which PDAC sense and adapt to oxidative stress , as observed in other tissues exposed to chronic inflammation [ XREF_BIBR ] .	While somatic mutations in Nrf2 and Keap1 genes are rare in PDAC [XREF_BIBR], a dysregulated Nrf2 and Keap1 system may allow persistent Nrf2 activation, and thus represent an important mechanism by which PDAC sense and adapt to oxidative stress, as observed in other tissues exposed to chronic inflammation [XREF_BIBR].	20	26	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	20	21	25	26
Certain chemical inducers , such as heavy metals , oxidizable diphenols , and Michael acceptors , can modify the cysteine residues in Keap1 that act as nucleophiles and activate Nrf2 by suppressing the degradation of the protein [ XREF_BIBR ] .	Certain chemical inducers, such as heavy metals, oxidizable diphenols, and Michael acceptors, can modify the cysteine residues in Keap1 that act as nucleophiles and activate Nrf2 by suppressing the degradation of the protein [XREF_BIBR].	17	30	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	22	23	29	30
In keeping with the findings in Nrf2-transgenic mice , Keap1 null mutation induces constitutive Nrf2 activation leading to hyperkeratosis [ XREF_BIBR ] .	In keeping with the findings in Nrf2-transgenic mice, Keap1 null mutation induces constitutive Nrf2 activation leading to hyperkeratosis [XREF_BIBR].	9	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	14	15
Keap1 siRNA significantly increased nuclear Nrf2 , GST , NQO1 and HO-1 protein levels ( XREF_FIG D ) , and reduced ROS production ( XREF_FIG E ) ( 24h ) , as well as down-regulated TXNIP , NLRP3 , ASC , Caspase-1 , IL-1beta , SREBP-1 and SCD-1 , and up-regulated PPAR-alpha and CPT-1 , with the reduction of TG and TC levels ( 48h ) in fructose exposed BRL-3A cells .	Keap1 siRNA significantly increased nuclear Nrf2, GST, NQO1 and HO-1 protein levels (XREF_FIG D), and reduced ROS production (XREF_FIG E) (24h), as well as down-regulated TXNIP, NLRP3, ASC, Caspase-1, IL-1beta, SREBP-1 and SCD-1, and up-regulated PPAR-alpha and CPT-1, with the reduction of TG and TC levels (48h) in fructose exposed BRL-3A cells.	0	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	5	6
Under basal conditions , Nrf2 monomers are sequestered in cytoplasmic complexes through two-site binding to Keap1 homodimers which target Nrf2 for continuous ubiquitination and proteasomal degradation [ XREF_BIBR ] .	Under basal conditions, Nrf2 monomers are sequestered in cytoplasmic complexes through two-site binding to Keap1 homodimers which target Nrf2 for continuous ubiquitination and proteasomal degradation [XREF_BIBR].	15	27	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	15	16	19	20
Under homeostatic conditions , Keap1 constitutively mediates the proteasomal degradation Nrf2 .	Under homeostatic conditions, Keap1 constitutively mediates the proteasomal degradation Nrf2.	4	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	10	11
Under normal conditions , KEAP1 represses NRF2 activity by degrading the NRF2 protein .	Under normal conditions, KEAP1 represses NRF2 activity by degrading the NRF2 protein.	4	7	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	4	5	6	7
This observation indicates that promoter methylation of the KEAP1 gene enables Nrf2 to translocate from the cytoplasm to the nucleus .	This observation indicates that promoter methylation of the KEAP1 gene enables Nrf2 to translocate from the cytoplasm to the nucleus.	5	12	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	methylation of the KEAP1	keap1	Nrf2	Nrf2	nrf2	8	9	11	12
We suggest that Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination by the CUL3-ROC1 ligase and subsequent degradation by the proteasome .	We suggest that Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination by the CUL3-ROC1 ligase and subsequent degradation by the proteasome.	3	7	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	6	7
146 Recently , the fluorescein based biarsenical thiol labeling reagent ( FlAsH-EDT2 , 74 ) and phenylarsine oxide ( PAO , 75 ) were found to produce Keap1 dependent activation of Nrf2 .	146 Recently, the fluorescein based biarsenical thiol labeling reagent (FlAsH-EDT2, 74) and phenylarsine oxide (PAO, 75) were found to produce Keap1 dependent activation of Nrf2.	27	32	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	27	28	31	32
For example , we find that the Nrf2 transcriptional pathway , which protects against oxidative stress , is activated by interaction of the Nrf2 regulator Keap1 with the viral protein E1 .	For example, we find that the Nrf2 transcriptional pathway, which protects against oxidative stress, is activated by interaction of the Nrf2 regulator Keap1 with the viral protein E1.	7	26	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	25	26	7	8
The increased nuclear level of Keap1 restricts Nrf2 binding to ARE-sequences and directs Nrf2 to proteasomal degradation .	The increased nuclear level of Keap1 restricts Nrf2 binding to ARE-sequences and directs Nrf2 to proteasomal degradation.	3	14	directs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	level of Keap1	keap1	Nrf2	Nrf2	nrf2	5	6	13	14
Nrf2 ( nuclear factor [ erythroid derived 2 ]-like 2 ; the transcriptional master regulator of the antioxidant stress response ) is regulated through interaction with its cytoplasmic inhibitor Keap1 ( Kelch like ECH associated protein 1 ) , which under basal conditions targets Nrf2 for proteasomal degradation .	Nrf2 (nuclear factor [erythroid derived 2]-like 2; the transcriptional master regulator of the antioxidant stress response) is regulated through interaction with its cytoplasmic inhibitor Keap1 (Kelch like ECH associated protein 1), which under basal conditions targets Nrf2 for proteasomal degradation.	22	47	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	29	30	44	45
KEAP1 targets transcription factor Nrf2 for ubiquitination and degradation .	KEAP1 targets transcription factor Nrf2 for ubiquitination and degradation.	0	8	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	0	1	4	5
29 In addition , it was found that hepatocyte specific genetic ablation of Keap1 in mice increases nuclear Nrf2 and results in increases in a variety of transporters such as Mrp1 , Mrp3 , and organic anion transporter 1b2 , with the most dramatic increases in Mrp4 and Mrp5 expression .	29 In addition, it was found that hepatocyte specific genetic ablation of Keap1 in mice increases nuclear Nrf2 and results in increases in a variety of transporters such as Mrp1, Mrp3, and organic anion transporter 1b2, with the most dramatic increases in Mrp4 and Mrp5 expression.	11	19	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	18	19
35 When analyzed further , it was found that autophagy deficient cells accumulate aggregates of p62 ; these aggregates bind and inactivate the protein Keap1 , which normally targets the transcription factor Nrf2 for degradation .	35 When analyzed further, it was found that autophagy deficient cells accumulate aggregates of p62; these aggregates bind and inactivate the protein Keap1, which normally targets the transcription factor Nrf2 for degradation.	19	34	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	24	25	32	33
Indeed , the ubiquitinated aggregates of p62 and KEAP1 would induce activation of NRF2 and upregulation of MRP1 , leading to potential chemoresistance of anaplastic carcinoma with rhabdoid features .	Indeed, the ubiquitinated aggregates of p62 and KEAP1 would induce activation of NRF2 and upregulation of MRP1, leading to potential chemoresistance of anaplastic carcinoma with rhabdoid features.	4	15	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	8	9	13	14
Under basal or un stressed conditions , Nrf-2 is bound to Kelch like ECH associated protein1 ( Keap1 ) , which is an endogenous inhibitor that prevents Nrf-2 activation .	Under basal or un stressed conditions, Nrf-2 is bound to Kelch like ECH associated protein1 (Keap1), which is an endogenous inhibitor that prevents Nrf-2 activation.	15	28	prevents	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf-2	Nrf-2	Nrf-2	17	18	27	28
Keap1 is a substrate adapter protein for the Cullin3-Rbx1 E3 ligase complex and constitutively targets Nrf2 for proteasomal degradation .	Keap1 is a substrate adapter protein for the Cullin3-Rbx1 E3 ligase complex and constitutively targets Nrf2 for proteasomal degradation.	0	16	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	15	16
NRF2 activating signals inhibit KEAP1 mediated NRF2 turnover , resulting in KEAP1 becoming saturated with bound NRF2 .	NRF2 activating signals inhibit KEAP1 mediated NRF2 turnover, resulting in KEAP1 becoming saturated with bound NRF2.	4	7	mediated	Positive_early_activation	Negative_activation	Negative_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	4	5	6	7
Nrf2 is normally sequestered in the cytoplasm by the cysteine rich Keap1 protein , a substrate adaptor protein for a Cul3 dependent ubiquitin ligase complex that targets Nrf2 for proteasome mediated degradation .	Nrf2 is normally sequestered in the cytoplasm by the cysteine rich Keap1 protein, a substrate adaptor protein for a Cul3 dependent ubiquitin ligase complex that targets Nrf2 for proteasome mediated degradation.	11	29	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	27	28
These results suggest that the activation of Nrf2 by WN1316 may be associated with the inhibition of Keap1 mediated Nrf2 degradation in addition to the upregulation of Nrf2 mRNA and protein .	These results suggest that the activation of Nrf2 by WN1316 may be associated with the inhibition of Keap1 mediated Nrf2 degradation in addition to the upregulation of Nrf2 mRNA and protein.	15	20	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	19	20
Electrophilic stresses modify a cysteine residue of Keap1 , which allows Nrf2 to escape degradation and translocate to the nucleus .	Electrophilic stresses modify a cysteine residue of Keap1, which allows Nrf2 to escape degradation and translocate to the nucleus.	5	16	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	11	12
Thus , NRF2 can be activated by inactivation of KEAP1 .	Thus, NRF2 can be activated by inactivation of KEAP1.	2	10	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	9	10	2	3
In addition to Keap1 alkylation initiated Nrf2 activation , phosphorylation of Nrf2 through kinase signaling cascades has been reported to affect Nrf2 activity .	In addition to Keap1 alkylation initiated Nrf2 activation, phosphorylation of Nrf2 through kinase signaling cascades has been reported to affect Nrf2 activity.	3	7	initiated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	6	7
Upon modification of specific thiols by insult , Keap1 triggers the dissociation of Nrf2 from the Nrf2 and Keap1 complex in the cytoplasm and allows Nrf2 to translocate to the nucleus , where it subsequently activates AREs present in the promoter regions of an array of genes .	Upon modification of specific thiols by insult, Keap1 triggers the dissociation of Nrf2 from the Nrf2 and Keap1 complex in the cytoplasm and allows Nrf2 to translocate to the nucleus, where it subsequently activates AREs present in the promoter regions of an array of genes.	8	24	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	13	14
NRF2 is also targeted for degradation in the proteasome by a KEAP1 independent mechanism that implies the phosphorylation of specific serines in the NEH6 domain of NRF2 by glycogen synthase kinase-3 ( GSK3 ) and the interaction with the ubiquitin ligase adapter TrCP and the Cullin1 and Ring-Box 1 , E3 ubiquitin protein ligase ( RBX1 ) complex [ XREF_BIBR ] .	NRF2 is also targeted for degradation in the proteasome by a KEAP1 independent mechanism that implies the phosphorylation of specific serines in the NEH6 domain of NRF2 by glycogen synthase kinase-3 (GSK3) and the interaction with the ubiquitin ligase adapter TrCP and the Cullin1 and Ring-Box 1, E3 ubiquitin protein ligase (RBX1) complex [XREF_BIBR].	0	13	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	11	12	0	1
Mounting evidence revealed a darker side to Nrf2 in cancer , with many tumour types displaying elevated levels of the transcription factor , often due to loss-of-function mutations in the Keap1 gene that promote Nrf2 driven transcriptional activity [ XREF_BIBR ] .	Mounting evidence revealed a darker side to Nrf2 in cancer, with many tumour types displaying elevated levels of the transcription factor, often due to loss-of-function mutations in the Keap1 gene that promote Nrf2 driven transcriptional activity [XREF_BIBR].	30	35	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	30	31	34	35
This mechanism is independent of Keap1 mediated Nrf2 regulation .	This mechanism is independent of Keap1 mediated Nrf2 regulation.	3	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	7	8
Activation of NRF2 by SFP involves posttranslational modifications that result in its release from Keap 1 which normally targets NRF2 for degradation , NRF2 protein accumulation and translocation to the nucleus .	Activation of NRF2 by SFP involves posttranslational modifications that result in its release from Keap 1 which normally targets NRF2 for degradation, NRF2 protein accumulation and translocation to the nucleus.	9	27	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap 1	Keap 1	Keap 1	NRF2	NRF2	NRF2	14	16	19	20
Meanwhile , Keap1 constantly targets Nrf2 leading to ubiquitin dependent degradation and thereby maintains low levels of Nrf2 XREF_BIBR XREF_BIBR XREF_BIBR .	Meanwhile, Keap1 constantly targets Nrf2 leading to ubiquitin dependent degradation and thereby maintains low levels of Nrf2 XREF_BIBR XREF_BIBR XREF_BIBR.	2	13	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	5	6
It has been observed that autophagic deficient cells tend to accumulate p62 rich aggregates which in turn cause Nrf2 to be activated after separation from its interacting partner Keap1 which allows Nrf2 to mount an antioxidant response .	It has been observed that autophagic deficient cells tend to accumulate p62 rich aggregates which in turn cause Nrf2 to be activated after separation from its interacting partner Keap1 which allows Nrf2 to mount an antioxidant response.	21	33	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	28	29	31	32
Reversely , Keap1 silence , mutation or inhibition shall induce Nrf2 stabilization and accumulation [ XREF_BIBR , XREF_BIBR ] .	Reversely, Keap1 silence, mutation or inhibition shall induce Nrf2 stabilization and accumulation [XREF_BIBR, XREF_BIBR].	2	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	2	3	10	11
Other Keap1 antagonists include the naturally occurring isothiocyanate sulforaphane XREF_BIBR , and the compound Tecifidera ( BG-12 and dimethyl fumarate ; Biogen Idec ) which has recently been approved by the FDA for the treatment of multiple sclerosis , and believed to operate ( at least in part ) via Keap1 mediated activation of the Nrf2 pathway XREF_BIBR .	Other Keap1 antagonists include the naturally occurring isothiocyanate sulforaphane XREF_BIBR, and the compound Tecifidera (BG-12 and dimethyl fumarate; Biogen Idec) which has recently been approved by the FDA for the treatment of multiple sclerosis, and believed to operate (at least in part) via Keap1 mediated activation of the Nrf2 pathway XREF_BIBR.	50	57	mediated	Positive_early_activation	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	50	51	55	56
Keap1 is also an Nrf2 target gene [ XREF_BIBR ] , however , and may subsequently be upregulated to control Nrf2 activity following the initial exposure to Abeta42 in our study .	Keap1 is also an Nrf2 target gene [XREF_BIBR], however, and may subsequently be upregulated to control Nrf2 activity following the initial exposure to Abeta42 in our study.	0	21	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	20	21
A second example of this is the more established redox sensor KEAP1 , which normally targets the Nrf2 transcription factor for ubiquitination by a Skp and Cul3 ubiquitin ligase complex .	A second example of this is the more established redox sensor KEAP1, which normally targets the Nrf2 transcription factor for ubiquitination by a Skp and Cul3 ubiquitin ligase complex.	2	19	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	11	12	17	18
In unstressed cells , Keap1 sequesters Nrf2 in the cytoplasm by binding to the N-terminal Neh2 domain and facilitating the degradation of Nrf2 via the ubiquitin dependent proteosomal degradation pathway [ XREF_BIBR ] .	In unstressed cells, Keap1 sequesters Nrf2 in the cytoplasm by binding to the N-terminal Neh2 domain and facilitating the degradation of Nrf2 via the ubiquitin dependent proteosomal degradation pathway [XREF_BIBR].	4	9	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
The current model of the molecular mechanism for Nrf2 activation is that oxidative stress modifies cysteine residues of Keap1 , a component of the E3 ubiquitin ligase that targets Nrf2 for degradation , resulting in compromised E3 activity and enhanced Nrf2 protein stability .	The current model of the molecular mechanism for Nrf2 activation is that oxidative stress modifies cysteine residues of Keap1, a component of the E3 ubiquitin ligase that targets Nrf2 for degradation, resulting in compromised E3 activity and enhanced Nrf2 protein stability.	16	42	enhanced	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	18	19	40	41
Rats in the PL group overexpressed nuclear factor Nrf2 ( +260 % ) , while in the advanced HCC group Nrf-2 expression was reduced (-56% ) and Keap-1 was markedly overexpressed ( +308 % ) .	Rats in the PL group overexpressed nuclear factor Nrf2 (+260%), while in the advanced HCC group Nrf-2 expression was reduced (-56%) and Keap-1 was markedly overexpressed (+308%).	0	33	overexpressed	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap-1	Keap-1 was markedly overexpressed	keap-1	Nrf2	Nrf2	nrf2	27	28	8	9
During times of oxidative stress , the structure of Keap1 is modified in such a way that it can no longer bind Nrf2 , allowing Nrf2 to enter the nucleus and activate the antioxidant response .	During times of oxidative stress, the structure of Keap1 is modified in such a way that it can no longer bind Nrf2, allowing Nrf2 to enter the nucleus and activate the antioxidant response.	7	27	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	25	26
Keap1 inhibits Nrf2 signaling by promoting Nrf2 degradation through the proteasomal pathway [ XREF_BIBR ] .	Keap1 inhibits Nrf2 signaling by promoting Nrf2 degradation through the proteasomal pathway [XREF_BIBR].	0	3	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	2	3
Keap1 glutathionylation leads to dissociation of the Nrf2 and Keap1 complex , allowing Nrf2 to translocate to the nucleus and activate expression of target genes [ XREF_BIBR ] .	Keap1 glutathionylation leads to dissociation of the Nrf2 and Keap1 complex, allowing Nrf2 to translocate to the nucleus and activate expression of target genes [XREF_BIBR].	0	15	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	13	14
Under normal conditions , Nrf2 is anchored by Kelch like ECH associated protein-1 ( Keap1 ) , which constitutively targets Nrf2 for ubiquitination and proteasomal degradation .	Under normal conditions, Nrf2 is anchored by Kelch like ECH associated protein-1 (Keap1), which constitutively targets Nrf2 for ubiquitination and proteasomal degradation.	12	25	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	14	15	20	21
Nrf2 is constantly targeted for proteasomal degradation by Keap1 under unstressed condition XREF_BIBR .	Nrf2 is constantly targeted for proteasomal degradation by Keap1 under unstressed condition XREF_BIBR.	0	9	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	0	1
XREF_BIBR , XREF_BIBR Succination of KEAP1 allows NRF2 to be active and stimulate antioxidant genes .	XREF_BIBR, XREF_BIBR Succination of KEAP1 allows NRF2 to be active and stimulate antioxidant genes.	3	10	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	5	6	7	8
Under these conditions , Keap1 targets Nrf2 for ubiquitination and degradation by the 26S proteasome system , resulting in basal low-level expression of Nrf2 [ XREF_BIBR ] .	Under these conditions, Keap1 targets Nrf2 for ubiquitination and degradation by the 26S proteasome system, resulting in basal low-level expression of Nrf2 [XREF_BIBR].	2	17	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
Nrf2 inhibition induced by fructose was mostly reversed by Keap1 siRNA , whereas Nrf2 activator tBHQ pre-treatment failed to alter Keap1 in BRL-3A cells , indicating that Keap1 over-expression may act upstream of Nrf2 inactivation .	Nrf2 inhibition induced by fructose was mostly reversed by Keap1 siRNA, whereas Nrf2 activator tBHQ pre-treatment failed to alter Keap1 in BRL-3A cells, indicating that Keap1 over-expression may act upstream of Nrf2 inactivation.	0	10	reversed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	9	10	0	1
It was reiterated in this study that PKC phosphorylates Keap1 , a sequestering binding partner of Nrf2 , inducing dissociation and activation of Nrf2 and the transcription of antioxidant response genes .	It was reiterated in this study that PKC phosphorylates Keap1, a sequestering binding partner of Nrf2, inducing dissociation and activation of Nrf2 and the transcription of antioxidant response genes.	8	24	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	phosphorylates Keap1	keap1	Nrf2	Nrf2	nrf2	9	10	23	24
In this model , oxidative and electrophilic molecules modify cysteine residues of KEAP1 , which activates NRF2 .	In this model, oxidative and electrophilic molecules modify cysteine residues of KEAP1, which activates NRF2.	10	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	12	13	16	17
Under basal conditions , Keap1 based Cul3 complex targets Nrf2 for ubiquitin dependent degradation .	Under basal conditions, Keap1 based Cul3 complex targets Nrf2 for ubiquitin dependent degradation.	4	13	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	9	10
Keap1 tightly represses Nrf2 activity in normal conditions , and Nrf2 activity is induced by loss of Keap1 .	Keap1 tightly represses Nrf2 activity in normal conditions, and Nrf2 activity is induced by loss of Keap1.	0	4	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
For the mechanism study , we show that LV-MALAT1 induced Keap1 downregulation , leading to nuclear-factor-E2-related factor 2 ( Nrf2 ) stabilization and activation .	For the mechanism study, we show that LV-MALAT1 induced Keap1 downregulation, leading to nuclear-factor-E2-related factor 2 (Nrf2) stabilization and activation.	8	21	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	LV-MALAT1 induced Keap1	keap1	Nrf2	Nrf2	nrf2	10	11	19	20
Keap1 transfers Nrf2 to cullin-3 ( Cul3 ) , an ubiquitin E3 ligase , thereby targeting Nrf2 for proteosomal degradation [ XREF_BIBR , XREF_BIBR ] .	Keap1 transfers Nrf2 to cullin-3 (Cul3), an ubiquitin E3 ligase, thereby targeting Nrf2 for proteosomal degradation [XREF_BIBR, XREF_BIBR].	0	21	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	16	17
Another study by Shibata et al indicated that Keap1 gene mutations in gallbladder cancer may result in Nrf2 overexpression .	Another study by Shibata et al indicated that Keap1 gene mutations in gallbladder cancer may result in Nrf2 overexpression.	8	19	overexpression	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	8	9	17	18
Furthermore , the expression of KEAP1 , which targets NRF2 for ubiquitination and subsequent proteolysis , increased 1.00-fold ( p < 0.001 ) in mRNA expression and 0.82-fold ( p < 0.001 ) in protein expression following plasma treatment at 27.6 kV as compared with the control group .	Furthermore, the expression of KEAP1, which targets NRF2 for ubiquitination and subsequent proteolysis, increased 1.00-fold (p < 0.001) in mRNA expression and 0.82-fold (p < 0.001) in protein expression following plasma treatment at 27.6 kV as compared with the control group.	3	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	expression of KEAP1	keap1	NRF2	NRF2	nrf2	5	6	9	10
We found that systemic activation of NRF2 by Keap1 ( Kelch like ECH associated protein 1 ) knockdown ameliorated tissue inflammation and lethality in Sf mice .	We found that systemic activation of NRF2 by Keap1 (Kelch like ECH associated protein 1) knockdown ameliorated tissue inflammation and lethality in Sf mice.	4	9	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	NRF2	NRF2	NRF2	8	9	6	7
In the presence of oxidative stress , cysteine residues in KEAP1 are oxidized to inactivate the protein , promoting stabilization of NRF2 in the cytoplasm .	In the presence of oxidative stress, cysteine residues in KEAP1 are oxidized to inactivate the protein, promoting stabilization of NRF2 in the cytoplasm.	8	22	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	10	11	21	22
In the absence of stress , Nrf2 resides in the cytoplasm bound to the actin anchored protein Keap1 , which targets Nrf2 toward proteosomal degradation .	In the absence of stress, Nrf2 resides in the cytoplasm bound to the actin anchored protein Keap1, which targets Nrf2 toward proteosomal degradation.	15	24	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	21	22
In addition , using MALDI-TOF mass spectrometry and LC-MS/MS , it was demonstrated that the lipophilic extracts and ligustilide alkylated important cysteine residues in human Keap1 protein , such as C151 , thus activating Nrf2 and transcription of ARE regulated genes .	In addition, using MALDI-TOF mass spectrometry and LC-MS/MS, it was demonstrated that the lipophilic extracts and ligustilide alkylated important cysteine residues in human Keap1 protein, such as C151, thus activating Nrf2 and transcription of ARE regulated genes.	25	35	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	25	26	34	35
During normal levels of ROS generation , Nrf2 is retained in the cytoplasm by kelch like ECH associated protein 1 ( Keap1 ) , which targets Nrf2 to ubiquitin dependent degradation .	During normal levels of ROS generation, Nrf2 is retained in the cytoplasm by kelch like ECH associated protein 1 (Keap1), which targets Nrf2 to ubiquitin dependent degradation.	18	27	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	21	22	26	27
Looking at the full set of KEAP1 mutant tumors and the expression of 15 NRF2 target genes , a marginal but statistically significant difference was observed between phenotypically ' silent ' KEAP1 mutations and mutations which suppress KEAP1 driven NRF2 degradation ( XREF_SUPPLEMENTARY ) .	Looking at the full set of KEAP1 mutant tumors and the expression of 15 NRF2 target genes, a marginal but statistically significant difference was observed between phenotypically ' silent ' KEAP1 mutations and mutations which suppress KEAP1 driven NRF2 degradation (XREF_SUPPLEMENTARY).	36	40	driven	Positive_activation_token_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	37	38	39	40
In fumarate hydratase deficient RCC , fumarate induced succination of KEAP1 activates Nrf2 signaling .	In fumarate hydratase deficient RCC, fumarate induced succination of KEAP1 activates Nrf2 signaling.	8	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	Nrf2	Nrf2	Nrf2	10	11	12	13
237-241 However , it is still unclear whether the inhibition of NF-kappaB activation by plumbagin , shikonin and 1,4-naphthoquinone is solely mediated via Keap1 dependent activation of Nrf2 and ARE signaling or by other mechanisms , especially considering Keap1 independent mechanisms of regulating Nrf2 have been well documented 227 Furthermore , it is well established that 1,4-NQs are inhibitors of topoisomerases .	237-241 However, it is still unclear whether the inhibition of NF-kappaB activation by plumbagin, shikonin and 1,4-naphthoquinone is solely mediated via Keap1 dependent activation of Nrf2 and ARE signaling or by other mechanisms, especially considering Keap1 independent mechanisms of regulating Nrf2 have been well documented 227 Furthermore, it is well established that 1,4-NQs are inhibitors of topoisomerases.	23	28	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	23	24	27	28
Keap1 , a substrate adaptor protein for Cullin3 and Rbx1 ubiquitin ligase , normally continuously targets Nrf2 for degradation , but loses this ability in response to electrophiles and oxidants ( termed inducers ) .	Keap1, a substrate adaptor protein for Cullin3 and Rbx1 ubiquitin ligase, normally continuously targets Nrf2 for degradation, but loses this ability in response to electrophiles and oxidants (termed inducers).	0	21	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	16	17
Hypermethylation of KEAP1 caused final stimulation of Nrf2 target genes .	Hypermethylation of KEAP1 caused final stimulation of Nrf2 target genes.	0	9	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	Hypermethylation of KEAP1	keap1	Nrf2	Nrf2	nrf2	2	3	7	8
Similarly , because Keap1 targets Nrf2 for degradation through a physical association with Cullin3 , disrupting the Keap1-Cullin3 interface should also lead to Nrf2 stabilization and target gene induction .	Similarly, because Keap1 targets Nrf2 for degradation through a physical association with Cullin3, disrupting the Keap1-Cullin3 interface should also lead to Nrf2 stabilization and target gene induction.	2	21	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	3	4	5	6
Substantial efforts have led to the discovery of the molecular mechanisms of KEAP1 mediated NRF2 regulation .	Substantial efforts have led to the discovery of the molecular mechanisms of KEAP1 mediated NRF2 regulation.	10	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	12	13	14	15
Nrf2 is repressed by the cysteine rich Keap1 protein , which targets Nrf2 for ubiquitination and subsequent degradation by a Cul3 mediated ubiquitination complex .	Nrf2 is repressed by the cysteine rich Keap1 protein, which targets Nrf2 for ubiquitination and subsequent degradation by a Cul3 mediated ubiquitination complex.	7	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
Some tumors have increased methylation in the KEAP1 gene that suppresses Keap1 expression and activates Nrf2 .	Some tumors have increased methylation in the KEAP1 gene that suppresses Keap1 expression and activates Nrf2.	7	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	KEAP1 gene that suppresses Keap1 expression	keap1	Nrf2	Nrf2	nrf2	7	8	15	16
In parallel with repression by Keap1 , Nrf2 is also repressed by beta-transducin repeat containing protein ( beta-TrCP ) , present in the Skp1-cullin-1-F-box protein ( SCF ) ubiquitin ligase complex SCF beta-TrCP .	In parallel with repression by Keap1, Nrf2 is also repressed by beta-transducin repeat containing protein (beta-TrCP), present in the Skp1-cullin-1-F-box protein (SCF) ubiquitin ligase complex SCF beta-TrCP.	3	11	repressed	Negative_activation_syntax_4_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	7	8
Nrf2 activation is modulated by Keap1 , which is a sensor of environmental stress .	Nrf2 activation is modulated by Keap1, which is a sensor of environmental stress.	0	10	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	5	6	0	1
SFN modifies specific cysteine residues in Keap1 , enabling Nrf2 to escape from Keap1 mediated ubiquitination and degradation [ XREF_BIBR , XREF_BIBR ] .	SFN modifies specific cysteine residues in Keap1, enabling Nrf2 to escape from Keap1 mediated ubiquitination and degradation [XREF_BIBR, XREF_BIBR].	1	10	enabling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	6	7	9	10
The best characterized CUL3 substrate receptor is Keap1 , which targets the Nrf2 transcription factor for ubiquitination and degradation .	The best characterized CUL3 substrate receptor is Keap1, which targets the Nrf2 transcription factor for ubiquitination and degradation.	1	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	7	8	12	13
Moreover , dh404 suppressed Keap1 mediated Nrf2 degradation via a posttranscriptional modulation at the C151 residue in Keap1 ( XREF_FIG ) .	Moreover, dh404 suppressed Keap1 mediated Nrf2 degradation via a posttranscriptional modulation at the C151 residue in Keap1 (XREF_FIG).	4	7	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	4	5	6	7
Keap1 shRNA activates Nrf2 and protects human osteoblastic cells from Dex .	Keap1 shRNA activates Nrf2 and protects human osteoblastic cells from Dex.	0	4	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	3	4
XREF_BIBR , XREF_BIBR , XREF_BIBR Binding of a regulatory protein , Keap1 , sequesters Nrf2 in the cytoplasm , targeting Nrf2 for polyubiquitinylation and proteasomal degration and , thus , silencing the Nrf2 gene program .	XREF_BIBR, XREF_BIBR, XREF_BIBR Binding of a regulatory protein, Keap1, sequesters Nrf2 in the cytoplasm, targeting Nrf2 for polyubiquitinylation and proteasomal degration and, thus, silencing the Nrf2 gene program.	0	15	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	11	12	14	15
One of the well characterised BTB containing factors is KEAP1 , which targets the transcriptional factor NRF2 ( encoded by NFE2L2 ) for degradation , thereby regulating oxidative processes .	One of the well characterised BTB containing factors is KEAP1, which targets the transcriptional factor NRF2 (encoded by NFE2L2) for degradation, thereby regulating oxidative processes.	0	26	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	KEAP1	KEAP1	KEAP1	NRF2	NRF2	NRF2	9	10	16	17
Under non stressful physiological condition , Nrf2 is kept in the cytosol by Keap1 , a component of an E3 ubiquitin ligase complex that targets Nrf2 for proteasomal degradation [ XREF_BIBR , XREF_BIBR ] .	Under non stressful physiological condition, Nrf2 is kept in the cytosol by Keap1, a component of an E3 ubiquitin ligase complex that targets Nrf2 for proteasomal degradation [XREF_BIBR, XREF_BIBR].	8	30	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	13	14	25	26
Activation of Nrf2 is mainly regulated by its cytosolic inhibitor Kelch Like ECH Associated Protein 1 ( Keap1 ) , which under basal conditions targets Nrf2 for ubiquitin dependent proteasomal degradation XREF_BIBR .	Activation of Nrf2 is mainly regulated by its cytosolic inhibitor Kelch Like ECH Associated Protein 1 (Keap1), which under basal conditions targets Nrf2 for ubiquitin dependent proteasomal degradation XREF_BIBR.	14	31	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	17	18	25	26
In autophagy deficient cells , phosphorylated p62 aggregates with Keap1 in the cytoplasm , causing constant Nrf2 activation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In autophagy deficient cells, phosphorylated p62 aggregates with Keap1 in the cytoplasm, causing constant Nrf2 activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	5	23	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	phosphorylated p62 aggregates with Keap1	keap1	Nrf2	Nrf2	nrf2	9	10	16	17
P62 knockdown promotes the accumulation of Keap1 protein and enhanced Keap1 mediated Nrf2 degradation , suggesting that the interaction p62-Keap1 is responsible for Nrf2 expression during ferroptosis XREF_BIBR .	P62 knockdown promotes the accumulation of Keap1 protein and enhanced Keap1 mediated Nrf2 degradation, suggesting that the interaction p62-Keap1 is responsible for Nrf2 expression during ferroptosis XREF_BIBR.	9	15	mediated	Positive_early_activation	Negative_activation	Negative_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	10	11	12	13
Keap1 conjugates with the Cul3 containing E3 ubiquitin ligase and mediates Nrf2 and Bcl-2 for their ubiquitination and degradation .	Keap1 conjugates with the Cul3 containing E3 ubiquitin ligase and mediates Nrf2 and Bcl-2 for their ubiquitination and degradation.	0	13	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Keap1	Keap1	Keap1	Nrf2	Nrf2	Nrf2	0	1	11	12
Soluble ectodomains of LRIG1 are reportedly sufficient to inhibit the growth of cancer cells by attenuating EGFR activity XREF_BIBR , and more recently , a study showed that the LRIG1 ectodomain can be naturally shed and can function as a non-cell-autonomous regulator of EGFR signaling XREF_BIBR .	Soluble ectodomains of LRIG1 are reportedly sufficient to inhibit the growth of cancer cells by attenuating EGFR activity XREF_BIBR, and more recently, a study showed that the LRIG1 ectodomain can be naturally shed and can function as a non-cell-autonomous regulator of EGFR signaling XREF_BIBR.	1	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	3	4	16	17
19 Inhibition of EGFR signaling by Lrig1 results from a physical interaction between the extracellular domain of both proteins , inducing the recruitment of E3 ubiquitin ligases to the cytosolic part of the Lrig1 and EGFR complex , followed by internalization and enhanced lysosomal degradation of the protein complex .	19 Inhibition of EGFR signaling by Lrig1 results from a physical interaction between the extracellular domain of both proteins, inducing the recruitment of E3 ubiquitin ligases to the cytosolic part of the Lrig1 and EGFR complex, followed by internalization and enhanced lysosomal degradation of the protein complex.	3	7	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Lrig1	Lrig1	Lrig1	EGFR	EGFR	EGFR	6	7	3	4
XREF_BIBR , XREF_BIBR Recently , paracrine regulation of EGFR signaling by shed extracellular Lrig1 was demonstrated to occur naturally ; however , the mechanism of action of shed Lrig1 may not involve EGFR protein downregulation .	XREF_BIBR, XREF_BIBR Recently, paracrine regulation of EGFR signaling by shed extracellular Lrig1 was demonstrated to occur naturally; however, the mechanism of action of shed Lrig1 may not involve EGFR protein downregulation.	8	14	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Lrig1	Lrig1	Lrig1	EGFR	EGFR	EGFR	13	14	8	9
Restoration of LRIG1 suppresses bladder cancer cell growth by directly targeting EGFR activity .	Restoration of LRIG1 suppresses bladder cancer cell growth by directly targeting EGFR activity.	0	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	2	3	11	12
Knockdown of LRIG1 has been found to increase the cell surface expression of EGFR while ectopic expression of LRIG1 has been found to enhance the EGF stimulated internalization of EGFR , strongly suggesting that LRIG1 does engage the receptor internalization machinery .	Knockdown of LRIG1 has been found to increase the cell surface expression of EGFR while ectopic expression of LRIG1 has been found to enhance the EGF stimulated internalization of EGFR, strongly suggesting that LRIG1 does engage the receptor internalization machinery.	0	14	increase	Positive_regulation_syntax_1_verb	Negative_activation	Negative_regulation	LRIG1	LRIG1	lrig1	EGFR	expression of EGFR	egfr	2	3	13	14
The expression and phosphorylation of the LRIG1 targets EGFR , Met and c-Myc were also significantly decreased as was the phosphorylation of Akt .	The expression and phosphorylation of the LRIG1 targets EGFR, Met and c-Myc were also significantly decreased as was the phosphorylation of Akt.	1	13	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	LRIG1	expression and phosphorylation of the LRIG1	lrig1	EGFR	EGFR	egfr	6	7	8	9
LRIG1 and ACK1 enhance the internalization and degration of EGFR , while NHERF and HIP1 repress it .	LRIG1 and ACK1 enhance the internalization and degration of EGFR, while NHERF and HIP1 repress it.	0	10	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	0	1	9	10
Overexpression of DLL1 and LRIG1 resulted in enhanced extracellular matrix adhesion and increased caveolin dependent EGFR endocytosis .	Overexpression of DLL1 and LRIG1 resulted in enhanced extracellular matrix adhesion and increased caveolin dependent EGFR endocytosis.	0	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LRIG1	Overexpression of DLL1 and LRIG1	lrig1	EGFR	EGFR	egfr	4	5	15	16
In this study , we examine the regulation of EGFRvIII by the recently identified negative regulator , LRIG1 , which targets EGFR through recognition of its extracellular domain .	In this study, we examine the regulation of EGFRvIII by the recently identified negative regulator, LRIG1, which targets EGFR through recognition of its extracellular domain.	15	22	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	17	18	21	22
MG132 pre-treatment resulted in a relatively smaller increase in EGFR level , suggesting that LRIG1 induced EGFR depletion may be , at least partially , attributed to an increase in protein degradation by the proteasome .	MG132 pre-treatment resulted in a relatively smaller increase in EGFR level, suggesting that LRIG1 induced EGFR depletion may be, at least partially, attributed to an increase in protein degradation by the proteasome.	14	17	induced	Positive_early_activation	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	14	15	16	17
LRIG1 , a LIG family member akin to LINGO-1 , down-regulates EGFR by promoting lysosomal degradation of EGFR .	LRIG1, a LIG family member akin to LINGO-1, down-regulates EGFR by promoting lysosomal degradation of EGFR.	0	12	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LRIG1	LRIG1	LRIG1	EGFR	EGFR	EGFR	0	1	11	12
Based on the present results and previous works , our analyses provide evidence for the following conclusions : ( 1 ) Wnt signaling plays a role in FGF mediated fibroblast migration ; ( 2 ) PI3K and JNK acts at the downstream of FGF signaling to positively regulate GSK3beta and beta-catenin activity ; ( 3 ) a new role for FGF21 is identified in fibroblast migration ; and ( 4 ) beta-catenin also acts downstream of FGF signaling , but in turn activates transcription of bFGF and FGF21 , two FGF family member genes .	Based on the present results and previous works, our analyses provide evidence for the following conclusions : (1) Wnt signaling plays a role in FGF mediated fibroblast migration; (2) PI3K and JNK acts at the downstream of FGF signaling to positively regulate GSK3beta and beta-catenin activity; (3) a new role for FGF21 is identified in fibroblast migration; and (4) beta-catenin also acts downstream of FGF signaling, but in turn activates transcription of bFGF and FGF21, two FGF family member genes.	35	51	positively regulate	Positive_activation_syntax_1b_verb	Negative_activation	Positive_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	37	38	50	51
Moreover , inhibition of JNK , but not p38MAPK or MEK , decreased active and total beta-catenin ( XREF_FIG ) .	Moreover, inhibition of JNK, but not p38MAPK or MEK, decreased active and total beta-catenin (XREF_FIG).	2	18	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	4	5	16	17
These results indicate that the inhibition of JNK mediated beta-catenin signaling activates Bax ( XREF_FIG ) .	These results indicate that the inhibition of JNK mediated beta-catenin signaling activates Bax (XREF_FIG).	5	10	mediated	Positive_early_activation	Negative_activation	Negative_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	7	8	9	10
Smad2/3 and JNK were phosphorylated to promote the TGF-beta1-induced activation of beta-catenin and osteoblastic differentiation of AVICs , and metformin also alleviated TGF-beta1-induced activation of Smad2/3 and JNK .	Smad2/3 and JNK were phosphorylated to promote the TGF-beta1-induced activation of beta-catenin and osteoblastic differentiation of AVICs, and metformin also alleviated TGF-beta1-induced activation of Smad2/3 and JNK.	0	12	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	JNK were phosphorylated	jnk	beta-catenin	beta-catenin	beta-catenin	2	3	11	12
These findings suggest that JNK/14-3-3sigma axis is not critical to keep betacatenin bound with 14-3-3sigma and that JNK might rather induce betacatenin post-transcriptional modifications at critical residues for binding with 14-3-3sigma [ XREF_BIBR , XREF_BIBR ] .	These findings suggest that JNK/14-3-3sigma axis is not critical to keep betacatenin bound with 14-3-3sigma and that JNK might rather induce betacatenin post-transcriptional modifications at critical residues for binding with 14-3-3sigma [XREF_BIBR, XREF_BIBR].	17	23	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	JNK	JNK	betacatenin	betacatenin	betacatenin	17	18	21	22
Compared with the effects of Wnt5a knockdown cells , Wnt5a overexpressing cells triggered the phosphorylation of c-Jun N-terminal kinase ( JNK ) and beta-catenin , which leads to beta-catenin degradation and inactivates the canonical Wnt and beta-catenin pathway .	Compared with the effects of Wnt5a knockdown cells, Wnt5a overexpressing cells triggered the phosphorylation of c-Jun N-terminal kinase (JNK) and beta-catenin, which leads to beta-catenin degradation and inactivates the canonical Wnt and beta-catenin pathway.	9	37	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Jun N-terminal kinase	Wnt5a overexpressing cells triggered the phosphorylation of c-Jun N-terminal kinase	c-jun n-terminal kinase	beta-catenin	beta-catenin	beta-catenin	16	19	36	37
As expected for an FFL , ectopic JNK induces ectopic accumulation of microtubules ( XREF_FIG ) and actin ( XREF_FIG ) as well as E-Cadherin and beta-catenin ( XREF_FIG ) .	As expected for an FFL, ectopic JNK induces ectopic accumulation of microtubules (XREF_FIG) and actin (XREF_FIG) as well as E-Cadherin and beta-catenin (XREF_FIG).	6	28	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	7	8	26	27
We can assume that SP600125 revokes JNK induced phopshorylation of betacatenin at critical residues for 14-3-3 binding , while hindering 14-3-3sigma phosphorylation at a critical residue for CBY1 binding [ XREF_BIBR , XREF_BIBR ] .	We can assume that SP600125 revokes JNK induced phopshorylation of betacatenin at critical residues for 14-3-3 binding, while hindering 14-3-3sigma phosphorylation at a critical residue for CBY1 binding [XREF_BIBR, XREF_BIBR].	6	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	JNK	JNK	betacatenin	betacatenin	betacatenin	6	7	10	11
Further , JNK enhances the transcriptional activity of beta-catenin by phophorylating and activating c-Jun and AP-1 , a well characterized coactivator of the beta , catenin , Tcf , and Lef complex [ XREF_BIBR ] .	Further, JNK enhances the transcriptional activity of beta-catenin by phophorylating and activating c-Jun/AP-1, a well characterized coactivator of the beta, catenin, Tcf, and Lef complex [XREF_BIBR].	2	9	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	2	3	8	9
Wnt5a activated beta-catenin independent signaling including calmodulin dependent protein kinase II ( CaMKII ) , JNK , p38 , ERK1/2 , p65 and Akt .	Wnt5a activated beta-catenin independent signaling including calmodulin dependent protein kinase II (CaMKII), JNK, p38, ERK1/2, p65 and Akt.	2	23	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	JNK	JNK	JNK	beta-catenin	beta-catenin	beta-catenin	15	16	2	3
If JNK promotes the association of Bad with Bcl-2 and Bcl-x L through phosphorylation of 14-3-3 , the expression of 14-3-3zeta Ser184A should block the JNK induced interaction between Bad and Bcl-2 and Bcl-x L.	If JNK promotes the association of Bad with Bcl-2 and Bcl-x L through phosphorylation of 14-3-3, the expression of 14-3-3zeta Ser184A should block the JNK induced interaction between Bad and Bcl-2 and Bcl-x L.	1	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	JNK	JNK	Bcl-x L	Bcl-x L	Bcl-x L	1	2	10	12
Reduction of PTP1B in wild-type immortalized hepatocytes decreased APAP induced JNK phosphorylation and levels of the active caspase-3 fragment , and also maintained IGFIR tyrosine phosphorylation , IRS1 and IRS2 expression , Akt phosphorylation and abolished downregulation of BclxL upon APAP treatment ( XREF_FIG ) .	Reduction of PTP1B in wild-type immortalized hepatocytes decreased APAP induced JNK phosphorylation and levels of the active caspase-3 fragment, and also maintained IGFIR tyrosine phosphorylation, IRS1 and IRS2 expression, Akt phosphorylation and abolished downregulation of BclxL upon APAP treatment (XREF_FIG).	2	39	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	PTP1B in wild-type immortalized hepatocytes decreased APAP induced JNK phosphorylation	jnk	BclxL	BclxL	bclxl	10	11	38	39
The activation of JNK and PI3K and AKT signaling pathways promotes the induction of Bcl-XL while AKT activation also leads to Bad phosphorylation and down-regulation .	The activation of JNK and PI3K and AKT signaling pathways promotes the induction of Bcl-XL while AKT activation also leads to Bad phosphorylation and down-regulation.	1	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	JNK	JNK	Bcl-XL	Bcl-XL	Bcl-XL	3	4	14	15
The hyperactivation of JNK caused an alteration of Bcl-2 and Bcl-X L , thus resulting in a dysfunction of the mitochondria , including an altered respiration , transmembrane potential , and calcium buffering capacity ; however , the expression and phosphorylation of Bcl-2 and Bcl-X L seemed to be largely normal in G5pr -/- B cells .	The hyperactivation of JNK caused an alteration of Bcl-2 and Bcl-X L, thus resulting in a dysfunction of the mitochondria, including an altered respiration, transmembrane potential, and calcium buffering capacity; however, the expression and phosphorylation of Bcl-2 and Bcl-X L seemed to be largely normal in G5pr -/- B cells.	1	12	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK	JNK	JNK	Bcl-X L	Bcl-X L	Bcl-X L	3	4	10	12
These results strongly indicate that the anisomycin promoted apoptosis in Jurkat T cells through the JNK dependent activation of Bim and Bcl-xL .	These results strongly indicate that the anisomycin promoted apoptosis in Jurkat T cells through the JNK dependent activation of Bim and Bcl-xL.	15	22	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	JNK	JNK	JNK	Bcl-xL	Bcl-xL	Bcl-xL	15	16	21	22
These findings strongly prove that anisomycin promotes the apoptosis in Jurkat T cells through the JNK dependent activation of Bim and Bcl-xL .	These findings strongly prove that anisomycin promotes the apoptosis in Jurkat T cells through the JNK dependent activation of Bim and Bcl-xL.	15	22	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	JNK	JNK	JNK	Bcl-xL	Bcl-xL	Bcl-xL	15	16	21	22
We did not observe phosphorylated MST1 or LATS1 following PH to be reduced below their steady state levels , allowing us to speculate as to the importance of the flux of their expression in the control of YAP1 .	We did not observe phosphorylated MST1 or LATS1 following PH to be reduced below their steady state levels, allowing us to speculate as to the importance of the flux of their expression in the control of YAP1.	4	38	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LATS1	phosphorylated MST1 or LATS1	lats1	YAP1	YAP1	yap1	7	8	37	38
Based on these studies , we propose that TG2 associates with the alpha6 and beta4-integrins to increase FAK and Src signaling and that this leads to PI3K and PDK1 activation , and that PDK1 , in turn , suppresses LATS1 ( Hippo ) signaling leading to enhance nuclear accumulation of YAP1 which forms a complex with and stabilizes DeltaNp63alpha to enhance ECS cell survival ( XREF_FIG ) .	Based on these studies, we propose that TG2 associates with the alpha6 and beta4-integrins to increase FAK and Src signaling and that this leads to PI3K and PDK1 activation, and that PDK1, in turn, suppresses LATS1 (Hippo) signaling leading to enhance nuclear accumulation of YAP1 which forms a complex with and stabilizes DeltaNp63alpha to enhance ECS cell survival (XREF_FIG).	39	51	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LATS1	LATS1	LATS1	YAP1	YAP1	YAP1	39	40	50	51
TGF-beta1 increased LATS1 expression and induced the translocation of YAP1 from the nucleus to the cytoplasm .	TGF-beta1 increased LATS1 expression and induced the translocation of YAP1 from the nucleus to the cytoplasm.	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LATS1	TGF-beta1 increased LATS1 expression	lats1	YAP1	YAP1	yap1	2	3	9	10
We also found that overexpression of LATS1 led to a significant decrease in the growth of HCC cells in vitro , while downregulation of LATS1 expression promoted HCC cell growth and activated YAP1 .	We also found that overexpression of LATS1 led to a significant decrease in the growth of HCC cells in vitro, while downregulation of LATS1 expression promoted HCC cell growth and activated YAP1.	24	33	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LATS1	LATS1 expression	lats1	YAP1	YAP1	yap1	24	25	32	33
Furthermore , consistent with the insignificant changes in Lats1/2 phosphorylation ( XREF_FIG ) , Lats1 catalyzed Yap1 ( Ser127 ) kinase activity is largely unaffected by Mst1/2 inactivation ( XREF_FIG ) .	Furthermore, consistent with the insignificant changes in Lats1/2 phosphorylation (XREF_FIG), Lats1 catalyzed Yap1 (Ser127) kinase activity is largely unaffected by Mst1/2 inactivation (XREF_FIG).	9	24	catalyzed	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Lats1	Lats1	Lats1	Yap1	Yap1	Yap1	14	15	16	17
Kremen2 induces LRP6 down-regulation and Wnt and LRP6 signaling inhibition .	Kremen2 induces LRP6 down-regulation and Wnt and LRP6 signaling inhibition.	0	3	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Kremen2	Kremen2	Kremen2	LRP6	LRP6	LRP6	0	1	2	3
Kremen2 forms a ternary complex with Dkk1 and LRP6 , and induces rapid endocytosis and removal of the Wnt receptor LRP6 from the plasma membrane .	Kremen2 forms a ternary complex with Dkk1 and LRP6, and induces rapid endocytosis and removal of the Wnt receptor LRP6 from the plasma membrane.	0	21	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Kremen2	Kremen2	Kremen2	LRP6	LRP6	LRP6	0	1	20	21
However , their data predicts that Kremen2 mediates LRP6 internalization in the presence of Dkk1 within 5 minutes of chase at 37degreesC , suggesting that the cytosolic tail of Kremen has the potential to internalize by clathrin mediated endocytosis .	However, their data predicts that Kremen2 mediates LRP6 internalization in the presence of Dkk1 within 5 minutes of chase at 37degreesC, suggesting that the cytosolic tail of Kremen has the potential to internalize by clathrin mediated endocytosis.	6	9	mediates	Positive_activation_syntax_3a_verb	Negative_activation	Positive_activation	Kremen2	Kremen2	Kremen2	LRP6	LRP6	LRP6	6	7	8	9
It has been shown that Kremen2 forms a ternary complex with Dkk1 and LRP6 and induces rapid endocytosis and removal of LRP6 from the cell surface XREF_BIBR - XREF_BIBR .	It has been shown that Kremen2 forms a ternary complex with Dkk1 and LRP6 and induces rapid endocytosis and removal of LRP6 from the cell surface XREF_BIBR - XREF_BIBR.	5	22	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Kremen2	Kremen2	Kremen2	LRP6	LRP6	LRP6	5	6	21	22
Thus LIMK1 mediated CFL1 homeostasis is crucial for receptor function .	Thus LIMK1 mediated CFL1 homeostasis is crucial for receptor function.	1	6	mediated	Positive_early_activation	Negative_activation	Positive_activation	LIMK1	LIMK1	LIMK1	CFL1	CFL1	CFL1	1	2	3	4
We have identified a critical role of LIMK1 mediated CFL1 pathway and actin dynamics in modulating retinoid receptor mediated function and shown that LIMK1 mediated phosphocycling of CFL1 plays a crucial role in maintaining actin homeostasis and receptor activity .	We have identified a critical role of LIMK1 mediated CFL1 pathway and actin dynamics in modulating retinoid receptor mediated function and shown that LIMK1 mediated phosphocycling of CFL1 plays a crucial role in maintaining actin homeostasis and receptor activity.	5	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	LIMK1	LIMK1	LIMK1	CFL1	CFL1	CFL1	7	8	9	10
Our results indicate a critical role of LIMK1 mediated CFL1 pathway and actin dynamics in retinoid receptor function .	Our results indicate a critical role of LIMK1 mediated CFL1 pathway and actin dynamics in retinoid receptor function.	5	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	LIMK1	LIMK1	LIMK1	CFL1	CFL1	CFL1	7	8	9	10
LNX has been reported to target the cell fate determinant and Notch antagonist Numb for proteasome dependent degradation , thereby causing an increase in transactivational activity of Notch .	LNX has been reported to target the cell fate determinant and Notch antagonist Numb for proteasome dependent degradation, thereby causing an increase in transactivational activity of Notch.	0	14	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LNX	LNX	LNX	Numb	Numb	Numb	0	1	13	14
LNX1 can target Numb for proteasomal degradation , and Lnx mRNAs are prominently expressed in the nervous system , suggesting that LNX proteins play a role in neural development .	LNX1 can target Numb for proteasomal degradation, and Lnx mRNAs are prominently expressed in the nervous system, suggesting that LNX proteins play a role in neural development.	0	6	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LNX1	LNX1	LNX1	Numb	Numb	Numb	0	1	3	4
Suppressor of deltex and Itch and SCF Fbxw7 directly target NICD , whereas LNX degrades Numb , an antagonist of NICD .	Suppressor of deltex and Itch and SCF Fbxw7 directly target NICD, whereas LNX degrades Numb, an antagonist of NICD.	13	18	degrades	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	LNX	LNX	LNX	Numb	Numb	Numb	13	14	15	16
Because LATS2 phosphorylates serine 127 and causes cytoplasmic sequestration of YAP1 , failure of phosphorylation at serine 127 in the YAP1 protein causes constitutive translocation to the nucleus and transcription of its target genes [ XREF_BIBR , XREF_BIBR ] .	Because LATS2 phosphorylates serine 127 and causes cytoplasmic sequestration of YAP1, failure of phosphorylation at serine 127 in the YAP1 protein causes constitutive translocation to the nucleus and transcription of its target genes [XREF_BIBR, XREF_BIBR].	1	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LATS2	LATS2	LATS2	YAP1	YAP1	YAP1	1	2	10	11
KLF4 siRNA repressed CSE induced suppression of myocardin as well as SM- alpha-actin , SM-MHC and SM-22-alpha while a control GFP siRNA had no effect ( XREF_FIG ) .	KLF4 siRNA repressed CSE induced suppression of myocardin as well as SM- alpha-actin, SM-MHC and SM-22-alpha while a control GFP siRNA had no effect (XREF_FIG).	0	8	repressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KLF4	KLF4	KLF4	myocardin	myocardin	myocardin	0	1	7	8
siRNA targeting of KLF4 nearly blocked POVPC induced suppression of SMC marker genes , and myocardin .	siRNA targeting of KLF4 nearly blocked POVPC induced suppression of SMC marker genes, and myocardin.	1	16	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	KLF4	KLF4	KLF4	myocardin	myocardin	myocardin	3	4	15	16
In vitro LFNG may enhance DLL1 mediated signalling and inhibits Jagged1 mediated signalling through Notch1 , or potentiate both Jagged1- and DLL1 mediated signalling via Notch2 [ XREF_BIBR ] indicating a complex modulation of Notch activity by differential glycosylation .	In vitro LFNG may enhance DLL1 mediated signalling and inhibits Jagged1 mediated signalling through Notch1, or potentiate both Jagged1- and DLL1 mediated signalling via Notch2 [XREF_BIBR] indicating a complex modulation of Notch activity by differential glycosylation.	0	20	potentiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LFNG	LFNG	LFNG	Jagged1-	Jagged1-	Jagged1-	2	3	19	20
By contrast , JAG1 activation of Notch2 is potentiated by Lfng , thereby expanding the ligand-receptor combinations that are differentially modified by the Fringe enzymes .	By contrast, JAG1 activation of Notch2 is potentiated by Lfng, thereby expanding the ligand-receptor combinations that are differentially modified by the Fringe enzymes.	3	11	potentiated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Lfng	Lfng	Lfng	JAG1	JAG1	JAG1	10	11	3	4
Among 13 JAK2 V617F negative PV patients , JAK2 exon 12 mutation was detected as N542-E543del in 2 ( 15.4 % ) patients who presented with a phenotype of predominant erythrocytosis and erythroid colonic grown from their bone marrow samples in the absence of exogenous EPO , reduced serum erythropoietin ( EPO ) level , and no mutations in TET2 , ASXL1 or EZH2 genes .	Among 13 JAK2 V617F negative PV patients, JAK2 exon 12 mutation was detected as N542-E543del in 2 (15.4%) patients who presented with a phenotype of predominant erythrocytosis and erythroid colonic grown from their bone marrow samples in the absence of exogenous EPO, reduced serum erythropoietin (EPO) level, and no mutations in TET2, ASXL1 or EZH2 genes.	8	64	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	JAK2	JAK2	JAK2	EZH2	EZH2	EZH2	8	9	63	64
The muscle dedifferentiation factors Msx1 and Msx2 were strongly induced by the Lhx2 overexpression .	The muscle dedifferentiation factors Msx1 and Msx2 were strongly induced by the Lhx2 overexpression.	0	14	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Lhx2	Lhx2 overexpression	lhx2	Msx1	Msx1	msx1	12	13	4	5
These studies demonstrate that oncogenic JAK2 kinases promote myeloproliferative disease and erythroid differentiation , at least in part , by inactivating PRMT5 , and suggest that in the context of hematopoietic cells , inhibition of PRMT5 activity might impinge on EGFR signaling , thereby inducing cell proliferation and tumorigenesis .	These studies demonstrate that oncogenic JAK2 kinases promote myeloproliferative disease and erythroid differentiation, at least in part, by inactivating PRMT5, and suggest that in the context of hematopoietic cells, inhibition of PRMT5 activity might impinge on EGFR signaling, thereby inducing cell proliferation and tumorigenesis.	5	22	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JAK2	JAK2	JAK2	PRMT5	PRMT5	PRMT5	5	6	21	22
Thus , we first investigated whether Itch targets Smad7 to positively regulate TGF-beta signaling .	Thus, we first investigated whether Itch targets Smad7 to positively regulate TGF-beta signaling.	6	9	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Itch	Itch	Itch	Smad7	Smad7	Smad7	6	7	8	9
Medulloblastomas also have been shown to have loss of REN ( KCTD11 ) , a protein that antagonizes Gli mediated transactivation of the Hh target genes , ultimately resulting in activation of the Hh pathway downstream of cilia ( XREF_FIG ) .	Medulloblastomas also have been shown to have loss of REN (KCTD11), a protein that antagonizes Gli mediated transactivation of the Hh target genes, ultimately resulting in activation of the Hh pathway downstream of cilia (XREF_FIG).	7	19	antagonizes	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	KCTD11	loss of REN (KCTD11	kctd11	Gli	Gli	gli	11	12	18	19
Thereafter , phosphorylation of LRP6 leads to binding of AXIN complex to the receptors , thus disabling AXIN complex to degrade beta-catenin .	Thereafter, phosphorylation of LRP6 leads to binding of AXIN complex to the receptors, thus disabling AXIN complex to degrade beta-catenin.	2	18	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LRP6	phosphorylation of LRP6	lrp6	AXIN	AXIN	axin	4	5	17	18
As shown in XREF_FIG , PMA treatment induced significant down-regulation of EKLF , GATA-1 , c-Myc , and c-Myb but it up-regulated GATA-2 and Fli1 .	As shown in XREF_FIG, PMA treatment induced significant down-regulation of EKLF, GATA-1, c-Myc, and c-Myb but it up-regulated GATA-2 and Fli1.	9	25	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	EKLF	EKLF	EKLF	Fli1	Fli1	Fli1	11	12	24	25
Similar results were obtained from HEK293T cells , whereas SW480 cells were resistant , presumably due to strong RAS activity caused by mutated KRASG12V alleles that lead to cytosolic retention and inactivation of PPARgamma by MEK1 and ERK1/2 .	Similar results were obtained from HEK293T cells, whereas SW480 cells were resistant, presumably due to strong RAS activity caused by mutated KRASG12V alleles that lead to cytosolic retention and inactivation of PPARgamma by MEK1 and ERK1/2.	26	37	inactivation	Negative_activation_token_2_noun	Negative_activation	Negative_activation	MEK1	MEK1	MEK1	PPARgamma	PPARgamma	PPARgamma	35	36	33	34
In summary , both mechanisms of MAPK and PPAR-gamma interaction described above ( i.e ., the MAPK mediated PPAR-gamma phosphorylation as well as the MEK-1 driven nucleo cytoplasmic shuttle of PPAR-gamma ) , may represent a way for enabling PPAR-gamma nuclear genomic activity and support the protumor and antiapoptotic role of IGFI system and its downstream signal-transduction components Ras/Raf/MEK/ERK .	In summary, both mechanisms of MAPK and PPAR-gamma interaction described above (i.e., the MAPK mediated PPAR-gamma phosphorylation as well as the MEK-1 driven nucleo cytoplasmic shuttle of PPAR-gamma), may represent a way for enabling PPAR-gamma nuclear genomic activity and support the protumor and antiapoptotic role of IGFI system and its downstream signal-transduction components Ras/Raf/MEK/ERK.	16	31	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MEK-1	MAPK mediated PPAR-gamma phosphorylation as well as the MEK-1	mek-1	PPAR-gamma	PPAR-gamma	ppar-gamma	24	25	30	31
The MEK1 and ERK signaling pathway is known to promote adipogenesis by enhancing PPARgamma and CEBPalpha gene expression XREF_BIBR , XREF_BIBR , a step later to CEBPbeta induction and a cascade which is inversely regulated by atRA XREF_BIBR .	The MEK1 and ERK signaling pathway is known to promote adipogenesis by enhancing PPARgamma and CEBPalpha gene expression XREF_BIBR, XREF_BIBR, a step later to CEBPbeta induction and a cascade which is inversely regulated by atRA XREF_BIBR.	0	16	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MEK1	MEK1	MEK1	PPARgamma	PPARgamma	PPARgamma	1	2	13	14
Interestingly , we found that LRRK2 increases Tau secretion , possibly as a consequence of an impairment of Tau proteasomal degradation .	Interestingly, we found that LRRK2 increases Tau secretion, possibly as a consequence of an impairment of Tau proteasomal degradation.	5	8	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LRRK2	LRRK2	LRRK2	Tau	Tau	Tau	5	6	7	8
In this study , we demonstrate an interaction between LRRK2 and Tau and that LRRK2 promotes the accumulation of non monomeric and high-molecular weight ( HMW ) Tau species independent of its kinase activity .	In this study, we demonstrate an interaction between LRRK2 and Tau and that LRRK2 promotes the accumulation of non monomeric and high-molecular weight (HMW) Tau species independent of its kinase activity.	14	29	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LRRK2	LRRK2	LRRK2	Tau	Tau	Tau	14	15	27	28
LRRK2 Phosphorylates Tubulin Associated Tau but Not the Free Molecule : LRRK2 Mediated Regulation of the Tau-Tubulin Association and Neurite Outgrowth .	LRRK2 Phosphorylates Tubulin Associated Tau but Not the Free Molecule : LRRK2 Mediated Regulation of the Tau-Tubulin Association and Neurite Outgrowth.	11	17	Mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LRRK2	LRRK2	LRRK2	Tau-Tubulin	Tau-Tubulin	Tau-Tubulin	11	12	16	17
MACF1 possesses phosphorylation sites for GSK-3beta at the C-terminus and mediates GSK-3beta signaling [ XREF_BIBR , XREF_BIBR ] .	MACF1 possesses phosphorylation sites for GSK-3beta at the C-terminus and mediates GSK-3beta signaling [XREF_BIBR, XREF_BIBR].	0	12	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MACF1	MACF1	MACF1	GSK-3beta	GSK-3beta	GSK-3beta	0	1	11	12
This pattern matched that of CD13 and APN reporter gene expression , indicating that Maf modulation of c-Myb activity may be an important mechanism for the control of gene transcription during hematopoietic cell development .	This pattern matched that of CD13 and APN reporter gene expression, indicating that Maf modulation of c-Myb activity may be an important mechanism for the control of gene transcription during hematopoietic cell development.	14	18	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Maf	Maf	Maf	c-Myb	c-Myb	c-Myb	14	15	17	18
These results indicate that TC45 can inhibit the Delta EGFR mediated activation of ERK2 and suppress the tumorigenicity of Delta EGFR expressing glioblastoma cells in vivo .	These results indicate that TC45 can inhibit the Delta EGFR mediated activation of ERK2 and suppress the tumorigenicity of Delta EGFR expressing glioblastoma cells in vivo.	4	21	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK2	TC45 can inhibit the Delta EGFR mediated activation of ERK2	erk2	EGFR	EGFR	egfr	13	14	20	21
Mechanistic studies revealed that MAPK1 amplification could promote EGFR TKI resistance , at least in part , by enhancing internalization of EGFR .	Mechanistic studies revealed that MAPK1 amplification could promote EGFR TKI resistance, at least in part, by enhancing internalization of EGFR.	4	22	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK1	MAPK1	MAPK1	EGFR	EGFR	EGFR	4	5	21	22
Delta EGFR activity was necessary for the activation of ERK2 , and pharmacological inhibition of ERK2 inhibited the proliferation of Delta EGFR expressing U87MG cells .	Delta EGFR activity was necessary for the activation of ERK2, and pharmacological inhibition of ERK2 inhibited the proliferation of Delta EGFR expressing U87MG cells.	13	22	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK2	ERK2	ERK2	EGFR	EGFR	EGFR	15	16	21	22
These data strongly indicate that MAPK1 driven AREG production mediates activation of cellular EGFR signaling and confers sensitivity to erlotinib in the setting of MAPK1 E322K .	These data strongly indicate that MAPK1 driven AREG production mediates activation of cellular EGFR signaling and confers sensitivity to erlotinib in the setting of MAPK1 E322K.	5	16	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK1	MAPK1	MAPK1	EGFR	EGFR	EGFR	5	6	13	14
This is interesting to consider in light of findings that increased EGFR internalization , driven by ERK2 amplification , can increase the IC 50 for WZ4002 , an irreversible EGFR inhibitor , in PC9 cells .	This is interesting to consider in light of findings that increased EGFR internalization, driven by ERK2 amplification, can increase the IC 50 for WZ4002, an irreversible EGFR inhibitor, in PC9 cells.	11	17	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ERK2	ERK2	ERK2	EGFR	EGFR	EGFR	16	17	11	12
Our study found that MAPK1 and MAP2K1 knockdown suppressed p-MAPK1 , p-MAP2K1 and Slug involved in MAPK and Slug pathway .	Our study found that MAPK1 and MAP2K1 knockdown suppressed p-MAPK1, p-MAP2K1 and Slug involved in MAPK and Slug pathway.	4	12	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK1	MAPK1	MAPK1	p-MAP2K1	p-MAP2K1	p-MAP2K1	4	5	11	12
The actual densitometric band intensity results for three experiments were quantitated and are shown in XREF_FIG B. To investigate whether ERK2 activation was coincidental with or causal for the alterations in import observed , import cocktail was pretreated with 20 muM PD98059 , a specific inhibitor for the ERK2 activator MEK1 , as described in Materials and Methods .	The actual densitometric band intensity results for three experiments were quantitated and are shown in XREF_FIG B. To investigate whether ERK2 activation was coincidental with or causal for the alterations in import observed, import cocktail was pretreated with 20 muM PD98059, a specific inhibitor for the ERK2 activator MEK1, as described in Materials and Methods.	45	51	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK2	ERK2	ERK2	MEK1	MEK1	MEK1	48	49	50	51
Interestingly , western blot analysis demonstrated that phosphorylated and activated mitogen activated protein kinase kinase 1/2 ( MEK1/2 ) , the upstream activator of ERK2 , as well as ERK2 are incorporated into virions .	Interestingly, western blot analysis demonstrated that phosphorylated and activated mitogen activated protein kinase kinase 1/2 (MEK1/2), the upstream activator of ERK2, as well as ERK2 are incorporated into virions.	9	30	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK2	ERK2	ERK2	MEK1/2	MEK1/2	MEK1/2	29	30	17	18
Genetic deletion of the secreted ligand Fgf4 or the MEK target ERK2 mimics MEK inhibition and impedes ESC differentiation along multiple lineages [ XREF_BIBR , XREF_BIBR ] .	Genetic deletion of the secreted ligand Fgf4 or the MEK target ERK2 mimics MEK inhibition and impedes ESC differentiation along multiple lineages [XREF_BIBR, XREF_BIBR].	1	12	target	Positive_activation_token_1_noun	Negative_activation	Negative_activation	ERK2	ERK2	ERK2	MEK	MEK	MEK	11	12	9	10
Despite the intrinsic interest of MAP2Ks , as dual specificity kinases assuming a central role in MAP kinase modules , only one structural study has been reported , on the ERK2 activators MEK1/2 .	Despite the intrinsic interest of MAP2Ks, as dual specificity kinases assuming a central role in MAP kinase modules, only one structural study has been reported, on the ERK2 activators MEK1/2.	26	33	activators	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ERK2	ERK2	ERK2	MEK1/2	MEK1/2	MEK1/2	30	31	32	33
Our results suggest that the AR could be mediated by activation of the PKA , PIK3 , and MAPK1 pathways through a sequential action involving , successively , PIK3 and then PKA and MAPK1 activations .	Our results suggest that the AR could be mediated by activation of the PKA, PIK3, and MAPK1 pathways through a sequential action involving, successively, PIK3 and then PKA and MAPK1 activations.	4	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MAPK1	MAPK1	MAPK1	AR	AR	AR	18	19	5	6
Western blot analysis revealed silencing either ERK1 and/or ERK2 triggered cleavage ( activation ) of caspase 8 after 4 days and 6 days , with cleaved caspase 3 detected after 6 days of treatment .	Western blot analysis revealed silencing either ERK1 and/or ERK2 triggered cleavage (activation) of caspase 8 after 4 days and 6 days, with cleaved caspase 3 detected after 6 days of treatment.	6	17	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ERK2	ERK2	ERK2	caspase 8	caspase 8	caspase 8	8	9	15	17
For example , it has been reported that BCL XL and BIM -member of the Bcl2 family- are modulated by Erk2 but not by Erk1 XREF_BIBR .	For example, it has been reported that BCL XL and BIM -member of the Bcl2 family- are modulated by Erk2 but not by Erk1 XREF_BIBR.	11	25	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Erk1	Erk1	Erk1	BIM	BIM	BIM	24	25	11	12
The kinases Akt and Erk1 and Erk2 are activated downstream of the LAT complex and control T cell effector responses like survival , proliferation , and cytokine production [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The kinases Akt and Erk1 and Erk2 are activated downstream of the LAT complex and control T cell effector responses like survival, proliferation, and cytokine production [XREF_BIBR, XREF_BIBR, XREF_BIBR].	2	13	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Erk1	Erk1	Erk1	LAT	LAT	LAT	4	5	12	13
FSK treatment of osteoblasts , which raised intracellular cAMP levels and inhibited DNA synthesis , blocked PKC stimulated tyrosine phosphorylation of p44mapk ( ERK1 ) and p42mapk ( ERK2 ) as well as inhibited PKC stimulated MAPK and Raf-1 activities .	FSK treatment of osteoblasts, which raised intracellular cAMP levels and inhibited DNA synthesis, blocked PKC stimulated tyrosine phosphorylation of p44mapk (ERK1) and p42mapk (ERK2) as well as inhibited PKC stimulated MAPK and Raf-1 activities.	16	39	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p42mapk	PKC stimulated tyrosine phosphorylation of p44mapk (ERK1) and p42mapk	p42mapk	Raf-1	Raf-1	raf-1	26	27	38	39
Using this inhibitor , 11 , we determined that ERK5 inhibits the tumor suppressor activity of cellular promyelocytic leukemia protein ( PML ) and demonstrated efficacy and tolerability of the inhibitor against two tumor xenografts providing preliminary support for further exploration of ERK5 inhibitors as anti-cancer agents XREF_BIBR .	Using this inhibitor, 11, we determined that ERK5 inhibits the tumor suppressor activity of cellular promyelocytic leukemia protein (PML) and demonstrated efficacy and tolerability of the inhibitor against two tumor xenografts providing preliminary support for further exploration of ERK5 inhibitors as anti-cancer agents XREF_BIBR.	9	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	ERK5	ERK5	ERK5	promyelocytic leukemia protein	promyelocytic leukemia protein	promyelocytic leukemia protein	9	10	17	20
Since BMK1 negatively regulates PML tumor suppressor function and BMK1 is activated by a variety of deregulated oncogenes ( e.g ., Her2 , Ras and STAT3 ) , it is likely that the oncogene induced BMK1 activation increases the proliferation/survival/chemo-resistance potential of tumor cells by dampening the anti-cancer capacity of PML .	Since BMK1 negatively regulates PML tumor suppressor function and BMK1 is activated by a variety of deregulated oncogenes (e.g., Her2, Ras and STAT3), it is likely that the oncogene induced BMK1 activation increases the proliferation/survival/chemo-resistance potential of tumor cells by dampening the anti-cancer capacity of PML.	35	51	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	BMK1	BMK1	BMK1	PML	PML	PML	35	36	50	51
Without modifying the association of JIP1 with the MAPKs in the scaffold complex and with no apparent change of Akt phosphorylation , SHIP2 positively modulated the MLK3 and JIP1 mediated JNK1 activation .	Without modifying the association of JIP1 with the MAPKs in the scaffold complex and with no apparent change of Akt phosphorylation, SHIP2 positively modulated the MLK3 and JIP1 mediated JNK1 activation.	26	31	mediated	Positive_early_activation	Negative_activation	Positive_activation	JIP1	JIP1	JIP1	JNK1	JNK1	JNK1	28	29	30	31
We also found that RBP-Jk inhibits JIP1 mediated activation of the JNK1 signaling cascade and cell death .	We also found that RBP-Jk inhibits JIP1 mediated activation of the JNK1 signaling cascade and cell death.	6	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	JIP1	JIP1	JIP1	JNK1	JNK1	JNK1	6	7	11	12
JIP1 mediated the activation of JNK1 induced by glucose deprivation in mouse embryonic fibroblasts , and ectopic expression of Notch1-IC inhibited JNK activation and apoptosis triggered by glucose deprivation .	JIP1 mediated the activation of JNK1 induced by glucose deprivation in mouse embryonic fibroblasts, and ectopic expression of Notch1-IC inhibited JNK activation and apoptosis triggered by glucose deprivation.	0	6	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JIP1	JIP1	JIP1	JNK1	JNK1	JNK1	0	1	5	6
This study indicated that DEHP exposure causes gender specific damage to the dendritic growth of CA1 pyramidal neurons that may be related to the dysregulation of phosphorylated and total MAP2c and stathmin mediated by JNK1 .	This study indicated that DEHP exposure causes gender specific damage to the dendritic growth of CA1 pyramidal neurons that may be related to the dysregulation of phosphorylated and total MAP2c and stathmin mediated by JNK1.	17	35	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	JNK1	JNK1	JNK1	stathmin	stathmin	stathmin	34	35	31	32
The adverse impact may be related to the dysregulation of phosphorylated and total MAP2c and stathmin mediated by JNK1 .	The adverse impact may be related to the dysregulation of phosphorylated and total MAP2c and stathmin mediated by JNK1.	8	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	JNK1	JNK1	JNK1	stathmin	stathmin	stathmin	18	19	15	16
However , Jnk1 homozygous deficiency both overly rescued mTORC1 signaling and heightened translation in Hsf1 deficient livers ( XREF_FIG , f and XREF_SUPPLEMENTARY ) .	However, Jnk1 homozygous deficiency both overly rescued mTORC1 signaling and heightened translation in Hsf1 deficient livers (XREF_FIG, f and XREF_SUPPLEMENTARY).	2	16	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Jnk1	Jnk1	Jnk1	Hsf1	Hsf1	Hsf1	2	3	14	15
However , silencing JNK1 positively regulates IRS1 ( XREF_FIG / F ) .	However, silencing JNK1 positively regulates IRS1 (XREF_FIG / F).	2	7	positively regulates	Positive_activation_syntax_1b_verb	Negative_activation	Negative_activation	JNK1	JNK1	JNK1	IRS1	IRS1	IRS1	3	4	6	7
In this interaction network analysis combined with western blotting and RT-PCR , the IRE1 ( ERN1 ) and JNK ( MAPK8 ) axis was activated , which ultimately activates BAD 41 , a major component of apoptosis that promotes the leakage of cytochrome c ( CYCS ) into the cytoplasm .	In this interaction network analysis combined with western blotting and RT-PCR, the IRE1 (ERN1) and JNK (MAPK8) axis was activated, which ultimately activates BAD 41, a major component of apoptosis that promotes the leakage of cytochrome c (CYCS) into the cytoplasm.	18	34	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK8	MAPK8	MAPK8	BAD	BAD	BAD	20	21	29	30
Since it was demonstrated that ablation of JNK1 in hepatocytes induces insulin resistance and hepatic steatosis XREF_BIBR , our data suggest that besides the reported mechanisms triggering fat accumulation in the liver XREF_BIBR , JNK1 is also mediating the effects of Nur77 on hepatic metabolism .	Since it was demonstrated that ablation of JNK1 in hepatocytes induces insulin resistance and hepatic steatosis XREF_BIBR, our data suggest that besides the reported mechanisms triggering fat accumulation in the liver XREF_BIBR, JNK1 is also mediating the effects of Nur77 on hepatic metabolism.	34	42	mediating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JNK1	JNK1	JNK1	Nur77	Nur77	Nur77	34	35	41	42
Furthermore , we ascertained that JIP1 caused the cytoplasmic retention of RBP-Jk through an interaction between the C-terminal region of JIP1 including Src homology 3 domain and the proline rich domain of RBP-Jk .	Furthermore, we ascertained that JIP1 caused the cytoplasmic retention of RBP-Jk through an interaction between the C-terminal region of JIP1 including Src homology 3 domain and the proline rich domain of RBP-Jk.	5	12	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	JIP1	JIP1	JIP1	RBP-Jk	RBP-Jk	RBP-Jk	5	6	11	12
Furthermore , the top ranked path revealed a second route for regulation of the mTOR pathway by the ERK-MAPK pathway : MAPK3 can modulate TSC2 .	Furthermore, the top ranked path revealed a second route for regulation of the mTOR pathway by the ERK-MAPK pathway : MAPK3 can modulate TSC2.	21	25	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK3	MAPK3	MAPK3	TSC2	TSC2	TSC2	21	22	24	25
Because of this dynamic , in the event of stress , MDM2 can target MDMX for degradation , upon which its stabilization effect is gone causing MDM2 to ultimately be degraded .	Because of this dynamic, in the event of stress, MDM2 can target MDMX for degradation, upon which its stabilization effect is gone causing MDM2 to ultimately be degraded.	11	16	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	11	12	14	15
The functional role of the RING domain in MDM2 , which is conserved in all vertebrate species and jawless fish , is to form heterodimers with MDM4 stimulating MDM2 to ubiquitinate p53 [ XREF_BIBR ] .	The functional role of the RING domain in MDM2, which is conserved in all vertebrate species and jawless fish, is to form heterodimers with MDM4 stimulating MDM2 to ubiquitinate p53 [XREF_BIBR].	24	29	stimulating	Positive_activation_token_1_noun	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	28	29	26	27
15 In addition to P53 , MDM2 has been reported to promote the degradation of P21 , MDMX , retinoblastoma protein ( PRB ) , MTBP , Ecadherin , homeodomain interacting protein kinase 2 ( HIPK2 ) , junction mediating and regulatory protein ( IMY ) .	15 In addition to P53, MDM2 has been reported to promote the degradation of P21, MDMX, retinoblastoma protein (PRB), MTBP, Ecadherin, homeodomain interacting protein kinase 2 (HIPK2), junction mediating and regulatory protein (IMY).	6	42	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	6	7	17	18
Additionally MDM2 has been proposed to have an indirect role in regulating stress induced levels of p53 , by downregulating MDMX protein levels ; specifically , MDM2 can induce nuclear localization and E3 dependent degradation of MDMX following gamma irradiation of cancer cell lines , and downregulation of MDMX contributes to p53 activation by irradiation .	Additionally MDM2 has been proposed to have an indirect role in regulating stress induced levels of p53, by downregulating MDMX protein levels; specifically, MDM2 can induce nuclear localization and E3 dependent degradation of MDMX following gamma irradiation of cancer cell lines, and downregulation of MDMX contributes to p53 activation by irradiation.	26	39	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	26	27	36	37
However , despite the preferential association of p53 with MDM2 , both MDM2 knockdown and MDM4 knockdown weakly induced p53 ( XREF_FIG ) , and co-knockdown of MDM2 and MDM4 additively but still only modestly induced p53 ( XREF_SUPPLEMENTARY ) .	However, despite the preferential association of p53 with MDM2, both MDM2 knockdown and MDM4 knockdown weakly induced p53 (XREF_FIG), and co-knockdown of MDM2 and MDM4 additively but still only modestly induced p53 (XREF_SUPPLEMENTARY).	12	30	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	12	13	29	30
The question remains how Mdm2 can possess its reported auto-ubiquitination activity , as well as targeting Mdmx for degradation .	The question remains how Mdm2 can possess its reported auto-ubiquitination activity, as well as targeting Mdmx for degradation.	4	18	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mdm2	Mdm2	Mdm2	Mdmx	Mdmx	Mdmx	4	5	16	17
First , 17AAG reactivated MDM2 leads to self degradation of MDM2 and its physiological substrate MDMX ( XREF_FIG ) .	First, 17AAG reactivated MDM2 leads to self degradation of MDM2 and its physiological substrate MDMX (XREF_FIG).	4	17	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	4	5	15	16
MDMX is required to stabilize MDM2 and prolong its half-life , thereby allowing it to target p53 for degradation , while the nuclear localization sequence of MDM2 is required to direct MDMX into the nucleus to carry out functional inhibition of p53 [ XREF_BIBR ] .	MDMX is required to stabilize MDM2 and prolong its half-life, thereby allowing it to target p53 for degradation, while the nuclear localization sequence of MDM2 is required to direct MDMX into the nucleus to carry out functional inhibition of p53 [XREF_BIBR].	24	32	direct	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	26	27	31	32
Dissociation of MDM4 from MDM2 allows MDM4 activity .	Dissociation of MDM4 from MDM2 allows MDM4 activity.	2	7	allows	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	4	5	6	7
Mdm4 is also targeted by Mdm2 E3-ubiquitin ligase activity [ XREF_BIBR ] .	Mdm4 is also targeted by Mdm2 E3-ubiquitin ligase activity [XREF_BIBR].	0	10	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Mdm2	Mdm2	Mdm2	Mdm4	Mdm4	Mdm4	5	6	0	1
The overall negative control of MDM4 by p76 ( MDM2 ) reflects on p53 function as p76 ( MDM2 ) impairs MDM4 mediated inhibition of p53 activity .	The overall negative control of MDM4 by p76 (MDM2) reflects on p53 function as p76 (MDM2) impairs MDM4 mediated inhibition of p53 activity.	16	23	impairs	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	18	19	21	22
In tumors that retain wild-type p53 status ( 50 % of all cancers ) , its function is usually inactivated by overexpression of endogenous negative regulators , such as murine double minute-2 ( MDM2 ) and MDM4 ( also known as MDMX ) [ XREF_BIBR ] .	In tumors that retain wild-type p53 status (50% of all cancers), its function is usually inactivated by overexpression of endogenous negative regulators, such as murine double minute-2 (MDM2) and MDM4 (also known as MDMX) [XREF_BIBR].	19	44	overexpression	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	33	34	36	37
Here , we report that p76 ( MDM2 ) antagonizes MDM4 inhibitory function .	Here, we report that p76 (MDM2) antagonizes MDM4 inhibitory function.	5	12	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	7	8	10	11
Thus , the stress induced up-regulation of p53 increases the levels of Mdm2 thereby modulating the ratio of Mdm2 to MdmX and serving as a negative feedback loop by which p53 can regulate itself .	Thus, the stress induced up-regulation of p53 increases the levels of Mdm2 thereby modulating the ratio of Mdm2 to MdmX and serving as a negative feedback loop by which p53 can regulate itself.	10	21	modulating	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Mdm2	levels of Mdm2	mdm2	MdmX	MdmX	mdmx	12	13	20	21
We also demonstrate that DNA damage induced MDMX reduction is mediated by MDM2 , which targets MDMX for proteasomal degradation by a distinct mechanism that permits preferential MDMX degradation and therefore ensures optimal p53 activation .	We also demonstrate that DNA damage induced MDMX reduction is mediated by MDM2, which targets MDMX for proteasomal degradation by a distinct mechanism that permits preferential MDMX degradation and therefore ensures optimal p53 activation.	7	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	12	13	7	8
Despite disrupting Mdm2 mediated degradation of p53 and MdmX ( XREF_FIG and XREF_SUPPLEMENTARY ) , and higher levels of Mdm2 in Mdm2 Y487A and Y487A MEFs ( XREF_FIG ) , Mdm2 was degraded at a similar rate in Mdm2 Y487A and Y487A MEFs as in WT MEFs ( XREF_FIG ) .	Despite disrupting Mdm2 mediated degradation of p53 and MdmX (XREF_FIG and XREF_SUPPLEMENTARY), and higher levels of Mdm2 in Mdm2 Y487A and Y487A MEFs (XREF_FIG), Mdm2 was degraded at a similar rate in Mdm2 Y487A and Y487A MEFs as in WT MEFs (XREF_FIG).	3	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Mdm2	levels of Mdm2	mdm2	MdmX	MdmX	mdmx	19	20	8	9
Both proteins inhibit the transcriptional regulation by p53 , while Mdm2 also functions as an E3 ubiquitin ligase to target both p53 and Mdmx for proteasomal degradation .	Both proteins inhibit the transcriptional regulation by p53, while Mdm2 also functions as an E3 ubiquitin ligase to target both p53 and Mdmx for proteasomal degradation.	10	24	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mdm2	Mdm2	Mdm2	Mdmx	Mdmx	Mdmx	10	11	23	24
Based on our observations from ChIP datamining studies , we postulate that ERalpha dependent overexpression of MDM4 and MDM2 in human breast cancer is mediated , at least in part , by the ability of ERalpha to directly bind to and transcriptionally upregulate the MDM4 and MDM2 genes .	Based on our observations from ChIP datamining studies, we postulate that ERalpha dependent overexpression of MDM4 and MDM2 in human breast cancer is mediated, at least in part, by the ability of ERalpha to directly bind to and transcriptionally upregulate the MDM4 and MDM2 genes.	14	47	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	overexpression of MDM4 and MDM2	mdm2	MDM4	MDM4	mdm4	18	19	44	45
Overexpression of MDM2 caused its association to MDM4 and the dissociation of HIPK2 ( XREF_FIG ) independently of protein degradation as assessed by MG132 treatment ( XREF_FIG , XREF_SUPPLEMENTARY ) .	Overexpression of MDM2 caused its association to MDM4 and the dissociation of HIPK2 (XREF_FIG) independently of protein degradation as assessed by MG132 treatment (XREF_FIG, XREF_SUPPLEMENTARY).	0	10	caused	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	MDM2	Overexpression of MDM2	mdm2	MDM4	MDM4	mdm4	2	3	7	8
To further explore this mechanism of Mdm2 mediated MdmX destabilization in response to MLN4924 , we generated several MCF7 and U87 cell lines by viral transduction : vector control , wildtype MdmX , or MdmX with a C-terminal truncation that lacks a RING domain ( DeltaC MdmX ) and is unable to interact with Mdm2 [ XREF_BIBR ] .	To further explore this mechanism of Mdm2 mediated MdmX destabilization in response to MLN4924, we generated several MCF7 and U87 cell lines by viral transduction : vector control, wildtype MdmX, or MdmX with a C-terminal truncation that lacks a RING domain (DeltaC MdmX) and is unable to interact with Mdm2 [XREF_BIBR].	4	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	Mdm2	Mdm2	Mdm2	MdmX	MdmX	MdmX	6	7	8	9
Overex-pression of a RING finger domain deleted MDMX mutant in transformed fibroblasts did not provide protection to cells against Nutlin-3 , indicating that the MDM2-MDMX interaction is required for protective function of MDMX , probably for the MDM2 mediated ubiquitinization of MDMX .	Overex-pression of a RING finger domain deleted MDMX mutant in transformed fibroblasts did not provide protection to cells against Nutlin-3, indicating that the MDM2-MDMX interaction is required for protective function of MDMX, probably for the MDM2 mediated ubiquitinization of MDMX.	36	42	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	37	38	41	42
In tumors with wild-type p53 , there is often overexpression of MDM2 or MDM4 leading to functional inactivation of p53 .	In tumors with wild-type p53, there is often overexpression of MDM2 or MDM4 leading to functional inactivation of p53.	7	14	is often overexpression	Positive_activation_copula_1	Negative_activation	Positive_activation	MDM2	overexpression of MDM2	mdm2	MDM4	MDM4	mdm4	11	12	13	14
74 Mdm2 also targets MdmX for proteasomal dependent degradation following DNA damage .	74 Mdm2 also targets MdmX for proteasomal dependent degradation following DNA damage.	0	8	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mdm2	Mdm2	Mdm2	MdmX	MdmX	MdmX	1	2	4	5
These functions are mediated by the interaction of the C-terminal RING domains of MDM2 and MDMX to form a MDM2 and MDMX heterocomplex that is essential for the E3 ubiquitin ligase activity of MDM2 .	These functions are mediated by the interaction of the C-terminal RING domains of MDM2 and MDMX to form a MDM2 and MDMX heterocomplex that is essential for the E3 ubiquitin ligase activity of MDM2.	3	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDMX	MDMX	MDMX	13	14	21	22
These results suggest that dissociation of MDM2 from MDM4 allows MDM4 to promote HIPK2 activity .	These results suggest that dissociation of MDM2 from MDM4 allows MDM4 to promote HIPK2 activity.	4	12	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	MDM4	MDM4	MDM4	6	7	10	11
Also , unlike Mdm2 , Mdm4 expression levels are not dependent on p53 , though Mdm2 targets Mdm4 and itself for proteasomal degradation [ XREF_BIBR ] .	Also, unlike Mdm2, Mdm4 expression levels are not dependent on p53, though Mdm2 targets Mdm4 and itself for proteasomal degradation [XREF_BIBR].	10	18	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Mdm2	Mdm2	Mdm2	Mdm4	Mdm4	Mdm4	15	16	17	18
Intriguingly , overexpression of Mdm2 also rescues the Mdm4 -/- embryonic lethality , implying that high levels of Mdm2 can compensate for loss of Mdm4 possibly through inhibition of p53 activities .	Intriguingly, overexpression of Mdm2 also rescues the Mdm4 -/- embryonic lethality, implying that high levels of Mdm2 can compensate for loss of Mdm4 possibly through inhibition of p53 activities.	2	11	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mdm2	overexpression of Mdm2	mdm2	Mdm4	Mdm4	mdm4	4	5	8	9
Mcl-1 downregulation promotes activation of Bak .	Mcl-1 downregulation promotes activation of Bak.	0	6	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	0	1	5	6
BH3-mimetics recapitulate the actions of BH3-only proteins and circumvent the actions of anti-apoptotic Bcl-2 family members , including Bcl-2 , Bcl-xL , and in some cases Mcl-1 , promoting activation of Bak and Bax , accompanied by Bax mitochondrial translocation , culminating in mitochondrial injury and apoptosis .	BH3-mimetics recapitulate the actions of BH3-only proteins and circumvent the actions of anti-apoptotic Bcl-2 family members, including Bcl-2, Bcl-xL, and in some cases Mcl-1, promoting activation of Bak and Bax, accompanied by Bax mitochondrial translocation, culminating in mitochondrial injury and apoptosis.	10	35	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	26	27	31	32
This finding is further supported by our results using roscovitine which , like CHX , caused loss of Mcl-1 and induced Bax and Bak dependent cell death .	This finding is further supported by our results using roscovitine which, like CHX, caused loss of Mcl-1 and induced Bax and Bak dependent cell death.	9	26	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	roscovitine which, like CHX, caused loss of Mcl-1	mcl-1	Bak	Bak	bak	18	19	23	24
Nevertheless , simultaneous disruption of the p38 MAPK pathway was required to suppress MCL-1 expression , thereby allowing tBID to activate the proapoptotic BCL-2 family member BAK and stimulate mitochondrial outer membrane permeabilization ( MOMP ) .	Nevertheless, simultaneous disruption of the p38 MAPK pathway was required to suppress MCL-1 expression, thereby allowing tBID to activate the proapoptotic BCL-2 family member BAK and stimulate mitochondrial outer membrane permeabilization (MOMP).	6	27	allowing	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	p38 MAPK pathway was required to suppress MCL-1 expression	mcl-1	BAK	BAK	bak	13	14	26	27
Taken together , these results point to a mechanism , where degradation of Mcl-1 and Bcl-xL protein during mitotic arrest relieves Bak from inhibition , allowing it to form pores that permeabilize the outer mitochondrial membrane and trigger cell death .	Taken together, these results point to a mechanism, where degradation of Mcl-1 and Bcl-xL protein during mitotic arrest relieves Bak from inhibition, allowing it to form pores that permeabilize the outer mitochondrial membrane and trigger cell death.	13	22	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	13	14	21	22
Ultimately , reduced Mcl-1 levels allow pro apoptotic BH3-only proteins , such as Noxa , Bim , and Puma , to promote activation of Bax and Bak [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Ultimately, reduced Mcl-1 levels allow pro apoptotic BH3-only proteins, such as Noxa, Bim, and Puma, to promote activation of Bax and Bak [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	27	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1 levels	mcl-1	Bak	Bak	bak	3	4	26	27
Interestingly , in response to MazF induction , NBK and BIK activated BAK by displacing it from anti-apoptotic proteins MCL-1 and BCL-X ( L ) that sequester BAK .	Interestingly, in response to MazF induction, NBK and BIK activated BAK by displacing it from anti-apoptotic proteins MCL-1 and BCL-X (L) that sequester BAK.	11	28	sequester	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MCL-1	MCL-1	MCL-1	BAK	BAK	BAK	19	20	27	28
Mcl1 destruction relieves its inhibition of Bax and Bak ( pro apoptotic factors ) , allowing them to bind the mitochondrial outer membrane to induce an apoptotic cell death [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Mcl1 destruction relieves its inhibition of Bax and Bak (pro apoptotic factors), allowing them to bind the mitochondrial outer membrane to induce an apoptotic cell death [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	9	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl1	Mcl1	Mcl1	Bak	Bak	Bak	0	1	8	9
Although Mcl-1 can also interact with Bim , a recent study suggests that Mcl-1 may target Bak , as deficiency in Bak partially restores the survival and blocks in T-cell development found in Mcl-1-deficient animals .	Although Mcl-1 can also interact with Bim, a recent study suggests that Mcl-1 may target Bak, as deficiency in Bak partially restores the survival and blocks in T-cell development found in Mcl-1-deficient animals.	13	17	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	13	14	16	17
As proposed from studies on the apoptosis of fibroblasts , the experiments involving MLM demonstrated that engagement of Mcl-1- and Bcl-x L -like proteins initiates Bak mediated mitochondrial permeability ( XREF_FIG and XREF_FIG ) .	As proposed from studies on the apoptosis of fibroblasts, the experiments involving MLM demonstrated that engagement of Mcl-1- and Bcl-x L -like proteins initiates Bak mediated mitochondrial permeability (XREF_FIG and XREF_FIG).	18	28	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1-	Mcl-1-	Mcl-1-	Bak	Bak	Bak	18	19	25	26
Indeed , Mcl-1 downregulation can promote activation of Bax and Bak .	Indeed, Mcl-1 downregulation can promote activation of Bax and Bak.	2	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	2	3	10	11
Additionally , PI103 decreases expression of Mcl-1 , XIAP , and cFLIP , thereby promoting Bax and Bak activation , mitochondrial perturbations , and caspase dependent apoptosis .	Additionally, PI103 decreases expression of Mcl-1, XIAP, and cFLIP, thereby promoting Bax and Bak activation, mitochondrial perturbations, and caspase dependent apoptosis.	2	18	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	PI103 decreases expression of Mcl-1	mcl-1	Bak	Bak	bak	6	7	17	18
Experiments have shown that down-regulation of Mcl-1 dramatically potentiates lethality of ABT-737 by releasing Bak from both Bcl-X L and Mcl-1 which results in simultaneous induction of Bak and Bax [ XREF_BIBR ] .	Experiments have shown that down-regulation of Mcl-1 dramatically potentiates lethality of ABT-737 by releasing Bak from both Bcl-X L and Mcl-1 which results in simultaneous induction of Bak and Bax [XREF_BIBR].	4	15	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	6	7	14	15
In addition , the downregulation of Mcl-1 can activate Bak , for example , in the presence of ATO XREF_BIBR .	In addition, the downregulation of Mcl-1 can activate Bak, for example, in the presence of ATO XREF_BIBR.	4	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	6	7	9	10
Noxa and Mcl-1 were coimmunoprecipitated , and activated BAK .	Noxa and Mcl-1 were coimmunoprecipitated, and activated BAK.	0	9	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	BAK	BAK	BAK	2	3	8	9
In contrast , CDK- and JNK mediated Mcl-1 phosphorylation at S64 increases Mcl-1 binding to Noxa , Bak and Bim , thereby potentiating its anti-apoptotic activity [ XREF_BIBR ] .	In contrast, CDK- and JNK mediated Mcl-1 phosphorylation at S64 increases Mcl-1 binding to Noxa, Bak and Bim, thereby potentiating its anti-apoptotic activity [XREF_BIBR].	5	18	increases	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Mcl-1	JNK mediated Mcl-1 phosphorylation at S64	mcl-1	Bak	Bak	bak	7	8	17	18
Elimination of Mcl-1 is required to initiate the apoptotic pathway by releasing Bak for the Mcl-1 and Bak complex .	Elimination of Mcl-1 is required to initiate the apoptotic pathway by releasing Bak for the Mcl-1 and Bak complex.	0	13	initiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bak	Bak	Bak	2	3	12	13
In accord with this notion , our findings that enforced expression of Mcl-1 , essentially diminished quercetin induced Bax activation , strongly support that Mcl-1 plays an important role in regulating the function of Bax .	In accord with this notion, our findings that enforced expression of Mcl-1, essentially diminished quercetin induced Bax activation, strongly support that Mcl-1 plays an important role in regulating the function of Bax.	10	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	expression of Mcl-1	mcl-1	Bax	Bax	bax	12	13	18	19
49 How does neutralization of Bcl-xL and Mcl-1 activate Bax and Bak ?	49 How does neutralization of Bcl-xL and Mcl-1 activate Bax and Bak?	3	11	activate	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	7	8	9	10
When compared with the heat stressed Ad-empty group , PAR1 overexpression significantly decreased the heat stress induced high protein expression levels of Mcl-1 and significantly increased those of Bax at 6 h ( XREF_FIG ) .	When compared with the heat stressed Ad-empty group, PAR1 overexpression significantly decreased the heat stress induced high protein expression levels of Mcl-1 and significantly increased those of Bax at 6 h (XREF_FIG).	9	29	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	PAR1 overexpression significantly decreased the heat stress induced high protein expression levels of Mcl-1	mcl-1	Bax	Bax	bax	22	23	28	29
Overexpression of Mcl-1 , but not Bcl-2 , was found to accelerate this shuttling , as well as Bax .	Overexpression of Mcl-1, but not Bcl-2, was found to accelerate this shuttling, as well as Bax.	0	19	accelerate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Overexpression of Mcl-1	mcl-1	Bax	Bax	bax	2	3	18	19
Under apoptosis induction , the disappearance of Mcl-1 allows Bim to exercise its pro apoptotic function and to activate Bax .	Under apoptosis induction, the disappearance of Mcl-1 allows Bim to exercise its pro apoptotic function and to activate Bax.	5	20	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	Mcl-1	Mcl-1	Bax	Bax	Bax	7	8	19	20
Our data also suggest that Bax is not restrained by Mcl-1 in human cells and the differential expression levels of Mcl-1 in MEFs and HCT116 cells might underlie the distinct phenotypes of Bax deficiency in these two species .	Our data also suggest that Bax is not restrained by Mcl-1 in human cells and the differential expression levels of Mcl-1 in MEFs and HCT116 cells might underlie the distinct phenotypes of Bax deficiency in these two species.	18	33	underlie	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mcl-1	levels of Mcl-1	mcl-1	Bax	Bax	bax	20	21	32	33
Phosphorylation of MEK1/2 and p38 has been implicated in the pathogenesis of many chronic inflammatory diseases and increased production of IFN-gamma may be a result of increased MEK1/2 and p38 in CD56 bright CD16 dim/- NK cells from CFS/ME patients [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Phosphorylation of MEK1/2 and p38 has been implicated in the pathogenesis of many chronic inflammatory diseases and increased production of IFN-gamma may be a result of increased MEK1/2 and p38 in CD56 bright CD16 dim/- NK cells from CFS/ME patients [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	33	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MEK1/2	Phosphorylation of MEK1/2	mek1/2	MEK1/2	MEK1/2	mek1/2	2	3	27	28
MEK1/2 themselves are activated through phosphorylation by three distinct MAPKK kinases ( MAP3K or MAPKKK ) , Raf , c-Mos , and MEK kinase ( MEKK ) .	MEK1/2 themselves are activated through phosphorylation by three distinct MAPKK kinases (MAP3K or MAPKKK), Raf, c-Mos, and MEK kinase (MEKK).	0	23	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MEK	MEK	MEK	MEK1/2	MEK1/2	MEK1/2	22	23	0	1
Moreover , in response to cell adhesion to fibronectin , p21 activated kinase mediates MEK1/2 phosphorylation at Ser 298 , which subsequently promotes phosphorylation of Ser 218 and Ser 222 and activates MEK1/2 [ XREF_BIBR ] .	Moreover, in response to cell adhesion to fibronectin, p21 activated kinase mediates MEK1/2 phosphorylation at Ser 298, which subsequently promotes phosphorylation of Ser-218 and Ser-222 and activates MEK1/2 [XREF_BIBR].	10	34	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MEK1/2	p21 activated kinase mediates MEK1/2 phosphorylation at Ser 298	mek1/2	MEK1/2	MEK1/2	mek1/2	14	15	32	33
Other known transcriptional targets of MEK and ERK signaling present in the signature are the Ets variant transcription factors , alongside other MEK family members ( MAP2K3 ) potentially coactivated by signals activating MEK1/2 .	Other known transcriptional targets of MEK and ERK signaling present in the signature are the Ets variant transcription factors, alongside other MEK family members (MAP2K3) potentially coactivated by signals activating MEK1/2.	22	34	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MEK	MEK	MEK	MEK1/2	MEK1/2	MEK1/2	22	23	33	34
In response to cell adhesion to fibronectin , PAK mediates MEK1/2 phosphorylation at Ser 298 , which subsequently promotes phosphorylation of Ser 218 and Ser 222 and activates MEK1/2 [ XREF_BIBR ] .	In response to cell adhesion to fibronectin, PAK mediates MEK1/2 phosphorylation at Ser 298, which subsequently promotes phosphorylation of Ser-218 and Ser-222 and activates MEK1/2 [XREF_BIBR].	8	30	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MEK1/2	PAK mediates MEK1/2 phosphorylation at Ser 298	mek1/2	MEK1/2	MEK1/2	mek1/2	10	11	28	29
HDM2 has been shown to attenuate P73 protein function by suppressing P73 transcriptional activity .	HDM2 has been shown to attenuate P73 protein function by suppressing P73 transcriptional activity.	0	8	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	HDM2	HDM2	HDM2	P73	P73	P73	0	1	6	7
It will be interesting to further address the effect of Mdm2 on Itch mediated p73 regulation and function .	It will be interesting to further address the effect of Mdm2 on Itch mediated p73 regulation and function.	8	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mdm2	Mdm2	Mdm2	p73	p73	p73	10	11	14	15
E2F1 , c-Myc , and E1A mediated p73 up-regulation leads to activation of the p73 transcription function , as shown by p73 responsive reporter activity and by induction of known endogenous p73 target gene products such as p21 and HDM2 .	E2F1, c-Myc, and E1A mediated p73 up-regulation leads to activation of the p73 transcription function, as shown by p73 responsive reporter activity and by induction of known endogenous p73 target gene products such as p21 and HDM2.	31	40	products	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	HDM2	HDM2	HDM2	p73	p73	p73	39	40	31	32
In p53-null and mutant cells it was demonstrated that dissociation of p73 and MDM2 by Nutlin-3 increased p73 transcriptional activity , with up-regulation of p73 target genes PUMA and Noxa .	In p53-null and mutant cells it was demonstrated that dissociation of p73 and MDM2 by Nutlin-3 increased p73 transcriptional activity, with up-regulation of p73 target genes PUMA and Noxa.	9	19	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	p73	p73	p73	13	14	17	18
Luciferase reporter assays demonstrated that HCV core protein enhances the p73 dependent luciferase activity driven by MDM2 promoter , whereas p73 dependent transactivation of BAX is significantly inhibited by HCV core protein .	Luciferase reporter assays demonstrated that HCV core protein enhances the p73 dependent luciferase activity driven by MDM2 promoter, whereas p73 dependent transactivation of BAX is significantly inhibited by HCV core protein.	10	17	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	p73	p73	p73	16	17	10	11
MDM2 does not target p73 for degradation , 29 but the E3 mutant MDM2 C464A also inhibited the transcriptional activity of TAp73alpha and TAp73gamma ( XREF_FIG ) .	MDM2 does not target p73 for degradation, 29 but the E3 mutant MDM2 C464A also inhibited the transcriptional activity of TAp73alpha and TAp73gamma (XREF_FIG).	0	5	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	p73	p73	p73	0	1	4	5
MDM2 ' s anti-apoptotic roles also include its interaction with well-known apoptosis mediators such as p73 ( MDM2 mediates p73 NEDDylation and prevents p53 transactivation ) XREF_BIBR , XREF_BIBR and FOXO3a ( MDM2 decreases FOXO3a protein stability ) XREF_BIBR .	MDM2 's anti-apoptotic roles also include its interaction with well-known apoptosis mediators such as p73 (MDM2 mediates p73 NEDDylation and prevents p53 transactivation) XREF_BIBR, XREF_BIBR and FOXO3a (MDM2 decreases FOXO3a protein stability) XREF_BIBR.	17	22	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	p73	p73	p73	17	18	19	20
Interestingly , p63 and p73 can also interact with MDM2 and MDM4 , but MDM2 and MDM4 do not cause p63 or p73 degradation [ XREF_BIBR ] .	Interestingly, p63 and p73 can also interact with MDM2 and MDM4, but MDM2 and MDM4 do not cause p63 or p73 degradation [XREF_BIBR].	14	25	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	p73	p73	p73	14	15	22	23
This is probably due to the fact that MDM2 can target p53 , but not p73 , for degradation .	This is probably due to the fact that MDM2 can target p53, but not p73, for degradation.	8	16	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	p73	p73	p73	8	9	15	16
We also found that the half-life of p73 was much longer in MDM2-KO p53 -/- HCT116 cells than isogenic p53 -/- HCT116 cells , suggesting that TAp73 protein stability is regulated by MDM2 , consistent with a recent report that MDM2 targets p73 for degradation [ XREF_BIBR ] .	We also found that the half-life of p73 was much longer in MDM2-KO p53 -/- HCT116 cells than isogenic p53 -/- HCT116 cells, suggesting that TAp73 protein stability is regulated by MDM2, consistent with a recent report that MDM2 targets p73 for degradation [XREF_BIBR].	32	46	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	p73	p73	p73	40	41	42	43
We show here that , in sharp contrast to p53 , MDM2 induces p73 to form nuclear aggregates that colocalize with MDM2 but are distinct from the promyelocytic leukemia dots .	We show here that, in sharp contrast to p53, MDM2 induces p73 to form nuclear aggregates that colocalize with MDM2 but are distinct from the promyelocytic leukemia dots.	11	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	p73	p73	p73	11	12	13	14
We would also like to mention that since MDM2 is found to modulate p53 mRNA translation [ XREF_BIBR ] , MDM2 may cooperate with RPL26 to modulate p73 mRNA translation .	We would also like to mention that since MDM2 is found to modulate p53 mRNA translation [XREF_BIBR], MDM2 may cooperate with RPL26 to modulate p73 mRNA translation.	20	29	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MDM2	MDM2	MDM2	p73	p73	p73	20	21	27	28
Depletion of MDM2 by siRNA activates p73 dependent transactivation and apoptosis .	Depletion of MDM2 by siRNA activates p73 dependent transactivation and apoptosis.	0	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MDM2	MDM2	MDM2	p73	p73	p73	2	3	6	7
Interestingly , knockdown of HuR strongly inhibits MK2 mediated translational stimulation of TTP mRNA and leads to the accumulation of TTP mRNA in mRNPs ( XREF_FIG ) .	Interestingly, knockdown of HuR strongly inhibits MK2 mediated translational stimulation of TTP mRNA and leads to the accumulation of TTP mRNA in mRNPs (XREF_FIG).	7	13	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MK2	MK2	MK2	TTP	TTP	TTP	7	8	12	13
MK2 phosphorylation increased TTP protein stability but reduced ARE affinity XREF_BIBR .	MK2 phosphorylation increased TTP protein stability but reduced ARE affinity XREF_BIBR.	0	5	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MK2	MK2 phosphorylation	mk2	TTP	TTP	ttp	0	1	3	4
Substitution of the two key phosphoacceptor sites of endogenous TTP protein protected mice from endotoxemia by preventing MK2 mediated TTP inactivation .	Substitution of the two key phosphoacceptor sites of endogenous TTP protein protected mice from endotoxemia by preventing MK2 mediated TTP inactivation.	17	20	mediated	Positive_early_activation	Negative_activation	Positive_activation	MK2	MK2	MK2	TTP	TTP	TTP	17	18	19	20
These findings indicate that catalytic activity of MK2 also stimulates translation of TTP mRNA in the cytosol .	These findings indicate that catalytic activity of MK2 also stimulates translation of TTP mRNA in the cytosol.	5	13	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MK2	MK2	MK2	TTP	TTP	TTP	7	8	12	13
It has been suggested that phosphorylation of MK2 , which occurs upstream of TTP , modulates the activity and expression of TTP .	It has been suggested that phosphorylation of MK2, which occurs upstream of TTP, modulates the activity and expression of TTP.	5	22	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MK2	phosphorylation of MK2	mk2	TTP	TTP	ttp	7	8	21	22
Ectopic over expression of MK2 can rescue the transcription of TTP mRNA in MK2/3 deficient cells , further indicating that MK2 induces de novo synthesis of TTP at the transcriptional level [ XREF_BIBR ] .	Ectopic over expression of MK2 can rescue the transcription of TTP mRNA in MK2/3 deficient cells, further indicating that MK2 induces de novo synthesis of TTP at the transcriptional level [XREF_BIBR].	20	27	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MK2	MK2	MK2	TTP	TTP	TTP	20	21	26	27
Tethered function assays provided evidence that MK2 modulates TTP function by means other than the regulation of RNA binding .	Tethered function assays provided evidence that MK2 modulates TTP function by means other than the regulation of RNA binding.	6	9	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MK2	MK2	MK2	TTP	TTP	TTP	6	7	8	9
MK2 activates Hsp27 ( v12.85 ) , which binds to and inactivates the pro apoptotic molecules caspase-3 , caspase-9 and cytochrome c XREF_BIBR .	MK2 activates Hsp27 (v12.85), which binds to and inactivates the pro apoptotic molecules caspase-3, caspase-9 and cytochrome c XREF_BIBR.	0	19	activates	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	MK2	MK2	mk2	Hsp27	Hsp27 (v12.85), which binds to and inactivates the pro apoptotic molecules caspase-3, caspase-9	hsp27	0	1	2	3
MAPKAPK2 is a direct target of P38MAPK and HSP27 was identified as the major substrate of MAPKAPK2 , which are known to transduce a range of extracellular signals that result in cell division and differentiation , apoptosis , and change in cell motility [ XREF_BIBR ] .	MAPKAPK2 is a direct target of P38MAPK and HSP27 was identified as the major substrate of MAPKAPK2, which are known to transduce a range of extracellular signals that result in cell division and differentiation, apoptosis, and change in cell motility [XREF_BIBR].	0	9	is a direct target	Positive_activation_copula_1	Negative_activation	Positive_activation	MAPKAPK2	MAPKAPK2	MAPKAPK2	HSP27	HSP27	HSP27	0	1	8	9
GM-CSF also induced Hsp 27 phosphorylation in neutrophils in a range similar to that observed in MO7 cells , suggesting that MAPKAP kinase 2 mediated Hsp 27 activation occurs independently of proliferation .	GM-CSF also induced Hsp 27 phosphorylation in neutrophils in a range similar to that observed in MO7 cells, suggesting that MAPKAP kinase 2 mediated Hsp 27 activation occurs independently of proliferation.	21	27	mediated	Positive_early_activation	Negative_activation	Positive_activation	MAPKAP kinase 2	MAPKAP kinase 2	MAPKAP kinase 2	Hsp 27	Hsp 27	Hsp 27	21	24	25	27
In cultured neurons , PAR-1 and MARK phosphorylation can induce mislocalization of tau from the axon to dendrite [ XREF_BIBR , XREF_BIBR ] , an early marker of tau abnormality under disease conditions .	In cultured neurons, PAR-1 and MARK phosphorylation can induce mislocalization of tau from the axon to dendrite [XREF_BIBR, XREF_BIBR], an early marker of tau abnormality under disease conditions.	4	13	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MARK	MARK phosphorylation	mark	tau	tau	tau	6	7	12	13
BX 795 , an inhibitor of MARK1 and SIK , reduced 12E8 immunolabelling of tau in rat cortical neurons .	BX 795, an inhibitor of MARK1 and SIK, reduced 12E8 immunolabelling of tau in rat cortical neurons.	4	15	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MARK1	MARK1	MARK1	tau	tau	tau	6	7	14	15
NS1 TAD2 domain activates ATR-CHK1 , p38-MK2 , and MARK3 kinases that potentially regulate CDC25C activity but without induction of hallmarks of DDR .	NS1 TAD2 domain activates ATR-CHK1, p38-MK2, and MARK3 kinases that potentially regulate CDC25C activity but without induction of hallmarks of DDR.	9	15	potentially regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MARK3	MARK3	MARK3	CDC25C	CDC25C	CDC25C	9	10	14	15
At last , conjugation of ubiquitin by LNX , Siah-1 , Mdm2 targets Numb for proteasomal degradation .	At last, conjugation of ubiquitin by LNX, Siah-1, Mdm2 targets Numb for proteasomal degradation.	11	14	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Mdm2	Mdm2	Mdm2	Numb	Numb	Numb	11	12	13	14
MCM10 directly regulates the RECQL4 DNA helicase , and this interaction may be modulated by cyclin dependent kinase phosphorylation .	MCM10 directly regulates the RECQL4 DNA helicase, and this interaction may be modulated by cyclin dependent kinase phosphorylation.	0	6	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MCM10	MCM10	MCM10	RECQL4	RECQL4	RECQL4	0	1	4	5
In addition , MAPK8 , besides its ability to activate PAX2 and promote cancer cell proliferation 35 , can trigger YWHAZ and inhibit DNA fragmentation process during apoptosis by interacting with DFF-45 36 .	In addition, MAPK8, besides its ability to activate PAX2 and promote cancer cell proliferation 35, can trigger YWHAZ and inhibit DNA fragmentation process during apoptosis by interacting with DFF-45 36.	3	22	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MAPK8	MAPK8	MAPK8	YWHAZ	YWHAZ	YWHAZ	3	4	20	21
Like in the case of p14ARF , an inhibitor of the E3 ubiquitin ligase Mdm2 , pharmacological antagonists of gene silencers , for example , histone deacetylases ( HDACs ) or DNA methyltransferases , may act in part through augmenting iASPP levels and thereby preventing BRMS1 mediated p300 and CBP degradation .	Like in the case of p14ARF, an inhibitor of the E3 ubiquitin ligase Mdm2, pharmacological antagonists of gene silencers, for example, histone deacetylases (HDACs) or DNA methyltransferases, may act in part through augmenting iASPP levels and thereby preventing BRMS1 mediated p300 and CBP degradation.	8	50	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mdm2	Mdm2	Mdm2	p300	p300	p300	14	15	47	48
20 CXCL12 and CXCL11 induced the mTOR targets p-P70S6K and p-4EBP1 ; whereas the CXCL12 induction was inhibited by AMD3100 and CCX771 , CXCL11 mediated inductions were inhibited only by the specific CXCR7 inhibitor , suggesting that CXCR7 signals on mTOR .	20 CXCL12 and CXCL11 induced the mTOR targets p-P70S6K and p-4EBP1; whereas the CXCL12 induction was inhibited by AMD3100 and CCX771, CXCL11 mediated inductions were inhibited only by the specific CXCR7 inhibitor, suggesting that CXCR7 signals on mTOR.	5	11	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p-4EBP1	p-4EBP1	p-4EBP1	6	7	10	11
In contrast , mTOR inhibition alone using RAD001 treatment decreased pS6 and p4E-BP1 , while Akt phosphorylation levels increased in SKOV3 and OVCAR5 cells , and remained unchanged in IGROV1 cells ( XREF_FIG ) .	In contrast, mTOR inhibition alone using RAD001 treatment decreased pS6 and p4E-BP1, while Akt phosphorylation levels increased in SKOV3 and OVCAR5 cells, and remained unchanged in IGROV1 cells (XREF_FIG).	3	13	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p4E-BP1	p4E-BP1	p4E-BP1	3	4	12	13
The mTOR kinase responds to both nutrient and growth factor signals to activate p70S6K and 4EBP1 to increase protein translation as part of a cell growth response [ XREF_BIBR ] .	The mTOR kinase responds to both nutrient and growth factor signals to activate p70S6K and 4EBP1 to increase protein translation as part of a cell growth response [XREF_BIBR].	1	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	1	2	15	16
Activation of S6K and inactivation of 4E-BP1 through phosphorylation by mTOR lead to increased protein synthesis , cell proliferation , and VEGF secretion and ultimately to tumorigenesis .	Activation of S6K and inactivation of 4E-BP1 through phosphorylation by mTOR lead to increased protein synthesis, cell proliferation, and VEGF secretion and ultimately to tumorigenesis.	0	11	Activation	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	10	11	6	7
When 4EBP1 is activated by mtor , it dissociates from eIF-4E ( eukaryotic translation factor ) , and leads to cap dependent messenger ( mrna ) translation .	When 4EBP1 is activated by mtor, it dissociates from eIF-4E (eukaryotic translation factor), and leads to cap dependent messenger (mrna) translation.	1	6	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	mtor	mtor	mtor	4EBP1	4EBP1	4EBP1	5	6	1	2
Our data suggest that targeting mTROC1 with the ATP-site mTOR kinase inhibitors that can effectively activate 4E-BP1 repressive function on cap dependent translation may provide a promising treatment strategy for blocking metastatic progression of cancer .	Our data suggest that targeting mTROC1 with the ATP-site mTOR kinase inhibitors that can effectively activate 4E-BP1 repressive function on cap dependent translation may provide a promising treatment strategy for blocking metastatic progression of cancer.	9	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	9	10	16	17
This option can be envisioned for cancer cells lacking the mTOR targets 4E-BP1 and 4E-BP2 ( due to either a primary or an acquired loss of expression , see above ) .	This option can be envisioned for cancer cells lacking the mTOR targets 4E-BP1 and 4E-BP2 (due to either a primary or an acquired loss of expression, see above).	9	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	10	11	12	13
Among its targets , AKT controls the activation of the downstream pathway effector , the mammalian target of rapamycin ( mTOR ) , which activates two key substrates 4EBP1 and p70S6K .	Among its targets, AKT controls the activation of the downstream pathway effector, the mammalian target of rapamycin (mTOR), which activates two key substrates 4EBP1 and p70S6K.	15	30	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	4EBP1	4EBP1	4EBP1	15	19	28	29
Interestingly , MEK inhibitor treatment induced upregulation of p4E-BP1 in the MDA-MB231 line , and marked downregulation p4E-BP1 was noted only with PI-103 ( PI3K and mTOR inhibitor ) in the alternative dosing experiments , but not with ZSTK474 ( with a PI3K inhibitor alone ) , suggesting mTOR mediated activation of 4E-BP1 in response to MEK inhibition .	Interestingly, MEK inhibitor treatment induced upregulation of p4E-BP1 in the MDA-MB231 line, and marked downregulation p4E-BP1 was noted only with PI-103 (PI3K and mTOR inhibitor) in the alternative dosing experiments, but not with ZSTK474 (with a PI3K inhibitor alone), suggesting mTOR mediated activation of 4E-BP1 in response to MEK inhibition.	48	54	mediated	Positive_early_activation	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	48	49	52	53
This observation was significant since the mTOR integrates mitogenic signals and intracellular nutrient levels to activate 4EBP1 and p70S6K that control protein translation and cell cycle progression .	This observation was significant since the mTOR integrates mitogenic signals and intracellular nutrient levels to activate 4EBP1 and p70S6K that control protein translation and cell cycle progression.	5	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	6	7	16	17
Indeed , AKT and mTOR activation of 4EBP1 leads to increased mitochondrial biogenesis , and may represent an additional means by which matrix stiffness regulates metabolism through a FAK/PI3K/AKT pathway .	Indeed, AKT and mTOR activation of 4EBP1 leads to increased mitochondrial biogenesis, and may represent an additional means by which matrix stiffness regulates metabolism through a FAK/PI3K/AKT pathway.	2	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	4	5	7	8
In the present research we further found that NS5A increased phosphorylation levels of two mTOR targeted substrates , S6K1 and 4EBP1 , in Huh7 in the absence of serum .	In the present research we further found that NS5A increased phosphorylation levels of two mTOR targeted substrates, S6K1 and 4EBP1, in Huh7 in the absence of serum.	8	21	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	NS5A increased phosphorylation levels of two mTOR	mtor	4EBP1	4EBP1	4ebp1	14	15	20	21
The mTOR targets p-4EBP1 and p-S6 were exclusively found in FLT3-ITD stem and progenitor cells , but not in their normal counterparts , suggesting both as novel targets in FLT3 mutated AML .	The mTOR targets p-4EBP1 and p-S6 were exclusively found in FLT3-ITD stem and progenitor cells, but not in their normal counterparts, suggesting both as novel targets in FLT3 mutated AML.	0	8	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p-4EBP1	p-4EBP1	p-4EBP1	1	2	3	4
It could be verified by the pharmacological and behavioral tests : pre-administration of rapamycin , the specific inhibitor of mTOR , significantly suppressed the activation of mTOR , as well as p70 S6K and 4E-BP1 , which attenuating pain related behaviors accordingly .	It could be verified by the pharmacological and behavioral tests : pre-administration of rapamycin, the specific inhibitor of mTOR, significantly suppressed the activation of mTOR, as well as p70 S6K and 4E-BP1, which attenuating pain related behaviors accordingly.	17	37	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	19	20	34	35
In addition , a lower expression of mTOR target 4E-BP1 was found in activated T cells cultured with MDSC , compared to control stimulated T cells .	In addition, a lower expression of mTOR target 4E-BP1 was found in activated T cells cultured with MDSC, compared to control stimulated T cells.	5	10	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	7	8	9	10
mTOR specifically leads to the activation of ribosomal protein S6 kinase ( p70S6K ) and eIF4E binding protein 1 ( 4E-BP1 ) .	mTOR specifically leads to the activation of ribosomal protein S6 kinase (p70S6K) and eIF4E binding protein 1 (4E-BP1).	0	21	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	0	1	20	21
S6K , Akt , and 4E-BP1 were modulated by mTOR mediators only in the presence of increased eIF4E .	S6K, Akt, and 4E-BP1 were modulated by mTOR mediators only in the presence of increased eIF4E.	0	10	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	9	10	5	6
This raises the possibility that , in vivo , an unidentified kinase analogous to p70 ( S6k ) is activated by RAFT1 phosphorylation and acts at the rapamycin sensitive phosphorylation sites of 4E-BP1 .	This raises the possibility that, in vivo, an unidentified kinase analogous to p70 (S6k) is activated by RAFT1 phosphorylation and acts at the rapamycin sensitive phosphorylation sites of 4E-BP1.	19	33	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RAFT1	RAFT1 phosphorylation	raft1	4E-BP1	4E-BP1	4e-bp1	21	22	32	33
Expression of a kinase dead PKC-eta ( PKC-etaKR ) construct reduced the basal and PMA evoked proliferation of PKC-eta-expressing U-251 GBM cells , as well as abrogated the PMA induced activation of Akt , mTOR , and the mTOR targets 4E-BP1 and STAT-3 .	Expression of a kinase dead PKC-eta (PKC-etaKR) construct reduced the basal and PMA evoked proliferation of PKC-eta-expressing U-251 GBM cells, as well as abrogated the PMA induced activation of Akt, mTOR, and the mTOR targets 4E-BP1 and STAT-3.	30	42	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	34	35	40	41
Once induced , mTOR increases cell growth and proliferation through activation of two effector molecules p70S6K and 4EBP1 leading to a global increase in protein translation .	Once induced, mTOR increases cell growth and proliferation through activation of two effector molecules p70S6K and 4EBP1 leading to a global increase in protein translation.	3	18	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	3	4	17	18
Alternatively , hyperphosphorylation of mTOR induces dissociation of 4E-BP1 from eukaryotic translation initiation factor ( eIF4E ) , which facilitates mRNA translation .	Alternatively, hyperphosphorylation of mTOR induces dissociation of 4E-BP1 from eukaryotic translation initiation factor (eIF4E), which facilitates mRNA translation.	2	9	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	hyperphosphorylation of mTOR	mtor	4E-BP1	4E-BP1	4e-bp1	4	5	8	9
Thus , inhibition of neither mTOR nor MEK alone was sufficient to abolish the activity of p-RPS6 and 4E-BP1 .	Thus, inhibition of neither mTOR nor MEK alone was sufficient to abolish the activity of p-RPS6 and 4E-BP1.	2	19	abolish	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	5	6	18	19
The Akt and mTOR pathway targets the 4E-BP1 and S6K to regulate a common translation mechanism .	The Akt and mTOR pathway targets the 4E-BP1 and S6K to regulate a common translation mechanism.	1	9	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	3	4	7	8
Akt directly and indirectly activates mTOR activity , which then promotes the downstream molecules 4E-BP1 and S6K to enhance cell differentiation , growth , and survival .	Akt directly and indirectly activates mTOR activity, which then promotes the downstream molecules 4E-BP1 and S6K to enhance cell differentiation, growth, and survival.	5	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	5	6	14	15
Although 4E-BP1 is a downstream effector of mTOR , pharmacological disruption ( i.e. using rapamycin ) of mTOR signaling in vivo only transiently inhibits 4E-BP1 activity ( up to a couple of hours , unpublished data ) , and thus can not be used to study circadian functions of 4E-BP1 .	Although 4E-BP1 is a downstream effector of mTOR, pharmacological disruption (i.e. using rapamycin) of mTOR signaling in vivo only transiently inhibits 4E-BP1 activity (up to a couple of hours, unpublished data), and thus can not be used to study circadian functions of 4E-BP1.	17	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	17	18	24	25
The activation of mTOR leads to hierarchical phosphorylation of 4E-BP1 , dislodging 4E-BP1 from eIF4E , and subsequently increasing cap dependent translation [ XREF_BIBR ] .	The activation of mTOR leads to hierarchical phosphorylation of 4E-BP1, dislodging 4E-BP1 from eIF4E, and subsequently increasing cap dependent translation [XREF_BIBR].	1	13	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	3	4	12	13
Since both P70S6K and 4E-BP1 are directly regulated by mTOR , and since mTOR and its binding partner , RAPTOR , were identified as direct targets for the SO in our proteomics screen we next examined whether the inhibitory effects of the SO on this pathway were mediated by disrupting the kinase activity of mTOR itself .	Since both P70S6K and 4E-BP1 are directly regulated by mTOR, and since mTOR and its binding partner, RAPTOR, were identified as direct targets for the SO in our proteomics screen we next examined whether the inhibitory effects of the SO on this pathway were mediated by disrupting the kinase activity of mTOR itself.	2	10	directly regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	9	10	4	5
The resulting effect on protein translation by modulating mTOR targets 4E-BP1 and S6 kinase could explain the delayed surface expression of CD25 and CD69 reported above .	The resulting effect on protein translation by modulating mTOR targets 4E-BP1 and S6 kinase could explain the delayed surface expression of CD25 and CD69 reported above.	8	13	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	8	9	10	11
For instance , in leishmaniasis the primary effect of mTOR blockade in APCs by the metalloprotease Gp63 is to reduce translation by activating the translational repressor 4E-BP1 .	For instance, in leishmaniasis the primary effect of mTOR blockade in APCs by the metalloprotease Gp63 is to reduce translation by activating the translational repressor 4E-BP1.	9	27	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	9	10	26	27
Note that even though phospho-AMPK has been shown to inhibit protein synthesis via mTOR signaling in some conditions , it is unlikely that protein synthesis is impaired in skeletal muscles of TIF2 ( i ) skm-/- mice , as the phosphorylation level of the mTOR target 4E-BP1 was similar in skeletal muscles of control and mutant mice ( XREF_FIG ) , and as their skeletal muscle weight and fiber size were similar ( see above ) .	Note that even though phospho-AMPK has been shown to inhibit protein synthesis via mTOR signaling in some conditions, it is unlikely that protein synthesis is impaired in skeletal muscles of TIF2 (i) skm-/- mice, as the phosphorylation level of the mTOR target 4E-BP1 was similar in skeletal muscles of control and mutant mice (XREF_FIG), and as their skeletal muscle weight and fiber size were similar (see above).	41	47	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	44	45	46	47
The Akt activates many downstream factors , including mTOR , which in turn activates 4EBP1 and p70S6K1 .	The Akt activates many downstream factors, including mTOR, which in turn activates 4EBP1 and p70S6K1.	5	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	8	9	14	15
MTOR modulates 4EBP1 by direct phosphorylation and thereby releases bound eIF4E , regulating the translational machinery .	MTOR modulates 4EBP1 by direct phosphorylation and thereby releases bound eIF4E, regulating the translational machinery.	0	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MTOR	MTOR	MTOR	4EBP1	4EBP1	4EBP1	0	1	2	3
Akt affects protein synthesis by allowing assembly of a translation initiation complex through GSK3beta and mTOR , of which mTOR activates and inhibits its downstream targets ribosomal protein S6 kinase ( S6k ) and eukaryotic translation initiation factor 4E binding protein 1 ( 4E-BP1 ) , respectively .	Akt affects protein synthesis by allowing assembly of a translation initiation complex through GSK3beta and mTOR, of which mTOR activates and inhibits its downstream targets ribosomal protein S6 kinase (S6k) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), respectively.	19	44	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	19	20	43	44
Because mTOR modulates activity of downstream 4E-BP1 and p70S6kinase to regulate RNA translation and protein synthesis respectively , these proteins were evaluated in response to drug treatment .	Because mTOR modulates activity of downstream 4E-BP1 and p70S6kinase to regulate RNA translation and protein synthesis respectively, these proteins were evaluated in response to drug treatment.	1	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	1	2	6	7
The main function is exhibited by mTOR that activates the two molecules S6K and 4EBP1 , leading to an enhanced translation capacity and cell growth .	The main function is exhibited by mTOR that activates the two molecules S6K and 4EBP1, leading to an enhanced translation capacity and cell growth.	4	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	6	7	14	15
Activation of mTOR target p-4EBP1 was observed in samples from all AML samples but none of the normal samples , with high activities restricted to A1-A4 in the majority of AML samples .	Activation of mTOR target p-4EBP1 was observed in samples from all AML samples but none of the normal samples, with high activities restricted to A1-A4 in the majority of AML samples.	0	5	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p-4EBP1	p-4EBP1	p-4EBP1	2	3	4	5
OXL significantly increased the protein levels of p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 in the DRG tissues as compared with control rats ( n = 8-10 ) .	OXL significantly increased the protein levels of p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 in the DRG tissues as compared with control rats (n = 8-10).	5	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	levels of p-mTOR and mTOR	mtor	p-4E-BP1	p-4E-BP1	p-4e-bp1	9	10	13	14
In addition to the impact of mTOR mediated 4E-BP1 on the translation of cell cycle regulators cMyc and Cyclin D1 , recent studies indicate that mTOR activation is required HIF1alpha induction , a transcription factor driving the glycolytic pathway .	In addition to the impact of mTOR mediated 4E-BP1 on the translation of cell cycle regulators cMyc and Cyclin D1, recent studies indicate that mTOR activation is required HIF1alpha induction, a transcription factor driving the glycolytic pathway.	4	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	6	7	8	9
SCI significantly increased the protein levels of p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 in the superficial dorsal horn as compared with control rats ( all P values < 0.05 , SCI rats vs. control rats , number of rats = 6-10 in each group ) .	SCI significantly increased the protein levels of p-mTOR and mTOR mediated p-S6K1 and p-4E-BP1 in the superficial dorsal horn as compared with control rats (all P values < 0.05, SCI rats vs. control rats, number of rats = 6-10 in each group).	5	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	levels of p-mTOR and mTOR	mtor	p-4E-BP1	p-4E-BP1	p-4e-bp1	9	10	13	14
The mTOR target 4EBP1 was initially considered a tumour suppressor gene , as a result of its role in negatively regulating the translational machinery through binding to EIF4E [ XREF_BIBR ] .	The mTOR target 4EBP1 was initially considered a tumour suppressor gene, as a result of its role in negatively regulating the translational machinery through binding to EIF4E [XREF_BIBR].	0	6	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	1	2	3	4
In a xenograft study , the 4EBP1 activity of tumor cells and peripheral blood mononuclear cells ( PBMC ) is also reduced by mTOR inhibition [ XREF_BIBR , XREF_BIBR ] .	In a xenograft study, the 4EBP1 activity of tumor cells and peripheral blood mononuclear cells (PBMC) is also reduced by mTOR inhibition [XREF_BIBR, XREF_BIBR].	6	24	reduced	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	23	24	6	7
Major downstream targets of mTOR are p70S6K and 4E-BP1 , which is activated by mTOR and then dissociates from the eukaryotic translation factor ( eIF-4E ) and activates protein synthesis [ XREF_BIBR ] .	Major downstream targets of mTOR are p70S6K and 4E-BP1, which is activated by mTOR and then dissociates from the eukaryotic translation factor (eIF-4E) and activates protein synthesis [XREF_BIBR].	6	15	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	14	15	8	9
CYP significantly increased the protein levels of p-mTOR- and mTOR mediated p-S6K1 and p-4E-BP1 in the superficial dorsal horn as compared with control rats .	CYP significantly increased the protein levels of p-mTOR- and mTOR mediated p-S6K1 and p-4E-BP1 in the superficial dorsal horn as compared with control rats.	5	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	levels of p-mTOR- and mTOR	mtor	p-4E-BP1	p-4E-BP1	p-4e-bp1	9	10	13	14
Overexpression of PTEN was shown to down-regulate the expression of MAPK , CCND1 , AKT , MTOR , S6K1 , STAT5 , SREBP1 , PPARgamma , PRLR , and GLUT1 genes , or up-regulate EIF4EBP1 gene , which are important for lactation related signaling pathways [ XREF_BIBR ] .	Overexpression of PTEN was shown to down-regulate the expression of MAPK, CCND1, AKT, MTOR, S6K1, STAT5, SREBP1, PPARgamma, PRLR, and GLUT1 genes, or up-regulate EIF4EBP1 gene, which are important for lactation related signaling pathways [XREF_BIBR].	0	35	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MTOR	Overexpression of PTEN was shown to down-regulate the expression of MAPK, CCND1, AKT, MTOR	mtor	EIF4EBP1	EIF4EBP1	eif4ebp1	16	17	34	35
CXCL12 induced the mTOR targets p-S6K1 and p-4EBP1 in BON cells and the CXCL12-induction was inhibited by the specific CXCR4 antagonist , AMD3100 .	CXCL12 induced the mTOR targets p-S6K1 and p-4EBP1 in BON cells and the CXCL12-induction was inhibited by the specific CXCR4 antagonist, AMD3100.	2	8	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p-4EBP1	p-4EBP1	p-4EBP1	3	4	7	8
In cancer cells it has been shown that mTOR activates its downstream effector 4E-BP1 and p70S6K , which subsequently leads to translation of pro apoptotic proteins XREF_BIBR , XREF_BIBR as well as phosphorylates and inactivation of the anti-apoptotic protein Bcl-2 28 .	In cancer cells it has been shown that mTOR activates its downstream effector 4E-BP1 and p70S6K, which subsequently leads to translation of pro apoptotic proteins XREF_BIBR, XREF_BIBR as well as phosphorylates and inactivation of the anti-apoptotic protein Bcl-2 28.	8	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	8	9	13	14
4E-BP1 is also targeted by the MAPK effector , RSK1 , by IFN independently of mTOR .	4E-BP1 is also targeted by the MAPK effector, RSK1, by IFN independently of mTOR.	0	16	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	15	16	0	1
Since this motif does not bind raptor , mTOR must signal to 4E-BP1 via additional mechanisms that are independent of raptor .	Since this motif does not bind raptor, mTOR must signal to 4E-BP1 via additional mechanisms that are independent of raptor.	8	18	signal	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	8	9	12	13
Besides , it impaired the mTORC1 signaling by inhibiting the activity of its downstream factors , such as 4E-BP1 and p70 S6K , all of which could obviously rescued by the mTOR activator MHY1485 .	Besides, it impaired the mTORC1 signaling by inhibiting the activity of its downstream factors, such as 4E-BP1 and p70 S6K, all of which could obviously rescued by the mTOR activator MHY1485.	18	33	rescued	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	31	32	18	19
CXCL12 induced the mTOR targets p-P70S6K and p-4EBP1 in SN12C and A498 cells and the CXCR4 antagonist , AMD3100 , inhibited this induction , suggesting that CXCL12 signals on mTOR .	CXCL12 induced the mTOR targets p-P70S6K and p-4EBP1 in SN12C and A498 cells and the CXCR4 antagonist, AMD3100, inhibited this induction, suggesting that CXCL12 signals on mTOR.	2	8	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p-4EBP1	p-4EBP1	p-4EBP1	3	4	7	8
Furthermore , higher proliferation indices ( indicated by Ki-67 ) were associated with significantly higher mTOR and 4EBP1 expression , as well as with higher activation of the mTOR targets 4EBP1 , p70S6K and eIF4E ( indicated by phosphorylation ) XREF_BIBR .	Furthermore, higher proliferation indices (indicated by Ki-67) were associated with significantly higher mTOR and 4EBP1 expression, as well as with higher activation of the mTOR targets 4EBP1, p70S6K and eIF4E (indicated by phosphorylation) XREF_BIBR.	25	40	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4EBP1	4EBP1	4EBP1	28	29	30	31
Some studies have shown that mTOR kinase inhibitors block p4EBP1 more effectively than rapalogs [ XREF_BIBR ] , suggesting mTORC2 as a candidate in 4EBP1 regulation .	Some studies have shown that mTOR kinase inhibitors block p4EBP1 more effectively than rapalogs [XREF_BIBR], suggesting mTORC2 as a candidate in 4EBP1 regulation.	5	10	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p4EBP1	p4EBP1	p4EBP1	5	6	9	10
Here , we show that VV activated host PI3K to stimulate downstream mammalian target of rapamycin ( mTOR ) , a kinase that inactivates the translational repressor 4E-BP1 .	Here, we show that VV activated host PI3K to stimulate downstream mammalian target of rapamycin (mTOR), a kinase that inactivates the translational repressor 4E-BP1.	12	28	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	4E-BP1	4E-BP1	4E-BP1	12	16	27	28
Similarly , insulin , another known MTOR activator , was not able to induce MTOR , and 4E-BP1 in Gnmt-KO hepatocytes or in WT hepatocytes cultured in the presence of SAMe and methionine ( XREF_SUPPLEMENTARY ) .	Similarly, insulin, another known MTOR activator, was not able to induce MTOR, and 4E-BP1 in Gnmt-KO hepatocytes or in WT hepatocytes cultured in the presence of SAMe and methionine (XREF_SUPPLEMENTARY).	6	18	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MTOR	MTOR	MTOR	4E-BP1	4E-BP1	4E-BP1	6	7	17	18
This increase in the AMP : ATP ratio correlated with concomitant increase in tamoxifen- induced AMPK phosphorylation of the downstream signaling target acetyl-CoA carboxylase ( ACC ) and dephosphorylation of the mTOR targets P70S6K , S6 and 4EBP1 , in both MCF7 ( XREF_FIG ) and MDA-MB-231 cells ( XREF_FIG ) .	This increase in the AMP : ATP ratio correlated with concomitant increase in tamoxifen- induced AMPK phosphorylation of the downstream signaling target acetyl-CoA carboxylase (ACC) and dephosphorylation of the mTOR targets P70S6K, S6 and 4EBP1, in both MCF7 (XREF_FIG) and MDA-MB-231 cells (XREF_FIG).	28	38	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	dephosphorylation of the mTOR	mtor	4EBP1	4EBP1	4ebp1	31	32	37	38
These results suggest that mTOR , or other upstream receptors , may upregulate p-p70S6kinase and p-4E-BP1 to mediate tumor resistance to c-Met inhibitors .	These results suggest that mTOR, or other upstream receptors, may upregulate p-p70S6kinase and p-4E-BP1 to mediate tumor resistance to c-Met inhibitors.	4	16	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p-4E-BP1	p-4E-BP1	p-4E-BP1	4	5	15	16
We have already previously shown that rapamycin inhibits phosphorylation of the mTOR targets 4E-BP1 and P70S6K in KG1a cells [ XREF_BIBR ] .	We have already previously shown that rapamycin inhibits phosphorylation of the mTOR targets 4E-BP1 and P70S6K in KG1a cells [XREF_BIBR].	8	15	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	phosphorylation of the mTOR	mtor	4E-BP1	4E-BP1	4e-bp1	11	12	13	14
The mTOR targets p-4EBP1 and p-S6 were exclusively found in FLT3-ITD stem and progenitor cells , but not in their normal counterparts .	The mTOR targets p-4EBP1 and p-S6 were exclusively found in FLT3-ITD stem and progenitor cells, but not in their normal counterparts.	0	8	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p-4EBP1	p-4EBP1	p-4EBP1	1	2	3	4
Activation of mTOR leads to the phosphorylation of eukaryotic initiation factor 4E binding protein-1 ( 4E-BP1 ) , dissociating 4E-BP1 from the mRNA cap binding protein eIF4E to promote protein synthesis .	Activation of mTOR leads to the phosphorylation of eukaryotic initiation factor 4E binding protein-1 (4E-BP1), dissociating 4E-BP1 from the mRNA cap binding protein eIF4E to promote protein synthesis.	0	20	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	2	3	19	20
OXA-01 and OSI-027 inhibited mTOR signaling of phospho-4E-BP1 with an IC 50 of 1.1 muM and 1muM respectively ( XREF_FIG ) .	OXA-01 and OSI-027 inhibited mTOR signaling of phospho-4E-BP1 with an IC 50 of 1.1 muM and 1muM respectively (XREF_FIG).	4	8	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	phospho-4E-BP1	phospho-4E-BP1	phospho-4E-BP1	4	5	7	8
Under basal conditions , TSC2 negatively regulates mTOR , so that Akt mediated TSC2 phosphorylation activates mTOR , which in turns activates p70S6K and 4E-BP1 , promoting translation of mRNAs important to cancer cell growth [ XREF_BIBR , XREF_BIBR ] .	Under basal conditions, TSC2 negatively regulates mTOR, so that Akt mediated TSC2 phosphorylation activates mTOR, which in turns activates p70S6K and 4E-BP1, promoting translation of mRNAs important to cancer cell growth [XREF_BIBR, XREF_BIBR].	15	25	activates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	16	17	24	25
Treatment of slice cultures from these xenograft tumors with the PI3K inhibitor BKM120 induced cell death at concentrations that inhibited phosphorylation of the serine/threonine kinase AKT ( Serine 473 ) and the mTOR targets S6RP and 4E-BP1 ( XREF_FIG ) .	Treatment of slice cultures from these xenograft tumors with the PI3K inhibitor BKM120 induced cell death at concentrations that inhibited phosphorylation of the serine/threonine kinase AKT (Serine 473) and the mTOR targets S6RP and 4E-BP1 (XREF_FIG).	31	37	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	4E-BP1	4E-BP1	4E-BP1	32	33	36	37
It has been shown that H5N1 induces the autophagy via the inhibition of mTOR , which interplays with Atg1 ( ULK1 in the mammalian ) and triggers ULK1 as well as mammalian Atg13 to suppress autophagy [ XREF_BIBR - XREF_BIBR ] .	It has been shown that H5N1 induces the autophagy via the inhibition of mTOR, which interplays with Atg1 (ULK1 in the mammalian) and triggers ULK1 as well as mammalian Atg13 to suppress autophagy [XREF_BIBR - XREF_BIBR].	11	32	triggers	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	13	14	27	28
A catalytic inhibitor of mTOR ( torin2 ) abolished p-ULK1 ( S757 ) and p-4EBP1 ( S65 ) ( XREF_FIG ) along with IL-2 and IFN-y production ( XREF_FIG ) .	A catalytic inhibitor of mTOR (torin2) abolished p-ULK1 (S757) and p-4EBP1 (S65) (XREF_FIG) along with IL-2 and IFN-y production (XREF_FIG).	2	11	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	p-ULK1	p-ULK1	p-ULK1	4	5	9	10
XREF_BIBR During the autophagic initiation step , dephosphorylation and inactivation of mTOR allows for the association of ATG13 and ATG1 , thereby activating the ATG1 kinase activity and thus initiating autophagy ( XREF_FIG ) .	XREF_BIBR During the autophagic initiation step, dephosphorylation and inactivation of mTOR allows for the association of ATG13 and ATG1, thereby activating the ATG1 kinase activity and thus initiating autophagy (XREF_FIG).	7	26	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	dephosphorylation and inactivation of mTOR	mtor	ATG1	ATG1	atg1	11	12	24	25
Western blotting analysis revealed that chitosan film culture increased the levels of S575 of ULK1 ( inactive form ) , which were reduced by rapamycin treatment or mTOR knockdown .	Western blotting analysis revealed that chitosan film culture increased the levels of S575 of ULK1 (inactive form), which were reduced by rapamycin treatment or mTOR knockdown.	12	28	reduced	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	27	28	14	15
mTOR inactivation by SAHA restores the function of the ULK1 complex and thereby induces autophagy .	mTOR inactivation by SAHA restores the function of the ULK1 complex and thereby induces autophagy.	0	10	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	0	1	9	10
mTOR negatively regulates autophagy by suppressing the function of the kinases ULK1 or ULK2 .	mTOR negatively regulates autophagy by suppressing the function of the kinases ULK1 or ULK2.	0	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	0	1	11	12
mTOR inactivation by SAHA thus rescues ULK1 activation and thereby induces autophagy .	mTOR inactivation by SAHA thus rescues ULK1 activation and thereby induces autophagy.	0	7	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	0	1	6	7
Importantly , ULK1 has been well studied in the context of nutrient and oxygen deprivation , in which the mechanistic target of rapamycin complex 1 ( mTORC1 ) negatively regulates ULK1 through hyper-phosphorylation in nutrient rich environments ; while AMP activated protein kinase ( AMPK ) binds and phosphorylates ULK1 to activate autophagy under hypoxic and nutrient deprivation .	Importantly, ULK1 has been well studied in the context of nutrient and oxygen deprivation, in which the mechanistic target of rapamycin complex 1 (mTORC1) negatively regulates ULK1 through hyper-phosphorylation in nutrient rich environments; while AMP activated protein kinase (AMPK) binds and phosphorylates ULK1 to activate autophagy under hypoxic and nutrient deprivation.	19	31	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	ULK1	ULK1	ULK1	19	23	30	31
11 Conversely , MTOR negatively regulates autophagy by inhibiting the activity of ULK1 through direct phosphorylation of Ser757 .	11 Conversely, MTOR negatively regulates autophagy by inhibiting the activity of ULK1 through direct phosphorylation of Ser757.	3	13	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MTOR	MTOR	MTOR	ULK1	ULK1	ULK1	3	4	12	13
However , the mechanism by which mTOR is controlled to activate ULK1 activity for autophagy induction has not yet been clearly elucidated .	However, the mechanism by which mTOR is controlled to activate ULK1 activity for autophagy induction has not yet been clearly elucidated.	6	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	6	7	11	12
XREF_BIBR The formation of the autophagosome begins with the mammalian target of rapamycin ( mTOR ) which modulates the initiator protein Ulk1 .	XREF_BIBR The formation of the autophagosome begins with the mammalian target of rapamycin (mTOR) which modulates the initiator protein Ulk1.	12	22	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	Ulk1	Ulk1	Ulk1	14	15	21	22
Under nutrient rich condition , mTOR suppresses autophagy by inhibiting Atg13 and Atg1 ( ULK1/2 ) complex , while blockage of mTOR upon nutrient starvation or stress launches autophagy in eukaryotes [ XREF_BIBR ] .	Under nutrient rich condition, mTOR suppresses autophagy by inhibiting Atg13 and Atg1 (ULK1/2) complex, while blockage of mTOR upon nutrient starvation or stress launches autophagy in eukaryotes [XREF_BIBR].	5	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Atg1	Atg1	Atg1	5	6	12	13
Next , when cells were treated with two different mTOR inhibitors , rapamycin and Torin1 at 4 h of starvation , we found that mTOR inhibition effectively suppressed both ULK1 protein level restoration and ULK1 neophosphorylayion by mTOR ( XREF_FIG ) , suggesting an involvement of mTOR reactivation in ULK1 restoration .	Next, when cells were treated with two different mTOR inhibitors, rapamycin and Torin1 at 4 h of starvation, we found that mTOR inhibition effectively suppressed both ULK1 protein level restoration and ULK1 neophosphorylayion by mTOR (XREF_FIG), suggesting an involvement of mTOR reactivation in ULK1 restoration.	24	32	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	24	25	29	30
When growth conditions are favorable , mTOR inhibits autophagy by inhibiting the ULK1 complex , which is required for the biogenesis of autophagosomes .	When growth conditions are favorable, mTOR inhibits autophagy by inhibiting the ULK1 complex, which is required for the biogenesis of autophagosomes.	6	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	6	7	12	13
mTOR inactivation by SAHA restores functions of ULK1 [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	mTOR inactivation by SAHA restores functions of ULK1 [XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	13	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	0	1	7	8
Gammaherpesviruses interfere with upstream autophagy signalling by targeting the ' nutrient sensor ' , mammalian target of rapamycin complex 1 ( mTORC1 ) , which integrates metabolic signals from the microenvironment of the cell and represses the autophagy initiating ULK1 complex XREF_BIBR - XREF_BIBR ( XREF_FIG ) .	Gammaherpesviruses interfere with upstream autophagy signalling by targeting the ' nutrient sensor ', mammalian target of rapamycin complex 1 (mTORC1), which integrates metabolic signals from the microenvironment of the cell and represses the autophagy initiating ULK1 complex XREF_BIBR - XREF_BIBR (XREF_FIG).	14	41	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	ULK1	ULK1	ULK1	14	18	39	40
ULK1 activity is stimulated by AMP activated protein kinase ( AMPK , in response to increased AMP and ATP ratios ) and inhibited by mammalian target of rapamycin complex 1 ( mTORC1 ) .	ULK1 activity is stimulated by AMP activated protein kinase (AMPK, in response to increased AMP and ATP ratios) and inhibited by mammalian target of rapamycin complex 1 (mTORC1).	0	28	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	ULK1	ULK1	ULK1	24	28	0	1
However , during prolonged autophagy , while the ULK1 protein undergoes this inhibition , ULK1 mRNA is actively transcribed , translated and then inhibited again by MTOR dependent inhibitory phosphorylation .	However, during prolonged autophagy, while the ULK1 protein undergoes this inhibition, ULK1 mRNA is actively transcribed, translated and then inhibited again by MTOR dependent inhibitory phosphorylation.	14	30	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	MTOR	MTOR dependent inhibitory phosphorylation	mtor	ULK1	ULK1	ulk1	26	27	14	15
AMPK promotes autophagy by promoting Ulk1 phosphorylation at Ser317 and Ser777 and conversely mTOR inhibits autophagy by inhibiting Ulk1 by phosphorylation at Ser 757 .	AMPK promotes autophagy by promoting Ulk1 phosphorylation at Ser317 and Ser777 and conversely mTOR inhibits autophagy by inhibiting Ulk1 by phosphorylation at Ser 757.	13	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	Ulk1	Ulk1	Ulk1	13	14	18	19
The study of XREF_BIBR shows that reactivation of mTOR allows resynthesis of ULK1 to establish a new pool of ULK1 .	The study of XREF_BIBR shows that reactivation of mTOR allows resynthesis of ULK1 to establish a new pool of ULK1.	6	13	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	8	9	12	13
In addition , phosphorylation at either serine residue was not affected by hyperosmotic treatment for up to 72h , suggesting that hyperosmolarity fails to affect both MTOR and AMPK modulation of ULK1 activity in NP cells .	In addition, phosphorylation at either serine residue was not affected by hyperosmotic treatment for up to 72h, suggesting that hyperosmolarity fails to affect both MTOR and AMPK modulation of ULK1 activity in NP cells.	26	32	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MTOR	MTOR	MTOR	ULK1	ULK1	ULK1	26	27	31	32
ULK1 is one of the core machinery of initiation of autophagy , which is reversely regulated by MTOR and PRKAA1 kinase : PRKAA1 activates autophagy via ULK1-S555 site phosphorylation , while MTOR inhibits autophagy by reducing ULK1 kinase activity through the ULK1-S757 site phosphorylation 31 .	ULK1 is one of the core machinery of initiation of autophagy, which is reversely regulated by MTOR and PRKAA1 kinase : PRKAA1 activates autophagy via ULK1-S555 site phosphorylation, while MTOR inhibits autophagy by reducing ULK1 kinase activity through the ULK1-S757 site phosphorylation 31.	31	38	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MTOR	MTOR	MTOR	ULK1	ULK1	ULK1	31	32	36	37
MTOR promotes translation in a number of ways including the activation of RPS6KB1/2 ( ribosomal protein S6 kinase , 70 kDa , polypeptide 1/2 ) and inhibition of EIF4EBP1 ( eukaryotic translation initiation factor 4E binding protein 1 ) and blocks autophagy by inhibiting the Atg1 and ULK1 ( unc-51-like kinase 1 ) kinase complex .	MTOR promotes translation in a number of ways including the activation of RPS6KB1/2 (ribosomal protein S6 kinase, 70 kDa, polypeptide 1/2) and inhibition of EIF4EBP1 (eukaryotic translation initiation factor 4E binding protein 1) and blocks autophagy by inhibiting the Atg1 and ULK1 (unc-51-like kinase 1) kinase complex.	0	52	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MTOR	MTOR	MTOR	unc-51-like kinase 1	unc-51-like kinase 1	unc-51-like kinase 1	0	1	49	52
As the most cell signaling axis , Akt and mTOR can negatively regulate autophagy by inhibiting ULK1 .	As the most cell signaling axis, Akt and mTOR can negatively regulate autophagy by inhibiting ULK1.	7	17	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	9	10	16	17
These studies show that both mTOR and AMPK directly regulate Ulk1 and coordinate the mammalian autophagy initiation .	These studies show that both mTOR and AMPK directly regulate Ulk1 and coordinate the mammalian autophagy initiation.	4	12	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	Ulk1	Ulk1	Ulk1	5	6	10	11
Recent studies revealed that activated AMPK was involved in processes that synergize to activate autophagy , by directly activating UNC-51-like autophagy activating kinase 1 ( ULK1 ) , a key initiator of the autophagic processes , and indirectly impairing mammalian target of rapamycin ( mTOR )-dependent inhibition of ULK1 [ XREF_BIBR - XREF_BIBR ] .	Recent studies revealed that activated AMPK was involved in processes that synergize to activate autophagy, by directly activating UNC-51-like autophagy activating kinase 1 (ULK1), a key initiator of the autophagic processes, and indirectly impairing mammalian target of rapamycin (mTOR)-dependent inhibition of ULK1 [XREF_BIBR - XREF_BIBR].	39	52	inhibition	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	ULK1	ULK1	ULK1	39	43	48	49
Under stress conditions , such as nutrient deprivation or bacterial invasion , mTOR gets inactivated , enabling the ULK1 complex to recruit and activate PI3KC3 .	Under stress conditions, such as nutrient deprivation or bacterial invasion, mTOR gets inactivated, enabling the ULK1 complex to recruit and activate PI3KC3.	12	19	enabling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	12	13	18	19
In detail , mTOR inhibits autophagy by suppressing the ULK1 complex , which consists of several autophagy related proteins ( ULK1 , Atg13 , FIP200 ) .	In detail, mTOR inhibits autophagy by suppressing the ULK1 complex, which consists of several autophagy related proteins (ULK1, Atg13, FIP200).	3	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	3	4	9	10
During cell stress , nutrient deprivation or growth factor withdrawal , autophagy is induced above basal levels by inactivation of mTOR and subsequent activation of Ulk1 and its targets within the PI3K Vps34 and Beclin 1 complex .	During cell stress, nutrient deprivation or growth factor withdrawal, autophagy is induced above basal levels by inactivation of mTOR and subsequent activation of Ulk1 and its targets within the PI3K Vps34 and Beclin 1 complex.	20	26	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	Ulk1	Ulk1	Ulk1	20	21	25	26
In fact , nutrient starvation or rapamycin treatment can activate autophagy by inhibiting MTOR ( mechanistic target of rapamycin [ serine/threonine kinase ] ) thereby activating the ULK1 ( unc-51 like autophagy activating kinase 1 ) and ULK2 proteins that , in turn , recruit other ATG proteins such as MAP1LC3B and ATG16L1 to the forming autophagosome .	In fact, nutrient starvation or rapamycin treatment can activate autophagy by inhibiting MTOR (mechanistic target of rapamycin [serine/threonine kinase]) thereby activating the ULK1 (unc-51 like autophagy activating kinase 1) and ULK2 proteins that, in turn, recruit other ATG proteins such as MAP1LC3B and ATG16L1 to the forming autophagosome.	12	38	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MTOR	MTOR	MTOR	ULK1	ULK1	ULK1	13	14	27	28
Activation and inhibition of mTOR , respectively , repress and enhance autophagy , most likely by controlling the assembly of ATG1 complex during the induction of autophagy XREF_BIBR , XREF_BIBR , XREF_BIBR .	Activation and inhibition of mTOR, respectively, repress and enhance autophagy, most likely by controlling the assembly of ATG1 complex during the induction of autophagy XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	21	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ATG1	ATG1	ATG1	4	5	20	21
mTOR negatively regulates autophagy by inhibiting the function of the unc-51-like kinase 1 ( ULK1 ) and ULK2 complex , which plays an important role in autophagy initiation 22 .	mTOR negatively regulates autophagy by inhibiting the function of the unc-51-like kinase 1 (ULK1) and ULK2 complex, which plays an important role in autophagy initiation 22.	0	18	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	0	1	14	15
In a nutrient-poor condition , another energetic sensor is activated , AMPK , which directly inhibits mTOR by its direct phosphorylation as well as directly activates the ULK1 ( ATG protein family ) ( ATG , genes related to autophagy ) , stimulating autophagy [ XREF_BIBR ] .	In a nutrient-poor condition, another energetic sensor is activated, AMPK, which directly inhibits mTOR by its direct phosphorylation as well as directly activates the ULK1 (ATG protein family) (ATG, genes related to autophagy), stimulating autophagy [XREF_BIBR].	16	34	directly activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	ULK1	ULK1	ULK1	16	17	27	28
In conclusion , Akt mediated mTOR inactivation originating by SAHA treatment promotes ULK1 activation and thereby induces autophagy .	In conclusion, Akt mediated mTOR inactivation originating by SAHA treatment promotes ULK1 activation and thereby induces autophagy.	3	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	Akt mediated mTOR	mtor	ULK1	ULK1	ulk1	5	6	12	13
Also , the presence of anti-apoA-I IgG in autoimmune disease has been associated with dysfunctional HDLs , which could be generated by myeloperoxidase catalyzed apoA-I oxidation .	Also, the presence of anti-apoA-I IgG in autoimmune disease has been associated with dysfunctional HDLs, which could be generated by myeloperoxidase catalyzed apoA-I oxidation.	20	25	catalyzed	Positive_activation_token_1_verb	Negative_activation	Positive_activation	myeloperoxidase	myeloperoxidase	myeloperoxidase	apoA-I	apoA-I	apoA-I	22	23	24	25
XREF_BIBR Recent studies have shown that MPO can selectively target apoA-I as a result of direct binding and that it catalyses apoA-I nitration and halogenation within human atheroma .	XREF_BIBR Recent studies have shown that MPO can selectively target apoA-I as a result of direct binding and that it catalyses apoA-I nitration and halogenation within human atheroma.	6	11	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	6	7	10	11
ApoA-I aggregation in vitro is accelerated under acidic conditions and by myeloperoxidase catalyzed oxidation associated with inflammatory diseases such as atherosclerosis .	ApoA-I aggregation in vitro is accelerated under acidic conditions and by myeloperoxidase catalyzed oxidation associated with inflammatory diseases such as atherosclerosis.	0	13	catalyzed	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	myeloperoxidase	myeloperoxidase	myeloperoxidase	ApoA-I	ApoA-I	ApoA-I	11	12	0	1
Myeloperoxidase induced chlorination of apoA-I , the major protein component of HDL , impairs the ability of apoA-I to promote cholesterol efflux through ABCA1 , the macrophage ATP binding cassette transporter [ XREF_BIBR , XREF_BIBR ] .	Myeloperoxidase induced chlorination of apoA-I, the major protein component of HDL, impairs the ability of apoA-I to promote cholesterol efflux through ABCA1, the macrophage ATP binding cassette transporter [XREF_BIBR, XREF_BIBR].	0	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Myeloperoxidase	Myeloperoxidase	Myeloperoxidase	apoA-I	apoA-I	apoA-I	0	1	4	5
Thus , the site directed substitution and cholesterol efflux data indicate that neither methionine nor tyrosine serve as the oxidant sensitive residue involved in MPO induced apoAI inactivation .	Thus, the site directed substitution and cholesterol efflux data indicate that neither methionine nor tyrosine serve as the oxidant sensitive residue involved in MPO induced apoAI inactivation.	22	27	induced	Positive_early_activation	Negative_activation	Positive_activation	MPO	MPO	MPO	apoAI	apoAI	apoAI	24	25	26	27
In the context of atherosclerosis , increased oxidative modification of ApoA-I mediated by myeloperoxidase led to decreased ABCA1 dependent cholesterol efflux from macrophages [ XREF_BIBR ] as well as impaired activation of LCAT [ XREF_BIBR ] .	In the context of atherosclerosis, increased oxidative modification of ApoA-I mediated by myeloperoxidase led to decreased ABCA1 dependent cholesterol efflux from macrophages [XREF_BIBR] as well as impaired activation of LCAT [XREF_BIBR].	8	14	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	myeloperoxidase	myeloperoxidase	myeloperoxidase	ApoA-I	ApoA-I	ApoA-I	13	14	10	11
Herein we used tandem mass spectrometry to map the sites of MPO mediated apoA-I nitration and chlorination in vitro and in vivo and to relate the degree of site specific modifications to loss of apoA-I lipid binding and cholesterol efflux functions .	Herein we used tandem mass spectrometry to map the sites of MPO mediated apoA-I nitration and chlorination in vitro and in vivo and to relate the degree of site specific modifications to loss of apoA-I lipid binding and cholesterol efflux functions.	9	14	mediated	Positive_early_activation	Negative_activation	Positive_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	11	12	13	14
Similarly , MPO intermediates ( e.g ., hypothiocyanous and hypochlorous acid ) induce apoA-1 oxidation , which would impair its cholesterol efflux capacity and consequently its anti-atherogenic functions [ XREF_BIBR , XREF_BIBR ] .	Similarly, MPO intermediates (e.g., hypothiocyanous and hypochlorous acid) induce apoA-1 oxidation, which would impair its cholesterol efflux capacity and consequently its anti-atherogenic functions [XREF_BIBR, XREF_BIBR].	2	14	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apoA-1	apoA-1	apoA-1	2	3	13	14
Apo A-I is targeted by myeloperoxidase , and , when oxidized and nitrated , impairs ABCA1 dependent cholesterol efflux .	Apo A-I is targeted by myeloperoxidase, and, when oxidized and nitrated, impairs ABCA1 dependent cholesterol efflux.	0	6	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	myeloperoxidase	myeloperoxidase	myeloperoxidase	Apo A-I	Apo A-I	Apo A-I	5	6	0	2
While we observed some macrophage uptake of HDL particles with unmodified protein in vitro , this may be explained by the activity of myeloperoxidase ( MPO ) , which is secreted by macrophages and neutrophils and may cause oxidative damage to apo A-I .	While we observed some macrophage uptake of HDL particles with unmodified protein in vitro, this may be explained by the activity of myeloperoxidase (MPO), which is secreted by macrophages and neutrophils and may cause oxidative damage to apo A-I.	21	43	cause	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	myeloperoxidase	myeloperoxidase	myeloperoxidase	apo A-I	apo A-I	apo A-I	23	24	41	43
4.3 MPO mediated chlorination , but not nitration , of apoA-I impairs cholesterol transport by ABCA1 .	4.3 MPO mediated chlorination, but not nitration, of apoA-I impairs cholesterol transport by ABCA1.	0	11	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	1	2	10	11
While we observed some macrophage uptake of HDL particles containing unmodified protein in vitro ( XREF_FIG ) , this may be explained by the activity of myeloperoxidase ( MPO ) , which is secreted by macrophages and neutrophils and may cause oxidative damage to apo A-I and consequently target these particles to macrophages [ XREF_BIBR ] .	While we observed some macrophage uptake of HDL particles containing unmodified protein in vitro (XREF_FIG), this may be explained by the activity of myeloperoxidase (MPO), which is secreted by macrophages and neutrophils and may cause oxidative damage to apo A-I and consequently target these particles to macrophages [XREF_BIBR].	26	46	cause	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apo A-I	apo A-I	apo A-I	28	29	44	46
MPO promotes oxidation of low-density lipoprotein ( LDL ) [ XREF_BIBR ] , and apolipoprotein A-I in high-density lipoproteins ( HDL ) , which impairs its ability to promote reverse cholesterol transport [ XREF_BIBR - XREF_BIBR ] .	MPO promotes oxidation of low-density lipoprotein (LDL) [XREF_BIBR], and apolipoprotein A-I in high-density lipoproteins (HDL), which impairs its ability to promote reverse cholesterol transport [XREF_BIBR - XREF_BIBR].	0	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	0	1	14	16
Thus , the site directed substitution and cholesterol efflux data indicate that neither methionine nor tyrosine serve as the oxidant sensitive residue , involved in MPO induced apoAI inactivation , specifically the loss of alpha helix content , and the loss of tryptophan and lysine residues [ XREF_BIBR , XREF_BIBR ] .	Thus, the site directed substitution and cholesterol efflux data indicate that neither methionine nor tyrosine serve as the oxidant sensitive residue, involved in MPO induced apoAI inactivation, specifically the loss of alpha helix content, and the loss of tryptophan and lysine residues [XREF_BIBR, XREF_BIBR].	23	28	induced	Positive_early_activation	Negative_activation	Positive_activation	MPO	MPO	MPO	apoAI	apoAI	apoAI	25	26	27	28
In the group of patients with MPO200-300ng/ml higher MPO concentration caused deterioration of apoAI concentration , increased levels of markers of inflammation and a significant increase MPO and apoAI and MPO and HDL-C ratios .	In the group of patients with MPO200-300ng/ml higher MPO concentration caused deterioration of apoAI concentration, increased levels of markers of inflammation and a significant increase MPO and apoAI and MPO and HDL-C ratios.	8	14	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apoAI	apoAI	apoAI	8	9	13	14
MPO has been shown to promote the oxidation of low density protein ( LDL ) and apolipoprotein A-I , thus , reducing its ability to cause cholesterol efflux .	MPO has been shown to promote the oxidation of low density protein (LDL) and apolipoprotein A-I, thus, reducing its ability to cause cholesterol efflux.	0	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apolipoprotein A-I	apolipoprotein A-I	apolipoprotein A-I	0	1	16	18
Our studies demonstrated that MPO mediated chlorination ( but not nitration ) of apoA-I markedly reduces the protein ' s ability to remove cholesterol from cells by the ABCA1 pathway .	Our studies demonstrated that MPO mediated chlorination (but not nitration) of apoA-I markedly reduces the protein 's ability to remove cholesterol from cells by the ABCA1 pathway.	4	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	4	5	13	14
Our early work showed that myeloperoxidase mediated oxidation could modify tryptophan in apoAI and thus impair the cholesterol acceptor activity of apoAI 11 .	Our early work showed that myeloperoxidase mediated oxidation could modify tryptophan in apoAI and thus impair the cholesterol acceptor activity of apoAI 11.	5	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myeloperoxidase	myeloperoxidase	myeloperoxidase	apoAI	apoAI	apoAI	5	6	12	13
Although it has been established that HOCl ( hypochlorous acid ) produced by MPO targets apoA-I ( apolipoprotein A-I ) , the major apolipoprotein of HDLs , the role of the other major oxidant generated by MPO , HOSCN ( hypothiocyanous acid ) , in the generation of dysfunctional HDLs has not been examined .	Although it has been established that HOCl (hypochlorous acid) produced by MPO targets apoA-I (apolipoprotein A-I), the major apolipoprotein of HDLs, the role of the other major oxidant generated by MPO, HOSCN (hypothiocyanous acid), in the generation of dysfunctional HDLs has not been examined.	11	18	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	13	14	15	16
31 In addition , a recent study in mice linked myeloperoxidase mediated oxidation of apoA1 to impairment of reverse cholesterol transport in vivo and the ability of apoA1 to reduce lipid and macrophage content in atherosclerotic lesions .	31 In addition, a recent study in mice linked myeloperoxidase mediated oxidation of apoA1 to impairment of reverse cholesterol transport in vivo and the ability of apoA1 to reduce lipid and macrophage content in atherosclerotic lesions.	9	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myeloperoxidase	myeloperoxidase	myeloperoxidase	apoA1	apoA1	apoA1	10	11	14	15
One apparent consequence of MPO catalyzed apoA-I oxidation includes the functional impairment of the ability of HDL to promote cellular cholesterol efflux via the adenosine triphosphate binding cassette-1 transport system .	One apparent consequence of MPO catalyzed apoA-I oxidation includes the functional impairment of the ability of HDL to promote cellular cholesterol efflux via the adenosine triphosphate binding cassette-1 transport system.	2	7	catalyzed	Positive_activation_token_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	4	5	6	7
XREF_BIBR This methylated apoAI retained its cholesterol acceptor activity ; and , it was equally susceptible as wild type apoAI to the MPO mediated loss of function , implying that lysine modification is not responsible for the MPO mediated apoAI dysfunction .	XREF_BIBR This methylated apoAI retained its cholesterol acceptor activity; and, it was equally susceptible as wild type apoAI to the MPO mediated loss of function, implying that lysine modification is not responsible for the MPO mediated apoAI dysfunction.	36	40	mediated	Positive_early_activation	Negative_activation	Positive_activation	MPO	MPO	MPO	apoAI	apoAI	apoAI	37	38	39	40
It is known that myeloperoxidase ( MPO )-derived hypochlorous acid ( HOCl ) induces changes in HDL function by causing oxidative modification of apoA-I [ XREF_BIBR ] .	It is known that myeloperoxidase (MPO)-derived hypochlorous acid (HOCl) induces changes in HDL function by causing oxidative modification of apoA-I [XREF_BIBR].	4	25	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myeloperoxidase	myeloperoxidase	myeloperoxidase	apoA-I	apoA-I	apoA-I	4	5	23	24
These studies indicate that MPO mediated oxidation renders apoA-I dysfunctional and unable to promote reverse cholesterol transport , or mediate beneficial changes in atherosclerotic plaques , or decrease inflammation in plaque macrophages [ XREF_BIBR ] .	These studies indicate that MPO mediated oxidation renders apoA-I dysfunctional and unable to promote reverse cholesterol transport, or mediate beneficial changes in atherosclerotic plaques, or decrease inflammation in plaque macrophages [XREF_BIBR].	4	27	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apoA-I	apoA-I	apoA-I	4	5	8	9
Site specific MPO mediated chlorination and nitration of apoA-1 residues impair HDL function XREF_BIBR , XREF_BIBR .	Site specific MPO mediated chlorination and nitration of apoA-1 residues impair HDL function XREF_BIBR, XREF_BIBR.	0	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apoA-1	apoA-1	apoA-1	2	3	8	9
Within atherosclerotic lesions , MPO is enriched and promotes site specific oxidative modification of apoA1 at residue Trp72 .	Within atherosclerotic lesions, MPO is enriched and promotes site specific oxidative modification of apoA1 at residue Trp72.	4	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MPO	MPO	MPO	apoA1	apoA1	apoA1	4	5	14	15
HDL functions are impaired by myeloperoxidase ( MPO ) , which selectively targets and oxidizes human apoA1 .	HDL functions are impaired by myeloperoxidase (MPO), which selectively targets and oxidizes human apoA1.	3	17	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myeloperoxidase	myeloperoxidase	myeloperoxidase	apoA1	apoA1	apoA1	5	6	16	17
Myostatin induced atrophy is associated with increases in E3-ligase atrogin-1 expression and protein degradation and decreases in Akt and mechanistic target of rapamycin ( mTOR ) signaling and protein synthesis .	Myostatin induced atrophy is associated with increases in E3-ligase atrogin-1 expression and protein degradation and decreases in Akt and mechanistic target of rapamycin (mTOR) signaling and protein synthesis.	0	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	17	18
The repressive effects of myostatin on muscle growth appear to attenuate Akt and mTOR signaling , which suggests that interventions that block myostatin may stimulate Akt and/or mTOR to promote muscle hypertrophy .	The repressive effects of myostatin on muscle growth appear to attenuate Akt and mTOR signaling, which suggests that interventions that block myostatin may stimulate Akt and/or mTOR to promote muscle hypertrophy.	2	14	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	4	5	11	12
Myostatin inhibits activation of the Akt and mammalian target of rapamycin ( mTOR )/p70S6 protein synthesis pathway , which mediates both differentiation in myoblasts and hypertrophy in myotubes .	Myostatin inhibits activation of the Akt and mammalian target of rapamycin (mTOR)/p70S6 protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes.	0	8	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	0	1	5	6
We examined the functional role of myostatin modulation of Akt in C2C12 myotubes , a well established in vitro model of skeletal muscle hypertrophy .	We examined the functional role of myostatin modulation of Akt in C2C12 myotubes, a well established in vitro model of skeletal muscle hypertrophy.	6	10	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	6	7	9	10
IGF-I has been shown to block the effects of myostatin on Akt when applied to myoblasts or myotubes , suggesting that IGF-I and Akt signaling is dominant over myostatin induced activation of Akt .	IGF-I has been shown to block the effects of myostatin on Akt when applied to myoblasts or myotubes, suggesting that IGF-I and Akt signaling is dominant over myostatin induced activation of Akt.	26	33	induced	Positive_early_activation	Negative_activation	Positive_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	28	29	32	33
These data suggest that myostatin may negatively regulate cell size by blocking activation of Akt and NFAT3 in cardiomyocytes .	These data suggest that myostatin may negatively regulate cell size by blocking activation of Akt and NFAT3 in cardiomyocytes.	4	16	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	4	5	14	15
In fibroblasts , myostatin induces activation of the Smad , p38 MAPK and AKT pathways to promote ECM synthesis [ XREF_BIBR ] .	In fibroblasts, myostatin induces activation of the Smad, p38 MAPK and AKT pathways to promote ECM synthesis [XREF_BIBR].	3	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myostatin	myostatin	myostatin	AKT	AKT	AKT	3	4	13	14
The group of Freyssenet reported recently that myostatin may also contribute to the regulation of skeletal muscle mass in adulthood by showing that myostatin overexpression induced a marked down-regulation of Akt and mTOR signalling pathway but failed to increase expression of atrogenes ( MURF1 , MAFbx , Nedd4 and ZNF216 ) and regulate the catalytic activities of the proteasome [ XREF_BIBR , XREF_BIBR ] .	The group of Freyssenet reported recently that myostatin may also contribute to the regulation of skeletal muscle mass in adulthood by showing that myostatin overexpression induced a marked down-regulation of Akt and mTOR signalling pathway but failed to increase expression of atrogenes (MURF1, MAFbx, Nedd4 and ZNF216) and regulate the catalytic activities of the proteasome [XREF_BIBR, XREF_BIBR].	23	34	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myostatin	myostatin overexpression	myostatin	Akt	Akt	akt	23	24	30	31
Myostatin inhibition caused increased activation of Akt and NFAT3 ( activated by dephosphorylation ) compared to LacZ control , while myostatin overexpression caused decreased activation of Akt and NFAT3 compared to LacZ control ( XREF_FIG ) .	Myostatin inhibition caused increased activation of Akt and NFAT3 (activated by dephosphorylation) compared to LacZ control, while myostatin overexpression caused decreased activation of Akt and NFAT3 compared to LacZ control (XREF_FIG).	20	28	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin overexpression	myostatin	Akt	Akt	akt	20	21	26	27
It has been previously reported that myostatin can modulate Akt signaling in NCM ' s XREF_BIBR , perhaps by upregulating or stabilizing PTEN XREF_BIBR .	It has been previously reported that myostatin can modulate Akt signaling in NCM 's XREF_BIBR, perhaps by upregulating or stabilizing PTEN XREF_BIBR.	6	10	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	6	7	9	10
It was also shown that MSTN activates GSK-3beta and decreases cyclin D1 by inhibiting the PI3K and Akt pathway and this has been proposed to be involved in the progression of muscle-disuse atrophy [ XREF_BIBR ] .	It was also shown that MSTN activates GSK-3beta and decreases cyclin D1 by inhibiting the PI3K and Akt pathway and this has been proposed to be involved in the progression of muscle-disuse atrophy [XREF_BIBR].	5	18	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MSTN	MSTN	MSTN	Akt	Akt	Akt	5	6	17	18
Lifting the inhibition of Akt signalling mediated by Myostatin is also a potent means of inducing the formation of glycolytic muscle fibres .	Lifting the inhibition of Akt signalling mediated by Myostatin is also a potent means of inducing the formation of glycolytic muscle fibres.	4	9	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Myostatin	Myostatin	Myostatin	Akt	Akt	Akt	8	9	4	5
Previous research found that myostatin signaling reversed the insulin like growth factor 1/phosphatidyl inositol 3-kinase/protein kinase B ( IGF-1/PI3K/Akt ) hypertrophy pathway by inhibiting AKT , allowing for increased expression of atrophy related genes XREF_BIBR , XREF_BIBR .	Previous research found that myostatin signaling reversed the insulin like growth factor 1/phosphatidyl inositol 3-kinase/protein kinase B (IGF-1/PI3K/Akt) hypertrophy pathway by inhibiting AKT, allowing for increased expression of atrophy related genes XREF_BIBR, XREF_BIBR.	4	25	reversed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	AKT	AKT	AKT	4	5	24	25
Moreover , both myostatin and FoxO have been shown to inhibit protein synthesis by decreasing the activity of the components of the Akt and mammalian target of rapamycin pathway XREF_BIBR , XREF_BIBR - XREF_BIBR .	Moreover, both myostatin and FoxO have been shown to inhibit protein synthesis by decreasing the activity of the components of the Akt and mammalian target of rapamycin pathway XREF_BIBR, XREF_BIBR - XREF_BIBR.	2	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	myostatin	myostatin	myostatin	Akt	Akt	Akt	3	4	22	23
Finally , rapamycin , an FDA approved drug , which activates autophagy through inhibition of mTOR ( and thus stimulation of TFEB function ) has been used in vitro and in vivo to reduce ~-synuclein pathology [ XREF_BIBR , XREF_BIBR ] .	Finally, rapamycin, an FDA approved drug, which activates autophagy through inhibition of mTOR (and thus stimulation of TFEB function) has been used in vitro and in vivo to reduce ~-synuclein pathology [XREF_BIBR, XREF_BIBR].	13	22	stimulation	Positive_activation_syntax_7_noun	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	15	16	21	22
Several recent reports in the literature have found antihelmintics to induce an anti-proliferative effect in cancer cell lines by indirectly inhibiting the mTOR pathway thus inducing TFEB activity , which may explain their PLD like transcriptional response .	Several recent reports in the literature have found antihelmintics to induce an anti-proliferative effect in cancer cell lines by indirectly inhibiting the mTOR pathway thus inducing TFEB activity, which may explain their PLD like transcriptional response.	22	27	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	22	23	26	27
The above findings reveal that mTOR maximally induced cytoplasmic TFEB retention in all HeLa cells , but fractionally in MCF7 cells .	The above findings reveal that mTOR maximally induced cytoplasmic TFEB retention in all HeLa cells, but fractionally in MCF7 cells.	5	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	5	6	9	10
In agreement with the work of Puertollano and co-workers and Ballabio and co-workers , we found that under AGE stimulation , activated mTOR induced TFEB accumulation in the cytosol .	In agreement with the work of Puertollano and co-workers and Ballabio and co-workers, we found that under AGE stimulation, activated mTOR induced TFEB accumulation in the cytosol.	22	25	induced	Positive_early_activation	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	22	23	24	25
We propose an indirect pathway , in which mTOR activity inhibits proteasomal degradation of a positive TFEB regulator .	We propose an indirect pathway, in which mTOR activity inhibits proteasomal degradation of a positive TFEB regulator.	8	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	8	9	16	17
Conversely , Puertollano and co-workers and Ballabio and co-workers observed that under nutrient rich conditions , active mTOR induced sequestration of TFEB in the cytosol , whereas under starvation or lysosome disruption , mTOR inactivation triggered TFEB transport into the nucleus and transcription of autophagy associated genes 11 , 12 .	Conversely, Puertollano and co-workers and Ballabio and co-workers observed that under nutrient rich conditions, active mTOR induced sequestration of TFEB in the cytosol, whereas under starvation or lysosome disruption, mTOR inactivation triggered TFEB transport into the nucleus and transcription of autophagy associated genes 11, 12.	33	37	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	33	34	36	37
An opportunity for pharmacological activation of TFEB has stemmed from cell based studies that indicate that TFEB is negatively regulated by the mechanistic target of rapamycin complex 1 ( mTORC1 ) XREF_BIBR XREF_BIBR XREF_BIBR , the main known factor restricting autophagy induction .	An opportunity for pharmacological activation of TFEB has stemmed from cell based studies that indicate that TFEB is negatively regulated by the mechanistic target of rapamycin complex 1 (mTORC1) XREF_BIBR XREF_BIBR XREF_BIBR, the main known factor restricting autophagy induction.	16	26	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	TFEB	TFEB	TFEB	22	26	16	17
In this study , a synthesized curcumin derivative termed C1 is identified as a novel MTOR independent activator of TFEB .	In this study, a synthesized curcumin derivative termed C1 is identified as a novel MTOR independent activator of TFEB.	15	20	activator	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	MTOR	MTOR	MTOR	TFEB	TFEB	TFEB	15	16	19	20
Importantly , we found that mTOR inactivation failed to maximally activate TFEB in all cells of a cell population .	Importantly, we found that mTOR inactivation failed to maximally activate TFEB in all cells of a cell population.	5	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	5	6	11	12
Serine 142 of TFEB has been characterized as a key residue for phosphorylation and regulation of TFEB by the mammalian target of rapamycin complex 1 ( mTORC1 ) , which is known to negatively regulate TFEB activity by impairing its shuttling into the nucleus XREF_BIBR XREF_BIBR .	Serine 142 of TFEB has been characterized as a key residue for phosphorylation and regulation of TFEB by the mammalian target of rapamycin complex 1 (mTORC1), which is known to negatively regulate TFEB activity by impairing its shuttling into the nucleus XREF_BIBR XREF_BIBR.	19	36	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	TFEB	TFEB	TFEB	19	23	35	36
Consistent with previous studies of starvation induced TFEB activation , we observed a faster migrating endogenous TFEB band in cells deprived of amino acids or treated with the mTOR catalytic inhibitor torin 1 compared with untreated cells ( XREF_FIG ) .	Consistent with previous studies of starvation induced TFEB activation, we observed a faster migrating endogenous TFEB band in cells deprived of amino acids or treated with the mTOR catalytic inhibitor torin 1 compared with untreated cells (XREF_FIG).	16	31	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	28	29	16	17
As mTOR inhibition by torin 1 completely eliminated the detection of TFEB by the anti-14-3-3 binding site antibody ( XREF_FIG ) while the S211A mutant reduced but did not abolish this signal ( XREF_FIG ) , there must be additional mTOR dependent phosphorylation sites on TFEB .	As mTOR inhibition by torin 1 completely eliminated the detection of TFEB by the anti-14-3-3 binding site antibody (XREF_FIG) while the S211A mutant reduced but did not abolish this signal (XREF_FIG), there must be additional mTOR dependent phosphorylation sites on TFEB.	1	12	eliminated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	TFEB	TFEB	TFEB	1	2	11	12
XREF_BIBR TFEB is phosphorylated by MTOR and is also associated with the lysosomal surface in well fed cells , and it gets released from there when MTOR is inactivated and released , enabling TFEB to translocate to the nucleus and induce the expression of its target genes .	XREF_BIBR TFEB is phosphorylated by MTOR and is also associated with the lysosomal surface in well fed cells, and it gets released from there when MTOR is inactivated and released, enabling TFEB to translocate to the nucleus and induce the expression of its target genes.	26	34	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	MTOR	MTOR	MTOR	TFEB	TFEB	TFEB	26	27	33	34
On the contrary , we demonstrate here that myogenin directly regulates MuRF1 and atrogin-1 , which promote the loss of muscle mass in response to denervation , revealing a mechanistic basis for neurogenic muscle atrophy and a previously unrecognized function for myogenin in this pathological process .	On the contrary, we demonstrate here that myogenin directly regulates MuRF1 and atrogin-1, which promote the loss of muscle mass in response to denervation, revealing a mechanistic basis for neurogenic muscle atrophy and a previously unrecognized function for myogenin in this pathological process.	8	16	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myogenin	myogenin	myogenin	atrogin-1	atrogin-1	atrogin-1	8	9	13	14
Taken together , these data are consistent with the idea that Myog mediates its effects on muscle atrophy by directly regulating Atrogin-1 promoter activity .	Taken together, these data are consistent with the idea that Myog mediates its effects on muscle atrophy by directly regulating Atrogin-1 promoter activity.	11	23	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Myog	Myog	Myog	Atrogin-1	Atrogin-1	Atrogin-1	11	12	21	22
Indeed Myog over-expression in innervated muscle stimulates Atrogin-1 gene expression and Myog over-expression stimulates Atrogin-1 promoter activity .	Indeed Myog over-expression in innervated muscle stimulates Atrogin-1 gene expression and Myog over-expression stimulates Atrogin-1 promoter activity.	11	16	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Myog	Myog over-expression	myog	Atrogin-1	Atrogin-1	atrogin-1	11	12	14	15
As an alternate mechanism , we assessed the HDAC4-myogenin axis , as deletion of either HDAC4 or myogenin renders skeletal muscles resistant to neurogenic atrophy and prevents the up-regulation of MuRF1 and atrogin1 .	As an alternate mechanism, we assessed the HDAC4-myogenin axis, as deletion of either HDAC4 or myogenin renders skeletal muscles resistant to neurogenic atrophy and prevents the up-regulation of MuRF1 and atrogin1.	12	33	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	myogenin	myogenin	myogenin	atrogin1	atrogin1	atrogin1	17	18	32	33
Increased myogenin in turn upregulates the ubiquitin E3 ligases MuRF1 and atrogin1 , causing skeletal muscle atrophy [ XREF_BIBR ] .	Increased myogenin in turn upregulates the ubiquitin E3 ligases MuRF1 and atrogin1, causing skeletal muscle atrophy [XREF_BIBR].	0	12	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myogenin	myogenin	myogenin	atrogin1	atrogin1	atrogin1	1	2	11	12
These studies demonstrated that myogenin activates the expression of the E3 ubiquitin ligases atrogin-1 and MuRF1 , and that myogenin knockout mice fail to upregulate atrogin-1 and MuRF1 following denervation and are protected from atrophy .	These studies demonstrated that myogenin activates the expression of the E3 ubiquitin ligases atrogin-1 and MuRF1, and that myogenin knockout mice fail to upregulate atrogin-1 and MuRF1 following denervation and are protected from atrophy.	4	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myogenin	myogenin	myogenin	atrogin-1	atrogin-1	atrogin-1	4	5	13	14
These results suggest that Myog may directly activate the Atrogin-1 promoter .	These results suggest that Myog may directly activate the Atrogin-1 promoter.	4	10	directly activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Myog	Myog	Myog	Atrogin-1	Atrogin-1	Atrogin-1	4	5	9	10
In addition , MyoD and MyoG , two main regulators of skeletal muscle development , were downregulated in these mutants , implying the potential negative regulation of FBXO32 on myogenesis factors ; however , normal levels of Myf5 may explain the presence of myogenesis in mutants .	In addition, MyoD and MyoG, two main regulators of skeletal muscle development, were downregulated in these mutants, implying the potential negative regulation of FBXO32 on myogenesis factors; however, normal levels of Myf5 may explain the presence of myogenesis in mutants.	3	28	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	MyoG	MyoG	MyoG	FBXO32	FBXO32	FBXO32	5	6	27	28
Furthermore , myogenin , but not MyoD , increases MAFbx and MuRF1 mRNA when expressed in myoblasts XREF_BIBR , which partially accords with the increased expression of atrogenes in the current study .	Furthermore, myogenin, but not MyoD, increases MAFbx and MuRF1 mRNA when expressed in myoblasts XREF_BIBR, which partially accords with the increased expression of atrogenes in the current study.	2	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	myogenin	myogenin	myogenin	MAFbx	MAFbx	MAFbx	2	3	9	10
XREF_BIBR - XREF_BIBR Active mTOR signaling promotes receptor dissociation and protein degradation of IRS-1 , an effect mitigated by inhibition of mTORC1 .	XREF_BIBR - XREF_BIBR Active mTOR signaling promotes receptor dissociation and protein degradation of IRS-1, an effect mitigated by inhibition of mTORC1.	4	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	4	5	13	14
mTOR activation causes the downregulation of IRS1 and other signaling intermediates and inhibition of the HER and IGF1-R and Insulin receptor tyrosine kinases as well .	mTOR activation causes the downregulation of IRS1 and other signaling intermediates and inhibition of the HER and IGF1-R and Insulin receptor tyrosine kinases as well.	0	10	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	IRS1	IRS1	IRS1	0	1	6	7
and Tzatsos & Kandror suggest that the PI3K/Akt/mammalian target of rapamycin ( mTOR ) pathway activates IRS1 degradation , while others reported that the activation of PI3K independent of mTOR signaling is required for IRS1 degradation .	and Tzatsos & Kandror suggest that the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway activates IRS1 degradation, while others reported that the activation of PI3K independent of mTOR signaling is required for IRS1 degradation.	10	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	IRS1	IRS1	IRS1	12	13	16	17
These data indicate that the compensatory increase in P-Akt expression seen in AICAR treated ALL cells results from both activation of IRS-1 by AMPK , and inhibition of the mTOR mediated feedback loop inhibition of IRS-1 activity .	These data indicate that the compensatory increase in P-Akt expression seen in AICAR treated ALL cells results from both activation of IRS-1 by AMPK, and inhibition of the mTOR mediated feedback loop inhibition of IRS-1 activity.	26	36	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	29	30	35	36
PDK1 , mTOR , and MAPK inhibitors did not block insulin induced reduction of IRS-1 , suggesting that the PI3K serine kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation .	PDK1, mTOR, and MAPK inhibitors did not block insulin induced reduction of IRS-1, suggesting that the PI3K serine kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation.	0	15	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	2	3	14	15
Its principal mechanism of action is thought to be activation of AMP activated protein kinase ( AMPK ) , which inactivates the mTOR and p70S6K mediated negative feedback loop to insulin receptor substrate-1 , thus enhancing insulin signaling 18 .	Its principal mechanism of action is thought to be activation of AMP activated protein kinase (AMPK), which inactivates the mTOR and p70S6K mediated negative feedback loop to insulin receptor substrate-1, thus enhancing insulin signaling 18.	21	33	mediated	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	22	23	30	33
Functional studies showed that mTOR inhibition suppressed both IRS-1 and S6K activity , leading in turn to the reciprocal activation of AKT , a finding confirmed both in vitro and in clinical studies of glioblastoma [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] ( XREF_FIG ) .	Functional studies showed that mTOR inhibition suppressed both IRS-1 and S6K activity, leading in turn to the reciprocal activation of AKT, a finding confirmed both in vitro and in clinical studies of glioblastoma [XREF_BIBR, XREF_BIBR, XREF_BIBR] (XREF_FIG).	4	11	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	4	5	8	9
26 The first hypothesis postulates that permanent activation of the mammalian target of rapamycin complex 1 and serine kinases pathway mediated by BCAA inactivates insulin receptor substrate-1 and insulin receptor substrate-2 , and stimulates pancreatic beta cells to enhance insulin secretion resulting in hyperinsulinemia , beta cell exhaustion and thus risk to develop T2DM .	26 The first hypothesis postulates that permanent activation of the mammalian target of rapamycin complex 1 and serine kinases pathway mediated by BCAA inactivates insulin receptor substrate-1 and insulin receptor substrate-2, and stimulates pancreatic beta cells to enhance insulin secretion resulting in hyperinsulinemia, beta cell exhaustion and thus risk to develop T2DM.	10	27	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	10	14	24	27
By amplifying insulin action downstream of PI3K , leptin exerts negative feedback on insulin signaling via mTOR dependent pathways that target IRS-1 for serine phosphorylation and protein degradation .	By amplifying insulin action downstream of PI3K, leptin exerts negative feedback on insulin signaling via mTOR dependent pathways that target IRS-1 for serine phosphorylation and protein degradation.	16	27	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	IRS-1	IRS-1	IRS-1	16	17	21	22
Mammalian target of rapamycin and ERK have been reported to negatively regulate IRS-1 via their downstream mediator p70S6K , providing a negative feedback mechanism for turning off activation of AKT .	Mammalian target of rapamycin and ERK have been reported to negatively regulate IRS-1 via their downstream mediator p70S6K, providing a negative feedback mechanism for turning off activation of AKT.	0	19	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	IRS-1	IRS-1	IRS-1	0	4	12	13
Since mTOR inhibits DEPTOR expression , we determined if mTOR inactivation by glucose deprivation would cause DEPTOR accumulation and autophagy induction .	Since mTOR inhibits DEPTOR expression, we determined if mTOR inactivation by glucose deprivation would cause DEPTOR accumulation and autophagy induction.	9	17	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	DEPTOR	DEPTOR	DEPTOR	9	10	16	17
Inhibition of the mTOR signaling pathway blocks DEPTOR destruction .	Inhibition of the mTOR signaling pathway blocks DEPTOR destruction.	3	8	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	DEPTOR	DEPTOR	DEPTOR	3	4	7	8
XREF_BIBR , XREF_BIBR mTOR complex 2 ( mTORC2 ) comprises mTOR , rapamycin insensitive companion of mTOR ( Rictor ) , stress activated protein kinase interacting protein 1 ( mSIN1 ) , Protor , GbetaL , Deptor , and mLST8 ( XREF_FIG ) .	XREF_BIBR, XREF_BIBR mTOR complex 2 (mTORC2) comprises mTOR, rapamycin insensitive companion of mTOR (Rictor), stress activated protein kinase interacting protein 1 (mSIN1), Protor, GbetaL, Deptor, and mLST8 (XREF_FIG).	10	37	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	Deptor	Deptor	Deptor	10	11	36	37
On the other hand , consistent with a previous report , inhibition of the PI3K and mTOR pathway with either LY294002 or rapamycin blocked DEPTOR destruction to an extent equivalent to that observed with MG132 .	On the other hand, consistent with a previous report, inhibition of the PI3K and mTOR pathway with either LY294002 or rapamycin blocked DEPTOR destruction to an extent equivalent to that observed with MG132.	14	25	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	DEPTOR	DEPTOR	DEPTOR	16	17	24	25
In the PC12 cells , the expression level of DEPTOR was reduced by 40 % after 6 hours treatment of NGF ( XREF_FIG ) , consistent with degradation of DEPTOR caused by mTOR activation .	In the PC12 cells, the expression level of DEPTOR was reduced by 40% after 6 hours treatment of NGF (XREF_FIG), consistent with degradation of DEPTOR caused by mTOR activation.	27	33	caused	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	DEPTOR	DEPTOR	DEPTOR	32	33	29	30
Similarly , inhibition of mTOR by PP242 efficiently blocked DEPTOR destruction , which supports a model that both mTORC1 and mTORC2 are involved in this process ( XREF_FIG ) .	Similarly, inhibition of mTOR by PP242 efficiently blocked DEPTOR destruction, which supports a model that both mTORC1 and mTORC2 are involved in this process (XREF_FIG).	2	10	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	DEPTOR	DEPTOR	DEPTOR	4	5	9	10
mTOR drives its own activation via SCF beta-TRCP -dependent degradation of the mTOR inhibitor DEPTOR .	mTOR drives its own activation via SCF beta-TRCP -dependent degradation of the mTOR inhibitor DEPTOR.	0	15	drives	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	mTOR	mTOR	mTOR	DEPTOR	DEPTOR	DEPTOR	0	1	14	15
These results support a model in which endogenous MIB1 promotes the turnover of full-length RYK through ubiquitination and degradation .	These results support a model in which endogenous MIB1 promotes the turnover of full-length RYK through ubiquitination and degradation.	7	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MIB1	MIB1	MIB1	RYK	RYK	RYK	8	9	14	15
We found that MIB1 overexpression activates Wnt and CTNNB1 signaling in an RYK dependent manner and that endogenous RYK and MIB1 were required for the Wnt dependent activation of Wnt and CTNNB1 signaling .	We found that MIB1 overexpression activates Wnt and CTNNB1 signaling in an RYK dependent manner and that endogenous RYK and MIB1 were required for the Wnt dependent activation of Wnt and CTNNB1 signaling.	3	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MIB1	MIB1 overexpression	mib1	RYK	RYK	ryk	3	4	12	13
We next investigated whether MIB1 could enhance the conjugation of endogenous ubiquitin to RYK .	We next investigated whether MIB1 could enhance the conjugation of endogenous ubiquitin to RYK.	4	14	enhance	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	MIB1	MIB1	MIB1	RYK	RYK	RYK	4	5	13	14
MIB1 promotes the turnover of RYK .	MIB1 promotes the turnover of RYK.	0	6	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MIB1	MIB1	MIB1	RYK	RYK	RYK	0	1	5	6
MIB1 activates Wnt and CTNNB1 signaling in an RYK dependent manner .	MIB1 activates Wnt and CTNNB1 signaling in an RYK dependent manner.	0	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MIB1	MIB1	MIB1	RYK	RYK	RYK	0	1	8	9
Thus , MIB1 can promote the turnover of full-length RYK but not the RYKICD .	Thus, MIB1 can promote the turnover of full-length RYK but not the RYKICD.	2	10	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	MIB1	MIB1	MIB1	RYK	RYK	RYK	2	3	9	10
In contrast , inhibition of mTOR by rapamycin blocks the interaction of Atg13 with ULK1 ( unc-51 like autophagy activating kinase 1 ) to activate the autophagy pathway XREF_BIBR , XREF_BIBR .	In contrast, inhibition of mTOR by rapamycin blocks the interaction of Atg13 with ULK1 (unc-51 like autophagy activating kinase 1) to activate the autophagy pathway XREF_BIBR, XREF_BIBR.	3	13	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	Atg13	Atg13	Atg13	5	6	12	13
In zebrafish , the two isoforms of MRAP2 , zMRAP2a and zMRAP2b , have opposite effects on MC4R signaling and here we demonstrate that mammalian MRAP2 , which had previously been shown to potentiate MC4R signaling , strongly inhibits PKR1 and PKR2 signaling .	In zebrafish, the two isoforms of MRAP2, zMRAP2a and zMRAP2b, have opposite effects on MC4R signaling and here we demonstrate that mammalian MRAP2, which had previously been shown to potentiate MC4R signaling, strongly inhibits PKR1 and PKR2 signaling.	24	38	potentiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MRAP2	MRAP2	MRAP2	MC4R	MC4R	MC4R	25	26	34	35
MRAP2 has previously been shown to potentiate MC4R signaling to promote leanness XREF_BIBR , XREF_BIBR and to inhibit the PKR1 12 , an anorexigenic GPCR expressed in POMC neurons 20 .	MRAP2 has previously been shown to potentiate MC4R signaling to promote leanness XREF_BIBR, XREF_BIBR and to inhibit the PKR1 12, an anorexigenic GPCR expressed in POMC neurons 20.	0	8	potentiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MRAP2	MRAP2	MRAP2	MC4R	MC4R	MC4R	0	1	7	8
Melanocortin 2 receptor accessory protein 2 ( MRAP2 ) modulates the function of MC4R .	Melanocortin 2 receptor accessory protein 2 (MRAP2) modulates the function of MC4R.	3	14	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MRAP2	MRAP2	MRAP2	MC4R	MC4R	MC4R	7	8	13	14
Initial MSI2 target analysis in the blood was focused on the negative regulator of Notch signaling , NUMB , as previous studies demonstrated that MSI1 can target NUMB mRNA and reduce its translation to potentiate the Notch pathway .	Initial MSI2 target analysis in the blood was focused on the negative regulator of Notch signaling, NUMB, as previous studies demonstrated that MSI1 can target NUMB mRNA and reduce its translation to potentiate the Notch pathway.	24	30	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MSI1	MSI1	MSI1	NUMB	NUMB	NUMB	24	25	27	28
Although Numb was markedly increased by Msi1 KD in A549 cells , intracellular Notch was below detection in both control and Msi1 KD cells , making the association between Numb and Notch inconclusive .	Although Numb was markedly increased by Msi1 KD in A549 cells, intracellular Notch was below detection in both control and Msi1 KD cells, making the association between Numb and Notch inconclusive.	1	7	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Msi1	Msi1	Msi1	Numb	Numb	Numb	6	7	1	2
Therefore , lack of MSI1 expression will result in activation of NUMB and MAML1 under expression as the main regulator of NOTCH transcription machinery .	Therefore, lack of MSI1 expression will result in activation of NUMB and MAML1 under expression as the main regulator of NOTCH transcription machinery.	4	13	result in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	MSI1	MSI1 expression	msi1	NUMB	NUMB	numb	4	5	11	12
Myocardin is a coactivator of SRF and KLF4 can affect both myocardin and SRF .	Myocardin is a coactivator of SRF and KLF4 can affect both myocardin and SRF.	0	8	is a coactivator	Positive_activation_copula_1	Negative_activation	Positive_activation	Myocardin	Myocardin	Myocardin	KLF4	KLF4	KLF4	0	1	7	8
Myocardin significantly enhanced the promoter activity of KLF4 and KLF8 .	Myocardin significantly enhanced the promoter activity of KLF4 and KLF8.	0	9	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Myocardin	Myocardin	Myocardin	KLF4	KLF4	KLF4	0	1	7	8
Myocardin significantly stimulated the promoter activity of KLF4 ( XREF_FIG ) , and the co-transfection of KLF4 significantly enhanced the promoter activity of KLF8 ( XREF_FIG ) .	Myocardin significantly stimulated the promoter activity of KLF4 (XREF_FIG), and the co-transfection of KLF4 significantly enhanced the promoter activity of KLF8 (XREF_FIG).	0	9	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Myocardin	Myocardin	Myocardin	KLF4	KLF4	KLF4	0	1	7	8
In regards to immune mediated therapies that may be effective against neurodegenerative disorders such as Alzheimer ' s disease [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] , WISP1 can protect central nervous system microglial cells against Abeta toxicity by employing mTOR downstream pathways that modulate PRAS40 [ XREF_BIBR ] and TSC2 [ XREF_BIBR ] to increase mTOR activity [ XREF_BIBR ] .	In regards to immune mediated therapies that may be effective against neurodegenerative disorders such as Alzheimer 's disease [XREF_BIBR, XREF_BIBR - XREF_BIBR], WISP1 can protect central nervous system microglial cells against Abeta toxicity by employing mTOR downstream pathways that modulate PRAS40 [XREF_BIBR] and TSC2 [XREF_BIBR] to increase mTOR activity [XREF_BIBR].	40	47	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	PRAS40	PRAS40	PRAS40	40	41	45	46
Immune precipitation of mTOR followed by analysis by mass spectrometry allowed identification of the protein PRAS40 ( proline rich AKT and PKB substrate 40 kDa ) XREF_BIBR .	Immune precipitation of mTOR followed by analysis by mass spectrometry allowed identification of the protein PRAS40 (proline rich AKT and PKB substrate 40 kDa) XREF_BIBR.	1	26	allowed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	mTOR	mTOR	mTOR	PRAS40	PRAS40	PRAS40	3	4	15	16
Other studies suggest that Mest may act to attenuate Wnt signaling in 3T3-L1 cells by inhibiting the maturation and exit of LRP6 from the endoplasmic reticulum by controlling its glycosylated state [ XREF_BIBR ] .	Other studies suggest that Mest may act to attenuate Wnt signaling in 3T3-L1 cells by inhibiting the maturation and exit of LRP6 from the endoplasmic reticulum by controlling its glycosylated state [XREF_BIBR].	4	22	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Mest	Mest	Mest	LRP6	LRP6	LRP6	4	5	21	22
MRAP increased MC 2 receptor on the cell membrane and inhibited MC 4 receptor trafficking at the same concentrations .	MRAP increased MC 2 receptor on the cell membrane and inhibited MC 4 receptor trafficking at the same concentrations.	0	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	MRAP	MRAP	MRAP	MC 2	MC 2	MC 2	0	1	2	4
Cells overexpressing menin had normal telomerase activity , and tumors with homozygous MEN1 mutations showed no aberrations in telomere length , indicating that menin does not directly regulate telomerase activity .	Cells overexpressing menin had normal telomerase activity, and tumors with homozygous MEN1 mutations showed no aberrations in telomere length, indicating that menin does not directly regulate telomerase activity.	23	29	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	menin	menin	menin	telomerase	telomerase	telomerase	23	24	28	29
These data demonstrate that Msx1 and Msx2 are direct transcriptional targets of Lhx2 .	These data demonstrate that Msx1 and Msx2 are direct transcriptional targets of Lhx2.	4	13	are direct transcriptional targets	Positive_activation_copula_1	Negative_activation	Positive_activation	Msx1	Msx1	Msx1	Lhx2	Lhx2	Lhx2	4	5	12	13
In our study , smad3 promoted HCC cells apoptosis by induction of p21 and repression of c-myc and bcl2 with the treatment of cisplatin .	In our study, smad3 promoted HCC cells apoptosis by induction of p21 and repression of c-myc and bcl2 with the treatment of cisplatin.	4	18	promoted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	c-myc	c-myc	c-myc	smad3	smad3	smad3	16	17	4	5
Ectopic HH signaling blocks the expression of Noggin , an inhibitor of the BMP ( bone morphogenic protein ) pathway , leading to increased BMP4 signaling and resulting in failed stratification of the columnar epithelium and a BE phenotype [ XREF_BIBR ] .	Ectopic HH signaling blocks the expression of Noggin, an inhibitor of the BMP (bone morphogenic protein) pathway, leading to increased BMP4 signaling and resulting in failed stratification of the columnar epithelium and a BE phenotype [XREF_BIBR].	7	27	leading to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	7	8	24	25
Third , we show that downregulation of BMP4 signalling by BMP antagonist Noggin , which is present at high levels in the AoV and especially in intra-aortic clusters as revealed here by in vivo observations , is required for HSC development .	Third, we show that downregulation of BMP4 signalling by BMP antagonist Noggin, which is present at high levels in the AoV and especially in intra-aortic clusters as revealed here by in vivo observations, is required for HSC development.	7	13	signalling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	12	13	7	8
We presented strong evidence in hESCs that NOGGIN is a direct target of BMP4 .	We presented strong evidence in hESCs that NOGGIN is a direct target of BMP4.	7	14	is a direct target	Positive_activation_copula_1	Negative_activation	Positive_activation	NOGGIN	NOGGIN	NOGGIN	BMP4	BMP4	BMP4	7	8	13	14
In the present study , we found that chemical activation of canonical Wnt signaling pathway by LiCl could synergize with Activin A mediated Nodal signaling pathway to promote induction of DE cells , and inhibition of Bmp4 signaling by Noggin along with Activin A/LiCl further improved the efficiency of DE cell differentiation .	In the present study, we found that chemical activation of canonical Wnt signaling pathway by LiCl could synergize with Activin A mediated Nodal signaling pathway to promote induction of DE cells, and inhibition of Bmp4 signaling by Noggin along with Activin A/LiCl further improved the efficiency of DE cell differentiation.	36	40	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	Bmp4	Bmp4	Bmp4	39	40	36	37
Consistently with NOGGIN being a direct transcriptional target of BMP4 , the NOGGIN in situ profiles matched the pSMAD1 profiles for both low and high BMP4 concentrations and were edge dominated at low concentrations and spatially homogeneous at high concentrations ( XREF_FIG ) .	Consistently with NOGGIN being a direct transcriptional target of BMP4, the NOGGIN in situ profiles matched the pSMAD1 profiles for both low and high BMP4 concentrations and were edge dominated at low concentrations and spatially homogeneous at high concentrations (XREF_FIG).	0	16	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	NOGGIN	NOGGIN	NOGGIN	BMP4	BMP4	BMP4	2	3	9	10
Ventral marginal zone explants ectopically expressing BMP-4 form less muscle when treated with soluble noggin protein or when juxtaposed to a normal Spemann organizer in comparison to control explants .	Ventral marginal zone explants ectopically expressing BMP-4 form less muscle when treated with soluble noggin protein or when juxtaposed to a normal Spemann organizer in comparison to control explants.	6	15	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	noggin	noggin	noggin	BMP-4	BMP-4	BMP-4	14	15	6	7
Noggin alone had no effect on LNCaP proliferation , but was able to completely block the inhibitory effects of BMP-4 and BMP-2 on LNCaP proliferation ( XREF_FIG ) .	Noggin alone had no effect on LNCaP proliferation, but was able to completely block the inhibitory effects of BMP-4 and BMP-2 on LNCaP proliferation (XREF_FIG).	0	21	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP-4	BMP-4	BMP-4	0	1	19	20
However , the question regarding how the inhibition of BMP4 signaling by noggin might induce an influx of Ca 2+ influx remains to be clarified .	However, the question regarding how the inhibition of BMP4 signaling by noggin might induce an influx of Ca 2+ influx remains to be clarified.	9	13	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	12	13	9	10
Noggin contributes to neural induction by antagonizing BMP4 .	Noggin contributes to neural induction by antagonizing BMP4.	0	8	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	0	1	7	8
The inhibition of BMP4 signaling by Noggin induces neural differentiation by activating the phosphatidylinositol 3-kinase/Akt signaling pathway and by increasing Pax6 expression .	The inhibition of BMP4 signaling by Noggin induces neural differentiation by activating the phosphatidylinositol 3-kinase/Akt signaling pathway and by increasing Pax6 expression.	3	7	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	6	7	3	4
Noggin increased BMP-4 transcripts , suggesting autocrine control of BMP-4 expression .	Noggin increased BMP-4 transcripts, suggesting autocrine control of BMP-4 expression.	0	3	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP-4	BMP-4	BMP-4	0	1	2	3
We also found that Noggin triggered Bmp4 endocytosis at concentrations that exceeded stoichiometric equivalence with Bmp4 ( XREF_FIG ) .	We also found that Noggin triggered Bmp4 endocytosis at concentrations that exceeded stoichiometric equivalence with Bmp4 (XREF_FIG).	4	7	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	Bmp4	Bmp4	Bmp4	4	5	6	7
We conducted further studies to determine whether Noggin also targets Bmp4 for the lysosome and whether Bmper has this effect on Chordin ( XREF_FIG ) .	We conducted further studies to determine whether Noggin also targets Bmp4 for the lysosome and whether Bmper has this effect on Chordin (XREF_FIG).	7	13	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	Bmp4	Bmp4	Bmp4	7	8	10	11
These data demonstrate that during NI of hESCs , noggin was able to antagonize the inhibitory effect of exogenous BMP4 .	These data demonstrate that during NI of hESCs, noggin was able to antagonize the inhibitory effect of exogenous BMP4.	9	20	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	9	10	19	20
Furthermore , Noggin ( a BMP inhibitor ) was able to reverse the negative effects of BMP4 with respect to both CYP17A1 transcription and DHEA secretion in the H295R cell line .	Furthermore, Noggin (a BMP inhibitor) was able to reverse the negative effects of BMP4 with respect to both CYP17A1 transcription and DHEA secretion in the H295R cell line.	2	17	reverse	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	2	3	16	17
This suggests that modulation of BMP4 signaling by noggin is essential for hair growth phase induction in postnatal skin and that the hair growth inducing effect of noggin is mediated , at least in part , by Shh .	This suggests that modulation of BMP4 signaling by noggin is essential for hair growth phase induction in postnatal skin and that the hair growth inducing effect of noggin is mediated, at least in part, by Shh.	5	9	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	8	9	5	6
The BMP4 inhibitor noggin blocked the BMP4 induced phenotype , and decreased autocrine BMP4 mediated OvCa cell motility and adherence .	The BMP4 inhibitor noggin blocked the BMP4 induced phenotype, and decreased autocrine BMP4 mediated OvCa cell motility and adherence.	0	14	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	3	4	13	14
This cascade is deemed necessary for this as disruption of BMP4 signaling by noggin blocks the preadipocyte phenotype .	This cascade is deemed necessary for this as disruption of BMP4 signaling by noggin blocks the preadipocyte phenotype.	10	14	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	13	14	10	11
Impaired endothelium dependent relaxations , exaggerated endothelium dependent contractions , and reactive oxygen species ( ROS ) production were observed in BMP4 treated mouse aortae , which were prevented by the BMP4 antagonist noggin .	Impaired endothelium dependent relaxations, exaggerated endothelium dependent contractions, and reactive oxygen species (ROS) production were observed in BMP4 treated mouse aortae, which were prevented by the BMP4 antagonist noggin.	28	34	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	noggin	noggin	noggin	BMP4	BMP4	BMP4	33	34	31	32
Interestingly , the BMP4 antagonist Noggin was unaffected in our study at all-time points , suggesting a Noggin independent modulation of BMP4 .	Interestingly, the BMP4 antagonist Noggin was unaffected in our study at all-time points, suggesting a Noggin independent modulation of BMP4.	2	15	antagonist	Negative_activation_token_1_noun	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	5	6	3	4
The chemical activation of the canonical Wnt signaling pathway synergized with the activin A mediated nodal signaling pathway to promote the induction of DE cells , and inhibition of BMP4 signaling by Noggin and activin A further improved the efficiency of DE cell differentiation .	The chemical activation of the canonical Wnt signaling pathway synergized with the activin A mediated nodal signaling pathway to promote the induction of DE cells, and inhibition of BMP4 signaling by Noggin and activin A further improved the efficiency of DE cell differentiation.	29	33	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP4	BMP4	BMP4	32	33	29	30
In this pathway , the inhibitor of kappaB ( IkappaBalpha ) sequesters the p65 : p50 heterodimer in an inactive state in the cytoplasm .	In this pathway, the inhibitor of kappaB (IkappaBalpha) sequesters the p65 : p50 heterodimer in an inactive state in the cytoplasm.	5	16	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	9	10	15	16
We demonstrate here that eight melanoma cell lines exhibit increased IkappaB kinase ( IKK ) activity , enhanced phosphorylation of IkappaBalpha and p65 , and enhanced nuclear localization of p65 and p50 in comparison to normal human epidermal melanocytes .	We demonstrate here that eight melanoma cell lines exhibit increased IkappaB kinase (IKK) activity, enhanced phosphorylation of IkappaBalpha and p65, and enhanced nuclear localization of p65 and p50 in comparison to normal human epidermal melanocytes.	10	32	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaBalpha	IkappaB kinase (IKK) activity, enhanced phosphorylation of IkappaBalpha	ikappabalpha	p50	p50	p50	20	21	31	32
POP1 is reported to inhibit cytosolic IKKalpha and beta upstream of IkBalpha phosphorylation , thus preventing nuclear translocation of p50 : p65 heterodimers in epithelial cells .	POP1 is reported to inhibit cytosolic IKKalpha and beta upstream of IkBalpha phosphorylation, thus preventing nuclear translocation of p50 : p65 heterodimers in epithelial cells.	0	20	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkBalpha	POP1 is reported to inhibit cytosolic IKKalpha and beta upstream of IkBalpha phosphorylation	ikbalpha	p50	p50	p50	11	12	19	20
IkappaBalpha is known to bind to NF-kappaB and block the nuclear localization signal , causing retention of the NF and kappaB dimer ( p50 and p65 ) in the cytoplasm .	IkappaBalpha is known to bind to NF-kappaB and block the nuclear localization signal, causing retention of the NF and kappaB dimer (p50 and p65) in the cytoplasm.	0	25	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	0	1	23	24
TLR2 ligation also induces IkappaBalpha phosphorylation and degradation , a process that allows the canonical NFkappaB p50 and p65 transcription factor to translocate to the nucleus and drive inflammatory responses [ XREF_BIBR , XREF_BIBR ] .	TLR2 ligation also induces IkappaBalpha phosphorylation and degradation, a process that allows the canonical NFkappaB p50 and p65 transcription factor to translocate to the nucleus and drive inflammatory responses [XREF_BIBR, XREF_BIBR].	0	17	allows	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	IkappaBalpha	TLR2 ligation also induces IkappaBalpha phosphorylation	ikappabalpha	NFkappaB p50	NFkappaB p50	nfkappab p50	4	5	15	17
NFKBIA ( nuclear factor of kappa light chain gene enhancer in B-cells inhibitor , alpha ) inhibits apoptosis by inhibiting apoptosis activator NFKB1 ( nuclear factor of kappa light chain gene enhancer in B-cells 1 , p105 ) .	NFKBIA (nuclear factor of kappa light chain gene enhancer in B-cells inhibitor, alpha) inhibits apoptosis by inhibiting apoptosis activator NFKB1 (nuclear factor of kappa light chain gene enhancer in B-cells 1, p105).	0	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NFKBIA	NFKBIA	NFKBIA	NFKB1	NFKB1	NFKB1	0	1	22	23
In addition , the NFKB pathway , which is typically activated by NFKBIA release from the inactive complex via IKK mediated NFKBIA phosphorylation , transcriptionally controls a large set of target genes and is frequently activated in many kinds of cancers , including HCC .	In addition, the NFKB pathway, which is typically activated by NFKBIA release from the inactive complex via IKK mediated NFKBIA phosphorylation, transcriptionally controls a large set of target genes and is frequently activated in many kinds of cancers, including HCC.	4	13	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	NFKBIA	NFKBIA	NFKBIA	NFKB	NFKB	NFKB	12	13	4	5
Phosphorylation of the IkappaBalpha subunit of the NF and kappaB complex by IKK leads to proteasomal degradation , allowing nuclear translocation of the p50 and p65 subunits .	Phosphorylation of the IkappaBalpha subunit of the NF and kappaB complex by IKK leads to proteasomal degradation, allowing nuclear translocation of the p50 and p65 subunits.	0	26	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaBalpha	Phosphorylation of the IkappaBalpha	ikappabalpha	p50	p50	p50	3	4	23	24
Absence of IkappaBalpha feedback , however , did not promote RelB : p50 activity at 8h in IkappaBalpha deficient MEFs ( XREF_FIG ) indicating that additional mechanisms potentiate this late activity .	Absence of IkappaBalpha feedback, however, did not promote RelB : p50 activity at 8h in IkappaBalpha deficient MEFs (XREF_FIG) indicating that additional mechanisms potentiate this late activity.	2	13	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	2	3	12	13
We further demonstrated that the survival promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT , which facilitated MDM2 mediated TP53 degradation , and NFKBIA- and IKK mediated transcriptional activity of NFKB in HCC cells .	We further demonstrated that the survival promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2 mediated TP53 degradation, and NFKBIA- and IKK mediated transcriptional activity of NFKB in HCC cells.	32	40	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NFKBIA-	NFKBIA-	NFKBIA-	NFKB	NFKB	NFKB	32	33	39	40
Furthermore , STAT3 elements mediate some effects of NFKB , a transcription factor whose functional activity is most likely perturbed by the upregulation in NFKB modulators NFKBI and NFKBIZ ( XREF_TABLE ) .	Furthermore, STAT3 elements mediate some effects of NFKB, a transcription factor whose functional activity is most likely perturbed by the upregulation in NFKB modulators NFKBI and NFKBIZ (XREF_TABLE).	19	30	modulators	Positive_activation_token_1_noun	Negative_activation	Positive_activation	NFKBI	NFKBI	NFKBI	NFKB	NFKB	NFKB	26	27	24	25
The activation of IKKbeta leads to the phosphorylation and subsequent degradation of the inhibitor of NF-kappaB , IkappaBalpha , which enables the NF-kappaB proteins p50 and p65 to translocate to the nucleus and induce anti-apoptosis and inflammatory responses .	The activation of IKKbeta leads to the phosphorylation and subsequent degradation of the inhibitor of NF-kappaB, IkappaBalpha, which enables the NF-kappaB proteins p50 and p65 to translocate to the nucleus and induce anti-apoptosis and inflammatory responses.	15	33	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	p50	p50	p50	17	18	24	25
TNF is known to induce rapid activation of NF-kappaB by inducing a phosphorylation dependent ubiquitination and proteasomal degradation of IkappaBalpha , which otherwise sequesters p50 : p65 heterodimers from transcriptional activity .	TNF is known to induce rapid activation of NF-kappaB by inducing a phosphorylation dependent ubiquitination and proteasomal degradation of IkappaBalpha, which otherwise sequesters p50 : p65 heterodimers from transcriptional activity.	0	25	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	IkappaBalpha	TNF is known to induce rapid activation of NF-kappaB by inducing a phosphorylation dependent ubiquitination and proteasomal degradation of IkappaBalpha	ikappabalpha	p50	p50	p50	19	20	24	25
The phosphorylation of IkappaBalpha promotes the activation and translocation of the nuclear factor-kappaB ( NF-kappaB ) subunits p65 and p50 to the nucleus .	The phosphorylation of IkappaBalpha promotes the activation and translocation of the nuclear factor-kappaB (NF-kappaB) subunits p65 and p50 to the nucleus.	1	22	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaBalpha	phosphorylation of IkappaBalpha	ikappabalpha	p50	p50	p50	3	4	19	20
This PPAR and IkappaBalpha SUMOylation leads to NF-KB activation and to an uncontrolled inflammatory response .	This PPAR and IkappaBalpha SUMOylation leads to NF-KB activation and to an uncontrolled inflammatory response.	1	8	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	IkappaBalpha	IkappaBalpha SUMOylation	ikappabalpha	NF-KB	NF-KB	nf-kb	3	4	7	8
NF-kappaB signaling consists of two distinct pathways : the canonical NF-kappaB pathway that is indicated by the degradation of the NF-kappaB inhibitor IkappaBalpha that allows the transcriptional factors NF-kappaB1 ( RelA ) and p50 to enter into nucleus .	NF-kappaB signaling consists of two distinct pathways : the canonical NF-kappaB pathway that is indicated by the degradation of the NF-kappaB inhibitor IkappaBalpha that allows the transcriptional factors NF-kappaB1 (RelA) and p50 to enter into nucleus.	17	33	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaBalpha	IkappaBalpha	IkappaBalpha	NF-kappaB1	NF-kappaB1	NF-kappaB1	22	23	28	29
We next determined whether LT induced IkappaBalpha phosphorylation was sufficient to induce the nuclear translocation of the NF-kappaB p50 and p65 subunits during ETEC infection .	We next determined whether LT induced IkappaBalpha phosphorylation was sufficient to induce the nuclear translocation of the NF-kappaB p50 and p65 subunits during ETEC infection.	4	19	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IkappaBalpha	LT induced IkappaBalpha phosphorylation	ikappabalpha	NF-kappaB p50	NF-kappaB p50	nf-kappab p50	6	7	17	19
Gene silencing of noggin by small interfering RNA ( siRNA ) is a promising approach for the treatment of bone defects , because noggin deactivates bone morphogenetic protein-2 ( BMP-2 ) and suppresses osteogenic differentiation .	Gene silencing of noggin by small interfering RNA (siRNA) is a promising approach for the treatment of bone defects, because noggin deactivates bone morphogenetic protein-2 (BMP-2) and suppresses osteogenic differentiation.	23	32	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	noggin	noggin	noggin	bone morphogenetic protein-2	bone morphogenetic protein-2	bone morphogenetic protein-2	23	24	25	28
This suggestion was confirmed by strong inhibition of the KM11073 mediated enhancement of ALP induction in the presence of BMP-2 by noggin post-treatment .	This suggestion was confirmed by strong inhibition of the KM11073 mediated enhancement of ALP induction in the presence of BMP-2 by noggin post-treatment.	10	22	mediated	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	21	22	19	20
By antagonizing BMP2 , Noggin accelerates the proliferation of gastric cancer cells [ XREF_BIBR ] .	By antagonizing BMP2, Noggin accelerates the proliferation of gastric cancer cells [XREF_BIBR].	1	6	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	4	5	2	3
Although Noggin and Gremlin increased BMP2 uptake , Chordin blocked BMP2 uptake , which was concentration dependent in both cases .	Although Noggin and Gremlin increased BMP2 uptake, Chordin blocked BMP2 uptake, which was concentration dependent in both cases.	1	6	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	1	2	5	6
BMP2 , 4 , or 7 were able to reverse the inhibition caused by noggin .	BMP2, 4, or 7 were able to reverse the inhibition caused by noggin.	0	15	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	noggin	noggin	noggin	BMP2	BMP2	BMP2	14	15	0	1
We next evaluated M-CSF production in C2C12 cells undergoing BMP2 and Wnt3a and BMP2 signaling further modulated by Noggin and Dkk1 .	We next evaluated M-CSF production in C2C12 cells undergoing BMP2 and Wnt3a and BMP2 signaling further modulated by Noggin and Dkk1.	13	20	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	18	19	13	14
Finally , to determine whether inhibition of BMP2 action is involved in modulating BMP2 action , cells were treated with exogenous Noggin in addition to blocking the effects of BMP inhibitors using specific antibodies .	Finally, to determine whether inhibition of BMP2 action is involved in modulating BMP2 action, cells were treated with exogenous Noggin in addition to blocking the effects of BMP inhibitors using specific antibodies.	7	22	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	21	22	7	8
Interestingly , cotreatment with the physiological BMP inhibitor Noggin increased BMP2 uptake and transfer , albeit activation of Smad signaling in neighboring cells was completely suppressed .	Interestingly, cotreatment with the physiological BMP inhibitor Noggin increased BMP2 uptake and transfer, albeit activation of Smad signaling in neighboring cells was completely suppressed.	2	11	increased	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Noggin	Noggin	Noggin	BMP2	BMP2	BMP2	8	9	10	11
In this study , however , we also used the scaffold to simultaneously deliver noggin directed shRNA and BMP-2 .	In this study, however, we also used the scaffold to simultaneously deliver noggin directed shRNA and BMP-2.	13	19	directed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	14	15	18	19
These results suggest that in HMSC , the anabolic action of inflammation on bone formation occurs through the induction of noggin , which then induces BMP-2 receptor and BMP-2 leading to the activation of the differentiation process .	These results suggest that in HMSC, the anabolic action of inflammation on bone formation occurs through the induction of noggin, which then induces BMP-2 receptor and BMP-2 leading to the activation of the differentiation process.	18	26	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	noggin	noggin	noggin	BMP-2	BMP-2	BMP-2	20	21	25	26
Activation of c-Abl by Nck SH3 domains provides a robust experimental system for analyzing the mechanisms that normally repress Abl activity and how that normal regulation can be perturbed .	Activation of c-Abl by Nck SH3 domains provides a robust experimental system for analyzing the mechanisms that normally repress Abl activity and how that normal regulation can be perturbed.	0	6	Activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Nck	Nck	Nck	c-Abl	c-Abl	c-Abl	4	5	2	3
Of note , Nck directly binds to and promotes Abl activation and signaling [ XREF_BIBR , XREF_BIBR ] , and associates with p60 v-src in vitro [ XREF_BIBR ] .	Of note, Nck directly binds to and promotes Abl activation and signaling [XREF_BIBR, XREF_BIBR], and associates with p60 v-src in vitro [XREF_BIBR].	3	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Nck	Nck	Nck	Abl	Abl	Abl	3	4	9	10
Since Nck has multiple SH3 domains that interact with both c-Abl and N-WASP , it is tempting to speculate that Nck may enable c-Abl to phosphorylate N-WASP more efficiently by physically tethering the two proteins .	Since Nck has multiple SH3 domains that interact with both c-Abl and N-WASP, it is tempting to speculate that Nck may enable c-Abl to phosphorylate N-WASP more efficiently by physically tethering the two proteins.	20	24	enable	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Nck	Nck	Nck	c-Abl	c-Abl	c-Abl	20	21	23	24
An unmyristoylated Nck SH3 domain construct , which localizes to the cytosol and nucleus , also activated Abl but only at high levels of expression .	An unmyristoylated Nck SH3 domain construct, which localizes to the cytosol and nucleus, also activated Abl but only at high levels of expression.	2	18	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Nck	Nck	Nck	Abl	Abl	Abl	2	3	17	18
A myristoylated Nck SH3 domain construct , which is expected to localize to membranes , potently activated Abl when expressed at low levels .	A myristoylated Nck SH3 domain construct, which is expected to localize to membranes, potently activated Abl when expressed at low levels.	2	20	activated	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Nck	Nck	nck	Abl	Abl when expressed	abl	2	3	17	18
In contrast , a parallel literature has revealed loss of NCOR1 and NCOR2 and SMRT is associated with the ADT-RCaP phenotype and enhances AR transcriptional programs [ XREF_BIBR , XREF_BIBR ] .	In contrast, a parallel literature has revealed loss of NCOR1 and NCOR2 and SMRT is associated with the ADT-RCaP phenotype and enhances AR transcriptional programs [XREF_BIBR, XREF_BIBR].	14	25	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMRT	SMRT	SMRT	AR	AR	AR	14	15	23	24
In contrast , other studies have shown that down-regulated NCOR1 and NCOR2 and SMRT enhanced AR transcriptional programs in CaP [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In contrast, other studies have shown that down-regulated NCOR1 and NCOR2 and SMRT enhanced AR transcriptional programs in CaP [XREF_BIBR, XREF_BIBR, XREF_BIBR].	9	16	enhanced	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SMRT	SMRT	SMRT	AR	AR	AR	13	14	15	16
XREF_BIBR , XREF_BIBR However , the extent to which NCoR and SMRT recruitment contributes to the antagonist activity of bicalutamide is not clear , as bicalutamide still functions as an AR antagonist in cells treated with NCoR and SMRT small interfering RNA .	XREF_BIBR, XREF_BIBR However, the extent to which NCoR and SMRT recruitment contributes to the antagonist activity of bicalutamide is not clear, as bicalutamide still functions as an AR antagonist in cells treated with NCoR and SMRT small interfering RNA.	30	39	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	SMRT	SMRT	SMRT	AR	AR	AR	38	39	30	31
The androgen receptor ( AR ) activates target gene expression in the presence of agonist ligands via the recruitment of transcriptional coactivators , but recent work shows that overexpression of the nuclear corepressors NCoR and SMRT attenuates this agonist mediated AR activation .	The androgen receptor (AR) activates target gene expression in the presence of agonist ligands via the recruitment of transcriptional coactivators, but recent work shows that overexpression of the nuclear corepressors NCoR and SMRT attenuates this agonist mediated AR activation.	28	41	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMRT	overexpression of the nuclear corepressors NCoR and SMRT	smrt	AR	AR	ar	35	36	40	41
Overexpression of NCOR2 is demonstrated to activate the activity of the androgen receptor in a cell type specific context .	Overexpression of NCOR2 is demonstrated to activate the activity of the androgen receptor in a cell type specific context.	0	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NCOR2	Overexpression of NCOR2	ncor2	androgen receptor	androgen receptor	androgen receptor	2	3	11	13
It is known that certain co-repressors such as NCoR and SMRT mediate PPARgamma transrepression of target genes , which is commonly ligand independent XREF_BIBR , XREF_BIBR .	It is known that certain co-repressors such as NCoR and SMRT mediate PPARgamma transrepression of target genes, which is commonly ligand independent XREF_BIBR, XREF_BIBR.	5	13	mediate	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SMRT	SMRT	SMRT	PPARgamma	PPARgamma	PPARgamma	10	11	12	13
Overall this phenotype suggests a role for SMRT in repression of PPARgamma signaling in adipose tissue as haploinsufficiency of SMRT enhances PPARgamma signaling .	Overall this phenotype suggests a role for SMRT in repression of PPARgamma signaling in adipose tissue as haploinsufficiency of SMRT enhances PPARgamma signaling.	17	22	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMRT	SMRT	SMRT	PPARgamma	PPARgamma	PPARgamma	19	20	21	22
While we confirmed that SMRT mRID MEFs had increased PPARgamma activity , their ability to handle oxidative stress was comparable to wt cells .	While we confirmed that SMRT mRID MEFs had increased PPARgamma activity, their ability to handle oxidative stress was comparable to wt cells.	4	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMRT	SMRT	SMRT	PPARgamma	PPARgamma	PPARgamma	4	5	9	10
Conversely , in dystrophic muscles a decrease of nNOS activity reduces HDAC2 S nytrosilation , increasing chromatin binding and determining the repression of target genes and microRNAs .	Conversely, in dystrophic muscles a decrease of nNOS activity reduces HDAC2 S nytrosilation, increasing chromatin binding and determining the repression of target genes and microRNAs.	8	13	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	nNOS	nNOS	nNOS	HDAC2	HDAC2	HDAC2	8	9	11	12
This is why nNOS repression also decreases neuronal ratio in LV-HDAC2 shRNA infected cultures .	This is why nNOS repression also decreases neuronal ratio in LV-HDAC2 shRNA infected cultures.	3	13	decreases	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	nNOS	nNOS	nNOS	LV-HDAC2	LV-HDAC2	LV-HDAC2	3	4	10	11
For example , in neuronal development , brain derived neurotrophic factor activates nNOS , which S-nitrosylates histone deacetylase 2 ( HDAC2 ; cysteines 262 and 274 ) , causing HDAC2 to dissociate from chromatin [ XREF_BIBR ] .	For example, in neuronal development, brain derived neurotrophic factor activates nNOS, which S-nitrosylates histone deacetylase 2 (HDAC2; cysteines 262 and 274), causing HDAC2 to dissociate from chromatin [XREF_BIBR].	12	30	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	nNOS	nNOS	nNOS	HDAC2	HDAC2	HDAC2	12	13	29	30
Future studies will determine whether direct interaction of GRK2 with p105 might block IKKbeta phosphorylation of p105 thus preventing p105 degradation and TPL2 release .	Future studies will determine whether direct interaction of GRK2 with p105 might block IKKbeta phosphorylation of p105 thus preventing p105 degradation and TPL2 release.	8	23	preventing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p105	GRK2 with p105 might block IKKbeta phosphorylation of p105	p105	TPL2	TPL2	tpl2	16	17	22	23
Activation of TPL-2 and ERK signaling by IKK induced p105 proteolysis , therefore , induced a negative feedback loop to downregulate NF-kappaB-dependent expression of the proinflammatory cytokine interleukin-12 ( IL-12 ) .	Activation of TPL-2 and ERK signaling by IKK induced p105 proteolysis, therefore, induced a negative feedback loop to downregulate NF-kappaB-dependent expression of the proinflammatory cytokine interleukin-12 (IL-12).	2	10	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	p105	IKK induced p105	p105	TPL-2	TPL-2	tpl-2	9	10	2	3
Thus , the inability of SMRT or NCoR to interact with agonist activated PR when assayed in vivo may relate more to the increased affinity of PR for coactivators , with a subsequent displacement of corepressors , than to an inherent low affinity for the corepressor proteins .	Thus, the inability of SMRT or NCoR to interact with agonist activated PR when assayed in vivo may relate more to the increased affinity of PR for coactivators, with a subsequent displacement of corepressors, than to an inherent low affinity for the corepressor proteins.	3	14	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMRT	SMRT	SMRT	PR	PR	PR	5	6	13	14
Estrogen independent cells were still estrogen responsive and PR , nuclear receptor corepressor ( N-CoR ) and SMRT expression was increased whereas steroid receptor coactivator-1 ( SRC-1a ) and CBP related protein p300 ( p300 ) expression decreased .	Estrogen independent cells were still estrogen responsive and PR, nuclear receptor corepressor (N-CoR) and SMRT expression was increased whereas steroid receptor coactivator-1 (SRC-1a) and CBP related protein p300 (p300) expression decreased.	5	21	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMRT	SMRT expression	smrt	PR	PR	pr	17	18	8	9
Recombinant neurofibromin GRD also stimulated the GTPase activity of yeast RAS2 and human H-Ras [ XREF_BIBR ] , thus functionally verifying this neurofibromin domain ' s ability to inactivate Ras .	Recombinant neurofibromin GRD also stimulated the GTPase activity of yeast RAS2 and human H-Ras [XREF_BIBR], thus functionally verifying this neurofibromin domain 's ability to inactivate Ras.	1	15	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	neurofibromin	neurofibromin	neurofibromin	H-Ras	H-Ras	H-Ras	1	2	13	14
Neurofibromin enhances the inactivation of protooncogene p21ras and has been suggested to function as a regulator of cell growth and differentiation .	Neurofibromin enhances the inactivation of protooncogene p21ras and has been suggested to function as a regulator of cell growth and differentiation.	0	12	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Neurofibromin	Neurofibromin	Neurofibromin	p21ras	p21ras	p21ras	0	1	6	7
The dominant function of adipocyte NCoR1 is to transrepress PPARgamma and promote PPARgamma ser 273 phosphorylation by recruiting cyclin dependent kinase 5 ( Cdk5 and CDK5 ) ; such that Ncor1 deletion leads to adipogenesis , reduced inflammation , and enhanced systemic insulin sensitivity [ XREF_BIBR ] .	The dominant function of adipocyte NCoR1 is to transrepress PPARgamma and promote PPARgamma ser 273 phosphorylation by recruiting cyclin dependent kinase 5 (Cdk5 and CDK5); such that Ncor1 deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity [XREF_BIBR].	2	13	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NCoR1	NCoR1	NCoR1	PPARgamma	PPARgamma	PPARgamma	5	6	12	13
Nevertheless , compromised hepatic AP1 function in L Delta1 ,2 mice ( XREF_SUPPLEMENTARY ) may contribute to decreased expression of Ncor1 and Nrip1 ( XREF_SUPPLEMENTARY ) , and indirectly increase PPARgamma pathway activity by reducing co-repressor expression .	Nevertheless, compromised hepatic AP1 function in L Delta1,2 mice (XREF_SUPPLEMENTARY) may contribute to decreased expression of Ncor1 and Nrip1 (XREF_SUPPLEMENTARY), and indirectly increase PPARgamma pathway activity by reducing co-repressor expression.	4	32	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ncor1	AP1 function in L Delta1,2 mice (XREF_SUPPLEMENTARY) may contribute to decreased expression of Ncor1	ncor1	PPARgamma	PPARgamma	ppargamma	20	21	30	31
Silencing NEK11 prevents ubiquitin dependent proteolysis of Cdc25A , in both unsynchronized and DNA damaged cells .	Silencing NEK11 prevents ubiquitin dependent proteolysis of Cdc25A, in both unsynchronized and DNA damaged cells.	0	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	NEK11	NEK11	NEK11	Cdc25A	Cdc25A	Cdc25A	1	2	7	8
Depletion of NEK11 prevents proteasome dependent degradation of CDC25A , both in unperturbed and DNA damaged cells .	Depletion of NEK11 prevents proteasome dependent degradation of CDC25A, both in unperturbed and DNA damaged cells.	0	9	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NEK11	NEK11	NEK11	CDC25A	CDC25A	CDC25A	2	3	8	9
Downregulation of ninein enhances JAK2 activation .	Downregulation of ninein enhances JAK2 activation.	0	5	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ninein	ninein	ninein	JAK2	JAK2	JAK2	2	3	4	5
Similar to the poly-ubiquitin modification of Smad3 induced by NEDD4L [ XREF_BIBR ] , interaction between Smurf2 and Smad3 as well as Smurf2 induced mono-ubiquitination of Smad3 requires phosphorylation of T179 and the adjacent PY motif ( PPGY ) in the linker region [ XREF_BIBR ] .	Similar to the poly-ubiquitin modification of Smad3 induced by NEDD4L [XREF_BIBR], interaction between Smurf2 and Smad3 as well as Smurf2 induced mono-ubiquitination of Smad3 requires phosphorylation of T179 and the adjacent PY motif (PPGY) in the linker region [XREF_BIBR].	4	11	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	NEDD4L	NEDD4L	NEDD4L	Smad3	Smad3	Smad3	9	10	6	7
In HEK293A cells transfected with luciferase reporter constructs , necdin relieves Bmi1 dependent repression of p16 promoter activity , whereas Bmi1 counteracts necdin mediated repression of E2F1 dependent Cdk1 promoter activity .	In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1 dependent repression of p16 promoter activity, whereas Bmi1 counteracts necdin mediated repression of E2F1 dependent Cdk1 promoter activity.	9	13	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	necdin	necdin	necdin	Bmi1	Bmi1	Bmi1	9	10	11	12
Since the regulation of Notch signaling by Numb is considered as a method to treat breast cancers [ XREF_BIBR , XREF_BIBR ] , future examination and utilization of Numb isoforms can contribute to the development of proper treatment for glioma and glioblastoma .	Since the regulation of Notch signaling by Numb is considered as a method to treat breast cancers [XREF_BIBR, XREF_BIBR], future examination and utilization of Numb isoforms can contribute to the development of proper treatment for glioma and glioblastoma.	4	8	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	7	8	4	5
Post-translational interactions such as Numb mediated degradation of membrane bound Notch or translational inhibition of Numb by RNA binding proteins such as Musashi1 could similarly act to inhibit or promote Notch signalling respectively [ XREF_BIBR ] .	Post-translational interactions such as Numb mediated degradation of membrane bound Notch or translational inhibition of Numb by RNA binding proteins such as Musashi1 could similarly act to inhibit or promote Notch signalling respectively [XREF_BIBR].	15	31	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	15	16	30	31
Brain vascular phenotypes have been reported in mice lacking Notch signaling mediators such as presenilin-1 9 and Numb .	Brain vascular phenotypes have been reported in mice lacking Notch signaling mediators such as presenilin-1 9 and Numb.	9	18	mediators	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	17	18	9	10
Downregulation of NUMB prevents inhibition of NOTCH signaling , therefore promoting cell growth and tumorigenesis .	Downregulation of NUMB prevents inhibition of NOTCH signaling, therefore promoting cell growth and tumorigenesis.	0	7	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	2	3	6	7
In mammalian cells , Numb promotes Notch targeting to late endosome compartments through the ubiquitin ligase Itch .	In mammalian cells, Numb promotes Notch targeting to late endosome compartments through the ubiquitin ligase Itch.	4	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	6	7
In contrast , Numb promoted the proliferation , migration , and invasion of squamous cell carcinoma cells , but did not induce any consistent changes in Notch signaling .	In contrast, Numb promoted the proliferation, migration, and invasion of squamous cell carcinoma cells, but did not induce any consistent changes in Notch signaling.	3	27	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	3	4	26	27
Notch signaling is mediated by the down-regulated expression of Numb , Tom , and sca , and the up-regulated expression of bun and Nedd4 ( XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY ) .	Notch signaling is mediated by the down-regulated expression of Numb, Tom, and sca, and the up-regulated expression of bun and Nedd4 (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).	0	14	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Numb	expression of Numb	numb	Notch	Notch	notch	9	10	0	1
Secretion of Wnt3a by Kupffer cells induces neighboring progenitor cells to express Numb , which then suppresses Notch transcriptional targets , including cholangiocyte associated genes .	Secretion of Wnt3a by Kupffer cells induces neighboring progenitor cells to express Numb, which then suppresses Notch transcriptional targets, including cholangiocyte associated genes.	11	19	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	12	13	17	18
Conversely , depletion of Numb and numblike abolishes this effect and increases Notch signaling activity .	Conversely, depletion of Numb and numblike abolishes this effect and increases Notch signaling activity.	2	14	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	12	13
This implies that low NUMB expression and high Notch1 expression in BLBC may be involved in a potential role for NUMB mediated control of Notch signaling in this subtype .	This implies that low NUMB expression and high Notch1 expression in BLBC may be involved in a potential role for NUMB mediated control of Notch signaling in this subtype.	20	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	20	21	24	25
Interestingly , asymmetrical intracellular localization of Numb was detected in dividing cardiomyocytes at day 1 ( XREF_FIG ) , which suggests that Numb mediated Notch down-regulation might participate in the loss of replicative potential and differentiation of ICMs .	Interestingly, asymmetrical intracellular localization of Numb was detected in dividing cardiomyocytes at day 1 (XREF_FIG), which suggests that Numb mediated Notch down-regulation might participate in the loss of replicative potential and differentiation of ICMs.	22	25	mediated	Positive_early_activation	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	22	23	24	25
Here , Numb promotes endocytosis of Notch in order to down-regulate signaling specifically in the pIIb daughter of the pI division [ XREF_BIBR ] .	Here, Numb promotes endocytosis of Notch in order to down-regulate signaling specifically in the pIIb daughter of the pI division [XREF_BIBR].	2	7	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	2	3	6	7
To further test whether NUMB inhibits tumor growth of TNBC by blocking the Notch pathway in vivo , mouse tumors derived from vector and NUMB expressing cells were analyzed using immunoblotting .	To further test whether NUMB inhibits tumor growth of TNBC by blocking the Notch pathway in vivo, mouse tumors derived from vector and NUMB expressing cells were analyzed using immunoblotting.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	4	5	13	14
Manipulation of Notch signaling by Numb or by Notch1-IC did not significantly impact definitive hematopoietic development ( XREF_FIG ) .	Manipulation of Notch signaling by Numb or by Notch1-IC did not significantly impact definitive hematopoietic development (XREF_FIG).	2	6	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	2	3
Numb and L ( 2 ) gl antagonize a pool of Notch receptors , and Numb promotes Notch targeting to late endosomes in Drosophila neural progenitors to regulate Notch signaling and cell fate .	Numb and L (2) gl antagonize a pool of Notch receptors, and Numb promotes Notch targeting to late endosomes in Drosophila neural progenitors to regulate Notch signaling and cell fate.	15	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	15	16	17	18
These findings have led to the hypothesis that Numb modulates Notch signaling by using endocytosis and proteasomes to directly reduce Notch protein levels at the cell surface .	These findings have led to the hypothesis that Numb modulates Notch signaling by using endocytosis and proteasomes to directly reduce Notch protein levels at the cell surface.	8	11	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	8	9	10	11
This implies that low NUMB expression and high Notch1 expression in TNBC may be involved in a potential role for NUMB mediated antagonism of Notch signaling in this subtype .	This implies that low NUMB expression and high Notch1 expression in TNBC may be involved in a potential role for NUMB mediated antagonism of Notch signaling in this subtype.	20	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	20	21	24	25
Gene regulation data for several organs and mammalian cell lines suggest that the best established targets of Msi-1 are Notch signaling regulators , such as Numb .	Gene regulation data for several organs and mammalian cell lines suggest that the best established targets of Msi-1 are Notch signaling regulators, such as Numb.	19	26	signaling regulators	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	25	26	19	20
The asymmetric cell fate determinant Numb is thought to promote differentiation of skeletal muscle and other lineages by negatively regulating Notch signaling .	The asymmetric cell fate determinant Numb is thought to promote differentiation of skeletal muscle and other lineages by negatively regulating Notch signaling.	0	21	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	5	6	20	21
This early and sustained upregulation of numb RNA in response to the absence of the queen raises the possibility that Numb may target the Notch receptor for degradation in the germaria of queen-less worker bees .	This early and sustained upregulation of numb RNA in response to the absence of the queen raises the possibility that Numb may target the Notch receptor for degradation in the germaria of queen-less worker bees.	20	25	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	20	21	24	25
This study was purposed to figure out the contribution of Numb induced Notch signaling to the development of diabetic nephropathy ( DN ) .	This study was purposed to figure out the contribution of Numb induced Notch signaling to the development of diabetic nephropathy (DN).	8	13	induced	Positive_early_activation	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	10	11	12	13
Down-regulation of endogenous Numb in cultured intestinal cells using RNA interference increased Notch signaling , resulting in the up-regulation of Hes1 XREF_BIBR .	Down-regulation of endogenous Numb in cultured intestinal cells using RNA interference increased Notch signaling, resulting in the up-regulation of Hes1 XREF_BIBR.	0	13	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	3	4	12	13
In agreement with this finding , knockdown of Numb and Numbl abrogated the ability of tethered Notch to lower active beta-Catenin protein levels ( XREF_FIG ) .	In agreement with this finding, knockdown of Numb and Numbl abrogated the ability of tethered Notch to lower active beta-Catenin protein levels (XREF_FIG).	6	17	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	8	9	16	17
Conversely , the protein Numb is thought to antagonize Notch signaling byincreasing Notch degradation through polyubiquitination .	Conversely, the protein Numb is thought to antagonize Notch signaling byincreasing Notch degradation through polyubiquitination.	2	13	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	4	5	12	13
In Drosophila , Numb promotes neuronal differentiation by antagonizing Notch signaling .	In Drosophila, Numb promotes neuronal differentiation by antagonizing Notch signaling.	3	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	3	4	9	10
Inhibition of only one NUMB family protein is sufficient to modify cancer cell properties , since a partial decrease in NUMB or NUMBL is sufficient to increase Notch pathway activation and cancer stem like properties .	Inhibition of only one NUMB family protein is sufficient to modify cancer cell properties, since a partial decrease in NUMB or NUMBL is sufficient to increase Notch pathway activation and cancer stem like properties.	18	29	increase	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	20	21	27	28
Subsequently , RBM5 and RBM10 exhibited differential influences on the radiosensitivity and proliferation of lung adenocarcinoma cells through NUMB mediated Notch signaling [ XREF_BIBR ] .	Subsequently, RBM5 and RBM10 exhibited differential influences on the radiosensitivity and proliferation of lung adenocarcinoma cells through NUMB mediated Notch signaling [XREF_BIBR].	5	21	mediated	Positive_early_activation	Negative_activation	Positive_activation	NUMB	NUMB	NUMB	Notch	Notch	Notch	18	19	20	21
Experiments were then designed to test whether the presence of Numb enhances miR-34a regulation of Notch as a cell fate switch .	Experiments were then designed to test whether the presence of Numb enhances miR-34a regulation of Notch as a cell fate switch.	8	16	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	10	11	15	16
In Drosophila , recent studies in SOP cells showed that Numb inhibits Notch and Sanpodo oligomer membrane targeting .	In Drosophila, recent studies in SOP cells showed that Numb inhibits Notch and Sanpodo oligomer membrane targeting.	10	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	10	11	12	13
Thus , inhibition of the Notch signaling by Numb is necessary but not sufficient to limit the GMC potential .	Thus, inhibition of the Notch signaling by Numb is necessary but not sufficient to limit the GMC potential.	5	9	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	8	9	5	6
In 50 % of human mammary carcinomas , the control of NOTCH signalling by NUMB is abrogated by ubiquitination and proteasomal degradation of NUMB .	In 50% of human mammary carcinomas, the control of NOTCH signalling by NUMB is abrogated by ubiquitination and proteasomal degradation of NUMB.	11	15	signalling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	NUMB	NUMB	NUMB	NOTCH	NOTCH	NOTCH	14	15	11	12
Thus , in principle , its inhibition could revert a possible increase in Notch activity caused by the loss of endogenous Notch inhibition by Numb and Numblike .	Thus, in principle, its inhibition could revert a possible increase in Notch activity caused by the loss of endogenous Notch inhibition by Numb and Numblike.	13	26	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	24	25	13	14
FACS similarly revealed that HSC express proteins that regulate Notch signaling , including the Notch ligand , Jagged-1 , Notch-1 and Notch-2 receptors , and Numb , a Notch signaling repressor ( XREF_FIG , XREF_SUPPLEMENTARY ) .	FACS similarly revealed that HSC express proteins that regulate Notch signaling, including the Notch ligand, Jagged-1, Notch-1 and Notch-2 receptors, and Numb, a Notch signaling repressor (XREF_FIG, XREF_SUPPLEMENTARY).	9	30	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	25	26	9	10
In fact , in the CK19-ve areas , the lower expression of Numb ( an endogenous inhibitor of Notch ) would , actually make hepatocytes more prone to Notch activation .	In fact, in the CK19-ve areas, the lower expression of Numb (an endogenous inhibitor of Notch) would, actually make hepatocytes more prone to Notch activation.	10	19	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Positive_activation	Numb	expression of Numb	numb	Notch	Notch	notch	12	13	18	19
Notch signaling is mediated by the down-regulated expression of Numb , Tom , and sca and the up-regulated expression of bun and Nedd4 ( XREF_SUPPLEMENTARY ) .	Notch signaling is mediated by the down-regulated expression of Numb, Tom, and sca and the up-regulated expression of bun and Nedd4 (XREF_SUPPLEMENTARY).	0	14	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Numb	expression of Numb	numb	Notch	Notch	notch	9	10	0	1
Nonetheless , it appears that the mechanism of Numb mediated asymmetric cell fate acquisition is a synapomorphy of Notch pathway activity in Bilateria .	Nonetheless, it appears that the mechanism of Numb mediated asymmetric cell fate acquisition is a synapomorphy of Notch pathway activity in Bilateria.	6	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	8	9	18	19
During neural stem cell division , asymmetric segregation of the cell fate determinant , Numb , into daughter cells is thought to promote neuronal differentiation by antagonizing Notch .	During neural stem cell division, asymmetric segregation of the cell fate determinant, Numb, into daughter cells is thought to promote neuronal differentiation by antagonizing Notch.	12	28	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	14	15	27	28
During asymmetric divisions of sensory organ precursor cells , Numb promotes endocytosis of the Notch receptor [ XREF_BIBR , XREF_BIBR ] .	During asymmetric divisions of sensory organ precursor cells, Numb promotes endocytosis of the Notch receptor [XREF_BIBR, XREF_BIBR].	9	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	9	10	14	15
Numb also increases endocytic trafficking of the Notch receptor [ XREF_BIBR ] .	Numb also increases endocytic trafficking of the Notch receptor [XREF_BIBR].	0	10	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	0	1	7	8
By contrast , attenuation of Notch signaling by Numb , a Notch inhibitor , results in the progression of myogenesis from myoblast proliferation to differentiation .	By contrast, attenuation of Notch signaling by Numb, a Notch inhibitor, results in the progression of myogenesis from myoblast proliferation to differentiation.	5	9	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	8	9	5	6
We then tested whether the presence of Numb enhances miR-34a regulation of Notch to be more bimodal as the computational analysis predicted .	We then tested whether the presence of Numb enhances miR-34a regulation of Notch to be more bimodal as the computational analysis predicted.	5	13	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Notch	Notch	Notch	7	8	12	13
Sanpodo , a four-pass transmembrane protein that interacts with Notch , promotes Notch receptor endocytosis , whereas Numb inhibits membrane targeting of Notch and Sanpodo in the pIIb cell .	Sanpodo, a four-pass transmembrane protein that interacts with Notch, promotes Notch receptor endocytosis, whereas Numb inhibits membrane targeting of Notch and Sanpodo in the pIIb cell.	17	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Numb	Numb	Numb	Notch	Notch	Notch	17	18	22	23
Short heterodimer partner ( SHP ) enhances the competitive ability of FTF .	Short heterodimer partner (SHP) enhances the competitive ability of FTF.	0	12	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Short heterodimer partner	Short heterodimer partner	Short heterodimer partner	FTF	FTF	FTF	0	3	11	12
Both phospholipids were able to induce activation of LRH-1 specific promoters such as Shp and Oct4 while closely related phospholipids such as dipalmitoyl PC ( DPPC ; C16 :0/C16 :0 ) did not .	Both phospholipids were able to induce activation of LRH-1 specific promoters such as Shp and Oct4 while closely related phospholipids such as dipalmitoyl PC (DPPC; C16 :0/C16 :0) did not.	8	15	promoters	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Shp	Shp	Shp	LRH-1	LRH-1	LRH-1	13	14	8	9
LRH-1 was induced by the SHP and the apoM mRNA levels were upregulated .	LRH-1 was induced by the SHP and the apoM mRNA levels were upregulated.	0	6	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	5	6	0	1
The nuclear receptor Small Heterodimer Partner ( SHP ) is a transcriptional target and inhibitor of Liver Receptor Homolog 1 ( LRH-1 ) , the transcriptional regulator of intestinal glucocorticoid ( GC ) synthesis .	The nuclear receptor Small Heterodimer Partner (SHP) is a transcriptional target and inhibitor of Liver Receptor Homolog 1 (LRH-1), the transcriptional regulator of intestinal glucocorticoid (GC) synthesis.	3	26	is a transcriptional target	Positive_activation_copula_1	Negative_activation	Positive_activation	Small Heterodimer Partner	Small Heterodimer Partner	Small Heterodimer Partner	LRH-1	LRH-1	LRH-1	3	6	21	22
Nr5a2 +/- pancreata displayed reduced Nr0b2 levels , lower occupancy of AP-1 promoters by Nr0b2 , reduced binding of Nr5a2 at the Nr0b2 promoter , and reduced complexing of Nr5a2 with Nr0b2 ( XREF_FIG ) , suggesting that Nr0b2 normally represses AP-1 expression .	Nr5a2 +/- pancreata displayed reduced Nr0b2 levels, lower occupancy of AP-1 promoters by Nr0b2, reduced binding of Nr5a2 at the Nr0b2 promoter, and reduced complexing of Nr5a2 with Nr0b2 (XREF_FIG), suggesting that Nr0b2 normally represses AP-1 expression.	5	30	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Nr0b2	Nr0b2 levels	nr0b2	Nr5a2	Nr5a2	nr5a2	5	6	29	30
Earlier in vitro studies had shown that SHP can repress luciferase reporter gene activity by binding to and inhibiting HNF4a and LRH-1 transcription factors that normally activate Cyp7a1 and/or Cyp8b1 .	Earlier in vitro studies had shown that SHP can repress luciferase reporter gene activity by binding to and inhibiting HNF4a and LRH-1 transcription factors that normally activate Cyp7a1 and/or Cyp8b1.	7	22	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	7	8	21	22
SHP siRNAs also drastically enhanced the ability of the LRH-1 agonist RJW100 to induce miR-200c and downregulate ZEB1 and ZEB2 proteins .	SHP siRNAs also drastically enhanced the ability of the LRH-1 agonist RJW100 to induce miR-200c and downregulate ZEB1 and ZEB2 proteins.	0	11	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	0	1	9	10
One major target of hepatic FXR is the small heterodimer partner ( SHP ) , which inhibits transcription factor liver receptor homolog-1 ( LRH-1 ) , a known positive regulator of CYP7A1 .	One major target of hepatic FXR is the small heterodimer partner (SHP), which inhibits transcription factor liver receptor homolog-1 (LRH-1), a known positive regulator of CYP7A1.	10	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	liver receptor homolog-1	liver receptor homolog-1	liver receptor homolog-1	12	13	19	22
Knockdown of SHP dramatically enhanced the ability of the LRH-1 agonist RJW100 to induce miR-200c .	Knockdown of SHP dramatically enhanced the ability of the LRH-1 agonist RJW100 to induce miR-200c.	0	11	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	LRH-1	LRH-1	LRH-1	2	3	9	10
We validated 266-6 acinar cells as a model to assess the effects of caerulein on AP-1 and inflammatory genes ( XREF_FIG ) : upon Nr0b2 expression , c-Jun mRNA - but not inflammatory transcripts - were reduced and Nr0b2 knock-down modestly increased Nr5a2 occupancy of inflammatory gene promoters ( XREF_FIG ) .	We validated 266-6 acinar cells as a model to assess the effects of caerulein on AP-1 and inflammatory genes (XREF_FIG) : upon Nr0b2 expression, c-Jun mRNA - but not inflammatory transcripts - were reduced and Nr0b2 knock-down modestly increased Nr5a2 occupancy of inflammatory gene promoters (XREF_FIG).	38	43	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Nr0b2	Nr0b2	Nr0b2	Nr5a2	Nr5a2	Nr5a2	38	39	42	43
The increase in SHP expression decreases bile acid biosynthesis by inhibiting LRH-1 induction of bile acid metabolizing enzymes including CYP7A1 .	The increase in SHP expression decreases bile acid biosynthesis by inhibiting LRH-1 induction of bile acid metabolizing enzymes including CYP7A1.	3	12	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP	SHP expression	shp	LRH-1	LRH-1	lrh-1	3	4	11	12
Extensive biochemical and biophysical studies were performed by XREF_BIBR to characterize the importance of Ex3 in Numb mediated control of Mdm2 and p53 stability .	Extensive biochemical and biophysical studies were performed by XREF_BIBR to characterize the importance of Ex3 in Numb mediated control of Mdm2 and p53 stability.	14	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Mdm2	Mdm2	Mdm2	16	17	20	21
In another example , the closure of macropinosomes during the uptake of adenovirus 3 requires a signaling cascade in which the Rac1 GTPase activates PAK1 ( p21 activated kinase 1 ) and PAK1 subsequently activates CtBP1 ( C-terminal binding protein 1 ) XREF_BIBR .	In another example, the closure of macropinosomes during the uptake of adenovirus 3 requires a signaling cascade in which the Rac1 GTPase activates PAK1 (p21 activated kinase 1) and PAK1 subsequently activates CtBP1 (C-terminal binding protein 1) XREF_BIBR.	32	42	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PAK1	PAK1	PAK1	CtBP1	CtBP1	CtBP1	32	33	35	36
CtBP1 and BARS was shown recently to regulate macropinocytosis donwstream of Pak1 kinase , which activates CtBP1 and BARS by phosphorylation XREF_BIBR .	CtBP1 and BARS was shown recently to regulate macropinocytosis donwstream of Pak1 kinase, which activates CtBP1 and BARS by phosphorylation XREF_BIBR.	11	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pak1	Pak1	Pak1	CtBP1	CtBP1	CtBP1	11	12	16	17
We demonstrate that the Hedgehog transcription factor Gli1 is targeted by Numb for Itch dependent ubiquitination , which suppresses Hedgehog signals , thus arresting growth and promoting cell differentiation .	We demonstrate that the Hedgehog transcription factor Gli1 is targeted by Numb for Itch dependent ubiquitination, which suppresses Hedgehog signals, thus arresting growth and promoting cell differentiation.	3	12	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Numb	Numb	Numb	Gli1	Gli1	Gli1	11	12	7	8
We observed SHP homodimerization in the nucleus of mammalian cells and showed dissociation of SHP homodimers upon heterodimerization with ligand activated ERalpha .	We observed SHP homodimerization in the nucleus of mammalian cells and showed dissociation of SHP homodimers upon heterodimerization with ligand activated ERalpha.	14	22	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP	SHP	SHP	ERalpha	ERalpha	ERalpha	14	15	21	22
Previous studies have reported links between SHP and estrogen signaling , such as the direct interaction of SHP with ERs [ XREF_BIBR ] , inhibition ER mediated transcriptional activation by SHP [ XREF_BIBR ] and ER dependent transcriptional regulation of SHP in a feedback loop [ XREF_BIBR ] .	Previous studies have reported links between SHP and estrogen signaling, such as the direct interaction of SHP with ERs [XREF_BIBR], inhibition ER mediated transcriptional activation by SHP [XREF_BIBR] and ER dependent transcriptional regulation of SHP in a feedback loop [XREF_BIBR].	21	38	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	SHP	SHP	SHP	ER	ER	ER	30	31	25	26
To investigate whether disruption of the binding of PP1beta MYPT1 to NUAK1 might also promote NUAK1 phosphorylation and hence interaction with SCF betaTrCP , we mutated the three GILK motifs in NUAK1 that mediate PP1beta MYPT1 phosphatase binding [ XREF_BIBR ] and observed that this significantly enhanced binding of betaTrCP ( XREF_FIG C ) .	To investigate whether disruption of the binding of PP1beta MYPT1 to NUAK1 might also promote NUAK1 phosphorylation and hence interaction with SCF betaTrCP, we mutated the three GILK motifs in NUAK1 that mediate PP1beta MYPT1 phosphatase binding [XREF_BIBR] and observed that this significantly enhanced binding of betaTrCP (XREF_FIG C).	25	52	mediate	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	NUAK1	NUAK1	nuak1	MYPT1	MYPT1 phosphatase binding	mypt1	31	32	35	36
Phosphorylation of Ser ( 445 ) , Ser ( 472 ) , and Ser ( 910 ) of MYPT1 by NUAK1 promoted the interaction of MYPT1 with 14-3-3 adaptor proteins , thereby suppressing phosphatase activity .	Phosphorylation of Ser (445), Ser (472), and Ser (910) of MYPT1 by NUAK1 promoted the interaction of MYPT1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity.	0	29	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NUAK1	Phosphorylation of Ser (445), Ser (472), and Ser (910) of MYPT1 by NUAK1	nuak1	MYPT1	MYPT1	mypt1	20	21	25	26
Furthermore , Pak1 has been implicated in the cell survival pathway via the direct phosphorylation of cell death promoting Bad , which suggests Pak1 could neurons survive in control mice [ XREF_BIBR , XREF_BIBR ] .	Furthermore, Pak1 has been implicated in the cell survival pathway via the direct phosphorylation of cell death promoting Bad, which suggests Pak1 could neurons survive in control mice [XREF_BIBR, XREF_BIBR].	2	22	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pak1	Pak1	Pak1	Bad	Bad	Bad	2	3	19	20
We have shown that Bad expression in islets was increased by chronic exposure to hyperglycemic conditions , or could be induced by depletion of PAK1 in the absence of glucose .	We have shown that Bad expression in islets was increased by chronic exposure to hyperglycemic conditions, or could be induced by depletion of PAK1 in the absence of glucose.	4	25	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PAK1	PAK1	PAK1	Bad	Bad	Bad	24	25	4	5
This study demonstrates a novel protective mechanism of ANP against pathologic hyperpermeability and suggests a novel pharmacological intervention for the prevention of increased vascular leak via PAK1 dependent modulation of GEF-H1 activity .	This study demonstrates a novel protective mechanism of ANP against pathologic hyperpermeability and suggests a novel pharmacological intervention for the prevention of increased vascular leak via PAK1 dependent modulation of GEF-H1 activity.	26	31	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PAK1	PAK1	PAK1	GEF-H1	GEF-H1	GEF-H1	26	27	30	31
Our previous work demonstrated that LRP-1 on fibroblasts mediates multiple tPA signaling cascades to promote fibroblast activation , transdifferentiation , growth and survival , leading to renal fibrosis : 1 ) tPA induces matrix metalloproteinases ( MMPs ) production to initiate the epithelial mesenchymal transition ( EMT ) through LRP-1-mediate MAPK pathway [ XREF_BIBR ] ; 2 ) tPA promotes the survival , proliferation , and interstitial accumulation of fibroblasts in the diseased kidneys through p90RSK mediated Bad or GSK3beta signaling [ XREF_BIBR , XREF_BIBR ] .	Our previous work demonstrated that LRP-1 on fibroblasts mediates multiple tPA signaling cascades to promote fibroblast activation, transdifferentiation, growth and survival, leading to renal fibrosis : 1) tPA induces matrix metalloproteinases (MMPs) production to initiate the epithelial mesenchymal transition (EMT) through LRP-1-mediate MAPK pathway [XREF_BIBR]; 2) tPA promotes the survival, proliferation, and interstitial accumulation of fibroblasts in the diseased kidneys through p90RSK mediated Bad or GSK3beta signaling [XREF_BIBR, XREF_BIBR].	59	80	mediated	Positive_early_activation	Negative_activation	Positive_activation	p90RSK	p90RSK	p90RSK	Bad	Bad	Bad	75	76	77	78
In the OKER cell line , the selective blockade of MEK1/2 and its target p90RSK reduced p-LKB1 ( Ser428 ) and induced p-AMPKalpha ( Thr172 ) , triggering apoptosis .	In the OKER cell line, the selective blockade of MEK1/2 and its target p90RSK reduced p-LKB1 (Ser428) and induced p-AMPKalpha (Thr172), triggering apoptosis.	8	22	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p90RSK	p90RSK	p90RSK	p-LKB1	p-LKB1	p-LKB1	14	15	16	17
Furthermore , PAK1 specific inhibitors CEP-1347 and WR-PAK18 selectively inhibit the growth of NF2 deficient cancer cells , but not NF2 positive cells .	Furthermore, PAK1 specific inhibitors CEP-1347 and WR-PAK18 selectively inhibit the growth of NF2 deficient cancer cells, but not NF2 positive cells.	2	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PAK1	PAK1	PAK1	NF2	NF2	NF2	2	3	13	14
Recent studies suggest that MCAK is directly regulated by Pak1 to control MT dynamic instability and that Pak1 is capable of regulating centrosomal Aurora A , although this effect was found to be RhoGTPase independent .	Recent studies suggest that MCAK is directly regulated by Pak1 to control MT dynamic instability and that Pak1 is capable of regulating centrosomal Aurora A, although this effect was found to be RhoGTPase independent.	4	11	directly regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Pak1	Pak1	Pak1	MCAK	MCAK	MCAK	9	10	4	5
Constitutive over-expression of COUP-TF II cDNA in mouse C2C12 myogenic cells suppressed the levels of myoD mRNA and blocked the induction of myogenin mRNA , whereas constitutive expression of anti-sense COUP-TF II cDNA significantly increased the steady state levels of myoD mRNA and hyper-induced myogenin mRNA .	Constitutive over-expression of COUP-TF II cDNA in mouse C2C12 myogenic cells suppressed the levels of myoD mRNA and blocked the induction of myogenin mRNA, whereas constitutive expression of anti-sense COUP-TF II cDNA significantly increased the steady state levels of myoD mRNA and hyper-induced myogenin mRNA.	30	41	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	COUP-TF II	COUP-TF II	COUP-TF II	myoD	myoD	myoD	30	32	40	41
As observed for NTSR1 , the addition of NTS to B-CLL lymphocytes promoted sustained activation of NTSR2 and its downstream cascade , including phosphorylation of Src kinase ( XREF_FIG ) and expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL ( XREF_FIG ) .	As observed for NTSR1, the addition of NTS to B-CLL lymphocytes promoted sustained activation of NTSR2 and its downstream cascade, including phosphorylation of Src kinase (XREF_FIG) and expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL (XREF_FIG).	6	20	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NTS	NTS	NTS	NTSR2	NTSR2	NTSR2	8	9	16	17
These results demonstrate the role of the c-Met - Rac1 - PAK1 axis in the HGF induced modulation of stathmin activity and MT dynamics .	These results demonstrate the role of the c-Met - Rac1 - PAK1 axis in the HGF induced modulation of stathmin activity and MT dynamics.	11	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PAK1	PAK1	PAK1	stathmin	stathmin	stathmin	11	12	19	20
It is well known that PHLPP1 being a tumor suppressor promotes apoptosis by negatively regulating Akt .	It is well known that PHLPP1 being a tumor suppressor promotes apoptosis by negatively regulating Akt.	5	16	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	5	6	15	16
Knock-down of PHLPP restores the activation of Akt in Tregs .	Knock-down of PHLPP restores the activation of Akt in Tregs.	0	9	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	2	3	7	8
In addition , depletion of PHLPP by siRNA increases the level and duration of agonist evoked Akt signaling , causing apoptosis and decreased cell proliferation [ XREF_BIBR , XREF_BIBR ] .	In addition, depletion of PHLPP by siRNA increases the level and duration of agonist evoked Akt signaling, causing apoptosis and decreased cell proliferation [XREF_BIBR, XREF_BIBR].	3	17	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	5	6	16	17
These results strongly suggest that p50 regulated miR190 and PHLPP1 expression mediates Akt activation , leading to induction of FoxO3a phosphorylation and inhibition of transactivation activity .	These results strongly suggest that p50 regulated miR190 and PHLPP1 expression mediates Akt activation, leading to induction of FoxO3a phosphorylation and inhibition of transactivation activity.	7	13	mediates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PHLPP1	PHLPP1 expression	phlpp1	Akt	Akt	akt	9	10	12	13
Therefore , the GSK3-beta-TrCP destruction of PHLPP1 enhances Akt activity which would paradoxically promote greater GSK3 inhibition .	Therefore, the GSK3-beta-TrCP destruction of PHLPP1 enhances Akt activity which would paradoxically promote greater GSK3 inhibition.	4	9	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	6	7	8	9
The ability of miR-199a-5p and miR-375 to target PHLPP1 ( PH domain and leucine rich repeat protein phosphatase 1 ) , a tumor suppressor that negatively regulates the AKT pathway , accounts , at least in part , for their drug-resistance activity .	The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AKT pathway, accounts, at least in part, for their drug-resistance activity.	7	29	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	PHLPP1	PHLPP1	PHLPP1	AKT	AKT	AKT	8	9	28	29
miR190 has recently been shown to suppress expression of Leucine Rich Repeat Protein Phosphatase PHLPP XREF_BIBR which in turn negatively regulates AKT signaling .	miR190 has recently been shown to suppress expression of Leucine Rich Repeat Protein Phosphatase PHLPP XREF_BIBR which in turn negatively regulates AKT signaling.	0	22	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	miR190 has recently been shown to suppress expression of Leucine Rich Repeat Protein Phosphatase PHLPP	phlpp	AKT	AKT	akt	14	15	21	22
PPM subfamily members PHLPP dephosphorylated AKT serine 473 in AKT and promotes apoptosis , whereas further characterization showed that PHLPP isoforms targeted specific AKT isoforms .	PPM subfamily members PHLPP dephosphorylated AKT serine 473 in AKT and promotes apoptosis, whereas further characterization showed that PHLPP isoforms targeted specific AKT isoforms.	19	24	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP	PHLPP	PHLPP	AKT	AKT	AKT	19	20	23	24
While both Akt and PKC are modulated by PHLPP , the rescue experiments indicate that PHLPP mediated growth inhibition is largely due to its negative regulation of Akt signaling .	While both Akt and PKC are modulated by PHLPP, the rescue experiments indicate that PHLPP mediated growth inhibition is largely due to its negative regulation of Akt signaling.	1	9	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	8	9	2	3
Activated Akt is dephosphorylated at the activation loop by okadaic acid sensitive phosphatases such as PP2A XREF_BIBR , XREF_BIBR and at the hydrophobic motif by the recently discovered PH domain leucine rich repeat protein phosphatase ( PHLPP ) , XREF_BIBR , XREF_BIBR resulting in inhibition of activity and promotion of apoptosis .	Activated Akt is dephosphorylated at the activation loop by okadaic acid sensitive phosphatases such as PP2A XREF_BIBR, XREF_BIBR and at the hydrophobic motif by the recently discovered PH domain leucine rich repeat protein phosphatase (PHLPP), XREF_BIBR, XREF_BIBR resulting in inhibition of activity and promotion of apoptosis.	0	37	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP	PHLPP	PHLPP	Akt	Akt	Akt	36	37	1	2
Furthermore , downregulation of PHLPP1 increases AKT activity , enhances the proliferation of melanoma cells and melanocytes and results in anchorage independent growth of melanocytes 53 .	Furthermore, downregulation of PHLPP1 increases AKT activity, enhances the proliferation of melanoma cells and melanocytes and results in anchorage independent growth of melanocytes 53.	2	7	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP1	PHLPP1	PHLPP1	AKT	AKT	AKT	4	5	6	7
In neurons , both PHLPP1 KD and experimental PHLPP inhibitors activated AKT and ameliorated staurosporine ( STS )-induced cell death .	In neurons, both PHLPP1 KD and experimental PHLPP inhibitors activated AKT and ameliorated staurosporine (STS)-induced cell death.	4	12	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP1	PHLPP1	PHLPP1	AKT	AKT	AKT	4	5	11	12
Therefore , the aims of the present study were : ( 1 ) to determine whether PHLPP-1 may contribute to the desensitization of insulin-Akt responses and cardioprotection decline in I/R injured aging heart ; ( 2 ) to examine whether insulin plays a downregulating role in PHLPP-1 protein level and then intensify cardiac Akt activation .	Therefore, the aims of the present study were : (1) to determine whether PHLPP-1 may contribute to the desensitization of insulin-Akt responses and cardioprotection decline in I/R injured aging heart; (2) to examine whether insulin plays a downregulating role in PHLPP-1 protein level and then intensify cardiac Akt activation.	16	54	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP-1	PHLPP-1	PHLPP-1	Akt	Akt	Akt	16	17	53	54
PHLPP1 KO rescued Akt activity and completely prevented CGC loss caused by calpain-1 KO , prevented the decrease in GluR2 subunits at PF-PC synapses and partially reversed the decrease in synaptic efficiency at these synapse .	PHLPP1 KO rescued Akt activity and completely prevented CGC loss caused by calpain-1 KO, prevented the decrease in GluR2 subunits at PF-PC synapses and partially reversed the decrease in synaptic efficiency at these synapse.	0	4	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	0	1	3	4
An explanation for these different roles of PHLPP1 and PHLPP2 in PDAC is provided by our finding that PHLPP1 and PHLPP2 selectively target the 2 Akt isoforms in PaCa cells ; PHLPP1 specifically dephosphorylates Akt2 , whereas PHLPP2 dephosphorylates Akt1 ( XREF_FIG ) .	An explanation for these different roles of PHLPP1 and PHLPP2 in PDAC is provided by our finding that PHLPP1 and PHLPP2 selectively target the 2 Akt isoforms in PaCa cells; PHLPP1 specifically dephosphorylates Akt2, whereas PHLPP2 dephosphorylates Akt1 (XREF_FIG).	18	26	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP1	PHLPP1	PHLPP1	Akt	Akt	Akt	18	19	25	26
Given the importance of phosphorylation for Akt maximal activation , it remains to be established whether insulin leads to diminished PHLPP-1 protein level and consequently enhances Akt activation as well as cardiomyocyte survival .	Given the importance of phosphorylation for Akt maximal activation, it remains to be established whether insulin leads to diminished PHLPP-1 protein level and consequently enhances Akt activation as well as cardiomyocyte survival.	16	27	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP-1 protein	insulin leads to diminished PHLPP-1 protein level	phlpp-1 protein	Akt	Akt	akt	20	22	26	27
The translation of PHLPP is positively regulated by mTORC1 , consistent with a feedback loop wherein loss of BMX and subsequent decreases in receptor tyrosine kinase signaling to mTORC1 through PI3K-AKT and MAPKs ( mitogen activated protein kinases ) result in decreased mTORC1 activity , decreased PHLPP , and increased pSer 473 AKT .	The translation of PHLPP is positively regulated by mTORC1, consistent with a feedback loop wherein loss of BMX and subsequent decreases in receptor tyrosine kinase signaling to mTORC1 through PI3K-AKT and MAPKs (mitogen activated protein kinases) result in decreased mTORC1 activity, decreased PHLPP, and increased pSer 473 AKT.	1	53	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP	PHLPP	PHLPP	AKT	AKT	AKT	3	4	52	53
Moreover , PHLPP depletion abrogated the suppression of AKT and mTOR signaling , proliferation inhibition , G1 arrest , and apoptosis induction caused by SNORA74B silencing , indicating that SNORA74B-silencing-mediated antitumor activities depends on PHLPP function .	Moreover, PHLPP depletion abrogated the suppression of AKT and mTOR signaling, proliferation inhibition, G1 arrest, and apoptosis induction caused by SNORA74B silencing, indicating that SNORA74B-silencing-mediated antitumor activities depends on PHLPP function.	2	11	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	PHLPP	PHLPP	AKT	AKT	AKT	2	3	8	9
SNORA74B silencing induced PHLPP expression and suppressed activation of AKT and mTOR pathway .	SNORA74B silencing induced PHLPP expression and suppressed activation of AKT and mTOR pathway.	0	12	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHLPP	SNORA74B silencing induced PHLPP expression	phlpp	AKT	AKT	akt	3	4	9	10
XREF_BIBR - XREF_BIBR Phosphorylation of RKIP at Serine 153 by protein kinase C abolishes RKIP ' s inhibition of Raf-1 and converts it to an inhibitor of the G protein coupled receptor kinase , GRK-2 , and in addition , Lorentz et al 59 reported that this process facilitated the cross-talk between the EGF and GPCR signaling pathways .	XREF_BIBR - XREF_BIBR Phosphorylation of RKIP at Serine 153 by protein kinase C abolishes RKIP 's inhibition of Raf-1 and converts it to an inhibitor of the G protein coupled receptor kinase, GRK-2, and in addition, Lorentz et al 59 reported that this process facilitated the cross-talk between the EGF and GPCR signaling pathways.	3	20	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	RKIP	Phosphorylation of RKIP at Serine 153	rkip	Raf-1	Raf-1	raf-1	5	6	19	20
Raf-1 kinase inhibitory protein ( RKIP ) , also known as phosphatidylethanolamine binding protein 1 , suppresses Raf-1 kinase activity in the MAP kinase pathway [ XREF_BIBR ] .	Raf-1 kinase inhibitory protein (RKIP), also known as phosphatidylethanolamine binding protein 1, suppresses Raf-1 kinase activity in the MAP kinase pathway [XREF_BIBR].	3	19	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	5	6	17	18
Phosphorylation of RKIP by protein PKC at serine 153 mediates the release of Raf-1 from RKIP ( Corbit etal .	Phosphorylation of RKIP by protein PKC at serine 153 mediates the release of Raf-1 from RKIP (Corbit etal.	0	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RKIP	Phosphorylation of RKIP by protein PKC at serine 153	rkip	Raf-1	Raf-1	raf-1	2	3	13	14
15-HETE-PE appears to activate ERK signaling by binding PEBP1 , allowing the release of Raf-1 .	15-HETE-PE appears to activate ERK signaling by binding PEBP1, allowing the release of Raf-1.	3	15	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PEBP1	PEBP1	PEBP1	Raf-1	Raf-1	Raf-1	8	9	14	15
RKIP siRNA treatment potentiates PMA induced Raf-1 and Erk activation in V7 cells , as shown by increased Raf-1 Ser338 and Erk phosphorylation .	RKIP siRNA treatment potentiates PMA induced Raf-1 and Erk activation in V7 cells, as shown by increased Raf-1 Ser338 and Erk phosphorylation.	0	9	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	0	1	6	7
16 RKIP activates mitotic checkpoints and cell-cycle arrest by binding to Raf-1 , which in turn suppresses the MAPK pathway that controls mitotic spindle assembly .	16 RKIP activates mitotic checkpoints and cell-cycle arrest by binding to Raf-1, which in turn suppresses the MAPK pathway that controls mitotic spindle assembly.	0	16	activates	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	1	2	11	12
17 Phosphorylation of RKIP at the S153 site by PKC ( protein kinase C ) has been suggested to induce the release of Raf-1 from its binding pocket on RKIP , thereby activating the MAPK pathway .	17 Phosphorylation of RKIP at the S153 site by PKC (protein kinase C) has been suggested to induce the release of Raf-1 from its binding pocket on RKIP, thereby activating the MAPK pathway.	1	24	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RKIP	Phosphorylation of RKIP at the S153	rkip	Raf-1	Raf-1	raf-1	3	4	23	24
Phosphorylation of RKIP at Serine 153 by protein kinase C abolishes RKIP ' s inhibition of Raf-1 XREF_BIBR and converts it to an inhibitor of the G protein coupled receptor kinase , GRK-2 , thus facilitating cross-talk between the EGF and GPCR signaling pathways XREF_BIBR .	Phosphorylation of RKIP at Serine 153 by protein kinase C abolishes RKIP 's inhibition of Raf-1 XREF_BIBR and converts it to an inhibitor of the G protein coupled receptor kinase, GRK-2, thus facilitating cross-talk between the EGF and GPCR signaling pathways XREF_BIBR.	0	17	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	RKIP	Phosphorylation of RKIP at Serine 153	rkip	Raf-1	Raf-1	raf-1	2	3	16	17
Down-regulation of RKIP potentiated PMA induced Raf-1 and Erk activation in V7 cells , as shown by the increased Raf-1 Ser338 and Erk phosphorylation .	Down-regulation of RKIP potentiated PMA induced Raf-1 and Erk activation in V7 cells, as shown by the increased Raf-1 Ser338 and Erk phosphorylation.	0	9	potentiated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RKIP	RKIP	RKIP	Raf-1	Raf-1	Raf-1	2	3	6	7
And , as previously reported and shown here , PEBP1 phosphorylation led to the activation of Raf-1 signaling .	And, as previously reported and shown here, PEBP1 phosphorylation led to the activation of Raf-1 signaling.	9	17	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PEBP1	PEBP1 phosphorylation	pebp1	Raf-1	Raf-1	raf-1	9	10	16	17
These findings suggest that activation of 15-LOX causes oxygenation of the PE bound to PEBP1 , which leads to the release of Raf-1 from inhibition by PEBP1 .	These findings suggest that activation of 15-LOX causes oxygenation of the PE bound to PEBP1, which leads to the release of Raf-1 from inhibition by PEBP1.	17	27	leads	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	PEBP1	PEBP1	PEBP1	Raf-1	Raf-1	Raf-1	26	27	22	23
In conclusion , Pdx1 activates downstream transcription factors Ngn3 and Pax6 , and may be one of the mechanisms that promote differentiation of iPSCs into islet beta cells .	In conclusion, Pdx1 activates downstream transcription factors Ngn3 and Pax6, and may be one of the mechanisms that promote differentiation of iPSCs into islet beta cells.	3	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pdx1	Pdx1	Pdx1	Pax6	Pax6	Pax6	3	4	10	11
Interestingly , here we also found that down-regulation of PHB2 in RD cells enhanced the binding of MyoD to the promoter of rDNA , suggesting that PHB2 not only represses the transcriptional activity of MyoD but also alleviates the repressive effect of MyoD on rRNA transcription .	Interestingly, here we also found that down-regulation of PHB2 in RD cells enhanced the binding of MyoD to the promoter of rDNA, suggesting that PHB2 not only represses the transcriptional activity of MyoD but also alleviates the repressive effect of MyoD on rRNA transcription.	26	37	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHB2	PHB2	PHB2	MyoD	MyoD	MyoD	26	27	34	35
On the other hand , PHB2 inhibits differentiation by repressing the activity of MyoD .	On the other hand, PHB2 inhibits differentiation by repressing the activity of MyoD.	5	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PHB2	PHB2	PHB2	MyoD	MyoD	MyoD	5	6	13	14
Activation of gamma-PAK in human embryonic kidney 293T cells by cotransfection with constitutively active Cdc42 induces activation of c-Abl , resulting in increased phosphotyrosine levels .	Activation of gamma-PAK in human embryonic kidney 293T cells by cotransfection with constitutively active Cdc42 induces activation of c-Abl, resulting in increased phosphotyrosine levels.	0	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	gamma-PAK	gamma-PAK	gamma-PAK	c-Abl	c-Abl	c-Abl	2	3	18	19
Activation of PDX1 expression was seen in colon epithelium of CDX2P-CreER T2 Cdx2 fl/fl mice as early as 7 days after TAM injection to target the Cdx2 alleles ( XREF_FIG ) .	Activation of PDX1 expression was seen in colon epithelium of CDX2P-CreER T2 Cdx2 fl/fl mice as early as 7 days after TAM injection to target the Cdx2 alleles (XREF_FIG).	2	27	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PDX1	PDX1 expression	pdx1	Cdx2	Cdx2	cdx2	2	3	26	27
Our data indicate that highly expressed PAK2 mediates chemotherapeutic resistance in human breast invasive ductal carcinoma by negatively regulating caspase-7 activity .	Our data indicate that highly expressed PAK2 mediates chemotherapeutic resistance in human breast invasive ductal carcinoma by negatively regulating caspase-7 activity.	5	20	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PAK2	PAK2	PAK2	caspase-7	caspase-7	caspase-7	6	7	19	20
The introduction of activated PHLPP1 specific targets AKT2 or AKT3 also promoted melanoma metastasis , while the non PHLPP1 target AKT1 did not .	The introduction of activated PHLPP1 specific targets AKT2 or AKT3 also promoted melanoma metastasis, while the non PHLPP1 target AKT1 did not.	16	21	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PHLPP1	PHLPP1	PHLPP1	AKT1	AKT1	AKT1	18	19	20	21
Recently , a small non catalytic protein , PEA-15 , has also been demonstrated to promote a cytoplasmic ERK2 localization .	Recently, a small non catalytic protein, PEA-15, has also been demonstrated to promote a cytoplasmic ERK2 localization.	6	19	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PEA-15	PEA-15	PEA-15	ERK2	ERK2	ERK2	8	9	18	19
XREF_BIBR showed that Phlpp1 deficiency increased Akt2 activity , diminishing FoxO1 levels and inducing Fgf18 expression to stimulate Erk1/2 activity and chondrocyte proliferation .	XREF_BIBR showed that Phlpp1 deficiency increased Akt2 activity, diminishing FoxO1 levels and inducing Fgf18 expression to stimulate Erk1/2 activity and chondrocyte proliferation.	3	7	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Phlpp1	Phlpp1	Phlpp1	Akt2	Akt2	Akt2	3	4	6	7
In initial experiments we examined the effect of PIAS3 on EGF stimulated STAT3 luciferase activity using A549 and H1299 cells .	In initial experiments we examined the effect of PIAS3 on EGF stimulated STAT3 luciferase activity using A549 and H1299 cells.	6	14	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	8	9	12	13
In cancer cells , the expression of the Pias3 protein is post-transcriptionally suppressed and promotes the oncogenic effects of activated STAT3 .	In cancer cells, the expression of the Pias3 protein is post-transcriptionally suppressed and promotes the oncogenic effects of activated STAT3.	5	21	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pias3	expression of the Pias3	pias3	STAT3	STAT3	stat3	8	9	20	21
Absence of PIAS-3 has been shown to enhance STAT3 transcriptional activity and subsequent cell proliferation in glioblastoma multiforme tumors [ XREF_BIBR ] .	Absence of PIAS-3 has been shown to enhance STAT3 transcriptional activity and subsequent cell proliferation in glioblastoma multiforme tumors [XREF_BIBR].	0	10	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS-3	PIAS-3	PIAS-3	STAT3	STAT3	STAT3	2	3	8	9
PIAS3 codes for the Protein Inhibitor of Activated STAT3 .	PIAS3 codes for the Protein Inhibitor of Activated STAT3.	0	9	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	0	1	8	9
Based on the above results , we speculated PIAS3 reduces ROS production by impeding STAT3 mediated signalling and consequently inhibiting ox-LDL-induced VSMC proliferation .	Based on the above results, we speculated PIAS3 reduces ROS production by impeding STAT3 mediated signalling and consequently inhibiting ox-LDL-induced VSMC proliferation.	8	15	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	8	9	14	15
We found that ectopic PIAS3 overexpression increased the activation of STAT3 in ER positive MCF7 cells and decreased the activation of STAT3 in MDA-MB-231 cells ( Additional file 2 : Figure S2A ) .	We found that ectopic PIAS3 overexpression increased the activation of STAT3 in ER positive MCF7 cells and decreased the activation of STAT3 in MDA-MB-231 cells (Additional file 2 : Figure S2A).	4	22	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3 overexpression	pias3	STAT3	STAT3	stat3	4	5	21	22
One well characterized mechanism is the degradation of STAT3 protein initiated by the proteins SOCS3 and PIAS3 .	One well characterized mechanism is the degradation of STAT3 protein initiated by the proteins SOCS3 and PIAS3.	8	17	initiated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	16	17	8	9
Inhibition of SOCS3 and TC-PTP lead to prolonged and stable activated STAT3 , whereas inhibition of PIAS3 accelerates the rate of activated STAT3 decay by inducing accumulation of cytoplasmic STAT3 .	Inhibition of SOCS3 and TC-PTP lead to prolonged and stable activated STAT3, whereas inhibition of PIAS3 accelerates the rate of activated STAT3 decay by inducing accumulation of cytoplasmic STAT3.	14	23	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	16	17	22	23
Consequently , Smad6 reduces PIAS3 mediated STAT3 inhibition and promotes glioma cell growth and stem like cell initiation .	Consequently, Smad6 reduces PIAS3 mediated STAT3 inhibition and promotes glioma cell growth and stem like cell initiation.	3	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	4	5	6	7
It comprised four members : PIAS1 , PIAS3 , PIASx , and PIASy that can directly bind to STATs and block phosphorylation , DNA binding , and transactivation ; STAT3 is targeted primarily by the PIAS3 protein .	It comprised four members : PIAS1, PIAS3, PIASx, and PIASy that can directly bind to STATs and block phosphorylation, DNA binding, and transactivation; STAT3 is targeted primarily by the PIAS3 protein.	29	36	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	35	36	29	30
Knockdown of PIAS-3 by small interfering RNA prevented inhibition of STAT3 and cytotoxicity by BSN .	Knockdown of PIAS-3 by small interfering RNA prevented inhibition of STAT3 and cytotoxicity by BSN.	0	12	prevented	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PIAS-3	PIAS-3	PIAS-3	STAT3	STAT3	STAT3	2	3	10	11
The miR-17-92 cluster encodes miR-18a , which can promote STAT3 and its downstream effectors including Myc , survivin , and Bcl-xl through inhibiting PIAS3 , which negatively regulates STAT3 .	The miR-17-92 cluster encodes miR-18a, which can promote STAT3 and its downstream effectors including Myc, survivin, and Bcl-xl through inhibiting PIAS3, which negatively regulates STAT3.	15	29	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	23	24	28	29
Further mechanical investigations demonstrated that Smad6 is a novel PIAS3 interacting protein that antagonizes PIAS3 mediated STAT3 transcriptional inhibition by accelerating PIAS3 ubiquitination and degradation .	Further mechanical investigations demonstrated that Smad6 is a novel PIAS3 interacting protein that antagonizes PIAS3 mediated STAT3 transcriptional inhibition by accelerating PIAS3 ubiquitination and degradation.	13	18	mediated	Positive_early_activation	Negative_activation	Positive_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	14	15	16	17
Thus , the targeting of STAT3 by PIAS3 as a mechanism for tumor inhibition may represent a promising treatment in SCC .	Thus, the targeting of STAT3 by PIAS3 as a mechanism for tumor inhibition may represent a promising treatment in SCC.	3	10	targeting	Positive_activation_token_2_noun	Negative_activation	Positive_activation	PIAS3	PIAS3	PIAS3	STAT3	STAT3	STAT3	7	8	5	6
Overexpression of PIAS3 up-regulates STAT3 independent , apoptosis promoting genes CIDEC and DAPK2 .	Overexpression of PIAS3 up-regulates STAT3 independent, apoptosis promoting genes CIDEC and DAPK2.	0	5	up-regulates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PIAS3	Overexpression of PIAS3	pias3	STAT3	STAT3	stat3	2	3	4	5
We also made a novel observation that PHLPPL , a serine/threonine phosphatase , potentiates the effect of Akt and thereby enhances the binding of HK-II to mitochondria .	We also made a novel observation that PHLPPL, a serine/threonine phosphatase, potentiates the effect of Akt and thereby enhances the binding of HK-II to mitochondria.	7	20	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPPL	PHLPPL	PHLPPL	Akt	Akt	Akt	7	8	17	18
These observations thus suggest that contactin-1 enhances AKT activation in part by preventing PHLPP2 mediated AKT dephosphrorylation .	These observations thus suggest that contactin-1 enhances AKT activation in part by preventing PHLPP2 mediated AKT dephosphrorylation.	13	16	mediated	Positive_early_activation	Negative_activation	Positive_activation	PHLPP2	PHLPP2	PHLPP2	AKT	AKT	AKT	13	14	15	16
Polymorphism at the PHLPP2 phosphatase which activates Akt was observed in 13.5 % of the patient samples .	Polymorphism at the PHLPP2 phosphatase which activates Akt was observed in 13.5% of the patient samples.	3	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP2	PHLPP2	PHLPP2	Akt	Akt	Akt	3	4	7	8
It is particularly intriguing that a bona fide tumor suppressing Akt phosphatase , Phlpp2 , is co-opted by Myc to drive proliferation by suppressing Akt activity .	It is particularly intriguing that a bona fide tumor suppressing Akt phosphatase, Phlpp2, is co-opted by Myc to drive proliferation by suppressing Akt activity.	11	25	drive	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Phlpp2	Phlpp2	Phlpp2	Akt	Akt	Akt	13	14	24	25
However , we observed that morin limited PHLPP2 mediated deactivation of Akt ( XREF_FIG A ) which lies upstream of Fyn kinase axis .	However, we observed that morin limited PHLPP2 mediated deactivation of Akt (XREF_FIG A) which lies upstream of Fyn kinase axis.	5	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP2	PHLPP2	PHLPP2	Akt	Akt	Akt	7	8	11	12
Taken together , these findings confirm that miR-27a promotes GC cell proliferation and metastasis by regulating PHLPP2 mediated activation of the Akt and GSK3beta pathway .	Taken together, these findings confirm that miR-27a promotes GC cell proliferation and metastasis by regulating PHLPP2 mediated activation of the Akt and GSK3beta pathway.	16	24	mediated	Positive_early_activation	Negative_activation	Positive_activation	PHLPP2	PHLPP2	PHLPP2	Akt	Akt	Akt	16	17	21	22
Thus , our findings suggest that the strong association of PHLPP1 expression with survival of patients with PDAC ( XREF_FIG ) is due to the fact that Akt2 , which is a substrate for PHLPP1 ( but not Akt1 , which is targeted by PHLPP2 ) , mediates development of PDAC .	Thus, our findings suggest that the strong association of PHLPP1 expression with survival of patients with PDAC (XREF_FIG) is due to the fact that Akt2, which is a substrate for PHLPP1 (but not Akt1, which is targeted by PHLPP2), mediates development of PDAC.	34	45	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PHLPP2	PHLPP2	PHLPP2	Akt1	Akt1	Akt1	44	45	38	39
In contrast , dephosphorylation of S473 by PHLPP does indicate some selectivity , whereby the PHLPP1 isoform appears to dephosphorylate Akt2 and Akt3 , whereas PHLPP2 targets Akt1 and 3 .	In contrast, dephosphorylation of S473 by PHLPP does indicate some selectivity, whereby the PHLPP1 isoform appears to dephosphorylate Akt2 and Akt3, whereas PHLPP2 targets Akt1 and 3.	19	29	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PHLPP2	PHLPP2	PHLPP2	Akt1	Akt1	Akt1	25	26	27	28
Unlike PHLPP1 , overexpression of PHLPP2 did not affect phosphorylation of either MEK1/2 or ERK1/2 , and while PHLPP1 specifically dephosphorylated Akt2 and 3 , PHLPP2 targeted Akt1 and 3 .	Unlike PHLPP1, overexpression of PHLPP2 did not affect phosphorylation of either MEK1/2 or ERK1/2, and while PHLPP1 specifically dephosphorylated Akt2 and 3, PHLPP2 targeted Akt1 and 3.	25	29	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP2	PHLPP2	PHLPP2	Akt1	Akt1	Akt1	25	26	27	28
PHLPP1 dephosphorylates and thereby inactivates Akt2 , whereby PHLPP2 targets Akt1 for dephosphorylation [ XREF_BIBR ] .	PHLPP1 dephosphorylates and thereby inactivates Akt2, whereby PHLPP2 targets Akt1 for dephosphorylation [XREF_BIBR].	8	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP2	PHLPP2	PHLPP2	Akt1	Akt1	Akt1	8	9	10	11
16 Studies indicate that the cellular levels of PHLPP2 , the isoform that specifically targets Akt1 , 17 affect proliferative potential of tumorigenic cells , XREF_BIBR , XREF_BIBR , XREF_BIBR highlighting its role in promoting apoptotic events .	16 Studies indicate that the cellular levels of PHLPP2, the isoform that specifically targets Akt1, 17 affect proliferative potential of tumorigenic cells, XREF_BIBR, XREF_BIBR, XREF_BIBR highlighting its role in promoting apoptotic events.	6	17	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	PHLPP2	levels of PHLPP2	phlpp2	Akt1	Akt1	akt1	8	9	15	16
Cdk1 and cyclin B activity and mitotic entry are further controlled by additional superimposed feedback mechanisms upregulating the mitotic kinases Plk1 and Aurora A , and the Aurora and Plk1 activator Bora , coupling mitotic entry to centrosome maturation , and stimulating expression of proteins of the mitotic entry network , such as cyclin B XREF_BIBR .	Cdk1 and cyclin B activity and mitotic entry are further controlled by additional superimposed feedback mechanisms upregulating the mitotic kinases Plk1 and Aurora A, and the Aurora and Plk1 activator Bora, coupling mitotic entry to centrosome maturation, and stimulating expression of proteins of the mitotic entry network, such as cyclin B XREF_BIBR.	20	32	activator	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	Bora	Bora	Bora	29	30	31	32
This not only allows Aurora A to phosphorylate Plk1 at T210 but additionally targets Bora itself as a substrate of Plk1 , since phosphorylation by Plk1 targets Bora for betaTrCP dependent proteasomal degradation .	This not only allows Aurora A to phosphorylate Plk1 at T210 but additionally targets Bora itself as a substrate of Plk1, since phosphorylation by Plk1 targets Bora for betaTrCP dependent proteasomal degradation.	14	28	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	Bora	Bora	Bora	25	26	27	28
Plk1 and Plx1 targets its co-activator Bora for degradation , but it remains unclear how embryonic oscillations in Plx1 activity are generated , and how Plk1 and Plx1 activity is sustained during mitosis .	Plk1 and Plx1 targets its co-activator Bora for degradation, but it remains unclear how embryonic oscillations in Plx1 activity are generated, and how Plk1 and Plx1 activity is sustained during mitosis.	0	8	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	Bora	Bora	Bora	0	1	6	7
If DNA damage occurs , but Plk1 has yet to be activated , ATM and ATR prevents Plk1 activation by triggering the degradation of the Plk1 activator Bora through a phosphorylation event [ XREF_BIBR ] .	If DNA damage occurs, but Plk1 has yet to be activated, ATM and ATR prevents Plk1 activation by triggering the degradation of the Plk1 activator Bora through a phosphorylation event [XREF_BIBR].	22	28	activator	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Bora	Bora	Bora	25	26	27	28
Knockdown of Plk1 also increased the half-life of Bora ( XREF_FIG ) , although this effect could be indirect , as depletion of Plk1 also delays the entry into mitosis , a cell cycle phase in which Bora is degraded .	Knockdown of Plk1 also increased the half-life of Bora (XREF_FIG), although this effect could be indirect, as depletion of Plk1 also delays the entry into mitosis, a cell cycle phase in which Bora is degraded.	0	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	Bora	Bora	Bora	2	3	8	9
Emi1 is targeted for destruction through phosphorylation by the Plk1 kinase , which creates a phosphodegron recognized by the SCF beta-TrCP ubiquitin ligase , and our results are consistent with the phenotype of cells depleted of Plk1 by siRNA or treated with a Plk1 inhibitor in which Emi1 is stabilized but cyclin A is destroyed as normal in prometaphase .	Emi1 is targeted for destruction through phosphorylation by the Plk1 kinase, which creates a phosphodegron recognized by the SCF beta-TrCP ubiquitin ligase, and our results are consistent with the phenotype of cells depleted of Plk1 by siRNA or treated with a Plk1 inhibitor in which Emi1 is stabilized but cyclin A is destroyed as normal in prometaphase.	0	10	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	Emi1	Emi1	Emi1	9	10	0	1
These data support the hypothesis that Plk1 activates the APC by directing the SCF dependent destruction of Emi1 in prophase .	These data support the hypothesis that Plk1 activates the APC by directing the SCF dependent destruction of Emi1 in prophase.	6	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	Emi1	Emi1	Emi1	6	7	17	18
Strong inhibition of Plk1 activity , if any , during S does not block centriole disengagement and mother centriole reduplication in Emi1 depleted cells .	Strong inhibition of Plk1 activity, if any, during S does not block centriole disengagement and mother centriole reduplication in Emi1 depleted cells.	3	22	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	Emi1	Emi1	Emi1	3	4	21	22
We show here that the polo like kinase Plk1 is strictly required for Emi1 destruction and that overexpression of Plk1 is sufficient to trigger Emi1 destruction .	We show here that the polo like kinase Plk1 is strictly required for Emi1 destruction and that overexpression of Plk1 is sufficient to trigger Emi1 destruction.	17	25	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	overexpression of Plk1	plk1	Emi1	Emi1	emi1	19	20	24	25
SOCS1 and SOCS3 target JAK1 and gp130 , respectively , near the plasma membrane to prevent cytoplasmic STATs from being activated , whereas PIAS1 principally targets activated STAT1 in the cell nucleus and prevents it from binding to DNA .	SOCS1 and SOCS3 target JAK1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic STATs from being activated, whereas PIAS1 principally targets activated STAT1 in the cell nucleus and prevents it from binding to DNA.	23	33	targets activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	23	24	27	28
PIAS1 modulates STAT1 activity , and STAT1 and PIAS1 interaction is also reported to be modulated by methylation of STAT1 .	PIAS1 modulates STAT1 activity, and STAT1 and PIAS1 interaction is also reported to be modulated by methylation of STAT1.	0	3	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	0	1	2	3
PIAS1 ( protein inhibitor of the activated signal transducer and activator of transcription STAT1 ) is a SUMO E3 ligase that binds to chromatin to repress transcription .	PIAS1 (protein inhibitor of the activated signal transducer and activator of transcription STAT1) is a SUMO E3 ligase that binds to chromatin to repress transcription.	0	19	activator	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	0	1	13	14
Through a systematic search of proteins SUMOylated by ARF , we identified PIAS1 , an inhibitor of IFN activated transcription factor STAT1 , as a novel ARF binding partner and SUMOylation target .	Through a systematic search of proteins SUMOylated by ARF, we identified PIAS1, an inhibitor of IFN activated transcription factor STAT1, as a novel ARF binding partner and SUMOylation target.	12	22	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS1	PIAS1	PIAS1	STAT1	STAT1	STAT1	12	13	21	22
Western blot results showed that p110beta expression increased from 5dpp in ovaries with the activation of primordial follicles , indicating a functional role of p110beta in follicle activation .	Western blot results showed that p110beta expression increased from 5dpp in ovaries with the activation of primordial follicles, indicating a functional role of p110beta in follicle activation.	5	25	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p110beta	p110beta expression	p110beta	p110beta	p110beta	p110beta	5	6	24	25
We hypothesize that elevated synaptic p110beta protein levels in the absence of FMRP increase the amount of p110beta subunits recruited into gp1 mGluR signaling complexes at synapses under basal conditions , and thus contribute to excess PI3K activity resulting in exaggerated mGluR signaling and increased basal protein synthesis in FXS ( XREF_FIG ) .	We hypothesize that elevated synaptic p110beta protein levels in the absence of FMRP increase the amount of p110beta subunits recruited into gp1 mGluR signaling complexes at synapses under basal conditions, and thus contribute to excess PI3K activity resulting in exaggerated mGluR signaling and increased basal protein synthesis in FXS (XREF_FIG).	5	18	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p110beta	p110beta protein levels	p110beta	p110beta	p110beta	p110beta	5	6	17	18
Although different PI3K catalytic subunits are known to play distinct roles , the specific in vivo function of p110beta ( the product of the PIK3CB gene ) is not clear .	Although different PI3K catalytic subunits are known to play distinct roles, the specific in vivo function of p110beta (the product of the PIK3CB gene) is not clear.	16	25	product	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	p110beta	p110beta	p110beta	PIK3CB	PIK3CB	PIK3CB	18	19	24	25
Overexpression of active Nek2 or Plk1 causes premature displacement of Nlp from interphase centrosomes .	Overexpression of active Nek2 or Plk1 causes premature displacement of Nlp from interphase centrosomes.	0	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Overexpression of active Nek2 or Plk1	plk1	Nlp	Nlp	nlp	5	6	10	11
We propose that Nlp plays an important role in microtubule organization during interphase , and that the activation of Plk1 at the onset of mitosis triggers the displacement of Nlp from the centrosome , allowing the establishment of a mitotic scaffold with enhanced microtubule nucleation activity .	We propose that Nlp plays an important role in microtubule organization during interphase, and that the activation of Plk1 at the onset of mitosis triggers the displacement of Nlp from the centrosome, allowing the establishment of a mitotic scaffold with enhanced microtubule nucleation activity.	17	30	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	Nlp	Nlp	Nlp	19	20	29	30
Overexpression of Plk1 promotes protein turnover of PinX1 , a process that depends on ubiquitin associated proteasomal degradation .	Overexpression of Plk1 promotes protein turnover of PinX1, a process that depends on ubiquitin associated proteasomal degradation.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Overexpression of Plk1	plk1	PinX1	PinX1	pinx1	2	3	7	8
Depletion of Plk1 using siRNA increases the stability of PinX1 at protein level in mitosis .	Depletion of Plk1 using siRNA increases the stability of PinX1 at protein level in mitosis.	0	10	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	PinX1	PinX1	PinX1	2	3	9	10
During checkpoint recovery , cells rely on Plk1 ( Polo like kinase 1 ) , which targets both Wee1 and Claspin ( an essential cofactor of ATR ) for proteasomal degradation [ XREF_BIBR - XREF_BIBR ] .	During checkpoint recovery, cells rely on Plk1 (Polo like kinase 1), which targets both Wee1 and Claspin (an essential cofactor of ATR) for proteasomal degradation [XREF_BIBR - XREF_BIBR].	5	21	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	Claspin	Claspin	Claspin	7	8	20	21
Interestingly , these elegant studies showed that Plk1 dependent phosphorylation directs Claspin to Skp/Cullin/F-box-beta-Transducin repeat containing protein ( SCF-betaTrCP )-mediated ubiquitination and proteolysis [ XREF_BIBR - XREF_BIBR ] .	Interestingly, these elegant studies showed that Plk1 dependent phosphorylation directs Claspin to Skp/Cullin/F-box-beta-Transducin repeat containing protein (SCF-betaTrCP)-mediated ubiquitination and proteolysis [XREF_BIBR - XREF_BIBR].	7	12	directs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1 dependent phosphorylation	plk1	Claspin	Claspin	claspin	7	8	11	12
Small-molecule drugs targeting SYK , Bruton ' s tyrosine kinase ( BTK ) , or PI3K isoform p110delta ( PI3Kdelta ) show impressive results in patients with relapsed and refractory as well as in treatment naive CLL .	Small-molecule drugs targeting SYK, Bruton 's tyrosine kinase (BTK), or PI3K isoform p110delta (PI3Kdelta) show impressive results in patients with relapsed and refractory as well as in treatment naive CLL.	1	20	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PI3Kdelta	PI3Kdelta	PI3Kdelta	p110delta	p110delta	p110delta	19	20	17	18
Because PIM1 does not upregulate p27 ( XREF_FIG ) , a protein critical to the induction of senescence by AKT1 in prostate cells , it is likely that the mechanism by which these protein kinases function to induce senescence is markedly different .	Because PIM1 does not upregulate p27 (XREF_FIG), a protein critical to the induction of senescence by AKT1 in prostate cells, it is likely that the mechanism by which these protein kinases function to induce senescence is markedly different.	1	11	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIM1	PIM1	PIM1	p27	p27	p27	1	2	5	6
243 S19 deficiency dramatically destabilizes PIM1 , which increases p27 , inhibits cell cycle progression and reduces cell proliferation , even in the absence of p53 ( XREF_FIG ) .	243 S19 deficiency dramatically destabilizes PIM1, which increases p27, inhibits cell cycle progression and reduces cell proliferation, even in the absence of p53 (XREF_FIG).	5	16	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIM1	PIM1	PIM1	p27	p27	p27	5	6	9	10
We hypothesized that PIAS4 could modulate SMAD3 activity in the liver .	We hypothesized that PIAS4 could modulate SMAD3 activity in the liver.	3	7	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PIAS4	PIAS4	PIAS4	SMAD3	SMAD3	SMAD3	3	4	6	7
Our finding that PKN1 is required for WNT3A dependent internalization of LRP6 is consistent with data showing that PKN1 promotes RHOB dependent endocytosis of the EGF receptor .	Our finding that PKN1 is required for WNT3A dependent internalization of LRP6 is consistent with data showing that PKN1 promotes RHOB dependent endocytosis of the EGF receptor.	18	27	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKN1	PKN1	PKN1	EGF receptor	EGF receptor	EGF receptor	18	19	25	27
Consistent with this notion , depletion of Plk1 prolongs PBIP1 localization to the centromeres ( Y. H. Kang and K. S. Lee , unpublished ) , suggesting that Plk1 negatively regulates PBIP1 localization to the centromeres .	Consistent with this notion, depletion of Plk1 prolongs PBIP1 localization to the centromeres (Y. H. Kang and K. S. Lee, unpublished), suggesting that Plk1 negatively regulates PBIP1 localization to the centromeres.	28	32	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	PBIP1	PBIP1	PBIP1	28	29	31	32
The phosphatase PHLPP has also been shown to target p70S6K [ XREF_BIBR ] .	The phosphatase PHLPP has also been shown to target p70S6K [XREF_BIBR].	0	11	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PHLPP	PHLPP	PHLPP	p70S6K	p70S6K	p70S6K	2	3	9	10
Notably , Wip1 is a transcriptional target of p53 , and is stimulated after genotoxic stress 99 .	Notably, Wip1 is a transcriptional target of p53, and is stimulated after genotoxic stress 99.	2	12	is a transcriptional target	Positive_activation_copula_1	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	2	3	8	9
For example , a recent report indicates that miR-29a represses Ppm1d phosphatase , which in turn enhances p53 activity and suppresses the growth of liver cancer cells XREF_BIBR .	For example, a recent report indicates that miR-29a represses Ppm1d phosphatase, which in turn enhances p53 activity and suppresses the growth of liver cancer cells XREF_BIBR.	10	18	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ppm1d	Ppm1d	Ppm1d	p53	p53	p53	10	11	17	18
We have also found that miR-29 represses Ppm1d phosphatase , which in turn enhances p53 activity .	We have also found that miR-29 represses Ppm1d phosphatase, which in turn enhances p53 activity.	7	15	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ppm1d	Ppm1d	Ppm1d	p53	p53	p53	7	8	14	15
In view of findings above that p53 activity is higher in Wip1 -/- MEFs compared to Wip1 +/+ MEFs ; one interpretation of these in vivo tumor results is that homozygous loss of Wip1 ( i.e.Tax + Wip1 -/-) reduces the level of p53 inactivation in Tax expressing cells compared to counterpart cells that expresses both Wip1 and Tax ( i.e. Tax + Wip1 +/+ ) ; this reduced inactivation of p53 could explain the increased tumor-free survival observed in the Tax + Wip1 -/- over the Tax + Wip1 +/+ mice .	In view of findings above that p53 activity is higher in Wip1 -/- MEFs compared to Wip1 +/+ MEFs; one interpretation of these in vivo tumor results is that homozygous loss of Wip1 (i.e.Tax + Wip1 -/-) reduces the level of p53 inactivation in Tax expressing cells compared to counterpart cells that expresses both Wip1 and Tax (i.e. Tax + Wip1 +/+); this reduced inactivation of p53 could explain the increased tumor-free survival observed in the Tax + Wip1 -/- over the Tax + Wip1 +/+ mice.	31	44	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	loss of Wip1	wip1	p53	p53	p53	33	34	43	44
By inactivating the p53 pathway , WIP1 promotes recovery from the G2 checkpoint [ XREF_BIBR , XREF_BIBR ] .	By inactivating the p53 pathway, WIP1 promotes recovery from the G2 checkpoint [XREF_BIBR, XREF_BIBR].	3	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WIP1	WIP1	WIP1	p53	p53	p53	6	7	3	4
Our present study reveals that Wip1 also modulates the p53 regulatory loop by regulating MdmX .	Our present study reveals that Wip1 also modulates the p53 regulatory loop by regulating MdmX.	5	11	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	5	6	9	10
Thus , downregulation of WIP1 in U-2 OS cells helps to activate p53 , but does not result in major changes in expression of the cell-cycle regulators we examined ( RB , CDC2 ) .	Thus, downregulation of WIP1 in U-2 OS cells helps to activate p53, but does not result in major changes in expression of the cell-cycle regulators we examined (RB, CDC2).	2	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WIP1	WIP1	WIP1	p53	p53	p53	4	5	12	13
Conversely , loss of WIP1 significantly delays tumor development in mice and similarly depletion of WIP1 by RNA interference allows reactivation of p53 pathway and inhibits proliferation in p53-proficient tumors .	Conversely, loss of WIP1 significantly delays tumor development in mice and similarly depletion of WIP1 by RNA interference allows reactivation of p53 pathway and inhibits proliferation in p53-proficient tumors.	13	23	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	15	16	22	23
Northern blot analysis of PPM1D expression in HCT116 p53 +/+ cells showed that PPM1D mRNA levels increased after exposure to 10 Gy IR in p53 +/+ cells with the maximum induction occurring 3 h post-irradiation ( XREF_FIG A ) .	Northern blot analysis of PPM1D expression in HCT116 p53 +/+ cells showed that PPM1D mRNA levels increased after exposure to 10 Gy IR in p53 +/+ cells with the maximum induction occurring 3 h post-irradiation (XREF_FIG A).	13	26	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPM1D	PPM1D mRNA levels	ppm1d	p53	p53	p53	13	14	24	25
We found no evidence that hyperactive WIP1 can modulate the ability of p53 to activate the promoters either of endogenous genes or the promoters cloned in reporter vectors ( XREF_FIG , XREF_FIG , XREF_FIG ) .	We found no evidence that hyperactive WIP1 can modulate the ability of p53 to activate the promoters either of endogenous genes or the promoters cloned in reporter vectors (XREF_FIG, XREF_FIG, XREF_FIG).	5	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WIP1	WIP1	WIP1	p53	p53	p53	6	7	12	13
Wip1 phosphatase modulates p53 activity .	Wip1 phosphatase modulates p53 activity.	0	4	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	0	1	3	4
Furthermore , we showed that PPM1D modulates p53 mRNA translation and p53 dependent growth suppression through dephosphorylation of RBM38 .	Furthermore, we showed that PPM1D modulates p53 mRNA translation and p53 dependent growth suppression through dephosphorylation of RBM38.	5	9	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	5	6	7	8
As the p53 dependent induction of large gene size targets , including Wip1 , previously had been shown to be inhibited at high doses of UV radiation , the authors speculated that unrepaired lesions in the PPM1D gene in XPB cells prevented its transcription and expression .	As the p53 dependent induction of large gene size targets, including Wip1, previously had been shown to be inhibited at high doses of UV radiation, the authors speculated that unrepaired lesions in the PPM1D gene in XPB cells prevented its transcription and expression.	2	13	induction	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	12	13	2	3
The potentiating effects of Wip1 overexpression on chemotherapeutic agents were directed only to tumor cells lacking p53 .	The potentiating effects of Wip1 overexpression on chemotherapeutic agents were directed only to tumor cells lacking p53.	4	17	directed	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1 overexpression	wip1	p53	p53	p53	4	5	16	17
Since PPM1D is a target of p53 , the effect of RBM38 on PPM1D expression was measured in p53 -/- HCT116 cells .	Since PPM1D is a target of p53, the effect of RBM38 on PPM1D expression was measured in p53 -/- HCT116 cells.	1	7	is a target	Positive_activation_copula_1	Negative_activation	Positive_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	1	2	6	7
Loss of Wip1 function has been reported to sensitize mouse embryonic fibroblasts to stress induced apoptosis via a p38 and p53 induced mechanism XREF_BIBR , therefore , it ' s reasonable that pharmacological inhibition of Wip1 would potentiate p53 activity and result in increased chemo-sensitivity in NB cell lines .	Loss of Wip1 function has been reported to sensitize mouse embryonic fibroblasts to stress induced apoptosis via a p38 and p53 induced mechanism XREF_BIBR, therefore, it 's reasonable that pharmacological inhibition of Wip1 would potentiate p53 activity and result in increased chemo-sensitivity in NB cell lines.	33	39	potentiate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	35	36	38	39
In addition , gain-of-function mutations in PPM1D promote cell proliferation by overcoming p53 function , and conversely , loss of PPM1D slows down proliferation only in p53-proficient cells further supporting the model in which active WIP1 allows cells to overcome the tumor suppressing barrier imposed by p53 pathway .	In addition, gain-of-function mutations in PPM1D promote cell proliferation by overcoming p53 function, and conversely, loss of PPM1D slows down proliferation only in p53-proficient cells further supporting the model in which active WIP1 allows cells to overcome the tumor suppressing barrier imposed by p53 pathway.	4	13	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	6	7	12	13
Previous studies have shown that PPM1D promotes tumorigenesis in a p53 dependent manner .	Previous studies have shown that PPM1D promotes tumorigenesis in a p53 dependent manner.	5	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	5	6	10	11
Knockdown of WIP1 protein in U-2 OS cells helps to activate p53 .	Knockdown of WIP1 protein in U-2 OS cells helps to activate p53.	2	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1	WIP1	p53	p53	p53	2	3	11	12
GSK2830371 Inhibits WIP1 Cellular Signaling in a Wild-Type TP53 Dependent Manner .	GSK2830371 Inhibits WIP1 Cellular Signaling in a Wild-Type TP53 Dependent Manner.	2	10	Signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	WIP1	WIP1	WIP1	TP53	TP53	TP53	2	3	8	9
These results support the hypothesis that WIP1 overexpression modulates genotoxic responsiveness by negatively regulating p53 in medulloblastoma cells .	These results support the hypothesis that WIP1 overexpression modulates genotoxic responsiveness by negatively regulating p53 in medulloblastoma cells.	6	15	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WIP1	WIP1 overexpression	wip1	p53	p53	p53	6	7	14	15
The co-expression of WIP1 did not significantly modulate the ability of p53 to transactivate BAX or MDM2 promoters .	The co-expression of WIP1 did not significantly modulate the ability of p53 to transactivate BAX or MDM2 promoters.	1	12	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WIP1	co-expression of WIP1	wip1	p53	p53	p53	3	4	11	12
Wip1 depletion enhances the transactivation function of p53 and contributes to the synthetic lethality .	Wip1 depletion enhances the transactivation function of p53 and contributes to the synthetic lethality.	0	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1	Wip1	p53	p53	p53	0	1	7	8
p21 , Wip1 , and MDM2 are direct transcriptional targets of p53 .	p21, Wip1, and MDM2 are direct transcriptional targets of p53.	0	12	are direct transcriptional targets	Positive_activation_copula_1	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	2	3	11	12
Wild-type p53 induced phosphatase 1 ( Wip1 or PPM1D ) is involved in DNA repair and cell cycle checkpoint pathways and Wip1 is frequently amplified or overexpressed in different human cancers , promoting tumor growth by switching off major checkpoint kinases and p53 XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR .	Wild-type p53 induced phosphatase 1 (Wip1 or PPM1D) is involved in DNA repair and cell cycle checkpoint pathways and Wip1 is frequently amplified or overexpressed in different human cancers, promoting tumor growth by switching off major checkpoint kinases and p53 XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.	21	43	promoting	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	Wip1 is frequently amplified or overexpressed	wip1	p53	p53	p53	21	22	42	43
Therefore , Wip1 allows the normal development of T lymphocytes and the maintenance of the functional organization of the thymus as a key organ of the immune system by preventing the hyperactivation of the p53 and p38MAPK pathways in thymic cells during maturation .	Therefore, Wip1 allows the normal development of T lymphocytes and the maintenance of the functional organization of the thymus as a key organ of the immune system by preventing the hyperactivation of the p53 and p38MAPK pathways in thymic cells during maturation.	2	37	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	2	3	34	35
In addition , Wip1 targets p53 itself at Ser15 , implicating Wip1 as a major inhibitor of p53 function .	In addition, Wip1 targets p53 itself at Ser15, implicating Wip1 as a major inhibitor of p53 function.	1	6	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	3	4	5	6
Cluster 2 represents genes induced only by cisplatin and were also enriched for p53 targets including PLK2 and PPM1D suggesting that 5-aza induces a subset of the p53 target genes induced by the DNA damaging agent cisplatin .	Cluster 2 represents genes induced only by cisplatin and were also enriched for p53 targets including PLK2 and PPM1D suggesting that 5-aza induces a subset of the p53 target genes induced by the DNA damaging agent cisplatin.	13	19	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	18	19	13	14
Stable expression of WIP1 enhances growth of TP53 wild-type medulloblastoma cells , compared with cells with stable expression of an empty-vector or mutant WIP1 .	Stable expression of WIP1 enhances growth of TP53 wild-type medulloblastoma cells, compared with cells with stable expression of an empty-vector or mutant WIP1.	1	10	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WIP1	expression of WIP1	wip1	TP53	TP53	tp53	3	4	7	8
Activated p53 then transactivates Wip1 , a phosphatase that dephosphorylates activated ATM .	Activated p53 then transactivates Wip1, a phosphatase that dephosphorylates activated ATM.	0	7	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	4	5	1	2
Neither version of PPM1D ( wild-type , Arg458X , Lys469Glu ) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes ( BAX and MDM2 ) .	Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes (BAX and MDM2).	1	17	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	3	4	16	17
In the model , two delays are considered because the transcription of Mdm2 by p53 needs time [ XREF_BIBR ] and wip1 expression with a delay would allow p53 induced cell repair [ XREF_BIBR ] .	In the model, two delays are considered because the transcription of Mdm2 by p53 needs time [XREF_BIBR] and wip1 expression with a delay would allow p53 induced cell repair [XREF_BIBR].	21	29	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	wip1	wip1 expression	wip1	p53	p53	p53	21	22	28	29
Since , Wip1 , a phosphatase , is a radiation responsive protein known to regulate the p53-MDM2 auto-regulatory loop through dephosphorylation of p53 and dephosphorylated p53 is subjected to MDM2 mediated ubiquitination and its subsequent degradation via proteasome XREF_BIBR , abrogation of Wip1 is believed to allow p53 accumulation and thus block tumorigenesis .	Since, Wip1, a phosphatase, is a radiation responsive protein known to regulate the p53-MDM2 auto-regulatory loop through dephosphorylation of p53 and dephosphorylated p53 is subjected to MDM2 mediated ubiquitination and its subsequent degradation via proteasome XREF_BIBR, abrogation of Wip1 is believed to allow p53 accumulation and thus block tumorigenesis.	40	48	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	42	43	47	48
In tumors with preserved wild type p53 pathway Wip1 inhibition increases tumor suppressive effect of p53 , but this strategy should take into account that Wip1 inhibition in normal tissues and their stem cell compartment significantly increases sensitivity to current day anti-cancer therapy .	In tumors with preserved wild type p53 pathway Wip1 inhibition increases tumor suppressive effect of p53, but this strategy should take into account that Wip1 inhibition in normal tissues and their stem cell compartment significantly increases sensitivity to current day anti-cancer therapy.	8	16	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	8	9	15	16
The intracellular dynamics of p53 , namely its activation and regulation in response to DNA damage caused by gamma radiation or some drugs in chemotherapy , involves the kinase ATM as a damage sensor and activator of p53 , and the downstream p53 targets Wip1 and Mdm2 that regulate p53 through protein protein interactions ( phosphorylation and ubiquitination ) and its subsequent degradation .	The intracellular dynamics of p53, namely its activation and regulation in response to DNA damage caused by gamma radiation or some drugs in chemotherapy, involves the kinase ATM as a damage sensor and activator of p53, and the downstream p53 targets Wip1 and Mdm2 that regulate p53 through protein protein interactions (phosphorylation and ubiquitination) and its subsequent degradation.	26	46	targets	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	44	45	42	43
Thus the lack of WIP1 potentiates p53 dependent tumor suppression to a level sufficient to protect B-cells from Myc induced lymphomagenesis , even in the absence of functional p19 ARF .	Thus the lack of WIP1 potentiates p53 dependent tumor suppression to a level sufficient to protect B-cells from Myc induced lymphomagenesis, even in the absence of functional p19 ARF.	2	19	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WIP1	WIP1	WIP1	p53	p53	p53	4	5	6	7
Despite limited transfection efficiency , extra WIP1 expression appeared to antagonize p53 activity even in the absence of genotoxic stress .	Despite limited transfection efficiency, extra WIP1 expression appeared to antagonize p53 activity even in the absence of genotoxic stress.	6	12	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	WIP1	WIP1 expression	wip1	p53	p53	p53	6	7	11	12
At a cellular level , Wip1 knockout NPCs exhibit a prolonged cell cycle , an accumulation at G ( 2 ) to M phase transition , and enhanced p53 activity .	At a cellular level, Wip1 knockout NPCs exhibit a prolonged cell cycle, an accumulation at G (2) to M phase transition, and enhanced p53 activity.	5	29	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	5	6	28	29
It is well known the autoregulation mediated by Hdm2 targeting p53 for degradation in the proteasome XREF_BIBR , and it has been detected in the case of other activating kinases such as ATM XREF_BIBR and CHK2 XREF_BIBR , but this action requires a p53 induction of phosphatases , such as PPM1D XREF_BIBR and Wip1 XREF_BIBR .	It is well known the autoregulation mediated by Hdm2 targeting p53 for degradation in the proteasome XREF_BIBR, and it has been detected in the case of other activating kinases such as ATM XREF_BIBR and CHK2 XREF_BIBR, but this action requires a p53 induction of phosphatases, such as PPM1D XREF_BIBR and Wip1 XREF_BIBR.	43	51	induction	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	PPM1D	PPM1D	PPM1D	p53	p53	p53	50	51	43	44
Interestingly , despite the fact that many consequences of Wip1 deletion are linked to hyperactivation of the p53 pathway , Wip1 mediated accumulation of HSC is a p53 independent process .	Interestingly, despite the fact that many consequences of Wip1 deletion are linked to hyperactivation of the p53 pathway, Wip1 mediated accumulation of HSC is a p53 independent process.	20	29	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	20	21	27	28
We linked this observation to a Wip1 mediated p53 effect because we found that Wip1 -/- MEFs have significantly increased p53 activity over their Wip1 +/+ counterparts .	We linked this observation to a Wip1 mediated p53 effect because we found that Wip1 -/- MEFs have significantly increased p53 activity over their Wip1 +/+ counterparts.	14	21	increased	Positive_activation_syntax_3a_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	p53	p53	p53	14	15	20	21
WIP1 loss delays tumor development in mice , allows reactivation of p53 pathway , and inhibits proliferation in tumors endowed with p53 .	WIP1 loss delays tumor development in mice, allows reactivation of p53 pathway, and inhibits proliferation in tumors endowed with p53.	0	12	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WIP1	WIP1	WIP1	p53	p53	p53	0	1	11	12
In addition , peroxisome proliferator activated receptor gamma ( PPARgamma ) , p53 , and activating transcription factor 2 ( ATF2 ) can also transcriptionally upregulate PTEN by binding to its promoter , while transforming growth factor ( TGF )-beta , nuclear factor kappaB ( NF-kappaB ) , and Jun negatively regulate PTEN mRNA expression .	In addition, peroxisome proliferator activated receptor gamma (PPARgamma), p53, and activating transcription factor 2 (ATF2) can also transcriptionally upregulate PTEN by binding to its promoter, while transforming growth factor (TGF)-beta, nuclear factor kappaB (NF-kappaB), and Jun negatively regulate PTEN mRNA expression.	3	28	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	peroxisome proliferator activated receptor gamma	peroxisome proliferator activated receptor gamma	peroxisome proliferator activated receptor gamma	PTEN	PTEN	PTEN	3	8	26	27
PPARgamma induces phosphatase PTEN which is an inhibitor of PI3K pathway [ XREF_BIBR , XREF_BIBR ] .	PPARgamma induces phosphatase PTEN which is an inhibitor of PI3K pathway [XREF_BIBR, XREF_BIBR].	0	7	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	0	1	3	4
The activation of PPAR-gamma induces phosphatase and tensin homolog ( PTEN ) , which ultimately inhibits OPC proliferation through inducing cell cycle inhibitory proteins [ XREF_BIBR , XREF_BIBR ] .	The activation of PPAR-gamma induces phosphatase and tensin homolog (PTEN), which ultimately inhibits OPC proliferation through inducing cell cycle inhibitory proteins [XREF_BIBR, XREF_BIBR].	1	9	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	3	4	5	9
The current study extends these findings in the mouse lung and examines the mechanism by which PPARgamma ligands modulate PTEN in HPASMC .	The current study extends these findings in the mouse lung and examines the mechanism by which PPARgamma ligands modulate PTEN in HPASMC.	16	21	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	16	17	19	20
The tumor suppressor gene PTEN , which is transcriptionally activated by PPARgamma and acts as a major negative regulator of the PI3K and Akt signaling , was also increased by alpha-Tocopherol .	The tumor suppressor gene PTEN, which is transcriptionally activated by PPARgamma and acts as a major negative regulator of the PI3K and Akt signaling, was also increased by alpha-Tocopherol.	0	28	activated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	11	12	4	5
As mentioned before , FOXO proteins are negatively regulated by PI3k-AKT-mediated phosphorylation ; consequently , PPARgamma , inducing PTEN , may block AKT activation and hence may , indirectly , increase FOXO activity .	As mentioned before, FOXO proteins are negatively regulated by PI3k-AKT-mediated phosphorylation; consequently, PPARgamma, inducing PTEN, may block AKT activation and hence may, indirectly, increase FOXO activity.	15	21	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	15	16	18	19
Additionally , as previously mentioned , expression of PTEN increases in non small cell lung cancer ( NSCLC ) treated with the PPARgamma agonists , rosiglitazone XREF_BIBR .	Additionally, as previously mentioned, expression of PTEN increases in non small cell lung cancer (NSCLC) treated with the PPARgamma agonists, rosiglitazone XREF_BIBR.	8	23	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	22	23	8	9
PPARgamma upregulates PTEN via its selective ligand rosiglitazone on peroxisome proliferator response elements ( PPRE ) identified on the PTEN promoter region [ XREF_BIBR ] .	PPARgamma upregulates PTEN via its selective ligand rosiglitazone on peroxisome proliferator response elements (PPRE) identified on the PTEN promoter region [XREF_BIBR].	0	7	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	0	1	2	3
Results from Rousseaux et al suggest 5-ASA increases PPARgamma activity XREF_BIBR which may increase PTEN function XREF_BIBR and reduce PI3K signaling .	Results from Rousseaux et al suggest 5-ASA increases PPARgamma activity XREF_BIBR which may increase PTEN function XREF_BIBR and reduce PI3K signaling.	8	16	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	8	9	14	15
PPARgamma activation by Rosiglitazone causes positive regulation of the phosphatase and tensin homolog gene ( PTEN ) in Caco-2 cells and other cells types [ XREF_BIBR ] .	PPARgamma activation by Rosiglitazone causes positive regulation of the phosphatase and tensin homolog gene (PTEN) in Caco-2 cells and other cells types [XREF_BIBR].	0	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	0	1	9	13
Similar observation was made by treatment with CGN ( XREF_FIG ) suggesting that LOV mediated PPAR-gamma activation induces PTEN , which in turn accelerate the differentiation of OPCs .	Similar observation was made by treatment with CGN (XREF_FIG) suggesting that LOV mediated PPAR-gamma activation induces PTEN, which in turn accelerate the differentiation of OPCs.	13	23	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPAR-gamma	LOV mediated PPAR-gamma	ppar-gamma	PTEN	PTEN	pten	15	16	18	19
Moreover , it has been shown that PPARgamma activation induces PTEN , which serves as a PI ( 3,4,5 ) P 3 lipid phosphatase and antagonizes PI3-kinase-mediated cell signaling [ XREF_BIBR ] .	Moreover, it has been shown that PPARgamma activation induces PTEN, which serves as a PI (3,4,5) P 3 lipid phosphatase and antagonizes PI3-kinase-mediated cell signaling [XREF_BIBR].	7	25	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	7	8	10	11
We investigated whether costimulation of PPARgamma and RAR could synergistically up-regulate PTEN in human leukemia cells and consequently potentiate the inhibition of growth and cell cycle progression of these cells .	We investigated whether costimulation of PPARgamma and RAR could synergistically up-regulate PTEN in human leukemia cells and consequently potentiate the inhibition of growth and cell cycle progression of these cells.	3	15	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	5	6	11	12
In vitro data has demonstrated that PPARgamma agonists can induce functional PTEN protein that controls cellular growth .	In vitro data has demonstrated that PPARgamma agonists can induce functional PTEN protein that controls cellular growth.	6	12	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	6	7	11	12
PTEN induction by PPARgamma appears to be important for an antagonistic effect of the nuclear receptor towards TGFbeta signaling , similar to its role in PPARgamma antagonism towards NF-kappaB ( XREF_FIG ) .	PTEN induction by PPARgamma appears to be important for an antagonistic effect of the nuclear receptor towards TGFbeta signaling, similar to its role in PPARgamma antagonism towards NF-kappaB (XREF_FIG).	0	4	induction	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	3	4	0	1
The PTEN gene can be upregulated by p53 and PPARgamma , while NF-kappaB and TGF-beta downregulate PTEN expression [ XREF_BIBR , XREF_BIBR ] .	The PTEN gene can be upregulated by p53 and PPARgamma, while NF-kappaB and TGF-beta downregulate PTEN expression [XREF_BIBR, XREF_BIBR].	1	10	upregulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	9	10	1	2
These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level .	These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level.	17	21	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	17	18	20	21
In conclusion , the result showing that PPARgamma activation upregulates PTEN , which has also been implicated in tumor-inhibitory or anti-inflammatory actions of PPARgamma [ XREF_BIBR , XREF_BIBR ] , gives credence to the concept that PPARgamma activators induce PTEN during S6K1 inhibition , and consequently causes TGFbeta1 repression .	In conclusion, the result showing that PPARgamma activation upregulates PTEN, which has also been implicated in tumor-inhibitory or anti-inflammatory actions of PPARgamma [XREF_BIBR, XREF_BIBR], gives credence to the concept that PPARgamma activators induce PTEN during S6K1 inhibition, and consequently causes TGFbeta1 repression.	7	16	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	7	8	10	11
It was also suggested that statins may signal through the transcription factor sterol response element binding protein ( SREBP ) to encourage PPARgamma mediated upregulation of PTEN [ XREF_BIBR ] .	It was also suggested that statins may signal through the transcription factor sterol response element binding protein (SREBP) to encourage PPARgamma mediated upregulation of PTEN [XREF_BIBR].	22	28	upregulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	22	23	26	27
Because PTEN abrogates the stimulation of collagen production and myofibroblasts differentiation [ XREF_BIBR ] , pharmacological stimulation of PTEN by PPAR-gamma ligands may be a potential therapeutic approach in fibrosis .	Because PTEN abrogates the stimulation of collagen production and myofibroblasts differentiation [XREF_BIBR], pharmacological stimulation of PTEN by PPAR-gamma ligands may be a potential therapeutic approach in fibrosis.	16	21	stimulation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	PTEN	PTEN	PTEN	20	21	18	19
The phosphotase PTEN is induced by PPAR-gamma [ XREF_BIBR ] .	The phosphotase PTEN is induced by PPAR-gamma [XREF_BIBR].	0	8	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	PTEN	PTEN	PTEN	6	7	2	3
Antisense mediated disruption of PPARgamma expression prevented the upregulation of PTEN that normally accompanies monocyte differentiation and reduced the proportion of macrophages undergoing apoptosis , while electrophoretic mobility shift assays showed that PPARgamma is able to bind two response elements in the genomic sequence upstream of PTEN .	Antisense mediated disruption of PPARgamma expression prevented the upregulation of PTEN that normally accompanies monocyte differentiation and reduced the proportion of macrophages undergoing apoptosis, while electrophoretic mobility shift assays showed that PPARgamma is able to bind two response elements in the genomic sequence upstream of PTEN.	4	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma expression	ppargamma	PTEN	PTEN	pten	4	5	10	11
The second one involves , at least in part , a PPARgamma dependent activation of PTEN which results in Akt inactivation .	The second one involves, at least in part, a PPARgamma dependent activation of PTEN which results in Akt inactivation.	11	16	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	11	12	15	16
Treatment of lung carcinoma cell lines with rosiglitazone decreased proliferation via PPARgamma dependent upregulation of PTEN and inhibition of Akt activity , and also via PPARgamma independent inhibition of the mTOR pathway [ XREF_BIBR , XREF_BIBR ] .	Treatment of lung carcinoma cell lines with rosiglitazone decreased proliferation via PPARgamma dependent upregulation of PTEN and inhibition of Akt activity, and also via PPARgamma independent inhibition of the mTOR pathway [XREF_BIBR, XREF_BIBR].	11	20	upregulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	11	12	15	16
PPARgamma agonists were found to upregulate PTEN , subsequently inhibiting the PI3K-Akt signaling pathway , and thus enhancing the anticancer activity of gefitinib ( a first generation EGFR TKI ) .	PPARgamma agonists were found to upregulate PTEN, subsequently inhibiting the PI3K-Akt signaling pathway, and thus enhancing the anticancer activity of gefitinib (a first generation EGFR TKI).	0	7	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	0	1	6	7
Past literature reported that the effect of miR-130b in colorectal cancer are due to PPARgamma suppression that in turn deregulates PTEN , E-cadherin and so on XREF_BIBR .	Past literature reported that the effect of miR-130b in colorectal cancer are due to PPARgamma suppression that in turn deregulates PTEN, E-cadherin and so on XREF_BIBR.	14	26	deregulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	14	15	20	21
The PPARgamma dependent increase in PTEN caused by PTER-ITC in our experiments not only indicates that the tumor suppressor gene contributes to the growth-inhibitory activities of the compound , but might also trigger its pro apoptotic actions .	The PPARgamma dependent increase in PTEN caused by PTER-ITC in our experiments not only indicates that the tumor suppressor gene contributes to the growth-inhibitory activities of the compound, but might also trigger its pro apoptotic actions.	1	6	increase	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	1	2	5	6
PPARgamma agonists increased PTEN with consequent inhibition of PI3K XREF_BIBR .	PPARgamma agonists increased PTEN with consequent inhibition of PI3K XREF_BIBR.	0	4	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	0	1	3	4
Peroxisome proliferator activated receptor gamma , p53 , and activating transcription factor 2 can transcriptionally upregulate PTEN , while transforming growth factor- ( TGF-) beta , NF-kappaB , and Jun negatively regulate PTEN expression .	Peroxisome proliferator activated receptor gamma, p53, and activating transcription factor 2 can transcriptionally upregulate PTEN, while transforming growth factor- (TGF-) beta, NF-kappaB, and Jun negatively regulate PTEN expression.	0	34	upregulate	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Peroxisome proliferator activated receptor gamma	Peroxisome proliferator activated receptor gamma	peroxisome proliferator activated receptor gamma	PTEN	PTEN expression	pten	0	5	32	33
We show here that the PPARgamma agonist Rosiglitazone , along with Lovastatin , induce PTEN in a dose- and time dependent manner .	We show here that the PPARgamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time dependent manner.	5	21	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	PTEN	PTEN	PTEN	5	6	14	15
Whether the altered cellular homeostasis in cancer cells is called addiction or amnesia , studies suggest that the reversal of Plk1 addiction is sufficient for inducing selective cellular senescence or apoptosis in oncogenic RAS- or inactivated TP53 containing cancer cells .	Whether the altered cellular homeostasis in cancer cells is called addiction or amnesia, studies suggest that the reversal of Plk1 addiction is sufficient for inducing selective cellular senescence or apoptosis in oncogenic RAS- or inactivated TP53 containing cancer cells.	20	37	inactivated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	TP53	TP53	TP53	20	21	36	37
Taken together , our results suggest that p53 dependent downregulation of Survivin , CDC25C , and PLK1 upon doxorubicin induced DNA damage requires the CDE and CHR elements and a p53- and p21 dependent shift from MMB to DREAM complexes binding to the promoters .	Taken together, our results suggest that p53 dependent downregulation of Survivin, CDC25C, and PLK1 upon doxorubicin induced DNA damage requires the CDE and CHR elements and a p53- and p21 dependent shift from MMB to DREAM complexes binding to the promoters.	9	36	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PLK1	PLK1	PLK1	p53-	p53-	p53-	16	17	30	31
Plk1 phosphorylates S260 in MDM2 and stimulates MDM2 mediated turnover of p53 [ XREF_BIBR ] .	Plk1 phosphorylates S260 in MDM2 and stimulates MDM2 mediated turnover of p53 [XREF_BIBR].	0	13	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	0	1	11	12
In our study , results of the custom mRNA array revealed regulation of genes in the p21 and p53 pathway when cells were treated with the MEK and Plk1 combination .	In our study, results of the custom mRNA array revealed regulation of genes in the p21 and p53 pathway when cells were treated with the MEK and Plk1 combination.	16	29	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	p53	p53	p53	28	29	18	19
Plk1 is repressed by the tumor suppressor p53 36 and increased Plk1 levels can simply reflect p53 inactivation in cancer cells 37 .	Plk1 is repressed by the tumor suppressor p53 36 and increased Plk1 levels can simply reflect p53 inactivation in cancer cells 37.	0	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	p53	p53	p53	0	1	16	17
Given that PLK-1 directly modulates p53 functions as well as indirectly by modulating MDM2 functions , we wanted to determine inhibiting PLK-1 would sensitize cells to the effects of nutlin-3 , an inhibitor of MDM2 .	Given that PLK-1 directly modulates p53 functions as well as indirectly by modulating MDM2 functions, we wanted to determine inhibiting PLK-1 would sensitize cells to the effects of nutlin-3, an inhibitor of MDM2.	2	12	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PLK-1	PLK-1	PLK-1	p53	p53	p53	2	3	5	6
Studies have shown that depletion and inhibition of Aurora A , Aurora B , Plk1 , or Bub1 induces cellular senescence or cell death in a p53 dependent or -independent but p73 dependent manner in many different cell types [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Studies have shown that depletion and inhibition of Aurora A, Aurora B, Plk1, or Bub1 induces cellular senescence or cell death in a p53 dependent or -independent but p73 dependent manner in many different cell types [XREF_BIBR, XREF_BIBR - XREF_BIBR].	4	27	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Plk1	Plk1	Plk1	p53	p53	p53	14	15	26	27
In addition , PLK1 targeting nanoparticles induced significant upregulation of cellular p53 , Bax and p21 , whereas the level of Bcl-2 was impaired in HCC cells .	In addition, PLK1 targeting nanoparticles induced significant upregulation of cellular p53, Bax and p21, whereas the level of Bcl-2 was impaired in HCC cells.	3	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PLK1	PLK1	PLK1	p53	p53	p53	3	4	11	12
Plk1 directly targets Topor and GSTE1 to down regulate p53 .	Plk1 directly targets Topor and GSTE1 to down regulate p53.	0	10	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	p53	p53	p53	0	1	9	10
Interestingly , Plk1 contributes to a negative feedback loop regulating p53 , both directly and indirectly .	Interestingly, Plk1 contributes to a negative feedback loop regulating p53, both directly and indirectly.	2	11	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	p53	p53	p53	2	3	10	11
Plk1 overexpression also induced upregulation of the tumor suppressor p53 as well as its target p21 Cip1 and led to the generation of senescent cells characterized by the expression of senescence associated beta-galactosidase and flat morphology .	Plk1 overexpression also induced upregulation of the tumor suppressor p53 as well as its target p21 Cip1 and led to the generation of senescent cells characterized by the expression of senescence associated beta-galactosidase and flat morphology.	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1 overexpression	plk1	tumor suppressor p53	tumor suppressor p53	tumor suppressor p53	0	1	7	10
Since PLK-1 is a negative modulator of p53 , inhibition of PLK-1 would relieve the negative regulation on wild-type p53 and potentially restore its transactivation and apoptotic functions .	Since PLK-1 is a negative modulator of p53, inhibition of PLK-1 would relieve the negative regulation on wild-type p53 and potentially restore its transactivation and apoptotic functions.	1	8	is a negative modulator	Positive_activation_copula_1	Negative_activation	Positive_activation	PLK-1	PLK-1	PLK-1	p53	p53	p53	1	2	7	8
Support for this comes from the study showing that Plk1 phosphorylation of GTSE1 is essential for cellular recovery from G 2 DNA damage checkpoints , suggesting that elevated Plk1 mediated p53 inactivation is one mechanism of premature checkpoint termination , eventually leading to aneuploidy and chromosome instability .	Support for this comes from the study showing that Plk1 phosphorylation of GTSE1 is essential for cellular recovery from G 2 DNA damage checkpoints, suggesting that elevated Plk1 mediated p53 inactivation is one mechanism of premature checkpoint termination, eventually leading to aneuploidy and chromosome instability.	27	34	mediated	Positive_early_activation	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	p53	p53	p53	28	29	30	31
Interestingly , it has recently been shown that Plk1 mediated p53 inactivation contributes to doxorubicin resistance .	Interestingly, it has recently been shown that Plk1 mediated p53 inactivation contributes to doxorubicin resistance.	8	12	mediated	Positive_early_activation	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	p53	p53	p53	8	9	10	11
Moreover , despite apparent partial rescue of gametogenesis in some Atm -/- Wip1 -/- animals , these mice never produced offspring in continuous mating with wildtype mice , suggesting that absence of Wip1 was unable to functionally rescue reproductive capacity in Atm null mice .	Moreover, despite apparent partial rescue of gametogenesis in some Atm -/- Wip1 -/- animals, these mice never produced offspring in continuous mating with wildtype mice, suggesting that absence of Wip1 was unable to functionally rescue reproductive capacity in Atm null mice.	30	43	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	Atm	Atm	Atm	32	33	41	42
Absence of Wip1 largely rescues lymphomagenesis in Atm null mice .	Absence of Wip1 largely rescues lymphomagenesis in Atm null mice.	0	9	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	Atm	Atm	Atm	2	3	7	8
As described here , removal of Wip1 from Atm null mice partially rescued a number of Atm deficiency phenotypes .	As described here, removal of Wip1 from Atm null mice partially rescued a number of Atm deficiency phenotypes.	4	18	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	Atm	Atm	Atm	6	7	16	17
Absence of Wip1 partially rescues Atm deficiency phenotypes in mice .	Absence of Wip1 partially rescues Atm deficiency phenotypes in mice.	0	7	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	Atm	Atm	Atm	2	3	5	6
In this context , p53 induces of the expression of DUSP6 and WIP1 phosphatases targeting ATM [ XREF_BIBR - XREF_BIBR ] , and that of the DUSP4 phosphatase targeting VRK1 [ XREF_BIBR , XREF_BIBR ] .	In this context, p53 induces of the expression of DUSP6 and WIP1 phosphatases targeting ATM [XREF_BIBR - XREF_BIBR], and that of the DUSP4 phosphatase targeting VRK1 [XREF_BIBR, XREF_BIBR].	8	17	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WIP1	expression of DUSP6 and WIP1	wip1	ATM	ATM	atm	12	13	15	16
However , even in those cases when the level of ATM is lowered to reduce apoptosis and cause lymphoma development in wild-type mice , deficiency in Wip1 phosphatase will activate the remaining pool of ATM .	However, even in those cases when the level of ATM is lowered to reduce apoptosis and cause lymphoma development in wild-type mice, deficiency in Wip1 phosphatase will activate the remaining pool of ATM.	26	35	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	26	27	34	35
We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes .	We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes.	4	11	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	Atm	Atm	Atm	6	7	9	10
However , we noted one main difference : the network responding to DSBs includes a negative feedback between p53 and ATM mediated by Wip1 .	However, we noted one main difference : the network responding to DSBs includes a negative feedback between p53 and ATM mediated by Wip1.	13	24	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	23	24	20	21
A complex feedback through ATM mediated by Wip1 is essential for the maintenance of p53 pulsatility [ XREF_BIBR ] .	A complex feedback through ATM mediated by Wip1 is essential for the maintenance of p53 pulsatility [XREF_BIBR].	2	8	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	7	8	4	5
F2 Negative feedback ATM --> p53 ARRESTER --> Wip1 -| ATM : ATM activates p53 to the p53 ARRESTER form which activates transcription of Wip1 , which in turn deactivates ATM .	F2 Negative feedback ATM --> p53 ARRESTER --> Wip1 -| ATM : ATM activates p53 to the p53 ARRESTER form which activates transcription of Wip1, which in turn deactivates ATM.	17	31	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wip1	p53 ARRESTER form which activates transcription of Wip1	wip1	ATM	ATM	atm	24	25	30	31
XREF_BIBR , XREF_BIBR PPM1D also targets proteins downstream of ATM .	XREF_BIBR, XREF_BIBR PPM1D also targets proteins downstream of ATM.	0	10	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPM1D	PPM1D	PPM1D	ATM	ATM	ATM	3	4	9	10
As Wip1 deficiency resulted in up-regulation of ATM activity , which could not be fully explained by changes in Ser1981 phosphorylation , we asked whether Wip1 could dephosphorylate other autophosphorylation sites on ATM .	As Wip1 deficiency resulted in up-regulation of ATM activity, which could not be fully explained by changes in Ser1981 phosphorylation, we asked whether Wip1 could dephosphorylate other autophosphorylation sites on ATM.	1	8	resulted in up-regulation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	1	2	7	8
Absence of Wip1 fails to rescue other Atm deficiency phenotypes .	Absence of Wip1 fails to rescue other Atm deficiency phenotypes.	0	9	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	Atm	Atm	Atm	2	3	7	8
Here , we show that the absence of Wip1 in an Atm null background partially rescues some Atm deficiency phenotypes .	Here, we show that the absence of Wip1 in an Atm null background partially rescues some Atm deficiency phenotypes.	6	19	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	Atm	Atm	Atm	8	9	17	18
An important difference , however , is that the network responding to gamma radiation includes an additional negative feedback between p53 and ATM mediated by Wip1 ( XREF_FIG ) .	An important difference, however, is that the network responding to gamma radiation includes an additional negative feedback between p53 and ATM mediated by Wip1 (XREF_FIG).	14	27	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	25	26	22	23
mir-16 suppression of Wip1 prevents a premature inactivation of the ATM signaling and allows a functional completion of the early DNA damage response [ XREF_BIBR ] .	mir-16 suppression of Wip1 prevents a premature inactivation of the ATM signaling and allows a functional completion of the early DNA damage response [XREF_BIBR].	1	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Wip1	Wip1	Wip1	ATM	ATM	ATM	3	4	10	11
PPARgamma has been reported to specifically enhance phospho-STAT3 .	PPARgamma has been reported to specifically enhance phospho-STAT3.	0	8	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	phospho-STAT3	phospho-STAT3	phospho-STAT3	0	1	7	8
In the present study , we found that PPAR-gamma siRNA enhanced STAT3 activation , but did not affect JAK2 activation in cerulein stimulated cells .	In the present study, we found that PPAR-gamma siRNA enhanced STAT3 activation, but did not affect JAK2 activation in cerulein stimulated cells.	8	12	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	STAT3	STAT3	STAT3	8	9	11	12
In these studies , PPARgamma ligands abrogated IL-6-dependent multiple myeloma cell growth by inhibiting the transactivation of IL-6 and STAT3 .	In these studies, PPARgamma ligands abrogated IL-6-dependent multiple myeloma cell growth by inhibiting the transactivation of IL-6 and STAT3.	4	20	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	4	5	19	20
In fact , PPARgamma agonists negatively modulate STAT3 through direct and/or indirect mechanisms in cancer cells , and it could also be one of the mechanisms of TGZ .	In fact, PPARgamma agonists negatively modulate STAT3 through direct and/or indirect mechanisms in cancer cells, and it could also be one of the mechanisms of TGZ.	3	8	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	3	4	7	8
PPARgamma agonists negatively modulate STAT3 through direct and/or indirect mechanisms in cancer cells .	PPARgamma agonists negatively modulate STAT3 through direct and/or indirect mechanisms in cancer cells.	0	5	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	0	1	4	5
PPARgamma agonists inhibited MM cell survival by specifically blocking the IL-6-dependent transactivation of STAT3 ( signal transducer and activator of transcription )-activated genes , including c-myc and mcl-1 [ XREF_BIBR ] .	PPARgamma agonists inhibited MM cell survival by specifically blocking the IL-6-dependent transactivation of STAT3 (signal transducer and activator of transcription)-activated genes, including c-myc and mcl-1 [XREF_BIBR].	0	18	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	0	1	13	14
Inhibitors of PPARgamma or STAT3 abolished the PGZ induced neuroprotection and the increase in p-STAT3 .	Inhibitors of PPARgamma or STAT3 abolished the PGZ induced neuroprotection and the increase in p-STAT3.	0	15	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	p-STAT3	p-STAT3	p-STAT3	2	3	14	15
In addition , a PPARgamma synthetic agonist rescues adipogenesis following RNAi induced knock-down of STAT3 , suggesting that STAT3 regulation of adipocyte differentiation occurs upstream of PPARgamma activation [ XREF_BIBR ] .	In addition, a PPARgamma synthetic agonist rescues adipogenesis following RNAi induced knock-down of STAT3, suggesting that STAT3 regulation of adipocyte differentiation occurs upstream of PPARgamma activation [XREF_BIBR].	4	15	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	4	5	14	15
XREF_BIBR In fact , PPARgamma agonists negatively modulate STAT3 through direct and/or indirect mechanisms in cancer cells XREF_BIBR ( XREF_FIG ) .	XREF_BIBR In fact, PPARgamma agonists negatively modulate STAT3 through direct and/or indirect mechanisms in cancer cells XREF_BIBR (XREF_FIG).	4	9	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPARgamma	PPARgamma	PPARgamma	STAT3	STAT3	STAT3	4	5	8	9
In fact , PPAR-gamma agonists negatively modulate STAT-3 through direct and/or indirect mechanisms in several normal and cancer models .	In fact, PPAR-gamma agonists negatively modulate STAT-3 through direct and/or indirect mechanisms in several normal and cancer models.	3	8	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPAR-gamma	PPAR-gamma	PPAR-gamma	STAT-3	STAT-3	STAT-3	3	4	7	8
Furthermore , PEDF treatment ( 10nmol ) cardiomyocytes showed reduced PLN phosphorylation , which would decrease SERCA2 activity and SR Ca 2+ load .	Furthermore, PEDF treatment (10nmol) cardiomyocytes showed reduced PLN phosphorylation, which would decrease SERCA2 activity and SR Ca 2+ load.	10	17	decrease	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PLN	PLN phosphorylation	pln	SERCA2	SERCA2	serca2	10	11	16	17
Sarcoplasmic reticulum ( SR ) calcium reuptake rate is mainly regulated by the SERCA2 activity which , in turn , is modulated by a small molecular weight protein , the phospholamban ( PLB ) .	Sarcoplasmic reticulum (SR) calcium reuptake rate is mainly regulated by the SERCA2 activity which, in turn, is modulated by a small molecular weight protein, the phospholamban (PLB).	13	33	modulated	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	PLB	PLB	PLB	SERCA2	SERCA2	SERCA2	32	33	13	14
However , phosphorylation of Thr17 and Ser16 was similar in hearts of AE3-null and WT mice during pacing in vivo , indicating that reduced phosphorylation of PLN , which would limit SERCA2 activity , does not contribute to the differences in FFR between the two genotypes .	However, phosphorylation of Thr17 and Ser16 was similar in hearts of AE3-null and WT mice during pacing in vivo, indicating that reduced phosphorylation of PLN, which would limit SERCA2 activity, does not contribute to the differences in FFR between the two genotypes.	24	32	limit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PLN	phosphorylation of PLN	pln	SERCA2	SERCA2	serca2	26	27	31	32
Thus , spontaneous PLB up-regulation in SERCA2 b/b mice is beneficial by reducing SERCA2b ' s high Ca 2+ affinity .	Thus, spontaneous PLB up-regulation in SERCA2 b/b mice is beneficial by reducing SERCA2b 's high Ca 2+ affinity.	3	8	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PLB	PLB	PLB	SERCA2	SERCA2	SERCA2	3	4	6	7
A positive FFR has been observed in isolated mouse myocytes , in a range of frequencies ( up to 300 bpm ) that are below those occurring in vivo , and appeared to be dependent on increased phosphorylation of PLN on Thr17 , which increases SERCA2 activity .	A positive FFR has been observed in isolated mouse myocytes, in a range of frequencies (up to 300 bpm) that are below those occurring in vivo, and appeared to be dependent on increased phosphorylation of PLN on Thr17, which increases SERCA2 activity.	37	46	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PLN	phosphorylation of PLN on Thr17	pln	SERCA2	SERCA2	serca2	39	40	45	46
PLK1 is also known to directly regulate WEE1 activity by phosphorylation of Ser53 , which leads to ubiquitination and subsequent proteasomal degradation of WEE1 .	PLK1 is also known to directly regulate WEE1 activity by phosphorylation of Ser53, which leads to ubiquitination and subsequent proteasomal degradation of WEE1.	0	8	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PLK1	PLK1	PLK1	WEE1	WEE1	WEE1	0	1	7	8
Moreover , our data indicate that RO3280 mediated PLK1 inhibition resulted in the activation of Wee1 , as assessed by the increased Tyr15 phosphorylation of cell division cycle protein 2 ( CDC2 ) , unscheduled mitotic entry and apoptosis .	Moreover, our data indicate that RO3280 mediated PLK1 inhibition resulted in the activation of Wee1, as assessed by the increased Tyr15 phosphorylation of cell division cycle protein 2 (CDC2), unscheduled mitotic entry and apoptosis.	6	16	activation	Positive_activation_syntax_results_in	Negative_activation	Negative_activation	PLK1	RO3280 mediated PLK1	plk1	Wee1	Wee1	wee1	8	9	15	16
Because previous work shows that down-regulation of PLK1 causes accumulation of Wee1 protein XREF_BIBR , this result suggests that compounds DH281 , DH285 and DH287 inhibit the kinase activity of PLK1 in vivo .	Because previous work shows that down-regulation of PLK1 causes accumulation of Wee1 protein XREF_BIBR, this result suggests that compounds DH281, DH285 and DH287 inhibit the kinase activity of PLK1 in vivo.	5	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PLK1	PLK1	PLK1	Wee1	Wee1	Wee1	7	8	11	12
Firstly , PLK1 and Aurora-A directly regulate CDC25 and WEE1 .	Firstly, PLK1 and Aurora-A directly regulate CDC25 and WEE1.	2	10	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PLK1	PLK1	PLK1	WEE1	WEE1	WEE1	2	3	9	10
In addition , the here reported increase of PGC-1alpha prevents the activation of atrogenes by blocking the FoxO3a function .	In addition, the here reported increase of PGC-1alpha prevents the activation of atrogenes by blocking the FoxO3a function.	6	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3a	FoxO3a	FoxO3a	8	9	17	18
PGC-1alpha and PGC-1beta reduce protein breakdown by inhibiting the transcriptional activity of FoxO3 and NF-kappaB , but they do not affect protein synthesis .	PGC-1alpha and PGC-1beta reduce protein breakdown by inhibiting the transcriptional activity of FoxO3 and NF-kappaB, but they do not affect protein synthesis.	0	14	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3	FoxO3	FoxO3	0	1	12	13
PGC-1alpha reduces protein breakdown by inhibiting the transcriptional activity of FoxO3 and NF-kappaB [ XREF_BIBR ] .	PGC-1alpha reduces protein breakdown by inhibiting the transcriptional activity of FoxO3 and NF-kappaB [XREF_BIBR].	0	14	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO3	FoxO3	FoxO3	0	1	10	11
PGC1alpha and PGC1beta reduce protein breakdown by inhibiting the transcriptional activity of FoxO3 and NFkappaB , but they do not affect protein synthesis .	PGC1alpha and PGC1beta reduce protein breakdown by inhibiting the transcriptional activity of FoxO3 and NFkappaB, but they do not affect protein synthesis.	0	14	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PGC1alpha	PGC1alpha	PGC1alpha	FoxO3	FoxO3	FoxO3	0	1	12	13
PGC-1alpha promotes FOXO GlcNacylation .	PGC-1alpha promotes FOXO GlcNacylation.	0	3	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FOXO	FOXO	FOXO	0	1	2	3
This indicates that one of the mechanisms by which the co-activator PGC-1alpha activates FoxO dependent gene expression is via targeting OGT to FoxO transcription factors .	This indicates that one of the mechanisms by which the co-activator PGC-1alpha activates FoxO dependent gene expression is via targeting OGT to FoxO transcription factors.	9	14	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PGC-1alpha	PGC-1alpha	PGC-1alpha	FoxO	FoxO	FoxO	11	12	13	14
In the same way , Plk2 dependent phosphorylation at S176 induces destabilization of Fbw7 and the concomitant accumulation of cyclin E [ XREF_BIBR ] .	In the same way, Plk2 dependent phosphorylation at S176 induces destabilization of Fbw7 and the concomitant accumulation of cyclin E [XREF_BIBR].	5	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk2	Plk2 dependent phosphorylation at S176	plk2	Fbw7	Fbw7	fbw7	5	6	13	14
As Ppm1b inhibits IKKbeta in HeLa but not in L929 and HT-29 cells , and Rip3 is expressed in L929 and HT-29 but not in HeLa ( XREF_FIG ) , one would ask whether the presence of Rip3 makes Ppm1b unable to target IKKbeta .	As Ppm1b inhibits IKKbeta in HeLa but not in L929 and HT-29 cells, and Rip3 is expressed in L929 and HT-29 but not in HeLa (XREF_FIG), one would ask whether the presence of Rip3 makes Ppm1b unable to target IKKbeta.	39	44	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ppm1b	Ppm1b	Ppm1b	IKKbeta	IKKbeta	IKKbeta	39	40	43	44
These results demonstrate that Plk1 modulates Topors activity in suppressing p53 function and identify a likely mechanism for the tumorigenic potential of Plk1 .	These results demonstrate that Plk1 modulates Topors activity in suppressing p53 function and identify a likely mechanism for the tumorigenic potential of Plk1.	4	13	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk1	Plk1	Plk1	Topors	Topors	Topors	4	5	6	7
Moreover , ectopic expression followed by cycloheximide or pulse-chase treatment demonstrated that phospho-mutants exhibited a much longer half-life than the wild-type counterpart , strongly suggesting that Plk3 directly regulates HIF-1alpha stability in vivo .	Moreover, ectopic expression followed by cycloheximide or pulse-chase treatment demonstrated that phospho-mutants exhibited a much longer half-life than the wild-type counterpart, strongly suggesting that Plk3 directly regulates HIF-1alpha stability in vivo.	26	30	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Plk3	Plk3	Plk3	HIF-1alpha	HIF-1alpha	HIF-1alpha	26	27	29	30
Moreover , phosphate tensin homolog on chromosome 10 depletion in human kidney-2 cells resulted in loss of expression and decreased nuclear levels of PPM1A , which enhanced SMAD3 mediated fibrotic gene induction and growth arrest that were reversed by ectopic PPM1A expression .	Moreover, phosphate tensin homolog on chromosome 10 depletion in human kidney-2 cells resulted in loss of expression and decreased nuclear levels of PPM1A, which enhanced SMAD3 mediated fibrotic gene induction and growth arrest that were reversed by ectopic PPM1A expression.	27	42	reversed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PPM1A	PPM1A expression	ppm1a	SMAD3	SMAD3	smad3	40	41	27	28
PLK3 mediated Cdc25A stabilization did not translate into a significant increase in tumorigenesis in vivo , however , suggesting that PLK3 mediated Cdc25A turnover may not be a major pathway to control in vivo functions of Cdc25A .	PLK3 mediated Cdc25A stabilization did not translate into a significant increase in tumorigenesis in vivo, however, suggesting that PLK3 mediated Cdc25A turnover may not be a major pathway to control in vivo functions of Cdc25A.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	PLK3	PLK3	PLK3	Cdc25A	Cdc25A	Cdc25A	0	1	2	3
Two protein phosphatases , PPM1B and PP2Aalpha , appeared to up-regulate p53 at marginal levels ( ~ 50 % ) .	Two protein phosphatases, PPM1B and PP2Aalpha, appeared to up-regulate p53 at marginal levels (~ 50%).	2	12	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PP2Aalpha	PP2Aalpha	PP2Aalpha	p53	p53	p53	6	7	11	12
Indeed , quantitative RT-PCR analysis showed that the pp2a b ' alphabeta double mutant expressed these AKS activated KAT1 , KAT2 , and AKT1 genes at reduced levels compared to wild type ( XREF_SUPPLEMENTARY and XREF_FIG ) .	Indeed, quantitative RT-PCR analysis showed that the pp2a b ' alphabeta double mutant expressed these AKS activated KAT1, KAT2, and AKT1 genes at reduced levels compared to wild type (XREF_SUPPLEMENTARY and XREF_FIG).	8	24	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pp2a	pp2a	pp2a	AKT1	AKT1	AKT1	8	9	23	24
Thus , a negative feedback mechanism is unlikely involved in PPP2CA modulation of ERK1/2 , AKT1 , and p38 MAPK activation in OFPAE cells .	Thus, a negative feedback mechanism is unlikely involved in PPP2CA modulation of ERK1/2, AKT1, and p38 MAPK activation in OFPAE cells.	10	16	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PPP2CA	PPP2CA	PPP2CA	AKT1	AKT1	AKT1	10	11	15	16
PP2a promotes cell survival by negatively regulating the PI3K and Akt pathway , by associating to and directly dephosphorylating Akt , with consequent inactivation of the kinase [ XREF_BIBR ] ( XREF_FIG ) .	PP2a promotes cell survival by negatively regulating the PI3K and Akt pathway, by associating to and directly dephosphorylating Akt, with consequent inactivation of the kinase [XREF_BIBR] (XREF_FIG).	0	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PP2a	PP2a	PP2a	Akt	Akt	Akt	0	1	10	11
In the AKT pathway , genes associated with AKT activation including PIK3R1 , PIK3CA , and PPP2CA were coordinately up-regulated in the LTNP group ( versus VIR ) in CD4+ and CD8+ T cells .	In the AKT pathway, genes associated with AKT activation including PIK3R1, PIK3CA, and PPP2CA were coordinately up-regulated in the LTNP group (versus VIR) in CD4+ and CD8+ T cells.	8	17	activation	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	PPP2CA	PPP2CA	PPP2CA	AKT	AKT	AKT	16	17	8	9
By removing this valine residue , PRCP produces alpha-MSH 1-12 from alpha-MSH 1-13 .	By removing this valine residue, PRCP produces alpha-MSH 1-12 from alpha-MSH 1-13.	6	11	produces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	6	7	8	9
The molecular mechanisms underlying the suppression of food intake in PRCP deficient mice or by the inhibitor of PRCP clearly provide physiological evidence that PRCP is an inactivator of alpha-MSH .	The molecular mechanisms underlying the suppression of food intake in PRCP deficient mice or by the inhibitor of PRCP clearly provide physiological evidence that PRCP is an inactivator of alpha-MSH.	24	30	is an inactivator	Positive_activation_copula_1	Negative_activation	Positive_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	24	25	29	30
Thus the release of PRCP from other neuronal populations that send efferents to areas where alpha-MSH is released from axon terminals could serve to modulate the strength of the alpha-MSH signal at the MC 4 receptor .	Thus the release of PRCP from other neuronal populations that send efferents to areas where alpha-MSH is released from axon terminals could serve to modulate the strength of the alpha-MSH signal at the MC 4 receptor.	2	30	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	4	5	29	30
This suggests that PRCP is an endogenous inactivator of alpha-MSH and an appetite stimulant .	This suggests that PRCP is an endogenous inactivator of alpha-MSH and an appetite stimulant.	3	13	is an endogenous inactivator	Positive_activation_copula_1	Negative_activation	Positive_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	3	4	9	10
Thus , if PRCP is responsible for alpha-MSH degradation , then depletion of PRCP will allow the accumulation of alpha-MSH and induce a prolonged effect of alpha-MSH in these regions of the hypothalamus .	Thus, if PRCP is responsible for alpha-MSH degradation, then depletion of PRCP will allow the accumulation of alpha-MSH and induce a prolonged effect of alpha-MSH in these regions of the hypothalamus.	11	27	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PRCP	PRCP	PRCP	alpha-MSH	alpha-MSH	alpha-MSH	13	14	26	27
Smad4 dependent suppressor pituitary homeobox 2 promotes PPP2R2A mediated inhibition of Akt pathway in pancreatic cancer .	Smad4 dependent suppressor pituitary homeobox 2 promotes PPP2R2A mediated inhibition of Akt pathway in pancreatic cancer.	7	12	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PPP2R2A	PPP2R2A	PPP2R2A	Akt	Akt	Akt	7	8	11	12
HMGA1 silencing augmented PPP2R2A protein expression and inhibited Akt signaling , resulting in significantly retarded cell growth response to IGF-I .	HMGA1 silencing augmented PPP2R2A protein expression and inhibited Akt signaling, resulting in significantly retarded cell growth response to IGF-I.	0	9	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PPP2R2A	HMGA1 silencing augmented PPP2R2A protein expression	ppp2r2a	Akt	Akt	akt	3	4	8	9
By upregulating PI3K and MMP2 , it promotes cell migration and invasion [ XREF_BIBR , XREF_BIBR ] and by activating miR-222 oncomiR , it induces PPP2R2A mediated AKT signaling in NSCLC [ XREF_BIBR ] .	By upregulating PI3K and MMP2, it promotes cell migration and invasion [XREF_BIBR, XREF_BIBR] and by activating miR-222 oncomiR, it induces PPP2R2A mediated AKT signaling in NSCLC [XREF_BIBR].	24	28	mediated	Positive_early_activation	Negative_activation	Positive_activation	PPP2R2A	PPP2R2A	PPP2R2A	AKT	AKT	AKT	25	26	27	28
In nasopharyngeal carcinoma , reduced PPP2R2B expression activates PDK1 and MYC pathways to induce BEZ235 resistance [ XREF_BIBR ] .	In nasopharyngeal carcinoma, reduced PPP2R2B expression activates PDK1 and MYC pathways to induce BEZ235 resistance [XREF_BIBR].	5	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PPP2R2B	PPP2R2B expression	ppp2r2b	PDK1	PDK1	pdk1	5	6	8	9
PKCalpha can also elicit a p21 Cip1 -dependent enhancement of proliferation as seen in glioma cells .	PKCalpha can also elicit a p21 Cip1 -dependent enhancement of proliferation as seen in glioma cells.	0	8	elicit	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	p21 Cip1	p21 Cip1	p21 Cip1	0	1	5	7
Based on these results , we can assert that PKCalpha is recruited by LAV-BPIFB4 to modulate eNOS and vascular tone .	Based on these results, we can assert that PKCalpha is recruited by LAV-BPIFB4 to modulate eNOS and vascular tone.	9	19	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	eNOS	eNOS	eNOS	9	10	16	17
The caveolin-1 peptide mimics the region of caveolin-1 that binds to eNOS XREF_BIBR , XREF_BIBR and completely reversed the increased production of superoxide from eNOS activated by PKCalpha , which is consistent with the findings of other studies XREF_BIBR , XREF_BIBR .	The caveolin-1 peptide mimics the region of caveolin-1 that binds to eNOS XREF_BIBR, XREF_BIBR and completely reversed the increased production of superoxide from eNOS activated by PKCalpha, which is consistent with the findings of other studies XREF_BIBR, XREF_BIBR.	3	31	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	eNOS	eNOS	eNOS	27	28	24	25
PKCalpha increases the transcription of NOS3 gene and upregulates eNOS activity , leading to enhanced NO production and vasodilation .	PKCalpha increases the transcription of NOS3 gene and upregulates eNOS activity, leading to enhanced NO production and vasodilation.	0	10	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCalpha	PKCalpha increases the transcription	pkcalpha	eNOS	eNOS	enos	0	1	9	10
PKCalpha can mediate activation of eNOS by phosphorylation at residue Ser1179 and increase NO production [ XREF_BIBR ] .	PKCalpha can mediate activation of eNOS by phosphorylation at residue Ser1179 and increase NO production [XREF_BIBR].	0	6	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	eNOS	eNOS	eNOS	0	1	5	6
Studies are being initiated to test the hypothesis that T1D induced PKCalpha mediates NOS3 dysfunction in the mTAL .	Studies are being initiated to test the hypothesis that T1D induced PKCalpha mediates NOS3 dysfunction in the mTAL.	11	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	NOS3	NOS3	NOS3	11	12	13	14
Increased phosphorylation of PKC-alpha is required for Cav-1 and eNOS dissociation and enhanced eNOS activity ( 10 , 22 ) .	Increased phosphorylation of PKC-alpha is required for Cav-1 and eNOS dissociation and enhanced eNOS activity (10, 22).	1	14	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKC-alpha	phosphorylation of PKC-alpha	pkc-alpha	eNOS	eNOS	enos	3	4	13	14
Moreover , ACEi increases tissue bradykinin levels , stimulating bradykinin receptors on endothelial cells , which may result in NOS3 upregulation mediated by PKCalpha , as reviewed elsewhere .	Moreover, ACEi increases tissue bradykinin levels, stimulating bradykinin receptors on endothelial cells, which may result in NOS3 upregulation mediated by PKCalpha, as reviewed elsewhere.	19	24	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	NOS3	NOS3	NOS3	23	24	19	20
Dominant negative PKC-alpha abolished the effect of CPI-17 on actin cytoskeleton , suggesting that the PKC-alpha isoform is most likely responsible for CPI-17 activation in the endothelium .	Dominant negative PKC-alpha abolished the effect of CPI-17 on actin cytoskeleton, suggesting that the PKC-alpha isoform is most likely responsible for CPI-17 activation in the endothelium.	0	8	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PKC-alpha	PKC-alpha	PKC-alpha	CPI-17	CPI-17	CPI-17	2	3	7	8
Because PKCalpha is proposed to activate CPI-17 , we proceeded to determine the spatial-temporal distribution of CPI-17 in these tissues under similar conditions .	Because PKCalpha is proposed to activate CPI-17, we proceeded to determine the spatial-temporal distribution of CPI-17 in these tissues under similar conditions.	1	7	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	CPI-17	CPI-17	CPI-17	1	2	6	7
PKCalpha-CT localizes to nuclei and directly promotes nucleo cytoplasmic shuttling of HDAC5 , which induces expression of apoptosis and other deleterious genes , leading to heart failure [ XREF_BIBR , XREF_BIBR ] .	PKCalpha-CT localizes to nuclei and directly promotes nucleo cytoplasmic shuttling of HDAC5, which induces expression of apoptosis and other deleterious genes, leading to heart failure [XREF_BIBR, XREF_BIBR].	0	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCalpha-CT	PKCalpha-CT	PKCalpha-CT	HDAC5	HDAC5	HDAC5	0	1	11	12
PKCalpha-CT constitutively localizes to nuclei and directly promotes nucleo cytoplasmic shuttling of HDAC5 , inducing expression of apoptosis and other deleterious genes .	PKCalpha-CT constitutively localizes to nuclei and directly promotes nucleo cytoplasmic shuttling of HDAC5, inducing expression of apoptosis and other deleterious genes.	0	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCalpha-CT	PKCalpha-CT	PKCalpha-CT	HDAC5	HDAC5	HDAC5	0	1	12	13
Prior studies from our laboratory have demonstrated that E. coli K1 induces actin polymerization beneath the bacteria by inducing PKC-alpha phosphorylation , which allows MARCKS to translocate from membranes to the cytosol in human brain microvascular endothelial cells ( HBMEC ) .	Prior studies from our laboratory have demonstrated that E. coli K1 induces actin polymerization beneath the bacteria by inducing PKC-alpha phosphorylation, which allows MARCKS to translocate from membranes to the cytosol in human brain microvascular endothelial cells (HBMEC).	19	26	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKC-alpha	PKC-alpha phosphorylation	pkc-alpha	MARCKS	MARCKS	marcks	19	20	24	25
We conclude that activation of classic PKCs , mainly PKC-alpha , inhibits PKC-zeta and may mediate the action of PED on glucose uptake in L6 skeletal muscle cells .	We conclude that activation of classic PKCs, mainly PKC-alpha, inhibits PKC-zeta and may mediate the action of PED on glucose uptake in L6 skeletal muscle cells.	6	20	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKC-alpha	PKC-alpha	PKC-alpha	PED	PED	PED	9	10	19	20
The reduced PKCbeta expression impairs eNOS activation , which can be reversed by a PKCbeta specific synthetic inhibitor , LY379196 [ XREF_BIBR ] .	The reduced PKCbeta expression impairs eNOS activation, which can be reversed by a PKCbeta specific synthetic inhibitor, LY379196 [XREF_BIBR].	5	15	reversed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PKCbeta	PKCbeta	PKCbeta	eNOS	eNOS	eNOS	14	15	5	6
Next , PKCalpha mediates c-Met travel along the microtubule network towards the late perinuclear compartments .	Next, PKCalpha mediates c-Met travel along the microtubule network towards the late perinuclear compartments.	2	5	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCalpha	PKCalpha	PKCalpha	c-Met	c-Met	c-Met	2	3	4	5
The total membrane levels of PKCepsilon were also increased in the hearts of CGL-Tg + mice ( p < 0.05 vs. Non Tg ) , indicating translocation of PKCepsilon to the membrane .	The total membrane levels of PKCepsilon were also increased in the hearts of CGL-Tg + mice (p < 0.05 vs. Non Tg), indicating translocation of PKCepsilon to the membrane.	3	29	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCepsilon	levels of PKCepsilon	pkcepsilon	PKCepsilon	PKCepsilon	pkcepsilon	5	6	28	29
The latter activity was associated with modulation of PKCepsilon phosphorylation , where DHS restored the phosphorylated and total PKCepsilon ratio to the levels observed in control cells .	The latter activity was associated with modulation of PKCepsilon phosphorylation, where DHS restored the phosphorylated and total PKCepsilon ratio to the levels observed in control cells.	8	19	restored	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	PKCepsilon	PKCepsilon phosphorylation	pkcepsilon	PKCepsilon	PKCepsilon	pkcepsilon	8	9	18	19
The total membrane levels of PKCepsilon were also increased during this time period ( p < 0.05 vs. Sham , ) , indicating translocation of PKCepsilon to the membrane .	The total membrane levels of PKCepsilon were also increased during this time period (p < 0.05 vs. Sham,), indicating translocation of PKCepsilon to the membrane.	3	26	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCepsilon	levels of PKCepsilon	pkcepsilon	PKCepsilon	PKCepsilon	pkcepsilon	5	6	25	26
Pyruvate carboxylase ASO treatment decreased hepatic DAG content in cytosol and membrane fractions , decreased activation of PKCepsilon , and increased insulin mediated hepatic Akt Ser 367 phosphorylation ( XREF_FIG ) , a key node of the insulin signaling pathway .	Pyruvate carboxylase ASO treatment decreased hepatic DAG content in cytosol and membrane fractions, decreased activation of PKCepsilon, and increased insulin mediated hepatic Akt Ser 367 phosphorylation (XREF_FIG), a key node of the insulin signaling pathway.	14	28	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKCepsilon	PKCepsilon, and increased insulin mediated hepatic Akt Ser 367 phosphorylation	pkcepsilon	PKCepsilon	PKCepsilon	pkcepsilon	17	18	17	18
In addition , propofol increased phosphorylation of PKCepsilon as well as TRPV1 and stimulated translocation of PKCepsilon from cytosolic to membrane fraction .	In addition, propofol increased phosphorylation of PKCepsilon as well as TRPV1 and stimulated translocation of PKCepsilon from cytosolic to membrane fraction.	3	17	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCepsilon	propofol increased phosphorylation of PKCepsilon	pkcepsilon	PKCepsilon	PKCepsilon	pkcepsilon	7	8	16	17
Moreover , propofol ( 10 muM ) stimulates the phosphorylation of PKCepsilon at S729 and induces the translocation of PKCepsilon from cytosolic to membrane fractions , indicating PKCepsilon activation Effect of Propofol on Restoration of TRPV1 Sensitivity in Mouse DRG Neurons .	Moreover, propofol (10 muM) stimulates the phosphorylation of PKCepsilon at S729 and induces the translocation of PKCepsilon from cytosolic to membrane fractions, indicating PKCepsilon activation Effect of Propofol on Restoration of TRPV1 Sensitivity in Mouse DRG Neurons.	2	20	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCepsilon	propofol (10 muM) stimulates the phosphorylation of PKCepsilon at S729	pkcepsilon	PKCepsilon	PKCepsilon	pkcepsilon	11	12	19	20
Regulation of hnRNP K activation by PKCdelta was studied in MCT cells .	Regulation of hnRNP K activation by PKCdelta was studied in MCT cells.	2	7	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	hnRNP K	hnRNP K	hnRNP K	6	7	2	4
hnRNPK immunoprecipitation experiments in SaOS2-K-WT and SaOS2-K-2RK cells treated with etoposide and PKCdelta overexpression showed that 2RK hnRNPK exhibited higher Ser302 phosphorylation than WT hnRNPK , as shown in Figure XREF_FIG .	hnRNPK immunoprecipitation experiments in SaOS2-K-WT and SaOS2-K-2RK cells treated with etoposide and PKCdelta overexpression showed that 2RK hnRNPK exhibited higher Ser302 phosphorylation than WT hnRNPK, as shown in Figure XREF_FIG.	0	13	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	hnRNPK	hnRNPK	hnRNPK	12	13	0	1
To examine whether PKCdelta modulates EGFR transactivation as an upstream signaling molecule , H. pylori induced EGFR phosphorylation was assessed .	To examine whether PKCdelta modulates EGFR transactivation as an upstream signaling molecule, H. pylori induced EGFR phosphorylation was assessed.	3	6	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	EGFR	EGFR	EGFR	3	4	5	6
In view of the previously reported data indicating that COX-2 transcriptional activation by PMA is mediated via PKCdelta XREF_BIBR , we investigated the role of PKCdelta in PMA induced p300 HAT activation .	In view of the previously reported data indicating that COX-2 transcriptional activation by PMA is mediated via PKCdelta XREF_BIBR, we investigated the role of PKCdelta in PMA induced p300 HAT activation.	23	31	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	p300 HAT	p300 HAT	p300 HAT	25	26	29	31
We now report a novel association between alpha-synuclein ( alphasyn ) , a protein associated with the pathogenesis of Parkinson ' s diseases ( PD ) , and PKCdelta , in which alphasyn negatively modulates the p300 and NFkappaB dependent transactivation to down-regulate proapoptotic kinase PKCdelta expression and thereby protects against apoptosis in dopaminergic neuronal cells .	We now report a novel association between alpha-synuclein (alphasyn), a protein associated with the pathogenesis of Parkinson 's diseases (PD), and PKCdelta, in which alphasyn negatively modulates the p300 and NFkappaB dependent transactivation to down-regulate proapoptotic kinase PKCdelta expression and thereby protects against apoptosis in dopaminergic neuronal cells.	9	49	modulates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	p300	p300	p300	28	29	36	37
Additional studies demonstrated that PKCdelta activates eNOS to reduce atherosclerosis through altered platelet aggregation in postmenopausal women with type 2 diabetes .	Additional studies demonstrated that PKCdelta activates eNOS to reduce atherosclerosis through altered platelet aggregation in postmenopausal women with type 2 diabetes.	4	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	eNOS	eNOS	eNOS	4	5	6	7
For example , PKCtheta and -epsilon induce insulin resistance by inhibiting insulin receptor substrate 1 ( IRS1 ) and the insulin pathway , while PKCdelta and -lambda have the opposite effect and stimulate the insulin pathway by activating IRS1 [ XREF_BIBR ] .	For example, PKCtheta and -epsilon induce insulin resistance by inhibiting insulin receptor substrate 1 (IRS1) and the insulin pathway, while PKCdelta and -lambda have the opposite effect and stimulate the insulin pathway by activating IRS1 [XREF_BIBR].	24	40	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCdelta	PKCdelta	PKCdelta	IRS1	IRS1	IRS1	24	25	38	39
XREF_FIG shows that very well known activators of PKCgamma such as TPA , H 2 O 2 and IGF-1 induce the disappearance of junctional Cx43 ( XREF_FIG ) .	XREF_FIG shows that very well known activators of PKCgamma such as TPA, H 2 O 2 and IGF-1 induce the disappearance of junctional Cx43 (XREF_FIG).	6	26	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKCgamma	PKCgamma	PKCgamma	Cx43	Cx43	Cx43	8	9	24	25
Nuclear PTEN mediates growth suppression independent of AKT down-regulation and is essential for maintaining chromosomal integrity through physical association with the kinetochore .	Nuclear PTEN mediates growth suppression independent of AKT down-regulation and is essential for maintaining chromosomal integrity through physical association with the kinetochore.	0	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	7	8
XREF_BIBR , XREF_BIBR Reduced or absent PTEN expression results in the hyperactivation PI3K and AKT signaling and is related to poor prognosis as well as resistance to chemotherapy and hormone therapy in breast cancer .	XREF_BIBR, XREF_BIBR Reduced or absent PTEN expression results in the hyperactivation PI3K and AKT signaling and is related to poor prognosis as well as resistance to chemotherapy and hormone therapy in breast cancer.	6	16	signaling	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	6	7	14	15
We also identified p110alpha and p110delta as the major isoforms mediating the PI3K and AKT signaling driven by NTRK2 activation and PTEN deficiency in leukocytes .	We also identified p110alpha and p110delta as the major isoforms mediating the PI3K and AKT signaling driven by NTRK2 activation and PTEN deficiency in leukocytes.	12	22	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	21	22	14	15
The tumor suppressor gene , phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) , antagonizes the PI3-K pathway and subsequently inhibits the downstream effectors of PI3-K , Akt and mTOR .	The tumor suppressor gene, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), antagonizes the PI3-K pathway and subsequently inhibits the downstream effectors of PI3-K, Akt and mTOR.	5	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	5	9	30	31
It is interesting that Huang and colleagues demonstrated that PTEN down regulation results in upregulation of Akt and Bcl-2 , thus illustrating the possible cross-talk between the Bcl-2 and PI3K and Akt pathway [ XREF_BIBR ] .	It is interesting that Huang and colleagues demonstrated that PTEN down regulation results in upregulation of Akt and Bcl-2, thus illustrating the possible cross-talk between the Bcl-2 and PI3K and Akt pathway [XREF_BIBR].	9	18	upregulation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	16	17
Inhibition of Akt by either triciribine treatment ( XREF_FIG ) or siRNA mediated knockdown ( XREF_FIG ) induced HIF-2alpha activity , consistent with our finding that PTEN antagonism of Akt signaling results induction of HIF-2alpha activity ( XREF_FIG ) .	Inhibition of Akt by either triciribine treatment (XREF_FIG) or siRNA mediated knockdown (XREF_FIG) induced HIF-2alpha activity, consistent with our finding that PTEN antagonism of Akt signaling results induction of HIF-2alpha activity (XREF_FIG).	26	30	antagonism	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	26	27	29	30
Ectopic expression of the tumor suppressor PTEN which inhibits PI3K and Akt pathway sensitized cisplatin resistant ovarian cancer 2008/C13 * cells containing wild-type p53 but not in A2780/CP cells containing mutant p53 [ XREF_BIBR ] .	Ectopic expression of the tumor suppressor PTEN which inhibits PI3K and Akt pathway sensitized cisplatin resistant ovarian cancer 2008/C13 * cells containing wild-type p53 but not in A2780/CP cells containing mutant p53 [XREF_BIBR].	1	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of the tumor suppressor PTEN	pten	Akt	Akt	akt	6	7	11	12
Although downregulation of PTEN and subsequent activation of AKT signalling is necessary for miR-200c to facilitate metastasis , there may be exist other downstream targets of miR-200c required for metastasis progression that need to be identified and investigated by future studies .	Although downregulation of PTEN and subsequent activation of AKT signalling is necessary for miR-200c to facilitate metastasis, there may be exist other downstream targets of miR-200c required for metastasis progression that need to be identified and investigated by future studies.	3	9	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	8	9
As a result , the downregulation of PTEN may increase phosphatidylinositol ( 3 , 4 , 5 ) triphosphate ( PIP3 ) and produce subsequent activation of AKT .	As a result, the downregulation of PTEN may increase phosphatidylinositol (3, 4, 5) triphosphate (PIP3) and produce subsequent activation of AKT.	5	28	produce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	27	28
Inactivation of PTEN was reported to cause Akt activation and activated Akt phosphorylates beta-catenin , a main effector of the Wnt pathway , resulting in beta-catenin ' s nuclear localization .	Inactivation of PTEN was reported to cause Akt activation and activated Akt phosphorylates beta-catenin, a main effector of the Wnt pathway, resulting in beta-catenin 's nuclear localization.	0	8	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	7	8
VPA mediated inhibition of histone de-acetylase , in fact , could rescue PTEN expression , and consequently down-regulate the AKT pathway and glucose uptake in these cells .	VPA mediated inhibition of histone de-acetylase, in fact, could rescue PTEN expression, and consequently down-regulate the AKT pathway and glucose uptake in these cells.	4	20	down-regulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	histone de-acetylase, in fact, could rescue PTEN expression	pten	AKT	AKT	akt	12	13	19	20
In particular , nearly 70 % of advanced PCa exhibit loss of PTEN or consequent activation of the PI3K and AKT pathway , which leads to enhanced cell survival , metastasis , and castration resistant growth .	In particular, nearly 70% of advanced PCa exhibit loss of PTEN or consequent activation of the PI3K and AKT pathway, which leads to enhanced cell survival, metastasis, and castration resistant growth.	12	21	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	12	13	20	21
PTEN down-regulation increases AKT activation and enhances cell survival after UVB damage .	PTEN down-regulation increases AKT activation and enhances cell survival after UVB damage.	0	4	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	3	4
Accordingly , these results confirmed that trastuzumab resistance of NCI-N87/TR cells was related to the PI3K-AKT signaling pathway which was activated by PTEN gene down-regulation and mutation and over-activity of IGF-1R signaling pathway .	Accordingly, these results confirmed that trastuzumab resistance of NCI-N87/TR cells was related to the PI3K-AKT signaling pathway which was activated by PTEN gene down-regulation and mutation and over-activity of IGF-1R signaling pathway.	15	24	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	22	23	15	16
44 Similar to JNK3 pathway and Ubiquitin signaling cascade , here we proposed the PTEN mediated Akt and PKB signaling pathway which plays an important role in axonal growth and stability of motor neurons through the regulation of its downstream cellular functions .	44 Similar to JNK3 pathway and Ubiquitin signaling cascade, here we proposed the PTEN mediated Akt and PKB signaling pathway which plays an important role in axonal growth and stability of motor neurons through the regulation of its downstream cellular functions.	13	20	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	16	17
Immunohistochemical analysis ( XREF_FIG ) , as well as protein blot detection of Pten ( XREF_FIG ) , confirmed that both Pten hy/+ and Pten +/- tumors retained Pten protein expression according to their genotype , and increased activation of the Akt protein ( as indicated by phosphorylation at Ser473 ) as the levels of Pten were reduced , strongly suggesting that these tumors do not arise from subpopulations of cells expressing lower levels of the TSG .	Immunohistochemical analysis (XREF_FIG), as well as protein blot detection of Pten (XREF_FIG), confirmed that both Pten hy/+ and Pten +/- tumors retained Pten protein expression according to their genotype, and increased activation of the Akt protein (as indicated by phosphorylation at Ser473) as the levels of Pten were reduced, strongly suggesting that these tumors do not arise from subpopulations of cells expressing lower levels of the TSG.	20	42	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	21	22	41	42
The hypoacetylated TRB3 and PTEN can inhibit the Akt activity in a rat model of prenatal alcohol exposure , which suggests that HDACI treatment could inhibit the activity of TRB3 and PTEN , which in turn would enhance the Akt signaling .	The hypoacetylated TRB3 and PTEN can inhibit the Akt activity in a rat model of prenatal alcohol exposure, which suggests that HDACI treatment could inhibit the activity of TRB3 and PTEN, which in turn would enhance the Akt signaling.	2	9	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	8	9
Tbeta4- and miR-200-induced down-regulation of PTEN , therefore , induced AKT activation .	Tbeta4- and miR-200-induced down-regulation of PTEN, therefore, induced AKT activation.	3	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	10	11
Moreover , we have demonstrated that PTEN deficient cells had higher basal ROS production , elevated inflammatory mediator secretion , and increased tumor cell growth , as well as enhanced activation of Akt and p38 MAPK and decreased activation of ERK1/2 .	Moreover, we have demonstrated that PTEN deficient cells had higher basal ROS production, elevated inflammatory mediator secretion, and increased tumor cell growth, as well as enhanced activation of Akt and p38 MAPK and decreased activation of ERK1/2.	6	35	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	32	33
By contrast , when transducted with AdPTENWT , the phosphorylation levels of PDK1 ( ser 241 ) , AKT ( Ser 473 and Thr 308 ) , and ERK1/2 were significantly reduced to 0.38-fold ( P < 0.05 ) , 0.21-fold ( P < 0.05 ) , 0.28-fold ( P < 0.05 ) , and 0.61-fold ( P < 0.05 ) of the control , respectively , suggesting that overexpression of PTEN modulates the basal activities of both PI3K-AKT and MAPK-ERK cascades .	By contrast, when transducted with AdPTENWT, the phosphorylation levels of PDK1 (ser 241), AKT (Ser 473 and Thr 308), and ERK1/2 were significantly reduced to 0.38-fold (P < 0.05), 0.21-fold (P < 0.05), 0.28-fold (P < 0.05), and 0.61-fold (P < 0.05) of the control, respectively, suggesting that overexpression of PTEN modulates the basal activities of both PI3K-AKT and MAPK-ERK cascades.	69	81	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	overexpression of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	71	72	78	79
In these cell lines , addition of histone deacetylase ( HDAC ) inhibitor treatment overcame Nutlin-3 resistance , and was associated with PTEN and p21 up-regulation and inactivation of AKT .	In these cell lines, addition of histone deacetylase (HDAC) inhibitor treatment overcame Nutlin-3 resistance, and was associated with PTEN and p21 up-regulation and inactivation of AKT.	22	30	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	22	23	29	30
Interestingly , loss of the tumor suppressor phosphatase PTEN ( which occurs in 29 % of TNBC ) , results in up-regulation of the PI3K and Akt pathway , and is associated with lack of response to MEK inhibitors .	Interestingly, loss of the tumor suppressor phosphatase PTEN (which occurs in 29% of TNBC), results in up-regulation of the PI3K and Akt pathway, and is associated with lack of response to MEK inhibitors.	2	27	results in up-regulation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	loss of the tumor suppressor phosphatase PTEN	pten	Akt	Akt	akt	8	9	26	27
PTEN is a key molecule in the development of many diseases because PTEN modulates cell proliferation , survival , apoptosis and metabolism via its target molecules , phosphoinositide-3kinase ( PI3K ) and Akt [ XREF_BIBR ] .	PTEN is a key molecule in the development of many diseases because PTEN modulates cell proliferation, survival, apoptosis and metabolism via its target molecules, phosphoinositide-3kinase (PI3K) and Akt [XREF_BIBR].	12	34	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	12	13	32	33
There was no change in total expression of p-PTEN ( an activator of Akt ) in any of the other groups .	There was no change in total expression of p-PTEN (an activator of Akt) in any of the other groups.	6	16	activator	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	p-PTEN	expression of p-PTEN	p-pten	Akt	Akt	akt	8	9	13	14
By contrast , the down-regulation of PTEN by small interfering RNAs enhanced Akt and PKB activation and glucose uptake in response to insulin [ XREF_BIBR ] .	By contrast, the down-regulation of PTEN by small interfering RNAs enhanced Akt and PKB activation and glucose uptake in response to insulin [XREF_BIBR].	4	15	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	12	13
These PTEN -/- mice have activated Akt ( serine/threonine protein kinase ) and MAPK ( mitogen activated protein kinase ) , steatohepatitis , and an increase in hepatocellular carcinomas .	These PTEN -/- mice have activated Akt (serine/threonine protein kinase) and MAPK (mitogen activated protein kinase), steatohepatitis, and an increase in hepatocellular carcinomas.	0	25	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	6	7
PTEN deficiency causes Akt ( Protein Kinase B , or PKB ) hyperactivition and in consequence tumor initiation and progression .	PTEN deficiency causes Akt (Protein Kinase B, or PKB) hyperactivition and in consequence tumor initiation and progression.	0	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	0	1	10	11
Since lapatinib blocks AKT phosphorylation by inhibiting both EGFR and HER2 , its activity does not depend on phosphatase and tensin homolog ( PTEN ) , the phosphatase that negatively regulates AKT and is required for trastuzumab anti-tumor activity .	Since lapatinib blocks AKT phosphorylation by inhibiting both EGFR and HER2, its activity does not depend on phosphatase and tensin homolog (PTEN), the phosphatase that negatively regulates AKT and is required for trastuzumab anti-tumor activity.	18	32	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	18	22	31	32
In addition , PTEN could inhibited tumor cell growth and invasion by suppressing the PI3k and Akt pathway .	In addition, PTEN could inhibited tumor cell growth and invasion by suppressing the PI3k and Akt pathway.	3	17	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	16	17
Moreover , TOPK phosphorylates and inactivates PTEN , which in turn activates Akt that leads to proper G2/M progression .	Moreover, TOPK phosphorylates and inactivates PTEN, which in turn activates Akt that leads to proper G2/M progression.	2	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	TOPK phosphorylates and inactivates PTEN	pten	Akt	Akt	akt	6	7	12	13
Mir-494 has also been shown to regulate the accumulation and activity of myeloid derived suppressor cells by targeting PTEN mediated activation of the AKT signaling pathway [ XREF_BIBR ] .	Mir-494 has also been shown to regulate the accumulation and activity of myeloid derived suppressor cells by targeting PTEN mediated activation of the AKT signaling pathway [XREF_BIBR].	18	25	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	18	19	23	24
Genetic ablation of PTEN causes Akt overactivation , apoptosis resistance and cavitation blockade .	Genetic ablation of PTEN causes Akt overactivation, apoptosis resistance and cavitation blockade.	1	6	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	5	6
Moreover , PTEN lipid phosphatase inactivation promoted the PI3K and Akt pathway , and disruption of YAP-TEAD-driven transcription decreased the activation of Akt in a dose dependent manner .	Moreover, PTEN lipid phosphatase inactivation promoted the PI3K and Akt pathway, and disruption of YAP-TEAD-driven transcription decreased the activation of Akt in a dose dependent manner.	2	11	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	10	11
PTEN increases sensitivity to cell death in response to several apoptotic stimuli by negatively regulating the PI3K and AKT pathway [ XREF_BIBR ] .	PTEN increases sensitivity to cell death in response to several apoptotic stimuli by negatively regulating the PI3K and AKT pathway [XREF_BIBR].	0	21	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	18	19
PTEN Negatively Regulates hTERT by Inhibiting the PI3K and AKT Pathway .	PTEN Negatively Regulates hTERT by Inhibiting the PI3K and AKT Pathway.	0	10	Negatively Regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	9	10
Accordingly , inactivated PTEN should augment beta-catenin signaling by favoring retention of inactive phospho-( S 9 ) GSK3beta and active phospho-( S 473 ) Akt kinase .	Accordingly, inactivated PTEN should augment beta-catenin signaling by favoring retention of inactive phospho-(S 9) GSK3beta and active phospho-(S 473) Akt kinase.	3	25	augment	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	24	25
They were also shown to elevate the reduced PTEN expression in a resistant and ABCG2 overexpressing cell model , which inhibit the PI3K-Akt pathway and lead to the relocalization of ABCG2 from the plasma membrane to the cytoplasma , thus apparently circumventing the ABCG2 mediated MDR .	They were also shown to elevate the reduced PTEN expression in a resistant and ABCG2 overexpressing cell model, which inhibit the PI3K-Akt pathway and lead to the relocalization of ABCG2 from the plasma membrane to the cytoplasma, thus apparently circumventing the ABCG2 mediated MDR.	8	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	PI3K-Akt	PI3K-Akt	pi3k-akt	8	9	22	23
shRNA mediated depletion of PTEN , which induces AKT activation , disrupts BRAF V600E -induced senescence in both primary human fibroblasts and primary human melanocytes .	shRNA mediated depletion of PTEN, which induces AKT activation, disrupts BRAF V600E -induced senescence in both primary human fibroblasts and primary human melanocytes.	2	9	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	8	9
The mechanism of action with regard to latency reversal appears to be through depletion of the intracellular protein PTEN , which in turn activates the Akt signaling pathway to initiate proviral transcription in an NFkB dependent manner [ XREF_BIBR ] .	The mechanism of action with regard to latency reversal appears to be through depletion of the intracellular protein PTEN, which in turn activates the Akt signaling pathway to initiate proviral transcription in an NFkB dependent manner [XREF_BIBR].	13	27	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	25	26
Previous studies have shown that the activation of the PI3K and Akt signaling network plays a critical role in MDR and loss of PTEN induced activation of Akt .	Previous studies have shown that the activation of the PI3K and Akt signaling network plays a critical role in MDR and loss of PTEN induced activation of Akt.	19	28	induced	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	23	24	27	28
The tumor suppressor phosphatase and tensin homolog ( PTEN ) , whose expression is also induced by TP53 [ XREF_BIBR ] , can also suppress mTORC1 by inhibiting PI3K and AKT signaling [ XREF_BIBR ] , a well established signaling pathway that stimulates mTORC1 .	The tumor suppressor phosphatase and tensin homolog (PTEN), whose expression is also induced by TP53 [XREF_BIBR], can also suppress mTORC1 by inhibiting PI3K and AKT signaling [XREF_BIBR], a well established signaling pathway that stimulates mTORC1.	3	31	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	30	31
21 PTEN is a potent inhibitor of the oncogenic Akt pathway , and PTEN inactivation causes hyperactivation of Akt .	21 PTEN is a potent inhibitor of the oncogenic Akt pathway, and PTEN inactivation causes hyperactivation of Akt.	13	19	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	18	19
Our recent studies have found that Cd down-regulation of PTEN results in activation of Akt and mTOR signaling and apoptosis of neuronal cells , which is attenuated by rapamycin [ XREF_BIBR ] .	Our recent studies have found that Cd down-regulation of PTEN results in activation of Akt and mTOR signaling and apoptosis of neuronal cells, which is attenuated by rapamycin [XREF_BIBR].	7	17	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	14	15
Akt activity is also negatively modulated by the PTEN .	Akt activity is also negatively modulated by the PTEN.	0	9	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	0	1
The finding that expression of the PTEN C2 domain constructs in cultured cells could activate Akt and PKB suggests that it is possible that the C2 domain of PTEN directly interferes with PI3K dependent directional sensing through an unknown mechanism , resulting in the observed random migration .	The finding that expression of the PTEN C2 domain constructs in cultured cells could activate Akt and PKB suggests that it is possible that the C2 domain of PTEN directly interferes with PI3K dependent directional sensing through an unknown mechanism, resulting in the observed random migration.	3	17	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	expression of the PTEN	pten	Akt	Akt	akt	6	7	15	16
We therefore hypothesized that miR-494 might inhibit the expression of PTEN , which activates the PI3K and AKT pathway and reduces the H/R induced hepatic apoptosis .	We therefore hypothesized that miR-494 might inhibit the expression of PTEN, which activates the PI3K and AKT pathway and reduces the H/R induced hepatic apoptosis.	4	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	miR-494 might inhibit the expression of PTEN	pten	AKT	AKT	akt	10	11	17	18
AKT is activated by PTEN and cell growth is enhanced via mTOR .	AKT is activated by PTEN and cell growth is enhanced via mTOR.	0	5	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	0	1
In liver cancer , miR-21 inhibited PTEN and human sulfate-1 ( sulfatase-1 , hSulf-1 ) expression , resulting in activation of the AKT and ERK pathway and ; XREF_BIBR a similar effect was seen in cholangiocarcinoma , XREF_BIBR and clear cell renal carcinoma .	In liver cancer, miR-21 inhibited PTEN and human sulfate-1 (sulfatase-1, hSulf-1) expression, resulting in activation of the AKT and ERK pathway and; XREF_BIBR a similar effect was seen in cholangiocarcinoma, XREF_BIBR and clear cell renal carcinoma.	6	25	resulting in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	22	23
PTEN reduces glucose uptake by suppressing the PI3K and AKT pathway , whereas it enhances the stability of glutaminase by inhibiting proteasome dependent protein degradation in a PI3K independent manner .	PTEN reduces glucose uptake by suppressing the PI3K and AKT pathway, whereas it enhances the stability of glutaminase by inhibiting proteasome dependent protein degradation in a PI3K independent manner.	0	10	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	9	10
PTEN negatively regulates Akt activation , and activated Akt phosphorylates and inactivates EZH2 [ XREF_BIBR ] .	PTEN negatively regulates Akt activation, and activated Akt phosphorylates and inactivates EZH2 [XREF_BIBR].	0	13	activated	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	PTEN	PTEN	pten	Akt	Akt phosphorylates and inactivates EZH2	akt	0	1	8	9
We previously showed that K-ras activation and Pten haploinsufficiency cooperate to activate P-AKT in pre-cancerous lesions and accelerate tumor development in our mouse model of PDAC , suggesting that PTEN loss of function is a critical factor for determining the onset of lethal tumor development .	We previously showed that K-ras activation and Pten haploinsufficiency cooperate to activate P-AKT in pre-cancerous lesions and accelerate tumor development in our mouse model of PDAC, suggesting that PTEN loss of function is a critical factor for determining the onset of lethal tumor development.	7	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	P-AKT	P-AKT	P-AKT	7	8	12	13
It has been reported by our laboratory that increased expression of miR-21 leads to decreased expression of PTEN , a known tumor suppressor , which inhibits PI3K and Akt signaling pathway in cancers XREF_BIBR , XREF_BIBR .	It has been reported by our laboratory that increased expression of miR-21 leads to decreased expression of PTEN, a known tumor suppressor, which inhibits PI3K and Akt signaling pathway in cancers XREF_BIBR, XREF_BIBR.	15	30	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	17	18	28	29
Restriction of glycogenesis was proved to be conducted through PTEN mediated AKT and GSK pathway inhibition .	Restriction of glycogenesis was proved to be conducted through PTEN mediated AKT and GSK pathway inhibition.	7	15	mediated	Positive_early_activation	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	11	12
Mutations in PI3K , PTEN , RAS , or other upstream regulators can activate the AKT kinase which has central roles in supporting cell proliferation and survival .	Mutations in PI3K, PTEN, RAS, or other upstream regulators can activate the AKT kinase which has central roles in supporting cell proliferation and survival.	0	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	15	16
Thus PTEN , by suppressing PI3K and Akt signaling , also suppresses the downstream mTOR kinase activity .	Thus PTEN, by suppressing PI3K and Akt signaling, also suppresses the downstream mTOR kinase activity.	1	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	7	8
PTEN phosphatase negatively regulates integrin growth signaling by inhibiting Akt .	PTEN phosphatase negatively regulates integrin growth signaling by inhibiting Akt.	0	10	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	9	10
Our data suggest that UA inhibits miR-21 expression and increases PTEN expression , which in turn inhibits Akt and mTOR and restores normal levels of autophagy .	Our data suggest that UA inhibits miR-21 expression and increases PTEN expression, which in turn inhibits Akt and mTOR and restores normal levels of autophagy.	4	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	UA inhibits miR-21 expression and increases PTEN expression	pten	Akt	Akt	akt	10	11	17	18
In response to hypoxia a portion of PTEN migrates to the nucleus and complexes with p53 , while cytoplasmic PTEN prevents Mdm2 nuclear localization by attenuating Akt signaling .	In response to hypoxia a portion of PTEN migrates to the nucleus and complexes with p53, while cytoplasmic PTEN prevents Mdm2 nuclear localization by attenuating Akt signaling.	18	27	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	19	20	26	27
In addition , it is notable that HCC1937 has a phosphatase and tensin homolog on chromosome 10 ( PTEN ) deletion , and the PTEN inactivation causes an increase in cellular PIP3 levels subsequently activating PI3K and AKT signaling .	In addition, it is notable that HCC1937 has a phosphatase and tensin homolog on chromosome 10 (PTEN) deletion, and the PTEN inactivation causes an increase in cellular PIP3 levels subsequently activating PI3K and AKT signaling.	24	38	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	24	25	37	38
miRNA-21 inhibits PTEN , which in turn activates the prosurvival Akt kinase pathway to promote several cardioprotective mediators including eNOS , HSP-70 , AP-1 , and heat shock transcription factor 1 ( XREF_FIG ) .	miRNA-21 inhibits PTEN, which in turn activates the prosurvival Akt kinase pathway to promote several cardioprotective mediators including eNOS, HSP-70, AP-1, and heat shock transcription factor 1 (XREF_FIG).	1	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	10	11
The results suggest a decline of the survival capacity of aging outer hair cells due to a decrease in PIP 3 / Akt signaling caused by an increase of PTEN .	The results suggest a decline of the survival capacity of aging outer hair cells due to a decrease in PIP 3 / Akt signaling caused by an increase of PTEN.	22	30	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	29	30	22	23
To characterize further the inhibition of EMT and directional migration seen with these C-terminal polypeptides , we investigated their effects on PI3K dependent signaling , finding that expression of the PTEN C2 domain was also found to cause a small but reproducible activation of Akt and PKB in cultured cells lacking PTEN .	To characterize further the inhibition of EMT and directional migration seen with these C-terminal polypeptides, we investigated their effects on PI3K dependent signaling, finding that expression of the PTEN C2 domain was also found to cause a small but reproducible activation of Akt and PKB in cultured cells lacking PTEN.	27	46	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	expression of the PTEN	pten	Akt	Akt	akt	30	31	44	45
TOPK phosphorylates and inactivates PTEN , which in turn activates Akt that leads to proper G2/M progression [ XREF_BIBR ] .	TOPK phosphorylates and inactivates PTEN, which in turn activates Akt that leads to proper G2/M progression [XREF_BIBR].	0	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	TOPK phosphorylates and inactivates PTEN	pten	Akt	Akt	akt	4	5	10	11
27 These findings suggested that downregulation of TET1 reduces the expression of PTEN , which subsequently activate AKT and MTOR pathway in COX-2-driven HCC .	27 These findings suggested that downregulation of TET1 reduces the expression of PTEN, which subsequently activate AKT and MTOR pathway in COX-2-driven HCC.	7	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	TET1 reduces the expression of PTEN	pten	AKT	AKT	akt	12	13	17	18
Synergistic Akt activation by combined PTEN and NHERF1 silencing leads to the identification of PHLPP proteins as novel NHERF1 ligands .	Synergistic Akt activation by combined PTEN and NHERF1 silencing leads to the identification of PHLPP proteins as novel NHERF1 ligands.	1	8	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	1	2
For downstream signaling molecules , the downregulation or deficiency of phosphatase and tensin homolog ( PTEN ) [ XREF_BIBR , XREF_BIBR ] and amplification or E545K mutation of the PIK3CA gene , which encodes the catalytic subunit of PI3K [ XREF_BIBR , XREF_BIBR ] , activate the PI3K and AKT signaling pathway and contribute to EGFR TKI resistance .	For downstream signaling molecules, the downregulation or deficiency of phosphatase and tensin homolog (PTEN) [XREF_BIBR, XREF_BIBR] and amplification or E545K mutation of the PIK3CA gene, which encodes the catalytic subunit of PI3K [XREF_BIBR, XREF_BIBR], activate the PI3K and AKT signaling pathway and contribute to EGFR TKI resistance.	6	51	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	15	16	49	50
Thus , Snail prevents IR mediated PTEN upregulation and activates the Akt pathway , thereby increasing radioresistance [ XREF_BIBR ] .	Thus, Snail prevents IR mediated PTEN upregulation and activates the Akt pathway, thereby increasing radioresistance [XREF_BIBR].	2	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Snail prevents IR mediated PTEN	pten	Akt	Akt	akt	6	7	11	12
AKT activation was further increased by two-fold in TRbeta PV/PV Pten +/- mice thyroids , leading to increased activity of the downstream mammalian target of rapamycin ( mTOR )-p70S6K signalling and decreased activity of the forkhead family member FOXO3a .	AKT activation was further increased by two-fold in TRbeta PV/PV Pten +/- mice thyroids, leading to increased activity of the downstream mammalian target of rapamycin (mTOR)-p70S6K signalling and decreased activity of the forkhead family member FOXO3a.	0	15	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	AKT	AKT	AKT	10	11	0	1
miR-21 Regulates PTEN mediated Akt Activation in Human Glomerular Mesangial Cells .	miR-21 Regulates PTEN mediated Akt Activation in Human Glomerular Mesangial Cells.	1	5	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	4	5
PTEN inactivation occurs commonly in human cancers and putatively activates the PI3K and AKT / mTOR pathway .	PTEN inactivation occurs commonly in human cancers and putatively activates the PI3K and AKT / mTOR pathway.	0	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	13	14
Specifically , LPS activation of the p38 , JNK1/2 and ERK1/2 MAPK signaling pathways that regulate proinflammatory gene expression in macrophages were significantly reduced in PTEN -/- macrophages , which have enhanced Akt activation .	Specifically, LPS activation of the p38, JNK1/2 and ERK1/2 MAPK signaling pathways that regulate proinflammatory gene expression in macrophages were significantly reduced in PTEN -/- macrophages, which have enhanced Akt activation.	25	33	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	25	26	32	33
In this study , overexpression of PFKP was detected in human glioblastoma ( GBM ) and resulted from AKT activation that , in turn , was induced by phosphatase and tensin homologue ( PTEN ) loss and epidermal growth factor receptor ( EGFR )-dependent phosphoinositide 3-kinase ( PI3K ) activation .	In this study, overexpression of PFKP was detected in human glioblastoma (GBM) and resulted from AKT activation that, in turn, was induced by phosphatase and tensin homologue (PTEN) loss and epidermal growth factor receptor (EGFR)-dependent phosphoinositide 3-kinase (PI3K) activation.	18	35	induced	Positive_activation_syntax_6_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	33	34	18	19
Absent expression of PTEN leads to accumulation of PIP3 and then increases activity of AKT .	Absent expression of PTEN leads to accumulation of PIP3 and then increases activity of AKT.	1	15	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	expression of PTEN	pten	AKT	AKT	akt	3	4	14	15
Previous studies suggest that the antagonism of PI3K and AKT signaling by PTEN may be mediated by a nonphosphorylated form of the protein resident within the multiprotein complex .	Previous studies suggest that the antagonism of PI3K and AKT signaling by PTEN may be mediated by a nonphosphorylated form of the protein resident within the multiprotein complex.	7	13	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	12	13	9	10
Akt activators such as Kras , Shh , EGFR and PTEN have been implicated in PDA XREF_BIBR - XREF_BIBR .	Akt activators such as Kras, Shh, EGFR and PTEN have been implicated in PDA XREF_BIBR - XREF_BIBR.	0	11	activators	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	0	1
In addition , PI3K and PTEN are major upstream activators of Akt , as they determine the production of PIP 3 , which is responsible for PDPK1 and Akt activation through conformational changes and/or translocation to the plasma membrane .	In addition, PI3K and PTEN are major upstream activators of Akt, as they determine the production of PIP 3, which is responsible for PDPK1 and Akt activation through conformational changes and/or translocation to the plasma membrane.	3	12	are major upstream activators	Positive_activation_copula_1	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	11	12
Thus , PTEN expression downregulation can activate PI3K-Akt signaling pathway , which is associated with the development of cancers [ XREF_BIBR ] .	Thus, PTEN expression downregulation can activate PI3K-Akt signaling pathway, which is associated with the development of cancers [XREF_BIBR].	2	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	2	3	7	8
Although it lacked tyrosine phosphorylation activity , the RONDelta165 E2 variant could phosphorylate phosphatase and tensin homolog ( PTEN ) , thereby activating the PI3K and AKT pathway .	Although it lacked tyrosine phosphorylation activity, the RONDelta165 E2 variant could phosphorylate phosphatase and tensin homolog (PTEN), thereby activating the PI3K and AKT pathway.	12	27	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphorylate phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	akt	13	17	26	27
For this reason , loss of pre-BCR and CD19 expression in response to deletion of Pten suggests PTEN mediated feedback regulation of these PI3K-AKT activating receptors .	For this reason, loss of pre-BCR and CD19 expression in response to deletion of Pten suggests PTEN mediated feedback regulation of these PI3K-AKT activating receptors.	16	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	17	18	23	24
Utilizing Cre-loxP technology to specifically inactivate the Pten gene in dopamine neurons ( DA-PTEN-KO mice ) , we and others found that PTEN ablation in dopamine neurons enhances Akt signalling , suppresses apoptosis and preserves striatal innervation following nigrostriatal lesions .	Utilizing Cre-loxP technology to specifically inactivate the Pten gene in dopamine neurons (DA-PTEN-KO mice), we and others found that PTEN ablation in dopamine neurons enhances Akt signalling, suppresses apoptosis and preserves striatal innervation following nigrostriatal lesions.	22	29	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	22	23	28	29
An increase in cellular phosphatidylinositol 3,4,5-trisphosphate in response to dysregulated PTEN activity , even in the absence of stimuli , is sufficient to activate numerous downstream effectors , most notably AKT , extracellular signal regulated kinase ( ERK ) , and mammalian target of rapamycin ( mTOR ) .	An increase in cellular phosphatidylinositol 3,4,5-trisphosphate in response to dysregulated PTEN activity, even in the absence of stimuli, is sufficient to activate numerous downstream effectors, most notably AKT, extracellular signal regulated kinase (ERK), and mammalian target of rapamycin (mTOR).	10	33	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	30	31
However , mutation or malfunctioning of the tumor suppressor protein PTEN activates Akt by constitutively maintaining the PI 3 kinase product PIP 3 leading to sustained growth of tumor cells [ XREF_BIBR - XREF_BIBR ] .	However, mutation or malfunctioning of the tumor suppressor protein PTEN activates Akt by constitutively maintaining the PI 3 kinase product PIP 3 leading to sustained growth of tumor cells [XREF_BIBR - XREF_BIBR].	2	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	12	13
We show here that PTEN modulates the PI3K-Akt pathway in glioblastoma within a tumor suppressor network that includes NHERF1 and PHLPP1 .	We show here that PTEN modulates the PI3K-Akt pathway in glioblastoma within a tumor suppressor network that includes NHERF1 and PHLPP1.	4	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	4	5	7	8
Thus PTEN or Hsp25 could serve as potential therapeutic targets to modulate Akt activation and control p38 MAPK mediated diabetic complications .	Thus PTEN or Hsp25 could serve as potential therapeutic targets to modulate Akt activation and control p38 MAPK mediated diabetic complications.	1	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	12	13
This indicated that loss of PTEN function alone could not deregulate the AKT pathway , a notion that was further strengthened by a strong negative correlation between AKT- and p53-pathway activities in the double PTEN and p53 deficient tumors .	This indicated that loss of PTEN function alone could not deregulate the AKT pathway, a notion that was further strengthened by a strong negative correlation between AKT- and p53-pathway activities in the double PTEN and p53 deficient tumors.	5	13	deregulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	12	13
PTEN in general functions as a dephosphorylase of PI ( 3,4,5 ) P3 , a product of PI3K mediating the activation of PDK-1 and Akt .	PTEN in general functions as a dephosphorylase of PI (3,4,5) P3, a product of PI3K mediating the activation of PDK-1 and Akt.	0	25	mediating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	24	25
Previous studies have also shown that PTEN modulates cell cycle progression by regulating phosphatidylinositol 3,4,5-trisphosphate and Akt signaling pathway XREF_BIBR but the precise mechanism of PTEN activation and inactivation during particular phase of the cell cycle is not known .	Previous studies have also shown that PTEN modulates cell cycle progression by regulating phosphatidylinositol 3,4,5-trisphosphate and Akt signaling pathway XREF_BIBR but the precise mechanism of PTEN activation and inactivation during particular phase of the cell cycle is not known.	6	19	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	16	17
The results from our study indicate that decreased Tgfbr1 expression in Tgfbr1 cKO mice leads to increased cell proliferation and cell survival through PTEN independent activation of PI3K and Akt pathway .	The results from our study indicate that decreased Tgfbr1 expression in Tgfbr1 cKO mice leads to increased cell proliferation and cell survival through PTEN independent activation of PI3K and Akt pathway.	23	30	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	23	24	29	30
Inactivation of PTEN function promotes protein kinase B ( also called Akt ) activation which in turn stimulates the activity of several target genes involved in cell proliferation XREF_BIBR .	Inactivation of PTEN function promotes protein kinase B (also called Akt) activation which in turn stimulates the activity of several target genes involved in cell proliferation XREF_BIBR.	2	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	11	12
TET1 knockdown activated AKT and FAK pathways , which were suppressed by PTEN .	TET1 knockdown activated AKT and FAK pathways, which were suppressed by PTEN.	3	13	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	12	13	3	4
However , energy stress mediated by PTEN activates AKT and mTOR , specifically complex I ( mTORC1 ) .	However, energy stress mediated by PTEN activates AKT and mTOR, specifically complex I (mTORC1).	4	13	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	8	9
miR-29a targets phosphatase and tensin homolog ( PTEN ) mRNA , and it thereby increases the activity of the AKT signalling pathway .	miR-29a targets phosphatase and tensin homolog (PTEN) mRNA, and it thereby increases the activity of the AKT signalling pathway.	5	21	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	19	20
Its oncogenic function is reflected by down-regulation of PTEN ( phosphatase and tensin homolog deleted on chromosome ten ) , TP53 and E2F1 , causing the activation of the PI3K and AKT pathway and inhibiting cellular apoptosis .	Its oncogenic function is reflected by down-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten), TP53 and E2F1, causing the activation of the PI3K and AKT pathway and inhibiting cellular apoptosis.	6	32	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	31	32
This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I , inducing its cytosolic translocation and preserving in this way AKT activity .	This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I, inducing its cytosolic translocation and preserving in this way AKT activity.	5	29	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	phosphorylation of the phosphatase PTEN	pten	AKT	AKT	akt	9	10	28	29
In the case presented here , however , the tumor carries both a KRAS activating mutation and complete inactivation of PTEN , supporting dual activation of both the MEK and ERK and the PI3K and AKT axes .	In the case presented here, however, the tumor carries both a KRAS activating mutation and complete inactivation of PTEN, supporting dual activation of both the MEK and ERK and the PI3K and AKT axes.	18	36	supporting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	20	21	35	36
Mir-21 can also target PTEN and PRAS40 , which in turn may activate Akt and TORC1 respectively , causing renal fibrosis and hypertrophy 79 .	Mir-21 can also target PTEN and PRAS40, which in turn may activate Akt and TORC1 respectively, causing renal fibrosis and hypertrophy 79.	4	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	13	14
Early studies showed that aberrant PTEN expression leads to the activation of PI3K and Akt signaling pathway , targeting NF-kappaB and c-Myc transcription factors [ XREF_BIBR ] .	Early studies showed that aberrant PTEN expression leads to the activation of PI3K and Akt signaling pathway, targeting NF-kappaB and c-Myc transcription factors [XREF_BIBR].	5	16	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	5	6	14	15
The different sensitivities of H 2 O 2 to the phosphorylation of Akt and IR might be derived from the difference in threshold levels of H 2 O 2 for the inactivation of various phosphatases , such as PTEN and PTP1B that target Akt and IR , respectively .	The different sensitivities of H 2 O 2 to the phosphorylation of Akt and IR might be derived from the difference in threshold levels of H 2 O 2 for the inactivation of various phosphatases, such as PTEN and PTP1B that target Akt and IR, respectively.	31	45	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	38	39	43	44
Knockdown of PTEN in cells containing wild-type PTEN enhanced nuclear P-AKT , whereas expression of wild-type PTEN , but not phosphatase dead mutants ( C124S or G129E ) , markedly reduced nuclear P-AKT in PTEN null cells .	Knockdown of PTEN in cells containing wild-type PTEN enhanced nuclear P-AKT, whereas expression of wild-type PTEN, but not phosphatase dead mutants (C124S or G129E), markedly reduced nuclear P-AKT in PTEN null cells.	0	11	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	P-AKT	P-AKT	P-AKT	2	3	10	11
The down-regulation of PTEN levels is a key step during tumorigenesis and potentiates the activation of AKT and mTOR growth and survival signaling .	The down-regulation of PTEN levels is a key step during tumorigenesis and potentiates the activation of AKT and mTOR growth and survival signaling.	3	19	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN levels	pten	AKT	AKT	akt	3	4	16	17
Mechanistically , we found that lncARSR physically associates with PTEN mRNA , promotes PTEN mRNA degradation , decreases PTEN expression , and activates PI3K and Akt pathway .	Mechanistically, we found that lncARSR physically associates with PTEN mRNA, promotes PTEN mRNA degradation, decreases PTEN expression, and activates PI3K and Akt pathway.	5	26	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	lncARSR physically associates with PTEN mRNA, promotes PTEN mRNA degradation, decreases PTEN expression	pten	Akt	Akt	akt	18	19	25	26
Oxidation of the active site of phosphatases , such as PTEN , inhibits their activity and inhibition of PTEN results in activation of Akt and its anti-apoptotic pathways [ XREF_BIBR ] .	Oxidation of the active site of phosphatases, such as PTEN, inhibits their activity and inhibition of PTEN results in activation of Akt and its anti-apoptotic pathways [XREF_BIBR].	14	24	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	23	24
In numerous cell types , PTEN loss-of-function mutations result in unopposed Akt signaling , producing numerous effects on cells .	In numerous cell types, PTEN loss-of-function mutations result in unopposed Akt signaling, producing numerous effects on cells.	5	13	signaling	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	11	12
Because PTEN is a negative regulator of Akt , inactivation of PTEN by these multiple modes of respiratory deficiency may result in activation of Akt [ XREF_BIBR ] .	Because PTEN is a negative regulator of Akt, inactivation of PTEN by these multiple modes of respiratory deficiency may result in activation of Akt [XREF_BIBR].	9	26	result in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	24	25
Thus , we examined whether NEDD4 ubiquitinates and down-regulates PTEN and activates the PI3K and AKT pathway .	Thus, we examined whether NEDD4 ubiquitinates and down-regulates PTEN and activates the PI3K and AKT pathway.	5	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	NEDD4 ubiquitinates and down-regulates PTEN	pten	AKT	AKT	akt	9	10	15	16
PTEN restoration induced the expression change of Akt .	PTEN restoration induced the expression change of Akt.	0	8	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	7	8
We have previously demonstrated that overexpression of PTEN in MCF-7 breast cancer cells causes G ( 1 ) arrest followed by cell death , the latter of which is believed to be mediated by the phosphoinositol-3-kinase ( PI3K ) and Akt and PKB pro apoptotic pathways .	We have previously demonstrated that overexpression of PTEN in MCF-7 breast cancer cells causes G (1) arrest followed by cell death, the latter of which is believed to be mediated by the phosphoinositol-3-kinase (PI3K) and Akt and PKB pro apoptotic pathways.	5	43	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	overexpression of PTEN	pten	PKB	PKB	pkb	7	8	42	43
Second , mTORC1 hyperactivation due to SC specific deletion of TSC1 or the negative regulator of PI3K-Akt signaling PTEN delayed onset of myelination ( Beirowski et al ., 2017 ; Figlia et al ., 2017 ) , while even higher mTORC1 activity following deletion of TSC2 persistently arrested onset of myelination ( Beirowski et al ., 2017 ) .	Second, mTORC1 hyperactivation due to SC specific deletion of TSC1 or the negative regulator of PI3K-Akt signaling PTEN delayed onset of myelination (Beirowski et al., 2017; Figlia et al., 2017), while even higher mTORC1 activity following deletion of TSC2 persistently arrested onset of myelination (Beirowski et al., 2017).	14	19	signaling	Positive_activation_token_1_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	18	19	16	17
We hypothesize that loss of PTEN and subsequent activation of Akt , frequent occurrences in prostate cancer , regulate the CXCL12 and CXCR4 signaling axis in tumor growth and bone metastasis .	We hypothesize that loss of PTEN and subsequent activation of Akt, frequent occurrences in prostate cancer, regulate the CXCL12 and CXCR4 signaling axis in tumor growth and bone metastasis.	5	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	10	11
Posttranslational inactivation of PTEN by miR-19 promotes activation of the PI3K and Akt pathway , and incontrollable proliferation of T cells [ XREF_BIBR , XREF_BIBR ] .	Posttranslational inactivation of PTEN by miR-19 promotes activation of the PI3K and Akt pathway, and incontrollable proliferation of T cells [XREF_BIBR, XREF_BIBR].	1	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	12	13
These PTPs have multiple functions encountering protein tyrosine kinases ; one of the best examples for PTP target is the regulation of AKT signaling by dual specificity phosphatase , phosphatase and tensin homolog protein ( PTEN ) .	These PTPs have multiple functions encountering protein tyrosine kinases; one of the best examples for PTP target is the regulation of AKT signaling by dual specificity phosphatase, phosphatase and tensin homolog protein (PTEN).	22	33	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	29	33	22	23
Fine Tuning of PI3K and AKT Signalling by the Tumour Suppressor PTEN Is Required for Maintenance of Flight Muscle Function and Mitochondrial Integrity in Ageing Adult Drosophila melanogaster .	Fine Tuning of PI3K and AKT Signalling by the Tumour Suppressor PTEN Is Required for Maintenance of Flight Muscle Function and Mitochondrial Integrity in Ageing Adult Drosophila melanogaster.	5	12	Signalling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	11	12	5	6
Odontogenic ameloblast associated protein ( ODAM ) inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K and AKT signaling .	Odontogenic ameloblast associated protein (ODAM) inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K and AKT signaling.	17	25	elevation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	17	18	24	25
Further investigation revealed that increased PTEN instability mediates constitutive Akt activation .	Further investigation revealed that increased PTEN instability mediates constitutive Akt activation.	5	10	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	9	10
Mechanistically , we demonstrated that miR-155-5p induced HCC cell proliferation , invasion and migration , but inhibited apoptosis by repressing PTEN , which further activated the PI3K and Akt pathway .	Mechanistically, we demonstrated that miR-155-5p induced HCC cell proliferation, invasion and migration, but inhibited apoptosis by repressing PTEN, which further activated the PI3K and Akt pathway.	19	29	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	20	21	28	29
In conclusion , our data demonstrate that the IPF fibroblast phenotype is characterized by persistent activation of the PI3K-Akt pathway caused by inappropriately low PTEN activity that confers a pathological proliferative response with the capacity to elude the antiproliferative properties of fibrillar collagen .	In conclusion, our data demonstrate that the IPF fibroblast phenotype is characterized by persistent activation of the PI3K-Akt pathway caused by inappropriately low PTEN activity that confers a pathological proliferative response with the capacity to elude the antiproliferative properties of fibrillar collagen.	18	25	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	24	25	18	19
Mechanistically activation of AKT by PTEN deficiency induces inhibition of FOXO1/3 that led to the upregulation of Runx2 .	Mechanistically activation of AKT by PTEN deficiency induces inhibition of FOXO1/3 that led to the upregulation of Runx2.	1	6	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	3	4
The AKT and mTOR pathway might be additionally activated mainly by loss-of-function mutations or deletions of the inhibiting phosphatase PTEN .	The AKT and mTOR pathway might be additionally activated mainly by loss-of-function mutations or deletions of the inhibiting phosphatase PTEN.	1	20	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	19	20	1	2
In many cancers , this PTEN tumour suppressor function is not active , allowing pi3k to activate Akt .	In many cancers, this PTEN tumour suppressor function is not active, allowing pi3k to activate Akt.	5	18	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	17	18
Consistent with the role of PTEN in antagonizing PI3K signaling , PTEN depletion strongly induced AKT activation and BKM120 as single-agent significantly attenuated PI3K/AKT/mTOR signaling pathway ( XREF_SUPPLEMENTARY ) .	Consistent with the role of PTEN in antagonizing PI3K signaling, PTEN depletion strongly induced AKT activation and BKM120 as single-agent significantly attenuated PI3K/AKT/mTOR signaling pathway (XREF_SUPPLEMENTARY).	11	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	11	12	15	16
Reconstitution of PTEN function in MDA468 cells through tet inducible expression restored gefitinib sensitivity and re-established EGFR stimulated Akt signalling .	Reconstitution of PTEN function in MDA468 cells through tet inducible expression restored gefitinib sensitivity and re-established EGFR stimulated Akt signalling.	2	19	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	18	19
P-Rex2 inhibits the activity of phosphatase and tensin homolog ( PTEN ) , which increases Akt activation XREF_BIBR .	P-Rex2 inhibits the activity of phosphatase and tensin homolog (PTEN), which increases Akt activation XREF_BIBR.	8	17	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	15	16
Conversely , inhibitors of PI3K and AKT activation such as PTEN and Cbl-b are important for Foxp3 expression and serve to restrain PI3K and AKT activation during Treg induction .	Conversely, inhibitors of PI3K and AKT activation such as PTEN and Cbl-b are important for Foxp3 expression and serve to restrain PI3K and AKT activation during Treg induction.	4	12	activation	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	6	7
Activation of PI3K and AKT signaling by PTEN inactivation stimulates cell cycle progression and survival and , consequently , induces tumorigenesis XREF_BIBR , as demonstrated by the induction of prostate cancer after Pten homozygous deletion in mice XREF_BIBR .	Activation of PI3K and AKT signaling by PTEN inactivation stimulates cell cycle progression and survival and, consequently, induces tumorigenesis XREF_BIBR, as demonstrated by the induction of prostate cancer after Pten homozygous deletion in mice XREF_BIBR.	2	8	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	4	5
Supporting evidence comes from a study of BMP1a deficient mice in which the inactivation of either PTEN or BMP signaling activates Akt , which in-turn coordinates with the Wnt signal to fully activate beta-catenin in intestinal stem cells ( ISC ) [ XREF_BIBR ] .	Supporting evidence comes from a study of BMP1a deficient mice in which the inactivation of either PTEN or BMP signaling activates Akt, which in-turn coordinates with the Wnt signal to fully activate beta-catenin in intestinal stem cells (ISC) [XREF_BIBR].	13	32	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	21	22
PTEN negatively regulates the PI3K/AKT/PKB pathway by blocking Akt signaling via the reduction of intracellular levels of phosphatidylinositol-3 ,4,5-triphosphate .	PTEN negatively regulates the PI3K/AKT/PKB pathway by blocking Akt signaling via the reduction of intracellular levels of phosphatidylinositol-3,4,5-triphosphate.	0	9	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	8	9
PTEN downregulation by miR-21 allows the accumulation of PI-3K-generated PIP3 at the plasma membrane and promotes the activation of Akt .	PTEN downregulation by miR-21 allows the accumulation of PI-3K-generated PIP3 at the plasma membrane and promotes the activation of Akt.	0	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	19	20
Genetic inactivation of the PTEN function , which is oncogenic , activates the PI3K and Akt pathway XREF_BIBR , XREF_BIBR .	Genetic inactivation of the PTEN function, which is oncogenic, activates the PI3K and Akt pathway XREF_BIBR, XREF_BIBR.	4	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	15	16
In addition , we found that down-regulation of PTEN relieves its inhibitory effect on PI3K-Akt pathway and triggers cumulative activation of Akt .	In addition, we found that down-regulation of PTEN relieves its inhibitory effect on PI3K-Akt pathway and triggers cumulative activation of Akt.	6	22	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	21	22
Alkylation of the Tumor Suppressor PTEN Activates Akt and beta-Catenin Signaling : A Mechanism Linking Inflammation and Oxidative Stress with Cancer .	Alkylation of the Tumor Suppressor PTEN Activates Akt and beta-Catenin Signaling : A Mechanism Linking Inflammation and Oxidative Stress with Cancer.	0	10	Activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	7	8
Since Akt can be modulated by PTEN 30 , we also evaluate the Ser/Thr phosphorylated PTEN inactivation form .	Since Akt can be modulated by PTEN 30, we also evaluate the Ser/Thr phosphorylated PTEN inactivation form.	1	7	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	1	2
Over-expression of wild-type PTEN enhanced celastrol inhibition of Cd activated Akt and mTOR signaling and cell death in neuronal cells .	Over-expression of wild-type PTEN enhanced celastrol inhibition of Cd activated Akt and mTOR signaling and cell death in neuronal cells.	0	13	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Over-expression of wild-type PTEN	pten	Akt	Akt	akt	3	4	10	11
The down-regulation of PTEN protein using PTEN specific siRNA activated the PI3K and Akt pathway , down-regulated the DAF and decreased the adhesion of Dr + E. coli .	The down-regulation of PTEN protein using PTEN specific siRNA activated the PI3K and Akt pathway, down-regulated the DAF and decreased the adhesion of Dr + E. coli.	3	14	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	13	14
Inactivation of PTEN leads to constitutively activate PI3K and Akt pathway .	Inactivation of PTEN leads to constitutively activate PI3K and Akt pathway.	0	10	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	9	10
In vitro and preclinical studies have also shown that inactivation of PTEN leads to constitutively activated Akt and mTOR , as well as deregulation of cell size and cell growth [ XREF_BIBR ] .	In vitro and preclinical studies have also shown that inactivation of PTEN leads to constitutively activated Akt and mTOR, as well as deregulation of cell size and cell growth [XREF_BIBR].	9	23	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	16	17
Activation of AKT by PTEN deficiency promotes Runx2 upregulation and VSMC calcification .	Activation of AKT by PTEN deficiency promotes Runx2 upregulation and VSMC calcification.	0	5	Activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	2	3
In summary , we have demonstrated that geridonin and paclitaxel act synergistically to suppress the growth of gastric cancer cells both in vitro and in vivo through ROS mediated PTEN activation and deactivation of the PI3K and Akt signaling pathway .	In summary, we have demonstrated that geridonin and paclitaxel act synergistically to suppress the growth of gastric cancer cells both in vitro and in vivo through ROS mediated PTEN activation and deactivation of the PI3K and Akt signaling pathway.	27	39	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	ROS mediated PTEN	pten	Akt	Akt	akt	29	30	37	38
Taken together , our study identified a tumor suppressive role of Gas5 in PTC cells acting as a ceRNA , effectively becoming a sink for miR-222-3p , modulating the expression of PTEN , which lead to PTEN and AKT pathway activation and proliferation suppression .	Taken together, our study identified a tumor suppressive role of Gas5 in PTC cells acting as a ceRNA, effectively becoming a sink for miR-222-3p, modulating the expression of PTEN, which lead to PTEN and AKT pathway activation and proliferation suppression.	29	39	lead	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	PTEN	expression of PTEN	pten	AKT	AKT	akt	31	32	38	39
Western blotting revealed that the miR-130b inhibitor upregulated the expression of PTEN , inhibited AKT pathway activation , upregulated the tumor suppressor gene p27 , and suppressed cyclin D1 , matrix metalloproteinase 2 and 9 expression .	Western blotting revealed that the miR-130b inhibitor upregulated the expression of PTEN, inhibited AKT pathway activation, upregulated the tumor suppressor gene p27, and suppressed cyclin D1, matrix metalloproteinase 2 and 9 expression.	5	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	miR-130b inhibitor upregulated the expression of PTEN	pten	AKT	AKT	akt	11	12	14	15
Inactivating mutations or deletions of the tumor suppressor gene PTEN activate the P13K and AKT pathway and constitute the genetic basis for follicular thyroid cell tumor genesis in Cowden syndrome ( Dahia et al ., 1997 ) .	Inactivating mutations or deletions of the tumor suppressor gene PTEN activate the P13K and AKT pathway and constitute the genetic basis for follicular thyroid cell tumor genesis in Cowden syndrome (Dahia et al., 1997).	1	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	14	15
As more than 40 % of melanoma in clinical samples show a combined elevation of MAPK and AKT signaling , we also tested our hypothesis in a group of melanoma cell lines harboring BRAFV600E and mutated PTEN , which activates AKT pathway .	As more than 40% of melanoma in clinical samples show a combined elevation of MAPK and AKT signaling, we also tested our hypothesis in a group of melanoma cell lines harboring BRAFV600E and mutated PTEN, which activates AKT pathway.	35	41	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	36	37	40	41
Inhibition of mTORC1 activity in PTEN conditional knockout mice rescues soma hypertrophy and seizure frequencies [ XREF_BIBR , XREF_BIBR ] ; however , mTORC1 inhibition only partially reverses morphological abnormalities , suggesting that Akt activation by PTEN deletion may exert pathological effects independent of mTORC1 [ XREF_BIBR ] .	Inhibition of mTORC1 activity in PTEN conditional knockout mice rescues soma hypertrophy and seizure frequencies [XREF_BIBR, XREF_BIBR]; however, mTORC1 inhibition only partially reverses morphological abnormalities, suggesting that Akt activation by PTEN deletion may exert pathological effects independent of mTORC1 [XREF_BIBR].	33	37	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	36	37	33	34
Recently , functional studies have revealed that LIM-homeobox family-4 ( LHX-4 ) suppresses hepatocarcinogenesis through reducing AFP expression [ XREF_BIBR ] , and we have found that AFP interacts with and inhibits the activity of phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) , stimulating the transduction of the PI3K and AKT signaling pathway [ XREF_BIBR ] .	Recently, functional studies have revealed that LIM-homeobox family-4 (LHX-4) suppresses hepatocarcinogenesis through reducing AFP expression [XREF_BIBR], and we have found that AFP interacts with and inhibits the activity of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), stimulating the transduction of the PI3K and AKT signaling pathway [XREF_BIBR].	35	56	stimulating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	35	39	54	55
Mutations in PTEN gene causes activation of PI3K and Akt oncogenic signals in MSI cells .	Mutations in PTEN gene causes activation of PI3K and Akt oncogenic signals in MSI cells.	2	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	9	10
Although AKT pathway activation can explain many of the phenotypes associated with PTEN inactivation , PTEN gene targeting and genetic activation of AKT do not have completely overlapping biological consequences .	Although AKT pathway activation can explain many of the phenotypes associated with PTEN inactivation, PTEN gene targeting and genetic activation of AKT do not have completely overlapping biological consequences.	15	23	targeting	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	15	16	22	23
IGF-1R silencing increases PTEN expression and negatively regulates the PI3K and AKT tyrosine kinase activities to enhance the anticancer effect in PDAC .	IGF-1R silencing increases PTEN expression and negatively regulates the PI3K and AKT tyrosine kinase activities to enhance the anticancer effect in PDAC.	0	14	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	IGF-1R silencing increases PTEN expression	pten	AKT	AKT	akt	3	4	11	12
Furthermore , PTEN oxidation can occur in cells in response to growth factors and insulin to promote Akt signaling .	Furthermore, PTEN oxidation can occur in cells in response to growth factors and insulin to promote Akt signaling.	2	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	17	18
The reduction of phosphorylation Akt and glycogen synthase kinase-3beta ( GSK3beta ) induced by OGD was restored by Bai , which was associated with preserved levels of phosphorylation of PTEN , the phophatase that negatively regulates Akt .	The reduction of phosphorylation Akt and glycogen synthase kinase-3beta (GSK3beta) induced by OGD was restored by Bai, which was associated with preserved levels of phosphorylation of PTEN, the phophatase that negatively regulates Akt.	27	37	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	PTEN	phosphorylation of PTEN	pten	Akt	Akt	akt	29	30	36	37
With regard to the mechanism of latency reversal , an in vitro study demonstrated that disulfiram depletes the intracellular protein PTEN , which in turn activates the Akt signaling pathway to initiate proviral transcription in an NF-kappaB-dependent manner ( XREF_FIG ) .	With regard to the mechanism of latency reversal, an in vitro study demonstrated that disulfiram depletes the intracellular protein PTEN, which in turn activates the Akt signaling pathway to initiate proviral transcription in an NF-kappaB-dependent manner (XREF_FIG).	13	29	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	20	21	27	28
Still , in support to our observations , it is noteworthy that XREF_BIBR previously reported that 1-week administration of rapamycin before the surgery of glioblastoma lacking PTEN expression induced Akt activation in the subset of patients with the shorter time-to-progression .	Still, in support to our observations, it is noteworthy that XREF_BIBR previously reported that 1-week administration of rapamycin before the surgery of glioblastoma lacking PTEN expression induced Akt activation in the subset of patients with the shorter time-to-progression.	26	30	induced	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	26	27	29	30
PTEN dependent activation of Akt in basal like breast cancer .	PTEN dependent activation of Akt in basal like breast cancer.	0	5	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	4	5
Notably , PI3K and AKT axis can be modulated by PTEN , a tumor suppressor which removes the 3 ' phosphate of PIP3 and attenuates signaling downstream of the activated PI3K .	Notably, PI3K and AKT axis can be modulated by PTEN, a tumor suppressor which removes the 3 ' phosphate of PIP3 and attenuates signaling downstream of the activated PI3K.	2	14	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	4	5
Depletion of PTEN activates the AKT signaling pathway in human PASMCs .	Depletion of PTEN activates the AKT signaling pathway in human PASMCs.	0	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	5	6
Elevated PTEN promoter methylation , which silences PTEN expression and promotes AKT hyperactivation , has been observed in diverse cancer cell lines and patient samples .	Elevated PTEN promoter methylation, which silences PTEN expression and promotes AKT hyperactivation, has been observed in diverse cancer cell lines and patient samples.	1	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN promoter methylation	pten	AKT	AKT	akt	1	2	11	12
Since PIP 3 is an activator of PH domain proteins such as PDK1 and Akt , oxidation of PTEN ultimately activates Akt .	Since PIP 3 is an activator of PH domain proteins such as PDK1 and Akt, oxidation of PTEN ultimately activates Akt.	16	22	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	21	22
Second , PTEN +/- mutation enhanced AKT signaling in SERT deficient mice and improved their glucose tolerance .	Second, PTEN +/- mutation enhanced AKT signaling in SERT deficient mice and improved their glucose tolerance.	2	13	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	6	7
The downregulation of PTEN promotes the Akt signaling pathway , resulting in increased NF-kappaB .	The downregulation of PTEN promotes the Akt signaling pathway, resulting in increased NF-kappaB.	1	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	6	7
It has been shown that the phosphatase activity of PTEN is required for inhibition of the PI3K and AKT signalling pathway [ XREF_BIBR ] , and this suggests that decreased PTEN dependent up-regulation of the PI3K and AKT pathway plays a role in tumour progression [ XREF_BIBR ] .	It has been shown that the phosphatase activity of PTEN is required for inhibition of the PI3K and AKT signalling pathway [XREF_BIBR], and this suggests that decreased PTEN dependent up-regulation of the PI3K and AKT pathway plays a role in tumour progression [XREF_BIBR].	30	38	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	30	31	37	38
Thus , inactivating PTEN activates Akt and mTOR , facilitates the RGCs survival after optic neuropathy .	Thus, inactivating PTEN activates Akt and mTOR, facilitates the RGCs survival after optic neuropathy.	3	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	5	6
Loss of PTEN disrupts bistability of both AKT and ERK signaling which induces proliferation of cancer cells .	Loss of PTEN disrupts bistability of both AKT and ERK signaling which induces proliferation of cancer cells.	0	10	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Loss of PTEN	pten	AKT	AKT	akt	2	3	7	8
Downregulation of PTEN probably might cause AKT , which causes drug-resistance to imatinib ( XREF_FIG ) .	Downregulation of PTEN probably might cause AKT, which causes drug-resistance to imatinib (XREF_FIG).	0	9	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	6	7
Additionally , the expression of PTEN itself is down regulated by IGFBP-2 indicating that PTEN dependent activation of PI3K and AKT might also be important in upstream and downstream events regulating IGFBP-2 expression .	Additionally, the expression of PTEN itself is down regulated by IGFBP-2 indicating that PTEN dependent activation of PI3K and AKT might also be important in upstream and downstream events regulating IGFBP-2 expression.	14	21	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	20	21
Does PTEN loss , which promotes unfettered PI3K and AKT signaling , mitigate the effects of mTOR mediated feedback on upstream RTK activity ?	Does PTEN loss, which promotes unfettered PI3K and AKT signaling, mitigate the effects of mTOR mediated feedback on upstream RTK activity?	1	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	9	10
Taken together , miR-21 inhibited PTEN expression , which in turn decreased AKT and ERK activation for inhibiting HIF-1alpha and VEGF expression , thus inducing tumor angiogenesis .	Taken together, miR-21 inhibited PTEN expression, which in turn decreased AKT and ERK activation for inhibiting HIF-1alpha and VEGF expression, thus inducing tumor angiogenesis.	3	15	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	miR-21 inhibited PTEN expression	pten	AKT	AKT	akt	5	6	12	13
Given that PTEN inhibits tumor cell growth and invasion by blocking the PI3K and AKT pathway XREF_BIBR , we reached a conclusion that miR-21 induces proliferation and inhibits apoptosis in NPC by targeting PTEN-AKT pathway .	Given that PTEN inhibits tumor cell growth and invasion by blocking the PI3K and AKT pathway XREF_BIBR, we reached a conclusion that miR-21 induces proliferation and inhibits apoptosis in NPC by targeting PTEN-AKT pathway.	2	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	14	15
Keratinocyte specific deficiency of Pten caused Akt activation , and subsequently resulted in postnatal death due to esophageal hyperkeratosis XREF_BIBR .	Keratinocyte specific deficiency of Pten caused Akt activation, and subsequently resulted in postnatal death due to esophageal hyperkeratosis XREF_BIBR.	2	7	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	4	5	6	7
One such marker for prostate cancer is phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) , a tumor suppressor that negatively regulates the PI3K and Akt pathway .	One such marker for prostate cancer is phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor that negatively regulates the PI3K and Akt pathway.	7	29	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	7	11	28	29
Our results identify CK2 as a new target of PD-1 and reveal an unexpected mechanism by which PD-1 decreases PTEN protein expression while increasing PTEN activity , thereby inhibiting the PI3K and Akt signaling axis .	Our results identify CK2 as a new target of PD-1 and reveal an unexpected mechanism by which PD-1 decreases PTEN protein expression while increasing PTEN activity, thereby inhibiting the PI3K and Akt signaling axis.	17	34	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PD-1 decreases PTEN protein expression	pten	Akt	Akt	akt	19	20	32	33
Inactivation of PTEN results in activation of the PI3K and AKT pathway and subsequent increase in cell cycle progression , migration and survival XREF_BIBR XREF_BIBR .	Inactivation of PTEN results in activation of the PI3K and AKT pathway and subsequent increase in cell cycle progression, migration and survival XREF_BIBR XREF_BIBR.	0	11	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	10	11
Inhibition of proteasome function ameliorates pulmonary arterial remodeling by suppressing UPS mediated PTEN degradation and subsequent inhibition of PI3K and Akt pathway , indicating that UPS might be a novel target for prevention of PAH .	Inhibition of proteasome function ameliorates pulmonary arterial remodeling by suppressing UPS mediated PTEN degradation and subsequent inhibition of PI3K and Akt pathway, indicating that UPS might be a novel target for prevention of PAH.	10	21	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	PTEN	UPS mediated PTEN	pten	Akt	Akt	akt	12	13	20	21
In particular , AQP8 affected VEGF induced redox signaling by increasing the sulfenation of the tumor suppressor PTEN , which resulted in its inactivation and , in turn , caused Akt activation .	In particular, AQP8 affected VEGF induced redox signaling by increasing the sulfenation of the tumor suppressor PTEN, which resulted in its inactivation and, in turn, caused Akt activation.	12	31	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	17	18	30	31
Phosphatase and tensin homolog ( PTEN ) activation inhibits AKT and mTOR signaling , and current studies have confirmed that microRNA ( miRNA ) -21 targets PTEN to activate the AKT and mTOR pathway , which plays an important role in the key pathological damage observed in DN [ XREF_BIBR , XREF_BIBR ] .	Phosphatase and tensin homolog (PTEN) activation inhibits AKT and mTOR signaling, and current studies have confirmed that microRNA (miRNA) -21 targets PTEN to activate the AKT and mTOR pathway, which plays an important role in the key pathological damage observed in DN [XREF_BIBR, XREF_BIBR].	20	33	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	26	27	30	31
Since miR-21 regulates PTEN protein level , which in turn activates Akt , we tested the role of this kinase in renal cancer cell proliferation in relation to miR-21 .	Since miR-21 regulates PTEN protein level, which in turn activates Akt, we tested the role of this kinase in renal cancer cell proliferation in relation to miR-21.	3	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN protein level	pten	Akt	Akt	akt	3	4	11	12
The observed PI3K and AKT activation is PTEN dependent and is at least in part mediated by enhanced phosphorylation of PTEN .	The observed PI3K and AKT activation is PTEN dependent and is at least in part mediated by enhanced phosphorylation of PTEN.	4	21	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	phosphorylation of PTEN	pten	AKT	AKT	akt	20	21	4	5
The PI 3 kinase inhibitor Ly294002 and expression of tumor suppressor protein PTEN inhibited Akt kinase activity , resulting in the attenuation of FoxO1 phosphorylation and preventing the downregulating effect of H ( 2 ) O ( 2 ) on catalase protein level .	The PI 3 kinase inhibitor Ly294002 and expression of tumor suppressor protein PTEN inhibited Akt kinase activity, resulting in the attenuation of FoxO1 phosphorylation and preventing the downregulating effect of H (2) O (2) on catalase protein level.	7	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of tumor suppressor protein PTEN	pten	Akt	Akt	akt	12	13	14	15
Epigenetic inactivation of PTEN thus can result in activation of the AKT pathway and lead to tumor development .	Epigenetic inactivation of PTEN thus can result in activation of the AKT pathway and lead to tumor development.	1	12	result in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	11	12
PTEN insufficiency promotes hyperactivation of the kinase AKT , leading to pro survival and pro proliferative signaling .	PTEN insufficiency promotes hyperactivation of the kinase AKT, leading to pro survival and pro proliferative signaling.	0	8	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	7	8
Although PTEN staining was higher , so was staining for inactive p-PTEN , suggesting that inactive p-PTEN accumulation may underlie Akt activation in these tumors .	Although PTEN staining was higher, so was staining for inactive p-PTEN, suggesting that inactive p-PTEN accumulation may underlie Akt activation in these tumors.	16	21	underlie	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p-PTEN	p-PTEN	p-PTEN	Akt	Akt	Akt	16	17	20	21
In mammalian cells , SIRT1 decreases PTEN acetylation and inactivates the AKT pathway in a SIRT1 deacetylase dependent manner .	In mammalian cells, SIRT1 decreases PTEN acetylation and inactivates the AKT pathway in a SIRT1 deacetylase dependent manner.	4	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	SIRT1 decreases PTEN acetylation	pten	AKT	AKT	akt	6	7	11	12
Our data further revealed that inactivating Pten elevates PI3K and AKT signaling activity in neural crest derivatives , and confirmed that attenuation of PI3K and AKT activity led to decreased neural crest cell proliferation and differentiation both in vitro and in vivo .	Our data further revealed that inactivating Pten elevates PI3K and AKT signaling activity in neural crest derivatives, and confirmed that attenuation of PI3K and AKT activity led to decreased neural crest cell proliferation and differentiation both in vitro and in vivo.	6	19	elevates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	AKT	AKT	AKT	6	7	10	11
PTEN is a tumor suppressor gene that is frequently mutated in different types of cancer , and loss of PTEN leads to elevation of PI3K lipid products and thus activating the Akt pathway [ XREF_BIBR ] .	PTEN is a tumor suppressor gene that is frequently mutated in different types of cancer, and loss of PTEN leads to elevation of PI3K lipid products and thus activating the Akt pathway [XREF_BIBR].	0	32	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	31	32
In 2010 , phosphatase and tensin homolog ( PTEN ) enzyme inhibitors and phosphatidylinositol-3 kinase activators were used to activate the AKT pathway in dormant follicles in murine and human ovaries , suggesting the possibility that patients with POI with residual follicles could be activated to develop into preovulatory follicles for egg retrieval .	In 2010, phosphatase and tensin homolog (PTEN) enzyme inhibitors and phosphatidylinositol-3 kinase activators were used to activate the AKT pathway in dormant follicles in murine and human ovaries, suggesting the possibility that patients with POI with residual follicles could be activated to develop into preovulatory follicles for egg retrieval.	6	22	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	21	22
Given that PTEN negatively mediates Akt activity by dephosphorylating phosphoinositide substrates , PTEN suppression is likely to increase axon growth by enhancing activity of PI3K and Akt signaling .	Given that PTEN negatively mediates Akt activity by dephosphorylating phosphoinositide substrates, PTEN suppression is likely to increase axon growth by enhancing activity of PI3K and Akt signaling.	2	6	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	5	6
This was further verified in CCRCC tissue specimens from patients The results of the present study suggested that loss of PTEN , which deactivated Akt and HDM2 signaling followed by degradation of p53 , may contribute to the development of etoposide resistance in CCRCC .	This was further verified in CCRCC tissue specimens from patients The results of the present study suggested that loss of PTEN, which deactivated Akt and HDM2 signaling followed by degradation of p53, may contribute to the development of etoposide resistance in CCRCC.	18	27	deactivated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	loss of PTEN	pten	Akt	Akt	akt	20	21	24	25
It has been shown that inactivation of Pten function induces the activation of the PI3K and AKT signaling pathway in human cancer cells XREF_BIBR , XREF_BIBR .	It has been shown that inactivation of Pten function induces the activation of the PI3K and AKT signaling pathway in human cancer cells XREF_BIBR, XREF_BIBR.	7	18	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	AKT	AKT	AKT	7	8	16	17
miR-181a regulates the proliferation and invasion of HCC cells by targeting PTEN , the reduction of which activates the PI3K and Akt pathway [ XREF_BIBR ] .	miR-181a regulates the proliferation and invasion of HCC cells by targeting PTEN, the reduction of which activates the PI3K and Akt pathway [XREF_BIBR].	10	22	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	21	22
These are expected to shift the apoptotic threshold in cancer cells after treatment with chemotherapy and might be a way in counteracting the effects of loss of the tumour suppressor PTEN , which normally acts to inhibit PKB .	These are expected to shift the apoptotic threshold in cancer cells after treatment with chemotherapy and might be a way in counteracting the effects of loss of the tumour suppressor PTEN, which normally acts to inhibit PKB.	25	38	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	loss of the tumour suppressor PTEN	pten	PKB	PKB	pkb	30	31	37	38
Thus , inactivation of PTEN induces Akt activity culminating in the activation of mTOR , which is a central regulator of cellular protein synthesis , autophagy , growth and survival .	Thus, inactivation of PTEN induces Akt activity culminating in the activation of mTOR, which is a central regulator of cellular protein synthesis, autophagy, growth and survival.	2	7	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	6	7
Overexpression of PTEN causes G1 cell cycle arrest [ XREF_BIBR ] and apoptosis of SMCs by down-regulating the PI3K-AKT and PKB pathway [ XREF_BIBR ] .	Overexpression of PTEN causes G1 cell cycle arrest [XREF_BIBR] and apoptosis of SMCs by down-regulating the PI3K-AKT and PKB pathway [XREF_BIBR].	0	23	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Overexpression of PTEN	pten	PKB	PKB	pkb	2	3	20	21
Negative adjustment of PI3K as well as deactivation of AKT are accomplished by the protein phosphatase PTEN , which converts PI ( 3,4,5 ) P3 into PI ( 4,5 ) P2 and subsequently causes AKT suppression .	Negative adjustment of PI3K as well as deactivation of AKT are accomplished by the protein phosphatase PTEN, which converts PI (3,4,5) P3 into PI (4,5) P2 and subsequently causes AKT suppression.	11	35	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	16	17	34	35
PTEN , a tumor suppressor that antagonizes the PI3K and AKT pathway , is inactivated in a wide range of tumors , including 40-50 % of human liver cancers .	PTEN, a tumor suppressor that antagonizes the PI3K and AKT pathway, is inactivated in a wide range of tumors, including 40-50% of human liver cancers.	0	14	antagonizes	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	10	11
Hyperactivation of the PI3K and Akt signaling pathway triggered by PTEN inactivation has been found to correlate with increased breast cancer risks , poor prognosis and resistance to hormone therapy XREF_BIBR .	Hyperactivation of the PI3K and Akt signaling pathway triggered by PTEN inactivation has been found to correlate with increased breast cancer risks, poor prognosis and resistance to hormone therapy XREF_BIBR.	5	11	triggered	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	5	6
The present study provides the first critical in vivo evidence showing a causal link between the activation of Akt signaling induced by PTEN deficiency and gastric tumorigenesis .	The present study provides the first critical in vivo evidence showing a causal link between the activation of Akt signaling induced by PTEN deficiency and gastric tumorigenesis.	18	23	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	22	23	18	19
Mechanisms which contribute to increased mTOR activity in ALL may be the activation of PI3K and AKT by mutations of the tumor suppressor gene PTEN XREF_BIBR , and by abberant signals from TCL1 , BCR-ABL , growth factor receptors ( such as IGF-1R and c-kit ) , IL-7R , flt-3 XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR and oncogenic NOTCH1 , the latter one specifically in T-ALL .	Mechanisms which contribute to increased mTOR activity in ALL may be the activation of PI3K and AKT by mutations of the tumor suppressor gene PTEN XREF_BIBR, and by abberant signals from TCL1, BCR-ABL, growth factor receptors (such as IGF-1R and c-kit), IL-7R, flt-3 XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR and oncogenic NOTCH1, the latter one specifically in T-ALL.	12	25	activation	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	24	25	16	17
Our results showed that COMT suppressed the activation of Akt and activated PTEN , an upstream suppressor of the PI3K/Akt/mTOR pathway .	Our results showed that COMT suppressed the activation of Akt and activated PTEN, an upstream suppressor of the PI3K/Akt/mTOR pathway.	7	13	activated	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	12	13	9	10
Treatment with CDDO-Me reduced PTEN which negatively regulates PI3K and Akt signaling through dephorylation of PIP3 .	Treatment with CDDO-Me reduced PTEN which negatively regulates PI3K and Akt signaling through dephorylation of PIP3.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	10	11
Taken together , these results demonstrate that inactivation of PTEN and subsequent activation of the PI3k and Akt kinase pathway may play an important role in the overexpression of the FAS protein in cancer cells .	Taken together, these results demonstrate that inactivation of PTEN and subsequent activation of the PI3k and Akt kinase pathway may play an important role in the overexpression of the FAS protein in cancer cells.	9	19	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	17	18
Nuclear localization of PTEN seems to mediate tumor suppressive activities independent of the AKT pathway through inhibiting anchorage independent growth .	Nuclear localization of PTEN seems to mediate tumor suppressive activities independent of the AKT pathway through inhibiting anchorage independent growth.	1	14	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	13	14
PTEN is a regulator of PI3K mediated Akt signaling pathways and has been recognized as a therapeutic target in glioblastoma .	PTEN is a regulator of PI3K mediated Akt signaling pathways and has been recognized as a therapeutic target in glioblastoma.	0	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	7	8
In mammalian cells , SIRT1 decreases PTEN acetylation and inactivates the Akt pathway in a SIRT1 deacetylase dependent manner .	In mammalian cells, SIRT1 decreases PTEN acetylation and inactivates the Akt pathway in a SIRT1 deacetylase dependent manner.	4	12	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	SIRT1 decreases PTEN acetylation	pten	Akt	Akt	akt	6	7	11	12
Importantly , MAGI3 and PTEN and MMAC cooperate to modulate the kinase activity of AKT and PKB .	Importantly, MAGI3 and PTEN and MMAC cooperate to modulate the kinase activity of AKT and PKB.	2	17	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PKB	PKB	PKB	4	5	16	17
Besides the PTEN inactivation dependent activation of the PI3K and AKT pathway , also the Ras plays an important role in the activation of the PI3K and AKT pathway via interaction with its p110 catalytic subunit containing the Ras binding site .	Besides the PTEN inactivation dependent activation of the PI3K and AKT pathway, also the Ras plays an important role in the activation of the PI3K and AKT pathway via interaction with its p110 catalytic subunit containing the Ras binding site.	2	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	10	11
The PI3K-Akt signaling pathway is modulated by the levels of PTEN and PI3K , which are responsible for Akt activation .	The PI3K-Akt signaling pathway is modulated by the levels of PTEN and PI3K, which are responsible for Akt activation.	1	12	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	levels of PTEN	pten	PI3K-Akt	PI3K-Akt	pi3k-akt	10	11	1	2
PTEN downregulation promotes Akt signaling and results in increased NF-kappaB [ XREF_BIBR ] .	PTEN downregulation promotes Akt signaling and results in increased NF-kappaB [XREF_BIBR].	0	4	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
Surprisingly , Pten deletion reduced the total level of AKT protein ( XREF_FIG ) .	Surprisingly, Pten deletion reduced the total level of AKT protein (XREF_FIG).	2	10	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	AKT	AKT	AKT	2	3	9	10
Protein levels of phosphorylated Akt and its downstream effecter MDM2 were also up-regulated by NAC and GSH , which suggests that ROS may act as an upstream mediator for PTEN mediated Akt inactivation .	Protein levels of phosphorylated Akt and its downstream effecter MDM2 were also up-regulated by NAC and GSH, which suggests that ROS may act as an upstream mediator for PTEN mediated Akt inactivation.	27	32	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	29	30	31	32
PTEN suppresses tumor cell proliferation , survival , and growth mainly by inhibiting the PI3K-Akt signaling pathway through dephosphorylation of phosphatidylinositol 3,4,5-triphosphate .	PTEN suppresses tumor cell proliferation, survival, and growth mainly by inhibiting the PI3K-Akt signaling pathway through dephosphorylation of phosphatidylinositol 3,4,5-triphosphate.	0	16	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	14	15
PTEN is an upstream target of Akt , mTOR and p70s6k for regulating survivin expression by CRP .	PTEN is an upstream target of Akt, mTOR and p70s6k for regulating survivin expression by CRP.	0	10	is an upstream target	Positive_activation_copula_1	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	6	7
Meanwhile , low phosphatase and tensin homolog ( PTEN ) activity enhances the PI3K and Akt signal pathway to induce cell proliferation .	Meanwhile, low phosphatase and tensin homolog (PTEN) activity enhances the PI3K and Akt signal pathway to induce cell proliferation.	2	17	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	3	7	15	16
Inactivation of PTEN not only leads to accumulation of PIP3 , but also increases activity of the kinase AKT , which contributes to oncogenesis in numerous cancers , including glioblastoma , prostate and liver cancers .	Inactivation of PTEN not only leads to accumulation of PIP3, but also increases activity of the kinase AKT, which contributes to oncogenesis in numerous cancers, including glioblastoma, prostate and liver cancers.	0	21	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	18	19
In order to investigate a new treatment fot GIST , we hypothesized the effect of miR-374b targeting PTEN gene mediated PI3K and Akt signal transduction pathway on proliferation and apoptosis of human gastrointestinal stromal tumor ( GIST ) cells .	In order to investigate a new treatment fot GIST, we hypothesized the effect of miR-374b targeting PTEN gene mediated PI3K and Akt signal transduction pathway on proliferation and apoptosis of human gastrointestinal stromal tumor (GIST) cells.	17	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	17	18	22	23
In response to PTEN mediated Akt inactivation by p17 , at least two downstream targets of AKT , including GSK3alpha and beta and FoxO1/3a [ XREF_BIBR - XREF_BIBR ] , were examined in this study .	In response to PTEN mediated Akt inactivation by p17, at least two downstream targets of AKT, including GSK3alpha and beta and FoxO1/3a [XREF_BIBR - XREF_BIBR], were examined in this study.	1	6	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	5	6
To examine whether the mechanism of PTEN induction of HIF-2alpha activity and the MT1-MMP promoter was mediated by the ability of this tumor suppressor to antagonize PI3K and Akt signaling , we first treated the 786-0 cells with inhibitors of PI3K , Akt , or mTOR , and measured both HIF-2alpha and YY1 protein expression .	To examine whether the mechanism of PTEN induction of HIF-2alpha activity and the MT1-MMP promoter was mediated by the ability of this tumor suppressor to antagonize PI3K and Akt signaling, we first treated the 786-0 cells with inhibitors of PI3K, Akt, or mTOR, and measured both HIF-2alpha and YY1 protein expression.	6	29	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	28	29
24 Axons at 96 h after OGD exhibited a substantial reduction of phosphorylated PTEN ( XREF_FIG ) , but levels of total and phosphorylated cdk5 did not significantly change compared with the levels in the control group ( data not shown ) , suggesting that downregulation of PTEN activates Akt , while cdk5 may not play an important role in OGD elevated pNFH .	24 Axons at 96 h after OGD exhibited a substantial reduction of phosphorylated PTEN (XREF_FIG), but levels of total and phosphorylated cdk5 did not significantly change compared with the levels in the control group (data not shown), suggesting that downregulation of PTEN activates Akt, while cdk5 may not play an important role in OGD elevated pNFH.	45	50	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	47	48	49	50
PTEN deficient LT-HSCs display increased PI3K and AKT signalling and a hyperproliferative phenotype with long-term exhaustion XREF_BIBR XREF_BIBR XREF_BIBR .	PTEN deficient LT-HSCs display increased PI3K and AKT signalling and a hyperproliferative phenotype with long-term exhaustion XREF_BIBR XREF_BIBR XREF_BIBR.	0	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	7	8
This result may be related to the inhibition of Akt activation caused by PTEN upregulation .	This result may be related to the inhibition of Akt activation caused by PTEN upregulation.	9	14	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	9	10
Thus , we speculated that the PTEN gene can inhibit the generation of new blood vessels by inhibiting the PI3K and Akt signaling pathway and inhibiting VEGF generation .	Thus, we speculated that the PTEN gene can inhibit the generation of new blood vessels by inhibiting the PI3K and Akt signaling pathway and inhibiting VEGF generation.	6	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	21	22
The deregulated expression of phosphatase and tensin homolog leads to the aberrant activation of Akt as well as its downstream effectors , including mTOR , in prostate cancer .	The deregulated expression of phosphatase and tensin homolog leads to the aberrant activation of Akt as well as its downstream effectors, including mTOR, in prostate cancer.	2	15	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	expression of phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	4	8	14	15
AKT , or protein kinase B , signaling cascade is activated by receptor mediated production of phosphatidylinositol-( 3,4,5 ) - trisphosphates ( PIP3 ) by PI3K , and is inhibited by the tumor-suppressor PTEN through dephosphorylating PIP3 back to PIP2 .	AKT, or protein kinase B, signaling cascade is activated by receptor mediated production of phosphatidylinositol-(3,4,5) - trisphosphates (PIP3) by PI3K, and is inhibited by the tumor-suppressor PTEN through dephosphorylating PIP3 back to PIP2.	0	34	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	33	34	0	1
PTEN deficiency is a hallmark of many human tumours and is accompanied by enhanced cell proliferation , decreased cell apoptosis and increased Akt activity .	PTEN deficiency is a hallmark of many human tumours and is accompanied by enhanced cell proliferation, decreased cell apoptosis and increased Akt activity.	0	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	22	23
Mutations in PTEN , amplifications and mutations in PIK3CA and AKT genes , the MAGI3-AKT3 gene fusion [ XREF_BIBR ] , activate the PI3K and AKT pathway whereas mutations in MAP3K1 , MAP3K13 and MAP2K4 inactivate the JUN and MAPK pathway .	Mutations in PTEN, amplifications and mutations in PIK3CA and AKT genes, the MAGI3-AKT3 gene fusion [XREF_BIBR], activate the PI3K and AKT pathway whereas mutations in MAP3K1, MAP3K13 and MAP2K4 inactivate the JUN and MAPK pathway.	0	26	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	25	26
Rather , PTEN , a lipid phosphatase that activates AKT , was found to mediate the MAG inhibitory signal , suggesting the existence of other , as yet unknown , receptors .	Rather, PTEN, a lipid phosphatase that activates AKT, was found to mediate the MAG inhibitory signal, suggesting the existence of other, as yet unknown, receptors.	2	14	activates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	9	10
Here we demonstrate that the Pten heterozygosity in mouse embryonic fibroblasts enhances cell adhesion dependent PI3K and Akt signaling , cell spreading , and proliferation , while Pten and Mgat5 double mutant cells are normalized .	Here we demonstrate that the Pten heterozygosity in mouse embryonic fibroblasts enhances cell adhesion dependent PI3K and Akt signaling, cell spreading, and proliferation, while Pten and Mgat5 double mutant cells are normalized.	5	18	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	5	6	17	18
Some mutations or deletions of PTEN induce hyperactivation of the PI3K and AKT signaling pathway and activation of HIF complexes .	Some mutations or deletions of PTEN induce hyperactivation of the PI3K and AKT signaling pathway and activation of HIF complexes.	1	14	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	12	13
Considering that PTEN may modulate both AKT and ERK pathways , it is crucial to evaluate both the pathways in future research .	Considering that PTEN may modulate both AKT and ERK pathways, it is crucial to evaluate both the pathways in future research.	0	13	modulate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	6	7
PTEN can also induce G 1 -phase cell cycle arrest by negatively regulating the PI3K and Akt signaling pathway .	PTEN can also induce G 1 -phase cell cycle arrest by negatively regulating the PI3K and Akt signaling pathway.	0	18	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	16	17
Data from our group showed that mutations in PTEN enhance PI3K and Akt signaling and pbeta-cat levels , leading to increased polyp formation [ XREF_BIBR ] .	Data from our group showed that mutations in PTEN enhance PI3K and Akt signaling and pbeta-cat levels, leading to increased polyp formation [XREF_BIBR].	6	13	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	12	13
We report that inhibition of PI3K and Akt , either by the PI3K inhibitor Ly294002 or by expression of PTEN , synergized the ability of the MDM2 antagonist nutlin-3 to induce apoptosis in acute lymphoblastic leukemia ( ALL ) .	We report that inhibition of PI3K and Akt, either by the PI3K inhibitor Ly294002 or by expression of PTEN, synergized the ability of the MDM2 antagonist nutlin-3 to induce apoptosis in acute lymphoblastic leukemia (ALL).	3	22	synergized	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	19	20	7	8
PTEN lipid phosphatase inactivation activates the PI3K and Akt pathway in a hippo pathway dependent manner .	PTEN lipid phosphatase inactivation activates the PI3K and Akt pathway in a hippo pathway dependent manner.	0	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	8	9
PTEN deficiency augments PI3K signaling to AKT while diminishing cellular responsiveness to IGF inhibition .	PTEN deficiency augments PI3K signaling to AKT while diminishing cellular responsiveness to IGF inhibition.	0	7	augments	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	6	7
In glioblastoma where PTEN loss is found in 60-80 % of cases , a study showed that this loss of PTEN and subsequent up-regulation of the PI3K-AKT pathway resulted in increased constitutive expression of PD-L1 and is associated with immune resistance .	In glioblastoma where PTEN loss is found in 60-80% of cases, a study showed that this loss of PTEN and subsequent up-regulation of the PI3K-AKT pathway resulted in increased constitutive expression of PD-L1 and is associated with immune resistance.	20	27	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	20	21	26	27
We used wild type ( WT ) peritoneal macrophages ( PMs ) , and PMs from PTEN flox and flox / LysMCre mice ( PTEN -/- PMs ) , which have increased Akt activity .	We used wild type (WT) peritoneal macrophages (PMs), and PMs from PTEN flox and flox / LysMCre mice (PTEN -/- PMs), which have increased Akt activity.	16	33	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	32	33
In the end , the low expression of PTEN activates the PI3K and Akt pathway , thus forming a circulation .	In the end, the low expression of PTEN activates the PI3K and Akt pathway, thus forming a circulation.	6	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	8	9	13	14
PTEN expression was not detected in 3/4 cell lines tested , suggesting the loss of PTEN mediated Akt activation .	PTEN expression was not detected in 3/4 cell lines tested, suggesting the loss of PTEN mediated Akt activation.	13	18	mediated	Positive_early_activation	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	15	16	17	18
Indeed , high Morgana expression levels by excessively inhibiting ROCK I activity , destabilize PTEN , hence triggering the PI3K and AKT survival pathway 14 .	Indeed, high Morgana expression levels by excessively inhibiting ROCK I activity, destabilize PTEN, hence triggering the PI3K and AKT survival pathway 14.	13	23	triggering	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	21	22
Notably , inhibition of miR-221/222 significantly reduced the phosphorylation of AKT , a down-stream target of PTEN and key mediator of tumor cell survival , suggesting that the in vivo anti-MM activity of miR-221 inhibitors is related to PTEN up-regulation and impairment of AKT activation within tumors .	Notably, inhibition of miR-221/222 significantly reduced the phosphorylation of AKT, a down-stream target of PTEN and key mediator of tumor cell survival, suggesting that the in vivo anti-MM activity of miR-221 inhibitors is related to PTEN up-regulation and impairment of AKT activation within tumors.	38	44	up-regulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	38	39	43	44
In other words , overexpression of miR-21 led to decreased expression of PTEN and subsequent activation of Akt .	In other words, overexpression of miR-21 led to decreased expression of PTEN and subsequent activation of Akt.	12	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	12	13	17	18
Together with the previous finding that PRL3 also down-regulates PTEN through increasing its degradation XREF_BIBR , our studies also suggest that the oncogenic potential of all PRLs is underscored by their ability to down-regulate PTEN thereby activating the Akt pathway .	Together with the previous finding that PRL3 also down-regulates PTEN through increasing its degradation XREF_BIBR, our studies also suggest that the oncogenic potential of all PRLs is underscored by their ability to down-regulate PTEN thereby activating the Akt pathway.	33	39	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	34	35	38	39
They are also consistent with results showing that haplodeficiency of Pten in IRS-2 -/- mice elevates Akt activity , and improves beta-cell function and glucose homeostasis [ XREF_BIBR ] .	They are also consistent with results showing that haplodeficiency of Pten in IRS-2 -/- mice elevates Akt activity, and improves beta-cell function and glucose homeostasis [XREF_BIBR].	8	17	elevates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	10	11	16	17
This increase is likely to contribute to the resistance by inhibiting sorafenib induced autophagy through downregulating PTEN and sequential activation of the Akt pathway .	This increase is likely to contribute to the resistance by inhibiting sorafenib induced autophagy through downregulating PTEN and sequential activation of the Akt pathway.	16	23	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	22	23
MiR-21 was highly expressed in the renal cortex of OVE26 type-1 diabetic mice , and by targeting Pten it promotes Akt and mTOR activation , all factors associated with DN ( XREF_FIG ) .	MiR-21 was highly expressed in the renal cortex of OVE26 type-1 diabetic mice, and by targeting Pten it promotes Akt and mTOR activation, all factors associated with DN (XREF_FIG).	16	23	promotes	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	17	18	20	21
PTEN expression limited this BRAFi elicited PI3K-AKT signaling , which could be rescued by introduction of a mutant AKT1 ( Q79K ) kown to confer acquired BRAFi resistance .	PTEN expression limited this BRAFi elicited PI3K-AKT signaling, which could be rescued by introduction of a mutant AKT1 (Q79K) kown to confer acquired BRAFi resistance.	0	7	elicited	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	0	1	6	7
It has been reported that miR-181b reduces IGF-1R expression in tumor cells , and inhibits VEGF induced PI3K-Akt signaling ; 54 in contrast , in T cells it may reduce PTEN expression , thereby promoting PI3K-Akt signaling .	It has been reported that miR-181b reduces IGF-1R expression in tumor cells, and inhibits VEGF induced PI3K-Akt signaling; 54 in contrast, in T cells it may reduce PTEN expression, thereby promoting PI3K-Akt signaling.	5	36	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	miR-181b reduces IGF-1R expression in tumor cells, and inhibits VEGF induced PI3K-Akt signaling; 54 in contrast, in T cells it may reduce PTEN expression	pten	PI3K-Akt	PI3K-Akt	pi3k-akt	30	31	35	36
Inactivation of PTEN enhances intrinsic growth signals and survival potential of mature neurons , by permitting the constitutive activation of the serine threonine Akt signalling pathway , also known as the protein kinase B pathway .	Inactivation of PTEN enhances intrinsic growth signals and survival potential of mature neurons, by permitting the constitutive activation of the serine threonine Akt signalling pathway, also known as the protein kinase B pathway.	0	25	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	23	24
It has previously been shown that PTEN depletion , which activates PI3K and AKT signaling , mediates RGC survival after optic nerve injury .	It has previously been shown that PTEN depletion, which activates PI3K and AKT signaling, mediates RGC survival after optic nerve injury.	6	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	13	14
Therefore , we conclude that HBx in liver cells down-regulates the expression of PTEN and activates AKT .	Therefore, we conclude that HBx in liver cells down-regulates the expression of PTEN and activates AKT.	5	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	HBx in liver cells down-regulates the expression of PTEN	pten	AKT	AKT	akt	13	14	16	17
Ezh2 binds to the PTEN locus and downregulates PTEN expression , which consequently activates the Akt pathway , stabilizes Vimentin , downregulates E-cadherin , and protects Sox2 and Oct4 from degradation , thus ultimately leads to the acquisition of EMT and pluripotent phenotype of GC cells .	Ezh2 binds to the PTEN locus and downregulates PTEN expression, which consequently activates the Akt pathway, stabilizes Vimentin, downregulates E-cadherin, and protects Sox2 and Oct4 from degradation, thus ultimately leads to the acquisition of EMT and pluripotent phenotype of GC cells.	8	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	8	9	15	16
Interestingly , AKT pathway activity was only modestly elevated in the Pten-only or p53 deficient tumors relative to MMTV-Neu , but strongly induced in Pten and p53 double-mutant tumors ( Fig XREF_FIG D and E ) , indicating that loss of Pten alone does not fully dysregulate the PI3K and AKT pathway .	Interestingly, AKT pathway activity was only modestly elevated in the Pten-only or p53 deficient tumors relative to MMTV-Neu, but strongly induced in Pten and p53 double-mutant tumors (Fig XREF_FIG D and E), indicating that loss of Pten alone does not fully dysregulate the PI3K and AKT pathway.	39	51	dysregulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	loss of Pten	pten	AKT	AKT	akt	41	42	50	51
We concluded that selenite induced PTEN was associated with the AKT/FoxO3a/Bim pathway and apoptosis in HCT116 and SW480 CRC cells , which is consistent with the findings from other groups showing that PTEN directly regulates AKT and FoxO3a under various circumstances .	We concluded that selenite induced PTEN was associated with the AKT/FoxO3a/Bim pathway and apoptosis in HCT116 and SW480 CRC cells, which is consistent with the findings from other groups showing that PTEN directly regulates AKT and FoxO3a under various circumstances.	32	37	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	32	33	35	36
We previously showed that glycogen synthase kinase ( GSK )-3beta facilitates IFN-gamma-activated STAT1 by inhibiting SHP2 [ XREF_BIBR ] , and aberrant PI3K and a decrease in PTEN increase AKT activation and GSK-3beta inactivation to cause SHP2 activated IFN-gamma resistance in gastric cancer AGS cells [ XREF_BIBR ] .	We previously showed that glycogen synthase kinase (GSK)-3beta facilitates IFN-gamma-activated STAT1 by inhibiting SHP2 [XREF_BIBR], and aberrant PI3K and a decrease in PTEN increase AKT activation and GSK-3beta inactivation to cause SHP2 activated IFN-gamma resistance in gastric cancer AGS cells [XREF_BIBR].	27	30	increase	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	27	28	29	30
Moreover , TOPK phosphorylates and inactivates PTEN , which in turn activates Akt that leads to proper G2 to M progression .	Moreover, TOPK phosphorylates and inactivates PTEN, which in turn activates Akt that leads to proper G2 to M progression.	2	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	TOPK phosphorylates and inactivates PTEN	pten	Akt	Akt	akt	6	7	12	13
Alternatively , activation might be achieved by knockdown of negative regulators of Akt signaling such as PTEN , protein phosphatase 2a or of proteins discussed above that may lead to Akt inactivation such as RTP801 and alpha-synuclein .	Alternatively, activation might be achieved by knockdown of negative regulators of Akt signaling such as PTEN, protein phosphatase 2a or of proteins discussed above that may lead to Akt inactivation such as RTP801 and alpha-synuclein.	12	17	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	12	13
Collectively , TET1 as a tumor suppressor increases PTEN expression and inhibits AKT and FAK , thus limiting the induction of metastasis .	Collectively, TET1 as a tumor suppressor increases PTEN expression and inhibits AKT and FAK, thus limiting the induction of metastasis.	2	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	TET1 as a tumor suppressor increases PTEN expression	pten	AKT	AKT	akt	8	9	12	13
Mechanistically , overexpression of PTEN prevented serum induced Akt phosphorylation , whereas siRNA mediated knock down of PTEN augmented Akt activation .	Mechanistically, overexpression of PTEN prevented serum induced Akt phosphorylation, whereas siRNA mediated knock down of PTEN augmented Akt activation.	14	20	augmented	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	17	18	19	20
PTEN modulates the downstream signaling pathway of PI3K and AKT , which plays a critical role in cell cycling , protein translation , and metastasis by AKT mediated phosphorylation [ XREF_BIBR ] .	PTEN modulates the downstream signaling pathway of PI3K and AKT, which plays a critical role in cell cycling, protein translation, and metastasis by AKT mediated phosphorylation [XREF_BIBR].	0	12	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	9	10
More intriguingly , the ectopically expressed mito-PTEN was capable of significantly inhibiting Akt phosphorylation ( Fig XREF_FIG B ) , suggesting that mitochondrial PTEN can signal to Akt .	More intriguingly, the ectopically expressed mito-PTEN was capable of significantly inhibiting Akt phosphorylation (Fig XREF_FIG B), suggesting that mitochondrial PTEN can signal to Akt.	22	28	signal	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	23	24	27	28
As a tumor suppressor gene , downregulation of PTEN in certain types of malignant cancer activates AKT , promoting cell proliferation , survival , migration and angiogenesis .	As a tumor suppressor gene, downregulation of PTEN in certain types of malignant cancer activates AKT, promoting cell proliferation, survival, migration and angiogenesis.	6	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	16	17
Since PPAR has been shown to positively regulate PTEN gene expression , inhibition of PPAR would be predicted to suppress PTEN expression thereby increasing PI3k-Akt signaling .	Since PPAR has been shown to positively regulate PTEN gene expression, inhibition of PPAR would be predicted to suppress PTEN expression thereby increasing PI3k-Akt signaling.	20	25	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	PI3k-Akt	PI3k-Akt	pi3k-akt	20	21	24	25
The tumor suppressor phosphatase and tensin homolog ( PTEN ) inhibits AKT activation by dephosphorylation of PIP3 to PIP2 [ XREF_BIBR ] .	The tumor suppressor phosphatase and tensin homolog (PTEN) inhibits AKT activation by dephosphorylation of PIP3 to PIP2 [XREF_BIBR].	0	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	AKT	AKT	AKT	3	7	11	12
PTEN deficiency in smooth muscle cells activates AKT in the mouse vasculature XREF_BIBR - XREF_BIBR , which contributes to increased smooth muscle cell proliferation that leads to intimal hyperplasia in mouse vascular development XREF_BIBR , XREF_BIBR and in response to injury 22 .	PTEN deficiency in smooth muscle cells activates AKT in the mouse vasculature XREF_BIBR - XREF_BIBR, which contributes to increased smooth muscle cell proliferation that leads to intimal hyperplasia in mouse vascular development XREF_BIBR, XREF_BIBR and in response to injury 22.	0	25	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	7	8
Previous studies have reported that depletion of PTEN protein or loss of PTEN function reversely increases PI3K and Akt activity and causes drug resistance in a variety of cell types [ XREF_BIBR - XREF_BIBR ] .	Previous studies have reported that depletion of PTEN protein or loss of PTEN function reversely increases PI3K and Akt activity and causes drug resistance in a variety of cell types [XREF_BIBR - XREF_BIBR].	7	19	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	18	19
17beta-Oestradiol generated ROS-inactivate PTEN and CDC25A , which may activate AKT and ERK1/2 , respectively .	17beta-Oestradiol generated ROS-inactivate PTEN and CDC25A, which may activate AKT and ERK1/2, respectively.	1	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	10	11
Galangin reduced Akt activation and cell proliferation was abolished by PTEN knockdown , which might be associated with the over-expression of phosphatidylinositol-3 ,4,5-triphosphate ( PIP3 )/diphosphate product ( PIP2 ) .	Galangin reduced Akt activation and cell proliferation was abolished by PTEN knockdown, which might be associated with the over-expression of phosphatidylinositol-3,4,5-triphosphate (PIP3)/diphosphate product (PIP2).	2	11	abolished	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	2	3
A phenotype with multiple primary dendrites is associated with loss of Pten , which inhibits the PI3K and AKT pathway [ XREF_BIBR ] .	A phenotype with multiple primary dendrites is associated with loss of Pten, which inhibits the PI3K and AKT pathway [XREF_BIBR].	9	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Pten	loss of Pten	pten	AKT	AKT	akt	11	12	18	19
The PI3K-AKT signal transduction pathway , which is negatively regulated by the PTEN tumor suppressor , mediates oncogenic signaling downstream of growth factor receptors and is frequently dysregulated in human cancer .	The PI3K-AKT signal transduction pathway, which is negatively regulated by the PTEN tumor suppressor, mediates oncogenic signaling downstream of growth factor receptors and is frequently dysregulated in human cancer.	1	14	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	12	13	1	2
To investigate whether PI3K and PTEN mediated Akt signaling activates beta-catenin to regulate innate immunity networks in vitro , we next used PI3K inhibitor ( LY 294002 ) in LPS stimulated BMM cultures .	To investigate whether PI3K and PTEN mediated Akt signaling activates beta-catenin to regulate innate immunity networks in vitro, we next used PI3K inhibitor (LY 294002) in LPS stimulated BMM cultures.	3	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	7	8
The data have shown that the over-expressed PTEN gene led to reduced HSCs activation and viability , caspase-3 activity and cell cycle arrest in the G0/G1 and G2/M phases , as well as negative regulation of the PI3K and Akt and FAK and ERK signaling pathways in vitro .	The data have shown that the over-expressed PTEN gene led to reduced HSCs activation and viability, caspase-3 activity and cell cycle arrest in the G0/G1 and G2/M phases, as well as negative regulation of the PI3K and Akt and FAK and ERK signaling pathways in vitro.	7	40	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	39	40
In summary , deletions of PTEN and simultaneous activation of the PI3K and Akt pathway are associated with poor prognosis and therapy resistance in endometrial , breast , lung , and prostate cancers .	In summary, deletions of PTEN and simultaneous activation of the PI3K and Akt pathway are associated with poor prognosis and therapy resistance in endometrial, breast, lung, and prostate cancers.	5	14	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	13	14
There are well established genetic alterations associated with PCa , such as the upregulation of AR signaling , the overexpression of c-Myc , the loss of the tumor-suppressor gene Pten ( and subsequent activation of the Akt pathway ) , and the fusion of Ets genes with upstream AR regulated promoter sequences ( with TMPRSS2-Erg being the most frequently observed fusion gene ) .	There are well established genetic alterations associated with PCa, such as the upregulation of AR signaling, the overexpression of c-Myc, the loss of the tumor-suppressor gene Pten (and subsequent activation of the Akt pathway), and the fusion of Ets genes with upstream AR regulated promoter sequences (with TMPRSS2-Erg being the most frequently observed fusion gene).	24	37	activation	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	Pten	loss of the tumor-suppressor gene Pten	pten	Akt	Akt	akt	29	30	36	37
Given the known suppression of AKT activation by PTEN , we anticipated that Pten deletion would restore lens cell survival to FGFR2 deficient lens cells .	Given the known suppression of AKT activation by PTEN, we anticipated that Pten deletion would restore lens cell survival to FGFR2 deficient lens cells.	5	9	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	5	6
Modulation of Akt signaling by PTEN correction in 42MGBA cells but not T98G cells .	Modulation of Akt signaling by PTEN correction in 42MGBA cells but not T98G cells.	0	6	Modulation	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	5	6	2	3
Lack of PTEN allows aberrant Akt activation [ XREF_BIBR ] , which in combination with the lack of p53 , may confer such cells a survival advantage and IR- and RSV-resistance .	Lack of PTEN allows aberrant Akt activation [XREF_BIBR], which in combination with the lack of p53, may confer such cells a survival advantage and IR- and RSV-resistance.	0	6	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	5	6
Therefore , PTEN ablation in PIKE-/- neurons should restore the PI3K and Akt function , thus rescuing the defective arborization .	Therefore, PTEN ablation in PIKE-/- neurons should restore the PI3K and Akt function, thus rescuing the defective arborization.	2	13	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	12	13
We then investigated the role of PTEN , a key upstream suppressor for PI3K and AKT signaling that has been widely assumed to be a minimally relevant tumor suppressor in PDAC , in the IGFBP2 activated PI3K and Akt pathway .	We then investigated the role of PTEN, a key upstream suppressor for PI3K and AKT signaling that has been widely assumed to be a minimally relevant tumor suppressor in PDAC, in the IGFBP2 activated PI3K and Akt pathway.	4	39	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	38	39
In UVB irradiated mouse skin , CsA increased the incidence of Ki67 positive cells ( XREF_FIG ) , suppressed PTEN expression ( XREF_FIG , XREF_SUPPLEMENTARY ) , and increased AKT activation ( XREF_FIG ) , consistent with our recent in vitro findings .	In UVB irradiated mouse skin, CsA increased the incidence of Ki67 positive cells (XREF_FIG), suppressed PTEN expression (XREF_FIG, XREF_SUPPLEMENTARY), and increased AKT activation (XREF_FIG), consistent with our recent in vitro findings.	6	30	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	CsA increased the incidence of Ki67 positive cells (XREF_FIG), suppressed PTEN expression	pten	AKT	AKT	akt	19	20	29	30
Ectopic PTEN also inhibited two downstream targets of the PI3K-Akt pathway , S6K1 and translation initiation factor eIF4F ( XREF_FIG ) , and inhibited DNA synthesis in IPF fibroblasts cultured on polymerized collagen ( XREF_FIG ) .	Ectopic PTEN also inhibited two downstream targets of the PI3K-Akt pathway, S6K1 and translation initiation factor eIF4F (XREF_FIG), and inhibited DNA synthesis in IPF fibroblasts cultured on polymerized collagen (XREF_FIG).	0	23	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	1	2	9	10
PTEN inactivation could result in uncontrolled PI3K and Akt signaling activation , a mechanism of tumor formation .	PTEN inactivation could result in uncontrolled PI3K and Akt signaling activation, a mechanism of tumor formation.	0	11	signaling activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	8	9
In order to determine whether loss of PTEN and concomitant sustained activation of AKT alter the subcellular localization of CHK1 , PTEN was depleted in DU145 cells before irradiation with 2Gy and CHK1 subcellular localization was monitored by indirect immunofluorescence .	In order to determine whether loss of PTEN and concomitant sustained activation of AKT alter the subcellular localization of CHK1, PTEN was depleted in DU145 cells before irradiation with 2Gy and CHK1 subcellular localization was monitored by indirect immunofluorescence.	7	14	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	13	14
All of these findings suggested that PTEN mediated AKT pathway activation may be associated with EHMT2 mediated EGFR-TKI resistance in NSCLC cells .	All of these findings suggested that PTEN mediated AKT pathway activation may be associated with EHMT2 mediated EGFR-TKI resistance in NSCLC cells.	6	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	8	9
Phosphatase and tensin homolog deleted from chromosome 10 ( PTEN ) functions as a negative regulator of PI 3-kinase signaling , thus blocking Akt activation .	Phosphatase and tensin homolog deleted from chromosome 10 (PTEN) functions as a negative regulator of PI 3-kinase signaling, thus blocking Akt activation.	0	24	blocking	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Akt	Akt	Akt	0	4	23	24
The deletion of Akt2 in Pten +/- mice did not significantly reduce total Akt activity , except in the thyroid .	The deletion of Akt2 in Pten +/- mice did not significantly reduce total Akt activity, except in the thyroid.	3	14	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	5	6	13	14
Moreover , PTEN is a suppressor of the PI3K and Akt pathway and therefore , the enhanced expression of PTEN induced by GA would have definitely blocked the PI3K and Akt signaling pathway .	Moreover, PTEN is a suppressor of the PI3K and Akt pathway and therefore, the enhanced expression of PTEN induced by GA would have definitely blocked the PI3K and Akt signaling pathway.	17	32	blocked	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	expression of PTEN	pten	Akt	Akt	akt	19	20	30	31
S nitrosylation of PTEN ( forming SNO-PTEN ) inhibits enzymatic activity and consequently stimulates the downstream Akt cascade , indicating that Cys 83 is a critical site for redox regulation of PTEN function .	S nitrosylation of PTEN (forming SNO-PTEN) inhibits enzymatic activity and consequently stimulates the downstream Akt cascade, indicating that Cys 83 is a critical site for redox regulation of PTEN function.	1	17	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	16	17
XREF_BIBR The activation of PTEN targets the Akt pathway to regulate both survival genes and cell proliferation , which manipulate the progression of pulmonary and cardiovascular diseases .	XREF_BIBR The activation of PTEN targets the Akt pathway to regulate both survival genes and cell proliferation, which manipulate the progression of pulmonary and cardiovascular diseases.	2	8	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	7	8
In our study , we confirmed that miR-222-3p can promote the proliferation of PTC cells by targeting PTEN consequently activating PTEN and AKT pathway .	In our study, we confirmed that miR-222-3p can promote the proliferation of PTC cells by targeting PTEN consequently activating PTEN and AKT pathway.	16	23	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	17	18	22	23
Genetic engineering has enabled investigators to study downstream effectors of PI3K by directly over-expressing activated forms of AKT in cells of the skeletal lineage or deleting Pten which leads to a constitutively active AKT .	Genetic engineering has enabled investigators to study downstream effectors of PI3K by directly over-expressing activated forms of AKT in cells of the skeletal lineage or deleting Pten which leads to a constitutively active AKT.	25	34	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	AKT	AKT	AKT	26	27	33	34
PTEN inactivation by alkylation of PTEN activates Akt in HEK-293 human embryonic kidney cells [ XREF_BIBR ] .	PTEN inactivation by alkylation of PTEN activates Akt in HEK-293 human embryonic kidney cells [XREF_BIBR].	0	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	7	8
Furthermore , PI3K and AKT are negatively modulated by PTEN , which is a key molecule in various diseases that modulates cell proliferation , survival , apoptosis and metabolism .	Furthermore, PI3K and AKT are negatively modulated by PTEN, which is a key molecule in various diseases that modulates cell proliferation, survival, apoptosis and metabolism.	2	15	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	4	5
It was demonstrated that the PTEN and AKT signaling pathway also participated in their function ; SNAI1 was found to inhibit the expression of PTEN and activate Akt .	It was demonstrated that the PTEN and AKT signaling pathway also participated in their function; SNAI1 was found to inhibit the expression of PTEN and activate Akt.	16	28	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	SNAI1 was found to inhibit the expression of PTEN	pten	Akt	Akt	akt	24	25	27	28
GSK-3beta also regulates the F-box protein FBXW7 to induce degradation of Aurora-A ; this process is impaired in cancer , after loss of the tumor suppressor PTEN causes inhibition of AKT and GSK-3beta [ XREF_BIBR ] .	GSK-3beta also regulates the F-box protein FBXW7 to induce degradation of Aurora-A; this process is impaired in cancer, after loss of the tumor suppressor PTEN causes inhibition of AKT and GSK-3beta [XREF_BIBR].	21	34	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	loss of the tumor suppressor PTEN	pten	AKT	AKT	akt	26	27	30	31
As in epithelial cells , Snail1 over-expression down-regulated PTEN levels and stimulated Akt activity , determined measuring the extent of the phosphorylation at the key residue Ser473 ( XREF_FIG ) .	As in epithelial cells, Snail1 over-expression down-regulated PTEN levels and stimulated Akt activity, determined measuring the extent of the phosphorylation at the key residue Ser473 (XREF_FIG).	5	13	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Snail1 over-expression down-regulated PTEN levels	pten	Akt	Akt	akt	8	9	12	13
AKT is inhibited by the tumour-suppressor PTEN ; hence this pathway is activated in tumour cells containing a mutated PTEN .	AKT is inhibited by the tumour-suppressor PTEN; hence this pathway is activated in tumour cells containing a mutated PTEN.	0	7	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	0	1
Deletions lead to inactivation of tumor suppression proteins , such as PTEN ( antagonist of the PI3K and Akt pathway ) , retinoblastoma protein ( pRb ) , cyclin dependent kinase inhibitors ( CKI ) , p53 , etc ..	Deletions lead to inactivation of tumor suppression proteins, such as PTEN (antagonist of the PI3K and Akt pathway), retinoblastoma protein (pRb), cyclin dependent kinase inhibitors (CKI), p53, etc..	3	39	antagonist	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	18	19
Since the inactivation of PTEN activates Akt signalling at a point downstream of HER3 , a role for HER3 in mediating drug resistance in PTEN deleted tumours may be redundant .	Since the inactivation of PTEN activates Akt signalling at a point downstream of HER3, a role for HER3 in mediating drug resistance in PTEN deleted tumours may be redundant.	2	7	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	6	7
PTEN , a tumor suppressor gene , suppresses cell survival , growth , apoptosis , cell migration and DNA damage repair by inhibiting the PI3K and AKT signaling pathway .	PTEN, a tumor suppressor gene, suppresses cell survival, growth, apoptosis, cell migration and DNA damage repair by inhibiting the PI3K and AKT signaling pathway.	0	28	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	26	27
Interestingly , RNAi mediated knockdown of EZH2 restored PTEN expression and down-regulated the AKT and mTOR activities in Evi1 transduced BM cells , suggesting that Evi1 functions as a platform to recruit PcG proteins to the PTEN locus .	Interestingly, RNAi mediated knockdown of EZH2 restored PTEN expression and down-regulated the AKT and mTOR activities in Evi1 transduced BM cells, suggesting that Evi1 functions as a platform to recruit PcG proteins to the PTEN locus.	6	16	down-regulated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	EZH2 restored PTEN expression	pten	AKT	AKT	akt	8	9	13	14
XREF_BIBR , XREF_BIBR Phosphatase and tensin homolog ( PTEN ) loss activates PI3K and AKT signaling , thus controlling cell proliferation and growth 69 and is associated with poor prognosis .	XREF_BIBR, XREF_BIBR Phosphatase and tensin homolog (PTEN) loss activates PI3K and AKT signaling, thus controlling cell proliferation and growth 69 and is associated with poor prognosis.	2	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Phosphatase and tensin homolog	Phosphatase and tensin homolog	Phosphatase and tensin homolog	AKT	AKT	AKT	3	7	14	15
Herein , we reported that 3,3 '-diselenodipropionic acid ( DSeA ) , a Selenocysteine derivative , could synergistically enhance the growth inhibitory effect of TRAIL on A375 melanoma cells though induction of ROS dependent apoptosis with involvement of PTEN mediated Akt inactivation and DNA damage mediated p53 phosphorylation , which subsequently activated mitochondrial and death receptor apoptotic pathways .	Herein, we reported that 3,3 '-diselenodipropionic acid (DSeA), a Selenocysteine derivative, could synergistically enhance the growth inhibitory effect of TRAIL on A375 melanoma cells though induction of ROS dependent apoptosis with involvement of PTEN mediated Akt inactivation and DNA damage mediated p53 phosphorylation, which subsequently activated mitochondrial and death receptor apoptotic pathways.	36	41	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	38	39	40	41
This hypothesis was confirmed upon discovering that mutational loss of PTEN and consequent constitutive activation of the PI3K-AKT pathway was present in GSI resistant T-ALL lines , but not in GSI sensitive leukemias .	This hypothesis was confirmed upon discovering that mutational loss of PTEN and consequent constitutive activation of the PI3K-AKT pathway was present in GSI resistant T-ALL lines, but not in GSI sensitive leukemias.	10	18	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	10	11	17	18
XREF_BIBR We investigated whether NOS1 nitrosylates PTEN to activate AKT and mTOR signaling .	XREF_BIBR We investigated whether NOS1 nitrosylates PTEN to activate AKT and mTOR signaling.	4	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	9	10
We predict that both Pten deficiency and constitutive activation of p110alpha * may activate AKT .	We predict that both Pten deficiency and constitutive activation of p110alpha * may activate AKT.	4	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	AKT	AKT	AKT	4	5	14	15
The PI3K inhibitor , LY294002 , and a tumor suppressor , PTEN , negatively regulate the PI3K and Akt pathway and repress AR activity .	The PI3K inhibitor, LY294002, and a tumor suppressor, PTEN, negatively regulate the PI3K and Akt pathway and repress AR activity.	9	19	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	18	19
These results suggest that high glucose induced expression of miR-26a regulates PTEN mediated Akt activation in mesangial cells .	These results suggest that high glucose induced expression of miR-26a regulates PTEN mediated Akt activation in mesangial cells.	10	14	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	13	14
A key cell-intrinsic inhibitor of Akt signaling is phosphatase and tensin homolog ( Pten ) , a lipid phosphatase that prevents Akt activation by dephosphorylating PI3K generated inositol phospholipids .	A key cell-intrinsic inhibitor of Akt signaling is phosphatase and tensin homolog (Pten), a lipid phosphatase that prevents Akt activation by dephosphorylating PI3K generated inositol phospholipids.	8	22	prevents	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	8	12	21	22
It has also been shown that expression of wild type PTEN in rhabdomyosarcoma and myoblast cell lines reduces Akt phosphorylation at Ser473 but not Thr308 , and the authors suggest a role for regulation of the putative PDK2 proteins by PTEN , which would target Ser473 Akt specifically .	It has also been shown that expression of wild type PTEN in rhabdomyosarcoma and myoblast cell lines reduces Akt phosphorylation at Ser473 but not Thr308, and the authors suggest a role for regulation of the putative PDK2 proteins by PTEN, which would target Ser473 Akt specifically.	29	47	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	40	41	46	47
Consequently , PTEN inhibits tumor cell growth and invasion by blocking the PI3K and AKT pathway [ XREF_BIBR , XREF_BIBR ] .	Consequently, PTEN inhibits tumor cell growth and invasion by blocking the PI3K and AKT pathway [XREF_BIBR, XREF_BIBR].	2	19	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	14	15
To determine whether the hypersensitivity of PTEN deficient prostate cancer cells to ROS induced cell death is PI3K and Akt dependent , we first restored PTEN expression in the Pten deficient cells and silenced Pten in the Pten-proficient cells .	To determine whether the hypersensitivity of PTEN deficient prostate cancer cells to ROS induced cell death is PI3K and Akt dependent, we first restored PTEN expression in the Pten deficient cells and silenced Pten in the Pten-proficient cells.	4	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	19	20
As such , loss of Cdh1 activates WWP2 , leading to reduced abundance of WWP2 substrates including PTEN , which subsequently activates PI3K and Akt oncogenic signaling to facilitate tumorigenesis .	As such, loss of Cdh1 activates WWP2, leading to reduced abundance of WWP2 substrates including PTEN, which subsequently activates PI3K and Akt oncogenic signaling to facilitate tumorigenesis.	15	26	activates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	17	18	24	25
The role of trastuzumab in abrogating the PI3K and Akt signaling pathway has been addressed in two preclinical studies , where treatment of HER2-gene-amplified breast cancer cells with trastuzumab caused growth inhibition through PTEN upregulation and downregulation of PI3K activity and Akt function [ XREF_BIBR , XREF_BIBR ] .	The role of trastuzumab in abrogating the PI3K and Akt signaling pathway has been addressed in two preclinical studies, where treatment of HER2-gene-amplified breast cancer cells with trastuzumab caused growth inhibition through PTEN upregulation and downregulation of PI3K activity and Akt function [XREF_BIBR, XREF_BIBR].	33	42	upregulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	33	34	41	42
Inactivation of PTEN elevates the AKT activity ( XREF_FIG ) .	Inactivation of PTEN elevates the AKT activity (XREF_FIG).	0	6	elevates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	5	6
In the present study , we clearly showed that overexpression of miR-494 reduced the levels of PTEN , ROCK1 and CaMKIIdelta , which might work in concert to activate the Akt signaling , a critical survival pathway in the myocardium .	In the present study, we clearly showed that overexpression of miR-494 reduced the levels of PTEN, ROCK1 and CaMKIIdelta, which might work in concert to activate the Akt signaling, a critical survival pathway in the myocardium.	12	31	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	30	31
The OHPg and PR-B dependent induction of PTEN causes the down-regulation of PI3K and AKT signal , switching on the autophagy process through an enhanced expression of UVRAG and leading to a reduced cell survival .	The OHPg and PR-B dependent induction of PTEN causes the down-regulation of PI3K and AKT signal, switching on the autophagy process through an enhanced expression of UVRAG and leading to a reduced cell survival.	1	15	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	14	15
It must be noted that AKT is constitutively activated in Jurkat due to the lack of PTEN expression , an inhibitory phosphatase that prevents AKT activation .	It must be noted that AKT is constitutively activated in Jurkat due to the lack of PTEN expression, an inhibitory phosphatase that prevents AKT activation.	16	25	prevents	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	16	17	24	25
However , Pten haploinsufficiency restores Akt signaling in these tumors and dramatically enhances their severity .	However, Pten haploinsufficiency restores Akt signaling in these tumors and dramatically enhances their severity.	2	6	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	2	3	5	6
PTEN deficiency activates Akt signaling and results in a variety of human malignancies .	PTEN deficiency activates Akt signaling and results in a variety of human malignancies.	0	4	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	3	4
PTEN has been shown to inhibit tumor cell growth and invasion by blocking the PI3K and Akt pathway [ XREF_BIBR ] ; it can dephosphatize PI3K at the 3-phosphate site and negatively regulates the Akt signal pathway .	PTEN has been shown to inhibit tumor cell growth and invasion by blocking the PI3K and Akt pathway [XREF_BIBR]; it can dephosphatize PI3K at the 3-phosphate site and negatively regulates the Akt signal pathway.	0	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	16	17
We previously showed that IGF1R knockdown blocked survival of prostate cancer cells in which Akt activation was deregulated by PTEN loss .	We previously showed that IGF1R knockdown blocked survival of prostate cancer cells in which Akt activation was deregulated by PTEN loss.	14	20	deregulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	19	20	14	15
This redox dependent modification in PTEN is important for supporting the survival and proliferative capacity of energy deprived cancer cells , signifying an important compensatory role for AMPK to support cell homeostasis via PTEN mediated activation of Akt signaling .	This redox dependent modification in PTEN is important for supporting the survival and proliferative capacity of energy deprived cancer cells, signifying an important compensatory role for AMPK to support cell homeostasis via PTEN mediated activation of Akt signaling.	33	38	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	33	34	37	38
Inactivating PTEN might activate Akt and mTOR and enhance neuronal survival and axonal regeneration in optic neuropathy ( Park et al ., 2008 ; Leibinger et al ., 2016 ) .	Inactivating PTEN might activate Akt and mTOR and enhance neuronal survival and axonal regeneration in optic neuropathy (Park et al., 2008; Leibinger et al., 2016).	0	8	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	4	5
Thus , ligand activated PPARdelta confers resistance to Ang II induced senescence by up-regulation of PTEN and ensuing modulation of the PI3K and Akt signaling to reduce ROS generation in vascular cells .	Thus, ligand activated PPARdelta confers resistance to Ang II induced senescence by up-regulation of PTEN and ensuing modulation of the PI3K and Akt signaling to reduce ROS generation in vascular cells.	15	24	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	15	16	23	24
Our studies demonstrated that PTEN lipid phosphatase inactivation activated PI3K and Akt and regulated downstream molecules , such as FoxO , GSK-3beta , beta-catenin , p27 and Bad .	Our studies demonstrated that PTEN lipid phosphatase inactivation activated PI3K and Akt and regulated downstream molecules, such as FoxO, GSK-3beta, beta-catenin, p27 and Bad.	4	12	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	11	12
miR-21 targets and downregulates the AKT suppressor PTEN .	miR-21 targets and downregulates the AKT suppressor PTEN.	3	8	suppressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	5	6
A previous study revealed that the thyroid specific loss of phosphatase and tensin homolog ( PTEN ) , a known tumor suppressor , attenuated Akt signaling activation in 10-week-old mice .	A previous study revealed that the thyroid specific loss of phosphatase and tensin homolog (PTEN), a known tumor suppressor, attenuated Akt signaling activation in 10-week-old mice.	8	26	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	phosphatase and tensin homolog	loss of phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	10	14	24	25
An example is provided by PTEN mutations : Inactivation of the tumor suppressor gene PTEN results in activation of the AKT kinase ( XREF_FIG ) .	An example is provided by PTEN mutations : Inactivation of the tumor suppressor gene PTEN results in activation of the AKT kinase (XREF_FIG).	8	21	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	20	21
Lack of the PTEN phosphatase , a frequent mutation in breast tumors , enhances Akt activation and phosphotyrosine signaling , which diminishes the efficacy of drugs that block RTK or SFK [ XREF_BIBR ] .	Lack of the PTEN phosphatase, a frequent mutation in breast tumors, enhances Akt activation and phosphotyrosine signaling, which diminishes the efficacy of drugs that block RTK or SFK [XREF_BIBR].	3	15	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	14	15
When miR-21 is upregulated in hypoxic conditions AKT2 downregulates PTEN which then activates the other two Akt isoforms .	When miR-21 is upregulated in hypoxic conditions AKT2 downregulates PTEN which then activates the other two Akt isoforms.	8	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	16	17
Similar to PTEN , under expression of inositol polyphosphate-5-phosphatase J ( INPP5J ) is observed in triple negative breast cancer and increases in vivo PI3K and Akt signaling and oncogene induced transformation and tumor growth while reducing metastasis in mouse models .	Similar to PTEN, under expression of inositol polyphosphate-5-phosphatase J (INPP5J) is observed in triple negative breast cancer and increases in vivo PI3K and Akt signaling and oncogene induced transformation and tumor growth while reducing metastasis in mouse models.	0	27	increases	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	26	27
EGFR and FGFR signaling pathways depend on PTEN PIP3 activation in the AKT signaling , promoting cell survival and opposing apoptosis by a variety of routes .	EGFR and FGFR signaling pathways depend on PTEN PIP3 activation in the AKT signaling, promoting cell survival and opposing apoptosis by a variety of routes.	7	13	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	12	13
The tumor suppressor phosphatase and tensin homolog ( PTEN ) antagonizes this PI3K and Akt pathway .	The tumor suppressor phosphatase and tensin homolog (PTEN) antagonizes this PI3K and Akt pathway.	0	15	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	3	7	14	15
Other negative regulators of PI3K and Akt signaling such as PTEN are important for Foxp3 + Treg generation .	Other negative regulators of PI3K and Akt signaling such as PTEN are important for Foxp3 + Treg generation.	4	11	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	6	7
Co-deletion of PTEN reverses the PI3K and AKT activation defects and prevents the induction of anergy .	Co-deletion of PTEN reverses the PI3K and AKT activation defects and prevents the induction of anergy.	0	9	reverses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	7	8
PTEN modulates the PI3K and AKT signaling pathway , thus inhibiting tumor survival , growth , and proliferation [ XREF_BIBR ] .	PTEN modulates the PI3K and AKT signaling pathway, thus inhibiting tumor survival, growth, and proliferation [XREF_BIBR].	0	7	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
Given its central node position in the canonical PI3K pathway , AKT can be activated by either upstream PIK3CA activation or PTEN inactivation .	Given its central node position in the canonical PI3K pathway, AKT can be activated by either upstream PIK3CA activation or PTEN inactivation.	11	22	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	21	22	11	12
In human aortic smooth muscle cells , the forced expression of miR-221/222 silences phosphatase and tensin homolog deleted on chromosome ten ( PTEN ) and subsequently activates the Akt signaling .	In human aortic smooth muscle cells, the forced expression of miR-221/222 silences phosphatase and tensin homolog deleted on chromosome ten (PTEN) and subsequently activates the Akt signaling.	9	29	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	expression of miR-221/222 silences phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	13	17	28	29
Conversely , the 3 '-phosphoinositide phosphatase PTEN reverses PIP 3 production , decreasing Akt signaling and activating autophagy [ XREF_BIBR ] .	Conversely, the 3 '-phosphoinositide phosphatase PTEN reverses PIP 3 production, decreasing Akt signaling and activating autophagy [XREF_BIBR].	2	14	reverses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	13	14
The expression of NDRG2 is frequently downregulated in ATLL , resulting in enhanced phosphorylation of PTEN at the Ser380/Thr382/Thr383 cluster and enhanced activation of the PI3K-AKT pathway .	The expression of NDRG2 is frequently downregulated in ATLL, resulting in enhanced phosphorylation of PTEN at the Ser380/Thr382/Thr383 cluster and enhanced activation of the PI3K-AKT pathway.	1	26	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	expression of NDRG2 is frequently downregulated in ATLL, resulting in enhanced phosphorylation of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	15	16	25	26
Alkylation of PTEN activates Akt and beta-catenin .	Alkylation of PTEN activates Akt and beta-catenin.	0	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	4	5
Additionally , co-transfection of miR-32-5p mimics and PTEN expressing vector or co-transfection of miR-32-5p inhibitor and siPTEN abolished the effects of miR-32-5p mimics or inhibitor alone , indicating that miR-32-5p targets PTEN activates the PI3K and Akt pathway to promote EMT process .	Additionally, co-transfection of miR-32-5p mimics and PTEN expressing vector or co-transfection of miR-32-5p inhibitor and siPTEN abolished the effects of miR-32-5p mimics or inhibitor alone, indicating that miR-32-5p targets PTEN activates the PI3K and Akt pathway to promote EMT process.	29	37	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	31	32	36	37
Since PTEN may modulate a broad range of PI3K and Akt independent signaling pathways in different cell types , the enhancement of eNOS phosphorylation following PTEN knockdown most plausibly reflects the effects of PTEN on a phosphorylation pathway distinct from PI3K and Akt .	Since PTEN may modulate a broad range of PI3K and Akt independent signaling pathways in different cell types, the enhancement of eNOS phosphorylation following PTEN knockdown most plausibly reflects the effects of PTEN on a phosphorylation pathway distinct from PI3K and Akt.	1	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	10	11
XREF_BIBR , XREF_BIBR , XREF_BIBR Also , constitutively activation of the PI3K and AKT pathway and inactivation of the tumor suppressor PTEN ( mainly by LOH of the PTEN locus ) are common events in UM tumors .	XREF_BIBR, XREF_BIBR, XREF_BIBR Also, constitutively activation of the PI3K and AKT pathway and inactivation of the tumor suppressor PTEN (mainly by LOH of the PTEN locus) are common events in UM tumors.	8	29	activation	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	28	29	13	14
Downstream of PTEN , miR-21 promotes activation of Akt , and consequently increases activation of NF-kappaB pathway .	Downstream of PTEN, miR-21 promotes activation of Akt, and consequently increases activation of NF-kappaB pathway.	0	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	8	9
Recently , it was described that PTEN gene is mutated in C33A cells [ XREF_BIBR ] and loss of PTEN protein expression induces Akt constitutive activation and proliferation of C33A cells [ XREF_BIBR ] .	Recently, it was described that PTEN gene is mutated in C33A cells [XREF_BIBR] and loss of PTEN protein expression induces Akt constitutive activation and proliferation of C33A cells [XREF_BIBR].	19	25	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN protein expression	pten	Akt	Akt	akt	19	20	23	24
In cancer , sustained activation of the PTEN target AKT increased Nrf2 nuclear localization [ XREF_BIBR ] .	In cancer, sustained activation of the PTEN target AKT increased Nrf2 nuclear localization [XREF_BIBR].	4	10	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	9	10
PTEN mediated Akt activates beta-catenin and negatively regulates Foxo1 signaling in vitro .	PTEN mediated Akt activates beta-catenin and negatively regulates Foxo1 signaling in vitro.	0	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	2	3
In addition , silencing of PTP1B or PTEN using lentivirus mediated shRNA expression significantly alleviated the suppressed activation state ( phosphorylation ) of AKT in MDFs treated with IGF-1 in the presence of rotenone ( Fig XREF_FIG ) .	In addition, silencing of PTP1B or PTEN using lentivirus mediated shRNA expression significantly alleviated the suppressed activation state (phosphorylation) of AKT in MDFs treated with IGF-1 in the presence of rotenone (Fig XREF_FIG).	3	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	23	24
Therefore , inactivation of PTEN leads to increased levels of phosphatidylinositol-3 ,4,5 triphosphate and increased Akt activation XREF_BIBR .	Therefore, inactivation of PTEN leads to increased levels of phosphatidylinositol-3,4,5 triphosphate and increased Akt activation XREF_BIBR.	2	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	15	16
PTEN inhibits activation of Akt by converting PIP 3 into PIP 2 , and reduction of the level of PTEN causes the activation of Akt in pulmonary fibrosis .	PTEN inhibits activation of Akt by converting PIP 3 into PIP 2, and reduction of the level of PTEN causes the activation of Akt in pulmonary fibrosis.	0	5	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	4	5
PI3K and Akt pathway plays important roles in regulating cell death induced by TRAIL , while DSeA was sufficient to overcome PI3K and Akt pathway mediated TRAIL resistance in A375 cells by enhancement of PTEN expression .	PI3K and Akt pathway plays important roles in regulating cell death induced by TRAIL, while DSeA was sufficient to overcome PI3K and Akt pathway mediated TRAIL resistance in A375 cells by enhancement of PTEN expression.	0	36	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	34	35	2	3
Phosphorylation of PTEN decreases its activity and thus stimulates the protective activity of AKT 37 .	Phosphorylation of PTEN decreases its activity and thus stimulates the protective activity of AKT 37.	0	14	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Phosphorylation of PTEN	pten	AKT	AKT	akt	2	3	13	14
The rescue of activation of both AKT and IRS1 by PTEN ablation suggests that suppression of IGF signaling by PTEN may not be simply due to its lipid phosphatase activity .	The rescue of activation of both AKT and IRS1 by PTEN ablation suggests that suppression of IGF signaling by PTEN may not be simply due to its lipid phosphatase activity.	3	11	activation	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	10	11	6	7
The down-regulation of PTEN that was induced by hypoxia caused activation of downstream Akt and mTOR signaling , which was demonstrated by elevated levels of phosphorylation of Akt and mTOR .	The down-regulation of PTEN that was induced by hypoxia caused activation of downstream Akt and mTOR signaling, which was demonstrated by elevated levels of phosphorylation of Akt and mTOR.	1	20	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	13	14
Compellingly , PTEN depletion induced the activation of AKT and also led to an increase in MKRN1 , suggesting that active pAKT might affect MKRN1 ( XREF_FIG , lane 4 ) .	Compellingly, PTEN depletion induced the activation of AKT and also led to an increase in MKRN1, suggesting that active pAKT might affect MKRN1 (XREF_FIG, lane 4).	2	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	8	9
9 However , PTEN monoubiquitination enhances its nuclear import and antitumor effect perhaps by preventing nuclear AKT activity and genomic instability .	9 However, PTEN monoubiquitination enhances its nuclear import and antitumor effect perhaps by preventing nuclear AKT activity and genomic instability.	3	17	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN monoubiquitination	pten	AKT	AKT	akt	3	4	16	17
Recent evidence suggests that PHLPP1 forms a tumor suppressor network with PTEN in regulating Akt signaling , and that , upon loss of PTEN , PHLPP1 acts as a brake to counteract PTEN deficiency induced Akt activation .	Recent evidence suggests that PHLPP1 forms a tumor suppressor network with PTEN in regulating Akt signaling, and that, upon loss of PTEN, PHLPP1 acts as a brake to counteract PTEN deficiency induced Akt activation.	32	36	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	32	33	35	36
Mutations in the PTEN gene enhanced insulin sensitivity by modulating the PI3K-AKT pathway XREF_BIBR .	Mutations in the PTEN gene enhanced insulin sensitivity by modulating the PI3K-AKT pathway XREF_BIBR.	3	13	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	3	4	11	12
PTEN modulates the activation of AKT through converting PIP3 , generated by PI3K , to PIP2 by dephosphorylation [ XREF_BIBR ] .	PTEN modulates the activation of AKT through converting PIP3, generated by PI3K, to PIP2 by dephosphorylation [XREF_BIBR].	0	6	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
Hence , PTEN negatively modulates the PI3K and AKT pathway , and thereby may have a crucial effect on the control of cell cycle and cell survival [ XREF_BIBR ] .	Hence, PTEN negatively modulates the PI3K and AKT pathway, and thereby may have a crucial effect on the control of cell cycle and cell survival [XREF_BIBR].	2	14	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	8	9
Mutations in PIK3R1 , PIK3CA , or PTEN activate the PI3K-AKT signalling cascade , and were reported in 4 , 6 and 15 % of paediatric T-LBL cases , respectively .	Mutations in PIK3R1, PIK3CA, or PTEN activate the PI3K-AKT signalling cascade, and were reported in 4, 6 and 15% of paediatric T-LBL cases, respectively.	0	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	7	8	10	11
In NSCLC , the lack of PTEN induced up-regulation of PI3K and Akt , which demonstrated that PTEN/PI3K/Akt signaling pathway contributed to the tumorigenesis and development of NSCLC .	In NSCLC, the lack of PTEN induced up-regulation of PI3K and Akt, which demonstrated that PTEN/PI3K/Akt signaling pathway contributed to the tumorigenesis and development of NSCLC.	4	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	12	13
For example , if PDK1 constitutively activates Akt , thus activating the PI3k pathway , Akt activation occurs independently of PTEN loss or retention , resulting in PTEN independent constitutive activation of the PI3k and Akt pathway .	For example, if PDK1 constitutively activates Akt, thus activating the PI3k pathway, Akt activation occurs independently of PTEN loss or retention, resulting in PTEN independent constitutive activation of the PI3k and Akt pathway.	27	36	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	27	28	35	36
The pharmacological inhibition of PTEN was reported to reduce neurological damage after ischemic brain injury by upregulating PI3K and Akt activity .	The pharmacological inhibition of PTEN was reported to reduce neurological damage after ischemic brain injury by upregulating PI3K and Akt activity.	2	20	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	19	20
Our results showed that the knockdown of HES1 increased PTEN expression and decreased p-AKT protein levels and AKT activity , and overexpression of HES1 decreased PTEN expression and increased the p-AKT protein levels and AKT activity .	Our results showed that the knockdown of HES1 increased PTEN expression and decreased p-AKT protein levels and AKT activity, and overexpression of HES1 decreased PTEN expression and increased the p-AKT protein levels and AKT activity.	21	35	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	overexpression of HES1 decreased PTEN expression	pten	AKT	AKT	akt	25	26	34	35
Likewise , it was noticed that miR-222 and miR-29 inhibitors changed the drug-resistance and restored the sensitivity to these drugs through targeting PTEN ( phosphatase and tensin homolog ) , activating the Akt and mTOR pathway ( Akt Serine/Threonine Kinase 1/Mechanistic Target of Rapamycin ) [ XREF_BIBR ] .	Likewise, it was noticed that miR-222 and miR-29 inhibitors changed the drug-resistance and restored the sensitivity to these drugs through targeting PTEN (phosphatase and tensin homolog), activating the Akt and mTOR pathway (Akt Serine/Threonine Kinase 1/Mechanistic Target of Rapamycin) [XREF_BIBR].	21	35	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	22	23	32	33
C-Met inhibition with 10 microM SU11274 decreased Akt activation by ~ 30 % in both U87 and U251 glioma cell lines ( P < 0.05 ) , whereas PTEN reconstitution alone and in combination with 10 microM SU11274 decreased Akt activation by 90 % in both cell lines ( P < 0.05 ) ( XREF_FIG ) .	C-Met inhibition with 10 microM SU11274 decreased Akt activation by ~ 30% in both U87 and U251 glioma cell lines (P < 0.05), whereas PTEN reconstitution alone and in combination with 10 microM SU11274 decreased Akt activation by 90% in both cell lines (P < 0.05) (XREF_FIG).	28	40	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	28	29	39	40
In GBM , inhibition of miR-21 activity increased PTEN expression and decreased tumorigenicity , EGFR expression and Akt activation XREF_BIBR .	In GBM, inhibition of miR-21 activity increased PTEN expression and decreased tumorigenicity, EGFR expression and Akt activation XREF_BIBR.	5	19	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	miR-21 activity increased PTEN expression	pten	Akt	Akt	akt	8	9	17	18
Through targeting PTEN and subsequent activation of Akt pathway , miR-21 may be involved in both EMT and endothelial-to-mesenchymal transition ( EndMT ) [ XREF_BIBR - XREF_BIBR ] .	Through targeting PTEN and subsequent activation of Akt pathway, miR-21 may be involved in both EMT and endothelial-to-mesenchymal transition (EndMT) [XREF_BIBR - XREF_BIBR].	2	8	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	7	8
The pathway study suggests that cavtratin induces the phosphorylation of both AKT and PTEN and thus activates the AKT pathway to support the protective phenotype of microglial cells .	The pathway study suggests that cavtratin induces the phosphorylation of both AKT and PTEN and thus activates the AKT pathway to support the protective phenotype of microglial cells.	5	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	cavtratin induces the phosphorylation of both AKT and PTEN	pten	AKT	AKT	akt	13	14	18	19
In addition to DNA sequence mutations , LOH of PTEN is a well-known event in many malignancies and serves to activate the PI3K and AKT pathway .	In addition to DNA sequence mutations, LOH of PTEN is a well-known event in many malignancies and serves to activate the PI3K and AKT pathway.	7	25	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	24	25
Taken together , these findings suggest that blockade of PI3K and Akt signaling by PTEN may render breast cancer cells more dependent on the MEK and Erk pathway for their proliferation and survival .	Taken together, these findings suggest that blockade of PI3K and Akt signaling by PTEN may render breast cancer cells more dependent on the MEK and Erk pathway for their proliferation and survival.	9	15	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	11	12
Down-regulation of FOG2 and PTEN promotes the activation of Akt and its downstream signaling pathways to enhance the expansion and immune suppressive potential of MDSCs .	Down-regulation of FOG2 and PTEN promotes the activation of Akt and its downstream signaling pathways to enhance the expansion and immune suppressive potential of MDSCs.	0	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	9	10
The PI3K and Akt pathway is negatively regulated by the tumor-suppressor gene PTEN , which is localized to chromosome 10 .	The PI3K and Akt pathway is negatively regulated by the tumor-suppressor gene PTEN, which is localized to chromosome 10.	1	16	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	12	13	3	4
Many natural compounds are also reported to inactivate the PI3K-AKT pathway either by activating PTEN or inactivating oncogenes that drive AKT activation .	Many natural compounds are also reported to inactivate the PI3K-AKT pathway either by activating PTEN or inactivating oncogenes that drive AKT activation.	7	21	drive	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	20	21
Our data suggest that PTEN may regulate telomerase activity by a novel mechanism in which inhibition of Akt activation by PTEN leads to decreased hTERT mRNA levels .	Our data suggest that PTEN may regulate telomerase activity by a novel mechanism in which inhibition of Akt activation by PTEN leads to decreased hTERT mRNA levels.	17	21	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	20	21	17	18
Overexpression of PTENP1 ( XREF_SUPPLEMENTARY ) in ACHN and SN12PM6 cells upregulated PTEN expression ( XREF_FIG ) and activated AKT , a PTEN downstream target ( XREF_SUPPLEMENTARY ) .	Overexpression of PTENP1 (XREF_SUPPLEMENTARY) in ACHN and SN12PM6 cells upregulated PTEN expression (XREF_FIG) and activated AKT, a PTEN downstream target (XREF_SUPPLEMENTARY).	0	26	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	Overexpression of PTENP1 (XREF_SUPPLEMENTARY) in ACHN and SN12PM6 cells upregulated PTEN expression	pten	AKT	AKT	akt	12	13	19	20
Recently , we have further observed that Cd inactivation of PTEN results in activation of Akt and mTOR signaling and apoptosis of neuronal cells , implying that loss of PTEN function may promote development of neurodegenerative disorders .	Recently, we have further observed that Cd inactivation of PTEN results in activation of Akt and mTOR signaling and apoptosis of neuronal cells, implying that loss of PTEN function may promote development of neurodegenerative disorders.	8	18	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	10	11	15	16
Alternatively , inactivation of PTEN constitutively activates the AKT pathway , a major player in colon cancer carcinogenesis .	Alternatively, inactivation of PTEN constitutively activates the AKT pathway, a major player in colon cancer carcinogenesis.	2	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	8	9
In the present study , we found that PTEN deficiency further increased the activation of AKT by an additional ~ 2 to 3-fold in the thyroids of TRbeta PV/PV mice .	In the present study, we found that PTEN deficiency further increased the activation of AKT by an additional ~ 2 to 3-fold in the thyroids of TRbeta PV/PV mice.	8	16	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	8	9	15	16
The pro survival cellular mechanisms alleviating the requirement of PI3K and PTEN mediated AKT activation is becoming increasingly apparent .	The pro survival cellular mechanisms alleviating the requirement of PI3K and PTEN mediated AKT activation is becoming increasingly apparent.	7	14	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	11	12	13	14
Finally , NF-kappaB down-regulates the expression of phosphatase and tensin homolog ( PTEN ) to activate Akt to promote cell survival and proliferation .	Finally, NF-kappaB down-regulates the expression of phosphatase and tensin homolog (PTEN) to activate Akt to promote cell survival and proliferation.	2	17	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	NF-kappaB down-regulates the expression of phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	akt	7	11	16	17
Phosphatase and tensin homolog ( PTEN ) mutations , which activate AKT , have been described in RCC in association with more aggressive disease ( Kondo et al , 2001 ; Shin Lee et al , 2003 ) .	Phosphatase and tensin homolog (PTEN) mutations, which activate AKT, have been described in RCC in association with more aggressive disease (Kondo et al, 2001; Shin Lee et al, 2003).	3	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	5	6	11	12
Enhanced Akt activity is observed in Pten null tumor cells of castrated Pten LoxP and LoxP : Osr1-Cre .	Enhanced Akt activity is observed in Pten null tumor cells of castrated Pten LoxP and LoxP : Osr1-Cre.	0	13	Enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	12	13	1	2
The analysis of nutrient uptake in PTEN -/- non transformed thymocytes allows an assessment of the ability of PtdIns ( 3,4,5 ) P 3 and AKT to drive nutrient transport in T cells .	The analysis of nutrient uptake in PTEN -/- non transformed thymocytes allows an assessment of the ability of PtdIns (3,4,5) P 3 and AKT to drive nutrient transport in T cells.	4	27	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	25	26
The percentage of active form of PTEN is decreased in PAI-1 -/- ECs ( XREF_FIG ) suggesting that Akt activation associated with PAI-1 genetic deficiency is partly mediated by PTEN inactivation .	The percentage of active form of PTEN is decreased in PAI-1 -/- ECs (XREF_FIG) suggesting that Akt activation associated with PAI-1 genetic deficiency is partly mediated by PTEN inactivation.	18	30	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	29	30	18	19
It has been demonstrated that deficiency of PTEN resulted in activation of Akt , followed by phosphorylation of its downstream substrates .	It has been demonstrated that deficiency of PTEN resulted in activation of Akt, followed by phosphorylation of its downstream substrates.	5	13	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	7	8	12	13
Moreover , Akt activity can be deregulated by constitutive activation or by inhibition of PTEN and MMAC1 , a phosphatase that directly counteracts Akt through the dephosphorylation of PI-3-, 4-, 5-P 3 ( Stambolic et al , 1998 ) .	Moreover, Akt activity can be deregulated by constitutive activation or by inhibition of PTEN and MMAC1, a phosphatase that directly counteracts Akt through the dephosphorylation of PI-3-, 4-, 5-P 3 (Stambolic et al, 1998).	2	16	deregulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	2	3
Akt activation is usually up-regulated by PI3-K and down-regulated by the PTEN tumor suppressor .	Akt activation is usually up-regulated by PI3-K and down-regulated by the PTEN tumor suppressor.	0	13	down-regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	0	1
Hence , in the absence of PTEN induced downregulation of AKT , FOXO transcription factors are constitutively phosphorylated , thereby inhibiting the activation of the programmed cell death pathway .	Hence, in the absence of PTEN induced downregulation of AKT, FOXO transcription factors are constitutively phosphorylated, thereby inhibiting the activation of the programmed cell death pathway.	4	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	10	11
PTEN gene expression was reduced both by early protein restriction ( P < 0.05 ) and HPD ( P < 0.01 ) , which may induce Akt in cell survival pathways .	PTEN gene expression was reduced both by early protein restriction (P < 0.05) and HPD (P < 0.01), which may induce Akt in cell survival pathways.	0	27	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN gene expression was reduced both by early protein restriction (P < 0.05) and HPD	pten	Akt	Akt	akt	0	1	26	27
Our results are consistent with prior studies showing that PTEN and PIK3CA activate mTOR signaling downstream of AKT in non redundant ways .	Our results are consistent with prior studies showing that PTEN and PIK3CA activate mTOR signaling downstream of AKT in non redundant ways.	9	21	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	17	18
PTEN inactivation by point mutations or deletion aberrantly activates PI3K-AKT pathway , promoting cell growth , survival and proliferation .	PTEN inactivation by point mutations or deletion aberrantly activates PI3K-AKT pathway, promoting cell growth, survival and proliferation.	0	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	0	1	9	10
Downregulation of NDRG2 in adult T-cell leukemia-lymphoma ( ATLL ) enhances PTEN phosphorylation and promotes the PI3K-AKT pathway .	Downregulation of NDRG2 in adult T-cell leukemia-lymphoma (ATLL) enhances PTEN phosphorylation and promotes the PI3K-AKT pathway.	2	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	NDRG2 in adult T-cell leukemia-lymphoma (ATLL) enhances PTEN phosphorylation	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	11	12	16	17
Thus , it is possible that in PTEN mKO mice , PTEN deficiency enhanced Akt and FoxO1 signaling in macrophages .	Thus, it is possible that in PTEN mKO mice, PTEN deficiency enhanced Akt and FoxO1 signaling in macrophages.	11	17	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	14	15
PTEN gene activation of the PI3K and AKT signaling pathway is thought to promote the development of follicular and anaplastic thyroid carcinomas , as well as breast cancer [ XREF_BIBR ] .	PTEN gene activation of the PI3K and AKT signaling pathway is thought to promote the development of follicular and anaplastic thyroid carcinomas, as well as breast cancer [XREF_BIBR].	0	9	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	7	8
The other one includes activation of alternative pro tumorigenic pathways such as the PI3K and AKT pathway that can be caused by phosphatase and tensin homolog ( PTEN ) loss [ XREF_BIBR ] or by an increase in signaling driven by receptor tyrosine kinases ( RTK ) .	The other one includes activation of alternative pro tumorigenic pathways such as the PI3K and AKT pathway that can be caused by phosphatase and tensin homolog (PTEN) loss [XREF_BIBR] or by an increase in signaling driven by receptor tyrosine kinases (RTK).	13	29	caused	Positive_activation_syntax_6_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	27	28	15	16
75 In addition to E-cadherin , Snail can directly suppress the transcription of genes involved in anoikis , such as PTEN , downregulation of which activates the PI3-K and Akt pathway and inactivates the proapoptotic protein Bad , thus contributing to anoikis resistance .	75 In addition to E-cadherin, Snail can directly suppress the transcription of genes involved in anoikis, such as PTEN, downregulation of which activates the PI3-K and Akt pathway and inactivates the proapoptotic protein Bad, thus contributing to anoikis resistance.	16	39	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	20	21	29	30
PTEN Plays a Role in Thrombin Mediated Activation of the PI3K and AKT Signaling Pathway .	PTEN Plays a Role in Thrombin Mediated Activation of the PI3K and AKT Signaling Pathway.	0	14	Mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	12	13
Mutational inactivation of PTEN or activation of PI3K increases AKT and mTOR signaling that promotes growth , proliferation , and survival , while mutation of TP53 promotes cell survival and proliferation .	Mutational inactivation of PTEN or activation of PI3K increases AKT and mTOR signaling that promotes growth, proliferation, and survival, while mutation of TP53 promotes cell survival and proliferation.	1	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	9	10
Additionally , Pten removal increased AKT and ERK activation , above the levels of controls , in the presence or absence of Fgfr2 .	Additionally, Pten removal increased AKT and ERK activation, above the levels of controls, in the presence or absence of Fgfr2.	2	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	AKT	AKT	AKT	2	3	5	6
The demonstration that respiration defects lead to activation of the Akt pathway caused by the accumulation of NADH and inactivation of PTEN reveals a novel mechanism by which cancer cells survive under respiration compromised conditions .	The demonstration that respiration defects lead to activation of the Akt pathway caused by the accumulation of NADH and inactivation of PTEN reveals a novel mechanism by which cancer cells survive under respiration compromised conditions.	10	22	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	21	22	10	11
However , PTEN haploinsufficiency restores Akt signaling in these tumors and dramatically enhances tumorigenesis .	However, PTEN haploinsufficiency restores Akt signaling in these tumors and dramatically enhances tumorigenesis.	2	6	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	2	3	5	6
Western blot analysis showed that knockdown of Sall4 increased PTEN expression and induced inactivation of PI3K and AKT signaling .	Western blot analysis showed that knockdown of Sall4 increased PTEN expression and induced inactivation of PI3K and AKT signaling.	7	18	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	Sall4 increased PTEN expression	pten	AKT	AKT	akt	9	10	17	18
The Palomero group found that transcriptional downregulation of PTEN mediates physiologic upregulation of the PI3K-AKT pathway ; mutational loss of PTEN and aberrant Akt activation induce resistance to GSI in T-cell leukemia [ XREF_BIBR ] .	The Palomero group found that transcriptional downregulation of PTEN mediates physiologic upregulation of the PI3K-AKT pathway; mutational loss of PTEN and aberrant Akt activation induce resistance to GSI in T-cell leukemia [XREF_BIBR].	6	15	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3K-AKT	PI3K-AKT	PI3K-AKT	8	9	14	15
Taken together , these data indicate that reintroduction of PTEN abrogates miR-21-induced P13K and AKT protein reduction .	Taken together, these data indicate that reintroduction of PTEN abrogates miR-21-induced P13K and AKT protein reduction.	7	16	abrogates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	14	15
The downregulated PTEN upregulates PI3K and AKT signaling enhancing cell proliferation , migration and chemoresistance XREF_BIBR .	The downregulated PTEN upregulates PI3K and AKT signaling enhancing cell proliferation, migration and chemoresistance XREF_BIBR.	0	7	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	6	7
AKT is activated by EGFR activation and loss of PTEN function XREF_BIBR , XREF_BIBR .	AKT is activated by EGFR activation and loss of PTEN function XREF_BIBR, XREF_BIBR.	0	11	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	0	1
Taken together , our work strongly suggests that during IPF fibroblast interaction with polymerized collagen , inappropriately low PTEN function aberrantly activates Akt , which suppresses FoxO3a activity .	Taken together, our work strongly suggests that during IPF fibroblast interaction with polymerized collagen, inappropriately low PTEN function aberrantly activates Akt, which suppresses FoxO3a activity.	18	25	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	18	19	22	23
Likewise , Akt association with IRAK2 is increased considerably by overexpression of PTEN ( phosphatase and tensin homologue deleted on chromosome 10 ) , while it is completely abrogated by overexpression of phosphoinositide dependent protein kinase 1 .	Likewise, Akt association with IRAK2 is increased considerably by overexpression of PTEN (phosphatase and tensin homologue deleted on chromosome 10), while it is completely abrogated by overexpression of phosphoinositide dependent protein kinase 1.	2	13	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	overexpression of PTEN	pten	Akt	Akt	akt	12	13	2	3
The absence of PTEN causing Akt hyperactivation was evident by the higher expressions of p-Ser 473 Akt and p-Thr 308 Akt without a significant change in the total Akt ( XREF_FIG ) .	The absence of PTEN causing Akt hyperactivation was evident by the higher expressions of p-Ser 473 Akt and p-Thr 308 Akt without a significant change in the total Akt (XREF_FIG).	1	6	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	5	6
Activation of the PI3K and Akt pathway by PTEN regulation .	Activation of the PI3K and Akt pathway by PTEN regulation.	0	9	Activation	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	5	6
S nitrosylation of PTEN by low concentrations of NO at Cys 83 inhibited its enzymatic activity [ XREF_BIBR ] and consequently stimulated the downstream Akt cascade , which is essential for cell survival [ XREF_BIBR ] .	S nitrosylation of PTEN by low concentrations of NO at Cys 83 inhibited its enzymatic activity [XREF_BIBR] and consequently stimulated the downstream Akt cascade, which is essential for cell survival [XREF_BIBR].	1	25	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	24	25
Interestingly , HDAC6 inhibitor treatment led to inactivating phosphorylation of PTEN ( P-PTEN Ser380 ) , which likely led to the increased P-AKT in cells that express PTEN .	Interestingly, HDAC6 inhibitor treatment led to inactivating phosphorylation of PTEN (P-PTEN Ser380), which likely led to the increased P-AKT in cells that express PTEN.	2	23	led	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	PTEN	HDAC6 inhibitor treatment led to inactivating phosphorylation of PTEN (P-PTEN Ser380	pten	P-AKT	P-AKT	p-akt	10	11	22	23
The tumor suppressor , PTEN , blocks the PI3K and AKT pathway and modulates the AKT-mTOR pathway by dephosphorylating compounds such as intrinsic plasma membrane protein 3 ; when not phosphorylated , these compounds interact through synergism with interacting acting protein 1 to suppress AKT1 activation [ XREF_BIBR ] .	The tumor suppressor, PTEN, blocks the PI3K and AKT pathway and modulates the AKT-mTOR pathway by dephosphorylating compounds such as intrinsic plasma membrane protein 3; when not phosphorylated, these compounds interact through synergism with interacting acting protein 1 to suppress AKT1 activation [XREF_BIBR].	2	11	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	10	11
Previous studies found that PTEN inactivation in neonatal cardiomyocytes by overexpression of dominant negative PTEN H123Y mutant activates the Akt prosurvival pathway , reduces apoptosis , and increases survival XREF_BIBR .	Previous studies found that PTEN inactivation in neonatal cardiomyocytes by overexpression of dominant negative PTEN H123Y mutant activates the Akt prosurvival pathway, reduces apoptosis, and increases survival XREF_BIBR.	4	21	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	4	5	19	20
Our examination of the signaling molecules related to Akt signaling including PTEN and GSK3beta revealed little role in the Akt negative regulator PTEN in LPS- and Akt activation induced myocardial responsiveness .	Our examination of the signaling molecules related to Akt signaling including PTEN and GSK3beta revealed little role in the Akt negative regulator PTEN in LPS- and Akt activation induced myocardial responsiveness.	8	13	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	8	9
Similar PTEN elevation and inhibition of AKT by ODAM was observed in MDA-MB-231 breast cancer cells while ODAM expression had no effect in PTEN deficient BT-549 breast cancer cells .	Similar PTEN elevation and inhibition of AKT by ODAM was observed in MDA-MB-231 breast cancer cells while ODAM expression had no effect in PTEN deficient BT-549 breast cancer cells.	1	8	elevation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	1	2	6	7
As a future study , it will be also important to determine whether Pfn1 dependent PTEN upregulation and suppression of AKT activation are i ) generalized phenomena in other variants of adenocarcinoma , and ii ) accounts for growth inhibition and impaired tumorigenicity of Pfn1 overexpressing breast cancer cell lines .	As a future study, it will be also important to determine whether Pfn1 dependent PTEN upregulation and suppression of AKT activation are i) generalized phenomena in other variants of adenocarcinoma, and ii) accounts for growth inhibition and impaired tumorigenicity of Pfn1 overexpressing breast cancer cell lines.	15	21	upregulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	15	16	20	21
The PI-3-kinase and Akt pathway is frequently activated in human tumors by suppression or deletion of the PTEN tumor suppressor , or through mutational activation or amplification of PI-3-kinase .	The PI-3-kinase and Akt pathway is frequently activated in human tumors by suppression or deletion of the PTEN tumor suppressor, or through mutational activation or amplification of PI-3-kinase.	1	19	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	17	18	3	4
GSK-3beta is regulated upstream by PI3K and Akt , which is negatively modulated by PTEN .	GSK-3beta is regulated upstream by PI3K and Akt, which is negatively modulated by PTEN.	3	15	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	14	15	7	8
The target of miR-21 is the phosphate and tensin homolog ( PTEN ) tumour suppressor gene which in turn activates the PKI3 and AKt pathway that triggers cellular apoptosis [ XREF_BIBR ] .	The target of miR-21 is the phosphate and tensin homolog (PTEN) tumour suppressor gene which in turn activates the PKI3 and AKt pathway that triggers cellular apoptosis [XREF_BIBR].	9	24	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKt	AKt	AKt	11	12	23	24
PTEN negatively regulates PI3K signalling by dephosphorylating PtdIns ( 3,4,5 ) P 3 to PtdIns ( 4,5 ) P 2 and thus mediates its tumour-suppressor function by inactivating downstream oncogenic AKT mediated signalling 19 .	PTEN negatively regulates PI3K signalling by dephosphorylating PtdIns (3,4,5) P 3 to PtdIns (4,5) P 2 and thus mediates its tumour-suppressor function by inactivating downstream oncogenic AKT mediated signalling 19.	0	31	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	30	31
Down-regulated PTEN gene expression , however , was not associated with an enhancement of HASMC migration , but activated PI3K and AKT signal pathway and inhibited Ras-Raf-MEK1/2-ERK1/2 signal pathway .	Down-regulated PTEN gene expression, however, was not associated with an enhancement of HASMC migration, but activated PI3K and AKT signal pathway and inhibited Ras-Raf-MEK1/2-ERK1/2 signal pathway.	1	23	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN gene expression	pten	AKT	AKT	akt	1	2	21	22
Thus , inactivation of Pten , which inhibits PI3K , should activate Akt and promotes muscle hypertrophy .	Thus, inactivation of Pten, which inhibits PI3K, should activate Akt and promotes muscle hypertrophy.	2	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	4	5	12	13
The schematic model demonstrated that OIP5 regulates tumor growth and metastasis through AKT activation , which is mediated by both mTORC2 activation and p38 and PTEN inactivation .	The schematic model demonstrated that OIP5 regulates tumor growth and metastasis through AKT activation, which is mediated by both mTORC2 activation and p38 and PTEN inactivation.	12	26	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	25	26	12	13
PTEN also has an active site Cys sensitive to oxidation and its oxidation by RNS inhibits PTEN activating anti-apoptotic Akt signaling .	PTEN also has an active site Cys sensitive to oxidation and its oxidation by RNS inhibits PTEN activating anti-apoptotic Akt signaling.	16	20	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	16	17	19	20
To this , we found that an embryonic stem cell ( ESC )-specific microRNA , miR-302 , silences phosphatase and tensin homolog ( PTEN ) to activate Akt signaling , which subsequently stimulates nuclear factor erythroid 2 related factor 2 ( Nrf2 )/heme oxygenase-1 ( HO-1 ) elevation and hence inhibits Abeta induced neurotoxicity .	To this, we found that an embryonic stem cell (ESC)-specific microRNA, miR-302, silences phosphatase and tensin homolog (PTEN) to activate Akt signaling, which subsequently stimulates nuclear factor erythroid 2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) elevation and hence inhibits Abeta induced neurotoxicity.	18	28	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	23	24	27	28
These observations suggest that the major target of chr19 loss is the Pten tumor-suppressor gene , which consequently activates the PI3K and Akt signaling pathway in this glioma model .	These observations suggest that the major target of chr19 loss is the Pten tumor-suppressor gene, which consequently activates the PI3K and Akt signaling pathway in this glioma model.	12	24	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	Akt	Akt	Akt	12	13	22	23
Pten deficiency in hepatocytes induced excessive activation of the PI3K and AKT pathway , increased lipogenesis and reduced lipolysis , resulting in hepatic lipid accumulation and injuries .	Pten deficiency in hepatocytes induced excessive activation of the PI3K and AKT pathway, increased lipogenesis and reduced lipolysis, resulting in hepatic lipid accumulation and injuries.	0	12	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	AKT	AKT	AKT	0	1	11	12
On the whole , our study identified that the downregulation of miR-382 by propranolol inhibits the progression of IHs via the PTEN mediated AKT and mTOR pathway .	On the whole, our study identified that the downregulation of miR-382 by propranolol inhibits the progression of IHs via the PTEN mediated AKT and mTOR pathway.	18	26	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	21	22	23	24
We have established that downregulation of PTEN due to increased miR-21 expression in renal cancer cells activates Akt ( XREF_FIG ) , which contributes to proliferation and migration of these cells ( XREF_FIG and XREF_FIG ) .	We have established that downregulation of PTEN due to increased miR-21 expression in renal cancer cells activates Akt (XREF_FIG), which contributes to proliferation and migration of these cells (XREF_FIG and XREF_FIG).	4	23	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	17	18
In another transgenic model of EOC a conditional knock out of Dicer and Pten led to activation of the phosphatidylinositol 3-kinase ( PI3K ) and AKT pathway , and resulted in the development of high grade serous adenocarcinomas from the oviduct .	In another transgenic model of EOC a conditional knock out of Dicer and Pten led to activation of the phosphatidylinositol 3-kinase (PI3K) and AKT pathway, and resulted in the development of high grade serous adenocarcinomas from the oviduct.	13	29	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	AKT	AKT	AKT	13	14	25	26
Together these data demonstrate that loss of PTEN expression attenuates lapatinib sensitivity in vitro and in vivo possibly by maintaining the activation of the AKT signalling pathway .	Together these data demonstrate that loss of PTEN expression attenuates lapatinib sensitivity in vitro and in vivo possibly by maintaining the activation of the AKT signalling pathway.	7	26	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	7	8	24	25
Previous studies have revealed that overexpression of miR-21 can down-regulate PTEN expression and consequently activate the PI3K and Akt signaling pathway , while anti-miR-21 strategy strongly reduced phospho-AKT levels and enhanced apoptosis when used in combination with gemcitabine [ XREF_BIBR ] .	Previous studies have revealed that overexpression of miR-21 can down-regulate PTEN expression and consequently activate the PI3K and Akt signaling pathway, while anti-miR-21 strategy strongly reduced phospho-AKT levels and enhanced apoptosis when used in combination with gemcitabine [XREF_BIBR].	5	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	overexpression of miR-21 can down-regulate PTEN expression	pten	Akt	Akt	akt	10	11	18	19
Bmi-1 binds to the PTEN locus and downregulates PTEN expression , which consequently activates the PI3K and AKT pathway , stabilizes Snail , and downregulates E-cadherin , ultimately leading to enhanced invasiveness of epithelial cells [ XREF_BIBR ] .	Bmi-1 binds to the PTEN locus and downregulates PTEN expression, which consequently activates the PI3K and AKT pathway, stabilizes Snail, and downregulates E-cadherin, ultimately leading to enhanced invasiveness of epithelial cells [XREF_BIBR].	8	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	8	9	17	18
For instance , PI3K-AKT activation caused by Pten deficiency in combination with Keap1 deficiency in the mouse liver results in massive accumulation of NRF2 and NRF2 dependent proliferation of hepatocytes and cholangiocytes.63 , 75 , 76 Thus , quantitative increases of the NRF2 protein under proliferative signals substantiates the dominant role played by NRF2 in leading cancer cells to NRF2 addiction .	For instance, PI3K-AKT activation caused by Pten deficiency in combination with Keap1 deficiency in the mouse liver results in massive accumulation of NRF2 and NRF2 dependent proliferation of hepatocytes and cholangiocytes.63, 75, 76 Thus, quantitative increases of the NRF2 protein under proliferative signals substantiates the dominant role played by NRF2 in leading cancer cells to NRF2 addiction.	3	8	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	PI3K-AKT	PI3K-AKT	PI3K-AKT	7	8	3	4
PTEN suppresses cell proliferation by inhibiting the PI3K-Akt signaling pathway at the cell membrane .	PTEN suppresses cell proliferation by inhibiting the PI3K-Akt signaling pathway at the cell membrane.	0	9	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	PI3K-Akt	PI3K-Akt	PI3K-Akt	0	1	7	8
The phosphatase and tensin homologue ( PTEN ) is critical to activate PI3K and Akt pathway and thus increase muscle mass and growth by altering the level of PI ( 3,4,5 ) P ( 3 ) .	The phosphatase and tensin homologue (PTEN) is critical to activate PI3K and Akt pathway and thus increase muscle mass and growth by altering the level of PI (3,4,5) P (3).	4	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	14	15
In the absence of Txnip , oxidative inactivation of PTEN and subsequent activation of Akt attenuated mitochondrial respiration , resulting in the accumulation of NADH , a competitive inhibitor of thioredoxin NADPH-reductive activation of PTEN .	In the absence of Txnip, oxidative inactivation of PTEN and subsequent activation of Akt attenuated mitochondrial respiration, resulting in the accumulation of NADH, a competitive inhibitor of thioredoxin NADPH-reductive activation of PTEN.	9	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	9	10	14	15
Down-regulation of PTEN function induces a concomitant activation of AKT , which can regulate cell survival and growth pathways , including nuclear factor ( NF )-kappaB-dependent inflammation , as well as mechanistic target of Rapamycin , glycogen synthase kinase-3beta , and Raf .	Down-regulation of PTEN function induces a concomitant activation of AKT, which can regulate cell survival and growth pathways, including nuclear factor (NF)-kappaB-dependent inflammation, as well as mechanistic target of Rapamycin, glycogen synthase kinase-3beta, and Raf.	2	13	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	9	10
Therefore , it is anticipitated that PTEN ablation in PIKE -/- neurons should restore the PI3K and Akt function , thus rescuing the defective arborization .	Therefore, it is anticipitated that PTEN ablation in PIKE -/- neurons should restore the PI3K and Akt function, thus rescuing the defective arborization.	6	18	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	17	18
In contrast , knock-down of BRAFV600E in A2058 and HT144 did not elevate pAKT , consistent with the idea that PTEN dysfunction dominantly drives the AKT signaling ( XREF_SUPPLEMENTARY ) .	In contrast, knock-down of BRAFV600E in A2058 and HT144 did not elevate pAKT, consistent with the idea that PTEN dysfunction dominantly drives the AKT signaling (XREF_SUPPLEMENTARY).	20	26	drives	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	20	21	25	26
The tumor-suppressor gene PTEN ( located on 10q23 ) encodes a lipid phosphatase that negatively regulates the PI3K and AKT pathway , and loss of PTEN leads to constitutive PI3K-AKT signaling .	The tumor-suppressor gene PTEN (located on 10q23) encodes a lipid phosphatase that negatively regulates the PI3K and AKT pathway, and loss of PTEN leads to constitutive PI3K-AKT signaling.	23	30	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	loss of PTEN	pten	PI3K-AKT	PI3K-AKT	pi3k-akt	25	26	29	30
Alternatively , it is possible that blockade of mTORC1 may feed back to inhibit other regulators of Akt activation ( such as PTEN ) , so that the phosphorylation of Akt is increased .	Alternatively, it is possible that blockade of mTORC1 may feed back to inhibit other regulators of Akt activation (such as PTEN), so that the phosphorylation of Akt is increased.	17	23	activation	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	22	23	17	18
Phosphatidylinositol-3-kinase and protein kinase B ( PI3K and Akt ) signaling is over-activated in many types of cancers , including carcinoid tumors , through either constitutive activation of PI3K , which indirectly promotes Akt phosphorylation and activation , or downregulation or mutation of the endogenous inhibitor of PI3K and Akt signaling PTEN ( phosphatase and tensin homolog deleted on chromosome ten ) .	Phosphatidylinositol-3-kinase and protein kinase B (PI3K and Akt) signaling is over-activated in many types of cancers, including carcinoid tumors, through either constitutive activation of PI3K, which indirectly promotes Akt phosphorylation and activation, or downregulation or mutation of the endogenous inhibitor of PI3K and Akt signaling PTEN (phosphatase and tensin homolog deleted on chromosome ten).	45	52	signaling	Positive_activation_token_1_noun	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	51	52	49	50
The inactivation of PTEN activates Akt signaling , which reduces apoptosis and increases survival [ XREF_BIBR - XREF_BIBR ] .	The inactivation of PTEN activates Akt signaling, which reduces apoptosis and increases survival [XREF_BIBR - XREF_BIBR].	1	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	5	6
Of interest , the levels of PIB5PA and PTEN were significantly correlated , and loss of both was associated with particularly high levels of Akt activation in fresh melanoma isolates , suggesting that consistent with the finding in melanoma cell lines , downregulation of PIB5PA and PTEN may cooperatively promote activation of PI3K and Akt signalling in vivo , and that melanomas deficient in both PIB5PA and PTEN may be more profoundly dependent on survival advantages afforded by activation of the pathway .	Of interest, the levels of PIB5PA and PTEN were significantly correlated, and loss of both was associated with particularly high levels of Akt activation in fresh melanoma isolates, suggesting that consistent with the finding in melanoma cell lines, downregulation of PIB5PA and PTEN may cooperatively promote activation of PI3K and Akt signalling in vivo, and that melanomas deficient in both PIB5PA and PTEN may be more profoundly dependent on survival advantages afforded by activation of the pathway.	42	55	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	46	47	54	55
We demonstrated that HMW-FGF2 overexpression is associated with reduced expression of PTEN , the negative regulator of PI3K and Akt pathway , leading to activated Akt signaling , which might be responsible for enhanced proliferative activity of T98G cells .	We demonstrated that HMW-FGF2 overexpression is associated with reduced expression of PTEN, the negative regulator of PI3K and Akt pathway, leading to activated Akt signaling, which might be responsible for enhanced proliferative activity of T98G cells.	11	26	leading to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	11	12	25	26
For instance , PTEN functions as a tumour suppressor by negatively regulating the PI3K and AKT signalling and , in 30-50 % of prostate cancer cases , loss of PTEN function causes PI3K and AKT signalling upregulation [ XREF_BIBR ] .	For instance, PTEN functions as a tumour suppressor by negatively regulating the PI3K and AKT signalling and, in 30-50% of prostate cancer cases, loss of PTEN function causes PI3K and AKT signalling upregulation [XREF_BIBR].	3	36	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	3	4	34	35
Being one of the most frequently disrupted tumor suppressors in cancer , a mutation in the phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) , the natural antagonist of PI3K , relieves the repression of the PI3K and Akt signaling axis in PDAC .	Being one of the most frequently disrupted tumor suppressors in cancer, a mutation in the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), the natural antagonist of PI3K, relieves the repression of the PI3K and Akt signaling axis in PDAC.	16	43	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	phosphatase and tensin homolog	phosphatase and tensin homolog	phosphatase and tensin homolog	Akt	Akt	Akt	16	20	41	42
Altogether , our findings indicate that PTEN deficiency further activated AKT and altered AKT-downstream signalling pathways to increase cell proliferation and survival in TRbeta PV/PV thyroids , thereby accelerating thyroid cancer progression and invasiveness .	Altogether, our findings indicate that PTEN deficiency further activated AKT and altered AKT-downstream signalling pathways to increase cell proliferation and survival in TRbeta PV/PV thyroids, thereby accelerating thyroid cancer progression and invasiveness.	6	15	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	6	7	10	11
Both PTEN degradation and inhibiting its phosphatase activity will lead to activation of Akt and downstream signaling cascades .	Both PTEN degradation and inhibiting its phosphatase activity will lead to activation of Akt and downstream signaling cascades.	0	17	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	1	2	13	14
As a molecular mechanism of BRG1 affecting cell proliferation , we provided evidence that BRG1 possibly suppressed PTEN expression at the mRNA and protein levels and then downregulated the PI3K-Akt signalling pathway .	As a molecular mechanism of BRG1 affecting cell proliferation, we provided evidence that BRG1 possibly suppressed PTEN expression at the mRNA and protein levels and then downregulated the PI3K-Akt signalling pathway.	14	31	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	BRG1 possibly suppressed PTEN expression	pten	PI3K-Akt	PI3K-Akt	pi3k-akt	17	18	29	30
Moreover , it markedly reduced the serum levels of pro inflammatory mediators , along with down-regulation of PTEN expression , enhanced Akt activity , as well as significantly higher immunostaining of the anti-apoptotic marker ( Bcl-2 ) .	Moreover, it markedly reduced the serum levels of pro inflammatory mediators, along with down-regulation of PTEN expression, enhanced Akt activity, as well as significantly higher immunostaining of the anti-apoptotic marker (Bcl-2).	17	22	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	Akt	Akt	akt	17	18	21	22
95 Increasing numbers of studies have reported oxidation of the catalytic cysteines within the active site of PTEN in response to exposure to ROS , and have shown that redox modification of PTEN potentiates Akt activation .	95 Increasing numbers of studies have reported oxidation of the catalytic cysteines within the active site of PTEN in response to exposure to ROS, and have shown that redox modification of PTEN potentiates Akt activation.	30	35	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	32	33	34	35
Moreover , suppression of PTEN in TRIM29 repressed cells rescued AKT and mTOR activities of NPC cells .	Moreover, suppression of PTEN in TRIM29 repressed cells rescued AKT and mTOR activities of NPC cells.	2	13	repressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	4	5	10	11
Furthermore , Spry2 gain-of-function can suppress hyperactivation of AKT caused by the absence of PTEN .	Furthermore, Spry2 gain-of-function can suppress hyperactivation of AKT caused by the absence of PTEN.	6	15	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	14	15	8	9
Activation of PTEN in GHR silenced cells efficiently enhances apoptosis and inhibits proliferation by suppressing the active status of PI3K and AKT and its intermediates .	Activation of PTEN in GHR silenced cells efficiently enhances apoptosis and inhibits proliferation by suppressing the active status of PI3K and AKT and its intermediates.	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	21	22
However , as cells were at resting ( not stimulated ) state , we hypothesize that the observed effect could be a gene expression feedback system , i.e. in the presence of MYO1C , there is less need for the PI3K and AKT modulating PTEN protein , hence PTEN gene expression has become down-regulated .	However, as cells were at resting (not stimulated) state, we hypothesize that the observed effect could be a gene expression feedback system, i.e. in the presence of MYO1C, there is less need for the PI3K and AKT modulating PTEN protein, hence PTEN gene expression has become down-regulated.	42	45	modulating	Positive_activation_token_1_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	44	45	42	43
PTEN inactivation may promote the sustained activation of PI3K and Akt pathway that in turn can induce HIF-1alpha stabilization and transcriptional expression of its target genes , and thereby contribute to the survival of GBM cells under normoxic and hypoxic conditions [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	PTEN inactivation may promote the sustained activation of PI3K and Akt pathway that in turn can induce HIF-1alpha stabilization and transcriptional expression of its target genes, and thereby contribute to the survival of GBM cells under normoxic and hypoxic conditions [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	0	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	0	1	10	11
Thus , decreased PTEN would lead to increased Akt activation and the increase in P280-Chk1 we observed is consistent with this .	Thus, decreased PTEN would lead to increased Akt activation and the increase in P280-Chk1 we observed is consistent with this.	3	9	lead to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	3	4	8	9
XREF_BIBR He et al reported that PTEN deficiency increased PI3K and Akt activation resulting in excessive proliferation and crypt fissioning within small bowel ( SB ) polyps .	XREF_BIBR He et al reported that PTEN deficiency increased PI3K and Akt activation resulting in excessive proliferation and crypt fissioning within small bowel (SB) polyps.	6	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	6	7	11	12
100 Taken together , the oxidative modification of PTEN activates Akt while oxidation of Akt contributes to Akt inactivation , thereby negatively or positively regulating the transcriptional activity of FoxOs , respectively .	100 Taken together, the oxidative modification of PTEN activates Akt while oxidation of Akt contributes to Akt inactivation, thereby negatively or positively regulating the transcriptional activity of FoxOs, respectively.	6	11	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	8	9	10	11
PTEN inactivation results in hyperactive AKT signaling and is associated with tumor growth , progression and poor clinical outcome XREF_BIBR .	PTEN inactivation results in hyperactive AKT signaling and is associated with tumor growth, progression and poor clinical outcome XREF_BIBR.	0	7	signaling	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	0	1	5	6
We expressed BMCC1 in BMCC1 negative HeLa cells and LNCaP cells with AKT hyperactivation induced by PTEN ( phosphatase and tensin homolog ) mutation 27 ( XREF_FIG and XREF_SUPPLEMENTARY ) .	We expressed BMCC1 in BMCC1 negative HeLa cells and LNCaP cells with AKT hyperactivation induced by PTEN (phosphatase and tensin homolog) mutation 27 (XREF_FIG and XREF_SUPPLEMENTARY).	12	23	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	16	17	12	13
Together , these findings demonstrate that suppression of PI3K and Akt signaling by PTEN is crucial for proper neuronal differentiation and normal retinal network formation .	Together, these findings demonstrate that suppression of PI3K and Akt signaling by PTEN is crucial for proper neuronal differentiation and normal retinal network formation.	8	14	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	13	14	10	11
AKT and mTOR signaling which is negatively modulated by PTEN is a key pathway in cell survival , cellular proliferation , and tumor growth [ XREF_BIBR ] .	AKT and mTOR signaling which is negatively modulated by PTEN is a key pathway in cell survival, cellular proliferation, and tumor growth [XREF_BIBR].	0	10	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	9	10	0	1
The PDK1 K465E and K465E PTEN +/- mice were of an intermediate size and only ~ 20 % smaller than wild-type PDK1 +/+ PTEN +/+ mice , suggesting that deficiency of PTEN can partially restore normal Akt pathway activity during development and therefore rescue the small size phenotype .	The PDK1 K465E and K465E PTEN +/- mice were of an intermediate size and only ~ 20% smaller than wild-type PDK1 +/+ PTEN +/+ mice, suggesting that deficiency of PTEN can partially restore normal Akt pathway activity during development and therefore rescue the small size phenotype.	29	38	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt	Akt	Akt	31	32	36	37
In agreement with their antioncogenetic role , PTEN mediates cell proliferation , migration , apoptosis , and angiogenesis by activating the AKT pathway .	In agreement with their antioncogenetic role, PTEN mediates cell proliferation, migration, apoptosis, and angiogenesis by activating the AKT pathway.	7	22	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	7	8	21	22
Second , suppression of PTEN expression by shRNA in Hes1 repressed CNE2 cells rescued PI3K and AKT activities and the migration and invasion of cancer cells .	Second, suppression of PTEN expression by shRNA in Hes1 repressed CNE2 cells rescued PI3K and AKT activities and the migration and invasion of cancer cells.	4	17	repressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	4	5	16	17
This clearly suggests that transfer of miR-130a from EVs derived from H+ C treated macrophages play a crucial role in stimulating smooth muscle proliferation by directly downregulating the PTEN expression which , in turn , activates downstream AKT signaling .	This clearly suggests that transfer of miR-130a from EVs derived from H+C-treated macrophages play a crucial role in stimulating smooth muscle proliferation by directly downregulating the PTEN expression which, in turn, activates downstream AKT signaling.	28	38	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	AKT	AKT	akt	28	29	37	38
Inactivation of PTEN in PTEN +/+ embryonic fibroblasts increases AKT activity and suppresses apoptosis in contractile collagen matrices ; inhibition of AKT activity restores the sensitivity of PTEN null cells to collagen contraction induced apoptosis .	Inactivation of PTEN in PTEN +/+ embryonic fibroblasts increases AKT activity and suppresses apoptosis in contractile collagen matrices; inhibition of AKT activity restores the sensitivity of PTEN null cells to collagen contraction induced apoptosis.	0	10	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT	AKT	AKT	2	3	9	10
Inhibiting the synthesis of provitamin D 3 impairs Ptc1 mediated repression of Smo .	Inhibiting the synthesis of provitamin D 3 impairs Ptc1 mediated repression of Smo.	8	13	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	8	9	12	13
This relieves the repression of SMO by PTCH and results in the accumulation of SMO in the primary cilium .	This relieves the repression of SMO by PTCH and results in the accumulation of SMO in the primary cilium.	1	8	repression	Negative_activation_token_2_noun	Negative_activation	Positive_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	7	8	5	6
The removal of PTCH triggers the entry of SMO into and the exit of GPR161 from the primary cilium .	The removal of PTCH triggers the entry of SMO into and the exit of GPR161 from the primary cilium.	1	9	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	3	4	8	9
21 How PTCH1 modulates SMO was enigmatic until quite recently , as the two proteins do not physically associate .	21 How PTCH1 modulates SMO was enigmatic until quite recently, as the two proteins do not physically associate.	2	6	modulates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	2	3	4	5
In the absence of SHH protein bound to PTCH1 , PTCH1 represses down stream targets of SHH signaling by inhibiting the activity of SMO at the substoichiometric level [ XREF_BIBR ] .	In the absence of SHH protein bound to PTCH1, PTCH1 represses down stream targets of SHH signaling by inhibiting the activity of SMO at the substoichiometric level [XREF_BIBR].	10	24	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	10	11	23	24
These include Ptch knockout mice and mice overexpressing Hh , oncogenic Smo , Gli1 or Gli2 specifically in the skin using the keratin ( K ) 5 , 6 , or 14 promoters .	These include Ptch knockout mice and mice overexpressing Hh, oncogenic Smo, Gli1 or Gli2 specifically in the skin using the keratin (K) 5, 6, or 14 promoters.	2	15	overexpressing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	2	3	11	12
This binding relieves the PTCH mediated suppression of the transmembrane protein smoothened ( SMO ) , leading to multiple intracellular events that result in the stabilization , nuclear translocation and activation of the glioma associated oncogene ( Gli ) family of transcription factors , which initiate transcription of HH target genes .	This binding relieves the PTCH mediated suppression of the transmembrane protein smoothened (SMO), leading to multiple intracellular events that result in the stabilization, nuclear translocation and activation of the glioma associated oncogene (Gli) family of transcription factors, which initiate transcription of HH target genes.	3	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	4	5	13	14
The PTCH protein serves as a receptor for the Secreted Shh ( SHH ) protein , and inhibits the signaling pathway by repressing the activity of Smoothened ( SMO ) , another transmembranous protein XREF_BIBR .	The PTCH protein serves as a receptor for the Secreted Shh (SHH) protein, and inhibits the signaling pathway by repressing the activity of Smoothened (SMO), another transmembranous protein XREF_BIBR.	1	34	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	1	2	28	29
In oncogenic contexts , loss of PTCH1 and mutagenic activation of SMO are the most common alterations that induce inappropriate activation of the HH pathway .	In oncogenic contexts, loss of PTCH1 and mutagenic activation of SMO are the most common alterations that induce inappropriate activation of the HH pathway.	6	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	6	7	11	12
IHH in chondrocytes increases expression of PTCH , which then can activate SMO , allowing for increased chondrocyte proliferation .	IHH in chondrocytes increases expression of PTCH, which then can activate SMO, allowing for increased chondrocyte proliferation.	0	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH	IHH in chondrocytes increases expression of PTCH	ptch	SMO	SMO	smo	6	7	12	13
In figure XREF_FIG , Ptc1 catalyzes Smo inactivation .	In figure XREF_FIG, Ptc1 catalyzes Smo inactivation.	4	7	catalyzes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	4	5	6	7
The binding of Hedgehog ligand to the receptor Patched1 ( Ptc1 ) activates smoothened ( Smo ) and the transcriptional activity of Gli1 , which up-regulates the expression of a panel of target genes , including Patched1 and FOXM1 [ XREF_BIBR , XREF_BIBR ] .	The binding of Hedgehog ligand to the receptor Patched1 (Ptc1) activates smoothened (Smo) and the transcriptional activity of Gli1, which up-regulates the expression of a panel of target genes, including Patched1 and FOXM1 [XREF_BIBR, XREF_BIBR].	1	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	10	11	15	16
This study demonstrated that Ptch1 induces apoptosis independent of Smo and Gli activity by acting as a dependence receptor , binding caspases , and inducing apoptosis .	This study demonstrated that Ptch1 induces apoptosis independent of Smo and Gli activity by acting as a dependence receptor, binding caspases, and inducing apoptosis.	4	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	9	10
The mechanism by which Ptch1 activates Smo is not known but is proposed to be through small molecule intermediates and is likely to involve the phosphorylation of Smo .	The mechanism by which Ptch1 activates Smo is not known but is proposed to be through small molecule intermediates and is likely to involve the phosphorylation of Smo.	4	9	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	4	5	6	7
Binding of Hedgehog ligands to the receptor Patched ( Ptch1 ) triggers the IFT dependent accumulation of the transmembrane protein Smoothened ( Smo ) within the cilium ( Corbit et al ., 2005 ) .	Binding of Hedgehog ligands to the receptor Patched (Ptch1) triggers the IFT dependent accumulation of the transmembrane protein Smoothened (Smo) within the cilium (Corbit et al., 2005).	0	26	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	9	10	22	23
How Ptch might target Smo to govern this event has not yet been established , but a number of models have been proposed ( XREF_FIG ) .	How Ptch might target Smo to govern this event has not yet been established, but a number of models have been proposed (XREF_FIG).	1	6	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	1	2	4	5
Binding of Shh to the inhibitory receptor , Patched1 ( Ptc1 ) , results in activation of Smoothened ( Smo ) and subsequent activation of Gli transcription factors .	Binding of Shh to the inhibitory receptor, Patched1 (Ptc1), results in activation of Smoothened (Smo) and subsequent activation of Gli transcription factors.	8	23	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	10	11	19	20
The canonical Hh pathway is activated upon Hh ligand binding to the cognate receptor Ptch1 , which enables SMO to activate Gli proteins .	The canonical Hh pathway is activated upon Hh ligand binding to the cognate receptor Ptch1, which enables SMO to activate Gli proteins.	5	20	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	SMO	SMO	SMO	14	15	18	19
Upon binding with Shh , Ptc1 inactivation allows Smo to initiate signaling XREF_BIBR , XREF_BIBR , XREF_BIBR through the Gli family of transcription factors .	Upon binding with Shh, Ptc1 inactivation allows Smo to initiate signaling XREF_BIBR, XREF_BIBR, XREF_BIBR through the Gli family of transcription factors.	5	10	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	5	6	8	9
However , binding of Hh ligands leads to internalization of PTCH1 allowing the activation of SMO .	However, binding of Hh ligands leads to internalization of PTCH1 allowing the activation of SMO.	8	16	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	10	11	15	16
When Shh binds to Ptc1 , the Ptc1 is lost from the cilium , allowing Smo to accumulate in the ciliary membrane and activate signaling [ XREF_BIBR ] .	When Shh binds to Ptc1, the Ptc1 is lost from the cilium, allowing Smo to accumulate in the ciliary membrane and activate signaling [XREF_BIBR].	6	23	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	7	8	15	16
Upon binding to the receptor , PTCH is displaced from the cilia , thus allowing the accumulation and activation of SMO .	Upon binding to the receptor, PTCH is displaced from the cilia, thus allowing the accumulation and activation of SMO.	6	21	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	6	7	20	21
Instead , the existence of endogenous small molecules , gated by Ptch , which are able to modulate Smo activity , is currently under discussion [ XREF_BIBR ] .	Instead, the existence of endogenous small molecules, gated by Ptch, which are able to modulate Smo activity, is currently under discussion [XREF_BIBR].	9	19	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	11	12	18	19
The aim of our study was to investigate whether the mRNA expression analysis of two Hedgehog ( Hh ) stemness signaling molecules , Smoothened ( SMO ) and Patched-1 ( PTCH1 ) , could predict upcoming molecular relapse .	The aim of our study was to investigate whether the mRNA expression analysis of two Hedgehog (Hh) stemness signaling molecules, Smoothened (SMO) and Patched-1 (PTCH1), could predict upcoming molecular relapse.	19	31	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	30	31	25	26
In the absence of SHH protein bound to PTCH1 , PTCH1 represses down stream targets of SHH signaling by inhibiting the activity of SMO at the substoichiometrical level XREF_BIBR .	In the absence of SHH protein bound to PTCH1, PTCH1 represses down stream targets of SHH signaling by inhibiting the activity of SMO at the substoichiometrical level XREF_BIBR.	10	24	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	10	11	23	24
In mammals , when the pathway is off , the inhibitory receptor , Patched ( PTCH ) , prevents the signaling receptor , Smooth ened ( SMO ) , from reaching the plasma membrane ; instead , inactive SMO is held inside the cytoplasm within a vesicle .	In mammals, when the pathway is off, the inhibitory receptor, Patched (PTCH), prevents the signaling receptor, Smooth ened (SMO), from reaching the plasma membrane; instead, inactive SMO is held inside the cytoplasm within a vesicle.	11	27	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	15	16	26	27
Hh ligands binding to PTCH induce SMO activation and downstream signaling of the Hh pathway .	Hh ligands binding to PTCH induce SMO activation and downstream signaling of the Hh pathway.	2	7	induce	Positive_activation_token_1_verb	Negative_activation	Positive_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	4	5	6	7
Binding of the secretory Hh ligands ( Sonic , Indian , or Desert , SHH , IHH or DHH ) to their transmembrane receptor Patched ( Ptch1 ) initiates the classical Hh signaling pathway by releasing Smoothened ( Smo ) from Ptch1 dependent suppression .	Binding of the secretory Hh ligands (Sonic, Indian, or Desert, SHH, IHH or DHH) to their transmembrane receptor Patched (Ptch1) initiates the classical Hh signaling pathway by releasing Smoothened (Smo) from Ptch1 dependent suppression.	5	43	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	26	27	38	39
Upon Hh binding , the inhibitory function of PTCH on SMO is abolished , resulting in SMO activation .	Upon Hh binding, the inhibitory function of PTCH on SMO is abolished, resulting in SMO activation.	6	17	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	8	9	16	17
PTCH , when bound by Shh , relieves its inhibition of SMO [ XREF_BIBR ] which then initiates a complex cascade of events leading to cell cycle progression .	PTCH, when bound by Shh, relieves its inhibition of SMO [XREF_BIBR] which then initiates a complex cascade of events leading to cell cycle progression.	0	13	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	0	1	11	12
To more conclusively test whether the CRD mediates the regulatory action of Ptch on Smo , as suggested by the partial loss of SmoDeltaCRD response to ShhN stimulation , we examined the effect of elevated levels of Ptch1 on basal and Hh induced activation of this Smo deletion mutant .	To more conclusively test whether the CRD mediates the regulatory action of Ptch on Smo, as suggested by the partial loss of SmoDeltaCRD response to ShhN stimulation, we examined the effect of elevated levels of Ptch1 on basal and Hh induced activation of this Smo deletion mutant.	35	48	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch1	levels of Ptch1	ptch1	Smo	Smo	smo	37	38	46	47
When Hh binds Ptch , Ptch is internalized and removed from the cilia , allowing Smo to enter and accumulate in the cilia , where it activates the transcriptional effector Gli by relieving its inhibition by Suppressor of Fused ( Sufu ) [ XREF_BIBR , XREF_BIBR ] .	When Hh binds Ptch, Ptch is internalized and removed from the cilia, allowing Smo to enter and accumulate in the cilia, where it activates the transcriptional effector Gli by relieving its inhibition by Suppressor of Fused (Sufu) [XREF_BIBR, XREF_BIBR].	5	19	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	5	6	15	16
In the absence of Shh ligand , Ptc1 functions to inhibit the pathway by suppressing the activity of the transmembrane protein Smoothened ( Smo ) XREF_BIBR .	In the absence of Shh ligand, Ptc1 functions to inhibit the pathway by suppressing the activity of the transmembrane protein Smoothened (Smo) XREF_BIBR.	7	24	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	7	8	23	24
Lastly , the detection of Ptch and Smo in the primary cilium of hippocampal neurons in vitro ( XREF_FIG ) and of choroid plexus in vivo ( XREF_FIG ) -- the structures where Shh signaling is known to take place and the expression of Ptch and Smo has been shown -- further supports the specificity of our Ptch and Smo labeling .	Lastly, the detection of Ptch and Smo in the primary cilium of hippocampal neurons in vitro (XREF_FIG) and of choroid plexus in vivo (XREF_FIG) -- the structures where Shh signaling is known to take place and the expression of Ptch and Smo has been shown -- further supports the specificity of our Ptch and Smo labeling.	3	60	supports	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	5	6	59	60
PTCH1 , a receptor of Hedgehog signaling pathway , can suppress the pathway by inhibiting SMO .	PTCH1, a receptor of Hedgehog signaling pathway, can suppress the pathway by inhibiting SMO.	0	16	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	0	1	15	16
Ptch1 transiently exits the primary cilium after inactivation by Hh ligand , allowing entry of active Smo into the cilium that binds to and inhibits Sufu , resulting in Gli transcriptional activity ( XREF_FIG ) .	Ptch1 transiently exits the primary cilium after inactivation by Hh ligand, allowing entry of active Smo into the cilium that binds to and inhibits Sufu, resulting in Gli transcriptional activity (XREF_FIG).	0	17	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	0	1	16	17
Ptch then activates Smoothened ( Smo ) , a 7-transmembrane spanning protein and the central transducer of the Hedgehog signal .	Ptch then activates Smoothened (Smo), a 7-transmembrane spanning protein and the central transducer of the Hedgehog signal.	0	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	0	1	5	6
In mammals , the binding of Hh ligand to its 12-transmembrane protein receptor Patched-1 ( Ptch-1 ) relieves Ptch1 mediated inhibition of Smoothened ( Smo ) , a seven-pass transmembrane protein with homology to G-protein-coupled receptors ( GPCRs ) .	In mammals, the binding of Hh ligand to its 12-transmembrane protein receptor Patched-1 (Ptch-1) relieves Ptch1 mediated inhibition of Smoothened (Smo), a seven-pass transmembrane protein with homology to G-protein-coupled receptors (GPCRs).	4	30	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch-1	Ptch-1	Ptch-1	Smo	Smo	Smo	15	16	24	25
When Hh is present and binds to Ptch1 , Ptch1 releases its inhibition on Smo and allows Smo to translocate into cilia .	When Hh is present and binds to Ptch1, Ptch1 releases its inhibition on Smo and allows Smo to translocate into cilia.	9	19	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	9	10	17	18
XREF_BIBR , XREF_BIBR The signaling pathway is activated when hedgehog signaling ligands , such as sonic hedgehog , bind to the membrane receptor patched ( PTCH ) , and thus stop the suppression of the signaling molecule smoothened ( SMO ) caused by PTCH .	XREF_BIBR, XREF_BIBR The signaling pathway is activated when hedgehog signaling ligands, such as sonic hedgehog, bind to the membrane receptor patched (PTCH), and thus stop the suppression of the signaling molecule smoothened (SMO) caused by PTCH.	37	44	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTCH	PTCH	PTCH	SMO	SMO	SMO	43	44	39	40
Ptch1 haploinsufficiency ( Ptch1 +/-) mice have increased bone mass as a result of reduced suppression of Smo by Ptch .	Ptch1 haploinsufficiency (Ptch1 +/-) mice have increased bone mass as a result of reduced suppression of Smo by Ptch.	15	20	suppression	Negative_activation_token_2_noun	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	19	20	17	18
Ciliary Ptch prevents pathway activation by blocking the entry of Smo into the primary cilium .	Ciliary Ptch prevents pathway activation by blocking the entry of Smo into the primary cilium.	0	11	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	1	2	10	11
In contrast , cells that expressed high levels of the Hedgehog ligand gene Indian hedgehog ( IHH ) and the target genes patched 1 ( PTCH1 ) and GLI1 were sensitive to modulation of both SMO and GLI , suggesting ligand dependent activation .	In contrast, cells that expressed high levels of the Hedgehog ligand gene Indian hedgehog (IHH) and the target genes patched 1 (PTCH1) and GLI1 were sensitive to modulation of both SMO and GLI, suggesting ligand dependent activation.	23	37	were sensitive to modulation	Positive_activation_copula_1	Negative_activation	Positive_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	25	26	35	36
XREF_BIBR Because Ptc1 inhibits Hh pathway activation by repressing Smo function and is also a target gene , removing both Ptc1 alleles results in constitutive pathway activation and beta-gal expression .	XREF_BIBR Because Ptc1 inhibits Hh pathway activation by repressing Smo function and is also a target gene, removing both Ptc1 alleles results in constitutive pathway activation and beta-gal expression.	2	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	2	3	9	10
Binding of Hedgehog to its receptor , Ptch , relieves inhibition of Smo activity by Ptch via a largely uncharacterized mechanism .	Binding of Hedgehog to its receptor, Ptch, relieves inhibition of Smo activity by Ptch via a largely uncharacterized mechanism.	0	13	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	7	8	12	13
Upon ligand binding , PTCH1 inhibition on SMO is relieved , allowing SMO to engage downstream effectors consisting in glioma associated oncogene homolog ( GLI ) transcription factors .	Upon ligand binding, PTCH1 inhibition on SMO is relieved, allowing SMO to engage downstream effectors consisting in glioma associated oncogene homolog (GLI) transcription factors.	4	14	relieved	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	4	5	12	13
The regulation of Smo activation by Ptch1 is altered in many cancers .	The regulation of Smo activation by Ptch1 is altered in many cancers.	3	7	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	6	7	3	4
As local stromal loss of Ptch1 and non epithelial activation of Smo promote a DCIS like phenotype in mammary epithelium , perhaps stromal Ptch1 loss promotes cancer associated phenotypes .	As local stromal loss of Ptch1 and non epithelial activation of Smo promote a DCIS like phenotype in mammary epithelium, perhaps stromal Ptch1 loss promotes cancer associated phenotypes.	5	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	5	6	11	12
Binding of the secretory HH ligands to their transmembrane receptor Patched ( Ptch1 ) initiates the classical HH signaling pathway , by releasing Smo from Ptch1 dependent suppression .	Binding of the secretory HH ligands to their transmembrane receptor Patched (Ptch1) initiates the classical HH signaling pathway, by releasing Smo from Ptch1 dependent suppression.	5	24	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptch1	Ptch1	Ptch1	Smo	Smo	Smo	12	13	23	24
Specificity of Smo staining was confirmed by staining Smo induced by the Ptch +/- radiation model ( XREF_SUPPLEMENTARY ) .	Specificity of Smo staining was confirmed by staining Smo induced by the Ptch +/- radiation model (XREF_SUPPLEMENTARY).	7	17	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Ptch	Ptch	Ptch	Smo	Smo	Smo	12	13	8	9
This removal of PTCH1 allows the protein smoothened ( SMO ) to translocate into the cilium where , upon activation , it triggers a signal cascade within the cell .	This removal of PTCH1 allows the protein smoothened (SMO) to translocate into the cilium where, upon activation, it triggers a signal cascade within the cell.	1	12	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	3	4	9	10
PTCH1 inactivation abolishes its negative regulation of the SMO oncogene and thus initiates the growth of multiple basal-cell carcinomas .	PTCH1 inactivation abolishes its negative regulation of the SMO oncogene and thus initiates the growth of multiple basal-cell carcinomas.	0	9	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	0	1	8	9
A second order reaction and an enzyme catalyzed reaction , both involving activation of Smo by Ptc1 , are implemented with fuzzy rules and examined here .	A second order reaction and an enzyme catalyzed reaction, both involving activation of Smo by Ptc1, are implemented with fuzzy rules and examined here.	11	17	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Ptc1	Ptc1	Ptc1	Smo	Smo	Smo	16	17	14	15
The activation of the PTCH1 relieves the inhibition of the Smoothened ( Smo ) , thereby leading to the activation of Glioma associated oncogene 1 transcription factors [ XREF_BIBR ] .	The activation of the PTCH1 relieves the inhibition of the Smoothened (Smo), thereby leading to the activation of Glioma associated oncogene 1 transcription factors [XREF_BIBR].	1	13	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTCH1	PTCH1	PTCH1	Smo	Smo	Smo	4	5	12	13
2 PTCH1 is a receptor for Sonic Hedgehog , and negatively regulates the Hedgehog pathway by inhibiting smoothened ( SMO ) , a Frizzled class receptor .	2 PTCH1 is a receptor for Sonic Hedgehog, and negatively regulates the Hedgehog pathway by inhibiting smoothened (SMO), a Frizzled class receptor.	0	25	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTCH1	PTCH1	PTCH1	SMO	SMO	SMO	1	2	19	20
Thus , mutations in presenilin-1 may increase neuronal apoptosis by altering the stability of beta-catenin , predisposing individuals to early-onset Alzheimer ' s disease .	Thus, mutations in presenilin-1 may increase neuronal apoptosis by altering the stability of beta-catenin, predisposing individuals to early-onset Alzheimer 's disease.	2	15	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	presenilin-1	presenilin-1	presenilin-1	beta-catenin	beta-catenin	beta-catenin	4	5	14	15
PS-1 may contribute to the tumorigenesis of GC in a gamma-secretase-dependent manner by regulating E-cadherin cleavage and beta-catenin nuclear accumulation , which plays a key signaling role in the activation of TCF and LEF-1 .	PS-1 may contribute to the tumorigenesis of GC in a gamma-secretase-dependent manner by regulating E-cadherin cleavage and beta-catenin nuclear accumulation, which plays a key signaling role in the activation of TCF/LEF-1.	0	19	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PS-1	PS-1	PS-1	beta-catenin	beta-catenin	beta-catenin	0	1	17	18
Inducible overexpression of PS1 led to increased association of beta-catenin with glycogen synthase kinase-3beta ( GSK-3beta ) , a negative regulator of beta-catenin , and accelerated the turnover of endogenous beta-catenin .	Inducible overexpression of PS1 led to increased association of beta-catenin with glycogen synthase kinase-3beta (GSK-3beta), a negative regulator of beta-catenin, and accelerated the turnover of endogenous beta-catenin.	1	31	accelerated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	overexpression of PS1	ps1	beta-catenin	beta-catenin	beta-catenin	3	4	30	31
Overexpression of wild-type Psen1 in psen1 -/- fibroblasts restored the turnover of beta-catenin , whereas it was only partially restored by the DeltaX9 familial AD mutant .	Overexpression of wild-type Psen1 in psen1 -/- fibroblasts restored the turnover of beta-catenin, whereas it was only partially restored by the DeltaX9 familial AD mutant.	0	13	restored	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Psen1	Overexpression of wild-type Psen1	psen1	beta-catenin	beta-catenin	beta-catenin	3	4	12	13
Thus , our results indicate that PS1 normally promotes the turnover of beta-catenin , whereas PS1 mutants partially interfere with this process , possibly by failing to recruit GSK-3beta into the PS1 , beta , and catenin complex .	Thus, our results indicate that PS1 normally promotes the turnover of beta-catenin, whereas PS1 mutants partially interfere with this process, possibly by failing to recruit GSK-3beta into the PS1, beta, and catenin complex.	6	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	6	7	12	13
Thus , the PS1 and gamma-secretase system stimulates disassembly of the E-cadherin- catenin complex and increases the cytosolic pool of beta-catenin , a key regulator of the Wnt signaling pathway .	Thus, the PS1 and gamma-secretase system stimulates disassembly of the E-cadherin- catenin complex and increases the cytosolic pool of beta-catenin, a key regulator of the Wnt signaling pathway.	3	24	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	3	4	20	21
Using primary mouse embryonic fibroblasts deficient in PS1 , we demonstrated that PS1 negatively modulates the cytosolic ( and hence signaling ) pool of beta-catenin .	Using primary mouse embryonic fibroblasts deficient in PS1, we demonstrated that PS1 negatively modulates the cytosolic (and hence signaling) pool of beta-catenin.	12	25	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	12	13	24	25
In support of this model and consistent with our results , TGF-beta has been shown by others to increase the expression levels and activity of PS-1 , 41 and that PS-1 can cleave E-cadheren and promote beta-catenin signaling .	In support of this model and consistent with our results, TGF-beta has been shown by others to increase the expression levels and activity of PS-1, 41 and that PS-1 can cleave E-cadheren and promote beta-catenin signaling.	23	37	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PS-1	PS-1	PS-1	beta-catenin	beta-catenin	beta-catenin	25	26	36	37
Although PS1 appears to modulate beta-catenin stability in vitro , controversial data have been reported .	Although PS1 appears to modulate beta-catenin stability in vitro, controversial data have been reported.	1	6	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PS1	PS1	PS1	beta-catenin	beta-catenin	beta-catenin	1	2	5	6
Furthermore , PS-1 enhanced the cytosolic and nuclear accumulation of beta-catenin and boosted the expression of E-cad and CTF -2 in the cytoplasm .	Furthermore, PS-1 enhanced the cytosolic and nuclear accumulation of beta-catenin and boosted the expression of E-cad and CTF -2 in the cytoplasm.	2	12	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PS-1	PS-1	PS-1	beta-catenin	beta-catenin	beta-catenin	2	3	10	11
Additionally , N-cadherin and PSEN1 appear to increase the trafficking of each other and beta-catenin to the plasma membrane to enhance cellular adhesion in neuroblastoma SH-SY5Y cells [ XREF_BIBR , XREF_BIBR ] .	Additionally, N-cadherin and PSEN1 appear to increase the trafficking of each other and beta-catenin to the plasma membrane to enhance cellular adhesion in neuroblastoma SH-SY5Y cells [XREF_BIBR, XREF_BIBR].	2	15	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PSEN1	PSEN1	PSEN1	beta-catenin	beta-catenin	beta-catenin	4	5	14	15
Modulation of beta-Catenin Signaling by PS1 Requires the Interaction of both Proteins .	Modulation of beta-Catenin Signaling by PS1 Requires the Interaction of both Proteins.	2	6	Signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PS1	PS1	PS1	beta-Catenin	beta-Catenin	beta-Catenin	5	6	2	3
20 Taken together , our data imply that in gastric cancer cells Notch1 and PTEN were downstream targets of AKT1 / NFkappaB pathway ; transcription factor NFkappaB was a positive regulator of Notch-1 transcription .	20 Taken together, our data imply that in gastric cancer cells Notch1 and PTEN were downstream targets of AKT1 / NFkappaB pathway; transcription factor NFkappaB was a positive regulator of Notch-1 transcription.	12	20	were downstream targets	Positive_activation_copula_1	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT1	AKT1	AKT1	14	15	19	20
PTEN expression is upregulated in ISP8 thymocytes lacking PKBalpha .	PTEN expression is upregulated in ISP8 thymocytes lacking PKBalpha.	0	9	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN expression	pten	PKBalpha	PKBalpha	pkbalpha	0	1	8	9
Moreover , under these conditions , reduced PTEN expression was associated with higher levels of Akt1 phosphorylation in HUVEC treated with pre-miR-92a while increased PTEN expression was associated with slightly lower levels of Akt1 phosphorylation in HUVEC treated with anti-miR-92a ( XREF_FIG ) .	Moreover, under these conditions, reduced PTEN expression was associated with higher levels of Akt1 phosphorylation in HUVEC treated with pre-miR-92a while increased PTEN expression was associated with slightly lower levels of Akt1 phosphorylation in HUVEC treated with anti-miR-92a (XREF_FIG).	15	25	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	Akt1	Akt1	Akt1	24	25	15	16
Since AKT1 phosphorylation is regulated by P2RX7 mediated PTEN activation 67 , P2rx7 deletion would affect PTEN mediated AKT1 activity , independent of HSPB1 expression and PIK3 activity .	Since AKT1 phosphorylation is regulated by P2RX7 mediated PTEN activation 67, P2rx7 deletion would affect PTEN mediated AKT1 activity, independent of HSPB1 expression and PIK3 activity.	15	19	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	AKT1	AKT1	AKT1	16	17	18	19
Mechanistically , evidence suggests that activation of protein kinase B by PTEN plays a major role in modulating MDM2 dependent ( Mouse double minute 2 homolog ) p53 breakdown XREF_BIBR , XREF_BIBR , but p53 is a short lived protein that its stabilization is vital for its tumor suppressive function .	Mechanistically, evidence suggests that activation of protein kinase B by PTEN plays a major role in modulating MDM2 dependent (Mouse double minute 2 homolog) p53 breakdown XREF_BIBR, XREF_BIBR, but p53 is a short lived protein that its stabilization is vital for its tumor suppressive function.	5	12	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	protein kinase B	protein kinase B	protein kinase B	11	12	7	10
Loss of the tumor suppressor PTEN is found in 70 % of prostate cancers and leads to the activation of AKT1 , a common early event in prostate cancer tumorigenesis .	Loss of the tumor suppressor PTEN is found in 70% of prostate cancers and leads to the activation of AKT1, a common early event in prostate cancer tumorigenesis.	0	25	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTEN	Loss of the tumor suppressor PTEN	pten	AKT1	AKT1	akt1	5	6	20	21
PRL at 100 ng/ml elicited a maximum stimulation of LPL activity .	PRL at 100 ng/ml elicited a maximum stimulation of LPL activity.	0	10	elicited	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PRL	PRL	PRL	LPL	LPL	LPL	0	1	9	10
Prolactin replacement in T3 treated rats restored LPL activity in the mammary gland , but did not increase the amount of dietary [ 14C ] lipid transferred to the milk .	Prolactin replacement in T3 treated rats restored LPL activity in the mammary gland, but did not increase the amount of dietary [14C] lipid transferred to the milk.	0	8	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Prolactin	Prolactin	Prolactin	LPL	LPL	LPL	0	1	7	8
Prolactin stabilizes and promotes transcription of casein mRNA ; may stimulate synthesis of alpha-lactalbumin , the regulatory protein of the lactose synthetase enzyme system ; and increases lipoprotein lipase activity in the mammary gland .	Prolactin stabilizes and promotes transcription of casein mRNA; may stimulate synthesis of alpha-lactalbumin, the regulatory protein of the lactose synthetase enzyme system; and increases lipoprotein lipase activity in the mammary gland.	0	29	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Prolactin	Prolactin stabilizes and promotes transcription	prolactin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	0	1	27	29
It is hypothesized that these different fat change patterns result from differential activity of adipose tissue lipoprotein lipase , which is itself mediated by serum prolactin concentration .	It is hypothesized that these different fat change patterns result from differential activity of adipose tissue lipoprotein lipase, which is itself mediated by serum prolactin concentration.	16	26	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	prolactin	prolactin	prolactin	lipoprotein lipase	lipoprotein lipase	lipoprotein lipase	25	26	16	18
When Northern hybridization techniques were employed , PRL was also found to increase the tissue content of LPL mRNA ; this effect was initially detected after a 6-hr PRL treatment employing PRL concentrations of 50 ng/ml and above .	When Northern hybridization techniques were employed, PRL was also found to increase the tissue content of LPL mRNA; this effect was initially detected after a 6-hr PRL treatment employing PRL concentrations of 50 ng/ml and above.	7	18	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PRL	PRL	PRL	LPL	LPL	LPL	7	8	17	18
On the other hand , treatment with Go6976 , an inhibitor of classical PKCs and PKD , totally prevented the nuclear exclusion of HDAC7 by PMA treatment ( XREF_FIG B ) .	On the other hand, treatment with Go6976, an inhibitor of classical PKCs and PKD, totally prevented the nuclear exclusion of HDAC7 by PMA treatment (XREF_FIG B).	10	24	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PKD	PKD	PKD	HDAC7	HDAC7	HDAC7	15	16	23	24
Although other pathways may be involved , these results establish a mechanism by which BMP-2 signaling regulates Runx2 activity via PKD dependent inhibition of HDAC7 transcriptional repression .	Although other pathways may be involved, these results establish a mechanism by which BMP-2 signaling regulates Runx2 activity via PKD dependent inhibition of HDAC7 transcriptional repression.	20	26	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Positive_activation	PKD	PKD	PKD	HDAC7	HDAC7	HDAC7	20	21	24	25
In contrast , inhibition of PKD prevents TCR mediated nuclear exclusion of HDAC7 and associated Nur77 activation .	In contrast, inhibition of PKD prevents TCR mediated nuclear exclusion of HDAC7 and associated Nur77 activation.	3	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PKD	PKD	PKD	HDAC7	HDAC7	HDAC7	5	6	12	13
These results establish a novel pathway by which BMP signaling regulates Runx2 activity via PKD dependent inhibition of HDAC7 transcriptional repression .	These results establish a novel pathway by which BMP signaling regulates Runx2 activity via PKD dependent inhibition of HDAC7 transcriptional repression.	14	20	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Positive_activation	PKD	PKD	PKD	HDAC7	HDAC7	HDAC7	14	15	18	19
Previous work [ XREF_BIBR ] has shown that HDAC5 and HDAC7 are activated by BCR stimulation in a PKD dependent manner .	Previous work [XREF_BIBR] has shown that HDAC5 and HDAC7 are activated by BCR stimulation in a PKD dependent manner.	8	20	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PKD	PKD	PKD	HDAC7	HDAC7	HDAC7	18	19	10	11
The increase in nuclear PRKD1 then causes HDAC5 to be exported from the nucleus 20 .	The increase in nuclear PRKD1 then causes HDAC5 to be exported from the nucleus 20.	1	8	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PRKD1	PRKD1	PRKD1	HDAC5	HDAC5	HDAC5	4	5	7	8
These observations imply that PKD negatively regulates HCV secretion and release by attenuating OSBP and CERT functions by phosphorylation inhibition .	These observations imply that PKD negatively regulates HCV secretion and release by attenuating OSBP and CERT functions by phosphorylation inhibition.	4	16	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PKD	PKD	PKD	CERT	CERT	CERT	4	5	15	16
This suggests that PKD mediated inhibition of OSBP Golgi association may affect CERT activity and SM synthesis , thus acting as a distinct mechanism of PKD signaling that influences SM metabolism .	This suggests that PKD mediated inhibition of OSBP Golgi association may affect CERT activity and SM synthesis, thus acting as a distinct mechanism of PKD signaling that influences SM metabolism.	3	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PKD	PKD	PKD	CERT	CERT	CERT	3	4	12	13
Of these , the regulation of IR signaling by both PTPN1 and PTPN2 has been extensively characterized [ reviewed in XREF_BIBR ] , while targeting of IGF1-R and TYK2 by PTPN1 , as well as interactions between PTPN2 and JAK1 and JAK3 have also been reviewed [ XREF_BIBR ] .	Of these, the regulation of IR signaling by both PTPN1 and PTPN2 has been extensively characterized [reviewed in XREF_BIBR], while targeting of IGF1-R and TYK2 by PTPN1, as well as interactions between PTPN2 and JAK1 and JAK3 have also been reviewed [XREF_BIBR].	6	12	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTPN1	PTPN1	PTPN1	IR	IR	IR	10	11	6	7
These results suggest that PTP1B targets the IR through a novel binding element and that binding is required for the physiological effects of PTP1B on IR signal transduction .	These results suggest that PTP1B targets the IR through a novel binding element and that binding is required for the physiological effects of PTP1B on IR signal transduction.	4	8	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	IR	IR	IR	4	5	7	8
Furthermore , the requisite phosphatase PTP1b that reactivates the insulin receptor , does so by an obligatory oxidation of its cysteine residues ( step 2 ) in turn controlled by activation of NOX to generate physiologically normal and required oxyradicals .	Furthermore, the requisite phosphatase PTP1b that reactivates the insulin receptor, does so by an obligatory oxidation of its cysteine residues (step 2) in turn controlled by activation of NOX to generate physiologically normal and required oxyradicals.	2	12	reactivates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1b	PTP1b	PTP1b	insulin receptor	insulin receptor	insulin receptor	5	6	9	11
We have recently demonstrated that PTP1B deficiency increases GLUT2 and insulin receptor ( IR ) A complexes and glucose uptake in suckling , but not adult , primary hepatocytes .	We have recently demonstrated that PTP1B deficiency increases GLUT2 and insulin receptor (IR) A complexes and glucose uptake in suckling, but not adult, primary hepatocytes.	5	12	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	5	6	10	12
The expression of PTP1B increased in model group , thus inhibiting IRS1-Akt-GLUT4 signaling pathway and resulting in IR .	The expression of PTP1B increased in model group, thus inhibiting IRS1-Akt-GLUT4 signaling pathway and resulting in IR.	1	18	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	expression of PTP1B	ptp1b	IR	IR	ir	3	4	17	18
However , in 16-month old , nonobese PTP1B -/- mice activation of IR and PI 3-kinase-mediated insulin signaling was comparable to the response of these mice at 3 months of age .	However, in 16-month old, nonobese PTP1B -/- mice activation of IR and PI 3-kinase-mediated insulin signaling was comparable to the response of these mice at 3 months of age.	7	14	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	IR	IR	IR	7	8	12	13
Our data strongly suggest that TNF-alpha-induced PTP-1B overexpression may contribute to hepatic IR in obesity and diabetes , and NF-kappaB is involved in rosiglitazone attenuated PTP- 1B upregulation by TNF-alpha .	Our data strongly suggest that TNF-alpha-induced PTP-1B overexpression may contribute to hepatic IR in obesity and diabetes, and NF-kappaB is involved in rosiglitazone attenuated PTP- 1B upregulation by TNF-alpha.	6	16	contribute	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	PTP-1B	PTP-1B overexpression	ptp-1b	IR	IR	ir	6	7	12	13
In agreement with previous findings , which demonstrated that hepatic PTP1B directly targets the IR and IRS1 [ XREF_BIBR ] , Alb-Ptp1b -/- mice had increased levels of phosphorylation of the IR compared to Ptp1b fl/fl mice .	In agreement with previous findings, which demonstrated that hepatic PTP1B directly targets the IR and IRS1 [XREF_BIBR], Alb-Ptp1b -/- mice had increased levels of phosphorylation of the IR compared to Ptp1b fl/fl mice.	9	18	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	IR	IR	IR	10	11	14	15
XREF_BIBR , XREF_BIBR PTP1B inhibition by oleic acid prevents the inactivation of the insulin receptor , thereby increasing insulin receptor signaling .	XREF_BIBR, XREF_BIBR PTP1B inhibition by oleic acid prevents the inactivation of the insulin receptor, thereby increasing insulin receptor signaling.	3	15	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	3	4	13	15
In vivo in normal state constitutive low level of NOX4 activation and the released H 2 O 2 as a second messenger could be an important positive regulator of insulin signaling by inhibiting the protein-tyrosine phosphatase 1B ( PTP1B ) , that targets IR signaling XREF_BIBR , XREF_BIBR .	In vivo in normal state constitutive low level of NOX4 activation and the released H 2 O 2 as a second messenger could be an important positive regulator of insulin signaling by inhibiting the protein-tyrosine phosphatase 1B (PTP1B), that targets IR signaling XREF_BIBR, XREF_BIBR.	34	45	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	protein-tyrosine phosphatase 1B	protein-tyrosine phosphatase 1B	protein-tyrosine phosphatase 1B	IR	IR	IR	34	37	43	44
PTP1B is oxidized following platelet derived growth factor stimulation XREF_BIBR , XREF_BIBR , resulting in an enhanced mitogenic response , and is also transiently oxidized in response to insulin , promoting insulin receptor and leptin signalling 37 .	PTP1B is oxidized following platelet derived growth factor stimulation XREF_BIBR, XREF_BIBR, resulting in an enhanced mitogenic response, and is also transiently oxidized in response to insulin, promoting insulin receptor and leptin signalling 37.	0	33	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	0	1	31	33
Due to hepatic PTP1B directly targeting IR and IRS1 within the insulin signaling pathway and MR acting downstream to amplify PKB and Akt phosphorylation ; the aim of this study was to determine if there was a synergistic effect of a dual-therapy on hepatic insulin signaling and whole-body glucose homeostasis .	Due to hepatic PTP1B directly targeting IR and IRS1 within the insulin signaling pathway and MR acting downstream to amplify PKB and Akt phosphorylation; the aim of this study was to determine if there was a synergistic effect of a dual-therapy on hepatic insulin signaling and whole-body glucose homeostasis.	0	30	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	IR	IR	IR	3	4	6	7
PTP1B antagonizes insulin signaling by reducing the activation state of the insulin receptor kinase , thereby inhibiting post-receptor signaling in insulin responsive tissue .	PTP1B antagonizes insulin signaling by reducing the activation state of the insulin receptor kinase, thereby inhibiting post-receptor signaling in insulin responsive tissue.	0	13	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTP1B	PTP1B	PTP1B	insulin receptor	insulin receptor	insulin receptor	0	1	11	13
We tested whether SHP2 depletion induces secretion of a STAT1 agonist cytokine .	We tested whether SHP2 depletion induces secretion of a STAT1 agonist cytokine.	3	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	STAT1	STAT1	STAT1	3	4	9	10
SHP2 depletion upregulates p-STAT1 in PC3 and DU145 cells but not in LNCaP cells .	SHP2 depletion upregulates p-STAT1 in PC3 and DU145 cells but not in LNCaP cells.	0	4	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	p-STAT1	p-STAT1	p-STAT1	0	1	3	4
Expression of WT SHP2 decreased basal and induced pSTAT1 ( XREF_FIG ) , SHP2 depletion upregulated basal levels of pSTAT1 and total STAT1 ( XREF_FIG ) and significantly augmented TAP1/2 expression by IFN-gamma in STAT1 expressing cells but not in STAT1 deficient cells ( XREF_FIG ) .	Expression of WT SHP2 decreased basal and induced pSTAT1 (XREF_FIG), SHP2 depletion upregulated basal levels of pSTAT1 and total STAT1 (XREF_FIG) and significantly augmented TAP1/2 expression by IFN-gamma in STAT1 expressing cells but not in STAT1 deficient cells (XREF_FIG).	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP2	Expression of WT SHP2	shp2	pSTAT1	pSTAT1	pstat1	3	4	8	9
Because IFN-gamma significantly upregulated the activation of STAT1 , we hypothesized that the failure of STAT1 activation by SHP2 depletion may be related to the lack of JAK1 expression in LNCaP cells .	Because IFN-gamma significantly upregulated the activation of STAT1, we hypothesized that the failure of STAT1 activation by SHP2 depletion may be related to the lack of JAK1 expression in LNCaP cells.	15	19	activation	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	STAT1	STAT1	STAT1	18	19	15	16
SHP2 depletion upregulates pSTAT1 , pJAK1/2 and total STAT1 in HNC cells .	SHP2 depletion upregulates pSTAT1, pJAK1/2 and total STAT1 in HNC cells.	0	5	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	pSTAT1	pSTAT1	pSTAT1	0	1	3	4
SHP2 downregulates Jak2 and STAT3 in the mouse forebrain [ XREF_BIBR ] and SHP2 inhibits STAT1 and STAT3 differentially .	SHP2 downregulates Jak2 and STAT3 in the mouse forebrain [XREF_BIBR] and SHP2 inhibits STAT1 and STAT3 differentially.	13	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	STAT1	STAT1	STAT1	13	14	15	16
To determine whether SHP2 induced the upregulation of p-STAT3 and the downregulation of p-STAT1 , PCa cells were treated with SHP2 siRNA ( 50 nM ) for 48 hours .	To determine whether SHP2 induced the upregulation of p-STAT3 and the downregulation of p-STAT1, PCa cells were treated with SHP2 siRNA (50 nM) for 48 hours.	3	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP2	SHP2	SHP2	p-STAT1	p-STAT1	p-STAT1	3	4	13	14
SHP2 depletion upregulated p-STAT1 , HLA-ABC , and PD-L1 while downregulating ERK phosphorylation .	SHP2 depletion upregulated p-STAT1, HLA-ABC, and PD-L1 while downregulating ERK phosphorylation.	0	8	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	p-STAT1	p-STAT1	p-STAT1	0	1	3	4
SHP2 depletion by SHP2 siRNA significantly increased the expression of p-STAT1 Tyr701 but not total STAT1 , p-STAT3 Tyr705 , or total STAT3 in DU145 and PC3 cells .	SHP2 depletion by SHP2 siRNA significantly increased the expression of p-STAT1 Tyr701 but not total STAT1, p-STAT3 Tyr705, or total STAT3 in DU145 and PC3 cells.	0	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	SHP2	SHP2	STAT1	STAT1	STAT1	0	1	15	16
Many studies have shown that SHP-2 is required to activate wild-type EGFR signaling pathways .	Many studies have shown that SHP-2 is required to activate wild-type EGFR signaling pathways.	5	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP-2	SHP-2	SHP-2	EGFR	EGFR	EGFR	5	6	11	12
Our data suggest that the silencing of miR-489 expression , and subsequent overexpression of PTPN11 , leads to abnormal EGFR signalling .	Our data suggest that the silencing of miR-489 expression, and subsequent overexpression of PTPN11, leads to abnormal EGFR signalling.	12	20	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	PTPN11	overexpression of PTPN11	ptpn11	EGFR	EGFR	egfr	14	15	19	20
In this regard the phosphatase that targets ERBB1 , SHP2 , is different from the phosphatase that targets c-Met , receptor protein tyrosine phosphatase beta .	In this regard the phosphatase that targets ERBB1, SHP2, is different from the phosphatase that targets c-Met, receptor protein tyrosine phosphatase beta.	4	10	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP2	SHP2	SHP2	ERBB1	ERBB1	ERBB1	9	10	7	8
These findings confirm the immunoblotting data and further show that SHP2 suppresses ligand induced EGFR degradation by modulating the process of sorting .	These findings confirm the immunoblotting data and further show that SHP2 suppresses ligand induced EGFR degradation by modulating the process of sorting.	10	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP2	SHP2	SHP2	EGFR	EGFR	EGFR	10	11	14	15
Inhibition of SHP-2 expression by Shp-2 siRNA inhibited cell growth , transformation and altered morphology of these EGFRvIII transformed GBM cells .	Inhibition of SHP-2 expression by Shp-2 siRNA inhibited cell growth, transformation and altered morphology of these EGFRvIII transformed GBM cells.	0	18	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP-2	Inhibition of SHP-2 expression by Shp-2	shp-2	EGFRvIII	EGFRvIII	egfrviii	5	6	17	18
To understand the molecular mechanisms by which this oncoprotein alters transforming phenotypes , and since our previous work indicated that SHP-2 protein tyrosine phosphatase activity modulated EGFRvIII activation and downstream signaling , we examined whether SHP-2 plays a role in EGFRvIII induced oncogenesis by using both PTEN deficient U87MG.EGFRvIII and PTEN-intact LN229.EGFRvIII cells .	To understand the molecular mechanisms by which this oncoprotein alters transforming phenotypes, and since our previous work indicated that SHP-2 protein tyrosine phosphatase activity modulated EGFRvIII activation and downstream signaling, we examined whether SHP-2 plays a role in EGFRvIII induced oncogenesis by using both PTEN deficient U87MG.EGFRvIII and PTEN-intact LN229.EGFRvIII cells.	20	27	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP-2	SHP-2	SHP-2	EGFRvIII	EGFRvIII	EGFRvIII	20	21	26	27
These findings suggest that SHP2 suppresses EGFR degradation to promote elevated expression .	These findings suggest that SHP2 suppresses EGFR degradation to promote elevated expression.	4	7	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP2	SHP2	SHP2	EGFR	EGFR	EGFR	4	5	6	7
To our knowledge , this is the first study showing that the protein tyrosine phosphatase , SHP-2 mediates oncogenic EGFRvIII signals .	To our knowledge, this is the first study showing that the protein tyrosine phosphatase, SHP-2 mediates oncogenic EGFRvIII signals.	14	20	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP-2	SHP-2	SHP-2	EGFRvIII	EGFRvIII	EGFRvIII	16	17	19	20
These results were also supported by the finding that quercetin decreased the expression of SHP2 and subsequently downregulated the activation of epidermal growth factor receptor ( EGFR ) in HeLa cervical cancer cells [ XREF_BIBR ] .	These results were also supported by the finding that quercetin decreased the expression of SHP2 and subsequently downregulated the activation of epidermal growth factor receptor (EGFR) in HeLa cervical cancer cells [XREF_BIBR].	9	25	downregulated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SHP2	quercetin decreased the expression of SHP2	shp2	epidermal growth factor receptor	epidermal growth factor receptor	epidermal growth factor receptor	14	15	21	25
It is not clear why PTEN mutated tumors are selectively dependent upon GPCR activation of PI3Kbeta with little or no input from RTK activated PI3Kalpha .	It is not clear why PTEN mutated tumors are selectively dependent upon GPCR activation of PI3Kbeta with little or no input from RTK activated PI3Kalpha.	5	25	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PI3Kalpha	PI3Kalpha	PI3Kalpha	5	6	24	25
Collectively , 28 patients had tumors with PI3K and AKT pathway alterations , including complete PTEN loss , decreased PTEN ( H-score 1-200 ) , and PIK3CA or AKT mutations ; however , none of these patients had radiographic RECIST responses .	Collectively, 28 patients had tumors with PI3K and AKT pathway alterations, including complete PTEN loss, decreased PTEN (H-score 1-200), and PIK3CA or AKT mutations; however, none of these patients had radiographic RECIST responses.	15	29	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	15	16	26	27
Since mutationally activated NRAS is reported to simultaneously activate both RAF- and PI3K mediated signaling , silencing of PTEN or mutational activation of PIK3CA occurs rarely in NRAS mutated melanomas .	Since mutationally activated NRAS is reported to simultaneously activate both RAF- and PI3K mediated signaling, silencing of PTEN or mutational activation of PIK3CA occurs rarely in NRAS mutated melanomas.	18	24	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	18	19	23	24
This genome-wide DNA sequencing effort also revealed non overlapping activating mutations in PIK3CA and Ras , and inactivating mutations in PTEN .	This genome-wide DNA sequencing effort also revealed non overlapping activating mutations in PIK3CA and Ras, and inactivating mutations in PTEN.	9	21	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	PIK3CA	PIK3CA	PIK3CA	20	21	12	13
PTP1B-EGFR interaction occurs through membrane contact between multivesicular bodies ( MVB ) and the ER , with PTP1B promoting the sequestration of EGFR to MVB [ XREF_BIBR ] .	PTP1B-EGFR interaction occurs through membrane contact between multivesicular bodies (MVB) and the ER, with PTP1B promoting the sequestration of EGFR to MVB [XREF_BIBR].	2	23	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	EGFR	EGFR	EGFR	17	18	22	23
Yet , ER-MVB contacts were recently identified as sites for PTB1B mediated EGFR downregulation , preceding sorting of inactive EGFR onto ILVs for degradation [ XREF_BIBR ] .	Yet, ER-MVB contacts were recently identified as sites for PTB1B mediated EGFR downregulation, preceding sorting of inactive EGFR onto ILVs for degradation [XREF_BIBR].	8	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTB1B	PTB1B	PTB1B	EGFR	EGFR	EGFR	10	11	12	13
The population of EGFR interacting with PTP1B is the same population that undergo ESCRT mediated ( endosomal sorting complex required for transport ) sorting within MVBs , and PTP1B activity promotes the sequestration of EGFR on to MVB internal vesicles .	The population of EGFR interacting with PTP1B is the same population that undergo ESCRT mediated (endosomal sorting complex required for transport) sorting within MVBs, and PTP1B activity promotes the sequestration of EGFR on to MVB internal vesicles.	28	35	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	EGFR	EGFR	EGFR	28	29	34	35
Loss of PTP1B function abrogated trafficking of Met and EGF receptor to Rab5- and phosphatidylinositol 3-phosphate ( Pl3P )-positive early endosomes and subsequent trafficking through the degradative pathway .	Loss of PTP1B function abrogated trafficking of Met and EGF receptor to Rab5- and phosphatidylinositol 3-phosphate (Pl3P)-positive early endosomes and subsequent trafficking through the degradative pathway.	2	11	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	EGF receptor	EGF receptor	EGF receptor	2	3	9	11
Integrating this process with EGFR endocytosis suggests that the recycling rate of PTP1B would directly regulate the lifetime of active EGFR and therefore the amplitude of endosomal EGFR signaling .	Integrating this process with EGFR endocytosis suggests that the recycling rate of PTP1B would directly regulate the lifetime of active EGFR and therefore the amplitude of endosomal EGFR signaling.	10	21	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	EGFR	EGFR	EGFR	12	13	20	21
Conversely , deficiency in the Ptpn1 gene enhanced the IGF-IR and Akt survival signaling in the retina [ XREF_BIBR ] in agreement with another study showing that intravitreal administration of a PTP1B inhibitor prevented the cleavage of caspase 3 during light stress [ XREF_BIBR ] .	Conversely, deficiency in the Ptpn1 gene enhanced the IGF-IR and Akt survival signaling in the retina [XREF_BIBR] in agreement with another study showing that intravitreal administration of a PTP1B inhibitor prevented the cleavage of caspase 3 during light stress [XREF_BIBR].	5	13	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Ptpn1	Ptpn1	Ptpn1	Akt	Akt	Akt	5	6	11	12
Reexpression of PTP-1B in spontaneously immortalized fibroblasts resulted in decreased IGF-IR and AKT activation , as well as decreased protection from apoptosis and decreased motility .	Reexpression of PTP-1B in spontaneously immortalized fibroblasts resulted in decreased IGF-IR and AKT activation, as well as decreased protection from apoptosis and decreased motility.	0	14	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	PTP-1B	Reexpression of PTP-1B	ptp-1b	AKT	AKT	akt	2	3	12	13
We speculate that PTPN1 downregulation may similarly activate AKT in HSPCs , resulting in myeloid skewing and a block in B cell differentiation .	We speculate that PTPN1 downregulation may similarly activate AKT in HSPCs, resulting in myeloid skewing and a block in B cell differentiation.	3	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN1	PTPN1	PTPN1	AKT	AKT	AKT	3	4	8	9
We have previously shown in the IBH-6 cells that the overactivation of AKT1 decreased , whereas the overexpression of PTEN increased FAK levels XREF_BIBR .	We have previously shown in the IBH-6 cells that the overactivation of AKT1 decreased, whereas the overexpression of PTEN increased FAK levels XREF_BIBR.	17	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	overexpression of PTEN	pten	FAK	FAK	fak	19	20	21	22
The results of the present study demonstrate that H. pylori infection enhances this dysregulation by promoting the phosphorylation of PTEN , which subsequently increases FAK activation and gastric epithelial cell invasion .	The results of the present study demonstrate that H. pylori infection enhances this dysregulation by promoting the phosphorylation of PTEN, which subsequently increases FAK activation and gastric epithelial cell invasion.	17	25	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTEN	phosphorylation of PTEN	pten	FAK	FAK	fak	19	20	24	25
The simultaneous inhibition of Shp1 and Shp2 reduced Phase I WIN55212-2-stimulated FAK 576/577 Tyr P ( 1 min 93.37 % +/- 4.61 inhibition ; 2 min 84.97 % +/- 6.80 inhibition ) , as well as WIN55212-2-stimulated FAK 397 Tyr P ( 1 min 58.25 % +/- 11.40 inhibition ; 2 min 44.82 % +/- 8.68 inhibition ) ( XREF_FIG ) .	The simultaneous inhibition of Shp1 and Shp2 reduced Phase I WIN55212-2-stimulated FAK 576/577 Tyr P (1 min 93.37% +/- 4.61 inhibition; 2 min 84.97% +/- 6.80 inhibition), as well as WIN55212-2-stimulated FAK 397 Tyr P (1 min 58.25% +/- 11.40 inhibition; 2 min 44.82% +/- 8.68 inhibition) (XREF_FIG).	2	38	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Shp2	Shp2	Shp2	FAK	FAK	FAK	6	7	37	38
The current study now reveals that Shp2 mediates stretch signaling to FAK in rat neonatal cardiomyocytes .	The current study now reveals that Shp2 mediates stretch signaling to FAK in rat neonatal cardiomyocytes.	6	15	mediates	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Shp2	Shp2	Shp2	FAK	FAK	FAK	6	7	11	12
Interestingly , deletion of Shp2 resulted in constitutive tyrosine phosphorylation of FAK on these sites in the absence of SDF-1alpha stimulation , thereby disrupting the cycling of FAK between unphosphorylated and phosphorylated forms .	Interestingly, deletion of Shp2 resulted in constitutive tyrosine phosphorylation of FAK on these sites in the absence of SDF-1alpha stimulation, thereby disrupting the cycling of FAK between unphosphorylated and phosphorylated forms.	2	32	disrupting	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Shp2	Shp2	Shp2	FAK	FAK	FAK	4	5	27	28
We recently reported that SHP-2 mediates the aggressive phenotype of RA FLS by promoting activation of FAK .	We recently reported that SHP-2 mediates the aggressive phenotype of RA FLS by promoting activation of FAK.	4	17	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP-2	SHP-2	SHP-2	FAK	FAK	FAK	4	5	16	17
Other recent studies have demonstrated that certain PTEN deficient human cancer cell lines are sensitive to inactivation of p110beta rather than p110alpha .	Other recent studies have demonstrated that certain PTEN deficient human cancer cell lines are sensitive to inactivation of p110beta rather than p110alpha.	6	19	are sensitive to inactivation	Negative_activation_copula_1	Negative_activation	Negative_activation	PTEN	PTEN	PTEN	p110beta	p110beta	p110beta	7	8	18	19
Pten deficiency led to a significant increase in the number of LSK cells , as well as LT-HSCs , short-term HSCs ( ST-HSCs ) and progenitors in the spleens of Pten Delta and Delta animals ( XREF_FIG ; XREF_SUPPLEMENTARY ) XREF_BIBR XREF_BIBR , which was partially suppressed in the spleens of Pten Delta and Delta ; p110beta Delta and Delta animals ( XREF_FIG ; XREF_SUPPLEMENTARY ) .	Pten deficiency led to a significant increase in the number of LSK cells, as well as LT-HSCs, short-term HSCs (ST-HSCs) and progenitors in the spleens of Pten Delta and Delta animals (XREF_FIG; XREF_SUPPLEMENTARY) XREF_BIBR XREF_BIBR, which was partially suppressed in the spleens of Pten Delta and Delta; p110beta Delta and Delta animals (XREF_FIG; XREF_SUPPLEMENTARY).	0	57	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Pten	Pten	Pten	p110beta	p110beta	p110beta	0	1	56	57
Protein tyrosine phosphatase 1B ( PTP1B ) negatively modulates IGF-IR signaling , but its involvement in inflammation during DR remains unknown .	Protein tyrosine phosphatase 1B (PTP1B) negatively modulates IGF-IR signaling, but its involvement in inflammation during DR remains unknown.	3	10	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	IGF-IR	IGF-IR	IGF-IR	5	6	9	10
Shp-2 Mediates Gab1 Enhanced HGF Mitogenicity .	Shp-2 Mediates Gab1 Enhanced HGF Mitogenicity.	0	3	Mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shp-2	Shp-2	Shp-2	Gab1	Gab1	Gab1	0	1	2	3
Fyn and PTP-PEST Modulate WASp Effects on Induction of Actin Polymerization and Immunological Synapse Formation .	Fyn and PTP-PEST Modulate WASp Effects on Induction of Actin Polymerization and Immunological Synapse Formation.	0	5	Modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP-PEST	PTP-PEST	PTP-PEST	WASp	WASp	WASp	2	3	4	5
In view of the effects of Fyn and PTP-PEST on WASp tyrosine phosphorylation and relevance of Y291 phosphorylation to WASp function , the possibility that Fyn and/or PTP-PEST modulate the ability of WASp to activate the Arp2/3 complex was directly tested using a pyrene fluorescence in vitro assay of actin polymerization .	In view of the effects of Fyn and PTP-PEST on WASp tyrosine phosphorylation and relevance of Y291 phosphorylation to WASp function, the possibility that Fyn and/or PTP-PEST modulate the ability of WASp to activate the Arp2/3 complex was directly tested using a pyrene fluorescence in vitro assay of actin polymerization.	25	33	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP-PEST	PTP-PEST	PTP-PEST	WASp	WASp	WASp	27	28	32	33
Notably , given that Wnt signaling plays significant roles in human cancer [ XREF_BIBR ] and that a recent study has shown that knockdown of PTK7 can inhibit Wnt and beta-catenin activity [ XREF_BIBR ] , it is conceivable that PTK7 may also be involved in cancer development and progression .	Notably, given that Wnt signaling plays significant roles in human cancer [XREF_BIBR] and that a recent study has shown that knockdown of PTK7 can inhibit Wnt and beta-catenin activity [XREF_BIBR], it is conceivable that PTK7 may also be involved in cancer development and progression.	23	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTK7	PTK7	PTK7	beta-catenin	beta-catenin	beta-catenin	25	26	30	31
Besides CE phenotypes , we now show that PTK7 protein knockdown also inhibits Wnt and beta-catenin activity .	Besides CE phenotypes, we now show that PTK7 protein knockdown also inhibits Wnt and beta-catenin activity.	8	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTK7	PTK7	PTK7	beta-catenin	beta-catenin	beta-catenin	8	9	15	16
It is tempting to speculate that the inactivation of eNOS as a consequence of its phosphorylation by PYK2 may play an important role ; certainly in the setting of atherosclerosis , PYK2 may be sufficiently activated to influence eNOS .	It is tempting to speculate that the inactivation of eNOS as a consequence of its phosphorylation by PYK2 may play an important role; certainly in the setting of atherosclerosis, PYK2 may be sufficiently activated to influence eNOS.	31	39	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PYK2	PYK2	PYK2	eNOS	eNOS	eNOS	31	32	38	39
70 Inhibitors of either Pyk2 or c-Src blocked NOS3 production in glomeruli in response to dietary salt .	70 Inhibitors of either Pyk2 or c-Src blocked NOS3 production in glomeruli in response to dietary salt.	1	9	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Pyk2	Pyk2	Pyk2	NOS3	NOS3	NOS3	4	5	8	9
We recently reported that COX-2 and PGE2 induces Akt and GSK-3beta and wnt signaling ( beta-catenin and T-cell factor and lymphoid enhancer factor ) to increase MIG-7 that inhibits protein phosphatase 2A ( PP2A ) to positively feedback on Akt and GSK-3beta signaling and sustain cancer cell migration and invasion [ XREF_BIBR ] .	We recently reported that COX-2 and PGE2 induces Akt and GSK-3beta and wnt signaling (beta-catenin and T-cell factor and lymphoid enhancer factor) to increase MIG-7 that inhibits protein phosphatase 2A (PP2A) to positively feedback on Akt and GSK-3beta signaling and sustain cancer cell migration and invasion [XREF_BIBR].	4	25	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	COX-2	COX-2	COX-2	GSK-3beta	GSK-3beta	GSK-3beta	4	5	10	11
Moreover , evidence is presented which indicates that SHP2 , a major determinant of balance between mESC self-renewal and differentiation , directly regulates Spry1 activity to modulate ERK1/2 signaling and lineage specific differentiation in mESCs .	Moreover, evidence is presented which indicates that SHP2, a major determinant of balance between mESC self-renewal and differentiation, directly regulates Spry1 activity to modulate ERK1/2 signaling and lineage specific differentiation in mESCs.	8	24	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHP2	SHP2	SHP2	Spry1	Spry1	Spry1	8	9	23	24
Using substrate trapping mutants , we mapped PTPs to their putative substrates and found that only PTPN12 could target ABL1 .	Using substrate trapping mutants, we mapped PTPs to their putative substrates and found that only PTPN12 could target ABL1.	15	20	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN12	PTPN12	PTPN12	ABL1	ABL1	ABL1	16	17	19	20
The binding of PIN1 to phosphorylated FAK S910 and the prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397 , leading to the dynamic turnover of focal adhesions in these regions .	The binding of PIN1 to phosphorylated FAK S910 and the prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397, leading to the dynamic turnover of focal adhesions in these regions.	11	16	cause	Positive_activation_token_1_noun	Negative_activation	Positive_activation	PTP-PEST	PTP-PEST	PTP-PEST	FAK	FAK	FAK	15	16	13	14
In addition to the boosting of GLI1 activity by betaCAT ( see above ) , we show that GLI1 transcriptional activity can also be enhanced by cMYC , oncogenic KRAS-MEK and AKT and loss of PTEN and p53 .	In addition to the boosting of GLI1 activity by betaCAT (see above), we show that GLI1 transcriptional activity can also be enhanced by cMYC, oncogenic KRAS-MEK and AKT and loss of PTEN and p53.	18	37	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTEN	PTEN	PTEN	GLI1	GLI1	GLI1	35	36	18	19
PTP1B , RPTPe , and TCPTP all target the JAK2 and STAT3 pathway , and JAK2 is a direct substrate for both PTP1B and RPTPe .	PTP1B, RPTPe, and TCPTP all target the JAK2 and STAT3 pathway, and JAK2 is a direct substrate for both PTP1B and RPTPe.	0	12	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	JAK2	JAK2	JAK2	0	1	9	10
In the present study , we demonstrated that PTP1B deficiency enhanced the activity of JAK2 and STAT3 , thereby promoting the production of MDSCs , which , in turn , suppressed the inflammation and tissue damage induced by DSS treatment .	In the present study, we demonstrated that PTP1B deficiency enhanced the activity of JAK2 and STAT3, thereby promoting the production of MDSCs, which, in turn, suppressed the inflammation and tissue damage induced by DSS treatment.	8	16	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	JAK2	JAK2	JAK2	8	9	14	15
Western blot experiments combined with microscopy suggest that PTP1B does not directly regulate Jak2 activation but is found in the same transitory signaling complexes .	Western blot experiments combined with microscopy suggest that PTP1B does not directly regulate Jak2 activation but is found in the same transitory signaling complexes.	8	14	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Jak2	Jak2	Jak2	8	9	13	14
PTP1B also targets Jak2 and Stat in the leptin pathway , thereby impeding leptin signals .	PTP1B also targets Jak2 and Stat in the leptin pathway, thereby impeding leptin signals.	0	5	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Jak2	Jak2	Jak2	0	1	3	4
Moreover , they do not exclude the possibility that the combined PTP1B and TCPTP deficiency may lead to synergistic effects on leptin induced JAK2 activation and STAT-3 signaling , so that leptin signaling alone promotes WAT browning .	Moreover, they do not exclude the possibility that the combined PTP1B and TCPTP deficiency may lead to synergistic effects on leptin induced JAK2 activation and STAT-3 signaling, so that leptin signaling alone promotes WAT browning.	9	24	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	JAK2	JAK2	JAK2	11	12	23	24
One mechanism that may facilitate the inactivation of Stat5 in metastatic cells is the upregulation of the protein tyrosine phosphatase 1B ( PTP1B ) that targets active Jak2 .	One mechanism that may facilitate the inactivation of Stat5 in metastatic cells is the upregulation of the protein tyrosine phosphatase 1B (PTP1B) that targets active Jak2.	14	28	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Jak2	Jak2	Jak2	22	23	27	28
We speculate that the concomitant oxidation of PTP1B and TCPTP in the livers of HFF mice might promote the coordinated activation of hepatic JAK-2 and STAT-5 in response to insulin .	We speculate that the concomitant oxidation of PTP1B and TCPTP in the livers of HFF mice might promote the coordinated activation of hepatic JAK-2 and STAT-5 in response to insulin.	5	25	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	JAK-2	JAK-2	JAK-2	7	8	23	24
To test this hypothesis , we therefore investigated whether PTP1B could modulate Jak2 activation .	To test this hypothesis, we therefore investigated whether PTP1B could modulate Jak2 activation.	9	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Jak2	Jak2	Jak2	9	10	12	13
In order to determine whether PTP1B modulated Jak2 activity , we first used confocal microscopy to determine whether Jak2 and PTP1B could be found in the same signaling complex .	In order to determine whether PTP1B modulated Jak2 activity, we first used confocal microscopy to determine whether Jak2 and PTP1B could be found in the same signaling complex.	5	8	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	Jak2	Jak2	Jak2	5	6	7	8
TCPTP deficiency in human BC cell lines increased SFK and STAT3 signaling and its reconstitution severely impaired cell proliferation and suppressed anchorage independent growth in vitro and xenograft growth in vivo .	TCPTP deficiency in human BC cell lines increased SFK and STAT3 signaling and its reconstitution severely impaired cell proliferation and suppressed anchorage independent growth in vitro and xenograft growth in vivo.	0	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TCPTP	TCPTP	TCPTP	STAT3	STAT3	STAT3	0	1	10	11
These results are consistent with TCPTP heterozygous deficiency promoting both IR and STAT3 signaling in hepatocytes to suppress gluconeogenic gene expression .	These results are consistent with TCPTP heterozygous deficiency promoting both IR and STAT3 signaling in hepatocytes to suppress gluconeogenic gene expression.	5	13	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TCPTP	TCPTP	TCPTP	STAT3	STAT3	STAT3	5	6	12	13
Homozygous TCPTP deficiency in murine mammary fat pads in vivo is associated with elevated SFK and STAT3 signaling , whereas TCPTP deficiency in human breast cancer cell lines enhances SFK and STAT3 signaling .	Homozygous TCPTP deficiency in murine mammary fat pads in vivo is associated with elevated SFK and STAT3 signaling, whereas TCPTP deficiency in human breast cancer cell lines enhances SFK and STAT3 signaling.	20	32	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TCPTP	TCPTP	TCPTP	STAT3	STAT3	STAT3	20	21	31	32
PTPN2 mediated STAT3 activity , thus , contributes to the exit of ESCs from the pluripotent ground state .	PTPN2 mediated STAT3 activity, thus, contributes to the exit of ESCs from the pluripotent ground state.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	PTPN2	PTPN2	PTPN2	STAT3	STAT3	STAT3	0	1	2	3
Previous studies have established the capacity of TCPTP to dephosphorylate STAT3 , whereas our studies demonstrate that TCPTP deficiency specifically enhances IL-6-induced STAT3 signaling in hepatocytes and HeLa cells .	Previous studies have established the capacity of TCPTP to dephosphorylate STAT3, whereas our studies demonstrate that TCPTP deficiency specifically enhances IL-6-induced STAT3 signaling in hepatocytes and HeLa cells.	17	23	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TCPTP	TCPTP	TCPTP	STAT3	STAT3	STAT3	17	18	22	23
Therefore , we hypothesized that PTPN2 could have a direct effect on the phosphorylation of tyrosine residues of Src kinase , indirectly modulating the activation of Src downstream signaling including the NF-kappaB , ERK and p38 signaling pathways .	Therefore, we hypothesized that PTPN2 could have a direct effect on the phosphorylation of tyrosine residues of Src kinase, indirectly modulating the activation of Src downstream signaling including the NF-kappaB, ERK and p38 signaling pathways.	5	28	modulating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN2	PTPN2	PTPN2	Src	Src	Src	5	6	26	27
We showed that PTPN2 could directly target the Src protein to regulate the downstream signaling through the enhancement and reduction of the phosphorylation of Src at Tyr416 and Tyr527 residues , respectively .	We showed that PTPN2 could directly target the Src protein to regulate the downstream signaling through the enhancement and reduction of the phosphorylation of Src at Tyr416 and Tyr527 residues, respectively.	3	9	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN2	PTPN2	PTPN2	Src	Src	Src	3	4	8	9
We also performed an in vitro phosphorylation assay to examine whether PTPN2 directly activates Src protein .	We also performed an in vitro phosphorylation assay to examine whether PTPN2 directly activates Src protein.	11	15	directly activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN2	PTPN2	PTPN2	Src	Src	Src	11	12	14	15
ER stress coincided with the inhibition of Src family kinases ( SFKs ) , which was exacerbated by PTP1B overexpression and largely prevented by TCPTP knockdown .	ER stress coincided with the inhibition of Src family kinases (SFKs), which was exacerbated by PTP1B overexpression and largely prevented by TCPTP knockdown.	7	25	prevented	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	TCPTP	TCPTP	TCPTP	Src	Src	Src	24	25	7	8
PTPN2 associates and activates Src kinase through dephosphorylation of Tyrosine 527 .	PTPN2 associates and activates Src kinase through dephosphorylation of Tyrosine 527.	0	5	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN2	PTPN2	PTPN2	Src	Src	Src	0	1	4	5
Our results suggest that early after cell contact with the matrix , PTP1B cooperates with beta3 integrins to activate a Src and FAK signaling pathway leading to the transient repression of RhoA and myosin dependent contractility , allowing adhesion and lamellipodium assembly .	Our results suggest that early after cell contact with the matrix, PTP1B cooperates with beta3 integrins to activate a Src and FAK signaling pathway leading to the transient repression of RhoA and myosin dependent contractility, allowing adhesion and lamellipodium assembly.	12	24	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	FAK	FAK	FAK	12	13	22	23
Here we demonstrate that PTP1B activation of Src and FAK signaling downregulates RhoA-myosin activity , and as a consequence restricts contractility at the cell cortex , events that are functionally linked to the development of the lamellipodium and adhesions .	Here we demonstrate that PTP1B activation of Src and FAK signaling downregulates RhoA-myosin activity, and as a consequence restricts contractility at the cell cortex, events that are functionally linked to the development of the lamellipodium and adhesions.	4	10	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	FAK	FAK	FAK	4	5	9	10
Inhibition of PTP1B reduced Phase I WIN55212-2-stimulated FAK 576/577 Tyr P ( 1 min 62.40 % +/- 6.85 inhibition ; 2 min 71.05 % +/- 10.02 inhibition ) , as well as WIN55212-2-stimulated FAK 397 Tyr P ( 1 min 75.59 % +/- 22.01 inhibition ; 2 min 80.18 % +/- 11.68 inhibition ) ( XREF_FIG ) .	Inhibition of PTP1B reduced Phase I WIN55212-2-stimulated FAK 576/577 Tyr P (1 min 62.40% +/- 6.85 inhibition; 2 min 71.05% +/- 10.02 inhibition), as well as WIN55212-2-stimulated FAK 397 Tyr P (1 min 75.59% +/- 22.01 inhibition; 2 min 80.18% +/- 11.68 inhibition) (XREF_FIG).	0	34	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	FAK	FAK	FAK	2	3	33	34
In summary , PTP1B up-regulation in podocytes induces a migratory response by activating SFKs and FAK , leading to foot process effacement and proteinuria .	In summary, PTP1B up-regulation in podocytes induces a migratory response by activating SFKs and FAK, leading to foot process effacement and proteinuria.	3	16	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	FAK	FAK	FAK	3	4	15	16
To reduce the complexity of the system , we abrogated all cross-talk by switching off ROS production and regulation by the common phosphatase PTP1B to get the independent signaling systems shown in XREF_FIG .	To reduce the complexity of the system, we abrogated all cross-talk by switching off ROS production and regulation by the common phosphatase PTP1B to get the independent signaling systems shown in XREF_FIG.	15	24	production	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	ROS	ROS	ROS	23	24	15	16
We then wondered how PTP1B inhibition could suppress ROS induced toxicity .	We then wondered how PTP1B inhibition could suppress ROS induced toxicity.	4	9	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	ROS	ROS	ROS	4	5	8	9
In 3T3-L1 adipocytes , Nox4 , but not Nox2 , appears to be a major mediator of insulin induced ROS production that was associated with oxidative inhibition of protein tyrosine phosphatase ( PTP ) , PTP1B activity .	In 3T3-L1 adipocytes, Nox4, but not Nox2, appears to be a major mediator of insulin induced ROS production that was associated with oxidative inhibition of protein tyrosine phosphatase (PTP), PTP1B activity.	18	36	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	ROS	ROS	ROS	35	36	19	20
Also , the Nox4 induced ROS partly regulated the activity of tyrosine phosphatase-1B ( PTP1B ) , a well established redox sensor that can mediate ROS induced intracellular signaling [ XREF_BIBR ] .	Also, the Nox4 induced ROS partly regulated the activity of tyrosine phosphatase-1B (PTP1B), a well established redox sensor that can mediate ROS induced intracellular signaling [XREF_BIBR].	12	26	mediate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	ROS	ROS	ROS	14	15	25	26
Therefore , we hypothesized that PTP1B inhibition may primarily attenuate downstream processes of ROS such as ER stress .	Therefore, we hypothesized that PTP1B inhibition may primarily attenuate downstream processes of ROS such as ER stress.	5	17	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	ROS	ROS	ROS	5	6	13	14
In such experiments our data show that in response to adiponectin , PTP1B expression increased 3.5 fold ( XREF_FIG ) and PTP1B activity 200 % ( XREF_FIG ) .	In such experiments our data show that in response to adiponectin, PTP1B expression increased 3.5 fold (XREF_FIG) and PTP1B activity 200% (XREF_FIG).	12	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B expression	ptp1b	PTP1B	PTP1B	ptp1b	12	13	21	22
Sumoylation of PTP1B reduces its catalytic activity and inhibits the negative effect of PTP1B on insulin receptor signalling and on transformation by the oncogene v-crk .	Sumoylation of PTP1B reduces its catalytic activity and inhibits the negative effect of PTP1B on insulin receptor signalling and on transformation by the oncogene v-crk.	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	Sumoylation of PTP1B	ptp1b	PTP1B	PTP1B	ptp1b	2	3	13	14
We demonstrate that IL-4 induces PTP1B mRNA expression in a phosphatidylinositol 3-kinase-dependent manner and enhances PTP1B protein stability to suppress IL-4-induced STAT6 signaling .	We demonstrate that IL-4 induces PTP1B mRNA expression in a phosphatidylinositol 3-kinase-dependent manner and enhances PTP1B protein stability to suppress IL-4-induced STAT6 signaling.	3	17	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	IL-4 induces PTP1B mRNA expression	ptp1b	PTP1B	PTP1B	ptp1b	5	6	15	16
In addition , STEP may also indirectly modulate GluN2B function by preventing the autophosphoryation of Fyn , a member of the Src family kinases .	In addition, STEP may also indirectly modulate GluN2B function by preventing the autophosphoryation of Fyn, a member of the Src family kinases.	3	18	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	3	4	15	16
These actions compliment the actions of cAMP dependent STEP inactivation , because inactivation of STEP activates Fyn and ERK , and leads to NMDAR internalization .	These actions compliment the actions of cAMP dependent STEP inactivation, because inactivation of STEP activates Fyn and ERK, and leads to NMDAR internalization.	12	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	14	15	16	17
As a result , STEP promotes the internalization of surface glutamate receptors ( NMDARs and AMPARs ) , inactivation of Fyn , Pyk2 and ERK1/2 kinases , or regulation of PTPalpha localization .	As a result, STEP promotes the internalization of surface glutamate receptors (NMDARs and AMPARs), inactivation of Fyn, Pyk2 and ERK1/2 kinases, or regulation of PTPalpha localization.	4	25	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	STEP	STEP	STEP	Fyn	Fyn	Fyn	4	5	20	21
In the absence of GPx1 , excess ROS in the pancreatic islets oxidize PTPN2 , promoting STAT1 signaling which results in downregulating key enzymes of the insulin production and secretory pathway , such as Pdx1 .	In the absence of GPx1, excess ROS in the pancreatic islets oxidize PTPN2, promoting STAT1 signaling which results in downregulating key enzymes of the insulin production and secretory pathway, such as Pdx1.	12	34	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN2	PTPN2	PTPN2	STAT1	STAT1	STAT1	13	14	16	17
These data demonstrate that the phosphatase PTPN2 is a major modulator of IFN-gamma-induced STAT1 and STAT3 activity in beta-cells .	These data demonstrate that the phosphatase PTPN2 is a major modulator of IFN-gamma-induced STAT1 and STAT3 activity in beta-cells.	4	18	is a major modulator	Positive_activation_copula_1	Negative_activation	Positive_activation	PTPN2	PTPN2	PTPN2	STAT1	STAT1	STAT1	6	7	13	14
We have recently shown that KD of PTPN2 in pancreatic beta-cells exposed to IFN-gamma augments STAT1 signalling and increases apoptosis .	We have recently shown that KD of PTPN2 in pancreatic beta-cells exposed to IFN-gamma augments STAT1 signalling and increases apoptosis.	5	16	augments	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN2	PTPN2	PTPN2	STAT1	STAT1	STAT1	7	8	15	16
TCPTP modulates c-Met signaling by dephosphorylating the tyrosines in the kinase domain , and dEP1 downregulates c-Met signaling by dephosphorylating the docking tyrosines [ XREF_BIBR , XREF_BIBR ] .	TCPTP modulates c-Met signaling by dephosphorylating the tyrosines in the kinase domain, and dEP1 downregulates c-Met signaling by dephosphorylating the docking tyrosines [XREF_BIBR, XREF_BIBR].	0	3	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TCPTP	TCPTP	TCPTP	c-Met	c-Met	c-Met	0	1	2	3
PTPN2 enhances chronic myeloid leukemia by activating STAT5A , a member of STAT family or beta-catenin pathway , and is associated with Crohn ' s disease .	PTPN2 enhances chronic myeloid leukemia by activating STAT5A, a member of STAT family or beta-catenin pathway, and is associated with Crohn 's disease.	0	20	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN2	PTPN2	PTPN2	STAT5A	STAT5A	STAT5A	0	1	7	8
Similarly , we found that UVB irradiation induced ERK phosphorylation , but its activation was not affected by TC-PTP or TC-PTP-mediated activation of Flk-1 .	Similarly, we found that UVB irradiation induced ERK phosphorylation, but its activation was not affected by TC-PTP or TC-PTP-mediated activation of Flk-1.	18	24	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	TC-PTP	TC-PTP	TC-PTP	Flk-1	Flk-1	Flk-1	18	19	23	24
Very recent studies showed that the loss of the phosphatase PTPN2 -- which can inhibit both Lck and Fyn activation -- leads to more vigorous lymphopenia induced proliferation in naive T cells .	Very recent studies showed that the loss of the phosphatase PTPN2 -- which can inhibit both Lck and Fyn activation -- leads to more vigorous lymphopenia induced proliferation in naive T cells.	6	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN2	loss of the phosphatase PTPN2	ptpn2	Fyn	Fyn	fyn	10	11	18	19
Knockdown of PTPN2 directs EGFR signaling toward increased PI3K activation and increased suppression of epithelial chloride secretory responses .	Knockdown of PTPN2 directs EGFR signaling toward increased PI3K activation and increased suppression of epithelial chloride secretory responses.	0	5	directs	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	PTPN2	PTPN2	PTPN2	EGFR	EGFR	EGFR	2	3	4	5
VEGF stimulated activation of VEGFR2 on GBM cells recruited the cytoplasmic phosphotyrosine phosphatase PTP1B toward HGF activated c-Met , leading to c-Met dephosphorylation and suppression of cell motility ( XREF_FIG ) .	VEGF stimulated activation of VEGFR2 on GBM cells recruited the cytoplasmic phosphotyrosine phosphatase PTP1B toward HGF activated c-Met, leading to c-Met dephosphorylation and suppression of cell motility (XREF_FIG).	9	18	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTP1B	PTP1B	PTP1B	c-Met	c-Met	c-Met	13	14	17	18
We have previously shown that , in the HD cell-line U-HO1-PTPN1 , PTPN1 induced down-regulation of STAT5A was associated with multi-nuclearity and high apoptotic index compared to the U-HO1 cell-line [ Knecht et al ., XREF_BIBR ] .	We have previously shown that, in the HD cell-line U-HO1-PTPN1, PTPN1 induced down-regulation of STAT5A was associated with multi-nuclearity and high apoptotic index compared to the U-HO1 cell-line [Knecht et al., XREF_BIBR].	12	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN1	PTPN1	PTPN1	STAT5A	STAT5A	STAT5A	12	13	16	17
PTP-1B targets Tyk2 and JAK2 [ XREF_BIBR ] whereas the related TC-PTP binds JAK1 and JAK3 [ XREF_BIBR ] .	PTP-1B targets Tyk2 and JAK2 [XREF_BIBR] whereas the related TC-PTP binds JAK1 and JAK3 [XREF_BIBR].	0	14	targets	Positive_regulation_token_1_verb	Negative_activation	Positive_regulation	PTP-1B	PTP-1B	ptp-1b	Tyk2	Tyk2 and JAK2 [XREF_BIBR] whereas the related TC-PTP binds JAK1	tyk2	0	1	2	3
While small amounts of CD45 ( 3 % of normal levels in mice ) can be sufficient to activate Lck by dephosphorylating Y505 , close to the full wild type concentration is required to prevent excess Lck activity by dephosphorylating Y394 [ XREF_BIBR ] .	While small amounts of CD45 (3% of normal levels in mice) can be sufficient to activate Lck by dephosphorylating Y505, close to the full wild type concentration is required to prevent excess Lck activity by dephosphorylating Y394 [XREF_BIBR].	2	20	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	amounts of CD45	cd45	Lck	Lck	lck	4	5	19	20
Here we provide evidence that CD45 can modulate the binding of the Lck to an 11 amino acid tyrosine phosphorylated peptide containing the carboxy-terminus of Lck ( lckP ) .	Here we provide evidence that CD45 can modulate the binding of the Lck to an 11 amino acid tyrosine phosphorylated peptide containing the carboxy-terminus of Lck (lckP).	5	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	5	6	12	13
Because the protein tyrosine phosphatase ( PTP ) CD45 induces Lck activity by dephosphorylating a tyrosine residue in the negative regulatory site of this kinase , we examined CHC phosphorylation in the CD45 deficient Jurkat T cell line , J45.01 , in which Lck activity is attenuated .	Because the protein tyrosine phosphatase (PTP) CD45 induces Lck activity by dephosphorylating a tyrosine residue in the negative regulatory site of this kinase, we examined CHC phosphorylation in the CD45 deficient Jurkat T cell line, J45.01, in which Lck activity is attenuated.	1	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	8	9	10	11
The first event is activation of the Src family protein tyrosine kinases ( SFKs ) Fyn and Lck through the dephosphorylation of their crucial tyrosine residues mediated by CD45 XREF_BIBR , XREF_BIBR .	The first event is activation of the Src family protein tyrosine kinases (SFKs) Fyn and Lck through the dephosphorylation of their crucial tyrosine residues mediated by CD45 XREF_BIBR, XREF_BIBR.	15	29	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	28	29	17	18
However , the controversy about methodologies used lipid raft studies and the questions about their very existence as well as the fact that CD45 can either activate and deactivate Lck prevent a clear understanding of the lipid rafts role in the control of Lck distribution .	However, the controversy about methodologies used lipid raft studies and the questions about their very existence as well as the fact that CD45 can either activate and deactivate Lck prevent a clear understanding of the lipid rafts role in the control of Lck distribution.	23	30	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	23	24	29	30
Thus , in theory , CD45 inhibition may also be able to decrease Lck activity because of increased levels of Tyr505 phosphorylation .	Thus, in theory, CD45 inhibition may also be able to decrease Lck activity because of increased levels of Tyr505 phosphorylation.	5	14	decrease	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	5	6	13	14
By isolating CD45- mutants from Jurkat cells , we observed that surface expression of the tyrosine phosphatase CD45 is required in order to increase p56lck activity following CD2 stimulation , while CD4 induced activation of the kinase remained unchanged .	By isolating CD45- mutants from Jurkat cells, we observed that surface expression of the tyrosine phosphatase CD45 is required in order to increase p56lck activity following CD2 stimulation, while CD4 induced activation of the kinase remained unchanged.	12	25	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	expression of the tyrosine phosphatase CD45	cd45	p56lck	p56lck	p56lck	17	18	24	25
The CD45 tyrosine phosphatase has been reported to activate the src family tyrosine kinases Lck and Fyn by dephosphorylating regulatory COOH-terminal tyrosine residues 505 and 528 , respectively .	The CD45 tyrosine phosphatase has been reported to activate the src family tyrosine kinases Lck and Fyn by dephosphorylating regulatory COOH-terminal tyrosine residues 505 and 528, respectively.	1	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	1	2	14	15
In T and B cells , increasing CD45 expression across this series reduces phosphorylation of the inhibitory tyrosines of Lck and Lyn , respectively .	In T and B cells, increasing CD45 expression across this series reduces phosphorylation of the inhibitory tyrosines of Lck and Lyn, respectively.	7	21	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45 expression	cd45	Lck	Lck	lck	7	8	19	20
Importantly , and in disagreement with the model that CD45 only activates Lck in vivo , the kinase activity of Lck from cells lacking CD45 was substantially increased .	Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased.	9	14	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	9	10	12	13
As a further confirmation , we inhibited the protein tyrosine phosphatase CD45 , which activates Lck by dephosphorylating its inhibitory pY505 .	As a further confirmation, we inhibited the protein tyrosine phosphatase CD45, which activates Lck by dephosphorylating its inhibitory pY505.	6	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	11	12	15	16
Relatively low amounts of active CD45 are sufficient to activate Lck by dephosphorylating tyrosine 505 , but even a slight loss of CD45 activity impairs its ability to restrict the kinase activity of Lck by dephosphorylating tyrosine 394 , meaning that minor decreases in CD45 activity result in hypersensitive T cell signalling and enhanced proliferation [ XREF_BIBR ] .	Relatively low amounts of active CD45 are sufficient to activate Lck by dephosphorylating tyrosine 505, but even a slight loss of CD45 activity impairs its ability to restrict the kinase activity of Lck by dephosphorylating tyrosine 394, meaning that minor decreases in CD45 activity result in hypersensitive T cell signalling and enhanced proliferation [XREF_BIBR].	2	11	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	amounts of active CD45	cd45	Lck	Lck	lck	5	6	10	11
Therefore , loss of CD45 phosphatase activity drastically reduces the abundance of active Lck .	Therefore, loss of CD45 phosphatase activity drastically reduces the abundance of active Lck.	4	14	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	4	5	13	14
However , CD45 also deactivates several targets of Lck at antigen receptors and thus it was proposed , first in a speculative mode by Springer and later with experimental support by van der Merwe and Dustin that CD45 exclusion would be a key initial event in TCR triggering .	However, CD45 also deactivates several targets of Lck at antigen receptors and thus it was proposed, first in a speculative mode by Springer and later with experimental support by van der Merwe and Dustin that CD45 exclusion would be a key initial event in TCR triggering.	2	9	deactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CD45	CD45	CD45	Lck	Lck	Lck	2	3	8	9
Lck Y192 Variants Prevent CD45 Mediated Activation of Lck Independently of SH2 Phosphopeptide Affinity .	Lck Y192 Variants Prevent CD45 Mediated Activation of Lck Independently of SH2 Phosphopeptide Affinity.	3	13	Mediated	Positive_early_activation	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	4	5	8	9
Thus it is likely that TS enzymatic modulation of CD45 and downstream activation of Src family kinases Lck and Fyn reduce the threshold for TCR activation of naive T cells , leading to the increased responses to subdominant TS epitopes .	Thus it is likely that TS enzymatic modulation of CD45 and downstream activation of Src family kinases Lck and Fyn reduce the threshold for TCR activation of naive T cells, leading to the increased responses to subdominant TS epitopes.	9	19	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	9	10	17	18
This is at least partly explained by CD45 being required to activate Lck by dephosphorylating an inhibitory tyrosine at the C-terminus of the kinase 2 .	This is at least partly explained by CD45 being required to activate Lck by dephosphorylating an inhibitory tyrosine at the C-terminus of the kinase 2.	5	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	7	8	12	13
CD45 activates the Src family protein-tyrosine kinases , p56lck and p59fyn , by dephosphorylating a negative regulatory tyrosine in the carboxyl terminus .	CD45 activates the Src family protein-tyrosine kinases, p56lck and p59fyn, by dephosphorylating a negative regulatory tyrosine in the carboxyl terminus.	0	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	p56lck	p56lck	p56lck	0	1	8	9
Therefore , the primary role of CD45 is to prevent deactivation of Lck .	Therefore, the primary role of CD45 is to prevent deactivation of Lck.	4	13	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lck	Lck	Lck	6	7	12	13
LCK and BTK were modulated by PTPRC via the T-cell receptor and B-cell receptor pathways , respectively [ XREF_BIBR ] .	LCK and BTK were modulated by PTPRC via the T-cell receptor and B-cell receptor pathways, respectively [XREF_BIBR].	0	16	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTPRC	PTPRC	PTPRC	LCK	LCK	LCK	6	7	0	1
Previous analyses have suggested that the CD45 tyrosine phosphatase activates src family tyrosine kinases p56lck and p59fyn by dephosphorylating regulatory COOH-terminal residues .	Previous analyses have suggested that the CD45 tyrosine phosphatase activates src family tyrosine kinases p56lck and p59fyn by dephosphorylating regulatory COOH-terminal residues.	6	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	p56lck	p56lck	p56lck	6	7	14	15
Our previous data already demonstrated that recruitment of the IL-6R complex to lipid rafts and CD45 activates Lyn by inducing a Lyn membrane confirmation change [ XREF_BIBR ] .	Our previous data already demonstrated that recruitment of the IL-6R complex to lipid rafts and CD45 activates Lyn by inducing a Lyn membrane confirmation change [XREF_BIBR].	10	18	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lyn	Lyn	Lyn	15	16	17	18
These results are consistent with our hypothesis that CD148 predominantly regulates an inhibitory pathway through Lyn that can lead to SHP-1 phosphorylation and activation ( presumably via phosphorylation and recruitment to an ITIM containing receptor ) , while CD45 with less preference , targets Lyn , Hck and Fgr , thereby positively regulating chemoattractant signaling ( XREF_SUPPLEMENTARY ) .	These results are consistent with our hypothesis that CD148 predominantly regulates an inhibitory pathway through Lyn that can lead to SHP-1 phosphorylation and activation (presumably via phosphorylation and recruitment to an ITIM containing receptor), while CD45 with less preference, targets Lyn, Hck and Fgr, thereby positively regulating chemoattractant signaling (XREF_SUPPLEMENTARY).	38	52	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lyn	Lyn	Lyn	38	39	44	45
Moreover , our results suggest that CD45 and CD148 preferentially target different SFK members Hck and Fgr vs Lyn , respectively , to positively and negatively regulate GPCR pathways .	Moreover, our results suggest that CD45 and CD148 preferentially target different SFK members Hck and Fgr vs Lyn, respectively, to positively and negatively regulate GPCR pathways.	6	20	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lyn	Lyn	Lyn	6	7	18	19
The noted increase in the translocation of CD45 to lipid raft signalling domains is likely to be relevant to reduced Lyn expression since CD45 promotes Lyn activation , ultimately its degradation in the proteasome [ XREF_BIBR ] .	The noted increase in the translocation of CD45 to lipid raft signalling domains is likely to be relevant to reduced Lyn expression since CD45 promotes Lyn activation, ultimately its degradation in the proteasome [XREF_BIBR].	23	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CD45	CD45	CD45	Lyn	Lyn	Lyn	23	24	25	26
Here , we found that PtkA mediated phosphorylation of PtPA on Tyr 128 and Tyr 129 enhances the PtPA phosphatase activity .	Here, we found that PtkA mediated phosphorylation of PtPA on Tyr 128 and Tyr 129 enhances the PtPA phosphatase activity.	5	20	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PtPA	PtkA mediated phosphorylation of PtPA on Tyr 128 and Tyr 129	ptpa	PtPA	PtPA	ptpa	9	10	18	19
PtkA , encoded within the same operon as ptpA , phosphorylates PtpA 19 , thereby enhancing PtpA phosphatase activity 23 .	PtkA, encoded within the same operon as ptpA, phosphorylates PtpA 19, thereby enhancing PtpA phosphatase activity 23.	0	18	enhancing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PtpA	PtkA, encoded within the same operon as ptpA, phosphorylates PtpA	ptpa	PtpA	PtpA	ptpa	11	12	16	17
Furthermore , binding of Mtb PtpA to ubiquitin via a ubiquitin interacting motif like region activates PtpA to dephosphorylate JNK , p38 , and VPS33B , leading to suppression of innate immunity .	Furthermore, binding of Mtb PtpA to ubiquitin via a ubiquitin interacting motif like region activates PtpA to dephosphorylate JNK, p38, and VPS33B, leading to suppression of innate immunity.	2	17	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PtpA	binding of Mtb PtpA	ptpa	PtpA	PtpA	ptpa	5	6	16	17
These results match the phenotype of the DeltaptpA deletion mutant XREF_BIBR , XREF_BIBR suggesting that PtkA inhibition of phagosomal acidification may be mediated via PtpA function , either through PtkA phosphorylation of PtpA , which enhances PtpA phosphatase activity 23 , and/or via PtkA dependent PtpA secretion .	These results match the phenotype of the DeltaptpA deletion mutant XREF_BIBR, XREF_BIBR suggesting that PtkA inhibition of phagosomal acidification may be mediated via PtpA function, either through PtkA phosphorylation of PtpA, which enhances PtpA phosphatase activity 23, and/or via PtkA dependent PtpA secretion.	29	38	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PtpA	PtkA phosphorylation of PtpA	ptpa	PtpA	PtpA	ptpa	32	33	36	37
While our results overruled a direct interaction between STAT3 and PTPN6 , PTPN6 may potentially regulate STAT3 activity by interacting with upstream JAK kinases such as JAK1 , JAK2 and JAK3 .	While our results overruled a direct interaction between STAT3 and PTPN6, PTPN6 may potentially regulate STAT3 activity by interacting with upstream JAK kinases such as JAK1, JAK2 and JAK3.	12	17	potentially regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN6	PTPN6	PTPN6	STAT3	STAT3	STAT3	12	13	16	17
Taken together these results indicate that via disrupting phosphatase activity of PTPN6 , genetic mutations in PTPN6 potentiate oncogenic effects of STAT3 .	Taken together these results indicate that via disrupting phosphatase activity of PTPN6, genetic mutations in PTPN6 potentiate oncogenic effects of STAT3.	14	22	potentiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPN6	PTPN6	PTPN6	STAT3	STAT3	STAT3	16	17	21	22
To test the hypothesis that the transmembrane PTPase LAR can modulate insulin receptor signaling in vivo , antisense RNA expression was used to specifically suppress LAR protein levels by 63 % in the rat hepatoma cell line , McA-RH7777 .	To test the hypothesis that the transmembrane PTPase LAR can modulate insulin receptor signaling in vivo, antisense RNA expression was used to specifically suppress LAR protein levels by 63% in the rat hepatoma cell line, McA-RH7777.	5	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LAR	LAR	LAR	insulin receptor	insulin receptor	insulin receptor	8	9	11	13
Given that PTPRD inactivation may increase STAT3 activity , the use of STAT3 inhibitors may have relevance in the treatment of osteosarcomas with PTPRD mutations [ XREF_BIBR ] .	Given that PTPRD inactivation may increase STAT3 activity, the use of STAT3 inhibitors may have relevance in the treatment of osteosarcomas with PTPRD mutations [XREF_BIBR].	2	7	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	PTPRD	PTPRD	PTPRD	STAT3	STAT3	STAT3	2	3	6	7
Consistently , E2F1 downregulation observed in our study indicates that the Raf/MEK/ERK pathway can inhibit E2F1 activity via a mechanism in addition to Rb mediated E2F1 sequestration .	Consistently, E2F1 downregulation observed in our study indicates that the Raf/MEK/ERK pathway can inhibit E2F1 activity via a mechanism in addition to Rb mediated E2F1 sequestration.	14	26	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	23	24	25	26
Interestingly , we found that PLD1 inactivation reduced the expression of RB1 as analyzed by a microarray ; thus , down-regulation of RB1 by targeting PLD1 may release active E2F1 and induce E2F1 trans-activation .	Interestingly, we found that PLD1 inactivation reduced the expression of RB1 as analyzed by a microarray; thus, down-regulation of RB1 by targeting PLD1 may release active E2F1 and induce E2F1 trans-activation.	20	33	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RB1	RB1	RB1	E2F1	E2F1	E2F1	22	23	32	33
Current dogma suggests that phosphorylation of pRB during mid- to late-G1 leads to release of E2F-1 and E2F-1 dependent transcriptional activation of essential S-phase genes .	Current dogma suggests that phosphorylation of pRB during mid- to late-G1 leads to release of E2F-1 and E2F-1 dependent transcriptional activation of essential S-phase genes.	4	17	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRB	phosphorylation of pRB	prb	E2F-1	E2F-1	e2f-1	6	7	15	16
Hyposphorylated pRb represses E2F-1 action in early G1 phase , while in late G1 , pRb hyperphosphorylation leads to E2F-1 release and activation .	Hyposphorylated pRb represses E2F-1 action in early G1 phase, while in late G1, pRb hyperphosphorylation leads to E2F-1 release and activation.	15	20	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	pRb	pRb hyperphosphorylation	prb	E2F-1	E2F-1	e2f-1	15	16	19	20
TLR3 promoter analysis showed that Rb modulates the transcription factor E2F1 , which directly binds to the proximal promoter of TLR3 .	TLR3 promoter analysis showed that Rb modulates the transcription factor E2F1, which directly binds to the proximal promoter of TLR3.	5	11	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb	Rb	transcription factor E2F1	transcription factor E2F1	transcription factor E2F1	5	6	8	11
Phosphorylation of Rb achieved by CDK4-6 , cyclin D and CDK2-cyclin E allows the release of the transcription factor E2F1 , leading to G1-S transition .	Phosphorylation of Rb achieved by CDK4-6, cyclin D and CDK2-cyclin E allows the release of the transcription factor E2F1, leading to G1-S transition.	0	20	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Phosphorylation of Rb	rb	transcription factor E2F1	transcription factor E2F1	transcription factor e2f1	2	3	17	20
Moreover , it was experimentally shown in breast cancer cells that Rb indirectly suppresses H19 expression by repressing E2F1 [ XREF_BIBR ] , while in colorectal cancer cells [ XREF_BIBR ] and in hepatocellular carcinoma cells [ XREF_BIBR ] , H19 derived miR-675 negatively regulates Rb expression .	Moreover, it was experimentally shown in breast cancer cells that Rb indirectly suppresses H19 expression by repressing E2F1 [XREF_BIBR], while in colorectal cancer cells [XREF_BIBR] and in hepatocellular carcinoma cells [XREF_BIBR], H19 derived miR-675 negatively regulates Rb expression.	11	20	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	11	12	18	19
Thus , downregulation of cyclin D1 reduces Rb phosphorylation , inhibits E2F1 release , and ultimately hampers the entry of cells into S phase .	Thus, downregulation of cyclin D1 reduces Rb phosphorylation, inhibits E2F1 release, and ultimately hampers the entry of cells into S phase.	4	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	cyclin D1 reduces Rb phosphorylation	rb	E2F1	E2F1	e2f1	7	8	11	12
Phosphorylation of Rb leads to release of E2F-1 , which in turn facilitates the transcription of genes necessary for entry into the S phase of the cell cycle .	Phosphorylation of Rb leads to release of E2F-1, which in turn facilitates the transcription of genes necessary for entry into the S phase of the cell cycle.	0	15	leads	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Rb	Phosphorylation of Rb	rb	E2F-1	E2F-1, which in turn facilitates the transcription	e2f-1	2	3	7	8
To establish the anti-proliferative properties of P276-00 via G1 arrest , we have investigated the status of CCND1 and pRB mediated E2F1 signaling components in FaDu cells treated with or without P276-00 .	To establish the anti-proliferative properties of P276-00 via G1 arrest, we have investigated the status of CCND1 and pRB mediated E2F1 signaling components in FaDu cells treated with or without P276-00.	15	23	mediated	Positive_early_activation	Negative_activation	Positive_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	19	20	21	22
It is known that the hypo phosphorylated form of pRb binds to E2F1 , thus preventing its nuclear translocation and activation of target genes XREF_BIBR , while hyper-phosphorylation of pRb stimulates the release of transcriptionally active E2F1 .	It is known that the hypo phosphorylated form of pRb binds to E2F1, thus preventing its nuclear translocation and activation of target genes XREF_BIBR, while hyper-phosphorylation of pRb stimulates the release of transcriptionally active E2F1.	27	37	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRb	hyper-phosphorylation of pRb	prb	E2F1	E2F1	e2f1	29	30	36	37
Upon phosphorylation by Cdks , pRb releases E2f1 allowing E2f1 to activate its target genes to initiate proliferation [ XREF_BIBR ] and [ XREF_BIBR ] .	Upon phosphorylation by Cdks, pRb releases E2f1 allowing E2f1 to activate its target genes to initiate proliferation [XREF_BIBR] and [XREF_BIBR].	5	11	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRb	pRb	pRb	E2f1	E2f1	E2f1	5	6	9	10
This model is supported by three central observations : pRB is induced to bind both E2F1 and the histone acetylase P/CAF in DNA damaged cells ; ChIP-reChIP assays show unequivocally that pRB is bound to the promoters of pro apoptotic genes that are transcriptionally active ; and knockdown and genetic ablation experiments confirm that pRB-loss typically reduced the apoptotic response to DNA damage by 34-50 % .	This model is supported by three central observations : pRB is induced to bind both E2F1 and the histone acetylase P/CAF in DNA damaged cells; ChIP-reChIP assays show unequivocally that pRB is bound to the promoters of pro apoptotic genes that are transcriptionally active; and knockdown and genetic ablation experiments confirm that pRB-loss typically reduced the apoptotic response to DNA damage by 34-50%.	9	20	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	9	10	15	16
The tumor suppressor , retinoblastoma protein ( Rb ) negatively regulates transcriptional activity of E2F-1 by masking its transactivation domain .	The tumor suppressor, retinoblastoma protein (Rb) negatively regulates transcriptional activity of E2F-1 by masking its transactivation domain.	4	15	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	E2F-1	E2F-1	E2F-1	4	6	14	15
As TGFbeta maintains pRb in a hypophosphorylated form , causing E2F1 to remain bound to pRb and suppressing activation of E2F1 responsive cell-cycle regulatory genes , 38 it is likely that the TGFbeta effect on E2F1 protein levels is mediated through induction of pRb-E2F1 association , revealing a new level of E2F1 regulation .	As TGFbeta maintains pRb in a hypophosphorylated form, causing E2F1 to remain bound to pRb and suppressing activation of E2F1 responsive cell-cycle regulatory genes, 38 it is likely that the TGFbeta effect on E2F1 protein levels is mediated through induction of pRb-E2F1 association, revealing a new level of E2F1 regulation.	15	21	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	15	16	20	21
Whether pRb uses these mechanisms to activate apoptotic target genes of E2F1 to suppress tumorigenesis requires further study .	Whether pRb uses these mechanisms to activate apoptotic target genes of E2F1 to suppress tumorigenesis requires further study.	1	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRb	pRb	pRb	E2F1	E2F1	E2F1	1	2	11	12
Cleavages of pRb by caspase 3 and 7 were previously reported to trigger apoptosis but were thought to promote E2F-1 transcriptional activity by inducing the release of E2F-1 from pRb .	Cleavages of pRb by caspase 3 and 7 were previously reported to trigger apoptosis but were thought to promote E2F-1 transcriptional activity by inducing the release of E2F-1 from pRb.	0	21	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRb	pRb	pRb	E2F-1	E2F-1	E2F-1	2	3	19	20
Retinoblastoma protein ( Rb ) blocks cell cycle progression by inhibiting E2F1 and blocking subsequent transcriptional activation of genes important for entry into S phase .	Retinoblastoma protein (Rb) blocks cell cycle progression by inhibiting E2F1 and blocking subsequent transcriptional activation of genes important for entry into S phase.	1	12	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	3	4	11	12
Studies of the retinoblastoma protein RB1 further support a major role of E2F1 in metabolism XREF_BIBR .	Studies of the retinoblastoma protein RB1 further support a major role of E2F1 in metabolism XREF_BIBR.	3	15	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	retinoblastoma protein	retinoblastoma protein	retinoblastoma protein	E2F1	E2F1	E2F1	3	5	12	13
P276-00 targeted CCND1 and pRB mediated E2F1 pathway causing G1 arrest in FaDu cells .	P276-00 targeted CCND1 and pRB mediated E2F1 pathway causing G1 arrest in FaDu cells.	2	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	4	5	6	7
Inactivation of Rb can initiate E2F1 mediated transactivation of pro apoptotic genes , resulting in p53 independent apoptosis ( Nahle etal ., 2002 ; Polager & Ginsberg , 2008 ) .	Inactivation of Rb can initiate E2F1 mediated transactivation of pro apoptotic genes, resulting in p53 independent apoptosis (Nahle etal., 2002; Polager & Ginsberg, 2008).	0	7	initiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	2	3	5	6
22 During MCE , Rb phosphorylation causes it to release E2F-1 , allowing upregulation of their target genes that drive the adipogenic program to the completion .	22 During MCE, Rb phosphorylation causes it to release E2F-1, allowing upregulation of their target genes that drive the adipogenic program to the completion.	4	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb phosphorylation	rb	E2F-1	E2F-1	e2f-1	4	5	10	11
GCIP , a newly identified cyclin D interacting protein , was found to reduce the phosphorylation of retinoblastoma protein and inhibit E2F1 mediated transcriptional activity .	GCIP, a newly identified cyclin D interacting protein, was found to reduce the phosphorylation of retinoblastoma protein and inhibit E2F1 mediated transcriptional activity.	0	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	retinoblastoma protein	GCIP, a newly identified cyclin D interacting protein, was found to reduce the phosphorylation of retinoblastoma protein	retinoblastoma protein	E2F1	E2F1	e2f1	17	19	21	22
RB also increases E2F1 stability by inhibiting its proteasome mediated degradation , but the consequences of this post-translational regulation of E2F1 remain unknown .	RB also increases E2F1 stability by inhibiting its proteasome mediated degradation, but the consequences of this post-translational regulation of E2F1 remain unknown.	0	4	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RB	RB	RB	E2F1	E2F1	E2F1	0	1	3	4
Together , these data indicated that E2F1 suppresses TLR3 transcription , but during immune stimulation , Rb is upregulated to block the inhibitory effect of E2F1 on TLR3 , highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells .	Together, these data indicated that E2F1 suppresses TLR3 transcription, but during immune stimulation, Rb is upregulated to block the inhibitory effect of E2F1 on TLR3, highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells.	16	26	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	16	17	25	26
We identified suppressors of an mat3 null allele that had recessive mutations in DP1 or dominant mutations in E2F1 , loci encoding homologs of a heterodimeric transcription factor that is targeted by RB related proteins .	We identified suppressors of an mat3 null allele that had recessive mutations in DP1 or dominant mutations in E2F1, loci encoding homologs of a heterodimeric transcription factor that is targeted by RB related proteins.	9	34	targeted	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	RB	RB	RB	E2F1	E2F1	E2F1	32	33	18	19
Because E2F1 is activated by Rb1 deficiency , we depleted E2f1 in Rb1 KO GS cells to examine whether E2f1 is required for DNA DSBs .	Because E2F1 is activated by Rb1 deficiency, we depleted E2f1 in Rb1 KO GS cells to examine whether E2f1 is required for DNA DSBs.	1	6	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Rb1	Rb1	Rb1	E2F1	E2F1	E2F1	5	6	1	2
Hyperphosphorylation of pRb prior to S phase leads to dissociation of the pRb-E2F1 repressive complex allowing E2F1 to transactivate target genes involved in DNA replication such as DNA polymerase-alpha , dihydrofloate reductase , and proliferating cell nuclear antigen .	Hyperphosphorylation of pRb prior to S phase leads to dissociation of the pRb-E2F1 repressive complex allowing E2F1 to transactivate target genes involved in DNA replication such as DNA polymerase-alpha, dihydrofloate reductase, and proliferating cell nuclear antigen.	0	18	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRb	Hyperphosphorylation of pRb	prb	E2F1	E2F1	e2f1	2	3	16	17
In previous reports , CDK4 was observed to be a nuclear expressed protein that forms a complex with CCND1 , CDK6 , and p21 , and modulates the expression of pRB activating transcription factor E2F1 [ XREF_BIBR ] .	In previous reports, CDK4 was observed to be a nuclear expressed protein that forms a complex with CCND1, CDK6, and p21, and modulates the expression of pRB activating transcription factor E2F1 [XREF_BIBR].	28	35	activating	Positive_activation_token_1_verb	Negative_activation	Positive_activation	pRB	expression of pRB	prb	transcription factor E2F1	transcription factor E2F1	transcription factor e2f1	30	31	32	35
Furthermore , inactivation of Rb , the repressor of E2F dependent transcription , markedly induces PDK4 and triggers the enrichment of E2F1 occupancy onto the PDK4 promoter as detected by chromatin immunoprecipitation analysis .	Furthermore, inactivation of Rb, the repressor of E2F dependent transcription, markedly induces PDK4 and triggers the enrichment of E2F1 occupancy onto the PDK4 promoter as detected by chromatin immunoprecipitation analysis.	2	22	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	4	5	21	22
When it is time for a cell to enter S phase , complexes of cyclin dependent kinase and cyclins phosphorylate RB to p-RB , allowing E2F1 to dissociate from RB and become active 51 .	When it is time for a cell to enter S phase, complexes of cyclin dependent kinase and cyclins phosphorylate RB to p-RB, allowing E2F1 to dissociate from RB and become active 51.	19	27	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RB	phosphorylate RB	rb	E2F1	E2F1	e2f1	20	21	25	26
The retinoblastoma ( Rb ) pathway , which governs cell cycle progression , is frequently genetically altered in cancer , causing deregulated expression of the E2F-1 transcription factor , which promotes DNA synthesis and cell cycle progression .	The retinoblastoma (Rb) pathway, which governs cell cycle progression, is frequently genetically altered in cancer, causing deregulated expression of the E2F-1 transcription factor, which promotes DNA synthesis and cell cycle progression.	3	27	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb	Rb	E2F-1	E2F-1	E2F-1	3	4	25	26
Depletion of p28GANK inhibited HCC cell growth and tumorigenesis , enhanced dephosphorylation of RB1 , and decreased transcription activity of E2F-1 in HuH-7 cells .	Depletion of p28GANK inhibited HCC cell growth and tumorigenesis, enhanced dephosphorylation of RB1, and decreased transcription activity of E2F-1 in HuH-7 cells.	2	21	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	RB1	p28GANK inhibited HCC cell growth and tumorigenesis, enhanced dephosphorylation of RB1	rb1	E2F-1	E2F-1	e2f-1	13	14	20	21
This leads to Rb phosphorylation , which in turn enables the transcription factor E2F1 to drive cell cycle forward , as well as to further induce EZH2 expression , hence establishing a positive feedback loop that enables clonal expansion and thus immunoglobulin affinity maturation during the humoral immune response .	This leads to Rb phosphorylation, which in turn enables the transcription factor E2F1 to drive cell cycle forward, as well as to further induce EZH2 expression, hence establishing a positive feedback loop that enables clonal expansion and thus immunoglobulin affinity maturation during the humoral immune response.	3	14	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb phosphorylation	rb	transcription factor E2F1	transcription factor E2F1	transcription factor e2f1	3	4	11	14
Therefore , although Rb1 KO GS cells contained a normal chromosome number ( XREF_FIG ) , Rb1 deficiency may induce DNA DSBs by activating E2F1 .	Therefore, although Rb1 KO GS cells contained a normal chromosome number (XREF_FIG), Rb1 deficiency may induce DNA DSBs by activating E2F1.	16	25	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb1	Rb1	Rb1	E2F1	E2F1	E2F1	16	17	24	25
HBx has been shown to activate the pRb-E2F1 signaling pathway by inducing pRb phosphorylation XREF_BIBR , XREF_BIBR and enhance E2F1 transcriptional activity by interacting to E2F1 XREF_BIBR .	HBx has been shown to activate the pRb-E2F1 signaling pathway by inducing pRb phosphorylation XREF_BIBR, XREF_BIBR and enhance E2F1 transcriptional activity by interacting to E2F1 XREF_BIBR.	0	21	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRb	HBx has been shown to activate the pRb-E2F1 signaling pathway by inducing pRb phosphorylation	prb	E2F1	E2F1	e2f1	12	13	19	20
Restoration of Rb function led to the association of Rb/E2F1 repressor complexes with ICOVIR-5 ectopic E2F1 promoter and subsequent down-modulation of E1A , dramatically impairing adenoviral replication .	Restoration of Rb function led to the association of Rb/E2F1 repressor complexes with ICOVIR-5 ectopic E2F1 promoter and subsequent down-modulation of E1A, dramatically impairing adenoviral replication.	2	16	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	2	3	15	16
Cell cycle progression through the G1-S phase checkpoint is driven by phosphorylation of the retinoblastoma protein ( Rb ) by CDK4/6 , allowing release of the key transcription factor E2F1 .	Cell cycle progression through the G1-S phase checkpoint is driven by phosphorylation of the retinoblastoma protein (Rb) by CDK4/6, allowing release of the key transcription factor E2F1.	11	30	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	retinoblastoma protein	phosphorylation of the retinoblastoma protein	retinoblastoma protein	transcription factor E2F1	transcription factor E2F1	transcription factor e2f1	14	16	27	30
We first established that IGF-I increases expression of cyclin A , causes hyperphosphorylation of RB , and augments the mass of E2F-1 in a time dependent manner .	We first established that IGF-I increases expression of cyclin A, causes hyperphosphorylation of RB, and augments the mass of E2F-1 in a time dependent manner.	4	22	augments	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RB	IGF-I increases expression of cyclin A, causes hyperphosphorylation of RB	rb	E2F-1	E2F-1	e2f-1	14	15	21	22
For example , within the G1 phase , Cdk mediated phosphorylation of Rb leads to E2F-1 transcription factor activation and upregulation of the genes required for the transition into S phase .	For example, within the G1 phase, Cdk mediated phosphorylation of Rb leads to E2F-1 transcription factor activation and upregulation of the genes required for the transition into S phase.	8	18	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Rb	Cdk mediated phosphorylation of Rb	rb	E2F-1	E2F-1	e2f-1	12	13	15	16
CyclinD1 binds to CDK4 and CDK6 ( cyclin dependent kinase 4/6 ) to phosphorylate retinoblastoma protein and activate the transcription factor E2F-1 .	CyclinD1 binds to CDK4 and CDK6 (cyclin dependent kinase 4/6) to phosphorylate retinoblastoma protein and activate the transcription factor E2F-1.	0	22	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	retinoblastoma protein	CyclinD1 binds to CDK4 and CDK6 (cyclin dependent kinase 4/6) to phosphorylate retinoblastoma protein	retinoblastoma protein	E2F-1	E2F-1	e2f-1	14	16	21	22
Hyperphosphrylation of the pRB protein would increase the activity of the transcription factor E2F1 which in turn , would bind the promoter of p14 ARF and induce an increase in its levels .	Hyperphosphrylation of the pRB protein would increase the activity of the transcription factor E2F1 which in turn, would bind the promoter of p14 ARF and induce an increase in its levels.	3	25	increase	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	pRB	pRB	prb	transcription factor E2F1	transcription factor E2F1 which in turn, would bind the promoter of p14 ARF	transcription factor e2f1	3	4	11	14
These exosomes could shuttle and relocate miR-429 into their surrounded target cells , targeting Rb binding protein 4 ( RBBP4 ) expression and further promoting the transcriptional activity of E2F1 , finally upregulating the expression of POU class 5 homeobox 1 ( POU5F1 ) [ XREF_BIBR ] in recipient cells .	These exosomes could shuttle and relocate miR-429 into their surrounded target cells, targeting Rb binding protein 4 (RBBP4) expression and further promoting the transcriptional activity of E2F1, finally upregulating the expression of POU class 5 homeobox 1 (POU5F1) [XREF_BIBR] in recipient cells.	14	30	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb binding protein 4 (RBBP4) expression	rb	E2F1	E2F1	e2f1	14	15	29	30
These results suggested that activation of E2F1 by Rb1 deficiency causes DNA DSBs and apoptosis , thereby reducing SSC activity .	These results suggested that activation of E2F1 by Rb1 deficiency causes DNA DSBs and apoptosis, thereby reducing SSC activity.	4	9	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Rb1	Rb1	Rb1	E2F1	E2F1	E2F1	8	9	6	7
Bortezomib stabilizes CDK inhibitors p21 and p27 leading to hypophosphorylation of RB , which in turn prevents E2F1 from binding to its target genes including the E2F1 promoter , thereby repressing E2F1 transcription .	Bortezomib stabilizes CDK inhibitors p21 and p27 leading to hypophosphorylation of RB, which in turn prevents E2F1 from binding to its target genes including the E2F1 promoter, thereby repressing E2F1 transcription.	9	18	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	hypophosphorylation of RB	rb	E2F1	E2F1	e2f1	11	12	17	18
The GM-CSF induced increase in the levels of cyclin D1 and the subsequent phosphorylation of the retinoblastoma ( Rb ) protein activated E2F-1 , resulting in the upregulation of the transcription of cyclin E. Furthermore , the induction of cyclin D1 expression and cell cycle progression by GM-CSF was mediated by the PI3K and Akt , JNK and ERK signaling pathways through the phosphorylation of GSK3beta or the activation of AP-1 transcription factors .	The GM-CSF induced increase in the levels of cyclin D1 and the subsequent phosphorylation of the retinoblastoma (Rb) protein activated E2F-1, resulting in the upregulation of the transcription of cyclin E. Furthermore, the induction of cyclin D1 expression and cell cycle progression by GM-CSF was mediated by the PI3K and Akt, JNK and ERK signaling pathways through the phosphorylation of GSK3beta or the activation of AP-1 transcription factors.	13	23	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	phosphorylation of the retinoblastoma (Rb	rb	E2F-1	E2F-1	e2f-1	18	19	22	23
Attempts were made to understand how RRD-251 or the ISNGFGFK peptide reversed the transcriptional repression of E2F1 mediated by the Rb protein .	Attempts were made to understand how RRD-251 or the ISNGFGFK peptide reversed the transcriptional repression of E2F1 mediated by the Rb protein.	14	21	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	20	21	16	17
Interestingly , loss of the tumor suppressor Rb1 , which inhibits the E2F1 transcription factor , is associated with aneuploidy .	Interestingly, loss of the tumor suppressor Rb1, which inhibits the E2F1 transcription factor, is associated with aneuploidy.	2	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb1	loss of the tumor suppressor Rb1	rb1	E2F1	E2F1	e2f1	7	8	12	13
Not surprisingly , overexpression or gain-of-function mutations of CDK4/6 can also result in E2F1 pathway activation since enhanced CDK phosphorylation of pRB promotes release of E2F1 .	Not surprisingly, overexpression or gain-of-function mutations of CDK4/6 can also result in E2F1 pathway activation since enhanced CDK phosphorylation of pRB promotes release of E2F1.	18	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRB	CDK phosphorylation of pRB	prb	E2F1	E2F1	e2f1	21	22	25	26
Notably , Rb depletion induced the cell cycle related genes CCNE1 , SKP2 , E2F1 , RBL1 , CCNB1 , and CDK1 in cone precursors and induced p53 responsive genes in sorted RPCs and glia ( XREF_FIG ) .	Notably, Rb depletion induced the cell cycle related genes CCNE1, SKP2, E2F1, RBL1, CCNB1, and CDK1 in cone precursors and induced p53 responsive genes in sorted RPCs and glia (XREF_FIG).	2	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Rb	Rb	E2F1	E2F1	E2F1	2	3	14	15
Cdk4/6 phosphorylates Rb protein , inducing the release of the transcription factor E2F1 , which in turn induces the synthesis of the proteins necessary for DNA replication .	Cdk4/6 phosphorylates Rb protein, inducing the release of the transcription factor E2F1, which in turn induces the synthesis of the proteins necessary for DNA replication.	0	13	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Cdk4/6 phosphorylates Rb	rb	transcription factor E2F1	transcription factor E2F1	transcription factor e2f1	2	3	10	13
Therefore , the authors speculate that maintenance of Rb expression would be required to prevent E2F1 inhibition of beta-catenin function .	Therefore, the authors speculate that maintenance of Rb expression would be required to prevent E2F1 inhibition of beta-catenin function.	8	16	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	Rb expression	rb	E2F1	E2F1	e2f1	8	9	15	16
Further studies revealed that , upon syncytialization , human chorionic gonadotropin reduced the phosphorylation of retinoblastoma protein ( pRB ) via activation of the cAMP and PKA pathway , which sequesters E2F transcription factor 1 ( E2F1 ) , the transcription factor for EZH2 expression .	Further studies revealed that, upon syncytialization, human chorionic gonadotropin reduced the phosphorylation of retinoblastoma protein (pRB) via activation of the cAMP and PKA pathway, which sequesters E2F transcription factor 1 (E2F1), the transcription factor for EZH2 expression.	9	41	sequesters	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pRB	chorionic gonadotropin reduced the phosphorylation of retinoblastoma protein (pRB	prb	E2F1	E2F1	e2f1	18	19	36	37
Hyperphosphorylation of retinoblastoma protein ( pRb ) , a pocket protein , leads to release of E2F1 , resulting in transition from G1 to S phase .	Hyperphosphorylation of retinoblastoma protein (pRb), a pocket protein, leads to release of E2F1, resulting in transition from G1 to S phase.	0	17	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	retinoblastoma protein	Hyperphosphorylation of retinoblastoma protein	retinoblastoma protein	E2F1	E2F1	e2f1	2	4	16	17
HMGA2 instead has been reported to associate with the transcriptional repressor p120 E4F and to activate the cyclin A gene and more recently to interact with pRB inducing E2F1 activity playing a crucial role in pituitary tumorigenesis .	HMGA2 instead has been reported to associate with the transcriptional repressor p120 E4F and to activate the cyclin A gene and more recently to interact with pRB inducing E2F1 activity playing a crucial role in pituitary tumorigenesis.	24	29	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	26	27	28	29
On the contrary , P16 inhibits phosphorylation of RB protein and attenuates E2F1 activity .	On the contrary, P16 inhibits phosphorylation of RB protein and attenuates E2F1 activity.	4	13	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	P16 inhibits phosphorylation of RB	rb	E2F1	E2F1	e2f1	8	9	12	13
We observed down-modulation of cell-cycle promoting and up-regulation of cell-cycle inhibitory genes ; enhanced interaction of retinoblastoma protein ( RB ) with E2F-1 transcription factor ; inhibition of phosphorylation of RB , resulting in sequestration of E2F-1 and subsequent down-regulation of S phase genes ; decreased interaction of E2F-1 with its consensus binding sites ; inhibition of cell motility and invasiveness ; and inhibition of the AKT pathway .	We observed down-modulation of cell-cycle promoting and up-regulation of cell-cycle inhibitory genes; enhanced interaction of retinoblastoma protein (RB) with E2F-1 transcription factor; inhibition of phosphorylation of RB, resulting in sequestration of E2F-1 and subsequent down-regulation of S phase genes; decreased interaction of E2F-1 with its consensus binding sites; inhibition of cell motility and invasiveness; and inhibition of the AKT pathway.	28	63	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	RB	phosphorylation of RB	rb	E2F-1	E2F-1	e2f-1	30	31	48	49
Nutlin-3 increased the phosphorylation of retinoblastoma protein causing E2F1 release leading to induction of Siva-1 .	Nutlin-3 increased the phosphorylation of retinoblastoma protein causing E2F1 release leading to induction of Siva-1.	0	9	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	retinoblastoma protein	Nutlin-3 increased the phosphorylation of retinoblastoma protein	retinoblastoma protein	E2F1	E2F1	e2f1	5	7	8	9
Loss of Rb inhibits the formation of Rb , E2F1-P , and CAF complex , which results in a decrease of proapoptotic genes TAp73 and Caspase7 , and leads to the radioresistance .	Loss of Rb inhibits the formation of Rb, E2F1-P, and CAF complex, which results in a decrease of proapoptotic genes TAp73 and Caspase7, and leads to the radioresistance.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rb	Loss of Rb	rb	E2F1-P	E2F1-P	e2f1-p	2	3	9	10
The up-regulation of these two proteins and the release of p130 and pRB from E2F4 complexes allows formation of E2F1 complexes not only with pRB but also with p130 and p107 as well as the formation of p107-E2F4 complexes .	The up-regulation of these two proteins and the release of p130 and pRB from E2F4 complexes allows formation of E2F1 complexes not only with pRB but also with p130 and p107 as well as the formation of p107-E2F4 complexes.	8	20	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pRB	pRB	pRB	E2F1	E2F1	E2F1	12	13	19	20
Overexpression of the human retinoblastoma suppressor gene product RB suppressed E2F-1 mediated transcriptional activation , indicating an E2F dependent regulation of promoter activity during the G1-to-S-phase transition .	Overexpression of the human retinoblastoma suppressor gene product RB suppressed E2F-1 mediated transcriptional activation, indicating an E2F dependent regulation of promoter activity during the G1-to-S-phase transition.	0	11	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RB	Overexpression of the human retinoblastoma suppressor gene product RB	rb	E2F-1	E2F-1	e2f-1	8	9	10	11
As a consequence of this inhibition , presence of p120-GAP enhanced the regeneration of Ha-Ras .	As a consequence of this inhibition, presence of p120-GAP enhanced the regeneration of Ha-Ras.	7	15	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p120-GAP	p120-GAP	p120-GAP	Ha-Ras	Ha-Ras	Ha-Ras	9	10	14	15
p120GAP stimulates the GTPase activity of p21ras and hence acts as a negative regulator of ras proteins .	p120GAP stimulates the GTPase activity of p21ras and hence acts as a negative regulator of ras proteins.	0	9	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p120GAP	p120GAP	p120GAP	p21ras	p21ras	p21ras	0	1	6	7
CRAF phosphorylation on Serine 338 ( due to P21 activated kinases ) promotes CRAF association with and inactivation of the pro apoptotic kinases ASK1 and MST2 .	CRAF phosphorylation on Serine 338 (due to P21 activated kinases) promotes CRAF association with and inactivation of the pro apoptotic kinases ASK1 and MST2.	0	26	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CRAF	CRAF phosphorylation on Serine 338	craf	MST2	MST2	mst2	0	1	25	26
Intriguingly , this regulation is independently of Raf-1 protein kinase activity because kinase negative Raf-1 also could inhibit MST2 activation and apoptosis XREF_BIBR .	Intriguingly, this regulation is independently of Raf-1 protein kinase activity because kinase negative Raf-1 also could inhibit MST2 activation and apoptosis XREF_BIBR.	12	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Raf-1	Raf-1	Raf-1	MST2	MST2	MST2	14	15	18	19
In another study , reconstitution of Raf1 in Raf1 -/- cells caused Mst2 homodimers to disassemble .	In another study, reconstitution of Raf1 in Raf1 -/- cells caused Mst2 homodimers to disassemble.	4	13	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Raf1	Raf1	Raf1	Mst2	Mst2	Mst2	6	7	12	13
In cultured mammalian cells , Raf-1 has been shown to promote cell survival by antagonizing ASK1 [ XREF_BIBR ] , a JNK activator [ XREF_BIBR ] .	In cultured mammalian cells, Raf-1 has been shown to promote cell survival by antagonizing ASK1 [XREF_BIBR], a JNK activator [XREF_BIBR].	5	24	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Raf-1	Raf-1	Raf-1	ASK1	ASK1	ASK1	5	6	15	16
Alternatively , Raf kinase activity may be dispensable for maintenance of cell viability , as Raf-1 has been shown to prevent apoptosis independent of its kinase activity by binding to and inhibiting the activity of the proapoptotic kinase ASK-1 ( Chen et al , 2001 ) .	Alternatively, Raf kinase activity may be dispensable for maintenance of cell viability, as Raf-1 has been shown to prevent apoptosis independent of its kinase activity by binding to and inhibiting the activity of the proapoptotic kinase ASK-1 (Chen et al, 2001).	15	40	prevent	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Raf-1	Raf-1	Raf-1	ASK-1	ASK-1	ASK-1	15	16	38	39
Indeed , treatment of cells derived from three individual wnt1-tumors and transfected with a reporter for wnt1 pathway activation ( TCF and beta-catenin activity ) , when treated with an RARalpha antagonist , Ro415253 produced a significant ( P = 0.01 ) two-fold increase in the reporter ( luciferase ) activity ( results not shown ) .	Indeed, treatment of cells derived from three individual wnt1-tumors and transfected with a reporter for wnt1 pathway activation (TCF and beta-catenin activity), when treated with an RARalpha antagonist, Ro415253 produced a significant (P = 0.01) two-fold increase in the reporter (luciferase) activity (results not shown).	20	31	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	RARalpha	RARalpha	RARalpha	beta-catenin	beta-catenin	beta-catenin	30	31	22	23
Either X-RAR , PML and RARalpha and PLZF and RARalpha or AML-1 and ETO activate Wnt signaling by upregulating gamma-catenin and beta-catenin .	Either X-RAR, PML and RARalpha and PLZF and RARalpha or AML-1 and ETO activate Wnt signaling by upregulating gamma-catenin and beta-catenin.	1	22	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RARalpha	RARalpha	RARalpha	beta-catenin	beta-catenin	beta-catenin	5	6	21	22
Interestingly , the chimera construct harboring the N-terminal region of RASSF1A and the C-terminal region of RASSF6 activates MST2 [ XREF_BIBR ] .	Interestingly, the chimera construct harboring the N-terminal region of RASSF1A and the C-terminal region of RASSF6 activates MST2 [XREF_BIBR].	14	20	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	RASSF6	RASSF6	RASSF6	MST2	MST2	MST2	16	17	18	19
Importantly , RASSF2 , RASSF4 , and RASSF6 inhibit MST2 under the same condition , and the chimera construct harboring the N-terminal region of RASSF1A and the C-terminal region of RASSF6 activates MST2 , supporting that the activation of MST2 is specific for RASSF1A and is mediated by the N-terminal region of RASSF1A .	Importantly, RASSF2, RASSF4, and RASSF6 inhibit MST2 under the same condition, and the chimera construct harboring the N-terminal region of RASSF1A and the C-terminal region of RASSF6 activates MST2, supporting that the activation of MST2 is specific for RASSF1A and is mediated by the N-terminal region of RASSF1A.	28	33	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	RASSF6	RASSF6	RASSF6	MST2	MST2	MST2	30	31	32	33
Quantitative Smad2 export assay revealed NLS-R attenuated RanBP3 mediated Smad2 export in a dose dependent manner ( XREF_FIG ) .	Quantitative Smad2 export assay revealed NLS-R attenuated RanBP3 mediated Smad2 export in a dose dependent manner (XREF_FIG).	7	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	RanBP3	RanBP3	RanBP3	Smad2	Smad2	Smad2	7	8	9	10
ALK receptor activity in cancer can be up-regulated by amplification , overexpression , ligand binding , mutations in the intracellular domain of the receptor and by activity of the receptor tyrosine phosphatase PTPRz .	ALK receptor activity in cancer can be up-regulated by amplification, overexpression, ligand binding, mutations in the intracellular domain of the receptor and by activity of the receptor tyrosine phosphatase PTPRz.	0	33	up-regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	PTPRz	PTPRz	PTPRz	ALK	ALK	ALK	32	33	0	1
We also show that ectopic expression of Rb induces apoptosis in Abl dependent tumor cells by inhibiting the Abl tyrosine kinase activity , and that Rb induced apoptosis is compromised by Abl catalysed phosphorylation of Rb at Y805 .	We also show that ectopic expression of Rb induces apoptosis in Abl dependent tumor cells by inhibiting the Abl tyrosine kinase activity, and that Rb induced apoptosis is compromised by Abl catalysed phosphorylation of Rb at Y805.	5	14	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rb	expression of Rb	rb	Abl	Abl	abl	7	8	11	12
The authors conclude from these experiments that the top-level precursors are regulated by canonical Notch signaling mediated by RBP-J .	The authors conclude from these experiments that the top-level precursors are regulated by canonical Notch signaling mediated by RBP-J.	14	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	18	19	14	15
In some contexts , for example , marginal zone B-cell development ( Zhang etal , 2012 ) or maintenance of muscle progenitor cells ( Vasyutina etal , 2007 ) , loss of RBPJ results in the inhibition of Notch target genes and blocks the regulation of Notch driven physiological states .	In some contexts, for example, marginal zone B-cell development (Zhang etal, 2012) or maintenance of muscle progenitor cells (Vasyutina etal, 2007), loss of RBPJ results in the inhibition of Notch target genes and blocks the regulation of Notch driven physiological states.	30	47	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPJ	loss of RBPJ	rbpj	Notch	Notch	notch	32	33	46	47
Unlike the wildtype sequence , the mutant SM22 promoter was not inhibited by collagen in co-culture experiments , suggesting that collagen inhibits canonical RBP-jK mediated Notch signaling ( XREF_FIG ) .	Unlike the wildtype sequence, the mutant SM22 promoter was not inhibited by collagen in co-culture experiments, suggesting that collagen inhibits canonical RBP-jK mediated Notch signaling (XREF_FIG).	22	26	mediated	Positive_early_activation	Negative_activation	Positive_activation	RBP-jK	RBP-jK	RBP-jK	Notch	Notch	Notch	23	24	25	26
In adult mice , greater numbers of ectopic K8+ cells were created by Atoh1 induction during anagen versus telogen and following disruption of Notch signaling by conditional deletion of Rbpj in the epidermis .	In adult mice, greater numbers of ectopic K8+ cells were created by Atoh1 induction during anagen versus telogen and following disruption of Notch signaling by conditional deletion of Rbpj in the epidermis.	21	30	disruption	Negative_activation_syntax_1_noun	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	29	30	23	24
We approached this question by determining the effect of WA treatment on luciferase activities associated with RBP-Jk and downstream targets of Notch including HES-1A/B and HEY-1 .	We approached this question by determining the effect of WA treatment on luciferase activities associated with RBP-Jk and downstream targets of Notch including HES-1A/B and HEY-1.	16	25	targets	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	RBP-Jk	RBP-Jk	RBP-Jk	Notch	Notch	Notch	16	17	21	22
Canonical Notch signaling occurs through the NICD-RBPJ-MAML transcriptional activation complex , and Rbpj deletion or DNMAML1 mediated complex disruption recapitulates Notch receptor deletion in lymphocytes .	Canonical Notch signaling occurs through the NICD-RBPJ-MAML transcriptional activation complex, and Rbpj deletion or DNMAML1 mediated complex disruption recapitulates Notch receptor deletion in lymphocytes.	12	22	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	12	13	20	21
The aortic hyperbranching phenotype of S1pr1 knockout embryos was not observed in the EC specific deletion of Notch target Rbp-j .	The aortic hyperbranching phenotype of S1pr1 knockout embryos was not observed in the EC specific deletion of Notch target Rbp-j.	15	20	target	Positive_activation_token_1_noun	Negative_activation	Negative_activation	Rbp-j	Rbp-j	Rbp-j	Notch	Notch	Notch	19	20	17	18
Significant differences in the expressions of Hes1 and Hey1 mRNA were observed in the myocardium of Myh6-RBP-J fl/wt mice and RBP-J fl/fl mice , which indicates that a specific haploid knockout of the RBP-J genes in the myocardium will also block the RBP-J-mediated Notch signaling pathway .	Significant differences in the expressions of Hes1 and Hey1 mRNA were observed in the myocardium of Myh6-RBP-J fl/wt mice and RBP-J fl/fl mice, which indicates that a specific haploid knockout of the RBP-J genes in the myocardium will also block the RBP-J-mediated Notch signaling pathway.	33	45	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	33	34	43	44
Together , these findings indicate that RBP-Jkappa mediated Notch signaling is not required for cardiac specification and negatively regulates specific stages of cardiomyogenesis .	Together, these findings indicate that RBP-Jkappa mediated Notch signaling is not required for cardiac specification and negatively regulates specific stages of cardiomyogenesis.	6	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	Notch	Notch	Notch	6	7	8	9
To determine if RBP-J mediates the Notch regulation of beta-Catenin in vivo , we deleted Notch1 or RBP-J in CPCs by inter crossing Notch1 tm2Rko 8 ( Notch1 floxed allele ) or RBP-J flox and flox mice 9 with mice containing Cre recombinase in the Isl1 locus ( Isl1 Cre ) 10 .	To determine if RBP-J mediates the Notch regulation of beta-Catenin in vivo, we deleted Notch1 or RBP-J in CPCs by inter crossing Notch1 tm2Rko 8 (Notch1 floxed allele) or RBP-J flox and flox mice 9 with mice containing Cre recombinase in the Isl1 locus (Isl1 Cre) 10.	3	7	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	3	4	6	7
Deletion of Csl and Rbpjkappa in chondrocytes enhances proliferation , and reverses the effects of Notch in limb buds , demonstrating that Notch regulates chondrogenesis acting through the canonical pathway [ XREF_BIBR ; XREF_BIBR ] .	Deletion of Csl and Rbpjkappa in chondrocytes enhances proliferation, and reverses the effects of Notch in limb buds, demonstrating that Notch regulates chondrogenesis acting through the canonical pathway [XREF_BIBR; XREF_BIBR].	0	16	reverses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Rbpjkappa	Rbpjkappa	Rbpjkappa	Notch	Notch	Notch	4	5	15	16
These findings raise the possibility that Rbpj mediated Notch signaling does not directly regulate proliferation of main duct cells , but instead drives the maintenance of a distal centroacinar cell pool that contributes to more proximal ducts during postnatal organ growth .	These findings raise the possibility that Rbpj mediated Notch signaling does not directly regulate proliferation of main duct cells, but instead drives the maintenance of a distal centroacinar cell pool that contributes to more proximal ducts during postnatal organ growth.	6	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	6	7	8	9
So in practice , inhibition of Rbpj function will abrogate Notch receptor signaling XREF_BIBR .	So in practice, inhibition of Rbpj function will abrogate Notch receptor signaling XREF_BIBR.	6	13	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	6	7	10	11
When the repression of rbpj by Celf1 is abolished by the TP MO , rbpj overexpression leads to high , FGF independent Notch signalling that results in cyp26a overexpression and RA attenuation ( XREF_FIG ) .	When the repression of rbpj by Celf1 is abolished by the TP MO, rbpj overexpression leads to high, FGF independent Notch signalling that results in cyp26a overexpression and RA attenuation (XREF_FIG).	14	23	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	rbpj	rbpj overexpression	rbpj	Notch	Notch	notch	14	15	22	23
Importantly , in this report , we demonstrate that similar clonally expanded T cell populations were observed in the thymus and periphery of Ik -/- mice both in the presence ( RBPJ + Ik - ) or absence ( RBPJ - Ik - ) of RBPJ with similar kinetics , showing that RBPJ mediated Notch target gene activation is not required for the survival of the clonally expanded populations that arise during Ik -/- leukemogenesis .	Importantly, in this report, we demonstrate that similar clonally expanded T cell populations were observed in the thymus and periphery of Ik -/- mice both in the presence (RBPJ + Ik -) or absence (RBPJ - Ik -) of RBPJ with similar kinetics, showing that RBPJ mediated Notch target gene activation is not required for the survival of the clonally expanded populations that arise during Ik -/- leukemogenesis.	52	57	mediated	Positive_early_activation	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	52	53	54	55
Downstream effectors of Notch signaling such as RBP-J and Stra13 appear to play crucial roles in mediating Notch signaling in activated satellite cells .	Downstream effectors of Notch signaling such as RBP-J and Stra13 appear to play crucial roles in mediating Notch signaling in activated satellite cells.	3	9	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	7	8	3	4
In support of this model , we demonstrate that unlike lack of Ikaros , RBPJ deletion does not induce derepression of Notch target genes .	In support of this model, we demonstrate that unlike lack of Ikaros, RBPJ deletion does not induce derepression of Notch target genes.	14	23	induce	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	14	15	21	22
Although according to this traditionally accepted model , RBPjK actively represses activation of Notch targets in the absence of Notch signaling , recent work has indicated that Notch transcriptional regulation may be more complex than previously realized .	Although according to this traditionally accepted model, RBPjK actively represses activation of Notch targets in the absence of Notch signaling, recent work has indicated that Notch transcriptional regulation may be more complex than previously realized.	8	14	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPjK	RBPjK	RBPjK	Notch	Notch	Notch	8	9	13	14
When Notch signaling is completely blocked by deletion of Rbpj in ependymal cells , they do not give rise to any astrocytes but only neurons , demonstrating the pivotal role for Notch signaling in the fate of ependymal cell derived cells .	When Notch signaling is completely blocked by deletion of Rbpj in ependymal cells, they do not give rise to any astrocytes but only neurons, demonstrating the pivotal role for Notch signaling in the fate of ependymal cell derived cells.	1	10	blocked	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	9	10	1	2
We suggest that the regulation of FGF1 expression and release by CBF1 mediated Notch signaling can play an important role in tumor formation .	We suggest that the regulation of FGF1 expression and release by CBF1 mediated Notch signaling can play an important role in tumor formation.	7	14	mediated	Positive_early_activation	Negative_activation	Positive_activation	CBF1	CBF1	CBF1	Notch	Notch	Notch	11	12	13	14
We found that stress independent non classical export of FGF1 is induced when dominant negative forms of transcription factors CBF1 and MAML inhibit the CBF1 dependent Notch signaling .	We found that stress independent non classical export of FGF1 is induced when dominant negative forms of transcription factors CBF1 and MAML inhibit the CBF1 dependent Notch signaling.	15	27	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	CBF1	CBF1	CBF1	Notch	Notch	Notch	19	20	26	27
Although the interpretation in this study was that Notch has Rbpj independent oncogenic activity , our findings suggest that RBPJ loss prevents tumor cell death independent of Notch receptor activation , thereby promoting tumorigenesis .	Although the interpretation in this study was that Notch has Rbpj independent oncogenic activity, our findings suggest that RBPJ loss prevents tumor cell death independent of Notch receptor activation, thereby promoting tumorigenesis.	19	29	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	19	20	27	28
Genetic deletion of Jag1 in mice is embryonic lethal , 10 and canonical RBPjkappa mediated Notch signaling regulates the activity of skeletal stem cells during development .	Genetic deletion of Jag1 in mice is embryonic lethal, 10 and canonical RBPjkappa mediated Notch signaling regulates the activity of skeletal stem cells during development.	1	16	mediated	Positive_early_activation	Negative_activation	Positive_activation	RBPjkappa	RBPjkappa	RBPjkappa	Notch	Notch	Notch	13	14	15	16
These findings are consistent with previous studies where Wt1 and Foxc1a can inhibit the ability of NICD1 to activate a synthetic Notch reporter driven by Rbpj sites XREF_BIBR and suggest a model where Wt1 and FoxC1/2 have antagonistic effects on Notch signaling in the mature podocyte .	These findings are consistent with previous studies where Wt1 and Foxc1a can inhibit the ability of NICD1 to activate a synthetic Notch reporter driven by Rbpj sites XREF_BIBR and suggest a model where Wt1 and FoxC1/2 have antagonistic effects on Notch signaling in the mature podocyte.	21	27	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	25	26	21	22
The co-factor RBP-Jk and mastermind like ( MAML ) mediate the signaling cascade of the canonical Notch pathway .	The co-factor RBP-Jk and mastermind like (MAML) mediate the signaling cascade of the canonical Notch pathway.	0	17	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBP-Jk	RBP-Jk	RBP-Jk	Notch	Notch	Notch	2	3	16	17
Therefore , deletion of Rbpj would be expected to completely abolish canonical Notch signaling .	Therefore, deletion of Rbpj would be expected to completely abolish canonical Notch signaling.	2	13	abolish	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	4	5	12	13
In addition to the Hh pathway , the canonical Rbpj mediated Notch pathway has been shown to regulate neural stem cells XREF_BIBR .	In addition to the Hh pathway, the canonical Rbpj mediated Notch pathway has been shown to regulate neural stem cells XREF_BIBR.	7	17	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	9	10	11	12
Notch target gene expression is repressed by RBPJ through recruiting a corepressor complex , which includes NCOR2 .	Notch target gene expression is repressed by RBPJ through recruiting a corepressor complex, which includes NCOR2.	0	8	repressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	7	8	0	1
The molecules in the above cluster seem to be highly connected to cluster 6 , which comprises proteins such as RBPJ ( an important mediator of Notch signaling ) , Notch 2 and 3 , DLL4 that are also integral parts of the Notch signaling pathway .	The molecules in the above cluster seem to be highly connected to cluster 6, which comprises proteins such as RBPJ (an important mediator of Notch signaling), Notch 2 and 3, DLL4 that are also integral parts of the Notch signaling pathway.	17	33	mediator	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	20	21	26	27
Notch inhibition by RBP-J deletion does not alter this phenotype .	Notch inhibition by RBP-J deletion does not alter this phenotype.	0	4	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	3	4	0	1
Therefore , the objective of this study was to determine the importance of Notch signaling in regulating bone fracture healing by using a temporally controlled inducible transgenic mouse model to impair RBPjkappa mediated canonical Notch signaling in all cells during repair .	Therefore, the objective of this study was to determine the importance of Notch signaling in regulating bone fracture healing by using a temporally controlled inducible transgenic mouse model to impair RBPjkappa mediated canonical Notch signaling in all cells during repair.	30	35	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPjkappa	RBPjkappa	RBPjkappa	Notch	Notch	Notch	31	32	34	35
Taken together , these data suggest that Dll1 deficiency in CD4 + T cells does not affect the expression of Notch and Rbpj mediated Notch signaling .	Taken together, these data suggest that Dll1 deficiency in CD4 + T cells does not affect the expression of Notch and Rbpj mediated Notch signaling.	18	25	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	22	23	24	25
Loss of CBF-1 also suppressed Notch induction of calponin and SM actin transcripts , but at only < 50 % reduction , which suggests that Notch is also activating alternative pathways leading to induction of SMC markers .	Loss of CBF-1 also suppressed Notch induction of calponin and SM actin transcripts, but at only < 50% reduction, which suggests that Notch is also activating alternative pathways leading to induction of SMC markers.	0	6	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	CBF-1	Loss of CBF-1	cbf-1	Notch	Notch	notch	2	3	5	6
Although Wt1 , foxc1a and Notch signaling synergized in the context of the Hey1 promoter , we found that Wt1 and foxc1a inhibited the ability of NICD1 to activate a synthetic Notch reporter driven by Rbpj sites .	Although Wt1, foxc1a and Notch signaling synergized in the context of the Hey1 promoter, we found that Wt1 and foxc1a inhibited the ability of NICD1 to activate a synthetic Notch reporter driven by Rbpj sites.	31	36	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	35	36	31	32
Endothelial and endocardial restricted ablation of Notch 1 or its co-factor RBPjk lead to a defect in ventricular trabeculation , strongly supporting the role of Notch signaling in the development of ventricular wall .	Endothelial and endocardial restricted ablation of Notch 1 or its co-factor RBPjk lead to a defect in ventricular trabeculation, strongly supporting the role of Notch signaling in the development of ventricular wall.	11	26	supporting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPjk	RBPjk	RBPjk	Notch	Notch	Notch	11	12	25	26
Notably , Rbpj mediated Notch activity in satellite cell precursors themselves is required for niche colonization [ XREF_BIBR ] .	Notably, Rbpj mediated Notch activity in satellite cell precursors themselves is required for niche colonization [XREF_BIBR].	2	5	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	2	3	4	5
This complex is recruited to Notch regulated promoters by the transcription factor RBP-Jkappa ( also known as CBF-1 or CSL ) and represses their transcription in the absence of Notch activation .	This complex is recruited to Notch regulated promoters by the transcription factor RBP-Jkappa (also known as CBF-1 or CSL) and represses their transcription in the absence of Notch activation.	5	13	promoters	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	factor RBP-Jkappa	factor RBP-Jkappa	factor RBP-Jkappa	Notch	Notch	Notch	11	13	5	6
To address the role of CBF1 mediated Notch signaling in FGF1 export , we stably transfected NIH 3T3 cells with an expression construct that encodes dnCBF1 containing the point mutation R218H in the DNA binding domain of CBF1 , which converts it into a potent negative regulator of the CBF1 dependent transcription apparently as a result of sequestration of NICD .	To address the role of CBF1 mediated Notch signaling in FGF1 export, we stably transfected NIH 3T3 cells with an expression construct that encodes dnCBF1 containing the point mutation R218H in the DNA binding domain of CBF1, which converts it into a potent negative regulator of the CBF1 dependent transcription apparently as a result of sequestration of NICD.	3	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	CBF1	CBF1	CBF1	Notch	Notch	Notch	5	6	7	8
NICD generated from any of the four Notch receptors can bind to RBP-J , and loss of RBP-J inhibits canonical Notch signaling from all four Notch receptors in mice .	NICD generated from any of the four Notch receptors can bind to RBP-J, and loss of RBP-J inhibits canonical Notch signaling from all four Notch receptors in mice.	15	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBP-J	loss of RBP-J	rbp-j	Notch	Notch	notch	17	18	20	21
Simultaneous loss of Notch1 and Notch2 resembled the total loss of Rbpj mediated canonical Notch signaling ; thus , Notch2 functions are not compensated in NSCs , and Notch2 is indispensable for the maintenance of NSC quiescence in the adult V-SVZ .	Simultaneous loss of Notch1 and Notch2 resembled the total loss of Rbpj mediated canonical Notch signaling; thus, Notch2 functions are not compensated in NSCs, and Notch2 is indispensable for the maintenance of NSC quiescence in the adult V-SVZ.	9	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rbpj	loss of Rbpj	rbpj	Notch	Notch	notch	11	12	14	15
Embryos mutant for the Notch ligand Delta like 1 ( Dll1 ) , the primary mediator of Notch signaling RBPjk , or doubly mutant for the receptors Notch1 and Notch2 have randomized laterality .	Embryos mutant for the Notch ligand Delta like 1 (Dll1), the primary mediator of Notch signaling RBPjk, or doubly mutant for the receptors Notch1 and Notch2 have randomized laterality.	15	20	signaling	Positive_activation_token_1_noun	Negative_activation	Positive_activation	RBPjk	RBPjk	RBPjk	Notch	Notch	Notch	19	20	17	18
Mice and zebrafish lacking components of Notch signaling including Notch1 , Jagged1 , Rbpj , and Mind bomb ( a ubiquitin ligase essential for activation of Notch signaling ) fail to execute definitive hematopoiesis at the AGM region .	Mice and zebrafish lacking components of Notch signaling including Notch1, Jagged1, Rbpj, and Mind bomb (a ubiquitin ligase essential for activation of Notch signaling) fail to execute definitive hematopoiesis at the AGM region.	6	14	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	13	14	6	7
Notch signaling is mediated by the Notch intracellular domain ( NICD ) and the transcription factor RBP-J , and studies in animals have shown that Notch1 , Notch4 , RBP-J , and Dll1 , as well as two downstream targets of Notch , Hes1 and Hey1 , are essential for arterial formation in the developing vasculature XREF_BIBR XREF_BIBR .	Notch signaling is mediated by the Notch intracellular domain (NICD) and the transcription factor RBP-J, and studies in animals have shown that Notch1, Notch4, RBP-J, and Dll1, as well as two downstream targets of Notch, Hes1 and Hey1, are essential for arterial formation in the developing vasculature XREF_BIBR XREF_BIBR.	0	17	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	16	17	0	1
Inhibition of Notch signalling by Rbpj knockout in chondrocytes after skeletal development suppresses OA development in a murine surgical model , and injection of the gamma-secretase inhibitor DAPT into the knee joints of the wild-type OA model mice results in a similar protective effect [ XREF_BIBR ] .	Inhibition of Notch signalling by Rbpj knockout in chondrocytes after skeletal development suppresses OA development in a murine surgical model, and injection of the gamma-secretase inhibitor DAPT into the knee joints of the wild-type OA model mice results in a similar protective effect [XREF_BIBR].	2	6	signalling	Positive_activation_syntax_2_noun	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	5	6	2	3
These data imply that RBPJ activates a subset of Notch target genes .	These data imply that RBPJ activates a subset of Notch target genes.	4	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	4	5	9	10
In endothelial cells from the bone marrow , the canonical effector of Notch signaling RBP-jkappa inhibits MicroRNA-155 , NF-kappaB activation and subsequent production of proinflammatory cytokines [ XREF_BIBR ] .	In endothelial cells from the bone marrow, the canonical effector of Notch signaling RBP-jkappa inhibits MicroRNA-155, NF-kappaB activation and subsequent production of proinflammatory cytokines [XREF_BIBR].	10	15	signaling	Positive_activation_token_1_noun	Negative_activation	Positive_activation	RBP-jkappa	RBP-jkappa	RBP-jkappa	Notch	Notch	Notch	14	15	12	13
The mammalian homologue of CSL is called C promoter binding factor 1 ( CBF1 ) or recombination signal binding protein for immunoglobulin kappa J region ( RBPJ ) , which mediates canonical Notch signaling [ XREF_BIBR ] .	The mammalian homologue of CSL is called C promoter binding factor 1 (CBF1) or recombination signal binding protein for immunoglobulin kappa J region (RBPJ), which mediates canonical Notch signaling [XREF_BIBR].	24	33	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	26	27	32	33
XREF_BIBR Moreover , the importance of the Notch canonical pathway in skeletal development was demonstrated in our recent study showing that the osteosclerotic phenotype caused by Notch1 ICD overactivation in osteoblasts is completely dependent on Rbpj mediated Notch signaling .	XREF_BIBR Moreover, the importance of the Notch canonical pathway in skeletal development was demonstrated in our recent study showing that the osteosclerotic phenotype caused by Notch1 ICD overactivation in osteoblasts is completely dependent on Rbpj mediated Notch signaling.	33	38	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	35	36	37	38
In addition , Notch signaling is essential for the maintenance of stem cell characteristics , possibly through the canonical Rbpj mediated Notch signaling cascade XREF_BIBR .	In addition, Notch signaling is essential for the maintenance of stem cell characteristics, possibly through the canonical Rbpj mediated Notch signaling cascade XREF_BIBR.	6	24	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	19	20	21	22
Hence , it is conceivable that one could still have basal levels of canonical Notch signaling even in the absence of intracellular Notch and RBPJ mediated canonical Notch signaling .	Hence, it is conceivable that one could still have basal levels of canonical Notch signaling even in the absence of intracellular Notch and RBPJ mediated canonical Notch signaling.	19	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	24	25	27	28
Our group has provided evidence that Notch inhibition by GSI or RBP-J knockout skews macrophage polarization in tumor , hepatic fibrosis and spinal cord injury XREF_BIBR XREF_BIBR XREF_BIBR .	Our group has provided evidence that Notch inhibition by GSI or RBP-J knockout skews macrophage polarization in tumor, hepatic fibrosis and spinal cord injury XREF_BIBR XREF_BIBR XREF_BIBR.	6	12	inhibition	Negative_activation_syntax_2_noun	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	11	12	6	7
RBPjk mediates Notch function in suppressing osteoblast differentiation .	RBPjk mediates Notch function in suppressing osteoblast differentiation.	0	3	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPjk	RBPjk	RBPjk	Notch	Notch	Notch	0	1	2	3
Because the Notch pathway represses dlc and cyp26a is under Rbpj control , these observations indicate that rbpj overexpression stimulates Notch signalling in the posterior PSM .	Because the Notch pathway represses dlc and cyp26a is under Rbpj control, these observations indicate that rbpj overexpression stimulates Notch signalling in the posterior PSM.	17	21	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	rbpj	rbpj overexpression	rbpj	Notch	Notch	notch	17	18	20	21
An inhibitory effect of Wt1 and foxc1a on the activation of Notch genes driven by Rbpj sites may provide a novel mechanism to prevent activation of these targets in mature podocytes .	An inhibitory effect of Wt1 and foxc1a on the activation of Notch genes driven by Rbpj sites may provide a novel mechanism to prevent activation of these targets in mature podocytes.	11	16	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	15	16	11	12
Altogether , our results indicate that RBP-J mediated Notch signaling not only governs cell-type differentiation , but also participates in cellular organization during retinal development , which ensure the exquisite process of retinogenesis .	Altogether, our results indicate that RBP-J mediated Notch signaling not only governs cell-type differentiation, but also participates in cellular organization during retinal development, which ensure the exquisite process of retinogenesis.	6	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	6	7	8	9
We have previously shown that RBPJ-kappa mediated Notch signaling is important for maintenance of ARC progenitors in the HVZ and plays a role in repressing the canonical pro neural gene Mash1 expressed within the ARC .	We have previously shown that RBPJ-kappa mediated Notch signaling is important for maintenance of ARC progenitors in the HVZ and plays a role in repressing the canonical pro neural gene Mash1 expressed within the ARC.	5	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	RBPJ-kappa	RBPJ-kappa	RBPJ-kappa	Notch	Notch	Notch	5	6	7	8
Delta and Notch signaling , mediated by the critical transcription factor RBP-J , acts to prevent progenitor cells in the RP from premature differentiation through Hes1 , one of the downstream target genes of the Notch pathway .	Delta and Notch signaling, mediated by the critical transcription factor RBP-J, acts to prevent progenitor cells in the RP from premature differentiation through Hes1, one of the downstream target genes of the Notch pathway.	0	12	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	11	12	2	3
TAAs identified represent a diverse range of cellular proteins , some of which were shown to be implicated in cancer development , particularly lectin , galactoside binding , soluble , 3 binding protein ( LGALS3BP ) [ XREF_BIBR ] , double-strand break repair factor RAD50 [ XREF_BIBR ] , nuclear protein with unknown function FAM50A [ XREF_BIBR ] , poly ( A ) binding protein cytoplasmic 4 ( PABPC4 ) [ XREF_BIBR ] , mediator of Notch signaling RBPJ [ XREF_BIBR ] and transcription factor LRRFIP1 [ XREF_BIBR ] .	TAAs identified represent a diverse range of cellular proteins, some of which were shown to be implicated in cancer development, particularly lectin, galactoside binding, soluble, 3 binding protein (LGALS3BP) [XREF_BIBR], double-strand break repair factor RAD50 [XREF_BIBR], nuclear protein with unknown function FAM50A [XREF_BIBR], poly (A) binding protein cytoplasmic 4 (PABPC4) [XREF_BIBR], mediator of Notch signaling RBPJ [XREF_BIBR] and transcription factor LRRFIP1 [XREF_BIBR].	74	80	signaling	Positive_activation_token_1_noun	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	78	79	76	77
First , Rbpj , the core component of all four Notch receptors , was deleted to block Notch signaling at the transcriptional events .	First, Rbpj, the core component of all four Notch receptors, was deleted to block Notch signaling at the transcriptional events.	2	18	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	2	3	17	18
Therefore , the objective of this study was to determine the importance of Notch signaling in regulating bone fracture healing by using a temporally controlled inducible transgenic mouse model ( Mx1-Cre ; dnMAML f/-) to impair RBPjkappa mediated canonical Notch signaling .	Therefore, the objective of this study was to determine the importance of Notch signaling in regulating bone fracture healing by using a temporally controlled inducible transgenic mouse model (Mx1-Cre; dnMAML f/-) to impair RBPjkappa mediated canonical Notch signaling.	35	40	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPjkappa	RBPjkappa	RBPjkappa	Notch	Notch	Notch	36	37	39	40
Similarly , in Xenopus segmentation , TP MO mediated rbpj overexpression could either enhance or attenuate Notch signalling .	Similarly, in Xenopus segmentation, TP MO mediated rbpj overexpression could either enhance or attenuate Notch signalling.	7	17	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	rbpj	MO mediated rbpj overexpression	rbpj	Notch	Notch	notch	9	10	16	17
Canonical Notch signaling is mediated by the transcription factor CSL ( CBF-1 , Suppressor of Hairless , Lag-1 ) , also known as RBP-Jkappa .	Canonical Notch signaling is mediated by the transcription factor CSL (CBF-1, Suppressor of Hairless, Lag-1), also known as RBP-Jkappa.	1	17	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CBF-1	CBF-1	CBF-1	Notch	Notch	Notch	11	12	1	2
Since Rbpj mediates canonical Notch signaling , we have used it as a proxy to interrogate the role of Notch signaling in the liver vasculature ; however , to confirm that the phenotypes we observed following Rbpj deletion reflect loss of canonical Notch signaling , we investigated the role of the Notch1 in the liver vasculature .	Since Rbpj mediates canonical Notch signaling, we have used it as a proxy to interrogate the role of Notch signaling in the liver vasculature; however, to confirm that the phenotypes we observed following Rbpj deletion reflect loss of canonical Notch signaling, we investigated the role of the Notch1 in the liver vasculature.	1	5	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	1	2	4	5
T6709-detection correlates with Notch activation XREF_BIBR , suggesting that RBPJ in the heart might repress gene expression basally and mediate Notch signalling after MI and pressure overload .	T6709-detection correlates with Notch activation XREF_BIBR, suggesting that RBPJ in the heart might repress gene expression basally and mediate Notch signalling after MI and pressure overload.	9	21	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	9	10	20	21
However , little is known about the role of Notch signalling in perinatal and juvenile muscle growth because Notch1 -/- mice mutants [ XREF_BIBR , XREF_BIBR ] or embryos lacking components required for Notch signalling such as its main transcriptional repressor RBP-Jk [ XREF_BIBR ] die at midgestation or around birth with severe defects in somitogenesis , vasculogenesis , cardiogenesis and/or neurogenesis [ XREF_BIBR ] .	However, little is known about the role of Notch signalling in perinatal and juvenile muscle growth because Notch1 -/- mice mutants [XREF_BIBR, XREF_BIBR] or embryos lacking components required for Notch signalling such as its main transcriptional repressor RBP-Jk [XREF_BIBR] die at midgestation or around birth with severe defects in somitogenesis, vasculogenesis, cardiogenesis and/or neurogenesis [XREF_BIBR].	33	43	signalling	Positive_activation_syntax_noun_Hearst	Negative_activation	Negative_activation	RBP-Jk	RBP-Jk	RBP-Jk	Notch	Notch	Notch	41	42	33	34
The NTg mouse carries a hemizygous allele of Notch signaling CBF-1 response element and a minimal SV40 promoter driven enhanced green fluorescent protein ( eGFP ) .	The NTg mouse carries a hemizygous allele of Notch signaling CBF-1 response element and a minimal SV40 promoter driven enhanced green fluorescent protein (eGFP).	8	12	signaling	Positive_activation_token_1_noun	Negative_activation	Positive_activation	CBF-1	CBF-1	CBF-1	Notch	Notch	Notch	10	11	8	9
Conversely , RBPJ deficiency causes up-regulation of recognized Notch target genes , such as those of the HEY gene family , even in the presence of DAPT which inhibits Notch receptor processing and activation .	Conversely, RBPJ deficiency causes up-regulation of recognized Notch target genes, such as those of the HEY gene family, even in the presence of DAPT which inhibits Notch receptor processing and activation.	2	10	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	2	3	8	9
rbpj overexpression modulates Notch signalling in the presomitic mesoderm .	rbpj overexpression modulates Notch signalling in the presomitic mesoderm.	0	4	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	rbpj	rbpj overexpression	rbpj	Notch	Notch	notch	0	1	3	4
PlexinD1 regulation occurs at the promoter level , through the canonical Notch signaling pathway mediated by RBPjk and CBF1 transcription factor .	PlexinD1 regulation occurs at the promoter level, through the canonical Notch signaling pathway mediated by RBPjk and CBF1 transcription factor.	11	20	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	RBPjk	RBPjk	RBPjk	Notch	Notch	Notch	16	17	11	12
As shown in XREF_FIG , treatment of LNCaP and , PC-3 cells with 5 microM PEITC resulted in a statistically significant increase in luciferase reporter activity of RBP-Jk ( a downstream modulator of Notch signaling ) compared with dimethyl sulfoxide ( DMSO )-treated controls .	As shown in XREF_FIG, treatment of LNCaP and, PC-3 cells with 5 microM PEITC resulted in a statistically significant increase in luciferase reporter activity of RBP-Jk (a downstream modulator of Notch signaling) compared with dimethyl sulfoxide (DMSO)-treated controls.	25	34	modulator	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	RBP-Jk	RBP-Jk	RBP-Jk	Notch	Notch	Notch	27	28	33	34
Rbpj mediated Notch signaling is known as the canonical pathway , and the families of Hes ( hairy and enhancer of split ) and Hesr ( hes related , also known as Hey/Herp/Hrt/Chf ) are known as primary targets of Notch signaling .	Rbpj mediated Notch signaling is known as the canonical pathway, and the families of Hes (hairy and enhancer of split) and Hesr (hes related, also known as Hey/Herp/Hrt/Chf) are known as primary targets of Notch signaling.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	0	1	2	3
Hepatoblasts also require the Notch mediator RBPJ and the Notch target gene Hes1 , and biliary tubulogenesis requires Notch signaling .	Hepatoblasts also require the Notch mediator RBPJ and the Notch target gene Hes1, and biliary tubulogenesis requires Notch signaling.	2	12	mediator	Positive_activation_token_1_noun	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	6	7	4	5
Upon tumor infiltration , a subset of TAMs undergo local proliferation and are dependent on the transcriptional regulator of Notch signaling RBPJ ( recombining binding protein suppressor of hairless gene ) for terminal differentiation .	Upon tumor infiltration, a subset of TAMs undergo local proliferation and are dependent on the transcriptional regulator of Notch signaling RBPJ (recombining binding protein suppressor of hairless gene) for terminal differentiation.	17	33	signaling	Positive_activation_token_1_noun	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	21	22	19	20
KO mouse prostates were able to involute and regenerate similarly to WT prostates in response to fluctuating serum testosterone levels , suggesting that RBP-J mediated Notch signaling is not essential for the regenerative capacity of prostate epithelia ( XREF_SUPPLEMENTARY ) .	KO mouse prostates were able to involute and regenerate similarly to WT prostates in response to fluctuating serum testosterone levels, suggesting that RBP-J mediated Notch signaling is not essential for the regenerative capacity of prostate epithelia (XREF_SUPPLEMENTARY).	23	26	mediated	Positive_early_activation	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	23	24	25	26
Wt1a , Foxc1a , and the Notch mediator Rbpj Physically Interact and Regulate the Formation of Podocytes in Zebrafish .	Wt1a, Foxc1a, and the Notch mediator Rbpj Physically Interact and Regulate the Formation of Podocytes in Zebrafish.	6	9	mediator	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	8	9	6	7
Gene targeted elimination of Pofut1 in mice result in embryonic lethality with Notch like phenotypes that are similar to those in mice lacking core components of Notch signaling like RBP-Jk [ XREF_BIBR ] .	Gene targeted elimination of Pofut1 in mice result in embryonic lethality with Notch like phenotypes that are similar to those in mice lacking core components of Notch signaling like RBP-Jk [XREF_BIBR].	26	31	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	RBP-Jk	RBP-Jk	RBP-Jk	Notch	Notch	Notch	29	30	26	27
Thus loss of RBPJ may both derepress a subset of Notch target genes and potentially block Notch signaling at other targets .	Thus loss of RBPJ may both derepress a subset of Notch target genes and potentially block Notch signaling at other targets.	1	17	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPJ	loss of RBPJ	rbpj	Notch	Notch	notch	3	4	16	17
Because RBP-J mediates both transcriptional repression and activation of Notch target genes , this phenotype might reflect the contradictory effects of both impaired repression and impaired activation .	Because RBP-J mediates both transcriptional repression and activation of Notch target genes, this phenotype might reflect the contradictory effects of both impaired repression and impaired activation.	1	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	1	2	9	10
In the absence of Notch signals RBP-J could potentially function as a transcriptional repressor , so loss of RBP-J may have an effect even on cells that do not usually require active Notch signalling .	In the absence of Notch signals RBP-J could potentially function as a transcriptional repressor, so loss of RBP-J may have an effect even on cells that do not usually require active Notch signalling.	4	9	signals	Positive_activation_token_1_noun	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	6	7	4	5
The RBPJ and NICD containing coactivator complex displaces the RBPJ associated repressor complex and mediates the transcriptional activation of Notch target genes ( XREF_FIG ) .	The RBPJ and NICD containing coactivator complex displaces the RBPJ associated repressor complex and mediates the transcriptional activation of Notch target genes (XREF_FIG).	0	21	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	1	2	19	20
However , in our present studies , the deletion of Dll1 in CD4 + T cells did not affect Rbpj mediated Notch target genes .	However, in our present studies, the deletion of Dll1 in CD4 + T cells did not affect Rbpj mediated Notch target genes.	18	23	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	19	20	21	22
RBPJ mediated NOTCH signaling is also important for mesenchyimal cell proliferation , skeletal formation [ XREF_BIBR ] epidermis , and hair follicle development [ XREF_BIBR ] and vascular structure formation .	RBPJ mediated NOTCH signaling is also important for mesenchyimal cell proliferation, skeletal formation [XREF_BIBR] epidermis, and hair follicle development [XREF_BIBR] and vascular structure formation.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	NOTCH	NOTCH	NOTCH	0	1	2	3
Thus , even though Rbpj mediated Notch function does not account for all of the consequences of Notch gain of function , Notch suppression of Sox9 appears to be Rbpj dependent .	Thus, even though Rbpj mediated Notch function does not account for all of the consequences of Notch gain of function, Notch suppression of Sox9 appears to be Rbpj dependent.	4	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	4	5	6	7
This confirms that Cre mediated loss of RBPj in the excitatory neurons would eliminate all canonical Notch signaling .	This confirms that Cre mediated loss of RBPj in the excitatory neurons would eliminate all canonical Notch signaling.	3	17	eliminate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	RBPj	Cre mediated loss of RBPj	rbpj	Notch	Notch	notch	7	8	16	17
RBPJ also binds and targets both the EBV transcriptional activator EBNA2 and the Notch-IC effector of the Notch signaling pathway to DNA .	RBPJ also binds and targets both the EBV transcriptional activator EBNA2 and the Notch-IC effector of the Notch signaling pathway to DNA.	0	19	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RBPJ	RBPJ	RBPJ	Notch	Notch	Notch	0	1	17	18
We have recently demonstrated that Notch blockade by RBP-J disruption skews TAMs toward M2 polarization to facilitate tumor progression .	We have recently demonstrated that Notch blockade by RBP-J disruption skews TAMs toward M2 polarization to facilitate tumor progression.	5	9	blockade	Negative_activation_syntax_2_noun	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	8	9	5	6
In one of the studies XREF_BIBR , Notch signals were abrogated by T-cell-specific deletion of the co-repressor RBP-J or of both Notch1 and Notch2 .	In one of the studies XREF_BIBR, Notch signals were abrogated by T-cell-specific deletion of the co-repressor RBP-J or of both Notch1 and Notch2.	7	18	abrogated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	RBP-J	RBP-J	RBP-J	Notch	Notch	Notch	17	18	7	8
Rbpj mediated signaling is attenuated in IPCs compared to RGCs , and knockout of Rbpj in mice abolishes Notch signaling and leads to premature depletion of RGCs in favor of IPCs and neurons .	Rbpj mediated signaling is attenuated in IPCs compared to RGCs, and knockout of Rbpj in mice abolishes Notch signaling and leads to premature depletion of RGCs in favor of IPCs and neurons.	12	19	abolishes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	14	15	18	19
Thus , in the absence of Notch signaling RBP-Jkappa functions as a transcriptional repressor .	Thus, in the absence of Notch signaling RBP-Jkappa functions as a transcriptional repressor.	4	9	signaling	Positive_activation_token_1_noun	Negative_activation	Positive_activation	RBP-Jkappa	RBP-Jkappa	RBP-Jkappa	Notch	Notch	Notch	8	9	6	7
Next , to determine whether the Notch GOF phenotype was solely dependent upon the Rbpj mediated Notch signaling pathway , we intercrossed Rbpj conditional knock-out XREF_BIBR mice ( Col2a1-cre ; Rbpj f/f ) with Notch GOF mice , so as to generate Rbpj deficiency on the Notch GOF background .	Next, to determine whether the Notch GOF phenotype was solely dependent upon the Rbpj mediated Notch signaling pathway, we intercrossed Rbpj conditional knock-out XREF_BIBR mice (Col2a1-cre; Rbpj f/f) with Notch GOF mice, so as to generate Rbpj deficiency on the Notch GOF background.	13	18	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	14	15	16	17
Rbpj-kappa mediated Notch signaling plays a critical role in development of hypothalamic Kisspeptin neurons .	Rbpj-kappa mediated Notch signaling plays a critical role in development of hypothalamic Kisspeptin neurons.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rbpj-kappa	Rbpj-kappa	Rbpj-kappa	Notch	Notch	Notch	0	1	2	3
By transfection analyses performed in HeLa cells , we demonstrate that overexpressed CBF1 acts as a negative regulator of IL-6 gene transcription and is unable to elicit Notch dependent activation of this gene .	By transfection analyses performed in HeLa cells, we demonstrate that overexpressed CBF1 acts as a negative regulator of IL-6 gene transcription and is unable to elicit Notch dependent activation of this gene.	11	29	elicit	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CBF1	CBF1	CBF1	Notch	Notch	Notch	12	13	27	28
This is in contrast to the vertebrae column of Col2a1-cre Rbpj flox and flox mice , which show no difference from the control mice , suggesting other factors than Rbpj may be recruited to mediate Notch GOF in the vertebrae .	This is in contrast to the vertebrae column of Col2a1-cre Rbpj flox and flox mice, which show no difference from the control mice, suggesting other factors than Rbpj may be recruited to mediate Notch GOF in the vertebrae.	29	36	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rbpj	Rbpj	Rbpj	Notch	Notch	Notch	29	30	35	36
In human monocytes , heterodimers of p65 and p50 activate the pro inflammatory genes TNF-alpha and IL-1beta [ XREF_BIBR ] as well as other molecules and enzymes , including acute phase proteins and iNOS , which can have a favorable effect on cell survival in the presence of bacterial pathogens .	In human monocytes, heterodimers of p65 and p50 activate the pro inflammatory genes TNF-alpha and IL-1beta [XREF_BIBR] as well as other molecules and enzymes, including acute phase proteins and iNOS, which can have a favorable effect on cell survival in the presence of bacterial pathogens.	4	18	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p65	p65	p65	IL-1beta	IL-1beta	IL-1beta	6	7	16	17
As expected , PD pretreatment could apparently limit TLR4 and NF-kappaB p65 expression and thus suppress the formation of inflammatory cytokines ( TNF-alpha , IL-1beta , and IL-6 ) , suggesting that PD provides anti-inflammatory effect against ethanol induced liver injury via suppressing the TLR4 and NF-kappaB p65 signal pathway .	As expected, PD pretreatment could apparently limit TLR4 and NF-kappaB p65 expression and thus suppress the formation of inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), suggesting that PD provides anti-inflammatory effect against ethanol induced liver injury via suppressing the TLR4 and NF-kappaB p65 signal pathway.	3	25	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	NF-kappaB p65	PD pretreatment could apparently limit TLR4 and NF-kappaB p65 expression	nf-kappab p65	IL-1beta	IL-1beta	il-1beta	10	12	24	25
Importantly , suppression of the NF-kappaB p65 component significantly blocked the inductive effect of IL-1beta on the expression of ADAMTS-4 and ADAMTS-5 protein and mRNA levels , as well as aggrecan degradation .	Importantly, suppression of the NF-kappaB p65 component significantly blocked the inductive effect of IL-1beta on the expression of ADAMTS-4 and ADAMTS-5 protein and mRNA levels, as well as aggrecan degradation.	5	15	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	IL-1beta	IL-1beta	IL-1beta	5	7	14	15
In response to stress , p65 was activated to promote production of pro-IL-1beta , and then cleaved to mature IL-1beta by NOD like receptor protein 3 ( NLRP3 ) inflammasome pathway in hippocampus of CUMS mice .	In response to stress, p65 was activated to promote production of pro-IL-1beta, and then cleaved to mature IL-1beta by NOD like receptor protein 3 (NLRP3) inflammasome pathway in hippocampus of CUMS mice.	5	13	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p65	p65	p65	pro-IL-1beta	pro-IL-1beta	pro-IL-1beta	5	6	12	13
Pre-treatment of fish with vitamin D3 protected the fish intestine from the LPS induced increase of TNF-alpha , IL-1beta , IL-6 and IL-8 mainly by downregulating TLR4 , Myd88 and NF-kappaB p65 mRNA expression ( P < 0.05 ) .	Pre-treatment of fish with vitamin D3 protected the fish intestine from the LPS induced increase of TNF-alpha, IL-1beta, IL-6 and IL-8 mainly by downregulating TLR4, Myd88 and NF-kappaB p65 mRNA expression (P < 0.05).	13	34	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	NF-kappaB p65	NF-kappaB p65 mRNA expression	nf-kappab p65	IL-1beta	IL-1beta	il-1beta	30	32	18	19
Remarkably , blockage of NF-kappaB p65 and/or MAPK p38 with their specific inhibitors strongly attenuated B7-H3-amplified TNF-alpha , IL-1beta , IL-6 , and MCP-1 production in the brain of S. pneumoniae infected mice , suggesting that B7-H3-induced additional activation of both NF-kappaB p65 and MAPK p38 is predominantly responsible for B7-H3-amplified inflammatory response during experimental pneumococcal meningitis .	Remarkably, blockage of NF-kappaB p65 and/or MAPK p38 with their specific inhibitors strongly attenuated B7-H3-amplified TNF-alpha, IL-1beta, IL-6, and MCP-1 production in the brain of S. pneumoniae infected mice, suggesting that B7-H3-induced additional activation of both NF-kappaB p65 and MAPK p38 is predominantly responsible for B7-H3-amplified inflammatory response during experimental pneumococcal meningitis.	4	19	attenuated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	NF-kappaB p65	NF-kappaB p65	NF-kappaB p65	IL-1beta	IL-1beta	IL-1beta	4	6	18	19
In contrast , U-LPS stimulation of p65 Deltamye BMDMs did not induce a pronounced IL1beta , IL-6 , and TNF-alpha response .	In contrast, U-LPS stimulation of p65 Deltamye BMDMs did not induce a pronounced IL1beta, IL-6, and TNF-alpha response.	6	20	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p65	p65	p65	IL1beta	IL1beta	IL1beta	6	7	14	15
The results of western blot analysis revealed that NF-kappaB p65 expression increased in response to IL-1beta ( XREF_FIG ) .	The results of western blot analysis revealed that NF-kappaB p65 expression increased in response to IL-1beta (XREF_FIG).	8	17	increased	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	NF-kappaB p65	NF-kappaB p65 expression	nf-kappab p65	IL-1beta	IL-1beta	il-1beta	8	10	15	16
Thus , it is possible that Rheb stimulates the dissociation of FKBP38 from mTOR by activating PLD1 and generating PA ..	Thus, it is possible that Rheb stimulates the dissociation of FKBP38 from mTOR by activating PLD1 and generating PA..	6	13	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rheb	Rheb	Rheb	FKBP38	FKBP38	FKBP38	6	7	11	12
Previous studies have shown that the small GTPase Rheb increases mTOR activity by sequestering the mTOR inhibitor FKBP-38 .	Previous studies have shown that the small GTPase Rheb increases mTOR activity by sequestering the mTOR inhibitor FKBP-38.	5	18	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rheb	Rheb	Rheb	FKBP-38	FKBP-38	FKBP-38	8	9	17	18
The Rheb activates mTOR by antagonizing its endogenous inhibitor FKBP38 .	The Rheb activates mTOR by antagonizing its endogenous inhibitor FKBP38.	0	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rheb	Rheb	Rheb	FKBP38	FKBP38	FKBP38	1	2	9	10
The Rheb activates mTOR by antagonizing its endogenous inhibitor FKBP38 XREF_BIBR .	The Rheb activates mTOR by antagonizing its endogenous inhibitor FKBP38 XREF_BIBR.	0	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rheb	Rheb	Rheb	FKBP38	FKBP38	FKBP38	1	2	9	10
Rheb can activate mTORC1 by disrupting the binding of the inhibitory protein FKBP38 , but reportedly inhibits mTORC2 XREF_BIBR .	Rheb can activate mTORC1 by disrupting the binding of the inhibitory protein FKBP38, but reportedly inhibits mTORC2 XREF_BIBR.	0	16	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Rheb	Rheb	Rheb	FKBP38	FKBP38	FKBP38	0	1	12	13
Recently Rpl22 +/- or Rpl22 -/- primary mouse embryonic fibroblasts ( MEFs ) were found to grow faster and display increased transformation potential relative to MEFs isolated from Rpl22 +/+ littermates XREF_BIBR To further evaluate the effect of Rpl22 and Rpl22Ll1 expression on growth rates , Rpl22 +/+ or Rpl22 -/- 3T9 fibroblasts were transduced with one of 2 different tet-on shRNA lentivirus constructs ( shRNA # 1- and shRNA # 2-Rpl22l1 ) that target Rpl22l1 mRNA to acutely knock-down its expression .	Recently Rpl22 +/- or Rpl22 -/- primary mouse embryonic fibroblasts (MEFs) were found to grow faster and display increased transformation potential relative to MEFs isolated from Rpl22 +/+ littermates XREF_BIBR To further evaluate the effect of Rpl22 and Rpl22Ll1 expression on growth rates, Rpl22 +/+ or Rpl22 -/- 3T9 fibroblasts were transduced with one of 2 different tet-on shRNA lentivirus constructs (shRNA # 1- and shRNA # 2-Rpl22l1) that target Rpl22l1 mRNA to acutely knock-down its expression.	34	76	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rpl22	Rpl22	Rpl22	Rpl22l1	Rpl22l1	Rpl22l1	46	47	75	76
Additionally , RPL22 directly represses the expression of RPL22L1 mRNA , and a lack of RPL22 causes a compensatory increase in RPL22L1 [ XREF_BIBR , XREF_BIBR ] .	Additionally, RPL22 directly represses the expression of RPL22L1 mRNA, and a lack of RPL22 causes a compensatory increase in RPL22L1 [XREF_BIBR, XREF_BIBR].	13	25	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RPL22	RPL22	RPL22	RPL22L1	RPL22L1	RPL22L1	15	16	21	22
Unlike after c-Kit stimulation , inhibiting p90RSK-1 did not abolish the band shift of MiTF protein , nor did it abolish the UVC mediated MiTF degradation , suggesting that phosphorylation on serine 73 by Erk1/2 is a key event after UVC .	Unlike after c-Kit stimulation, inhibiting p90RSK-1 did not abolish the band shift of MiTF protein, nor did it abolish the UVC mediated MiTF degradation, suggesting that phosphorylation on serine 73 by Erk1/2 is a key event after UVC.	5	15	abolish	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p90RSK-1	p90RSK-1	p90RSK-1	MiTF	MiTF	MiTF	6	7	14	15
After subretinal delivery of the replacement gene in the mutant mice , human RPGRIP1 was expressed specifically in photoreceptors , localized correctly in the connecting cilia , and restored the normal localization of RPGR .	After subretinal delivery of the replacement gene in the mutant mice, human RPGRIP1 was expressed specifically in photoreceptors, localized correctly in the connecting cilia, and restored the normal localization of RPGR.	12	34	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RPGRIP1	RPGRIP1 was expressed	rpgrip1	RPGR	RPGR	rpgr	13	14	33	34
Nonetheless , the results of XREF_FIG suggest that manipulation of mTORC1 signaling by KSHV is being effected through the release from inhibition by TSC2 that is induced by ERK2 mediated activation of RSK1 .	Nonetheless, the results of XREF_FIG suggest that manipulation of mTORC1 signaling by KSHV is being effected through the release from inhibition by TSC2 that is induced by ERK2 mediated activation of RSK1.	16	33	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	RSK1	ERK2 mediated activation of RSK1	rsk1	TSC2	TSC2	tsc2	32	33	23	24
Dual ROCK1/2 and selective ROCK2 inhibition reduced pMYPT1 to normal unlasered levels ( XREF_FIG ) .	Dual ROCK1/2 and selective ROCK2 inhibition reduced pMYPT1 to normal unlasered levels (XREF_FIG).	4	8	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	ROCK2	ROCK2	ROCK2	pMYPT1	pMYPT1	pMYPT1	4	5	7	8
Moreover , SET is able to suppress the DNase activity of NM23-H1 tumor suppressor , increase AP-1 activity , activate MAPK signaling , and regulate granzyme B and interferon-gamma production in human NK cells .	Moreover, SET is able to suppress the DNase activity of NM23-H1 tumor suppressor, increase AP-1 activity, activate MAPK signaling, and regulate granzyme B and interferon-gamma production in human NK cells.	2	24	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SET	SET	SET	NM23-H1	NM23-H1	NM23-H1	2	3	11	12
SET is a substrate for Granzyme A ( GzmA ) and upon cytotoxic T-lymphocyte ( CTL ) attack , GzmA cleaves SET , which then allows nm23-H1 to exert its exonuclease activity .	SET is a substrate for Granzyme A (GzmA) and upon cytotoxic T-lymphocyte (CTL) attack, GzmA cleaves SET, which then allows nm23-H1 to exert its exonuclease activity.	20	28	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SET	SET	SET	nm23-H1	nm23-H1	nm23-H1	21	22	26	27
SET cleavage activates NM23-H1 to generate single stranded DNA nicks .	SET cleavage activates NM23-H1 to generate single stranded DNA nicks.	0	4	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SET	SET	SET	NM23-H1	NM23-H1	NM23-H1	0	1	3	4
In addition , it has been reported that SET inhibits the DNase activity of the tumor-suppressor NM23-H1 and that the cleavage of SET by Granzyme A during the cytotoxic T lymphocyte induced apoptosis releases NM23-H1 from inhibition and triggers NM23-H1 to translocate into the nucleus , where it cleaves the DNA .	In addition, it has been reported that SET inhibits the DNase activity of the tumor-suppressor NM23-H1 and that the cleavage of SET by Granzyme A during the cytotoxic T lymphocyte induced apoptosis releases NM23-H1 from inhibition and triggers NM23-H1 to translocate into the nucleus, where it cleaves the DNA.	20	40	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SET	SET	SET	NM23-H1	NM23-H1	NM23-H1	22	23	39	40
In cancer cells , the COG112-SET interaction releases the SET mediated inhibition of PP2A and augments the activity of the metastasis suppressor nm23-H1 .	In cancer cells, the COG112-SET interaction releases the SET mediated inhibition of PP2A and augments the activity of the metastasis suppressor nm23-H1.	8	23	augments	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SET	SET	SET	nm23-H1	nm23-H1	nm23-H1	9	10	22	23
Proteolytic cleavage or antagonism of SET will reverse suppression of NM23H1 , resulting in anti-metastatic activity or the caspase independent apoptosis.25 4.4 Gene transcription .	Proteolytic cleavage or antagonism of SET will reverse suppression of NM23H1, resulting in anti-metastatic activity or the caspase independent apoptosis.25 4.4 Gene transcription.	1	11	reverse	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SET	SET	SET	NM23H1	NM23H1	NM23H1	5	6	10	11
In response to a drop in intracellular pH in neurons , a lysosomal protease , asparagine endopeptidase ( AEP ) , is activated to cleave SET , which in turn activates NM23-H1 and TREX1 to damage DNA .	In response to a drop in intracellular pH in neurons, a lysosomal protease, asparagine endopeptidase (AEP), is activated to cleave SET, which in turn activates NM23-H1 and TREX1 to damage DNA.	24	33	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SET	SET	SET	NM23-H1	NM23-H1	NM23-H1	25	26	31	32
COG112 treatment releases the SET mediated inhibition of the tumor suppressor PP2A , as well as the metastasis suppressor nm23-H1 .	COG112 treatment releases the SET mediated inhibition of the tumor suppressor PP2A, as well as the metastasis suppressor nm23-H1.	3	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SET	SET	SET	nm23-H1	nm23-H1	nm23-H1	4	5	19	20
28 DNA cleavage activity of NME1 was also implicated in Granzyme A mediated cytotoxicity , XREF_BIBR , XREF_BIBR with NME1 proposed as a component of the Granzyme A activated SET complex .	28 DNA cleavage activity of NME1 was also implicated in Granzyme A mediated cytotoxicity, XREF_BIBR, XREF_BIBR with NME1 proposed as a component of the Granzyme A activated SET complex.	12	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SET	SET	SET	NME1	NME1	NME1	29	30	19	20
Initially , it was shown that SEMA3A injection into adult mouse skin induces vascular hyperpermeability in a NRP1 dependent mechanism .	Initially, it was shown that SEMA3A injection into adult mouse skin induces vascular hyperpermeability in a NRP1 dependent mechanism.	6	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SEMA3A	SEMA3A	SEMA3A	NRP1	NRP1	NRP1	6	7	17	18
For these functions , NRP1 signalling in MNs is activated by Sema3A XREF_BIBR XREF_BIBR XREF_BIBR .	For these functions, NRP1 signalling in MNs is activated by Sema3A XREF_BIBR XREF_BIBR XREF_BIBR.	4	14	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Sema3A	Sema3A	Sema3A	NRP1	NRP1	NRP1	11	12	4	5
Nevertheless , the mechanism by which SEMA3A modulates the expression pattern and activity of NRP1 and , consequently , the phenotype of the tumor requires further study .	Nevertheless, the mechanism by which SEMA3A modulates the expression pattern and activity of NRP1 and, consequently, the phenotype of the tumor requires further study.	6	20	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SEMA3A	SEMA3A	SEMA3A	NRP1	NRP1	NRP1	6	7	14	15
It is shown that both VEGF165 and Sema3A induced the upregulation of VEGFR2 and Nrp1 receptors .	It is shown that both VEGF165 and Sema3A induced the upregulation of VEGFR2 and Nrp1 receptors.	5	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sema3A	Sema3A	Sema3A	Nrp1	Nrp1	Nrp1	7	8	14	15
One attractive possibility is that Sema3A , coming from the top of the cortex , contacts the upper side of a multipolar cell , activates PlxB2 , Nrp1 and RhoA locally , inducing and stabilizing a pia directed process .	One attractive possibility is that Sema3A, coming from the top of the cortex, contacts the upper side of a multipolar cell, activates PlxB2, Nrp1 and RhoA locally, inducing and stabilizing a pia directed process.	5	28	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sema3A	Sema3A	Sema3A	Nrp1	Nrp1	Nrp1	5	6	27	28
Alternatively , SGK-1 may directly regulate DAF-16 and FoxO activity in a small number of cells , which in turn could control lifespan by influencing other cells in a DAF-16 and FoxO independent manner .	Alternatively, SGK-1 may directly regulate DAF-16 and FoxO activity in a small number of cells, which in turn could control lifespan by influencing other cells in a DAF-16 and FoxO-independent manner.	2	9	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK-1	SGK-1	SGK-1	FoxO	FoxO	FoxO	2	3	8	9
Phosphorylation at conserved serine/threonine residues by protein kinase B ( PKB ) and by serum- and glucocorticoid induced kinase ( SGK ) induces the association of FOXO transcription factors with 14-3-3 proteins and their nuclear export and inactivation .	Phosphorylation at conserved serine/threonine residues by protein kinase B (PKB) and by serum- and glucocorticoid induced kinase (SGK) induces the association of FOXO transcription factors with 14-3-3 proteins and their nuclear export and inactivation.	18	28	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK	SGK	SGK	FOXO	FOXO	FOXO	20	21	26	27
In mammalian cell culture , Sgk inhibits FoxO3 activity , and in C. elegans , SGK-1 is thought to limit lifespan by inhibiting DAF-16 and FoxO activity .	In mammalian cell culture, Sgk inhibits FoxO3 activity, and in C. elegans, SGK-1 is thought to limit lifespan by inhibiting DAF-16 and FoxO activity.	15	26	limit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SGK-1	SGK-1	SGK-1	FoxO	FoxO	FoxO	15	16	25	26
As our lifespan data are consistent with a model in which SGK-1 promotes longevity by activating DAF-16 and FoxO , we sought to determine the influence of sgk-1 mutations on the subcellular localization of DAF-16 and FoxO .	As our lifespan data are consistent with a model in which SGK-1 promotes longevity by activating DAF-16 and FoxO, we sought to determine the influence of sgk-1 mutations on the subcellular localization of DAF-16 and FoxO.	11	19	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK-1	SGK-1	SGK-1	FoxO	FoxO	FoxO	11	12	18	19
It is possible that DAF-16 and FoxO activation by SGK-1 is attenuated in backgrounds such as akt-1 ( null ) and hcf-1 ( null ) in which DAF-16 and FoxO is already activated .	It is possible that DAF-16 and FoxO activation by SGK-1 is attenuated in backgrounds such as akt-1 (null) and hcf-1 (null) in which DAF-16 and FoxO is already activated.	4	10	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	SGK-1	SGK-1	SGK-1	FoxO	FoxO	FoxO	9	10	6	7
The dependence of sgk-1 ( gf ) lifespan extension on daf-16 and FoxO suggests that SGK-1 may increase lifespan by activating DAF-16 and FoxO , even in the absence of a significant effect on DAF-16A : : GFP localization .	The dependence of sgk-1 (gf) lifespan extension on daf-16 and FoxO suggests that SGK-1 may increase lifespan by activating DAF-16 and FoxO, even in the absence of a significant effect on DAF-16A : : GFP localization.	15	24	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK-1	SGK-1	SGK-1	FoxO	FoxO	FoxO	15	16	23	24
Note that SGK-1 mediated FOXO3 T32 phosphorylation was not only abrogated by AICAR , but also by concomitant treatment with 2-deoxyglucose ( XREF_SUPPLEMENTARY ) .	Note that SGK-1 mediated FOXO3 T32 phosphorylation was not only abrogated by AICAR, but also by concomitant treatment with 2-deoxyglucose (XREF_SUPPLEMENTARY).	0	18	mediated	Positive_early_activation	Negative_activation	Positive_activation	SGK-1	SGK-1	SGK-1	FOXO3	FOXO3	FOXO3	2	3	4	5
Moreover , SGK1 silencing decreased pFoxo3a ( S253 )-LC3 and pFoxo3a ( S253 )-p27 interactions ( XREF_FIG ) .	Moreover, SGK1 silencing decreased pFoxo3a (S253)-LC3 and pFoxo3a (S253)-p27 interactions (XREF_FIG).	2	10	decreased	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK1	SGK1	SGK1	pFoxo3a	pFoxo3a	pFoxo3a	2	3	5	6
Ethanol feeding suppressed beta-catenin signaling and led to less SGK1 expression which in turn promoted Foxo3A upregulation to induce hepatocyte apoptosis , whereas Wnt agonist administration reversed this process .	Ethanol feeding suppressed beta-catenin signaling and led to less SGK1 expression which in turn promoted Foxo3A upregulation to induce hepatocyte apoptosis, whereas Wnt agonist administration reversed this process.	0	16	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK1	Ethanol feeding suppressed beta-catenin signaling and led to less SGK1 expression	sgk1	Foxo3A	Foxo3A	foxo3a	9	10	15	16
SGK , like Akt , promotes proliferation through phosphorylation mediated inactivation of the forkhead transcription factor FoxO3 , thus preventing its continuous induction of cell cycle arrest genes .	SGK, like Akt, promotes proliferation through phosphorylation mediated inactivation of the forkhead transcription factor FoxO3, thus preventing its continuous induction of cell cycle arrest genes.	0	17	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK	SGK	SGK	FoxO3	FoxO3	FoxO3	0	1	16	17
Moreover , the SGK1 inhibitor reversed the effects of LiCl and Wnt agonist on expression of Foxo3A and cleaved-caspase 3 in the presence of etoposide , an apoptosis inducer ( XREF_FIG ) , suggesting that SGK1 functional kinase activity was required for Wnt and beta-catenin mediated Foxo3A associated apoptosis .	Moreover, the SGK1 inhibitor reversed the effects of LiCl and Wnt agonist on expression of Foxo3A and cleaved-caspase 3 in the presence of etoposide, an apoptosis inducer (XREF_FIG), suggesting that SGK1 functional kinase activity was required for Wnt and beta-catenin mediated Foxo3A associated apoptosis.	35	47	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK1	SGK1	SGK1	Foxo3A	Foxo3A	Foxo3A	35	36	46	47
As shown in XREF_FIG , SGK1 silencing induced nuclear accumulation of Foxo3a , whereas ectopic expression of SGK1 triggered translocation of Foxo3a from the nucleus into the cytoplasm .	As shown in XREF_FIG, SGK1 silencing induced nuclear accumulation of Foxo3a, whereas ectopic expression of SGK1 triggered translocation of Foxo3a from the nucleus into the cytoplasm.	15	22	triggered	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK1	expression of SGK1	sgk1	Foxo3a	Foxo3a	foxo3a	17	18	21	22
Firstly , mTORC1 and S6K1 promote insulin receptor substrate-1 degradation [ XREF_BIBR ] .	Firstly, mTORC1 and S6K1 promote insulin receptor substrate-1 degradation [XREF_BIBR].	2	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	S6K1	S6K1	S6K1	insulin receptor substrate-1	insulin receptor substrate-1	insulin receptor substrate-1	4	5	6	9
It is known that angiotensin II inhibits the insulin metabolic signalling by promoting S6K1 mediated IRS-1 serine phosphorylation XREF_BIBR .	It is known that angiotensin II inhibits the insulin metabolic signalling by promoting S6K1 mediated IRS-1 serine phosphorylation XREF_BIBR.	13	18	mediated	Positive_early_activation	Negative_activation	Positive_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	13	14	15	16
Ang II promotes insulin resistance and inhibits insulin metabolic signalling by activating mTOR and thus promoting S6K1 mediated IRS-1 serine phosphorylation XREF_BIBR .	Ang II promotes insulin resistance and inhibits insulin metabolic signalling by activating mTOR and thus promoting S6K1 mediated IRS-1 serine phosphorylation XREF_BIBR.	15	21	mediated	Positive_early_activation	Negative_activation	Positive_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	16	17	18	19
Rapamycin enhances Akt activation by relieving a negative feedback loop in which S6K1 targets IRS-1 [ XREF_BIBR ] or growth factor receptors [ XREF_BIBR ] to downregulate Akt signaling through PI3K .	Rapamycin enhances Akt activation by relieving a negative feedback loop in which S6K1 targets IRS-1 [XREF_BIBR] or growth factor receptors [XREF_BIBR] to downregulate Akt signaling through PI3K.	12	16	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	S6K1	S6K1	S6K1	IRS-1	IRS-1	IRS-1	12	13	14	15
These studies suggest that , through serine phosphorylation , Raptor-mTOR and S6K1 cell autonomously promote the depletion of IRS1 from specific intracellular pools in pathological states of insulin and IGF-I resistance and thus potentially in lesions associated with tuberous sclerosis .	These studies suggest that, through serine phosphorylation, Raptor-mTOR and S6K1 cell autonomously promote the depletion of IRS1 from specific intracellular pools in pathological states of insulin and IGF-I resistance and thus potentially in lesions associated with tuberous sclerosis.	11	22	promote	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	S6K1	S6K1	S6K1	IRS1	IRS1	IRS1	11	12	18	19
This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase , increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates , constitutive activation of p70 S6 protein kinase , and an increased association of Grb2 with Shc in the absence of ligand .	This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates, constitutive activation of p70 S6 protein kinase, and an increased association of Grb2 with Shc in the absence of ligand.	5	30	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p70	p70	p70	IRS-1	IRS-1	IRS-1	27	28	7	8
Deletion of the NH 2 -terminal segment of SARM , which consists of the ARM-repeat domains required for nuclear shuttling , as documented in this study ( see XREF_FIG ) , enhanced inhibition of TRIF- and MyD88 mediated signaling XREF_BIBR .	Deletion of the NH 2 -terminal segment of SARM, which consists of the ARM-repeat domains required for nuclear shuttling, as documented in this study (see XREF_FIG), enhanced inhibition of TRIF- and MyD88 mediated signaling XREF_BIBR.	6	39	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SARM	SARM	SARM	TRIF-	TRIF-	TRIF-	8	9	34	35
Human SARM functions as a negative regulator of TIR-domain-containing adaptor protein inducing IFNbeta ( TRIF )-dependent signalling downstream of TLR3 and TLR4 ( XREF_FIG ) XREF_BIBR .	Human SARM functions as a negative regulator of TIR-domain-containing adaptor protein inducing IFNbeta (TRIF)-dependent signalling downstream of TLR3 and TLR4 (XREF_FIG) XREF_BIBR.	1	19	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	1	2	14	15
Negative regulators of TLR signaling include SIGIRR , MyD88s and IRAK-M , which block MyD88 dependent activation , or Triad3A and SARM , which block the TRIF dependent pathway .	Negative regulators of TLR signaling include SIGIRR, MyD88s and IRAK-M, which block MyD88 dependent activation, or Triad3A and SARM, which block the TRIF dependent pathway.	6	28	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	21	22	26	27
SARM associated with TRIF , and ' knockdown ' of endogenous SARM expression by interfering RNA led to enhanced TRIF dependent cytokine and chemokine induction .	SARM associated with TRIF, and ' knockdown ' of endogenous SARM expression by interfering RNA led to enhanced TRIF dependent cytokine and chemokine induction.	0	21	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	SARM	SARM	SARM	TRIF	TRIF	TRIF	0	1	19	20
We showed that RXRalpha activated the Wnt and beta-catenin and NF-kappaB survival pathways to induce CCA cell growth .	We showed that RXRalpha activated the Wnt and beta-catenin and NF-kappaB survival pathways to induce CCA cell growth.	3	14	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RXRalpha	RXRalpha	RXRalpha	beta-catenin	beta-catenin	beta-catenin	3	4	8	9
In conclusion , our study showed that RXRalpha is able to simultaneously activate the Wnt and beta-catenin and NF-kappaB pathways to promote CCA cell proliferation and survival .	In conclusion, our study showed that RXRalpha is able to simultaneously activate the Wnt and beta-catenin and NF-kappaB pathways to promote CCA cell proliferation and survival.	7	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RXRalpha	RXRalpha	RXRalpha	beta-catenin	beta-catenin	beta-catenin	7	8	16	17
Retinoid X receptor alpha knockdown inhibits activation of Wnt and beta-catenin pathway .	Retinoid X receptor alpha knockdown inhibits activation of Wnt and beta-catenin pathway.	0	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Retinoid X receptor alpha	Retinoid X receptor alpha	Retinoid X receptor alpha	beta-catenin	beta-catenin	beta-catenin	0	4	10	11
At first , this may appear to contradict recent work showing LAP is dependent on Rubicon mediated VPS34 activity and PI3P ( Martinez etal , 2015 ) .	At first, this may appear to contradict recent work showing LAP is dependent on Rubicon mediated VPS34 activity and PI3P (Martinez etal, 2015).	13	18	mediated	Positive_early_activation	Negative_activation	Positive_activation	Rubicon	Rubicon	Rubicon	VPS34	VPS34	VPS34	15	16	17	18
To examine whether Rubicon also modulates the Vps34 lipid kinase activity , we performed the above described lipid kinase assay .	To examine whether Rubicon also modulates the Vps34 lipid kinase activity, we performed the above described lipid kinase assay.	3	10	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Rubicon	Rubicon	Rubicon	Vps34	Vps34	Vps34	3	4	7	8
Finally , our data suggests that the function of beclin 1 in endosome pathways depends on the interaction between beclin 1 and UVRAG , but not Atg14L or RUBICON , all of which are important binding partners of beclin 1 that exist in distinct beclin 1 complexes and modulate VPS34 lipid kinase activity .	Finally, our data suggests that the function of beclin 1 in endosome pathways depends on the interaction between beclin 1 and UVRAG, but not Atg14L or RUBICON, all of which are important binding partners of beclin 1 that exist in distinct beclin 1 complexes and modulate VPS34 lipid kinase activity.	17	52	modulate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	RUBICON	RUBICON	RUBICON	VPS34	VPS34	VPS34	28	29	49	50
RSPO1 promotes WNT signaling by inducing membrane clearance of ZNRF3 , and the related molecule RNF43 , and given the elevated levels of Rspo1 in the XX gonad at the sex determining stage , we conclude that ZNRF3 activity is reduced in XX supporting cells and therefore elevated in XY cells .	RSPO1 promotes WNT signaling by inducing membrane clearance of ZNRF3, and the related molecule RNF43, and given the elevated levels of Rspo1 in the XX gonad at the sex determining stage, we conclude that ZNRF3 activity is reduced in XX supporting cells and therefore elevated in XY cells.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RSPO1	RSPO1	RSPO1	ZNRF3	ZNRF3	ZNRF3	0	1	9	10
Data have shown that RSPO1 induces the clearance of Znrf3 from the membrane by interacting with the extracellular domains of Lgr4 and Znrf3 , which stabilize the Frizzled and Lrp6 receptors in order to enhance Wnt and beta-catenin signalling [ XREF_BIBR ] .	Data have shown that RSPO1 induces the clearance of Znrf3 from the membrane by interacting with the extracellular domains of Lgr4 and Znrf3, which stabilize the Frizzled and Lrp6 receptors in order to enhance Wnt and beta-catenin signalling [XREF_BIBR].	4	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	RSPO1	RSPO1	RSPO1	Znrf3	Znrf3	Znrf3	4	5	9	10
Importantly , concomitant Rspo1 overexpression completely reversed LGR5 , Znrf3 or Rnf43 ECD repression of Lgr5 + ISCs , underscoring specificity ( XREF_FIG ) .	Importantly, concomitant Rspo1 overexpression completely reversed LGR5, Znrf3 or Rnf43 ECD repression of Lgr5 + ISCs, underscoring specificity (XREF_FIG).	3	13	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Rspo1	Rspo1 overexpression	rspo1	Znrf3	Znrf3	znrf3	3	4	9	10
XREF_BIBR , XREF_BIBR Thus , we first evaluated the p27 level in HCT116 cells treated with the SGK1 overexpression plasmids or SGK1 inhibitor .	XREF_BIBR, XREF_BIBR Thus, we first evaluated the p27 level in HCT116 cells treated with the SGK1 overexpression plasmids or SGK1 inhibitor.	9	19	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	SGK1	SGK1	SGK1	p27	p27	p27	17	18	9	10
The placement of p27 downstream of various AGC kinases ( SGK , RSK , AKT ) highlights the tremendous potential for PI3K and mTOR inhibitors to restore normal p27 function .	The placement of p27 downstream of various AGC kinases (SGK, RSK, AKT) highlights the tremendous potential for PI3K and mTOR inhibitors to restore normal p27 function.	1	29	restore	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK	SGK	SGK	p27	p27	p27	10	11	28	29
Similarly , when T47D and Wnt1 or SkBr3 and Wnt1 cells were treated with sFRP1 for 2 hours prior to lysis of the cells , the level of ERK1/2 phosphorylation was strongly decreased .	Similarly, when T47D and Wnt1 or SkBr3 and Wnt1 cells were treated with sFRP1 for 2 hours prior to lysis of the cells, the level of ERK1/2 phosphorylation was strongly decreased.	3	15	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	sFRP1	sFRP1	sFRP1	Wnt1	Wnt1	Wnt1	14	15	5	6
The observation that SGK1 targets FOXO1 in differentiating human endometrium , together with its distinct temporal and spatial expression pattern and increased expression in infertile patients , suggest a major role for this kinase in early pregnancy events .	The observation that SGK1 targets FOXO1 in differentiating human endometrium, together with its distinct temporal and spatial expression pattern and increased expression in infertile patients, suggest a major role for this kinase in early pregnancy events.	1	7	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SGK1	SGK1	SGK1	FOXO1	FOXO1	FOXO1	3	4	5	6
Association with Skp2 targets p27 for degradation .	Association with Skp2 targets p27 for degradation.	0	5	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	2	3	4	5
This was surprising because studies described above in rodents and humans suggest that p27 kip1 downregulation is important for a normal progression of beta-cell cycle , and that Skp2 mediated p27 kip1 proteolysis is the principal regulator of p27 kip1 in beta-cells in mice .	This was surprising because studies described above in rodents and humans suggest that p27 kip1 downregulation is important for a normal progression of beta-cell cycle, and that Skp2 mediated p27 kip1 proteolysis is the principal regulator of p27 kip1 in beta-cells in mice.	28	36	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27 kip1	p27 kip1	p27 kip1	28	29	30	32
Surprisingly , it was discovered that inactivation of SKP2 in RB deficient cells did not inhibit proliferation , but rather induced a p27 dependent apoptotic programme .	Surprisingly, it was discovered that inactivation of SKP2 in RB deficient cells did not inhibit proliferation, but rather induced a p27 dependent apoptotic programme.	6	25	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	8	9	22	23
FKA treatments do not affect Skp2 expression at the transcriptional levels ( data not shown ) , but down-regulates the protein expression of Skp2 and induces the accumulation of p27 protein , a Skp2 substrate , in prostate cancer cell lines in a dose and time manner .	FKA treatments do not affect Skp2 expression at the transcriptional levels (data not shown), but down-regulates the protein expression of Skp2 and induces the accumulation of p27 protein, a Skp2 substrate, in prostate cancer cell lines in a dose and time manner.	0	30	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	FKA treatments do not affect Skp2 expression at the transcriptional levels (data not shown), but down-regulates the protein expression of Skp2	skp2	p27	p27	p27	23	24	29	30
These results suggest that salinomycin induced Skp2 downregulation , which allows the p27Kip1 accumulation that is critical for G1 arrest and cell growth inhibition .	These results suggest that salinomycin induced Skp2 downregulation, which allows the p27Kip1 accumulation that is critical for G1 arrest and cell growth inhibition.	6	13	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27Kip1	p27Kip1	p27Kip1	6	7	12	13
This was in part due to MYC dependent induction of SKP2 , a component of the ubiquitin ligase complex that targets p27 for degradation .	This was in part due to MYC dependent induction of SKP2, a component of the ubiquitin ligase complex that targets p27 for degradation.	8	23	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	10	11	21	22
SIRT2 inhibits non small cell lung cancer cell growth through impairing Skp2 mediated p27 [ XREF_BIBR ] .	SIRT2 inhibits non small cell lung cancer cell growth through impairing Skp2 mediated p27 [XREF_BIBR].	8	14	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	11	12	13	14
Up-regulation of Skp2 triggers the G1-S phase transition in precursor cells by regulating p27 and thus stimulates quiescent cochlear precursor cells to proliferate [ XREF_BIBR ] , and this suggests a potential role in cell cycle regulation in ALPs .	Up-regulation of Skp2 triggers the G1-S phase transition in precursor cells by regulating p27 and thus stimulates quiescent cochlear precursor cells to proliferate [XREF_BIBR], and this suggests a potential role in cell cycle regulation in ALPs.	0	14	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	2	3	13	14
Increased expression of Skp2 , the predominant ubiquitin ligase that targets p27 for degradation , has been correlated with decreased p27 levels and poor prognosis in young women with breast cancer and in patients with Her2- breast tumors [ XREF_BIBR , XREF_BIBR ] .	Increased expression of Skp2, the predominant ubiquitin ligase that targets p27 for degradation, has been correlated with decreased p27 levels and poor prognosis in young women with breast cancer and in patients with Her2- breast tumors [XREF_BIBR, XREF_BIBR].	1	13	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	3	4	11	12
In several human cancers , overexpression of Skp2 ( S-phase kinase associated protein 2 ) , which targets p27 for degradation , portends a poorer prognosis .	In several human cancers, overexpression of Skp2 (S-phase kinase associated protein 2), which targets p27 for degradation, portends a poorer prognosis.	5	20	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	overexpression of Skp2	skp2	p27	p27	p27	7	8	18	19
Moreover , silencing of SKP2 abrogated the MYC mediated down-regulation of p27 .	Moreover, silencing of SKP2 abrogated the MYC mediated down-regulation of p27.	2	12	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	4	5	11	12
For example , in HepG2 human hepatoma cells , Skp2 induces cell cycle progression via the activation of c-Myc transcriptional activity and independently of p27 kip1 expression XREF_BIBR .	For example, in HepG2 human hepatoma cells, Skp2 induces cell cycle progression via the activation of c-Myc transcriptional activity and independently of p27 kip1 expression XREF_BIBR.	9	27	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27 kip1	p27 kip1	p27 kip1	9	10	24	26
Specific Small Molecule Inhibitors of Skp2 Mediated p27 Degradation .	Specific Small Molecule Inhibitors of Skp2 Mediated p27 Degradation.	3	8	Mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	5	6	7	8
Previous reports from our lab have shown that increased Skp2 targets p27 for ubiquitylation and proteasome degradation in adipocytes XREF_BIBR , XREF_BIBR .	Previous reports from our lab have shown that increased Skp2 targets p27 for ubiquitylation and proteasome degradation in adipocytes XREF_BIBR, XREF_BIBR.	8	12	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	9	10	11	12
In the presence of ALK F1174L signaling , MYCN induces the expression of the ubiquitin ligase SKP2 ( S-phase kinase associated protein 2 ) , which targets p27 for degradation and is also upregulated in high-risk NB .	In the presence of ALK F1174L signaling, MYCN induces the expression of the ubiquitin ligase SKP2 (S-phase kinase associated protein 2), which targets p27 for degradation and is also upregulated in high-risk NB.	8	28	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	MYCN induces the expression of the ubiquitin ligase SKP2	skp2	p27	p27	p27	16	17	27	28
Knockdown of SKP2 in both HTB2 and HT1376 indeed relieved the repression of p27 that occurred in the AMPKalpha2 knockdown cells ( XREF_FIG ) .	Knockdown of SKP2 in both HTB2 and HT1376 indeed relieved the repression of p27 that occurred in the AMPKalpha2 knockdown cells (XREF_FIG).	0	22	relieved	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	2	3	13	14
Furthermore , we demonstrate that ATRA promotes the ubiquitylation of Skp2 , an F-box protein that targets p27 for degradation .	Furthermore, we demonstrate that ATRA promotes the ubiquitylation of Skp2, an F-box protein that targets p27 for degradation.	5	19	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	ATRA promotes the ubiquitylation of Skp2	skp2	p27	p27	p27	10	11	17	18
In the present study , we investigated whether degradation of p27 targeted by Skp2 is required for the development of tubulointerstitial injury in UUO kidneys by comparing WT , Skp2 -/- and p27 -/- mice with Skp2 -/- p27 -/- mice .	In the present study, we investigated whether degradation of p27 targeted by Skp2 is required for the development of tubulointerstitial injury in UUO kidneys by comparing WT, Skp2 -/- and p27 -/- mice with Skp2 -/- p27 -/- mice.	8	14	targeted	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	13	14	10	11
Since miR221/222 and Skp2 must both be inhibited to prevent p27 down-regulation ( refer to XREF_FIG ) and since Skp2 is required in S phase , we propose that miR221/222 has a major role tranducing the effect of cicaprost on G1 phase p27 .	Since miR221/222 and Skp2 must both be inhibited to prevent p27 down-regulation (refer to XREF_FIG) and since Skp2 is required in S phase, we propose that miR221/222 has a major role tranducing the effect of cicaprost on G1 phase p27.	1	11	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	10	11
In epithelial cells , TGFbeta signaling targets p27 for stability XREF_BIBR , XREF_BIBR - XREF_BIBR , and such effect is mediated by TGFbeta induction of Skp2 degradation XREF_BIBR .	In epithelial cells, TGFbeta signaling targets p27 for stability XREF_BIBR, XREF_BIBR - XREF_BIBR, and such effect is mediated by TGFbeta induction of Skp2 degradation XREF_BIBR.	4	27	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	25	26	7	8
In the androgen depleted cells , Skp2 expression was low while p27 was high , suggesting that androgens play a role in decreasing Skp2 expression which leads to increased p27 and cell cycle arrest .	In the androgen depleted cells, Skp2 expression was low while p27 was high, suggesting that androgens play a role in decreasing Skp2 expression which leads to increased p27 and cell cycle arrest.	23	33	leads	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Skp2	Skp2 expression	skp2	p27	p27	p27	23	24	29	30
SIRT2 inhibits non small cell lung cancer cell growth through impairing Skp2 mediated p27 degradation .	SIRT2 inhibits non small cell lung cancer cell growth through impairing Skp2 mediated p27 degradation.	8	14	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	11	12	13	14
Previous studies have shown that in contrast to nuclear Skp2 which targets nuclear p27 as shown above , cytoplasmic Skp2 has a distinct set of substrates , including forkhead box O ( FoxO ) transcription factors which are important pro apoptotic transcription factors that block cellular proliferation , promote cell death and drives cells into a quiescent state .	Previous studies have shown that in contrast to nuclear Skp2 which targets nuclear p27 as shown above, cytoplasmic Skp2 has a distinct set of substrates, including forkhead box O (FoxO) transcription factors which are important pro apoptotic transcription factors that block cellular proliferation, promote cell death and drives cells into a quiescent state.	6	15	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	9	10	13	14
The association of p27 with the ubiquitin ligase subunit Skp2 targets p27 for degradation .	The association of p27 with the ubiquitin ligase subunit Skp2 targets p27 for degradation.	3	13	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	9	10	11	12
It also remains to be seen whether SKP2 targets p27 in the context of a ternary complex with MYC , whether SKP2 induced ubiquitylation and degradation of p27 and MYC occurs at chromatin as part of a coactivator function and how this affects MYC driven transcription mechanistically .	It also remains to be seen whether SKP2 targets p27 in the context of a ternary complex with MYC, whether SKP2 induced ubiquitylation and degradation of p27 and MYC occurs at chromatin as part of a coactivator function and how this affects MYC driven transcription mechanistically.	7	30	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	7	8	9	10
Both Skp2-deficiency and treatment with the Skp2 inhibitor SZL-P1-41 increased p27 levels in the BLM infused model suggesting that Skp2 targets p27 for degradation in pulmonary fibrosis ; however , it has been reported that Skp2 targets many important proteins in addition to p27 , including p21 , p57 , p130 , p300 , Tob1 , FOXO1 , Akt , and RASSF for ubiquitin mediated proteasomal degradation [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	Both Skp2-deficiency and treatment with the Skp2 inhibitor SZL-P1-41 increased p27 levels in the BLM infused model suggesting that Skp2 targets p27 for degradation in pulmonary fibrosis; however, it has been reported that Skp2 targets many important proteins in addition to p27, including p21, p57, p130, p300, Tob1, FOXO1, Akt, and RASSF for ubiquitin mediated proteasomal degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	17	26	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	19	20	21	22
Our observation that Skp2 promotes the activity of CDKs by downregulating p27 suggests that Skp2 may positively regulate MAD2 expression via CDKs-E2F1 axis .	Our observation that Skp2 promotes the activity of CDKs by downregulating p27 suggests that Skp2 may positively regulate MAD2 expression via CDKs-E2F1 axis.	3	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	11	12
Finally , the expression of skp2 , the ubiquitin ligase that targets p27 for degradation , was seen to increase with androgen administration , preceding maximal proliferation and concomitantly to augmented p27 degradation activity .	Finally, the expression of skp2, the ubiquitin ligase that targets p27 for degradation, was seen to increase with androgen administration, preceding maximal proliferation and concomitantly to augmented p27 degradation activity.	3	14	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	skp2	expression of skp2	skp2	p27	p27	p27	5	6	12	13
In yet another report it was found that retinoic acid downregulates the expression of the Cks1 and Skp2 proteins thus slowing down p27 Kip1 degradation in lymphoblastoid B cell lines [ XREF_BIBR ] .	In yet another report it was found that retinoic acid downregulates the expression of the Cks1 and Skp2 proteins thus slowing down p27 Kip1 degradation in lymphoblastoid B cell lines [XREF_BIBR].	12	24	slowing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	expression of the Cks1 and Skp2	skp2	p27 Kip1	p27 Kip1	p27 kip1	17	18	22	24
In addition , an ubiquitin E3 ligase , the SCF ( SKP2 ) complex , mediates p27 ( Kip1 ) ubiquitin dependent proteolysis .	In addition, an ubiquitin E3 ligase, the SCF (SKP2) complex, mediates p27 (Kip1) ubiquitin dependent proteolysis.	11	22	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	11	12	16	17
Collectively , the results in XREF_SUPPLEMENTARY and 3 indicate that either the Skp2 or miR221/222 pathway is sufficient to stimulate p27 downregulation .	Collectively, the results in XREF_SUPPLEMENTARY and 3 indicate that either the Skp2 or miR221/222 pathway is sufficient to stimulate p27 downregulation.	10	21	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	12	13	20	21
Overexpression of wild-type Skp-2 in SMCs decreased p27 ( Kip1 ) levels , whereas dominant negative F-box deleted mutant ( DeltaF-Skp-2 ) Skp-2 increased p27 ( Kip1 ) levels .	Overexpression of wild-type Skp-2 in SMCs decreased p27 (Kip1) levels, whereas dominant negative F-box deleted mutant (DeltaF-Skp-2) Skp-2 increased p27 (Kip1) levels.	22	25	increased	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Skp-2	Skp-2	Skp-2	p27	p27	p27	22	23	24	25
Moreover , cdc kinase subunit 1 ( Cks1 ) is required for degradation of p27 mediated by Skp2 XREF_BIBR .	Moreover, cdc kinase subunit 1 (Cks1) is required for degradation of p27 mediated by Skp2 XREF_BIBR.	12	18	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	17	18	14	15
In addition , there remains a p53 independent cellular senescence mechanism that still depends on its authentic downstream target , p21 Waf1/Cip1/Cdkn1a , among others , such as Arf and p27 Kip1 and Cdkn1b triggered by Skp2 inactivation XREF_BIBR .	In addition, there remains a p53 independent cellular senescence mechanism that still depends on its authentic downstream target, p21 Waf1/Cip1/Cdkn1a, among others, such as Arf and p27 Kip1 and Cdkn1b triggered by Skp2 inactivation XREF_BIBR.	28	38	triggered	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	36	37	30	32
Talking all our findings into consideration , it is suggested that degradation of p27 targeted by Skp2 accelerated the progression of renal tubular epithelial cell proliferation , tubular dilation and tubulointerstitial fibrosis in UUO renal injury .	Talking all our findings into consideration, it is suggested that degradation of p27 targeted by Skp2 accelerated the progression of renal tubular epithelial cell proliferation, tubular dilation and tubulointerstitial fibrosis in UUO renal injury.	11	17	targeted	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	16	17	13	14
These findings suggest a pathogenic role of the reduction in p27 targeted by Skp2 in the progression of nephropathy in UUO mice .	These findings suggest a pathogenic role of the reduction in p27 targeted by Skp2 in the progression of nephropathy in UUO mice.	8	14	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	13	14	10	11
Zearalenone treatment of MCF-7 cells elicited expression of F-box protein S phase kinase associated protein 2 ( p45 ( SKP2 ) ) , a substrate specific component of the ubiquitin and ligase complex that targets p27 ( KIP1 ) for degradation in the proteasome .	Zearalenone treatment of MCF-7 cells elicited expression of F-box protein S phase kinase associated protein 2 (p45 (SKP2)), a substrate specific component of the ubiquitin and ligase complex that targets p27 (KIP1) for degradation in the proteasome.	14	40	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	19	20	35	36
XREF_FIG B shows that AMPKalpha2 knockdown significantly reduced p27 Kip1 protein level ( p < 0.05 versus control siRNA transfection ) , while prior depletion of Skp2 abrogated the reduction of p27 Kip1 , which increased from 0.50-fold to 1.30-fold over control siRNA ( p < 0.01 versus control siRNA + AMPKalpha2 siRNA transfection ) .	XREF_FIG B shows that AMPKalpha2 knockdown significantly reduced p27 Kip1 protein level (p < 0.05 versus control siRNA transfection), while prior depletion of Skp2 abrogated the reduction of p27 Kip1, which increased from 0.50-fold to 1.30-fold over control siRNA (p < 0.01 versus control siRNA + AMPKalpha2 siRNA transfection).	24	33	abrogated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	26	27	31	33
This surprising finding has led to the notion that there must be mechanisms compensating for loss of Skp2 mediated p27 degradation .	This surprising finding has led to the notion that there must be mechanisms compensating for loss of Skp2 mediated p27 degradation.	15	20	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	17	18	19	20
Thus , PGI 2 can regulate p27 levels even when Skp2 mediated p27 proteolysis is absent .	Thus, PGI 2 can regulate p27 levels even when Skp2 mediated p27 proteolysis is absent.	10	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	10	11	12	13
Skp2 overexpression is known to promote cell proliferation by triggering p27 degradation XREF_BIBR , XREF_BIBR .	Skp2 overexpression is known to promote cell proliferation by triggering p27 degradation XREF_BIBR, XREF_BIBR.	0	12	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2 overexpression	skp2	p27	p27	p27	0	1	10	11
In this study , we investigated a role of Skp2 , which targets CDK2 inhibitor p27 and Kip1 , in actin damage induced tetraploid G1 arrest .	In this study, we investigated a role of Skp2, which targets CDK2 inhibitor p27 and Kip1, in actin damage induced tetraploid G1 arrest.	7	17	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	9	10	15	16
50 In addition to using the CUL1 containing SCF complex , Skp2 interacts with CUL4A-DDB1-associated COP9 signalosomes to induce proteolysis of p27Kip1 .	50 In addition to using the CUL1 containing SCF complex, Skp2 interacts with CUL4A-DDB1-associated COP9 signalosomes to induce proteolysis of p27Kip1.	11	22	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27Kip1	p27Kip1	p27Kip1	11	12	21	22
Nuclear p27 is targeted for degradation by Skp2 E3 ligase .	Nuclear p27 is targeted for degradation by Skp2 E3 ligase.	0	9	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	7	8	1	2
Foxo3a is found to be a transcriptional repressor of Skp2 gene expression by directly binding to the Skp2 promoter , thereby inhibiting Skp2 protein expression , which in turn promotes p27 Kip1 stability .	Foxo3a is found to be a transcriptional repressor of Skp2 gene expression by directly binding to the Skp2 promoter, thereby inhibiting Skp2 protein expression, which in turn promotes p27 Kip1 stability.	22	32	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2 protein expression	skp2	p27 Kip1	p27 Kip1	p27 kip1	22	23	30	32
Early reports demonstrated that Skp2 recognizes and targets cell cycle inhibitors p21 Cip1 and WAF and p27 Kip1 , leads to their ubiquitination and degradation , and further causes cell cycle progression [ XREF_BIBR ] .	Early reports demonstrated that Skp2 recognizes and targets cell cycle inhibitors p21 Cip1 and WAF and p27 Kip1, leads to their ubiquitination and degradation, and further causes cell cycle progression [XREF_BIBR].	4	28	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	4	5	16	18
Using this new approach , we characterized in ACC a previously unknown population of tumorigenic CD133 + cells that expressed SOX10 , NOTCH1 , activated intracellular NOTCH1 domain ( N1ICD ) , and canonical NOTCH1 targets including SKP2 , an E3 ubiquitin ligase that targets p27Kip1 for degradation and stimulates proliferation of CSC .	Using this new approach, we characterized in ACC a previously unknown population of tumorigenic CD133 + cells that expressed SOX10, NOTCH1, activated intracellular NOTCH1 domain (N1ICD), and canonical NOTCH1 targets including SKP2, an E3 ubiquitin ligase that targets p27Kip1 for degradation and stimulates proliferation of CSC.	35	46	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27Kip1	p27Kip1	p27Kip1	37	38	45	46
Despite redundant functions between Cks1 and Cks2 XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR , sequence divergence in the Skp2 binding region results in opposing roles during degradation of the Skp2 target p27 .	Despite redundant functions between Cks1 and Cks2 XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, sequence divergence in the Skp2 binding region results in opposing roles during degradation of the Skp2 target p27.	27	33	target	Positive_activation_token_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	30	31	32	33
This demonstrates that Skp2 alone is sufficient to promote p27 Kip1 downregulation and VSMC proliferation in the absence of major medial injury .	This demonstrates that Skp2 alone is sufficient to promote p27 Kip1 downregulation and VSMC proliferation in the absence of major medial injury.	3	11	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	3	4	9	11
The expression of Skp2 , the ubiquitin ligase subunit that targets p27 ( Kip1 ) for degradation , is commonly overexpressed in human cancers .	The expression of Skp2, the ubiquitin ligase subunit that targets p27 (Kip1) for degradation, is commonly overexpressed in human cancers.	1	16	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	3	4	11	12
We extended this line of pituitary studies to Skp2 target p27 .	We extended this line of pituitary studies to Skp2 target p27.	1	11	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	8	9	10	11
Similarly , expression of a dominant negative form of SKP2 ( SKP2DeltaF ) that prevents p27 Kip1 degradation , increased rates of differentiation in HL-60 cells which indicated a direct impact of SKP2 on cell differentiation .	Similarly, expression of a dominant negative form of SKP2 (SKP2DeltaF) that prevents p27 Kip1 degradation, increased rates of differentiation in HL-60 cells which indicated a direct impact of SKP2 on cell differentiation.	7	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27 Kip1	p27 Kip1	p27 Kip1	9	10	15	17
In addition to the CUL1 containing SCF SKP2 complex , SKP2 can also target p27 for ubiquitylation and degradation by another SCF complex containing CUL4A and the damaged DNA binding protein DDB1 , which is associated with the COP9 signalosome , a complex with isopeptidase activity [ XREF_BIBR ] .	In addition to the CUL1 containing SCF SKP2 complex, SKP2 can also target p27 for ubiquitylation and degradation by another SCF complex containing CUL4A and the damaged DNA binding protein DDB1, which is associated with the COP9 signalosome, a complex with isopeptidase activity [XREF_BIBR].	10	18	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	10	11	14	15
The accurately ordered cell cycle also includes the timely degradation of many regulatory proteins via ubiquitin mediated proteolysis ; the SCF complexes represent a big family of ubiquitin ligases that determine the abundance of cell cycle regulatory proteins ; Skp2 promotes the ubiquitinylation of the CDKIs , p21 , and p27 , thereby enhancing CDK2 activation at the G1/S border [ XREF_BIBR , XREF_BIBR ] .	The accurately ordered cell cycle also includes the timely degradation of many regulatory proteins via ubiquitin mediated proteolysis; the SCF complexes represent a big family of ubiquitin ligases that determine the abundance of cell cycle regulatory proteins; Skp2 promotes the ubiquitinylation of the CDKIs, p21, and p27, thereby enhancing CDK2 activation at the G1/S border [XREF_BIBR, XREF_BIBR].	39	51	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	39	40	50	51
In the absence of growth promoting signals , pRB interacts with the N terminus of SKP2 and inhibits SKP2 mediated p27 KIP1 degradation [ XREF_BIBR ] .	In the absence of growth promoting signals, pRB interacts with the N terminus of SKP2 and inhibits SKP2 mediated p27 KIP1 degradation [XREF_BIBR].	18	22	mediated	Positive_early_activation	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27 KIP1	p27 KIP1	p27 KIP1	18	19	20	22
After activated by the phosphorylated Akt ( Akt-P ) , Skp-2 mediates the proteolysis of p27 kip1 [ XREF_BIBR ] .	After activated by the phosphorylated Akt (Akt-P), Skp-2 mediates the proteolysis of p27 kip1 [XREF_BIBR].	10	18	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp-2	Skp-2	Skp-2	p27 kip1	p27 kip1	p27 kip1	10	11	15	17
Ectopic expression of Skp2 led to a marked decrease in cyclin E1 expression and restored the rapid down-regulation of p27 in response to serum growth factors ( XREF_FIG E ) .	Ectopic expression of Skp2 led to a marked decrease in cyclin E1 expression and restored the rapid down-regulation of p27 in response to serum growth factors (XREF_FIG E).	1	20	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	3	4	19	20
Of remarkable importance is the finding that PD-1 blocks T-cell cycle progression through the G 1 phase by suppressing the transcription of SKP2 , a factor encoding a component of the ubiquitin ligase SCF Skp2 able to degrade p27 kip1 , an inhibitor of cyclin dependent kinases [ XREF_BIBR ] .	Of remarkable importance is the finding that PD-1 blocks T-cell cycle progression through the G 1 phase by suppressing the transcription of SKP2, a factor encoding a component of the ubiquitin ligase SCF Skp2 able to degrade p27 kip1, an inhibitor of cyclin dependent kinases [XREF_BIBR].	7	40	degrade	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	SKP2	PD-1 blocks T-cell cycle progression through the G 1 phase by suppressing the transcription of SKP2	skp2	p27 kip1	p27 kip1	p27 kip1	22	23	38	40
subsequently described the SKP2 autoinduction loop comprising pRB-E2F , SKP2 , p27 KIP1 , and Cyclin E-CDK2 , in which SKP2 expression initiates proteolysis of p27 KIP1 , activation of Cyclin E-CDK2 which feeds back to sustain pRB inactivation , E2F release , and further induction of the SKP2 gene .	subsequently described the SKP2 autoinduction loop comprising pRB-E2F, SKP2, p27 KIP1, and Cyclin E-CDK2, in which SKP2 expression initiates proteolysis of p27 KIP1, activation of Cyclin E-CDK2 which feeds back to sustain pRB inactivation, E2F release, and further induction of the SKP2 gene.	20	27	initiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2 expression	skp2	p27 KIP1	p27 KIP1	p27 kip1	20	21	25	27
Skp2 , which targets p27 for degradation , was significantly lower and inversely related to p27 protein levels in hypoxic cells .	Skp2, which targets p27 for degradation, was significantly lower and inversely related to p27 protein levels in hypoxic cells.	0	13	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	4	5
Cone precursor features that collaborated with Rb loss included cone lineage factors ( TRbeta2 , RXRgamma ) , highly expressed oncoproteins ( MYCN and MDM2 ) , and p27 down-regulation likely mediated by SKP2 .	Cone precursor features that collaborated with Rb loss included cone lineage factors (TRbeta2, RXRgamma), highly expressed oncoproteins (MYCN and MDM2), and p27 down-regulation likely mediated by SKP2.	28	34	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	33	34	28	29
These findings suggest that the decrease in p27 targeted by Skp2 is involved in the progression of UUO renal injury .	These findings suggest that the decrease in p27 targeted by Skp2 is involved in the progression of UUO renal injury.	5	11	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	10	11	7	8
SKP2 has been shown to target P27 Kip1 and cyclin E for degradation and control the cell cycle at the G1-S transition XREF_BIBR .	SKP2 has been shown to target P27 Kip1 and cyclin E for degradation and control the cell cycle at the G1-S transition XREF_BIBR.	0	14	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	P27 Kip1	P27 Kip1	P27 Kip1	0	1	6	8
Rac activation normally promotes VSMC proliferation and neointima formation , whereas inhibition of Rac by PKA and EPAC1 leads to upregulation of the cell cycle inhibitor p27 ( KIP1 ) through suppression of Skp2 , an F-box protein component of the Skp-Cullin-F-box ( Skp2 ) ubiquitin ligase , which normally targets p27 ( KIP1 ) for proteolytic degradation during S phase XREF_BIBR ( XREF_FIG ) .	Rac activation normally promotes VSMC proliferation and neointima formation, whereas inhibition of Rac by PKA and EPAC1 leads to upregulation of the cell cycle inhibitor p27 (KIP1) through suppression of Skp2, an F-box protein component of the Skp-Cullin-F-box (Skp2) ubiquitin ligase, which normally targets p27 (KIP1) for proteolytic degradation during S phase XREF_BIBR (XREF_FIG).	43	57	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	43	44	51	52
We have shown recently that Tax stablizes p27 protein in part by causing APC/C mediated poly-ubiquitination and degradation of Skp2 , the substrate-recognition subunit of SCF Skp2 , the E3 ubiquitin ligase that targets p27 for destruction XREF_BIBR .	We have shown recently that Tax stablizes p27 protein in part by causing APC/C mediated poly-ubiquitination and degradation of Skp2, the substrate-recognition subunit of SCF Skp2, the E3 ubiquitin ligase that targets p27 for destruction XREF_BIBR.	13	37	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	APC/C mediated poly-ubiquitination and degradation of Skp2	skp2	p27	p27	p27	19	20	34	35
Wu et al demonstrated that Skp2 alone is sufficient to promote p27 down-regulation and vascular smooth muscle cell proliferation XREF_BIBR .	Wu et al demonstrated that Skp2 alone is sufficient to promote p27 down-regulation and vascular smooth muscle cell proliferation XREF_BIBR.	5	12	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	5	6	11	12
Here we present evidence that lovastatin can induce the degradation of Skp2 , a subunit of the SCF Skp2 ubiquitin ligase that targets p27 Kip1 and p21 Cip1 for proteasomal destruction .	Here we present evidence that lovastatin can induce the degradation of Skp2, a subunit of the SCF Skp2 ubiquitin ligase that targets p27 Kip1 and p21 Cip1 for proteasomal destruction.	9	25	targets	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	11	12	23	25
Studies in mice show that Fbxl1 mediated degradation of the negative cell cycle regulator p27 is critical for female gamete development [ XREF_BIBR ] .	Studies in mice show that Fbxl1 mediated degradation of the negative cell cycle regulator p27 is critical for female gamete development [XREF_BIBR].	5	15	degradation	Negative_activation_syntax_3_noun	Negative_activation	Positive_activation	Fbxl1	Fbxl1	Fbxl1	p27	p27	p27	5	6	14	15
We conclude that miR-221/222 compensates for loss of Skp2 mediated p27 degradation during cell cycling , contributes to proteasome dependent G1 phase regulation of p27 , and accounts for the anti-mitogenic effect of cAMP during growth inhibition .	We conclude that miR-221/222 compensates for loss of Skp2 mediated p27 degradation during cell cycling, contributes to proteasome dependent G1 phase regulation of p27, and accounts for the anti-mitogenic effect of cAMP during growth inhibition.	6	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	8	9	10	11
Inhibition of serum induced miR221/222 by cicaprost was seen in both WT and p27T187A VSMCs ( XREF_SUPPLEMENTARY ) , indicating that Skp2 mediated p27 degradation is not required for the effect .	Inhibition of serum induced miR221/222 by cicaprost was seen in both WT and p27T187A VSMCs (XREF_SUPPLEMENTARY), indicating that Skp2 mediated p27 degradation is not required for the effect.	21	27	mediated	Positive_early_activation	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27	p27	p27	21	22	23	24
To further examine the mechanism of the troglitazone induced p27 ( Kip1 ) protein accumulation , 2 major systems for regulation of p27 ( Kip1 ) protein , proteasome activity and Skp2 , an F-box protein that targets p27 ( Kip1 ) for degradation , were evaluated .	To further examine the mechanism of the troglitazone induced p27 (Kip1) protein accumulation, 2 major systems for regulation of p27 (Kip1) protein, proteasome activity and Skp2, an F-box protein that targets p27 (Kip1) for degradation, were evaluated.	29	46	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	31	32	38	39
Stabilization of p27kip1 by LXR ligands was mediated by supressing the transcriptional activation of the S phase kinase associated protein 2 ( Skp2 ) , an F-box protein that targets p27Kip1 for degradation .	Stabilization of p27kip1 by LXR ligands was mediated by supressing the transcriptional activation of the S phase kinase associated protein 2 (Skp2), an F-box protein that targets p27Kip1 for degradation.	19	32	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27Kip1	p27Kip1	p27Kip1	22	23	30	31
On the other hand , SKP2 , the E3 ligase of the SKP1-Cullin1-F-box protein ( SCF ) complex , targets the CDK inhibitor p27 for degradation and plays an oncogenic role in breast cancer [ XREF_BIBR - XREF_BIBR ] .	On the other hand, SKP2, the E3 ligase of the SKP1-Cullin1-F-box protein (SCF) complex, targets the CDK inhibitor p27 for degradation and plays an oncogenic role in breast cancer [XREF_BIBR - XREF_BIBR].	5	27	targets	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p27	p27	p27	5	6	23	24
We showed that Skp2 siRNA transfection decreased Skp2 protein and induced the accumulation of p27 protein in oral squamous cell carcinoma cells .	We showed that Skp2 siRNA transfection decreased Skp2 protein and induced the accumulation of p27 protein in oral squamous cell carcinoma cells.	3	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	14	15
The expression of Skp2 , the ubiquitin ligase that targets p27 for degradation , was inversely related to p27 expression .	The expression of Skp2, the ubiquitin ligase that targets p27 for degradation, was inversely related to p27 expression.	1	12	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	3	4	10	11
Rb loss alone in this case would be sufficient to raise Skp2 levels , reduce p27 further and thus efficiently activate Cdk2 ( XREF_FIG ) .	Rb loss alone in this case would be sufficient to raise Skp2 levels, reduce p27 further and thus efficiently activate Cdk2 (XREF_FIG).	0	16	reduce	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Rb loss alone in this case would be sufficient to raise Skp2 levels	skp2	p27	p27	p27	11	12	15	16
These results indicated that simvastatin treatment downregulated Skp2 expression at the transcriptional level and then promoted p27 accumulation to induce G0/G1 cell cycle arrest .	These results indicated that simvastatin treatment downregulated Skp2 expression at the transcriptional level and then promoted p27 accumulation to induce G0/G1 cell cycle arrest.	4	17	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	simvastatin treatment downregulated Skp2 expression	skp2	p27	p27	p27	7	8	16	17
We showed that Skp2 siRNA transfection decreased Skp2 protein and induced the accumulation of p27 protein in MCF-7 cells .	We showed that Skp2 siRNA transfection decreased Skp2 protein and induced the accumulation of p27 protein in MCF-7 cells.	3	15	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	14	15
Co-deletion of Skp2 , Rb1 and Trp53 blocks tumorigenesis in the mouse pituitary and prostate in a p27 KIP1 -dependent manner 34 .	Co-deletion of Skp2, Rb1 and Trp53 blocks tumorigenesis in the mouse pituitary and prostate in a p27 KIP1 -dependent manner 34.	0	19	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 KIP1	p27 KIP1	p27 KIP1	2	3	17	19
Immunoblotting revealed that Skp2 knockdown eliminated inhibitor mediated p27 induction ( XREF_FIG , lane 1 versus 2 , 3 ) , where as the 501 Mel cells expressing control shEmpty shRNA retained marked induction of p27 ( XREF_FIG , lane 4 versus 5 , 6 ) .	Immunoblotting revealed that Skp2 knockdown eliminated inhibitor mediated p27 induction (XREF_FIG, lane 1 versus 2, 3), where as the 501 Mel cells expressing control shEmpty shRNA retained marked induction of p27 (XREF_FIG, lane 4 versus 5, 6).	3	9	eliminated	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	8	9
Ectopic expression of Skp2 restores p27 down-regulation and DNA synthesis to the levels observed in parental cells , whereas inactivation of Skp2 abrogates the inhibitory effect of p107 on S phase entry .	Ectopic expression of Skp2 restores p27 down-regulation and DNA synthesis to the levels observed in parental cells, whereas inactivation of Skp2 abrogates the inhibitory effect of p107 on S phase entry.	1	6	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	3	4	5	6
In response to DNA damage , the level of p27 gradually increased in normal cells independently of the ataxia telangiectasia mutated and p53 pathway , whereas Skp2 , an F-box protein component of an SCF ubiquitin ligase complex that targets p27 , was reduced .	In response to DNA damage, the level of p27 gradually increased in normal cells independently of the ataxia telangiectasia mutated and p53 pathway, whereas Skp2, an F-box protein component of an SCF ubiquitin ligase complex that targets p27, was reduced.	26	43	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	26	27	40	41
As E3 ligase Skp2 potentially targeting p27 and p21 for degradations , we propose Skp2 may contribute to this axis .	As E3 ligase Skp2 potentially targeting p27 and p21 for degradations, we propose Skp2 may contribute to this axis.	0	13	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	3	4	6	7
The F-box protein SKP2 mediates androgen control of p27 stability in LNCaP human prostate cancer cells .	The F-box protein SKP2 mediates androgen control of p27 stability in LNCaP human prostate cancer cells.	1	9	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	F-box protein SKP2	F-box protein SKP2	F-box protein SKP2	p27	p27	p27	1	4	8	9
Skp2 predominantly modulates p27 , a cell cycle inhibitor that partakes in an essential role in mediating tumor suppression .	Skp2 predominantly modulates p27, a cell cycle inhibitor that partakes in an essential role in mediating tumor suppression.	0	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	3	4
This corresponded with a decreased number of cells in G1-phase and increased number of cells in S-phase as revealed by FACS analysis , consistent with the hypothesis that the decline of Skp2 promotes the accumulation of p21 and p27 in lovastatin arrested cells .	This corresponded with a decreased number of cells in G1-phase and increased number of cells in S-phase as revealed by FACS analysis, consistent with the hypothesis that the decline of Skp2 promotes the accumulation of p21 and p27 in lovastatin arrested cells.	29	39	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	31	32	38	39
miR-221/222 Compensates for Loss of Skp2 mediated p27 Degradation .	miR-221/222 Compensates for Loss of Skp2 mediated p27 Degradation.	3	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	5	6	7	8
Further , we show that expression of Skp2 in SK-UT-1B cells rescues the cyclin D1 and p27 degradation defect observed in this cell line .	Further, we show that expression of Skp2 in SK-UT-1B cells rescues the cyclin D1 and p27 degradation defect observed in this cell line.	5	18	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	expression of Skp2	skp2	p27	p27	p27	7	8	16	17
Using Skp2 -/- p27 -/- mice , we investigated whether Skp2 specifically targets p27 in the progressive nephropathy mediated by UUO .	Using Skp2 -/- p27 -/- mice, we investigated whether Skp2 specifically targets p27 in the progressive nephropathy mediated by UUO.	10	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	10	11	13	14
SKP2 has been identified as a molecule downstream of AKT XREF_BIBR and can target p21 and p27 for proteasomal degradation XREF_BIBR .	SKP2 has been identified as a molecule downstream of AKT XREF_BIBR and can target p21 and p27 for proteasomal degradation XREF_BIBR.	0	17	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	0	1	16	17
On the basis of these results , we postulate that KIF14 knockdown downregulates the expression of Skp2 and Cks1 , which target p27 Kip1 for degradation by the 26S proteasome , leading to accumulation of p27 Kip1 .	On the basis of these results, we postulate that KIF14 knockdown downregulates the expression of Skp2 and Cks1, which target p27 Kip1 for degradation by the 26S proteasome, leading to accumulation of p27 Kip1.	10	24	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	KIF14 knockdown downregulates the expression of Skp2	skp2	p27 Kip1	p27 Kip1	p27 kip1	16	17	22	24
The molecular pathway that compensates for loss of Skp2 mediated p27 degradation has remained elusive .	The molecular pathway that compensates for loss of Skp2 mediated p27 degradation has remained elusive.	6	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	8	9	10	11
Skp2 deficiency triggers p53 independent , p27 dependent cellular senescence and apoptosis .	Skp2 deficiency triggers p53 independent, p27 dependent cellular senescence and apoptosis.	0	9	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	6	7
These authors further demonstrate that the immediate activity in cell cycle arrest comes from the pRB C-terminus ' ability to interfere with Skp2 targeting p27 for degradation .	These authors further demonstrate that the immediate activity in cell cycle arrest comes from the pRB C-terminus ' ability to interfere with Skp2 targeting p27 for degradation.	20	26	targeting	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	22	23	24	25
However , RA also decreases Skp2 levels thus impairing the ability of p27 to be ubiquitinated .	However, RA also decreases Skp2 levels thus impairing the ability of p27 to be ubiquitinated.	2	13	impairing	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	RA also decreases Skp2 levels	skp2	p27	p27	p27	5	6	12	13
Our data thus suggest that SCF ( Skp2 ) specifically targets p27 for degradation during cell-cycle progression .	Our data thus suggest that SCF (Skp2) specifically targets p27 for degradation during cell-cycle progression.	5	13	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	7	8	11	12
PUM1 and PUM2 inhibit p27 at the translational level , by rendering the p27 transcript available to interact with two oncomiRs ( miR-221 and miR-222 ) , while the oncoprotein SKP2 inhibits the CDK inhibitor at the post-translational level by triggering the proteasomal degradation of p27 , showing that miR-340 affected not only the synthesis but also the decay of p27 .	PUM1 and PUM2 inhibit p27 at the translational level, by rendering the p27 transcript available to interact with two oncomiRs (miR-221 and miR-222), while the oncoprotein SKP2 inhibits the CDK inhibitor at the post-translational level by triggering the proteasomal degradation of p27, showing that miR-340 affected not only the synthesis but also the decay of p27.	28	46	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	30	31	45	46
Skp2 siRNA treatment in melanoma cells results in p27 upregulation and reduced cell growth .	Skp2 siRNA treatment in melanoma cells results in p27 upregulation and reduced cell growth.	0	10	upregulation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	0	1	8	9
Accumulative evidence demonstrates that Skp2 could mediate p27 and E-cadherin degradation [ XREF_BIBR ] .	Accumulative evidence demonstrates that Skp2 could mediate p27 and E-cadherin degradation [XREF_BIBR].	4	12	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	4	5	7	8
As SKP2 target p27 and other CKIs for degradation , it can be considered an oncogene .	As SKP2 target p27 and other CKIs for degradation, it can be considered an oncogene.	0	13	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	1	2	3	4
Both rexinoids increased the stability of the cell cycle inhibitor , p27kip1 protein , in part , through targeting components involved in the ubiquitination-proteasome system : 1 ) decreasing SKP2 , a F-box protein that binds and targets p27kip1 for degradation by 26S proteasome and 2 ) suppressing 20S proteasome activity ( cell line dependent ) through downregulation of PSMA7 , a component of the 20S proteolytic complex in 26S proteasome .	Both rexinoids increased the stability of the cell cycle inhibitor, p27kip1 protein, in part, through targeting components involved in the ubiquitination-proteasome system : 1) decreasing SKP2, a F-box protein that binds and targets p27kip1 for degradation by 26S proteasome and 2) suppressing 20S proteasome activity (cell line dependent) through downregulation of PSMA7, a component of the 20S proteolytic complex in 26S proteasome.	28	47	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27kip1	p27kip1	p27kip1	29	30	38	39
We used as a model system the SCF ( Skp2 ) complex that targets p27 ( Kip1 ) for ubiquitination and subsequent degradation ; this process requires an adapter protein , Cks1 .	We used as a model system the SCF (Skp2) complex that targets p27 (Kip1) for ubiquitination and subsequent degradation; this process requires an adapter protein, Cks1.	9	22	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	9	10	14	15
Overexpression of Skp2 , the ubiquitin ligase subunit that targets p27 for degradation , is often observed in cancers , and is associated with aggressive tumor proliferation and poor prognosis .	Overexpression of Skp2, the ubiquitin ligase subunit that targets p27 for degradation, is often observed in cancers, and is associated with aggressive tumor proliferation and poor prognosis.	0	12	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Skp2	Overexpression of Skp2	skp2	p27	p27	p27	2	3	10	11
Overexpression of CKS1B or SKP2 contributes to increased p27 ( Kip1 ) turnover , cell proliferation , and a poor prognosis in many tumor types .	Overexpression of CKS1B or SKP2 contributes to increased p27 (Kip1) turnover, cell proliferation, and a poor prognosis in many tumor types.	0	10	contributes	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	SKP2	Overexpression of CKS1B or SKP2	skp2	p27	p27	p27	4	5	8	9
To directly investigate the hypothesis that Skp2 decline is driving accumulation of p27 and subsequent inhibition of proliferation , we generated virally transduced cell lines stably overexpressing the Skp2 cDNA .	To directly investigate the hypothesis that Skp2 decline is driving accumulation of p27 and subsequent inhibition of proliferation, we generated virally transduced cell lines stably overexpressing the Skp2 cDNA.	6	13	driving	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	6	7	12	13
Phosphorylation of p27 Kip1 at T187 has been shown to be required for Skp2 mediated p27 Kip1 proteolysis , which also requires Cks1 association with Skp2 .	Phosphorylation of p27 Kip1 at T187 has been shown to be required for Skp2 mediated p27 Kip1 proteolysis, which also requires Cks1 association with Skp2.	11	17	mediated	Positive_early_activation	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	13	14	15	17
The F-box protein , Skp2 , is the E3 ligase in the SCF complex responsible for substrate recognition and promotes the degradation of p27 Cdk inhibitor during S-phase [ XREF_BIBR ] .	The F-box protein, Skp2, is the E3 ligase in the SCF complex responsible for substrate recognition and promotes the degradation of p27 Cdk inhibitor during S-phase [XREF_BIBR].	2	25	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p27	p27	p27	4	5	23	24
We therefore asked whether SKP2 mediated p27 downregulation in MIB arrested LNCaP cells was able to actually bring about CDK2 activation .	We therefore asked whether SKP2 mediated p27 downregulation in MIB arrested LNCaP cells was able to actually bring about CDK2 activation.	4	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	4	5	6	7
While PUM1 and PUM2 inhibit p27 at the translational level , by rendering the p27 transcript available to interact with two oncomiRs ( miR-221 and miR-222 ) overexpressed in lung and glioblastoma tumor cells , SKP2 inhibits the CDK inhibitor at the posttranslational level , by triggering the proteasomal degradation of p27 ( summarized in XREF_FIG ) .	While PUM1 and PUM2 inhibit p27 at the translational level, by rendering the p27 transcript available to interact with two oncomiRs (miR-221 and miR-222) overexpressed in lung and glioblastoma tumor cells, SKP2 inhibits the CDK inhibitor at the posttranslational level, by triggering the proteasomal degradation of p27 (summarized in XREF_FIG).	35	53	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p27	p27	p27	35	36	51	52
To enhance detection , we used human embryonic kidney ( HEK ) 293T cells , which express more p27 Kip1 than do U2OS cells , and we depleted them of Skp2 , an F box protein that targets p27 Kip1 for destruction in the proteasome .	To enhance detection, we used human embryonic kidney (HEK) 293T cells, which express more p27 Kip1 than do U2OS cells, and we depleted them of Skp2, an F box protein that targets p27 Kip1 for destruction in the proteasome.	27	40	targets	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	30	31	38	40
Although we do not yet know the reason for this observation , we postulate that in the presence of high Cks1 levels Skp2 degradation of p27 Kip1 is more efficient and that lower levels of Skp2 are therefore required to down-regulate p27 Kip1 .	Although we do not yet know the reason for this observation, we postulate that in the presence of high Cks1 levels Skp2 degradation of p27 Kip1 is more efficient and that lower levels of Skp2 are therefore required to down-regulate p27 Kip1.	22	27	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p27 Kip1	p27 Kip1	p27 Kip1	22	23	25	27
Additionally , SIRT1 inhibits p53 through deacetylation , thus increasing the possibility of neoplastic transformation [ XREF_BIBR ] , p53 regulates SIRT1 transcription through a negative feedback loop , decreasing SIRT1 activity , which , in turn , increases TP53 activity [ XREF_BIBR ] .	Additionally, SIRT1 inhibits p53 through deacetylation, thus increasing the possibility of neoplastic transformation [XREF_BIBR], p53 regulates SIRT1 transcription through a negative feedback loop, decreasing SIRT1 activity, which, in turn, increases TP53 activity [XREF_BIBR].	30	40	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	TP53	TP53	TP53	30	31	39	40
SIRT1 has been shown to target p53 , FOXO3 , and eNOS for deacetylation , negatively regulating oxidative stress [ XREF_BIBR - XREF_BIBR ] .	SIRT1 has been shown to target p53, FOXO3, and eNOS for deacetylation, negatively regulating oxidative stress [XREF_BIBR - XREF_BIBR].	0	11	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	6	7
They further found that SirT1 cause p53 localization to mitochondria for regulating self-renewal and limiting ROS toxicity in embryonic stem cells .	They further found that SirT1 cause p53 localization to mitochondria for regulating self-renewal and limiting ROS toxicity in embryonic stem cells.	4	7	cause	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SirT1	SirT1	SirT1	p53	p53	p53	4	5	6	7
Furthermore , SIRT1 was shown to mediate activation of p53 by miR-34a .	Furthermore, SIRT1 was shown to mediate activation of p53 by miR-34a.	2	10	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	9	10
Sirt1 and Sirt7 , both localized to the nucleus , modulate p53 activity to act in a protective manner against apoptosis .	Sirt1 and Sirt7, both localized to the nucleus, modulate p53 activity to act in a protective manner against apoptosis.	0	12	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	0	1	11	12
These data suggest that miR-34a affects SIRT1 expression by post-transcriptional regulation and miR-34a directly targets the SIRT1 and p53 signaling pathway in human chondrocytes .	These data suggest that miR-34a affects SIRT1 expression by post-transcriptional regulation and miR-34a directly targets the SIRT1 and p53 signaling pathway in human chondrocytes.	6	20	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1 expression	sirt1	p53	p53	p53	6	7	18	19
SIRT-1 activation by resveratrol increases survival of motor neurons from transgenic ALS mice and reduces learning impairment and neurodegeneration in AD mouse models by decreasing the acetylation of SIRT1 substrates PGC-1alpha and p53 XREF_BIBR .	SIRT-1 activation by resveratrol increases survival of motor neurons from transgenic ALS mice and reduces learning impairment and neurodegeneration in AD mouse models by decreasing the acetylation of SIRT1 substrates PGC-1alpha and p53 XREF_BIBR.	0	33	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT-1	SIRT-1	SIRT-1	p53	p53	p53	0	1	32	33
Resveratrol prevents cell death in HSR and exerts a protective effect on the mitochondria in a hepatocyte model of hypoxic injury reoxygenation possibly via Sirt-1 modulation of p53 and NF-kappaB activity .	Resveratrol prevents cell death in HSR and exerts a protective effect on the mitochondria in a hepatocyte model of hypoxic injury reoxygenation possibly via Sirt-1 modulation of p53 and NF-kappaB activity.	24	30	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Sirt-1	Sirt-1	Sirt-1	p53	p53	p53	24	25	27	28
SIRT1 Ser682 phosphorylation modulates p53 regulated gene expression and apoptosis .	SIRT1 Ser682 phosphorylation modulates p53 regulated gene expression and apoptosis.	0	5	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1 Ser682 phosphorylation	sirt1	p53	p53	p53	0	1	4	5
SIRT1 induces p27 dependent , but p53- or p16 independent , cell senescence .	SIRT1 induces p27 dependent, but p53- or p16 independent, cell senescence.	0	7	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53-	p53-	p53-	0	1	6	7
Additionally , silent information regulator type-1 ( SIRT1 ) , one of the sirtuin NAD dependent protein and histone deacetylase family , can promote the survival of EPCs by restraining p53- and non-p53-dependent apoptosis in response to DNA damage and oxidative stress [ XREF_BIBR ] .	Additionally, silent information regulator type-1 (SIRT1), one of the sirtuin NAD dependent protein and histone deacetylase family, can promote the survival of EPCs by restraining p53- and non-p53-dependent apoptosis in response to DNA damage and oxidative stress [XREF_BIBR].	5	33	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53-	p53-	p53-	7	8	30	31
Therefore , through SIRT1 mediated p53 and mitochondrial pathways and the induction of caspase-3-dependent apoptosis in DBTRG-05MG GBM cells , CCF-NLs could be a more effective method for treating chemical resistant GBM .	Therefore, through SIRT1 mediated p53 and mitochondrial pathways and the induction of caspase-3-dependent apoptosis in DBTRG-05MG GBM cells, CCF-NLs could be a more effective method for treating chemical resistant GBM.	2	26	mediated	Positive_early_activation	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	5	6
It has been documented that p53 activity can be modulated by SIRT1 in particular ; overexpression of SIRT1 not only abrogated p53 dependent apoptosis in response to oxidative stress , DNA damage , and ionizing radiation , but also sensitised cells to apoptosis induced by these factors [ XREF_BIBR , XREF_BIBR ] .	It has been documented that p53 activity can be modulated by SIRT1 in particular; overexpression of SIRT1 not only abrogated p53 dependent apoptosis in response to oxidative stress, DNA damage, and ionizing radiation, but also sensitised cells to apoptosis induced by these factors [XREF_BIBR, XREF_BIBR].	5	12	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	11	12	5	6
In addition , SIRT1 activates p53 through deacetylation of Lys382 [ XREF_BIBR ] , countering acetylation by p300 and CBP .	In addition, SIRT1 activates p53 through deacetylation of Lys382 [XREF_BIBR], countering acetylation by p300 and CBP.	3	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	3	4	5	6
XREF_BIBR , XREF_BIBR On the contrary , downregulation of SIRT1 upregulates acetylated p53 , causes transcriptional activation of p53 targets genes viz p21 , NOXA and PUMA and thus induces apoptosis .	XREF_BIBR, XREF_BIBR On the contrary, downregulation of SIRT1 upregulates acetylated p53, causes transcriptional activation of p53 targets genes viz p21, NOXA and PUMA and thus induces apoptosis.	7	20	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	18	19
As p53 was the first found target of Sirt1 and Sirt1 could inactivate p53 through deacetylating it in an LPS treated model , we next determined whether p53 contributes to the LPS induced loss of beta-catenin .	As p53 was the first found target of Sirt1 and Sirt1 could inactivate p53 through deacetylating it in an LPS treated model, we next determined whether p53 contributes to the LPS induced loss of beta-catenin.	6	14	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	8	9	13	14
Additionally , miRNAs have been shown to downregulate other important cell cycle promoters such as SIRT1 ( a direct modulator of the p16-Rb and p53 pathways ) , Sp1 ( a transcription factor regulating the expression of p53 and many other genes involved in cell cycle ) , and CDK6 ( which phosphorylates pRb to delay senescence ) .	Additionally, miRNAs have been shown to downregulate other important cell cycle promoters such as SIRT1 (a direct modulator of the p16-Rb and p53 pathways), Sp1 (a transcription factor regulating the expression of p53 and many other genes involved in cell cycle), and CDK6 (which phosphorylates pRb to delay senescence).	12	28	modulator	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	15	16	24	25
SIRT1 deacetylates and directly regulates p53 , which has been linked to reprogramming , tumorigenesis , DNA damage repair , and the recruitment of histone modifiers .	SIRT1 deacetylates and directly regulates p53, which has been linked to reprogramming, tumorigenesis, DNA damage repair, and the recruitment of histone modifiers.	0	10	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	5	6
This complex directly binds to the SIRT1 promoter , consequently represses the transcriptional activity of the SIRT1gene , and thereby inhibits SIRT1 mediated p53 inactivation .	This complex directly binds to the SIRT1 promoter, consequently represses the transcriptional activity of the SIRT1gene, and thereby inhibits SIRT1 mediated p53 inactivation.	20	24	mediated	Positive_early_activation	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	21	22	23	24
Conversely , Sirt1 inactivation results in activation of p65 NF-kappaB and p53 by increasing acetylation of the transcription factors [ XREF_BIBR - XREF_BIBR ] .	Conversely, Sirt1 inactivation results in activation of p65 NF-kappaB and p53 by increasing acetylation of the transcription factors [XREF_BIBR - XREF_BIBR].	2	12	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	2	3	11	12
Especially , the inhibitory role of DBC1 on SIRT1 supported the possibility that DBC1 could be tumor suppressor because SIRT1 inactivates various tumor suppressors , especially p53 [ XREF_BIBR , XREF_BIBR ] .	Especially, the inhibitory role of DBC1 on SIRT1 supported the possibility that DBC1 could be tumor suppressor because SIRT1 inactivates various tumor suppressors, especially p53 [XREF_BIBR, XREF_BIBR].	19	30	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	19	20	26	27
Resveratrol is known as an activator of silent mating type information regulation 2 homolog ( Sirt1 ) that modulates p53 activity by deacetylation XREF_BIBR , XREF_BIBR .	Resveratrol is known as an activator of silent mating type information regulation 2 homolog (Sirt1) that modulates p53 activity by deacetylation XREF_BIBR, XREF_BIBR.	13	20	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	15	16	19	20
Thus , inactivation of p53 signalling , observed after multiple exposures to UVB and heat , may be attributed to the SIRT1 mediated post-translational modification of the p53 protein .	Thus, inactivation of p53 signalling, observed after multiple exposures to UVB and heat, may be attributed to the SIRT1 mediated post-translational modification of the p53 protein.	18	28	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	21	22	27	28
Lowenstein and colleagues went on to show that SIRT1 led to apoptosis in wild-type p53 human colon cancer cells but not in human colon cancer lacking p53 .	Lowenstein and colleagues went on to show that SIRT1 led to apoptosis in wild-type p53 human colon cancer cells but not in human colon cancer lacking p53.	8	27	led	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	8	9	26	27
In endothelial cells , SIRT1 modulates the transcriptional activity of Foxo1 and p53 , and activates the enzymatic activity of endothelial nitric oxide synthase ( eNOS ) .	In endothelial cells, SIRT1 modulates the transcriptional activity of Foxo1 and p53, and activates the enzymatic activity of endothelial nitric oxide synthase (eNOS).	4	15	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	12	13
Genotoxic stress activates p53 , the strongest inducer of miR-34a that inhibits SIRT1 expression , which in turn inactivates p53 by its deacetylation .	Genotoxic stress activates p53, the strongest inducer of miR-34a that inhibits SIRT1 expression, which in turn inactivates p53 by its deacetylation.	3	20	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	p53, the strongest inducer of miR-34a that inhibits SIRT1 expression	sirt1	p53	p53	p53	12	13	19	20
The DBC1 dependent modulation of the SIRT1 target p53 was also shown to be regulated by post-translational modification ( PTM ) .	The DBC1 dependent modulation of the SIRT1 target p53 was also shown to be regulated by post-translational modification (PTM).	3	9	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	8	9
SIRT1 activation appears to induce post-translational modifications of the p53 protein , affecting the ability of this protein to regulate the expression of downstream gene targets important for regulating DNA damage repair and apoptosis .	SIRT1 activation appears to induce post-translational modifications of the p53 protein, affecting the ability of this protein to regulate the expression of downstream gene targets important for regulating DNA damage repair and apoptosis.	0	10	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	9	10
SIRT1 activation is known to prevent senescence by promoting P53 degradation , whereas its inactivation increases the transcriptional activity of p53 .	SIRT1 activation is known to prevent senescence by promoting P53 degradation, whereas its inactivation increases the transcriptional activity of p53.	0	10	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	P53	P53	P53	0	1	9	10
Oct-3/4 represses the activity of p53 by regulating the expression of Sirt1 , a protein deacetylase that inactivates p53 in hESC .	Oct-3/4 represses the activity of p53 by regulating the expression of Sirt1, a protein deacetylase that inactivates p53 in hESC.	0	20	inactivates	Negative_activation_syntax_5_verb	Negative_activation	Negative_activation	Sirt1	Oct-3/4 represses the activity of p53 by regulating the expression of Sirt1	sirt1	p53	p53	p53	11	12	18	19
SIRT1 is a key metabolic sensor and regulator in cells and directly deacetylates and modulates some important metabolic regulators , including PGC-1alpha ( peroxisome proliferator activated receptor gamma coactivator 1-alpha ) , peroxisome proliferator activated receptors ( PPARs ) , p53 , and forkhead box protein O1 ( FOXO1 ) which change the expression of transcriptional programs that modulate cholesterol , lipid and energy homeostasis [ XREF_BIBR ] .	SIRT1 is a key metabolic sensor and regulator in cells and directly deacetylates and modulates some important metabolic regulators, including PGC-1alpha (peroxisome proliferator activated receptor gamma coactivator 1-alpha), peroxisome proliferator activated receptors (PPARs), p53, and forkhead box protein O1 (FOXO1) which change the expression of transcriptional programs that modulate cholesterol, lipid and energy homeostasis [XREF_BIBR].	0	41	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	40	41
In addition , SIRT1 -/- cells have been identified to be more susceptible to killing by the genotoxic agents cisplatin and staurosporine [ XREF_BIBR ] , indicating that SIRT1 abrogation may enhance p53 function .	In addition, SIRT1 -/- cells have been identified to be more susceptible to killing by the genotoxic agents cisplatin and staurosporine [XREF_BIBR], indicating that SIRT1 abrogation may enhance p53 function.	28	33	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	28	29	32	33
If DBC1 regulates p53 level through SIRT1 , we would expect that inhibiting SIRT1 would rescue p53 loss in Dbc1 -/- cells .	If DBC1 regulates p53 level through SIRT1, we would expect that inhibiting SIRT1 would rescue p53 loss in Dbc1 -/- cells.	11	17	rescue	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	13	14	16	17
To date , seven human sirtuins ( SIRT1-SIRT7 ) have been identified ; among these , SIRT1 is the closest homologue of yeast Sir2 and modulates p53 , nuclear factor ( NF )-kappaB , peroxisome proliferator activated receptor-gamma coactivator ( PGC )-1alpha , liver X receptor ( LXR ) and Fork head transcription factors .	To date, seven human sirtuins (SIRT1-SIRT7) have been identified; among these, SIRT1 is the closest homologue of yeast Sir2 and modulates p53, nuclear factor (NF)-kappaB, peroxisome proliferator activated receptor-gamma coactivator (PGC)-1alpha, liver X receptor (LXR) and Fork head transcription factors.	16	35	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	16	17	26	27
Accordingly , such CHFR malfunction may lead to SIRT1 stabilization , which in turn represses p53 and other tumour suppressors to accelerate tumour initiation and metastasis .	Accordingly, such CHFR malfunction may lead to SIRT1 stabilization, which in turn represses p53 and other tumour suppressors to accelerate tumour initiation and metastasis.	8	19	represses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	8	9	15	16
SIRT1 has been shown to inhibit senescence by targeting p53 , a transcription factor that becomes acetylated at Lys 382 as a result of DNA damage .	SIRT1 has been shown to inhibit senescence by targeting p53, a transcription factor that becomes acetylated at Lys 382 as a result of DNA damage.	0	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	9	10
miR-132 targets the p53-down-regulator SIRT1 , which in turn promotes p53 expression XREF_BIBR .	miR-132 targets the p53-down-regulator SIRT1, which in turn promotes p53 expression XREF_BIBR.	1	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	10	11
Similarly , miR-34 is induced by p53 and targets SIRT1 ( a modulator of p53 activity ) thus making a mir-34-p53 positive feedback loop .	Similarly, miR-34 is induced by p53 and targets SIRT1 (a modulator of p53 activity) thus making a mir-34-p53 positive feedback loop.	4	18	modulator	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	14	15
Sirtinol is a specific inhibitor of the class III NAD dependent deacetylases SIRT1 and SIRT2 that execute essential functions in the regulation of mitosis , survival , and senescence , and are known to target p53 .	Sirtinol is a specific inhibitor of the class III NAD dependent deacetylases SIRT1 and SIRT2 that execute essential functions in the regulation of mitosis, survival, and senescence, and are known to target p53.	11	36	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	12	13	35	36
In our study , the treatment of 10mM nicotinamide downregulated p21WAF1 expression in various human cells including p53 negative or SIRT1-knockdown cells indicating gene regulation not mediated by p53 or SIRT1 .	In our study, the treatment of 10mM nicotinamide downregulated p21WAF1 expression in various human cells including p53 negative or SIRT1-knockdown cells indicating gene regulation not mediated by p53 or SIRT1.	9	31	mediated	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	30	31	17	18
Downregulation of SIRT 1 , by miR-128 , elevates activated p53 that foment Puma indirectly .	Downregulation of SIRT 1, by miR-128, elevates activated p53 that foment Puma indirectly.	0	12	elevates activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT 1	SIRT 1	SIRT 1	p53	p53	p53	2	4	10	11
Using this approach , tenovin-6 was identified as a potent SIRT1 and SIRT2 inhibitor that indirectly activated p53 at single-digit micromolar concentrations .	Using this approach, tenovin-6 was identified as a potent SIRT1 and SIRT2 inhibitor that indirectly activated p53 at single-digit micromolar concentrations.	6	18	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	10	11	17	18
In MDA-MB-231 cells p53 is mutated so , although SIRT1 knock down causes an increase in acetyl p53 , the p53 protein is non functional XREF_BIBR .	In MDA-MB-231 cells p53 is mutated so, although SIRT1 knock down causes an increase in acetyl p53, the p53 protein is non functional XREF_BIBR.	9	18	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	17	18
That is , following acute exercise we observed a robust increase in nuclear p53 abundance in WT but not SIRT1 mKO mice , indicating that SIRT1 mediated deacetylation might alter the cellular location of p53 in response to exercise ( XREF_FIG ) .	That is, following acute exercise we observed a robust increase in nuclear p53 abundance in WT but not SIRT1 mKO mice, indicating that SIRT1 mediated deacetylation might alter the cellular location of p53 in response to exercise (XREF_FIG).	25	35	mediated	Positive_early_regulation	Negative_activation	Positive_regulation	SIRT1	SIRT1	sirt1	p53	deacetylation might alter the cellular location of p53	p53	25	26	34	35
CCF-NL-induced cell death through the SIRT1 mediated p53 signaling pathway .	CCF-NL-induced cell death through the SIRT1 mediated p53 signaling pathway.	2	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	5	6	7	8
Collectively these data indicate that miR34a functions as a potential tumor suppressor by its antagonism of SIRT1 mediated p53 negative regulation , which , in turn increases miR34a expression via upregulation of p53 transcriptional activity .	Collectively these data indicate that miR34a functions as a potential tumor suppressor by its antagonism of SIRT1 mediated p53 negative regulation, which, in turn increases miR34a expression via upregulation of p53 transcriptional activity.	14	20	mediated	Positive_early_activation	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	16	17	18	19
Phosphorylation of SIRT1 by CK2 increases its substrate binding affinity and deacetylation rate , especially in regard to p53 .	Phosphorylation of SIRT1 by CK2 increases its substrate binding affinity and deacetylation rate, especially in regard to p53.	0	19	increases	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	SIRT1	Phosphorylation of SIRT1	sirt1	p53	p53	p53	2	3	18	19
XREF_FIG , p53 knockout MEFs are resistant to UV induced cell death and SIRT1 induced protective effects are almost abolished in p53 knockout MEFs .	XREF_FIG, p53 knockout MEFs are resistant to UV induced cell death and SIRT1 induced protective effects are almost abolished in p53 knockout MEFs.	11	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	13	14	21	22
Finally , miR-34 has been shown to target Sirt1 and also to be regulated by p53 , which in turn is activated by Sirt1 [ XREF_BIBR - XREF_BIBR ] .	Finally, miR-34 has been shown to target Sirt1 and also to be regulated by p53, which in turn is activated by Sirt1 [XREF_BIBR - XREF_BIBR].	13	27	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	23	24	15	16
Recent data have suggested that SIRT1 targets p53 XREF_BIBR , Ku70 XREF_BIBR and the forkhead transcription factors XREF_BIBR for deacetylation , and thus regulates stress responses , apoptosis and cellular senescence XREF_BIBR .	Recent data have suggested that SIRT1 targets p53 XREF_BIBR, Ku70 XREF_BIBR and the forkhead transcription factors XREF_BIBR for deacetylation, and thus regulates stress responses, apoptosis and cellular senescence XREF_BIBR.	5	8	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	5	6	7	8
We next tested the possible role SIRT1 in UV induced p53 activation .	We next tested the possible role SIRT1 in UV induced p53 activation.	3	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	10	11
Against this a recent study has shown that Sirtinol treatment did increase the acetylation level of the Sirt1 target p53 in MCF-7 breast cancer cells , as well as inducing cell death via both apoptotic and autophagic mechanisms XREF_BIBR .	Against this a recent study has shown that Sirtinol treatment did increase the acetylation level of the Sirt1 target p53 in MCF-7 breast cancer cells, as well as inducing cell death via both apoptotic and autophagic mechanisms XREF_BIBR.	14	29	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	17	18	19	20
SirT1 haploinsufficiency promotes spontaneous tumor development in TP53 +/- mice , while overexpression of SirT1 in lymphocyte progenitors reduces the incidence of thymic lymphomas in TP53 +/- mice post gamma irradiation , consistent with a tumor-suppressor function of SirT1 .	SirT1 haploinsufficiency promotes spontaneous tumor development in TP53 +/- mice, while overexpression of SirT1 in lymphocyte progenitors reduces the incidence of thymic lymphomas in TP53 +/- mice post gamma irradiation, consistent with a tumor-suppressor function of SirT1.	0	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SirT1	SirT1	SirT1	TP53	TP53	TP53	0	1	7	8
So , although Sirt1 inactivation promoted p53 dependent transcriptional activation , the hepatocytes were actually protected against TNF-alpha-induced apoptosis .	So, although Sirt1 inactivation promoted p53 dependent transcriptional activation, the hepatocytes were actually protected against TNF-alpha-induced apoptosis.	3	7	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	3	4	6	7
Thus , the data from our study suggest that SIRT1 attenuates CIRI by targeting the p53 and microRNA -22 axix , while suppressing apoptosis , inflammation , COX-2 and iNOS expression .	Thus, the data from our study suggest that SIRT1 attenuates CIRI by targeting the p53 and microRNA -22 axix, while suppressing apoptosis, inflammation, COX-2 and iNOS expression.	9	19	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	9	10	15	16
miR-34a is transcriptionally regulated by p53 and targets SIRT1 ( a modulator of p53 activity ) thus making a mir-34-p53 positive feedback loop .	miR-34a is transcriptionally regulated by p53 and targets SIRT1 (a modulator of p53 activity) thus making a mir-34-p53 positive feedback loop.	3	17	modulator	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	8	9	13	14
Induction Cdkn1 occurs through deacetylation and thereby activation of the nonhistone SIRT1 target p53 .	Induction Cdkn1 occurs through deacetylation and thereby activation of the nonhistone SIRT1 target p53.	7	14	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	11	12	13	14
Taken together , findings suggest that the modulation of p53 by SIRT1 could be a possible target to attenuate cisplatin induced kidney injury .	Taken together, findings suggest that the modulation of p53 by SIRT1 could be a possible target to attenuate cisplatin induced kidney injury.	7	12	modulation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	11	12	9	10
It is known that Sirt1 mediates miR-34a-induced apoptosis by regulating p53 activity , and a positive feedback loop has been identified , wherein p53 induces miR-34a expression , thus suppressing Sirt1 and increasing p53 activity [ XREF_BIBR ] .	It is known that Sirt1 mediates miR-34a-induced apoptosis by regulating p53 activity, and a positive feedback loop has been identified, wherein p53 induces miR-34a expression, thus suppressing Sirt1 and increasing p53 activity [XREF_BIBR].	4	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	4	5	10	11
Although the modulation of p53 by SIRT1 partially inhibited the oxidative stress induced cell death , the knockdown of FOXO1 , FOXO3a , and FOXO4 completely abolished the cell-protective effect of the SIRT1 activator RSV .	Although the modulation of p53 by SIRT1 partially inhibited the oxidative stress induced cell death, the knockdown of FOXO1, FOXO3a, and FOXO4 completely abolished the cell-protective effect of the SIRT1 activator RSV.	2	7	modulation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	4	5
SIRT1 has also been demonstrated to mediate the p53 regulatory pathway , decreasing the sensitivity of cells to DNA damage and oxidative stress XREF_BIBR .	SIRT1 has also been demonstrated to mediate the p53 regulatory pathway, decreasing the sensitivity of cells to DNA damage and oxidative stress XREF_BIBR.	0	10	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	8	9
A previous study showed that expression of the mouse Sirt1 could be induced by acute nutrient withdrawal , and the induction was mediated via two p53 binding sites present in the Sirt1 promoter in a p53 dependent manner [ XREF_BIBR ] .	A previous study showed that expression of the mouse Sirt1 could be induced by acute nutrient withdrawal, and the induction was mediated via two p53 binding sites present in the Sirt1 promoter in a p53 dependent manner [XREF_BIBR].	31	37	promoter	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p53	p53	p53	31	32	35	36
SIRT1 activation rescues anti-inflammatory phenotype and p53 signaling in HO-1-deficient macrophages .	SIRT1 activation rescues anti-inflammatory phenotype and p53 signaling in HO-1-deficient macrophages.	0	7	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	6	7
Induction of SIRT1 contributes to p53 mediated apoptosis by stabilizing p53 .	Induction of SIRT1 contributes to p53 mediated apoptosis by stabilizing p53.	0	11	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	10	11
First , SIRT1 knockdown , the catalytically inactive H363Y allele , or specific inhibition of SIRT1 in cells does not affect cell viability or cell growth and is not sufficient to induce activation of endogenous p53 .	First, SIRT1 knockdown, the catalytically inactive H363Y allele, or specific inhibition of SIRT1 in cells does not affect cell viability or cell growth and is not sufficient to induce activation of endogenous p53.	13	36	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	15	16	35	36
In a murine model of hepatic warm IRI , myeloid specific HO-1 deletion lacked SIRT1 and p53 , exacerbated liver inflammation and IR-hepatocellular death , whereas adjunctive SIRT1 activation restored p53 signaling and rescued livers from IR-damage .	In a murine model of hepatic warm IRI, myeloid specific HO-1 deletion lacked SIRT1 and p53, exacerbated liver inflammation and IR-hepatocellular death, whereas adjunctive SIRT1 activation restored p53 signaling and rescued livers from IR-damage.	27	31	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	27	28	30	31
Indeed , a number of studies have demonstrated a crosstalk between p53 and p21 and waf1 with mTOR pathways via regulations of mouse double minute 2 homolog ( MDM2 ) and sirtuin 1 ( SIRT1 ) , both of which modulate p53 accumulation [ XREF_BIBR - XREF_BIBR ] .	Indeed, a number of studies have demonstrated a crosstalk between p53 and p21 and waf1 with mTOR pathways via regulations of mouse double minute 2 homolog (MDM2) and sirtuin 1 (SIRT1), both of which modulate p53 accumulation [XREF_BIBR - XREF_BIBR].	31	42	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	34	35	41	42
SIRT1 dependent activation of p53 , target of rapamycin complex 1 ( TORC1 ) , forkhead box O3a ( FOXO3A ) , and peroxisome proliferator activated receptor ( PPAR ) gamma coactivator 1alpha ( PGC-1alpha ) pathways in the brain have been hypothesized as the molecular mechanisms by which SIRT1 promotes cell survival and confers neuroprotection in HD [ XREF_BIBR ] .	SIRT1 dependent activation of p53, target of rapamycin complex 1 (TORC1), forkhead box O3a (FOXO3A), and peroxisome proliferator activated receptor (PPAR) gamma coactivator 1alpha (PGC-1alpha) pathways in the brain have been hypothesized as the molecular mechanisms by which SIRT1 promotes cell survival and confers neuroprotection in HD [XREF_BIBR].	0	17	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	4	5
Since the absence of SIRT1 increased p53 activity , it was suspected that embryonic lethality of SIRT1 mutant embryos is due , at least in part , to p53 activation .	Since the absence of SIRT1 increased p53 activity, it was suspected that embryonic lethality of SIRT1 mutant embryos is due, at least in part, to p53 activation.	2	7	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	6	7
In a autoregulatory loop analogous to SIRT1 suppression of E2F transcriptional activity and p53 transcriptional repressor activity ( discussed above ) , because HIC1 is a transcriptional repressor of the SIRT1 gene , one result of SIRT1 interactions with HIC1 containing transcriptional repressor complexes is down-regulation of SIRT1 gene expression [ XREF_BIBR ] .	In a autoregulatory loop analogous to SIRT1 suppression of E2F transcriptional activity and p53 transcriptional repressor activity (discussed above), because HIC1 is a transcriptional repressor of the SIRT1 gene, one result of SIRT1 interactions with HIC1 containing transcriptional repressor complexes is down-regulation of SIRT1 gene expression [XREF_BIBR].	6	15	suppression	Negative_activation_syntax_3_noun	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	13	14
Rather , these data are consistent with the phenotypes of SIRT1 compromised cells [ XREF_BIBR , XREF_BIBR ] and support the hypothesis that DHC mediated SIRT1 inhibition enhances p53 stabilization and increases apoptosis .	Rather, these data are consistent with the phenotypes of SIRT1 compromised cells [XREF_BIBR, XREF_BIBR] and support the hypothesis that DHC mediated SIRT1 inhibition enhances p53 stabilization and increases apoptosis.	23	29	enhances	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SIRT1	DHC mediated SIRT1	sirt1	p53	p53	p53	25	26	28	29
89 SIRT1 was shown to redistribute on chromatin to promote DNA damage repair and maintain genomic stability in response to oxidative stress , which may contribute to the prolonged survival of p53 +/- mice treated with alleged SIRT1 activators .	89 SIRT1 was shown to redistribute on chromatin to promote DNA damage repair and maintain genomic stability in response to oxidative stress, which may contribute to the prolonged survival of p53 +/- mice treated with alleged SIRT1 activators.	29	38	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	37	38	31	32
We also discovered that SIRT1 mediates miR-34a activation of apoptosis by regulating p53 activity .	We also discovered that SIRT1 mediates miR-34a activation of apoptosis by regulating p53 activity.	4	13	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	12	13
Myeloid specific HO-1 deficiency exacerbates liver IRI while SIRT1 rescues IR-livers by restoring p19 and p53 signaling .	Myeloid specific HO-1 deficiency exacerbates liver IRI while SIRT1 rescues IR-livers by restoring p19 and p53 signaling.	8	16	rescues	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	8	9	15	16
Because SIRT1 mutant cells displayed p53 hyperacetylation upon DNA damage and increased ionizing radiation induced apoptosis in thymocytes , it was suspected that the SIRT1 deficiency might activate p53 , leading to the lethality of mutant mice .	Because SIRT1 mutant cells displayed p53 hyperacetylation upon DNA damage and increased ionizing radiation induced apoptosis in thymocytes, it was suspected that the SIRT1 deficiency might activate p53, leading to the lethality of mutant mice.	24	29	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	24	25	28	29
In particular , upregulation of the HIC1 target gene SIRT1 , a histone deacetylase , can promote tumor growth by inactivating TP53 .	In particular, upregulation of the HIC1 target gene SIRT1, a histone deacetylase, can promote tumor growth by inactivating TP53.	3	22	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	TP53	TP53	TP53	9	10	21	22
SIRT1 is markedly increased in malignant ovarian tumors ( especially , in serous carcinoma ) compared to corresponding normal tissues , and up-regulated SIRT1 inactivates p53 by deacetylation [ XREF_BIBR ] .	SIRT1 is markedly increased in malignant ovarian tumors (especially, in serous carcinoma) compared to corresponding normal tissues, and up-regulated SIRT1 inactivates p53 by deacetylation [XREF_BIBR].	0	26	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	25	26
In contrast , expression of a catalytically inactive Sirt1 protein potentiates p53 dependent apoptosis and radiosensitivity .	In contrast, expression of a catalytically inactive Sirt1 protein potentiates p53 dependent apoptosis and radiosensitivity.	3	13	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	expression of a catalytically inactive Sirt1	sirt1	p53	p53	p53	8	9	11	12
Importantly , SIRT1 can also inactivate the p53 tumor suppressor via deacetylation , suggesting a role in oncogenesis .	Importantly, SIRT1 can also inactivate the p53 tumor suppressor via deacetylation, suggesting a role in oncogenesis.	2	9	inactivate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	2	3	7	8
It has been confirmed that SIRT1 mediates miR-34a-induced apoptosis by regulating p53 activity .	It has been confirmed that SIRT1 mediates miR-34a-induced apoptosis by regulating p53 activity.	5	12	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	5	6	11	12
The mechanism is further supported by analyzing the expression of the SIRT1 downstream targets in the p53 pathway XREF_BIBR , which showed that Nanog mRNA expression was significantly increased by RSV but decreased by SIRT1 siRNA treatments in iPSC colonies .	The mechanism is further supported by analyzing the expression of the SIRT1 downstream targets in the p53 pathway XREF_BIBR, which showed that Nanog mRNA expression was significantly increased by RSV but decreased by SIRT1 siRNA treatments in iPSC colonies.	8	18	targets	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	SIRT1	expression of the SIRT1	sirt1	p53	p53	p53	11	12	16	17
Recently , some studies have suggested that SIRT1 could be over-expressed in breast , prostate and colon cancers and up-regulated SIRT1 inactivates p53 by deacetylation .	Recently, some studies have suggested that SIRT1 could be over-expressed in breast, prostate and colon cancers and up-regulated SIRT1 inactivates p53 by deacetylation.	7	23	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	7	8	22	23
47 By focusing on SIRT1-p53 molecular communication at the macrophage level , our study , to the best of our knowledge , is the first to document that SIRT1 upregulates p53 .	47 By focusing on SIRT1-p53 molecular communication at the macrophage level, our study, to the best of our knowledge, is the first to document that SIRT1 upregulates p53.	0	31	upregulates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	28	29	30	31
Recent data suggest that SIRT1 targets p53 XREF_BIBR , FoxO1 XREF_BIBR , and NF-kappaB XREF_BIBR for deacetylation and thus regulates stress responses , inflammation , cellular senescence and apoptosis XREF_BIBR .	Recent data suggest that SIRT1 targets p53 XREF_BIBR, FoxO1 XREF_BIBR, and NF-kappaB XREF_BIBR for deacetylation and thus regulates stress responses, inflammation, cellular senescence and apoptosis XREF_BIBR.	4	7	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	6	7
It was found that SIRT1 mediates miR-34a activation of apoptosis by regulating p53 activity , suggesting a positive feedback loop in which p53 induces expression of miR-34a , which suppresses SIRT1 , increasing p53 activity .	It was found that SIRT1 mediates miR-34a activation of apoptosis by regulating p53 activity, suggesting a positive feedback loop in which p53 induces expression of miR-34a, which suppresses SIRT1, increasing p53 activity.	4	13	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	12	13
It confirmed that the SIRT1 caused the dysregulation of FoxO3 and p53 rather than Vit C in RPEs .	It confirmed that the SIRT1 caused the dysregulation of FoxO3 and p53 rather than Vit C in RPEs.	3	12	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	4	5	11	12
Thus , despite p53 deacetylation , SIRT1 induction was able to enhance p53 signaling and suppress macrophage activation .	Thus, despite p53 deacetylation, SIRT1 induction was able to enhance p53 signaling and suppress macrophage activation.	6	13	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	6	7	12	13
The SIRT1 mediated p53 signaling pathway may be one of the signal pathways regulated by CCF-NLs that engage the Bcl-2 family and mitochondrial activity through ROS independent SIRT1 mediated p53 signal pathway mechanisms , either via the necrotic pathway through ROS ( ROS mediated p53 ) by CCF regulation of Bcl-2 expression or via mitochondrial mRNA mechanisms .	The SIRT1 mediated p53 signaling pathway may be one of the signal pathways regulated by CCF-NLs that engage the Bcl-2 family and mitochondrial activity through ROS independent SIRT1 mediated p53 signal pathway mechanisms, either via the necrotic pathway through ROS (ROS mediated p53) by CCF regulation of Bcl-2 expression or via mitochondrial mRNA mechanisms.	0	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	1	2	3	4
Taken together , our findings suggest that the modulation of p53 by SIRT1 could be a possible target to attenuate cisplatin induced kidney injury .	Taken together, our findings suggest that the modulation of p53 by SIRT1 could be a possible target to attenuate cisplatin induced kidney injury.	8	13	modulation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	12	13	10	11
The mRNA expression of Mdm2 , Sirt1 and miR-125b , each of which negatively regulates p53 activity , was not modulated by DIO , relative to control , in Wnt-1 p53 +/+ or Wnt-1 p53 +/- mammary tumor tissue ( XREF_FIG ) .	The mRNA expression of Mdm2, Sirt1 and miR-125b, each of which negatively regulates p53 activity, was not modulated by DIO, relative to control, in Wnt-1 p53 +/+ or Wnt-1 p53 +/- mammary tumor tissue (XREF_FIG).	2	40	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	expression of Mdm2, Sirt1	sirt1	p53	p53	p53	6	7	30	31
SIRT1 modulates the transcription factors p53 , a tumor suppressor and inducer of apoptosis , and the forkhead O ( FOXO ) family , both of which play roles for cell survival and cell death .	SIRT1 modulates the transcription factors p53, a tumor suppressor and inducer of apoptosis, and the forkhead O (FOXO) family, both of which play roles for cell survival and cell death.	0	22	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p53	p53	p53	0	1	5	6
Given that the accumulation of Smo in the PC is one of the earliest hallmarks of canonical Shh pathway activation , we reasoned that the functionality of this organelle could be evaluated by over-expressing a constitutively active SmoA1-Flag construct that has been shown to preferentially localize to the PC in a manner similar to wild type SMO after Shh mediated inactivation of PTC1 [ XREF_BIBR ] .	Given that the accumulation of Smo in the PC is one of the earliest hallmarks of canonical Shh pathway activation, we reasoned that the functionality of this organelle could be evaluated by over-expressing a constitutively active SmoA1-Flag construct that has been shown to preferentially localize to the PC in a manner similar to wild type SMO after Shh mediated inactivation of PTC1 [XREF_BIBR].	58	64	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	PTC1	PTC1	PTC1	58	59	62	63
Overexpression of GsCA in GNPs suppressed the upregulation of Shh targets Gli1 , Ptch1 , Myc-N and Ccnd1 induced by a Shh agonist SAG ( XREF_FIG ) , indicating that Gsalpha activation inhibits hedgehog signaling .	Overexpression of GsCA in GNPs suppressed the upregulation of Shh targets Gli1, Ptch1, Myc-N and Ccnd1 induced by a Shh agonist SAG (XREF_FIG), indicating that Gsalpha activation inhibits hedgehog signaling.	7	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	9	10	13	14
The authors suggested that the expression of tumor suppressor PTCH and the oncogene SHH might cause loss of PTCH function and lead to OKC development .	The authors suggested that the expression of tumor suppressor PTCH and the oncogene SHH might cause loss of PTCH function and lead to OKC development.	5	19	cause	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHH	expression of tumor suppressor PTCH and the oncogene SHH	shh	PTCH	PTCH	ptch	13	14	18	19
However , when Shh is overexpressed , the tissue morphology and growth rate are normal in cancer cell lines and overexpression of Shh does not cause abnormally high levels of activation of Ptch1 or Gli1 in LNCaP cells .	However, when Shh is overexpressed, the tissue morphology and growth rate are normal in cancer cell lines and overexpression of Shh does not cause abnormally high levels of activation of Ptch1 or Gli1 in LNCaP cells.	20	34	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	overexpression of Shh	shh	Ptch1	Ptch1	ptch1	22	23	32	33
Additionally , commercial recombinant preparation of SHH up-regulates PTCH and leads to production of pro inflammatory cytokines in human peripheral blood mononuclear cells ( PBMC ) .	Additionally, commercial recombinant preparation of SHH up-regulates PTCH and leads to production of pro inflammatory cytokines in human peripheral blood mononuclear cells (PBMC).	4	9	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHH	SHH	SHH	PTCH	PTCH	PTCH	6	7	8	9
Collectively , these findings indicate that elevated Shh signaling in Ptch1 Wig and Wig embryos leads to a down-regulation of canonical Wnt dependent survival signaling , resulting in elevated neural crest cell death and consequently cranial nerve developmental defects .	Collectively, these findings indicate that elevated Shh signaling in Ptch1 Wig and Wig embryos leads to a down-regulation of canonical Wnt dependent survival signaling, resulting in elevated neural crest cell death and consequently cranial nerve developmental defects.	7	11	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	7	8	10	11
Increased transcription was also detected for another Shh target Ptch1 following IFN-gamma treatment .	Increased transcription was also detected for another Shh target Ptch1 following IFN-gamma treatment.	4	12	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	7	8	9	10
Binding of Shh to its receptor , patched 1 ( Ptc1 ) , blocks the inhibitory effect of Ptc1 on smoothened ( Smo ) , which in turn activates the transcription factor Gli1 .	Binding of Shh to its receptor, patched 1 (Ptc1), blocks the inhibitory effect of Ptc1 on smoothened (Smo), which in turn activates the transcription factor Gli1.	0	19	blocks	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	2	3	18	19
FD cells had 50-80 % less intracellular folate , associated with aberrant hypomethylation of the Shh promoter , than control cells , and increased binding of nuclear NF-kappaB subunit p65 to the Shh promoter region , which coincided with increased Shh expression and protein production of Shh ligand ; in addition , the FD induced Shh signaling targeted Gli1 transcription activator as well as Ptch receptor .	FD cells had 50-80% less intracellular folate, associated with aberrant hypomethylation of the Shh promoter, than control cells, and increased binding of nuclear NF-kappaB subunit p65 to the Shh promoter region, which coincided with increased Shh expression and protein production of Shh ligand; in addition, the FD induced Shh signaling targeted Gli1 transcription activator as well as Ptch receptor.	53	65	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	FD induced Shh	shh	Ptch	Ptch	ptch	55	56	64	65
Curcumin has been shown to downregulate SHH , leading to decreased downstream targets GLI1 and PTCH1 and cytotoxicity in cell lines MED-4 , MED-5 , and DAOY [ XREF_BIBR ] .	Curcumin has been shown to downregulate SHH, leading to decreased downstream targets GLI1 and PTCH1 and cytotoxicity in cell lines MED-4, MED-5, and DAOY [XREF_BIBR].	5	16	leading	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SHH	SHH	SHH	PTCH1	PTCH1	PTCH1	6	7	15	16
It should be noted that it is likely that human Shh driven MB , harboring a mutation in Ptch , also respond to beta-catenin activation with reduction of Gli1 .	It should be noted that it is likely that human Shh driven MB, harboring a mutation in Ptch, also respond to beta-catenin activation with reduction of Gli1.	9	21	driven	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch	Ptch	Ptch	10	11	18	19
Our results suggest that Shh and transforming growth factor beta signaling cooperate to promote Ptch1 associated cataract development by activating EMT , and that the Nanog marker of pluripotent cells may act as the primary transcription factor on which both signaling pathways converge after damage .	Our results suggest that Shh and transforming growth factor beta signaling cooperate to promote Ptch1 associated cataract development by activating EMT, and that the Nanog marker of pluripotent cells may act as the primary transcription factor on which both signaling pathways converge after damage.	4	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	4	5	14	15
Ectopic enhancement of Shh signaling strongly induces Gli1 and Ptc1 in the entire thalamic progenitor domains .	Ectopic enhancement of Shh signaling strongly induces Gli1 and Ptc1 in the entire thalamic progenitor domains.	3	10	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	3	4	9	10
The addition of 5 muM SHh or 10 mug/ml SAG to H1 hESCs for 18 h up-regulated GLI1 ( approximately twofold ) and PTC1 ( approximately fivefold ) mRNA levels compared with baseline levels of these components without exogenous ligand stimulation , as determined by real-time PCR with GAPDH as an internal control ( XREF_FIG ) .	The addition of 5 muM SHh or 10 mug/ml SAG to H1 hESCs for 18 h up-regulated GLI1 (approximately twofold) and PTC1 (approximately fivefold) mRNA levels compared with baseline levels of these components without exogenous ligand stimulation, as determined by real-time PCR with GAPDH as an internal control (XREF_FIG).	1	26	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHh	SHh	SHh	PTC1	PTC1	PTC1	5	6	23	24
These findings indicated that loss of Sufu resulted in the upregulation of the Shh target Ptch1 , a potential consequence of reduced Gli3R levels .	These findings indicated that loss of Sufu resulted in the upregulation of the Shh target Ptch1, a potential consequence of reduced Gli3R levels.	10	19	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	13	14	15	16
It has recently been shown that , in mouse , the villus cluster expression of Bmp4 and the general Shh target Ptc1 are downstream of hedgehog signaling .	It has recently been shown that, in mouse, the villus cluster expression of Bmp4 and the general Shh target Ptc1 are downstream of hedgehog signaling.	13	22	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	19	20	21	22
Additionally , in agreement with these data , Ptc1 immunolabeling of collagen trapped nsps treated with Shh revealed higher expression of the receptor in comparison to control condition either without growth factors or only EGF plus FGF-2 , confirming that indeed cells within the nsps are actively responding to their ligand Shh ( XREF_FIG C ) .	Additionally, in agreement with these data, Ptc1 immunolabeling of collagen trapped nsps treated with Shh revealed higher expression of the receptor in comparison to control condition either without growth factors or only EGF plus FGF-2, confirming that indeed cells within the nsps are actively responding to their ligand Shh (XREF_FIG C).	8	17	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	16	17	8	9
We did not observe interaction between mammalian Smurfs and Smo by Co-IP experiments ( XREF_FIG ) , and found that Shh induction of Ptch1 turnover proceeded unabatedly even in the absence of Smo ( XREF_FIG ) .	We did not observe interaction between mammalian Smurfs and Smo by Co-IP experiments (XREF_FIG), and found that Shh induction of Ptch1 turnover proceeded unabatedly even in the absence of Smo (XREF_FIG).	20	24	induction	Positive_activation_syntax_3_noun	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	20	21	23	24
In effect , Ptch1 serves two roles in Shh signaling : first , it acts cell autonomously in suppressing the downstream pathway , and second , the excessive Ptch1 induced by Shh acts as a sink in limiting the spread of the ligand , thereby affecting the neighboring cells in a non cell autonomous fashion .	In effect, Ptch1 serves two roles in Shh signaling : first, it acts cell autonomously in suppressing the downstream pathway, and second, the excessive Ptch1 induced by Shh acts as a sink in limiting the spread of the ligand, thereby affecting the neighboring cells in a non cell autonomous fashion.	24	32	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	31	32	28	29
Our previous studies have shown that the LNCaP , PC3 and 22RV1 cell lines fail to exhibit transcription of the canonical Hh target genes Ptc1 or Gli1 when treated with either Shh ligand or transfected with activated Smo [ XREF_BIBR ] .	Our previous studies have shown that the LNCaP, PC3 and 22RV1 cell lines fail to exhibit transcription of the canonical Hh target genes Ptc1 or Gli1 when treated with either Shh ligand or transfected with activated Smo [XREF_BIBR].	17	32	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	31	32	24	25
As development proceeds cHairy2 expression in the ventral neural tube mirrors that of the Shh target Ptch1 , both spatially and temporally : expression is high in the floor plate and P3 progenitor domains in the caudal neuraxis , whereas , in more anterior developmentally mature regions , expression is downregulated in the floor plate but maintained in the adjacent P3 progenitor domain .	As development proceeds cHairy2 expression in the ventral neural tube mirrors that of the Shh target Ptch1, both spatially and temporally : expression is high in the floor plate and P3 progenitor domains in the caudal neuraxis, whereas, in more anterior developmentally mature regions, expression is downregulated in the floor plate but maintained in the adjacent P3 progenitor domain.	11	17	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	14	15	16	17
Activation of the hedgehog pathway in MC3T3 cells was a direct and immediate effect of Shh action since exogenous Shh peptide ( Shh-N ) increased Gli1 and Ptc1 message as early as 24 h following treatment .	Activation of the hedgehog pathway in MC3T3 cells was a direct and immediate effect of Shh action since exogenous Shh peptide (Shh-N) increased Gli1 and Ptc1 message as early as 24 h following treatment.	19	28	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	19	20	27	28
Shh signaling is mediated by the Shh receptor Patched ( Ptc1 ) , which activates another transmembrane protein Smoothened ( Smo ) and inhibits processing of the Gli3 transcription factor to a transcriptional repressor .	Shh signaling is mediated by the Shh receptor Patched (Ptc1), which activates another transmembrane protein Smoothened (Smo) and inhibits processing of the Gli3 transcription factor to a transcriptional repressor.	0	23	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	0	1	10	11
We therefore explored whether cranial placode development was altered in association with elevated Shh signaling in Ptch1 Wig and Wig mutant embryos .	We therefore explored whether cranial placode development was altered in association with elevated Shh signaling in Ptch1 Wig and Wig mutant embryos.	13	17	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	13	14	16	17
We show that at these stages in the murine mandibular arch in the absence of epithelium , the Shh targets Ptc1 and Gli1 are upregulated in diastema mesenchyme , an edentulous region between the sites of molar and incisor tooth formation .	We show that at these stages in the murine mandibular arch in the absence of epithelium, the Shh targets Ptc1 and Gli1 are upregulated in diastema mesenchyme, an edentulous region between the sites of molar and incisor tooth formation.	17	24	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	18	19	20	21
Mutations in the Shh signaling pathway that target Ptch1 , Smo and Gli1 are associated with cancers of the prostate , skin , and esophagus [ XREF_BIBR - XREF_BIBR ] .	Mutations in the Shh signaling pathway that target Ptch1, Smo and Gli1 are associated with cancers of the prostate, skin, and esophagus [XREF_BIBR - XREF_BIBR].	3	12	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	3	4	8	9
Thus , increased Shh signaling in Ptch1 Wig and Wig mutants , which results in the apoptosis of neural crest cells destined for the trigeminal and facial nerves is associated with the diminished integration between neural crest and placode cells .	Thus, increased Shh signaling in Ptch1 Wig and Wig mutants, which results in the apoptosis of neural crest cells destined for the trigeminal and facial nerves is associated with the diminished integration between neural crest and placode cells.	3	7	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	3	4	6	7
The mechanisms of dissemination have recently been studied in SHH driven Ptch1 heterozygous and p53 mutant MB models , that were combined with a Sleeping Beauty system [ XREF_BIBR ] for functional cancer gene discovery .	The mechanisms of dissemination have recently been studied in SHH driven Ptch1 heterozygous and p53 mutant MB models, that were combined with a Sleeping Beauty system [XREF_BIBR] for functional cancer gene discovery.	7	21	driven	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SHH	SHH	SHH	Ptch1	Ptch1	Ptch1	9	10	11	12
PTCH1 is upregulated by SHH in both ectoderm and underlying mesenchyme XREF_BIBR .	PTCH1 is upregulated by SHH in both ectoderm and underlying mesenchyme XREF_BIBR.	0	5	upregulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SHH	SHH	SHH	PTCH1	PTCH1	PTCH1	4	5	0	1
SHH activates signal transduction by binding its primary transmembrane receptor PTCH1 , relieving inhibition of the signaling function of a second transmembrane protein , Smoothened ( SMO ) .	SHH activates signal transduction by binding its primary transmembrane receptor PTCH1, relieving inhibition of the signaling function of a second transmembrane protein, Smoothened (SMO).	0	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHH	SHH	SHH	PTCH1	PTCH1	PTCH1	0	1	10	11
To delineate the requirement of Smurfs for Shh induced Ptch1 turnover , we took the advantage of the conditional Smurf1 -/-; Smurf2 fl/fl MEFs , and quantified the turnover rate of exogenously expressed Ptch1-FLAG following cyclohexamide treatment without or with removal of the Smurf2 alleles following Ad-cre infection .	To delineate the requirement of Smurfs for Shh induced Ptch1 turnover, we took the advantage of the conditional Smurf1 -/-; Smurf2 fl/fl MEFs, and quantified the turnover rate of exogenously expressed Ptch1-FLAG following cyclohexamide treatment without or with removal of the Smurf2 alleles following Ad-cre infection.	7	10	induced	Positive_early_activation	Negative_activation	Negative_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	7	8	9	10
Recently , Shh ligands were shown to induce accumulation of Ptch1 and the E3 ubiquitin ligases Smurf1 and Smurf2 in lipid rafts , which are molecularly distinct domains of the cell membrane .	Recently, Shh ligands were shown to induce accumulation of Ptch1 and the E3 ubiquitin ligases Smurf1 and Smurf2 in lipid rafts, which are molecularly distinct domains of the cell membrane.	2	11	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	2	3	10	11
So , an increase in the Shh signal strength would cause a corresponding increase in both the production of Ptch1 and its rate of turnover en route from the primary cilium to the lipid rafts and to the endosomes and lysosomes .	So, an increase in the Shh signal strength would cause a corresponding increase in both the production of Ptch1 and its rate of turnover en route from the primary cilium to the lipid rafts and to the endosomes and lysosomes.	6	20	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	6	7	19	20
The direct up-regulation of Ptch1 by Shh is a conserved feature , not just during limb development , but also in all known examples of hedgehog signalling .	The direct up-regulation of Ptch1 by Shh is a conserved feature, not just during limb development, but also in all known examples of hedgehog signalling.	2	7	up-regulation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	6	7	4	5
Alternatively , Hhip maintains the ability to inhibit Shh in vivo , because feedback mechanisms are in place where endogenous Hhip and Ptch1 are upregulated by the activated Shh response .	Alternatively, Hhip maintains the ability to inhibit Shh in vivo, because feedback mechanisms are in place where endogenous Hhip and Ptch1 are upregulated by the activated Shh response.	20	29	upregulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	28	29	22	23
Shh and IGF promote GCP growth and constitutive activation of the Shh and Ptch and IGF pathway are found in medulloblastomas in mouse and man .	Shh and IGF promote GCP growth and constitutive activation of the Shh and Ptch and IGF pathway are found in medulloblastomas in mouse and man.	0	14	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch	Ptch	Ptch	0	1	13	14
Shh treatment also increased Gli1 and Ptch1 at the protein level ( XREF_FIG ) .	Shh treatment also increased Gli1 and Ptch1 at the protein level (XREF_FIG).	0	7	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	0	1	6	7
Following the demonstration that Shh directly induces Ptc1 up-regulation in MSCs in vivo , we performed in vitro experiments to evaluate the effects of Shh treatment and inhibition on the proliferation of myoblast cells .	Following the demonstration that Shh directly induces Ptc1 up-regulation in MSCs in vivo, we performed in vitro experiments to evaluate the effects of Shh treatment and inhibition on the proliferation of myoblast cells.	4	8	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	4	5	7	8
We therefore used the Hedgehog palmitoylase ( Hhat ) loss-of function mutant ( Hhat Creface and Creface ) to lower the levels of Shh signaling in Ptch1 Wig and Wig mutants by producing compound mutants .	We therefore used the Hedgehog palmitoylase (Hhat) loss-of function mutant (Hhat Creface and Creface) to lower the levels of Shh signaling in Ptch1 Wig and Wig mutants by producing compound mutants.	23	27	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	23	24	26	27
In agreement evidences from the literature show that activation of Shh signaling in Ptch1 +/- mice critically alters the cell division mode in neural progenitors by enhancing symmetrical division of NSCs during cerebellar neurogenesis and in adult SVZ .	In agreement evidences from the literature show that activation of Shh signaling in Ptch1 +/- mice critically alters the cell division mode in neural progenitors by enhancing symmetrical division of NSCs during cerebellar neurogenesis and in adult SVZ.	10	15	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	10	11	13	14
To accomplish this , we took advantage of two independent assays of Shh signaling : immunostaining for Ptch1 , which is induced by Shh signaling , and a new transgenic reporter mouse -- Tg ( GBS-GFP ) -- in which eight concatemerized binding sites for Gli transcription factors regulate GFP expression ( XREF_FIG available online ) .	To accomplish this, we took advantage of two independent assays of Shh signaling : immunostaining for Ptch1, which is induced by Shh signaling, and a new transgenic reporter mouse -- Tg (GBS-GFP) -- in which eight concatemerized binding sites for Gli transcription factors regulate GFP expression (XREF_FIG available online).	15	24	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	23	24	17	18
Similarly , CNBP levels were higher in Ptch -/- cells , compared to control cells and in GCPs treated with Shh peptide ( XREF_FIG and XREF_SUPPLEMENTARY ) .	Similarly, CNBP levels were higher in Ptch -/- cells, compared to control cells and in GCPs treated with Shh peptide (XREF_FIG and XREF_SUPPLEMENTARY).	7	21	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch	Ptch	Ptch	20	21	7	8
In human aortic endothelial cells ( HAEC ) , which express high levels of HIP , the addition of Shh containing conditioned medium did not cause induction of Ptc-1 , even though these cells express the receptor components Ptc-1 and Smo .	In human aortic endothelial cells (HAEC), which express high levels of HIP, the addition of Shh containing conditioned medium did not cause induction of Ptc-1, even though these cells express the receptor components Ptc-1 and Smo.	17	29	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc-1	Ptc-1	Ptc-1	19	20	28	29
The results showed that the Shh signaling molecules SHH , PTCH , SMO , GLI1 , and GLI2 were intact and activated in both types of cells .	The results showed that the Shh signaling molecules SHH, PTCH, SMO, GLI1, and GLI2 were intact and activated in both types of cells.	4	21	signaling	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	PTCH	PTCH	PTCH	5	6	10	11
Taken together , these results suggest that Shh stimulation induces a conformational change in Ptc1 that increases its affinity for GRK2 at the expense of its interaction with cyclin B1 .	Taken together, these results suggest that Shh stimulation induces a conformational change in Ptc1 that increases its affinity for GRK2 at the expense of its interaction with cyclin B1.	7	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	7	8	14	15
Gli1 and Ptch1 are induced by Shh signaling in the limbs as they are in the neural tube .	Gli1 and Ptch1 are induced by Shh signaling in the limbs as they are in the neural tube.	0	7	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	6	7	2	3
Ptch1 and another cell surface protein , Hhip1 , are induced by Shh signaling , and each binds and sequesters Shh , consequently limiting the magnitude and range of signaling .	Ptch1 and another cell surface protein, Hhip1, are induced by Shh signaling, and each binds and sequesters Shh, consequently limiting the magnitude and range of signaling.	0	13	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	12	13	0	1
Shh signaling in Ptch1 +/- / SKH-1 enhances inflammatory microenvironment in the skin .	Shh signaling in Ptch1 +/- / SKH-1 enhances inflammatory microenvironment in the skin.	0	4	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	0	1	3	4
The Shh dependent upregulation of Ptc1 , and possibly other inhibitors of Shh signalling , results in the cell autonomous desensitization of cells to Shh over time XREF_BIBR , XREF_BIBR .	The Shh dependent upregulation of Ptc1, and possibly other inhibitors of Shh signalling, results in the cell autonomous desensitization of cells to Shh over time XREF_BIBR, XREF_BIBR.	1	6	upregulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	1	2	5	6
The SHh ligand , produced by the malignant epithelial cells , signaled to the transmembrane protein Ptch on the stromal cells which subsequently relocated Smo to the cell surface [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The SHh ligand, produced by the malignant epithelial cells, signaled to the transmembrane protein Ptch on the stromal cells which subsequently relocated Smo to the cell surface [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	17	signaled	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	SHh	SHh	SHh	Ptch	Ptch	Ptch	1	2	16	17
Fourth , neither SHH nor SAG increased PTC1 transcripts , and GLI1 transcripts remained very low .	Fourth, neither SHH nor SAG increased PTC1 transcripts, and GLI1 transcripts remained very low.	2	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHH	SHH	SHH	PTC1	PTC1	PTC1	3	4	7	8
Furthermore , we find that Shh induces a strong response in Ptch1 (-/-) ; Shh (-/-) cells , and that Ptch1 (-/-) fibroblasts retain their ability to migrate towards Shh , demonstrating that Ptch1 (-/-) cells remain sensitive to Shh .	Furthermore, we find that Shh induces a strong response in Ptch1 (-/-); Shh (-/-) cells, and that Ptch1 (-/-) fibroblasts retain their ability to migrate towards Shh, demonstrating that Ptch1 (-/-) cells remain sensitive to Shh.	5	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	5	6	11	12
To the best of our knowledge , we show here for the first time that Shh signaling activation in Ptch1 +/- mice causes patterning defects in the DG , detectable as elongation and thinning of the blades .	To the best of our knowledge, we show here for the first time that Shh signaling activation in Ptch1 +/- mice causes patterning defects in the DG, detectable as elongation and thinning of the blades.	15	21	signaling activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	15	16	19	20
Taken together , these results suggest that Shh stimulation may induce a conformational change in Ptc1 that increases its affinity for GRK2 at the expense of its interaction with Cyclin B1 .	Taken together, these results suggest that Shh stimulation may induce a conformational change in Ptc1 that increases its affinity for GRK2 at the expense of its interaction with Cyclin B1.	7	16	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptc1	Ptc1	Ptc1	7	8	15	16
Therefore we investigated the possibility that elevated Shh signaling in the Ptch1 Wig and Wig mutants regulates canonical Wnt signaling in the migratory crest and/or placodes , leading to the pathogenesis of cranial nerve defects .	Therefore we investigated the possibility that elevated Shh signaling in the Ptch1 Wig and Wig mutants regulates canonical Wnt signaling in the migratory crest and/or placodes, leading to the pathogenesis of cranial nerve defects.	7	12	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	7	8	11	12
The current paradigm stipulates that Shh induces Ptch1 exit from the primary cilium during signaling .	The current paradigm stipulates that Shh induces Ptch1 exit from the primary cilium during signaling.	5	8	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	5	6	7	8
Next , we tested the response of control and hop and hop MEFs to the chemical agonist SAG , which activates Smo directly and induces Shh signaling independently of Ptch1 XREF_BIBR .	Next, we tested the response of control and hop and hop MEFs to the chemical agonist SAG, which activates Smo directly and induces Shh signaling independently of Ptch1 XREF_BIBR.	25	30	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch1	Ptch1	Ptch1	25	26	29	30
Expression of Shh in the AER of Msx2-Shh limbs in our study leads to induction of Ptch , a sensitive indicator of activation of Shh signaling , throughout the entire AER and in a wide band extending anteriorly across the entire extent of the Msx2-Shh limb mesoderm subjacent to the AER .	Expression of Shh in the AER of Msx2-Shh limbs in our study leads to induction of Ptch, a sensitive indicator of activation of Shh signaling, throughout the entire AER and in a wide band extending anteriorly across the entire extent of the Msx2-Shh limb mesoderm subjacent to the AER.	0	17	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	Shh	Expression of Shh	shh	Ptch	Ptch	ptch	2	3	16	17
During the G1/S transition , p21 proteolysis is mediated by Skp2 ; however , p21 reaccumulates in G2 and is degraded again in prometaphase .	During the G1/S transition, p21 proteolysis is mediated by Skp2; however, p21 reaccumulates in G2 and is degraded again in prometaphase.	5	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p21	p21	p21	10	11	5	6
Consistent with this , the Skp2 target p21 was suppressed in the doubly treated group , indicating that the FoxM1-Skp2 activation may also contribute to the suppression of senescence caused by beta-catenin .	Consistent with this, the Skp2 target p21 was suppressed in the doubly treated group, indicating that the FoxM1-Skp2 activation may also contribute to the suppression of senescence caused by beta-catenin.	2	8	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p21	p21	p21	5	6	7	8
Skp2 also targets p57 , p21 , cyclin E1 and origin recognition complex 1 ( Orc1 ) for degradation [ XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	Skp2 also targets p57, p21, cyclin E1 and origin recognition complex 1 (Orc1) for degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR].	0	6	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p21	p21	p21	0	1	5	6
Since it has been reported that p21 regulates interstitial cells in UUO kidneys XREF_BIBR , the decrease in p21 targeted by Skp2 may be involved in the progression of interstitial cell proliferation in UUO kidneys .	Since it has been reported that p21 regulates interstitial cells in UUO kidneys XREF_BIBR, the decrease in p21 targeted by Skp2 may be involved in the progression of interstitial cell proliferation in UUO kidneys.	16	22	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p21	p21	p21	21	22	18	19
SKP2 is also known to target tumour suppressor proteins p21 and CDKN1C , resulting in protein degradation ( Frescas and Pagano , 2008 ) .	SKP2 is also known to target tumour suppressor proteins p21 and CDKN1C, resulting in protein degradation (Frescas and Pagano, 2008).	0	11	target	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SKP2	SKP2	SKP2	p21	p21	p21	0	1	9	10
In mammalian cells , silencing Skp2 induced the accumulation of Cyclin D and p21 .	In mammalian cells, silencing Skp2 induced the accumulation of Cyclin D and p21.	4	14	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Skp2	Skp2	Skp2	p21	p21	p21	5	6	13	14
Notably , p21 is targeted by Skp2 , DDB1 , and APC/C Cdc20 in G 1 , S , and M phase , respectively .	Notably, p21 is targeted by Skp2, DDB1, and APC/C Cdc20 in G 1, S, and M phase, respectively.	2	8	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p21	p21	p21	6	7	2	3
Skp2 overexpression increased Skp2 levels in glioma cells and reversed the inhibition of Skp2 and p-AKT and upregulation of P21 induced by PF ( XREF_FIG ) .	Skp2 overexpression increased Skp2 levels in glioma cells and reversed the inhibition of Skp2 and p-AKT and upregulation of P21 induced by PF (XREF_FIG).	0	20	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Skp2	Skp2 overexpression	skp2	P21	P21	p21	0	1	19	20
Given that SKP2 , a component of the SCF ubiquitin E3 ligase , can target p21 for proteasomal degradation , we further determined if the effect of HBx on p21 degradation is dependent on SKP2 .	Given that SKP2, a component of the SCF ubiquitin E3 ligase, can target p21 for proteasomal degradation, we further determined if the effect of HBx on p21 degradation is dependent on SKP2.	2	16	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SKP2	SKP2	SKP2	p21	p21	p21	2	3	15	16
We have shown that p21 accumulation in UUO kidneys is moderately enhanced by Skp2 deficiency [ XREF_BIBR ] .	We have shown that p21 accumulation in UUO kidneys is moderately enhanced by Skp2 deficiency [XREF_BIBR].	4	16	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Skp2	Skp2	Skp2	p21	p21	p21	13	14	4	5
In contrast , activation of SIRT1 signaling through the use of the small molecules SRT1720 or SRT2183 inhibited DLL4 mediated induction of HEY1 and HEY2 expression , indicating that SIRT1 negatively modulated DLL4 and Notch1 signaling in lung cancer derived ECs ( XREF_SUPPLEMENTARY ) .	In contrast, activation of SIRT1 signaling through the use of the small molecules SRT1720 or SRT2183 inhibited DLL4 mediated induction of HEY1 and HEY2 expression, indicating that SIRT1 negatively modulated DLL4 and Notch1 signaling in lung cancer derived ECs (XREF_SUPPLEMENTARY).	29	35	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	29	30	34	35
Here , we found that endothelial SIRT1 dysfunction causes activation of endothelial Notch1 signaling , which leads to PTC rarefaction and fibrosis following kidney injury .	Here, we found that endothelial SIRT1 dysfunction causes activation of endothelial Notch1 signaling, which leads to PTC rarefaction and fibrosis following kidney injury.	6	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	6	7	12	13
SIRT1 functions as an NICD deacetylase , which opposes the acetylation induced stabilization of NICD [ XREF_BIBR ] .	SIRT1 functions as an NICD deacetylase, which opposes the acetylation induced stabilization of NICD [XREF_BIBR].	0	16	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	NICD	NICD	NICD	0	1	14	15
SIRT1 directly regulates Notch1 by deacetylating conserved lysines in the NICD .	SIRT1 directly regulates Notch1 by deacetylating conserved lysines in the NICD.	0	4	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	0	1	3	4
These data indicate that SIRT1 might negatively regulate Notch signalling by promoting NICD degradation .	These data indicate that SIRT1 might negatively regulate Notch signalling by promoting NICD degradation.	4	13	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	NICD	NICD	NICD	4	5	12	13
Our results present evidence , for the first time , that dysfunction of endothelial SIRT1 enhances Notch1 signaling , which aggravates kidney injury .	Our results present evidence, for the first time, that dysfunction of endothelial SIRT1 enhances Notch1 signaling, which aggravates kidney injury.	11	17	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	14	15	16	17
Therefore , we hypothesized that SIRT1 inactivation augments Notch1 signaling in PTC MVECs .	Therefore, we hypothesized that SIRT1 inactivation augments Notch1 signaling in PTC MVECs.	5	9	augments	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	Notch1	Notch1	Notch1	5	6	8	9
Sirt1 increases the degradation parameter of NICD ( the active fragment of notch ; [ Sirt1 ] = 1 corresponds to our original model , refer to Materials and Methods for details ) .	Sirt1 increases the degradation parameter of NICD (the active fragment of notch; [Sirt1] = 1 corresponds to our original model, refer to Materials and Methods for details).	0	29	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	NICD	NICD	NICD	0	1	6	7
Expression of SIRT1 but not SIRT1HY increased levels of ADAM10 RNA and NICD protein in SIRT1 -/- MEFs , indicating that the deacetylase activity of SIRT1 is required for ADAM10 activation .	Expression of SIRT1 but not SIRT1HY increased levels of ADAM10 RNA and NICD protein in SIRT1 -/- MEFs, indicating that the deacetylase activity of SIRT1 is required for ADAM10 activation.	0	13	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	Expression of SIRT1	sirt1	NICD	NICD	nicd	2	3	12	13
Abnormal Shh signaling in CP tumour cells .	Abnormal Shh signaling in CP tumour cells.	1	6	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	CP	CP	CP	1	2	4	5
The qPCR result further revealed that Shh signaling in CP was mediated through Gli1 but not Gli2 as Gli1 transcript was subject to a 3-fold up-regulation whereas Gli2 transcript remained unaffected ( XREF_FIG ) .	The qPCR result further revealed that Shh signaling in CP was mediated through Gli1 but not Gli2 as Gli1 transcript was subject to a 3-fold up-regulation whereas Gli2 transcript remained unaffected (XREF_FIG).	6	10	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Shh	Shh	Shh	CP	CP	CP	6	7	9	10
Shh drives CP tumour cell proliferation .	Shh drives CP tumour cell proliferation.	0	5	drives	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	CP	CP	CP	0	1	2	3
Thus Shh in E15-17 embryonic neocortex can signal CP to adopt an oligodendrocyte fate and favors expansion of this lineage .	Thus Shh in E15-17 embryonic neocortex can signal CP to adopt an oligodendrocyte fate and favors expansion of this lineage.	1	15	signal	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	CP	CP	CP	1	2	8	9
SHH and NOTCH signaling in human CP tumours .	SHH and NOTCH signaling in human CP tumours.	0	7	signaling	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	SHH	SHH	SHH	CP	CP	CP	0	1	6	7
Inactivation of Sirt1 in hepatocyte promotes and prolongs NF-kappaB-binding activity by maintaining p65 in an acetylated , DNA binding competent state .	Inactivation of Sirt1 in hepatocyte promotes and prolongs NF-kappaB-binding activity by maintaining p65 in an acetylated, DNA binding competent state.	0	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	p65	p65	p65	2	3	12	13
Further , IkappaBalpha and p65 were significantly activated and phosphorylated by Sirt1 overexpression , and the protein expression of Bcl-3 was significantly upregulated .	Further, IkappaBalpha and p65 were significantly activated and phosphorylated by Sirt1 overexpression, and the protein expression of Bcl-3 was significantly upregulated.	2	13	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Sirt1	Sirt1 overexpression	sirt1	p65	p65	p65	11	12	4	5
This is explained by the finding that cigarette smoke derived oxidants ( ROS and RNS ) caused post-transcriptional modifications of SIRT1 and subsequent degradation thereby disrupting SIRT1 , RelA , and p65 complex and increased the release of pro inflammatory mediators .	This is explained by the finding that cigarette smoke derived oxidants (ROS and RNS) caused post-transcriptional modifications of SIRT1 and subsequent degradation thereby disrupting SIRT1, RelA, and p65 complex and increased the release of pro inflammatory mediators.	20	32	disrupting	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p65	p65	p65	20	21	31	32
Thus , in diabetes , increase in oxidative stress inhibits Sirt1 and p65 is hyperacetylated , increasing the binding of p65 at MMP-9 promoter .	Thus, in diabetes, increase in oxidative stress inhibits Sirt1 and p65 is hyperacetylated, increasing the binding of p65 at MMP-9 promoter.	10	21	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1 and p65 is hyperacetylated	sirt1	p65	p65	p65	10	11	20	21
Results in XREF_FIG show that IkappaBalpha and p65 were significantly activated and phosphorylated by Sirt1 overexpression ( p < 0.01 or p < 0.001 ) .	Results in XREF_FIG show that IkappaBalpha and p65 were significantly activated and phosphorylated by Sirt1 overexpression (p < 0.01 or p < 0.001).	5	16	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Sirt1	Sirt1 overexpression	sirt1	p65	p65	p65	14	15	7	8
The SUMO specific protease SSP3 relieved SIRT1 repression of p300 .	The SUMO specific protease SSP3 relieved SIRT1 repression of p300.	6	10	repression	Negative_activation_syntax_3_noun	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	6	7	9	10
We found that SIRT1 induced p300 down-regulation via the ubiquitin-proteasome pathway by deacetylation of lysine residues for ubiquitination .	We found that SIRT1 induced p300 down-regulation via the ubiquitin-proteasome pathway by deacetylation of lysine residues for ubiquitination.	3	6	induced	Positive_early_activation	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	3	4	5	6
In addition to Suv39h1 , SIRT1 can modulate the activity of p300 histone acetyltransferase .	In addition to Suv39h1, SIRT1 can modulate the activity of p300 histone acetyltransferase.	5	13	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT1	SIRT1	SIRT1	p300	p300	p300	5	6	11	12
[ XREF_BIBR ] SIRT7 is the least studied Sirtuin family member , but until now it has been investigated that SIRT7 as deacetylase can target substates p53 , H3K18 , PAF53 and so on .	[XREF_BIBR] SIRT7 is the least studied Sirtuin family member, but until now it has been investigated that SIRT7 as deacetylase can target substates p53, H3K18, PAF53 and so on.	20	32	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIRT7	SIRT7	SIRT7	p53	p53	p53	20	21	26	27
We observed a strong association of SLAP2 with ligand stimulated FLT3 .	We observed a strong association of SLAP2 with ligand stimulated FLT3.	4	11	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SLAP2	SLAP2	SLAP2	FLT3	FLT3	FLT3	6	7	10	11
Therefore , it is possible that SLAP2 competes with SRC and loss of SLAP2 expression potentiates FLT3 signaling through SRC .	Therefore, it is possible that SLAP2 competes with SRC and loss of SLAP2 expression potentiates FLT3 signaling through SRC.	13	17	potentiates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SLAP2	SLAP2 expression	slap2	FLT3	FLT3	flt3	13	14	16	17
SLAP2 associated with ligand stimulated FLT3 through its SH2 domain .	SLAP2 associated with ligand stimulated FLT3 through its SH2 domain.	0	6	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SLAP2	SLAP2	SLAP2	FLT3	FLT3	FLT3	0	1	5	6
Synphilin-1 inhibition can be relieved by co-expression of Siah-1 that targets synphilin-1 to degradation .	Synphilin-1 inhibition can be relieved by co-expression of Siah-1 that targets synphilin-1 to degradation.	0	9	relieved	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Siah-1	co-expression of Siah-1	siah-1	Synphilin-1	Synphilin-1	synphilin-1	8	9	0	1
Siah-1 was found to abrogate the inhibitory effects of synphilin-1 on dopamine release .	Siah-1 was found to abrogate the inhibitory effects of synphilin-1 on dopamine release.	0	10	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Siah-1	Siah-1	Siah-1	synphilin-1	synphilin-1	synphilin-1	0	1	9	10
Consistent with this , and with our results above , we found that parkin , but not Siah-1 or several other related E3 members , promotes synphilin-1 accumulation in the Triton-X-insoluble P fraction ( XREF_SUPPLEMENTARY ) .	Consistent with this, and with our results above, we found that parkin, but not Siah-1 or several other related E3 members, promotes synphilin-1 accumulation in the Triton-X-insoluble P fraction (XREF_SUPPLEMENTARY).	17	27	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Siah-1	Siah-1	Siah-1	synphilin-1	synphilin-1	synphilin-1	17	18	26	27
Global SIK2 knockout mice have enhanced CRTC2 and CREB activity in white adipocytes , which contributes to insulin resistance , hyperglycemia , and hypertriglyceridemia in that model XREF_BIBR .	Global SIK2 knockout mice have enhanced CRTC2 and CREB activity in white adipocytes, which contributes to insulin resistance, hyperglycemia, and hypertriglyceridemia in that model XREF_BIBR.	1	9	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIK2	SIK2	SIK2	CRTC2	CRTC2	CRTC2	1	2	6	7
We speculate that SIK2 mediates CRTC2 inactivation in the cytoplasm under the basal condition in Y-1 cells .	We speculate that SIK2 mediates CRTC2 inactivation in the cytoplasm under the basal condition in Y-1 cells.	3	6	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIK2	SIK2	SIK2	CRTC2	CRTC2	CRTC2	3	4	5	6
SGK3 also modulates GSK3beta .	SGK3 also modulates GSK3beta.	0	4	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SGK3	SGK3	SGK3	GSK3beta	GSK3beta	GSK3beta	0	1	3	4
We found that ShhN ( soluble N-terminal Shh ) was able to induce the Hh response both in Ptch1 +/LacZ ; Shh -/- and Ptch1 LacZ and LacZ ; Shh -/- nEBs but not in Ptch1 LacZ and LacZ ; Ptch2 -/-; Shh -/- nEBs , ( XREF_FIG ) , corroborating our report that Ptch1 -/- cells respond to Shh via Ptch2 .	We found that ShhN (soluble N-terminal Shh) was able to induce the Hh response both in Ptch1 +/LacZ; Shh -/- and Ptch1 LacZ and LacZ; Shh -/- nEBs but not in Ptch1 LacZ and LacZ; Ptch2 -/-; Shh -/- nEBs, (XREF_FIG), corroborating our report that Ptch1 -/- cells respond to Shh via Ptch2.	3	50	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Shh	Shh	Shh	Ptch2	Ptch2	Ptch2	7	8	40	41
Experiments in chick explants have shown that PTCH2 is expressed in the preneural tube in a SHH and FGF dependent way indicating the existence of an enhanced feedback loop where SHH activates PTCH2 more efficiently in regions of high FGF signaling .	Experiments in chick explants have shown that PTCH2 is expressed in the preneural tube in a SHH and FGF dependent way indicating the existence of an enhanced feedback loop where SHH activates PTCH2 more efficiently in regions of high FGF signaling.	30	33	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SHH	SHH	SHH	PTCH2	PTCH2	PTCH2	30	31	32	33
Based on these findings , we hypothesized that , in IBD mucosa , reduced Sirt1 activity contributes to enhance Smad7 protein stability and expression , while high Smad7 helps propagate signals that culminate in Sirt1 downregulation .	Based on these findings, we hypothesized that, in IBD mucosa, reduced Sirt1 activity contributes to enhance Smad7 protein stability and expression, while high Smad7 helps propagate signals that culminate in Sirt1 downregulation.	14	21	contributes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	Smad7	Smad7	Smad7	14	15	19	20
Similarly , it remains to establish whether , in cells overexpressing p300 , a protein with intrinsic acetyltransferase activity enhancing Smad7 stability , Sirt1 activation can eventually cause Smad7 protein downregulation .	Similarly, it remains to establish whether, in cells overexpressing p300, a protein with intrinsic acetyltransferase activity enhancing Smad7 stability, Sirt1 activation can eventually cause Smad7 protein downregulation.	23	30	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sirt1	Sirt1	Sirt1	Smad7	Smad7	Smad7	23	24	28	29
SIK2 was shown to enhance insulin secretion via phosphorylation and degradation of CDK5R1 and p35 , and SAD-A was implicated as a regulator of beta cell size and GSIS .	SIK2 was shown to enhance insulin secretion via phosphorylation and degradation of CDK5R1 and p35, and SAD-A was implicated as a regulator of beta cell size and GSIS.	0	14	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SIK2	SIK2	SIK2	CDK5R1	CDK5R1	CDK5R1	0	1	12	13
Ski expression has been shown to inhibit vascular smooth muscle cell proliferation by suppressing Tgfb and Smad3 signaling but up-regulating p38 signaling [ XREF_BIBR ] .	Ski expression has been shown to inhibit vascular smooth muscle cell proliferation by suppressing Tgfb and Smad3 signaling but up-regulating p38 signaling [XREF_BIBR].	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Ski	Ski expression	ski	Smad3	Smad3	smad3	0	1	16	17
Interaction mapping experiments and functional analyses confirmed this interaction and showed that endogenous Siah1 targets Numb for degradation in the LTR6 myeloid leukemia cell line .	Interaction mapping experiments and functional analyses confirmed this interaction and showed that endogenous Siah1 targets Numb for degradation in the LTR6 myeloid leukemia cell line.	13	17	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Siah1	Siah1	Siah1	Numb	Numb	Numb	13	14	15	16
This finding is consistent lack of effect of removal of the SBE in the Smad7 promoter and impairment of TGB-beta and Smad3 signaling ( Figs .	This finding is consistent lack of effect of removal of the SBE in the Smad7 promoter and impairment of TGB-beta and Smad3 signaling (Figs.	14	24	promoter	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	14	15	21	22
TGF-beta inhibition via overexpression of SMAD7 ( or knockdown of SMAD2 , SMAD3 , or SMAD4 ) consistently reduced formation and growth of liver tumors in mice that expressed activated RAS plus shRNA against p53 , or in mice that expressed activated RASand TAZ .	TGF-beta inhibition via overexpression of SMAD7 (or knockdown of SMAD2, SMAD3, or SMAD4) consistently reduced formation and growth of liver tumors in mice that expressed activated RAS plus shRNA against p53, or in mice that expressed activated RASand TAZ.	3	17	knockdown	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	SMAD7	overexpression of SMAD7	smad7	SMAD3	SMAD3	smad3	5	6	12	13
Inhibiting canonical TGF-beta-signaling through deletion of Smad3 or Smad4 or by increased expression of inhibitory Smad7 promotes gut inflammation .	Inhibiting canonical TGF-beta-signaling through deletion of Smad3 or Smad4 or by increased expression of inhibitory Smad7 promotes gut inflammation.	0	16	Inhibiting	Negative_activation_syntax_3_verb	Negative_activation	Positive_activation	Smad7	expression of inhibitory Smad7	smad7	Smad3	Smad3	smad3	15	16	6	7
Smad7 antagonizes TGF-beta signaling by suppressing Smad2 and Smad3 .	Smad7 antagonizes TGF-beta signaling by suppressing Smad2 and Smad3.	0	9	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	0	1	8	9
This antibody immunoprecipitated target DNA from a known Smad3 binding region in the Smad7 promoter in Smad3 wild-type but not Smad3 null mouse mammary epithelial cells .	This antibody immunoprecipitated target DNA from a known Smad3 binding region in the Smad7 promoter in Smad3 wild-type but not Smad3 null mouse mammary epithelial cells.	13	17	promoter	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	13	14	16	17
Most importantly , they display i ) loss of cytostatic effects upon TGF-beta treatment ( except late proliferation inhibition in HuH6 cells ) , ii ) transient phosphorylation of Smad2 upon TGF-beta treatment , iii ) elevated endogenous ERK phosphorylation , iv ) low induction of CAGA reporter and v ) low Smad3 and TbetaRI and vi ) high TGF-beta1 and Smad7 expression .	Most importantly, they display i) loss of cytostatic effects upon TGF-beta treatment (except late proliferation inhibition in HuH6 cells), ii) transient phosphorylation of Smad2 upon TGF-beta treatment, iii) elevated endogenous ERK phosphorylation, iv) low induction of CAGA reporter and v) low Smad3 and TbetaRI and vi) high TGF-beta1 and Smad7 expression.	44	63	induction	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	Smad7	Smad7 expression	smad7	Smad3	Smad3	smad3	61	62	52	53
[ XREF_BIBR ] TGF-beta exerts its renal fibrotic action mainly through downstream signaling molecules Smad2 and Smad3 , which , interestingly , are negatively regulated by inhibitory Smad7 , which inhibits renal fibrosis and inflammation .	[XREF_BIBR] TGF-beta exerts its renal fibrotic action mainly through downstream signaling molecules Smad2 and Smad3, which, interestingly, are negatively regulated by inhibitory Smad7, which inhibits renal fibrosis and inflammation.	13	30	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	27	28	16	17
Smad7 antagonizes TGF-beta signaling by interacting with the TGF-beta type I receptor ( TbetaRI ) and inhibiting activation of Smad2 and Smad3 [ XREF_BIBR , XREF_BIBR ] .	Smad7 antagonizes TGF-beta signaling by interacting with the TGF-beta type I receptor (TbetaRI) and inhibiting activation of Smad2 and Smad3 [XREF_BIBR, XREF_BIBR].	0	23	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	0	1	21	22
Second , Axins facilitate phosphorylation of the inhibitory Smad7 , which competitively inhibits Smad3 activity .	Second, Axins facilitate phosphorylation of the inhibitory Smad7, which competitively inhibits Smad3 activity.	4	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	phosphorylation of the inhibitory Smad7	smad7	Smad3	Smad3	smad3	8	9	13	14
This notion is supported by a recent report showing that nuclear Smad7 can promote myogenesis independent of TGF-beta and Smad3 signaling [ XREF_BIBR ] .	This notion is supported by a recent report showing that nuclear Smad7 can promote myogenesis independent of TGF-beta and Smad3 signaling [XREF_BIBR].	10	22	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	11	12	19	20
SMAD7 , which is an inhibitory Smad that negatively regulates Smad2 and Smad3 activation , is a negative regulator of TGF-beta signaling , and is a predicted target gene of miR-21 .	SMAD7, which is an inhibitory Smad that negatively regulates Smad2 and Smad3 activation, is a negative regulator of TGF-beta signaling, and is a predicted target gene of miR-21.	0	18	negatively regulates	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	SMAD7	SMAD7	SMAD7	Smad3	Smad3	Smad3	0	1	12	13
Increased expression of Smad7 , an inhibitory Smad that binds TbetaRI , that can be induced by Jak and STAT signaling might also inhibit TGF-beta-induced Smad3 activation ; however , TpIC decreased Smad7 mRNA expression ( XREF_FIG ) .	Increased expression of Smad7, an inhibitory Smad that binds TbetaRI, that can be induced by Jak and STAT signaling might also inhibit TGF-beta-induced Smad3 activation; however, TpIC decreased Smad7 mRNA expression (XREF_FIG).	1	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad7	expression of Smad7	smad7	Smad3	Smad3	smad3	3	4	25	26
Knock-down of Smad7 with a specific antisense oligonucleotide restores TGF-beta1 and Smad3 signalling , thus resulting in a marked suppression of inflammatory cytokine production and attenuation of murine colitis .	Knock-down of Smad7 with a specific antisense oligonucleotide restores TGF-beta1 and Smad3 signalling, thus resulting in a marked suppression of inflammatory cytokine production and attenuation of murine colitis.	0	12	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	Smad3	Smad3	Smad3	2	3	11	12
Multiple studies in mutant mice lacking the TGF-beta1 and Smad3 pathway have implicated a regeneration phenotype in mice : mice lacking TGF-beta1 show an increase in wound closure and epithelialization [ XREF_BIBR ] ; transgenic mice null for Smad3 show increased re-epithelialization and tissue renewal [ XREF_BIBR ] ; and Smad7 over-expression leads to Smad3 down -regulation and to enhanced liver regeneration through the TGF-beta/Smad3/p21 pathway [ XREF_BIBR ] .	Multiple studies in mutant mice lacking the TGF-beta1 and Smad3 pathway have implicated a regeneration phenotype in mice : mice lacking TGF-beta1 show an increase in wound closure and epithelialization [XREF_BIBR]; transgenic mice null for Smad3 show increased re-epithelialization and tissue renewal [XREF_BIBR]; and Smad7 over-expression leads to Smad3 down -regulation and to enhanced liver regeneration through the TGF-beta/Smad3/p21 pathway [XREF_BIBR].	50	56	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad7	Smad7 over-expression	smad7	Smad3	Smad3	smad3	50	51	54	55
SMO activity at cilia promotes transport of GLI and SUFU to the tip of the cilium , allowing the GLI transcription factors to dissociate from SUFU and enter the nucleus to transcribe target genes .	SMO activity at cilia promotes transport of GLI and SUFU to the tip of the cilium, allowing the GLI transcription factors to dissociate from SUFU and enter the nucleus to transcribe target genes.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMO	SMO	SMO	SUFU	SUFU	SUFU	0	1	9	10
Activated SMO promotes SUFU disassociation from the GLI DNA binding proteins thus licensing them for gene transcriptional activation XREF_BIBR , XREF_BIBR .	Activated SMO promotes SUFU disassociation from the GLI DNA binding proteins thus licensing them for gene transcriptional activation XREF_BIBR, XREF_BIBR.	0	4	promotes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SMO	SMO	SMO	SUFU	SUFU	SUFU	1	2	3	4
While the relationship between Sufu and cilia remains to be defined , the data are consistent with a model in which Smo activates the pathway at the cilia tip by antagonizing the activity of Sufu , thereby promoting activation of Gli transcription factors 40 ( XREF_FIG ) .	While the relationship between Sufu and cilia remains to be defined, the data are consistent with a model in which Smo activates the pathway at the cilia tip by antagonizing the activity of Sufu, thereby promoting activation of Gli transcription factors 40 (XREF_FIG).	21	35	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smo	Smo	Smo	Sufu	Sufu	Sufu	21	22	34	35
Active SMO ultimately antagonizes the inhibitory effect of PKA and SUFU on the GLI proteins .	Active SMO ultimately antagonizes the inhibitory effect of PKA and SUFU on the GLI proteins.	0	11	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SMO	SMO	SMO	SUFU	SUFU	SUFU	1	2	10	11
Hh proteins bind Patched-1 ( PTCH ) receptor derepressing the membrane protein Smoothened ( SMO ) and activated SMO then triggers Gli and its subsequent downstream target SUFU XREF_BIBR .	Hh proteins bind Patched-1 (PTCH) receptor derepressing the membrane protein Smoothened (SMO) and activated SMO then triggers Gli and its subsequent downstream target SUFU XREF_BIBR.	17	28	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMO	SMO	SMO	SUFU	SUFU	SUFU	18	19	27	28
Shh stimulation of Smo -/- MEFs does not increase ciliary SuFu and Gli , indicating that signal dependent recruitment of SuFu and Gli requires Smo .	Shh stimulation of Smo -/- MEFs does not increase ciliary SuFu and Gli, indicating that signal dependent recruitment of SuFu and Gli requires Smo.	3	12	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smo	Smo	Smo	SuFu	SuFu	SuFu	3	4	10	11
Activated SMO promotes SUFU disassociation from GLI proteins thus allowing them to activate transcription XREF_BIBR , XREF_BIBR .	Activated SMO promotes SUFU disassociation from GLI proteins thus allowing them to activate transcription XREF_BIBR, XREF_BIBR.	0	4	promotes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SMO	SMO	SMO	SUFU	SUFU	SUFU	1	2	3	4
SMO then activates the cytoplasmic protein SUFU , which releases the GLI family of transcription factors , GLI1 and GLI2 .	SMO then activates the cytoplasmic protein SUFU, which releases the GLI family of transcription factors, GLI1 and GLI2.	0	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMO	SMO	SMO	SUFU	SUFU	SUFU	0	1	6	7
Non canonical signaling downstream of Smo may involve activation of G i proteins and/or modulation of Sufu activity by the cytoplasmic C-tail of Smo .	Non canonical signaling downstream of Smo may involve activation of G i proteins and/or modulation of Sufu activity by the cytoplasmic C-tail of Smo.	14	24	modulation	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	Smo	Smo	Smo	Sufu	Sufu	Sufu	23	24	16	17
These observations support the model that Sufu is the major negative regulator of FP induction and that activated Smo restricts the inhibitory function of Sufu through Kif7 .	These observations support the model that Sufu is the major negative regulator of FP induction and that activated Smo restricts the inhibitory function of Sufu through Kif7.	17	25	restricts	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smo	Smo	Smo	Sufu	Sufu	Sufu	18	19	24	25
Smo signaling promotes the transport of Gli and SuFu to the tip of the cilium , allowing Glis to dissociate from SuFu and enter the nucleus to transcribe target genes .	Smo signaling promotes the transport of Gli and SuFu to the tip of the cilium, allowing Glis to dissociate from SuFu and enter the nucleus to transcribe target genes.	0	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smo	Smo	Smo	SuFu	SuFu	SuFu	0	1	8	9
Active Smo allows dissociation of Sufu from Gli [ XREF_BIBR ] .	Active Smo allows dissociation of Sufu from Gli [XREF_BIBR].	0	6	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smo	Smo	Smo	Sufu	Sufu	Sufu	1	2	5	6
Smo activation , in turn , causes Kif7 , Sufu and Gli proteins to travel to the tip of the cilium , with Kif7 , in particular , required for efficient Gli2 and Gli3 accumulation .	Smo activation, in turn, causes Kif7, Sufu and Gli proteins to travel to the tip of the cilium, with Kif7, in particular, required for efficient Gli2 and Gli3 accumulation.	0	12	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smo	Smo	Smo	Sufu	Sufu	Sufu	0	1	9	10
Smurf1 inhibits osteoblast differentiation by targeting Runx2 to degradation .	Smurf1 inhibits osteoblast differentiation by targeting Runx2 to degradation.	0	7	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	0	1	6	7
Next , we examined the levels of E3 ubiquitin ligases Smurf1 and Smurf2 since studies have shown that TNF-alpha up-regulates Smurf1 and Smurf2 , which , in turn , promotes Runx2 protein degradation XREF_BIBR , XREF_BIBR .	Next, we examined the levels of E3 ubiquitin ligases Smurf1 and Smurf2 since studies have shown that TNF-alpha up-regulates Smurf1 and Smurf2, which, in turn, promotes Runx2 protein degradation XREF_BIBR, XREF_BIBR.	19	33	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	20	21	30	31
Another important mechanism by which TNF inhibits osteoblastic bone formation is by the induction of the E3-ubiquitin ligase Smurf1 , which targets the critical osteoblast transcription factor Runx2 for proteolysis [ XREF_BIBR ] .	Another important mechanism by which TNF inhibits osteoblastic bone formation is by the induction of the E3-ubiquitin ligase Smurf1, which targets the critical osteoblast transcription factor Runx2 for proteolysis [XREF_BIBR].	13	28	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	18	19	27	28
To ascertain that the phosphorylation of Smurf1 at S148 is needed to target Runx2 for degradation , we performed a GST-Pull-down assay and observed that the interaction between Smurf1 and Runx2 that occurred upon phosphorylation of Smurf1 by AMPK was abrogated when S148 was mutated to alanine .	To ascertain that the phosphorylation of Smurf1 at S148 is needed to target Runx2 for degradation, we performed a GST-Pull-down assay and observed that the interaction between Smurf1 and Runx2 that occurred upon phosphorylation of Smurf1 by AMPK was abrogated when S148 was mutated to alanine.	4	14	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	phosphorylation of Smurf1 at S148	smurf1	Runx2	Runx2	runx2	6	7	13	14
This acetylation increases RUNX2 activity and inhibits degradation of RUNX2 by SMURF1 .	This acetylation increases RUNX2 activity and inhibits degradation of RUNX2 by SMURF1.	6	12	degradation	Negative_activation_token_2_noun	Negative_activation	Positive_activation	SMURF1	SMURF1	SMURF1	RUNX2	RUNX2	RUNX2	11	12	9	10
Under physiologic conditions , Smurf1 inhibits osteoblast differentiation by limiting the accumulation of BMP Smad , Runx2 , and JunB proteins through proteasome degradation .	Under physiologic conditions, Smurf1 inhibits osteoblast differentiation by limiting the accumulation of BMP Smad, Runx2, and JunB proteins through proteasome degradation.	4	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	4	5	16	17
For 8-month-old BMP-2 n / Smurf1 e subgroup of osteoporotic mice , ( DSS ) 6 -chalcone derivative also showed comparable bone anabolic action with PTH , dramatically inhibited Smurf1 activity and increased p-Smad1 , Runx2 activation , and osteocalcin mRNA in osteoblasts .	For 8-month-old BMP-2 n / Smurf1 e subgroup of osteoporotic mice, (DSS) 6 -chalcone derivative also showed comparable bone anabolic action with PTH, dramatically inhibited Smurf1 activity and increased p-Smad1, Runx2 activation, and osteocalcin mRNA in osteoblasts.	3	36	increased	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	5	6	35	36
The E3 ubiquitin ligase Smurf1 targets the master regulator of osteoblast differentiation Runx2 , for degradation yet the function of Smurf1 if any during osteoblast differentiation in vivo is ill defined .	The E3 ubiquitin ligase Smurf1 targets the master regulator of osteoblast differentiation Runx2, for degradation yet the function of Smurf1 if any during osteoblast differentiation in vivo is ill defined.	0	13	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	4	5	12	13
Additionally , other factors have been implicated in mediating Runx2 degradation by recruiting E3-ligases , such as Smad 6 , which binds to Runx2 and serves as an adaptor for Smurf1 induced Runx2 degradation XREF_BIBR , XREF_BIBR .	Additionally, other factors have been implicated in mediating Runx2 degradation by recruiting E3-ligases, such as Smad 6, which binds to Runx2 and serves as an adaptor for Smurf1 induced Runx2 degradation XREF_BIBR, XREF_BIBR.	28	34	induced	Positive_early_activation	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Runx2	Runx2	Runx2	30	31	32	33
Recently , we analyzed the reported co-structure of Smad1 and Smurf1 WW domains interaction , which affects Smurf1 activating Smad1 , and identified a binding hydrophobic pocket providing the position for this interaction .	Recently, we analyzed the reported co-structure of Smad1 and Smurf1 WW domains interaction, which affects Smurf1 activating Smad1, and identified a binding hydrophobic pocket providing the position for this interaction.	16	20	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	17	18	19	20
It has been reported that Smurf1 , a member of the Hect family E3 ubiquitin ligases , can target Smad1 to 26S proteasome for degradation .	It has been reported that Smurf1, a member of the Hect family E3 ubiquitin ligases, can target Smad1 to 26S proteasome for degradation.	5	20	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	5	6	19	20
For example , Smurf1 targets SMAD1 and 5 for destruction in unstimulated cells .	For example, Smurf1 targets SMAD1 and 5 for destruction in unstimulated cells.	3	6	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	SMAD1	SMAD1	SMAD1	3	4	5	6
Smurf1 induced Smad 1 degradation is blocked by LIM mineralization protein-1 ( LMP-1 ) .	Smurf1 induced Smad 1 degradation is blocked by LIM mineralization protein-1 (LMP-1).	0	6	induced	Positive_early_activation	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad 1	Smad 1	Smad 1	0	1	2	4
Smurf1 TARGETS Smad1 AND Runx2 PROTEINS IN OSTEOBLAST PRECURSOR CELLS .	Smurf1 TARGETS Smad1 AND Runx2 PROTEINS IN OSTEOBLAST PRECURSOR CELLS.	0	5	TARGETS	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	0	1	2	3
Smurf1 targets Smad1 and Smad5 for ubiquitination and subsequent proteasome mediated degradation [ XREF_BIBR ] .	Smurf1 targets Smad1 and Smad5 for ubiquitination and subsequent proteasome mediated degradation [XREF_BIBR].	0	4	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	0	1	2	3
33 Consistently , inhibition of Smurf1 mediated Smad1 degradation results in activation of osteoblast differentiation .	33 Consistently, inhibition of Smurf1 mediated Smad1 degradation results in activation of osteoblast differentiation.	3	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad1	Smad1	Smad1	5	6	7	8
Therefore , the mechanism by which Smad7 targets TbetaRI for degradation is important for the turnover of TbetaRI and IFNgamma dependent inhibition of TGFbeta signaling .	Therefore, the mechanism by which Smad7 targets TbetaRI for degradation is important for the turnover of TbetaRI and IFNgamma dependent inhibition of TGFbeta signaling.	6	10	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	TbetaRI	TbetaRI	TbetaRI	6	7	8	9
We also showed that SMAD7 enhanced porcine GC apoptosis by interrupting TGFBR1 and the TGF-beta signaling pathway .	We also showed that SMAD7 enhanced porcine GC apoptosis by interrupting TGFBR1 and the TGF-beta signaling pathway.	4	16	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMAD7	SMAD7	SMAD7	TGFBR1	TGFBR1	TGFBR1	4	5	11	12
siRNA mediated knockdown of Smad7 moderately inhibited TGF-beta and ALK5 signaling using ( CAGA ) 12 -luc as read-out .	siRNA mediated knockdown of Smad7 moderately inhibited TGF-beta and ALK5 signaling using (CAGA) 12 -luc as read-out.	2	10	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	ALK5	ALK5	ALK5	4	5	9	10
Moreover , Smad7 promotes the internalization and degradation of TbetaRI and competes with R-Smads for receptor binding .	Moreover, Smad7 promotes the internalization and degradation of TbetaRI and competes with R-Smads for receptor binding.	2	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	TbetaRI	TbetaRI	TbetaRI	2	3	9	10
By contrast , Smad7 inhibits Smad2 and Smad3 activation by causing the degradation of TbetaRI and Smads via the ubiquitin-proteasome degradation mechanism XREF_BIBR , XREF_BIBR , XREF_BIBR .	By contrast, Smad7 inhibits Smad2 and Smad3 activation by causing the degradation of TbetaRI and Smads via the ubiquitin-proteasome degradation mechanism XREF_BIBR, XREF_BIBR, XREF_BIBR.	3	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	TbetaRI	TbetaRI	TbetaRI	3	4	14	15
By using double-transgenic mice , we also found that Smurf1 supports Smad6 function in vivo .	By using double-transgenic mice, we also found that Smurf1 supports Smad6 function in vivo.	9	12	supports	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad6	Smad6	Smad6	9	10	11	12
Smurf1 ( CA ) induced cytoplasmic localization of Smad6 and Smad7 in both COS7 cells and HepG2 cells ( XREF_FIG ) .	Smurf1 (CA) induced cytoplasmic localization of Smad6 and Smad7 in both COS7 cells and HepG2 cells (XREF_FIG).	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad6	Smad6	Smad6	0	1	8	9
These results provided evidence that Smurf1 supports Smad6 function in vivo .	These results provided evidence that Smurf1 supports Smad6 function in vivo.	5	8	supports	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad6	Smad6	Smad6	5	6	7	8
The overexpression of Smurf1 in Smad6 and Smurf1 double-transgenic mice enhanced phenotypes of Smad6 transgenic mice .	The overexpression of Smurf1 in Smad6 and Smurf1 double-transgenic mice enhanced phenotypes of Smad6 transgenic mice.	1	15	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	overexpression of Smurf1	smurf1	Smad6	Smad6	smad6	3	4	13	14
So Smad3 overexpression enhances the levels of RUNX2 and other transcription factors required for the differentiation of either mesenchymal cells or bone marrow stromal cells to osteoblasts XREF_BIBR , XREF_BIBR ,.	So Smad3 overexpression enhances the levels of RUNX2 and other transcription factors required for the differentiation of either mesenchymal cells or bone marrow stromal cells to osteoblasts XREF_BIBR, XREF_BIBR,.	1	8	enhances	Positive_regulation_syntax_1_verb	Negative_activation	Positive_regulation	Smad3	Smad3 overexpression	smad3	RUNX2	levels of RUNX2	runx2	1	2	7	8
Premature hypertrophy was also observed in Smad3 deficient mice and mice that overexpress Runx2 in chondrocytes .	Premature hypertrophy was also observed in Smad3 deficient mice and mice that overexpress Runx2 in chondrocytes.	6	15	overexpress	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad3	Smad3	Smad3	Runx2	Runx2	Runx2	6	7	13	14
Phospho-Smad3 promotes Runx2 function and early chondrocyte differentiation XREF_BIBR .	Phospho-Smad3 promotes Runx2 function and early chondrocyte differentiation XREF_BIBR.	0	3	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Phospho-Smad3	Phospho-Smad3	Phospho-Smad3	Runx2	Runx2	Runx2	0	1	2	3
Consequently , either excessive Smad3 or lack of Smad3 will result in Runx2 activation .	Consequently, either excessive Smad3 or lack of Smad3 will result in Runx2 activation.	2	14	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Smad3	Smad3	Smad3	Runx2	Runx2	Runx2	4	5	12	13
Although the Runx binding element is required for RUNX2 mediated repression of FSHbeta induction by either activin or Smad3 , confirming a functional role of this novel site , protein interactions in addition to those between RUNX2 and Smads are necessary to account for full repression of activin induction .	Although the Runx binding element is required for RUNX2 mediated repression of FSHbeta induction by either activin or Smad3, confirming a functional role of this novel site, protein interactions in addition to those between RUNX2 and Smads are necessary to account for full repression of activin induction.	8	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Smad3	Smad3	Smad3	RUNX2	RUNX2	RUNX2	18	19	8	9
We show here that Smurf1 targets Smad7 to the plasma membrane through its N-terminal conserved 2 ( C2 ) domain .	We show here that Smurf1 targets Smad7 to the plasma membrane through its N-terminal conserved 2 (C2) domain.	4	14	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad7	Smad7	Smad7	4	5	6	7
Smurf1 also modulates the inhibitory activity and the stability of Smad7 and , hence , the TGF-beta signaling output .	Smurf1 also modulates the inhibitory activity and the stability of Smad7 and, hence, the TGF-beta signaling output.	0	11	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad7	Smad7	Smad7	0	1	10	11
A Smad ubiquitin regulatory factor 1 ( Smurf1 ) , being a HECT-type E3 ( Homologous to the E6-AP C Terminus ) ubiquitin ligase , interacts with inhibitory Smad7 and induces cytoplasmic localization of Smad7 .	A Smad ubiquitin regulatory factor 1 (Smurf1), being a HECT-type E3 (Homologous to the E6-AP C Terminus) ubiquitin ligase, interacts with inhibitory Smad7 and induces cytoplasmic localization of Smad7.	2	35	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad7	Smad7	Smad7	7	8	34	35
While not sufficient to promote osteoblastogenesis , knockdown of Smad3 using a specific shRNA prevented the RA mediated stimulation of differentiation and displacement of C/EBPbeta from the Runx2 P1 promoter .	While not sufficient to promote osteoblastogenesis, knockdown of Smad3 using a specific shRNA prevented the RA mediated stimulation of differentiation and displacement of C/EBPbeta from the Runx2 P1 promoter.	7	25	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad3	Smad3	Smad3	C/EBPbeta	C/EBPbeta	C/EBPbeta	9	10	24	25
Thus , it may be speculated that inhibited Smad3 expression further promoted the activity of C/EBPbeta on the TGF-beta1 promoter via a positive feedback mechanism .	Thus, it may be speculated that inhibited Smad3 expression further promoted the activity of C/EBPbeta on the TGF-beta1 promoter via a positive feedback mechanism.	8	16	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad3	Smad3 expression	smad3	C/EBPbeta	C/EBPbeta	c/ebpbeta	8	9	15	16
On the other hand , Smad3 has also been shown to repress gene transcription by inhibiting the transactivation of MyoD XREF_BIBR , Pax6 XREF_BIBR and AR XREF_BIBR , by interfering with the binding of the transcription factors to DNA .	On the other hand, Smad3 has also been shown to repress gene transcription by inhibiting the transactivation of MyoD XREF_BIBR, Pax6 XREF_BIBR and AR XREF_BIBR, by interfering with the binding of the transcription factors to DNA.	5	23	repress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Smad3	Smad3	Smad3	Pax6	Pax6	Pax6	5	6	22	23
We therefore investigated the possible relationship between Pax6 and activated Smad3 ( phosphorylated Smad3 , p-Smad3 ) in the eyelid at E15.5 .	We therefore investigated the possible relationship between Pax6 and activated Smad3 (phosphorylated Smad3, p-Smad3) in the eyelid at E15.5.	5	11	activated	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Smad3	Smad3	Smad3	Pax6	Pax6	Pax6	10	11	7	8
The type I BMP receptor ALK3 lies immediately upstream of SMAD1 in the BMP pathway , and ALK3 is targeted for ubiquitylation by SMAD6 via recruitment of E3 ubiquitin ligases [ XREF_BIBR ] .	The type I BMP receptor ALK3 lies immediately upstream of SMAD1 in the BMP pathway, and ALK3 is targeted for ubiquitylation by SMAD6 via recruitment of E3 ubiquitin ligases [XREF_BIBR].	17	25	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SMAD6	SMAD6	SMAD6	ALK3	ALK3	ALK3	23	24	17	18
SMAD6 , a transcriptional target of BMP , negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin mediated degradation .	SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin mediated degradation.	0	21	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD6	SMAD6	SMAD6	ALK3	ALK3	ALK3	0	1	20	21
For instance , the active form of SMAD6 competes with SMAD4 on target gene binding and thus prevents the targeted genes of SMAD4 from being transcribed [ XREF_BIBR ] .	For instance, the active form of SMAD6 competes with SMAD4 on target gene binding and thus prevents the targeted genes of SMAD4 from being transcribed [XREF_BIBR].	5	25	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SMAD6	SMAD6	SMAD6	SMAD4	SMAD4	SMAD4	7	8	22	23
In contrast , Smad6 had no effect on TGF-beta and Smad signaling in podocytes and enhanced Smad3 signaling in mesangial cells .	In contrast, Smad6 had no effect on TGF-beta and Smad signaling in podocytes and enhanced Smad3 signaling in mesangial cells.	3	17	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad6	Smad6	Smad6	Smad3	Smad3	Smad3	3	4	16	17
Smad6 binds to receptor activated Smad1 , preventing Smad1 association with Smad4 .	Smad6 binds to receptor activated Smad1, preventing Smad1 association with Smad4.	0	6	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad6	Smad6	Smad6	Smad1	Smad1	Smad1	0	1	5	6
Further detailed studies in vitro are required to mechanistically dissect how SMCR8 and C9ORF72 modulate ULK1 kinase activity in a substrate specific manner .	Further detailed studies in vitro are required to mechanistically dissect how SMCR8 and C9ORF72 modulate ULK1 kinase activity in a substrate specific manner.	11	17	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SMCR8	SMCR8	SMCR8	ULK1	ULK1	ULK1	11	12	15	16
Smad2 or Smad7 mutants defective in Smad4 interaction failed to induce Smurf1 mediated down-regulation of Smad4 .	Smad2 or Smad7 mutants defective in Smad4 interaction failed to induce Smurf1 mediated down-regulation of Smad4.	10	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	Smad4	Smad4	Smad4	11	12	15	16
Because of conflicting results and interpretations , we have re-examined this issue in Xenopus and chick embryos using the powerful and general TGFbeta inhibitor , Smad7 , which inhibits both Smad1- ( BMP ) and Smad2- ( Nodal and Activin ) mediated pathways .	Because of conflicting results and interpretations, we have re-examined this issue in Xenopus and chick embryos using the powerful and general TGFbeta inhibitor, Smad7, which inhibits both Smad1- (BMP) and Smad2- (Nodal and Activin) mediated pathways.	23	42	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	Smad1-	Smad1-	Smad1-	25	26	30	31
These data suggest that like Smad7 , PP1alpha is a direct ALK1 target .	These data suggest that like Smad7, PP1alpha is a direct ALK1 target.	4	13	target	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Smad7	Smad7	Smad7	ALK1	ALK1	ALK1	5	6	11	12
These results indicated that STAT3 activation was increased by neuronal and glial SOCS3 deficiency , which may lead to the observed increase in Vegfa .	These results indicated that STAT3 activation was increased by neuronal and glial SOCS3 deficiency, which may lead to the observed increase in Vegfa.	4	13	increased	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	12	13	4	5
Also the increased levels of STAT3 in IL-6-conditioned HuMCs might be a consequence of diminished SOCS3 mediated degradation of STAT3 as SOCS3 is reported to promote degradation of signaling proteins such as the JAKs and STATs .	Also the increased levels of STAT3 in IL-6-conditioned HuMCs might be a consequence of diminished SOCS3 mediated degradation of STAT3 as SOCS3 is reported to promote degradation of signaling proteins such as the JAKs and STATs.	12	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	15	16	19	20
One potential mechanism for such leptin resistance is an increased hypothalamic expression of Suppressor of cytokine signaling 3 ( Socs3 ) , a feedback inhibitor of the Jak-Stat pathway that prevents Stat3 activation .	One potential mechanism for such leptin resistance is an increased hypothalamic expression of Suppressor of cytokine signaling 3 (Socs3), a feedback inhibitor of the Jak-Stat pathway that prevents Stat3 activation.	11	32	prevents	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	Suppressor of cytokine signaling 3	expression of Suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	Stat3	Stat3	stat3	13	18	31	32
IL-6 has been shown to promote myogenesis XREF_BIBR and SOCS3 promotes myogenic differentiation by down regulating the STAT3 signaling pathway XREF_BIBR .	IL-6 has been shown to promote myogenesis XREF_BIBR and SOCS3 promotes myogenic differentiation by down regulating the STAT3 signaling pathway XREF_BIBR.	9	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	9	10	17	18
SOCS3 , for example , has been shown to suppress Th17 differentiation by binding to the IL-6R and inhibiting STAT3 activation , while SOCS5 has been shown to bind to the IL-4R and inhibit STAT6 activation in Th1 cells [ XREF_BIBR ] .	SOCS3, for example, has been shown to suppress Th17 differentiation by binding to the IL-6R and inhibiting STAT3 activation, while SOCS5 has been shown to bind to the IL-4R and inhibit STAT6 activation in Th1 cells [XREF_BIBR].	0	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	19	20
Interestingly , the silencing of Hif-1alpha normalized the glycolytic metabolism of Stat3 C/C MEFs , down-regulating Pdk-1 , Glut-1 , Pfk-L and Eno-1 mRNAs but not the glycolysis unrelated STAT3 target Socs3 .	Interestingly, the silencing of Hif-1alpha normalized the glycolytic metabolism of Stat3 C/C MEFs, down-regulating Pdk-1, Glut-1, Pfk-L and Eno-1 mRNAs but not the glycolysis unrelated STAT3 target Socs3.	27	32	target	Positive_activation_token_1_noun	Negative_activation	Positive_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	31	32	29	30
In non immune cells , SOCS3 suppresses inflammatory reactions by inhibiting STAT3 .	In non immune cells, SOCS3 suppresses inflammatory reactions by inhibiting STAT3.	5	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	5	6	11	12
To explore the role of the STAT3 target SOCS3 on insulin action , L6 myotubes were transfected with a SOCS3 specific siRNA or a scrambled sequence .	To explore the role of the STAT3 target SOCS3 on insulin action, L6 myotubes were transfected with a SOCS3 specific siRNA or a scrambled sequence.	3	9	target	Positive_activation_token_1_noun	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	8	9	6	7
Moreover , recent studies have shown that SOCS3 may play a role in controlling regulatory T cell responses because SOCS3 deficient T cells demonstrate a Th3 like phenotype with increased TGF-beta and IL-10 and increased STAT3 activation .	Moreover, recent studies have shown that SOCS3 may play a role in controlling regulatory T cell responses because SOCS3 deficient T cells demonstrate a Th3 like phenotype with increased TGF-beta and IL-10 and increased STAT3 activation.	19	36	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	19	20	35	36
Conversely , ablation of the gp130 signaling inhibitor SOCS3 increased STAT3 activation and accelerated PanIN progression .	Conversely, ablation of the gp130 signaling inhibitor SOCS3 increased STAT3 activation and accelerated PanIN progression.	2	11	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	8	9	10	11
Because SOCS-3 is a transcriptional target of STAT-3 , the parallel , elevated expression of both activated STAT-3 and SOCS-3 proteins in GBM is plausible , and may contribute to the anti-apoptotic and radioresistant phenotype of GBMs .	Because SOCS-3 is a transcriptional target of STAT-3, the parallel, elevated expression of both activated STAT-3 and SOCS-3 proteins in GBM is plausible, and may contribute to the anti-apoptotic and radioresistant phenotype of GBMs.	1	8	is a transcriptional target	Positive_activation_copula_1	Negative_activation	Positive_activation	SOCS-3	SOCS-3	SOCS-3	STAT-3	STAT-3	STAT-3	1	2	7	8
Let-7 re-expression in poorly differentiated PDAC cell lines can enhance the cytoplasmic expression of suppressor of cytokine signaling 3 ( SOCS3 ) , which blocks STAT3 activation by JAK2 , and reduce the phosphorylation of STAT3 and its downstream signaling events , thereby reduce the growth and migration of PDAC cells XREF_BIBR .	Let-7 re-expression in poorly differentiated PDAC cell lines can enhance the cytoplasmic expression of suppressor of cytokine signaling 3 (SOCS3), which blocks STAT3 activation by JAK2, and reduce the phosphorylation of STAT3 and its downstream signaling events, thereby reduce the growth and migration of PDAC cells XREF_BIBR.	12	26	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	expression of suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	stat3	14	19	25	26
Thus , loss of feedback inhibition of STAT3 activation by SHP-2/Ras/ERK and SOCS3 results in constitutive oncogenic signaling by STAT3 dimers .	Thus, loss of feedback inhibition of STAT3 activation by SHP-2/Ras/ERK and SOCS3 results in constitutive oncogenic signaling by STAT3 dimers.	7	13	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	12	13	7	8
Since in contrast to IL-10 , STAT3 activation by IL-6 is negatively regulated by the suppressor of cytokine signaling 3 ( SOCS3 ) , a member of the family of SH2 containing E3 ligases , this lack of effectiveness could be related to the observed SOCS3 up-regulation in obese adipose tissue ( XREF_FIG ) .	Since in contrast to IL-10, STAT3 activation by IL-6 is negatively regulated by the suppressor of cytokine signaling 3 (SOCS3), a member of the family of SH2 containing E3 ligases, this lack of effectiveness could be related to the observed SOCS3 up-regulation in obese adipose tissue (XREF_FIG).	6	20	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	STAT3	15	20	6	7
SOCS3 protein may inhibit proliferation of PASMCs by lowering the tyrosine phosphorylated level of STAT3 protein under hypoxia .	SOCS3 protein may inhibit proliferation of PASMCs by lowering the tyrosine phosphorylated level of STAT3 protein under hypoxia.	0	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	14	15
Phosphorylated STAT3 ( p-STAT3 ) functions as a transcriptional factor , and suppressor of cytokine signaling 3 ( SOCS3 ) is a potential inhibitor of STAT3 .	Phosphorylated STAT3 (p-STAT3) functions as a transcriptional factor, and suppressor of cytokine signaling 3 (SOCS3) is a potential inhibitor of STAT3.	12	26	is a potential inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	STAT3	12	17	25	26
The authors also identified higher levels of STAT3 phosphorylation in miR-122 silenced cells treated with IFN-alpha besides decreased SOCS3 expression .	The authors also identified higher levels of STAT3 phosphorylation in miR-122 silenced cells treated with IFN-alpha besides decreased SOCS3 expression.	7	19	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	18	19	7	8
An in vivo study has shown that Socs3 deficient mice produced a prolonged activation of STAT3 after IL-6 treatment [ XREF_BIBR ] , indicating a crucial role of SOCS3 in IL-6/JAK/STAT signaling axis .	An in vivo study has shown that Socs3 deficient mice produced a prolonged activation of STAT3 after IL-6 treatment [XREF_BIBR], indicating a crucial role of SOCS3 in IL-6/JAK/STAT signaling axis.	7	16	produced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	7	8	15	16
Suppressors of cytokine signaling ( SOCS ) 1 and SOCS3 , SH2 domain containing phosphatase ( SHP2 ) and protein inhibitors of activated STAT3 ( PIAS3 ) are known to inhibit STAT3 signal transduction , while their expression statuses in the four grades of astrocytomas and relevance with STAT3 activation remain to be described .	Suppressors of cytokine signaling (SOCS) 1 and SOCS3, SH2 domain containing phosphatase (SHP2) and protein inhibitors of activated STAT3 (PIAS3) are known to inhibit STAT3 signal transduction, while their expression statuses in the four grades of astrocytomas and relevance with STAT3 activation remain to be described.	0	33	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	9	10	31	32
This signaling amplifier is activated in F759 mice , for example , in which IL-6-mediated STAT3 activation is enhanced by the lack of SOCS3 mediated negative feedback .	This signaling amplifier is activated in F759 mice, for example, in which IL-6-mediated STAT3 activation is enhanced by the lack of SOCS3 mediated negative feedback.	15	24	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	23	24	15	16
These results suggest that miR-218 regulated neuropathic pain and neuroinflammation by regulating SOCS3 expression , which negatively mediated STAT3 signaling .	These results suggest that miR-218 regulated neuropathic pain and neuroinflammation by regulating SOCS3 expression, which negatively mediated STAT3 signaling.	12	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	12	13	18	19
Paradoxically , SOCS3 deficient mice , which have enhanced Stat3 activity , display a similar gene transcription profile , with the implication that IFNgamma like responses could contribute to the lethal inflammatory phenotype [ XREF_BIBR , XREF_BIBR ] .	Paradoxically, SOCS3 deficient mice, which have enhanced Stat3 activity, display a similar gene transcription profile, with the implication that IFNgamma like responses could contribute to the lethal inflammatory phenotype [XREF_BIBR, XREF_BIBR].	2	10	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	Stat3	Stat3	Stat3	2	3	9	10
Because SOCS3 is a transcriptional target of activated STAT3 , the parallel , elevated expression of both activated STAT3 and SOCS3 in GBM is plausible and might contribute to the anti-apoptotic and radio resistant phenotype of GBMs .	Because SOCS3 is a transcriptional target of activated STAT3, the parallel, elevated expression of both activated STAT3 and SOCS3 in GBM is plausible and might contribute to the anti-apoptotic and radio resistant phenotype of GBMs.	1	9	is a transcriptional target	Positive_activation_copula_1	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	1	2	8	9
EOC derived exosomes down-regulate the expression of SOCS3 and activate SOCS3 and STAT3 signaling pathway in macrophages .	EOC derived exosomes down-regulate the expression of SOCS3 and activate SOCS3 and STAT3 signaling pathway in macrophages.	0	14	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	EOC derived exosomes down-regulate the expression of SOCS3	socs3	STAT3	STAT3	stat3	7	8	12	13
Here , we showed that the repression of SOCS3 and sustained activation of IL-6 and STAT3 pathway in HBV producing HCC cells were caused by HBV induced mitochondrial ROS accumulation .	Here, we showed that the repression of SOCS3 and sustained activation of IL-6 and STAT3 pathway in HBV producing HCC cells were caused by HBV induced mitochondrial ROS accumulation.	8	16	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	8	9	15	16
Neuronal and glial Socs3 deficiency feedback enhanced STAT3 activation .	Neuronal and glial Socs3 deficiency feedback enhanced STAT3 activation.	3	8	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	3	4	7	8
Socs3 deficiency results in prolonged activation of Stat1 and Stat3 by IL-6 , but normal Stat1 activation after IFNgamma treatment .	Socs3 deficiency results in prolonged activation of Stat1 and Stat3 by IL-6, but normal Stat1 activation after IFNgamma treatment.	0	10	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Socs3	Socs3	Socs3	Stat3	Stat3	Stat3	0	1	9	10
The STAT3 pathway can be inhibited by suppressor of cytokine signaling 3 ( SOCS3 ) and protein inhibitors of activated STATs ( PIAS ) [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	The STAT3 pathway can be inhibited by suppressor of cytokine signaling 3 (SOCS3) and protein inhibitors of activated STATs (PIAS) [XREF_BIBR, XREF_BIBR, XREF_BIBR].	1	17	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	STAT3	7	12	1	2
Given that STAT3 prolongs nuclear retention of NF-kappaB , SOCS3 mediated STAT3 inactivation may be also responsible for decreased NF-kappaB activity .	Given that STAT3 prolongs nuclear retention of NF-kappaB, SOCS3 mediated STAT3 inactivation may be also responsible for decreased NF-kappaB activity.	9	12	mediated	Positive_early_activation	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	9	10	11	12
SOCS-3 , which specifically targets STAT3 , is inactivated in K562-R cells , is resulting in activation of STAT3 signaling and resistance mechanisms .	SOCS-3, which specifically targets STAT3, is inactivated in K562-R cells, is resulting in activation of STAT3 signaling and resistance mechanisms.	0	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS-3	SOCS-3	SOCS-3	STAT3	STAT3	STAT3	0	1	5	6
Lack of SOCS3 in retinal neuronal and glial cells increased neuronal STAT3 activation and promoted vascular endothelial growth factor ( VEGF ) production in neuronal cells to increase signaling in endothelial cells , leading to proliferative retinopathy .	Lack of SOCS3 in retinal neuronal and glial cells increased neuronal STAT3 activation and promoted vascular endothelial growth factor (VEGF) production in neuronal cells to increase signaling in endothelial cells, leading to proliferative retinopathy.	0	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	2	3	11	12
The observations that Socs3 , Tbx21 , Bcl6 and Prdm1 are direct targets of STAT3 53 , together with reduced expression of these genes in Stat3 -/- murine CD8 + T cells post-infection with LCMV 49 , and of SOCS3 and BCL6 in ex vivo isolated STAT3 deficient human naive CD8 + T cells 30 , suggest that STAT3 regulates CD8 + T cell differentiation by controlling expression of transcription factors .	The observations that Socs3, Tbx21, Bcl6 and Prdm1 are direct targets of STAT3 53, together with reduced expression of these genes in Stat3 -/- murine CD8 + T cells post-infection with LCMV 49, and of SOCS3 and BCL6 in ex vivo isolated STAT3 deficient human naive CD8 + T cells 30, suggest that STAT3 regulates CD8 + T cell differentiation by controlling expression of transcription factors.	3	31	are direct targets	Positive_activation_copula_1	Negative_activation	Positive_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	3	4	14	15
On the other hand , in NK cells and DC precursors , SOCS3 may be a key mediator of STAT3 driven immunosuppression .	On the other hand, in NK cells and DC precursors, SOCS3 may be a key mediator of STAT3 driven immunosuppression.	12	20	be a key mediator	Positive_activation_copula_1	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	12	13	19	20
XREF_BIBR Remission of SOCS3 expression causes constitutive STAT3 activation , XREF_BIBR which is considered to be important for linkage between inflammation and cancer .	XREF_BIBR Remission of SOCS3 expression causes constitutive STAT3 activation, XREF_BIBR which is considered to be important for linkage between inflammation and cancer.	3	8	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	3	4	7	8
Studies of conditional SOCS3 deficient mice have shown that SOCS3 deficiency , but not SOCS1 deficiency , results in sustained activation of STAT3 in response to IL-6 [ XREF_BIBR , XREF_BIBR ] .	Studies of conditional SOCS3 deficient mice have shown that SOCS3 deficiency, but not SOCS1 deficiency, results in sustained activation of STAT3 in response to IL-6 [XREF_BIBR, XREF_BIBR].	9	24	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	9	10	22	23
Additionally , the transcription and translation of the STAT3 target gene SOCS3 was attenuated by CK2 inhibition , supporting the functional consequences of STAT3 inhibition .	Additionally, the transcription and translation of the STAT3 target gene SOCS3 was attenuated by CK2 inhibition, supporting the functional consequences of STAT3 inhibition.	3	24	supporting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	transcription and translation of the STAT3 target gene SOCS3	socs3	STAT3	STAT3	stat3	11	12	23	24
SOCS3 deficiency in T helper cells resulted in constitutive STAT3 activation , which in turn enhances TGFbeta1 and IL-10 production XREF_BIBR .	SOCS3 deficiency in T helper cells resulted in constitutive STAT3 activation, which in turn enhances TGFbeta1 and IL-10 production XREF_BIBR.	0	11	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	9	10
Leptin forms a feedback loop with SOCS3 , a negative cytokine regulator which inhibits Jak2 and STAT3 signaling following prolonged receptor ( OB-R ) activation [ XREF_BIBR ] .	Leptin forms a feedback loop with SOCS3, a negative cytokine regulator which inhibits Jak2 and STAT3 signaling following prolonged receptor (OB-R) activation [XREF_BIBR].	1	17	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	6	7	16	17
IL-27 has been shown to activate STAT3 [ XREF_BIBR , XREF_BIBR ] , and STAT3 activation is known to induce expression of SOCS3 [ XREF_BIBR ] and the Bcl family of proteins [ XREF_BIBR - XREF_BIBR ] .	IL-27 has been shown to activate STAT3 [XREF_BIBR, XREF_BIBR], and STAT3 activation is known to induce expression of SOCS3 [XREF_BIBR] and the Bcl family of proteins [XREF_BIBR - XREF_BIBR].	5	24	activate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	SOCS3	STAT3 activation is known to induce expression of SOCS3	socs3	STAT3	STAT3	stat3	22	23	6	7
IL-6 treatment induced SOCS3 expression in NS-1 cells and led to STAT3 activation .	IL-6 treatment induced SOCS3 expression in NS-1 cells and led to STAT3 activation.	0	12	led to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	SOCS3	IL-6 treatment induced SOCS3 expression	socs3	STAT3	STAT3	stat3	3	4	11	12
The suppressor of cytokine signaling ( SOCS ) family of proteins , especially SOCS1 and SOCS3 , inhibit STAT3 in a cytokine inducible manner by binding to and inhibiting upstream JAKs .	The suppressor of cytokine signaling (SOCS) family of proteins, especially SOCS1 and SOCS3, inhibit STAT3 in a cytokine inducible manner by binding to and inhibiting upstream JAKs.	1	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	15	16	18	19
Thus SCI induced increases in the expression of both P-STAT3 Tyr and SOCS3 , which reached peak levels 1 day ( XREF_FIG ) and 2 days ( XREF_FIG ) post-SCI , respectively , support the previous findings that SOCS3 is an activity dependent and STAT3 inducible gene in neurons .	Thus SCI induced increases in the expression of both P-STAT3 Tyr and SOCS3, which reached peak levels 1 day (XREF_FIG) and 2 days (XREF_FIG) post-SCI, respectively, support the previous findings that SOCS3 is an activity dependent and STAT3 inducible gene in neurons.	6	46	support	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	expression of both P-STAT3 Tyr and SOCS3	socs3	STAT3	STAT3	stat3	12	13	44	45
These findings suggested that STAT3 could also be activated by increased Tnf and Tnfaip3 signals that further led to reduced Socs3 level in Vldlr -/- retinas .	These findings suggested that STAT3 could also be activated by increased Tnf and Tnfaip3 signals that further led to reduced Socs3 level in Vldlr -/- retinas.	4	22	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Socs3	Tnf and Tnfaip3 signals that further led to reduced Socs3 level	socs3	STAT3	STAT3	stat3	20	21	4	5
The key molecule that determines the half-life of STAT3 phosphorylation is suppressor of cytokine signaling-3 ( SOCS3 ) , which inactivates and degrades STAT3 XREF_BIBR .	The key molecule that determines the half-life of STAT3 phosphorylation is suppressor of cytokine signaling-3 (SOCS3), which inactivates and degrades STAT3 XREF_BIBR.	2	24	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling-3	suppressor of cytokine signaling-3	suppressor of cytokine signaling-3	STAT3	STAT3	STAT3	11	15	23	24
SOCS3 , acting as an anti-inflammatory regulator , mediates IL-6-gp130 signalling by preventing the activation of STAT3 in macrophages .	SOCS3, acting as an anti-inflammatory regulator, mediates IL-6-gp130 signalling by preventing the activation of STAT3 in macrophages.	0	17	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	16	17
SOCS3 has been proposed to mediate the anti-inflammatory function of STAT3 , yet Socs3 gene ablation in mice is protective against LPS induced sepsis shock 33 .	SOCS3 has been proposed to mediate the anti-inflammatory function of STAT3, yet Socs3 gene ablation in mice is protective against LPS induced sepsis shock 33.	0	11	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	10	11
Activation of suppressor of cytokine signaling 3 ( SOCS3 ) , a negative regulator of STAT3 signaling , inhibits STAT3 signaling pathway to suppress the proliferation of OSCC [ XREF_BIBR ] .	Activation of suppressor of cytokine signaling 3 (SOCS3), a negative regulator of STAT3 signaling, inhibits STAT3 signaling pathway to suppress the proliferation of OSCC [XREF_BIBR].	0	21	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	STAT3	2	7	19	20
Further , Suppressor of Cytokine Signaling 3 ( SOCS3 ) or protein inhibitors of activated STATS ( PIAS ) can also inhibit STAT3 activation .	Further, Suppressor of Cytokine Signaling 3 (SOCS3) or protein inhibitors of activated STATS (PIAS) can also inhibit STAT3 activation.	2	23	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Suppressor of Cytokine Signaling 3	Suppressor of Cytokine Signaling 3	Suppressor of Cytokine Signaling 3	STAT3	STAT3	STAT3	2	7	22	23
miR-122 and miR-155 targeting of SOCS1 releases the inhibition of STAT1 ( and STAT5a/b ) , and mIR-19a regulation of SOCS1 and SOCS3 effectively prolongs activation of both STAT1 and STAT3 .	miR-122 and miR-155 targeting of SOCS1 releases the inhibition of STAT1 (and STAT5a/b), and mIR-19a regulation of SOCS1 and SOCS3 effectively prolongs activation of both STAT1 and STAT3.	18	31	prolongs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	22	23	30	31
19 Furthermore , increased levels of Socs3 have been shown to inhibit inflammatory response by suppressing JAK2 and STAT3 signaling in a caerulein induced AP model both in vitro and in vivo .	19 Furthermore, increased levels of Socs3 have been shown to inhibit inflammatory response by suppressing JAK2 and STAT3 signaling in a caerulein induced AP model both in vitro and in vivo.	4	19	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Socs3	levels of Socs3	socs3	STAT3	STAT3	stat3	6	7	18	19
SOCS3 , a downstream target of IL6R-STAT3 signaling was induced approximately 2-fold ( XREF_FIG ) , further confirming STAT3 activation in ABCG1 KO EC .	SOCS3, a downstream target of IL6R-STAT3 signaling was induced approximately 2-fold (XREF_FIG), further confirming STAT3 activation in ABCG1 KO EC.	0	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	18	19
SOCS3 negatively regulated OSM induced P- STAT3 Ser in mitochondria .	SOCS3 negatively regulated OSM induced P- STAT3 Ser in mitochondria.	0	7	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	6	7
Well controlled studies in other human muscle wasting conditions , including COPD [ XREF_BIBR ] , chronic kidney disease [ XREF_BIBR ] , aging [ XREF_BIBR ] and pediatric burn injury [ XREF_BIBR ] , do demonstrate increased JAK and STAT3 pathway activation and target gene expression in muscle , particularly SOCS3 , strongly suggestive that increased STAT3 transcriptional activity could be a common mediator of human cachexia .	Well controlled studies in other human muscle wasting conditions, including COPD [XREF_BIBR], chronic kidney disease [XREF_BIBR], aging [XREF_BIBR] and pediatric burn injury [XREF_BIBR], do demonstrate increased JAK and STAT3 pathway activation and target gene expression in muscle, particularly SOCS3, strongly suggestive that increased STAT3 transcriptional activity could be a common mediator of human cachexia.	48	59	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	51	52	57	58
For instance , IFN-gamma stimulation upregulates suppressor of cytokine signaling 1 ( SOCS1 ) and suppressor of cytokine signaling 3 ( SOCS3 ) , and , in turn , inhibit the action of STAT1 and STAT3 , respectively .	For instance, IFN-gamma stimulation upregulates suppressor of cytokine signaling 1 (SOCS1) and suppressor of cytokine signaling 3 (SOCS3), and, in turn, inhibit the action of STAT1 and STAT3, respectively.	6	36	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	STAT3	15	20	35	36
SOCS3 is a transcriptional target of STAT3 , and in turn promotes the proteasomal degradation of phosphorylated STAT3 in a negative feedback loop .	SOCS3 is a transcriptional target of STAT3, and in turn promotes the proteasomal degradation of phosphorylated STAT3 in a negative feedback loop.	0	7	is a transcriptional target	Positive_activation_copula_1	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	6	7
Given that flavanoids inhibit CK2 ( casein kinase 2 ) [ XREF_BIBR ] , an enzyme known to antagonize cAMP production [ XREF_BIBR ] , and that resveratrol has recently been described as an inhibitor of PDE4 activity [ XREF_BIBR ] , we decided to test the involvement of cAMP in flavone induced SOCS3 induction and inhibition of STAT3 activation .	Given that flavanoids inhibit CK2 (casein kinase 2) [XREF_BIBR], an enzyme known to antagonize cAMP production [XREF_BIBR], and that resveratrol has recently been described as an inhibitor of PDE4 activity [XREF_BIBR], we decided to test the involvement of cAMP in flavone induced SOCS3 induction and inhibition of STAT3 activation.	51	59	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	SOCS3	flavone induced SOCS3	socs3	STAT3	STAT3	stat3	53	54	58	59
However , our data show that the absence of SOCS3 resulted in enhanced T. gondii induced STAT3 signaling .	However, our data show that the absence of SOCS3 resulted in enhanced T. gondii induced STAT3 signaling.	7	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	9	10	16	17
Absence of SOCS3 Enhances STAT3 Activation and BM Differentiation into Gr-1 + CD11b + MDSCs .	Absence of SOCS3 Enhances STAT3 Activation and BM Differentiation into Gr-1 + CD11b + MDSCs.	0	5	Enhances	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	2	3	4	5
However , let-7 re-expression enhanced cytoplasmic expression of suppressor of cytokine signaling 3 ( SOCS3 ) , which blocks STAT3 activation by JAK2 .	However, let-7 re-expression enhanced cytoplasmic expression of suppressor of cytokine signaling 3 (SOCS3), which blocks STAT3 activation by JAK2.	6	20	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	expression of suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	stat3	8	13	19	20
These findings indicate that KLF6 directly binds to STAT3 transcriptional targets , such as Socs3 , to repress their expression .	These findings indicate that KLF6 directly binds to STAT3 transcriptional targets, such as Socs3, to repress their expression.	8	15	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	14	15	8	9
Activated STAT3 upregulates SOCS3 , which serves as both a feedback inhibitor of leptin signaling and a repressor of apoptotic pathways .	Activated STAT3 upregulates SOCS3, which serves as both a feedback inhibitor of leptin signaling and a repressor of apoptotic pathways.	0	6	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	3	4	1	2
We therefore examined whether two inhibitors of ERK activation , the MEK ( MAPK and ERK kinase ) inhibitors PD184352 and AZD6244 , could antagonize the actions of flavone on SOCS3 induction and inhibition of STAT3 activation .	We therefore examined whether two inhibitors of ERK activation, the MEK (MAPK and ERK kinase) inhibitors PD184352 and AZD6244, could antagonize the actions of flavone on SOCS3 induction and inhibition of STAT3 activation.	30	36	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	30	31	35	36
SOCS3 deficiency significantly increases STAT3 activation in response to in vivo administration of G-CSF which leads to toxic effects .	SOCS3 deficiency significantly increases STAT3 activation in response to in vivo administration of G-CSF which leads to toxic effects.	0	5	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	4	5
To investigate the mechanisms maintaining STAT3 aberrantly phosphorylated using transcriptional protein and functional assays , we analyzed interleukin ( IL ) -6 and suppressor of cytokine signaling-3 ( SOCS3 ) , 2 key factors of the JAK and STAT pathway that induce and inhibit STAT3 activation , respectively .	To investigate the mechanisms maintaining STAT3 aberrantly phosphorylated using transcriptional protein and functional assays, we analyzed interleukin (IL) -6 and suppressor of cytokine signaling-3 (SOCS3), 2 key factors of the JAK and STAT pathway that induce and inhibit STAT3 activation, respectively.	26	45	induce	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	28	29	44	45
The changes led to 51 % higher cardiac ATP levels ( 17.7 +/-2.1 micromol/g heart in ad libitum versus 26.7 +/-1.9 micromol/g heart in diet restriction ) , higher ATP/ADP ratio , and ( 3 ) increased cardiac erythropoietin and decreased suppressor of cytokine signaling 3 , which upregulates cardioprotective JAK and STAT3 pathway .	The changes led to 51% higher cardiac ATP levels (17.7 +/-2.1 micromol/g heart in ad libitum versus 26.7 +/-1.9 micromol/g heart in diet restriction), higher ATP/ADP ratio, and (3) increased cardiac erythropoietin and decreased suppressor of cytokine signaling 3, which upregulates cardioprotective JAK and STAT3 pathway.	40	53	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	STAT3	41	46	52	53
The inhibition of STAT3 activation by SOCS3 was presented in other human and animal studies in different inflammatory settings .	The inhibition of STAT3 activation by SOCS3 was presented in other human and animal studies in different inflammatory settings.	3	7	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	6	7	3	4
Relapsing patients showed high levels of pSTAT3 and low expression of SOCS3 and leptin administration induced an up-regulation of pSTAT3 only in monocytes from patients in relapse .	Relapsing patients showed high levels of pSTAT3 and low expression of SOCS3 and leptin administration induced an up-regulation of pSTAT3 only in monocytes from patients in relapse.	9	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	expression of SOCS3	socs3	pSTAT3	pSTAT3	pstat3	11	12	19	20
Signalling through STAT3 is only transient and is in part down-regulated by SOCS 3 ( a target of STAT3 ) in a negative feed-back loop , hypothesized to protect cells from prolonged cytokine signaling XREF_BIBR .	Signalling through STAT3 is only transient and is in part down-regulated by SOCS 3 (a target of STAT3) in a negative feed-back loop, hypothesized to protect cells from prolonged cytokine signaling XREF_BIBR.	10	26	target	Positive_activation_syntax_7_noun	Negative_activation	Positive_activation	SOCS 3	SOCS 3	SOCS 3	STAT3	STAT3	STAT3	12	14	18	19
XREF_BIBR SOCS3 overexpression suppressed growth of malignant fibrous histiocytoma cell lines by inhibiting STAT3 and IL-6 production .	XREF_BIBR SOCS3 overexpression suppressed growth of malignant fibrous histiocytoma cell lines by inhibiting STAT3 and IL-6 production.	1	16	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 overexpression	socs3	STAT3	STAT3	stat3	1	2	13	14
We postulated that TGF-beta might inhibit SOCS3 expression induced by IL-6 and IL-21 , thus enhancing STAT3 activation and Th17 cell development .	We postulated that TGF-beta might inhibit SOCS3 expression induced by IL-6 and IL-21, thus enhancing STAT3 activation and Th17 cell development.	3	17	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	TGF-beta might inhibit SOCS3 expression	socs3	STAT3	STAT3	stat3	6	7	16	17
Our results could indicate SOCS3 mediated pSTAT3 signaling may be responsible to the continued production of cytokines and the subsequent neuroinflammation found in the EMD mice .	Our results could indicate SOCS3 mediated pSTAT3 signaling may be responsible to the continued production of cytokines and the subsequent neuroinflammation found in the EMD mice.	3	7	mediated	Positive_early_activation	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	pSTAT3	pSTAT3	pSTAT3	4	5	6	7
In conclusion , the present study demonstrated that HG exposure increased SOCS3 expression , induced the activation of the JAK2 and STAT3 pathway and potentiated the production of proinflammatory cytokines in A549 cells .	In conclusion, the present study demonstrated that HG exposure increased SOCS3 expression, induced the activation of the JAK2 and STAT3 pathway and potentiated the production of proinflammatory cytokines in A549 cells.	8	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	HG exposure increased SOCS3 expression	socs3	STAT3	STAT3	stat3	11	12	21	22
Suppressor of cytokine signalling 3 ( SOCS3 ) negatively regulates STAT3 activation in response to several cytokines such as those in the gp130 containing IL-6 receptor family .	Suppressor of cytokine signalling 3 (SOCS3) negatively regulates STAT3 activation in response to several cytokines such as those in the gp130 containing IL-6 receptor family.	0	11	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	6	7	10	11
However , SOCS1 has greater anti-inflammatory capabilities than does SOCS3 , which is manifested in SOCS1 primarily targeting STAT1 , whereas SOCS3 targets STAT3 .	However, SOCS1 has greater anti-inflammatory capabilities than does SOCS3, which is manifested in SOCS1 primarily targeting STAT1, whereas SOCS3 targets STAT3.	9	24	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	21	22	23	24
Socs3 deficiency results in prolonged activation of Stat3 after IL-6 stimulation and , interestingly , also promotes lipogenesis , thereby leading to fat accumulation and inflammation in the liver [ XREF_BIBR , XREF_BIBR ] .	Socs3 deficiency results in prolonged activation of Stat3 after IL-6 stimulation and, interestingly, also promotes lipogenesis, thereby leading to fat accumulation and inflammation in the liver [XREF_BIBR, XREF_BIBR].	0	8	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Socs3	Socs3	Socs3	Stat3	Stat3	Stat3	0	1	7	8
The genes differentially regulated by STAT3C included those previously reported to be STAT3 targets such as SOCS3 XREF_BIBR , lipopolysaccharide binding protein ( LBP ) XREF_BIBR , Jun , JunB XREF_BIBR , Myc XREF_BIBR , HIF1A XREF_BIBR , Pim1 XREF_BIBR and VEGF XREF_BIBR .	The genes differentially regulated by STAT3C included those previously reported to be STAT3 targets such as SOCS3 XREF_BIBR, lipopolysaccharide binding protein (LBP) XREF_BIBR, Jun, JunB XREF_BIBR, Myc XREF_BIBR, HIF1A XREF_BIBR, Pim1 XREF_BIBR and VEGF XREF_BIBR.	12	17	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	16	17	12	13
Suppressor of cytokine signaling 3 ( SOCS3 ) prevents STAT3 activation by shielding phospho-tyrosine residues of upstream kinases [ XREF_BIBR , XREF_BIBR ] , while protein inhibitor of activated STAT protein 3 ( PIAS3 ) prevents binding of STAT3 dimers to DNA [ XREF_BIBR ] .	Suppressor of cytokine signaling 3 (SOCS3) prevents STAT3 activation by shielding phospho-tyrosine residues of upstream kinases [XREF_BIBR, XREF_BIBR], while protein inhibitor of activated STAT protein 3 (PIAS3) prevents binding of STAT3 dimers to DNA [XREF_BIBR].	0	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Suppressor of cytokine signaling 3	Suppressor of cytokine signaling 3	Suppressor of cytokine signaling 3	STAT3	STAT3	STAT3	0	5	9	10
For example , STAT3 dependent transcription is rapidly inactivated by suppressor of cytokine signaling 3 ( SOCS3 ) , which is itself an IL-6 target gene [ XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	For example, STAT3 dependent transcription is rapidly inactivated by suppressor of cytokine signaling 3 (SOCS3), which is itself an IL-6 target gene [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	15	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	STAT3	10	15	3	4
Here , we observed that : 1 ) gender differences existed in myocardial STAT3 activation and SOCS3 expression following I/R ; 2 ) depletion of endogenous testosterone significantly increased activation of myocardial STAT3 and SOCS3 in male hearts , whereas blockade of testosterone receptor only increased SOCS3 levels in males subjected to I/R ; 3 ) Administration of exogenous testosterone to castrated male and female hearts decreased their STAT3 activity and SOCS3 level .	Here, we observed that : 1) gender differences existed in myocardial STAT3 activation and SOCS3 expression following I/R; 2) depletion of endogenous testosterone significantly increased activation of myocardial STAT3 and SOCS3 in male hearts, whereas blockade of testosterone receptor only increased SOCS3 levels in males subjected to I/R; 3) Administration of exogenous testosterone to castrated male and female hearts decreased their STAT3 activity and SOCS3 level.	16	34	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3 expression	socs3	STAT3	STAT3	stat3	16	17	32	33
The JAK2 and STAT3 pathway is negatively regulated by protein tyrosine phosphatase 1B ( PTP1B ) and suppressor of cytokine signaling 3 ( SOCS3 ) .	The JAK2 and STAT3 pathway is negatively regulated by protein tyrosine phosphatase 1B (PTP1B) and suppressor of cytokine signaling 3 (SOCS3).	1	23	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	suppressor of cytokine signaling 3	STAT3	STAT3	STAT3	17	22	3	4
SOCS3 is a transcriptional target of STAT3 that promotes the proteasomal degradation of phosphorylated STAT3 in a negative feedback loop XREF_BIBR XREF_BIBR XREF_BIBR .	SOCS3 is a transcriptional target of STAT3 that promotes the proteasomal degradation of phosphorylated STAT3 in a negative feedback loop XREF_BIBR XREF_BIBR XREF_BIBR.	0	7	is a transcriptional target	Positive_activation_copula_1	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	6	7
Thus , treatment of SOCS3 -/- macrophages with GCM promotes enhanced and prolonged STAT3 activation , due to the absence of SOCS3 .	Thus, treatment of SOCS3 -/- macrophages with GCM promotes enhanced and prolonged STAT3 activation, due to the absence of SOCS3.	4	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	4	5	13	14
In addition , SOCS3 overexpression can inhibit VSMC inflammation in vitro by inhibiting STAT3 activation XREF_BIBR , while multiple studies have demonstrated that EPAC1 inducible SOCS3 can limit proinflammatory JAK-STAT and ERK1/2 signalling by IL-6 trans-signalling complexes and leptin in VECs XREF_BIBR .	In addition, SOCS3 overexpression can inhibit VSMC inflammation in vitro by inhibiting STAT3 activation XREF_BIBR, while multiple studies have demonstrated that EPAC1 inducible SOCS3 can limit proinflammatory JAK-STAT and ERK1/2 signalling by IL-6 trans-signalling complexes and leptin in VECs XREF_BIBR.	3	15	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3 overexpression	socs3	STAT3	STAT3	stat3	3	4	13	14
Visual dysfunction and decreased rhodopsin levels both correlated with increased STAT3 activation enhanced by SOCS3 deficiency .	Visual dysfunction and decreased rhodopsin levels both correlated with increased STAT3 activation enhanced by SOCS3 deficiency.	10	15	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	14	15	10	11
The absence of SOCS3 and resultant increase in STAT3 signaling did not change the amount of IgG in the serum ( XREF_FIG ) .	The absence of SOCS3 and resultant increase in STAT3 signaling did not change the amount of IgG in the serum (XREF_FIG).	3	9	increase	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	3	4	8	9
Among these , previously identified STAT3 targets such as Bcl3 and Socs3 were found .	Among these, previously identified STAT3 targets such as Bcl3 and Socs3 were found.	5	12	targets	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Socs3	Socs3	Socs3	STAT3	STAT3	STAT3	11	12	5	6
XREF_BIBR Tyr 985 also binds suppressor of cytokine signaling-3 ( SOCS3 ) which act as a negative regulator to inhibit STAT3 signaling .	XREF_BIBR Tyr 985 also binds suppressor of cytokine signaling-3 (SOCS3) which act as a negative regulator to inhibit STAT3 signaling.	4	21	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling-3	suppressor of cytokine signaling-3	suppressor of cytokine signaling-3	STAT3	STAT3	STAT3	5	9	20	21
SOCS3 protein might inhibit proliferation of A549 cells by lowering the tyrosine phosphorylated level of STAT3 protein .	SOCS3 protein might inhibit proliferation of A549 cells by lowering the tyrosine phosphorylated level of STAT3 protein.	0	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	15	16
Thus , SOCS3 deficiency after PH accelerates liver regeneration , prolongs STAT3 activation and the acute-phase response , and enhance ERK1/2 activation .	Thus, SOCS3 deficiency after PH accelerates liver regeneration, prolongs STAT3 activation and the acute-phase response, and enhance ERK1/2 activation.	2	12	prolongs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	2	3	11	12
Conversely , colonic expression of Socs3 , a direct downstream target of Stat3 activation , was significantly increased in Stat3 DeltaIEC mice at day 28 , likely reflecting the increased lamina propria Stat3 activation observed at this time point ( p < .04 ) ( XREF_FIG ) .	Conversely, colonic expression of Socs3, a direct downstream target of Stat3 activation, was significantly increased in Stat3 DeltaIEC mice at day 28, likely reflecting the increased lamina propria Stat3 activation observed at this time point (p <.04) (XREF_FIG).	3	33	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Socs3	expression of Socs3	socs3	Stat3	Stat3	stat3	5	6	32	33
SOCS3 is an important target of STAT3 in CD8 + T cells and we propose that SOCS3 acts as an insulator to shield MPCs from cytokine signals that drive TE-fates .	SOCS3 is an important target of STAT3 in CD8 + T cells and we propose that SOCS3 acts as an insulator to shield MPCs from cytokine signals that drive TE-fates.	0	11	is an important target	Positive_activation_copula_1	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	0	1	6	7
Upregulation of Socs3 in leptin receptor neurons leads to upregulation of total STAT3 protein and increased pSTAT3 signaling .	Upregulation of Socs3 in leptin receptor neurons leads to upregulation of total STAT3 protein and increased pSTAT3 signaling.	0	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Socs3	Socs3	Socs3	pSTAT3	pSTAT3	pSTAT3	2	3	16	17
However , glucocorticoids do not increase IL-6-induced STAT3 phosphorylation in Th17 cells [ XREF_BIBR ] , suggesting factors other than SOCS3 underlie the maintenance of STAT3 activity in Th17 cells .	However, glucocorticoids do not increase IL-6-induced STAT3 phosphorylation in Th17 cells [XREF_BIBR], suggesting factors other than SOCS3 underlie the maintenance of STAT3 activity in Th17 cells.	20	26	underlie	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	STAT3	STAT3	STAT3	20	21	25	26
Moreover , LPS induced osteoclastogenesis and bone destruction in vivo were suppressed in SOCS1 ( +/-) mice compared with those in wild-type mice , suggesting that SOCS1 antagonizes the inhibitory effect of IFN-gamma on osteoclastogenesis .	Moreover, LPS induced osteoclastogenesis and bone destruction in vivo were suppressed in SOCS1 (+/-) mice compared with those in wild-type mice, suggesting that SOCS1 antagonizes the inhibitory effect of IFN-gamma on osteoclastogenesis.	26	33	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	26	27	32	33
The inhibition of interferon-gamma signaling by SOCS1 has been shown to depend strictly on the presence of Tyr441 in the interferon-gamma receptor subunit 1 [ XREF_BIBR ] .	The inhibition of interferon-gamma signaling by SOCS1 has been shown to depend strictly on the presence of Tyr441 in the interferon-gamma receptor subunit 1 [XREF_BIBR].	3	7	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	interferon-gamma	interferon-gamma	interferon-gamma	6	7	3	4
The suppressor of cytokine signaling-1 ( SOCS-1 ) blocks IFNgamma induced signaling and prevents diabetes in the non obese diabetic mouse .	The suppressor of cytokine signaling-1 (SOCS-1) blocks IFNgamma induced signaling and prevents diabetes in the non obese diabetic mouse.	0	13	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling-1	suppressor of cytokine signaling-1	suppressor of cytokine signaling-1	IFNgamma	IFNgamma	IFNgamma	1	5	9	10
A fate mapping study revealed that Socs1 deficiency accelerated the conversion of Tregs to Foxp3 - IFN-gamma + ex-Tregs in the tumor microenvironment and suppressed tumor growth .	A fate mapping study revealed that Socs1 deficiency accelerated the conversion of Tregs to Foxp3 - IFN-gamma + ex-Tregs in the tumor microenvironment and suppressed tumor growth.	6	22	accelerated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Socs1	Socs1	Socs1	IFN-gamma	IFN-gamma	IFN-gamma	6	7	16	17
Disruption of the SOCS1 gene restored the IFN-gamma inhibition of cell proliferation in intermediately activated HSCs .	Disruption of the SOCS1 gene restored the IFN-gamma inhibition of cell proliferation in intermediately activated HSCs.	3	8	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	3	4	7	8
XREF_BIBR Although SOCS1 deficient T cells shift to Th1 cell differentiation and produce IFN-gamma in the absence of TCR ligation , XREF_BIBR T cell specific SOCS1 deficient mice do not develop spontaneous inflammatory pathologies , and their T cells are resistant to Th17 cell differentiation .	XREF_BIBR Although SOCS1 deficient T cells shift to Th1 cell differentiation and produce IFN-gamma in the absence of TCR ligation, XREF_BIBR T cell specific SOCS1 deficient mice do not develop spontaneous inflammatory pathologies, and their T cells are resistant to Th17 cell differentiation.	2	14	produce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	2	3	13	14
Suppressor of cytokine signaling-1 ( SOCS-1 ) is a crucial inhibitor of cytokine signaling , particularly of IFN-gamma .	Suppressor of cytokine signaling-1 (SOCS-1) is a crucial inhibitor of cytokine signaling, particularly of IFN-gamma.	0	18	is a crucial inhibitor	Negative_activation_copula_1	Negative_activation	Negative_activation	Suppressor of cytokine signaling-1	Suppressor of cytokine signaling-1	Suppressor of cytokine signaling-1	IFN-gamma	IFN-gamma	IFN-gamma	0	4	17	18
Another study analyzed 20 genes involved in IFN-gamma signaling such as IFNG , IFNGR1 , IFNGR2 , IRF1 , IL12A , IL12B , IL12RB1 , IL12RB2 , IL23A , IL23R , IL27 , EBI3 , IL27RA , IL6ST , SOCS1 , STAT1 , STAT4 , JAK2 , TYK2 , and TBX21 in a Ghanaian population but no significant result was observed in TB .	Another study analyzed 20 genes involved in IFN-gamma signaling such as IFNG, IFNGR1, IFNGR2, IRF1, IL12A, IL12B, IL12RB1, IL12RB2, IL23A, IL23R, IL27, EBI3, IL27RA, IL6ST, SOCS1, STAT1, STAT4, JAK2, TYK2, and TBX21 in a Ghanaian population but no significant result was observed in TB.	7	40	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	39	40	7	8
Refractiveness to IFNgamma was restored when the cells were treated with the SOCS-1 mimetic Tkip at the time of IFNgamma treatment where 100 U / ml of IFNgamma activity was significantly blocked by as little as 2.5 muM of SOCS-1 mimetic ( XREF_FIG ) .	Refractiveness to IFNgamma was restored when the cells were treated with the SOCS-1 mimetic Tkip at the time of IFNgamma treatment where 100 U / ml of IFNgamma activity was significantly blocked by as little as 2.5 muM of SOCS-1 mimetic (XREF_FIG).	0	14	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	SOCS-1	SOCS-1	SOCS-1	IFNgamma	IFNgamma	IFNgamma	12	13	2	3
IL-6 is usually produced by cells and tissues involved in chronic inflammation , and IL-6 and IL-6R signaling can upregulate suppressor of cytokine signaling 1 ( SOCS1 ) that down-regulates IFN-gamma and IFN-gammaR signaling .	IL-6 is usually produced by cells and tissues involved in chronic inflammation, and IL-6 and IL-6R signaling can upregulate suppressor of cytokine signaling 1 (SOCS1) that down-regulates IFN-gamma and IFN-gammaR signaling.	19	33	down-regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 1	suppressor of cytokine signaling 1	suppressor of cytokine signaling 1	IFN-gamma	IFN-gamma	IFN-gamma	20	25	30	31
The SOCS-1 antagonist synergized with IFNgamma to enhance the IFNgamma anti-HSV-1 effect in the macrophages , which suggests that innate immunity via TLR signaling is dampened by SOCS-1 , which occurs at multiple stages , including JAK2 and TYK2 IFN signaling , as well as MyD88 and MAL signaling .	The SOCS-1 antagonist synergized with IFNgamma to enhance the IFNgamma anti-HSV-1 effect in the macrophages, which suggests that innate immunity via TLR signaling is dampened by SOCS-1, which occurs at multiple stages, including JAK2 and TYK2 IFN signaling, as well as MyD88 and MAL signaling.	1	11	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS-1	SOCS-1	SOCS-1	IFNgamma	IFNgamma	IFNgamma	1	2	9	10
Intracellular Delivery of a Cell Penetrating SOCS1 that Targets IFN-gamma Signaling .	Intracellular Delivery of a Cell Penetrating SOCS1 that Targets IFN-gamma Signaling.	1	10	Targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	6	7	9	10
Functionally , the regulation of IFNgamma signaling by SOCS1 is mediated by inhibition of JAK2 activity , but potentially also through the regulation of tyrosine kinases TYK2 and JAK1 .	Functionally, the regulation of IFNgamma signaling by SOCS1 is mediated by inhibition of JAK2 activity, but potentially also through the regulation of tyrosine kinases TYK2 and JAK1.	5	9	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	8	9	5	6
Retroviral transduction of wild-type SOCS1 relieved the growth-inhibitory effects of IFN-gamma in SOCS1 (-/-) fibroblasts by inhibiting STAT1 activation .	Retroviral transduction of wild-type SOCS1 relieved the growth-inhibitory effects of IFN-gamma in SOCS1 (-/-) fibroblasts by inhibiting STAT1 activation.	1	14	relieved	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	4	5	10	11
In conclusion , SOCS1 interference reduced the proliferation ability of Mel526 human melanoma cells and increased their sensitivity to IFN-gamma .	In conclusion, SOCS1 interference reduced the proliferation ability of Mel526 human melanoma cells and increased their sensitivity to IFN-gamma.	3	20	increased	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	3	4	19	20
We propose that elevated SOCS-1 expression in OCP antagonizes the inhibitory effects of IFN-gamma and enhances receptor activator of NF-kB ligand ( RANKL ) signaling which drives osteoclast differentiation and activation .	We propose that elevated SOCS-1 expression in OCP antagonizes the inhibitory effects of IFN-gamma and enhances receptor activator of NF-kB ligand (RANKL) signaling which drives osteoclast differentiation and activation.	4	14	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS-1	SOCS-1 expression	socs-1	IFN-gamma	IFN-gamma	ifn-gamma	4	5	13	14
SOCS1 deficient DCs induced higher IFN-gamma production from naive T cells than wild-type ( WT ) DCs in vitro .	SOCS1 deficient DCs induced higher IFN-gamma production from naive T cells than wild-type (WT) DCs in vitro.	0	6	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	0	1	5	6
Furthermore , the lack of IFN-gamma-mediated SOCS1 expression allows IL-2 to drive STAT5b mediated production of IFN-gamma without negative regulation .	Furthermore, the lack of IFN-gamma-mediated SOCS1 expression allows IL-2 to drive STAT5b mediated production of IFN-gamma without negative regulation.	6	17	drive	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1 expression	socs1	IFN-gamma	IFN-gamma	ifn-gamma	6	7	16	17
Consistent with the kinetics with which Socs1 and Socs3 mRNAs were induced , SOCS3 desensitized cells to IL-6 rapidly , whereas SOCS1 mediated desensitization to IFNgamma occurred at later time points .	Consistent with the kinetics with which Socs1 and Socs3 mRNAs were induced, SOCS3 desensitized cells to IL-6 rapidly, whereas SOCS1 mediated desensitization to IFNgamma occurred at later time points.	21	26	mediated	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	21	22	25	26
We note that SOCS1 increases in IFN-gamma activated microglia and is regulated by Parkinson protein 7 XREF_BIBR .	We note that SOCS1 increases in IFN-gamma activated microglia and is regulated by Parkinson protein 7 XREF_BIBR.	3	7	increases	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	3	4	6	7
For example , studies on SOCS1 deficient mouse models have suggested that SOCS1 is an important modulator of interferon-gamma ( IFN-gamma ) and allows it to exert protective effects without the risk of hyper-response to viral infection .	For example, studies on SOCS1 deficient mouse models have suggested that SOCS1 is an important modulator of interferon-gamma (IFN-gamma) and allows it to exert protective effects without the risk of hyper-response to viral infection.	12	23	is an important modulator	Positive_activation_copula_1	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	interferon-gamma	interferon-gamma	interferon-gamma	12	13	18	19
Thus , the SOCS-1 antagonist enhanced IFNgamma effects against HSV-1 in a macrophage cell line .	Thus, the SOCS-1 antagonist enhanced IFNgamma effects against HSV-1 in a macrophage cell line.	3	7	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS-1	SOCS-1	SOCS-1	IFNgamma	IFNgamma	IFNgamma	3	4	6	7
Functionally , expression of TRIM8 and GERP decreases the repression of interferon-gamma signaling mediated by SOCS-1 .	Functionally, expression of TRIM8 and GERP decreases the repression of interferon-gamma signaling mediated by SOCS-1.	11	16	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SOCS-1	SOCS-1	SOCS-1	interferon-gamma	interferon-gamma	interferon-gamma	15	16	11	12
Interestingly , many of these genes could be grouped into an IFN-gamma response gene module including SOCS1 and SOCS3 ( suppressor of cytokines signaling 1 and 3 ) , IRF1 ( IFN regulatory factor 1 ) , IL-6 , MCP1 and MCP2 ( monocyte chemotactic protein 1 and 2 ) , and GBP1 .	Interestingly, many of these genes could be grouped into an IFN-gamma response gene module including SOCS1 and SOCS3 (suppressor of cytokines signaling 1 and 3), IRF1 (IFN regulatory factor 1), IL-6, MCP1 and MCP2 (monocyte chemotactic protein 1 and 2), and GBP1.	11	18	module	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	16	17	11	12
Full inhibition of IFN-gamma signaling by SOCS1 requires the phosphorylation of tyrosine 441 in the IFNGR1 subunit , thus suggesting that SOCS1 interacts first with the IFNGR and then binds to JAK2 to inhibit its kinase activity .	Full inhibition of IFN-gamma signaling by SOCS1 requires the phosphorylation of tyrosine 441 in the IFNGR1 subunit, thus suggesting that SOCS1 interacts first with the IFNGR and then binds to JAK2 to inhibit its kinase activity.	3	7	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFN-gamma	IFN-gamma	IFN-gamma	6	7	3	4
In addition , although IL-6-mediated up-regulation of suppressor of cytokine signaling 1 has been shown to inhibit IFN-gamma receptor and STAT1 dependent Th1 differentiation in vitro ,33 in vivo roles of these signaling components remain unclear .	In addition, although IL-6-mediated up-regulation of suppressor of cytokine signaling 1 has been shown to inhibit IFN-gamma receptor and STAT1 dependent Th1 differentiation in vitro,33 in vivo roles of these signaling components remain unclear.	5	18	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 1	suppressor of cytokine signaling 1	suppressor of cytokine signaling 1	IFN-gamma	IFN-gamma	IFN-gamma	7	12	17	18
TRIM8 , a protein that is induced by IFNgamma in many cells , was shown to interact with SOCS1 ( XREF_FIG ) and to inhibit SOCS1 mediated downregulation of IFNgamma signalling in transfection experiments .	TRIM8, a protein that is induced by IFNgamma in many cells, was shown to interact with SOCS1 (XREF_FIG) and to inhibit SOCS1 mediated downregulation of IFNgamma signalling in transfection experiments.	24	30	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	25	26	29	30
Under lymphopenic conditions , SOCS1 deficient Tregs from LckCre-cKO mice lost Foxp3 and were converted into Th1 to produce IFNgamma with accelerated methylation of DNAs in the CNS2 region of the Foxp3 promoter and enhancer .	Under lymphopenic conditions, SOCS1 deficient Tregs from LckCre-cKO mice lost Foxp3 and were converted into Th1 to produce IFNgamma with accelerated methylation of DNAs in the CNS2 region of the Foxp3 promoter and enhancer.	4	20	produce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1	SOCS1	IFNgamma	IFNgamma	IFNgamma	4	5	19	20
We hypothesized that compromised IFN-gamma signaling mediated by SOCS-1 prevents effective suppression of osteoclast differentiation .	We hypothesized that compromised IFN-gamma signaling mediated by SOCS-1 prevents effective suppression of osteoclast differentiation.	4	9	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SOCS-1	SOCS-1	SOCS-1	IFN-gamma	IFN-gamma	IFN-gamma	8	9	4	5
Importantly , IL6 can cause hepatic insulin resistance by increasing the expression of SOCS3 [ XREF_BIBR ] , an adapter protein that can bind IRS1 and the insulin receptor , and can target IRS1 for ubiquitin mediated degradation [ XREF_BIBR - XREF_BIBR ] .	Importantly, IL6 can cause hepatic insulin resistance by increasing the expression of SOCS3 [XREF_BIBR], an adapter protein that can bind IRS1 and the insulin receptor, and can target IRS1 for ubiquitin mediated degradation [XREF_BIBR - XREF_BIBR].	2	34	target	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	SOCS3	IL6 can cause hepatic insulin resistance by increasing the expression of SOCS3	socs3	IRS1	IRS1	irs1	13	14	33	34
SOCS1 and SOCS3 target IRS-1 in inflammation induced insulin resistance possibly by involving the elongin BC ubiquitin-ligase [ XREF_BIBR ] .	SOCS1 and SOCS3 target IRS-1 in inflammation induced insulin resistance possibly by involving the elongin BC ubiquitin-ligase [XREF_BIBR].	0	7	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	IRS-1	IRS-1	IRS-1	2	3	4	5
To further examine the direct effects of TNF-alpha and SOCS3 on IRS-1 signaling , we also treated with recombinant TNF-alpha or SOCS3 to create an excess of these factors following transfection of cells with IRS-1 plasmid or mutant plasmid .	To further examine the direct effects of TNF-alpha and SOCS3 on IRS-1 signaling, we also treated with recombinant TNF-alpha or SOCS3 to create an excess of these factors following transfection of cells with IRS-1 plasmid or mutant plasmid.	11	22	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	IRS-1	IRS-1	IRS-1	21	22	11	12
SOCS3 could block insulin signaling by targeting insulin receptor substrate 1 ( IRS1 ) and insulin receptor substrate 2 ( IRS2 ) [ XREF_BIBR ] .	SOCS3 could block insulin signaling by targeting insulin receptor substrate 1 (IRS1) and insulin receptor substrate 2 (IRS2) [XREF_BIBR].	0	20	block	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IRS1	IRS1	IRS1	0	1	12	13
SOCS3 also can promote ubiquitinization of IRS-1 , thus blocking insulin signal transduction XREF_BIBR .	SOCS3 also can promote ubiquitinization of IRS-1, thus blocking insulin signal transduction XREF_BIBR.	0	7	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	IRS-1	IRS-1	IRS-1	0	1	6	7
Alternatively , SOCS3 can promote ubiquinitization of IRS-1 , thus eliminating IRS-1 from the complex [ XREF_BIBR ] .	Alternatively, SOCS3 can promote ubiquinitization of IRS-1, thus eliminating IRS-1 from the complex [XREF_BIBR].	2	8	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	IRS-1	IRS-1	IRS-1	2	3	7	8
These data indicate that HBx promotes the SOCS3 mediated downregulation of the IRS1 protein .	These data indicate that HBx promotes the SOCS3 mediated downregulation of the IRS1 protein.	6	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	IRS1	IRS1	IRS1	7	8	12	13
We show that SOCS1 or SOCS3 targeted IRS1 and IRS2 , two critical signaling molecules for insulin action , for ubiquitin mediated degradation .	We show that SOCS1 or SOCS3 targeted IRS1 and IRS2, two critical signaling molecules for insulin action, for ubiquitin mediated degradation.	3	13	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	IRS1	IRS1	IRS1	5	6	7	8
Notably , these changes in IRS-1 protein levels coincided with the peak in STAT3 activation and Socs3 expression ( XREF_FIG ) , as SOCS3 is reported to target and degrade IRS-1 protein and thereby further repress hepatic insulin signaling .	Notably, these changes in IRS-1 protein levels coincided with the peak in STAT3 activation and Socs3 expression (XREF_FIG), as SOCS3 is reported to target and degrade IRS-1 protein and thereby further repress hepatic insulin signaling.	23	34	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	IRS-1	IRS-1	IRS-1	23	24	30	31
SOCS3 also blocks insulin signaling by targeting insulin receptor substrate 1 ( IRS1 ) and insulin receptor substrate 2 ( IRS2 ) , two critical signaling molecules for insulin action , and forces their ubiquitination and degradation , contributing to insulin resistance [ XREF_BIBR ] .	SOCS3 also blocks insulin signaling by targeting insulin receptor substrate 1 (IRS1) and insulin receptor substrate 2 (IRS2), two critical signaling molecules for insulin action, and forces their ubiquitination and degradation, contributing to insulin resistance [XREF_BIBR].	0	25	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IRS1	IRS1	IRS1	0	1	12	13
There is a large body of evidence supporting that SOCS3 disrupts insulin signaling by binding to specific sites on IR , and IRS-1 and IRS-2 , as well as targeting IRS-1 and IRS-2 for degradation [ XREF_BIBR ] .	There is a large body of evidence supporting that SOCS3 disrupts insulin signaling by binding to specific sites on IR, and IRS-1 and IRS-2, as well as targeting IRS-1 and IRS-2 for degradation [XREF_BIBR].	9	36	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IRS-1	IRS-1	IRS-1	9	10	30	31
IL-27 signaling also induces SOCS3 , a suppressor of IL-27 signaling that directly binds to and inhibits the gp130 receptor subunit and associated Janus kinases and later facilitates their degradation .	IL-27 signaling also induces SOCS3, a suppressor of IL-27 signaling that directly binds to and inhibits the gp130 receptor subunit and associated Janus kinases and later facilitates their degradation.	3	20	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	4	5	18	19
The interaction with this valine adds 10-fold to the affinity with which SOCS3 targets gp130 [ XREF_BIBR ] ( K D = 100nM ) compared to a typical SH2-target interaction which is usually of micromolar affinity [ XREF_BIBR ] .	The interaction with this valine adds 10-fold to the affinity with which SOCS3 targets gp130 [XREF_BIBR] (K D = 100nM) compared to a typical SH2-target interaction which is usually of micromolar affinity [XREF_BIBR].	12	16	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	12	13	14	15
Therefore , we hypothesized that inhibition of gp130 signaling by SOCS3 would change cardiac myocyte susceptibility to virus infection without affecting IFN signaling .	Therefore, we hypothesized that inhibition of gp130 signaling by SOCS3 would change cardiac myocyte susceptibility to virus infection without affecting IFN signaling.	7	11	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	10	11	7	8
SOCS3 then targets GP130 , a receptor for IL6 , but not IL10R , and this difference in receptor targeting by SOCS3 results in shorter IL6 driven STAT3 activity , while IL10 driven STAT3 activation is prolonged XREF_BIBR .	SOCS3 then targets GP130, a receptor for IL6, but not IL10R, and this difference in receptor targeting by SOCS3 results in shorter IL6 driven STAT3 activity, while IL10 driven STAT3 activation is prolonged XREF_BIBR.	0	12	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	GP130	GP130	GP130	0	1	3	4
SOCS3 targets the activated gp130 receptor to inhibit the IL-6 receptor complex signaling but at the same time SOCS 1 and SOCS3 have been reported to target GHR as well [ XREF_BIBR ] .	SOCS3 targets the activated gp130 receptor to inhibit the IL-6 receptor complex signaling but at the same time SOCS 1 and SOCS3 have been reported to target GHR as well [XREF_BIBR].	0	5	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	0	1	4	5
Cells derived from gp130 F/F mice , harbouring a gp130 Y757F mutation to ablate SOCS3 binding to gp130 , show an exaggerated gp130 mediated STAT3 signalling as a consequence of an impaired negative feedback loop by SOCS3 to down-modulate gp130 and STAT3 signalling XREF_BIBR .	Cells derived from gp130 F/F mice, harbouring a gp130 Y757F mutation to ablate SOCS3 binding to gp130, show an exaggerated gp130 mediated STAT3 signalling as a consequence of an impaired negative feedback loop by SOCS3 to down-modulate gp130 and STAT3 signalling XREF_BIBR.	19	37	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	36	37	22	23
SOCS3 siRNA knockdown and SOCS3 deletion in astrocytes enhanced the synergistic effect of IL-6/R and IL-17 on IL-6 gene expression , which was due to enhanced activation of the NF-kappaB and MAPK pathways ( XREF_FIG ) .	SOCS3 siRNA knockdown and SOCS3 deletion in astrocytes enhanced the synergistic effect of IL-6/R and IL-17 on IL-6 gene expression, which was due to enhanced activation of the NF-kappaB and MAPK pathways (XREF_FIG).	0	15	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS3	SOCS3	SOCS3	IL-6/R	IL-6/R	IL-6/R	0	1	13	14
Accordingly , we hypothesized that the loss of gp130 mediated upregulation of SOCS3 induces sustained activation of gp130 signaling in the cardiomyocyte , leading to cardiomyopathy and heart failure .	Accordingly, we hypothesized that the loss of gp130 mediated upregulation of SOCS3 induces sustained activation of gp130 signaling in the cardiomyocyte, leading to cardiomyopathy and heart failure.	10	18	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	gp130	gp130	gp130	12	13	17	18
JAK2 activation might be enhanced by hypermethylation of the negative regulator SOCS3 .	JAK2 activation might be enhanced by hypermethylation of the negative regulator SOCS3.	0	12	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SOCS3	hypermethylation of the negative regulator SOCS3	socs3	JAK2	JAK2	jak2	11	12	0	1
SOCS3 and SOCS1-3 stimulated the ATPase activity of JAK2 by nearly 2-fold .	SOCS3 and SOCS1-3 stimulated the ATPase activity of JAK2 by nearly 2-fold.	0	9	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	0	1	8	9
Inhibition of SOCS3 mediated JAK2 degradation by TrkC increases total JAK2 and STAT3 expression , and then leads to upregulation of Twist-1 through activation of JAK2 and STAT3 cascade .	Inhibition of SOCS3 mediated JAK2 degradation by TrkC increases total JAK2 and STAT3 expression, and then leads to upregulation of Twist-1 through activation of JAK2 and STAT3 cascade.	0	5	mediated	Positive_early_activation	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	JAK2	JAK2	JAK2	2	3	4	5
Quercetin treatment for 24h dose-dependently upregulated the decreased p-Jak2 and p-Stat3 ( XREF_FIG ) , as well as reduced Socs3 expression ( XREF_FIG ) in fructose incubated INS-1 beta-cells .	Quercetin treatment for 24h dose-dependently upregulated the decreased p-Jak2 and p-Stat3 (XREF_FIG), as well as reduced Socs3 expression (XREF_FIG) in fructose incubated INS-1 beta-cells.	5	21	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Socs3	Socs3 expression	socs3	p-Jak2	p-Jak2	p-jak2	19	20	8	9
So , we propose that the aberrant promoter hypermethylation of SOCS3 we have detected in T-LBL samples might be contributing to a partial inactivation of this gene and , consequently , to enhance JAK2 activation in these primary lymphomas .	So, we propose that the aberrant promoter hypermethylation of SOCS3 we have detected in T-LBL samples might be contributing to a partial inactivation of this gene and, consequently, to enhance JAK2 activation in these primary lymphomas.	8	34	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	hypermethylation of SOCS3	socs3	JAK2	JAK2	jak2	10	11	33	34
miR-322/503 directly interacts with Smurf2 mRNA via its 3 '-UTR and represses Smurf2 translation , thus positively modulating the TGF-beta and Smad2 signaling pathway .	miR-322/503 directly interacts with Smurf2 mRNA via its 3 '-UTR and represses Smurf2 translation, thus positively modulating the TGF-beta and Smad2 signaling pathway.	12	23	modulating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf2	Smurf2	Smurf2	Smad2	Smad2	Smad2	12	13	21	22
These data suggest that the decrease in Smad2 resulted from enhanced ubiquitin dependent degradation of Smad2 mediated by Smurf2 , and is involved in the regulation of Smad2 mediated TGF-beta signaling in nephritic glomeruli .	These data suggest that the decrease in Smad2 resulted from enhanced ubiquitin dependent degradation of Smad2 mediated by Smurf2, and is involved in the regulation of Smad2 mediated TGF-beta signaling in nephritic glomeruli.	13	19	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	Smurf2	Smurf2	Smurf2	Smad2	Smad2	Smad2	18	19	15	16
In miR-322-silenced cells , increased Smurf2 suppressed TGF-beta-induced Smad2 activation by enhancing p-Smad2 degradation ( XREF_FIG ) .	In miR-322-silenced cells, increased Smurf2 suppressed TGF-beta-induced Smad2 activation by enhancing p-Smad2 degradation (XREF_FIG).	5	13	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf2	Smurf2	Smurf2	p-Smad2	p-Smad2	p-Smad2	5	6	12	13
These results indicate that increased Smurf2 by miR-322/503 silencing inhibits TGF-beta and Smad2 activation by enhancing p-Smad2 degradation .	These results indicate that increased Smurf2 by miR-322/503 silencing inhibits TGF-beta and Smad2 activation by enhancing p-Smad2 degradation.	4	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf2	Smurf2	Smurf2	p-Smad2	p-Smad2	p-Smad2	5	6	16	17
Likewise , a suppressor of cytokine signaling-1 ( SOCS-1 ) can suppress IRAK activity as well as degrade tyrosine phosphorylated TIRAP to inhibit TLR4 signaling .	Likewise, a suppressor of cytokine signaling-1 (SOCS-1) can suppress IRAK activity as well as degrade tyrosine phosphorylated TIRAP to inhibit TLR4 signaling.	6	13	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS-1	SOCS-1	SOCS-1	IRAK	IRAK	IRAK	8	9	12	13
Subsequently , WNT5A responsive protein inhibitors of activated STAT ( PIAS-1 ) and suppressor of cytokine signaling 1 ( SOCS-1 ) mediate the downregulation of IRAK-1 , IRAK-4 , and MyD88 , resulting in decreased expression of interleukin 12 ( IL-12 ) , IL-1beta , and tumor necrosis factor alpha ( TNF-alpha ) .	Subsequently, WNT5A responsive protein inhibitors of activated STAT (PIAS-1) and suppressor of cytokine signaling 1 (SOCS-1) mediate the downregulation of IRAK-1, IRAK-4, and MyD88, resulting in decreased expression of interleukin 12 (IL-12), IL-1beta, and tumor necrosis factor alpha (TNF-alpha).	5	27	mediate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 1	suppressor of cytokine signaling 1	suppressor of cytokine signaling 1	IRAK-1	IRAK-1	IRAK-1	13	18	25	26
Among the negative regulators , SOCS1 suppresses the upstream LPS signaling pathway by inhibiting IRAK-1 XREF_BIBR .	Among the negative regulators, SOCS1 suppresses the upstream LPS signaling pathway by inhibiting IRAK-1 XREF_BIBR.	5	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	SOCS1	SOCS1	IRAK-1	IRAK-1	IRAK-1	5	6	14	15
For example , suppressor of cytokine signaling 1 , which is the downstream element of cytokine signaling such as interferon and IL-6 , has been found to inhibit both NF-kappaB ( p65 ) and IRAK1 activation .	For example, suppressor of cytokine signaling 1, which is the downstream element of cytokine signaling such as interferon and IL-6, has been found to inhibit both NF-kappaB (p65) and IRAK1 activation.	3	35	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	suppressor of cytokine signaling 1	suppressor of cytokine signaling 1	suppressor of cytokine signaling 1	IRAK1	IRAK1	IRAK1	3	8	34	35
Consistent with the activation of the Par6 and Smurf1 pathway downstream of TGFbetaR3 , targeting ALK5 , Par6 , or Smurf1 significantly inhibited EMT in response to either TGFbeta2 or BMP-2 .	Consistent with the activation of the Par6 and Smurf1 pathway downstream of TGFbetaR3, targeting ALK5, Par6, or Smurf1 significantly inhibited EMT in response to either TGFbeta2 or BMP-2.	6	20	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	ALK5	ALK5	ALK5	8	9	15	16
TbetaRI down-regulation is mediated by E3 ligase Smad ubiquitination regulatory factor 1 ( Smurf1 ) while TbetaRII down-regulation is mediated by E3 ligase Smad ubiquitination regulatory factor 2 ( Smurf2 ) , both belong to the HECT class of ubiquitin ligases .	TbetaRI down-regulation is mediated by E3 ligase Smad ubiquitination regulatory factor 1 (Smurf1) while TbetaRII down-regulation is mediated by E3 ligase Smad ubiquitination regulatory factor 2 (Smurf2), both belong to the HECT class of ubiquitin ligases.	0	14	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Smurf1	Smurf1	Smurf1	TbetaRI	TbetaRI	TbetaRI	13	14	0	1
Smurf2 can also target TGF-beta type I receptor for degradation .	Smurf2 can also target TGF-beta type I receptor for degradation.	0	8	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Smurf2	Smurf2	Smurf2	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	0	1	4	8
Smurf2 targets TGF-beta type I receptor , Smad1 , Smad2 , Smad7 , and the transcriptional repressor SnoN for degradation by the proteasome [ XREF_BIBR - XREF_BIBR ] .	Smurf2 targets TGF-beta type I receptor, Smad1, Smad2, Smad7, and the transcriptional repressor SnoN for degradation by the proteasome [XREF_BIBR - XREF_BIBR].	0	24	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Smurf2	Smurf2	Smurf2	TGF-beta type I receptor	TGF-beta type I receptor	TGF-beta type I receptor	0	1	2	6
In nontransformed cells , the induction of SOCS1 acts as a negative feedback loop to suppress Jak and STAT function , but v-Abl phosphorylates SOCS1 and inhibits its targeting of Jak1 for degradation .	In nontransformed cells, the induction of SOCS1 acts as a negative feedback loop to suppress Jak and STAT function, but v-Abl phosphorylates SOCS1 and inhibits its targeting of Jak1 for degradation.	22	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOCS1	v-Abl phosphorylates SOCS1	socs1	Jak1	Jak1	jak1	24	25	30	31
Finally , the rescue of HAGE or SOCS1 expression by ectopic expression in FM82 shRNA1 promoted the ubiquitination status of p-Jak1 ( XREF_FIG ) .	Finally, the rescue of HAGE or SOCS1 expression by ectopic expression in FM82 shRNA1 promoted the ubiquitination status of p-Jak1 (XREF_FIG).	7	22	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS1	SOCS1 expression	socs1	p-Jak1	p-Jak1	p-jak1	7	8	20	21
In breast cancer cells , SOSTDC1 modestly increases Wnt3a signaling , decreases BMP-7 signaling , and does not affect BMP-2-induced signaling .	In breast cancer cells, SOSTDC1 modestly increases Wnt3a signaling, decreases BMP-7 signaling, and does not affect BMP-2-induced signaling.	5	18	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOSTDC1	SOSTDC1	SOSTDC1	Wnt3a	Wnt3a	Wnt3a	5	6	8	9
In breast cancer cells , SOSTDC1 modestly increases Wnt3a signalling , decreases BMP-7 signalling , whilst eliciting little effect on BMP-2-induced signalling .	In breast cancer cells, SOSTDC1 modestly increases Wnt3a signalling, decreases BMP-7 signalling, whilst eliciting little effect on BMP-2-induced signalling.	5	9	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOSTDC1	SOSTDC1	SOSTDC1	Wnt3a	Wnt3a	Wnt3a	5	6	8	9
Interestingly , all three DUBs that form a complex with SMAD7 and therefore potentially SMURF2 affected the ubiquitination levels of SMURF2 .	Interestingly, all three DUBs that form a complex with SMAD7 and therefore potentially SMURF2 affected the ubiquitination levels of SMURF2.	8	15	potentially	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	SMURF2	SMURF2	SMURF2	SMAD7	SMAD7	SMAD7	14	15	10	11
However , Smad7 is lost in the fibrosing tissue , which is induced by Smurf2 , an E3 ligase that targets Smad7 for ubiquitin degradation [ XREF_BIBR , XREF_BIBR ] .	However, Smad7 is lost in the fibrosing tissue, which is induced by Smurf2, an E3 ligase that targets Smad7 for ubiquitin degradation [XREF_BIBR, XREF_BIBR].	12	24	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Smurf2	Smurf2	Smurf2	Smad7	Smad7	Smad7	14	15	21	22
The elevated levels of pJAK1 in SOCS3 DSB and DSB ES cells correlated with reduced clearance of pJAK1 , which was proteasome dependent in wild type cells , suggesting that SOCS3 normally targets pJAK1 for degradation through its SOCS box .	The elevated levels of pJAK1 in SOCS3 DSB and DSB ES cells correlated with reduced clearance of pJAK1, which was proteasome dependent in wild type cells, suggesting that SOCS3 normally targets pJAK1 for degradation through its SOCS box.	30	35	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SOCS3	SOCS3	SOCS3	pJAK1	pJAK1	pJAK1	30	31	33	34
Differences in SNX9 expression levels or changes in its subcellular localization likely contribute to alterations of signaling involving EGFR and ADAM proteins .	Differences in SNX9 expression levels or changes in its subcellular localization likely contribute to alterations of signaling involving EGFR and ADAM proteins.	2	21	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SNX9	SNX9 expression levels	snx9	EGFR	EGFR	egfr	2	3	18	19
As predicted from this role , ectodin -/- mice have significantly less renal fibrosis and EMT attributable to reduced TGF-beta1 activity and enhanced BMP-7 signaling compared with wild-type mice subjected to UUO or cisplatin initiated renal damage .	As predicted from this role, ectodin -/- mice have significantly less renal fibrosis and EMT attributable to reduced TGF-beta1 activity and enhanced BMP-7 signaling compared with wild-type mice subjected to UUO or cisplatin initiated renal damage.	6	34	enhanced	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	ectodin	ectodin	ectodin	BMP-7	BMP-7	BMP-7	6	7	23	24
It has been suggested that Smurf2 targets Smad1 , Smad2 , Smad7 and the TGF-beta receptor for degradation and is involved in the establishment of neuronal polarity via ubiquitination of the GTPase Rap1B .	It has been suggested that Smurf2 targets Smad1, Smad2, Smad7 and the TGF-beta receptor for degradation and is involved in the establishment of neuronal polarity via ubiquitination of the GTPase Rap1B.	3	20	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Smurf2	Smurf2	Smurf2	Smad1	Smad1	Smad1	5	6	7	8
The EGFR and Src signaling pathway was found to mediate the regulation of cortactin by asporin .	The EGFR and Src signaling pathway was found to mediate the regulation of cortactin by asporin.	3	14	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	cortactin	cortactin	cortactin	3	4	13	14
MIM and CTTN appear to be two such factors , with MIM promoting cilia formation and Src activated p-CTTN promoting cilia disassembly .	MIM and CTTN appear to be two such factors, with MIM promoting cilia formation and Src activated p-CTTN promoting cilia disassembly.	14	19	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Src	Src	Src	p-CTTN	p-CTTN	p-CTTN	16	17	18	19
CTTN is activated by Src kinase dependent phosphorylation and is inactivated by acetylation [ XREF_BIBR , XREF_BIBR ] .	CTTN is activated by Src kinase dependent phosphorylation and is inactivated by acetylation [XREF_BIBR, XREF_BIBR].	0	10	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Src	Src kinase dependent phosphorylation	src	CTTN	CTTN	cttn	4	5	0	1
While Src activity alone is sufficient to activate cortactin , FAK can not compensate for the loss of Src activity .	While Src activity alone is sufficient to activate cortactin, FAK can not compensate for the loss of Src activity.	1	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	cortactin	cortactin	cortactin	1	2	8	9
Overall , our observations would be compatible with a model where signaling pathways such as insulin like growth factor-1R and Akt or Src induce CTTN mediated alteration of K V 10.1 expression at the cell surface .	Overall, our observations would be compatible with a model where signaling pathways such as insulin like growth factor-1R and Akt or Src induce CTTN mediated alteration of K V 10.1 expression at the cell surface.	18	25	induce	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Src	Src	Src	CTTN	CTTN	CTTN	22	23	24	25
Collectively , our findings suggest a crucial role for Src mediated activation of cortactin in cell migration , reorganization of actin cytoskeleton and phosphotyrosine cortactin localization to the focal adhesions in human breast cancer cell lines upon both IGF-1 and EGF stimulation .	Collectively, our findings suggest a crucial role for Src mediated activation of cortactin in cell migration, reorganization of actin cytoskeleton and phosphotyrosine cortactin localization to the focal adhesions in human breast cancer cell lines upon both IGF-1 and EGF stimulation.	9	25	mediated	Positive_early_activation	Negative_activation	Positive_activation	Src	Src	Src	cortactin	cortactin	cortactin	9	10	13	14
Together theses results indicate that Src activity alone is sufficient to activate cortactin , and FAK can not compensate for the loss of Src activity .	Together theses results indicate that Src activity alone is sufficient to activate cortactin, and FAK can not compensate for the loss of Src activity.	5	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	cortactin	cortactin	cortactin	5	6	12	13
Namely , after phosphorylation at Y1311 and Y1320 in a Src- and Fyn dependent manner , PTPRJ then dephosphorylated the Y529 inhibitory site of Src , activated it , and caused vascular endothelial growth factor ( VEGF )-induced phosphorylation of vascular endothelial ( VE )-cadherin and cortactin XREF_BIBR , XREF_BIBR .	Namely, after phosphorylation at Y1311 and Y1320 in a Src- and Fyn dependent manner, PTPRJ then dephosphorylated the Y529 inhibitory site of Src, activated it, and caused vascular endothelial growth factor (VEGF)-induced phosphorylation of vascular endothelial (VE)-cadherin and cortactin XREF_BIBR, XREF_BIBR.	16	47	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	PTPRJ then dephosphorylated the Y529 inhibitory site of Src	src	cortactin	cortactin	cortactin	24	25	46	47
We chose this approach because MDA231 cells readily form FAs , whereas exogenous expression of constitutively active Src strongly induces the formation of numerous cortactin rich invadopodia compared with parental cells .	We chose this approach because MDA231 cells readily form FAs, whereas exogenous expression of constitutively active Src strongly induces the formation of numerous cortactin rich invadopodia compared with parental cells.	13	26	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	expression of constitutively active Src	src	cortactin	cortactin	cortactin	17	18	24	25
Src activation of cortactin resulted in the localization of Nck1 and N-WASP at invadopodia , in addition to the disengagement of cofilin , all of which are required for Arp2/3 mediated actin polymerization to promote invadopodia formation XREF_BIBR , XREF_BIBR .	Src activation of cortactin resulted in the localization of Nck1 and N-WASP at invadopodia, in addition to the disengagement of cofilin, all of which are required for Arp2/3 mediated actin polymerization to promote invadopodia formation XREF_BIBR, XREF_BIBR.	0	4	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Src	Src	Src	cortactin	cortactin	cortactin	0	1	3	4
This suggests that tyrosine phosphorylated by Src allows cortactin to localize to Shigella induced projections and to determine actin polymerization .	This suggests that tyrosine phosphorylated by Src allows cortactin to localize to Shigella induced projections and to determine actin polymerization.	4	9	allows	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Src	Src	Src	cortactin	cortactin	cortactin	6	7	8	9
Quantitative analysis demonstrated that Src enhances the affinity of cortactin for dynamin-2 by more than 3-fold .	Quantitative analysis demonstrated that Src enhances the affinity of cortactin for dynamin-2 by more than 3-fold.	4	11	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	cortactin	cortactin	cortactin	4	5	9	10
Src phosphorylation of cortactin is required for transferrin receptor CME XREF_BIBR , XREF_BIBR , indicating that cortactin is also targeted by Src during endocytosis .	Src phosphorylation of cortactin is required for transferrin receptor CME XREF_BIBR, XREF_BIBR, indicating that cortactin is also targeted by Src during endocytosis.	16	22	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Src	Src	Src	cortactin	cortactin	cortactin	21	22	16	17
PAK and Src target cortactin , a protein that promotes F-actin elaboration and stabilization in many cellular systems .	PAK and Src target cortactin, a protein that promotes F-actin elaboration and stabilization in many cellular systems.	0	7	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Src	Src	Src	cortactin	cortactin	cortactin	2	3	4	5
Regarding cortactin , 997,5 g , oral L3837 and blood L3881 strains also activated cortactin phosphorylation by Src at the Y 466 residue ; this phosphorylation was sustained for at least 180 min of Candida-HeLa cell contact .	Regarding cortactin, 997,5 g, oral L3837 and blood L3881 strains also activated cortactin phosphorylation by Src at the Y 466 residue; this phosphorylation was sustained for at least 180 min of Candida-HeLa cell contact.	0	18	activated	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	Src	Src	Src	cortactin	cortactin	cortactin	17	18	1	2
These identified signaling axes include : PI3-kinase and the guanine exchange factor , Frabin dependent activation of the small GTPase , CDC42 and c-Src -dependent activation of cortactin [ XREF_BIBR , XREF_BIBR ] .	These identified signaling axes include : PI3-kinase and the guanine exchange factor, Frabin dependent activation of the small GTPase, CDC42 and c-Src -dependent activation of cortactin [XREF_BIBR, XREF_BIBR].	19	29	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	c-Src	c-Src	c-Src	cortactin	cortactin	cortactin	23	24	27	28
Accordingly , we find increased Src activation in Cav1 -/- fibroblasts , and when these cells were reconstituted with a Src-insensitive Y14F caveolin-1 mutant , the normal phenotype was not restored .	Accordingly, we find increased Src activation in Cav1 -/- fibroblasts, and when these cells were reconstituted with a Src-insensitive Y14F caveolin-1 mutant, the normal phenotype was not restored.	5	10	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Src	Src	Src	Cav1	Cav1	Cav1	5	6	8	9
In conclusion , these results demonstrated that EGF induced DNA synthesis and cell migration are mediated by caveolin-1 , which is activated by Src , FAK , PI3K and Akt , ERK , and MMP-2 signals in mouse ES cells .	In conclusion, these results demonstrated that EGF induced DNA synthesis and cell migration are mediated by caveolin-1, which is activated by Src, FAK, PI3K and Akt, ERK, and MMP-2 signals in mouse ES cells.	15	31	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Src	Src	Src	caveolin-1	caveolin-1	caveolin-1	23	24	17	18
We then attempted to understand the mechanistic basis for endothelial dysfunction by characterizing the stoichiometry of Cav-1-dependent regulation of eNOS expression and activity , determined whether this was dependent on eNOS and/or Src mediated posttranslational modifications to Cav-1 , and also assessed whether eNOS derived NO regulates critical Cav-1 scaffolding and endocytosis functions in ECs .	We then attempted to understand the mechanistic basis for endothelial dysfunction by characterizing the stoichiometry of Cav-1-dependent regulation of eNOS expression and activity, determined whether this was dependent on eNOS and/or Src mediated posttranslational modifications to Cav-1, and also assessed whether eNOS derived NO regulates critical Cav-1 scaffolding and endocytosis functions in ECs.	32	41	mediated	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	Src	Src	Src	Cav-1	Cav-1	Cav-1	32	33	37	38
Inhibitors of Src and the Mek1-Erk1/2 and p38 MAP kinase pathways also inhibit up-regulation of caveolin-1 by rosiglitazone .	Inhibitors of Src and the Mek1-Erk1/2 and p38 MAP kinase pathways also inhibit up-regulation of caveolin-1 by rosiglitazone.	0	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	caveolin-1	caveolin-1	caveolin-1	2	3	15	16
Caveolin-1 was phosphorylated at Y14 , in accordance with a prior report showing Src activation of caveolin-1 , 49 and calphostin C reduced caveolin-1 phosphorylation , consistent with a signaling cascade from PKC to caveolin-1 through cSrc .	Caveolin-1 was phosphorylated at Y14, in accordance with a prior report showing Src activation of caveolin-1, 49 and calphostin C reduced caveolin-1 phosphorylation, consistent with a signaling cascade from PKC to caveolin-1 through cSrc.	13	17	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Src	Src	Src	caveolin-1	caveolin-1	caveolin-1	13	14	16	17
Similarly , as observed with the FAK inhibitor , Src blockage significantly prevented upregulation of caveolin-1 in hepatocytes on protein and mRNA levels .	Similarly, as observed with the FAK inhibitor, Src blockage significantly prevented upregulation of caveolin-1 in hepatocytes on protein and mRNA levels.	9	16	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	caveolin-1	caveolin-1	caveolin-1	9	10	15	16
Thus , the dissociation of G alphai from caveolin-1 induced by dn-Src suggests an important role of Src in regulating the integrity of the caveolin-1/G alphai signaling complex .	Thus, the dissociation of G alphai from caveolin-1 induced by dn-Src suggests an important role of Src in regulating the integrity of the caveolin-1/G alphai signaling complex.	6	12	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	dn-Src	dn-Src	dn-Src	caveolin-1	caveolin-1	caveolin-1	11	12	8	9
XREF_BIBR - XREF_BIBR The detection of Src in the MAPK-ERK signal pathway upstream and caveolin-1 downstream showed that the phosphorylation of Src and caveolin-1 were increased , and as a result , the phosphorylation of Src activated the MAPK-ERK pathway , and then activated caveolin-1 , which has the capacity to enhance the activation of transcription .	XREF_BIBR - XREF_BIBR The detection of Src in the MAPK-ERK signal pathway upstream and caveolin-1 downstream showed that the phosphorylation of Src and caveolin-1 were increased, and as a result, the phosphorylation of Src activated the MAPK-ERK pathway, and then activated caveolin-1, which has the capacity to enhance the activation of transcription.	33	47	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	phosphorylation of Src	src	caveolin-1	caveolin-1	caveolin-1	35	36	44	45
The results presented in this study not only confirmed previous reports that Y265 of Cx43 is a primary site phosphorylated by v-Src but also identified Y247 as an additional major site of Cx43 targeted by activated Src in vitro and in intact cells .	The results presented in this study not only confirmed previous reports that Y265 of Cx43 is a primary site phosphorylated by v-Src but also identified Y247 as an additional major site of Cx43 targeted by activated Src in vitro and in intact cells.	30	39	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Src	Src	Src	Cx43	Cx43	Cx43	36	37	32	33
c-Src activation and Cx43 downregulation preceded the peak of Hx-2 and cyclin D3 expression , suggesting that c-Src could mediate the effect of Cx43 on glucose uptake and proliferation in reactive astrocytes after an excitotoxic insult .	c-Src activation and Cx43 downregulation preceded the peak of Hx-2 and cyclin D3 expression, suggesting that c-Src could mediate the effect of Cx43 on glucose uptake and proliferation in reactive astrocytes after an excitotoxic insult.	17	28	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-Src	c-Src	c-Src	Cx43	Cx43	Cx43	17	18	23	24
We have shown that the Cx43 dependent survival effect of bisphosphonates on osteocytes is mediated by activation of Src and the survival kinases ERKs .	We have shown that the Cx43 dependent survival effect of bisphosphonates on osteocytes is mediated by activation of Src and the survival kinases ERKs.	5	23	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Src	Src	Src	Cx43	Cx43	Cx43	18	19	5	6
Inhibition of c-Src prevents Cx43 remodeling and ventricular arrhythmia caused by of angiotensin II activation and oxidative stress .	Inhibition of c-Src prevents Cx43 remodeling and ventricular arrhythmia caused by of angiotensin II activation and oxidative stress.	0	5	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	c-Src	c-Src	c-Src	Cx43	Cx43	Cx43	2	3	4	5
Since c-Src has been shown to up-regulate HIF-1alpha XREF_BIBR , XREF_BIBR , XREF_BIBR , we investigated whether c-Src mediates the effect of ET-1 and Cx43 on glucose uptake .	Since c-Src has been shown to up-regulate HIF-1alpha XREF_BIBR, XREF_BIBR, XREF_BIBR, we investigated whether c-Src mediates the effect of ET-1 and Cx43 on glucose uptake.	17	25	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-Src	c-Src	c-Src	Cx43	Cx43	Cx43	17	18	24	25
The present study also demonstrated that ERK1/2 and JNK and SAPK were significantly activated by AGE-BSA and that Src , ERK1/2 , and JNK and SAPK inhibitors significantly reversed the reduction of Cx32 and Cx43 proteins by AGE-BSA .	The present study also demonstrated that ERK1/2 and JNK and SAPK were significantly activated by AGE-BSA and that Src, ERK1/2, and JNK and SAPK inhibitors significantly reversed the reduction of Cx32 and Cx43 proteins by AGE-BSA.	18	35	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	Cx43	Cx43	Cx43	18	19	34	35
These observations suggest that ROS induced PTEN nuclear accumulation and increased oxidized nuclear PTEN are mediated by SRC activation .	These observations suggest that ROS induced PTEN nuclear accumulation and increased oxidized nuclear PTEN are mediated by SRC activation.	12	18	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SRC	SRC	SRC	PTEN	PTEN	PTEN	17	18	13	14
Cowden syndrome associated germline SDHD variants alter PTEN nuclear translocation through SRC induced PTEN oxidation .	Cowden syndrome associated germline SDHD variants alter PTEN nuclear translocation through SRC induced PTEN oxidation.	9	14	induced	Positive_early_activation	Negative_activation	Positive_activation	SRC	SRC	SRC	PTEN	PTEN	PTEN	11	12	13	14
In this study , therefore , we sought to address our hypothesis that CS/CSL associated germline variants in SDHD could alter PTEN nuclear localization through SRC induced PTEN oxidation in thyroid cancer cells .	In this study, therefore, we sought to address our hypothesis that CS/CSL associated germline variants in SDHD could alter PTEN nuclear localization through SRC induced PTEN oxidation in thyroid cancer cells.	20	28	induced	Positive_early_activation	Negative_activation	Positive_activation	SRC	SRC	SRC	PTEN	PTEN	PTEN	25	26	27	28
CD24 and Src induced miR-21 Expression Downregulates Pdcd4 and PTEN .	CD24 and Src induced miR-21 Expression Downregulates Pdcd4 and PTEN.	0	10	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	PTEN	PTEN	PTEN	2	3	9	10
SRC inhibition blocked nuclear PTEN accumulation and decreased migration in papillary thyroid cancer cells expressing SDHDv .	SRC inhibition blocked nuclear PTEN accumulation and decreased migration in papillary thyroid cancer cells expressing SDHDv.	0	5	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SRC	SRC	SRC	PTEN	PTEN	PTEN	0	1	4	5
Src tyrosine kinases have been suggested to activate p21-ras .	Src tyrosine kinases have been suggested to activate p21-ras.	0	9	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	p21-ras	p21-ras	p21-ras	0	1	8	9
Inhibition of Src kinase prevented cell proliferation and activation of H-Ras by GSNO at the Golgi .	Inhibition of Src kinase prevented cell proliferation and activation of H-Ras by GSNO at the Golgi.	2	11	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	H-Ras	H-Ras	H-Ras	2	3	10	11
PI3K and Src activate HRAS and CRAF , and trans-activate EGFR that results in the paradoxical activation of MEK , during the treatment with vemurafenib .	PI3K and Src activate HRAS and CRAF, and trans-activate EGFR that results in the paradoxical activation of MEK, during the treatment with vemurafenib.	0	6	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	HRAS	HRAS	HRAS	2	3	4	5
In HaCaT cells , stimulation of the Src kinase family mediated FVIIa dependent p21Ras activation .	In HaCaT cells, stimulation of the Src kinase family mediated FVIIa dependent p21Ras activation.	7	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	p21Ras	p21Ras	p21Ras	7	8	13	14
We investigated the mechanistic role of Src and Ras , important oncoproteins implicated in the pathogenesis of many human cancers , in taxane induced apoptosis using v-src or c-H-ras transfected HAG-1 human gallbladder epithelial cells .	We investigated the mechanistic role of Src and Ras, important oncoproteins implicated in the pathogenesis of many human cancers, in taxane induced apoptosis using v-src or c-H-ras transfected HAG-1 human gallbladder epithelial cells.	4	29	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	c-H-ras	c-H-ras	c-H-ras	6	7	28	29
These results suggested that beta-catenin might be the key molecule by which SOX17 suppressed the proliferation of cervical cancer cells by inhibiting the activity of the Wnt and beta-catenin signaling pathway .	These results suggested that beta-catenin might be the key molecule by which SOX17 suppressed the proliferation of cervical cancer cells by inhibiting the activity of the Wnt and beta-catenin signaling pathway.	12	30	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	12	13	28	29
Silencing Sox17 abolished the activation of beta-catenin induced by TSB , whereas TSB mediated Notch1 activation was slightly increased after silencing Sox17 .	Silencing Sox17 abolished the activation of beta-catenin induced by TSB, whereas TSB mediated Notch1 activation was slightly increased after silencing Sox17.	0	7	abolished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	1	2	6	7
Several studies demonstrated that SOX17 inhibited the carcinogenesis by suppressing activity of the Wnt and beta-catenin signaling pathway XREF_BIBR , XREF_BIBR , XREF_BIBR - XREF_BIBR .	Several studies demonstrated that SOX17 inhibited the carcinogenesis by suppressing activity of the Wnt and beta-catenin signaling pathway XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR.	4	16	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SOX17	SOX17	SOX17	beta-catenin	beta-catenin	beta-catenin	4	5	15	16
Xenopus Sox17 alpha , Sox17 beta , and Sox3 are reported to negatively modulate the WNT - beta-catenin - TCF signaling pathway .	Xenopus Sox17 alpha, Sox17 beta, and Sox3 are reported to negatively modulate the WNT - beta-catenin - TCF signaling pathway.	1	18	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	1	2	17	18
Another study has also demonstrated that the suppression of Wnt and beta-catenin signaling by Sox17 enhances progenitor cell maturation .	Another study has also demonstrated that the suppression of Wnt and beta-catenin signaling by Sox17 enhances progenitor cell maturation.	9	15	signaling	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Sox17	Sox17	Sox17	beta-catenin	beta-catenin	beta-catenin	14	15	11	12
We hypothesized that a small molecule inhibitor of Src might reduce the growth and reverse Src mediated deregulation of p27 in Barrett ' s esophagus cells .	We hypothesized that a small molecule inhibitor of Src might reduce the growth and reverse Src mediated deregulation of p27 in Barrett 's esophagus cells.	14	20	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	p27	p27	p27	15	16	19	20
Since p27 is required for growth inhibition by ER blockade , and since Src activates p27 proteolysis , we tested if the Src family kinase inhibitor saracatinib could restore fulvestrant efficacy in resistant ER+ OVCA .	Since p27 is required for growth inhibition by ER blockade, and since Src activates p27 proteolysis, we tested if the Src family kinase inhibitor saracatinib could restore fulvestrant efficacy in resistant ER+ OVCA.	13	16	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	p27	p27	p27	13	14	15	16
Many human cancers have increased Src levels or activity , which would increase tyrosine phosphorylation p27 to promote SCF SKP2 -mediated p27 proteolysis .	Many human cancers have increased Src levels or activity, which would increase tyrosine phosphorylation p27 to promote SCF SKP2 -mediated p27 proteolysis.	5	16	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src levels	src	p27	p27	p27	5	6	15	16
Furthermore , ROS induce cell-cell dissociation by endocytosis of N-cadherin mediated by Src kinase phosphorylation and internalization of p120-catenin , which implies loss of epithelial integrity and transient Rho and Rho kinase pathway activation ( as it occurs in the initial phase of EMT ) .	Furthermore, ROS induce cell-cell dissociation by endocytosis of N-cadherin mediated by Src kinase phosphorylation and internalization of p120-catenin, which implies loss of epithelial integrity and transient Rho and Rho kinase pathway activation (as it occurs in the initial phase of EMT).	7	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Src	Src kinase phosphorylation	src	N-cadherin	N-cadherin	n-cadherin	12	13	9	10
The knock-down of c-Src induced formation of mature N-cadherin junctions , which appear as linear staining for N-cadherin all along the cell-cell borders of Block-iT positive cells .	The knock-down of c-Src induced formation of mature N-cadherin junctions, which appear as linear staining for N-cadherin all along the cell-cell borders of Block-iT positive cells.	1	9	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	c-Src	c-Src	c-Src	N-cadherin	N-cadherin	N-cadherin	3	4	8	9
Knockdown of c-Src promotes differentiation initiation by inducing maturation of N-cadherin junctions .	Knockdown of c-Src promotes differentiation initiation by inducing maturation of N-cadherin junctions.	0	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	c-Src	c-Src	c-Src	N-cadherin	N-cadherin	N-cadherin	2	3	10	11
In agreement , SRC overexpression also increased N-cadherin and decreased E-cadherin , although the effect was weak compared to the effect of SRC downregulation .	In agreement, SRC overexpression also increased N-cadherin and decreased E-cadherin, although the effect was weak compared to the effect of SRC downregulation.	3	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SRC	SRC overexpression	src	N-cadherin	N-cadherin	n-cadherin	3	4	7	8
Indeed , PP2 disrupts the Src dependent activation of vinculin and tension development in airway smooth muscle cells .	Indeed, PP2 disrupts the Src dependent activation of vinculin and tension development in airway smooth muscle cells.	5	12	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	Src	Src	Src	vinculin	vinculin	vinculin	5	6	9	10
Inhibition of Galpha 13 or Src also diminished agonist and shear dependent PS exposure and MV release , further indicating a role for integrin outside-in signaling .	Inhibition of Galpha 13 or Src also diminished agonist and shear dependent PS exposure and MV release, further indicating a role for integrin outside-in signaling.	0	16	diminished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	MV	MV	MV	5	6	15	16
In the regulatory network of the DEGs , CAV2 were targeted by SRC , indicating that CAV2 might also be involved in ALI by mediating SRC .	In the regulatory network of the DEGs, CAV2 were targeted by SRC, indicating that CAV2 might also be involved in ALI by mediating SRC.	8	13	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	SRC	SRC	SRC	CAV2	CAV2	CAV2	12	13	8	9
Furthermore , in the regulatory network of the DEGs , SRC had interaction relationships with PTK2 , as well as CAV2 were targeted by SRC .	Furthermore, in the regulatory network of the DEGs, SRC had interaction relationships with PTK2, as well as CAV2 were targeted by SRC.	11	25	targeted	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	SRC	SRC	SRC	CAV2	CAV2	CAV2	24	25	20	21
Our observations suggest that srGAP3 promotes neurite outgrowth and filopodial growth cones by interacting with Robo2 to inactivate Rac1 in mammalian DRG neurons .	Our observations suggest that srGAP3 promotes neurite outgrowth and filopodial growth cones by interacting with Robo2 to inactivate Rac1 in mammalian DRG neurons.	4	19	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	srGAP3	srGAP3	srGAP3	Rac1	Rac1	Rac1	4	5	18	19
We show that RNAi mediated depletion of srGAP3 promotes Rac dependent , anchorage independent growth of partially transformed human mammary epithelial cells ( HMECs ) .	We show that RNAi mediated depletion of srGAP3 promotes Rac dependent, anchorage independent growth of partially transformed human mammary epithelial cells (HMECs).	5	14	promotes	Positive_activation_token_1_verb	Negative_activation	Negative_activation	srGAP3	srGAP3	srGAP3	Rac	Rac	Rac	7	8	9	10
Inhibition of ERK , Src , or Akt suppressed telomerase activity in HSC-1 cells , but to a lesser extent than did treatment with AG 1478 .	Inhibition of ERK, Src, or Akt suppressed telomerase activity in HSC-1 cells, but to a lesser extent than did treatment with AG 1478.	0	10	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	telomerase	telomerase	telomerase	4	5	9	10
Telomerase reverse transcriptase , an enzyme that is required for telomere maintenance , is believed to be critical for proper endothelial cell functions and is inactivated by Src kinase in situations of excessive oxidative stress .	Telomerase reverse transcriptase, an enzyme that is required for telomere maintenance, is believed to be critical for proper endothelial cell functions and is inactivated by Src kinase in situations of excessive oxidative stress.	0	28	inactivated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	Src	Src	Src	Telomerase reverse transcriptase	Telomerase reverse transcriptase	Telomerase reverse transcriptase	27	28	0	3
Vascular permeability and ALI were reduced in the anti-MHC Class I induced model of TRALI when E-selectin or CD11b and CD18 ( Mac-1 ) were blocked with monoclonal antibodies or by administration of a Src kinase inhibitor .	Vascular permeability and ALI were reduced in the anti-MHC Class I induced model of TRALI when E-selectin or CD11b and CD18 (Mac-1) were blocked with monoclonal antibodies or by administration of a Src kinase inhibitor.	16	36	blocked	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	Src	Src	Src	CD18	CD18	CD18	34	35	20	21
TDM induced Mincle signaling activates MAPKs , and the Src family inhibitor prevents CD11b and CD18 upregulation in neutrophils .	TDM induced Mincle signaling activates MAPKs, and the Src family inhibitor prevents CD11b and CD18 upregulation in neutrophils.	9	16	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	CD18	CD18	CD18	9	10	15	16
76 It therefore appears to be warranted to further investigate whether the autophagic elimination of Src kinase activity is required to allow an efficient activation of caspase-8 activation on autophagosomal membranes .	76 It therefore appears to be warranted to further investigate whether the autophagic elimination of Src kinase activity is required to allow an efficient activation of caspase-8 activation on autophagosomal membranes.	15	27	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	caspase-8	caspase-8	caspase-8	15	16	26	27
We next hypothesized that if phosphorylation plays a role in beta-DG nuclear localization , it is expected that inhibition of c-Src , the kinase that phosphorylates beta-DG at Tyr 890 16 would prevent beta-DG nuclear accumulation .	We next hypothesized that if phosphorylation plays a role in beta-DG nuclear localization, it is expected that inhibition of c-Src, the kinase that phosphorylates beta-DG at Tyr 890 16 would prevent beta-DG nuclear accumulation.	18	35	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	c-Src	c-Src	c-Src	beta-DG	beta-DG	beta-DG	20	21	33	34
Knockdown of beta2-adaptin resulted in activation of Src tyrosine kinase and inhibition of Src activity suppressed the ability of beta2-adaptin knockdown cells to degrade matrix .	Knockdown of beta2-adaptin resulted in activation of Src tyrosine kinase and inhibition of Src activity suppressed the ability of beta2-adaptin knockdown cells to degrade matrix.	13	21	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	beta2-adaptin	beta2-adaptin	beta2-adaptin	13	14	19	20
However , PI3K can not account for the Src independent pathway , since simultaneous inhibition of both PI3K and Src did not completely block effects of R-Ras on FAK phosphorylation .	However, PI3K can not account for the Src independent pathway, since simultaneous inhibition of both PI3K and Src did not completely block effects of R-Ras on FAK phosphorylation.	14	27	block	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Src	Src	Src	R-Ras	R-Ras	R-Ras	19	20	26	27
These findings suggest that Spry4 suppresses cell spreading by inhibiting the kinase activity of TESK1 .	These findings suggest that Spry4 suppresses cell spreading by inhibiting the kinase activity of TESK1.	4	15	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Spry4	Spry4	Spry4	TESK1	TESK1	TESK1	4	5	14	15
A mechanistically interesting aspect in our study is that the different Sclerostin mediated inhibition of the two Wnt factors Wnt1 and Wnt3a , both of which are reported to signal via the canonical Wnt and beta-Catenin pathway , differs XREF_BIBR , XREF_BIBR .	A mechanistically interesting aspect in our study is that the different Sclerostin mediated inhibition of the two Wnt factors Wnt1 and Wnt3a, both of which are reported to signal via the canonical Wnt and beta-Catenin pathway, differs XREF_BIBR, XREF_BIBR.	9	29	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sclerostin	Sclerostin	Sclerostin	Wnt3a	Wnt3a	Wnt3a	11	12	21	22
SPEN , also known as MINT , has been reported to repress NOTCH signaling by physically interacting with and causing inhibition of the transcription factor RBPJ , which is implicated in the NOTCH signaling cascade .	SPEN, also known as MINT, has been reported to repress NOTCH signaling by physically interacting with and causing inhibition of the transcription factor RBPJ, which is implicated in the NOTCH signaling cascade.	0	29	repress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SPEN	SPEN	SPEN	RBPJ	RBPJ	RBPJ	0	1	25	26
p300 can also serve as a coactivator with HNF4 , and it synergizes with SRC-1 to further augment the activity of HNF4 .	p300 can also serve as a coactivator with HNF4, and it synergizes with SRC-1 to further augment the activity of HNF4.	14	22	augment	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SRC-1	SRC-1	SRC-1	HNF4	HNF4	HNF4	14	15	21	22
Disappearance of SUFU in steps 15-18 ( stages I-VI ) spermatids allows GLI1 to be reactivated in the late steps of spermiogenesis .	Disappearance of SUFU in steps 15-18 (stages I-VI) spermatids allows GLI1 to be reactivated in the late steps of spermiogenesis.	0	15	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	GLI1	GLI1	GLI1	2	3	12	13
Sufu ubiquitylation by Fbxl17 allows Gli dissociation for Hedgehog signaling activation .	Sufu ubiquitylation by Fbxl17 allows Gli dissociation for Hedgehog signaling activation.	0	6	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu ubiquitylation	sufu	Gli	Gli	gli	0	1	5	6
GLI1 protein can be phosphorylated by activated S6K1 at ser84 , and this phosphorylation enhances GLI1 function by attenuating SuFu mediated Gli1 inhibition [ XREF_BIBR ] .	GLI1 protein can be phosphorylated by activated S6K1 at ser84, and this phosphorylation enhances GLI1 function by attenuating SuFu mediated Gli1 inhibition [XREF_BIBR].	19	22	mediated	Positive_early_activation	Negative_activation	Negative_activation	SuFu	SuFu	SuFu	Gli1	Gli1	Gli1	19	20	21	22
In cilia , active Smo causes the dissociation of Gli from Suppressor of Fused ( SUFU ) , which allows Gli to be processed into its activated form XREF_BIBR .	In cilia, active Smo causes the dissociation of Gli from Suppressor of Fused (SUFU), which allows Gli to be processed into its activated form XREF_BIBR.	11	23	allows	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	Gli	Gli	Gli	15	16	20	21
In summary , Hh signaling causes the rapid dissociation of SuFu from Gli , suggesting a simple mechanism for relieving the inhibition of Gli by SuFu .	In summary, Hh signaling causes the rapid dissociation of SuFu from Gli, suggesting a simple mechanism for relieving the inhibition of Gli by SuFu.	19	26	inhibition	Negative_activation_token_2_noun	Negative_activation	Positive_activation	SuFu	SuFu	SuFu	Gli	Gli	Gli	25	26	23	24
Furthermore , addition of zebrafish or fly Sufu restores Gli protein function in Sufu deficient mammalian cells .	Furthermore, addition of zebrafish or fly Sufu restores Gli protein function in Sufu deficient mammalian cells.	6	11	restores	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	7	8	9	10
In the current study , we demonstrate that mouse Suppressor of Fused ( Sufu ) interacts with Gli proteins and inhibits Gli activator activity in the absence of cilia .	In the current study, we demonstrate that mouse Suppressor of Fused (Sufu) interacts with Gli proteins and inhibits Gli activator activity in the absence of cilia.	11	23	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	13	14	21	22
The ubiquitylation of Sufu , mediated by Fbxl17 , allows the release of Gli1 from Sufu for proper Hh signal transduction .	The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction.	1	14	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	ubiquitylation of Sufu	sufu	Gli1	Gli1	gli1	3	4	13	14
In addition , it has been reported that mammalian Sufu directly modulates the transcriptional activity of Gli in the nucleus through recruitment of a corepressor complex .	In addition, it has been reported that mammalian Sufu directly modulates the transcriptional activity of Gli in the nucleus through recruitment of a corepressor complex.	8	19	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	9	10	16	17
Distinct regulation of Gli activator and Gli3 repressor by Sufu .	Distinct regulation of Gli activator and Gli3 repressor by Sufu.	3	10	activator	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	9	10	3	4
On the other hand , Suppressor of Fused Homolog ( SUFU ) suppresses Hh signaling by regulating the localization of the transcription factor GLI XREF_BIBR .	On the other hand, Suppressor of Fused Homolog (SUFU) suppresses Hh signaling by regulating the localization of the transcription factor GLI XREF_BIBR.	5	24	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Suppressor of Fused Homolog	Suppressor of Fused Homolog	Suppressor of Fused Homolog	GLI	GLI	GLI	5	9	23	24
Hh stimulation leads to the rapid dissociation of the SuFu and Gli complex , suggesting a simple mechanism in which Gli activation is the consequence of relieving its inhibition by SuFu , which allows Gli to enter the nucleus ( XREF_FIG ) .	Hh stimulation leads to the rapid dissociation of the SuFu and Gli complex, suggesting a simple mechanism in which Gli activation is the consequence of relieving its inhibition by SuFu, which allows Gli to enter the nucleus (XREF_FIG).	26	36	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SuFu	SuFu	SuFu	Gli	Gli	Gli	30	31	34	35
In addition to be regulated by ubiquitination , Gli1 can also be modulated by SUFU , which interacts with and inhibits Gli1 activation by sequestering it in the cytosol .	In addition to be regulated by ubiquitination, Gli1 can also be modulated by SUFU, which interacts with and inhibits Gli1 activation by sequestering it in the cytosol.	12	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	SUFU	SUFU	SUFU	Gli1	Gli1	Gli1	14	15	21	22
In the absence of SHH , suppressor of Fused ( SUFU ) inhibits GLI transcriptional activity .	In the absence of SHH, suppressor of Fused (SUFU) inhibits GLI transcriptional activity.	8	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	10	11	13	14
Hedgehog dependent Gli mediated transactivation of target genes is negatively regulated by suppressor of fused homolog ( Sufu ) ; it is required for normal embryonic development and its loss leads to unfettered Hh activation and lethality [ XREF_BIBR ] .	Hedgehog dependent Gli mediated transactivation of target genes is negatively regulated by suppressor of fused homolog (Sufu); it is required for normal embryonic development and its loss leads to unfettered Hh activation and lethality [XREF_BIBR].	0	16	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	suppressor of fused homolog	suppressor of fused homolog	suppressor of fused homolog	Gli	Gli	Gli	12	16	2	3
While many additional aspects of hedgehog signaling remain to be worked out , an intriguing question is how transit of Sufu : Gli complexes to cilia tips promotes Sufu : Gli dissociation .	While many additional aspects of hedgehog signaling remain to be worked out, an intriguing question is how transit of Sufu : Gli complexes to cilia tips promotes Sufu : Gli dissociation.	18	31	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	20	21	30	31
We do not yet know whether SuFu dissociation from Gli is sufficient to activate Gli or if posttranslational changes are also required such as Gli phosphorylation .	We do not yet know whether SuFu dissociation from Gli is sufficient to activate Gli or if posttranslational changes are also required such as Gli phosphorylation.	6	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SuFu	SuFu	SuFu	Gli	Gli	Gli	6	7	14	15
SUFU acts down-stream of SMO and mediates the post-transcriptional inactivation of the GLI transcription factors , and SUFU inactivation leads to aberrant Hh pathway activation .	SUFU acts down-stream of SMO and mediates the post-transcriptional inactivation of the GLI transcription factors, and SUFU inactivation leads to aberrant Hh pathway activation.	0	14	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	0	1	12	13
Overexpressed SIL attenuated SUFU mediated cytoplasmic tethering and target gene suppression of GLI1 .	Overexpressed SIL attenuated SUFU mediated cytoplasmic tethering and target gene suppression of GLI1.	3	13	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	GLI1	GLI1	GLI1	3	4	12	13
Our identification of a prosurvival BCL-2 recognition sequence in the transcriptional regulator SUFU not only extends the potential utility of BH3 mimetics to include cancers typically associated with mutations in HH pathway components , but also enables the use of GLI targets genes as biomarkers of BCL-2 family protein activity in homeostatic and cancerous contexts ( XREF_SUPPLEMENTARY ) .	Our identification of a prosurvival BCL-2 recognition sequence in the transcriptional regulator SUFU not only extends the potential utility of BH3 mimetics to include cancers typically associated with mutations in HH pathway components, but also enables the use of GLI targets genes as biomarkers of BCL-2 family protein activity in homeostatic and cancerous contexts (XREF_SUPPLEMENTARY).	12	41	enables	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	12	13	40	41
Our cultured cell data suggest : 1 ) that Hh signaling does not induce Gli mediated transcriptional activity by general inactivation of Sufu ( XREF_FIG ) ; 2 ) that ciliary trafficking of Gli2 , required for its activation , occurs by a distinct mechanism from trafficking of Sufu ( XREF_FIG ) ; and 3 ) that Gli2 activity can be regulated by ShhN signaling independently of Sufu suppression ( XREF_FIG ) .	Our cultured cell data suggest : 1) that Hh signaling does not induce Gli mediated transcriptional activity by general inactivation of Sufu (XREF_FIG); 2) that ciliary trafficking of Gli2, required for its activation, occurs by a distinct mechanism from trafficking of Sufu (XREF_FIG); and 3) that Gli2 activity can be regulated by ShhN signaling independently of Sufu suppression (XREF_FIG).	13	24	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	22	23	14	15
Our studies illustrate a novel mechanism by which lithium suppresses Hh signaling via simultaneously promoting ITCH dependent Gli1 ubiquitination and degradation and SUFU mediated Gli1 inhibition .	Our studies illustrate a novel mechanism by which lithium suppresses Hh signaling via simultaneously promoting ITCH dependent Gli1 ubiquitination and degradation and SUFU mediated Gli1 inhibition.	18	25	mediated	Positive_early_activation	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	Gli1	Gli1	Gli1	22	23	24	25
We first addressed the contribution of the GLI regulator SUFU to prosurvival BCL-2 protein mediated GLI regulation ( see XREF_FIG ) .	We first addressed the contribution of the GLI regulator SUFU to prosurvival BCL-2 protein mediated GLI regulation (see XREF_FIG).	9	16	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	9	10	15	16
We also found that Sufu knockdown reduced Hh downstream target genes Gli and Ptch1 in cervical squamous cell lines ( SiHa and HCC94 ) rather than in adenocarcinoma cell line ( HeLa ) .	We also found that Sufu knockdown reduced Hh downstream target genes Gli and Ptch1 in cervical squamous cell lines (SiHa and HCC94) rather than in adenocarcinoma cell line (HeLa).	4	29	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli	Gli	Gli	4	5	11	12
Sufu inhibited Gli1 nuclear localization and promoted Gli1 proteolysis .	Sufu inhibited Gli1 nuclear localization and promoted Gli1 proteolysis.	0	6	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli1	Gli1	Gli1	0	1	2	3
S6K1 promotes GLI dependent transcription by phosphorylating GLI1 , which prevents an inhibitory interaction with SUFU that allows GLI to enter into the nucleus and turn on target genes .	S6K1 promotes GLI dependent transcription by phosphorylating GLI1, which prevents an inhibitory interaction with SUFU that allows GLI to enter into the nucleus and turn on target genes.	10	25	allows	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	GLI	GLI	GLI	15	16	18	19
The ubiquitylation of Sufu , mediated by Fbxl17 , allows the release of Gli1 for full activation of the Hh signaling .	The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 for full activation of the Hh signaling.	1	14	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	ubiquitylation of Sufu	sufu	Gli1	Gli1	gli1	3	4	13	14
AMPK induced phosphorylation of AS160 removes the GAP inhibition on Rab GTPases and allows translocation of GLUT4 vesicles to the cell surface [ XREF_BIBR , XREF_BIBR ] .	AMPK induced phosphorylation of AS160 removes the GAP inhibition on Rab GTPases and allows translocation of GLUT4 vesicles to the cell surface [XREF_BIBR, XREF_BIBR].	0	17	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AMPK induced phosphorylation of AS160	as160	GLUT4	GLUT4	glut4	4	5	16	17
The insulin stimulated phosphorylation of AS160 appears to relieve this restraint and allow GLUT4 to be recruited to the cell surface membranes .	The insulin stimulated phosphorylation of AS160 appears to relieve this restraint and allow GLUT4 to be recruited to the cell surface membranes.	1	16	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	insulin stimulated phosphorylation of AS160	as160	GLUT4	GLUT4	glut4	5	6	13	14
XREF_BIBR , XREF_BIBR In our study , Ang-( 1-7 ) reduced AS160 protein levels , which functionally promotes increased Glut4 at the myocyte plasma membrane , 37 independent of changes in classical Akt signaling .	XREF_BIBR, XREF_BIBR In our study, Ang-(1-7) reduced AS160 protein levels, which functionally promotes increased Glut4 at the myocyte plasma membrane, 37 independent of changes in classical Akt signaling.	11	24	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AS160 protein levels	as160	Glut4	Glut4	glut4	11	12	19	20
The basal retention seen in CHO cells with the addition of AS160 suggests that AS160 may be sufficient to mediate this aspect of normal GLUT4 trafficking .	The basal retention seen in CHO cells with the addition of AS160 suggests that AS160 may be sufficient to mediate this aspect of normal GLUT4 trafficking.	14	25	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	14	15	24	25
After insulin stimulation , AS160 is phosphorylated by Akt , promoting the translocation of GLUT4 to the cell surface .	After insulin stimulation, AS160 is phosphorylated by Akt, promoting the translocation of GLUT4 to the cell surface.	4	15	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AS160 is phosphorylated	as160	GLUT4	GLUT4	glut4	4	5	14	15
Based on a previous mutation study [ XREF_BIBR ] this indicates that alpha-MSH-induced glucose uptake occurs independently of TBC1D4 mediated GLUT4 translocation .	Based on a previous mutation study [XREF_BIBR] this indicates that alpha-MSH-induced glucose uptake occurs independently of TBC1D4 mediated GLUT4 translocation.	15	21	mediated	Positive_early_activation	Negative_activation	Positive_activation	TBC1D4	TBC1D4	TBC1D4	GLUT4	GLUT4	GLUT4	18	19	20	21
Previous studies showed that Akt phosphorylation of AS160 stimulates GLUT4 trafficking , but not the GSV-PM fusion step in cultured adipocytes , suggesting that other Akt2 substrate ( s ) might be required for the last step of GLUT4 translocation .	Previous studies showed that Akt phosphorylation of AS160 stimulates GLUT4 trafficking, but not the GSV-PM fusion step in cultured adipocytes, suggesting that other Akt2 substrate (s) might be required for the last step of GLUT4 translocation.	4	10	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	Akt phosphorylation of AS160	as160	GLUT4	GLUT4	glut4	7	8	9	10
Phosphorylation of AS160 promotes the translocation of GLUT4 and glucose uptake [ XREF_BIBR ] .	Phosphorylation of AS160 promotes the translocation of GLUT4 and glucose uptake [XREF_BIBR].	0	12	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	Phosphorylation of AS160	as160	GLUT4	GLUT4	glut4	2	3	7	8
The AKT substrate of 160 kDa ( AS160 ) has emerged as a point of convergence for both effectors of glucose transport and seems to modulate GLUT4 trafficking .	The AKT substrate of 160 kDa (AS160) has emerged as a point of convergence for both effectors of glucose transport and seems to modulate GLUT4 trafficking.	5	27	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	7	8	26	27
One model proposes that TBC1D4 modulates GLUT4 vesicle release from retention without altering vesicle tethering , docking or fusion with cell surface membranes [ XREF_BIBR ] .	One model proposes that TBC1D4 modulates GLUT4 vesicle release from retention without altering vesicle tethering, docking or fusion with cell surface membranes [XREF_BIBR].	4	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TBC1D4	TBC1D4	TBC1D4	GLUT4	GLUT4	GLUT4	4	5	6	7
AS160 was first shown to modulate GLUT4 trafficking in insulin sensitive 3T3-L1 adipocytes .	AS160 was first shown to modulate GLUT4 trafficking in insulin sensitive 3T3-L1 adipocytes.	0	7	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	0	1	6	7
These studies strongly support a model of AS160 function in which both full-length AS160 and AS160_v2 , when phosphorylated , augment the actions of insulin to promote GLUT4 cell surface localization .	These studies strongly support a model of AS160 function in which both full-length AS160 and AS160_v2, when phosphorylated, augment the actions of insulin to promote GLUT4 cell surface localization.	11	30	augment	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	13	14	27	28
In response to insulin , AS160 is phosphorylated on a number of Akt consensus sequences , allowing the translocation of GLUT4 to the plasma membrane ( Sano etal .	In response to insulin, AS160 is phosphorylated on a number of Akt consensus sequences, allowing the translocation of GLUT4 to the plasma membrane (Sano etal.	5	21	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AS160 is phosphorylated	as160	GLUT4	GLUT4	glut4	5	6	20	21
Removal of AS160 from the vesicle causes an accelerated rate of GLUT4 exocytosis , leading to greater accumulation at the plasma membrane culminating in elevated cellular glucose uptake .	Removal of AS160 from the vesicle causes an accelerated rate of GLUT4 exocytosis, leading to greater accumulation at the plasma membrane culminating in elevated cellular glucose uptake.	0	12	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	2	3	11	12
Since knockdown or knockout of AS160 only partially disrupts insulin control of Glut4 , Akt substrates in addition to AS160 are required for insulin stimulated Glut4 translocation in adipocytes .	Since knockdown or knockout of AS160 only partially disrupts insulin control of Glut4, Akt substrates in addition to AS160 are required for insulin stimulated Glut4 translocation in adipocytes.	1	13	disrupts	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AS160	AS160	Glut4	Glut4	Glut4	5	6	12	13
Further , overexpression of RAB10 in individual 3T3-L1 adipocytes as well as adipocytes lacking AS160 increases GLUT4 translocation above levels seen in control cells in response to the same dose of insulin , suggesting that RAB10 levels act cell autonomously to regulate GLUT4 and that endogenous levels of RAB10 are limiting for GLUT4 trafficking .	Further, overexpression of RAB10 in individual 3T3-L1 adipocytes as well as adipocytes lacking AS160 increases GLUT4 translocation above levels seen in control cells in response to the same dose of insulin, suggesting that RAB10 levels act cell autonomously to regulate GLUT4 and that endogenous levels of RAB10 are limiting for GLUT4 trafficking.	14	17	increases	Positive_activation_token_1_verb	Negative_activation	Positive_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	14	15	16	17
Phosphorylation of AS160 prevents it from suppressing Rab activity and allows plasma membrane localization of GLUT4 .	Phosphorylation of AS160 prevents it from suppressing Rab activity and allows plasma membrane localization of GLUT4.	0	16	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	Phosphorylation of AS160	as160	GLUT4	GLUT4	glut4	2	3	15	16
Reexpression of wild-type AS160 restored normal GLUT4 behavior to the knockdown adipocytes , whereas reexpression of a GAP domain mutant did not revert the phenotype , providing the first direct evidence that AS160 GAP activity is required for basal GLUT4 retention .	Reexpression of wild-type AS160 restored normal GLUT4 behavior to the knockdown adipocytes, whereas reexpression of a GAP domain mutant did not revert the phenotype, providing the first direct evidence that AS160 GAP activity is required for basal GLUT4 retention.	0	7	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	Reexpression of wild-type AS160	as160	GLUT4	GLUT4	glut4	3	4	6	7
AS160 was the first component of the insulin signaling pathway found to directly promote GLUT4 membrane transport XREF_BIBR .	AS160 was the first component of the insulin signaling pathway found to directly promote GLUT4 membrane transport XREF_BIBR.	0	17	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	AS160	AS160	GLUT4	GLUT4	GLUT4	0	1	14	15
Ultimately , Akt phosphorylates and inactivates AS160 ( a Rab GTPase activating protein ) to allow Glut4 containing vesicles to fuse with the sarcolemma .	Ultimately, Akt phosphorylates and inactivates AS160 (a Rab GTPase activating protein) to allow Glut4 containing vesicles to fuse with the sarcolemma.	2	17	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	AS160	Akt phosphorylates and inactivates AS160	as160	Glut4	Glut4	glut4	6	7	16	17
The transcription factors PPARgamma and PPARdelta are activated by STAT6 and necessary for M2 polarization , and PPARdelta -/- Mphi exhibit enhanced activation of JNK following treatment with adipocyte conditioned medium , which contains the M2 cytokines IL-4 and IL-13 .	The transcription factors PPARgamma and PPARdelta are activated by STAT6 and necessary for M2 polarization, and PPARdelta -/- Mphi exhibit enhanced activation of JNK following treatment with adipocyte conditioned medium, which contains the M2 cytokines IL-4 and IL-13.	0	11	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	STAT6	STAT6	STAT6	PPARgamma	PPARgamma	PPARgamma	9	10	3	4
STAT6 Augments PPARgamma Activity on Target Gene Promoters .	STAT6 Augments PPARgamma Activity on Target Gene Promoters.	0	3	Augments	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	STAT6	STAT6	STAT6	PPARgamma	PPARgamma	PPARgamma	0	1	2	3
In contrast , in AAM , this metabolic program is antagonized by STAT6 dependent induction of PPARgamma and PPARdelta .	In contrast, in AAM, this metabolic program is antagonized by STAT6 dependent induction of PPARgamma and PPARdelta.	12	18	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	STAT6	STAT6	STAT6	PPARgamma	PPARgamma	PPARgamma	12	13	16	17
demonstrated that IL-4 and STAT-6 signalling resulted in augmented PPARgamma activation in macrophages independent of changes in ligand availability .	demonstrated that IL-4 and STAT-6 signalling resulted in augmented PPARgamma activation in macrophages independent of changes in ligand availability.	2	11	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	STAT-6	STAT-6	STAT-6	PPARgamma	PPARgamma	PPARgamma	4	5	9	10
XREF_BIBR , XREF_BIBR Transcriptional factors nuclear factor kappaB ( NF-kappaB ) , CCAAT and enhancer binding protein-alpha ( C/EBPalpha ) , PU.1 , and IFN regulatory factor 5 ( IRF5 ) participate in M1 activation , while STAT6 , peroxisome proliferator activated receptor-gamma ( PPARgamma ) , CCAAT and enhancer binding protein-beta ( C/EBPbeta ) , and Kruppel like factor 4 ( KLF4 ) are involved in the polarization of M2 phenotype .	XREF_BIBR, XREF_BIBR Transcriptional factors nuclear factor kappaB (NF-kappaB), CCAAT and enhancer binding protein-alpha (C/EBPalpha), PU.1, and IFN regulatory factor 5 (IRF5) participate in M1 activation, while STAT6, peroxisome proliferator activated receptor-gamma (PPARgamma), CCAAT and enhancer binding protein-beta (C/EBPbeta), and Kruppel like factor 4 (KLF4) are involved in the polarization of M2 phenotype.	37	53	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	STAT6	STAT6	STAT6	PPARgamma	PPARgamma	PPARgamma	37	38	44	45
IL-4- or IL-13-mediated activation of STAT6 not only directly upregulates expression of Arg1 , one of the most specific M2 macrophage markers , but also induces other key transcription factors ( i.e. PPAR-gamma and C/EBPbeta ) that synergize with STAT6 to regulate M2 specific genes .	IL-4- or IL-13-mediated activation of STAT6 not only directly upregulates expression of Arg1, one of the most specific M2 macrophage markers, but also induces other key transcription factors (i.e. PPAR-gamma and C/EBPbeta) that synergize with STAT6 to regulate M2 specific genes.	3	34	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	STAT6	STAT6	STAT6	PPAR-gamma	PPAR-gamma	PPAR-gamma	5	6	32	33
Moreover , inhibition of STAT6 with specific siRNAs or the pharmacological inhibitor AS1517499AS reversed the induction of PPAR-gamma , LXR-alpha , and ABCA1 by apoptotic Jurkat cells .	Moreover, inhibition of STAT6 with specific siRNAs or the pharmacological inhibitor AS1517499AS reversed the induction of PPAR-gamma, LXR-alpha, and ABCA1 by apoptotic Jurkat cells.	2	26	reversed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	STAT6	STAT6	STAT6	PPAR-gamma	PPAR-gamma	PPAR-gamma	4	5	17	18
In the presence of CXM , IL-4 could still enhance ligand induced FABP4 expression , suggesting that STAT6 augmented PPARgamma response did not require new protein synthesis .	In the presence of CXM, IL-4 could still enhance ligand induced FABP4 expression, suggesting that STAT6 augmented PPARgamma response did not require new protein synthesis.	17	20	augmented	Positive_activation_token_1_verb	Negative_activation	Positive_activation	STAT6	STAT6	STAT6	PPARgamma	PPARgamma	PPARgamma	17	18	19	20
We took several possible mechanisms of STAT6 mediated PPARgamma facilitation into consideration .	We took several possible mechanisms of STAT6 mediated PPARgamma facilitation into consideration.	4	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	STAT6	STAT6	STAT6	PPARgamma	PPARgamma	PPARgamma	6	7	8	9
A short promoter fragment that contained the composite element ( MacPPRE and the STAT6 element ) ( XREF_FIG J ) behaved similarly as the original 5 kb fragment ( XREF_FIG A ) , indicating that this fragment is responsible for the STAT6 augmented PPARgamma response .	A short promoter fragment that contained the composite element (MacPPRE and the STAT6 element) (XREF_FIG J) behaved similarly as the original 5 kb fragment (XREF_FIG A), indicating that this fragment is responsible for the STAT6 augmented PPARgamma response.	40	44	augmented	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	STAT6	STAT6	STAT6	PPARgamma	PPARgamma	PPARgamma	41	42	43	44
TGF-beta1 + rapamycin induced changes in Cdk2 localization similar to those induced by TGF-beta1 alone ( data not shown ) ; however , cells treated with TGF-beta1 + rapamycin were more rounded than TGF-beta1-treated cells , making it difficult to distinguish between cytoplasmic and nuclear Cdk2 staining .	TGF-beta1 + rapamycin induced changes in Cdk2 localization similar to those induced by TGF-beta1 alone (data not shown); however, cells treated with TGF-beta1 + rapamycin were more rounded than TGF-beta1-treated cells, making it difficult to distinguish between cytoplasmic and nuclear Cdk2 staining.	0	7	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	Cdk2	Cdk2	Cdk2	0	1	6	7
TGF-beta1 increased the active form of cdk2 ( XREF_FIG ) .	TGF-beta1 increased the active form of cdk2 (XREF_FIG).	0	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	cdk2	cdk2	cdk2	0	1	6	7
Regulation of these two cell cycle components resulted in decreased cyclin D2 and cdk2 complex and in increased p27 ( KIP1 ) association with cdk2 in C4HD cells treated with TGF-beta1 .	Regulation of these two cell cycle components resulted in decreased cyclin D2 and cdk2 complex and in increased p27 (KIP1) association with cdk2 in C4HD cells treated with TGF-beta1.	7	31	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	cdk2	cdk2	cdk2	30	31	24	25
In HMECs TGF-beta1 treatment induced a more cytoplasmic localization of Cdk2 with partial exclusion from the nucleus .	In HMECs TGF-beta1 treatment induced a more cytoplasmic localization of Cdk2 with partial exclusion from the nucleus.	2	11	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	Cdk2	Cdk2	Cdk2	2	3	10	11
Therefore , we carried out a series of experiments to test the possibility that autocrine production of TGF-beta1 may be responsible for the failure of Ang II to activate Cdk2 and induce DNA synthesis in aortic SMC .	Therefore, we carried out a series of experiments to test the possibility that autocrine production of TGF-beta1 may be responsible for the failure of Ang II to activate Cdk2 and induce DNA synthesis in aortic SMC.	15	30	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	Cdk2	Cdk2	Cdk2	17	18	29	30
XREF_FIG ( left panel ) , Cdk2 was largely nuclear in control NMuMG cells , but TGF-beta1 induced a diffuse localization of Cdk2 throughout the entire cell volume .	XREF_FIG (left panel), Cdk2 was largely nuclear in control NMuMG cells, but TGF-beta1 induced a diffuse localization of Cdk2 throughout the entire cell volume.	16	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	Cdk2	Cdk2	Cdk2	16	17	22	23
Because we showed previously that TGF-beta1 and rapamycin cooperate to induce cell cycle arrest [ XREF_BIBR ] , these results are consistent with the idea that decreases induced in nuclear Cdk2 concentrations by TGF-beta1 + rapamycin constitute a novel mechanism by which TGF-beta1 mediates cell cycle arrest .	Because we showed previously that TGF-beta1 and rapamycin cooperate to induce cell cycle arrest [XREF_BIBR], these results are consistent with the idea that decreases induced in nuclear Cdk2 concentrations by TGF-beta1 + rapamycin constitute a novel mechanism by which TGF-beta1 mediates cell cycle arrest.	27	35	induced	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	TGF-beta1	TGF-beta1	TGF-beta1	Cdk2	Cdk2	Cdk2	33	34	30	31
At early stages of corticogenesis , we have shown that Sufu modulates Shh signaling by controlling the stability of full-length Gli2 and Gli3 [ XREF_BIBR ] .	At early stages of corticogenesis, we have shown that Sufu modulates Shh signaling by controlling the stability of full-length Gli2 and Gli3 [XREF_BIBR].	10	24	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli3	Gli3	Gli3	10	11	22	23
Genetic studies have shown that the Hh hyperactivation in Sufu knockout neural tube depends on the enhanced activator activity of Gli1/2 and to a lesser extent decreased levels of Gli3 repressor [ XREF_BIBR - XREF_BIBR ] .	Genetic studies have shown that the Hh hyperactivation in Sufu knockout neural tube depends on the enhanced activator activity of Gli1/2 and to a lesser extent decreased levels of Gli3 repressor [XREF_BIBR - XREF_BIBR].	7	32	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Sufu	Sufu	Sufu	Gli3	Gli3	Gli3	9	10	29	30
In addition , Sufu mediates proteolytic processing of Gli2 and Gli3 by beta-TrCP and SCF-type E3 ubiquitin ligase to generate the N-terminal fragment , Gli REP [ XREF_BIBR , XREF_BIBR ] .	In addition, Sufu mediates proteolytic processing of Gli2 and Gli3 by beta-TrCP and SCF-type E3 ubiquitin ligase to generate the N-terminal fragment, Gli REP [XREF_BIBR, XREF_BIBR].	3	11	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli3	Gli3	Gli3	3	4	10	11
In addition , Sufu antagonizes the complete degradation of Gli2 FL and Gli3 FL by antagonizing SPOP , which recruits ubiquitin ligase [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, Sufu antagonizes the complete degradation of Gli2 FL and Gli3 FL by antagonizing SPOP, which recruits ubiquitin ligase [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	13	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli3	Gli3	Gli3	3	4	12	13
SUFU and PKA promote the proteolytic conversion of GLI3 into a transcriptional repressor ( GLI3R ) and also block the formation of the transcriptional activators GLI2A and GLI3A .	SUFU and PKA promote the proteolytic conversion of GLI3 into a transcriptional repressor (GLI3R) and also block the formation of the transcriptional activators GLI2A and GLI3A.	0	18	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	GLI3	GLI3	GLI3	0	1	8	9
T396I Mutation of Mouse Sufu Reduces the Stability and Activity of Gli3 Repressor .	T396I Mutation of Mouse Sufu Reduces the Stability and Activity of Gli3 Repressor.	1	12	Reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli3	Gli3	Gli3	4	5	11	12
As is the case for FOXP3 and its interaction partners , one could imagine that a change in the relative levels of T-bet or GATA3 could shift the balance and allow GATA3 to bind to Th2 sites .	As is the case for FOXP3 and its interaction partners, one could imagine that a change in the relative levels of T-bet or GATA3 could shift the balance and allow GATA3 to bind to Th2 sites.	20	33	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	T-bet	levels of T-bet	t-bet	GATA3	GATA3	gata3	22	23	31	32
Recently , it was shown that T-bet directly modulates GATA3 function , suggesting that transcription factors compete in the early differentiation phase of T cells , potentially integrating environmental signals to finally imprint the T cell phenotype [ XREF_BIBR , XREF_BIBR ] .	Recently, it was shown that T-bet directly modulates GATA3 function, suggesting that transcription factors compete in the early differentiation phase of T cells, potentially integrating environmental signals to finally imprint the T cell phenotype [XREF_BIBR, XREF_BIBR].	6	10	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	T-bet	T-bet	T-bet	GATA3	GATA3	GATA3	6	7	9	10
We also found that ST2 blockade not only decreased the expression of the Th1 transcription factor Tbet and the corresponding inflammatory cytokine IFN-gamma , but also increased the production of the Th2 transcription factor GATA3 and Th2 cytokine IL-4 , skewing the Th1 and Th2 balance toward a Th2 phenotype , which protects against severe GVHD .	We also found that ST2 blockade not only decreased the expression of the Th1 transcription factor Tbet and the corresponding inflammatory cytokine IFN-gamma, but also increased the production of the Th2 transcription factor GATA3 and Th2 cytokine IL-4, skewing the Th1 and Th2 balance toward a Th2 phenotype, which protects against severe GVHD.	4	40	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tbet	ST2 blockade not only decreased the expression of the Th1 transcription factor Tbet	tbet	GATA3	GATA3	gata3	16	17	34	35
GATA3 can also interfere with STAT4 and IL-12Receptor expression , while Tbet negatively regulates Th2 development by reducing induction of GATA3 .	GATA3 can also interfere with STAT4 and IL-12Receptor expression, while Tbet negatively regulates Th2 development by reducing induction of GATA3.	11	21	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tbet	Tbet	Tbet	GATA3	GATA3	GATA3	11	12	20	21
For instance , human T H 1 cells produce interferon-gamma and Tbet , T H 2 cells produce IL-4 and GATA3 , and T H 17 cells produce IL-17A and RORC , which is orthologous to retinoic acid receptor related orphan receptor gammat ( RORgammat ) in mice .	For instance, human T H 1 cells produce interferon-gamma and Tbet, T H 2 cells produce IL-4 and GATA3, and T H 17 cells produce IL-17A and RORC, which is orthologous to retinoic acid receptor related orphan receptor gammat (RORgammat) in mice.	11	21	produce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tbet	Tbet	Tbet	GATA3	GATA3	GATA3	11	12	20	21
To uncouple Sufu mediated Gli2 and Gli3 regulation at the genetic and biochemical level , we generated an allelic series of Sufu point mutations using the RIKEN ENU based gene driven mutagenesis system [ XREF_BIBR ] .	To uncouple Sufu mediated Gli2 and Gli3 regulation at the genetic and biochemical level, we generated an allelic series of Sufu point mutations using the RIKEN ENU based gene driven mutagenesis system [XREF_BIBR].	1	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli2	Gli2	Gli2	2	3	4	5
Concomitantly , suppressor of fused ( Sufu ) stabilizes Gli proteins to suppress transcriptional activity of Gli2 .	Concomitantly, suppressor of fused (Sufu) stabilizes Gli proteins to suppress transcriptional activity of Gli2.	2	17	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Sufu	Sufu	Sufu	Gli2	Gli2	Gli2	6	7	16	17
By contrast , lack of STAT6 increased STAT1 activation , significantly inhibiting cell-cell fusion and decreasing OC-STAMP and DC-STAMP expression in IL-4-induced FBGCs .	By contrast, lack of STAT6 increased STAT1 activation, significantly inhibiting cell-cell fusion and decreasing OC-STAMP and DC-STAMP expression in IL-4-induced FBGCs.	3	8	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	STAT6	STAT6	STAT6	STAT1	STAT1	STAT1	5	6	7	8
Together , our results demonstrated that Pten and Lkb1 deficient endometrial tumors rely strongly on deregulated mTOR signaling , and they provided evidence that LKB1 status may modulate the response of PTEN deficient tumors to PI3K or mTOR inhibitors .	Together, our results demonstrated that Pten and Lkb1 deficient endometrial tumors rely strongly on deregulated mTOR signaling, and they provided evidence that LKB1 status may modulate the response of PTEN deficient tumors to PI3K or mTOR inhibitors.	24	33	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LKB1	LKB1	LKB1	PTEN	PTEN	PTEN	24	25	31	32
Because of the induction of PTEN , p53 , and p21 proteins by LKB1 XREF_BIBR , XREF_BIBR , XREF_BIBR , loss of LKB1 function activates the PI3K/Akt/mTOR pathway to promote proliferation and metastasis XREF_BIBR .	Because of the induction of PTEN, p53, and p21 proteins by LKB1 XREF_BIBR, XREF_BIBR, XREF_BIBR, loss of LKB1 function activates the PI3K/Akt/mTOR pathway to promote proliferation and metastasis XREF_BIBR.	3	14	induction	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	LKB1	LKB1	LKB1	PTEN	PTEN	PTEN	13	14	5	6
Cripto and GRP78 also acted together to increase colony growth and attenuate the growth inhibitory effects of TGF-beta1 on PC3 cells in soft agar .	Cripto and GRP78 also acted together to increase colony growth and attenuate the growth inhibitory effects of TGF-beta1 on PC3 cells in soft agar.	0	18	attenuate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Cripto	Cripto	Cripto	TGF-beta1	TGF-beta1	TGF-beta1	0	1	17	18
Notably , this finding resembles our previous demonstration that co-expression of Cripto and GRP78 caused TGF-beta1 to switch from having cytostatic effects to having pro proliferative effects on PC3 prostate carcinoma cells .	Notably, this finding resembles our previous demonstration that co-expression of Cripto and GRP78 caused TGF-beta1 to switch from having cytostatic effects to having pro proliferative effects on PC3 prostate carcinoma cells.	9	16	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cripto	co-expression of Cripto	cripto	TGF-beta1	TGF-beta1	tgf-beta1	11	12	15	16
Thus , our results indicate that Cripto and GRP78 can cooperate to promote tumor growth in part by facilitating mitogenic effects of Nodal and causing activin-A and TGF-beta1 to switch from being cytostatic to pro proliferative in nature .	Thus, our results indicate that Cripto and GRP78 can cooperate to promote tumor growth in part by facilitating mitogenic effects of Nodal and causing activin-A and TGF-beta1 to switch from being cytostatic to pro proliferative in nature.	6	28	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cripto	Cripto	Cripto	TGF-beta1	TGF-beta1	TGF-beta1	6	7	27	28
However , many AR targets were minimally affected or unaltered by the targeted STK4 signaling ( XREF_TABLE ) , suggesting that the regulation of AR targets by STK4 is selective or context dependent .	However, many AR targets were minimally affected or unaltered by the targeted STK4 signaling (XREF_TABLE), suggesting that the regulation of AR targets by STK4 is selective or context dependent.	24	28	targets	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	STK4	STK4	STK4	AR	AR	AR	27	28	24	25
The results showed that several AR targets were upregulated or downregulated by STK4 expression in these subcellular compartments , further validating our RNAseq data .	The results showed that several AR targets were upregulated or downregulated by STK4 expression in these subcellular compartments, further validating our RNAseq data.	5	14	downregulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	STK4	STK4 expression	stk4	AR	AR	ar	12	13	5	6
Since the p53 and TAF1 complex was pre-assembled on the promoter before adding ATP , this result indicates that TAF1 phosphorylation occurred on the promoter and promoted p53 dissociation from the promoter .	Since the p53 and TAF1 complex was pre-assembled on the promoter before adding ATP, this result indicates that TAF1 phosphorylation occurred on the promoter and promoted p53 dissociation from the promoter.	19	28	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TAF1	TAF1 phosphorylation	taf1	p53	p53	p53	19	20	27	28
We found that TAF1 induces G1 progression in a p53 dependent manner .	We found that TAF1 induces G1 progression in a p53 dependent manner.	3	11	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TAF1	TAF1	TAF1	p53	p53	p53	3	4	9	10
We found that Syk activation occurs in three different mouse models of AD , overexpressing Abeta or tau , showing that Syk activation is triggered by both Abeta deposits and tau pathological species .	We found that Syk activation occurs in three different mouse models of AD, overexpressing Abeta or tau, showing that Syk activation is triggered by both Abeta deposits and tau pathological species.	3	18	overexpressing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Syk	Syk	Syk	tau	tau	tau	3	4	17	18
Cripto mediated myostatin signaling is dependent on both epidermal growth factor ( EGF )-like and Cripto-FRL1-cryptic ( CFC ) domains , whereas activin signaling is solely conferred by the CFC domain .	Cripto mediated myostatin signaling is dependent on both epidermal growth factor (EGF)-like and Cripto-FRL1-cryptic (CFC) domains, whereas activin signaling is solely conferred by the CFC domain.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	Cripto	Cripto	Cripto	myostatin	myostatin	myostatin	0	1	2	3
Moreover , we provide evidence that Cripto modulates myogenic cell determination and promotes proliferation by antagonizing the TGF-beta ligand myostatin .	Moreover, we provide evidence that Cripto modulates myogenic cell determination and promotes proliferation by antagonizing the TGF-beta ligand myostatin.	6	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Cripto	Cripto	Cripto	myostatin	myostatin	myostatin	6	7	19	20
In addition to stabilizing Glis3 , SUFU has been shown to modulate Glis3 mediated transactivation of the Ins2 promoter .	In addition to stabilizing Glis3, SUFU has been shown to modulate Glis3 mediated transactivation of the Ins2 promoter.	6	14	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	SUFU	SUFU	SUFU	Glis3	Glis3	Glis3	6	7	12	13
Loss of LKB1 activity reduces PAK1 and cdc42 activity , presumably resulting in the aberrant cell polarity observed XREF_BIBR .	Loss of LKB1 activity reduces PAK1 and cdc42 activity, presumably resulting in the aberrant cell polarity observed XREF_BIBR.	2	8	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	LKB1	LKB1	LKB1	PAK1	PAK1	PAK1	2	3	5	6
The authors further revealed that this migration defect is correlated with a defect in centrosomal movement , and that LKB1 mediated inactivation of GSK3beta by Ser9 phosphorylation at the leading process tip to stabilize the MT plus-end-binding protein APC for proper forward movement of centrosomes .	The authors further revealed that this migration defect is correlated with a defect in centrosomal movement, and that LKB1 mediated inactivation of GSK3beta by Ser9 phosphorylation at the leading process tip to stabilize the MT plus-end-binding protein APC for proper forward movement of centrosomes.	19	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	LKB1	LKB1	LKB1	GSK3beta	GSK3beta	GSK3beta	19	20	23	24
Has been shown that ERK phosphorylates TSC2 , predominantly on serine 664 , leading to the disruption of the TSC1 and TSC2 complex , and increasing mRNA translation and mTOR activity [ XREF_BIBR ] .	Has been shown that ERK phosphorylates TSC2, predominantly on serine 664, leading to the disruption of the TSC1 and TSC2 complex, and increasing mRNA translation and mTOR activity [XREF_BIBR].	5	30	increasing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	phosphorylates TSC2, predominantly on serine 664	tsc2	mTOR	mTOR	mtor	6	7	29	30
The acquired resistance was induced by the crosstalk of GSK3beta , a WNT and beta-catenin kinase , with TSC2 , a PI3K/AKT/mTOR pathway gene , which modulated mTOR activity , as well as the stimulation of canonical WNT transcription , which further strengthened WNT and beta-catenin signaling .	The acquired resistance was induced by the crosstalk of GSK3beta, a WNT and beta-catenin kinase, with TSC2, a PI3K/AKT/mTOR pathway gene, which modulated mTOR activity, as well as the stimulation of canonical WNT transcription, which further strengthened WNT and beta-catenin signaling.	4	34	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	18	19	27	28
For ovine conceptus development during implantation and placentation , integrin activation by SPP1 binding and arginine are proposed to stimulate remodeling of trophectoderm for elongation and adherence to uterine LE/sGE via cytoskeletal reorganization that facilitates cell motility , stabilizes adhesion , and collectively activates MTOR signaling pathways mediated by protein kinase b-alpha ( AKT1 ) , tuberous sclerosis 1 and 2 ( TSC1 and TSC2 ) and MTORC1 ( cell proliferation and mRNA translation ) , as well as mTORC2 ( cell migration , cell survival and cytoskeletal organization ) in trophectoderm cells .	For ovine conceptus development during implantation and placentation, integrin activation by SPP1 binding and arginine are proposed to stimulate remodeling of trophectoderm for elongation and adherence to uterine LE/sGE via cytoskeletal reorganization that facilitates cell motility, stabilizes adhesion, and collectively activates MTOR signaling pathways mediated by protein kinase b-alpha (AKT1), tuberous sclerosis 1 and 2 (TSC1 and TSC2) and MTORC1 (cell proliferation and mRNA translation), as well as mTORC2 (cell migration, cell survival and cytoskeletal organization) in trophectoderm cells.	44	65	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	MTOR	MTOR	MTOR	64	65	44	45
Such a modification of tuberin influences its activity within the complex with hamartin and positively or negatively modulates mTOR regulated protein translation and cellular proliferation .	Such a modification of tuberin influences its activity within the complex with hamartin and positively or negatively modulates mTOR regulated protein translation and cellular proliferation.	2	19	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	4	5	18	19
As TSC2 has been shown to inhibit Notch in an mTOR independent fashion , 31 inactivation of TSC2 may also activate Notch signaling independent of mTOR regulation in intestinal cells .	As TSC2 has been shown to inhibit Notch in an mTOR independent fashion, 31 inactivation of TSC2 may also activate Notch signaling independent of mTOR regulation in intestinal cells.	15	26	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	17	18	25	26
The PTEN and TSC2 tumor suppressors function to antagonize mTOR ( mammalian target of rapamycin ) activation by Akt ; hence , compound heterozygous inactivation of Pten and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner .	The PTEN and TSC2 tumor suppressors function to antagonize mTOR (mammalian target of rapamycin) activation by Akt; hence, compound heterozygous inactivation of Pten and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner.	3	12	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	3	4	9	10
The hyperactivation of mTOR induced by Tsc1 and Tsc2 heterozygosity can be inhibited by mTOR inhibitors , such as the macrolide rapamycin .	The hyperactivation of mTOR induced by Tsc1 and Tsc2 heterozygosity can be inhibited by mTOR inhibitors, such as the macrolide rapamycin.	1	9	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	8	9	3	4
Hamartin and tuberin , the protein products of TSC1 and TSC2 , inhibit mammalian target of rapamycin ( mTOR ) .	Hamartin and tuberin, the protein products of TSC1 and TSC2, inhibit mammalian target of rapamycin (mTOR).	6	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	10	11	13	17
Independent of TSC2 , AKT also stimulates mTOR activity directly by inhibiting PRAS40 .	Independent of TSC2, AKT also stimulates mTOR activity directly by inhibiting PRAS40.	0	8	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	7	8
Activated AKT inhibits the formation of the tuberous sclerosis proteins TSC1 and TSC2 , thus allowing activation of MTOR .	Activated AKT inhibits the formation of the tuberous sclerosis proteins TSC1 and TSC2, thus allowing activation of MTOR.	0	19	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	MTOR	MTOR	MTOR	12	13	18	19
Phosphorylation of TSC2 by PKB or ERK1/2 leads to the disruption of its complex with TSC1 , and results in mTOR activation .	Phosphorylation of TSC2 by PKB or ERK1/2 leads to the disruption of its complex with TSC1, and results in mTOR activation.	0	22	activation	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	2	3	20	21
Akt , Tuberin and Rheb activate mTOR when it is part of a protein complex called mTORC1 ( mTOR complex 1 ) , which is exquisitely sensitive to the drug rapamycin .	Akt, Tuberin and Rheb activate mTOR when it is part of a protein complex called mTORC1 (mTOR complex 1), which is exquisitely sensitive to the drug rapamycin.	0	7	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tuberin	Tuberin	Tuberin	mTOR	mTOR	mTOR	2	3	6	7
TSC1 and TSC2 proteins act cellularly to suppress mammalian target of rapamycin ( mTOR ) .	TSC1 and TSC2 proteins act cellularly to suppress mammalian target of rapamycin (mTOR).	0	12	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	2	3	8	12
These findings support impaired hamartin- and tuberin mediated mTOR pathway regulation .	These findings support impaired hamartin- and tuberin mediated mTOR pathway regulation.	4	10	mediated	Positive_early_activation	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	6	7	8	9
In contrast , activation of the PI3K and Akt pathway by growth factors promotes the phosphorylation of TSC2 on S924 and T1518 , inactivates the TSC complex , and restores Rheb and mTOR activity [ XREF_BIBR ] .	In contrast, activation of the PI3K and Akt pathway by growth factors promotes the phosphorylation of TSC2 on S924 and T1518, inactivates the TSC complex, and restores Rheb and mTOR activity [XREF_BIBR].	6	35	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	PI3K and Akt pathway by growth factors promotes the phosphorylation of TSC2 on S924 and T1518	tsc2	mTOR	mTOR	mtor	17	18	32	33
The TSC2 : TSC1 complex is the principal cellular inhibitor of the mammalian target of rapamycin .	The TSC2 : TSC1 complex is the principal cellular inhibitor of the mammalian target of rapamycin.	0	16	inhibitor	Negative_activation_syntax_7_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	1	2	12	16
Phosphorylation of TSC2 by Akt releases its inhibitory effect on mTOR and upregulates mTOR activity .	Phosphorylation of TSC2 by Akt releases its inhibitory effect on mTOR and upregulates mTOR activity.	0	14	upregulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	2	3	13	14
The products of the TSC1 ( hamartin ) and TCS2 ( tuberin ) tumor suppressor genes negatively regulate cell growth by inhibiting mTOR signaling .	The products of the TSC1 (hamartin) and TCS2 (tuberin) tumor suppressor genes negatively regulate cell growth by inhibiting mTOR signaling.	9	23	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	11	12	22	23
On the other hand , insulin receptor signaling inhibits TSC1 and TSC2 via Akt , thereby activating the mTOR pathway .	On the other hand, insulin receptor signaling inhibits TSC1 and TSC2 via Akt, thereby activating the mTOR pathway.	8	19	activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	11	12	18	19
Here , we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin ( mTOR )-mediated signaling to eukaryotic initiation factor 4E binding protein 1 ( 4E-BP1 ) and ribosomal protein S6 kinase 1 ( S6K1 ) .	Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1).	5	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	7	8	12	16
Furthermore , Tsc2 deficiency and hyperactive Rheb constitutively activate mTOR and inhibit ephrin induced growth cone collapse .	Furthermore, Tsc2 deficiency and hyperactive Rheb constitutively activate mTOR and inhibit ephrin induced growth cone collapse.	2	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	2	3	9	10
Phosphorylation of TSC2 by Akt releases its inhibitory effect on mTOR and up-regulates mTOR activity .	Phosphorylation of TSC2 by Akt releases its inhibitory effect on mTOR and up-regulates mTOR activity.	0	14	up-regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	2	3	13	14
Tuberin , serving as a substrate of AKT and AMPK , mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth , proliferation , and survival .	Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival.	0	13	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tuberin	Tuberin	Tuberin	mTOR	mTOR	mTOR	0	1	12	13
Mutations in the proteins known to inhibit mTOR signaling including NF1 , PTEN , TSC1 , and TSC2 are all linked to neurological disease and autistic like behavioral phenotypes .	Mutations in the proteins known to inhibit mTOR signaling including NF1, PTEN, TSC1, and TSC2 are all linked to neurological disease and autistic like behavioral phenotypes.	7	18	signaling	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	17	18	7	8
Our study provides the following evidences in support of a MYC driven activation of mTOR in our system : First , MYC is known to downregulate the mTOR negative regulator TSC2 ( Ravitz etal , 2007 ) , as also found in our experiments .	Our study provides the following evidences in support of a MYC driven activation of mTOR in our system : First, MYC is known to downregulate the mTOR negative regulator TSC2 (Ravitz etal, 2007), as also found in our experiments.	23	40	downregulate	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	30	31	27	28
Upon starvation and activation of calcium signaling , AMPK phosphorylates and activates TSC2 , which inhibits mTOR signaling .	Upon starvation and activation of calcium signaling, AMPK phosphorylates and activates TSC2, which inhibits mTOR signaling.	8	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK phosphorylates and activates TSC2	tsc2	mTOR	mTOR	mtor	12	13	16	17
Inactivation of TSC2 via loss of expression or phosphorylation occurred frequently in endometrial carcinoma to activate mTOR signaling .	Inactivation of TSC2 via loss of expression or phosphorylation occurred frequently in endometrial carcinoma to activate mTOR signaling.	0	17	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	16	17
Activation of PI3K and AKT , involved in the phosphorylation of TSC1 and TSC2 promoted mTOR activity .	Activation of PI3K and AKT, involved in the phosphorylation of TSC1 and TSC2 promoted mTOR activity.	9	16	promoted	Positive_activation_token_1_verb	Negative_activation	Positive_activation	TSC2	phosphorylation of TSC1 and TSC2	tsc2	mTOR	mTOR	mtor	13	14	15	16
Likewise , phosphorylation of TSC2 by the MAP kinase regulated protein , MK2 , reportedly inhibits TSC2 and leads to activation of mTOR [ XREF_BIBR ] .	Likewise, phosphorylation of TSC2 by the MAP kinase regulated protein, MK2, reportedly inhibits TSC2 and leads to activation of mTOR [XREF_BIBR].	2	24	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	4	5	22	23
Activation of AMPK , a target of several glucose lowering agents used in diabetes treatment , including metformin and the thiazolidenediones , stimulates insulin action in peripheral tissues , acting to phosphorylate and stimulate the TSC1 : TSC2 complex , which subsequently inactivates mammalian target of rapamycin and regulatory associated protein of mTOR ( mTOR and Raptor ) .	Activation of AMPK, a target of several glucose lowering agents used in diabetes treatment, including metformin and the thiazolidenediones, stimulates insulin action in peripheral tissues, acting to phosphorylate and stimulate the TSC1 : TSC2 complex, which subsequently inactivates mammalian target of rapamycin and regulatory associated protein of mTOR (mTOR and Raptor).	31	47	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylate and stimulate the TSC1 : TSC2	tsc2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	37	38	43	47
However , because hamartin and tuberin mediate signal transduction from PKB to mTOR , which is required for phosphorylation and synaptic trafficking of GluR1 containing AMPA-Rs , synaptic and spine plasticity , and associative learning , it is possible that mutations of TSC1 and TSC2 cause learning impairment by stimulating abnormally high PKB -- mTOR signaling .	However, because hamartin and tuberin mediate signal transduction from PKB to mTOR, which is required for phosphorylation and synaptic trafficking of GluR1 containing AMPA-Rs, synaptic and spine plasticity, and associative learning, it is possible that mutations of TSC1 and TSC2 cause learning impairment by stimulating abnormally high PKB -- mTOR signaling.	40	55	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	44	45	54	55
Interestingly , TSC1 or TSC2 removal constitutively activates rapamycin sensitive functions of mTOR independently of Akt .	Interestingly, TSC1 or TSC2 removal constitutively activates rapamycin sensitive functions of mTOR independently of Akt.	2	15	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	4	5	12	13
In the abundance of growth factors activation of the PI3K ( phosphatidylinositol 3-kinase ) activates and phosphorylates AKT , that in turn leads to the downstream phosphorylation of TSC2 and inhibits its GAP activity towards RHEB , allowing RHEB to activate mTOR [ XREF_BIBR , XREF_BIBR ] .	In the abundance of growth factors activation of the PI3K (phosphatidylinositol 3-kinase) activates and phosphorylates AKT, that in turn leads to the downstream phosphorylation of TSC2 and inhibits its GAP activity towards RHEB, allowing RHEB to activate mTOR [XREF_BIBR, XREF_BIBR].	9	45	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	PI3K (phosphatidylinositol 3-kinase) activates and phosphorylates AKT, that in turn leads to the downstream phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	28	29	41	42
Akt phosphorylates TSC2 to disrupt its complex with TSC1 and thus activates mTOR .	Akt phosphorylates TSC2 to disrupt its complex with TSC1 and thus activates mTOR.	0	13	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Akt phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	2	3	12	13
Akt can activate mTOR by phosphorylating and inactivating the tumor suppressor protein tubersclerosis complex 2 ( TSC2 ) , which negatively regulates mTOR activity .	Akt can activate mTOR by phosphorylating and inactivating the tumor suppressor protein tubersclerosis complex 2 (TSC2), which negatively regulates mTOR activity.	0	23	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Akt can activate mTOR by phosphorylating and inactivating the tumor suppressor protein tubersclerosis complex 2 (TSC2	tsc2	mTOR	mTOR	mtor	16	17	22	23
Subsequently , some cases of autism were found to be caused by mutations in PTEN , TSC2 and NF1 , three proteins with a shared function to repress the mammalian target of rapamycin ( mTOR ) pathway that is important for activity dependent initiation of new translation [ XREF_BIBR ] .	Subsequently, some cases of autism were found to be caused by mutations in PTEN, TSC2 and NF1, three proteins with a shared function to repress the mammalian target of rapamycin (mTOR) pathway that is important for activity dependent initiation of new translation [XREF_BIBR].	10	33	caused	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	16	17	29	33
This was observed to occur via enhanced expression of regulated in development and DNA damage response protein 1 ( REDD1 ) and its downstream target , TSC2 , which inhibits mTOR activity .	This was observed to occur via enhanced expression of regulated in development and DNA damage response protein 1 (REDD1) and its downstream target, TSC2, which inhibits mTOR activity.	24	31	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	26	27	30	31
To determine if tuberin phosphorylation activates mTOR in tumor kidney tissue , phospho S6k expression was measured in kidney tissue homogenates of normal and tumor tissue from patients with TSC by western blot .	To determine if tuberin phosphorylation activates mTOR in tumor kidney tissue, phospho S6k expression was measured in kidney tissue homogenates of normal and tumor tissue from patients with TSC by western blot.	3	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin phosphorylation	tuberin	mTOR	mTOR	mtor	3	4	6	7
Indeed , loss-of-function mutations in TSC2 have been shown to reduce mTOR and s6k activity XREF_BIBR .	Indeed, loss-of-function mutations in TSC2 have been shown to reduce mTOR and s6k activity XREF_BIBR.	3	15	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	5	6	11	12
This conversion from PIP3 to PIP2 negates the activity of PI3K and results in elevation of mTOR since the processes downstream -- Akt activation , Akt mediated phosphorylation and inhibition of TSC2 , release inhibition of Rheb which activates mTOR .	This conversion from PIP3 to PIP2 negates the activity of PI3K and results in elevation of mTOR since the processes downstream -- Akt activation, Akt mediated phosphorylation and inhibition of TSC2, release inhibition of Rheb which activates mTOR.	22	40	activates	Positive_activation_syntax_5_verb	Negative_activation	Negative_activation	TSC2	Akt activation, Akt mediated phosphorylation and inhibition of TSC2	tsc2	mTOR	mTOR	mtor	31	32	39	40
Another target enzyme is tuberous sclerosis protein 2 ( TSC2 ) , which when phosphorylated , releases the protein Rheb to interact with and activate the mTOR kinase .	Another target enzyme is tuberous sclerosis protein 2 (TSC2), which when phosphorylated, releases the protein Rheb to interact with and activate the mTOR kinase.	2	27	activate	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	9	10	26	27
In addition , deletion of TSC2 , inhibits mTOR , and suppresses the inflammatory response following lipopolysaccharide ( LPS ) - or bacteria induced inflammation [ XREF_BIBR , XREF_BIBR , XREF_BIBR ] .	In addition, deletion of TSC2, inhibits mTOR, and suppresses the inflammatory response following lipopolysaccharide (LPS) - or bacteria induced inflammation [XREF_BIBR, XREF_BIBR, XREF_BIBR].	3	9	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	5	6	8	9
mTORC1 , the rapamycin sensitive complex , can be activated indirectly through Akt via phosphorylation of the tuberous sclerosis complex protein 2 ( TSC2 ) , which prevents mTOR inhibition .	mTORC1, the rapamycin sensitive complex, can be activated indirectly through Akt via phosphorylation of the tuberous sclerosis complex protein 2 (TSC2), which prevents mTOR inhibition.	14	29	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	phosphorylation of the tuberous sclerosis complex protein 2 (TSC2	tsc2	mTOR	mTOR	mtor	23	24	28	29
These results may be generalizable and applicable to humans because TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling [ XREF_BIBR ] .	These results may be generalizable and applicable to humans because TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling [XREF_BIBR].	10	20	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2 is phosphorylated	tsc2	mTOR	mTOR	mtor	10	11	19	20
ERK dependent phosphorylation on serine 664 of TSC2 leads to TSC1-TSC2 dissociation and impairment of TSC2 ability to inhibit mTOR signaling , suggesting that the Ras and MAPK pathway upstream of the TSC complex and that ERK may modulate mTOR signaling pathway and contribute to disease progression through phosphorylation and inactivation of TSC2 [ XREF_BIBR ] .	ERK dependent phosphorylation on serine 664 of TSC2 leads to TSC1-TSC2 dissociation and impairment of TSC2 ability to inhibit mTOR signaling, suggesting that the Ras and MAPK pathway upstream of the TSC complex and that ERK may modulate mTOR signaling pathway and contribute to disease progression through phosphorylation and inactivation of TSC2 [XREF_BIBR].	2	20	leads	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation on serine 664 of TSC2	tsc2	mTOR	mTOR	mtor	7	8	19	20
Growth factor signaling mediated by PI3K through AKT , TSC1 and TSC2 activates mTOR .	Growth factor signaling mediated by PI3K through AKT, TSC1 and TSC2 activates mTOR.	3	14	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	11	12	13	14
The heterodimer of hamartin ( encoded by TSC1 ) and tuberin ( TSC2 ) suppress the mammalian target of rapamycin ( mTOR ) , a major regulator of cell cycle progression , cell growth , and proliferation XREF_BIBR , XREF_BIBR .	The heterodimer of hamartin (encoded by TSC1) and tuberin (TSC2) suppress the mammalian target of rapamycin (mTOR), a major regulator of cell cycle progression, cell growth, and proliferation XREF_BIBR, XREF_BIBR.	1	20	suppress	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	10	11	16	20
On the other hand , deficiency in tuberin leads to activate of mTOR through upregulate its 2 downstream effectors : S6K ( p70S6K ) and 4EBP1 ( eukaryotic initiation factor 4E binding protein 1 ) , which are required for biosynthesis of the cellular translational apparatus , a critical component for cell growth .	On the other hand, deficiency in tuberin leads to activate of mTOR through upregulate its 2 downstream effectors : S6K (p70S6K) and 4EBP1 (eukaryotic initiation factor 4E binding protein 1), which are required for biosynthesis of the cellular translational apparatus, a critical component for cell growth.	5	13	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	7	8	12	13
The gene products of TSC1 and TSC2 , also known as hamartin and tuberin , respectively , form a physical and functional complex and inhibit the mammalian target of rapamycin complex 1 ( mTORC1 ) signaling .	The gene products of TSC1 and TSC2, also known as hamartin and tuberin, respectively, form a physical and functional complex and inhibit the mammalian target of rapamycin complex 1 (mTORC1) signaling.	2	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	6	7	26	30
Akt phosphorylated by PI-3K at Ser 473 phosphorylates and inactivates TSC2 and leads to the activation of mTOR [ XREF_BIBR ] .	Akt phosphorylated by PI-3K at Ser 473 phosphorylates and inactivates TSC2 and leads to the activation of mTOR [XREF_BIBR].	0	19	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	Akt phosphorylated by PI-3K at Ser 473 phosphorylates and inactivates TSC2	tsc2	mTOR	mTOR	mtor	10	11	17	18
TSC2 reduces cell growth by inhibiting mTOR as the GTPase activating protein for RHEB ( Ras homolog enriched in brain ) .	TSC2 reduces cell growth by inhibiting mTOR as the GTPase activating protein for RHEB (Ras homolog enriched in brain).	0	7	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	0	1	6	7
Because the product of the TSC2 and Tsc2 gene ( tuberin ) together with hamartin , the product of another TSC gene ( TSC1 and Tsc1 ) , suppresses mammalian and mechanistic target of rapamycin complex 1 ( mTORC1 ) , rapalogs have been used as therapeutic drugs for TSC .	Because the product of the TSC2 and Tsc2 gene (tuberin) together with hamartin, the product of another TSC gene (TSC1 and Tsc1), suppresses mammalian and mechanistic target of rapamycin complex 1 (mTORC1), rapalogs have been used as therapeutic drugs for TSC.	5	35	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	5	6	31	35
In contrast , we found that while Tsc2 heterozygosity unmasks Pten haploinsufficiency in growth and tumor suppression , tumorigenesis in Tsc2 +/- mutants is surprisingly not accelerated by Pten heterozygosity , even though mTOR activation is cooperatively enhanced by compound Pten and Tsc2 heterozygosity .	In contrast, we found that while Tsc2 heterozygosity unmasks Pten haploinsufficiency in growth and tumor suppression, tumorigenesis in Tsc2 +/- mutants is surprisingly not accelerated by Pten heterozygosity, even though mTOR activation is cooperatively enhanced by compound Pten and Tsc2 heterozygosity.	33	43	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	42	43	33	34
These findings provide novel evidence in mouse models that Tsc2 mutations intrinsically cause a more severe neurological phenotype than Tsc1 mutations and suggest that the difference in phenotype may be related to the degree to which Tsc1 and Tsc2 inactivation causes abnormal mTOR activation .	These findings provide novel evidence in mouse models that Tsc2 mutations intrinsically cause a more severe neurological phenotype than Tsc1 mutations and suggest that the difference in phenotype may be related to the degree to which Tsc1 and Tsc2 inactivation causes abnormal mTOR activation.	36	43	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	38	39	42	43
The upstream mTOR regulators PTEN and TSC2 are often mutated , -downregulated or altered in their protein expression level , causing mTOR activation in pancreatic NETs .	The upstream mTOR regulators PTEN and TSC2 are often mutated, -downregulated or altered in their protein expression level, causing mTOR activation in pancreatic NETs.	4	22	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	6	7	21	22
Here we demonstrate that Kaposi ' s sarcomagenesis involves stimulation of tuberin ( TSC2 ) phosphorylation by vGPCR , promoting the activation of mTOR through both direct and paracrine mechanisms .	Here we demonstrate that Kaposi 's sarcomagenesis involves stimulation of tuberin (TSC2) phosphorylation by vGPCR, promoting the activation of mTOR through both direct and paracrine mechanisms.	9	24	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	stimulation of tuberin (TSC2) phosphorylation by vGPCR	tuberin	mTOR	mTOR	mtor	11	12	23	24
The gene products hamartin and tuberin form the TSC complex that acts as GTPase activating protein for Rheb and negatively regulates the mammalian target of rapamycin complex 1 ( mTORC1 ) .	The gene products hamartin and tuberin form the TSC complex that acts as GTPase activating protein for Rheb and negatively regulates the mammalian target of rapamycin complex 1 (mTORC1).	3	26	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	5	6	22	26
Mammalian target of rapamycin ( mTOR ) regulates various cellular functions , including tumorigenesis , and is inhibited by the tuberous sclerosis 1 ( TSC1 ) and TSC2 complex .	Mammalian target of rapamycin (mTOR) regulates various cellular functions, including tumorigenesis, and is inhibited by the tuberous sclerosis 1 (TSC1) and TSC2 complex.	0	28	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Mammalian target of rapamycin	Mammalian target of rapamycin	Mammalian target of rapamycin	27	28	0	4
Metformin activates AMPK indirectly via a suppressor protein , liver kinase B1 ( LKB1 ) , and via the activation of tuberous sclerosis complex 2 ( TSC-2 ) which inhibits the mammalian target of rapamycin ( mTOR ) protein , one of the key proteins in regulating cell division , protein synthesis , growth and angiogenic processes [ XREF_BIBR , XREF_BIBR ] .	Metformin activates AMPK indirectly via a suppressor protein, liver kinase B1 (LKB1), and via the activation of tuberous sclerosis complex 2 (TSC-2) which inhibits the mammalian target of rapamycin (mTOR) protein, one of the key proteins in regulating cell division, protein synthesis, growth and angiogenic processes [XREF_BIBR, XREF_BIBR].	19	35	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC-2	TSC-2	TSC-2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	26	27	31	35
P-AKT subsequently phosphorylates TSC2 and finally leads to activation of the mTOR pathway .	P-AKT subsequently phosphorylates TSC2 and finally leads to activation of the mTOR pathway.	0	12	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	P-AKT subsequently phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	3	4	11	12
ERK dependent phosphorylation of tuberin prevents its association with hamartin and the inhibition of Rheb and mTOR by the tuberin and hamartin complex .	ERK dependent phosphorylation of tuberin prevents its association with hamartin and the inhibition of Rheb and mTOR by the tuberin and hamartin complex.	0	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	ERK dependent phosphorylation of tuberin	tuberin	mTOR	mTOR	mtor	4	5	16	17
Phosphorylation of TSC2 by Erk on Ser664 results in dissociation of the TSC2 : TSC1 complex , leading to diminished inhibition of mTOR and hindering the ability of TSC2 to inhibit cell proliferation and oncogenic transformation .	Phosphorylation of TSC2 by Erk on Ser664 results in dissociation of the TSC2 : TSC1 complex, leading to diminished inhibition of mTOR and hindering the ability of TSC2 to inhibit cell proliferation and oncogenic transformation.	9	23	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	12	13	22	23
AKT can directly phosphorylate mTOR at ser 2448 and activate it , as well as cause indirect activation of mTOR by phosphorylating and inactivating TSC2 ( tuberous sclerosis complex 2 , also called tuberin ) .	AKT can directly phosphorylate mTOR at ser 2448 and activate it, as well as cause indirect activation of mTOR by phosphorylating and inactivating TSC2 (tuberous sclerosis complex 2, also called tuberin).	17	28	activation	Positive_activation_token_2_noun	Negative_activation	Positive_activation	TSC2	phosphorylating and inactivating TSC2	tsc2	mTOR	mTOR	mtor	24	25	19	20
AKT phosphorylates TSC2 to inhibit its tumor suppressor function and activate mTOR signaling .	AKT phosphorylates TSC2 to inhibit its tumor suppressor function and activate mTOR signaling.	0	12	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	AKT phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	2	3	11	12
Phosphorylation of TSC2 following insulin or IGF1 receptor mediated activation of the MAP and PI3K kinase pathways promotes dissociation of the TSC complex and stimulates mTOR signaling resulting in the phosphorylation of S6K and changes in gene transcription .	Phosphorylation of TSC2 following insulin or IGF1 receptor mediated activation of the MAP and PI3K kinase pathways promotes dissociation of the TSC complex and stimulates mTOR signaling resulting in the phosphorylation of S6K and changes in gene transcription.	0	26	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	2	3	25	26
The simple model that best fits the data is that unregulated mTOR activity caused by the Tsc2 +/- mutation suppresses the protein synthesis that is required for mGluR-LTD ( XREF_FIG ) .	The simple model that best fits the data is that unregulated mTOR activity caused by the Tsc2 +/- mutation suppresses the protein synthesis that is required for mGluR-LTD (XREF_FIG).	11	18	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	16	17	11	12
Similarly , loss of TSC2 , which inhibits mTOR , an effector of the PI3K and AKT pathway , often results in macrocephaly associated with ASD , ID and seizures .	Similarly, loss of TSC2, which inhibits mTOR, an effector of the PI3K and AKT pathway, often results in macrocephaly associated with ASD, ID and seizures.	2	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	loss of TSC2	tsc2	mTOR	mTOR	mtor	4	5	8	9
This tuberin mediated decrease in Rheb-GTP levels inactivates mTOR signaling , leading to inactivation of ribosomal protein S6 kinase ( S6K ) and 4E-BP1 , resulting in decreased protein synthesis and cell growth .	This tuberin mediated decrease in Rheb-GTP levels inactivates mTOR signaling, leading to inactivation of ribosomal protein S6 kinase (S6K) and 4E-BP1, resulting in decreased protein synthesis and cell growth.	0	9	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	1	2	8	9
Increased phosphorylation of TSC2 is thought to activate mTOR in part through raising the phosphorylation state of mTOR in transformed cells in culture .	Increased phosphorylation of TSC2 is thought to activate mTOR in part through raising the phosphorylation state of mTOR in transformed cells in culture.	1	10	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	3	4	8	9
Some studies have suggested that TSC2 also mediates the control of mTOR by amino acids .	Some studies have suggested that TSC2 also mediates the control of mTOR by amino acids.	5	12	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	5	6	11	12
These protein kinases regulate initiation of translation by phosphorylating and inactivating TSC2 , a tumour suppressor that in a complex with TSC1 inhibits the mTOR protein kinase .	These protein kinases regulate initiation of translation by phosphorylating and inactivating TSC2, a tumour suppressor that in a complex with TSC1 inhibits the mTOR protein kinase.	8	26	inhibits	Negative_activation_syntax_5_verb	Negative_activation	Positive_activation	TSC2	phosphorylating and inactivating TSC2	tsc2	mTOR	mTOR	mtor	11	12	24	25
AKT activation suppresses TSC1 and TSC2 , which indirectly activates mTOR kinase activity through the GTP binding protein Ras homolog enriched in brain ( Rheb ) .	AKT activation suppresses TSC1 and TSC2, which indirectly activates mTOR kinase activity through the GTP binding protein Ras homolog enriched in brain (Rheb).	2	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	5	6	10	11
These TSC1 and TSC2 loss of function mutations activate mammalian target of rapamycin ( mTOR ) protein kinases , which promote both cell proliferation and survival , have been implicated in various types of cancer [ XREF_BIBR ] .	These TSC1 and TSC2 loss of function mutations activate mammalian target of rapamycin (mTOR) protein kinases, which promote both cell proliferation and survival, have been implicated in various types of cancer [XREF_BIBR].	1	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	3	4	9	13
AMPK can inhibit activity of mTOR complex ( mTORC1 ) either by directly phosphorylating Raptor , a regulatory component of mTORC1 , or by phosphorylating tuberous sclerosis protein 2 ( TSC2 ) , which subsequently suppresses mTOR activity 71 .	AMPK can inhibit activity of mTOR complex (mTORC1) either by directly phosphorylating Raptor, a regulatory component of mTORC1, or by phosphorylating tuberous sclerosis protein 2 (TSC2), which subsequently suppresses mTOR activity 71.	24	37	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylating tuberous sclerosis protein 2 (TSC2	tsc2	mTOR	mTOR	mtor	30	31	36	37
Although Akt has many substrates within the cell , phosphorylation of two substrates , TSC2 and PRAS40 , leads to activation of mTOR .	Although Akt has many substrates within the cell, phosphorylation of two substrates, TSC2 and PRAS40, leads to activation of mTOR.	9	23	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC2	phosphorylation of two substrates, TSC2	tsc2	mTOR	mTOR	mtor	14	15	22	23
Downregulation of TSC2 promotes the activation of RheB and mTOR and S6K1 .	Downregulation of TSC2 promotes the activation of RheB and mTOR and S6K1.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	9	10
A concerted anabolic signal is generated by leucine which facilitates the translocation of the kinase mTOR to the surface of the lysosome , where it is activated by Rheb , and by IGF-I which relieves the inherent inhibition of mTOR by TSC2 .	A concerted anabolic signal is generated by leucine which facilitates the translocation of the kinase mTOR to the surface of the lysosome, where it is activated by Rheb, and by IGF-I which relieves the inherent inhibition of mTOR by TSC2.	34	42	inhibition	Negative_activation_token_2_noun	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	41	42	39	40
Furthermore , Pam knockdown by RNA interference ( RNAi ) in rat primary neurons elevates the level of tuberin , and subsequently inhibits the mTOR pathway .	Furthermore, Pam knockdown by RNA interference (RNAi) in rat primary neurons elevates the level of tuberin, and subsequently inhibits the mTOR pathway.	2	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	Pam knockdown by RNA interference (RNAi) in rat primary neurons elevates the level of tuberin	tuberin	mTOR	mTOR	mtor	18	19	24	25
In unstimulated cells , TSC2 heterodimerizes with TS1 and causes mTOR inactivation .	In unstimulated cells, TSC2 heterodimerizes with TS1 and causes mTOR inactivation.	4	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	4	5	10	11
The protein products of these genes function as negative effectors of the mTOR and raptor complex ( mTORC ) ; thus , mutations in TSC1 and TSC2 , NF1 or PTEN activate mTOR signaling .	The protein products of these genes function as negative effectors of the mTOR and raptor complex (mTORC); thus, mutations in TSC1 and TSC2, NF1 or PTEN activate mTOR signaling.	22	33	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	26	27	32	33
Inhibition of mTOR through rapamycin treatment caused the monocytes to differentiate toward a M1 phenotype , whereas activation of mTOR by RNA interference mediated knockdown of the mTOR repressor TSC2 induced the differentiation of monocytes toward a M2 macrophage phenotype [ XREF_BIBR ] .	Inhibition of mTOR through rapamycin treatment caused the monocytes to differentiate toward a M1 phenotype, whereas activation of mTOR by RNA interference mediated knockdown of the mTOR repressor TSC2 induced the differentiation of monocytes toward a M2 macrophage phenotype [XREF_BIBR].	24	30	repressor	Negative_activation_token_1_noun	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	29	30	27	28
These data indicate that tuberin deficiency in angiomyolipoma enhances mTOR activation by phosphorylation of S6K and downregulation of protein and mRNA expression of OGG1 resulted in accumulation of oxidized DNA in patients with TSC .	These data indicate that tuberin deficiency in angiomyolipoma enhances mTOR activation by phosphorylation of S6K and downregulation of protein and mRNA expression of OGG1 resulted in accumulation of oxidized DNA in patients with TSC.	4	10	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	4	5	9	10
AMPK phosphorylates the tumor suppressor TSC2 and the mTORC1 partner RAPTOR to inhibit mTOR ( XREF_FIG ) [ XREF_BIBR - XREF_BIBR ] .	AMPK phosphorylates the tumor suppressor TSC2 and the mTORC1 partner RAPTOR to inhibit mTOR (XREF_FIG) [XREF_BIBR - XREF_BIBR].	0	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK phosphorylates the tumor suppressor TSC2	tsc2	mTOR	mTOR	mtor	5	6	13	14
TSC2 inhibits mammalian target of rapamycin complex 1 ( mTORC1 ) , a protein complex essential for protein translation and cell growth .	TSC2 inhibits mammalian target of rapamycin complex 1 (mTORC1), a protein complex essential for protein translation and cell growth.	0	6	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	2	6
In this study , we provide some genetic evidence to show that the tumor suppressor tuberous sclerosis complex 2 ( Tsc2 ) , which negatively regulates mammalian target of rapamycin complex 1 ( mTORC1 ) , functions in oocytes to maintain the dormancy of primordial follicles .	In this study, we provide some genetic evidence to show that the tumor suppressor tuberous sclerosis complex 2 (Tsc2), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the dormancy of primordial follicles.	10	33	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc2	Tsc2	Tsc2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	20	21	26	30
Despite the TGFbeta modulation of protein synthesis via mTOR not having previously been reported , this model is consistent with a previous report that ERK signaling is implicated in translational control upstream of mTOR via phosphorylation of TSC2 enabling mTOR signaling , and with the observation that another cytokine , Cyr61 , upregulates hypoxia inducing factor-1alpha protein in gastric cancer cells via mTOR dependent stimulation of de novo protein synthesis .	Despite the TGFbeta modulation of protein synthesis via mTOR not having previously been reported, this model is consistent with a previous report that ERK signaling is implicated in translational control upstream of mTOR via phosphorylation of TSC2 enabling mTOR signaling, and with the observation that another cytokine, Cyr61, upregulates hypoxia inducing factor-1alpha protein in gastric cancer cells via mTOR dependent stimulation of de novo protein synthesis.	35	40	enabling	Positive_activation_token_1_verb	Negative_activation	Positive_activation	TSC2	phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	37	38	39	40
Through the small G protein Rheb , the TSC proteins , hamartin and tuberin , negatively regulate mammalian target of rapamycin complex 1 ( mTORC1 ) signaling .	Through the small G protein Rheb, the TSC proteins, hamartin and tuberin, negatively regulate mammalian target of rapamycin complex 1 (mTORC1) signaling.	9	21	negatively regulate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	13	14	17	21
Inactivation of TSC2 results in activation of mTOR via the Ras related small GTPase ( Rheb ) .	Inactivation of TSC2 results in activation of mTOR via the Ras related small GTPase (Rheb).	0	13	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	7	8
Phosphorylation of TSC2 and TSC1 results in the disruption of the TSC1/2 complex , and thereby activates the oncogenic mTOR signaling contributing to tumor progression .	Phosphorylation of TSC2 and TSC1 results in the disruption of the TSC1/2 complex, and thereby activates the oncogenic mTOR signaling contributing to tumor progression.	0	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	2	3	19	20
Tuberin deficient cells derived from TSC tumors have increased mTOR activity and are sensitive to apoptosis .	Tuberin deficient cells derived from TSC tumors have increased mTOR activity and are sensitive to apoptosis.	0	10	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tuberin	Tuberin	Tuberin	mTOR	mTOR	mTOR	0	1	9	10
In contrast , AKT in the PI3K pathway opposes AMPK ' s inhibitory effects on the mTOR pathway , both through inhibition of AMPK and TSC2 and direct activation of mTOR itself ( XREF_FIG ) .	In contrast, AKT in the PI3K pathway opposes AMPK 's inhibitory effects on the mTOR pathway, both through inhibition of AMPK and TSC2 and direct activation of mTOR itself (XREF_FIG).	25	33	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	25	26	30	31
The mTOR is activated by functional inactivation of tuberin after its phosphorylation by Akt 16 , 17 .	The mTOR is activated by functional inactivation of tuberin after its phosphorylation by Akt 16, 17.	0	9	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	8	9	1	2
It is known that the Tsc2 -/- tumors in this mouse model have constitutively activated mTOR kinase [ XREF_BIBR ] , and a similar defect in mTOR signaling is observed in brain and kidney tumors associated with TSC [ XREF_BIBR , XREF_BIBR ] .	It is known that the Tsc2 -/- tumors in this mouse model have constitutively activated mTOR kinase [XREF_BIBR], and a similar defect in mTOR signaling is observed in brain and kidney tumors associated with TSC [XREF_BIBR, XREF_BIBR].	5	16	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	5	6	15	16
TSC2 protein complexes with TSC1 and blocks the ability of the Rheb ( Ras homolog enriched in brain ) GTPase to activate mTOR ( mammalian target of rapamycin ) , a crucial signal transducer which regulates protein synthesis and cell growth .	TSC2 protein complexes with TSC1 and blocks the ability of the Rheb (Ras homolog enriched in brain) GTPase to activate mTOR (mammalian target of rapamycin), a crucial signal transducer which regulates protein synthesis and cell growth.	0	28	activate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	24	28
Data in Figure XREF_FIG A & B showed significant decreased in tuberin expression was associated with increased in mTOR activity that measured by phosphorylation of p70S6K at Thr 389 confirming that deficiency in of tuberin activates mTOR in kidney of TSC patients .	Data in Figure XREF_FIG A & B showed significant decreased in tuberin expression was associated with increased in mTOR activity that measured by phosphorylation of p70S6K at Thr 389 confirming that deficiency in of tuberin activates mTOR in kidney of TSC patients.	31	37	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	34	35	36	37
Downregulation of TSC2 ( tuberous sclerosis 2 ) by EZH2 elicited MTOR activation , which in turn modulated subsequent MTOR pathway related events , including inhibition of autophagy .	Downregulation of TSC2 (tuberous sclerosis 2) by EZH2 elicited MTOR activation, which in turn modulated subsequent MTOR pathway related events, including inhibition of autophagy.	0	12	elicited	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	MTOR	MTOR	MTOR	2	3	11	12
Activation of canonical survival pathways by AKT1 induced by loss of GUCY2C was reflected by increased downstream TSC1 and TSC2 degradation following TSC2 phosphorylation , which , in turn , increased mTOR signaling , a key integrator coordinating proliferative and metabolic signals required for cell growth and survival ( XREF_FIG , green ) .	Activation of canonical survival pathways by AKT1 induced by loss of GUCY2C was reflected by increased downstream TSC1 and TSC2 degradation following TSC2 phosphorylation, which, in turn, increased mTOR signaling, a key integrator coordinating proliferative and metabolic signals required for cell growth and survival (XREF_FIG, green).	22	32	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2 phosphorylation	tsc2	mTOR	mTOR	mtor	22	23	31	32
Loss of Tsc2 blocks mTOR inactivation by EphA receptors .	Loss of Tsc2 blocks mTOR inactivation by EphA receptors.	0	5	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc2	Loss of Tsc2	tsc2	mTOR	mTOR	mtor	2	3	4	5
One of the downstream targets of AMPK is the tumour-suppressor protein TSC2 that inhibits mTOR .	One of the downstream targets of AMPK is the tumour-suppressor protein TSC2 that inhibits mTOR.	4	15	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	11	12	14	15
Phosphorylation of TSC2 by ERK promoted dissociation of the tuberous sclerosis complex and attenuated TSC2 mediated inhibition of mTOR in cells .	Phosphorylation of TSC2 by ERK promoted dissociation of the tuberous sclerosis complex and attenuated TSC2 mediated inhibition of mTOR in cells.	14	19	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	14	15	18	19
Mutations in TSC1 and TSC2 , NF1 , or PTEN activate the mTOR and PI3K pathway and lead to syndromic ASD with tuberous sclerosis , neurofibromatosis , or macrocephaly .	Mutations in TSC1 and TSC2, NF1, or PTEN activate the mTOR and PI3K pathway and lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly.	0	15	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	4	5	12	13
In the presence of growth factors such as insulin or insulin like growth factors , stimulated Akt and extracellular signal regulated protein kinases 1 and 2 ( ERK1/2 ) can phosphorylate and disrupt the tuberous sclerosis complex 1/2 ( TSC1 and TSC2 ) , which activates mTOR inhibition and thus inhibiting autophagy [ XREF_BIBR ] .	In the presence of growth factors such as insulin or insulin like growth factors, stimulated Akt and extracellular signal regulated protein kinases 1 and 2 (ERK1/2) can phosphorylate and disrupt the tuberous sclerosis complex 1/2 (TSC1 and TSC2), which activates mTOR inhibition and thus inhibiting autophagy [XREF_BIBR].	18	47	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	extracellular signal regulated protein kinases 1 and 2 (ERK1/2) can phosphorylate and disrupt the tuberous sclerosis complex 1/2 (TSC1 and TSC2	tsc2	mTOR	mTOR	mtor	41	42	46	47
To test the effect of the high-fat diet and aerobic exercise on total TSC2 protein expression , which inhibits the mammalian target of rapamycin ( mTOR ) and p70S6K , we performed immunohistochemical staining .	To test the effect of the high-fat diet and aerobic exercise on total TSC2 protein expression, which inhibits the mammalian target of rapamycin (mTOR) and p70S6K, we performed immunohistochemical staining.	13	24	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2 protein expression	tsc2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	13	14	20	24
Once activated , AKT mediated phosphorylation of TSC2 ( tuberous sclerosis complex 2 ) inhibits the TSC1 and TSC2 complex function , and thus activates mTOR signaling .	Once activated, AKT mediated phosphorylation of TSC2 (tuberous sclerosis complex 2) inhibits the TSC1 and TSC2 complex function, and thus activates mTOR signaling.	3	26	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	AKT mediated phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	7	8	25	26
Here we further show that mTOR inhibition is required for gerosuppression by hypoxia , at least in some cellular models , because depletion of TSC2 abolished mTOR inhibition and gerosupression by hypoxia .	Here we further show that mTOR inhibition is required for gerosuppression by hypoxia, at least in some cellular models, because depletion of TSC2 abolished mTOR inhibition and gerosupression by hypoxia.	22	27	abolished	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	24	25	26	27
In TSC2 +/- hearts , the phosphorylation level of S6K was increased ( XREF_FIG ) compared with that in WT mouse hearts , indicating that mTOR activity was stimulated by down-regulation of TSC2 .	In TSC2 +/- hearts, the phosphorylation level of S6K was increased (XREF_FIG) compared with that in WT mouse hearts, indicating that mTOR activity was stimulated by down-regulation of TSC2.	25	33	stimulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	32	33	25	26
AKT phosphorylation of TSC2 at Ser 939 and Thr 1462 activates mTOR through additional signaling molecules .	AKT phosphorylation of TSC2 at Ser 939 and Thr 1462 activates mTOR through additional signaling molecules.	0	12	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	AKT phosphorylation of TSC2 at Ser 939 and Thr 1462	tsc2	mTOR	mTOR	mtor	3	4	11	12
Activated Akt subsequently phosphorylates numerous substrates that promote tumorigenesis , including tuberous sclerosis complex 2 ( TSC2 ) , which in turn activates mTOR complex 1 ( mTORC1 ) .	Activated Akt subsequently phosphorylates numerous substrates that promote tumorigenesis, including tuberous sclerosis complex 2 (TSC2), which in turn activates mTOR complex 1 (mTORC1).	0	24	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	16	17	23	24
Phosphorylation of TSC2 by Akt inactivates the TSC tumor suppressor and relieves repression of mTOR .	Phosphorylation of TSC2 by Akt inactivates the TSC tumor suppressor and relieves repression of mTOR.	0	15	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	2	3	14	15
mTOR function can be decreased by three mechanisms : 1 ) TSC2 phosphorylation by AMPK deactivates Rheb GTPase and , consequently , inhibits TORC1 ; 2 ) inhibition of Raptor and RPTOR , a component of TORC1 , results in TORC1 recruitment to 14-3-3 proteins , and 3 ) amino acid starvation can decrease mTOR activity through Rag GTPases .	mTOR function can be decreased by three mechanisms : 1) TSC2 phosphorylation by AMPK deactivates Rheb GTPase and, consequently, inhibits TORC1; 2) inhibition of Raptor and RPTOR, a component of TORC1, results in TORC1 recruitment to 14-3-3 proteins, and 3) amino acid starvation can decrease mTOR activity through Rag GTPases.	11	55	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2 phosphorylation	tsc2	mTOR	mTOR	mtor	11	12	54	55
The PI3K and AKT pathway regulates many cellular functions through a wide range of downstream targets , including the tuberous sclerosis complex 2 ( TSC2 ) , which negatively regulates the mammalian target of rapamycin ( mTOR ) .	The PI3K and AKT pathway regulates many cellular functions through a wide range of downstream targets, including the tuberous sclerosis complex 2 (TSC2), which negatively regulates the mammalian target of rapamycin (mTOR).	12	35	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	24	25	31	35
mTOR was activated in these cells by a knockdown of its negative regulator TSC2 ( XREF_SUPPLEMENTARY ) .	mTOR was activated in these cells by a knockdown of its negative regulator TSC2 (XREF_SUPPLEMENTARY).	0	15	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	13	14	0	1
However , PEX5 depletion with siRNA significantly decreased the starvation induced expression of TSC2 mRNA , which in turn upregulated mTOR activity .	However, PEX5 depletion with siRNA significantly decreased the starvation induced expression of TSC2 mRNA, which in turn upregulated mTOR activity.	11	21	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	expression of TSC2	tsc2	mTOR	mTOR	mtor	13	14	20	21
Loss of tuberin , the product of TSC2 gene , increases mammalian target of rapamycin ( mTOR ) signaling , promoting cell growth and tumor development .	Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development.	0	15	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	Loss of tuberin	tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	2	3	11	15
GSK-3beta activates TSC2 and consequently further suppresses mTOR , whereas Akt inhibits TSC2 thus decreasing TSC2 suppression of mTOR .	GSK-3beta activates TSC2 and consequently further suppresses mTOR, whereas Akt inhibits TSC2 thus decreasing TSC2 suppression of mTOR.	11	19	decreasing	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	12	13	18	19
TSC2 deficiency induces constitutive activation of mTOR , leading to a state of insulin resistance due to a negative feedback regulation , resulting in reduced Akt phosphorylation .	TSC2 deficiency induces constitutive activation of mTOR, leading to a state of insulin resistance due to a negative feedback regulation, resulting in reduced Akt phosphorylation.	0	7	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	0	1	6	7
Although mutations in either TSC1 or TSC2 are sufficient to cause dysregulation of mTOR , patients with TSC2 mutations often manifest more severe disease than those with TSC1 mutations , suggesting that there are additional functions of tuberin that are currently unknown .	Although mutations in either TSC1 or TSC2 are sufficient to cause dysregulation of mTOR, patients with TSC2 mutations often manifest more severe disease than those with TSC1 mutations, suggesting that there are additional functions of tuberin that are currently unknown.	1	14	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	6	7	13	14
As a GTP activating protein ( GAP ) , TSC2 or tuberin inactivates Ras homologue enriched in brain ( Rheb ) which can directly bind to and activate mTOR .	As a GTP activating protein (GAP), TSC2 or tuberin inactivates Ras homologue enriched in brain (Rheb) which can directly bind to and activate mTOR.	9	29	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	mTOR	mTOR	mTOR	11	12	28	29
The 2 TSC proteins , hamartin and tuberin , antagonize the mammalian target of rapamycin ( mTOR ) signaling pathway , thus regulating cell growth and proliferation .	The 2 TSC proteins, hamartin and tuberin, antagonize the mammalian target of rapamycin (mTOR) signaling pathway, thus regulating cell growth and proliferation.	3	15	antagonize	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	7	8	11	15
TSC2 contains a GTPase activating protein ( GAP ) domain and acts on the rheb GTPase to inhibit rheb-GTP-dependent stimulation of the mammalian target of rapamycin ( mTOR ) [ XREF_BIBR ] .	TSC2 contains a GTPase activating protein (GAP) domain and acts on the rheb GTPase to inhibit rheb-GTP-dependent stimulation of the mammalian target of rapamycin (mTOR) [XREF_BIBR].	0	26	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	22	26
Mutations in both Tsc1 and Tsc2 cause mTOR hyperactivation and ASD like behaviors in mice .	Mutations in both Tsc1 and Tsc2 cause mTOR hyperactivation and ASD like behaviors in mice.	0	8	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tsc2	Tsc2	Tsc2	mTOR	mTOR	mTOR	5	6	7	8
Akt phosphorylation of Tsc2 induces mTOR signaling by derepressing the Tsc2 GTPase protein activity toward Rheb [ XREF_BIBR ] ( Box 2 and XREF_FIG ) [ XREF_BIBR , XREF_BIBR ] .	Akt phosphorylation of Tsc2 induces mTOR signaling by derepressing the Tsc2 GTPase protein activity toward Rheb [XREF_BIBR] (Box 2 and XREF_FIG) [XREF_BIBR, XREF_BIBR].	0	6	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tsc2	Akt phosphorylation of Tsc2	tsc2	mTOR	mTOR	mtor	3	4	5	6
These results conclusively demonstrate that miR-21-mediated phosphorylation and inactivation of tuberin activates Rheb to increase mTOR activity .	These results conclusively demonstrate that miR-21-mediated phosphorylation and inactivation of tuberin activates Rheb to increase mTOR activity.	6	16	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	phosphorylation and inactivation of tuberin	tuberin	mTOR	mTOR	mtor	10	11	15	16
Tuberous sclerosis complex 1 ( TSC1 ) and TSC2 are suppressors of mechanistic target of rapamycin ( mTOR ) .	Tuberous sclerosis complex 1 (TSC1) and TSC2 are suppressors of mechanistic target of rapamycin (mTOR).	5	16	are suppressors	Negative_activation_copula_1	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	8	9	12	16
In fact , Myc inhibits mTOR repressor TSC2 , thus increasing mTOR activity to facilitate cap dependent translation through S6K and 4E-BP phosphorylation [ XREF_BIBR ] .	In fact, Myc inhibits mTOR repressor TSC2, thus increasing mTOR activity to facilitate cap dependent translation through S6K and 4E-BP phosphorylation [XREF_BIBR].	4	10	repressor	Negative_activation_token_1_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	7	8	5	6
We hypothesized that mutations in PTEN ( a cause of HMEG associated with Proteus syndrome ) , TSC1 or TSC2 ( tuberous sclerosis complex ) genes , which are known to modulate beta-catenin and mTOR signaling could cause sporadic HMEG .	We hypothesized that mutations in PTEN (a cause of HMEG associated with Proteus syndrome), TSC1 or TSC2 (tuberous sclerosis complex) genes, which are known to modulate beta-catenin and mTOR signaling could cause sporadic HMEG.	5	35	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	19	20	34	35
A link between the LKB1-AMPK pathway and disease pathways is the protein tuberin , the product of the tuberous sclerosis complex 2 gene ( TSC2 ) , that represses mammalian target of rapamycin ( mTOR ) activity when phosphorylated by AMPK on S1387 XREF_BIBR .	A link between the LKB1-AMPK pathway and disease pathways is the protein tuberin, the product of the tuberous sclerosis complex 2 gene (TSC2), that represses mammalian target of rapamycin (mTOR) activity when phosphorylated by AMPK on S1387 XREF_BIBR.	1	33	represses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	tuberin	tuberin	tuberin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	12	13	29	33
In TSC , the result of inactivating mutations in TSC1 or TSC2 is to reduce inhibition of the mTOR pathway and therefore hyperactivate downstream targets of mTOR [ XREF_BIBR ] .	In TSC, the result of inactivating mutations in TSC1 or TSC2 is to reduce inhibition of the mTOR pathway and therefore hyperactivate downstream targets of mTOR [XREF_BIBR].	7	19	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	11	12	18	19
Local cap dependent mRNA translation is also controlled by mammalian target of rapamycin ( mTOR ) , which in turn is negatively regulated by the tuberous sclerosis complex proteins TSC1 and TSC2 .	Local cap dependent mRNA translation is also controlled by mammalian target of rapamycin (mTOR), which in turn is negatively regulated by the tuberous sclerosis complex proteins TSC1 and TSC2.	9	32	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	31	32	9	13
Recently , the TSC1 and TSC2 protein complex was shown to inhibit the kinase mTOR ( mammalian target of rapamycin ) .	Recently, the TSC1 and TSC2 protein complex was shown to inhibit the kinase mTOR (mammalian target of rapamycin).	5	20	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	5	6	16	20
Gene products of TSC1 ( hamartin ) and TSC2 ( tuberin ) form a physical and functional complex and inhibit the mammalian target of rapamycin complex 1 signaling and spontaneous mutations seen in 60 %-70% cases .	Gene products of TSC1 (hamartin) and TSC2 (tuberin) form a physical and functional complex and inhibit the mammalian target of rapamycin complex 1 signaling and spontaneous mutations seen in 60%-70% cases.	1	25	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	8	9	21	25
Activation of AMPK , which phosphorylates TSC2 and stimulates its GAP activity and subsequent mTOR inhibition XREF_BIBR is mediated through the products of two p53 target genes , Sestrin 1 and 2 .	Activation of AMPK, which phosphorylates TSC2 and stimulates its GAP activity and subsequent mTOR inhibition XREF_BIBR is mediated through the products of two p53 target genes, Sestrin 1 and 2.	2	16	stimulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	AMPK, which phosphorylates TSC2	tsc2	mTOR	mTOR	mtor	6	7	14	15
This destabilization of the tumor suppressors tsc1 and tsc2 subsequently activates mtor via a small protein called Rheb ( ras homolog enriched in brain ) .	This destabilization of the tumor suppressors tsc1 and tsc2 subsequently activates mtor via a small protein called Rheb (ras homolog enriched in brain).	1	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tsc2	tsc2	tsc2	mtor	mtor	mtor	8	9	11	12
Inhibition of TSC2 by pUL38 dysregulates the mTOR pathway and induces survival signal in infected cells .	Inhibition of TSC2 by pUL38 dysregulates the mTOR pathway and induces survival signal in infected cells.	0	8	dysregulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	2	3	7	8
On the other hand , growth inhibiting signals can activate the AMP activated protein kinase ( AMPK ) that directly phosphorylates and activates TSC1 and TSC2 and therefore causes mTOR inhibition [ XREF_BIBR ] .	On the other hand, growth inhibiting signals can activate the AMP activated protein kinase (AMPK) that directly phosphorylates and activates TSC1 and TSC2 and therefore causes mTOR inhibition [XREF_BIBR].	16	30	causes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	AMPK) that directly phosphorylates and activates TSC1 and TSC2	tsc2	mTOR	mTOR	mtor	25	26	29	30
XREF_BIBR , XREF_BIBR Mutations in TSC1 and TSC2 can also upregulate mTOR and have been associated with renal angiomyolipomas and kidney cancer .	XREF_BIBR, XREF_BIBR Mutations in TSC1 and TSC2 can also upregulate mTOR and have been associated with renal angiomyolipomas and kidney cancer.	3	12	upregulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	mTOR	mTOR	mTOR	7	8	11	12
Phosphorylation of TSC2 is thought to allow TSC1 and TSC2 to disassociate and stimulate mTOR activity .	Phosphorylation of TSC2 is thought to allow TSC1 and TSC2 to disassociate and stimulate mTOR activity.	0	15	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	mTOR	mTOR	mtor	2	3	14	15
Following activation , p53 translocates into the cytosol and triggers the oligomerization of Bcl-2 with BAD , resulting in the inhibition of Bcl-2 activity [ XREF_BIBR ] .	Following activation, p53 translocates into the cytosol and triggers the oligomerization of Bcl-2 with BAD, resulting in the inhibition of Bcl-2 activity [XREF_BIBR].	3	14	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	13	14
Apoptosis induced by SLC5A8 and pyruvate in MCF7 cells is associated with up-regulation of p53 , Bax , tumor necrosis factor related apoptosis inducing ligand ( TRAIL ) , TRAIL receptor ( TRAILR ) 1 , and TRAILR2 and down-regulation of Bcl2 and survivin .	Apoptosis induced by SLC5A8 and pyruvate in MCF7 cells is associated with up-regulation of p53, Bax, tumor necrosis factor related apoptosis inducing ligand (TRAIL), TRAIL receptor (TRAILR) 1, and TRAILR2 and down-regulation of Bcl2 and survivin.	14	43	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	14	15	41	42
To exclude that apoptosis resulted from p53 modulation of anti-apoptotic BCL-2 proteins rather than direct activation of BAX , we inhibited BCL-xL and BCL -2 in serum starved cells with the inhibitor ABT-737 and again observed that Pin1 enabled p53 mediated apoptosis in the presence of CHX ( XREF_SUPPLEMENTARY ) .	To exclude that apoptosis resulted from p53 modulation of anti-apoptotic BCL-2 proteins rather than direct activation of BAX, we inhibited BCL-xL and BCL -2 in serum starved cells with the inhibitor ABT-737 and again observed that Pin1 enabled p53 mediated apoptosis in the presence of CHX (XREF_SUPPLEMENTARY).	6	11	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	6	7	10	11
Although HIF-1 predominantly stimulates survival through various biological processes , proapoptotic signaling may also occur in the presence of DNA damage via p53 mediated activation of proapoptotic BCL2 family members that are upregulated by HIF-1 .	Although HIF-1 predominantly stimulates survival through various biological processes, proapoptotic signaling may also occur in the presence of DNA damage via p53 mediated activation of proapoptotic BCL2 family members that are upregulated by HIF-1.	22	29	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	BCL2	BCL2	BCL2	22	23	27	28
Moreover , upregulation of p53 , proapoptotic modulation of Bcl-2 family members ( Bax , Noxa , Mcl-1 , Bcl-2 ) , and induction of apoptotic cell death were observed .	Moreover, upregulation of p53, proapoptotic modulation of Bcl-2 family members (Bax, Noxa, Mcl-1, Bcl-2), and induction of apoptotic cell death were observed.	4	11	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	4	5	9	10
The role of miR-486 expression level in the regulation of P53 mediated BCL-2 associated mitochondrial apoptotic pathway in cardiomyocytes was also investigated .	The role of miR-486 expression level in the regulation of P53 mediated BCL-2 associated mitochondrial apoptotic pathway in cardiomyocytes was also investigated.	8	13	mediated	Positive_early_activation	Negative_activation	Positive_activation	P53	P53	P53	BCL-2	BCL-2	BCL-2	10	11	12	13
In addition to initiating apoptosis transcriptionally , p53 can also trigger apoptosis by direct binding to Bcl-2 to shut down anti-apoptosis signaling or interacting with Bax to result in mitochondrial outer membrane permeabilization ( MOMP ) XREF_BIBR .	In addition to initiating apoptosis transcriptionally, p53 can also trigger apoptosis by direct binding to Bcl-2 to shut down anti-apoptosis signaling or interacting with Bax to result in mitochondrial outer membrane permeabilization (MOMP) XREF_BIBR.	7	17	trigger	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	7	8	16	17
Similarly , inhibition of p53 by its siRNA transfection suppressed the changes of Bcl-2 family proteins , caspases activation , and PARP cleavage that had stimulated after Cr ( VI ) exposure ( XREF_FIG ) .	Similarly, inhibition of p53 by its siRNA transfection suppressed the changes of Bcl-2 family proteins, caspases activation, and PARP cleavage that had stimulated after Cr (VI) exposure (XREF_FIG).	2	15	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	4	5	13	14
Quicker repair is accompanied by attenuated p53 activation and expression of the anti-apoptotic factor B-cell lymphoma 2 ( Bcl-2 ) , which maintains bulge stem cell number after DNA damage infliction .	Quicker repair is accompanied by attenuated p53 activation and expression of the anti-apoptotic factor B-cell lymphoma 2 (Bcl-2), which maintains bulge stem cell number after DNA damage infliction.	6	22	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	6	7	18	19
Additionally , cytosolic p53 can induce transcription independent apoptosis by interacting at the mitochondria with B-cell lymphoma 2 ( Bcl2 ) [ XREF_BIBR ] .	Additionally, cytosolic p53 can induce transcription independent apoptosis by interacting at the mitochondria with B-cell lymphoma 2 (Bcl2) [XREF_BIBR].	2	22	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	3	4	19	20
Upon internal and external stimuli , such as oxidative stress and viral infection , p53 may activate or suppress a number of downstream target genes involved in apoptosis , such as bax , p53 upregulated modulator of apoptosis and bcl-2 .	Upon internal and external stimuli, such as oxidative stress and viral infection, p53 may activate or suppress a number of downstream target genes involved in apoptosis, such as bax, p53 upregulated modulator of apoptosis and bcl-2.	33	40	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	33	34	39	40
Noxa is a BH3-only member of the Bcl-2 family , upregulated by p53 as a response to DNA damage .	Noxa is a BH3-only member of the Bcl-2 family, upregulated by p53 as a response to DNA damage.	7	13	upregulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	12	13	7	8
Mechanistically , we show that IL-1beta activates the tumor suppressor p53 through an oxidative stress dependent mechanism resulting in p53 mediated induction of the cyclin dependent kinase inhibitor p21 and the proapoptotic Bcl-2 ( B-cell lymphoma-2 ) family members Puma ( p53 upregulated modulator of apoptosis ) and Noxa .	Mechanistically, we show that IL-1beta activates the tumor suppressor p53 through an oxidative stress dependent mechanism resulting in p53 mediated induction of the cyclin dependent kinase inhibitor p21 and the proapoptotic Bcl-2 (B-cell lymphoma-2) family members Puma (p53 upregulated modulator of apoptosis) and Noxa.	19	35	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	19	20	32	33
The underlying mechanism can be explained by p53 , which is a transcription factor that responds to stress stimuli and induces pro apoptotic Bcl-2 family members .	The underlying mechanism can be explained by p53, which is a transcription factor that responds to stress stimuli and induces pro apoptotic Bcl-2 family members.	5	25	induces	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	7	8	23	24
miR-221 can regulate the cell cycle , differentiation and apoptosis , as well as participate in the occurrence and development of tumor by adjusting the expression of p27 , p53 upregulated modulator of apoptosis ( PUMA ) , Bcl-2 modifying factor ( BMF ) , c-kit , and DNA-damage-inducible transcript 4 protein ( DDIT4 ) .	miR-221 can regulate the cell cycle, differentiation and apoptosis, as well as participate in the occurrence and development of tumor by adjusting the expression of p27, p53 upregulated modulator of apoptosis (PUMA), Bcl-2 modifying factor (BMF), c-kit, and DNA-damage-inducible transcript 4 protein (DDIT4).	29	40	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	29	30	38	39
Two patients ( P3 and P8 ) were selected for ex vivo treatment experiments and determination of protein expression of the p53 targeted genes BAX and BCL-2 , and showed an appropriate induction of these p53 regulated gene products in concordance with mRNA expression .	Two patients (P3 and P8) were selected for ex vivo treatment experiments and determination of protein expression of the p53 targeted genes BAX and BCL-2, and showed an appropriate induction of these p53 regulated gene products in concordance with mRNA expression.	18	27	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	expression of the p53	p53	BCL-2	BCL-2	bcl-2	21	22	26	27
This network encompasses direct effectors of these processes , including the cyclin dependent kinase inhibitor 1A ( p21 ) , the p53 upregulated modulator of apoptosis ( PUMA ) and the BCL2 associated X protein ( BAX ) , but also involves many indirect effects and cross-talks with ( proto-) oncogenes and other tumor suppressors [ XREF_BIBR ] .	This network encompasses direct effectors of these processes, including the cyclin dependent kinase inhibitor 1A (p21), the p53 upregulated modulator of apoptosis (PUMA) and the BCL2 associated X protein (BAX), but also involves many indirect effects and cross-talks with (proto-) oncogenes and other tumor suppressors [XREF_BIBR].	20	41	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL2	BCL2	BCL2	21	22	31	32
c release and caspase-3 activation , and increased PS levels in UCB treated platelets as compared to untreated platelets ( XREF_FIG ) , indicating that UCB triggers apoptosis in platelets via p53 mediated activation of Bcl-2 family proteins and caspases .	c release and caspase-3 activation, and increased PS levels in UCB treated platelets as compared to untreated platelets (XREF_FIG), indicating that UCB triggers apoptosis in platelets via p53 mediated activation of Bcl-2 family proteins and caspases.	31	37	mediated	Positive_early_activation	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	31	32	35	36
PMC-A mediated apoptosis through p53 independent activation of p38 and Bcl-2 downregulation in HCT-116 human colon cancer cells .	PMC-A mediated apoptosis through p53 independent activation of p38 and Bcl-2 downregulation in HCT-116 human colon cancer cells.	4	11	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	4	5	10	11
In our study , it was demonstrated that decitabine increased cytotoxic effect in chemoresistant AML cells via DNA damage associated P53 activation and inhibition of survivin and Bcl-2 .	In our study, it was demonstrated that decitabine increased cytotoxic effect in chemoresistant AML cells via DNA damage associated P53 activation and inhibition of survivin and Bcl-2.	20	28	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	P53	P53	P53	Bcl-2	Bcl-2	Bcl-2	20	21	27	28
Activation of p53 induces p21 dependent cell-cycle arrest , or increases proapoptotic Bcl-2 family proteins , such as Bax and Puma and BBC3 , thus inducing apoptosis in a cell context dependent manner .	Activation of p53 induces p21 dependent cell-cycle arrest, or increases proapoptotic Bcl-2 family proteins, such as Bax and Puma and BBC3, thus inducing apoptosis in a cell context dependent manner.	0	14	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	12	13
Bcl-2 and Bax is directly regulated by the tumor suppressor P53 and has been shown to be involved in P53 mediated apoptosis .	Bcl-2 and Bax is directly regulated by the tumor suppressor P53 and has been shown to be involved in P53 mediated apoptosis.	0	17	directly regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	tumor suppressor P53	tumor suppressor P53	tumor suppressor P53	Bcl-2	Bcl-2	Bcl-2	8	11	0	1
As previously mentioned , luteolin can modify p53 activity indirectly XREF_BIBR , XREF_BIBR or directly , XREF_BIBR and p53 mediates the intrinsic apoptotic pathway by regulating Bcl-2 family proteins , specifically through inhibition of Bcl-2 and Bax integration into the mitochondrial membrane .	As previously mentioned, luteolin can modify p53 activity indirectly XREF_BIBR, XREF_BIBR or directly, XREF_BIBR and p53 mediates the intrinsic apoptotic pathway by regulating Bcl-2 family proteins, specifically through inhibition of Bcl-2 and Bax integration into the mitochondrial membrane.	16	28	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	18	19	26	27
Ultraviolet radiation or DNA damaging drugs induce the intrinsic pathway via p53 mediated transcriptional upregulation of proapoptotic factors of B cell lymphoma 2 ( BCL-2 ) family members such as BAX , APAF-1 , PUMA , and NOXA genes .	Ultraviolet radiation or DNA damaging drugs induce the intrinsic pathway via p53 mediated transcriptional upregulation of proapoptotic factors of B cell lymphoma 2 (BCL-2) family members such as BAX, APAF-1, PUMA, and NOXA genes.	9	27	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	11	12	24	25
These findings further confirm that the p53 Pro variant enhances decay of the anti-apoptotic Bcl-2 and thereby sensitizes cells to Dox induced cell death .	These findings further confirm that the p53 Pro variant enhances decay of the anti-apoptotic Bcl-2 and thereby sensitizes cells to Dox induced cell death.	6	15	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	6	7	14	15
Blockage of p53 by si-RNA transfection suppressed mitochondrial changes of Bcl-2 family composition , mitochondrial membrane depolarization , caspase activation and PARP cleavage , leading to the inhibition of Cr ( VI )-induced apoptosis .	Blockage of p53 by si-RNA transfection suppressed mitochondrial changes of Bcl-2 family composition, mitochondrial membrane depolarization, caspase activation and PARP cleavage, leading to the inhibition of Cr (VI)-induced apoptosis.	0	12	suppressed	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	10	11
When DNA damage can not be repaired , p53 induces apoptosis by increasing Bcl 2 associated protein X ( BAX ) expression and the formation of BAX homodimers .	When DNA damage can not be repaired, p53 induces apoptosis by increasing Bcl 2 associated protein X (BAX) expression and the formation of BAX homodimers.	8	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl 2	Bcl 2	Bcl 2	8	9	13	15
More precisely , sPIF ( i ) decreases the phosphorylation of p53 at Ser 15 , ( ii ) enhances the B-cell lymphoma-2 ( BCL2 ) expression and ( iii ) reduces the BCL2 associated X protein ( BAX ) and BCL2 homologous antagonist killer ( BAK ) mRNA expression levels .	More precisely, sPIF (i) decreases the phosphorylation of p53 at Ser 15, (ii) enhances the B-cell lymphoma-2 (BCL2) expression and (iii) reduces the BCL2 associated X protein (BAX) and BCL2 homologous antagonist killer (BAK) mRNA expression levels.	3	34	reduces	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	sPIF (i) decreases the phosphorylation of p53 at Ser 15	p53	BCL2	BCL2	bcl2	11	12	33	34
p53 directly activates the proapoptotic Bcl-2 protein BAX to permeabilize mitochondria , which results in the release of mitochondrial factors , such as cytochrome c , that signal apoptotic cell death .	p53 directly activates the proapoptotic Bcl-2 protein BAX to permeabilize mitochondria, which results in the release of mitochondrial factors, such as cytochrome c, that signal apoptotic cell death.	0	7	directly activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	5	6
In this study , we used H 2 O 2 to induce apoptosis in primary cardiomyocytes in vitro to detect the correlation between the p53 mediated BCL-2 associated mitochondrial apoptotic pathway and apoptosis in cardiomyocytes , and to study the regulatory effect of miR-486 on this pathway .	In this study, we used H 2 O 2 to induce apoptosis in primary cardiomyocytes in vitro to detect the correlation between the p53 mediated BCL-2 associated mitochondrial apoptotic pathway and apoptosis in cardiomyocytes, and to study the regulatory effect of miR-486 on this pathway.	21	27	mediated	Positive_early_activation	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	24	25	26	27
As shown in XREF_FIG , inhibition of ERK1/2 and p53 prevented the Dox induced upregulation of Bax and the downregulation of Bcl-2 .	As shown in XREF_FIG, inhibition of ERK1/2 and p53 prevented the Dox induced upregulation of Bax and the downregulation of Bcl-2.	5	22	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	9	10	21	22
The activation of p53 activates the intrinsic apoptotic pathway by triggering the permeability of the outer mitochondrial membrane and coordinating pro apoptotic Bax and anti-apoptotic Bcl-2 .	The activation of p53 activates the intrinsic apoptotic pathway by triggering the permeability of the outer mitochondrial membrane and coordinating pro apoptotic Bax and anti-apoptotic Bcl-2.	1	26	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	25	26
Increased expression of p53 induces an increase in the Bax : Bcl-2 ratio , resulting in cytochrome-c , caspase activation , and , ultimately , apoptosis .	Increased expression of p53 induces an increase in the Bax : Bcl-2 ratio, resulting in cytochrome-c, caspase activation, and, ultimately, apoptosis.	1	12	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	expression of p53	p53	Bcl-2	Bcl-2	bcl-2	3	4	11	12
In this context , p53 can up-regulate the proapoptotic Bcl-2 family member Bax and possibly transcriptionally repress the antiapoptotic protein Bcl-2 XREF_BIBR .	In this context, p53 can up-regulate the proapoptotic Bcl-2 family member Bax and possibly transcriptionally repress the antiapoptotic protein Bcl-2 XREF_BIBR.	4	16	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	4	5	9	10
The co-delivery of p53 plasmid DNA and bcl-2 AS ODN in PEI-CA complexes enhanced therapeutic activities of both p53 plasmid DNA and bcl-2 AS ODN .	The co-delivery of p53 plasmid DNA and bcl-2 AS ODN in PEI-CA complexes enhanced therapeutic activities of both p53 plasmid DNA and bcl-2 AS ODN.	3	24	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	3	4	22	23
The p53 protein directly activates the proapoptotic Bcl-2 family member Bax , which results in cytochrome c release , loss of mitochondrial membrane potential , and caspase-9 and caspase-3 processing .	The p53 protein directly activates the proapoptotic Bcl-2 family member Bax, which results in cytochrome c release, loss of mitochondrial membrane potential, and caspase-9 and caspase-3 processing.	1	10	directly activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	1	2	7	8
Activation of p53 could mediate the up-regulation of Bax ( B-cell associated X protein ) , down-regulation of Bcl-2 , and PARP cleavage [ XREF_BIBR ] .	Activation of p53 could mediate the up-regulation of Bax (B-cell associated X protein), down-regulation of Bcl-2, and PARP cleavage [XREF_BIBR].	0	19	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	18	19
Initially , the mechanism was thought to be simply activation or repression of Bcl-2 family members by p53 .	Initially, the mechanism was thought to be simply activation or repression of Bcl-2 family members by p53.	9	18	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	17	18	13	14
The present study was designed to investigate the clinical and prognostic relevance of immunohistochemical expression of p53 targeted genes mdm-2 , p21WAF1 and bcl-2 alone and in combination with p53 for the indirect assessment of p53 gene status in breast cancer .	The present study was designed to investigate the clinical and prognostic relevance of immunohistochemical expression of p53 targeted genes mdm-2, p21WAF1 and bcl-2 alone and in combination with p53 for the indirect assessment of p53 gene status in breast cancer.	14	24	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	expression of p53	p53	bcl-2	bcl-2	bcl-2	16	17	23	24
miR-34a downregulates both Bcl2 and XIAP ( X linked inhibitor of apoptosis protein ) , both anti-apoptotic proteins and miR-34a is activated by p53 , which is pro apoptotic .	miR-34a downregulates both Bcl2 and XIAP (X linked inhibitor of apoptosis protein), both anti-apoptotic proteins and miR-34a is activated by p53, which is pro apoptotic.	1	28	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	23	24	3	4
Additionally , TMZ treatment greatly increased the levels of p53 ( roughly 3- and 5-fold for 1205Lu and A375 , respectively ) , which is known to induce pro apoptotic Bcl-2 family members .	Additionally, TMZ treatment greatly increased the levels of p53 (roughly 3- and 5-fold for 1205Lu and A375, respectively), which is known to induce pro apoptotic Bcl-2 family members.	2	32	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	TMZ treatment greatly increased the levels of p53	p53	Bcl-2	Bcl-2	bcl-2	9	10	30	31
p53 Mediated activation of the pro apoptotic BCL2 family proteins , including PUMA , NOXA , BAX and BAK , induces mitochondrial outer membrane permeabilization ( MOMP ) and subsequent release from the mitochondria of apoptogenic factors such as cytochrome c.	p53 Mediated activation of the pro apoptotic BCL2 family proteins, including PUMA, NOXA, BAX and BAK, induces mitochondrial outer membrane permeabilization (MOMP) and subsequent release from the mitochondria of apoptogenic factors such as cytochrome c.	0	9	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	BCL2	BCL2	BCL2	0	1	7	8
To investigate the expression changes of intrinsic cytokines TGF-beta ( 1 ) and TNF-alpha , telomerase activity and bcl-2 during ongoing apoptosis of HL-60 and K562 cells induced by p53 .	To investigate the expression changes of intrinsic cytokines TGF-beta (1) and TNF-alpha, telomerase activity and bcl-2 during ongoing apoptosis of HL-60 and K562 cells induced by p53.	16	30	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	29	30	18	19
In this model , p53 dependent signals , like the induction of Bax and direct inhibition of Bcl2 , may synergize with p53 independent signals including the induction of Bim to antagonize Bcl2 function and promote apoptosis .	In this model, p53 dependent signals, like the induction of Bax and direct inhibition of Bcl2, may synergize with p53 independent signals including the induction of Bim to antagonize Bcl2 function and promote apoptosis.	4	33	synergize	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	4	5	32	33
Activation of p53 promoted the intrinsic apoptosis pathway by triggering permeabilization of the outer mitochondrial membrane and coordinating pro apoptotic Bax and anti-apoptotic Bcl-2 .	Activation of p53 promoted the intrinsic apoptosis pathway by triggering permeabilization of the outer mitochondrial membrane and coordinating pro apoptotic Bax and anti-apoptotic Bcl-2.	0	24	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	23	24
The tumor suppressor protein p53 influences apoptosis and can modulate levels of the Bcl-2 protein family XREF_BIBR .	The tumor suppressor protein p53 influences apoptosis and can modulate levels of the Bcl-2 protein family XREF_BIBR.	0	16	modulate	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	4	5	13	14
p53 activation in ASCs , however , does not seem to promote the Bcl-2 apoptotic pathway because no increased expression of Puma and Bax pro apoptotic genes was observed compared with BM MSCs .	p53 activation in ASCs, however, does not seem to promote the Bcl-2 apoptotic pathway because no increased expression of Puma and Bax pro apoptotic genes was observed compared with BM MSCs.	0	15	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	13	14
p53 induced proapoptotic Bcl-2 family member PUMAalpha in renal tubular cells upon treatment with cisplatin , and dominant negative p53 suppressed the expression of PUMAalpha .	p53 induced proapoptotic Bcl-2 family member PUMAalpha in renal tubular cells upon treatment with cisplatin, and dominant negative p53 suppressed the expression of PUMAalpha.	0	6	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	3	4
Expression of p53 shown in this study is able to activate proapoptotic factors ( Bax , Bak , Bcl- Xs , and Bad ) and antiapoptotic ( Bcl-2 , BclXL , and Bcl-W ) .	Expression of p53 shown in this study is able to activate proapoptotic factors (Bax, Bak, Bcl- Xs, and Bad) and antiapoptotic (Bcl-2, BclXL, and Bcl-W).	0	32	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	Expression of p53	p53	Bcl-2	Bcl-2	bcl-2	2	3	27	28
These include p53 upregulated modulator of apoptosis ( PUMA ) , NADPH oxidase activator ( NOXA ) , XREF_BIBR , XREF_BIBR , XREF_BIBR Bcl-2 family members Bax and Bid , XREF_BIBR , XREF_BIBR and apoptotic peptidase activating factor 1 ( Apaf-1 ) .	These include p53 upregulated modulator of apoptosis (PUMA), NADPH oxidase activator (NOXA), XREF_BIBR, XREF_BIBR, XREF_BIBR Bcl-2 family members Bax and Bid, XREF_BIBR, XREF_BIBR and apoptotic peptidase activating factor 1 (Apaf-1).	2	25	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	23	24
PUMA , p53 inducible gene , is closely related to strong apoptosis and modulates anti-apoptotic Bcl-2 and pro apoptotic Bax , thereby activating caspase-3 and -9 [ XREF_BIBR ] .	PUMA, p53 inducible gene, is closely related to strong apoptosis and modulates anti-apoptotic Bcl-2 and pro apoptotic Bax, thereby activating caspase-3 and -9 [XREF_BIBR].	2	22	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	15	16
Taken together , the findings of the current study reveal a novel mechanism whereby p53 negatively modulates Bcl-2 by controlling miR-1915 .	Taken together, the findings of the current study reveal a novel mechanism whereby p53 negatively modulates Bcl-2 by controlling miR-1915.	14	18	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	14	15	17	18
We previously showed that Bcl-2 homology domain 3 ( BH3 )-only proteins , such as PUMA and NOXA , are induced by TPEN in a p53 dependent manner .	We previously showed that Bcl-2 homology domain 3 (BH3)-only proteins, such as PUMA and NOXA, are induced by TPEN in a p53 dependent manner.	4	27	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	25	26	4	5
Similar phenomena also occurred in p53 signals showing p53 could modulate Bcl2 at the transcriptional level to regulate cell apoptosis , and at the same time p53 could also function through the miR34 family to regulate the apoptosis [ XREF_BIBR ] .	Similar phenomena also occurred in p53 signals showing p53 could modulate Bcl2 at the transcriptional level to regulate cell apoptosis, and at the same time p53 could also function through the miR34 family to regulate the apoptosis [XREF_BIBR].	8	12	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	8	9	11	12
Recently , the product of the p53 tumor suppressor gene , a protein reported to play a critical role in regulating cell proliferation and death , has been shown to directly modulate the transcriptional activity of the bcl-2 and bax genes .	Recently, the product of the p53 tumor suppressor gene, a protein reported to play a critical role in regulating cell proliferation and death, has been shown to directly modulate the transcriptional activity of the bcl-2 and bax genes.	6	40	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	6	7	37	38
The acetyltransferase TIP60 is regulated by phosphorylation , and we have previously shown that phosphorylation of TIP60 on S86 by GSK-3 promotes p53 mediated induction of the BCL-2 protein PUMA .	The acetyltransferase TIP60 is regulated by phosphorylation, and we have previously shown that phosphorylation of TIP60 on S86 by GSK-3 promotes p53 mediated induction of the BCL-2 protein PUMA.	22	29	induction	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	22	23	27	28
These findings indicate that p53 induces apoptosis by differentially affecting a broad spectrum of BCL-2 proteins and that p53 mediated apoptosis possibly overcomes resistance to any single BH3-only protein .	These findings indicate that p53 induces apoptosis by differentially affecting a broad spectrum of BCL-2 proteins and that p53 mediated apoptosis possibly overcomes resistance to any single BH3-only protein.	4	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	4	5	14	15
The tumor suppressor protein , p53 , targets both Bcl-2 and Bax and promotes growth arrest and cell death in response to cell damage .	The tumor suppressor protein, p53, targets both Bcl-2 and Bax and promotes growth arrest and cell death in response to cell damage.	3	11	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	5	6	9	10
The association of p53 with Bcl-2 can promote Bcl-2 dissociation from the mitochondria and accelerate the permeabilization of the mitochondrial membrane .	The association of p53 with Bcl-2 can promote Bcl-2 dissociation from the mitochondria and accelerate the permeabilization of the mitochondrial membrane.	1	9	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	8	9
p53 modulates Bcl-2 during apoptosis in two ways : by direct trans-repression of Bcl-2 transcription and by transcription independent , direct binding to Bcl-2 .	p53 modulates Bcl-2 during apoptosis in two ways : by direct trans-repression of Bcl-2 transcription and by transcription independent, direct binding to Bcl-2.	0	3	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	2	3
PUMA is a BH3-only member of the Bcl-2 family , up-regulated by p53 as a response to DNA damage .	PUMA is a BH3-only member of the Bcl-2 family, up-regulated by p53 as a response to DNA damage.	7	13	up-regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	12	13	7	8
p53 has been reported to mediate the down-regulation of BCL2 either directly or indirectly through the NRE XREF_BIBR .	p53 has been reported to mediate the down-regulation of BCL2 either directly or indirectly through the NRE XREF_BIBR.	0	10	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL2	BCL2	BCL2	0	1	9	10
miR-486 may regulate cardiomyocyte apoptosis via p53 mediated BCL-2 associated mitochondrial apoptotic pathway .	miR-486 may regulate cardiomyocyte apoptosis via p53 mediated BCL-2 associated mitochondrial apoptotic pathway.	4	9	mediated	Positive_early_activation	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	6	7	8	9
CIP inhibits gamma-H2AX formation and promotes p-53 phosphorylation and inhibits Bcl-2 basal levels to increase cell death in irradiated TK6 cells , while CIP inhibits p53 phosphorylation and increases Bcl-2 production to reduce cell death in normal healthy cells .	CIP inhibits gamma-H2AX formation and promotes p-53 phosphorylation and inhibits Bcl-2 basal levels to increase cell death in irradiated TK6 cells, while CIP inhibits p53 phosphorylation and increases Bcl-2 production to reduce cell death in normal healthy cells.	23	30	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	CIP inhibits p53 phosphorylation	p53	Bcl-2	Bcl-2	bcl-2	25	26	29	30
As a master regulator of cell apoptosis , p53 dependent apoptosis also contributes to chemotherapy induced cell death by transcriptionally activating pro apoptotic Bcl-2 family members ( e.g ., Bax , Bak , PUMA , and Noxa ) and repressing anti-apoptotic Bcl-2 proteins ( Bcl-2 , Bcl-XL ) and IAPs ( survivin ) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR .	As a master regulator of cell apoptosis, p53 dependent apoptosis also contributes to chemotherapy induced cell death by transcriptionally activating pro apoptotic Bcl-2 family members (e.g., Bax, Bak, PUMA, and Noxa) and repressing anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL) and IAPs (survivin) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.	8	25	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	8	9	23	24
This strategy was explored in the current study , where p53 downstream target miR-34 was restored in p53-mutant gastric cancer Kato III cells with a high level of Bcl-2 and low levels of miR-34 , resulting in downregulation of Bcl-2 and Notch and HMGA2 , tumor cell growth inhibition and accumulation in G1 phase , and chemosensitization and Caspase-3 activation and apoptosis .	This strategy was explored in the current study, where p53 downstream target miR-34 was restored in p53-mutant gastric cancer Kato III cells with a high level of Bcl-2 and low levels of miR-34, resulting in downregulation of Bcl-2 and Notch and HMGA2, tumor cell growth inhibition and accumulation in G1 phase, and chemosensitization and Caspase-3 activation and apoptosis.	10	43	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	10	11	39	40
Since p53 gene inactivation occurs in over half of human cancers , it is possible that loss of p53 mediated repression of bcl-2 gene expression accounts , at least in part , for the frequent abnormalities in bcl-2 protein production seen in tumours .	Since p53 gene inactivation occurs in over half of human cancers, it is possible that loss of p53 mediated repression of bcl-2 gene expression accounts, at least in part, for the frequent abnormalities in bcl-2 protein production seen in tumours.	16	25	mediated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	loss of p53	p53	bcl-2	bcl-2	bcl-2	18	19	22	23
EGCG also increases the expression of p53 ( wild type ) , p21 and wild type P53 activated fragment 1 ( WAF1 ) protein , and Bcl2 associated X protein ( Bax )/B-cell lymphoma 2 ( Bcl-2 ) protein in LNCaP prostate cancer cells , leading to cell cycle arrest and apoptotic cell death .	EGCG also increases the expression of p53 (wild type), p21 and wild type P53 activated fragment 1 (WAF1) protein, and Bcl2 associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) protein in LNCaP prostate cancer cells, leading to cell cycle arrest and apoptotic cell death.	4	27	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	P53	expression of p53 (wild type), p21 and wild type P53	p53	Bcl2	Bcl2	bcl2	16	17	26	27
p53 can up-regulate Bax and down-regulatie Bcl-2 or Bcl-xL , affecting the apoptosis of cancer cells , and changing the permeability of mitochondria , thus affecting the function of downstream pro apoptotic genes [ XREF_BIBR ] .	p53 can up-regulate Bax and down-regulatie Bcl-2 or Bcl-xL, affecting the apoptosis of cancer cells, and changing the permeability of mitochondria, thus affecting the function of downstream pro apoptotic genes [XREF_BIBR].	0	8	up-regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	6	7
Curcumol treatment also resulted in the suppression of xenograft growth in vivo ( 100 or 200 microg/kg for 21 days ) , as well as G 1 phase arrest and an apoptotic response , which were accompanied by the upregulation of p73 expression and the activation of the expression of p53 upregulated modulator of apoptosis ( PUMA ) and Bcl-2 antagonistic killer ( Bak ) .	Curcumol treatment also resulted in the suppression of xenograft growth in vivo (100 or 200 microg/kg for 21 days), as well as G 1 phase arrest and an apoptotic response, which were accompanied by the upregulation of p73 expression and the activation of the expression of p53 upregulated modulator of apoptosis (PUMA) and Bcl-2 antagonistic killer (Bak).	48	61	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	expression of p53	p53	Bcl-2	Bcl-2	bcl-2	50	51	59	60
Of the several apoptotic genes that p53 can directly target , NOXA and PUMA ( pro apoptotic Bcl-2 family ) are induced by p53 in cell types that express pro apoptotic Bcl-2 family members , although Noxa and Puma can also be induced by p53 independent mechanisms .	Of the several apoptotic genes that p53 can directly target, NOXA and PUMA (pro apoptotic Bcl-2 family) are induced by p53 in cell types that express pro apoptotic Bcl-2 family members, although Noxa and Puma can also be induced by p53 independent mechanisms.	17	24	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	23	24	17	18
MiR-486could influence the process of cardiomyocyte apoptosis by regulating P53 mediated BCL-2 associated mitochondrial apoptotic pathway .	MiR-486could influence the process of cardiomyocyte apoptosis by regulating P53 mediated BCL-2 associated mitochondrial apoptotic pathway.	8	12	mediated	Positive_early_activation	Negative_activation	Positive_activation	P53	P53	P53	BCL-2	BCL-2	BCL-2	9	10	11	12
We can not conclude whether hair graying was delayed or prevented by loss of p53 in Bcl-2 -/- mice because double knockout mice all died by 12 weeks of age .	We can not conclude whether hair graying was delayed or prevented by loss of p53 in Bcl-2 -/- mice because double knockout mice all died by 12 weeks of age.	10	17	prevented	Negative_activation_syntax_3_verb	Negative_activation	Negative_activation	p53	loss of p53	p53	Bcl-2	Bcl-2	bcl-2	14	15	16	17
Several proapoptotic BCL-2 family members , including BAX , XREF_BIBR , XREF_BIBR , XREF_BIBR BBC3 ( PUMA ) 181 and PMAIP1 ( NOXA ) , 182 are activated by p53 .	Several proapoptotic BCL-2 family members, including BAX, XREF_BIBR, XREF_BIBR, XREF_BIBR BBC3 (PUMA) 181 and PMAIP1 (NOXA), 182 are activated by p53.	2	30	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	29	30	2	3
183 The translocation of p53 to the outer membrane modulates members of the bcl-2 family and impacts susceptibility to programmed cell death .	183 The translocation of p53 to the outer membrane modulates members of the bcl-2 family and impacts susceptibility to programmed cell death.	0	14	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	4	5	13	14
Also , p53 promotes apoptosis by antagonizing the anti-apoptotic effects of Bcl-xL and Bcl-2 at the outer mitochondrial membrane .	Also, p53 promotes apoptosis by antagonizing the anti-apoptotic effects of Bcl-xL and Bcl-2 at the outer mitochondrial membrane.	2	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	13	14
p53 promotes the activation of the pro apoptotic Bcl-2 family proteins and the release of cytochrome C. Dysregulation of p53 is reported in numerous types of cancer .	p53 promotes the activation of the pro apoptotic Bcl-2 family proteins and the release of cytochrome C. Dysregulation of p53 is reported in numerous types of cancer.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	8	9
XREF_BIBR , XREF_BIBR Thus , the increased p53 protein expression induced by CPT may promote activation of proapoptotic Bcl-2 family members , thereby facilitating ABT-737-induced apoptosis .	XREF_BIBR, XREF_BIBR Thus, the increased p53 protein expression induced by CPT may promote activation of proapoptotic Bcl-2 family members, thereby facilitating ABT-737-induced apoptosis.	7	20	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53 protein expression	p53	Bcl-2	Bcl-2	bcl-2	7	8	18	19
Moreover , the pro apoptotic and pro autophagic effect of FK-16 required p53 dependent upregulation of Bax and downregulation of Bcl-2 .	Moreover, the pro apoptotic and pro autophagic effect of FK-16 required p53 dependent upregulation of Bax and downregulation of Bcl-2.	12	21	upregulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	12	13	20	21
The Trp53 tumor suppressor gene product ( p53 ) functions in the nucleus to regulate proapoptotic genes , whereas cytoplasmic p53 directly activates proapoptotic Bcl-2 proteins to permeabilize mitochondria and initiate apoptosis .	The Trp53 tumor suppressor gene product (p53) functions in the nucleus to regulate proapoptotic genes, whereas cytoplasmic p53 directly activates proapoptotic Bcl-2 proteins to permeabilize mitochondria and initiate apoptosis.	19	25	directly activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	20	21	24	25
In addition to the upregulation of death receptors , p53 induced the pro apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein .	In addition to the upregulation of death receptors, p53 induced the pro apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein.	9	21	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	9	10	14	15
Extrinsic pathway is activated through the induction of Fas , DR5 and PERP XREF_BIBR - XREF_BIBR whereas in case of intrinsic pathway , p53 target Bcl-2 family proteins at mitochondrial level thus ultimately releasing cytochrome c XREF_BIBR .	Extrinsic pathway is activated through the induction of Fas, DR5 and PERP XREF_BIBR - XREF_BIBR whereas in case of intrinsic pathway, p53 target Bcl-2 family proteins at mitochondrial level thus ultimately releasing cytochrome c XREF_BIBR.	23	27	target	Positive_activation_token_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	23	24	25	26
The hRSV encoded fusion ( F ) protein , which is expressed at a later time point as compared to the NS proteins [ XREF_BIBR ] , has been found to be critical in the activation of apoptosis by p53 mediated activation of pro apoptotic Bcl-2 family proteins [ XREF_BIBR ] .	The hRSV encoded fusion (F) protein, which is expressed at a later time point as compared to the NS proteins [XREF_BIBR], has been found to be critical in the activation of apoptosis by p53 mediated activation of pro apoptotic Bcl-2 family proteins [XREF_BIBR].	39	47	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	39	40	45	46
It has been demonstrated that p53 is able to induce a number of Bcl-2 family genes , including Bad XREF_BIBR , XREF_BIBR .	It has been demonstrated that p53 is able to induce a number of Bcl-2 family genes, including Bad XREF_BIBR, XREF_BIBR.	5	15	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	5	6	13	14
9 We show here , using as a paradigm wt p53 DLBCL cells that carry t ( 14 ; 18 ) ( q32 ; q21 ) and overexpress BCL2 , that isolated overexpression of BCL2 in this context can not impede the execution of the p53 mediated apoptotic program .	9 We show here, using as a paradigm wt p53 DLBCL cells that carry t (14; 18) (q32; q21) and overexpress BCL2, that isolated overexpression of BCL2 in this context can not impede the execution of the p53 mediated apoptotic program.	10	31	overexpress	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL2	BCL2	BCL2	10	11	28	29
In addition , p53 can activate pro apoptotic members of Bcl-2 family such as Bax , Noxa and PUMA , which are involved in the permeabilization of the outer mitochondrial membrane .	In addition, p53 can activate pro apoptotic members of Bcl-2 family such as Bax, Noxa and PUMA, which are involved in the permeabilization of the outer mitochondrial membrane.	3	11	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	10	11
Tetrameric p53 is the preferred partner for CypD interaction ( XREF_FIG ) , while it is debated whether mitochondrial p53 that directly triggers Bcl-2 family mediated apoptosis at the OMM acts as monomer or tetramer .	Tetrameric p53 is the preferred partner for CypD interaction (XREF_FIG), while it is debated whether mitochondrial p53 that directly triggers Bcl-2 family mediated apoptosis at the OMM acts as monomer or tetramer.	18	30	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	19	20	23	24
p53-up-regulated modulator of apoptosis ( PUMA ) is a recently discovered Bcl-2 family member that is rapidly induced by p53 and that exerts strong pro apoptotic effects .	p53-up-regulated modulator of apoptosis (PUMA) is a recently discovered Bcl-2 family member that is rapidly induced by p53 and that exerts strong pro apoptotic effects.	11	20	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	19	20	11	12
Stimulation of p53 can initiate apoptosis by activating proapoptotic Bcl-2 family member , such as Bax , and repressing antiapoptotic Bcl-2 proteins , such as Bcl-2 and Bcl-xl .	Stimulation of p53 can initiate apoptosis by activating proapoptotic Bcl-2 family member, such as Bax, and repressing antiapoptotic Bcl-2 proteins, such as Bcl-2 and Bcl-xl.	0	11	initiate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	9	10
As underlying mechanism , doxorubicin activated p53 , p53 induced cell-cycle arrest , and cell-cycle arrest disabled inactivation of antiapoptotic Bcl-2 family members by vincristine ; therefore , vincristine was unable to activate downstream apoptosis signaling .	As underlying mechanism, doxorubicin activated p53, p53 induced cell-cycle arrest, and cell-cycle arrest disabled inactivation of antiapoptotic Bcl-2 family members by vincristine; therefore, vincristine was unable to activate downstream apoptosis signaling.	8	22	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	8	9	20	21
Repression of anti-apoptotic members , including Bcl-2 and Bcl-xL , which are transcriptionally suppressed by p53 , preserves the integrity of the mitochondria .	Repression of anti-apoptotic members, including Bcl-2 and Bcl-xL, which are transcriptionally suppressed by p53, preserves the integrity of the mitochondria.	0	16	suppressed	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	15	16	6	7
Remarkably , p53 has been demonstrated to modulate Bcl-2 family members that regulate apoptosis by controlling mitochondrial permeability .	Remarkably, p53 has been demonstrated to modulate Bcl-2 family members that regulate apoptosis by controlling mitochondrial permeability.	2	10	modulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	8	9
In addition , the expression levels of pro apoptotic proteins , caspase-3 , caspase-8 , caspase-9 , poly ADP ribose polymerase ( PARP ) p53 and apoptosis inducing factor ( AIF ) , as well as anti-apoptotic markers , B-cell lymphoma 2 ( Bcl-2 ) and myeloid cell leukemia 1 ( Mcl-1 ) , were analyzed by western blotting .	In addition, the expression levels of pro apoptotic proteins, caspase-3, caspase-8, caspase-9, poly ADP ribose polymerase (PARP) p53 and apoptosis inducing factor (AIF), as well as anti-apoptotic markers, B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia 1 (Mcl-1), were analyzed by western blotting.	20	44	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	24	25	43	44
The steroid did not cause significant changes in the expression levels of B-cell lymphoma 2 ( Bcl-2 ) family proteins , Bcl-2-like protein 11 , p53 upregulated modulator of apoptosis , Bcl-2-associated X protein , BH3 interacting-domain death agonist , Bcl-2-associated death promoter and Bcl-2 , but it significantly downregulated induced myeloid leukemia cell differentiation protein Mcl-1 ( Mcl-1 ) in melanoma cells , suggesting the key role of Mcl-1 in regulating apoptosis of melanoma cells induced by the steroid .	The steroid did not cause significant changes in the expression levels of B-cell lymphoma 2 (Bcl-2) family proteins, Bcl-2-like protein 11, p53 upregulated modulator of apoptosis, Bcl-2-associated X protein, BH3 interacting-domain death agonist, Bcl-2-associated death promoter and Bcl-2, but it significantly downregulated induced myeloid leukemia cell differentiation protein Mcl-1 (Mcl-1) in melanoma cells, suggesting the key role of Mcl-1 in regulating apoptosis of melanoma cells induced by the steroid.	25	45	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	25	26	44	45
The increased phosphorylation and accumulation of p53 may lead to mitochondrial apoptosis by upregulating and derepressing proapoptotic members of the bcl-2 family , such as bax , bak , bad , bid , puma and so on , while on the other hand downregulating and repressing antiapoptotic members , such as bcl-2 , bcl-xl , Mcl-1 and so on .	The increased phosphorylation and accumulation of p53 may lead to mitochondrial apoptosis by upregulating and derepressing proapoptotic members of the bcl-2 family, such as bax, bak, bad, bid, puma and so on, while on the other hand downregulating and repressing antiapoptotic members, such as bcl-2, bcl-xl, Mcl-1 and so on.	2	21	lead	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	phosphorylation and accumulation of p53	p53	bcl-2	bcl-2	bcl-2	6	7	20	21
Overexpression of p53 could trigger mitochondria mediated apoptosis pathway and induce the disruption of MMP , downregulation of Bcl-2 , cyto-C release , and activation of caspase-3 .	Overexpression of p53 could trigger mitochondria mediated apoptosis pathway and induce the disruption of MMP, downregulation of Bcl-2, cyto-C release, and activation of caspase-3.	0	21	induce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	Overexpression of p53	p53	Bcl-2	Bcl-2	bcl-2	2	3	18	19
For example , SemRep extracts the predication in ( 2 ) from the sentence in ( 1 ) : In addition to the upregulation of death receptors , p53 induced the pro apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein .	For example, SemRep extracts the predication in (2) from the sentence in (1) : In addition to the upregulation of death receptors, p53 induced the pro apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein.	28	40	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	28	29	33	34
EBV expressed miRNAs include MiR-BHRF1-1 , which inhibits the tumor suppressor gene p53 and miR-BART1 , which activates BCL-2 , an anti-apoptotic protein [ XREF_BIBR , XREF_BIBR - XREF_BIBR ] .	EBV expressed miRNAs include MiR-BHRF1-1, which inhibits the tumor suppressor gene p53 and miR-BART1, which activates BCL-2, an anti-apoptotic protein [XREF_BIBR, XREF_BIBR - XREF_BIBR].	7	22	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	12	13	18	19
XREF_BIBR The most intensively studied p53 target genes include cyclin dependent kinase inhibitor 1A ( CDKN1A , known as p21 ) , which promotes cell-cycle arrest or senescence , and p53 upregulated modulator of apoptosis ( PUMA , also known as BCL2 binding component 3 [ BBC3 ] ) and BCL2 associated X protein ( BAX , also known as BCL-2-like protein-4 ) , which are activated to induce apoptosis when cellular damage is irreparable .	XREF_BIBR The most intensively studied p53 target genes include cyclin dependent kinase inhibitor 1A (CDKN1A, known as p21), which promotes cell-cycle arrest or senescence, and p53 upregulated modulator of apoptosis (PUMA, also known as BCL2 binding component 3 [BBC3]) and BCL2 associated X protein (BAX, also known as BCL-2-like protein-4), which are activated to induce apoptosis when cellular damage is irreparable.	30	51	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL2	BCL2	BCL2	30	31	50	51
XREF_BIBR Wild-type p53 in diffuse large-B-cell lymphoma can target overexpressed BCL2 and induce cell arrest and apoptosis , but cell death is reduced when p53 is inhibited .	XREF_BIBR Wild-type p53 in diffuse large-B-cell lymphoma can target overexpressed BCL2 and induce cell arrest and apoptosis, but cell death is reduced when p53 is inhibited.	0	12	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL2	BCL2	BCL2	2	3	10	11
Although SiHa and C-33A cell lines showed the best response to the Ad-ET and RAD therapy ( XREF_FIG ) , we used Hela-S3 cells for the tumor study as our previous work showed that this tumor cell line responded well to dual therapy of p53 targeted oncolytic adenovirus H101 and Bcl2 RNAi XREF_BIBR .	Although SiHa and C-33A cell lines showed the best response to the Ad-ET and RAD therapy (XREF_FIG), we used Hela-S3 cells for the tumor study as our previous work showed that this tumor cell line responded well to dual therapy of p53 targeted oncolytic adenovirus H101 and Bcl2 RNAi XREF_BIBR.	42	52	targeted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	44	45	50	51
As expected , p53 mediated induction of p21 and bcl2 pro apoptotic targets did not occur in irradiated Trp53 -/- HSPCs and MPs ( XREF_FIG ) .	As expected, p53 mediated induction of p21 and bcl2 pro apoptotic targets did not occur in irradiated Trp53 -/- HSPCs and MPs (XREF_FIG).	3	10	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	bcl2	bcl2	bcl2	3	4	9	10
Using genetically modified mouse models , we report here that p53 upregulated modulator of apoptosis ( Puma ) and Bcl-2 interacting mediator of cell death ( Bim ) , two pro apoptotic members of the B-cell lymphoma protein-2 ( Bcl-2 ) family of proteins , cooperate in causing bone marrow and gastrointestinal tract toxicity in response to chemo and radiation therapy .	Using genetically modified mouse models, we report here that p53 upregulated modulator of apoptosis (Puma) and Bcl-2 interacting mediator of cell death (Bim), two pro apoptotic members of the B-cell lymphoma protein-2 (Bcl-2) family of proteins, cooperate in causing bone marrow and gastrointestinal tract toxicity in response to chemo and radiation therapy.	10	21	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	10	11	19	20
Recent reports indicated that the p53 tumor suppressor gene can directly regulate a host of Bcl-2 family proteins such as Bcl-2 anti-apoptotic and Bax pro apoptotic proteins XREF_BIBR .	Recent reports indicated that the p53 tumor suppressor gene can directly regulate a host of Bcl-2 family proteins such as Bcl-2 anti-apoptotic and Bax pro apoptotic proteins XREF_BIBR.	5	17	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	5	6	15	16
The underlying mechanism was investigated and it was found that ET-770 sensitized the cells by activating the p53 protein , which in turn down-regulated anti-apoptotic myeloid cell leukemia sequence-1 ( MCL1 ) and up-regulated BCL2 associated X protein ( BAX ) proteins .	The underlying mechanism was investigated and it was found that ET-770 sensitized the cells by activating the p53 protein, which in turn down-regulated anti-apoptotic myeloid cell leukemia sequence-1 (MCL1) and up-regulated BCL2 associated X protein (BAX) proteins.	17	35	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL2	BCL2	BCL2	17	18	34	35
p53 also activates proapoptotic members of the Bcl2 family : Bax , Noxa , and Puma involved in the permeabilization of the outer mitochondrial membrane [ XREF_BIBR ] .	p53 also activates proapoptotic members of the Bcl2 family : Bax, Noxa, and Puma involved in the permeabilization of the outer mitochondrial membrane [XREF_BIBR].	0	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	0	1	7	8
In this case p53 promotes the transcriptional activation of Bcl-2 superfamily genes .	In this case p53 promotes the transcriptional activation of Bcl-2 superfamily genes.	3	11	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	9	10
Bcl2 , another p53 target , was induced in pSIREN and shRNA cells by H. pylori with some downregulation by p53 overexpression ( XREF_FIG and Supplementary Figure 2 ) .	Bcl2, another p53 target, was induced in pSIREN and shRNA cells by H. pylori with some downregulation by p53 overexpression (XREF_FIG and Supplementary Figure 2).	0	22	induced	Positive_activation_syntax_4_verb	Negative_activation	Positive_activation	p53	p53 overexpression	p53	Bcl2	Bcl2	bcl2	20	21	0	1
Bcl-2 and Bax modify this pathway or directly regulated by p53 .	Bcl-2 and Bax modify this pathway or directly regulated by p53.	0	11	directly regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	10	11	0	1
This includes an increase in p53 ( wild-type ) , a decrease in BCL2 , a p53 dependent increase in the BCL2 family member BAX , and increases in Growth Arrest and DNA Damage inducible ( GADD ) genes such as GADD45 ; these changes occur as early events in a sequence that culminates in DNA damage induced apoptosis .	This includes an increase in p53 (wild-type), a decrease in BCL2, a p53 dependent increase in the BCL2 family member BAX, and increases in Growth Arrest and DNA Damage inducible (GADD) genes such as GADD45; these changes occur as early events in a sequence that culminates in DNA damage induced apoptosis.	16	24	increase	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	BCL2	BCL2	BCL2	16	17	21	22
The activation of p53 pathway causes mitochondrial dysfunction by regulating the expression levels of pro survival and pro apoptotic Bcl-2 family members .	The activation of p53 pathway causes mitochondrial dysfunction by regulating the expression levels of pro survival and pro apoptotic Bcl-2 family members.	3	21	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	19	20
A systematic investigation of the apoptosis related Bcl-2 family modulated by p53 in HCC is lacking .	A systematic investigation of the apoptosis related Bcl-2 family modulated by p53 in HCC is lacking.	7	13	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	11	12	7	8
As seen above for the neuronal protection of APC , 3K3A-APC inhibited p53 expression , decreased favorably the Bax : Bcl-2 ratio ( XREF_FIG ) ( one-way ANOVA followed by Tukey ' s post-hoc test , P < 0.05 ; n = 4 different blots per group ; XREF_FIG ) and blocked the activation of caspase-9 and -3 ( one-way ANOVA followed by Tukey ' s post-hoc test , P < 0.05 ; n = 5 independent cultures per treatment ; XREF_FIG ) ; its effects were more pronounced than those obtained with wt-APC .	As seen above for the neuronal protection of APC, 3K3A-APC inhibited p53 expression, decreased favorably the Bax : Bcl-2 ratio (XREF_FIG) (one-way ANOVA followed by Tukey 's post-hoc test, P < 0.05; n = 4 different blots per group; XREF_FIG) and blocked the activation of caspase-9 and -3 (one-way ANOVA followed by Tukey 's post-hoc test, P < 0.05; n = 5 independent cultures per treatment; XREF_FIG); its effects were more pronounced than those obtained with wt-APC.	10	21	decreased	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	3K3A-APC inhibited p53 expression	p53	Bcl-2	Bcl-2	bcl-2	12	13	20	21
P53 can trigger apoptosis by activating the pro apoptotic proteins of Bcl-2 family and consequently cause abnormal mitochondrial functioning : mitochondrial outer membrane permeabilisation ( MOMP ) .	P53 can trigger apoptosis by activating the pro apoptotic proteins of Bcl-2 family and consequently cause abnormal mitochondrial functioning : mitochondrial outer membrane permeabilisation (MOMP).	0	15	trigger	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	P53	P53	P53	Bcl-2	Bcl-2	Bcl-2	0	1	11	12
We define a p53 independent modulation of the Bcl-2 family of proteins as the mediator of PMC-A induced apoptosis .	We define a p53 independent modulation of the Bcl-2 family of proteins as the mediator of PMC-A induced apoptosis.	3	9	modulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	8	9
The p53 dependent regulation of apoptosis occurs through transcription dependent and transcription independent mechanisms to either activate or in activate multidomain pro- and anti-apoptotic Bcl-2 proteins [ XREF_BIBR ] .	The p53 dependent regulation of apoptosis occurs through transcription dependent and transcription independent mechanisms to either activate or in activate multidomain pro- and anti-apoptotic Bcl-2 proteins [XREF_BIBR].	1	25	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	1	2	24	25
A previously conducted study proved that p53 up-regulated bcl-2 gene expression XREF_BIBR .	A previously conducted study proved that p53 up-regulated bcl-2 gene expression XREF_BIBR.	6	11	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	6	7	8	9
Both ATF3 and ATM increase the stability of p53 , which in turn can activate proapoptotic Bcl-2 proteins such as PUMA and Noxa , which we found overexpressed in HIV-1-infected cells , whether Vpr + or Vpr -.	Both ATF3 and ATM increase the stability of p53, which in turn can activate proapoptotic Bcl-2 proteins such as PUMA and Noxa, which we found overexpressed in HIV-1-infected cells, whether Vpr + or Vpr -.	6	17	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	8	9	16	17
These data provide evidence that p53 is required in the apoptotic response upon NF-Y RNAi , suggesting that decreased levels of anti-apoptotic genes are not sufficient to induce apoptosis , as pro apoptotic members of the Bcl-2 family activated by p53 play a significant role in this phenomenon .	These data provide evidence that p53 is required in the apoptotic response upon NF-Y RNAi, suggesting that decreased levels of anti-apoptotic genes are not sufficient to induce apoptosis, as pro apoptotic members of the Bcl-2 family activated by p53 play a significant role in this phenomenon.	36	41	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	40	41	36	37
Bax is directly activated by the p53 tumor suppressor proteins following stress induction or indirectly through the p53 activation of the Bcl-2 pro apoptotic member Noxa and PUMA , or throught the p53-independant mechanisms .	Bax is directly activated by the p53 tumor suppressor proteins following stress induction or indirectly through the p53 activation of the Bcl-2 pro apoptotic member Noxa and PUMA, or throught the p53-independant mechanisms.	17	22	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	17	18	21	22
MiR-486 overexpression in cardiomyocytes can effectively reduce the activation of p53 mediated BCL-2 apoptotic pathway , thus protecting the cardiomyocytes , and conversely , reduced miR-486 expression would increase cardiomyocyte apoptosis .	MiR-486 overexpression in cardiomyocytes can effectively reduce the activation of p53 mediated BCL-2 apoptotic pathway, thus protecting the cardiomyocytes, and conversely, reduced miR-486 expression would increase cardiomyocyte apoptosis.	8	14	mediated	Positive_early_activation	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	10	11	12	13
This study aimed to explore the mechanism of microRNA-486 ( miR-486 ) in cardiomyocyte apoptosis by interfering with the p53 activated BCL-2 associated mitochondrial pathway .	This study aimed to explore the mechanism of microRNA-486 (miR-486) in cardiomyocyte apoptosis by interfering with the p53 activated BCL-2 associated mitochondrial pathway.	16	22	activated	Positive_activation_token_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	19	20	21	22
Under stress conditions , the increased activity of p53 can increase the susceptibility of cells to death signals by shifting the balance between proapoptotic ( Bax , Noxa , and Puma ) and antiapoptotic ( Bcl2 , Birc5 ) proteins of the Bcl2 family , which regulate the activity of proteolytic enzymes called caspases .	Under stress conditions, the increased activity of p53 can increase the susceptibility of cells to death signals by shifting the balance between proapoptotic (Bax, Noxa, and Puma) and antiapoptotic (Bcl2, Birc5) proteins of the Bcl2 family, which regulate the activity of proteolytic enzymes called caspases.	6	43	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	8	9	42	43
p53 directly activated the proapoptotic Bcl-2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program .	p53 directly activated the proapoptotic Bcl-2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program.	0	7	directly activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	5	6
Indeed , in these conditions the pro apototic Bax , Noxa and PUMA genes and the anti-apoptotic BCL-2 gene which are not known as direct target genes of HIC1 but as direct P53 target genes are activated or repressed , respectively by P53 [ XREF_BIBR ] .	Indeed, in these conditions the pro apototic Bax, Noxa and PUMA genes and the anti-apoptotic BCL-2 gene which are not known as direct target genes of HIC1 but as direct P53 target genes are activated or repressed, respectively by P53 [XREF_BIBR].	17	44	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	P53	P53	P53	BCL-2	BCL-2	BCL-2	42	43	17	18
Death protein 5 ( DP5 ) , p53 upregulated modulator of apoptosis ( PUMA ) and BCL2 like protein 11 ( Bim ) are members of the BCL-2 ( B-cell lymphoma 2 ) family and have been shown to contribute to cytokine induced beta cell death .	Death protein 5 (DP5), p53 upregulated modulator of apoptosis (PUMA) and BCL2 like protein 11 (Bim) are members of the BCL-2 (B-cell lymphoma 2) family and have been shown to contribute to cytokine induced beta cell death.	4	33	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	7	8	27	28
The notion that p53 modulates the Bcl-2 apoptotic rheostat directly , by behaving as a BH3-only protein , and indirectly by increasing the levels of sensitizer BH3-only proteins , provides a rationale to combine HDM2 inhibitors with BH3 mimetics .	The notion that p53 modulates the Bcl-2 apoptotic rheostat directly, by behaving as a BH3-only protein, and indirectly by increasing the levels of sensitizer BH3-only proteins, provides a rationale to combine HDM2 inhibitors with BH3 mimetics.	3	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	3	4	6	7
These data indicate that in the kidney bcl-2 and bax are not modulated by p53 or by c-myc and imply the existence of other regulators of bcl-2 family members in kidney as reported for p53 in neurons .	These data indicate that in the kidney bcl-2 and bax are not modulated by p53 or by c-myc and imply the existence of other regulators of bcl-2 family members in kidney as reported for p53 in neurons.	7	19	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	bcl-2	bcl-2	bcl-2	14	15	7	8
Dehy , CD and VOSL treatment all can up-regulate the expression of p53 , and increase the ratio of BAX to BCL-2 .	Dehy, CD and VOSL treatment all can up-regulate the expression of p53, and increase the ratio of BAX to BCL-2.	2	22	increase	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	p53	CD and VOSL treatment all can up-regulate the expression of p53	p53	BCL-2	BCL-2	bcl-2	12	13	21	22
MiR-486 regulates cardiomyocyte apoptosis by p53 mediated BCL-2 associated mitochondrial apoptotic pathway .	MiR-486 regulates cardiomyocyte apoptosis by p53 mediated BCL-2 associated mitochondrial apoptotic pathway.	1	8	mediated	Positive_early_activation	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	5	6	7	8
Furthermore , low Ku70/80 expression was strongly related to suppressed BAX ( p < 0.001 ) and , to a lesser extent , upregulated BCL-2 ( p = 0.042 ) , altered p53 ( p = 0.038 ) , and increased proliferation ( p = 0.002 ) .	Furthermore, low Ku70/80 expression was strongly related to suppressed BAX (p < 0.001) and, to a lesser extent, upregulated BCL-2 (p = 0.042), altered p53 (p = 0.038), and increased proliferation (p = 0.002).	7	35	upregulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL-2	BCL-2	BCL-2	32	33	24	25
p53 transfers to the mitochondria and then changes the mitochondrial membrane potential and induces the inter-reaction of the Bcl-2 family .	p53 transfers to the mitochondria and then changes the mitochondrial membrane potential and induces the inter-reaction of the Bcl-2 family.	0	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	0	1	18	19
Despite the fact that Siva-1 lacks even a minimal BH3 domain , similar to other proapoptotic Bcl2 family members induced by p53 , we showed that Siva-1 mediated apoptosis is characterized by Bax oligomerization and cytochrome c leakage from mitochondria .	Despite the fact that Siva-1 lacks even a minimal BH3 domain, similar to other proapoptotic Bcl2 family members induced by p53, we showed that Siva-1 mediated apoptosis is characterized by Bax oligomerization and cytochrome c leakage from mitochondria.	16	22	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl2	Bcl2	Bcl2	21	22	16	17
However , since BCL2 family members can be modulated by JNK and p53 in apoptosis , the inhibition of NOXA expression by PLX4720 and vemurafenib ( XREF_FIG ) likely reflects p53 independent regulation of NOXA given that p53 is mutant in HaCaT cells , p53 is undetectable in SRB12 cells , and p53 levels do not change with radiation in SRB1 , COLO16 , or HaCaT cells , ( XREF_FIG ) .	However, since BCL2 family members can be modulated by JNK and p53 in apoptosis, the inhibition of NOXA expression by PLX4720 and vemurafenib (XREF_FIG) likely reflects p53 independent regulation of NOXA given that p53 is mutant in HaCaT cells, p53 is undetectable in SRB12 cells, and p53 levels do not change with radiation in SRB1, COLO16, or HaCaT cells, (XREF_FIG).	3	13	modulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	BCL2	BCL2	BCL2	12	13	3	4
Recently , p53 has been shown to directly activate the pro apoptotic Bcl-2 protein Bax allowing for mitochondrial membrane permeabilization and apoptosis .	Recently, p53 has been shown to directly activate the pro apoptotic Bcl-2 protein Bax allowing for mitochondrial membrane permeabilization and apoptosis.	2	14	directly activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-2	Bcl-2	Bcl-2	2	3	12	13
Phosphorylation of TSC2 by activated AKT disrupts its interaction with TSC1 , which prevents mTOR inhibition and leads to activation of protein synthesis via p70 S6 kinase and inactivation of the eukaryotic initiation factor 4E binding protein 1 ( an inhibitor of translation ) [ XREF_BIBR ] .	Phosphorylation of TSC2 by activated AKT disrupts its interaction with TSC1, which prevents mTOR inhibition and leads to activation of protein synthesis via p70 S6 kinase and inactivation of the eukaryotic initiation factor 4E binding protein 1 (an inhibitor of translation) [XREF_BIBR].	6	17	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	10	11	14	15
The IKKbeta mediated TSC1 phosphorylation impairs the integrity of the tuberous sclerosis complex ( TSC1 , hamartin / TSC2 , tuberin ) complex and activates the mTOR pathway .	The IKKbeta mediated TSC1 phosphorylation impairs the integrity of the tuberous sclerosis complex (TSC1, hamartin / TSC2, tuberin) complex and activates the mTOR pathway.	1	27	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	IKKbeta mediated TSC1 phosphorylation	tsc1	mTOR	mTOR	mtor	3	4	26	27
Phosphorylation of TSC1 by IKK2 at S487 and S511 results in the suppression of TSC1/2 complex and induces mTOR activation .	Phosphorylation of TSC1 by IKK2 at S487 and S511 results in the suppression of TSC1/2 complex and induces mTOR activation.	0	19	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	Phosphorylation of TSC1 by IKK2 at S487	tsc1	mTOR	mTOR	mtor	2	3	18	19
Mutations have also been identified in the negative regulators of mTOR signaling TSC1 and TSC2 .	Mutations have also been identified in the negative regulators of mTOR signaling TSC1 and TSC2.	8	14	signaling	Positive_activation_token_1_noun	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	12	13	10	11
To determine whether upregulation of the GluN2C and D-NMDAR component in L4 is a direct consequence of enhanced mTOR signalling caused by Tsc1 inactivation , we performed experiments in Tsc1 +/- mice chronically treated with the mTOR inhibitor rapamycin ( see Methods section ) .	To determine whether upregulation of the GluN2C and D-NMDAR component in L4 is a direct consequence of enhanced mTOR signalling caused by Tsc1 inactivation, we performed experiments in Tsc1 +/- mice chronically treated with the mTOR inhibitor rapamycin (see Methods section).	18	23	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	22	23	18	19
Additionally , chromosome 9 harbors the TSC1 tumor suppressor which downregulates the well-known anti-apoptotic Akt and mTOR pathway .	Additionally, chromosome 9 harbors the TSC1 tumor suppressor which downregulates the well-known anti-apoptotic Akt and mTOR pathway.	6	17	downregulates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	6	7	16	17
Thus , TSC2 may retain some function in the absence of TSC1 , while TSC1 , lacking a catalytic domain , would be unable to inhibit mammalian target of rapamycin signaling without TSC2 [ XREF_BIBR ] .	Thus, TSC2 may retain some function in the absence of TSC1, while TSC1, lacking a catalytic domain, would be unable to inhibit mammalian target of rapamycin signaling without TSC2 [XREF_BIBR].	14	30	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	14	15	26	30
Next , we aimed to determine whether Tsc1 deficiency resulted in hyperactive mTOR signaling in the pancreas .	Next, we aimed to determine whether Tsc1 deficiency resulted in hyperactive mTOR signaling in the pancreas.	7	14	signaling	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	7	8	12	13
XREF_BIBR reported that autophagy repression involved suppression of TSC1 , which triggered the mTOR pathway .	XREF_BIBR reported that autophagy repression involved suppression of TSC1, which triggered the mTOR pathway.	6	14	triggered	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	8	9	13	14
For instance , IKKbeta phosphorylation of TSC1 activates mTOR pathway , whereas phosphorylation of FoxO3 by IKKbeta deactivates FoxO related transcription independently from the NF-kappaB pathway ( Chariot 2009 ) .	For instance, IKKbeta phosphorylation of TSC1 activates mTOR pathway, whereas phosphorylation of FoxO3 by IKKbeta deactivates FoxO related transcription independently from the NF-kappaB pathway (Chariot 2009).	3	9	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	IKKbeta phosphorylation of TSC1	tsc1	mTOR	mTOR	mtor	6	7	8	9
Neurogenin3 driven deletion of tuberous sclerosis complex 1 ( Tsc1 ) activated mechanistic target of rapamycin complex 1 ( mTORC1 ) measured by the upregulation of mTOR and S6 phosphorylation in islet cells .	Neurogenin3 driven deletion of tuberous sclerosis complex 1 (Tsc1) activated mechanistic target of rapamycin complex 1 (mTORC1) measured by the upregulation of mTOR and S6 phosphorylation in islet cells.	2	16	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	9	10	12	16
Importantly , the network model showed that mTOR complex 2 ( mTORC2 ) would be deactivated by TSC1 deletion , and that the mTORC2 interacts with RhoA ( Rhoa ) , MAPK ( Map2k1/2 via Prkcb ) , and Pik3 and Akt ( Pik3r1/ca via Prkcb ) pathways that could modulate the activity of the actin cytoskeleton regulation .	Importantly, the network model showed that mTOR complex 2 (mTORC2) would be deactivated by TSC1 deletion, and that the mTORC2 interacts with RhoA (Rhoa), MAPK (Map2k1/2 via Prkcb), and Pik3 and Akt (Pik3r1/ca via Prkcb) pathways that could modulate the activity of the actin cytoskeleton regulation.	7	18	deactivated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	17	18	7	8
Moreover the activation of mTOR in epithelial cells , by genetic ablation of two of its upstream regulators Pten and Tsc1 , accelerate cutaneous wound healing .	Moreover the activation of mTOR in epithelial cells, by genetic ablation of two of its upstream regulators Pten and Tsc1, accelerate cutaneous wound healing.	2	21	activation	Positive_activation_syntax_1_noun	Negative_activation	Positive_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	20	21	4	5
These results suggest that TSC1 inactivation enhances mTOR activity in the pulmonary epithelia .	These results suggest that TSC1 inactivation enhances mTOR activity in the pulmonary epithelia.	4	8	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	4	5	7	8
This is in accordance with previous work showing that blocking HSC differentiation by TSC1 mediated mTOR pathway inhibition is accompanied by a decrease in mitochondrial mass XREF_BIBR .	This is in accordance with previous work showing that blocking HSC differentiation by TSC1 mediated mTOR pathway inhibition is accompanied by a decrease in mitochondrial mass XREF_BIBR.	9	17	mediated	Positive_early_activation	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	13	14	15	16
Defective or deficient TSC1 or TSC2 activity leads to unchecked activation of mTOR and formation of characteristic hamartomas [ XREF_BIBR XREF_BIBR XREF_BIBR ] .	Defective or deficient TSC1 or TSC2 activity leads to unchecked activation of mTOR and formation of characteristic hamartomas [XREF_BIBR XREF_BIBR XREF_BIBR].	0	14	leads to	Positive_activation_nested_syntax_2_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	3	4	12	13
Phosphorylation of TSC-1 by IKKbeta activates the mTOR pathway and enhances angiogenesis , and phosphorylation of FOXO3a induces its degradation , leading to enhanced cell proliferation and survival .	Phosphorylation of TSC-1 by IKKbeta activates the mTOR pathway and enhances angiogenesis, and phosphorylation of FOXO3a induces its degradation, leading to enhanced cell proliferation and survival.	0	8	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC-1	Phosphorylation of TSC-1	tsc-1	mTOR	mTOR	mtor	2	3	7	8
After retinoic acid ( RA ) differentiation , TSC1 +/-cells maintained lower levels of TSC1 and hamartin and increased mTOR activity .	After retinoic acid (RA) differentiation, TSC1 +/-cells maintained lower levels of TSC1 and hamartin and increased mTOR activity.	8	20	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	8	9	19	20
Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures .	Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.	0	6	repressors	Negative_activation_token_1_noun	Negative_activation	Positive_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	4	5	2	3
While the authors suggested it was unlikely that a monoallelic mutation in TSC1 could cooperate with a germline TSC2 mutation to drive MTOR activation , we feel that together , our reports with similar observations from unique patients supports the idea that trans-heterozygous TSC1 and TSC2 mutations may contribute to tumorigenesis in TSC .	While the authors suggested it was unlikely that a monoallelic mutation in TSC1 could cooperate with a germline TSC2 mutation to drive MTOR activation, we feel that together, our reports with similar observations from unique patients supports the idea that trans-heterozygous TSC1 and TSC2 mutations may contribute to tumorigenesis in TSC.	10	23	drive	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	MTOR	MTOR	MTOR	12	13	22	23
Tuberous sclerosis complex 1 ( TSC1 ) inhibits mammalian target of rapamycin ( mTOR ) , a central promotor of cell growth and proliferation .	Tuberous sclerosis complex 1 (TSC1) inhibits mammalian target of rapamycin (mTOR), a central promotor of cell growth and proliferation.	2	12	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	5	6	8	12
Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 ( Tsc1 ) , which negatively regulates mammalian target of rapamycin complex 1 ( mTORC1 ) , functions in oocytes to maintain the quiescence of primordial follicles .	Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles.	6	29	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	16	17	22	26
TSC1 deletion in the myeloid lineage constitutively activated mechanistic target of rapamycin complex 1 ( mTORC1 ) , increased M1 polarisation in synovial macrophages and exacerbated experimental OA in both CIOA and DMM models , while Rheb deletion inhibited mTORC1 , enhanced M2 polarisation and alleviated CIOA in mice .	TSC1 deletion in the myeloid lineage constitutively activated mechanistic target of rapamycin complex 1 (mTORC1), increased M1 polarisation in synovial macrophages and exacerbated experimental OA in both CIOA and DMM models, while Rheb deletion inhibited mTORC1, enhanced M2 polarisation and alleviated CIOA in mice.	0	12	activated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1	TSC1	mechanistic target of rapamycin	mechanistic target of rapamycin	mechanistic target of rapamycin	0	1	8	12
The study aimed to investigate the mechanism of electroacupuncture reducing weight via tuberous sclerosis complex 1 ( Tsc1 ) promoter methylation , inhibiting the mammalian target of rapamycin complex 1 ( mTORC1 ) pathway .	The study aimed to investigate the mechanism of electroacupuncture reducing weight via tuberous sclerosis complex 1 (Tsc1) promoter methylation, inhibiting the mammalian target of rapamycin complex 1 (mTORC1) pathway.	10	28	inhibiting	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc1	Tsc1	Tsc1	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	17	18	24	28
TSC1 -/- produces a hyperactive mTOR phenotype that is fatal in mice from gestation day 13.5 .	TSC1 -/- produces a hyperactive mTOR phenotype that is fatal in mice from gestation day 13.5.	0	6	produces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	0	1	5	6
These results suggest that sustained hyperactivation of mTOR caused by Tsc1 ablation activates the apoptotic pathway during the onset of OPC differentiation .	These results suggest that sustained hyperactivation of mTOR caused by Tsc1 ablation activates the apoptotic pathway during the onset of OPC differentiation.	5	11	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	10	11	7	8
In determining the phosphorylation status of S6K1 at T389 [ pS6K1 ( T389 ) ] and 4EBP1 at S65 [ p4EBP1 ( S65 ) ] , which are two downstream phosphorylation sites of mTOR , we found higher expression of pS6K1 ( T389 ) and p4EBP1 ( S65 ) in 453-TSC1 ( SSDD ) stable transfectants than in MDA-MB-453-TSC1 ( WT ) or MDA-MB-453- TSC1 ( SSAA ) stable transfectants ( XREF_FIG ) , confirming our previous finding that IKKbeta phosphorylation of TSC1 activates the mTOR pathway .	In determining the phosphorylation status of S6K1 at T389 [pS6K1 (T389)] and 4EBP1 at S65 [p4EBP1 (S65)], which are two downstream phosphorylation sites of mTOR, we found higher expression of pS6K1 (T389) and p4EBP1 (S65) in 453-TSC1 (SSDD) stable transfectants than in MDA-MB-453-TSC1 (WT) or MDA-MB-453- TSC1 (SSAA) stable transfectants (XREF_FIG), confirming our previous finding that IKKbeta phosphorylation of TSC1 activates the mTOR pathway.	79	86	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	IKKbeta phosphorylation of TSC1	tsc1	mTOR	mTOR	mtor	82	83	85	86
Consistently , we demonstrate that pancreatic acinar cells do not tolerate hyperactive mTOR signaling induced by Tsc1 deficiency and undergo apoptosis , likely in a p53 dependent way .	Consistently, we demonstrate that pancreatic acinar cells do not tolerate hyperactive mTOR signaling induced by Tsc1 deficiency and undergo apoptosis, likely in a p53 dependent way.	12	17	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	16	17	12	13
Study of one patient is highly instructive , in which two distinct and spatially separate mutations in TSC1 and MTOR join along the PI3K/AKT/mTOR pathway and activate mTOR kinase through different mechanisms [ XREF_BIBR ] .	Study of one patient is highly instructive, in which two distinct and spatially separate mutations in TSC1 and MTOR join along the PI3K/AKT/mTOR pathway and activate mTOR kinase through different mechanisms [XREF_BIBR].	15	28	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	17	18	27	28
It has been reported that TSC1 also activates mTOR independent pathways such as RAF and NOTCH .	It has been reported that TSC1 also activates mTOR independent pathways such as RAF and NOTCH.	5	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1	TSC1	mTOR	mTOR	mTOR	5	6	8	9
In a second phase , we postulate that calpain activation , through PTEN , hamartin and tuberin degradation relieves mTOR inhibition and stimulates protein synthesis , which might be critical for providing long-term consolidation of modified spine structures .	In a second phase, we postulate that calpain activation, through PTEN, hamartin and tuberin degradation relieves mTOR inhibition and stimulates protein synthesis, which might be critical for providing long-term consolidation of modified spine structures.	9	20	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	hamartin	hamartin	hamartin	mTOR	mTOR	mTOR	14	15	19	20
For instance , phosphorylation of Foxo3 or beta-catenin by IKKbeta deactivates Foxo- and beta-catenin-dependent transcription , respectively , while IKKbeta phosphorylation of TSC1 activates the mTOR pathway .	For instance, phosphorylation of Foxo3 or beta-catenin by IKKbeta deactivates Foxo- and beta-catenin-dependent transcription, respectively, while IKKbeta phosphorylation of TSC1 activates the mTOR pathway.	19	26	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	IKKbeta phosphorylation of TSC1	tsc1	mTOR	mTOR	mtor	22	23	25	26
Tsc1 ablation in Schwann cell progenitors in mice resulted in activation of mTOR signaling , and caused over-proliferation of Schwann cells and blocked their differentiation , leading to hypomyelination .	Tsc1 ablation in Schwann cell progenitors in mice resulted in activation of mTOR signaling, and caused over-proliferation of Schwann cells and blocked their differentiation, leading to hypomyelination.	0	13	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	Tsc1	Tsc1	Tsc1	mTOR	mTOR	mTOR	0	1	12	13
These findings imply that AKT mediated phosphorylation of tuberin does not directly alter the rates at which tuberin enhances the GTPase activity of Rheb , at least in vitro .	These findings imply that AKT mediated phosphorylation of tuberin does not directly alter the rates at which tuberin enhances the GTPase activity of Rheb, at least in vitro.	17	24	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	Rheb	Rheb	Rheb	17	18	23	24
It is currently thought that , under basal conditions , the GAP domain of TSC2 stimulates Rheb ' s intrinsic GTPase activity which converts active GTP-Rheb into inactive GDP-Rheb , and thus leads to a repression of mTORC1 signaling [ XREF_BIBR - XREF_BIBR ] .	It is currently thought that, under basal conditions, the GAP domain of TSC2 stimulates Rheb 's intrinsic GTPase activity which converts active GTP-Rheb into inactive GDP-Rheb, and thus leads to a repression of mTORC1 signaling [XREF_BIBR - XREF_BIBR].	12	18	stimulates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	14	15	16	17
XREF_BIBR , XREF_BIBR AKT dependent phosphorylation of TSC2 prevents RHEB inhibition , leading to MTORC1 activation and autophagy inhibition .	XREF_BIBR, XREF_BIBR AKT dependent phosphorylation of TSC2 prevents RHEB inhibition, leading to MTORC1 activation and autophagy inhibition.	3	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	AKT dependent phosphorylation of TSC2	tsc2	RHEB	RHEB	rheb	7	8	9	10
TSC2 has GTPase activating protein ( GAP ) activity towards the Ras family small GTPase Rheb ( ras homolog enriched in brain ) and thereby can enhance the conversion of Rheb into its GDP bound inactive state , leading to inactivation of the mTORC1 .	TSC2 has GTPase activating protein (GAP) activity towards the Ras family small GTPase Rheb (ras homolog enriched in brain) and thereby can enhance the conversion of Rheb into its GDP bound inactive state, leading to inactivation of the mTORC1.	0	31	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	0	1	30	31
In basal conditions , TSC2 stimulates Rheb ' s GTPase activity , which , in turn , leads to conversion of active GTP-Rheb into inactive GDP-Rheb , thereby repressing mTORC1 activity .	In basal conditions, TSC2 stimulates Rheb 's GTPase activity, which, in turn, leads to conversion of active GTP-Rheb into inactive GDP-Rheb, thereby repressing mTORC1 activity.	4	10	stimulates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	4	5	6	7
Indeed , activated Akt phosphorylates and inhibits tuberous sclerosis 2 ( TSC2 ) , allowing Ras homolog enriched in brain ( Rheb ) to accumulate in the GTP bound state and trigger activation of the mTOR complex1 ( mTORC1 ) pathway .	Indeed, activated Akt phosphorylates and inhibits tuberous sclerosis 2 (TSC2), allowing Ras homolog enriched in brain (Rheb) to accumulate in the GTP bound state and trigger activation of the mTOR complex1 (mTORC1) pathway.	8	20	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	11	12	15	20
The Akt mediated phosphorylation of TSC2 protein , which combined with TSC1 protein forms a Ras homologue enriched in brain ( Rheb ) inhibiting complex , allows Rheb to be released and activated .	The Akt mediated phosphorylation of TSC2 protein, which combined with TSC1 protein forms a Ras homologue enriched in brain (Rheb) inhibiting complex, allows Rheb to be released and activated.	1	30	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Akt mediated phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	5	6	27	28
Phosphorylation of TSC1 and TSC2 dissociates with and thereby activates Rheb .	Phosphorylation of TSC1 and TSC2 dissociates with and thereby activates Rheb.	0	11	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC1 and TSC2	tsc2	Rheb	Rheb	rheb	4	5	10	11
These findings demonstrate that Akt mediated phosphorylation impairs the ability of TSC2 to inhibit Rheb and mTORC1 .	These findings demonstrate that Akt mediated phosphorylation impairs the ability of TSC2 to inhibit Rheb and mTORC1.	4	16	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Akt mediated phosphorylation impairs the ability of TSC2	tsc2	Rheb	Rheb	rheb	11	12	14	15
Once Akt is activated , it phosphorylates tumor sclerosis complex 2 ( TSC2 ) , relieving its suppression of the guanosine triphosphatase ( GTPase ) Rheb , which leads to the activation of mTORC1 .	Once Akt is activated, it phosphorylates tumor sclerosis complex 2 (TSC2), relieving its suppression of the guanosine triphosphatase (GTPase) Rheb, which leads to the activation of mTORC1.	6	28	relieving	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	phosphorylates tumor sclerosis complex 2 (TSC2	tsc2	Rheb	Rheb	rheb	12	13	25	26
Downregulation of TSC2 may reduce the GAP activity of TSC2 and promotes RheB activation , resulting in the activation of mTOR and S6K1 .	Downregulation of TSC2 may reduce the GAP activity of TSC2 and promotes RheB activation, resulting in the activation of mTOR and S6K1.	0	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	RheB	RheB	RheB	2	3	12	13
In response to growth signals , tuberin is phosphorylated by AKT and translocates to the cytosol , relieving Rheb repression .	In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression.	6	19	relieving	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	tuberin	tuberin is phosphorylated by AKT and translocates to the cytosol	tuberin	Rheb	Rheb	rheb	6	7	18	19
There is also a functional link between Tsc2 and Pkd1 : in human cells , TSC2 protein alternates from an inactive , phosphorylated form in the cytosol to an active , non phosphorylated form at the plasma membrane bound to the intracellular , carboxy-terminal tail of polycystin-1 ; in this subcellular position , TSC2 protein activates the GTPase of Rheb , resulting in the inactivation of the mTOR pathway [ XREF_BIBR ] .	There is also a functional link between Tsc2 and Pkd1 : in human cells, TSC2 protein alternates from an inactive, phosphorylated form in the cytosol to an active, non phosphorylated form at the plasma membrane bound to the intracellular, carboxy-terminal tail of polycystin-1; in this subcellular position, TSC2 protein activates the GTPase of Rheb, resulting in the inactivation of the mTOR pathway [XREF_BIBR].	53	60	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	53	54	59	60
To investigate the function of TSC2 and Rheb in mTOR signaling , we analyzed the TSC2 stimulated Rheb GTPase activity .	To investigate the function of TSC2 and Rheb in mTOR signaling, we analyzed the TSC2 stimulated Rheb GTPase activity.	14	19	stimulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	15	16	17	18
Co-expression of a human TSC2 harboring a disease associated point mutation in the GAP domain , failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1 [ XREF_BIBR , XREF_BIBR ] .	Co-expression of a human TSC2 harboring a disease associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1 [XREF_BIBR, XREF_BIBR].	0	21	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Co-expression of a human TSC2	tsc2	Rheb	Rheb	rheb	4	5	19	20
Akt phosphorylates and inactivates TSC2 , thereby allowing increased activity of Rheb , TOR , and S6 kinase .	Akt phosphorylates and inactivates TSC2, thereby allowing increased activity of Rheb, TOR, and S6 kinase.	0	12	allowing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Akt phosphorylates and inactivates TSC2	tsc2	Rheb	Rheb	rheb	4	5	11	12
Since TSC1/2 is a negative regulator of the mTORC1 activator RHEB , AKT mediated TSC2 phosphorylation allows GTP loaded RHEB to bind and activate mTORC1 .	Since TSC1/2 is a negative regulator of the mTORC1 activator RHEB, AKT mediated TSC2 phosphorylation allows GTP loaded RHEB to bind and activate mTORC1.	12	23	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	AKT mediated TSC2 phosphorylation	tsc2	RHEB	RHEB	rheb	14	15	19	20
Phosphorylation of TSC2 leading to its inactivation allows Rheb kept in the GTP bound state , further inducing increased mTOR activation [ XREF_BIBR ] .	Phosphorylation of TSC2 leading to its inactivation allows Rheb kept in the GTP bound state, further inducing increased mTOR activation [XREF_BIBR].	0	9	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	2	3	8	9
In this in vitro assay , WT-TSC2 promoted the intrinsic GTPase activity of Rheb as observed by accumulation of [ alpha- 32 P ]-GDP bound Rheb , while none of the PxBS mutants functioned as a Rheb GAP , similar to what was observed in control experiments with the TSC2 GAP domain mutant ( L1624P ) protein ( XREF_FIG ) .	In this in vitro assay, WT-TSC2 promoted the intrinsic GTPase activity of Rheb as observed by accumulation of [alpha- 32 P]-GDP bound Rheb, while none of the PxBS mutants functioned as a Rheb GAP, similar to what was observed in control experiments with the TSC2 GAP domain mutant (L1624P) protein (XREF_FIG).	6	14	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WT-TSC2	WT-TSC2	WT-TSC2	Rheb	Rheb	Rheb	6	7	13	14
This dephosphorylation of Thr 308 ( but not the Ser 473 residue ) subsequently leads to a reduction in the Akt mediated phosphorylation of TSC2 , followed by TSC2 mediated stimulation of Rheb GTPase activity .	This dephosphorylation of Thr 308 (but not the Ser 473 residue) subsequently leads to a reduction in the Akt mediated phosphorylation of TSC2, followed by TSC2 mediated stimulation of Rheb GTPase activity.	28	34	stimulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	28	29	32	33
We demonstrate that TSC2 localization is modulated by arginine together with the classical TSC regulators , growth factors , to tightly control Rheb and ultimately mTORC1 activity in a spatial and temporal manner .	We demonstrate that TSC2 localization is modulated by arginine together with the classical TSC regulators, growth factors, to tightly control Rheb and ultimately mTORC1 activity in a spatial and temporal manner.	3	26	modulated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	3	4	22	23
Interestingly , the defect in mTOR activation could be circumvented by over expression of Rheb but not by relieving the natural inhibition of Rheb by TSC2 .	Interestingly, the defect in mTOR activation could be circumvented by over expression of Rheb but not by relieving the natural inhibition of Rheb by TSC2.	12	26	relieving	Negative_regulation_syntax_3_verb	Negative_activation	Negative_regulation	TSC2	TSC2	tsc2	Rheb	expression of Rheb	rheb	25	26	14	15
In particular , the direct phosphorylation of TSC2 by Akt promotes the release of Rheb from the TSC complex and activates mTORC1 [ XREF_BIBR , XREF_BIBR ] .	In particular, the direct phosphorylation of TSC2 by Akt promotes the release of Rheb from the TSC complex and activates mTORC1 [XREF_BIBR, XREF_BIBR].	5	15	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	7	8	14	15
Finally , coexpression of a human TSC2 cDNA harboring a disease associated point mutation in the GAP domain , failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1 .	Finally, coexpression of a human TSC2 cDNA harboring a disease associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1.	2	24	stimulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	coexpression of a human TSC2	tsc2	Rheb	Rheb	rheb	6	7	22	23
The TSC2 and TSC1 tuberous sclerosis complex , acting downstream of AKT , negatively regulates mTORC1 by inhibiting the GTPase activity of Rheb ( Ras Homolog Enriched in Brain ) , which is a positive regulator of mTORC1 .	The TSC2 and TSC1 tuberous sclerosis complex, acting downstream of AKT, negatively regulates mTORC1 by inhibiting the GTPase activity of Rheb (Ras Homolog Enriched in Brain), which is a positive regulator of mTORC1.	0	35	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	1	2	22	23
The phosphorylation of TSC2 blocks TSC2 mediated inhibition of the GTPase Ras homolog enriched in brain ( RHEB ) .	The phosphorylation of TSC2 blocks TSC2 mediated inhibition of the GTPase Ras homolog enriched in brain (RHEB).	5	16	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Ras homolog enriched in brain	Ras homolog enriched in brain	Ras homolog enriched in brain	5	6	11	16
AKT mediated phosphorylation of TSC2 relieves its inhibition of Rheb activity , leading to activation of the rapamycin and sensitivemTOR complex mTORC1 .	AKT mediated phosphorylation of TSC2 relieves its inhibition of Rheb activity, leading to activation of the rapamycin and sensitivemTOR complex mTORC1.	0	10	relieves	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	AKT mediated phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	4	5	9	10
This includes the inhibition of mTOR through the phosphorylation of the tumor suppressor TSC2 , which inactivates Rheb and dampens mTOR activity .	This includes the inhibition of mTOR through the phosphorylation of the tumor suppressor TSC2, which inactivates Rheb and dampens mTOR activity.	8	19	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	phosphorylation of the tumor suppressor TSC2	tsc2	Rheb	Rheb	rheb	13	14	17	18
AMPK can phosphorylate Raptor ( regulatory associated protein of mTOR ) , an essential component of mTOR complex 1 ( mTORC1 ) , the activity of which blocks autophagy or can phosphorylate TSC2 ( tuberous sclerosis complex 2 ) that directly inhibits Ras homolog enriched in brain ( Rheb )-mediated mTORC1activation .	AMPK can phosphorylate Raptor (regulatory associated protein of mTOR), an essential component of mTOR complex 1 (mTORC1), the activity of which blocks autophagy or can phosphorylate TSC2 (tuberous sclerosis complex 2) that directly inhibits Ras homolog enriched in brain (Rheb)-mediated mTORC1activation.	3	47	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	Raptor (regulatory associated protein of mTOR), an essential component of mTOR complex 1 (mTORC1), the activity of which blocks autophagy or can phosphorylate TSC2	tsc2	Ras homolog enriched in brain	Ras homolog enriched in brain	ras homolog enriched in brain	32	33	42	47
In amino-acid-starved mammalian cells , Tsc2 is recruited to lysosomal membranes by the Rag GTPases and inhibits Rheb , resulting in inactivation of mTORC1 .	In amino-acid-starved mammalian cells, Tsc2 is recruited to lysosomal membranes by the Rag GTPases and inhibits Rheb, resulting in inactivation of mTORC1.	5	18	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Tsc2	Tsc2 is recruited to lysosomal membranes	tsc2	Rheb	Rheb	rheb	5	6	17	18
Phosphorylation of TSC2 by Akt results in activation of the Rheb GTPase while phosphorylation of the PRAS40 induces the dissociation of this inhibitory component from the mTORC1 complex .	Phosphorylation of TSC2 by Akt results in activation of the Rheb GTPase while phosphorylation of the PRAS40 induces the dissociation of this inhibitory component from the mTORC1 complex.	0	11	results in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	2	3	10	11
Tsc2 encodes tuberin , a GTPase activating protein that activates Rheb , an activator of mTor .	Tsc2 encodes tuberin, a GTPase activating protein that activates Rheb, an activator of mTor.	1	13	activates	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	tuberin	tuberin	tuberin	Rheb	Rheb	Rheb	2	3	10	11
Based on current evidence , it appears that the GAP domain of TSC2 stimulates Rheb ' s intrinsic GTPase activity , and in turn , converts active GTP-Rheb into inactive GDP-Rheb .	Based on current evidence, it appears that the GAP domain of TSC2 stimulates Rheb 's intrinsic GTPase activity, and in turn, converts active GTP-Rheb into inactive GDP-Rheb.	10	16	stimulates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	12	13	14	15
Tsc2 serves as a GTPase activating protein for the small G protein Rheb ( Ras homologue enriched in brain ) and , thus , accelerates the inactivation of Rheb .	Tsc2 serves as a GTPase activating protein for the small G protein Rheb (Ras homologue enriched in brain) and, thus, accelerates the inactivation of Rheb.	0	29	accelerates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tsc2	Tsc2	Tsc2	Rheb	Rheb	Rheb	0	1	28	29
Consistent with the findings in TSC2 knockout cells , overexpressing Rheb in HEK293 cells also led to a higher rate of readthrough and misincorporation errors during translation of Fluc mutants ( XREF_SUPPLEMENTARY ) .	Consistent with the findings in TSC2 knockout cells, overexpressing Rheb in HEK293 cells also led to a higher rate of readthrough and misincorporation errors during translation of Fluc mutants (XREF_SUPPLEMENTARY).	5	13	overexpressing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	5	6	10	11
Phosphorylation of TSC2 suppresses the inhibition of Rheb , leading to the activation of mTORC1 , a key regulator of cell metabolism and protein synthesis .	Phosphorylation of TSC2 suppresses the inhibition of Rheb, leading to the activation of mTORC1, a key regulator of cell metabolism and protein synthesis.	0	8	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	2	3	7	8
RHEB in turn is negatively regulated by the GTPase activating domain of the TSC2 tumor suppressor , which relays signals from multiple growth factor and stress pathways 17 .	RHEB in turn is negatively regulated by the GTPase activating domain of the TSC2 tumor suppressor, which relays signals from multiple growth factor and stress pathways 17.	0	15	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	RHEB	RHEB	RHEB	13	14	0	1
XREF_BIBR In addition , AKT phosphorylates and inactivates TSC2 , which allows RHEB to activate mTORC1 ( XREF_FIG ) .	XREF_BIBR In addition, AKT phosphorylates and inactivates TSC2, which allows RHEB to activate mTORC1 (XREF_FIG).	4	14	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	AKT phosphorylates and inactivates TSC2	tsc2	RHEB	RHEB	rheb	8	9	12	13
PI3K stimulates mTORC1 by increasing Akt activity , which in turn phosphorylates TSC2 and relieves TSC1 and TSC2 inhibition of the mTORC1 activating GTPase Rheb .	PI3K stimulates mTORC1 by increasing Akt activity, which in turn phosphorylates TSC2 and relieves TSC1 and TSC2 inhibition of the mTORC1 activating GTPase Rheb.	15	25	inhibition	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	17	18	24	25
Phosphorylation of TSC2 , by Akt , prevent its inhibition of Rheb from promoting mTORC1 activity .	Phosphorylation of TSC2, by Akt, prevent its inhibition of Rheb from promoting mTORC1 activity.	0	12	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Phosphorylation of TSC2	tsc2	Rheb	Rheb	rheb	2	3	11	12
We suggest that OT slows translation initiation by decreasing fully active pAkt ( pAkt T308-S473 ) by greater reductions of pAkt T308 than pAkt S473 and , that this results in less TSC2 inhibition , which reduces Rheb GTPase activity , decreasing the phosphorylation of S6K1 and 4E-BP1 as a result of reduced mTORC1 complex activation .	We suggest that OT slows translation initiation by decreasing fully active pAkt (pAkt T308-S473) by greater reductions of pAkt T308 than pAkt S473 and, that this results in less TSC2 inhibition, which reduces Rheb GTPase activity, decreasing the phosphorylation of S6K1 and 4E-BP1 as a result of reduced mTORC1 complex activation.	32	39	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	32	33	37	38
Akt phosphorylates and inhibits the tumour suppressor TSC2 and thereby indirectly activates RHEB , which in turn is a positive regulator of mTOR [ XREF_BIBR ] .	Akt phosphorylates and inhibits the tumour suppressor TSC2 and thereby indirectly activates RHEB, which in turn is a positive regulator of mTOR [XREF_BIBR].	0	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	Akt phosphorylates and inhibits the tumour suppressor TSC2	tsc2	RHEB	RHEB	rheb	7	8	12	13
The TSC2 and TSC1 tuberous sclerosis complex , acting as downstream of AKT , negatively regulates mTORC1 by inhibiting the GTPase activity of Rheb , which is a positive regulator of mTORC1 .	The TSC2 and TSC1 tuberous sclerosis complex, acting as downstream of AKT, negatively regulates mTORC1 by inhibiting the GTPase activity of Rheb, which is a positive regulator of mTORC1.	0	29	negatively regulates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	1	2	23	24
TSC2 phosphorylation consequently promotes the activation of the Ras homolog enriched in brain ( Rheb ) and the activation of mTOR [ XREF_BIBR ] .	TSC2 phosphorylation consequently promotes the activation of the Ras homolog enriched in brain (Rheb) and the activation of mTOR [XREF_BIBR].	0	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2 phosphorylation	tsc2	Ras homolog enriched in brain	Ras homolog enriched in brain	ras homolog enriched in brain	0	1	8	13
By contrast , activation of Akt can inhibit the activity of TSC2 , which promotes Rheb accumulation and results in mTOR activation [ XREF_BIBR , XREF_BIBR ] .	By contrast, activation of Akt can inhibit the activity of TSC2, which promotes Rheb accumulation and results in mTOR activation [XREF_BIBR, XREF_BIBR].	9	18	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	Rheb	Rheb	Rheb	11	12	15	16
The study found that the protein kinase Akt inactivates TSC-2 ( tuberous sclerosis complex 2 ) , which activates the GTP-ase Rheb .	The study found that the protein kinase Akt inactivates TSC-2 (tuberous sclerosis complex 2), which activates the GTP-ase Rheb.	8	22	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC-2	TSC-2	TSC-2	Rheb	Rheb	Rheb	9	10	21	22
We next tested whether VPS34 mediated downegulation of TSC2 resulted in activation of RheB .	We next tested whether VPS34 mediated downegulation of TSC2 resulted in activation of RheB.	6	14	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	RheB	RheB	RheB	8	9	13	14
Loss of function of either TSC1 or TSC2 inhibits RHEB inactivation , leading to hyperactive mTORC1 signaling .	Loss of function of either TSC1 or TSC2 inhibits RHEB inactivation, leading to hyperactive mTORC1 signaling.	2	10	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC2	TSC2	TSC2	RHEB	RHEB	RHEB	7	8	9	10
The hamartin and tuberin complex inhibits the mammalian target of rapamycin pathway that controls cell growth and proliferation .	The hamartin and tuberin complex inhibits the mammalian target of rapamycin pathway that controls cell growth and proliferation.	1	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	hamartin	hamartin and tuberin complex	hamartin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	1	2	7	11
These data indicate that activity of the TSC1 and TSC2 complex is dynamically regulated in cells undergoing ER stress and may mediate the modulation of mTOR activity in response to ER stress .	These data indicate that activity of the TSC1 and TSC2 complex is dynamically regulated in cells undergoing ER stress and may mediate the modulation of mTOR activity in response to ER stress.	7	26	mediate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	7	8	25	26
Protein products of these genes have been shown to form a heterodimer ( TSC1 and TSC2 complex ) that inhibits the mammalian target of rapamycin ( mTOR ) signaling cascade .	Protein products of these genes have been shown to form a heterodimer (TSC1 and TSC2 complex) that inhibits the mammalian target of rapamycin (mTOR) signaling cascade.	13	25	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 complex	tsc1	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	13	14	21	25
XREF_BIBR Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin ( mTOR ) protein kinase , which is a key regulator of several cellular functions , including nutrient sensing , protein synthesis , and cellular growth and proliferation .	XREF_BIBR Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin (mTOR) protein kinase, which is a key regulator of several cellular functions, including nutrient sensing, protein synthesis, and cellular growth and proliferation.	0	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hamartin	Hamartin and tuberin form a heterodimer	hamartin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	1	2	10	14
Hamartin and tuberin , encoded by the tumor suppressor genes TSC1 and TSC2 , form a heterodimeric protein complex that inhibits mTOR activity .	Hamartin and tuberin, encoded by the tumor suppressor genes TSC1 and TSC2, form a heterodimeric protein complex that inhibits mTOR activity.	0	22	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hamartin	Hamartin and tuberin, encoded by the tumor suppressor genes TSC1 and TSC2, form a heterodimeric	hamartin	mTOR	mTOR	mtor	0	1	21	22
Disruption of TSC1 and TSC2 complex only marginally restored curcumin mediated inhibition of mTOR signaling .	Disruption of TSC1 and TSC2 complex only marginally restored curcumin mediated inhibition of mTOR signaling.	2	14	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	2	3	13	14
By contrast in ADPKD , PC1 dysfunction precludes the TSC1 and TSC2 complex formation promoting mTOR activation , through a mechanism involving the cAMP dependent B-Raf and ERK pathway XREF_BIBR , XREF_BIBR .	By contrast in ADPKD, PC1 dysfunction precludes the TSC1 and TSC2 complex formation promoting mTOR activation, through a mechanism involving the cAMP dependent B-Raf and ERK pathway XREF_BIBR, XREF_BIBR.	7	16	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	9	10	15	16
Hamartin and tuberin , the TSC1 and TSC2 gene products , form a complex that inhibits mammalian target of rapamycin ( mTOR ) in a conserved cellular signaling pathway ( PI3kinase- Akt-mTOR pathway ) that regulates nutrient uptake , growth and protein translation XREF_BIBR , XREF_BIBR , XREF_BIBR .	Hamartin and tuberin, the TSC1 and TSC2 gene products, form a complex that inhibits mammalian target of rapamycin (mTOR) in a conserved cellular signaling pathway (PI3kinase- Akt-mTOR pathway) that regulates nutrient uptake, growth and protein translation XREF_BIBR, XREF_BIBR, XREF_BIBR.	0	20	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hamartin	Hamartin and tuberin, the TSC1 and TSC2 gene products, form a complex	hamartin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	16	20
We recently found that the TSC1 and TSC2 complex promotes the activity of mTOR complex 2 ( mTORC2 ) , an upstream activator of Akt , and this occurs independent of its inhibitory effects on mTORC1 .	We recently found that the TSC1 and TSC2 complex promotes the activity of mTOR complex 2 (mTORC2), an upstream activator of Akt, and this occurs independent of its inhibitory effects on mTORC1.	5	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	5	6	13	14
6 TSC1 and TSC2 proteins form a heterodimer complex that inhibits the mammalian target of rapamycin ( mTOR ) complex 1 ( mTORc1 ) .	6 TSC1 and TSC2 proteins form a heterodimer complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (mTORc1).	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 proteins form a heterodimer	tsc1	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	1	2	12	16
In cells , hamartin and tuberin form a complex which inhibits the mammalian target of rapamycin ( mTOR ) , a central controller of cell growth and proliferation .	In cells, hamartin and tuberin form a complex which inhibits the mammalian target of rapamycin (mTOR), a central controller of cell growth and proliferation.	3	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	hamartin	hamartin and tuberin form a complex	hamartin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	3	4	12	16
The TSC1 and TSC2 complex inactivates Rheb to inhibit mTOR signaling XREF_BIBR , XREF_BIBR .	The TSC1 and TSC2 complex inactivates Rheb to inhibit mTOR signaling XREF_BIBR, XREF_BIBR.	1	11	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1 and TSC2 complex	tsc1	mTOR	mTOR	mtor	1	2	9	10
The TSC1 and TSC2 proteins form a complex that inhibits mammalian target of rapamycin complex 1 ( mTORC1 ) signaling .	The TSC1 and TSC2 proteins form a complex that inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling.	1	14	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TSC1	TSC1 and TSC2 proteins form a complex	tsc1	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	1	2	10	14
The hamartin and tuberin complex can also inhibit the mammalian target of rapamycin ( mTOR ) signaling , resulting in the inhibition of translational initiator S6 kinase 1 and of the inhibitor of translational initiation 4E binding protein 1 [ XREF_BIBR ] .	The hamartin and tuberin complex can also inhibit the mammalian target of rapamycin (mTOR) signaling, resulting in the inhibition of translational initiator S6 kinase 1 and of the inhibitor of translational initiation 4E binding protein 1 [XREF_BIBR].	1	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	hamartin	hamartin and tuberin complex	hamartin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	1	2	9	13
The hamartin and tuberin complex inhibits the mammalian target of rapamycin pathway , which controls cell growth and proliferation .	The hamartin and tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation.	1	11	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	hamartin	hamartin and tuberin complex	hamartin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	1	2	7	11
This is the result of defects in the TSC1 and/or TSC2 tumor suppressor genes , encoding the hamartin and tuberin complex that inhibits the mammalian target of rapamycin pathway .	This is the result of defects in the TSC1 and/or TSC2 tumor suppressor genes, encoding the hamartin and tuberin complex that inhibits the mammalian target of rapamycin pathway.	17	28	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	hamartin	hamartin and tuberin complex	hamartin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	17	18	24	28
By activating the tuberous sclerosis complex TSC1 and TSC2 leading the activation of mTOR , Akt may represent a mechanistic link between S1P signaling and mTOR signaling as S1P regulates Akt phosphorylation as a ligand for five high-affinity G coupled receptors ( S1P 1-5 ) 46 in various physiological conditions .	By activating the tuberous sclerosis complex TSC1 and TSC2 leading the activation of mTOR, Akt may represent a mechanistic link between S1P signaling and mTOR signaling as S1P regulates Akt phosphorylation as a ligand for five high-affinity G coupled receptors (S1P 1-5) 46 in various physiological conditions.	2	14	leading	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	complex TSC1 and TSC2	tsc1	mTOR	mTOR	mtor	6	7	13	14
Hamartin and tuberin , the products of TSC1 and TSC2 , respectively , form heterodimers and inhibit the mammalian target of rapamycin .	Hamartin and tuberin, the products of TSC1 and TSC2, respectively, form heterodimers and inhibit the mammalian target of rapamycin.	0	22	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hamartin	Hamartin and tuberin, the products of TSC1 and TSC2, respectively, form heterodimers	hamartin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	18	22
tsc 1 and 2 produce hamartin and tuberin complex proteins that inhibit the mammalian target of rapamycin ( RPM ) pathway .	tsc 1 and 2 produce hamartin and tuberin complex proteins that inhibit the mammalian target of rapamycin (RPM) pathway.	0	17	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	hamartin	tsc 1 and 2 produce hamartin and tuberin complex	hamartin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	5	6	13	17
Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin complex 1 ( mTORC1 ) kinase , a major cellular regulator of protein translation , cell growth and proliferation .	Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin complex 1 (mTORC1) kinase, a major cellular regulator of protein translation, cell growth and proliferation.	0	13	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Hamartin	Hamartin and tuberin form a heterodimer	hamartin	mammalian target of rapamycin	mammalian target of rapamycin	mammalian target of rapamycin	0	1	9	13
Combined sulindac and ATO treatment also activated p53 expression , and inhibition of p53 expression by small interfering RNA ( siRNA ) prevented sulindac and ATO induced down-regulation of survivin , suggesting that survivin expression is negatively regulated by p53 .	Combined sulindac and ATO treatment also activated p53 expression, and inhibition of p53 expression by small interfering RNA (siRNA) prevented sulindac and ATO induced down-regulation of survivin, suggesting that survivin expression is negatively regulated by p53.	33	40	negatively regulated	Negative_regulation_syntax_2_verb	Negative_activation	Negative_regulation	p53	p53	p53	survivin	survivin expression	survivin	39	40	33	34
These results indicate that survivin down-regulation by As 2 O 3 is mediated by p53 activation .	These results indicate that survivin down-regulation by As 2 O 3 is mediated by p53 activation.	4	15	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	survivin	survivin	survivin	14	15	4	5
p53 inhibition by transfection with p53 siRNA prevented the down-regulation of survivin by As 2 O 3 .	p53 inhibition by transfection with p53 siRNA prevented the down-regulation of survivin by As 2 O 3.	0	12	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	survivin	survivin	survivin	0	1	11	12
In this context , we examined the role of Mdm2 in the p53 mediated downregulation of survivin induced by inhibition of HDAC2 .	In this context, we examined the role of Mdm2 in the p53 mediated downregulation of survivin induced by inhibition of HDAC2.	9	17	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	survivin	survivin	survivin	12	13	16	17
p53 inhibition by siRNA prevented the down-regulation of survivin by As 2 O 3 and prevented the As 2 O 3 -induced cytotoxicity of WSU-CLL cells .	p53 inhibition by siRNA prevented the down-regulation of survivin by As 2 O 3 and prevented the As 2 O 3 -induced cytotoxicity of WSU-CLL cells.	0	9	prevented	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	survivin	survivin	survivin	0	1	8	9
To test if other p53 negative colon cancer cells also fail to repress survivin , we treated three short-term cultured colon cancer cell lines ( HROBMC01 , HROC43 , HROC239 ) with L-OHP .	To test if other p53 negative colon cancer cells also fail to repress survivin, we treated three short-term cultured colon cancer cell lines (HROBMC01, HROC43, HROC239) with L-OHP.	4	14	repress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	survivin	survivin	survivin	4	5	13	14
XREF_BIBR Moreover , megakaryocytic p53 is potentially increased to directly abrogate the antideath effects of survivin .	XREF_BIBR Moreover, megakaryocytic p53 is potentially increased to directly abrogate the antideath effects of survivin.	3	16	abrogate	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	survivin	survivin	survivin	4	5	15	16
The apoptosis inhibitor survivin is negatively regulated by wild-type p53 and upregulated at the G2/M-phase of the cell cycle .	The apoptosis inhibitor survivin is negatively regulated by wild-type p53 and upregulated at the G2/M-phase of the cell cycle.	1	10	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	p53	p53	p53	apoptosis inhibitor survivin	apoptosis inhibitor survivin	apoptosis inhibitor survivin	9	10	1	4
Notably , p53 ( HR = 3.2 ) seems to negatively enhance the effect of survivin on survival .	Notably, p53 (HR = 3.2) seems to negatively enhance the effect of survivin on survival.	2	17	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	survivin	survivin	survivin	2	3	15	16
XREF_BIBR , XREF_BIBR - XREF_BIBR Recently , multiple studies have described a potentially relevant mechanism of survivin downregulation mediated by activation of p53 and transcriptional repressor machinery through ROS inducing drug treatments .	XREF_BIBR, XREF_BIBR - XREF_BIBR Recently, multiple studies have described a potentially relevant mechanism of survivin downregulation mediated by activation of p53 and transcriptional repressor machinery through ROS inducing drug treatments.	16	26	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	survivin	survivin	survivin	22	23	16	17
In support of this notion , Survivin and RPRM are suppressed or enhanced , respectively , by p53 [ XREF_BIBR , XREF_BIBR ] .	In support of this notion, Survivin and RPRM are suppressed or enhanced, respectively, by p53 [XREF_BIBR, XREF_BIBR].	6	21	enhanced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Survivin	Survivin	Survivin	17	18	6	7
Next , we tested the role of p53 in HDAC2 siRNA mediated downregulation of survivin in p53 wild-type A549 lung cancer cells .	Next, we tested the role of p53 in HDAC2 siRNA mediated downregulation of survivin in p53 wild-type A549 lung cancer cells.	5	15	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	survivin	survivin	survivin	7	8	14	15
Mechanistically , our data demonstrated that NgBR knockdown increases the protein levels of p53 and decreases survivin , which is an apoptosis inhibitor .	Mechanistically, our data demonstrated that NgBR knockdown increases the protein levels of p53 and decreases survivin, which is an apoptosis inhibitor.	6	22	decreases	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	NgBR knockdown increases the protein levels of p53	p53	survivin	survivin	survivin	13	14	16	17
It was shown that silencing the expression of SNAIL can potentiates the TRAIL induced apoptosis by p53 upregulation and downregulation of Bcl-X L , survivin and Raf-1 of the NF-kappaB pathway .	It was shown that silencing the expression of SNAIL can potentiates the TRAIL induced apoptosis by p53 upregulation and downregulation of Bcl-X L, survivin and Raf-1 of the NF-kappaB pathway.	16	23	upregulation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	p53	p53	p53	Bcl-X L	Bcl-X L	Bcl-X L	16	17	21	23
p53 modulates both the inhibition of BCL-xL by ABT-737 and death signals downstream of BCL-xL .	p53 modulates both the inhibition of BCL-xL by ABT-737 and death signals downstream of BCL-xL.	0	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	p53	p53	p53	BCL-xL	BCL-xL	BCL-xL	0	1	6	7
In addition , PFD down-regulated the mRNA expression of CsA induced p53 and Fas-ligand ( P < 0.01 ) and increased that of Bcl-xL , previously reduced by CsA ( P < 0.01 ) .	In addition, PFD down-regulated the mRNA expression of CsA induced p53 and Fas-ligand (P < 0.01) and increased that of Bcl-xL, previously reduced by CsA (P < 0.01).	3	26	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	PFD down-regulated the mRNA expression of CsA induced p53	p53	Bcl-xL	Bcl-xL	bcl-xl	11	12	23	24
In addition , PFD downregulated mRNA expression of CsA induced p53 and Fas-ligand and increased that of Bcl-xL , which had previously been reduced by CsA .	In addition, PFD downregulated mRNA expression of CsA induced p53 and Fas-ligand and increased that of Bcl-xL, which had previously been reduced by CsA.	3	23	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	PFD downregulated mRNA expression of CsA induced p53	p53	Bcl-xL	Bcl-xL	bcl-xl	10	11	17	18
Finally , by analyzing the effect of inactivation of wild-type p53 on CIAPIN1 induced up-regulation of P-gp and Bcl-xL , we determined that CIAPIN1 could exhibit its MDR related function independently of the p53 signaling pathway .	Finally, by analyzing the effect of inactivation of wild-type p53 on CIAPIN1 induced up-regulation of P-gp and Bcl-xL, we determined that CIAPIN1 could exhibit its MDR related function independently of the p53 signaling pathway.	7	19	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-xL	Bcl-xL	Bcl-xL	10	11	18	19
p53 can increase Bax and Bcl -2 ( or Bcl-X L ) pro apoptotic ratio through transcriptional Bax upregulation and/or Bax oligomerization .	p53 can increase Bax and Bcl -2 (or Bcl-X L) pro apoptotic ratio through transcriptional Bax upregulation and/or Bax oligomerization.	0	11	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53	p53	Bcl-X L	Bcl-X L	Bcl-X L	0	1	9	11
Furthermore , we demonstrated that decreased p53 levels prevent the neurogenic effect of Bcl-XL and ATP on hNPC differentiation ( XREF_FIG , XREF_FIG ) .	Furthermore, we demonstrated that decreased p53 levels prevent the neurogenic effect of Bcl-XL and ATP on hNPC differentiation (XREF_FIG, XREF_FIG).	6	15	prevent	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p53	p53 levels	p53	Bcl-XL	Bcl-XL	bcl-xl	6	7	13	14
In addition to data from our lab , Ono and colleagues showed that CTMP activates AKT signaling and contributes to oncogenesis through a direct interaction in breast cancer [ XREF_BIBR , XREF_BIBR ] .	In addition to data from our lab, Ono and colleagues showed that CTMP activates AKT signaling and contributes to oncogenesis through a direct interaction in breast cancer [XREF_BIBR, XREF_BIBR].	13	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CTMP	CTMP	CTMP	AKT	AKT	AKT	13	14	15	16
Taken together , we demonstrated that CTMP promotes AKT activation resulting in trastuzumab resistance in patients with HER2 enriched breast cancer .	Taken together, we demonstrated that CTMP promotes AKT activation resulting in trastuzumab resistance in patients with HER2 enriched breast cancer.	6	9	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CTMP	CTMP	CTMP	AKT	AKT	AKT	6	7	8	9
RNA-interference-mediated depletion of CTMP in a clinically relevant model of stroke restores Akt activity and rescues hippocampal neurons .	RNA-interference-mediated depletion of CTMP in a clinically relevant model of stroke restores Akt activity and rescues hippocampal neurons.	1	13	restores	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	CTMP	CTMP	CTMP	Akt	Akt	Akt	3	4	12	13
However depending on cell and cancer type , THEM4 has also been reported to activate Akt [ XREF_BIBR , XREF_BIBR ] .	However depending on cell and cancer type, THEM4 has also been reported to activate Akt [XREF_BIBR, XREF_BIBR].	8	19	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	THEM4	THEM4	THEM4	Akt	Akt	Akt	8	9	15	16
CTMP activates AKT signaling in breast cancer and over-activation of AKT has been reported to contribute to trastuzumab resistance .	CTMP activates AKT signaling in breast cancer and over-activation of AKT has been reported to contribute to trastuzumab resistance.	0	3	activates	Positive_activation_token_1_verb	Negative_activation	Positive_activation	CTMP	CTMP	CTMP	AKT	AKT	AKT	0	1	2	3
Accordingly , we hypothesize that AKT signaling activated by CTMP contributes to trastuzumab resistance in breast cancer .	Accordingly, we hypothesize that AKT signaling activated by CTMP contributes to trastuzumab resistance in breast cancer.	5	10	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	CTMP	CTMP	CTMP	AKT	AKT	AKT	9	10	5	6
Time dependent expression of p-CTMP , p-Akt , p-CREB , and CTMP indicate that LPS and IFN-gamma-induced phosphorylation of CTMP can activate Akt and CREB signaling , whereas lately emerging enhancement of CTMP can inhibit it .	Time dependent expression of p-CTMP, p-Akt, p-CREB, and CTMP indicate that LPS and IFN-gamma-induced phosphorylation of CTMP can activate Akt and CREB signaling, whereas lately emerging enhancement of CTMP can inhibit it.	14	25	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CTMP	LPS and IFN-gamma-induced phosphorylation of CTMP	ctmp	Akt	Akt	akt	19	20	22	23
In addition , CTMP expression positively correlated with AKT activity ( R 2 = 0.608 ) , suggesting that CTMP may promote AKT activation in vivo .	In addition, CTMP expression positively correlated with AKT activity (R 2 = 0.608), suggesting that CTMP may promote AKT activation in vivo.	19	23	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CTMP	CTMP	CTMP	AKT	AKT	AKT	19	20	22	23
These findings indicate that CTMP miRNA restores , at least in part , Akt functional outcome in neurons destined to die .	These findings indicate that CTMP miRNA restores, at least in part, Akt functional outcome in neurons destined to die.	4	15	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CTMP	CTMP	CTMP	Akt	Akt	Akt	4	5	13	14
In order to further examine whether CTMP mediated tratuzumab resistance involves AKT , the AKT activation status was examined in CTMP manipulated SkBR3 or BT-483 cells with or without trastuzumab treatment .	In order to further examine whether CTMP mediated tratuzumab resistance involves AKT, the AKT activation status was examined in CTMP manipulated SkBR3 or BT-483 cells with or without trastuzumab treatment.	6	12	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	CTMP	CTMP	CTMP	AKT	AKT	AKT	6	7	11	12
TNFalpha increases IRS-1 Ser307 in REC .	TNFalpha increases IRS-1 Ser307 in REC.	0	3	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	IRS-1	IRS-1	IRS-1	0	1	2	3
In this study , we analyzed the effects of aspirin ( acetylsalicylic acid ) on serine phosphorylation of insulin receptor substrate 1 ( IRS-1 ) in cells treated with tumor necrosis factor ( TNF )-alpha .	In this study, we analyzed the effects of aspirin (acetylsalicylic acid) on serine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells treated with tumor necrosis factor (TNF)-alpha.	16	32	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	tumor necrosis factor	tumor necrosis factor	tumor necrosis factor	IRS-1	IRS-1	IRS-1	29	32	23	24
Anti-TNF-alpha neutralization antibody and silencing of TNF-alpha receptor 1 ( TNFR1 ) diminished the TCDD induced downregulation of IRbeta , IRS1 , and GLUT4 .	Anti-TNF-alpha neutralization antibody and silencing of TNF-alpha receptor 1 (TNFR1) diminished the TCDD induced downregulation of IRbeta, IRS1, and GLUT4.	6	21	diminished	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	IRS1	IRS1	IRS1	6	7	20	21
Taken together , TCDD stimulates expression and secretion of TNF-alpha in adipocytes through activation of AhR , ERK1/2 , and JNK , and the secreted TNF-alpha causes the downregulation of IRbeta , IRS1 , and GLUT4 through TNFR1 , resulting in insulin resistance .	Taken together, TCDD stimulates expression and secretion of TNF-alpha in adipocytes through activation of AhR, ERK1/2, and JNK, and the secreted TNF-alpha causes the downregulation of IRbeta, IRS1, and GLUT4 through TNFR1, resulting in insulin resistance.	3	33	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TNF-alpha	TCDD stimulates expression and secretion of TNF-alpha	tnf-alpha	IRS1	IRS1	irs1	9	10	32	33
Additionally , since we have previously demonstrated that beta-adrenergic receptors can decrease tumor necrosis factor ( TNF ) alpha levels [ XREF_BIBR ] , and TNFalpha is known to increase IRS-1 Ser307 , we hypothesize that salmeterol , a beta-2-adrenergic receptor agonist , requires IRS-1 actions to decrease apoptosis of retinal Muller cells .	Additionally, since we have previously demonstrated that beta-adrenergic receptors can decrease tumor necrosis factor (TNF) alpha levels [XREF_BIBR], and TNFalpha is known to increase IRS-1 Ser307, we hypothesize that salmeterol, a beta-2-adrenergic receptor agonist, requires IRS-1 actions to decrease apoptosis of retinal Muller cells.	25	31	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	IRS-1	IRS-1	IRS-1	25	26	30	31
SP600125 , a JNK inhibitor , prevented PMA and TNFalpha induced IRS1 Ser 307 phosphorylation .	SP600125, a JNK inhibitor, prevented PMA and TNFalpha induced IRS1 Ser 307 phosphorylation.	6	12	induced	Positive_early_activation	Negative_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	IRS1	IRS1	IRS1	9	10	11	12
In a recent study , we showed that IKK2 ( IKKbeta ) inhibits IRS-1 function through activation of S6K , which directly phosphorylates IRS-1 at multiple sites such as S312/307 and S270/265 in cells treated with TNF-alpha [ XREF_BIBR , XREF_BIBR ] .	In a recent study, we showed that IKK2 (IKKbeta) inhibits IRS-1 function through activation of S6K, which directly phosphorylates IRS-1 at multiple sites such as S312/307 and S270/265 in cells treated with TNF-alpha [XREF_BIBR, XREF_BIBR].	22	40	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	IRS-1	IRS-1	IRS-1	36	37	23	24
Results of the in vitro tyrosine phosphorylation assay indicated that tyrosine phosphorylation of IRS-1 by insulin receptor was decreased when IRS-1 was contained in IRSomes prepared from 3T3-L1 adipocytes treated with TNF-alpha .	Results of the in vitro tyrosine phosphorylation assay indicated that tyrosine phosphorylation of IRS-1 by insulin receptor was decreased when IRS-1 was contained in IRSomes prepared from 3T3-L1 adipocytes treated with TNF-alpha.	20	32	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	IRS-1	IRS-1	IRS-1	31	32	20	21
TNFalpha increased suppressor of cytokine signaling 3 ( SOCS3 ) signaling , as well as insulin receptor substrate 1 ( IRS-1 ) Ser307 and insulin receptor ( IR ) Tyr960 phosphorylation , leading to inhibition of normal insulin signaling under high-glucose conditions [ XREF_BIBR ] .	TNFalpha increased suppressor of cytokine signaling 3 (SOCS3) signaling, as well as insulin receptor substrate 1 (IRS-1) Ser307 and insulin receptor (IR) Tyr960 phosphorylation, leading to inhibition of normal insulin signaling under high-glucose conditions [XREF_BIBR].	0	22	increased	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TNFalpha	TNFalpha	TNFalpha	IRS-1	IRS-1	IRS-1	0	1	20	21
Additionally , we demonstrated in retinal endothelial cells that TNFalpha activation of SOCS3 and IRS-1 Ser307 leads to decreased insulin signal transduction , which likely underlies insulin resistance .	Additionally, we demonstrated in retinal endothelial cells that TNFalpha activation of SOCS3 and IRS-1 Ser307 leads to decreased insulin signal transduction, which likely underlies insulin resistance.	9	15	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	TNFalpha	TNFalpha	TNFalpha	IRS-1	IRS-1	IRS-1	9	10	14	15
Via neuronal receptors , microglial IL-1 , IL-6 and TNF-alpha activate IRS-1 serine kinases known by the acronyms IKK , JNK and Erk2 [ XREF_BIBR ] .	Via neuronal receptors, microglial IL-1, IL-6 and TNF-alpha activate IRS-1 serine kinases known by the acronyms IKK, JNK and Erk2 [XREF_BIBR].	5	13	activate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	IRS-1	IRS-1	IRS-1	9	10	11	12
Pretreatment with oleate prevented serine phosphorylation and maintained Tyr phosphorylation on IRS-1 induced by TNF-alpha or palmitate .	Pretreatment with oleate prevented serine phosphorylation and maintained Tyr phosphorylation on IRS-1 induced by TNF-alpha or palmitate.	7	16	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	TNF-alpha	TNF-alpha	TNF-alpha	IRS-1	IRS-1	IRS-1	14	15	11	12
Knocking down TRIB3 increased Akt activity .	Knocking down TRIB3 increased Akt activity.	0	5	increased	Positive_activation_token_1_verb	Negative_activation	Positive_activation	TRIB3	TRIB3	TRIB3	Akt	Akt	Akt	2	3	4	5
Since the inhibition of Akt has been shown to be a causal mediator of cell death , the blocking of Akt activation by TRB3 might induce cell death under conditions where IGF-1 stimulation of Akt is necessary for chondrocyte survival .	Since the inhibition of Akt has been shown to be a causal mediator of cell death, the blocking of Akt activation by TRB3 might induce cell death under conditions where IGF-1 stimulation of Akt is necessary for chondrocyte survival.	20	24	activation	Positive_activation_syntax_2_noun	Negative_activation	Positive_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	23	24	20	21
Subsequently , this decrease in phospho- AKT caused by TRIB3 resulted in an enhanced Bax expression in the outer mitochondrial membrane to further promote apoptosis .	Subsequently, this decrease in phospho- AKT caused by TRIB3 resulted in an enhanced Bax expression in the outer mitochondrial membrane to further promote apoptosis.	3	10	caused	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	TRIB3	TRIB3	TRIB3	AKT	AKT	AKT	9	10	6	7
These results suggest that the increase in Trib3 by SNRK does not cause a sufficient deficit in Akt activity to cause cell death , as SNRK also exerts protective effects by improving mitochondrial efficiency .	These results suggest that the increase in Trib3 by SNRK does not cause a sufficient deficit in Akt activity to cause cell death, as SNRK also exerts protective effects by improving mitochondrial efficiency.	5	18	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Trib3	Trib3	Trib3	Akt	Akt	Akt	7	8	17	18
Thus , a more likely explanation is the profound repression of Trb3 , which activates Akt independently of any effects on mTORC1 .	Thus, a more likely explanation is the profound repression of Trb3, which activates Akt independently of any effects on mTORC1.	9	19	activates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Trb3	Trb3	Trb3	Akt	Akt	Akt	11	12	15	16
TRIB3 is known to promote apoptosis by negatively regulating the Akt signaling pathway under ER stress conditions .	TRIB3 is known to promote apoptosis by negatively regulating the Akt signaling pathway under ER stress conditions.	0	12	promote	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TRIB3	TRIB3	TRIB3	Akt	Akt	Akt	0	1	10	11
As discussed above , mirn23a also has the potential to regulate immune cell development through the AKT and FoxO1 pathway , which is directly targeted by Trib3 .	As discussed above, mirn23a also has the potential to regulate immune cell development through the AKT and FoxO1 pathway, which is directly targeted by Trib3.	16	27	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Trib3	Trib3	Trib3	AKT	AKT	AKT	26	27	16	17
TRB3 gene silencing reduced the collagen I-to-III ratio and regulated Akt and MAPK pathway .	TRB3 gene silencing reduced the collagen I-to-III ratio and regulated Akt and MAPK pathway.	0	13	reduced	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	0	1	10	11
TRB3 induction as a component of the UPR is predicted to lower the apoptotic threshold of cardiac myocytes by blocking Akt activity .	TRB3 induction as a component of the UPR is predicted to lower the apoptotic threshold of cardiac myocytes by blocking Akt activity.	0	21	lower	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TRB3	TRB3	TRB3	Akt	Akt	Akt	0	1	20	21
DcR2 was significantly more abundant in tumor cells than in non neoplastic ones and may contribute to partial resistance to TRAIL in some prostate tumor cells .	DcR2 was significantly more abundant in tumor cells than in non neoplastic ones and may contribute to partial resistance to TRAIL in some prostate tumor cells.	0	25	contribute	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	DcR2	DcR2	DcR2	TRAIL	TRAIL	TRAIL	0	1	20	21
The receptor expression study showed that TRAIL decoy receptors DcR1 and DcR2 were down-regulated , but DR4 and DR5 expression remained no changes , suggesting that DcR1 and DcR2 expression disregulation might contribute to the susceptibility of HIV-1 infected MDM cells to TRAIL and/or AD5-10 induced cell death .	The receptor expression study showed that TRAIL decoy receptors DcR1 and DcR2 were down-regulated, but DR4 and DR5 expression remained no changes, suggesting that DcR1 and DcR2 expression disregulation might contribute to the susceptibility of HIV-1 infected MDM cells to TRAIL and/or AD5-10 induced cell death.	28	43	contribute	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	DcR2	DcR2	DcR2	TRAIL	TRAIL	TRAIL	28	29	42	43
Therefore DcR1 and DcR2 receptors may contribute to physiological resistance to TRAIL .	Therefore DcR1 and DcR2 receptors may contribute to physiological resistance to TRAIL.	1	12	contribute	Positive_activation_syntax_7_verb	Negative_activation	Positive_activation	DcR2	DcR2	DcR2	TRAIL	TRAIL	TRAIL	3	4	11	12
Our results suggest that PARP13 could have important functions in regulating TRAIL resistance and that modulation of PARP13 may have the potential to overcome TRAILR4 mediated TRAIL resistance .	Our results suggest that PARP13 could have important functions in regulating TRAIL resistance and that modulation of PARP13 may have the potential to overcome TRAILR4 mediated TRAIL resistance.	23	27	mediated	Positive_early_activation	Negative_activation	Positive_activation	TRAILR4	TRAILR4	TRAILR4	TRAIL	TRAIL	TRAIL	24	25	26	27
As DcR2 depletion increased the rate of cell death in response to TRAIL ( XREF_FIG and XREF_SUPPLEMENTARY ) , we analyzed how this decoy receptor modulates the composition of TRAIL signaling complex ( es ) .	As DcR2 depletion increased the rate of cell death in response to TRAIL (XREF_FIG and XREF_SUPPLEMENTARY), we analyzed how this decoy receptor modulates the composition of TRAIL signaling complex (es).	1	16	increased	Positive_activation_syntax_7_verb	Negative_activation	Negative_activation	DcR2	DcR2	DcR2	TRAIL	TRAIL	TRAIL	1	2	12	13
However , unlike MDM2 , TRIM24 also targets activated p53 to terminate p53 regulated response to DNA damage .	However, unlike MDM2, TRIM24 also targets activated p53 to terminate p53 regulated response to DNA damage.	5	11	targets activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	5	6	9	10
However , reduced TRIM24 expression causing p53 upregulation has not been confirmed in human breast cancer tissues and head and neck squamous cell carcinoma samples [ XREF_BIBR , XREF_BIBR ] .	However, reduced TRIM24 expression causing p53 upregulation has not been confirmed in human breast cancer tissues and head and neck squamous cell carcinoma samples [XREF_BIBR, XREF_BIBR].	3	7	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TRIM24	TRIM24 expression	trim24	p53	p53	p53	3	4	6	7
Here , we present evidence that a multi-functional protein , TRIM24 , which is an E3-ubiquitin ligase that targets p53 XREF_BIBR and is broadly associated with chromatin silencing XREF_BIBR , relies on tandem PHD finger and Bromodomain ( designated PHD-Bromo ) to recognize specific , combinatorial histone modifications and activate estrogen dependent genes associated with cellular proliferation and tumor development .	Here, we present evidence that a multi-functional protein, TRIM24, which is an E3-ubiquitin ligase that targets p53 XREF_BIBR and is broadly associated with chromatin silencing XREF_BIBR, relies on tandem PHD finger and Bromodomain (designated PHD-Bromo) to recognize specific, combinatorial histone modifications and activate estrogen dependent genes associated with cellular proliferation and tumor development.	8	20	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	10	11	19	20
Indeed , TRIM24 directly ubiquitinates p53 via its RING domain , and depletion of TRIM24 in human breast cancer cells induced p53 dependent apoptosis .	Indeed, TRIM24 directly ubiquitinates p53 via its RING domain, and depletion of TRIM24 in human breast cancer cells induced p53 dependent apoptosis.	12	23	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	14	15	21	22
Recently , TRIM24 , which has been shown to target p53 for degradation , 17 and estrogen responsive finger protein ( TRIM25 ) have been shown to enhance breast tumor growth , XREF_BIBR , XREF_BIBR with the latter also being implicated as a tumor suppressor in the pathogenesis of hepatocellular carcinoma .	Recently, TRIM24, which has been shown to target p53 for degradation, 17 and estrogen responsive finger protein (TRIM25) have been shown to enhance breast tumor growth, XREF_BIBR, XREF_BIBR with the latter also being implicated as a tumor suppressor in the pathogenesis of hepatocellular carcinoma.	2	27	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	2	3	10	11
First , we detected the expression of apoptosis related proteins such as p53 , Bcl-2 , Bax , Caspase-8 , and Survivin by western blotting and found that depletion of TRIM24 up-regulated p53 , Bax , and Caspase-8 , and down-regulated Bcl-2 and Survivin .	First, we detected the expression of apoptosis related proteins such as p53, Bcl-2, Bax, Caspase-8, and Survivin by western blotting and found that depletion of TRIM24 up-regulated p53, Bax, and Caspase-8, and down-regulated Bcl-2 and Survivin.	28	37	up-regulated	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	30	31	32	33
Biochemical purification of endogenous , tagged p53 protein complexes from mouse embryonic stem cells , and peptide analysis by mass spectrometry , revealed a new RING-domain E3-ubiquitin ligase TRIM24 that targets p53 for degradation .	Biochemical purification of endogenous, tagged p53 protein complexes from mouse embryonic stem cells, and peptide analysis by mass spectrometry, revealed a new RING-domain E3-ubiquitin ligase TRIM24 that targets p53 for degradation.	22	33	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TRIM24	TRIM24	TRIM24	p53	p53	p53	28	29	31	32
Phosphorylation of TSC2 by Akt promotes dissociation of the TSC1 and TSC2 complex , which activates the guanosine triphosphatase Rheb ; Rheb activity subsequently upregulates mTOR , stimulating its activity to promote messenger mRNA translation .	Phosphorylation of TSC2 by Akt promotes dissociation of the TSC1 and TSC2 complex, which activates the guanosine triphosphatase Rheb; Rheb activity subsequently upregulates mTOR, stimulating its activity to promote messenger mRNA translation.	0	20	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	Phosphorylation of TSC2 by Akt promotes dissociation of the TSC1 and TSC2 complex	tsc1	Rheb	Rheb	rheb	9	10	19	20
mTORC1 and the Drosophila TORC1 are inhibited by the TSC1 and TSC2 heterodimer acting as a GAP for the small GTPase Rheb , thereby inhibiting Rheb activity , which is required for TORC1 activation .	mTORC1 and the Drosophila TORC1 are inhibited by the TSC1 and TSC2 heterodimer acting as a GAP for the small GTPase Rheb, thereby inhibiting Rheb activity, which is required for TORC1 activation.	6	26	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1 and TSC2 heterodimer	tsc1	Rheb	Rheb	rheb	9	10	25	26
The phosphorylation of TSC2 prevents TSC1 and TSC2 complex formation , which drives the small GTPase Rheb into the GTP bound active state [ XREF_BIBR ] , leading to the activation of mTORC1 at Ser2448 [ XREF_BIBR , XREF_BIBR ] .	The phosphorylation of TSC2 prevents TSC1 and TSC2 complex formation, which drives the small GTPase Rheb into the GTP bound active state [XREF_BIBR], leading to the activation of mTORC1 at Ser2448 [XREF_BIBR, XREF_BIBR].	5	17	drives	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	TSC1 and TSC2 complex	tsc1	Rheb	Rheb	rheb	5	6	16	17
Akt mediated phosphorylation of TSC2 prevents TSC1 and TSC2 complex formation , which drives the small GTPase Rheb into the GTP bound active state [ XREF_BIBR ] , leading to the phosphorylation and activation of mTORC1 at Ser2448 [ XREF_BIBR , XREF_BIBR ] .	Akt mediated phosphorylation of TSC2 prevents TSC1 and TSC2 complex formation, which drives the small GTPase Rheb into the GTP bound active state [XREF_BIBR], leading to the phosphorylation and activation of mTORC1 at Ser2448 [XREF_BIBR, XREF_BIBR].	0	18	drives	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TSC1	Akt mediated phosphorylation of TSC2 prevents TSC1 and TSC2 complex	tsc1	Rheb	Rheb	rheb	6	7	17	18
[ XREF_BIBR ] Physiologically , the hamartin and tuberin complex activates the protein Ras homolog enriched in brain ( Rheb ) and exerts inhibitory control over mTOR .	[XREF_BIBR] Physiologically, the hamartin and tuberin complex activates the protein Ras homolog enriched in brain (Rheb) and exerts inhibitory control over mTOR.	6	18	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	hamartin	hamartin and tuberin complex	hamartin	Ras homolog enriched in brain	Ras homolog enriched in brain	ras homolog enriched in brain	6	7	13	18
According to our finding , downregulation of DcR1 using siRNA , in p53 wild-type colon cancer cells , restored oxaliplatin and TRAIL synergistic apoptotic activity .	According to our finding, downregulation of DcR1 using siRNA, in p53 wild-type colon cancer cells, restored oxaliplatin and TRAIL synergistic apoptotic activity.	5	24	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DcR1	DcR1	DcR1	TRAIL	TRAIL	TRAIL	7	8	21	22
Thus , upregulation of DcR3 may increase cellularity by neutralizing FasL , and prevent fibrosis via neutralizing LIGHT in skin .	Thus, upregulation of DcR3 may increase cellularity by neutralizing FasL, and prevent fibrosis via neutralizing LIGHT in skin.	2	11	increase	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	4	5	10	11
It has been demonstrated that DcR3 is up-regulated in lung and colon cancers , thus promoting tumor growth by neutralizing the cytotoxic effects of FasL and LIGHT .	It has been demonstrated that DcR3 is up-regulated in lung and colon cancers, thus promoting tumor growth by neutralizing the cytotoxic effects of FasL and LIGHT.	5	26	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DcR3	DcR3	DcR3	FasL	FasL	FasL	5	6	24	25
Our results revealed that the silencing of DcR3 expression enhanced the inhibitory effects of FasL and reduced the capabiltiy of the cells for proliferation and colony formation in vitro .	Our results revealed that the silencing of DcR3 expression enhanced the inhibitory effects of FasL and reduced the capabiltiy of the cells for proliferation and colony formation in vitro.	7	15	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	DcR3	DcR3 expression	dcr3	FasL	FasL	fasl	7	8	14	15
As we saw in Figure XREF_FIG and XREF_FIG , Sp1 and Ets-1 are upregulated by GOF p53 .	As we saw in Figure XREF_FIG and XREF_FIG, Sp1 and Ets-1 are upregulated by GOF p53.	9	17	upregulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	p53	p53	p53	Ets-1	Ets-1	Ets-1	16	17	11	12
This result confirms that GILZ promotes FOXO3A nuclear exclusion in dormant DMC derived melanoma cells , as in T-cells XREF_BIBR XREF_BIBR , thereby validating that GILZ is a dormant cell specific deactivator of FOXO3A in melanoma cells .	This result confirms that GILZ promotes FOXO3A nuclear exclusion in dormant DMC derived melanoma cells, as in T-cells XREF_BIBR XREF_BIBR, thereby validating that GILZ is a dormant cell specific deactivator of FOXO3A in melanoma cells.	4	8	promotes	Positive_activation_token_1_verb	Negative_activation	Positive_activation	GILZ	GILZ	GILZ	FOXO3A	FOXO3A	FOXO3A	4	5	6	7
XREF_BIBR , XREF_BIBR , XREF_BIBR , XREF_BIBR In light of these findings , we hypothesized that aberrant TTK expression inhibits the tumor suppressive functions of c-Abl by facilitating its cytoplasmic retention in TNBCs that express mutant p53 .	XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR In light of these findings, we hypothesized that aberrant TTK expression inhibits the tumor suppressive functions of c-Abl by facilitating its cytoplasmic retention in TNBCs that express mutant p53.	17	26	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	TTK	TTK expression	ttk	c-Abl	c-Abl	c-abl	17	18	25	26
Human Mps1 has been reported to be activated by oxidative stress to control c-Abl cellular localization .	Human Mps1 has been reported to be activated by oxidative stress to control c-Abl cellular localization.	0	15	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Mps1	Mps1	Mps1	c-Abl	c-Abl	c-Abl	1	2	13	14
In previous work from our group , we used a GILZ recombinant lentivirus and showed that GILZ overexpression suppresses inflammatory reactions by inhibiting NF-kappaB p65 nuclear translocation .	In previous work from our group, we used a GILZ recombinant lentivirus and showed that GILZ overexpression suppresses inflammatory reactions by inhibiting NF-kappaB p65 nuclear translocation.	16	25	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	GILZ	GILZ overexpression	gilz	NF-kappaB p65	NF-kappaB p65	nf-kappab p65	16	17	23	25
We next sought to determine whether TRAP150 directly regulates the binding of PSF to the CD45 ESS1 RNA using purified proteins ( XREF_SUPPLEMENTARY ) .	We next sought to determine whether TRAP150 directly regulates the binding of PSF to the CD45 ESS1 RNA using purified proteins (XREF_SUPPLEMENTARY).	6	13	directly regulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TRAP150	TRAP150	TRAP150	PSF	PSF	PSF	6	7	12	13
Tollip ( Toll interacting protein ) modulates IRAK function in the TLR signalling pathway .	Tollip (Toll interacting protein) modulates IRAK function in the TLR signalling pathway.	0	8	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Tollip	Tollip	Tollip	IRAK	IRAK	IRAK	0	1	7	8
TTBK1 has been shown to co-localize with diffuse phospho-Ser422 tau in pre-tangle Alzheimer ' s disease neurons XREF_BIBR , and increased levels of TTBK1 have been observed in AD frontal cortex XREF_BIBR and enhance the toxicity of tau in a P301L mouse model XREF_BIBR .	TTBK1 has been shown to co-localize with diffuse phospho-Ser422 tau in pre-tangle Alzheimer 's disease neurons XREF_BIBR, and increased levels of TTBK1 have been observed in AD frontal cortex XREF_BIBR and enhance the toxicity of tau in a P301L mouse model XREF_BIBR.	21	43	enhance	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	TTBK1	levels of TTBK1	ttbk1	tau	tau	tau	23	24	37	38
Also , TIMP-3 can inhibit further EC morphogenic events by blocking MT1-MMP function .	Also, TIMP-3 can inhibit further EC morphogenic events by blocking MT1-MMP function.	2	12	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	TIMP-3	TIMP-3	TIMP-3	MT1-MMP	MT1-MMP	MT1-MMP	2	3	11	12
Thus , a mutation in the VHL gene reduces the efficiency of HIF1alpha and HIF2alpha degradation , which leads to the accumulation of these factors and constitutive activation of their targets .	Thus, a mutation in the VHL gene reduces the efficiency of HIF1alpha and HIF2alpha degradation, which leads to the accumulation of these factors and constitutive activation of their targets.	6	15	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	6	7	12	13
VHL mediated HIF-1alpha regulation is a major pathway involved in RCC biology and tumorigenesis .	VHL mediated HIF-1alpha regulation is a major pathway involved in RCC biology and tumorigenesis.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	2	3
This suggests that the normal VHL mediated HIF-1alpha degradation pathway still functions in HPV infected cells regardless of any effects E7 may have on other aspects the VHL pathway .	This suggests that the normal VHL mediated HIF-1alpha degradation pathway still functions in HPV infected cells regardless of any effects E7 may have on other aspects the VHL pathway.	3	11	mediated	Positive_early_activation	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	5	6	7	8
Mutated VHL prevents appropriate normoxic degradation of HIF-1alpha and , as such , CAIX is highly expressed in mutated VHL related tumours , independently of the extent of tumour necrosis ( Swinson et al , 2003 ) .	Mutated VHL prevents appropriate normoxic degradation of HIF-1alpha and, as such, CAIX is highly expressed in mutated VHL related tumours, independently of the extent of tumour necrosis (Swinson et al, 2003).	1	8	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	1	2	7	8
Inflammation was rather enhanced when Treg cells overexpress HIF-1alpha due to the lack of von Hippel-Lindau tumor suppressor ( VHL ) , which degrades HIF-1alpha protein in normoxic conditions .	Inflammation was rather enhanced when Treg cells overexpress HIF-1alpha due to the lack of von Hippel-Lindau tumor suppressor (VHL), which degrades HIF-1alpha protein in normoxic conditions.	17	26	degrades	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha protein	HIF-1alpha protein	HIF-1alpha protein	19	20	24	26
Hydroxylation of these two prolyl residues mediates binding of von Hippel-Lindau tumour suppressor protein ( pVHL ) , which is the recognition component of the E3 ubiquitin ligase complex that targets HIF-1alpha for ubiquitination and degradation by the 26S proteasome [ XREF_BIBR ] ( XREF_FIG ) .	Hydroxylation of these two prolyl residues mediates binding of von Hippel-Lindau tumour suppressor protein (pVHL), which is the recognition component of the E3 ubiquitin ligase complex that targets HIF-1alpha for ubiquitination and degradation by the 26S proteasome [XREF_BIBR] (XREF_FIG).	13	35	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	15	16	31	32
XREF_BIBR , XREF_BIBR Prolyl hydroxylation of HIF-1alpha is required for binding of the von Hippel-Lindau tumor suppressor protein ( VHL ) , which is the recognition component of an E3 ubiquitin protein ligase that targets HIF-1alpha for proteasomal degradation .	XREF_BIBR, XREF_BIBR Prolyl hydroxylation of HIF-1alpha is required for binding of the von Hippel-Lindau tumor suppressor protein (VHL), which is the recognition component of an E3 ubiquitin protein ligase that targets HIF-1alpha for proteasomal degradation.	17	38	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	19	20	35	36
HIF-1alpha has been shown to be upregulated in the synovium of a patient with rheumatoid arthritis [ XREF_BIBR ] , perhaps indicating a loss of VHL mediated degradation of HIF-1alpha in autoimmune disease .	HIF-1alpha has been shown to be upregulated in the synovium of a patient with rheumatoid arthritis [XREF_BIBR], perhaps indicating a loss of VHL mediated degradation of HIF-1alpha in autoimmune disease.	25	32	degradation	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	25	26	29	30
pVHL defective clear cell renal carcinomas produce HIF2alpha alone or both HIF1alpha and HIF2alpha 19 .	pVHL defective clear cell renal carcinomas produce HIF2alpha alone or both HIF1alpha and HIF2alpha 19.	0	13	produce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF1alpha	HIF1alpha	HIF1alpha	0	1	11	12
In this complex , pVHL targets the alpha-subunit of hypoxia inducible factor 1 ( HIF-1alpha ) and hypoxia inducible factor 2 ( HIF-2alpha , also known as EPAS1 ) transcription factors for ubiquitin mediated proteolysis .	In this complex, pVHL targets the alpha-subunit of hypoxia inducible factor 1 (HIF-1alpha) and hypoxia inducible factor 2 (HIF-2alpha, also known as EPAS1) transcription factors for ubiquitin mediated proteolysis.	4	15	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	4	5	14	15
As intrauterine oxygen tension is difficult to manipulate in experimental animals , researchers at the University of California in San Francisco used mice with either targeted deletions of HIF1alpha and HIF2alpha , or lack of VHL mediated HIF1alpha and HIF2alpha decay in the oligodendroglial lineage .	As intrauterine oxygen tension is difficult to manipulate in experimental animals, researchers at the University of California in San Francisco used mice with either targeted deletions of HIF1alpha and HIF2alpha, or lack of VHL mediated HIF1alpha and HIF2alpha decay in the oligodendroglial lineage.	33	40	mediated	Positive_early_activation	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	35	36	37	38
miR-101 could directly target VHL , a negative regulator of HIF1alpha , resulting in HIF1alpha induction in the absence of hypoxic signal .	miR-101 could directly target VHL, a negative regulator of HIF1alpha, resulting in HIF1alpha induction in the absence of hypoxic signal.	4	16	induction	Positive_activation_syntax_results_in	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	4	5	14	15
The modification is required for the binding of the von Hippel-Lindau ( VHL ) tumor suppressor protein , the recognition component of an E3 ubiquitin protein ligase that targets HIF-1alpha for proteasomal degradation .	The modification is required for the binding of the von Hippel-Lindau (VHL) tumor suppressor protein, the recognition component of an E3 ubiquitin protein ligase that targets HIF-1alpha for proteasomal degradation.	10	32	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	12	13	29	30
Under normoxic conditions , HIF-1alpha is hydroxylated at two proline residues ( P402 and P564 ) by prolyl hydroxylase-domain proteins and is subsequently recongnized by Von Hippel-Lindau ( VHL ) , a component of an E3 ubiquitin protein ligase that targets HIF-1alpha for degradation by the proteasome .	Under normoxic conditions, HIF-1alpha is hydroxylated at two proline residues (P402 and P564) by prolyl hydroxylase-domain proteins and is subsequently recongnized by Von Hippel-Lindau (VHL), a component of an E3 ubiquitin protein ligase that targets HIF-1alpha for degradation by the proteasome.	26	43	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	28	29	41	42
In addition , re-expression of VHL in the RCC4 cells , restored OGT knockdown mediated regulation of HIF-1alpha ( XREF_SUPPLEMENTARY ) suggesting that O-GlcNAc regulation of HIF-1alpha is pVHL dependent in multiple cell types .	In addition, re-expression of VHL in the RCC4 cells, restored OGT knockdown mediated regulation of HIF-1alpha (XREF_SUPPLEMENTARY) suggesting that O-GlcNAc regulation of HIF-1alpha is pVHL dependent in multiple cell types.	3	19	restored	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	re-expression of VHL	vhl	HIF-1alpha	HIF-1alpha	hif-1alpha	5	6	17	18
CA9 is not expressed in healthy renal tissue but is expressed in most clear cell renal cell carcinomas ( CCRCC ) through HIF-1alpha accumulation driven by hypoxia and inactivation of the VHL gene .	CA9 is not expressed in healthy renal tissue but is expressed in most clear cell renal cell carcinomas (CCRCC) through HIF-1alpha accumulation driven by hypoxia and inactivation of the VHL gene.	22	32	driven	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	31	32	22	23
Therefore , we analyzed the effect of erioflorin on the stability of HIF-1alpha protein , which is targeted for proteasomal degradation by the E3-ligase von Hippel-Lindau protein ( pVHL ) XREF_BIBR .	Therefore, we analyzed the effect of erioflorin on the stability of HIF-1alpha protein, which is targeted for proteasomal degradation by the E3-ligase von Hippel-Lindau protein (pVHL) XREF_BIBR.	12	30	targeted	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha protein	HIF-1alpha protein	HIF-1alpha protein	28	29	12	14
Interestingly , VHL , which also mediates HIF-1alpha destabilization and degradation , was indeed downregulated by hypoxia , but restored by simvastatin .	Interestingly, VHL, which also mediates HIF-1alpha destabilization and degradation, was indeed downregulated by hypoxia, but restored by simvastatin.	2	19	mediates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	2	3	7	8
The mechanism by which hypoxia induces gene transcription involves the inhibition of hypoxia inducible factor ( HIF )-1alpha prolyl hydroxylase activity , which prevents von Hippel-Lindau ( vHL )-dependent targeting of HIF-1alpha to the ubiquitin-proteasome pathway .	The mechanism by which hypoxia induces gene transcription involves the inhibition of hypoxia inducible factor (HIF)-1alpha prolyl hydroxylase activity, which prevents von Hippel-Lindau (vHL)-dependent targeting of HIF-1alpha to the ubiquitin-proteasome pathway.	27	32	targeting	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	vHL	vHL	vHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	27	28	31	32
To confirm and quantify these findings , FACS for CD41 : GFP was performed at 36hpf , and demonstrated that the significant increase in HSPCs caused by loss of VHL mediated Hif1alpha regulation ( p < 0.05 ) was blocked by pdgfrb knockdown ( p < 0.05 ) ( XREF_FIG ) .	To confirm and quantify these findings, FACS for CD41 : GFP was performed at 36hpf, and demonstrated that the significant increase in HSPCs caused by loss of VHL mediated Hif1alpha regulation (p < 0.05) was blocked by pdgfrb knockdown (p < 0.05) (XREF_FIG).	27	32	mediated	Positive_early_activation	Negative_activation	Positive_activation	VHL	VHL	VHL	Hif1alpha	Hif1alpha	Hif1alpha	29	30	31	32
We therefore conclude that mTORC1 regulates the synthesis of HIF-1alpha ( via both mRNA transcription and protein translation ) whilst VHL mediates HIF-1alpha protein turnover ( see XREF_FIG ) .	We therefore conclude that mTORC1 regulates the synthesis of HIF-1alpha (via both mRNA transcription and protein translation) whilst VHL mediates HIF-1alpha protein turnover (see XREF_FIG).	20	24	mediates	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VHL	VHL	VHL	HIF-1alpha protein	HIF-1alpha protein	HIF-1alpha protein	20	21	22	24
HIF-1alpha is subjected to post-translational regulation , as it is degraded at high oxygen tensions by an oxygen mediated hydroxylation of conserved prolyl and asparaginyl residues , to which the von Hippel-Lindau protein ( pVHL ) E3 ligase binds targeting HIF-1alpha to proteasomal degradation .	HIF-1alpha is subjected to post-translational regulation, as it is degraded at high oxygen tensions by an oxygen mediated hydroxylation of conserved prolyl and asparaginyl residues, to which the von Hippel-Lindau protein (pVHL) E3 ligase binds targeting HIF-1alpha to proteasomal degradation.	29	41	targeting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	34	35	40	41
Thus , we examined the role of STAT3 in the mechanism of pVHL mediated HIF-1alpha stability .	Thus, we examined the role of STAT3 in the mechanism of pVHL mediated HIF-1alpha stability.	10	15	mediated	Positive_early_activation	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	12	13	14	15
Hydroxylation of human HIF-1alpha at two proline residues ( Pro402 and Pro564 ) by prolyl hydroxylase domain ( PHD ) proteins creates binding sites for VHL E3 ubiquitin ligase complex that targets HIF-1alpha for proteasomal degradation .	Hydroxylation of human HIF-1alpha at two proline residues (Pro402 and Pro564) by prolyl hydroxylase domain (PHD) proteins creates binding sites for VHL E3 ubiquitin ligase complex that targets HIF-1alpha for proteasomal degradation.	25	35	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	25	26	32	33
The drug consists of the following three functional domains : the protein transduction domain ( PTD ) , which efficiently delivers the fusion protein to hypoxic tumor cells , the ODD domain , which has a VHL mediated protein destruction motif of human HIF-1alpha protein and confers hypoxia dependent stabilization to the fusion proteins , and the human procaspase-3 proenzyme responsible for the cytocidal activity of the protein drug .	The drug consists of the following three functional domains : the protein transduction domain (PTD), which efficiently delivers the fusion protein to hypoxic tumor cells, the ODD domain, which has a VHL mediated protein destruction motif of human HIF-1alpha protein and confers hypoxia dependent stabilization to the fusion proteins, and the human procaspase-3 proenzyme responsible for the cytocidal activity of the protein drug.	34	45	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha protein	HIF-1alpha protein	HIF-1alpha protein	36	37	43	45
Little is known about the regulation of HIF-1alpha mediated by pVHL after microtubule alteration during early hypoxia .	Little is known about the regulation of HIF-1alpha mediated by pVHL after microtubule alteration during early hypoxia.	5	11	mediated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	10	11	7	8
Hence , we propose that in VHL derived tumors two complementary mechanisms play a role in stabilizing HIF1alpha : the loss of VHL dependent targeting of HIF1alpha for proteasome mediated degradation , and a second mechanism that is dependent on low levels of HIF1alpha hydroxylation resulting from complex II dysfunction .	Hence, we propose that in VHL derived tumors two complementary mechanisms play a role in stabilizing HIF1alpha : the loss of VHL dependent targeting of HIF1alpha for proteasome mediated degradation, and a second mechanism that is dependent on low levels of HIF1alpha hydroxylation resulting from complex II dysfunction.	22	28	targeting	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	22	23	26	27
Impaired pVHL fails to degrade HIF1alpha resulting in increased VEGFA levels and therefore combined CXCR4 and VEGFA inhibition could be of potential benefit for VHL patients .	Impaired pVHL fails to degrade HIF1alpha resulting in increased VEGFA levels and therefore combined CXCR4 and VEGFA inhibition could be of potential benefit for VHL patients.	0	6	degrade	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF1alpha	HIF1alpha	HIF1alpha	1	2	5	6
The protein level of HIF1alpha is regulated by prolyl hydroxylase enzymes , which promote VHL mediated destruction of HIF1alpha .	The protein level of HIF1alpha is regulated by prolyl hydroxylase enzymes, which promote VHL mediated destruction of HIF1alpha.	14	19	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	14	15	18	19
Under normoxic conditions , HIF-1alpha is hydoxylated by prolyl hydroxylases and targeted for degradation by the VHL E3 ubiquitin ligase complex .	Under normoxic conditions, HIF-1alpha is hydoxylated by prolyl hydroxylases and targeted for degradation by the VHL E3 ubiquitin ligase complex.	4	20	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	16	17	4	5
Aberrations on chromosome 3p are associated with inactivation of the tumor suppressor gene von-Hippel Lindau ( VHL ) , which activates the hypoxia inducible factors HIF1alpha and HIF2alpha .	Aberrations on chromosome 3p are associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), which activates the hypoxia inducible factors HIF1alpha and HIF2alpha.	5	27	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	16	17	25	26
On the protein levels , however , in VHL deficient cell lines , both HIF-alpha subunits are constitutively expressed , whereas re-introduction of a functional VHL gene restores the instability of HIF-1alpha and HIF-2alpha proteins under normoxic conditions .	On the protein levels, however, in VHL deficient cell lines, both HIF-alpha subunits are constitutively expressed, whereas re-introduction of a functional VHL gene restores the instability of HIF-1alpha and HIF-2alpha proteins under normoxic conditions.	25	34	restores	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	25	26	31	32
When oxygen is available , HIF1A is hydroxylated by specific prolyl hydroxylases XREF_BIBR XREF_BIBR and recognized by the von Hippel-Lindau tumor suppressor ( VHL ) protein that targets HIF1A for polyubiquitination and subsequent degradation by the proteasome XREF_BIBR .	When oxygen is available, HIF1A is hydroxylated by specific prolyl hydroxylases XREF_BIBR XREF_BIBR and recognized by the von Hippel-Lindau tumor suppressor (VHL) protein that targets HIF1A for polyubiquitination and subsequent degradation by the proteasome XREF_BIBR.	23	33	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1A	HIF1A	HIF1A	23	24	28	29
VHL , which targets HIF1alpha for degradation , promotes ciliogenesis by stabilizing microtubules .	VHL, which targets HIF1alpha for degradation, promotes ciliogenesis by stabilizing microtubules.	0	8	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	0	1	4	5
These results argue that U19 and Eaf2 modulates the degradation of HIF1alpha , presumably mediated by pVHL .	These results argue that U19 and Eaf2 modulates the degradation of HIF1alpha, presumably mediated by pVHL.	9	17	mediated	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	pVHL	pVHL	pVHL	HIF1alpha	HIF1alpha	HIF1alpha	16	17	11	12
In mouse models of this disorder , disruptions in Vhl increase Hif1alpha and Hif2alpha activity and production of erythropoietin .	In mouse models of this disorder, disruptions in Vhl increase Hif1alpha and Hif2alpha activity and production of erythropoietin.	7	12	increase	Positive_activation_token_1_verb	Negative_activation	Positive_activation	Vhl	Vhl	Vhl	Hif1alpha	Hif1alpha	Hif1alpha	9	10	11	12
Recently , we developed a hypoxia targeting protein , TOP3 , which consisted of procaspase-3 with the VHL mediated protein destruction motif of HIF-1alpha .	Recently, we developed a hypoxia targeting protein, TOP3, which consisted of procaspase-3 with the VHL mediated protein destruction motif of HIF-1alpha.	12	24	mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	17	18	23	24
For example , the unique binding pocket on EloC where the N terminus of Cul2 interacts is an attractive target for a small molecule that would inhibit the VHL mediated HIF-1alpha downregulation pathway .	For example, the unique binding pocket on EloC where the N terminus of Cul2 interacts is an attractive target for a small molecule that would inhibit the VHL mediated HIF-1alpha downregulation pathway.	27	32	mediated	Positive_early_activation	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	28	29	30	31
Hydroxylation of proline residues in HIF-1alpha promotes binding of the pVHL ubiquitylation complex , which then targets HIF-1alpha for proteasomal degradation .	Hydroxylation of proline residues in HIF-1alpha promotes binding of the pVHL ubiquitylation complex, which then targets HIF-1alpha for proteasomal degradation.	0	20	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	Hydroxylation of proline residues in HIF-1alpha promotes binding of the pVHL ubiquitylation	pvhl	HIF-1alpha	HIF-1alpha	hif-1alpha	10	11	17	18
Interestingly , HIF-1alpha is independently negatively regulated by the VHL tumor suppressor , providing another link between the mTOR pathway and cancer .	Interestingly, HIF-1alpha is independently negatively regulated by the VHL tumor suppressor, providing another link between the mTOR pathway and cancer.	2	11	negatively regulated	Negative_activation_syntax_2_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	9	10	2	3
Normally , VHL directs HIF-1alpha towards degradation , while VHL alterations prevent the degradation of HIF-1alpha XREF_BIBR .	Normally, VHL directs HIF-1alpha towards degradation, while VHL alterations prevent the degradation of HIF-1alpha XREF_BIBR.	2	6	directs	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	2	3	4	5
For example , sequestration of ubiquitin ligases MDM2 , and von Hippel-Lindau disease tumor suppressor ( VHL ) enhances the stability of their targets p53 and hypoxia inducible factor 1 alpha ( HIF1alpha ) , respectively [ XREF_BIBR , XREF_BIBR ] .	For example, sequestration of ubiquitin ligases MDM2, and von Hippel-Lindau disease tumor suppressor (VHL) enhances the stability of their targets p53 and hypoxia inducible factor 1 alpha (HIF1alpha), respectively [XREF_BIBR, XREF_BIBR].	10	33	enhances	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	von Hippel-Lindau disease tumor suppressor	von Hippel-Lindau disease tumor suppressor	von Hippel-Lindau disease tumor suppressor	HIF1alpha	HIF1alpha	HIF1alpha	10	15	32	33
Therefore , a VHL deficiency is also considered to cause the accumulation of the HIF-1alpha protein , even in the presence of oxygen [ XREF_BIBR ] .	Therefore, a VHL deficiency is also considered to cause the accumulation of the HIF-1alpha protein, even in the presence of oxygen [XREF_BIBR].	3	16	cause	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha protein	HIF-1alpha protein	HIF-1alpha protein	3	4	14	16
Here we show a non canonical , hypoxia independent mechanism of HIF-1alpha induction in EC , in which phosphorylation of Pfn-1 at Tyr 129 inhibits VHL mediated HIF-1alpha degradation by direct , competitive inhibition of VHL binding to HIF-1alpha .	Here we show a non canonical, hypoxia independent mechanism of HIF-1alpha induction in EC, in which phosphorylation of Pfn-1 at Tyr 129 inhibits VHL mediated HIF-1alpha degradation by direct, competitive inhibition of VHL binding to HIF-1alpha.	24	28	mediated	Positive_early_activation	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	25	26	27	28
The finding that YC-1 , mitomycin C and camptothecin could reduce HIF-1alpha protein concentrations when prolyl hydroxylase- and pVHL mediated HIF-1alpha degradation was blocked suggests that these compounds either inhibit HIF-1alpha mRNA or protein synthesis or that they induce HIF-1alpha protein degradation that is independent of the prolyl hydroxylase- and pVHL mediated pathway .	The finding that YC-1, mitomycin C and camptothecin could reduce HIF-1alpha protein concentrations when prolyl hydroxylase- and pVHL mediated HIF-1alpha degradation was blocked suggests that these compounds either inhibit HIF-1alpha mRNA or protein synthesis or that they induce HIF-1alpha protein degradation that is independent of the prolyl hydroxylase- and pVHL mediated pathway.	16	21	mediated	Positive_early_activation	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	18	19	20	21
The von-Hippel-Lindau ( VHL ) syndrome is caused by a mutation in the E3-ligease ( VHL ) reducing degradation of HIF1alpha and leading to increased signaling of pro angiogenic cytokines which further supports the key role of degradation in the regulation of growth factor signaling .	The von-Hippel-Lindau (VHL) syndrome is caused by a mutation in the E3-ligease (VHL) reducing degradation of HIF1alpha and leading to increased signaling of pro angiogenic cytokines which further supports the key role of degradation in the regulation of growth factor signaling.	1	21	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	3	4	20	21
It is known that HDAC-1 induces the downexpression of VHL which leads HIF-1alpha to proteasomal degradation [ XREF_BIBR , XREF_BIBR ] .	It is known that HDAC-1 induces the downexpression of VHL which leads HIF-1alpha to proteasomal degradation [XREF_BIBR, XREF_BIBR].	4	13	leads	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	HDAC-1 induces the downexpression of VHL	vhl	HIF-1alpha	HIF-1alpha	hif-1alpha	9	10	12	13
The VHL protein targets the Hypoxia Inducible Factors 1 and 2a ( HIF1a and HIF2a ) for proteasomal degradation in cells exposed to a normal range of oxygen concentration .	The VHL protein targets the Hypoxia Inducible Factors 1 and 2a (HIF1a and HIF2a) for proteasomal degradation in cells exposed to a normal range of oxygen concentration.	1	14	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1a	HIF1a	HIF1a	1	2	12	13
Vhl -/- EMSCs had increased amounts of HIF-1alpha , HIF-2alpha and WNT11 proteins compared to non infected or GFP infected control EMSCs under standard culture conditions ( 21 % O 2 ) .	Vhl -/- EMSCs had increased amounts of HIF-1alpha, HIF-2alpha and WNT11 proteins compared to non infected or GFP infected control EMSCs under standard culture conditions (21% O 2).	0	12	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Vhl	Vhl	Vhl	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	7	8
HIF-1alpha , a component of HIF-1 , can be induced by hypoxia or mutations of PTEN , VHL , succinate dehydrogenase ( SDH ) , or fumarate hydratase ( FH ) , as well as by the activation of ERBB2 , SRC , endothelin-1 ( ET-1 ) , the RAS and MARK pathway , and the phosphoinositide 3-kinase ( PI3K )-Akt-mTOR pathway .	HIF-1alpha, a component of HIF-1, can be induced by hypoxia or mutations of PTEN, VHL, succinate dehydrogenase (SDH), or fumarate hydratase (FH), as well as by the activation of ERBB2, SRC, endothelin-1 (ET-1), the RAS and MARK pathway, and the phosphoinositide 3-kinase (PI3K)-Akt-mTOR pathway.	0	20	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	17	18	0	1
In the presence of oxygen , HIF1alpha is targeted for destruction by the E3 Ub ligase VHL .	In the presence of oxygen, HIF1alpha is targeted for destruction by the E3 Ub ligase VHL.	6	17	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	16	17	6	7
The half-life of the HIF-1alpha subunit is determined by oxygen dependent prolyl hydroxylation , which is required for binding of the von Hippel-Lindau protein ( VHL ) , the recognition component of an E3 ubiquitin ligase that targets HIF-1alpha for ubiquitination and degradation .	The half-life of the HIF-1alpha subunit is determined by oxygen dependent prolyl hydroxylation, which is required for binding of the von Hippel-Lindau protein (VHL), the recognition component of an E3 ubiquitin ligase that targets HIF-1alpha for ubiquitination and degradation.	23	42	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	25	26	38	39
The stabilization of HIF1alpha is dependent on the activity of the E3 protein ligase , pVHL , which targets HIF1alpha towards proteasomal degradation .	The stabilization of HIF1alpha is dependent on the activity of the E3 protein ligase, pVHL, which targets HIF1alpha towards proteasomal degradation.	13	22	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF1alpha	HIF1alpha	HIF1alpha	15	16	19	20
No studies have reported a role for epigenetic mechanisms in the regulation of Hif1 expression however , epigenetic regulation of von Hippel-Lindau ( VHL ) , an ubiquitin ligase that targets HIF1a for proteosomal destruction under normoxic conditions , has been reported .	No studies have reported a role for epigenetic mechanisms in the regulation of Hif1 expression however, epigenetic regulation of von Hippel-Lindau (VHL), an ubiquitin ligase that targets HIF1a for proteosomal destruction under normoxic conditions, has been reported.	21	34	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1a	HIF1a	HIF1a	23	24	31	32
In some cancers , accumulation of HIF-1alpha can result from loss-of-function mutations in proteins that cause HIF-1alpha degradation , such as the Von Hippel-Lindau tumor suppressor ( pVHL ) or the enzymes that produce cofactors for the prolyl hydroxylases ( PHDs ) .	In some cancers, accumulation of HIF-1alpha can result from loss-of-function mutations in proteins that cause HIF-1alpha degradation, such as the Von Hippel-Lindau tumor suppressor (pVHL) or the enzymes that produce cofactors for the prolyl hydroxylases (PHDs).	16	28	degradation	Negative_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	27	28	16	17
Oxygen dependent hydroxylation at two prolyl residues ( Pro402 and Pro564 in human HIF-1alpha ) mediates its interactions with E3 , von Hippel-Lindau ( VHL ) , which targets HIF-1alpha for rapid proteasomal degradation [ XREF_BIBR - XREF_BIBR ] .	Oxygen dependent hydroxylation at two prolyl residues (Pro402 and Pro564 in human HIF-1alpha) mediates its interactions with E3, von Hippel-Lindau (VHL), which targets HIF-1alpha for rapid proteasomal degradation [XREF_BIBR - XREF_BIBR].	22	37	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	24	25	29	30
The non steroidal anti-inflammatory drugs ( NSAIDs ) interfere with hypoxia induced HIF-1alpha accumulation , VEGF gene activation and angiogenesis through upregulation of von Hippel- Lindau ( VHL ) tumor suppressor , which activates degradation of HIF-1alpha protein .	The non steroidal anti-inflammatory drugs (NSAIDs) interfere with hypoxia induced HIF-1alpha accumulation, VEGF gene activation and angiogenesis through upregulation of von Hippel- Lindau (VHL) tumor suppressor, which activates degradation of HIF-1alpha protein.	11	28	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	27	28	12	13
Mechanistically , p62 induces hypoxia-inducible-factor 1alpha ( HIF1alpha ) signaling though the upregulation of mTORC1 and NF-kappaB activity , and the downregulation of VHL E3 ubiquitin ligase activity , thus inducing HIF1alpha activation , glucose uptake and lactate production , and growth in soft agar .	Mechanistically, p62 induces hypoxia-inducible-factor 1alpha (HIF1alpha) signaling though the upregulation of mTORC1 and NF-kappaB activity, and the downregulation of VHL E3 ubiquitin ligase activity, thus inducing HIF1alpha activation, glucose uptake and lactate production, and growth in soft agar.	23	32	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	23	24	31	32
The VHL protein function as an ubiquitin ligase and targets the hypoxia inducible transcription factors HIF-1alpha and HIF-2alpha for degradation .	The VHL protein function as an ubiquitin ligase and targets the hypoxia inducible transcription factors HIF-1alpha and HIF-2alpha for degradation.	0	19	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	1	2	15	16
As the higher levels of HIF-1alpha in EMT fractions could be produced by either reduced degradation or increased production of the protein , we assessed the Von Hippel-Lindau protein ( pVHL ) that targets HIF-1alpha for proteasomal degradation .	As the higher levels of HIF-1alpha in EMT fractions could be produced by either reduced degradation or increased production of the protein, we assessed the Von Hippel-Lindau protein (pVHL) that targets HIF-1alpha for proteasomal degradation.	28	37	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	30	31	34	35
In normal cells the product of the VHL tumour suppressor gene targets the regulatory HIF subunits ( HIF-1alpha and HIF-2alpha ) for oxygen dependent proteolysis , acting as the substrate recognition component of an E3 ubiquitin ligase .	In normal cells the product of the VHL tumour suppressor gene targets the regulatory HIF subunits (HIF-1alpha and HIF-2alpha) for oxygen dependent proteolysis, acting as the substrate recognition component of an E3 ubiquitin ligase.	7	19	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	17	18
At normal oxygen tensions , the alpha-subunit of the protein ( Hif-1alpha ) undergoes prolyl hydroxylation , which initiates recognition by the von Hippel-Lindau ( Vhl ) tumor suppressor protein , a component of the E3 ubiquitin ligase that targets Hif-1alpha for proteasomal degradation .	At normal oxygen tensions, the alpha-subunit of the protein (Hif-1alpha) undergoes prolyl hydroxylation, which initiates recognition by the von Hippel-Lindau (Vhl) tumor suppressor protein, a component of the E3 ubiquitin ligase that targets Hif-1alpha for proteasomal degradation.	23	43	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	Vhl	Vhl	Vhl	Hif-1alpha	Hif-1alpha	Hif-1alpha	25	26	40	41
It results from a Von Hippel-Lindau ( VHL ) gene mutation ( C598T ) that causes increased HIF-1alpha activity and erythrocyte production in the face of normoxia .	It results from a Von Hippel-Lindau (VHL) gene mutation (C598T) that causes increased HIF-1alpha activity and erythrocyte production in the face of normoxia.	5	18	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	17	18
Mutations in VHL and SDH result in accumulation of succinate which directly inhibits prolyl hydroxylase ( PHD ) , thereby inducing Hif-1alpha accumulation ; Hif-1alpha causes PCC tumorogenesis by increasing angiogenesis , proliferation , invasion and metastasis .	Mutations in VHL and SDH result in accumulation of succinate which directly inhibits prolyl hydroxylase (PHD), thereby inducing Hif-1alpha accumulation; Hif-1alpha causes PCC tumorogenesis by increasing angiogenesis, proliferation, invasion and metastasis.	0	22	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	Hif-1alpha	Hif-1alpha	Hif-1alpha	2	3	21	22
Microtubular Stability Affects pVHL Mediated Regulation of HIF-1alpha via the p38 and MAPK Pathway in Hypoxic Cardiomyocytes .	Microtubular Stability Affects pVHL Mediated Regulation of HIF-1alpha via the p38 and MAPK Pathway in Hypoxic Cardiomyocytes.	2	13	Mediated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	3	4	7	8
pVHL , a component of the E3 ubiquitin protein and ligase complex , functions to target HIF-1alpha for degradation via the ubiquitin proteasome pathway XREF_BIBR XREF_BIBR .	pVHL, a component of the E3 ubiquitin protein and ligase complex, functions to target HIF-1alpha for degradation via the ubiquitin proteasome pathway XREF_BIBR XREF_BIBR.	0	17	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	0	1	16	17
VHL inactivation by genetic mechanisms , such as mutation and loss of heterozygosity , inhibits HIF1A degradation , even in the presence of oxygen , and induces a pseudohypoxic response .	VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response.	0	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1A	HIF1A	HIF1A	0	1	15	16
It has been well established that VHL deficiency induces the accumulation of HIF-1alpha , and the subsequent upregulation of HIF-1alpha-inducible genes .	It has been well established that VHL deficiency induces the accumulation of HIF-1alpha, and the subsequent upregulation of HIF-1alpha-inducible genes.	6	13	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	6	7	12	13
This triggers its interaction with the pVHL protein , which targets HIF-1alpha for degradation by the 26S proteosome [ XREF_BIBR ] .	This triggers its interaction with the pVHL protein, which targets HIF-1alpha for degradation by the 26S proteosome [XREF_BIBR].	6	13	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	6	7	11	12
However , other studies suggest that VHL is also able to target HIF1alpha for destruction in an hydroxylation independent manner during hypoxia XREF_BIBR .	However, other studies suggest that VHL is also able to target HIF1alpha for destruction in an hydroxylation independent manner during hypoxia XREF_BIBR.	6	14	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF1alpha	HIF1alpha	HIF1alpha	6	7	12	13
46 Overexpression of the tumor suppressor protein pVHL inhibits HCC growth in mice by downregulating HIF-1alpha and HIF-2alpha .	46 Overexpression of the tumor suppressor protein pVHL inhibits HCC growth in mice by downregulating HIF-1alpha and HIF-2alpha.	1	17	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	pVHL	Overexpression of the tumor suppressor protein pVHL	pvhl	HIF-1alpha	HIF-1alpha	hif-1alpha	7	8	15	16
Mutation in VHL tumor suppressor gene causes the stabilization of HIF-1alpha and initiates gene transcription of its target genes , leading to up-regulation of several angiogenic factors and growth factors [ XREF_BIBR - XREF_BIBR ] .	Mutation in VHL tumor suppressor gene causes the stabilization of HIF-1alpha and initiates gene transcription of its target genes, leading to up-regulation of several angiogenic factors and growth factors [XREF_BIBR - XREF_BIBR].	2	11	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	2	3	10	11
As expected , pVHL missense mutants induced the proteasome dependent proteolysis of HIF-1alpha , and this proteolysis was inhibited by MG132 .	As expected, pVHL missense mutants induced the proteasome dependent proteolysis of HIF-1alpha, and this proteolysis was inhibited by MG132.	3	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	3	4	12	13
The stability of HIF-1alpha protein is determined by oxygen dependent prolyl hydroxylation , which is required for binding of the von Hippel-Lindau protein ( VHL ) , the recognition component of an E3 ubiquitin ligase that targets HIF-1alpha for ubiquitination and degradation .	The stability of HIF-1alpha protein is determined by oxygen dependent prolyl hydroxylation, which is required for binding of the von Hippel-Lindau protein (VHL), the recognition component of an E3 ubiquitin ligase that targets HIF-1alpha for ubiquitination and degradation.	22	41	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	24	25	37	38
In aerobic conditions , HIF-1alpha is destabilized by the PHD prolyl-hydroxylases that target HIF-1alpha for proteolysis via the von Hippel-Lindau protein ( pVHL ) and further inactivated by the FIH asparaginyl-hydroxylase that precludes the recruitment of transcription coactivators .	In aerobic conditions, HIF-1alpha is destabilized by the PHD prolyl-hydroxylases that target HIF-1alpha for proteolysis via the von Hippel-Lindau protein (pVHL) and further inactivated by the FIH asparaginyl-hydroxylase that precludes the recruitment of transcription coactivators.	10	23	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	22	23	13	14
At later times , however , HuR likely helps to ' shut off ' hypoxic gene expression as it also enhances the levels of pVHL , which targets HIF-1alpha for degradation , thereby helping to restore the levels of hypoxia inducible proteins to basal conditions ( XREF_FIG ) .	At later times, however, HuR likely helps to ' shut off ' hypoxic gene expression as it also enhances the levels of pVHL, which targets HIF-1alpha for degradation, thereby helping to restore the levels of hypoxia inducible proteins to basal conditions (XREF_FIG).	22	30	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	levels of pVHL	pvhl	HIF-1alpha	HIF-1alpha	hif-1alpha	24	25	28	29
In some cancers , HIF1a stabilization may be promoted by VHL promoter hypermethylation [ XREF_BIBR ] .	In some cancers, HIF1a stabilization may be promoted by VHL promoter hypermethylation [XREF_BIBR].	4	13	promoted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	VHL	VHL promoter hypermethylation	vhl	HIF1a	HIF1a	hif1a	10	11	4	5
The reporter assays further confirmed that the transcriptional activity of HIF-1alpha was strikingly reduced when p53 and VHL were cotransfected , whereas increased levels of LANA coexpressed rescued HIF-1alpha transcriptional activity most likely through targeting and degrading the HIF-1alpha suppressors p53 and VHL ( XREF_SUPPLEMENTARY ) .	The reporter assays further confirmed that the transcriptional activity of HIF-1alpha was strikingly reduced when p53 and VHL were cotransfected, whereas increased levels of LANA coexpressed rescued HIF-1alpha transcriptional activity most likely through targeting and degrading the HIF-1alpha suppressors p53 and VHL (XREF_SUPPLEMENTARY).	27	43	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	42	43	28	29
The role of HIF1alpha in VHL disease , especially in ccRCC carcinogenesis , is of interest because HIF1alpha is directly regulated by pVHL , which is usually lost or silenced in ccRCC .	The role of HIF1alpha in VHL disease, especially in ccRCC carcinogenesis, is of interest because HIF1alpha is directly regulated by pVHL, which is usually lost or silenced in ccRCC.	17	29	directly regulated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF1alpha	HIF1alpha	HIF1alpha	22	23	17	18
At the molecular level , TAM-CXB suppresses VHL mediated HIF-1alpha activation , responsible for expression of COX-2 , MMP-2 and VEGF .	At the molecular level, TAM-CXB suppresses VHL mediated HIF-1alpha activation, responsible for expression of COX-2, MMP-2 and VEGF.	6	20	mediated	Positive_early_activation	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	7	8	9	10
In an oxygen rich environment , Hif-1alpha gets hydroxylized through the HIF prolyl hydroxylase , triggering a subsequent ubiquitination by the von Hippel-Lindau protein ( pVHL ) that targets Hif-1alpha for rapid degradation in the proteasome [ XREF_BIBR ] .	In an oxygen rich environment, Hif-1alpha gets hydroxylized through the HIF prolyl hydroxylase, triggering a subsequent ubiquitination by the von Hippel-Lindau protein (pVHL) that targets Hif-1alpha for rapid degradation in the proteasome [XREF_BIBR].	23	32	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	Hif-1alpha	Hif-1alpha	Hif-1alpha	25	26	29	30
For example , HIF-1alpha can be activated by oncogenic mutations of PTEN ( phosphatase and tensin homolog ) , VHL , succinate dehydrogenase ( SDH ) , and fumarate dehydrogenase ( FH ) .	For example, HIF-1alpha can be activated by oncogenic mutations of PTEN (phosphatase and tensin homolog), VHL, succinate dehydrogenase (SDH), and fumarate dehydrogenase (FH).	3	20	activated	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	19	20	3	4
Unlike the normal ubiquitin-proteasome pathway dependent turnover of HIF-alpha proteins which occurs in normoxia , the hypericin induced HIF-1alpha catabolism can occur independently of cellular oxygen levels or pVHL promoted ubiquitin ligation of HIF-1alpha .	Unlike the normal ubiquitin-proteasome pathway dependent turnover of HIF-alpha proteins which occurs in normoxia, the hypericin induced HIF-1alpha catabolism can occur independently of cellular oxygen levels or pVHL promoted ubiquitin ligation of HIF-1alpha.	28	34	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	28	29	33	34
XREF_BIBR - XREF_BIBR In further support of the importance of HIF2alpha , pVHL defective clear-cell RCC produce both HIF1alpha and HIF2alpha or , informatively , HIF2alpha alone .	XREF_BIBR - XREF_BIBR In further support of the importance of HIF2alpha, pVHL defective clear-cell RCC produce both HIF1alpha and HIF2alpha or, informatively, HIF2alpha alone.	12	25	produce	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF1alpha	HIF1alpha	HIF1alpha	12	13	18	19
Independence of VHL and proline hydroxylation in the MGO induced destabilization of HIF-1alpha .	Independence of VHL and proline hydroxylation in the MGO induced destabilization of HIF-1alpha.	2	13	induced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VHL	VHL and proline hydroxylation	vhl	HIF-1alpha	HIF-1alpha	hif-1alpha	2	3	12	13
For example , pVHL defective renal carcinoma cell lines and tumors produce both HIF1alpha and HIF2alpha or HIF2alpha alone and the appearance of HIF2alpha in preneoplastic lesions in the kidneys of VHL patients correlates with increased histological evidence of impending malignancy .	For example, pVHL defective renal carcinoma cell lines and tumors produce both HIF1alpha and HIF2alpha or HIF2alpha alone and the appearance of HIF2alpha in preneoplastic lesions in the kidneys of VHL patients correlates with increased histological evidence of impending malignancy.	3	21	produce	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF1alpha	HIF1alpha	HIF1alpha	3	4	13	14
51,52 Prolyl hydroxylation of HIF-1alpha is required for binding of the von Hippel-Lindau tumor suppressor protein ( VHL ) , the recognition component of an E3 ubiquitin protein ligase that targets HIF-1alpha for proteasomal degradation .	51,52 Prolyl hydroxylation of HIF-1alpha is required for binding of the von Hippel-Lindau tumor suppressor protein (VHL), the recognition component of an E3 ubiquitin protein ligase that targets HIF-1alpha for proteasomal degradation.	15	34	targets	Positive_activation_syntax_5_verb	Negative_activation	Positive_activation	VHL	VHL	VHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	17	18	31	32
Therefore , by promoting degradation of HIF-1alpha , pVHL can suppress HIF-1alpha stimulated transcription and function as a key tumor suppressor [ XREF_BIBR ] .	Therefore, by promoting degradation of HIF-1alpha, pVHL can suppress HIF-1alpha stimulated transcription and function as a key tumor suppressor [XREF_BIBR].	4	11	suppress	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	pVHL	pVHL	pVHL	HIF-1alpha	HIF-1alpha	HIF-1alpha	8	9	6	7
Tan IIA was also demonstrated to suppress IAP3 expression , which in turn activated Caspase 3 and Caspase 9 , as well as induction of cell apoptosis .	Tan IIA was also demonstrated to suppress IAP3 expression, which in turn activated Caspase 3 and Caspase 9, as well as induction of cell apoptosis.	0	23	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	IAP3	Tan IIA was also demonstrated to suppress IAP3 expression	iap3	Caspase 3	Caspase 3	caspase 3	7	8	14	16
In response to TRAIL and CHX , C-XIAP-C D148A was slightly less efficient in maintaining Smac inside mitochondria at late times ( XREF_FIG ) , probably because of caspase-8 directly activating caspase-3 and the latter cleaving XIAP between the BIR2 and 3 domains into fragments that can no longer bind efficiently to Smac .	In response to TRAIL and CHX, C-XIAP-C D148A was slightly less efficient in maintaining Smac inside mitochondria at late times (XREF_FIG), probably because of caspase-8 directly activating caspase-3 and the latter cleaving XIAP between the BIR2 and 3 domains into fragments that can no longer bind efficiently to Smac.	14	42	directly activating	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	36	37	31	32
Thus , overexpressed XIAP can partially inhibit cell death by blocking caspase 3 alone , which is consistent with the idea that there is a feedback loop where caspase 3 can process caspase 9 .	Thus, overexpressed XIAP can partially inhibit cell death by blocking caspase 3 alone, which is consistent with the idea that there is a feedback loop where caspase 3 can process caspase 9.	2	13	inhibit	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	3	4	11	13
10 There is some , albeit limited , evidence that the ubiquitin ligase activities of XIAP and cIAP1 may target active caspase-3 for proteasomal degradation .	10 There is some, albeit limited, evidence that the ubiquitin ligase activities of XIAP and cIAP1 may target active caspase-3 for proteasomal degradation.	13	22	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	15	16	21	22
In contrast , downregulation of XIAP in combination with TRAIL caused full processing of pro-caspase-3 to its active subunits ( XREF_FIG , right ) .	In contrast, downregulation of XIAP in combination with TRAIL caused full processing of pro-caspase-3 to its active subunits (XREF_FIG, right).	3	15	caused	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	pro-caspase-3	pro-caspase-3	pro-caspase-3	5	6	14	15
These findings are consistent with our hypothesis that FAK processing is in part mediated by caspase 3 , the activation of which is modulated by Xiap .	These findings are consistent with our hypothesis that FAK processing is in part mediated by caspase 3, the activation of which is modulated by Xiap.	13	26	modulated	Positive_activation_syntax_6_verb	Negative_activation	Positive_activation	Xiap	Xiap	Xiap	caspase 3	caspase 3	caspase 3	25	26	15	17
Inhibition assays showed that , while caspase-3 could be effectively inhibited by XIAP , survivin had no detectable inhibitory activity against the enzyme , even at concentrations several thousand-fold higher than XIAP .	Inhibition assays showed that, while caspase-3 could be effectively inhibited by XIAP, survivin had no detectable inhibitory activity against the enzyme, even at concentrations several thousand-fold higher than XIAP.	6	13	inhibited	Negative_activation_syntax_2_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	12	13	6	7
XIAP is considered as the IAP family member with the strongest antiapoptotic activities and blocks apoptosis by binding to and inhibiting activation of caspase-3 , -7 , and -9 .	XIAP is considered as the IAP family member with the strongest antiapoptotic activities and blocks apoptosis by binding to and inhibiting activation of caspase-3, -7, and -9.	0	28	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	23	24
In fact , the sequence EFES is homologous to a loop unique to the executioner caspase-3 and caspase-7 that are targeted by XIAP .	In fact, the sequence EFES is homologous to a loop unique to the executioner caspase-3 and caspase-7 that are targeted by XIAP.	11	23	targeted	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	22	23	15	16
The inhibitor of apoptosis ( IAP ) family negatively regulates this process , and the most potent human IAP protein XIAP inhibits the activity of both caspase 9 and caspase 3 [ XREF_BIBR ] .	The inhibitor of apoptosis (IAP) family negatively regulates this process, and the most potent human IAP protein XIAP inhibits the activity of both caspase 9 and caspase 3 [XREF_BIBR].	14	32	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	20	21	29	31
Furthermore , the reduction in XIAP reduces its ability to bind and inhibit caspase 3 , 7 and 9 , leading to a more significant level of apoptosis .	Furthermore, the reduction in XIAP reduces its ability to bind and inhibit caspase 3, 7 and 9, leading to a more significant level of apoptosis.	3	15	reduces	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	5	6	13	15
Downregulation of XIAP resulted in activation of caspase-3 and caspase-9 to trigger apoptosis in glioma cells .	Downregulation of XIAP resulted in activation of caspase-3 and caspase-9 to trigger apoptosis in glioma cells.	0	9	resulted in activation	Positive_activation_syntax_8_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	2	3	7	8
In addition , we found that cisplatin induced apoptosis following activation of caspase-3 , and that the overexpression of XIAP inhibited apoptosis by attenuating caspase-3 activity .	In addition, we found that cisplatin induced apoptosis following activation of caspase-3, and that the overexpression of XIAP inhibited apoptosis by attenuating caspase-3 activity.	17	25	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	overexpression of XIAP	xiap	caspase-3	caspase-3	caspase-3	19	20	24	25
XIAP may also target active caspase-3 for ubiquitination and degradation by the proteasome , thereby inhibiting apoptosis .	XIAP may also target active caspase-3 for ubiquitination and degradation by the proteasome, thereby inhibiting apoptosis.	0	9	target	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	5	6
These results confirm that downregulation of XIAP in mice tumor brains induces the activation of caspase-3 , which induced apoptosis .	These results confirm that downregulation of XIAP in mice tumor brains induces the activation of caspase-3, which induced apoptosis.	4	18	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	6	7	15	16
XREF_BIBR , XREF_BIBR XIAP directly binds to activated caspase-3 , -7 , and -9 using its BIR domains , inhibiting the caspases ' function .	XREF_BIBR, XREF_BIBR XIAP directly binds to activated caspase-3, -7, and -9 using its BIR domains, inhibiting the caspases ' function.	2	14	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	3	4	8	9
XIAP blocks apoptosis downstream of mitochondria by binding to and inhibiting caspase-3 and caspase-9 .	XIAP blocks apoptosis downstream of mitochondria by binding to and inhibiting caspase-3 and caspase-9.	0	13	blocks	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	11	12
Apoptotic cell populations were quantified using antibodies to active caspase-3-PE by flow cytometry ( XREF_FIG ) , which revealed a significant increase in the number of cells positive for active caspase-3 protein in the A2780MNU1-MLH1 cells treated with XIAP siRNA compared with the A2780MNU1 vector .	Apoptotic cell populations were quantified using antibodies to active caspase-3-PE by flow cytometry (XREF_FIG), which revealed a significant increase in the number of cells positive for active caspase-3 protein in the A2780MNU1-MLH1 cells treated with XIAP siRNA compared with the A2780MNU1 vector.	30	39	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	38	39	30	31
Inactivation of the XIAP gene activates CASP3 and apoptosis [ XREF_BIBR ] .	Inactivation of the XIAP gene activates CASP3 and apoptosis [XREF_BIBR].	3	10	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	CASP3	CASP3	CASP3	3	4	6	7
If XIAP was the key inhibitor of apoptosis in HL derived B cells , removal of XIAP should relieve the inhibition of caspase-3 activation .	If XIAP was the key inhibitor of apoptosis in HL derived B cells, removal of XIAP should relieve the inhibition of caspase-3 activation.	14	23	relieve	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	16	17	22	23
X linked inhibitor of apoptosis ( XIAP ) inhibits the proteolytic activity of caspase-3 via direct binding , is highly expressed in CLL cells , and plays an important role in TRAIL induced apoptosis [ XREF_BIBR ] .	X linked inhibitor of apoptosis (XIAP) inhibits the proteolytic activity of caspase-3 via direct binding, is highly expressed in CLL cells, and plays an important role in TRAIL induced apoptosis [XREF_BIBR].	4	16	inhibits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	6	7	13	14
Further analysis revealed that the sensitization of platinums was associated with platinums induced suppression of nuclear factor-kappaB ( NFkappaB ) and subsequent downregulation of X linked inhibitor of apoptosis protein ( XIAP ) , which rescued caspase-3 from inhibition .	Further analysis revealed that the sensitization of platinums was associated with platinums induced suppression of nuclear factor-kappaB (NFkappaB) and subsequent downregulation of X linked inhibitor of apoptosis protein (XIAP), which rescued caspase-3 from inhibition.	29	37	rescued	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	31	32	36	37
A proteasome inhibitor suppressed the degradation of caspase-3 by XIAP , suggesting the involvement of a ubiquitin-proteasome pathway in the degradation .	A proteasome inhibitor suppressed the degradation of caspase-3 by XIAP, suggesting the involvement of a ubiquitin-proteasome pathway in the degradation.	3	10	degradation	Negative_activation_token_2_noun	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	9	10	7	8
In addition , we found that taxol treatment induced the cleavage of pro-caspase-3 , followed by apoptosis , and that the overexpression of XIAP inhibited apoptosis by attenuating the cleavage of pro-caspase-3 and caspase-3 activity .	In addition, we found that taxol treatment induced the cleavage of pro-caspase-3, followed by apoptosis, and that the overexpression of XIAP inhibited apoptosis by attenuating the cleavage of pro-caspase-3 and caspase-3 activity.	21	34	inhibited	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	overexpression of XIAP	xiap	pro-caspase-3	pro-caspase-3	pro-caspase-3	23	24	31	32
We show here that AFP cancels XIAP mediated inhibition of endogenous active caspases in cytosolic lysates of tumor cells , as well as XIAP induced blockage of active recombinant caspase 3 in a reconstituted cell-free system .	We show here that AFP cancels XIAP mediated inhibition of endogenous active caspases in cytosolic lysates of tumor cells, as well as XIAP induced blockage of active recombinant caspase 3 in a reconstituted cell-free system.	8	33	induced	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	23	24	29	31
XIAP suppresses apoptosis by directly inhibiting caspase-3 and -9 [ XREF_BIBR , XREF_BIBR ] .	XIAP suppresses apoptosis by directly inhibiting caspase-3 and -9 [XREF_BIBR, XREF_BIBR].	0	12	suppresses	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	0	1	6	7
Re-expression of ARHI further increased the cisplatin mediated suppression of Bcl-2 and XIAP expression and enhanced the accumulation of activated caspase-3 and cleaved PARP .	Re-expression of ARHI further increased the cisplatin mediated suppression of Bcl-2 and XIAP expression and enhanced the accumulation of activated caspase-3 and cleaved PARP.	0	21	enhanced	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	Re-expression of ARHI further increased the cisplatin mediated suppression of Bcl-2 and XIAP expression	xiap	caspase-3	caspase-3	caspase-3	12	13	20	21
Downregulation of Xiap by antisense Xiap oligonucleotides increased caspase-3 activity and sensitized cisplatin resistant cells to cisplatin treatment .	Downregulation of Xiap by antisense Xiap oligonucleotides increased caspase-3 activity and sensitized cisplatin resistant cells to cisplatin treatment.	0	9	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Xiap	Xiap	Xiap	caspase-3	caspase-3	caspase-3	2	3	8	9
Down-regulation of XIAP and subsequent activation of caspase-8 and caspase-3 as well as downstream substrates such as PARP-1 also occurs .	Down-regulation of XIAP and subsequent activation of caspase-8 and caspase-3 as well as downstream substrates such as PARP-1 also occurs.	2	10	activation	Positive_activation_syntax_3_noun	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	2	3	9	10
Therefore , degradation of XIAP by mu-calpain in our system may decrease the activation threshold of caspase-3 normally held in check by the IAPs and/or lead to auto-activation of other caspases .	Therefore, degradation of XIAP by mu-calpain in our system may decrease the activation threshold of caspase-3 normally held in check by the IAPs and/or lead to auto-activation of other caspases.	2	18	decrease	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	4	5	16	17
Interestingly , while MEFs express high levels of XIAP , which is rapidly degraded in response to FasL treatment , hepatocytes express only little XIAP that allows most caspase-3 to be directly activated by caspase-8 .	Interestingly, while MEFs express high levels of XIAP, which is rapidly degraded in response to FasL treatment, hepatocytes express only little XIAP that allows most caspase-3 to be directly activated by caspase-8.	21	32	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP	XIAP	caspase-3	caspase-3	caspase-3	24	25	28	29
XIAP blocks the activity of activated caspase 9 in the apoptosome by binding to the neo-N-terminal sequence ( ATPF ) , preventing activation of caspase 3 and , in addition , XIAP can directly inhibit activated caspase 3 .	XIAP blocks the activity of activated caspase 9 in the apoptosome by binding to the neo-N-terminal sequence (ATPF), preventing activation of caspase 3 and, in addition, XIAP can directly inhibit activated caspase 3.	31	38	inhibit activated	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	XIAP	XIAP	XIAP	caspase 3	caspase 3	caspase 3	31	32	36	38
Activated Caspase-3 can be inhibited by the X linked inhibitor of apoptosis ( XIAP ) , an E3 ligase that directly binds and inhibits catalytic activity of Caspase-3 .	Activated Caspase-3 can be inhibited by the X linked inhibitor of apoptosis (XIAP), an E3 ligase that directly binds and inhibits catalytic activity of Caspase-3.	0	28	Activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XIAP	XIAP), an E3 ligase that directly binds and inhibits catalytic activity of Caspase-3	xiap	Caspase-3	Caspase-3	caspase-3	13	14	1	2
The threshold is defined by factors opposing CDK1 activation , including PP1 and PP2A phosphatases and Wee1 and Myt1 kinases .	The threshold is defined by factors opposing CDK1 activation, including PP1 and PP2A phosphatases and Wee1 and Myt1 kinases.	7	19	activation	Positive_activation_syntax_noun_Hearst	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	16	17	7	8
These higher levels of replicative stress could stem from a reduced inactivation of CDK1 by WEE1 , as CDK1 can promote unscheduled origin firing XREF_BIBR , XREF_BIBR .	These higher levels of replicative stress could stem from a reduced inactivation of CDK1 by WEE1, as CDK1 can promote unscheduled origin firing XREF_BIBR, XREF_BIBR.	7	16	inactivation	Negative_activation_token_2_noun	Negative_activation	Positive_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	15	16	13	14
This cdc2 activation was induced by Wee1 kinase down-regulation .	This cdc2 activation was induced by Wee1 kinase down-regulation.	1	8	induced	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	cdc2	cdc2	cdc2	6	7	1	2
Rather , it appears that the activity of Wee1 can be restrained to allow a low level of Cdk1 activity to be generated in early mitosis .	Rather, it appears that the activity of Wee1 can be restrained to allow a low level of Cdk1 activity to be generated in early mitosis.	6	19	allow	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	8	9	18	19
In addition , the phosphorylation of CDK1 at the conserved Thr14 and Tyr15 residues by Myt1 and Wee1 kinases causes inactivation of the mitotic CDK1 activity XREF_BIBR at the end of mitosis XREF_BIBR , XREF_BIBR .	In addition, the phosphorylation of CDK1 at the conserved Thr14 and Tyr15 residues by Myt1 and Wee1 kinases causes inactivation of the mitotic CDK1 activity XREF_BIBR at the end of mitosis XREF_BIBR, XREF_BIBR.	4	26	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	phosphorylation of CDK1 at the conserved Thr14 and Tyr15 residues by Myt1 and Wee1	wee1	CDK1	CDK1	cdk1	17	18	24	25
Cytophysiological downregulation of WEE1 and claspin by enhanced activity of PLK1 promotes CDK1 activation and leads to mitotic entry .	Cytophysiological downregulation of WEE1 and claspin by enhanced activity of PLK1 promotes CDK1 activation and leads to mitotic entry.	1	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	3	4	12	13
Time course simulations ( XREF_FIG D ) show that , at GVBD , an initial rapid fall in Wee1 and rise in Cdc25 activity allows Cdk1 activity to increase almost to the level of total CycB , as inhibitory tyrosine phosphorylation is lost .	Time course simulations (XREF_FIG D) show that, at GVBD, an initial rapid fall in Wee1 and rise in Cdc25 activity allows Cdk1 activity to increase almost to the level of total CycB, as inhibitory tyrosine phosphorylation is lost.	16	26	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	18	19	25	26
We have previously shown that WEE1 deficiency activated CDK1 and the anaphase promoting complex , leading to both premature entry into mitosis and the block in mitosis progression XREF_BIBR XREF_BIBR .	We have previously shown that WEE1 deficiency activated CDK1 and the anaphase promoting complex, leading to both premature entry into mitosis and the block in mitosis progression XREF_BIBR XREF_BIBR.	5	11	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	5	6	8	9
Two-dimensional separations of CDK1 from cells treated with Wee1 siRNAs confirm that Y15 and T161 phosphorylations were not coupled ( XREF_FIG ) .	Two-dimensional separations of CDK1 from cells treated with Wee1 siRNAs confirm that Y15 and T161 phosphorylations were not coupled (XREF_FIG).	1	9	treated with	Positive_activation_surface_treated_with	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	8	9	3	4
Collectively , these findings suggest that AZD1775 induced Chk1 activation , leading to cdc2 and Cdk1 T14 phosphorylation , represents a compensatory response to Wee1 disruption that limits cdc2 and Cdk1 activation and checkpoint abrogation .	Collectively, these findings suggest that AZD1775 induced Chk1 activation, leading to cdc2 and Cdk1 T14 phosphorylation, represents a compensatory response to Wee1 disruption that limits cdc2 and Cdk1 activation and checkpoint abrogation.	24	31	limits	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	cdc2	cdc2	cdc2	24	25	28	29
Wee1 turnover increases Cdk1 activity and mitotic entry .	Wee1 turnover increases Cdk1 activity and mitotic entry.	0	4	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	0	1	3	4
Low expression of wee1 activates CDK1 and promotes cell progression from the G 2 phase to the M phase .	Low expression of wee1 activates CDK1 and promotes cell progression from the G 2 phase to the M phase.	1	6	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	wee1	expression of wee1	wee1	CDK1	CDK1	cdk1	3	4	5	6
In response to DNA damage , Wee1 causes inactivation of CDC2 and consequently leads to G 2 arrest that gives tumor cells survival advantage by allowing time to repair their damaged DNA .	In response to DNA damage, Wee1 causes inactivation of CDC2 and consequently leads to G 2 arrest that gives tumor cells survival advantage by allowing time to repair their damaged DNA.	6	13	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	CDC2	CDC2	CDC2	6	7	10	11
Consistently , Vpr induces G2 arrest by inhibiting the Cdc25 phosphatase through direct interaction and activation of the Wee1 kinase ; both Cdc25 and Wee1 enzymes directly regulate Cdc2 and CDK1 .	Consistently, Vpr induces G2 arrest by inhibiting the Cdc25 phosphatase through direct interaction and activation of the Wee1 kinase; both Cdc25 and Wee1 enzymes directly regulate Cdc2 and CDK1.	22	31	directly regulate	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	24	25	30	31
Survivin inactivates and blocks CDK1 by increasing the level of Wee1 and thus , inactivates and blocks the pro apoptotic activity of CDK1 .	Survivin inactivates and blocks CDK1 by increasing the level of Wee1 and thus, inactivates and blocks the pro apoptotic activity of CDK1.	0	23	inactivates	Negative_activation_syntax_1_verb	Negative_activation	Negative_activation	Wee1	Survivin inactivates and blocks CDK1 by increasing the level of Wee1	wee1	CDK1	CDK1	cdk1	10	11	22	23
However , the catalytic activity of the total pool of cyclin E/Cdk2 was not reduced and persisted in embryos overexpressing Wee1 , consistent with the cell cycle delay and delayed degradation of cyclin E. Therefore , like Chk1 and Chk2 , Wee1 causes tyrosine phosphoryation of Cdk1 and Cdk2 in X. laevis embryos .	However, the catalytic activity of the total pool of cyclin E/Cdk2 was not reduced and persisted in embryos overexpressing Wee1, consistent with the cell cycle delay and delayed degradation of cyclin E. Therefore, like Chk1 and Chk2, Wee1 causes tyrosine phosphoryation of Cdk1 and Cdk2 in X. laevis embryos.	41	48	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	Cdk1	Cdk1	Cdk1	41	42	46	47
Accordingly , vertebrate cells overexpressing CDK1 with T14A and Y15F substitutions or treated with Wee1 small interfering RNAs undergo mitotic catastrophe ( i.e ., entry into mitosis before completion of DNA replication , resulting in aberrant mitosis and cell death ) .	Accordingly, vertebrate cells overexpressing CDK1 with T14A and Y15F substitutions or treated with Wee1 small interfering RNAs undergo mitotic catastrophe (i.e., entry into mitosis before completion of DNA replication, resulting in aberrant mitosis and cell death).	4	16	treated with	Positive_activation_surface_treated_with	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	CDK1	CDK1	CDK1	14	15	5	6
In cells lacking normal p53 activity , each treatment activated CDC25C and inactivated Wee1 , which in turn activated cdc2 and sent cells rapidly through the G2/M checkpoint and into mitosis .	In cells lacking normal p53 activity, each treatment activated CDC25C and inactivated Wee1, which in turn activated cdc2 and sent cells rapidly through the G2/M checkpoint and into mitosis.	12	21	activated	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	cdc2	cdc2	cdc2	13	14	19	20
During S-phase WEE1 also modulates the activity of CDK1 and CDK2 present at replication origins to control replication initiation ( XREF_FIG ) .	During S-phase WEE1 also modulates the activity of CDK1 and CDK2 present at replication origins to control replication initiation (XREF_FIG).	2	10	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	2	3	8	9
Wee1 protein kinase allows cdc2 inactivation by phosphorylation of cdc2 on tyrosine -15 [ XREF_BIBR , XREF_BIBR ] .	Wee1 protein kinase allows cdc2 inactivation by phosphorylation of cdc2 on tyrosine -15 [XREF_BIBR, XREF_BIBR].	0	5	allows	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	cdc2	cdc2	cdc2	0	1	4	5
Progression through the cell cycle requires PLK1 mediated degradation of WEE1 , which increases CDK1 activity and promotes M-phase [ XREF_BIBR ] .	Progression through the cell cycle requires PLK1 mediated degradation of WEE1, which increases CDK1 activity and promotes M-phase [XREF_BIBR].	8	17	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	WEE1	WEE1	WEE1	CDK1	CDK1	CDK1	10	11	14	15
VRK1 knockdown was reported to reduce the mobility of BAF in the nucleus , likely due to enhanced nucleoplasmic DNA binding by nonphosphorylated BAF , whereas knockdown of VRK2 , which , being NE tethered , would only phosphorylate the NE associated BAF population , actually enhanced BAF dissociation from the NE .	VRK1 knockdown was reported to reduce the mobility of BAF in the nucleus, likely due to enhanced nucleoplasmic DNA binding by nonphosphorylated BAF, whereas knockdown of VRK2, which, being NE tethered, would only phosphorylate the NE associated BAF population, actually enhanced BAF dissociation from the NE.	0	10	reduce	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	VRK1	VRK1	VRK1	BAF	BAF	BAF	0	1	9	10
VRK1 depletion increases the immobile fraction of BAF at the nuclear periphery and disturbs nuclear envelope architecture .	VRK1 depletion increases the immobile fraction of BAF at the nuclear periphery and disturbs nuclear envelope architecture.	0	8	increases	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	VRK1	VRK1	VRK1	BAF	BAF	BAF	0	1	7	8
VRK1 mediated BAF re-localization is essential process for DNA release during G1/S transition .	VRK1 mediated BAF re-localization is essential process for DNA release during G1/S transition.	0	3	mediated	Positive_early_activation	Negative_activation	Positive_activation	VRK1	VRK1	VRK1	BAF	BAF	BAF	0	1	2	3
VRK1 , a cellular homolog of B1 , targets BAF on the same residues as B1 .	VRK1, a cellular homolog of B1, targets BAF on the same residues as B1.	0	10	targets	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	VRK1	VRK1	VRK1	BAF	BAF	BAF	0	1	9	10
Furthermore , interferon-beta-mediated XAF1 induction promoted formation of an endogenous XIAP , XAF1 , and Survivin complex .	Furthermore, interferon-beta-mediated XAF1 induction promoted formation of an endogenous XIAP, XAF1, and Survivin complex.	3	16	promoted	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XAF1	XAF1	XAF1	XIAP	XIAP	XIAP	3	4	10	11
Expression of XAF1 triggers a redistribution of XIAP from the cytosol to the nucleus .	Expression of XAF1 triggers a redistribution of XIAP from the cytosol to the nucleus.	0	8	triggers	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	XAF1	Expression of XAF1	xaf1	XIAP	XIAP	xiap	2	3	7	8
By suppressing CDK2 activity during DNA synthesis , Wee1 prevents unscheduled initiation of replication that may potentially lead to DNA lesions XREF_BIBR .	By suppressing CDK2 activity during DNA synthesis, Wee1 prevents unscheduled initiation of replication that may potentially lead to DNA lesions XREF_BIBR.	2	10	prevents	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	Wee1	Wee1	CDK2	CDK2	CDK2	8	9	2	3
Overexpression of Wee1 promotes the persistence of Cdc25A , cyclin E and Cdk2 activity .	Overexpression of Wee1 promotes the persistence of Cdc25A, cyclin E and Cdk2 activity.	0	13	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	Wee1	Overexpression of Wee1	wee1	Cdk2	Cdk2	cdk2	2	3	12	13
The group also demonstrated that WSB1 knockdown by RNA interference increased stability and durability of HIPK2 [ XREF_BIBR ] .	The group also demonstrated that WSB1 knockdown by RNA interference increased stability and durability of HIPK2 [XREF_BIBR].	5	17	increased	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	WSB1	WSB1	WSB1	HIPK2	HIPK2	HIPK2	5	6	15	16
The degradation of HIPK2 induced by Siah1 or WSB1 was shown to be suppressed upon DNA damage XREF_BIBR , XREF_BIBR .	The degradation of HIPK2 induced by Siah1 or WSB1 was shown to be suppressed upon DNA damage XREF_BIBR, XREF_BIBR.	1	9	induced	Positive_activation_syntax_2_verb	Negative_activation	Negative_activation	WSB1	WSB1	WSB1	HIPK2	HIPK2	HIPK2	8	9	3	4
The constitutive activation of FLT3 in our STS1 and STS2 dKO model causes neither HSC exhaustion nor leukemia development as in the CBL or Itch KO model .	The constitutive activation of FLT3 in our STS1 and STS2 dKO model causes neither HSC exhaustion nor leukemia development as in the CBL or Itch KO model.	4	26	causes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	STS1	STS1	STS1	CBL	CBL	CBL	7	8	22	23
XAF1 also antagonizes the cellular inhibitor of apoptosis genes C-IAP1 and C-IAP2 XREF_BIBR , and may sensitize cells to Fas mediated apoptosis XREF_BIBR , which is thought to play a role in sarcoidosis XREF_BIBR , XREF_BIBR .	XAF1 also antagonizes the cellular inhibitor of apoptosis genes C-IAP1 and C-IAP2 XREF_BIBR, and may sensitize cells to Fas mediated apoptosis XREF_BIBR, which is thought to play a role in sarcoidosis XREF_BIBR, XREF_BIBR.	0	16	antagonizes	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	XAF1	XAF1	XAF1	C-IAP2	C-IAP2	C-IAP2	0	1	11	12
In addition , PRKAA1 directly activates autophagy by ULK1 phosphorylation in response to fluctuations in the AMP : ATP ratio XREF_BIBR .	In addition, PRKAA1 directly activates autophagy by ULK1 phosphorylation in response to fluctuations in the AMP : ATP ratio XREF_BIBR.	3	10	directly activates	Positive_activation_syntax_2_verb	Negative_activation	Positive_activation	ULK1	ULK1 phosphorylation	ulk1	PRKAA1	PRKAA1	prkaa1	8	9	3	4
Phosphorylation of BAD by p-Akt leads to the isolation of BAD by the 14-3-3 protein family and a subsequent anti-apoptotic effect [ XREF_BIBR ] .	Phosphorylation of BAD by p-Akt leads to the isolation of BAD by the 14-3-3 protein family and a subsequent anti-apoptotic effect [XREF_BIBR].	5	15	leads	Positive_activation_syntax_3_verb	Negative_activation	Positive_activation	14-3-3 protein	14-3-3 protein	14-3-3 protein	BAD	BAD	BAD	13	15	10	11
The cleavage of the 14-3-3 protein promotes cell death by releasing the associated BAD from the 14-3-3 protein , facilitating BAD translocation to the mitochondria and its interaction with Bcl-x [ XREF_BIBR ] .	The cleavage of the 14-3-3 protein promotes cell death by releasing the associated BAD from the 14-3-3 protein, facilitating BAD translocation to the mitochondria and its interaction with Bcl-x [XREF_BIBR].	4	14	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	14-3-3 protein	14-3-3 protein	14-3-3 protein	BAD	BAD	BAD	4	6	13	14
The present study suggests that the cleavage of 14-3-3 protein during apoptosis promotes cell death by releasing the associated Bad from the 14-3-3 protein and facilitates Bad translocation to the mitochondria and its interaction with Bcl-x ( L ) .	The present study suggests that the cleavage of 14-3-3 protein during apoptosis promotes cell death by releasing the associated Bad from the 14-3-3 protein and facilitates Bad translocation to the mitochondria and its interaction with Bcl-x (L).	8	20	promotes	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	14-3-3 protein	14-3-3 protein	14-3-3 protein	Bad	Bad	Bad	8	10	19	20
Upon exposure to oxidative stress including alcohol , it is suggested that JNK phosphorylation can lead to phosphorylation of the 14-3-3 protein inducing dissociation of Bad , a pro apoptotic member of the Bcl2 family , which can bind and prevent anti-apoptotic proteins including Bcl2 and Bcl-xl .	Upon exposure to oxidative stress including alcohol, it is suggested that JNK phosphorylation can lead to phosphorylation of the 14-3-3 protein inducing dissociation of Bad, a pro apoptotic member of the Bcl2 family, which can bind and prevent anti-apoptotic proteins including Bcl2 and Bcl-xl.	12	30	inducing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	14-3-3 protein	JNK phosphorylation can lead to phosphorylation of the 14-3-3 protein	14-3-3 protein	Bad	Bad	bad	20	22	25	26
The mechanism by which FOG-2 modulates GATA-4 activity is yet to be fully elucidated .	The mechanism by which FOG-2 modulates GATA-4 activity is yet to be fully elucidated.	4	7	modulates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	FOG-2	FOG-2	FOG-2	GATA-4	GATA-4	GATA-4	4	5	6	7
The GATA repressor protein friend of GATA 2 ( FOG-2 ) , also known as zinc finger protein multitype-2 , attenuates the effect of GATA-4 and may also have a role to play in the regulation of CYP2C19 transcription .	The GATA repressor protein friend of GATA 2 (FOG-2), also known as zinc finger protein multitype-2, attenuates the effect of GATA-4 and may also have a role to play in the regulation of CYP2C19 transcription.	0	28	attenuates	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	friend of GATA 2	friend of GATA 2	friend of GATA 2	GATA-4	GATA-4	GATA-4	4	8	24	25
MTA1 silencing impairs FOG2 dependent repression of GATA4 target genes .	MTA1 silencing impairs FOG2 dependent repression of GATA4 target genes.	3	9	repression	Negative_activation_syntax_3_noun	Negative_activation	Negative_activation	FOG2	FOG2	FOG2	GATA4	GATA4	GATA4	3	4	7	8
Akt kinases phosphorylate FOXO at multiple sites and create binding sites for 14-3-3 proteins , causing sequestration of FOXO factors in the cytosol [ XREF_BIBR ] .	Akt kinases phosphorylate FOXO at multiple sites and create binding sites for 14-3-3 proteins, causing sequestration of FOXO factors in the cytosol [XREF_BIBR].	2	19	causing	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	14-3-3 proteins	phosphorylate FOXO at multiple sites and create binding sites for 14-3-3 proteins	14-3-3 proteins	FOXO	FOXO	foxo	12	14	18	19
Following Akt phosphorylation , FoxOs interact with 14-3-3 proteins promoting the cytoplasmic localization of FoxO and alterations in cell signaling independent of DNA binding .	Following Akt phosphorylation, FoxOs interact with 14-3-3 proteins promoting the cytoplasmic localization of FoxO and alterations in cell signaling independent of DNA binding.	7	16	promoting	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	14-3-3 proteins	14-3-3 proteins	14-3-3 proteins	FoxO	FoxO	FoxO	7	9	14	15
Lastly , p38 induces CDC25C cytoplasmic sequestration in response to DNA damage thereby inactivating CDC25C indirectly via MK2 kinase [ XREF_BIBR ] .	Lastly, p38 induces CDC25C cytoplasmic sequestration in response to DNA damage thereby inactivating CDC25C indirectly via MK2 kinase [XREF_BIBR].	2	15	induces	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p38	p38	p38	CDC25C	CDC25C	CDC25C	2	3	14	15
Furthermore , ERK is required to upregulate G 2 / M progression by disrupting cyclin B1 and Cdc2 complex [ XREF_BIBR ] and p38 MAPK increases the mitotic stage by activating Cdc25C [ XREF_BIBR ] .	Furthermore, ERK is required to upregulate G 2 / M progression by disrupting cyclin B1 and Cdc2 complex [XREF_BIBR] and p38 MAPK increases the mitotic stage by activating Cdc25C [XREF_BIBR].	23	33	increases	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	p38 MAPK	p38 MAPK	p38 MAPK	Cdc25C	Cdc25C	Cdc25C	23	25	31	32
ZNRF3 also promotes the turnover of frizzled receptors and LRP6 .	ZNRF3 also promotes the turnover of frizzled receptors and LRP6.	0	10	promotes	Positive_activation_syntax_1_verb	Negative_activation	Negative_activation	ZNRF3	ZNRF3	ZNRF3	LRP6	LRP6	LRP6	0	1	9	10
Mutagenesis study for ZNF76 suggests a correlation between interaction with TBP and effect on p53 mediated transactivation , supporting the conclusion that ZNF76 targets TBP for transcriptional repression .	Mutagenesis study for ZNF76 suggests a correlation between interaction with TBP and effect on p53 mediated transactivation, supporting the conclusion that ZNF76 targets TBP for transcriptional repression.	20	25	targets	Positive_activation_token_1_verb	Negative_activation	Positive_activation	ZNF76	ZNF76	ZNF76	TBP	TBP	TBP	22	23	24	25
An inhibitor of ERKs , but not phosphoinositide 3-kinase or p38 MAPKs , blocked NFAT3 activation by H ( 2 ) O ( 2 ) .	An inhibitor of ERKs, but not phosphoinositide 3-kinase or p38 MAPKs, blocked NFAT3 activation by H (2) O (2).	10	15	blocked	Negative_activation_syntax_1_verb	Negative_activation	Positive_activation	p38 MAPKs	p38 MAPKs	p38 MAPKs	NFAT3	NFAT3	NFAT3	10	12	14	15
Taken together , the evidence reviewed above indicates that aberrant expression of ZNF423 and ZNF521 , triggered by diverse mechanisms , may contribute to the pathogenesis of B-lymphoid malignancies by perturbing the activity of EBF1 , a central component of the regulatory network that governs normal B-lymphopoiesis .	Taken together, the evidence reviewed above indicates that aberrant expression of ZNF423 and ZNF521, triggered by diverse mechanisms, may contribute to the pathogenesis of B-lymphoid malignancies by perturbing the activity of EBF1, a central component of the regulatory network that governs normal B-lymphopoiesis.	10	38	contribute	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	ZNF521	expression of ZNF423 and ZNF521	znf521	EBF1	EBF1	ebf1	14	15	34	35
Consequently , in the Er mutant epidermis , the keratinocytes progenitors continue proliferating and fail to undergo differentiation ( XREF_FIG ) , suggesting that 14-3-3 mediated Yap1 function is critical for maintain the keratinocyte proliferation .	Consequently, in the Er mutant epidermis, the keratinocytes progenitors continue proliferating and fail to undergo differentiation (XREF_FIG), suggesting that 14-3-3 mediated Yap1 function is critical for maintain the keratinocyte proliferation.	24	29	mediated	Positive_early_activation	Negative_activation	Positive_activation	14-3-3	14-3-3	14-3-3	Yap1	Yap1	Yap1	24	25	26	27
For instance , YY1 transcription factor , which has previously been associated molecular responses to oxidative stress and heart disease XREF_BIBR , XREF_BIBR , activates the transcription of Notch 1 transcription factor ( N1IC ) XREF_BIBR .	For instance, YY1 transcription factor, which has previously been associated molecular responses to oxidative stress and heart disease XREF_BIBR, XREF_BIBR, activates the transcription of Notch 1 transcription factor (N1IC) XREF_BIBR.	3	35	activates	Positive_activation_syntax_1_verb	Negative_activation	Positive_activation	YY1	YY1	YY1	Notch 1	Notch 1	Notch 1	3	4	28	30
